PMID- 26225110 TI - Management of Buccal Gap and Resorption of Buccal Plate in Immediate Implant Placement: A Clinical Case Report. AB - When a dental implant is placed into a fresh extraction socket, a space between the implant periphery and surrounding bone occurs. A gap can occur on any aspect of an immediately placed implant: Buccal, lingual or proximally. The objective of immediate implant placement is to provide an osseointegrated fixture suitable for an aesthetic and functional restoration. Bone fill in the gap between the implant and the peripheral bone is important. Surgical management of the buccal gap to obtain an optimal result is controversial and confusing with respect to the best techniques to achieve the following: Optimal bone fills in the gap, most coronal level of bone-to-implant contact, and the least amount of buccal bone loss and soft tissue recession. This clinical case report illustrates the management of the buccal gap and reducing buccal plate resorption when contemplating immediate implant placement. PMID- 26225111 TI - Odontogenic Keratocysts in Gorlin-Goltz Syndrome: A Case Report. AB - Gorlin-Goltz syndrome is an autosomal dominant inherited condition comprising the principle triad of basal cell carcinomas, multiple jaw keratocysts, and skeletal anomalies. The presence of jaw cysts are the early diagnostic feature of this syndrome, and this can be incidentally identified by routine radiographs. A patient presented with signs and symptoms of Gorlin-Goltz syndrome to us in her early stages. PMID- 26225112 TI - Prosthetic Rehabilitation of Bilateral External Nasal Valve Area after Nasal Reconstruction for a Congenitally Missing Nose: A Clinical Report. AB - Deformities of the nostrils and alar region are among the very common clinically defects, which interfere with the functional anatomy of the nose. This case paper exemplifies the management of a bilateral external nasal valve area defect in a patient following a nasal reconstruction done using a forehead flap. The nasal stents were rendered to the patient for comfortable breathing by maintaining patency of the nasal passage after the surgical procedure and also improve speech and esthetics. PMID- 26225113 TI - A Mini-review on the Effect of Mini-implants on Contemporary Orthodontic Science. AB - The purpose of this literature review was to screen the valuable published articles regarding to the impacts of mini-implants on orthodontic science, briefly. The searching category was performed on the Pubmed using MeSH words such as "dental (mini) implants, orthodontic anchorage procedures, and orthodontic appliances." After preliminary sketch, they were grouped as follow: Those evaluating (a) common appliances for providing orthodontic anchorage, (b) biomechanical details of mini-implants and their insertion, (c) clinical application of mini-implants for orthognathic treatments, (d) limitations and possible complications. In conclusion, mini-implant evolved the orthodontic treatment plans and compromised the required orthognathic surgery. Malocclusion treatment and pure orthodontic or orthopedic movements in the three-dimensions have become recently possible by using mini-implant to provide skeletal anchorage. PMID- 26225114 TI - The Differential Diagnosis of Desquamative Gingivitis: Review of the Literature and Clinical Guide for Dental Undergraduates. AB - BACKGROUND: Desquamative gingivitis is an elucidating term used to demonstrate epithelial desquamation, erythema, erosions, and/or vesiculobullous lesions of the gingiva. Detection and differentiation between conditions that manifest desquamative gingivitis have been almost a continuing problem for dental undergraduates. Several studies have described the association between desquamative gingivitis and other relevant conditions. This study aimed to review the current literature on desquamative gingivitis and to formulate a clinical guide for the differential diagnosis of desquamative gingivitis designated as a teaching aid tool for dental undergraduates. MATERIALS AND METHODS: A search strategy based on the key words "desquamative gingivitis, guidelines, diagnosis, undergraduate, teaching" was performed in Medline and Google Scholar. Papers published between 1932 and December 2014 were scrutinized. Only articles that describe the terminology and classification of DG-associated disorders or the diagnostic procedures of DG were selected, then obtained in full text and analyzed. RESULTS: 47 studies were included and reviewed narratively. CONCLUSION: The clinical signs and symptoms of desquamative gingivitis are insufficient to make a definitive diagnosis. We proposed a clinical flowchart aimed to help dental undergraduates achieving their goal in making an accurate and easy diagnosis. However, this guideline needs further evaluation. PMID- 26225115 TI - Denture Adhesives in Prosthodontics: An Overview. AB - The use of denture adhesives is common among denture wearers, and it is also prescribed by many dentists. Prescribing denture adhesives has been viewed by many prosthodontists as a means of compensating for any defects in the fabrication procedures. Denture adhesives add to the retention and thereby improve chewing ability, reduce any instability, provide comfort and eliminate the accumulation of food debris beneath the dentures. Consequently, they increase the patient's sense of security and satisfaction. However, obtaining the advice of the dental practitioner prior to the use of adhesives is a must. PMID- 26225116 TI - Cone Beam Computed Tomography-Dawn of A New Imaging Modality in Orthodontics. AB - Today, we are in a world of innovations, and there are various diagnostics aids that help to take a decision regarding treatment in a well-planned way. Cone beam computed tomography (CBCT) has been a vital tool for imaging diagnostic tool in orthodontics. This article reviews case reports during orthodontic treatment and importance of CBCT during the treatment evaluation. PMID- 26225117 TI - Insight into the Evolving Concepts on the Origin of Salivary Gland Neoplasms. PMID- 26225118 TI - A Comparison of First Time and Repeat Rural DUI Offenders. AB - The purpose of the current study was to examine whether the differences found between first time and repeat rural DUI offenders were the same as those found previously in urban samples. A total of 118 rural DUI offenders were interviewed, approximately half (51.7%) of which were repeat offenders. Although demographic and mental health characteristics were similar across the two groups, repeat offenders reported more extensive substance use and criminal histories. Results suggest that the pattern of differences between rural first time and repeat DUI offenders may be different from the pattern found in prior urban-based studies. Treatment implications are discussed. PMID- 26225119 TI - Ongoing expansion of the worldwide invader Didemnum vexillum (Ascidiacea) in the Mediterranean Sea: high plasticity of its biological cycle promotes establishment in warm waters. AB - Non-indigenous ascidians are of particular concern to aquaculture industry and, paradoxically, the activities associated with it represent an important way to translocate these species worldwide. In 2012 a non-indigenous ascidian was found covering the oyster crops in the Ebro Delta (Western Mediterranean). We have identified the ascidian genetically and morphologically as Didemnum vexillum Kott, 2002. This finding indicates that the species is currently expanding its distribution in the Mediterranean Sea, as it has recently been found in the eastern basin (Venice, Adriatic Sea). Introduced populations of D. vexillum are found in temperate and cold waters worldwide, and a successful establishment in the Mediterranean implies a remarkable capacity of adaptability to warm, subtropical conditions. We assessed the life cycle (growth and reproduction) of the ascidian at the studied site. The species has a marked seasonal cycle, with regression in the warmest months and reappearance during winter. In spring D. vexillum reaches its maximum abundance, followed by a peak in reproduction just before regression. This cycle is reversed with respect to the one observed in colder waters, highlighting a plastic biological cycle of this invader and an hitherto unknown ability to establish itself in warm waters. We also analysed the genetic structure of the population of the Ebro Delta and the one established in the Lagoon of Venice using COI sequence data. The low genetic diversity in our samples (three haplotypes) was consistent with what is observed in the introduced populations worldwide. It is likely that the ascidian was introduced with oyster stock from bivalve cultures in the Atlantic French coasts, where the same three haplotypes have been reported. The high boating activity in the Ebro Delta makes further human-mediated transport of the species highly likely, and nearby fishing grounds can be severely affected if invaded. It is urgent to implement measures to prevent the continuous expansion of this ascidian pest in the Mediterranean. PMID- 26225120 TI - Neurogenesis in directly and indirectly developing enteropneusts: of nets and cords. AB - Concerning the evolution of deuterostomes, enteropneusts (acorn worms) occupy a pivotal role as they share some characteristics with chordates (e.g., tunicates and vertebrates) but are also closely related to echinoderms (e.g., sea urchin). The nervous system in particular can be a highly informative organ system for evolutionary inferences, and advances in fluorescent microscopy have revealed overwhelming data sets on neurogenesis in various clades. However, immunocytochemical descriptions of neurogenesis of juvenile enteropneusts are particularly scarce, impeding the reconstruction of nervous system evolution in this group. We followed morphogenesis of the nervous system in two enteropneust species, one with direct (Saccoglossus kowalevskii) and the other with indirect development (Balanoglossus misakiensis), using an antibody against serotonin and electron microscopy. We found that all serotonin-like immunoreactive (LIR) neurons in both species are bipolar ciliary neurons that are intercalated between other epidermal cells. Unlike the tornaria larva of B. misakiensis, the embryonic nervous system of S. kowalevskii lacks serotonin-LIR neurons in the apical region as well as an opisthotroch neurite ring. Comparative analysis of both species shows that the projections of the serotonin-LIR somata initially form a basiepidermal plexus throughout the body that disappears within the trunk region soon after settlement before the concentrated dorsal and ventral neurite bundles emerge. Our data reveal a highly conserved mode of neurogenesis in enteropneusts that is independent of the developing mode and is inferred to be a common feature for Enteropneusta. Moreover, all detected serotonin-LIR neurons are presumably receptor cells, and the absence of serotonin-LIR interneurons from the enteropneust nervous system, which are otherwise common in various bilaterian central nervous systems, is interpreted as a loss that might have occurred already in the last common ancestor of Ambulacraria. PMID- 26225121 TI - Mechanistic attributes of S100A7 (psoriasin) in resistance of anoikis resulting tumor progression in squamous cell carcinoma of the oral cavity. AB - BACKGROUND: Squamous cell carcinoma of the oral cavity (SCCOC) is the dominant origin of cancer associated mortality. Previous findings by our study reported that acquisition of anoikis resistance has a significant role in tumor progression of oral cavity. Several genes were over-expressed in anoikis resistant cells under detached conditions which we confirmed earlier by microarray. Normal oral squamous epithelia grow adherent to a basement membrane, and when detached from the extracellular matrix, undergoes programmed cell death. The acquisition of anoikis-resistance is crucial phenomena in oral tumor advancement. In the current study, we have identified S100A7 expression as contributing factor for anoikis resistance and tumorigenicity in human oral cancer cells. Further, we have explored that elevated S100A7 expression in anoikis-sensitive oral keratinocytes and cancer cells reshape them more resistant to anoikis and apoptosis inducers via activation of cellular intrinsic and extrinsic avenue. METHODS: A subset of human cancer cell lines TU167, JMAR, JMARC39, JMARC42 and MDA-MB-468 were utilized for the generation of resistant stable cell lines. Further, immunohistochemistry, western blot and immunoprecipitation, assays of apoptosis, soft agar assay, orthotopic animal model and signaling elucidation were performed to establish our hypothesis. RESULTS: S100A7 gene is found to be responsible for anoikis resistance and tumorigenicity in human oral cancer cells. We have observed up-regulation of S100A7 in anoikis resistant cell lines, orthotropic model and patients samples with head and neck cancer. It is also noticed that secretion of S100A7 protein in conditioned medium by anoikis resistant head & neck cancer cell and in saliva of head and neck cancer patients. Up-regulation of S100A7 expression has triggered enhanced tumorigenicity and anchorage-independent growth of cancer cells through Akt phosphorylation leading to development of aniokis resistance in head and neck cancer cells. CONCLUSIONS: These data have led us to conclude that S100A7 is the major contributing factor in mediating anoikis-resistance of oral cancer cells and local tumor progression, and S100A7 might be useful as diagnostic marker for early detection of primary and recurrent squamous cell cancer. PMID- 26225122 TI - In vitro myotoxic effects of bupivacaine on rhabdomyosarcoma cells, immortalized and primary muscle cells. AB - BACKGROUND: Rhabdomyosarcoma is a rare malignant skeletal muscle tumor. It mainly occurs in children and young adults and has an unsatisfactory prognosis. Prior studies showed a direct myotoxic effect of bupivacaine on differentiated muscle cells in vitro and in vivo. Exact mechanisms of this myotoxicity are still not fully understood, but a myotoxic effect on malignant muscle tumor cells has not been examined so far. Thus, the aim of this study was to examine if bupivacaine has cytotoxic effects on rhabdomyosarcoma cells, immortalized muscle cells and differentiated muscle cells. METHODS: Cell lines of rhabdomyosarcoma cells, immortalized muscle cells and differentiated muscle cells were established. After microscopic identification, cells were exposed to various concentrations of bupivacaine (500, 1,000, 1,750, 2,500 and 5,000 ppm) for 1 and 2 h, respectively. 24 and 28 h after incubation the cultures were stained with propidium iodid and analyzed by flow cytometry. The fraction of dead cells was calculated for each experiment and the concentration with 50% cell survival (IC50) was computed. Cell groups as well as incubation and recovery time were compared (ANOVA/Bonferroni p < 0.01). RESULTS: The total number of cultured cells was similar for the different local anesthetics and examined concentrations. Increasing concentrations of bupivacaine led to a decrease in survival of muscle cells. IC50 was highest for immortalized cells, followed by rhabdomyosarcoma cells and differentiated cells. Exposure time, but not recovery time, had an influence on survival. CONCLUSION: Bupivacaine has clear but different cytotoxic effects on various muscle cell types in vitro. Differentiated primary cells seem to be more vulnerable than tumor cells possibly because of more differentiated intracellular structures. PMID- 26225123 TI - Inhibition of CDK4/6 as a novel therapeutic option for neuroblastoma. AB - BACKGROUND: Neuroblastoma is a neural crest-derived tumor and is the most common cancer in children less than 1 year of age. We hypothesized that aberrations in genes that control the cell cycle could play an important role in the pathogenesis of neuroblastoma and could provide a tractable therapeutic target. METHODS: In this study, we screened 131 genes involved in cell cycle regulation at different levels by analyzing the effect of siRNA-mediated gene silencing on the proliferation of neuroblastoma cells. RESULTS: Marked reductions in neuroblastoma cellular proliferation were recorded after knockdown of CCND1 or PLK1. We next showed that pharmacological inhibition of cyclin D1 dependent kinases 4/6 (CDK4/6) with PD 0332991 (palbociclib) reduced the growth of neuroblastoma cell lines, induced G1 cell cycle arrest, and inhibited the cyclin D1-Rb pathway. CONCLUSION: Selective inhibition of CDK4/6 using palbociclib may provide a new therapeutic option for treating neuroblastoma. PMID- 26225124 TI - Is air pollution a risk factor for rheumatoid arthritis? AB - Rheumatoid arthritis is a chronic inflammatory debilitating disease triggered by a complex interaction involving genetic and environmental factors. Active smoking and occupational exposures such as silica increase its risk, suggesting that initial inflammation and generation of rheumatoid arthritis-related autoantibodies in the lungs may precede the clinical disease. This hypothesis paved the way to epidemiological studies investigating air pollution as a potential determinant of rheumatoid arthritis. Studies designed for epidemiology of rheumatoid arthritis found a link between traffic, a surrogate of air pollution, and this disease. Furthermore, a small case-control study recently found an association between wood smoke exposure and anticyclic citrullinated protein/peptide antibody in sera of patients presenting wood-smoke-related chronic obstructive pulmonary disease. However, reports addressing impact of specific pollutants on rheumatoid arthritis incidence and severity across populations are somewhat conflicting. In addition to the link reported between other systemic autoimmune rheumatic diseases and particulate matters/gaseous pollutants, experimental observation of exacerbated rheumatoid arthritis incidence and severity in mice models of collagen-induced arthritis after diesel exhaust particles exposure as well as hypovitaminosis D-related autoimmunity can help understand the role of air pollution in rheumatoid arthritis. All these considerations highlight the necessity to extend high quality epidemiological researches investigating different sources of atmospheric pollution across populations and particularly in low-and-middle countries, in order to further explore the biological plausibility of air pollution's effect in the pathogenesis of rheumatoid arthritis. This should be attempted to better inform policies aiming to reduce the burden of rheumatoid arthritis. PMID- 26225125 TI - iTRAQ-based proteomic profiling of Vibrio parahaemolyticus under various culture conditions. AB - BACKGROUND: Vibrio parahaemolyticus is a common pathogen infecting humans and marine animals; this pathogen has become a major concern of marine food products and trade. In this study, V. parahaemolyticus isolated from sewage was exposed to different culture conditions and analyzed by isobaric tag for relative and absolute quantitation (iTRAQ) based reversed-phase liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique. Our goal is to gain further insights into the proteomics of V. parahaemolyticus, particularly differentially expressed proteins closely correlated with growth conditions and pathogenicity associated proteins. RESULTS: In this study, a total of 2,717 proteins including numerous membrane proteins were significantly identified, and 616 proteins displayed significant differential expression under different conditions. Of them, 12 proteins mainly participating in metabolism showed the most elastic expression differentiation between different culture conditions. Some membrane proteins such as type I secretion outer membrane protein, TolC, lipoprotein, efflux system proteins iron-regulated protein A and putaive Fe-regulated protein B, ferric siderophore receptor homolog and several V. parahaemolyticus virulence-associated proteins were differentially regulated under different conditions. Some differentially regulated proteins were analyzed and confirmed at gene expression level by quantitative real time polymerase chain reaction (qRT-PCR). CONCLUSIONS: Proteomics analysis results revealed the characteristics of V. parahaemolyticus proteome expression, provided some promising biomarkers related with growth conditions, the results likely advance insights into the mechanism involved in the response of V. parahaemolyticus to different conditions. Some virulence associated proteins were discovered to be differentially expressed under different conditions. PMID- 26225126 TI - In-depth Proteomic mapping of mouse (Mus musculus) epididymal constructive basis for sperm maturation. AB - BACKGROUND: The mouse epididymis performs an essential role in sperm maturation, but global protein expression data in mouse epididymis are still lacking. Here, we reported the first in-depth gel-based profiling of mouse epididymis proteome and established a 2-DE map. RESULTS: A total of 832 protein spots were detected in the reproducible gels, and 625 spots corresponding to 355 unique protein entries have been successfully identified by MALDI-TOF-MS. The confidence of proteome data was validated by Western blot. Functional annotations showed that these proteins were mainly related to general metabolism, antioxidant and structural molecule activity. Immunohistochemistry disclosed two structural proteins (myosin regulatory light polypeptide 9 and alpha-2 type I collagen) continuously expressed in the myoid cell since postpartum. CONCLUSION: This study provides a first-draft reference map of the mouse epididymis proteome, which will greatly expand the knowledge of the epididymal structural basis and contribute to the better understanding of those proteins in the process of mouse epididymal sperm maturation. PMID- 26225127 TI - The longitudinal age and birth cohort trends of regular exercise among adults aged 16-63 years in Sweden: a 24-year follow-up study. AB - BACKGROUND: The aim of this study is to analyze longitudinally, based on four measurements at intervals of eight years, the annual effect of age group and birth cohort on regular exercise in the Swedish population from 1980-1981 to 2004 2005. METHODS: We followed a randomly drawn subsample of individuals aged 16-63 years, interviewed by professional interviewers, from the Swedish Annual Level of Living Survey. We applied a mixed model with a random intercept and a random slope in order to analyze the annual effects. RESULTS: The prevalence of regular exercise increased annually by 0.3 % among men and 0.7 % among women. For every one-unit increase in BMI, the odds of regular physical activity decreased by 6 % among men and 5 % among women. While the female birth cohorts all increased over time the male birth cohorts showed a different pattern, as only the three oldest birth cohorts (1926-1933, 1934-1941, 1942-1949) showed an increase in regular exercise. The three youngest birth cohorts (1958-1965, 1966-1973, 1974-1981) instead showed a decreased prevalence of regular exercise. There was an inverse relationship between regular exercise and age, although the differences between age groups tended to decrease over time. Differences related to educational level increased over time as the prevalence of exercise among those with higher educational attainment increased more than among those with lower educational attainment. The most dramatic relative increase in exercise over time (almost two fold) was found among those who were obese or who reported a poor health status. CONCLUSIONS: The prevalence of regular exercise increased in all studied sub groups. However, the increased difference related to education level is worrying. To reduce the risk for ill health in these groups, there is a need for targeted interventions. PMID- 26225128 TI - From Practice to Research: Training Health Care Providers to Conduct Culturally Relevant Community Focus Groups. AB - Qualitative data from focus groups can provide an "insiders' view" of the culture of those being studied. Such data can help health care providers and program planners understand how people perceive themselves, and therefore guide providers and planners in developing culturally appropriate outcome measures that can strengthen the planning, implementation, and evaluation of future programs. This article discusses the process used to train Latino and African American health care providers to moderate focus groups that will be conducted as one phase of a research study looking at health beliefs and health practices in an urban arthritis health center. After taking part in two lecture and discussion training sessions, members of the training class were asked to participate in a pilot focus group. The 1/2 to 2 hour focus group included nine individuals who fulfilled the roles of moderator, facilitator, or respondent. Community health center practitioners provided valuable insight into the design and feasibility of the focus groups during their training sessions. PMID- 26225130 TI - The efficacy of a beta-hydroxy-beta-methylbutyrate supplementation on physical capacity, body composition and biochemical markers in elite rowers: a randomised, double-blind, placebo-controlled crossover study. AB - BACKGROUND: beta-hydroxy-beta-methylbutyric acid (HMB) is an interesting supplement in sports. However, literature sources present a limited number of studies that verify the efficacy of HMB intake over a longer time period among endurance athletes. For this reason, the aim of this study was to assess the effect of HMB supplementation on physical capacity, body composition and levels of biochemical markers in rowers. METHODS: Sixteen elite male rowers were administered a 12-week HMB supplementation (3*1 gHMB . day(-1)) and placebo administration (PLA) following the model of a randomised, placebo controlled, double-blind crossover study with a 10 days washout period. Over the course of the experiment, aerobic (maximal oxygen uptake, ventilatory threshold) and anaerobic (anaerobic power indices) capacity were determined, while analyses were conducted on body composition as well as levels of creatine kinase, lactate dehydrogenase, testosterone, cortisol and the T/C ratio. A normal distribution of variables was tested using the paired 2-tailed t-tests; the Mann-Whitney U-test or the Wilcoxon-signed rank test were applied for non-normally distributed variables. RESULTS: Following HMB supplementation, [Formula: see text] increased (+2.7 mL . min(-1) . kg(-1)) significantly (p < 0.001) in comparison to its reduction after PLA (-1.0 mL . min(-1) . kg(-1)). In turn, at the ventilatory threshold, a longer time was required to reach this point (+1.2 minHMB vs. -0.2 minPLA, p = 0.012), while threshold load (+0.42 W . kg(-1) HMB vs. -0.06 W . kg( 1) PLA, p = 0.002) and threshold heart rate (+9 bpmHMB vs. +1 bpmPLA, p < 0.001) increased. After HMB supplementation, fat mass decreased (-0.9 kgHMB vs. +0.8 kgPLA, p = 0.03). In relation to the initial values after HMB supplementation, the refusal time to continue in the progressive test was extended (p = 0.04), maximum load (p = 0.04) and anaerobic peak power (p = 0.02) increased. However, in relation to the placebo, no differences were observed in anaerobic adaptation or blood marker levels. CONCLUSIONS: The results indicate that HMB intake in endurance training has an advantageous effect on the increase in aerobic capacity and the reduction of fat mass. It may also stimulate an increase in peak anaerobic power, while it seems to have no effect on other indices of anaerobic adaptation and levels of investigated markers in the blood. PMID- 26225131 TI - Improved Open- Circuit Voltage in ZnO-PbSe Quantum Dot Solar Cells by Understanding and Reducing Losses Arising from the ZnO Conduction Band Tail. AB - Colloidal quantum dot solar cells (CQDSCs) are attracting growing attention owing to significant improvements in efficiency. However, even the best depleted heterojunction CQDSCs currently display open-circuit voltages (VOCs) at least 0.5 V below the voltage corresponding to the bandgap. We find that the tail of states in the conduction band of the metal oxide layer can limit the achievable device efficiency. By continuously tuning the zinc oxide conduction band position via magnesium doping, we probe this critical loss pathway in ZnO-PbSe CQDSCs and optimize the energetic position of the tail of states, thereby increasing both the VOC (from 408 mV to 608 mV) and the device efficiency. PMID- 26225129 TI - Fetal MRI: A Technical Update with Educational Aspirations. AB - Fetal magnetic resonance imaging (MRI) examinations have become well-established procedures at many institutions and can serve as useful adjuncts to ultrasound (US) exams when diagnostic doubts remain after US. Due to fetal motion, however, fetal MRI exams are challenging and require the MR scanner to be used in a somewhat different mode than that employed for more routine clinical studies. Herein we review the techniques most commonly used, and those that are available, for fetal MRI with an emphasis on the physics of the techniques and how to deploy them to improve success rates for fetal MRI exams. By far the most common technique employed is single-shot T2-weighted imaging due to its excellent tissue contrast and relative immunity to fetal motion. Despite the significant challenges involved, however, many of the other techniques commonly employed in conventional neuro- and body MRI such as T1 and T2*-weighted imaging, diffusion and perfusion weighted imaging, as well as spectroscopic methods remain of interest for fetal MR applications. An effort to understand the strengths and limitations of these basic methods within the context of fetal MRI is made in order to optimize their use and facilitate implementation of technical improvements for the further development of fetal MR imaging, both in acquisition and post-processing strategies. PMID- 26225132 TI - The association of active and secondhand smoking with oral health in adults: Japan public health center-based study. AB - BACKGROUND: Smoking is one of the major risk factors for oral diseases, and many studies have found that active smoking is closely associated with the prevalence or severity of periodontal disease and fewer remaining teeth. In contrast to the established association between active smoking and oral health, there have been very few studies investigating the effects of secondhand smoking on oral health, and whether secondhand smoking deteriorates oral health has not been fully clarified. The purpose of the present study was to examine whether active and secondhand smoking were associated with the prevalence of severe periodontal disease and number of teeth among Japanese adults. METHODS: Subjects were 1,164 dentate adults aged 55-75 years as of May 2005 who participated in both the Japan Public Health Center-Based Study Cohort I in 1990 and a dental survey in 2005. The dental survey was implemented in the Yokote health center jurisdiction, Akita Prefecture. Participating subjects completed a self-administered questionnaire and a clinical oral examination. The association of smoking status with prevalence of periodontal disease was analyzed using a logistic regression, and with number of teeth or functional tooth units of natural teeth (n-FTUs) using a generalized linear model. RESULTS: After adjusting for age, education level, history of diabetes, BMI, alcohol consumption, perceived mental stress, presence of a family dentist, and oral hygiene, the odds ratio (OR) of risk for periodontal disease in male subjects was significantly increased in non-smokers with secondhand smoking only at home (OR = 3.14, 95 % CI: 1.08-9.12, p = 0.036), non-smokers with secondhand smoking both at home and other places (OR = 3.61, 95 % CI: 1.33-9.81, p = 0.012) and current smokers (OR = 3.31, 95 % CI: 1.54-7.08, p = 0.002), compared to non-smokers without secondhand smoking. Further in men, current smokers had significantly fewer numbers of teeth (19.7 +/- 6.82) and n FTUs (4.92 +/- 4.12) than non-smokers without secondhand smoking (22.2 +/- 6.92, p = 0.014 and 6.56 +/- 4.18, p = 0.007). Such significant relationships of smoking status with periodontal disease and dentition were not observed in women. CONCLUSIONS: The present study indicates that active smoking as well as secondhand smoking may have harmful effects on periodontal health in men. Therefore, it is imperative for health and oral health professionals to enlighten people about the negative influence of smoking, not only on their own health but also on others' health. PMID- 26225133 TI - Smoking Habit in Severe Obese after bariatric procedures. AB - BACKGROUND: Bariatric procedures provide an effective means of short term weight loss and sustained weight control for the morbidly obese. The effect of bariatric procedures on smoking habit in obese subjects is not well known. Therefore, we examined the short term effect of bariatric surgery on smoking habit of severe obese patients up to 12 months from the intervention. PATIENTS AND METHODS: Smoking habit was assessed in a cohort of 78 morbid smoking obese patients followed at our clinic for bariatric procedures. They underwent non surgical intra-gastric balloon (IB) or surgical procedures such as lap-band laparoscopic surgery (LAGB) or sleeve gastrectomy/gastric by-pass (SPG). Subjects were administered a written questionnaire about their smoking habit before and 3, 6 and 12 months after the procedures. RESULTS: No differences were found among the three groups at 6 and 12 months after the procedures (IB 21 %, LAGB 6 %, SPG 5 %; and IB 14 %, LAGB 3 %, SPG 5 %). Only after 3 months, the rate of quitting of the IB group was higher than LAGB and SPG groups (36 %, 6 % and 5 %, respectively; p = 0.02). CONCLUSIONS: Bariatric procedures have no effects on smoking habit of moderate-to-heavy smoker severe obese patients. The use of other traditional smoking cessation methods in patients undergone to bariatric procedures should be implemented. PMID- 26225134 TI - Arachidonic Acid and Cerebral Ischemia Risk: A Systematic Review of Observational Studies. AB - BACKGROUND: Arachidonic acid (ARA) is a precursor of various lipid mediators. ARA metabolites such as thromboxane A2 cause platelet aggregation and vasoconstriction, thus may lead to atherosclerotic disease. It is unclear whether dietary ARA influences the ARA-derived lipid mediator balance and the risk for atherosclerotic diseases, such as cerebral ischemia. Considering the function of ARA in atherosclerosis, it is reasonable to focus on the atherothrombotic type of cerebral ischemia risk. However, no systematic reviews or meta-analyses have been conducted to evaluate the effect of habitual ARA exposure on cerebral ischemia risk. We aimed to systematically evaluate observational studies available on the relationship between ARA exposure and the atherothrombotic type of cerebral ischemia risk in free-living populations. SUMMARY: The PubMed database was searched for articles registered up to June 24, 2014. We designed a PubMed search formula as follows: key words for humans AND brain ischemia AND study designs AND ARA exposure. Thirty-three articles were reviewed against predefined criteria. There were 695 bibliographies assessed from the articles that included both ARA and cerebral ischemia descriptions. Finally, we identified 11 eligible articles and categorized them according to their reporting and methodological quality. We used the Strengthening the Reporting of Observational Studies in Epidemiology Statement (STROBE) checklist to score the reporting quality. The methodological quality was qualitatively assessed based on the following aspects: subject selection, ARA exposure assessment, outcome diagnosis, methods for controlling confounders, and statistical analysis. We did not conduct a meta-analysis due to the heterogeneity among the studies. All eligible studies measured blood ARA levels as an indicator of exposure. Our literature search did not identify any articles that evaluated dietary ARA intake and tissue ARA as assessments of exposure. Seven of the 11 eligible articles were considered to be of low quality. No articles reported a dose-dependent positive association between an increased cerebral ischemia risk and ARA exposure. However, most studies did not assess the risk in each subtype of cerebral ischemia, thus various etiological types of cerebral ischemia risk were involved in their results. KEY MESSAGES: We did not find a positive association between ARA exposure and cerebral ischemia risk. Eligible studies reported inconsistent findings: cerebral ischemia risk did not change or significantly decreased. We could not draw any conclusions due to the limited number of eligible high-quality studies. Further evidence from well designed observational studies is required. Simultaneously, in order to develop effective preventive measures against cerebral ischemia, it is imperative to establish standardized definitions, nomenclatures, classifications, and diagnostic procedures. PMID- 26225135 TI - Endovascular Stroke Therapy Results Improve over Time: The 'Learning Curve' at a New Comprehensive Stoke Center. AB - BACKGROUND: The requirements for a comprehensive stroke center (CSC) include the capability to perform endovascular stroke therapy (EST). EST is a complex process requiring early identification of appropriate patients and effective delivery of intervention. In order to provide prompt intervention for stroke, CSCs have been established away from large academic centers in community-based hospitals. We hypothesized that quantifiable improvements would occur during the first 2 years of a community-based CSC as the processes and personnel evolved. We report the results over time of EST at a new community-based CSC. METHODS: We have retrospectively analyzed demographic data and outcome metrics of EST from the initiation phase of a new community-based CSC. Data was divided into year 1 and year 2. Statistical analysis (Student's t test and Fisher's exact test) was performed to compare the patient population and outcomes across the two time periods. Outcome variables included the thrombolysis in cerebral infarction (TICI) score, a change in the NIH stroke scale score and the modified Rankin Scale (mRS) score. Analysis of variance (ANOVA) was used to statistically analyze the relationship between population variables and outcome. Computed tomography (CT) angiography and CT perfusion analysis were used to select patients for EST. Approximately half of the patients undergoing EST were excluded from receiving intravenous recombinant tissue plasminogen activator (IV rt-PA) by standard criteria, while the other half showed no sign of improvement following 1 h of IV rt-PA treatment. Mechanical thrombolysis with a stentriever was performed in the majority of cases with or without intra-arterial medication. The majority of treated occlusions were in the middle cerebral artery. RESULTS: A total of 18 patients underwent EST during year 1 and year 2. A statistically significant increase in good outcomes (mRS score <=2 at discharge) was seen from year 1 to year 2 (p = 0.05). There were trends towards faster interventions, decreased complications and mortality as well as an improved TICI score from year 1 to year 2. With ANOVA, mortality was statistically correlated with age (p = 0.06), while decreases in the NIH stroke scale (NIHSS) score following EST correlated with decreased mortality (p = 0.01). A higher TICI score was significantly associated with a decreased NIHSS score following EST (p = 0.01). CONCLUSIONS: At a new community-based CSC, improved outcome occurred from year 1 to year 2, and trends towards decreased mortality, fewer complications, and improved revascularization were observed. Furthermore, the data shows that improvement in NIHSS score after EST is associated with decreased mortality following stroke in this setting, implying a net benefit. PMID- 26225136 TI - Consumption of sugar sweetened beverage is associated with incidence of metabolic syndrome in Tehranian children and adolescents. AB - BACKGROUND: Intakes of high sugar-sweetened beverages (SSBs) in adults can escalate risk of metabolic syndrome (MetS); however, data of longitudinal studies in children and adolescents are lacking. In this study we assessed consumption of SSBs in relation to incidence of MetS among children and adolescents during a 3.6 year follow-up. METHODS: This study was a population-based longitudinal study, in which 424 subjects, aged 6-18 years, from the Tehran Lipid and Glucose Study with complete data on dietary intake, blood pressure, anthropometry, and biochemical indices were followed for 3.6 years. Dietary intake was collected using a valid and reliable food frequency questionnaire. MetS was defined according to the Cook criteria. Sugar sweetened beverages included all kinds of sugar sweetened carbonated soft drinks (SSSDs) and fruit juice drinks. RESULTS: Average daily intakes of SSSD and fruit juice drinks were 38.5 +/- 75.0 and 32.3 +/- 60.1 g, respectively. After adjustment for confounders, compared to the first quartile, the odds ratio of incident MetS in the highest quartile of SSB and SSSD was 3.20 (95 % CI: 1.06-9.90) and 3.01 (95 % CI: 1.17-7.74), respectively. Regarding incidence of MetS components, compared with the lowest quartile, the highest quartile of SSSDs showed odds ratios of 2.49 (95 % CI: 1.00-6.53) for abdominal obesity and 2.79 (95 % CI: 1.02-7.64) for hypertension. No significant association was found between consumption of fruit juice drink and SSSD with other components of MetS. CONCLUSIONS: Children and adolescents with high intakes of carbonated beverages could be at increased risk of MetS, abdominal obesity, and hypertension. PMID- 26225137 TI - The selection of diagnostic modalities in the management of pelvic fracture patients requiring transfers. AB - INTRODUCTION: Pelvic fractures can result in life-threatening hemorrhages. Therefore, pelvic fracture patients must usually be transferred to a trauma center for additional management. We attempted to analyze transferred pelvic fracture patients to determine which diagnostic modalities to use in different treatment settings. MATERIALS AND METHODS: From May 1, 2008, to February 28, 2014, patients with pelvic fractures who were transferred from other local hospitals within 24 hours after the trauma were enrolled. We compared the pre transfer conditions and pelvic X-ray results from the local hospitals between the group of patients that underwent further angioembolization at the trauma center and the group that did not. The role of computed tomography (CT) in the decision making process (i.e., regarding additional angioembolization) at the different institutions was discussed. RESULTS: In total, 751 patients were enrolled in the current study. Of the patients who received further angioembolization at the trauma center, 77.6 % (121/156) had sacro-iliac (SI) joint disruption on their pre-transfer pelvic X-ray; this rate was significantly higher than that of the patients who did not undergo further embolization (77.6 % vs. 25.5 %, p < 0.001). There was no significant difference in the use of pre-transfer CT scans at the local hospitals between the patients who underwent angioembolization and those who did not (53.8 % vs. 50.3 %, p = 0.472). Furthermore, of these patients, there was no significant difference in the length of emergency department stay (from arrival to angioembolization) at the trauma center among the patients who underwent pre-transfer CT scans and those who did not (97.4 +/- 69.3 minutes vs. 108.6 +/- 21.8 minutes, p = 0.461). CONCLUSION: When managing patients with pelvic fractures, the more attention should be paid to those with SI joint disruption on pelvic X-ray. Because these patients are more likely to require further angioembolization, they should be transferred earlier. Additional CT may be performed after the patient's transfer to the trauma center to determine subsequent treatment. PMID- 26225138 TI - Inhibitory effect of (-)-epigallocatechin-3-gallate and bleomycin on human pancreatic cancer MiaPaca-2 cell growth. AB - BACKGROUND: Human pancreatic cancer is currently one of the deadliest cancers with high mortality rate. It has been previously shown that (-)-epigallocatechin 3-gallate (EGCG), the most abundant catechin found in green tea, has showed suppressive effects on human pancreatic cancer cells. Bleomycin, (BLM), an anti cancer chemotherapeutic drug that induces DNA damage, has antitumor effects by induction of apoptosis in several cancer cell lines and also in pancreatic cancer cells. The present study investigated for the first time, the inhibitory effect of EGCG and BLM on pancreatic cancer cell growth. METHODS: Using the pancreatic cancer cell lines MIA PaCa-2 cells the efficacy and synergism of EGCG and BLM were evaluated by in vitro tests. Inhibition of cell proliferation was determined by MTT assay. Mitochondrial depolarization was performed with JC-1 probe. Viability and apoptosis were determined by Flow Cytometry with annexin V, propidium iodide staining and DNA fragmentation assay. RESULTS: Cell proliferation assay revealed significant additive inhibitory effects with combination of EGCG and BLM at 72 h in a dose dependent manner. The combination of EGCG and BLM induced cell cycle S-phase arrest and mitochondrial depolarization. Viability, apoptosis and DNA fragmentation assay indicated that the combination of EGCG and bleomycin potentiated apoptosis. CONCLUSIONS: Our results indicate that EGCG and BLM have additive anti-proliferative effects in vitro by induction of apoptosis of MIA PaCa-2 cells. This combination could represent a new strategy with potential advantages for treatment of pancreatic cancer. To date, this is the first report published of the inhibitory effect of EGCG and BLM on human pancreatic cancer MIA Paca-2 cell growth. PMID- 26225139 TI - Comparative cytogenetics in the genus Hoplias (Characiformes, Erythrinidae) highlights contrasting karyotype evolution among congeneric species. AB - BACKGROUND: The Erythrinidae fish family contains three genera, Hoplias, Erythrinus and Hoplerythrinus widely distributed in Neotropical region. Remarkably, species from this family are characterized by an extensive karyotype diversity, with 2n ranging from 39 to 54 chromosomes and the occurrence of single and/or multiple sex chromosome systems in some species. However, inside the Hoplias genus, while H. malabaricus was subject of many studies, the cytogenetics of other congeneric species remains poorly explored. In this study, we have investigated chromosomal characteristics of four Hoplias species, namely H. lacerdae, H. brasiliensis, H. intermedius and H. aimara. We used conventional staining techniques (C-banding, Ag-impregnation and CMA3 -fluorescence) as well as fluorescence in situ hybridization (FISH) with minor and major rDNA and microsatellite DNAs as probes in order to analyze the karyotype evolution within the genus. RESULTS: All species showed invariably 2n = 50 chromosomes and practically identical karyotypes dominated only by meta- and submetacentric chromosomes, the absence of heteromorphic sex chromosomes, similar pattern of C positive heterochromatin blocks and homologous Ag-NOR-bearing pairs. The cytogenetic mapping of five repetitive DNA sequences revealed some particular interspecific differences between them. However, the examined chromosomal characteristics indicate that their speciation was not associated with major changes in their karyotypes. CONCLUSION: Such conserved karyotypes contrasts with the extensive karyotype diversity that has been observed in other Erythrinidae species, particularly in the congeneric species H. malabaricus. Nevertheless, what forces drive such particularly different modes of karyotype evolution among closely related species? Different life styles, population structure and inner chromosomal characteristics related to similar cases in other vertebrate groups can also account for the contrasting modes of karyotype evolution in Hoplias genus. PMID- 26225141 TI - Eyes on the Vulnerable. PMID- 26225142 TI - Negative Pressure, a "Solution" in the Treatment of Infected Knee Prosthesis? AB - INTRODUCTION: Negative-pressure wound therapy is a therapeutic technique that uses a vacuum dressing in order to promote healing in acute or chronic wounds. The continued vacuum draws out fluid from the wound and increases blood flow to the area. The aim of this study was to establish the effectiveness of negative pressure therapy increasing this way the chances of rehabilitation after knee prosthesis infections. MATERIAL AND METHOD: 11 patients with septic complications after total knee joint replacement were involved into this study, from the Department of Orthopaedic and Traumatology of Bucharest Emergency University Hospital. In all of the cases negative pressure wound treatment was applied. The surgical approach was chosen according to the surgeon's preferences or along the pre-existing surgical approach. RESULTS AND DISCUSSIONS: Time from the knee arthroplasty to the clinical and biological manifestation of septic complications was about 35 days with limits between 21 and 42 days. In most cases we managed to keep the implant, the outcome obviously being conditioned by using the negative pressure. Knee infections are still a hazardous problem in orthopedic surgery. Negative-pressure system increased the granulation tissue formation and the local blood flow and enhanced the bacterial clearance function. CONCLUSIONS: The clinical outcome in our cases indicates that the Negative-Pressure Wound Therapy can be a valuable contribution to the treatment of knee joint infections. PMID- 26225140 TI - An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-beta concentrations collected by lumbar puncture and indwelling lumbar catheter. AB - INTRODUCTION: Amyloid-beta (Abeta) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Abeta fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Abeta variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF Abeta concentrations over time. METHODS: Grouped analysis of CSF Abeta levels from multiple industry and academic groups collected by either lumbar puncture (n=83) or indwelling lumbar catheter (n=178). Participants were either placebo or untreated subjects from clinical drug trials or observational studies. Participants had CSF collected by lumbar puncture or lumbar catheter for quantitation of Abeta concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for Abeta40 and Abeta42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of Abeta concentrations over time. RESULTS: Analysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of Abeta40 and Abeta42 as well as an Abeta diurnal pattern in all of the sponsors' studies. In contrast, Abeta concentrations from CSF samples collected at two time points by lumbar puncture showed no significant differences. Repeated measures analysis of variance found that only time and draw frequency were significantly associated with the slope of linear rise in Abeta40 and Abeta42 concentrations during the first 6 hours of collection. CONCLUSIONS: Based on our findings, we recommend minimizing the frequency of CSF draws in studies measuring Abeta levels and keeping the frequency standardized between experimental groups. The Abeta diurnal pattern was noted in all sponsors' studies and was not an artifact of study design. Averaging Abeta concentrations at each time point is recommended to minimize the effect of individual variability. Indwelling lumbar catheters are an invaluable research tool for following changes in CSF Abeta over 24-48 hours, but factors affecting Abeta concentration such as linear rise and diurnal variation need to be accounted for in planning study designs. PMID- 26225143 TI - Eosinopenia as a Marker of Outcome in Acute Exacerbations of Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common cause of hospitalization and mortality. Recent studies have shown the usefulness of eosinopenia in predicting the outcomes of patients admitted to the intensive care unit. This study examined the association of eosinopenia with the outcomes of patients with AECOPD. METHODS: This is a prospective study. Patients with AECOPD were divided into two cohorts: patients with eosinopenia and those without eosinopenia. Duration of hospitalization, need of mechanical ventilation, in-hospital mortality, rehospitalization, or death within 30 days after discharge were compared between the two cohorts. Eosinopenia was defined as eosinophil count of >40 cells/mm(3). RESULTS: Among 100 patients with AECOPD, 44 were eosinopenic and 56 were non-eosinopenic. Duration of hospitalization of patients with eosinopenia was 12.38 +/- 9.85 days and that of patients without eosinopenia was 7.35 +/- 5.68 days (p = 0.001). In all, 16 (36%) patients with eosinopenia and seven (12%) patients without eosinopenia needed mechanical ventilation (p = 0.005). In-hospital mortality rate among eosinopenic and noneosinopenic patients was 37.5% (12/44) and 7.6% (4/56), respectively (p = 0.006). Among 100 patients with AECOPD, 16 died in the hospital. Of these, 12 (27.27%) were eosinopenic and 4 (7.6%) were noneosinopenic (p = 0.006). The mean eosinophil count of patients who died in the hospital (n = 16) was 44.00 cells/ml whereas that of survivors (n = 84) was 107.41 cells/ml (p = 0.022). CONCLUSION: We conclude that a significant relationship exists between eosinopenia and outcomes of patients with AECOPD. Thus, eosinopenia can be a useful, easy-to-measure, and inexpensive biomarker for predicting the prognosis of patients with AECOPD. PMID- 26225144 TI - Mucinous Breast Cancer: a Review Study of 5 Year Experience from a Hospital-Based Series of Cases. AB - BACKGROUND: Mucinous carcinoma (also known as colloid carcinoma) is a particular type of breast cancer characterized by the presence of extracellular mucin and is linked with a more favorable prognosis than invasive breast carcinoma of no special type. Mucinous carcinoma of the breast is an uncommon form of breast tumor, often presenting as a lobulated, moderately well circumscribed mass on mammography, sonography, and MRI imaging. It accounts for 1 to 7% of all breast cancers. Pure mucinous breast carcinomas are rare and account for about 2% of all primary breast carcinomas. Metastatic disease happens at a lower rate than in other types of invasive carcinoma. METHODS: We present our 5 year experience with this particular pathology in a retrospective review study. RESULTS: We identified 25 patients with mixed and pure mucinous breast cancer, the tumor size varied greatly from 2 to 19 cm in diameter. A subset of mixed mucinous carcinomas (8 cases) showed neuroendocrine differentiation or other associated premalignant lessions. CONCLUSION: Mucinous carcinoma of the breast is a rare entity with a favorable prognosis due to low incidence of lymph node metastases. Pure mucinous breast carcinoma has an even rare. PMID- 26225145 TI - Dual X-Ray Absorptiometry Whole Body Composition of Bone Tissue in Rheumatoid Arthritis - a Cross-Sectional Study. AB - OBJECTIVES: Previous studies of bone tissue in rheumatoid arthritis (RA) using dual X-ray absorptiometry (DXA) concentrated on regions of interest that were used to diagnose osteoporosis. This study aimed to compare the whole body bone tissue (wbBT) of RA patients with healthy subjects and to identify the RA variables which significantly predict wbBT. METHODS: The study was cross sectionally designed to include postmenopausal RA patients and age-matched healthy female controls. All 107 RA patients and all 104 controls underwent clinical examination, laboratory tests and whole body DXA composition, which recorded total and regional bone indices. Non-parametric standard statistical test and regression models after data normalization were used to assess correlations, associations and differences. RESULTS: Compared to controls, RA patients had significantly lower whole body and regional bone mass (14.9 kg compared to 15.5 kg; p = 0.031). Disease duration (r = -0.402 ; p < 0.001), C reactive protein (r = -0.279; p = 0.015) and inflammation (2.5% wbBT compared to 2.9%; p = 0.043), radiographic damage (14.3 kg compared to 16.2 kg; p < 0.001), disease activity scores (r = -0.275 ; p = 0.018 for HAQ) are significantly correlated/associated with lower wbBT. Clinical structural damage is associated with lower wbBT and it can significantly predict them (R2 = 0.014; p = 0.001), while glucocorticoid treatment, even in low doses, was associated with lower wbBT percent (2.6% compared to 2.8%; p = 0.045). Treatment with biologics was associated with a lower rate of whole body osteoporosis (0% compared to 22.2%; p = 0.013). CONCLUSIONS: The main associated factors with the generalized bone loss in female RA patients are disease duration and disease activity. Clinical structural damage is the most powerful predictor of the whole body bone loss. These results suggest a general disturbance of skeletal bone metabolism in RA and could explain a greater risk of fragility fractures of non-central sites (e.g. ribs, tibia, ankles etc.) compared to post-menopause osteoporosis. PMID- 26225146 TI - Influence of the JAK2 V617F Mutation and Inherited Thrombophilia on the Thrombotic Risk among Patients with Myeloproliferative Disorders. AB - BACKGROUND: A number of studies showed that the JAK2 V617F mutation increases the thrombotic risk in patients with myeloproliferative disorders (MPN) while others did not reveal this correlation, and it is unknown whether inherited thrombophilia is an additive risk factor in mutated subjects. Our aim was to clarify the contribution of JAK2 V617F to a hypercoagulable state, as well as its interaction with other thrombophilic factors in patients with thrombosis and myeloproliferative disorders. METHOD: We studied 192 patients with myeloproliferative disorders, 90 with Essential thrombocytemia (ET), 42 with Polycythemia vera (PV) and 60 with Primary or idiopathic myelofibrosis (PMI). From these patients a subgroup of only 62 patients underwent laboratory screening for thrombophilia. RESULTS: The JAK2 V617F mutation was present in 62.8% patients with myeloproliferative disorders, 97.6% with PV, 54.5 % with ET and 53.44% patients with PMI. The mutated patients had a relative risk (RR) for thrombosis at any time of 2.94 in comparison with "wild-type" patients which was 0.93; in those patients having both the mutation and thrombophilia the RR was 3.56 (95% CI 2.41-7.34) compared to patients with neither the mutation nor thrombophilia, suggesting an additive interaction between the two risk factors. CONCLUSION: In patients with myeloproliferatives neoplasias, the thrombotic risk is higher in the JAK2 V617F-mutated subgroup and it is further increased by the presence of inherited thrombophilia (especially by the presence of mutated F V Leiden and lupus anticoagulant). PMID- 26225147 TI - Non-High-Density Lipoproteins Cholesterol and Cardio-Metabolic Risk. AB - BACKGROUND: The concept of cardio metabolic risk and risk stratification for cardiovascular events are two distinct entities related with different stages of vascular development of the atherogenic process. In our analytical transversal study, we analyzed non-high-density lipoprotein cholesterol behavior and the correlations with traditional cardiovascular risk factors in a subpopulation with coronary pain and indication of angio coronarography. We tried to build a mathematical model in order to predict the non-HDLc, allowing additional cardiovascular risk reassesment. METHODS: We included 214 patients hospitalized for symptoms and signs suggestive of coronary artery disease and thus indication of vascular invasive evaluation. The protocol of the vascular evaluation included: assessment of cardiovascular risk for fatal cardiovascular event within the next 10 years, the lipidic risk profile, coronarography and statistical analysis. RESULTS: We found a positive and highly statistically significant association between carotid artery intima-media thickness (c-IMT) and non-HDLc value (p <0.001). The mathematical model of linear regression showed the variability of non-HDLc depending on the following numeric variables: total cholesterol (TC), low density lipoproteins (LDL), triglycerides (TG), metabolic syndrome (MS); 97.5% of the non-HDLc variability was dependent on these variables. CONCLUSIONS: Non-HDLc is a useful prognostic factor in cardio metabolic risk quantification. The interdependent relation between non-HDLc and cardio-metabolic risk factors justifies the inclusion of this parameter in cardio metabolic risk prediction equation in subjects with metabolic syndrome. PMID- 26225148 TI - The Daily Functionality in a Major Depressive Episode Cohort of Romanian Patients - a Non-Interventional Study. AB - OBJECTIVES: The aim of this non-interventional, investigator driven study was to assess the functionality of patients with major depression under treatment with agomelatine in real life clinical practice. MATERIAL AND METHODS: The study was multicenter, non-interventional and evaluated the functionality of the adult patients with a DSM-IV diagnosis of MDD (single or recurrent episode and no treatment in the previous 6 months). It took place in Romania and it was a 10 weeks study. After the clinicians took the medical decision of treatment with agomelatine and if the patient agreed to be evaluated more accurate in this study, in order to assess functionality, patients completed at each visit the Sheehan Disability Scale (SDS). Patients were assessed also with QIDS-C (Quick Inventory of Depressive Symptomatology), a measure of depression symptoms severity and CGI scale severity (CGI-S), CGI scale improvement (CGI-I) and therapeutic index. Also, data about demographics and disease were collected during clinical interviews and from medical records. RESULTS: The functionality as assessed with SDS showed a significant functional impairment at baseline with scores >6 for each of the 3 inter-related domains of work/school, social and family life. At the end of the study, all functional aspects were improved although a mild impairment still persist requiring further treatment. A total of 1191 patients were analyzed (mean age: 47 years, 68% female). Mean QIDS-16 total score at baseline was 14.3 and decreased over the 10-week prospective period to 2.3. Most patients were treated with agomelatine. CONCLUSION: This study outcome confirms the fast on set of functionality improvement of agomelatine and further treatment need for the total remission of clinical depressive symptomatology after 10 weeks of treatment. PMID- 26225149 TI - A Challenging Case of Primary Breast Hodgkin's Lymphoma. AB - Primary breast lymphoma (PBL) is a rare entity accounting for less than 1% of all breast malignancies. Diagnostic criteria for primary Hodgkin's lymphoma of the breast are: the presence of sufficient tissue for diagnosis, close interaction between mammary tissue and lymphomatous infiltrate and no evidence or prior diagnosis of widespread lymphoma. Our case illustrates an unusual presentation of Hodgkin's lymphoma of the breast: clinically as inflammatory breast cancer and core biopsy as granulomatous mastitis, the final diagnosis requiring surgical biopsy. Current information regarding this entity is scant, mainly build upon its rarity. In this paper we assess the clinical presentation, the step-by-step diagnosis, the treatment and the importance of immunohistochemistry in this uncommon condition. PMID- 26225150 TI - Skeletal Dysplasia Presenting as a Neuromuscular Disorder - Report of a Family with Camurati-Engelmann Syndrome. AB - We report the case of a 28-year-old female with progressive diaphyseal dysplasia, who presented with history of a similar neuromuscular condition. Clinical, radiological and molecular data confirmed Camurati-Engelmann Disease (CED). This is the first Romanian family who was diagnosed with CED. PMID- 26225151 TI - A Case of Death Caused by 2700 degrees C Molten Magnesite Burns. AB - Magnesite (MgCO3) is a mineral which is theoretically composed of 52.2% CO2, 47.8% MgO, and very scarce amounts of Fe2O3 with a degree of hardness varying between 3.4-4.5 kgf, and specific gravity of 2.9-3.1 g/cm(3). Its color varies between white, yellow or gray, and brown. Magnesite is used in agriculture, and drug industry, brick, iron-steel, paper, and sugar industries. Our case was a 30 year-old male whose dead was reportedly associated with exposure to 2700 degrees C molten magnesite in the melting potansiyel of the plant where he was working as a metal worker. At autopsy, on external examination, except from his left forearm, all over his body was charred from severe burns. Both of his legs from ankles, and right forearm from its middle third were nearly amputated, and body muscles were partly detached because of high temperature. Widespread areas of thermal rupture were observed. On internal examination scalded appearance of internal organs was noted. Blood, and urine analysis did not reveal any substance abuse. Herein, we have aimed to discuss, and evaluate dead events because of exposure to very high temperatures from the perspective of forensic medicine, and occupational safety. PMID- 26225152 TI - Impressive Subcutaneous Calcifications in Systemic Lupus Erythematosus. AB - Dystrophic calcinosis cutis was commonly described in long-term dermatomyositis or systemic sclerosis, being rarely reported in other connective tissue diseases. We report the case of a 65-years old woman with an only 5-years history of systemic lupus erythematosus, who presents with multiple, impressive subcutaneous calcified masses and biological normal serum calcium and phosphate levels. PMID- 26225153 TI - Wandering Spleen: Whirlpool Appearance in Color Doppler Ultrasonography. A Case Report. AB - Wandering spleen is an unusual surgical condition that is generally asymptomatic, but the long and mobile vascular pedicle of the spleen predisposes it to torsion. Various imaging modalities can be used to diagnose a wandering spleen. We present the case of a 23 year-old female patient with abdominal pain, in whom torsion of the spleen was diagnosed preoperatively, using color Doppler sonography, as a whirlpool appearance. PMID- 26225154 TI - Evolution of Choroidal Neovascular Membrane in Best Disease after Single Intravitreal Bevacizumab. Case Report. AB - BACKGROUND: Best's disease is a hereditary form of macular dystrophy that starts in childhood and progresses until visual symptoms occur. In evolution it can be complicated with choroidal neovascularization, condition very rare in children. We report an important visual improvement in a 8-year-old caucasian girl after successful treatment with one intravitreal bevacizumab injection. There are few cases reported in literature (1-7), and the patient presented here have important particularities: one of the youngest children ever-mentioned with this complication, the third-member of her family with this disease and the first patient who didn't receive a second intravitreal bevacizumab at six weeks after first treatment, even though BCVA was lower than expected. The girl accused decrease of vision in the RE for the past 3-4 months. BCVA at presentation was 1/10. After 6 weeks from the intravitreal treatment, BCVA improved, but not very satisfactory (5/10). Because fundus and OCT aspects were encouraging, we waited another 4 weeks before the second injection. BCVA doubled in this period (8/10). Visual acuity, fundus and OCT aspects stabilized for 18 months of follow-up. CONCLUSION: We note that choroidal neovascular membrane associated with Best's disease can appear at such young children, this fact being very important in the phase of diagnosis, when the clinician should also take in consideration this possibility. Another important idea underlined here is the long-term efficacy of a single intravitreal anti-VEGF injection and also the no-need for imminent, fast re-treatment when the fundus and OCT aspects are encouraging through the follow up. PMID- 26225155 TI - Peripheral Nerve Regeneration - an Appraisal of the Current Treatment Options. AB - During the last decades significant progress was made in the understanding of the physiopathology of the peripheral nerve regeneration. Although the evolution of therapy is not as spectacular, a series of new treatment solutions were developed. The gold standard in therapy remains the use of autografts. We present the current concepts and therapeutic options available. PMID- 26225156 TI - Genetic Testing Is Not Required for Diagnosing Left Ventricular Hypertrabeculation / Non-Compaction. PMID- 26225157 TI - Global DNA methylation changes and differential gene expression in Anaplasma phagocytophilum-infected human neutrophils. AB - BACKGROUND: Anaplasma phagocytophilum is an obligate intracellular prokaryotic pathogen that both infects and replicates within human neutrophils. The bacterium represses multiple antimicrobial functions while simultaneously increasing proinflammatory functions by reprogramming the neutrophil genome. Previous reports show that many observed phenotypic changes are in part explained by altered gene transcription. We recently identified that large chromosomal regions of the neutrophil genome are differentially expressed during A. phagocytophilum infection. Because of this, we sought to determine whether gene expression programs altered by infection were the result of changes in the host neutrophil DNA methylome. RESULTS: Within 24 h of infection, marked increases in DNA methylation were observed genome-wide as compared with mock-infected controls and pharmacologic inhibition of DNA methyltransferases resulted in decreased bacterial growth. New regions of DNA methylation were enriched at intron and exon junctions; however, intragenic methylation did not correlate with altered gene expression. In contrast, intergenic DNA methylation was associated with A. phagocytophilum-induced gene expression changes. Within the major histocompatibility complex locus on chromosome 6, a region with marked changes in infection-induced differential gene expression, new regions of methylation were localized to boundaries of active and inactive chromatin. CONCLUSIONS: These data strongly suggest that A. phagocytophilum infection, in addition to altering histone structure, alters DNA methylation and the epigenome of its host cell to promote survival and replication, providing evidence that such bacterial infection can radically alter the epigenome of its host cell. PMID- 26225158 TI - Codifying active surveillance. PMID- 26225159 TI - 70 never looked so good! PMID- 26225160 TI - [Not Available]. PMID- 26225161 TI - Mentorship in Urology. PMID- 26225162 TI - Canadian guidelines for the management of small renal masses (SRM). PMID- 26225163 TI - Canadian guidelines for SRMs: How Canadian are they? PMID- 26225164 TI - Management of advanced kidney cancer: Canadian Kidney Cancer Forum consensus update. PMID- 26225165 TI - Active surveillance for the management of localized prostate cancer: Guideline recommendations. AB - INTRODUCTION: The objective is to provide guidance on the role of active surveillance (AS) as a management strategy for low-risk prostate cancer patients and to ensure that AS is offered to appropriate patients assessed by a standardized protocol. Prostate cancer is often a slowly progressive or sometimes non-progressive indolent disease diagnosed at an early stage with localized tumours that are unlikely to cause morbidity or death. Standard active treatments for prostate cancer include radiotherapy (RT) or radical prostatectomy (RP), but the harms from over diagnosis and overtreatment are of a significant concern. AS is increasingly being considered as a management strategy to avoid or delay the potential harms caused by unnecessary radical treatment. METHODS: A literature search of MEDLINE, EMBASE, the Cochrane library, guideline databases and relevant meeting proceedings was performed and a systematic review of identified evidence was synthesized to make recommendations relating to the role of AS in the management of localized prostate cancer. RESULTS: No exiting guidelines or reviews were suitable for use in the synthesis of evidence for the recommendations, but 59 reports of primary studies were identified. Due to studies being either non-comparative or heterogeneous, pooled meta-analyses were not conducted. CONCLUSION: The working group concluded that for patients with low risk (Gleason score <=6) localized prostate cancer, AS is the preferred disease management strategy. Active treatment (RP or RT) is appropriate for patients with intermediate-risk (Gleason score 7) localized prostate cancer. For select patients with low-volume Gleason 3+4=7 localized prostate cancer, AS can be considered. PMID- 26225166 TI - Health-related quality of life in robotic versus open radical prostatectomy. AB - INTRODUCTION: It is unclear whether health-related quality of life (HRQoL) outcomes are superior in robot-assisted radical prostatectomy (RARP) compared to open prostatectomy (ORP). METHODS: We retrospectively analyzed records from men who received ORP or RARP at our institution between January 2009 and December 2012. Patients completed a demographics questionnaire and the Patient-Oriented Prostate Utility Scale (PORPUS), a validated disease-specific HRQoL instrument prior to surgery and every 3 months up to 15 months after surgery. RESULTS: In total, 974 men met the inclusion criteria (643 ORP and 331 RARP patients). At baseline, RARP patients were significantly younger (p < 0.001), had lower body mass index (BMI) (p < 0.001), lower preoperative prostate-specific antigen (PSA) (p < 0.001), fewer comorbidities (p < 0.004), and higher baseline PORPUS scores (p = 0.024). On follow-up, unadjusted PORPUS scores were significantly higher in the RARP group at each point. On multivariable analysis adjusting for age, ORP versus RARP procedure, Gleason score, BMI, first PSA, comorbidity, ethnicity, and baseline PORPUS scores, PORPUS score was higher for the RARP group at 3 months (p = 0.038) and 9 months (p = 0.037), but not at 6, 12, and 15 months (p = 0.014). No difference met pre-defined thresholds of clinical significant. CONCLUSIONS: Though unadjusted HRQoL outcomes appeared improved with RARP compared to ORP differences, adjusted differences were seen at only 2 of 5 postoperative time points, and did not meet pre-defined thresholds of clinical significance. Further randomized trials are needed to assess whether one treatment option provides consistently better HRQoL outcomes. PMID- 26225167 TI - Quality of life after radical prostatectomy: Continuing to improve on our track record. PMID- 26225168 TI - External validation of the S.T.O.N.E. nephrolithometry scoring system. AB - INTRODUCTION: We perform external validation of the S.T.O.N.E. nephrolithometry scoring system for the preoperative assessment of percutaneous nephrolithotomy (PCNL) outcomes. METHODS: After obtaining institutional review board approval, all PCNLs performed from 2009 to 2013 at a tertiary referral centre were reviewed. The S.T.O.N.E. score was calculated and correlated with stone-free status, estimated blood loss (EBL), operative time, length of hospital stay (LOS), and postoperative complications. RESULTS: A total of 155 PCNLs were included, with 100 (64.5%) males and 55 (35.5%) females. The mean age was 54.9 +/ 1.2 years (range: 17-85), with a mean body mass index of 26.9 +/- 0.5 kg/m(2) (range: 17.2-51). The mean S.T.O.N.E. score was 7.67 +/- 0.1 (range: 5-12), with a mean stone size of 609.8 +/- 48.4 mm(2) (range: 250-4030), a mean Hounsfield unit of 887.7 +/- 25.3 (range: 222-1766), a mean tract length of 97.3 +/- 1.9 mm (range: 53-175), a mean operative time of 100.1 +/- 2.8 min (range: 60-240), and a mean LOS of 4.2 +/- 0.3 days (range: 1-18). The overall stone-free rate after the primary procedure was 71.6%. The S.T.O.N.E. score significantly affected stone-free status (p = 0.001) and EBL (p = 0.003). There was significant correlation between the S.T.O.N.E. score and operative time (r = 0.4; p < 0.001) and LOS (r = 0.3; p = 0.001). Therefore, the higher the S.T.O.N.E. score, the longer the operative time, the higher the EBL, the longer the LOS, and the lower the chance of being stone-free. The overall complication rate after the primary procedure was 15.5%, which did not correlate with the S.T.O.N.E. score (p = 0.9). CONCLUSION: Although this study externally validates the S.T.O.N.E. scoring system, its accuracy is comparable to stone size and number of involved calyces in predicting stone-free status post-PCNL. PMID- 26225169 TI - The S.T.O.N.E. nephrolithometry scoring system: How valid is it? PMID- 26225170 TI - Positional pelvic organ prolapse (POP) evaluation using open, weight-bearing magnetic resonance imaging (MRI). AB - INTRODUCTION: Magnetic resonance imaging (MRI) of patients with pelvic organ prolapse (POP) is completed in the supine position. Open magnetic resonance imaging (MRO) uses vertical magnets, allowing imaging in a variety of upright postures. This pilot study used MRO to evaluate the change of prolapse in different positions compared to non-prolapsed images. METHODS: In total, 11 women (6 POP, 5 controls) aged 24 to 65 years had 12 MRO images (midline sagittal pelvic line) consecutively when supine, sitting and standing with a full and empty bladder. Lengths between the lowest point of the bladder to the pubococcygeal (PC) and pubopromontoreal (PP) lines in each image were compared, and the ratio of bladder area under the PC and PP lines to the total bladder area. RESULTS: Significant elongation between the PC line and lowest point of the bladder was evident in subjects with POP comparing supine and standing images (p = 0.03), but not controls (p = 0.07). Similarly, this axis was significantly longer in cystocele subjects versus controls only in the standing position. Bladder area under the PC line was significantly increased between supine and standing positions only among subjects with cystocele (p < 0.01), and significantly larger among the study group in the standing position (p < 0.005), less significant in the supine position (p = 0.015), and not significant in the sitting position (p = 0.3). CONCLUSIONS: MRO imaging allows us to investigate the effects of upright position and weight bearing on the staging of POP. Imaging patients when sitting and standing identified that significant changes occur in the maximal descent of the bladder. PMID- 26225171 TI - Still room for print. PMID- 26225172 TI - Still room for print: Editors' response. PMID- 26225173 TI - Efficacy of dextranomer hyaluronic acid and polyacrylamide hydrogel in endoscopic treatment of vesicoureteral reflux: A comparative study. AB - INTRODUCTION: Various bulking agents are available for vesicoureteral reflux (VUR) endoscopic treatment, but their inconsistent success rates and costs are concerns for urologists. Recently, polyacrylamide hydrogel (PAHG) has been shown to have a good overall success rate, which seems comparable to dextranomer hyaluronic acid (Dx/HA), currently the most popular bulking agent. Our objective was to compare the short-term success rate of PAHG and Dx/HA for VUR endoscopic treatment in children. METHODS: We performed a prospective non-randomized study using PAHG and Dx/HA to treat VUR grades I to IV in pediatric patients. All patients underwent endoscopic sub-ureteric injection of PAHG or Dx/HA, using the double-HIT technique, followed by a 3-month postoperative renal ultrasound and voiding cystourethrogram. Treatment success was defined as the absence of de novo or worsening hydronephrosis and absence of VUR. RESULTS: A total of 90 pediatric patients underwent an endoscopic injection: 45 patients (78 ureters) with PAHG and 45 patients (71 ureters) with Dx/HA. The mean injected volume of PAHG and Dx/HA was 1.1 mL and 1.0 mL, respectively. The overall success rate 3 months after a single treatment was 73.1% for PAHG and 77.5% for Dx/HA. Postoperatively, 1 patient in each group presented with acute pyelonephritis and 2 patients in the Dx/HA group developed symptomatic ureteral obstruction. CONCLUSION: Success rates of PAGH and Dx/HA in endoscopic injections for VUR treatment were comparable. The rate of resolution obtained with Dx/HA was equivalent to those previously published. The lower cost of PAHG makes it an interesting option. PMID- 26225175 TI - XGEVA((r)) (denosumab). PMID- 26225174 TI - Perioperative outcomes after radical cystectomy at NCI-designated centres: Are they any better? AB - INTRODUCTION: In 1971, the National Cancer Institute (NCI) introduced a network of NCI-designated Cancer Centers (CC), which underwent a comprehensive approval process relying on research, education and prevention activities. In this study, we examine the effect of CC status on perioperative outcomes after radical cystectomy (RC). METHODS: Within the Nationwide Inpatient Sample, we focused on RC performed from 2006 to 2010. As all recognized centres were residency teaching institutions, we stratified according to teaching and CC-teaching status. We examined the rates of in-hospital mortality, intra- and postoperative complications, prolonged length of hospital stay, as well as blood transfusion. Multivariable logistic regression analyses were further adjusted for confounding factors. RESULTS: Overall, 22 840 RC patients (5451 at non-teaching, 10 857 at residency teaching, 6532 at CC-teaching institutions) were identified. Patients treated at residency teaching and CC-teaching institutions were younger, had less comorbidities, and more likely to have private insurance. In multivariable analyses, patients treated at residency and CC-teaching institutions were less likely to experience postoperative complications (odds ratio [OR] 0.73 and 0.66, respectively) and blood transfusions (OR 0.77 and 0.53, respectively) relative to patients treated at non-teaching institutions. In addition, CC patients were also less likely to experience in-hospital mortality (OR 0.61, all p < 0.001) as compared to non-teaching institutions. CONCLUSIONS: On average, patients treated at residency and CC-teaching institutions are less likely to experience unfavourable outcomes after RC. Moreover, patients treated at CC fared better than patients treated at residency teaching institutions. Our findings acknowledge the quality of RC care at accredited centres. PMID- 26225176 TI - [Not Available]. PMID- 26225177 TI - Artificial urinary sphincter erosion after radical prostatectomy in patients treated with and without radiation. AB - INTRODUCTION: There has been increasing evidence supporting the use of adjuvant radiotherapy after radical prostatectomy (RP) for prostate cancer. Significant stress incontinence after RP is not uncommon and the artificial urinary sphincter (AUS) is the gold standard of treatment. Our objective was to assess if increased use of radiotherapy after RP has changed the rate of erosion and infection in the face of improvement in radiation technique and equipment in men who had an AUS implanted in the last 10 years. METHODS: We retrospectively examined 118 patients from December 2001 to January 2012 who underwent a RP with or without postoperative radiotherapy and subsequently had an AUS implanted. We divided the patients into two cohorts (Group 1: December 2001-December 2006 and Group 2: January 2007-January 2012). We reviewed all patient records for age, cuff size implanted, history of postoperative radiotherapy, previous incontinence surgery, revisions, and complications (erosion/infection). RESULTS: There were 36 and 82 patients in Groups 1 and 2, respectively. The mean age was similar between groups, 67 years both groups (p = 0.980). The number of patients treated with postoperative radiotherapy was similar between groups (36% vs. 32%, p = 0.640, respectively). There was no difference in the incidence of erosion or infection between Group 1 and 2 (p = 0.848 and p = 0.178, respectively). The overall relative risk (RR) of erosion was significantly higher in those who had radiotherapy compared to those who did not (RR 4.05, 95% confidence interval 1.1 15.3). CONCLUSIONS: Over the last 10 years, there has not been an increase in the number of patients receiving an AUS after RP and radiotherapy at our centre. During this time, the incidence of erosion and infection has not increased. However, our study reaffirms that the relative risk of erosion remains higher in patients who have had radiotherapy despite improvement in radiation treatment techniques and equipment. PMID- 26225178 TI - Accuracy capabilities comparisons between Karakiewicz, Kattan and Cindolo nomograms in predicting outcomes for renal cancer carcinoma: A systematic review and meta-analysis. AB - INTRODUCTION: Several prognostic models have been proposed to predict outcomes of patients affected by renal cell carcinoma. We analyze the discriminative capabilities of Karakiewicz, Kattan and Cindolo nomograms and perform a meta analysis to yield pooled area under the receiver operator curves (AUCs) for model comparison. The end points of interest were disease-recurrence free survival (DFS) and cancer-specific survival (CSS). METHODS: An electronic search of the Medline and Embase was undertaken until July 2014. The AUC value, total number of patients, number of disease recurrence, and cancer-related deaths were extracted from the included references. AUCs of the models were converted to odds ratios (ORs). For the meta-analysis, ln(OR) was used for data pooling. For each nomogram, the combined OR was transformed back to a converted AUC (cAUC). RESULTS: A total of 16 studies were identified including 26 710 patients. The derived comparison of cAUC values revealed better predictive capability of DFS for the postoperative Karakiewicz nomogram versus Kattan nomogram (p < 0.01), but not versus Cindolo (p = 0.432) and between Cindolo versus Kattan (p = 0.03). The Mantel-Haenszel derived comparison of cAUC values revealed better predictive capability for the preoperative Karakiewicz nomogram versus the Kattan nomogram (p < 0.01) and versus the Cindolo model (p < 0.01), but also between the postoperative Karakiewicz model versus the Kattan model (p < 0.01) and the Cindolo model (p < 0.01). The Kattan model showed better discriminative capability versus the Cindolo model (p < 0.01). CONCLUSIONS: The predictive abilities of the pre- and postoperative Karakiewicz models are higher than Kattan or Cindolo in predicting DFS and CSS. PMID- 26225179 TI - Initial experience with ketamine-based analgesia in patients undergoing robotic radical cystectomy and diversion. AB - INTRODUCTION: We instituted a ketamine-predominant analgesic regimen in the peri- and postoperative periods to limit the effects of narcotic analgesia on bowel function in patients undergoing radical cystectomy. The primary end points of interest were time to return of bowel function, time to discharge, and efficacy of the analgesic regimen. METHODS: We performed a retrospective chart review of patients undergoing robotic-assisted laparoscopic cystectomy (RARC) with urinary diversion by a single surgeon at our institution from January 1, 2011 to June 30, 2012. Patients receiving the opioid-minimizing ketamine protocol were compared to a cohort of patients undergoing RARC with an opioid-predominant analgesic regimen. RESULTS: In total, 15 patients (Group A) were included in the ketamine predominant regimen and 25 patients (Group B) in the opioid-predominant control group. Three patients (19%) in Group A discontinued the protocol due to ketamine side effects. The mean time to bowel movement and length of stay in Group A versus Group B was 3 versus 6 days (p < 0.001), and 4 versus 8 days, respectively (p < 0.001). Group A patients received an average of 13.0 mg of morphine versus 97.5 mg in Group B (p < 0.001). CONCLUSIONS: Patients who received our ketamine pain control regimen had a shorter time to return of bowel function and length of hospitalization after RARC. Our study has its limitations as a retrospective, single surgeon, single institution study and the non-randomization of patients. Notwithstanding these limitations, this study was not designed to show inferiority of one approach, but instead to show that our protocol is safe and efficacious, warranting further study in a prospective fashion. PMID- 26225180 TI - The utility of provincial AS guidelines. PMID- 26225181 TI - Retrovesical hydatic cyst: About 4 cases. AB - INTRODUCTION: The hydatid cyst is a real public health problem in Tunisia. The retrovesical localization is rare. It is considered an aberrant or ectopic location defined by the development of the parasite in the subvesical and retrovesical fat. METHODS: From 2004 to 2013, 4 patients with retrovesical hydatid cyst were hospitalized and operated in the Department of Urology at the Charles Nicolle hospital of Tunis in Tunisia. The average patient age was 40.75 years (range: 23-76). Signs of bladder irritation were the most frequent presenting complaint. No cases of hydaturia were noted. The diagnosis was made on the ultrasound and the computed tomographic urography. Hydatid serology was positive for 3 patients. In 3 cases, a hydatid cyst of the liver was associated. A total cysto-pericystectomy was performed for 1 patient, for others it was partial. RESULTS: The postoperative course was uneventful. No urinary fistula or infection of the residual cavity was observed. One patient had a retroperitoneal cyst recurrence requiring reoperation. CONCLUSION: Retrovesical location of hydatid cyst is rare and treatment is primarily surgical. PMID- 26225182 TI - Clinical benefits of tubeless umbilical cutaneous ureterostomy. AB - INTRODUCTION: We assess a novel technique of tubeless bilateral cutaneous ureterostomy, with a single umbilical stoma, for bladder cancer patients with short ureters after cystectomy. The benefit of cutaneous ureterostomy is equal to other incontinent urinary diversions, when the tubeless procedure is successfully achieved. This simple technique makes it easy to monitor the upper urinary tract (UUT) and is beneficial to patients with a high risk of UUT recurrence. METHODS: This old and new surgical technique was used to perform total cystectomy and urinary diversion on three patients with bladder cancer at a high risk of UUT recurrence. RESULTS: Two men and one woman (mean age: 73 years) underwent this surgery and the mean follow-up period was 8.3 years. The surgical approaches were laparotomy (n = 2) and laparoscopy (n = 1). One case developed para-stomal erosion, whereas another developed ureteral stenosis requiring catheter reinsertion. Although postoperative hydronephrosis was observed in all cases, the mean preoperative and postoperative serum creatinine levels were 0.70 and 0.76, respectively. UUT recurrence was not observed during the follow-up period. CONCLUSION: This tubeless umbilical cutaneous ureterostomy procedure greatly improves the outcome of urinary diversion for cancer patients with short ureters at a high risk of UUT recurrence. The benefits are equivalent to other urinary diversions when the tubeless procedure is successfully achieved. PMID- 26225183 TI - A guidewire introducer as a ureteral foreign body: A case report. AB - A 63-year-old male, previously treated for a ureteral tumour by a right-sided segmental ureterectomy and end-to-end anastomosis of ureteral segments, was referred to our clinic for endoscopic follow-up. During his follow-up, he was diagnosed with partial right-sided ureteral stricture which eventually progressed to complete obstruction. During the ureteroscopy, as the stenotic segment did not allow passage of an hydrophilic guidewire, an antegrade-retrograde approach was decided. On the antegrade endoscopic view, a near-complete stenosis was diagnosed and a nephrostomy catheter (12 Fr) was placed. A second intervention was planned and from the nephrostomy tract, the ureteroscope was placed into the right pyelocaliceal system. The diagnostic ureteroscopy revealed a foreign object proximal to the stenotic area. Right-sided segmental ureterectomy of the stenotic segment with ureteroneocystostomy and removal of the foreign object was performed. This is the only case in literature to reveal a guidewire introducer as a ureteral foreign body. This case also highlights the importance of the fragility of the ureter, the importance of the equipment, of always being watchful during a surgery, and the importance of checking the integrity of the equipment at the end of each procedure. PMID- 26225184 TI - Port site metastasis in prostate cancer. AB - Port-site metastasis of prostatic adenocarcinoma is rare and usually associated with poor prognosis. We report a case of a young man with a rising prostate specific antigen (PSA) 4.5 years after robot-assisted laparoscopic prostatectomy (RALP) and extended pelvic lymphadenectomy (ePLND) for a Gleason 7 (4+3) prostate cancer (pT3b pN0 cM0). Choline positron emission tomography-computed tomography (PET-CT) demonstrated a PET positive subcutaneous recurrence in a previous trocar site accompanied by a PET positive ipsilateral inguinal lymph node. Excision of both lesions was performed, confirming the diagnosis of metastatic prostate cancer. The patient's PSA dropped significantly postoperatively enabling postponement of androgen deprivation treatment up to this date. The etiology of port-site metastasis is multifactorial, including patient and surgery related factors. Such metastases have been scarcely reported following ePLND with or without RALP. Certain surgical precautions can be made to prevent the occurrence. We summarize previously reported mechanisms of development and possible precautionary measures. PMID- 26225185 TI - Cholesterol granuloma of the paratesticular tissue: A case report. AB - A 38-year-old man was admitted to our clinic with an enlarging right scrotal mass that had been present for 7 years. Right radical inguinal orchiectomy was performed and a histopathological diagnosis confirmed a very rare case of cholesterol granuloma of the paratesticular tissue. It can be very difficult to preoperatively distinguish testicular tumours from cholesterol granulomas of the testis or epididymis. Cholesterol granuloma should be kept in mind in patients with large and non-tender scrotal masses. PMID- 26225186 TI - Successful neoadjuvant chemotherapy for primary invasive small-cell carcinoma of the ureter. AB - We report a case of invasive small-cell carcinoma (SCC) of the ureter successfully treated by neoadjuvant chemotherapy and laparoscopic nephroureterectomy. SCC of the ureter is an extremely rare condition characterized by aggressive behaviour. A 70-year-old male presented with left flank pain; he was diagnosed with SCC of the ureter, cT3N0M0, by ureteroscopic biopsy. The patient received 3 cycles of neoadjuvant chemotherapy with cisplatin and irinotecan (IP) and underwent laparoscopic nephroureterectomy. The pathological diagnosis was urothelial carcinoma, high grade, without a small-cell component. The pathological stage was down-staged to pT2N0M0. Adjuvant chemotherapy was not performed. The patient has been free of local recurrence or distant metastasis for 38 months postoperatively. This is the first reported case of primary invasive SCC of the upper urinary tract treated by neoadjuvant chemotherapy followed by nephroureterectomy. PMID- 26225187 TI - Iatrogenic hepatic subcapsular biloma following PCNL: Diagnosis and management. AB - After the first description in 1976, percutaneous nephrolithotomy (PCNL) remains the treatment of choice for large renal stones. Adjacent organ injuries are rare complications, with pulmonary and colonic representing the most common, while hepatic represents one of the rarest. We describe our case of hepatic subcapsular biloma following a subcostal PCNL, conservatively managed by percutaneous drainage and endoscopic biliary stenting. PMID- 26225188 TI - An integrative review and severity classification of complications related to pessary use in the treatment of female pelvic organ prolapse. AB - INTRODUCTION: Pessary use is the preferred non-surgical treatment option for female pelvic organ prolapse. As pessaries can be used chronically to alter pelvic floor anatomy, consideration of short-and long-term complications is important in patient management. We systematically reviewed articles describing the complications of pessary use to determine frequency and severity. METHODS: A systematic search via MEDLINE and PubMed using the key terms "complications," "pessary," "pelvic organ prolapse," "side effects" was conducted for the years 1952 to 2014 inclusively. Selected articles cited in the publications identified were also considered. Only full-text material published in English was reviewed. All pessary-related complications described were collated; overall frequency within case reports and case series were calculated and severity was graded using the Clavien-Dindo classification. RESULTS: In total, 61 articles met the inclusion criteria. The most common complications reported were vaginal discharge/vaginitis, erosion, and bleeding. Complications were related to pessary shape and material, and duration in situ. Clavien-Dindo classification of complication severity found that all 5 grade levels were attributed to pessary use; serious grade 4 and 5 complications included cancer, adjacent organ fistula and death. CONCLUSION: There are few detailed reports of complications of pessary use relative to the estimated frequency of pessary use worldwide. Prospective studies documenting complications by shape, material, and size, and objectively classifying complication severity are required. As serious grade 4 and 5 complications of pessary use occur, further development of clinical follow-up guidelines for long-term pessary users is justified. PMID- 26225189 TI - Fournier's gangrene: A retrospective analysis of 26 cases in a Canadian hospital and literature review. AB - We performed a systematic review of all cases of Fournier's Gangrene (FG) at our hospital over a 12-year period. A total of 26 cases were assessed. Our goal was to determine the mortality rate and to identify risk factors associated with FG. We also wanted to examine three potential prognostic factors in relation to patient survival, including the time delay from emergency room admission to surgery, the initial extent of the disease, and the impact of more than one debridement procedure under general anesthesia. The time between emergency room admission and the beginning of surgical debridement was not statistically different between survivors and non-survivors. The extent of surgical debridement was close to the margin of statistical significance (p = 0.07) and can be considered an index of the extent of the disease. FG extending to the thighs or to the abdominal wall carries a worse prognosis. The number of surgical debridement procedures done under anesthesia was statistically different between survivors and non-survivors. Patients were 4.8 times more at risk of dying if they are required to have more than one surgical debridement under general anesthesia. This presumably reflects persistent gangrene following initial surgical debridement, fluid resuscitation, and wide spectrum antibiotic treatment. PMID- 26225192 TI - Is gall bladder cancer a bad cancer per se? AB - Gall bladder cancer (GBC) has one of the poorest outcomes of all cancers. Early GBC is difficult to diagnose on even computed tomography. GB has no submucosa and the cancer infiltrates directly into the muscularis propria. GB wall is thin and important adjacent organs viz. liver, duodenum and pancreas get easily infiltrated. Tumor in the GB neck often needs extended right hepatectomy. Infiltration of duodenum/pancreas may necessitate pancreato-duodenectomy or even hepato-pancreato-duodenectomy. Mortality of surgical procedures, when performed for GBC, is higher than when performed for other cancers. Survival in GBC, even after R0 resection, is poor. There is no proven role of neo-adjuvant or adjuvant therapy for loco-regionally advanced GBC. There is no role of palliative surgery in metastatic GBC. Early GBC is diagnosed incidentally after cholecystectomy for stones and requires reoperation for completion extended cholecystectomy but unfortunately, most surgeons are not aware of this. GBC has a peculiar epidemiology and is uncommon in the West and has, therefore, not received much attention. Preventive cholecystectomy for asymptomatic stones is not recommended and there is no serum marker for screening. With all factors pitched against it, it does appear that GBC is a bad cancer per se! PMID- 26225191 TI - Perspective of laparoscopic liver resection for hepatocellular carcinoma. AB - Liver resection (LR) for hepatocellular carcinoma (HCC) in patients with chronic liver disease (CLD) is associated with high risks of developing significant postoperative complications and multicentric metachronous lesions, which can result in the need for repeated treatments. Studies comparing laparoscopic procedures to open LR consistently report reduced blood loss and transfusions requirements, lower postoperative morbidity, and shorter hospital stays, with no differences in oncologic outcomes. In addition, laparoscopic LR is associated with reduced postoperative ascites and a lower incidence of liver failure for HCC patients with CLD, due to the reduced surgery-induced parenchymal injury to the residual liver and limited destruction of the collateral blood/lymphatic flow around the liver. Finally, this procedure facilitates subsequent repeat LR due to minimal adhesion formation and improved vision/manipulation between adhesions. These characteristics of laparoscopic LR may lead to an expansion of the indications for LR. This editorial is based on the review and meta-analysis presented at the 2(nd) International Consensus Conference on Laparoscopic Liver Resection in Iwate, Japan, in October 2014 (Chairperson of the congress is Professor Go Wakabayashi from the Department of Surgery, Iwate Medical University School of Medicine), which is published in the Journal of Hepato-Biliary Pancreatic Sciences. PMID- 26225193 TI - Capillary refill time as a guide for operational decision-making process of autoimmune pancreatitis: Preliminary results. AB - AIM: To investigate the efficacy of a novel intraoperative diagnostic technique for patients with preliminary diagnosis of autoimmune pancreatitis (AIP). METHODS: Patients with pancreatic surgery were reviewed to identify those who received a preliminary diagnosis of AIP between January 2010 and January 2014. The following data were collected prospectively for patients with a pathological diagnosis of AIP: clinical and demographic features, radiological and operative findings, treatment procedure, and intraoperative capillary refill time (CRT) in the pancreatic bed. RESULTS: Eight patients (six males, two females; mean age: 51.4 years) met the eligibility criteria of pathologically confirmed diagnosis. The most frequent presenting symptoms were epigastric pain and weight loss. The most commonly conducted preoperative imaging studies were computed tomography and endoscopic retrograde pancreaticodoudenography. The most common intraoperative macroscopic observations were mass formation in the pancreatic head and diffuse hypervascularization in the pancreatic bed. All patients showed decreased CRT (median value: 0.76 s, range: 0.58-1.35). One-half of the patients underwent surgical resection and the other half received medical treatment without any further surgical intervention. CONCLUSION: This preliminary study demonstrates a novel experience with measurement of CRT in the pancreatic bed during the intraoperative evaluation of patients with AIP. PMID- 26225190 TI - Influence of Alternative Tubulin Inhibitors on the Potency of a Epirubicin Immunochemotherapeutic Synthesized with an Ultra Violet Light-Activated Intermediate: Influence of incorporating an internal/integral disulfide bond structure and Alternative Tubulin/Microtubule Inhibitors on the Cytotoxic Anti Neoplastic Potency of Epirubicin-(C3-amide)-Anti-HER2/neu Synthesized Utilizing a UV-Photoactivated Anthracycline Intermediate. AB - Immunochemotherapeutics, epirubicin-(C3-amide)-SS-[anti-HER2/neu] with an internal disulfide bond, and epirubicin-(C3-amide)-[anti-HER2/neu] were synthesized utilizing succinimidyl 2-[(4,4'-azipentanamido) ethyl]-1,3' dithioproprionate or succinimidyl 4,4-azipentanoate respectively. Western blot analysis was used to determine the presence of any immunoglobulin fragmentation or IgG-IgG polymerization. Retained HER2/neu binding characteristics of epirubicin-(C3-amide)-[anti-HER2/neu] and epirubicin-(C3-amide)-SS-[anti HER2/neu] were validated by cell-ELISA using a mammary adenocarcinoma (SKBr-3) population that highly over-expresses trophic HER2/neu receptor complexes. Cytotoxic anti-neoplastic potency of epirubicin-(C3-amide)-[anti-HER2/neu] and epirubicin-(C3-amide)-SS-[anti-HER2/neu] between epirubicin-equivalent concentrations of 10-10 M and 10-6 M was determined by measuring the vitality/proliferation of chemotherapeutic-resistant mammary adenocarcinoma (SKBr 3 cell type). Cytotoxic anti-neoplastic potency of benzimidazoles (albendazole, flubendazole, membendazole) and griseofulvin were assessed between 0-to-2 MUg/ml and 0-to-100 MUg/ml respectively while mebendazole and griseofulvin were analyzed at fixed concentrations of 0.35 MUg/ml and 35 g/ml respectively in dual combination with gradient concentrations of epirubicin-(C3-amide)-[anti-HER2/neu] and epirubicin-(C3-amide)-SS-[anti-HER2/neu]. Cytotoxic anti-neoplastic potency for epirubicin-(C3-amide)-[anti-HER2/neu] and epirubicin-(C3-amide)-SS-[anti HER2/neu] against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) was nearly identical at epirubicin-equivalent concentrations of 10-10 M and 10-6 M. The benzimadazoles also possessed cytotoxic anti-neoplastic activity with flubendazole and albendazole being the most and least potent respectively. Similarly, griseofulvin had cytotoxic anti-neoplastic activity and was more potent than methylselenocysteine. Both mebendazole and griseofulvin when applied in dual combination with either epirubicin-(C3-amide)-[anti-HER2/neu] or epirubicin-(C3-amide)-SS-[anti-HER2/neu] produced enhanced levels of cytotoxic anti-neoplatic potency. PMID- 26225194 TI - Accuracy of computed tomography in nodal staging of colon cancer patients. AB - AIM: To predict node-positive disease in colon cancer using computed tomography (CT). METHODS: American Joint Committee on Cancer stage I-III colon cancer patients who underwent curavtive-intent colectomy between 2007-2010 were identified at a single comprehensive cancer center. All patients had preoperative CT scans with original radiology reports from referring institutions. CT images underwent blinded secondary review by a surgeon and a dedicated abdominal radiologist at our institution to identify pericolonic lymph nodes (LNs). Comparison of outside CT reports to our independent imaging review was performed in order to highlight differences in detection in actual clinical practice. CT reviews were compared with final pathology. Results of the outside radiologist review, secondary radiologist review, and surgeon review were compared with the final pathologic exam to determine sensitivity, specificity, positive and negative predictive values, false positive and negative rates, and accuracy of each review. Exclusion criteria included evidence of metastatic disease on CT, rectal or appendiceal involvement, or absence of accompanying imaging from referring institutions. RESULTS: From 2007 to 2010, 64 stageI-III colon cancer patients met the eligibility criteria of our study. The mean age of the cohort was 68 years, and 26 (41%) patients were male and 38 (59%) patients were female. On final pathology, 26 of 64 (40.6%) patients had node-positive (LN+) disease and 38 of 64 (59.4%) patients had node-negative (LN-) disease. Outside radiologic review demonstrated sensitivity of 54% (14 of 26 patients) and specificity of 66% (25 of 38 patients) in predicting LN+ disease, whereas secondary radiologist review demonstrated 88% (23 of 26) sensitivity and 58% (22 of 38) specificity. On surgeon review, sensitivity was 69% (18 of 26) with 66% specificity (25 of 38). Secondary radiology review demonstrated the highest accuracy (70%) and the lowest false negative rate (12%), compared to the surgeon review at 67% accuracy and 31% false negative rate and the outside radiology review at 61% accuracy and 46% false negative rate. CONCLUSION: CT LN staging of colon cancer has moderate accuracy, with administration of NCT based on CT potentially resulting in overtreatment. Active search for LN+ may improve sensitivity at the cost of specificity. PMID- 26225195 TI - Delayed esophageal perforation occurring with endoscopic submucosal dissection: A report of two cases. AB - We report two cases of delayed esophageal perforation occurring with endoscopic submucosal dissection. Our cases involved delayed perforation after 10 d in case 1 and after 6 d in case 2. Both cases were related to solid food. We performed subtotal esophagectomy with gastric tube reconstruction of the esophagus via the subcutaneous route anterior to the thoracic wall without conservative treatment because both cases involved chest pain and major leakage of food into the mediastinum. Postoperative complications were a local factor (including suture failure and esophageal stricture) in case 1, and we performed endoscopic balloon dilatation five times for esophageal stricture. There was no intrathoracic and mediastinal infection in either case. Surgical treatment for delayed esophageal perforation can be performed safely and surely if diagnosis and assessment are not delayed. PMID- 26225196 TI - Night time blood pressure dip. AB - The advent of ambulatory blood pressure monitoring permitted examination of blood pressures during sleep and recognition of the associated circadian fall in pressure during this period. The fall in pressure, called the "dip", is defined as the difference between daytime mean systolic pressure and nighttime mean systolic pressure expressed as a percentage of the day value. Ten percent to 20% is considered normal. Dips less than 10%, referred to as blunted or absent, have been considered as predicting an adverse cardiovascular event. This view and the broader concept that white coat hypertension itself is a forerunner of essential hypertension is disputable. This editorial questions whether mean arterial pressures over many hours accurately represent the systolic load, whether nighttime dipping varies from measure to measure or is a fixed phenomenon, whether the abrupt morning pressure rise is a risk factor or whether none of these issues are as important as the actual night time systolic blood pressure itself. The paper discusses the difference between medicated and nonmedicated white coat hypertensives in regard to the cardiovascular risk and suggests that further work is necessary to consider whether the quality and duration of sleep are important factors. PMID- 26225197 TI - Hemoglobin optimization and transfusion strategies in patients undergoing cardiac surgery. AB - Although red blood cells (RBCs) transfusion is sometimes associated with adverse reactions, anemia could also lead to increased morbidity and mortality in high risk patients. For these reasons, the definition of perioperative strategies that aims to detect and treat preoperative anemia, prevent excessive blood loss, and define "optimal" transfusion algorithms is crucial. Although the treatment with preoperative iron and erythropoietin has been recommended in some specific conditions, several controversies exist regarding the benefit-to-risk balance associated with these treatments. Further studies are needed to better define the indications, dosage, and route of administration for preoperative iron with or without erythropoietin supplementation. Although restrictive transfusion strategies in patients undergoing cardiac surgery have been shown to effectively reduce the incidence and the amount of RBCs transfusion without increase in side effects, some high-risk patients (e.g., symptomatic acute coronary syndrome) could benefit from higher hemoglobin concentrations. Despite all efforts made last decade, a significant amount of work remains to be done to improve hemoglobin optimization and transfusion strategies in patients undergoing cardiac surgery. PMID- 26225199 TI - Peritoneal dialysis for chronic cardiorenal syndrome: Lessons learned from ultrafiltration trials. AB - The current models of cardiorenal syndrome (CRS) are mainly based on a cardiocentric approach; they assume that worsening renal function is an adverse consequence of the decline in cardiac function rather than a separate and independent pathologic phenomenon. If this assumption were true, then mechanical extraction of fluid (i.e., ultrafiltration therapy) would be expected to portend positive impact on renal hemodynamics and function through improvement in cardio circulatory physiology and reduction in neurohormonal activation. However, currently available ultrafiltration trials, whether in acute heart failure (AHF) or in CRS, have so far failed to show any improvement in renal function; they have reported no impact or even observed adverse renal outcomes in this setting. Moreover, the presence or absence of renal dysfunction seems to affect the overall safety and efficacy of ultrafiltration therapy in AHF. This manuscript briefly reviews cardiorenal physiology in AHF and concludes that therapeutic options for CRS should not only target cardio-circulatory status of the patients, but they need to also have the ability of addressing the adverse homeostatic consequences of the associated decline in renal function. Peritoneal dialysis (PD) can be such an option for the chronic cases of CRS as it has been shown to provide efficient intracorporeal ultrafiltration and sodium extraction in volume overloaded patients while concurrently correcting the metabolic consequences of diminished renal function. Currently available trials on PD in heart failure have shown the safety and efficacy of this therapeutic modality for patients with chronic CRS and suggest that it could represent a pathophysiologically and conceptually relevant option in this setting. PMID- 26225198 TI - Impairment of aspirin antiplatelet effects by non-opioid analgesic medication. AB - Aspirin is the mainstay in prophylaxis of cardiovascular diseases. Impaired aspirin antiplatelet effects are associated with enhanced incidence of cardiovascular events. Comedication with non-opioid analgesic drugs has been described to interfere with aspirin, resulting in impaired aspirin antiplatelet effects. Additionally, non-opioid analgesic medication has been shown to enhance the risk of cardiovascular events and death. Pain is very frequent and many patients rely on analgesic drugs to control pain. Therefore effective analgesic options without increased risk of cardiovascular events are desirable. This review focuses on commonly used non-opioid analgesics, interactions with aspirin medication and impact on cardiovascular risk. PMID- 26225200 TI - Prognostic impact of atrial fibrillation on clinical outcomes of acute coronary syndromes, heart failure and chronic kidney disease. AB - Atrial fibrillation (AF) is the most common type of sustained arrhythmia, which is now on course to reach epidemic proportions in the elderly population. AF is a commonly encountered comorbidity in patients with cardiac and major non-cardiac diseases. Morbidity and mortality associated with AF makes it a major healthcare burden. The objective of our article is to determine the prognostic impact of AF on acute coronary syndromes, heart failure and chronic kidney disease. Multiple studies have been conducted to determine if AF has an independent role in the overall mortality of such patients. Our review suggests that AF has an independent adverse prognostic impact on the clinical outcomes of acute coronary syndromes, heart failure and chronic kidney disease. PMID- 26225201 TI - Cholesterol confusion and statin controversy. AB - The role of blood cholesterol levels in coronary heart disease (CHD) and the true effect of cholesterol-lowering statin drugs are debatable. In particular, whether statins actually decrease cardiac mortality and increase life expectancy is controversial. Concurrently, the Mediterranean diet model has been shown to prolong life and reduce the risk of diabetes, cancer, and CHD. We herein review current data related to both statins and the Mediterranean diet. We conclude that the expectation that CHD could be prevented or eliminated by simply reducing cholesterol appears unfounded. On the contrary, we should acknowledge the inconsistencies of the cholesterol theory and recognize the proven benefits of a healthy lifestyle incorporating a Mediterranean diet to prevent CHD. PMID- 26225202 TI - Cardiac involvement in Duchenne and Becker muscular dystrophy. AB - Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked muscular diseases responsible for over 80% of all muscular dystrophies. Cardiac disease is a common manifestation, not necessarily related to the degree of skeletal myopathy; it may be the predominant manifestation with or without any other evidence of muscular disease. Death is usually due to ventricular dysfunction, heart block or malignant arrhythmias. Not only DMD/BMD patients, but also female carriers may present cardiac involvement. Clinically overt heart failure in dystrophinopathies may be delayed or absent, due to relative physical inactivity. The commonest electrocardiographic findings include conduction defects, arrhythmias (supraventricular or ventricular), hypertrophy and evidence of myocardial necrosis. Echocardiography can assess a marked variability of left ventricular dysfunction, independently of age of onset or mutation groups. Cardiovascular magnetic resonance (CMR) has documented a pattern of epicardial fibrosis in both dystrophinopathies' patients and carriers that can be observed even if overt muscular disease is absent. Recently, new CMR techniques, such as postcontrast myocardial T1 mapping, have been used in Duchenne muscular dystrophy to detect diffuse myocardial fibrosis. A combined approach using clinical assessment and CMR evaluation may motivate early cardioprotective treatment in both patients and asymptomatic carriers and delay the development of serious cardiac complications. PMID- 26225203 TI - Feasibility of real-time magnetic resonance imaging-guided endomyocardial biopsies: An in-vitro study. AB - AIM: To investigate if magnetic resonance (MR)-guided biopsy can improve the performance and safety of such procedures. METHODS: A novel MR-compatible bioptome was evaluated in a series of in-vitro experiments in a 1.5T magnetic resonance imaging (MRI) system. The bioptome was inserted into explanted porcine and bovine hearts under real-time MR-guidance employing a steady state free precession sequence. The artifact produced by the metal element at the tip and the signal voids caused by the bioptome were visually tracked for navigation and allowed its constant and precise localization. RESULTS: Cardiac structural elements and the target regions for the biopsy were clearly visible. Our method allowed a significantly better spatial visualization of the bioptoms tip compared to conventional X-ray guidance. The specific device design of the bioptome avoided inducible currents and therefore subsequent heating. The novel MR compatible bioptome provided a superior cardiovascular magnetic resonance (imaging) soft-tissue visualization for MR-guided myocardial biopsies. Not at least the use of MRI guidance for endomyocardial biopsies completely avoided radiation exposure for both patients and interventionalists. CONCLUSION: MRI guided endomyocardial biopsies provide a better than conventional X-ray guided navigation and could therefore improve the specificity and reproducibility of cardiac biopsies in future studies. PMID- 26225204 TI - Electrocardiographic changes during induced therapeutic hypothermia in comatose survivors after cardiac arrest. AB - AIM: To assess the safety of therapeutic hypothermia (TH) concerning arrhythmias we analyzed serial electrocardiograms (ECG) during TH. METHODS: All patients recovered from a cardiac arrest with Glasgow < 9 at admission were treated with induced mild TH to 32-34 degrees C. TH was obtained with cool fluid infusion or a specific intravascular device. Twelve-lead ECG before, during, and after TH, as well as ECG telemetry data was recorded in all patients. From a total of 54 patients admitted with cardiac arrest during the study period, 47 patients had the 3 ECG and telemetry data available. ECG analysis was blinded and performed with manual caliper by two independent cardiologists from blinded copies of original ECG, recorded at 25 mm/s and 10 mm/mV. Coronary care unit staff analyzed ECG telemetry for rhythm disturbances. Variables measured in ECG were rhythm, RR, PR, QT and corrected QT (QTc by Bazett formula, measured in lead v2) intervals, QRS duration, presence of Osborn's J wave and U wave, as well as ST segment displacement and T wave amplitude in leads II, v2 and v5. RESULTS: Heart rate went down an average of 19 bpm during hypothermia and increased again 16 bpm with rewarming (P < 0.0005, both). There was a non-significant prolongation of the PR interval during TH and a significant decrease with rewarming (P = 0.041). QRS duration significantly prolonged (P = 0.041) with TH and shortened back (P < 0.005) with rewarming. QTc interval presented a mean prolongation of 58 ms (P < 0.005) during TH and a significant shortening with rewarming of 22.2 ms (P = 0.017). Osborn or J wave was found in 21.3% of the patients. New arrhythmias occurred in 38.3% of the patients. Most frequent arrhythmia was non-sustained ventricular tachycardia (19.1%), followed by severe bradycardia or paced rhythm (10.6%), accelerated nodal rhythm (8.5%) and atrial fibrillation (6.4%). No life threatening arrhythmias (sustained ventricular tachycardia, polymorphic ventricular tachycardia or ventricular fibrillation) occurred during TH. CONCLUSION: A 38.3% of patients had cardiac arrhythmias during TH but without life-threatening arrhythmias. A concern may rise when inducing TH to patients with long QT syndrome. PMID- 26225205 TI - Giant and thrombosed left ventricular aneurysm. AB - Left ventricular aneurysms are a frequent complication of acute extensive myocardial infarction and are most commonly located at the ventricular apex. A timely diagnosis is vital due to the serious complications that can occur, including heart failure, thromboembolism, or tachyarrhythmias. We report the case of a 78-year-old male with history of previous anterior myocardial infarction and currently under evaluation by chronic heart failure. Transthoracic echocardiogram revealed a huge thrombosed and calcified anteroapical left ventricular aneurysm. Coronary angiography demonstrated that the left anterior descending artery was chronically occluded, and revealed a big and spherical mass with calcified borders in the left hemithorax. Left ventriculogram confirmed that this spherical mass was a giant calcified left ventricular aneurysm, causing very severe left ventricular systolic dysfunction. The patient underwent cardioverter defibrillator implantation for primary prevention. PMID- 26225206 TI - Constraint and diversification of developmental trajectories in cichlid facial morphologies. AB - BACKGROUND: A major goal of evolutionary biology is to understand the origins of phenotypic diversity. Changes in development, for instance heterochrony, can be a potent source of phenotypic variation. On the other hand, development can also constrain the spectrum of phenotypes that can be produced. In order to understand these dual roles of development in evolution, we examined the developmental trajectory of a trait central to the extensive adaptive radiation of East African cichlid fishes: craniofacial adaptations that allow optimal exploitation of ecological niches. Specifically, we use geometric morphometric analysis to compare morphological ontogenies among six species of Lake Malawi cichlids (n > 500 individuals) that span a major ecomorphological axis. We further evaluate how modulation of Wnt signaling impacts the long-term developmental trajectory of facial development. RESULTS: We find that, despite drastic differences in adult craniofacial morphologies, there are general similarities in the path of craniofacial ontogeny among species, suggesting that natural selection is working within a conserved developmental program. However, we also detect species specific differences in the timing, direction, and/or duration of particular developmental trajectories, including evidence of heterochrony. Previous work in cichlids and other systems suggests that species-specific differences in adult morphology are due to changes in molecular signaling pathways that regulate early craniofacial development. In support of this, we demonstrate that modulation of Wnt signaling at early stages can shift a developmental trajectory into morphospace normally occupied by another species. However, without sustained modulation, craniofacial shape can recover by juvenile stages. This underscores the idea that craniofacial development is robust and that adult head shapes are the product of many molecular changes acting over extended periods of development. CONCLUSIONS: Our results are consistent with the hypothesis that development acts to both constrain and promote morphological diversity. They also illustrate the modular nature of the craniofacial skeleton and hence the ability of selection to act upon distinct anatomical features in an independent manner. We propose that trophic diversity among cichlids has been achieved via shifts in both specific (e.g., stage-specific changes in gene expression) and global (e.g., heterochrony) ontogenetic processes acting within a conserved developmental program. PMID- 26225207 TI - Influence of partial and complete glutamine-and glucose deprivation of breast-and cervical tumorigenic cell lines. AB - BACKGROUND: Due to their high proliferative requirements, tumorigenic cells possess altered metabolic systems whereby cells utilize higher quantities of glutamine and glucose. These altered metabolic requirements make it of interest to investigate the effects of physiological non-tumorigenic concentrations of glucose and glutamine on tumorigenic cells since deprivation of either results in a canonical amino acid response in mammalian cell. METHODS: The influence of short-term exposure of tumorigenic cells to correlating decreasing glutamine- and glucose quantities were demonstrated in a highly glycolytic metastatic breast cell line and a cervical carcinoma cell line. Thereafter, cells were propagated in medium containing typical physiological concentrations of 1 mM glutamine and 6 mM glucose for 7 days. The effects on morphology were investigated by means of polarization-optical transmitted light differential interference contrast. Flow cytometry was used to demonstrate the effects of glutamine-and glucose starvation on cell cycle progression and apoptosis induction. Fluorometrics were also conducted to investigate the effects on intrinsic apoptosis induction (mitocapture), reactive oxygen species production (2,7-dichlorofluorescein diacetate) and acidic vesicle formation (acridine orange). RESULTS: Morphological data suggests that glutamine-and glucose deprivation resulted in reduced cell density and rounded cells. Glutamine-and glucose starvation also resulted in an increase in the G2M phase and a sub-G1 peak. Complete starvation of glutamine and glucose resulted in the reduction of the mitochondrial membrane potential in both cell lines with MDA-MB-231 cells more prominently affected when compared to HeLa cells. Further, starved cells could not be rescued sufficiently by propagating since cells possessed an increase in reactive oxygen species, acidic compartments and vacuole formation. CONCLUSION: Starvation from glutamine and glucose for short periods resulted in decreased cell density, rounded cells and apoptosis induction by means of reactive oxygen species generation and mitochondrial dysfunction. In addition, the metastatic cell line reacted more prominently to glutamine-and glucose starvation due to their highly glycolytic nature. Satisfactory cellular rescue was not possible as cells demonstrated oxidative stress and depolarized mitochondrial membrane potential. This study contributes to the knowledge regarding the in vitro effects and signal transduction of glucose and/or l-glutamine deprivation in tumorigenic cell lines. PMID- 26225208 TI - Blue-green endoscopy in a dog presenting chronic vomiting-regurgitation. AB - A 2-year-old male Maremma sheepdog presenting with chronic vomiting-regurgitation was examined at the University Veterinary Teaching Hospital, Camerino University. An oesophagogastroscopy with a single blue + green (BG) filter restricting wavelengths from 400 to 550 nm was carried out. A conventional white light endoscopy showed a dilated oesophagus with mildly diffuse erythematous mucosa (more accentuated proximal to the cardia); some portions of the gastric mucosa were covered with fluids and appeared only slightly erythematous. A blue green endoscopy highlighted the oesophageal lesions in dark blue, which made them appear more clearly defined from the remaining mucosa. In the gastric antrum, a small, slightly darker blue roundish area was visible. This area did not show up under the white light endoscopy. A histopathological assessment of biopsy specimens from the distal oesophagus, antrum (including the area highlighted only by BG endoscopy) and gastric body showed chronic-active hyperplastic esophagitis and superficial squamous epithelial dysplasia, while gastric samples showed severe diffuse hyperaemic gastritis of the antrum and superficial diffuse atrophy of the gastric body. The authors believe that the use of a BG endoscopy could be useful in veterinary medicine to increase the diagnostic potential of endoscopic assessment in animals. PMID- 26225209 TI - End-user support for primary care electronic medical records: a qualitative case study of users' needs, expectations and realities. AB - Support is considered an important factor for realizing the benefits of health information technology (HIT) but there is a dearth of research on the topic of support, especially in primary care. We conducted a qualitative multiple case study of 4 family health teams (FHTs) and one family health organization (FHO) in Ontario, Canada in an attempt to gain insight into users' expectations and needs, and the realities of end-user support for primary care electronic medical records (EMRs). Data were collected by semi-structured interviews, documents review, and observation of training sessions. The analysis highlights the important role of on-site information technology (IT) staff and super-users in liaising with various stakeholders to solve technical problems and providing hardware and functional ('how to') support; the local development of data support practices to ensure consistent documentation; and the gaps that exist in users' and support personnel's understanding of each other's work processes. PMID- 26225210 TI - Mitochondrial dynamic abnormalities in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease characterized by progressive loss of motor neurons in the brainstem and spinal cord. Currently, there is no cure or effective treatment for ALS and the cause of disease is unknown in the majority of ALS cases. Neuronal mitochondria dysfunction is one of the earliest features of ALS. Mitochondria are highly dynamic organelles that undergo continuous fission, fusion, trafficking and turnover, all of which contribute to the maintenance of mitochondrial function. Abnormal mitochondrial dynamics have been repeatedly reported in ALS and increasing evidence suggests altered mitochondrial dynamics as possible pathomechanisms underlying mitochondrial dysfunction in ALS. Here, we provide an overview of mitochondrial dysfunction and dynamic abnormalities observed in ALS, and discuss the possibility of targeting mitochondrial dynamics as a novel therapeutic approach for ALS. PMID- 26225211 TI - The impact of abdominal adiposity measured by sonography on the pulmonary function of pre-menopausal females. AB - BACKGROUND: The Body Mass Index (BMI) is a widely used parameter to study obesity; however it does not assess the distribution of body adiposity. Ultrasonography is a reliable method of measuring subcutaneous (SAT), visceral (VAT) and Total adipose tissue of the abdomen (TAT) to determine the influence of abdominal fat on pulmonary function by directly measuring abdominal adipose tissue. METHODS: Eighty pre-menopausal, non-smoker, sedentary females with no history of pulmonary disease were subdivided into three groups: 25 normal-weight, 28 overweight, 27 obese. Absolute and predictive spirometric values were obtained: FVC, FEV1, FEV1/FVC, IC, ERV. RESULTS: A positive correlation between increased %IC and decreased %ERV was observed with increased BMI (p < 0.02; 0.001 respectively); %FVC, %FEV1 and %ERV decreased significantly as SAT (p = 0.01, p = 0.02; p < 0.001) and TAT (p = 0.01, p = 0.03, p < 0.001) increased, whereas VAT was negatively correlated only with %ERV (p < 0.001). Increments of 5 mm in TAT, VAT and SAT were followed by a reduction of 0.83 %, 0.81 %, 1.90 % in %FVC, respectively, as well as a reduction of 4.25 %, 4.31 % and 9.44 % in %ERV, respectively. CONCLUSIONS: Subcutaneous abdominal adipose tissue deposition in obese females has a greater negative influence on pulmonary function than visceral adipose tissue deposition. PMID- 26225214 TI - Determination of hydrogen cyanide concentration in mainstream smoke of tobacco products by polarography. AB - BACKGROUND: There has been a worldwide concern for the health risks of cigarette smoking and hydrogen cyanide (HCN) considered as one of the hazardous tobacco compounds which is needed to be determined in order to reduce the dose related to smoke disease risk. In this study, we prepare the experimental procedure to entrap the HCN from mainstream smoke of different brands of Tehran cigarette, through simulating human inhalation and determine its concentration applying polarography. RESULTS: The HCN level of the 50 commonly consumed tobacco products (47 cigarettes and 3 cigars) obtained from local store is ranged between 17.56 +/ 1.02 and 1553.98 +/- 0.56 MUg per stick, this acquired amount is more than FDA approval (10 MUg per stick), so the harmful effects of smoking is indicative. CONCLUSIONS: The comparative study of the results shows that the price and the weight of each product do not indicate HCN level. As can be seen, R(2) value which is a statistical measure of how close the data are to the fitted regression line is low (R(2) < 0.2). So it should not be deceived by names such as ultra light or infinite gravity to suck, because this names or the price haven(')t effect on the amount of HCN and its destructive effects. PMID- 26225215 TI - Participants' Perceptions of Deep Brain Stimulation Research for Treatment Resistant Depression: Risks, Benefits, and Therapeutic Misconception. AB - BACKGROUND: Deep brain stimulation (DBS) for treatment-resistant depression (TRD) is the focus of great interest and numerous studies. Given the state of this research, the risks of DBS, the uncertainty of direct benefits, and the potential for therapeutic misconception (TM), examination of research participants' perspectives is critical to addressing concerns about the adequacy of consent among people with TRD. METHODS: Among 31 participants considering DBS studies at two sites, self-report questionnaires were used to examine three dimensions of TM (eight true/false items). Additional Likert-scale items assessed perceptions of risks, potential benefits, and altruistic motivations. RESULTS: Participants correctly identified the surgery itself as the riskiest study procedure, although only four participants rated the surgery as "high risk." Most participants rated the entire DBS study as "moderate" or lower risk. Participants rated the likelihood of others benefiting in the future more strongly than they did the likelihood of personal benefit. Participants held positive attitudes toward research, and were moderately altruistic. Nearly two-thirds of the 31 participants (64.5%) answered at least one of the true/false TM items incorrectly. CONCLUSIONS: Individuals considering DBS studies for TRD demonstrated reasonable perceptions of risks and benefits, distinguished among procedural risks, and expressed hopes for personal benefit as well as altruism. Findings related to TM were mixed: Participants understood the experimental stage of DBS for depression and endorsed the possibility of no personal benefit, yet there was some evidence for TM. Although these findings are reassuring, investigators must nevertheless remain vigilant about identifying and addressing potential misconceptions. PMID- 26225217 TI - International Collaborative Research Partnerships: Blending Science with Management and Diplomacy. AB - As globalization progressively connects and impacts the health of people across the world, collaborative research partnerships provide mutual advantages by sharing knowledge and resources to address locally and globally relevant scientific and public health questions. Partnerships undertaken for scientific research are similar to business collaborations in that they require attention to partner systems, whether local, international, political, academic, or non academic. Scientists, like diplomats or entrepreneurs, are representatives of their field, culture, and country and become obligatory agents in health diplomacy. This role significantly influences current and future collaborations with not only the immediate partner but with other in country partners as well. Research partnerships need continuous evaluation of the collaboration's productivity, perspectives of all partners, and desired outcomes for success to avoid engaging in "research tourism", particularly in developing regions. International engagement is a cornerstone in addressing the impact of infectious diseases globally. Global partnerships are strategically aligned with national, partner and global health priorities and may be based on specific requests for assistance from the partnering country governments. Here we share experiences from select research collaborations to highlight principles that we have found key in building long-term relationships with collaborators and in meeting the aim to address scientific questions relevant to the host country and strategic global health initiatives. PMID- 26225216 TI - Synthesis of Gemcitabine-(C4-amide)-[anti-HER2/neu] Utilizing a UV-Photoactivated Gemcitabine Intermediate: Cytotoxic Anti-Neoplastic Activity against Chemotherapeutic-Resistant Mammary Adenocarcinoma SKBr-3. AB - Gemcitabine is a pyrimidine nucleoside analog that becomes triphosphorylated intracellularly where it competitively inhibits cytidine incorporation into DNA strands. Another mechanism-of-action of gemcitabine (diphosphorylated form) involves irreversible inhibition of the enzyme ribonucleotide reductase thereby preventing deoxyribonucleotide synthesis. Functioning as a potent chemotherapeutic gemcitabine promote decreases in neoplastic cell proliferation and apoptosis which is frequently found to be effective for the treatment of several leukemias and a wide spectrum of carcinomas. A brief plasma half-life in part due to rapid deamination and chemotherapeutic-resistance restricts the utility of gemcit-abine in clinical oncology. Selective "targeted" delivery of gemcitabine represents a potential molecular strategy for simultaneously prolonging its plasma half-life and minimizing innocient tissues and organ systems exposure to chemotherapy. The molecular design and an organic chemistry based synthesis reaction is described that initially generates a UV photoactivated gemcitabine intermediate. In a subsequent phase of the synthesis method the UV-photoactivated gemcitabine intermediate is covalently bonded to a monoclonal immunoglobulin yielding an end-product in the form of gemcitabine-(C4 amide)-[anti-HER2/neu]. Analysis by SDS-PAGE/chemiluminescent auto-radiography did not detect evidence of gemcitabine-(C4-amide)-[anti-HER2/neu] polymerization or degradative fragmentation while cell-ELISA demonstrated retained binding avidity for HER2/neu trophic membrane receptor complexes highly over-expressed by chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Compared to chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3), the covalent immunochemotherapeutic, gemcitabine-(C4-amide)-[anti-HER2/neu] is anticipated to exert greater levels of cytotoxic anti-neoplastic potency against other neoplastic cell types like pancreatic carcinoma, small-cell lung carcinoma, neuroblastoma, glioblastoma, oral squamous cell carcinoma, cervical epitheliod carcinoma, or leukemia/lymphoid neoplastic cell types based on their reported sensitivity to gemcitabine and gemcitabine covalent conjugates. PMID- 26225218 TI - Willingness to Participate in Cardiovascular Clinical Research among African Americans. PMID- 26225220 TI - Pharmacometrics: Focus on the Patient. AB - Pharmacometrics, whether using simple or complex models, has contributed to rational and efficient drug development,(1-3) with the main focus on early drug development.(4) This article describes why opportunities more directly focused on the patient abound in late stage development, illustrating the concept with three innovative examples which focus on benefits to patients, enabling drugs that are truly efficacious to reach the market faster in diseases with high unmet medical needs, while maintaining adequate safety. PMID- 26225221 TI - Using a Systems Pharmacology Approach to Study the Effect of Statins on the Early Stage of Atherosclerosis in Humans. AB - More than 100,000 people have participated in controlled trials of statins (lowering cholesterol drugs) since the introduction of lovastatin in the 1980s. Meta-analyses of this data have shown that statins have a beneficial effect on treated groups compared to control groups, reducing cardiovascular risk. Inhibiting the HMG-CoA reductase in the liver, statins can reduce cholesterol levels, thus reducing LDL levels in circulation. Published data from intravascular ultrasound studies (IVUS) was used in this work to develop and validate a unique integrative system model; this consisted of analyzing control groups from two randomized controlled statins trials (24/97 subjects respectively), one treated group (40 subjects, simvastatin trial), and 27 male subjects (simvastatin, pharmacokinetic study). The model allows to simulate the pharmacokinetics of statins and its effect on the dynamics of lipoproteins (e.g., LDL) and the inflammatory pathway while simultaneously exploring the effect of flow-related variables (e.g., wall shear stress) on atherosclerosis progression. PMID- 26225219 TI - Anti-Neoplastic Cytotoxicity of Gemcitabine-(C4-amide)-[anti-HER2/neu] in Combination with Griseofulvin against Chemotherapeutic-Resistant Mammary Adenocarcinoma (SKBr-3). AB - INTRODUCTION: Gemcitabine is a pyrimidine nucleoside analog that becomes triphosphorylated and in this form it competitively inhibits cytidine incorporation into DNA strands. Diphosphorylated gemcitabine irreversibly inhibits ribonucleotide reductase thereby preventing deoxyribonucleotide synthesis. Functioning as a potent chemotherapeutic, gemcitabine decreases neoplastic cell proliferation and induces apoptosis which accounts for its effectiveness in the clinical treatment of several leukemia and carcinoma cell types. A brief plasma half-life due to rapid deamination, chemotherapeuticresistance and sequelae restricts gemcitabine utility in clinical oncology. Selective "targeted" gemcitabine delivery represents a molecular strategy for prolonging its plasma half-life and minimizing innocent tissue/organ exposure. METHODS: A previously described organic chemistry scheme was applied to synthesize a UV-photoactivated gemcitabine intermediate for production of gemcitabine-(C4-amide)-[anti-HER2/neu]. Immunodetection analysis (Western-blot) was applied to detect the presence of any degradative fragmentation or polymerization. Detection of retained binding-avidity for gemcitabine-(C4-amide) [anti-HER2/neu] was determined by cell-ELISA using populations of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) that highly over express the HER2/neu trophic membrane receptor. Anti-neoplastic cytotoxicity of gemcitabine-(C4-amide)-[anti-HER2/neu] and the tubulin/microtubule inhibitor, griseofulvin was established against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Related investigations evaluated the potential for gemcitabine-(C4-amide)-[anti-HER2/neu] in dual combination with griseofulvin to evoke increased levels of anti-neoplastic cytotoxicity compared to gemcitabine (C4-amide)-[anti-HER2/neu]. RESULTS: Covalent gemcitabine-(C4-amide)-[anti HER2/neu] immunochemotherapeutic and griseofulvin exerted anti-neoplastic cytotoxicity against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Covalent gemcitabine-(C4-amide)-[anti-HER2/neu] immunochemotherapeutic or gemcitabine in dual combination with griseofulvin created increased levels of anti-neoplastic cytotoxicity that were greater than was attainable with gemcitabine-(C4-amide)-[anti-HER2/neu] or gemcitabine alone. CONCLUSION: Gemcitabine-(C4-amide)-[anti-HER2/neu] in dual combination with griseofulvin can produce enhanced levels of anti-neoplastic cytotoxicity and potentially provide a basis for treatment regimens with a wider margin-of-safety. Such benefits would be possible through the collective properties of; [i] selective "targeted" gemcitabine delivery; [ii] relatively lower toxicity of griseofulvin compared to many if not most conventional chemotherapeutics; [iii] reduced total dosage requirements faciliated by additive or synergistic anti-cancer properties; and [iv] differences in sequelae for gemcitabine-(C4-amide)-[anti-HER2/neu] compared to griseofulvin functioning as a tubulin/microtubule inhibitor. PMID- 26225223 TI - The Effects of a GLP-1 Analog on Glucose Homeostasis in Type 2 Diabetes Mellitus Quantified by an Integrated Glucose Insulin Model. AB - In recent years, several glucagon-like peptide-1 (GLP-1)-based therapies for the treatment of type 2 diabetes mellitus (T2DM) have been developed. The aim of this work was to extend the semimechanistic integrated glucose-insulin model to include the effects of a GLP-1 analog on glucose homeostasis in T2DM patients. Data from two trials comparing the effect of steady-state liraglutide vs. placebo on the responses of postprandial glucose and insulin in T2DM patients were used for model development. The effect of liraglutide was incorporated in the model by including a stimulatory effect on insulin secretion. Furthermore, for one of the trials an inhibitory effect on glucose absorption was included to account for a delay in gastric emptying. As other GLP-1 receptor agonists have similar modes of action, it is believed that the model can also be used to describe the effect of other receptor agonists on glucose homeostasis. PMID- 26225222 TI - A Model-Based Illustrative Exploratory Approach to Optimize the Dosing of Peg IFN/RBV in Cirrhotic Hepatitis C Patients Treated With Triple Therapy. AB - Hezode et al. recently reported the frequent occurrence of anemia and thrombocytopenia in the ANRS-CO20-CUPIC cohort of hepatitis C virus (HCV) cirrhotic experienced patients treated with pegylated-interferon (Peg-IFN), ribavirin (RBV), and telaprevir or boceprevir.1,2 Using frequent measurements of serum drug concentrations, hemoglobin, and platelet concentrations obtained in 15 patients of this cohort, we show how an on-treatment model-based approach could be used to individualize dose regimen and avoid the occurrence of RBV-induced anemia and Peg-IFN-induced thrombocytopenia. PMID- 26225224 TI - Evaluating the Use of Linear Mixed-Effect Models for Inference of the Concentration-QTc Slope Estimate as a Surrogate for a Biological QTc Model. AB - In concentration-QTc modeling, oscillatory functions have been used to characterize biological rhythms in QTc profiles. Fitting such functions is not always feasible because it requires sufficient electrocardiograph sampling. In this study, drug concentration and QTc data were simulated using a published biological QTc model (oscillatory functions). Then, linear mixed-effect models and the biological model were fitted and evaluated in terms of biases, precisions, and qualities of inferences. The simpler linear mixed-effect model with day and time as a factor variables provided similar accuracy of the concentration-QTc slope estimates to the complex biological model and was able to accurately predict the drug-induced QTc prolongation with less than 1 ms bias, despite its empirical nature to account for biological rhythm. The current study may guide a concentration-QTc modeling strategy that can be easily prespecified, does not suffer from poor convergence, and achieves little bias in drug-induced QTc estimates. PMID- 26225227 TI - DIGRE: Drug-Induced Genomic Residual Effect Model for Successful Prediction of Multidrug Effects. AB - Multidrug regimens are a promising strategy for improving therapeutic efficacy and reducing side effects, especially for complex disorders such as cancer. However, the use of multidrug therapies is very challenging, due to a lack of understanding of the mechanisms of drug interactions. We herein present a novel computational approach-Drug-Induced Genomic Residual Effect (DIGRE) Computational Model-to predict drug combination effects by explicitly modeling drug response curves and gene expression changes after drug treatments. The prediction performance of DIGRE was evaluated using two datasets: (i) OCI-LY3 B-lymphoma cells treated with 14 different drugs and (ii) MCF breast cancer cells treated with combinations of gefitinib and docetaxel at different doses. In both datasets, the predicted drug combination effects significantly correlated with the experimental results. The results indicated the model was useful in predicting drug combination effects, which may greatly facilitate the discovery of new, effective multidrug therapies. PMID- 26225225 TI - Developing Exposure/Response Models for Anticancer Drug Treatment: Special Considerations. AB - Anticancer agents often have a narrow therapeutic index (TI), requiring precise dosing to ensure sufficient exposure for clinical activity while minimizing toxicity. These agents frequently have complex pharmacology, and combination therapy may cause schedule-specific effects and interactions. We review anticancer drug development, showing how integration of modeling and simulation throughout development can inform anticancer dose selection, potentially improving the late-phase success rate. This article has a companion article in Clinical Pharmacology & Therapeutics with practical examples. PMID- 26225228 TI - A Systems Pharmacology Model of Erythropoiesis in Mice Induced by Small Molecule Inhibitor of Prolyl Hydroxylase Enzymes. AB - Mammalian erythropoiesis is a conserved process tightly controlled by the hypoxia inducible factor (HIF1) pathway. In this study, a small molecule inhibitor (PHI 1) of prolyl-hydroxylase-2 (PHD2) enzyme involved in regulating HIF1alpha levels was orally administered to male BALB/c mice at 10 and 30 mg/kg. A systems pharmacology model was developed based on the measured PHI-1 plasma exposures, kidney HIF1alpha, kidney erythropoietin (EPO) mRNA, plasma EPO, reticulocyte counts, red blood cells, and hemoglobin levels. The model fit resulted in the estimation of drug potency (IC50: 1.7MUM), and systems parameters such as EPO mRNA turnover (kdeg_EPOmRNA: 0.43 hr(-1)) and mean lifespan of reticulocytes (Tr : 81 hours). The model correctly described the observed 30-40-fold increase in kidney HIF1alpha protein, ~1,000 fold increase in EPO mRNA and 2-3-fold increase in the reticulocytes at 30 mg/kg. This study presents the first parsimonious systems model of erythropoiesis to quantitatively describe the in vivo effects of PHD2 inhibition. PMID- 26225229 TI - Target Mediated Drug Disposition Model of CPHPC in Patients with Systemic Amyloidosis. AB - The amyloid deposits that cause disease in systemic amyloidosis always contain the normal plasma protein, serum amyloid P (SAP) component. SAP is the target of a novel immunotherapy approach now being developed to eliminate amyloid deposits. The treatment is enabled by, and critically depends on, the use of the drug (R)-1 [6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC, GSK2315698, Ro 63-8695), which depletes circulating SAP almost completely but leaves some SAP in amyloid deposits for specific recognition by subsequently administered therapeutic anti-SAP antibodies. Herein, we report a mechanistic model that predicts, with clinically acceptable precision, the exposure-response relationship for CPHPC, both in healthy individuals and in patients with systemic amyloidosis. The model covariates are gender, renal function, total amyloid load, and presence of hepatic amyloid, all of which are known at baseline. The model is being used to predict individualized dosing regimens in an ongoing, first-in human study with anti-SAP antibodies. PMID- 26225230 TI - Development of a Pediatric Physiologically Based Pharmacokinetic Model for Sirolimus: Applying Principles of Growth and Maturation in Neonates and Infants. AB - This study describes the maturation of sirolimus clearance in a cohort of very young pediatric patients with vascular anomalies. The relationship between allometrically scaled in vivo clearance and age was described by the Emax model in patients aged 1 month to 2 years. Consistent with the observed increase, in vitro intrinsic clearance of sirolimus using pediatric liver microsomes showed a similar age-dependent increase. In children older than 2 years, allometrically scaled sirolimus clearance did not show further maturation. Simulated clearance estimates with a sirolimus physiologically based pharmacokinetic model that included CYP3A4/5/7 and CYP2C8 maturation profiles were in close agreement with observed in vivo clearance values. In addition, physiologically based pharmacokinetic model-simulated sirolimus pharmacokinetic profiles predicted the actual observations well. These results demonstrate the utility of a physiologically based pharmacokinetic modeling approach for the prediction of the developmental trajectory of sirolimus metabolic activity and its effects on total body clearance in neonates and infants. PMID- 26225231 TI - Improving Drug Sensitivity Prediction Using Different Types of Data. AB - The algorithms and models used to address the two subchallenges that are part of the NCI-DREAM (Dialogue for Reverse Engineering Assessments and Methods) Drug Sensitivity Prediction Challenge (2012) are presented. In subchallenge 1, a bidirectional search algorithm is introduced and optimized using an ensemble scheme and a nonlinear support vector machine (SVM) is then applied to predict the effects of the drug compounds on breast cancer cell lines. In subchallenge 2, a weighted Euclidean distance method is introduced to predict and rank the drug combinations from the most to the least effective in reducing the viability of a diffuse large B-cell lymphoma (DLBCL) cell line. PMID- 26225232 TI - BioModels: Content, Features, Functionality, and Use. AB - BioModels is a reference repository hosting mathematical models that describe the dynamic interactions of biological components at various scales. The resource provides access to over 1,200 models described in literature and over 140,000 models automatically generated from pathway resources. Most model components are cross-linked with external resources to facilitate interoperability. A large proportion of models are manually curated to ensure reproducibility of simulation results. This tutorial presents BioModels' content, features, functionality, and usage. PMID- 26225234 TI - A New Drug Combinatory Effect Prediction Algorithm on the Cancer Cell Based on Gene Expression and Dose-Response Curve. AB - Gene expression data before and after treatment with an individual drug and the IC20 of dose-response data were utilized to predict two drugs' interaction effects on a diffuse large B-cell lymphoma (DLBCL) cancer cell. A novel drug interaction scoring algorithm was developed to account for either synergistic or antagonistic effects between drug combinations. Different core gene selection schemes were investigated, which included the whole gene set, the drug-sensitive gene set, the drug-sensitive minus drug-resistant gene set, and the known drug target gene set. The prediction scores were compared with the observed drug interaction data at 6, 12, and 24 hours with a probability concordance (PC) index. The test result shows the concordance between observed and predicted drug interaction ranking reaches a PC index of 0.605. The scoring reliability and efficiency was further confirmed in five drug interaction studies published in the GEO database. PMID- 26225235 TI - Quantification of the Forgiveness of Drugs to Imperfect Adherence. AB - The circumstance of how sensitive therapeutic success is under imperfect adherence is driven by the property known as forgiveness. To date, no studies have considered variability in the pharmacokinetic-pharmacodynamic process in conjunction with imperfect adherence patterns in order to develop a comparative criterion to determine the forgiveness of a drug. In this study, we have proposed a criterion to quantify forgiveness; illustrated the criterion for a theoretical example and evaluated the forgiveness of a motivating example, namely warfarin. A forgiveness criterion, relative forgiveness, is defined as the number of times more likely that a target is successfully attained under perfect adherence compared to imperfect adherence; or when comparing two drugs under a standard setting of imperfect adherence. The relative forgiveness criterion may have important implications for both drug development and clinical practice since the choice of drug can account for the likely influence of its forgiveness. PMID- 26225236 TI - Physiologically Based Pharmacokinetic Modeling of Fluorescently Labeled Block Copolymer Nanoparticles for Controlled Drug Delivery in Leukemia Therapy. AB - A physiologically based pharmacokinetic (PBPK) model was developed that describes the concentration and biodistribution of fluorescently labeled nanoparticles in mice used for the controlled delivery of dexamethasone in acute lymphoblastic leukemia (ALL) therapy. The simulated data showed initial spikes in nanoparticle concentration in the liver, spleen, and kidneys, whereas concentration in plasma decreased rapidly. These simulation results were consistent with previously published in vivo data. At shorter time scales, the simulated data predicted decrease of nanoparticles from plasma with concomitant increase in the liver, spleen, and kidneys before decaying at longer timepoints. Interestingly, the simulated data predicted an unaccounted accumulation of about 50% of the injected dose of nanoparticles. Incorporation of an additional compartment into the model justified the presence of unaccounted nanoparticles in this compartment. Our results suggest that the proposed PBPK model can be an excellent tool for prediction of optimal dose of nanoparticle-encapsulated drugs for cancer treatment. PMID- 26225239 TI - FDA Advisory Meeting Clinical Pharmacology Review Utilizes a Quantitative Systems Pharmacology (QSP) Model: A Watershed Moment? AB - In the evolving discipline of quantitative systems pharmacology (QSP), QSP model (QSPM) applications are expanding. Recently, a QSPM was used by US Food and Drug Administration (FDA) clinical pharmacologists to evaluate the appropriateness of a proposed dosing regimen for a new biologic. This application expands the use horizon for QSPMs into the regulatory domain. Here we retrace the evolution of the model and suggest a question-based approach to directing model scope, identifying applications, and understanding overall QSPM value. PMID- 26225238 TI - Model-Based Design of a Decision Tree for Treating HER2+ Cancers Based on Genetic and Protein Biomarkers. AB - Human cancers are incredibly diverse with regard to molecular aberrations, dependence on oncogenic signaling pathways, and responses to pharmacological intervention. We wished to assess how cellular dependence on the canonical PI3K vs. MAPK pathways within HER2+ cancers affects responses to combinations of targeted therapies, and biomarkers predictive of their activity. Through an integrative analysis of mechanistic model simulations and in vitro cell line profiling, we designed a six-arm decision tree to stratify treatment of HER2+ cancers using combinations of targeted agents. Activating mutations in the PI3K and MAPK pathways (PIK3CA and KRAS), and expression of the HER3 ligand heregulin determined sensitivity to combinations of inhibitors against HER2 (lapatinib), HER3 (MM-111), AKT (MK-2206), and MEK (GSK-1120212; trametinib), in addition to the standard of care trastuzumab (Herceptin). The strategy used to identify effective combinations and predictive biomarkers in HER2-expressing tumors may be more broadly extendable to other human cancers. PMID- 26225237 TI - Modeling and Simulation Approaches for Cardiovascular Function and Their Role in Safety Assessment. AB - Systems pharmacology modeling and pharmacokinetic-pharmacodynamic (PK/PD) analysis of drug-induced effects on cardiovascular (CV) function plays a crucial role in understanding the safety risk of new drugs. The aim of this review is to outline the current modeling and simulation (M&S) approaches to describe and translate drug-induced CV effects, with an emphasis on how this impacts drug safety assessment. Current limitations are highlighted and recommendations are made for future effort in this vital area of drug research. PMID- 26225240 TI - Interactive Pharmacometric Applications Using R and the Shiny Package. AB - Interactive applications, developed using Shiny for the R programming language, have the potential to revolutionize the sharing and communication of pharmacometric model simulations. Shiny allows customization of the application's user-interface to provide an elegant environment for displaying user-input controls and simulation output-where the latter simultaneously updates with changing input. The flexible nature of the R language makes simulations of population variability possible thus promoting the combination of Shiny with R in model visualization. PMID- 26225241 TI - Systems Pharmacology Approach Toward the Design of Inhaled Formulations of Rifampicin and Isoniazid for Treatment of Tuberculosis. AB - Conventional oral therapies for the treatment of tuberculosis are limited by poor antibiotic distribution in granulomas, which contributes to lengthy treatment regimens and inadequate bacterial sterilization. Inhaled formulations are a promising strategy to increase antibiotic efficacy and reduce dose frequency. We develop a multiscale computational approach that accounts for simultaneous dynamics of a lung granuloma, carrier release kinetics, pharmacokinetics, and pharmacodynamics. Using this computational platform, we predict that a rationally designed inhaled formulation of isoniazid given at a significantly reduced dose frequency has better sterilizing capabilities and reduced toxicity than the current oral regimen. Furthermore, we predict that inhaled formulations of rifampicin require unrealistic carrier antibiotic loadings that lead to early toxicity concerns. Lastly, we predict that targeting carriers to macrophages has limited effects on treatment efficacy. Our platform can be extended to account for additional antibiotics and provides a new tool for rapidly prototyping the efficacy of inhaled formulations. PMID- 26225242 TI - PhIN: A Protein Pharmacology Interaction Network Database. AB - Network pharmacology is a new and hot concept in drug discovery for its ability to investigate the complexity of polypharmacology, and becomes more and more important in drug development. Here we report a protein pharmacology interaction network database (PhIN), aiming to assist multitarget drug discovery by providing comprehensive and flexible network pharmacology analysis. Overall, PhIN contains 1,126,060 target-target interaction pairs in terms of shared compounds and 3,428,020 pairs in terms of shared scaffolds, which involve 12,419,700 activity data, 9,414 targets, 314 viral targets, 652 pathways, 1,359,400 compounds, and 309,556 scaffolds. Using PhIN, users can obtain interacting target networks within or across human pathways, between human and virus, by defining the number of shared compounds or scaffolds under an activity cutoff. We expect PhIN to be a useful tool for multitarget drug development. PhIN is freely available at http://cadd.pharmacy.nankai.edu.cn/phin/. PMID- 26225243 TI - Bridging Systems Medicine and Patient Needs. AB - While there is widespread consensus on the need both to change the prevailing research and development (R&D) paradigm and provide the community with an efficient way to personalize medicine, ecosystem stakeholders grapple with divergent conceptions about which quantitative approach should be preferred. The primary purpose of this position paper is to contrast these approaches. The second objective is to introduce a framework to bridge simulation outputs and patient outcomes, thus empowering the implementation of systems medicine. PMID- 26225245 TI - Physiologically Based Models in Regulatory Submissions: Output From the ABPI/MHRA Forum on Physiologically Based Modeling and Simulation. AB - Under the remit of the Ministerial Industry Strategy Group (MISG), the Association of the British Pharmaceutical Industry (ABPI) and Medicines and Healthcare products Regulatory Agency (MHRA) hosted a meeting to explore physiologically based pharmacokinetic modeling and simulation, focusing on the clinical component of regulatory applications. The meeting took place on 30 June 2014 with international representatives from industry, academia, and regulatory agencies. Discussion topics were selected to be complementary to those discussed at an earlier US Food and Drug Administration (FDA) meeting. This report summarizes the meeting outcomes, focusing on the European regulatory perspective. PMID- 26225246 TI - Application of Physiologically Based Pharmacokinetic (PBPK) Modeling to Support Dose Selection: Report of an FDA Public Workshop on PBPK. AB - The US Food and Drug Administration (FDA) public workshop, entitled "Application of Physiologically-based Pharmacokinetic (PBPK) Modeling to Support Dose Selection focused on the role of PBPK in drug development and regulation. Representatives from industry, academia, and regulatory agencies discussed the issues within plenary and panel discussions. This report summarizes the discussions and provides current perspectives on the application of PBPK in different areas, including its utility, predictive performance, and reporting for regulatory submissions. PMID- 26225247 TI - HCV Kinetic Models and Their Implications in Drug Development. AB - Chronic infection with hepatitis C virus (HCV) affects about 170 million people worldwide and is a major cause of liver complications. Mathematical modeling of viral kinetics under treatment has provided insight into the viral life cycle, treatment effectiveness, and drugs' mechanisms of action. Here we review the implications of viral kinetic models at the different stages of development of anti-HCV agents. PMID- 26225248 TI - Quantifying and Communicating Uncertainty in Preclinical Human Dose-Prediction. AB - Human dose-prediction is fundamental for ranking lead-optimization compounds in drug discovery and to inform design of early clinical trials. This tutorial describes how uncertainty in such predictions can be quantified and efficiently communicated to facilitate decision-making. Using three drug-discovery case studies, we show how several uncertain pieces of input information can be integrated into one single uncomplicated plot with key predictions, including their uncertainties, for many compounds or for many scenarios, or both. PMID- 26225249 TI - Use of Longitudinal Dose-Response Modeling to Support the Efficacy and Tolerability of Alitretinoin in Severe Refractory Chronic Hand Eczema (CHE). AB - Longitudinal dose-response analyses of alitretinoin (an investigational agent in the US) were conducted to supplement results from phase III studies in severe, refractory chronic hand eczema, with objectives to address several outstanding development issues (e.g., optimal dose, possible factors affecting efficacy and/or tolerability). Models were fitted to the physicians' global assessment score and triglycerides over time. Five hundred trials were simulated to evaluate the relevance of findings. Analyses clarified that the optimal dose of alitretinoin was 30 mg once daily, where response rates were ~10% over placebo at 12 weeks and increased by 5-7% over placebo for every 4 weeks thereafter, for up to 24 weeks. Elderly subjects had higher magnitudes of efficacy and an increased probability of high triglycerides. Results from analyses sufficiently addressed the development issues, thereby adding to the weight of evidence supporting the efficacy and safety of alitretinoin in the treatment of severe, refractory chronic hand eczema. PMID- 26225251 TI - Erratum. PMID- 26225250 TI - Dynamic Modeling of the Interaction Between Autophagy and Apoptosis in Mammalian Cells. AB - Autophagy is a conserved biological stress response in mammalian cells that is responsible for clearing damaged proteins and organelles from the cytoplasm and recycling their contents via the lysosomal pathway. In cases of mild stress, autophagy acts as a survival mechanism, while in cases of severe stress cells may switch to programmed cell death. Understanding the decision process that moves a cell from autophagy to apoptosis is important since abnormal regulation of autophagy occurs in many diseases, including cancer. To integrate existing knowledge about this decision process into a rigorous, analytical framework, we built a mathematical model of cell fate decisions mediated by autophagy. Our dynamical model is consistent with existing quantitative measurements of autophagy and apoptosis in rat kidney proximal tubular cells responding to cisplatin-induced stress. PMID- 26225253 TI - A Joint Model for the Kinetics of CTC Count and PSA Concentration During Treatment in Metastatic Castration-Resistant Prostate Cancer. AB - Assessment of treatment efficacy in metastatic castration-resistant prostate cancer (mCRPC) is limited by frequent nonmeasurable bone metastases. The count of circulating tumor cells (CTCs) is a promising surrogate marker that may replace the widely used prostate-specific antigen (PSA). The purpose of this study was to quantify the dynamic relationships between the longitudinal kinetics of these markers during treatment in patients with mCRPC. Data from 223 patients with mCRPC treated by chemotherapy and/or hormonotherapy were analyzed for up to 6 months of treatment. A semimechanistic model was built, combining the following several pharmacometric advanced features: (1) Kinetic-Pharmacodynamic (K-PD) compartments for treatments (chemotherapy and hormonotherapy); (2) a latent variable linking both marker kinetics; (3) modeling of CTC kinetics with a cell lifespan model; and (4) a negative binomial distribution for the CTC random sampling. Linked with survival, this model would potentially be useful for predicting treatment efficacy during drug development or for therapeutic adjustment in treated patients. PMID- 26225254 TI - Integration of Physiologically-Based Pharmacokinetic Modeling into Early Clinical Development: An Investigation of the Pharmacokinetic Nonlinearity. AB - BMS-911543, a promising anticancer agent, exhibited time-dependent and dose dependent nonlinear pharmacokinetics (PKs) in its first-in-human (FIH) study. Initial physiologically based pharmacokinetic (PBPK) modeling efforts using CYP1A2-mediated clearance kinetics were unsuccessful; however, further model analysis revealed that CYP1A2 time-dependent inhibition (TDI) and perhaps other factors could be keys to the nonlinearity. Subsequent experiments in human liver microsomes showed that the compound was a time-dependent inhibitor of CYP1A2 and were used to determine the enzyme inactivation parameter values. In addition, a rat tissue distribution study was conducted and human plasma samples were profiled to support the refinement of the PBPK model. It was concluded that the interplay between four BMS-911543 properties, namely, low solubility, saturation of the metabolizing enzyme CYP1A2, CYP1A2 TDI, and CYP1A2 induction likely resulted in the time-dependent and dose-dependent nonlinear PKs. The methodology of PBPK model-guided unmasking of compound properties can serve as a general practice for mechanistic understanding of a new compound's disposition. PMID- 26225255 TI - A Population Approach to Characterize Interferon Beta-1b Effect on Contrast Enhancing Lesions in Patients With Relapsing Remitting Multiple Sclerosis. AB - In patients with relapsing-remitting multiple sclerosis (RRMS), interferon beta 1b (IFNbeta-1b) reduces the occurrence of contrast enhancing lesions (CELs) on magnetic resonance imaging (MRI). Questions remain on the stability of IFNbeta-1b effect over time and its action beyond the reduction of CELs. In this study, we described the IFNbeta-1b effect by a mixed effects model, quantifying the interpatient variability associated with its parameters. Using a negative binomial distribution model as a natural history model, the effect of IFNbeta-1b was evaluated using different mathematical functions of time. IFNbeta-1b produced a decrease in the expected CEL numbers, inhibiting the formation of new CELs but did not promote the resolution of the already-formed ones. Based on the final selected model, simulations were carried out to optimize the combined IFNbeta-1b corticosteroid therapy as a proof-of-concept. In summary, we provide evidence on the dynamics of CELs under IFNbeta-1b treatment that can be used to monitor the effects of therapies in MS. PMID- 26225256 TI - In Vivo Tissue Pharmacokinetics of Carbon-11-Labeled Clozapine in Healthy Volunteers: A Positron Emission Tomography Study. AB - We investigated clozapine (CLZ) tissue pharmacokinetics in vivo by using carbon 11-labeled CLZ ((11)C-CLZ) and positron emission tomography (PET). Eight healthy volunteers underwent (11)C-CLZ studies wherein computed tomography image acquisition was followed by PET scans (whole-body, four; brain, four). After bolus intravenous (11)C-CLZ injection, PET images were acquired at various timepoints for 2-3 hours. Tissue (11)C-CLZ signals were plotted over time, and pharmacokinetic parameters were determined. High (11)C-CLZ radioactivity was detected in the liver and brain, implying CLZ hepatic metabolism and efficient blood-brain barrier penetration. The urinary and hepatobiliary tracts were involved in (11)C-CLZ excretion. Moderate to high radioactivity was observed in the dopaminergic and serotonergic receptor-rich brain regions, indicating CLZ binding to multiple receptor types. To our knowledge, this is the first study to report the determination of (11)C-CLZ tissue pharmacokinetics in humans. PET using radiolabeled drugs can provide valuable information that could complement plasma pharmacokinetic data. PMID- 26225258 TI - Physiologically Based Pharmacokinetics Is Impacting Drug Development and Regulatory Decision Making. AB - It is no coincidence that the reports of two meetings, one organized by the US Food and Drug Administration (FDA), in March 2014, and the other by the UK Medicines and Healthcare Products Regulatory (MHRA), in collaboration with ABPI (the Association of British Pharmaceutical Industry), in June 2014, have been published in tandem in CPT-PSP.12 Both reports deal with the same topic, namely, the impact of physiologically based pharmacokinetics (PBPK) in clinical drug development and the best practices for such applications. This reflects the transition of PBPK from academic curiosity to industrial norm, manifested by the regulatory agencies encouraging its use and receiving an increasing number of submissions containing PBPK models. The goal of both meetings was to help determine the need and facilitate the development of regulatory guidances on this subject within the conceptual framework of model informed drug development and regulatory decision-making. A further reflection of this intent is the publication by the European Medicines Agency of a Concept Paper on PBPK.3 One is reminded of a similar train of events surrounding the introduction of population PK/PD and nonlinear mixed effects modeling in the early-late 1990s, again with encouragement and receptivity of regulatory agencies leading to FDA guidance on the topic.4 Indeed, the intention of PBPK modeling and simulation is to complement other approaches, such as compartmental modeling, or, in some cases, replace them with a more mechanistic approach. PBPK models represent an important class of models that characterize absorption, distribution, metabolism, excretion (ADME) processes and their underlying biological and physiological drivers. An increased understanding of these drivers and their unique interactions with drug substance and formulation factors provides critical insights into how drugs will behave in healthy volunteers and patients with disease. PMID- 26225260 TI - Resistance Development: A Major Piece in the Jigsaw Puzzle of Tumor Size Modeling. AB - Mathematical models of tumor size (TS) dynamics and tumor growth inhibition (TGI) need to place more emphasis on resistance development, given its relevant implications for clinical outcomes. A deeper understanding of the underlying processes, and effective data integration at different complexity levels, can foster the incorporation of new mechanistic aspects into modeling approaches, improving anticancer drug effect prediction. As such, we propose a general framework for developing future semi-mechanistic TS/TGI models of drug resistance. PMID- 26225259 TI - Pharmacometrics Markup Language (PharmML): Opening New Perspectives for Model Exchange in Drug Development. AB - The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps. PMID- 26225261 TI - A Tutorial on Target-Mediated Drug Disposition (TMDD) Models. AB - Target-mediated drug disposition (TMDD) is the phenomenon in which a drug binds with high affinity to its pharmacological target site (such as a receptor) to such an extent that this affects its pharmacokinetic characteristics.1 The aim of this Tutorial is to provide an introductory guide to the mathematical aspects of TMDD models for pharmaceutical researchers. Examples of Berkeley Madonna2 code for some models discussed in this Tutorial are provided in the Supplementary Materials. PMID- 26225262 TI - A Mechanistic Pharmacokinetic Model for Liver Transporter Substrates Under Liver Cirrhosis Conditions. AB - Liver cirrhosis is a disease characterized by the loss of functional liver mass. Physiologically based pharmacokinetic (PBPK) modeling was applied to interpret and predict how the interplay among physiological changes in cirrhosis affects pharmacokinetics. However, previous PBPK models under cirrhotic conditions were developed for permeable cytochrome P450 substrates and do not directly apply to substrates of liver transporters. This study characterizes a PBPK model for liver transporter substrates in relation to the severity of liver cirrhosis. A published PBPK model structure for liver transporter substrates under healthy conditions and the physiological changes for cirrhosis are combined to simulate pharmacokinetics of liver transporter substrates in patients with mild and moderate cirrhosis. The simulated pharmacokinetics under liver cirrhosis reasonably approximate observations. This analysis includes meta-analysis to obtain system-dependent parameters in cirrhosis patients and a top-down approach to improve understanding of the effect of cirrhosis on transporter-mediated drug disposition under cirrhotic conditions. PMID- 26225263 TI - Network-Based Analysis of Nutraceuticals in Human Hepatocellular Carcinomas Reveals Mechanisms of Chemopreventive Action. AB - Chronic inflammation is associated with the development of human hepatocellular carcinoma (HCC), an essentially incurable cancer. Anti-inflammatory nutraceuticals have emerged as promising candidates against HCC, yet the mechanisms through which they influence the cell signaling machinery to impose phenotypic changes remain unresolved. Herein we implemented a systems biology approach in HCC cells, based on the integration of cytokine release and phospoproteomic data from high-throughput xMAP Luminex assays to elucidate the action mode of prominent nutraceuticals in terms of topology alterations of HCC specific signaling networks. An optimization algorithm based on SigNetTrainer, an Integer Linear Programming formulation, was applied to construct networks linking signal transduction to cytokine secretion by combining prior knowledge of protein connectivity with proteomic data. Our analysis identified the most probable target phosphoproteins of interrogated compounds and predicted translational control as a new mechanism underlying their anticytokine action. Induced alterations corroborated with inhibition of HCC-driven angiogenesis and metastasis. PMID- 26225264 TI - Semiphysiologically Based Pharmacokinetic Model of Leflunomide Disposition in Rheumatoid Arthritis Patients. AB - A semiphysiologically based pharmacokinetic (semi-PBPK) population model was used to evaluate the influence of enterohepatic recycling and protein binding, as well as the effect of genetic variability in CYP1A2, CYP2C19, and ABCG2, on the large interindividual variability of teriflunomide (active metabolite) concentrations following leflunomide administration in rheumatoid arthritis (RA) patients. The model was developed with total and free teriflunomide concentrations determined in RA patients taking leflunomide, as well as mean teriflunomide concentrations following the administration of leflunomide or teriflunomide extracted from the literature. Once developed, the 15-compartment model was able to predict total and free teriflunomide concentrations and was used to screen demographic and genotypic covariates, of which only fat-free mass and liver function (ALT) improved prediction. This approach effectively evaluated the effects of multiple covariates on both total and free teriflunomide concentrations, which have only been explored previously through simplistic one-compartment models for total teriflunomide. PMID- 26225266 TI - Low Starch/Low Dairy Diet Results in Successful Treatment of Obesity and Co Morbidities Linked to Polycystic Ovary Syndrome (PCOS). AB - BACKGROUND: Polycystic Ovary Syndrome (PCOS) affects approximately 15% of reproductive-age women and increases risk of insulin resistance, type 2 diabetes mellitus, cardiovascular disease, cancer and infertility. Hyperinsulinemia is believed to contribute to or worsen all of these conditions, and increases androgens in women with PCOS. Carbohydrates are the main stimulators of insulin release, but research shows that dairy products and starches elicit greater postprandial insulin secretion than non-starchy vegetables and fruits. The purpose of this study was to determine whether an 8-week low-starch/low-dairy diet results in weight loss, increased insulin sensitivity, and reduced testosterone in women with PCOS. METHODS: Prospective 8-week dietary intervention using an ad libitum low starch/low dairy diet in 24 overweight and obese women (BMI >= 25 kg/m2 and <= 45 kg/m2) with PCOS. Diagnosis of PCOS was based on the Rotterdam criteria. Weight, BMI, Waist Circumference (WC), Waist-to-Height Ratio (WHtR), fasting and 2-hour glucose and insulin, homeostasis model assessment of Insulin Resistance (HOMA-IR), HbA1c, total and free testosterone, and Ferriman Gallwey scores were measured before and after the 8-week intervention. RESULTS: There was a reduction in weight (-8.61 +/- 2.34 kg, p<0.001), BMI (-3.25 +/- 0.88 kg/m2, p<0.001), WC (-8.4 +/- 3.1 cm, p<0.001), WHtR (-0.05 +/- 0.02 inches, p<0.001), fasting insulin (-17.0 +/- 13.6 MUg/mL, p<0.001) and 2-hour insulin ( 82.8 +/- 177.7 MUg/mL, p=0.03), and HOMA-IR (-1.9 +/- 1.2, p<0.001) after diet intervention. Total testosterone (-10.0 +/- 17.0 ng/dL, p=0.008), free testosterone (-1.8 pg/dL, p=0.043) and Ferriman-Gallwey scores (-2.1 +/- 2.7 points (p=0.001) were also reduced from pre- to post-intervention. CONCLUSION: An 8-week low-starch/low-dairy diet resulted in weight loss, improved insulin sensitivity and reduced testosterone in women with PCOS. PMID- 26225267 TI - Using Concept Mapping in the Development of a School of Public Health. AB - Schools of Public Health have a wide variety of essential stakeholders. Broad input in program planning should assist in ensuring well-developed plans and strong community buy-in. The planning of a school can better address the needs of multiple stakeholders from systematic broad-based input from these constituents using concept mapping. In this study, we used concept mapping to prioritize a set of recommendations from diverse stakeholders to assist in the process of planning a school. A set of statements was generated on essential elements for the proposed school from a broad group of stakeholders. The statements were then distilled into unique themes, which were then rated on importance and feasibility. Cluster maps and pattern matches were used to analyze the ratings. Unique themes (N = 147) were identified and grouped into 12 clusters. Cluster themes included leadership, faculty, culture, school, and curriculum. Pattern matches revealed a significant, modest correlation between importance and feasibility (r = 0.27). A broad range of perspectives was used to identify relevant areas to address in the development of a school. PMID- 26225268 TI - A Case of Bordetella brochiseptica at a Military Medical Facility in Hawai'i: Phenotypic and Molecular Testing of an Uncommon Human Pathogen. AB - Bordetella bronchiseptica (B. bronchiseptica) is rarely implicated in human disease. Human infections typically occur in the context of immunosuppression and while human infection has been sporadically reported in the literature, the majority of these reports are largely descriptive and do not explore the molecular and phenotypic properties of the isolates in question. Here we report the isolation and characterization of a B. bronchiseptica isolate derived from an HIV positive patient at Tripler Army Medical Center on O'ahu. This case represents the first published report of human infection of B. bronchiseptica in the state of Hawai'i and the most detailed description of the biochemical and molecular features of a Hawaiian isolate to date. PMID- 26225269 TI - A Survey of Physicians' Attitudes and Practices about the Human Papillomavirus (HPV) Vaccine in Hawai'i. AB - The human papillomavirus (HPV) vaccine has the potential to decrease the incidence of several cancers that affect women and men. Despite recommendations by the medical and public health community, and the incorporation of the vaccine into the adolescent immunization schedule, uptake of the vaccine remains well below target goals. To understand potential physician barriers to recommendation and provision of the vaccine, a cross-sectional survey was administered to Hawai'i pediatricians and family physicians from July 2012 to September 2012 on their attitudes, practices, and perceived barriers regarding HPV vaccination. Surveys were mailed to 465 members of the local pediatrics and family medicine professional chapters, and 87 responses were received for a response rate of 19%. After excluding 14 responses, 73 surveys were included in the analysis. Although almost all of the respondents reported stocking and administering the HPV vaccine in their offices, only 71% reported strongly recommending the HPV vaccine to girls 11-12 years, and only 57% strongly recommend the vaccine to boys 11-12 years old. Lack of insurance coverage and other financial considerations were barriers to provision of the vaccine by physicians. Physicians who felt it is necessary to discuss sexuality with patients prior to recommending the vaccine were significantly less likely to strongly recommend the vaccine to boys 11-12 years old. Public health efforts should focus on addressing the financial barriers and encouraging physicians to recommend the HPV vaccine according to the guidelines. PMID- 26225270 TI - Medical School Hotline: Last Lecture--Six Lessons To Live By: 2015 Convocation Ceremony of the John A. Burns School of Medicine University of Hawai'i at Manoa, Honolulu, Hawai'i, May 17, 2015. PMID- 26225271 TI - Insights in Public Health: The Importance of Considering Educational Inequity and Health Literacy to Understand Racial/Ethnic Health Disparities. PMID- 26225272 TI - The Daniel K. Inouye College of Pharmacy Scripts: Pharm2Pharm: Leveraging Medication Expertise Across the Continuum of Care. PMID- 26225274 TI - Minimally Invasive Surgery for Traumatic Fractures in Ankylosing Spinal Diseases. AB - Study Design Retrospective case series. Objective Ankylosing spondylitis (AS) and diffuse idiopathic skeletal hyperostosis (DISH) are two related diseases that significantly increase the risk of unstable spinal fractures from seemingly trivial trauma. Given the older age and higher surgical risk profile of most of these patients, minimally invasive (MIS) approaches to the treatment of such fractures may reduce operative risk and physiologic stress. Methods Eleven consecutive patients with hyperextension thoracolumbar injuries and a diagnosis of AS or DISH admitted to a single level I trauma center between June 2009 and June 2014 were retrospectively reviewed. All patients were treated with MIS stabilization. In addition, the patients were administered the Oswestry Disability Index and EuroQol-5D surveys to evaluate patient-reported outcomes regarding disability and health-related quality of life, respectively. Results Of the 11 patients, 10 were alive at the time of review. The mean follow-up time was 28 months. The average age was 77 years old with a mean body mass index of 34. All patients had severe systemic disease, American Society of Anesthesiologists grade III, with multiple medical comorbidities. Seven segments on average were included in the operative construct. There were no instrumentation failures or nonunions requiring revision surgery. The average postoperative Oswestry disability index was 21.5% (range: 0 to 34%), corresponding to low to moderate disability, and the average EuroQol-5D utility score was 0.77 (range: 0.60 to 1), a similar average postoperative utility value to those published in the literature on elective surgery for degenerative lumbar conditions. Conclusions MIS stabilization, when used on patients with good preoperative neurologic status, can successfully manage spinal fractures in patients with AS and DISH and preserve a favorable postoperative quality of life with limited disability. PMID- 26225275 TI - When Is It Safe to Return to Driving After Spinal Surgery? AB - Study Design Prospective study. Objective Surgeons' recommendations for a safe return to driving following cervical and lumbar surgery vary and are based on empirical data. Driver reaction time (DRT) is an objective measure of the ability to drive safely. There are limited data about the effect of cervical and lumbar surgery on DRT. The purpose of our study was to use the DRT to determine when the patients undergoing a spinal surgery may safely return to driving. Methods We tested 37 patients' DRT using computer software. Twenty-three patients (mean 50.5 +/- 17.7 years) received lumbar surgery, and 14 patients had cervical surgery (mean 56.7 +/- 10.9 years). Patients were compared with 14 healthy male controls (mean 32 +/- 5.19 years). The patients having cervical surgery were subdivided into the anterior versus posterior approach and myelopathic versus nonmyelopathic groups. Patients having lumbar spinal surgery were subdivided by decompression versus fusion with or without decompression and single-level versus multilevel surgery. The patients were tested preoperatively and at 2 to 3, 6, and 12 weeks following the surgery. The use of opioids was noted. Results Overall, the patients having cervical and lumbar surgery showed no significant differences between pre- and postoperative DRT (cervical p = 0.49, lumbar p = 0.196). Only the patients having single-level procedures had a significant improvement from a preoperative DRT of 0.951 seconds (standard deviation 0.255) to 0.794 seconds (standard deviation 0.152) at 2 to 3 weeks (p = 0.012). None of the other subgroups had a difference in the DRT. Conclusions Based on these findings, it may be acceptable to allow patients having a single-level lumbar fusion who are not taking opioids to return to driving as early as 2 weeks following the spinal surgery. PMID- 26225276 TI - Biomechanical Determination of Distal Level for Fusions across the Cervicothoracic Junction. AB - Study Design In vitro testing. Objective To determine whether long cervical and cervicothoracic fusions increase the intradiscal pressure at the adjacent caudal disk and to determine which thoracic end vertebra causes the least increase in the adjacent-level intradiscal pressure. Methods A bending moment was applied to six cadaveric cervicothoracic spine specimens with intact rib cages. Intradiscal pressures were recorded from C7-T1 to T9-10 before and after simulated fusion by anterior cervical plating and posterior thoracic pedicle screw constructs. The changes in the intradiscal pressure from baseline were calculated and compared. Results No significant differences where found when the changes of the juxtafusion intradiscal pressure at each level were compared for the flexion, extension, and left and right bending simulations. However, combining the pressures for all directions of bending at each level demonstrated a decrease in the pressures at the T2-T3 level. Exploratory analysis comparing changes in the pressure at T2-T3 to other levels showed a significant decrease in the pressures at this level (p = 0.005). Conclusions Based on the combined intradiscal pressures alone it may be advantageous to end long constructs spanning the cervicothoracic junction at the T2 level if there are no other mitigating factors. PMID- 26225277 TI - The Impact of Obesity on Perioperative Resource Utilization after Elective Spine Surgery for Degenerative Disease. AB - Study Design Retrospective case series. Objective To determine the effect of obesity on the resource utilization and cost in 3270 consecutive patients undergoing elective noninstrumented decompressive surgeries for degenerative spine disease at Mayo Clinic Rochester between 2005 and 2012. Methods Groups were assessed for baseline differences (age, gender, and American Society of Anesthesiologists [ASA] classification, procedure type, and number of operative levels). Outcome variables included the transfusion requirements during surgery, the total anesthesia and surgical times, intensive care unit (ICU) admissions, standardized costs, as well as the ICU and hospital length of stay (LOS). Regression analysis was used to evaluate for strength of association between obesity and outcome variables. Results Baseline differences between the groups (nonobese: n = 1,853; obese: n = 1,417) were found with respect to age, ASA class, gender, procedure type, and number of operative levels. After correcting for differences, we found significant associations between obesity and surgical (p < 0.0001) and anesthesia times (p < 0.0001) and hospital LOS (p < 0.0001). Additionally, ICU admission rates (p = 0.02) and requirement for postoperative ventilation (p = 0.048) were significantly higher in obese patients. Finally, mean difference in total cost ($1,632, p < 0.0001) was significantly higher for the obese cohort. Conclusion Obesity is associated with increased resource utilization and cost in patients undergoing a noninstrumented decompressive surgery for degenerative spine disease. PMID- 26225278 TI - Prevalence of Klippel-Feil Syndrome in a Surgical Series of Patients with Cervical Spondylotic Myelopathy: Analysis of the Prospective, Multicenter AOSpine North America Study. AB - Study Design Prospective study. Objective To evaluate the prevalence of Klippel Feil syndrome (KFS) in a prospective data set of patients undergoing surgical treatment for cervical spondylotic myelopathy (CSM) and to evaluate if magnetic resonance imaging (MRI) features in patients with KFS are more pronounced than those of non-KFS patients with CSM. Methods A retrospective analysis of baseline MRI data from the AOSpine prospective and multicenter CSM-North American study was conducted. All the patients presented with at least one clinical sign of myelopathy and underwent decompression surgery. The MRIs and radiographs were reviewed by three investigators. The clinical and imaging findings were compared with patients without KFS but with CSM. Results Imaging analysis discovered 5 of 131 patients with CSM (~3.82%) had single-level congenital fusion of the cervical spine. The site of fusion differed for all the patients. One patient underwent posterior surgery and four patients received anterior surgery. Postoperative follow-up was available for four of the five patients with KFS and indicated stable or improved functional status. All five patients demonstrated pathologic changes of adjacent segments and hyperintensity signal changes in the spinal cord on T2-weighted MRI. Multiple MRI features, most notably maximum canal compromise (p = 0.05) and T2 signal hyperintensity area (p = 0.05), were worse in patients with CSM and KFS. Conclusions The high prevalence of KFS in our surgical series of patients with CSM may serve as an indication that these patients are prone to increased biomechanical use of segments adjacent to fused vertebra. This supposition is supported by a tendency of patients with KFS to present with more extensive MRI evidence of degeneration than non-KFS patients with CSM. PMID- 26225279 TI - Does Balloon Kyphoplasty Deliver More Cement Safely into Osteoporotic Vertebrae with Compression Fractures Compared with Vertebroplasty? A Study in Vertebral Analogues. AB - Study Design A biomechanical and radiographic study using vertebral analogues. Objectives Kyphoplasty and vertebroplasty are widely used techniques to alleviate pain in fractures secondary to osteoporosis. However, cement leakage toward vital structures like the spinal cord can be a major source of morbidity and even mortality. We define safe cement injection as the volume of the cement injected into a vertebra before the cement leakage occurs. Our objective is to compare the amount of cement that can be safely injected into an osteoporotic vertebra with simulated compression fracture using either vertebroplasty or balloon kyphoplasty techniques. Methods Forty artificial vertebral analogues made of polyurethane with osteoporotic cancellous matrix representing the L3 vertebrae were used for this study and were divided into four groups of 10 vertebrae each. The four groups tested were: low-viscosity cement injected using vertebroplasty, high viscosity cement injected using vertebroplasty, low-viscosity cement injected using balloon kyphoplasty, and high-viscosity cement injected using balloon kyphoplasty. The procedures were performed under fluoroscopic guidance. The injection was stopped when the cement started protruding from the created vascular channel in the osteoporotic vertebral fracture model. The main outcome measured was the volume of the cement injected safely into a vertebra before leakage through the posterior vascular channel. Results The highest volume of the cement injected was in the vertebroplasty group using high-viscosity cement, which was almost twice the injected volume in the other three groups. One-way analysis of variance comparing the four groups showed a statistically significant difference (p < 0.005). Conclusions High-viscosity cement injected using vertebroplasty delivers more cement volume before cement leakage and fills the vertebral body more uniformly when compared with balloon kyphoplasty in osteoporotic vertebrae with compression fractures. PMID- 26225280 TI - Outcomes of Two Different Techniques Using the Lateral Approach for Lumbar Interbody Arthrodesis. AB - Study Design Retrospective cohort study. Objective To determine the short-term outcomes of two different lateral approaches to the lumbar spine. Methods This was a retrospective review performed with four fellowship-trained spine surgeons from a single institution. Two different approach techniques were identified. (1) Traditional transpsoas (TP) approach: dissection was performed through the psoas performed using neuromonitored sequential dilation. (2) Direct visualization (DV) approach: retractors are placed superficial to the psoas followed by directly visualized dissection through psoas. Outcome measures included radiographic fusion and adverse event (AE) rate. Results In all, 120 patients were identified, 79 women and 41 men. Average age was 64.2 years (22 to 86). When looking at all medical and surgical AEs, 31 patients (25.8%) had one or more AEs; 22 patients (18.3%) had a total of 24 neurologically related AEs; 15 patients (12.5%) had anterior/lateral thigh dysesthesias; 6 patients (5.0%) had radiculopathic pain; and 3 patients (2.5%) had postoperative weakness. Specifically, for neurologic AEs, the DV group had a rate of 28.0% and the TP group had a rate of 14.2% (p < 0.18). When looking at the rate of neurologic AEs in patients undergoing single level fusions only, the DV group rate was 28.6% versus 10.2% for the TP group (p < 0.03). Conclusion Overall, 18.3% of patients sustained a postoperative neurologic AE following lateral interbody fusions. The TP approach had a statistically lower rate of neurologic-specific AE for single-level fusions. PMID- 26225281 TI - Risk Prediction for Development of Traumatic Cervical Spinal Cord Injury without Spinal Instability. AB - Study Design Retrospective comparative study. Objective A narrow spinal canal is an important risk factor for predicting a spinal cord injury (SCI); however, the radiologic parameters have not been fully established. The authors conducted a comparative study to forecast SCI risk by determining a predictive spinal canal diameter (SCD) cutoff value from magnetic resonance image (MRI) in the Korean population. Methods On T2-weighted MRI of the cervical spine, the SCD at the pedicle (SCDpedicle) and the intervertebral disk level (SCDdisk) were measured in patients with SCI without spinal instability and in healthy subjects. Additionally, the vertebral body diameter (Dvertebral body) and intervertebral disk diameter (Dintervertebral disk) were measured, and the two ratios (SCDpedicle to Dvertebral body and SCDdisk to Dintervertebral disk) were calculated. In the SCI group, the extent of high signal intensity on the T2 weighted midsagittal MRI was determined. Results The data obtained from 20 patients in the SCI group (18 men, mean age 61.35 years) and 65 individuals in the control group (47 men, mean age 57.05 years) was compared. All the parameters including the SCD and the calculated ratios were significantly smaller in the SCI group than in the control group. Among them, the area under the receiver operating curve (AUC) value for the SCDdisk-to-Dintervertebral disk ratio at C2 C3, with a cutoff ratio value of 0.59, provided the greatest positive predictive value. A low SCDdisk-to-Dintervertebral disk ratio at C4-C5 and the presence of >40 mm of high signal intensity on the MRI were related with the presence of complete SCI. Conclusion Because the C2-C3 level is relatively wide compared with the subaxial cervical spine, a small ratio at C2-C3 provided the greatest positive predictive value in SCI. Complete SCI is associated with a small SCDdisk to-Dintervertebral disk ratio at C4-C5 and with extensive high signal intensity on MRI. PMID- 26225282 TI - A Randomized Controlled Trial Comparing Transforaminal Lumbar Interbody Fusion and Uninstrumented Posterolateral Fusion in the Degenerative Lumbar Spine. AB - Study Design Randomized controlled trial. Objective Despite a large number of publications of outcomes after spinal fusion surgery, there is still no consensus on the efficacy of the several different fusion methods. The aim of this study was to determine whether transforaminal lumbar interbody fusion (TLIF) results in an improved clinical outcome compared with uninstrumented posterolateral fusion (PLF) in the surgical treatment for chronic low back pain. Methods This study included 135 patients with degenerative disk disease (n = 96) or postdiskectomy syndrome (n = 39). Inclusion criteria were at least 1 year of back pain with or without leg pain in patients aged 20 to 65 with one- or two-level disease. Exclusion criteria were sequestration of disk hernia, psychosocial instability, isthmic spondylolisthesis, drug abuse, and previous spine surgery other than diskectomy. Pain was assessed by visual analog scale (pain index). Functional disability was quantified by the disability rating index and Oswestry Disability Index. The global outcome was assessed by the patient and classified as much better, better, unchanged, or worse. The patients were randomized to conventional uninstrumented PLF (n = 67) or TLIF (n = 68). PLF was performed in a standardized fashion using autograft. TLIF was performed with pedicle titanium screw fixation and a porous tantalum interbody spacer with interbody and posterolateral autograft. The clinical outcome measurements were obtained preoperatively and at 12 and 24 months postoperatively. The 2-year follow-up rate was 98%. Results The two treatment groups improved significantly from preoperatively to 2 years' follow-up. At final follow-up, the results in the TLIF group were significantly superior to those in the PLF group in pain index (2.0 versus 3.9, p = 0.007) and in disability rating index (22 versus 36, p = 0.003). The Oswestry Disability Index was better in the TLIF group (20 versus 28, p = 0.110, not significant). The global assessment was clearly superior in the TLIF group: 63% of patients scored "much better" in the TLIF group as compared with 48% in the PLF group (p = 0.017). Conclusions The results of the current study support the use of TLIF rather than uninstrumented PLF in the surgical treatment of the degenerative lumbar spine. The less optimal outcome after uninstrumented PLF may be explained by the much higher reoperation rate. PMID- 26225283 TI - Fundamentals of Clinical Outcomes Assessment for Spinal Disorders: Clinical Outcome Instruments and Applications. AB - Study Design A broad narrative review. Objectives Outcome assessment in spinal disorders is imperative to help monitor the safety and efficacy of the treatment in an effort to change the clinical practice and improve patient outcomes. The following article, part two of a two-part series, discusses the various outcome tools and instruments utilized to address spinal disorders and their management. Methods A thorough review of the peer-reviewed literature was performed, irrespective of language, addressing outcome research, instruments and tools, and applications. Results Numerous articles addressing the development and implementation of health-related quality-of-life, neck and low back pain, overall pain, spinal deformity, and other condition-specific outcome instruments have been reported. Their applications in the context of the clinical trial studies, the economic analyses, and overall evidence-based orthopedics have been noted. Additional issues regarding the problems and potential sources of bias utilizing outcomes scales and the concept of minimally clinically important difference were discussed. Conclusion Continuing research needs to assess the outcome instruments and tools used in the clinical outcome assessment for spinal disorders. Understanding the fundamental principles in spinal outcome assessment may also advance the field of "personalized spine care." PMID- 26225284 TI - Can a Thoracolumbar Injury Severity Score Be Uniformly Applied from T1 to L5 or Are Modifications Necessary? AB - Study Design Literature review. Objective The aim of this review is to highlight challenges in the development of a comprehensive surgical algorithm to accompany the AOSpine Thoracolumbar Spine Injury Classification System. Methods A narrative review of the relevant spine trauma literature was undertaken with input from the multidisciplinary AOSpine International Trauma Knowledge Forum. Results The transitional areas of the spine, in particular the cervicothoracic junction, pose unique challenges. The upper thoracic vertebrae have a transitional anatomy with elements similar to the subaxial cervical spine. When treating these fractures, the surgeon must be aware of the instability due to the junctional location of these fractures. Additionally, although the narrow spinal canal makes neurologic injuries common, the small pedicles and the inability to perform an anterior exposure make decompression surgery challenging. Similarly, low lumbar fractures and fractures at the lumbosacral junction cannot always be treated in the same manner as fractures in the more cephalad thoracolumbar spine. Although the unique biomechanical environment of the low lumbar spine makes a progressive kyphotic deformity less likely because of the substantial lordosis normally present in the low lumbar spine, even a fracture leading to a neutral alignment may dramatically alter the patient's sagittal balance. Conclusion Although the new AOSpine Thoracolumbar Spine Injury Classification System was designed to be a comprehensive thoracolumbar classification, fractures at the cervicothoracic junction and the lumbosacral junction have properties unique to these junctional locations. The specific characteristics of injuries in these regions may alter the most appropriate treatment, and so surgeons must use clinical judgment to determine the optimal treatment of these complex fractures. PMID- 26225285 TI - Traumatic Spondylolisthesis of the Axis Vertebra in Adults. AB - Study Design Narrative review. Objective To elucidate the current concepts in diagnosis and treatment of traumatic spondylolisthesis of the axis. Methods Literature review using PubMed, Google Scholar, and Cochrane databases. Results The traumatic spondylolisthesis of the axis accounts to 5% of all cervical spine injuries and is defined by a bilateral separation of the C2 vertebral body from the neural arch. The precise location of the fracture line may vary widely. For understanding the pathobiomechanics, the involvement of the C2-C3 disk is essential. Although its synonym "hangman's fracture" suggests an extension moment as primary injury mechanism, flexion moments are also proven to cause such fracture morphology. The axial force vector (distraction versus compression) is thought to have a significant effect on the neurologic involvement. The most widely accepted classifications, according to Effendi and modified by Levine, regard the displacement of the C2 vertebral body and possible locking of the facet joints. For decisions on conservative versus surgical therapy, a definitive statement about the stability is essential. The stability is determined by involvement of the C2-C3 disk and longitudinal ligaments, which frequently cannot be assessed by X-ray or computed tomography alone. The assessment of this soft tissue injury therefore requires additional imaging either by magnetic resonance imaging to display the disk and longitudinal ligaments or dynamic fluoroscopy to assess functional behavior of the C2-C3 motion segment. If stability is proven, an immobilization of the cervical spine in a semirigid cervical collar is sufficient. Unstable lesions require surgical stabilization. The standard procedure is an anterior C2-C3 diskectomy and fusion, because of the lower morbidity of the anterior approach and the motion preservation between C1 and C2. In rare cases (irreducible locked facet joints, the necessity of decompression of the vertebral artery, contraindication for anterior approach), a posterior approach is sometimes necessary. Isolated direct screw osteosynthesis is of little value, because it only makes sense in cases with an intact C2-C3 disk, which is usually regarded as stable and therefore might be treated conservatively. Conclusions Overall, the clinical evidence regarding traumatic spondylolisthesis of the axis is very low and mainly based on small case series, expert opinion, laboratory findings, and theoretical considerations. PMID- 26225286 TI - Intradural Neurocysticercosis of Lumbar Spine: A Case Report. AB - Study Design Case report. Objective Cysticercosis (parasitic infection caused by Taenia solium) is the most common parasitic infection of the nervous system. However, spinal neurocysticercosis is rare. It can present as an extraspinal or intraspinal lesion, with intramedullary being the rarest location. The symptoms can vary from vague backache and radiculopathy to cauda equine syndrome. Methods We report a 32-year-old man who presented with neurocysticercosis in the lumbar spine and cauda equine syndrome. He had low backache for 1 month, hesitancy in micturition, and decreased perianal sensation for the previous 2 days. Magnetic resonance imaging revealed an intradural extramedullary lesion extending from L2 S1 that was hyperintense in T2- and hypointense in T1-weighted images. Results Because the patient presented with cauda equine syndrome, urgent decompressive laminectomy was done from L2-S1, and the thin-walled cysts with clear fluid were removed. Histopathologic examination confirmed neurocysticercosis. The perianal sensation and the bladder control recovered completely. Conclusion Neurocysticercosis should be considered in the differential diagnosis in patients presenting with a similar picture, and urgent surgical decompression should be attempted to prevent further worsening of the neurologic symptoms. PMID- 26225287 TI - Neurogenic Shock Immediately following Posterior Lumbar Interbody Fusion: Report of Two Cases. AB - Study Design Case report. Objective To present two cases of neurogenic shock that occurred immediately following posterior lumbar interbody fusion (PLIF) and that appeared to have been caused by the vasovagal reflex after dural injury and incarceration of the cauda equina. Case Report We present two cases of neurogenic shock that occurred immediately following PLIF. One patient had bradycardia, and the other developed cardiac arrest just after closing the surgical incision and opening the drainage tube. Cardiopulmonary resuscitation was performed immediately, and the patients recovered successfully, but they showed severe motor loss after awakening. The results of laboratory data, chest X-ray, electrocardiogram, computed tomography, and echocardiography ruled out pulmonary embolism, hemorrhagic shock, and cardiogenic shock. Although the reasons for the postoperative shock were obscure, reoperation was performed to explore the cause of paralysis. At reoperation, a cerebrospinal fluid collection and the incarceration of multiple cauda equina rootlets through a small dural tear were observed. The incarcerated cauda equina rootlets were reduced, and the dural defect was closed. In both cases, the reoperation was uneventful. From the intraoperative findings at reoperation, it was thought that the pathology was neurogenic shock via the vasovagal reflex. Conclusion Incarceration of multiple cauda equina rootlets following the accidental dural tear by suction drainage caused a sudden decrease of cerebrospinal fluid pressure and traction of the cauda equina, which may have led to the vasovagal reflex. PMID- 26225288 TI - Global Reconstruction for Extensive Destruction in Tuberculosis of the Lumbar Spine and Lumbosacral Junction: A Case Report. AB - Study Design Case report. Objective To analyze the surgical difficulties in restoring global spinal stability and to describe an effective surgical option for tuberculosis with extensive destruction of the lumbosacral spine. Advanced tuberculosis with destruction of the lumbosacral spine can result in a kyphosis or hypolordosis, leading to back pain, spinal instability, and neurological deficits. The conventional treatment goals of lumbosacral tuberculosis are to correct and prevent a lumbar kyphosis, treat or prevent a neurological deficit, and restore global spinal stability. Instrumentation at the lumbosacral junction is technically demanding due to the complex local anatomy, the unique biomechanics, and the difficult fixation in the surrounding diseased bone. Methods We report a 21-year-old woman with tuberculosis from L1 to S2 with back pain and spinal instability. The radiographs showed a kyphosis of the lumbar spine. The magnetic resonance imaging and computed tomography scans revealed extensive destruction of the lumbar and lumbosacral spine. Spinopelvic stabilization combined with anterior debridement and reconstruction with free fibular strut graft was performed. Results The radiographs at follow-up showed a good correction of the kyphosis and excellent graft incorporation and fusion. Conclusions Anterior column reconstruction with a fibular strut graft helps restore and maintain the vertebral height. Posterior stabilization with spinopelvic fixation can be an effective surgical option for reconstructing the spine in extensive lumbosacral tuberculosis with sacral body destruction, requiring long fusions to the sacrum. It augments spinal stability, prevents graft-related complications, and accelerates the graft incorporation and fusion, thereby permitting early mobilization and rehabilitation. In spinal tuberculosis, antitubercular therapy may have to be prolonged in cases with large disease load, based on the clinicoradiographic and laboratory parameters. PMID- 26225289 TI - Extensive Deep Venous Thrombosis Resulting from Anterior Lumbar Spine Surgery in a Patient with Iliac Vein Compression Syndrome: A Case Report and Literature Review. AB - Study Design Case report. Objective Although May-Thurner syndrome or iliac vein compression syndrome is covered in the vascular literature, it remains absent from the orthopedic and neurosurgery literature and has not been previously reported to occur in concordance with spine surgery. We review the salient points of disease presentation, diagnosis, and treatment. Methods A 33-year-old woman was followed postoperatively via clinical and radiographic findings. Her presentation, operative treatment, postoperative extensive deep venous thrombosis (DVT) formation, and management are described. Results We present a unique case of a healthy 33-year-old woman who developed an extensive left iliac vein DVT after anterior lumbar spine fusion. Although she had multiple risk factors for thrombosis, the size of the thrombus was atypical. A subsequent venogram showed compression of the left common iliac vein by the right common iliac artery, consistent with May-Thurner syndrome. Conclusions May-Thurner syndrome or iliac vein compression syndrome is a rare diagnosis that is absent from the spine literature. The condition can predispose patients to extensive iliac vein DVT. The contributing anatomy and subsequent clot often require catheter-directed thrombolysis and stenting to achieve a favorable outcome. PMID- 26225290 TI - Pediatric Upper Cervical Spine Giant Cell Tumor: Case Report. AB - Study Design Case report. Objective The purpose of this work is to report the case of a giant cell tumor involving the second cervical vertebra in a pediatric patient. Surgical management included a combined posterior and anterior cervical approach. There has been no recurrence in 2 years of follow-up. Case Report A 13 year-old girl presented with scoliosis with incidentally lytic lesion involving the second cervical vertebra. The radiologic investigations and biopsy result indicated a giant cell tumor of the bone. A combined posterior and anterior cervical approach was performed to resect the lesion, reconstruct the spine, and restore stability. Two years of follow-up revealed no recurrence of the lesion with stable reconstruction of the spine. Results The lesion was surgically managed for excision and spinal fusion by combining a posterior occipitocervical arthrodesis with an anterior retropharyngeal cervical approach. The final histopathology result confirmed a giant cell tumor of the bone. Conclusions Giant cell tumor involving the second cervical vertebra is uncommon; this tumor can be managed surgically by using a combined posterior and anterior cervical retropharyngeal approach. The presented case was unique in terms of the tumor location, patient age, and surgical management. PMID- 26225291 TI - Cervical Synovial Cyst Causing Cervical Radiculomyelopathy: Case Report and Review of the Literature. AB - Study Design Case report. Objective Synovial cysts in the subaxial cervical spine are rare and are most commonly reported at the cervicothoracic junction. Only six cases of symptomatic C5-C6 synovial cysts have been reported in the literature; the condition is usually treated with decompressive laminectomy. We present a patient with a synovial cyst arising from the C5-C6 facet joint, associated with spondylolisthesis, and causing radiculomyelopathy. The patient was treated with a posterior excision of the cyst, decompressive laminectomy, and fusion. Methods A 67-year-old man had vertebral canal stenosis at C5-C6 secondary to a synovial cyst and spondylolisthesis with symptoms and signs of radiculopathy and myelopathy. Surgical management involved C5-C6 posterior decompressive laminectomy and excision of the cyst and C4-C6 instrumented fusion with lateral mass screws and rods. A literature review of symptomatic cervical synovial cysts is presented. Results The imaging studies identified grade I spondylolisthesis and a 3.3 * 4.3-mm extradural lentiform-like mass associated with focal compression of the spinal cord and exiting the C6 nerve root. After the surgery, the patient had an immediate full recovery and was asymptomatic by the 6-month examination. No operative complications were reported. The histologic report confirmed the presence of a synovial cyst. Conclusions C5-C6 is an unusual localization for symptomatic synovial cysts. Similar cases reported in the literature achieved excellent results after cyst excision and decompressive laminectomy. Because spondylolisthesis plus laminectomy are risk factors for segmental instability in the cervical spine, we report a case of a C5-C6 facet synovial cyst successfully treated with posterior laminectomy and C4-C6 fusion. PMID- 26225292 TI - Merkel Cell Spinal Metastasis: Management in the Setting of a Poor Prognosis. AB - Study Design Case report. Objective Merkel cell carcinoma is an aggressive neuroendocrine carcinoma with a poor prognosis. Metastatic epidural spinal cord compression (MESCC) is a debilitating disease causing neurologic deficits. The surgical management for MESCC depends on pathology. Methods We report a case of Merkel cell carcinoma of the spine and evaluate the treatment paradigms utilized in the prior reports. Result A 76-year-old man with a history of Merkel cell carcinoma presented with 2-week history of progressive difficulty ambulating and a solitary T5 epidural mass encasing the spinal cord. The patient underwent a T5 corpectomy with cage placement and T3 to T7 posterior fusion with postoperative neurologic improvement and a return to ambulation. Three weeks postoperatively, the patient re-presented with new-onset weakness and widespread metastatic spinal disease with epidural compression at the T8 level. Six weeks postoperatively, he was placed in hospice care. Conclusion Prior reports in the literature demonstrated a poor prognosis for Merkel cell carcinoma metastasis to the spine with survival ranging from 1 to 9 months after diagnosis. Although neurologic decline necessitates a surgical intervention, the assessment of operative benefit should take into account the prognosis associated with the primary tumor subtype. PMID- 26225293 TI - Indocyanine Green Videoangiography in Negative: Spinal Dural Arteriovenous Fistula. AB - Introduction This work reports the first indocyanine green videoangiography (IGV) in negative published with video format support. This technique, so called because its first phase is performed with occlusion of the vessel suspected of being pathologic, is used for the diagnosis of spinal arteriovenous fistula (sDAVF). Case Report The authors present the case of a 68-year-old man with an sDAVF fed by the right T7 segmentary artery. IGV was initially performed with the presumptive fistula feeder occluded for less than 1 minute, which provided both diagnostic and postexclusion control in one procedure. This technique therefore is reversible by not prolonging vascular exclusion times. Discussion IGV in negative is an extremely visual and intuitive procedure that represents an improvement over conventional IGV. Conclusion Studies with larger sample sizes are necessary to determine whether IGV in negative can further reduce the need for postoperative digital subtraction angiography. PMID- 26225294 TI - First Confirmed Metastatic Adamantinoma of the Spine: Case Report and Literature Review. AB - Study Design Case report and literature review. Objective To present the first case of metastatic adamantinoma of the spine with immunohistochemical confirmation and an updated literature review. Summary of Background Data Spinal metastatic disease could be difficult to diagnose because of the multiple differential diagnoses involved. Spinal surgeons must be aware of unusual primary extra-axial tumors that metastasize to the spine because in certain cases the primary surgery must determine the prognosis of this lesion. Methods We present a fully documented case of a middle-aged man with tibial adamantinoma who developed spine metastasis, confirmed by immunohistochemistry. A literature review was done. Results Based on clinical, imaging, and pathology findings, we provide evidence for the first proven metastatic adamantinoma of the spine, adding this condition to the long list of differential diagnoses of secondary spinal disease. Conclusions Adamantinoma is a very rare bone tumor representing ~1% of primary bone tumors. Spinal metastatic adamantinoma with immunohistochemical confirmation has not been described previously. Due to the lack of specific image findings or serum markers and multiple differential diagnoses, biopsy with immunohistochemical confirmation is mandatory, because "en block resection" might prove to be curative treatment. PMID- 26225295 TI - Effects of low intensity laser irradiation during healing of infected skin wounds in the rat. AB - BACKGROUND AND OBJECTIVE: Low intensity laser irradiation remains a controversial treatment for non-healing wounds. This study examines the effect of low intensity light on healing of infected skin wounds in the rat. MATERIALS AND METHODS: Wounds on the rat dorsum were inoculated with Pseudomonas aeruginosa. Wounds were irradiated or sham-irradiated three times weekly from day 1 to 19 using 635-nm or 808-nm diode lasers delivering continuous wave (CW) or intensity modulated (3800 Hz) laser radiation, all at radiant exposures of 1 and 20 J/cm2. Wound area and bacterial growth on the wound surface were evaluated three times a week. Histological and immunohistochemical analyses were performed at day 8 and 19. RESULTS: Wounds that were irradiated using a wavelength of 635 nm (1 and 20 J/cm2) or intensity modulated 808-nm laser light at 20 J/cm2 were smaller in area at day 19 than the sham-irradiated controls (achieved significance level=0.0105 0.0208) and were similar to controls in respect of bacterial growth. The remaining light protocols had no effect on wound area at day 19 although they increased Staphylococcus aureus growth across the time line compared with controls (p<0.0001 to p<0.004). CW 808-nm light at 20 J/cm2 significantly delayed half-heal time. Histological and immunohistochemical analyses supported wound closure findings: improved healing was associated with faster resolution of inflammation during the acute phase and increased signs of late repair at day 19. Significant inflammation was seen at day 19 in all irradiated groups regardless of radiant exposure, except when using 635 nm at 1 J/cm2. CONCLUSIONS: Red light improved healing of wounds. Only one 808-nm light protocol enhanced healing; lack of benefit using the remaining 808-nm light protocols may have been due to stimulatory effects of the light on S. aureus growth. PMID- 26225296 TI - Reconstruction Using Locoregional Flaps for Large Skull Base Defects. AB - We present a modified locoregional flap for the reconstruction of large anterior skull base defects that should be reconstructed with a free flap according to Yano's algorithm. No classification of skull base defects had been proposed for a long time. Yano et al suggested a new classification in 2012. The lb defect of Yano's classification extends horizontally from the cribriform plate to the orbital roof. According to Yano's algorithm for subsequent skull base reconstructive procedures, a lb defect should be reconstructed with a free flap such as an anterolateral thigh free flap or rectus abdominis myocutaneous free flap. However, our modified locoregional flap has also enabled reconstruction of lb defects. In this case series, we used a locoregional flap for lb defects. No major postoperative complications occurred. We present our modified locoregional flap that enables reconstruction of lb defects. PMID- 26225297 TI - Hearing Outcomes after Surgical Drainage of Petrous Apex Cholesterol Granuloma. AB - Objective This study aims to assess the hearing outcomes of patients undergoing surgical management of petrous apex cholesterol granuloma and to discuss the role of otic capsule-sparing approaches in drainage of petrous apex cholesterol granulomas. Design Retrospective case series. Setting Tertiary care medical center. Participants Eight patients underwent surgery for presumed or definitive cholesterol granuloma between 2002 and 2011 and met the inclusion criteria for this study. Main Outcome Measures Pre- and postoperative audiogram results as measured by pure tone thresholds and word recognition scores. Results Four patients (50%) demonstrated improvement in speech discrimination. One patient had an increase from 0 to 67% in word recognition scores. Four patients (50%) demonstrated worsening of pure tone thresholds, including two patients with anacusis. Conclusion Perilabyrinthine drainage of petrous apex cholesterol granulomas may result in hearing preservation or hearing improvement, even in the setting of otic capsule erosion. Patients should be counseled about the potential risk of significant hearing loss. PMID- 26225298 TI - Anatomy Relationship around Internal Carotid Artery in the Endoscopic Surgery of Nasopharynx: A Study Based on Computed Tomography Angiography. AB - Objective Anatomic knowledge is needed to avoid injury to internal carotid artery (ICA) during the endoscopic surgery around nasopharynx and its surrounding space. Design We prospectively studied the computed tomography angiography (CTA) data of 28 patients with image processing software. Special attention was given to ICA and various landmarks around nasopharynx. Results The anatomic relationship between ICA and different landmarks around nasopharynx was clearly presented in three-dimension. The fossa of Rosenmuller is the nearest point of the nasopharyngeal cavity to ICA. The opening of the Vidian canal in the middle cranial fossa could be either above, below, or at the level of the horizontal segment of petrous ICA. The pharyngeal trunk of the ascending pharyngeal artery can also be clearly identified in most reconstructed CTA images. Multiple anatomic relationships were also quantified. Conclusions Reconstructed CTA can provide key anatomic information for a safe and accurate endoscopic dissection around nasopharynx. PMID- 26225299 TI - The Transcallosal Anterior Interfoniceal Approach: A Microsurgical Anatomy Study. AB - Objectives A plethora of surgical strategies have been described to reach deep seated lesions situated within the third ventricle including the Rosenfeld, or transcallosal anterior interfoniceal (TAIF), approach. First introduced in 2001, it consists of a small callosotomy followed by the midline transseptal dissection of fornices to enter the roof of the third ventricle. The aim of this microsurgical anatomy study is to describe and show each stage of the surgical procedure, focusing on the possible trajectories to anatomical landmarks. Participants A total of 20 adult cadaveric specimens were used in this study. Using *3 to *40 magnifications, the surgical dissection was performed in a stepwise fashion, and the transcallosal anterior interforniceal approach was performed, analyzed, and described. Results In 5 specimens of 10, a cavum septum pellucidum was depicted. In 5 cases of 20 after the callosotomy ,the lateral ventricular cavities were reached. Different orientation of the microscope allowed us to define three surgical trajectories to visualize the region of interest without exposing important functional areas. Conclusion The TAIF represents a minimally invasive approach to the third ventricle; its tricky surgical steps make appropriate anatomical dissection training essential to become confident and skilled in performing this approach. PMID- 26225300 TI - Techniques for Preservation of the Frontotemporal Branch of Facial Nerve during Orbitozygomatic Approaches. AB - Background During orbitozygomatic (OZ) approaches, the frontotemporal branch (FTB) of the facial nerve is exposed to injury if proper measures are not taken. This article describes in detail the nuances of the two most common techniques (interfascial and subfascial dissection). Design The FTB of the facial nerve was dissected and followed in its tissue planes on fresh-frozen cadaver heads. The interfascial and subfascial dissections were performed, and every step was photographed and examined. Results The interfascial dissection is safe to be started from the most anterior part of the superior temporal line and followed to the root of the zygoma. The dissection is continued on the deep temporalis fascia (DTF), and the interfascial fat pad is elevated. With the subfascial dissection, both the superficial temporalis fascia and the DTF are elevated. The interfascial dissection exposes the zygomatic arch directly, whereas the subfascial dissection requires an additional cut on the DTF to expose the zygomatic arch. Proper subperiosteal dissection on the zygomatic arch is another important step in FTB preservation. Conclusion Detailed understanding of the complex relationship of the tissue planes in the frontotemporal region is needed to perform OZ exposures safely. PMID- 26225301 TI - Indicators of a Reduced Intercarotid Artery Distance in Patients Undergoing Endoscopic Transsphenoidal Surgery. AB - Objective To identify clinicopathologic factors associated with a reduced intercarotid distance (ICD) and subgroups at risk for internal carotid artery injury during transsphenoidal surgery. Design A retrospective case-control study. Setting This study was conducted at the McGill University Health Centre, a university-affiliated tertiary care center. Participants Patients with a sellar or parasellar tumor and nontumor controls were included in the study. Main Outcome Measures The smallest distance between the internal carotid arteries at the clival, cavernous, and paraclinoid segments on coronal magnetic resonance imaging was measured. Demographic profiles, cephalometric measurements, tumor dimensions, and sphenoid configuration were assessed as potential determinants of the ICD. Results A total of 212 cases and 34 controls were analyzed. Widening of the ICD at the three segments of the internal carotid arteries was found in patients with pituitary macroadenomas (p < 0.01). Patients with a growth hormone secreting adenoma had a markedly reduced ICD at the clivus compared with controls (1.59 cm versus 1.77 cm; p = 0.02; 95% confidence interval [CI], 0.03-0.32). The paraclinoid ICD was reduced in patients with an anterior fossa meningioma (1.24 cm versus 1.33 cm; p = 0.04; 95% CI, 0.01-0.45). Conclusion Identifying clinicopathologic factors affecting the ICD can help surgeons recognize constraints to endoscopic access of the skull base and avoid inadvertent arterial injury. PMID- 26225302 TI - Supine No-Retractor Method in Microvascular Decompression for Hemifacial Spasm: Results of 100 Consecutive Operations. AB - Objectives In microvascular decompression (MVD) for hemifacial spasm (HFS), the patient is placed in the lateral or park-bench position that is complicated and uncomfortable for anesthesiologists, nurses, and even the patient. Careless retraction of the cerebellum by a spatula could be the major cause of surgical complications. In our method, a patient is laid supine avoiding the complicated positioning. The subfloccular approach from a small cranial window sited on the more lateral and basal side of the occipital cranium enables the surgeon to reach all the segments of the facial nerve root without a spatula. We introduce our surgical procedures in detail along with our excellent results. Methods A total of 100 consecutive patients experiencing primary HFS were operated on with MVD by a single surgeon in our institution from August 2012 to April 2014. Results Overall, 94 patients showed the complete disappearance or a satisfactory alleviation of HFS. De novo neurologic deficits were not encountered after surgery including hearing impairment. In 47 cases, multiple offending vessels were observed in multiple possible affected sites in addition to the root entry/exit zone. Conclusions We believe this approach is superior for the safe and precise decompression of any part of the facial nerve root. PMID- 26225303 TI - Predictors of Survival in Sinonasal Adenocarcinoma. AB - Objectives To identify factors associated with disease-specific survival (DSS) in intestinal and nonintestinal sinonasal adenocarcinoma. Design Retrospective review. Setting Surveillance Epidemiology and End Results database. Participants Adult patients with sinonasal adenocarcinoma. Main Outcome Measures DSS. Results We identified 325 patients; of these, 300 had the nonintestinal type and 25 had intestinal type histologies. The 5-year DSS rates for patients who had no treatment, radiation (RT), surgery, and surgery and postoperative RT were 42.5, 46.1, 85.6, and 72.6%, respectively (log-rank test; p < 0.001). Black race, age >= 75 years, paranasal sinus involvement, and high grade were independently associated with decreased DSS. Compared with RT, surgery (hazard ratio [HR]: 0.34; 95% confidence interval [CI]: 0.15-0.77), and adjuvant RT (HR: 0.47; 95% CI, 0.26-0.86) were associated with improved DSS. Conclusions There is no difference in prognosis between intestinal and nonintestinal subtypes of sinonasal adenocarcinoma. Treatment with surgery alone or adjuvant RT is associated with a more favorable prognosis. PMID- 26225304 TI - Dural Septation on the Inner Surface of the Jugular Foramen: An Anatomical Study. AB - Introduction Preserving cranial nerve (CN) function during tumor removal at the jugular foramen is challenging. No anatomical study has better defined the relevant dural septations on the inner surface of the jugular foramen. This study was undertaken to elucidate this anatomy. Methods Fourteen cadaveric heads (28 sides) were dissected, and relationships of the meningeal coverings of the jugular foramen and adjacent CNs documented. A classification scheme was created to better describe the dural septations of the inner surface of the jugular foramen. Results Four types of dural septations were noted. Type I: 10 sides (36%) where a dural septation was seen between CNs IX anteriorly and X and XI posteriorly. Of these, the septum was ossified in 20%. Type II (32%) was defined as a jugular foramen with no dural septation. Type III (7%) was defined as septation between CNs IX and X anteriorly and XI posteriorly. Type IV (7 sides, 25%) or the chaotic form was defined as multiple septations within the jugular foramen that housed and divided CN rootlets. Conclusions The dural septations defined here can be used in future studies to help correlate operative strategy to meningeal morphology within the jugular foramen. PMID- 26225305 TI - Preoperative Lateralization Modalities for Cushing Disease: Is Dynamic Magnetic Resonance Imaging or Cavernous Sinus Sampling More Predictive of Intraoperative Findings? AB - Objective To analyze whether cavernous sinus sampling (CSS) and dynamic magnetic resonance imaging (dMRI) are consistent with intraoperative findings in Cushing disease (CD) patients. Design Retrospective outcomes study. Setting Oregon Health & Science University; 2006 and 2013. Participants A total of 37 CD patients with preoperative dMRI and CSS to confirm central adrenocorticotropic hormone (ACTH) hypersecretion. Patients were 78% female; mean age was 41 years (at diagnosis), and all had a minimum of 6 months of follow-up. Main Outcome Measures Correlations among patient characteristics, dMRI measurements, CSS results, and intraoperative findings. Results All CSS indicated presence of CD. Eight of 37 patients had no identifiable tumor on dMRI. Three of 37 patients had no tumor at surgery. dMRI tumor size was inversely correlated with age (rs = - 0.4; p = 0.01) and directly correlated to intraoperative lateralization (rs = 0.3; p < 0.05). Preoperative dMRI was directly correlated to intraoperative lateralization (rs = 0.5; p < 0.002). CSS lateralization showed no correlation with intraoperative findings (rs = 0.145; p = 0.40) or lateralization observed on preoperative dMRI (rs = 0.17; p = 0.29). Postoperative remission rate was 68%. Conclusion dMRI localization was most consistent with intraoperative findings; CSS results were less reliable. Results suggest that small ACTH-secreting tumors continue to pose a challenge to reliable preoperative localization. PMID- 26225306 TI - Predicting Consistency of Meningioma by Magnetic Resonance Imaging. AB - Objective Meningioma consistency is important because it affects the difficulty of surgery. To predict preoperative consistency, several methods have been proposed; however, they lack objectivity and reproducibility. We propose a new method for prediction based on tumor to cerebellar peduncle T2-weighted imaging intensity (TCTI) ratios. Design The magnetic resonance (MR) images of 20 consecutive patients were evaluated preoperatively. An intraoperative consistency scale was applied to these lesions prospectively by the operating surgeon based on Cavitron Ultrasonic Surgical Aspirator (Valleylab, Boulder, Colorado, United States) intensity. Tumors were classified as A, very soft; B, soft/intermediate; or C, fibrous. Using T2-weighted MR sequence, the TCTI ratio was calculated. Tumor consistency grades and TCTI ratios were then correlated. Results Of the 20 tumors evaluated prospectively, 7 were classified as very soft, 9 as soft/intermediate, and 4 as fibrous. TCTI ratios for fibrous tumors were all <= 1; very soft tumors were >= 1.8, except for one outlier of 1.66; and soft/intermediate tumors were > 1 to < 1.8. Conclusion We propose a method using quantifiable region-of-interest TCTIs as a uniform and reproducible way to predict tumor consistency. The intraoperative consistency was graded in an objective and clinically significant way and could lead to more efficient tumor resection. PMID- 26225307 TI - Endoscopic Resection of Vestibular Schwannomas. AB - Objective To report our results and the technical details of fully endoscopic resection of vestibular schwannomas. Design Prospective observational study. Setting A single academic institution involving neurosurgery and neurotology. Participants Twelve consecutive patients who underwent fully endoscopic resection of a vestibular schwannoma. Main Outcome Measures Hearing preservation, based on the American Association of Otolaryngology-Head and Neck Surgeons (AAO-HNS) score as well as the Gardener and Robertson Modified Hearing Classification (GR). Facial nerve preservation based on the House-Brackmann (HB) score. Results All patients successfully underwent gross total resection. Facial nerve preservation rate was 92% with 11 of 12 patients retaining an HB score of 1/6 postoperatively. Hearing preservation rate was 67% with 8 of 12 patients maintaining a stable AAO HNS grade and GR score at follow-up. Mean tumor size was 1.5 cm (range: 1-2 cm). No patients experienced postoperative cerebrospinal fluid leak, infection, or cranial nerve palsy for a complication rate of 0%. Mean operative time was 261.6 minutes with an estimated blood loss of 56.3 mL and average length of hospital stay of 3.6 days. Conclusion A purely endoscopic approach is a safe and effective option for hearing preservation surgery for vestibular schwannomas in appropriately selected patients. PMID- 26225309 TI - Response to Letter to the Editor on "Extended Inferior Turbinate Flap for Endoscopic Reconstruction of Skull Base Defects." J Neurol Surg B 2014;75(B4):225 230. PMID- 26225308 TI - Optic Nerve Decompression through a Supraorbital Approach. AB - Objective We propose a stepwise decompression of the optic nerve (ON) through a supraorbital minicraniotomy and describe the surgical anatomy of the ON as seen through this approach. We also discuss the clinical applications of this approach. Methods Supraorbital approaches were performed on 10 preserved cadaveric heads (20 sides). First, 3.5-cm skin incisions were made along the supraciliary arch from the medial third of the orbit and extended laterally. A 2 * 3-cm bone flap was fashioned and extradural dissections were completed. A 180 degree unroofing of the ON was achieved, and the length and width of the proximal and distal portions of the optic canal (OC) were measured. Results The supraorbital minicraniotomy allowed for identification of the anterior clinoid process and other surgical landmarks and adequate drilling of the roof of the OC with a comfortable working angle. A 25-degree contralateral head rotation facilitated visualization of the ON. Conclusion The supraorbital approach is a minimally invasive and cosmetically favorable alternative to more extended approaches with longer operative times used for the management of ON decompression in posttraumatic or compressive optic neuropathy from skull base pathologies extending into the OC. The relative ease of this approach provides a relatively short learning curve for developing neurosurgeons. PMID- 26225310 TI - Combined Balloon Test Occlusion and SPECT Analysis for Carotid Sacrifice: Angiographic Predictors for Success or Failure? AB - Objectives To evaluate angiographic patterns that may predict the success or failure of carotid artery balloon test occlusion (BTO) and single-photon emission computed tomography (SPECT) analysis for carotid sacrifice. Study Design This is a retrospective nonrandomized study. Study Setting Conducted at the University of California Davis Medical Center, Sacramento, California. Patients A total of 31 patients, ranging from 24 to 83 years of age, with a mean age of 61 years (22 men, 9 women) with head and neck cancer (26 patients), malignant glomus tumor (1 patient) or giant carotid aneurysms (4 patients) as possible candidates for surgical carotid artery sacrifice were evaluated from September 2005 to September 2012. Methods All patients underwent unilateral internal carotid artery balloon test occlusion with SPECT analysis (20 mCi technetium 99m-hexamethyl propyleneamine oxime [HMPAO]) imaging before and during carotid occlusion. Carotid angiography with carotid cross-compression (manual compression of the cervical artery contralateral to the side of contrast injection) was used to analyze filling through the anterior communicating artery to the contralateral hemisphere. Intervention The balloon occlusion was terminated in two patients because of deterioration of the neurologic exam. Main Outcome Measures All patients who passed the neurologic examination during BTO and also passed the SPECT occlusive study underwent successful carotid sacrifice without neurologic sequelae. Patients failing the occlusive neurologic examination and/or the SPECT study elected chemoradiation, with the exception of one patient who underwent a successful carotid bypass graft and carotid resection. Results The success of carotid sacrifice in patients passing both the occlusive test and the SPECT analysis for carotid sacrifice was 100%. Three patients failed both the BTO and the SPECT, with two demonstrating no anterior circulation cross-fill, but one showed some cross-fill. Six additional patients passed the BTO but failed the SPECT, with poor cross-fill in five patients. In addition, three patients who had excellent cross-fill through the anterior communicating artery to the contralateral hemisphere failed the SPECT examination in two cases and failed both tests in another case. PMID- 26225311 TI - Systematic Analysis of Outcomes for Surgical Resection and Radiotherapy in Patients with Papillary Meningioma. AB - Introduction Papillary meningiomas (PMs) are characterized by their aggressive nature and high rate of recurrence. Due to their rarity, studies examining the relationship between treatment and clinical outcomes for this disease are limited. Gross total resection (GTR) with or without radiotherapy (RT) is considered the standard treatment; however, when GTR is not feasible, subtotal resection (STR) followed by RT may be an effective alternative. In this study, we analyzed the clinical outcomes in patients who either underwent GTR alone, GTR followed by RT, STR alone, or STR followed by RT. Methods A systematic analysis was performed to identify PM patients with sufficient follow-up and outcome data, as measured by recurrence. Patient data lacking extent of resection, follow-up, or recurrence information were excluded. Results A total of 29 patients with PM were treated with resections (23 GTRs and 6 STRs).The mean age and mean follow-up of patients in this study were 32.3 years and 42.1 months, respectively. Of these patients, 58.6% experienced recurrence. Overall, 47.8% of patients who underwent GTR experienced recurrence. These patients also demonstrated improved survival compared with STR. Among patients whose tumors were only partially excised, a recurrence rate of 83% was observed. Conclusion Our results confirm that GTR results in fewer recurrences compared with STR, supporting GTR as the treatment of choice for PM. Furthermore, GTR in conjunction with RT resulted in improved survival compared with GTR alone. When GTR was not feasible, STR with RT was associated with improved survival compared with STR alone. Future studies with more outcome data are needed to elucidate the optimal treatment for this rare disease. PMID- 26225312 TI - Reconstruction of Lateral Skull Base Defects with Radial Forearm Free Flaps: The Double-Layer Technique. AB - Introduction The radial forearm flap has fallen out of favor in lateral skull base reconstruction in recent literature. However, especially when used in a double layer, a radial forearm may be able to provide the thickness of a large flap while taking advantage of the pliability for which the flap is renowned. Objective To report the results of the double-layer technique of radial forearm free flap reconstruction of lateral temporal bone defects. Design A retrospective chart review. Setting A tertiary care institution. Participants All consecutive patients who underwent lateral temporal bone resections and were reconstructed with free flaps from 2006 to 2012. Major Outcome Measures Flap success rate, complications, and rate of revision surgery. Results A total of 17 patients were identified with free flap reconstruction of the lateral skull base. Seven received reconstruction with a double-layer radial forearm flap. Reconstruction related complications in this group included one case of facial cellulitis. The flap success rate was 100%. These results were comparable with patients who had other flaps. Conclusions The radial forearm free flap may be an effective reconstruction option for lateral temporal bone defects especially when used in the double-layer technique. PMID- 26225313 TI - Endonasal Access to the Upper Cervical Spine: Part 2-Cadaveric Analysis. AB - Objectives The study aims to determine factors that augment endonasal exposure of the cervical spine. Setting We used fluoroscopy and endoscopy to study endonasal visualization of the upper cervical spine. Participants Ten cadavers with normal anatomy were studied. Main Outcome Measures Endoscopic visualization was simulated with projected lines from an endoscope to the cervical spine in multiple positions. Results Neck position alone did not affect the extent of endonasal exposure of the upper cervical spine, although there was a trend correlating the extended neck position with more caudal exposure. The greatest impact was with concurrent use of a 30-degree endoscope and neck extension, and more caudal access was achieved by tilting the endoscope against the piriform aperture, using the posterior tip of the hard palate as the fulcrum. Conclusions Concurrent use of a 30-degree endoscope and neck extension increased the degree of exposure down the cervical spine. Maximum endonasal exposure of the upper cervical spine was obtained by maneuvering instruments at the fulcrum of the posterior hard palate and the nares, rather than changing the position of the neck alone. These results complement radiographic morphometric data in Part 1 of this study for preoperative assessment and surgical planning. PMID- 26225314 TI - Cholesterol Granuloma of the Petrous Apex: A 5-Year Review of Radiology Reports with Follow-Up of Progression and Treatment. AB - Objectives To assess the stability and outcomes of patients with cholesterol granulomas at Brigham and Women's Hospital. Design A retrospective review of neuroradiology magnetic resonance imaging (MRI) studies was performed. The number of newly diagnosed cases of cholesterol granuloma per year was determined. Additional data included age and gender, clinical presentation if applicable, growth on imaging follow-up, and recurrence on postoperative follow-up if applicable. Participants Inclusion criteria included patients who underwent MRI studies between January 1, 2009 and July 1, 2013. Upon review of imaging of these patients, 18 patients had findings compatible with cholesterol granuloma. Results During the study period, an average of three cases of cholesterol granuloma were diagnosed on MRI per year. Three of 18 patients underwent treatment. Two underwent surgery, both of whom demonstrated recurrence on postoperative follow up imaging. One patient who underwent computed tomography-guided percutaneous aspiration and Gelfoam (Pfizer, New York, United States) embolization had no recurrence on imaging follow-up of up to 23 months. Among the patients who were observed without intervention, growth was identified in only one patient. Conclusions Cholesterol granulomas are a rare entity; however, their appearance on imaging may be greater than previously reported. Most of the lesions demonstrate stability and can be observed. PMID- 26225315 TI - Ossification of the Posterior Petroclinoid Dural Fold: A Cadaveric Study with Neurosurgical Significance. AB - Objectives The roof of the porus trigeminus, composed of the posterior petroclinoid dural fold, is an important landmark to the skull base surgeon. Ossification of the posterior petroclinoid dural fold is an anatomical variation rarely mentioned in the literature. Such ossification results in the trigeminal nerve traversing a bony foramen as it enters Meckel cave. The authors performed this study to better elucidate this anatomical variation. Design Fifteen adult cadaveric head halves were subjected to dissection of the middle cranial fossa. Microdissection techniques were used to examine the posterior petroclinoid dural folds. Skull base osteology was also studied in 71 dry human skulls with attention paid to the attachment point of the posterior petroclinoid dural folds at the trigeminal protuberances. Setting Cadaver laboratory Main Outcome Measures Measurements were made using a microcaliper. Digital images were made of the dissections. Results Completely ossified posterior petroclinoid folds were present in 20% of the specimens. Of the 142 dry skull sides examined, 9% had large trigeminal protuberances. Conclusions Based on this study, the posterior petroclinoid dural fold may completely ossify in adults that may lead to narrowing of the porus trigeminus and potential compression of the trigeminal nerve at the entrance to Meckel cave. PMID- 26225316 TI - Human Temporal Bone Removal: The Skull Base Block Method. AB - Objectives To describe a technique for harvesting larger temporal bone specimens from human cadavers for the training of otolaryngology residents and fellows on the various approaches to the lateral and posterolateral skull base. Design Human cadaveric anatomical study. The calvarium was excised 6 cm above the superior aspect of the ear canal. The brain and cerebellum were carefully removed, and the cranial nerves were cut sharply. Two bony cuts were performed, one in the midsagittal plane and the other in the coronal plane at the level of the optic foramen. Setting Medical school anatomy laboratory. Participants Human cadavers. Main Outcome Measures Anatomical contents of specimens and technical effort required. Results Larger temporal bone specimens containing portions of the parietal, occipital, and sphenoidal bones were consistently obtained using this technique of two bone cuts. All specimens were inspected and contained pertinent surface and skull base landmarks. Conclusions The skull base block method allows for larger temporal bone specimens using a two bone cut technique that is efficient and reproducible. These specimens have the necessary anatomical bony landmarks for studying the complexity, utility, and limitations of lateral and posterolateral approaches to the skull base, important for the education of otolaryngology residents and fellows. PMID- 26225317 TI - Sellar Reconstruction and Rates of Delayed Cerebrospinal Fluid Leak after Endoscopic Pituitary Surgery. AB - Objectives Delayed cerebrospinal fluid (CSF) leaks are a complication in transsphenoidal surgery, potentially causing morbidity and longer hospital stays. Sella reconstruction can limit this complication, but is it necessary in all patients? Design Retrospective review. Setting Single-surgeon team (2005-2012) addresses this trend toward graded reconstruction. Participants A total of 264 consecutive patients with pituitary adenomas underwent endoscopic transsphenoidal resections. Sellar defects sizable to accommodate a fat graft were reconstructed. Main outcomes Delayed CSF leak and autograft harvesting. Results Overall, 235 (89%) had reconstruction with autograft (abdominal fat, septal bone/cartilage) and biological glue. Delayed CSF leak was 1.9%: 1.7%, and 3.4% for reconstructed and nonreconstructed sellar defects, respectively (p = 0.44). Complications included one reoperation for leak, two developed meningitis, and autograft harvesting resulted in abdominal hematoma in 0.9% and wound infection in 0.4%. Conclusion In our patients, delayed CSF leaks likely resulted from missed intraoperative CSF leaks or postoperative changes. Universal sellar reconstruction can preemptively treat missed leaks and provide a barrier for postoperative changes. When delayed CSF leaks occurred, sellar reconstruction often allowed for conservative treatment (i.e., lumbar drain) without repeat surgery. We found universal reconstruction provides a low risk of delayed CSF leak with minimal complications. PMID- 26225318 TI - Stereotactic Radiosurgery versus Natural History in Patients with Growing Vestibular Schwannomas. AB - Objective To describe our experience with stereotactic radiosurgery and its efficacy on growing tumors, and then to compare this result with the natural history of a similar cohort of non-radiation-treated lesions. Study Design A retrospective chart review and cohort comparison. Methods The long-term control rates of patients having undergone radiosurgery were collected and calculated, and this population was then compared with a group of untreated patients from the same period of time with growing lesions. Results A total of 61 patients with growing vestibular schwannomas treated with radiosurgery were included. After a mean of 160 months, we observed a control rate of 85.2%. When compared with a group of 36 patients with growing tumors who were yet to receive treatment (previously published), we found a corrected control rate or relative risk reduction of only 76.8%. Conclusion Radiosurgery for growing vestibular schwannomas is less effective than previously reported in unselected series. Although radiosurgery still has a role in managing this disease, consideration should be given to the actual efficacy that may be calculated when the natural history is known. We hope other centers will similarly report their experience on this cohort of patients. PMID- 26225319 TI - Endoscopic Endonasal Repair of Congenital Defects of the Anterior Skull Base: Developmental Considerations and Surgical Outcomes. AB - Techniques of endoscopic endonasal surgery, initially developed primarily for intracranial neoplasms, have been adapted to treat a wide variety of pathologies previously addressed with open craniotomy including congenital and acquired defects of the anterior skull base. Congenital defects can lead to herniation of leptomeninges containing cerebrospinal fluid alone or with brain tissue. Specific types of encephalocele can be defined on the basis of the associated abnormal bony anatomy. Endoscopic endonasal surgery represents a relatively recent development in the treatment of these entities. Technical considerations include relatively younger age range of the patient population, dimensions of preexisting bony defect, volume of herniated meninges and brain tissue, and distorted anatomy from abnormal development of the affected craniofacial skeleton. Recent highly detailed anatomical studies have quantitatively verified the utility of endoscopic endonasal surgery in the pediatric population. Particular attention has been directed toward adequacy of nasoseptal flap reconstruction in pediatric patients. Several reports have described patients with encephalocele of the anterior cranial fossa successfully treated with endoscopic surgery. The literature on endoscopic repair of congenital encephalocele is reviewed. Outcomes have generally been reported as favorable, although long-term follow-up and systematic studies have not been pursued. PMID- 26225320 TI - Hemostasis in Endoscopic Endonasal Skull Base Surgery. AB - William Halsted established the basic principles of modern surgical technique highlighting the importance of meticulous hemostasis and careful tissue handling. These concepts hold true today and are even more critical for endoscopic visualization, making hemostasis one of the most relevant cornerstones for the safe practice of endoscopic endonasal surgery (EES) of the skull base. During preoperative assessment, patients at higher risk for serious hemorrhagic complications must be recognized. From an anatomical point of view, EES can be grossly divided in two major components: sinonasal surgery and sellar-cranial base surgery. This division affects the choice of appropriate technique for control of bleeding that relies mainly on the source of hemorrhage, the tissue involved, and the proximity of critical neurovascular structures. Pistol-grip or single-shaft instruments constitute the most important and appropriately designed instruments available for EES. Electrocoagulation and a variety of hemostatic materials are also important tools and should be applied wisely. This article describes the experience of our team in the management of hemorrhagic events during EES with an emphasis on technical nuances. PMID- 26225321 TI - Banked Fascia Lata in Sellar Dura Reconstruction after Endoscopic Transsphenoidal Skull Base Surgery. AB - Objectives Cerebrospinal fluid (CSF) leakage is an undesirable complication of transsphenoidal skull base surgery. The issue of the most appropriate sellar dura repair remains unresolved, although a multilayer technique using autologous fascia lata is widely used. We describe the novel application of a homologous banked fascia lata graft as an alternative to an autologous one in the reconstruction of sellar dura defects in endoscopic transsphenoidal surgery. Design The clinical records of patients who underwent endoscopic transsphenoidal surgery at our department from June 2012, when we started using homologous fascia lata, up to July 2014 were reviewed retrospectively. The data concerning diagnosis, reconstruction technique, and surgical outcome were analyzed. Results We treated 16 patients successfully with banked fascia lata. Twelve patients presented intraoperative CSF leakage, and four patients were treated for postoperative rhinoliquorrhea. Banked fascia lata was used in a single-to multilayer technique, depending on the anatomical features of the defect and of the sellar floor. No complications or failures in sella reconstruction occurred. Conclusion A banked fascia lata graft proved reliable and safe in providing an effective sellar dura reconstruction. Used in a multilayer strategy, it should be considered a viable alternative to an autologous fascia lata graft. PMID- 26225322 TI - Comparative Analysis of Transpetrosal Approaches to the Internal Acoustic Meatus Using Three-Dimensional Radio-Anatomical Models. AB - Background The transcrusal approach that involves partial removal of the labyrinth was recently described to approach lesions of the cerebellopontine angle. It carries the benefit of hearing preservation and was suggested to have equivalent exposure of the petroclival surface compared with the transcochlear/transotic approaches. The current study was designed to assess if the transcrusal approach could achieve as good access to the internal auditory meatus (IAM) as the more destructive translabyrinthine exposure. Methods Fifty disease-free high-resolution computed tomography scans of the temporal bone were reviewed. Surgical freedom, angle of attack, and angle of trajectory to the internal acoustic canal were measured in three-dimensional models. Results Surgical freedom and angles of attack showed steady increments with the progression of petrous bone resection from the retrolabyrinthine-transcrusal translabyrinthine approaches. The angle of access to the IAM axis was dramatically reduced in the translabyrinthine approach compared with the transcrusal and retrolabyrinthine approaches (37.51 +/- 5.7, 24.56 +/- 4.6, and 3.17 +/- 2.85 degrees, respectively; n = 50; average plus or minus standard deviation, p < 0.001). Conclusion Using this novel radio-anatomical system, we demonstrate the advantage of the translabyrinthine approach to the axis of the internal auditory canal. The transcrusal approach lags behind the translabyrinthine corridor and should be considered alongside the subtemporal and retrosigmoid approaches designed to spare hearing. PMID- 26225323 TI - Planum-Clival Angle Classification: A Novel Preoperative Evaluation for Sellar/Parasellar Surgery. AB - Objective Endonasal approaches are increasingly used to treat sellar pathologies, leading to increased interest in achieving maximal safe resection. We propose a tool-the planum-clival angle (PCA)-and explore its surgical implications for sellar pathology resections. Design Retrospective analysis. Participants Consecutive patients with pituitary lesions between 2003 and 2013. Outcome Measures The PCA and suprasellar extension ratios; head position and extent of surgical resection. Results We enrolled 89 patients (ages 21-88 years). There were 15 type A patients (17%), 13 with suprasellar extension (89%) and ratios between 0.12 and 0.70. There were 61 type B patients (70%), 49 with suprasellar extension (81%) and ratios from 0.09 to 0.66. Finally, there were 13 type C patients (13%), 10 with suprasellar extension (73%) and ratios from 0.21 to 0.76. Type B was treated with a sphenoidectomy and neutral head positioning, type A with 10 to 20 degrees of flexion and an additional posterior ethmoidectomy with or without posterior planum resection, and type C with 10 to 20 degrees of extension and an additional superior clival resection. Conclusions Sellar anatomy and PCA influence the growth patterns of sellar lesions. Thus PCA should allow for better surgical planning and thereby improve surgical efficacy. PMID- 26225324 TI - Pilot Study on Early Postoperative Discharge in Pituitary Adenoma Patients: Effect of Socioeconomic Factors and Benefit of Specialized Pituitary Centers. AB - Introduction Pituitary neoplasms are benign entities that require distinct diagnostic and treatment considerations. Recent advances in endoscopic transsphenoidal surgery have resulted in shorter lengths of stay (LOS). We implemented a postoperative day (POD) 1 discharge paradigm involving a multidisciplinary approach and detailed preoperative evaluation and review of both medical and socioeconomic factors. Methods The experience of a single neurosurgeon/ears, nose, throat (ENT) team was reviewed, generating a preliminary retrospective database of the first 30 patients who underwent resection of pituitary lesions under the POD 1 discharge paradigm. We assessed multiple axes from their preoperative, in-house, and postoperative care. Results There were 14 men and 16 women with an average age of 53.8 years (range: 27-76 years). There were 22 nonsecretory and 8 secretory tumors with average size of 2.80 cm (range: 1.3-5.0 cm). All 30 patients underwent preoperative ENT evaluation. Average LOS was 1.5 +/- 0.7 days. A total of 18 of 30 patients were discharged on POD 1. The insurance status included 15 with public insurance such as emergency Medicaid and 15 with private insurance. Four patients had transient diabetes insipidus (DI); none had permanent DI. Overall, 28 of 30 patients received postoperative steroids. Factors that contributed to LOS > 1 day included public insurance status, two or more medical comorbidities, diabetes mellitus, transient panhypopituitarism, and DI. Conclusion The implementation of a POD 1 discharge plan for pituitary tumors is feasible and safe for elective patients. This implementation requires the establishment of a dedicated Pituitary Center model with experienced team members. The consistent limitation to early discharge was socioeconomic status. Efforts that incorporate the analysis of social disposition parameters with proper management of clinical sequelae are crucial to the maintenance of ideal LOS and optimal patient outcomes. PMID- 26225325 TI - Setting Up a Haplobank: Issues and Solutions. AB - The development of induced pluripotent stem cells offers the possibility of the scalable manufacture of cellular therapies for regenerative medicine. Moreover, donors can be selected on the basis of major transplant antigen systems to match the widest possible number of recipients worldwide, reducing the likely risk of immunological rejection and the degree of immune suppression or tolerance required. If such cell lines are to be broadly available, there will need to be mutual recognition of common standards across different jurisdictions. Extensive international collaboration will be required around issues such as determination of the optimal homozygous human leukocyte antigens (HLA) panel, donor selection, screening and consent, good manufacturing practice (GMP), standards and quality control and regulatory legislation. The challenges in establishing a global GMP induced pluripotent stem cell (iPSC) haplobank are formidable. We argue that now is the time to attempt to reach international agreement around common standards for GMP iPSC manufacture before the field develops in a fragmented manner. PMID- 26225326 TI - Hair dye dermatitis and p-phenylenediamine contact sensitivity: A preliminary report. AB - BACKGROUND: The contact allergic reactions from p-phenylenediamine (PPD) in hair dyes vary from mild contact dermatitis to severe life- threatening events (angioedema, bronchospasm, asthma, renal impairment). OBJECTIVES: To study the clinical patterns and PPD contact sensitivity in patients with hair-dye dermatitis. MATERIALS AND METHODS: Eighty (M:F 47:33) consecutive patients aged between 18 and 74 years suspected to have contact allergy from hair dye were studied by patch testing with Indian Standard Series including p-phenylenediamine (PPD, 1.0% pet). RESULTS: 54 Fifty-four (M:F 21:33) patients showed positive patch tests from PPD. Eight of these patients also showed positive patch test reaction from fragrance mix, thiuram mix, paraben mix, or colophony. Fifty-seven (71%) patients affected were aged older than 40 years. The duration of dermatitis varied from < 1 month to > 1 year with exacerbation following hair coloring. Forty-nine patients had dermatitis of scalp and/or scalp margins and 23 patients had face and neck dermatitis. Periorbital dermatitis, chronic actinic dermatitis, and erythema multiforme-like lesions were seen in 4, 2, and 1 patients, respectively. CONCLUSIONS: Hair dyes and PPD constitute a significant cause of contact dermatitis. There is an urgent need for creating consumer awareness regarding hair-dyes contact sensitivity and the significance of performing sensitivity testing prior to actual use. PMID- 26225327 TI - Hair dye dermatitis and para-phenylenediamine contact sensitivity. PMID- 26225328 TI - Correlation of serum antithyroid microsomal antibody and autologous serum skin test in patients with chronic idiopathic urticaria. AB - BACKGROUND: About 25-45% of patients of chronic urticaria (CU) have been stated to have histamine releasing autoantibodies in their blood. The term autoimmune urticaria is increasingly being accepted for this subgroup of patients. Review of the literature suggests high autologous serum skin test (ASST) positivity and presence of antithyroid microsomal antibodies in patients with autoimmune urticaria. AIMS: To study prevalence of ASST positivity and antithyroid microsomal antibodies in chronic "idiopathic" urticaria and to study the correlation between the two parameters. METHODS: All patients of chronic idiopathic urticaria satisfying inclusion/exclusion criteria were enrolled in the study after written informed consent. Patients of CU secondary to infections and infestations, physical urticaria including dermatographism, mastocytosis, urticarial vasculitis and those on treatment with immunosuppressive drugs for urticaria were excluded from the study. In all of these patients, complete blood count; ASST, serum T3/T4/thyroid stimulating hormone levels, antithyroid microsomal antibody (AMA) levels were done. Statistical analysis was done by Chi square test, Fisher exact test and Kappa statistics. RESULTS: Study included 24 males and 26 females with mean age of 39.54 years. Majority of patients belonged to 20-40 years of age. Females showed more ASST positivity. A total of 12 out of 50 (24%) patients showed positive ASST. A total of four out of 12 (33.33%) had positive ASST and raised AMA levels. CONCLUSION: Only 25% of patients of chronic idiopathic urticaria had positive ASST. ASST and AMA levels were positively correlated in our study. Further studies are required to authenticate this association. PMID- 26225329 TI - Serum levels of hypersensitive-C-reactive protein in moderate and severe acne. AB - BACKGROUND: Elevation of C-reactive protein (CRP) has been reported to occur in psoriasis, urticaria, acne, rosacea and many other dermatological and nondermatological conditions. Chronic systemic inflammation has been implicated in the development of neuropsychiatric/degenerative disorders, atherosclerosis, coronary artery disease, diabetes mellitus and even carcinogenesis. The present study is designed to determine whether the level of inflammation created by acne vulgaris could be high enough to raise the serum levels of high-sensitive CRP. MATERIALS AND METHODS: Forty-two patients with moderate and severe acne vulgaris were enrolled, along with 44 age and sex matched healthy blood donors as controls. Hypersensitive-CRP (Hs-CRP) was measured in both groups. RESULTS: Hypersensitive-C-reactive protein levels in the case group varied between 0 and 28.1 MUg/ml with an average of 2.24 +/- 4.87 MUg/ml (mean +/- standard deviation) and a median of 0.6 MUg/ml (interquartile range [IQR] =0.3, 1.4 MUg/ml). Hs-CRP levels of the control group varied between 0 and 14 MUg/ml with an average of 3.12 +/- 3.67 MUg/ml and a median of 1.5 MUg/ml (IQR = 0.55, 5.0 MUg/ml). No significant difference of Hs-CRP level between the two groups was seen (t = 0.961, 95% confidence interval: Lower = -2.6942, upper = 0.9377; P = 0.339). Additionally, no significant difference in the level of Hs-CRP was noted between the moderate and severe acne groups (95% confidence interval: Lower = -5.2495, upper = 1.6711; P = 0.165). CONCLUSION: Acne vulgaris, even in its severe grades (excluding acne fulminans and acne conglobata), does not induce significant inflammation at the systemic level. PMID- 26225330 TI - Assessment of clinical diagnostic accuracy compared with pathological diagnosis of basal cell carcinoma. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common type of skin cancer, afflicting light skin more than dark skin people. This malignancy metastasizes rarely and has unique histological properties. AIMS AND OBJECTIVES: We focused on the accuracy of clinical diagnoses of BCC by specialists. MATERIALS AND METHODS: Patients' information for 4-year period between 2007 and 2011 was extracted from files at a Pathology Department. The results were analyzed using the Chi-square method and SPSS software. RESULTS: From 367 referred cases dermatologists diagnosed 41% as direct BCC cases, 43.4% through excluding other skin diseases, 4% incorrectly and 1.11% unidentified. For other specialists (including plastic surgeons, ophthalmologists, general surgeons, and general practitioners) these were respectively 47.8%, 22.4%, 6.3% and 23.5%. Dermatologists had diagnosed 107 cases of all skin diseases as BCC through clinical examination of which 78.5% were correctly and 21.5% incorrectly diagnosed. The same parameters for all other specialists were respectively 77.36% and 22.64%. Diagnostic sensitivity, positive reportability, clinical conjecture indicator (CCI) and clinical diagnostic indicator were respectively 84.4%, 78.5%, 121.5% and 75.6%; whereas for other specialists these indicators were 70 among cases diagnosed by dermatologists as BCC, where pathological results showed other causes. The most common diagnosis by pathologists and other specialists was reported as squamous cell carcinoma (SCC). Among cases not diagnosed by dermatologists as BCC, where pathological results indicated BCC, the most common clinical diagnosis was malignant melanoma by dermatologists and SCC by other specialists. CONCLUSION: Dermatologists diagnosed BCC with higher sensitivity and positive reportability; also, CCIs and clinical diagnostic correctness was higher among dermatologists. The necessity for consulting with dermatologists and referring all skin diseases samplings to pathologist is thus clearly visible. PMID- 26225331 TI - An atypical presentation of antiphospholipid antibody syndrome. AB - Cutaneous manifestations in antiphospholipid antibody syndrome (APS) though common, are extremely diverse and it is important to know which dermatological finding should prompt consideration of antiphospholipid syndrome. The cutaneous manifestations of APS vary from livedo reticularis to cutaneous necrosis, and systemic involvement is invariably an accomplice in APS. Cutaneous ulcers with sharp margins can be seen in APS and they are usually seen on the legs. This case had an atypical presentation, as the initial presentation was painful necrotic ulcers over the legs, which resembled pyoderma gangrenosum and she had no systemic manifestations. There was no history of any arterial or venous thrombosis or any abortions. Antiphospholipid syndrome can be tricky to diagnose when cutaneous lesions are atypical. Nonetheless, it is very important to pin down this syndrome early due to its systemic complications. PMID- 26225332 TI - A tufted angioma. AB - Tufted angioma (TA) is a rare, benign, cutaneous angiomatous proliferation. It is more common in children, usually presenting as red-purple painful plaques on the trunk. We describe here a TA observed at nine months of age, appearing initially over the retroauricular area, gradually extending to involve skin of neck and trunk by two years of age. This case of a large TA (7 * 12 cm) in an Indian male child is reported here due to its rare presentation. PMID- 26225333 TI - Merkel cell carcinoma of the abdominal wall. AB - Merkel cell carcinoma also known as neuroendocrine carcinoma of the skin is a very rare skin tumor. It commonly presents in the old age and the common sites are head, neck and extremities. The diagnosis requires histopathological examination with immunohistochemical correlation. We report a case of Merkel cell carcinoma stage IIIB with bilateral inguinal lymphadenopathy that on FNAB showed metastatic deposits of the tumor. PMID- 26225334 TI - Idiopathic eruptive macular pigmentation in a Chinese child. AB - We present a case of a healthy 8-year-old boy who presented with disseminated asymptomatic brown macules on the face, neck, trunk, and proximal extremities for 3 months. Dermatologic examination revealed multiple, smooth, nonscaly, brown macules involving the face, neck, trunk, and proximal limbs. The Darier's sign was negative. Histopathologic study showed normal epidermis and basal membrane, and increasingly scattered melanophages in the papillary dermis. The final diagnosis was idiopathic eruptive macular pigmentation. PMID- 26225335 TI - Intravascular papillary endothelial hyperplasia: An unusual histopathological entity. AB - Intravascular papillary endothelial hyperplasia (Masson's tumor) is a benign lesion of the skin and subcutaneous tissue consisting of a reactive proliferation of endothelial cells with papillary formations related to a thrombus. It poses a diagnostic challenge as the clinical signs and symptoms are nonspecific and may mimic a soft tissue sarcoma. The diagnosis is based on histopathology. Here we report two cases of Masson's hemangioma occurring on the upper lip and on the left hand. PMID- 26225336 TI - Clinical course of disseminated Kaposi sarcoma in a HIV and hepatitis B co infected heterosexual male. AB - AIDS associated Kaposi sarcoma (AIDS-KS) was first reported from India in 1993. Since then only 16 cases have been reported. Three of them had proven Human Herpesvirus 8 (HHV-8) infection. We report a case of disseminated KS in a heterosexual male from India with HIV, hepatitis B and HHV-8 infection. He was given six cycles of chemotherapy with liposomal doxorubicin over three months to which he showed a good response. The case highlights the clinical course and management of a HHV-8 positive disseminated KS in a patient co-infected with Hepatitis B and HIV. PMID- 26225337 TI - A solitary auricular polyp. PMID- 26225338 TI - Dermpath Quiz. PMID- 26225339 TI - Vertically growing nail - A rare entity. PMID- 26225340 TI - Why do nails grow vertically? PMID- 26225341 TI - Two cases of lymphangioma circumscriptum successfully treated with pulsed dye laser and cryotherapy. PMID- 26225342 TI - Treatment options of lymphangioma circumscriptum. PMID- 26225343 TI - An interesting observation of polymorphous light eruption occurring on hypopigmented scars. PMID- 26225344 TI - Perforating granuloma annulare in a young male following application of the tattoo. PMID- 26225345 TI - A rare areolar growth developing late in pregnancy. PMID- 26225346 TI - Expression of p16 in psoriasis and chronic spongiotic dermatitis. PMID- 26225347 TI - SkIndia Quiz 19: Soft tumors in segmental fashion. PMID- 26225348 TI - Eccrine poroma. PMID- 26225349 TI - Porokeratotic eccrine ostial and dermal duct nevus: Case report of a rare entity. PMID- 26225350 TI - Osler's sign revisited. PMID- 26225351 TI - Plica neuropathica. PMID- 26225352 TI - Neonatal umbilical myiasis. PMID- 26225353 TI - Erratum: Could cryosurgery be an alternative treatment for basal cell carcinoma of the vulva?: Erratum. AB - [This corrects the article on p. 160 in vol. 5, PMID: 24860751.]. PMID- 26225354 TI - Total Virus and Bacteria Concentrations in Indoor and Outdoor Air. AB - Viruses play important roles in microbial ecology and some infectious diseases, but relatively little is known about concentrations, sources, transformation, and fate of viruses in the atmosphere. We have measured total airborne concentrations of virus-like and bacteria-like particles (VLPs between 0.02 MUm and 0.5 MUm in size and BLPs between 0.5 MUm and 5 MUm) in nine locations: a classroom, a daycare center, a dining facility, a health center, three houses, an office, and outdoors. Indoor concentrations of both VLPs and BLPs were ~105 particles m-3, and the virus-to-bacteria ratio was 0.9 +/- 0.1 (mean +/- standard deviation across different locations). There were no significant differences in concentration between different indoor environments. VLP and BLP concentrations in outdoor air were 2.6 and 1.6 times higher, respectively, than in indoor air. At the single outdoor site, the virus-to-bacteria ratio was 1.4. PMID- 26225355 TI - Clinical Utility of Amyloid Imaging in a Complex Case of Corticobasal Syndrome Presenting with Psychiatric Symptoms. AB - Clinical indications of amyloid imaging in atypical dementia remain unclear. We report a 68-year-old female without past psychiatric history who was hospitalized for auditory hallucinations and persecutory delusions associated with cognitive and motor deficits. Although psychotic symptoms resolved with antipsychotic treatment, cognitive and motor impairments remained. She further showed severe visuoconstructive and executive deficits, ideomotor apraxia, elements of Gerstmann's syndrome, bilateral agraphesthesia and discrete asymmetric motor deficits. Blood tests were unremarkable. Structural brain imaging revealed diffuse fronto-temporo-parietal atrophy, which was most severe in the parietal regions. Meanwhile, FDG-PET suggested asymmetrical fronto-temporo-parietal hypometabolism, with sparing of the posterior cingulate gyrus. A diagnosis of possible corticobasal syndrome (CBS) was made. Amyloid-PET using the novel tracer NAV4694 was ordered, and revealed significant deposition of fibrillar amyloid (SUVR 2.05). The primary diagnosis was CBS with underlying Alzheimer pathology and treatment with a cholinesterase inhibitor was initiated. Determination of underlying pathological CBS subtype is not simple even when based on extensive investigation including clinical presentation, atrophy patterns on MRI, and regional hypometabolism on FDG-PET. By contrast, amyloid imaging quickly confirmed Alzheimer pathology, and allowed rapid initiation of treatment in this complex case with early psychiatric symptoms. This case study illustrates the clinical utility of amyloid imaging in the setting of atypical cases seen in a tertiary memory clinic. PMID- 26225357 TI - Plasmalemma Vesicle Associated Protein Truncation Causes Lethal Protein-Losing Enteropathy in Humans. PMID- 26225356 TI - Endovascular Gene Delivery from a Stent Platform: Gene- Eluting Stents. AB - A synergistic impact of research in the fields of post-angioplasty restenosis, drug-eluting stents and vascular gene therapy over the past 15 years has shaped the concept of gene-eluting stents. Gene-eluting stents hold promise of overcoming some biological and technical problems inherent to drug-eluting stent technology. As the field of gene-eluting stents matures it becomes evident that all three main design modules of a gene-eluting stent: a therapeutic transgene, a vector and a delivery system are equally important for accomplishing sustained inhibition of neointimal formation in arteries treated with gene delivery stents. This review summarizes prior work on stent-based gene delivery and discusses the main optimization strategies required to move the field of gene-eluting stents to clinical translation. PMID- 26225358 TI - Can Genetic Testing Provide Information to Develop Customized Nutrigenomic Solutions for Reward Deficiency Syndrome? PMID- 26225370 TI - Continuous fluorometric method for measuring beta-glucuronidase activity: comparative analysis of three fluorogenic substrates. AB - E. coli beta-glucuronidase (GUS) activity assays are routinely used in fields such as plant molecular biology, applied microbiology and healthcare. Methods based on the optical detection of GUS using synthetic fluorogenic substrates are widely employed since they don't require expensive instrumentation and are easy to perform. In this study three fluorogenic substrates and their respective fluorophores were studied for the purpose of developing a continuous fluorometric method for GUS. The fluorescence intensity of 6-chloro-4-methyl-umbelliferone (6 CMU) at pH 6.8 was found to be 9.5 times higher than that of 4-methyl umbelliferone (4-MU) and 3.2 times higher than the fluorescence of 7 hydroxycoumarin-3-carboxylic acid (3-CU). Michaelis-Menten kinetic parameters of GUS catalysed hydrolysis of 6-chloro-4-methyl-umbelliferyl-beta-D-glucuronide (6 CMUG) were determined experimentally (Km = 0.11 mM, Kcat = 74 s(-1), Kcat/Km = 6.93 * 10(5) s(-1) M(-1)) and compared with the ones found for 4-methyl umbelliferyl-beta-D-glucuronide (4-MUG) (Km = 0.07 mM, Kcat = 92 s(-1), Kcat/Km = 1.29 * 10(6) s(-1) M(-1)) and 3-carboxy-umbelliferyl-beta-D-glucuronide (3-CUG) (Km = 0.48 mM, Kcat = 35 s(-1), Kcat/Km = 7.40 * 10(4) s(-1) M(-1)). Finally a continuous fluorometric method based on 6-CMUG as a fluorogenic substrate has been developed for measuring GUS activity. When compared with the highly used discontinuous method based on 4-MUG as a substrate it was found that the new method is more sensitive and reproducible (%RSD = 4.88). Furthermore, the developed method is less laborious, faster and more economical and should provide an improved alternative for GUS assays and kinetic studies. PMID- 26225371 TI - Ion-neutral collisional cross sections of carbohydrate isomers as divalent cation adducts and their electron transfer products. AB - As the gravity of glycoscience continues to amass, a commensurate demand for rapid, sensitive, and structurally comprehensive glycoanalytical tools has arisen. Among the most elusive but desirable analytical capabilities is the ability to expeditiously and unambiguously detect, distinguish, and resolve carbohydrates that differ only in their constitutional isomerism and/or stereoisomerism. While ion mobility spectrometry (IMS) has proven a highly promising tool for such analyses, the facility of this method to discriminate larger oligosaccharides is still somewhat limited. In an effort to expand the capabilities of IMS to discriminate among carbohydrate isomers, the present investigation was focused on IMS studies of four trisaccharide isomers, four pentasaccharide isomers, and two hexasaccharide isomers, each as group II metal ion adducts and their corresponding gas-phase electron transfer (ET) products. These studies were also evaluated in the context of previously investigated group I metal ion adducts of the same saccharides. The orientationally averaged ion neutral collisional cross sections (CCSs) of the various carbohydrate/metal ion adducts were found to be dependent on the structures of specific carbohydrate isomers, sensitive to the electronic characteristics of the bound cation, and responsive to the attachment of an additional electron (in the case of divalent metal ion adducts). Overall, these results underscore the utility of metal ions for probing carbohydrate structure in concert with IMS, and the capacity of gas phase ion chemistry to expand the menu of such probes. PMID- 26225372 TI - A single quantum dot-based biosensor for DNA point mutation assay. AB - Sensitive and selective detection of point mutation is essential to molecular biology research and early clinical diagnosis. Here, we demonstrate a single quantum dot (QD)-based biosensor for DNA point mutation assay. In this assay, a mutant target (G/C) remains unchanged after the endonuclease treatment, and the polymerase chain reaction (PCR) may be initiated with the assistance of primers and polymerase, generating a large number of mutant targets. The amplified mutant targets can be captured by biotinylated probes during the process of denaturation and annealing, and Cy5-dGTP may be assembled into the biotinylated probe with the catalysis of polymerase, leading to the formation of Cy5-labeled biotinylated probes. The Cy5-labeled biotinylated probes can be further assembled onto the QD surface to obtain a Cy5-DNA-QD complex, resulting in the generation of fluorescence resonance energy transfer (FRET) between the QD donor and the Cy5 receptor. The mutant targets can be quantitatively evaluated by the measurement of Cy5 counts by total internal reflection fluorescence (TIRF) microscopy. While in the presence of wild-type targets (T/A), no Cy5-dGTP can be assembled into the biotinylated probe due to the presence of a mismatch and consequently no FRET is observed. This single QD-based biosensor exhibits high sensitivity with a detection limit of 5.3 aM (or 32 copies) and can even discriminate as low as 0.01% variant frequency from the mixture of mutant targets and wild-type ones. Importantly, this biosensor can be used for genomic analysis in human lung cancer cells, and may be further applied for an early clinical diagnosis and personalized medicine. PMID- 26225373 TI - Response. PMID- 26225374 TI - Response. PMID- 26225375 TI - Response. PMID- 26225376 TI - Response. PMID- 26225377 TI - Response. PMID- 26225378 TI - Response. PMID- 26225379 TI - Response. PMID- 26225381 TI - Clinical governance: a key, but under-researched, health system foundation. PMID- 26225380 TI - Reply to Traissac et al. PMID- 26225382 TI - Developmental Changes of Normal Pupil Size and Reactivity in Children. AB - PURPOSE: The goal of this study was to establish normative values for measurements of quantitative pupillometry in children. METHODS: Quantitative pupillometry measurements were obtained from children between 1 and 18 years of age being seen for either a well child check or other outpatient appointment. RESULTS: Maximum and minimum pupil size increased slightly with age; however, the correlation was weak (r = 0.29 and 0.19, respectively). Similarly weak correlations with age also were observed for maximum constriction velocity (r = 0.29) and dilation velocity (r = 0.27). Maximum (5.56 vs. 4.97 mm) and minimum (3.74 vs. 3.40 mm) pupil sizes were significantly larger in whites than in African Americans. CONCLUSIONS: Pupil size and reactivity show little correlation with age and are therefore suitable for further exploration in using pupillometry as a biomarker across the pediatric age range. Differences in race should be taken into consideration when pupillometry is used in mixed populations. PMID- 26225383 TI - Instructions to Patients and Families Following Strabismus Surgery. AB - PURPOSE: To analyze postoperative instructions provided to patients and families after strabismus surgery. METHODS: In April 2012, a 12-question electronic survey was sent to all members of the American Association for Pediatric Ophthalmology and Strabismus (AAPOS) regarding their instructions to patients undergoing strabismus surgery. The questions specifically addressed patients' daily activities, such as their resumption of school and work, sports, swimming, normal showering and bathing, and contact lens use. RESULTS: One hundred two responses were completed; 96% were from pediatric ophthalmologists regularly performing strabismus surgery. Participation was greater by North American members (86%) and respondents with more than 10 years of experience (75%). Fifty percent of the respondents advised patients to resume normal showering and bathing 24 hours after surgery. Conversely, respondents recommended that children wait 3 to 4 days before resuming schoolwork (52%) and at least 2 weeks before playing in a sandbox (47%). Furthermore, respondents indicated that patients should refrain from participating in sports-related activities for at least 1 week (43%) and should not go swimming for at least 2 weeks (56%). Finally, 47% advised their patients not to wear contact lenses for 2 weeks after surgery. CONCLUSIONS: Overall, the responses indicated a high regard among AAPOS members for promoting normal healing and prevention of infection and other postoperative complications; however, certain trends, such as the recommendation regarding normal showering, may intimate a lack of further infection prevention. PMID- 26225384 TI - Analysis of Choroidal Thickness Using Spectral-Domain OCT in Children With Unilateral Amblyopia. AB - PURPOSE: To compare the subfoveal, parafoveal, and peripapillary choroidal thickness in amblyopic eyes with those of fellow and control eyes. METHODS: This institutional study involved 114 eyes from 38 patients with unilateral amblyopia and 19 healthy children, aged 6 to 17 years. The cause of amblyopia was identified as hyperopic anisometropia in 17 cases and strabismus in 21 cases. All patients underwent central macular thickness (CMT) and choroidal thickness measurement at seven retinal sites with spectral-domain optical coherence tomography (OCT). Statistical analysis was performed to compare the CMT and choroidal thickness of amblyopic and fellow eyes with control eyes. RESULTS: Average CMT was 248.31 +/- 24.18 MUm in amblyopic eyes, 249.76 +/- 26.08 MUm in fellow eyes, and 243.65 +/- 31.96 MUm in controls (P = .604). Average subfoveal choroidal thickness was 394.15 +/- 71.03 MUm in amblyopic eyes, 356.07 +/- 79.93 MUm in fellow eyes, and 319.44 +/- 87.29 MUm in controls (P = .000). The choroidal thickness of the subfoveal area and at 750-MUm intervals temporal and nasal to the fovea was significantly thicker in amblyopic eyes than in controls (P < .05). The choroidal thickness was significantly thicker in amblyopic eyes than in fellow eyes only at 750 MUm nasal to the fovea. Type and depth of amblyopia did not differ significantly between foveal or parafoveal choroidal thickness (P > .05). There was a significant negative correlation between the nasal peripapillary choroidal thickness and the axial length in the amblyopic eyes (r = -0.37, P = .022). The choroidal thickness in the peripapillary area was not significantly different in the three groups (P > .05). CONCLUSIONS: This study demonstrated that choroidal thickness can be measured by spectral-domain OCT in children with amblyopia. Subfoveal choroidal thickness in amblyopic eyes was significantly thicker than in control eyes. The amblyopic process may involve the choroid, but not the macula. However, further evaluation is needed. PMID- 26225385 TI - [In Process Citation]. PMID- 26225386 TI - [In Process Citation]. PMID- 26225387 TI - [In Process Citation]. PMID- 26225388 TI - Developing an integrated training pathway for clinical academics: notes from the first binational summit meeting. PMID- 26225389 TI - Medicine in small doses. PMID- 26225390 TI - Response. PMID- 26225391 TI - Recurrent pyogenic cholangitis. PMID- 26225392 TI - Spontaneous aorto-left renal vein fistula: a rare complication of abdominal aortic aneurysm. PMID- 26225393 TI - Author response. PMID- 26225394 TI - Author response. PMID- 26225415 TI - Ordered Fe(II)Ti(IV)O3 Mixed Monolayer Oxide on Rutile TiO2(011). AB - Oxide monolayers supported or intermixed with an oxide support are potential nanocatalysts whose properties are determined by the interplay with the support. For fundamental studies of monolayer oxides on metal oxide supports, well-defined systems are needed, but so far, the synthesis of monolayer oxides with long-range order on single-crystal oxide surfaces is rare. Here, we show by a combination of scanning tunneling microscopy, photoemission spectroscopy, and density functional theory (DFT)-based computational analysis that the rutile TiO2(011) surface supports the formation of an ordered mixed FeTiO3 monolayer. Deposition of iron in a slightly oxidizing atmosphere (10(-8) Torr O2) and annealing to 300 degrees C results in a well-ordered surface structure with Fe in a 2+ charge state and Ti in a 4+ charge states. Low-energy ion scattering suggests that the cation surface composition is close to half Fe and half Ti. This surface is stable in ultrahigh vacuum to annealing temperatures of 300 degrees C before the iron is reduced. DFT simulations confirm that a surface structure with coverage of 50% FeO units is stable and forms an ordered structure. Although distinct from known bulk phases of the iron-titanium oxide systems, the FeTiO3 monolayer exhibits some resemblance to the ilmenite structure, which may suggest that a variety of different mixed oxide phases (of systems that exist in a bulk ilmenite phase) may be synthesized in this way on the rutile TiO2(011) substrate. PMID- 26225416 TI - Comparison of Human and Bovine Insulin Amyloidogenesis under Uniform Shear. AB - A diverse range of proteins can assemble into amyloid fibrils, a process that generally results in a loss of function and an increase in toxicity. The occurrence and rate of conversion is strongly dependent on several factors including molecular structure and exposure to hydrodynamic forces. To investigate the origins of shear-induced enhancement in the rate of fibrillization, a stable rotating Couette flow was used to evaluate the kinetics of amyloid formation under uniform shear for two similar insulin species (human and bovine) that demonstrate unique fibrillization kinetics. The presence of shear-induced nuclei predicted by previous studies is supported by observations of a lag between the consumption of soluble insulin and the precipitation of amyloid aggregates. The apparent fibrillization rate generally increases with shear. However, a two parameter kinetic model revealed that the nucleation rate has a maximum value at intermediate shear rates. The fibril elongation rate increases monotonically with shear and is similar for both insulin variants, suggesting that increased elongation rates are related to mixing. Differences between human and bovine insulin kinetics under shear are attributable to the nucleation step. PMID- 26225417 TI - Maternal Infection Is a Risk Factor for Early Childhood Infection in Filariasis. AB - BACKGROUND: Global Program to Eliminate Lymphatic Filariasis (GPELF) launched by WHO aims to eliminate the disease by 2020. To achieve the goal annual mass drug administration (MDA) with diethylcarbamazine (DEC) plus albendazole (ABZ) has been introduced in all endemic countries. The current policy however excludes pregnant mothers and children below two years of age from MDA. Since pregnancy and early childhood are critical periods in determining the disease outcome in older age, the present study was undertaken to find out the influence of maternal filarial infection at the time of pregnancy on the susceptibility outcome of children born in a community after implementation of MDA for the first time. METHODOLOGY AND PRINCIPAL FINDINGS: The participants in this cohort consists of pregnant mothers and their subsequently born children living in eight adjacent villages endemic for filarial infections, in Khurda District, Odisha, India, where MDA has reduced microfilariae (Mf) rate from 12% to 0.34%. Infection status of mother and their children were assessed by detection of Mf as well as circulating filarial antigen (CFA) assay. The present study reveals a high rate of acquiring filarial infection by the children born to infected mother than uninfected mothers even though Mf rate has come down to < 1% after implementation of ten rounds of MDA. SIGNIFICANCE: To attain the target of eliminating lymphatic filariasis the current MDA programme should give emphasis on covering the women of child bearing age. Our study recommends incorporating supervised MDA to Adolescent Reproductive and Sexual Health Programme (ARSH) to make the adolescent girls free from infection by the time of pregnancy so as to achieve the goal. PMID- 26225418 TI - One-pot in situ redox synthesis of hexacyanoferrate/conductive polymer hybrids as lithium-ion battery cathodes. AB - An efficient and adaptable method is demonstrated for the synthesis of lithium hexacyanoferrate/conductive polymer hybrids for Li-ion battery cathodes. The hybrids were synthesized via a one-pot method, involving a redox-coupled reaction between pyrrole monomers and the Li3Fe(CN)6 precursor. The hybrids showed much better cyclability relative to reported Prussian Blue (PB) analogs. PMID- 26225419 TI - An Example-Based Multi-Atlas Approach to Automatic Labeling of White Matter Tracts. AB - We present an example-based multi-atlas approach for classifying white matter (WM) tracts into anatomic bundles. Our approach exploits expert-provided example data to automatically classify the WM tracts of a subject. Multiple atlases are constructed to model the example data from multiple subjects in order to reflect the individual variability of bundle shapes and trajectories over subjects. For each example subject, an atlas is maintained to allow the example data of a subject to be added or deleted flexibly. A voting scheme is proposed to facilitate the multi-atlas exploitation of example data. For conceptual simplicity, we adopt the same metrics in both example data construction and WM tract labeling. Due to the huge number of WM tracts in a subject, it is time consuming to label each WM tract individually. Thus, the WM tracts are grouped according to their shape similarity, and WM tracts within each group are labeled simultaneously. To further enhance the computational efficiency, we implemented our approach on the graphics processing unit (GPU). Through nested cross validation we demonstrated that our approach yielded high classification performance. The average sensitivities for bundles in the left and right hemispheres were 89.5% and 91.0%, respectively, and their average false discovery rates were 14.9% and 14.2%, respectively. PMID- 26225420 TI - Gene Expression Data from the Moon Jelly, Aurelia, Provide Insights into the Evolution of the Combinatorial Code Controlling Animal Sense Organ Development. AB - In Bilateria, Pax6, Six, Eya and Dach families of transcription factors underlie the development and evolution of morphologically and phyletically distinct eyes, including the compound eyes in Drosophila and the camera-type eyes in vertebrates, indicating that bilaterian eyes evolved under the strong influence of ancestral developmental gene regulation. However the conservation in eye developmental genetics deeper in the Eumetazoa, and the origin of the conserved gene regulatory apparatus controlling eye development remain unclear due to limited comparative developmental data from Cnidaria. Here we show in the eye bearing scyphozoan cnidarian Aurelia that the ectodermal photosensory domain of the developing medusa sensory structure known as the rhopalium expresses sine oculis (so)/six1/2 and eyes absent/eya, but not optix/six3/6 or pax (A&B). In addition, the so and eya co-expression domain encompasses the region of active cell proliferation, neurogenesis, and mechanoreceptor development in rhopalia. Consistent with the role of so and eya in rhopalial development, developmental transcriptome data across Aurelia life cycle stages show upregulation of so and eya, but not optix or pax (A&B), during medusa formation. Moreover, pax6 and dach are absent in the Aurelia genome, and thus are not required for eye development in Aurelia. Our data are consistent with so and eya, but not optix, pax or dach, having conserved functions in sensory structure specification across Eumetazoa. The lability of developmental components including Pax genes relative to so-eya is consistent with a model of sense organ development and evolution that involved the lineage specific modification of a combinatorial code that specifies animal sense organs. PMID- 26225421 TI - Cytokine Signature in Infective Endocarditis. AB - Infective endocarditis (IE) is a severe disease with high mortality rate. Cytokines participate in its pathogenesis and may contribute to early diagnosis improving the outcome. This study aimed to evaluate the cytokine profile in IE. Serum concentrations of interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12 and tumor necrosis factor (TNF)-alpha were measured by cytometric bead array (CBA) at diagnosis in 81 IE patients, and compared with 34 healthy subjects and 30 patients with non-IE infections, matched to the IE patients by age and gender. Mean age of the IE patients was 47+/-17 years (range, 15-80 years), and 40 (50%) were male. The IE patients had significantly higher serum concentrations of IL 1beta, IL-6, IL-8, IL-10 and TNF-alpha as compared to the healthy individuals. The median levels of IL-1beta, TNF-alpha and IL-12 were higher in the IE than in the non-IE infections group. TNF-alpha and IL-12 levels were higher in staphylococcal IE than in the non-staphylococcal IE subgroup. There was a higher proportion of both low IL-10 producers and high producers of IL-1beta, TNF-alpha and IL-12 in the staphylococcal IE than in the non-staphylococcal IE subgroup. This study reinforces a relationship between the expression of proinflammatory cytokines, especially IL-1beta, IL-12 and TNF-alpha, and the pathogenesis of IE. A lower production of IL-10 and impairment in cytokine network may reflect the severity of IE and may be useful for risk stratification. PMID- 26225422 TI - Is Tit-for-Tat the Answer? On the Conclusions Drawn from Axelrod's Tournaments. AB - Axelrod's celebrated Prisoner's Dilemma computer tournaments, published in the early 1980s, were designed to find effective ways of acting in everyday interactions with the strategic properties of the iterated Prisoner's Dilemma game. The winner of both tournaments was tit-for-tat, a program that cooperates on the first round and then, on every subsequent round, copies the co-player's choice from the previous round. This has been interpreted as evidence that tit for-tat is an effective general-purpose strategy. By re-analyzing data from the first tournament and some more recent data, we provide new results suggesting that the efficacy of tit-for-tat is contingent on the design of the tournament, the criterion used to determine success, and the particular values chosen for the Prisoner's Dilemma payoff matrix. We argue that this places in doubt the generality of the results and the policy implications drawn from them. PMID- 26225423 TI - Virtual Screening of Peptide and Peptidomimetic Fragments Targeted to Inhibit Bacterial Dithiol Oxidase DsbA. AB - Antibacterial drugs with novel scaffolds and new mechanisms of action are desperately needed to address the growing problem of antibiotic resistance. The periplasmic oxidative folding system in Gram-negative bacteria represents a possible target for anti-virulence antibacterials. By targeting virulence rather than viability, development of resistance and side effects (through killing host native microbiota) might be minimized. Here, we undertook the design of peptidomimetic inhibitors targeting the interaction between the two key enzymes of oxidative folding, DsbA and DsbB, with the ultimate goal of preventing virulence factor assembly. Structures of DsbB--or peptides--complexed with DsbA revealed key interactions with the DsbA active site cysteine, and with a hydrophobic groove adjacent to the active site. The present work aimed to discover peptidomimetics that target the hydrophobic groove to generate non covalent DsbA inhibitors. The previously reported structure of a Proteus mirabilis DsbA active site cysteine mutant, in a non-covalent complex with the heptapeptide PWATCDS, was used as an in silico template for virtual screening of a peptidomimetic fragment library. The highest scoring fragment compound and nine derivatives were synthesized and evaluated for DsbA binding and inhibition. These experiments discovered peptidomimetic fragments with inhibitory activity at millimolar concentrations. Although only weakly potent relative to larger covalent peptide inhibitors that interact through the active site cysteine, these fragments offer new opportunities as templates to build non-covalent inhibitors. The results suggest that non-covalent peptidomimetics may need to interact with sites beyond the hydrophobic groove in order to produce potent DsbA inhibitors. PMID- 26225424 TI - Rapidly Evolving Genes Are Key Players in Host Specialization and Virulence of the Fungal Wheat Pathogen Zymoseptoria tritici (Mycosphaerella graminicola). AB - The speciation of pathogens can be driven by divergent host specialization. Specialization to a new host is possible via the acquisition of advantageous mutations fixed by positive selection. Comparative genome analyses of closely related species allows for the identification of such key substitutions via inference of genome-wide signatures of positive selection. We previously used a comparative genomics framework to identify genes that have evolved under positive selection during speciation of the prominent wheat pathogen Zymoseptoria tritici (synonym Mycosphaerella graminicola). In this study, we conducted functional analyses of four genes exhibiting strong signatures of positive selection in Z. tritici. We deleted the four genes in Z. tritici and confirm a virulence-related role of three of the four genes DeltaZt80707, DeltaZt89160 and DeltaZt103264. The two mutants DeltaZt80707 and DeltaZt103264 show a significant reduction in virulence during infection of wheat; the DeltaZt89160 mutant causes a hypervirulent phenotype in wheat. Mutant phenotypes of DeltaZt80707, DeltaZt89160 and DeltaZt103264 can be restored by insertion of the wild-type genes. However, the insertion of the Zt80707 and Zt89160 orthologs from Z. pseudotritici and Z. ardabiliae do not restore wild-type levels of virulence, suggesting that positively selected substitutions in Z. tritici may relate to divergent host specialization. Interestingly, the gene Zt80707 encodes also a secretion signal that targets the protein for cell secretion. This secretion signal is however only transcribed in Z. tritici, suggesting that Z. tritici-specific substitutions relate to a new function of the protein in the extracellular space of the wheat Z. tritici interaction. Together, the results presented here highlight that Zt80707, Zt103264 and Zt89160 represent key genes involved in virulence and host specific disease development of Z. tritici. Our findings illustrate that evolutionary predictions provide a powerful tool for the identification of novel traits crucial for host adaptation and pathogen evolution. PMID- 26225425 TI - All-Trans Retinoic Acid Induces TGF-beta2 in Intestinal Epithelial Cells via RhoA and p38alpha MAPK-Mediated Activation of the Transcription Factor ATF2. AB - OBJECTIVE: We have shown previously that preterm infants are at risk of necrotizing enterocolitis (NEC), an inflammatory bowel necrosis typically seen in infants born prior to 32 weeks' gestation, because of the developmental deficiency of transforming growth factor (TGF)-beta2 in the intestine. The present study was designed to investigate all-trans retinoic acid (atRA) as an inducer of TGF-beta2 in intestinal epithelial cells (IECs) and to elucidate the involved signaling mechanisms. METHODS: AtRA effects on intestinal epithelium were investigated using IEC6 cells. TGF-beta2 expression was measured using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and Western blots. Signaling pathways were investigated using Western blots, transiently-transfected/transduced cells, kinase arrays, chromatin immunoprecipitation, and selective small molecule inhibitors. RESULTS: AtRA treatment of IEC6 cells selectively increased TGF-beta2 mRNA and protein expression in a time- and dose-dependent fashion, and increased the activity of the TGF-beta2 promoter. AtRA effects were mediated via RhoA GTPase, Rho associated, coiled-coil-containing protein kinase 1 (ROCK1), p38alpha MAPK, and activating transcription factor (ATF)-2. AtRA increased phospho-ATF2 binding to the TGF-beta2 promoter and increased histone H2B acetylation in the TGF-beta2 nucleosome, which is typically associated with transcriptional activation. CONCLUSIONS: AtRA induces TGF-beta2 expression in IECs via RhoA- and p38alpha MAPK-mediated activation of the transcription factor ATF2. Further studies are needed to investigate the role of atRA as a protective/therapeutic agent in gut mucosal inflammation. PMID- 26225426 TI - Estrogen Receptor beta Agonists Differentially Affect the Growth of Human Melanoma Cell Lines. AB - BACKGROUND: Cutaneous melanoma is an aggressive malignancy; its incidence is increasing worldwide and its prognosis remains poor. Clinical observations indicate that estrogen receptor beta (ERbeta) is expressed in melanoma tissues and its expression decreases with tumor progression, suggesting its tumor suppressive function. These experiments were performed to investigate the effects of ERbeta activation on melanoma cell growth. METHODS AND RESULTS: Protein expression was analyzed by Western blot and immunofluorescence assays. Cell proliferation was assessed by counting the cells by hemocytometer. ERbeta transcriptional activity was evaluated by gene reporter assay. Global DNA methylation was analyzed by restriction enzyme assay and ERbeta isoforms were identified by qRT-PCR. We demonstrated that ERbeta is expressed in a panel of human melanoma cell lines (BLM, WM115, A375, WM1552). In BLM (NRAS-mutant) cells, ERbeta agonists significantly and specifically inhibited cell proliferation. ERbeta activation triggered its cytoplasmic-to-nuclear translocation and transcriptional activity. Moreover, the antiproliferative activity of ERbeta agonists was associated with an altered expression of G1-S transition-related proteins. In these cells, global DNA was found to be hypomethylated when compared to normal melanocytes; this DNA hypomethylation status was reverted by ERbeta activation. ERbeta agonists also decreased the proliferation of WM115 (BRAF V600D mutant) cells, while they failed to reduce the growth of A375 and WM1552 (BRAF V600E-mutant) cells. Finally, we could observe that ERbeta isoforms are expressed at different levels in the various cell lines. Specific oncogenic mutations or differential expression of receptor isoforms might be responsible for the different responses of cell lines to ERbeta agonists. CONCLUSIONS: Our results demonstrate that ERbeta is expressed in melanoma cell lines and that ERbeta agonists differentially regulate the proliferation of these cells. These data confirm the notion that melanoma is a heterogeneous tumor and that genetic profiling is mandatory for the development of effective personalized therapeutic approaches for melanoma patients. PMID- 26225429 TI - Seashells by the zinc shore: a meeting report of the International Society for Zinc Biology, Asilomar, CA 2014. PMID- 26225428 TI - Molecular Typing of Enterobacteriaceae from Pig Holdings in North-Western Germany Reveals Extended- Spectrum and AmpC beta-Lactamases Producing but no Carbapenem Resistant Ones. AB - The increase of extended- spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) in humans and in food-producing animals is of public health concern. The latter could contribute to spreading of these bacteria or their resistance genes to humans. Several studies have reported the isolation of third generation cephalosporin resistant bacteria in livestock animals. However, the number of samples and the methodology used differ considerably between studies limiting comparability and prevalence assessment. In the present study, a total of 564 manure and dust samples were collected from 47 pig farms in Northern Germany and analysed to determine the prevalence of ESBL-E. Molecular typing and characterization of resistance genes was performed for all ESBL-E isolates. ESBL E isolates were found in 55.3% of the farms. ESBL-Escherichia coli was found in 18.8% of the samples, ESBL-Klebsiella pneumoniae in 0.35%. The most prevalent ESBL genes among E. coli were CTX-M-1 like (68.9%), CTX-M-15 like (16%) and CTX-M 9 group (14.2%). In 20% of the latter two, also the OXA-1 like gene was found resulting in a combination of genes typical for isolates from humans. Genetic relation was found between isolates not only from the same, but also from different farms, with multilocus sequence type (ST) 10 being predominant among the E. coli isolates. In conclusion, we showed possible spread of ESBL-E between farms and the presence of resistance genes and STs previously shown to be associated with human isolates. Follow-up studies are required to monitor the extent and pathways of ESBL-E transmission between farms, animals and humans. PMID- 26225427 TI - Local Activity and Causal Connectivity in Children with Benign Epilepsy with Centrotemporal Spikes. AB - The aim of the current study was to localize the epileptic focus and characterize its causal relation with other brain regions, to understand the cognitive deficits in children with benign childhood epilepsy with centrotemporal spikes (BECTS). Resting-state functional magnetic resonance imaging (fMRI) was performed in 37 children with BECTS and 25 children matched for age, sex and educational achievement. We identified the potential epileptogenic zone (EZ) by comparing the amplitude of low frequency fluctuation (ALFF) of spontaneous blood oxygenation level dependent fMRI signals between the groups. Granger causality analysis was applied to explore the causal effect between EZ and the whole brain. Compared with controls, children with BECTS had significantly increased ALFF in the right postcentral gyrus and bilateral calcarine, and decreased ALFF in the left anterior cingulate cortex, bilateral putaman/caudate, and left cerebellum. ALFF values in the putaman/caudate were positively correlated with verbal IQ scores in patients. The ALFF values in cerebellum and performance IQ scores were negatively correlated in patients. These results suggest that ALFF disturbances in the putaman/caudate and cerebellum play an important role in BECTS cognitive dysfunction. Compared with controls, the patients showed increased driving effect from the EZ to the right medial frontal cortex and posterior cingulate cortex and decreased causal effects from the EZ to left inferior frontal gyrus. The causal effect of the left inferior frontal gyrus negatively correlated with disease duration, which suggests a relation between the epileptiform activity and language impairment. All together, these findings provide additional insight into the neurophysiological mechanisms of epilepitogenisis and cognitive dysfunction associated with BECTS. PMID- 26225430 TI - Impact of Outpatient Rehabilitation Medicare Reimbursement Caps on Utilization and Cost of Rehabilitation Care After Ischemic Stroke: Do Caps Contain Costs? AB - OBJECTIVE: To estimate the proportion of patients with ischemic stroke who fall within and above the total outpatient rehabilitation caps before and after the Balanced Budget Act of 1997 took effect; and to estimate the cost of poststroke outpatient rehabilitation cost and resource utilization in these patients before and after the implementation of the caps. DESIGN: Retrospective cohort study. SETTING: Medicare reimbursement system. PARTICIPANTS: Medicare beneficiaries from the state of South Carolina: the 1997 stroke cohort sample (N=2667) and the 2004 stroke cohort sample (N=2679). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Proportion of beneficiaries with bills within and above the cap before and after the cap was enacted, and total estimated 1-year rehabilitation Medicare payments before and after the cap. RESULTS: The proportion of patients with stroke exceeding the cap in 2004 after the Balanced Budget Act of 1997 was enacted was significantly lower (5.8%) than those in 1997 (9.5%) had there been a cap at that time (P=.004). However, when the proportion of individuals exceeding the cap among both the outpatient provider and facility files was examined, there was a greater proportion of patients with stroke in 2004 (64.6%) than in 1997 (31.9%) who exceeded the cap (P<.0001). The estimated average 1-year Medicare payments for rehabilitation services, when examining only the Part B outpatient provider bills, did not differ between the cohorts (P=.12), and in fact, decreased slightly from $1052 in 1997 to $833 in 2004. However, when examining rehabilitation costs using all available outpatient Medicare bills, the average estimated payments greatly increased (P<.0001) from $5691 in 1997 to $9606 in 2004. CONCLUSIONS: These findings suggest that billing practices may have changed after outpatient rehabilitation services caps were enacted by the Balanced Budget Act of 1997. Rehabilitation services billing may have shifted from Part B provider bills to being more frequently included in facility charges. PMID- 26225431 TI - Distinct Responses of Mycobacterium smegmatis to Exposure to Low and High Levels of Hydrogen Peroxide. AB - Hydrogen peroxide (H2O2) is a natural oxidant produced by aerobic organisms and gives rise to oxidative damage, including DNA mutations, protein inactivation and lipid damage. The genus Mycobacterium utilizes redox sensors and H2O2 scavenging enzymes for the detoxification of H2O2. To date, the precise response to oxidative stress has not been fully elucidated. Here, we compared the effects of different levels of H2O2 on transcription in M. smegmatis using RNA-sequencing. A 0.2 mM H2O2 treatment had little effect on the growth and viability of M. smegmatis whereas 7 mM H2O2 was lethal. Analysis of global transcription showed that 0.2 mM H2O2 induced relatively few changes in gene expression, whereas a large proportion of the mycobacterial genome was found to be differentially expressed after treatment with 7 mM H2O2. Genes differentially expressed following treatment with 0.2 mM H2O2 included those coding for proteins involved in glycolysis-gluconeogenesis and fatty acid metabolism pathways, and expression of most genes encoding ribosomal proteins was lower following treatment with 7 mM H2O2. Our analysis shows that M. smegmatis utilizes the sigma factor MSMEG_5214 in response to 0.2 mM H2O2, and the RpoE1 sigma factors MSMEG_0573 and MSMEG_0574 in response to 7 mM H2O2. In addition, different transcriptional regulators responded to different levels of H2O2: MSMEG_1919 was induced by 0.2 mM H2O2, while high-level induction of DevR occurred in response to 7 mM H2O2. We detected the induction of different detoxifying enzymes, including genes encoding KatG, AhpD, TrxB and Trx, at different levels of H2O2 and the detoxifying enzymes were expressed at different levels of H2O2. In conclusion, our study reveals the changes in transcription that are induced in response to different levels of H2O2 in M. smegmatis. PMID- 26225432 TI - Biochemical Characterization of the Split Class II Ribonucleotide Reductase from Pseudomonas aeruginosa. AB - The opportunistic pathogen Pseudomonas aeruginosa can grow under both aerobic and anaerobic conditions. Its flexibility with respect to oxygen load is reflected by the fact that its genome encodes all three existing classes of ribonucleotides reductase (RNR): the oxygen-dependent class I RNR, the oxygen-indifferent class II RNR, and the oxygen-sensitive class III RNR. The P. aeruginosa class II RNR is expressed as two separate polypeptides (NrdJa and NrdJb), a unique example of a split RNR enzyme in a free-living organism. A split class II RNR is also found in a few closely related gamma-Proteobacteria. We have characterized the P. aeruginosa class II RNR and show that both subunits are required for formation of a biologically functional enzyme that can sustain vitamin B12-dependent growth. Binding of the B12 coenzyme as well as substrate and allosteric effectors resides in the NrdJa subunit, whereas the NrdJb subunit mediates efficient reductive dithiol exchange during catalysis. A combination of activity assays and activity independent methods like surface plasmon resonance and gas phase electrophoretic macromolecule analysis suggests that the enzymatically active form of the enzyme is a (NrdJa-NrdJb)2 homodimer of heterodimers, and a combination of hydrogen deuterium exchange experiments and molecular modeling suggests a plausible region in NrdJa that interacts with NrdJb. Our detailed characterization of the split NrdJ from P. aeruginosa provides insight into the biochemical function of a unique enzyme known to have central roles in biofilm formation and anaerobic growth. PMID- 26225433 TI - Systemic Administration of Glibenclamide Fails to Achieve Therapeutic Levels in the Brain and Cerebrospinal Fluid of Rodents. AB - Activating mutations in the Kir6.2 (KCNJ11) subunit of the ATP-sensitive potassium channel cause neonatal diabetes (ND). Patients with severe mutations also suffer from neurological complications. Glibenclamide blocks the open KATP channels and is the treatment of choice for ND. However, although glibenclamide successfully restores normoglycaemia, it has a far more limited effect on the neurological problems. To assess the extent to which glibenclamide crosses the blood-brain barrier (BBB) in vivo, we quantified glibenclamide concentrations in plasma, cerebrospinal fluid (CSF), and brain tissue of rats, control mice, and mice expressing a human neonatal diabetes mutation (Kir6.2-V59M) selectively in neurones (nV59M mice). As only small sample volumes can be obtained from rodents, we developed a highly sensitive method of analysis, using liquid chromatography tandem mass spectrometry acquisition with pseudo-selected reaction monitoring, achieving a quantification limit of 10ng/ml (20nM) glibenclamide in a 30MUl sample. Glibenclamide was not detectable in the CSF or brain of rats after implantation with subcutaneous glibenclamide pellets, despite high plasma concentrations. Further, one hour after a suprapharmacological glibenclamide dose was administered directly into the lateral ventricle of the brain, the plasma concentration was twice that of the CSF. This suggests the drug is rapidly exported from the CSF. Elacridar, an inhibitor of P-glycoprotein and breast cancer resistance protein (major multidrug resistance transporters at the BBB), did not affect glibenclamide levels in CSF and brain tissue. We also identified a reduced sensitivity to volatile anaesthetics in nV59M mice and showed this was not reversed by systemic delivery of glibenclamide. Our results therefore suggest that little glibenclamide reaches the central nervous system when given systemically, that glibenclamide is rapidly removed across the BBB when given intracranioventricularly, and that any glibenclamide that does enter (and is below our detection limit) is insufficient to influence neuronal function as assessed by anaesthesia sensitivity. PMID- 26225434 TI - An integrated biodegradation and nano-oxidation used for the remediation of naphthalene from aqueous solution. AB - The remediation of toxic persistent organic contaminants in the environment has raised a need for effective cleanup methods. In this study, an integrated remediation technique based on biodegradation of naphthalene using Bacillus fusiformis and Fenton oxidation of their degraded metabolites using nanoscale zero-valent iron (nZVI). A 99.0% naphthalene was biodegraded by B. fusiformis in 96h, while only 59.4% chemical oxygen demand (COD) was removed, indicating that the degraded metabolites existed in solution. To further degrade the metabolites, nanoscale zero-valent iron (nZVI) was used as heterogeneous catalyst for Fenton like oxidation of the metabolites after biodegradation lasting 40h. Results showed that the total the removal COD increased from 36.4% to 91.6% at pH 3.0, 1.0gL(-1) nZVI, 10.0mML(-1) H2O2 and temperature of 35 degrees C. Scanning electron microscopy (SEM) showed the aggregation and corrosion of nZVI. X-ray diffraction (XRD) confirmed the existence of Fe(0) and the presence of iron oxide (Fe(II)) and iron oxohydroxide (Fe(III)). A possible degradation pathway was proposed since two naphthalene metabolites (1-Naphthalenol and 1,4 Naphthalenedione) were detected by GC-MS. PMID- 26225435 TI - Correction: Determinants of Health-Related Quality of Life in School-Aged Children: A General Population Study in the Netherlands. AB - [This corrects the article DOI: 10.1371/journal.pone.0125083.]. PMID- 26225436 TI - Drug gastrointestinal absorption in rat: Strain and gender differences. AB - Predictive animal models of intestinal drug absorption are essential tools in drug development to identify compounds with promising biopharmaceutical properties. In situ perfusion absorption studies are routinely used in the preclinical setting to screen drug candidates. The objective of this work is to explore the differences in magnitude and variability on intestinal absorption associated with rat strain and gender. Metoprolol and Verapamil absorption rate coefficients were determined using the in situ closed loop perfusion model in four strains of rats and in both genders. Strains used were Sprague-Dawley, Wistar-Han, Wistar-Unilever, Long-Evans and CD*IGS. In the case of Metoprolol only CD*IGS and Wistar Unilever showed differences between males and females. For Verapamil, Wistar Han and Sprague-Dawley strains do not show differences between male and female rats. That means that in these strains permeability data from male and female could be combined. In male rats, which are commonly used for permeability estimation, there were differences for Metoprolol permeability between Sprague-Dawley (with lower permeability values) and the other strains, while for Verapamil Sprague-Dawley and Wistar-Han showed the lower permeability values. In conclusion, the selection of rat's strain and gender for intestinal absorption experiments is a relevant element during study design and data from different strains may not be always comparable. PMID- 26225439 TI - Rapid-melt Dynamic Nuclear Polarization. AB - In recent years, Dynamic Nuclear Polarization (DNP) has re-emerged as a means to ameliorate the inherent problem of low sensitivity in nuclear magnetic resonance (NMR). Here, we present a novel approach to DNP enhanced liquid-state NMR based on rapid melting of a solid hyperpolarized sample followed by 'in situ' NMR detection. This method is applicable to small (10nl to 1MUl) sized samples in a microfluidic setup. The method combines generic DNP enhancement in the solid state with the high sensitivity of stripline (1)H NMR detection in the liquid state. Fast cycling facilitates options for signal averaging or 2D structural analysis. Preliminary tests show solid-state (1)H enhancement factors of up to 500 for H2O/D2O/d6-glycerol samples doped with TEMPOL radicals. Fast paramagnetic relaxation with nitroxide radicals, In nonpolar solvents such as toluene, we find proton enhancement factors up to 400 with negligible relaxation losses in the liquid state, using commercially available BDPA radicals. A total recycling delay (including sample freezing, DNP polarization and melting) of about 5s can be used. The present setup allows for a fast determination of the hyper-polarization as function of the microwave frequency and power. Even at the relatively low field of 3.4T, the method of rapid melting DNP can facilitate the detection of small quantities of molecules in the picomole regime. PMID- 26225441 TI - Heterocyclization Approach for Electrooxidative Coupling of Functional Primary Alkylamines with Aromatics. AB - A new approach for electrooxidative coupling of aromatic compounds and primary alkylamines bearing a functional group such as a hydroxyl group and an amino group was developed. The key to the success of the transformation is heterocyclization of functional primary alkylamines. Treatment of primary alkylamines bearing a functional group with nitriles or their equivalents gives the corresponding heterocycles. The electrochemical oxidation of aromatic substrates in the presence of the heterocycles followed by chemical reaction under nonoxidative conditions gave the desired coupling products. PMID- 26225440 TI - 3D pulse EPR imaging from sparse-view projections via constrained, total variation minimization. AB - Tumors and tumor portions with low oxygen concentrations (pO2) have been shown to be resistant to radiation therapy. As such, radiation therapy efficacy may be enhanced if delivered radiation dose is tailored based on the spatial distribution of pO2 within the tumor. A technique for accurate imaging of tumor oxygenation is critically important to guide radiation treatment that accounts for the effects of local pO2. Electron paramagnetic resonance imaging (EPRI) has been considered one of the leading methods for quantitatively imaging pO2 within tumors in vivo. However, current EPRI techniques require relatively long imaging times. Reducing the number of projection scan considerably reduce the imaging time. Conventional image reconstruction algorithms, such as filtered back projection (FBP), may produce severe artifacts in images reconstructed from sparse-view projections. This can lower the utility of these reconstructed images. In this work, an optimization based image reconstruction algorithm using constrained, total variation (TV) minimization, subject to data consistency, is developed and evaluated. The algorithm was evaluated using simulated phantom, physical phantom and pre-clinical EPRI data. The TV algorithm is compared with FBP using subjective and objective metrics. The results demonstrate the merits of the proposed reconstruction algorithm. PMID- 26225442 TI - Effects of Government Supervision on Quality of Integrated Diabetes Care: A Cluster Randomized Controlled Trial. AB - OBJECTIVES: The quality of integrated diabetes care is important for reducing the burden of diabetes. Therefore, we have evaluated the effect of a supervision program on the quality of integrated diabetes care in the Netherlands in the 2011 2012 period. METHODS: In this cluster RCT, the supervision program was assigned to randomly selected care groups providing care to diabetes patients. The supervision program included announcements of inspections, site visits, and sending individualized reports. Indicators of effectiveness were derived from the structures, processes, and outcomes of care. These indicators were collected from patients' files, before and after the supervision program. Hierarchical linear and logistic regression models were used to analyze data from 356 patients of 10 intervention and 8 control care groups. RESULTS: Structures and processes of care did not improve more in the intervention groups than in the control care groups. Moreover, health outcomes did not improve more in the intervention groups than in the control care groups. Although structures of care improved over time in the total population of intervention and control care groups, there were no changes in process of care or health outcomes. CONCLUSIONS: In this cluster RCT, we could not demonstrate improvements in quality of integrated diabetes care resulting from the supervision program. Although structures of care did improve over time, other quality-improvement initiatives are necessary to substantially strengthen integrated care for diabetes patients. PMID- 26225444 TI - Reducing Time-dependent Bias in Estimates of the Attributable Cost of Health Care associated Methicillin-resistant Staphylococcus aureus Infections: A Comparison of Three Estimation Strategies. AB - BACKGROUND: Previous estimates of the excess costs due to health care-associated infection (HAI) have scarcely addressed the issue of time-dependent bias. OBJECTIVE: We examined time-dependent bias by estimating the health care costs attributable to an HAI due to methicillin-resistant Staphylococcus aureus (MRSA) using a unique dataset in the Department of Veterans Affairs (VA) that makes it possible to distinguish between costs that occurred before and after an HAI. In addition, we compare our results to those from 2 other estimation strategies. METHODS: Using a historical cohort study design to estimate the excess predischarge costs attributable to MRSA HAIs, we conducted 3 analyses: (1) conventional, in which costs for the entire inpatient stay were compared between patients with and without MRSA HAIs; (2) post-HAI, which included only costs that occurred after an infection; and (3) matched, in which costs for the entire inpatient stay were compared between patients with an MRSA HAI and subset of patients without an MRSA HAI who were matched based on the time to infection. RESULTS: In our post-HAI analysis, estimates of the increase in inpatient costs due to MRSA HAI were $12,559 (P<0.0001) and $24,015 (P<0.0001) for variable and total costs, respectively. The excess variable and total cost estimates were 33.7% and 31.5% higher, respectively, when using the conventional methods and 14.6% and 11.8% higher, respectively, when using matched methods. CONCLUSIONS: This is the first study to account for time-dependent bias in the estimation of incremental per-patient health care costs attributable to HAI using a unique dataset in the VA. We found that failure to account for this bias can lead to overestimation of these costs. Matching on the timing of infection can reduce this bias substantially. PMID- 26225445 TI - Development of a Hospital Outcome Measure Intended for Use With Electronic Health Records: 30-Day Risk-standardized Mortality After Acute Myocardial Infarction. AB - BACKGROUND: Electronic health records (EHRs) offer the opportunity to transform quality improvement by using clinical data for comparing hospital performance without the burden of chart abstraction. However, current performance measures using EHRs are lacking. METHODS: With support from the Centers for Medicare & Medicaid Services (CMS), we developed an outcome measure of hospital risk standardized 30-day mortality rates for patients with acute myocardial infarction for use with EHR data. As no appropriate source of EHR data are currently available, we merged clinical registry data from the Action Registry-Get With The Guidelines with claims data from CMS to develop the risk model (2009 data for development, 2010 data for validation). We selected candidate variables that could be feasibly extracted from current EHRs and do not require changes to standard clinical practice or data collection. We used logistic regression with stepwise selection and bootstrapping simulation for model development. RESULTS: The final risk model included 5 variables available on presentation: age, heart rate, systolic blood pressure, troponin ratio, and creatinine level. The area under the receiver operating characteristic curve was 0.78. Hospital risk standardized mortality rates ranged from 9.6% to 13.1%, with a median of 10.7%. The odds of mortality for a high-mortality hospital (+1 SD) were 1.37 times those for a low-mortality hospital (-1 SD). CONCLUSIONS: This measure represents the first outcome measure endorsed by the National Quality Forum for public reporting of hospital quality based on clinical data in the EHR. By being compatible with current clinical practice and existing EHR systems, this measure is a model for future quality improvement measures. PMID- 26225446 TI - The Quality of Diabetes Management Among Mexican Adults in California: Does Generational Status Matter? AB - BACKGROUND: Although there is increasing knowledge regarding the association between generational status on diabetes risk, less is known about the effects of generational status on diabetes management among Mexicans. OBJECTIVES: We test whether generational status is associated with variations in diabetes processes of care among Mexican adults to optimize disease management. RESEARCH DESIGN: Weighted multivariate logistic regression was used to test the association between generational status on the quality of diabetes care processes and health care utilization adjusting for socioeconomic/demographic factors. Four generational cohorts were constructed: first generation immigrant; second generation; generation 2.5; and third generation. SUBJECTS: We conducted analyses of 3072 self-identified foreign and US-born Mexican adults with diabetes who participated in the 2005, 2007, 2009, and 2011/2012 California Health Interview Surveys. MEASURES: Three diabetes process outcomes were measured, including receipt of at least 1 eye examination, 1 foot examination, or 1 hemoglobin A1C test (HbA1c) in the past year. One secondary prevention outcome was measured, receipt of an annual influenza vaccine. Finally, we measured whether an individual with diabetes received an annual doctor visit. RESULTS: A gradient of progressively decreased odds of receiving an eye examination and HbA1c test were observed and significant for most of the higher generations. Higher generations also had significantly decreased odds of receiving an annual flu vaccine. CONCLUSIONS: Data collection on generational granularity and a specific focus on mixed acculturation status can vitally inform health system improvements in diabetes care among Mexicans in the United States. PMID- 26225447 TI - Prevalence, Geographic Variation, and Trends in Hospital Services Relevant to the Care of Older Adults: Development of the Senior Care Services Scale and Examination of Measurement Properties. AB - BACKGROUND: The availability of hospital services for older adults nationwide is not well understood. OBJECTIVE: To present the development of the Senior Care Services Scale (SCSS) through: (1) identification of hospital services relevant to the care of older adults; (2) development of a taxonomy classifying these services; and (3) description of prevalence, geographic variation, and trends in service provision in US hospitals over time. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of US hospitals in 1999 and 2006 rounds of American Hospital Association Annual Survey of Hospitals (n=4998 and 4831 hospitals, respectively). Exploratory factor analysis was used to create the SCSS, and confirmatory factor analysis was used to examine services over time. The paper reports prevalence of services nationwide. RESULTS: The SCSS consisted of 2 service groups: (1) Inpatient Specialty Care (IP): geriatrics, palliative care, psychiatric geriatrics, pain management, social work, case management, rehabilitation, and hospice; and (2) Postacute Community Care (PA): skilled nursing, intermediate care, other long-term care, assisted living, retirement housing, adult day care, and home health services. Over time, hospitals offered more IP services and fewer PA services. The distribution of services did not mirror the distribution of where older adults reside in the United States. CONCLUSIONS: The development of the SCSS provides important information about senior care services before the passage of the Affordable Care Act. The apparent mismatch of hospital services and demographic trends suggests that many US hospitals may not provide a seamless continuum of care for an increasing population of older adults. PMID- 26225451 TI - Influence of Cardiac MR Imaging on DNA Double-Strand Breaks in Human Blood Lymphocytes. AB - PURPOSE: To evaluate the ability of magnetic resonance (MR) imaging to induce deoxyribonucleic acid (DNA) damage in patients who underwent cardiac MR imaging in daily routine by using gamma-H2AX immunofluorescence microscopy. MATERIALS AND METHODS: This study complies with the Declaration of Helsinki and was performed according to local ethics committee approval. Informed patient consent was obtained. Blood samples from 45 patients (13 women, 32 men; mean age, 50.3 years [age range, 20-89 years]) were obtained before and after contrast agent-enhanced cardiac MR imaging. MR imaging-induced double-strand breaks (DSBs) were quantified in isolated blood lymphocytes by using immunofluorescence microscopy after staining the phosphorylated histone variant gamma-H2AX. Twenty-nine patients were examined with a myocarditis protocol (group A), 10 patients with a stress-testing protocol (group B), and six patients with flow measurements and angiography (group C). Paired t test was performed to compare excess foci before and after MR imaging. RESULTS: The mean baseline DSB level before MR imaging and 5 minutes after MR imaging was, respectively, 0.116 DSB per cell +/- 0.019 (standard deviation) and 0.117 DSB per cell +/- 0.019 (P = .71). There was also no significant difference in DSBs in these subgroups (group A: DSB per cell before and after MR imaging, respectively, 0.114 and 0.114, P = .91; group B: DSB per cell before and after MR imaging, respectively, 0.123 and 0.124, P = .78; group C: DSB per cell before and after MR imaging, respectively, 0.114 and 0.115, P = .36). CONCLUSION: By using gamma-H2AX immunofluorescence microscopy, no DNA DSBs were detected after cardiac MR imaging. PMID- 26225452 TI - Oxidation of N,N-Disubstituted Hydroxylamines to Nitrones with Hypervalent Iodine Reagents. AB - Hypervalent iodine compounds are viable reagents for the oxidation of N,N disubstituted hydroxylamines to the corresponding nitrones, with IBX performing best. The procedure is very simple and user-friendly and affords the target compounds with high efficiency and regioselectivity, highlighting IBX as the reagent of choice for preparation of aldonitrones from nonsymmetric hydroxylamines. Evidence for a mechanism involving nitrogen to iodine coordination has been collected. PMID- 26225450 TI - AlphaSpace: Fragment-Centric Topographical Mapping To Target Protein-Protein Interaction Interfaces. AB - Inhibition of protein-protein interactions (PPIs) is emerging as a promising therapeutic strategy despite the difficulty in targeting such interfaces with drug-like small molecules. PPIs generally feature large and flat binding surfaces as compared to typical drug targets. These features pose a challenge for structural characterization of the surface using geometry-based pocket-detection methods. An attractive mapping strategy--that builds on the principles of fragment-based drug discovery (FBDD)--is to detect the fragment-centric modularity at the protein surface and then characterize the large PPI interface as a set of localized, fragment-targetable interaction regions. Here, we introduce AlphaSpace, a computational analysis tool designed for fragment-centric topographical mapping (FCTM) of PPI interfaces. Our approach uses the alpha sphere construct, a geometric feature of a protein's Voronoi diagram, to map out concave interaction space at the protein surface. We introduce two new features- alpha-atom and alpha-space--and the concept of the alpha-atom/alpha-space pair to rank pockets for fragment-targetability and to facilitate the evaluation of pocket/fragment complementarity. The resulting high-resolution interfacial map of targetable pocket space can be used to guide the rational design and optimization of small molecule or biomimetic PPI inhibitors. PMID- 26225453 TI - Endophytes as in vitro production platforms of high value plant secondary metabolites. AB - Many reports have been published on bioprospecting of endophytic fungi capable of producing high value bioactive molecules like, paclitaxel, vincristine, vinblastine, camptothecin and podophyllotoxin. However, commercial exploitation of endophytes for high value-low volume plant secondary metabolites remains elusive due to widely reported genomic instability of endophytes in the axenic culture. While most of the endophyte research focuses on screening endophytes for novel or existing high value biomolecules, very few reports seek to explore the possible mechanisms of production of host-plant associated or novel secondary metabolites in these organisms. With an overview of host-endophyte relationship and its possible impact on the secondary metabolite production potential of endophytes, the review highlights the evidence reported for and against the presence of host-independent biosynthetic machinery in endophytes. The review aims to address the question, why should and how can endophytes be exploited for large scale in vitro production of high value phytochemicals? In this regard, various bioprocess optimization strategies that have been applied to sustain and enhance the product yield from the endophytes have also been described in detail. Further, techniques like mixed fermentation/co-cultivation and use of epigenetic modifiers have also been discussed as potential strategies to activate cryptic gene clusters in endophytes, thereby aiding in novel metabolite discovery and overcoming the limitations associated with axenic culture of endophytes. PMID- 26225454 TI - The Sequence of Swallowing Events During the Chin-Down Posture. AB - PURPOSE: This study investigated the effect of the chin-down posture on the sequence of swallowing events in healthy adults. METHOD: Sixteen healthy participants performed 45 5-ml thin liquid swallows during videofluoroscopy: 5 neutral head position, 30 chin-down posture, and then 10 neutral head position. Eight swallowing events were measured: the time of hyoid burst, bolus head in the pharynx, bolus tail in the pharynx, laryngeal vestibule closure (LVC), upper esophageal sphincter (UES) opening, bolus head in the UES, bolus tail exiting the pharynx, and laryngeal vestibule opening (LVO). RESULTS: Our key finding is that LVC was one of the first 3 swallowing events in 69% of neutral swallows and in 78% of chin-down swallows (p = .006). Also, LVO occurred last in 14% of chin-down swallows but never occurred last in the preceding neutral swallows (p <= .001). Thus, in chin-down swallows, LVC occurred earlier and LVO occurred later. CONCLUSIONS: The chin-down posture may be beneficial for individuals with delayed onset of LVC and reduced duration of the LVC. Future studies are needed to examine this effect in individuals with dysphagia. PMID- 26225455 TI - Insect pathogens as biological control agents: Back to the future. AB - The development and use of entomopathogens as classical, conservation and augmentative biological control agents have included a number of successes and some setbacks in the past 1years. In this forum paper we present current information on development, use and future directions of insect-specific viruses, bacteria, fungi and nematodes as components of integrated pest management strategies for control of arthropod pests of crops, forests, urban habitats, and insects of medical and veterinary importance. Insect pathogenic viruses are a fruitful source of microbial control agents (MCAs), particularly for the control of lepidopteran pests. Most research is focused on the baculoviruses, important pathogens of some globally important pests for which control has become difficult due to either pesticide resistance or pressure to reduce pesticide residues. Baculoviruses are accepted as safe, readily mass produced, highly pathogenic and easily formulated and applied control agents. New baculovirus products are appearing in many countries and gaining an increased market share. However, the absence of a practical in vitro mass production system, generally higher production costs, limited post application persistence, slow rate of kill and high host specificity currently contribute to restricted use in pest control. Overcoming these limitations are key research areas for which progress could open up use of insect viruses to much larger markets. A small number of entomopathogenic bacteria have been commercially developed for control of insect pests. These include several Bacillus thuringiensis sub-species, Lysinibacillus (Bacillus) sphaericus, Paenibacillus spp. and Serratia entomophila. B. thuringiensis sub-species kurstaki is the most widely used for control of pest insects of crops and forests, and B. thuringiensis sub-species israelensis and L. sphaericus are the primary pathogens used for control of medically important pests including dipteran vectors. These pathogens combine the advantages of chemical pesticides and MCAs: they are fast acting, easy to produce at a relatively low cost, easy to formulate, have a long shelf life and allow delivery using conventional application equipment and systemics (i.e. in transgenic plants). Unlike broad spectrum chemical pesticides, B. thuringiensis toxins are selective and negative environmental impact is very limited. Of the several commercially produced MCAs, B. thuringiensis (Bt) has more than 50% of market share. Extensive research, particularly on the molecular mode of action of Bt toxins, has been conducted over the past two decades. The Bt genes used in insect resistant transgenic crops belong to the Cry and vegetative insecticidal protein families of toxins. Bt has been highly efficacious in pest management of corn and cotton, drastically reducing the amount of broad spectrum chemical insecticides used while being safe for consumers and non-target organisms. Despite successes, the adoption of Bt crops has not been without controversy. Although there is a lack of scientific evidence regarding their detrimental effects, this controversy has created the widespread perception in some quarters that Bt crops are dangerous for the environment. In addition to discovery of more efficacious isolates and toxins, an increase in the use of Bt products and transgenes will rely on innovations in formulation, better delivery systems and ultimately, wider public acceptance of transgenic plants expressing insect-specific Bt toxins. Fungi are ubiquitous natural entomopathogens that often cause epizootics in host insects and possess many desirable traits that favor their development as MCAs. Presently, commercialized microbial pesticides based on entomopathogenic fungi largely occupy niche markets. A variety of molecular tools and technologies have recently allowed reclassification of numerous species based on phylogeny, as well as matching anamorphs (asexual forms) and teleomorphs (sexual forms) of several entomopathogenic taxa in the Phylum Ascomycota. Although these fungi have been traditionally regarded exclusively as pathogens of arthropods, recent studies have demonstrated that they occupy a great diversity of ecological niches. Entomopathogenic fungi are now known to be plant endophytes, plant disease antagonists, rhizosphere colonizers, and plant growth promoters. These newly understood attributes provide possibilities to use fungi in multiple roles. In addition to arthropod pest control, some fungal species could simultaneously suppress plant pathogens and plant parasitic nematodes as well as promote plant growth. A greater understanding of fungal ecology is needed to define their roles in nature and evaluate their limitations in biological control. More efficient mass production, formulation and delivery systems must be devised to supply an ever increasing market. More testing under field conditions is required to identify effects of biotic and abiotic factors on efficacy and persistence. Lastly, greater attention must be paid to their use within integrated pest management programs; in particular, strategies that incorporate fungi in combination with arthropod predators and parasitoids need to be defined to ensure compatibility and maximize efficacy. Entomopathogenic nematodes (EPNs) in the genera Steinernema and Heterorhabditis are potent MCAs. Substantial progress in research and application of EPNs has been made in the past decade. The number of target pests shown to be susceptible to EPNs has continued to increase. Advancements in this regard primarily have been made in soil habitats where EPNs are shielded from environmental extremes, but progress has also been made in use of nematodes in above-ground habitats owing to the development of improved protective formulations. Progress has also resulted from advancements in nematode production technology using both in vivo and in vitro systems; novel application methods such as distribution of infected host cadavers; and nematode strain improvement via enhancement and stabilization of beneficial traits. Innovative research has also yielded insights into the fundamentals of EPN biology including major advances in genomics, nematode-bacterial symbiont interactions, ecological relationships, and foraging behavior. Additional research is needed to leverage these basic findings toward direct improvements in microbial control. PMID- 26225456 TI - Liquid chromatography, in combination with a quadrupole time-of-flight instrument, with sequential window acquisition of all theoretical fragment-ion spectra acquisition: validated quantification of 39 antidepressants in whole blood as part of a simultaneous screening and quantification procedure. AB - Sequential window acquisition of all theoretical fragment ion spectra (SWATH) is a data independent acquisition (DIA) method for very fast scanning quadrupole time-of-flight (QTOF) instruments. SWATH repeatedly cycles through 28 consecutive 20 Da precursor isolation windows detecting all precursor ions and fragments MS ALL like and yet fast enough to generate more than 10 data points over the chromatographic peak. It was already shown in previous publications that SWATH, despite its wide Q1 windows, allows the identification of different substances and that SWATH has a higher identification rate than data dependent acquisition approaches. The aim of this study was a proof of concept study whether these same data sets can also enable validated quantification according to international guidelines, exemplified for 39 antidepressants. The validation included recovery, matrix effects, process efficiency, ion suppression, and enhancement of coeluting ions, selectivity, accuracy, precision, and stability. The method using SWATH acquisition proved to be selective, sensitive, accurate, and precise enough for 33 out of the 39 antidepressants. The applicability of SWATH for screening and validated quantification in the same run was successfully tested with authentic whole blood samples containing different antidepressants and other drugs thus proving the QUAL/QUAN abilities of SWATH. In an additional systematic investigation, it could be shown that calibration curves injected a few days after or before the actual sample can be used for quantification with acceptable accuracy. PMID- 26225457 TI - A 30 MUm Coaxial Nanowire Photoconductor Enabling Orthogonal Carrier Collection. AB - We describe the preparation and properties of a coaxial, three-layer, gold-CdSe gold nanowire 30 MUm in length that functions as a monolithic photodetector. The gold (Au) electrode core of this sandwich structure is prepared using the lithographically patterned nanowire electrodeposition (LPNE) method on a glass surface. A CdSe shell of defined thickness, dCdSe, from 200 to 280 nm is then electrodeposited on this Au nanowire. Finally, a conformal gold layer is electrodeposited on top of the CdSe shell. The two concentric gold electrodes within this architecture measure the photoconductivity of the ultrathin CdSe absorbing layer in the direction orthogonal to the nanowire axis. This architecture enables accelerated response/recovery of the nanowire to light while simultaneously maximizing the photoconductive gain without relinquishing any of the photoresponsive area of a "bare" nanowire. Characterization by scanning electron microscopy (SEM) of focused ion beam (FIB) cross sections together with electron dispersive X-ray spectroscopy (EDS) reveal the distinct core-multishell nanostructure, layer thicknesses, and layer compositions. The position-dependent photoresponse along the axis of the nanowire, probed using a laser spot, shows that the Au nanoshell significantly enhances the photocurrent. The performance of Au-CdSe-Au core-multishell nanowire photodetectors depend sensitively on the thickness of CdSe nanoshell over the range of from 200 nm < dCdSe < 280 nm. The highest performance was obtained for the dCdSe = 250 nm this device, which showed a photoconductive gain of 2172, a responsivity of 209 A.W(-1), a response time of 17 MUs, and a recovery time of 96 MUs. PMID- 26225458 TI - Immune monitoring of immunosuppression withdrawal of liver transplant recipients. AB - Several studies have shown that some liver transplant recipients may tolerate immunosuppression withdrawal. Mechanisms and biomarkers of tolerance are not well known. METHODS: Twenty-four LT patients with immunosuppression side-effects underwent progressive immunosuppression withdrawal. Peripheral lymphocyte populations and secretion of cytokines were analyzed at baseline and during withdrawal until tolerance (n = 15) or rejection (n = 9), as well as 3 months after tolerance achievement or rejection resolution (as follow-up). Immunological markers were compared among groups. RESULTS: The percentages of CD3+CD4+ cells progressively decreased in both groups. CD3+CD8+ cells gradually increased in tolerant patients. B lymphocytes gradually decreased in tolerant and initially in non-tolerant patients, reverting at rejection. Regulatory T cells progressively increased until rejection in non-tolerants, decreasing to basal levels after renewing immunosuppression; no significant changes were found in tolerant patients. The percentages and absolute counts of natural killer cells significantly increased in both groups, being more evident in tolerant patients. The secretion of several cytokines was higher in non-tolerant patients when rejection was diagnosed. CONCLUSIONS: The greater increase of natural killer cells in tolerant patients suggests their potential role in the tolerance phenomenon. PMID- 26225459 TI - Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2 yl)pyrimidin-4-yl]benzonitrile). AB - Fragment screening of a thermostabilized mGlu5 receptor using a high concentration radioligand binding assay enabled the identification of moderate affinity, high ligand efficiency (LE) pyrimidine hit 5. Subsequent optimization using structure-based drug discovery methods led to the selection of 25, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu5 receptor complexed with 25 and another molecule in the series, 14, were determined at resolutions of 2.6 and 3.1 A, respectively. PMID- 26225460 TI - The stress protein TP53INP1 plays a tumor suppressive role by regulating metabolic homeostasis. AB - In the recent years, we have provided evidence that Tumor Protein 53-Induced Nuclear Protein 1 (TP53INP1) is a key stress protein with antioxidant-associated tumor suppressive function. The TP53INP1 gene, which is highly conserved in mammals, is over-expressed during stress responses including inflammation. This gene encodes two protein isoforms with nuclear or cytoplasmic subcellular localization depending on the context. TP53INP1 contributes to stress responses, thus preventing stress-induced dysfunctions leading to pathologies such as cancer. Two major mechanisms by which TP53INP1 functions have been unveiled. First, in the nucleus, TP53INP1 was shown to regulate the transcriptional activity of p53 and p73 by direct interaction, and to mediate the antioxidant activity of p53. Second, independently of p53, TP53INP1 contributes to autophagy and more particularly mitophagy through direct interaction with molecular actors of autophagy. TP53INP1 is thus required for the homeostasis of the mitochondrial compartment, and is therefore involved in the regulation of energetic metabolism. Finally, the antioxidant function of TP53INP1 stems from the control of mitochondrial reactive oxygen species production. In conclusion, TP53INP1 is a multifaceted protein endowed with multiple functions, including metabolic regulation, as is its main functional partner p53. PMID- 26225462 TI - Spatially-resolved analyses of aerodynamic fallout from a uranium-fueled nuclear test. AB - Five silicate fallout glass spherules produced in a uranium-fueled, near-surface nuclear test were characterized by secondary ion mass spectrometry, electron probe microanalysis, autoradiography, scanning electron microscopy, and energy dispersive x-ray spectroscopy. Several samples display compositional heterogeneity suggestive of incomplete mixing between major elements and natural U ((238)U/(235)U = 0.00725) and enriched U. Samples exhibit extreme spatial heterogeneity in U isotopic composition with 0.02 < (235)U/(238)U < 11.84 among all five spherules and 0.02 < (235)U/(238)U < 7.41 within a single spherule. In two spherules, the (235)U/(238)U ratio is correlated with changes in major element composition, suggesting the agglomeration of chemically and isotopically distinct molten precursors. Two samples are nearly homogenous with respect to major element and uranium isotopic composition, suggesting extensive mixing possibly due to experiencing higher temperatures or residing longer in the fireball. Linear correlations between (234)U/(238)U, (235)U/(238)U, and (236)U/(238)U ratios are consistent with a two-component mixing model, which is used to illustrate the extent of mixing between natural and enriched U end members. PMID- 26225461 TI - The PCR detection and phylogenetic characterization of Babesia microti in questing ticks in Mongolia. AB - Babesia microti is a tick-transmitted zoonotic hemoprotozoan parasite. In the present study, we investigated B. microti infection in questing ticks in Mongolia. A total of 219 questing ticks were collected from three different Mongolian provinces (Bayan-Olgii, Khovsgol, and Selenge). Of these, 63 from Selenge were identified as Ixodes persulcatus, while the remaining 156 (from all three provinces) were identified as Dermacentor nuttalli. When the tick DNA samples were screened using a B. microti-specific nested PCR, 19 (30.2%) of the 63 I. persulcatus ticks were found to be B. microti-positive. The parasite was not detected in D. nuttalli. Subsequently, the 18S rRNA, cox1, and tufA sequences of B. microti were amplified, sequenced, and subjected to phylogenetic analyses. Sequencing analyses showed that the Mongolian 18S rRNA, cox1, and tufA sequences were 99.6-100%, 96.7-97.2%, and 94.7-95.3% homologous, respectively, with B. microti R1 strain US-type sequences from humans. In the phylogenetic analyses, the Mongolian cox1 and tufA sequences were found to be separate lineages, which formed sister-clades to the R1 strain sequences, while all of the Mongolian B. microti 18S rRNA sequences were clustered within US-type clade containing several other sequences of human origin. In conclusion, in addition to reporting the presence of B. microti for the first time in questing ticks in Mongolia, the present study found that Mongolian I. persulcatus ticks were infected with US type B. microti. These findings warrant large-scale studies to detect and characterize B. microti in ticks, small mammals, and humans. Such studies should provide us with a better understanding of zoonotic Babesia epidemiology in Mongolia. PMID- 26225463 TI - Parent HPV vaccine perspectives and the likelihood of HPV vaccination of adolescent males. AB - In 2013, approximately one-third of US adolescent males age 13-17 y had received >=1 doses of HPV vaccines and only 14% had received >=3 doses. This study used a nationally representative, online survey to explore experiences and attitudes related to HPV vaccination among parents with adolescent sons. Analyses compared the perspective of parents who do not intend to initiate HPV vaccine for >=1 adolescent son to that of parents who are likely to initiate or continue HPV vaccination. Of 809 parents of sons age 11-17 years, half were classified as Unlikely to Initiate HPV vaccination and 39% as Likely to Vaccinate. A higher proportion of the Likely to Vaccinate group felt their son's doctor was knowledgeable about HPV vaccine, did a good job explaining its purpose, and spent more time discussing HPV vaccine; in contrast, over half of the Unlikely to Initiate group had never discussed HPV vaccine with their child's doctor. The majority of parents in both groups showed favorable attitudes to adolescent vaccination in general, with lower levels of support for HPV vaccine-specific statements. Physician-parent communication around HPV vaccine for adolescent males should build on positive attitude toward vaccines in general, while addressing parents' HPV vaccine-specific concerns. PMID- 26225464 TI - The role of interpersonal processes in shaping inflammatory responses to social evaluative threat. AB - In response to social-evaluative threat induced in the laboratory, lower (compared to higher) subjective social class of a participant predicts greater increases in the inflammatory cytokine interleukin-6 (IL-6). In spite of the interpersonal nature of social-evaluation, little work has explored whether characteristics of the evaluator shape physiological responses in this context. In the current study, in a sample of 190 college students (male=66), we explored whether one's subjective social class interacts with the perceived social class of an evaluator to predict changes in Oral Mucosal Transudate (OMT) IL-6 in response to the Trier Social Stress Test (TSST). Participants were randomly assigned to be the speaker or the evaluator. Extending past work, we found that while speakers low in subjective social class consistently respond with strong increases in IL-6 regardless of their perception of their evaluator's social class, speakers high in subjective social class responded with greater increases in IL-6 when their evaluator was perceived as high social class compared to when they were perceived as low social class. This finding highlights the importance of perceptions of the evaluator in informing inflammatory responses to a social evaluative task. PMID- 26225465 TI - Juvenile onset depression alters cardiac autonomic balance in response to psychological and physical challenges. AB - Cardiac autonomic balance (CAB) indexes the ratio of parasympathetic to sympathetic activation (Berntson, Norman, Hawkley, & Cacioppo, 2008), and is believed to reflect overall autonomic flexibility in the face of environmental challenges. However, CAB has not been examined in depression. We examined changes in CAB and other physiological variables in 179 youth with a history of juvenile onset depression (JOD) and 161 healthy controls, in response to two psychological (unsolvable puzzle, sad film) and two physical (handgrip, and forehead cold pressor) challenges. In repeated measures analyses, controls showed expected reductions in CAB for both the handgrip and unsolvable puzzle, reflecting a shift to sympathetic relative to parasympathetic activation. By contrast, JOD youth showed increased CAB from baseline for both tasks (p's<.05). No effects were found for the forehead cold pressor or sad film tasks, suggesting that CAB differences may arise under conditions requiring greater attentional control or sustained effort. PMID- 26225467 TI - Thermosensation and the TRPV channel in Rhodnius prolixus. AB - The thermal sense of triatomine bugs, vectors of Chagas disease, is unique among insects. Not only do these bugs exhibit the highest sensitivity to heat known in any animal up to date, but they can also perceive the infrared radiation emitted by the body of their warm-blooded hosts. The sensory basis of this capacity has just started to be unravelled. To shed additional light on our understanding of thermosensation, we initiated an analysis of the genetic basis of the thermal sense in Rhodnius prolixus. We tested the hypothesis that a TRPV (transient receptor potential vanilloid) channel receptor is involved in the evaluation of heat in this species. Two different approaches were adopted. Initially, we analysed the expression of a TRPV candidate for this function, i.e., RproIav, in different tissues. Subsequently, we tested the effects of capsaicin and capsazepine, two molecules known to interact with mammal TRPV1, using three different behavioural protocols for evaluating thermal responses: (1) proboscis extension response (PER), (2) thermopreference in a temperature gradient and (3) spatial learning in an operant conditioning context. Bioinformatic analyses confirmed that the characteristic features typical of the TRPV channel subfamily are found in the RproIav protein sequence. Molecular analysis showed that RproIav is expressed in R. prolixus, not only in the antennae, but also in other body structures bearing sensory organs. Behavioural experiments consistently revealed that capsaicin treated insects are less responsive to heat stimuli and prefer lower temperatures than non-treated insects, and that they fail to orient in space. Conversely, capsazepine induces the opposite behaviours. The latter data suggest that triatomine thermoreception is based on the activation of a TRP channel, with a similar mechanism to that described for mammal TRPV1. The expression of RproIav in diverse sensory structures suggests that this receptor channel is potentially involved in bug thermoreception. This constitutes solid evidence that thermosensation could be based on the activation of TRP receptors that are expressed in different tissues in R. prolixus. Whether RproIav channel is a potential target for the compounds tested and whether it mediates the observed effects on behaviour still deserves to be confirmed by further research. PMID- 26225468 TI - TiO2, SiO2, and Al2O3 coated nanopores and nanotubes produced by ALD in etched ion-track membranes for transport measurements. AB - Low-temperature atomic layer deposition (ALD) of TiO2, SiO2, and Al2O3 was applied to modify the surface and to tailor the diameter of nanochannels in etched ion-track polycarbonate membranes. The homogeneity, conformity, and composition of the coating inside the nanochannels are investigated for different channel diameters (18-55 nm) and film thicknesses (5-22 nm). Small angle x-ray scattering before and after ALD demonstrates conformal coating along the full channel length. X-ray photoelectron spectroscopy and energy dispersive x-ray spectroscopy provide evidence of nearly stoichiometric composition of the different coatings. By wet-chemical methods, the ALD-deposited film is released from the supporting polymer templates providing 30 MUm long self-supporting nanotubes with walls as thin as 5 nm. Electrolytic ion-conductivity measurements provide proof-of-concept that combining ALD coating with ion-track nanotechnology offers promising perspectives for single-pore applications by controlled shrinking of an oversized pore to a preferred smaller diameter and fine-tuning of the chemical and physical nature of the inner channel surface. PMID- 26225466 TI - Metal Stabilization of Collagen and de Novo Designed Mimetic Peptides. AB - We explore the design of metal binding sites to modulate triple-helix stability of collagen and collagen-mimetic peptides. Globular proteins commonly utilize metals to connect tertiary structural elements that are well separated in sequence, constraining structure and enhancing stability. It is more challenging to engineer structural metals into fibrous protein scaffolds, which lack the extensive tertiary contacts seen in globular proteins. In the collagen triple helix, the structural adjacency of the carboxy-termini of the three chains makes this region an attractive target for introducing metal binding sites. We engineered His3 sites based on structural modeling constraints into a series of designed homotrimeric and heterotrimeric peptides, assessing the capacity of metal binding to improve stability and in the case of heterotrimers, affect specificity of assembly. Notable enhancements in stability for both homo- and heteromeric systems were observed upon addition of zinc(II) and several other metal ions only when all three histidine ligands were present. Metal binding affinities were consistent with the expected Irving-Williams series for imidazole. Unlike other metals tested, copper(II) also bound to peptides lacking histidine ligands. Acetylation of the peptide N-termini prevented copper binding, indicating proline backbone amide metal-coordination at this site. Copper similarly stabilized animal extracted Type I collagen in a metal-specific fashion, highlighting the potential importance of metal homeostasis within the extracellular matrix. PMID- 26225469 TI - Experimental and numerical study of a dual configuration for a flapping tidal current generator. AB - In this study, we conduct experimental and consecutive numerical analyses of a flapping tidal current generator with a mirror-type dual configuration with front swing and rear-swing flappers. An experimental analysis of a small-scale prototype is conducted in a towing tank, and a numerical analysis is conducted by means of two-dimensional computational fluid dynamics simulations with an in house code. An experimental study with a controller to determine the target arm angle shows that the resultant arm angle is dependent on the input arm angle, the frequency, and the applied load, while a high pitch is obtained simply with a high input arm angle. Through a parametric analysis conducted while varying these factors, a high applied load and a high input arm angle were found to be advantageous. Moreover, the optimal reduced frequency was found to be 0.125 in terms of the power extraction. In consecutive numerical investigations with the kinematics selected from the experiments, it was found that a rear-swing flapper contributes to the total amount of power more than a front-swing flapper with a distance of two times the chord length and with a 90 degrees phase difference between the two. The high contribution stems from the high power generated by the rear-swing flapper, which mimics the tail fin movement of a dolphin along a flow, compared to a plunge system or a front-swing system, which mimics the tail fin movement of a dolphin against a flow. It is also due to the fact that the shed vorticities of the front-swing flapper slightly affect negatively or even positively the power performance of the rear-swing system at a given distance and phase angle. PMID- 26225470 TI - Synthesis of novel lanthanide acylpyrazolonato ligands with long aliphatic chains and immobilization of the Tb complex on the surface of silica pre-modified via hydrophobic interactions. AB - Five new complexes Ln(Q(C17))3(H2O)(Solv) (Ln = Y, Solv = H2O, Ln = Tb, Dy, Sm or Eu, Solv = EtOH) were synthesized with the acylpyrazolonato ligand Q(C17) bearing a long aliphatic C17H35 chain in the acyl moiety, and the crystal structure of Y(Q(C17))3(H2O)2 shows the three aliphatic chains from the coordinated ligands positioned in the same direction, affording plane layers built by Y(Q(C17))3(H2O)2 molecules connected through H-bonding interactions. The layers are stitched to each other like in "hook & loop" tapes. Luminescence of complexes was determined and the complex Tb(Q(C17))3(H2O)(EtOH) was immobilized on the surface of silica preprocessed using a C17H35CONH(CH2)3Si(OEt)3 reagent via hydrophobic interactions of long aliphatic chains. Luminescent properties and micromorphology of the obtained hybrid particles and hybrid films were investigated. Intensive green emission of the complex retains after grafting onto the silica surface. Inclusion of the complex on the surface of silica materials occurs as separate molecules, after the disruption of the H-bonding network present in the crystalline phase of the pure terbium sample. PMID- 26225471 TI - The interplay between GRP78 expression and Akt activation in human colon cancer cells under celecoxib treatment. AB - It has been reported previously that celecoxib shows antitumor effects in many types of cancers. Here, we detected its effects on DLD-1 and SW480 (two human colon cancer cell lines) and investigated the dynamic relationship between the 78 kDa glucose-regulatory protein (GRP78) and the phosphoinositide 3-kinase (PI3K)/Akt pathway. Gene expression was detected by real-time PCR and western blot analysis; the cytotoxicity was determined by the MTT assay and flow cytometry. First, the results showed that celecoxib induced cytotoxicity in a dose-dependent and time-dependent manner. Furthermore, we found the celecoxib triggered unfolded protein response and the bidirectional regulation of Akt activation in both cell lines. Inhibiting the Akt activation by the PI3K inhibitor LY294002 markedly enhanced GRP78 expression. Besides, silencing the GRP78 expression regulated Akt activation in a time-dependent manner and increased the induction of the C/EBP homologous protein (CHOP) as well as considerably promoted celecoxib-induced apoptosis. In conclusion, these findings provide evidence that under the celecoxib treatment, GRP78 plays a protective role by modulating Akt activation and abrogating CHOP expression. However, Akt activation can provide a feedback loop to inhibit GRP78 expression. These studies can lead to novel therapeutic strategies for human colon cancer. PMID- 26225472 TI - Structure, Phase Transitions, and Isotope Effects in [(CH3)4N]2PuCl6. AB - The single-crystal X-ray diffraction structure of [(CH3)4N]2PuCl6 is presented for the first time, resolving long-standing confusion and speculation regarding the structure of this compound in the literature. A temperature-dependent study of this compound shows that the structure of [(CH3)4N]2PuCl6 undergoes no fewer than two phase transitions between 100 and 360 K. The phase of [(CH3)4N]2PuCl6 at room temperature is Fd3c a = 26.012(3) A. At 360 K, the structure is in space group Fm3m, with a = 13.088(1) A. The plutonium octahedra and tetramethylammonium cations undergo a rotative displacement, and the degree of rotation varies with temperature, giving rise to the phase transition from Fm3m to Fd3c as the crystal is cooled. Synthesis and structural studies of the deuterated salt [(CD3)4N]2PuCl6 suggest that there is an isotopic effect associated with this phase transition, as revealed by a changing transition temperature in the deuterated versus protonated compound, indicating that the donor-acceptor interactions between the tetramethylammonium cations and the hexachloroplutonate anions are driving the phase transformation. PMID- 26225473 TI - First mitochondrial genome for the red crab (Charybdis feriata) with implication of phylogenomics and population genetics. AB - In this study, we first described the complete mitochondrial genome for the red crab (Charybdis feriata), elucidated its phylogenetic relationship among 20 species within Decapoda, and estimated the population genetic diversity. The mitochondrial genome was 15,660 bp in size and encoded 13 protein-coding genes, 22 transfer RNA (tRNA) genes, and two ribosomal RNA genes. The gene arrangement of the mitochondrial genome was the same as that of its sister species, C. japonica. Phylogenomic analysis suggested that genus Charybdis should be classified into subfamily Portuninae but not into subfamily Thalamitinae. Moreover, a total of 33 haplotypes of complete cytochrome c oxidase subunit I gene were defined in 70 individuals of C. feriata derived from three localities. Haplotype diversity and nucleotide diversity values among three localities indicated a high level of genetic diversity in C. feriata. AMOVA analysis suggested a low level of genetic differentiation among the three localities (FST = 0.0023, P > 0.05). Neutrality tests and mismatch analysis revealed that C. feriata might have undergone a population expansion event that possibly occurred in the last 61,498 to 43,814 years. This study should be helpful to better understand the evolutionary status, and population genetic diversity of C. feriata and related species. PMID- 26225474 TI - IL-35 Is Involved in the Pathogenesis of Guillain-Barre Syndrome Through Its Influence on the Function of CD4+ T Cells. AB - CD4+ T cells and many cytokines play critical roles in the pathogenesis of Guillain-Barre Syndrome (GBS), an immune-mediated inflammatory disease. However, the role of IL-35, a novel member of the IL-12 cytokine family, in this kind of disease has not yet been elucidated. In this study, we investigated the functional changes of CD4+ T cells from GBS patients with IL-35 treatment in vitro. This study involved 21 GBS patients and an equal number of healthy controls (HCs). The results indicated that the average concentration of IL-35 in the plasma of GBS patients was lower than that of healthy controls (HCs). Increased levels of STAT1, STAT3 and STAT4 proteins and T-bet, ROR gammat, IFN gamma and IL-17A mRNA were observed in CD4+ T cells from GBS patients. In contrast, the levels of STAT5 and STAT6 proteins and GATA3, Foxp3, IL-4 and TGF beta1 mRNAs were decreased in GBS patients in comparison with those of HCs. In addition, treatment of CD4+ T cells from GBS patients with IL-35 upregulated IL 35, STAT5 and STAT6 protein and T-bet, GATA3, Foxp3, IFN-gamma, IL-4, IL-17A and TGF-beta1 mRNA while inhibited levels of STAT3 and STAT4 protein and RORgammat and IL-17A mRNA. These results indicate that IL-35 might play a potential role in GBS pathogenesis. Further studies are required in order to evaluate its role in GBS. PMID- 26225475 TI - Prevalence of Disability and Disability Type Among Adults--United States, 2013. AB - Understanding the prevalence of disability is important for public health programs to be able to address the needs of persons with disabilities. Beginning in 2013, to measure disability prevalence by functional type, the Behavioral Risk Factor Surveillance System (BRFSS), added five questions to identify disability in vision, cognition, mobility, self-care, and independent living. CDC analyzed data from the 2013 BRFSS to assess overall prevalence of any disability, as well as specific types of disability among noninstitutionalized U.S. adults. Across all states, disabilities in mobility and cognition were the most frequently reported types. State-level prevalence of each disability type ranged from 2.7% to 8.1% (vision); 6.9% to 16.8% (cognition); 8.5% to 20.7% (mobility); 1.9% to 6.2% (self-care) and 4.2% to 10.8% (independent living). A higher prevalence of any disability was generally seen among adults living in states in the South and among women (24.4%) compared with men (19.8%). Prevalences of any disability and disability in mobility were higher among older age groups. These are the first data on functional disability types available in a state-based health survey. This information can help public health programs identify the prevalence of and demographic characteristics associated with different disability types among U.S. adults and better target appropriate interventions to reduce health disparities. PMID- 26225477 TI - Aviation-Related Wildland Firefighter Fatalities--United States, 2000-2013. AB - Airplanes and helicopters are integral to the management and suppression of wildfires, often operating in high-risk, low-altitude environments. To update data on aviation-related wildland firefighting fatalities, identify risk factors, and make recommendations for improved safety, CDC's National Institute for Occupational Safety and Health (NIOSH) analyzed reports from multiple data sources for the period 2000-2013. Among 298 wildland firefighter fatalities identified during 2000-2013, 78 (26.2%) were aviation-related occupational fatalities that occurred during 41 separate events involving 42 aircraft. Aircraft crashes accounted for 38 events. Pilots, copilots, and flight engineers represented 53 (68%) of the aviation-related fatalities. The leading causes of fatal aircraft crashes were engine, structure, or component failure (24%); pilot loss of control (24%); failure to maintain clearance from terrain, water, or objects (20%); and hazardous weather (15%). To reduce fatalities from aviation related wildland firefighting activities, stringent safety guidelines need to be followed during all phases of firefighting, including training exercises. Crew resource management techniques, which use all available resources, information, equipment, and personnel to achieve safe and efficient flight operations, can be applied to firefighting operations. PMID- 26225476 TI - National, Regional, State, and Selected Local Area Vaccination Coverage Among Adolescents Aged 13-17 Years--United States, 2014. AB - Routine immunization is recommended for adolescents aged 11-12 years by the Advisory Committee on Immunization Practices (ACIP) for protection against diseases including pertussis, meningococcal disease, and human papillomavirus (HPV)-associated cancers. To assess vaccination coverage among adolescents, CDC analyzed data collected regarding 20,827 adolescents through the 2014 National Immunization Survey-Teen (NIS-Teen). From 2013 to 2014, coverage among adolescents aged 13-17 years increased for all routinely recommended vaccines: from 84.7% to 87.6% for >=1 tetanus-diphtheria-acellular pertussis (Tdap) vaccine dose, from 76.6% to 79.3% for >=1 meningococcal conjugate (MenACWY) vaccine dose, from 56.7% to 60.0% and from 33.6% to 41.7% for >=1 HPV vaccine dose among females and males, respectively.? Coverage differed by state and local area. Despite overall progress in vaccination coverage among adolescents, HPV vaccination coverage continues to lag behind Tdap and MenACWY coverage at state and national levels. Seven public health jurisdictions achieved significant increases in >=1- or >=3-dose HPV vaccination coverage among females in 2014, demonstrating that substantial improvement in HPV vaccination coverage is feasible. PMID- 26225478 TI - Current Cigarette Smoking Among Workers in Accommodation and Food Services- United States, 2011-2013. AB - Tobacco use is the leading cause of preventable disease and death in the United States. One of the Healthy People 2020 objectives calls for reducing the proportion of U.S. adults who smoke cigarettes to <=12% (objective TU-1.1). Despite progress in reducing smoking prevalence over the past several decades, nearly one in five U.S. adults, including millions of workers, still smoke cigarettes. During 2004-2010, nearly one fifth (19.6%) of U.S. working adults aged >=18 years smoked cigarettes, and of all the industry sectors, current smoking prevalence among the accommodation and food services sector workers (30%) was the highest. CDC analyzed National Health Interview Survey (NHIS) data for 2011-2013 to estimate current cigarette smoking prevalence among adults working in the accommodation and food services sector, and found that these workers had higher cigarette smoking prevalence (25.9%) than all other workers (17.3%). Among workers in accommodation and food services sector, the highest smoking prevalences were observed among males, non-Hispanic whites, those aged 25-44 years, those with a high school diploma or a General Educational Development (GED) certificate and no college education, those with an annual family income <$35,000, those with no health insurance, and those working in the food services and drinking places industry. These results indicate a need to better understand the reasons for higher smoking prevalence observed among accommodation and food services workers (e.g., workplace culture), so that appropriate intervention strategies can be developed and implemented. Evidence suggests that smoke-free worksites and workplace cessation programs, including comprehensive worksite smoke-free policies, health promotion, access to smoking cessation programs, and increasing the cost of tobacco products, can substantially reduce smoking among workers. PMID- 26225479 TI - Large Outbreak of Botulism Associated with a Church Potluck Meal--Ohio, 2015. AB - On April 21, 2015, the Fairfield Medical Center (FMC) and Fairfield Department of Health contacted the Ohio Department of Health (ODH) about a patient suspected of having botulism in Fairfield County, Ohio. Botulism is a severe, potentially fatal neuroparalytic illness.* A single case is a public health emergency, because it can signal an outbreak. Within 2 hours of health department notification, four more patients with similar clinical features arrived at FMC's emergency department. Later that afternoon, one patient died of respiratory failure shortly after arriving at the emergency department. All affected persons had eaten at the same widely attended church potluck meal on April 19. CDC's Strategic National Stockpile sent 50 doses of botulinum antitoxin to Ohio. FMC, the Fairfield Department of Health, ODH, and CDC rapidly responded to confirm the diagnosis, identify and treat additional patients, and determine the source. PMID- 26225480 TI - Multistate Outbreak of Human Salmonella Poona Infections Associated with Pet Turtle Exposure--United States, 2014. AB - In May 2014, a cluster of human Salmonella Poona infections was identified through PulseNet, the national molecular subtyping network for foodborne disease surveillance. Historically, this rare serotype has been identified in multiple Salmonella outbreaks associated with pet turtle exposure and has posed a particular risk to small children. Although the sale and distribution of small turtles (those with carapace [upper shell] lengths <4 inches [<10.2 cm]) is prohibited by federal law, they are still available for legal purchase online for "bona-fide" scientific, educational, or exhibition purposes, other than use as pets. In addition, small turtles are still available for illegal purchase through transient street vendors, at flea markets, and at fairs. PMID- 26225481 TI - Atypical Presentations of Hand, Foot, and Mouth Disease Caused by Coxsackievirus A6--Minnesota, 2014. AB - In June, 2014, the Minnesota Department of Health (MDH) was notified of a suspected varicella case in a child aged 2 years. The patient had a generalized rash with relative sparing of the trunk and was hospitalized overnight for treatment of dehydration. The child's mother, who was near the end of a pregnancy, also had a generalized rash, which included the perineal area. Identifying the cause of the rash was important to determine whether administration of varicella zoster immune globulin was indicated to prevent neonatal varicella. Enterovirus was detected in specimens from the woman and child by reverse transcriptase-polymerase chain reaction (RT-PCR) testing performed at MDH; partial genome sequencing by CDC showed that both patients were infected with coxsackievirus A6 (CVA6), one of the members of the genus Enterovirus that causes hand, foot, and mouth disease (HFMD). PMID- 26225482 TI - Development of reverse transcription recombinase polymerase amplification assay for avian influenza H5N1 HA gene detection. AB - The 2006 outbreaks of H5N1 avian influenza in Egypt interrupted poultry production and caused staggering economic damage. In addition, H5N1 avian influenza viruses represent a significant threat to public health. Therefore, the rapid detection of H5 viruses is very important in order to control the disease. In this study, a qualitative reverse transcription recombinase polymerase amplification (RT-RPA) assay for the detection of hemagglutinin gene of H5 subtype influenza viruses was developed. The results were compared to the real time reverse transcription polymerase chain reaction (RT-PCR). An in vitro transcribed RNA standard of 970 nucleotides of the hemagglutinin gene was developed and used to determine the assay sensitivity. The developed H5 RT-RPA assay was able to detect one RNA molecule within 7 min, while in real-time RT PCR, at least 90 min was required. H5 RT-RPA assay did not detect nucleic acid extracted from H5 negative samples or from other pathogens producing respiratory manifestation in poultry. The clinical performance of the H5 RT-RPA assay was tested in 30 samples collected between 2014 and 2015; the sensitivity of H5 RT RPA and real-time RT-PCR was 100%. In conclusion, H5 RT-RPA was faster than real time RT-PCR and easily operable in a portable device. Moreover, it had an equivalent sensitivity and specificity. PMID- 26225483 TI - Dendritic nanofibers of gold formed by the electron transfer at the interface between water and a highly hydrophobic ionic liquid. AB - Gold nanofibers have been found to be formed via a heterogeneous electron transfer reaction at the ionic liquid|water interface. The tips of the nanofibers show a dendritic structure and the dendrites are bundled to nanofibers except around the tips. The roles of the ionic liquid for the dendritic nanofiber formation have been discussed. PMID- 26225484 TI - Diagnostic and Therapeutic Challenges. PMID- 26225485 TI - PERIPHERAL AVASCULAR RETINA WITH DISK ANOMALY AND HIGH MYOPIA: A Novel Association in a Hereditary Isolated Ocular Disorder. AB - PURPOSE: To describe a family pedigree with a previously undescribed association of autosomal dominantly inherited ocular abnormalities. METHODS: Case series study performed on 15 family members. Examination included history taking, visual acuity, intraocular pressure, slit-lamp, gonioscopy, indirect ophthalmoscopy (10 members), fluorescein angiography (5 members), general examination and renal ultrasound (4 members), and hemoglobin electrophoresis for the proband and another member. RESULTS: Family pedigree revealed autosomal-dominant inheritance. Visual acuity ranged from 6/36 to no light perception. Examination revealed rubeosis in 7 eyes and atrophia bulbi in 11 eyes. Indirect ophthalmoscopy for 11 eyes revealed evidence of an ocular triad of peripheral avascular retina, disk anomaly (cavitary optic disk anomaly or disk dysplasia), and tessellated fundus of high myopia. The authors also observed new vessels elsewhere with or without extensive subretinal exudations in 6 eyes. All patients with any residual vision (up to perception of light) had nystagmus. Four affected members underwent general examination, renal ultrasound, and serum creatinine level (to exclude papillorenal syndrome), and all were normal. Hemoglobin electrophoresis (to exclude sickle cell retinopathy) revealed within normal values. CONCLUSION: To the authors' knowledge, the aforementioned ocular triad has not been previously described, in association, with an autosomal-dominant pattern of inheritance. PMID- 26225486 TI - Corrigendum: Differential gene retention as an evolutionary mechanism to generate biodiversity and adaptation in yeasts. PMID- 26225487 TI - Longitudinal Effect of CPAP on BP in Resistant and Nonresistant Hypertension in a Large Clinic-Based Cohort. AB - BACKGROUND: Clinic-based effectiveness studies of sleep-disordered breathing (SDB) treatment in reducing BP in resistant hypertension (RHTN) vs non-RHTN are sparse. We hypothesize that CPAP use in SDB reduces BP significantly in RHTN and non-RHTN in a large clinic-based cohort. METHODS: Electronic medical records were reviewed in patients with SDB and comorbid RHTN and non-RHTN for CPAP therapy initiation (baseline) and subsequent visits. We estimated generalizable BP changes from multivariable mixed-effects linear models for systolic BP (SBP), diastolic BP, and mean arterial pressure, adjusting for RHTN status, age, sex, race, BMI, cardiac history, and diabetes and repeated measure correlation. RESULTS: Of 894 patients, 130 (15%) had RHTN at baseline (age, 58 +/- 12 years; 52% men; BMI, 36 +/- 9 kg/m(2)). Patients with RHTN had significantly higher BP overall (P < .001), most notably for SBP (6.9 mm Hg; 95% CI, 3.84, 9.94). In the year following CPAP initiation, improvements in BP indexes did not generally differ based on RHTN status in which RHTN status was a fixed effect. However, there was a significant decrease in SBP (3.08 mm Hg; 95% CI, 1.79, 4.37), diastolic BP (2.28; 95% CI, 1.56, 3.00), and mean arterial pressure (2.54 mm Hg; 95% CI, 1.73, 3.36) in both groups. CONCLUSIONS: In this clinic-based effectiveness study involving patients closely followed for BP control, a significant reduction of BP measures (strongest for SBP) was observed in response to CPAP which was similar in RHTN and non-RHTN groups thus informing expected clinical CPAP treatment response. PMID- 26225488 TI - Biochemical and gene expression effects of 1-alkyl-3-methylimidazolium tetrafluoroborate on Vibrio qinghaiensis sp.-Q67. AB - Applications of 1-alkyl-3-methylimidazolium salts ([amim]X) in pharmaceuticals call for studies on the biological effects. Previously, [amim]Cl and [amim]Br caused time-dependent stimulatory effects on Vibrio qinghaiensis sp.-Q67 (Q67). Further studies are still needed to answer the question whether [amim]X with other anions have similar effects, and to explain such stimulatory effects. Here, effects of four [amim]BF4 with different alkyl side chains on Q67 were investigated. At the apical level, they inhibited luminescence at high concentrations and the toxicities decreased with time increasing from 0.25 to 12h. Meanwhile, they stimulated luminescence at low concentrations, and the stimulations increased over time. The maximum stimulations followed an order of [emim]BF4>[bmim]BF4>[hmim]BF4>[omim]BF4. Compared with [emim]BF4, imidazole caused lower stimulations, while NaBF4 caused significantly higher ones. Overview on effects of [amim]BF4, imidazole and NaBF4 indicated significant anionic contributions. At biochemical and molecular levels, favin mono-nucleotide (FMN) and nicotinamide adenine dinucleotide (NADH) increased over time, and expressions of luxA and luxB (encoding luciferase that catalyzes FMN:NADH reaction) in Q67 showed up-regulations, suggesting an overall enhancement of the bioactivities. Moreover, superoxide dismutase and catalase showed inductions with up-regulations on their encoding genes, indicating improved antioxidant responses. PMID- 26225489 TI - Copper Ion Elicits Defense Response in Arabidopsis thaliana by Activating Salicylate- and Ethylene-Dependent Signaling Pathways. PMID- 26225490 TI - Vaccines for Adults. PMID- 26225491 TI - Fluorescent chemosensor for pyridine based on N-doped carbon dots. AB - Fluorescent carbon dots (CDs) and its nitrogen doped (N-CDs) nanoparticles have been synthesized from lactose as precursor using a bottom-up hydrothermal methodology. The synthesized nanoparticles have been characterized by elemental analysis, FTIR, Raman, TEM, DLS, XPS, and steady-state and life-time fluorescence. The synthesized carbon nanoparticles, CDs and N-CDs, have a size at about 7.7+/-2.4 and 50+/-15nm, respectively, and quantum yields of 8% (CDs) and 11% (N-CDs). These techniques demonstrated the effectiveness of the synthesis procedure and the functionalization of the CDs surface with amine and amide groups in the presence of NH3 in aqueous media. The effect of excitation wavelength and pH on the luminescent properties was studied. Under the optimal conditions, the nitrogen doped nanoparticles can be used as pyridine sensor in aqueous media because they show an enhancement of its fluorescence with a good linear relationship. The analytical method is simple, reproducible and very sensitive for pyridine determination. PMID- 26225492 TI - Multi-laminated metal hydroxide nanocontainers for oral-specific delivery for bioavailability improvement and treatment of inflammatory paw edema in mice. AB - Multiple layers of pH-sensitive enteric copolymers were coated over layered double hydroxide (LDH) nanoparticles for controllable drug release and improved solubility of hydrophobic drugs. The nano-sized LDH carriers significantly improved the accessibility of sulfasalazine molecules that have positively charged frameworks. In addition, the successful encapsulation of negatively charged enteric copolymers was achieved via electrostatic attractions. The multi layered enteric polymer coating could potentially protect nanoparticle dissolution at gastric pH and accelerate the dissolution velocity, which would improve the drug bioavailability in the colon. Next, biological studies of this formulation indicated a highly protective effect from the scavenging of superoxide free radicals and diethyl maleate (DEM) induced lipid peroxidation, which are major cell signalling pathways for inflammation. The histological view of the liver and kidney sections revealed that the nanoformulation is safe and highly biocompatible. The animal studies conducted via paw inflammation induced by complete Freund's adjuvant (CFA) revealed that enteric-coated LDH sulfasalazine nanoparticles provided a sustained release that maintained the sulfasalazine concentrations in a therapeutic window. Therefore, this nanoformulation exhibited preferential efficacy in reducing the CFA-induced inflammation especially at day 4. PMID- 26225493 TI - Optimization of paeonol-loaded microparticle formulation by response surface methodology. AB - In this study, a central composite rotatable design based on response surface methodology (RSM) was employed to design and formulate an appropriate paeonol microparticle formulation. Five levels of a three-factor, rotatable, central composite design were used to evaluate the critical formulation variables. The optimum conditions for preparing paeonol-loaded microparticles were predicted to be: polyvinyl alcohol (PVA) content (2.84%), the ratio of drug to polymer (6.88) and the stirring rate (1007.59 rpm). The optimized responses for production yield and loading efficiency were found to be 68.86% and 55.90%, respectively, and the particle size were 23.27 +/- 0.76 um and the sorting coefficient (sigma) was 0.732. Furthermore, in vitro release study suggested that microparticle could be a suitable delivery system in treating skin disease for its sustained release of drug. In conclusion, RSM can be successfully used to optimize the effect of formulation variables. PMID- 26225494 TI - Experimental models of vaginal candidiasis and inflammation. PMID- 26225495 TI - Postoperative nausea and vomiting: The role of the dopamine D2 receptor TaqIA polymorphism. AB - BACKGROUND: The risk of developing postoperative nausea and vomiting (PONV), apart from conventional risk factors, probably includes a genetic background. OBJECTIVES: We examined the association of the DRD2 TaqIA polymorphism with PONV in a high-risk cohort of patients. DESIGN: A prospective, double-blind observational trial. SETTING: Single-centre primary care in Western Germany. PATIENTS: A total of 306 patients undergoing elective strabismus surgery under anaesthesia with etomidate/alfentanil/mivacurium (induction) and sevoflurane in air (maintenance). MAIN OUTCOME MEASURES: Nausea as well as retching/vomiting was recorded for 24 h postoperatively. The DRD2 TaqIA polymorphism (rs1800497) was genotyped using a Taqman assay and the relationship between DRD2 TaqIA polymorphism and PONV was examined by univariate and multivariate analysis. RESULTS: Regarding known risk factors for developing PONV, no patient with the A1A1 genotype (n = 15) had a history of PONV, while A1A2 carriers (n = 115) and A2A2 carriers (n = 176) had a history of PONV in 22.6 and 10.8% of patients, respectively (P = 0.005). Overall, the incidence of nausea was 40.1% and the incidence of vomiting/retching was 32.7%. Univariate analysis showed that postoperative nausea was not associated with TaqIA genotypes, but the incidence of retching/vomiting in A1A2 and A2A2 genotypes was more than 34% compared with zero in A1A1 genotypes (P = 0.022). Age, sex, smoking status and a history of PONV were independent predictors for nausea as well as for retching/vomiting, as expected, while DRD2 TaqIA polymorphism showed no independent significant impact. CONCLUSION: In a white cohort, the TaqIA A2 allele is significantly associated with a history of PONV, which may explain the increased incidence of PONV but has no further independent influence. TRIAL REGISTRATION: German registry of clinical trials identifier: DRKS00005681. PMID- 26225496 TI - Life-threatening complications after postoperative intermediate care unit discharge: A retrospective, observational study. AB - BACKGROUND: Postoperative patients who require intensive monitoring, intervention with an arterial line, vasoactive drugs and prolonged ventilator weaning are admitted to the postoperative intermediate care unit (IMCU). OBJECTIVES: The aim of this study was to estimate the prevalence of life-threatening complications within 7 days after IMCU discharge. Furthermore, we searched for associations between perioperative risk factors and these life-threatening complications. DESIGN: A retrospective observational study. SETTING: The postoperative IMCU of a university hospital in Tokyo, Japan, between 2010 and 2012. PATIENTS: All adult patients who stayed in the postoperative IMCU and who were discharged to general wards without being transferred to the ICU were included. MAIN OUTCOME MEASURES: A composite outcome of life-threatening complications needing unplanned ICU admission within 7 days after IMCU stay, or death within 7 days after IMCU stay. RESULTS: Forty out of 3093 patients (1.3%) presented a life-threatening complication; all had an unplanned ICU admission, and none died. Patients with life-threatening complications had a longer length of hospital stay [median 38.0 (interquartile range, IQR 21.3 to 56.8) days vs. 12.0 (IQR 8.0 to 23.0), P < 0.001] and a higher in-hospital mortality (12.5 vs. 0.7%, P < 0.001). Independent risk factors were an emergency operation before IMCU admission [vs. elective; odds ratio (OR) 20.5; 95% confidence interval (95% CI) 12.2 to 36.0, P < 0.001], higher cumulative perioperative fluid load during the surgical operation and IMCU stay (3000 to 4999 vs. <1000 ml; OR 5.7; 95% CI 1.6 to 23.7, P = 0.009; >=5000 vs. <1000 ml; OR 7.2; 95% CI 1.3 to 39.6, P = 0.021), mechanical ventilation during IMCU stay less than 6 h (vs. no use; OR 3.6; 95% CI 1.4 to 9.2, P = 0.007). CONCLUSION: More than 1% of patients had a life-threatening complication within 7 days after IMCU discharge, but with no deaths. Risk factors were an emergency operation before IMCU admission, higher cumulative perioperative fluid load and a short period of mechanical ventilation during the IMCU stay. PMID- 26225497 TI - Efficacy and safety of sugammadex in the reversal of deep neuromuscular blockade induced by rocuronium in patients with end-stage renal disease: A comparative prospective clinical trial. AB - BACKGROUND: Renal failure affects the pharmacology of nondepolarizing neuromuscular blockers making recovery of neuromuscular function unpredictable. Sugammadex antagonises rocuronium-induced neuromuscular blockade by encapsulating rocuronium, creating a stable complex molecule that is mainly excreted by the kidneys. Previous studies suggest that sugammadex is effective in reversing moderate neuromuscular block in the presence of renal failure, but no data are available regarding reversal of profound neuromuscular block in patients with renal failure. OBJECTIVE: The objective of this study is to compare the efficacy and safety of sugammadex in reversing profound neuromuscular block induced by rocuronium in patients with end-stage renal disease and those with normal renal function. DESIGN: A prospective clinical trial. SETTING: Two university hospitals, from 1 October 2011 to 31 January 2012. PATIENTS: Forty patients undergoing kidney transplant: 20 with renal failure [creatinine clearance (ClCr) <30 ml min] and 20 control patients (ClCr >90 ml min). INTERVENTION: Neuromuscular monitoring was performed by acceleromyography and train-of-four (TOF) stimulation. Profound neuromuscular block (posttetanic count, one to three responses) was maintained during surgery. Sugammadex 4 mg kg was administered on completion of skin closure. Recovery of the TOF ratio to 0.9 was recorded. Monitoring of neuromuscular function continued in the postanesthesia care unit for a further 2 h. MAIN OUTCOME MEASURES: The efficacy of sugammadex was evaluated by the time taken for the TOF ratio to recover to 0.9. The safety of sugammadex was assessed by monitoring for recurrence of neuromuscular block every 15 min for 2 h. Secondary variables were time to recovery of TOF ratio to 0.7 and 0.8. RESULTS: After sugammadex administration, the mean time for recovery of the TOF ratio to 0.9 was prolonged in the renal failure group (5.6 +/- 3.6 min) compared with the control group (2.7 +/- 1.3 min, P = 0.003). No adverse events or evidence of recurrence of neuromuscular block were observed. CONCLUSION: In patients with renal failure, sugammadex (4 mg kg) effectively and safely reversed profound rocuronium induced neuromuscular block, but the recovery was slower than healthy patients. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01785758. PMID- 26225498 TI - Preoxygenation by spontaneous breathing or noninvasive positive pressure ventilation with and without positive end-expiratory pressure: A randomised controlled trial. AB - BACKGROUND: In emergency situations requiring rapid airway control, shortening preoxygenate time is desirable. OBJECTIVES: The objective of this study is to compare the time to achieve an expired O2 fraction FeO2 of 90% (FeO2 90%) during preoxygenation with spontaneous breathing and positive pressure ventilation with and without positive end-expiratory pressure (PEEP). DESIGN: A randomised controlled trial. SETTING: Primary care in a university hospital in France from October 2006 to January 2008. PATIENTS: Adults patients scheduled for elective surgery. Exclusion criteria were rapid sequence induction, anticipated difficult airway management and refusal to provide consent. INTERVENTION: Patients were randomly allocated to preoxygenation with spontaneous breathing or positive pressure ventilation (positive inspiratory pressure: 12 cmH2O) without PEEP and with PEEP (positive inspiratory pressure: 12 cmH2O, PEEP: 6 cmH2O). MAIN OUTCOME MEASURES: Time to achieve an expired O2 fraction of 90% measured from positioning the face mask, and the time it took after endotracheal intubation for the SpO2 to fall to 93% (SpO2 93%) while the patient was apnoeic. Patient discomfort was recorded (visual analogue scale). Data are median (quartile 25th to 75). RESULTS: The time to achieve an FeO2 90% was shorter with positive pressure ventilation, with PEEP [140 (100 to 200) s] and without PEEP [153 (120 to 218) s], than with spontaneous breathing [190 (130 to 264) s; P = 0.002]. At 3 in, 47, 60 and 74% of patients achieved an FeO2 of 90% or more in the spontaneous breathing, positive pressure ventilation without and with PEEP groups, respectively (P = 0.01). Cox proportional-hazards regression showed that positive pressure ventilation with PEEP [hazard ratio 2.18; 95% confidence interval (95% CI) 1.42 to 3.36); P < 0.001] and without PEEP (hazard ratio 1.62; 95% CI 1.05 to 2.50; P = 0.03) were associated with a shorter time to an FeO2 90%. The time until SpO2 93% was not significantly different between spontaneous breathing [305 (263 to 383) s], positive pressure ventilation without PEEP [370 (300 to 450) s] and with PEEP [345 (245 to 435) s; P = 0.08]. The discomfort reported was 0 (0 to 18) mm and was comparable between groups (P = 0.22). CONCLUSION: Compared with spontaneous breathing, positive pressure ventilation with and without PEEP shortened preoxygenation time. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02313766. PMID- 26225499 TI - Effects of melatonin premedication to prevent emergence agitation after general anaesthesia in children: A systematic review and meta-analysis with trial sequential analysis. AB - BACKGROUND: Emergence agitation is a common phenomenon in children recovering from general anaesthesia. An emergence agitation reaction increases the risk of injuring the surgical repair, the patient and the caregivers. OBJECTIVE: The objective of this study is to examine the efficacy of melatonin premedication in emergence agitation prevention. DESIGN: A systematic review and meta-analysis of randomised controlled trials (RCTs) with trial sequential analysis (TSA) and meta regression analysis. DATA SOURCES: We searched MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, Web of Science, clinicaltrials.gov and UMIN Clinical Trials Registry up to 4 April 2014. ELIGIBILITY CRITERIA: RCTs reporting effects of melatonin on the incidence of emergence agitation in children who underwent general anaesthesia were included. RESULTS: Four studies (358 participants) were analysed. A conventional random-effects meta-analysis showed that compared with placebo, melatonin premedication may be effective in emergence agitation prevention [risk ratio 0.31, 95% confidence interval (CI) 0.16 to 0.60; I2 = 0%]. However, TSA corrected the 95% CI to 0.07 to 1.47 and showed that 22.5% of the required information size (RIS) was achieved. The effect of melatonin compared with that of midazolam was not statistically significant (risk ratio 0.48, 95% CI 0.15 to 1.52) with significant heterogeneity (I2 = 36.8%). TSA-adjusted 95% CI could not be calculated because of the small information size (4% of RIS). Meta-regression showed that, compared with midazolam, melatonin dose was significantly correlated with the effect (P = 0.024). The risk ratios (95% CI) of low and high-dose melatonin were 1.02 (0.39 to 2.65) and 0.22 (0.08 to 0.58), respectively. There was no effect of melatonin compared with dexmedetomidine (risk ratio 1.0, 95% CI 0.15 to 6.55). TSA-adjusted 95% CI could not be calculated (0.9% of RIS). CONCLUSION: Compared with placebo, melatonin premedication may be effective in preventing emergence agitation in children (GRADE: low). This TSA suggests that further studies are required to confirm the results. Compared with midazolam, high-dose melatonin might have a significant effect in preventing emergence agitation (GRADE: very low). The study protocol was registered in the UMIN Clinical Trials Registry (registration number: UMIN000011841). PMID- 26225500 TI - Quadratus lumborum block for postoperative pain after caesarean section: A randomised controlled trial. AB - BACKGROUND: Effective postoperative analgesia after caesarean section is important because it enables early ambulation and facilitates breast-feeding. Several case reports have shown that local anaesthetic injection around the quadratus lumborum muscle is effective in providing pain relief after various abdominal operations and in patients with chronic pain. The quadratus lumborum block (QLB) is performed in close proximity to the surface and uses a fascial compartment path to extend the distribution of local anaesthesia into the posterior abdominal wall and paravertebral space. This central effect can be of vital importance when managing the visceral pain after caesarean section. OBJECTIVE: We hypothesised that the QLB after caesarean section can provide adequate pain relief as part of a multimodal approach. DESIGN: Double-blind, randomised and controlled clinical trial. SETTING: A single centre between June 2014 and December 2014. PATIENTS: Fifty patients who were American Society of Anesthesiologists physical status 1 or 2, with normal singleton pregnancies with a gestation of at least 37 weeks, and scheduled for elective caesarean section under spinal anaesthesia, were enrolled into the study. They were randomly assigned to receive a QLB (n = 25) with 0.125% bupivacaine 0.2 ml kg-1 (Group 1) or a QLB (n = 25) with 0.9% Normal saline 0.2 ml kg-1 (Group 2). MAIN OUTCOME MEASURES: The primary outcome measure for the study was the morphine demands and doses delivered by a patient-controlled analgesia system at predetermined intervals (1, 2, 4, 6, 12, 24 and 48 h) after surgery. The secondary endpoints were visual analogue scale (VAS) for pain at rest and on movement (dynamic), heart rate, blood pressure, pruritus, itching, nausea, vomiting and sedation. RESULTS: The patients who received local anaesthetic used significantly less morphine than the control group (P < 0.001) at 6 and 12 h, but not at 24 and 48 hours after caesarean section. The local anaesthetic group had significantly less morphine demand than the control group (P < 0.001) 6, 12, 24 and 48 h after caesarean section. The VAS was significantly lower in the local anaesthetic group than the control group, including VAS for pain at rest at all times except 24 h after caesarean section, and VAS for pain on movement (dynamic) at all times. CONCLUSION: The QLB after caesarean section was effective and provided satisfactory analgesia in combination with a typical postoperative analgesic regimen. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02328378. PMID- 26225501 TI - The relationship between pulmonary artery acceleration time and mean pulmonary artery pressure in patients undergoing cardiac surgery: An observational study. AB - BACKGROUND: A noninvasive method of estimating pulmonary arterial pressures is required, as the use of the pulmonary artery catheter (PAC) is decreasing in cardiac anaesthesia. Pulmonary hypertension is defined as a mean pulmonary artery pressure (MPAP) at least 25 mmHg and this can be estimated echocardiographically by measuring the pulmonary acceleration time (PAT). This relationship has not been validated when measured using transoesophageal echocardiography (TOE) in anaesthetised patients having cardiac surgery. OBJECTIVE: We hypothesised that there was a quantifiable relationship between PAT and MPAP. We aimed to assess this relationship in cardiac surgical patients undergoing general anaesthesia with TOE. DESIGN: An observational study. SETTING: Catholic University Hospital, Leuven, Belgium, between August and December 2013. PATIENTS: Ninety-eight patients having cardiac surgery, where intraoperative TOE was used and a PAC was inserted as part of routine care. INTERVENTIONS: Nil. MAIN OUTCOME MEASURES: PAT and MPAP were measured simultaneously with TOE and the PAC and this relationship was assessed. RESULTS: PAT and MPAP measurements were possible in all patients. There was a curvilinear relationship between PAT and MPAP with a PAT of less than 107 ms detecting pulmonary hypertension with a sensitivity of 75% and a specificity of 94.8%. The area under the receiver operating characteristic (ROC) curve was 0.87 [95% confidence interval (95% CI) 0.80 to 0.95]. Below a PAT of 107 ms, the relationship was relatively linear and could be described by the equation MPAP (mmHg) = 77 - (0.49 x PAT). Ninety-five percent of the pressures estimated by this equation are within +/-13.8 mmHg of the measured pressure. CONCLUSION: Estimation of PAT with TOE in anaesthetised cardiac surgical patients is possible. PAT is good at discriminating between patients with and without pulmonary hypertension, with a cut-off of less than 107 ms detecting pulmonary hypertension with a sensitivity of 75% and specificity of 94.8%. PMID- 26225503 TI - Addressing Consent Issues in Donation After Circulatory Determination of Death. AB - Given the widening gap between the number of individuals on transplant waiting lists and the availability of donated organs, as well as the recent plateau in donations based on neurological criteria (i.e., brain death), there has been a growing interest in expanding donation after circulatory determination of death. While the prevalence of this form of organ donation continues to increase, many thorny ethical issues remain, often creating moral distress in both clinicians and families. In this article, we address one of these issues, namely, the challenges surrounding patient and surrogate informed consent for donation after circulatory determination of death. First we discuss several general concerns regarding consent related to this form of organ donation, and then we address additional issues that are unique to three different patient categories: adult patients with medical decision-making capacity or potential capacity, adult patients who lack capacity, and pediatric patients. PMID- 26225502 TI - Persistent Problems in Death and Dying. PMID- 26225504 TI - Harmonizing Standards for Death Determination in DCDD. PMID- 26225505 TI - What's in a Name? Conceptual Confusion About Death and Consent in Donation After Cardiac Determination of Death. PMID- 26225506 TI - The Problem With DCDD Is the Dead Donor Rule. PMID- 26225507 TI - Organ Donation Beyond Brain Death: Donors as Ends and Maximal Utility. PMID- 26225508 TI - Benefits and Harms to Organ Donors. PMID- 26225509 TI - DCDD and Children: A Defense of the "Best Interests" Standard. PMID- 26225510 TI - Pediatric Donation After Circulatory Determination of Death: Respecting the Interests of Children Through Routine Consideration of Donation Opportunities. PMID- 26225511 TI - The Impossibility of Obtaining Informed Consent to Donation After Circulatory Determination of Death. PMID- 26225512 TI - Responding to cDCDD Ethical Challenges: Translating Analysis Into Policy Action. PMID- 26225513 TI - Resolving Some, But Not All Informed Consent Issues in DCDD--the Swiss Experiences. PMID- 26225514 TI - Death at the Door of the Operating Room. PMID- 26225515 TI - The Texas Advanced Directive Law: Unfinished Business. AB - The Texas Advance Directive Act allows physicians and hospitals to overrule patient or family requests for futile care. Purposefully not defining futility, the law leaves its determination in specific cases to an institutional process. While the law has received several criticisms, it does seem to work constructively in the cases that come to the review process. We introduce a new criticism: While the law has been justified by an appeal to professional values such as avoiding harm to patients, avoiding the provision of unseemly care, and good stewardship of medical resources, it is applied incompletely. It allows physicians and institutional committees to refuse "futile" treatments desired by patients and families while at the same time providing no way of regulating physicians who recommend or even push "futile" treatments in similar cases. In this sense, the TADA is incomplete on its own terms. PMID- 26225516 TI - Pining for Courts to Resolve Intractable Disputes Between Families and Physicians Is a Pipe Dream. PMID- 26225517 TI - The Texas Advance Directives Act: Must a Death Panel Be a Star Chamber? PMID- 26225518 TI - Futility and Fairness: A Defense of the Texas Advance Directive Law. PMID- 26225519 TI - The Texas Advance Directives Act Is Not About Professional Integrity. PMID- 26225520 TI - A Texas Perspective on TADA: Physician Autonomy and the Corporate Practice of Medicine Act. PMID- 26225521 TI - The Unfinished Business of Developing Standards for End-of-Life Care: Leveraging Quality Improvement and Peer Review. PMID- 26225522 TI - The Misleading Vividness of a Physician Requesting Futile Treatment. PMID- 26225523 TI - Professionally Responsible Clinical Ethical Judgments of Futility. PMID- 26225524 TI - TADA Is Still Unfair. PMID- 26225525 TI - Finishing the Texas Advance Directives Law. PMID- 26225526 TI - Health and Social Justice: Which Inequalities Matter (Most)? Response to Open Peer Commentaries on "The Social Determinants of Health: Why Should We Care?". PMID- 26225530 TI - Response to "The Mysterious Disappearance of the Object of Inquiry: Jacobs and Arora's Defense of Circumcision". PMID- 26225533 TI - Predicted and measured retinal nerve fiber layer thickness from time-domain optical coherence tomography compared with spectral-domain optical coherence tomography. AB - IMPORTANCE: New methods are needed to compare peripapillary retinal nerve fiber layer thickness (pRNFLT) measurements taken from time-domain optical coherence tomography (TD-OCT) and spectral-domain OCT (SD-OCT). OBJECTIVE: To compare the agreement of measured and predicted pRNFLT using different equations based on pRNFLT measurements obtained by TD-OCT and SD-OCT. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional single-center study that took place at the Department of Ophthalmology, University of Erlangen-Nuremberg from November 16, 2005, to June 3, 2015, and included 138 eyes of control participants, 126 eyes of patients with ocular hypertension, 128 eyes of patients with preperimetric glaucoma, and 160 eyes of patients with perimetric glaucoma. All participants had standard clinical examinations to obtain TD-OCT (via Stratus OCT) and SD-OCT (via Spectralis OCT) measurements of pRNFLT. Two groups were matched for diagnostic subgroup, eye side, sex, and age. The TD-OCT measurements of the first group were used to predict the mean SD-OCT and 6-sector vertical-split pRNFLT measurements of the second group and vice versa. The agreement between the predicted pRNFLT calculations of conversion equations and measured pRNFLT of the second group was evaluated by intraclass correlation coefficients and Bland-Altman plots. MAIN OUTCOMES AND MEASURES: Mean and sectoral pRNFLT measurements obtained by TD-OCT and SD-OCT as well as the agreement between measured and predicted pRNFLT. RESULTS: The agreement for all investigated equations to predict mean pRNFLT measurements with intraclass correlation coeffecients ranged from 0.937 to 0.939. Bland-Altman plots demonstrated systemic biases between -0.7 MUm and +1.1 MUm for measured and predicted mean pRNFLT measurements. The ratio method demonstrated an intraclass correlation coefficient of 0.969 for the temporal-inferior sector. The best color-code agreement between both OCT devices was achieved by the no conversion method, with kappa = 0.731 (95% CI, 0.656-0.806) for the mean pRNFLT. CONCLUSIONS AND RELEVANCE: These data suggest that the prediction of mean pRNFLT values by equations derived from TD-OCT and SD-OCT can be conducted with high levels of agreement. In individual cases and singular sectors, high prediction errors may occur. When longitudinal imaging data from both TD-OCT and SD-OCT are available, conversion equations may provide longitudinal comparability. PMID- 26225535 TI - Controlled Assembly of Fibronectin Nanofibrils Triggered by Random Copolymer Chemistry. AB - Fibronectin fibrillogenesis is the physiological process by which cells elaborate a fibrous FN matrix. Poly(ethyl acrylate), PEA, has been described to induce a similar process upon simple adsorption of fibronectin (FN) from a protein solution-in the absence of cells-leading to the so-called material-driven fibronectin fibrillogenesis. Poly(methyl acrylate), PMA, is a polymer with very similar chemistry to PEA, on which FN is adsorbed, keeping the globular conformation of the protein in solution. We have used radical polymerization to synthesize copolymers with controlled EA/MA ratio, seeking to modulate the degree of FN fibrillogenesis. The physicochemical properties of the system were studied using dynamic-mechanical analysis, differential scanning calorimetry, and water contact angle. Both the degree of FN fibrillogenesis and the availability of the integrin binding region of FN directly depend on the percentage of EA in the copolymer, whereas the same total amount of FN was adsorbed regardless the EA/MA ratio. Cell morphology adhesion and differentiation of murine C2C12 were shown to depend on the degree of FN fibrillogenesis previously attained on the material surface. Myogenic differentiation was enhanced on the copolymers with higher EA content, i.e. more interconnected FN fibrils. PMID- 26225536 TI - PoLi: A Virtual Screening Pipeline Based on Template Pocket and Ligand Similarity. AB - Often in pharmaceutical research the goal is to identify small molecules that can interact with and appropriately modify the biological behavior of a new protein target. Unfortunately, most proteins lack both known structures and small molecule binders, prerequisites of many virtual screening, VS, approaches. For such proteins, ligand homology modeling, LHM, that copies ligands from homologous and perhaps evolutionarily distant template proteins, has been shown to be a powerful VS approach to identify possible binding ligands. However, if we want to target a specific pocket for which there is no homologous holo template protein structure, then LHM will not work. To address this issue, in a new pocket-based approach, PoLi, we generalize LHM by exploiting the fact that the number of distinct small molecule ligand-binding pockets in proteins is small. PoLi identifies similar ligand-binding pockets in a holo template protein library, selectively copies relevant parts of template ligands, and uses them for VS. In practice, PoLi is a hybrid structure and ligand-based VS algorithm that integrates 2D fingerprint-based and 3D shape-based similarity metrics for improved virtual screening performance. On standard DUD and DUD-E benchmark databases, using modeled receptor structures, PoLi achieves an average enrichment factor of 13.4 and 9.6, respectively, in the top 1% of the screened library. In contrast, traditional docking-based VS using AutoDock Vina and homology-based VS using FINDSITE(filt) have an average enrichment of 1.6 (3.0) and 9.0 (7.9) on the DUD (DUD-E) sets, respectively. Experimental validation of PoLi predictions on dihydrofolate reductase, DHFR, using differential scanning fluorimetry, DSF, identifies multiple ligands with diverse molecular scaffolds, thus demonstrating the advantage of PoLi over current state-of-the-art VS methods. PMID- 26225537 TI - Characterization of Oxygen Bridged Manganese Model Complexes Using Multifrequency (17)O-Hyperfine EPR Spectroscopies and Density Functional Theory. AB - Multifrequency pulsed EPR data are reported for a series of oxygen bridged (MU oxo/MU-hydroxo) bimetallic manganese complexes where the oxygen is labeled with the magnetically active isotope (17)O (I = 5/2). Two synthetic complexes and two biological metallocofactors are examined: a planar bis-MU-oxo bridged complex and a bent, bis-MU-oxo-MU-carboxylato bridge complex; the dimanganese catalase, which catalyzes the dismutation of H2O2 to H2O and O2, and the recently identified manganese/iron cofactor of the R2lox protein, a homologue of the small subunit of the ribonuclotide reductase enzyme (class 1c). High field (W-band) hyperfine EPR spectroscopies are demonstrated to be ideal methods to characterize the (17)O magnetic interactions, allowing a magnetic fingerprint for the bridging oxygen ligand to be developed. It is shown that the MU-oxo bridge motif displays a small positive isotropic hyperfine coupling constant of about +5 to +7 MHz and an anisotropic/dipolar coupling of -9 MHz. In addition, protonation of the bridge is correlated with an increase of the hyperfine coupling constant. Broken symmetry density functional theory is evaluated as a predictive tool for estimating hyperfine coupling of bridging species. Experimental and theoretical results provide a framework for the characterization of the oxygen bridge in Mn metallocofactor systems, including the water oxidizing cofactor of photosystem II, allowing the substrate/solvent interface to be examined throughout its catalytic cycle. PMID- 26225538 TI - Reverse Water-Gas Shift on Interfacial Sites Formed by Deposition of Oxidized Molybdenum Moieties onto Gold Nanoparticles. AB - We show that MoO(x)-promoted Au/SiO2 catalysts are active for reverse water-gas shift (RWGS) at 573 K. Results from reactivity measurements, CO FTIR studies, Raman spectroscopy, and X-ray absorption spectroscopy (XAS) indicate that the deposition of Mo onto Au nanoparticles occurs preferentially on under-coordinated Au sites, forming Au/MoO(x) interfacial sites active for reverse water-gas shift (RWGS). Au and AuMo sites are quantified from FTIR spectra of adsorbed CO collected at subambient temperatures (e.g., 150-270 K). Bands at 2111 and 2122 cm(-1) are attributed to CO adsorbed on under-coordinated Au(0) and Au(delta+) species, respectively. Clausius-Clapeyron analysis of FTIR data yields a heat of CO adsorption (DeltaH(ads)) of -31 kJ mol(-1) for Au(0) and -64 kJ mol(-1) for Au(delta+) at 33% surface coverage. Correlations of RWGS reactivity with changes in FTIR spectra for samples containing different amounts of Mo indicate that interfacial sites are an order of magnitude more active than Au sites for RWGS. Raman spectra of Mo/SiO2 show a feature at 975 cm(-1), attributed to a dioxo (O?)2Mo(-O-Si)2 species not observed in spectra of AuMo/SiO2 catalysts, indicating preferential deposition of Mo on Au. XAS results indicate that Mo is in a +6 oxidation state, and therefore Au and Mo exist as a metal-metal oxide combination. Catalyst calcination increases the quantity of under-coordinated Au sites, increasing RWGS activity. This strategy for catalyst synthesis and characterization enables quantification of Au active sites and interfacial sites, and this approach may be extended to describe reactivity changes observed in other reactions on supported gold catalysts. PMID- 26225539 TI - Alloy Fluctuations Act as Quantum Dot-like Emitters in GaAs-AlGaAs Core-Shell Nanowires. AB - GaAs-AlxGa1-xAs (AlGaAs) core-shell nanowires show great promise for nanoscale electronic and optoelectronic devices, but the application of these nonplanar heterostructures in devices requires improved understanding and control of nanoscale alloy composition and interfaces. Multiple researchers have observed sharp emission lines of unknown origin below the AlGaAs band edge in photoluminescence (PL) spectra of core-shell nanowires; point defects, alloy composition fluctuations, and self-assembled quantum dots have been put forward as candidate structures. Here we employ laser-assisted atom probe tomography to reveal structural and compositional features that give rise to the sharp PL emission spectra. Nanoscale ellipsoidal Ga-enriched clusters resulting from random composition fluctuations are identified in the AlGaAs shell, and their compositions, size distributions, and interface characteristics are analyzed. Simulations of exciton transition energies in ellipsoidal quantum dots are used to relate the Ga nanocluster distribution with the distribution of sharp PL emission lines. We conclude that the Ga rich clusters can act as discrete emitters provided that the major diameter is >=4 nm. Smaller clusters are under represented in the PL spectrum, and spectral lines of larger clusters are broadened, due to quantum tunneling between clusters. PMID- 26225540 TI - Bis(amino)cyclopropenylidene-Catalyzed 1,6-Conjugate Addition of Aromatic Aldehydes to para-Quinone Methides: Expedient Access to alpha,alpha'-Diarylated Ketones. AB - A bis(amino)cyclopropenylidene-catalyzed direct method for the synthesis of alpha,alpha'-diarylated ketones from aromatic as well as heteroaromatic aldehydes has been developed. This unprecedented organocatalytic protocol offers access to a wide range of alpha,alpha'-diarylated ketones in moderate to excellent yields under mild conditions through umpolung of aldehydes followed by 1,6-conjugate addition with para-quinone methides. PMID- 26225541 TI - Optical Emission of Individual GaN Nanocolumns Analyzed with High Spatial Resolution. AB - Selective area growth has been applied to fabricate a homogeneous array of GaN nanocolumns (NC) with high crystal quality. The structural and optical properties of single NCs have been investigated at the nanometer-scale by transmission electron microscopy (TEM) and highly spatially resolved cathodoluminescence (CL) spectroscopy performed in a scanning transmission electron microscope (STEM) at liquid helium temperatures. TEM cross-section analysis reveals excellent structural properties of the GaN NCs. Sporadically, isolated basal plane stacking faults (BSF) can be found resulting in a remarkably low BSF density in the almost entire NC ensemble. Both, defect-free NCs and NCs with few BSFs have been investigated. The low defect density within the NCs allows the characterization of individual BSFs, which is of high interest for studying their optical properties. Direct nanometer-scale correlation of the CL and STEM data clearly exhibits a spatial correlation of the emission at 360.6 nm (3.438 eV) with the location of basal plane stacking faults of type I1. PMID- 26225542 TI - Correction to an orally active phenylaminotetralin-chemotype serotonin 5-HT7 and 5-HT1A receptor partial agonist that corrects motor stereotypy in mouse models. PMID- 26225543 TI - An Iridium(III) Complex Inhibits JMJD2 Activities and Acts as a Potential Epigenetic Modulator. AB - A novel iridium(III) complex was synthesized and evaluated for its ability to target JMJD2 enzymatic activity. The iridium(III) complex 1 can inhibit JMJD2 activity and was selective for JMJD2 activity over JARID, JMJD3, and HDAC activities. Moreover, 1 suppressed the trimethylation of the p21 promoter on H3K9me3 and interrupted the JMJD2D-H3K9me3 interactions in human cells, suggesting that it could act as an epigenetic modulator. To our knowledge, 1 represents the first metal-based JMJD2 inhibitor reported in the literature. PMID- 26225545 TI - The synthesis of the heterocubane cluster [{CpMn}4(MU3-P)4] as a tetrahedral shaped starting material for the formation of polymeric coordination compounds. AB - Thermolysis of [CpMn(eta(6)-cht)] with P4 in 1,3-diisopropylbenzene leads to the formation of the heterocubane [Cp4Mn4P4] () in high yields, as a rare example of 'naked' phosphorus containing complexes of manganese. Compound is characterized and studied by DFT calculations and reflection measurements. 1D coordination polymers [{(CpMn)4(MU3-P)4}(CuX)]n (2-Cl: X = Cl; 2-Br: X = Br) are obtained in the reaction with CuX. Furthermore, it is shown that all four P atoms in can be addressed for a coordination towards cymantrene resulting in [{(CpMn)4(MU3 P)4}{CpMn(CO)2}n] (: n = 1; : n = 2; : n = 3; : n = 4), and shows that is a tetra topic building block in coordination chemistry. PMID- 26225546 TI - A self-assembled octanuclear complex bearing the uncommon close-packed {Fe4Mn4(MU4-O)4(MU-O)4} molecular core. AB - A one-pot open-air reaction of manganese powder with iron(ii) chloride in DMF solution of the Schiff base (H2L) formed in situ from salicylaldehyde and hydroxylamine hydrochloride yields the heterometallic complex [Fe4(MU4 O)4Mn4(L)8(DMF)4].2DMF (). Single crystal X-ray analysis shows that its molecular structure is based on the octanuclear core {Fe4Mn4(MU4-O)4(MU-O)4} with a quite rare molecular structure type {M8(MU4-X)4(MU-X)4}, where the central cube-like iron motif is modified with four terminal manganese fragments, the whole core being presented as the {Fe4(MU4-O)4} + 4{Mn(MU-O)} combination. Using the data from the Cambridge Structural Database (CSD), an analysis of the octanuclear structures with similar central {M4(MU4-X)4} fragments was performed. The hierarchical order of molecular structure types with the general formula M8Xn for such compounds was proposed and the topological features as well as the factors that influence the molecular type formation are discussed. Variable-temperature (1.8-300 K) magnetic susceptibility measurements reveal an antiferromagnetic coupling among the magnetic centres in . PMID- 26225544 TI - Polyphosphates form antigenic complexes with platelet factor 4 (PF4) and enhance PF4-binding to bacteria. AB - Short chain polyphosphates (polyP) are pro-coagulant and pro-inflammatory platelet released inorganic polymers. The platelet chemokine platelet factor 4 (PF4) binds to lipid A on bacteria, inducing an antibody mediated host defense mechanism, which can be misdirected against PF4/heparin complexes leading to the adverse drug reaction heparin-induced thrombocytopenia (HIT). Here, we demonstrate that PF4 complex formation with soluble short chain polyP contributes to host defense mechanisms. Circular dichroism spectroscopy and isothermal titration calorimetry revealed that PF4 changed its structure upon binding to polyP in a similar way as seen in PF4/heparin complexes. Consequently, PF4/polyP complexes exposed neoepitopes to which human anti-PF4/heparin antibodies bound. PolyP enhanced binding of PF4 to Escherichia coli, hereby facilitating bacterial opsonisation and, in the presence of human anti-PF4/polyanion antibodies, phagocytosis. Our study indicates a role of polyP in enhancing PF4-mediated defense mechanisms of innate immunity. PMID- 26225547 TI - Tuning luminescence and reducing reabsorption of CdSe quantum disks forluminescent solar concentrators. AB - Cadmium selenide (CdSe) quantum disks (QDs) have been synthesized for application in luminescent solar concentrators (LSCs). Luminescence tuning and reabsorption reduction of the QDs were achieved by controlling their size using a hot injection method. The overlap of the absorption and photoluminescence spectra of the as-prepared CdSe QDs was negligible. The as-prepared CdSe QDs were incorporated into polymethylmethacrylate without aggregation and luminescence quenching. The obtained highly transparent composites with non-affecting light emitting properties were used as LSCs. The placement of a CdSe QDs doped LSC prototype (10 * 1 * 0.1 cm) on a Si-cell resulted in a 201% increase in the electrical power output of the Si-cell compared with that of the bare Si-cell. PMID- 26225548 TI - Alternative testing methods for skin sensitization: NMR spectroscopy for probing the reactivity and classification of potential skin sensitizers. AB - Evaluating consumer products for potentially harmful side effects of chemical ingredients is important for the protection of both the consumer and those involved in the manufacturing process. In order to assess the risk potential of chemicals, regulatory agencies have encouraged the development of several in silico, in vitro, and in chemico methods as alternatives to eliminate or minimize the use of animals. To add structural information to the existing in chemico methods, an NMR-based method is proposed for probing the reactivity and classification of the potential electrophiles (E) using a model thiol, DCYA, as a nucleophile. The major advantage of the NMR method is the quantitation of the actual adduct, DCYA-E. The degree of reaction is here provided as a direct measurement of adduct formation and/or electrophile depletion, in contrast to other in chemico assays, e.g., ADRA and DPRA, where the reactivity is inferred from the quantification of the test nucleophile depletion. Moreover, the developed NMR method should serve as a qualitative and quantitative tool in understanding the site of reaction and other structural information associated with test sensitizer. This is particularly valuable and advantageous over methods encouraged by regulatory agencies, which merely provide quantification of the reaction but lack any structural information. Several compounds with multiple reaction sites were successfully tested with the proposed NMR method. Otherwise, these compounds have proven to be a challenge to identify and classify using existing alternative methods. PMID- 26225549 TI - Effect of decellularized adipose tissue particle size and cell density on adipose derived stem cell proliferation and adipogenic differentiation in composite methacrylated chondroitin sulphate hydrogels. AB - An injectable composite scaffold incorporating decellularized adipose tissue (DAT) as a bioactive matrix within a hydrogel phase capable of in situ polymerization would be advantageous for adipose-derived stem cell (ASC) delivery in the filling of small or irregular soft tissue defects. Building on previous work, the current study investigates DAT milling methods and the effects of DAT particle size and cell seeding density on the response of human ASCs encapsulated in photo-cross-linkable methacrylated chondroitin sulphate (MCS)-DAT composite hydrogels. DAT particles were generated by milling lyophilized DAT and the particle size was controlled through the processing conditions with the goal of developing composite scaffolds with a tissue-specific 3D microenvironment tuned to enhance adipogenesis. ASC proliferation and adipogenic differentiation were assessed in vitro in scaffolds incorporating small (average diameter of 38 +/- 6 MUm) or large (average diameter of 278 +/- 3 MUm) DAT particles in comparison to MCS controls over a period of up to 21 d. Adipogenic differentiation was enhanced in the composites incorporating the smaller DAT particles and seeded at the higher density of 5 * 10(5) ASCs/scaffold, as measured by glycerol-3-phosphate dehydrogenase (GPDH) enzyme activity, semi quantitative analysis of perilipin expression and oil red O staining of intracellular lipid accumulation. Overall, this study demonstrates that decellularized tissue particle size can impact stem cell differentiation through cell-cell and cell-matrix interactions, providing relevant insight towards the rational design of composite biomaterial scaffolds for adipose tissue engineering. PMID- 26225550 TI - A [2]rota[2]catenane, constructed from a pillar[5]arene-crown ether fused double cavity macrocycle: synthesis and structural characterization. AB - A topologically novel [2]rota[2]catenane containing both a pillar[5]arene imidazolium based [2]rotaxane subunit and a crown ether-tetracationic cyclophane based [2]catenane one was designed and constructed. The structure of the [2]rota[2]catenane was thoroughly characterized by NMR spectra, MS spectrometry and single crystal X-ray diffraction analysis. PMID- 26225551 TI - The impact of positive peritoneal cytology on prognosis in patients with cervical cancer: a meta-analysis. AB - BACKGROUND: The impact of positive peritoneal cytology on the prognosis of cervical cancer is controversial. Thus, we performed a meta-analysis to determine its impact on recurrence, and to investigate correlations between abnormal cytology and/or lymph node metastasis in cervical cancer. METHODS: A systematic literature review was conducted through July 2014. Odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated by standard meta-analysis techniques with the fixed-effects models, if there was no significant statistical heterogeneity across studies by using I(2). RESULTS: Of 303 studies retrieved, 6 were included in the meta-analysis. These six case-control observational studies included 1360 cervical cancer patients who showed negative peritoneal cytology and 64 who showed positive peritoneal cytology. Over the combined study period, 20 of 45 in the positive peritoneal cytology group experienced recurrence, whereas 88 of 539 controls did. The meta-analysis based on the fixed-effects model indicated a significant increase in the risk of recurrence in the positive peritoneal cytology group relative to the control group (OR: 4.47; 95% CI: 2.33 8.58, P<0.001, I(2)=0.0%). Moreover, the results of our meta-analysis suggested that the positive peritoneal cytology group displayed more lymph node metastasis than the negative peritoneal cytology group (OR: 3.73; 95% CI: 2.13-6.53, P<0.001, I(2)=0.0%). CONCLUSIONS: Although based mainly on retrospective observational studies, our meta-analysis indicates that abnormal peritoneal cytology may be strongly associated with poor prognosis in patients with cervical cancer. Future research should verify this relationship through prospective observational studies over a longer term. PMID- 26225552 TI - Policy Advocacy to Promote Healthy Aging: The Time to Engage Is Now. PMID- 26225554 TI - Increased Incidence of Mitochondrial Cytochrome C Oxidase 1 Gene Mutations in Patients with Primary Ovarian Insufficiency. AB - Primary ovarian insufficiency (POI), also known as premature ovarian failure (POF), is defined as more than six months of cessation of menses before the age of 40 years, with two serum follicle stimulating hormone (FSH) levels (at least 1 month apart) falling in the menopause range. The cause of POI remains undetermined in the majority of cases, although some studies have reported increased levels of reactive oxygen species (ROS) in idiopathic POF. The role of mitochondrial DNA in the pathogenesis of POI has not been studied extensively. This aim of this study was to uncover underlying mitochondrial genetic defects in patients with POI. The entire region of the mitochondrial genome was amplified in subjects with idiopathic POI (n=63) and age-matched healthy female controls (n=63) using nine pair sets of primers, followed by screening of the mitochondrial genome using an Illumina MiSeq. We identified a total of 96 non synonymous mitochondrial variations in POI patients and 93 non-synonymous variations in control subjects. Of these, 21 (9 in POI and 12 in control) non synonymous variations had not been reported previously. Eight mitochondrial cytochrome coxidase 1 (MT-CO1) missense variants were identified in POI patients, whereas only four missense mutations were observed in controls. A high incidence of MT-CO1 missense variants were identified in POI patients compared with controls, and the difference between the groups was statistically significant (13/63 vs. 5/63, p=0.042). Our results show that patients with primary ovarian insufficiency exhibit an increased incidence of mitochondrial cytochrome c oxidase 1 gene mutations, suggesting that MT-CO1 gene mutation may be causal in POI. PMID- 26225553 TI - A Scoping Review of Empirical Research Relating to Quality and Effectiveness of Research Ethics Review. AB - BACKGROUND: To date there is no established consensus of assessment criteria for evaluating research ethics review. METHODS: We conducted a scoping review of empirical research assessing ethics review processes in order to identify common elements assessed, research foci, and research gaps to aid in the development of assessment criteria. Electronic searches of Ovid Medline, PsychInfo, and the Cochrane DSR, ACP Journal Club, DARE, CCTR, CMR, HTA, and NHSEED, were conducted. After de-duplication, 4234 titles and abstracts were reviewed. Altogether 4036 articles were excluded following screening of titles, abstracts and full text. A total of 198 articles included for final data extraction. RESULTS: Few studies originated from outside North America and Europe. No study reported using an underlying theory or framework of quality/effectiveness to guide study design or analyses. We did not identify any studies that had involved a controlled trial- randomised or otherwise--of ethics review procedures or processes. Studies varied substantially with respect to outcomes assessed, although tended to focus on structure and timeliness of ethics review. DISCUSSION: Our findings indicate a lack of consensus on appropriate assessment criteria, exemplified by the varied study outcomes identified, but also a fragmented body of research. To date research has been largely quantitative, with little attention given to stakeholder experiences, and is largely cross sectional. A lack of longitudinal research to date precludes analyses of change or assessment of quality improvement in ethics review. PMID- 26225555 TI - West Nile Virus: High Transmission Rate in North-Western European Mosquitoes Indicates Its Epidemic Potential and Warrants Increased Surveillance. AB - BACKGROUND: West Nile virus (WNV) is a highly pathogenic flavivirus transmitted by Culex spp. mosquitoes. In North America (NA), lineage 1 WNV caused the largest outbreak of neuroinvasive disease to date, while a novel pathogenic lineage 2 strain circulates in southern Europe. To estimate WNV lineage 2 epidemic potential it is paramount to know if mosquitoes from currently WNV-free areas can support further spread of this epidemic. METHODOLOGY/PRINCIPAL FINDINGS: We assessed WNV vector competence of Culex pipiens mosquitoes originating from north western Europe (NWE) in direct comparison with those from NA. We exposed mosquitoes to infectious blood meals of lineage 1 or 2 WNV and determined the infection and transmission rates. We explored reasons for vector competence differences by comparing intrathoracic injection versus blood meal infection, and we investigated the influence of temperature. We found that NWE mosquitoes are highly competent for both WNV lineages, with transmission rates up to 25%. Compared to NA mosquitoes, transmission rates for lineage 2 WNV were significantly elevated in NWE mosquitoes due to better virus dissemination from the midgut and a shorter extrinsic incubation time. WNV infection rates further increased with temperature increase. CONCLUSIONS/SIGNIFICANCE: Our study provides experimental evidence to indicate markedly different risk levels between both continents for lineage 2 WNV transmission and suggests a degree of genotype genotype specificity in the interaction between virus and vector. Our experiments with varying temperatures explain the current localized WNV activity in southern Europe, yet imply further epidemic spread throughout NWE during periods with favourable climatic conditions. This emphasizes the need for intensified surveillance of virus activity in current WNV disease-free regions and warrants increased awareness in clinics throughout Europe. PMID- 26225556 TI - Effects of Residue Management on Decomposition in Irrigated Rice Fields Are Not Related to Changes in the Decomposer Community. AB - Decomposers provide an essential ecosystem service that contributes to sustainable production in rice ecosystems by driving the release of nutrients from organic crop residues. During a single rice crop cycle we examined the effects of four different crop residue management practices (rice straw or ash of burned straw scattered on the soil surface or incorporated into the soil) on rice straw decomposition and on the abundance of aquatic and soil-dwelling invertebrates. Mass loss of rice straw in litterbags of two different mesh sizes that either prevented or allowed access of meso- and macro-invertebrates was used as a proxy for decomposition rates. Invertebrates significantly increased total loss of litter mass by up to 30%. Initially, the contribution of invertebrates to decomposition was significantly smaller in plots with rice straw scattered on the soil surface; however, this effect disappeared later in the season. We found no significant responses in microbial decomposition rates to management practices. The abundance of aquatic fauna was higher in fields with rice straw amendment, whereas the abundance of soil fauna fluctuated considerably. There was a clear separation between the overall invertebrate community structure in response to the ash and straw treatments. However, we found no correlation between litter mass loss and abundances of various lineages of invertebrates. Our results indicate that invertebrates can contribute to soil fertility in irrigated paddy fields by decomposing rice straw, and that their abundance as well as efficiency in decomposition may be promoted by crop residue management practices. PMID- 26225557 TI - Outcome in Heart Failure with Preserved Ejection Fraction: The Role of Myocardial Structure and Right Ventricular Performance. AB - BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is recognized as a major cause of cardiovascular morbidity and mortality. Thus, a profound understanding of the pathophysiologic changes in HFpEF is needed to identify risk factors and potential treatment targets in this specific patient population. Therefore, we aimed to comprehensively assess the impact of left- and right ventricular function and hemodynamics on long-term mortality and morbidity in order to improve risk prediction in patients with HFpEF. METHODS AND RESULTS: We prospectively included 142 consecutive patients with HFpEF into our observational, non-interventional registry. Echocardiography, cardiac magnetic resonance imaging and invasive hemodynamic assessments including myocardial biopsy were performed at baseline. We detected significant correlations between left ventricular extracellular matrix and left ventricular end-diastolic diameter (r = -0.64;p = 0.03) and stroke volume (r = -0.53;p = 0.04). Hospitalization for heart failure and/or cardiac death was observed over a median follow up of 10 months. The strongest risk factors were reduced right ventricular function (adj. HR 6.62;95%CI 3.12- 14.02;p<0.001), systolic pulmonary arterial pressure (adj. HR per 1-SD 1.55;95%CI 1.15- 2.09;p = 0.004) and the pulmonary artery wedge pressure (adj. HR per 1-SD 1.51;95%CI 1.09-2.08; p = 0.012). The area under the ROC curve for right ventricular function was 0.63, for systolic pulmonary arterial pressure 0.75, and for pulmonary artery wedge pressure 0.68. CONCLUSION: The current study emphasizes the importance of right ventricular function and pulmonary pressures on outcome in patients with HFpEF providing pathophysiological insights into the hemodynamic changes in HFpEF. PMID- 26225559 TI - Correction: Data-Driven Method to Estimate Nonlinear Chemical Equivalence. AB - [This corrects the article DOI: 10.1371/journal.pone.0130494.]. PMID- 26225558 TI - Genome-Wide Analyses Suggest Mechanisms Involving Early B-Cell Development in Canine IgA Deficiency. AB - Immunoglobulin A deficiency (IgAD) is the most common primary immune deficiency disorder in both humans and dogs, characterized by recurrent mucosal tract infections and a predisposition for allergic and other immune mediated diseases. In several dog breeds, low IgA levels have been observed at a high frequency and with a clinical resemblance to human IgAD. In this study, we used genome-wide association studies (GWAS) to identify genomic regions associated with low IgA levels in dogs as a comparative model for human IgAD. We used a novel percentile groups-approach to establish breed-specific cut-offs and to perform analyses in a close to continuous manner. GWAS performed in four breeds prone to low IgA levels (German shepherd, Golden retriever, Labrador retriever and Shar-Pei) identified 35 genomic loci suggestively associated (p <0.0005) to IgA levels. In German shepherd, three genomic regions (candidate genes include KIRREL3 and SERPINA9) were genome-wide significantly associated (p <0.0002) with IgA levels. A ~20kb long haplotype on CFA28, significantly associated (p = 0.0005) to IgA levels in Shar-Pei, was positioned within the first intron of the gene SLIT1. Both KIRREL3 and SLIT1 are highly expressed in the central nervous system and in bone marrow and are potentially important during B-cell development. SERPINA9 expression is restricted to B-cells and peaks at the time-point when B-cells proliferate into antibody-producing plasma cells. The suggestively associated regions were enriched for genes in Gene Ontology gene sets involving inflammation and early immune cell development. PMID- 26225560 TI - Therapeutic Effect of Berberine on Huntington's Disease Transgenic Mouse Model. AB - Huntington disease (HD) represents a family of neurodegenerative diseases that are caused by misfolded proteins. The misfolded proteins accumulate in the affected brain regions in an age-dependent manner to cause late-onset neurodegeneration. Transgenic mouse models expressing the HD protein, huntingtin, have been widely used to identify therapeutics that may retard disease progression. Here we report that Berberine (BBR), an organic small molecule isolated from plants, has protective effects on transgenic HD (N171-82Q) mice. We found that BBR can reduce the accumulation of mutant huntingtin in cultured cells. More importantly, when given orally, BBR could effectively alleviate motor dysfunction and prolong the survival of transgenic N171-82Q HD mice. We found that BBR could promote the degradation of mutant huntingtin by enhancing autophagic function. Since BBR is an orally-taken drug that has been safely used to treat a number of diseases, our findings suggest that BBR can be tested on different HD animal models and HD patients to further evaluate its therapeutic effects. PMID- 26225561 TI - Efficient fdCas9 Synthetic Endonuclease with Improved Specificity for Precise Genome Engineering. AB - The Cas9 endonuclease is used for genome editing applications in diverse eukaryotic species. A high frequency of off-target activity has been reported in many cell types, limiting its applications to genome engineering, especially in genomic medicine. Here, we generated a synthetic chimeric protein between the catalytic domain of the FokI endonuclease and the catalytically inactive Cas9 protein (fdCas9). A pair of guide RNAs (gRNAs) that bind to sense and antisense strands with a defined spacer sequence range can be used to form a catalytically active dimeric fdCas9 protein and generate double-strand breaks (DSBs) within the spacer sequence. Our data demonstrate an improved catalytic activity of the fdCas9 endonuclease, with a spacer range of 15-39 nucleotides, on surrogate reporters and genomic targets. Furthermore, we observed no detectable fdCas9 activity at known Cas9 off-target sites. Taken together, our data suggest that the fdCas9 endonuclease variant is a superior platform for genome editing applications in eukaryotic systems including mammalian cells. PMID- 26225562 TI - Essential and Checkpoint Functions of Budding Yeast ATM and ATR during Meiotic Prophase Are Facilitated by Differential Phosphorylation of a Meiotic Adaptor Protein, Hop1. AB - A hallmark of the conserved ATM/ATR signalling is its ability to mediate a wide range of functions utilizing only a limited number of adaptors and effector kinases. During meiosis, Tel1 and Mec1, the budding yeast ATM and ATR, respectively, rely on a meiotic adaptor protein Hop1, a 53BP1/Rad9 functional analog, and its associated kinase Mek1, a CHK2/Rad53-paralog, to mediate multiple functions: control of the formation and repair of programmed meiotic DNA double strand breaks, enforcement of inter-homolog bias, regulation of meiotic progression, and implementation of checkpoint responses. Here, we present evidence that the multi-functionality of the Tel1/Mec1-to-Hop1/Mek1 signalling depends on stepwise activation of Mek1 that is mediated by Tel1/Mec1 phosphorylation of two specific residues within Hop1: phosphorylation at the threonine 318 (T318) ensures the transient basal level Mek1 activation required for viable spore formation during unperturbed meiosis. Phosphorylation at the serine 298 (S298) promotes stable Hop1-Mek1 interaction on chromosomes following the initial phospho-T318 mediated Mek1 recruitment. In the absence of Dmc1, the phospho-S298 also promotes Mek1 hyper-activation necessary for implementing meiotic checkpoint arrest. Taking these observations together, we propose that the Hop1 phospho-T318 and phospho-S298 constitute key components of the Tel1/Mec1 based meiotic recombination surveillance (MRS) network and facilitate effective coupling of meiotic recombination and progression during both unperturbed and challenged meiosis. PMID- 26225563 TI - High-Field Functional Imaging of Pitch Processing in Auditory Cortex of the Cat. AB - The perception of pitch is a widely studied and hotly debated topic in human hearing. Many of these studies combine functional imaging techniques with stimuli designed to disambiguate the percept of pitch from frequency information present in the stimulus. While useful in identifying potential "pitch centres" in cortex, the existence of truly pitch-responsive neurons requires single neuron-level measures that can only be undertaken in animal models. While a number of animals have been shown to be sensitive to pitch, few studies have addressed the location of cortical generators of pitch percepts in non-human models. The current study uses high-field functional magnetic resonance imaging (fMRI) of the feline brain in an attempt to identify regions of cortex that show increased activity in response to pitch-evoking stimuli. Cats were presented with iterated rippled noise (IRN) stimuli, narrowband noise stimuli with the same spectral profile but no perceivable pitch, and a processed IRN stimulus in which phase components were randomized to preserve slowly changing modulations in the absence of pitch (IRNo). Pitch-related activity was not observed to occur in either primary auditory cortex (A1) or the anterior auditory field (AAF) which comprise the core auditory cortex in cats. Rather, cortical areas surrounding the posterior ectosylvian sulcus responded preferentially to the IRN stimulus when compared to narrowband noise, with group analyses revealing bilateral activity centred in the posterior auditory field (PAF). This study demonstrates that fMRI is useful for identifying pitch-related processing in cat cortex, and identifies cortical areas that warrant further investigation. Moreover, we have taken the first steps in identifying a useful animal model for the study of pitch perception. PMID- 26225564 TI - Systematic Reviewers in Clinical Neurology Do Not Routinely Search Clinical Trials Registries. AB - We examined the use of clinical trials registries in published systematic reviews and meta-analyses from clinical neurology. A review of publications between January 1, 2008 and December 31, 2014 from five neuroscience journals (Annals of Neurology, Brain, Lancet Neurology, Neurology, and The Neuroscientist) was performed to identify eligible systematic reviews. The systematic reviews comprising the final sample were independently appraised to determine if clinical trials registries had been included as part of the search process. Studies acknowledging the use of a trials registry were further examined to determine whether trial data had been incorporated into the analysis. The initial search yielded 194 studies, of which 78 systematic reviews met the selection criteria. Of those, five acknowledged the use of a specific clinical trials registry: four reviewed unpublished trial data and two incorporated unpublished trial data into their results. Based on our sample of systematic reviews, there was no increase in the use of trials registries in systematic review searches over time. Few systematic reviews published in clinical neurology journals included data from relevant clinical trials registries. PMID- 26225565 TI - Mastermind-Like 1 Is Ubiquitinated: Functional Consequences for Notch Signaling. AB - Early studies demonstrated the involvement of ubiquitination of the Notch intracellular domain for rapid turnover of the transcriptional complex at Notch target genes. It was shown that this ubiquitination was promoted by the co activator Mastermind like 1 (MAML1). MAML1 also contains numerous lysine residues that may also be ubiquitinated and necessary for protein regulation. In this study, we show that over-expressed MAML1 is ubiquitinated and identify eight conserved lysine residues which are required for ubiquitination. We also show that p300 stimulates ubiquitination and that Notch inhibits ubiquitination. Furthermore, we show that a mutant MAML1 that has decreased ubiquitination shows increased output from a HES1 reporter gene assay. Therefore, we speculate that ubiquitination of MAML1 might be a mechanism to maintain low levels of the protein until needed for transcriptional activation. In summary, this study identifies that MAML1 is ubiquitinated in the absence of Notch signaling to maintain low levels of MAML1 in the cell. Our data supports the notion that a precise and tight regulation of the Notch pathway is required for this signaling pathway. PMID- 26225567 TI - Correction: Century-Long Warming Trends in the Upper Water Column of Lake Tanganyika. AB - [This corrects the article DOI: 10.1371/journal.pone.0132490.]. PMID- 26225568 TI - Biomaterials in Sports Medicine: A Review of Clinical Applications. PMID- 26225569 TI - Biodegradable Materials: Anchors and Interference Screws. AB - Biodegradable implants allow clarity in postoperative imaging, easier revision, and fewer concerns about associated tissue damage. It is important to appreciate that different biodegradable materials have different properties and different degradation rates. Faster degradation can be associated with a greater inflammatory response. However, inflammation is a normal part of the degradation process. The concern arises when the inflammation is clinically significant. PMID- 26225566 TI - An In-Depth Comparison of Latency-Reversing Agent Combinations in Various In Vitro and Ex Vivo HIV-1 Latency Models Identified Bryostatin-1+JQ1 and Ingenol B+JQ1 to Potently Reactivate Viral Gene Expression. AB - The persistence of latently infected cells in patients under combinatory antiretroviral therapy (cART) is a major hurdle to HIV-1 eradication. Strategies to purge these reservoirs are needed and activation of viral gene expression in latently infected cells is one promising strategy. Bromodomain and Extraterminal (BET) bromodomain inhibitors (BETi) are compounds able to reactivate latent proviruses in a positive transcription elongation factor b (P-TEFb)-dependent manner. In this study, we tested the reactivation potential of protein kinase C (PKC) agonists (prostratin, bryostatin-1 and ingenol-B), which are known to activate NF-kappaB signaling pathway as well as P-TEFb, used alone or in combination with P-TEFb-releasing agents (HMBA and BETi (JQ1, I-BET, I-BET151)). Using in vitro HIV-1 post-integration latency model cell lines of T-lymphoid and myeloid lineages, we demonstrated that PKC agonists and P-TEFb-releasing agents alone acted as potent latency-reversing agents (LRAs) and that their combinations led to synergistic activation of HIV-1 expression at the viral mRNA and protein levels. Mechanistically, combined treatments led to higher activations of P-TEFb and NF-kappaB than the corresponding individual drug treatments. Importantly, we observed in ex vivo cultures of CD8+-depleted PBMCs from 35 cART-treated HIV-1+ aviremic patients that the percentage of reactivated cultures following combinatory bryostatin-1+JQ1 treatment was identical to the percentage observed with anti-CD3+anti-CD28 antibodies positive control stimulation. Remarkably, in ex vivo cultures of resting CD4+ T cells isolated from 15 HIV-1+ cART-treated aviremic patients, the combinations bryostatin-1+JQ1 and ingenol-B+JQ1 released infectious viruses to levels similar to that obtained with the positive control stimulation. The potent effects of these two combination treatments were already detected 24 hours post-stimulation. These results constitute the first demonstration of LRA combinations exhibiting such a potent effect and represent a proof-of-concept for the co-administration of two different types of LRAs as a potential strategy to reduce the size of the latent HIV-1 reservoirs. PMID- 26225570 TI - Autologous Chondrocyte Implantation With Collagen Membrane. AB - The first-generation autologous chondrocyte implantation (ACI-P) described by Peterson and colleagues used a periosteal patch to form a watertight cover over the articular cartilage defect, under which the autologous chondrocyte suspension was injected. Although good to excellent outcomes were often seen in >80% of patients and the durability of the repair documented up to 20 years, the procedure was noted to have a high rate of subsequent surgical procedures, most often for arthroscopic debridement of periosteal hypertrophy or incomplete incorporation. Consequently, the surgical technique advanced to use a porcine derived bilayer of type I/III collagen with a porous layer that favors cell attachment and a smooth, compact layer that is cell occlusive. In use of the collagen membrane ACI, prospective studies have shown no diminution in clinical results and a marked reduction in subsequent surgeries from graft hypertrophy to <3%. Use of the collage membrane for ACI-C in the United States is currently an off-label use of an FDA-approved membrane, which should be discussed with the patient before surgery. PMID- 26225571 TI - DeNovo NT Particulated Juvenile Cartilage Implant. AB - Biological repair of focal chondral defects represents a significant clinical challenge as cartilage lacks intrinsic healing ability. Although it can be difficult to measure the objective success of cartilage repair techniques, the primary objective is symptom relief leading to less pain and improved function for the patient. Likely, the most important key to success is proper clinical indications. Second to this, the type of cartilage treatment utilized should be based on lesion location, size, depth, and other patient factors. One such treatment is DeNovo Natural Tissue. This method relies on the ability of juvenile chondrocytes to migrate from cartilage explants after being secured in a cartilage defect. Although approximately 8700 cases have been performed since 2007, long-term clinical outcomes are not yet available. However, basic science and early clinical data are promising. PMID- 26225572 TI - Massive Irreparable Rotator Cuff Tears: A Solution That Bridges the Gap. AB - The successful treatment of symptomatic chronic, massive irreparable rotator cuff tears remains a difficult problem for many shoulder surgeons. Multiple procedures have been attempted to address this problem including latissimus dorsi transfer, arthroscopic shoulder debridement, and reverse total shoulder arthroplasty. Not every patient is a candidate for the above procedures and those that do undergo one of the above procedures has no guarantee of experiencing clinical improvement. Therefore, many shoulder surgeons have looked toward additional methods to manage the chronic, massive irreparable rotator cuff tear. Acellular human dermal allograft is a "graft" material that we have been using to reliably and successfully restore function to patients with these otherwise irreparable rotator cuff tears. PMID- 26225573 TI - Postmeniscectomy Meniscus Growth With Stem Cells: Where Are We Now? AB - Arthroscopic meniscal repair and debridement are some of the most common procedures performed in the field of orthopedic surgery. Further, recent research has suggested poor long-term outcomes for patients with meniscectomies with increased incidence of osteoarthritis, leaving a need to develop technology to regenerate meniscal tissue following meniscectomy. Mesenchymal stem cells, are cells that can be harvested from multiple organs and retain the ability to differentiate into a variety of tissues, including osteoblasts, adipocytes, and chondroblasts. They have been shown to stimulate the regeneration of meniscal tissue in several animal models and recently in humans, as well. This study reviews the current research and clinical data regarding mesenchymal stem cells, specifically with regard to postmeniscectomy meniscus growth with stem cells. PMID- 26225574 TI - BioCartilage: A New Biomaterial to Treat Chondral Lesions. AB - Articular cartilage damage affects almost everyone at some point. Our ability to heal these defects has been very limited. Microfracture, which is one of the most common attempted surgeries for chondral lesions, has resulted in poor long-term outcomes. Other solutions like allograft osteochondral autograft transfer system, DeNovo, or autologous chondrocyte implantation are more extensive, difficult, expensive surgeries, and are better served for larger lesions. Smaller lesions have shown good short-term outcomes with microfracture but result in creation of fibrocartilage, which is weaker and softer and does not hold up long term. A simple, inexpensive, longer-term solution is needed. BioCartilage is dehydrated, micronized allogeneic cartilage that can be implanted with platelet-rich plasma into these smaller cartilage defects. BioCartilage acts as scaffold, allowing for the creation of hyaline-like cartilage. PMID- 26225575 TI - Complications of Biodegradable Materials: Anchors and Interference Screws. AB - Metal, plastic, and biodegradable implants can all cause problems. The advantage of the biodegradable implant is clarity in postoperative imaging, easier revision, and fewer concerns about associated tissue damage. Although biodegradable implants do degrade over time, this time varies considerably, depends upon the polymer present, and is often measured in years. Before that occurring, the implant is a rigid device. Problems in the operative or immediate postoperative period include implant breakage during insertion, loss of initial fixation, incompletely buried or "proud" implants within a joint that could damage articular cartilage, and possible implant migration. Later occurring problems include the development of inflammatory reactions leading to lytic changes, cyst formation, intra-articular granuloma formation along with swelling, and sterile pretibial abscesses. Despite this list of potential problems on balance biodegradable implants are safe and effective and present no greater concerns (and arguably fewer ones) than metal or plastic implants. PMID- 26225576 TI - Clinical Application of Scaffolds for Partial Meniscus Replacement. AB - Meniscal tears are common injuries often treated by partial meniscectomy. This may result in altered joint contact mechanics which in turn may lead to worsening symptoms and an increased risk of osteoarthritis. Meniscal scaffolds have been proposed as a treatment option aimed at reducing symptoms while also potentially reducing progression of degenerative change. There are 2 scaffolds available for clinical use at the present time; Collagen Meniscus Implant and Actifit. Medium term to long-term data (4.9 to 11.3 y) demonstrate efficacy of partial meniscus replacement. The patients who seem to benefit most are chronic postmeniscectomy rather than acute meniscal injuries. Herein we report on available clinical data for Collagen Meniscus Implant and Actifit while describing our preferred surgical technique and postoperative rehabilitation program. PMID- 26225577 TI - NeoCart Update: Review of Technique and Early Clinical Results. AB - Regenerative medicine technology is currently being used to create hyaline-like cartilage tissue from autologous cartilage cells. NeoCart is one such investigational scaffold-based cartilage implant used to treat knee cartilage injuries. There are limited data available regarding this specific treatment option, as NeoCart is currently undergoing a phase III clinical trial at several cartilage restoration centers across the United States. PMID- 26225578 TI - Coated Sutures. AB - The addition of specific proteins or growth factors onto sutures would provide a direct application of exogenous factors to promote tissue repair. The higher levels of growth factors and cytokines may optimize the healing environment and promote tissue recovery. Despite this proposed benefit, the current orthopedic literature on the use of coated sutures is limited. Although several of the published studies investigating healing improvement by coated sutures have shown promising results, these data are only based on in vitro or small animal experiments. Recent meta-analyses have reported positive effects of triclosan coated antimicrobial sutures in regards to reduction of surgical site complications. However, biologically coated sutures are not yet widely accepted due to several unanswered questions (concentration, release kinematics, tissue reactions, etc.) in addition to the high costs of such products. Further studies are needed to demonstrate the efficacy of coated sutures in orthopedic surgery. PMID- 26225579 TI - Novel CDKN2A mutations in Austrian melanoma patients. AB - CDKN2A is the most prominent familial melanoma gene, with mutations occurring in up to 40% of the families. Numerous mutations in the gene are known, several of them representing regional founder mutations. We sought to determine, for the first time, germline mutations in CDKN2A in Austria to identify novel mutations. In total, 700 individuals (136 patients with a positive family history and 164 with at least two primary melanomas as the high-risk groups; 200 with single primary melanomas; and 200 healthy individuals as the control groups) were Sanger sequenced for CDKN2A exon 1alpha, 1beta, and 2. The 136 patients with affected relatives were also sequenced for CDK4 exon 2. We found the disease-associated mutations p.R24P (8*), p.N71T (1*), p.G101W (1*), and p.V126D (1*) in the group with affected relatives and p.R24P (2*) in the group with several primary melanomas. Furthermore, we discovered four mutations of unknown significance, two of which were novel: p.A34V and c.151-4 G>C, respectively. Computational effect prediction suggested p.A34V as conferring a high risk for melanoma, whereas c.151 4 G>C, although being predicted as a splice site mutation by MutationTaster, could not functionally be confirmed to alter splicing. Moreover, computational effect prediction confirmed accumulation of high-penetrance mutations in high risk groups, whereas mutations of unknown significance were distributed across all groups. p.R24P is the most common high-risk mutation in Austria. In addition, we discovered two new mutations in Austrian melanoma patients, p.A34V and c.151-4 G>C, respectively. PMID- 26225580 TI - Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients. AB - Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription. PMID- 26225581 TI - DNA methylation contributes toward silencing of antioncogenic microRNA-203 in human and canine melanoma cells. AB - Melanoma is a poor-prognosis cancer in both humans and dogs. We have elucidated the antitumor mechanisms of antioncogenic microRNA (miR)-203 which is downregulated in human melanoma, as well as in canine melanoma. The aim of this study was to clarify the mechanism of this downregulation. We focused on epigenetic aberration of miR-203 transcription. Treatment with 5-aza-2' deoxycitidine (5-aza) markedly upregulated the expression level of miR-203 in almost all of the cell lines tested. Furthermore, bisulfite sequencing or methylation-specific PCR showed DNA methylation of CpG islands upstream of the miR-203 coding region (MIR203) in both human and canine melanoma cells, as well as in canine clinical specimens, but not in human normal melanocytes. The results of a luciferase activity assay showed obvious suppression of the transcription of miR-203 by DNA methylation. The use of the luciferase activity assay for CREB1 and an inhibition assay of miR-203 function performed with an miR-203 inhibitor confirmed the contribution of miR-203 upregulation toward the negative regulation of the target gene of miR-203. These results indicate that canine melanoma might be a preclinical model of human melanoma for epigenetic studies. In addition, this study suggests that agents that can demethylate MIR203 could be a common promising therapeutic agent for the treatment of human and canine melanomas. PMID- 26225582 TI - A pilot study of chromosomal aberrations and epigenetic changes in peripheral blood samples to identify patients with melanoma. AB - Prognosis is markedly improved when melanoma is diagnosed early. Improved methods are needed for earlier detection and screening. We hypothesized that epigenetic analysis of blood samples could discriminate patients with melanoma from patients with other cutaneous lesions and from healthy volunteers. After institutional review board approval and consent, whole blood was obtained from 59 patients with melanoma, 20 patients with other skin cancers, 20 patients with benign skin conditions, and 20 healthy volunteers. Fifteen conformation biomarkers from five gene loci were analyzed on chromatin with the EpiSwitch technology using a modified chromatin conformation capture assay. Differentiation between patients with melanoma and those with nonmelanoma skin cancers was correct 85% of the time, resulting in a sensitivity of 88% and a specificity of 82%. Differentiation of patients with melanoma from healthy controls was correct 80% of the time, resulting in a sensitivity of 85% and a specificity of 75%. The noninvasive test was more accurate in early-stage melanoma (1/10 and 1/16 stage I and stage II patients were misclassified, respectively) and became less accurate with more advanced disease (3/14 and 4/19 stage III and IV patients were misclassified, respectively). We report the results of a noninvasive test using chromosomal aberrations and epigenetic changes identified in peripheral blood that, in this pilot study, distinguished patients with early-stage melanoma from other cohorts. PMID- 26225583 TI - Analysis of Association Between the Insertion Location of Iris Root and Narrow Angle. AB - AIM: To study the association between the insertion location of iris root and narrow angle. METHODS: This was a prospective observational study. A total of 142 eyes of 142 subjects were recruited, including 78 with narrow angles and 64 normals. All participants underwent ultrasound biomicroscopy and customized software was used to quantitatively analyze the images. An eye was considered to have narrow angle if there was iridotrabecular contact for at least 180 degrees on nonindentation gonioscopy in the primary position. The difference in various parameters between subjects with narrow angle and normal controls were analyzed. The association between the distance from the iris root to scleral spur (IrisD) and angle open distance was also analyzed. RESULTS: Significant differences between narrow angle and normal eyes were found for anterior chamber depth (ACD, 2.01+/-0.26 vs. 2.66+/-0.34 mm, P<=0.001), anterior chamber width (ACW, 10.96+/ 0.45 vs. 11.19+/-0.39 mm, P=0.003), IrisD (0.083+/-0.091 vs. 0.174+/-0.094 mm, P<0.001), and iris thickness at 1500 um from the scleral spur (IT1500, 0.533+/ 0.087 vs. 0.503+/-0.081 mm, P=0.007). After adjusting for age, sex, ACD, ACW, and IT1500, a smaller IrisD was associated significantly with narrow angle (odds ratio, 104.3; 95% confidence interval, 5.9-1852, comparing highest with lowest quartile). In terms of distinguishing narrow angle subjects from open angle subjects, IrisD [area under the receiver operator characteristic curve (AUC) 0.76] performed relatively poorer compared with ACD (AUC 0.95). CONCLUSIONS: A smaller distance from iris root to scleral spur was associated with the presence of narrow angle. PMID- 26225584 TI - Flat cells come full sphere: Are mutant cytoskeletal-related proteins oncoprotein monsters or useful immunogens? AB - Osteogenesis imperfecta is inherited as a dominant disease because if one allele is mutated, it contributes a mutant, destructive subunit polypeptide to collagen, which requires many subunits to form normal, polymeric, collagenous structures. Recent cancer genome atlas (TCGA) data indicate that cytoskeletal-related proteins are among the most commonly mutated proteins in human cancers, in distinct mutation frequency groups, i.e., including low mutation frequency groups. Part of the explanation for this observation is likely to be the fact that many of the coding regions for these proteins are very large, and indeed, it is likely these coding regions are mutated in many cells that never become cancerous. However, it would not be surprising if mutations in cytoskeletal proteins, when combined with oncoprotein or tumor suppressor protein mutations, had significant impacts on cancer development, for a number of reasons, including results obtained almost 5 decades ago indicating that well-spread cells in tissue culture, with well-formed cytoskeletons, were less tumorigenic than spherical cells with disrupted cytoskeletons. This raises the question, are mutant cytoskeletal proteins, which would likely interfere with polymer formation, a new class of oncoproteins, in particular, dominant negative oncoproteins? If these proteins are so commonly mutant, could they be the bases for common cancer vaccines? PMID- 26225587 TI - Sharing Your Practice Expertise: Writing Clinical Manuscripts for Publication. AB - Please do not be afraid of the writing process; we are here to help you through this journey. If you need mentorship through the process, consider looking to an expert or mentor on your unit or at a nearby university. If you do not find the mentorship you are seeking nearby, please let us know. We will put you in contact with 1 of our editorial board members to help guide you through the writing process. We want you to be successful so please have an outline of your idea and the type of manuscript you are planning to write developed. When you contact us, please share your questions openly-there are no "dumb" questions. Please refer often to our author guidelines during the writing process. Details for how best to submit a manuscript for the Clinical Issues in Neonatal Care section are outlined within the author guidelines. Finally, it is important to remember that ANC is a 4-color journal, so please submit full-color tables, graphs, and pictures to enhance the readability of your manuscript. During the editorial process we will do everything we can to facilitate and enhance your work. We will make recommendations that we believe will increase its scholarly application to improving neonatal care and outcomes. Revisions are often requested. After peer review, the section editor and coeditors will review the manuscript well in advance of the production deadline and provide additional feedback as needed. The end goal is excellent presentation of materials for our readers. If you are a reviewer for ANC , the next time you are asked to review a Clinical Issues in Neonatal Care manuscript, please consider the quality of the manuscript in relationship to guiding clinical care at the bedside and make recommendations to improve the manuscript so that staff nurses will best relate to the content. Do not be afraid to make recommendations about missing content or suggestions about ways to enhance the content and make it easier for clinicians to understand. Help us and the authors to increase their creativity and enhance their work. We want ANC to be the best clinical and research journal in neonatal care with articles of all styles that help us to enhance our caregiving and patient outcomes! PMID- 26225588 TI - Rare Disease Issue: What Do Neonatal Nurses Need to Know About Rare Diseases? PMID- 26225590 TI - NANN Shares Member Spotlight, 2015 Conference Highlights. PMID- 26225591 TI - Palliative and End-of-Life Care for Newborns and Infants: From the National Association of Neonatal Nurses. PMID- 26225592 TI - Deconstructing Black Swans: An Introductory Approach to Inherited Metabolic Disorders in the Neonate. AB - BACKGROUND: Inherited metabolic disorders (IMDs) are individually rare but collectively common disorders that frequently require rapid or urgent therapy. PURPOSE: This article provides a generalized approach to IMDs, as well as some investigations and safe therapies that may be initiated pending the metabolic consult. METHODS/SEARCH STRATEGY: An overview of the research supporting management strategies is provided. In addition, the newborn metabolic screen is reviewed. FINDINGS/RESULTS: Caring for infants with IMDs can seem difficult because each of the types is rarely seen; however, collectively the management can be seen as similar. IMPLICATIONS FOR PRACTICE: When an IMD is suspected, a metabolic specialist should be consulted for expert advice regarding appropriate laboratory investigations and management. Because rapid intervention of IMDs before the onset of symptoms may prevent future irreversible sequelae, each abnormal newborn screen must be addressed promptly. IMPLICATIONS FOR RESEARCH: Management can be difficult. Research in this area is limited and can be difficult without multisite coordination since sample sizes of any significance are difficult to achieve. PMID- 26225593 TI - Important Considerations in the Initial Clinical Evaluation of the Dysmorphic Neonate. AB - BACKGROUND: The approach to clinical evaluation of the dysmorphic neonate can be challenging and multifaceted. It requires specialized knowledge of rare diagnoses and awareness of immediate versus long-term needs for the newborn and the family. PURPOSE: This review summarizes important considerations in the initial evaluation of genetic syndromes, which can present in the neonatal period with variable aspects of dysmorphism. METHODS: An overview of the literature in this area is provided. FINDINGS/RESULTS: Several overlapping areas of concern for working with this population are addressed, including communication with the family, fundamentals of the physical examination, common genetic disorders, syndromes, as well as palliative care and end of life decision making for the newborn in the context of family needs. IMPLICATIONS FOR PRACTICE: The initial approach for the neonatal practitioner needs to focus on various aspects of the newborn's care, including medical stabilization, determining whether immediate laboratory or imaging studies are needed, careful physical examination with particular attention to detail, appropriate and timely communication with the family, and knowledge of various specific aspects of rare diseases. IMPLICATIONS FOR RESEARCH: More research is needed to better understand how to best support the newborn born with dysmorphia or a rare disease. Particular attention needs to be focused on strategies to best support the family who is often in crisis during the neonatal period. PMID- 26225594 TI - Pentalogy of Cantrell: Case Report With Review of the Literature. AB - BACKGROUND: Pentalogy of Cantrell is a rare, congenital disorder characterized by lower sternal defects, diaphragmatic defect, pericardial defect, supraumbilical abdominal wall abnormalities, and/or intracardiac defects. The collective defects result from failure of either differentiation or migration of mesenchymal or mesodermal structures during the embryonic phase of development. Mortality of the disease complex is high, and treatment, when appropriate, revolves around surgical correction of the associated defects. PURPOSE: This article presents a case of pentalogy of Cantrell and examines the literature to report the most current evidence relative to the embryology and pathophysiology. In addition, the methods of pre- and postnatal diagnosis, management, and prognostic indicators are examined. METHODS/SEARCH STRATEGY: Case report was gathered from the medical records and is provided as it occurred. The literature was searched for evidence of best management strategies as well as care implications for families. FINDINGS/RESULTS: A female newborn was delivered at (Equation is included in full text article.)weeks' gestation secondary to premature onset of labor. Prenatal ultrasonography identified an abdominal wall defect, diaphragmatic hernia, sternal defect, ventricular septal defect, and open neural tube defect. Examination immediately after delivery confirmed prenatal findings and a diagnosis of pentalogy of Cantrell was assigned. IMPLICATIONS FOR PRACTICE: Patients with the diagnosis of pentalogy of Cantrell should receive antenatal counseling relative to mortality and morbidity risks. An interprofessional approach in the immediate timeframe after delivery facilitates timely diagnostics and offers families prompt confirmation of antenatal findings. IMPLICATIONS FOR RESEARCH: Future research can focus on further elucidating genetic etiologies of pentalogy of Cantrell. PMID- 26225595 TI - Lily's Story: STAR Syndrome. AB - BACKGROUND: Lily was born 7 years ago with an illness that did not have a name; she had only a constellation of anomalies. The hope of happiness that most parents experience when expecting a baby was lost halfway through my pregnancy when we heard the words "survival" and "termination of the pregnancy." Lily did survive and has taught us, her parents, and members of her medical team the meaning of courage and collaboration. PURPOSE: This article describes our journey. Today that lesson has blossomed into a patient/parent/family engagement program changing the culture of healthcare and the future for hospitalized infants. IMPLICATIONS FOR PRACTICE: We share our story so that others might learn from our experiences. Hope and survival are so important to parents and families and health professionals need to be aware that taking away hope can devastate a family. IMPLICATIONS FOR RESEARCH: More research is needed about when a baby who was expected to die lives anyway and how that experience can best be supported for families. This is an area where the experience is unique and little is really known. PMID- 26225596 TI - Emergence of a Genetic Diagnosis: Case Presentation of a Preterm Infant With Cardiofaciocutaneous Syndrome. AB - BACKGROUND: Advanced prenatal screening and diagnostic testing have increased the number of newborns born with a confirmed diagnosis. Not all infants, however, are born with a known diagnosis. In fact, for some conditions, physical findings evolve over time and diagnosis can be further delayed because of premature birth. PURPOSE: This article shares a case report of a dysmorphic preterm infant admitted to the intensive care nursery for routine care. The emergence of physical findings as the baby matured during the first weeks of life and the stepwise, diagnostic approach used to confirm a rare genetic condition, cardiofaciocutaneous (CFC) syndrome, is provided. CASE FINDINGS/RESULTS: Key physical differences apparent at birth prompted screening for several genetic syndromes and a number of inborn errors of metabolism. As the phenotype emerged, a type of RASopathy entered the differential, the most likely of which was CFC syndrome. IMPLICATIONS FOR PRACTICE: Although CFC syndrome is rare, the combined incidence rate of RASopathies is greater, and as such, providers should be familiar with such conditions. Classic features may not be apparent in preterm infants so providers must remain astute to physical changes and communicate them with genetic consultants. IMPLICATIONS FOR RESEARCH: Gaining a better understanding of how providers can best support parents through the lengthy, diagnostic odyssey of genetic testing is important. In addition, ongoing research is needed to try to identify a genotype-phenotype correlation for CFC syndrome to guide patient surveillance and provide prognostic information to parents. PMID- 26225597 TI - A Case Study of Trisomy 13: Balancing Hope and Reality. AB - BACKGROUND: Trisomy 13, also known as Patau syndrome, occurs in 1/10,000 live births. Trisomy 13 is traditionally considered "lethal" with death as an outcome to be expected quickly. With regard to treatment decisions, families may feel that they are being judged by the medical community and their perception of quality of life. PURPOSE: This case describes an intrauterine growth restricted preterm female presenting with multiple dysmorphic features. METHODS: Using a case description as an example, the use of palliative care and alternative approaches to caregiving with the family of an infant with Trisomy 13 are explored. FINDINGS/RESULTS: A definitive diagnosis of trisomy 13 was made and discussed with the family at day 4 of life. Palliative care was initially used along with life-extending care. IMPLICATIONS FOR PRACTICE: With progression of the disease palliative care comes more to the forefront to help relieve physical and emotional suffering for not only the infant but the family, too. Offering nontraditional opportunities can help create a legacy and allow the families to know that their baby's life had meaning. IMPLICATIONS FOR RESEARCH: Providing caregiver information on the diagnosis and specialized palliative care may improve infant and family outcomes. PMID- 26225598 TI - Prader-Willi Syndrome: A Case Study and Parent Perspective. AB - BACKGROUND: Having a newborn diagnosed with a rare disorder is fraught with many challenges and opportunities for families and healthcare providers alike. PURPOSE: This article presents one mother's journey through the daily blessings and challenges of having a child with a rare disorder. METHODS: Storytelling and reflection interwoven with a case presentation. FINDINGS/RESULTS: Prader-Willi syndrome can be a diagnosis that is missed in the immediate postpartum period. Careful assessment and evaluation of the infant is needed. Attention to detail will support an accurate and timely diagnosis. IMPLICATIONS FOR PRACTICE: Those involved in the care of infants in the neonatal intensive care unit with special needs owing to a rare disorder must guide families through the difficult process of establishing a diagnosis and coping with the short- and long-term implications of that diagnosis. IMPLICATIONS FOR RESEARCH: Research about the needs of families with children with rare diseases is sorely needed. Finding strategies to best support these families is an area of great need. PMID- 26225601 TI - Katrina: Stories from the storm. PMID- 26225602 TI - Human versus veterinary POC glucometers. PMID- 26225603 TI - Is it time to retire the use of intrauterine glass balls for estrus suppression in mares? PMID- 26225604 TI - What Is Your Diagnosis? Pneumothorax. PMID- 26225605 TI - Animal Behavior Case of the Month. Vitreous degeneration. PMID- 26225606 TI - Pathology in Practice. Blastomycosis in an indoor-only cat. PMID- 26225607 TI - Pathology in Practice. Necrotizing leukoencephalitis (NLE). PMID- 26225608 TI - Effect of feeding a weight loss food beyond a caloric restriction period on body composition and resistance to weight gain in cats. AB - OBJECTIVE: To determine the effect of feeding a food with coconut oil and supplemental L-carnitine, lysine, leucine, and fiber on weight loss and maintenance in cats. DESIGN: Prospective clinical study. ANIMALS: 50 overweight cats. PROCEDURES: The study consisted of 2 trials. During trial 1, 30 cats were allocated to 3 groups (10 cats/group) to be fed a dry maintenance cat food to maintain body weight (group 1) or a dry test food at the same amount on a mass (group 2) or energy (group 3) basis as group 1. During trial 2, each of 20 cats was fed the test food and caloric intake was adjusted to maintain a weight loss rate of 1%/wk (weight loss phase). Next, each cat was fed the test food in an amount calculated to maintain the body weight achieved at the end of the weight loss phase (weight maintenance phase). Cats were weighed and underwent dual energy x-ray absorptiometry monthly. Metabolomic data were determined before (baseline) and after each phase. RESULTS: During trial 1, cats in groups 2 and 3 lost significantly more weight than did those in group 1. During trial 2, cats lost a significant amount of body weight and fat mass but retained lean body mass during the weight loss phase and continued to lose body weight and fat mass but gained lean body mass during the weight maintenance phase. Evaluation of metabolomic data suggested that fat metabolism was improved from baseline for cats fed the test food. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that feeding overweight cats the test food caused weight loss and improvements in body condition during the weight maintenance phase, possibly because the food composition improved energy metabolism. PMID- 26225609 TI - Effect of feeding a weight loss food beyond a caloric restriction period on body composition and resistance to weight gain in dogs. AB - OBJECTIVE: To determine the effect of feeding a food with coconut oil and supplemental L-carnitine, lipoic acid, lysine, leucine, and fiber on weight loss and maintenance in dogs. DESIGN: Prospective clinical study. ANIMALS: 50 overweight dogs. PROCEDURES: The study consisted of 2 trials. During trial 1, 30 dogs were allocated to 3 groups (10 dogs/group) to be fed a dry maintenance dog food to maintain body weight (group 1) or a dry test food at the same amount on a mass (group 2) or energy (group 3) basis as group 1. During trial 2, each of 20 dogs was fed the test food and caloric intake was adjusted to maintain a weight loss rate of 1% to 2%/wk (weight loss phase). Next, each dog was fed the test food in an amount calculated to maintain the body weight achieved at the end of the weight loss phase (weight maintenance phase). Dogs were weighed and underwent dual-energy x-ray absorptiometry monthly. Metabolomic data were determined before (baseline) and after each phase. RESULTS: During trial 1, dogs in groups 2 and 3 lost significantly more weight than did those in group 1. During trial 2, dogs lost a significant amount of body weight and fat mass but retained lean body mass (LBM) during the weight loss phase and continued to lose body fat but gained LBM during the weight maintenance phase. Evaluation of metabolomic data suggested that fat metabolism and LBM retention were improved from baseline for dogs fed the test food. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that feeding overweight dogs the test food caused weight loss and improvements in body condition during the weight-maintenance phase, possibly because the food composition improved energy metabolism. PMID- 26225610 TI - Assessment of protein and amino acid concentrations and labeling adequacy of commercial vegetarian diets formulated for dogs and cats. AB - OBJECTIVE: To determine measured crude protein (CP) and amino acid (AA) concentrations and assess labeling adequacy of vegetarian diets formulated for dogs and cats. DESIGN: Cross-sectional study. SAMPLE: 13 dry and 11 canned vegetarian diets for dogs and cats. PROCEDURES: Concentrations of CP and AAs were determined for each diet. Values were compared with the Association of American Feed Control Officials (AAFCO) Dog and Cat Food Nutrient Profiles. Product labels were assessed for compliance with AAFCO regulations. RESULTS: CP concentration (dry-matter basis) ranged from 19.2% to 40.3% (median, 29.8%). Minimum CP concentrations for the specified species and life stage were met by 23 diets; the remaining diet passed appropriate AAFCO feeding trials. Six diets did not meet all AA minimums, compared with the AAFCO nutrient profiles. Of these 6 diets, 1 was below AAFCO minimum requirements in 4 AAs (leucine, methionine, methionine cystine, and taurine), 2 were below in 3 AAs (methionine, methionine-cystine, and taurine), 2 were below in 2 AAs (lysine and tryptophan), and 1 was below in 1 AA (tryptophan). Only 3 and 8 diets (with and without a statement of calorie content as a requirement, respectively) were compliant with all pet food label regulations established by the AAFCO. CONCLUSION AND CLINICAL RELEVANCE: Most diets assessed in this study were not compliant with AAFCO labeling regulations, and there were concerns regarding adequacy of AA content. Manufacturers should ensure regulatory compliance and nutritional adequacy of all diets, and pets fed commercially available vegetarian diets should be monitored and assessed routinely. PMID- 26225611 TI - Survival time of dogs with splenic hemangiosarcoma treated by splenectomy with or without adjuvant chemotherapy: 208 cases (2001-2012). AB - OBJECTIVE: To determine survival time for dogs with splenic hemangiosarcoma treated with splenectomy alone, identify potential prognostic factors, and evaluate the efficacy of adjuvant chemotherapy. DESIGN: Retrospective case series. ANIMALS: 208 dogs. PROCEDURES: Medical records were reviewed, long-term follow-up information was obtained, and survival data were analyzed statistically. RESULTS: 154 dogs were treated with surgery alone, and 54 were treated with surgery and chemotherapy. Twenty-eight dogs received conventional chemotherapy, 13 received cyclophosphamide-based metronomic chemotherapy, and 13 received both conventional and metronomic chemotherapy. Median survival time of dogs treated with splenectomy alone was 1.6 months. Clinical stage was the only prognostic factor significantly associated with survival time. When the entire follow-up period was considered, there was no significant difference in survival time between dogs treated with surgery alone and dogs treated with surgery and chemotherapy. However, during the first 4 months of follow-up, after adjusting for the effects of clinical stage, survival time was significantly prolonged among dogs receiving any type of chemotherapy (hazard ratio, 0.6) and among dogs receiving both conventional and metronomic chemotherapy (hazard ratio, 0.4). CONCLUSIONS AND CLINICAL RELEVANCE: Clinical stage was strongly associated with prognosis for dogs with splenic hemangiosarcoma. Chemotherapy was effective in prolonging survival time during the early portion of the follow-up period. Combinations of doxorubicin-based conventional protocols and cyclophosphamide based metronomic protocols appeared to be more effective than either type of chemotherapy alone, but prolongations in survival time resulting from current protocols were modest. PMID- 26225612 TI - Venous blood gas analytes during isoflurane anesthesia in black-tailed prairie dogs (Cynomys ludovicianus). AB - OBJECTIVE: To describe changes in venous blood gas analytes during isoflurane anesthesia in black-tailed prairie dogs (Cynomys ludovicianus). DESIGN: Prospective study. ANIMALS: 16 black-tailed prairie dogs. PROCEDURES: Black tailed prairie dogs were placed in an anesthesia chamber for induction of general anesthesia, which was maintained with isoflurane in oxygen delivered via mask. Immediately following anesthetic induction, a venous blood sample was obtained from the medial saphenous vein; a second venous blood sample was obtained just prior to anesthetic gas shutoff. An evaluation of venous blood gas analytes was performed on each sample. General linear mixed models with repeated measures were used for data analyses. RESULTS: Median anesthetic time was 90 minutes (range, 60 to 111 minutes). A significant increase from immediately after induction to completion of anesthesia was observed in Pco2 and mean blood chloride ion, BUN, and creatinine concentrations. A decrease in Po2, mean blood pH, and anion gap was observed from induction of anesthesia to completion. No significant differences during anesthesia were observed in mean base excess or blood bicarbonate, sodium, potassium, calcium, magnesium, blood glucose, lactate, and total CO2 concentrations. No complications occurred during or after anesthesia for any animal. CONCLUSIONS AND CLINICAL RELEVANCE: Examination of prairie dogs often requires general anesthesia, with isoflurane currently the inhalation agent of choice. Results suggested respiratory acidosis and relative azotemia may occur during isoflurane anesthesia of prairie dogs. Given the increased risk associated with anesthesia in small mammals and the propensity for respiratory disease in prairie dogs, insight into physiologic changes associated with isoflurane anesthesia in healthy prairie dogs can aid in perioperative evaluation and anesthetic monitoring in this rodent species. PMID- 26225613 TI - Pain management framework in the emergency department: patterns in 40 emergency departments worldwide. AB - Many studies illustrate variation in pain management protocols in emergency medicine. This study examines analgesia frameworks in emergency departments (EDs) in multiple countries, compares them with the recent literature, and illuminates the variability in protocols and treatment. A survey was conducted assessing the pain management framework and practices in a convenience sample of 40 hospitals distributed over 22 countries. Most EDs (80%) indicated that pain intensity was routinely documented, most commonly (42.5%) using a verbal numerical 0-10 scale. Most (57.5%) reported specific protocols for specific conditions, with 56.5% reporting that these protocols were mandatory. Structured training was reported by 27.5% of responders. All (100%) reported analgesia administration in the trauma room. Oral paracetamol (67.5%) and intravenous morphine (92.5%) were the most commonly used analgesics. The variability in the pain management framework is high among EDs worldwide, highlighting the need for more international uniformity in analgesia practices in the ED. PMID- 26225614 TI - Short-term predictive capacity of two different triage systems in patients with acute heart failure: TRICA-EAHFE study. AB - OBJECTIVE: To evaluate whether prioritization of patients with acute heart failure (AHF) in the Andorran Triage Model/Spanish Triage System (MAT/SET) and the Manchester Triage System (MTS) also allows the identification of different profiles of outcome and prognosis and determine whether either system has a better predictive capacity of outcomes. PATIENTS AND METHODS: Patients with AHF included in the Spanish EAHFE registry from hospitals using the MAT/SET or MTS were selected and divided according to the triage system used. Outcome variables included hospital admission, length of stay, death during admission, 3, 7, and 30 day all-cause mortality, and emergency department (ED) reconsultation at 30 days. The results were compared according to the level of priority and the triage system used. RESULTS: We included 3837 patients (MAT/SET=2474; MTS=1363) classified as follows: 4.0% level 1; 34.7% level 2; 55.1% level 3; and 6.3% levels 4-5. Both systems associated greater priority with higher rates of admission and mortality; the MTS associated greater priority with greater ED reconsultation and the MAT/SET found greater priority to be associated with less ED reconsultation. The discriminative capacity of the two scales for adverse outcomes was statistically significant, albeit poor, for almost all the outcome events and it was of scarce clinical relevance (Area under the curve of the receiver operating characteristic between 0.458 and 0.661). CONCLUSION: The prediction of the outcome of patients with AHF determined with the MAT/SET or MTS showed scarce differences between the two systems, and their discriminative capacity does not seem to be clinically relevant. PMID- 26225615 TI - Incidence and etiology of mortality in polytrauma patients in a Dutch level I trauma center. AB - BACKGROUND: Earlier studies assessing mortality in polytrauma patients have focused on improving trauma care and reducing complications during hospital stay. The same studies have shown that the complication rate in these patients is high, often resulting in death. The aim of this study was to assess the incidence and causes of mortality in polytrauma patients in our institute. Secondarily, we assessed the donation and autopsy rates and outcome in these patients. PATIENTS AND METHODS: All polytrauma patients (injury severity score>=16) transported to and treated in our institute during a period of 6 years were retrospectively analyzed. We included all patients who died during hospital stay. Prehospital and in-hospital data were collected on patients' condition, diagnostics, and treatment. The chance of survival was calculated according to the TRISS methodology. Patients were categorized according to the complications during treatment and causes of death. Logistic regression analysis was used to design a prediction model for mortality in major trauma. A statistical analysis was carried out. RESULTS: Of the 1073 polytrauma patients who were treated in our institute during the study period, 205 (19.1%) died during hospital stay. The median age of the deceased patients was 58.8 years and 125 patients were men. Their mean injury severity score was 30.4. The most common mechanism of injury involved fall from height, followed by bicycle accidents. Almost 50% of the patients underwent an emergency intervention. Almost 92% of the total population died because of the effects of the accident (primary trauma). Of these, 24% died during primary assessment in the emergency department. Most patients died because of the effects of severe head injury (63.4%), followed by exsanguination (17.6%). The most common type of complications causing death during treatment was respiratory failure (6.3%), followed by multiple organ failure (1.5%). Autopsy was performed in 10.4%. Organ donation procedure was performed in 14.5%. Permission for donation was not provided in almost 20% of the population. CONCLUSION: The mortality rate in polytrauma patients in our institute is considerable and comparable with the international literature. Most patients die because of the effects of the accident (primary trauma). Autopsy and organ donation rates are low in our institution and leave room for substantial improvements in the future. PMID- 26225616 TI - Health Care for Americans with Disabilities--25 Years after the ADA. PMID- 26225617 TI - Towards high-throughput microfluidic Raman-activated cell sorting. AB - Raman-activated cell sorting (RACS) is a promising single-cell analysis technology that is able to identify and isolate individual cells of targeted type, state or environment from an isogenic population or complex consortium of cells, in a label-free and non-invasive manner. However, compared with those widely used yet labeling-required or staining-dependent cell sorting technologies such as FACS and MACS, the weak Raman signal greatly limits the further development of the existing RACS systems to achieve higher throughput. Strategies that can tackle this bottleneck include, first, improvement of Raman-acquisition efficiency and quality based on advanced Raman spectrometers and enhanced Raman techniques; second, development of novel microfluidic devices for cell sorting followed by integration into a complete RACS system. Exploiting these strategies, prototypes for a new generation of RACS have been demonstrated, such as flow based OT-RACS, DEP-RACS, and SERS/CARS flow cytometry. Such high-throughput microfluidic RACS can provide biologists with a powerful single-cell analysis tool to explore the scientific questions or applications that have been beyond the reach of FACS and MACS. PMID- 26225618 TI - Genetic and Clinical Analyses of Southern Chinese Children with Peutz-Jeghers Syndrome. AB - BACKGROUND: Children with Peutz-Jeghers syndrome (PJS) suffer from the continuous growth of polyps in their gastrointestinal tracts. Limited research on PJS has found that truncating mutations of the serine/threonine kinase 11 (STK11) gene may correlate with early symptoms and a greater number of polyps. Thus, further studies correlating the genetic and clinical characteristics of PJS would increase our understanding of this condition and improve recommendations for treatment. AIMS: Our study was designed to characterize the genetic and clinical characteristics of four Chinese PJS children (two girls and two boys) and their affected relatives from Southern China. RESULTS: One recurrent missense mutation (c.487G>C) and two novel nonsense (truncation) mutations (c.717G>A and c.871G>T) in the STK11 gene were identified. The two boys with nonsense mutations underwent their first surgeries at younger ages (2 and 4 years) compared to the others. The two girls underwent their first surgeries at similar ages, though the girl with the nonsense mutation underwent more surgeries than the girl with the missense mutation. The children with truncation mutations had medium to high counts of hamartomatous polyps, whereas the girl with the missense mutation had a lower count. The clinical findings were similar among affected individuals within each of the three families. CONCLUSIONS: These cases are consistent with previous findings, thus we conclude that children with nonsense mutations in STK11 should be closely monitored for polyp formation. PMID- 26225619 TI - The Mediating Role of Perceived Descriptive and Injunctive Norms in the Effects of Media Messages on Youth Smoking. AB - This research advances and tests a normative mediation model of media effects on youth smoking. The model predicts that exposure to various types of smoking related media messages, including anti-smoking ads, cigarette ads, and smoking scenes in movies and television shows, exerts indirect effects on youth smoking intentions through the mediation of perceived descriptive and injunctive norms. Analysis of the data from the 3rd Legacy Media Tracking Survey offers general support for the proposed model with some unexpected findings, revealing a complex picture of media influence on youth smoking via normative and non-normative mechanisms. Theoretical and practical implications of the findings are discussed. PMID- 26225623 TI - Black-to-Transmissive Electrochromism with Visible-to-Near-Infrared Switching of a Co(II)-Based Metallo-Supramolecular Polymer for Smart Window and Digital Signage Applications. AB - Black-to-transmissive electrochromism has been obtained with a Co(II)-based metallo-supramolecular polymer (polyCo). Thin films of polyCo, based on bisterpyridine ligand assembled with Co(II) metal ion, were constructed by spray casting the polymer onto ITO glass. With such simple fabricating means to form good-quality films, polyCo films show stable switching at the central metal ion of the Co(II)/Co(I) redox reaction when immersed in aqueous solution. With an increase in the pH of the aqueous electrolyte solution from neutral, the film exhibits a color response due to the interaction between the d-orbital electron and hydroxide ions affecting the d-d* transition. As a result, a nearly transparent-to-black electrochromic performance can be achieved with a transmittance difference at 550 nm of 74.3% (81.9-7.6%) in pH 13 solution. The light absorption of the film can be tuned over light regions from visible to near infrared with a large attenuation. PMID- 26225624 TI - Recent Applications of Oxetanes in the Synthesis of Heterocyclic Compounds. AB - Oxetanes are valuable intermediates in organic synthesis, and strategic manipulations of this strained heterocycle continue to emerge. In this Synopsis, recent, distinct approaches to construct heterocyclic systems using oxetanes are described. These include ring expansion, ring opening, and C-2 functionalization. PMID- 26225625 TI - Correction to Approved Drugs Containing Thiols as Inhibitors of Metallo-beta lactamases: Strategy To Combat Multidrug-Resistant Bacteria. PMID- 26225626 TI - Orientational Control of Colloidal 2D-Layered Transition Metal Dichalcogenide Nanodiscs via Unusual Electrokinetic Response. AB - We report an unusual response of colloidal layered transition metal dichalcogenide (TMDC) nanodiscs to the electric field, where the orientational order is created transiently only during the time-varying period of the electric field while no orientational order is created by the DC field. This result is in stark contrast to the typical electrokinetic response of various other colloidal nanoparticles, where the permanent dipole or (and) anisotropic-induced dipole creates a sustaining orientational order under the DC field. This indicates the lack of a sizable permanent dipole or (and) anisotropic-induced dipole in colloidal TMDC nanodiscs, despite their highly anisotropic lattice structure. While the orientational order is created only transiently by the time-varying field, a near-steady-state orientational order can be obtained by using an AC electric field. We demonstrate the utility of this method for the controlled orientation of colloidal nanoparticles that cannot be controlled via the usual interaction of the electric field with the nanoparticle dipole. PMID- 26225627 TI - Sex-Related Differences in Ocular Blood Flow of Healthy Subjects Using Laser Speckle Flowgraphy. AB - PURPOSE: To evaluate sex-related differences in ocular blood flow of healthy subjects using laser speckle flowgraphy (LSFG). METHODS: In this prospective cross-sectional study, we examined 103 healthy volunteers (47 males, 56 females; mean age: 39.3 +/- 15.6 years and 42.1 +/- 18.7 years, respectively). The blood flow to the optic nerve head (ONH) and choroid was assessed with LSFG, including mean blur rate (MBR) and pulse waveform variables. We evaluated sex-related differences in these variables and compared them with those in other clinical parameters. RESULTS: A linear single regression showed that the ONH-MBR (r = 0.402, P < 0.001) and five ONH pulse waveforms were significantly correlated with sex. A multiple stepwise regression analysis revealed that sex (beta = 0.389, P < 0.001) and age (beta = -0.290, P = 0.002) were independent factors, indicating the ONH-MBR, age (beta = -0.394, P < 0.001), and subfoveal choroidal thickness (beta = 0.221, P = 0.016) were independent factors indicating the choroidal MBR. Moreover, sex was an independent factor indicating the five ONH pulse waveform parameters that were consistent with results of the linear single regression. The optic nerve head MBR in the female group was significantly higher than that in the male group (P < 0.001), but no differences were observed in the choroid between the groups (P > 0.05). CONCLUSIONS: Sex-related differences are present in ocular blood flow in the ONH, but not in the choroid in healthy subjects. We believe that these differences should be considered when interpreting blood flow data in ocular diseases. PMID- 26225628 TI - Aqueous Humor Outflow Physiology in NOS3 Knockout Mice. AB - PURPOSE: To investigate the role of endothelial nitric oxide synthase (eNOS) on conventional outflow function using NOS3 knockout (KO) mice. METHODS: Intraocular pressure was measured in both NOS3 KO and wild type (WT) by rebound tonometry. Outflow facility was measured by perfusing enucleated mouse eyes at multiple pressure steps. A subset of eyes was sectioned and stained for histology. Mock aqueous humor +/- the nitric oxide (NO) donors nitroprusside dihydrate (SNP) or S Nitroso-N-Acetyl-D,L-Penicillamine (SNAP) was perfused into enucleated eyes. SNP and SNAP was administered topically at 0, 1, 2, and 3 hours while the contralateral eyes served as vehicle controls. Intraocular pressure was measured in both eyes before and after the last drug treatment. RESULTS: Intraocular pressure was higher in KO mice (18.2 +/- 0.7 mm Hg vs. 13.9 +/- 0.5 mm Hg, mean +/- SEM, n = 30, P < 0.05), and pressure-dependent conventional drainage was significantly lower (0.0058 +/- 0.0005 MUL/min/mm Hg, mean +/- SEM, n = 21) compared with WT mice (0.0082 +/- 0.0013 MUL/min/mm Hg, n = 23, P < 0.05). No obvious morphological differences in iridiocorneal angle tissues were observed in hematoxylin and eosin (H&E)-stained sections. SNP and SNAP significantly increased pressure-dependent drainage in KO animals (n = 12, P < 0.05). In WT mice, SNP and SNAP caused a significant increase in pressure dependent drainage (n = 12, P < 0.05) to a similar degree as in KO mice. Topical application of SNP significantly reduced IOP in WT and KO mice (n = 12, P < 0.05), but SNAP did not change IOP significantly (n = 19). CONCLUSIONS: NOS3 KO mice have elevated IOP, which is likely the result of reduced pressure-dependent drainage. These findings are consistent with human data showing polymorphisms in the NOS3 gene associate with ocular hypertension and the development of glaucoma. PMID- 26225630 TI - Herpes Simplex Keratitis: Bilateral Effects. PMID- 26225629 TI - In Vivo Confocal Microscopy Demonstrates Bilateral Loss of Endothelial Cells in Unilateral Herpes Simplex Keratitis. AB - PURPOSE: To report bilateral corneal endothelial cell density (ECD), as well as its correlation with subbasal nerve changes, in patients with unilateral herpes simplex keratitis (HSK). METHODS: Thirty-six eyes of 36 patients with corneal scarring caused by HSK, as well as their respective contralateral clinically unaffected eyes, were prospectively studied and compared with 26 eyes of 26 healthy volunteers. In vivo confocal microscopy and corneal sensation of the central cornea were performed bilaterally in all patients and in one random eye of controls. The ECD and subbasal corneal nerve density, including the lengths of total nerves, main trunks, and branches were evaluated and correlated to central corneal sensation. RESULTS: The ECD was significantly lower in eyes affected with HSK than in controls (2304 +/- 578 vs. 2940 +/- 370 cells/mm(2), P < 0.0001). Surprisingly, lower ECD was also detected in contralateral clinically unaffected eyes (2548 +/- 423), compared to controls (P = 0.02). Both affected and contralateral eyes showed decrease in total nerve length, compared to controls (10.0 +/- 6.3 vs. 17.6 +/- 6.3 vs. 21.9 +/- 4.3 mm/mm2, respectively; P < 0.05 for all). The ECD correlated positively with total nerve length (r = 0.39, P = 0.0009) and with corneal sensation (r = 0.31, P = 0.009). CONCLUSIONS: In vivo confocal microscopy findings demonstrated alterations in corneal ECD in both affected and clinically unaffected contralateral eyes of patients with unilateral HSK. Moreover, the positive significant correlation between the ECD and the subbasal nerve density may suggest a potential link between corneal innervation and corneal endothelial cell homeostasis. PMID- 26225631 TI - Desiccating Stress-Induced MMP Production and Activity Worsens Wound Healing in Alkali-Burned Corneas. AB - PURPOSE: To evaluate the effects of dry eye on ocular surface protease activity and sight threatening corneal complications following ocular surface chemical injury. METHODS: C57BL/6 mice were subjected to unilateral alkali burn (AB) with or without concomitant dry eye for 2 or 5 days. Mice were observed daily for appearance of corneal perforation. Whole corneas were harvested and lysed for RNA extraction. Quantitative real-time PCR was performed to measure expression of inflammation cytokines, matrix metalloproteinases (MMP). Matrix metalloproteinase 9 activity, gelatinase activity, and myeloperoxidase (MPO) activity were evaluated in corneal lysates. Presence of infiltrating neutrophils was evaluated by immunohistochemistry and flow cytometry. RESULTS: Eyes subjected to the combined model of AB and dry eye (CM) had 20% sterile corneal perforation rate as soon as 1 day after the initial injury, which increased to 35% by 5 days, delayed wound closure and increased corneal opacity. Increased levels of IL-1beta, -6, and MMPs-1, -3, -8, -9, and -13, and chemokine (C-X-C motif) ligand 1 (CSCL1) transcripts were found after 2 days in CM compared with AB corneas. Increased MMP 1, -3, -9, and -13 immunoreactivity and gelatinolytic activity were seen in CM corneas compared with AB. Increased neutrophil infiltration and MPO activity was noted in the CM group compared with AB 2 days post injury. CONCLUSIONS: Desiccating stress worsens outcome of ocular AB, creating a cytokine and protease storm with greater neutrophil infiltration, increasing the risk of corneal perforation. PMID- 26225633 TI - Disc Torsion and Vertical Disc Tilt Are Related to Subfoveal Scleral Thickness in Open-Angle Glaucoma Patients With Myopia. AB - PURPOSE: To find out the characteristics of optic disc morphology in glaucomatous eyes and to evaluate related ocular factors, including the scleral thickness measured from swept-source optical coherence tomography (OCT). METHODS: We compared disc torsion and tilt between 180 normal controls and 180 patients with open-angle glaucoma, matched according to age and axial length based on propensity scores. In a subset of 63 glaucoma and matched control eyes with high myopia, swept-source OCT images of the optic nerve head obtained. The disc ovality and torsion degree were measured from disc photographs, and tilt degree was measured from cross-sectional images of the optic nerve head using swept source OCT. Scleral thickness was measured from swept-source OCT images at the subfoveal point and 1000 MUm away superiorly, inferiorly, temporally, and nasally from the subfoveal point. RESULTS: The degree of disc tilt and torsion was significantly different between glaucoma (9.3 +/- 6.3 degrees and 28.2 +/- 19.8 degrees , respectively) and control eyes (6.2 +/- 4.1 degrees and 14.1 +/- 8.0 degrees , respectively) with similar axial length. The thickness of the inferior sclera and the superior-inferior difference were significantly different between control and glaucomatous eyes with high myopia (P < 0.001 and P = 0.031). The thickness of the inferior sclera and the superior-inferior difference were significantly related to the disc tilt (P = 0.034 for inferior sclera and P < 0.001 for superior-inferior difference) and torsion (P < 0.001 and P < 0.001, respectively) in glaucomatous eyes with high myopia. CONCLUSIONS: Disc tilt and torsion were prominent features of glaucomatous eyes when compared to normal controls with similar axial length and were significantly related to the thickness of the inferior sclera in glaucomatous eyes with myopia. PMID- 26225632 TI - Transcriptome Profiling of Developing Murine Lens Through RNA Sequencing. AB - PURPOSE: Transcriptome is the entire repertoire of transcripts present in a cell at any particular time. We undertook a next-generation whole transcriptome sequencing approach to gain insight into the transcriptional landscape of the developing mouse lens. METHODS: We ascertained mouse lenses at six developmental time points including two embryonic (E15 and E18) and four postnatal stages (P0, P3, P6, and P9). The ocular tissue at each time point was maintained as two distinct pools serving as biological replicates for each developmental stage. The mRNA and small RNA libraries were paired-end sequenced on Illumina HiSeq 2000 and subsequently analyzed using bioinformatics tools. RESULTS: Mapping of mRNA and small RNA libraries generated 187.56 and 154.22 million paired-end reads, respectively. We detected a total of 14,465 genes in the mouse ocular lens at the above-mentioned six developmental stages. Of these, 46 genes exhibited a 40-fold differential (higher or lower) expression at one the five developmental stages (E18, P0, P3, P6, and P9) compared with their expression level at E15. Likewise, small RNA profiling identified 379 microRNAs (miRNAs) expressed in mouse lens at six developmental time points. Of these, 49 miRNAs manifested an 8-fold differential (higher or lower) expression at one the five developmental stages, as mentioned above compared with their expression level at E15. CONCLUSIONS: We report a comprehensive profile of developing murine lens transcriptome including both mRNA and miRNA through next-generation RNA sequencing. A complete repository of the lens transcriptome of six developmental time points will be monumental in elucidating processes essential for the development of the ocular lens and maintenance of its transparency. PMID- 26225634 TI - Manganese-Enhanced MRI for Preclinical Evaluation of Retinal Degeneration Treatments. AB - PURPOSE: Apply manganese-enhanced magnetic resonance imaging (MEMRI) to assess ion channel activity and structure of retinas from mice subject to light-induced retinal degeneration treated with prophylactic agents. METHODS: Abca4(-/-)Rdh8(-/ ) double knockout mice with and without prophylactic retinylamine (Ret-NH2) treatment were illuminated with strong light. Manganese-enhanced MRI was used to image the retina 2 hours after intravitreous injection of MnCl2 into one eye. Contrast-enhanced MRIs of the retina and vitreous humor in each experimental group were assessed and correlated with the treatment. Findings were compared with standard structural and functional assessments of the retina by optical coherence tomography (OCT), histology, and electroretinography (ERG). RESULTS: Manganese-enhanced MRI contrast in the retina was high in nonilluminated and illuminated Ret-NH2-treated mice, whereas no enhancement was evident in the retina of the light-illuminated mice without Ret-NH2 treatment (P < 0.0005). A relatively high signal enhancement was also observed in the vitreous humor of mice treated with Ret-NH2. Strong MEMRI signal enhancement in the retinas of mice treated with retinylamine was correlated with their structural integrity and function evidenced by OCT, histology, and a strong ERG light response. CONCLUSIONS: Manganese-enhanced MRI has the potential to assess the response of the retina to prophylactic treatment based on the measurement of ion channel activity. This approach could be used as a complementary tool in preclinical development of new prophylactic therapies for retinopathies. PMID- 26225635 TI - Topography of Lymphatic Markers in Human Iris and Ciliary Body. AB - PURPOSE: Reports of lymphatics in the anterior human uvea are contradictory. This might be caused due to a certain topography, which has not been considered yet. Therefore, here we systematically analyze iris and adjacent ciliary body with immunohistochemistry by combining various lymphatic markers. METHODS: Human iris and ciliary body were obtained from cornea donors and prepared for cryosectioning. Cross sections of tissue blocks at 12/3/6/9 o'clock position and at corresponding intersections (1:30/4:30/7:30/10:30) were processed for immunohistochemistry of LYVE-1, PDPN, PROX1, FOXC2, VEGFR3, and CCL21, and when necessary, these lymphatic markers were combined with CD31, alpha-smooth muscle actin, CD68, and 4',6-diamidino-2 phenylindole dihydrochloride (DAPI). Double, triple, and quadruple marker combinations were documented using confocal microscopy. RESULTS: Numerous podoplanin+ cells were mainly located at the anterior border of the iris while LYVE-1+ cells were distributed throughout the nonpigmented part. Both cell populations were PROX1/FOXC2/CCL21/VEGFR3-. Blood vessels, iris smooth muscles, and individual cells were VEGFR3+. While PDPN+ cells were rarely detected posteriorly of the iris root, many LYVE-1+ cells were present within the ciliary body muscle and villi. Within the muscle, occasionally PDPN+ vessel-like structures were detectable, but these were never colocalized with LYVE-1. Similar vessel-like structures were VEGFR3+/PROX1-/CCL21-, but CD31+. Further, ciliary muscle fibers and ciliary epithelium were immunoreactive for VEGFR3/CCL21, but were LYVE-1/PDPN-. A certain topography of structures at the various uvea-positions investigated was not obvious. The majority of LYVE-1+ cells displayed immunoreactivity for CD68. CONCLUSIONS: Lymphatic vessels colocalizing for at least two lymphatic markers were not detectable. Therefore, if present, putative lymphatic channels of the anterior uvea might display a different marker panel than generally presumed. PMID- 26225636 TI - Hearing Loss After Vestibular Implantation in Sand Rats With Normal Hearing. AB - IMPORTANCE: Bilateral vestibular failure is a debilitating condition that may lead to oscillopia and adversely affect quality of life. Researchers have suggested that vestibular function might be restored with implantation of an external mechanical stimulation device. However, it is essential that such a device must not interfere with normal hearing. OBJECTIVE: To evaluate the effect of vestibular implant insertion on hearing in a sand rat model with normal hearing. DESIGN, SETTING, AND SUBJECTS: The study was conducted in a tertiary medical center in accord with the guidelines of the Rabin Medical Center Animal Care and Use Committee. The experiment was performed in 6 adult, 6-month-old, fat sand rats (Psammomys obesus), which have a unique aural anatomy that permits access to the inner ear. The study dates were March 2013 to March 2014. INTERVENTIONS: The sand rats were anesthetized and electrodes were implanted unilaterally (in 6 sand rats) or bilaterally (in 2 sand rats) in all 3 semicircular canals (lateral, then posterior, and then superior) by fenestration of the respective ampullas. To measure air and bone conduction thresholds, auditory nerve brainstem evoked responses to alternating polarity clicks and 1 kHz tone bursts were tested before surgery, at each operative stage, and after surgery. MAIN OUTCOMES AND MEASURES: Air or bone conduction threshold shifts after implantation of a vestibular implant electrode array in each semicircular canal. RESULTS: After unilateral implantation of the vestibular implant, sand rats showed a sideways head tilt, whereas after bilateral implantation, sand rats ran around in circles and were unable to stand still or walk on a treadmill. On statistical analysis, statistically significant differences from preoperative values were obtained across all stages of surgery for air conduction thresholds. The largest and statistically significant air conduction shift for 1-kHz stimuli (mean [SD, 13.7 [2.8] dB; P < .004) as well as for clicks (12.5 [2.1] dB; P < .002) was found for the superior canal electrode insertion. For the posterior canal, the air conduction thresholds to 1-kHz stimuli and to clicks shifted significantly after electrode insertion (mean [SD], 7.5 [2.3] dB; P < .01 and 7.5 [0.9] dB; P < .001). For the lateral canal, only the threshold to clicks changed significantly (mean [SD], 5.5 [1.7] dB; P < .02). Bone conduction thresholds did not change significantly after vestibular electrode insertion. CONCLUSIONS AND RELEVANCE: Implantation of a vestibular device is associated with mild to moderate conductive hearing loss in fat sand rats with normal hearing, especially when the device is placed in the posterior and superior semicircular canals. Bilateral implantation is associated with major vestibular pathologic results. Further studies are needed in animals with cochlear or vestibular disorders before it can be definitively concluded that vestibular implantation carries only a minor risk to hearing. PMID- 26225637 TI - Ordering of the Serum Angiotensin-Converting Enzyme Test in Patients Receiving Angiotensin-Converting Enzyme Inhibitor Therapy: An Avoidable but Common Error. AB - BACKGROUND: Serum angiotensin-converting enzyme (ACE) levels may be decreased by use of ACE inhibitor (ACEI) medication. In this study, we determined how often ACE levels were measured in patients receiving ACEI therapy. METHODS: ACE levels analyzed over a 54-month preintervention time period at an academic medical center were reviewed retrospectively for tests performed during ACEI therapy. These data were compared with a large, deidentified dataset of ACE levels measured at a national reference laboratory; in vitro studies of ACEI inhibition; and liquid chromatography time-of-flight mass spectrometry detection of lisinopril in a subset of clinical specimens. RESULTS: Over a 54-month period, 1,292 patients had ACE levels measured, with 108 patients (8.4%) receiving ACEI therapy at the time of testing. ACE levels measured for patients receiving ACEI therapy were substantially lower. In general, clinical teams did not recognize a medication effect on ACE levels. Introduction of a warning prompt in the electronic health record reduced the ordering of ACE levels in patients receiving ACEIs by > 60% in a 17-month postintervention time period. The deidentified dataset of ACE levels at a reference laboratory showed a bimodal distribution, with a peak of very low ACE levels. Using liquid chromatography time-of-flight mass spectrometry, the presence of lisinopril was confirmed in a subset of specimens with low ACE activity. In vitro studies of two different ACE assays showed significant inhibition of activity at clinically relevant concentrations. CONCLUSIONS: Assessment of ACE activity is often measured for patients receiving ACEIs, potentially leading to low ACE concentrations and inaccurate interpretations. PMID- 26225638 TI - Creating a Conversation About Immunizations. PMID- 26225639 TI - Chiral Conjugated Corrals. AB - We present here a new design motif for strained, conjugated macrocycles that incorporates two different aromatics into the cycle with an -A-B-A-B- pattern. In this study, we demonstrate the concept by alternating electron donors and acceptors in a conjugated cycle. The donor is a bithiophene, and the acceptor is a perylene diimide derivative. The macrocycle formed has a persistent elliptiform cavity that is lined with the sulfur atoms of the thiophenes and the pi-faces of the perylene diimide. Due to the linkage of the perylene diimide subunits, the macrocycles exist in both chiral and achiral forms. We separate the three stereoisomers using chiral high-performance liquid chromatography and study their interconversion. The mechanism for interconversion involves an "intramolecular somersault" in which one of the PDIs rotates around its transverse axis, thereby moving one of its diimide heads through the plane of the cavity. These unusual macrocycles are black in color with an absorption spectrum that spans the visible range. Density functional theory calculations reveal a photoinduced electron transfer from the bithiophene to the perylene diimide. PMID- 26225640 TI - Simultaneous Electro-Optical Tracking for Nanoparticle Recognition and Counting. AB - We present the first detailed experimental observation and analysis of nanoparticle electrophoresis through a nanochannel obtained with synchronous high bandwidth electrical and camera recordings. Optically determined particle diffusion coefficients agree with values extracted from fitting electrical transport measurements to distributions from 1D Fokker-Planck diffusion-drift theory. This combined tracking strategy enables optical recognition and electrical characterization of nanoparticles in solution, which can have a broad range of applications in biology and materials science. PMID- 26225642 TI - Epidemiology of Prostate Cancer. AB - Prostate cancer is the most common malignancy among males worldwide, and is the second leading cause of cancer death among men in United States. According to GLOBOCAN (2012), an estimated 1.1 million new cases and 307,000 deaths were reported in 2012. The reasons for the increase of this disease are not known, but increasing life expectancy and modified diagnostic techniques have been suggested as causes. The established risk factors for this disease are advancing age, race, positive family history of prostate cancer and western diet (use of fat items). Several other risk factors, such as obesity, physical activity, sexual activity, smoking and occupation have been also associated with prostate cancer risk, but their roles in prostate cancer etiology remain uncertain. This mini-review aims to provide risk factors, disease knowledge, prevalence and awareness about prostate cancer. PMID- 26225641 TI - Enzyme Selectivity of HIV Reverse Transcriptase: Conformations, Ligands, and Free Energy Partition. AB - Atomically detailed simulations of HIV RT are performed to investigate the contributions of the conformational transition to the overall rate and specificity of enzyme catalysis. A number of different scenarios are considered within Milestoning theory to provide a more complete picture of the process of opening and closing the enzyme. We consider the open to closed transition in the absence of and with the correct and incorrect substrates. We also consider the free energy profile and the kinetics of the conformational change after the chemistry step in which a new base was added to the DNA, but the DNA was not yet displaced. We partition the free energy along the reaction coordinate and analyze the importance of different protein domains. Strikingly, significant influence on the free energy profile is detected for amino acids far from the active site. The overall long-range impact is about 50 percent of the total. We also illustrate that the overall rate is not necessarily determined by the highest free energy barrier along the reaction path (with respect to the free enzyme and substrate) and that the specificity is not necessarily determined by the same reaction step that determines the rate. PMID- 26225643 TI - Contradictory Relationships between Cancer and Normal Cells and Implications for Anti-cancer Therapy. AB - Cancer treatment remains a serious problem worldwide. Analysis of the relationship between cancer cells and normal cells reveals that these two share characteristics in contradiction, thus could be analyzed by using contradictory principles. Under the theory of contradictory principles, induction of a dormant state or reversal of cancer cells is an important treatment strategy beyond traditional cytotoxic therapy. Normal cells are also the targets and under the influence of anti-cancer treatments and should be considered during therapy. Findings based on crosstalk between these two cell types may offer opportunities for the development of new biomarkers and therapies. PMID- 26225644 TI - Expression of Cancer-Testis Antigens in Pediatric Cancers. AB - Cancer-testis antigens (CTAs) are a group of tumor-associated antigens with more than 140 members whose expression has been shown to be limited to gametogenic tissues and placenta among normal tissues. However, malignant tissues of different origins have shown aberrant and elevated expression of these antigens. Such a pattern of expression endows beneficial properties for use as cancer biomarkers as well as immunotherapeutic targets as a result of the immune privileged status of the testes. CTAs have been shown to be expressed in pediatric brain tumors, different types of sarcomas, leukemias, and lymphomas as well as neuroblastomas. Although data regarding their expression pattern in childhood tumors are not as comprehensive as for adult tumors, it is supposed that CTA-based immunotherapeutic approaches can also be used for pediatric cancers. However, there are limited data about the objective clinical responses following immunotherapy in such patients. Here we try to review the available information. PMID- 26225645 TI - Human Papillomavirus Genotype Distribution among Thai Women with High-Grade Cervical Intraepithelial Lesions and Invasive Cervical Cancer: a Literature Review. AB - Infection with high-risk human papillomavirus (HR-HPV) is an essential cause of cervical cancer. Because of substantial geographical variation in the HPV genotype distribution, data regarding HPV type-specific prevalence for a particular country are mandatory for providing baseline information to estimate effectiveness of currently implemented HPV-based cervical cancer prevention. Accordingly, this review was conducted to evaluate the HR-HPV genotype distribution among Thai women with precancerous cervical lesions i.e. cervical intraepithelial neoplasia grade 2-3 (CIN 2-3), adenocarcinoma in situ (AIS), and invasive cervical cancer by reviewing the available literature. The prevalence of HR-HPV infection among Thai women with CIN 2-3 ranged from 64.8% to 90.1% and the three most common genotypes were HPV 16 (38.5%), HPV 58 (20.0%), and HPV 18 (5.5%). There were high squamous cell carcinoma/CIN 2-3 prevalence ratios in women with CIN 2-3 infected with HPV 33 and HPV 58 (1.40 and 1.38, respectively), emphasizing the importance of these subtypes in the risk of progression to invasive cancer among Thai women. Data regarding the prevalence and genotype distribution of HR-HPV in Thai women with AIS remain unavailable. Interesting findings about the distribution of HPV genotype in cervical cancer among Thai women include: (1) a relatively high prevalence of HPV 52 and HPV 58 in invasive squamous cell carcinoma; (2) the prevalence of HPV 18-related adenocarcinoma is almost double thepreviously reported prevalence, and (3) 75% of neuroendocrine carcinomas are HPV18-positive when taking into account both single and multiple infections. PMID- 26225646 TI - Evaluation of Inflammation Parameters in Philadelphia Negative Chronic Myeloproliferative Neoplasia Patients. AB - BACKGROUND: Chronic myeloproliferative diseases are clonal stem cell diseases which occur as a result of uncontrollable growth and reproduction of hematopoietic stem cells, which are the myeloid series source in bone marrow. Recent studies have suggested that chronic inflammation can be a triggering factor in the clonal change in chronic myeloproliferative neoplasia (CMPN). In our study, we evaluated the existence of a chronic inflammation process in our Philadelphia negative (Ph-)CMPN patients using inflammation parameters in combination with demographic, laboratory and clinical characteristics of the patients. MATERIALS AND METHODS: Demographic characteristics, clinical and laboratorial data, and thrombosis histories of 99 Ph-CMPN patients, who were diagnosed at our outpatient clinic of hematology in accordance with WHO 2008 criteria, were analyzed retrospectively,with 80 healthy individuals of matching gender and age included as controls. Complete blood counts, sedimentation, C reactive protein (CRP), JAK V617F gene mutations, abdomen ultrasound images and previous thrombosis histories of these patients were retrospectively analyzed. RESULTS: Ph-CMPN and healthy control groups included 99 and 80 cases, respectively. PV, ET and MF diagnoses of patients were 43 (%43.4), 44 (44.4%) and 12 (12.1%), respectively. JAK V617F gene mutation was found to be positive in 64 (71.1%) of all cases and in 27(65.8%), 32 (82%), 5 (50%) of the cases in PV, ET and PMF groups, respectively. Thrombosis was determined as 12 (12%) in the entire group, 12.5% in the JAK V617F negative and 15.3% in the positive patients, with no statistical significance (p=0.758). No significant difference was observed between patients with and without previous thrombosis history in respect to hemogram parameters, sedimentation and CRP (p>0.05), neutrophil to lymphocyte ratio (NLR), erythrocyte distribution width (RDW), mean platelet volume (MPV) and sedimentation levels of the patient. PMID- 26225647 TI - What are the Endoscopic and Pathological Characteristics of Colorectal Polyps? AB - BACKGROUND: Colon polyps need to be excised upon detection during colonoscopy due to the risk of malignancy irrespective of their size. In our study, we retrospectively evaluated the clinicopathological characteristics of polyps detected during colonoscopy. MATERIALS AND METHODS: We assessed 379 patients with polyps detected during colonoscopy between January 2010 and May 2012. The demographics, complaints, colonoscopy findings (shape, place and size of the polyp) and histopathological findings were recorded. We carried out statistical analysis using PASW 18.0 for Windows. RESULTS: There were 227 males (59.9%) and 152 females (40.1%) in the trial. The mean age was 53.8 years (32-90). The most common complaint was rectal bleeding (36.1%), followed by abdominal pain (35.4%). Polyps were detected most commonly in the rectosigmoid region (43.8%), followed by the descending colon (17.4%). Some 239 patients had a single polyp (63.1%) while 140 were found to have multiple polyps (36.9%). While tubular adenoma was the most common pathological type, occurring in 181 patients (47.8%), tubulovillous adenoma (14.2%) and hyperplastic polyp (12.7%) followed, occurring in 54 and 48 patients respectively. While 313 patients (82.6%) did not feature dysplasia, 37 patients (9.7%) exhibited low- grade dysplasia, 28 (7.7%) had high grade dysplasia and 4 had cancer (1.1%). The rates of villous components and dysplasia were detected to be high among pedunculated polyps and polyps larger than 1 cm (p<0.001). CONCLUSIONS: Due to the fact that large-diameter polyps with malignant potential are commonly located in the left colon and have a high prevalence among the middle-aged individuals, it would be appropriate to screen this population at regular intervals via rectosigmoidoscopy. PMID- 26225648 TI - Retrospective Study of Adjuvant Chemotherapy Effects on Survival Rate after Three Field Lymph Node Dissection for Stage IIA Esophageal Cancer. AB - To determine the efficacy of postoperative adjuvant chemotherapy with paclitaxel plus cisplatin (Taxol+DDP, TP therapy) for stage IIA esophageal squamous cell carcinoma (ESCC) and to investigate the expression of RUNX3 in lymph node metastasis-negative esophageal cancer and its relationship with medical prognosis, a retrospective summary of clinical treatment of 143 cases of stage IIA esophageal squamous cell carcinoma patients was made. The patients were divided into two groups, a surgery alone control group (52 patients) and a chemotherapy group that received postoperative TP therapy (91 patients). The disease-free and 5 year survival rates were compared between the groups and a multivariate analysis of prognostic factors was performed. The same analysis was performed for cases classified as RUNX3 positive and negative, with post operative specimens assessed by immunohistochemistry. Although the disease-free and 5 year survival rates in control and chemotherapy groups did not significantly differ and there was no significance in RUNX3 negative cases, postoperative adjuvant chemotherapy in the chemotherapy group was shown to improve disease-free and 5 year survival rate compared to the control group in RUNX3 positive cases. On Cox regression multivariate analysis, postoperative adjuvant chemotherapy (P<0.01) was an independent prognostic factor for RUNX3 positive cases, suggesting that postoperative TP may be effective as adjuvant chemotherapy for stage IIA esophageal cancer patients with RUNX3 positive lesions. PMID- 26225649 TI - Early and Late Complications after Inguinofemoral Lymphadenectomy for Vulvar Cancer. AB - BACKGROUND: We aimed to determine the frequency of early and late complications following groin surgery for vulvar cancer and analyze possible risk factors. MATERIALS AND METHODS: This retrospective cohort study included 99 women who underwent for vulvar cancer. The early (<=1 month) complications were wound infection, breakdown and lymphocyst and late (>1 month) complications were lower limb lymphedema, incontinence and erysipelas. The risk factors for developing each of the complications were analyzed with regression analysis. RESULTS: In the entire cohort, 29 (29.3%) women experienced early and 12 (12.1%) had late complications. Wound complications including infection and breakdown were the leading early complications (23.2%). In the multivariate analysis, both obesity (body mass index>=30 kg/m2) and advanced age (>=65 years) were found as independent predictive factors for early complications. Obese women of advanced age had 6.32 times more risk of experiencing any of the early complications, when compared to non-obese and young women (55.6% vs 8.7%). The most common late complication was lower limb lymphedema (10.1%) that was more frequently seen in young women. However, neither age nor lymph node count were significantly associated with the occurrence of lower limb lymphedema. CONCLUSIONS: More than 40% of the women suffered from postoperative complications after inguinofemoral lymphadenectomy in the current study. While advanced age and obesity were the significant predictors for any of the early complications, there was no identified risk factor for lower limb lymphedema. PMID- 26225650 TI - Aberrant Expression of CCAT1 Regulated by c-Myc Predicts the Prognosis of Hepatocellular Carcinoma. AB - BACKGROUND: CCAT1 has been reported to be linked with pathogenesis of malignancies including colon cancer and gastric cancer. However, the regulatory effect of CCAT1 in hepatocellular carcinoma (HCC) remains unclear. The purpose of this research was to identify any role of CCAT1 in the progression of HCC. MATERIALS AND METHODS: Real time-PCR was performed to test the relative expression of CCAT1 in HCC tissues. A computation screen of CCAT1 promoter was conducted to search for transcription-factor-binding sites. The association of c Myc with CCAT1 promoter in vivo was tested by Pearson correlation analysis and chromatin immunoprecipitation assay. Additionally, Kaplan-Meier analysis and Cox proportional hazards analyses were performed. RESULTS: c-Myc directly binds to the E-box element in the promoter region of CCAT, and when ectopically expressed increases promoter activity and expression of CCAT1. Moreover, Kaplan-Meier analysis demonstrated that the patients with low expression of CCAT1 demonstrated better overall and relapse-free survival compared with the high expression group. Cox proportional hazards analyses showed that CCAT1 expression was an independent prognostic factor for HCC patients. CONCLUSIONS: The findings demonstrated CCAT1, acting as a potential biomarker in predicting the prognosis of HCC, is regulated by c-Myc. PMID- 26225651 TI - beta-Catenin Alterations in Squamous Cell Carcinoma of the Lip. AB - This study aimed to investigate the correlation between beta-catenin immunoexpression and histopathological grades of lower lip squamous cell carcinoma (LSCC). beta-Catenin abnormal expression was found in 29% of the squamous cells of well differentiated LSCC, 63% of moderately differentiated and 86% of poorly differentiated, and therefor was significantly associated with histological grade (p=0.000). Nuclear beta-catenin expression appeared in 5% of the cells and was also correlated with the histological grades (p=0.000). In 14.7% of the cells it was localized in the cytoplasm, again correlating with histology (p=0.002). According to this study the expression of beta-catenin is an independent prognostic factor for histological grade and to the tumor differentiation. This appears to reflect a structural association and the role of beta-catenin in tumor progression. PMID- 26225652 TI - Arsenic Trioxide Promotes Paclitaxel Cytotoxicity in Resistant Breast Cancer Cells. AB - A partial response or resistance to chemotherapeutic agents is considered as a main obstacle in treatment of patients with cancer, including breast cancer. Refining taxane-based treatment procedures using adjuvant or combination treatment is a novel strategy to increase the efficiency of chemotherapy. PPM1D is a molecule activated by reactive oxygen species. whose expression is reported to modulate the recruitment of DNA repair molecules. In this study we examined the impact of arsenic trioxide on efficacy of paclitaxel-induced apoptosis in paclitaxel-resistant MCF-7 cells. We also investigated the expression of PPM1D and TP53 genes in response to this combination treatment. Resistant cells were developed from the parent MCF-7 cell line by applying increasing concentrations of paclitaxel. MTT assays were applied to determine the rate of cell survival. DAPI staining using fluorescent microscopy was employed to study apoptotic bodies. Real-time RT-PCR analysis was also applied to determine PPM1D mRNA levels. Our results revealed that combination of arsenic trioxide and paclitaxel elevates the efficacy of the latter in induction of apoptosis in MCF-7/PAC resistant cells. Applying arsenic trioxide also caused significant decreases in PPM1D mRNA levels (p<0.05). Our findings suggest that arsenic trioxide increases paclitaxel-induced apoptosis by down regulation of PPM1D expression. PPM1D dependent signaling can be considered as a novel target to improve the efficacy of chemotherapeutic agents in resistant breast cancer cells. PMID- 26225653 TI - Serum 8 Hydroxydeoxyguanosine and Cytotoxin Associated Gene A as Markers for Helicobacter pylori Infection. AB - BACKGROUND: Helicobacter pylori (H.pylori) is associated with chronic gastritis, peptic ulcers, gastric adenocarcinomas and mucosa associated tissue lymphomas. Cytotoxin associated gene A (CagA) is one of the virulence factors of H.pylori. It is hypothesized that reactive oxygen species (ROS) play roles in H.pylori associated disease especially in development of gastric adenocarcinoma. Individuals infected with H.pylori bearing CagA produce more ROS than others. 8 hydroxydeoxyguanosine (8OHdG) is an in vitro marker of DNA damage and oxidative stress. The aim of this study was to investigate the relationship between 8OHdG level, H.pylori infection and CagA and alterations of serum 8OHdG level after H.pylori eradication. MATERIALS AND METHODS: Patients admitted with dyspeptic complaints and upper gastrointestinal endoscopy were assessed. H.pylori was determined from histopathology of specimens. Serum 8OHdG levels of three groups (H.pylori negative, H. pylori positive CagA negative and H.pylori positive CagA positive) were compared. Patients with H.pylori infection received eradication therapy. Serum 8OHdG levels pretreatment and posttreatment were also compared. RESULTS: In total, 129 patients (M/F, 57/72) were enrolled in the study. Serum 8OHdG level of H.pylori negative, H. pylori positive CagA negative and H.pylori positive CagA positive groups were significantly different (5.77+/-1.35 ng/ml, 5.43+/-1.14 ng/ml and 7.57+/-1.25 ng/ml respectively, p=0.05). Furthermore, eradication therapy reduced serum 8OHdG level (6.10+/-1.54 ng/ml vs 5.55+/-1.23 ng/ml, p=0.05). CONCLUSIONS: Individuals infected with H.pylori bearing CagA strains have the highest serum 8OHdG level and eradication therapy decreases the serum 8OHdG level. To the best of our knowledge this is the first study that evaluated the effect of CagA virulence factor on serum 8OHdG level and the effect of eradication therapy on serum 8OHdG levels together. Eradication of CagA bearing H.pylori may prevent gastric adenocarcinoma by decreasing ROS. 8OHdG level may thus be a good marker for prevention from gastric adenocarcinoma. PMID- 26225654 TI - Effects of Acute Lymphoblastic Leukemia on Ceruloplasmin Oxidase, Copper and Several Markers of Oxidative Damage, in Children. AB - BACKGROUND: Acute leukaemia is characterized by fast growth of abnormal clones of haemopoietic precursor cells inside bone marrow leading to undue accumulation in the bone marrow. Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer. MATERIALS AND METHODS: The study concerned 50 children diagnosed with ALL (mean age, 8.55+/-2.54) compared to 40 healthy controls (mean age, 8.00+/-1.85). The Hb, serum copper, ceruloplasmin oxidase, advanced oxidation protein products (AOPPs), total antioxidant activity (TAA) and protein were measured in all groups. One proteinous component was isolated by gel filtration chromatography from the precipitate produced by polyethylene glycol. RESULTS: Significantly higher levels of AOPP, copper and decrease in total antioxidant activity were noted in the cases. Statistical analysis also showed a significant increase (p<0.01) in the activity of serum ceruloplasmin oxidase in patients with ALL compared to normal subjects. The maximum velocity (Vmax) and Michaelis constant had values of 104.2 U/L and 11.7 mM, respectively. The DeltaH* values for ceruloplasmin oxidase in ALL patients were positive, confirming the reaction to be endothermic. CONCLUSIONS: The results from this study showed a significant increase in AOPP, ceruloplasmine oxidase and decrease in total antioxidant activity .These parameters may play a role in development of DNA damage in childhood patients with acute lymphoblastic leukemia (ALL). The DeltaS* and DeltaG* values were negative, these refer that the reaction of ES formation is spontaneous, but needs energy in a so-called endergonic reaction. Also the negative DeltaS* value of ceruloplasmin oxidase indicates that the complex [ES*] is further modulated through increasing structure arrangement. PMID- 26225655 TI - Targeted Resequencing of 30 Genes Improves the Detection of Deleterious Mutations in South Indian Women with Breast and/or Ovarian Cancers. AB - BACKGROUND: We earlier used PCR-dHPLC for mutation analysis of BRCA1 and BRCA2. In this article we report application of targeted resequencing of 30 genes involved in hereditary cancers. MATERIALS AND METHODS: A total of 91 patient samples were analysed using a panel of 30 genes in the Illumina HiScan SQ system. CLCBio was used for mapping reads to the reference sequences as well as for quality-based variant detection. All the deleterious mutations were then reconfirmed using Sanger sequencing. Kaplan Meier analysis was conducted to assess the effect of deleterious mutations on disease free and overall survival. RESULTS: Seventy four of the 91 samples had been run earlier using the PCR-dHPLC and no deleterious mutations had been detected while 17 samples were tested for the first time. A total of 24 deleterious mutations were detected, 11 in BRCA1, 4 in BRCA2, 5 in p53, one each in RAD50, RAD52, ATM and TP53BP1. Some 19 deleterious mutations were seen in patients who had been tested earlier with PCR dHPLC [19/74] and 5/17 in the samples tested for the first time, Together with our earlier detected 21 deleterious mutations in BRCA1 and BRCA2, we now had 45 mutations in 44 patients. BRCA1c.68_69delAG;p.Glu23ValfsX16 mutation was the most common, seen in 10/44 patients. Kaplan Meier survival analysis did not show any difference in disease free and overall survival in the patients with and without deleterious mutations. CONCLUSIONS: The NGS platform is more sensitive and cost effective in detecting mutations in genes involved in hereditary breast and/or ovarian cancers. PMID- 26225656 TI - Genotyping of Peroxisome Proliferator-Activated Receptor gamma in Iranian Patients with Helicobacter pylori Infection. AB - Helicobacter pylori (H. pylori) infection as a serious problem in both adults and children can induce chronic gastritis, peptic ulcer disease (PUD), and possibly gastric cancer. The aim of the current study was to survey antibiotic resistance and also to determine influence of PPARgamma polymorphism in patients with H. pylori infection. During an 11-month-period, 98 H. pylori isolates were collected from 104 biopsy specimens. In vitro susceptibility of H. pylori isolates to 4 antimicrobial agents metronidazole, clarithromycin, amoxicillin and tetracycline were assessed by quantitative method according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) guideline. PPARgamma polymorphism was determined using polymerase chain reaction-restriction fragment length polymorphism assay. The frequency of H. pylori infection in our study was 94.2%. In vitro susceptibility data showed that highest level of resistance was related to metronidazole (66.3%), and the majority of H. pylori isolates were highly susceptible to amoxicillin and tetracycline (94.9% and 96.9%, respectively). Genotypic frequencies were 25.5% for CC (Pro12Pro), 40.8% for GC (Pro12Ala) and 33.7% for GG (Ala12Ala). In our study, CG genotype had highest distributions among infected patients with H. pylori. The study suggests that the PPAR-gamma Pro12Ala polymorphism could be evaluated as a potential genetic marker for susceptibility to gastric cancer in the presence of H. pylori infection. PMID- 26225657 TI - Spatial analysis of Relative Risks for skin cancer morbidity and mortality in Iran, 2008-2010. AB - BACKGROUND: One of the most prevalent cancers in whole world is skin cancer and its prevalence is growing. The present research sought to estimate relative risk of morbidity and mortality due to skin cancer. MATERIALS AND METHODS: In this cross-sectional study. The required data were gathered from the registered cancer reports of Cancer Control Office in the Center for Non Communicable Disease of the Iranian Ministry of Health (MOH). The data were extracted at province level in the time span of 2008-10. WINBUGS software was used to analyze the data and to identify high risk regions. ArcGIS10 was utilized to map the distribution of skin cancer and to demonstrate high risk provinces by using classic and fully Bayesian models taking into account spatial correlations of adjacent regions separately for men and women. RESULTS: Relative risk of morbidity for women in Yazd and for men in Kurdistan and relative risk of mortality for women in Bushehr and for men in Kohgiluyeh were found to be the highest. Bayesian model due to regarding adjacent regions correlation, have precise estimation in comparing to classical model. More frequent epidemiological studies to enact skin cancer prevention programs. CONCLUSIONS: High risk regions in Iran include central and highland regions. Therefore it is suggested that health decision makers enact public education, using anti UV creams and sunglasses for those parts as a short preventing program. PMID- 26225658 TI - Knowledge, Attitude and Behavior of Healthcare Providers towards Breast Cancer in Malaysia: a Systematic Review. AB - Breast cancer is the most common cancer among women in Malaysia. Therefore, it is highly important for the public to be educated on breast cancer and to know the steps to detect it early on. Healthcare providers are in the prime position to provide such education to the public due to their high knowledge regarding health and their roles in healthcare. The present systematic review involved studies conducted in recent years to analyze the knowledge, attitudes and behavior of Malaysian healthcare providers regarding breast cancer, in attempts to obtain an overall picture of how well equipped our healthcare providers are to provide optimal breast cancer education, and to see their perceptions and actual involvement in said education. The systematic review was conducted via a primary search of various databases and journal websites, and a secondary search of references used by eligible studies. Criteria for eligibility included being published from the year 2008 till present, being conducted in Malaysia, and being written in the English language. A total of two studies were eligible for this review. Findings show that Malaysian future and current healthcare providers have moderate knowledge on breast cancer, have a positive towards involvement of breast cancer education, but have poor actual involvement. PMID- 26225659 TI - Effect of Screening on Variation in Cervical Cancer Survival by Socioeconomic Determinants--a Study from Rural South India. AB - BACKGROUND: Socioeconomic factors are associated with screening in terms of reducing the risk of cervical cancer. This study aimed to clearly establish the effect of screening on variation in socio-economic factor-specific survival estimates. MATERIALS AND METHODS: Survival estimates were calculated using the life table method for 165 women from the routine care control arm and 67 from the visual inspection with acetic acid screening arm diagnosed with cervical cancer during 2000-2006 in rural south India. Kaplan-Meier survival curves were plotted to compare the variation in survival by socioeconomic factors. RESULTS: Whereas there was a significant variation in survival estimates of the different categories of age at diagnosis among the screen-detected cancers with women aged<50 years having an improved survival, no significant variation was noted among women diagnosed with cervical cancer from the control arm. Compared to the variation among the cancer cases detected in the unscreened control group, screening widened the variation in survival estimates by age and type of house, and reduced the variation by education. The direction of the magnitude of the survival estimates was reversed within the different categories of occupation, marital status and household income in the screen-detected cancer cases compared to control group cancer cases. Also, women diagnosed with stage 1 disease had a very good survival. CONCLUSIONS: Screening changed the pattern of survival by socio-economic factors. We found improved survival rates in screened women aged <50 years, with no formal education, manual workers and married women. PMID- 26225660 TI - Breast Cancer Awareness at the Community Level among Women in Delhi, India. AB - BACKGROUND: To assess women's awareness from diverse sections of society in Delhi regarding various aspects of breast cancer (BC)--perceptions, signs and symptoms, risk factors, prevention, screening and treatment. MATERIALS AND METHODS: Community-level survey was undertaken in association with the Indian Cancer Society (ICS), Delhi during May 2013-March 2014. Women attending BC awareness workshops by ICS were given self-administered questionnaires before the workshop in the local language to assess BC literacy. Information provided by 2017 women was converted into awareness scores (aware=1) for analysis using SPSS. Awareness scores were dichotomized with median score=19 as cut off, create more aware and less aware categories. Bivariate and multivariate analysis provided P-values, odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Broadly, 53.4% women were aware about various aspects of BC. Notably, 49.1% women believed that BC was incurable and 73.9% women believed pain to be an initial BC symptom. Only 34.9% women performed breast self-examination (BSE) and 6.9% women had undergone clinical breast-examination/mammography. 40.5% women had higher awareness (awareness score>median score of 19), which was associated with education [graduates (OR=2.31; 95%CI=1.78, 3.16), post-graduates (OR=7.06; 95%CI=4.14, 12.05) compared to <=high school] and socio-economic status (SES) [low-middle (OR=4.20; 95%CI=2.72, 6.49), middle (OR=6.00; 95%CI=3.82, 9.42) and upper (OR=6.97; 95%CI=4.10, 11.84) compared to low SES]. CONCLUSIONS: BC awareness of women in Delhi was suboptimal and was associated with low SES and education. Awareness must be drastically increased via community outreach and use of media as a first step in the fight against BC. PMID- 26225661 TI - Mortality and Morbidity and Disease Free Survival after D1 and D2 Gastrectomy for Stomach Adenocarcinomas. AB - BACKGROUND: A number of randomized trials addressing alternative operative and multimodality approaches to gastric cancer have characterized early postoperative morbidity and mortality rates. The aim of this study was to compare mortality and morbidity and disease free survival after D1 and D2 gastrectomy for adenocarcinomas of the stomach MATERIALS AND METHODS: From June 2006 to January 2012, patients were selected according to information of the cancer administrator center of Ahvaz Jundishapur Medical University. The inclusion criteria were age between 20-85 years and histologically proven adenocarcinoma of the stomach without evidence of distant metastasis. Patients were excluded if they had previous or coexisting cancer or disability disease. In this research, D1 was compared to D2 gastrectomy. RESULTS: 131 patients were randomised, 49 allocated to D1 and 82 to D2 gastrectomy. The two groups were comparable for age, sex, site of tumors, and type of resection performed. The overall post-operative morbidity rate was 17.5%. Complications developed in 14.2% of patients after D1 and in 19.5% of patients after D2 gastrectomy (p=0.07). Postoperative mortality rate was 0.8% (one death); it was 2% after D1 and 0% after D2 gastrectomy. In this research disease free-survival after 3 years was 71.2 % with 63.2% after D1 and 76.8% after D2 gasterctomy. CONCLUSIONS: This study indicates that D2 gastrectomy with pancreas preservation is not followed by significantly higher morbidity and mortality than D1 resection. Based on the results of present study, D2 resection should be recommended as the standard surgical approach for resectable gastric cancer. PMID- 26225662 TI - Increasing Trend in Colorectal Cancer Incidence in the Southeast of Iran 2003 2013: A Population Based Cancer Registry Study. AB - Rates based on age-adjusted incidence of colorectal cancers over a 10-year period in Kerman, the biggest province of Iran, were estimated from 2003 to 2013. Data were obtained from the population-based cancer registry unit of Kerman University of Medical Sciences (CR-KMU). Information included age, sex, city, ICD-O and year of registry. Our trend analyses cover 3.91% of the Iranian population. The data set comprised cases diagnosed from 2003 to 2013.The population of over 20 years was interpolated using 2003 and 2010 censuses. Then, truncated age-adjusted incidence rates were calculated. Increase was noted from 2003-2009 to 2010-2013 for 731 cancer cases considered in the analysis. The increases was most prominent in 2009. Totally, the frequency of the cancer was greater in males. Moreover, calculating truncated age-adjusted incidence rate indicated that the most prevalent age of colorectal incidence was in the 50-59 year age group except in 2007-2008 and 2012- 2013, when greatest incidences occurred in people aged 60-69 years. Our data revealed that the incidence rates of colorectal cancer have increased over the past decade in our region of Iran. PMID- 26225663 TI - Diagnostic Role of Serum Free-to-Total Prostate Specific Antigen (PSA) Ratio in Prostate Cancer with Serum Total Concentration of PSA below 4 ng/mL. AB - PURPOSE: To examine the effectiveness of serum free-to-total prostate specific antigen ratio (%fPSA) for the detection of prostate cancer (PCa) in men with different serum total PSA (tPSA) categories. MATERIALS AND METHODS: From January 2010 to December 2013, a total of 225 patients with lower urinary tract symptoms (LUTS) underwent tPSA and %fPSA measurements. Histological examination with calculation of Gleason score and whole body bone scans were performed in identified cases of PCa. RESULTS: PCa was diagnosed in 44 (19.6%) patients and the remaining 181 patients had benign prostate disease. PCa was detected in 5 (23.8%), 13 (8.7%) and 26 (47.3%) cases with tPSA level ranges<=4 ng/ml, 4 to 10 ng/ml and >10 ng/ml, respectively. The average Gleason score was 7.2+/-0.2. Some 6 (13.6%) out of 44 PCa patients had bone metastases. The sensitivity was 80% and specificity was 81.3% at the cut-off %fPSA of 15% in PCa patients with a tPSA level below 4 ng/ mL. A lower %fPSA was associated with PCa patients with Gleason score>=7 than those with Gleason score<=6 (11.7+/-0.98 vs. 16.5+/-2.25%, P=0.029). No obvious relation of %fPSA to the incidence of bone metastasis was apparent in this study. CONCLUSIONS: The clinical application of %fPSA could help to discriminate PCa from benign prostate disease in men with a tPSA concentration below 4 ng/mL. PMID- 26225664 TI - Pectic-Oligoshaccharides from Apples Induce Apoptosis and Cell Cycle Arrest in MDA-MB-231 Cells, a Model of Human Breast Cancer. AB - BACKGROUND: The effects of plant products on cancer cells has become a field of major importance. Many substancesmay induce apoptosis in anti-cancer treatment. Pectins, a family of complex polysaccharides, and their degradation products may for exasmple exert apoptotic effects in cancer cells. Apples and citrus fruits are the main sources of pectin which can be applied for anti-cancer research. The present study concerned an intact form of pectic-oligoshaccharide named pectic acid (poly galactronic acid). MATERIALS AND METHODS: Inhibition of cell proliferation assays (MTT), light microscopy, fluorescence microscopy (acridin orange/ethidium bromide), DNA fragmentation tests, cell cycle analysis, annexin PI and Western blotting methods were applied to evaluate apoptosis. RESULTS: The results indicated that pectic acid inhibited cell growth and reduced cell attachment after 24h incubation. This did not appear to be due to necrosis, since morphological features of apoptosis were detected with AO/EB staining and cell cycling was blocked in the sub-G1 phase. Annexin/PI and DNA fragmentation findings indicated that apoptosis frequency increased after 24h incubation with pectic acid. In addition, the data showed pectic acid induced caspase-dependent apoptosis. CONCLUSIONS: These data indicate that apple pectic acid without any modification could trigger apoptosis in MDA-MB-231 human breast cancer cells and has potential to improve cancer treatment as a natural product. PMID- 26225665 TI - Parameters Involved in Autophosphorylation in Chronic Myeloid Leukemia: a Systems Biology Approach. AB - BACKGROUND: Chronic myeloid leukemia (CML) is a stem cell disorder characterized by the fusion of two oncogenes namely BCR and ABL with their aberrant expression. Autophosphorylation of BCR-ABL oncogenes results in proliferation of CML. The study deals with estimation of rate constant involved in each step of the cellular autophosphorylation process, which are consequently playing important roles in the proliferation of cancerous cells. MATERIALS AND METHODS: A mathematical model was proposed for autophosphorylation of BCR-ABL oncogenes utilizing ordinary differential equations to enumerate the rate of change of each responsible system component. The major difficulty to model this process is the lack of experimental data, which are needed to estimate unknown model parameters. Initial concentration data of each substrate and product for BCR-ABL systems were collected from the reported literature. All parameters were optimized through time interval simulation using the fminsearch algorithm. RESULTS: The rate of change versus time was estimated to indicate the role of each state variable that are crucial for the systems. The time wise change in concentration of substrate shows the convergence of each parameter in autophosphorylation process. CONCLUSIONS: The role of each constituent parameter and their relative time dependent variations in autophosphorylation process could be inferred. PMID- 26225666 TI - Outcomes for Pituitary Adenoma Patients Treated with Linac- Based Stereotactic Radiosurgery and Radiotherapy: a Long Term Experience in Thailand. AB - BACKGROUND: The study analyzed the long term clinical outcomes of pituitary adenoma cases treated with the first Thailand installation of a dedicated Linac based stereotactic radiation machine (X-Knife). MATERIALS AND METHODS: A retrospective review of 115 consecutive pituitary adenoma patients treated with X Knife at the Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand from 1997 to 2003 was performed. Stereotactic radiosurgery (SRS) was selected for 21 patients (18%) including those with small tumors (<=3 cm) located >=5 mm. from the optic apparatus, whereas the remaining 94 patients (82%) were treated with fractionated stereotactic radiotherapy (FSRT). RESULTS: With a median follow-up time of 62 months (range, 21-179), the six-year progression free survival was 95% (93% for SRS and 95% for FSRT). The overall hormone normalization at 3 and 5 years was 20% and 30%, respectively, with average time required for normalization of approximately 16 months for SRS and 20 months for FSRT. The incidence of new hypopituitarism was 10% in the SRS group and 9% in the FSRT group. Four patients (5%) developed optic neuropathy (1 in the SRS group and 3 in the FSRT group). CONCLUSIONS: Linac-based SRS and FSRT achieved similar high local control rates with few complications in pituitary adenoma cases. However, further well designed, randomized comparative studies between SRS versus FSRT particularly focusing on hormone normalization rates are required. PMID- 26225667 TI - Hepatitis B Virus Infection Is Associated with Poor Prognosis in Patients with Advanced Non Small Cell Lung Cancer. AB - BACKGROUND: Hepatitis B virus (HBV) infection has been reported to be associated with inferior prognosis in hepatocellular and pancreatic carcinoma cases, but has not been studied with respect to non small cell lung cancer (NSCLC). The purpose of this study was to investigate the prognostic significance of HBV infection in advanced NSCLC patients. MATERIALS AND METHODS: A retrospective cohort of 445 advanced NSCLC patients was recruited at our hospital from January 1, 2003 until August 30, 2014. Serum HBV markers were tested by enzyme-linked immunosorbent assay. COX proportional hazards analysis was used to evaluate associations of HBV infection with overall survival (OS). RESULTS: Of 445 patients who were qualified for the study, 68 patients were positive for HBsAg, also considered as HBV infection. Patients in HBsAg negative group were found to have better OS (12.6 months [12.2-12.9]) than those in HBsAg positive group (11.30 months [10.8-11.9]; p=0.001). Furthermore, COX multivariate analysis identified HBV infection as an independent prognostic factor for OS (HR 0.740 [0.560, 0.978], p=0.034). CONCLUSIONS: Our study found that HBsAg-positive status was an independent prognostic factor for OS in patients with advanced NSCLC. Future prospective studies are required to confirm our findings. PMID- 26225668 TI - Individualized Chemotherapy for Metastatic Gastric Cancer: Retrospective Data from a University Hospital in Brazil. AB - BACKGROUND: Despite the decreased incidence, gastric cancer is still a frequent cause of cancer related death. The 1st line 2 or 3 drugs regimen is still a debatable issue. HER2 targeted therapy has emerged as the standard of care, but it is unavailable in the Brazilian Public Health System. The end-point of this trial was overall survival (OS) in patients with metastatic gastric cancer treated in a public university hospital in Brazil. The secondary end-points were efficacy and safety of regimens with 2 (F+P) or 3 (EOX) drugs to develop an institutional guideline to facilitate optimal treatments. MATERIALS AND METHODS: In this retrospective study, 1st line regimens were evaluated for OS and PFS stratified by age and ECOG using Cox regression. RESULTS: 47 patients were treated over the last 3 years. In 1st line, 29 were treated with F+P (mean 59.3 years, 34.5% ECOG 2 and a mean of 5.69 cycles) and 16 with EOX (mean 47 years, 18.8% ECOG 2 and a mean of 5.44 cycles). The median OS was 13.8 months (95%CI 10.7-16.9). Response was evaluated in 40 cases and was 64.3% for EOX and 37.5% for F+P (p=0.25). The median PFS was 9.5 months for EOX and 5.6 months for F+P (HR 0.85, 95%CI 0.41-1.74). However, among patients with ECOG 2 mPFS was 3.70 vs 5.40 months, respectively (p=0.86). Regimens showed similar manageable adverse events. A total of 34 patients suffered progression and 14 received 2nd line therapy. Diffuse histology (HR 1.89, 95%CI 1.22-2.88), achieving 2nd line (HR: 0.25, 95%CI 0.11-0.58) and treatment response (HR 0.23, 95%CI 0.12-0.47) were OS prognostic factors. CONCLUSIONS: Patients treated in our hospital had outcomes compatible with the literature. The regimen choice should be related to patient features. Second line treatment should be considered. PMID- 26225669 TI - Trends and Analysis of Cancer Incidence for Common Male and Female Cancers in the Population of Punjab Province of Pakistan during 1984 to 2014. AB - BACKGROUND: The Pakistan Atomic Energy Commission Cancer Registry (PAECCR) program has made availability of a common cancer incidence database possible in Pakistan. The cancer incidence data from nuclear medicine and oncology institutes were gathered and presented. MATERIALS AND METHODS: The cancer incidence data for the last 30 years (1984-2014) are included to describe a data set of male and female patients. The data analysis concerning occurrence, trends of common cancers in male and female patients, stage-wise distribution, and mortality/follow-up cases is also incorporated for the last 10 years (2004-2014). RESULTS: The total population of provincial capital Lahore is 9,800,000. The total number of cancer cases was 80,390 (males 32,156, females 48,134). The crude incidence rates in PAECCR areas were 580.8/105 during 2010 to 885.4/105 in 2014 (males 354.1/105, females 530.1/105). The cancer incidence rates for head and neck (15.70%), brain tumors (10.5%), and non-Hodgkin lymphoma (NHL, 9.53%) were found to be the highest in male patients, whereas breast cancer (46.7%), ovary tumors (6.80%), and cervix (6.31%) cancer incidence rates were observed to be the most common in female patients. The age range distribution of diagnosed and treated patients in conjunction with the percentage contribution of cancer patients from 15 different cities of Punjab province treated at the Institute of Nuclear Medicine and Oncology, Lahore are also included. Leukemia was found to be the most common cancer for the age group of 1-12 years. It has been identified that the maximum number of diagnosed cases were found in the age range of 51-60 years for males and 41-50 years for female cancer patients. CONCLUSIONS: Overall cancer incidence of the thirty years demonstrated that head and neck and breast cancers in males and in females respectively are the most common cancers in Punjab province in Pakistan, at rates almost the highest in Asia, requiring especial attention. The incidence of brain, NHL, and prostate cancers among males and ovarian and cervix cancers among females have increased rapidly. These data from a major population of Punjab province should be helpful for implementation of appropriate planning, prevention and cancer control measures and for determination of risk factors within the country. PMID- 26225670 TI - Do Leukocyte and Platelet Counts Have Benefit for ?Preoperative Evaluation of Endometrial Cancer? AB - PURPOSE: The aim of this study was to investigate the association between preoperative leukocyte and platelet counts and the stage of the disease in patients with endometrial cancer. MATERIALS AND METHODS: Data for 100 patients undergoing total abdominal hysterectomy and bilateral salpingoophorectomy for benign uterine diseases and 177 patients surgically staged for endometrial cancer at Ondokuz Mayis University, Department of Gynecology and Obstetrics between 2005 and 2013, with preoperative complete blood count in the week prior to surgery including WBC, platelet count, pathologic evaluation for both benign and malign endometrium lesions, tumor stage and presence of lymphovascular space invasion (LVI), were retrospectively analyzed. RESULTS: The preoperative leukocyte count was significantly higher in patients with endometrial cancer when compared to the patients with benign diseases. However, there were no significant differences in platelet counts between the groups. Patients with advanced stage endometrial cancer had higher preoperative leukocyte counts when compared to the early stage disease whereas there was no difference in platelet count. Multivariate regression analysis identified preoperative leukocytosis as an independent prognostic factor for endometrial cancer. The optimal cut-off point for WBC was calculated as 10,500 to differentiate stage 1-2-3 and 4 with 88.9% sensitivity and 86.3% specificity (AUC: 0.901, 95% CI: 0.829-0.973, p<0.001, PPV: 25.8%, NPV: 99.3%). CONCLUSIONS: Preoperative leukocytosis is independently associated with advanced endometrial cancer. PMID- 26225671 TI - Binding Pattern Elucidation of NNK and NNAL Cigarette Smoke Carcinogens with NER Pathway Enzymes: an Onco- Informatics Study. AB - Cigarette smoke derivatives like NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1 butanone) and NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol) are well known carcinogens. We analyzed the interaction of enzymes involved in the NER (nucleotide excision repair) pathway with ligands (NNK and NNAL). Binding was characterized for the enzymes sharing equivalent or better interaction as compared to +Ve control. The highest obtained docking energy between NNK and enzymes RAD23A, CCNH, CDK7, and CETN2 were -7.13 kcal/mol, -7.27 kcal/mol, -8.05 kcal/mol and -7.58 kcal/mol respectively. Similarly the highest obtained docking energy between NNAL and enzymes RAD23A, CCNH, CDK7, and CETN2 were -7.46 kcal/mol, -7.94 kcal/mol, -7.83 kcal/mol and -7.67 kcal/mol respectively. In order to find out the effect of NNK and NNAL on enzymes involved in the NER pathway applying protein-protein interaction and protein-complex (i.e. enzymes docked with NNK/NNAL) interaction analysis. It was found that carcinogens are well capable to reduce the normal functioning of genes like RAD23A (HR23A), CCNH, CDK7 and CETN2. In silico analysis indicated loss of functions of these genes and their corresponding enzymes, which possibly might be a cause for alteration of DNA repair pathways leading to damage buildup and finally contributing to cancer formation. PMID- 26225672 TI - Prognostic Factors in Oligodendrogliomas: a Clinical Study of Twenty-Five Consecutive Patients. AB - BACKGROUND: The purpose of this study was to evaluate the prognostic significance of Ki-67 and subjective microvascular density (SMVD) indexes together with other factors in patients with oligodendroglioma. MATERIALS AND METHODS: In this retrospective study, oligodendroglioma specimens obtained from twenty-five consecutive patients were evaluated for Ki-67 and SMVD indices to help determine histological grading and investigate the fidelity of these markers in clinical prognosis. Other potentially prognostic factors were Karnofsky performance scale, tumor histological grade, and adjuvant radiotherapy. RESULTS: The Ki-67 proliferation index appeared to have a strong correlation with the grade of the tumor and the survival. Age, gender, adjuvant radiotherapy, surgical resection type (complete versus incomplete) did not have any influence on recurrence. The SMVD index correlated significantly with the 3 to 5-year survival. CONCLUSIONS: Ki-67 and MVD indexes are important and useful markers in estimating the prognosis of oligodendrogliomas. PMID- 26225673 TI - Anti-proliferative and Apoptotic Effects of Dendrosomal Farnesiferol C on Gastric Cancer Cells. AB - Farnesiferol C is a natural compound with various anti-cancer properties that belongs to the class of sesquiterpene coumarins. However, the low bioavailability of farnesiferol C limits its therapeutic potential. Here, we overcame this problem utilizing dendrosome nano-particles and evaluated the anti-cancer effect of dendrosomal farnesiferol C (DFC) on the AGS gastric cancer cell line. The 3 (4,5-dimethyl-thiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and reverse transcriptase-polymerase chain reaction (RT-PCR) were respectively used to detect the anti-proliferative properties of DFC and expression ratio of Bax/Bcl-2 as a hallmark of apoptosis. Compared to the void farnesiferol C (FC), our data showed that DFC significantly suppresses the proliferation of AGS cells in a time- and dose-dependent manner (P<0.01). Also, DFC meaningfully increased the expression ratio of Bax/Bcl-2 in AGS cells (P<0.01). The findings demonstrate that our nano-based formulation of farnesiferol C could be considered as a potential therapeutic agent in cancer targeting. PMID- 26225674 TI - Is Surgical Staging Necessary for Patients with Low-risk Endometrial Cancer? A Retrospective Clinical Analysis. AB - PURPOSE: The aim of this study was to compare the tumor-free and overall survival rates between patients with low-risk endometrial cancer who underwent surgical staging and those who did not undergo surgical staging. MATERIALS AND METHODS: Data, including demographic characteristics, grade of the tumor, myometrial invasion, cervical involvement, peritoneal washing, lymph node involvement, lymphovascular space invasion, postoperative complication, adjuvant treatment, cancer recurrence, and tumor-free and overall survival rates, for patients with low-risk endometrioid endometrial cancer who were treated surgically with and without pelvic and paraaortic lymph node dissection (LND) were analyzed retrospectively. The patients diagnosed with endometrioid endometrial cancer including the following criteria were considered low-risk: 1) a grade 1 (G1) or grade 2 (G2) endometrioid histology; 2) myometrial invasion of <50% upon magnetic resonance imaging (MRI); 3) no stromal glandular or stromal invasion upon MRI; and 4) no evidence of intra-abdominal metastasis. Then the patients at low-risk were divided into two groups; group 1 (n=117): patients treated surgically with pelvic and paraaortic LND and group 2 (n=170): patients treated surgically without pelvic and paraaortic LND. RESULTS: There was no statistical significance when the groups were compared in terms of lymphovascular space invasion, cervical involvement, positive cytology, and recurrence, whereas the administration of an adjuvant therapy was higher in group 2 (p<0.005). The number of patients with positive pelvic nodes and the number of metastatic pelvic nodes were significantly higher in the group with positive LVI than in the group without LVI (p<0.005). No statistically significant differences were detected between the groups in terms of tumor-free survival (p=0.981) and overall survival (p=0.166). CONCLUSIONS: Total hysterectomy with bilateral salpingo-oophorectomy and stage adapted postoperative adjuvant therapy without pelvic and/or paraaortic lymphadenectomy may be safe and efficient treatments for low-risk endometrial cancer. PMID- 26225675 TI - Leu432Val Polymorphism of CYP1B1 is Not Associated with Squamous Cell Carcinoma of Esophagus--a Case-Control Study from Kashmir, India. AB - BACKGROUND: Individual susceptibility to cancer has been attributed to polymorphisms in xenobiotic metabolizing genes. To evaluate the association of the Leu432Val polymorphism of cytochrome P4501B1 (CYP1B1) with esophageal squamous cell carcinoma (ESCC), we conducted a case control study in Kashmir, India, an area with a relatively high incidence of ESCC. MATERIALS AND METHODS: We recruited 404 histopathologically confirmed ESCC cases, and an equal number of controls, individually matched for sex, age and district of residence to respective cases. Information was obtained on various dietary, lifestyle and environmental factors in face to face interviews, using a structured questionnaire, from each subject. Genotypes were analysed by polymerase chain reaction, restriction fragment length polymorphism and sequencing of randomly selected samples. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Among the three possible variants, we did not find any Leu432Leu genotype of CYP1B1 in the study population and the genotypic distribution of Val432Val and Leu432Val carriers was nearly equal in both cases (89.6% and 10.4%) and controls (88.9% and 11.1%) respectively. We did not find any risk associated with this polymorphism in the current study (OR=0.64; 95% CI: 0.55-1.64). CONCLUSIONS: The study indicates that (Leu432Val) polymorphism of CYP1B1, is not associated with ESCC risk. However, replicative studies with larger sample size are needed to substantiate the findings. PMID- 26225676 TI - Increased Oxidative Stress and RUNX3 Hypermethylation in Patients with Hepatitis B Virus-Associated Hepatocellular Carcinoma (HCC) and Induction of RUNX3 Hypermethylation by Reactive Oxygen Species in HCC Cells. AB - Promoter hypermethylation of the runt-related transcription factor 3 (RUNX3) gene is associated with increased risk of hepatocellular carcinoma (HCC). Oxidative stress plays a vital role in both carcinogenesis and progression of HCC. However, whether oxidative stress and RUNX3 hypermethylation in HCC have a cause- and effect relationship is not known. In this study, plasma protein carbonyl and total antioxidant capacity (TAC) in patients with hepatitis B virus (HBV) associated HCC (n=60) and age-matched healthy subjects (n=80) was determined. RUNX3 methylation in peripheral blood mononuclear cells (PBMC) of subjects was measured by methylation-specific PCR. Effect of reactive oxygen species (ROS) on induction of RUNX3 hypermethylation in HCC cells was investigated. Plasma protein carbonyl content was significantly higher, whereas plasma TAC was significantly lower, in HCC patients than healthy controls. Based on logistic regression, increased plasma protein carbonyl and decreased plasma TAC were independently associated with increased risk for HCC. PBMC RUNX3 methylation in the patient group was significantly greater than in the healthy group. RUNX3 methylation in hydrogen peroxide (H2O2)-treated HepG2 cells was significantly higher than in untreated control cells. In conclusion, increase in oxidative stress in Thai patients with HBV-associated HCC was demonstrated. This oxidative increment was independently associated with an increased risk for HCC development. RUNX3 in PBMC was found to be hypermethylated in the HCC patients. In vitro, RUNX3 hypermethylation was experimentally induced by H2O2. Our findings suggest that oxidative stress is a cause of RUNX3 promoter hypermethylation in HCC cells. PMID- 26225677 TI - Association of Knowledge and Cultural Perceptions of Malaysian Women with Delay in Diagnosis and Treatment of Breast Cancer: a Systematic Review. AB - BACKGROUND: Breast cancer is the most common cancer and the leading cause of cancer mortality among women of all ethnic and age groups in Malaysia. Delay in seeking help for breast cancer symptoms is preventable and by identifying possible factors for delayed diagnosis, patient prognosis and survival rates could be improved. OBJECTIVES: This narrative review aimed to understand and evaluate the level of in-depth breast cancer knowledge in terms of clinical breast examination and breast self-examination, and other important aspects such as side-effects and risk factors in Malaysian females. Since Malaysia is multicultural, this review assessed social perceptions, cultural beliefs and help seeking behaviour in respect to breast cancer among different ethnic groups, since these may impinge on efforts to 'avoid' the disease. MATERIALS AND METHODS: A comprehensive literature search of seven databases was performed from December 2015 to January 2015. Screening of relevant published journals was also undertaken to identify available information related to the knowledge, perception and help-seeking behaviour of Malaysian women in relation to breast cancer. RESULTS: A total of 42 articles were appraised and included in this review. Generally, women in Malaysia had good awareness of breast cancer and its screening tools, particularly breast self-examination, but only superficial in depth knowledge about the disease. Women in rural areas had lower levels of knowledge than those in urban areas. It was also shown that books, magazines, brochures and television were among the most common sources of breast cancer information. Delay in presentation was attributed mainly to a negative social perception of the disease, poverty, cultural and religion practices, and a strong influence of complementary and alternative medicine, rather than a lack of knowledge. CONCLUSIONS: This review highlighted the need for an intensive and in depth breast cancer education campaigns using media and community health programmes, even with the existing good awareness of breast cancer. This is essential in order to avoid misconceptions and to frame the correct mind-set about breast cancer among women in Malaysia. Socio-cultural differences and religious practices should be taken into account by health care professionals when advising on breast cancer. Women need to be aware of the risk factors and symptoms of breast cancer so that early diagnosis can take place and the chances of survival improved. PMID- 26225678 TI - Expression of Granulysin and FOXP3 in Cutaneous T Cell Lymphoma and Sezary Syndrome. AB - BACKGROUND: Multiple complex pathways are operable in the evolution of cutaneous T cell lymphomas (CTCLs). These pathways involve interaction between neoplastic T cells and cells of the immune system (especially dendritic cells and the non malignant T cells). Granulysin is a proinflammatory antimicrobial peptide which has an immune alarmin function, activating dendritic cells, as well as an active role in tumor immunology and prognosis. FOXP3+ regulatory T cells Tregs are an important player in the immune system. Much controversy is found in the literature about the role of Tregs in CTCL. AIM: The present study aimed to investigate the expression of granulysin and FOXP3 in mycosis fungoides (MF), its precursor lesion large plaque parapsoriasis and its leukemic form Sezary syndrome (SS). MATERIALS AND METHODS: Immunohistochemical expression of granulysin and FOXP3 were assessed in lesional skin biopsies taken from 58 patients (4 large plaque parapsoriasis, 48 MF and 6 SS). RESULTS: Granulysin positivity was cytoplasmic and higher in MF than in parapsoriasis en plaque and higher in the more advanced stages of MF (p<0.001). All groups showed significant differences between each other except between MF tumor stage and SS. FOXP3 positivity was nuclear and higher in early stage MF (plaque and patch stages) than in tumor stages and SS (p<0.001). However the FOXP3 count was lower in parapsoriasis en plaque than in other stages of MF. All the groups showed significant differences between each other except between parapsoriasis and SS and between patch and plaque stages of MF. CONCLUSIONS: The present study supports a role for granulysin in MF progression and proposes a novel hypothesis about the effect of FOXP3 +veTregs in the suppression of the activity of the neoplastic cells in MF. PMID- 26225679 TI - Comparison of the Formula of PSA, Age, Prostate Volume and Race Versus PSA Density and the Detection of Primary Malignant Circulating Prostate Cells in Predicting a Positive Initial Prostate Biopsy in Chilean Men with Suspicion of Prostate Cancer. AB - BACKGROUND: Combining risk factors for prostate cancer into a predictive tool may improve the detection of prostate cancer while decreasing the number of benign biopsies. We compare one such tool, age multiplied by prostate volume divided by total serum PSA (PSA-AV) with PSA density and detection of primary malignant circulating prostate cells (CPCs) in a Chilean prostate cancer screening program. The objectives were not only to determine the predictive values of each, but to determine the number of clinically significant cancers that would have been detected or missed. MATERIALS AND METHODS: A prospective study was conducted of all men undergoing 12 core ultrasound guided prostate biopsy for suspicion of cancer attending the Hospital DIPRECA and Hospital de Carabineros de Chile. Total serum PSA was registered, prostate volumecalculated at the moment of biopsy, and an 8 ml blood simple taken immediately before the biopsy procedure. Mononuclear cells were obtained from the blood simple using differential gel centrifugation and CPCs identified using immunocytchemistry with anti- PSA and anti-P504S. Biopsy results were classed as positive or negative for cancer and if positive the Gleason score, number of positive cores and percent infiltration recorded. RESULTS: A total of 664 men participated, of whom 234 (35.2%) had cancer detected. They were older, had higher mean PSA, PSA density and lower PSA-AV. Detection of CPCs had high predictive score, sensitivity, sensibility and positive and negative predictive values, PSA-AV was not significantly different from PSA density in this population. The use of CPC detection avoided more biopsies and missed fewer significant cancers. CONCLUSIONS: In this screening population the use of CPC detection predicted the presence of clinically significant prostate cancer better than the other parameters. The high negative predictive value would allow men CPC negative to avoid biopsy but remain in follow up. The formula PSA-AV did not add to the predictive performance using PSA density. PMID- 26225680 TI - Antioxidant Effect of Berberine and its Phenolic Derivatives Against Human Fibrosarcoma Cells. AB - Berberine (B1), isolated from stems of Coscinium fenestratum (Goetgh.) Colebr, was used as a principle structure to synthesize three phenolic derivatives: berberrubine (B2) with a single phenolic group, berberrubine chloride (B3) as a chloride counter ion derivative, and 2,3,9,10-tetra-hydroxyberberine chloride (B4) with four phenolic groups, to investigate their direct and indirect antioxidant activities. For DPPH assay, compounds B4, B3, and B2 showed good direct antioxidant activity (IC50 values=10.7+/-1.76, 55.2+/-2.24, and 87.4+/ 6.65 MUM, respectively) whereas the IC50 value of berberine was higher than 500 MUM. Moreover, compound B4 exhibited a better DPPH scavenging activity than BHT as a standard antioxidant (IC50=72.7+/-7.22 MUM) due to the ortho position of hydroxyl groups and its capacity to undergo intramolecular hydrogen bonding. For cytotoxicity assay against human fibrosarcoma cells (HT1080) using MTT reagent, the sequence of IC50 value at 7-day treatment stated that B10.05). D-D abnormal rate increased with age and was statistically significant among different age groups (p<0.05). Regarding staging of tumor, D-D abnormal rate in patients with phase I was 2.0%, 6.2% in phase II, 47.6% in phase III and 83.1% in phase IV, with statistically significant differences between phase III and II, as well as phase III and IV (p<0.01). CONCLUSIONS: A prethrombotic state was closely related to malignancy of tumors. The risk factors for a prethrombotic state include age and tumor stage. PMID- 26225698 TI - Comparison of Perioperative and Oncologic Outcomes with Laparotomy, and Laparoscopic or Robotic Surgery for Women with Endometrial Cancer. AB - PURPOSE: To compare perioperative outcomes and oncologic outcomes in endometrial cancer patients treated with laparotomy, and laparoscopic or robotic surgery. MATERIALS AND METHODS: Endometrial cancer patients who underwent primary surgery from January 2011 to December 2014 were retrospectively reviewed. Perioperative outcomes, including estimated blood loss (EBL), operation time, number of lymph nodes retrieved, and intra and postoperative complications, were reviewed. Recovery time, disease free survival (DFS) and overall survival (OS) were compared. RESULTS: Of the total of 218 patients, 143 underwent laparotomy, 47 laparoscopy, and 28 robotic surgery. The laparotomy group had the highest EBL (300, 200, 200 ml, p<0.05) while the robotic group had the longest operative time (302 min) as compared with laparoscopy (180 min) and laparotomy (125 min) (p<0.05). Intra and postoperative complications were not different with any of the surgical approaches. No significant difference in number of lymph nodes retrieved was identified. The longest hospital stay was reported in the laparotomy group (four days) but there was no difference between the laparoscopy (three days) and robotic (three days) groups. Recovery was significantly faster in robotic group than laparotomy group (14 and 28 days, p=0.003). No significant difference in DFS and OS at 21 months of median follow up time was observed among the three groups. CONCLUSIONS: Minimally invasive surgery has more favorable outcomes, including lower blood loss, shorter hospital stay, and faster recovery time than laparotomy. It also has equivalent perioperative complications and short term oncologic outcomes. MIS is feasible as an alternative option to surgery of endometrial cancer. PMID- 26225699 TI - Differential Expression of Cytokeratin 13 in Non-Neoplastic, Dysplastic and Neoplastic Oral Mucosa in a High Risk Pakistani Population. AB - BACKGROUND: Gradual loss of cytokeratin 13 (CK13) may be linked with the severity of dysplastic changes and transformation to malignancy. In this study we assessed the differential expression of CK13 in normal, hyperplastic, dysplastic and cancerous oral mucosa. MATERIALS AND METHODS: A total of 93 oral biopsies were collected during the 2011-2014 period. The biopsies were characterized as normal (19), hyperplastic (21), severely dysplastic/carcinoma in situ (16) and invasive oral squamous cell carcinoma (OSCC) (37) after morphological assessment. Formalin fixed paraffin embedded sections were stained with a monoclonal antibody against CK13 using the Envision technique. Immunohistochemically stained slides were then analyzed for CK13 expression. RESULTS: CK13 was consistently and diffusely expressed in all normal and hyperplastic tissue biopsies from oral mucosa. Severely dysplastic/carcinoma in situ biopsies showed complete loss in 50% of cases, while in the remaining 50% expression was very focal and weak. OSCC cases showed complete or near complete loss of CK13 in all cases. Few cases showed weak expression in keratin pearls only. CONCLUSIONS: This study validates the utility of CK13 IHC as a useful immunohistochemical marker in routine diagnostic practice to make distinction between non-neoplastic from dysplastic and neoplastic (malignant) oral lesions. PMID- 26225700 TI - Total and Partial Prevalence of Cancer Across Kerman Province, Iran, in 2014, Using an Adapted Generalized Network Scale-Up Method. AB - Due to the lack of nationwide population-based cancer registration, the total cancer prevalence in Iran is unknown. Our previous work in which we used a basic network scale-up (NSU) method, failed to provide plausible estimates of total cancer prevalence in Kerman. The aim of the present study was to estimate total and partial prevalence of cancer in southeastern Iran using an adapted version of the generalized network scale-up method. A survey was conducted in 2014 using multi-stage cluster sampling. A total of 1995 face-to-face gender-matched interviews were performed based on an adapted version of the NSU questionnaire. Interviewees were asked about their family cancer history. Total and partial prevalence were estimated using a generalized NSU estimator. The Monte Carlo method was adopted for the estimation of upper/lower bounds of the uncertainty range of point estimates. One-yr, 2-3 yr, and 4-5 yr prevalence (per 100,000 people) was respectively estimated at 78 (95%CI, 66, 90), 128 (95%CI, 118, 147), and 59 (95%CI, 49, 70) for women, and 48 (95%CI, 38, 58), 78 (95%CI, 66, 91), and 42 (95%CI, 32, 52) for men. The 5-yr prevalence of all cancers was estimated at 0.18 percent for men, and 0.27 percent for women. This study showed that the generalized familial network scale-up method is capable of estimating cancer prevalence, with acceptable precision. PMID- 26225701 TI - Cancer Care Burden among Primary Family Caregivers of Iranian Hematologic Cancer Patients. AB - BACKGROUND: Providing care for hematologic cancer patients may lead to many negative complications in different aspects of life in their family caregivers. Based on a wide review of relevant literature, there are limited data about the burden of giving care for hematologic cancer patients on their primary family caregivers in Iran or other Middle Eastern countries. Therefore, the aim of this study was to investigate the cancer care burden on primary family caregivers of hematologic cancer patients, in terms of physical, psychological, social, spiritual, and financial aspects. MATERIALS AND METHODS: In this descriptive study, 151 primary family caregivers of hematologic cancer patients referred to two cancer care centers in East Azerbaijan Province in northwest of Iran participated. The Financial Distress/Financial Well-being Scale, Hospital Anxiety and Depression Scale, Vaux Social Support Questionnaire, Spiritual Well-being Scale, and SF-36 were used for data collection. Data analysis was performed with SPSS software. RESULTS: The findings of this study indicated that the primary family caregivers experience a high level of financial distress and a significant percentage of them suffered from anxiety and depression. In addition, the physical quality of life in these caregivers was moderate. On the other hand, spiritual health and social support of participants was at an acceptable level. CONCLUSIONS: Iranian primary family caregivers of hematologic cancer patients experience many problems in physical, psychological, and financial aspects of their life. Therefore, developing care plans for reducing these problems appears necessary. PMID- 26225702 TI - Momordica cochinchinensis Aril Extract Induced Apoptosis in Human MCF-7 Breast Cancer Cells. AB - Momordica cochinchinensis Spreng (MC) has been used in traditional medicine due to its high carotenoid content. The objective of this study was to investigate mechanisms underlying apoptotic effects of MC on human MCF-7 breast cancer cells. A lycopene-enriched aril extract of MC (AE) showed cytotoxicity and antiestrogenicity to MCF-7 cells. On DAPI staining, AE induced cell shrinkage and chromatin condensation were evident. With flow cytometric analysis, AE increased the percentage of cells in an early apoptosis stage when compared with the control group. RT-PCR analysis showed AE to significantly increase the expression of the proapoptotic bax gene without effect on expression of the anti-apoptotic bcl-2 gene. Moreover, AE enhanced caspase 6, 8 and 9 activity. Taken together, we conclude that AE of MC fruit has anticancer effects on human MCF-7 breast cancer cells by induction of cell apoptosis via both intrinsic and extrinsic pathways of signaling. PMID- 26225704 TI - Systematic Analysis of Icotinib Treatment for Patients with Non-Small Cell Lung Cancer. AB - PURPOSE: This analysis was conducted to evaluate the efficacy and safety of icotinib based regimens in treating patients with non-small cell lung cancer (NSCLC). METHODS: Clinical studies evaluating the efficacy and safety of icotinib based regimens with regard to response and safety for patients with NSCLC were identified using a predefined search strategy. Pooled response rates of treatment were calculated. RESULTS: With icotinib-based regimens, 7 clinical studies which including 5,985 Chinese patients with NSCLC were considered eligible for inclusion. The pooled analysis suggested that, in all patients, the positive reponse rate was 30.1% (1,803/5,985) with icotinib-based regimens. Mild skin itching, rashes and diarrhea were the main side effects. No grade III or IV renal or liver toxicity was observed. No treatment-related death occurred in patients treated with icotinib-based regimens. CONCLUSIONS: This evidence based analysis suggests that icotinib based regimens are associated with mild response rate and acceptable toxicity for treating Chinese patients with NSCLC. PMID- 26225703 TI - Single Nucleotide Polymorphism of Interferon Lambda-4 Gene is not Associated with Treatment Response to Pegylated Interferon in Thai Patients with Chronic Hepatitis B. AB - The single nucleotide polymorphism (SNP) ss469415590 in the interferon lambda-4 (IFNL4) gene has recently been reported to have an association with treatment response in chronic hepatitis C. However, any importance of the SNP in association with response to pegylated interferon (PEG-IFN) therapy in patients with chronic hepatitis B (CHB) is unclear. We retrospectively analyzed data for Thai patients with CHB treated with PEG-IFN for 48 weeks. Virological response (VR) for HBeAg-positive CHB was defined as HBeAg seroconversion plus HBV DNA level<2,000 IU/mL at 24 weeks post-treatment. VR for HBeAg-negative CHB was defined as an HBV DNA level<2,000 IU/mL at 48 weeks. The SNP was identified by real time PCR using the TaqMan genotyping assay with MGB probes. A total 254 patients (107 HBeAg-positive and 147 HBeAg-negative) were enrolled in the study. The distribution of TT/TT, DeltaG/TT and DeltaG/DeltaG genotypes was 221 (87.0%), 32 (12.6%) and 1 (0.4%), respectively. Patients with non-TT/TT genotypes had significantly higher baseline HBV DNA levels than patients with the TT/TT genotype. In HBeAg-positive CHB, 41.2% of patients with TT/TT genotype versus 50.0% with non-TT/TT genotype achieved VR (P=0.593). In HBeAg-negative CHB, the corresponding figures were 40.3% and 43.5%, respectively (P=0.777). There was no significant correlation between the SNP genotypes and HBsAg clearance in both groups of patients. In summary, ss469415590 genotypes were not associated with response to PEG-IFN in Thai patients with HBeAg-positive and HBeAg-negative CHB. PMID- 26225705 TI - Saliva-Based Screening of High-Risk Human Papillomavirus Strains: Detection in Female Indonesian and Thai Dental Students. AB - BACKGROUND: Currently it is believed that human papillomaviruses (HPV) are associated with the development of some oral/oropharyngeal cancers. It has been suggested that these viruses influence carcinogenesis in both smokers and non smokers. Data on the prevalence of HPV in healthy adults are thus needed to estimate the risk of oral/oropharyngeal cancer. The aim of this study was to assess the prevalence of oral HPV in healthy female adults in Indonesia and Thailand. MATERIALS AND METHODS: Healthy female students from the Faculties of Dentistry of Universitas Indonesia and Chiang Mai University were asked to participate in this pilot study. DNA was extracted from saliva specimens and screened for HPV16 and HPV18 using PCR. RESULTS: The age, marital status and sexual experience of the subjects between the two countries were not significantly different. Eight (4%) and 4 (2%) samples were positive for HPV16 and HPV18, respectively. Fisher's Exact test found a significant difference between HPV16 positivity in subjects who were married and had sexual intercourse but not for HPV18. CONCLUSIONS: This study successfully detected presence of HPV16 and HPV18 DNA in a number of saliva samples from female dental school students. Marital status, experience of sexual intercourse and safe sexual practice are related to the possibility of finding HPV DNA finding in saliva. Dentists, physicians and other health care professionals may gain significant value from the findings of this study, which provide an understanding of the nature of HPV infection and its risk to patient health and disease. PMID- 26225706 TI - Association of Cigarette Prices with the Prevalence of Smoking in Korean University Students: Analysis of Effects of the Tobacco Control Policy. AB - BACKGROUND: Increased pricing of cigarettes might be one of the most effective approaches for reducing the prevalence of smoking. This study aimed to investigate the effects of increasing cigarette prices through taxation by a tobacco intervention policy on the changes in smoking prevalence in Korean university students. MATERIALS AND METHODS: The participants in this study were 23,047 healthy university students aged 18-29 years from a health examination in 2011-2015. We investigated the adjusted prevalence of daily and occasional smoking before and after increasing cigarette prices through taxation. RESULTS: The prevalence of occasional smoking was significantly decreased in 2015 from 2014 in both male (from 10.7% in 2014 to 5.4%) and female (from 3.6% to 1.1%) students, but the prevalence of daily smoking did not decrease significantly. The frequency of individuals who had attempted smoking cessation during the past year was significantly higher among occasional smokers in male students (90.2%) compared with daily smokers (64.9%). For female students, there were no differences in experience of smoking cessation, willingness for smoking cessation, or E-cigarette experience between daily and occasional smokers. CONCLUSIONS: We found that a policy of increasing cigarette prices through taxation is associated with decreases in the prevalence of occasional smokers, who have relatively lower nicotine dependence compared with individuals who smoke daily. The results of our study suggest that social support and direct intervention for smoking cessation at the community level are needed for university students alongside the pricing policy. PMID- 26225707 TI - Pre-treatment Elevated Platelet Count Associates with HER2 Overexpression and Prognosis in Patients with Breast Cancer. AB - PURPOSE: To research the association between pre-treatment elevated platelet count and clinicopathologic characteristics in breast cancer (BC), as well as explore the relationship between pre-treatment elevated platelet count and HER2 status and prognosis of BC patients. MATERIALS AND METHODS: A retrospective cohort of BC patients who were newly diagnosed or treated by surgery only and had pathological detection results and platelet values in the Department of Oncology, the First Affiliated Hospital of Liaoning Medical College were enrolled from 1/1/2008 until 31/12/2009, and followed up until 31/12/2014. Age, thrombocyte parameters before chemotherapy and/or radiotherapy, immunohistochemical (IHM) indexes, and regional lymph node (LN) involvement and progression-free survival (PFS) were recorded. RESULTS: A total of 447 eligible subjects were included in this research. As we analyzed, for HER2, positive and negative, the incidence rates of elevated platelet count were 25.8% and 14.7% (P<0.05). In the Cox proportional hazards model both variables were independent risk factors for BC (for HER2, OR, 0.592, 95% confidence interval, CI, 0.355 to 0.985, P=0.044;f or PLT, OR, 0.998, 95% CI, 0.996 to 1.000, P=0.042). For ER, PR, Ki67 and LN involvement, the differences were not statistically significant (P>0.05). CONCLUSIONS: In this research, pre-treatment elevated level of platelet count demostrated a significantrelationship with HER2 amplification/overexpression, and both variables significantly influenced the prognosis of BC. However, elevated platelet count did not exhibit any association with ER, PR, Ki67 and LN involvement. PMID- 26225708 TI - Systematic Review of Single Large and/or Multinodular Hepatocellular Carcinoma: Surgical Resection Improves Survival. AB - BACKGROUND: The role of surgical resection for patients with single large (>=5 cm) and/or multinodular (>=2) hepatocellular carcinoma (HCC) is still controversial. This systematic review was performed to evaluate the safety and efficacy of resection for patients with single large and/or multinodular HCC. MATERIALS AND METHODS: Databases (the PubMed, Web of Science, Embase, and Cochrane databases) were systematically searched to identify relevant studies exploring the safety and efficacy of resection for single large and/or multinodular HCC, published between January 2000 and December 2014. Perioperative morbidity and mortality, overall survival, and disease-free survival of the resection group were calculated. In addition, these outcome variables were also calculated for the control group in the included studies. RESULTS: One randomized controlled trial and 42 non- randomized studies involving 9,580 patients were eligible for analysis. Eight (1,594 patients) of the 43 studies also reported the outcomes of transarterial chemoembolization (TACE). Although 51.4% of patients featured cirrhosis, 90.7% of them demonstrated Child-Pugh A liver function in the resection group. The median rates of morbidity (24.5%) and mortality (2.5%) after resection were significantly higher than that of TACE (11.0%, P<0.001; 1.9%, P<0.001). However, patients who underwent resection had significantly higher median one-, three-, and five-year overall survival (76.1%, 51.7%, and 37.4%) than those who underwent TACE (68.3%, 31.5%, and 17.5%, all P<0.001). The median 1-, 3-, and 5-year DFS rates after resection were 58.3%, 34.6%, and 24.0%, respectively. CONCLUSIONS: Although tumor recurrence after resection for patients with single large and/ or multinodular HCC continues to be a major problem, resection should be considered as a strategy to achieve long-term survival. PMID- 26225709 TI - Estimation of Completeness of Cancer Registration for Patients Referred to Shiraz Selected Centers through a Two Source Capture Re-capture Method, 2009 Data. AB - BACKGROUND: Cancer has important social consequences with cancer registration as the basis of moving towards prevention. The present study aimed to estimate the completeness of registration of the ten most common cancers in patients referred to selected hospitals in Shiraz, Iran by using capture-recapture method. MATERIALS AND METHODS: This cross-sectional analytical study was performed in 2014 based on the data of 2009, on a total of 4,388 registered cancer patients. After cleaning data from two sources, using capture-recapture common findings were identified. Then, the percentage of the completeness of cancer registration was estimated using Chapman and Chao methods. Finally, the effects of demographic and treatment variables on the completeness of cancer registration were investigated. RESULTS: The results showed that the percentages of completeness of cancer registration in the selected hospitals of Shiraz were 58.6% and 58.4%, and influenced by different variables. The age group between 40-49 years old was the highest represented and for the age group under 20 years old was the lowest for cancer registration. Breast cancer had the highest registration level and after that, thyroid and lung cancers, while colorectal cancer had the lowest registration level. CONCLUSIONS: According to the results, the number of cancers registered was very few and it seems that factors like inadequate knowledge of some doctors, imprecise diagnosis about the types of cancer, incorrectly filled out medical documents, and lack of sufficient accuracy in recording data on the computer cause errors and defects in cancer registration. This suggests a necessity to educate and teach doctors and other medical workers about the methods of documenting information related to cancer and also conduct additional measures to improve the cancer registration system. PMID- 26225710 TI - Association of Cytochrome-17 (MspA1) Gene Polymorphism with Risk of Gall Bladder Stones and Cancer in North India. AB - BACKGROUND: Cholelithiasis is associated in 54%-98% of patients with carcinoma of the gallbladder, and a high incidence among females suggests a role of female hormones in the etiology of the disease. Cytochrome P450C17alpha (CYP-17) is a key enzyme involved in estrogen metabolism and polymorphisms in CYP-17 are associated with altered serum levels of estrogens. Thus, we investigated whether the CYP-17 MspA1 gene polymorphism might impact on risk of gall bladder cancers or gallstones, as well as to determine if this gene polymorphism might be linked with estrogen serum levels and lipid profile among the North Indian gall bladder cancer or gallstone patients. MATERIALS AND METHODS: CYP-17 gene polymorphisms (MspA1) were genotyped with PCR-RFLP in cancer patients (n=96), stone patients (n=102), cancer+stone patients (n=52) and age/sex matched control subjects (n=256). Lipid profile was estimated using a commercial kit and serum estrogen was measured using ELISA. RESULTS: The majority of the patients in all groups were females. The lipid profile and estrogen level were significantly higher among the study as compared to control groups. The frequency of mutant allele A2 of CYP17 MspA1 gene polymorphism was higher among cancer (OR=5.13, 95% CI+3.10 8.51, p=0.0001), stone (OR=5.69, 95%CI=3.46-9.37, p=0.0001) and cancer+stone (OR=3.54, 95%CI=1.90-6.60, p=0.0001) when compared with the control group. However there was no significant association between genotypes of CYP17 MspA1 gene polymorphism and circulating serum level of estrogen and lipid profile. CONCLUSIONS: A higher frequency of mutant genotype A1A2 as well as mutant allele A2 of CYP-17 gene polymorphism is significantly associated with risk of gallbladder cancer and stones. Elevated levels of estrogen and an altered lipid profile can be used as predictors ofgall bladder stones and cancer in post menopausal females in India. PMID- 26225711 TI - Genetic Association between ERCC5 rs17655 Polymorphism and Colorectal Cancer Risk: Evidence Based on a Meta-analysis. AB - BACKGROUND: Previous studies evaluating the association between the excision repair cross complementing group 5 (ERCC5) gene rs17655 polymorphism and colorectal cancer susceptibility generated controversial results. To generate large-scale evidence on whether the ERCC5 rs17655 polymorphism might indeed be associated with colorectal cancer susceptibility, the present meta-analysis was performed. MATERIALS AND METHODS: Data were collected from PubMed, Embase and Web of Science, with the last report up to Apr 03, 2015. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of any association. RESULTS: A total of nine studies including 5,102 cases and 6,326 controls based on the search criteria were included and significant associations were found between ERCC5 rs17655 polymorphism CG vs GG overall (OR=1.29, 95% CI=1.18~1.40) and in the dominant model (OR=1.23, 95% CI=1.13~1.33). On subgroup analysis by ethnicity and source of controls, the ERCC5 rs17655 polymorphism was found to correlate with the pathogenesis of colorectal cancer among Asians and Caucasians and with hospital-based populations. CONCLUSIONS: This meta-analysis suggests that the ERCC5 rs17655 polymorphism might contribute to genetic susceptibility to colorectal cancer. PMID- 26225712 TI - Hepatic Re-resection Versus Transarterial Chemoembolization for the Treatment of Recurrent Hepatocellular Carcinoma after Initial Resection: a Systematic Review and Meta-analysis. AB - BACKGROUND: A systematic review and meta-analysis were performed to compare the post-recurrence survival with hepatic re-resection versus transarterial chemoembolization (TACE) for recurrent hepatocellular carcinoma (HCC) after initial resection. MATERIALS AND METHODS: All relevant papers were searched via PubMed, EMBASE, and Cochrane Library databases. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Subgroup analysis was performed according to country. Sensitivity analysis was performed in studies which clearly reported the recurrent regions, in moderate/high-quality studies, in studies published in full-text form, and in studies published after 2005. RESULTS: In total, twelve papers were included in our study. Five and seven of them were of moderate- and poor-quality, respectively. The overall meta analysis demonstrated a statistically significantly higher post-recurrence survival in the hepatic re-resection group than in those undergoing TACE (HR=0.64, 95%CI=0.52-0.79, P<0.0001). Heterogeneity was statistically significant and statistical significance remained in the subgroup analysis. Sensitivity analyses were also consistent with the overall analysis. CONCLUSIONS: Hepatic re resection might provide a better post-recurrence survival than TACE for recurrent HCC after initial resection. However, considering the low quality of published studies and the potential bias of treatment selection, further randomized trials should be warranted to confirm these findings. PMID- 26225713 TI - The Single Cigarette Economy in India--a Back of the Envelope Survey to Estimate its Magnitude. AB - BACKGROUND: Sale of single cigarettes is an important factor for early experimentation, initiation and persistence of tobacco use and a vital factor in the smoking epidemic in India as it is globally. Single cigarettes also promote the sale of illicit cigarettes and neutralises the effect of pack warnings and effective taxation, making tobacco more accessible and affordable to minors. This is the first study to our knowledge which estimates the size of the single stick market in India. MATERIALS AND METHODS: In February 2014, a 10 jurisdiction survey was conducted across India to estimate the sale of cigarettes in packs and sticks, by brands and price over a full business day. RESULTS: We estimate that nearly 75% of all cigarettes are sold as single sticks annually, which translates to nearly half a billion US dollars or 30 percent of the India's excise revenues from all cigarettes. This is the price which the consumers pay but is not captured through tax and therefore pervades into an informal economy. CONCLUSIONS: Tracking the retail price of single cigarettes is an efficient way to determine the willingness to pay by cigarette smokers and is a possible method to determine the tax rates in the absence of any other rationale. PMID- 26225714 TI - HCV, Interferon Therapy Response, Direct Acting Antiviral Therapy Revolution and Pakistan: Future Perspectives. PMID- 26225715 TI - Comments on--Neoadjuvant Chemo-radiation with IMRT in Resectable and Borderline Resectable Pancreatic Cancer. PMID- 26225716 TI - Retraction Notice to: Normalization of CA19-9 Following Resection for Pancreatic Ductal Adenocarcinoma is not Tantamount to being Cured? PMID- 26225717 TI - Hydroxytyrosol-Derived Compounds: A Basis for the Creation of New Pharmacological Agents for Cancer Prevention and Therapy. AB - Hydroxytyrosol [2-(3,4-dihydroxyphenyl)ethanol, HTyr] is a phenolic compound found in olive leaves and fruits and extra-virgin olive oil, which has well-known strong antioxidant and radical-scavenging properties. Recently, it has received particular attention for its antiproliferative and apoptotic activities and its anti-inflammatory properties. During the past few years, more efforts have been focused on synthesizing HTyr-derived compounds with enhanced biological activities for their potential use in different chronic degenerative diseases. In this paper, we report a dissertation on the current knowledge of selected synthetic HTyr derivatives and analogues and their potential use in cancer prevention and therapy, which are related to their antioxidant, antiproliferative/apoptotic, and anti-inflammatory properties. On the basis of the perspective of using HTyr-derived compounds as anticancer agents, we have taken into account only studies that were performed in experimental cell-based models. PMID- 26225718 TI - Direct Comparison of Disaccharide Interaction with Lipid Membranes at Reduced Hydrations. AB - Understanding sugar-lipid interactions during desiccation and freezing is an important step in the elucidation of cryo- and anhydro-protection mechanisms. We determine sucrose, trehalose, and water concentration distributions in intra bilayer volumes between opposing dioleoylphosphatidylcholine bilayers over a range of reduced hydrations and sugar concentrations. Stacked lipid bilayers at reduced hydration provide a suitable system to mimic environmental dehydration effects, as well as a suitable system for direct probing of sugar locations by neutron membrane diffraction. Sugar distributions show that sucrose and trehalose both behave as typical uncharged solutes, largely excluded from the lipid bilayers regardless of sugar identity, and with no correlation between sugar distribution and the lipid headgroup position as the hydration is changed. These results are discussed in terms of current opinions about cryo- and anhydro protection mechanisms. PMID- 26225719 TI - Erratum. PMID- 26225720 TI - Enhancing Bulge Stabilization through Linear Extension of C8-Aryl-Guanine Adducts to Promote Polymerase Blockage or Strand Realignment to Produce a C:C Mismatch. AB - Aryl radicals can react at the C8-site of 2'-deoxyguanosine (dG) to produce DNA adducts with a C8-C linkage (denoted C-linked). Such adducts are structurally distinct from those possessing a flexible amine (N-linked) or ether (O-linked) linkage, which separates the C8-aryl moiety from the guanine nucleobase. In the current study, two model C-linked C8-dG adducts, namely, C8-benzo[b]thienyl-dG ([BTh]G) and C8-(pyren-1-yl)-dG ([Py]G), were incorporated into the NarI (12mer, NarI(12) and 22mer, NarI(22)) hotspot sequence for frameshift mutations in bacteria. For the first time, C-linked C8-dG adducts are shown to stabilize the 2 deletion duplex within the NarI sequence. Primer-elongation assays employing Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) demonstrates the influence of C8-aryl ring size and shape in promoting Dpo4 blockage or strand realignment to produce a C:C mismatch downstream of the adduct site. Molecular dynamics simulations of the -2 deletion duplex suggest that both anti and syn adduct structures are energetically accessible. These findings provide a rationale for describing the biochemical outcome induced by C-linked C8-dG adducts when processed by Dpo4. PMID- 26225721 TI - An amino acid ionic liquid-based tough ion gel membrane for CO2 capture. AB - A tough and thin double-network gel membrane containing amino acid ionic liquids as a CO2 carrier exhibited superior CO2 permeability and stability under pressurized conditions. PMID- 26225722 TI - Achievement of Target Blood Pressure Levels among Japanese Workers with Hypertension and Healthy Lifestyle Characteristics Associated with Therapeutic Failure. AB - BACKGROUND: Few studies have examined Japanese with regard to the achievement rates for target blood pressure levels, or the relationship between these rates and healthy lifestyle characteristics in patients with hypertension as defined by the newly established hypertension management guidelines (JSH2014). The aim of this study was to elucidate achievement rates and examine healthy lifestyle characteristics associated with achievement status among Japanese. METHODS: This cross-sectional study, conducted in January-December 2012, examined blood pressure control and healthy lifestyle characteristics in 8,001 Japanese workers with hypertension (mean age, 57.0 years; 78.8% were men) who participated in a workplace health checkup. Data were collected from workplace medical checkup records and participants' self-administered questionnaires. We divided into 5 groups [G1; young, middle-aged, and early-phase elderly patients (65-74 years old) without diabetes mellitus or chronic kidney disease (CKD) (<140/90 mmHg), G2; late-phase elderly patients (>=75 years old) without diabetes mellitus or CKD (<150/90 mmHg), G3; diabetic patients (<130/80 mmHg), G4; patients with CKD (<130/80 mmHg), and G5; patients with cerebrovascular and/or coronary artery diseases (<140/90 mmHg)] according to JSH2014. And then, achievement rates were calculated in each group. Multivariate analysis identified healthy lifestyle characteristics associated with "therapeutic failure" of target blood pressure. RESULTS: Target blood pressures were achieved by 60.2% of young, middle-aged, and early-phase elderly patients (G1), 71.4% of late-phase elderly patients (G2), 30.5% of diabetic patients (G3), 33.4% of those with chronic kidney disease (G4), and 66.0% of those with cerebrovascular and/or coronary artery diseases (G5). A body mass index of 18.5-24.9 and non-daily alcohol consumption were protective factors, and adequate sleep was found to contribute to therapeutic success. DISCUSSION: We found low achievement rates for treatment goals among patients with chronic kidney disease and diabetes mellitus. Maintaining an ideal body weight and adequate alcohol consumption may help with blood pressure control. Lifestyle modification may be necessary for better management of hypertension. PMID- 26225724 TI - Recent developments in metal-metalloporphyrin frameworks. AB - Metal-organic frameworks (MOFs) based on porphyrin or metalloporphyrin components are of particular interest due to their potential applications in molecular sorption, light-harvesting, and heterogeneous catalysis. This perspective is focused on recent advances in the syntheses and functional properties of metal metalloporphyrin frameworks, which are classified according to coordination moieties on the porphyrin ligands. PMID- 26225726 TI - In situ plasma sputtering synthesis of ZnO nanorods-Ag nanoparticles hybrids and their application in non-enzymatic hydrogen peroxide sensing. AB - In this paper, ZnO nanorods-Ag nanoparticles hybrids were first synthesized via a facile, rapid, and in situ plasma sputtering method without using any silver precursor. The obtained materials were then characterized by scanning electron microscopy, high-resolution transmission electron microscopy, energy-dispersive x ray spectroscopy, and cyclic voltammetry. Based on the electrochemical catalytic properties of the obtained nanohybrids, a non-enzymatic hydrogen peroxide biosensor was constructed by immobilizing the obtained ZnO nanorods-Ag nanoparticles hybrids on the surface of a glassy carbon electrode. Under optimal conditions, the resulting biosensor displayed a good response for H2O2 with a linear range of 0.2 to 12.8 mM, and a detection limit of 7.8 MUM at a signal-to noise ratio of 3. In addition, it exhibited excellent anti-interference ability and fast response. The current work provides a feasible platform to fabricate a variety of non-enzymatic biosensors. PMID- 26225727 TI - Correction: Differences in the Faecal Microbiome in Schistosoma haematobium Infected Children vs. Uninfected Children. PMID- 26225725 TI - Development of a bone substitute material based on alpha-tricalcium phosphate scaffold coated with carbonate apatite/poly-epsilon-caprolactone. AB - Interconnected porous tricalcium phosphate ceramics are considered to be potential bone substitutes. However, insufficient mechanical properties when using tricalcium phosphate powders remain a challenge. To mitigate these issues, we have developed a new approach to produce an interconnected alpha-tricalcium phosphate (alpha-TCP) scaffold and to perform surface modification on the scaffold with a composite layer, which consists of hybrid carbonate apatite / poly-epsilon-caprolactone (CO3Ap/PCL) with enhanced mechanical properties and biological performance. Different CO3Ap combinations were tested to evaluate the optimal mechanical strength and in vitro cell response of the scaffold. The alpha TCP scaffold coated with CO3Ap/PCL maintained a fully interconnected structure with a porosity of 80% to 86% and achieved an improved compressive strength mimicking that of cancellous bone. The addition of CO3Ap coupled with the fully interconnected microstructure of the alpha-TCP scaffolds coated with CO3Ap/PCL increased cell attachment, accelerated proliferation and resulted in greater alkaline phosphatase (ALP) activity. Hence, our bone substitute exhibited promising potential for applications in cancellous bone-type replacement. PMID- 26225728 TI - Von Willebrand factor, hemostasis and inflammation. PMID- 26225729 TI - An inflammatory link in atherosclerosis and obesity. Co-stimulatory molecules. AB - Atherosclerosis and obesity-induced metabolic dysfunction are lipid-driven inflammatory pathologies responsible for a major part of cardiovascular complications. Immune cell activation as well as interactions between the different immune cells is dependent on and controlled by a variety of co stimulatory signals. These co-stimulatory signals can either aggravate or ameliorate the disease depending on the stage of the disease, the cell-types involved and the signal transduction cascades initiated. This review focuses on the diverse roles of the most established co-stimulatory molecules of the B7 and Tumor Necrosis Factor Receptor (TNFR) families, ie the CD28/CTLA4-CD80/CD86 and CD40L/CD40 dyads in the pathogenesis of atherosclerosis and obesity. In addition, we will explore their potential as therapeutic targets in both atherosclerosis and obesity. PMID- 26225723 TI - The Impact of HCV Infection Duration on HIV Disease Progression and Response to cART amongst HIV Seroconverters in the UK. AB - INTRODUCTION: The effect of HCV infection on HIV disease progression remains unclear; the effect of HCV infection duration on HIV disease progression is unknown. METHODS: We used data from a cohort of HIV seroconverters to investigate the effect of HCV infection duration on time from HIV seroconversion to CD4 <350 cells/mm3, AIDS or death, censoring at the earlier of cART initiation or last clinic visit, adjusting for confounders and splitting data into follow up periods from HIV seroconversion (<2, 2-4 and >4 years). We additionally compared CD4 cell decline following HCV infection to that of mono-infected individuals with similar HIV infection duration by fitting a random effects model. In a separate analysis, we used linear mixed models to we examine the effect of HCV infection and its duration on CD4 increase over 48 weeks following cART. RESULTS: Of 1655 individuals, 97 (5.9%) were HCV co-infected. HCV<1 year was associated with a higher risk of endpoint in each follow-up period from HIV seroconversion (HR [95% CI] 2.58 [1.51, 4.41], p = 0.001; 3.80 [1.20, 12.03], p = 0.023; 2.03 [0.88, 4.71], p = 0.098 for <2, 2-4 and >4 years respectively), compared to mono infected individuals. However, we found no evidence of an association for those with HCV>2 years (all p>0.89). Individuals experienced a somewhat greater decrease in CD4 count following HCV infection lasting 13 months, relative to individuals with HIV alone, (estimate = -3.33, 95% CI [-7.29, 0.63] cells/mm3 per month, p = 0.099). Of 1502 initiating cART, 106 (7.1%) were HCV co-infected, with no evidence of HCV duration at cART being associated with immunological response (p = 0.45). CONCLUSIONS: The impact of HCV co-infection on HIV disease progression appears to be restricted to the first year after HCV infection. PMID- 26225730 TI - Diverse mixtures of 2,4-dihydroxy tautomers and O4 protonated conformers of uridine and 2'-deoxyuridine coexist in the gas phase. AB - The gas-phase conformations of protonated uridine, [Urd+H](+), and its modified form, protonated 2'-deoxyuridine, [dUrd+H](+), generated by electrospray ionization are investigated using infrared multiple photon dissociation (IRMPD) action spectroscopy techniques. IRMPD action spectra of [Urd+H](+) and [dUrd+H](+) are measured over the IR fingerprint and hydrogen-stretching regions. [Urd+H](+) and [dUrd+H](+) exhibit very similar IRMPD spectral profiles. However, the IRMPD yields of [Urd+H](+) exceed those of [dUrd+H](+) in both the IR fingerprint and hydrogen-stretching regions. The measured spectra are compared to the linear IR spectra predicted for the stable low-energy structures of these species computed at the B3LYP/6-311+G(d,p) level of theory to determine the tautomeric conformations populated by electrospray ionization. Both B3LYP and MP2 methods find O4 and O2 protonated canonical as well as 2,4-dihydroxy tautomers among the stable low-energy structures of [Urd+H](+) and [dUrd+H](+). Comparison between the measured IRMPD and calculated linear IR spectra suggests that these species exist in their ring-closed forms and that both 2,4-dihydroxy tautomers as well as O4 protonated canonical conformers coexist in the population generated by electrospray ionization for both [Urd+H](+) and [dUrd+H](+). The 2'-deoxy modification of [dUrd+H](+) reduces the variety of 2,4-dihydroxy tautomers populated in the experiments vs. those of [Urd+H](+). PMID- 26225732 TI - beta-Amyloid pathogenesis: Chemical properties versus cellular levels. AB - Although genetic Abeta variants cause early-onset Alzheimer's disease, literature reports on Abeta properties are heterogeneous, obscuring molecular mechanisms, as illustrated by recent failures of Abeta-level targeting trials. Thus, we combined available data on Abeta levels and ratios, aggregation propensities, toxicities, and patient data for Abeta variants and correlated these data to identify heterogeneity, significant relations, and basis for consensus. Despite heterogeneity, age of disease onset correlates to Abeta levels (R(2) = 0.38, P = .018), but not to toxicities, Abeta42 levels, Abeta42/Abeta40 ratios, or aggregation propensities. Cytotoxicity correlates inversely with total Abeta42 (R(2) = 0.65, P = .016) and Abeta42/Abeta40 ratios (R(2) = 0.76, P = .005), i.e., chemical properties that increase Abeta42 also reduce toxicity. The complexity and heterogeneity of data reveal the need to understand these phenotypes better, e.g., by focusing on the chemical properties of the involved Abeta species. PMID- 26225731 TI - Singlet oxygen treatment of tumor cells triggers extracellular singlet oxygen generation, catalase inactivation and reactivation of intercellular apoptosis inducing signaling. AB - Intracellular singlet oxygen generation in photofrin-loaded cells caused cell death without discrimination between nonmalignant and malignant cells. In contrast, extracellular singlet oxygen generation caused apoptosis induction selectively in tumor cells through singlet oxygen-mediated inactivation of tumor cell protective catalase and subsequent reactivation of intercellular ROS mediated apoptosis signaling through the HOCl and the NO/peroxynitrite signaling pathway. Singlet oxygen generation by extracellular photofrin alone was, however, not sufficient for optimal direct inactivation of catalase, but needed to trigger the generation of cell-derived extracellular singlet oxygen through the interaction between H2O2 and peroxynitrite. Thereby, formation of peroxynitrous acid, generation of hydroxyl radicals and formation of perhydroxyl radicals (HO2(.)) through hydroxyl radical/H2O2 interaction seemed to be required as intermediate steps. This amplificatory mechanism led to the formation of singlet oxygen at a sufficiently high concentration for optimal inactivation of membrane associated catalase. At low initial concentrations of singlet oxygen, an additional amplification step needed to be activated. It depended on singlet oxygen-dependent activation of the FAS receptor and caspase-8, followed by caspase-8-mediated enhancement of NOX activity. The biochemical mechanisms described here might be considered as promising principle for the development of novel approaches in tumor therapy that specifically direct membrane-associated catalase of tumor cells and thus utilize tumor cell-specific apoptosis-inducing ROS signaling. PMID- 26225733 TI - Editorial Comment. PMID- 26225734 TI - Determination of adenine based on the fluorescence recovery of the L-Tryptophan Cu(2+) complex. AB - A simple and sensitive method for determination of adenine was developed based on fluorescence quenching and recovery of L-Tryptophan (L-Trp). The fluorescence of L-Trp could efficiently quenched by copper ion compared with other common metal ions. Upon addition of adenine (Ade) in L-Trp-Cu(II) system, the fluorescence was reoccurred. Under the optimum conditions, the recovery fluorescence intensity was linearly correlated with the concentration of adenine in the range from 0.34 to 25.0MUmolL(-1), with a correlation coefficient (R(2)) of 0.9994. The detection limit (3sigma/k) was 0.046MUmolL(-1), indicating that this method could applied to detect trace adenine. In this study, amino acids including L-Trp, D-Trp, L Tyr, D-Tyr, L-Phe, D-Phe were investigated and only L-Trp could well chelated copper ion. Additionally, the mechanism of quench and recovery also were discussed and the method was successfully applied to detect the adenine in DNA with satisfactory results. PMID- 26225735 TI - In vitro and ex vivo hemocompatibility of off-the-shelf modified poly(vinyl alcohol) vascular grafts. AB - Synthetic small diameter vascular grafts with mechanical properties of native arteries, resistance to thrombosis and capacity to stimulate in situ endothelialization are an unmet clinical need. Poly(vinyl alcohol) hydrogel (PVA) is an excellent candidate as a vascular graft due to its tunable mechanical properties. However, the hydrophilicity and bio-inertness of PVA prevents endothelialization in vivo. We hypothesize that the modification of PVA with biomolecules and topographies creates a hemocompatible environment that also enhances bioactivity. PVA modified with fibronectin, RGDS peptide, cyclicRGD (cRGD) peptide, or heparin provided cell-adhesion motifs, which were confirmed by detection of nitrogen through X-ray photoelectron spectroscopy. Protein- and peptide-modified surfaces showed a slight increase in human vascular endothelial cell proliferation over unmodified PVA. With the exception of fibronectin modification, modified surfaces showed in vitro hemocompatibility comparable with unmodified PVA. To further improve bioactivity, cRGD-PVA was combined with gratings and microlens topographies. Combined modifications of 2 MUm gratings or convex topography and cRGD significantly improved human vascular endothelial cell viability on PVA. In vitro hemocompatibility testing showed that topography on cRGD-PVA did not significantly trigger an increase of platelet adhesion or activation compared with unpatterned PVA. Using the more physiologically relevant ex vivo hemocompatibility testing, all PVA grafts tested showed similar platelet adhesion to ePTFE and significantly lower platelet accumulation compared to collagen-coated ePTFE grafts. The biochemical and topographical modification of PVA demonstrates excellent hemocompatibility with enhanced bioactivity of PVA, thus highlighting its potential as a vascular graft. STATEMENT OF SIGNIFICANCE: New synthetic small diameter vascular grafts with mechanical properties, blood clot resistance and endothelial lining mimicking native arteries remains an unresolved critical clinical need. We aim to achieve this by modifying the mechanically-tunable poly(vinyl alcohol) hydrogel (PVA) vascular graft with both biochemical and biophysical cues in the lumenal surface. PVA modified with cyclic RGD peptide and ordered micrometer-sized topography showed low platelet adhesion in both a rabbit in vitro and baboon ex vivo blood compatibility assay. Modified PVA also exhibited significant enhancement of human vascular endothelial cell viability and proliferation in vitro. The readily available, modified PVA grafts are the first to show biophysical and biochemical modification in a three dimensional scaffold with hemocompatibility, biofunctionality and excellent potential for clinical application. PMID- 26225736 TI - Stealth monoolein-based nanocarriers for delivery of siRNA to cancer cells. AB - While the delivery of small interfering RNAs (siRNAs) is an attractive strategy to treat several clinical conditions, siRNA-nanocarriers' stability after intravenous administration is still a major obstacle for the development of RNA interference based therapies. But, although the need for stability is well recognized, the notion that strong stabilization can decrease nanocarriers' efficiency is sometimes neglected. In this work we evaluated two stealth functionalization strategies to stabilize the previously validated dioctadecyldimethylammonium bromide (DODAB):monoolein (MO) siRNA-lipoplexes. The nanocarriers were pre- and post-pegylated, forming vectors with different stabilities in biological fluids. The stealth nanocarriers' behavior was tested under biological mimetic conditions, as the production of stable siRNA-lipoplexes is determinant to achieve efficient intravenous siRNA delivery to cancer cells. Upon incubation in human serum for 2h, by fluorescence Single Particle Tracking microscopy, PEG-coated lipoplexes were found to have better colloidal stability as they could maintain a relatively stable size. In addition, using fluorescence fluctuation spectroscopy, post-pegylation also proved to avoid siRNA dissociation from the nanocarriers in human serum. Concomitantly it was found that PEG-coated lipoplexes improved cellular uptake and transfection efficiency in H1299 cells, and had the ability to silence BCR-ABL, affecting the survival of K562 cells. Based on an efficient cellular internalization, good silencing effect, good siRNA retention and good colloidal stability in human serum, DODAB:MO (2:1) siRNA lipoplexes coated with PEG-Cer are considered promising nanocarriers for further in vivo validation. STATEMENT OF SIGNIFICANCE: This work describes two stealth functionalization strategies for the stabilization of the previously validated dioctadecyldimethylammonium bromide (DODAB):monoolein (MO) siRNA-lipoplexes. These nanocarriers are capable of efficiently incorporating and delivering siRNA molecules to cells in order to silence genes whose expression is implicated in a pathological condition. The main objective was to functionalize these nanocarriers with a coating conferring protection to siRNA in blood without compromising its efficient delivery to cancer cells, validating the potential of DODAB:MO (2:1) siRNA-lipoplexes as therapeutic vectors. We show that the stealth strategy is determinant to achieve a stable and efficient nanocarrier, and that DODAB:MO mixtures have a very promising potential for systemic siRNA delivery to leukemic cells. PMID- 26225737 TI - A framework model for investigating the export of phosphorus to surface waters in forested watersheds: Implications to management. AB - The present study was developed in four sub-basins of rivers Cavado and Douro, located in the North of mainland Portugal. The goal was to identify main stressors as well as driving and attenuating processes responsible for the presence of phosphorus in masses of surface water in those catchments. To accomplish the goal, the basins were selected where a quality station was present at the outlet, the forest occupation was greater than 75% and the phosphorus concentrations have repeatedly exceeded the threshold for the good ecological status in the period 2000-2006. Further, in two basins the quality station was installed in a lotic (free-flow water) environment whereas in the other two was placed in a lentic (dammed water) environment. The ArcMap GIS-based software package was used for the spatial analysis of stressors and processes. The yields of phosphorus vary widely across the studied basins, from 0.2-30 kg.ha(-1).yr( 1). The results point to post-fire soil erosion and hardwood clear cuttings as leading factors of phosphorus exports across the watersheds, with precipitation intensity being the key variable of erosion. However, yields can be attenuated by sediment deposition along the pathway from burned or managed areas to water masses. The observed high yields and concentrations of phosphorus in surface water encompass serious implications for water resources management in the basins, amplified in the lentic cases by potential release of phosphorus from lake sediments especially during the summer season. Therefore, a number of measures were proposed as regards wildfire combat, reduction of phosphorus exports after tree cuts, attenuation of soil erosion and improvement of riparian buffers, all with the purpose of preventing phosphorus concentrations to go beyond the regulatory good ecological status. PMID- 26225738 TI - Using DET and DGT probes (ferrihydrite and titanium dioxide) to investigate arsenic concentrations in soil porewater of an arsenic-contaminated paddy field in Bangladesh. AB - Arsenic concentration in the pore water of paddy fields (Csoln) irrigated with arsenic-rich groundwater is a key parameter in arsenic uptake by rice. Pore water extracts from cores and in situ deployment of DET and DGT probes were used to measure the arsenic concentration in the pore water. Ferrihydrite (Fe) and titanium dioxide (Ti) were used as DGT binding agents. Six sampling events during different growing stages of the rice, inducing different biogeochemical conditions, were performed in one rice field. A time series of DGT experiments allow the determination of an in situ arsenic diffusion coefficient in the diffusive gel (3.34*10(-6) cm(2) s(-1)) needed to calculate the so-called CDGT(Fe) and CDGT(Ti) concentrations. Over 3 days of a given sampling event and for cores sampled at intervals smaller than 50 cm, great variability in arsenic Csoln concentrations between vertical profiles was observed, with maxima of concentrations varying from 690 to 2800 MUg L(-1). Comparisons between arsenic measured Csol and CDET and calculated CDGT(Fe) and CDGT(Ti) concentrations show either, in a few cases, roughly similar vertical profiles, or in other cases, significantly different profiles. An established iron oxyhydroxide precipitation in the DET gel may explain why measured arsenic CDET concentrations occasionally exceeded Csoln. The large spread in results suggests limitations to the use of DET and type of DGT probes used here for similarly representing the spatio temporal variations of arsenic content in soil pore water in specific environmental such as paddy soils. PMID- 26225739 TI - Review of the indoor environmental quality and energy consumption studies for low income households in Europe. AB - The term energy poverty is used to describe a situation of a household not able to satisfy socially and materially the required levels of its energy services. Energy and fuel poverty is an increasing problem in the European Union. Although the specific conditions vary from country to country the drivers defining fuel and energy poverty are similar in all Europe. This paper aims to present the state of the art regarding the energy demand and indoor environmental quality of low income households in Europe. The characteristics of this specific population group are presented including details on the specific energy consumption, the indoor comfort and finally the impact of the specific living conditions on the occupants' health. PMID- 26225740 TI - Trends in stimulant use in Australia: A comparison of wastewater analysis and population surveys. AB - Levels of community drug use are usually described by national surveys; data relied upon by decision makers in health and law enforcement. In recent years the analysis of wastewater for drugs and their metabolites has become prominent. Both methods convey unique drug use information. This paper demonstrates differences arising from the two approaches, using methamphetamine, 3,4 methylenedioxymethamphetamine (MDMA) and cocaine data from the state of South Australia. The proportion of people using each drug, obtained from three prominent drug surveys, was compared with estimates of total community drug use derived by wastewater analysis. Temporal trends were compared for available years of the surveys and wastewater analysis from 2010 to 2013. Wastewater results showed methamphetamine to be the most prevalent stimulant in Adelaide, South Australia, with an average of 24.4+/-1.7 doses per day per 1000 inhabitants for 2013, while consumption of MDMA and cocaine were much lower at 0.52+/-0.12 and 0.42+/-0.06 doses per day per 1000 inhabitants, respectively. Survey data typically had MDMA as the most used stimulant on a proportion of the population basis. The difference in magnitude of drug use between MDMA and methamphetamine was also less apparent. Temporal trends of the proportion of the population using a drug by surveys did not generally reflect total use within the community which was observed by wastewater analysis. Survey data are excellent for describing users demographically. However, discrepancies between the proportion of the population who are users and the magnitude of drug use can lead to misrepresentation of the overall scale of use. The results from this study indicate methamphetamine was used to a much greater extent than suggested by the surveys. Together, wastewater analysis and survey data give a comprehensive view of the drug problem enabling more informed decisions on drug policy. PMID- 26225741 TI - Sick building syndrome (SBS) among office workers in a Malaysian university- Associations with atopy, fractional exhaled nitric oxide (FeNO) and the office environment. AB - There are few studies on sick building syndrome (SBS) including clinical measurements for atopy and fractional exhaled nitric oxide (FeNO). Our aim was to study associations between SBS symptoms, selected personal factors, office characteristics and indoor office exposures among office workers from a university in Malaysia. Health data were collected by a questionnaire (n=695), skin prick test (SPT) (n=463) and FeNO test (n=460). Office settled dust was vacuumed and analyzed for endotoxin, (1,3)-beta-glucan and house dust mites (HDM) allergens group 1 namely Dermatophagoides pteronyssinus (Der p 1) and Dermatophagoides farinae (Der f 1). Office indoor temperature, relative air humidity (RH), carbon monoxide (CO) and carbon dioxide (CO2) were measured by a direct reading instrument. Associations were studied by two-levels multiple logistic regression with mutual adjustment and stratified analysis. The prevalence of weekly dermal, mucosal and general symptoms was 11.9%, 16.0% and 23.0% respectively. A combination of SPT positivity (allergy to HDM or cat) and high FeNO level (>=25 ppb) was associated with dermal (p=0.002), mucosal (p<0.001) and general symptoms (p=0.05). Der f1 level in dust was associated with dermal (p<0.001), mucosal (p<0.001) and general (p=0.02) symptoms. Among those with allergy to D. farinae, associations were found between Der f 1 levels in dust and dermal (p=0.003), mucosal (p=0.001) and general symptoms (p=0.007). Office-related symptoms were associated with Der f 1 levels in dust (p=0.02), low relative air humidity (p=0.04) and high office temperature (p=0.05). In conclusion, a combination of allergy to cat or HDM and high FeNO is a risk factor for SBS symptoms. Der f 1 allergen in dust can be a risk factor for SBS in the office environment, particularly among those sensitized to Der f 1 allergen. PMID- 26225742 TI - Arsenic relative bioavailability from diet and airborne exposures: Implications for risk assessment. AB - Major human environmental health concern has been associated with inorganic arsenic (iAs) in drinking water in which dissolved iAs is highly bioavailable. More recently health concerns have been raised regarding the extent of iAs exposure via food and other potential sources. Arsenic relative bioavailability (RBA) in soil is known to be variable; the extent and role of iAs bioavailability in food are not well characterized. iAs in coal fly ash and bottom ash are other potential exposure media for which RBA has not been well characterized. A comprehensive literature search was conducted to support evaluation of the contribution of food and coal fly ash to iAs exposure. Few studies were found that investigated bioavailability associated with As-containing coal ash or airborne As-containing particles; estimated bioavailability in these studies ranged from 11% to 50%. The implications and potential usefulness of iAs bioavailability associated with inhalation exposure to human health risk assessment remain unknown at this time. Main sources of dietary iAs intake in the U.S. include rice and other grains, vegetables, and fruits. Due to low concentrations of iAs, seafood is not a primary contributor to dietary iAs intake. Three general kinds of food studies were identified: studies of As bioaccessibility in composites, As bioavailability and bioaccessibility in specific foods, and As consumption and urinary excretion in human volunteers. One in vivo study was identified that examined As bioavailability in food. A variety of experimental in vitro gastro-intestinal protocols have been used, however, few studies have included As speciation before and after the in vitro extraction. Current data suggest that the bioaccessibility of iAs in rice is quite high, typically 70% or more indicating that iAs in rice is highly bioavailable. Adjusting for RBA may not have a meaningful impact on iAs exposure estimates for rice-based foods. PMID- 26225743 TI - The acute toxicity of thallium to freshwater organisms: Implications for risk assessment. AB - The acute toxicity of Tl(I) to the microalga, Pseudokirchneriella subcapitata, the planktonic crustaceans, Daphnia magna and Daphnia pulex, and early-life stage of the zebrafish, Danio rerio, has been studied according to OECD protocols. Toxicological end-point concentrations for the microalga ranged from 17 MUg l(-1) for a 72 h EyC25 (yield inhibition) to 80 MUg l(-1) for a 72 h ErC50 (growth inhibition). Daphnia were less sensitive to Tl, with 48 h EC50s of about 1000 MUg l(-1) and 1200 MUg l(-1) for D. magna and D. pulex, respectively; however, end point concentrations were reduced considerably (to about 510 MUg l(-1) and 730 MUg l(-1), respectively) when experiments were repeated in dechlorinated Plymouth tap water (rather than OECD medium). The 96 h LC50 for D. rerio was 870 MUg l(-1) but a variety of sub-lethal effects, including enlargement of yolk sac and reduction in heart beat rate, were observed when larvae were exposed to lower concentrations. Based on these results, a predicted no effect concentration (PNEC) for Tl in freshwaters of 0.087 MUg l(-1) is proposed. The PNEC is an order of magnitude lower than the only (Canadian) water quality guideline for Tl that appears to exist, and is lower than Tl concentrations reported in freshwaters impacted by historical or contemporary metal mining. Our results are also consistent with previous studies that employ different organisms and end-points in that Tl toxicity is dependent on the concentration of K+, the biogeochemical analogue of Tl+. Accordingly, regulation of Tl in the freshwater environment should factor in the relative abundance of K. PMID- 26225744 TI - Short branched-chain C6 carboxylic acids result in increased growth, novel 'unnatural' fatty acids and increased membrane fluidity in a Listeria monocytogenes branched-chain fatty acid-deficient mutant. AB - Listeria monocytogenes is a psychrotolerant food borne pathogen, responsible for the high fatality disease listeriosis, and expensive food product recalls. Branched-chain fatty acids (BCFAs) of the membrane play a critical role in providing appropriate membrane fluidity and optimum membrane biophysics. The fatty acid composition of a BCFA-deficient mutant is characterized by high amounts of straight-chain fatty acids and even-numbered iso fatty acids, in contrast to the parent strain where odd-numbered anteiso fatty acids predominate. The presence of 2-methylbutyrate (C5) stimulated growth of the mutant at 37 degrees C and restored growth at 10 degrees C along with the content of odd numbered anteiso fatty acids. The C6 branched-chain carboxylic acids 2 ethylbutyrate and 2-methylpentanoate also stimulated growth to a similar extent as 2-methylbutyrate. However, 3-methylpentanoate was ineffective in rescuing growth. 2-Ethylbutyrate and 2-methylpentanoate led to novel major fatty acids in the lipid profile of the membrane that were identified as 12-ethyltetradecanoic acid and 12-methylpentadecanoic acid respectively. Membrane anisotropy studies indicated that growth of strain MOR401 in the presence of these precursors increased its membrane fluidity to levels of the wild type. Cells supplemented with 2-methylpentanoate or 2-ethylbutyrate at 10 degrees C shortened the chain length of novel fatty acids, thus showing homeoviscous adaptation. These experiments use the mutant as a tool to modulate the membrane fatty acid compositions through synthetic precursor supplementation, and show how existing enzymes in L. monocytogenes adapt to exhibit non-native activity yielding unique 'unnatural' fatty acid molecules, which nevertheless possess the correct biophysical properties for proper membrane function in the BCFA-deficient mutant. PMID- 26225745 TI - Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development. AB - Fibrinogen like protein-1 (Fgl1) is a predominantly liver expressed protein that has been implicated as both a hepatoprotectant and a hepatocyte mitogen. Fgl1 expression is decreased in hepatocellular carcinoma (HCC) and its loss correlates with a poorly differentiated phenotype. To better elucidate the role of Fgl1 in hepatocarcinogenesis, we treated mice wild type or null for Fgl1 with diethyl nitrosamine and monitored for incidence of hepatocellular cancer. We find that mice lacking Fgl1 develop HCC at more than twice the rate of wild type mice. We show that hepatocellular cancers from Fgl1 null mice are molecularly distinct from those of the wild type mice. In tumors from Fgl1 null mice there is enhanced activation of Akt and downstream targets of the mammalian target of rapamycin (mTOR). In addition, there is paradoxical up regulation of putative hepatocellular cancer tumor suppressors; tripartite motif-containing protein 35 (Trim35) and tumor necrosis factor super family 10b (Tnfrsf10b). Taken together, these findings suggest that Fgl1 acts as a tumor suppressor in hepatocellular cancer through an Akt dependent mechanism and supports its role as a potential therapeutic target in HCC. PMID- 26225747 TI - Metformin decreases growth of pancreatic cancer cells by decreasing reactive oxygen species: Role of NOX4. AB - BACKGROUND: Retrospective epidemiologic studies show that metformin reduced the incidence of pancreatic cancer in diabetic patients. One potential mechanism may be by altering reactive oxygen species (ROS) and apoptosis. In this in vitro study, we explore the role of ROS and apoptosis in mediating the growth inhibitory effects of metformin in pancreatic cancer cells. METHODS: We cultured MIA PaCa and Panc1 pancreatic cancer cells in medium containing physiological concentrations of glucose (5 mM) or supra-physiological concentrations of glucose and then treated cells with metformin. Cell viability, ROS production, apoptosis, and protein levels of manganese superoxide dismutase (MnSOD), NADPH oxidase (NOX) 2, and NOX4 were measured. RESULTS: Metformin decreased viability of MIA PaCa and Panc1 cells under physiological glucose conditions in comparison to untreated cells; metformin did not have any effect on human pancreatic normal epithelial (HPNE) cells. The decrease in cell survival was associated with decreased intracellular ROS, increased protein levels of MnSOD, and decreased levels of NOX2 and NOX4 proteins in MIA PaCa and Panc1 cells but not HPNE cells. Transfecting MIA PaCa and Panc1 cells with pcDNA3NOX4 protected against the anti survival effects of metformin. CONCLUSION: Our findings suggest that metformin decreases cell survival by reducing ROS production, in part through down regulation of NOX4 protein expression. PMID- 26225746 TI - Dopamine or biopterin deficiency potentiates phosphorylation at (40)Ser and ubiquitination of tyrosine hydroxylase to be degraded by the ubiquitin proteasome system. AB - The protein amount of tyrosine hydroxylase (TH), that is the rate-limiting enzyme for the biosynthesis of dopamine (DA), should be tightly regulated, whereas its degradation pathway is largely unknown. In this study, we analyzed how the TH protein is chemically modified and subsequently degraded under deficiencies of DA and tetrahydrobiopterin (BH4), a cofactor for TH, by using pharmacological agents in PC12D cells and cultured mesencephalic neurons. When inhibition of DA- or BH4 synthesizing enzymes greatly reduced the DA contents in PC12D cells, a marked and persistent increase in phosphorylated TH at (40)Ser (p40-TH) was concomitantly observed. This phosphorylation was mediated by D2 dopamine auto-receptor and cAMP dependent protein kinase (PKA). Our immunoprecipitation experiments showed that the increase in the p40-TH level was accompanied with its poly-ubiquitination. Treatment of PC12D cells with cycloheximide showed that total-TH protein level was reduced by the DA- or BH4-depletion. Notably, this reduction in the total-TH protein level was sensitive not only to a 26S proteasomal inhibitor, MG-132, but also to a PKA inhibitor, H-89. These data demonstrated that DA deficiency should induce compensatory activation of TH via phosphorylation at (40)Ser through D2 autoreceptor and PKA-mediated pathways, which in turn give a rise to its degradation through an ubiquitin-proteasome pathway, resulting in a negative spiral of DA production when DA deficiency persists. PMID- 26225748 TI - Localization and osteoblastic differentiation potential of neural crest-derived cells in oral tissues of adult mice. AB - In embryos, neural crest cells emerge from the dorsal region of the fusing neural tube and migrate throughout tissues to differentiate into various types of cells including osteoblasts. In adults, subsets of neural crest-derived cells (NCDCs) reside as stem cells and are considered to be useful cell sources for regenerative medicine strategies. Numerous studies have suggested that stem cells with a neural crest origin persist into adulthood, especially those within the mammalian craniofacial compartment. However, their distribution as well as capacity to differentiate into osteoblasts in adults is not fully understood. To analyze the precise distribution and characteristics of NCDCs in adult oral tissues, we utilized an established line of double transgenic (P0-Cre/CAG-CAT EGFP) mice in which NCDCs express green fluorescent protein (GFP) throughout their life. GFP-positive cells were scattered like islands throughout tissues of the palate, gingiva, tongue, and buccal mucosa in adult mice, with those isolated from the latter shown to form spheres, typical cell clusters composed of stem cells, under low-adherent conditions. Furthermore, GFP-positive cells had markedly increased alkaline phosphatase (a marker enzyme of osteoblast differentiation) activity and mineralization as shown by alizarin red staining, in the presence of bone morphogenetic protein (BMP)-2. These results suggest that NCDCs reside in various adult oral tissues and possess potential to differentiate into osteoblastic cells. NCDCs in adults may be a useful cell source for bone regeneration strategies. PMID- 26225749 TI - p53 is required for metformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. AB - The p53 tumor repressor gene is commonly mutated in human cancers. The tumor inhibitory effect of metformin on p53-mutated breast cancer cells remains unclear. Data from the present study demonstrated that p53 knockdown or mutation has a negative effect on metformin or phenformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. We also found that p53 reactivating agent nutlin-3alpha and CP/31398 promoted metformin-induced growth inhibition, senescence and apoptosis in MCF-7 (wt p53) and MDA-MB-231 (mt p53) cells, respectively. Treatment of MCF-7 cells with metformin or phenformin induced increase in p53 protein levels and the transcription of its downstream target genes, Bax and p21, in a dose-dependent manner. Moreover, we demonstrated that AMPK-mTOR signaling played a role in metformin-induced p53 up-regulation. The present study showed that p53 is required for metformin or phenformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. The combination of metformin with p53 reactivating agents, like nutlin-3alpha and CP/31398, is a promising strategy for improving metformin-mediated anti-cancer therapy, especially for tumors with p53 mutations. PMID- 26225750 TI - Analysis of the Bombyx mori nucleopolyhedrovirus ie-1 promoter in insect, mammalian, plant, and bacterial cells. AB - The Bombyx mori nucleopolyhedrovirus (BmNPV) ie-1 promoter exhibits strong transcriptional activity and is used in transient foreign gene expression systems in insect cells. In a reporter assay experiment using the BmNPV ie-1 promoter, we found that it exhibited activity even in non-host mammalian BHK cells, plant BY-2 cells, and also bacterial Escherichia coli cells. An analysis using a deletion series of the BmNPV ie-1 promoter demonstrated that the core promoter region of this promoter was sufficient to display promoter activity in BHK cells, BY-2 cells, and E. coli cells, whereas upstream elements were required for higher activity in insect cells. Furthermore, we found that the BmNPV ie-1 promoter exhibited sufficient activity for a beta-galactosidase assay in E. coli cells. The results obtained here suggest that the BmNPV ie-1 promoter has potential as a universal promoter for transient expression systems in insect, mammalian, plant, and bacterial cells. PMID- 26225751 TI - Neuronal death after perinatal cerebral hypoxia-ischemia: Focus on autophagy mediated cell death. AB - Neonatal hypoxic-ischemic encephalopathy is a critical cerebral event occurring around birth with high mortality and neurological morbidity associated with long term invalidating sequelae. In view of the great clinical importance of this condition and the lack of very efficacious neuroprotective strategies, it is urgent to better understand the different cell death mechanisms involved with the ultimate aim of developing new therapeutic approaches. The morphological features of three different cell death types can be observed in models of perinatal cerebral hypoxia-ischemia: necrotic, apoptotic and autophagic cell death. They may be combined in the same dying neuron. In the present review, we discuss the different cell death mechanisms involved in neonatal cerebral hypoxia-ischemia with a special focus on how autophagy may be involved in neuronal death, based: (1) on experimental models of perinatal hypoxia-ischemia and stroke, and (2) on the brains of human neonates who suffered from neonatal hypoxia-ischemia. PMID- 26225752 TI - Internalization and desensitization of the human glucose-dependent-insulinotropic receptor is affected by N-terminal acetylation of the agonist. AB - How incretins regulate presence of their receptors at the cell surface and their activity is of paramount importance for the development of therapeutic strategies targeting these receptors. We have studied internalization of the human Glucose Insulinotropic Polypeptide receptor (GIPR). GIP stimulated rapid robust internalization of the GIPR, the major part being directed to lysosomes. GIPR internalization involved mainly clathrin-coated pits, AP-2 and dynamin. However, neither GIPR C-terminal region nor beta-arrestin1/2 was required. Finally, N acetyl-GIP recognized as a dipeptidyl-IV resistant analogue, fully stimulated cAMP production with a ~15-fold lower potency than GIP and weakly stimulated GIPR internalization and desensitization of cAMP response. Furthermore, docking N acetyl-GIP in the binding site of modeled GIPR showed slighter interactions with residues of helices 6 and 7 of GIPR compared to GIP. Therefore, incomplete or partial activity of N-acetyl-GIP on signaling involved in GIPR desensitization and internalization contributes to the enhanced incretin activity of this peptide. PMID- 26225753 TI - Seven key investments for health equity across the lifecourse: Scotland versus the rest of the UK. AB - While widespread lip service is given in the UK to the social determinants of health (SDoH), there are few published comparisons of how the UK's devolved jurisdictions 'stack up', in terms of implementing SDoH-based policies and programmes, to improve health equity over the life-course. Based on recent SDoH publications, seven key societal-level investments are suggested, across the life course, for increasing health equity by socioeconomic position (SEP). We present hard-to-find comparable analyses of routinely collected data to gauge the relative extent to which these investments have been pursued and achieved expected goals in Scotland, as compared with England and Wales, in recent decades. Despite Scotland's longstanding explicit goal of reducing health inequalities, it has recently been doing slightly better than England and Wales on only one broad indicator of health-equity-related investments: childhood poverty. However, on the following indicators of other 'best investments for health equity', Scotland has not achieved demonstrably more equitable outcomes by SEP than the rest of the UK: infant mortality and teenage pregnancy rates; early childhood education implementation; standardised educational attainment after primary/secondary school; health care system access and performance; protection of the population from potentially hazardous patterns of food, drink and gambling use; unemployment. Although Scotland did not choose independence on September 18th, 2014, it could still (under the planned increased devolution of powers from Westminster) choose to increase investments in the underperforming categories of interventions for health equity listed above. However, such discussion is largely absent from the current post-referendum debate. Without further significant investments in such policies and programmes, Scotland is unlikely to achieve the 'healthier, fairer society' referred to in the current Scottish Government's official aspirations for the nation. PMID- 26225755 TI - Inactivation of Bacillus subtilis spores by combined pulsed light and thermal treatments. AB - The combined effect of pulsed light (PL) and heat processing was evaluated on the inactivation of Bacillus subtilis spores. Those processes were applied separately and the time between both treatments was modified to evaluate whether the effect of the first treatment is maintained for a long time. B. subtilis spores subjected to sublethal pre-treatments were more sensitive to subsequent treatments (PL or thermal treatments) than untreated spores. Heating followed by PL was the most effective combination in reducing B. subtilis counts. Bacterial spores remained sensitized to subsequent treatment for at least 24 h of storage in water, whatever the temperature was (4 or 30 degrees C). Sensitivity of B. subtilis cells to PL or heat processing increased after germination in a nutrient broth, being equally sensitive from 3 to 24 h. Vegetative cells maintained their enhanced sensitivity to subsequent processing after spore germination. The results of this work demonstrate that the combination of heating and PL treatment is a promising preservation method for microbial inactivation. PMID- 26225754 TI - Combined treatment of adenosine nucleoside inhibitor NITD008 and histone deacetylase inhibitor vorinostat represents an immunotherapy strategy to ameliorate West Nile virus infection. AB - West Nile virus (WNV), a member of the Flaviviridae family, is the leading cause of viral encephalitis in the United States. Despite efforts to control the spread of WNV, there has been an increase in the number of outbreaks and clinical cases with neurological problems. There are no antiviral compounds currently in trials for WNV. NITD008 is an adenosine analogue inhibitor that interrupts the RNA dependent RNA polymerase of flaviviruses. Previous studies demonstrated NITD008 as a potent antiviral for dengue virus, however this drug was associated with preclinical toxicity. The ability of NITD008 to block WNV replication is only shown in Vero cells. Neuroinflammation is also a major cause of the WNV associated pathology, therefore we evaluated the effect of NITD008 and a newly characterized anti-inflammatory drug vorinostat (SAHA), a histone deacetylase inhibitor, on WNV replication and disease progression in a mouse model. When administered at 10 and 25mg/kg at days 1-6 after WNV infection in C57BL/6 mice, NITD008 conferred complete protection from clinical symptoms and death, which correlated with reduced viral load in the serum and restriction of virus-CNS entry. Delay of NITD008 treatment to days 3-6 and days 5-9 after infection, when WNV replication was high in the periphery and brain, resulted in the gradual loss of protection against WNV infection. However, co-treatment with SAHA and NITD008 during the CNS phase of disease improved disease outcome significantly by reducing inflammation and neuronal death. Our results support potential synergistic effect of combination therapy of NITD008 with SAHA for the treatment of WNV encephalitis. PMID- 26225756 TI - Monitoring the Activation of the DNA Damage Response Pathway in a 3D Spheroid Model. AB - Monitoring the DNA-Damage Response (DDR) activated pathway in multicellular tumor spheroid models is an important challenge as these 3D models have demonstrated their major relevance in pharmacological evaluation. Herein we present DDR-Act FP, a fluorescent biosensor that allows detection of DDR activation through monitoring of the p21 promoter p53-dependent activation. We show that cells expressing the DDR-Act-FP biosensor efficiently report activation of the DDR pathway after DNA damage and its pharmacological manipulation using ATM kinase inhibitors. We also report the successful use of this assay to screen a small compound library in order to identify activators of the DDR response. Finally, using multicellular spheroids expressing the DDR-Act-FP we demonstrate that DDR activation and its pharmacological manipulation with inhibitory and activatory compounds can be efficiently monitored in live 3D spheroid model. This study paves the way for the development of innovative screening and preclinical evaluation assays. PMID- 26225757 TI - Social Inequalities in Young Children's Meal Skipping Behaviors: The Generation R Study. AB - BACKGROUND: Regular meal consumption is considered an important aspect of a healthy diet. While ample evidence shows social inequalities in breakfast skipping among adolescents, little is known about social inequalities in breakfast skipping and skipping of other meals among young school-aged children. Such information is crucial in targeting interventions aimed to promote a healthy diet in children. METHODS: We examined data from 4704 ethnically diverse children participating in the Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. Information on family socioeconomic position (SEP), ethnic background, and meal skipping behaviors was assessed by parent reported questionnaire when the child was 6 years old. Multiple logistic regression analyses were performed to assess the associations of family SEP (educational level, household income, employment status, family composition) and ethnic background with meal skipping behaviors, using high SEP children and native Dutch children as reference groups. RESULTS: Meal skipping prevalence ranged from 3% (dinner) to 11% (lunch). The prevalence of meal skipping was higher among low SEP children and ethnic minority children. Maternal educational level was independently associated with breakfast skipping ([low maternal educational level] OR: 2.21; 95% CI: 1.24,3.94). Paternal educational level was independently associated with lunch skipping ([low paternal educational level] OR: 1.53; 95% CI: 1.06,2.20) and dinner skipping ([mid-high paternal educational level] OR: 0.39; 95% CI: 0.20,0.76). Household income was independently associated with breakfast skipping ([low income] OR: 2.43, 95% CI: 1.40,4.22) and dinner skipping ([low income] OR: 2.44; 95% CI: 1.22,4.91). In general, ethnic minority children were more likely to skip breakfast, lunch, and dinner compared with native Dutch children. Adjustment for family SEP attenuated the associations of ethnic minority background with meal skipping behaviors considerably. CONCLUSION: Low SEP children and ethnic minority children are at an increased risk of breakfast, lunch, and dinner skipping compared with high SEP children and native Dutch children, respectively. Given these inequalities, interventions aimed to promote regular meal consumption, breakfast consumption in particular, should target children from low socioeconomic groups and ethnic minority children. More qualitative research to investigate the pathways underlying social inequalities in children's meal skipping behaviors is warranted. PMID- 26225758 TI - Mitochondrial Apoptotic Pathway Is Activated by H2O2-Mediated Oxidative Stress in BmN-SWU1 Cells from Bombyx mori Ovary. AB - Apoptosis is a known regulator of morphogenetic events. In mammals, the critical role of oxidative stress-induced apoptosis has been well-studied; however, in insects the role of oxidative stress in apoptosis is not clear. In a previous study, we showed that apoptosis-related genes are present in the silkworm Bombyx mori, an important lepidopteran insect model. In this study, we evaluated the effect of H2O2-induced oxidative stress on apoptosis, reactive oxygen species (ROS) levels, mitochondrial response, cytochrome c release and apoptosis-related gene expression in the BmN-SWU1 cell line from B. mori ovaries. Our results showed that BmN-SWU1 cells exposed to H2O2 showed cell protuberances, cytoplasmic condensation, apoptotic bodies, DNA ladder formation and caspase activities indicating apoptosis. H2O2-induced apoptosis also increased intracellular ROS level, changed mitochondrial distribution, reduced mitochondrial membrane potential and increased the release of cytochrome c from mitochondria. Furthermore, western blot analysis revealed a significant increase in p53 and cytochrome c expression, and a decrease in Bcl-2 expression compared to the controls. Moreover, quantitative real-time PCR (qRT-PCR) showed an increase in the transcript levels of BmICE, Bmapaf-1 and BmEndoG by 439.5%, 423.9% and 42.2%, respectively, after treatment with 1 MUM H2O2 for 24 h. However, the transcript levels of Bmbuffy declined by 41.4% after 24 h of exposure to 1 MUM H2O2. These results show that H2O2 treatment induced apoptosis in BmN-SWU1 cells via the mitochondrial apoptotic pathway. Further, it appears that oxidative stress induced by H2O2 activates both caspase-dependent and caspase-independent mitochondrial apoptotic pathways in silkworm cells. Taken together, these findings improve our knowledge of apoptosis in silkworm and the apoptotic pathways in insects. PMID- 26225759 TI - Linguistic and Cultural Challenges in Communication and Translation in US Sponsored HIV Prevention Research in Emerging Economies. AB - Linguistic and cultural differences can impede comprehension among potential research participants during the informed consent process, but how researchers and IRBs respond to these challenges in practice is unclear. We conducted in depth interviews with 15 researchers, research ethics committee (REC) chairs and members from 8 different countries with emerging economies, involved in HIV related research sponsored by HIV Prevention Trials Network (HPTN), regarding the ethical and regulatory challenges they face in this regard. In the interviews, problems with translating study materials often arose as major concerns. Four sets of challenges were identified concerning linguistic and cultural translations of informed consent documents and other study materials, related to the: (1) context, (2) process, (3) content and (4) translation of these documents. Host country contextual issues included low literacy rates, education (e.g., documents may need to be written below 5th grade reading level), and experiences with research, and different views of written documentation. Certain terms and concepts may not exist in other languages, or have additional connotations that back translations do not always reveal. Challenges arise because of not only the content of word-for-word, literal translation, but the linguistic form of the language, such as tone (e.g., appropriate forms of politeness vs. legalese, seen as harsh), syntax, manner of questions posed, and the concept of the consent); and the contexts of use affect meaning. Problems also emerged in bilateral communications--US IRBs may misunderstand local practices, or communicate insufficiently the reasons for their decisions to foreign RECs. In sum, these data highlight several challenges that have received little, if any, attention in past literature on translation of informed consent and study materials, and have crucial implications for improving practice, education, research and policy, suggesting several strategies, including needs for broader open-source multilingual lexicons, and more awareness of the complexities involved. PMID- 26225760 TI - The Phylogeny and Evolutionary Timescale of Muscoidea (Diptera: Brachycera: Calyptratae) Inferred from Mitochondrial Genomes. AB - Muscoidea is a significant dipteran clade that includes house flies (Family Muscidae), latrine flies (F. Fannidae), dung flies (F. Scathophagidae) and root maggot flies (F. Anthomyiidae). It is comprised of approximately 7000 described species. The monophyly of the Muscoidea and the precise relationships of muscoids to the closest superfamily the Oestroidea (blow flies, flesh flies etc) are both unresolved. Until now mitochondrial (mt) genomes were available for only two of the four muscoid families precluding a thorough test of phylogenetic relationships using this data source. Here we present the first two mt genomes for the families Fanniidae (Euryomma sp.) (family Fanniidae) and Anthomyiidae (Delia platura (Meigen, 1826)). We also conducted phylogenetic analyses containing of these newly sequenced mt genomes plus 15 other species representative of dipteran diversity to address the internal relationship of Muscoidea and its systematic position. Both maximum-likelihood and Bayesian analyses suggested that Muscoidea was not a monophyletic group with the relationship: (Fanniidae + Muscidae) + ((Anthomyiidae + Scathophagidae) + (Calliphoridae + Sarcophagidae)), supported by the majority of analysed datasets. This also infers that Oestroidea was paraphyletic in the majority of analyses. Divergence time estimation suggested that the earliest split within the Calyptratae, separating (Tachinidae + Oestridae) from the remaining families, occurred in the Early Eocene. The main divergence within the paraphyletic muscoidea grade was between Fanniidae + Muscidae and the lineage ((Anthomyiidae + Scathophagidae) + (Calliphoridae + Sarcophagidae)) which occurred in the Late Eocene. PMID- 26225761 TI - Self-Averaging Property of Minimal Investment Risk of Mean-Variance Model. AB - In portfolio optimization problems, the minimum expected investment risk is not always smaller than the expected minimal investment risk. That is, using a well known approach from operations research, it is possible to derive a strategy that minimizes the expected investment risk, but this strategy does not always result in the best rate of return on assets. Prior to making investment decisions, it is important to an investor to know the potential minimal investment risk (or the expected minimal investment risk) and to determine the strategy that will maximize the return on assets. We use the self-averaging property to analyze the potential minimal investment risk and the concentrated investment level for the strategy that gives the best rate of return. We compare the results from our method with the results obtained by the operations research approach and with those obtained by a numerical simulation using the optimal portfolio. The results of our method and the numerical simulation are in agreement, but they differ from that of the operations research approach. PMID- 26225762 TI - Visual and Non-Visual Navigation in Blind Patients with a Retinal Prosthesis. AB - Human adults with normal vision can combine visual landmark and non-visual self motion cues to improve their navigational precision. Here we asked whether blind individuals treated with a retinal prosthesis could also benefit from using the resultant new visual signal together with non-visual information when navigating. Four patients (blind for 15-52 years) implanted with the Argus II retinal prosthesis (Second Sight Medical Products Inc. Sylmar, CA), and five age-matched and six younger controls, participated. Participants completed a path reproduction and a triangle completion navigation task, using either an indirect visual landmark and non-visual self-motion cues or non-visual self-motion cues only. Control participants wore goggles that approximated the field of view and the resolution of the Argus II prosthesis. In both tasks, control participants showed better precision when navigating with reduced vision, compared to without vision. Patients, however, did not show similar improvements when navigating with the prosthesis in the path reproduction task, but two patients did show improvements in the triangle completion task. Additionally, all patients showed greater precision than controls in both tasks when navigating without vision. These results indicate that the Argus II retinal prosthesis may not provide sufficiently reliable visual information to improve the precision of patients on tasks, for which they have learnt to rely on non-visual senses. PMID- 26225763 TI - Immune interventions to preserve beta cell function in type 1 diabetes. AB - Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to destruction of pancreatic beta cells, lifelong dependence on insulin, and increased morbidity and mortality from diabetes-related complications. Preservation of residual beta cells at diagnosis is a major goal because higher levels of endogenous insulin secretion are associated with better short- and long-term outcomes. For the past 3 decades, a variety of immune interventions have been evaluated in the setting of new-onset T1D, including nonspecific immunosuppression, pathway-specific immune modulation, antigen-specific therapies, and cellular therapies. To date, no single intervention has produced durable remission off therapy in most treated patients, but the field has gained valuable insights into disease mechanisms and potential immunologic correlates of success. In particular, T-cell-directed therapies, including therapies that lead to partial depletion or modulation of effector T cells and preservation or augmentation of regulatory T cells, have shown the most success and will likely form the backbone of future approaches. The next phase will see evaluation of rational combinations, comprising one or more of the following: an effector T-depleting or -modulating drug, a cytokine based tolerogenic (regulatory T-cells-promoting) agent, and an antigen-specific component. The long term goal is to reestablish immunologic tolerance to beta cells, thereby preserving residual beta cells early after diagnosis or enabling restoration of beta-cell mass from autologous stem cells or induced neogenesis in patients with established T1D. PMID- 26225765 TI - Affinity Maturation of Monoclonal Antibody 1E11 by Targeted Randomization in CDR3 Regions Optimizes Therapeutic Antibody Targeting of HER2-Positive Gastric Cancer. AB - Anti-HER2 murine monoclonal antibody 1E11 has strong and synergistic anti-tumor activity in HER2-overexpressing gastric cancer cells when used in combination with trastuzumab. We presently optimized this antibody for human therapeutics. First, the complementarity determining regions (CDRs) of the murine antibody were grafted onto human germline immunoglobulin variable genes. No difference in affinity and biological activity was observed between chimeric 1E11 (ch1E11) and humanized 1E11 (hz1E11). Next, affinity maturation of hz1E11 was performed by the randomization of CDR-L3 and H3 residues followed by stringent biopanning selection. Milder selection pressure favored the selection of more diverse clones, whereas higher selection stringency resulted in the convergence of the panning output to a smaller number of clones with improved affinity. Clone 1A12 had four amino acid substitutions in CDR-L3, and showed a 10-fold increase in affinity compared to the parental clone and increased potency in an in vitro anti proliferative activity assay with HER2-overepxressing gastric cancer cells. Clone 1A12 inhibited tumor growth of NCI-N87 xenograft model with similar efficacy to trastuzumab alone, and the combination treatment of 1A12 and trastuzumab completely removed the established tumors. These results suggest that humanized and affinity matured monoclonal antibody 1A12 is a highly optimized molecule for future therapeutic development against HER2-positive tumors. PMID- 26225764 TI - Loss of DDB1 Leads to Transcriptional p53 Pathway Activation in Proliferating Cells, Cell Cycle Deregulation, and Apoptosis in Zebrafish Embryos. AB - DNA damage-binding protein 1 (DDB1) is a large subunit of the heterodimeric DDB complex that recognizes DNA lesions and initiates the nucleotide excision repair process. DDB1 is also a component of the CUL4 E3 ligase complex involved in a broad spectrum of cellular processes by targeted ubiquitination of key regulators. Functions of DDB1 in development have been addressed in several model organisms, however, are not fully understood so far. Here we report an ENU induced mutant ddb1 allele (ddb1m863) identified in zebrafish (Danio rerio), and analyze its effects on development. Zebrafish ddb1 is expressed broadly, both maternally and zygotically, with enhanced expression in proliferation zones. The (ddb1m863 mutant allele affects the splice acceptor site of exon 20, causing a splicing defect that results in truncation of the 1140 amino acid protein after residue 800, lacking part of the beta-propeller domain BPC and the C-terminal helical domain CTD. ddb1m863 zygotic mutant embryos have a pleiotropic phenotype, including smaller and abnormally shaped brain, head skeleton, eyes, jaw, and branchial arches, as well as reduced dopaminergic neuron groups. However, early forming tissues develop normally in zygotic ddb1m863 mutant embryos, which may be due to maternal rescue. In ddb1m863 mutant embryos, pcna-expressing proliferating cell populations were reduced, concurrent with increased apoptosis. We also observed a concomitant strong up-regulation of transcripts of the tumor suppressor p53 (tp53) and the cell cycle inhibitor cdkn1a (p21a/bCIP1/WAF1) in proliferating tissues. In addition, transcription of cyclin genes ccna2 and ccnd1 was deregulated in ddb1m863 mutants. Reduction of p53 activity by anti-sense morpholinos alleviated the apoptotic phenotype in ddb1m863 mutants. These results imply that Ddb1 may be involved in maintaining proper cell cycle progression and viability of dividing cells during development through transcriptional mechanisms regulating genes involved in cell cycle control and cell survival. PMID- 26225766 TI - Longitudinal Evaluation of Stair Walking Biomechanics in Patients with ACL Injury. AB - PURPOSE: After anterior cruciate ligament (ACL) injury and reconstruction, abnormal biomechanics during daily tasks may have prominent and detrimental long term consequences on knee joint health. The purpose of this study was to longitudinally evaluate hip and knee joint biomechanics during stair ascent and descent in patients with acute ACL injury and at return to activity after ACL reconstruction. METHODS: Twenty individuals with unilateral ACL injury (age, 20.9 +/- 4.4 yr; height, 172.4 +/- 7.5 cm; mass, 76.2 +/- 12.2 kg) that were scheduled to undergo surgical reconstruction were compared with 20 healthy matched controls (age, 21.7 +/- 3.7 yr; height, 173.7 +/- 9.9 cm; mass, 76.1 +/- 19.7 kg). Lower extremity biomechanics were recorded using three-dimensional motion analysis during stair ascent and descent at two testing sessions (before surgery and at approximately 6 months after surgery or when they were allowed to return to unrestricted physical activity). Time between sessions for healthy participants was matched on the basis of the ACL group. Peak sagittal and frontal plane knee and hip joint angles and moments, joint angles at initial contact, and joint excursions across stance phase were evaluated. RESULTS: The ACL-injured limb of patients experienced smaller knee extension moments than the uninjured limb and healthy controls during stair ascent and descent (P < 0.05) before and 6 months after ACL reconstruction. During stair ascent, ACL patients experienced more extended knee joint positions and less sagittal plane knee joint excursions, coupled with greater frontal plane hip joint excursions (P < 0.05). CONCLUSIONS: Patients with ACL injury experience reductions in knee flexion angle and knee extension moments during stair walking. These alterations were observed both before and after reconstruction, suggesting that early gait retraining interventions may be beneficial in these patients. PMID- 26225768 TI - Endurance Training on Congenital Valvular Regurgitation: An Athlete Case Series. AB - BACKGROUND: Both intense endurance training and valvular regurgitation place a volume load on the right and left ventricles, potentially leading to dilation, but their effects in combination are not well-known. PURPOSE: The purpose of this case series is to describe the combined volume load of intense endurance athletic training and regurgitant valvular disease as well as the challenging assessment of each component's cardiovascular effect. METHODS: In this article, the clinical course of three elite endurance athletes with congenital valvular disease were reviewed. RESULTS: A swimmer with aortic regurgitation, a cyclist with aortic regurgitation, and a cyclist with pulmonary regurgitation were found to have severe dilation of the associated ventricles despite continuing to train at an elite level without symptoms. CONCLUSIONS: Because of the cumulative effects of endurance training and valvular regurgitation, each athlete manifested ventricular dilation out of proportion to their valvular disease and symptoms. Although the effects of congenital valvular disease and athletic remodeling on ventricular dilation have been thoroughly studied individually, their cumulative effect is not well understood. This complicates the assessment of athletes with valvular regurgitation and underscores the need for athlete-specific recommendations for valve replacement. PMID- 26225767 TI - Aerobic Exercise Training and Arterial Changes in African Americans versus Caucasians. AB - African Americans (AA) have increased carotid artery intima-media thickness and decreased vascular function compared with their Caucasian (CA) peers. Aerobic exercise prevents and potentially reverses arterial dysfunction. PURPOSE: The purpose of this study was to examine the effect of 8 wk of moderate- to high intensity aerobic training in young healthy sedentary AA and CA men and women. METHODS: Sixty-four healthy volunteers (men, 28; women, 36) with mean age 24 yr underwent measures of arterial structure, function, and blood pressure (BP) variables at baseline, after the 4-wk control period, and 8 wk after training. RESULTS: There was a significant increase in VO2peak among both groups after exercise training. Brachial systolic BP decreased significantly after the control period in both groups but not after exercise training. Carotid pulse pressure decreased significantly in both groups after exercise training as compared with that in baseline. There was no change in any of the other BP variables. AA had higher intima-media thickness at baseline and after the control period but it significantly decreased after exercise training compared with that of CA. AA had significantly lower baseline forearm blood flow and reactive hyperemia compared with those of CA, but exercise training had no effect on these variables. There was no significant difference in arterial stiffness (central pulse wave velocity) and wave-reflection (augmentation index) between the two groups at any time point. CONCLUSIONS: This is the first study to show that 8 wk of aerobic exercise training causes significant improvement in the arterial structure in young, healthy AA, making it comparable with the CA and with minimal effects on BP variables. PMID- 26225769 TI - Power and Performance Management in Nonlinear Virtualized Computing Systems via Predictive Control. AB - The problem of power and performance management captures growing research interest in both academic and industrial field. Virtulization, as an advanced technology to conserve energy, has become basic architecture for most data centers. Accordingly, more sophisticated and finer control are desired in virtualized computing systems, where multiple types of control actions exist as well as time delay effect, which make it complicated to formulate and solve the problem. Furthermore, because of improvement on chips and reduction of idle power, power consumption in modern machines shows significant nonlinearity, making linear power models(which is commonly adopted in previous work) no longer suitable. To deal with this, we build a discrete system state model, in which all control actions and time delay effect are included by state transition and performance and power can be defined on each state. Then, we design the predictive controller, via which the quadratic cost function integrating performance and power can be dynamically optimized. Experiment results show the effectiveness of the controller. By choosing a moderate weight, a good balance can be achieved between performance and power: 99.76% requirements can be dealt with and power consumption can be saved by 33% comparing to the case with open loop controller. PMID- 26225770 TI - The c-MET Network as Novel Prognostic Marker for Predicting Bladder Cancer Patients with an Increased Risk of Developing Aggressive Disease. AB - Previous studies have shown that c-MET is overexpressed in cases of aggressive bladder cancer (BCa). Identification of crosstalk between c-MET and other RTKs such as AXL and PDGFR suggest that c-MET network genes (c-MET-AXL-PDGFR) may be clinically relevant to BCa. Here, we examine whether expression of c-MET network genes can be used to identify BCa patients at increased risk of developing aggressive disease. In vitro analysis, c-MET knockdown suppressed cell proliferation, invasion, and migration, and increased sensitivity to cisplatin induced apoptosis. In addition, c-MET network gene (c-MET, AXL, and PDGFR) expression allowed discrimination of BCa tissues from normal control tissues and appeared to predict poor disease progression in non-muscle invasive BCa patients and poor overall survival in muscle invasive BCa patients. These results suggest that c-MET network gene expression is a novel prognostic marker for predicting which BCa patients have an increased risk of developing aggressive disease. These genes might be a useful marker for co-targeting therapy, and are expected to play an important role in improving both response to treatment and survival of BCa patients. PMID- 26225771 TI - Synergistic Reactivation of Latent HIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced p-TEFb Activation. AB - Although anti-retroviral therapy (ART) is highly effective in suppressing HIV replication, it fails to eradicate the virus from HIV-infected individuals. Stable latent HIV reservoirs are rapidly established early after HIV infection. Therefore, effective strategies for eradication of the HIV reservoirs are urgently needed. We report that ingenol-3-angelate (PEP005), the only active component in a previously FDA approved drug (PICATO) for the topical treatment of precancerous actinic keratosis, can effectively reactivate latent HIV in vitro and ex vivo with relatively low cellular toxicity. Biochemical analysis showed that PEP005 reactivated latent HIV through the induction of the pS643/S676 PKCdelta/theta-IkappaBalpha/epsilon-NF-kappaB signaling pathway. Importantly, PEP005 alone was sufficient to induce expression of fully elongated and processed HIV RNAs in primary CD4+ T cells from HIV infected individuals receiving suppressive ART. Furthermore, PEP005 and the P-TEFb agonist, JQ1, exhibited synergism in reactivation of latent HIV with a combined effect that is 7.5-fold higher than the effect of PEP005 alone. Conversely, PEP005 suppressed HIV infection of primary CD4+ T cells through down-modulation of cell surface expression of HIV co-receptors. This anti-cancer compound is a potential candidate for advancing HIV eradication strategies. PMID- 26225772 TI - Protein kinase R-like ER kinase and its role in endoplasmic reticulum stress decided cell fate. AB - Over the past few decades, understandings and evidences concerning the role of endoplasmic reticulum (ER) stress in deciding the cell fate have been constantly growing. Generally, during ER stress, the signal transductions are mainly conducted by three ER stress transducers: protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring kinase 1 (IRE1) and activating transcription factor 6 (ATF6). Consequently, the harmful stimuli from the ER stress transducers induce apoptosis and autophagy, which share several crosstalks and eventually decide the cell fate. The dominance of apoptosis or autophagy induced by ER stress depends on the type and degree of the stimuli. When ER stress is too severe and prolonged, apoptosis is induced to eliminate the damaged cells; however, when stimuli are mild, cell survival is promoted to maintain normal physiological functions by inducing autophagy. Although all the three pathways participate in ER stress-induced apoptosis and autophagy, PERK shows several unique characteristics by interacting with some specific downstream effectors. Notably, there are some preliminary findings on PERK-dependent mechanisms switching autophagy and apoptosis. In this review, we particularly focused on the novel, intriguing and complicated role of PERK in ER stress decided cell fate, and also discussed more roles of PERK in restoring cellular homeostasis. However, more in-depth knowledge of PERK in the future would facilitate our understanding about many human diseases and benefit in searching for new molecular therapeutic targets. PMID- 26225774 TI - Mitochondrial complex II is a source of the reserve respiratory capacity that is regulated by metabolic sensors and promotes cell survival. AB - The survival of a cell depends on its ability to meet its energy requirements. We hypothesized that the mitochondrial reserve respiratory capacity (RRC) of a cell is a critical component of its bioenergetics that can be utilized during an increase in energy demand, thereby, enhancing viability. Our goal was to identify the elements that regulate and contribute to the development of RRC and its involvement in cell survival. The results show that activation of metabolic sensors, including pyruvate dehydrogenase and AMP-dependent kinase, increases cardiac myocyte RRC via a Sirt3-dependent mechanism. Notably, we identified mitochondrial complex II (cII) as a target of these metabolic sensors and the main source of RRC. Moreover, we show that RRC, via cII, correlates with enhanced cell survival after hypoxia. Thus, for the first time, we show that metabolic sensors via Sirt3 maximize the cellular RRC through activating cII, which enhances cell survival after hypoxia. PMID- 26225775 TI - Where Next for Genetics and Genomics? AB - The last few decades have utterly transformed genetics and genomics, but what might the next ten years bring? PLOS Biology asked eight leaders spanning a range of related areas to give us their predictions. Without exception, the predictions are for more data on a massive scale and of more diverse types. All are optimistic and predict enormous positive impact on scientific understanding, while a recurring theme is the benefit of such data for the transformation and personalization of medicine. Several also point out that the biggest changes will very likely be those that we don't foresee, even now. PMID- 26225773 TI - SIRT1 is involved in oncogenic signaling mediated by GPER in breast cancer. AB - A number of tumors exhibit an altered expression of sirtuins, including NAD+ dependent histone deacetylase silent information regulator 1 (SIRT1) that may act as a tumor suppressor or tumor promoter mainly depending on the tumor types. For instance, in breast cancer cells SIRT1 was shown to exert an essential role toward the oncogenic signaling mediated by the estrogen receptor-alpha (ERalpha). In accordance with these findings, the suppression of SIRT1 led to the inhibition of the transduction pathway triggered by ERalpha. As the regulation of SIRT1 has not been investigated in cancer cells lacking ER, in the present study we ascertained the expression and function of SIRT1 by estrogens in ER-negative breast cancer cells and cancer-associated fibroblasts obtained from breast cancer patients. Our results show that 17beta-estradiol (E2) and the selective ligand of GPER, namely G-1, induce the expression of SIRT1 through GPER and the subsequent activation of the EGFR/ERK/c-fos/AP-1 transduction pathway. Moreover, we demonstrate that SIRT1 is involved in the pro-survival effects elicited by E2 through GPER, like the prevention of cell cycle arrest and cell death induced by the DNA damaging agent etoposide. Interestingly, the aforementioned actions of estrogens were abolished silencing GPER or SIRT1, as well as using the SIRT1 inhibitor Sirtinol. In addition, we provide evidence regarding the involvement of SIRT1 in tumor growth stimulated by GPER ligands in breast cancer cells and xenograft models. Altogether, our data suggest that SIRT1 may be included in the transduction network activated by estrogens through GPER toward the breast cancer progression. PMID- 26225777 TI - Higher Order Aberrations and Visual Outcomes in Wavefront-Optimized Sub-Bowman Keratomileusis: Flap Creation Using Femtosecond Laser Versus Mechanical Microkeratome. AB - PURPOSE: The aim of this study was to compare the outcomes of wavefront-optimized sub-Bowman keratomileusis (SBK) performed using the 150 KHz IntraLase femtosecond (IFS) laser (Abbot Medical Optics) with those using the Moria Evo 3 One Use-Plus SBK mechanical microkeratome (Moria SA). DESIGN: A prospective comparative clinical trial. METHODS: Fifty patients had bilateral wavefront-optimized SBK performed for myopia or myopic astigmatism. In 25 patients, the flap was created with the 150 KHz IFS laser (group 1) and in the other 25 with the Moria One Use Plus SBK mechanical microkeratome (group 2). All other treatment parameters were the same. Results were reported for 1 eye per patient in each group (ie, 25 eyes in each group). RESULTS: Efficacy, refractive stability, predictability, and safety profiles were comparable between the 2 groups. Although higher order aberrations (HOAs) increased significantly in both groups after laser in situ keratomileusis, intergroup comparison revealed that group 1 was associated with a significantly higher induction of both total HOAs [mean root mean square (RMS), 0.63 +/- 0.20 in group 1 vs 0.52 +/- 0.14 in group 2; P = 0.031] and spherical aberrations (RMS, 0.37 +/- 0.17 in group 1 vs 0.22 +/- 0.09 in group 2; P < 0.001) as compared with group 2. CONCLUSIONS: Flaps created using the Moria Evo 3 One Use-Plus SBK mechanical microkeratome were associated with significantly lower induction of total HOAs and spherical aberrations as compared with 150 KHz IFS flaps at the end of 3 months follow-up. PMID- 26225778 TI - Role of Concomitant Triamcinolone Acetonide Injection in Small-Gauge Vitrectomy for Idiopathic Epiretinal Membrane Peel. AB - PURPOSE: The concomitant use of triamcinolone acetonide (TA) at the completion of pars plana vitrectomy for the treatment of epiretinal membrane may speed up the anatomical and functional outcomes of surgery. We report the outcome of patients undergoing small-gauge vitrectomy for idiopathic epiretinal membrane peel with or without adjuvant TA therapy. DESIGN: This is a retrospective, single-center case series. METHODS: We included 75 eyes of 75 individual patients. Twenty-six patients (group A) had an adjuvant TA injection during surgery, whereas 49 patients (group B) were not injected. We assessed the patients for change in visual acuity (VA) and central macular thickness before and after surgery. RESULTS: Group A had a mean logarithm of the minimum angle of resolution VA of 0.63 +/- 0.33 and 0.51 +/- 0.31 preoperatively and 3 months after surgery, respectively. Group B had a mean logarithm of the minimum angle of resolution VA of 0.47 +/- 0.17 and 0.36 +/- 0.17 preoperatively and 3 months after surgery, respectively. No significant difference was found between the groups in change of VA. The mean central macular thickness for groups A and B patients before surgery was 474.12 +/- 120 MUm and 445 +/- 85 MUm, decreasing to 369 +/- 70 MUm and 386 +/- 60 MUm at the final visit, respectively. The difference in macular thickness reduction between the groups was statistically significant. CONCLUSIONS: Anatomical and functional improvement was found in both groups after surgery. Macular thickness was further reduced in the group of patients treated with adjuvant TA. PMID- 26225780 TI - Prospective, Randomized Study Comparing the Effect of 0.1% Nepafenac and 0.4% Ketorolac Tromethamine on Macular Thickness in Cataract Surgery Patients With Low Risk for Cystoid Macular Edema. AB - PURPOSE: This study aimed to compare the short-term efficacy of 0.1% nepafenac with that of 0.4% ketorolac tromethamine in patients with low risk factors for cystoid macular edema (CME) undergoing phacoemulsification. DESIGN: A prospective, randomized, parallel-assignment efficacy trial. METHODS: Two hundred eyes of 200 patients were randomized into 2 groups, one receiving nepafenac and the other receiving ketorolac perioperatively. Primary outcome measures were change in central macular thickness (CMT) at the 30th postoperative day and the incidence of possible subclinical CME (increase in CMT of >10 and >40 MUm from baseline) on ocular coherence tomography (OCT). Secondary outcomes measured were the incidence of definite subclinical CME on OCT (>40 MUm increase in CMT from baseline) and clinically significant CME at 1-month follow-up. A subgroup analysis of diabetic and hypertensive patients included in the study was made postoperatively. RESULTS: Difference in CMT at 1 month (P = 0.43) and presence of possible subclinical CME (P = 0.18) were comparable in both groups. The incidence of possible subclinical CME was 22.7%. None of the patients developed clinical CME or definite subclinical CME. In the diabetic subgroup, nepafenac showed significantly less CMT difference than ketorolac did at 1 week after the operation (P = 0.04) but not at 1 month (P = 0.09). CONCLUSIONS: Postoperative macular thickening after cataract surgery in eyes with low CME risk is similar with nepafenac and ketorolac. A larger population of diabetic patients should be studied to verify any beneficial effect of nepafenac on this subgroup. PMID- 26225779 TI - Outcomes of 3 or 4 Horizontal Muscles Surgery in Large-Angle Exotropia. AB - PURPOSE: To evaluate motor and sensory outcomes of 3 or 4 horizontal muscles surgery for the treatment of large-angle exotropia and to evaluate factors influencing the success rate and the relationship between initial postoperative and final motor outcomes. DESIGN: A retrospective analytical study. METHODS: Medical records of patients with primary large-angle exotropia [>50 prism diopters (PD)] who had 3 or 4 horizontal muscles surgery were reviewed. Motor outcomes were categorized as successful (esotropia 1-8 PD, orthotropia or exotropia 1-10 PD), acceptable (exotropia 11-20 PD), and poor (esotropia >8 PD or exotropia >20 PD). Results were evaluated only at the last follow-up visit if patients were followed up for less than 2 years. Those who were followed up for more than 2 years were evaluated at both the 2-year and final follow-up visits. Factors influencing the success rate and the relationship between initial postoperative and final motor outcomes were analyzed. RESULTS: A total of 36 patients were enrolled in this study. The median follow-up time was 18 months (range, 3-60 months). The success rate was 69% at the last follow-up and 75% at the follow-up at 2 years, respectively. Stereopsis improved in 43% at the last follow-up and 56% at 2 years. Initial postoperative deviation was found to correlate with the success rate at the last follow-up (P = 0.018). Initial postoperative overcorrection of 8 to 14 PD had the highest possibility of gaining successful final motor outcomes. CONCLUSIONS: Three or 4 horizontal muscles surgery in large-angle exotropia can achieve successful motor outcomes and improve stereopsis. Surgeons should aim for initial overcorrection in order to maximize long-term success. PMID- 26225781 TI - Teleportation of a Toffoli gate among distant solid-state qubits with quantum dots embedded in optical microcavities. AB - Teleportation of unitary operations can be viewed as a quantum remote control. The remote realization of robust multiqubit logic gates among distant long-lived qubit registers is a key challenge for quantum computation and quantum information processing. Here we propose a simple and deterministic scheme for teleportation of a Toffoli gate among three spatially separated electron spin qubits in optical microcavities by using local linear optical operations, an auxiliary electron spin, two circularly-polarized entangled photon pairs, photon measurements, and classical communication. We assess the feasibility of the scheme and show that the scheme can be achieved with high average fidelity under the current technology. The scheme opens promising perspectives for constructing long-distance quantum communication and quantum computation networks with solid state qubits. PMID- 26225782 TI - White matter hyperintensities, hot flushes and estrogen - are they related? AB - White matter hyperintensities (WMH) are areas of high intensity observed in brain MRI scans. They are usually seen in normal aging but also in a number of neurological and psychiatric disorders. One of the underlying mechanisms is ischemia, expressed as small vessel disease. Since the volume of WMH may correlate with cognition, and an ongoing debate links postmenopausal hormone therapy with stroke and a decline in certain cognitive domains, several MRI studies have addressed this potential association. Two major randomized, placebo controlled trials - WHIMS and KEEPS, the first including elderly women and the second recruiting recently menopausal women, did not demonstrate any safety concerns in this respect in hormone users. PMID- 26225792 TI - Akt promotes tumorigenesis in part through modulating genomic instability via phosphorylating XLF. AB - To maintain genome stability, mammalian cells have developed a delicate, yet efficient, system to sense and repair damaged DNA, including two evolutionarily conserved DNA damage repair (DDR) pathways: homologous recombination (HR) and non homologous-end-joining (NHEJ). Deregulation in these repair pathways may lead to genomic instability and subsequent human diseases, including cancer. On the other hand, hyper-activation of the oncogenic Akt signaling pathway has been observed in almost all solid tumors. Emerging evidence has begun to reveal a possible role of active Akt in regulating DDR, possibly through suppression of HR. However, whether and how Akt regulates NHEJ remains largely undefined. To this end, we recently reported that Akt impairs NHEJ by phosphorylating XLF at T181, to trigger its dissociation from the functional DNA ligase IV (LIG4)/XRCC4 complex. Here, we provide an additional perspective discussing how Akt is activated upon DNA damage to regulate DNA repair pathways as well as the cellular apoptotic responses. PMID- 26225793 TI - Dutasteride improves bone mineral density in male patients with lower urinary tract symptoms and prostatic enlargement: a preliminary study. AB - INTRODUCTION: We studied the effect of dutasteride on bone mineral density (BMD) in aging male patients with lower urinary tract symptoms (LUTS) and prostatic enlargement. METHODS: We prospectively studied 17 patients with LUTS and prostatic enlargement. Before and 1 year after dutasteride (0.5 mg daily), we assessed International Prostate Symptom Score (IPSS), prostatic volume (PV), serum prostatic-specific antigen (PSA) and testosterone. BMD in the lumbar and femur was measured by DEXA method. RESULTS: Dutasteride significantly reduced PV (from 51 +/- 24 to 34 +/- 17 ml, p < 0.001) and improved IPSS (from 15.1 +/- 9.8 to 11.7 +/- 10.3, p < 0.05). Serum PSA was significantly decreased (from 3.2 +/- 2.6 to 1.0 +/- 0.8 ng/ml, p < 0.001), while serum testosterone "was not changed" significantly. BMD of the lumbar "was not changed" significantly after dutasteride. BMD of the femur was significantly improved (from 0.75 +/- 0.14 to 0.82 +/- 0.16 g/cm(2), p < 0.01). In nine patients whose testosterone was increased after dutasteride, BMD of the lumbar (from 1.18 +/- 0.26 to 1.22 +/- 0.25 g/cm(2), p < 0.05) and femur (from 0.76 +/- 0.12 to 0.84 +/- 0.16 g/cm(2), p < 0.05) was significantly improved. CONCLUSIONS: Dutasteride has a potential to improve BMD with elevation of serum testosterone in aging male patients with LUTS and prostatic enlargement. PMID- 26225794 TI - Efficacy of 5alpha-reductase inhibitors for patients with large benign prostatic hyperplasia (>80 mL) after transurethral resection of the prostate. AB - PURPOSE: To prospectively evaluate 5alpha-reductase inhibitors (5alphaRIs) for benign prostatic hyperplasia (BPH) patients with a large prostate (>80 mL) after transurethral resection of the prostate (TURP). MATERIALS AND METHODS: Eighty seven patients were recruited from January 2007 to October 2014. Patients were randomized into a trial and a control group. The trial group was treated with 5alphaRIs for 3 years after TURP, while the control group received a placebo. We evaluated the indicators before, peri and after TURP. RESULTS: There were no significant differences in the indicators before and peri-TURP. Six months later, there were significant differences in PSA and hematuria (HU). Three years after TURP, there were significant differences in prostate volume (PV), level of prostate-specific antigen (PSA), the maximum flow rate (Qm), and HU between the trial and control groups. Additionally, there were significant differences in the PV, PSA, international prostate symptom score (IPSS), patient quality of life (QoL) in the trial group alone between those treated with finasteride and those treated with dutasteride. CONCLUSIONS: After TURP for large BPH, administration of 5alphaRIs for 3 years improved PV, PSA, Qm and HU. Additionally, dutasteride produced superior improvements in PV, PSA, IPSS and QoL compared with finasteride. PMID- 26225795 TI - Intermittent hormone therapy versus continuous hormone therapy for locally advanced prostate cancer: a meta-analysis. AB - Few randomized studies have compared intermittent hormone therapy (IHT) with continuous hormone therapy (CHT) for the treatment of locally advanced prostate cancer (PCa). Here, we report the results of a meta-analysis of a randomized controlled trial, evaluating the effectiveness of IHT versus CHT for patients with locally advanced PCa. Types of intervention were IHT versus CHT. The primary endpoint of this study is overall mortality and the secondary endpoints are any progression of disease, quality of life (QOL) and adverse effects between two groups. Six randomized controlled trials totaling 2996 patients were included. Results are as follows: after hormone therapy, patients undergoing IHT demonstrated no significant difference from those undergoing CHT in terms of the overall mortality (OR = 1.0, 95% CI [0.86, 1.17]) and disease progression (OR = 1.16, 95% CI [0.86, 1.57]). Men treated with IHT also reported better QOL, fewer adverse effects and considerable economic benefit for the individual and the community. With no difference in overall mortality and incidence of progression, current clinical studies confirm that both therapeutic methods were safe and effective. However, our study also takes into account QOL. When these secondary measures are considered, IHT may be a better option over CHT as patients report a more affordable treatment with improved QOL and fewer adverse effects. PMID- 26225796 TI - Tumor-Homing Cell-Penetrating Peptide Linked to Colloidal Mesoporous Silica Encapsulated (-)-Epigallocatechin-3-gallate as Drug Delivery System for Breast Cancer Therapy in Vivo. AB - Chemotherapy is the use of chemical drugs to prevent cancer cell proliferation, invasion, and metastasis, but a serious obstacle is that chemotherapeutics strikes not only on cancerous cells, but also on normal cells. Thus, anticancer drugs without side effects should be developed and extracted. (-) Epigallocatechin-3-gallate (EGCG), a major ingredient of green tea, possesses excellent medicinal values, such as anticancer effects, DNA-protective effects, etc. However, EGCG will be mostly metabolized if it is directly orally ingested. Here, we report a drug delivery system (DDS) for loading EGCG to enhance its stability, promising target and anticancer effects in vitro and in vivo. The designed DDS is composed of three main moieties: anticancer drug, EGCG; drug vector, colloidal mesoporous silica (CMS); target ligand, breast tumor-homing cell-penetrating peptide (PEGA-pVEC peptide). Based on the results of CCK-8 assay, confocal imaging, cell cycle analysis, and Western blot, the anticancer effect of EGCG was increased by loading of EGCG into CMS and CMS@peptide. In vivo treatment displayed that CMS had a not obvious influence on breast tumor bearing mice, but CMS@peptide@EGCG showed the greatest tumor inhibition rate, with about 89.66%. H&E staining of organs showed no tissue injury in all experimental groups. All the above results prove that EGCG is an excellent anticancer drug without side effects and CMS@peptide could greatly promote the efficacy of EGCG on breast tumors by targeted accumulation and release, which provide much evidence for the CMS@peptide as a promising and targeting vector for DDS. PMID- 26225797 TI - Dangerous Liaisons: Connecting CRISPR/Cas9 to Clinical Science. PMID- 26225799 TI - Correction to Design, Synthesis, and Antitumor Evaluation of Novel Histone Deacetylase Inhibitors Equipped with a Phenylsulfonylfuroxan Module as a Nitric Oxide Donor. PMID- 26225798 TI - Early Oral Tongue Squamous Cell Carcinoma: Sampling of Margins From Tumor Bed and Worse Local Control. AB - IMPORTANCE: Positive margins are associated with poor prognosis among patients with oral tongue squamous cell carcinoma (SCC). However, wide variation exists in the margin sampling technique. OBJECTIVE: To determine the effect of the margin sampling technique on local recurrence (LR) in patients with stage I or II oral tongue SCC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective study was conducted from January 1, 1986, to December 31, 2012, in 5 tertiary care centers following tumor resection and elective neck dissection in 280 patients with pathologic (p)T1-2 pN0 oral tongue SCC. Analysis was conducted from June 1, 2013, to January 20, 2015. INTERVENTIONS: In group 1 (n = 119), tumor bed margins were not sampled. In group 2 (n = 61), margins were examined from the glossectomy specimen, found to be positive or suboptimal, and revised with additional tumor bed margins. In group 3 (n = 100), margins were primarily sampled from the tumor bed without preceding examination of the glossectomy specimen. The margin status (both as a binary [positive vs negative] and continuous [distance to the margin in millimeters] variable) and other clinicopathologic parameters were compared across the 3 groups and correlated with LR. MAIN OUTCOMES AND MEASURES: Local recurrence. RESULTS: Age, sex, pT stage, lymphovascular or perineural invasion, and adjuvant radiation treatment were similar across the 3 groups. The probability of LR-free survival at 3 years was 0.9 and 0.8 in groups 1 and 3, respectively (P = .03). The frequency of positive glossectomy margins was lowest in group 1 (9 of 117 [7.7%]) compared with groups 2 and 3 (28 of 61 [45.9%] and 23 of 95 [24.2%], respectively) (P < .001). Even after excluding cases with positive margins, the median distance to the closest margin was significantly narrower in group 3 (2 mm) compared with group 1 (3 mm) (P = .008). The status (positive vs negative) of margins obtained from the glossectomy specimen correlated with LR (P = .007), while the status of tumor bed margins did not. The status of the tumor bed margin was 24% sensitive (95% CI, 16%-34%) and 92% specific (95% CI, 85%-97%) for detecting a positive glossectomy margin. CONCLUSIONS AND RELEVANCE: The margin sampling technique affects local control in patients with oral tongue SCC. Reliance on margin sampling from the tumor bed is associated with worse local control, most likely owing to narrower margin clearance and greater incidence of positive margins. A resection specimen-based margin assessment is recommended. PMID- 26225800 TI - Chemical contrast observed in thermal images of blood-stained fabrics exposed to steam. AB - Thermal imaging is not ordinarily a good way to visualize chemical contrast. In recent work, however, we observed strong and reproducible images with chemical contrasts on blood-stained fabrics, especially on more hydrophobic fabrics like acrylic and polyester. PMID- 26225803 TI - Copper-Catalyzed Synthesis of Trifluoroethylarenes from Benzylic Bromodifluoroacetates. AB - Trifluoroethylarenes are found in a variety of biologically active molecules, and strategies for accessing this substructure are important for developing therapeutic candidates and biological probes. Trifluoroethylarenes can be directly accessed via nucleophilic trifluoromethylation of benzylic electrophiles; however, current catalytic methods do not effectively transform electron-deficient substrates and heterocycles. To address this gap, we report a Cu-catalyzed decarboxylative trifluoromethylation of benzylic bromodifluoroacetates. To account for the tolerance of sensitive functional groups, we propose an inner-sphere mechanism of decarboxylation. PMID- 26225805 TI - Pulmonary Disease Due to Nontuberculous Mycobacteria: Current State and New Insights. AB - Since pulmonary nontuberculous mycobacteria (PNTM) lung disease was last reviewed in CHEST in 2008, new information has emerged spanning multiple domains, including epidemiology, transmission and pathogenesis, clinical presentation, diagnosis, and treatment. The overall prevalence of PNTM is increasing, and in the United States, areas of highest prevalence are clustered in distinct geographic locations with common environmental and socioeconomic factors. Although the accepted paradigm for transmission continues to be inhalation from the environment, provocative reports suggest that person-to-person transmission may occur. A panoply of host factors have been investigated in an effort to elucidate why infection from this bacteria develops in ostensibly immunocompetent patients, and there has been clarification that immunocompetent patients exhibit different histopathology from immunocompromised patients with nontuberculous mycobacteria infection. It is now evident that Mycobacterium abscessus, an increasingly prevalent cause of PNTM lung disease, can be classified into three separate subspecies with differing genetic susceptibility or resistance to macrolides. Recent publications also raise the possibility of improved control of PNTM through enhanced adherence to current treatment guidelines as well as new approaches to treatment and even prevention. These and other recent developments and insights that may inform our approach to PNTM lung disease are reviewed and discussed. PMID- 26225806 TI - Enantioselective Effects of o,p'-DDT on Cell Invasion and Adhesion of Breast Cancer Cells: Chirality in Cancer Development. AB - The o,p'-dichlorodiphenyltrichloroethane (DDT) with a chiral center possesses enantioselective estrogenic activity, in which R-(-)-o,p'-DDT exerts a more potent estrogenic effect than S-(+)-o,p'-DDT. Although concern regarding DDT exposure and breast cancer has increased in recent decades, the mode of enantioselective action of o,p'-DDT in breast cancer development is still unknown. Herein, we conducted a systematic study of the effect of o,p'-DDT on stereoselective breast tumor cell progression in a widely used in vitro breast tumor cell model, MCF-7 cells. We demonstrated that R-(-)-o,p'-DDT promoted more cancer cell invasion mediated by the human estrogen receptor (ER) by inducing invasion-promoted genes (matrix metalloproteinase-2 and -9 and human telomerase reverse transcriptase) and inhibiting invasion-inhibited genes (tissue inhibitor of metalloproteinase-1 and -4). Molecular docking verified that the binding affinity between R-(-)-o,p'-DDT and human ER was stronger than that of S-(+)-o,p' DDT. The enantioselective-induced decrease in cell-to-cell adhesion may involve the downregulation of adhesion-promoted genes (E-cadherin and beta-catenin). For the first time, these results reveal that estrogenic-like chiral compounds are of significant concern in the progression of human cancers and that human health risk assessment of chiral chemicals should consider enantioselectivity. PMID- 26225807 TI - Respiratory source control using a surgical mask: An in vitro study. AB - Cough etiquette and respiratory hygiene are forms of source control encouraged to prevent the spread of respiratory infection. The use of surgical masks as a means of source control has not been quantified in terms of reducing exposure to others. We designed an in vitro model using various facepieces to assess their contribution to exposure reduction when worn at the infectious source (Source) relative to facepieces worn for primary (Receiver) protection, and the factors that contribute to each. In a chamber with various airflows, radiolabeled aerosols were exhaled via a ventilated soft-face manikin head using tidal breathing and cough (Source). Another manikin, containing a filter, quantified recipient exposure (Receiver). The natural fit surgical mask, fitted (SecureFit) surgical mask and an N95-class filtering facepiece respirator (commonly known as an "N95 respirator") with and without a Vaseline-seal were tested. With cough, source control (mask or respirator on Source) was statistically superior to mask or unsealed respirator protection on the Receiver (Receiver protection) in all environments. To equal source control during coughing, the N95 respirator must be Vaseline-sealed. During tidal breathing, source control was comparable or superior to mask or respirator protection on the Receiver. Source control via surgical masks may be an important adjunct defense against the spread of respiratory infections. The fit of the mask or respirator, in combination with the airflow patterns in a given setting, are significant contributors to source control efficacy. Future clinical trials should include a surgical mask source control arm to assess the contribution of source control in overall protection against airborne infection. PMID- 26225808 TI - Synthesis of Acyl Alkenylindium Reagents and Their Application in the Synthesis of (Z)-alpha,beta-Unsaturated Ketones via Palladium-Catalyzed Cross-Coupling Reaction. AB - A synthetic method for the preparation of acyl alkenylindium reagents was developed involving the hydroindation reaction of allenyl ketones with indium and indium chloride in methanol under mild conditions. Their synthetic applications were demonstrated from Pd-catalyzed cross-coupling reactions with aryl bromides and iodides and alkenyl and aryl triflates for the synthesis of (Z)-alpha,beta unsaturated ketones. PMID- 26225809 TI - Risk Factors and Prevalence of Penile Cancer. PMID- 26225810 TI - Luciferins behave like drugs. AB - The light emission chemistry of firefly luciferase can be harnessed to reveal otherwise invisible biological processes occurring in the brains of live animals. Though powerful, the need for the luciferase substrate D-luciferin to traverse the blood-brain barrier poses limitations on the sensitivity and interpretation of these experiments. In this Viewpoint, we discuss bioluminescent imaging probes for the enzyme fatty acid amide hydrolase (FAAH) and the broader implications for optical imaging and drug delivery in the brain. PMID- 26225817 TI - The Link Between Self-Assembly and Molecular Conformation of Amphiphilic Block Copolymers Monolayers at the Air/Water Interface: The Spreading Parameter. AB - Two amphiphilic block copolymers, namely polystyrene-b-poly(methyl-methacrylate) (PS-b-PMMA), at the air/water interface were studied combining the in situ structural characterization, by means of X-ray reflectivity (XRR) and grazing incidence small-angle X-ray scattering (GISAXS), and the ex situ morphological one, by atomic force microscopy (AFM). We observed that the conformation of the hydrophilic block spread on the water surface is dramatically influenced by the morphology of the monolayer. Our results showed that the hydrophilic PMMA block adopts an expanded conformation when thermodynamically stable nanodots are formed, whereas a coiled conformation is observed when the block copolymer formed kinetically frozen nanostrands. This effect is interpreted in terms of the spreading parameter, which changes with the relative length ratio between the two blocks. Finally, we proved that, even for block copolymer monolayer with fixed block length ratio, it is possible to change the morphology, and in turn the conformation of the hydrophilic block, by changing the spreading parameter value. PMID- 26225816 TI - Chemistry and Pharmacology of a Series of Unichiral Analogues of 2-(2 Pyrrolidinyl)-1,4-benzodioxane, Prolinol Phenyl Ether, and Prolinol 3-Pyridyl Ether Designed as alpha4beta2-Nicotinic Acetylcholine Receptor Agonists. AB - Some unichiral analogues of 2R,2'S-2-(1'-methyl-2'-pyrrolidinyl)-7-hydroxy-1,4 benzodioxane, a potent and selective alpha4beta2-nAChR partial agonist, were designed by opening dioxane and replacing hydroxyl carbon with nitrogen. The resulting 3-pyridyl and m-hydroxyphenyl ethers have high alpha4beta2 affinity and good subtype selectivity, which get lost if OH is removed from phenyl or the position of pyridine nitrogen is changed. High alpha4beta2 affinity and selectivity are also attained by meta hydroxylating the 3-pyridyl and the phenyl ethers of (S)-N-methylprolinol and the phenyl ether of (S)-2-azetidinemethanol, known alpha4beta2 agonists, although the interaction mode of the aryloxymethylene substructure cannot be assimilated to that of benzodioxane. Indeed, the alpha4beta2 and alpha3beta4 functional tests well differentiate behaviors that the binding tests homologize: both the 3-hydroxyphenyl and the 5-hydroxy-3 pyridyl ether of N-methylprolinol are alpha4beta2 full agonists, but only the latter is highly alpha4beta2/alpha3beta4 selective, while potent and selective partial alpha4beta2 agonism characterizes the hydroxybenzodioxane derivative and its two opened semirigid analogues. PMID- 26225818 TI - The stereoselective formation of highly substituted CF3-dihydropyrans as versatile building blocks. AB - The highly enantioselective dienamine-mediated formation of 5-bromo-6 (trifluoromethyl)-3,4-dihydro-2H-pyrans from alpha,beta-unsaturated aldehydes and alpha-bromo-(trifluoromethyl)-enones employing a C2-symmetric aminocatalyst is described. The products are demonstrated to be applicable in coupling reactions directly onto the ring, thereby granting access to a broad scope of highly substituted 6-(trifluoromethyl)-dihydropyran compounds. PMID- 26225819 TI - Surface properties of nanocrystalline TiO2 coatings in relation to the in vitro plasma protein adsorption. AB - This study reports on the selective adsorption of whole plasma proteins on hydrothermally (HT) grown TiO2-anatase coatings and its dependence on the three main surface properties: surface charge, wettability and roughness. The influence of the photo-activation of TiO2 by UV irradiation was also evaluated. Even though the protein adhesion onto Ti-based substrates was only moderate, better adsorption of any protein (at pH = 7.4) occurred for the most negatively charged and hydrophobic substrate (Ti non-treated) and for the most nanorough and hydrophilic surface (HT Ti3), indicating that the mutual action of the surface characteristics is responsible for the attraction and adhesion of the proteins. The HT coatings showed a higher adsorption of certain proteins (albumin 'passivation' layer, apolipoproteins, vitamin D-binding protein, ceruloplasmin, alpha-2-HS-glycoprotein) and higher ratios of albumin to fibrinogen and albumin to immunoglobulin gamma-chains. The UV pre-irradiation affected the surface properties and strongly reduced the adsorption of the proteins. These results provide in-depth knowledge about the characterization of nanocrystalline TiO2 coatings for body implants and provide a basis for future studies on the hemocompatibility and biocompatibility of such surfaces. PMID- 26225820 TI - Electron transport within transparent assemblies of tin-doped indium oxide colloidal nanocrystals. AB - Stripe-like compact assemblies of tin-doped indium oxide (ITO) colloidal nanocrystals (NCs) are fabricated by stop-and-go convective self-assembly (CSA). Systematic evaluation of the electron transport mechanisms in these systems is carried out by varying the length of carboxylate ligands protecting the NCs: butanoate (C4), octanoate (C8) and oleate (C18). The interparticle edge-to-edge distance L0, along with a number of carbon atoms in the alkyl chain of the coating ligand, are deduced from small-angle x-ray scattering (SAXS) measurements and exhibit a linear relationship with a slope of 0.11 nm per carbon pair unit. Temperature-dependent resistance characteristics are analyzed using several electron transport models: Efros-Shklovskii variable range hopping (ES-VRH), inelastic cotunneling (IC), regular island array and percolation. The analysis indicated that the first two models (ES-VRH and IC) fail to explain the observed behavior, and that only simple activated transport takes place in these systems under the experimental conditions studied (T = 300 K to 77 K). Related transport parameters were then extracted using the regular island array and percolation models. The effective tunneling decay constant betaeff of the ligands and the Coulomb charging energy EC are found to be around 5.5 nm(-1) and 25 meV, respectively, irrespective of ligand lengths. The theoretical tunneling decay constant beta calculated using the percolation model is in the range 9 nm(-1). Electromechanical tests on the ITO nanoparticle assemblies indicate that their sensitivities are as high as ~30 and remain the same regardless of ligand lengths, which is in agreement with the constant effective betaeff extracted from regular island array and percolation models. PMID- 26225821 TI - Catalytic etching of monolayer graphene at low temperature via carbon oxidation. AB - In this work, an easy method to etch monolayer graphene is shown by catalytic oxidation in the presence of ZnO nanoparticles (NPs). The catalytic etching of monolayer graphene, which was transferred to the channel of field-effect transistors (FETs), was performed at low temperature by heating the FETs several times under an inert gas atmosphere (ZnO + C -> Zn + CO or CO2). As the etching process proceeded, diverse etched structures in the shape of nano-channels and pits were observed under microscopic observation. To confirm the evolution of etching, current-voltage characteristics of monolayer graphene were measured after every step of etching by catalytic oxidation. As a result, the conductance of monolayer graphene decreased with the development of etched structures. This decrease in conductance was analyzed by percolation theory in a honeycomb structure. Finally, well-patterned graphene was obtained by oxidizing graphene under air in the presence of NPs, where Al was deposited on graphene as a mask for designed patterns. This method can substitute graphene etching via carbon hydrogenation using H2 at high temperature. PMID- 26225822 TI - Modeling driver stop/run behavior at the onset of a yellow indication considering driver run tendency and roadway surface conditions. AB - The ability to model driver stop/run behavior at signalized intersections considering the roadway surface condition is critical in the design of advanced driver assistance systems. Such systems can reduce intersection crashes and fatalities by predicting driver stop/run behavior. The research presented in this paper uses data collected from two controlled field experiments on the Smart Road at the Virginia Tech Transportation Institute (VTTI) to model driver stop/run behavior at the onset of a yellow indication for different roadway surface conditions. The paper offers two contributions. First, it introduces a new predictor related to driver aggressiveness and demonstrates that this measure enhances the modeling of driver stop/run behavior. Second, it applies well-known artificial intelligence techniques including: adaptive boosting (AdaBoost), random forest, and support vector machine (SVM) algorithms as well as traditional logistic regression techniques on the data in order to develop a model that can be used by traffic signal controllers to predict driver stop/run decisions in a connected vehicle environment. The research demonstrates that by adding the proposed driver aggressiveness predictor to the model, there is a statistically significant increase in the model accuracy. Moreover the false alarm rate is significantly reduced but this reduction is not statistically significant. The study demonstrates that, for the subject data, the SVM machine learning algorithm performs the best in terms of optimum classification accuracy and false positive rates. However, the SVM model produces the best performance in terms of the classification accuracy only. PMID- 26225824 TI - Cardiovascular effects of low versus high-dose beta-carotene in a rat model. AB - beta-carotene (BC), a lipid-soluble tetraterpene precursor to vitamin A, widely distributed in plants, including many used in human diet, has well-known health enhancing properties, including reducing risk of and treatment for certain diseases. Nevertheless, BC may also act to promote disease through the activity of BC derivatives that form in the presence of external toxicants such as cigarette smoke and endogenously-produced reactive oxygen species. The present investigation evaluates the dose-dependent cardioprotective and possibly harmful properties of BC in a rat model. Adult male rats were gavage-fed BC for 4 weeks, at dosages of either 0, 30 or 150 mg/kg/day. Then, hearts excised from the animals were mounted in a "working heart" apparatus and subjected to 30 min of global ischemia, followed by 120 min of reperfusion. A panel of cardiac functional evaluations was conducted on each heart. Infarct size and total antioxidant capacity of the myocardium were assessed. Heart tissue content of heme oxygenase-1 (HO-1) by Western blot analysis; and potential direct cytotoxic effects of BC by MTT assay were evaluated. Hearts taken from rats receiving 30 mg/kg/day BC exhibited significantly improved heart function at lower reperfusion times, but lost this protection at higher BC dosage and longer reperfusion times. Myocardial HO-1 content was significantly elevated dose-responsively to both BC dosage. Finally, in vitro evaluation of BC on H9c2 cells showed that the agent significantly improved vitality of these cells in a dose range of 2.5-10 MUM. Although data presented here do not allow for a comprehensive mechanistic explanation for reduced cardioprotection at high dose BC, it is speculated that since Fe2+ produced as a metabolite of HO-1 activity, may determine whether BC acts as an antioxidant or prooxidant agent, the strong induction of this enzyme in response to ischemia/reperfusion-induced oxidative stress may account for the high-dose BC loss of cardioprotection. PMID- 26225823 TI - Effect of Environmental Factors on Fusarium Species and Associated Mycotoxins in Maize Grain Grown in Poland. AB - Maize is one of the most important crops and Poland is the fifth largest producing country in Europe. Diseases caused by Fusarium spp. can affect the yield and grain quality of maize because of contamination with numerous mycotoxins produced by these fungi. The present study was performed to identify the prevailing Fusarium species and the environmental factors affecting their frequencies and the contamination of grain with the main mycotoxins deoxynivalenol (DON), zearalenone (ZON) and fumonisin B1 (FB1). Thirty kernel samples were collected in three locations in 2011 and in seven locations in 2012 from three hybrids. On average, 25.24% kernels were colonized by Fusarium spp. (424 strains were isolated). Fusarium verticillioides and F. temperatum were the most prevalent species, F. subglutinans, F. proliferatum and F. graminearum were in minor abundance. In total, 272 isolates of F. verticillioides and 81 isolates of F. temperatum were identified. Fusarium temperatum frequency ranged from 1.70% to 28.57% and differences between locations were significant. Fumonisin B1 was found in all tested samples. DON was found in 66.67% and ZON in 43.33% of samples. Rainfall amount positively affected F. temperatum and F. subglutinans frequency in opposite to mean temperatures in July. On the other hand, relationships between frequency of these species and historical data from 1950 2000 for annual temperature range were negative in contrast to the coldest quarter temperatures. PMID- 26225826 TI - The prognostic role of neutrophils to lymphocytes ratio and platelet count in gastric cancer: A meta-analysis. AB - BACKGROUND: Systemic inflammatory response was reported to be associate with a poor survival in gastric cancer. However, these results remain inconsistent. The purpose of this meta-analysis was to evaluate the prognostic role of neutrophils to lymphocytes ratio (NLR) and platelet count in gastric cancer. METHODS: Relevant studies were identified by searching PubMed, Embase and Cochrane Library. Data was pooled using a fixed-effects models or random-effects models. RESULTS: A total of 29 studies were included for meta-analysis (19 for NLR, 10 for platelet count). Elevated NLR and platelet count were associated with an increased lymph node metastasis and serosal invasion (T3+T4) risk with individual ORs being 1.70 (95% CI: 1.05-2.75) and 2.93 (95% CI: 2.27-3.78), 1.62 (95% CI: 1.08-2.42) and 2.09 (95% CI: 1.57-2.77), respectively. The incidence of stage (III + IV) in elevated NLR group was higher than in normal NLR group (OR = 1.87, 95% CI: 1.48-2.35). The disease-free survival in patients with elevated NLR was markedly shorter (HR = 1.61; 95% CI: 1.28-1.94). For the overall survival, both indicators were strong predictors with individual HRs being 1.65 (95% CI: 1.47 1.83), 1.61 (95% CI: 1.35-1.86), respectively. CONCLUSIONS: This meta-analysis suggests that elevated NLR and platelet count predict poor survival in patients with gastric cancer, and may provides some useful evidence for the clinical application of the two prognostic indicators in gastric cancer. PMID- 26225828 TI - An unusual cause of constipation: sacral chordoma. PMID- 26225825 TI - Blunt Chest Trauma in Mice after Cigarette Smoke-Exposure: Effects of Mechanical Ventilation with 100% O2. AB - Cigarette smoking (CS) aggravates post-traumatic acute lung injury and increases ventilator-induced lung injury due to more severe tissue inflammation and apoptosis. Hyper-inflammation after chest trauma is due to the physical damage, the drop in alveolar PO2, and the consecutive hypoxemia and tissue hypoxia. Therefore, we tested the hypotheses that 1) CS exposure prior to blunt chest trauma causes more severe post-traumatic inflammation and thereby aggravates lung injury, and that 2) hyperoxia may attenuate this effect. Immediately after blast wave-induced blunt chest trauma, mice (n=32) with or without 3-4 weeks of CS exposure underwent 4 hours of pressure-controlled, thoraco-pulmonary compliance titrated, lung-protective mechanical ventilation with air or 100% O2. Hemodynamics, lung mechanics, gas exchange, and acid-base status were measured together with blood and tissue cytokine and chemokine concentrations, heme oxygenase-1 (HO-1), activated caspase-3, and hypoxia-inducible factor 1-alpha (HIF-1alpha) expression, nuclear factor-kappaB (NF-kappaB) activation, nitrotyrosine formation, purinergic receptor 2X4 (P2XR4) and 2X7 (P2XR7) expression, and histological scoring. CS exposure prior to chest trauma lead to higher pulmonary compliance and lower PaO2 and Horovitz-index, associated with increased tissue IL-18 and blood MCP-1 concentrations, a 2-4-fold higher inflammatory cell infiltration, and more pronounced alveolar membrane thickening. This effect coincided with increased activated caspase-3, nitrotyrosine, P2XR4, and P2XR7 expression, NF-kappaB activation, and reduced HIF-1alpha expression. Hyperoxia did not further affect lung mechanics, gas exchange, pulmonary and systemic cytokine and chemokine concentrations, or histological scoring, except for some patchy alveolar edema in CS exposed mice. However, hyperoxia attenuated tissue HIF-1alpha, nitrotyrosine, P2XR7, and P2XR4 expression, while it increased HO-1 formation in CS exposed mice. Overall, CS exposure aggravated post-traumatic inflammation, nitrosative stress and thereby organ dysfunction and injury; short term, lung-protective, hyperoxic mechanical ventilation have no major beneficial effect despite attenuation of nitrosative stress, possibly due to compensation of by regional alveolar hypoxia and/or consecutive hypoxemia, resulting in down regulation of HIF-1alpha expression. PMID- 26225829 TI - Giant cell ependymoma of the spinal cord: a rare variant. PMID- 26225827 TI - Differences in Early Stages of Tactile ERP Temporal Sequence (P100) in Cortical Organization during Passive Tactile Stimulation in Children with Blindness and Controls. AB - Compared to their seeing counterparts, people with blindness have a greater tactile capacity. Differences in the physiology of object recognition between people with blindness and seeing people have been well documented, but not when tactile stimuli require semantic processing. We used a passive vibrotactile device to focus on the differences in spatial brain processing evaluated with event related potentials (ERP) in children with blindness (n = 12) vs. normally seeing children (n = 12), when learning a simple spatial task (lines with different orientations) or a task involving recognition of letters, to describe the early stages of its temporal sequence (from 80 to 220 msec) and to search for evidence of multi-modal cortical organization. We analysed the P100 of the ERP. Children with blindness showed earlier latencies for cognitive (perceptual) event related potentials, shorter reaction times, and (paradoxically) worse ability to identify the spatial direction of the stimulus. On the other hand, they are equally proficient in recognizing stimuli with semantic content (letters). The last observation is consistent with the role of P100 on somatosensory-based recognition of complex forms. The cortical differences between seeing control and blind groups, during spatial tactile discrimination, are associated with activation in visual pathway (occipital) and task-related association (temporal and frontal) areas. The present results show that early processing of tactile stimulation conveying cross modal information differs in children with blindness or with normal vision. PMID- 26225830 TI - Angiotensin-(1-7) Suppresses Hepatocellular Carcinoma Growth and Angiogenesis via Complex Interactions of Angiotensin II Type 1 Receptor, Angiotensin II Type 2 Receptor and Mas Receptor. AB - We recently confirmed that angiotensin II (Ang II) type 1 receptor (AT1R) was overexpressed in hepatocellular carcinoma tissue using a murine hepatoma model. Angiotensin(Ang)-(1-7) has been found beneficial in ameliorating lung cancer and prostate cancer. Which receptor of Ang-(1-7) is activated to mediate its effects is much speculated. This study was designed to investigate the effects of Ang-(1 7) on hepatocellular carcinoma, as well as the probable mechanisms. H22 hepatoma bearing mice were randomly divided into five groups for treatment: mock group, low-dose Ang-(1-7), high-dose Ang-(1-7), high-dose Ang-(1-7) + A779 and high-dose Ang-(1-7) + PD123319. Ang-(1-7) treatment inhibited tumor growth time- and dose dependently by arresting tumor proliferation and promoting tumor apoptosis as well as inhibiting tumor angiogenesis. The effects of Ang-(1-7) on tumor proliferation and apoptosis were reversed by coadministration with A779 or PD123319, whereas the effects on tumor angiogenesis were completely reversed by A779 but not by PD123319. Moreover, Ang-(1-7) downregulated AT1R mRNA, upregulated mRNA levels of Ang II type 2 receptor (AT2R) and Mas receptor (MasR) and p38-MAPK phosphorylation and suppressed H22 cell-endothelial cell communication. Thus, Ang-(1-7) administration suppresses hepatocellular carcinoma via complex interactions of AT1R, AT2R and MasR and may provide a novel and promising approach for the treatment of hepatocellular carcinoma. PMID- 26225831 TI - Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia. AB - Biliary atresia (BA) is a devastating liver disease of unknown etiology affecting children generally within the first 3 months of life. The disease is manifested by inflammation and subsequent obstruction of the extrahepatic bile ducts, fibrosis and liver failure. The mechanisms responsible for disease pathogenesis are not fully understood, but a number of factors controlled by the SMAD signaling pathway have been implicated. In this study, we investigated the role of a known proinflammatory factor, extracellular cyclophilin A (CypA), in the pathogenesis of biliary atresia using the rhesus rotavirus (RRV) murine model. We used a unique cyclosporine A derivative, MM284, which does not enter cells and therefore inactivates exclusively extracellular cyclophilins, as a potential treatment. We demonstrated that levels of CypA in plasma of RRV-infected mice were increased significantly, and that treatment of mice with MM284 prior to or one day after disease initiation by RRV infection significantly improved the status of mice with experimental BA: weight gain was restored, bilirubinuria was abrogated, liver infiltration by inflammatory cells was reduced and activation of the SMAD pathway and SMAD-controlled fibrosis mediators and tissue inhibitor of metalloproteinases (TIMP)-4 and matrix metalloproteinase (MMP)-7 was alleviated. Furthermore, treatment of human hepatic stellate cells with recombinant cyclophilin recapitulated SMAD2/3 activation, which was also suppressed by MM284 treatment. Our data provide the first evidence that extracellular cyclophilins activate the SMAD pathway and promote inflammation in experimental BA, and suggest that MM284 may be a promising therapeutic agent for treating BA and possibly other intrahepatic chronic disorders. PMID- 26225833 TI - Radon as a tracer of daily, seasonal and spatial air movements in the Underground Tourist Route "Coal Mine" (SW Poland). AB - The surveys of radon concentrations in the Underground Tourist Route "Coal Mine" were carried out using passive and active measurement techniques. Passive methods with application of Solid State Nuclear Track Detectors LR115 were used at 4 points in years 2004-2007 and at 21 points in year 2011. These detectors were exchanged at the beginning of every season in order to get information about seasonal and spatial changes of radon concentrations. The average radon concentration noted in this facility was 799 Bq m(-3) and is consistent with radon concentrations noted in Polish coal mines. Seasonal variations, observed in this underground tourist route, were as follows: the highest radon concentrations were noted during summers, the lowest during winters, during springs and autumns intermediate but higher in spring than in autumn. The main external factor that affected seasonal changes of radon concentrations was the seasonal variation of outside temperature. No correlation between seasonal variations of radon concentrations and seasonal average atmospheric pressures was found. Spatial variations of radon concentrations corresponded with air movements inside the Underground Tourist Route "Coal Mine". The most vivid air movements were noted along the main tunnel in adit and at the place located near no blinded (in the upper part) shaft. Daily variations of radon concentrations were recorded in May 2012 using RadStar RS-230 as the active measurement technique. Typical daily variations of radon concentrations followed the pattern that the highest radon concentrations were recorded from 8-9 a.m. to 7-8 p.m. and the lowest during nights. The main factor responsible for hourly variations of radon concentrations was the daily variation of outside temperatures. No correlations were found between radon concentration and other meteorological parameters such as atmospheric pressure, wind velocity or precipitation. Additionally, the influence of human factor on radon concentrations was noticed. As human factor, we consider open entrance door during restorations works carried out inside the underground facility. Comprehensive surveys of radon concentrations in the Underground Tourist Route "Coal Mine", which included hourly, seasonal and spatial measurements, have revealed that radon can be the excellent tracer of air movements inside the underground facilities that are not equipped with mechanical ventilation system. The main external factor that affects hourly, seasonal and even spatial changes of radon concentrations inside Underground Tourist Route "Coal Mine" is the variation of outside temperature. The maximum effective dose received by employees during 2000 working hours in a year was 5.8 mSv y(-1) and the minimum was 3.5 mSv y(-1). Tourist guides, who usually spend underground about 1000 h y(-1), received effective dose from 1.7 mSv y(-1) to 2.3 mSv y(-1). According to Polish Law, employees, receiving effective dose for occupational exposure higher than 1 mSv y(-1) but below 6 mSv y(-1), are allocated to category B of workers and the level of radiation in their place of work should be controlled and continuously monitored. The radiation monitoring system in the Underground Tourist Route "Coal Mine" does not exist. None of Polish tourist routes or caves has installed radiation monitoring system although effective doses received by employees, in some of them, exceed values defined by law. Effective dose received by tourist during one trip was lower than 0.001 mSv y(-1) and risk of cancer induction was lower than 0.00001%. The probability, that tourists inside the Underground Tourist Route "Coal Mine" receive effective dose exceeding allowable annual limit for members of the public of 1 mSv y(-1) does not exist. The Underground Tourist Route Coal Mine is a safe place for tourists from radiological point of view. PMID- 26225834 TI - Assessment of co-contaminant effects on uranium and thorium speciation in freshwater using geochemical modelling. AB - Speciation modelling of uranium (as uranyl) and thorium, in four freshwaters impacted by mining activities, was used to evaluate (i) the influence of the co contaminants present on the predicted speciation, and (ii) the influence of using nine different model/database combinations on the predictions. Generally, co contaminants were found to have no significant effects on speciation, with the exception of Fe(III) in one system, where formation of hydrous ferric oxide and adsorption of uranyl to its surface impacted the predicted speciation. Model and database choice on the other hand clearly influenced speciation prediction. Complexes with dissolved organic matter, which could be simulated by three of the nine model/database combinations, were predicted to be important in a slightly acidic, soft water. Model prediction of uranyl and thorium speciation needs to take account of database comprehensiveness and cohesiveness, including the capability of the model and database to simulate interactions with dissolved organic matter. Measurement of speciation in natural waters is needed to provide data that may be used to assess and improve model capabilities and to better constrain the type of predictive modelling work presented here. PMID- 26225832 TI - Cooperativity in CYP2E1 metabolism of acetaminophen and styrene mixtures. AB - Risk assessment for exposure to mixtures of drugs and pollutants relies heavily on in vitro characterization of their bioactivation and/or metabolism individually and extrapolation to mixtures assuming no interaction. Herein, we demonstrated that in vitro CYP2E1 metabolic activation of acetaminophen and styrene mixtures could not be explained through the Michaelis-Menten mechanism or any models relying on that premise. As a baseline for mixture studies with styrene, steady-state analysis of acetaminophen oxidation revealed a biphasic kinetic profile that was best described by negative cooperativity (Hill coefficient=0.72). The best-fit mechanism for this relationship involved two binding sites with differing affinities (Ks=830MUM and Kss=32mM). Introduction of styrene inhibited that reaction less than predicted by simple competition and thus provided evidence for a cooperative mechanism within the mixture. Likewise, acetaminophen acted through a mixed-type inhibition mechanism to impact styrene epoxidation. In this case, acetaminophen competed with styrene for CYP2E1 (Ki=830MUM and Ksi=180MUM for catalytic and effector sites, respectively) and resulted in cooperative impacts on binding and catalysis. Based on modeling of in vivo clearance, cooperative interactions between acetaminophen and styrene resulted in profoundly increased styrene activation at low styrene exposure levels and therapeutic acetaminophen levels. Current Michaelis-Menten based toxicological models for mixtures such as styrene and acetaminophen would fail to detect this concentration-dependent relationship. Hence, future studies must assess the role of alternate CYP2E1 mechanisms in bioactivation of compounds to improve the accuracy of interpretations and predictions of toxicity. PMID- 26225835 TI - Transcriptome meta-analysis reveals common differential and global gene expression profiles in cystic fibrosis and other respiratory disorders and identifies CFTR regulators. AB - A meta-analysis of 13 independent microarray data sets was performed and gene expression profiles from cystic fibrosis (CF), similar disorders (COPD: chronic obstructive pulmonary disease, IPF: idiopathic pulmonary fibrosis, asthma), environmental conditions (smoking, epithelial injury), related cellular processes (epithelial differentiation/regeneration), and non-respiratory "control" conditions (schizophrenia, dieting), were compared. Similarity among differentially expressed (DE) gene lists was assessed using a permutation test, and a clustergram was constructed, identifying common gene markers. Global gene expression values were standardized using a novel approach, revealing that similarities between independent data sets run deeper than shared DE genes. Correlation of gene expression values identified putative gene regulators of the CF transmembrane conductance regulator (CFTR) gene, of potential therapeutic significance. Our study provides a novel perspective on CF epithelial gene expression in the context of other lung disorders and conditions, and highlights the contribution of differentiation/EMT and injury to gene signatures of respiratory disease. PMID- 26225836 TI - The importance of re-examination with deep biopsies in diagnosing cervical malignancies despite multiple negative pathology reports: A case report. AB - INTRODUCTION: Clinical symptoms of female genital tract lymphoma are often non specific, and mimic other more common gynecological malignancies. Diagnosis can only be confirmed by histology. CASE PRESENTATION: We report the case of a 48 year-old multiparous woman who underwent subtotal hysterectomy because of enlarged myomatous uterus and persistent heavy vaginal bleeding. "2 months later", postoperative pelvic and abdominal CT scan performed because of flank pain, revealed bilateral hydronephrosis. Pelvic and colposcopic exam and cervical biopsy under anesthesia showed benign histology, as reported by two pathologists. Referral to a third pathologist and immunohistochemical (IHC) exam revealed malignant lymphoproliferative disorder. CONCLUSION: Despite multiple negative pathology reports of the cervical biopsies, bimanual pelvic exam with deep biopsies by a gynecologist, allowed accurate final diagnosis of this unusual case. PMID- 26225837 TI - Solid cystic pseudopapillary tumor of pancreas with splenic metastasis: Case report and review of literature. AB - INTRODUCTION: Solid-cystic pseudopapillary tumor of the pancreas is rare and most commonly seen in young women. We present a young women with solid-cystic pseudopapillary tumor of the pancreas and discuss the literature. PRESENTATION OF CASE: Thirty nine years old female patient with a mass about 12cm in the pancreas with splenic invasion seen in our clinic. After having CT and PET-CT view, patient underwent surgery. Distal pancreatectomy with mass excision and splenectomy was performed. Microscopic examination result was solid cystic pseudopapillary tumor with spleen invasion. DISCUSSION: Solid-cystic pseudopapillary tumor of the pancreas has cystic solid pseudopapillary structures. Prognosis of tumor is better than other pancreatic tumor. Complete resection of tumor with splenic inclusion is surgical treatment. CONCLUSION: In case of large slow growing pancreatic tumor with splenic metastasis, solid-cystic pseudopapillary tumor of the pancreas should be considered in the diagnosis. Complete surgical resection is associated with long-term survival even in the presence of metastatic disease. Close follow-up is necessary after surgery. PMID- 26225838 TI - Superoxide induces protein oxidation in plasma and TNF-alpha elevation in macrophage culture: Insights into mechanisms of neurotoxicity following doxorubicin chemotherapy. AB - Chemotherapy-induced cognitive impairment (CICI) is a quality of life-altering consequence of chemotherapy experienced by a large percentage of cancer survivors. Approximately half of FDA-approved anti-cancer drugs are known to produce ROS. Doxorubicin (Dox), a prototypical ROS-generating chemotherapeutic agent, generates superoxide (O2(-)*) via redox cycling. Our group previously demonstrated that Dox, which does not cross the BBB, induced oxidative damage to plasma proteins leading to TNF-alpha elevation in the periphery and, subsequently, in brain following cancer chemotherapy. We hypothesize that such processes play a central role in CICI. The current study tested the notion that O2(-)* is involved and likely responsible for Dox-induced plasma protein oxidation and TNF-alpha release. Addition of O2(-)* as the potassium salt (KO2) to plasma resulted in significantly increased oxidative damage to proteins, indexed by protein carbonyl (PC) and protein-bound HNE levels. We then adapted this protocol for use in cell culture. Incubation of J774A.1 macrophage culture using this KO2-18crown6 protocol with 1 and 10 uM KO2 resulted in dramatically increased levels of TNF-alpha produced. These findings, together with our prior results, provide strong evidence that O2(-)* and its resulting reactive species are critically involved in Dox-induced plasma protein oxidation and TNF-alpha release. PMID- 26225839 TI - Integrated genomic analyses identify KDM1A's role in cell proliferation via modulating E2F signaling activity and associate with poor clinical outcome in oral cancer. AB - The histone demethylase KDM1A specifically demethylates lysine residues and its deregulation has been implicated in the initiation and progression of various cancers. However, KDM1A's molecular role and its pathological consequences, and prognostic significance in oral cancer remain less understood. In the present study, we sought to investigate the expression of KDM1A and its downstream role in oral cancer pathogenesis. By comparing mRNA expression profiles, we identified an elevated KDM1A expression in oral tumors when compared to normal oral tissues. In silico pathway prediction identified the association between KDM1A and E2F1 signaling in oral cancer. Pathway scanning, functional annotation analysis and In vitro assays showed the KDM1A's involvement in oral cancer cell proliferation and the cell cycle. Moreover, real time PCR and luciferase assays confirmed KDM1A's role in regulation of E2F1 signaling activity in oral cancer. Elevated KDM1A expression is associated with poor clinical outcome in oral cancer. Our data indicate that deregulated KDM1A expression is positively associated with proliferative phenotype of oral cancer and confers poor clinical outcome. These cumulative data suggest that KDM1A might be a potential diagnostic and therapeutic target for oral cancer. PMID- 26225840 TI - Hsp90 inhibition by AUY922 as an effective treatment strategy against myxoid liposarcoma. AB - Liposarcoma is one of the most common soft tissue sarcomas in adults. Recognized histological subtypes include well differentiated/dedifferentiated liposarcoma (WD/DDLS), myxoid liposarcoma (MLS) and pleomorphic liposarcoma. Currently, there are no proper subtype-specific treatments due to the genetic, histological and clinical heterogeneity of the liposarcoma subentities. In the past decade, the rising understanding of the various genetic and molecular aberrations in liposarcoma led to the development of novel alternative therapeutic strategies. One such therapy is the inhibition of the heat shock protein 90 (Hsp90) which is overexpressed in liposarcomas. In this study, we dissect the functional role of a novel potent Hsp90 inhibitor NVP-AUY922 (AUY922) in different cell lines of myxoid (MLS402, MLS1765) and undifferentiated (SW872) liposarcomas. We show that compared with 17-AAG treatment, lower concentrations of AUY922 achieve markedly cytotoxic effects on tumor cell viability. Combination treatment of AUY922 (20 nM) with Doxorubicin (300 nM) yielded a further reduction in cell viability in comparison to Doxorubicin alone. In vivo, we document an inhibition of tumor growth after AUY922 treatment. Further analyses revealed that Hsp90-inhibition induces apoptotic cell death and cell cycle arrest. In addition, we report striking perturbations of subtype-specific pattern in Raf/MEK/ERK and PI3K signaling after AUY922 application. In conclusion, our results provide evidence that Hsp90-inhibition by AUY922 may be a promising alternative therapeutic strategy for myxoid liposarcoma patients. PMID- 26225841 TI - Enhanced nitric oxide bioavailability in coronary arteries prevents the onset of heart failure in rats with myocardial infarction. AB - AIM: The endothelium, mainly via nitric oxide (NO) release, adjusts the coronary flow. Cardiac function is closely linked to blood flow; thus, we tested the hypothesis that NO modulation in coronary arteries could be differentially adjusted after myocardial infarction (MI) in the presence or absence of heart failure (HF). METHODS AND RESULTS: Four weeks after coronary occlusion, the infarcted rats were subdivided into rats without (MI) or with HF signs according to haemodynamic parameters. The septal coronary arteries were subsequently used to perform functional and molecular experiments. Acetylcholine (ACh)-induced relaxation was decreased in the coronary arteries following HF, whereas it was enhanced in the arteries of the MI compared with those of SHAM-operated (SO) rats. The relaxation induced by the NO donor was similar among the groups. NO production, which was evaluated by 4,5-diaminofluorescein diacetate, was reduced in the coronary arteries of the HF group and increased in the arteries with MI after ACh-induced stimulation. HF coronary arteries exhibited oxidative stress, which was evaluated via ethidium bromide-positive nuclei, whereas it was decreased in MI. To evaluate the mechanisms involved in the enhanced ACh-induced relaxation in the arteries following MI, certain septal coronary arteries were pre-incubated with L-NAME (a nonselective NO synthase (NOS) inhibitor), 7-NI (a selective neuronal NOS (nNOS) inhibitor) or LY294002 (a PI3-kinase inhibitor). L NAME and LY294002 reduced ACh-induced relaxation in the MI and SO rats; however, these effects were greater in the MI arteries. 7-NI reduced only the ACh relaxation in MI. In addition, the eNOS, nNOS, Akt, and superoxide dismutase isoform protein expressions were greater in the coronary arteries of the MI than in those of the SO groups. CONCLUSION: Our data suggested that endothelial function was closely related to cardiac function after coronary occlusion. The coronary arteries from the HF rats exhibited reduced NO bioavailability, whereas the MI rats exhibited increased NO bioavailability because of increased eNOS/nNOS/PI3-kinase/Akt pathway and a reduction in ROS generation. These results suggest that enhanced NO modulation can prevent the onset of HF. PMID- 26225842 TI - Irisin improves endothelial function in type 2 diabetes through reducing oxidative/nitrative stresses. AB - Vascular complications are the major causes of death in patients with diabetes, and endothelial dysfunction is the earliest event in vascular complications of diabetes. It has been reported that plasma irisin level is significantly reduced in patients with type 2 diabetic patients. The present study aimed to investigate whether irisin improved endothelial function in type 2 diabetes as well as the underlying mechanisms. The type 2 diabetes model was established by feeding C57BL/6 mice with high-fat diet. The type 2 diabetic mice exhibited reduced serum irisin level and impaired endothelial function. Irisin treatment (0.5 mg/kg/d) for two weeks improved vascular function based on the evaluation of endothelium dependent vasorelaxation and p-VASP levels. To investigate the direct endothelial protective effects of irisin, diabetic aortic segments were incubated with irisin (1 MUg/ml) ex vivo. Exposure to irisin improved endothelium-dependent vasorelaxation of diabetic aortas. Mechanically, the diabetic aortic segments exhibited increased oxidative/nitrative stresses. Irisin reduced the diabetes induced oxidative/nitrative stresses evidenced by reducing overproduction of superoxide and peroxynitrite, and down-regulation of iNOS and gp91(phox). To further investigate the protective effects of irisin on endothelial cells and the underlying mechanisms, human umbilical vein endothelial cells (HUVECs) cultured in high-glucose/high-fat (HG/HF) medium were pre-incubated with irisin. Irisin (1 MUg/ml) reduced the oxidative/nitrative stresses and apoptosis induced by HG/HF in HUVECs probably via inhibiting activation of PKC-beta/NADPH oxidase and NF kappaB/iNOS pathways. Taken together, irisin alleviates endothelial dysfunction in type 2 diabetes partially via reducing oxidative/nitrative stresses through inhibiting signaling pathways implicating PKC-beta/NADPH oxidase and NF kappaB/iNOS, suggesting that irisin may be a promising molecule for the treatment of vascular complications of diabetes. PMID- 26225843 TI - D-Cycloserine acts via increasing the GluN1 protein expressions in the frontal cortex and decreases the avoidance and risk assessment behaviors in a rat traumatic stress model. AB - D-cycloserine (DCS), an FDA approved anti-tuberculosis drug has extensively been studied for its cognitive enhancer effects in psychiatric disorders. DCS may enhance the effects of fear extinction trainings in animals during exposure therapy and hence we investigated the effects of DCS on distinct behavioral parameters in a predator odor stress model and tested the optimal duration for repeated daily administrations of the agent. Cat fur odor blocks were used to produce stress and avoidance and risk assessment behavioral parameters were used where DCS or saline were used as treatments in adjunct to extinction trainings. We observed that DCS facilitated extinction training by providing further extinction of avoidance responses, risk assessment behaviors and increased the contact with the cue in a setting where DCS was administered before extinction trainings for 3 days without producing a significant tolerance. In amygdala and hippocampus, GluN1 protein expressions decreased 72h after the fear conditioning in the traumatic stress group suggesting a possible down-regulation of NMDARs. We observed that extinction learning increased GluN1 proteins both in the amygdaloid complex and the dorsal hippocampus of the rats receiving extinction training or extinction training with DCS. Our findings also indicate that DCS with extinction training increased GluN1 protein levels in the frontal cortex. We may suggest that action of DCS relies on enhancement of the consolidation of fear extinction in the frontal cortex. PMID- 26225844 TI - Impulsivity and sensitivity to amount and delay of reinforcement in an animal model of ADHD. AB - Previous research has been inconclusive about the degree of impulsivity displayed by spontaneously hypertensive rats (SHR), an animal model of Attention Deficit Hyperactivity Disorder (ADHD). In the present set of experiments, concurrent chains schedules were employed in order to explore SHR's impulsivity, sensitivity to delay, and sensitivity to amount of reinforcement; Wistar rats (WIS) were used as comparison group. In the three experiments - performed with different subjects - non-independent variable interval 30s schedules were presented in the initial links; the difference between experiments was in the terminal links. For exploring impulsivity, one of the terminal links (SS) was associated to a short delay (2s) and a small reinforcer (1 pellet), whereas the other terminal link (LL) was associated to a longer delay (28s) and a larger reinforcer (4 pellets). The results indicated a remarkably higher impulsivity in SHR. Because this impulsivity may have as potential mechanisms an increased sensitivity to delay and/or a decreased sensitivity to the amount of reinforcement, in experiments 2 and 3 these possibilities were examined. For assessing sensitivity to delay, the following pairs of fixed interval (FI) schedules were used in the terminal links in five conditions: 2-28, 6-24, 15-15, 24-6, 28-2s; the magnitude of reinforcement was 1 pellet in all conditions for both alternatives. For assessing sensitivity to amount, in five conditions the alternatives were associated with different magnitudes of reinforcement: 1-5 pellets, 2-4, 3-3, 4-2 and 5-1 in left right alternatives, respectively; the delay to reinforcement was controlled by a FI 15s in all conditions and for both alternatives. The sensitivity to delay and the sensitivity to amount were calculated according to the Generalized Matching Law. The results indicated a higher sensitivity to delay in SHR, and the same sensitivity to amount in SHR and WIS rats. These results suggest that the increased sensitivity to delay influences the high level of impulsivity observed in SHR. PMID- 26225845 TI - The effect of transcranial alternating current stimulation (tACS) at alpha and beta frequency on motor learning. AB - At present it remains elusive to what extent motor-cortical alpha (8-12Hz) and beta (13-30Hz) oscillations are associated with motor sequence learning. In order to interact with motor-cortical oscillations, the present study applied transcranial alternating current stimulation (tACS) at 10Hz, 20Hz and sham stimulation over the left primary motor cortex (M1) during a serial reaction time task (SRTT) in 13 healthy volunteers. In a control experiment, tACS at 35Hz was applied in another sample of 13 volunteers. The participants performed the task with the right hand. A sequential pattern was interleaved by a randomly varying pattern serving as interference from sequence learning. Reaction times were determined as dependent variable. Both 10 and 20Hz tACS facilitated SRTT acquisition in contrast to sham and 35Hz tACS. After acquisition, the interfering condition led to increased reaction times comparable to baseline level during 10Hz, sham and 35Hz tACS. In contrast, during 20Hz tACS the initial learning success was retained despite interference. While motor-cortical tACS at 10 and 20Hz likewise facilitates the acquisition, tACS at 20Hz frequency additionally stabilizes the newly learned motor sequence indicated by less susceptibility to interference. PMID- 26225846 TI - Folic acid in pregnant women associated with reduced prevalence of severe congenital heart defects in their children: a national population-based case control study. AB - OBJECTIVE: Previous Hungarian intervention trials have shown an association between periconceptional folic-acid-containing multivitamin supplementation and significantly reduced risk of congenital heart defects (CHDs). These findings were confirmed in observational multivitamin studies in the USA, and studies in the Netherlands and China regarding folic acid. The objective of this observational population-based study was to estimate the possible preventive effect of folic acid supplementation for different CHDs during their critical period of development. STUDY DESIGN: Evaluation of medically recorded use of folic acid (calculated daily average 5.6mg) during the critical period of development of eight types of CHD (verified through autopsy reports or after catheter examination and/or surgical correction) in the population-based Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), 1980 1996, containing 22,843 cases with congenital abnormalities and 38,151 population controls without any CHDs, including 5395 matched controls of 3567 live-born cases with various CHDs. A conditional logistic regression model was used to estimate the relative risk/protection [odds ratio (OR) with 95% confidence intervals (CI)] of folic acid in the mothers of cases with various types of CHD and their matched controls. RESULTS: There was a significant decrease in the prevalence of cases with ventricular septal defect (OR 0.57, 95% CI 0.45-0.73), tetralogy of Fallot (OR 0.53, 95% CI 0.17-0.94), d-transposition of great arteries (OR 0.47, 95% CI 0.26-0.86) and atrial septal defect secundum (OR 0.63, 95% CI 0.40-0.98) in infants born to mothers who had taken high doses of folic acid during the critical period of CHD development. CONCLUSIONS: The risk of development of certain types of CHD was significantly reduced in pregnant women who were supplemented with folic acid. Thus, CHDs should be included as a secondary assessment in neural-tube-defect preventive programs. PMID- 26225847 TI - Model Uracil-Rich RNAs and Membrane Protein mRNAs Interact Specifically with Cold Shock Proteins in Escherichia coli. AB - Are integral membrane protein-encoding mRNAs (MPRs) different from other mRNAs such as those encoding cytosolic mRNAs (CPRs)? This is implied from the emerging concept that MPRs are specifically recognized and delivered to membrane-bound ribosomes in a translation-independent manner. MPRs might be recognized through uracil-rich segments that encode hydrophobic transmembrane helices. To investigate this hypothesis, we designed DNA sequences encoding model untranslatable transcripts that mimic MPRs or CPRs. By utilizing in vitro synthesized biotinylated RNAs mixed with Escherichia coli extracts, we identified a highly specific interaction that takes place between transcripts that mimic MPRs and the cold shock proteins CspE and CspC, which are normally expressed under physiological conditions. Co-purification studies with E. coli expressing 6His-tagged CspE or CspC confirmed that the specific interaction occurs in vivo not only with the model uracil-rich untranslatable transcripts but also with endogenous MPRs. Our results suggest that the evolutionarily conserved cold shock proteins may have a role, possibly as promiscuous chaperons, in the biogenesis of MPRs. PMID- 26225848 TI - Applying the Triangle Taste Test to Assess Differences between Low Sodium Salts and Common Salt: Evidence from Peru. AB - BACKGROUND: In resourced-constrained settings, daily cooking practices are still the norm. Replacing sodium in regular salt to produce potassium-enriched salts are potential alternative routes to reduce sodium intake, paired with the benefit associated with potassium intake. This change would likely have effects on palatability and taste of prepared foods, yet a threshold to discriminate sensorial changes can be determined. The main goal of this study was to assess if the use of potassium-enriched salt substitutes lead to perceived differences in taste utilizing a sensory discrimination test. METHODS AND RESULTS: A triangle taste test was conducted and participants were offered samples of cooked rice prepared with different salts. The only ingredient that differed in the preparation was the salt used: 100%NaCl (regular salt) and salts where sodium was replaced by 50%, 33% or 25% KCl (potassium-enriched salt). Comparisons were carried out according to the minimum number of correct judgments. A total of 156 subjects, 49% males, mean age 41.0 years (SD+/-15.5) years, participated in the study. Samples using 25% potassium-enrichment were indistinguishable in terms of taste from regular salt, whereas samples with 33% and 50% potassium-enrichment were distinguishable. Results were consistent when stratified by sex and age. Less than 10% of participants attributed the differences to bitterness or metallic flavor. CONCLUSIONS: The 25% potassium-enriched salt is indistinguishable from regular salt. These findings suggest a potential to achieve sodium intake reduction strategies in cooking practices by substituting regular salt with potassium-enriched salt without affecting palatability. PMID- 26225850 TI - Bearing Witness: Personal and Poetic Descriptions of Seizure Therapy. AB - Many voices comment on personal experience with induced seizures. The encouraging voices of professionals are contrasted with those in theater and film that stigmatize the treatments. The negative images have done much to support restrictive legislation. PMID- 26225849 TI - Trophic ecology of Atlantic Bluefin Tuna (Thunnus thynnus) [corrected] larvae from the Gulf of Mexico and NW Mediterranean spawning grounds: A Comparative Stable Isotope Study. AB - The present study uses stable isotopes of nitrogen and carbon (delta15Nanddelta13C) as trophic indicators for Atlantic bluefin tuna larvae (BFT) (6-10 mm standard length) in the highly contrasting environmental conditions of the Gulf of Mexico (GOM) and the Balearic Sea (MED). These regions are differentiated by their temperature regime and relative productivity, with the GOM being significantly warmer and more productive. MED BFT larvae showed the highest delta15N signatures, implying an elevated trophic position above the underlying microzooplankton baseline. Ontogenetic dietary shifts were observed in the BFT larvae from the GOM and MED which indicates early life trophodynamics differences between these spawning habitats. Significant trophic differences between the GOM and MED larvae were observed in relation to delta15N signatures in favour of the MED larvae, which may have important implications in their growth during their early life stages.These low delta15N levels in the zooplankton from the GOM may be an indication of a shifting isotopic baseline in pelagic food webs due to diatrophic inputs by cyanobacteria. Lack of enrichment for delta15N in BFT larvae compared to zooplankton implies an alternative grazing pathway from the traditional food chain of phytoplankton-zooplankton-larval fish. Results provide insight for a comparative characterization of the trophic pathways variability of the two main spawning grounds for BFT larvae. PMID- 26225851 TI - The Practice of Electroconvulsive Therapy in US Correctional Facilities: A Nationwide Survey. AB - OBJECTIVES: There are little data regarding the practice of electroconvulsive therapy (ECT) in correctional settings in the United States. A survey was conducted to study the current practice of ECT in US prisons. We hypothesize that ECT is underutilized in the correctional setting. We also review the ethical aspects of using ECT for the treatment of mental illness in the prison population. METHODS: A 12-question survey via a Survey Monkey link was emailed to chiefs of psychiatry, or the equivalent, of each state's department of corrections. We examined the frequency of Likert-type responses, tabulated individual comments for qualitative review, and grouped for comparison. RESULTS: Email contacts for chiefs of psychiatry, or the equivalent, for the department of corrections in 45 states (90%) were obtained and a survey link was sent. Thirty one (68.9%) of 45 responded to the survey. Respondent estimates of the number of inmates with mental illness in 31 prison systems varied from less than 500 to more than 4500. Of these 31, 12 (38.7%) had more than 4500 inmates with mental illness. Four systems reported the use of ECT within the last 5 years. Of those, one reported use in the last 1 to 6 months, and 3 reported use in the last 2 to 5 years. Of these 4 prison systems, all felt that they had up to 10 patients who would benefit if ECT continued to be offered or became available in the future. None of these systems provided ECT within the prison. The inmates were referred to a local state psychiatric facility, a university hospital, or other institutions. The reasons for not using ECT as reported by the respondents are grouped under subheadings of stigma, ethical concerns, logistical concerns, and others. CONCLUSIONS: Considering the high prevalence of mental illness in prisons, one might expect a high prevalence of ECT responsive mental illness and, hence, provision of ECT to some prisoners with mental illness. However, our survey suggests that the use of ECT in prisons in the United States is low. Stigma, ethical concerns, and logistical concerns were the main hindrances for providing ECT to prisoners with mental illness. Given that ECT is the standard of care in certain clinical scenarios, physicians are obligated to offer such treatment to inmates when necessary. It can be argued that failure of the prison to offer the standard of care is unethical and unconstitutional. PMID- 26225852 TI - Carbonic Anhydrase Protects Fatty Liver Grafts against Ischemic Reperfusion Damage. AB - Carbonic anhydrases (CAs) are ubiquitous metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. CAs are involved in numerous physiological and pathological processes, including acid base homeostasis, electrolyte balance, oxygen delivery to tissues and nitric oxide generation. Given that these processes are found to be dysregulated during ischemia reperfusion injury (IRI), and taking into account the high vulnerability of steatotic livers to preservation injury, we hypothesized a new role for CA as a pharmacological agent able to protect against ischemic damage. Two different aspects of the role of CA II in fatty liver grafts preservation were evaluated: 1) the effect of its addition to Institut Georges Lopez (IGL-1) storage solution after cold ischemia; 2) and after 24h of cold storage followed by two hours of normothermic ex-vivo perfusion. In all cases, liver injury, CA II protein concentration, CA II mRNA levels and CA II activity were determined. In case of the ex-vivo perfusion, we further assessed liver function (bile production, bromosulfophthalein clearance) and Western blot analysis of phosphorylated adenosine monophosphate activated protein kinase (AMPK), mitogen activated protein kinases family (MAPKs) and endoplasmic reticulum stress (ERS) parameters (GRP78, PERK, IRE, eIF2alpha and ATF6). We found that CA II was downregulated after cold ischemia. The addition of bovine CA II to IGL-1 preservation solution efficiently protected steatotic liver against cold IRI. In the case of reperfusion, CA II protection was associated with better function, AMPK activation and the prevention of ERS and MAPKs activation. Interestingly, CA II supplementation was not associated with enhanced CO2 hydration. The results suggest that CA II modulation may be a promising target for fatty liver graft preservation. PMID- 26225853 TI - Designing Psychological Treatments for Scalability: The PREMIUM Approach. AB - INTRODUCTION: Lack of access to empirically-supported psychological treatments (EPT) that are contextually appropriate and feasible to deliver by non-specialist health workers (referred to as 'counsellors') are major barrier for the treatment of mental health problems in resource poor countries. To address this barrier, the 'Program for Effective Mental Health Interventions in Under-resourced Health Systems' (PREMIUM) designed a method for the development of EPT for severe depression and harmful drinking. This was implemented over three years in India. This study assessed the relative usefulness and costs of the five 'steps' (Systematic reviews, In-depth interviews, Key informant surveys, Workshops with international experts, and Workshops with local experts) in the first phase of identifying the strategies and theoretical model of the treatment and two 'steps' (Case series with specialists, and Case series and pilot trial with counsellors) in the second phase of enhancing the acceptability and feasibility of its delivery by counsellors in PREMIUM with the aim of arriving at a parsimonious set of steps for future investigators to use for developing scalable EPT. DATA AND METHODS: The study used two sources of data: the usefulness ratings by the investigators and the resource utilization. The usefulness of each of the seven steps was assessed through the ratings by the investigators involved in the development of each of the two EPT, viz. Healthy Activity Program for severe depression and Counselling for Alcohol Problems for harmful drinking. Quantitative responses were elicited to rate the utility (usefulness/influence), followed by open-ended questions for explaining the rankings. The resources used by PREMIUM were computed in terms of time (months) and monetary costs. RESULTS: The theoretical core of the new treatments were consistent with those of EPT derived from global evidence, viz. Behavioural Activation and Motivational Enhancement for severe depression and harmful drinking respectively, indicating the universal applicability of these theories. All the steps of both phases in PREMIUM contributed to the development of the final EPT. However, if there were significant resource constraints, the steps can be limited to workshops with international and local experts in the first phase, and case series with specialists, and case series and pilot trial with counsellors in the second phase. CONCLUSIONS: Integrating global evidence with local knowledge and practices are complementary and feasible goals to contribute to the development of contextually appropriate and feasible EPT in resource poor country settings. The emerging EPT share similar theoretical frameworks to those described in the global evidence. The PREMIUM method has relevance for any setting where populations have poor access to EPT as its explicit goal is to develop scalable treatments. PMID- 26225855 TI - Neural Placode Tissue Derived From Myelomeningocele Repair Serves as a Viable Source of Oligodendrocyte Progenitor Cells. AB - BACKGROUND: The presence, characteristics, and potential clinical relevance of neural progenitor populations within the neural placodes of myelomeningocele patients remain to be studied. Neural stem cells are known to reside adjacent to ependyma-lined surfaces along the central nervous system axis. OBJECTIVE: Given such neuroanatomic correlation and regenerative capacity in fetal development, we assessed myelomeningocele-derived neural placode tissue as a potentially novel source of neural stem and progenitor cells. METHODS: Nonfunctional neural placode tissue was harvested from infants during the surgical repair of myelomeningocele and subsequently further analyzed by in vitro studies, flow cytometry, and immunofluorescence. To assess lineage potential, neural placode-derived neurospheres were subjected to differential media conditions. Through assessment of platelet-derived growth factor receptor alpha (PDGFRalpha) and CD15 cell marker expression, Sox2+Olig2+ putative oligodendrocyte progenitor cells were successfully isolated. RESULTS: PDGFRalphaCD15 cell populations demonstrated the highest rate of self-renewal capacity and multipotency of cell progeny. Immunofluorescence of neural placode-derived neurospheres demonstrated preferential expression of the oligodendrocyte progenitor marker, CNPase, whereas differentiation to neurons and astrocytes was also noted, albeit to a limited degree. CONCLUSION: Neural placode tissue contains multipotent progenitors that are preferentially biased toward oligodendrocyte progenitor cell differentiation and presents a novel source of such cells for use in the treatment of a variety of pediatric and adult neurological disease, including spinal cord injury, multiple sclerosis, and metabolic leukoencephalopathies. PMID- 26225856 TI - Seizure Outcomes in Patients With Surgically Treated Cerebral Arteriovenous Malformations. AB - BACKGROUND: Epilepsy is the second most common symptom in cerebral arteriovenous malformation (AVM) patients. The consecutive reduction of life quality is a clinically underrated problem because treatment usually focuses on the prevention of intracerebral hemorrhage. OBJECTIVE: To evaluate postoperative seizure outcome with the aim of more accurate counseling for postoperative seizure outcome. METHODS: From 1985 to 2012, 293 patients with an AVM were surgically treated by J.S. One hundred twenty-six patients with preoperative seizures or epilepsy could be identified; 103 of 126 had a follow-up of at least 12 months and were included in the analysis. The different epilepsy subtypes were categorized (sporadic seizures, chronic epilepsy, drug-resistant epilepsy [DRE]). Preoperative workup and surgical technique were evaluated. Seizure outcome was analyzed by using International League Against Epilepsy classification. RESULTS: Sporadic seizures were identified in 41% of patients (chronic epilepsy and DRE were identified in 36% and 23%, respectively). Detailed preoperative epileptological workup was done in 13%. Seizure freedom was achieved in 77% (79% at 5 years, 84% at 10 years). Outcome was significantly poorer in DRE cases. More extensive resection was performed in 11 cases with longstanding symptoms (>24 months) and resulted in better seizure outcome as well as the short duration of preoperative seizure history. CONCLUSION: Patients presenting with AVM-associated epilepsy have a favorable seizure outcome after surgical treatment. Long-standing epilepsy and the progress into DRE markedly deteriorate the chances to obtain seizure freedom and should be considered an early factor in establishing the indication for AVM removal. PMID- 26225854 TI - Cost Comparison of Surgical and Endovascular Treatment of Unruptured Giant Intracranial Aneurysms. AB - BACKGROUND: Giant intracranial aneurysms (GIAs), which are defined as intracranial aneurysms (IAs) with a diameter of >=25 mm, are most likely associated with the highest treatment costs of all IAs. However, the treatment costs of unruptured GIAs have so far not been reported. OBJECTIVE: To examine direct costs of endovascular and surgical treatment of unruptured GIAs. METHODS: We retrospectively examined 55 patients with unruptured GIAs treated surgically (37 patients) or endovascularly (18 patients) between April 2004 and March 2014. We analyzed the costs of all hospital stays, interventions, and imaging with a median follow-up of 46 months. RESULTS: There was no difference in the costs of hospital stay between surgical and endovascular treatment groups ($10,565 vs. $14,992; P = .37). Imaging costs were significantly higher in the surgical group than in the endovascular treatment group ($2890 vs. $1612; P < .01), as were the costs of the intervention room and personnel involved in the intervention ($5566 vs. $1520; P < .01). Implants used per patient were more expensive in the endovascular group than in the surgical treatment group ($20,885 vs. $167). The total direct treatment costs were higher in the endovascular group ($52,325) than in the surgical treatment group ($20,619; P < .01). Treatment costs were associated with the type of treatment and GIA location but not with patient age, sex, or GIA size. CONCLUSION: Endovascular GIA treatment produced higher direct costs than surgical GIA treatment mainly due to higher implant costs. Reducing endovascular implant costs may be the most effective tool to decrease direct costs of GIA treatment. PMID- 26225858 TI - Association of Visceral Fat Area, Smoking, and Alcohol Consumption with Reflux Esophagitis and Barrett's Esophagus in Japan. AB - BACKGROUND: Central obesity has been suggested as a risk factor for gastroesophageal reflux disease. The aim of this study was to evaluate the association of visceral fat area and other lifestyle factors with reflux esophagitis or Barrett's esophagus in Japanese population. METHODS: Individuals who received thorough medical examinations including the measurement of visceral fat area by abdominal computed tomography were enrolled. Factors associated with the presence of reflux esophagitis, the severity of reflux esophagitis, or the presence of Barrett's esophagus were determined using multivariable logistic regression models. RESULTS: A total of 2608 individuals were eligible for the analyses. Visceral fat area was associated with the presence of reflux esophagitis both in men (odds ratio, 1.21 per 50 cm2; 95% confident interval, 1.01 to 1.46) and women (odds ratio, 2.31 per 50 cm2; 95% confident interval, 1.57 to 3.40). Current smoking and serum levels of triglyceride were also associated with the presence of reflux esophagitis in men. However, significant association between visceral fat area and the severity of reflux esophagitis or the presence of Barrett's esophagus was not shown. In men, excessive alcohol consumption on a drinking day, but not the frequency of alcohol drinking, was associated with both the severity of reflux esophagitis (odds ratio, 2.13; 95% confident interval, 1.03 to 4.41) and the presence of Barrett's esophagus (odds ratio, 1.71; 95% confident interval, 1.14 to 2.56). CONCLUSION: Visceral fat area was independently associated with the presence of reflux esophagitis, but not with the presence of Barrett's esophagus. On the other hand, quantity of alcohol consumption could play a role in the development of severe reflux esophagitis and Barrett's esophagus in Japanese population. PMID- 26225859 TI - Physiological and Molecular Responses to Excess Boron in Citrus macrophylla W. AB - This work provides insight into several mechanisms involved in boron (B) regulation pathway in response to high B conditions in Citrus. The study was carried out in Citrus macrophylla W. (Cm) seedlings cultured "in vitro" in media with 50 or 400 MUM H3BO3 (control, Ct, and B-excess, +B, plants, respectively). Growth parameters, B concentration, leaf chlorophyll (Chl) concentration, the expression of the main putative genes involved in B transport and distribution, and leaf and root proline and malonaldehyde (MDA) concentrations, were assessed. Excess B led to high B concentration in +B plants (3.8- and 1.4-fold in leaves and roots, respectively) when compared with Ct ones. However, a minor effect was recorded in the plant (incipient visual symptoms, less than 27% reduction in root growth and 26% decrease in Chl b concentration). B toxicity down-regulated by half the expression level of putative B transporter genes NIP5 and PIP1. CmBOR1 gene was not repressed in +B plants and B accumulated in the shoots. High B level increased the transcripts of putative gene TIP5, involved in B transport across the tonoplast, by 3.3- and 2.4-fold in leaves and roots, respectively. The activity of V-PPiase proton pump, related with the electrochemical gradient in the vacuole, was also enhanced in +B organs. B toxicity up-regulated putative BOR4 gene (2.1- and 2.7-fold in roots and leaves, respectively), which codifies for an active efflux B transporter. Accordingly, B was located in +B plants preferently in an insoluble form on cell walls. Finally, excess B caused a significant rise in proline concentration (51% and 34% in roots and leaves, respectively), while the MDA level did not exceed 20%. In conclusion, Cm tolerance to a high B level is likely based on the synergism of several specific mechanisms against B toxicity, including: 1/ down-regulation of NIP5 and PIP1 boron transporters; 2/ activation of B efflux from cells due to the up-regulation of putative BOR4 gene; 3/ compartmentation of B in the vacuole through TIP5 transporter activation and the acidification of the organelle; 4/ insolubilisation of B and deposition in cell walls preventing from cytoplasm damage; and, 5/ induction of an efficient antioxidant system through proline accumulation. PMID- 26225860 TI - Protective Effect of RNase on Unilateral Nephrectomy-Induced Postoperative Cognitive Dysfunction in Aged Mice. AB - Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially for elderly patients. Administration of RNase has been reported to exhibit neuroprotective effects in acute stroke. However, the potential role of RNase on POCD is unknown. Therefore, we sought to investigate whether RNase treatment could mitigate unilateral nephrectomy induced-cognitive deficit in aged mice. In the present study, twelve-month-old mice were administered RNase or an equal amount of normal saline perioperatively. All mice underwent Morris Water Maze (MWM) training 3 times per day for 7 days to acclimatize them to the water maze before surgical operation, and testing on days 1, 3 and 7 after surgery. We found that perioperative administration of RNase: 1) attenuated unilateral nephrectomy-induced cognitive impairment at day 3 after surgery; 2) reduced the hippocampal cytokines mRNA production and serum cytokines protein production at day 1 and day 7 (for MCP-1) after surgery, and; 3) inhibited hippocampal apoptosis as indicated by cleaved caspase-3 western blot and TUNEL staining at day 1 after surgery. In addition, a trend decrease of total serum RNA levels was detected in the RNase treated group after surgery compared with the untreated group. Further, our protocol of RNase administration had no impact on the arterial blood gas analysis right after surgery, kidney function and mortality rate at the observed days postoperatively. In conclusion, perioperative RNase treatment attenuated unilateral nephrectomy-induced cognitive impairment in aged mice. PMID- 26225861 TI - Genetic Diversity Strategy for the Management and Use of Rubber Genetic Resources: More than 1,000 Wild and Cultivated Accessions in a 100-Genotype Core Collection. AB - The rubber tree [Hevea brasiliensis (Willd. ex Adr. de Juss.) Muell. Arg.] is the only plant species worldwide that is cultivated for the commercial production of natural rubber. This study describes the genetic diversity of the Hevea spp. complex that is available in the main ex situ collections of South America, including Amazonian populations that have never been previously described. Genetic data were analyzed to determine the genetic structure of the wild populations, quantify the allelic diversity and suggest the composition of a core collection to capture the maximum genetic diversity within a minimal sample size. A total of 1,117 accessions were genotyped with 13 microsatellite markers. We identified a total of 408 alleles, 319 of which were shared between groups and 89 that were private in different groups of accessions. In a population structure and principal component analysis, the level of clustering reflected a primary division into the following two subgroups: cluster 1, which consisted of varieties from the advanced breeding germplasm that originated from the Wickham and Mato Grosso accessions; and cluster 2, which consisted of the wild germplasm from the Acre, Amazonas, Para and Rondonia populations and Hevea spp. The analyses revealed a high frequency of gene flow between the groups, with the genetic differentiation coefficient (GST) estimated to be 0.018. Additionally, no distinct separation among the H. brasiliensis accessions and the other species from Amazonas was observed. A core collection of 99 accessions was identified that captured the maximum genetic diversity. Rubber tree breeders can effectively utilize this core collection for cultivar improvement. Furthermore, such a core collection could provide resources for forming an association panel to evaluate traits with agronomic and commercial importance. Our study generated a molecular database that should facilitate the management of the Hevea germplasm and its use for subsequent genetic and genomic breeding. PMID- 26225862 TI - Biocompatibility of Polypyrrole with Human Primary Osteoblasts and the Effect of Dopants. AB - Polypyrrole (PPy) is a conducting polymer that enables controlled drug release upon electrical stimulation. We characterized the biocompatibility of PPy with human primary osteoblasts, and the effect of dopants. We investigated the biocompatibility of PPy comprising various dopants, i.e. p-toluene sulfonate (PPy pTS), chondroitin sulfate (PPy-CS), or dodecylbenzenesulfonate (PPy-DBS), with human primary osteoblasts. PPy-DBS showed the roughest appearance of all surfaces tested, and its wettability was similar to the gold-coated control. The average number of attached cells was 45% higher on PPy-DBS than on PPy-CS or PPy-pTS, although gene expression of the proliferation marker Ki-67 was similar in osteoblasts on all surfaces tested. Osteoblasts seeded on PPy-DBS or gold showed similar vinculin attachment points, vinculin area per cell area, actin filament structure, and Feret's diameter, while cells seeded on PPY-CS or PPY-pTS showed disturbed focal adhesions and were enlarged with disorganized actin filaments. Osteoblasts grown on PPy-DBS or gold showed enhanced alkaline phosphatase activity and osteocalcin gene expression, but reduced osteopontin gene expression compared to cells grown on PPy-pTS and PPy-CS. In conclusion, PPy doped with DBS showed excellent biocompatibility, which resulted in maintaining focal adhesions, cell morphology, cell number, alkaline phosphatase activity, and osteocalcin gene expression. Taken together, conducting polymers doped with DBS are well tolerated by osteoblasts. Our results could provide a basis for the development of novel orthopedic or dental implants with controlled release of antibiotics and pharmaceutics that fight infections or focally enhance bone formation in a tightly controlled manner. PMID- 26225863 TI - Abdominal Symptoms Are Common and Benefit from Biofeedback Therapy in Patients with Dyssynergic Defecation. AB - OBJECTIVES: Dyssynergic defecation (DD) is a subtype of chronic constipation that responds to biofeedback therapy (BFT). Abdominal, anorectal, and stool symptoms are commonly reported by DD patients, but limited data exist to demonstrate the improvement of these associated symptoms to BFT. Aims to prospectively study the response of constipation and associated abdominal, rectal, and stool symptoms to biofeedback in a population with dyssynergia. METHODS: Patients with DD as determined by anorectal manometry and balloon expulsion testing were included into the study. All patients completed a validated survey, the Personal Assessment of Constipation Symptom (PAC-SYM) questionnaire, before and following BFT. The PAC-SYM is a clinical tool to assess constipation-related symptom frequency and severity. RESULTS: Seventy-seven dyssynergic patients fulfilled the study requirements. Abdominal symptoms were present in up to 74% of patients with dyssynergia. PAC-SYM summation scores improved following completion of biofeedback by 48%, from 22.08 to 11.48 (P<0.001). The proportion of patients with at least moderate symptoms decreased in all 12 questionnaire items, including all abdominal symptoms, after completing BFT (46.8% to 14.3%, P<0.001). CONCLUSIONS: Abdominal symptoms are common in patients with dyssynergia. BFT improves both anorectal-related constipation symptoms and associated abdominal symptoms in patients with DD. Limitations of this study are observational design, lack of control group, and lack of long-term follow-up. PMID- 26225864 TI - Healthcare Contacts after Myocardial Infarction According to Mental Health and Socioeconomic Position: A Population-Based Cohort Study. AB - OBJECTIVE: To examine the long-term use of healthcare contacts to general practice (GP) and hospital after a first-time myocardial infarction (MI) according to mental health and socioeconomic position. METHODS: Population-based cohort study of all patients discharged with first-time MI in the Central Denmark Region in 2009 (n=908) using questionnaires and nationwide registers. We estimated adjusted incidence rates and incidence rate ratios (IRR) for GP and hospital contacts according to depressive and anxiety symptoms, educational level and cohabitation status. RESULTS: During the 24-month period after the MI, patients with anxiety symptoms had 24% more GP contacts (adjusted IRR 1.24, 95% confidence interval (CI) 1.12-1.36) than patients with no anxiety symptoms. In contrast, patients with depressive symptoms (1.05, 0.94-1.16) and with short and medium education (<10 years: 0.96, 0.84-1.08; 10-12 years: 0.91, 0.80-1.03) and patients living alone (0.95, 0.87-1.04) had the same number of GP contacts as their counterparts (patients with no depressive symptoms, with long education [>12 years] and patients living with a partner). During the first 6 months after the MI, patients living alone had 13% fewer hospital contacts (0.87, 0.77-0.99), patients with short education had 16% fewer hospital contacts (<10 years: 0.84, 0.72-0.98) and patients with anxiety symptoms had 27% fewer hospital contacts (0.73, 0.62-0.86) than their counterparts. In contrast, patients with depressive symptoms (0.92, 0.77-1.10) and medium education (10-12 years: 1.05, 0.91-1.22) had the same number of hospital contacts as their counterparts. CONCLUSIONS: This study indicates that patients with depressive symptoms, short and medium education and patients living alone have a lower long-term use of healthcare contacts following MI than patients without these risk factors. Patients with depressive symptoms and low socioeconomic position would be expected to have a higher need of healthcare after MI as they have a poorer prognosis. PMID- 26225865 TI - Ubiquilin 1 Promotes IFN-gamma-Induced Xenophagy of Mycobacterium tuberculosis. AB - The success of Mycobacterium tuberculosis (Mtb) as a pathogen rests upon its ability to grow intracellularly in macrophages. Interferon-gamma (IFN-gamma) is critical in host defense against Mtb and stimulates macrophage clearance of Mtb through an autophagy pathway. Here we show that the host protein ubiquilin 1 (UBQLN1) promotes IFN-gamma-mediated autophagic clearance of Mtb. Ubiquilin family members have previously been shown to recognize proteins that aggregate in neurodegenerative disorders. We find that UBQLN1 can interact with Mtb surface proteins and associates with the bacilli in vitro. In IFN-gamma activated macrophages, UBQLN1 co-localizes with Mtb and promotes the anti-mycobacterial activity of IFN-gamma. The association of UBQLN1 with Mtb depends upon the secreted bacterial protein, EsxA, which is involved in permeabilizing host phagosomes. In autophagy-deficient macrophages, UBQLN1 accumulates around Mtb, consistent with the idea that it marks bacilli that traffic through the autophagy pathway. Moreover, UBQLN1 promotes ubiquitin, p62, and LC3 accumulation around Mtb, acting independently of the E3 ligase parkin. In summary, we propose a model in which UBQLN1 recognizes Mtb and in turn recruits the autophagy machinery thereby promoting intracellular control of Mtb. Thus, polymorphisms in ubiquilins, which are known to influence susceptibility to neurodegenerative illnesses, might also play a role in host defense against Mtb. PMID- 26225866 TI - Inferring Pairwise Interactions from Biological Data Using Maximum-Entropy Probability Models. AB - Maximum entropy-based inference methods have been successfully used to infer direct interactions from biological datasets such as gene expression data or sequence ensembles. Here, we review undirected pairwise maximum-entropy probability models in two categories of data types, those with continuous and categorical random variables. As a concrete example, we present recently developed inference methods from the field of protein contact prediction and show that a basic set of assumptions leads to similar solution strategies for inferring the model parameters in both variable types. These parameters reflect interactive couplings between observables, which can be used to predict global properties of the biological system. Such methods are applicable to the important problems of protein 3-D structure prediction and association of gene-gene networks, and they enable potential applications to the analysis of gene alteration patterns and to protein design. PMID- 26225867 TI - Evaluation of esophageal motility after endoscopic submucosal dissection for superficial esophageal cancer. AB - INTRODUCTION: Endoscopic submucosal dissection (ESD) is a standard treatment for superficial esophageal cancer. Some patients complain of dysphagia after ESD even without any postoperative strictures. Although ineffective esophageal motility might be associated with dysphagia after ESD, its effect on esophageal motility after ESD remains unknown. Therefore, we aimed to elucidate esophageal motility after ESD and the cause of dysphagia using high-resolution manometry (HRM). PATIENTS AND METHODS: Seventy-six patients (men/women, 64/12; mean age, 71.2 years) who had undergone ESD for superficial esophageal cancer were enrolled. The results of ESD were retrospectively investigated using endoscopic images from the ESD and patient questionnaire for dysphagia. Each patient underwent HRM, and the results were evaluated using metrics and contraction patterns, according to the Chicago classification. RESULTS: Data were obtained from 71 patients. The circumferential mucosal defect ratio (beta=0.284, P=0.017), number of ESD (beta=0.346, P=0.003), and number of endoscopic balloon dilatations (EBDs) (beta=0.416, P<0.001) were correlated with the number of weak contraction with large breaks on HRM. The circumferential mucosal defect (odds ratio=1.074, P<0.001) and number of EBDs (odds ratio=1.200, P=0.035) were also significant predictors for dysphagia after ESD. CONCLUSION: Circumferential mucosal defect ratio, EBD, and repeated ESD were predictors for impaired esophageal motility after ESD. Because circumferential mucosal defect ratios and EBD were also correlated with dysphagia after ESD, impaired esophageal motility could explain dysphagia after ESD. PMID- 26225869 TI - Usefulness of thromboelastometry in predicting the risk of bleeding in cirrhotics who undergo invasive procedures. AB - OBJECTIVES: The management of patients with liver cirrhosis undergoing invasive procedures is controversial and haemostasis assessment using routine laboratory is inappropriate. We evaluated the following: (a) the ability of thromboelastometry to predict the risk of bleeding in cirrhotic patients undergoing invasive procedures and enable a decision on the prophylactic transfusional strategy; (b) the contribution of platelet adhesion and aggregation tests in the assessment of haemostasis. PATIENTS AND METHODS: Seventeen cirrhotic patients undergoing invasive procedures were analyzed retrospectively (training set). To obtain preliminary data, an observational study was carried out in 58 patients (test set). All 75 patients were evaluated by thromboelastometry. Platelet adhesion and aggregation were evaluated in 16 patients using Multiplate, PFA-100 and Light Transmission Aggregometry. Factor VIII was dosed in all patients of the test set. RESULTS: In the training set, thromboelastometry confirmed the haemostatic assessment shown by the conventional test only in 6/17 (35%) patients. In the test set, thromboelastometry identified all patients who had a bleeding event. In patients with a high risk of bleeding, the use of thromboelastometry was cost-effective, reducing the platelet infusions by 64%. Platelet adhesion/aggregation abnormalities were observed in 15/16 (94%) patients, but bleeding events occurred only in 2/15 (13%) patients. CONCLUSION: Thromboelastometry appears to be useful to screen cirrhotic patients undergoing invasive procedures to identify the risk of bleeding and to optimize the transfusional strategy. Adhesion/aggregation tests are not useful in identifying patients at risk of bleeding and their application is not cost-effective. PMID- 26225868 TI - Risk of community-acquired pneumonia in patients with a diagnosis of pernicious anemia: a population-based retrospective cohort study. AB - OBJECTIVE: Pernicious anemia (PA) is an autoimmune disease that causes achlorhydria or profound hypochlorhydria. We conducted a population-based study to determine whether individuals with PA are at an increased risk for community acquired pneumonia (CAP). METHODS: We performed a retrospective cohort study using The Health Improvement Network (THIN) from the UK (1993-2009). The eligible study cohort included individuals 18 years of age or older, with at least 1 year of THIN follow-up. The exposed group consisted of individuals with a diagnosis code for PA. The unexposed group consisted of individuals without a diagnosis of PA and was frequency matched with the exposed group with respect to age, sex, and practice site. Cox regression analysis was used to determine the hazard ratio with the 95% confidence interval for CAP associated with PA, accounting for a comprehensive list of potential confounders. RESULTS: The study included 13,605 individuals with PA and 50,586 non-PA individuals. The crude incidence rate of CAP was 9.4/1000 person-years for those with PA, versus 6.4/1000 person-years for those without PA. The multivariable adjusted hazard ratio for CAP associated with PA was 1.18 (95% confidence interval 1.08-1.29). CONCLUSION: In this large population-based cohort study, individuals with PA and presumed chronic achlorhydria were at an increased risk for CAP. PMID- 26225870 TI - A systematic review and meta-analysis on outcomes after Rx or R1 endoscopic resection of superficial gastric cancer. AB - OBJECTIVE: Endoscopic resection is a standard treatment for gastric superficial lesions. A positive or a nonevaluable margin is considered a noncurative criterion. We aimed to systematically review recurrence, residual disease, lymph node metastasis (LNM) and cancer-related death following Rx/R1 resection of gastric lesions in the absence of other noncurative criteria. MATERIALS AND METHODS: MEDLINE systematic review and meta-analysis by July 2014. RESULTS: Data were extracted from 31 manuscripts. Definitions and results differed significantly. However, nonevaluable (HMx) and positive horizontal margins (HM1) were associated with 10% [95% confidence interval (CI) 5-15%] and 36% (95% CI 24 48%) rates of recurrence/residual disease, respectively, with an odds ratio of 2.85 (95% CI 1.6-5.8, P<0.01) for HM1 compared with HMx. Nonevaluable (VMx) or positive (VM1) vertical margin was associated with a 43% (95% CI 17-68%) rate of recurrence/residual. VMx/VM1 was associated with a higher risk of recurrence/residual compared with HMx/HM1 (odds ratio 3.76, 95% CI 1.71-6.82, P<0.01). The most common strategy after HMx/HM1 was endoscopic surveillance and retreatment, whereas surgery was recommended after VMx/VM1. No cases of LNM or cancer-related death were noticeable if neither submucosal invasion more than 500 um nor lymphovascular infiltration was also reported. CONCLUSION: Rx/R1 resection in the absence of other noncurative criteria does not appear to be a significant risk factor for LNM or cancer-related death. The risk of recurrence/residual disease is higher after HM1 than HMx and higher after VMx/VM1 than HMx/HM1. However, considerable heterogeneity was found in studies. Standard definitions should be created and applied in future studies. PMID- 26225872 TI - Cutaneous anthrax: evaluation of 28 cases in the Eastern Anatolian region of Turkey. AB - CONTEXT: Anthrax is an endemic disease in developing countries. Human cases are usually associated with animal products. About 95% of naturally acquired cases are cutaneous anthrax. OBJECTIVE: In this study, cutaneous anthrax cases from the Elazig province (the Eastern Anatolian region) of Turkey seen in our hospital within a 6-year period were evaluated with respect to epidemiological and clinical features, diagnosis, treatment and outcome. METHODS: Twenty-eight patients with cutaneous anthrax observed between January 2009 and December 2014 were investigated retrospectively. The diagnosis of cutaneous anthrax was based on detailed history, dermatologic findings, including painless, ulcers covered by a characteristic black eschar and/or microbiological procedures, including Gram stain and culture of materials obtained from the lesions. RESULTS: Of the 28 patients followed up with cutaneous anthrax diagnosis, 14 (50%) were female and 14 (50%) were male. The mean age of the cases was 39.6 years (age range 17-65 years). The patients have an incubation period in the range of 1-9 days (mean 4.6 +/- 0.5 days). The cases were seen between April and November of each year during the study period. Twenty-three cases (82%) had a history of contact with animals or animal products. Twenty patients (71.4%) showed malignant pustules and eight (28.6%) malignant edema. Bacillus anthracis was isolated in three cases (10.7%) and Gram stain smear were positive in five cases (17.8%). All patients were treated successfully with penicillin or ciprofloxacin. Systemic corticosteroids were added to the antibiotic treatment in six patients with malignant edema. Sepsis no developed in patients, all the cases recovered. CONCLUSION: Anthrax is still a serious public health problem in Turkey. Cutaneous anthrax must always be kept in mind when characteristic lesions such as a painless ulcer with vesicles, edema, and a history of contact with animals or animal products are observed in an individual. Early and correct diagnosis significantly affects course of the disease. Protective precautions such as vaccination of animals against anthrax and education of the population would reduce the incidence of the disease. PMID- 26225871 TI - Regulation of endomembrane biogenesis in arabidopsis by phospatidic acid hydrolase. AB - Coordination of membrane lipid biosynthesis is important for cell function during plant growth and development. Here we summarize our recent work on PHOSPHATIDIC ACID PHOSPHOHYDROLASE (PAH) which suggests that this enzyme is a key regulator of phosphaticylcholine (PC) biosynthesis in Arabidopsis thaliana. Disruption of PAH activity elevates phosphatidic acid (PA) levels and stimulates PC biosynthesis and biogenesis of the endoplasmic reticulum (ER). Furthermore, the activity of PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE (CCT), which is the key enzyme controlling the rate of PC biosynthesis, is directly stimulated by PA and expression of a constitutively active version of CCT replicates the effects of PAH disruption. Hence PAH activity can control the abundance of PA, which in turn can modulate CCT activity to govern the rate of PC biosynthesis. Crucially it is not yet clear how PAH activity is regulated in Arabidopsis but there is evidence that PAH1 and PAH2 are both phosphorylated and further work will be required to investigate whether this is functionally significant. PMID- 26225873 TI - Evaluation of the peripapillary retinal nerve fiber layer and ganglion cell-inner plexiform layer measurements in patients with iron deficiency anemia with optical coherence tomography. AB - OBJECTIVE: To evaluate the thickness of the peripapillary retinal fiber layer (RNFL) and macula ganglion cell-inner plexiform layer (GCL+) using optical coherence tomography (OCT) in patients with iron deficiency (ID) anemia. METHODS: This study included 73 eyes of 39 patients with ID anemia and 68 eyes of 34 age- and sex-matched healthy subjects. The measurements included the peripapillary RNFL thicknesses as average, 4 quadrant and 12 clock-hour (CH) based and macula GCL+ thicknesses as average and 6 quadrant based. All measurements were completed with Cirrus HD-OCT and the results were compared between the groups. RESULTS: A total of 73 eyes of 39 patients with ID anemia and 68 eyes of 34 healthy subjects were included to the study. Regarding peripapillary RNFL thicknesses of the study and control patients, the values of average and quadrants revealed no significant differences between the groups. In CH sectors comparison, peripapillary RNFL thicknesses were significantly decreased only in CH4 (68.7 +/- 14.5 MUm in study versus 72.0 +/- 13.4 MUm in control patients, p = 0.049) and CH5 (93.4 +/- 20.0MUm in study versus 102.2 +/- 20.1 MUm in control patients, p = 0.01) sectors. All measured quadrants were statistically similar, when macula GCL+ thicknesses were compared between the groups. When the correlations between peripapillary RNFL and macula GCL+ thicknesses and serum hemoglobin and ferritin levels of study and control patients were calculated, the only statistically significant parameter was the correlation of peripapillary RNFL thickness in CH10 sector with serum ferritin level (p = 0.032, Spearman correlation coefficient: 0.369). CONCLUSION: The study revealed that peripapillary RNFL is thinner in nasal-inferior quadrant in patients with ID anemia. The measurements of macula GCL+ thicknesses were similar between the groups. Analyzing the retinal layers using OCT may provide valuable information in neurodegenerative events. PMID- 26225874 TI - Oral mucosal involvement and petechial lesions: a SDRIFE case with unusual findings. AB - Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a type IV hypersensitivity reaction characterized by a symmetrical erythematous rash in the gluteal and intertriginous areas. SDRIFE was previously considered to be the same presentation as Baboon Syndrome, however, has been suggested to be a different entity in the recent publications. The lesions are generally maculopapular and there is no mucosal involvement. To date, no case with petechial findings and mucosal involvement has been reported in the literature. The present study reports a SDRIFE case with a symmetrical erythematous petechial rash and oral mucosal involvement after taking oral amoxicillin. PMID- 26225885 TI - Using the HSE stress indicator tool in a military context. AB - An assessment of the Health and Safety Executive's (HSE) stress indicator tool was conducted to determine whether it was suitable for use with Ministry of Defence (MoD) personnel. A total of 1031 respondents from the Army, Navy, Air Force and MoD civilians completed a questionnaire containing the HSE tool and supplementary measures of work-life balance, engagement, deployment, leave taken and hours of work. Six measures of adverse reaction to the stressors were also reported: perceptions of job stress, job stress and health, psychological strain, fatigue after work, work ability and quality of working life. The stressor scales, particularly the 'demands' and 'relationships' scales, were associated with adverse outcomes as was the work-life balance scale. The HSE tool had some validity when used with MoD personnel, but its content was too narrow. The content validity of the tool can be improved for use in a military context with the addition of a 'work-life balance' scale'. PRACTITIONER SUMMARY: The HSE stress tool was tested with a mixed sample of MoD employees. The 'Demands and "Relationships" scales were associated with adverse outcomes. An additional Work Life Balance' scale improved the content validity, demonstrating the importance of assessing the psychometric qualities of scales when used within particular contexts to ensure validity. PMID- 26225886 TI - Erratum: Tumor Invasion Optimization by Mesenchymal-Amoeboid Heterogeneity. PMID- 26225887 TI - Tailoring Dielectric Properties and Energy Density of Ferroelectric Polymer Nanocomposites by High-k Nanowires. AB - High dielectric constant (k) polymer nanocomposites have shown great potential in dielectric and energy storage applications in the past few decades. The introduction of high-k nanomaterials into ferroelectric polymers has proven to be a promising strategy for the fabrication of high-k nanocomposites. One dimensional large-aspect-ratio nanowires exhibit superiority in enhancing k values and energy density of polymer nanocomposites in comparison to their spherical counterparts. However, the impact of their intrinsic properties on the dielectric properties of polymer nanocomposites has been seldom investigated. Herein, four kinds of nanowires (Na2Ti3O7, TiO2, BaTiO3, and SrTiO3) with different inherent characteristics are elaborately selected to fabricate high-k ferroelectric polymer nanocomposites. Dopamine functionalization facilitates the excellent dispersion of these nanowires in the ferroelectric polymer matrix because of the strong polymer/nanowire interfacial adhesion. A thorough comparative study on the dielectric properties and energy storage capability of the nanowires-based nanocomposites has been presented. The results reveal that, among the four types of nanowires, BaTiO3 NWs show the best potential in improving the energy storage capability of the proposed nanocomposites, resulting from the most signficant increase of k while retaining the rather low dielectric loss and leakage current. PMID- 26225889 TI - Clinician-Guided Personality Assessment. PMID- 26225888 TI - Drowning deaths among anglers: Are waders a contributing factor? AB - Recreational fishing has been a popular activity for Australians over at least the past two centuries. While the use of waders for recreational fishing is widely adopted by participants, there is considerable speculation as to whether waders are contributing to fishing-related drowning deaths. This study involved a comprehensive search of peer-reviewed and grey literature to identify relevant information and a pilot investigation in a swimming pool to understand the accuracy of the currently available information. Extensive searching indicated that there is no published peer-reviewed evidence on the contribution of waders to drowning deaths, although the grey literature and personal communication with fishers offer a range of opinions, some that aim to discredit the claim that waders contribute to drowning, and others that support it. Improved understanding of the actual effect of waders based on biomechanical buoyancy principles and a pilot study of submersion in controlled conditions contributes to enhanced safety of fishers who choose to wear waders, dispels current myths and informs future studies of fishers wearing waders. PMID- 26225890 TI - A stable bidentate protein binder achieved via DNA self-assembly driven ligand migration. AB - Herein we disclose the development of two complementary single stranded DNA-small molecule chimeras (DCs) that by themselves only bind weakly to a protein target (human serum albumin; HSA). However, upon self-assembly, the DC duplex facilitates a ligand migration reaction leading to a covalently fastened high affinity, bidentate, protein-binder that resides at the terminus of only one of the DC strands. Due to this specific localization, the bidentate projection remains intact-and thus the system continues to strongly bind HSA-even under conditions that denature and degrade the DNA scaffolds. PMID- 26225893 TI - Melanoma and a Headache. Diagnosis: Hypophysitis. PMID- 26225894 TI - Reductive Lithiation in the Absence of Aromatic Electron Carriers. A Steric Effect Manifested on the Surface of Lithium Metal Leads to a Difference in Relative Reactivity Depending on Whether the Aromatic Electron Carrier Is Present or Absent. AB - One of the most widely used methods of preparation of organolithium compounds is by the reductive lithiation of alkyl phenyl thioethers or, usually less conveniently, alkyl halides with either aromatic radical-anions of lithium or lithium metal in the presence of an aromatic electron-transfer catalyst. Here we present results showing that lithium dispersion can achieve reductive lithiation in the absence of the electron-transfer agent. This procedure is more efficient, and surprisingly, the order of reactivity of substrates is reversed depending on whether the electron-transfer agent is present or absent. For example, in the presence of a preformed radical-anion, tert-butyl phenyl sulfide cleaves significantly faster than methyl phenyl sulfide, whereas in the absence of the radical-anion, it is just the opposite. Density functional theory calculations reveal that the exothermicity of the cleavage of the C-S bond in alkyl phenyl thioethers on the lithium surface is dependent on the size of the alkyl group, the smaller the alkyl group the greater the exothermicity. The increased reactivity is attributed to the smaller steric repulsion between the alkyl group and the lithium surface. The methodology includes, but may not be limited to, the lithium dispersion reductive lithiation of phenyl thioethers, alkyl chlorides, acrolein diethyl acetal, and isochroman. PMID- 26225895 TI - Vaccines and Pregnancy. PMID- 26225896 TI - Control of X-ray Induced Electron and Nuclear Dynamics in Ammonia and Glycine Aqueous Solution via Hydrogen Bonding. AB - Recently, a new family of autoionization processes has been identified in aqueous phases. The processes are initiated by core-electron ionization of a solute molecule and involve proton transfer along the solute-solvent hydrogen bond. As a result, short-lived singly charged cations form with structures sharing a proton between solute and solvent molecules. These molecular transients decay by autoionization, which creates reactive dicationic species with the positive charges delocalized over the entire molecular entity. Here, we investigate the ultrafast electron and nuclear dynamics following the core ionization of hydrated ammonia and glycine. Both molecules serve as models for exploring the possible role of the nonlocal relaxation processes in the chemical reactivity at the interface between, for instance, a protein surface and aqueous solution. The nature of the postionization dynamical processes is revealed by high-accuracy Auger-electron spectroscopy measurements on liquid microjets in vacuum. The proton-transfer-mediated processes are identified by electron signals in the high energy tail of the Auger spectra with no analogue in the Auger spectra of the corresponding gas-phase molecule. This high-energy tail is suppressed for deuterated molecules. Such an isotope effect is found to be smaller for aqueous ammonia as compared to the hydrated H2O molecule, wherein hydrogen bonds are strong. An even weaker hydrogen bonding for the hydrated amino groups in glycine results in a negligibly small proton transfer. The dynamical processes and species formed upon the nitrogen-1s core-level ionization are interpreted using methods of quantum chemistry and molecular dynamics. With the assistance of such calculations, we discuss the conditions for the proton-transfer-mediated relaxation processes to occur. We also consider the solvent librational dynamics as an alternative intermolecular ultrafast relaxation pathway. In addition, we provide experimental evidence for the umbrella-type motion in aqueous ammonia upon core ionization. This intramolecular channel proceeds in parallel with intermolecular relaxation processes in the solution. PMID- 26225897 TI - Synthetic Study on Naphthospironone A: Construction of Benzobicyclo[3.2.1]octene Skeleton with Oxaspirocycle. AB - In connection with the total synthesis of naphthospironone A, a model study has revealed a promising approach to construct a benzobicyclo[3.2.1]octene skeleton possessing an oxaspirocycle by employing an intramolecular aldol cyclization. PMID- 26225898 TI - Molecular Modes and Dynamics of HCl and DCl Guests of Gas Clathrate Hydrates. AB - Recent years have yielded advances in the placement of unusual molecules as guests within clathrate hydrates (CHs) without severe distortion of the classic lattice structures. Reports describing systems for which observable but limited distortion does occur are available for methanol, ammonia, acetone, and small ether molecules. In these particular examples, the large-cage molecules often participate as non-classical guests H-bonded to the cage walls. Here, we expand the list of such components to include HCl/DCl and HBr as small-cage guests. Based on FTIR spectra of nanocrystalline CHs from two distinct preparative methods combined with critical insights derived from on-the-fly molecular dynamics and ab initio computational data, a coherent argument emerges that these strong acids serve as a source of molecular small-cage guests, ions, and orientational defects. Depending on the HCl/DCl content the ions, defects and molecular guests determine the CH structures, some of which form in sub-seconds via an all-vapor preparative method. PMID- 26225899 TI - Sleep Bruxism in Respiratory Medicine Practice. AB - Sleep bruxism (SB) consists of involuntary episodic and repetitive jaw muscle activity characterized by occasional tooth grinding or jaw clenching during sleep. Prevalence decreases from 20% to 14% in childhood to 8% to 3% in adulthood. Although the causes and mechanisms of idiopathic primary SB are unknown, putative candidates include psychologic risk factors (eg, anxiety, stress due to life events, hypervigilance) and sleep physiologic reactivity (eg, sleep arousals with autonomic activity, breathing events). Although certain neurotransmitters (serotonin, dopamine, noradrenalin, histamine) have been proposed to play an indirect role in SB, their exact contribution to rhythmic masticatory muscle activity (RMMA) (the electromyography marker of SB) genesis remains undetermined. No specific gene is associated with SB; familial environmental influence plays a significant role. To date, no single explanation can account for the SB mechanism. Secondary SB with sleep comorbidities that should be clinically assessed are insomnia, periodic limb movements during sleep, sleep-disordered breathing (eg, apnea-hypopnea), gastroesophageal reflux disease, and neurologic disorders (eg, sleep epilepsy, rapid eye movement behavior disorder). SB is currently quantified by scoring RMMA recordings in parallel with brain, respiratory, and heart activity recordings in a sleep laboratory or home setting. RMMA confirmation with audio-video recordings is recommended for better diagnostic accuracy in the presence of neurologic conditions. Management strategies (diagnostic tests, treatment) should be tailored to the patient's phenotype and comorbidities. In the presence of sleep-disordered breathing, a mandibular advancement appliance or CPAP treatment is preferred over single occlusal splint therapy on the upper jaw. PMID- 26225900 TI - An Umpolung Approach for the Chemoselective Arylation of Selenocysteine in Unprotected Peptides. AB - Herein we report an umpolung strategy for the bioconjugation of selenocysteine in unprotected peptides. This mild and operationally simple approach takes advantage of the electrophilic character of an oxidized selenocysteine (Se-S bond) to react with a nucleophilic arylboronic acid to provide the arylated selenocysteine within hours. This reaction is amenable to a wide range of boronic acids with different biorelevant functional groups and is unique to selenocysteine. Experimental evidence indicates that under oxidative conditions the arylated derivatives are more stable than the corresponding alkylated selenocysteine. PMID- 26225901 TI - Fast Response and High Sensitivity of ZnO Nanowires-Cobalt Phthalocyanine Heterojunction Based H2S Sensor. AB - The room temperature chemiresistive response of n-type ZnO nanowire (ZnO NWs) films modified with different thicknesses of p-type cobalt phthalocyanine (CoPc) has been studied. With increasing thickness of CoPc (>15 nm), heterojunction films exhibit a transition from n- to p-type conduction due to uniform coating of CoPc on ZnO. The heterojunction films prepared with a 25 nm thick CoPc layer exhibit the highest response (268% at 10 ppm of H2S) and the fastest response (26 s) among all samples. The X-ray photoelectron spectroscopy and work function measurements reveal that electron transfer takes place from ZnO to CoPc, resulting in formation of a p-n junction with a barrier height of 0.4 eV and a depletion layer width of ~8.9 nm. The detailed XPS analysis suggests that these heterojunction films with 25 nm thick CoPc exhibit the least content of chemisorbed oxygen, enabling the direct interaction of H2S with the CoPc molecule, and therefore exhibit the fastest response. The improved response is attributed to the high susceptibility of the p-n junctions to the H2S gas, which manipulates the depletion layer width and controls the charge transport. PMID- 26225902 TI - Pharmacological treatment for psychotic depression. AB - BACKGROUND: Evidence is limited regarding the most effective pharmacological treatment for psychotic depression: combination of an antidepressant plus an antipsychotic, monotherapy with an antidepressant or monotherapy with an antipsychotic. This is an update of a review first published in 2005 and last updated in 2009. OBJECTIVES: 1. To compare the clinical efficacy of pharmacological treatments for patients with an acute psychotic depression: antidepressant monotherapy, antipsychotic monotherapy and the combination of an antidepressant plus an antipsychotic, compared with each other and/or with placebo.2. To assess whether differences in response to treatment in the current episode are related to non-response to prior treatment. SEARCH METHODS: A search of the Cochrane Central Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register (CCDANCTR) was carried out (to 12 April 2013). These registers include reports of randomised controlled trials from the following bibliographic databases: EMBASE (1970-), MEDLINE (1950-) and PsycINFO (1960-). Reference lists of all studies and related reviews were screened and key authors contacted. SELECTION CRITERIA: All randomised controlled trials (RCTs) that included participants with acute major depression with psychotic features, as well as RCTs consisting of participants with acute major depression with or without psychotic features, that reported separately on the subgroup of participants with psychotic features. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias in the included studies, according to the criteria of the Cochrane Handbook for Systematic Reviews of Interventions. Data were entered into RevMan 5.1. We used intention-to-treat data. For dichotomous efficacy outcomes, the risk ratio (RR) with 95% confidence intervals (CIs) was calculated. For continuously distributed outcomes, it was not possible to extract data from the RCTs. Regarding the primary outcome of harm, only overall dropout rates were available for all studies. MAIN RESULTS: The search identified 3659 abstracts, but only 12 RCTs with a total of 929 participants could be included in the review. Because of clinical heterogeneity, few meta-analyses were possible. The main outcome was reduction of severity (response) of depression, not of psychosis.We found no evidence for the efficacy of monotherapy with an antidepressant or an antipsychotic.However, evidence suggests that the combination of an antidepressant plus an antipsychotic is more effective than antidepressant monotherapy (three RCTs; RR 1.49, 95% CI 1.12 to 1.98, P = 0.006), more effective than antipsychotic monotherapy (four RCTs; RR 1.83, 95% CI 1.40 to 2.38, P = 0.00001) and more effective than placebo (two identical RCTs; RR 1.86, 95% CI 1.23 to 2.82, P = 0.003).Risk of bias is considerable: there were differences between studies with regard to diagnosis, uncertainties around randomisation and allocation concealment, differences in treatment interventions (pharmacological differences between the various antidepressants and antipsychotics) and different outcome criteria. AUTHORS' CONCLUSIONS: Psychotic depression is heavily understudied, limiting confidence in the conclusions drawn. Some evidence indicates that combination therapy with an antidepressant plus an antipsychotic is more effective than either treatment alone or placebo. Evidence is limited for treatment with an antidepressant alone or with an antipsychotic alone. PMID- 26225903 TI - Activation of kappa Opioid Receptors in Cutaneous Nerve Endings by Conorphin-1, a Novel Subtype-Selective Conopeptide, Does Not Mediate Peripheral Analgesia. AB - Selective activation of peripheral kappa opioid receptors (KORs) may overcome the dose-limiting adverse effects of conventional opioid analgesics. We recently developed a vicinal disulfide-stabilized class of peptides with subnanomolar potency at the KOR. The aim of this study was to assess the analgesic effects of one of these peptides, named conorphin-1, in comparison with the prototypical KOR selective small molecule agonist U-50488, in several rodent pain models. Surprisingly, neither conorphin-1 nor U-50488 were analgesic when delivered peripherally by intraplantar injection at local concentrations expected to fully activate the KOR at cutaneous nerve endings. While U-50488 was analgesic when delivered at high local concentrations, this effect could not be reversed by coadministration with the selective KOR antagonist ML190 or the nonselective opioid antagonist naloxone. Instead, U-50488 likely mediated its peripheral analgesic effect through nonselective inhibition of voltage-gated sodium channels, including peripheral sensory neuron isoforms NaV1.8 and NaV1.7. Our study suggests that targeting the KOR in peripheral sensory nerve endings innervating the skin is not an alternative analgesic approach. PMID- 26225904 TI - Oral histories: a simple method of assigning chronological age to isotopic values from human dentine collagen. AB - BACKGROUND: Stable isotope ratios of carbon (delta(13)C) and nitrogen (delta(15)N) in bone and dentine collagen have been used for over 30 years to estimate palaeodiet, subsistence strategy, breastfeeding duration and migration within burial populations. Recent developments in dentine microsampling allow improved temporal resolution for dietary patterns. AIM: A simple method is proposed which could be applied to human teeth to estimate chronological age represented by dentine microsamples in the direction of tooth growth, allowing comparison of dietary patterns between individuals and populations. The method is tested using profiles from permanent and deciduous teeth of two individuals. SUBJECTS AND METHODS: Using a diagrammatic representation of dentine development by approximate age for each human tooth (based on the Queen Mary University of London Atlas), this study estimated the age represented by each dentine section. Two case studies are shown: comparison of M1 and M2 from a 19th century individual from London, England, and identification of an unknown tooth from an Iron Age female adult from Scotland. RESULTS AND CONCLUSIONS: The isotopic profiles demonstrate that variations in consecutively-forming teeth can be aligned using this method to extend the dietary history of an individual or identify an unknown tooth by matching the profiles. PMID- 26225905 TI - Dirchromones: Cytotoxic Organic Sulfur Compounds Isolated from Dirca palustris. AB - Eight novel organic sulfur compounds featuring an unprecedented structure among natural organosulfur molecules are reported. The identified compounds, named dirchromones (1-8), were isolated from a dichloromethane extract of the roots, bark, and wood of Dirca palustris, an endemic shrub of eastern North America. Their identification was based on thorough NMR, IR, and HRMS spectroscopic data interpretation. These compounds showed cytotoxic and mild Gram-positive antibacterial activities in vitro, while being inactive against Gram-negative Escherichia coli and the yeast Candida albicans. This is the first report of sulfur-containing compounds from a species of the Thymelaeaceae. PMID- 26225906 TI - alpha-Helical Domains Affecting the Oligomerization of Vipp1 and Its Interaction with Hsp70/DnaK in Chlamydomonas. AB - Vesicle-inducing protein in plastids 1 (Vipp1) forms >1 MDa ordered homo oligomeric complexes in chloroplasts and is involved in the biogenesis of photosynthetic machinery. The Hsp70 chaperone system has been shown to interact with Vipp1, influencing its higher-order structure. In this study, a series of deletion mutants in Chlamydomonas reinhardii Vipp1 (CrVipp1) is used to investigate the role of the alpha-helical domains (H1-H7) in mediating its structure and interaction with DnaK, an Hsp70 orthologue. Results from these analyses demonstrate that alpha-helical domains H1-H6 of CrVipp1 are required for its efficient accumulation in protease-resistant large complexes, termed superoligomers. Deletions of these alpha-helical domains, either individually or in combination, cause CrVipp1 to assemble into a heterogeneous mixture of smaller, protease-sensitive oligomers. Furthermore, domains H2 and H3 are required to form a stable structural core in mutant oligomers, whereas domains H1 and H4-H6 likely function downstream in assembly of the superoligomer. DnaK binds only weakly to any form of CrVipp1 that efficiently assembles into superoligomers. In contrast, the interaction with DnaK is much more robust with certain misfolded CrVipp1 oligomers in a process mediated by their H4 and H7 domains. DnaK also interacts with full-length CrVipp1 at an early stage of CrVipp1 biosynthesis, perhaps during initial steps in the oligomerization pathway. Taken together, these data suggest that not only alpha-helical domains but also the oligomeric states of CrVipp1 influence its interaction with DnaK. It is therefore plausible that the Hsp70/DnaK system may be involved in the assembly of Vipp1 superoligomers. PMID- 26225907 TI - Stabilization of 1T-MoS2 Sheets by Imidazolium Molecules in Self-Assembling Hetero-layered Nanocrystals. AB - We report a facile, room-temperature assembly of MoS2-based hetero-layered nanocrystals (NCs) containing embedded monolayers of imidazolium (Im), 1-butyl-3 methylimidazolium (BuMeIm), 2-phenylimidazolium, and 2-methylbenzimidazolium molecules. The NCs are readily formed in water solutions by self-organization of the negatively charged, chemically exfoliated 0.6 nm thick MoS2 sheets and corresponding cationic imidazole moieties. As evidenced by transmission electron microscopy, the obtained NCs are anisotropic in shape, with thickness varying in the range 5-20 nm and lateral dimensions of hundreds of nanometers. The NCs exhibit almost turbostratic stacking of the MoS2 sheets, though the local order is preserved in the orientation of the imidazolium molecules with respect to the sulfide sheets. The atomic structure of NCs with BuMeIm molecules was solved from powder X-ray diffraction data assisted by density functional theory calculations. The performed studies evidenced that the MoS2 sheets of the NCs are of the nonconventional 1T-MoS2 (metallically conducting) structure. The sheets' puckered outer surface is formed by the S atoms and the positioning of the BuMeIm molecules follows the sheet nanorelief. According to thermal analysis data, the presence of the BuMeIm cations significantly increases the stability of the 1T MoS2 modification and raises the temperature for its transition to the conventional 2H-MoS2 (semiconductive) counterpart by ~70 degrees C as compared to pure 1T-MoS2 (~100 degrees C). The stabilizing interaction energy between inorganic and organic layers was estimated as 21.7 kcal/mol from the calculated electron density distribution. The results suggest a potential for the design of few-layer electronic devices exploiting the charge transport properties of monolayer thin MoS2. PMID- 26225908 TI - First-principles evaluation of multi-valent cation insertion into orthorhombic V2O5. AB - A systematic first-principles evaluation of the insertion behavior of multi valent cations in orthorhombic V2O5 is performed. Layer spacing, voltage, phase stability, and ion mobility are computed for Li(+), Mg(2+), Zn(2+), Ca(2+), and Al(3+) intercalation in the alpha and delta polymorphs. PMID- 26225909 TI - Beta Hairpin Peptide Hydrogels as an Injectable Solid Vehicle for Neurotrophic Growth Factor Delivery. AB - There is intense interest in developing novel methods for the sustained delivery of low levels of clinical therapeutics. MAX8 is a peptide-based beta-hairpin hydrogel that has unique shear thinning properties that allow for immediate rehealing after the removal of shear forces, making MAX8 an excellent candidate for injectable drug delivery at a localized injury site. The current studies examined the feasibility of using MAX8 as a delivery system for nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), two neurotrophic growth factors currently used in experimental treatments of spinal cord injuries. Experiments determined that encapsulation of NGF and BDNF within MAX8 did not negatively impact gel formation or rehealing and that shear thinning did not result in immediate growth factor release. ELISA, microscopy, rheology, and Western blotting experiments collectively demonstrate the functional capabilities of the therapeutic-loaded hydrogels to (i) maintain a protective environment against in vitro degradation of encapsulated therapeutics for at least 28 days; and (ii) allow for sustained release of NGF and BDGF capable of initiating neurite-like extensions of PC12 cells, most likely due to NGF/BDGF signaling pathways. Importantly, while the 21 day release profiles could be tuned by adjusting the MAX8 hydrogel concentration, the initial shear thinning of the hydrogel (e.g., during injection) does not induce significant premature loss of the encapsulated therapeutic, most likely due to effective trapping of growth factors within structurally robust domains that are maintained during the application of shear forces. Together, our data suggests that MAX8 allows for greater dosage control and sustained therapeutic growth factor delivery, potentially alleviating side effects and improving the efficacy of current therapies. PMID- 26225910 TI - Chiral probe development for circularly polarised luminescence: comparative study of structural factors determining the degree of induced CPL with four heptacoordinate europium(III) complexes. AB - A series of bright, europium(iii) complexes has been prepared based on an achiral heptadentate triazacyclononane ligand bearing two strongly absorbing, coordinated aralkynyl pyridyl moieties. The binding of chiral carboxylates, including alpha hydroxy acids such as lactate and mandelate, has been monitored by emission spectroscopy and is signalled by the switching on of strong circularly polarised emission. In each case, an R-chiral carboxylate gave rise to emission typical of a Delta complex, most clearly shown in the form of the DeltaJ = 4 transition manifold around 700 nm. Variations in the sign and magnitude of the CPL allow the enantiomeric purity and absolute configuration of the acid to be assessed in a sample. Analysis of the relative energies of the parent aqua complexes and their stereoisomeric adducts has been aided by lifetime measurements and density functional theory calculations. PMID- 26225911 TI - Fabrication and characterization of layered chitosan/silk fibroin/nano hydroxyapatite scaffolds with designed composition and mechanical properties. AB - Chitosan/nano-hydroxyapatite (HA) composites were first prepared and then used together with chitosan and silk fibroin (SF) to produce a type of four-layer porous scaffold that is potentially applicable for articular cartilage repair. The bottom layer of the scaffold was built with the chitosan/HA composite and the other three layers of the scaffold were fabricated using chitosan/SF composites in which the content of the chitosan and SF was altered in a mutually reversed trend. The so-produced chitosan/SF/HA scaffolds were further crosslinked using tripolyphosphate to achieve enhanced mechanical properties. Interconnected porous microstructures throughout the scaffolds were constructed using a temperature gradient processing technique, and the resultant scaffolds were endowed with graded pore-sizes and porosities as well as porous interface zones between contiguous layers without visual clefts. The compressive modulus and stress at 10% strain of the scaffolds in wet state showed a gradient-changed trend which partially mimics the compressive mechanical properties of an articular cartilage matrix. Cell culture on some chitosan/SF/HA scaffolds for a period of time of up to 14 d showed that the scaffolds were able to well support the growth and infiltration of cells, suggesting that the presently developed chitosan/SF/HA scaffolds have promising potential for articular cartilage repair. PMID- 26225913 TI - Nuclear quantum fluctuations in ice I(h). AB - We discuss the role of nuclear quantum fluctuations in ice Ih, focusing on the hydrogen-bond (HB) structure and the molecular dipole-moment distribution. For this purpose we carry out DFT-based first-principles molecular dynamics and path integral molecular dynamics simulations at T = 100 K. We analyze the HB structure in terms of a set of parameters previously employed to characterize molecular structures in the liquid phase and compute the molecular dipole moments using the maximally-localized Wannier functions. The results show that the protons experience very large digressions driven by quantum fluctuations, accompanied by major rearrangements in the electronic density. As a result of these protonic quantum fluctuations the molecular dipole-moment distribution is substantially broadened as well as shifted to a larger mean value when compared to the results obtained when such fluctuations are neglected. In terms of dielectric constants, the reconciliation between the greater mean dipole moment and experimental indications that the dielectric constant of H2O ice is lower than that of D2O ice would indicate that the topology of the HB network is sensitive to protonic quantum fluctuations. PMID- 26225912 TI - Statistical reconstruction for cone-beam CT with a post-artifact-correction noise model: application to high-quality head imaging. AB - Non-contrast CT reliably detects fresh blood in the brain and is the current front-line imaging modality for intracranial hemorrhage such as that occurring in acute traumatic brain injury (contrast ~40-80 HU, size > 1 mm). We are developing flat-panel detector (FPD) cone-beam CT (CBCT) to facilitate such diagnosis in a low-cost, mobile platform suitable for point-of-care deployment. Such a system may offer benefits in the ICU, urgent care/concussion clinic, ambulance, and sports and military theatres. However, current FPD-CBCT systems face significant challenges that confound low-contrast, soft-tissue imaging. Artifact correction can overcome major sources of bias in FPD-CBCT but imparts noise amplification in filtered backprojection (FBP). Model-based reconstruction improves soft-tissue image quality compared to FBP by leveraging a high-fidelity forward model and image regularization. In this work, we develop a novel penalized weighted least-squares (PWLS) image reconstruction method with a noise model that includes accurate modeling of the noise characteristics associated with the two dominant artifact corrections (scatter and beam-hardening) in CBCT and utilizes modified weights to compensate for noise amplification imparted by each correction. Experiments included real data acquired on a FPD-CBCT test-bench and an anthropomorphic head phantom emulating intra-parenchymal hemorrhage. The proposed PWLS method demonstrated superior noise-resolution tradeoffs in comparison to FBP and PWLS with conventional weights (viz. at matched 0.50 mm spatial resolution, CNR = 11.9 compared to CNR = 5.6 and CNR = 9.9, respectively) and substantially reduced image noise especially in challenging regions such as skull base. The results support the hypothesis that with high-fidelity artifact correction and statistical reconstruction using an accurate post-artifact correction noise model, FPD-CBCT can achieve image quality allowing reliable detection of intracranial hemorrhage. PMID- 26225914 TI - Effects of arginine on multimodal anion exchange chromatography. AB - The effects of arginine on binding and elution properties of a multimodal anion exchanger, Capto adhere, were examined using bovine serum albumin (BSA) and a monoclonal antibody against interleukin-8 (mAb-IL8). Negatively charged BSA was bound to the positively charged Capto adhere and was readily eluted from the column with a stepwise or gradient elution using 1M NaCl at pH 7.0. For heat treated BSA, small oligomers and remaining monomers were also eluted using a NaCl gradient, whereas larger oligomers required arginine for effective elution. The positively charged mAb-IL8 was bound to Capto adhere at pH 7.0. Arginine was also more effective for elution of the bound mAb-IL8 than was NaCl. The results imply that arginine interacts with the positively charged Capto adhere. The mechanism underlying the interactions of arginine with Capto adhere was examined by calculating the binding free energy between an arginine molecule and a Capto adhere ligand in water through molecular dynamics simulations. The overall affinity of arginine for Capto adhere is attributed to the hydrophobic and pi-pi interactions between an arginine side chain and the aromatic moiety of the ligand as well as hydrogen bonding between arginine and the ligand hydroxyl group, which may account for the characteristics of protein elution using arginine. PMID- 26225915 TI - Deficits in joint action explain why socially anxious individuals are less well liked. AB - BACKGROUND AND OBJECTIVES: Socially anxious individuals elicit less positive reactions from interlocutors than non-anxious individuals, but evidence for a distinctive social anxiety linked behaviour deficit to explain this finding has been sparse. We investigated whether socially anxious individuals engage less in joint action--a process which promotes rapport and usually arises spontaneously between conversation partners when they actively attend to the conversation. METHODS: In Study 1, participants with high fear of negative evaluation, and low fear of negative evaluation conversed with a peer. Study 2 simulated the cognitive impact of anxiety-linked threat focus in non-anxious participants via a partial distraction task and measured the social consequences. RESULTS: In Study 1, listeners with high fear of negative evaluation made fewer collaborative contributions to a partner's anecdote (an index of joint action). In Study 2, non anxious distracted listeners showed the same behavioural pattern (fewer collaborative responses) and were less well-liked by their conversation partners, compared to non-distracted listeners. LIMITATIONS: We coded for only one marker of joint action. Future research should identify further indices of connectedness between partners. In addition, both studies were conducted with small groups of university students, and future research should be conducted on larger samples selected on the basis of social anxiety, not fear of negative evaluation alone. CONCLUSIONS: Together, these findings indicate that socially anxious individuals engage less in the shared task of conversation, and this behaviour attracts less positive responses from conversation partners. PMID- 26225916 TI - The ecological and physiological responses of the microbial community from a semiarid soil to hydrocarbon contamination and its bioremediation using compost amendment. AB - The linkage between phylogenetic and functional processes may provide profound insights into the effects of hydrocarbon contamination and biodegradation processes in high-diversity environments. Here, the impacts of petroleum contamination and the bioremediation potential of compost amendment, as enhancer of the microbial activity in semiarid soils, were evaluated in a model experiment. The analysis of phospholipid fatty-acids (PLFAs) and metaproteomics allowed the study of biomass, phylogenetic and physiological responses of the microbial community in polluted semiarid soils. Petroleum pollution induced an increase of proteobacterial proteins during the contamination, while the relative abundance of Rhizobiales lowered in comparison to the non-contaminated soil. Despite only 0.55% of the metaproteome of the compost-treated soil was involved in biodegradation processes, the addition of compost promoted the removal of polycyclic aromatic hydrocarbons (PAHs) and alkanes up to 88% after 50 days. However, natural biodegradation of hydrocarbons was not significant in soils without compost. Compost-assisted bioremediation was mainly driven by Sphingomonadales and uncultured bacteria that showed an increased abundance of catabolic enzymes such as catechol 2,3-dioxygenases, cis-dihydrodiol dehydrogenase and 2-hydroxymuconic semialdehyde. For the first time, metaproteomics revealed the functional and phylogenetic relationships of petroleum contamination in soil and the microbial key players involved in the compost-assisted bioremediation. PMID- 26225918 TI - Automated systems for the de-identification of longitudinal clinical narratives: Overview of 2014 i2b2/UTHealth shared task Track 1. AB - The 2014 i2b2/UTHealth Natural Language Processing (NLP) shared task featured four tracks. The first of these was the de-identification track focused on identifying protected health information (PHI) in longitudinal clinical narratives. The longitudinal nature of clinical narratives calls particular attention to details of information that, while benign on their own in separate records, can lead to identification of patients in combination in longitudinal records. Accordingly, the 2014 de-identification track addressed a broader set of entities and PHI than covered by the Health Insurance Portability and Accountability Act - the focus of the de-identification shared task that was organized in 2006. Ten teams tackled the 2014 de-identification task and submitted 22 system outputs for evaluation. Each team was evaluated on their best performing system output. Three of the 10 systems achieved F1 scores over .90, and seven of the top 10 scored over .75. The most successful systems combined conditional random fields and hand-written rules. Our findings indicate that automated systems can be very effective for this task, but that de-identification is not yet a solved problem. PMID- 26225917 TI - Expression of Prostaglandin E2 Enzymes in the Synovium of Arthralgia Patients at Risk of Developing Rheumatoid Arthritis and in Early Arthritis Patients. AB - OBJECTIVE: Arthralgia may precede the development of synovial inflammation in autoantibody-positive individuals at risk of developing rheumatoid arthritis (RA). A major pathway involved in pain is the prostaglandin (PG) E2 pathway. We investigated this pathway in the synovium of individuals with RA-specific autoantibodies and in early arthritis patients. METHODS: Nineteen autoantibody positive individuals (IgM-rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies) with arthralgia (n=15) and/or a positive family history of RA (n=8), who had been prospectively followed for at least 2 years, were included. In addition, we included early arthritis patients (disease-modifying antirheumatic drug naive) who after 2 years follow up fulfilled classification criteria for RA (n=63), spondyloarthritis (SpA; n=14), or had unclassified arthritis (UA; n=27). In all subjects we assessed pain and performed synovial biopsy sampling by mini-arthroscopy at baseline. Tissue sections were examined by immunohistochemistry to detect and quantify PGE2 pathway enzymes expression levels (mPGES-1; COX-1 and -2; 15-PGDH). RESULTS: In both study groups synovial expression of PGE2 enzymes was not clearly related to pain sensation. Expression levels at baseline were not associated with the development of arthritis after follow up (6 out of 19 autoantibody-positive individuals). However, in early SpA patients the expression levels of mPGES-1 and COX-1 were significantly increased compared to RA and UA patients. CONCLUSION: Pain in autoantibody-positive individuals without synovial inflammation who are at risk of developing RA and in early arthritis patients may be regulated by pathways other than the PGE2 pathway or originate at sites other than the synovium. In contrast, in SpA, the PGE2 pathway may be inherently linked to the pathophysiology/etiology of the disease. PMID- 26225919 TI - The Drosophila Transcription Factors Tinman and Pannier Activate and Collaborate with Myocyte Enhancer Factor-2 to Promote Heart Cell Fate. AB - Expression of the MADS domain transcription factor Myocyte Enhancer Factor 2 (MEF2) is regulated by numerous and overlapping enhancers which tightly control its transcription in the mesoderm. To understand how Mef2 expression is controlled in the heart, we identified a late stage Mef2 cardiac enhancer that is active in all heart cells beginning at stage 14 of embryonic development. This enhancer is regulated by the NK-homeodomain transcription factor Tinman, and the GATA transcription factor Pannier through both direct and indirect interactions with the enhancer. Since Tinman, Pannier and MEF2 are evolutionarily conserved from Drosophila to vertebrates, and since their vertebrate homologs can convert mouse fibroblast cells to cardiomyocytes in different activator cocktails, we tested whether over-expression of these three factors in vivo could ectopically activate known cardiac marker genes. We found that mesodermal over-expression of Tinman and Pannier resulted in approximately 20% of embryos with ectopic Hand and Sulphonylurea receptor (Sur) expression. By adding MEF2 alongside Tinman and Pannier, a dramatic expansion in the expression of Hand and Sur was observed in almost all embryos analyzed. Two additional cardiac markers were also expanded in their expression. Our results demonstrate the ability to initiate ectopic cardiac fate in vivo by the combination of only three members of the conserved Drosophila cardiac transcription network, and provide an opportunity for this genetic model system to be used to dissect the mechanisms of cardiac specification. PMID- 26225920 TI - ACEA (a highly selective cannabinoid CB1 receptor agonist) stimulates hippocampal neurogenesis in mice treated with antiepileptic drugs. AB - Hippocampal neurogenesis plays a very important role in learning and memory functions. In a search for best neurological drugs that protect neuronal cells and stimulate neurogenesis with no side effects, cannabinoids proved to be a strong group of substances having many beneficial properties. The aim of this study was to evaluate the impact of ACEA (arachidonyl-2'-chloroethylamide--a highly selective cannabinoid CB1 receptor agonist) combined with a classical antiepileptic drug sodium valproate (VPA) on neural precursor cells' proliferation and differentiation in the mouse brain. All experiments were performed on adolescent CB57/BL male mice injected i.p. with VPA (10mg/kg), ACEA (10mg/kg) and PMSF (30 mg/kg) (phenylmethylsulfonyl fluoride--a substance protecting ACEA against degradation by the fatty-acid amidohydrolase) for 10 days. Next an acute response of proliferating neural precursor cells to ACEA and VPA administration was evaluated with Ki-67 staining (Time point 1). Next, in order to determine whether acute changes translated into long-term alterations in neurogenesis, proliferating cells were labeled with 5-bromo-2deoxyuridine (BrdU) followed by confocal microscopy used to determine the percentage of BrdU-labeled cells that showed mature cell phenotypes (Time point 2). Results indicate that ACEA with PMSF significantly increase the total number of Ki-67-positive cells when compared to the control group. Moreover, ACEA in combination with VPA increased the number of Ki-67-positive cells, whereas VPA administered alone had no impact on proliferating cells' population. Accordingly, neurogenesis study results indicate that the combination of ACEA+PMSF administered alone and in combination with VPA considerably increases the total number of BrdU-positive cells in comparison to the control group while ACEA+PMSF alone and in combination with VPA increased total numbers of BrdU-positive cells, newly born neurons and astrocytes as compared to VPA group but not to the control group. VPA administered alone decreased the number of newly born neurons with no significant impact on neurogenesis. These data provide substantial evidence that VPA administered chronically slightly decreases the proliferation and differentiation of newly born cells while combination of VPA+ACEA significantly increases the level of newborn neurons in the dentate subgranular zone. PMID- 26225921 TI - Adolescent exposure to methylphenidate impairs serial pattern learning in the serial multiple choice (SMC) task in adult rats. AB - The long-term effects of adolescent exposure to methylphenidate (MPD) on adult cognitive capacity are largely unknown. We utilized a serial multiple choice (SMC) task, which is a sequential learning paradigm for studying complex learning, to observe the effects of methylphenidate exposure during adolescence on later serial pattern acquisition during adulthood. Following 20.0mg/kg/day MPD or saline exposure for 5 days/week for 5 weeks during adolescence, male rats were trained to produce a highly structured serial response pattern in an octagonal operant chamber for water reinforcement as adults. During a transfer phase, a violation to the previously-learned pattern structure was introduced as the last element of the sequential pattern. Results indicated that while rats in both groups were able to learn the training and transfer patterns, adolescent exposure to MPD impaired learning for some aspects of pattern learning in the training phase which are learned using discrimination learning or serial position learning. In contrast adolescent exposure to MPD had no effect on other aspects of pattern learning which have been shown to tap into rule learning mechanisms. Additionally, adolescent MPD exposure impaired learning for the violation element in the transfer phase. This indicates a deficit in multi-item learning previously shown to be responsible for violation element learning. Thus, these results clearly show that adolescent MPD produced multiple cognitive impairments in male rats that persisted into adulthood long after MPD exposure ended. PMID- 26225922 TI - Protected Areas' Impacts on Brazilian Amazon Deforestation: Examining Conservation-Development Interactions to Inform Planning. AB - Protected areas are the leading forest conservation policy for species and ecoservices goals and they may feature in climate policy if countries with tropical forest rely on familiar tools. For Brazil's Legal Amazon, we estimate the average impact of protection upon deforestation and show how protected areas' forest impacts vary significantly with development pressure. We use matching, i.e., comparisons that are apples-to-apples in observed land characteristics, to address the fact that protected areas (PAs) tend to be located on lands facing less pressure. Correcting for that location bias lowers our estimates of PAs' forest impacts by roughly half. Further, it reveals significant variation in PA impacts along development-related dimensions: for example, the PAs that are closer to roads and the PAs closer to cities have higher impact. Planners have multiple conservation and development goals, and are constrained by cost, yet still conservation planning should reflect what our results imply about future impacts of PAs. PMID- 26225923 TI - Antitumor effect and underlying mechanism of RGD-modified adenovirus mediated IL 24 expression on myeloid leukemia cells. AB - Interleukin-24 (IL-24), a member of the IL-10 cytokine gene family, causes growth suppression and apoptosis in various solid tumor cells. However, the effects of IL-24 on hematopoietic malignant cells have not been extensively explored. In this report, we constructed an RGD-engineered recombinant adenoviral vector, Ad.RGD-IL-24, and assessed its effects on human myeloid leukemia cells. Ad vector mediates gene transfer into leukemia cells with high efficiency. Ectopic over expression of IL-24 has significant growth inhibition and differentiation inducement effects on these cells. Treatment with Ad.RGD-IL-24 could potentially induce leukemia cells' cell-cycle arrest. In addition, IL-24 expression could significantly induce apoptosis of the THP-1 cells. Ad.RGD-IL-24 had a potent effect on the up-regulation of the expression of GRP78/Bip, GADD34 and Bax, down regulation of the expression of Bcl-2 and Mcl-1, and induced the activation of Caspase-3, which may be responsible for its apoptosis-inducing effect on THP-1 cells. Furthermore, IL-24 expression could retard transplanted leukemia cell tumor growth in vivo in athymic nude mice. These findings showed the marked antitumor activity of IL-24 and provided potential perspectives in designing therapeutic or vaccine strategies in immuno-gene therapy of myeloid leukemia. PMID- 26225924 TI - Amelioration of cyclosporine induced nephrotoxicity by dipeptidyl peptidase inhibitor vildagliptin. AB - Cyclosporine A (CsA) is an immunosuppressive drug used in organ transplantation and autoimmune diseases but its clinical uses may be limited due to its dose related nephrotoxicity. This study was carried out to evaluate the possible protective effects of vildagliptin (VLD) against CsA-induced nephrotoxicity in rats. Animals were divided into four groups treated as follows: control group (CsA & VLD vehicle); VLD group (10mg/kg/day, orally); CsA group (20mg/kg in sunflower oil, S.C.); and CsA-VLD group (CsA &VLD). Induced nephrotoxicity was evidenced by a significant elevation of serum creatinine, blood urea nitrogen (BUN), lactate dehydrogenase (LDH) and urinary micro total proteins (MTP), while serum albumin and urinary creatinine clearance were significantly decreased compared to the control group. Moreover, renal dysfunction was further confirmed by a significant increase in renal lipid peroxide that was measured as renal malondialdehyde (MDA). Renal reduced glutathione (GSH) and superoxide dismutase (SOD) were significantly decreased. Nephrotoxicity was further confirmed by renal tissue histopathology. Also, a high protein expression of Bax with decreased Bcl 2 was revealed in the renal tissue of the CsA treated group. Administration of VLD significantly ameliorated the nephrotoxic effects of CsA suggesting antioxidant, anti-inflammatory and anti-apoptotic benefits of VLD in CsA-induced nephrotoxicity. PMID- 26225925 TI - Resveratrol attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation. AB - Resveratrol is a natural polyphenol enriched in Polygonum cuspidatum and has been found to afford neuroprotective effects against neuroinflammation in the brain. Activated microglia can secrete various pro-inflammatory cytokines and neurotoxic mediators, which may contribute to hypoxic brain injuries. The aim of this study is to investigate the potential role of resveratrol in attenuating hypoxia induced neurotoxicity via its anti-inflammatory actions through in vitro models of the BV-2 microglial cell line and primary microglia. We found that resveratrol significantly inhibited hypoxia-induced microglial activation and reduced subsequent release of pro-inflammatory factors. In addition, resveratrol inhibited the hypoxia-induced degradation of IkappaB-alpha and phosphorylation of p65 NF-kappaB protein. Hypoxia-induced ERK1/2 and JNK phosphorylation was also strongly inhibited by resveratrol, whereas resveratrol had no effect on hypoxia stimulated p38 MAPK phosphorylation. Importantly, treating primary cortical neurons with conditioned medium (CM) from hypoxia-stimulated microglia induced neuronal apoptosis, which was reversed by CM co-treated with resveratrol. Taken together, resveratrol exerts neuroprotection against hypoxia-induced neurotoxicity through its anti-inflammatory effects in microglia. These effects were mediated, at least in part, by suppressing the activation of NF-KB, ERK and JNK MAPK signaling pathways. PMID- 26225926 TI - Effect and mechanism of evodiamine against ethanol-induced gastric ulcer in mice by suppressing Rho/NF-kB pathway. AB - Evodiamine (EVD), a major alkaloid compound extracted from the dry unripened fruit Evodia fructus (Evodia rutaecarpa Benth., Rutaceae), has various pharmacological effects. The purpose of the present study was to investigate the possible anti-ulcerogenic potential of EVD and explore the underlying mechanism against ethanol-induced gastric ulcer in mice. Administration of EVD at the doses of 20, 40mg/kg body weight prior to the ethanol ingestion could effectively protect the stomach from ulceration. The gastric lesion was significantly ameliorated in the EVD group compared with that in the model group. Pre-treatment with EVD prevented the oxidative damage and decreased the levels of prostaglandin E2 (PGE2) content, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF alpha). In addition, EVD pretreatment markedly increased the serum levels of glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT), decreased malonaldehyde (MDA) content in serum and activity of myeloperoxidase (MPO) in stomach tissues compared with those in the model group. In the mechanistic study, significant elevation of Rho, Rho-kinase 1 (ROCK1), ROCK2, cytosolic and nucleic NF-kappaBp65 expressions were observed in the gastric mucosa group, whereas EVD effectively suppressed the protein expressions of Rho, Rho-kinase 1 (ROCK1), ROCK2, cytosolic and nucleic NF-kappaBp65 in mice. Moreover, EVD showed protective activity on ethanol-induced GES-1 cells, while the therapeutic effects were not due to its cytotoxity. Taken together, these results strongly indicated that EVD exerted a gastro-protective effect against gastric ulceration. The underlying mechanism might be associated with the improvement of antioxidant and anti-inflammatory status through Rho/NF-kappaB pathway. PMID- 26225927 TI - Antinociceptive effect of intrathecal amiloride on neuropathic pain in rats. AB - The aim of this study was to investigate the antinociception of intrathecal amiloride and examine its effect on the neuropathic pain-induced activation of c Fos and p-p38 MAPK in the rat spinal dorsal horn (SDH). Sprague-Dawley rats were chronically implanted with intrathecal catheters, and the ability of intrathecal amiloride to alleviate nociceptive behaviours in rats with neuropathic pain was tested. Immunohistochemical techniques were utilized to detect the expression of c-Fos and p-p38 in SDH in the control and amiloride (100MUg) groups. Intrathecal amiloride produced dose- and time-dependent antinociception in rats. Additionally, immunohistochemical experiments showed that the expression of c-Fos and p-p38 dramatically decreased in the superficial laminae of the ipsilateral SDH in the 100-MUg amiloride group (P<0.01), whereas, there was no statistical significance on the contralateral side, compared with the control group. Intrathecally administered amiloride develops dose- and time-dependent antinociceptive action in rats with neuropathic pain. It most likely reduces spinal neurons and microglia activation via inhibiting c-Fos and p-p38 MAPK in the SDH of rats. PMID- 26225928 TI - Early expression of the high molecular weight neurofilament subunit attenuates axonal neurite outgrowth. AB - Phospho-dependent interactions of the C-terminal region of the high molecular weight NF subunit (NF-H) with each other and with other cytoskeletal elements stabilize the axonal cytoskeleton and contribute to an increase in axonal caliber. The same kinase cascades that mediate axonal pathfinding via growth cone dynamics are those that foster NF-mediated axonal stabilization, yet there is a developmental delay in the accumulation of NF C-terminal phosphorylation. Moreover, the phospho-mediated C-terminal NF-H interactions that stabilize the axonal cytoskeleton also inhibit axonal elongation. We hypothesized that a delay in expression and/or accumulation of NF-H within developing axons is essential to allow axonal elongation and pathfinding. We tested this hypothesis in differentiating NB2a/d1 cells. The first 3 days of differentiation of NB2a/d1 cells is normally accompanied by rapid elongation of axonal neurites. This period is followed by the accumulation of C-terminally phosphorylated NF-H, cessation of axonal elongation and an increase in axonal caliber. Herein, overexpression of GFP-tagged NF-H simultaneously with induction of differentiation fostered accumulation of C-terminally phosphorylated NF-H within developing axonal neurites within 48hr, which was accompanied by retardation of axonal elongation and a hastened increase in caliber. These effects were prevented by treatment with inhibitors of kinases that mediate the association of NFs with other cytoskeletal elements. Overexpression of GFP-NF-H lacking the C-terminal 187 amino acids (which mediate NF-NF interactions) did not retard elongation nor increase caliber. These findings support the hypothesis that a developmental delay in NF-H C-terminal phosphorylation is essential to allow appropriate axonal elongation prior to stabilization. PMID- 26225929 TI - Origins of movements following stunning and during bleeding in cattle. AB - At slaughter, after stunning, the absence of certain physical signs such as eye movements/reflexes or rhythmic breathing helps determine whether the loss of consciousness was actually achieved. Cattle frequently show movements of neck and/or legs during the post-stun period. We evaluated 1) the origins of these movements in stunned unconscious cattle and 2) relationships with presence of ocular signs or breathing and shot characteristics. In stunned unconscious cattle, movements appear to be reflex-like, generated in the brain stem and/or spinal cord. First, in stunned unconscious cattle, movements could continue until 3 min after the start of bleeding. Second, severing the spinal cord in stunned unconscious cattle did not influence amount of movements. Third, in reaction to the skin cut and sticking, some unconscious animals showed a nociceptive withdrawal reflex. In bulls, following longer stun-stick delays, this response was weaker. Shot placement, post-stun movements and initial bleeding efficiency seemed related but the underlying mechanisms remain to be elucidated. PMID- 26225930 TI - The physical and biochemical changes in springbok (Antidorcas marsupialis) Longissimus thoracis et lumborum and Biceps femoris muscle during ageing. AB - This study aimed to determine the optimum ageing period for vacuum-packed springbok (Antidorcas marsupialis) Longissimus thoracis et lumborum (LTL) and Biceps femoris (BF) muscle stored at 5.4 +/- 1.0 degrees C. Portions of muscle from seven male and six female springbok were aged 1, 2, 5, 8, 14 or 21 days. The Warner Bratzler shear force declined most during the first five days post-mortem (PM), while purge and cooking losses increased significantly with ageing. Calpains I and II and calpastatin activity declined significantly up to five days PM, suggesting that they may be responsible for tenderization. Cathepsins B, BL and H activity increased significantly during ageing. The BF muscle had significantly higher pH, lower purge loss, higher cooking loss, higher WBSF and higher calpain and calpastatin activity than the LTL. No significant differences between the genders or muscles were found for the collagen content or collagen solubility. Springbok LTL and BF muscles should not be aged for longer than five days. PMID- 26225931 TI - Effect of vaccination against gonadotropin-releasing hormone (GnRH) in heavy male pigs for Italian typical dry-cured ham production. AB - The aim of this study was to evaluate immunocastration (vaccination against GnRH using Improvac(r) vaccine), as an alternative to surgical castration in heavy male pigs (average live weight 165 +/- 10 kg), used in the production of Italian typical dry-cured ham. A total of 60 Landrace * Large White male pigs were assigned to three groups of 20 units, including one group of surgically castrated (SC), and two of immunocastrated pigs, with two (IC2) or three (IC3) vaccine treatments, respectively. The groups were compared for green ham traits, processing weight losses, chemo-physical, and sensory properties of dry-cured hams. While IC3 were not different (P>0.05) from SC group, IC2 hams were found to differ (P<0.05) both from SC and IC3 groups in ham traits, final weight losses, texture and sensory boar taint in finished hams. Therefore, vaccination with three doses could be taken into account to control boar taint in the manufacturing of typical Italian dry-cured ham. PMID- 26225932 TI - Molecular control of stress transmission in the microtubule cytoskeleton. AB - In this article, we will summarize recent progress in understanding the mechanical origins of rigidity, strength, resiliency and stress transmission in the MT cytoskeleton using reconstituted networks formed from purified components. We focus on the role of network architecture, crosslinker compliance and dynamics, and molecular determinants of single filament elasticity, while highlighting open questions and future directions for this work. PMID- 26225933 TI - The effect of minimum impact education on visitor spatial behavior in parks and protected areas: An experimental investigation using GPS-based tracking. AB - The unmanaged impacts of recreation and tourism can often result in unacceptable changes in resource conditions and quality of the visitor experience. Minimum impact visitor education programs aim to reduce the impacts of recreation by altering visitor behaviors. Specifically, education seeks to reduce impacts resulting from lack of knowledge both about the consequences of one's actions and impact-minimizing best practices. In this study, three different on-site minimum impact education strategies ("treatments") and a control condition were applied on the trails and summit area of Sargent Mountain in Acadia National Park, Maine. Treatment conditions were designed to encourage visitors to stay on marked trails and minimize off-trail travel. Treatments included a message delivered via personal contact, and both an ecological-based message and an amenity-based message posted on signs located alongside the trail. A control condition of current trail markings and directional signs was also assessed. The efficacy of the messaging was evaluated through the use of Global Positioning System (GPS) tracking of visitor spatial behavior on/off trails. Spatial analysis of GPS tracks revealed statistically significant differences among treatments, with the personal contact treatment yielding significantly less dispersion of visitors on the mountain summit. Results also indicate that the signs deployed in the study were ineffective at limiting off-trail use beyond what can be accomplished with trail markers and directional signs. These findings suggest that personal contact by a uniformed ranger or volunteer may be the most effective means of message delivery for on-site minimum impact education. PMID- 26225934 TI - Changes in soil microbial community functionality and structure in a metal polluted site: The effect of digestate and fly ash applications. AB - Soil from Trhove Dusniky (Pribram, Czech Republic) is characterized by its high polymetallic accumulations in Pb-Ag-Zn due to mining and smelting activities. In previous studies performed in our research group, we have evaluated the potential use of amendments that would reduce the mobility and availability of metals such as Hg. We have observed that the application of digestate and fly ash in metal polluted soil has an impact in immobilizing these metals. However, until now we have lacked information about the effect of these amendments on soil microbial functionality and communities. The multi-contaminated soil was used to grow wheat in a pot experiment to evaluate the impact of digestate and fly ash application in soil microbial communities. Soil samples were collected after 30 and 60 days of treatment. The digestate application improved chemical attributes such as the content in total organic carbon (TOC), water soluble carbon (WSOC), total soluble carbon (C), total soluble nitrogen (N), and inorganic N forms (NO3(-)) as consequence of high content in C and N which is contained in digestate. Likewise, microbial activity was greatly enhanced by digestate application, as was physiological diversity. Bacterial and fungal communities were increased, and the microbial biomass was highly enhanced. These effects were evident after 30 and 60 days of treatment. In contrast, fly ash did not have a remarkable effect when compared to digestate, but soil microbial biomass was positively affected as a consequence of macro- and micro-nutrient sources applied by the addition of fly ash. This study indicates that digestate can be used successfully in the remediation of metal-contaminated soil. PMID- 26225935 TI - Pain Sensitivity in Adolescent Males with Attention-Deficit/Hyperactivity Disorder: Testing for Associations with Conduct Disorder and Callous and Unemotional Traits. AB - BACKGROUND: Reduced processing and experience of aversive emotional cues is a common component of theories on the development and persistence of aggression and antisocial behaviour. Yet physical pain, arguably the most basic aversive cue, has attracted comparatively little attention. METHODS: This study measured pain sensitivity and physiological response to painful stimuli (skin conductance level, SCL) in adolescent boys with Attention-Deficit/Hyperactivity Disorder (ADHD; n = 183), who are at high risk for antisocial behaviour. We compared boys with ADHD with and without a comorbid diagnosis of Conduct Disorder (CD) on pain sensitivity, and examined patterns of association between pain measures, on the one hand, and problem severity and callous and unemotional (CU) traits, on the other. RESULTS: Boys with comorbid CD exhibited a higher pain threshold and tolerance than boys with ADHD alone, but the groups did not differ in physiology at the time the pain threshold and tolerance were reported. Regression analyses showed that ADHD problem severity positively predicted pain sensitivity, whereas levels of CU traits negatively predicted pain sensitivity. CONCLUSIONS: These findings on physical pain processing extend evidence of impairments in aversive cue processing among those at risk of antisocial behaviour. The study highlights the importance of considering comorbidity and heterogeneity of disorders when developing interventions. The current findings could be used to identify subgroups within those with ADHD who might be less responsive to interventions that use corrective feedback to obtain behaviour change. PMID- 26225936 TI - The Effect of Statin Therapy on Coronary Plaque Composition Using Virtual Histology Intravascular Ultrasound: A Meta-Analysis. AB - OBJECTIVE: Previous studies have indicated that statin therapy may promote plaque regression. However, the impact of statin therapy on plaque composition has not been clearly elucidated. We performed a meta-analysis to investigate the effect of statin therapy on coronary plaque composition as assessed by virtual histology intravascular ultrasound (VH-IVUS). METHODS: Online databases were searched from inception to March 1, 2015. Studies providing VH-IVUS volumetric analyses of coronary plaque composition at baseline and follow-up in patients receiving statin therapy were included. Weighted mean difference (WMD) using a random effects model was used. RESULTS: Ten studies involving 682 patients were included. There was a substantial reduction in fibrous volume between baseline and follow-up (WMD: -2.37 mm3, 95% confidence interval (CI) -4.01 to -0.74 mm3, P=0.004), and a significant increase in dense calcium (DC) volume (WMD: 0.89 mm3, 95% CI 0.70 to 1.08 mm3, P<0.00001). No significant change was seen in fibro fatty and necrotic core (NC) volumes. In stratified analyses, the fibrous volume was decreased significantly (WMD: -3.39 mm3, 95% CI -6.56 to -0.21 mm3, P=0.04) and the absolute DC volume (WMD: 0.99 mm3, 95% CI 0.23 to 1.76 mm3, P=0.01) was increased in the subgroup with >=12 months follow-up, whereas no significant change was observed in the subgroup with < 12 months follow-up. Similarly, a substantial decrease in fibrous volume (WMD: -2.01 mm3, 95% CI -3.05 to -0.96 mm3, P< 0.0002) and an increase in DC volume (WMD: 0.90 mm3, 95% CI 0.70 to 1.10 mm3, P< 0.00001) were observed in the subgroup with high-intensive statin therapy, while the change in fibrous and DC volumes approached statistical significance (P=0.05 and P=0.05, respectively) in the subgroup with low-intensive statin therapy. CONCLUSIONS: Statin treatment, particularly of high-intensity and long-term duration, induced a marked modification in coronary plaque composition including a decrease in fibrous tissue and an increase in DC. PMID- 26225937 TI - Comparison of Apparent Diffusion Coefficient and Intravoxel Incoherent Motion for Differentiating among Glioblastoma, Metastasis, and Lymphoma Focusing on Diffusion-Related Parameter. AB - BACKGROUND AND PURPOSE: Brain tumor cellularity has been assessed by using apparent diffusion coefficient (ADC). However, the ADC value might be influenced by both perfusion and true molecular diffusion, and the perfusion effect on ADC can limit the reliability of ADC in the characterization of tumor cellularity, especially, in hypervascular brain tumors. In contrast, the IVIM technique estimates parameter values for diffusion and perfusion effects separately. The purpose of our study was to compare ADC and IVIM for differentiating among glioblastoma, metastatic tumor, and primary CNS lymphoma (PCNSL) focusing on diffusion-related parameter. MATERIALS AND METHODS: We retrospectively reviewed the data of 128 patients with pathologically confirmed glioblastoma (n = 55), metastasis (n = 31), and PCNSL (n = 42) prior to any treatment. Two neuroradiologists independently calculated the maximum IVIM-f (fmax) and minimum IVIM-D (Dmin) by using 16 different b-values with a bi-exponential fitting of diffusion signal decay, minimum ADC (ADCmin) by using 0 and 1000 b-values with a mono-exponential fitting and maximum normalized cerebral blood volume (nCBVmax). The differences in fmax, Dmin, nCBVmax, and ADCmin among the three tumor pathologies were determined by one-way ANOVA with multiple comparisons. The fmax and Dmin were correlated to the corresponding nCBV and ADC using partial correlation analysis, respectively. RESULTS: Using a mono-exponential fitting of diffusion signal decay, the mean ADCmin was significantly lower in PCNSL than in glioblastoma and metastasis. However, using a bi-exponential fitting, the mean Dmin did not significantly differ in the three groups. The mean fmax significantly increased in the glioblastomas (reader 1, 0.103; reader 2, 0.109) and the metastasis (reader 1, 0.105; reader 2, 0.107), compared to the primary CNS lymphomas (reader 1, 0.025; reader 2, 0.023) (P < .001 for each). The correlation between fmax and the corresponding nCBV was highest in glioblastoma group, and the correlation between Dmin and the corresponding ADC was highest in primary CNS lymphomas group. CONCLUSION: Unlike ADC value derived from a mono exponential fitting of diffusion signal, diffusion-related parametric value derived from a bi-exponential fitting with separation of perfusion effect doesn't differ among glioblastoma, metastasis, and PCNSL. PMID- 26225938 TI - Control of a Supernumerary Robotic Hand by Foot: An Experimental Study in Virtual Reality. AB - In the operational theater, the surgical team could highly benefit from a robotic supplementary hand under the surgeon's full control. The surgeon may so become more autonomous; this may reduce communication errors with the assistants and take over difficult tasks such as holding tools without tremor. In this paper, we therefore examine the possibility to control a third robotic hand with one foot's movements. Three experiments in virtual reality were designed to assess the feasibility of this control strategy, the learning curve of the subjects in different tasks and the coordination of foot movements with the two natural hands. Results show that the limbs are moved simultaneously, in parallel rather than serially. Participants' performance improved within a few minutes of practice without any specific difficulty to complete the tasks. Subjective assessment by the subjects indicated that controlling a third hand by foot has been easy and required only negligible physical and mental efforts. The sense of ownership was reported to improve through the experiments. The mental burden was not directly related to the level of motion required by a task, but depended on the type of activity and practice. The most difficult task was moving two hands and foot in opposite directions. These results suggest that a combination of practice and appropriate tasks can enhance the learning process for controlling a robotic hand by foot. PMID- 26225939 TI - Use of resting myocardial 18F-FDG imaging in the detection of unstable angina. AB - OBJECTIVE: Increased myocardial glucose metabolism occurs with the onset of myocardial ischemia and may persist even after the restoration of blood flow, termed as 'ischemic memory'. Previous studies have demonstrated that 18F fluorodeoxyglucose (18F-FDG) is a sensitive marker of myocardial ischemia and may have potential utility in diagnosing unstable angina (UA). This study aimed to explore the value of F-FDG PET/CT in diagnosing UA. PATIENTS AND METHODS: Thirty four patients (17 male patients; mean age, 59 +/- 6 years) with suspected UA were prospectively recruited. Resting myocardial F-FDG PET/CT imaging was performed 21 +/- 9 h (2-46 h) after the latest onset of angina pectoris. Resting or exercise myocardial perfusion imaging (MPI) and coronary angiography were performed. 'Focal' or 'focal on diffuse' myocardial F-FDG uptake was defined as abnormal, whereas other patterns of myocardial uptake, including 'focal' uptake on the basal segments, were considered as normal. The final diagnosis of UA was based on a comprehensive analysis of ECG, MPI, and coronary angiography. RESULTS: Of the 21 patients with a final diagnosis of UA, 18 had increased 18F-FDG uptake (sensitivity 85.7%), whereas, of the 13 patients without UA, only one had abnormal 18F-FDG uptake (specificity 92.3%). The sensitivity of resting 18F-FDG imaging was higher than that of resting MPI (85.7 vs. 52.4%, P=0.016). Moreover, six UA patients with only exercise-induced ischemia showed abnormal F-FDG uptake at rest. CONCLUSION: This pilot study demonstrated that resting 18F-FDG PET/CT imaging is an accurate and sensitive technique for the identification of UA. PMID- 26225940 TI - Bone marrow uptake of indolent non-Hodgkin lymphoma on PET/CT with histopathological correlation. AB - OBJECTIVE: To evaluate the diagnostic accuracy of PET/computed tomography (CT) in detecting marrow infiltration in indolent non-Hodgkin lymphoma (NHL) with histopathological correlation. METHODS: All treatment-naive newly diagnosed indolent NHL with staging PET/CT were retrospectively evaluated for marrow infiltration and categorized on the basis of the PET/CT uptake pattern: normal (PET/CT negative), focal/diffuse (PET/CT positive). Bone marrow biopsy (BMB) was considered the standard, except in focal PET/CT uptake, which was confirmed to be positive or negative by serial PET/CT. The BMB pattern was assessed as diffuse and nondiffuse and the degree of lymphoid infiltration was documented. RESULTS: Forty-six patients (mean age 59 +/- 15 years) were evaluated. In the PET/CT positive group of 22 cases (diffuse = 15, focal = 7), BMB was positive in 21 cases. In 80% of diffuse PET/CT uptake cases, a diffuse BMB infiltrative pattern was observed. However, in cases with focal PET/CT uptake, no predominant histological pattern was observed. No correlation was found between semiquantitative uptake and degree of lymphoid infiltration on BMB (r = 0.2, P = 0.434). In the PET/CT-negative group of 24 cases, 20 cases were BMB negative and four cases were positive. The overall diagnostic accuracy of PET/CT in determining marrow infiltration was 89% (sensitivity 84%, specificity 95%, positive predictive value 95% and negative predictive value 83%). CONCLUSION: PET/CT showed high specificity and positive predictive value with moderate accuracy in detecting marrow disease in indolent NHL. The metabolic uptake lacked a significant correlation with the degree of lymphoid infiltration, but a potential relationship may exist between the pattern of metabolic uptake and the BMB infiltrative pattern. PMID- 26225941 TI - Benefit of ECG-gated rest and stress N-13 cardiac PET imaging for quantification of LVEF in ischemic patients. AB - BACKGROUND: ECG-gated rest-stress cardiac PET can lead to simultaneous quantification of both left ventricular ejection fraction and flow impairment. In this study, our aim was to assess the benefit of rest and stress PET ejection fraction (EF) (EFp) in relation to single-photon emission computed tomography (SPECT) EF (EFs) and echocardiography EF (EFe). To this effect, the EFp was compared with EFs and EFe. Further, the relation between rest and stress EFp was also assessed. METHODS: ECG-gated N-13 ammonia rest and stress PET imaging was performed in 26 patients. EFp values were obtained using gated reconstruction of the data in Flowquant. In 13 patients, EFs and EFe values were obtained through chart review. Correlation, analysis of variance, and Bland-Altman analyses were performed. P values less than 0.05 were used for statistical significance. RESULTS: The rest and stress EFp values correlated significantly (r=0.80 and 0.71, respectively; P<0.05) with EFs values. There was moderate correlation with statistical significance (P<0.05) between the rest and stress EFp and EFe values (r=0.58 and 0.50, respectively). The mean rest and stress EFp values were not significantly different from mean EFs values. Also, the rest EFp and stress EFp values correlated well (r=0.81, P<0.05) and were not significantly different. Bland-Altman analysis showed no significant bias between the rest and stress EFp, and EFs, and EFe values. CONCLUSION: Rest and stress EFp values obtained through an ECG-gated PET scan can be used for clinical diagnosis in place of conventional methods like SPECT and echocardiography. PMID- 26225942 TI - Clinicopathologic features and prognostic factors of tall cell variant of papillary thyroid carcinoma: comparison with classic variant of papillary thyroid carcinoma. AB - OBJECTIVE: Tall cell variant (TCV), an aggressive form of papillary thyroid carcinoma (PTC), frequently presents with extrathyroidal disease and recurrence. The aim of this study was to evaluate the clinicopathologic features and outcomes of patients with TCV by comparing them with a larger group of patients with classic variant of papillary thyroid carcinoma (cPTC). PATIENTS AND METHODS: A total of 2500 patients with differentiated thyroid carcinoma were treated and monitored during a 23-year period (1992-2015). Of them, 2250 (90%) had PTC and 235 (9.5%) had follicular thyroid carcinoma. Of the 2250 patients, 862 (38.3%) and 70 (3.1%) had cPTC and TCV, respectively. Cases of TCV and cPTC of PTC were compared on the basis of risk factors. RESULTS: Patients with TCV were significantly older compared with cPTC patients (P<0.001). Tumor size was significantly bigger (P=0.01) and preablation thyroglobulin level was significantly higher (P<0.001) in TCV patients than in cPTC patients. The incidence of capsule invasion, extrathyroidal extension, and vascular invasion was significantly higher in TCV (P=0.003, <0.001, and 0.011, respectively). The incidence of initial lymph node metastasis was significantly higher in TCV (P<0.001). Patients with TCV were mostly at an advanced stage compared with patients with cPTC (P<0.001). Development of local or distant metastasis during the follow-up was significantly higher in TCV than in cPTC. Sex and multifocality were not statistically significant. CONCLUSION: TCV has a higher incidence of local or distant metastasis and mortality rate. Thus, it must be treated with the highest possible I ablation doses and followed up carefully. PMID- 26225943 TI - The Era of "Digital Colposcopy" Will Be Here Soon. PMID- 26225944 TI - Malignant Melanoma of Vulva and Vagina: A Histomorphological Review and Mutation Analysis--A Single-Center Study. AB - OBJECTIVES: The aim of this work was to determine molecular characteristics and specifically, the frequency of BRAF, C-KIT, and NRAS mutations in vulvar and vaginal melanomas. METHODS: A retrospective review of all cases of vulvar and vaginal melanoma between 2002 and 2013 was performed. We reviewed the clinical and histological characteristics of all cases and performed genotyping studies on cases that had tissue available for the study, using next-generation sequencing. RESULTS: We identified 33 vulvar and 11 vaginal melanomas in women with mean ages 58 and 61 years, respectively. Next-generation sequencing analysis on 20 cases (15 vulvar and 5 vaginal) identified a BRAF mutation in 7.6%, C-KIT mutation in 27.6%, NRAS mutation in 27.6%, and TP53 mutation in 7.6% of the vulvar cases. We detected only a single TP53 mutation in the vaginal cases. We did not identify any statistically significant relationship between the mutation status and patients' outcome, depth of invasion, ulceration, stage at presentation, or lymph node metastasis. CONCLUSIONS: BRAF mutations are infrequent, whereas C-KIT and NRAS mutations are seen with higher frequency in vulvar melanomas than melanomas of other sites. These mutations can be considered as potential therapeutic targets in patients harboring them. Further studies are necessary to increase our understanding of mutational events occurring in melanoma of the lower female genital tract and their relationship with clinical parameters/outcome. PMID- 26225945 TI - Cost-Effectiveness of High-Risk Human Papillomavirus Testing With Messenger RNA Versus DNA Under United States Guidelines for Cervical Cancer Screening. AB - OBJECTIVES: To compare the cost-effectiveness of high-risk human papillomavirus (hrHPV) testing using a hrHPV DNA and a hrHPV messenger RNA (mRNA) assay under current US cervical cancer screening guidelines. METHODS: We constructed a Markov model for stochastic cost-effectiveness analysis using published data. We compared screening efficiency using DNA and mRNA testing for the following: (1) cotesting with cytology in women 30 to 65 years, and (2) triage of women with mild cervical cytological abnormalities (atypical squamous cells of undetermined significance [ASC-US]) in the United States. Screening end point is histologically confirmed high-grade lesions (cervical intraepithelial neoplasia grade 2, 3, or invasive cancer). Sensitivity and specificity estimates of DNA and mRNA testing to detect cervical intraepithelial neoplasia grade 2, 3, or invasive cancer were obtained from 2 published trials: the US Clinical Evaluation of APTIMA mRNA (CLEAR) study for ASC-US triage and the French APTIMA Screening Evaluation (FASE) study for cotesting. Costs of DNA and mRNA testing were assumed identical. Costs of screening, diagnosis, and treatment of cervical neoplasia and cancer were from previously published estimates, adjusted to 2012 US dollars. Inputs were modeled as distributions for Monte Carlo probabilistic sensitivity analysis. Model outcomes were costs per life-year saved for each strategy, discounted at 3% annually. RESULTS: For both cotesting and ASC-US triage, mRNA testing cost less than DNA testing, whereas life expectancies were widely overlapping. There was a 100% probability that DNA testing was not cost-effective at $100,000/life-year saved threshold for ASC-US triage and a 55% probability that DNA testing was not cost-effective at the same threshold for cotesting. CONCLUSIONS: Based on the available evidence, mRNA testing for cotesting or ASC US triage is likely to be more efficient than DNA testing under current US cervical cancer screening guidelines. PMID- 26225946 TI - Metabolic Analysis of Various Date Palm Fruit (Phoenix dactylifera L.) Cultivars from Saudi Arabia to Assess Their Nutritional Quality. AB - Date palm is an important crop, especially in the hot-arid regions of the world. Date palm fruits have high nutritional and therapeutic value and possess significant antibacterial and antifungal properties. In this study, we performed bioactivity analyses and metabolic profiling of date fruits of 12 cultivars from Saudi Arabia to assess their nutritional value. Our results showed that the date extracts from different cultivars have different free radical scavenging and anti lipid peroxidation activities. Moreover, the cultivars showed significant differences in their chemical composition, e.g., the phenolic content (10.4-22.1 mg/100 g DW), amino acids (37-108 MUmol.g-1 FW) and minerals (237-969 mg/100 g DW). Principal component analysis (PCA) showed a clear separation of the cultivars into four different groups. The first group consisted of the Sokary, Nabtit Ali cultivars, the second group of Khlas Al Kharj, Khla Al Qassim, Mabroom, Khlas Al Ahsa, the third group of Khals Elshiokh, Nabot Saif, Khodry, and the fourth group consisted of Ajwa Al Madinah, Saffawy, Rashodia, cultivars. Hierarchical cluster analysis (HCA) revealed clustering of date cultivars into two groups. The first cluster consisted of the Sokary, Rashodia and Nabtit Ali cultivars, and the second cluster contained all the other tested cultivars. These results indicate that date fruits have high nutritive value, and different cultivars have different chemical composition. PMID- 26225947 TI - Diastereodivergent and Enantioselective [4+2] Annulations of gamma-Butenolides with Cyclic 1-Azadienes. AB - An asymmetric annulation reaction of gamma-butenolides and cyclic 1-azadienes containing a 1,2-benzoisothiazole-1,1-dioxide motif has been studied, proceeding in a tandem Michael addition-aza-Michael addition sequence. Endo-type cycloadducts bearing fused tetracyclic skeletons were isolated in fair yields and with high enantioselectivity (up to >99% ee) under the catalysis of modified cinchona alkaloid (DHQD)2PHAL. Besides, exo-type diastereomers could be produced using beta-isocupreidine (beta-ICD) as the catalyst, though with moderate enantioselectivity. PMID- 26225948 TI - Steroidal Saponins from the Roots and Rhizomes of Tupistra chinensis. AB - Two new furostanol saponins 1-2 and a new spirostanol saponin 3 were isolated together with two known furostanol saponins 4-5 from the roots and rhizomes of Tupistra chinensis. Their structures were characterized as 1beta,2beta,3beta,4beta,5beta,26-hexahydroxyfurost-20(22), 25(27)-dien-5,26-O beta-d-glucopyranoside (1), 1beta,2beta,3beta,4beta,5beta,6beta,7alpha,23xi,26 nona-hydroxyfurost- 20(22),25(27)-dien-26-O-beta-d-glucopyranoside (2), (20S,22R) spirost-25 (27)-en-1beta,3beta,5beta- trihydroxy-1-O-beta-d-xyloside (3), tupisteroide B (4) and 5beta-furost-Delta25(27)-en 1beta,2beta,3beta,4beta,5beta,7alpha, 22xi,26-octahydroxy-6-one-26-O-beta-d glucopyranoside (5), respectively, by extensive use of spectroscopic techniques and chemical evidence. Additionally, the in vitro cytotoxic activity of 1-4 was evaluated on human A549 and H1299 tumor cell lines, and compound 3 exhibited cytotoxicity against A549 cells (IC50 86.63 +/- 2.33 MUmol.L-1) and H1299 cells (IC50 88.21 +/- 1.34 MUmol.L-1). PMID- 26225950 TI - Glycoprotein Quality Control and Endoplasmic Reticulum Stress. AB - The endoplasmic reticulum (ER) supports many cellular processes and performs diverse functions, including protein synthesis, translocation across the membrane, integration into the membrane, folding, and posttranslational modifications including N-linked glycosylation; and regulation of Ca2+ homeostasis. In mammalian systems, the majority of proteins synthesized by the rough ER have N-linked glycans critical for protein maturation. The N-linked glycan is used as a quality control signal in the secretory protein pathway. A series of chaperones, folding enzymes, glucosidases, and carbohydrate transferases support glycoprotein synthesis and processing. Perturbation of ER associated functions such as disturbed ER glycoprotein quality control, protein glycosylation and protein folding results in activation of an ER stress coping response. Collectively this ER stress coping response is termed the unfolded protein response (UPR), and occurs through the activation of complex cytoplasmic and nuclear signaling pathways. Cellular and ER homeostasis depends on balanced activity of the ER protein folding, quality control, and degradation pathways; as well as management of the ER stress coping response. PMID- 26225949 TI - Oleanolic Acid, a Compound Present in Grapes and Olives, Protects against Genotoxicity in Human Mammary Epithelial Cells. AB - Oleanolic acid (AO) and maslinic acid (MA) are constituents of the skins of different fruits, including olives and white or red grapes. Although both compounds are known to have beneficial properties against different types of cancers, thus far, there are no studies about their chemopreventive effects in human breast cancer. Thus, we sought to elucidate whether both compounds possess chemopreventive activity. Two cell lines of human breast cancer cells and one noncancerous human mammary epithelial cells were used to determine the effects of OA and MA. The results showed that OA inhibited the proliferation and increased the oxidative stress of highly invasive cells. Additionally, OA decreased oxidative stress and oxidative damage to the DNA in human mammary epithelial cells. These results suggest that OA could act as a chemopreventive agent in human breast cancer and could inhibit the proliferation of highly invasive breast cancer cells. PMID- 26225951 TI - Inhibition of Oral Streptococci Growth Induced by the Complementary Action of Berberine Chloride and Antibacterial Compounds. AB - Synergistic interactions between natural bioactive compounds from medicinal plants and antibiotics may exhibit therapeutic benefits, acting against oral cariogenic and opportunistic pathogens. The aim of the presented work was to assess the antibacterial activity of berberine chloride (BECl) in light of the effect exerted by common antibiotics on selected reference strains of oral streptococci (OST), and to evaluate the magnitude of interactions. Three representative oral microorganisms were investigated: Streptococcus mutans ATCC 25175 (SM), S. sanguinis ATCC 10556 (SS), S. oralis ATCC 9811 (SO) and microdilution tests, along with disc diffusion assays were applied. Here, we report that growth (viability) of all oral streptococci was reduced by exposure to BECl and was dependent primarily on exposure/ incubation time. A minimum inhibitory concentrations (MIC) of BECl against OST ranged from 512 ug/mL (SS) to 1024 ug/mL (SM, SO). The most noticeable antibacterial effects were observed for S. sanguinis (MIC 512 ug/mL) and the most significant synergistic action was found for the combinations BECl-penicillin, BECl-clindamycin and BECl erythromycin. The S. oralis reflects the highest MBC value as assessed by the AlamarBlue assay (2058 ug/mL). The synergy between berberine and common antibiotics demonstrates its potential use as a novel antibacterial tool for opportunistic infections and also provides a rational basis for the use of berberine as an oral hygiene measure. PMID- 26225952 TI - Phenolic Compounds from the Roots of Rhodiola crenulata and Their Antioxidant and Inducing IFN-gamma Production Activities. AB - In the present study, two new phenolic compounds 1 and 11, a pair of lignan isomers 12 and 13 with their absolute configurations established for the first time, were isolated from the ethanol extract of the roots of Rhodiola crenulata, together with 13 known phenolic compounds, and their structures were elucidated via NMR, HRESIMS, UV, IR and CD analyses. All the isolated compounds were evaluated for their in vitro antioxidant activities using the 2,2-diphenyl-1 picryhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging assays. Ten of them exhibited significant antioxidant activities compared to ascorbic acid. Furthermore, the inducibilities of the isolated compounds to IFN-gamma production were also assessed. Compounds 1, 8, 9, 12, 13, 14 and 15 could moderately stimulate IFN-gamma expression. PMID- 26225953 TI - Discovery of 5-(5,5-Dimethylbutenolide-3-ethylidene)-2-amino-imidazolinone Derivatives as Fungicidal Agents. AB - The novel fungicidal agents 5-(5,5-dimethylbutenolide-3-ethylidene)-2-amino imidazolinone derivatives, were designed and synthesized in moderate to excellent yields in four steps by alphaa-hydroxyketone and diketene as raw materials and characterized by HR-ESI-MS and 1H-NMR. The preliminary bioassay showed that some of these compounds, such as 4a, 4e and 5g exhibit 94.9%, 92.8% and 81.4% inhibition rates against Sclerotinia scleotiorum at the concentration of 50 ug/mL, respectively. The EC50 values of compounds 4e and 4i were 4.14 and 3.27 uM against Alternaria Solani, and 5g had EC50 value of 3.23 uM against S. scleotiorum. Compounds 4d and 4g displayed 98.0% and 97.8% control of spore germination against Botrytis cinerea at the concentration of 100 ug/mL, respectively. PMID- 26225954 TI - Identification of Eupatilin from Artemisia argyi as a Selective PPARalpha Agonist Using Affinity Selection Ultrafiltration LC-MS. AB - Peroxisome proliferator-activated receptors (PPARs) are key nuclear receptors and therapeutic targets for the treatment of metabolic diseases through the regulation of insulin resistance, diabetes, and dyslipidemia. Although a few drugs that target PPARs have been approved, more diverse and novel PPAR ligands are necessary to improve the safety and efficacy of available drugs. To expedite the search for new natural agonists of PPARs, we developed a screening assay based on ultrafiltration liquid chromatography-mass spectrometry (LC-MS) that is compatible with complex samples such as dietary foods or botanical extracts. The known PPARalpha and/or PPARgamma ligands resveratrol and rosiglitazone were used as positive controls to validate the developed method. When applied to the screening of an Artemisia argyi extract, eupatilin was identified as a selective PPARalpha ligand. A PPAR competitive binding assay based on FRET detection also confirmed eupatilin as a selective PPARalpha agonist exhibiting a binding affinity of 1.18 MUM (IC50). Furthermore, eupatilin activation of the transcriptional activity of PPARalpha was confirmed using a cell-based transactivation assay. Thus, ultrafiltration LC-MS is a suitable assay for the identification of PPAR ligands in complex matrixes such as extracts of dietary foods and botanicals. PMID- 26225955 TI - MicroRNA Profiling of B Cell Subsets from Systemic Lupus Erythematosus Patients Reveals Promising Novel Biomarkers. AB - MicroRNAs control the differentiation and function of B cells, which are considered key elements in the pathogenesis of systemic lupus erythematosus (SLE). However, a common micro(mi)RNA signature has not emerged since published data includes patients of variable ethnic background, type of disease, and organ involvement, as well as heterogeneous cell populations. Here, we aimed at identifying a miRNA signature of purified B cells from renal and non-renal severe SLE patients of Latin American background, a population known to express severe disease. Genome-wide miRNA expression analyses were performed on naive and memory B cells and revealed two categories of miRNA signatures. The first signature represents B cell subset-specific miRNAs deregulated in SLE: 11 and six miRNAs discriminating naive and memory B cells of SLE patients from healthy controls (HC), respectively. Whether the miRNA was up or down-regulated in memory B cells as compared with naive B cells in HC, this difference was abolished in SLE patients, and vice versa. The second signature identifies six miRNAs associated with specific pathologic features affecting renal outcome, providing a further understanding for SLE pathogenesis. Overall, the present work provided promising biomarkers in molecular diagnostics for disease severity as well as potential new targets for therapeutic intervention in SLE. PMID- 26225956 TI - Molecular Characterization of Bovine SMO Gene and Effects of Its Genetic Variations on Body Size Traits in Qinchuan Cattle (Bos taurus). AB - Smoothened (Smo)-mediated Hedgehog (Hh) signaling pathway governs the patterning, morphogenesis and growth of many different regions within animal body plans. This study evaluated the effects of genetic variations of the bovine SMO gene on economically important body size traits in Chinese Qinchuan cattle. Altogether, eight single nucleotide polymorphisms (SNPs: 1-8) were identified and genotyped via direct sequencing covering most of the coding region and 3'UTR of the bovine SMO gene. Both the p.698Ser.>Ser. synonymous mutation resulted from SNP1 and the p.700Ser.>Pro. non-synonymous mutation caused by SNP2 mapped to the intracellular C-terminal tail of bovine Smo protein; the other six SNPs were non-coding variants located in the 3'UTR. The linkage disequilibrium was analyzed, and five haplotypes were discovered in 520 Qinchuan cattle. Association analyses showed that SNP2, SNP3/5, SNP4 and SNP6/7 were significantly associated with some body size traits (p < 0.05) except SNP1/8 (p > 0.05). Meanwhile, cattle with wild-type combined haplotype Hap1/Hap1 had significantly (p < 0.05) greater body length than those with Hap2/Hap2. Our results indicate that variations in the SMO gene could affect body size traits of Qinchuan cattle, and the wild-type haplotype Hap1 together with the wild-type alleles of these detected SNPs in the SMO gene could be used to breed cattle with superior body size traits. Therefore, our results could be helpful for marker-assisted selection in beef cattle breeding programs. PMID- 26225958 TI - The Role of CzcRS Two-Component Systems in the Heavy Metal Resistance of Pseudomonas putida X4. AB - The role of different czcRS genes in metal resistance and the cross-link between czcRS and czcCBA in Pseudomonas putida X4 were studied to advance understanding of the mechanisms by which P. putida copes with metal stress. Similar to P. putida KT2440, two complete czcRS1 and czcRS2 two-component systems, as well as a czcR3 without the corresponding sensing component were amplified in P. putida X4. The histidine kinase genes czcS1 and czcS2 were inactivated and fused to lacZ by homologous recombination. The lacZ fusion assay revealed that Cd2+ and Zn2+ caused a decrease in the transcription of czcRS1, whereas Cd2+ treatment enhanced the transcription of czcRS2. The mutation of different czcRSs showed that all czcRSs are necessary to facilitate full metal resistance in P. putida X4. A putative gene just downstream of czcR3 is related to metal ion resistance, and its transcription was activated by Zn2+. Data from quantitative real-time polymerase chain reaction (qRT-PCR) strongly suggested that czcRSs regulate the expression of czcCBA, and a cross-link exists between different czcRSs. PMID- 26225957 TI - Evaluating the Oxidative Stress in Inflammation: Role of Melatonin. AB - Oxygen is used by eukaryotic cells for metabolic transformations and energy production in mitochondria. Under physiological conditions, there is a constant endogenous production of intermediates of reactive oxygen (ROI) and nitrogen species (RNI) that interact as signaling molecules in physiological mechanisms. When these species are not eliminated by antioxidants or are produced in excess, oxidative stress arises. Oxidative stress can damage proteins, lipids, DNA, and organelles. It is a process directly linked to inflammation; in fact, inflammatory cells secrete a large number of cytokines and chemokines responsible for the production of ROI and RNI in phagocytic and nonphagocytic cells through the activation of protein kinases signaling. Currently, there is a wide variety of diseases capable of producing inflammatory manifestations. While, in the short term, most of these diseases are not fatal they have a major impact on life quality. Since there is a direct relationship between chronic inflammation and many emerging disorders like cancer, oral diseases, kidney diseases, fibromyalgia, gastrointestinal chronic diseases or rheumatics diseases, the aim of this review is to describe the use and role of melatonin, a hormone secreted by the pineal gland, that works directly and indirectly as a free radical scavenger, like a potent antioxidant. PMID- 26225959 TI - miR-198 Represses the Proliferation of HaCaT Cells by Targeting Cyclin D2. AB - BACKGROUND: MiR-198 has been considered as an inhibitor of cell proliferation, invasion, migration and a promoter of apoptosis in most cancer cells, while its effect on non-cancer cells is poorly understood. METHODS: The effect of miR-198 transfection on HaCaT cell proliferation was firstly detected using Cell Count Kit-8 and the cell cycle progression was analyzed by flow cytometry. Using bioinformatics analyses and luciferase assay, a new target of miR-198 was searched and identified. Then, the effect of the new target gene of miR-198 on cell proliferation and cell cycle was also detected. RESULTS: Here we showed that miR-198 directly bound to the 3'-UTR of CCND2 mRNA, which was a key regulator in cell cycle progression. Overexpressed miR-198 repressed CCND2 expression at mRNA and protein levels and subsequently led to cell proliferation inhibition and cell cycle arrest in the G1 phase. Transfection ofSiCCND2 in HaCaT cells showed similar inhibitory effects on cell proliferation and cell cycle progression. CONCLUSION: In conclusion, we have identified that miR-198 inhibited HaCaT cell proliferation by directly targeting CCND2. PMID- 26225960 TI - Ethanol versus Phytochemicals in Wine: Oral Cancer Risk in a Light Drinking Perspective. AB - This narrative review aims to summarize the current controversy on the balance between ethanol and phytochemicals in wine, focusing on light drinking and oral cancer. Extensive literature search included PUBMED and EMBASE databases to identify in human studies and systematic reviews (up to March 2015), which contributed to elucidate this issue. Independently from the type of beverage, meta-analyses considering light drinking (<=1 drinks/day or <=12.5 g/day of ethanol) reported relative risks (RR) for oral, oro-pharyngeal, or upper aero digestive tract cancers, ranging from 1.0 to 1.3. One meta-analysis measured the overall wine-specific RR, which corresponded to 2.1. Although little evidence exists on light wine intake, phytochemicals seem not to affect oral cancer risk, being probably present below the effective dosages and/or due to their low bioavailability. As expected, the risk of oral cancer, even in light drinking conditions, increases when associated with smoking habit and high-risk genotypes of alcohol and aldehyde dehydrogenases. PMID- 26225962 TI - The Photoprotective Effect of S-Methylmethionine Sulfonium in Skin. AB - S-Methylmethionine sulfonium (SMMS) was reported to have wound-healing effects; we therefore have investigated the photoprotective effect of SMMS in the present study. SMMS increased the viability of keratinocyte progenitor cells (KPCs) and human dermal fibroblasts (hDFs) following ultraviolet B (UVB) irradiation, and reduced the UVB-induced apoptosis in these cells. SMMS increased the phosphorylation of extracellular signal-regulated kinases (ERK), and the inhibitor of the mitogen-activated protein kinase pathway significantly decreased the SMMS-induced viability of KPCs and hDFs. In addition, SMMS attenuated the UVB induced reactive oxygen species (ROS) generation in KPCs and hDFs. SMMS induced the collagen synthesis and reduced the matrix metalloproteinase-1 expression in UVB-irradiated hDFs. In animal studies, application of 5% and 10% SMMS before and after UVB-irradiation significantly decreased the UVB-induced erythema index and depletion of Langerhans cells. In summary, SMMS protects KPCs and hDFs from UVB irradiation, and reduces UVB-induced skin erythema and immune suppression. Therefore, SMMS can be used as a cosmetic raw material, and protect skin from UVB. PMID- 26225963 TI - Opportunities for Bio-Based Solvents Created as Petrochemical and Fuel Products Transition towards Renewable Resources. AB - The global bio-based chemical market is growing in size and importance. Bio-based solvents such as glycerol and 2-methyltetrahydrofuran are often discussed as important introductions to the conventional repertoire of solvents. However adoption of new innovations by industry is typically slow. Therefore it might be anticipated that neoteric solvent systems (e.g., ionic liquids) will remain niche, while renewable routes to historically established solvents will continue to grow in importance. This review discusses bio-based solvents from the perspective of their production, identifying suitable feedstocks, platform molecules, and relevant product streams for the sustainable manufacturing of conventional solvents. PMID- 26225964 TI - Recent Breakthroughs in the Antioxidant and Anti-Inflammatory Effects of Morella and Myrica Species. AB - Oxidative stress is one of the risk factors for the development of several chronic diseases, such as diabetes, cancer, cardiovascular and neurodegenerative diseases. Antioxidants are therefore highly sought and can be seen as a type of preventive medicine against several diseases. Myrica and Morella genus (Myricaceae) are taxonomically very close and their species are trees or shrubs with edible fruits that exhibit relevant uses in traditional medicine, for instance in Chinese or Japanese folk medicine they are used to treat diarrhea, digestive problems, headache, burns and skin diseases. Nearly 36 compounds were isolated from different morphological parts of Myrica and/or Morella species and their antioxidant and anti-inflammatory activities evaluated. Thirteen of these compounds exhibit greater effects than the positive controls used. Adenodimerin A was the most active compound reported (in a 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay EC50= 7.9 +/- 0.3 uM). These results are just one aspect of the antioxidant and anti-inflammatory evaluations reported regarding Myrica and Morella species, so a comprehensive overview on the current status, highlighting the antioxidant health promoting effect of these species, their key antioxidant compounds as well as the compounds with protective effects against oxidative stress related diseases such as inflammation, is relevant. PMID- 26225961 TI - Milk--A Nutrient System of Mammalian Evolution Promoting mTORC1-Dependent Translation. AB - Based on own translational research of the biochemical and hormonal effects of cow's milk consumption in humans, this review presents milk as a signaling system of mammalian evolution that activates the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), the pivotal regulator of translation. Milk, a mammary gland-derived secretory product, is required for species-specific gene-nutrient interactions that promote appropriate growth and development of the newborn mammal. This signaling system is highly conserved and tightly controlled by the lactation genome. Milk is sufficient to activate mTORC1, the crucial regulator of protein, lipid, and nucleotide synthesis orchestrating anabolism, cell growth and proliferation. To fulfill its mTORC1-activating function, milk delivers four key metabolic messengers: (1) essential branched-chain amino acids (BCAAs); (2) glutamine; (3) palmitic acid; and (4) bioactive exosomal microRNAs, which in a synergistical fashion promote mTORC1-dependent translation. In all mammals except Neolithic humans, postnatal activation of mTORC1 by milk intake is restricted to the postnatal lactation period. It is of critical concern that persistent hyperactivation of mTORC1 is associated with aging and the development of age-related disorders such as obesity, type 2 diabetes mellitus, cancer, and neurodegenerative diseases. Persistent mTORC1 activation promotes endoplasmic reticulum (ER) stress and drives an aimless quasi-program, which promotes aging and age-related diseases. PMID- 26225965 TI - Prognostic Value of Preoperative Serum Levels of Periostin (PN) in Early Breast Cancer (BCa). AB - PN is a secreted cell adhesion protein critical for carcinogenesis. Elevated serum levels of PN have been implicated as playing an important role in different types of cancer, and a few reports suggest a potential role as a prognostic marker. We evaluated the prognostic significance of preoperative serum PN concentration in patients with BCa receiving curative surgery. Enzyme-Linked Immunosorbent Assay (ELISA) was performed to determine the preoperative serum PN level in 182 patients. The correlations between serum PN concentration with clinical pathological features and PN expression in primary tumor samples were analyzed. The prognostic impact of serum PN levels with all-cause and BCa specific mortality was also investigated. Appropriate statistics were used. Elevated serum PN levels were significantly associated with patient age (p = 0.005), adjuvant systemic therapy (p = 0.04) and progesterone receptor (PgR) status (p = 0.02). No correlation between PN preoperative serum levels and other clinical-pathological parameters, including either the epithelial or the stromal PN expression of primary tumor or the combination of the two, was found. Similarly, no association between serum PN levels and either all-cause or BCa specific mortality was found. However, subgroup analysis revealed a correlation between higher PN serum levels and all-cause mortality in patients with node negative disease (p = 0.05) and in those with a low PgR expression (p = 0.03). Higher levels of serum PN were also found to correlate with BCa-specific mortality in the subgroup of patients who did not receive any adjuvant systemic therapy (p = 0.04). Our findings suggest that PN was detectable in the serum of early BCa patients before surgery and increased base-line serum levels predicted worse long-term survival outcomes in specific subgroups of patients. PMID- 26225967 TI - Mapping of Powdery Mildew Resistance Gene pmCH89 in a Putative Wheat-Thinopyrum intermedium Introgression Line. AB - Powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a globally serious disease adversely affecting wheat production. The Bgt-resistant wheat breeding line CH09W89 was derived after backcrossing a Bgt resistant wheat Thinopyrum intermedium partial amphiploid TAI7045 with susceptible wheat cultivars. At the seedling stage, CH09W89 exhibited immunity or high resistance to Bgt pathotypes E09, E20, E21, E23, E26, Bg1, and Bg2, similar to its donor line TAI7045 and Th. intermedium. No Th. intermedium chromatin was detected based on genomic in situ hybridization of mitotic chromosomes. To determine the mode of inheritance of the Bgt resistance and the chromosomal location of the resistance gene, CH09W89 was crossed with two susceptible wheat cultivars. The results of the genetic analysis showed that the adult resistance to Bgt E09 in CH09W89 was controlled by a single recessive gene, which was tentatively designated as pmCH89. Two polymorphic SSR markers, Xwmc310 and Xwmc125, were linked to the resistance gene with genetic distances 3.1 and 2.7 cM, respectively. Using the Chinese Spring aneuploid and deletion lines, the resistance gene and its linked markers were assigned to chromosome arm 4BL in the bin 0.68-0.78. Due to its unique position on chromosome 4BL, pmCH89 appears to be a new locus for resistance to powdery mildew. These results will be of benefit for improving powdery mildew resistance in wheat breeding programs. PMID- 26225969 TI - Distance-Constraint k-Nearest Neighbor Searching in Mobile Sensor Networks. AB - The kappa-Nearest Neighbors ( kappaNN) query is an important spatial query in mobile sensor networks. In this work we extend kappaNN to include a distance constraint, calling it a l-distant kappa-nearest-neighbors (l-kappaNN) query, which finds the kappa sensor nodes nearest to a query point that are also at or greater distance from each other. The query results indicate the objects nearest to the area of interest that are scattered from each other by at least distance l. The l-kappaNN query can be used in most kappaNN applications for the case of well distributed query results. To process an l-kappaNN query, we must discover all sets of kappaNN sensor nodes and then find all pairs of sensor nodes in each set that are separated by at least a distance l. Given the limited battery and computing power of sensor nodes, this l-kappaNN query processing is problematically expensive in terms of energy consumption. In this paper, we propose a greedy approach for l-kappaNN query processing in mobile sensor networks. The key idea of the proposed approach is to divide the search space into subspaces whose all sides are l. By selecting kappa sensor nodes from the other subspaces near the query point, we guarantee accurate query results for l kappaNN. In our experiments, we show that the proposed method exhibits superior performance compared with a post-processing based method using the kappaNN query in terms of energy efficiency, query latency, and accuracy. PMID- 26225970 TI - In-Situ Cure Monitoring of Wind Turbine Blades by Using Fiber Bragg Grating Sensors and Fresnel Reflection Measurement. AB - A fiber-optic cure monitoring system is proposed to measure curing status of composite structure such as a large scale wind turbine blade. The monitoring is based on the measurement of Fresnel reflectivity at the optical fiber/epoxy resin interface. The refractive index of epoxy resin varies throughout curing stages, changing the Fresnel reflectivity. The curing status is decided by monitoring the reflected intensity variation. The usage of fiber Bragg grating (FBG) sensor helps to separate the temperature-induced cross effects. A Gaussian curve fitting algorithm was applied to FBG spectra which were distorted in curing procedure. The substantial measurement errors could be minimized by locating the centroids of the Gaussian curve-fitted spectra. From the experiments performed in various isothermal conditions, the proposed system successfully identified the onset of gelation and the completion of curing of epoxy resins. PMID- 26225966 TI - Protein Folding and Mechanisms of Proteostasis. AB - Highly sophisticated mechanisms that modulate protein structure and function, which involve synthesis and degradation, have evolved to maintain cellular homeostasis. Perturbations in these mechanisms can lead to protein dysfunction as well as deleterious cell processes. Therefore in recent years the etiology of a great number of diseases has been attributed to failures in mechanisms that modulate protein structure. Interconnections among metabolic and cell signaling pathways are critical for homeostasis to converge on mechanisms associated with protein folding as well as for the preservation of the native structure of proteins. For instance, imbalances in secretory protein synthesis pathways lead to a condition known as endoplasmic reticulum (ER) stress which elicits the adaptive unfolded protein response (UPR). Therefore, taking this into consideration, a key part of this paper is developed around the protein folding phenomenon, and cellular mechanisms which support this pivotal condition. We provide an overview of chaperone protein function, UPR via, spatial compartmentalization of protein folding, proteasome role, autophagy, as well as the intertwining between these processes. Several diseases are known to have a molecular etiology in the malfunction of mechanisms responsible for protein folding and in the shielding of native structure, phenomena which ultimately lead to misfolded protein accumulation. This review centers on our current knowledge about pathways that modulate protein folding, and cell responses involved in protein homeostasis. PMID- 26225968 TI - Advances in the Study of the Antiatherogenic Function and Novel Therapies for HDL. AB - The hypothesis that raising high-density lipoprotein cholesterol (HDL-C) levels could improve the risk for cardiovascular disease (CVD) is facing challenges. There is multitudinous clear clinical evidence that the latest failures of HDL-C raising drugs show no clear association with risks for CVD. At the genetic level, recent research indicates that steady-state HDL-C concentrations may provide limited information regarding the potential antiatherogenic functions of HDL. It is evident that the newer strategies may replace therapeutic approaches to simply raise plasma HDL-C levels. There is an urgent need to identify an efficient biomarker that accurately predicts the increased risk of atherosclerosis (AS) in patients and that may be used for exploring newer therapeutic targets. Studies from recent decades show that the composition, structure and function of circulating HDL are closely associated with high cardiovascular risk. A vast amount of data demonstrates that the most important mechanism through which HDL antagonizes AS involves the reverse cholesterol transport (RCT) process. Clinical trials of drugs that specifically target HDL have so far proven disappointing, so it is necessary to carry out review on the HDL therapeutics. PMID- 26225971 TI - Sol-Gel Material-Enabled Electro-Optic Polymer Modulators. AB - Sol-gels are an important material class, as they provide easy modification of material properties, good processability and are easy to synthesize. In general, an electro-optic (EO) modulator transforms an electrical signal into an optical signal. The incoming electrical signal is most commonly information encoded in a voltage change. This voltage change is then transformed into either a phase change or an intensity change in the light signal. The less voltage needed to drive the modulator and the lower the optical loss, the higher the link gain and, therefore, the better the performance of the modulator. In this review, we will show how sol-gels can be used to enhance the performance of electro-optic modulators by allowing for designs with low optical loss, increased poling efficiency and manipulation of the electric field used for driving the modulator. The optical loss is influenced by the propagation loss in the device, as well as the losses occurring during fiber coupling in and out of the device. In both cases, the use of sol-gel materials can be beneficial due to the wide range of available refractive indices and low optical attenuation. The influence of material properties and synthesis conditions on the device performance will be discussed. PMID- 26225972 TI - Optical Characterization of Lorentz Force Based CMOS-MEMS Magnetic Field Sensor. AB - Magnetic field sensors are becoming an essential part of everyday life due to the improvements in their sensitivities and resolutions, while at the same time they have become compact, smaller in size and economical. In the work presented herein a Lorentz force based CMOS-MEMS magnetic field sensor is designed, fabricated and optically characterized. The sensor is fabricated by using CMOS thin layers and dry post micromachining is used to release the device structure and finally the sensor chip is packaged in DIP. The sensor consists of a shuttle which is designed to resonate in the lateral direction (first mode of resonance). In the presence of an external magnetic field, the Lorentz force actuates the shuttle in the lateral direction and the amplitude of resonance is measured using an optical method. The differential change in the amplitude of the resonating shuttle shows the strength of the external magnetic field. The resonance frequency of the shuttle is determined to be 8164 Hz experimentally and from the resonance curve, the quality factor and damping ratio are obtained. In an open environment, the quality factor and damping ratio are found to be 51.34 and 0.00973 respectively. The sensitivity of the sensor is determined in static mode to be 0.034 um/mT when a current of 10 mA passes through the shuttle, while it is found to be higher at resonance with a value of 1.35 um/mT at 8 mA current. Finally, the resolution of the sensor is found to be 370.37 uT. PMID- 26225973 TI - A Comparative Study on the Suitability of Smartphones and IMU for Mobile, Unsupervised Energy Expenditure Calculi. AB - The metabolic equivalent of task (MET) is currently the most used indicator for measuring the energy expenditure (EE) of a physical activity (PA) and has become an important measure for determining and supervising a person's state of health. The use of new devices which are capable of measuring inertial movements by means of built-in accelerometers enable the PA to be measured objectively on the basis of the reckoning of "counts". These devices are also known as inertial measurement units (IMUs) and each count is an aggregated value indicating the intensity of a movement and can be used in conjunction with other parameters to determine the MET rate of a particular physical activity and thus it's associated EE. Various types of inertial devices currently exist that enable count calculus and physical activity to be monitored. The advent of mobile devices, such as smartphones, with empowered computation capabilities and integrated inertial sensors, has enabled EE to be measure in a distributed, ubiquitous and natural way, thereby overcoming the reluctance of users and practitioners associated with in-lab studies. From the point of view of the process analysis and infrastructure needed to manage data from inertial devices, there are also various differences in count computing: extra devices are required, out-of-device processing, etc. This paper presents a study to discover whether the estimation of energy expenditure is dependent on the accelerometer of the device used in measurements and to discover the suitability of each device for performing certain physical activities. In order to achieve this objective, we have conducted several experiments with different subjects on the basis of the performance of various daily activities with different smartphones and IMUs. PMID- 26225974 TI - Distributed Synchronization Technique for OFDMA-Based Wireless Mesh Networks Using a Bio-Inspired Algorithm. AB - In this paper, a distributed synchronization technique based on a bio-inspired algorithm is proposed for an orthogonal frequency division multiple access (OFDMA)-based wireless mesh network (WMN) with a time difference of arrival. The proposed time- and frequency-synchronization technique uses only the signals received from the neighbor nodes, by considering the effect of the propagation delay between the nodes. It achieves a fast synchronization with a relatively low computational complexity because it is operated in a distributed manner, not requiring any feedback channel for the compensation of the propagation delays. In addition, a self-organization scheme that can be effectively used to construct 1 hop neighbor nodes is proposed for an OFDMA-based WMN with a large number of nodes. The performance of the proposed technique is evaluated with regard to the convergence property and synchronization success probability using a computer simulation. PMID- 26225975 TI - The Different Sensitive Behaviors of a Hydrogen-Bond Acidic Polymer-Coated SAW Sensor for Chemical Warfare Agents and Their Simulants. AB - A linear hydrogen-bond acidic (HBA) linear functionalized polymer (PLF), was deposited onto a bare surface acoustic wave (SAW) device to fabricate a chemical sensor. Real-time responses of the sensor to a series of compounds including sarin (GB), dimethyl methylphosphonate (DMMP), mustard gas (HD), chloroethyl ethyl sulphide (2-CEES), 1,5-dichloropentane (DCP) and some organic solvents were studied. The results show that the sensor is highly sensitive to GB and DMMP, and has low sensitivity to HD and DCP, as expected. However, the sensor possesses an unexpected high sensitivity toward 2-CEES. This good sensing performance can't be solely or mainly attributed to the dipole-dipole interaction since the sensor is not sensitive to some high polarity solvents. We believe the lone pair electrons around the sulphur atom of 2-CEES provide an electron-rich site, which facilitates the formation of hydrogen bonding between PLF and 2-CEES. On the contrary, the electron cloud on the sulphur atom of the HD molecule is offset or depleted by its two neighbouring strong electron-withdrawing groups, hence, hydrogen bonding can hardly be formed. PMID- 26225976 TI - A Non-Contact Measurement System for the Range of Motion of the Hand. AB - An accurate and standardised tool to measure the active range of motion (ROM) of the hand is essential to any progressive assessment scenario in hand therapy practice. Goniometers are widely used in clinical settings for measuring the ROM of the hand. However, such measurements have limitations with regard to inter rater and intra-rater reliability and involve direct physical contact with the hand, possibly increasing the risk of transmitting infections. The system proposed in this paper is the first non-contact measurement system utilising Intel Perceptual Technology and a Senz3D Camera for measuring phalangeal joint angles. To enhance the accuracy of the system, we developed a new approach to achieve the total active movement without measuring three joint angles individually. An equation between the actual spacial position and measurement value of the proximal inter-phalangeal joint was established through the measurement values of the total active movement, so that its actual position can be inferred. Verified by computer simulations, experimental results demonstrated a significant improvement in the calculation of the total active movement and successfully recovered the actual position of the proximal inter-phalangeal joint angles. A trial that was conducted to examine the clinical applicability of the system involving 40 healthy subjects confirmed the practicability and consistency in the proposed system. The time efficiency conveyed a stronger argument for this system to replace the current practice of using goniometers. PMID- 26225977 TI - Feasibility of Using Synthetic Aperture Radar to Aid UAV Navigation. AB - This study explores the potential of Synthetic Aperture Radar (SAR) to aid Unmanned Aerial Vehicle (UAV) navigation when Inertial Navigation System (INS) measurements are not accurate enough to eliminate drifts from a planned trajectory. This problem can affect medium-altitude long-endurance (MALE) UAV class, which permits heavy and wide payloads (as required by SAR) and flights for thousands of kilometres accumulating large drifts. The basic idea is to infer position and attitude of an aerial platform by inspecting both amplitude and phase of SAR images acquired onboard. For the amplitude-based approach, the system navigation corrections are obtained by matching the actual coordinates of ground landmarks with those automatically extracted from the SAR image. When the use of SAR amplitude is unfeasible, the phase content can be exploited through SAR interferometry by using a reference Digital Terrain Model (DTM). A feasibility analysis was carried out to derive system requirements by exploring both radiometric and geometric parameters of the acquisition setting. We showed that MALE UAV, specific commercial navigation sensors and SAR systems, typical landmark position accuracy and classes, and available DTMs lead to estimated UAV coordinates with errors bounded within +/-12 m, thus making feasible the proposed SAR-based backup system. PMID- 26225978 TI - From Laser Scanning to Finite Element Analysis of Complex Buildings by Using a Semi-Automatic Procedure. AB - In this paper, a new semi-automatic procedure to transform three-dimensional point clouds of complex objects to three-dimensional finite element models is presented and validated. The procedure conceives of the point cloud as a stacking of point sections. The complexity of the clouds is arbitrary, since the procedure is designed for terrestrial laser scanner surveys applied to buildings with irregular geometry, such as historical buildings. The procedure aims at solving the problems connected to the generation of finite element models of these complex structures by constructing a fine discretized geometry with a reduced amount of time and ready to be used with structural analysis. If the starting clouds represent the inner and outer surfaces of the structure, the resulting finite element model will accurately capture the whole three-dimensional structure, producing a complex solid made by voxel elements. A comparison analysis with a CAD-based model is carried out on a historical building damaged by a seismic event. The results indicate that the proposed procedure is effective and obtains comparable models in a shorter time, with an increased level of automation. PMID- 26225979 TI - Tip Effect of the Tapping Mode of Atomic Force Microscope in Viscous Fluid Environments. AB - Atomic force microscope with applicable types of operation in a liquid environment is widely used to scan the contours of biological specimens. The contact mode of operation allows a tip to touch a specimen directly but sometimes it damages the specimen; thus, a tapping mode of operation may replace the contact mode. The tapping mode triggers the cantilever of the microscope approximately at resonance frequencies, and so the tip periodically knocks the specimen. It is well known that the cantilever induces extra liquid pressure that leads to drift in the resonance frequency. Studies have noted that the heights of protein surfaces measured via the tapping mode of an atomic force microscope are ~25% smaller than those measured by other methods. This discrepancy may be attributable to the induced superficial hydrodynamic pressure, which is worth investigating. In this paper, we introduce a semi-analytical method to analyze the pressure distribution of various tip geometries. According to our analysis, the maximum hydrodynamic pressure on the specimen caused by a cone-shaped tip is ~0.5 Pa, which can, for example, pre-deform a cell by several nanometers in compression before the tip taps it. Moreover, the pressure calculated on the surface of the specimen is 20 times larger than the pressure without considering the tip effect; these results have not been motioned in other papers. Dominating factors, such as surface heights of protein surface, mechanical stiffness of protein increasing with loading velocity, and radius of tip affecting the local pressure of specimen, are also addressed in this study. PMID- 26225980 TI - A Novel Speed Compensation Method for ISAR Imaging with Low SNR. AB - In this paper, two novel speed compensation algorithms for ISAR imaging under a low signal-to-noise ratio (SNR) condition have been proposed, which are based on the cubic phase function (CPF) and the integrated cubic phase function (ICPF), respectively. These two algorithms can estimate the speed of the target from the wideband radar echo directly, which breaks the limitation of speed measuring in a radar system. With the utilization of non-coherent accumulation, the ICPF-based speed compensation algorithm is robust to noise and can meet the requirement of speed compensation for ISAR imaging under a low SNR condition. Moreover, a fast searching implementation strategy, which consists of coarse search and precise search, has been introduced to decrease the computational burden of speed compensation based on CPF and ICPF. Experimental results based on radar data validate the effectiveness of the proposed algorithms. PMID- 26225981 TI - AlGaN/GaN High Electron Mobility Transistor-Based Biosensor for the Detection of C-Reactive Protein. AB - In this paper, we propose an AlGaN/GaN high electron mobility transistor (HEMT) based biosensor for the detection of C-reactive protein (CRP) using a null balancing circuit. A null-balancing circuit was used to measure the output voltage of the sensor directly. The output voltage of the proposed biosensor was varied by antigen-antibody interactions on the gate surface due to CRP charges. The AlGaN/GaN HFET-based biosensor with null-balancing circuit applied shows that CRP can be detected in a wide range of concentrations, varying from 10 ng/mL to 1000 ng/mL. X-ray photoelectron spectroscopy was carried out to verify the immobilization of self-assembled monolayer with Au on the gated region. PMID- 26225983 TI - An Accurate Calibration Method Based on Velocity in a Rotational Inertial Navigation System. AB - Rotation modulation is an effective method to enhance the accuracy of an inertial navigation system (INS) by modulating the gyroscope drifts and accelerometer bias errors into periodically varying components. The typical RINS drives the inertial measurement unit (IMU) rotation along the vertical axis and the horizontal sensors' errors are modulated, however, the azimuth angle error is closely related to vertical gyro drift, and the vertical gyro drift also should be modulated effectively. In this paper, a new rotation strategy in a dual-axis rotational INS (RINS) is proposed and the drifts of three gyros could be modulated, respectively. Experimental results from a real dual-axis RINS demonstrate that the maximum azimuth angle error is decreased from 0.04 degrees to less than 0.01 degrees during 1 h. Most importantly, the changing of rotation strategy leads to some additional errors in the velocity which is unacceptable in a high-precision INS. Then the paper studies the basic reason underlying horizontal velocity errors in detail and a relevant new calibration method is designed. Experimental results show that after calibration and compensation, the fluctuation and stages in the velocity curve disappear and velocity precision is improved. PMID- 26225982 TI - Automated Mobile System for Accurate Outdoor Tree Crop Enumeration Using an Uncalibrated Camera. AB - This paper demonstrates an automated computer vision system for outdoor tree crop enumeration in a seedling nursery. The complete system incorporates both hardware components (including an embedded microcontroller, an odometry encoder, and an uncalibrated digital color camera) and software algorithms (including microcontroller algorithms and the proposed algorithm for tree crop enumeration) required to obtain robust performance in a natural outdoor environment. The enumeration system uses a three-step image analysis process based upon: (1) an orthographic plant projection method integrating a perspective transform with automatic parameter estimation; (2) a plant counting method based on projection histograms; and (3) a double-counting avoidance method based on a homography transform. Experimental results demonstrate the ability to count large numbers of plants automatically with no human effort. Results show that, for tree seedlings having a height up to 40 cm and a within-row tree spacing of approximately 10 cm, the algorithms successfully estimated the number of plants with an average accuracy of 95.2% for trees within a single image and 98% for counting of the whole plant population in a large sequence of images. PMID- 26225984 TI - Lindgomycin, an Unusual Antibiotic Polyketide from a Marine Fungus of the Lindgomycetaceae. AB - An unusual polyketide with a new carbon skeleton, lindgomycin (1), and the recently described ascosetin (2) were extracted from mycelia and culture broth of different Lindgomycetaceae strains, which were isolated from a sponge of the Kiel Fjord in the Baltic Sea (Germany) and from the Antarctic. Their structures were established by spectroscopic means. In the new polyketide, two distinct domains, a bicyclic hydrocarbon and a tetramic acid, are connected by a bridging carbonyl. The tetramic acid substructure of compound 1 was proved to possess a unique 5 benzylpyrrolidine-2,4-dione unit. The combination of 5-benzylpyrrolidine-2,4 dione of compound 1 in its tetramic acid half and 3-methylbut-3-enoic acid pendant in its decalin half allow the assignment of a new carbon skeleton. The new compound 1 and ascosetin showed antibiotic activities with IC50 value of 5.1 (+/-0.2) uM and 3.2 (+/-0.4) MUM, respectively, against methicillin-resistant Staphylococcus aureus. PMID- 26225986 TI - The Effect of Urban Heat Island on Climate Warming in the Yangtze River Delta Urban Agglomeration in China. AB - The Yangtze River Delta (YRD) has experienced rapid urbanization and dramatic economic development since 1978 and the Yangtze River Delta urban agglomeration (YRDUA) has been one of the three largest urban agglomerations in China. We present evidence of a significant urban heat island (UHI) effect on climate warming based on an analysis of the impacts of the urbanization rate, urban population, and land use changes on the warming rate of the daily average, minimal (nighttime) and maximal (daytime) air temperature in the YRDUA using 41 meteorological stations observation data. The effect of the UHI on climate warming shows a large spatial variability. The average warming rates of average air temperature of huge cities, megalopolises, large cities, medium-sized cities, and small cities are 0.483, 0.314 +/- 0.030, 0.282 +/- 0.042, 0.225 +/- 0.044 and 0.179 +/- 0.046 degrees C/decade during the period of 1957-2013, respectively. The average warming rates of huge cities and megalopolises are significantly higher than those of medium-sized cities and small cities, indicating that the UHI has a significant effect on climate warming (t-test, p < 0.05). Significantly positive correlations are found between the urbanization rate, population, built up area and warming rate of average air temperature (p < 0.001). The average warming rate of average air temperature attributable to urbanization is 0.124 +/- 0.074 degrees C/decade in the YRDUA. Urbanization has a measurable effect on the observed climate warming in the YRD aggravating the global climate warming. PMID- 26225985 TI - Crambescin C1 Exerts a Cytoprotective Effect on HepG2 Cells through Metallothionein Induction. AB - The Mediterranean marine sponge Crambe crambe is the source of two families of guanidine alkaloids known as crambescins and crambescidins. Some of the biological effects of crambescidins have been previously reported while crambescins have undergone little study. Taking this into account, we performed comparative transcriptome analysis to examine the effect of crambescin-C1 (CC1) on human tumor hepatocarcinoma cells HepG2 followed by validation experiments to confirm its predicted biological activities. We report herein that, while crambescin-A1 has a minor effect on these cells, CC1 protects them against oxidative injury by means of metallothionein induction even at low concentrations. Additionally, at high doses, CC1 arrests the HepG2 cell cycle in G0/G1 and thus inhibits tumor cell proliferation. The findings presented here provide the first detailed approach regarding the different effects of crambescins on tumor cells and provide a basis for future studies on other possible cellular mechanisms related to these bioactivities. PMID- 26225987 TI - Relationship Between Tobacco Retailers' Point-of-Sale Marketing and the Density of Same-Sex Couples, 97 U.S. Counties, 2012. AB - The reasons for higher rates of smoking among lesbian, gay, and bisexual (LGB) people than among heterosexual people are not well known. Research on internal migration and neighborhood selection suggests that LGB people are more likely to live in neighborhoods where the tobacco industry has historically targeted their marketing efforts (lower income, more racial/ethnic diversity). We used multi level models to assess the relationship between the rate of same-sex couples per 1000 coupled households and 2012 marketing characteristics of tobacco retailers (n = 2231) in 1696 census tracts in 97 U.S. counties. We found no evidence of tobacco marketing at retailers differing by same-sex couple rates in census tracts with the exception of three findings in the opposite direction of our hypotheses: a small, significant positive relationship for the rate of same-sex male couples and the price of Newport Green (mentholated) cigarettes. For male and female same-sex couples, we also found a small negative relationship between tobacco advertisements and same-sex household rate. Tobacco retailers' tobacco marketing characteristics do not differ substantially by the rate of same-sex couples in their neighborhood in ways that would promote LGB health disparities. Further work is needed to determine if these patterns are similar for non partnered LGB people. PMID- 26225988 TI - Accumulation of Heavy Metals and Metalloid in Foodstuffs from Agricultural Soils around Tarkwa Area in Ghana, and Associated Human Health Risks. AB - This study was carried out to assess the extent of heavy metals and metalloid accumulation from agricultural soils to foodstuffs (viz, M. esculenta (cassava) and Musa paradisiaca (plantain)) around thirteen neighboring communities within Tarkwa, Ghana; and to estimate the human health risk associated with consumption of these foodstuffs. Concentrations of As, Cd, Co, Cr, Cu, Ni, Pb, and Zn were measured with an inductively coupled plasma-mass spectrometer and mercury analysis was done using a mercury analyzer. From the results, 30% of cassava samples collected, contained higher concentrations of Pb when compared to Codex Alimentarius Commission standard values. Bioconcentration factor indicated that Ni had higher capacity of absorption into food crops from soil than the other heavy metals. For both children and adults, the target hazard quotient (THQ) of Pb in cassava in communities such as Techiman, Wangarakrom, Samahu, and Tebe (only children) were greater than 1, which is defined as an acceptable risk value. This indicated that residents could be exposed to significant health risks associated with cassava consumption. PMID- 26225989 TI - Do Nanoparticle Physico-Chemical Properties and Developmental Exposure Window Influence Nano ZnO Embryotoxicity in Xenopus laevis? AB - The growing global production of zinc oxide nanoparticles (ZnONPs) suggests a realistic increase in the environmental exposure to such a nanomaterial, making the knowledge of its biological reactivity and its safe-by-design synthesis mandatory. In this study, the embryotoxicity of ZnONPs (1-100 mg/L) specifically synthesized for industrial purposes with different sizes, shapes (round, rod) and surface coatings (PEG, PVP) was tested using the frog embryo teratogenesis assay Xenopus (FETAX) to identify potential target tissues and the most sensitive developmental stages. The ZnONPs did not cause embryolethality, but induced a high incidence of malformations, in particular misfolded gut and abdominal edema. Smaller, round NPs were more effective than the bigger, rod ones, and PEGylation determined a reduction in embryotoxicity. Ingestion appeared to be the most relevant exposure route. Only the embryos exposed from the stomodeum opening showed anatomical and histological lesions to the intestine, mainly referable to a swelling of paracellular spaces among enterocytes. In conclusion, ZnONPs differing in shape and surface coating displayed similar toxicity in X. laevis embryos and shared the same target organ. Nevertheless, we cannot exclude that the physico-chemical characteristics may influence the severity of such effects. Further research efforts are mandatory to ensure the synthesis of safer nano-ZnO containing products. PMID- 26225990 TI - BnSGS3 Has Differential Effects on the Accumulation of CMV, ORMV and TuMV in Oilseed Rape. AB - Virus diseases greatly affect oilseed rape (Brassica napus) production. Investigating antiviral genes may lead to the development of disease-resistant varieties of oilseed rape. In this study, we examined the effects of the suppressor of gene silencing 3 in Brassica napus (BnSGS3, a putative antiviral gene) with different genus viruses by constructing BnSGS3-overexpressing (BnSGS3 Ov) and BnSGS3-silenced (BnSGS3-Si) oilseed rape (cv. Zhongshuang No. 6) plants. These three viruses are Oilseed rape mosaic virus (ORMV), Turnip mosaic virus (TuMV) and Cucumber mosaic virus (CMV). The native BnSGS3 expressed in all examined tissues with the highest expression in siliques. All three viruses induced BnSGS3 expression, but ORMV induced a dramatic increase in the BnSGS3-Ov plants, followed by TuMV and CMV. Upon inoculation with three different viruses, transcript abundance of BnSGS3 gene follows: BnSGS3-Ov > non-transgenic plants > BnSGS3-Si. The accumulation quantities of ORMV and TuMV exhibited a similar trend. However, CMV accumulation showed an opposite trend where virus accumulations were negatively correlated with BnSGS3 expression. The results suggest that BnSGS3 selectively inhibits CMV accumulation but promotes ORMV and TuMV accumulation. BnSGS3 should be used in different ways (up- and down regulation) for breeding virus-resistant oilseed rape varieties. PMID- 26225991 TI - CCR5 Targeted Cell Therapy for HIV and Prevention of Viral Escape. AB - Allogeneic transplantation with CCR5-delta 32 (CCR5-d32) homozygous stem cells in an HIV infected individual in 2008, led to a sustained virus control and probably eradication of HIV. Since then there has been a high degree of interest to translate this approach to a wider population. There are two cellular ways to do this. The first one is to use a CCR5 negative cell source e.g., hematopoietic stem cells (HSC) to copy the initial finding. However, a recent case of a second allogeneic transplantation with CCR5-d32 homozygous stem cells suffered from viral escape of CXCR4 quasi-species. The second way is to knock down CCR5 expression by gene therapy. Currently, there are five promising techniques, three of which are presently being tested clinically. These techniques include zinc finger nucleases (ZFN), clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9 nuclease (CRISPR/Cas9), transcription activator-like effectors nuclease (TALEN), short hairpin RNA (shRNA), and a ribozyme. While there are multiple gene therapy strategies being tested, in this review we reflect on our current knowledge of inhibition of CCR5 specifically and whether this approach allows for consequent viral escape. PMID- 26225994 TI - Dietary Assessment on a Mobile Phone Using Image Processing and Pattern Recognition Techniques: Algorithm Design and System Prototyping. AB - Dietary assessment, while traditionally based on pen-and-paper, is rapidly moving towards automatic approaches. This study describes an Australian automatic food record method and its prototype for dietary assessment via the use of a mobile phone and techniques of image processing and pattern recognition. Common visual features including scale invariant feature transformation (SIFT), local binary patterns (LBP), and colour are used for describing food images. The popular bag of-words (BoW) model is employed for recognizing the images taken by a mobile phone for dietary assessment. Technical details are provided together with discussions on the issues and future work. PMID- 26225992 TI - Immune Modulation by Vitamin D and Its Relevance to Food Allergy. AB - Apart from its classical function in bone and calcium metabolism, vitamin D is also involved in immune regulation and has been linked to various cancers, immune disorders and allergic diseases. Within the innate and adaptive immune systems, the vitamin D receptor and enzymes in monocytes, dendritic cells, epithelial cells, T lymphocytes and B lymphocytes mediate the immune modulatory actions of vitamin D. Vitamin D insufficiency/deficiency early in life has been identified as one of the risk factors for food allergy. Several studies have observed an association between increasing latitude and food allergy prevalence, plausibly linked to lower ultraviolet radiation (UVR) exposure and vitamin D synthesis in the skin. Along with mounting epidemiological evidence of a link between vitamin D status and food allergy, mice and human studies have shed light on the modulatory properties of vitamin D on the innate and adaptive immune systems. This review will summarize the literature on the metabolism and immune modulatory properties of vitamin D, with particular reference to food allergy. PMID- 26225993 TI - The Effects of Supplementation with a Vitamin and Mineral Complex with Guarana Prior to Fasted Exercise on Affect, Exertion, Cognitive Performance, and Substrate Metabolism: A Randomized Controlled Trial. AB - Exercise undertaken in a fasted state can lead to higher post-exercise mental fatigue. The administration of a vitamin and mineral complex with guarana (MVM + G) has been shown to attenuate mental fatigue and improve performance during cognitively demanding tasks. This placebo-controlled, double-blind, randomized, balanced cross-over study examined the effect of MVM + G consumed prior to morning exercise on cognitive performance, affect, exertion, and substrate metabolism. Forty active males (age 21.4 +/- 3.0 year; body mass index (BMI) 24.0 +/- 2.4 kg/m2; maximal oxygen consumption (VO2max) 57.6 +/- 7.3 mL/min/kg) completed two main trials, consuming either MVM + G or placebo prior to a 30-min run at 60% VO2max. Supplementation prior to exercise led to a small but significant reduction in Rating of Perceived Exertion (RPE) during exercise compared to the placebo. The MVM + G combination also led to significantly increased accuracy of numeric working memory and increased speed of picture recognition, compared to the placebo. There were no significant effects of supplementation on any other cognitive or mood measures or on substrate metabolism during exercise. These findings demonstrate that consuming a vitamin and mineral complex containing guarana, prior to exercise, can positively impact subsequent memory performance and reduce perceived exertion during a moderate intensity run in active males. PMID- 26225995 TI - Black Beans, Fiber, and Antioxidant Capacity Pilot Study: Examination of Whole Foods vs. Functional Components on Postprandial Metabolic, Oxidative Stress, and Inflammation in Adults with Metabolic Syndrome. AB - Beans (Phaseolus vulgaris) contain bioactive components with functional properties that may modify cardiovascular risk. The aims of this pilot study were to evaluate the ability of black beans to attenuate postprandial metabolic, oxidative stress, and inflammatory responses and determine relative contribution of dietary fiber and antioxidant capacity of beans to the overall effect. In this randomized, controlled, crossover trial, 12 adults with metabolic syndrome (MetS) consumed one of three meals (black bean (BB), fiber matched (FM), and antioxidant capacity matched (AM)) on three occasions that included blood collection before (fasting) and five hours postprandially. Insulin was lower after the BB meal, compared to the FM or AM meals (p < 0.0001). A significant meal * time interaction was observed for plasma antioxidant capacity (p = 0.002) revealing differences over time: AM > BB > FM. Oxidized LDL (oxLDL) was not different by meal, although a trend for declining oxLDL was observed after the BB and AM meals at five hours compared to the FM meal. Triglycerides and interleukin-6 (IL-6) increased in response to meals (p < 0.0001). Inclusion of black beans with a typical Western-style meal attenuates postprandial insulin and moderately enhances postprandial antioxidant endpoints in adults with MetS, which could only be partly explained by fiber content and properties of antioxidant capacity. PMID- 26225996 TI - Assessment of Pre-Pregnancy Dietary Intake with a Food Frequency Questionnaire in Alberta Women. AB - PURPOSE: Pre-pregnancy is an under-examined and potentially important time to optimize dietary intake to support fetal growth and development as well as maternal health. The purpose of the study was to determine the extent to which dietary intake reported by non-pregnant women is similar to pre-pregnancy dietary intake reported by pregnant women using the same assessment tool. METHODS: The self-administered, semi-quantitative food frequency questionnaire (FFQ) was adapted from the Canadian version of the Diet History Questionnaire, originally developed by the National Cancer Institute in the United States. Pregnant women (n = 98) completed the FFQ which assessed dietary intake for the year prior to pregnancy. Non-pregnant women (n = 103) completed the same FFQ which assessed dietary intake for the previous year. Energy, macronutrients, and key micronutrients: long-chain omega-3 fatty acids, folate, vitamin B6, vitamin B12, calcium, vitamin D and iron were examined. RESULTS: Dietary intake between groups; reported with the FFQ; was similar except for saturated fat; trans fat; calcium; and alcohol. Pregnant women reported significantly higher intakes of saturated fat; trans fat; and calcium and lower intake of alcohol in the year prior to pregnancy compared to non-pregnant women who reported intake in the previous year. CONCLUSIONS: Despite limitations; a FFQ may be used to assist with retrospective assessment of pre-pregnancy dietary intake. PMID- 26225997 TI - Alcohol and Difficulty Conceiving in the SUN Cohort: A Nested Case-Control Study. AB - The role of alcohol on fertility remains unclear. We aimed to investigate the association between alcohol and specific alcoholic beverages consumption and the risk of difficulty getting pregnant. We used a case-control study nested within the Seguimiento Universidad de Navarra (SUN) cohort, a prospective, dynamic and multipurpose cohort of 21,705 Spanish university graduates, followed biennially with mailed questionnaires. We identified 686 case-control pairs, matched for age and time in the cohort. Cases were women reporting difficulty getting pregnant. Controls did not consult due to difficulty conceiving and had at least one child during follow-up. After adjustment for potential confounders, we found no association between self-reported difficulty getting pregnant and the number of alcoholic beverages consumed per week, (Odds Ratio [OR] > 5 drinks/week vs. none = 1.04, 95% Confidence Interval [CI] = 0.72-1.51). No association between types of alcoholic beverage and difficulty conceiving (OR > 5 drinks of wine/week vs. none = 1.16, 95% CI = 0.72-1.88; OR > 5 drinks of beer/week vs. none = 1.06, 95% CI = 0.82-1.37; OR > 5 drinks of spirits/week vs. none = 1.24, 95% CI = 0.84 1.64) was observed. In conclusion, we found no association between alcohol intake and risk of consulting a physician due to difficulty conceiving. More studies are needed to clearly elucidate the effects of alcohol intake on women's fertility. In the meantime, recommendations about alcohol intake to couples trying to conceive have to be given cautiously. PMID- 26225998 TI - Mamao Pomace Extract Alleviates Hypertension and Oxidative Stress in Nitric Oxide Deficient Rats. AB - Reactive oxygen species (ROS)-induced oxidative stress plays a major role in pathogenesis of hypertension. Antidesma thwaitesianum (local name: Mamao) is a tropical plant distributed in the tropical/subtropical areas of the world, including Thailand. Mamao pomace (MP), a by-product generated from Mamao fruits, contains large amounts of antioxidant polyphenolic compounds. The aim of this study was to investigate the antihypertensive and antioxidative effects of MP using hypertensive rats. For this purpose, male Sprague-Dawley rats were given Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelial nitric oxide synthase (eNOS), in drinking water (50 mg/kg) for three weeks. MP extract was orally administered daily at doses of 100 and 300 mg/kg. L-NAME administration induced marked increase in blood pressure, peripheral vascular resistance, and oxidative stress. MP treatment significantly prevented the increase in blood pressure, hindlimb blood flow and hindlimb vascular resistance of L-NAME treated hypertensive rats (p < 0.05). The antihypertensive effect of MP treatment was associated with suppression of superoxide production from carotid strips and also with an increase in eNOS protein expression and nitric oxide bioavailability. The present results provide evidence for the antihypertensive effect of MP and suggest that MP might be useful as a dietary supplement against hypertension. PMID- 26225999 TI - Is It the Appropriate Time to Stop Applying Selenium Enriched Salt in Kashin-Beck Disease Areas in China? AB - We aimed to identify significant factors of selenium (Se) nutrition of children in Kashin-Beck disease (KBD) endemic areas and non-KBD area in Shaanxi Province for providing evidence of whether it is the time to stop applying Se-enriched salt in KBD areas. A cross-sectional study contained 368 stratified randomly selected children aged 4-14 years was conducted with 24-h retrospective questionnaire based on a pre-investigation. Food and hair samples were collected and had Se contents determined with hydride generation atomic fluorescence spectrometry. Average hair Se content of 349.0 +/- 60.2 ng/g in KBD-endemic counties was significantly lower than 374.1 +/- 47.0 ng/g in non-KBD counties. It was significantly higher in the male children (365.2 +/- 52.3 ng/g) than in the female (345.0 +/- 62.2 ng/g, p = 0.002) and significantly higher in the 4.0-6.9 years group (375.2 +/- 58.9 ng/g) than the 7.0-14.0 years group (347.0 +/- 56.1 ng/g, p < 0.01). Gender, living area, Se intake without supplements, Se-enriched salt, oil source and protein intake were identified as significant factors of hair Se contents. Cereals, meat and milk were commonly included as significant food categories that mainly contributed to Se intake without supplement of the whole population. Balanced dietary structure without Se supplement could effectively enhance and maintain children's Se nutrition. It may be the time to stop applying Se-enriched salt in KBD areas in Shaanxi Province. PMID- 26226000 TI - Activities and Effects of Ergot Alkaloids on Livestock Physiology and Production. AB - Consumption of feedstuffs contaminated with ergot alkaloids has a broad impact on many different physiological mechanisms that alters the homeostasis of livestock. This change in homeostasis causes an increased sensitivity in livestock to perturbations in the ambient environment, resulting in an increased sensitivity to such stressors. This ultimately results in large financial losses in the form of production losses to livestock producers around the world. This review will focus on the underlying physiological mechanisms that are affected by ergot alkaloids that lead to decreases in livestock production. PMID- 26226001 TI - Induction of Suicidal Erythrocyte Death by Cantharidin. AB - The natural phosphoprotein phosphatase inhibitor cantharidin, primarily used for topical treatment of warts, has later been shown to trigger tumor cell apoptosis and is thus considered for the treatment of malignancy. Similar to apoptosis of tumor cells, erythrocytes may undergo eryptosis, a suicidal cell death characterized by cell shrinkage and translocation of cell membrane phosphatidylserine to the erythrocyte surface. Signaling of eryptosis includes increase of cytosolic Ca2+-activity ([Ca2+]i), ceramide, oxidative stress and dysregulation of several kinases. Phosphatidylserine abundance at the erythrocyte surface was quantified utilizing annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ceramide from antibody binding, and reactive oxidant species (ROS) from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence. A 48 h treatment of human erythrocytes with cantharidin significantly increased the percentage of annexin-V-binding cells (>=10 mg/mL), significantly decreased forward scatter (>=25 mg/mL), significantly increased [Ca2+]i (>=25 mg/mL), but did not significantly modify ceramide abundance or ROS. The up-regulation of annexin-V-binding following cantharidin treatment was not significantly blunted by removal of extracellular Ca2+ but was abolished by kinase inhibitor staurosporine (1 mM) and slightly decreased by p38 inhibitor skepinone (2 mM). Exposure of erythrocytes to cantharidin triggers suicidal erythrocyte death with erythrocyte shrinkage and erythrocyte membrane scrambling, an effect sensitive to kinase inhibitors staurosporine and skepinone. PMID- 26226002 TI - MicroRNAs in Cancer: A Historical Perspective on the Path from Discovery to Therapy. AB - Recent progress in microRNA (miRNA) therapeutics has been strongly dependent on multiple seminal discoveries in the area of miRNA biology during the past two decades. In this review, we focus on the historical discoveries that collectively led to transitioning miRNAs into the clinic. We highlight the pivotal studies that identified the first miRNAs in Caenorhabditis elegans to the more recent reports that have fueled the quest to understand the use of miRNAs as markers for cancer diagnosis and prognosis. In addition, we provide insights as to how unraveling basic miRNA biology has provided a solid foundation for advancing miRNAs, such as miR-34a, therapeutically. We conclude with a brief examination of the current challenges that still need to be addressed to accelerate the path of miRNAs to the clinic: including delivery vehicles, miRNA- and delivery-associated toxicity, dosage, and off target effects. PMID- 26226004 TI - Contribution of Topological Domains and Loop Formation to 3D Chromatin Organization. AB - Recent investigations on 3D chromatin folding revealed that the eukaryote genomes are both highly compartmentalized and extremely dynamic. This review presents the most recent advances in topological domains' organization of the eukaryote genomes and discusses the relationship to chromatin loop formation. CTCF protein appears as a central factor of these two organization levels having either a strong insulating role at TAD borders, or a weaker architectural role in chromatin loop formation. TAD borders directly impact on chromatin dynamics by restricting contacts within specific genomic portions thus confining chromatin loop formation within TADs. We discuss how sub-TAD chromatin dynamics, constrained into a recently described statistical helix conformation, can produce functional interactions by contact stabilization. PMID- 26226005 TI - Halophilic Archaea: Life with Desiccation, Radiation and Oligotrophy over Geological Times. AB - Halophilic archaebacteria (Haloarchaea) can survive extreme desiccation, starvation and radiation, sometimes apparently for millions of years. Several of the strategies that are involved appear specific for Haloarchaea (for example, the formation of halomucin, survival in fluid inclusions of halite), and some are known from other prokaryotes (dwarfing of cells, reduction of ATP). Several newly discovered haloarchaeal strategies that were inferred to possibly promote long term survival-halomucin, polyploidy, usage of DNA as a phosphate storage polymer, production of spherical dormant stages-remain to be characterized in detail. More information on potential strategies is desirable, since evidence for the presence of halite on Mars and on several moons in the solar system increased interest in halophiles with respect to the search for extraterrestrial life. This review deals in particular with novel findings and hypotheses on haloarchaeal long-term survival. PMID- 26226003 TI - Misdelivery at the Nuclear Pore Complex-Stopping a Virus Dead in Its Tracks. AB - Many viruses deliver their genomes into the host cell's nucleus before they replicate. While onco-retroviruses and papillomaviruses tether their genomes to host chromatin upon mitotic breakdown of the nuclear envelope, lentiviruses, such as human immunodeficiency virus, adenoviruses, herpesviruses, parvoviruses, influenza viruses, hepatitis B virus, polyomaviruses, and baculoviruses deliver their genomes into the nucleus of post-mitotic cells. This poses the significant challenge of slipping a DNA or RNA genome past the nuclear pore complex (NPC) embedded in the nuclear envelope. Quantitative fluorescence imaging is shedding new light on this process, with recent data implicating misdelivery of viral genomes at nuclear pores as a bottleneck to virus replication. Here, we infer NPC functions for nuclear import of viral genomes from cell biology experiments and explore potential causes of misdelivery, including improper virus docking at NPCs, incomplete translocation, virus-induced stress and innate immunity reactions. We conclude by discussing consequences of viral genome misdelivery for viruses and host cells, and lay out future questions to enhance our understanding of this phenomenon. Further studies into viral genome misdelivery may reveal unexpected aspects about NPC structure and function, as well as aid in developing strategies for controlling viral infections to improve human health. PMID- 26226006 TI - Prioritizing Approaches to Engage Community Members and Build Trust in Biobanks: A Survey of Attitudes and Opinions of Adults within Outpatient Practices at the University of Maryland. AB - BACKGROUND: Achieving high participation of communities representative of all sub populations is needed in order to ensure broad applicability of biobank study findings. This study aimed to understand potentially mutable attitudes and opinions commonly correlated with biobank participation in order to inform approaches to promote participation in biobanks. METHODS: Adults from two University of Maryland (UMD) Faculty Physicians, Inc. outpatient practices were invited to watch a video and complete a survey about a new biobank initiative. We used: Chi-square to assess the relationship between willingness to join the biobank and participant characteristics, other potentially mutable attitudes and opinions, and trust in the UMD. We also used t-test to assess the relationship with trust in medical research. We also prioritize proposed actions to improve attitudes and opinions about joining biobanks according to perceived responsiveness. RESULTS: 169 participants completed the study, 51% of whom indicated a willingness to join the biobank. Willingness to join the biobank was not associated with age, gender, race, or education but was associated with respondent comfort sharing samples and clinical information, concerns related to confidentiality, potential for misuse of information, trust in UMD, and perceived health benefit. In ranked order, potential actions we surveyed that might alleviate some of these concerns include: increase chances to learn more about the biobank, increase opportunities to be updated, striving to put community concerns first, including involving community members as leaders of biobank research, and involving community members in decision making. CONCLUSIONS: This study identified several attitudes and opinions that influence decisions to join a biobank, including many concerns that could potentially be addressed by engaging community members. We also demonstrate our method of prioritizing ways to improve attitudes and opinions about joining a biobank according to perceived responsiveness. PMID- 26226007 TI - The Internet Process Addiction Test: Screening for Addictions to Processes Facilitated by the Internet. AB - The Internet Process Addiction Test (IPAT) was created to screen for potential addictive behaviors that could be facilitated by the internet. The IPAT was created with the mindset that the term "Internet addiction" is structurally problematic, as the Internet is simply the medium that one uses to access various addictive processes. The role of the internet in facilitating addictions, however, cannot be minimized. A new screening tool that effectively directed researchers and clinicians to the specific processes facilitated by the internet would therefore be useful. This study shows that the Internet Process Addiction Test (IPAT) demonstrates good validity and reliability. Four addictive processes were effectively screened for with the IPAT: Online video game playing, online social networking, online sexual activity, and web surfing. Implications for further research and limitations of the study are discussed. PMID- 26226008 TI - The Regulation of Reverse Cholesterol Transport and Cellular Cholesterol Homeostasis by MicroRNAs. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that have the ability to post transcriptionally regulate gene expression. Hundreds of miRNAs have been identified in humans and they are involved in the regulation of almost every process, including cholesterol transport, metabolism, and maintenance of cholesterol homeostasis. Because of their small size and their ability to very specifically regulate gene expression, miRNAs are attractive targets for the regulation of dyslipidemias and other lipid-related disorders. However, the complex interactions between miRNAs, transcription factors, and gene expression raise great potential for side effects as a result of miRNA overexpression or inhibition. Many dietary components can also target specific miRNAs, altering the expression of downstream genes. Therefore, much more research is necessary to fully understand the role(s) of each miRNA in the body and how they may be impacted by diet and health. The present review aims to summarize the known roles of miRNAs in the regulation of reverse cholesterol transport and the maintenance of cholesterol homeostasis, as well as the potential clinical consequences of their manipulation. PMID- 26226009 TI - Introducing RISC: A New Video Inventory for Testing Social Perception. AB - Indirect forms of speech, such as sarcasm, jocularity (joking), and 'white lies' told to spare another's feelings, occur frequently in daily life and are a problem for many clinical populations. During social interactions, information about the literal or nonliteral meaning of a speaker unfolds simultaneously in several communication channels (e.g., linguistic, facial, vocal, and body cues); however, to date many studies have employed uni-modal stimuli, for example focusing only on the visual modality, limiting the generalizability of these results to everyday communication. Much of this research also neglects key factors for interpreting speaker intentions, such as verbal context and the relationship of social partners. Relational Inference in Social Communication (RISC) is a newly developed (English-language) database composed of short video vignettes depicting sincere, jocular, sarcastic, and white lie social exchanges between two people. Stimuli carefully manipulated the social relationship between communication partners (e.g., boss/employee, couple) and the availability of contextual cues (e.g. preceding conversations, physical objects) while controlling for major differences in the linguistic content of matched items. Here, we present initial perceptual validation data (N = 31) on a corpus of 920 items. Overall accuracy for identifying speaker intentions was above 80% correct and our results show that both relationship type and verbal context influence the categorization of literal and nonliteral interactions, underscoring the importance of these factors in research on speaker intentions. We believe that RISC will prove highly constructive as a tool in future research on social cognition, inter-personal communication, and the interpretation of speaker intentions in both healthy adults and clinical populations. PMID- 26226010 TI - The role of genetic variants in CRP in radiographic severity in African Americans with early and established rheumatoid arthritis. AB - This study investigates the association of CRP (C-reactive protein) single nucleotide polymorphisms (SNPs) with plasma CRP levels and radiographic severity in African Americans with early and established rheumatoid arthritis (RA). Using a cross-sectional case-only design, CRP SNPs were genotyped in two independent sets of African Americans with RA: Consortium for the Longitudinal Evaluation of African Americans with RA (CLEAR 1) and CLEAR 2. Radiographic data and CRP measurements were available for 294 individuals from CLEAR 1 (median (interquartile range (IQR) 25-75) disease duration of 1 (0.6-1.6) year) and in 407 persons from CLEAR 2 (median (IQR 25-75) disease duration of 8.9 (3.5-17.7) years). In CLEAR 1, in adjusted models, the minor allele of rs2808630 was associated with total radiographic score (incident rate ratio 0.37 (95% confidence interval (CI) 0.19-0.74), P-value=0.0051). In CLEAR 2, the minor allele of rs3093062 was associated with increased plasma CRP levels (P value=0.002). For each rs3093062 minor allele, the plasma CRP increased by 1.51 (95% CI 1.15-1.95) mg dl(-1) when all the other covariates remained constant. These findings have important implications for assessment of the risk of joint damage in African Americans with RA. PMID- 26226011 TI - The Crohn's disease-associated polymorphism in ATG16L1 (rs2241880) reduces SHIP gene expression and activity in human subjects. AB - Crohn's disease (CD) is a polygenic immune-mediated disease characterized by gastrointestinal inflammation. Mice deficient in the hematopoietic-restricted SH2 domain-containing inositolpolyphosphate 5'-phosphatase (SHIP) develop spontaneous CD-like ileal inflammation. Intriguingly, SHIP mRNA is not upregulated in biopsies from patients with ileal CD despite immune cell infiltration, but SHIP's role in human CD remains unknown. We analyzed SHIP mRNA expression and activity in biopsies and peripheral blood mononuclear cells (PBMCs) from control and treatment-naive subjects with ileal CD, and demonstrated that SHIP mRNA and activity were lower in hematopoietic cells in ileal biopsies and PBMCs from subjects with CD. In all tissues from our patient cohort and in PBMCs from a second healthy control cohort, subjects homozygous for the autophagy-related 16 like protein (ATG16L1) CD-associated gene variant (rs2241880), had low SHIP mRNA expression and activity. SHIP protein expression increased during autophagy and SHIP upregulation was dependent on ATG16L1 and/or autophagy, as well as the ATG16L1 CD-associated gene variant. Finally, homozygosity for the ATG16L1 risk variant and low SHIP mRNA expression is inversely related to increased (LPS+ATP) induced IL-1beta production by PBMCs in our cohorts and was regulated by increased transcription of ILIB. These data suggest a novel mechanism by which the ATG16L1 CD-associated gene variant may predispose people to develop intestinal inflammation. PMID- 26226013 TI - dTRPA1 Modulates Afternoon Peak of Activity of Fruit Flies Drosophila melanogaster. AB - Daily rhythms in Drosophila under semi-natural conditions (or SN) have received much recent attention. One of the striking differences in the behaviour of wild type flies under SN is the presence of an additional peak of activity in the middle of the day. This is referred to as the afternoon peak (A-peak) and is absent under standard laboratory regimes using gated light and temperature cues. Although previous reports identified the physical factors that contribute towards the A-peak there is no evidence for underlying molecular mechanisms or pathways that control A-peak. We report that the A-peak is mediated by thermosensitive dTRPA1 (drosophila Transient Receptor Potential- A1) ion channels as this peak is absent in dTRPA1 null mutants. Further, when natural cycles of light and temperature are simulated in the lab, we find that the amplitude of the A-peak is dTRPA1-dependent. Although a few circadian neurons express dTRPA1, we show that modulation of A-peak is primarily influenced by non-CRY dTRPA1 expressing neurons. Hence, we propose that A-peak of activity observed under SN is a temperature sensitive response in flies that is elicited through dTRPA1 receptor signalling. PMID- 26226012 TI - G-protein-coupled receptor kinases in inflammation and disease. AB - G-protein-coupled receptor kinases (GRKs) are serine/threonine protein kinases originally discovered for their role in G-protein-coupled receptor (GPCR) phosphorylation. Recent studies have demonstrated a much broader function for this kinase family including phosphorylation of cytosolic substrates involved in cell signaling pathways stimulated by GPCRs, as well as by non-GPCRs. In addition, GRKs modulate signaling via phosphorylation-independent functions. Because of these various biochemical functions, GRKs have been shown to affect critical physiological and pathophysiological processes, and thus are considered as drug targets in diseases such as heart failure. Role of GRKs in inflammation and inflammatory diseases is an evolving area of research and several studies including work from our lab in the recent years have demonstrated critical role of GRKs in the immune system. In this review, we discuss the classical and the newly emerging functions of GRKs in the immune system and their role in inflammation and disease processes. PMID- 26226014 TI - Identification of Habitat-Specific Biomes of Aquatic Fungal Communities Using a Comprehensive Nearly Full-Length 18S rRNA Dataset Enriched with Contextual Data. AB - Molecular diversity surveys have demonstrated that aquatic fungi are highly diverse, and that they play fundamental ecological roles in aquatic systems. Unfortunately, comparative studies of aquatic fungal communities are few and far between, due to the scarcity of adequate datasets. We combined all publicly available fungal 18S ribosomal RNA (rRNA) gene sequences with new sequence data from a marine fungi culture collection. We further enriched this dataset by adding validated contextual data. Specifically, we included data on the habitat type of the samples assigning fungal taxa to ten different habitat categories. This dataset has been created with the intention to serve as a valuable reference dataset for aquatic fungi including a phylogenetic reference tree. The combined data enabled us to infer fungal community patterns in aquatic systems. Pairwise habitat comparisons showed significant phylogenetic differences, indicating that habitat strongly affects fungal community structure. Fungal taxonomic composition differed considerably even on phylum and class level. Freshwater fungal assemblage was most different from all other habitat types and was dominated by basal fungal lineages. For most communities, phylogenetic signals indicated clustering of sequences suggesting that environmental factors were the main drivers of fungal community structure, rather than species competition. Thus, the diversification process of aquatic fungi must be highly clade specific in some cases.The combined data enabled us to infer fungal community patterns in aquatic systems. Pairwise habitat comparisons showed significant phylogenetic differences, indicating that habitat strongly affects fungal community structure. Fungal taxonomic composition differed considerably even on phylum and class level. Freshwater fungal assemblage was most different from all other habitat types and was dominated by basal fungal lineages. For most communities, phylogenetic signals indicated clustering of sequences suggesting that environmental factors were the main drivers of fungal community structure, rather than species competition. Thus, the diversification process of aquatic fungi must be highly clade specific in some cases. PMID- 26226015 TI - Intravitreally Injected Anti-VEGF Antibody Reduces Brown Fat in Neonatal Mice. AB - Anti-vascular endothelial growth factor (VEGF) agents are the mainstay treatment for various angiogenesis-related retinal diseases. Currently, bevacizumab, a recombinant humanized anti-VEGF antibody, is trailed in retinopathy of prematurity, a vasoproliferative retinal disorder in premature infants. However, the risks of systemic complications after intravitreal injection of anti-VEGF antibody in infants are not well understood. In this study, we show that intravitreally injected anti-VEGF antibody is transported into the systemic circulation into the periphery where it reduces brown fat in neonatal C57BL/6 mice. A considerable amount of anti-VEGF antibody was detected in serum after intravitreal injection. Furthermore, in interscapular brown adipose tissue, we found lipid droplet accumulation, decreased VEGF levels, loss of vascular network, and decreased expression of mitochondria-related genes, Ppargc1a and Ucp1, all of which are characteristics of "whitening" of brown fat. With increasing age and body weight, brown fat restored its morphology and vascularity. Our results show that there is a transient, but significant impact of intravitreally administered anti-VEGF antibody on brown adipose tissue in neonatal mice. We suggest that more attention should be focused on the metabolic and developmental significance of brown adipose tissue in bevacizumab treated retinopathy of prematurity infants. PMID- 26226016 TI - The Effects of Royal Jelly on Fitness Traits and Gene Expression in Drosophila melanogaster. AB - Royal Jelly (RJ) is a product made by honey bee workers and is required for queen differentiation and accompanying changes in queen body size, development time, lifespan and reproductive output relative to workers. Previous studies have reported similar changes in Drosophila melanogaster in response to RJ. Here, we quantified viability, development time, body size, productivity, lifespan and genome wide transcript abundance of D. melanogaster reared on standard culture medium supplemented with increasing concentrations of RJ. We found that lower concentrations of RJ do induce significant differences in body size in both sexes; higher concentrations reduce size, increase mortality, shorten lifespan and reduce productivity. Increased concentrations of RJ also consistently lengthened development time in both sexes. RJ is associated with changes in expression of 1,581 probe sets assessed using Affymetrix Drosophila 2.0 microarrays, which were enriched for genes associated with metabolism and amino acid degradation. The transcriptional changes are consistent with alterations in cellular processes to cope with excess nutrients provided by RJ, including biosynthesis and detoxification, which might contribute to accelerated senescence and reduced lifespan. PMID- 26226017 TI - A Report of At-Scale Distribution of Chlorhexidine Digluconate 7.1% Gel for Newborn Cord Care to 36,404 Newborns in Sokoto State, Nigeria: Initial Lessons Learned. AB - BACKGROUND: With an annual estimated 276,000 neonatal deaths, Nigeria has the second highest of any country in the world. Global progress in accelerating neonatal deaths is hinged to scaled-up interventions in Nigeria. We used routine data of chlorhexidine digluconate 7.1% gel utilized by 36,404 newborns delivered by 36,370 mothers, to study lessons associated with at-scale distribution in Sokoto State, North West Nigeria. METHODS AND FINDINGS: Under state government leadership, a community-based distribution system overseen by 244 ward development committees and over 3,440 community-based health volunteers and community drug keepers, was activated to deliver two locally stored medicines to women when labor commenced. Newborns and their mothers were tracked through 28 days and 42 days respectively, including verbal autopsy results. 36,404 or 26.3% of expected newborns received the gel from April 2013 to December 2013 throughout all 244 wards in the State. 99.97% of newborns survived past 28 days. There were 124 pre-verified neonatal deaths reported. Upon verification using verbal autopsy procedures, 76 deaths were stillborn and 48 were previously live births. Among the previous 48 live births, the main causes of death were sepsis (40%), asphyxia (29%) and prematurity (8%). Underuse of logistics management information by government in procurement decisions and not accounting for differences in LGA population sizes during commodity distribution, severely limited program scalability. CONCLUSIONS: Enhancements in the predictable availability and supply of chlorhexidine digluconate 7.1% gel to communities through better, evidence based logistics management by the state public sector will most likely dramatically increase program scalability. Infections as a cause of mortality in babies delivered in home settings may be much higher than previously conceived. In tandem with high prevalence of stillborn deaths, delivery, interventions designed to increase mothers' timely and regular use of quality antenatal care, and increased facility-based based delivery, need urgent attention. We call for accelerated investments in community health volunteer programs and the requisite community measurement systems to better track coverage. We also advocate for the development, refinement and use of routine community-based verbal autopsies to track newborn and maternal survival. PMID- 26226018 TI - A NEW ERA FOR HEALTHCARE: PRECISION MEDICINE. PMID- 26226019 TI - Experiences of Individuals With Liver Cirrhosis: A Qualitative Study. AB - Liver cirrhosis is one of the main causes of mortality and morbidity worldwide. Health-related quality of life in cirrhotic patients is affected by the disease's complications. The purpose of this article was to describe the experiences of individuals with liver cirrhosis during critical illness. The aim was to investigate the disease experiences of liver cirrhosis. The authors conducted a phenomenological qualitative study, using a Colaizzi's seven-step method. Ten participants with liver cirrhosis participated in in-depth interviews. The data from this analysis were transformed into 119 codes, 11 subthemes, and 4 main themes including (1) confronting tension, (2) needs, (3) spirituality, and (4) interaction and effective communication. Findings could be used as a basis for information and emotional and social support interventions, as these can be effective in promoting adjustment to complications of cirrhosis by suitable interventions. Adequate adjustment through adaptation leads to successful completion of treatment and improved quality of life. PMID- 26226020 TI - Effect of Feeding and Suction on Gastric Impedance Spectroscopy Measurements. AB - A specific device and system has been developed and tested for clinical monitoring of gastric mucosal reactance in the critically ill as an early warning of splanchnic hypoperfusion associated with shock and sepsis. This device has been proven effective in clinical trials and is expected to become commercially available next year. The system uses a combination nasogastric tube and impedance spectroscopy probe as a single catheter. Because this device has a double function, the question is: Does enteral feeding or suction affect the gastric reactance measurements? This study was designed to evaluate the effect of feeding and suction on the measurement of gastric impedance spectroscopy in healthy volunteers. Impedance spectra were obtained from the gastric wall epithelia of 18 subjects. The spectra were measured for each of the following conditions: postinsertion of gastric probe, during active suction, postactive suction, and during enteral feeding (236 ml of nutritional supplement). Impedance spectra were reproducible in all volunteers under all conditions tested. There was a slight increase in impedance parameters after suction, and a decrease in impedance after feeding; however, these observed differences were insignificant compared to patient-to-patient variability, and truly negligible compared with previously observed changes associated with splanchnic ischemia in critically ill patients. Our results demonstrate that suction or feeding when using the impedance spectro metry probe/nasogastric tube does not significantly interfere with gastric impedance spectrometer measurements. PMID- 26226021 TI - A Comparative Study of Quality of Life in Persons With Irritable Bowel Syndrome and Inflammatory Bowel Disease. AB - Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder; however, it remains poorly understood. Inflammatory bowel disease (IBD) is a chronic, organic bowel disease characterized by young age of onset, debilitating symptoms, and invasive and toxic treatment options. This study aimed to determine the impact of IBS and IBD on health-related quality of life (HRQoL) and the ways by which these conditions affect HRQoL, with the purpose of informing nurse specialists in gastroenterology who are best placed to support HRQoL improvements. Quality of life, symptom, and demographic data were collected from patients with IBS and IBD and tabulated and examined. Analysis of data demonstrated that HRQoL is significantly lower in IBS than in IBD. However, the ways by which these two conditions affect HRQoL differs, with greater impairments in social and emotional aspects of life in individuals with IBS. Bowel symptoms were the same or worse in IBD. PMID- 26226022 TI - Jordanian Critical Care Nurses' Practices Regarding Enteral Nutrition. AB - In Jordan, there is a gap in literature regarding nurses' practices of enteral nutrition. Thus, the purpose of this study was to assess nurses' practices regarding enteral nutrition of critically ill adult patients. A descriptive, cross-sectional design was used to collect data through self-reported questionnaires and descriptive analyses were used to display the results of the study. The results revealed that some aspects of enteral nutrition practices were consistent with the current best evidences such as initiation time of enteral nutrition and backrest elevation. On the contrary, some aspects showed variations and inconsistency with current best evidences such as the amount of high gastric residual volume and its management. Nurses' practices regarding enteral nutrition were not consistent with international guidelines. This inconsistency can predispose patients to underfeeding. Enhancement of research utilization is highly recommended as well as establishing evidence-based guidelines. PMID- 26226023 TI - Looping and Abdominal Pressure: A Visual Guide to a Successful Colonoscopy. AB - Looping is a common occurrence during colonoscopy. Once a loop has occurred and the endoscopist has reduced it, abdominal pressure given by the technician will help the loop from re-forming. In this article, we discuss some of the common loops that are formed, the methods the endoscopist must employ to reduce the loop, and the type of abdominal pressure used by the technician to help prevent the loop from re-forming and, thus, help attain cecal intubation. Hand placement for abdominal pressure is discussed and illustrated to provide a visual guide for the technician. PMID- 26226025 TI - Informed Consent for GI Endoscopy-Do the Time and Place Matter? PMID- 26226026 TI - Reducing the Risk for Colon Cancer With Healthy Food Choices and Physical Activity. PMID- 26226028 TI - Gastroenterology Endoscopy Nurses as Important Evaluators of Gastroenterology Fellow Performance: A Proposed Model Evaluation Form. PMID- 26226044 TI - Basic Prion Science "Spreads" Insight. PMID- 26226029 TI - A Phase 1c Trial Comparing the Efficacy and Safety of a New Aqueous Formulation of Alphaxalone with Propofol. AB - BACKGROUND: PhaxanTM (PHAX, Chemic Labs, Canton, MA) is an aqueous solution of 10 mg/mL alphaxalone and 13% 7-sulfobutylether beta-cyclodextrin (betadex). In preclinical studies, PHAX is a fast onset-offset IV anesthetic like propofol, but causes less cardiovascular depression. This first-in-man study was designed to find the anesthetic dose of PHAX and to compare it with an equivalent dose of propofol for safety, efficacy, and quality of recovery from anesthesia and sedation. METHODS: The study adhered to compliance with Good Clinical Practices regulations (clinical trials registry number, ACTRN12611000343909). This randomized, double-blind study compared PHAX and propofol using a Bayesian algorithm to determine dose equivalence for effects on the bispectral index (BIS). Male volunteers, ASA physical status I, gave written informed consent (n = 12 per group; PHAX or propofol). Parameters assessed for 80 minutes after drug injection (single bolus dose) were pain on injection, involuntary movement, BIS, blood pressure, need for airway support, and, as measures of recovery from sedation, the Richmond Agitation and Sedation Scale and the Digit Symbol Substitution Test. Arterial blood was withdrawn for biochemistry, hematology, and complement levels. RESULTS: No subject complained of pain on injection with PHAX, whereas 8 of the 12 subjects given propofol did. Nine PHAX and 8 propofol subjects reached BIS values of <=50: median (interquartile range [IQR]) mg/kg dose = 0.5 (0.5-0.6) for PHAX and 2.9 (2.4-3.0) for propofol. The lowest median BIS reached was 27 to 28 for both agents with no significant differences between them for timing of onset and recovery of BIS. The concomitant median changes in systolic and diastolic blood pressures were -11% vs -19% for systolic and -25% vs -37% for diastolic in PHAX- and propofol-treated subjects, respectively. Nine of the 12 propofol-treated subjects and none of 12 PHAX-treated subjects required airway support. For subjects reaching an equivalent BIS of <=50: a Richmond Agitation and Sedation Scale score of 0 was reached at a median of 5 (IQR, 5-10) and 15 (IQR, 10-20) minutes after PHAX and propofol, respectively; BIS returned to 90 at a mean of 21 (SD, 10.1) and 21 (SD, 9.2) minutes after PHAX and propofol, respectively; and Digit Symbol Substitution Test scores returned to predrug injection values at median of 50 (IQR, 35-72.5) and 42.5 (IQR, 35-76.3) minutes after PHAX and propofol, respectively. There was no increase in C3 and C4 complement fractions after either drug. CONCLUSIONS: PHAX causes fast-onset, short-duration anesthesia with fast cognitive recovery similar to propofol, but with less cardiovascular depression, or airway obstruction and no pain on injection. PMID- 26226045 TI - School-based screening of plantar pressures during level walking with a backpack among overweight and obese schoolchildren. AB - Among children, postural modifications due to backpack carriage have direct consequences on how forces are exchanged between body and ground and thus on plantar pressure distribution. However, it is unknown whether such alterations are influenced by the foot structure and functionality typical of obesity. In this study, we tested 65 overweight/obese primary schoolchildren using a pressure platform while walking with and without the backpack. Contact areas, arch index, peak and mean plantar pressures in the forefoot, midfoot and rearfoot were compared with those from an additional 65 age- and gender-matched group of normal weight children. Backpack carriage modified pressure distribution similarly in both groups, with the exception of mean midfoot pressure, which increased significantly among normal-weight children but not in the overweight/obese group. Notably, the pressure values associated with mass excess and backpack carriage still raise some concerns regarding potential long-term adverse consequences on foot structure and functionality of overweight/obese children. Practitioner summary: Backpack carriage by overweight/obese schoolchildren altered plantar pressures similar to what was observed in their normal-weight peers. Yet, high pressures were found among the overweight/obese children. This raises concerns regarding potential long-term adverse consequences on foot structure and functionality, and supports establishing more specific limits for the carried load. PMID- 26226046 TI - Structural and Functional Studies of Influenza Virus A/H6 Hemagglutinin. AB - In June 2013, the first human infection by avian influenza A(H6N1) virus was reported in Taiwan. This incident raised the concern for possible human epidemics and pandemics from H6 viruses. In this study, we performed structural and functional investigation on the hemagglutinin (HA) proteins of the human infecting A/Taiwan/2/2013(H6N1) (TW H6) virus and an avian A/chicken/Guangdong/S1311/2010(H6N6) (GD H6) virus that transmitted efficiently in guinea pigs. Our results revealed that in the presence of HA1 Q226, the triad of HA1 S137, E190 and G228 in GD H6 HA allows the binding to both avian- and human-like receptors with a slight preference for avian receptors. Its conservation among the majority of H6 HAs provides an explanation for the broader host range of this subtype. Furthermore, the triad of N137, V190 and S228 in TW H6 HA may alleviate the requirement for a hydrophobic residue at HA1 226 of H2 and H3 HAs when binding to human-like receptors. Consequently, TW H6 HA has a slight preference for human receptors, thus may represent an intermediate towards a complete human adaptation. Importantly, the triad observed in TW H6 HA is detected in 74% H6 viruses isolated from Taiwan in the past 14 years, suggesting an elevated threat of H6 viruses from this region to human health. The novel roles of the triad at HA1 137, 190 and 228 of H6 HA in binding to receptors revealed here may also be used by other HA subtypes to achieve human adaptation, which needs to be further tested in laboratory and closely monitored in field surveillance. PMID- 26226047 TI - Identification and characterization of a novel ISG15-ubiquitin mixed chain and its role in regulating protein homeostasis. AB - As a ubiquitin-like modifier, ISG15 is conjugated to many cellular proteins in a process termed protein ISGylation. However, the crosstalk between protein ISGylation and the ubiquitin proteasome system is not fully understood. Here, we report that cellular ubiquitin is a substrate of ISG15 and Lys 29 on ubiquitin is the major ISG15 acceptor site. Using a model substrate, we demonstrate that ISG15 can modify ubiquitin, which is immobilized on its substrate, to form ISG15 ubiquitin mixed chains. Furthermore, our results indicate that ISG15-ubiquitin mixed chains do not serve as degradation signals for a ubiquitin fusion degradation substrate. Accordingly, an ISG15-ubiquitin fusion protein, which mimics an ISG15-ubiquitin mixed chain, negatively regulates cellular turnover of ubiquitylated proteins. In addition, ISG15-ubiquitin mixed chains, which are detectable on endogenously ubiquitylated proteins, dampen cellular turnover of these proteins. Thus, our studies unveil an unanticipated interplay between two protein modification systems and highlight its role in coordinating protein homeostasis. PMID- 26226048 TI - Optimal Prediction of Moving Sound Source Direction in the Owl. AB - Capturing nature's statistical structure in behavioral responses is at the core of the ability to function adaptively in the environment. Bayesian statistical inference describes how sensory and prior information can be combined optimally to guide behavior. An outstanding open question of how neural coding supports Bayesian inference includes how sensory cues are optimally integrated over time. Here we address what neural response properties allow a neural system to perform Bayesian prediction, i.e., predicting where a source will be in the near future given sensory information and prior assumptions. The work here shows that the population vector decoder will perform Bayesian prediction when the receptive fields of the neurons encode the target dynamics with shifting receptive fields. We test the model using the system that underlies sound localization in barn owls. Neurons in the owl's midbrain show shifting receptive fields for moving sources that are consistent with the predictions of the model. We predict that neural populations can be specialized to represent the statistics of dynamic stimuli to allow for a vector read-out of Bayes-optimal predictions. PMID- 26226050 TI - Charge Transfer-Induced Molecular Hole Doping into Thin Film of Metal-Organic Frameworks. AB - Despite the highly porous nature with significantly large surface area, metal organic frameworks (MOFs) can be hardly used in electronic and optoelectronic devices due to their extremely poor electrical conductivity. Therefore, the study of MOF thin films that require electron transport or conductivity in combination with the everlasting porosity is highly desirable. In the present work, thin films of Co3(NDC)3DMF4 MOFs with improved electronic conductivity are synthesized using layer-by-layer and doctor blade coating techniques followed by iodine doping. The as-prepared and doped films are characterized using FE-SEM, EDX, UV/visible spectroscopy, XPS, current-voltage measurement, photoluminescence spectroscopy, cyclic voltammetry, and incident photon to current efficiency measurements. In addition, the electronic and semiconductor properties of the MOF films are characterized using Hall Effect measurement, which reveals that, in contrast to the insulator behavior of the as-prepared MOFs, the iodine doped MOFs behave as a p-type semiconductor. This is caused by charge transfer-induced hole doping into the frameworks. The observed charge transfer-induced hole doping phenomenon is also confirmed by calculating the densities of states of the as prepared and iodine doped MOFs based on density functional theory. Photoluminescence spectroscopy demonstrates an efficient interfacial charge transfer between TiO2 and iodine doped MOFs, which can be applied to harvest solar radiations. PMID- 26226049 TI - Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2. AB - Hypoxia inducible factor (HIF) transcription factors reside at the center of signaling pathways used by mammalian cells to sense and respond to low oxygen levels. While essential to maintain oxygen homeostasis, misregulation of HIF protein activity correlates with tumor development and metastasis. To provide artificial routes to target misregulated HIF activity, we identified small molecule antagonists of the HIF-2 transcription factor that bind an internal cavity within the C-terminal PAS domain of the HIF-2alpha subunit. Here we describe a new class of chiral small molecule ligands that provide the highest affinity binding, the most effective, isoform-selective inhibition of HIF-2 in cells, and trigger the largest protein conformation changes reported to date. The current results further illuminate the molecular mechanism of HIF-2 antagonism and suggest additional routes to develop higher affinity and potency HIF-2 antagonists. PMID- 26226052 TI - Identification With a Violent and Sadistic Aggressor: A Rorschach Study of Criminal Debt Collectors. AB - This study examined personality functioning in a group of 27 incarcerated criminal debt collectors as assessed by the Rorschach Inkblot Method (RIM; Rorschach, 1921/1942) and the Psychopathy Checklist-Revised (PCL-R; Hare, 2003 ). To explore whether these individuals represent a distinct subgroup within the violent offender population, we compared them to a group of incarcerated homicide offenders (n = 23) without a previous history of significant violence and a group who had committed less serious violent crimes (n = 21). Results revealed significantly more Rorschach indicators of past trauma (Trauma Content Index), aggressive urges (Aggressive Potential) and identification (Aggressive Content) among the debt collectors than the 2 other groups. In addition, debt collectors displayed significantly more interpersonal interest (Sum Human content), and significantly higher scores on the PCL-R. Our findings suggest that the debt collector might be viewed as a hostile variant of psychopathy. PMID- 26226051 TI - Interactions between the perception of age and ethnicity in faces: an event related potential study. AB - Face perception models propose that different facial attributes are processed by anatomically distinct neural pathways that partially overlap. Whether these attributes interact functionally is an open question. Our goal was to determine if there are interactions between age and ethnicity processing and, if so, at what temporal epoch these interactions are evident. We monitored event-related potentials on electroencephalography while subjects categorized faces by age or ethnicity in two conditions: a baseline in which the other of these two properties not being categorized was held constant and an interference condition in which it also varied, as modelled after the Garner interference paradigm. We found that, when participants were categorizing faces by age, variations in ethnicity increased the amplitude of the right face-selective N170 component. When subjects were categorizing faces by ethnicity, variations in age did not alter the N170. We concluded that there is an asymmetric pattern of influence between age and ethnicity on early face-specific stages of visual processing, which has parallels with behavioural evidence of asymmetric interactions between identity and expression processing of faces. PMID- 26226053 TI - Pickering Emulsion Gels Prepared by Hydrogen-Bonded Zein/Tannic Acid Complex Colloidal Particles. AB - Food-grade colloidal particles and complexes, which are formed via modulation of the noncovalent interactions between macromolecules and natural small molecules, can be developed as novel functional ingredients in a safe and sustainable way. For this study was prepared a novel zein/tannic acid (TA) complex colloidal particle (ZTP) based on the hydrogen-bonding interaction between zein and TA in aqueous ethanol solution by using a simple antisolvent approach. Pickering emulsion gels with high oil volume fraction (phi(oil) > 50%) were successfully fabricated via one-step homogenization. Circular dichroism (CD) and small-angle X ray scattering (SAXS) measurements, which were used to characterize the structure of zein/TA complexes in ethanol solution, clearly showed that TA binding generated a conformational change of zein without altering their supramolecular structure at pH 5.0 and intermediate TA concentrations. Consequently, the resultant ZTP had tuned near neutral wettability (theta(ow) ~ 86 degrees ) and enhanced interfacial reactivity, but without significantly decreased surface charge. These allowed the ZTP to stabilize the oil droplets and further triggered cross-linking to form a continuous network among and around the oil droplets and protein particles, leading to the formation of stable Pickering emulsion gels. Layer-by-layer (LbL) interfacial architecture on the oil-water surface of the droplets was observed, which implied a possibility to fabricate hierarchical interface microstructure via modulation of the noncovalent interaction between hydrophobic protein and natural polyphenol. PMID- 26226054 TI - Multicomponent covalent dye assembly for tight binding and sensitive sensing of L DOPA. AB - A mixture of two simple perylene-containing receptors was found to bind bifunctional L-DOPA synergistically and tightly via orthogonal boronate ester and imine bond formation in neutral aqueous solutions, the resulting three-component assembly forming optically active long fibrous aggregates. PMID- 26226055 TI - Persistent Salivary Human Papillomavirus DNA as a Surveillance Biomarker: Not Just Spitting in the Wind. PMID- 26226056 TI - Harnessing C-H Borylation/Deborylation for Selective Deuteration, Synthesis of Boronate Esters, and Late Stage Functionalization. AB - Ir-catalyzed deborylation can be used to selectively deuterate aromatic and heteroaromatic substrates. Combined with the selectivities of Ir-catalyzed C-H borylations, uniquely labeled compounds can be prepared. In addition, diborylation/deborylation reactions provide monoborylated regioisomers that complement those prepared by C-H borylation. Comparisons between Ir-catalyzed deborylations and Pd-catalyzed deborylations of diborylated indoles described by Movassaghi are made. The Ir-catalyzed process is more effective for deborylating aromatics and is generally more effective in the monodeborylation of diborylated thiophenes. These processes can be applied to complex molecules such as clopidogrel. PMID- 26226057 TI - Strain Discontinuity, Avalanche, and Memory in Carbon Nanotube Serpentine Systems. AB - This work addresses the problem of how a nano-object adheres to a supporting media. The case of study are the serpentine-like structures of single-wall carbon nanotubes (SWNTs) grown on vicinal crystalline quartz. We develop in situ nanomanipulation and confocal Raman spectroscopy in such systems, and to explain the results, we propose a dynamical equation in which static friction is treated phenomenologically and implemented as cutoff for velocities, via Heaviside step function and an adhesion force tensor. We demonstrate that the strain profiles observed along the SWNTs are due to anisotropic adhesion, adhesion discontinuities, strain avalanches, and memory effects. The equation is general enough to make predictions for various one- and two-dimensional nanosystems adhered to a supporting media. PMID- 26226059 TI - I2-Catalyzed C-O Bond Formation and Dehydrogenation: Facile Synthesis of Oxazolines and Oxazoles Controlled by Bases. AB - A general method for the synthesis of oxazolines and oxazoles was developed through I2-catalyzed C-O bond formation and dehydrogenation with the same oxidant, TBHP. By simply tuning reaction bases, either oxazolines or oxazoles were selectively produced from beta-acylamino ketones. PMID- 26226060 TI - Time-Resolved EPR as a Tool to Investigate Oxygen Quenching in Photoinitiated Radical Polymerizations. AB - It is challenging to obtain absolute rate constants for the quenching of organic radicals by molecular oxygen because they often do not present absorbance in the UV-vis range. Here, it is shown that time-resolved EPR (chemically induced dynamic electron polarization, or CIDEP) spectroscopy is useful in establishing rate constants for the addition of benzoyl radicals to molecular oxygen. It was found that benzoyl radicals are particularly reactive toward O2 and can, therefore, act as oxygen scavengers in the initiating phase of radical polymerizations. Kinetic simulations underpin this reactivity. PMID- 26226061 TI - NR2 and P3+: Accurate, Efficient Electron-Propagator Methods for Calculating Valence, Vertical Ionization Energies of Closed-Shell Molecules. AB - Two accurate and computationally efficient electron-propagator (EP) methods for calculating the valence, vertical ionization energies (VIEs) of closed-shell molecules have been identified through comparisons with related approximations. VIEs of a representative set of closed-shell molecules were calculated with EP methods using 10 basis sets. The most easily executed method, the diagonal, second-order (D2) EP approximation, produces results that steadily rise as basis sets are improved toward values based on extrapolated coupled-cluster singles and doubles plus perturbative triples calculations, but its mean errors remain unacceptably large. The outer valence Green function, partial third-order and renormalized partial third-order methods (P3+), which employ the diagonal self energy approximation, produce markedly better results but have a greater tendency to overestimate VIEs with larger basis sets. The best combination of accuracy and efficiency with a diagonal self-energy matrix is the P3+ approximation, which exhibits the best trends with respect to basis-set saturation. Several renormalized methods with more flexible nondiagonal self-energies also have been examined: the two-particle, one-hole Tamm-Dancoff approximation (2ph-TDA), the third-order algebraic diagrammatic construction or ADC(3), the renormalized third order (3+) method, and the nondiagonal second-order renormalized (NR2) approximation. Like D2, 2ph-TDA produces steady improvements with basis set augmentation, but its average errors are too large. Errors obtained with 3+ and ADC(3) are smaller on average than those of 2ph-TDA. These methods also have a greater tendency to overestimate VIEs with larger basis sets. The smallest average errors occur for the NR2 approximation; these errors decrease steadily with basis augmentations. As basis sets approach saturation, NR2 becomes the most accurate and efficient method with a nondiagonal self-energy. PMID- 26226063 TI - The Relative Effectiveness of Various Instructional Approaches During the Performance and Learning of Motor Skills. AB - The authors examined the relative effectiveness of explicit internal-oriented instructions, explicit external-oriented instructions, and unguided discovery learning on the performance, acquisition, and learning of a motor skill using novice youth soccer players. Thirty-seven players (age = 9.9 +/- 0.7 years) underwent 3 * 30 trials of instruction-specific blocks of practice. The accuracy of lofted soccer kicks was assessed under practice conditions (prior to and after the practice period and after each practice block) and transfer conditions (prior to and after the practice period). Our findings indicated that generalized explicit instructions have detrimental effects on performance, whereas the benefits of unguided discovery learning increase with the amount of practice undertaken and when performing under transfer conditions. PMID- 26226062 TI - Transient macular edema after intracameral injection of a moderately elevated dose of cefuroxime during phacoemulsification surgery. AB - IMPORTANCE: Intracameral injection of cefuroxime sodium (1 mg/0.1 mL) has been reported to reduce the risk of endophthalmitis following cataract surgery. In the United States it must be compounded, which is subject to dilution error. We describe a series of 13 eyes that received intracameral injection of cefuroxime sodium, 9 mg/0.1 mL, intraoperatively. OBSERVATIONS: On postoperative day 1, 6 of 13 eyes (46%; 95% CI, 19%-75%) had visual acuity of 20/70 or worse and macular edema. Spectral-domain optical coherence tomography of 2 eyes revealed central subfield thicknesses of 909 and 873 um. On postoperative day 4, the mean (SD) central subfield thickness was 309 (78) um in the 6 eyes with diagnosed macular edema, 279 (23) um in the fellow eyes, and 271 (38) um in the 7 exposed eyes without macular edema. The mean (SD) time to resolution of macular edema was 5.2 (1.3) days; the final central subfield thickness ranged from 193 to 293 um. All eyes, except 2 with preexisting ocular comorbidity, had a best-corrected final visual acuity at 1 month of 20/30 or better. Significant corneal edema was not observed. CONCLUSIONS AND RELEVANCE: Intracameral injection of cefuroxime sodium at a dose of 9 mg/0.1 mL was associated with transient macular edema and diminished visual acuity in 6 of 13 exposed eyes (46%), resolving largely within 1 week. PMID- 26226064 TI - Efficient Light Harvester Layer Prepared by Solid/Mist Interface Reaction for Perovskite Solar Cells. AB - A solid/mist reaction method is developed to produce well-crystallized light harvester layers without pinhole defects for perovskite solar cells. The reaction based on mist precursor can be facilely operated with low process temperature. And it can effectively control the volume of CH3NH3I solution and the reaction temperature, which affect the quality of perovskite harvester layers and the performance of perovskite solar cells remarkably. Under optimized condition, the efficiencies of devices reach 16.2% with the average efficiency of 14.9%. The solid/mist reaction is also used to fabricate planar junction solar cells and a PCE of 14.9% is obtained. PMID- 26226065 TI - Selective Monoesterification of Symmetrical Diols Using Resin-Bound Triphenylphosphine. AB - Coupling reactions to make esters and amides are among the most widely used organic transformations. We report efficient procedures for amide bond formation and for the monoesterification of symmetrical diols in excellent yields without any requirement for high dilution or slow addition using resin-bound triarylphosphonium iodide. Easy purification, low moisture sensitivity, and good to excellent yields of the products are the major advantages of this protocol. PMID- 26226066 TI - Implementation of Strategies to Recognize and Control Hypertension in a Multispecialty Clinic, Montana, 2012-2013. AB - Benefis Medical Group, in Great Falls, Montana, improved identification and treatment of hypertension through multifaceted interventions. The interventions included adopting policies for collection of vital signs, enhancing system-level reporting capability, tracking patients for the registry, and conducting patient outreach activities. From baseline to follow-up (December 2012 through September 2013), the percentage of patients with a documented blood pressure increased from 67% to 80%, the percentage diagnosed with hypertension increased from 16% to 36%, and the percentage with blood pressure control increased from 41% to 64%. Benefis Medical Group plans to sustain the successful evidence-based strategies that were adopted. PMID- 26226067 TI - Economic Evaluation of a Tai Ji Quan Intervention to Reduce Falls in People With Parkinson Disease, Oregon, 2008-2011. AB - INTRODUCTION: Exercise is effective in reducing falls in people with Parkinson disease. However, information on the cost effectiveness of this approach is lacking. We conducted a cost-effectiveness analysis of Tai Ji Quan for reducing falls among patients with mild-to-moderate Parkinson disease. METHODS: We used data from a previous intervention trial to analyze resource use costs related to intervention delivery and number of falls observed during a 9-month study period. Cost effectiveness was estimated via incremental cost-effectiveness ratio (ICER) in which Tai Ji Quan was compared with 2 alternative interventions (Resistance training and Stretching) on the primary outcome of per fall prevented and the secondary outcome of per participant quality-adjusted life years (QALY) gained. We also conducted subgroup and sensitivity analyses. RESULTS: Tai Ji Quan was more effective than either Resistance training or Stretching; it had the lowest cost and was the most effective in improving primary and secondary outcomes. Compared with Stretching, Tai Ji Quan cost an average of $175 less for each additional fall prevented and produced a substantial improvement in QALY gained at a lower cost. Results from subgroup and sensitivity analyses showed no variation in cost-effectiveness estimates. However, sensitivity analyses demonstrated a much lower ICER ($27) when only intervention costs were considered. CONCLUSION: Tai Ji Quan represents a cost-effective strategy for optimizing spending to prevent falls and maximize health gains in people with Parkinson disease. While these results are promising, they warrant further validation. PMID- 26226068 TI - Hookah-Related Twitter Chatter: A Content Analysis. AB - INTRODUCTION: Hookah smoking is becoming increasingly popular among young adults and is often perceived as less harmful than cigarette use. Prior studies show that it is common for youth and young adults to network about substance use behaviors on social media. Social media messages about hookah could influence its use among young people. We explored normalization or discouragement of hookah smoking, and other common messages about hookah on Twitter. METHODS: From the full stream of tweets posted on Twitter from April 12, 2014, to May 10, 2014 (approximately 14.5 billion tweets), all tweets containing the terms hookah, hooka, shisha, or sheesha were collected (n = 358,523). The hookah tweets from Twitter users (tweeters) with high influence and followers were identified (n = 39,824) and a random sample of 5,000 tweets was taken (13% of tweets with high influence and followers). The sample of tweets was qualitatively coded for normalization (ie, makes hookah smoking seem common and normal or portrays positive experiences with smoking hookah) or discouragement of hookah smoking, and other common themes using crowdsourcing. RESULTS: Approximately 87% of the sample of tweets normalized hookah use, and 7% were against hookah or discouraged its use. Nearly half (46%) of tweets that normalized hookah indicated that the tweeter was smoking hookah or wanted to smoke hookah, and 19% were advertisements/promotions for hookah bars or products. CONCLUSION: Educational campaigns about health harms from hookah use and policy changes regarding smoke free air laws and tobacco advertising on the Internet may be useful to help offset the influence of pro-hookah messages seen on social media. PMID- 26226069 TI - Implementing Legislation to Improve Hospital Support of Breastfeeding, New York State, 2009-2013. AB - INTRODUCTION: Increasing breastfeeding is a public health priority supported by strong evidence. In 2009, New York passed Public Health Law S 2505-a, requiring that hospitals support the World Health Organization's (WHO's) recommended "Ten Steps for Successful Breastfeeding" (Ten Steps). This legislation strengthened and codified existing New York State's hospital perinatal regulations. The purpose of this study was to assess hospital policy compliance with New York laws and regulations related to breastfeeding. METHODS: In 2009, 2011, and 2013, we collected written breastfeeding policies from 129 New York hospitals that provided maternity services. A policy review tool was developed to quantify compliance with the 28 components of breastfeeding support specified in New York Codes, Rules, and Regulations and the new legislation. In 2010 and 2012, hospitals received individual feedback from the New York State Department of Health, which informed hospitals in 2012 that formal regulatory enforcement, including potential fines, would be implemented for noncompliance. RESULTS: The number of components included in hospital policies increased from a mean of 10.4 in 2009, to 16.8 in 2011, and to 27.1 in 2013) (P < .001); a greater increase occurred from 2011 through 2013 than from 2009 through 2011 (P < .001). The percentage of hospitals with fully compliant policies increased from 0% in 2009, to 5% in 2011, and to 75% in 2013 (P < .001), and the percentage that included all WHO's 10 steps increased from 0% to 9% to 87%, respectively (P < .001). CONCLUSION: Although legislation or regulations requiring certain practices are important, monitoring with enforcement accelerates, and may be necessary for, full implementation. Future research is needed to evaluate the impact of improved hospital breastfeeding policies on breastfeeding outcomes in New York. PMID- 26226070 TI - Neolignans from Aristolochia fordiana Prevent Oxidative Stress-Induced Neuronal Death through Maintaining the Nrf2/HO-1 Pathway in HT22 Cells. AB - Bioassay-guided fractionation of the ethanolic extract of the stems of Aristolochia fordiana led to the isolation of six new dihydrobenzofuran neolignans (1-3 and 7-9), three new 2-aryldihydrobenzofurans (4-6), a new 8-O-4' neolignan (10), and 14 known analogues (11-24). The structures of compounds 1-10 were established by spectroscopic methods, and their absolute configurations were determined by analyses of the specific rotation and electronic circular dichroism data. The neuroprotective effects of compounds 1-24 against glutamate-induced cell death were tested in hippocampal neuronal cell line HT22. Compounds 17 and 20-24 exhibited moderate neuroprotective activity by increasing the endogenous antioxidant defense system. In addition, the neolignans activated the Nrf2 (nuclear factor E2-related factor 2) pathway, resulting in the increase of the expression of endogenous antioxidant protein HO-1 (heme oxygenase-1). The active compounds also preserved the levels of antiapoptotic protein Bcl-2 (B cell lymphoma/leukemia-2), which was decreased by glutamate. Collectively, these results suggested that the active neolignans protect neurons against glutamate induced cell death through maintaining the Nrf2/HO-1 signaling pathway as well as preserving the Bcl-2 protein and might be promising novel beneficial agents for oxidative stress-associated diseases. PMID- 26226071 TI - Complete Exchange of the Hydrophobic Dispersant Shell on Monodisperse Superparamagnetic Iron Oxide Nanoparticles. AB - High-temperature synthesized monodisperse superparamagnetic iron oxide nanoparticles are obtained with a strongly bound ligand shell of oleic acid and its decomposition products. Most applications require a stable presentation of a defined surface chemistry; therefore, the native shell has to be completely exchanged for dispersants with irreversible affinity to the nanoparticle surface. We evaluate by attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and thermogravimetric analysis/differential scanning calorimetry (TGA/DSC) the limitations of commonly used approaches. A mechanism and multiple exchange scheme that attains the goal of complete and irreversible ligand replacement on monodisperse nanoparticles of various sizes is presented. The obtained hydrophobic nanoparticles are ideally suited for magnetically controlled drug delivery and membrane applications and for the investigation of fundamental interfacial properties of ultrasmall core-shell architectures. PMID- 26226072 TI - A versatile thermally activated delayed fluorescence emitter for both highly efficient doped and non-doped organic light emitting devices. AB - A thermally activated delayed fluorescent (TADF) emitter (DMAC-TRZ) was reported either as the emitting dopant in a host or as the non-doped (neat) emitting layer to achieve high EL EQEs of up to 26.5% and 20% in OLEDs, respectively. PMID- 26226073 TI - Attentional Capacity Limits Gap Detection during Concurrent Sound Segregation. AB - Detecting a brief silent interval (i.e., a gap) is more difficult when listeners perceive two concurrent sounds rather than one in a sound containing a mistuned harmonic in otherwise in-tune harmonics. This impairment in gap detection may reflect the interaction of low-level encoding or the division of attention between two sound objects, both of which could interfere with signal detection. To distinguish between these two alternatives, we compared ERPs during active and passive listening with complex harmonic tones that could include a gap, a mistuned harmonic, both features, or neither. During active listening, participants indicated whether they heard a gap irrespective of mistuning. During passive listening, participants watched a subtitled muted movie of their choice while the same sounds were presented. Gap detection was impaired when the complex sounds included a mistuned harmonic that popped out as a separate object. The ERP analysis revealed an early gap-related activity that was little affected by mistuning during the active or passive listening condition. However, during active listening, there was a marked decrease in the late positive wave that was thought to index attention and response-related processes. These results suggest that the limitation in detecting the gap is related to attentional processing, possibly divided attention induced by the concurrent sound objects, rather than deficits in preattentional sensory encoding. PMID- 26226074 TI - Transcutaneous Vagus Nerve Stimulation Enhances Post-error Slowing. AB - People tend to slow down after they commit an error, a phenomenon known as post error slowing (PES). It has been proposed that slowing after negative feedback or unforeseen errors is linked to the activity of the locus coeruleus-norepinephrine (LC-NE) system, but there is little direct evidence for this hypothesis. Here, we assessed the causal role of the noradrenergic system in modulating PES by applying transcutaneous vagus nerve stimulation (tVNS), a new noninvasive and safe method to stimulate the vagus nerve and to increase NE concentrations in the brain. A single-blind, sham-controlled, between-group design was used to assess the effect of tVNS in healthy young volunteers (n = 40) during two cognitive tasks designed to measure PES. Results showed increased PES during active tVNS, as compared with sham stimulation. This effect was of similar magnitude for the two tasks. These findings provide evidence for an important role of the noradrenergic system in PES. PMID- 26226076 TI - Activation Patterns throughout the Word Processing Network of L1-dominant Bilinguals Reflect Language Similarity and Language Decisions. AB - A crucial aspect of bilingual communication is the ability to identify the language of an input. Yet, the neural and cognitive basis of this ability is largely unknown. Moreover, it cannot be easily incorporated into neuronal models of bilingualism, which posit that bilinguals rely on the same neural substrates for both languages and concurrently activate them even in monolingual settings. Here we hypothesized that bilinguals can employ language-specific sublexical (bigram frequency) and lexical (orthographic neighborhood size) statistics for language recognition. Moreover, we investigated the neural networks representing language-specific statistics and hypothesized that language identity is encoded in distributed activation patterns within these networks. To this end, German English bilinguals made speeded language decisions on visually presented pseudowords during fMRI. Language attribution followed lexical neighborhood sizes both in first (L1) and second (L2) language. RTs revealed an overall tuning to L1 bigram statistics. Neuroimaging results demonstrated tuning to L1 statistics at sublexical (occipital lobe) and phonological (temporoparietal lobe) levels, whereas neural activation in the angular gyri reflected sensitivity to lexical similarity to both languages. Analysis of distributed activation patterns reflected language attribution as early as in the ventral stream of visual processing. We conclude that in language-ambiguous contexts visual word processing is dominated by L1 statistical structure at sublexical orthographic and phonological levels, whereas lexical search is determined by the structure of both languages. Moreover, our results demonstrate that language identity modulates distributed activation patterns throughout the reading network, providing a key to language identity representations within this shared network. PMID- 26226075 TI - Extrastriate Visual Areas Integrate Form Features over Space and Time to Construct Representations of Stationary and Rigidly Rotating Objects. AB - When an object moves behind a bush, for example, its visible fragments are revealed at different times and locations across the visual field. Nonetheless, a whole moving object is perceived. Unlike traditional modal and amodal completion mechanisms known to support spatial form integration when all parts of a stimulus are simultaneously visible, relatively little is known about the neural substrates of the spatiotemporal form integration (STFI) processes involved in generating coherent object representations from a succession visible fragments. We used fMRI to identify brain regions involved in two mechanisms supporting the representation of stationary and rigidly rotating objects whose form features are shown in succession: STFI and position updating. STFI allows past and present form cues to be integrated over space and time into a coherent object even when the object is not visible in any given frame. STFI can occur whether or not the object is moving. Position updating allows us to perceive a moving object, whether rigidly rotating or translating, even when its form features are revealed at different times and locations in space. Our results suggest that STFI is mediated by visual regions beyond V1 and V2. Moreover, although widespread cortical activation has been observed for other motion percepts derived solely from form-based analyses [Tse, P. U. Neural correlates of transformational apparent motion. Neuroimage, 31, 766-773, 2006; Krekelberg, B., Vatakis, A., & Kourtzi, Z. Implied motion from form in the human visual cortex. Journal of Neurophysiology, 94, 4373-4386, 2005], increased responses for the position updating that lead to rigidly rotating object representations were only observed in visual areas KO and possibly hMT+, indicating that this is a distinct and highly specialized type of processing. PMID- 26226077 TI - Premotor Cortex Activation Elicited during Word Comprehension Relies on Access of Specific Action Concepts. AB - The relationship between the lexical-semantic and sensory-motor systems is an important topic in cognitive neuroscience. An important finding indicating that these two systems interact is that reading action verbs activates the motor system of the human brain. Two constraints have been proposed to modulate this activation: the effector information associated with the action concepts and statistical regularities between sublexical features and grammatical classes. Using fMRI, we examined whether these two types of information can activate the motor system in the absence of specific motor-semantic content by manipulating the existence of a sublexical cue, called the hand radical, which strongly indicates the semantic feature "hand-related" and grammatical class "verb." Although hand radical characters referring to specific manual actions evoked stronger activation in the premotor cortex than the control characters, hand radical pseudocharacters did not evoke specific activation within the motor system. These results indicated that activation of the premotor cortex during word reading relies on the access of specific action concepts. PMID- 26226078 TI - Visual Awareness Is Limited by the Representational Architecture of the Visual System. AB - Visual perception and awareness have strict limitations. We suggest that one source of these limitations is the representational architecture of the visual system. Under this view, the extent to which items activate the same neural channels constrains the amount of information that can be processed by the visual system and ultimately reach awareness. Here, we measured how well stimuli from different categories (e.g., faces and cars) blocked one another from reaching awareness using two distinct paradigms that render stimuli invisible: visual masking and continuous flash suppression. Next, we used fMRI to measure the similarity of the neural responses elicited by these categories across the entire visual hierarchy. Overall, we found strong brain-behavior correlations within the ventral pathway, weaker correlations in the dorsal pathway, and no correlations in early visual cortex (V1-V3). These results suggest that the organization of higher level visual cortex constrains visual awareness and the overall processing capacity of visual cognition. PMID- 26226079 TI - SMA Selectively Codes the Active Accumulation of Temporal, Not Spatial, Magnitude. AB - Estimating duration depends on the sequential integration (accumulation) of temporal information in working memory. Using fMRI, we directly compared the accumulation of information in temporal versus spatial domains. Participants estimated either the duration or distance of the dynamic trajectory of a moving dot or, in a control condition, a static line stimulus. Comparing the duration versus distance of static lines activated an extensive cortico-striatal network. By contrast, comparing the duration versus distance of dynamic trajectories, both of which required sequential integration of information, activated SMA alone. Indeed, activity in SMA, as well as right inferior occipital cortex, increased parametrically as a function of stimulus duration and also correlated with individual differences in the propensity to overestimate stimulus duration. By contrast, activity in primary visual cortex increased parametrically as a function of stimulus distance. Crucially, a direct comparison of the parametric responses to duration versus distance revealed that activity in SMA increased incrementally as a function of stimulus duration but not as a function of stimulus distance. Collectively, our results indicate that SMA responds to the active accumulation of information selectively in the temporal domain. PMID- 26226080 TI - Toroidal Packaging of pDNA into Block Ionomer Micelles Exerting Promoted in Vivo Gene Expression. AB - Selectively spooling single plasmid DNA (pDNA), as a giant polyelectrolyte, into a nanosized toroidal structure or folding it into a rod-like structure has been accomplished by polyion complexation with block catiomers to form polymeric micelles in varying NaCl concentrations. The interactive potency between the pDNA and block catiomers was determined to play a critical role in defining the ultimate structure of the pDNA; the formation of toroidal or rod-like structures was achieved by complexation in 600 or 0 mM NaCl solutions, respectively. Compared with the rod-like structure, the toroidal structure possessed superior biological functions capable not only of elevating in vitro transcription but also of elevating in vivo gene transduction efficiency. This demonstrated the great utility of the toroidal pDNA packaging as a distinct structured gene carrier. Furthermore, the fact that the NaCl concentration at which the toroidal structure was specifically formed corresponds to seawater stimulates interest in this ordered nanostructure as a possible inherent structure for DNA. PMID- 26226081 TI - EPI-CT: design, challenges and epidemiological methods of an international study on cancer risk after paediatric and young adult CT. AB - Computed tomography (CT) has great clinical utility and its usage has increased dramatically over the years. Concerns have been raised, however, about health impacts of ionising radiation exposure from CTs, particularly in children, who have a higher risk for some radiation induced diseases. Direct estimation of the health impact of these exposures is needed, but the conduct of epidemiological studies of paediatric CT populations poses a number of challenges which, if not addressed, could invalidate the results. The aim of the present paper is to review the main challenges of a study on the health impact of paediatric CTs and how the protocol of the European collaborative study EPI-CT, coordinated by the International Agency for Research on Cancer (IARC), is designed to address them. The study, based on a common protocol, is being conducted in Belgium, Denmark, France, Germany, the Netherlands, Norway, Spain, Sweden and the United Kingdom and it has recruited over one million patients suitable for long-term prospective follow-up. Cohort accrual relies on records of participating hospital radiology departments. Basic demographic information and technical data on the CT procedure needed to estimate organ doses are being abstracted and passive follow-up is being conducted by linkage to population-based cancer and mortality registries. The main issues which may affect the validity of study results include missing doses from other radiological procedures, missing CTs, confounding by CT indication and socioeconomic status and dose reconstruction. Sub-studies are underway to evaluate their potential impact. By focusing on the issues which challenge the validity of risk estimates from CT exposures, EPI-CT will be able to address limitations of previous CT studies, thus providing reliable estimates of risk of solid tumours and leukaemia from paediatric CT exposures and scientific bases for the optimisation of paediatric CT protocols and patient protection. PMID- 26226082 TI - Polyamine quinoline rhodium complexes: synthesis and pharmacological evaluation as antiparasitic agents against Plasmodium falciparum and Trichomonas vaginalis. AB - A series of mono- and bis-salicylaldimine ligands and their corresponding Rh(i) complexes were prepared. The compounds were characterised using standard spectroscopic techniques including NMR, IR spectroscopy and mass spectrometry. The salicylaldimine ligands and complexes were screened for antiparasitic activity against two strains of Plasmodium falciparum i.e. the NF54 CQ-sensitive and K1 CQ-resistant strain as well as against the G3 isolate of Trichomonas vaginalis. The monomeric salicylaldimine quinolines exhibited good activity against the NF54 strain and the dimeric salicylaldimine quinolines exhibited no cross resistance across the two strains. The binuclear 5-chloro Rh(i) complex displayed the best activity against the Trichomonas vaginalis parasite, possibly a consequence of its enhanced lipophilicity. The compounds were also screened for cytotoxicity in vitro against WHCO1 oesophageal cancer cells. The monomeric salicylaldimine quinolines exhibited high selectivity towards malaria parasites compared to cancer cells, while the dimeric compounds were less selective. PMID- 26226083 TI - Measurement of spatial response functions of dosimetric detectors. AB - The spatial response functions in lateral and longitudinal directions of four cylindrical ionization chambers of the types NE 2561, FC65-G, PTW 31010, and PTW 31016, two plane-parallel ionization chambers of the types PTW 34001 and PTW 34045, and one diode of the type PTW 60012 were measured in air in high-energy photon beams with nominal accelerating voltages of 4 MV, 8 MV, and 25 MV, and electron beams with nominal energies of 6 MeV, 15 MeV, and 20 MeV. The measurements were performed by moving the detectors in small steps across the edge of a lead block for the photon beams, and across a thin slit between two lead blocks for the electron beams. Monte-Carlo calculations were used to analyze the measurements and to identify contributions of the different parts of the chamber. Finally, a simple empirical model for describing the spatial response functions is established. PMID- 26226084 TI - The water-catalyzed mechanism of the ring-opening reaction of glucose. AB - The hexopyranose mutarotation is an important focus for carbohydrate chemistry for more than 150 years. The paper describes the results of advanced computational studies aimed at elucidating the ring-opening reaction of glucose. Molecular simulations based on the combination of the DFT method with the molecular dynamics formalism allowed for a detailed insight into the mechanism of the process accompanied by the information of the kinetic and dynamic nature. The results indicate that the process is initiated by deprotonation of the anomeric hydroxyl group by water molecules and the subsequent proton transfer to the ring oxygen atom. The latter event has been identified as a 'bottleneck' of the process triggering the ring cleavage. The most time-consuming steps of the ring opening reaction are the orientational rearrangements of water molecule(s) participating in the proton transfer(s) and the final extension of the newly formed aldehyde chain. The orientational preferences of the aldehyde group present in the acyclic form of D-hexopyranoses are responsible for the anomeric equilibrium characteristics. PMID- 26226085 TI - Synthesis of a series of novel heteroglycoclusters and homoglycoclusters and the study of their anti-adhesion activities. AB - A new series of mixed-type heteroglycoclusters containing mannose and lactose were synthesized. In the synthesis of rigid scaffold of heteroglycocluster, we found that trans-isomer could be prepared stereoselectively by means of Grubbs olefin cross-metathesis reactions. Moreover, sequential acylation using cyclic anhydride as scaffold could give cis-isomer. These two methods may provide complementarity of stereochemistry in heteroglycocluster assembling. The anti adhesion activities of these compounds were assessed by Surface Plasmon Resonance (SPR) and static state cell-based adhesion assay. These results indicated that the rigid scaffold might not affect the anti-adhesion activities. PMID- 26226086 TI - Neural correlates of merging number words. AB - Complex number words (e.g., "twenty two") are formed by merging together several simple number words (e.g., "twenty" and "two"). In the present study, we explored the neural correlates of this operation and investigated to what extent it engages brain areas involved processing numerical quantity and linguistic syntactic structure. Participants speaking two typologically distinct languages, French and Chinese, were required to read aloud sequences of simple number words while their cerebral activity was recorded by functional magnetic resonance imaging. Each number word could either be merged with the previous ones (e.g., 'twenty three') or not (e.g., 'three twenty'), thus forming four levels ranging from lists of number words to complex numerals. When a number word could be merged with the preceding ones, it was named faster than when it could not. Neuroimaging results showed that the number of merges correlated with activation in the left inferior frontal gyrus and in the left inferior parietal lobule. Consistent findings across Chinese and French participants suggest that these regions serve as the neural bases for forming complex number words in different languages. PMID- 26226087 TI - Reliability comparison of spontaneous brain activities between BOLD and CBF contrasts in eyes-open and eyes-closed resting states. AB - Blood oxygenation level dependent (BOLD) and arterial spin labeling (ASL) are two predominant resting-state fMRI techniques in mapping spontaneous brain activities. At single voxel level, cerebral blood flow (CBF) measured by ASL and amplitude of low frequency fluctuations (ALFF) of BOLD have been recognized as useful indices to characterize brain function in health and disease. However, no study has directly compared the test-retest reliability between BOLD and CBF contrasts on the same group of subjects at single voxel level. Moreover, both eyes-open and eyes-closed conditions have been employed as resting states, but it is still not clear which state is more reliable. Here we collected BOLD and ASL data during eyes-open and eyes-closed states across three scanning visits on twenty-two healthy young subjects. CBF-mean, BOLD- and CBF-ALFF were computed to characterize corresponding brain activities at single voxel level. Seed-based functional connectivity (FC) with the posterior cingulate cortex (PCC) was further calculated for both BOLD and CBF data. Intra-class correlation was used as the index of long-term reliability between visits 1 and 2 (two months apart) and short-term reliability between visits 2 and 3 (on the same day). Both short- and long-term reliabilities for CBF-mean and BOLD-ALFF were high, but were lower for CBF-ALFF, BOLD- and CBF-FC in both eyes-open and eyes-closed states. Direct comparisons showed that brain regions with the highest reliability of CBF-mean were mainly in the gray matter. The reliability of CBF-ALFF and BOLD-FC was lower than that of BOLD-ALFF, and the reliability of CBF-FC was lower than those of both CBF-ALFF and BOLD-FC. Furthermore, we observed that reliabilities of the eyes-open state were higher than those of the eyes-closed state for both imaging contrasts, though the effect size was small. Voxel-wise comparisons demonstrated that the long-term reliability of BOLD-ALFF was significantly higher with eyes open in the visual system, and both the short- and long-term reliability of BOLD FC was slightly higher with eyes open in the default mode network. Moreover, we showed that denoising decreased the reliability of both ALFF and FC of both BOLD and ASL contrasts. In conclusion, our results indicated that CBF-mean and BOLD ALFF could both be used as reliable indices for characterizing resting-state brain activities at single voxel level and recommended the eyes-open state for resting-state studies, especially for those targeting the visual system and default mode network. PMID- 26226089 TI - The impact of comorbid personality difficulties on response to IAPT treatment for depression and anxiety. AB - The UK's Improving Access to Psychological Therapies (IAPT) initiative provides evidence-based psychological interventions for mild to moderate common mental health problems in a primary care setting. Predictors of treatment response are unclear. This study examined the impact of personality disorder status on outcome in a large IAPT service. We hypothesised that the presence of probable personality disorder would adversely affect treatment response. METHOD: We used a prospective cohort design to study a consecutive sample of individuals (n = 1249). RESULTS: Higher scores on a screening measure for personality disorder were associated with poorer outcome on measures of depression, anxiety and social functioning, and reduced recovery rates at the end of treatment. These associations were not confounded by demographic status, initial symptom severity nor number of treatment sessions. The presence of personality difficulties independently predicted reduced absolute change on all outcome measures. CONCLUSIONS: The presence of co-morbid personality difficulties adversely affects treatment outcome among individuals attending for treatment in an IAPT service. There is a need to routinely assess for the presence of personality difficulties on all individuals referred to IAPT services. This information will provide important prognostic data and could lead to the provision of more effective, personalised treatment in IAPT. PMID- 26226088 TI - Heritability of the network architecture of intrinsic brain functional connectivity. AB - The brain's functional network exhibits many features facilitating functional specialization, integration, and robustness to attack. Using graph theory to characterize brain networks, studies demonstrate their small-world, modular, and "rich-club" properties, with deviations reported in many common neuropathological conditions. Here we estimate the heritability of five widely used graph theoretical metrics (mean clustering coefficient (gamma), modularity (Q), rich club coefficient (phinorm), global efficiency (lambda), small-worldness (sigma)) over a range of connection densities (k=5-25%) in a large cohort of twins (N=592, 84 MZ and 89 DZ twin pairs, 246 single twins, age 23 +/- 2.5). We also considered the effects of global signal regression (GSR). We found that the graph metrics were moderately influenced by genetic factors h(2) (gamma=47-59%, Q=38-59%, phinorm=0-29%, lambda=52-64%, sigma=51-59%) at lower connection densities (<= 15%), and when global signal regression was implemented, heritability estimates decreased substantially h(2) (gamma=0-26%, Q=0-28%, phinorm=0%, lambda=23-30%, sigma=0-27%). Distinct network features were phenotypically correlated (|r|=0.15 0.81), and gamma, Q, and lambda were found to be influenced by overlapping genetic factors. Our findings suggest that these metrics may be potential endophenotypes for psychiatric disease and suitable for genetic association studies, but that genetic effects must be interpreted with respect to methodological choices. PMID- 26226090 TI - Cognitive behavior therapy for comorbid migraine and/or tension-type headache and major depressive disorder: An exploratory randomized controlled trial. AB - Numerous studies have demonstrated comorbidity between migraine and tension-type headache on the one hand, and depression on the other. Presence of depression is a negative prognostic indicator for behavioral treatment of headaches. Despite the recognised comorbidity, there is a limited research literature evaluating interventions designed for comorbid headaches and depression. Sixty six participants (49 female, 17 male) suffering from migraine and/or tension-type headache and major depressive disorder were randomly allocated to a Routine Primary Care control group or a Cognitive Behavior Therapy group that also received routine primary care. The treatment program involved 12 weekly 50-min sessions administered by clinical psychologists. Participants in the treatment group improved significantly more than participants in the control group from pre to post-treatment on measures of headaches, depression, anxiety, and quality of life. Improvements achieved with treatment were maintained at four month follow up. Comorbid anxiety disorders were not a predictor of response to treatment, and the only significant predictor was gender (men improved more than women). The new integrated treatment program appears promising and worthy of further investigation. PMID- 26226091 TI - Predictors of dropout from internet-based self-help cognitive behavioral therapy for insomnia. AB - Dropout from self-help cognitive-behavioral therapy for insomnia (CBT-I) potentially diminishes therapeutic effect and poses clinical concern. We analyzed the characteristics of subjects who did not complete a 6-week internet-based CBT I program. Receiver operator characteristics (ROC) analysis was used to identify potential variables and cutoff for predicting dropout among 207 participants with self-report insomnia 3 or more nights per week for at least 3 months randomly assigned to self-help CBT-I with telephone support (n = 103) and self-help CBT-I (n = 104). Seventy-two participants (34.4%) did not complete all 6 sessions, while 42 of the 72 (56.9%) dropped out prior to the fourth session. Significant predictors of non-completion are total sleep time (TST) >= 6.82 h, Hospital Anxiety and Depression Scale depression score >= 9 and Insomnia Severity Index score < 13 at baseline in this ranking order. Only TST >= 5.92 h predicts early dropout. Longer TST and less severe insomnia predict dropout in this study of self-help CBT-I, in contrast to shorter TST as a predictor in 2 studies of face to-face CBT-I, while greater severity of depression predicts dropout in both this study and a study of face-to-face CBT-I. Strategies for minimizing dropout from internet-based CBT-I are discussed. PMID- 26226092 TI - Integrated Genomic Characterization of a Pineal Parenchymal Tumor of Intermediate Differentiation. AB - BACKGROUND: Pineal parenchymal tumors of intermediate differentiation (PPTIDs) are rare lesions. The differential diagnosis and management strategy for PPTIDs can be challenging because of the variable prognostic and pathologic characteristics of these tumors. METHODS: A 24-year-old man presented with progressive headaches, gait abnormalities, and abulia. Magnetic resonance imaging revealed a large T1-hypointense, T2-isointense, contrast-enhancing, partially cystic mass of the pineal and tectal region. Near-total resection was achieved in a 2-stage operation followed by focal and craniospinal irradiation and adjuvant chemotherapy. RESULTS: Immunohistochemical analysis including use of pineal lineage marker confirmed a diagnosis of PPTID. Targeted exome sequencing showed mutations in TSC1(L388P) and IKZF3(F206C), whereas high-resolution array cytogenetics revealed losses in chromosomes 2, 3, 4, 8, 10, 11, 17, and 20, leading to single-copy loss of PTEN and TP53. CONCLUSIONS: Pineal parenchymal tumors reflect a broad spectrum of malignancy potential and prognoses, which mandate better understanding of the disease mechanism for rational therapeutic strategies. We present a case of PPTID and report several mutations and chromosomal abnormalities previously unrecognized in this tumor subtype. Review of the literature highlights a need for surgical resection followed by adjuvant chemoradiation. Further investigation of these novel variants may improve understanding of the pathogenesis underlying pineal parenchymal tumors. PMID- 26226093 TI - Perspective on "China's Medical Education and Interventional Neuroradiology Training". PMID- 26226094 TI - Mixtures of benzo(a)pyrene, dichlorodiphenyltrichloroethane and tributyltin are more toxic to neotropical fish Rhamdia quelen than isolated exposures. AB - The effects of benzo(a)pyrene (BaP), dichlorodiphenyltrichloroethane (DDT) and tributyltin (TBT) association were investigated through a multi-biomarker approach. Ten Rhamdia quelen fish per group were exposed through intraperitoneal injections either to BaP (0.3; 3 or 30 mg kg(-1)), DDT or TBT (0.03; 0.3 or 3 mg kg(-1)) or BaP/DDT, BaP/TBT, DDT/TBT or BaP/DDT/TBT on their lowest doses. The experiments were divided in acute (one dose, 5-day) and sub-chronic (3 doses, 15 day). Control groups received an equal volume of PBS or canola oil (1 ml kg(-1)). The three tested contaminants altered AChE activity in brain and muscle in similar ways; the mixtures antagonized the increase evoked by the contaminants alone. BaP and TBT increased GSH content and mixtures reduced it. GPx activity was increased by DDT and TBT in the 15-day experiment and reduced by the mixtures. BaP increased GST activity in sub-chronic experiment while TBT reduced it in the acute experiment. BaP/TBT increased GST activity compared to all groups; the other mixtures reduced it compared to BaP or DDT in the 5-day experiment. BaP, DDT and TBT increased delta-ALAd activity mainly in acute exposure; the mixtures also increased delta-ALAd compared to DDT or TBT in 5 and 15-day. BaP, TBT and BaP/DDT decreased LPO in the acute experiment. In the sub chronic experiment DDT/TBT increased LPO when compared to TBT. None of the contaminants alone altered PCO, but all mixtures increased it compared to one or another contaminant. Contaminants isolated had a more acute effect in ALT plasma level; their lowest dose, which had no effect alone, in combination has led to an increase of this enzyme, especially after 15 days. DDT increased AST in the acute and sub-chronic experiments, while TBT did the same in the latter. DDT/TBT decreased AST opposing the effect of the contaminants alone in the 5-day experiment. Hepatic lesions index could be explained by a more acute effect of the contaminants alone or combined and by activation of cell defenses after the sub-chronic exposure. TBT increased melanomacrophages counting in the 5-day experiment and the mixtures increased it in the 5 and 15-day experiments. Overall, the majority of the biomarkers pointed to a more toxic effect when these contaminants were combined, leading to unexpected toxicities compared to individual exposure scenarios. These findings are relevant considering environmental exposure conditions, since organisms are often exposed to different combinations of contaminants. PMID- 26226095 TI - Incorporation of Noninvasive Measures of Liver Fibrosis Into Clinical Practice: Diagnosis and Prognosis. AB - Noninvasive methods are increasingly used for the assessment of liver fibrosis. Two categories of markers include serum-based markers (biologic properties) or ultrasound and magnetic resonance imaging-based techniques that use the principles of elastography (physical properties) to indirectly assess liver fibrosis. Serum markers can be either direct or indirect markers of the fibrosis process. Common elastography-based studies include vibration-controlled transient elastography, point shear wave elastography, and 2-dimensional shear wave elastography and magnetic resonance elastography. A common theme among all techniques is the inability to accurately differentiate between minimal or moderate stages of fibrosis but superior performance in identifying subjects with cirrhosis or normal liver parenchyma. Noninvasive markers may also serve as prognostic tools to course the natural history of chronic liver disease as well as identify cirrhotic patients at highest risk of future decompensation. Further research is needed to identify the role of noninvasive markers in following asymptomatic individuals, especially in patients with nonalcoholic fatty liver disease. PMID- 26226097 TI - Nonalcoholic Fatty Liver Disease Review: Diagnosis, Treatment, and Outcomes. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of abnormal serum aminotransferase levels in both developed and developing countries. Patients with nonalcoholic steatohepatitis (NASH), a subset of NAFLD, are at risk for progressive liver disease and in need of effective treatment options. A practical approach may be pursued by identifying patients with NAFLD with the highest likelihood for histologic evidence of NASH. Despite decades of clinical trials, no single treatment can be recommended to all patients with NASH. Importantly, there is no evidence that pioglitazone or vitamin E improves fibrosis. Bariatric surgeries may improve hepatic histology in morbidly obese patients with NASH, although randomized clinical trials are lacking. Currently, NASH is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. The primary and secondary prevention of NAFLD may require aggressive strategies for managing obesity, diabetes, and metabolic syndrome. PMID- 26226096 TI - Gastroesophageal Acid Reflux Control 5 Years After Antireflux Surgery, Compared With Long-term Esomeprazole Therapy. AB - BACKGROUND & AIMS: We compared the ability of laparoscopic antireflux surgery (LARS) and esomeprazole to control esophageal acid exposure, over a 5-year period, in patients with chronic gastroesophageal reflux disease (GERD). We also studied whether intraesophageal and intragastric pH parameters off and on therapy were associated with long-term outcomes. METHODS: We analyzed data from a prospective, randomized, open-label trial comparing the efficacy and safety of LARS vs esomeprazole (20 or 40 mg/d) over 5 years in patients with chronic GERD. Ambulatory intraesophageal and intragastric 24-hour pH monitoring data were compared between groups before LARS or the start of esomeprazole treatment, and 6 months and 5 years afterward. A secondary aim was to evaluate the association between baseline and 6-month pH parameters and esomeprazole dose escalation, reappearance of GERD symptoms, and treatment failure over 5 years in patients receiving LARS or esomeprazole. RESULTS: In the LARS group (n = 116), the median 24-hour esophageal acid exposure was 8.6% at baseline and 0.7% after 6 months and 5 years (P < .001 vs baseline). In the esomeprazole group (n = 151), the median 24-hour esophageal acid exposure was 8.8% at baseline, 2.1% after 6 months, and 1.9% after 5 years (P < .001, therapy vs baseline, and LARS vs esomeprazole). Gastric acidity was stable in both groups. Patients who required a dose increase to 40 mg/d had more severe supine reflux at baseline, and decreased esophageal acid exposure (P < .02) and gastric acidity after dose escalation. Esophageal and intragastric pH parameters, off and on therapy, did not predict long-term symptom breakthrough. CONCLUSIONS: In a prospective study of patients with chronic GERD, esophageal acid reflux was reduced greatly by LARS or esomeprazole therapy. However, patients receiving LARS had significantly greater reductions in 24-hour esophageal acid exposure after 6 months and 5 years. Esophageal and gastric pH, off and on therapy, did not predict long-term outcomes of patients. Abnormal supine acid exposure predicted esomeprazole dose escalation. ClinicalTrials.Gov identifier: NCT00251927 (available: http://clinicaltrials.gov/ct2/show/NCT00251927). PMID- 26226098 TI - A Rare Cause of Intermittent, Occult Lower Gastrointestinal Bleeding. PMID- 26226099 TI - Body Fat Distribution and Risk of Incident and Regressed Nonalcoholic Fatty Liver Disease. AB - BACKGROUND & AIMS: Some studies have examined correlations between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) with nonalcoholic fatty liver disease (NAFLD) or between VAT and NAFLD. We investigated the longitudinal association between body fat distribution (VAT vs SAT) and incidence and regression of NAFLD, adjusting for risk factors, in a large population-based cohort. METHODS: We collected data from adults who underwent abdominal ultrasonography (to identify liver fat), abdominal fat computed tomography scan, and blood tests from March 2007 through December 2008. Each patient underwent an anthropometric assessment and completed a questionnaire about their medical history, physical activity, and diet. Our final analysis involved 2017 subjects from the initial cohort who participated in a voluntary follow-up health screen performed in 2011 and 2013. The median follow-up time was 4.43 years. RESULTS: We found 288 incident cases of NAFLD; 159 patients had NAFLD regression during the follow-up period. An increasing area of VAT was associated with higher incidence of NAFLD in the multivariable analysis (highest quintile vs lowest quintile of VAT hazard ratio [HR], 2.23; 95% confidence interval [CI], 1.28-3.89; P for trend = .002; HR, 1.36 [per 1 standard deviation]; 95% CI, 1.16-1.59). An increased area of SAT was significantly associated with regression of NAFLD (highest quintile vs lowest quintile of SAT HR, 2.30; 95% CI, 1.28-4.12; P for trend = .002; HR, 1.36 [per 1 standard deviation]; 95% CI, 1.08-1.72). CONCLUSIONS: In a large cohort study, larger areas of VAT were longitudinally associated with higher risk of incident NAFLD (during a period of approximately 4 years). In contrast, larger areas of SAT were longitudinally associated with regression of NAFLD. These data indicate that certain types of body fat are risk factors for NAFLD, whereas other types could reduce risk for NAFLD. PMID- 26226100 TI - Novel restricted access to vasectomy in Iran: addressing changing trends in vasectomy clients' characteristics over 16 years in northwestern Iran. AB - OBJECTIVES: This study is designed to evaluate the popularity of vasectomy in Iran. The study was conducted to calculate the frequency of vasectomy over time, to compare vasectomy users' characteristics with the general population and whether these characteristics have changed over time. STUDY DESIGN: A cross sectional study of 7864 men undergoing vasectomy in a 16-year period was conducted in Urmia, Iran. Comparative statistics described differences between vasectomy users and nonusers. The data were analyzed separately in two 8-year periods, 1996-2003 and 2004-2011. The time period did not involve 2012, the year which vasectomy became outlawed in the whole country. RESULTS: During the study period, the contraceptive prevalence rate of vasectomy increased from 0.1% to 3.35%. Vasectomy users were predominantly older, better educated, had more children and more urban residents than the general male population (p<0.001). Over time, men who underwent vasectomy tended to be younger, have well-educated wife and rural resident (p<0.05). CONCLUSIONS: This study highlighted a dramatic rise in the use of vasectomy between 1996 and 2011 in Iran. While the characteristics of vasectomy users versus general population were different, especially in age, education, resident area, number and sex of their children, there were significant changes from two 8-year study time periods. PMID- 26226101 TI - Medication abortion failure in women with and without previous cesarean delivery. AB - OBJECTIVE: To investigate the association between previous cesarean delivery and medication abortion failure and the association between parity and failure. METHODS: Data were abstracted from 2035 consecutive charts of women who underwent medication abortion in 2011. All women were at 63 days gestation or less and received mifepristone 200mg orally and misoprostol 800 mcg buccally. We used multivariate logistic regression to assess the relationship between failure, defined as requiring either curettage or additional medication, and prior cesarean delivery. We also examined the relationship between failure and parity. RESULTS: Follow-up was available on 1609 (79%) patients. Overall, 4.5% of patients experienced failure. Neither cesarean delivery nor parity was associated with failure; 6.5% of women with prior cesarean delivery experienced failure, compared to 3.7% of nulliparous women [adjusted odds ratio (aOR), 1.79, 95% confidence interval (CI), 0.83-3.87]. With regard to parity, 4.7% of women with two or more previous births experienced failure, compared to 3.7% of nulliparous women (aOR, 1.07, 95% CI, 0.54-2.14). CONCLUSION: We did not find significant associations between prior cesarean delivery and failure or parity and failure. A previous study of patients who had received a less effective regimen reported significant associations between cesarean delivery and failure and parity and failure. While our results do not rule out the possibility of modest associations due to our limited statistical power, they are reassuring relative to previous findings. IMPLICATIONS: Our results suggest that if there are differences in women's odds of medication abortion failure by obstetric history, such differences are unlikely to be large. Providers and patients may factor this information into decision making about methods of pregnancy termination. PMID- 26226102 TI - Association between positive urine cultures and necrotizing enterocolitis in a large cohort of hospitalized infants. AB - OBJECTIVE: We used a large research database to examine the association between urinary tract infections and necrotizing enterocolitis (NEC) in premature infants. METHODS: This retrospective data analysis included infants <=32week gestational age and <=1500g at birth who had urine cultures obtained at one of 322 neonatal intensive care units managed by the Pediatrix Medical Group from 1997 to 2012. The primary outcome was a diagnosis of NEC within 7days after urine culture. We used multivariable conditional logistic regression conditioned on postnatal age and controlling for gestational age, inotropic support on the day of culture, and mechanical ventilation on the day of culture to evaluate the association between urine culture result and NEC. RESULTS: We identified 25,816 infants who had 43,556 urine cultures obtained; 6586 (15.1%) of the cultures were positive. A diagnosis of NEC within 7days after culture was made in 334 (5.1%) of the 6586 positive cultures versus 1582 (4.3%) of the 36,970 negative cultures (p<0.01). On multivariable analysis, infants with any positive urine culture had increased risk of NEC (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.02 1.31); the risk was higher when limited to Gram-negative organisms (OR 1.37, 95% CI 1.17-1.59). The risk of surgical NEC was increased in infants with any positive urine culture (OR 1.46, 95% CI 1.18-1.81) and was also higher when limited to Gram-negative organisms (OR 1.99, 95% CI 1.53-2.59). CONCLUSION: Positive urine cultures were associated with increased risk of NEC within 7days of culture. PMID- 26226103 TI - Changes to registration elements and results in a cohort of Clinicaltrials.gov trials were not reflected in published articles. AB - OBJECTIVES: To assess effectiveness of legislative initiatives to stimulate public registration of trial results, we assessed adherence to protocol and results reporting, changes to registry, and publication data for randomized controlled trials (RCTs) after introduction of Food and Drug Administration Amendment Act (FDAAA). STUDY DESIGN AND SETTING: Observational study of a cohort of ClinicalTrials.gov registered FDAAA-covered RCTs found through ClinicalTrials.gov between 2009 and 2012 and data from corresponding publications. WHO Minimum Data Set items were abstracted by one author and verified by the other author. RESULTS: Among 81 eligible trials, most were industry-funded, with a drug intervention in parallel assignment. Secondary outcomes at the initial and last registration were omitted for 17% and 19.7% of RCTs, respectively. RCT registration changes mostly involved scientific title (18.8%). Inclusion criteria omission was most common (88%) in publications. Inferential statistical methods for primary and secondary outcomes matched between registry and publication for 53.4% and 28.6% of RCTs, respectively. Serious and other adverse events (AEs) that were absent for 23.8% and 4.8% of RCTs, respectively, were published as nonoccurring. CONCLUSION: Discrepancies remain relatively high between registered and published outcomes, particularly regarding registered omissions in publications and concomitant reporting, nature of statistical method used, and reporting of AEs. This seriously undermines transparency of clinical trials and needs immediate attention of all stakeholders in health research. PMID- 26226104 TI - Donor Chimerism of B Cells and Nature Killer Cells Provides Useful Information to Predict Hematologic Relapse following Allogeneic Hematopoietic Stem Cell Transplantation. AB - In this study we investigated the correlation between donor chimerism status and disease relapse following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The chimerism of Fluorescence-activated cell sorter (FACS) sorted CD3+T lymphocytes of 153 cases, CD56+CD16+NK lymphocytes of 153 cases and CD19+B lymphocytes of 31 cases with acute B lymphoblastic leukemia (B-ALL) was analyzed post-transplant utilizing polymerase chain reaction amplification of short tandem repeats (PCR-STR). A total of 33 patients (33/153, 21.6%) had recurrent disease. The positive predictive values of declining donor chimerism for hematologic and isolated extramedullary relapse were 58.8% and 10% (P=0.018, Chi-Square). The positive predictive values of declining donor chimerism in BMB, BMT, BMNK and PBB for hematologic relapse were 11.6%, 0%, 0% and 0% under close monitoring in patients with B-ALL. Only the donor chimerism in BMB significantly decreased in the group with hematologic relapse as compared with the group without hematologic relapse (P=0.00, Independent-samples T test) in patients with B-ALL. The median drop of donor chimerism in PBT, BMT, PBNK and BMNK were 0%, 0%, 5.9% and 2.8% one or two weeks prior to hematologic relapse in patients with non-B-ALL. The donor chimerism in PBNK significantly decreased prior to hematologic relapse in the group with hematologic relapse as compared with the group without hematologic relapse (P=0.022, Independent-samples T test).These data suggest donor chimerism of BMB can be used to predict the occurrence of hematologic relapse in patients with B-ALL. Donor chimerism decrease in PBNK was associated with a somewhat increased risk of hematologic relapse in patients with non-B-ALL. Therefore, our results reveal a more effective path to individually predict for hematologic relapse by dynamic monitoring different cell lineages in different disease. PMID- 26226106 TI - Chiral analysis of methorphan in opiate-overdose related deaths by using capillary electrophoresis. AB - An enantioselective CE-based determination of methorphan and its main metabolites in blood is described. Enantiomeric separations were carried out in 50cm*50MUm (ID) uncoated fused silica capillaries, using a background electrolyte composed of 150mM sodium phosphate pH 4.4 added with 5mM 2-(hydroxypropyl)-beta cyclodextrin and methanol 20% (v/v), at a constant voltage of 25kV. Sample injections were performed under field amplified sample stacking conditions. Detection was by recording UV absorbance at the wavelength of 200nm. Linearity of response was assessed within a concentration range from 25 to 500ng/mL for dextrometorhan, levomethorphan and their main metabolites (namely dextrorphan and levorphanol, respectively). Folcodine was used as internal standard. Under these conditions, the limit of quantification resulted 25ng/mL for each one of the analytes. The intra-day and inter-day precision, in terms of coefficient of variation (CV) were below 3.7% and 14.9 % for migration times and peak areas, respectively. The present method was successfully applied to the analysis of post mortem blood samples from ten subjects died for heroin overdoses. Among the samples "positive" for methorphan (n=4), the d-enantiomer was found in concentrations ranging from 214 to 1282ng/mL. The concentration of its main metabolite dextrorphan in the same samples ranged from 49 to 389ng/mL. PMID- 26226105 TI - The Crosstalk between Nrf2 and TGF-beta1 in the Epithelial-Mesenchymal Transition of Pancreatic Duct Epithelial Cells. AB - Nrf2 and TGF-beta1 both affect tumorigenesis in a dual fashion, either by preventing carcinogen induced carcinogenesis and suppressing tumor growth, respectively, or by conferring cytoprotection and invasiveness to tumor cells during malignant transformation. Given the involvement of Nrf2 and TGF-beta1 in the adaptation of epithelial cells to persistent inflammatory stress, e.g. of the pancreatic duct epithelium during chronic pancreatitis, a crosstalk between Nrf2 and TGF-beta1 can be envisaged. By using premalignant human pancreatic duct cells (HPDE) and the pancreatic ductal adenocarcinoma cell line Colo357, we could show that Nrf2 and TGF-beta1 independently but additively conferred an invasive phenotype to HPDE cells, whereas acting synergistically in Colo357 cells. This was accompanied by differential regulation of EMT markers like vimentin, Slug, L1CAM and E-cadherin. Nrf2 activation suppressed E-cadherin expression through an as yet unidentified ARE related site in the E-cadherin promoter, attenuated TGF beta1 induced Smad2/3-activity and enhanced JNK-signaling. In Colo357 cells, TGF beta1 itself was capable of inducing Nrf2 whereas in HPDE cells TGF-beta1 per-se did not affect Nrf2 activity, but enhanced Nrf2 induction by tBHQ. In Colo357, but not in HPDE cells, the effects of TGF-beta1 on invasion were sensitive to Nrf2 knock-down. In both cell lines, E-cadherin re-expression inhibited the proinvasive effect of Nrf2. Thus, the increased invasion of both cell lines relates to the Nrf2-dependent downregulation of E-cadherin expression. In line, immunohistochemistry analysis of human pancreatic intraepithelial neoplasias in pancreatic tissues from chronic pancreatitis patients revealed strong Nrf2 activity already in premalignant epithelial duct cells, accompanied by partial loss of E-cadherin expression. Our findings indicate that Nrf2 and TGF-beta1 both contribute to malignant transformation through distinct EMT related mechanisms accounting for an invasive phenotype. Provided a crosstalk between both pathways, Nrf2 and TGF-beta1 mutually promote their tumorigenic potential, a condition manifesting already at an early stage during inflammation induced carcinogenesis of the pancreas. PMID- 26226107 TI - Involvenflavones A-F, six new flavonoids with 3'-aryl substituent from Selaginella involven. AB - Six new flavonoids, involvenflavones A-F (1-6), were isolated from Selaginella involven. Their structures were elucidated based on UV, IR, 1D and 2D NMR as well as HR-ESI-MS techniques. All compounds belong to apigenin derivatives with 3' aryl substituent. This is the first report of the apigenin derivatives with 3' aryl substituent from nature resources. These compounds also exhibited a potent effect against the injury of human umbilical vein endothelial cell (HUVECs) induced by high concentrations of glucose in vitro. PMID- 26226108 TI - Formation of the diuretic chlorazanil from the antimalarial drug proguanil- implications for sports drug testing. AB - Chlorazanil (Ordipan, N-(4-chlorophenyl)-1,3,5-triazine-2,4-diamine) is a diuretic agent and as such prohibited in sport according to the regulations of the World Anti-Doping Agency (WADA). Despite its introduction into clinical practice in the late 1950s, the worldwide very first two adverse analytical findings were registered only in 2014, being motive for an in-depth investigation of these cases. Both individuals denied the intake of the drug; however, the athletes did declare the use of the antimalarial prophylactic agent proguanil due to temporary residences in African countries. A structural similarity between chlorazanil and proguanil is given but no direct metabolic relation has been reported in the scientific literature. Moreover, chlorazanil has not been confirmed as a drug impurity of proguanil. Proguanil however is metabolized in humans to N-(4-chlorophenyl)-biguanide, which represents a chemical precursor in the synthesis of chlorazanil. In the presence of formic acid, formaldehyde, or formic acid esters, N-(4-chlorophenyl)-biguanide converts to chlorazanil. In order to probe for potential sources of the chlorazanil detected in the doping control samples, drug formulations containing proguanil and urine samples of individuals using proguanil as antimalarial drug were subjected to liquid chromatography-high resolution/high accuracy mass spectrometry. In addition, in vitro simulations with 4-chlorophenyl-biguanide and respective reactants were conducted in urine and resulting specimens analyzed for the presence of chlorazanil. While no chlorazanil was found in drug formulations, the urine samples of 2 out of 4 proguanil users returned findings for chlorazanil at low ng/mL levels, similar to the adverse analytical findings in the doping control samples. Further, in the presence of formaldehyde, formic acid and related esters, 4-chlorophenyl-biguanide was found to produce chlorazanil in human urine, suggesting that the detection of the obsolete diuretic agent was indeed the result of artefact formation and not of the illicit use of a prohibited substance. PMID- 26226109 TI - K-Shortest-Path-Based Evacuation Routing with Police Resource Allocation in City Transportation Networks. AB - Emergency evacuation aims to transport people from dangerous places to safe shelters as quickly as possible. Police play an important role in the evacuation process, as they can handle traffic accidents immediately and help people move smoothly on roads. This paper investigates an evacuation routing problem that involves police resource allocation. We propose a novel k-th-shortest-path-based technique that uses explicit congestion control to optimize evacuation routing and police resource allocation. A nonlinear mixed-integer programming model is presented to formulate the problem. The model's objective is to minimize the overall evacuation clearance time. Two algorithms are given to solve the problem. The first one linearizes the original model and solves the linearized problem with CPLEX. The second one is a heuristic algorithm that uses a police resource utilization efficiency index to directly solve the original model. This police resource utilization efficiency index significantly aids in the evaluation of road links from an evacuation throughput perspective. The proposed algorithms are tested with a number of examples based on real data from cities of different sizes. The computational results show that the police resource utilization efficiency index is very helpful in finding near-optimal solutions. Additionally, comparing the performance of the heuristic algorithm and the linearization method by using randomly generated examples indicates that the efficiency of the heuristic algorithm is superior. PMID- 26226110 TI - Phytotoxins produced by Phoma chenopodiicola, a fungal pathogen of Chenopodium album. AB - Two phytotoxins were isolated from the liquid culture of Phoma chenopodiicola, a fungal pathogen proposed for the biological control of Chenopodium album, a common worldwide weed of arable crops. The two phytotoxins appeared to be a new tetrasubstituted furopyran and a new ent-pimaradiene. From the same culture a new tetrasubstituted isocoumarin was also isolated. These compounds were characterized by using spectroscopic (essentially 1D and 2D NMR and HR ESI MS) and chemical methods as 3-(3-methoxy-2,6-dimethyl-7aH-furo[2,3-b]pyran-4-yl)-but 2-en-1-ol (chenopodolan D, 1) (1S,2S,3S,4S,5S,9R,10S,12S,13S)-1,3,12-triacetoxy 2,hydroxy-6-oxo-ent-pimara-7(8),15-dien-18-oic acid 2,18-lactone (chenopodolin B, 3), and, 4,5,7-trihydroxy-3-methyl-isochroman-1-one (chenisocoumarin, 2) The absolute configuration of chenisocoumarin was assigned by applying an advanced Mosher's method through the derivatization of its secondary hydroxylated carbon C 4, while that of chenopodolan D by application of quantum mechanical calculations of chiroptical (ECD and ORD) properties. When assayed by leaf puncture against non-host weeds, chenopodolan D and chenopodolin B showed phytotoxicity while chenisocoumarin and the 9-O-acetyl derivative of chenopodolan D were inactive. These results confirm that the nature of the side chain at C-4 in chenopodolans, and in particular its hydroxylation, are important features for activity. The activity of chenopodolin B could also be explained by its possible hydrolysis to chenopodolin. PMID- 26226111 TI - Protective effect of exercise and sildenafil on acute stress and cognitive function. AB - INTRODUCTION: There are contradictory results about the effects of exercise and sildenafil on cognitive functions. AIM: To investigate the effects of sildenafil pretreatment and chronic exercise on anxiety and cognitive functions. METHOD: Wistar rats (n=42) were divided as sedentary and exercise groups. A moderate intensity swimming exercise was performed for 6 weeks, 5 days/week, 1h/day. Some of the rats were administered orogastrically with sildenafil (25mg/kg/day) either acutely or chronically. Exposure to cat odor was used for induction of stress. The level of anxiety was evaluated by elevated plus maze test, while object recognition test was used to determine cognitive functions. Brain tissues were removed for the measurement of myeloperoxidase (MPO), malondialdehyde (MDA), nitric oxide levels, lucigenin-enhanced chemiluminescence, and for histological analysis. RESULTS: Increased MPO and MDA levels in sedentary-stressed rats were decreased with sildenafil applications. Chronic exercise inhibited the increase in MPO levels. Increased nitric oxide and lucigenin chemiluminescence levels in sedentary-stressed rats, were diminished with chronic sildenafil pretreatment. The time spent in the open arms of the plus maze was declined in sedentary stressed rats, while chronic sildenafil pretreatment increased the time back to that in non-stressed rats. Acute sildenafil application to exercised rats prolonged the time spent in open arms as compared to non-treated exercise group. The time spent with the novel object, which was decreased in sedentary-stressed rats, was increased with sildenafil pretreatment. Our results suggest that sildenafil pretreatment or exercise exerts a protective effect against acute stress and improves cognitive functions by decreasing oxidative damage. PMID- 26226112 TI - Development of a triage tool for neurodevelopmental risk in children aged 30 months. AB - Neurodevelopmental and neuropsychiatric disorders in young children predict educational, health and social problems. Early identification may significantly reduce this burden but relevant tools largely lack validation. We aimed to develop and evaluate the predictive validity of a simple screening tool for neurodevelopmental problems in a community sample of 30 month old children. A sample of children was selected from a community cohort screened at 30 months by health visitors using the Sure Start Language Measure (SSLM) and the Strengths and Difficulties Questionnaire (SDQ) in 2011. Predictive validity was assessed by comparing screening results with detailed psychometric data from the same sample 1-2 years later. Screening performance using different thresholds was explored using Receiver Operating Characteristic (ROC) with ROC area under the curve (AUC) and bootstrapping techniques. The SSLM predicted both language disorder identified by the New Reynell Developmental Language Scales (NRDLS) at follow-up (AUC 0.905) and global developmental delay assessed by the Griffiths Mental Development Scales (AUC 0.983). The SDQ administered at 30 months predicted psychiatric disorders identified by the Development and Wellbeing Assessment (DAWBA) at follow-up (AUC 0.821). Using optimal cut-offs for the SDQ and SSLM at 30 months, both tools together had sensitivity 87%; specificity 64%; positive predictive value 31%; and negative predictive value 97% in the prediction of any kind of neurodevelopmental problem 1-2 years later. The combined measure reported here is not yet sufficient as a stand-alone population screening tool for neurodevelopmental disorders. The SSLM and SDQ did however show promise in identifying preschool children at risk of ongoing language, psychiatric disorders and global developmental delay 1-2 years later but with fairly high false positive rates. Given that current developmental risk prediction in resource-poor settings is little better than random assignment, the SDQ and SSLM may aid clinical judgement when used as interim triage tools for practitioners with no specialist knowledge, in the context of longitudinal follow-up arrangements. PMID- 26226113 TI - Lower cardiovascular reactivity to acute stress in informal caregivers of people with autism spectrum disorder than in non-caregivers: Implications for health outcomes. AB - Caring for offspring with autism spectrum disorder (ASD) is associated with chronic stress. Such a situation could alter body homeostasis, and in turn, physiological systems associated with the stress response and health, such as the autonomic nervous system. The primary aim of the present study was to compare the cardiovascular response with a set of mental tasks in parents of people with (n=34) and without (n=36) ASD. The secondary aim was to explore a potential relationship between cardiovascular response and self-reported health. Caregivers had lower sympathetic activity than non-caregivers, especially during the acute stress period. Higher sympathetic activity was related to more self-reported somatic symptoms in caregivers. Further, caregivers were found to have lower sympathetic reactivity to the stressor, probably due to an adaptation mechanism. Such adaptation could be extremely important for protecting the health of caregivers. PMID- 26226114 TI - Mapping the human genome: Implications for practice. PMID- 26226115 TI - Development of a sickle cell disease readiness for transition assessment. AB - BACKGROUND: Instrumentation with established reliability and validity is not yet routinely utilized to assess readiness for transition from pediatric to adult care for youth and young adults with chronic conditions, including sickle cell disease (SCD). OBJECTIVE: The aim of this study was to develop a SCD specific readiness for transition assessment tool. SUBJECTS: Fifty-seven youths with SCD, ages 15-21 years, completed the initial version of the Transition Intervention Program - Readiness for Transition (TIP-RFT) assessment; 113 youths/young adults with SCD, ages 14-26 years, at two distinct sites of care completed a refined version of the TIP-RFT. METHODS: The TIP-RFT was constructed based on a literature review, provider and patient consensus and assessed domains including knowledge and skills in medical self-care, social support, health benefits and independent living and educational/vocational skills. We used principal components factor analysis to evaluate TIP-RFT responses and assessed differences in TIP-RFT scores in relation to age, gender, sickle cell diagnosis and site of care. RESULTS: The original TIP-RFT, which had demonstrated face validity, was reduced from 56 to 22 items. The revised instrument consisting of four subscales demonstrated good internal consistency reliability and construct validity. CONCLUSION: Our results support that the TIP-RFT is a valid and reliable tool for the assessment of transition readiness for youths with SCD. The TIP-RFT assessment can guide interventions to improve transition readiness and can provide a foundation for future research on other variables that might be associated with transition readiness. PMID- 26226116 TI - Self-efficacy and readiness for transition from pediatric to adult care in sickle cell disease. AB - BACKGROUND: Theories of self-care management, particularly the development of self-efficacy or confidence in one's ability to manage health-related goals, tasks, and challenges may provide a useful framework for developing programs to improve transition from pediatric to adult care for youth and young adults with sickle cell disease (SCD). OBJECTIVE: The aim of this study was to evaluate the hypothesis stating that ratings of self-efficacy is positively associated with self-ratings of transition readiness. SUBJECTS: A total of 113 individuals with SCD aged 14-26 years at two distinct sites of care were recruited for the study. MATERIALS AND METHODS: Participants completed the Transition Intervention Program Readiness for Transition (TIP-RFT) assessment, the Sickle Cell Self-Efficacy Scale and the Sickle Cell Stress -Adolescent scale. RESULTS: In multivariate regression models, self-efficacy was positively associated with scores on the total TIP-RFT and on the Education/Vocation Planning and Independent Living Skills scales. Older age was independently associated with higher scores on the Independent Living Skills scale and higher stress levels were independently associated with lower scores on Education/Vocation Planning scale. CONCLUSION: The TIP-RFT assessment, along with measures of self-efficacy and stress, appear to be useful measures of overall transition readiness for youth and young adults with SCD. Future studies should evaluate whether self-management skill development and health outcomes are indeed affected by programs to improve readiness for transition from pediatric to adult care. PMID- 26226117 TI - Hypomagnesemia due to two novel TRPM6 mutations. AB - BACKGROUND: Although most hypocalcemia with hypomagenesemia in the neonatal period is due to transient neonatal hypoparathyroidism, magnesium channel defects should also be considered. CASE: We report a case of persistent hypomagnesemia in an 8-day-old Hispanic male who presented with generalized seizures. He was initially found to have hypomagnesemia, hypocalcemia, hyperphosphatemia and normal parathyroid hormone. Serum calcium normalized with administration of calcitriol and calcium carbonate. Serum magnesium improved with oral magnesium sulfate. However, 1 week after magnesium was discontinued, serum magnesium declined to 0.5 mg/dL. Magnesium supplementation was immediately restarted, and periodic seizure activity resolved after serum magnesium concentration was maintained above 0.9 mg/dL. The child was eventually weaned off oral calcium and calcitriol with persistent normocalemia. However, supraphysiologic oral magnesium doses were necessary to prevent seizures and maintain serum magnesium at the low limit of normal. METHODS AND RESULTS: As his clinical presentation suggested primary renal magnesium wastage, TRPM6 gene mutations were suspected; subsequent genetic testing revealed the child to be compound heterozygous for TRPM6 mutations. CONCLUSION: Two novel TRPM6 mutations are described with a new geographic and ethnic origin. This case highlights the importance of recognizing disorders of magnesium imbalance and describing new genetic mutations. PMID- 26226118 TI - Molecular diagnosis of maturity-onset diabetes of the young (MODY) in Turkish children by using targeted next-generation sequencing. AB - AIM: To perform molecular analysis of pediatric maturity onset diabetes of the young (MODY) patients by next-generation sequencing, which enables simultaneous analysis of multiple genes in a single test, to determine the genetic etiology of a group of Turkish children clinically diagnosed as MODY, and to assess genotype phenotype relationship. METHODS: Forty-two children diagnosed with MODY and their parents were enrolled in the study. Clinical and laboratory characteristics of the patients at the time of diagnosis were obtained from hospital records. Molecular analyses of GCK, HNF1A, HNF4A, HNF1B, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, and BLK genes were performed on genomic DNA by using next-generation sequencing. Pathogenicity for novel mutations was assessed by bioinformatics prediction software programs and segregation analyses. RESULTS: A mutation in MODY genes was identified in 12 (29%) of the cases. GCK mutations were detected in eight cases, and HNF1B, HNF1A, PDX1, and BLK mutations in the others. We identified five novel missense mutations - three in GCK (p.Val338Met, p.Cys252Ser, and p.Val86Ala), one in HNF1A (p.Cys241Ter), and one in PDX1 (p.Gly55Asp), which we believe to be pathogenic. CONCLUSION: The results of this study showed that mutations in the GCK gene are the leading cause of MODY in our population. Moreover, genetic diagnosis could be made in 29% of Turkish patients, and five novel mutations were identified. PMID- 26226119 TI - Long-term treatment for hyperphenylalaninemia and phenylketonuria: a risk for nutritional vitamin B12 deficiency? AB - PURPOSE: The objective of the study was to determine the incidence of vitamin B12 deficiency in patients under long-term treatment for phenylketonuria (PKU) and hyperphenylalaninemia (HPA), as well as its associations with B12 vitamin parameters (holotranscobalamin - active vitamin B12, serum folate, total plasma homocysteine, and plasma methylmalonic acid concentration). PATIENTS AND METHODS: The group consisted of 51 PKU (n=29) and HPA (n=22) patients aged 3-48 years (28 children, 23 adults). RESULTS: A significant difference in serum folate levels was discovered between adult HPA patients and PKU patients (p=0.004, Mann-Whitney U-test). A significant difference in plasma homocysteine concentrations within the normal levels (p=0.032, chi2-test) was detected between adult HPA and PKU patients. In the group of adults, we also found significant differences in serum holotranscobalamin concentrations regarding both concentration levels and the proportion of patients with concentrations within the normal levels (p=0.031, Mann-Whitney U-test; p=0.006, chi2-test). CONCLUSION: We have proven that adult patients with PKU and HPA are at risk of vitamin B12 nutritional deficiency. The most effective parameter for these adults is the monitoring of holotranscobalamin in the serum. PMID- 26226120 TI - AMH levels at central precocious puberty and premature thelarche: is it a parameter? AB - BACKGROUND: The possible difference of antimullerian hormone (AMH) levels at central precocious puberty (CPP) and premature thelarche (PT) has not been properly evaluated. OBJECTIVE/HYPOTHESIS: By evaluating AMH levels in girls with diagnosed CPP and PT, we aim to show the change of AMH levels at the pubertal onset. SUBJECTS: Sixty-five girls who have breast development before the age of 8 years and 25 healthy girls were enrolled in the study. METHODS: The subjects were divided into two groups as CPP and PT, according to results of GnRH test. AMH levels were determined in the two groups. RESULTS: The mean AMH levels of the CPP group were significantly lower than those in the PT group (13.57+/-9.85 pmol/L and 58.42+/-12.78 pmol/L, respectively, p=0.022). CONCLUSION: These results suggest that the AMH levels decrease in the duration of the hypothalamus pituitary-ovarian axis activation. We thought that AMH might/may be a marker for distinguishing between CPP and PT. PMID- 26226121 TI - Children with hyperthyroidism younger than age 7 require higher mg/kg doses of methimazole to normalize free T4 compared to older children. AB - BACKGROUND: Hyperthyroidism is much less common in children <7 years vs. older children and less well studied. It was our impression that the youngest patients needed a higher weight-based dose of methimazole (MMI) to achieve euthyroidism. OBJECTIVES: To compare the mean MMI dose needed to normalize free T4 in younger (<7 years) vs. older children and the time taken to normalize free T4. METHODS: Based on chart review (2004-2012), patients were divided into groups based on age at diagnosis: <7 years (n=13), 7-12 years (n=30) and >12 years (n=40). Follow-up visits were reviewed until free T4 normalized. RESULTS: The mean dose of MMI (mg/kg/day) needed to normalize free T4 was 0.71 (+/-0.29) in the <7 group, significantly higher vs. the two older groups: 0.50 (+/-0.22) and 0.44 (+/-0.24). Months taken to achieve a euthyroid state was significantly longer in children <7 (6.23+/-3.91) vs. the older groups (3.10+/-2.12 and 3.18+/-2.86 months). CONCLUSION: Hyperthyroid children diagnosed before age 7 required higher initial doses of MMI and took a longer time to become euthyroid than older patients. Clinicians should consider starting with higher weight-based MMI doses when treating younger patients to more rapidly normalize free T4. PMID- 26226122 TI - Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia. AB - Hyperinsulinaemic hypoglycaemia (HH) is characterised by inappropriate insulin secretion and is the most common cause for persistent neonatal hypoglycaemia. The only treatment available for medically unresponsive hypoglycaemia is a near-total pancreatectomy. A neonate with severe HH, due to a homozygous ABCC8 mutation, was not responsive to treatment with maximal doses of diazoxide and subcutaneous daily octreotide, and underwent a near-total pancreatectomy; however, hypoglycaemia persisted. Introduction of sirolimus, an mTOR (mammalian target of rapamycin) inhibitor, obviated the requirement for glucose infusion. Euglycaemia was achieved with no significant adverse events from the drug. Sirolimus therapy was ceased at 13 months of age. No episodes of persistent hypoglycaemia were observed after cessation of sirolimus. This report demonstrates the successful use of sirolimus for persistent hypoglycaemia in the critically ill infant post pancreatectomy. Sirolimus could be considered in patients with severe HH not responsive to conventional medical and surgical therapy. However, the long-term efficacy and safety with this immunosuppressive drug in very young patients are not assured. PMID- 26226123 TI - Putting the pieces together: cryptorchidism - do we know everything? AB - Cryptorchidism is one of the most common birth defects in male children, and it has a potential impact on future health. It is the best-characterized risk factor for reduced fertility and testicular cancer. However, the etiology of cryptorchidism remains largely unknown. In the literature, we find different opinions and theories on this topic. Probably, the etiology is multifactorial, and hormonal, genetic and environmental factors may regulate testicular development and descent from intra-abdominal location into the bottom of the scrotum. The descent of the testis is a complex, two-stage process. A critical role in testicular descent has been attributed to androgens, insulin-like hormone 3 (insl3) and anti-Mullerian hormone. It is believed that interaction between Leydig and Sertoli cells may cause impaired spermatogenesis. Based on recent knowledge of germ cell development, it is believed that the best treatment for undescended testis is orchiopexy between 6th and 12th month of life. Long follow up studies are needed to focus on the effect of this recommendation. PMID- 26226124 TI - Pilot study on the dietary habits and lifestyles of girls with idiopathic precocious puberty from the city of Rome: potential impact of exposure to flame retardant polybrominated diphenyl ethers. AB - Puberty is regulated by the endocrine system, which when disrupted can affect reproductive health. Endocrine disrupters (ED) are involved in the pathogenesis of idiopathic central precocious puberty (ICPP). Polybrominated diphenyl ethers (PBDE) are lipophilic, persistent ED used as flame retardants in several products; thus, human population is exposed through food and domestic dust. PBDE exposure during the peripubertal period is suspected to interfere with reproductive development. The study aimed to investigate PBDE serum concentration in 31 girls with ICPP as well as describe their dietary habits and lifestyles. The PBDE median level was 59 ng/g of lipids, higher than in healthy girls in comparable studies. Interestingly, elder girls and girls with higher body mass index (BMI) showed higher PBDE serum levels. Considering the relevance of altered puberty onset as a risk factor for reproductive health, studies on food contribution to PBDE exposure in Italian children, and efforts to ameliorate risk assessment for emerging chemicals are suggested. PMID- 26226125 TI - Are obesity and metabolic syndrome associated with plasma adropin levels in children? AB - Studies performed on mice suggest that adropin is a peptide hormone playing a role in metabolic homeostasis and prevention of obesity-associated insulin resistance. Our study was conducted to investigate the role of adropin in children with obesity or metabolic syndrome. The study group consisted of 70 patients, including 42 obese and 28 with metabolic syndrome, and 26 healthy volunteers. After anthropometric variables and blood pressure of all participants were measured, serum lipids were analyzed, liver USG and oral glucose tolerance test were performed, and HOMA-IR values were calculated. Plasma adropin levels were collectively analyzed from collected plasma samples. In patient and control groups, no difference was observed in the levels of adropin (327.7+/-124.7 vs. 344.6+/-208.5 ng/L, respectively). The adropin levels of metabolic syndrome, obesity, and control groups also showed no difference (316+/-142.3, 335.8+/ 112.5, and 344.6+/-208.5 ng/L, respectively). While the adropin levels of patients with and without hepatic steatosis were 319.6+/-123.7 and 347.8+/-128.7 ng/L, respectively, patients with HOMA-IR values of <3.16 and >=3.16 had levels 342.3+/-124.8 and 296.5+/-136.7 ng/L, respectively. Although statistically insignificant, our findings are considered to support the hypothesis suggesting a nexus between adropin and obesity and metabolic syndrome. Small sample size in our study may have prevented our results to reach a more significant level. So, long-term follow-up studies with large population are needed to enlighten the role of adropin in metabolic homeostasis. PMID- 26226126 TI - Hawkinsinuria in two unrelated Greek newborns: identification of a novel variant, biochemical findings and treatment. AB - BACKGROUND: Hawkinsinuria is a rare inborn error of tyrosine metabolism. OBJECTIVES: To study novel hawkinsinuria cases by monitoring their biochemical profile and conducting a mutation analysis. SUBJECTS AND METHODS: Among 92,519 newborns that underwent expanded newborn screening, two unrelated cases with high tyrosine blood levels were further investigated by chromatographic techniques and via genetic testing for 4-hydroxyphenylpyruvate dioxygenase (HPD) gene. RESULTS: Elevated levels were monitored for blood/plasma tyrosine and for the specific diagnostic markers in urine. The two newborns were put on a special low tyrosine diet. Till completion of the 1st year of their life, liver function tests and brain MRI were normal. The mutation A33T was identified in both cases, while one neonate carried an additional novel mutation of HPD gene (V212M). CONCLUSIONS: Two mutations of HPD gene, A33T, which are associated with hawkinsinuria and a novel one (V212M) were detected for the 1st time in Greek newborns. PMID- 26226127 TI - Validating Paediatric Morphometrics: body proportion measurement using photogrammetric anthropometry. AB - BACKGROUND: Taking multiple anthropometric measurements for the description of body proportions in an accurate way is a time-consuming procedure that requires specific tools and skills. This is why we developed an alternative method based on digital photography for taking these measurements which is faster and easier to use, to make anthropometry more user-friendly and approachable to paediatricians. METHODS: We conducted a cross-sectional study in 54 children between 2 and 18 years of age. We compared manual measurements with photogrammetric measurements to validate our method. RESULTS: Inter-observer correlations of all measurements are >=0.96 and mean differences are 0.3-0.9 cm, except for arm span. Comparison of manual to photogrammetric measurements shows mean differences of 0.6-1.3 cm, with correlations >=0.92, except for sitting height and arm span. Correlations of ratios between methods are height/sitting height (r=0.77), biacromium/biiliacum (r=0.74) and subischial leg length/sitting height (r=0.75). CONCLUSION: Photogrammetric anthropometry is faster, easier to use and provides the paediatrician with more flexibility as taking the digital photographs and performing the analysis are separated. PMID- 26226128 TI - Receptor for advanced glycation end-products in neurodegenerative diseases. AB - This review, for the first time, aims to summarize the current knowledge in the emerging field of RAGE (receptor for advanced glycation end-products) studies in neurodegeneration and neurodegenerative diseases. RAGE, a member of the multiligand cell surface immunoglobulin family, has been implicated in numerous pathological conditions - from diabetes and cardiovascular diseases to tumors and neurodegenerative disorders, such as Alzheimer's disease, familial amyloid polyneuropathy, diabetic neuropathy, Parkinson's disease, and Huntington's disease. Until now, the detailed mechanisms of the contribution of RAGE to neurodegeneration remain elusive; however, mounting evidence suggests that its detrimental actions are triggered by its ligand interactions and contribute to increased neuroinflammation, neuronal degeneration, and apoptosis. Deciphering the role of RAGE in neurodegenerative disorders will be a milestone in our basic understanding of the mechanisms involved in the pathogenesis of neurodegeneration, helping to delineate molecular links between complex RAGE signaling pathways and neuronal dysfunction and neurodegeneration. PMID- 26226129 TI - Variable Selection for Confounder Control, Flexible Modeling and Collaborative Targeted Minimum Loss-Based Estimation in Causal Inference. AB - This paper investigates the appropriateness of the integration of flexible propensity score modeling (nonparametric or machine learning approaches) in semiparametric models for the estimation of a causal quantity, such as the mean outcome under treatment. We begin with an overview of some of the issues involved in knowledge-based and statistical variable selection in causal inference and the potential pitfalls of automated selection based on the fit of the propensity score. Using a simple example, we directly show the consequences of adjusting for pure causes of the exposure when using inverse probability of treatment weighting (IPTW). Such variables are likely to be selected when using a naive approach to model selection for the propensity score. We describe how the method of Collaborative Targeted minimum loss-based estimation (C-TMLE; van der Laan and Gruber, 2010 [27]) capitalizes on the collaborative double robustness property of semiparametric efficient estimators to select covariates for the propensity score based on the error in the conditional outcome model. Finally, we compare several approaches to automated variable selection in low- and high-dimensional settings through a simulation study. From this simulation study, we conclude that using IPTW with flexible prediction for the propensity score can result in inferior estimation, while Targeted minimum loss-based estimation and C-TMLE may benefit from flexible prediction and remain robust to the presence of variables that are highly correlated with treatment. However, in our study, standard influence function-based methods for the variance underestimated the standard errors, resulting in poor coverage under certain data-generating scenarios. PMID- 26226130 TI - Node sampling for protein complex estimation in bait-prey graphs. AB - In cellular biology, node-and-edge graph or "network" data collection often uses bait-prey technologies such as co-immunoprecipitation (CoIP). Bait-prey technologies assay relationships or "interactions" between protein pairs, with CoIP specifically measuring protein complex co-membership. Analyses of CoIP data frequently focus on estimating protein complex membership. Due to budgetary and other constraints, exhaustive assay of the entire network using CoIP is not always possible. We describe a stratified sampling scheme to select baits for CoIP experiments when protein complex estimation is the main goal. Expanding upon the classic framework in which nodes represent proteins and edges represent pairwise interactions, we define generalized nodes as sets of adjacent nodes with identical adjacency outside the set and use these as strata from which to select the next set of baits. Strata are redefined at each round of sampling to incorporate accumulating data. This scheme maintains user-specified quality thresholds for protein complex estimates and, relative to simple random sampling, leads to a marked increase in the number of correctly estimated complexes at each round of sampling. The R package seqSample contains all source code and is available at http://vault.northwestern.edu/~dms877/Rpacks/. PMID- 26226131 TI - Intravenous antibiotics for pulmonary exacerbations in people with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis is a multi-system disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. Intravenous antibiotics are commonly used in the treatment of acute deteriorations in symptoms (pulmonary exacerbations); however, recently the assumption that exacerbations are due to increases in bacterial burden has been questioned. OBJECTIVES: To establish if intravenous antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis improve short- and long term clinical outcomes. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews and ongoing trials registers.Date of last search of Cochrane trials register: 27 July 2015. SELECTION CRITERIA: Randomised controlled trials and the first treatment cycle of cross-over studies comparing intravenous antibiotics (given alone or in an antibiotic combination) with placebo, inhaled or oral antibiotics for people with cystic fibrosis experiencing a pulmonary exacerbation. DATA COLLECTION AND ANALYSIS: The authors assessed studies for eligibility and risk of bias and extracted data. MAIN RESULTS: We included 40 studies involving 1717 participants. The quality of the included studies was largely poor and, with a few exceptions, these comprised of mainly small, inadequately reported studies.When comparing treatment with a single antibiotic to a combined antibiotic regimen, those participants receiving a combination of antibiotics experienced a greater improvement in lung function when considered as a whole group across a number of different measurements of lung function, but with very low quality evidence. When limited to the four placebo-controlled studies (n = 214), no difference was observed, again with very low quality evidence. With regard to the review's remaining primary outcomes, there was no effect upon time to next exacerbation and no studies in any comparison reported on quality of life. There were no effects on the secondary outcomes weight or adverse effects. When comparing specific antibiotic combinations there were no significant differences between groups on any measure. In the comparisons between intravenous and nebulised antibiotic or oral antibiotic (low quality evidence), there were no significant differences between groups on any measure. No studies in any comparison reported on quality of life. AUTHORS' CONCLUSIONS: The quality of evidence comparing intravenous antibiotics with placebo is poor. No specific antibiotic combination can be considered to be superior to any other, and neither is there evidence showing that the intravenous route is superior to the inhaled or oral routes. There remains a need to understand host-bacteria interactions and in particular to understand why many people fail to fully respond to treatment. PMID- 26226133 TI - Human Neuroma-in-Continuity Contains Focal Deficits in Myelination. AB - Functional recovery does not occur in 10% of patients with neonatal brachial plexus palsy. In these patients, resection of a neuroma-in-continuity (NIC) and surgical nerve reconstruction are required. The formation of a NIC seems to prohibit functional recovery, but the underlying biologic mechanisms for this failure are poorly understood. We systematically analyzed a large series of NIC tissue samples from 17 neonatal and 3 adult patients using an array of immunohistochemical techniques. In a large proportion of patients (74%), the NIC contained multiple focal globular areas with markedly diminished myelination. These focal myelin deficits (FMDs) contain Schwann cells that enwrap axons in an apparently normal configuration but do not form myelin. Biomathematical analysis of a 2-cm neuroma predicted a higher-than-95% probability that an axon would encounter 10 FMDs. Axon segments in FMDs also had disturbed nodes of Ranvier (i.e., FMDs contained significantly fewer clustered Na(v)1.6 channels and decreased Caspr and ankyrin G). These observations indicate that axons in NIC course through multiple FMDs and that this may be the pathobiologic basis for conduction blocks in patients with neonatal brachial plexus palsy. These observations indicate the need for novel strategies to promote functional recovery after neonatal brachial plexus palsy by improving myelination in the NIC. PMID- 26226132 TI - Prion Disease Induces Alzheimer Disease-Like Neuropathologic Changes. AB - We examined the brains of 266 patients with prion disease (PrionD) and found that 46 patients (17%) had Alzheimer disease (AD)-like changes. To explore potential mechanistic links between PrionD and AD, we exposed human brain aggregates (BrnAggs) to a brain homogenate from a patient with sporadic Creutzfeldt-Jakob disease and found that neurons in human BrnAggs produced many beta-amyloid (Abeta; Abeta42) inclusions, whereas uninfected control-exposed human BrnAggs did not. Western blot analysis of 20 pooled Creutzfeldt-Jakob disease-infected BrnAggs verified Abeta42 levels higher than those in controls. We next examined the CA1 region of the hippocampus from 14 patients with PrionD and found that 5 patients had low levels of scrapie-associated prion protein (PrP), many Abeta42 intraneuronal inclusions, low apolipoprotein E-4 (APOE-4), and no significant nerve cell loss. Seven patients had high levels of PrP, low Abeta42, high APOE-4, and 40% nerve cell loss, suggesting that APOE-4 and PrP together cause neuron loss in PrionD. There were also increased levels of hyperphosphorylated tau protein (Htau) and Htau-positive neuropil threads and neuron bodies in both PrionD and AD groups. The brains of 6 age-matched control patients without dementia did not contain Abeta42 deposits; however, there were rare Htau-positive threads in 5 controls, and 2 controls had few Htau-positive nerve cell bodies. We conclude that PrionD may trigger biochemical changes similar to those triggered by AD and suggest that PrionD is a disease involving PrP, Abeta42, APOE-4, and abnormal tau. PMID- 26226134 TI - Differentiation of Donor-Derived Cells Into Microglia After Umbilical Cord Blood Stem Cell Transplantation. AB - Recent studies have indicated that microglia originate from immature progenitors in the yolk sac. After birth, microglial populations are maintained under normal conditions via self-renewal without the need to recruit monocyte-derived microglial precursors. Peripheral cell invasion of the brain parenchyma can only occur with disruption of the blood-brain barrier. Here, we report an autopsy case of an umbilical cord blood transplant recipient in whom cells derived from the donor blood differentiated into ramified microglia in the recipient brain parenchyma. Although the blood-brain barrier and glia limitans seemed to prevent invasion of these donor-derived cells, most of the invading donor-derived ramified cells were maintained in the cerebral cortex. This result suggests that invasion of donor-derived cells occurs through the pial membrane. PMID- 26226136 TI - Validation of a multiplex genotyping platform using a novel genomic database approach. AB - PURPOSE: Technological advances now allow for multiplex platforms to simultaneously test many genetic conditions. Typically, such platforms are validated by assaying samples with known genotypes and/or phenotypes and/or with synthetic plasmids; however, these methods have limitations and with the inclusion of rarer diseases and mutations, we can no longer rely solely on them. We used a novel genomic database to validate an expanded genetic carrier screening platform. METHODS: Our expanded carrier screening assay uses the Illumina Infinium iSelect HD Custom genotyping platform to test for 213 genetic diseases by assaying 1,663 pathogenic mutations. We leveraged two Coriell Institute biorepositories for validation: the Subcollection of Heritable Diseases and the 1000 Genomes Project. RESULTS: We measured 12,394 mutation observations in 206 samples, resulting in 246 true positives, 12,147 true negatives, 1 false positive, and no false negatives. Results demonstrated high sensitivity (99.99%) and specificity (99.99%). CONCLUSION: We successfully validated our platform with two biorepositories, demonstrating high sensitivity and specificity. The 1000 Genomes Project samples provided both positive and negative validation for mutations in genes not available through other biorepositories, expanding the depth of validated variants. We recommend including samples from the 1000 Genomes Project in the validation of future multiplex testing platforms.Genet Med advance online publication 30 July 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.101. PMID- 26226135 TI - GBM Derived Gangliosides Induce T Cell Apoptosis through Activation of the Caspase Cascade Involving Both the Extrinsic and the Intrinsic Pathway. AB - Previously we demonstrated that human glioblastoma cell lines induce apoptosis in peripheral blood T cells through partial involvement of secreted gangliosides. Here we show that GBM-derived gangliosides induce apoptosis through involvement of the TNF receptor and activation of the caspase cascade. Culturing T lymphocytes with GBM cell line derived gangliosides (10-20 MUg/ml) demonstrated increased ROS production as early as 18 hrs as indicated by increased uptake of the dye H2DCFDA while western blotting demonstrated mitochondrial damage as evident by cleavage of Bid to t-Bid and by the release of cytochrome-c into the cytosol. Within 48-72 hrs apoptosis was evident by nuclear blebbing, trypan blue positivity and annexinV/7AAD staining. GBM-ganglioside induced activation of the effector caspase-3 along with both initiator caspases (-9 and -8) in T cells while both the caspase-8 and -9 inhibitors were equally effective in blocking apoptosis (60% protection) confirming the role of caspases in the apoptotic process. Ganglioside-induced T cell apoptosis did not involve production of TNF alpha since anti-human TNFalpha antibody was unable to protect T cells from nuclear blebbing and subsequent cell death. However, confocal microscopy demonstrated co-localization of GM2 ganglioside with the TNF receptor and co immunoprecipitation experiments showed recruitment of death domains FADD and TRADD with the TNF receptor post ganglioside treatment, suggesting direct interaction of gangliosides with the TNF receptor. Further confirmation of the interaction between GM2 and TNFR1 was obtained from confocal microscopy data with wild type and TNFR1 KO (TALEN mediated) Jurkat cells, which clearly demonstrated co-localization of GM2 and TNFR1 in the wild type cells but not in the TNFR1 KO clones. Thus, GBM-ganglioside can mediate T cell apoptosis by interacting with the TNF receptor followed by activation of both the extrinsic and the intrinsic pathway of caspases. PMID- 26226138 TI - Taenia: An Uninvited Guest. AB - BACKGROUND: Taenia saginata and Taenia solium species are worldwide in distribution, causing bovine and porcine cysticercosis, and taeniasis in humans having the greatest economic and medical importance. CASE REPORT: A 55-year-old woman living in a village around Rasht (northern Iran) was referred to our hospital with a history of chronic abdominal pain and recent dyspepsia and epigastric fullness. According to her clinical history, she was a candidate for an upper gastrointestinal endoscopy. A large tape worm was seen in the stomach. Our efforts at extracting it from the stomach were unsuccessful. The endoscope was withdrawn and therapy with niclosamide was initiated. At the next visit, her symptoms were alleviated and she was relieved from the chronic pain. CONCLUSIONS: We believe that the retrograde migration of the tapeworm into the stomach may be due to low gastric acidity as a result of atrophic gastritis and chronic proton pump inhibitor use. PMID- 26226137 TI - Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort. AB - PURPOSE: Autosomal recessive nonsyndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity, with reported mutations in 58 different genes. This study was designed to detect deafness-causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES). METHODS: After excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador, and Puerto Rico to screen for mutations in all known ARNSD genes. RESULTS: We detected ARNSD causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%), and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes, suggesting founder effects. CONCLUSION: We report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.Genet Med 18 4, 364-371. PMID- 26226139 TI - Fish Oil Supplements Lower Serum Lipids and Glucose in Correlation with a Reduction in Plasma Fibroblast Growth Factor 21 and Prostaglandin E2 in Nonalcoholic Fatty Liver Disease Associated with Hyperlipidemia: A Randomized Clinical Trial. AB - Fish oil has been used effectively in the treatment of cardiovascular disease via triglyceride reduction and inflammation modulation. This study aimed to assess the effects of fish oil on patients with nonalcoholic fatty liver disease (NAFLD) associated with hyperlipidemia. Eighty participants with NAFLD associated with hyperlipidemia were randomly assigned to consume fish oil (n=40, 4 g/d) or corn oil capsules (n=40, 4 g/d) for 3 months in a double-blind, randomized clinical trial. Blood levels of lipids, glucose and insulin, liver enzymes, kidney parameters and cytokines at baseline and the end of the study were measured. Seventy people finished the trial. Plasma concentrations of eicosapentaenoic acid and docosahexaenoic acid significantly increased in the fish oil group after intervention. After adjustment for age, gender and BMI, fish oil significantly decreased fasting serum concentrations of total cholesterol, triglyceride, apolipoprotein B and glucose (by (mean+/-SD) 0.49+/-0.43 mmol/L, 0.58+/-0.89 mmol/L, 0.28+/-0.33 g/L and 0.76+/-0.56 mmol/L, respectively, P<0.05), as well as alanine aminotransferase and gamma-glutamyl transpeptidase levels (by (median (interquartile)) 9.0(0.5, 21.5) and 7.0(2.2, 20.0) IU/L, respectively, P<0.05), significantly increased serum adiponectin levels (by 1.29+/-0.62 MUg/mL, P<0.001), and reduced serum levels of tumor necrosis factor alpha, leukotrienes B4, fibroblast growth factor 21 (FGF21), cytokeratin 18 fragment M30 and prostaglandin E2 (by 1.70+/-1.18 pg/mL, 0.59+/-0.28 ng/mL, 121+/-31 pg/mL, 83+/ 60 IU/L and 10.9+/-2.3 pg/mL, respectively, P<0.001). Corn oil had no effect except for increasing serum creatinine concentrations by 7.7+/-8.9 MUmol/L (P=0.008). The effects of fish oil on lipids, glucose and gamma-glutamyl transpeptidase were positively correlated with the reductions of serum FGF21 and prostaglandin E2 concentrations after adjustment for age, gender and BMI (r = 0.275 to 0.360 and 0.261 to 0.375, respectively, P<0.05). In conclusion, our findings suggest that fish oil can benefit metabolic abnormalities associated with NAFLD treatment. TRIAL REGISTRATION: ChiCTR-TRC-12002380. PMID- 26226140 TI - Identifying Shifts in Leaf-Litter Ant Assemblages (Hymenoptera: Formicidae) across Ecosystem Boundaries Using Multiple Sampling Methods. AB - Global or regional environmental changes in climate or land use have been increasingly implied in shifts in boundaries (ecotones) between adjacent ecosystems such as beech or oak-dominated forests and forest-steppe ecotones that frequently co-occur near the southern range limits of deciduous forest biome in Europe. Yet, our ability to detect changes in biological communities across these ecosystems, or to understand their environmental drivers, can be hampered when different sampling methods are required to characterize biological communities of the adjacent but ecologically different ecosystems. Ants (Hymenoptera: Formicidae) have been shown to be particularly sensitive to changes in temperature and vegetation and they require different sampling methods in closed vs. open habitats. We compared ant assemblages of closed-forests (beech- or oak dominated) and open forest-steppe habitats in southwestern Carpathians using methods for closed-forest (litter sifting) and open habitats (pitfall trapping), and developed an integrated sampling approach to characterize changes in ant assemblages across these adjacent ecosystems. Using both methods, we collected 5,328 individual ant workers from 28 species. Neither method represented ant communities completely, but pitfall trapping accounted for more species (24) than litter sifting (16). Although pitfall trapping characterized differences in species richness and composition among the ecosystems better, with beech forest being most species poor and ecotone most species rich, litter sifting was more successful in identifying characteristic litter-dwelling species in oak-dominated forest. The integrated sampling approach using both methods yielded more accurate characterization of species richness and composition, and particularly so in species-rich forest-steppe habitat where the combined sample identified significantly higher number of species compared to either of the two methods on their own. Thus, an integrated sampling approach should be used to fully characterize changes in ant assemblages across ecosystem boundaries, or with vegetation change over time, and particularly so in species-rich habitats such as forest-steppe ecotones. PMID- 26226141 TI - Correction: A Potential Role for the Inhibition of PI3K Signaling in Glioblastoma Therapy. PMID- 26226142 TI - Ethnic Distribution of Microscopic Colitis in the United States. AB - BACKGROUND: A large electronic database of histopathology reports was used to study the ethnic distribution of microscopic colitis in the United States. METHODS: Miraca Life Sciences is a nation-wide pathology laboratory that receives biopsy specimens submitted by 1500 gastroenterologists distributed throughout the United States. In a case-control study, the prevalence of microscopic colitis in 4 ethnic groups (East Asians, Indians, Hispanics, and Jews) was compared with that of all other ethnic groups (composed of American Caucasians and African Americans), serving as reference group. RESULTS: A total of 11,706 patients with microscopic colitis were included in the analysis. In all ethnic groups alike, microscopic colitis was more common in women than men (78% versus 22%, odds ratio = 3.40, 95% confidence interval = 3.26-3.55). In all ethnic groups, the prevalence of microscopic colitis showed a continuous age-dependent rise. Hispanic patients with microscopic colitis were on average younger than the reference group (59.4 +/- 16.2 years versus 64.2 +/- 13.8 years, P < 0.001). Jewish patients with microscopic colitis were slightly older than the reference group (65.6 +/- 13.4 years, P = 0.015). Compared with the reference group (prevalence = 1.20%), microscopic colitis was significantly less common among patients of Indian (prevalence = 0.28%, odds ratio = 0.32, 95% confidence interval = 0.13-0.65), East Asian (0.22%, 0.19, 0.14-0.26), or Hispanic decent (0.48%, 0.40, 0.36-0.45) and significantly more common among Jewish patients (1.30%, 1.10, 1.01-1.21). CONCLUSIONS: Microscopic colitis shows striking variations of its occurrence among different ethnic groups. Such variations could point at differences in the exposure to environmental risk factors. PMID- 26226143 TI - Modeling autism-relevant behavioral phenotypes in rats and mice: Do 'autistic' rodents exist? AB - Autism spectrum disorders (ASD) are among the most severe developmental psychiatric disorders known today, characterized by impairments in communication and social interaction and stereotyped behaviors. However, no specific treatments for ASD are as yet available. By enabling selective genetic, neural, and pharmacological manipulations, animal studies are essential in ASD research. They make it possible to dissect the role of genetic and environmental factors in the pathogenesis of the disease, circumventing the many confounding variables present in human studies. Furthermore, they make it possible to unravel the relationships between altered brain function in ASD and behavior, and are essential to test new pharmacological options and their side-effects. Here, we first discuss the concepts of construct, face, and predictive validity in rodent models of ASD. Then, we discuss how ASD-relevant behavioral phenotypes can be mimicked in rodents. Finally, we provide examples of environmental and genetic rodent models widely used and validated in ASD research. We conclude that, although no animal model can capture, at once, all the molecular, cellular, and behavioral features of ASD, a useful approach is to focus on specific autism-relevant behavioral features to study their neural underpinnings. This approach has greatly contributed to our understanding of this disease, and is useful in identifying new therapeutic targets. PMID- 26226145 TI - Biphasic effects of anandamide on behavioural responses: emphasis on copulatory behaviour. AB - Endocannabinoids have emerged as important modulators of different neurotransmitter systems in the brain by acting as retrograde messengers. They are released from postsynaptic cell bodies, travel backwards across the synapsis and bind to their receptors located at the presynaptic terminal to inhibit neurotransmitter release. The fatty acid amide, arachidonoylethanolamide (anandamide), is an important endogenous ligand of the G-protein-coupled cannabinoid receptors CB1 and CB2. The aim of this mini-review is to outline the recent literature on the biphasic nature of the behavioural actions of anandamide, with particular focus on male rat sexual behaviour, and to examine whether dose-related activation of distinct receptors plays a role in the biphasic effects of this prototypical endocannabinoid. PMID- 26226144 TI - Drug effects on responses to emotional facial expressions: recent findings. AB - Many psychoactive drugs increase social behavior and enhance social interactions, which may, in turn, increase their attractiveness to users. Although the psychological mechanisms by which drugs affect social behavior are not fully understood, there is some evidence that drugs alter the perception of emotions in others. Drugs can affect the ability to detect, attend to, and respond to emotional facial expressions, which in turn may influence their use in social settings. Either increased reactivity to positive expressions or decreased response to negative expressions may facilitate social interaction. This article reviews evidence that psychoactive drugs alter the processing of emotional facial expressions using subjective, behavioral, and physiological measures. The findings lay the groundwork for better understanding how drugs alter social processing and social behavior more generally. PMID- 26226146 TI - Highest Resolution In Vivo Human Brain MRI Using Prospective Motion Correction. AB - High field MRI systems, such as 7 Tesla (T) scanners, can deliver higher signal to noise ratio (SNR) than lower field scanners and thus allow for the acquisition of data with higher spatial resolution, which is often demanded by users in the fields of clinical and neuroscientific imaging. However, high resolution scans may require long acquisition times, which in turn increase the discomfort for the subject and the risk of subject motion. Even with a cooperative and trained subject, involuntary motion due to heartbeat, swallowing, respiration and changes in muscle tone can cause image artifacts that reduce the effective resolution. In addition, scanning with higher resolution leads to increased sensitivity to even very small movements. Prospective motion correction (PMC) at 3T and 7T has proven to increase image quality in case of subject motion. Although the application of prospective motion correction is becoming more popular, previous articles focused on proof of concept studies and technical descriptions, whereas this paper briefly describes the technical aspects of the optical tracking system, marker fixation and cross calibration and focuses on the application of PMC to very high resolution imaging without intentional motion. In this study we acquired in vivo MR images at 7T using prospective motion correction during long acquisitions. As a result, we present images among the highest, if not the highest resolution of in vivo human brain MRI ever acquired. PMID- 26226150 TI - Compact Laser Doppler Flowmeter (LDF) Fundus Camera for the Assessment of Retinal Blood Perfusion in Small Animals. AB - PURPOSE: Noninvasive techniques for ocular blood perfusion assessment are of crucial importance for exploring microvascular alterations related to systemic and ocular diseases. However, few techniques adapted to rodents are available and most are invasive or not specifically focused on the optic nerve head (ONH), choroid or retinal circulation. Here we present the results obtained with a new rodent-adapted compact fundus camera based on laser Doppler flowmetry (LDF). METHODS: A confocal miniature flowmeter was fixed to a specially designed 3D rotating mechanical arm and adjusted on a rodent stereotaxic table in order to accurately point the laser beam at the retinal region of interest. The linearity of the LDF measurements was assessed using a rotating Teflon wheel and a flow of microspheres in a glass capillary. In vivo reproducibility was assessed in Wistar rats with repeated measurements (inter-session and inter-day) of retinal arteries and ONH blood velocity in six and ten rats, respectively. These parameters were also recorded during an acute intraocular pressure increase to 150 mmHg and after heart arrest (n = 5 rats). RESULTS: The perfusion measurements showed perfect linearity between LDF velocity and Teflon wheel or microsphere speed. Intraclass correlation coefficients for retinal arteries and ONH velocity (0.82 and 0.86, respectively) indicated strong inter-session repeatability and stability. Inter day reproducibility was good (0.79 and 0.7, respectively). Upon ocular blood flow cessation, the retinal artery velocity signal substantially decreased, whereas the ONH signal did not significantly vary, suggesting that it could mostly be attributed to tissue light scattering. CONCLUSION: We have demonstrated that, while not adapted for ONH blood perfusion assessment, this device allows pertinent, stable and repeatable measurements of retinal blood perfusion in rats. PMID- 26226151 TI - ElemeNT: a computational tool for detecting core promoter elements. AB - Core promoter elements play a pivotal role in the transcriptional output, yet they are often detected manually within sequences of interest. Here, we present 2 contributions to the detection and curation of core promoter elements within given sequences. First, the Elements Navigation Tool (ElemeNT) is a user-friendly web-based, interactive tool for prediction and display of putative core promoter elements and their biologically-relevant combinations. Second, the CORE database summarizes ElemeNT-predicted core promoter elements near CAGE and RNA-seq-defined Drosophila melanogaster transcription start sites (TSSs). ElemeNT's predictions are based on biologically-functional core promoter elements, and can be used to infer core promoter compositions. ElemeNT does not assume prior knowledge of the actual TSS position, and can therefore assist in annotation of any given sequence. These resources, freely accessible at http://lifefaculty.biu.ac.il/gershon-tamar/index.php/resources, facilitate the identification of core promoter elements as active contributors to gene expression. PMID- 26226152 TI - Ratcheting of RNA polymerase toward structural principles of RNA polymerase operations. AB - RNA polymerase (RNAP) performs various tasks during transcription by changing its conformational states, which are gradually becoming clarified. A recent study focusing on the conformational transition of RNAP between the ratcheted and tight forms illuminated the structural principles underlying its functional operations. PMID- 26226153 TI - Molecular Epidemiology of Helicobacter pylori Infection in Nepal: Specific Ancestor Root. AB - Prevalence of Helicobacter pylori infection in Nepal, a low-risk country for gastric cancer, is debatable. To our knowledge, no studies have examined H. pylori virulence factors in Nepal. We determined the prevalence of H. pylori infection by using three different tests, and the genotypes of virulence factors were determined by PCR followed by sequencing. Multilocus sequence typing was used to analyze the population structure of the Nepalese strains. The prevalence of H. pylori infection in dyspeptic patients was 38.4% (56/146), and was significantly related with source of drinking water. In total, 51 strains were isolated and all were cagA-positive. Western-type-cagA (94.1%), cagA pre-EPIYA type with no deletion (92.2%), vacA s1a (74.5%), and m1c (54.9%) were the predominant genotypes. Antral mucosal atrophy levels were significantly higher in patients infected with vacA s1 than in those infected with s2 genotypes (P = 0.03). Several Nepalese strains were H. pylori recombinants with genetic features of South Asian and East Asian genotypes. These included all East-Asian-type-cagA strains, with significantly lesser activity and inflammation in the corpus than the strains of the specific South Asian genotype (P = 0.03 and P = 0.005, respectively). Although the population structure confirmed that most Nepalese strains belonged to the hpAsia2 population, some strains shared hpEurope- and Nepalese-specific components. Nepalese patients infected with strains belonging to hpEurope showed higher inflammation in the antrum than strains from the Nepalese specific population (P = 0.05). These results support that ancestor roots of Kathmandu's people not only connected with India alone. PMID- 26226162 TI - Administration of Exogenous Growth Hormone Is Associated with Changes in Plasma and Intracellular Mammary Amino Acid Profiles and Abundance of the Mammary Gland Amino Acid Transporter SLC3A2 in Mid-Lactation Dairy Cows. AB - The objectives of this study were to (1) identify changes in plasma and mammary intracellular amino acid (AA) profiles in dairy cows treated with growth hormone (GH), and (2) evaluate the expression of mammary gland genes involved in the transport of AA identified in (1). Eight non-pregnant (n = 4 per group) lactating dairy cows were treated with a single subcutaneous injection of either a slow release formulation of commercially available GH (Lactotropin 500 mg) or physiological saline solution. Six days after treatment, cows were milked and blood collected from the jugular vein for the analysis of free AA in the plasma. Cows were euthanized and mammary tissue harvested. Treatment with GH increased milk, protein, fat and lactose yields, with no effect on dry matter intake. Plasma concentrations of lysine and group I AA decreased significantly, and arginine, methionine, tyrosine and arginine-family AA tended to decrease in GH treated cows. Concentrations of intracellular glycine, serine and glutamate increased significantly, with a trend for decreased arginine observed in the mammary gland of GH-treated cows. A trend for increased concentrations of intracellular total AA, NEAA and arginine-family AA were observed in the mammary gland of GH-treated cows. Variance in the concentration of plasma methionine, tyrosine, valine, alanine, ornithine, BCAA, EAA was significantly different between treatments. Variance in the concentration of intracellular lysine, valine, glutamine, EAA and group II was significantly different between treatments. AA changes were associated with increased mRNA abundance of the mammary gland AA transporter SLC3A2. We propose that these changes occur to support increased milk protein and fatty acid production in the mammary gland of GH-treated cows via potential mTOR pathway signaling. PMID- 26226163 TI - The Asian Rice Gall Midge (Orseolia oryzae) Mitogenome Has Evolved Novel Gene Boundaries and Tandem Repeats That Distinguish Its Biotypes. AB - The complete mitochondrial genome of the Asian rice gall midge, Orseolia oryzae (Diptera; Cecidomyiidae) was sequenced, annotated and analysed in the present study. The circular genome is 15,286 bp with 13 protein-coding genes, 22 tRNAs and 2 ribosomal RNA genes, and a 578 bp non-coding control region. All protein coding genes used conventional start codons and terminated with a complete stop codon. The genome presented many unusual features: (1) rearrangement in the order of tRNAs as well as protein coding genes; (2) truncation and unusual secondary structures of tRNAs; (3) presence of two different repeat elements in separate non-coding regions; (4) presence of one pseudo-tRNA gene; (5) inversion of the rRNA genes; (6) higher percentage of non-coding regions when compared with other insect mitogenomes. Rearrangements of the tRNAs and protein coding genes are explained on the basis of tandem duplication and random loss model and why intramitochondrial recombination is a better model for explaining rearrangements in the O. oryzae mitochondrial genome is discussed. Furthermore, we evaluated the number of iterations of the tandem repeat elements found in the mitogenome. This led to the identification of genetic markers capable of differentiating rice gall midge biotypes and the two Orseolia species investigated. PMID- 26226165 TI - A Scott bench with ergonomic thorax stabilisation pad improves body posture during preacher arm curl exercise. AB - We assessed whether the use of an ergonomic thorax stabilisation pad, during the preacher arm curl exercise, could significantly reduce the excessive shoulder protraction and thoracic kyphosis induced by the standard flat pad built into the existing preacher arm curl equipment. A 3D motion capture system and inclinometers were used to measure shoulder protraction and thoracic kyphosis in 15 subjects performing preacher arm curl with a plate-loaded machine provided with the standard flat pad. The same measures were repeated after replacing the flat pad with a new ergonomic pad, specifically designed to accommodate the thorax profile and improve body posture. Pad replacement significantly (p < 0.001) reduced shoulder protraction (from [Formula: see text] to [Formula: see text]) and thoracic kyphosis (from [Formula: see text] to [Formula: see text]), enabling postural and functional improvements within the entire spine, shoulder girdle and rib cage. The ergonomic pad may potentially allow a more effective training, prevent musculoskeletal discomfort and reduce the risk of injury. Practitioner summary: We have designed an ergonomic thorax stabilisation pad for the preacher arm curl exercise. The new ergonomic pad improves the poor posture conditions induced by the standard flat pad and may potentially allow a more effective training, prevent musculoskeletal discomfort, improve the breathing function and reduce the risk of injury. PMID- 26226164 TI - Protection of Gastrointestinal Mucosa from Acute Heavy Alcohol Consumption: The Effect of Berberine and Its Correlation with TLR2, 4/IL1beta-TNFalpha Signaling. AB - The purpose of the present study is to confirm the protective effect of berberine (BBR) on gastrointestinal injury caused by acute heavy alcohol exposure, an effect that has not been reported previously. Our research details how BBR protects against gastrointestinal injuries from acute alcohol exposure using both in vivo and in vitro experiments. Acute high alcohol concentrations lead to obvious damage to the gastrointestinal mucosa, resulting in necrosis of the intestinal mucosa. Oral administration of BBR was able to significantly reduce this alcohol-induced damage, inhibit increases of alcohol-induced TNFalpha and IL 1beta expression in gastrointestinal mucosa as well as their upstream signals TLR2 and TLR4, and regulate cytokines that modulate tight junctions. Alcohol consumption is a popular human social behavior worldwide, and the present study reports a comprehensive mechanism by which BBR protects against gastrointestinal injuries from alcohol stress, providing people with a novel application of BBR. PMID- 26226167 TI - Thermal Cycling Behavior of Zinc Antimonide Thin Films for High Temperature Thermoelectric Power Generation Applications. AB - The zinc antimonide compound ZnxSby is one of the most efficient thermoelectric materials known at high temperatures due to its exceptional low thermal conductivity. For this reason, it continues to be the focus of active research, especially regarding its glass-like atomic structure. However, before practical use in actual surroundings, such as near a vehicle manifold, it is imperative to analyze the thermal reliability of these materials. Herein, we present the thermal cycling behavior of ZnxSby thin films in nitrogen (N2) purged or ambient atmosphere. ZnxSby thin films were prepared by cosputtering and reached a power factor of 1.39 mW m(-1) K(-2) at 321 degrees C. We found maximum power factor values gradually decreased in N2 atmosphere due to increasing resistivity with repeated cycling, whereas the specimen in air kept its performance. X-ray diffraction and electron microscopy observations revealed that fluidity of Zn atoms leads to nanoprecipitates, porous morphologies, and even growth of a coating layer or fiber structures on the surface of ZnxSby after repetitive heating and cooling cycles. With this in mind, our results indicate that proper encapsulation of the ZnxSby surface would reduce these unwanted side reactions and the resulting degradation of thermoelectric performance. PMID- 26226166 TI - Green tea extract decreases starch digestion and absorption from a test meal in humans: a randomized, placebo-controlled crossover study. AB - Green tea is known worldwide for its beneficial effects on human health. However, objective data evaluating this influence in humans is scarce. The aim of the study was to assess the impact of green tea extract (GTE) on starch digestion and absorption. The study comprised of 28 healthy volunteers, aged 19 to 28 years. In all subjects, a starch (13)C breath test was performed twice. Subjects randomly ingested naturally (13)C-abundant cornflakes during the GTE test (GTE 4 g) or placebo test. The cumulative percentage dose recovery (CPDR) was significantly lower for the GTE test than for the placebo test (median [interquartile range]: 11.4% [5.5-15.5] vs. 16.1% [12.7-19.5]; p = 0.003). Likewise, CPDR expressed per hour was considerably lower in each point of the measurement. In conclusion, a single dose of green tea extract taken with a test meal decreases starch digestion and absorption. PMID- 26226168 TI - Evidence-Based Medicine Turned Upside Down. PMID- 26226169 TI - Dental Adhesion to Erbium-Lased Tooth Structure: A Review of the Literature. AB - OBJECTIVE: The aim of the present study was to conduct a review of the literature about adhesion on erbium laser prepared cavities, related to the specific conditions of the irradiated dentin substrate and the effects on bond strength values. BACKGROUND DATA: Advances in adhesive restorative techniques significantly influenced modern restorative dentistry. The concept of "minimally invasive dentistry" aims to perform more conservative treatment of cavities in which the removal of sound dentin is no longer necessary. This approach, which relies on the concept of adhesion of restorative materials to the mineralized dental tissues, is considered to be a contemporary outcome in dentistry. Similarly, laser technology in restorative dentistry opened new possibilities and strategies as alternatives to conventional treatment. Considering the clinical aspects of the use of erbium lasers for caries removal, cavity preparations, and substrate conditioning, treatment with lasers can be considered to be an efficient technique with wide acceptance by patients. METHODS: Computerized and manual searches were conducted for studies through 2015 that addressed the topic. RESULTS: According to the literature, there is no defined standard protocol concerning the information that articles must provide, making a definitive protocol very difficult to establish. Data varied from the type of adhesive and resin composite used, substrate, and parameters (power, energy density, pulse duration, irradiation time, distance, cooling system) to the bond strength test methodology used. CONCLUSIONS: Further studies are necessary in order to define a standard protocol with positive results and higher bond strength values when using erbium lasers. Detailed information concerning laser parameters should be implemented. Also, longitudinal clinical studies should be developed in the search for new parameters that behave favorably in the irradiated substrate. PMID- 26226170 TI - Serial Ultrasound Findings After Laser Ablation for Benign Breast Lesions on Long Term Follow-Up: Implications for Evaluation of Procedural Success. AB - OBJECTIVE: The purpose if this study was to describe the follow-up ultrasound (US) findings of percutaneous US-guided laser ablation for small benign breast lesions, and to define the procedural success. BACKGROUND DATA: There are limited reports on follow-up imaging after laser ablation, because the ablated tumors were generally resected by surgery. MATERIALS AND METHODS: US-guided laser ablation was performed on 19 benign breast lesions in 10 patients. The median size of the lesions was 7.8 mm (range, 3-11 mm). The lesions were diagnosed as image-pathology concordant benign by US-guided core biopsy. After ablation, we performed follow-up US with an interval of 3-12 months; the median follow-up period was 32 months (range, 30-36 months). We evaluated the morphologic and size changes by using serial follow-up US. RESULTS: US findings of the 13 cases followed within the first 6 months after ablation showed hypoechoic lesions having inner hyperechogenicity with or without a hypoechoic center. The size of these lesions during this period increased in comparison with the initial lesion size, and then decreased or became stable on serial follow-up US. On the last follow-up US examination, in 14 cases (73.6%), the lesions were invisible, 4 cases (21.1%) showed scar changes, and 1 case (5.3%) showed a hypoechoic remnant lesion. CONCLUSIONS: US findings within 6 months after laser ablation showed mixed echoic lesions with increased size, followed by gradual decrease in size. Therefore, the success of laser ablation may be evaluated by checking the changes in the lesions by comparing the size of the lesions with the first follow-up US within 6 months and not the original tumor. PMID- 26226171 TI - The Effects of Er:YAG, Nd:YAG, and Ho:YAG Laser Surface Treatments to Acrylic Resin Denture Bases on the Tensile Bond Strength of Silicone-Based Resilient Liners. AB - OBJECTIVE: The present study was to assess the effect of surface treatments of Er:YAG, Nd:YAG, and Ho:YAG lasers on the tensile bond strength of a silicone based resilient liner to an acrylic denture in an in vitro setting. METHODS: Experimental dumbbell-shaped specimens (75 mm) were produced by combining two acrylate pieces fabricated from heat-polymerized acrylic resin (36 mm) with 3 mm of Molloplast((r))-B filling between them. The specimens (n=200) were randomly divided in half for thermocycling, and each 100 specimen set was randomized into five groups (n=20) with different surface treatments: control (no surface treatment), sandblasting, Er:YAG laser, Nd:YAG laser, and Ho:YAG laser. A tensile bond strength test was performed. The effect of the laser surface treatments was examined with scanning electron microscopy. RESULTS: Only the Er:YAG laser increased the tensile bond strength compared with the other treatments. The other laser groups showed lower bond strengths. The Ho:YAG laser resulted in considerably reduced tensile bond strength. The scanning electron microscopy images showed that applying laser surface treatments modified the surface of the denture base resin. CONCLUSIONS: There was not an overall improvement with the use of the studied laser modalities in the adhesion quality of resilient denture liner to acrylic resin, although Er:YAG laser showed a potential to improve their adhesion. These laser modalities need to be subjected to further studies to determine optimal setup for use in prosthodontics. PMID- 26226172 TI - Laser Therapy in the Treatment of Paresthesia: A Retrospective Study of 125 Clinical Cases. AB - OBJECTIVE: The aim of this retrospective study was to evaluate the effectiveness of laser therapy for acceleration and recovery of nerve sensitivity after orthognathic or minor oral surgeries, by analysis of clinical records of patients treated at the Special Laboratory of Lasers in Dentistry (LELO, School of Dentistry, University of Sao Paulo), throughout the period 2007-2013. BACKGROUND DATA: Nerve tissue lesions may occur during various dental and routine surgical procedures, resulting in paresthesia. Laser therapy has been shown to be able to accelerate and enhance the regeneration of the affected nerve tissue; however, there are few studies in the literature that evaluate the effects of treatment with low-power laser on neural changes after orthognathic or minor oral surgeries. METHODS: A total of 125 clinical records were included, and the data on gender, age, origin of the lesion, nerve, interval between surgery and onset of laser therapy, frequency of laser irradiation (one or two times per week), final evolution, and if there was a need to change the irradiation protocol, were all recorded. These data were related to the recovery of sensitivity in the affected nerve area. Descriptive analyses and modeling for analysis of categorical data (alpha=5%) were performed. RESULTS: The results from both analyses showed that the recovery of sensitivity was correlated with patient age (p=0.015) and interval between surgery and onset of laser therapy (p=0.002). CONCLUSIONS: Within the limits of this retrospective study, it was found that low power laser therapy with beam emission band in the infrared spectrum (808 nm) can positively affect the recovery of sensitivity after orthognathic or minor oral surgeries. PMID- 26226173 TI - Comparison of Nd:YAG Laser and Surgical Stripping for Treatment of Gingival Hyperpigmentation: A Clinical Trial. AB - OBJECTIVE: The objective of this study is to evaluate and compare surgical stripping and neodymium-doped: yttrium, aluminum garnet (Nd:YAG) laser techniques for gingival depigmentation and to evaluate their effect on repigmentation. BACKGROUND DATA: Gingival depigmentation is often associated with repigmentation. Recurrence of pigmentation differs according to different treatment modalities. MATERIALS AND METHODS: In this study, 40 maxillary sites from 20 patients presenting bilateral melanin gingival hyperpigmentation were selected. Contralateral quadrants in the maxilla were randomly assigned to receive Nd:YAG laser at 3 W, 30 mJ per pulse, with contact mode, and with a handpiece with a 300 MUm diameter optic fiber and surgical stripping. Plaque index, Dummett Oral Pigmentation Index (DOPI), Hedin melanin index, size of pigmented area, time interval and extent of repigmentation, time taken for each of the procedures, assessment of pain, intraoperative bleeding index, and patient preference were compared from baseline to 6 months. RESULTS: Comparison between Nd:YAG laser and surgical stripping group for plaque index, DOPI, Hedin index, size of pigmented area, time interval, and extent of repigmentation, at 6 months was statistically nonsignificant. Intergroup comparison for time taken, pain, and patient preference was statistically significant. Intragroup comparison for Nd:YAG laser and surgical stripping at 6 months for DOPI, Hedin index, and size of pigmented area was statistically significant. CONCLUSIONS: From the present study it can be concluded that Nd:YAG laser can be used as an alternative technique for gingival depigmentation. However, surgical stripping continues to remain as a cost effective procedure. PMID- 26226174 TI - Medication-Related Osteonecrosis of the Jaw: An Autofluorescence-Guided Surgical Approach Performed with Er:YAG Laser. AB - OBJECTIVE: The aim of this study was to propose an autofluorescence (AF)-guided surgical approach performed with Er:YAG laser and Nd:YAG low-level laser therapy (LLLT). BACKGROUND DATA: Medication-related osteonecrosis of the jaw (MRONJ) therapy remains an unresolved problem. The proposed conservative and surgical treatment regimens are associated with contradictory success rates. However, the increased experience with MRONJ management suggests that surgical therapy can halt disease progression, and can allow a histology-based diagnosis of osteonecrosis. Surgical approach with Er:YAG laser is associated with significantly better results compared with medical treatment and traditional surgical approaches. One of the difficulties encountered during surgical removal of a MRONJ is the precise individuation of necrotic bone margins. PATIENT AND METHODS: A case of Stage III maxillary osteonecrosis treated with a new surgical approach is presented. RESULTS: After 7 months of follow-up, complete mucosal healing was evident, and the patient was free of symptoms. Such a technique allowed a highly accurate and minimally invasive approach through the selective ablation of the non-/hypofluorescent areas. CONCLUSIONS: Taking into account the advantages of laser therapy and the possible effectiveness of AF in highlighting surgical margins, this approach would probably achieve excellent outcomes. PMID- 26226175 TI - Millon's Contributions to Preadolescent and Adolescent Personality Assessment: Searching Onward and Upward. AB - Theodore Millon was one of the most influential personality theorists of the 20th century. His theory was originally rooted in biosocial learning models and later reconceptualized as an evolutionary model. This foundation of Millon's work encompasses the entire life span. He had a genuine concern for humankind, especially children. His theory encompasses a comprehensive understanding of the relationship among childhood experiences, parenting styles, and recurring events throughout the life span in shaping the personality. Notable contributions to child and adolescent assessment are the Millon Adolescent Personality Inventory (Millon, Green, & Meagher, 1982 ), the Millon Adolescent Clinical Inventory (Millon, Millon, & Davis, 1993 ), and the Millon Pre-Adolescent Clinical Inventory (M-PACI; Millon, Tringone, Millon, & Grossman, 2005 ). Given Millon's influence on the personality disorders section of the Diagnostic and Statistical Manual of Mental Disorders (DSM), the aforementioned instruments have personality constructs tied to familiar DSM categories, and among them, cover the age range of 9 to 18 years old. His development of the Millon Inventories revolutionized personality assessment in the United States and abroad. Millon's legacies will live on through his works and through the respect and compassion he demonstrated toward others. PMID- 26226176 TI - UPLC-ESI-TOF MS-Based Metabolite Profiling of the Antioxidative Food Supplement Garcinia buchananii. AB - Comparative antioxidative analyses of aqueous ethanolic extracts from leaf, root, and stem of Garcinia buchananii revealed high activity of all three organs. To investigate the metabolite composition of the different parts of G. buchananii, an untargeted metabolomics approach using UPLC-ESI-TOF MS with simultaneous acquisition of low- and high-collision energy mass spectra (MS(e)) was performed. Unsupervised statistics (PCA) highlighted clear differences in the metabolomes of the three organs. OPLS-DA revealed (2R,3S,2"R,3"R)-GB-1, (2R,3S)-morelloflavone, and (2R,3S)-volkensiflavone as the most decisive marker compounds discriminating leaf from root and stem extract. Leaves represent the best source to isolate GB 1, morelloflavone, and volkensiflavone. Root extract is the best organ to isolate xanthones and stem bark extract the best source to isolate (2R,3S,2"R,3"R) manniflavanone; the identified polyisoprenylated benzophenones are characteristic compounds for the leaf organ. Morelloflavone, volkensiflavone, and garcicowin C were isolated for the first time from G. buchananii, identified via MS, NMR, and CD spectroscopy, and showed in H2O2 scavenging, H/L-TEAC, and H/L-ORAC assays moderate to strong in vitro antioxidative activities. PMID- 26226177 TI - Nano-copper catalysed highly regioselective synthesis of 2,4-disubstituted pyrroles from terminal alkynes and isocyanides. AB - Nano-copper(0) stabilized on alumina prepared from Cu-Al hydrotalcite has been reported for completely regioselective synthesis of 2,4-disubstituted pyrroles from unactivated terminal aromatic/aliphatic alkynes and isocyanides. The reaction is operationally simple, involves ligand-free inexpensive nano-copper, and affords products in high yields. PMID- 26226178 TI - Expression and characterization of a recombinant psychrophilic gamma-carbonic anhydrase (NcoCA) identified in the genome of the Antarctic cyanobacteria belonging to the genus Nostoc. AB - Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the CO2 hydration/dehydration reversible reaction: CO2 + H2O ? [Formula: see text] + H(+). Living organisms encode for at least six distinct genetic families of such catalyst, the alpha-, beta-, gamma-, delta-, zeta- and eta-CAs. The main function of the CAs is to quickly process the CO2 derived by metabolic processes in order to regulate acid base homeostasis, connected to the production of protons (H(+)) and bicarbonate. Few data are available in the literature on Antarctic CAs and most of the scientific information regards CAs isolated from mammals or prokaryotes (as well as other mesophilic sources). It is of great interest to study the biochemical behavior of such catalysts identified in organism living in the Antarctic sea where temperatures average -1.9 degrees C all year round. The enzymes isolated from Antarctic organisms represent a useful tool to study the relations among structure, stability and function of proteins in organisms adapted to living at constantly low temperatures. In the present paper, we report in detail the cloning, purification, and physico-chemical properties of NcoCA, a gamma-CA isolated from the Antarctic cyanobacterium Nostoc commune. This enzyme showed a higher catalytic efficiency at lower temperatures compared to mesophilic counterparts belonging to alpha-, beta-, gamma-classes, as well as a limited stability at moderate temperatures. PMID- 26226179 TI - Synthesis and potential antitumor activity of 7-(4-substituted piperazin-1-yl)-4 oxoquinolines based on ciprofloxacin and norfloxacin scaffolds: in silico studies. AB - The potential antitumor activities of a series of 7-(4-substituted piperazin-1 yl)fluoroquinolone derivatives (1-14a,b) using ciprofloxacin and norfloxacin as scaffolds are described. These compounds exhibit potent and broad spectrum antitumor activities using 60 human cell lines in addition to the inherent antibacterial activity. Compounds 1a, 2a, 3b, 6b and 7a were found to be the most potent, while 2b, 5b, and 6a were found to have an average activity. The results of this study demonstrated that compounds 1a, 2a, 3b, 6b and 7a (mean GI50; 2.63 3.09 uM) are nearly 7-fold more potent compared with the positive control 5 fluorouracil (mean GI50; 22.60 uM). More interestingly, compounds 1a, 2a, 3b, 6b and 7a have an almost antitumor activity similar to gefitinib (mean GI50; 3.24 uM) and are nearly 2-fold more potent compared to erlotinib (mean GI50; 7.29 uM). In silico study and ADME-Tox prediction methodology were used to study the antitumor activity of the most active compounds and to identify the structural features required for antitumor activity. PMID- 26226180 TI - Novel synthesis scheme and in vitro antimicrobial evaluation of a panel of (E)-2 aryl-1-cyano-1-nitroethenes. AB - Drug resistance has become a major concern in the field of infection management, therefore searching for new antibacterial agents is getting more challenging. Our study presents an optimized and eco-friendly synthesis scheme for a panel of nitroalkenes bearing various functional groups in the aromatic moiety and bromine or cyano substituents in 1 position of nitrovinyl moiety. The presence of nitrolefine group outside the ring minimalizes genotoxic properties while conjugation of aryl group with nitrovinyl moiety increases stability of the compounds. Then our research focused on evaluation of biological properties of such obtained (E)-2-aryl-1-cyano-1-nitroethenes. As they exhibit strong bacteriostatic and bactericidal activities against reference bacteria and yeast species with no detectable cytotoxicity towards cultured human HepG2 and HaCaT cells, they could be promising candidates for the replacement of traditional nitrofurane-containing antibacterial drugs. Nevertheless, validation of the obtained data in an in vivo model and additional safety studies on mutagenicity are still required. PMID- 26226181 TI - Cost-effectiveness of Lung Cancer Screening in Canada. AB - IMPORTANCE: The US National Lung Screening Trial supports screening for lung cancer among smokers using low-dose computed tomographic (LDCT) scans. The cost effectiveness of screening in a publically funded health care system remains a concern. OBJECTIVE: To assess the cost-effectiveness of LDCT scan screening for lung cancer within the Canadian health care system. DESIGN, SETTING, AND PARTICIPANTS: The Cancer Risk Management Model (CRMM) simulated individual lives within the Canadian population from 2014 to 2034, incorporating cancer risk, disease management, outcome, and cost data. Smokers and former smokers eligible for lung cancer screening (30 pack-year smoking history, ages 55-74 years, for the reference scenario) were modeled, and performance parameters were calibrated to the National Lung Screening Trial (NLST). The reference screening scenario assumes annual scans to age 75 years, 60% participation by 10 years, 70% adherence to screening, and unchanged smoking rates. The CRMM outputs are aggregated, and costs (2008 Canadian dollars) and life-years are discounted 3% annually. MAIN OUTCOMES AND MEASURES: The incremental cost-effectiveness ratio. RESULTS: Compared with no screening, the reference scenario saved 51,000 quality adjusted life-years (QALY) and had an incremental cost-effectiveness ratio of CaD $52,000/QALY. If smoking history is modeled for 20 or 40 pack-years, incremental cost-effectiveness ratios of CaD $62,000 and CaD $43,000/QALY, respectively, were generated. Changes in participation rates altered life years saved but not the incremental cost-effectiveness ratio, while the incremental cost-effectiveness ratio is sensitive to changes in adherence. An adjunct smoking cessation program improving the quit rate by 22.5% improves the incremental cost-effectiveness ratio to CaD $24,000/QALY. CONCLUSIONS AND RELEVANCE: Lung cancer screening with LDCT appears cost-effective in the publicly funded Canadian health care system. An adjunct smoking cessation program has the potential to improve outcomes. PMID- 26226182 TI - The Stereoselective Reductions of Ketones to the Most Thermodynamically Stable Alcohols Using Lithium and Hydrated Salts of Common Transition Metals. AB - A simple method is presented for the highly stereoselective reductions of ketones to the most thermodynamically stable alcohols. In this procedure, the ketone is treated with lithium dispersion and either FeCl2.4H2O or CuCl2.2H2O in THF at room temperature. This protocol is applied to a large number and variety of ketones and is both more convenient and efficient than those commonly reported for the diastereoselective reduction of five- and six-membered cyclic ketones. PMID- 26226183 TI - Laboratory Diagnostics Market in East Africa: A Survey of Test Types, Test Availability, and Test Prices in Kampala, Uganda. AB - BACKGROUND: Diagnostic laboratory tests are routinely defined in terms of their sensitivity, specificity, and ease of use. But the actual clinical impact of a diagnostic test also depends on its availability and price. This is especially true in resource-limited settings such as sub-Saharan Africa. We present a first of-its-kind report of diagnostic test types, availability, and prices in Kampala, Uganda. METHODS: Test types (identity) and availability were based on menus and volumes obtained from clinical laboratories in late 2011 in Kampala using a standard questionnaire. As a measure of test availability, we used the Availability Index (AI). AI is the combined daily testing volumes of laboratories offering a given test, divided by the combined daily testing volumes of all laboratories in Kampala. Test prices were based on a sampling of prices collected in person and via telephone surveys in 2015. FINDINGS: Test volumes and menus were obtained for 95% (907/954) of laboratories in Kampala city. These 907 laboratories offered 100 different test types. The ten most commonly offered tests in decreasing order were Malaria, HCG, HIV serology, Syphilis, Typhoid, Urinalysis, Brucellosis, Stool Analysis, Glucose, and ABO/Rh. In terms of AI, the 100 tests clustered into three groups: high (12 tests), moderate (33 tests), and minimal (55 tests) availability. 50% and 36% of overall availability was provided through private and public laboratories, respectively. Point-of-care laboratories contributed 35% to the AI of high availability tests, but only 6% to the AI of the other tests. The mean price of the most commonly offered test types was $2.62 (range $1.83-$3.46). INTERPRETATION: One hundred different laboratory test types were in use in Kampala in late 2011. Both public and private laboratories were critical to test availability. The tests offered in point-of-care laboratories tended to be the most available tests. Prices of the most common tests ranged from $1.83-$3.46. PMID- 26226184 TI - Nano-Optomechanical Resonators in Microfluidics. AB - Operation of nanomechanical devices in liquid has been challenging due to the strong viscous damping that greatly impedes the mechanical motion. Here we demonstrate an optomechanical microwheel resonator integrated in microfluidic system that supports low-loss optical resonances at near-visible wavelength with quality factor up to 1.5 million, which allows the observation of the thermal Brownian motion of the mechanical mode in both air and water environment with high signal-to-background ratio. A numerical model is developed to calculate the hydrodynamic effect on the device due to the surrounding water, which agrees well with the experimental results. With its very high resonance frequency (170 MHz) and small loaded mass (75 pg), the present device has an estimated mass sensitivity at the attogram level in water. PMID- 26226186 TI - The Lancet Series on Midwifery: A Momentous Opportunity to Improve Maternal and Newborn Health. PMID- 26226185 TI - Forecasting Influenza Epidemics in Hong Kong. AB - Recent advances in mathematical modeling and inference methodologies have enabled development of systems capable of forecasting seasonal influenza epidemics in temperate regions in real-time. However, in subtropical and tropical regions, influenza epidemics can occur throughout the year, making routine forecast of influenza more challenging. Here we develop and report forecast systems that are able to predict irregular non-seasonal influenza epidemics, using either the ensemble adjustment Kalman filter or a modified particle filter in conjunction with a susceptible-infected-recovered (SIR) model. We applied these model-filter systems to retrospectively forecast influenza epidemics in Hong Kong from January 1998 to December 2013, including the 2009 pandemic. The forecast systems were able to forecast both the peak timing and peak magnitude for 44 epidemics in 16 years caused by individual influenza strains (i.e., seasonal influenza A(H1N1), pandemic A(H1N1), A(H3N2), and B), as well as 19 aggregate epidemics caused by one or more of these influenza strains. Average forecast accuracies were 37% (for both peak timing and magnitude) at 1-3 week leads, and 51% (peak timing) and 50% (peak magnitude) at 0 lead. Forecast accuracy increased as the spread of a given forecast ensemble decreased; the forecast accuracy for peak timing (peak magnitude) increased up to 43% (45%) for H1N1, 93% (89%) for H3N2, and 53% (68%) for influenza B at 1-3 week leads. These findings suggest that accurate forecasts can be made at least 3 weeks in advance for subtropical and tropical regions. PMID- 26226187 TI - Orientations between Red Antenna States of Photosystem I Monomers from Thermosynechococcus elongatus Revealed by Single-Molecule Spectroscopy. AB - Single-molecule spectroscopy at low temperature was used to study the spectral properties, heterogeneities, and spectral dynamics of the chlorophyll a (Chl a) molecules responsible for the fluorescence emission of photosystem I monomers (PS I-M) from the cyanobacterium Thermosynechococcus elongatus. The fluorescence spectra of single PS I-M are dominated by several red-shifted chlorophyll a molecules named C708 and C719. The emission spectra show broad spectral distributions and several zero-phonon lines (ZPLs). Compared with the spectra of the single PS I trimers, some contributions are missing due to the lower number of C719 Chl's in monomers. Polarization-dependent measurements show an almost perpendicular orientation between the emitters corresponding to C708 and C719. These contributions can be assigned to chlorophyll dimers B18B19, B31B32, and B32B33. PMID- 26226188 TI - A Quasi-relativistic Density Functional Theory Study of the Actinyl(VI, V) (An = U, Np, Pu) Complexes with a Six-Membered Macrocycle Containing Pyrrole, Pyridine, and Furan Subunits. AB - Actinyl(VI, V) (An = U, Np and Pu) complexes of the recently reported hybrid macrocycle, cyclo[1]furan[1]pyridine[4]pyrrole (denoted as H4L), have been studied using density functional theory in combination with the small-core scalar relativistic effective core potentials and corresponding (14s13p10d8f6g)/[ 10s9p5d4f3g] basis sets in the segmented contraction scheme. On the basis of our calculations, the pyrrole nitrogen atoms that possess the shortest An-L bonds and strongest basicity are the main donor atoms that contribute to the formation of actinyl(VI, V) complexes. The natural population analysis (NPA) suggests higher ligand-to-actinyl charge transfer in the actinyl(VI) complexes than in their actinyl(V) analogues, which account for the higher decomposition energies of the former. A significant actinide-to-ligand spin density delocalization in the uranyl(V) and neptunyl(V) complexes was observed owing to the redistribution of spin density caused by complexation. A thermodynamic analysis indicates that the formation of the actinyl(VI, V) complexes are exothermic reactions in CH2Cl2 solvent, where the uranyl cations show the highest selectivity. In aqueous solution containing chloride ions, for complexing with macrocycle H4L, the plutonyl(VI) and uranyl(V) cations possess the highest selectivity among actinyl(VI) and (V) cations, respectively. This work can shed light on the design of macrocycle complexes for actinide recognition and extraction in the future. PMID- 26226189 TI - New Heterocyclic Product Space for the Castagnoli-Cushman Three-Component Reaction. AB - Significant expansion of heterocyclic product space accessible by the Castagnoli Cushman reaction (CCR) has been achieved via the use of glutaric anhydride analogues containing endocyclic substitutions with oxygen, nitrogen, and sulfur. Incorporation of these heteroatoms in the anhydride's backbone results in enhanced reactivity and generally lower temperatures that are required for the reactions to go to completion. These findings are particularly significant in light of the CCR recently recognized as an efficient tool for lead-oriented synthesis. PMID- 26226190 TI - Atomistic Texture of Amorphous Manganese Oxides for Electrochemical Water Splitting Revealed by Ab Initio Calculations Combined with X-ray Spectroscopy. AB - Amorphous transition-metal (hydr)oxides are considered as the most promising catalysts that promote the oxidation of water to molecular oxygen, protons, and "energized" electrons, and, in turn, as fundamental parts of "artificial leaves" that can be exploited for large scale generation of chemical fuels (e.g., hydrogen) directly from sunlight. We present here a joint theoretical experimental investigation of electrodeposited amorphous manganese oxides with different catalytic activities toward water oxidation (MnCats). Combining the information content of X-ray absorption fine structure (XAFS) measurements with the predictive power of ab initio calculations based on density functional theory, we have been able to identify the essential structural and electronic properties of MnCats. We have elucidated (i) the localization and structural connection of Mn(II), Mn(III), and Mn(IV) ions in such amorphous oxides and (ii) the distribution of protons at the MnCat/water interface. Our calculations result in realistic 3D models of the MnCat atomistic texture, formed by the interconnection of small planar Mn-oxo sheets cross-linked through different kinds of defective Mn atoms, isolated or arranged in closed cubane-like units. Essential for the catalytic activity is the presence of undercoordinated Mn(III)O5 units located at the boundary of the amorphous network, where they are ready to act as hole traps that trigger the oxidation of neighboring water molecules when the catalyst is exposed to an external positive potential. The present validation of a sound 3D model of MnCat improves the accuracy of XAFS fits and opens the way for the development of mechanistic schemes of its functioning beyond a speculative level. PMID- 26226191 TI - Under the guise of retinitis. PMID- 26226192 TI - The Relationships Between Sense of Belonging to a Community GLB Youth Group; School, Teacher, and Peer Connectedness; and Depressive Symptoms: Testing of a Path Model. AB - Research indicates belonging to a gay, lesbian, and bisexual (GLB) support group is indirectly associated with fewer depressive symptoms, via higher levels of sense of belonging to the general community. The current study extended this research by testing a path model to determine whether school, teacher, and peer connectedness are influenced by sense of belonging to a community GLB youth group. A sample of 82 Australian GLB adolescents aged 14 to 18 years who currently attend high school completed the Center for Epidemiologic Studies Depression Scale, the Psychological Subscale of the Sense of Belonging Instrument, and the Social Questionnaire for Secondary Students. Results indicated very good model fit. Higher levels of belonging to a community GLB youth group were associated with higher levels of school, teacher, and peer connectedness, but only peer connectedness was directly associated with depressive symptoms. Higher levels of school and teacher connectedness were associated with higher levels of peer connectedness. Interventions aimed at increasing belonging to a community GLB youth group may have indirect benefits for the mental health of GLB adolescents, via higher levels of school, teacher, and peer connectedness. PMID- 26226193 TI - Self-Stratified Antimicrobial Acrylic Coatings via One-Step UV Curing. AB - We designed and synthesized a novel quaternary ammonium methacrylate compound (QAC-2) bearing a perfluoroalkyl tail on one end and an acrylic moiety on the other. Via one-step UV curing of QAC-2 and methyl methacrylate (MMA) with ethylene glycol dimethacrylate (EGDMA) as the cross-linker, we obtained cross linked coatings with excellent antimicrobial property, as demonstrated by the total kill against both Gram-negative Escherichia coli (E. coli) and Gram positive Staphylococcus epidermidis (S. epidermidis) at a QAC-2 concentration as low as ~0.06 mol % (~0.4 wt %) relative to MMA, which was substantially lower than the QAC amount needed in the coatings containing QACs with a hydrocarbon tail. A zone of inhibition test confirmed that the antimicrobial effect was on the basis of contact killing and there was no leaching of antimicrobial species from the cross-linked coating. The high antimicrobial potency in QAC-2-containing films was the consequence of strong surface enrichment of the fluorinated QAC, as confirmed by X-ray photoelectron spectroscopy (XPS). PMID- 26226194 TI - Leuckart-Wallach Route Toward Isocyanides and Some Applications. AB - Isocyanide-based multicomponent reactions (IMCR) are among the most important chemical reactions to efficiently generate molecular diversity and have found widespread use in industry and academia. Generally, isocyanides are synthesized in 1-2 steps starting from primary amines. Here, we provide experimental detail on an alternative approach toward formamides and, thus, isocyanides via the Leuckart-Wallach reaction in an improved variation. The resulting >50 synthesized and characterized formamides are useful starting materials for IMCR, as well as other chemistries. The advantage of using the Leuckart-Wallach pathway to formamides and isocyanides is the lower price, on average, of the starting materials, as well as their differential and complementary structural diversity, as compared to the primary amine pathway. PMID- 26226195 TI - Do associated auto-antibodies influence the outcome of myasthenia gravis after thymectomy? AB - Myasthenia gravis (MG) is a neuromuscular autoimmune disease, where antibodies against the acetylcholine receptor destroy this receptor. The role of thymectomy in the treatment of MG remains controversial. Because of the frequent association with other autoimmune diseases, we hypothesized that patients with multiple autoantibodies (autoAbs) might have a lower chance of reaching complete stable remission after thymectomy. We analyzed sera of 85 MG patients who underwent a thymectomy between April 2004 and December 2012. We used four different immunodot kits (D-Tek, Mons, Belgium): ANA25 Quantrix, Synthetase 10 Diver, Myositis 7 Diver and Liver 10 profile Diver, all automatized on the BlueDiver Instrument (D Tek). The Myasthenia Gravis Foundation of America (MGFA) postintervention status was used to determine the outcome after thymectomy. AutoAbs other than anti acetylcholine receptor (AChR) antibodies were detected in 29.4% of the patients of whom 16.5% clinically had a second autoimmune disease. In none of the seronegative patients other autoAbs were detected. No significant difference was observed in the 3-years remission rate after thymectomy in patients with or without antibodies other than anti-AChR antibodies. Although these autoAbs do not predict outcome in our MG patient cohort, screening for multiple autoAbs in MG patients might be warranted to identify patients with additional autoimmune diseases. PMID- 26226196 TI - Ultrasensitive Visual Sensing of Molybdate Based on Enzymatic-like Etching of Gold Nanorods. AB - Here, we have developed a novel approach to the visual detection of molybdate with high sensitivity and selectivity in aqueous media based on the combination of catalytic formation of iodine and iodine-mediated etching of gold nanorods. In weak acid solution, like peroxidase, molybdate can catalyze the reaction between H2O2 and I(-) to produce I2, a moderate oxidant, which then etches gold nanorods preferentially along the longitudinal direction in the presence of hexadecyltrimethylammonium bromide. The etching results in the longitudinal localized surface plasmon resonance extinction peak shifts to short wavelength, accompanied by a color change from blue to red. Under optimal conditions, this sensor exhibits good sensitivity with a detection limit of 1.0 nM. The approach is highlighted by its high selectivity and tolerance to interference, which enables the sensor to detect molybdate directly in real samples, such as tap water, drinking water, and seawater. In addition, perhaps the proposed sensing strategy can be also used for other targets that can selectively regulate the formation of I2 under given conditions. PMID- 26226197 TI - Men in Midwifery: A National Survey. AB - INTRODUCTION: Midwifery in the United States suffers from a lack of diversity. More than 91% of midwives are white, and more than 98% are women. Little research has explored the experiences of midwives who are men or transgender. METHODS: Invitation to an Internet survey was sent to the membership of the American College of Nurse-Midwives. Thirty-one participants who identified as men or transgender completed the survey, which included quantitative and open-ended questions about the impact of gender on education and practice. Data analysis of qualitative responses used qualitative description methodology to identify common themes. RESULTS: Four themes described participating men's experiences of education and practice of midwifery. Challenges included feeling singled out as different and being excluded. Supportive factors came from the social support of family, friends, colleagues, and patients, as well as from taking pride in one's work as a midwife. Midwives who identify as transgender described the challenges of others' confusion about their gender, having to hide their true gender identity, and struggling with the resulting loneliness. DISCUSSION: This survey highlights the challenges faced by midwives who are men or transgender in education and practice. Midwifery values of respect and acceptance for all women and families need to be applied internally to all members of the profession. This will support increased diversity and openness in midwifery. PMID- 26226198 TI - Carbon dioxide-enhanced photosynthesis of methane and hydrogen from carbon dioxide and water over Pt-promoted polyaniline-TiO2 nanocomposites. AB - The combination of polyaniline with TiO2 significantly enhanced the photocatalytic reduction of CO2 with H2O owing to the increased CO2 chemisorption and the facilitated separation of photogenerated electron-hole pairs. We discovered that CO2 played a unique role in enhancing the electron-hole separation and the photocatalytic activity for polyaniline-containing catalysts. PMID- 26226199 TI - Current Therapy of Acquired Ocular Toxoplasmosis: A Review. AB - Caused by the parasite Toxoplasma gondii, ocular toxoplasmosis (OT) is the most common form of posterior infectious uveitis. Combined antiparasitic therapy is the standard treatment for OT, but several other schemes have been proposed. The purpose of the present study was to review the literature on the treatment of OT and provide ophthalmologists with up-to-date information to help reduce OT related visual morbidity. In conclusion, no ideal treatment scheme was identified; currently prescribed therapeutic schemes yield statistically similar functional outcomes. PMID- 26226200 TI - Organ Distribution and Bone Tropism of Cellulose Nanocrystals in Living Mice. AB - Their physicochemical properties and relatively low cost make cellulose nanocrystals (CNCs) a potential candidate for future large-scale production in many fields including nanomedicine. Prior to a sustained and responsible development as theranostic agents, robust and reliable data concerning their safety, biocompatibility, and tissue distribution should be provided. In the present study, CNCs were extracted from Whatman filters functionalized with a fluorescent dye, and their interaction with living organisms has been thoroughly assessed. Our experimental evidence demonstrated that CNCs (1) are well tolerated by healthy mice after systemic injection; (2) are rapidly excreted, thus avoiding bioaccumulation in filter organs such as the kidneys and liver; (3) transiently migrate in bones; and (4) are able to penetrate in the cytoplasm of cancer cells without inducing material-related detrimental effects in terms of cell survival. Our results strongly suggest that the peculiar tropism to the bones is due to the chemical interaction between the Ca(2+) of the bone matrix and the active surface of negatively-charged CNCs. This feature, together with the ability to penetrate cancer cells, makes CNCs a potential nanodevice for theranostics in bone tumors. PMID- 26226201 TI - EPI-CT: design, challenges, and epidemiological methods of an international study on cancer risk after paediatric CT. PMID- 26226202 TI - Dinuclear iridium and rhodium complexes with bridging arylimidazolide-N(3),C(2) ligands: synthetic, structural, reactivity, electrochemical and spectroscopic studies. AB - Deprotonation of 1-arylimidazoles (aryl = mesityl (Mes), 2,6-diisopropylphenyl (Dipp)), with n-butyl lithium afforded the corresponding derivatives (1-aryl-1H imidazol-2-yl)lithium (1a, Ar = Mes; 1b, Ar = Dipp) in good yield. Reaction of 1a with 0.5 equiv. of [Ir(cod)(MU-Cl)]2 yielded two geometrical isomers of a doubly C2,N3-bridged dinuclear complex [Ir(cod){MU-C3H2N2(Mes)-kappaC2,kappaN3}]2 (3), 3H-H, a head-to-head (H-H) isomer of CS symmetry, and 3H-T, the thermodynamically preferred head-to-tail (H-T) isomer of C2 symmetry. The metallated carbon of the 4 electron donor anionic bridging ligands has some carbene character, reminiscent of the situation in N-metallated protic NHC complexes. Displacement of cod ligands from 3H-H and 3H-T afforded the tetracarbonyl complexes [Ir(CO)2{MU C3H2N2(Mes)-kappaC2,kappaN3}]24H-H and 4H-T, respectively. The reaction with PMe3, which gave only one complex, [Ir(CO)(PMe3){MU-C3H2N2(Mes) kappaC2,kappaN3}]2 (5), demonstrates that the isomerization of the central core Ir[MU-C3H2N2(Mes)-kappaC2,kappaN3]2Ir from H-H to H-T on going from 4H-H to 5 is readily triggered by phosphine substitution under mild conditions. Oxidative addition of MeI to 5 afforded the formally metal-metal bonded d(7)-d(7) complex [Ir2(CO)2(PMe3)2(Me)I{MU-C3H2N2(Mes)-kappaC2,kappaN3}2] (6). The blue [Ir(C2H4)2{MU-C3H2N2(Mes)-kappaC2,kappaN3}]2 (7) and purple [Rh(C2H4)2{MU C3H2N2(Dipp)-kappaC2,kappaN3}]2 (9) tetraethylene complexes were also obtained with only a H-T arrangement of the bridging ligands. Although only modestly efficient in alkane dehydrogenation, complex 7 was found to be a more active pre catalyst than 3H-T, 4H-T and 5, probably because of the favorable lability of the ethylene ligands. From cyclic voltammetry, exhaustive coulometry and spectroelectrochemistry studies, it was concluded that 3H-T undergoes a metal based one electron oxidation to generate the mixed-valent Ir(i)/Ir(ii) system. The energy of the intervalence band for the orange dirhodium complex [Rh(cod){MU C3H2N2(Mes)-kappaC2,kappaN3}]2 (8) is shifted toward lower energies in comparison with 3H-T, reflecting the decrease of the energy with the intermetallic distance. It was concluded from the EPR study that the Ir and Rh centres contribute substantially to the experimental magnetic anisotropy and thus to the singly occupied molecular orbital (SOMO) in the mixed-valent Ir(i)/Ir(ii) and Rh(i)/Rh(ii) systems. The molecular structures of 3H-H, 3H-T, 8 and 9 have been determined by X-ray diffraction. PMID- 26226203 TI - Simulation on the molecular radiosensitization effect of gold nanoparticles in cells irradiated by x-rays. AB - Abundant studies have focused on the radiosensitization effect of gold nanoparticles (GNPs) in the cellular environment with x-ray irradiation. To better understand the physical foundation and to initially study the molecular radiosensitization effect within the nucleus, a simple cell model with detailed DNA structure in the central nucleus was set up and complemented with different distributions of single and multiple GNPs in this work. With the biophysical Monte Carlo simulation code PARTRAC, the radiosensitization effects on both physical quantities and primary biological responses (DNA strand breaks) were simulated. The ratios of results under situations with GNPs compared to those without GNPs were defined as the enhancement factors (EFs). The simulation results show that the presence of GNP can cause a notable enhancement effect on the energy deposition within a few micrometers from the border of GNP. The greatest upshot appears around the border and is mostly dominated by Auger electrons. The enhancement effect on the DNA strand breakage becomes smaller because of the DNA distribution inside the nucleus, and the corresponding EFs are between 1 and 1.5. In the present simulation, multiple GNPs on the nucleus surface, the 60 kVp x-ray spectrum and the diameter of 100 nm are relatively more effective conditions for both physical and biological radiosensitization effects. These results preliminarily indicate that GNP can be a good radiosensitizer in x ray radiotherapy. Nevertheless, further biological responses (repair process, cell survival, etc) need to be studied to give more accurate evaluation and practical proposal on GNP's application in clinical treatment. PMID- 26226204 TI - Low temperature pollutant trapping and dissociation over two-dimensional tin. AB - Newly discovered two-dimensional tin, named stanene, has been theoretically predicted and found to have unique electronic properties. Stanene is found to have a buckled structure which could be a key structure against chemical reactivity. Hence, the reactivity of stanene against key air pollutants NO, NO2, SO, SO2, CO, and CO2 is investigated within first principles calculations. The results showed that stanene is reactive against those air pollutants. Furthermore, the dissociation activation energies of those pollutants over stanene are lower than previously reported catalysts. The physical origin of low dissociation barriers rests in the charge transfer from stanene to those pollutants, resulting in bond weakening. Hence, one can predict that unique reactivities of stanene offer low temperature trapping and dissociation of air pollutants. PMID- 26226205 TI - CEO update. PMID- 26226207 TI - Interdisciplinary Rehabilitation Referrals in a Concussion Clinic Cohort: An Exploratory Analysis. AB - OBJECTIVE: To assess the frequency and spectrum of referrals to rehabilitation disciplines in a concussion clinic population and factors associated with need for referral. DESIGN: Retrospective study. SETTING: Concussion clinic within the Physical Medicine and Rehabilitation Department of an academic medical center. PARTICIPANTS: Patients receiving physiatric management for concussion care. MAIN OUTCOME MEASURES: Referral to physical therapy (PT), occupational therapy, speech therapy (ST), neuropsychology, or any referral (Any), and reasons for referral. INTERVENTIONS: Demographic and clinical variables were analyzed for possible association with referral to rehabilitation disciplines. These independent variables included mechanism of injury, referral source, age, gender, provider, days since injury, presenting Sports Concussion Assessment Tool 2 (SCAT2) symptom score, insurance type, clinical risk factors, whether the injury was work related and whether the patient had been hospitalized. RESULTS: Among 262 patients meeting inclusion criteria, the most commonly prescribed individual therapy was physical therapy (74 patients; 28%), followed by speech therapy (60 patients, 23%), neuropsychology (27 patients, 10.3%), and occupational therapy (19 patients, 7.2%). In all, 121 (46%) of patients were referred to one or more disciplines. The most common reasons for referral were cognitive strategies (54 patients, 21%), balance/vestibular therapy (50 patients,19%), and neck pain (32 patients, 12%). Per multivariate logistic regression analysis, covariates associated with PT: age, SCAT2 symptom score, gender, provider, and (inversely) cognitive/learning disorder; ST: time elapsed since injury, gender, and referral source of internal clinic; Any: SCAT2 symptom score. Referrals did not significantly vary by mechanism of injury (sports, fall, vehicular, etc), whether work-related, or whether the patient had been hospitalized. Insurance factors were significant for PT and Any on the univariate analysis but not logistic regression. CONCLUSIONS: Relatively little has been described about the typical rehabilitation requirements of individuals recovering from concussion. Although rest and guided return to usual activities have been emphasized as mainstays of management, a large number of patients in this concussion cohort were determined to require additional rehabilitation services to assist in recovery. PMID- 26226208 TI - Spontaneous Iliopsoas Tendon Rupture: An Uncommon Cause of Hip Pain in Elderly Patients. AB - Iliopsoas tendon rupture is a relatively rare cause of hip pain. It has been described in children, in adults with pathologic avulsion secondary to metastatic disease, and in older individuals with multiple chronic illnesses. We are reporting a case of apparently spontaneous iliopsoas tendon rupture that occurred in an elderly patient presenting with severe debilitating hip pain whose etiology initially was unrecognized. Magnetic resonance imaging of the hip confirmed the diagnosis. This case highlights the importance of considering iliopsoas tear in the differential diagnosis of unexplained acute onset hip pain and illustrates that geriatric patients with this condition can be treated conservatively with satisfactory functional outcome. PMID- 26226209 TI - Single-Leg Squat Performance is Impaired 1 to 2 Years After Hip Arthroscopy. AB - OBJECTIVE: To evaluate single-leg squat performance 1-2 years after arthroscopy for intra-articular hip pathology compared with control subjects and the nonsurgical limb, and to investigate whether single-leg squat performance on the operated limb was associated with hip muscle strength. DESIGN: Cross-sectional study. SETTING: Private physiotherapy clinic and university laboratory. PARTICIPANTS: Thirty-four participants (17 women, 36.7 +/- 12.6 years) 1-2 years after hip arthroscopy and 34 gender-matched control subjects (17 women, 33.1 +/- 11.9 years). METHODS: Participants performed single-leg squats using a standardized testing procedure. Squat performance was captured using video. Video footage was uploaded and reformatted for analyses. Hip muscle strength was measured with handheld dynamometry using reliable methods. OUTCOME MEASURES: Frontal plane pelvic obliquity, hip adduction, and knee valgus were measured. Repeated measures analysis of variance evaluated between-group differences, with limb as a within-subjects factor (surgical versus nonsurgical) and gender as a between-subjects factor (P < .05). RESULTS: The hip arthroscopy group demonstrated significantly greater apparent hip adduction (mean difference 2.7 degrees , 95% confidence interval [CI] 0.7 degrees -4.8 degrees ) and apparent knee valgus (4.0 degrees , 95% CI 1.0 degrees -7.1 degrees ) at peak squat depth compared with control subjects. The operated limb also demonstrated significantly greater pelvic obliquity during single-leg stance compared with the nonsurgical limb (1.2 degrees , 95% CI 0.1 degrees -2.3 degrees ). Women had significantly greater apparent hip adduction (standing 1.6 degrees , 95% CI 0.5 degrees -2.6 degrees ; peak squat depth 2.4 degrees , 95% CI 0.3 degrees -4.4 degrees ) and apparent knee valgus (standing 3.3 degrees , 95% CI 1.8 degrees -4.7 degrees ; peak squat depth 3.1 degrees , 95% CI 0 degrees -6.1 degrees ). Significant positive correlations were found between frontal plane angles and hip flexor and extensor peak torque (P > .05). CONCLUSION: One to 2 years after hip arthroscopy, deficits in single-leg squat performance exist that have the potential to increase hip joint impingement and perpetuate postoperative symptoms. Rehabilitation after hip arthroscopy should target retraining in functional single-leg positions. PMID- 26226210 TI - Variation in Rehabilitation Treatment Patterns for Hip Fracture Treated With Arthroplasty. AB - BACKGROUND: Recommendations for health care redesign often advocate for comparative effectiveness research that is patient-centered. For patients who require rehabilitation services, a first step in this research process is to understand current practices for specific patient groups. OBJECTIVE: To document in detail the physical and occupational therapy treatment activities for inpatient hip fracture rehabilitation among 3 patient subgroups distinguished by their early rate of functional recovery between time of surgery to rehabilitation admission. DESIGN: Multicenter prospective observational cohort, practice-based evidence, study. SETTING: Seven skilled nursing facilities and 11 inpatient rehabilitation facilities across the United States. PARTICIPANTS: A total of 226 patients with hip fractures treated with hip arthroplasty. METHODS: Comparisons of physical and occupational therapy treatment activities among 3 groups with different initial recovery trajectory (IRT) rates (slower, moderate, faster). MAIN OUTCOME MEASURE(S): Percent of patients in each IRT group exposed to each physical and occupational therapy activity (exposure), and mean minutes per week for each activity (intensity). RESULTS: The number of patients exposed to different physical or occupational therapy activities varied within the entire sample. More specifically, among the 3 IRT groups, significant differences in exposure occurred for 44% of physical therapy activities and 39% of occupational therapy activities. More patients in the slower recovery group, IRT 1, received basic activities of daily living treatments and more patients in the faster recovery group, IRT 3, received advanced activities. The moderate recovery group, IRT 2, had some treatments similar to IRT 1 group and others similar to IRT 3 group. CONCLUSIONS: Analyses of practice-based evidence on inpatient rehabilitation of hip fracture patients treated with arthroplasty identified differences in therapy activities among three patient groups classified by IRT rates. These results may enhance physiatrists', other physicians', and rehabilitation teams' understanding of inpatient rehabilitation for these patients and help design future comparative effectiveness research. PMID- 26226206 TI - Inflammatory targets of therapy in sickle cell disease. AB - Sickle cell disease (SCD) is a monogenic globin disorder characterized by the production of a structurally abnormal hemoglobin (Hb) variant Hb S, which causes severe hemolytic anemia, episodic painful vaso-occlusion, and ultimately end organ damage. The primary disease pathophysiology is intracellular Hb S polymerization and consequent sickling of erythrocytes. It has become evident for more than several decades that a more complex disease process contributes to the myriad of clinical complications seen in patients with SCD with inflammation playing a central role. Drugs targeting specific inflammatory pathways therefore offer an attractive therapeutic strategy to ameliorate many of the clinical events in SCD. In addition, they are useful tools to dissect the molecular and cellular mechanisms that promote individual clinical events and for developing improved therapeutics to address more challenging clinical dilemmas such as refractoriness to opioids or hyperalgesia. Here, we discuss the prospect of targeting multiple inflammatory pathways implicated in the pathogenesis of SCD with a focus on new therapeutics, striving to link the actions of the anti inflammatory agents to a defined pathobiology, and specific clinical manifestations of SCD. We also review the anti-inflammatory attributes and the cognate inflammatory targets of hydroxyurea, the only Food and Drug Administration-approved drug for SCD. PMID- 26226211 TI - Male fertility and apoptosis in normal spermatogenesis are regulated by vacuolar ATPase isoform a2. AB - The a2 isoform of vacuolar-ATPase (ATP6V0A2, referred to as a2V) is required for normal spermatogenesis and maturation of sperm. Treatment of male mice with anti a2V disturbs the testicular cytokine/chemokine balance and leads to severe deficiencies of spermatogenesis. The aim of the present study was to investigate the role of a2V in male fertility and in the regulation of apoptotic pathways required for normal spermatogenesis in mice. To study the role of a2V single dose of anti-a2V monoclonal antibody or mouse IgG isotype (3MUg/animal) was injected i.p. into males on alternate days for 10 days. The expression of sperm maturation related molecules and pro-apoptotic molecules was measured by real-time PCR or immunohistochemistry in control and anti-a2V-treated testes. The caspase levels and their activity were measured by western blot and fluorometry. We found that the expression of the sperm maturation-related molecules SPAM1, ADAM1, and ADAM2 was significantly decreased in testes from anti-a2V-treated males. The expression of pro-apoptotic molecules (Bax, p53, and p21) and molecules involved in the intrinsic pathway of apoptosis (caspase-9, caspase-3, and PARP), which are crucial for normal spermatogenesis was significantly reduced in testes from anti a2V-treated males compared with the control. The total ATP level was significantly lower in anti-a2V-treated testes. The data provide novel evidence showing that a2V can regulate the apoptotic pathways, an essential testicular feature, and is necessary for efficient spermatogenesis. PMID- 26226212 TI - Galectin-1 reduced the effect of LPS on the IL-6 production in decidual cells by inhibiting LPS on the stimulation of IkappaBzeta. AB - Pregnancy is a complex process where several physiological pathways interact. The down-regulated inflammatory response and the abundance of anti-inflammatory molecules during gestation may explain the acceptance of the fetus and the lack of immune response against it, even though it is a foreign tissue for the mother. NF-kappaB is a key regulator of the transcription of inflammatory genes, such as IL-8, IL-1beta, TNF-alpha, or IL-6. Increased NF-kappaB activity that leads to the production of proinflammatory cytokines may induce obstetric disorders, such as preterm birth or abortion. Low activity of this transcription factor is associated with the beneficial anti-inflammatory environment during fetus development until delivery. Galectin-1 (Gal-1) is a lectin-type glycan-binding protein that is able to down-regulate inflammation. It has been shown that Gal-1 is abundantly expressed at the feto-maternal interface in humans, where it promotes maternal immune tolerance to the fetal semi-allograft. Gal-1 tolerance promoting mechanisms have been established for adaptive immune cells, such as T cells and dendritic cells. However, the role of this lectin has not been established in non-immune cells at the feto-maternal interface. Here, we determined that Gal-1 is able to block the stimulating effect of LPS on IL-6 in human decidua cells. Our results show that Gal-1 acts by inhibiting the stimulation of the LPS-induced IkappaBzeta expression, an NF-kappaB regulator involved in IL-6 gene transcription. PMID- 26226213 TI - Atrial flutter: Clinical risk factors and adverse outcomes in the Framingham Heart Study. AB - BACKGROUND: Few epidemiologic cohort studies have evaluated atrial flutter (flutter) as an arrhythmia distinct from atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to examine the clinical correlates of flutter and its associated outcomes to distinguish them from those associated with AF in the Framingham Heart Study. METHODS: We reviewed and adjudicated electrocardiograms (ECGs) previously classified as flutter or AF/flutter and another 100 ECGs randomly selected from AF cases. We examined the clinical correlates of flutter by matching up to 5 AF and 5 referents to each flutter case using a nested case referent design. We determined the 10-year outcomes associated with flutter with Cox models. RESULTS: During mean follow-up of 33.0 +/- 12.2 years, 112 participants (mean age 72 +/- 10 years, 30% women) developed flutter. In multivariable analyses, smoking (odds ratio [OR] 2.84, 95% confidence interval [CI] 1.54-5.23), increased PR interval (OR 1.28 per SD, 95% CI 1.03-1.60), myocardial infarction (OR 2.25, 95% CI 1.05-4.80) and heart failure (OR 5.22, 95% CI 1.26-21.64) were associated with incident flutter. In age- and sex-adjusted models, flutter (vs referents) was associated with 10-year increased risk of AF (hazard ratio [HR] 5.01, 95% CI 3.14-7.99), myocardial infarction (HR 3.05, 95% CI 1.42-6.59), heart failure (HR 4.14, 95% CI 1.90-8.99), stroke (HR 2.17, 95% CI 1.13-4.17), and mortality (HR 2.00, 95% CI 1.44-2.79). CONCLUSION: We identified the clinical correlates associated with flutter and observed that flutter was associated with multiple adverse outcomes. PMID- 26226214 TI - A swine model of infarct-related reentrant ventricular tachycardia: Electroanatomic, magnetic resonance, and histopathological characterization. AB - BACKGROUND: Human ventricular tachycardia (VT) after myocardial infarction usually occurs because of subendocardial reentrant circuits originating in scar tissue that borders surviving myocardial bundles. Several preclinical large animal models have been used to further study postinfarct reentrant VT, but with varied experimental methodologies and limited evaluation of the underlying substrate or induced arrhythmia mechanism. OBJECTIVE: We aimed to develop and characterize a swine model of scar-related reentrant VT. METHODS: Thirty-five Yorkshire swine underwent 180-minute occlusion of the left anterior descending coronary artery. Thirty-one animals (89%) survived the 6-8-week survival period. These animals underwent cardiac magnetic resonance imaging followed by electrophysiology study, detailed electroanatomic mapping, and histopathological analysis. RESULTS: Left ventricular (LV) ejection fraction measured using CMR imaging was 36% +/- 6.6% with anteroseptal wall motion abnormality and late gadolinium enhancement across 12.5% +/- 4.1% of the LV surface area. Low voltage measured using endocardial electroanatomic mapping encompassed 11.1% +/- 3.5% of the LV surface area (bipolar voltage <=1.5 mV) with anterior, anteroseptal, and anterolateral involvement. Reentrant circuits mapped were largely determined by functional rather than fix anatomical barriers, consistent with "pseudo-block" due to anisotropic conduction. Sustained monomorphic VT was induced in 28 of 31 swine (90%) (67 VTs; 2.4 +/- 1.1; range 1-4) and characterized as reentry. VT circuits were subendocardial, with an arrhythmogenic substrate characterized by transmural anterior scar with varying degrees of fibrosis and myocardial fiber disarray on the septal and lateral borders. CONCLUSION: This is a well characterized swine model of scar-related subendocardial reentrant VT. This model can serve as the basis for further investigation in the physiology and therapeutics of humanlike postinfarction reentrant VT. PMID- 26226215 TI - Biomarker Profiles in Asthma With High vs Low Airway Reversibility and Poor Disease Control. AB - BACKGROUND: High bronchodilator reversibility in adult asthma is associated with distinct clinical characteristics. This analysis compares lung function, biomarker profiles, and disease control in patients with high reversibility (HR) and low reversibility (LR) asthma. METHODS: A retrospective analysis was performed with data from two completed clinical trials of similar design. Patients were divided into HR and LR subgroups based on their response to bronchodilators (HR = DeltaFEV1 postbronchodilator >= 20%). Blood eosinophil count, serum IgE level, and fraction of exhaled nitric oxide concentration, biomarkers commonly used to stratify patients into T-helper (Th)-2-high vs Th2 low phenotypes, were measured in patients with not well controlled (1.5 <= Asthma Control Questionnaire [ACQ] <= 2.143) and very poorly controlled (ACQ > 2.143) disease. RESULTS: The majority of patients in the HR and LR subgroups displayed Th2-low biomarker profiles and very poor disease control. HR was more frequently associated with Th2-high biomarker profiles (40.1% vs 29.4%, P = .006), lower lung function (FEV1, 63.5 +/- 7.7% predicted vs 67.9 +/- 8.4% predicted; P < .001), and atopy (93.7% vs 86.5%, P = .005). CONCLUSIONS: HR is a physiologic indicator of reduced lung function and is more often associated with elevations in Th2 biomarkers than LR in moderate to severe asthma. However, the majority of patients with HR and LR asthma in this analysis had a Th2-low biomarker profile. Moreover, a Th2-high biomarker profile was not associated with worse disease control. PMID- 26226216 TI - Activation of PPAR alpha by fenofibrate inhibits apoptosis in vascular adventitial fibroblasts partly through SIRT1-mediated deacetylation of FoxO1. AB - Recent studies demonstrated that the ligand-activated transcription factor peroxisome proliferator-activated receptoralpha (PPARalpha) acts in association with histone deacetylase sirtuin 1 (SIRT1) in the regulation of metabolism and inflammation involved in cardiovascular diseases. PPARalpha activation also participates in the modulation of cell apoptosis. Our previous study found that SIRT1 inhibits the apoptosis of vascular adventitial fibroblasts (VAFs). However, whether the role of PPARalpha in apoptosis of VAFs is mediated by SIRT1 remains unknown. In this study, we aimed to determine the effect of PPARalpha agonist fenofibrate on cell apoptosis and SIRT1 expression and related mechanisms in ApoE(-/-) mice and VAFs in vitro. We found that fenofibrate inhibited cell apoptosis in vascular adventitia and up-regulated SIRT1 expression in aorta of ApoE(-/-) mice. Moreover, SIRT1 activator resveratrol (RSV) further enhanced these effects of fenofibrate. In vitro study showed that activation of PPARalpha by fenofibrate inhibited TNF-alpha-induced cell apoptosis and cell cycle arrest in VAFs. Meanwhile, fenofibrate up-regulated SIRT1 expression and inhibited SIRT1 translocation from nucleus to cytoplasm in VAFs stimulated with TNF-alpha. Moreover, the effects of fenofibrate on cell apoptosis and SIRT1 expression in VAFs were reversed by PPARalpha antagonist GW6471. Importantly, treatment of VAFs with SIRT1 siRNA or pcDNA3.1(+)-SIRT1 showed that the inhibitory effect of fenofibrate on cell apoptosis in VAFs through SIRT1. On the other hand, knockdown of FoxO1 decreased cell apoptosis of VAFs compared with fenofibrate group. Overexpression of FoxO1 increased cell apoptosis of VAFs compared with fenofibrate group. Further study found that fenofibrate decreased the expression of acetylated-FoxO1 in TNF-alpha-stimulated VAFs, which was abolished by SIRT1 knockdown. Taken together, these findings indicate that activation of PPARalpha by fenofibrate inhibits cell apoptosis in VAFs partly through the SIRT1-mediated deacetylation of FoxO1. PMID- 26226217 TI - High-resolution microscopy of active ribosomal genes and key members of the rRNA processing machinery inside nucleolus-like bodies of fully-grown mouse oocytes. AB - Nucleolus-like bodies (NLBs) of fully-grown (germinal vesicle, GV) mammalian oocytes are traditionally considered as morphologically distinct entities, which, unlike normal nucleoli, contain transcribed ribosomal genes (rDNA) solely at their surface. In the current study, we for the first time showed that active ribosomal genes are present not only on the surface but also inside NLBs of the NSN-type oocytes. The "internal" rRNA synthesis was evidenced by cytoplasmic microinjections of BrUTP as precursor and by fluorescence in situ hybridization with a probe to the short-lived 5'ETS segment of the 47S pre-rRNA. We further showed that in the NLB mass of NSN-oocytes, distribution of active rDNA, RNA polymerase I (UBF) and rRNA processing (fibrillarin) protein factors, U3 snoRNA, pre-rRNAs and 18S/28S rRNAs is remarkably similar to that in somatic nucleoli capable to make pre-ribosomes. Overall, these observations support the occurrence of rDNA transcription, rRNA processing and pre-ribosome assembly in the NSN-type NLBs and so that their functional similarity to normal nucleoli. Unlike the NSN type NLBs, the NLBs of more mature SN-oocytes do not contain transcribed rRNA genes, U3 snoRNA, pre-rRNAs, 18S and 28S rRNAs. These results favor the idea that in a process of transformation of NSN-oocytes to SN-oocytes, NLBs cease to produce pre-ribosomes and, moreover, lose their rRNAs. We also concluded that a denaturing fixative 70% ethanol used in the study to fix oocytes could be more appropriate for light microscopy analysis of nucleolar RNAs and proteins in mammalian fully-grown oocytes than a commonly used cross-linking aldehyde fixative, formalin. PMID- 26226218 TI - Nuclear actin and myosins in adenovirus infection. AB - Adenovirus serotypes have been shown to cause drastic changes in nuclear organization, including the transcription machinery, during infection. This ability of adenovirus to subvert transcription in the host cell facilitates viral replication. Because nuclear actin and nuclear myosin I, myosin V and myosin VI have been implicated as direct regulators of transcription and important factors in the replication of other viruses, we sought to determine how nuclear actin and myosins are involved in adenovirus infection. We first confirmed reorganization of the host's transcription machinery to viral replication centers. We found that nuclear actin also reorganizes to sites of transcription through the intermediate but not the advanced late phase of viral infection. Furthermore, nuclear myosin I localized with nuclear actin and sites of transcription in viral replication centers. Intriguingly, nuclear myosins V and VI, which also reorganized to viral replication centers, exhibited different localization patterns, suggesting specialized roles for these nuclear myosins. Finally, we assessed the role of actin in adenovirus infection and found both cytoplasmic and nuclear actin likely play roles in adenovirus infection and replication. Together our data suggest the involvement of actin and multiple myosins in the nuclear replication and late viral gene expression of adenovirus. PMID- 26226219 TI - A new, simple and precise method for measuring cyclotron proton beam energies using the activity vs. depth profile of zinc-65 in a thick target of stacked copper foils. AB - The proton beam energy of an isochronous 18MeV cyclotron was determined using a novel version of the stacked copper-foils technique. This simple method used stacked foils of natural copper forming 'thick' targets to produce Zn radioisotopes by the well-documented (p,x) monitor-reactions. Primary beam energy was calculated using the (65)Zn activity vs. depth profile in the target, with the results obtained using (62)Zn and (63)Zn (as comparators) in close agreement. Results from separate measurements using foil thicknesses of 100, 75, 50 or 25um to form the stacks also concurred closely. Energy was determined by iterative least-squares comparison of the normalized measured activity profile in a target stack with the equivalent calculated normalized profile, using 'energy' as the regression variable. The technique exploits the uniqueness of the shape of the activity vs. depth profile of the monitor isotope in the target stack for a specified incident energy. The energy using (65)Zn activity profiles and 50-MUm foils alone was 18.03+/-0.02 [SD] MeV (95%CI=17.98-18.08), and 18.06+/-0.12MeV (95%CI=18.02-18.10; NS) when combining results from all isotopes and foil thicknesses. When the beam energy was re-measured using (65)Zn and 50-MUm foils only, following a major upgrade of the ion sources and nonmagnetic beam controls the results were 18.11+/-0.05MeV (95%CI=18.00-18.23; NS compared with 'before'). Since measurement of only one Zn monitor isotope is required to determine the normalized activity profile this indirect yet precise technique does not require a direct beam-current measurement or a gamma-spectroscopy efficiency calibrated with standard sources, though a characteristic photopeak must be identified. It has some advantages over published methods using the ratio of cross sections of monitor reactions, including the ability to determine energies across a broader range and without need for customized beam degraders. PMID- 26226220 TI - Extension of the energy range of experimental activation cross-sections data of deuteron induced nuclear reactions on indium up to 50MeV. AB - The energy range of our earlier measured activation cross-sections data of longer lived products of deuteron induced nuclear reactions on indium were extended from 40MeV up to 50MeV. The traditional stacked foil irradiation technique and non destructive gamma spectrometry were used. No experimental data were found in literature for this higher energy range. Experimental cross-sections for the formation of the radionuclides (113,110)Sn, (116m,115m,114m,113m,111,110g,109)In and (115)Cd are reported in the 37-50MeV energy range, for production of (110)Sn and (110g,109)In these are the first measurements ever. The experimental data were compared with the results of cross section calculations of the ALICE and EMPIRE nuclear model codes and of the TALYS 1.6 nuclear model code as listed in the on-line library TENDL-2014. PMID- 26226221 TI - Kruppel-like factor 14 increases insulin sensitivity through activation of PI3K/Akt signal pathway. AB - Genome-wide association studies (GWAS) have shown that Kruppel-like factor 14 (KLF14) is associated with type 2 diabetes mellitus (T2DM). However, no report has demonstrated a relationship between KLF14 and glucose metabolism. The aim of this study was to determine whether KLF14 is associated with glucose metabolism and insulin signaling in vitro. The mRNA and protein expressions of KLF14 were determined by Real-time PCR and Western blotting. Glucose uptake was assessed by 2-[(3)H]-deoxyglucose (2-DG) uptake. Western blotting was used to identify the activation of insulin signaling proteins. KLF14 mRNA and protein in fat and muscle were significantly decreased in HFD-fed mice, db/db mice and T2DM patients. Overexpression of KLF14 enhanced insulin-stimulated glucose uptake and the activation of Akt kinase in Hepa1-6 cells. The phosphorylation of insulin receptor (InsR), insulin receptor substrate-1(IRS-1), glycogen synthase kinase 3beta (GSK-3beta) and Akt also elevated significantly by up-regulation of KLF14. KLF14 overexpression in Hepa1-6 cells prevented the inhibition of glucose uptake and Akt phosphorylation induced by high glucose and/or high insulin, or T2DM serum. However, KLF14's ability to increase glucose uptake and Akt activation was significantly attenuated by LY294002, a PI3-kinase inhibitor. These data suggested that KLF14 could increase insulin sensitivity probably through the PI3K/Akt pathway. PMID- 26226222 TI - Population data of 15 short tandem repeat loci in 1084 individuals from six Han and four ethnic populations in China. PMID- 26226223 TI - Developmental validation of the GlobalFiler((r)) Express PCR Amplification Kit: A 6-dye multiplex assay for the direct amplification of reference samples. AB - In order to increase the power of discrimination, reduce the possibility of adventitious matches, and expand global data sharing, the CODIS Core Loci Working Group made a recommendation to expand the CODIS core loci from the "required" 13 loci to 20 plus three additional "highly recommended" loci. The GlobalFiler((r)) Express Kit was designed to incorporate all 20 required and 3 highly recommended loci along with a novel male-specific Y insertion/deletion marker. The GlobalFiler((r)) Express Kit allows simultaneous amplification of the following loci: D3S1358, vWA, D16S539, CSF1PO, TPOX, Yindel, AMEL, D8S1179, D21S11, D18S51, DYS391, D2S441, D19S433, TH01, FGA, D22S1045, D5S818, D13S317, D7S820, SE33, D10S1248, D1S1656, D12S391, and D2S1338. The kit enables direct amplification from blood and buccal samples stored on paper or swab and the chemistry features an optimized PCR protocol that yields time to results in less than an hour. Developmental validation testing followed SWGDAM guidelines and demonstrated the quality and robustness of the GlobalFiler((r)) Express Kit over a number of variables. The validation results demonstrate that the 24-locus multiplex kit is a robust and reliable identification assay as required for forensic DNA typing and databasing. PMID- 26226224 TI - A SNP in the 3'-untranslated region of AMPKgamma1 may associate with serum ketone body and milk production of Holstein dairy cows. AB - AMPK is the key switch for providing the energy balance between cellular anabolic and catabolic processes. In this study, we aimed to screen the PRKAG1 (AMPKgamma1) gene in high, moderate, and low producing Holstein dairy cows. A sample of 100 pregnant dairy cows, comprising 41 high, 33 moderate, and 26 low milk yields were selected from three large dairy herds in Isfahan province of Iran. Body condition score (BCS) was estimated before parturition while beta hydroxyl butyric acid (BHBA) as a measure of ketone bodies was measured at the fifth day postpartum. In addition, using three primer pairs covering exons 2-11 and 3'-UTR of the PRKAG1 gene, a random sample of 10 high milk yield dairy cows were amplified and sequenced. The sequencing results showed the presence of a T12571C mutation in intron 6 and a T14280C mutation in the 3'-untranslated region (UTR) of the PRKAG1 gene. Following a PCR reaction for amplification of the 3' UTR amplicons, single strand conformation polymorphism (SSCP) assay was implemented for discrimination of the mutation in the studied population. Then, we evaluated if the mutation associates with the BCS, serum BHBA level, and production traits. The experimental analysis showed that the mutated allele significantly increased the BHBA level, BCS, as well as milk and protein yield. Bioinformatic study revealed that this 3'-UTR mutation distorts the target site of mir-423-5p microRNA which is one of the most highly expressed microRNAs in the bovine mammary gland, liver, and kidney. Given the role of AMPK in energy metabolism, the newly identified 3'-UTR mutation highlights the importance of AMPK and suggests a role of miRNAs for regulation of cellular metabolism, metabolism disorders, and production traits in Holstein dairy cows. PMID- 26226226 TI - Mesoscopic Community Structure of Financial Markets Revealed by Price and Sign Fluctuations. AB - The mesoscopic organization of complex systems, from financial markets to the brain, is an intermediate between the microscopic dynamics of individual units (stocks or neurons, in the mentioned cases), and the macroscopic dynamics of the system as a whole. The organization is determined by "communities" of units whose dynamics, represented by time series of activity, is more strongly correlated internally than with the rest of the system. Recent studies have shown that the binary projections of various financial and neural time series exhibit nontrivial dynamical features that resemble those of the original data. This implies that a significant piece of information is encoded into the binary projection (i.e. the sign) of such increments. Here, we explore whether the binary signatures of multiple time series can replicate the same complex community organization of the financial market, as the original weighted time series. We adopt a method that has been specifically designed to detect communities from cross-correlation matrices of time series data. Our analysis shows that the simpler binary representation leads to a community structure that is almost identical with that obtained using the full weighted representation. These results confirm that binary projections of financial time series contain significant structural information. PMID- 26226225 TI - A novel mutation in the TMC1 gene causes non-syndromic hearing loss in a Moroccan family. AB - Autosomal recessive non-syndromic hearing loss (ARNSHL) is one of the most common genetic diseases in human and is subject to important genetic heterogeneity, rendering molecular diagnosis difficult. Whole-exome sequencing is thus a powerful strategy for this purpose. After excluding GJB2 mutation and other common mutations associated with hearing loss in Morocco, whole-exome sequencing was performed to study the genetic causes of one sibling with ARSHNL in a consanguineous Moroccan family. After filtering data and Sanger sequencing validation, one novel pathogenic homozygous mutation c.1810C>G (p.Arg604Gly) was identified in TMC1, a gene reported to cause deafness in various populations. Thus, we identified here the first mutation in the TMC1 gene in the Moroccan population causing non-syndromic hearing loss. PMID- 26226227 TI - Effects of insulin treatment on the response to oleate and octanoate of food intake and fatty acid-sensing systems in rainbow trout. AB - We hypothesized that food intake and the response of fatty acid (FA)-sensing systems in hypothalamus, liver, and Brockmann bodies of rainbow trout to raised levels of oleate (OL) or octanoate (OCT) is modified by insulin treatment. To assess this hypothesis, 15 fish per group received intraperitoneally 10-mL/kg injection of saline solution alone (control), or containing insulin (2-mg bovine insulin/kg body mass), OL (300 MUg/kg), OCT (300 MUg/kg), insulin + OL, or insulin + OCT to be sampled 6 h later to assess parameters related to FA sensing. Our results suggest that the modulatory role of insulin on the responses of hypothalamic FA-sensing systems to changes in circulating levels of OL or OCT was of minor importance in contrast to the mammalian model. However, this is in contrast with the effects observed in another experiment assessing changes in food intake after similar treatments because insulin treatment enhanced the anorectic effects of FA alone, and the effect was especially relevant (P < 0.001) for OCT, in contrast with the mammalian model where this FA is not inducing an anorectic response. In liver and Brockmann bodies, insulin treatment enhanced the responses to OL or OCT treatment in parameters related to FA sensing. Therefore, we provide for the first time in fish, and in a non-mammalian vertebrate, evidence for the modulation of FA-sensing systems by insulin. PMID- 26226228 TI - A Prospective Evaluation of the Association between a Single Nucleotide Polymorphism rs3775291 in Toll-Like Receptor 3 and Breast Cancer Relapse. AB - BACKGROUND: Toll-like receptors (TLRs) regulate the balance between the innate and adaptive immune responses. Missense single nucleotide polymorphisms (SNPs) in TLRs might be functional and thus influence the risks of chronic infection and cancer development. Here, we investigated the association of two missense SNPs, rs3775291 (c.1234G>A) in the TLR3 gene and rs4833095 (c.743T>C) in the TLR1 gene, with relapse-free survival (RFS) in a cohort of prospectively observed breast cancer patients. METHODS: In this prospective observational study, rs3775291 in TLR3 and rs4833095 in TLR1 were genotyped in 715 patients with primary breast cancer in a Chinese population. RESULTS: Univariate analysis revealed that the patients with the AA genotype of rs3775291 had a shorter RFS compared with those carrying the G allele in the recessive model (P<0.01), but this finding was not observed with the dominant model (P = 0.31). The results remained significant after adjusting for the clinical parameters in the recessive model (HR = 3.53, 95% confidence interval [CI]: 1.98-6.31, P<0.01). Further survival analysis indicated that this SNP was significant in the luminal-B, triple-negative breast cancer (TNBC), and human epidermal growth factor receptor 2-positive (HER2+) patients using the recessive model but that it was not significant in the luminal A patients. The SNP rs4833095 showed a non-significant tendency toward an increased RFS rate in the patients with the TT genotype. CONCLUSION: Our results suggest that the SNP rs3775291 in TLR3 may influence patient outcome. Further studies with larger sample sizes should be conducted to validate our findings. PMID- 26226229 TI - Characterizing the Impact of Commercial Pollen Substitute Diets on the Level of Nosema spp. in Honey Bees (Apis mellifera L.). AB - Western honey bee (Apis mellifera L.) populations face declines commonly attributed to pesticide, pathogen, and parasite stress. One way beekeepers combat these stressors is by providing supplemental protein diets to honey bee colonies to ensure adequate colony nutrition. However Nosema spp., a microsporidian parasite of the honey bee, is thought to be associated closely with a colony's nutritional intake, thus possibly negating any benefit the bees otherwise would have received from a nutritional supplement. Through three objectives, we examined how adult bees' consumption of wildflower pollen or commercial pollen substitute diets affected Nosema levels in the bees' midguts. For our first objective, we investigated how method of inoculation with Nosema affects infection levels in inoculated bees. Bees were infected with spores of Nosema four days after emergence. On day 15, bees were collected from the cages and Nosema spores were quantified. We found that inoculation through the pollen diet resulted in the highest Nosema levels in inoculated bees. In our second and third objectives, we provided the test diets to caged, newly emerged bees for a period of 15 days. Bees consuming pollen and a sucrose solution had more Nosema in their midguts than did bees consuming the sucrose solution alone (control). The overall volume of diet consumed by the bees did not correlate with the level of Nosema in their midguts. The level of Nosema was higher in bees fed certain commercial pollen substitute diets than in bees fed wildflower pollen. Our study illustrates how providing nutritional supplements to adult honey bees can impact the intensity of Nosema in their midguts. PMID- 26226230 TI - Population dynamics and competitive outcome derive from resource allocation statistics: The governing influence of the distinguishability of individuals. AB - Model predictions for species competition outcomes highly depend on the assumed form of the population growth function. In this paper we apply an alternative inferential method based on statistical mechanics, maximizing Boltzmann entropy, to predict resource-constrained population dynamics and coexistence. Within this framework, population dynamics and competition outcome can be determined without assuming any particular form of the population growth function. The dynamics of each species is determined by two parameters: the mean resource requirement theta (related to the mean metabolic rate) and individual distinguishability Dr (related to intra- compared to interspecific functional variation). Our theory clarifies the condition for the energetic equivalence rule (EER) to hold, and provide a statistical explanation for the importance of species functional variation in determining population dynamics and coexistence patterns. PMID- 26226232 TI - Developmental study of vitamin C distribution in children's brainstems by immunohistochemistry. AB - Vitamin C (Vit C) is an important antioxidant, exerts powerful neuroprotective brain effects and plays a role in neuronal development and maturation. Vit C is present in brain tissue at higher concentrations than in other organs, but its detailed distribution in brain is unknown. Immunohistochemical detection of this vitamin has been performed by using a highly specific antibody against Vit C. The aim of the present work was to analyze the distribution of Vit C in children's brainstems during postnatal development, comparing two groups of ages: younger and older than one year of life. In general, the same areas showing neurons with Vit C in young cases are also immunostained at older ages. The distribution of neurons containing Vit C was broader in the brainstems of older children, suggesting that brainstem neurons maintain or even increase their ability to retain Vit C along the life span. Immunohistochemical labeling revealed only cell bodies containing this vitamin, and no immunoreactive fibers were observed. The distribution pattern of Vit C in children's brainstems suggests a possible role of Vit C in brain homeostatic regulation. In addition, the constant presence of Vit C in neurons of locus coeruleus supports the important role of Vit C in noradrenaline synthesis, which seemed to be maintained along postnatal development. PMID- 26226231 TI - The autophagic lysosomal system in outflow pathway physiology and pathophysiology. AB - Malfunction of the trabecular meshwork (TM)/schlemm's canal (SC) conventional outflow pathway is associated with elevated intraocular pressure (IOP) and, therefore, increased risk of developing glaucoma, a potentially blinding disease affecting more than 70 million people worldwide. This TM/SC tissue is subjected to different types of stress, including mechanical, oxidative, and phagocytic stress. Long-term exposure to these stresses is believed to lead to a progressive accumulation of damaged cellular and tissue structures causing permanent alterations in the tissue physiology, and contribute to the pathologic increase in aqueous humor (AH) outflow resistance. Autophagy is emerging as an essential cellular survival mechanism against a variety of stressors. In addition to performing basal functions, autophagy acts as a cellular survival pathway and represents an essential mechanism by which organisms can adapt to acute stress conditions and repair stress-induced damage. A decline in autophagy has been observed in most tissues with aging and has been considered responsible, at least in part, for the accumulation of damaged cellular components in almost all tissues of aging organisms. Dysfunction in the autophagy pathway is associated with several human diseases, from infectious diseases to cancer and neurodegeneration. In this review, we will summarize our current knowledge of the emerging roles of autophagy in outflow tissue physiology and pathophysiology, including novel evidence suggesting compromised autophagy in the glaucomatous outflow pathway. PMID- 26226233 TI - Genotypes of infectious bronchitis viruses circulating in the Middle East between 2009 and 2014. AB - We are reporting on the infectious bronchitis virus (IBV) genotypes circulating within seven Middle East countries and the alterations in genotype distributions between 2009 and 2014. Tissue samples on FTA cards were received over the six year period. Viral RNA was extracted using phenol chloroform and subjected to nested RT-PCR targeting a 393 bp region of the S1 gene before being followed by sequencing. From the 461 submitted samples, 363 were IBV positive by RT-PCR (77.01%). Of these, 355 (97.80%) gave sequences that can be genotyped. They belonged to six genotypes; 793B (43.66%), IS/1494/06 (18.31%), Massachusetts (Mass) (12.96%), IS/885/00 (11.27%), Q1 (11.27%) and D274 (2.25%). The prominence of 793B is not surprising, given that 793B vaccine strains are widely used in the Middle East. Sequence analysis demonstrated that the majority of 793B (67.13%) and Mass (81.13%) strains were closely related to vaccine strains based on 99 100% homology with the partial-S1 gene. Vaccinal strains belonging to the D274 genotype were present but only at a low level. Variable proportions of 793B, Mass, D274, IS/1494/06, IS/885/00 and Q1 field strains were identified in different countries. After 2012, the 793B field strain showed distinct clustering compared to strains from earlier years. Translated amino acid alterations were minimal but still may have played an important role in the persistence of this virus despite the use of live 793B vaccines. Huge challenges for an efficient protection against virulent IBVs and chicken production are posed by co circulating793B, Mass and D274 viruses with less than 99% homology to the respective vaccine strains, along with the recently emerged variant IBVs, despite active IBV vaccination strategies in the Middle East, continuous surveillance of IBV genotypes is essential in formulating optimal control strategies, including the choice and development of new vaccine strains and formulation of vaccination programmes. PMID- 26226234 TI - Solitary Extramedullary Plasmacytoma of the Orbital Apex and Dura Masquerading as Idiopathic Inflammation. AB - This is a retrospective case description of a single female patient found to have a primary solitary extramedullary plasmacytoma of the orbital apex and temporal/parietal dura. These monoclonal plasma cell neoplasms account for fewer than 5% of plasma cell neoplasms. Although most commonly found in the head and neck, orbital and dural solitary extramedullary plasmacytomas are extremely uncommon. The authors present a case of an extramedullary plasmacytoma involving both of these structures in a middle-age otherwise healthy female to highlight this rare entity and elucidate current treatment modalities and future considerations. PMID- 26226235 TI - Proliferative Fasciitis of the Orbit. AB - Proliferative fasciitis is a rare entity in the orbit. A 16-year-old boy presented with a growing right orbital mass, which was palpable just inferior to the medial right eyebrow. MRI demonstrated a 12 * 8 * 9 mm mass located medial to and slightly above the right globe within the subcutaneous soft tissues. An anterior orbitotomy with debulking of the lesion was performed. Histopathological examination confirmed a diagnosis of proliferative fasciitis. To the authors' knowledge, there is only one prior case in the literature demonstrating proliferative fasciitis of the orbit. PMID- 26226236 TI - Osteolytic Sarcoidosis of the Orbital Roof Masquerading as a Malignant Orbital Lesion. AB - A 51-year-old man without a significant past medical history presented with 4 weeks of progressive swelling and drooping of his left upper eyelid. A CT of the left orbit revealed an osteolytic mass lesion in the area of the lacrimal gland. A left orbitotomy with excisional biopsy was performed. The excised tissue was sent for infectious workup and histopathological examination, which revealed osteolytic sarcoidosis. The patient was treated with systemic and local injection corticosteroids, and followed over 10 months without evidence of recurrence. Systemic workup with CT of his chest, abdomen, and pelvis revealed no further evidence of sarcoidosis. To the best of the authors knowledge, this is the first report of an otherwise healthy patient presenting with isolated osteolytic sarcoidosis of the orbit and a negative systemic workup. PMID- 26226237 TI - Globe Loss From Intraocular Invasion of MIRAgel Scleral Buckle Components. AB - PURPOSE: To describe intraocular invasion of MIRAgel scleral buckles requiring evisceration. METHODS: This is an Institutional Review Board-approved retrospective consecutive case series of eyes requiring evisceration secondary to intraocular intrusion of MIRAgel implants performed at the Cole Eye Institute from 2000 to 2014. Charts were reviewed for age at surgery, gender, laterality, time between MIRAgel placement and evisceration, preoperative examination and imaging results, intraoperative findings, postoperative complications, and duration of follow up. RESULTS: Five eyes of 5 patients underwent evisceration due to a blind, painful eye secondary to MIRAgel expansion. The mean time between MIRAgel placement and evisceration was 21 years (range: 17-30 years). Preoperative ultrasound identified intraocular MIRAgel in 3 of 5 cases; however, intraocular MIRAgel was identified during surgery in all 5 cases. A transocular approach orbitotomy was performed at the time of evisceration in an effort to remove the MIRAgel. Postoperative complications included ptosis and inability to retain an ocular prosthesis. No cases of orbital implant extrusion occurred. CONCLUSION: Scleral invasion and intraocular penetration of MIRAgel may occur decades after placement. This may result in a blind, painful eye requiring evisceration and orbitotomy to remove residual material. Suspicion of intraocular penetration of implant should be high in blind, painful eyes. Surgical removal can be difficult due to MIRAgel fragmentation. Conjunctival insufficiency may result in the need for further surgery after evisceration. PMID- 26226239 TI - Incorrect panel of figure in the article by Margheri et al (Arthritis Rheum, August 2010). PMID- 26226238 TI - Dynamics of underwater legged locomotion: modeling and experiments on an octopus inspired robot. AB - This paper studies underwater legged locomotion (ULL) by means of a robotic octopus-inspired prototype and its associated model. Two different types of propulsive actions are embedded into the robot model: reaction forces due to leg contact with the ground and hydrodynamic forces such as the drag arising from the sculling motion of the legs. Dynamic parameters of the model are estimated by means of evolutionary techniques and subsequently the model is exploited to highlight some distinctive features of ULL. Specifically, the separation between the center of buoyancy (CoB)/center of mass and density affect the stability and speed of the robot, whereas the sculling movements contribute to propelling the robot even when its legs are detached from the ground. The relevance of these effects is demonstrated through robotic experiments and model simulations; moreover, by slightly changing the position of the CoB in the presence of the same feed-forward activation, a number of different behaviors (i.e. forward and backward locomotion at different speeds) are achieved. PMID- 26226240 TI - Can Grief be a Mental Disorder?: An Exploration of Public Opinion. AB - Despite growing empirical evidence, the distinction between normal and pathological grief remains controversial. Few studies have investigated public attitudes towards distinguishing normal from pathological grief. An international sample of 348 participants from a wide range of cultures was asked if certain expressions of grief could be considered a mental disorder and to explain their answer. Analysis revealed that the majority (74.7%) agreed that grief could be considered a mental disorder. The presence of pervasive distress, of harm to self and/or others, functional impairment, and persistent grief were described as the circumstances under which grief can be a mental disorder. Reasons grief is not a mental disorder were that it is normal, temporary, in response to an event, and that efforts to include it in diagnostic manuals will lead to medicalization and stigma. The investigation of public norms informs the inclusion of pathological grief in diagnostic nosology. PMID- 26226241 TI - Emotional Awareness, Relationship Quality, and Satisfaction in Patients With Parkinson's Disease and Their Spousal Caregivers. AB - This study aimed to evaluate the relationship quality and satisfaction in couples, in which one partner had PD, obtaining the perspective of both patients and partner and to examine the impact of alexithymia, empathy, depression, and anxiety on ratings of relationship quality and satisfaction. Fifteen PD patients and partners completed the following scales: the Dyadic Adjustment Scale; Couple Satisfaction Index (CSI); the 20-item Toronto Alexithymia Scale; the Empathy Quotient; the Hamilton Depression and the Hamilton Anxiety Rating Scale (HAM-A). We evaluated patients' motor functions by means of Unified Parkinson's Disease Rating Scale and patients' quality of life by means of the PD Questionnaire. Patients were significantly less satisfied with the relationship than their partners as revealed by CSI (p = 0.031) and they were more depressed (p = 0.003) and anxious (p = 0.015). A negative correlation between measures of relationship quality and satisfaction and alexithymia was found in the patients group. No correlations were found between measures of relationship quality and satisfaction (both of patients and partners) and any other demographical and clinical variables. CSI and HAM-A were predictors of patient's social support evaluation. The presence of alexithymia in PD is an important factor affecting relationship quality and satisfaction. PMID- 26226242 TI - Maternal/neonatal vitamin D deficiency: a risk factor for bronchopulmonary dysplasia in preterms? AB - OBJECTIVE: The objective of this study was to investigate the possible association between maternal/neonatal 25-hydroxy vitamin D (25-OHD) levels and development of bronchopulmonary dysplasia. STUDY DESIGN: One hundred and thirty two preterm infants ?32 weeks of gestation who were diagnosed with respiratory distress syndrome were enrolled. 25-OHD levels were determined in maternal/neonatal blood samples that were obtained at the time of admission to the neonatal intensive care unit. RESULT: A total of 100 infants were included and 31 (31%) developed bronchopulmonary dysplasia (BPD). Both maternal and neonatal 25-OHD levels in the BPD group were significantly lower compared with those in the no-BPD group (P=0.0001). A positive correlation was detected between maternal and neonatal 25-OHD levels. All of the infants with BPD had a 25-OHD level <10 ng ml(-1), which represented severe deficiency. Univariate logistic regression analysis revealed that maternal/neonatal vitamin D levels were a significant predictor of BPD (odds ratio (OR): 0.76 and 0.61, respectively, P<0.001). CONCLUSION: We demonstrated for the first time that lower maternal and neonatal vitamin 25-OHD levels were associated with BPD development in preterm infants. However, further studies with larger sample sizes are needed to delineate the possible link between vitamin D deficiency and BPD. PMID- 26226243 TI - Tranexamic acid and blood loss during and after cesarean section: a meta analysis. AB - OBJECTIVE: A meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate whether tranexamic acid (TXA) could significantly reduce blood loss during and after cesarean section (CS) when compared with no TXA. STUDY DESIGN: MEDLINE (PubMed), EMBASE, Cochrane Central Register of Controlled Trials and Web of Science were searched to identify RCTs that compared intravenous TXA with no TXA before CS for blood loss. The related data were extracted by two independent authors. The fixed or random-effect methods were used to combine data. RESULT: Eleven RCTs were included in this analysis with a total of 1276 women in TXA group and 1255 in no TXA (control) group. Total blood loss during and after CS was significantly less in TXA group than in control group (mean difference (MD) 141.61 ml, 95% confidence interval (CI) -207.09 to -76.14, P<0.01). There was a significant reduction in intraoperative and postpartum blood loss in TXA group as compared with control group (MD -143.36 ml, 95% CI -220.38 to -66.35, P<0.01; and MD -38.20 ml, 95% CI -59.27 to -17.12, P<0.01, respectively). Declines in hemoglobin and hematocrit values after CS were both significantly less in TXA group than in control group. The difference of postpartum hemorrhage rate was statistically significant between groups (risk ratio (RR) 0.57, 95% CI 0.37 to 0.89, P=0.01). The need for blood transfusion was significantly less in TXA group than control group (RR 0.23, 95% CI 0.10 to 0.57, P<0.01). CONCLUSION: Our results demonstrate that TXA offers an advantage over no TXA in reducing blood loss during and after CS. PMID- 26226244 TI - Early versus delayed umbilical cord clamping in infants with congenital heart disease: a pilot, randomized, controlled trial. AB - OBJECTIVE: Delayed umbilical cord clamping (DCC) at birth may provide a better neonatal health status than early umbilical cord clamping (ECC). However, the safety and feasibility of DCC in infants with congenital heart disease (CHD) have not been tested. This was a pilot, randomized, controlled trial to establish the safety and feasibility of DCC in neonates with CHD. STUDY DESIGN: Pregnant women admitted >37 weeks gestational age with prenatal diagnosis of critical CHD were enrolled and randomized to ECC or DCC. For ECC, the umbilical cord was clamped <10 s after birth; for DCC, the cord was clamped ~120 s after delivery. RESULTS: Thirty infants were randomized at birth. No differences between the DCC and ECC groups were observed in gestational age at birth or time of surgery. No differences were observed across all safety measures, although a trend for higher peak serum bilirubin levels (9.2+/-2.2 vs 7.3+/-3.2 mg dl(-1), P=0.08) in the DCC group than in the ECC group was noted. Although similar at later time points, hematocrits were higher in the DCC than in the ECC infants during the first 72 h of life. The proportion of infants not receiving blood transfusions throughout hospitalization was higher in the DCC than in the ECC infants (43 vs 7%, log-rank test P=0.02). CONCLUSION: DCC in infants with critical CHD appears both safe and feasible, with fewer infants exposed to red blood cell transfusions than with ECC. A more comprehensive appraisal of this practice is warranted. PMID- 26226245 TI - Elevated plasma and cerebrospinal fluid interleukin-1 beta and tumor necrosis factor-alpha concentration and combined outcome of death or abnormal neuroimaging in preterm neonates with early-onset clinical sepsis. AB - OBJECTIVE: Prematurity and sepsis are the major contributors of neonatal mortality and neurodevelopmental sequelae. The present study was conducted to measure the plasma and cerebrospinal fluid (CSF) concentration of interleukin (IL)-1beta and tumor necrotic factor (TNF)-alpha in preterm neonates with early onset clinical sepsis (EOCS), and to find out their association with combined outcome of death or abnormal neuroimaging. STUDY DESIGN: Thirty-two preterm (?34 weeks) neonates with EOCS and 32 gestational age-matched, healthy neonates served as cases and controls, respectively. Samples were collected soon after birth. Neonates were followed up clinically and by serial cranial ultrasonography (CUS) until discharge and subsequently by magnetic resonance imaging (MRI) of brain until 1 year. Developmental screening was done by Denver Developmental Screening test-II. RESULT: In EOCS group, no neonate had any clinical/microbiological evidence of meningitis. Blood culture was positive in 17 (53%). CUS was abnormal in 12 (37%) (intracranial hemorrhage-11, periventricular leukomalacia-1). Ten (31%) neonates expired. Significant elevation of plasma and CSF IL-1beta and TNF alpha was observed in the EOCS group. On follow-up, seven (22%) neonates showed evidence of white matter damage in MRI, two of them had developmental delay and microcephaly. Plasma and CSF IL-1beta and TNF-alpha concentration were significantly elevated in deceased neonates and those with abnormal neuroimaging. Both biomarkers demonstrated high predictive accuracy for poor outcome in receiver-operating curve analysis. CONCLUSION: Elevation of plasma and CSF IL 1beta and TNF-alpha is associated with an increase in the combined outcome of death or abnormal neuroimaging in preterm neonates with EOCS in the absence of clinical/microbiological evidence of meningitis with high predictive accuracy. PMID- 26226246 TI - Changes in infant mortality among extremely preterm infants: US vital statistics data 1990 vs 2000 vs 2010. AB - OBJECTIVE: Infant mortality among extremely preterm infants (22 to 28 weeks gestation) varies considerably by gestational age. The reduction in mortality over a 20-year period, when examined in gestational age week increments, may give a more precise estimate of progress or lack thereof in caring for these infants and provide information to better inform practitioners and parents of the risk of mortality among these small infants. The objective of this analysis is to examine infant mortality (birth to 365 days) by week of gestation for infants 22 to 28 weeks gestation comparing mortality rates, adjusting for maternal and infant birth characteristics, among US births for the years 1990, 2000 and 2010. STUDY DESIGN: US vital statistics period-linked birth and infant death certificate files for the years 1990, 2000 and 2010 were used. Maternal and infant characteristics for births at 22 to 28 weeks were abstracted from the files. A trimming procedure was used to remove records that had birth weights that exceeded the interquartile range of birth weights for a given week of gestational age. Infant mortality rates were calculated, and adjusted odds ratios for mortality were generated using logistic regression models. RESULT: A total of 15,593 live births, 22 to 28 weeks gestation were available for the year 1990; 17,095 for the year 2000; and 14,721 for the year 2010. Infant mortality rates ranged from 904 per 1000 live births at 22 weeks gestation in 1990, to 835 in 2000, to 866 in 2010. Across all gestational age groups there was an adjusted reduction in the odds ratio for mortality of ~50% from 1990 to the year 2000. However, between 2000 and 2010 there was no significant reduction in infant mortality except at 25 weeks gestation (adjusted odds ratio=0.81, 95% confidence interval=0.70, 0.93). CONCLUSION: Despite a significant reduction in infant mortality among extremely preterm infants between the years 1990 and 2000, there has been little progress in reducing mortality between the years 2000 and 2010. PMID- 26226247 TI - Intraplacental villous artery resistance indices and identification of placenta mediated diseases. AB - OBJECTIVE: Placenta-mediated diseases (PMDs) including preeclampsia and fetal growth restriction are often characterized by shallow trophoblast invasion and incomplete spiral artery remodeling leading to impaired placental perfusion. In this context, umbilical artery (UA) Doppler can be used to detect high resistance to flow characteristic of very late-stage placental disease. We propose that evaluation of intraplacental villous artery (IPVA) resistance can provide earlier detection of increased resistance in placental flow. STUDY DESIGN: Seventy-five patients were recruited from the Ottawa Hospital. All had scans at 18 to 20, 28 and 34 weeks of gestation. IPVAs arising perpendicular to the chorionic plate in three regions (placental tips 4 cm away from cord insertion and within 1 cm from cord insertion) were sampled at each gestational age for resistance index (RI) and pulsatility index (PI). UA Doppler was also obtained from a free loop of cord. Pregnancy outcomes were collected from a chart review. Data were analyzed using SAS version 9.4 and standard statistic tests (mean+/-s.d., Student's t test, mixed-effects modeling). RESULT: A total of 53 patients completed the study. Of these, 38 had normal pregnancy outcomes (controls) and 15 (cases) developed PMD (preeclampsia, n=8 and low birth weight/intrauterine growth restriction, n=7). Mean birth weight in the study group was 2482.1+/-518.85 g. At 18 to 20, 28 and 34 weeks gestation, the mean IPVA resistance indices in the control group were 0.86+/-0.16, 0.81+/-0.12 and 0.71+/-0.12 for PI and 0.57+/ 0.07, 0.55+/-0.06 and 0.49+/-0.06 for RI, respectively. However, in the cases developing PMDs, the PIs were 1.09+/-0.17, 0.95+/-0.21 and 0.78+/-0.07 and RIs 0.66+/-0.07, 0.60+/-0.07 and 0.54+/-0.04, respectively (P<0.05). UA PI and RI Doppler did not differ between the groups as early as 18 to 20 weeks gestation. CONCLUSION: Doppler measures of IPVA appear superior to UA in detecting early changes related to PMD. IPVA PI and RI Doppler may be useful in the early identification of patients at risk of PMD. PMID- 26226248 TI - Effect of 40-cm segment umbilical cord milking on hemoglobin and serum ferritin at 6 months of age in full-term infants of anemic and non-anemic mothers. AB - OBJECTIVE: To assess the effect of early clamping and milking of a 40-cm umbilical cord LUCM (long umbilical cord and milking) on hemoglobin (Hb) and serum ferritin concentrations at 6 months of age and to evaluate whether the effect is different in infants of anemic and non-anemic mothers. STUDY DESIGN: Eligible term-infants of anemic (maternal Hb<11.0 g dl(-1)) and non-anemic mothers (Hb ?11.0 g dl(-1)) were randomized to LUCM or control groups (N=100 each). In the LUCM group, the umbilical cord was clamped at 40-cm length and milked. The control group had the cord clamped at 5 cm and not milked. Neonatal morbidities until discharge and Hb and serum ferritin at 6 months of age were compared. Effects in infants of anemic and non-anemic mothers were compared. RESULT: Compared with infants of non-anemic mothers, cord Hb was similar (14.50+/ 1.90 g dl(-1) vs 14.67+/-1.73 g dl(-1)), but cord ferritin lower (85.8+/-55.4 ng ml(-1) vs 119.4+/-58.5 ng ml(-1), P<0.01) in infants of anemic mothers. Mean Hb concentration at 6 months was 9.60+/-1.42 g dl(-1) in the LUCM group and 9.07+/ 1.10 g dl(-1) in the control group (P=0.004). Mean serum-ferritin concentration at 6 months was 113.9+/-43.8 ng ml(-1) in the LUCM group and 70.8+/-39.5 ng/ml in the control group (P<0.001). The effectiveness of LUCM did not vary with the maternal anemia status. CONCLUSION: Keeping the umbilical cord long and milking may be an effective method for improving Hb and iron stores at 6 months of age in term-infants. PMID- 26226249 TI - HIV Prevalence, Estimated Incidence, and Risk Behaviors Among People Who Inject Drugs in Kenya. AB - OBJECTIVE: HIV infection in sub-Saharan Africa increasingly occurs among people who inject drugs (PWID). Kenya is one of the first to implement a national needle and syringe program. Our study undertook a baseline assessment as part of evaluating needle and syringe program in a seek, test, treat, and retain approach. METHODS: Participants enrolled between May and December 2012 from 10 sites. Respondent-driven sampling was used to reach 1785 PWID for HIV-1 prevalence and viral load determination and survey data. RESULTS: Estimated HIV prevalence, adjusted for differential network size and recruitment relationships, was 14.5% in Nairobi (95% CI: 10.8 to 18.2) and 20.5% in the Coast region (95% CI: 17.3 to 23.6). Viral load (log10 transformed) in Nairobi ranged from 1.71 to 6.12 (median: 4.41; interquartile range: 3.51-4.94) and in the Coast from 1.71 to 5.88 (median: 4.01; interquartile range: 3.44-4.72). Using log10 viral load 2.6 as a threshold for HIV viral suppression, the percentage of HIV-infected participants with viral suppression was 4.2% in Nairobi and 4.6% in the Coast. Heroin was the most commonly injected drug in both regions, used by 93% of participants in the past month, typically injecting 2-3 times/day. Receptive needle/syringe sharing at last injection was more common in Nairobi (23%) than in the Coast (4%). Estimated incidence among new injectors was 2.5/100 person-years in Nairobi and 1.6/100 person-years in the Coast. CONCLUSIONS: The HIV epidemic is well established among PWID in both Nairobi and Coast regions. Public health scale implementation of combination HIV prevention has the potential to greatly limit the epidemic in this vulnerable and bridging population. PMID- 26226250 TI - Intentional Medication Nonadherence Because of Interactive Toxicity Beliefs Among HIV-Positive Active Drug Users. AB - BACKGROUND: Drug use poses significant challenges to medical management of HIV infection. Although most research has focused on the influence of intoxication on unintentional adherence to HIV treatment, drug use may also lead to intentional nonadherence, particularly when individuals believe that mixing medications with drugs is harmful. This study examined whether interactive toxicity beliefs predict nonadherence to antiretroviral therapy (ART) over a prospective period of adherence monitoring. METHODS: Men and women living with HIV who screened positive for drug use and were being treated with ART (n = 530) completed computerized self-interviews and 3 prospective unannounced pill counts to measure ART adherence and provided urine specimens for drug screening and HIV viral load results from medical records. RESULTS: Results showed that 189 (35%) participants indicated that they intentionally miss their ART when they are using drugs. These participants also reported common beliefs regarding the perceived hazards of mixing HIV medications with alcohol and other drugs. Multivariable models controlled for demographic and health characteristics and frequency of alcohol use showed that intentional nonadherence predicted poorer ART adherence over the prospective month and also predicted poorer treatment outcomes as indexed by unsuppressed HIV viral load. CONCLUSIONS: These findings extend previous research to show that interactive toxicity beliefs and intentional nonadherence play a significant role in medication nonadherence for a substantial number of people living with HIV and should be actively addressed in HIV clinical care. PMID- 26226252 TI - First cases of severe congenital factor XIII deficiency in Southwestern Afghanistan in the vicinity of southeast of Iran. AB - Factor XIII deficiency (FXIIID) is an extremely rare bleeding disorder with the highest global incidence in southeast of Iran. Southwestern Afghanistan (Nimruz Province) is located near the border with Iran in the vicinity of Sistan and Baluchestan Province in southeast Iran, and there seems to be a high prevalence of FXIIID in Nimruz. Thus, this cross-sectional study was designed to assess the prevalence of FXIIID, molecular basis as well as clinical manifestations of FXIIID in Southwestern Afghanistan. During the course of the study, all patients suspected of FXIIID were clinically examined and assessed by routine coagulation tests, including bleeding time, activated partial thromboplastin time, prothrombin time, as well as platelet count and clot solubility test. Patients with normal routine coagulation tests, but abnormal clot solubility test, underwent further investigations by FXIII activity, as well as molecular analysis for FXIII-A gene mutation (Trp187Arg) by PCR-restriction fragment length polymorphism that confirmed by sequencing. Patients with confirmed FXIIID deficiency were registered to receive prophylaxis treatment. All data including demographic information, clinical manifestations, as well as therapeutic response and type and duration of treatment, were recorded, and the data were analyzed by SPSS software. In this cross-sectional study, we found five patients with abnormal clot solubility test, among whom two patients abandoned the study, whereas three patients remained for a more precise study. All the patients were residents of Zaranj city, the capital of Nimruz Province. All these patients had undetectable activity of FXIII, which indicates a severe deficiency. Molecular analysis of patients showed mutation of Trp187Arg in all of them. Hematoma was the most common clinical presentation leading to diagnosis of FXIIID in these patients (100%). Epistaxis (67%), gum bleeding (33%), and hematuria (33%) were other recurrent clinical presentations of the patients. Three cases of death due to FXIIID were detected in the family of these patients. There was a high prevalence of FXIIID in Zaranj city with a population of 50 000, which was appropriately equal to the prevalence of the disorder in southeast of Iran, which seemed to have the highest global prevalence of FXIIID, and underlines that the same mutation (Trp187Arg) in both regions is same. PMID- 26226253 TI - A new gap in the novel anticoagulants' era: undertreatment. AB - After long years of using warfarin for atrial fibrillation, new oral anticoagulants (NOACs) became available for decreasing the risk of ischemic stroke. Our aim was to observe the physicians prescribing patterns of NOACs. This prospective observational study included patients using NOACs applying consecutively to our outpatient clinic. Physical examination was performed, and patient history, electrocardiogram, transthoracic echocardiography, and biochemical results were collected. Bleeding and ischemic stroke risk scores (HAS BLED and CHA2DS2-VASc scores) were calculated. We evaluated patients' characteristics, risk factors, concomitant drug usage, and physicians' choices. The study consisted of 174 patients using NOACs (dabigatran 113 patients, rivaroxaban 61 patients), with a mean age of 70.7 +/- 8.8 years. The mean HAS BLED score was 1.74 +/- 0.9 and the mean CHA2DS2-VASc score was 3.7 +/- 1.2. Fifty-three (30.4%) patients were prescribed low-dose NOAC according to the optimal dose, and 12 (6.8%) patients were prescribed high-dose NOAC according to the optimal dose. We compared optimal dose and undertreatment groups to find out if there was any predicting factor for physicians to use low dose of NOACs, but there was no significant difference between the two groups for age, sex, concomitant chronic disease, and CHA2DS2-VASc and HAS-BLED scores. NOACs were prescribed to patients mostly with high CHA2DS2-VASc score and low HAS-BLED score. Low-dose NOAC usage according to the optimal dose was frequent. Frequent coagulation monitoring and drug incompliance are big deficiencies at atrial fibrillation in use of warfarin. NOACs overcome these difficulties; however, physicians' hesitation to use NOACs with the optimal dosage may be another limitation in real-world practice. PMID- 26226254 TI - Management and outcome of pregnancies in women with antithrombin deficiency: a single-center experience and review of literature. AB - Women with antithrombin (AT) deficiency have an increased risk for pregnancy associated venous thromboembolism (VTE) and adverse pregnancy outcome. AT deficiency is a rare thrombophilia with heterogeneous genetic background. Owing to the few cases reported in the literature, management strategies of pregnancy with AT deficiency are inconsistent. Our aim was to examine the type of the genetic defect, management, maternal, and pregnancy outcome in patients with hereditary AT deficiency. Five expectant mothers with AT deficiency were followed in our center to evaluate thrombotic events, and maternal and pregnancy outcomes. AT gene sequencing was performed in all cases, and levels of AT and anti activated factor X were regularly measured to guide the risk-adopted anticoagulant prophylaxis. Three mothers had homozygous type II heparin-binding site mutations and two had heterozygous type I mutations of the gene encoding AT. Two women had additional factor V Leiden heterozygous mutations. Three maternal VTEs--four healthy newborns and five pregnancy losses--were observed. The risk of patients to VTE and adverse pregnancy outcome was found to associate with the homozygous type II heparin-binding site mutation of the AT gene. High risk of maternal VTE and frequent pregnancy complications were observed to associate with AT deficiency. Our results support the need of individualized, risk-adopted anticoagulant therapy in patients with AT deficiency. PMID- 26226255 TI - Thrombomodulin gene proximal promoter polymorphisms in premature acute coronary syndrome patients in Bahrain. AB - Thrombomodulin is expressed on endothelial cells and monocytes (mTM) where it has an anticoagulant function. Enzymatic cleavage from the cell surface produces soluble thrombomodulin (sTM) in plasma. Abnormal levels of sTM and mutations in the thrombomodulin gene (THBD) are linked to cardiovascular disease. The aim of this study was to investigate THBD proximal promoter mutations and levels of sTM and mTM in men presenting with premature acute coronary syndrome (ACS). This prospective cross-sectional study included 100 adult men with premature ACS (age <55 years) and 60 healthy age-matched controls. Plasma sTM was assayed by ELISA. mTM expression was assessed by flow cytometry with CD141 antibody. The -33 G/A polymorphism was identified by PCR-restriction fragment length polymorphism analysis and the THBD proximal promoter region was sequenced. Significantly lower sTM (P < 0.001) and higher mTM (P < 0.001) were seen in ACS patients. Heterozygous THBD promoter polymorphisms -33 G/A and -9/-10 GG/AT were found in eight patients and five control individuals. In patients and control individuals, allele frequencies of A were 0.02 and 0.025, and that of AT were 0.025 and 0.017, respectively. There were no significant associations of these polymorphisms with ACS, sTM levels or mTM expression. THBD polymorphisms -33 G/A and -9/-10 GG/AT are present in low frequency in our patient population, and are more frequent in the South Asians as compared to the Arabs. The frequency of -33 G/A is lower, whereas that of -9/-10 GG/AT is higher than that reported in the Orientals. The presence of THBD proximal promoter polymorphisms do not explain variations in levels of sTM and mTM in this patient population. PMID- 26226256 TI - Assessment of the frequency of regulatory T cells (CD4+CD25+CD127-) in children with hemophilia A: relation to factor VIII inhibitors and disease severity. AB - A rapidly growing evidence showed that regulatory T cells (Tregs) play a crucial role in tolerance to coagulation factors and may be involved in the pathogenesis of inhibitor formation in patients with hemophilia. We determined the percentage of Tregs (CD4CD25CD127) in 45 children with hemophilia A compared with 45 healthy controls, and assessed their relation to the clinical characteristics of patients and factor VIII (FVIII) inhibitors. Patients were studied stressing on frequency of bleeding attacks, joint pain, history of viral hepatitis, and the received therapy (FVIII precipitate/cryotherapy). FVIII activity and FVIII inhibitors were assessed with flow cytometric analysis of CD4CD25CD127 Tregs. According to residual FVIII activity levels, 30 patients (66.7%) had mild/moderate hemophilia A, whereas 15 (33.3%) patients had severe hemophilia A. The frequency of Tregs was significantly lower among all patients with hemophilia A compared with controls (2.59 +/- 1.1 versus 3.73 +/- 1.12%; P = 0.002). Tregs were significantly decreased among patients with FVIII inhibitors compared with the inhibitor-negative group (P < 0.001). Patients with hematuria or severe hemophilia A had lower Tregs levels than those without (P = 0.34 and P = 0.011, respectively). A significant positive correlation was found between the percentage of Tregs and FVIII among hemophilia A patients. ROC curve analysis revealed that the cut-off value of Tregs at 1.91% could differentiate patients with and without FVIII inhibitors, with a sensitivity of 100% and a specificity of 91.3%. We suggest that alteration in the frequency of Tregs in young patients with hemophilia A may contribute to inhibitor formation and disease severity. PMID- 26226257 TI - Use of PCR Signal and Therapeutic Drug Monitoring in a Switch Cohort Study to Tenofovir/Emtricitabine/Rilpivirine: A W96 Follow-Up. AB - OBJECTIVE: To assess, in a clinical cohort, the efficacy of switching treatment in virologically-suppressed patients to tenofovir/emtricitabine/rilpivirine as a single-tablet regimen (STR) using the PCR signal of the viral load (VL) assay and plasma drug determination (C24h). PATIENTS AND METHODS: An observational single centre study enrolling patients with VL<50 copies/mL initiating rilpivirine-based STR. C24h and VL were performed until W48 and W96 of STR, respectively. PCRneg was defined as an undetected PCR signal. Medians (IQR) were presented. RESULTS: 116 patients were enrolled. At STR baseline, time since first antiretroviral therapy and time of virological suppression were 6 years (2-9) and 17 months (7 43), respectively. Before STR initiation, patients were receiving protease inhibitors and non-nucleoside reverse transcriptase inhibitors-based regimen in 44% and 47% of cases, respectively. Historical genotype showed virus resistant to one drug of the STR in 6 patients (5%). At W96, 17 (15%) discontinued STR due to adverse events. The proportion of patients maintaining VL <50 copies/mL on treatment was 98%, 99%, 100%, 100%, 100% and 100% at W12, W24, W36, W48, W72 and W96, respectively. Among them, 70%, 66%, 68%, 59%, 74%, 68% and 60% were PCRneg at baseline, W12, W24, W36, W48, W72 and W96, respectively. Median rilpivirine C24h was 91 ng/mL (57-141, n = 285), with 91% of rilpivirine C24h >50 ng/mL, the target effective concentration. CONCLUSIONS: In this clinical cohort of virologically-suppressed patients switching to a new STR, most subjects had adequate rilpivirine C24h and displayed a high level of virological suppression with no residual viremia until W96. PMID- 26226263 TI - Association of VH4-59 Antibody Variable Gene Usage with Recognition of an Immunodominant Epitope on the HIV-1 Gag Protein. AB - The human antibody response against HIV-1 infection recognizes diverse antigenic subunits of the virion, and includes a high level of antibodies to the Gag protein. We report here the isolation and characterization of a subset of Gag specific human monoclonal antibodies (mAbs) that were prevalent in the antibody repertoire of an HIV-infected individual. Several lineages of Gag-specifc mAbs were encoded by a single antibody heavy chain variable region, VH4-59, and a representative antibody from this group designated mAb 3E4 recognized a linear epitope on the globular head of the p17 subunit of Gag. We found no evidence that mAb 3E4 exhibited any function in laboratory studies aimed at elucidating the immunologic activity, including assays for neutralization, Ab-dependent cell mediated virus inhibition, or enhanced T cell reactivity caused by Gag-3E4 complexes. The findings suggest this immunodominant epitope in Gag protein, which is associated with VH4-59 germline gene usage, may induce a high level of B cells that encode binding but non-functional antibodies that occupy significant repertoire space following HIV infection. The studies define an additional specific molecular mechanism in the immune distraction activity of the HIV virion. PMID- 26226264 TI - N-acetylglucosamine Regulates Virulence Properties in Microbial Pathogens. PMID- 26226265 TI - A Social Network Approach Reveals Associations between Mouse Social Dominance and Brain Gene Expression. AB - Modelling complex social behavior in the laboratory is challenging and requires analyses of dyadic interactions occurring over time in a physically and socially complex environment. In the current study, we approached the analyses of complex social interactions in group-housed male CD1 mice living in a large vivarium. Intensive observations of social interactions during a 3-week period indicated that male mice form a highly linear and steep dominance hierarchy that is maintained by fighting and chasing behaviors. Individual animals were classified as dominant, sub-dominant or subordinate according to their David's Scores and I& SI ranking. Using a novel dynamic temporal Glicko rating method, we ascertained that the dominance hierarchy was stable across time. Using social network analyses, we characterized the behavior of individuals within 66 unique relationships in the social group. We identified two individual network metrics, Kleinberg's Hub Centrality and Bonacich's Power Centrality, as accurate predictors of individual dominance and power. Comparing across behaviors, we establish that agonistic, grooming and sniffing social networks possess their own distinctive characteristics in terms of density, average path length, reciprocity out-degree centralization and out-closeness centralization. Though grooming ties between individuals were largely independent of other social networks, sniffing relationships were highly predictive of the directionality of agonistic relationships. Individual variation in dominance status was associated with brain gene expression, with more dominant individuals having higher levels of corticotropin releasing factor mRNA in the medial and central nuclei of the amygdala and the medial preoptic area of the hypothalamus, as well as higher levels of hippocampal glucocorticoid receptor and brain-derived neurotrophic factor mRNA. This study demonstrates the potential and significance of combining complex social housing and intensive behavioral characterization of group-living animals with the utilization of novel statistical methods to further our understanding of the neurobiological basis of social behavior at the individual, relationship and group levels. PMID- 26226276 TI - Remodeling of Tight Junctions and Enhancement of Barrier Integrity of the CACO-2 Intestinal Epithelial Cell Layer by Micronutrients. AB - The micronutrients zinc, quercetin, butyrate, indole and berberine were evaluated for their ability to induce remodeling of epithelial tight junctions (TJs) and enhance barrier integrity in the CACO-2 gastrointestinal epithelial cell culture model. All five of these chemically very diverse micronutrients increased transepithelial electrical resistance (Rt) significantly, but only berberine also improved barrier integrity to the non-electrolyte D-mannitol. Increases of Rt as much as 200% of untreated controls were observed. Each of the five micronutrients also induced unique, signature-like changes in TJ protein composition, suggesting multiple pathways (and TJ arrangements) by which TJ barrier function can be enhanced. Decreases in abundance by as much as 90% were observed for claudin-2, and increases of over 300% could be seen for claudins -5 and -7. The exact effects of the micronutrients on barrier integrity and TJ protein composition were found to be highly dependent on the degree of differentiation of the cell layer at the time it was exposed to the micronutrient. The substratum to which the epithelial layer adheres was also found to regulate the response of the cell layer to the micronutrient. The implications of these findings for therapeutically decreasing morbidity in Inflammatory Bowel Disease are discussed. PMID- 26226278 TI - Erratum: Digital Ecology: Coexistence and Domination among Interacting Networks. PMID- 26226277 TI - Obestatin Accelerates the Recovery in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats. AB - OBJECTIVE: Several previous studies have shown that obestatin exhibits protective and regenerative effects in some organs including the stomach, kidney, and the brain. In the pancreas, pretreatment with obestatin inhibits the development of cerulein-induced acute pancreatitis, and promotes survival of pancreatic beta cells and human islets. However, no studies investigated the effect of obestatin administration following the onset of experimental acute pancreatitis. AIM: The aim of this study was to evaluate the impact of obestatin therapy in the course of ischemia/reperfusion-induced pancreatitis. Moreover, we tested the influence of ischemia/reperfusion-induced acute pancreatitis and administration of obestatin on daily food intake and pancreatic exocrine secretion. METHODS: Acute pancreatitis was induced by pancreatic ischemia followed by reperfusion of the pancreas. Obestatin (8 nmol/kg/dose) was administered intraperitoneally twice a day, starting 24 hours after the beginning of reperfusion. The effect of obestatin in the course of necrotizing pancreatitis was assessed between 2 and 14 days, and included histological, functional, and biochemical analyses. Secretory studies were performed on the third day after sham-operation or induction of acute pancreatitis in conscious rats equipped with chronic pancreatic fistula. RESULTS: Treatment with obestatin ameliorated morphological signs of pancreatic damage including edema, vacuolization of acinar cells, hemorrhages, acinar necrosis, and leukocyte infiltration of the gland, and led to earlier pancreatic regeneration. Structural changes were accompanied by biochemical and functional improvements manifested by accelerated normalization of interleukin-1beta level and activity of myeloperoxidase and lipase, attenuation of the decrease in pancreatic DNA synthesis, and by an improvement of pancreatic blood flow. Induction of acute pancreatitis by pancreatic ischemia followed by reperfusion significantly decreased daily food intake and pancreatic exocrine secretion. Administration of obestatin at doses used was without significant effect with regard to daily food intake or pancreatic exocrine secretion in sham-operated rats, as well as in rats with acute pancreatitis. On the other hand, obestatin abolished a statistical significance of difference in food intake between animals with AP and control animals without pancreatic fistula and induction of AP. CONCLUSION: Treatment with the exogenous obestatin reduces severity of ischemia/reperfusion-induced acute pancreatitis and accelerates recovery in this disease. The involved mechanisms are likely to be multifactorial, and are mediated, at least in part, by anti-inflammatory properties of obestatin. PMID- 26226279 TI - Syntheses and Biological Evaluation of Costunolide, Parthenolide, and Their Fluorinated Analogues. AB - Inspired by the biosynthesis of sesquiterpene lactones (SLs), herein we report the asymmetric total synthesis of the germacrane ring (24). The synthetic strategy features a selective aldol reaction between beta,gamma-unsaturated chiral sulfonylamide 15a and aldehyde 13, as well as the intramolecular alpha alkylation of sulfone 21 to construct a 10-membered carbocylic ring. The key intermediate 24 can be used to prepare the natural products costunolide and parthenolide (PTL), which are the key precursors for transformation into other SLs. Furthermore, the described synthetic sequences are amenable to the total synthesis of SL analogues, such as trifluoromethylated analogues 32 and 45. Analogues 32 and 45 maintained high activities against a series of cancer cell lines compared to their parent PTL and costunolide, respectively. In addition, 32 showed enhanced tolerance to acidic media compared with PTL. To our surprise, PTL and 32 showed comparable half-lives in rat plasma and in the presence of human liver microsomes. PMID- 26226280 TI - Non-Invasive Determination of Cardiac Output in Pre-Capillary Pulmonary Hypertension. AB - BACKGROUND: Cardiac output (CO) is a major diagnostic and prognostic factor in pre-capillary pulmonary hypertension (PH). Reference methods for CO determination, like thermodilution (TD), require invasive procedures and allow only steady-state measurements. The Modelflow (MF) method is an appealing technique for this purpose as it allows non-invasive and beat-by-beat determination of CO. METHODS: We aimed to compare CO values obtained simultaneously from non-invasive pulse wave analysis by MF (COMF) and by TD (COTD) to determine its precision and accuracy in pre-capillary PH. The study was performed on 50 patients with pulmonary arterial hypertension (PAH) or chronic thrombo-embolic PH (CTEPH). CO was determined at rest in all patients (n = 50) and during nitric oxide vasoreactivity test, fluid challenge or exercise (n = 48). RESULTS: Baseline COMF and COTD were 6.18 +/- 1.95 and 5.46 +/- 1.95 L.min 1, respectively. Accuracy and precision were 0.72 and 1.04 L.min-1, respectively. Limits of agreement (LoA) ranged from -1.32 to 2.76 L.min-1. Percentage error (PE) was +/-35.7%. Overall sensitivity and specificity of COMF for directional change were 95.2% and 82.4%, (n = 48) and 93.3% and 100% for directional changes during exercise (n = 16), respectively. After application of a correction factor (1.17 +/- 0.25), neither proportional nor fixed bias was found for subsequent CO determination (n = 48). Accuracy was -0.03 L.min-1 and precision 0.61 L.min-1. LoA ranged from -1.23 to 1.17 L.min-1 and PE was +/-19.8%. CONCLUSIONS: After correction against a reference method, MF is precise and accurate enough to determine absolute values and beat-by-beat relative changes of CO in pre capillary PH. PMID- 26226281 TI - Graphene Oxide Transparent Hybrid Film and Its Ultraviolet Shielding Property. AB - Herein, we first reported a facile strategy to prepare functional Poly(vinyl alcohol) (PVA) hybrid film with well ultraviolet (UV) shielding property and visible light transmittance using graphene oxide nanosheets as UV-absorber. The absorbance of ultraviolet light at 300 nm can be up to 97.5%, while the transmittance of visible light at 500 nm keeps 40% plus. This hybrid film can protect protein from UVA light induced photosensitive damage, remarkably. PMID- 26226282 TI - WARM-UP PROTOCOLS FOR HIGH SCHOOL STUDENTS. AB - The study compared the acute effects of three warm-up protocols on change-of direction speed, reaction time, and movement time of upper extremities. Participants were 27 Greek high school students from an urban area (M age=17.2 yr., SD=0.2, range=16.5-18.0). All participants performed the following warm-up protocols on three different days: (a) 3 min. jogging followed by 5 min. static stretching, (b) 3 min. jogging followed by 5 min. dynamic stretching, and (c) 3 min. jogging followed by 5 min. of rest without stretching. At the end of each protocol, participants performed sprints of moderate to submaximal intensity. After the warm-up protocols, participants performed the following tests: "505 change-of-direction-speed," reaction time, and movement time (arm movements). There was no significant effect of protocols on the performance tests. Pre exercise stretching may not be required for performance improvement in activities involving change-of-direction speed, reaction, and movement time if the final part of the warm-up involves sprinting. The advantage of a short duration warm-up is that it offers students more time to play in physical education lessons. However, it is generally important for students to learn the benefits of stretching and how to stretch for lifelong fitness. PMID- 26226283 TI - USE OF TRANS-CONTEXTUAL MODEL-BASED PHYSICAL ACTIVITY COURSE IN DEVELOPING LEISURE-TIME PHYSICAL ACTIVITY BEHAVIOR OF UNIVERSITY STUDENTS. AB - This study examined how a physical activity course based on the Trans-Contextual Model affected the variables of perceived autonomy support, autonomous motivation, determinants of leisure-time physical activity behavior, basic psychological needs satisfaction, and leisure-time physical activity behaviors. The participants were 70 Turkish university students (M age=23.3 yr., SD=3.2). A pre-test-post-test control group design was constructed. Initially, the participants were randomly assigned into an experimental (n=35) and a control (n=35) group. The experimental group followed a 12 wk. trans-contextual model based intervention. The participants were pre- and post-tested in terms of Trans Contextual Model constructs and of self-reported leisure-time physical activity behaviors. Multivariate analyses showed significant increases over the 12 wk. period for perceived autonomy support from instructor and peers, autonomous motivation in leisure-time physical activity setting, positive intention and perceived behavioral control over leisure-time physical activity behavior, more fulfillment of psychological needs, and more engagement in leisure-time physical activity behavior in the experimental group. These results indicated that the intervention was effective in developing leisure-time physical activity and indicated that the Trans-Contextual Model is a useful way to conceptualize these relationships. PMID- 26226284 TI - EFFECTIVE INDICES FOR MONITORING MENTAL WORKLOAD WHILE PERFORMING MULTIPLE TASKS. AB - This study identified several physiological indices that can accurately monitor mental workload while participants performed multiple tasks with the strategy of maintaining stable performance and maximizing accuracy. Thirty male participants completed three 10-min. simulated multitasks: MATB (Multi-Attribute Task Battery) with three workload levels. Twenty-five commonly used mental workload measures were collected, including heart rate, 12 HRV (heart rate variability), 10 EEG (electroencephalography) indices (alpha, beta, theta, alpha/theta, theta/beta from O1-O2 and F4-C4), and two subjective measures. Analyses of index sensitivity showed that two EEG indices, theta and alpha/theta (F4-C4), one time-domain HRV SDNN (standard deviation of inter-beat intervals), and four frequency-domain HRV: VLF (very low frequency), LF (low frequency), %HF (percentage of high frequency), and LF/HF were sensitive to differentiate high workload. EEG alpha/theta (F4-C4) and LF/HF were most effective for monitoring high mental workload. LF/HF showed the highest correlations with other physiological indices. EEG alpha/theta (F4 C4) showed strong correlations with subjective measures across different mental workload levels. Operation strategy would affect the sensitivity of EEG alpha (F4 C4) and HF. PMID- 26226285 TI - EFFECTS OF COLORS ON THE FEELING OF BEING DAZZLED EVOKED BY STIMULI WITH LUMINANCE GRADIENTS. AB - The sensation of being dazzled by light was investigated, and the effects of colors on the feeling were assessed using stimuli composed of a disk and a surrounding annulus with luminance gradient, which had a glowing appearance. The colors of the disk and annulus were varied, while the luminance of each pixel was unchanged. In addition, disk and maximum annulus luminances were also varied. Ten participants were asked to rate the feeling of being dazzled for the stimuli. Results of a four-way analysis of variance (ANOVA) indicated that the main effect of disk color was not significant, whereas the annulus color was. Furthermore, there was significant interaction of the disk color and the annulus color. On the whole, the feeling of being dazzled for the light-blue or pink annulus was stronger than that for the other colors, while the light-blue (pink) annulus did not significantly differ in that feeling from the yellow, green, or gray annulus when the disk color was light-blue (pink). This indicates that the same disk color as the annulus color tended to reduce the feeling of being dazzled. PMID- 26226286 TI - SELF-EFFICACY, EMOTIONAL STATES, AND PERFORMANCE IN CAROM BILLIARDS. AB - Based on an integrative approach to the study of the emotional-cognitive-motor linkage in sport competition, the purpose was to examine the mediating role of emotion-related (psychobiosocial) states in the relationship between self efficacy (technical and cognitive) and performance in carom billiards. Forty-five male players of master or intermediate categories, between 30 and 74 years of age (M=51.2, SD=10.8), participated in the study. Measures included scores of technical and cognitive self-efficacy, functional (i.e., facilitative to performance) and dysfunctional (i.e., debilitative to performance) psychobiosocial states, and performance outcome. The assessment took place prior to one game of a national or an international competition. Results showed technical self-efficacy, cognitive self-efficacy, functional states, and performance to be significantly and positively related among them. Functional psychobiosocial states mediated the effect of both technical and cognitive self efficacy on performance. Overall, the findings supported an integrative approach to the study of the linkage among cognition, emotion, and action in sport. PMID- 26226287 TI - A PILOT STUDY ON THE ENCODING OF A PERCEPTUAL LEARNING TASK FOLLOWING SLEEP DEPRIVATION. AB - Memory encoding sometimes must occur during a period of sleep deprivation. The question was whether one night of sleep deprivation inhibits encoding on a perceptual learning task (the texture discrimination task). The sample was 18 human participants (M age=22.1 yr., SEM=0.5; 8 men). The participants were randomized to a sleep deprivation or sleep control condition and, after the manipulation, were given two administrations of the texture discrimination task. All participants were given an opportunity for a 90 min. nap between the two administrations. Performance was measured by the interpolated stimulus-to-mask onset asynchrony (i.e., the inter-stimulus interval), at which the percentage of correct responses for the stimuli in the participant's peripheral vision fell below 80%. Offline consolidation was defined as a decrease in this index between the two administrations. Participants who were sleep deprived prior to encoding exhibited similar offline consolidation (M=-5.3 msec., SEM=2.3) compared to participants who were not sleep deprived prior to encoding (M=-6.2 msec., SEM=3.9); the two-way interaction between time and condition was not significant. In light of reports in the literature, these results indicate encoding following sleep deprivation may be influenced by both the type of task encoded and the brain regions involved in memory processing. PMID- 26226288 TI - METHODOLOGICAL CONSIDERATIONS TO ANALYZE THE RELATION OF PHYSICAL ACTIVITY WITH LEPTIN LEVELS IN CHILDREN: COMMENT ON CICCHELLA, ET AL. (2013). AB - A positive correlation was found between self-reported physical activity, leptin level, and Tanner stage 2 in children aged 10 to 12 years. However, several methodological considerations on the accuracy for assessing physical activity, misclassification of physical activity levels and weight status, the inclusion of possible confounds, and interpretation of the current findings should be examined to clarify the final interpretation. PMID- 26226289 TI - Increased Dietary Inflammatory Index (DII) Is Associated With Increased Risk of Prostate Cancer in Jamaican Men. AB - Prostate cancer is the most common nonskin malignancy, and it accounts for the most cancer deaths among Jamaican males. Diet has been implicated in the etiology of prostate cancer, including through its effects on inflammation. We examined the association between a newly developed dietary inflammatory index (DII) and prostate cancer in a case-control study of 40-80 yr old Jamaican males. A total of 229 incident cases and 250 controls attended the same urology out-patient clinics at 2 major hospitals and private practitioners in the Kingston, Jamaica metropolitan area between March 2005 and July 2007. The DII was computed based on dietary intake assessed using a previously validated food frequency questionnaire (FFQ) that was expanded to assess diet and cancer in this Jamaican population. Multivariable logistic regression was used to estimate odds ratios, with DII as continuous and expressed as quartiles. Logistic regression analysis adjusted for age, total energy intake, education, body mass index, smoking status, physical activity, and family history of prostate cancer. Men in the highest quartile of the DII were at higher risk of prostate cancer [odds ratio (OR) = 2.39; 95% confidence interval (CI) = 1.14-5.04; P(trend) = 0.08] compared to men in the lowest DII quartile. These data suggest a proinflammatory diet, as indicated by increasing DII score, may be a risk factor for prostate cancer in Jamaican men. PMID- 26226291 TI - Modified nanocarbon surfaces for high performance supercapacitor and electrocatalysis applications. AB - An efficient and easy method is described which allows modification of supported nanocarbon films with carbon nanotubes (CNTs) from an aqueous colloidal suspension. Subsequently CNTs can be decorated with Pt-nanoparticles directly from an aqueous solution of Pt ions without the need for reducing agents. High performance supercapacitors and electrocatalysts are obtained. PMID- 26226290 TI - Procyanidins Negatively Affect the Activity of the Phosphatases of Regenerating Liver. AB - Natural polyphenols like oligomeric catechins (procyanidins) derived from green tea and herbal medicines are interesting compounds for pharmaceutical research due to their ability to protect against carcinogenesis in animal models. It is nevertheless still unclear how intracellular pathways are modulated by polyphenols. Monomeric polyphenols were shown to affect the activity of some protein phosphatases (PPs). The three phosphatases of regenerating liver (PRLs) are close relatives and promising therapeutic targets in cancer. In the present study we show that several procyanidins inhibit the activity of all three members of the PRL family in the low micromolar range, whereas monomeric epicatechins show weak inhibitory activity. Increasing the number of catechin units in procyanidins to more than three does not further enhance the potency. Remarkably, the tested procyanidins showed selectivity in vitro when compared to other PPs, and over 10-fold selectivity toward PRL-1 over PRL-2 and PRL-3. As PRL overexpression induces cell migration compared to control cells, the effect of procyanidins on this phenotype was studied. Treatment with procyanidin C2 led to a decrease in cell migration of PRL-1- and PRL-3-overexpressing cells, suggesting the compound-dependent inhibition of PRL-promoted cell migration. Treatment with procyanidin B3 led to selective suppression of PRL-1 overexpressing cells, thereby corroborating the selectivity toward PRL-1- over PRL-3 in vitro. Together, our results show that procyanidins negatively affect PRL activity, suggesting that PRLs could be targets in the polypharmacology of natural polyphenols. Furthermore, they are interesting candidates for the development of PRL-1 inhibitors due to their low cellular toxicity and the selectivity within the PRL family. PMID- 26226292 TI - Correction: An Analysis of Predator Selection to Affect Aposematic Coloration in a Poison Frog Species. PMID- 26226293 TI - The human-microbe metaorganism, evolution and extraterrestrial colonization. PMID- 26226294 TI - Prognostic Implication of Persistent Human Papillomavirus Type 16 DNA Detection in Oral Rinses for Human Papillomavirus-Related Oropharyngeal Carcinoma. AB - IMPORTANCE: Human papillomavirus-related oropharyngeal carcinoma (HPV-OPC) is increasing in incidence in the United States. Although HPV-OPC has favorable prognosis, 10% to 25% of HPV-OPCs recur. Detection of human papillomavirus (HPV) DNA in oral rinses is associated with HPV-OPC, but its potential as a prognostic biomarker is unclear. OBJECTIVE: To determine whether HPV DNA detection in oral rinses after treatment for HPV-OPC is associated with recurrence and survival. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of patients with incident HPV-OPC diagnosed from 2009 to 2013 at 4 academic tertiary referral cancer centers in the United States. Oral rinse samples were collected at diagnosis and after treatment (9, 12, 18, and 24 months after diagnosis), and evaluated for HPV DNA. Among an initial cohort of 157 participants with incident HPV-OPC treated with curative intent, 124 had 1 or more posttreatment oral rinses available and were included in this study. MAIN OUTCOMES AND MEASURES: Disease free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and the association of HPV DNA detection in oral rinses with survival was evaluated using Cox regression analysis. RESULTS: Oral HPV type 16 (HPV16) DNA was common at diagnosis (67 of 124 participants [54%]). In contrast, oral HPV16 DNA was detected in only 6 participants after treatment (5%), including 5 with HPV16 DNA also detected at diagnosis (persistent oral HPV16 DNA). Two-year DFS and OS were 92% (95% CI, 94%-100%) and 98% (95% CI, 93%-99%). Persistent oral HPV16 DNA was associated with worse DFS (hazard ratio, 29.7 [95% CI, 9.0-98.2]) and OS (hazard ratio, 23.5 [95% CI, 4.7-116.9]). All 5 participants with persistent oral HPV16 DNA developed recurrent disease, 3 with local disease involvement. In contrast, just 9 of 119 participants (8%) without persistent oral HPV16 DNA developed recurrent disease, only 1 (11%) with local disease involvement. Median (range) time from earliest posttreatment oral HPV16 DNA detection to recurrence was 7.0 (3.7-10.9) months. CONCLUSIONS AND RELEVANCE: Human papillomavirus type 16 DNA in oral rinses is common at diagnosis but rare after treatment for HPV-OPC. Our data suggest that, although infrequent, persistent HPV16 DNA in posttreatment oral rinses is associated with poor prognosis and is a potential tool for long-term tumor surveillance, perhaps more so for local recurrence. PMID- 26226295 TI - SUMOylation of EHD3 Modulates Tubulation of the Endocytic Recycling Compartment. AB - Endocytosis defines the entry of molecules or macromolecules through the plasma membrane as well as membrane trafficking in the cell. It depends on a large number of proteins that undergo protein-protein and protein-phospholipid interactions. EH Domain containing (EHDs) proteins formulate a family, whose members participate in different stages of endocytosis. Of the four mammalian EHDs (EHD1-EHD4) EHD1 and EHD3 control traffic to the endocytic recycling compartment (ERC) and from the ERC to the plasma membrane, while EHD2 modulates internalization. Recently, we have shown that EHD2 undergoes SUMOylation, which facilitates its exit from the nucleus, where it serves as a co-repressor. In the present study, we tested whether EHD3 undergoes SUMOylation and what is its role in endocytic recycling. We show, both in-vitro and in cell culture, that EHD3 undergoes SUMOylation. Localization of EHD3 to the tubular structures of the ERC depends on its SUMOylation on lysines 315 and 511. Absence of SUMOylation of EHD3 has no effect on its dimerization, an important factor in membrane localization of EHD3, but has a dominant negative effect on its appearance in tubular ERC structures. Non-SUMOylated EHD3 delays transferrin recycling from the ERC to the cell surface. Our findings indicate that SUMOylation of EHD3 is involved in tubulation of the ERC membranes, which is important for efficient recycling. PMID- 26226296 TI - Esaki Diodes in van der Waals Heterojunctions with Broken-Gap Energy Band Alignment. AB - van der Waals (vdW) heterojunctions composed of two-dimensional (2D) layered materials are emerging as a solid-state materials family that exhibits novel physics phenomena that can power a range of electronic and photonic applications. Here, we present the first demonstration of an important building block in vdW solids: room temperature Esaki tunnel diodes. The Esaki diodes were realized in vdW heterostructures made of black phosphorus (BP) and tin diselenide (SnSe2), two layered semiconductors that possess a broken-gap energy band offset. The presence of a thin insulating barrier between BP and SnSe2 enabled the observation of a prominent negative differential resistance (NDR) region in the forward-bias current-voltage characteristics, with a peak to valley ratio of 1.8 at 300 K and 2.8 at 80 K. A weak temperature dependence of the NDR indicates electron tunneling being the dominant transport mechanism, and a theoretical model shows excellent agreement with the experimental results. Furthermore, the broken-gap band alignment is confirmed by the junction photoresponse, and the phosphorus double planes in a single layer of BP are resolved in transmission electron microscopy (TEM) for the first time. Our results represent a significant advance in the fundamental understanding of vdW heterojunctions and broaden the potential applications of 2D layered materials. PMID- 26226297 TI - Correction. PMID- 26226298 TI - Core Freezing and Size Segregation in Surfactant Core-Shell Micelles. AB - Nonionic surfactants containing poly(ethylene oxide) are chemically simple and biocompatible and form core-shell micelles at a wide range of conditions. For those reasons, they and their aggregates have been widely investigated. Recently, irregularities that were observed in the low-temperature behavior of surfactants of the kind [CH3(CH2)(n)O(CH2CH2O)(m)H], (abbreviated CnEm) were assigned to a freezing-melting phase transition in the micellar core. In this work we expand the focus from the case of single component systems to binary surfactant systems at temperatures between 1 and 15 degrees C. By applying small-angle X-ray scattering (SAXS), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), and density measurements in pure C18E20 and C18E100 solutions and their mixtures, we show that core freezing/melting is also present in mixtures. Additionally, comparing SAXS data obtained from the mixture with those from the single components, it was possible to demonstrate that the phase transition leads to a reversible segregation of the surfactants from mixed micelles to distinct kinds of micelles of the two components. PMID- 26226300 TI - Correction: Tissue Expression Pattern of PMK-2 p38 MAPK Is Established by the miR 58 Family in C. elegans. PMID- 26226299 TI - Analysis of Histones H3 and H4 Reveals Novel and Conserved Post-Translational Modifications in Sugarcane. AB - Histones are the main structural components of the nucleosome, hence targets of many regulatory proteins that mediate processes involving changes in chromatin. The functional outcome of many pathways is "written" in the histones in the form of post-translational modifications that determine the final gene expression readout. As a result, modifications, alone or in combination, are important determinants of chromatin states. Histone modifications are accomplished by the addition of different chemical groups such as methyl, acetyl and phosphate. Thus, identifying and characterizing these modifications and the proteins related to them is the initial step to understanding the mechanisms of gene regulation and in the future may even provide tools for breeding programs. Several studies over the past years have contributed to increase our knowledge of epigenetic gene regulation in model organisms like Arabidopsis, yet this field remains relatively unexplored in crops. In this study we identified and initially characterized histones H3 and H4 in the monocot crop sugarcane. We discovered a number of histone genes by searching the sugarcane ESTs database. The proteins encoded correspond to canonical histones, and their variants. We also purified bulk histones and used them to map post-translational modifications in the histones H3 and H4 using mass spectrometry. Several modifications conserved in other plants, and also novel modified residues, were identified. In particular, we report O acetylation of serine, threonine and tyrosine, a recently identified modification conserved in several eukaryotes. Additionally, the sub-nuclear localization of some well-studied modifications (i.e., H3K4me3, H3K9me2, H3K27me3, H3K9ac, H3T3ph) is described and compared to other plant species. To our knowledge, this is the first report of histones H3 and H4 as well as their post-translational modifications in sugarcane, and will provide a starting point for the study of chromatin regulation in this crop. PMID- 26226301 TI - Rational Design of Charge-Transfer Interactions in Halogen-Bonded Co-crystals toward Versatile Solid-State Optoelectronics. AB - Charge-transfer (CT) interactions between donor (D) and acceptor (A) groups, as well as CT exciton dynamics, play important roles in optoelectronic devices, such as organic solar cells, photodetectors, and light-emitting sources, which are not yet well understood. In this contribution, the self-assembly behavior, molecular stacking structure, CT interactions, density functional theory (DFT) calculations, and corresponding physicochemical properties of two similar halogen bonded co-crystals are comprehensively investigated and compared, to construct an "assembly-structure-CT-property" relationship. Bpe-IFB wire-like crystals (where Bpe = 1,2-bis(4-pyridyl)ethylene and IFB = 1,3,5-trifluoro-2,4,6-triiodobenzene), packed in a segregated stacking form with CT ground and excited states, are measured to be quasi-one-dimensional (1D) semiconductors and show strong violet blue photoluminescence (PL) from the lowest CT1 excitons (PhiPL = 26.1%), which can be confined and propagate oppositely along the 1D axial direction. In comparison, Bpe-F4DIB block-like crystals (F4DIB = 1,4-diiodotetrafluorobenzene), packed in a mixed stacking form without CT interactions, are determined to be insulators and exhibit unique white light emission and two-dimensional optical waveguide property. Surprisingly, it seems that the intrinsic spectroscopic states of Bpe and F4DIB do not change after co-crystallization, which is also confirmed by theoretical calculations, thus offering a new design principle for white light emitting materials. More importantly, we show that the CT interactions in co-crystals are related to their molecular packing and can be triggered or suppressed by crystal engineering, which eventually leads to distinct optoelectronic properties. These results help us to rationally control the CT interactions in organic D-A systems by tuning the molecular stacking, toward the development of a fantastic "optoelectronic world". PMID- 26226302 TI - Intraoperative optical coherence tomography: ocular surgery on a higher level or just nice pictures? PMID- 26226303 TI - First Iridium-Catalyzed Highly Enantioselective Hydrogenation of beta Nitroacrylates. AB - The first highly chemo- and enantioselective hydrogenation of beta-nitroacrylates was accomplished with an iridium catalyst (Ir-4) with yields and enantioselectivities of up to 96% and 98% ee, respectively. The resulting alpha chiral beta-nitro propionates are attractive building blocks for the synthesis of chiral beta(2)-amino acids, which are the core scaffolds of bioactive natural products, pharmaceuticals, and beta-peptides. PMID- 26226304 TI - The LGBQ Microaggressions on Campus Scale: A Scale Development and Validation Study. AB - Although LGBQ students experience blatant forms of heterosexism on college campuses, subtle manifestations such as sexual orientation microaggressions are more common. Similar to overt heterosexism, sexual orientation microaggressions may threaten LGBQ students' academic development and psychological wellbeing. Limited research exists in this area, in part due to lack of a psychometrically sound instrument measuring the prevalence of LGBQ microaggressions on college campuses. To address this gap, we created and tested the LGBQ Microaggressions on College Campuses Scale. Two correlated subscales were generated: Interpersonal LGBQ Microaggressions and Environmental LGBQ Microaggressions. The results indicated that the subscales demonstrate strong reliability and validity. PMID- 26226305 TI - Bioanalysis of antibody-drug conjugates. PMID- 26226306 TI - Challenges in antibody-drug conjugate discovery: a bioconjugation and analytical perspective. PMID- 26226307 TI - Insights on the immunogenicity of antibody-drug conjugates. PMID- 26226308 TI - An integrated multiplatform bioanalytical strategy for antibody-drug conjugates: a novel case study. AB - BACKGROUND: The bioanalytical strategy for antibody-drug conjugates (ADC) includes numerous measurements integrally designed to provide comprehensive characterization of PK, PD and immunogenicity. This manuscript describes the utilization of reagents specifically tailored to an ADC with a microtubule polymerization inhibitor payload and cathepsin B cleavable linker. METHODS: The PK strategy includes the evaluation of physiological levels of total antibody, active ADC, total ADC, antibody-conjugated payload and unconjugated payload. These data are evaluated in the context of target and antidrug antibody levels to elucidate bioactive ADC. RESULTS & CONCLUSION: Herein, we discuss how this strategy has been applied and present our preliminary observations. Continuously evolving to meet pipeline demands, the integrated bioanalytical data will provide critical insights into the exposure-response relationship. PMID- 26226309 TI - Bioanalytical approaches for characterizing catabolism of antibody-drug conjugates. AB - The in vivo stability and catabolism of antibody-drug conjugates (ADCs) directly impact their PK, efficacy and safety, and metabolites of the cytotoxic or small molecule drug component of an ADC can further complicate these factors. This perspective highlights the importance of understanding ADC catabolism and the associated bioanalytical challenges. We evaluated different bioanalytical approaches to qualitatively and quantitatively characterize ADC catabolites. Here we review and discuss the rationale and experimental strategies used to design bioanalytical assays for characterization of ADC catabolism and supporting ADME studies during ADC clinical development. This review covers both large and small molecule approaches, and uses examples from Kadcyla(r) (T-DM1) and a THIOMABTM antibody-drug conjugate to illustrate the process. PMID- 26226310 TI - Antibody-drug conjugates nonclinical support: from early to late nonclinical bioanalysis using ligand-binding assays. AB - The objective of antibody-drug conjugate (ADC) bioanalysis at different stages of drug development may vary and so are the associated bioanalytical challenges. While at early drug discovery stage involving candidate selection, optimization and preliminary nonclinical assessments, the goal of ADC bioanalysis is to provide PK, toxicity and efficacy data that assists in the design and selection of potential drug candidates, the late nonclinical and clinical drug development stage typically involves regulated ADC bioanalysis that delivers TK data to define and understand pharmacological and toxicological properties of the lead ADC candidate. Bioanalytical strategies and considerations involved in developing successful ligand binding assays for ADC characterization from early discovery to late nonclinical stages of drug development are presented here. PMID- 26226311 TI - Recommendations for the development and validation of confirmatory anti-drug antibody assays. AB - Identification and characterization of anti-drug antibodies is a critical component of biopharmaceutical drug development. The tiered approach for immunogenicity testing consists of screening, confirmatory, and characterization assays. Herein, we provide recommendations for confirmatory assays by expanding upon published guidance and present common practices across the industry. The authors recommend scientific approaches for development and validation of confirmatory assays using competition methods in ligand-binding assays, along with statistical formulae for routine use and validation. The paper will assist in understanding the confirmatory assay, and carefully implementing validation criteria a priori, as well as during sample analysis. These approaches represent the authors' current knowledge and practices, with the aim that more uniform practices will be applied across the industry. PMID- 26226312 TI - Integration of bioanalytical measurements using PK-PD modeling and simulation: implications for antibody-drug conjugate development. AB - Recent technological advances have enabled precise quantitation of various bioanalytical measurements pertaining to antibody-drug conjugates (ADCs). However, availability of bioanalytical data alone cannot guarantee the provision of correct go/no-go decisions at different stages of ADC development. Integration and comprehension of all the available data at each stage of ADC development is necessary to make a well informed and objective decision about moving the ADC forward to the clinic. In this manuscript, we have reviewed the application of PK PD modeling and simulation for quantitative integration of diverse bioanalytical data available from different stages of ADC development. We have also elaborated on how similar bioanalytical data can be characterized using different models to gain distinct insights into ADC development. PMID- 26226313 TI - In vivo biotransformations of antibody-drug conjugates. AB - The selective delivery of potent pharmacologically active compounds to target tissue or cells by antibody-drug conjugates makes this immuno-conjugate a promising modality for the treatment of cancers. A thorough understanding of the structural integrity of the linker, the payload and the conjugation site during biological exposure is critical throughout the process of novel linker-payload design and optimization of PK profile. This understanding is a key aspect of the effort to maximize efficacy while minimizing toxicity in preclinical testing and to ensure the translation to the clinical setting. The complexity of this bioconjugate modality is a source of significant challenge for analytical interrogation and analysis in vivo. Therefore, we report herein a survey of various types of biotransformation events that have been elucidated in recent years. PMID- 26226314 TI - Quantification of remifentanil and propofol in human plasma: a LC-MS/MS assay validated according to the EMA guideline. AB - BACKGROUND: Remifentanil and propofol are often used in combination for general anesthesia. We developed a method using LC-MS for their simultaneous measurement in human plasma. Methodology & results: After addition of remifentanil-(13)C6 and propofol-d18 (IS), 500 ul of plasma were extracted with ethylacetate/hexane. Analysis conditions included gradient elution (water/acetonitrile), electrospray ionization and detection with a triple quadripole mass spectrometer. Remifentanil and propofol were ionized in the positive and negative mode, respectively. The method was validated according to the European Medicines Agency guideline for the validation of bioanalytical methods, then successfully applied to clinical samples from three patients who had undergone liver transplantation. CONCLUSION: This method is suitable for the simultaneous quantification of remifentanil and propofol in clinical studies. PMID- 26226315 TI - Chemometrics-assisted determination of amiloride and triamterene in biological fluids with overlapped peaks and unknown interferences. AB - BACKGROUND: Amiloride (AMI) and triamterene (TRI) are both potassium-saving diuretics, which are ordinarily used as doping to enhance the performance of athletes in sports. For the similar structures and complex matrices existence, chromatography and extraction are commonly employed to realize the determination of AMI and TRI in biological fluids, which are very time-consuming and laborious. RESULTS: A novel method is presented to simultaneous interference-free determination of AMI and TRI in complex biological fluids samples using excitation-emission matrix fluorescence coupled with second-order calibration method based on alternating normalization-weight error algorithm. CONCLUSION: The proposed method can obtain accurate qualitative and quantitative information of the analytes, even in the presence of the interference from complex biological fluids, which requires few prior purification and separation procedures. PMID- 26226316 TI - Thousand-fold volumetric concentration of live cells with a recirculating acoustofluidic device. AB - The ability to concentrate cells from dilute samples into smaller volumes is an essential process step for most biological assays. Volumetric concentration is typically achieved via centrifugation, but this technique is not well suited for handling small number of cells, especially outside of the laboratory setting. In this work, we describe a novel device that combines acoustofluidics with a recirculating architecture to achieve >1000-fold enrichment of cells in a label free manner, at high volumetric throughput (>500 MUL min(-1)) and with high recovery (>98.7%). We demonstrate that our device can be used with a wide variety of different cell types and show that this concentration strategy does not affect cell viability. Importantly, our device could be readily adopted to serve as a "sample preparation" module that can be integrated with other microfluidic devices to allow analysis of dilute cellular samples in large volumes. PMID- 26226317 TI - Surface Complexation-Based Biocompatible Magnetofluorescent Nanoprobe for Targeted Cellular Imaging. AB - We report the synthesis of a magnetofluorescent biocompatible nanoprobe-following room temperature complexation reaction between Fe3O4-ZnS nanocomposite and 8 hydroxyquinoline (HQ). The composite nanoprobe exhibited high luminescence quantum yield, low rate of photobleaching, reasonable excited-state lifetime, luminescence stability especially in human blood serum, superparamagnetism and no apparent cytotoxicity. Moreover, the nanoprobe could be used for spatio controlled cell labeling in the presence of an external magnetic field. The ease of synthesis and cell labeling in vitro make it a suitable candidate for targeted bioimaging applications. PMID- 26226318 TI - Quaternary-Linked Changes in Structure and Dynamics That Modulate O2 Migration within Hemoglobin's Gas Diffusion Tunnels. AB - Atomistic molecular dynamics simulations of diffusion of O2 from the hemes to the external solvent in the alpha- and beta-subunits of the human hemoglobin (HbA) tetramer reveal transient gas tunnels that are not seen in crystal structures. We find here that the tunnel topology, which encompasses the reported experimental Xe binding cavities, is identical in HbA's T, R, and R2 quaternary states. However, the O2 population in the cavities and the preferred O2 escape portals vary significantly with quaternary structure. For example, most O2 molecules escape from the T beta-subunit via the cavity at the center of the tetramer, but direct exit from the distal heme pocket dominates in the R2 beta-subunit. To understand what triggers the quaternary-linked redistribution of O2 within its tunnels, we examined how the simulated tertiary structure and dynamics of each subunit differs among T, R, and R2 and report that minor adjustments in alpha chain dynamics and beta-heme position modulate O2 distribution and escape in HbA. Coupled to the beta-heme position, residue betaF71 undergoes quaternary-linked conformations that strongly regulate O2 migration between the beta-subunit and HbA's central cavity. Remarkably, the distal histidine (HisE7) remains in a closed conformation near the alpha- and beta-hemes in all states, but this does not prevent an average of 23, 31, and 46% of O2 escapes from the distal heme pockets of T, R, and R2, respectively, via several distal portals, with the balance of escapes occurring via the interior tunnels. Furthermore, preventing or restricting the access of O2 to selected cavities by mutating HisE7 and other heme pocket residues to tryptophan reveals how O2 migration adjusts to the bulky indole ring and sheds light on the experimental ligand binding kinetics of these variants. Overall, our simulations underscore the high gas porosity of HbA in its T, R, and R2 quaternary states and provide new mechanistic insights into why undergoing transitions among these states likely ensures effective O2 delivery by this tetrameric protein. PMID- 26226319 TI - Selective and broad spectrum amphiphilic small molecules to combat bacterial resistance and eradicate biofilms. AB - Rationally designed amphiphilic small molecules selectively kill drug-sensitive and drug-resistant bacteria over mammalian cells. The small molecules disperse preformed biofilms and reduce viable bacterial count in the biofilms. Moreover, this class of membrane-active molecules disarms the development of bacterial resistance. PMID- 26226320 TI - Controlling the Crystallinity of Thermoresponsive Poly(2-oxazoline)-Based Nanolayers to Cell Adhesion and Detachment. AB - Semicrystalline, thermoresponsive poly(2-isopropyl-2-oxazoline) (PIPOx) layers covalently bonded to glass or silica wafers were obtained via the surface termination of the living polymer chains. Polymer solutions in acetonitrile were exposed to 50 degrees C for various time periods and were poured onto the functionalized solid wafers. Fibrillar crystallites formed in polymerization solutions settled down onto the wafers next to the amorphous polymer. The amount of crystallites adsorbed on thermoresponsive polymer layers depended on the annealing time of the PIPOx solution. The wettability of PIPOx layers decreased with the increasing amount of crystallites. The higher content of crystallites weakened the temperature response of the layer, as evidenced by the philicity and thickness measurements. Semicrystalline thermoresponsive PIPOx layers were used as biomaterials for human dermal fibroblasts (HDFs) culture and detachment. The presence of crystallites on the PIPOx layers promoted the proliferation of HDFs. Changes in the physicochemical properties of the layer, caused by the temperature response of the polymer, led to the change in the cells shape from a spindle-like to an ellipsoidal shape, which resulted in their detachment. A supporting membrane was used to assist the detachment of the cells from PIPOx biosurfaces and to prevent the rolling of the sheet. PMID- 26226321 TI - Downstream Effects of End-of-Life Care for Older Adults with Serious Illness on Health Care Utilization of Family Caregivers. PMID- 26226322 TI - Unraveling the Base Excision Repair Mechanism of Human DNA Glycosylase. AB - Human DNA glycosylase, hOGG1, is known to perform DNA repair by cleaving oxidized guanine (8OG) from the DNA. Despite numerous experimental and theoretical investigations, the underlying selective molecular mechanism has remained a mystery. Here we present a mechanism that explains how hOGG1's catalytic pocket is able to host an undamaged guanine base, but is not able to cleave it from the DNA. Using linear-scaling quantum mechanics/molecular mechanics (QM/MM) techniques with more than 500 atoms in the QM-region, we have investigated previously proposed mechanisms that all rely on protonating the 8OG nucleobase. We have found that the repair mechanisms propagated in the literature to this date are not capable of differentiating between the G and 8OG nucleobase. Besides this nonselectivity, they also involve reaction barriers that are too high, hence rendering the corresponding reaction intermediates inaccessible. Instead, we present a completely different reaction mechanism, where hOGG1 initially targets the ribose moiety of the substrate and cleaves the glycosidic bond at the very last stage. Our ribose-protonated repair mechanism is not only energetically more preferable, but also explains the selectivity utilized by hOGG1 to block processing a guanine base. PMID- 26226323 TI - A novel convolution-based approach to address ionization chamber volume averaging effect in model-based treatment planning systems. AB - The ionization chamber volume averaging effect is a well-known issue without an elegant solution. The purpose of this study is to propose a novel convolution based approach to address the volume averaging effect in model-based treatment planning systems (TPSs). Ionization chamber-measured beam profiles can be regarded as the convolution between the detector response function and the implicit real profiles. Existing approaches address the issue by trying to remove the volume averaging effect from the measurement. In contrast, our proposed method imports the measured profiles directly into the TPS and addresses the problem by reoptimizing pertinent parameters of the TPS beam model. In the iterative beam modeling process, the TPS-calculated beam profiles are convolved with the same detector response function. Beam model parameters responsible for the penumbra are optimized to drive the convolved profiles to match the measured profiles. Since the convolved and the measured profiles are subject to identical volume averaging effect, the calculated profiles match the real profiles when the optimization converges. The method was applied to reoptimize a CC13 beam model commissioned with profiles measured with a standard ionization chamber (Scanditronix Wellhofer, Bartlett, TN). The reoptimized beam model was validated by comparing the TPS-calculated profiles with diode-measured profiles. Its performance in intensity-modulated radiation therapy (IMRT) quality assurance (QA) for ten head-and-neck patients was compared with the CC13 beam model and a clinical beam model (manually optimized, clinically proven) using standard Gamma comparisons. The beam profiles calculated with the reoptimized beam model showed excellent agreement with diode measurement at all measured geometries. Performance of the reoptimized beam model was comparable with that of the clinical beam model in IMRT QA. The average passing rates using the reoptimized beam model increased substantially from 92.1% to 99.3% with 3%/3 mm and from 79.2% to 95.2% with 2%/2 mm when compared with the CC13 beam model. These results show the effectiveness of the proposed method. Less inter-user variability can be expected of the final beam model. It is also found that the method can be easily integrated into model-based TPS. PMID- 26226324 TI - Berries and oxidative stress markers: an overview of human intervention studies. AB - Berries are an excellent source of bioactive compounds such as vitamins, minerals but above all polyphenols with anthocyanins as the most representative compounds. Several in vitro and in vivo studies documented the beneficial effects of berries and their bioactives in the modulation of numerous cell functions related to oxidative stress and/or antioxidant protection. The following review summarizes published results about the role of berries (either fresh, juice, freeze-dried or dehydrated) on total plasma and serum antioxidant status and on the modulation of biomarkers of oxidative stress in acute and chronic human intervention trials. The biomarkers considered include DNA, protein and lipid oxidation, and endogenous antioxidant enzymes. Though limited, there is indication that the consumption of berries may reduce oxidative stress by modulating protein and lipid oxidation, and by improving total antioxidant status. In particular, these effects are more evident following chronic dietary interventions with respect to postprandial studies. Benefits are observed in healthy subjects as well as in those with cardiovascular risk factors or other diseases. On the contrary, data regarding the effect of berries on DNA damage and endogenous antioxidant enzyme activities are still scarce and inconclusive. In conclusion, much remains to be elucidated before a comprehensive understanding of the effects of berries on the modulation of oxidative stress markers is achieved. Robust clinical evidence supporting the role of berries in counteracting oxidative stress in humans is encouraged. PMID- 26226325 TI - Is insight a godsend? Explicit knowledge in the serial response-time task has precursors in EEG potentials already at task onset. AB - Whether, and how, explicit knowledge about some regularity arises from implicit sensorimotor learning by practice has been a matter of long-standing debate. Previously, we had found in the number reduction task that participants who will acquire explicit knowledge differ from other participants in their event-related potentials (ERPs) already at task onset. In the present study, we investigated such ERP precursors and correlates both of explicit and of sensorimotor knowledge (response speeding) about the regular sequence in a large sample of participants (n~100) in the serial response time task. Already when perceiving random sequences at task onset, those participants had largest P3 amplitudes who would later gain explicit knowledge but whose responses were not speeded. Later in the task, sensorimotor knowledge was reflected in increased fronto-central negativity in irregular blocks, overlapping the early part of P3, and participants with later explicit knowledge generally had increased P3 amplitudes. These results support the notion that explicit knowledge about covert regularities is acquired in two ways: on the one hand by a particular subgroup of participants possibly independently of sequence-specific response speeding, and on the other hand by transforming such sensorimotor to explicit knowledge through practice. PMID- 26226326 TI - cis-Pt I2(NH3)2: a reappraisal. AB - The investigation of cis-PtI2(NH3)2, the diiodido analogue of cisplatin (cisPtI2 hereafter), has been unjustly overlooked so far mainly because of old claims of pharmacological inactivity. Some recent - but still fragmentary - findings prompted us to reconsider more systematically the chemical and biological profile of cisPtI2 in comparison with cisplatin. Its solution behaviour, interactions with DNA and cytotoxic properties versus selected cancer cell lines were thus extensively analysed through a variety of biophysical and computational methods. Notably, we found that cisPtI2 is highly cytotoxic in vitro toward a few solid tumour cell lines and that its DNA platination pattern closely reproduces that of cisplatin; cisPtI2 is also shown to completely overcome resistance to cisplatin in a platinum resistant cancer cell line. The differences in the biological actions of these two Pt complexes are most likely related to slight but meaningful differences in their solution behaviour and reactivity. Overall, a very encouraging and unexpected pharmacological profile emerges for cisPtI2 with relevant implications both in terms of mechanistic knowledge and of prospective clinical application. An ab initio DFT study is also included to support the interpretation of the solution behaviour of cisPtI2 under physiological and slightly acidic pH conditions. PMID- 26226327 TI - Acute Exacerbations of COPD Are Associated With Increased Expression of Heparan Sulfate and Chondroitin Sulfate in BAL. AB - BACKGROUND: Acute exacerbations of COPD (AECOPDs) are associated with accelerated aggravation of clinical symptoms and deterioration of pulmonary function. The mechanisms by which exacerbations may contribute to airway remodeling and declined lung function are poorly understood. We investigated whether AECOPDs are associated with differential expression of glycosaminoglycans in BAL in a cohort of 97 patients with COPD. METHODS: Patients with COPD with either stable disease (n = 53) or AECOPD (n = 44) and undergoing diagnostic bronchoscopy were matched for demographics and lung function parameters. Levels of heparan sulfate, chondroitin sulfate, dermatan sulfate, and matrix metalloproteinases (MMPs) in BAL were measured by enzyme-linked immunosorbent assay. RESULTS: Heparan sulfate and chondroitin sulfate were significantly increased in BAL of patients during exacerbations. Levels of heparan sulfate were higher in the BAL of patients with microbial infections. Chondroitin sulfate was negatively correlated with FEV1 % predicted but not with diffusing capacity of lung for carbon monoxide % predicted, indicating that chondroitin sulfate is associated with airway remodeling, leading to obstruction rather than to emphysema. Furthermore, heparan sulfate and chondroitin sulfate were significantly correlated with MMP-9, MMP-2, and MMP-12 in BAL, indicating that they were cleaved from their respective proteoglycans by MMPs and subsequently washed out in BAL. CONCLUSIONS: During AECOPD, there is increased expression of heparan sulfate and chondroitin sulfate in BAL. These molecules are significantly correlated with MMPs in BAL, indicating that they may be associated with airway remodeling and may lead to lung function decline during exacerbations of COPD. PMID- 26226328 TI - Central coordination of humanitarian aid in Nepal. PMID- 26226330 TI - Pharmacotherapy in the ageing patient: The impact of age per se (A review). AB - A literature search was carried out to review the influence of 'ageing' on pharmacotherapeutic decision-making, specifically how 'age' is defined and considered in the utilisation of medication. Embase, Medline, International Pharmaceutical Abstracts, and Google scholar were canvassed in a three-tiered search according to pre-established inclusion criteria. In tier 1, a total of 22 studies were identified highlighting the underutilisation of medication in elderly patients, with a particular focus on warfarin. Four studies highlighted an age-bias in medication-prescribing for elderly patients, specifically in relation to medicines for rheumatoid arthritis, angina, and hypertension. Tier 2 identified diverse definitions for 'elderly', including biological age, chronological age, physiological age, as well as various descriptions of 'elderly' in clinical trials and guidelines. Finally, medication optimisation tools were identified through the third tier, emphasising the use of chronological age to describe the 'elderly'. Old age influences pharmacotherapeutic decision-making at various levels, however, what complicates the situation is the absence of a comprehensive definition of 'elderly'. Clinical recommendations need to be based more on objective factors known to affect medication effectiveness and safety. PMID- 26226331 TI - A critical appraisal of vertebral fracture assessment in paediatrics. AB - PURPOSE: There is a need to improve our understanding of the clinical utility of vertebral fracture assessment (VFA) in paediatrics and this requires a thorough evaluation of its readability, reproducibility, and accuracy for identifying VF. METHODS: VFA was performed independently by two observers, in 165 children and adolescents with a median age of 13.4 years (range, 3.6, 18). In 20 of these subjects, VFA was compared to lateral vertebral morphometry assessment on lateral spine X-ray (LVM). RESULTS: 1528 (84%) of the vertebrae were adequately visualised by both observers for VFA. Interobserver agreement in vertebral readability was 94% (kappa, 0.73 [95% CI, 0.68, 0.73]). 93% of the non-readable vertebrae were located between T6 and T9. Interobserver agreement per-vertebra for the presence of VF was 99% (kappa, 0.85 [95% CI, 0.79, 0.91]). Interobserver agreement per-subject was 91% (kappa, 0.78 [95% CI, 0.66, 0.87]). Per-vertebra agreement between LVM and VFA was 95% (kappa 0.79 [95% CI, 0.62, 0.92]) and per subject agreement was 95% (kappa, 0.88 [95% CI, 0.58, 1.0]). Accepting LVM as the gold standard, VFA had a positive predictive value (PPV) of 90% and a negative predictive value (NPV) of 95% in per-vertebra analysis and a PPV of 100% and NPV of 93% in per-subject analysis. CONCLUSION: VFA reaches an excellent level of agreement between observers and a high level of accuracy in identifying VF in a paediatric population. The readability of vertebrae at the mid thoracic region is suboptimal and interpretation at this level should be exercised with caution. PMID- 26226332 TI - Balloon crushing of a protruding everolimus-eluting stent for isolated coronary stenosis at the side branch ostium. PMID- 26226333 TI - Antiplatelet therapy discontinuation and stent thrombosis after sirolimus-eluting stent implantation: five-year outcome of the j-Cypher Registry. AB - BACKGROUND: The influence of antiplatelet therapy discontinuation on the incidence of stent thrombosis, especially very late stent thrombosis, after drug eluting stent implantation has not been yet fully addressed. METHODS: Relationship between antiplatelet therapy discontinuation and stent thrombosis up to 5years was evaluated in 12,812 consecutive patients undergoing sirolimus eluting stents (SES) implantation in the j-Cypher registry. Data on status of antiplatelet therapy during follow-up were collected prospectively. RESULTS: Median follow-up interval was 1699days (interquartile range, 1184-1928days). Incidences of definite stent thrombosis were 0.34% at 30days, 0.55% at 1year, and 1.6% at 5years. Dual antiplatelet therapy was maintained in 97.4%, 63%, and 43.9% of patients at 30days, 1year, and 5years, respectively. The rates of stent thrombosis in patients who discontinued both thienopyridine and aspirin were significantly higher in the time intervals of 31-365days, 2-3years and 3-4years, and tended to be higher in the time intervals of 1-2years and 4-5years than those in patients who continued both (31-365days: 1.26% versus 0.2%, P<0.001; 1-2years: 0.59% versus 0.15%, P=0.06; 2-3years: 1.35% versus 0.2%, P=0.004; 3-4years: 1.09% versus 0.25%, P=0.0496; 4-5years: 1.35% versus 0.43%, P=0.17). Patients who discontinued either thienopyridine or aspirin only did not have an excess of stent thrombosis in any time intervals. CONCLUSIONS: In conclusion, discontinuation of both thienopyridine and aspirin, but not discontinuation of thienopyridine or aspirin only, was associated with an increased incidence of late and very late stent thrombosis up to 5years after SES implantation. PMID- 26226329 TI - ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target. AB - The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium ("KATP") channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The KATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is a result of ABCC9 mutations; we discuss neurologic manifestations of this genetic syndrome. More common brain disorders linked to ABCC9 gene variants include hippocampal sclerosis of aging (HS-Aging), sleep disorders, and depression. HS-Aging is a prevalent neurological disease with pathologic features of both neurodegenerative (aberrant TDP-43) and cerebrovascular (arteriolosclerosis) disease. As to potential therapeutic intervention, the human pharmacopeia features both SUR2 agonists and antagonists, so ABCC9/SUR2 may provide a "druggable target", relevant perhaps to both HS-Aging and Alzheimer's disease. We conclude that more work is required to better understand the roles of ABCC9/SUR2 in the human brain during health and disease conditions. PMID- 26226335 TI - Structure and diversity of ssDNA Microviridae viruses in two peri-alpine lakes (Annecy and Bourget, France). AB - Microviridae is a subset of single-stranded DNA (ssDNA) viruses infecting bacteria. This group of phages has been previously observed to be very abundant (representing >90% of the total known viral metagenomic sequences) in Lake Bourget. However, this observation was made only during one period (in summer) and from a single sample collected at a single depth (near surface). This result suggests the importance of these viruses, poorly examined thus far, especially in fresh waters. In this study, performed on the two largest natural lakes in France (e.g. Lakes Annecy and Bourget), Microviridae structure was determined each month throughout the year (2011) using PCR-DGGE, with primers that target the major capsid-protein-encoding gene VP1; cloning/sequencing was used to investigate their diversity. Our results confirm that Microviridae are diverse in peri-alpine lakes and are mainly represented by gokushoviruses. We also found for the first time ssDNA viruses belonging to Alpavirinae, another subfamily within Microviridae recently proposed by Krupovic and Forterre (2011), generally prophages infecting members of the Phylum Bacteroidetes. Our data also support highly variable community composition and dynamics of individual components whose patterns were different between lakes, suggesting distinct host communities and/or abiotic influences between the two ecosystems. We point out that most of the major observed ssDNA Microviridae viruses display boom-bust patterns (with a sharp increase/decline) in their dynamics, with high relative abundances, suggesting brutal control of hosts and rapid regulation of the host community structure. PMID- 26226334 TI - High hydrostatic pressure increases amino acid requirements in the piezo hyperthermophilic archaeon Thermococcus barophilus. AB - We have established a defined growth medium for the piezophilic hyperthermophilic archaeon Thermococcus barophilus, which allows growth yields of ca. 10(8) cells/ml under both atmospheric and high hydrostatic pressure. Our results demonstrate a major impact of hydrostatic pressure on amino acid metabolism, with increases from 3 amino acids required at atmospheric pressure to 17 at 40 MPa. We observe in T. barophilus and other Thermococcales a similar discrepancy between the presence/absence of amino acid synthesis pathways and amino acid requirements, which supports the existence of alternate, but yet unknown, amino acid synthesis pathways, and may explain the low number of essential amino acids observed in T. barophilus and other Thermococcales. T. barophilus displays a strong metabolic preference for organic polymers such as polypeptides and chitin, which may constitute a more readily available resource of carbon and energy in situ in deep-sea hydrothermal vents. We hypothesize that the low energy yields of fermentation of organic polymers, together with energetic constraints imposed by high hydrostatic pressure, may render de novo synthesis of amino acids ecologically unfavorable. Induction of this metabolic switch to amino acid recycling can explain the requirement for non-essential amino acids by Thermococcales for efficient growth in defined medium. PMID- 26226336 TI - Effects of hydrostatic pressure on yeasts isolated from deep-sea hydrothermal vents. AB - Hydrostatic pressure plays a significant role in the distribution of life in the biosphere. Knowledge of deep-sea piezotolerant and (hyper)piezophilic bacteria and archaea diversity has been well documented, along with their specific adaptations to cope with high hydrostatic pressure (HHP). Recent investigations of deep-sea microbial community compositions have shown unexpected micro eukaryotic communities, mainly dominated by fungi. Molecular methods such as next generation sequencing have been used for SSU rRNA gene sequencing to reveal fungal taxa. Currently, a difficult but fascinating challenge for marine mycologists is to create deep-sea marine fungus culture collections and assess their ability to cope with pressure. Indeed, although there is no universal genetic marker for piezoresistance, physiological analyses provide concrete relevant data for estimating their adaptations and understanding the role of fungal communities in the abyss. The present study investigated morphological and physiological responses of fungi to HHP using a collection of deep-sea yeasts as a model. The aim was to determine whether deep-sea yeasts were able to tolerate different HHP and if they were metabolically active. Here we report an unexpected taxonomic-based dichotomic response to pressure with piezosensitve ascomycetes and piezotolerant basidiomycetes, and distinct morphological switches triggered by pressure for certain strains. PMID- 26226337 TI - 131I-Zn-Chlorophyll derivative photosensitizer for tumor imaging and photodynamic therapy. AB - In recent years, the photodynamic therapy studies have gained considerable attention as an alternative method to surgery, chemotherapy and radiotherapy which is commonly used to fight cancer. In this study, biological potentials of a benzyloxy bearing zinc(II) pheophorbide-a (Zn-PH-A) were investigated via in vivo and in vitro experiments. Zn-PH-A was labeled with (131)I with high efficiency (95.3 +/- 2.7%) and its biodistribution studies were investigated on female Albino Wistar rats. The radiolabeled photosensitizer had been intravenously injected into the tail vein, and then the animals were sacrificed at 30, 60 and 120 min post injection. The percent of radioactivity per gram of organs (%ID/g) was determined. The radiolabeled Zn-PH-A showed high uptake in ovary. In addition, photodynamic therapy studies of the photosensitizer were conducted in EMT6, murine mammary carcinoma and HeLa, human cervix carcinoma cell lines. For the photodynamic therapy studies, the cells with Zn-PH-A were exposed to red light (650 nm) at the doses of 10-30 J/cm(2). The results showed that Zn-PH-A has stronger PDT effect in EMT6 than HeLa cell. Our present work demonstrates (131)I labeled photosensitizer as a bifunctional agent (PDT and nuclear imaging) which could be improved in future by using EMT6 growing tumor in nude mice. PMID- 26226338 TI - Dependence of tablet brittleness on tensile strength and porosity. AB - An analysis of data collected from 25 sets of diverse pharmaceutical powders has identified that an exponential growth function satisfactorily describes the relationship between tablet brittleness and tablet porosity while a power law function well describes the relationship between tablet brittleness and tensile strength. These equations have the potential to facilitate better characterization of tablet mechanical properties and to guide the design and optimization of pharmaceutical tablet products. PMID- 26226339 TI - Fuzzy complexes: Specific binding without complete folding. AB - Specific molecular recognition is assumed to require a well-defined set of contacts and devoid of conformational and interaction ambiguities. Growing experimental evidence demonstrates however, that structural multiplicity or dynamic disorder can be retained in protein complexes, termed as fuzziness. Fuzzy regions establish alternative contacts between specific partners usually via transient interactions. Nature often tailors the dynamic properties of these segments via post-translational modifications or alternative splicing to fine tune affinity. Most experimentally characterized fuzzy complexes are involved in regulation of gene-expression, signal transduction and cell-cycle regulation. Fuzziness is also characteristic to viral protein complexes, cytoskeleton structure, and surprisingly in a few metabolic enzymes. A plausible role of fuzzy complexes in increasing half-life of intrinsically disordered proteins is also discussed. PMID- 26226341 TI - Comparison of Tidal Volumes at the Endotracheal Tube and at the Ventilator. AB - OBJECTIVE: Lung protective ventilation for children with acute respiratory distress syndrome requires accurate assessment of tidal volume. Although modern ventilators compensate for ventilator tubing compliance, tidal volume measured at the ventilator may not be accurate, particularly in small children. Although ventilator-specific proximal flow sensors that measure tidal volume at the endotracheal tube have been developed, there is little information regarding their accuracy. We sought to test the accuracy of ventilator measured tidal volume with and without proximal flow sensors against a calibrated pneumotachometer in children. DESIGN: Prospective, observational. SETTING: Tertiary care PICU. PATIENTS: Fifty-one endotracheally intubated and mechanically ventilated children younger than 18 years. INTERVENTIONS: Tidal volumes were measured at the ventilator, using a ventilator-specific flow sensor, and a calibrated pneumotachometer connected to the SensorMedics 2600A Pediatric Pulmonary Function Cart. MEASUREMENTS AND MAIN RESULTS: In a pressure control mode of ventilation: median tidal volume measured with the pneumotachometer (9.5 mL/kg [interquartile range, 8.2-11.7 mL/kg]) was significantly higher than tidal volume measured either at the ventilator (8.2 mL/kg [7.1-9.6 mL/kg]) or at the proximal flow sensor (8.1 mL/kg [7.2-10.0 mL/kg]) (p < 0.001). In pressure regulated volume control mode of ventilation: median tidal volume measured with the pneumotachometer (10.2 mL/kg [8.8-12.4 mL/kg]) was significantly higher than tidal volume measured either at the ventilator (8.0 mL/kg [7.1-9.7 mL/kg]) or at the proximal flow sensor (8.5 mL/kg [7.3-10.4 mL/kg]) (p < 0.001). These findings were consistent when subgrouped by ventilator type and circuit size. CONCLUSIONS: Tidal volume measured either at the endotracheal tube with a proximal flow sensor or at the ventilator with compensation for tubing compliance are both significantly lower than tidal volume measured with a calibrated pneumotachometer. This underestimation of delivered tidal volume may be particularly important when managing children with acute respiratory distress syndrome. PMID- 26226340 TI - The Inhibitory Core of the Myostatin Prodomain: Its Interaction with Both Type I and II Membrane Receptors, and Potential to Treat Muscle Atrophy. AB - Myostatin, a muscle-specific transforming growth factor-beta (TGF-beta), negatively regulates skeletal muscle mass. The N-terminal prodomain of myostatin noncovalently binds to and suppresses the C-terminal mature domain (ligand) as an inactive circulating complex. However, which region of the myostatin prodomain is required to inhibit the biological activity of myostatin has remained unknown. We identified a 29-amino acid region that inhibited myostatin-induced transcriptional activity by 79% compared with the full-length prodomain. This inhibitory core resides near the N-terminus of the prodomain and includes an alpha-helix that is evolutionarily conserved among other TGF-beta family members, but suppresses activation of myostatin and growth and differentiation factor 11 (GDF11) that share identical membrane receptors. Interestingly, the inhibitory core co-localized and co-immunoprecipitated with not only the ligand, but also its type I and type II membrane receptors. Deletion of the inhibitory core in the full-length prodomain removed all capacity for suppression of myostatin. A synthetic peptide corresponding to the inhibitory core (p29) ameliorates impaired myoblast differentiation induced by myostatin and GDF11, but not activin or TGF beta1. Moreover, intramuscular injection of p29 alleviated muscle atrophy and decreased the absolute force in caveolin 3-deficient limb-girdle muscular dystrophy 1C model mice. The injection suppressed activation of myostatin signaling and restored the decreased numbers of muscle precursor cells caused by caveolin 3 deficiency. Our findings indicate a novel concept for this newly identified inhibitory core of the prodomain of myostatin: that it not only suppresses the ligand, but also prevents two distinct membrane receptors from binding to the ligand. This study provides a strong rationale for the use of p29 in the amelioration of skeletal muscle atrophy in various clinical settings. PMID- 26226342 TI - Corticosteroids in Pediatric Shock: A Call to Arms. AB - OBJECTIVE: To identify the issues needing to be resolved to design, implement, and complete a definitive randomized controlled trial of adjunctive corticosteroid use in children with septic shock. DESIGN: Pediatric studies from MEDLINE (1946 to January 2015) and Embase (1947 to January 2015) that addressed adrenal function or steroid use in critically ill children with systemic inflammatory response syndrome, sepsis, or septic shock were reviewed and their relevant points discussed. RESULTS: There is considerable interest in the field of corticosteroids in pediatric septic shock, which has not as yet translated into a much needed randomized controlled trial. We found that the issues that need to be resolved include identification of the target population, achievement of individual and community equipoise, selection of a patient centered, clinically meaningful primary outcome measure, and consideration of the adverse effects of corticosteroids. CONCLUSIONS: We strongly believe that the time has come to conduct a trial on the use of corticosteroids in pediatric septic shock and that the question to be answered is Will corticosteroids given to children with septic shock result in a benefit to some patients without resulting in harm to others? Answering this question will require a collaborative and committed effort on the parts of ethics boards, families, clinicians, and researchers to actually make it happen once and for all, and we propose an international planning meeting of interested parties to achieve agreement on these identified issues. PMID- 26226343 TI - Illumina MiSeq Phylogenetic Amplicon Sequencing Shows a Large Reduction of an Uncharacterised Succinivibrionaceae and an Increase of the Methanobrevibacter gottschalkii Clade in Feed Restricted Cattle. AB - Periodic feed restriction is used in cattle production to reduce feed costs. When normal feed levels are resumed, cattle catch up to a normal weight by an acceleration of normal growth rate, known as compensatory growth, which is not yet fully understood. Illumina Miseq Phylogenetic marker amplicon sequencing of DNA extracted from rumen contents of 55 bulls showed that restriction of feed (70% concentrate, 30% grass silage) for 125 days, to levels that caused a 60% reduction of growth rate, resulted in a large increase of relative abundance of Methanobrevibacter gottschalkii clade (designated as OTU-M7), and a large reduction of an uncharacterised Succinivibrionaceae species (designated as OTU S3004). There was a strong negative Spearman correlation (rho = -0.72, P = <1x10( 20)) between relative abundances of OTU-3004 and OTU-M7 in the liquid rumen fraction. There was also a significant increase in acetate:propionate ratio (A:P) in feed restricted animals that showed a negative Spearman correlation (rho = 0.69, P = <1x10(-20)) with the relative abundance of OTU-S3004 in the rumen liquid fraction but not the solid fraction, and a strong positive Spearman correlation with OTU-M7 in the rumen liquid (rho = 0.74, P = <1x10(-20)) and solid (rho = 0.69, P = <1x10(-20)) fractions. Reduced A:P ratios in the rumen are associated with increased feed efficiency and reduced production of methane which has a global warming potential (GWP 100 years) of 28. Succinivibrionaceae growth in the rumen was previously suggested to reduce methane emissions as some members of this family utilise hydrogen, which is also utilised by methanogens for methanogenesis, to generate succinate which is converted to propionate. Relative abundance of OTU-S3004 showed a positive Spearman correlation with propionate (rho = 0.41, P = <0.01) but not acetate in the liquid rumen fraction. PMID- 26226344 TI - Circumventing the blood-brain barrier: Local delivery of cyclosporin A stimulates stem cells in stroke-injured rat brain. AB - Drug delivery to the central nervous system is limited by the blood-brain barrier, which can be circumvented by local delivery. In applications of stroke therapy, for example, stimulation of endogenous neural stem/progenitor cells (NSPCs) by cyclosporin A (CsA) is promising. However, current strategies rely on high systemic drug doses to achieve small amounts of CsA in the brain tissue, resulting in systemic toxicity and undesirable global immunosuppression. Herein we describe the efficacy of local CsA delivery to the stroke-injured rat brain using an epi-cortically injected hydrogel composed of hyaluronan and methylcellulose (HAMC). CsA was encapsulated in poly(lactic-co-glycolic acid) microparticles dispersed in HAMC, allowing for its sustained release over 14days in vivo. Tissue penetration was sufficient to provide sustained CsA delivery to the sub-cortical NSPC niche. In comparison to systemic delivery using an osmotic minipump, HAMC achieved higher CsA concentrations in the brain while significantly reducing drug exposure in other organs. HAMC alone was beneficial in the stroke-injured rat brain, significantly reducing the stroke infarct volume relative to untreated stroke-injured controls. The combination of HAMC and local CsA release increased the number of proliferating cells in the lateral ventricles - the NSPC niche in the adult brain. Thus, we demonstrate a superior method of drug delivery to the rat brain that provides dual benefits of tissue protection and endogenous NSPC stimulation after stroke. PMID- 26226345 TI - Potential mechanisms and applications of statins on osteogenesis: Current modalities, conflicts and future directions. AB - Statins are known for their beneficial effects on cardiovascular diseases. Besides the lipid-lowering properties, statins exert their anabolic effects on the bone by differentiating mesenchymal cells to osteoblasts via upregulating BMP 2 and protecting osteoblasts from apoptosis. In addition, statins have been suggested to be anti-osteoclastic by reducing the osteoclast differentiation and activity. Several in vivo and clinical studies have confirmed the beneficial effects of statins in the treatment of osteoporosis and fracture injuries. However, controversial results exist showing statins may have no benefit and in some instances, they may retard bone repair. Different factors such as type, route of administration, dose and dosage of statins, and the injury model seem to be involved for such controversies. In the present study, the most important issues regarding statins have been reviewed to find out how statins may be beneficial and statin therapy can be improved for treating osteoporosis and fracture injuries. The lipophilic statins particularly simvastatin and atorvastatin are the most investigated statins with beneficial results on bone healing and turnover. Most of the in vivo and clinical studies performed systemic route of administration for treating osteoporosis, with much higher clinical doses than the lipid lowering therapy, which increases the statin related side and out of target effects. In contrast, most of the in vivo studies that used statins for fracture repair have applied local delivery methods with much lower doses via tissue engineering approaches. However, local delivery of statins and statin therapy for fracture repair both have low application in the clinical setting and such methods are still under in vivo investigation. Future clinical trials are needed to elucidate how delivery systems and tissue engineering technologies are able to improve the outcome of statin therapy. PMID- 26226346 TI - A microfluidic droplet digital PCR for simultaneous detection of pathogenic Escherichia coli O157 and Listeria monocytogenes. AB - Sensitive and rapid identification of pathogenic bacterial is extremely important due to the serious threat of pathogens to human health. In this study, we demonstrate the simultaneous and sensitive detection of pathogenic Escherichia coli O157 and Listeria monocytogenes using a novel duplex droplet digital PCR (ddPCR) platform. The ddPCR platform, which uses a mineral oil-saturated polydimethylsiloxane (OSP) chip to overcome the problem of droplet evaporation, integrates the functions of droplet generation, on-chip amplification and end point fluorescence readout. Simultaneous detection of two kinds of bacterial is achieved by the design of differentially labeled TaqMan-MGB fluorescent probes. Compared with a quantitative real-time PCR approach, the OSP chip-based duplex ddPCR platform exhibits high sensitivity, which is at the level of single molecule resolution without significant cross-assay interference. Moreover, the applicability of the proposed method is also evaluated in artificially contaminated drinking water sample, which displays a low detection limit down to 10 CFU/mL for both pathogenic bacterial within 2 h. PMID- 26226347 TI - Multiplex detection and genotyping of pathogenic bacteria on paper-based biosensor with a novel universal primer mediated asymmetric PCR. AB - Traditionary multiplex asymmetric polymerase chain reaction (PCR) can be applied to detect multiplex target organisms simultaneously, but complex optimizations of primer concentrations and staggered additions of primers are required to achieve equal amplification of multiplex genes. To overcome this shortcoming, we propose a novel method based on multiplex asymmetric PCR and paper-based nucleic acid diagnostics (PBNAD). In the asymmetric PCR, a universal primer was introduced to break the bottlenecks of low sensitivity and self-inhibition among different sets of primers. Amplification using the novel multiplex asymmetric PCR boosted the quantity of single-stranded amplicons, and the amplified products contained the same sequence at the 5' end. Therefore, only one gold nanoparticle-based signal probe was needed for the simultaneous detection of three genes using the PBNAD platform, and the detection signals could be observed with the naked eye. With this highly efficient, novel multiplex asymmetric PCR, as little as 1 pg/MUL genomic DNA can be detected. This method can also be applied to genotyping for reliable epidemiological investigations. This proof-of-concept study highlights the potential of the PBNAD platform for cost- and labor-effective applications in the detection of pathogenic bacteria. PMID- 26226349 TI - Efficiency of fish propulsion. AB - The system efficiency of a self-propelled flexible body is ill-defined, hence we introduce the concept of quasi-propulsive efficiency, defined as the ratio of the power needed to tow a body in rigid-straight condition over the power it requires for self-propulsion, both measured for the same speed. Through examples we show that the quasi-propulsive efficiency is a rational non-dimensional metric of the propulsive fitness of fish and fish-like mechanisms, consistent with the goal to minimize fuel consumption under size and velocity constraints. We perform two dimensional viscous simulations and apply the concept of quasi-propulsive efficiency to illustrate and discuss the efficiency of two-dimensional undulating foils employing first carangiform and then anguilliform kinematics. We show that low efficiency may be due to adverse body-propulsor hydrodynamic interactions, which cannot be accounted for by an increase in friction drag, as done previously, since at the Reynolds number Re = 5 000 considered in the simulations, pressure is a major contributor to both thrust and drag. PMID- 26226348 TI - HIV-1 RNAs are Not Part of the Argonaute 2 Associated RNA Interference Pathway in Macrophages. AB - BACKGROUND: MiRNAs and other small noncoding RNAs (sncRNAs) are key players in post-transcriptional gene regulation. HIV-1 derived small noncoding RNAs (sncRNAs) have been described in HIV-1 infected cells, but their biological functions still remain to be elucidated. Here, we approached the question whether viral sncRNAs may play a role in the RNA interference (RNAi) pathway or whether viral mRNAs are targeted by cellular miRNAs in human monocyte derived macrophages (MDM). METHODS: The incorporation of viral sncRNAs and/or their target RNAs into RNA-induced silencing complex was investigated using photoactivatable ribonucleoside-induced cross-linking and immunoprecipitation (PAR-CLIP) as well as high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP), which capture Argonaute2-bound miRNAs and their target RNAs. HIV-1 infected monocyte-derived macrophages (MDM) were chosen as target cells, as they have previously been shown to express HIV-1 sncRNAs. In addition, we applied small RNA deep sequencing to study differential cellular miRNA expression in HIV-1 infected versus non-infected MDMs. RESULTS AND CONCLUSION: PAR-CLIP and HITS-CLIP data demonstrated the absence of HIV-1 RNAs in Ago2-RISC, although the presence of a multitude of HIV-1 sncRNAs in HIV-1 infected MDMs was confirmed by small RNA sequencing. Small RNA sequencing revealed that 1.4% of all sncRNAs were of HIV-1 origin. However, neither HIV-1 derived sncRNAs nor putative HIV-1 target sequences incorporated into Ago2-RISC were identified suggesting that HIV-1 sncRNAs are not involved in the canonical RNAi pathway nor is HIV-1 targeted by this pathway in HIV-1 infected macrophages. PMID- 26226350 TI - The separate and combined effects of monoamine oxidase A inhibition and nicotine on the mismatch negativity event related potential. AB - The mismatch negativity (MMN) auditory event-related potential (ERP) has been extensively studied as a potential biomarker for abnormal auditory processing in schizophrenia (SZ), a population which exhibits abnormally high smoking rates. The relationship between nicotinic activation and cognition in SZ may be related to underlying nicotinic and NMDA receptor dysfunction within the disease. However, transient cognitive improvements via smoking in patients may also result from monoamine oxidase (MAO) inhibition, achieved through tobacco smoke. In 24 healthy non-smoking males, we investigated the separate and combined effects of nicotine and MAO-A inhibition via moclobemide (75mg) on the optimal-5 variation of the MMN paradigm. No significant drug effects were observed in our total sample, however, stratification of individuals into low (N=12) and high (N=12) baseline MMN amplitude groups revealed increases in duration MMN amplitude relative to placebo by nicotine, as well as moclobemide, but not after the combination of the two. Because previous research has shown there was no effect of monoamine modulation on MMN, this study shows an unexpected effect of moclobemide on duration MMN. PMID- 26226351 TI - Vicarious Trauma Among Sexual Assault Nurse Examiners. AB - Vicarious trauma (VT), the phenomenon of changes in cognition and worldview that result from empathic response and repeated exposure to narratives of trauma, is a risk for helping professionals. This descriptive, correlational study sought to examine levels of VT among sexual assault nurse examiners (SANEs) as compared with other women's health nurses. It also explored whether levels of VT are different for nurses who have experienced primary trauma alone, VT alone, or both personal trauma and VT. VT was assessed through an anonymous online survey using the nurses' total scores on the Trauma and Attachment Belief Scale. Trauma and Attachment Belief Scale scores were significantly higher for SANEs (M = 178.5, SD = 42.6) than for women's health nurses (M = 168.1, SD = 41.4; p = 0.025), indicating higher levels of trauma-related cognitive disruption in the SANE group. Scores were also significantly higher for both groups with personal trauma histories at the p < 0.05 level compared with the women's health nurses with no personal history. SANEs who had no personal history of trauma did not differ significantly from either group of nurses who did, suggesting that VT from working as an SANE is associated with levels of cognitive disruption similar to oneself having experienced trauma. Nurses should be aware of this phenomenon and its sequelae when choosing to pursue the specialty of sexual assault nursing. Hospitals and other organizations employing SANEs should also be aware of VT and provide a support system with resources in place to mitigate these effects. Future research should further explore effects of primary trauma versus VT, clinical manifestations and significance of varying levels of VT, and interventions and strategies for dealing with VT. PMID- 26226352 TI - Terbinafine hydrochloride loaded liposome film formulation for treatment of onychomycosis: in vitro and in vivo evaluation. AB - Onychomycosis is a fungal infection of nail unit that is caused by dermatophytes. Oral Terbinafine hydrochloride (TBF-HCl) is being used for the treatment of onychomycosis since 24 years. The side effects caused by the systemic application and limitations of topical administration of this drug regarding the diffusion through nail lead to the development of a new formulation based on, TBF-HCl loaded liposome. The newly obtained film formulations were prepared and characterized via several parameters, such as physical appearance, drug content, thickness, bioadhesive properties and tensile strength. In vitro and ex vivo permeation studies were performed to select an optimum film formulation for antifungal activity to show the efficiency of formulations regarding the treatment of onychomycosis. The in vitro release percentages of drug were found 71.6 +/- 3.28, 54.4 +/- 4.26, 56.1 +/- 7.48 and 46.0 +/- 2.43 for liposome loaded pullulan films (LI-P, LII-P) and liposome loaded Eudragit films (LI-E, LII-E), respectively. The accumulated drug in the nail plates were found 31.16 +/- 4.22, 24.81 +/- 5.35, 8.17 +/- 1.81 and 8.92 +/- 3.37 for LI-P, LII-P, LI-E and LII-E, respectively, which within therapeutic range for all film formulations. The accumulated drug in the nail plate was found within therapeutic range for all film formulations. The efficacy of the selected TBF-HCl-loaded liposome film formulation was compared with TBF-HCl-loaded liposome, ethosome, liposome poloxamer gel and ethosome chitosan gel formulations. It was found that TBF-HCl loaded liposome film formulation had better antifungal activity on fungal nails which make this liposome film formulation promising for ungual therapy of fungal nail infection. PMID- 26226353 TI - The genetics of the skin barrier in eczema and other allergic disorders. AB - PURPOSE OF REVIEW: We summarize current knowledge on the genetic determinants of skin barrier deficiency in relation to eczema and disease progression to other allergic manifestations. RECENT FINDINGS: There is increasing evidence that impairment of epidermal barrier function is not only a risk factor for the development of eczema but also for disease progression to allergic airway disease and food allergy. Support comes from recent association studies linking genetic variants in epidermal genes with eczema and food allergy, from monogenic diseases with severe skin barrier defects which display multiple allergic manifestations, and from mouse models providing a mechanism from skin inflammation to allergic reactions in the lung and intestine. SUMMARY: The key role of the skin barrier defect in the development of eczema and eczema-associated allergic diseases may have important implications for prevention and treatment strategies. Initial clinical trials with moisturizing creams revealed promising results for the prevention of eczema in early infancy. Their long-term effects will be critical to demonstrate the potential benefit of barrier repair therapy in allergic disease prevention. PMID- 26226354 TI - Difficult-to-control asthma: epidemiology and its link with environmental factors. AB - PURPOSE OF REVIEW: The aim of the present review was to discuss the epidemiology of inadequate asthma control with an examination of contributing environmental factors. RECENT FINDINGS: Despite advances in asthma therapies, a proportion of patients with asthma continue to have difficulty in gaining adequate asthma control. Asthma severity and control in childhood are of particular importance as they translate to asthma morbidity in adulthood. Children with comorbid severe allergic rhinitis were more likely to have uncontrolled asthma. Recent data suggest that mouse allergen, more so than cockroach allergen, may be the most relevant urban allergen exposure. Tobacco smoke exposure, even passive exposure, leads to increased asthma symptoms and decreased response to inhaled corticosteroids. Efforts to ban smoking in public places have resulted in promising asthma results for entire populations. Energy-saving efforts to tighten a home's air leaks can lead to increased indoor pollutant levels and, therefore, must be accompanied by efforts to reduce, filter, or exchange indoor pollutants. Obesity is independently associated with decreased asthma control. Furthermore, the detrimental effects of pollutant exposure are enhanced in an overweight individual with asthma. SUMMARY: Lack of asthma control can be because of a complex web of factors including adherence, intrinsic factors, and environmental exposures. Further research into intervention strategies is needed to achieve improved rates of asthma control. PMID- 26226355 TI - Biomarkers for atopic dermatitis: a systematic review and meta-analysis. AB - PURPOSE OF REVIEW: A large number of studies investigating the correlation between severity of atopic dermatitis and various biomarkers have been published over the past decades. The aim of this review was to identify, evaluate and synthesize the evidence examining the correlation of biomarkers with disease severity in atopic dermatitis patients, something that has not been performed previously. RECENT FINDINGS: Three electronic databases were systematically searched and relevant studies were selected for inclusion. A total of 222 articles, reporting on 115 different biomarkers in 30 063 patients, were critically appraised. Studies were divided into two main groups. The first group consisted of longitudinal randomized controlled trials and cohort studies, which reported measurements at multiple time points. The second contained cross sectional studies that reported only one measurement per patient. Out of 222 articles, 108 articles reported sufficient data for meta-analysis. Only four biomarkers were eligible for meta-analysis in the longitudinal group, and nine in the cross-sectional group. SUMMARY: Serum thymus and activation-regulated chemokine (TARC) was found to be the most reliable biomarker studied, showing pooled correlation coefficients of 0.60 (95% CI 0.48-0.70) and 0.64 (95% CI 0.57 0.70) in longitudinal and cross-sectional studies, respectively. Additional biomarkers that could prove useful but require additional research include serum cutaneous T-cell attracting chemokine (CTACK), sE-selectin, macrophage-derived chemokine (MDC), lactate dehydrogenase (LDH) and interleukin (IL)-18. PMID- 26226356 TI - miRWalk2.0: a comprehensive atlas of microRNA-target interactions. PMID- 26226357 TI - Comparative visualization of genotype-phenotype relationships. PMID- 26226358 TI - Clarifying the terminology that describes scientific reproducibility. PMID- 26226359 TI - Human phenotyping on a population scale. PMID- 26226360 TI - Single in the (Cell) City: a protein-folding story. PMID- 26226362 TI - Patient Survey on Satisfaction and Impact of 123I-Ioflupane Dopamine Transporter Imaging. AB - Patients were surveyed to assess the impact of dopamine transporter imaging on diagnostic confidence, change in treatment plan, effect on medication compliance, and subjective well-being. Surveys were sent to 140 patients who completed dopamine transporter imaging an average of 18 months prior. Sixty-five surveys from patients (46%) were returned. Questions assessed patients' perceived impact of the imaging on their care. Increased diagnostic confidence following imaging was reported by 69% of patients. Changes to treatment plan from imaging were reported by 24% of patients. Overall satisfaction with the study and its impact was reported by 70% of patients. Dopamine transporter imaging increased diagnostic confidence among patients and overall patient satisfaction with the impact of imaging on clinical care was high. PMID- 26226363 TI - Effect of Ecological Restoration on Body Condition of a Predator. AB - Ecological restoration attempts to recover the structure and function of ecosystems that have been degraded by human activities. A crucial test of ecosystem recovery would be to determine whether individuals in restored environments are as healthy as those in conserved environments. However, the impact of restoration on physiology of terrestrial animals has never been tested. Here, we evaluated the effect of two restoration methods on body condition measured as body size, body mass, lipid and muscle content of the spider Nephila clavipes in a tropical dry forest that has suffered chronic disturbance due to cattle grazing. We used experimental plots that had been excluded from disturbance by cattle grazing during eight years. Plots were either planted with native trees (i. e. maximal intervention), or only excluded from disturbance (i. e. minimal intervention), and were compared with control conserved (remnants of original forest) and disturbed plots (where cattle is allowed to graze). We predicted (1) better body condition in spiders of conserved and restored sites, compared to disturbed sites, and (2) better body condition in plots with maximal intervention than in plots with minimal intervention. The first prediction was not supported in males or females, and the second prediction was only supported in females: body dry mass was higher in planted than in conserved plots for spiders of both sexes and also higher that in disturbed plots for males, suggesting that plantings are providing more resources. We discuss how different life histories and environmental pressures, such as food availability, parasitism, and competition for resources can explain our contrasting findings in male and female spiders. By studying animal physiology in restoration experiments it is possible to understand the mechanistic basis of ecological and evolutionary processes that determine success of ecological restoration. PMID- 26226364 TI - Periodontal Diseases: Bug Induced, Host Promoted. PMID- 26226365 TI - Evidence of Positive Selection of Aquaporins Genes from Pontoporia blainvillei during the Evolutionary Process of Cetaceans. AB - BACKGROUND: Marine mammals are well adapted to their hyperosmotic environment. Several morphological and physiological adaptations for water conservation and salt excretion are known to be present in cetaceans, being responsible for regulating salt balance. However, most previous studies have focused on the unique renal physiology of marine mammals, but the molecular bases of these mechanisms remain poorly explored. Many genes have been identified to be involved in osmotic regulation, including the aquaporins. Considering that aquaporin genes were potentially subject to strong selective pressure, the aim of this study was to analyze the molecular evolution of seven aquaporin genes (AQP1, AQP2, AQP3, AQP4, AQP6, AQP7, and AQP9) comparing the lineages of cetaceans and terrestrial mammals. RESULTS: Our results demonstrated strong positive selection in cetacean specific lineages acting only in the gene for AQP2 (amino acids 23, 83, 107,179, 180, 181, 182), whereas no selection was observed in terrestrial mammalian lineages. We also analyzed the changes in the 3D structure of the aquaporin 2 protein. Signs of strong positive selection in AQP2 sites 179, 180, 181, and 182 were unexpectedly identified only in the baiji lineage, which was the only river dolphin examined in this study. Positive selection in aquaporins AQP1 (45), AQP4 (74), AQP7 (342, 343, 356) was detected in cetaceans and artiodactyls, suggesting that these events are not related to maintaining water and electrolyte homeostasis in seawater. CONCLUSIONS: Our results suggest that the AQP2 gene might reflect different selective pressures in maintaining water balance in cetaceans, contributing to the passage from the terrestrial environment to the aquatic. Further studies are necessary, especially those including other freshwater dolphins, who exhibit osmoregulatory mechanisms different from those of marine cetaceans for the same essential task of maintaining serum electrolyte balance. PMID- 26226374 TI - Erratum: Unraveling novel TF-miRNA regulatory crosstalk in metastasis of Soft Tissue Sarcoma. PMID- 26226373 TI - Preparation of Inactivated Human Skin Using High Hydrostatic Pressurization for Full-Thickness Skin Reconstruction. AB - We have reported that high-hydrostatic-pressure (HHP) technology is safe and useful for producing various kinds of decellularized tissue. However, the preparation of decellularized or inactivated skin using HHP has not been reported. The objective of this study was thus to prepare inactivated skin from human skin using HHP, and to explore the appropriate conditions of pressurization to inactivate skin that can be used for skin reconstruction. Human skin samples of 8 mm in diameter were packed in bags filled with normal saline solution (NSS) or distilled water (DW), and then pressurized at 0, 100, 150, 200 and 1000 MPa for 10 minutes. The viability of skin after HHP was evaluated using WST-8 assay. Outgrowth cells from pressurized skin and the viability of pressurized skin after cultivation for 14 days were also evaluated. The pressurized skin was subjected to histological evaluation using hematoxylin and eosin staining, scanning electron microscopy (SEM), immunohistochemical staining of type IV collagen for the basement membrane of epidermis and capillaries, and immunohistochemical staining of von Willebrand factor (vWF) for capillaries. Then, human cultured epidermis (CE) was applied on the pressurized skin and implanted into the subcutis of nude mice; specimens were subsequently obtained 14 days after implantation. Skin samples pressurized at more than 200 MPa were inactivated in both NSS and DW. The basement membrane and capillaries remained intact in all groups according to histological and immunohistological evaluations, and collagen fibers showed no apparent damage by SEM. CE took on skin pressurized at 150 and 200 MPa after implantation, whereas it did not take on skin pressurized at 1000 MPa. These results indicate that human skin could be inactivated after pressurization at more than 200 MPa, but skin pressurized at 1000 MPa had some damage to the dermis that prevented the taking of CE. Therefore, pressurization at 200 MPa is optimal for preparing inactivated skin that can be used for skin reconstruction. PMID- 26226375 TI - Morphologically Cryptic Amphipod Species Are "Ecological Clones" at Regional but Not at Local Scale: A Case Study of Four Niphargus Species. AB - Recent studies indicate that morphologically cryptic species may be ecologically more different than would be predicted from their morphological similarity and phylogenetic relatedness. However, in biodiversity research it often remains unclear whether cryptic species should be treated as ecologically equivalent, or whether detected differences have ecological significance. In this study, we assessed the ecological equivalence of four morphologically cryptic species of the amphipod genus Niphargus. All species live in a small, isolated area on the Istrian Peninsula in the NW Balkans. The distributional ranges of the species are partially overlapping and all species are living in springs. We reconstructed their ecological niches using morphological traits related to feeding, bioclimatic niche envelope and species' preference for epi-hypogean habitats. The ecological meaning of differences in niches was evaluated using distributional data and co-occurrence frequencies. We show that the species comprise two pairs of sister species. All species differ from each other and the degree of differentiation is not related to phylogenetic relatedness. Moreover, low co occurrence frequencies in sympatric zones imply present or past interspecific competition. This pattern suggests that species are not differentiated enough to reduce interspecific competition, nor ecologically equivalent to co-exist via neutral dynamics. We tentatively conclude that the question of ecological equivalence relates to the scale of the study: at a fine scale, species' differences may influence dynamics in a local community, whereas at the regional level these species likely play roughly similar ecological roles. PMID- 26226376 TI - Fish Oil Enhances T Cell Function and Tumor Infiltration and Is Correlated With a Cancer Prevention Effect in HER-2/neu But Not PyMT Transgenic Mice. AB - Few studies have explored the effects of omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation on immune modulation in murine models of mammary carcinogenesis. HER-2/neu and PyMT mice were randomized to 2 dietary interventions: AIN-93G-based diet with 1) 11% of diet (per gram weight) as corn oil (CO) or 2) 10% of diet as menhaden fish oil plus 1% of diet as corn oil (FO). FO significantly reduced the incidence and multiplicity of tumors (P < 0.001) in HER-2/neu, but not PyMT mice. FO-fed mice had significantly larger splenocyte counts than CO-fed mice in both the HER-2/neu and PyMT models; and in both models this was comprised of an increase in most cell types, including Gr-1(+)/CD11b(+) cells. T cells from FO-fed HER-2/neu mice produced significantly more interleukin 2 (P = 0.004) and interferon-gamma (P = 0.012) in response to in vitro stimulation with anti-CD3 (0.5 ug/ml). Lastly, FO-fed HER-2/neu mice had significantly more tumor immune infiltrates than CO-fed mice, including NK1.1(+), F4/80(+), and Gr-1(+)/CD11b(+) cells (P <= 0.05). Greater Th1 cytokine production and significantly more tumor immune infiltrates in FO-fed Her2/neu mice may account for the cancer prevention effect of fish oil in this model. PMID- 26226378 TI - Treatment response profiles: An extension of the double dissociation concept in neuropsychological research. AB - The presence of double dissociations in patients with neurological damage has long been used as evidence that the dissociated functions cannot be explained in terms of a common system or module. Shallice (1988) has suggested that a second procedure, the double critical variable method, can provide evidence for a similar conclusion. In this paper we examine the situation where double dissocations are not naturally present, suggesting that the two phenomena are merely aspects of the same underlying condition. We propose that the logic of the double critical variable method can be applied in this situation, whenever responses to treatment vary in a particular manner across syndromes and patients. This logic was previously used by Beschin, Cocchini, Allen, and Della Sala (2012) to show a dissociation between anosognosia and neglect in stroke patients; we suggest that it might have a more general application. As an aid in understanding the concept we also introduce the performance/performance curve; this builds on the existing idea of performance/resource curves to draw a single graph from two such curves, whose points may be derived from direct observation. It enables the empirical testing of hypotheses about the functional form of unobservable performance/resource relationships, and may be of use beyond the existing application to treatment response profiles. PMID- 26226377 TI - Dramatic Enhancement in Photoresponse of beta-In2S3 through Suppression of Dark Conductivity by Synthetic Control of Defect-Induced Carrier Compensation. AB - We report on the synthesis of dense and faceted indium sulfide (beta-In2S3) nano octahedron films on fluorine-doped tin oxide-coated glass by the hydrothermal method and their photoresponse properties in a flip chip device configuration. We have examined the temporal evolution of the phase constitution, morphology, and optoelectronic properties for films obtained after growth interruption at specific intervals. It is noted that, initially, an In(OH)3 film forms, which is gradually transformed to the beta-In2S3 phase over time. In the case of the film wherein most, but not all, of In(OH)3 is consumed, an exceptionally large photoresponse (light to dark current ratio) of ~10(4) and response time(s) (rise/fall) of ~88/280 ms are realized. This superior performance is attributed to nearly complete carrier compensation achievable in the system under high pressure growth leading to dramatic reduction of dark conductivity. It is argued that the temporally growth-controlled equilibrium between quasi-In interstitials and cation vacancies dictates the optoelectronic properties. PMID- 26226379 TI - Scaffold Diversity Inspired by the Natural Product Evodiamine: Discovery of Highly Potent and Multitargeting Antitumor Agents. AB - A critical question in natural product-based drug discovery is how to translate the product into drug-like molecules with optimal pharmacological properties. The generation of natural product-inspired scaffold diversity is an effective but challenging strategy to investigate the broader chemical space and identify promising drug leads. Extending our efforts to the natural product evodiamine, a diverse library containing 11 evodiamine-inspired novel scaffolds and their derivatives were designed and synthesized. Most of them showed good to excellent antitumor activity against various human cancer cell lines. In particular, 3 chloro-10-hydroxyl thio-evodiamine (66c) showed excellent in vitro and in vivo antitumor efficacy with good tolerability and low toxicity. Antitumor mechanism and target profiling studies indicate that compound 66c is the first-in-class triple topoisomerase I/topoisomerase II/tubulin inhibitor. Overall, this study provided an effective strategy for natural product-based drug discovery. PMID- 26226380 TI - Mesoporous materials modified by aptamers and hydrophobic groups assist ultra sensitive insulin detection in serum. AB - A novel mesoporous material modified with both insulin-binding-aptamers and hydrophobic methyl groups is synthesized. With rationally designed pore structures and surface chemistry, this material is applied in sample pre treatment for ELISA, and enables the quantification (0.25-5 pg ml(-1)) of insulin in serum, 30-fold enhancement of the limit-of-detection compared to the commercial ELISA kit. PMID- 26226381 TI - Emergence of Leadership within a Homogeneous Group. AB - Large scale coordination without dominant, consistent leadership is frequent in nature. How individuals emerge from within the group as leaders, however transitory this position may be, has become an increasingly common question asked. This question is further complicated by the fact that in many of these aggregations, differences between individuals are minor and the group is largely considered to be homogeneous. In the simulations presented here, we investigate the emergence of leadership in the extreme situation in which all individuals are initially identical. Using a mathematical model developed using observations of natural systems, we show that the addition of a simple concept of leadership tendencies which is inspired by observations of natural systems and is affected by experience can produce distinct leaders and followers using a nonlinear feedback loop. Most importantly, our results show that small differences in experience can promote the rapid emergence of stable roles for leaders and followers. Our findings have implications for our understanding of adaptive behaviors in initially homogeneous groups, the role experience can play in shaping leadership tendencies, and the use of self-assessment in adapting behavior and, ultimately, self-role-assignment. PMID- 26226382 TI - Distribution of nontuberculous mycobacteria in treated patients with pulmonary disease in Greece - relation to microbiological data. AB - AIMS: The aim was to assess the distribution of nontuberculous mycobacteria (NTM) in treated patients with pulmonary disease (PD) in Greece. PATIENTS & METHODS: Patients treated for NTM PD at the two largest chest diseases hospitals in Greece, in the period 1990-2013 were investigated. For the years 2005-2013 data on NTM isolation frequency were recorded. RESULTS: M. avium complex (MAC) was the predominant cause of NTM PD disease followed by M. kansasii and rapid growing mycobacteria (RGM). The pathogenicity of RGM was significantly lower than this of MAC and M. kansasii. An increase was observed in the percentage of isolated NTM species that were considered clinically significant over the study period. CONCLUSIONS: The increasing number of NTM PD in Greece is a consequence of their isolation being more frequently considered as clinically relevant. PMID- 26226383 TI - On-the-Fly Integration of Data from a Spin-Diffusion-Based NMR Experiment into Protein-Ligand Docking. AB - INPHARMA (interligand nuclear Overhauser enhancement for pharmacophore mapping) determines the relative orientation of two competitive ligands in the protein binding pocket. It is based on the observation of interligand transferred NOEs mediated by spin diffusion through protons of the protein and is, therefore, sensitive to the specific interactions of each of the two ligands with the protein. We show how this information can be directly included into a protein ligand docking program to guide the prediction of the complex structures. Agreement between the experimental and back-calculated spectra based on the full relaxation matrix approach is translated into a score contribution that is combined with the scoring function ChemPLP of our docking tool PLANTS. This combined score is then used to predict the poses of five weakly bound cAMP dependent protein kinase (PKA) ligands. After optimizing the setup, which finally also included trNOE data and optimized protonation states, very good success rates were obtained for all combinations of three ligands. For one additional ligand, no conclusive results could be obtained due to the ambiguous electron density of the ligand in the X-ray structure, which does not disprove alternative ligand poses. The failures of the remaining ligand are caused by suboptimal locations of specific protein side chains. Therefore, side-chain flexibility should be included in an improved INPHARMA-PLANTS version. This will reduce the strong dependence on the used protein input structure leading to improved scores overall, not only for this last ligand. PMID- 26226384 TI - Medicare Approves Coverage for Lung Cancer Screening: The Case for Symptomatic Screening. PMID- 26226386 TI - In Situ Synthesis of Carbon Nanotube Hybrids with Alternate MoC and MoS2 to Enhance the Electrochemical Activities of MoS2. AB - Molybdenum disulfides and carbides are effective catalysts for hydrogenation and hydridesulfurization, where MoS2 nanostructures are also highly promising materials for lithium ion batteries. High surface-to-volume ratio and strong interactions with conducting networks are crucial factors for their activities. A new hybrid structure of multiwalled carbon nanotube (MWCNT) with alternate MoC nanoparticles and MoS2 nanosheets (MoS2 + MoC-MWCNT) has been synthesized by controlled carburization of core-shell MoS2-MWCNT hybrid nanotubes and demonstrated by HRTEM, FFT, XRD, and Raman scattering. The MoS2 nanosheets (~10 nm) remain tightly connected to MWCNT surfaces with {001} planes in parallel to MWCNT walls and the highly crystallized alpha-MoC particles (~10 nm) are adhered to MWCNTs at angles of 60-80 degrees between {111} planes and MWCNT walls. The electrochemical performances of the hybrid structures have been demonstrated as anodes for lithium ion batteries to be significantly increased by breaking MoS2 nanotubes into nanosheets (patches) on MWCNT surfaces, especially at high current rates. The specific capacities of MoS2 + MoC-MWCNT sample with ~23% MoS2 have been demonstrated to be higher than those of MoS2-MWCNTs containing ~70% MoS2. PMID- 26226385 TI - Removal of Protein Capping Enhances the Antibacterial Efficiency of Biosynthesized Silver Nanoparticles. AB - The present study demonstrates an economical and environmental affable approach for the synthesis of "protein-capped" silver nanoparticles in aqueous solvent system. A variety of standard techniques viz. UV-visible spectroscopy, transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS) and X-ray diffraction (XRD) measurements were employed to characterize the shape, size and composition of nanoparticles. The synthesized nanoparticles were found to be homogenous, spherical, mono-dispersed and covered with multi-layered protein shell. In order to prepare bare silver nanoparticles, the protein shell was removed from biogenic nanoparticles as confirmed by UV-visible spectroscopy, FTIR and photoluminescence analysis. Subsequently, the antibacterial efficacy of protein-capped and bare silver nanoparticles was compared by bacterial growth rate and minimum inhibitory concentration assay. The results revealed that bare nanoparticles were more effective as compared to the protein-capped silver nanoparticles with varying antibacterial potential against the tested Gram positive and negative bacterial species. Mechanistic studies based on ROS generation and membrane damage suggested that protein-capped and bare silver nanoparticles demonstrate distinct mode of action. These findings were strengthened by the TEM imaging along with silver ion release measurements using inductively coupled plasma atomic emission spectroscopy (ICP-AES). In conclusion, our results illustrate that presence of protein shell on silver nanoparticles can decrease their bactericidal effects. These findings open new avenues for surface modifications of nanoparticles to modulate and enhance their functional properties. PMID- 26226387 TI - Correction. PMID- 26226388 TI - Predictive Calculation of the Crystallization Tendency of Model Pharmaceuticals in the Supercooled State from Molecular Dynamics Simulations. AB - Molecular dynamics (MD) simulations were used to perform a comparative study of the crystallization tendency from the melt of two model pharmaceutical compounds: felodipine and nifedipine. Two crystalline polymorphs of nifedipine (N(alpha), N(beta)) and felodipine (FI, FII) have been studied. Calculations were performed on liquid and crystal systems separately in order to determine their main physical properties (diffusivity, density, and enthalpy). A fair agreement was found between the simulation and the known experimental data confirming the ability of the force field GAFF to reproduce accurately the experimental data for both compounds. Simulations of the crystal-liquid interface enabled the determination of the melting temperature and the interfacial free energy of the different polymorphs. Guided by the classical nucleation theory (CNT) predictions and different growth mechanism models (normal, two-dimensional, and screw dislocation), the nucleation and growth rates have been determined. The present investigation particularly raises the very important role of the solid-liquid interfacial free energy and its interplay with the driving force during the crystallization. The origin of the higher crystallization tendency of nifedipine with respect to felodipine is discussed from the present computed kinetic and thermodynamical factors. PMID- 26226389 TI - Outcomes of an algorithmic approach to treating mild ocular alkali burns. PMID- 26226390 TI - Intramolecular Proton Transfer Boosts Water Oxidation Catalyzed by a Ru Complex. AB - We introduce a new family of complexes with the general formula [Ru(n)(tda)(py)2](m+) (n = 2, m = 0, 1; n = 3, m = 1, 2(+); n = 4, m = 2, 3(2+)), with tda(2-) being [2,2':6',2"-terpyridine]-6,6"-dicarboxylate, including complex [Ru(IV)(OH)(tda-kappa-N(3)O)(py)2](+), 4H(+), which we find to be an impressive water oxidation catalyst, formed by hydroxo coordination to 3(2+) under basic conditions. The complexes are synthesized, isolated, and thoroughly characterized by analytical, spectroscopic (UV-vis, nuclear magnetic resonance, electron paramagnetic resonance), computational, and electrochemical techniques (cyclic voltammetry, differential pulse voltammetry, coulometry), including solid-state monocrystal X-ray diffraction analysis. In oxidation state IV, the Ru center is seven-coordinated and diamagnetic, whereas in oxidation state II, the complex has an unbonded dangling carboxylate and is six-coordinated while still diamagnetic. With oxidation state III, the coordination number is halfway between the coordination of oxidation states II and IV. Species generated in situ have also been characterized by spectroscopic, computational, and electrochemical techniques, together with the related species derived from a different degree of protonation and oxidation states. 4H(+) can be generated potentiometrically, or voltammetrically, from 3(2+), and both coexist in solution. While complex 3(2+) is not catalytically active, the catalytic performance of complex 4H(+) is characterized by the foot of the wave analysis, giving an impressive turnover frequency record of 8000 s(-1) at pH 7.0 and 50 000 s(-1) at pH 10.0. Density functional theory calculations provide a complete description of the water oxidation catalytic cycle of 4H(+), manifesting the key functional role of the dangling carboxylate in lowering the activation free energies that lead to O-O bond formation. PMID- 26226391 TI - Copper-Mediated Oxidative Coupling of Benzamides with Maleimides via Directed C-H Cleavage. AB - A Cu(OAc)2/Cy2NMe-mediated oxidative direct coupling of benzamides with maleimides has been developed. The aromatic C-H alkenylation with the aid of an 8 aminoquinoline-based bidentate directing group is followed by an intramolecular aza-Michael-type addition to form the isoindolone-incorporated spirosuccinimides, which are of potent interest in medicinal chemistry. PMID- 26226392 TI - Identification of Subtype-Specific Prognostic Genes for Early-Stage Lung Adenocarcinoma and Squamous Cell Carcinoma Patients Using an Embedded Feature Selection Algorithm. AB - The existence of fundamental differences between lung adenocarcinoma (AC) and squamous cell carcinoma (SCC) in their underlying mechanisms motivated us to postulate that specific genes might exist relevant to prognosis of each histology subtype. To test on this research hypothesis, we previously proposed a simple Cox regression model based feature selection algorithm and identified successfully some subtype-specific prognostic genes when applying this method to real-world data. In this article, we continue our effort on identification of subtype specific prognostic genes for AC and SCC, and propose a novel embedded feature selection method by extending Threshold Gradient Descent Regularization (TGDR) algorithm and minimizing on a corresponding negative partial likelihood function. Using real-world datasets and simulated ones, we show these two proposed methods have comparable performance whereas the new proposal is superior in terms of model parsimony. Our analysis provides some evidence on the existence of such subtype-specific prognostic genes, more investigation is warranted. PMID- 26226393 TI - Same-Sex Adoption as a Welfare Alternative? Conservatism, Neoliberal Values, and Support for Adoption by Same-Sex Couples. AB - Despite conservatives' long-term opposition to gay and lesbian parenting, scholars theorize that a strong commitment to neoliberalism may influence conservative Americans to become more tolerant of same-sex adoption as a way to relieve the government from subsidizing poor families. Drawing on national survey data (2010 Baylor Religion Survey), we test whether holding neoliberal values is associated with greater support for same-sex adoption in general and across political or religious conservatives. We find no support for either theory emphatically the opposite, in fact. Neoliberal values are negatively associated with support for same-sex adoption for Americans in general and among political and religious conservatives. We find little evidence of a tension among conservatives regarding same-sex adoption as both their neoliberal values and moral beliefs incline them to oppose same-sex adoption along with other same-sex family relationships. PMID- 26226394 TI - Correction to Integer versus Fractional Charge Transfer at Metal(/Insulator)/Organic Interfaces: Cu(/NaCl)/TCNE. PMID- 26226395 TI - Sustained Magnetic Responses in Temporal Cortex Reflect Instantaneous Significance of Approaching and Receding Sounds. AB - Rising sound intensity often signals an approaching sound source and can serve as a powerful warning cue, eliciting phasic attention, perception biases and emotional responses. How the evaluation of approaching sounds unfolds over time remains elusive. Here, we capitalised on the temporal resolution of magnetoencephalograpy (MEG) to investigate in humans a dynamic encoding of perceiving approaching and receding sounds. We compared magnetic responses to intensity envelopes of complex sounds to those of white noise sounds, in which intensity change is not perceived as approaching. Sustained magnetic fields over temporal sensors tracked intensity change in complex sounds in an approximately linear fashion, an effect not seen for intensity change in white noise sounds, or for overall intensity. Hence, these fields are likely to track approach/recession, but not the apparent (instantaneous) distance of the sound source, or its intensity as such. As a likely source of this activity, the bilateral inferior temporal gyrus and right temporo-parietal junction emerged. Our results indicate that discrete temporal cortical areas parametrically encode behavioural significance in moving sound sources where the signal unfolded in a manner reminiscent of evidence accumulation. This may help an understanding of how acoustic percepts are evaluated as behaviourally relevant, where our results highlight a crucial role of cortical areas. PMID- 26226396 TI - Evaluating the image quality of cone beam CT acquired during rotational delivery. AB - OBJECTIVE: The aim of this work was to evaluate the quality of kilovoltage (kV) cone beam CT (CBCT) images acquired during arc delivery. METHODS: Arc plans were delivered on a Catphan((r)) 600 phantom (The Phantom Laboratory Inc., Salem, NY), and kV CBCT images were acquired during the treatment. The megavoltage (MV) scatter effect on kV CBCT image quality was evaluated using parameters such as Hounsfield unit (HU) accuracy, spatial resolution, contrast-to-noise ratio (CNR) and spatial non-uniformity (SNU). These CBCT images were compared with reference scans acquired with the same acquisition parameters without MV "beam on". This evaluation was carried out for different photon beams (6 and 15 MV), arc types (half vs full arc), static field sizes (10 * 10 and 25 * 25 cm(2)) and source-to imager distances (SID) (150 and 170 cm). RESULTS AND CONCLUSION: HU accuracy, CNR and SNU were considerably affected by MV scatter, and this effect was increased with increasing field size and decreasing photon energy, whereas the spatial resolution was almost unchanged. The MV scatter effect was observed to be more for full-rotation arc delivery than for half-arc delivery. In addition, increasing the SID resulted in decreased MV scatter effect and improved the image quality. ADVANCES IN KNOWLEDGE: Nowadays, volumetric modulated arc therapy (VMAT) is increasingly used in clinics, and this arc therapy enables us to acquire CBCT imaging simultaneously. But, the main issue of concurrent imaging is the "MV scatter" effect on CBCT imaging. This study aims to experimentally quantify the effect of MV scatter on CBCT image quality. PMID- 26226397 TI - Optically heated ultra-fast-cycling gas chromatography module for separation of direct sampling and online monitoring applications. AB - This work describes an ultrafast-cycling gas chromatography module (fast-GC module) for direct-sampling gas chromatography/mass spectrometry (GC-MS). The sample can be introduced into the fast-GC module using a common GC injector or any GC * GC modulator. The new fast-GC module offers the possibility to conduct a complete temperature cycle within 30 s. Its thermal mass is minimized by using a specially developed home-built fused silica capillary column stack and a halogen lamp for heat generation, both placed inside a gold-coated quartz glass cylinder. A high airflow blower enables rapid cooling. The new device is highly flexible concerning the used separation column, the applied temperature program, and the integration into existing systems. An application of the fast-GC module is shown in this work by thermal analysis coupled to gas chromatography-mass spectrometry (TA-GC-MS). The continuously evolving gases of the TA are modulated by a liquid CO2 modulator. Because of the rapid cycling of the fast-GC module, it is possible to obtain the best separation while maintaining the online character of the TA. Restrictions in separation and retention time shifting, known from isothermal and normal ramped fast-GC systems, are overcome. PMID- 26226398 TI - Reactivity of Uranium and Ferrous Iron with Natural Iron Oxyhydroxides. AB - Determining key reaction pathways involving uranium and iron oxyhydroxides under oxic and anoxic conditions is essential for understanding uranium mobility as well as other iron oxyhydroxide mediated processes, particularly near redox boundaries where redox conditions change rapidly in time and space. Here we examine the reactivity of a ferrihydrite-rich sediment from a surface seep adjacent to a redox boundary at the Rifle, Colorado field site. Iron(II)-sediment incubation experiments indicate that the natural ferrihydrite fraction of the sediment is not susceptible to reductive transformation under conditions that trigger significant mineralogical transformations of synthetic ferrihydrite. No measurable Fe(II)-promoted transformation was observed when the Rifle sediment was exposed to 30 mM Fe(II) for up to 2 weeks. Incubation of the Rifle sediment with 3 mM Fe(II) and 0.2 mM U(VI) for 15 days shows no measurable incorporation of U(VI) into the mineral structure or reduction of U(VI) to U(IV). Results indicate a significantly decreased reactivity of naturally occurring Fe oxyhydroxides as compared to synthetic minerals, likely due to the association of impurities (e.g., Si, organic matter), with implications for the mobility and bioavailability of uranium and other associated species in field environments. PMID- 26226400 TI - Correction: Regulation of Active DNA Demethylation by a Methyl-CpG-Binding Domain Protein in Arabidopsis thaliana. PMID- 26226399 TI - Regulatory B Cell Function Is Suppressed by Smoking and Obesity in H. pylori Infected Subjects and Is Correlated with Elevated Risk of Gastric Cancer. AB - Helicobacter pylori infection occurs in more than half of the world's population and is the main cause for gastric cancer. A series of lifestyle and nutritional factors, such as tobacco smoking and obesity, have been found to elevate the risk for cancer development. In this study, we sought to determine the immunological aspects during H. pylori infection and gastric cancer development. We found that B cells from H. pylori-infected patients presented altered composition and function compared to uninfected patients. IL-10-expressing CD24+CD38+ B cells were upregulated in H. pylori-infected patients, contained potent regulatory activity in inhibiting T cell pro-inflammatory cytokine secretion, and responded directly to H. pylori antigen stimulation. Interestingly, in H. pylori-infected smoking subjects and obese subjects, the number of IL-10+ B cells and CD24+CD38+ B cells were reduced compared to H. pylori-infected asymptomatic subjects. Regulatory functions mediated by CD24+CD38+ B cells were also impaired. In addition, gastric cancer positive patients had reduced IL-10-producing B cell frequencies after H. pylori-stimulation. Altogether, these data suggest that in H. pylori-infection, CD24+CD38+ B cell is upregulated and plays a role in suppressing pro-inflammatory responses, possibly through IL-10 production, a feature that was not observed in smoking and obese patients. PMID- 26226401 TI - O2 and Water Migration Pathways between the Solvent and Heme Pockets of Hemoglobin with Open and Closed Conformations of the Distal HisE7. AB - Hemoglobin transports O2 by binding the gas at its four hemes. Hydrogen bonding between the distal histidine (HisE7) and heme-bound O2 significantly increases the affinity of human hemoglobin (HbA) for this ligand. HisE7 is also proposed to regulate the release of O2 to the solvent via a transient E7 channel. To reveal the O2 escape routes controlled by HisE7 and to evaluate its role in gating heme access, we compare simulations of O2 diffusion from the distal heme pockets of the T and R states of HbA performed with HisE7 in its open (protonated) and closed (neutral) conformations. Irrespective of HisE7's conformation, we observe the same four or five escape routes leading directly from the alpha- or beta distal heme pockets to the solvent. Only 21-53% of O2 escapes occur via these routes, with the remainder escaping through routes that encompass multiple internal cavities in HbA. The conformation of the distal HisE7 controls the escape of O2 from the heme by altering the distal pocket architecture in a pH dependent manner, not by gating the E7 channel. Removal of the HisE7 side chain in the GlyE7 variant exposes the distal pockets to the solvent, and the percentage of O2 escapes to the solvent directly from the alpha- or beta-distal pockets of the mutant increases to 70-88%. In contrast to O2, the dominant water route from the bulk solvent is gated by HisE7 because protonation and opening of this residue dramatically increase the rate of influx of water into the empty distal heme pockets. The occupancy of the distal heme site by a water molecule, which functions as an additional nonprotein barrier to binding of the ligand to the heme, is also controlled by HisE7. Overall, analysis of gas and water diffusion routes in the subunits of HbA and its GlyE7 variant sheds light on the contribution of distal HisE7 in controlling polar and nonpolar ligand movement between the solvent and the hemes. PMID- 26226402 TI - Stereoselective synthesis of 2,3-disubstituted indoline, pyrrolidine and cyclic ether-fused 1,2-dihydroquinoline derivatives using alkyne iminium ion cyclization of vinylogous carbamates: switch of regioselectivity using an internal hydroxy group as a nucleophile. AB - An intramolecular, alkyne iminium ion cyclization of vinylogous carbamates derived from o-alkynyl anilines and N-protected homopropargyl amines is developed for the stereoselective construction of trans-2,3-disubstituted indolines and pyrrolidine derivatives, respectively. The regioselectivity of the alkyne iminium ion cyclization could be switched using a hydroxy group as an internal nucleophile resulting in cyclic ether-fused 1,2-dihydroquinolines. The entire process of nitrogen heterocycle formation can also be carried out in a 'one-pot' manner starting from o-iodo aniline derivatives. PMID- 26226403 TI - Brain Targeting of a Water Insoluble Antipsychotic Drug Haloperidol via the Intranasal Route Using PAMAM Dendrimer. AB - Delivery of therapeutics to the brain is challenging because many organic molecules have inadequate aqueous solubility and limited bioavailability. We investigated the efficiency of a dendrimer-based formulation of a poorly aqueous soluble drug, haloperidol, in targeting the brain via intranasal and intraperitoneal administration. Aqueous solubility of haloperidol was increased by more than 100-fold in the developed formulation. Formulation was assessed via different routes of administration for behavioral (cataleptic and locomotor) responses, and for haloperidol distribution in plasma and brain tissues. Dendrimer-based formulation showed significantly higher distribution of haloperidol in the brain and plasma compared to a control formulation of haloperidol administered via intraperitoneal injection. Additionally, 6.7 times lower doses of the dendrimer-haloperidol formulation administered via the intranasal route produced behavioral responses that were comparable to those induced by haloperidol formulations administered via intraperitoneal injection. This study demonstrates the potential of dendrimer in improving the delivery of water insoluble drugs to brain. PMID- 26226404 TI - Correction to "Recent Advances of Catalytic Asymmetric 1,3-Dipolar Cycloadditions". PMID- 26226406 TI - Vaccination with different doses of Dermatophagoides farinae in a mouse model of allergic asthma. AB - BACKGROUND: The efficacy of vaccination with different doses of a vaccine has not been clarified. The purpose of this study was to investigate the relationship between the doses of purified house dust mite allergen, and allergic airway inflammation and airway reactivity in a mouse model of allergic asthma. METHODS: C57BL/6 mice were sensitized with Dermatophagoides farinae (Der f) and randomly treated with saline, 0.1, 1, or 2 mg Der f vaccine, respectively. The airway hyperresponsiveness, the numbers of total cells and eosinophils and the levels of interferon-gamma and interleukin (IL)-4 in the bronchoalveolar lavage fluid (BALF) from individual mice were measured. The percentages of CD11c CD86 and CD11c MHC II+ dendritic cells were characterized, and the levels of IL-12 in the supernatants of cultured dendritic cells were measured. RESULTS: The airway hyperresponsiveness, the numbers of total cells and eosinophils in the BALF and the percentages of CD11c CD86 and CD11c MHC II+ dendritic cells were associated with immunologic downregulation. The levels of IFN-gamma in the BALF and the levels of IL-12 in the supernatants of cultured dendritic cells were associated with immunologic upregulation. It was found that vaccination with the medium dose of Der f showed a stronger inhibitory effect. CONCLUSIONS: There seems to be a dose-dependent response between allergen and both airway inflammation and hyperreactivity in the mouse model of allergic asthma. PMID- 26226405 TI - Emergency Room Utilization After Medically Complicated Pregnancies: A Medicaid Claims Analysis. AB - BACKGROUND: Women with pregnancy complications benefit from closer monitoring postpartum and beyond. Increased postpartum emergency room (ER) use may indicate unmet need for outpatient obstetrics and primary care. The purpose of this study was to evaluate whether women with pregnancy complications (gestational diabetes [GDM], gestational hypertension, and preeclampsia) have increased ER use in the first 6 months postpartum, compared with women without these complications. METHODS: We conducted a retrospective population-based cohort study using a 2003 2010 Maryland Medicaid managed care claims data set, linked with U.S. Census data. Data included claims for outpatient and ER visits for women aged 12-45 years who were continuously enrolled in Medicaid for at least 100 days of pregnancy and 90 days postpartum. We used logistic regression to calculate the association between pregnancy complications and having >=1 ER visit in the 6 months postpartum. RESULTS: We identified 26,074 pregnancies, of which 20% were complicated by GDM, gestational hypertension, or preeclampsia. Of these complicated pregnancies, 42.1% had GDM, 35.4% had gestational hypertension, and 42.5% had preeclampsia (diagnoses were not mutually exclusive). In the 6 months postpartum, 25% of women had >=1 ER visits. Of the complicated pregnancy group, 27.7% had >=1 ER visit, versus 23.6% of the comparison group (p<0.0001). In adjusted analyses, women with a pregnancy complication were more likely to have >=1 ER visit compared with women without these complications (odds ratio [OR]1.14, 95% confidence interval [CI] 1.05-1.23). The strength of association was highest in women under age 25 (OR 1.20, 95% CI 1.09-1.33). Preconception medical comorbidities (type 2 diabetes, chronic hypertension, obesity, asthma, mental health, and substance abuse diagnoses) were also strongly associated with postpartum ER use (OR 1.61, 95% CI 1.51-1.73). CONCLUSIONS: Pregnancy complications increased ER utilization during the 6 months postpartum, especially among women under age 25 years. Interventions that improve discharge planning and early postpartum care may decrease ER use. PMID- 26226407 TI - Microfluidic desalination techniques and their potential applications. AB - In this review we discuss recent developments in the emerging research field of miniaturized desalination. Traditionally desalination is performed to convert salt water into potable water and research is focused on improving performance of large-scale desalination plants. Microfluidic desalination offers several new opportunities in comparison to macro-scale desalination, such as providing a platform to increase fundamental knowledge of ion transport on the nano- and microfluidic scale and new microfluidic sample preparation methods. This approach has also lead to the development of new desalination techniques, based on micro/nanofluidic ion-transport phenomena, which are potential candidates for up scaling to (portable) drinking water devices. This review assesses microfluidic desalination techniques on their applications and is meant to contribute to further implementation of microfluidic desalination techniques in the lab-on-chip community. PMID- 26226409 TI - Impact of Human Herpesvirus-6 Reactivation on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation. AB - Human herpesvirus-6 (HHV-6) is known to reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with development of acute graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). However, the clinical significance of HHV-6 reactivation after allo-HSCT remains unclear. Therefore, we conducted a retrospective analysis to elucidate the impact of HHV-6 reactivation on transplantation outcomes. Of 236 patients who underwent allo HSCT, 138 (58.5%) developed HHV-6 reactivation and 98 (41.5%) did not. Univariate analysis indicated that at 3 years, patients with HHV-6 reactivation had significantly higher NRM (27.7% versus 13.7%, P = .003) and worse overall survival (42.1% versus 59.0%, P = .008) than those without reactivation. In multivariate analysis, HHV-6 reactivation was associated with higher incidence of acute GVHD (hazard ratio [HR], 1.87; P = .01), cytomegalovirus reactivation (HR, 2.24; P < .001), and NRM (HR, 2.73; P = .007). Subgroup analysis stratified according to conditioning intensity indicated that a significant impact of HHV-6 reactivation on acute GVHD was observed only in patients who received myeloablative conditioning (MAC). These results indicate that HHV-6 reactivation was associated with development of acute GVHD, cytomegalovirus reactivation, and NRM. Furthermore, adverse impact of HHV-6 reactivation on transplantation outcomes was prominent in the setting of MAC. PMID- 26226408 TI - Clinical Utility of Computed Tomography and Magnetic Resonance Imaging for Diagnosis of Posterior Reversible Encephalopathy Syndrome after Stem Cell Transplantation in Children and Adolescents. AB - Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by vision changes, altered mental status, and seizures, typically caused by an acute rise in blood pressure. PRES has been reported after hematopoietic stem cell transplantation (HSCT) in association with hypertension from calcineurin inhibitors and corticosteroids. The imaging evaluation of PRES after HSCT in children and young adults has not been well described. We performed a retrospective review of all HSCT recipients presenting to the intensive care unit with new neurologic symptoms. A neuroradiologist reviewed all radiologic images and compared computed tomography (CT) versus magnetic resonance imaging (MRI) findings indicative of diagnosis of PRES. Alternative imaging diagnoses explaining the patients' symptoms were also recorded. Fifty-four transplant recipients were admitted to the intensive care unit with new neurologic symptoms. Thirty-nine percent (21 of 54) of subjects had imaging findings consistent with PRES, 24% (13 of 54) had imaging findings consistent with an alternative diagnosis, 9% (5 of 54) had a nonspecific finding, and 28% (15 of 54) had no acute imaging findings. PRES was diagnosed at a median of 49 days (interquartile range, 29 to 94) after HSCT. The presenting symptom for the majority of patients with PRES was seizures (86%), whereas 14% presented with acute encephalopathy. Ninety-five percent of subjects diagnosed with PRES (20 of 21) underwent a head CT as their initial imaging evaluation. CT scan was diagnostic of PRES in 40% (8 of 20). Subsequently, 16 patients underwent brain MRI with 12 additional patients being diagnosed with PRES on MRI. The median time elapsed between negative CT and a positive MRI examination was 20 hours (range, 3.6 hours to 9 days). CT serves as an excellent screening test for acute pathology, such as intracranial hemorrhage; however, it lacks sensitivity for the diagnosis of PRES. Patients with clinical symptoms suggestive of PRES who have a negative CT should be treated appropriately for PRES and should undergo MRI of the brain as soon as clinically stable to confirm the diagnosis. PMID- 26226410 TI - Galactosylated magnetic nanovectors for regulation of lipid metabolism based on biomarker-specific RNAi and MR imaging. AB - The specific delivery of ribonucleic acid (RNA) interfering molecules to disease related cells is still a critical blockade for in vivo systemic treatment. Here, this study suggests a robust delivery carrier for targeted delivery of RNA interfering molecules using galactosylated magnetic nanovectors (gMNVs). gMNVs are an organic-inorganic polymeric nanomaterial composed of polycationics and magnetic nanocrystal for delivery of RNA-interfering molecules and tracking via magnetic resonance (MR) imaging. In particular, the surface of gMNVs was modified by galactosylgluconic groups for targeted delivering to asialoglycoprotein receptor (ASGPR) of hepatocytes. Moreover, the small interfering RNAs were used to regulate target proteins related with low-density lipoprotein level and in vivo MR imaging was conducted for tracking of nanovectors. The obtained results show that the prepared gMNVs demonstrate potential as a systemic theragnostic nanoplatform for RNA interference and MR imaging. PMID- 26226411 TI - COPD Exacerbations Are Associated With Proinflammatory Degradation of Hyaluronic Acid. AB - BACKGROUND: COPD is characterized by chronic airway inflammation and remodeling, with serious modifications of the extracellular matrix (ECM). Hyaluronic acid (HA) is an abundant ECM molecule in the lung with various biologic functions that depend on its molecular weight (MW). High-MW HA exhibits antiinflammatory and immunosuppressive effects, whereas low-MW HA is proinflammatory. In this study, we investigated whether acute exacerbations of COPD (AECOPDs), which affect patient quality of life and survival, are associated with altered HA turnover in BAL. METHODS: We used BAL from patients with stable COPD (n = 53) or during AECOPD (n = 44) matched for demographics and clinical characteristics and BAL from control subjects (n = 15). HA, HA synthase-1 (HAS-1), and hyaluronidase (HYAL) values were determined by enzyme-linked immunosorbent assay, and HYAL activity was determined by HA zymography. The MW of HA was analyzed by agarose electrophoresis. RESULTS: Levels of HA, HAS-1, and HYAL were significantly increased in BAL of patients with stable COPD and during exacerbations compared with control subjects. HYAL activity was significantly increased in BAL of patients with AECOPD, resulting in an increase of low-MW HA during exacerbations. In patients with AECOPD, we also observed a significant negative correlation of HA and HYAL levels with FEV1 % predicted but not with diffusing capacity of lung for carbon monoxide % predicted, indicating that increased HA degradation may be more associated with airway obstruction than with emphysema. CONCLUSIONS: AECOPDs are associated with increased HYAL activity in BAL and subsequent degradation of HA, which may contribute to airway inflammation and subsequent lung function decline during exacerbations. PMID- 26226412 TI - Diamagnetic molybdenum nitride complexes supported by diligating tripodal triamido-phosphine ligands as precursors to paramagnetic phosphine donors. AB - The reaction of the ligand precursors P[CH2NHAr(R)]3 () with (Me2N)3Mo[triple bond, length as m-dash]N generated the complexes P(CH2NAr(R))3Mo[triple bond, length as m-dash]N (), where Ar(R) = 3,5-(CH3)2C6H3 (), Ph (), and 3,5-(CF3)2C6H3 (), with (Me2N)3Mo[triple bond, length as m-dash]N generated the complexes P(CH2NAr(R))3Mo[triple bond, length as m-dash]N (). Complex was obtained in poor yield, due to the formation of P(CH2N-3,5-(CF3)2C6H3)2(CH2NH-3,5 (CF3)2C6H3)(NMe2H)(NMe2)Mo[triple bond, length as m-dash]N () as the major product. Reaction of with VMes3THF generated the paramagnetic complexes P(CH2NAr(R))3Mo(MU-N)V(Mes)3 (). The reaction of with Ni(acac)2 generated the Ni(0) complexes Ni[P(CH2NAr(R))3Mo[triple bond, length as m-dash]N]4 () in poor yield. These complexes were synthesized in higher yields from the reaction of with Ni(COD)2, where COD = 1,5-cyclooctadiene. Reaction of either with V(Mes)3THF or with Ni(COD)2 generated the paramagnetic nonanuclear complex Ni[P(CH2NAr(R))3Mo(MU-N)VMes3]4 (). PMID- 26226413 TI - Peripheral blood biomarkers in multiple sclerosis. AB - Multiple sclerosis is the most common autoimmune disorder affecting the central nervous system. The heterogeneity of pathophysiological processes in MS contributes to the highly variable course of the disease and unpredictable response to therapies. The major focus of the research on MS is the identification of biomarkers in biological fluids, such as cerebrospinal fluid or blood, to guide patient management reliably. Because of the difficulties in obtaining spinal fluid samples and the necessity for lumbar puncture to make a diagnosis has reduced, the research of blood-based biomarkers may provide increasingly important tools for clinical practice. However, currently there are no clearly established MS blood-based biomarkers. The availability of reliable biomarkers could radically alter the management of MS at critical phases of the disease spectrum, allowing for intervention strategies that may prevent evolution to long-term neurological disability. This article provides an overview of this research field and focuses on recent advances in blood-based biomarker research. PMID- 26226414 TI - Immunological GABAergic interactions and therapeutic applications in autoimmune diseases. AB - Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. However, it is also produced in other sites; notably by pancreatic beta cells and immune cells. The function of GABA in the immune system is at an early stage of study, but it exerts inhibitory effects that are relevant to autoimmune diseases. The study of GABAergic interactions in the immune system has centered on three main aspects: 1) the expression of GABA and the relevant GABAergic molecular machinery; 2) the in vitro response of immune cells; and 3) therapeutic applications in autoimmune diseases. T cells and macrophages can produce GABA, and express all the components necessary for a GABAergic response. There are two types of GABA receptors, but lymphocytes appear to express only type A (GABAAR); a ligand-gated chloride channel. Other immune cells may also express the type B receptor (GABABR); a G-protein coupled receptor. Activation of GABA receptors on T cells and macrophages inhibits responses such as production of inflammatory cytokines. In T cells, GABA blocks the activation-induced calcium signal, and it also inhibits NF-kappaB activation. In preclinical models, therapeutic application of GABA, or GABAergic (agonistic) drugs, protects against type 1 diabetes (T1D), experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA) and contact dermatitis. In addition, GABA exerts anti-apoptotic and proliferative effects on islet beta cells, which may be applicable to islet transplantation. Autoimmunity against glutamic acid decarboxylase 65 (GAD65; synthesizes GABA) occurs in T1D. Antigen therapy of T1D with GAD65 or proinsulin in mice has protective effects, which are markedly enhanced by combined GABA therapy. Clinically, autoantibodies against GAD65 and/or GABA receptors play a pathogenic role in several neurological conditions, including stiff person syndrome (SPS), some forms of encephalitis, and autoimmune epilepsy. GABAergic drugs are widely used in medicine, and include benzodiazepines, barbiturates, anticonvulsants, and anesthetic drugs such as propofol. Native GABA can be administered orally to humans as a drug, and has few adverse effects. However, the immune effects of GABAergic drugs in patients are not well documented. GABAergic immunobiology is a recent area of research, which shows potential for the development of new therapies for autoimmune diseases. PMID- 26226415 TI - Probability distribution function-based classification of structural MRI for the detection of Alzheimer's disease. AB - High-dimensional classification methods have been a major target of machine learning for the automatic classification of patients who suffer from Alzheimer's disease (AD). One major issue of automatic classification is the feature selection method from high-dimensional data. In this paper, a novel approach for statistical feature reduction and selection in high-dimensional magnetic resonance imaging (MRI) data based on the probability distribution function (PDF) is introduced. To develop an automatic computer-aided diagnosis (CAD) technique, this research explores the statistical patterns extracted from structural MRI (sMRI) data on four systematic levels. First, global and local differences of gray matter in patients with AD compared to healthy controls (HCs) using the voxel-based morphometric (VBM) technique with 3-Tesla 3D T1-weighted MRI are investigated. Second, feature extraction based on the voxel clusters detected by VBM on sMRI and voxel values as volume of interest (VOI) is used. Third, a novel statistical feature-selection process is employed, utilizing the PDF of the VOI to represent statistical patterns of the respective high-dimensional sMRI sample. Finally, the proposed feature-selection method for early detection of AD with support vector machine (SVM) classifiers compared to other standard feature selection methods, such as partial least squares (PLS) techniques, is assessed. The performance of the proposed technique is evaluated using 130 AD and 130 HC MRI data from the ADNI dataset with 10-fold cross validation(1). The results show that the PDF-based feature selection approach is a reliable technique that is highly competitive with respect to the state-of-the-art techniques in classifying AD from high-dimensional sMRI samples. PMID- 26226416 TI - Efficacy and safety evaluation of systemic extremely low frequency magnetic fields used in the healing of diabetic foot ulcers--phase II data. AB - BACKGROUND AND AIMS: Cellular and animal models investigating extremely low frequency magnetic fields (ELF-MF) have reported promotion of leukocyte endothelial interactions, angiogenesis, myofibroblast and keratinocyte proliferation, improvement of peripheral neuropathy and diabetic wound healing. In humans, it has also been reported that systemic exposure to ELF-MF stimulates peripheral blood mononuclear cells, promoting angiogenesis and healing of chronic leg ulcers. The aim of the study was to investigate the effect of exposing different blood volumes to specific ELF-MFs (120 Hz sinusoidal waves of 0.4-0.9 mT RMS) to induce healing of diabetic foot ulcers (DFUs). METHODS: Twenty six diabetic patients with non-responsive DFUs were divided into two exposure groups to receive treatment and record healing time. The forearm group, exposed to ELF MF 2 h/day, twice weekly (3.6 l of blood/session); and the thorax group, exposed 25 min/day, 2 times/week (162.5 l of blood/session). Treatment period was 100 days or upon complete healing. Ulcer recurrences and adverse effects were investigated during short-term (<1 year) and long-term (3.4-7.8 years) follow-up. RESULTS: Mean healing time was 61.48 +/- 33.08 days in the forearm group and 62.56 +/- 29.33 days for the thorax group. No adverse effects or ulcer recurrences in the original ulcer site were reported during treatment, the short term follow-up period or the long-term follow-up period in both groups. CONCLUSIONS: Healing time was independent of the amount of blood exposed to ELF MF used in this trial. ELF-MFs are effective and safe and could be applied to non healing DFUs in conjunction with other preventive interventions to reduce DFUs complications. PMID- 26226417 TI - The pH sensibility of actin-bundling LIM proteins is governed by the acidic properties of their C-terminal domain. AB - Actin-bundling Arabidopsis LIM proteins are subdivided into two subfamilies differing in their pH sensitivity. Widely-expressed WLIMs are active under low and high physiologically-relevant pH conditions, whereas pollen-enriched PLIMs are inactivated by pH values above 6.8. By a domain swapping approach we identified the C-terminal (Ct) domain of PLIMs as the domain responsible for pH responsiveness. Remarkably, this domain conferred pH sensitivity to LIM proteins, when provided "in trans" (i.e., as a single, independent, peptide), indicating that it operates through the interaction with another domain. An acidic 6xc-Myc peptide functionally mimicked the Ct domain of PLIMs and efficiently inhibited LIM actin bundling activity under high pH conditions. Together, our data suggest a model where PLIMs are regulated by an intermolecular interaction between their acidic Ct domain and another, yet unidentified, domain. PMID- 26226418 TI - Cell reprogramming and neuronal differentiation applied to neurodegenerative diseases: Focus on Parkinson's disease. AB - Adult cells from patients can be reprogrammed to induced pluripotent stem cells (iPSCs) which successively can be used to obtain specific cells such as neurons. This remarkable breakthrough represents a new way of studying diseases and brought new therapeutic perspectives in the field of regenerative medicine. This is particular true in the neurology field, where few techniques are amenable to study the affected tissue of the patient during illness progression, in addition to the lack of neuroprotective therapies for many diseases. In this review we discuss the advantages and unresolved issues of cell reprogramming and neuronal differentiation. We reviewed evidence using iPSCs-derived neurons from neurological patients. Focusing on data obtained from Parkinson's disease (PD) patients, we show that iPSC-derived neurons possess morphological and functional characteristics of this disease and build a case for the use of this technology to study PD and other neuropathologies while disease is in progress. These data show the enormous impact that this new technology starts to have on different purposes such as the study and design of future therapies of neurological disease, especially PD. PMID- 26226420 TI - A sweet code for glycoprotein folding. AB - Glycoprotein synthesis is initiated in the endoplasmic reticulum (ER) lumen upon transfer of a glycan (Glc3Man9GlcNAc2) from a lipid derivative to Asn residues (N glycosylation). N-Glycan-dependent quality control of glycoprotein folding in the ER prevents exit to Golgi of folding intermediates, irreparably misfolded glycoproteins and incompletely assembled multimeric complexes. It also enhances folding efficiency by preventing aggregation and facilitating formation of proper disulfide bonds. The control mechanism essentially involves four components, resident lectin-chaperones (calnexin and calreticulin) that recognize monoglucosylated polymannose protein-linked glycans, lectin-associated oxidoreductase acting on monoglucosylated glycoproteins (ERp57), a glucosyltransferase that creates monoglucosylated epitopes in protein-linked glycans (UGGT) and a glucosidase (GII) that removes the glucose units added by UGGT. This last enzyme is the only mechanism component sensing glycoprotein conformations as it creates monoglucosylated glycans exclusively in not properly folded glycoproteins or in not completely assembled multimeric glycoprotein complexes. Glycoproteins that fail to properly fold are eventually driven to proteasomal degradation in the cytosol following the ER-associated degradation pathway, in which the extent of N-glycan demannosylation by ER mannosidases play a relevant role in the identification of irreparably misfolded glycoproteins. PMID- 26226419 TI - Multivalent IDP assemblies: Unique properties of LC8-associated, IDP duplex scaffolds. AB - A wide variety of subcellular complexes are composed of one or more intrinsically disordered proteins (IDPs) that are multivalent, flexible, and characterized by dynamic binding of diverse partner proteins. These multivalent IDP assemblies, of broad functional diversity, are classified here into five categories distinguished by the number of IDP chains and the arrangement of partner proteins in the functional complex. Examples of each category are summarized in the context of the exceptional molecular and biological properties of IDPs. One type IDP duplex scaffolds - is considered in detail. Its unique features include parallel alignment of two IDP chains, formation of new self-associated domains, enhanced affinity for additional bivalent ligands, and ubiquitous binding of the hub protein LC8. For two IDP duplex scaffolds, dynein intermediate chain IC and nucleoporin Nup159, these duplex features, together with the inherent flexibility of IDPs, are central to their assembly and function. A new type of IDP-LC8 interaction, distributed binding of LC8 among multiple IDP recognition sites, is described for Nup159 assembly. PMID- 26226421 TI - Quaternary structure of Dioclea grandiflora lectin assessed by equilibrium sedimentation and crystallographic analysis of recombinant mutants. AB - The structural basis of the pH dependency of the dimer-tetramer transition exhibited by Brinda's type II Diocleinae lectins was investigated by equilibrium sedimentation and X-ray crystal structure determination of recombinant wild-type and site-directed single and double mutants of the pH-stable tetrameric Dioclea grandiflora lectin (r-alphaDGL). Releasing the peripheral site interdimeric contact between R60 and D78 rendered a mutant displaying dimer-tetramer equilibrium in the pH range equivalent to pKa+/-1 of the gamma-COOH. Mutation of both histidines 51 and 131, but not the mutation of each His separately, abolished the formation of the Diocleinae canonical tetramer in the pH range 2.5 8.5. The X-ray structure of the double mutant r-alphaDGL H51G/H131N suggests that H131 plays a crucial role in networking loop 114-125 residues from all four subunits at the central cavity of the tetrameric lectin, and that H51 maintains the central cavity loops in a proper spatial orientation to make H131-mediated interdimer contacts. PMID- 26226422 TI - Phosphoproteomic analysis of the mouse brain mu-opioid (MOP) receptor. AB - Many in vitro data have shown that the efficacy of several opioid drugs is correlated with differential mu-opioid (MOP) receptor phosphorylation. Label-free semiquantitative on-line nanoflow liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) analyses were performed to compare the endogenous MOP receptor phosphorylation patterns of mice administered with morphine, etonitazene and fentanyl. The analysis identified S363, T370 and S375 as phosphorylated residues in the carboxy-terminus. Only T370 and S375 were regulated by agonists, with a higher propensity to promote double phosphorylation for high efficacy agonists. Our study provides confirmation that differential agonist-driven multi-site phosphorylation of MOP receptor occurs in vivo and validate the use of MS to study endogenous GPCR phosphorylation. PMID- 26226423 TI - CD73 and CD39 ectonucleotidases in T cell differentiation: Beyond immunosuppression. AB - Extracellular ATP is a danger signal released by dying and damaged cells, and it functions as an immunostimulatory signal that promotes inflammation. However, extracellular adenosine acts as an immunoregulatory signal that modulates the function of several cellular components of the adaptive and innate immune response. Consequently, the balance between ATP and adenosine concentration is crucial in immune homeostasis. CD39 and CD73 are two ectonucleotidases that cooperate in the generation of extracellular adenosine through ATP hydrolysis, thus tilting the balance towards immunosuppressive microenvironments. Extracellular adenosine can prevent activation, proliferation, cytokine production and cytotoxicity in T cells through the stimulation of the A2A receptor; however, recent evidence has shown that adenosine may also affect other processes in T-cell biology. In this review, we discuss evidence that supports a role of CD73 and CD39 ectonucleotidases in controlling naive T-cell homeostasis and memory cell survival through adenosine production. Finally, we propose a novel hypothesis of a possible role of these ectonucleotidases and autocrine adenosine signaling in controlling T-cell differentiation. PMID- 26226424 TI - Structural disorder and its role in proteasomal degradation. AB - The ubiquitin proteasome system is responsible for the controlled degradation of a vast number of intracellular proteins. It targets misfolded or otherwise aberrant proteins as well as proteins no longer needed at a given point in time. The 26S proteasome is a large macromolecular machine comprising 33 distinct subunits as well as a number of transiently associating cofactors. Being essentially a non-specific protease, specificity is conferred by the ubiquitin system, which selects and marks substrates for degradation. Here, we review our current understanding of the structure and function of the 26S proteasome; in doing so we highlight the role of disordered protein regions. Disordered segments in substrates promote their degradation, whereas low complexity regions prevent their proteolysis. In the 26S proteasome itself a main role of disordered segments seems to be rendering the ubiquitin receptors mobile, possibly supporting recruitment of polyubiquitylated substrates. Thus, these structural features of substrates as well as of the 26S proteasome itself likely play important roles at different stages of the protein degradation process. PMID- 26226425 TI - Comprehensive transcriptome and improved genome annotation of Bacillus licheniformis WX-02. AB - The updated genome of Bacillus licheniformis WX-02 comprises a circular chromosome of 4286821 base-pairs containing 4512 protein-coding genes. We applied strand-specific RNA-sequencing to explore the transcriptome profiles of B. licheniformis WX-02 under normal and high-salt conditions (NaCl 6%). We identified 2381 co-expressed gene pairs constituting 871 operon structures. In addition, 1169 antisense transcripts and 90 small RNAs were detected. Systematic comparison of differentially expressed genes under different conditions revealed that genes involved in multiple functions were significantly repressed in long term high salt adaptation process. Genes related to promotion of glutamic acid synthesis were activated by 6% NaCl, potentially explaining the high yield of gamma-PGA under salt condition. This study will be useful for the optimization of crucial metabolic activities in this bacterium. PMID- 26226426 TI - Structure and intrinsic disorder of the proteins of the Trypanosoma brucei editosome. AB - Mitochondrial pre-mRNAs in trypanosomatids undergo RNA editing to be converted into translatable mRNAs. The reaction is characterized by the insertion and deletion of uridine residues and is catalyzed by a macromolecular protein complex called the editosome. Despite intensive research, structural information for the majority of editosome proteins is still missing and no high resolution structure for the editosome exists. Here we present a comprehensive structural bioinformatics analysis of all proteins of the Trypanosoma brucei editosome. We specifically focus on the interplay between intrinsic order and disorder. According to computational predictions, editosome proteins involved in the basal reaction steps of the processing cycle are mostly ordered. By contrast, thirty percent of the amino acid content of the editosome is intrinsically disordered, which includes most prominently proteins with OB-fold domains. Based on the data we suggest a functional model, in which the structurally disordered domains of the complex are correlated with the RNA binding and RNA unfolding activity of the T. brucei editosome. PMID- 26226428 TI - An explanatory heuristic gives rise to the belief that words are well suited for their referents. AB - The mappings between the words of a language and their meanings are arbitrary. There is, for example, nothing inherently dog-like about the word dog. And yet, building on prior evidence (e.g., Brook, 1970; Piaget, 1967), the six studies reported here (N=1062) suggest that both children and (at least to some extent) adults see a special "fit" between objects and their names, as if names were particularly suitable or appropriate for the objects they denote. These studies also provide evidence for a novel proposal concerning the source of these nominal fit beliefs. Specifically, beliefs about nominal fit may be a byproduct of the heuristic processes that people use to make sense of the world more generally (Cimpian & Salomon, 2014a). In sum, the present studies provide new insights into how people conceive of language and demonstrate that these conceptions are rooted in the processes that underlie broader explanatory reasoning. PMID- 26226427 TI - A rationally-designed chimeric KDM1A/KDM1B histone demethylase tower domain deletion mutant retaining enzymatic activity. AB - A target with therapeutic potential, lysine-specific demethylase 1A (KDM1A) is a regulator of gene expression whose tower domain is a protein-protein interaction motif. This domain facilitates the interaction of KDM1A with coregulators and multiprotein complexes that direct its activity to nucleosomes. We describe the design and characterization of a chimeric 'towerless' KDM1A, termed nDelta150 KDM1ADeltaTower KDM1B chimera (chKDM1ADeltaTower), which incorporates a region from the paralog lysine-specific demethylase 1B (KDM1B). This chimera copurifies with FAD and displays demethylase activity, but fails to bind the partner protein corepressor of the RE1-silencing transcription factor (CoREST). We conclude that KDM1A catalysis can be decoupled from tower-dependent interactions, lending chKDM1ADeltaTower useful for dissecting molecular contributions to KDM1A function. PMID- 26226429 TI - Detecting the severity of perinatal anxiety with the Perinatal Anxiety Screening Scale (PASS). AB - BACKGROUND: The Perinatal Anxiety Screening Scale (PASS; Somerville et al., 2014) reliably identifies perinatal women at risk of problematic anxiety when a clinical cut-off score of 26 is used. This study aimed to identify a severity continuum of anxiety symptoms with the PASS to enhance screening, treatment and research for perinatal anxiety. METHODS: Antenatal and postnatal women (n=410) recruited from the antenatal clinics and mental health services at an obstetric hospital completed the Edinburgh Postnatal Depression Scale (EPDS), the Depression, Anxiety and Stress Scale (DASS-21), the Spielberg State-Trait Anxiety Inventory (STAI), the Beck Depression Inventory II (BDI), and the PASS. The women referred to mental health services were assessed to determine anxiety diagnoses via a diagnostic interview conducted by an experienced mental health professional from the Department of Psychological Medicine - King Edward Memorial Hospital. Three normative groups for the PASS, namely minimal anxiety, mild-moderate anxiety, and severe anxiety, were identified based on the severity of anxiety indicated on the standardised scales and anxiety diagnoses. RESULTS: Two cut-off points for the normative groups were calculated using the Jacobson-Truax method (Jacobson and Truax, 1991) resulting in three severity ranges: 'minimal anxiety'; 'mild-moderate anxiety'; and 'severe anxiety'. LIMITATIONS: The most frequent diagnoses in the study sample were adjustment disorder, mixed anxiety and depression, generalised anxiety, and post-traumatic stress disorder. This may limit the generalisability of the severity range results to other anxiety diagnoses including obsessive compulsive disorder and specific phobia. CONCLUSIONS: Severity ranges for the PASS add value to having a clinically validated cut-off score in the detection and monitoring of problematic perinatal anxiety. The PASS can now be used to identify risk of an anxiety disorder and the severity ranges can indicate developing risk for early referrals for further assessments, prioritisation of access to resources and tracking of clinically significant deterioration, improvement or stability in anxiety over time. PMID- 26226430 TI - Clinical and sociodemographic correlates of severe insomnia in psychotropic drug free, Asian outpatients with major depressive disorder. AB - BACKGROUND: Little has been known regarding the correlates of severe insomnia in major depressive disorder (MDD). This post-hoc analysis aimed to examine the sociodemographic and clinical correlates of severe insomnia in psychotropic drug free, Asian adult outpatients with MDD. METHODS: Participants were psychotropic drug-free patients with MDD, aged 18-65 years. By using the Symptom Checklist-90 Items, Revised (SCL-90-R), a score of 4 (severe distress) on any one of three insomnia items was defined as severe insomnia. Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), the Fatigue Severity Scale (FSS), the nine psychopathology subscales of SCL-90-R, the Physical and Mental Component Summaries of Short Form Health Survey (SF-36 PCS and SF-36 MCS), and the Sheehan Disability Scale (SDS). RESULTS: Of 528 participants, their mean age being 39.5 (SD=13.26) years, 64.2% were females, and 239 (45.3%) had severe insomnia. The logistic regression model revealed that low educational qualifications (less than secondary school completion), high SCL-90-R Depression scores, high SCL-90-R Anxiety scores, and low SF-36 PCS scores were independently correlated with severe insomnia (p's<.05). LIMITATIONS: Insomnia was determined only by the patient's distress. Middle insomnia was not assessed. Psychotropic drug-free patients with MDD are not commonly seen in psychiatric practice. CONCLUSION: Severe insomnia is common in patients with MDD. It is closely related with low educational qualification, subjective depression and anxiety severity, and poor physical health. These findings may implicate the treatment of comorbid MDD and severe insomnia, for example, sleep hygiene education, pharmacological treatment. PMID- 26226431 TI - Validity of brief screening questionnaires to detect depression in primary care in Ethiopia. AB - BACKGROUND: Brief depression screening questionnaires may increase detection of depression in primary care settings but there have been few validation studies carried out in typical populations in low-income countries. METHODS: Cultural validation of the Patient Health Questionnaire (PHQ-9/PHQ-2), the 20-item Self Reporting Questionnaire (SRQ-20) and the Kessler scales (K6/K10) was carried out in 306 adults consecutively attending primary care facilities in small towns in Ethiopia. To assess criterion validity, the gold standard assessment for presence of Major Depressive Disorder (MDD) was made by Ethiopian psychiatric nurses using the Mini International Neuropsychiatric Interview. RESULTS: The prevalence of gold standard MDD was 5.9%, with irritability more common than depressed mood or anhedonia. The area under the receiver operating characteristic curve indicated good performance of the PHQ-9, SRQ-20, K6 and K10 (0.83-0.85) but only fair for the PHQ-2 (0.78). No cut-off score had acceptable sensitivity combined with adequate positive predictive value. All screening questionnaires were associated with disability and the PHQ-9 and SRQ-20 were associated with higher health service contacts, indicating convergent validity. Construct validity of all scales was indicated by unidimensionality on exploratory factor analysis. LIMITATIONS: Test-retest reliability was not assessed. CONCLUSIONS: Brief depression screening questionnaires were found to be valid in primary care in this low-income country. However, these questionnaires do not have immediate applicability in routine clinical settings. Further studies should evaluate utility of indicated screening embedded within health system changes that support MDD detection. Investigation of irritability as a core depression symptom is warranted. PMID- 26226432 TI - Neural correlates of self-referential processing and implicit self-associations in chronic depression. AB - BACKGROUND: Patients with depression tend to process negative information with regard to the self (i.e. self-referential processing). A better understanding of the neural underpinnings of self-referential processing in patients with depression is clinically important as it can inform on potential treatment targets. METHOD: This fMRI study sought to study the neural correlates of self referential processing in patients with chronic major depressive disorder (cMDD) (n=17) and non-patient controls (n=18) using a passive processing paradigm. Stimuli consisted of positive, negative, negative depression related and neutral personality trait words or non-words. Participants were instructed to indicate whether a presented word was an existing word or a non-word while undergoing an fMRI scan. Participants also completed an explicit and an implicit measure of positive and negative self-associations outside the scanner. RESULTS: Non-patient controls had relatively increased activity in the medial prefrontal cortex (mPFC) during processing of negative depression related vs. neutral words whereas patients with cMDD had relatively decreased activity. Non-patient controls had relatively increased dorsolateral prefrontal cortex (dlPFC) activity during processing of positive vs. neutral words whereas patients with cMDD had relatively decreased activity. Explicit but not implicit self-associations with depression related words were associated with neural activity in the mPFC and the dlPFC. LIMITATIONS: The study did not include a clinical control group and therefore the specificity of findings remains unknown. CONCLUSIONS: The distinct neural processing of emotional self-relevant stimuli in the mPFC and the dlPFC in patients with cMDD might represent an emotional blunting response towards negative self-relevant stimuli. PMID- 26226433 TI - The Chinese Version of the Gotland Male Depression Scale (GMDS): Mokken scaling. AB - OBJECTIVE: Invariant item ordering (IIO) is defined as the extent to which items have the same order for each respondent who completes a scale. IIO is crucial for establishing a scale hierarchy that is replicable across samples; however, no research has demonstrated IIO in the Gotland Male Depression Scale (GMDS). The aim of this study was to determine if an IIO hierarchy of depressive symptoms existed in a clinical sample of men who completed the GMDS. METHODS: A convenience sample of 231 men (age: mean (SD) = 46.1 (11.0) yrs) who visited a men's health polyclinic in Taiwan and completed the GMDS. Mokken scale analysis was conducted to evaluate the psychometric properties of the GMDS. RESULTS: All items on the GMDS formed a strong uni-dimensional scale (H=0.592). Except for item #9 (alcohol/drug abuse, or hyperactivity), IIO was found for the remaining 12 items (H(T)=0.366). These symptoms reflected the following hierarchy: positive family history (#13), complaining (#12), anxiety (#8), loss of vitality (#10), depressed mood (#11), indecisiveness (#6), aggression (#2), irritability (#5), stress (#1), burn-out (#3), fatigue (#4), and sleep problems (#7). CONCLUSION: The GMDS is a psychometrically sound measure of depressive symptoms in Taiwanese male outpatients. The GMDS has both cumulative and hierarchical properties. PMID- 26226434 TI - Stage-specific control of niche positioning and integrity in the Drosophila testis. AB - A fundamental question is how complex structures are maintained after their initial specification. Stem cells reside in a specialized microenvironment, called niche, which provides essential signals controlling stem cell behavior. We addressed this question by studying the Drosophila male stem cell niche, called the hub. Once specified, the hub cells need to maintain their position and architectural integrity through embryonic, larval and pupal stages of testis organogenesis and during adult life. The Hox gene Abd-B, in addition to its described role in male embryonic gonads, maintains the architecture and positioning of the larval hub from the germline by affecting integrin localization in the neighboring somatic cyst cells. We find that the AbdB Boss/Sev cascade affects integrin independent of Talin, while genetic interactions depict integrin as the central downstream player in this system. Focal adhesion and integrin-adaptor proteins within the somatic stem cells and cyst cells, such as Paxillin, Pinch and Vav, also contribute to proper hub integrity and positioning. During adult stages, hub positioning is controlled by Abd-B activity in the outer acto-myosin sheath, while Abd-B expression in adult spermatocytes exerts no effect on hub positioning and integrin localization. Our data point at a cell- and stage-specific function of Abd-B and suggest that the occurrence of new cell types and cell interactions in the course of testis organogenesis made it necessary to adapt the whole system by reusing the same players for male stem cell niche positioning and integrity in an alternative manner. PMID- 26226435 TI - Hid arbitrates collective cell death in the Drosophila wing. AB - Elimination of cells and tissues by apoptosis is a highly conserved and tightly regulated process. In Drosophila, the entire wing epithelium is completely removed shortly after eclosion. The cells that make up this epithelium are collectively eliminated through a highly synchronized form of apoptotic cell death, involving canonical apoptosome genes. Here we present evidence that collective cell death does not require cell-cell contact and show that transcription of the IAP antagonist, head involution defective, is acutely induced in wing epithelial cells prior to this process. hid mRNAs accumulate to levels that exceed a component of the ribosome and likewise, Hid protein becomes highly abundant in these same cells. hid function is required for collective cell death, since loss of function mutants shows persisting wing epithelial cells and, furthermore, silencing of the hormone bursicon in the CNS produced collective cell death defective phenotypes manifested in the wing epithelium. Taken together, our observations suggest that acute induction of Hid primes wing epithelial cells for collective cell death and that Bursicon is a strong candidate to trigger this process, possibly by activating the abundant pool of Hid protein already present. PMID- 26226436 TI - Pereskia aculeata Miller leaves present in vivo topical anti-inflammatory activity in models of acute and chronic dermatitis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Pereskia aculeata Miller (Cactaceae), known as Barbados gooseberry, are used in Brazilian traditional medicine as emollients and to treat skin wounds and inflammation. This study investigated the topical anti-inflammatory activity of the hexane fraction (HF) obtained from the methanol extract of the leaves of this species in models of acute and chronic ear dermatitis in mice. MATERIAL AND METHODS: Mice ear edema was induced by topical application of croton oil, arachidonic acid, capsaicin, ethyl-phenylpropiolate and phenol; and by subcutaneous injection of histamine. Ear biopsies were obtained to determine the levels of IL-1beta, IL-6 and TNF alpha cytokines by ELISA assay. Histopathological analysis was also performed to evaluate the HF activity in croton oil multiple application test. In addition, acute dermal irritation/corrosion test in rats was accomplished. HF chemical characterization was performed by GC-MS analysis. RESULTS: HF intensively reduced the inflammatory process induced by all irritant agents used, except for arachidonic acid. This activity is related, at least in part, to the reduction of IL-6 and TNF-alpha cytokines levels. Moreover, when the glucocorticoid receptor antagonist mifepristone was used, HF failed to respond to the croton oil application.The results strongly suggested a glucocorticoid-like effect, which was reinforced by the presence of considerable amounts of sterol compounds identified in HF. The acute dermal irritaton/corrosion test showed no signs of toxicity. CONCLUSIONS: This study showed that the acute and chronic anti inflammatory activity of P. aculeata leaves is very promising, and corroborates to better understand their ethnopharmacological applications. PMID- 26226437 TI - Huangkui capsule attenuates renal fibrosis in diabetic nephropathy rats through regulating oxidative stress and p38MAPK/Akt pathways, compared to alpha-lipoic acid. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine (TCM), Abelmoschus manihot (L.) medic (AM) is a natural medicinal plant used for the treatment of inflammatory diseases. Recently, Huangkui capsule (HKC), a Chinese patent medicine extracted from AM, has been widely applied to the clinical therapy of renal fibrosis in patients with early diabetic nephropathy (DN). However, the therapeutic mechanisms involved in vivo remain ambiguous. The goal of this study is to expound the mechanism in vivo of HKC in order to deepen the understanding of its clinical effects, by using the approaches of contrasting the dose-effects of HKC on oxidative stress (OS) in the kidney compared to alpha lipoic acid (LA), and then demonstrating whether and how anti-oxidative properties of HKC or LA might be beneficial for the treatment of renal fibrosis in vivo. MATERIALS AND METHODS: Thirty-three rats were divided into 5 groups, a Sham group, a Vehicle group, a L-HKC group, a H-HKC group and a LA group. The different doses of HKC, LA and distilled water were daily administrated for 8 weeks after the induction of DN by the unilateral nephrectomy combined with streptozotocin (STZ) intraperitoneal injections. Rat's general status, biochemical parameters, renal histological changes and OS indicators, as well as the key protein expressions in p38 mitogen-activated protein kinase (p38MAPK)/serine-threonine kinase (Akt) signaling pathways and downstream cytokines including transforming growth factor (TGF)-beta1 and tumor necrosis factor (TNF)-alpha were examined, respectively. RESULTS: HKC and LA ameliorated body weight, kidney weight, urinary albumin and renal function including blood urea nitrogen and serum uric acid, attenuated renal fibrosis including the cell numbers and extracellular matrix rate in glomerulus, and controlled OS indicators including malondialdehyde, total superoxide dismutase, 8-hydroxy-2' deoxyguanosine and nicotinamide adenine dinucleotide phosphate oxidase 4, but did not lower blood glucose in DN model rats. Among them, the anti-renal fibrosis effect of H-HKC was better than that of LA. In addition, HKC simultaneously down regulated the protein expressions of phosphorylated p38MAPK, phosphorylated Akt (p-Akt), TGF-beta1 and TNF-alpha in the kidney of DN model rats, unlike HKC, LA only down-regulated p-Akt and TNF-alpha protein expressions. CONCLUSION: We have demonstrated that HKC, similar to LA, is renoprotective via attenuating OS and renal fibrosis in the DN rat model. The potential mechanisms by which HKC and LA exert their therapeutic effects in vivo are respectively through down-regulating the activation of p38MAPK and/or Akt pathways as well as the expressions of TGF beta1 and/or TNF-alpha in the kidney. Our findings thus provide the useful information about a clinical combination of HKC and LA in early DN patients. PMID- 26226438 TI - FoxO1 regulates asymmetric dimethylarginine via downregulation of dimethylaminohydrolase 1 in human endothelial cells and subjects with atherosclerosis. AB - BACKGROUND AND AIMS: The O subfamily of forkhead (FoxO) 1 is a pivotal element in the regulation of endothelial activation. Compartmentalization and activity of FoxO1 is regulated by post translational modifications, but the implication in endothelial dysfunction and atherosclerosis remain controversial. Our aim was to identify FoxO1 related metabolic signatures in endothelial cells. METHODS AND RESULTS: Using metabolomics in human umbilical endothelial cells (HUVECs) overexpressing the wild type FoxO1 (FoxO1-WT), the acetylation defective mutant (FoxO1-KR), the unphosphorylated nuclear localized mutant (FoxO1-ADA) and the Green Fluorescent Protein (GFP) control vector, we identify metabolic pathways differentially affected by the different FoxO1 localization and activity. Among metabolites, asymmetric dimethylarginine (ADMA) was increased in FoxO1-ADA compared with FoxO1-WT and FoxO1-KR infected cells (p < 0.01). ADMA was further investigated to identify the molecular mechanisms to explain its link to FoxO1. We found that unrestrained FoxO1 activity leads to increase of ADMA via downregulation of its degrading enzyme, dimethylaminohydrolase (DDAH) 1. In human subjects (n = 89) the FoxO1/DDAH1/ADMA pathway marks unstable atherosclerosis. CONCLUSIONS: Our results point to ADMA as a biomarker to track deregulated FoxO1 activity in vivo. PMID- 26226440 TI - Safety and Tolerability of Doripenem in Hospitalized Children With Complicated Intra-Abdominal Infection, Complicated Urinary Tract Infections and Pneumonia. AB - Three multicenter, randomized, controlled studies evaluated doripenem in children 3 months to <18 years of age, with complicated intra-abdominal or urinary tract infections and bacterial pneumonia.In the 66 patients treated with doripenem before early termination of the studies for nonsafety reasons, doripenem was safe and generally well tolerated. Low enrollment limited ability to assess benefits and risks of doripenem in children. PMID- 26226439 TI - Polymer Photovoltaic Cells with Rhenium Oxide as Anode Interlayer. AB - The effect of a new transition metal oxide, rhenium oxide (ReO3), on the performance of polymer solar cells based on regioregular poly(3-hexylthiophene) (P3HT) and methanofullerene [6,6]-phenyl C61-butyric acid methyl ester (PCBM) blend as buffer layer was investigated. The effect of the thickness of ReO3 layer on electrical characteristics of the polymer solar cells was studied. It is found that insertion of ReO3 interfacial layer results in the decreased performance for P3HT: PCBM based solar cells. In order to further explore the mechanism of the decreasing of the open-circuit voltage (Voc), the X-ray photoelectron spectroscopy (XPS) is used to investigate the ReO3 oxidation states. Kelvin Probe method showed that the work function of the ReO3 is estimated to be 5.13eV after thermal evaporation. The results indicated the fact that a portion of ReO3 decomposed during thermal evaporation process, resulting in the formation of a buffer layer with a lower work function. As a consequence, a higher energy barrier was generated between the ITO and the active layer. PMID- 26226441 TI - Q Fever Chronic Osteomyelitis in Two Children. AB - We report 2 cases of chronic Q fever osteomyelitis in 10- and 5-year-old girls who presented with distal right femoral and left parasternal granulomatous osteomyelitis, respectively. Both were treated with ciprofloxacin and rifampin with good response. Q fever osteomyelitis is a challenging diagnosis in children, and the choice of antimicrobial treatment is difficult because of limited available data. PMID- 26226442 TI - Efavirenz Concentrations and Probability of HIV Replication in Children. AB - In 188 HIV-infected children receiving efavirenz, a lower mid-dose (C12) was associated with a higher risk of HIV-1 viral load >400 copies/mL (P = 0.03). Simulations for a normalized population receiving US Food and Drug Administration weight-band dosing predicted that 15% of children would have a C12 below target threshold (<1.0 mg/L) with a 23% risk of viral replication. PMID- 26226443 TI - Impact of the Pneumococcal Conjugate Vaccine and Antibiotic Use on Nasopharyngeal Colonization by Antibiotic Nonsusceptible Streptococcus pneumoniae, Alaska, 2000[FIGURE DASH]2010. AB - BACKGROUND: We describe the relative impact of the heptavalent pneumococcal conjugate vaccine (PCV7, introduced 2001) and antibiotic use on colonization by antibiotic-resistant pneumococci in urban Alaskan children during 2000-2010. METHODS: We obtained nasopharyngeal swab specimens from a convenience sample of children aged <5 years at clinics annually during 2000-2004 and 2008-2010. PCV7 status and antibiotic use <90 days before enrollment were determined by interview/medical records review. Pneumococci were characterized by serotype and susceptibility to penicillin (PCN). Isolates with full PCN resistance (PCN-R) or intermediate PCN resistance (PCN-I) were classified as PCN-NS. RESULTS: We recruited 3496 children (median, 452 per year). During 2000-2010, a range of 18 29% per year of children used PCN/amoxicillin (P value for trend = 0.09); the proportion age-appropriately vaccinated with PCV7 increased (0[FIGURE DASH]90%; P < 0.01). Among pneumococcal isolates, the PCV7-serotype proportion decreased (53 <1%; P < 0.01) and non[FIGURE DASH]PCV7-serotype proportion increased (43-95%; P < 0.01). PCN-R pneumococcal colonization prevalence decreased (23-9%; P < 0.01) and PCN-I pneumococcal colonization prevalence increased (13-24%; P < 0.01); overall PCN-NS pneumococcal colonization prevalence was unchanged. PCN-NS among colonizing PCV7-type and non[FIGURE DASH]PCV7-type pneumococci remained unchanged; a mean of 31% per year of PCV7-type and 10% per year of non[FIGURE DASH]PCV7-type isolates were PCN-R, and 10% per year of PCV7 and 20% per year of non[FIGURE DASH]PCV7-type isolates were PCN-I. CONCLUSIONS: Overall, PCN-NS pneumococcal colonization remained unchanged during 2000-2010 because increased colonization by predominantly PCN-I non-PCV7 serotypes offset decreased colonization by predominantly PCN-R PCV7 serotypes. Proportion PCN-NS did not increase within colonizing pneumococcal serotype groups (PCV7 vs. non-PCV7) despite stable PCN use in our population. PMID- 26226444 TI - Seroprevalence and Determinants of Immunity to Diphtheria for Children Living in Two Districts of Contrasting Incidence During an Outbreak in East Java, Indonesia. AB - BACKGROUND: In 2012, an ongoing outbreak of diphtheria in Indonesia was focused in the province of East Java. There was a need to assess vaccine coverage and immunity gaps in children. METHODS: We conducted a cross-sectional seroprevalence and vaccine coverage survey of children 1-15 years of age in 2 districts of East Java: one of high incidence (on the island of Madura) and one of low incidence (on the mainland). From each district, we sampled 150 children (10 children per year of age). Sera and throat swabs were taken to determine immunity and carriage status. Immunity was defined as >=0.1 international unit/mL of antibody to diphtheria toxin. RESULTS: A total of 297 children were selected to participate in the study. Coverage of three doses of combined vaccine for diphtheria, tetanus and pertussis was significantly lower (P < 0.001) in the high incidence district compared with the low [57%, 95% confidence interval (CI): 36-78 vs. 97%, 95% CI: 93-100]. Despite this higher vaccine coverage, seroprevalence of immunity was lower in the low incidence district compared with the high (71%, 95% CI: 63-80 vs. 83%, 95% CI: 76-90). Immunity in the high incidence district was associated with increased age, increased prevalence of toxigenic Corynebacterium diphtheriae carriers and with receipt of multiple (and likely more recent) boosters. CONCLUSIONS: Significant variation exists in vaccine coverage and seroprevalence of immunity to diphtheria in East Java. Immunity in high incidence districts is likely because of natural immunity acquired through exposure to toxigenic C. diphtheriae. Booster vaccines are essential for achieving protective levels of immunity. PMID- 26226445 TI - Decline in Pneumococcal Nasopharyngeal Carriage of Vaccine Serotypes After the Introduction of the 13-Valent Pneumococcal Conjugate Vaccine in Children in Atlanta, Georgia. AB - BACKGROUND: Streptococcus pneumoniae (SP) serotype distribution among nasopharyngeal (NP) carriage isolates changed significantly after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7). We evaluated the impact on NP carriage and invasive disease of SP after the introduction of the 13-valent PCV (PCV13) in March 2010. METHODS: NP swabs were collected from children 6-59 months of age in an emergency department from July 2010 to June 2013. After broth enrichment, samples were cultured for SP and isolates were serotyped. Clinical and immunization records were reviewed. Findings during 6 sequential 6-month study periods were compared. Surveillance isolates of invasive disease isolates were reviewed. RESULTS: A total of 2048 children were enrolled, and 656 (32%) were SP carriers. Mean age of carriers was 27 months, 54% were males. Carriage was higher among day-care attendees (P < 0.01) and children with respiratory tract illnesses (P < 0.5) and otitis media (P < 0.01). Commonly carried serotypes included 35B (15.2%), 15B/C (14.2%), 19A (9.6%), 11A (8%), 23B (5.6%), 6C (5.3%), 21 (5%), and 15A (5%); 13.9% were PCV13 serotypes. The proportion of children with SP carriage remained stable but the serotype distribution changed during the study period. Among carriers, PCV13 serotypes declined from 29% (36/124) to 3% (3/99; P < 0.0001), predominantly because of decline of serotype 19A from 25.8% (32/124) to 3% (3/99; P < 0.0001); non-PCV13 serotypes (excluding 6C) increased from 68.4% (78/114) to 97% (95/98; P < 0.0001); serotype 35B significantly increased from 8.9% (11/124) to 25.3% (25/99; P < 0.05). Nonsusceptibility to ceftriaxone declined from 22.6% (28/124) to 0% (0/99; P < 0.0001), with a similar decline in penicillin nonsusceptibility. CONCLUSIONS: Introduction of PCV13 for universal infant use was associated with significant reductions in nasopharyngeal carriage of PCV13 serotypes and resistant strains. Carriage of non-PCV13 serotypes increased modestly, particularly serotype 35B. Further investigation is warranted to determine whether nonvaccine pneumococcal serotypes carried in the nasopharynx are associated with significant replacement disease. PMID- 26226446 TI - The Role of Clinical Symptoms in the Diagnosis of Intrathoracic Tuberculosis in Young Children. AB - BACKGROUND: Childhood tuberculosis (TB) is usually Mycobacterium tuberculosis (MTB) culture negative. Furthermore, clinical presentation may be altered by active case finding, isoniazid prophylaxis and early treatment. We aimed to establish the value of presenting symptoms for intrathoracic TB case diagnosis among young children. METHODS: Healthy, HIV-uninfected, South African infants in an efficacy trial of a novel TB vaccine (MVA85A) were followed for 2 years for suspected TB. When suspected, investigation followed a standardized algorithm comprising symptom history, QuantiFERON Gold-in-Tube, chest radiography (CXR), MTB culture and Xpert MTB/RIF from paired gastric lavage and induced sputa. Adjusted odds ratios and 95% confidence intervals describe the associations between symptoms and positive MTB culture or Xpert MTB/RIF, and CXR compatible with intrathoracic TB. RESULTS: Persistent cough was present in 172/1017 (16.9%) of the children investigated for TB. MTB culture/Xpert MTB/RIF was positive in 38/1017 children (3.7%); and CXR was positive, that is, compatible with intrathoracic TB, in 131/1017 children (12.9%). Children with persistent cough had more than triple the odds of a positive MTB culture/Xpert MTB/RIF (adjusted odds ratios: 3.3, 95% confidence interval: 1.5-7.0) and positive CXR (adjusted odds ratios: 3.5, 95% confidence interval: 2.2-5.5). Persistent cough was the only symptom that differentiated children with severe (56.5%) from nonsevere intrathoracic TB disease (28.2%; P = 0.001). CONCLUSION: Persistent cough was the cardinal diagnostic symptom associated with microbiologic and radiologic evidence, and disease severity, of intrathoracic TB. Symptom-based definitions of TB disease for diagnostic, preventive and therapeutic studies should prioritize persistent cough above other symptoms compatible with childhood TB. PMID- 26226447 TI - Vascular Complications of Varicella: Description of 4 Cases and a Review of Literature. AB - Stroke and deep venous thrombosis are rare complications of varicella zoster infection. We report 3 cases of children with a stroke and 1 case of a boy with a deep venous thrombosis after recent chicken pox. PMID- 26226448 TI - Model-Based Individualized Treatment of Chemotherapeutics: Bayesian Population Modeling and Dose Optimization. AB - 6-Mercaptopurine (6-MP) is one of the key drugs in the treatment of many pediatric cancers, auto immune diseases and inflammatory bowel disease. 6-MP is a prodrug, converted to an active metabolite 6-thioguanine nucleotide (6-TGN) through enzymatic reaction involving thiopurine methyltransferase (TPMT). Pharmacogenomic variation observed in the TPMT enzyme produces a significant variation in drug response among the patient population. Despite 6-MP's widespread use and observed variation in treatment response, efforts at quantitative optimization of dose regimens for individual patients are limited. In addition, research efforts devoted on pharmacogenomics to predict clinical responses are proving far from ideal. In this work, we present a Bayesian population modeling approach to develop a pharmacological model for 6-MP metabolism in humans. In the face of scarcity of data in clinical settings, a global sensitivity analysis based model reduction approach is used to minimize the parameter space. For accurate estimation of sensitive parameters, robust optimal experimental design based on D-optimality criteria was exploited. With the patient-specific model, a model predictive control algorithm is used to optimize the dose scheduling with the objective of maintaining the 6-TGN concentration within its therapeutic window. More importantly, for the first time, we show how the incorporation of information from different levels of biological chain-of response (i.e. gene expression-enzyme phenotype-drug phenotype) plays a critical role in determining the uncertainty in predicting therapeutic target. The model and the control approach can be utilized in the clinical setting to individualize 6-MP dosing based on the patient's ability to metabolize the drug instead of the traditional standard-dose-for-all approach. PMID- 26226449 TI - Life as a moving fluid: fate of cytoplasmic macromolecules in dynamic fungal syncytia. AB - In fungal syncytia dozens, or even millions of nuclei may coexist in a single connected cytoplasm. Recent discoveries have exposed some of the adaptations that enable fungi to marshall these nuclei to produce complex coordinated behaviors, including cell growth, nuclear division, secretion and communication. In addition to shedding light on the principles by which syncytia (including embryos and osteoplasts) are organized, fungal adaptations for dealing with internal genetic diversity and physically dynamic cytoplasm may provide mechanistic insights into how cells generally are carved into different functional compartments. In this review we focus on enumerating the physical constraints associated with maintaining macromolecular distributions within a fluctuating and often flowing cytoplasmic interior. PMID- 26226450 TI - Phenylthiourea alters toxicity of mercury compounds in zebrafish larvae. AB - In recent years larval stage zebrafish have been emerging as a standard vertebrate model in a number of fields, ranging from developmental biology to pharmacology and toxicology. The tyrosinase inhibitor 1-phenyl-2-thiourea (PTU) is used very widely with larval zebrafish to generate essentially transparent organisms through inhibition of melanogenesis, which has enabled many elegant studies in areas ranging from neurological development to cancer research. Here we show that PTU can have dramatic synergistic and antagonistic effects on the chemical toxicology of different mercury compounds. Our results indicate that extreme caution should be used when employing PTU in toxicological studies, particularly when studying toxic metal ions. PMID- 26226452 TI - Prothrombotic genetic risk factors are associated with an increased risk of liver fibrosis in the general population: The Rotterdam Study. AB - BACKGROUND & AIMS: The coagulation system is known to be involved in fibrogenesis in patients with liver disease. We investigated whether common genetic prothrombotic risk factors are associated with an increased risk of fibrosis in the general population. METHODS: This investigation was part of the Rotterdam Study, an ongoing, population-based cohort study. Liver stiffness (LS) was measured using transient elastography (Fibroscan) and associated with single nucleotide polymorphisms determining blood group type and presence of the Factor V Leiden (FVL) mutation or prothrombin G20210A gene variant. RESULTS: Reliable LS measurements and genetic data were obtained from 1055 Caucasian participants. LS ?8.0 kPa, suggestive of clinically relevant fibrosis, was observed in 101 subjects (9.6%). Presence of FVL or prothrombin G20210A was independently associated with an increased risk of LS ?8.0 kPa (OR 2.09, 95%CI 1.07-4.07, p=0.03). Combination of blood group type non-O and the FVL mutation or prothrombin G20210A variant resulted in an even higher risk of LS ?8.0 kPa (OR 3.36, 95%CI 1.50-7.56, p=0.003). Presence of the FVL mutation or prothrombin G20210A variant in participants with blood group non-O was associated with a predicted probability of 14.3% (7.7-23.8) of LS ?8.0 kPa. CONCLUSIONS: Participants carrying the FVL mutation or prothrombin G20210A variant have an increased risk of clinically relevant liver fibrosis, which is even higher in blood group type non-O carriers. The fact that genetic prothrombotic risk factors are associated with an increased risk of liver fibrosis suggests that coagulation plays an important role in fibrogenesis in the general population. PMID- 26226453 TI - Solving obesity without addressing poverty: Fat chance. PMID- 26226451 TI - Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer. AB - The Hippo pathway and its regulatory target, YAP, has recently emerged as an important biochemical signaling pathway that tightly governs epithelial tissue growth. Initially defined in Drosophilia, this pathway has shown remarkable conservation in vertebrate systems with many components of the Hippo/YAP pathway showing biochemical and functional conservation. The liver is particularly sensitive to changes in Hippo/YAP signaling with rapid increases in liver size becoming manifest on the order of days to weeks after perturbation. The first identified direct targets of Hippo/YAP signaling were pro-proliferative and anti apoptotic gene programs, but recent work has now implicated this pathway in cell fate choice, stem cell maintenance/renewal, epithelial to mesenchymal transition, and oncogenesis. The mechanisms by which Hippo/YAP signaling is changed endogenously are beginning to come to light as well as how this pathway interacts with other signaling pathways, and important details for designing new therapeutic interventions. This review focuses on the known roles for Hippo/YAP signaling in the liver and promising avenues for future study. PMID- 26226454 TI - A Novel Clinical Test for Setting Intermittent Pneumatic Compression Parameters Based on Edema Fluid Hydromechanics in the Lymphedematous Calf. AB - BACKGROUND: Long-term observations confirm lasting effects and lack of complications of intermittent pneumatic compression (IPC) therapy. So far, no test has been designed that would provide data necessary for setting pressure and time parameters of the IPC device to obtain optimum decrease in limb volume. AIM: To design a test providing data on decrease of circumference under the inflated chamber in time depending on the applied compression pressure. METHODS: One chamber was placed above the ankle joint and inflated to 120 mmHg in order to occlude tissue fluid backflow during inflation of the proximally located test chamber. The latter was inflated sequentially to 50, 80, 100, and 120 mmHg, for 1 3 minutes each. Calf circumference changes were recorded continuously using the plethysmographic strain gauges placed under and proximally to the inflated chamber. RESULTS: Four different types of the recorded circumference change curves were observed during inflation of the test chamber. The first was decrease under and increase proximally to the inflated chamber, another showed decrease under the inflated chamber and little change proximally, the third small decrease under the chamber but increase proximally, and the fourth no change under and proximally. Depending on the steepness of the obtained curves, pressures and timing of IPC device were increased to values bringing about edema fluid mobilization. CONCLUSIONS: The two-chamber inflation-deflation test provides plethysmographic data on the circumference changes during calf IPC, time necessary to obtain optimum decrease of circumference, and an insight into tissue elasticity. These data are useful for setting the compression devices at levels bringing about a decrease in limb swelling as well as may be of prognostic value with respect to the efficacy of long-term use of IPC. PMID- 26226455 TI - The Efficacy and Safety of Entecavir and Interferon Combination Therapy for Chronic Hepatitis B Virus Infection: A Meta-Analysis. AB - The objective of this study was to evaluate the effectiveness and safety of entecavir (ETV) and interferon (IFN) combination therapy in the treatment of chronic hepatitis B (CHB) mono-infection via a meta-analysis of randomized controlled trials (RCTs). All eligible RCTs evaluating combination therapy for treating CHB were identified from nine electronic databases. A meta-analysis was performed in accordance with the Cochrane Systemic Review handbook. Eleven trials encompassing 1010 participants were included in this meta-analysis. It showed that at 12 and >= 96 weeks of therapy, the combination of ETV and IFN was not better than ETV in improving the undetectable HBV DNA (12 weeks: RR=1.12, 95% CI=0.88-1.42; >= 96 weeks: RR = 0.64, 95% CI=0.21-1.98, respectively) and HBeAg seroconversion rates (12 weeks: RR=1.35, 95% CI=0.60-3.04; >= 96 weeks: RR=1.36, 95% CI=0.75-2.64, respectively). But at 48 weeks of therapy and approximately 2 years of follow up, combination therapy was superior to ETV in improving the undetectable HBV DNA (48 weeks: RR=1.46, 95% CI=1.13-1.90; follow up: RR=2.20, 95% CI=1.26-3.81, respectively) and HBeAg seroconversion rates (48 weeks: RR=1.82, 95% CI=1.44-2.30; follow up: RR=1.92, 95% CI=1.19-3.11, respectively). When compared to IFN group, at 24 and 48 weeks of therapy, combination group showed a greater undetectable HBV DNA (24 weeks: RR=2.14, 95% CI=1.59-2.89; 48 weeks: RR=2.28, 95% CI=1.54-3.37, respectively) and ALT normalization rate (24 weeks: RR=1.56, 95% CI= 1.24-1.96; 48 weeks: RR=1.55, 95% CI = 1.16-2.07, respectively). At 48 weeks of therapy, combination group achieved a greater HBeAg seroconversion rate than IFN (48 weeks: RR=1.58, 95% CI=1.24-2.00). No significant differences were observed in the side effects of the three therapies. So we can conclude that ETV and IFN combination therapy is more effective than ETV or IFN mono-therapy in CHB treatment. ETV, IFN, and the combination of the two are safe in CHB treatment. PMID- 26226456 TI - Astragalus polysaccharides inhibits PCV2 replication by inhibiting oxidative stress and blocking NF-kappaB pathway. AB - Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated disease (PCVAD). Astragalus polysaccharide (APS), as one kind of biological macromolecule extracted from Astragalus, has antiviral activities. This study was undertaken to explore the effect of APS on PCV2 replication in vitro and the underlying mechanisms. Our results showed that adding APS before PCV2 infection decreased significantly PCV2 DNA copies, the number of infected cells, MDA level, ROS level and NF-kappaB activation in PK15 cells and increased significantly GSH contents and SOD activity compared to control without APS. Oxidative stress induced by BSO could eliminate the effect of PCV2 replication inhibition by APS. LPS, as a NF-kappaB activator, could attenuate the effect of PCV2 replication inhibition by APS. BAY 11-7082, as a NF kappaB inhibitor, could increase the effect of PCV2 replication inhibition by APS. In conclusion, APS inhibits PCV2 replication by decreasing oxidative stress and the activation of NF-kappaB signaling pathway, which suggests that APS might be employed for the prevention of PCV2 infection. PMID- 26226457 TI - Protein secondary structure of Green Lynx spider dragline silk investigated by solid-state NMR and X-ray diffraction. AB - In this study, the secondary structure of the major ampullate silk from Peucetia viridans (Green Lynx) spiders is characterized by X-ray diffraction and solid state NMR spectroscopy. From X-ray diffraction measurement, beta-sheet nanocrystallites were observed and found to be highly oriented along the fiber axis, with an orientational order, fc~0.98. The size of the nanocrystallites was determined to be on average 2.5nm*3.3nm*3.8nm. Besides a prominent nanocrystalline region, a partially oriented amorphous region was also observed with an fa~0.89. Two-dimensional (13)C-(13)C through-space and through-bond solid state NMR experiments were employed to elucidate structure details of P. viridans silk proteins. It reveals that beta-sheet nanocrystallites constitutes 40.0+/ 1.2% of the protein and are dominated by alanine-rich repetitive motifs. Furthermore, based upon the NMR data, 18+/-1% of alanine, 60+/-2% glycine and 54+/-2% serine are incorporated into helical conformations. PMID- 26226458 TI - Milled non-mulberry silk fibroin microparticles as biomaterial for biomedical applications. AB - Silk fibroin has been widely employed in various forms as biomaterials for biomedical applications due to its superb biocompatibility and tunable degradation and mechanical properties. Herein, silk fibroin microparticles of non mulberry silkworm species (Antheraea assamensis, Antheraea mylitta and Philosamia ricini) were fabricated via a top-down approach using a combination of wet milling and spray drying techniques. Microparticles of mulberry silkworm (Bombyx mori) were also utilized for comparative studies. The fabricated microparticles were physico-chemically characterized for size, stability, morphology, chemical composition and thermal properties. The silk fibroin microparticles of all species were porous (~5MUm in size) and showed nearly spherical morphology with rough surface as revealed from dynamic light scattering and microscopic studies. Non-mulberry silk microparticles maintained the typical silk-II structure with beta-sheet secondary conformation with higher thermal stability. Additionally, non-mulberry silk fibroin microparticles supported enhanced cell adhesion, spreading and viability of mouse fibroblasts than mulberry silk fibroin microparticles (p<0.001) as evidenced from fluorescence microscopy and cytotoxicity studies. Furthermore, in vitro drug release from the microparticles showed a significantly sustained release over 3 weeks. Taken together, this study demonstrates promising attributes of non-mulberry silk fibroin microparticles as a potential drug delivery vehicle/micro carrier for diverse biomedical applications. PMID- 26226459 TI - X-ray structure determination using low-resolution electron microscopy maps for molecular replacement. AB - Structures of multisubunit macromolecular machines are primarily determined either by electron microscopy (EM) or by X-ray crystallography. In many cases, a structure for a complex can be obtained at low resolution (at a coarse level of detail) with EM and at a higher resolution (with finer detail) by X-ray crystallography. The integration of these two structural techniques is becoming increasingly important for the generation of atomic models of macromolecular complexes. A low-resolution EM image can be a powerful tool for obtaining the 'phase' information that is missing from an X-ray crystallography experiment; however, integration of EM and X-ray diffraction data has been technically challenging. Here we present a step-by-step protocol that explains how low resolution EM maps can be placed in the crystallographic unit cell by molecular replacement, and how initial phases computed from the placed EM density are extended to high resolution by averaging maps over noncrystallographic symmetry. As the resolution gap between EM and X-ray crystallography continues to narrow, the use of EM maps to help with X-ray crystal structure determination, as described in this protocol, will become increasingly effective. PMID- 26226461 TI - A flow cytometry-based method to simplify the analysis and quantification of protein association to chromatin in mammalian cells. AB - Protein accumulation on chromatin has traditionally been studied using immunofluorescence microscopy or biochemical cellular fractionation followed by western immunoblot analysis. As a way to improve the reproducibility of this kind of analysis, to make it easier to quantify and to allow a streamlined application in high-throughput screens, we recently combined a classical immunofluorescence microscopy detection technique with flow cytometry. In addition to the features described above, and by combining it with detection of both DNA content and DNA replication, this method allows unequivocal and direct assignment of cell cycle distribution of protein association to chromatin without the need for cell culture synchronization. Furthermore, it is relatively quick (takes no more than a working day from sample collection to quantification), requires less starting material compared with standard biochemical fractionation methods and overcomes the need for flat, adherent cell types that are required for immunofluorescence microscopy. PMID- 26226462 TI - Incidence, Magnitude, and Predictors of Shortening in Young Femoral Neck Fractures. AB - OBJECTIVES: To describe the incidence and magnitude of femoral neck fracture shortening in patients age younger than 60 years. Secondarily, to examine predictors of fracture shortening. DESIGN: Retrospective chart review. SETTING: Level I trauma centre. PATIENTS/PARTICIPANTS: Sixty-five patients with a median age of 51 years (interquartile range: 42-56 years) were included. Seventy-one percent were male, 75% were displaced fractures, and 78% were treated with cancellous screws. INTERVENTION: Internal fixation with multiple cancellous screws or sliding hip screw (SHS) + derotation screw. MAIN OUTCOME MEASUREMENTS: Radiographic femoral neck shortening at a minimum of 6 weeks after fixation. RESULTS: Fifty-four percent of patients had >=5 mm of femoral neck shortening (22% had between >=5 and <10 mm and 32% >=10 mm). Initially, displaced fractures shortened more than undisplaced fractures (mean: 8.1 vs. 2.2 mm, P < 0.001), and fractures treated with SHS + derotation screw shortened more than fractures with cancellous screws alone (10.7 vs. 5.5 mm, P = 0.03). Even when adjusting for initial fracture displacement, fractures treated with SHS + derotation screw shortened an average of 2.2 mm more than fractures treated with screws alone (P = 0.03). CONCLUSIONS: The incidence of clinically significant shortening in our young femoral neck fracture population was higher than anticipated, and 32% of patients experienced severe shortening of >1 cm. Our findings highlight the need for further research to determine the impact of severe shortening on functional outcome and to determine if implant selection affects fracture shortening. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26226460 TI - Population-specific genotype imputations using minimac or IMPUTE2. AB - In order to meaningfully analyze common and rare genetic variants, results from genome-wide association studies (GWASs) of multiple cohorts need to be combined in a meta-analysis in order to obtain enough power. This requires all cohorts to have the same single-nucleotide polymorphisms (SNPs) in their GWASs. To this end, genotypes that have not been measured in a given cohort can be imputed on the basis of a set of reference haplotypes. This protocol provides guidelines for performing imputations with two widely used tools: minimac and IMPUTE2. These guidelines were developed and used by the Genome of the Netherlands (GoNL) consortium, which has created a population-specific reference panel for genetic imputations and used this reference to impute various Dutch biobanks. We also describe several factors that might influence the final imputation quality. This protocol, which has been used by the largest Dutch biobanks, should take approximately several days, depending on the sample size of the biobank and the computer resources available. PMID- 26226467 TI - Evaluation of Optical Coherence Tomography Meibography in Patients With Obstructive Meibomian Gland Dysfunction. AB - PURPOSE: To evaluate optical coherence tomography meibography (OCT-M) in patients with and without obstructive meibomian gland dysfunction (MGD) and to determine the relationship between OCT-M and ocular surface clinical tests. METHODS: Twenty two patients with MGD and 16 control subjects were included. Each patient underwent an evaluation of ocular surface disease symptoms, lid margin abnormality score, lipid layer thickness evaluation, and meibomian gland (MG) morphological changes using noncontact infrared meibography and OCT-M. OCT-M scans were acquired in 4 different locations. OCT-M parameters including the MG length and width and palpebral conjunctival thickness were evaluated. RESULTS: Within the OCT-M parameters, the mean length and width of MGs were significantly decreased in patients with MGD (310 +/- 60 MUm and 214 +/- 30 MUm, respectively) compared with the control group (361 +/- 53 MUm, P = 0.041 and 264 +/- 41 MUm, P = 0.021, respectively). The mean conjunctival thickness was also significantly increased in patients with MGD (448 +/- 68 MUm) than in the control group (356 +/ 59 MUm, P = 0.03). The mean length of MGs was correlated with symptoms (r = 0.34, P = 0.034), and the mean MG width was correlated with tear film breakup time (r = -0.412, P = 0.009) and the lid margin abnormality score (r = 0.334, P = 0.038). CONCLUSIONS: The MG length and width were significantly decreased in patients with MGD than in the control group. These parameters were correlated to both ocular surface symptoms and clinical signs. This new imaging technique may be a useful tool for MGD evaluation. PMID- 26226468 TI - Microbiologic, Pharmacokinetic, and Clinical Effects of Corneal Collagen Cross Linking on Experimentally Induced Pseudomonas Keratitis in Rabbits. AB - PURPOSE: To determine the effects of corneal collagen cross-linking (CXL) on the penetration of topical 0.5% moxifloxacin, on the number of colony-forming units (CFUs) in the cornea, and on the clinical course in a rabbit eye model of experimentally induced Pseudomonas aeruginosa keratitis. METHODS: In this prospective animal study, experimental Pseudomonas corneal ulcers were induced in 56 corneas of 28 albino New Zealand rabbits. The corneas were randomly divided into the following 4 groups: the control group (14 eyes), the MOX group (moxifloxacin) (14 eyes), the MOX + CXL group (14 eyes), and the CXL group (14 eyes). On day 4 of the experiment, the eyes in the control group were enucleated and CFU counting was performed. On day 10 of the experiment, all eyes were enucleated and CFU counting was performed. In the MOX and MOX + CXL groups, the moxifloxacin level in the cornea, aqueous humor, iris, plasma, and serum was measured by reverse-phase high-performance liquid chromatography. RESULTS: The difference in the corneal CFU count between the MOX group and the MOX + CXL group was not significant (P = 0.317). Clinical improvement was greatest in the MOX + CXL group (P < 0.001). The mean corneal moxifloxacin level was 0.391 +/- 0.09 MUg.mg in the MOX group versus 0.291 +/- 0.09 MUg.mg in the MOX + CXL group; as such, CXL did not have a significant effect on antibiotic penetrance (P = 0.386). CONCLUSIONS: Clinical improvement was greatest in the MOX + CXL group. The synergistic effect of CXL on corneal ulcer treatment is not through antibiotic penetrance. PMID- 26226469 TI - Corneal Power Measurement Obtained by Fourier-Domain Optical Coherence Tomography: Repeatability, Reproducibility, and Comparison With Scheimpflug and Automated Keratometry Measurements. AB - PURPOSE: To assess the repeatability and reproducibility of corneal power values obtained by a Fourier-domain optical coherence tomography (FD-OCT) system (RTVue) and to compare them with the values obtained by a Scheimpflug camera system (Pentacam HR) and by automated keratometry (IOL Master). METHODS: Thirty-two eyes from 32 healthy subjects were included in this prospective study. Two experienced observers measured each eye 3 consecutive times with the Pentacam, IOLMaster, and RTVue centered on either the pupil or corneal vertex. The conventional keratometry equivalent (CKE) and anterior (Ka), posterior (Kp), and net (Kn) corneal power values were determined. RESULTS: The corneal power values obtained by the RTVue showed high repeatability (all intraclass correlation coefficient >0.96) and reproducibility (coefficient of variation <1.0%). Pupil-centered FD OCT performed slightly better than corneal vertex-centered FD-OCT. Mean corneal values had higher reproducibly than any of the individual values. CKE, Ka, Kp, and Kn obtained by FD-OCT were 0.62 to 0.68 diopters (D), 0.70 to 0.76 D, 0.11 to 0.13 D, and 0.93 to 0.94 D higher than those obtained by the Pentacam HR, respectively. CKE and Ka obtained with the RTVue were also 0.60 to 0.74 D higher than those obtained with the IOLMaster, respectively. CONCLUSIONS: The corneal power measurements obtained by the RTVue FD-OCT system showed high repeatability and reproducibility. Measurements obtained by FD-OCT with pupil centration were more reproducible than those obtained by FD-OCT with corneal vertex centration. We recommend that pupil-centered FD-OCT be used in clinical applications. Neither RTVue versus Pentacam HR nor RTVue versus IOLMaster can be used interchangeably. PMID- 26226470 TI - Effectiveness of Autologous Serum Eye Drops Combined With Punctal Plugs for the Treatment of Sjogren Syndrome-Related Dry Eye. AB - PURPOSE: To evaluate the efficacy and safety of autologous serum (AS) eye drops combined with punctal plugs (PPs) in patients with Sjogren syndrome (SS)-related dry eye. METHODS: A retrospective clinical study was performed in patients with dry eye caused by SS. We evaluated the Schirmer test value, tear breakup time (tBUT), and fluorescein and Rose Bengal (RB) staining scores at baseline, 3 months, 6 months, 1 year, and >1 year after treatment. The dry eye indexes were also evaluated in 2 subgroups, which determined by the using of PPs, including the AS + PP group and AS only group. RESULTS: A total of 56 eyes of 28 patients were investigated with a mean follow-up of 42.3 +/- 26.1 months. After the application of AS eye drops, the Schirmer test showed no significant changes. The tBUT (2.7 +/- 1.9 seconds) was significantly improved at each time point (3.9 +/- 3.1, 4.5 +/- 3.1, 3.7 +/- 2.5, and 5.1 +/- 4.0; P < 0.01), fluorescein staining (4.3 +/- 2.8) was significantly improved at each time point (2.2 +/- 2.2, 1.9 +/- 1.9, 1.8 +/- 1.6, and 1.8 +/- 1.8; P < 0.01), and RB (2.6 +/- 3.0) staining was significantly improved from 6-month treatment (1.5 +/- 1.9, 1.9 +/- 1.9, and 1.4 +/- 1.8; P < 0.05, 0.01, and 0.01, respectively). When combined with PPs, the tBUT and RB staining scores were found to be significantly improved in the AS + PP group compared with those of the AS only group. CONCLUSIONS: Long-term application of AS eye drops was found to be an effective and apparently safe treatment for SS dry eye. Furthermore, PPs in combination with AS eye drops were considered to have an additive effect on SS dry eye. PMID- 26226471 TI - Comparison of Corneal Biomechanical Characteristics After Surface Ablation Refractive Surgery and Novel Lamellar Refractive Surgery. AB - PURPOSE: To investigate and compare corneal biomechanical changes in the form of corneal hysteresis (CH) and corneal resistance factor (CRF) after small-incision lenticule extraction (SMILE) and laser-assisted subepithelial keratectomy (LASEK). METHODS: In this retrospective observational study, patients who underwent either SMILE (36 eyes, 21 patients) or LASEK (35 eyes, 19 patients) were included. Data were collected preoperatively and at 1 and 3 months postoperatively, which included corneal topography and Ocular Response Analyzer values of CH, CRF, and intraocular pressure (IOP). Differences between both surgical groups and the relationships between variables were evaluated. RESULTS: CH, CRF, Goldmann IOP, and corneal compensated IOP after surgery were significantly lower than the preoperative values (P < 0.05) in both surgical groups. Lenticule thickness (LT) correlated with DeltaCRF (Delta = postoperative preoperative value) in the SMILE group (r = -0.513, P = 0.001), but the ablation depth (AD) and DeltaCRF showed no correlation in the LASEK group (r = -0.297, P = 0.083). In the SMILE group, DeltaCRF/LT (-0.036 +/- 0.01) and DeltaCH/LT (-0.021 +/- 0.01) values were significantly lower than DeltaCRF/AD (-0.048 +/- 0.02) and DeltaCH/AD (-0.026 +/- 0.02) values in the LASEK group (P < 0.05). CONCLUSIONS: Both SMILE and LASEK alter corneal biomechanical strength. However, the changes induced by SMILE are more predictable than those induced by LASEK. In terms of per unit tissue removed, SMILE seems to have less effect on corneal biomechanics than LASEK, which may be due to preservation of the stiffer anterior stroma. PMID- 26226472 TI - Periprosthetic Tissue Loss in Patients With Idiopathic Vitreous Inflammation After the Boston Keratoprosthesis. AB - PURPOSE: Idiopathic vitritis is a poorly understood complication after Boston keratoprosthesis surgery with unclear etiology. We sought to determine whether an association exists between periprosthetic corneal tissue loss and the development of idiopathic vitritis in keratoprosthesis recipients. METHODS: Thirteen Boston type I keratoprosthesis recipient eyes with a history of idiopathic vitritis and 34 type I keratoprosthesis recipient eyes with no history of idiopathic vitritis underwent anterior segment optical coherence tomography (AS-OCT) at a median time postoperatively of 2.4 years versus 1.9 years (range, 0.5-14.2 vs. 0.1-13.6 years), respectively. Areas of corneal graft tissue loss ("gaps") around the keratoprosthesis stem were identified and analyzed by 2 masked observers. The difference in the presence, number, and size of gaps was compared between cases and controls. RESULTS: A periprosthetic gap was identified more commonly in idiopathic vitritis cases than in controls on AS-OCT (11/13, 86% vs. 11/34, 33.3%, P < 0.001). The number of gaps between cases and controls was also significantly different (2.6 +/- 1.6 vs. 0.5 +/- 0.8, P < 0.001), but not the estimated gap area (0.056 +/- 0.049 mm2 vs. 0.039 +/- 0.025 mm2, P = 0.22). CONCLUSIONS: A significantly higher proportion of keratoprosthesis recipient eyes with idiopathic vitritis had corneal tissue loss around the keratoprosthesis stem than did controls. Tissue loss could serve as an entry point for debris or bacterial components, triggering idiopathic vitritis. Our study underscores the utility of AS-OCT imaging in the postoperative management of keratoprosthesis patients. PMID- 26226473 TI - Corneal Effects of the Dexamethasone-Releasing Biodegradable Intravitreous Implant. PMID- 26226474 TI - Analysis of Meibum Before and After Intraductal Meibomian Gland Probing in Eyes With Obstructive Meibomian Gland Dysfunction. AB - PURPOSE: To evaluate whether the amount of meibum and its viscosity change after intraductal meibomian gland probing in patients with refractory obstructive meibomian gland dysfunction (o-MGD). METHODS: Six lid margins of 3 patients with refractory o-MGD underwent intraductal meibomian gland probing. Meibum and the clinical outcome were evaluated before the procedure and at a 1-month postoperative visit. Meibum was quantified with a Meibometer, and its viscosity (Shimazaki grade) was assessed simultaneously. The tear film condition was evaluated by lipid layer interferometry (DR1, Kowa, Nagoya, Japan), and meibomian gland loss was analyzed by noncontact infrared meibography. Lid margin findings, tear break-up time, fluorescein score, and ocular symptoms were also assessed. RESULTS: At the postoperative visits, all cases showed improvements in meibum lipid levels (446-1376, 757-802, and 396-571 meibometer units) and meibum viscosity (grade 3-0, 3-1, and 3-2). Two cases showed an improvement in tear break-up time (2-5 and 0-6 seconds). No morphological changes in the meibomian gland were observed in any cases. CONCLUSIONS: Intraductal meibomian gland probing seems to improve meibomian gland lipid levels, and it may be a good treatment option for cases of o-MGD that are resistant to conventional treatment. PMID- 26226475 TI - Reply: To PMID 25747162. PMID- 26226476 TI - Refractive Lenticule Extraction Complications. AB - PURPOSE: To report the complications associated with refractive lenticule extraction (ReLEx) in its 2 modalities: femtosecond lenticule extraction (FLEx) and small incision lenticule extraction (SMILE). METHODS: In this retrospective review of a consecutive clinical case series, all patients who had a complicated ReLex FLEx or ReLEx SMILE procedure at the Cornea and External Disease Department at the Instituto de Oftalmologia Fundacion Conde de Valenciana, Mexico City, Mexico, were included. Demographic characteristics, type of complication, and final refraction and visual outcomes were recorded. RESULTS: Our study comprised 94 eyes in the FLEx group and 160 eyes in the SMILE group with a mean follow-up period of 36 months. In the FLEx group, 15 eyes (18.3%) presented surgery-related complications, including suction loss, black spots, bubbles in the interface, and lenticule misdissection. In the SMILE group, 43 eyes (26.9%) had complications, including an epithelial defect (the most frequent), suction loss, opaque bubble layer, cap rupture, and lenticule rupture. CONCLUSIONS: Although ReLEx complications can occur, most of them are related to inexperience and have a favorable resolution with no lasting effect on the patient's final visual acuity. PMID- 26226477 TI - Noninvasive Imaging of Tear Film Dynamics in Eyes With Ocular Surface Disease. AB - PURPOSE: To test the validity of ocular surface assessment tools offered by a corneal topographer (Oculus Keratograph 5M). METHODS: Over 9 months, 296 eyes were imaged and divided into 2 groups: ocular surface disease (OSD) group (223 eyes) with clinically diagnosed meibomian gland dysfunction or dry eye syndrome and control group (73 eyes). All eyes were imaged using the noninvasive Keratograph tear breakup time (NIKBUT), tear meniscus height (TMH), and meibography tools of the Oculus K5M. Traditional methods using fluorescein staining were used to measure tear breakup and meniscus height. Meibography images were graded using the hand tracing method and a novel blue boundary method. RESULTS: Oculus TMH values were statistically significantly higher in the OSD group than the control group (0.4:0.3 mm, P < 0.001), whereas traditional fluorescein values were higher in the control group (0.4:0.2 mm, P < 0.01). Oculus NIKBUT values were not statistically significantly different between the OSD and control groups (6.7:8.2 seconds, P = 0.69), whereas fluorescein breakup time values were statistically significantly higher in the control group (6.7:5.6 seconds, P < 0.05). The meibography hand tracing method showed higher sensitivity between the control group and glandular atrophy (17%:28%, P < 0.05), whereas the blue boundary method showed higher reproducibility (6.9%:23.8%, P < 0.001). CONCLUSIONS: The Oculus K5M can provide automated measurements of tear film dynamics and meibography images without using fluorescein or cobalt blue light. However, the automated TMH and NIKBUT were not in agreement with traditional measurements using fluorescein staining. Meibography highlights glandular architecture, which can be used to analyze glandular density and glandular atrophy. PMID- 26226478 TI - An improved quasi-steady aerodynamic model for insect wings that considers movement of the center of pressure. AB - A quasi-steady aerodynamic model in consideration of the center of pressure (C.P.) was developed for insect flight. A dynamically scaled-up robotic hawkmoth wing was used to obtain the translational lift, drag, moment and rotational force coefficients. The translational force coefficients were curve-fitted with respect to the angles of attack such that two coefficients in the Polhamus leading-edge suction analogy model were obtained. The rotational force coefficient was also compared to that derived by the standard Kutta-Joukowski theory. In order to build the accurate pitching moment model, the locations of the C.Ps. and its movements depending on the pitching velocity were investigated in detail. We found that the aerodynamic moment model became suitable when the rotational force component was assumed to act on the half-chord. This implies that the approximation borrowed from the conventional airfoil concept, i.e., the 'C.P. at the quarter-chord' may lead to an incorrect moment prediction. In the validation process, the model showed excellent time-course force and moment estimations in comparison with the robotic wing measurement results. A fully nonlinear multibody flight dynamic simulation was conducted to check the effect of the traveling C.P. on the overall flight dynamics. This clearly showed the importance of an accurate aerodynamic moment model. PMID- 26226481 TI - Efficacy and Safety of Risperidone and Quetiapine in Adolescents With Bipolar II Disorder Comorbid With Conduct Disorder. AB - Although a frequent co-occurrence between bipolar disorder (BD) and conduct disorder (CD) in youth has been frequently reported, data about pharmacological management are scarce and focused on BD type I. Second generation antipsychotics are frequently used in clinical practice, but no comparative studies are available. The aim of this exploratory study was to compare efficacy and safety of risperidone and quetiapine in a sample of adolescents presenting a BD type II comorbid with CD. Twenty-two patients diagnosed with a structured interview according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (male/female ratio, 12/10; mean (SD) age 15.0 (1.4) years) were randomized in 2 treatment groups (quetiapine [n = 12] vs risperidone [n = 10]), treated with flexible doses, and followed up for 12 weeks. Efficacy measures assessed manic symptoms, aggression, anxiety, depression, global clinical severity, and impairment. Safety measures included body mass index, serum prolactin, extrapyramidal adverse effects, and electrocardiogram. At the end of the study, all patients improved in all efficacy measures. Both treatments showed similar efficacy in reducing manic symptoms and aggression. Quetiapine was more effective in improving anxiety and depressive symptoms. A change in body mass index was found, and in a post hoc analysis, it was significant only in the risperidone group. Prolactin significantly increased only in the risperidone group. In BD type II, CD comorbidity, quetiapine, or risperidone monotherapy may be effective and relatively safe, although the small sample size, the limited duration of the study, and the design (lack of a blind assessments and of a placebo group) make it difficult to draw definitive conclusions. PMID- 26226482 TI - Spatial Scales of Genetic Structure in Free-Standing and Strangler Figs (Ficus, Moraceae) Inhabiting Neotropical Forests. AB - Wind-borne pollinating wasps (Agaonidae) can transport fig (Ficus sp., Moraceae) pollen over enormous distances (> 100 km). Because of their extensive breeding areas, Neotropical figs are expected to exhibit weak patterns of genetic structure at local and regional scales. We evaluated genetic structure at the regional to continental scale (Panama, Costa Rica, and Peru) for the free standing fig species Ficus insipida. Genetic differentiation was detected only at distances > 300 km (Jost's Dest = 0.68 +/- 0.07 & FST = 0.30 +/- 0.03 between Mesoamerican and Amazonian sites) and evidence for phylogeographic structure (RST>>permuted RST) was only significant in comparisons between Central and South America. Further, we assessed local scale spatial genetic structure (SGS, d <= 8 km) in Panama and developed an agent-based model parameterized with data from F. insipida to estimate minimum pollination distances, which determine the contribution of pollen dispersal on SGS. The local scale data for F. insipida was compared to SGS data collected for an additional free-standing fig, F. yoponensis (subgenus Pharmacosycea), and two species of strangler figs, F. citrifolia and F. obtusifolia (subgenus Urostigma) sampled in Panama. All four species displayed significant SGS (mean Sp = 0.014 +/- 0.012). Model simulations indicated that most pollination events likely occur at distances > > 1 km, largely ruling out spatially limited pollen dispersal as the determinant of SGS in F. insipida and, by extension, the other fig species. Our results are consistent with the view that Ficus develops fine-scale SGS primarily as a result of localized seed dispersal and/or clumped seedling establishment despite extensive long-distance pollen dispersal. We discuss several ecological and life history factors that could have species- or subgenus-specific impacts on the genetic structure of Neotropical figs. PMID- 26226483 TI - On and Under the Skin: Emerging Basidiomycetous Yeast Infections Caused by Trichosporon Species. PMID- 26226485 TI - Research on Taxiway Path Optimization Based on Conflict Detection. AB - Taxiway path planning is one of the effective measures to make full use of the airport resources, and the optimized paths can ensure the safety of the aircraft during the sliding process. In this paper, the taxiway path planning based on conflict detection is considered. Specific steps are shown as follows: firstly, make an improvement on A * algorithm, the conflict detection strategy is added to search for the shortest and safe path in the static taxiway network. Then, according to the sliding speed of aircraft, a time table for each node is determined and the safety interval is treated as the constraint to judge whether there is a conflict or not. The intelligent initial path planning model is established based on the results. Finally, make an example in an airport simulation environment, detect and relieve the conflict to ensure the safety. The results indicate that the model established in this paper is effective and feasible. Meanwhile, make comparison with the improved A*algorithm and other intelligent algorithms, conclude that the improved A*algorithm has great advantages. It could not only optimize taxiway path, but also ensure the safety of the sliding process and improve the operational efficiency. PMID- 26226484 TI - Genotype and Haplotype Analyses of TP53 Gene in Breast Cancer Patients: Association with Risk and Clinical Outcomes. AB - Variations in the TP53 gene have been suggested to play a role in many cancers, including breast. We previously observed an association between TP53 haplotypes based on four polymorphisms (rs17878362, rs1042522, rs12947788, and rs17884306) and the risk of colorectal and pancreatic cancer. Based on these results, in the present study, we have investigated the same polymorphisms and their haplotypes in 705 breast cancer cases and 611 healthy controls in relation to the disease risk, histopathological features of the tumor and clinical outcomes. In comparison to the most common haplotype A1-G-C-G, all the other identified haplotypes were globally associated with a significantly decreased breast cancer risk (P = 0.006). In particular, the A2-G-C-G haplotype was associated with a marked decreased risk of breast cancer when compared with the common haplotype (P = 0.0001). Moreover, rs1042522 in patients carrying the GC genotype and receiving only the anthracycline-based chemotherapy was associated with both overall and disease-free survival (recessive model for overall survival HR = 0.30 95% CI 0.11 0.80, P = 0.02 and for disease-free survival HR = 0.42 95% CI 0.21-0.84, P = 0.01). Present results suggest common genetic features in the susceptibility to breast and gastrointestinal cancers in respect to TP53 variations. In fact, similar haplotype distributions were observed for breast, colorectal, and pancreatic patients in associations with cancer risk. Rs1042522 polymorphism (even after applying the Dunn-Bonferroni correction for multiple testing) appears to be an independent prognostic marker in breast cancer patients. PMID- 26226486 TI - Early Diet and Later Cancer Risk: Prospective Associations of Dietary Patterns During Critical Periods of Childhood with the GH-IGF Axis, Insulin Resistance and Body Fatness in Younger Adulthood. AB - Early life, adiposity rebound, and puberty represent critical growth periods when food choices could have long-term relevance for cancer risk. We aimed to relate dietary patterns during these periods to the growth hormone-insulin-like-growth factor (GH-IGF) axis, insulin resistance, and body fatness in adulthood. Data from the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) Study participants with outcome data at 18-37 years, and >=2 dietary records during early life (1-2 yr; n = 128), adiposity rebound (4-6 years, n = 179), or puberty (girls 9-14, boys 10-15 yr; n = 213) were used. Dietary patterns at these ages were derived by 1) reduced rank regression (RRR) to explain variation in adult IGF-I, IGF-binding protein-3 (IGFBP-3), homoeostasis model assessment for insulin resistance (HOMA-IR) and fat-mass index; 2) principal component analysis (PCA). Regarding RRR, the patterns "cake/canned fruit/cheese & eggs" (early life), "sweets & dairy" (adiposity rebound) and "high-fat foods" (pubertal boys) were independently associated with higher adult HOMA-IR. Furthermore, the patterns "favorable carbohydrate sources" (early life), "snack & convenience foods" (adiposity rebound), and "traditional & convenience carbohydrates" (pubertal boys) were related to adult IGFBP-3 (P trend < 0.01). PCA identified "healthy" patterns for all periods, but none was associated with the outcomes (P trend > 0.1). In conclusion, dietary patterns during sensitive growth periods may be of long-term relevance for adult insulin resistance and IGFBP-3. PMID- 26226488 TI - Meshing complex macro-scale objects into self-assembling bricks. AB - Self-assembly provides an information-economical route to the fabrication of objects at virtually all scales. However, there is no known algorithm to program self-assembly in macro-scale, solid, complex 3D objects. Here such an algorithm is described, which is inspired by the molecular assembly of DNA, and based on bricks designed by tetrahedral meshing of arbitrary objects. Assembly rules are encoded by topographic cues imprinted on brick faces while attraction between bricks is provided by embedded magnets. The bricks can then be mixed in a container and agitated, leading to properly assembled objects at high yields and zero errors. The system and its assembly dynamics were characterized by video and audio analysis, enabling the precise time- and space-resolved characterization of its performance and accuracy. Improved designs inspired by our system could lead to successful implementation of self-assembly at the macro-scale, allowing rapid, on-demand fabrication of objects without the need for assembly lines. PMID- 26226487 TI - Effect of Previous Chemotherapy on the Quality of Cryopreserved Human Ovarian Tissue In Vitro. AB - BACKGROUND: Cryopreservation of ovarian tissue has been widely accepted as an option for fertility preservation among cancer patients. Some patients are exposed to chemotherapy prior to ovarian tissue cryopreservation. Consequently, assessment of the developmental capacity of human ovarian tissue after chemotherapy is of primary importance. MATERIALS: In order to study the impact of previous chemotherapy on in vitro development and viability of ovarian follicles, quality control samples from 34 female cancer patients at median age of 15 years (range 1-35), cryopreserved for fertility preservation before (n = 14) or after (n = 20) initiation of chemotherapy, were thawed and cultured for 7 days. The morphology and developmental stages of ovarian follicles were studied by light microscopy before and after culture. Possible associations between follicular densities, age and exposure to alkylating agents, expressed as cyclophosphamide equivalent dose (CED) were tested. RESULTS: Exposure to chemotherapy significantly impaired the survival and development of ovarian follicles in culture. After seven days, significantly higher densities of intermediary, primary and secondary follicles and lower densities of atretic follicles was detected in the samples collected before chemotherapy. Increasing dose of alkylating agents was identified by multivariate linear regression analysis as an independent predictor of a higher density of atretic follicles, whereas increasing age of the patient predicted a better outcome with less follicle atresia and a higher density of maturing follicles. CONCLUSION: This study provides quantitative in vitro evidence of the impact of chemotherapy on developmental capacity of cryopreserved human ovarian tissue. The results indicate that fertility preservation should be carried out, if possible, before initiation of alkylating agents in order to guarantee better in vitro survival of ovarian follicles. In addition, ovarian samples from younger girls show lower viability and fewer developing follicles in culture. PMID- 26226489 TI - High Resolution Prediction of Calcium-Binding Sites in 3D Protein Structures Using FEATURE. AB - Metal-binding proteins are ubiquitous in biological systems ranging from enzymes to cell surface receptors. Among the various biologically active metal ions, calcium plays a large role in regulating cellular and physiological changes. With the increasing number of high-quality crystal structures of proteins associated with their metal ion ligands, many groups have built models to identify Ca(2+) sites in proteins, utilizing information such as structure, geometry, or homology to do the inference. We present a FEATURE-based approach in building such a model and show that our model is able to discriminate between nonsites and calcium binding sites with a very high precision of more than 98%. We demonstrate the high specificity of our model by applying it to test sets constructed from other ions. We also introduce an algorithm to convert high scoring regions into specific site predictions and demonstrate the usage by scanning a test set of 91 calcium-binding protein structures (190 calcium sites). The algorithm has a recall of more than 93% on the test set with predictions found within 3 A of the actual sites. PMID- 26226490 TI - Novel Oxazolidinone-Based Peroxisome Proliferator Activated Receptor Agonists: Molecular Modeling, Synthesis, and Biological Evaluation. AB - A series of new peroxisome proliferator activated receptors (PPARs) chiral ligands have been designed following the accepted three-module structure comprising a polar head, linker, and hydrophobic tail. The majority of the ligands incorporate the oxazolidinone moiety as a novel polar head, and the nature of the hydrophobic tail has also been varied. Docking studies using the crystal structure of an agonist bound to the ligand binding domain of the PPARalpha receptor have been performed as a tool for their design. Suitable synthetic procedures have been developed, and compounds with different stereochemistries have been prepared. Evaluation of basal and ligand-induced activity proved that several compounds showed agonist activity at the PPARalpha receptor, thus validating the oxazolidinone template for PPAR activity. In addition, two compounds, 2 and 4, showed dual PPARalpha/PPARgamma agonism and interesting food intake reduction in rats. PMID- 26226491 TI - EFFECTS OF MEDICAL DISPUTES ON INTERNET COMMUNICATIONS OF NEGATIVE EMOTIONS AND NEGATIVE ONLINE WORD-OF-MOUTH. AB - Emotions play an important role in human behavior. Negative emotions resulting from medical disputes are problems for medical personnel to solve but also have a significant impact on a hospital's reputation and people's trust in the hospital. One medical dispute case was chosen from an Internet news source to assess the correlation between people's negative emotions and negative online word-of-mouth. Convenience sampling was used in school faculties and university students who had shared their medical treatment experiences online were the research participants. A total of 221 Taiwanese participants volunteered (158 women, 63 men; ages: 26.7% under 19, 22.6% 20-29, 30.8% 30-39,19.9% over 40). Four negative emotions were measured using rating scales: uncertainty, anger, disappointment, and sadness. Four negative online word-of-mouth measures were: venting, advice search, helping receiver, and revenge. A modeled relationship was assessed by partial least square method (PLS). Then, people's positive emotions were further analyzed to assess changes after spreading negative word-of-mouth. The results showed that uncertainty had a positive effect on venting and advice search. People who felt anger or regret spread word-of-mouth in order to help the receiver. Disappointment may trigger the revenge behavior of negative word-of-mouth. Negative emotions could be relieved after engaging in the behavior of helping the receiver. PMID- 26226492 TI - DISASTER RELIEF FOR THE JAPANESE EARTHQUAKE-TSUNAMI OF 2011: STRESS REDUCTION THROUGH THE TRANSCENDENTAL MEDITATION(r) TECHNIQUE. AB - This study examined changes in self-reported stress symptoms after instruction in the Transcendental Meditation((r)) technique among 171 residents of two cities (Sendai and Ishinomaki) directly affected by the 2011 Japan earthquake and tsunami disaster compared with 326 non-disaster Tokyo participants previously tested before and after learning the technique and a no-treatment control group (n = 68). The participants completed a rating checklist of mental and physical symptoms. Disaster area participants who learned the Transcendental Meditation((r)) technique in contrast to controls showed a significant drop in total symptom score from pre-test to post-test (effect size = -1.09). Results were comparable for an ordinal measure of symptom intensity. The findings suggest the potential value of this procedure for relief from disaster trauma. PMID- 26226493 TI - INTERNET DEPENDENCE IN CHINESE HIGH SCHOOL STUDENTS: RELATIONSHIP WITH SEX, SELF ESTEEM, AND SOCIAL SUPPORT. AB - This cross-sectional study investigated the relationships among self-esteem, social support, and Internet dependence. A sample of young people aged between 15 and 18 years old (M age = 16.3 yr., SD = 0.7; 470 boys, 441 girls) completed measures of the Rosenberg Self-Esteem Scale, the Perceived Social Support Scale, and the Internet Dependence Test. According to the cognitive-behavioral model of problematic Internet use, social support should mediate the relationship between self-esteem and Internet dependence. Furthermore, based on previous research it was predicted that boys would score higher on Internet dependence than women. Support for this model was obtained. Internet dependent students were more likely to be boys. Self-esteem and social support were negatively correlated with Internet dependence. The relationship between self-esteem and Internet dependence was mediated by social support. Although the effect sizes were small, the findings of the present study are of significance in investigating adolescents' Internet dependence. PMID- 26226494 TI - EFFECT OF SOLICITOR'S SUNTANNED FACE ON COMPLIANCE WITH A FACE-TO-FACE HELPING REQUEST: A BRIEF EXAMINATION IN A FIELD SETTING. AB - Psychologists have investigated why people want to have a tanned skin and how to prevent people's exposure to solar ultraviolet radiation. However, the effect of suntan on social behavior has not been investigated. In this experiment, conducted in France, a female confederate wearing, or not wearing, a self-tanning cream on her face asked 104 male and 111 female passersby (approximate ages 30 to 60 yr.) to participate in a survey. It was found that more passersby agreed with the request when the interviewer had a suntanned face (52%) than in the control condition (39%). Theoretical and practical interests are discussed. PMID- 26226495 TI - SCHOOL VIOLENCE AMONG ARAB ADOLESCENTS IN ISRAEL AND ITS RELATION TO SELF-CONTROL SKILLS AND SOCIAL SUPPORT. AB - In this paper, the author used a cross-sectional design to assess the association between the tendency toward school violence, on the one hand, and self-control, social support, and sex, on the other, among 148 Arab-Israeli adolescents in schools in northern Israel. Standard questionnaires on violence, self-control, and social support were administered. In line with expectations, self-reported violence was significantly associated with males, as well as low scores on self control and social support. PMID- 26226496 TI - THE CULTURAL AND THE UNIVERSAL IN NONBELIEVERS: COMMENT ON JING (2014). AB - The study by Jing (2014) is examined and analyzed within a broader theoretical framework. A general definition of religion is presented, together with a brief description of what makes religion a universal product of human cognition. What we have been observing is a general decrease in religiosity as well as an increase in the number of individuals who describe themselves as nonbelievers. Secularization does not mean that religious ideas disappear, but that there is a significant decline in the allocation of material and psychological resources to supernaturalism. Chinese nonbelievers studied by Jing are not very different than nonbelievers in other cultures. PMID- 26226497 TI - PRELIMINARY DEVELOPMENT OF A SCALE TO MEASURE LEADERSHIP POTENTIAL. AB - Based on the assumption that leadership can be developed and college students possess leadership potential before becoming adult leaders, a Leadership Potential Scale was developed for Korean college students. Factors of leadership were extracted and preliminary items were developed through a literature review and semi-structured interviews. The items were assessed by experts for face validity, and the 12 factors and 78 items of the Leadership Potential Scale were derived from a factor analysis of data from 305 college students. The results of a subsequent study (N = 320) indicate the scale is ready to be further validated in a known-groups design. PMID- 26226498 TI - THE LINK BETWEEN DEPRESSION AND SCHADENFREUDE: FURTHER EVIDENCE. AB - This replication examined the link between schadenfreude (i.e., pleasure from another's misfortune), freudenfreude (i.e., pleasure from another's success), and self-rated depression. Using the Freudenfreude and Schadenfreude Test (FAST), moderately depressed students reported more schadenfreude and less freudenfreude than their mildly depressed peers. The limitations of this study and further research directions are discussed. PMID- 26226499 TI - THE RELATIONSHIP BETWEEN CULTURAL IDENTITY AND SELF-ESTEEM AMONG CHINESE UYGHUR COLLEGE STUDENTS: THE MEDIATING ROLE OF ACCULTURATION ATTITUDES. AB - Most acculturation research throughout the world has been conducted in immigrant settings. In order to examine the generalizability of the previous conclusions in immigrant settings, the present study tried to explore the relationship between cultural identity and self-esteem and the mediating role of acculturation attitudes in China. Using the cross-sectional design, a total number of 342 Uyghur college students were asked to complete a survey comprising the Multi Group Ethnic/National Identity Measure-Revised Scale, the Acculturation Attitudes Scale, and the Rosenberg Self-Esteem Scale. Using hierarchical multiple regression, the results indicated that cultural identity was positively correlated with self-esteem. A significant mediation of acculturation was observed between cultural identity and self-esteem. These findings demonstrated the significance of cultural identity and acculturation attitudes in the adaptation of Chinese Uyghur college students, in which integration is an optimal acculturation attitude. PMID- 26226500 TI - pKa tuning in quadrupolar-type two-photon ratiometric fluorescent membrane probes. AB - Two bolaamphiphilic quadrupoles built from a fluorene core conjugated with azine endgroups were designed and successfully used to stain GUV membranes. Their quadrupolar character induces both a shift of the pKa values close to the physiological pH and large two-photon absorption responses (i.e. over 1000 GM for acidic forms). As such they hold promise as ratiometric two-photon pH probes for monitoring slight variations of pH near cell membranes using two-photon excitation in the NIR region. PMID- 26226501 TI - High-Impact Articles-Citations, Downloads, and Altmetric Score. PMID- 26226502 TI - Platinum Dendritic-Flowers Prepared by Tellurium Nanowires Exhibit High Electrocatalytic Activity for Glycerol Oxidation. AB - Dentritic Pt-based nanomaterials with enriched edge and corner atoms have recently attracted considerable attention as electrocatalysts. Meanwhile, Pt(111) facets are generally considered more active for the glycerol oxidation reaction (GOR). Thus, it is significant to construct the rational design and synthesis of dentritic Pt whose surface is mostly enclosed by {111} facets. Reported herein is a unique Pt-branched structure enriched by a large amount of valency unsaturated atoms prepared by the aggravation of the galvanic replacement strategy. The synthesis is developed to generate highly crystallized Pt nanoflowers using Te nanowires as a template. Furthermore, the electrochemical results show that Pt nanoflower is an excellent catalyst with higher mass activity and better structure stability than commercial Pt/C (20% Pt) for glycerol electro-oxidation. Besides, the template-broken approach could provide a novel potential way to synthesize Pt-based or other noble metals/alloys for their advanced functional applications. PMID- 26226503 TI - Can the addition of verapamil to bedaquiline-containing regimens improve tuberculosis treatment outcomes? A novel approach to optimizing TB treatment. PMID- 26226504 TI - Kruppel-Like Factor 4 Regulates Granule Cell Pax6 Expression and Cell Proliferation in Early Cerebellar Development. AB - Kruppel-like factor 4 (Klf4) is a transcription factor that regulates many important cellular processes in stem cell biology, cancer, and development. We used histological and molecular methods to study the expression of Klf4 in embryonic development of the normal and Klf4 knockout cerebellum. We find that Klf4 is expressed strongly in early granule cell progenitor development but tails off considerably by the end of embryonic development. Klf4 is also co-expressed with Pax6 in these cells. In the Klf4-null mouse, which is perinatal lethal, Klf4 positively regulates Pax6 expression and regulates the proliferation of neuronal progenitors in the rhombic lip, external granular layer and the neuroepithelium. This paper is the first to describe a role for Klf4 in the cerebellum and provides insight into this gene's function in neuronal development. PMID- 26226505 TI - Is the Cell Nucleus a Necessary Component in Precise Temporal Patterning? AB - One of the functions of the cell nucleus is to help regulate gene expression by controlling molecular traffic across the nuclear envelope. Here we investigate, via stochastic simulation, what effects, if any, does segregation of a system into the nuclear and cytoplasmic compartments have on the stochastic properties of a motif with a negative feedback. One of the effects of the nuclear barrier is to delay the nuclear protein concentration, allowing it to behave in a switch like manner. We found that this delay, defined as the time for the nuclear protein concentration to reach a certain threshold, has an extremely narrow distribution. To show this, we considered two models. In the first one, the proteins could diffuse freely from cytoplasm to nucleus (simple model); and in the second one, the proteins required assistance from a special class of proteins called importins. For each model, we generated fifty parameter sets, chosen such that the temporal profiles they effectuated were very similar, and whose average threshold time was approximately 150 minutes. The standard deviation of the threshold times computed over one hundred realizations were found to be between 1.8 and 7.16 minutes across both models. To see whether a genetic motif in a prokaryotic cell can achieve this degree of precision, we also simulated five variations on the coherent feed-forward motif (CFFM), three of which contained a negative feedback. We found that the performance of these motifs was nowhere near as impressive as the one found in the eukaryotic cell; the best standard deviation was 6.6 minutes. We argue that the significance of these results, the fact and necessity of spatio-temporal precision in the developmental stages of eukaryotes, and the absence of such a precision in prokaryotes, all suggest that the nucleus has evolved, in part, under the selective pressure to achieve highly predictable phenotypes. PMID- 26226506 TI - Hot Carrier Trapping Induced Negative Photoconductance in InAs Nanowires toward Novel Nonvolatile Memory. AB - We report a novel negative photoconductivity (NPC) mechanism in n-type indium arsenide nanowires (NWs). Photoexcitation significantly suppresses the conductivity with a gain up to 10(5). The origin of NPC is attributed to the depletion of conduction channels by light assisted hot electron trapping, supported by gate voltage threshold shift and wavelength-dependent photoconductance measurements. Scanning photocurrent microscopy excludes the possibility that NPC originates from the NW/metal contacts and reveals a competing positive photoconductivity. The conductivity recovery after illumination substantially slows down at low temperature, indicating a thermally activated detrapping mechanism. At 78 K, the spontaneous recovery of the conductance is completely quenched, resulting in a reversible memory device, which can be switched by light and gate voltage pulses. The novel NPC based optoelectronics may find exciting applications in photodetection and nonvolatile memory with low power consumption. PMID- 26226507 TI - Final-State Projection Method in Charge-Transfer Multiplet Calculations: An Analysis of Ti L-Edge Absorption Spectra. AB - A projection method to determine the final-state configuration character of all peaks in a charge transfer multiplet calculation of a 2p X-ray absorption spectrum is presented using a d(0) system as an example. The projection method is used to identify the most important influences on spectral shape and to map out the configuration weights. The spectral shape of a 2p X-ray absorption or L2,3 edge spectrum is largely determined by the ratio of the 2p core-hole interactions relative to the 2p3d atomic multiplet interaction. This leads to a nontrivial spectral assignment, which makes a detailed theoretical description of experimental spectra valuable for the analysis of bonding. PMID- 26226508 TI - Environmental Filtering of Microbial Communities in Agricultural Soil Shifts with Crop Growth. AB - Plant and soil properties cooperatively structure soil microbial communities, with implications for ecosystem functioning. However, the extent to which each factor contributes to community structuring is not fully understood. To quantify the influence of plants and soil properties on microbial diversity and composition in an agricultural context, we conducted an experiment within a corn based annual cropping system and a perennial switchgrass cropping system across three topographic positions. We sequenced barcoded 16S ribosomal RNA genes from whole soil three times throughout a single growing season and across two years in July. To target the belowground effects of plants, we also sampled rhizosphere soil in July. We hypothesized that microbial community alpha-diversity and composition (beta-diversity) would be more sensitive to cropping system effects (annual vs. perennial inputs) than edaphic differences among topographic positions, with greater differences occurring in the rhizosphere compared to whole soil. We found that microbial community composition consistently varied with topographic position, and cropping system and the rhizosphere influenced alpha-diversity. In July, cropping system and rhizosphere structured a small but specific group of microbes implying a subset of microbial taxa, rather than broad shifts in community composition, may explain previously observed differences in resource cycling between treatments. Using rank abundance analysis, we detected enrichment of Saprospirales and Actinomycetales, including cellulose and chitin degraders, in the rhizosphere soil and enrichment of Nitrospirales, Syntrophobacterales, and MND1 in the whole soil. Overall, these findings support environmental filtering for the soil microbial community first by soil and second by the rhizosphere. Across cropping systems, plants selected for a general rhizosphere community with evidence for plant-specific effects related to time of sampling. PMID- 26226509 TI - Bilateral, multiple, episodic retinal vein occlusions associated with common variable immunodeficiency. PMID- 26226511 TI - Systems Modelling of the Socio-Technical Aspects of Residential Electricity Use and Network Peak Demand. AB - Provision of network infrastructure to meet rising network peak demand is increasing the cost of electricity. Addressing this demand is a major imperative for Australian electricity agencies. The network peak demand model reported in this paper provides a quantified decision support tool and a means of understanding the key influences and impacts on network peak demand. An investigation of the system factors impacting residential consumers' peak demand for electricity was undertaken in Queensland, Australia. Technical factors, such as the customers' location, housing construction and appliances, were combined with social factors, such as household demographics, culture, trust and knowledge, and Change Management Options (CMOs) such as tariffs, price, managed supply, etc., in a conceptual 'map' of the system. A Bayesian network was used to quantify the model and provide insights into the major influential factors and their interactions. The model was also used to examine the reduction in network peak demand with different market-based and government interventions in various customer locations of interest and investigate the relative importance of instituting programs that build trust and knowledge through well designed customer-industry engagement activities. The Bayesian network was implemented via a spreadsheet with a tickbox interface. The model combined available data from industry-specific and public sources with relevant expert opinion. The results revealed that the most effective intervention strategies involve combining particular CMOs with associated education and engagement activities. The model demonstrated the importance of designing interventions that take into account the interactions of the various elements of the socio-technical system. The options that provided the greatest impact on peak demand were Off-Peak Tariffs and Managed Supply and increases in the price of electricity. The impact in peak demand reduction differed for each of the locations and highlighted that household numbers, demographics as well as the different climates were significant factors. It presented possible network peak demand reductions which would delay any upgrade of networks, resulting in savings for Queensland utilities and ultimately for households. The use of this systems approach using Bayesian networks to assist the management of peak demand in different modelled locations in Queensland provided insights about the most important elements in the system and the intervention strategies that could be tailored to the targeted customer segments. PMID- 26226510 TI - Irritable bowel syndrome: dietary interventions. AB - INTRODUCTION: The prevalence of irritable bowel syndrome (IBS) varies depending on the criteria used to diagnose it, but it ranges from about 5% to 20%. IBS is associated with abnormal gastrointestinal motor function and enhanced visceral perception, as well as psychosocial and genetic factors. People with IBS often have other bodily and psychiatric symptoms, and have an increased likelihood of having unnecessary surgery compared with people without IBS. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of dietary modification (gluten-free diet, a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols [FODMAPs]) in people with irritable bowel syndrome? We searched Medline, Embase, The Cochrane Library, and other important databases up to June 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). RESULTS: At this update, searching of electronic databases retrieved 33 studies. After deduplication and removal of conference abstracts, 19 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 14 studies and the further review of five full publications. Of the five full articles evaluated, three RCTs were included. Based upon their own search, the contributor(s) added two additional RCTs that did not meet Clinical Evidence inclusion criteria; these have been added to the Comment section. We performed a GRADE evaluation of the quality for two PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for two interventions based on information relating to the effectiveness and safety of dietary modification (gluten-free diet or a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols [FODMAPs]). PMID- 26226512 TI - Rational Constraints and the Evolution of Fairness in the Ultimatum Game. AB - Behavior in the Ultimatum Game has been well-studied experimentally, and provides a marked contrast between the theoretical model of a self-interested economic agent and that of an actual human concerned with social norms such as fairness. How did such norms evolve, when punishing unfair behavior can be costly to the punishing agent? The work described here simulated a series of Ultimatum Games, in which populations of agents earned resources based on their preferences for proposing and accepting (or rejecting) offers of various sizes. Two different systems governing the acceptance or rejection of offers were implemented. Under one system, the probability that an agent accepted an offer of a given size was independent of the probabilities of accepting the other possible offers. Under the other system, a simple, ordinal constraint was placed on the acceptance probabilities such that a given offer was at least as likely to be accepted as a smaller offer. For simulations under either system, agents' preferences and their corresponding behavior evolved over multiple generations. Populations without the ordinal constraint came to emulate maximizing economic agents, while populations with the constraint came to resemble the behavior of human players. PMID- 26226513 TI - Reactions of Titanium Hydrazides with Silanes and Boranes: N-N Bond Cleavage and N Atom Functionalization. AB - Reaction of Ti(N2(iPr)N)(NNPh2)(py) with Ph(R)SiH2 (R = H, Ph) or 9-BBN gave reductive cleavage of the N(alpha)-N(beta) bond and formation of new silyl- or boryl-amido ligands. The corresponding reactions of Cp*Ti{MeC(N(i)Pr)2}(NNR2) (R = Me or Ph) with HBPin or 9-BBN gave borylhydrazido-hydride or borylimido products, respectively. N(alpha) and N(beta) atom transfer and dehydrogenative coupling reactions are also reported. PMID- 26226514 TI - Overview of community-based studies of depression screening interventions among the elderly population in Japan. AB - OBJECTIVES: In most Western and Asian countries, a higher risk of suicide is found among elderly people than those in other age groups. However, the treatment needs of elderly people who are at risk of committing suicide are not well understood. We conducted an overview of studies that assessed the impact of suicide prevention interventions on suicide rates in elderly people in Japan. We interpreted the results of these studies, as well as prominent findings associated with other successful interventions, within a framework of the suicidal process and preventive strategies. METHOD: We assessed six quasi experimental studies of community-based interventions providing universal depression screening, subsequent care, and education to elderly people in Japan, and performed a combined analysis of outcome data. RESULTS: Screening interventions were associated with lower suicide rates. We also found a gender difference in the response to subsequent psychiatric or primary care. Two types of interventions decreased the rate of suicide among elderly people: crisis helplines and screening interventions. These interventions featured a close link between universal, selective, and indicated prevention strategies, which reflect different approaches tailored to the size and risk profile of the target individuals. CONCLUSION: Successful interventions appear to hinge on systematic links between multi-level prevention interventions. Multi-level interventions for depression screening may result in lower suicide rates among elderly individuals in communities, although primary care interventions alone appear to be insufficient in men. The benefit of linked multi-level prevention interventions may highlight the importance of the multiple steps and components of the suicidal process. PMID- 26226516 TI - Stereoselective Synthesis of Enantioenriched 2-Chloro-2-aroylaziridines by Cascade Reaction between Aryl Nitriles, Silyldichloromethanes, and tert Butanesulfinylimines. AB - The cascade coupling of aryl nitriles, silyldichloromethanes, and tert butanesulfinylimines is described, in which silyldichloromethyllithiums, generated from silyldichloromethanes in the presence of lithium diisopropylamide, undergo nucleophilic addition with aryl nitriles and subsequent [1,3]-aza-Brook rearrangement to give dichlorocarbanions bearing alpha-N-silyl imine (or their 1 azaenolate equivalents), which are then trapped by tert-butanesulfinylimines via an aza-Darzens-type transformation, affording enantioenriched 2-chloro-2 aroylaziridines after acidic hydrolysis of the N-silyl imine group. The stereochemistry of this cascade reaction can be tuned by selecting appropriate silyl groups on the silyldichloromethanes and altering the order of addition of the imines and the hexamethylphosphoramide additive. PMID- 26226515 TI - Prevalence and Molecular Characterization of Glucose-6-Phosphate Dehydrogenase Deficiency at the China-Myanmar Border. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked hereditary disease that predisposes red blood cells to oxidative damage. G6PD deficiency is particularly prevalent in historically malaria-endemic areas. Use of primaquine for malaria treatment may result in severe hemolysis in G6PD deficient patients. In this study, we systematically evaluated the prevalence of G6PD deficiency in the Kachin (Jingpo) ethnic group along the China-Myanmar border and determined the underlying G6PD genotypes. We surveyed G6PD deficiency in 1770 adult individuals (671 males and 1099 females) of the Kachin ethnicity using a G6PD fluorescent spot test. The overall prevalence of G6PD deficiency in the study population was 29.6% (523/1770), among which 27.9% and 30.6% were males and females, respectively. From these G6PD deficient samples, 198 unrelated individuals (147 females and 51 males) were selected for genotyping at 11 known G6PD single nucleotide polymorphisms (SNPs) in Southeast Asia (ten in exons and one in intron 11) using a multiplex SNaPshot assay. Mutations with known association to a deficient phenotype were detected in 43.9% (87/198) of cases, intronic and synonymous mutations were detected alone in 34.8% (69/198) cases and no mutation were found in 21.2% (42/198) cases. Five non-synonymous mutations, Mahidol 487G>A, Kaiping 1388G>A, Canton 1376G>T, Chinese 4 392G>T, and Viangchan 871G>A were detected. Of the 87 cases with known deficient mutations, the Mahidol variant was the most common (89.7%; 78/87), followed by the Kaiping (8.0%; 7/87) and the Viangchan (2.2%; 2/87) variants. The Canton and Chinese 4 variants were found in 1.1% of these 87 cases. Among them, two females carried the Mahidol/Viangchan and Mahidol/Kaiping double mutations, respectively. Interestingly, the silent SNPs 1311C>T and IVS11nt93T>C both occurred in the same 95 subjects with frequencies at 56.4% and 23.5% in tested females and males, respectively (P<0.05). It is noteworthy that 24 subjects carrying the Mahidol mutation and two carrying the Kaiping mutation also carried the 1311C>T/IVS11nt93T>C SNPs. Further studies are needed to determine the enzyme levels of the G6PD deficient people and presence of additional G6PD mutations in the study population. PMID- 26226517 TI - Correction: Genomics of Divergence along a Continuum of Parapatric Population Differentiation. PMID- 26226518 TI - Sulphate absorption across biological membranes. AB - 1. Sulphonation is unusual amongst the common Phase II (condensation; synthetic) reactions experienced by xenobiotics, in that the availability of the conjugating agent, sulphate, may become a rate-limiting factor. This sulphate is derived within the body via the oxygenation of sulphur moieties liberated from numerous ingested compounds including the sulphur-containing amino acids. Preformed inorganic sulphate also makes a considerable contribution to this pool. 2. There has been a divergence of opinion as to whether or not inorganic sulphate may be readily absorbed from the gastrointestinal tract and this controversy still continues in some quarters. Even more so, is the vexing question of potential absorption of inorganic sulphate via the lungs and through the skin. 3. This review examines the relevant diverse literature and concludes that sulphate ions may move across biological membranes by means of specific transporters and, although the gastrointestinal tract is by far the major portal of entry, some absorption across the lungs and the skin may take place under appropriate circumstances. PMID- 26226519 TI - Interplay of metabolizing enzymes and transporter of xenobiotics. AB - 1. Xenobiotics are metabolized and eliminated through the coordinated interplay of their metabolizing enzymes and transporters. However, these two activities in vitro are measured separately, with the addition of ATP as a pre-requisite. 2. We propose a human renal cell-line model which integrates the sulfate and glutathione conjugation of xenobiotics with the efflux of their respective conjugates. Sulfation and glutathionylation represent two major Phase II detoxification of xenobiotics in man. The reactions are catalyzed, respectively, by phenolsulfotransferase and glutathione-S-transferase followed by extrusion of their respective conjugates. 3. Using Ko-143, a specific inhibitor of breast cancer resistance protein (BCRP), an ATP-binding cassette (ABC) transporter, we identified this transporter to be responsible for the efflux of p-cresol sulfate, harmol sulfate and the glutathione conjugate of 1-chloro-2,4-dinitrobenzene. 4. The conjugation-cum-efflux was inhibited by oligomycin and uncouplers, which highlights the role of cellular mitochondria in providing ATP for the biosynthesis of their conjugating agents, 3'-phosphoadenosine-5'-phosphosulfate (PAPS) and reduced glutathione as well as for the transport function of BCRP. 5. The human 786-O renal cell-line provides a "3-in-1" system linking ATP biosynthesis to metabolism of xenobiotics and their ultimate transport and elimination by BCRP; this integrated system was not apparent in other human cell lines examined. PMID- 26226521 TI - Blue Water Navy Vietnam Veterans and Agent Orange Exposure. PMID- 26226520 TI - Effect of quercetin against mixture of four organophosphate pesticides induced nephrotoxicity in rats. AB - 1. It has been demonstrated that the ingestion of foods containing quercetin protects against the toxicity of single pesticides. The aim of this study is to make a comprehensive elaboration about the protective effect of quercetin against multi-organophosphorous pesticides induced nephrotoxicity by measuring indices in rat kidney, urine and serum. Rats were divided into six groups (n = 10/group): control, two different doses of quercetin, pesticide mixture (PM), and different doses of quercetin plus PM-treated groups. 2. The following parameters were significantly changed in PM-treated groups compared with the control (p < 0.01). In kidney, malondialdehyde level raised; catalase, superoxide dismutase activities and glutathione levels were decreased. Comet assay of nephrocytes showed that the proportion of DNA in the tail and tail length increased. In urine, beta2-microglobulin, retinol-conjugated protein levels and N-acetyl-beta-D glucosaminidase activity showed increasing response; meanwhile uric acid level was decreased. In serum, creatinine and urea nitrogen levels were increased. However, the anomaly changes of indexes mentioned above in PM-treated group were alleviated when simultaneously administrated with 50 mg/kg body weight/day quercetin (p < 0.05). 3. From the present findings, it can be evaluated that quercetin may protect against adverse effects resulted from multi organophosphorous pesticides with significant high levels of uptake in man provided. PMID- 26226523 TI - Use of Tranexamic Acid in Bleeding Combat Casualties. PMID- 26226525 TI - Tobacco Research in the Military: Reflections on 20 Years of Research in the United States Air Force. AB - The U.S. military is one of the world's largest employers. Approximately 30% of active duty military personnel smoke cigarettes and more than 14% use smokeless tobacco. The military has historically supported tobacco use and more recently is attempting to combat its use. Through 20 years of collaborative research with the United States Air Force, we have learned that smoking bans are effective, recruits who have never previously smoked cigarettes initiate tobacco use, smokeless tobacco serves as a gateway for smoking initiation, smoking is associated with discharge, smoking adds significant proximal training costs, tobacco use increases during deployment, and tobacco quitline counseling with a provision of medication is effective. Our findings may provide groundwork for future tobacco control efforts in the U.S. military. PMID- 26226526 TI - Veterans' Perspectives on Benefits and Drawbacks of Peer Support for Posttraumatic Stress Disorder. AB - Peer support has been increasingly utilized within the Department of Veterans Affairs and offers an opportunity to augment existing care for posttraumatic stress disorder (PTSD). The current study sought to examine Veterans' perspectives on the potential benefits and drawbacks of peer support for PTSD. A sample of 23 Veterans with substantial treatment experience completed one-time qualitative interviews that were transcribed and coded for thematic content using grounded theory methodology. Results indicated that Veterans identified numerous potential benefits to a peer support program, including social support, purpose and meaning, normalization of symptoms and hope, and therapeutic benefits. Veterans also identified ways that peer support could complement psychotherapy for PTSD by increasing initiation and adherence to treatment and supporting continued use of skills after termination. Results also indicated that Veterans may prefer peer support groups that are separated according to trauma type, gender, and era of service. Other findings highlighted the importance of the leadership and interpersonal skills of a peer support group leader. Overall, Veterans found peer support to be a highly acceptable complement to existing PTSD treatments with few drawbacks. PMID- 26226527 TI - Character Strengths and Hardiness of Australian Army Special Forces Applicants. AB - Australian Army Special Forces (SF) applicants (N = 95) were asked to rank themselves on 24 character strengths at the start of the selection process. Across all applicants, the character strength of integrity was most frequently assigned a top-four rank (45%), followed by team worker (41%), persistence (36%), and love of learning (25%). Successful applicants assigned a top-four rank to team worker significantly more often than unsuccessful applicants (65% versus 32%). The likelihood of passing when team worker was highly ranked (37.5%) was 2.6 times greater than without team worker listed in the top ranks (14.3%). Self ratings of hardiness revealed no discernible differences between successful and unsuccessful applicants, either alone or in combination with the team worker rankings. These results were largely consistent with the results of a previous study with a cohort of applicants for a different Australian SF unit. Results are discussed with respect to their implications for enhancing the assessment of SF applicants. PMID- 26226528 TI - Self-Reported Pain and Pain Management Strategies Among Veterans With Traumatic Brain Injury: A Pilot Study. AB - Reports of chronic pain such as headache, back and neck pain, and other musculoskeletal conditions are common among veterans with history of traumatic brain injury (TBI). This pilot study investigates self-reported pain and pain management strategies in a sample of veterans in postacute recovery from TBI. Participants included 24 outpatients with history of mild-to-moderate TBI who completed a series of self-report measures by mail, including the Pain Outcomes Questionnaire, the Pain Symptom Survey pain scale, and a detailed background survey. Seventy-nine percent of veterans surveyed reported frequent experiences with pain, typically headache, lower back, and joint pain of moderate severity. Two-thirds reported multiple pain locations, and more than half reported multiple concurrent mental health concerns, most frequently depression and post-traumatic stress disorder. Several different pain self-management strategies were identified with highly variable effects, though better perceived pain outcomes were reported with regular use of exercise and antidepressants. Many participants identified significant concerns regarding reinjury. Results suggest that opportunity exists for mental health professionals to address common anxieties pertaining to reinjury and to deliver concurrent interventions for chronic pain and affective disturbance. PMID- 26226529 TI - Tactical Damage Control Resuscitation. AB - Recently the Committee on Tactical Combat Casualty Care changed the guidelines on fluid use in hemorrhagic shock. The current strategy for treating hemorrhagic shock is based on early use of components: Packed Red Blood Cells (PRBCs), Fresh Frozen Plasma (FFP) and platelets in a 1:1:1 ratio. We suggest that lack of components to mimic whole blood functionality favors the use of Fresh Whole Blood in managing hemorrhagic shock on the battlefield. We present a safe and practical approach for its use at the point of injury in the combat environment called Tactical Damage Control Resuscitation. We describe pre-deployment preparation, assessment of hemorrhagic shock, and collection and transfusion of fresh whole blood at the point of injury. By approaching shock with goal-directed therapy, it is possible to extend the period of survivability in combat casualties. PMID- 26226530 TI - Expedited Partner Therapy to Combat Neisseria gonorrhoeae and Chlamydia trachomatis in Military Populations: Can We Apply This Best Practice? AB - Expedited Partner Therapy (EPT) is the practice of treating the partners of patients with sexually transmitted infections by providing medications for the patient to deliver to his or her sexual partner (s) without direct clinical assessment of the partner(s). EPT is an evidence-based option that can augment existing partner management strategies. For military health care providers, questions still loom as to the pragmatic medical, legal, and ethical uncertainties of EPT use in military populations. These issues, in addition to the absence of an explicit Department of Defense EPT policy may dissuade military clinicians from fully employing EPT to prevent reinfection and inhibit additional disease transmission in their patients. To advance the notion that EPT could not only be an efficient but also a vital measure to decrease the high sexually transmitted disease burden, this report highlights existing approaches utilized by military providers to treat partners of patients diagnosed with chlamydia and/or gonorrhea, benefits of using EPT in military populations, and specific challenges of implementing an EPT program. This report asserts that now is the time to "push the conversation" on the use of EPT as a viable choice for military providers. PMID- 26226531 TI - Post-traumatic Stress Disorder Among Navy Health Care Personnel Following Combat Deployment. AB - U.S. Navy health care personnel are exposed to an array of psychological stressors during combat deployment. This study compared rates of post-traumatic stress disorder (PTSD) among Navy health care personnel with nonhealth care personnel following single and repeated combat deployments. The study sample was identified from electronic records indicating deployment to Iraq, Kuwait, or Afghanistan, and included 3,416 heath care and 4,648 nonhealth care personnel. Health care personnel had higher PTSD rates and an increasing trend in PTSD rates across repeated deployments. After adjusting for combat exposure and other covariates, health care compared with nonhealth care personnel were more likely to be diagnosed with PTSD after one (odds ratio [OR] 2.02; 95% confidence interval [CI] 1.45-2.80), two (OR 2.27; 95% CI 1.26-4.08), and three deployments (OR 4.37; 95% CI 1.25-15.28). Exposure to wounded/dead friendly forces was associated with higher PTSD rates in health care personnel (OR 1.53; 95% CI 1.13 2.07). Health care personnel occupy a unique and essential role in current wartime operations, and are a high-risk group for PTSD. These findings suggest that further research is needed on the effects of caregiver stress, and refinements to postdeployment screening for health care personnel should be pursued. PMID- 26226532 TI - Challenges of Forward Naval Surgical Support for Maritime Forces. AB - The emphasis of naval operations has shifted from conventional naval warfare since World War II to Operations Other than War such as Peace Support Operations and Humanitarian Aid and Disaster Relief. Maritime forces are increasingly deployed in distant areas of operations such as the Somali Basin and Gulf of Aden for longer durations, in a possibly higher threat environment against nonconventional threats such as in counter piracy operations. There is therefore a need to balance the challenges of providing adequate forward naval surgical support with limitations in medical manpower, logistics as well as the need for a suitable surgical platform for these deployments. This article aims to share the Republic of Singapore Navy's experience in overcoming some of these challenges. This includes the ability to deploy surgical containers onboard the Landing Ship Tank and Civil Resource vessels, and the ability to convert existing spaces onboard the endurance class Landing Ship Tank and other platforms such as the formidable class Frigate into surgical facilities. The key success factors such as the development of deep expertise in naval operational medicine, operationalization of third generation surgical stores, and enhanced interoperability among maritime forces will also be highlighted. PMID- 26226533 TI - Veterans Speak Up: Current Warnings on Skin Cancer Miss the Target, Suggestions for Improvement. AB - BACKGROUND: Skin cancer is the most common cancer in the world and its incidence is increasing. Veterans may have increased exposure to risk factors, but data are lacking in terms of their perceptions of skin cancer and the types of prevention strategies that might resonate with this population. OBJECTIVE: This study examines veterans' awareness of the risk factors for skin cancer and importance of sun protection and seeks to identify effective communication and educational strategies for this at-risk population. METHODS: A telephone survey was conducted of 100 veterans, who have been diagnosed with skin cancer at the Audie Murphy Veteran's Hospital in San Antonio, Texas. RESULTS: The majority of respondents' said that their skin cancer resulted from sun exposure and that the best way to prevent skin cancer was to use sunscreen. However, when asked if they believed they were at risk for being diagnosed with skin cancer, most veterans responded that they believed they were at little risk. In response to why veterans did not heed warnings about skin cancer, many replied that they believed skin cancer would not happen to them. A statistically significant increase in usage of sunscreen and sun protectant garments occurred after being diagnosed with skin cancer and education by their physicians. Doctors talking to patients was rated the most effective communication method to inform them about the risks of skin cancer, followed by education during basic training. LIMITATIONS: Recall bias is the major limitation with a retrospective survey design. DISCUSSION: Our results reveal poor patient awareness of the risks of skin cancer and the benefits of sun protection before their diagnosis. The veterans agreed that the physician-patient interaction is the best and most effective means of communication, which is evident by the significant increase in sun protection and sunscreen usage after their diagnosis. Our survey revealed that other effective communication strategies included education in basic training, the use of a veteran spokes model with skin cancer, and the use of images to emphasize the severity of the disease. PMID- 26226534 TI - Architecting the Future U.S. Military Psychological Health Enterprise via Policy and Procedure Analysis. AB - Although researchers suggest that a systems approach is required to make meaningful advances in the U.S. psychological health care system for service members, limited research has considered such an approach. This research uses an enterprise architecting framework to identify the system's strengths and areas for opportunity as they relate to the Ecosystem, Stakeholders, Strategy, Process, Organization, Knowledge, Information, and Infrastructure. Codifying qualitative data from publicly available U.S. Defense Health Agency and U.S. Service Branch doctrine, policy guidance, and concepts of operations, our findings indicate that the psychological health care system is strongly process-oriented and mentions a variety of key stakeholders and their roles and responsibilities in the enterprise. Potential opportunities of improvement for the system include a stronger emphasis on the development and transfer of knowledge capabilities, and a stronger information-based infrastructure. PMID- 26226535 TI - Risk Factors for Sustaining a Lower Extremity Injury in an Army Reserve Officer Training Corps Cadet Population. AB - Injuries acquired during Reserve Officer Training Corps (ROTC) participation can potentially affect a cadet's future and career in the armed forces. The purpose of this study was to identify risk factors associated with lower extremity injuries in an Army ROTC cadet population. There were 195 (165M, 30F) cadets enrolled in an Army ROTC program, 18 to 33 years old, with an average body mass index (BMI) of 23.5 +/- 2.85. Injury data were retrospectively obtained from the electronic medical records maintained by a Certified Athletic Trainer. Descriptive statistics, frequencies, and incidence rate for physical training (PT) were calculated. Survival analysis determined association between injury and several variables (Military Science [MS] year, army physical fitness test scores, BMI, sex, previous lower extremity injury, PT exposures, most frequent boot worn, current and prior physical activity, and collision sport participation). Kaplan Meier curves were used for the categorical variables. Incidence rate was 60 lower extremity injuries/100 person-years during PT. The survival analysis revealed MS year (p < 0.001) and PT exposures (p < 0.001) were significant in predicting risk of injury. All other variables were not significant. On the basis of this preliminary data, footwear and activity have no implications on risk of lower extremity injury. Preventative measures should be focused toward younger cadets because of their increased risk for injury. PMID- 26226536 TI - Efficacy of a Tobacco Quitline in Active Duty Military and TRICARE Beneficiaries: A Randomized Trial. AB - A higher proportion of military personnel than civilians smoke cigarettes. Few randomized trials of tobacco use interventions have been conducted in the U.S. military. We evaluated the efficacy of a tobacco quitline (QL) in 1298 active duty military personnel, their dependents, reservists, and retirees who smoke cigarettes. Participants were randomized to either a proactive (counselor initiated) or reactive (participant-initiated) QL intervention for 8 weeks. The proactive condition included up to an 8-week supply of free nicotine replacement therapy, and the reactive condition included a 2-week supply. The primary outcome was 12-month smoking abstinence. The enrolled population was predominantly affiliated with the Air Force and Army. At the end of treatment, proactive treatment was associated with a greater odds of both prolonged (44.22% vs. 24.96%; odds ratio [OR] = 2.4, P < 0.0001) and 7-day point prevalence (49.92% vs. 28.20%; OR = 2.5, P < 0.0001) smoking abstinence, a difference that was maintained for prolonged smoking abstinence at 12 months (22.03% vs. 13.41%; OR = 1.8, P < 0.0001). Our findings provide evidence that a proactive QL with nicotine replacement therapy is highly efficacious among Air Force and Army active duty and TRICARE beneficiaries and would provide an effective telephonic treatment option for this population of smokers. PMID- 26226537 TI - John Paul Jones' Autopsy. PMID- 26226538 TI - Sickle Cell Trait-Related Exertional Deaths: Observations at Autopsy and Review of the Literature. AB - Sickle cell trait-related exertional deaths, although rare, are well-accepted in the field of forensic pathology; however, the increased risk of sudden unexpected deaths in persons with sickle cell trait undergoing strenuous physical activity may be an underappreciated acute phenomenon in the clinical realm. Herein, we report two cases of sickle cell trait-related exertional deaths of active duty military members, with a review of the literature including the pathophysiology of sickle cell trait-related deaths and current military screening guidelines. PMID- 26226539 TI - Sickle Cell Trait Complicated by Acute Rhabdomyolysis in Military Personnel: A Case Report. AB - Sickle cell trait, a trait known to be protective against falciparum malaria, is prevalent in the African American community. Unlike true sickle cell disease, sickle cell trait is currently not a disqualifying condition for military service. In the case below, we describe an occurrence, from Logar Provence, Afghanistan (2,072 m above mean sea level), of exertional acute rhabdomyolysis in an American service member known to be a sickle cell trait carrier. The case serves to educate Military Medical providers and Commanders alike, to the increased risk certain training and work environments have on sickle cell trait Service members; it raises the question of what duty limitations, if any, sickle cell carriers should have. PMID- 26226540 TI - Caffeine Toxicity Due to Supplement Use in Caffeine--Naive Individual: A Cautionary Tale. AB - Thousands of military members self-medicate with dietary supplements containing unknown quantities of pharmacologically active compounds. These poorly regulated substances can cause real harm to the military population, especially when they contain stimulants such as caffeine. When taken regularly, caffeine has several performance-enhancing benefits. However, when used excessively or in vulnerable populations, caffeine can cause several unwanted side effects such as nervousness, sensory disturbances, insomnia, arrhythmia, excitability, inattentiveness, restlessness, mood changes, gastrointestinal disturbances, and even psychosis. Vulnerable patients include the caffeine-naive, physiologically stressed, young, and mentally ill patients. One such case describes a caffeine naive service member who suffered an adverse reaction after taking an allegedly moderate dose of caffeine from a pill he obtained from a teammate. This case highlights the importance of supplement awareness among service members, increased provider vigilance, third party verification, and enhanced regulation on the approval and marketing of dietary supplements. PMID- 26226541 TI - Surfactant chemistry for fluorescence imaging of latent fingerprints using conjugated polyelectrolyte nanoparticles. AB - When aqueous conjugated-polyelectrolyte colloidal solutions containing an adequate amount of surfactant with an appropriate hydrophile-lipophile balance were sprayed onto latent fingerprints (LFPs), the polymer nanoparticles were readily transferred to the LFPs to reveal highly distinguishable fluorescent images, while the LFPs themselves remained intact. PMID- 26226542 TI - Detection limits for blood on four fabric types using infrared diffuse reflection spectroscopy in mid- and near-infrared spectral windows. AB - Detection limits (DL) for blood on four fabric types were estimated for calibrations derived using partial least squares regression applied to infrared (IR) diffuse reflection spectra. Samples were prepared by dip-coating acrylic, cotton, nylon, and polyester fabrics from solutions of diluted rat blood. While DLs often appear in terms of dilution factor in the forensic community, mass percentage, coverage (mass per unit area), or film thickness are often more relevant when comparing experimental methods. These alternate DL units are related to one another and presented here. The best IR diffuse reflection DLs for blood on acrylic and cotton fabrics were in the mid-IR spectral window corresponding to the protein Amide I/II absorption bands. These DLs were dilution by a factor of 2300 (0.019% w/w blood solids) for acrylic and a factor of 610 (0.055% w/w blood solids) for cotton. The best DL for blood on polyester was found in the mid-IR spectral window corresponding to the protein Amide A absorption band at dilution by a factor of 900 (0.034% w/w blood solids). Because of the similarity between the IR spectra of blood solids and nylon fabrics, no satisfactory IR DLs were determined for the calibration of blood on nylon. We compare our values to DLs reported for blood detection using the standard luminol method. The most commonly reported luminol DLs are of the order of 1000-fold dilution, which we estimate are a factor of 2-7 lower than our reported IR DLs on a coverage basis. PMID- 26226543 TI - Characterization and Biological Potency of Mono- to Tetra-Halogenated Carbazoles. AB - This paper deals with the characterization and aryl hydrocarbon receptor (AhR) agonist activities of a series of chlorinated, brominated, and mixed bromo/chlorocarbazoles, some of which have been identified in various environmental samples. Attention is directed here to the possibility that halogenated carbazoles may currently be emitted into the environment as a result of the production of carbazole-containing polymers present in a wide variety of electronic devices. We have found that any carbazole that is not substituted in the 1,3,6,8 positions may be lost during cleanup of environmental extracts if a multilayer column is utilized, as is common practice for polychlorinated dibenzo p-dioxin (dioxin) and related compounds. In the present study, (1)H NMR spectral shift data for 11 relevant halogenated carbazoles are reported, along with their gas chromatographic separation and analysis by mass spectrometry. These characterization data allow for confident structural assignments and the derivation of possible correlations between structure and toxicity based on the halogenation patterns of the isomers investigated. Some halogenated carbazoles exhibit characteristics of persistent organic pollutants and their potential dioxin-like activity was further investigated. The structure-dependent induction of CYP1A1 and CYP1B1 gene expression in Ah-responsive MDA-MB-468 breast cancer cells by these carbazoles was similar to that observed for other dioxin-like compounds, and the magnitude of the fold induction responses for the most active halogenated carbazoles was similar to that observed for 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). 2,3,6,7-Tetrachlorocarbazole was one of the most active halogenated carbazoles and, like TCDD, contains 4 lateral substituents; however, the estimated relative effect potency for this compound (compared to TCDD) was 0.0001 and 0.0032, based on induction of CYP1A1 and CYP1B1 mRNA, respectively. PMID- 26226544 TI - Cu(0)-Mediated Living Radical Polymerization: A Versatile Tool for Materials Synthesis. PMID- 26226545 TI - Light-Controlled Delivery of Monoclonal Antibodies for Targeted Photoinactivation of Ki-67. AB - The selective inhibition of intracellular and nuclear molecules such as Ki-67 holds great promise for the treatment of cancer and other diseases. However, the choice of the target protein and the intracellular delivery of the functional agent remain crucial challenges. Main hurdles are (a) an effective delivery into cells, (b) endosomal escape of the delivered agents, and (c) an effective, externally triggered destruction of cells. Here we show a light-controlled two step approach for selective cellular delivery and cell elimination of proliferating cells. Three different cell-penetrating nano constructs, including liposomes, conjugates with the nuclear localization sequence (NLS), and conjugates with the cell penetrating peptide Pep-1, delivered the light activatable antibody conjugate TuBB-9-FITC, which targets the proliferation associated protein Ki-67. HeLa cells were treated with the photosensitizer benzoporphyrin monoacid derivative (BPD) and the antibody constructs. In the first optically controlled step, activation of BPD at 690 nm triggered a controlled endosomal escape of the TuBB-9-FITC constructs. In more than 75% of Ki 67 positive, irradiated cells TuBB-9-FITC antibodies relocated within 24 h from cytoplasmic organelles to the cell nucleus and bound to Ki-67. After a second light irradiation at 490 nm, which activated FITC, cell viability decreased to approximately 13%. Our study shows an effective targeting strategy, which uses light-controlled endosomal escape and the light inactivation of Ki-67 for cell elimination. The fact that liposomal or peptide-assisted delivery give similar results leads to the additional conclusion that an effective mechanism for endosomal escape leaves greater variability for the choice of the delivery agent. PMID- 26226546 TI - Short- and Long-term Pulmonary Outcome of Palivizumab in Children Born Extremely Prematurely. AB - BACKGROUND: Palivizumab reduces the severity of respiratory syncytial virus infection in premature infants, but whether there is a protective effect beyond the preschool age is unknown. This study sought to assess the short- and long term effects of palivizumab immunization on respiratory morbidity and pulmonary function at school age in children born extremely prematurely. METHODS: Infants born before 29 weeks' gestation in 2000 to 2003 were assessed at school age by parental questionnaire, hospital chart review, and lung function tests. Children born immediately before the introduction of routine palivizumab prophylaxis were compared with age-matched children who received palivizumab prophylaxis during the first respiratory syncytial virus season. RESULTS: Sixty-three children with a mean age 8.9 years were included: 30 had received palivizumab and 33 had not (control subjects). The groups were similar in terms of gestational age, birth weight, need for mechanical ventilation, and oxygen supplementation. Fifty-three percent of the palivizumab group, compared with 39% of the control group, had bronchopulmonary dysplasia (P = .14). Wheezing occurred in the first 2 years of life in 27% of the palivizumab group and in 70% of control subjects (P = .008); respective hospitalization rates were 33% and 70% (P = .001). At school age, rates of hyperresponsiveness (provocative concentration leading to a 20% fall in FEV1 < 1 mg/mL) were 33% and 48%, respectively (P = .38). Spirometry, lung volumes, diffusion, and exhaled nitric oxide were within normal limits, with no significant differences between groups. CONCLUSION: Palivizumab prophylaxis was associated with reduced wheezing episodes and hospitalizations during the first 2 years of life in children born extremely prematurely. However, it did not affect pulmonary outcome at school age. PMID- 26226547 TI - Diabetes Worsens Ischemia-Reperfusion Brain Injury in Rats Through GSK-3beta. AB - BACKGROUND: Diabetes aggravates brain injury after cerebral ischemia/reperfusion (I/R). OBJECTIVE: To investigate whether limb I/R causes cerebral injury in a rat diabetes model and whether glycogen synthase kinase-3beta (GSK-3beta) is involved. METHODS: Male adult Sprague-Dawley rats were assigned into streptozotocin-induced diabetes (n = 30; blood glucose >=16.7 mmol/L) or control (n = 20) groups, further subdivided into diabetes I/R (3-hour femoral artery/vein clamping), diabetes-I/R + TDZD-8 (I/R plus GSK-3beta inhibitor), diabetes-sham, control-sham and control-I/R groups (n = 10 each). Cortical and hippocampal morphology (hematoxylin/eosin); hippocampal CA1 apoptosis (TUNEL assay); cleaved caspase-3 (apoptosis), and Iba1 (microglial activation) protein expression (immunohistochemistry); phosphorylated/total GSK-3beta and nuclear factor-kappaB (NF-kappaB) protein levels (Western blotting); and serum and brain tissue tumor necrosis factor (TNF)-alpha levels (enzyme-linked immunosorbent assay) were analyzed. RESULTS: The diabetes-I/R group showed greater cortical and hippocampal injury, apoptosis, cleaved caspase-3 expression and Iba1 expression than the control-I/R group; TDZD-8 reduced injury/apoptosis and cleaved caspase-3/Iba1 expressions. The diabetes-I/R group had lower p-GSK-3beta and p-NF-kappaBp65 expression than the control-I/R group (P < 0.05); TDZD-8 increased p-GSK-3beta expression but decreased p-NF-kappaBp65 expression (P < 0.05). The diabetes-I/R group showed higher elevation of serum and brain tissue TNF-alpha than the control-I/R group (P < 0.05); TDZD-8 reduced TNF-alpha production. CONCLUSIONS: Diabetes exacerbates limb I/R-induced cerebral damage and activates NF-kappaB and GSK-3beta. PMID- 26226548 TI - Effect of Inflammatory Bowel Disease-Related Characteristics and Treatment Interventions on Cardiovascular Disease Incidence. AB - BACKGROUND: An association between inflammatory bowel disease (IBD) and cardiovascular diseases has been shown in multiple studies. However, little is known about the effect of IBD-related characteristics on cardiovascular events. METHODS: The authors conducted a retrospective, nested case-control study of IBD patients who presented to the institution from 2000 to 2004, allowing for a 10 year follow-up period. One hundred eleven patients who developed cardiovascular events (cases) and 222 patients who did not develop cardiovascular events (cases) were included in the study after matching for Framingham cardiovascular risk score (2008). Relationships between predictor variables and cardiovascular outcome were assessed by conditional logistic regression. RESULTS: The cases and controls were similar in age, gender, smoking and cholesterol level. There was no difference in disease subtype (ulcerative colitis or Crohn's disease). On conditional logistic regression, thiopurine treatment (odds ratio [OR]: 0.42, 95% confidence interval [CI]: 0.19-0.87; P = 0.02) was associated with decreased cardiovascular events and tumor necrosis factor alpha antagonist use (OR: 2.63, 95% CI: 1.49-4.63; P = 0.001) was associated with increased cardiovascular events. Although not statistically significant, disease-related surgery (OR: 0.57, 95% CI: 0.32-1.02; P = 0.06) was associated with decreased cardiovascular events and disease-related hospitalization (OR: 1.58, 95% CI: 0.96-2.57; P = 0.07) was associated with increased incidence of cardiovascular disorders. CONCLUSIONS: The authors observed decreased incidence of cardiovascular diseases in patients with IBD who were treated with thiopurines and increased incidence of cardiovascular outcomes among patients treated with tumor necrosis factor alpha antagonist. PMID- 26226550 TI - The Poisson distribution and beyond: methods for microfluidic droplet production and single cell encapsulation. AB - There is a recognized and growing need for rapid and efficient cell assays, where the size of microfluidic devices lend themselves to the manipulation of cellular populations down to the single cell level. An exceptional way to analyze cells independently is to encapsulate them within aqueous droplets surrounded by an immiscible fluid, so that reagents and reaction products are contained within a controlled microenvironment. Most cell encapsulation work has focused on the development and use of passive methods, where droplets are produced continuously at high rates by pumping fluids from external pressure-driven reservoirs through defined microfluidic geometries. With limited exceptions, the number of cells encapsulated per droplet in these systems is dictated by Poisson statistics, reducing the proportion of droplets that contain the desired number of cells and thus the effective rate at which single cells can be encapsulated. Nevertheless, a number of recently developed actively-controlled droplet production methods present an alternative route to the production of droplets at similar rates and with the potential to improve the efficiency of single-cell encapsulation. In this critical review, we examine both passive and active methods for droplet production and explore how these can be used to deterministically and non deterministically encapsulate cells. PMID- 26226551 TI - Burnout and associated factors among members of the Society of Gynecologic Oncology. AB - OBJECTIVE: Burnout is specific to the work domain and in physicians is indicative of emotional exhaustion, depersonalization in relationships with coworkers and detachment from patients, and a sense of inadequacy or low personal accomplishment. The purpose of this study was to determine the burnout rate among gynecologic oncologists and evaluate other personal, professional, and psychosocial factors associated with this condition. STUDY DESIGN: This study used a cross-sectional design. Current members of the Society of Gynecologic Oncology were sent an anonymous email survey including 76 items measuring burnout, psychosocial distress, career satisfaction, and quality of life. RESULTS: A total of 1086 members were invited, 436 (40.1%) responded, and 369 (84.6%) of those completed the survey. Of physicians, 30% scored high for emotional exhaustion, 10% high for depersonalization, and 11% low for personal accomplishment. Overall, 32% of physicians scored above clinical cutoffs indicating burnout. In all, 33% screened positive for depression, 13% endorsed a history of suicidal ideation, 15% screened positive for alcohol abuse, and 34% reported impaired quality of life. Nonetheless, 70% reported high levels of personal accomplishment, and results suggested most were satisfied with their careers, as 89% would enter medicine again and 61% would encourage their child to enter medicine. Respondents with high burnout scores were less likely to report they would become a physician again (P = .002) or encourage a child to enter medicine (P < .001), and more likely to screen positive for depression (P < .001), alcohol abuse (P = .006), history of suicidal ideation (P < .001), and impaired quality of life (P < .001). CONCLUSION: Burnout is a significant problem associated with psychosocial distress and lower levels of career satisfaction in gynecologic oncologists. Burnout in obstetrics-gynecology and gynecologic oncology is of particular concern as young age and female gender are often identified as risk factors for this significant problem. Interventions targeted at improving quality of life, treatment of depression, or alcohol abuse may have an impact on burnout. However, significant barriers may exist as 44.5% of respondents in this study reported that they would be reluctant to seek medical care for depression, substance use, or other mental health issues due to concerns about their medical license. PMID- 26226552 TI - The use of clinical characteristics to help prevent morcellation of leiomyosarcoma: An analysis of 491 cases. PMID- 26226553 TI - Ultrasound-guided manipulation of fetal entrapment by a large uterine fibroid. PMID- 26226554 TI - Does prolapse equal hysterectomy? The role of uterine conservation in women with uterovaginal prolapse. AB - Hysterectomy has historically been a mainstay in the surgical treatment of uterovaginal prolapse, even in cases in which the removal of the uterus is not indicated. However, uterine-sparing procedures have a long history and are now becoming more popular. Whereas research on these operations is underway, hysteropexy for the treatment of prolapse is not as well studied as hysterectomy based repairs. Compared with hysterectomy and prolapse repair, hysteropexy is associated with a shorter operative time, less blood loss, and a faster return to work. Other advantages include maintenance of fertility, natural timing of menopause, and patient preference. Disadvantages include the lack of long-term prolapse repair outcomes and the need to continue surveillance for gynecological cancers. Although the rate of unanticipated abnormal pathology in this population is low, women who have uterine abnormalities or postmenopausal bleeding are not good candidates for uterine-sparing procedures. The most studied approaches to hysteropexy are the vaginal sacrospinous ligament hysteropexy and the abdominal sacrohysteropexy, which have similar objective and subjective prolapse outcomes compared with hysterectomy and apical suspension. Pregnancy and delivery have been documented after vaginal and abdominal hysteropexy approaches, although very little is known about outcomes following parturition. Uterine-sparing procedures require more research but remain an acceptable option for most patients with uterovaginal prolapse after a balanced and unbiased discussion reviewing the advantages and disadvantages of this approach. PMID- 26226555 TI - An update on inpatient hysterectomy routes in the United States. PMID- 26226556 TI - Risk factors for retained placenta. AB - OBJECTIVE: Retained placenta complicates 2-3% of vaginal deliveries and is a known cause of postpartum hemorrhage. Treatment includes manual or operative placental extraction, potentially increasing risks of hemorrhage, infections, and prolonged hospital stays. We sought to evaluate risk factors for retained placenta, defined as more than 30 minutes between the delivery of the fetus and placenta, in a large US obstetrical cohort. STUDY DESIGN: We included singleton, vaginal deliveries >=24 weeks (n = 91,291) from the Consortium of Safe Labor from 12 US institutions (2002-2008). Multivariable logistic regression analyses estimated the adjusted odds ratios (OR) and 95% confidence intervals (CI) for potential risk factors for retained placenta stratified by parity, adjusting for relevant confounding factors. Characteristics such as stillbirth, maternal age, race, and admission body mass index were examined. RESULTS: Retained placenta complicated 1047 vaginal deliveries (1.12%). Regardless of parity, significant predictors of retained placenta included stillbirth (nulliparous adjusted OR, 5.67; 95% CI, 3.10-10.37; multiparous adjusted OR, 4.56; 95% CI, 2.08-9.94), maternal age >=30 years, delivery at 24 0/7 to 27 6/7 compared with 34 weeks or later and delivery in a teaching hospital. In nulliparous women, additional risk factors were identified: longer first- or second-stage labor duration, whereas non-Hispanic black compared with non-Hispanic white race was found to be protective. Body mass index was not associated with an increased risk. CONCLUSION: Multiple risk factors for retained placenta were identified, particularly the strong association with stillbirth. It is plausible that there could be something intrinsic about stillbirth that causes a retained placenta, or perhaps there are shared pathways of certain etiologies of stillbirth and a risk of retained placenta. PMID- 26226557 TI - Short-Chain Chlorinated Paraffins in Zurich, Switzerland--Atmospheric Concentrations and Emissions. AB - Short-chain chlorinated paraffins (SCCPs) are of concern due to their potential for adverse health effects, bioaccumulation, persistence, and long-range transport. Data on concentrations of SCCPs in urban areas and underlying emissions are still scarce. In this study, we investigated the levels and spatial distribution of SCCPs in air, based on two separate, spatially resolved sampling campaigns in the city of Zurich, Switzerland. SCCP concentrations in air ranged from 1.8 to 17 ng.m(-3) (spring 2011) and 1.1 to 42 ng.m(-3) (spring 2013) with medians of 4.3 and 2.7 ng.m(-3), respectively. Both data sets show that atmospheric SCCP levels in Zurich can vary substantially and may be influenced by a number of localized sources within this urban area. Additionally, continuous measurements of atmospheric concentrations performed at one representative sampling site in the city center from 2011 to 2013 showed strong seasonal variations with high SCCP concentrations in summer and lower levels in winter. A long-term dynamic multimedia environmental fate model was parametrized to simulate the seasonal trends of SCCP concentrations in air and to back-calculate urban emissions. Resulting annual SCCP emissions in the city of Zurich accounted for 218-321 kg, which indicates that large SCCP stocks are present in urban areas of industrialized countries. PMID- 26226558 TI - Comparison of photoresponse of transistors based on graphene-quantum dot hybrids with layered and bulk heterojunctions. AB - Phototransistors based on graphene-quantum dot hybrids have a high responsivity and gain. However, the influence of the type of heterojunction on the photoresponse of the transistors is still undetermined. A comparison was performed on field-effect phototransistors (FEpTs) with two types of heterojunctions: layered heterojunctions (LHs) and bulk heterojunctions (BHs). Through a comparative study, it was shown that BH-FEpTs had electron and hole mobilities (MUE and MUH) of 677 and 527 cm(2) V(-1) s(-1) whereas LH-FEpTs had lower mobilities of MUE = 314 cm(2) V(-1) s(-1) and MUH = 367 cm(2) V(-1) s(-1). The large interfacial area in the BHs reduced the degree of channel order (alpha) by two orders of magnitude compared with the LHs. Although a higher mobility was achieved, an increase in the degree of channel disorder and the lack of an effective transfer mechanism limits the responsivity in BH-FEpTs. Therefore, LH FEpTs are more appropriate candidates for near infrared phototransistors. PMID- 26226559 TI - Allosteric Breakage of the Hydrogen Bond within the Dual-Histidine Motif in the Active Site of Human Pin1 PPIase. AB - Intimate cooperativity among active site residues in enzymes is a key factor for regulating elaborate reactions that would otherwise not occur readily. Peptidyl prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is the phosphorylation dependent cis-trans peptidyl-prolyl isomerase (PPIase) that specifically targets phosphorylated Ser/Thr-Pro motifs. Residues C113, H59, H157, and T152 form a hydrogen bond network in the active site, as in the noted connection. Theoretical studies have shown that protonation to thiolate C113 leads to rearrangement of this hydrogen bond network, with switching of the tautomeric states of adjacent histidines (H59 and H157) [Barman, A., and Hamelberg, D. (2014) Biochemistry 53, 3839-3850]. This is called the "dual-histidine motif". Here, C113A and C113S Pin1 mutants were found to alter the protonation states of H59 according to the respective residue type replaced at C113, and the mutations resulted in disruption of the hydrogen bond within the dual-histidine motif. In the C113A mutant, H59 was observed to be in exchange between epsilon- and delta-tautomers, which widened the entrance of the active site cavity, as seen by an increase in the distance between residues A113 and S154. The C113S mutant caused H59 to exchange between the epsilon-tautomer and imidazolium while not changing the active site structure. Moreover, the imidazole ring orientations of H59 and H157 were changed in the C113S mutant. These results demonstrated that a mutation at C113 modulates the hydrogen bond network dynamics. Thus, C113 acts as a pivot to drive the concerted function among the residues in the hydrogen bond network, as theoretically predicted. PMID- 26226560 TI - Light-induced nitric oxide release from physiologically stable porous coordination polymers. AB - The development of nitric oxide (NO) releasing materials has been of significant importance due to their application in cell biology and biomedicine. Besides the macromolecular scaffold dangling NO releasing moiety, porous materials have been used to host such NO releasing molecules. Here we synthesized a series of porous coordination polymers (PCPs), in which N-nitrosamine functional groups as photoactive NO donors were introduced into the framework scaffolds by post synthetic nitrosation of amine functionalized analogous PCPs. We further demonstrated a controlled release of NO from the PCPs by light irradiation. Though isoreticular frameworks based on octanuclear clusters of titanium or aluminium ions were chosen due to their water-stability, the frameworks showed difference in stability in cell culture media; while aluminium frameworks were less stable in water and physiological media, the titanium analogue was highly stable even under physiological conditions. PMID- 26226561 TI - CO2 pulse and acid-base status during increasing work rate exercise in health and disease. AB - The CO2 pulse (VCO2/heart rate), analogous to the O2 pulse (VO2/heart rate), was calculated during cardiopulmonary exercise testing and evaluated in normal and diseased states. Our aim was to define its application in its release in excess of that from VCO2/heart rate in the presence of impaired cardiovascular and lung function. In the current study, forty-five patients were divided into six physiological states: normal, exercise-induced myocardial ischemia, chronic heart failure, pulmonary vasculopathy, chronic obstructive pulmonary disease, and interstitial lung disease. We subtracted the O2 pulse from the CO2 pulse to determine the exhaled CO2 that could be attributed to CO2 pulse of buffering of lactic acid. The difference between the CO2 pulse and O2 pulse (VCO2/heart rate VO2/heart rate) includes CO2 generated from HCO3(-) buffering of lactic acid. The accumulated CO2 per body mass was found to be significantly correlated with the corresponding [HCO3(-)] decrease (R(2)=0.72; P<0.0001). In summary, the increase in CO2 pulse over the O2 pulse accounted for the anaerobically-generated excess CO2 in each of the physiological states and correlated with the decreases in the arterial Bicarbonate concentration. PMID- 26226562 TI - Efficient production of 2,3-butanediol in Saccharomyces cerevisiae by eliminating ethanol and glycerol production and redox rebalancing. AB - 2,3-Butanediol is a promising valuable chemical that can be used in various areas as a liquid fuel and a platform chemical. Here, 2,3-butanediol production in Saccharomyces cerevisiae was improved stepwise by eliminating byproduct formation and redox rebalancing. By introducing heterologous 2,3-butanediol biosynthetic pathway and deleting competing pathways producing ethanol and glycerol, metabolic flux was successfully redirected to 2,3-butanediol. In addition, the resulting redox cofactor imbalance was restored by overexpressing water-forming NADH oxidase (NoxE) from Lactococcus lactis. In a flask fed-batch fermentation with optimized conditions, the engineered adh1Deltaadh2Deltaadh3Deltaadh4Deltaadh5Deltagpd1Deltagpd2Delta strain overexpressing Bacillus subtilis alpha-acetolactate synthase (AlsS) and alpha acetolactate decarboxylase (AlsD), S. cerevisiae 2,3-butanediol dehydrogenase (Bdh1), and L. lactis NoxE from a single multigene-expression vector produced 72.9 g/L 2,3-butanediol with the highest yield (0.41 g/g glucose) and productivity (1.43 g/(L . h)) ever reported in S. cerevisiae. PMID- 26226563 TI - Sensitivity to musical emotions in congenital amusia. AB - The emotional experience elicited by music is largely dependent on structural characteristics such as pitch, rhythm, and dynamics. We examine here to what extent amusic adults, who have experienced pitch perception difficulties all their lives, still maintain some ability to perceive emotions from music. Amusic and control participants judged the emotions expressed by unfamiliar musical clips intended to convey happiness, sadness, fear and peacefulness (Experiment 1A). Surprisingly, most amusic individuals showed normal recognition of the four emotions tested here. This preserved ability was not due to some peculiarities of the music, since the amusic individuals showed a typical deficit in perceiving pitch violations intentionally inserted in the same clips (Experiment 1B). In Experiment 2, we tested the use of two major structural determinants of musical emotions: tempo and mode. Neutralization of tempo had the same effect on both amusics' and controls' emotional ratings. In contrast, amusics did not respond to a change of mode as markedly as controls did. Moreover, unlike the control participants, amusics' judgments were not influenced by subtle differences in pitch, such as the number of semitones changed by the mode manipulation. Instead, amusics showed normal sensitivity to fluctuations in energy, to pulse clarity, and to timbre differences, such as roughness. Amusics even showed sensitivity to key clarity and to large mean pitch differences in distinguishing happy from sad music. Thus, the pitch perception deficit experienced by amusic adults had only mild consequences on emotional judgments. In sum, emotional responses to music may be possible in this condition. PMID- 26226564 TI - Willingness of future A/H7N9 influenza vaccine uptake: A cross-sectional study of Hong Kong community. AB - We conducted a population telephone survey in Hong Kong during the second wave of influenza A/H7N9 outbreak in 2014. Among the respondents, 50.5% of the respondents would like to accept A/H7N9 vaccination in future. Respondents had poor knowledge of A/H7N9 influenza and vaccines. More than 60% of respondents mixed up seasonal influenza this year and A/H7N9 influenza. Results show that socio-demographic factors were all independent of the vaccine uptake willingness while anxiety level and vaccine history were the main affecting factors. Vaccine promotion strategies may focus on influenza knowledge, attitude and behavior. PMID- 26226565 TI - Digital Health: Hope, Hype, and Amara's Law. PMID- 26226566 TI - Trials and Tribulations: The Prevention of Variceal Rebleeding. PMID- 26226567 TI - Genetics and Genetic Testing in Hereditary Colorectal Cancer. AB - Colorectal cancer (CRC) remains the third most common cancer affecting men and women in the United States. Approximately one-third of CRCs are diagnosed in individuals who have family members also affected with the disease. Although the vast majority of colorectal neoplasms develop as a consequence of somatic genomic alterations arising in individual cells, approximately 5% of all CRCs arise in the setting of germline mutations in genes involved in key cellular processes. To date, multiple genes have been implicated in single-gene hereditary cancer syndromes, many of which are associated with increased risk for CRC, as well as other tumor types. This review outlines the clinical, pathologic, and genetic features of the hereditary cancer syndromes known to be associated with increased risk for CRC and delineates strategies for implementing genetic risk assessments in clinical settings. PMID- 26226568 TI - Lack of Survival Benefit Following Liver Transplantation With MELD Exception Points for Hepatocellular Carcinoma: Beyond the Unblinding of Lady Justice. PMID- 26226569 TI - Increasing the Impact of Randomized, Controlled Trials in Gastrointestinal Endoscopy. PMID- 26226570 TI - c-Kit as a Novel Potential Therapeutic Target in Colorectal Cancer. PMID- 26226571 TI - The FXR-FGF19 Gut-Liver Axis as a Novel "Hepatostat". PMID- 26226572 TI - Deficiency in lysophosphatidylcholine acyltransferase 3 reduces plasma levels of lipids by reducing lipid absorption in mice. AB - BACKGROUND & AIMS: Phosphatidylcholines (PCs) are structural and functional constituents of cell membranes. The activity of acyltransferase (lysophosphatidylcholine acyltransferase [LPCAT]) is required for addition of polyunsaturated fatty acids to the sn-2 position of PCs and is therefore required to maintain cell membrane structure and function. LPCAT3 is the most abundant isoform of LPCAT in the small intestine and liver, which are important sites of plasma lipoprotein metabolism. We investigated the effects of Lpcat3 disruption on lipid metabolism in mice. METHODS: We disrupted the gene Lpcat3 in C57BL/6J mice to create LPCAT3 knockout (KO) mice. Livers and small intestinal tissues were collected from LPCAT3 KO and C57BL/6J parental strain (controls), and levels of LPCAT messenger RNAs and protein were measured. Levels of lipids and lipoproteins were measured in plasma samples. We isolated enterocytes from mice and measured levels of RNAs and proteins involved in lipid uptake by real-time polymerase chain reaction and immunoblot assays, respectively. We assessed lipid absorption and PC subspecies in the enterocyte plasma membrane using liquid chromatography with tandem mass spectometry. RESULTS: LPCAT3 KO mice survived only 3 weeks after birth. Oil Red O staining showed that the control but not LPCAT3 KO mice accumulated lipids in the small intestine; levels of Niemann-Pick C1-like 1 (NPC1L1) and fatty acid transporter protein 4 (FATP4), which regulate lipid uptake, were greatly reduced in the small intestines of LPCAT3 KO mice. Oral administration of PC and olive oil allowed the LPCAT3 KO mice to survive with the same body weights as controls, but the KO mice had shorter and wider small-intestinal villi and longer and bigger small intestines. Plasma membranes of enterocytes from LPCAT3 KO mice also had significant reductions in the composition of polyunsaturated PCs and reduced levels of NPC1L1, CD36, and FATP4 proteins. These reductions were associated with reduced intestinal uptake of lipid by the small intestine and reduced plasma levels of cholesterol, phospholipid, and triglyceride. CONCLUSIONS: LPCAT3 KO mice have longer and larger small intestines than control mice, with shorter wide villi, reduced lipid absorption, and lower levels NPC1L1, CD36, and FATP4 proteins. Inhibition of LPCAT3 in the small intestine could be developed as an approach to treat hyperlipidemia. PMID- 26226573 TI - Consistency in polyclonal T-cell responses to gluten between children and adults with celiac disease. AB - BACKGROUND & AIMS: Developing antigen-specific approaches for diagnosis and treatment of celiac disease requires a detailed understanding of the specificity of T cells for gluten. The existing paradigm is that T-cell lines and clones from children differ from those of adults in the hierarchy and diversity of peptide recognition. We aimed to characterize the T-cell response to gluten in children vs adults with celiac disease. METHODS: Forty-one children with biopsy-proven celiac disease (median age, 9 years old; 17 male), who had been on strict gluten free diets for at least 3 months, were given a 3-day challenge with wheat; blood samples were collected and gluten-specific T cells were measured. We analyzed responses of T cells from these children and from 4 adults with celiac disease to a peptide library and measured T-cell receptor bias. We isolated T-cell clones that recognized dominant peptides and assessed whether gluten peptide recognition was similar between T-cell clones from children and adults. RESULTS: We detected gluten-specific responses by T cells from 30 of the children with celiac disease (73%). T cells from the children recognized the same peptides that were immunogenic to adults with celiac disease; deamidation of peptides increased these responses. Age and time since diagnosis did not affect the magnitude of T cell responses to dominant peptides. T-cell clones specific for dominant alpha- or omega-gliadin peptides from children with celiac disease had comparable levels of reactivity to wheat, rye, and barley peptides as T-cell clones from adults with celiac disease. The alpha-gliadin-specific T cells from children had biases in T-cell receptor usage similar to those in adults. CONCLUSIONS: T cells from children with celiac disease recognize similar gluten peptides as T cells from adults with celiac disease. The findings indicate that peptide-based diagnostics and therapeutics for adults may also be used for children. PMID- 26226574 TI - Claude C. Roy, MD, October 21, 1928-July 2, 2015. PMID- 26226575 TI - Next Generation Multigene Panel Testing: The Next Step for Identification of Hereditary Colorectal Cancer Syndromes? PMID- 26226576 TI - American Gastroenterological Association Technical Review on the Diagnosis and Management of Lynch Syndrome. PMID- 26226577 TI - American Gastroenterological Association Institute Guideline on the Diagnosis and Management of Lynch Syndrome. PMID- 26226578 TI - Blood-cell bioenergetics are associated with physical function and inflammation in overweight/obese older adults. AB - BACKGROUND: Physical function and strength decline with age and lead to limited mobility and independence in older adults. Alterations in mitochondrial function are thought to underlie numerous age-related changes, including declining physical ability. Recent studies suggest that systemic changes in bioenergetic capacity may be reported by analyzing mitochondrial function in circulating cells. The objective of this study was to determine whether the bioenergetic capacity of peripheral blood mononuclear cells (PBMCs) is related to differences in physical function among older, overweight/obese, adults. To address this, we tested the hypothesis that greater PBMC respirometric capacity would be associated with better physical function, muscular strength, leg lean mass, and muscle quality. Furthermore, we tested whether the respirometric capacity of PBMCs is related to cellular composition and inflammatory status reported by interleukin-6 (IL-6). METHODS: Fasted PBMC respiration (pmol/min/500,000 cells), expanded short physical performance battery (Ex-SPPB), peak knee extensor (KE) strength (Nm), grip strength (kg), leg lean mass (kg, via dual energy X-ray absorptiometry [DXA]), muscle quality (Nm/kg), and plasma IL-6 (pg/mL) were analyzed in 15 well-functioning, community-dwelling, sedentary overweight/obese older men (n=9) and women (n=6) aged 65 to 78 (mean 68.3 +/- 3.5 years). Pearson and partial correlations were calculated to determine associations between PBMC respiration and these variables. RESULTS: Higher maximal respiration of PBMCs was associated with better Ex-SPPB (r=0.58, p=0.02), greater KE strength (r=0.60, p=0.02), greater grip strength (r=0.52, p=0.05) and lower IL-6 (r=-0.58, p=0.04). Higher spare respiratory capacity was associated with better Ex-SPPB (r=0.59, p=0.02), greater KE strength (r=0.60, p=0.02), greater grip strength (r=0.54, p=0.04), greater leg muscle quality (r=0.56, p=0.04), and lower IL-6 (r=-0.55, p=0.05). Monocyte and lymphocyte counts were not related to PBMC respiratory capacity. CONCLUSIONS: Our results indicate that respirometric profiles of readily obtainable blood cells are associated with physical function and strength. Future studies should be undertaken in order to determine whether blood based bioenergetic profiling can provide an objective index of systemic mitochondrial health. PMID- 26226579 TI - Characterization of products from hydrothermal carbonization of orange pomace including anaerobic digestibility of process liquor. AB - In this study, the effect of the temperature and reaction time on hydrothermal carbonization (HTC) of orange pomace was investigated. In addition, a set of anaerobic batch tests were performed to determine the resulting biogas and methane potential of the spent liquor. Hydrochar yields followed a decreasing trend with the increasing temperature, whereas reaction time had no considerably effect on the yield. The evolution of the H/C and O/C atomic ratios from the raw material to the hydrochars suggested that dehydration reactions prevail during HTC. The hydrochars tended to become enriched in Ca, Mg and P minerals by increasing HTC temperature. The heavy metal contents in hydrochars were found below limits and no PAH compound was detected. Anaerobic digestion tests showed that the aqueous phase from HTC can be used as feedstocks for biogas production. PMID- 26226580 TI - Pyrolysis of mangaba seed: production and characterization of bio-oil. AB - The aim of this study was to evaluate the potential of Hancornia speciosa GOMES (mangaba) seeds as a novel matrix for the production of bio-oil. The study was divided into three steps: (i) characterization of the biomass (through elemental analysis (CHN), infrared spectroscopy (FTIR-ATR), thermogravimetry (TG), and determination of biomass composition; (ii) pyrolysis of mangaba seed to obtain the bio-oil; and (iii) characterization of the bio-oil (thermogravimetry and gas chromatography/mass spectrometry-GC/qMS). The TG of the sample showed a mass loss of around 90% in 450 degrees C. In the pyrolysis experiments the variables included temperature (450 and 600 degrees C), sample mass (5 and 11g) and prior heating (with or without), with the best conditions of 600 degrees C, 11g of seeds and prior heating of the furnace. The GC/qMS analysis identified carboxylic acids and hydrocarbons as the major components, besides the presence of other compounds such as furanes, phenols, nitriles, aldehydes, ketones, and amides. PMID- 26226581 TI - Techno-economic and uncertainty analysis of in situ and ex situ fast pyrolysis for biofuel production. AB - This study evaluates the techno-economic uncertainty in cost estimates for two emerging technologies for biofuel production: in situ and ex situ catalytic pyrolysis. The probability distributions for the minimum fuel-selling price (MFSP) indicate that in situ catalytic pyrolysis has an expected MFSP of $1.11 per liter with a standard deviation of 0.29, while the ex situ catalytic pyrolysis has a similar MFSP with a smaller deviation ($1.13 per liter and 0.21 respectively). These results suggest that a biorefinery based on ex situ catalytic pyrolysis could have a lower techno-economic uncertainty than in situ pyrolysis compensating for a slightly higher MFSP cost estimate. Analysis of how each parameter affects the NPV indicates that internal rate of return, feedstock price, total project investment, electricity price, biochar yield and bio-oil yield are parameters which have substantial impact on the MFSP for both in situ and ex situ catalytic pyrolysis. PMID- 26226582 TI - Bovine herpesvirus 1 productive infection and immediate early transcription unit 1 promoter are stimulated by the synthetic corticosteroid dexamethasone. AB - The primary site for life-long latency of bovine herpesvirus 1 (BHV-1) is sensory neurons. The synthetic corticosteroid dexamethasone consistently induces reactivation from latency; however the mechanism by which corticosteroids mediate reactivation is unclear. In this study, we demonstrate for the first time that dexamethasone stimulates productive infection, in part, because the BHV-1 genome contains more than 100 potential glucocorticoid receptor (GR) response elements (GREs). Immediate early transcription unit 1 (IEtu1) promoter activity, but not IEtu2 or VP16 promoter activity, was stimulated by dexamethasone. Two near perfect consensus GREs located within the IEtu1 promoter were necessary for dexamethasone-mediated stimulation. Electrophoretic mobility shift assays and chromatin immunoprecipitation studies demonstrated that the GR interacts with IEtu1 promoter sequences containing the GREs. Although we hypothesize that DEX mediated stimulation of IEtu1 promoter activity is important during productive infection and perhaps reactivation from latency, stress likely has pleiotropic effects on virus-infected cells. PMID- 26226584 TI - Medicine Is Not a Steak. PMID- 26226583 TI - Viral gene expression potentiates reovirus-induced necrosis. AB - Infection of some cell types by reovirus evokes a caspase-independent form of cell death resembling necrosis. While reovirus strain T3D induces necrosis much more efficiently than strain T1L, which viral components contribute to this difference is not known. In this study, we identified that the sialic acid binding property of the reovirus sigma1 protein affects necrosis efficiency. We found that in addition to sialic acid engagement by the virus particles, viral gene expression, in the form of viral RNA or protein synthesis, is also required for necrosis induction. Our studies reveal that sialic acid does not directly participate in necrosis induction by initiating a signaling pathway. Instead, sialic acid engagement augments necrosis induction indirectly, by increasing reovirus gene expression in each infected cell. Comparison of our results with previous studies suggests that reovirus-induced apoptosis and necrosis are initiated by distinct stages of viral infection. PMID- 26226585 TI - A Rare Cause of Abdominal Pain. Left Paraduodenal Hernia. PMID- 26226586 TI - An Elderly Woman With an Uncommon Cause of Dysphagia. Esophageal Leukoplakia. PMID- 26226587 TI - An Unusual Solid and Cystic Pancreatic Tumor in a 20-Year-Old Woman. Desmoid Tumor: Fibromatosis. PMID- 26226588 TI - An Unusual Cause of Abdominal Pain. Appendiceal Intussusception Owing to Cecal Adenocarcinoma. PMID- 26226589 TI - An Unusual Cause of Intestinal Obstruction in a Young Female. Transmural Migration of Gossypiboma With Small Bowel Obstruction. PMID- 26226590 TI - Predicting Consumer Biomass, Size-Structure, Production, Catch Potential, Responses to Fishing and Associated Uncertainties in the World's Marine Ecosystems. AB - Existing estimates of fish and consumer biomass in the world's oceans are disparate. This creates uncertainty about the roles of fish and other consumers in biogeochemical cycles and ecosystem processes, the extent of human and environmental impacts and fishery potential. We develop and use a size-based macroecological model to assess the effects of parameter uncertainty on predicted consumer biomass, production and distribution. Resulting uncertainty is large (e.g. median global biomass 4.9 billion tonnes for consumers weighing 1 g to 1000 kg; 50% uncertainty intervals of 2 to 10.4 billion tonnes; 90% uncertainty intervals of 0.3 to 26.1 billion tonnes) and driven primarily by uncertainty in trophic transfer efficiency and its relationship with predator-prey body mass ratios. Even the upper uncertainty intervals for global predictions of consumer biomass demonstrate the remarkable scarcity of marine consumers, with less than one part in 30 million by volume of the global oceans comprising tissue of macroscopic animals. Thus the apparently high densities of marine life seen in surface and coastal waters and frequently visited abundance hotspots will likely give many in society a false impression of the abundance of marine animals. Unexploited baseline biomass predictions from the simple macroecological model were used to calibrate a more complex size- and trait-based model to estimate fisheries yield and impacts. Yields are highly dependent on baseline biomass and fisheries selectivity. Predicted global sustainable fisheries yield increases ~4 fold when smaller individuals (< 20 cm from species of maximum mass < 1 kg) are targeted in all oceans, but the predicted yields would rarely be accessible in practice and this fishing strategy leads to the collapse of larger species if fishing mortality rates on different size classes cannot be decoupled. Our analyses show that models with minimal parameter demands that are based on a few established ecological principles can support equitable analysis and comparison of diverse ecosystems. The analyses provide insights into the effects of parameter uncertainty on global biomass and production estimates, which have yet to be achieved with complex models, and will therefore help to highlight priorities for future research and data collection. However, the focus on simple model structures and global processes means that non-phytoplankton primary production and several groups, structures and processes of ecological and conservation interest are not represented. Consequently, our simple models become increasingly less useful than more complex alternatives when addressing questions about food web structure and function, biodiversity, resilience and human impacts at smaller scales and for areas closer to coasts. PMID- 26226591 TI - Alcohol addiction and the mu-opioid receptor. AB - Alcohol addiction is one of the most common and devastating diseases in the world. Given the tremendous heterogeneity of alcohol addicted individuals, it is unlikely that one medication will help nearly all patients. Thus, there is a clear need to develop predictors of response to existing medications. Naltrexone is a mu-opioid receptor antagonist which has been approved in the United States for treatment of alcohol addiction since 1994. It has limited efficacy, in part due to noncompliance, but many patients do not respond despite high levels of compliance. There are reports that a mis-sense single nucleotide polymorphism (rs179919 or A118G) in the mu-opioid receptor gene predicts a favorable response to naltrexone if an individual carries a 'G' allele. This chapter will review the evidence for this hypothesis. The data are promising that the 'G' allele predisposes to a beneficial naltrexone response among alcohol addicted persons, but additional research is needed to prove this hypothesis in prospective clinical trials. PMID- 26226592 TI - The mitochondrial genome of the German wasp Vespula germanica (Fabricius, 1793) (Hymenoptera: Vespoidea: Vespidae). AB - The mitochondrial genome of the German wasp Vespula germanica (Fabricius, 1793) (Hymenoptera: Vespidae) (GenBank accession no. KR703583) was sequenced in the study. It represents the first mitochondrial genome from the genus Vespula. There are totally 163 42 bp in the currently sequenced portion of the genome, containing 13 protein-coding, two rRNA, and 18 tRNA genes and a partial A + T rich region. Four tRNA genes of trnI, trnQ, trnM and trnY located at the downstream of the A + T-rich region were failed to sequence. At least two rearrangement events occurred in the sequenced region compared with the pupative ancestral arrangement of insects, corresponding to the translocation or remote inversion of tnnY from trnW-trnC-trnY cluster to the region of trnI-trnQ-trnM cluster and translocation of trnL1 from the downstream to the upstream of nad1 gene. All protein-coding genes start with ATN codons. Twelve and one protein coding genes stop with termination codon TAA and T, respectively. Phylogenetic analysis using the Bayesian method based on all codon positions of the 13 protein coding genes supports the monophyly of Vespidae and Formicidae. Within the Formicidae, the Myrmicinae and Formicinae form a sister group and then sister to the Dolichoderinae, while within the Vespidae, the Eumeninae sister to the lineage of Vespinae + Polistinae. PMID- 26226593 TI - The complete sequence of mitochondrial genome of Siberian accentor (Prunella montanella). AB - The Siberian accentor, Prunella montanella (Passeriformes, Prunellidae), is a small passerine bird. In this study, the complete mitochondrial genome sequence of Siberian accentor was determined. It has a total length of 16 832 bp, and contains 13 protein coding genes, 22 tRNA genes, two ribosome RNA genes, and one control region. The nucleotide composition is 30.1% for A, 31.0% for C, 15.0% for G and 23.9% for T, respectively. The overall GC content is lower than AT. The phylogenetic tree of Siberian accentor and 10 other species belonging to order Passeriformes was built. The DNA data presented here will be useful to study the evolutionary relationships and genetic diversity of Siberian accentors. PMID- 26226594 TI - The complete mitochondrial genome of Sillago sihama (Perciformes: Sillaginidae). AB - In this study, the complete mitochondrial genome (mitogenome) sequence of Sillago sihama has been determined by long polymerase chain reaction and primer walking methods. The complete mitochondrial genome is a circular molecule of 17 003 bp in length and contains 37 mitochondrial genes and a control region. Within the control region, we identified the variable number tandem repeats, as well as the termination-associated sequence domain (TAS), the central conserved sequence block domains (CSB-F~CSB-A) and the conserved sequence block domains (CSB-1, CSB 2, and CSB-3). PMID- 26226595 TI - Complete mitochondrial genome of red goral (Naemorhedus baileyi) and a complete estimate of the phylogenetic relationships in Caprinae. AB - Naemorhedus baileyi belongs to the genera Naemorhedus within the subfamily Caprinae. Because of small population, narrow distribution and difficult sampling, the taxonomic status of red goral in Caprinae is still not clear. We extracted the sample DNA and amplified whole mtDNA genome with different primers. We downloaded other gene sequences of Caprinae from GenBank. All sequences included 24 species of 11 genera. Phylogenetic analyses confirmed that the subfamily Caprinae is not monophyletic, bootstrap support for this cluster is high (100%). PMID- 26226596 TI - Complete mitochondrial DNA sequences of Saccostrea mordax and Saccostrea cucullata: genome organization and phylogeny analysis. AB - Classified in the phylum mollusks, oysters are bivalves which are found in estuaries and coastal zones. Because of their plastic shell, mitochondrial DNA analysis of this species becomes an interesting field, necessary to investigate their phylogenetic and evolution of relations. In our study, two oyster species: Saccostrea mordax and Saccostrea cucullata from Indian Ocean (Madagascar) were investigated. The complete sequence of Saccostrea mordax (16 512 bp) and Saccostrea cucullata (16 396 bp) were described and determined, with their mitogenomes deposited in the GenBank with accession number KP769562 and KP967577 respectively. Both mitochondrial genome sequences contained 12 protein-coding genes, 23 tRNAs, and two rRNAs, all encoded in the same heavy strand. High levels of similarity in the gene arrangement of the two Saccostrea species were evident. The phylogenetic analysis shows a closer relationship between the two Saccostrea species and confirms the strong relationship within Saccostrea, Crassostrea and Ostrea genus in taxonomy of Ostreidae family. PMID- 26226597 TI - Placebo Responses in Genetically Determined Intellectual Disability: A Meta Analysis. AB - BACKGROUND: Genetically determined Intellectual Disability (ID) is an intractable condition that involves severe impairment of mental abilities such as learning, reasoning and predicting the future. As of today, little is known about the placebo response in patients with ID. OBJECTIVE: To determine if placebo response exists in patients with genetically determined ID. DATA SOURCES AND STUDY SELECTION: We searched Medline/PubMed, EMBASE, CENTRAL and PsycINFO to find all placebo-controlled double-blind randomized clinical trials (RCTs) in patients with genetically determined ID, published up to April 2013, focusing on core ID symptoms. DATA EXTRACTION AND SYNTHESIS: Two investigators extracted outcome data independently. MAIN OUTCOMES AND MEASURES: Bias-corrected standardized mean difference (Hedge's g) was computed for each outcome measure, using the Comprehensive Meta-Analysis software. A priori defined patient sub-groups were analyzed using a mixed-effect model. The relationship between pre-defined continuous variable moderators (age, IQ, year of publication and trial duration) and effect size was analyzed using meta-regression. RESULTS: Twenty-two placebo controlled double-blind RCTs met the inclusion criteria (n = 721, mean age = 17.1 years, 62% men, mean trial duration = 35 weeks). There was a significant overall placebo response from pre- to post-treatment in patients with ID (g = 0.468, p = 0.002), both for "subjective outcomes" (a third-person's evaluation of the patient) (g = 0.563, p = 0.022) and "objective outcomes" (direct evaluation of the patient's abilities) (g = 0.434, p = 0.036). Individuals with higher IQ had higher response to placebo (p = 0.02) and no placebo response was observed in ID patients with comorbid dementia. A significant effect of age (p = 0.02) was found, indicating higher placebo responses in treatment of younger patients. CONCLUSIONS AND RELEVANCE: Results suggest that patients with genetically determined ID improve in the placebo arm of RCTs. Several mechanisms may contribute to placebo effects in ID, including expectancy, implicit learning and "placebo-by-proxy" induced by clinicians/family members. As the condition is refractory, there is little risk that improvements are explained by spontaneous remission. While new avenues for treatment of genetically determined ID are emerging, our results demonstrate how contextual factors can affect clinical outcomes and emphasize the importance of being vigilant on the role of placebos when testing novel treatments in ID. PMID- 26226599 TI - Effect of molybdenum treatment on molybdenum concentration and nitrate reduction in maize seedlings. AB - Since 1940 molybdenum has been known as an essential trace element in plant nutrition and physiology. It has a central role in nitrogen metabolism, and its deficiency leads to nitrate accumulation in plants. In this study, we cultivated maize seedlings (Zea mays L. cv. Norma SC) in nutrient solution and soil (rhizoboxes) to investigate the effect of molybdenum treatment on the absorption of molybdenum, sulfur and iron. These elements have been previously shown to play important roles in nitrate reduction, because they are necessary for the function of the nitrate reductase enzyme. We also investigated the relationship between molybdenum treatments and different nitrogen forms in maize. Molybdenum treatments were 0, 0.96, 9.6 and 96 MUg kg(-1) in the nutrition solution experiments, and 0, 30, 90, 270 mg kg(-1) in the rhizobox experiments. On the basis of our results, the increased Mo level produced higher plant available Mo concentration in nutrient solution and in soil, which resulted increased concentration of Mo in shoots and roots of maize seedlings. In addition it was observed that maize seedlings accumulated more molybdenum in their roots than in their shoots at all treatments. In contrast, molybdenum treatments did not affect significantly either iron or sulfur concentrations in the plant, even if these elements (Mo, S and Fe) play alike important roles in nitrogen metabolism. Furthermore, the physiological molybdenum level (1* Mo = 0.01 MUM) reduced NO3-N and enhanced the NH4-N concentrations in seedlings, suggesting that nitrate reduction was more intense under a well-balanced molybdenum supply. PMID- 26226598 TI - Genomic resolution of an aggressive, widespread, diverse and expanding meningococcal serogroup B, C and W lineage. AB - OBJECTIVES: Neisseria meningitidis is a leading cause of meningitis and septicaemia. The hyperinvasive ST-11 clonal complex (cc11) caused serogroup C (MenC) outbreaks in the US military in the 1960s and UK universities in the 1990s, a global Hajj-associated serogroup W (MenW) outbreak in 2000-2001, and subsequent MenW epidemics in sub-Saharan Africa. More recently, endemic MenW disease has expanded in South Africa, South America and the UK, and MenC cases have been reported among European and North American men who have sex with men (MSM). Routine typing schemes poorly resolve cc11 so we established the population structure at genomic resolution. METHODS: Representatives of these episodes and other geo-temporally diverse cc11 meningococci (n = 750) were compared across 1546 core genes and visualised on phylogenetic networks. RESULTS: MenW isolates were confined to a distal portion of one of two main lineages with MenB and MenC isolates interspersed elsewhere. An expanding South American/UK MenW strain was distinct from the 'Hajj outbreak' strain and a closely related endemic South African strain. Recent MenC isolates from MSM in France and the UK were closely related but distinct. CONCLUSIONS: High resolution 'genomic' multilocus sequence typing is necessary to resolve and monitor the spread of diverse cc11 lineages globally. PMID- 26226603 TI - The Business Case for Tele-emergency. AB - BACKGROUND: Tele-emergency is an expanding telehealth service that provides real time audio/visual consultation delivered by an emergency medicine team to a remote, often rural, emergency department (ED). Financial analyses of tele emergency in the literature are limited. This article expands the tele-emergency literature to describe the business case for tele-emergency. "Business case" is defined as a reasoned argument, supported by objective data and/or qualitative judgment, to implement or continue a service or product. MATERIALS AND METHODS: To evaluate tele-emergency financing from the perspective of a critical access hospital (CAH), 10 financial analysis categories were defined. Telephone interviews, site visits, and financial data from the eEmergency program of Avera Health (Sioux Falls, SD) were used to populate the categories. Avera Health information was augmented with national data where available. Three financial scenarios were then analyzed for CAH profit/loss associated with tele-emergency. RESULTS: Tele-emergency financial analysis demonstrated an $187,614 profit in a high revenue/low expense scenario, $49,841 profit in a midrange scenario, and $69,588 loss in a low revenue/high expense scenario. CONCLUSIONS: Tele-emergency may be a profitable rural hospital service line if the participating hospital adjusts ED processes to take advantage of increased revenue/savings opportunities afforded by tele-emergency. Savings due to tele-emergency primarily accrue when physician ED backup and physician ED staffing costs are substituted. PMID- 26226604 TI - Emotional Valence, Arousal, and Threat Ratings of 160 Chinese Words among Adolescents. AB - This study was conducted to provide ratings of valence/pleasantness, arousal/excitement, and threat/potential harm for 160 Chinese words. The emotional valence classification (positive, negative, or neutral) of all of the words corresponded to that of the equivalent English language words. More than 90% of the participants, junior high school students aged between 12 and 17 years, understood the words. The participants were from both mainland China and Hong Kong, thus the words can be applied to adolescents familiar with either simplified (e.g. in mainland China) or traditional Chinese (e.g. in Hong Kong) with a junior secondary school education or higher. We also established eight words with negative valence, high threat, and high arousal ratings to facilitate future research, especially on attentional and memory biases among individuals prone to anxiety. Thus, the new emotional word list provides a useful source of information for affective research in the Chinese language. PMID- 26226605 TI - Development of Open-Set Word Recognition in Children: Speech-Shaped Noise and Two Talker Speech Maskers. AB - OBJECTIVE: The goal of this study was to establish the developmental trajectories for children's open-set recognition of monosyllabic words in each of two maskers: two-talker speech and speech-shaped noise. DESIGN: Listeners were 56 children (5 to 16 years) and 16 adults, all with normal hearing. Thresholds for 50% correct recognition of monosyllabic words were measured in a two-talker speech or a speech-shaped noise masker in the sound field using an open-set task. Target words were presented at a fixed level of 65 dB SPL throughout testing, while the masker level was adapted. A repeated-measures design was used to compare the performance of three age groups of children (5 to 7 years, 8 to 12 years, and 13 to 16 years) and a group of adults. The pattern of age-related changes during childhood was also compared between the two masker conditions. RESULTS: Listeners in all four age groups performed more poorly in the two-talker speech than the speech-shaped noise masker, but the developmental trajectories differed for the two masker conditions. For the speech-shaped noise masker, children's performance improved with age until about 10 years of age, with little systematic child-adult differences thereafter. In contrast, for the two-talker speech masker, children's thresholds gradually improved between 5 and 13 years of age, followed by an abrupt improvement in performance to adult-like levels. Children's thresholds in the two masker conditions were uncorrelated. CONCLUSIONS: Younger children require a more advantageous signal-to-noise ratio than older children and adults to achieve 50% correct word recognition in both masker conditions. However, children's ability to recognize words appears to take longer to mature and follows a different developmental trajectory for the two-talker speech masker than the speech-shaped noise masker. These findings highlight the importance of considering both age and masker type when evaluating children's masked speech perception abilities. PMID- 26226606 TI - Evaluation of Speech-Evoked Envelope Following Responses as an Objective Aided Outcome Measure: Effect of Stimulus Level, Bandwidth, and Amplification in Adults With Hearing Loss. AB - OBJECTIVES: The present study evaluated a novel test paradigm based on speech evoked envelope following responses (EFRs) as an objective aided outcome measure for individuals fitted with hearing aids. Although intended for use in infants with hearing loss, this study evaluated the paradigm in adults with hearing loss, as a precursor to further evaluation in infants. The test stimulus was a naturally male-spoken token /susa?i/, modified to enable recording of eight individual EFRs, two from each vowel for different formants and one from each fricative. In experiment I, sensitivity of the paradigm to changes in audibility due to varying stimulus level and use of hearing aids was tested. In experiment II, sensitivity of the paradigm to changes in aided audible bandwidth was evaluated. As well, experiment II aimed to test convergent validity of the EFR paradigm by comparing the effect of bandwidth on EFRs and behavioral outcome measures of hearing aid fitting. DESIGN: Twenty-one adult hearing aid users with mild to moderately severe sensorineural hearing loss participated in the study. To evaluate the effects of level and amplification in experiment I, the stimulus was presented at 50 and 65 dB SPL through an ER-2 insert earphone in unaided conditions and through individually verified hearing aids in aided conditions. Behavioral thresholds of EFR carriers were obtained using an ER-2 insert earphone to estimate sensation level of EFR carriers. To evaluate the effect of aided audible bandwidth in experiment II, EFRs were elicited by /susa?i/ low-pass filtered at 1, 2, and 4 kHz and presented through the programmed hearing aid. EFRs recorded in the 65 dB SPL aided condition in experiment I represented the full bandwidth condition. EEG was recorded from the vertex to the nape of the neck over 300 sweeps. Speech discrimination using the University of Western Ontario Distinctive Feature Differences test and sound quality rating using the Multiple-Stimulus Hidden Reference and Anchor paradigm were measured in the same bandwidth conditions. RESULTS: In experiment I, an increase in stimulus level above threshold and the use of amplification resulted in a significant increase in the number of EFRs detected per condition. At positive sensation levels, an increase in level demonstrated a significant increase in response amplitude in unaided and aided conditions. At 50 and 65 dB SPL, the use of amplification led to a significant increase in response amplitude for the majority of carriers. In experiment II, the number of EFR detections and the combined response amplitude of all eight EFRs improved with an increase in bandwidth up to 4 kHz. In contrast, behavioral measures continued to improve at wider bandwidths. Further change in EFR parameters was possibly limited by the hearing aid bandwidth. Significant positive correlations were found between EFR parameters and behavioral test scores in experiment II. CONCLUSIONS: The EFR paradigm demonstrates sensitivity to changes in audibility due to a change in stimulus level, bandwidth, and use of amplification in clinically feasible test times. The paradigm may thus have potential applications as an objective aided outcome measure. Further investigations exploring stimulus-response relationships in aided conditions and validation studies in children are warranted. PMID- 26226607 TI - Effect of Stimulus Level and Bandwidth on Speech-Evoked Envelope Following Responses in Adults With Normal Hearing. AB - OBJECTIVE: The use of auditory evoked potentials as an objective outcome measure in infants fitted with hearing aids has gained interest in recent years. This article proposes a test paradigm using speech-evoked envelope following responses (EFRs) for use as an objective-aided outcome measure. The method uses a running speech-like, naturally spoken stimulus token /susa?i/ (fundamental frequency [f0] = 98 Hz; duration 2.05 sec), to elicit EFRs by eight carriers representing low, mid, and high frequencies. Each vowel elicited two EFRs simultaneously, one from the region of formant one (F1) and one from the higher formants region (F2+). The simultaneous recording of two EFRs was enabled by lowering f0 in the region of F1 alone. Fricatives were amplitude modulated to enable recording of EFRs from high frequency spectral regions. The present study aimed to evaluate the effect of level and bandwidth on speech-evoked EFRs in adults with normal hearing. As well, the study aimed to test convergent validity of the EFR paradigm by comparing it with changes in behavioral tasks due to bandwidth. DESIGN: Single-channel electroencephalogram was recorded from the vertex to the nape of the neck over 300 sweeps in two polarities from 20 young adults with normal hearing. To evaluate the effects of level in experiment I, EFRs were recorded at test levels of 50 and 65 dB SPL. To evaluate the effects of bandwidth in experiment II, EFRs were elicited by /susa?i/ low-pass filtered at 1, 2, and 4 kHz, presented at 65 dB SPL. The 65 dB SPL condition from experiment I represented the full bandwidth condition. EFRs were averaged across the two polarities and estimated using a Fourier analyzer. An F test was used to determine whether an EFR was detected. Speech discrimination using the University of Western Ontario Distinctive Feature Differences test and sound quality rating using the Multiple Stimulus Hidden Reference and Anchors paradigm were measured in identical bandwidth conditions. RESULTS: In experiment I, the increase in level resulted in a significant increase in response amplitudes for all eight carriers (mean increase of 14 to 50 nV) and the number of detections (mean increase of 1.4 detections). In experiment II, an increase in bandwidth resulted in a significant increase in the number of EFRs detected until the low-pass filtered 4 kHz condition and carrier-specific changes in response amplitude until the full bandwidth condition. Scores in both behavioral tasks increased with bandwidth up to the full bandwidth condition. The number of detections and composite amplitude (sum of all eight EFR amplitudes) significantly correlated with changes in behavioral test scores. CONCLUSIONS: Results suggest that the EFR paradigm is sensitive to changes in level and audible bandwidth. This may be a useful tool as an objective-aided outcome measure considering its running speech-like stimulus, representation of spectral regions important for speech understanding, level and bandwidth sensitivity, and clinically feasible test times. This paradigm requires further validation in individuals with hearing loss, with and without hearing aids. PMID- 26226608 TI - Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease. AB - OBJECTIVES: MYH9-related disease (MYH9-RD) is an autosomal- dominant disorder deriving from mutations in MYH9, the gene for the nonmuscle myosin heavy chain (NMMHC)-IIA. MYH9-RD has a complex phenotype including congenital features, such as thrombocytopenia, and noncongenital manifestations, namely sensorineural hearing loss (SNHL), nephropathy, cataract, and liver abnormalities. The disease is caused by a limited number of mutations affecting different regions of the NMMHC-IIA protein. SNHL is the most frequent noncongenital manifestation of MYH9 RD. However, only scarce and anecdotal information is currently available about the clinical and audiometric features of SNHL of MYH9-RD subjects. The objective of this study was to investigate the severity and propensity for progression of SNHL in a large series of MYH9-RD patients in relation to the causative NMMHC-IIA mutations. DESIGN: This study included the consecutive patients diagnosed with MYH9-RD between July 2007 and March 2012 at four participating institutions. A total of 115 audiograms were analyzed from 63 patients belonging to 45 unrelated families with different NMMHC-IIA mutations. Cross-sectional analyses of audiograms were performed. Regression analysis was performed, and age-related typical audiograms (ARTAs) were derived to characterize the type of SNHL associated with different mutations. RESULTS: Severity of SNHL appeared to depend on the specific NMMHC-IIA mutation. Patients carrying substitutions at the residue R702 located in the short functional SH1 helix had the most severe degree of SNHL, whereas patients with the p.E1841K substitution in the coiled-coil region or mutations at the nonhelical tailpiece presented a mild degree of SNHL even at advanced age. The authors also disclosed the effects of different amino acid changes at the same residue: for instance, individuals with the p.R702C mutation had more severe SNHL than those with the p.R702H mutation, and the p.R1165L substitution was associated with a higher degree of hearing loss than the p.R1165C. In general, mild SNHL was associated with a fairly flat audiogram configuration, whereas severe SNHL correlated with downsloping configurations. ARTA plots showed that the most progressive type of SNHL was associated with the p.R702C, the p.R702H, and the p.R1165L substitutions, whereas the p.R1165C mutation correlated with a milder, nonprogressive type of SNHL than the p.R1165L. ARTA for the p.E1841K mutation demonstrated a mild degree of SNHL with only mild progression, whereas the ARTA for the mutations at the nonhelical tailpiece did not show any substantial progression. CONCLUSIONS: These data provide useful tools to predict the progression and the expected degree of severity of SNHL in individual MYH9-RD patients, which is especially relevant in young patients. Consequences in clinical practice are important not only for appropriate patient counseling but also for development of customized, genotype-driven clinical management. The authors recently reported that cochlear implantation has a good outcome in MYH9-RD patients; thus, stricter follow-up and earlier intervention are recommended for patients with unfavorable genotypes. PMID- 26226612 TI - Are All Biologics the Same? Optimal Treatment Strategies for Patients With Early Rheumatoid Arthritis: Systematic Review and Indirect Pairwise Meta-Analysis. AB - BACKGROUND: The use of biologic agents has revolutionized the treatment of rheumatoid arthritis (RA). However, there is much uncertainty about whether any agent may be preferable. PURPOSE: The aim of the study was to evaluate the comparative efficacy of biologic agents with a disease-modifying antirheumatic drug (DMARD) in RA patients without prior exposure to a DMARD, that is, DMARD naive. METHODS: MEDLINE, Cochrane, and Clinicaltrials.gov were searched from 1990 to August 2013 for randomized controlled trials comparing biologic agents in conjunction with a DMARD and DMARDs alone in DMARD (methotrexate [MTX])-naive RA patients. Information on patient characteristics, disease duration, and the American College of Rheumatology (ACR) 20/50/70/90 response rates after 52 weeks was extracted. RESULTS: Six randomized controlled trials totaling 9 study arms fulfilled the inclusion criteria. Data were analyzed by direct and indirect pairwise comparisons of 2 drugs against a common comparator. In the direct comparison, all 6 biologic therapies were associated with significantly higher likelihood of achieving an ACR20 compared with MTX alone (mean ORs, 1.43-2.99). For ACR50 and ACR70, all biologic agents except golimumab showed statistically significant mean ORs of 1.31 to 2.52 (ACR20) and 1.79 to 2.59 (ACR50). At ACR90, abatacept 10 mg/kg, adalimumab 40 mg, and rituximab 500 and 1000 mg were significantly better compared with MTX (mean ORs 1.92-2.89). The indirect comparison for ACR20 showed etanercept 50 mg significantly favored against adalimumab 40 mg (OR, 1.05-3.34), golimumab 50 mg (OR, 1.16-4.07), infliximab 3 mg/kg (OR, 1.21-3.61), and infliximab 6 mg/kg (OR, 1.02-3.06). At ACR50, etanercept 50 mg and rituximab 1000 mg showed significantly higher ORs compared with golimumab 100 mg at ORs 1.06 to 3.42 and ORs 1.07 to 3.42, respectively. No significant differences were observed in the biologic agents for indirect pairwise comparisons at ACR70 and ACR90.Lack of head-to-head clinical trial data directly comparing biologic agents makes indirect meta-analysis the only substitute. Safety and cost of these agents were not evaluated. Only a small number of trials could be evaluated because of the strict inclusion criteria required for an indirect meta-analysis. Unmeasured confounders could contribute to trial heterogeneity. The data on golimumab were difficult to reconcile with the other trials because of methodological differences. CONCLUSIONS: Overall, biological agents in conjunction with a DMARD performed similarly in the settings evaluated. However, there were some statistically significant differences. Etanercept 50 mg appears superior to adalimumab 40 mg, golimumab 50 mg, and infliximab 3 and 6 mg/kg at ACR20. Rituximab 1000 mg and etanercept 50 mg appeared superior to golimumab 100 mg at ACR50 in DMARD-naive patients. No agent was superior to all others at each ACR level. PMID- 26226613 TI - Making Mosquito Taxonomy Useful: A Stable Classification of Tribe Aedini that Balances Utility with Current Knowledge of Evolutionary Relationships. AB - The tribe Aedini (Family Culicidae) contains approximately one-quarter of the known species of mosquitoes, including vectors of deadly or debilitating disease agents. This tribe contains the genus Aedes, which is one of the three most familiar genera of mosquitoes. During the past decade, Aedini has been the focus of a series of extensive morphology-based phylogenetic studies published by Reinert, Harbach, and Kitching (RH&K). Those authors created 74 new, elevated or resurrected genera from what had been the single genus Aedes, almost tripling the number of genera in the entire family Culicidae. The proposed classification is based on subjective assessments of the "number and nature of the characters that support the branches" subtending particular monophyletic groups in the results of cladistic analyses of a large set of morphological characters of representative species. To gauge the stability of RH&K's generic groupings we reanalyzed their data with unweighted parsimony jackknife and maximum-parsimony analyses, with and without ordering 14 of the characters as in RH&K. We found that their phylogeny was largely weakly supported and their taxonomic rankings failed priority and other useful taxon-naming criteria. Consequently, we propose simplified aedine generic designations that 1) restore a classification system that is useful for the operational community; 2) enhance the ability of taxonomists to accurately place new species into genera; 3) maintain the progress toward a natural classification based on monophyletic groups of species; and 4) correct the current classification system that is subject to instability as new species are described and existing species more thoroughly defined. We do not challenge the phylogenetic hypotheses generated by the above-mentioned series of morphological studies. However, we reduce the ranks of the genera and subgenera of RH&K to subgenera or informal species groups, respectively, to preserve stability as new data become available. PMID- 26226614 TI - Activation of TLR2 and TLR6 by Dengue NS1 Protein and Its Implications in the Immunopathogenesis of Dengue Virus Infection. AB - Dengue virus (DV) infection is the most prevalent mosquito-borne viral disease and its manifestation has been shown to be contributed in part by the host immune responses. In this study, pathogen recognition receptors, Toll-like receptor (TLR) 2 and TLR6 were found to be up-regulated in DV-infected human PBMC using immunofluorescence staining, flow cytometry and Western blot analyses. Using ELISA, IL-6 and TNF-alpha, cytokines downstream of TLR2 and TLR6 signaling pathways were also found to be up-regulated in DV-infected PBMC. IL-6 and TNF alpha production by PBMC were reduced when TLR2 and TLR6 were blocked using TLR2 and TLR6 neutralizing antibodies during DV infection. These results suggested that signaling pathways of TLR2 and TLR6 were activated during DV infection and its activation contributed to IL-6 and TNF-alpha production. DV NS1 protein was found to significantly increase the production of IL-6 and TNF-alpha when added to PBMC. The amount of IL-6 and TNF-alpha stimulated by DV NS1 protein was reduced when TLR2 and TLR6 were blocked, suggesting that DV NS1 protein is the viral protein responsible for the activation of TLR2 and TLR6 during DV infection. Secreted alkaline phosphatase (SEAP) reporter assay was used to further confirm activation of TLR2 and TLR6 by DV NS1 protein. In addition, DV infected and DV NS1 protein-treated TLR6-/- mice have higher survivability compared to DV-infected and DV NS1 protein-treated wild-type mice. Hence, activation of TLR6 via DV NS1 protein could potentially play an important role in the immunopathogenesis of DV infection. PMID- 26226615 TI - Several Human Liver Cell Expressed Apolipoproteins Complement HCV Virus Production with Varying Efficacy Conferring Differential Specific Infectivity to Released Viruses. AB - Apolipoprotein E (ApoE), an exchangeable apolipoprotein, is necessary for production of infectious Hepatitis C virus (HCV) particles. However, ApoE is not the only liver-expressed apolipoprotein and the role of other apolipoproteins for production of infectious HCV progeny is incompletely defined. Therefore, we quantified mRNA expression of human apolipoproteins in primary human hepatocytes. Subsequently, cDNAs encoding apolipoproteins were expressed in 293T/miR-122 cells to explore if they complement HCV virus production in cells that are non permissive due to limiting endogenous levels of human apolipoproteins. Primary human hepatocytes expressed high mRNA levels of ApoA1, A2, C1, C3, E, and H. ApoA4, A5, B, D, F, J, L1, L2, L3, L4, L6, M, and O were expressed at intermediate levels, and C2, C4, and L5 were not detected. All members of the ApoA and ApoC family of lipoproteins complemented HCV virus production in HCV transfected 293T/miR-122 cells, albeit with significantly lower efficacy compared with ApoE. In contrast, ApoD expression did not support production of infectious HCV. Specific infectivity of released particles complemented with ApoA family members was significantly lower compared with ApoE. Moreover, the ratio of extracellular to intracellular infectious virus was significantly higher for ApoE compared to ApoA2 and ApoC3. Since apolipoproteins complementing HCV virus production share amphipathic alpha helices as common structural features we altered the two alpha helices of ApoC1. Helix breaking mutations in both ApoC1 helices impaired virus assembly highlighting a critical role of alpha helices in apolipoproteins supporting HCV assembly. In summary, various liver expressed apolipoproteins with amphipathic alpha helices complement HCV virus production in human non liver cells. Differences in the efficiency of virus assembly, the specific infectivity of released particles, and the ratio between extracellular and intracellular infectivity point to distinct characteristics of these apolipoproteins that influence HCV assembly and cell entry. This will guide future research to precisely pinpoint how apolipoproteins function during virus assembly and cell entry. PMID- 26226616 TI - Association between the Advanced Glycosylation End Product-Specific Receptor Gene and Cardiovascular Death in Older Men. AB - Advanced glycosylation end product-specific receptor (AGER) signaling has been implicated in atherosclerosis. The aim of this study was to evaluate whether a common genetic variation in the AGER gene is associated with cardiovascular (CV) death. We included 1304 older men who were genotyped for rs1035798:C>T, which is a single nucleotide polymorphism (SNP) mapped to the third intron of AGER. Cox proportional hazard analysis was used to estimate the association of rs1035798:C>T with CV death. In addition we analyzed total RNA extracted from carotid atherosclerosis biopsies of 18 patients that did or did not have recent symptoms of cerebral embolization by quantitative real-time reverse transcription PCR (qRT-PCR). The minor T-allele of rs1035798:C>T was found to be associated with CV death under dominant (HR = 1.43, 95% CI: 1.01-2.02, P = 0.04) and recessive (HR = 2.05, 95% CI: 1.11-3.81, P = 0.02) models of inheritance even after adjustment for traditional cardiovascular risk factors. No association was found between rs1035798:C>T and non-CV death. qRT-PCR results suggested that median relative expression of AGER isoform 1 and isoform 6 transcripts were approximately 6- (P = 0.01) and 2-fold (P = 0.02) greater, respectively, within carotid biopsies of symptomatic compared to asymptomatic patients. These data suggest that the minor (T) allele of rs1035798:C>T represents an independent susceptibility factor for CV death. The expression of AGER isoforms is different in atheroma from patients with recent symptoms. Further studies are needed to investigate if rs1035798:C>T influences the alternative splicing of AGER. PMID- 26226618 TI - Instructions of cooperation and competition influence the neural responses to others' pain: An ERP study. AB - Neural activities triggered by viewing other's in pain have been previously reported to be modulated by various factors. How instructions of cooperation and competition can influence these activities has not been explored yet. In the current study, participants were instructed to play a game cooperatively or competitively with a partner. During the game, pictures showing an anonymous individual's hand or foot in painful or non-painful situations were randomly presented in an oddball style. The event-related potentials (ERPs) when the participants passively observed these pictures under different instructions were compared. We found a significant interaction of Instruction * Picture on the P3 component, where only under competitive instruction did the painful pictures elicit significantly larger amplitudes than the non-painful pictures, but not under the cooperative instruction. This result indicates that the participants were more responsive to other's pain in a competitive context than in a cooperative context. PMID- 26226617 TI - Whole-Retina Reduced Electrophysiological Activity in Mice Bearing Retina Specific Deletion of Vesicular Acetylcholine Transporter. AB - BACKGROUND: Despite rigorous characterization of the role of acetylcholine in retinal development, long-term effects of its absence as a neurotransmitter are unknown. One of the unanswered questions is how acetylcholine contributes to the functional capacity of mature retinal circuits. The current study investigates the effects of disrupting cholinergic signalling in mice, through deletion of vesicular acetylcholine transporter (VAChT) in the developing retina, pigmented epithelium, optic nerve and optic stalk, on electrophysiology and structure of the mature retina. METHODS & RESULTS: A combination of electroretinography, optical coherence tomography imaging and histological evaluation assessed retinal integrity in mice bearing retina- targeted (embryonic day 12.5) deletion of VAChT (VAChTSix3-Cre-flox/flox) and littermate controls at 5 and 12 months of age. VAChTSix3-Cre-flox/flox mice did not show any gross changes in nuclear layer cellularity or synaptic layer thickness. However, VAChTSix3-Cre-flox/flox mice showed reduced electrophysiological response of the retina to light stimulus under scotopic conditions at 5 and 12 months of age, including reduced a-wave, b wave, and oscillatory potential (OP) amplitudes and decreased OP peak power and total energy. Reduced a-wave amplitude was proportional to the reduction in b wave amplitude and not associated with altered a-wave 10%-90% rise time or inner and outer segment thicknesses. SIGNIFICANCE: This study used a novel genetic model in the first examination of function and structure of the mature mouse retina with disruption of cholinergic signalling. Reduced amplitude across the electroretinogram wave form does not suggest dysfunction in specific retinal cell types and could reflect underlying changes in the retinal and/or extraretinal microenvironment. Our findings suggest that release of acetylcholine by VAChT is essential for the normal electrophysiological response of the mature mouse retina. PMID- 26226619 TI - Corrigendum: Single Fluorescence Channel-based Multiplex Detection of Avian Influenza Virus by Quantitative PCR with Intercalating Dye. PMID- 26226620 TI - Health Care Scheduling and Access: A Report From the IOM. PMID- 26226621 TI - Heavy water: a simple solution to increasing the brightness of fluorescent proteins in super-resolution imaging. AB - Photoactivatable fluorescent proteins (PA-FPs) are widely used in live single molecule super-resolution imaging but emit substantially fewer photons than organic dyes do. Herein, we show that in heavy water (D2O) instead of H2O, common PA-FPs emit 26-54% more photons, effectively improving the localization precision in super-resolution imaging. PMID- 26226622 TI - Detection of Volatile Organic Compounds Using Microfabricated Resonator Array Functionalized with Supramolecular Monolayers. AB - This paper describes the detection of volatile organic compounds (VOCs) using an e-nose type integrated microfabricated sensor array, in which each resonator is coated with different supramolecular monolayers: p-tert-butyl calix[8]arene (Calix[8]arene), 2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphine (Porphyrin), beta cyclodextrin (beta-CD), and cucurbit[8]uril (CB[8]). Supramolecular monolayers fabricated by Langmuir-Blodgett techniques work as specific sensing interface for different VOCs recognition which increase the sensor selectivity. Microfabricated ultrahigh working frequency film bulk acoustic resonator (FBAR) transducers (4.4 GHz) enable their high sensitivity toward monolayer gas sensing which facilitate the analyses of VOCs adsorption isotherms and kinetics. Two affinity constants (K1, K2) are obtained for each VOC, which indicate the gas molecule adsorption happen inside and outside of the supramolecular cavities. Additional kinetic information on adsorption and desorption rate constants (ka, kd) are obtained as well from exponential fitting results. The five parameters, one from the conventional frequency shift signals of mass transducers and the other four from the indirect analyses of monolayer adsorption behaviors, thus enrich the sensing matrix (Deltaf, K1, K2, ka, kd) which can be used as multiparameter fingerprint patterns for highly selective detection and discrimination of VOCs. PMID- 26226623 TI - Determination of feasibility and utility of microscope-integrated optical coherence tomography during ophthalmic surgery: the DISCOVER Study RESCAN Results. AB - IMPORTANCE: Optical coherence tomography (OCT) has transformed the clinical management of a myriad of ophthalmic conditions. Applying OCT to ophthalmic surgery may have implications for surgical decision making and patient outcomes. OBJECTIVE: To assess the feasibility and effect on surgical decision making of a microscope-integrated intraoperative OCT (iOCT) system. DESIGN, SETTING, AND PARTICIPANTS: Report highlighting the 1-year results (March 2014-February 2015) of the RESCAN 700 portion of the DISCOVER (Determination of Feasibility of Intraoperative Spectral Domain Microscope Combined/Integrated OCT Visualization During En Face Retinal and Ophthalmic Surgery) study, a single-site, multisurgeon, prospective consecutive case series regarding this investigational device. Participants included patients undergoing ophthalmic surgery. Data on clinical characteristics were collected, and iOCT was performed during surgical milestones, as directed by the operating surgeon. A surgeon questionnaire was issued to each surgeon and was completed after each case to evaluate the role of iOCT during surgery and its particular role in select surgical procedures. MAIN OUTCOMES AND MEASURES: Percentage of cases with successful acquisition of iOCT (ie, feasibility). Percentage of cases in which iOCT altered surgical decision making (ie, utility). RESULTS: During year 1 of the DISCOVER study, a total of 227 eyes (91 anterior segment cases and 136 posterior segment cases) underwent imaging with the RESCAN 700 system. Successful imaging (eg, the ability to acquire an OCT image of the tissue of interest) was obtained for 224 of 227 eyes (99% [95% CI, 98%-100%]). During lamellar keratoplasty, the iOCT data provided information that altered the surgeon's decision making in 38% of the cases (eg, complete graft apposition when the surgeon believed there was interface fluid). In membrane peeling procedures, iOCT information was discordant with the surgeon's impression of membrane peel completeness in 19% of cases (eg, lack of residual membrane or presence of occult membrane), thus affecting additional surgical maneuvers. CONCLUSIONS AND RELEVANCE: The DISCOVER study demonstrates the feasibility of real-time iOCT with a microscope-integrated iOCT system for ophthalmic surgery. The information gained from iOCT appears to allow surgeons to assess subtle details in a unique perspective from standard en face visualization, which can affect surgical decision making some of the time, although the effect of these changes in decision making on outcomes remains unknown. A prospective randomized masked trial is needed to confirm these results. PMID- 26226625 TI - Drug-resistant Plasmodium falciparum: are recent advances a cause for optimism? PMID- 26226624 TI - The Sirt1 Activators SRT2183 and SRT3025 Inhibit RANKL-Induced Osteoclastogenesis in Bone Marrow-Derived Macrophages and Down-Regulate Sirt3 in Sirt1 Null Cells. AB - Increased osteoclast-mediated bone resorption is characteristic of osteoporosis, malignant bone disease and inflammatory arthritis. Targeted deletion of Sirtuin1 (Sirt1), a key player in aging and metabolism, in osteoclasts results in increased osteoclast-mediated bone resorption in vivo, making it a potential novel therapeutic target to block bone resorption. Sirt1 activating compounds (STACs) were generated and were investigated in animal disease models and in humans however their mechanism of action was a source of controversy. We studied the effect of SRT2183 and SRT3025 on osteoclastogenesis in bone-marrow derived macrophages (BMMs) in vitro, and discovered that these STACs inhibit RANKL induced osteoclast differentiation, fusion and resorptive capacity without affecting osteoclast survival. SRT2183 and SRT3025 activated AMPK, increased Sirt1 expression and decreased RelA/p65 lysine310 acetylation, critical for NF kappaB activation, and an established Sirt1 target. However, inhibition of osteoclastogenesis by these STACs was also observed in BMMs derived from sirt1 knock out (sirt1-/-) mice lacking the Sirt1 protein, in which neither AMPK nor RelA/p65 lysine 310 acetylation was affected, confirming that these effects require Sirt1, but suggesting that Sirt1 is not essential for inhibition of osteoclastogenesis by these STACs under these conditions. In sirt1 null osteoclasts treated with SRT2183 or SRT3025 Sirt3 was found to be down-regulated. Our findings suggest that SRT2183 and SRT3025 activate Sirt1 and inhibit RANKL induced osteoclastogenesis in vitro however under conditions of Sirt1 deficiency can affect Sirt3. As aging is associated with reduced Sirt1 level and activity, the influence of STACs on Sirt3 needs to be investigated in vivo in animal and human disease models of aging and osteoporosis. PMID- 26226626 TI - Improving the Catalytic Performance of an Artificial Metalloenzyme by Computational Design. AB - Artifical metalloenzymes combine the reactivity of small molecule catalysts with the selectivity of enzymes, and new methods are required to tune the catalytic properties of these systems for an application of interest. Structure-based computational design could help to identify amino acid mutations leading to improved catalytic activity and enantioselectivity. Here we describe the application of Rosetta Design for the genetic optimization of an artificial transfer hydrogenase (ATHase hereafter), [(eta(5)-Cp*)Ir(pico)Cl] ? WT hCA II (Cp* = Me5C5(-)), for the asymmetric reduction of a cyclic imine, the precursor of salsolsidine. Based on a crystal structure of the ATHase, computational design afforded four hCAII variants with protein backbone-stabilizing and hydrophobic cofactor-embedding mutations. In dansylamide-competition assays, these designs showed 46-64-fold improved affinity for the iridium pianostool complex [(eta(5) Cp*)Ir(pico)Cl]. Gratifyingly, the new designs yielded a significant improvement in both activity and enantioselectivity (from 70% ee (WT hCA II) to up to 92% ee and a 4-fold increase in total turnover number) for the production of (S) salsolidine. Introducing additional hydrophobicity in the Cp*-moiety of the Ir catalyst provided by adding a propyl substituent on the Cp* moiety yields the most (S)-selective (96% ee) ATHase reported to date. X-ray structural data indicate that the high enantioselectivity results from embedding the piano stool moiety within the protein, consistent with the computational model. PMID- 26226627 TI - Role of Endogenous Opioid System in Ischemic-Induced Late Preconditioning. AB - BACKGROUND: Opioid receptors (OR) are involved in myocardial late preconditioning (LPC) induced by morphine and delta1-opioid receptor (delta1-OR) agonists. The role of OR in ischemic-induced LPC is unknown. We investigated whether 1) OR are involved in the trigger and/or mediation phase of LPC and 2) a time course effect on the expression of different opioid receptors and their endogenous ligands exists. METHODS: Male Wistar rats were randomly allocated to four groups (each group n = 8). Awake animals were ischemic preconditioned by a 5 minutes coronary occlusion. 24 hours later, anesthetized animals underwent 25 minutes coronary occlusion followed by 2 hours of reperfusion. The role of OR was investigated by treatment with intraperitoneal naloxone (Nal) 10 minutes prior to LPC (Nal-LPC; trigger phase) or 10 min prior to sustained ischemia (LPC-Nal; mediation phase). RESULTS: LPC reduced infarct size from 61+/-10% in controls to 25+/-9% (P<0.001). Naloxone during trigger or mediation phase completely abolished LPC-induced cardioprotection (59+/-9% and 62+/-9%; P<0.001 vs. LPC). 8, 12 and 24 hours after the ischemic stimulus, expression of delta-OR in the heart was increased, whereas MU-opioid receptor (MU-OR) and kappa-opioid receptor (kappa-OR) were not. Plasma concentrations of beta-endorphin and leu-enkephalin but not dynorphin were increased by LPC. CONCLUSION: Ischemic LPC is triggererd and mediated by OR. Expression of delta-OR and plasma levels of endogenous opioid peptides are increased after ischemic LPC. PMID- 26226629 TI - Macrophage Infiltration Induces Gastric Cancer Invasiveness by Activating the beta-Catenin Pathway. AB - BACKGROUND: Despite evidence that activated macrophages act in an inflammatory microenvironment to promote gastric tumorigenesis via beta-catenin signaling, the effects of beta-catenin signaling on gastric cancer cell metastasis and the relationship of these cells with surrounding tumor associated macrophages have not been directly studied. METHODS: Immunohistochemical staining was employed to analyze 103 patients. An invasion assay was used to evaluate the relationship between macrophages and gastric cancer cells. beta-catenin gain-of-function and loss-of-function approaches were performed. To assess the beta-catenin regulation mechanism in gastric cancer cells, Western blotting and reverse-transcription polymerase chain reaction were used. RESULTS: Increased density of macrophages was associated with advanced stage and poor survival. Gastric cancer cell lines co-cultured with macrophages conditioned medium showed increased nuclear accumulation of beta-catenin and increased invading ability. AKT but not ERK regulated beta-catenin translocation. MMP7 and CD44, both beta-catenin downstream genes, were involved in macrophage-activated gastric cancer cell invasion. CONCLUSION(S): Collectively, the clinical data suggest that macrophage infiltration is correlated with increased grade and poor prognosis for gastric cancer patients who underwent radical resection. Macrophages may induce invasiveness by activating the beta-catenin pathway. PMID- 26226628 TI - Distributions of Irritative Zones Are Related to Individual Alterations of Resting-State Networks in Focal Epilepsy. AB - Alterations in the connectivity patterns of the fMRI-based resting-state networks (RSNs) have been reported in several types of epilepsies. Evidence pointed out these alterations might be associated with the genesis and propagation of interictal epileptiform discharges (IEDs). IEDs also evoke blood-oxygen-level dependent (BOLD) responses, which have been used to delineate irritative zones during preoperative work-up. Therefore, one may expect a relationship between the topology of the IED-evoked BOLD response network and the altered spatial patterns of the RSNs. In this study, we used EEG recordings and fMRI data obtained simultaneously from a chronic model of focal epilepsy in Wistar rats to verify our hypothesis. We found that IED-evoked BOLD response networks comprise both cortical and subcortical structures with a rat-dependent topology. In all rats, IEDs evoke both activation and deactivation types of BOLD responses. Using a Granger causality method, we found that in many cases areas with BOLD deactivation have directed influences on areas with activation (p<0.05). We were able to predict topological properties (i.e., focal/diffused, unilateral/bilateral) of the IED-evoked BOLD response network by performing hierarchical clustering analysis on major spatial features of the RSNs. All these results suggest that IEDs and disruptions in the RSNs found previously in humans may be different manifestations of the same transient events, probably reflecting altered consciousness. In our opinion, the shutdown of specific nodes of the default mode network may cause uncontrollable excitability in other functionally connected brain areas. We conclude that IED-evoked BOLD responses (i.e., activation and deactivation) and alterations of RSNs are intrinsically related, and speculate that an understanding of their interplay is necessary to discriminate focal epileptogenesis and network propagation phenomena across different brain modules via hub-based connectivity. PMID- 26226631 TI - Mutations of Profilin-1 Associated with Amyotrophic Lateral Sclerosis Promote Aggregation Due to Structural Changes of Its Native State. AB - The PFN1 gene, coding for profilin-1, has recently been associated with familial amyotrophic lateral sclerosis (fALS), as three mutations, namely C71G, M114T, and G118V, have been found in patients with familial forms of the disease and another, E117G, has been proposed to be a moderate risk factor for disease onset. In this work, we have purified the four profilin-1 variants along with the wild type protein. The resulting aggregates appear to be fibrillar, to have a weak binding to ThT, and to possess a significant amount of intermolecular beta-sheet structure. Using ThT fluorescence assays, far-UV circular dichroism, and dynamic light scattering, we found that all four variants have an aggregation propensity higher than that of the wild-type counterpart. In particular, the C71G mutation was found to induce the most dramatic change in aggregation, followed by the G118V and M114T substitutions and then the E117G mutation. Such a propensity was found not to strictly correlate with the conformational stability in this group of profilin-1 variants, determined using both urea-induced denaturation at equilibrium and folding/unfolding kinetics. However, it correlated with structural changes of the folded states, as monitored with far-UV circular dichroism, intrinsic fluorescence spectroscopy, ANS binding, acrylamide quenching, and dynamic light scattering. Overall, the results suggest that all four mutations increase the tendency of profilin-1 to aggregate and that such aggregation behavior is largely determined by the mutation-induced structural changes occurring in the folded state of the protein. PMID- 26226630 TI - Regional Differences in the Accumulation of SNPs on the Male-Specific Portion of the Human Y Chromosome Replicate Autosomal Patterns: Implications for Genetic Dating. AB - Factors affecting the rate and pattern of the mutational process are being identified for human autosomes, but the same relationships for the male specific portion of the Y chromosome (MSY) are not established. We considered 3,390 mutations occurring in 19 sequence bins identified by sequencing 1.5 Mb of the MSY from each of 104 present-day chromosomes. The occurrence of mutations was not proportional to the amount of sequenced bases in each bin, with a 2-fold variation. The regression of the number of mutations per unit sequence against a number of indicators of the genomic features of each bin, revealed the same fundamental patterns as in the autosomes. By considering the sequences of the same region from two precisely dated ancient specimens, we obtained a calibrated region-specific substitution rate of 0.716 * 10-9/site/year. Despite its lack of recombination and other peculiar features, the MSY then resembles the autosomes in displaying a marked regional heterogeneity of the mutation rate. An immediate implication is that a given figure for the substitution rate only makes sense if bound to a specific DNA region. By strictly applying this principle we obtained an unbiased estimate of the antiquity of lineages relevant to the genetic history of the human Y chromosome. In particular, the two deepest nodes of the tree highlight the survival, in Central-Western Africa, of lineages whose coalescence (291 ky, 95% C.I. 253-343) predates the emergence of anatomically modern features in the fossil record. PMID- 26226632 TI - The Cytokinome Profile in Patients with Hepatocellular Carcinoma and Type 2 Diabetes. AB - Understanding the dynamics of the complex interaction network of cytokines, defined as ''cytokinome'', can be useful to follow progression and evolution of hepatocellular carcinoma (HCC) from its early stages as well as to define therapeutic strategies. Recently we have evaluated the cytokinome profile in patients with type 2 diabetes (T2D) and/or chronic hepatitis C (CHC) infection and/or cirrhosis suggesting specific markers for the different stages of the diseases. Since T2D has been identified as one of the contributory cause of HCC, in this paper we examined the serum levels of cytokines, growth factors, chemokines, as well as of other cancer and diabetes biomarkers in a discovery cohort of patients with T2D, chronic hepatitis C (CHC) and/or CHC-related HCC comparing them with a healthy control group to define a profile of proteins able to characterize these patients, and to recognize the association between diabetes and HCC. The results have evidenced that the serum levels of some proteins are significantly and differently up-regulated in all the patients but they increased still more when HCC develops on the background of T2D. Our results were verified also using a separate validation cohort. Furthermore, significant correlations between clinical and laboratory data characterizing the various stages of this complex disease, have been found. In overall, our results highlighted that a large and simple omics approach, such as that of the cytokinome analysis, supplemented by common biochemical and clinical data, can give a complete picture able to improve the prognosis of the various stages of the disease progression. We have also demonstrated by means of interactomic analysis that our experimental results correlate positively with the general metabolic picture that is emerging in the literature for this complex multifactorial disease. PMID- 26226633 TI - BMP Inhibition in Seminomas Initiates Acquisition of Pluripotency via NODAL Signaling Resulting in Reprogramming to an Embryonal Carcinoma. AB - Type II germ cell cancers (GCC) can be subdivided into seminomas and non seminomas. Seminomas are similar to carcinoma in situ (CIS) cells, the common precursor of type II GCCs, with regard to epigenetics and expression, while embryonal carcinomas (EC) are totipotent and differentiate into teratomas, yolk sac tumors and choriocarcinomas. GCCs can present as seminomas with a non seminoma component, raising the question if a CIS gives rise to seminomas and ECs at the same time or whether seminomas can be reprogrammed to ECs. In this study, we utilized the seminoma cell line TCam-2 that acquires an EC-like status after xenografting into the murine flank as a model for a seminoma to EC transition and screened for factors initiating and driving this process. Analysis of expression and DNA methylation dynamics during transition of TCam-2 revealed that many pluripotency- and reprogramming-associated genes were upregulated while seminoma markers were downregulated. Changes in expression level of 53 genes inversely correlated to changes in DNA methylation. Interestingly, after xenotransplantation 6 genes (GDF3, NODAL, DNMT3B, DPPA3, GAL, AK3L1) were rapidly induced, followed by demethylation of their genomic loci, suggesting that these 6 genes are poised for expression driving the reprogramming. We demonstrate that inhibition of BMP signaling is the initial event in reprogramming, resulting in activation of the pluripotency-associated genes and NODAL signaling. We propose that reprogramming of seminomas to ECs is a multi-step process. Initially, the microenvironment causes inhibition of BMP signaling, leading to induction of NODAL signaling. During a maturation phase, a fast acting NODAL loop stimulates its own activity and temporarily inhibits BMP signaling. During the stabilization phase, a slow acting NODAL loop, involving WNTs re-establishes BMP signaling and the pluripotency circuitry. In parallel, DNMT3B-driven de novo methylation silences seminoma-associated genes and epigenetically fixes the EC state. PMID- 26226634 TI - Ghrelin O-Acyl Transferase in Zebrafish Is an Evolutionarily Conserved Peptide Upregulated During Calorie Restriction. AB - Ghrelin is a multifunctional orexigenic hormone with a unique acyl modification enabled by ghrelin O-acyl transferase (GOAT). Ghrelin is well-characterized in nonmammals, and GOAT sequences of several fishes are available in the GenBank. However, endogenous GOAT in non-mammals remains poorly understood. In this research, GOAT sequence comparison, tissue-specific GOAT expression, and its regulation by nutrient status and exogenous ghrelin were studied. It was found that the bioactive core of zebrafish GOAT amino acid sequence share high identity with that of mammals. GOAT mRNA was most abundant in the gut. GOAT-like immunoreactivity (i.r.) was found colocalized with ghrelin in the gastric mucosa. Food deprivation increased, and feeding decreased GOAT and preproghrelin mRNA expression in the brain and gut. GOAT and ghrelin peptides in the gut and brain showed corresponding decrease in food-deprived state. Intraperitoneal injection of acylated fish ghrelin caused a significant decrease in GOAT mRNA expression, suggesting a feedback mechanism regulating its abundance. Together, these results provide the first in-depth characterization of GOAT in a non-mammal. Our results demonstrate that endogenous GOAT expression is responsive to metabolic status and availability of acylated ghrelin, providing further evidences for GOAT in the regulation of feeding in teleosts. PMID- 26226635 TI - The enterococcal cytolysin synthetase has an unanticipated lipid kinase fold. AB - The enterococcal cytolysin is a virulence factor consisting of two post translationally modified peptides that synergistically kill human immune cells. Both peptides are made by CylM, a member of the LanM lanthipeptide synthetases. CylM catalyzes seven dehydrations of Ser and Thr residues and three cyclization reactions during the biosynthesis of the cytolysin large subunit. We present here the 2.2 A resolution structure of CylM, the first structural information on a LanM. Unexpectedly, the structure reveals that the dehydratase domain of CylM resembles the catalytic core of eukaryotic lipid kinases, despite the absence of clear sequence homology. The kinase and phosphate elimination active sites that affect net dehydration are immediately adjacent to each other. Characterization of mutants provided insights into the mechanism of the dehydration process. The structure is also of interest because of the interactions of human homologs of lanthipeptide cyclases with kinases such as mammalian target of rapamycin. PMID- 26226636 TI - miR-965 controls cell proliferation and migration during tissue morphogenesis in the Drosophila abdomen. AB - Formation of the Drosophila adult abdomen involves a process of tissue replacement in which larval epidermal cells are replaced by adult cells. The progenitors of the adult epidermis are specified during embryogenesis and, unlike the imaginal discs that make up the thoracic and head segments, they remain quiescent during larval development. During pupal development, the abdominal histoblast cells proliferate and migrate to replace the larval epidermis. Here, we provide evidence that the microRNA, miR-965, acts via string and wingless to control histoblast proliferation and migration. Ecdysone signaling downregulates miR-965 at the onset of pupariation, linking activation of the histoblast nests to the hormonal control of metamorphosis. Replacement of the larval epidermis by adult epidermal progenitors involves regulation of both cell-intrinsic events and cell communication. By regulating both cell proliferation and cell migration, miR 965 contributes to the robustness of this morphogenetic system. PMID- 26226638 TI - Projecting Fine Particulate Matter-Related Mortality in East China. AB - China is suffering from severe air pollution from fine particulate matter [<= 2.5 MUm in aerodynamic diameter (PM2.5)], especially East China. But its future trends and potential health impacts remain unclear. The study objectives were to project future trends of PM2.5 and its short-term effect on mortality in East China by 2030. First, daily changes in PM2.5 concentrations between 2005 and 2030 were projected under the "current legislation" scenario (CLE) and the "maximum technically feasible reduction" scenario (MFR). Then, they were linked to six population projections, two mortality rate projections, and PM2.5-mortality associations to estimate the changes in PM2.5-related mortality in East China between 2005 and 2030. Under the CLE scenario, the annual mean PM2.5 concentration was projected to decrease by 0.62 MUg/m(3) in East China, which could cause up to 124,000 additional deaths, when considering the population growth. Under the MFR scenario, the annual mean PM2.5 concentration was projected to decrease by 20.41 MUg/m(3) in East China. At least 230,000 deaths could be avoided by such a large reduction in PM2.5 concentration under MFR scenario, even after accounting for the population growth. Therefore, our results suggest that reducing PM2.5 concentration substantially in East China would benefit the public health. Otherwise, it may still remain as a great health risk in the future, especially when the population keeps growing. PMID- 26226639 TI - The CROWN Initiative: Journal Editors Invite Researchers to Develop Core Outcomes in Women's Health. PMID- 26226637 TI - Prefrontal dopamine regulates fear reinstatement through the downregulation of extinction circuits. AB - Prevention of relapses is a major challenge in treating anxiety disorders. Fear reinstatement can cause relapse in spite of successful fear reduction through extinction-based exposure therapy. By utilising a contextual fear-conditioning task in mice, we found that reinstatement was accompanied by decreased c-Fos expression in the infralimbic cortex (IL) with reduction of synaptic input and enhanced c-Fos expression in the medial subdivision of the central nucleus of the amygdala (CeM). Moreover, we found that IL dopamine plays a key role in reinstatement. A reinstatement-inducing reminder shock induced c-Fos expression in the IL-projecting dopaminergic neurons in the ventral tegmental area, and the blocking of IL D1 signalling prevented reduction of synaptic input, CeM c-Fos expression, and fear reinstatement. These findings demonstrate that a dopamine dependent inactivation of extinction circuits underlies fear reinstatement and may explain the comorbidity of substance use disorders and anxiety disorders. PMID- 26226640 TI - Metabolic impacts of altering meal frequency and timing - Does when we eat matter? AB - Obesity prevalence continues to rise throughout the developed world, as a result of positive energy balance and reduced physical activity. At present, there is still a perception within the general community, and amongst some nutritionists, that eating multiple small meals spaced throughout the day is beneficial for weight control and metabolic health. However, intervention trials do not generally support the epidemiological evidence, and data is emerging to suggest that increasing the fasting period between meals may beneficially impact body weight and metabolic health. To date, this evidence is of short term duration, and it is becoming increasingly apparent that meal timing must also be considered if we are to ensure optimal health benefits in response to this dietary pattern. The purpose of this review is to summate the existing human literature on modifying meal frequency and timing on body weight control, appetite regulation, energy expenditure, and metabolic health under conditions of energy balance, restriction and surplus. PMID- 26226641 TI - Cavity morphogenesis: imaging mitotic forces in action. PMID- 26226642 TI - Expression of ferrochelatase has a strong correlation in protoporphyrin IX accumulation with photodynamic detection of bladder cancer. AB - BACKGROUND: The mechanism underlying the increased levels of protoporphyrin IX in bladder cancer remains unclear. Here, we focus on proteins associated with protoporphyrin IX accumulation in bladder cancer cells and investigate the protein that plays a key role in increased protoporphyrin IX accumulation in bladder cancer cells. METHODS: Western blotting was used to determine the expression of peptide transporter 1, hydroxymethylbilane synthase, ferrochelatase, ATP-binding cassette 2, and heme oxygenase-1 in bladder cancer cell line cells. We evaluated the correlation between the expression of each protein and accumulated protoporphyrin IX in these cells using Pearson's correlation analysis. Immunohistochemistry was used to estimate the expression of the same five proteins in samples from 75 patients who underwent transurethral resection of bladder tumors. The correlation between the expression of each protein in cells from resected bladder specimens and accumulated protoporphyrin IX in bladder cancer cells in voided urine was evaluated using Pearson's correlation analysis. RESULTS: The expression of ferrochelatase showed a significant negative correlation with protoporphyrin IX accumulation in vitro (p=0.04). The expression of peptide transporter 1 (p<0.01, R=0.39), heme oxygenase-1 (p<0.01, R=0.33), and ferrochelatase (p<0.01, R=0.75) in resected bladder specimens by immunohistochemistry was correlated with protoporphyrin IX accumulation in bladder cancer cells in voided urine. On multivariate analysis, the expression of ferrochelatase (p=0.03) was significant factors to predict positive 5-aminolevulinic acid-induced fluorescent cytology. CONCLUSION: The expression of ferrochelatase has a strong correlation in protoporphyrin IX accumulation with photodynamic detection of bladder cancer. PMID- 26226643 TI - Can residence time offer a useful strategy to target agonist drugs for sustained GPCR responses? AB - Residence time describes the how long a ligand is bound to its target, and is attracting interest in drug discovery as a potential means of improving clinical efficacy by increasing target coverage. This concept, as originally applied to antagonists, is more complicated for G-protein-coupled receptor (GPCR) agonists because of the transiency of receptor responses (via desensitization and internalization). However, in some cases sustained GPCR agonist responses have been observed, with evidence consistent with a role for slow binding kinetics. We propose a model to explain our understanding of how residence time and rebinding might influence sustained signaling by internalized receptors. We also highlight the anticipated benefit for drug discovery of fully understanding and exploiting these phenomena to target desirable receptor response profiles selectively. PMID- 26226644 TI - Preparation of a manganese titanate nanosensor: Application in electrochemical studies of captopril in the presence of para-aminobenzoic acid. AB - This study reports the synthesis and characterization of a novel nanostructure based electrode for electrochemical studies and determination of captopril (CP). At first manganese titanate nanoceramics were synthesized by the sol-gel method. The structural evaluations of the pure nanopowders were investigated by different techniques such as X-ray diffraction (XRD), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). Then it was used to prepare a new nanostructured manganese titanate carbon paste electrode (MnTiO3/CPE). The characterization of the modified sensor was carried out by comprehensive techniques such as electrochemical impedance spectroscopy (EIS), SEM, and voltammetry. Subsequently, the modified electrode was used for CP catalytic oxidation in the presence of para-aminobenzoic acid (PABA) as a mediator. The results showed that PABA has high catalytic activity for CP oxidation. The electrochemical behavior of CP was studied by cyclic voltammetry (CV), linear sweep voltammetry (LSV), chronoamperometry (CHA), and differential pulse voltammetry (DPV) techniques. Under the optimized conditions, the catalytic oxidation peak current of CP showed two linear dynamic concentration ranges of 1.0 * 10(-8) to 1.0 * 10(-7) and 1.0 * 10(-7) to 1.0 * 10(-6), with a detection limit of 1.6 nM (signal/noise = 3), using the DPV technique. Finally, the proposed method was successfully applied for determination of CP in pharmaceutical and biological samples. PMID- 26226645 TI - What Are the Histologic Effects of Surgical and Orthodontic Treatment on the Gingiva of Palatal Impacted Canines? AB - PURPOSE: To histologically evaluate changes in the marginal gingiva of palatal impacted maxillary canines after surgical exposure and orthodontic treatment. MATERIALS AND METHODS: A prospective case-and-control study was conducted of 10 patients presenting with bilateral palatal impaction of the maxillary canines. All patients underwent surgical exposure of the impacted canines with an open window technique, which was followed by orthodontic treatment to achieve proper arch alignment. Once the treatment was finalized, 4 samples of marginal gingival tissue from each patient were taken for histologic study. The 4 samples consisted of 1 from each of the repositioned maxillary canines (case teeth) and 1 from each of their respective adjacent first premolars (control teeth). RESULTS: Histologic examination of the case teeth tissue samples showed microscopic changes mainly in the nonkeratinized epithelium and connective tissue, whereas changes in the keratinized epithelium remained minimal. The control teeth showed a greater inflammatory reaction in the nonkeratinized epithelium. CONCLUSION: Orthodontic treatment of impacted maxillary canines used in conjunction with an open-window surgical technique results in predictable orthodontic eruption with few periodontal discrepancies of the marginal gingiva compared with their adjacent first premolars. PMID- 26226646 TI - Management of a sandbag accident in an MRI unit. AB - Our aim is to report the cause and management of a ferromagnetic sandbag accident that occurred when an unconscious patient was sent for brain MRI. A 2-kg sandbag had been placed in the vicinity of his right groin to aid hemostasis after a femoral venous puncture for thrombocytopenia. His clothing and blanket had not been examined thoroughly before he was moved to the scanner and the sandbag went unnoticed. Its attraction to the scanner and adherence to the scanner rim resulted in a minor abrasion and bruise on the patient's face. We decided to manually remove some of the pellets from the sandbag after cutting the vinyl bag at one corner with a nonferromagnetic screwdriver. Piece-meal removal of about two-thirds of the pellets facilitated removal of the remaining pellets and the sandbag as a whole. The word "sandbag" is misleading and led to a lack of communication between the clinical team and the MRI staff and failure by the MRI staff to recognize a sandbag as a ferromagnetic object. Careful manual removal of small amounts of pellets can be used to avoid more time- and labor-intensive strategies to deal with a sandbag accident (e.g., magnet quench or ramp-down). Installation of a ferromagnetic material detector to screen patients before entering the scanner room is recommended. PMID- 26226648 TI - Sorptive uptake of selenium with magnetite and its supported materials onto activated carbon. AB - Kinetic and equilibrium uptake studies of selenite in aqueous solution with synthetic magnetite (Mag-P), commercial magnetite (Mag-C), goethite, activated carbon (AC), and a composite material containing 19% magnetite supported on activated carbon (CM-19) were investigated. Kinetic uptake studies used a one-pot setup at pH 5.26 at variable temperature. Sampling of unbound selenite in-situ was achieved with analytical detection by atomic absorbance. The sorptive uptake at equilibrium and kinetic conditions are listed in descending order: goethite>Mag-P>Mag-C>CM-19. Kinetic uptake parameters reveal that Mag-P showed apparent negative values for the activation energy (E(a)) and the enthalpy of activation (DeltaH(?)), in agreement with a multi-step process for the kinetic uptake of selenite. By contrast, Mag-C, CM-19, and goethite showed positive values for E(a) and DeltaH(?). The uptake properties of the various sorbent materials with selenite are in accordance with the formation of inner- and out sphere complexes. Leaching of iron from the composite material (CM-19) was attenuated due to the stabilizing effect of the magnetite within the pore sites and the surface of AC. Supported iron oxide nanomaterial composites represent a unique sorbent material with tunable uptake properties toward inorganic selenite in aqueous solution. PMID- 26226647 TI - Improving the precision of fMRI BOLD signal deconvolution with implications for connectivity analysis. AB - An important, open problem in neuroimaging analyses is developing analytical methods that ensure precise inferences about neural activity underlying fMRI BOLD signal despite the known presence of confounds. Here, we develop and test a new meta-algorithm for conducting semi-blind (i.e., no knowledge of stimulus timings) deconvolution of the BOLD signal that estimates, via bootstrapping, both the underlying neural events driving BOLD as well as the confidence of these estimates. Our approach includes two improvements over the current best performing deconvolution approach; 1) we optimize the parametric form of the deconvolution feature space; and, 2) we pre-classify neural event estimates into two subgroups, either known or unknown, based on the confidence of the estimates prior to conducting neural event classification. This knows-what-it-knows approach significantly improves neural event classification over the current best performing algorithm, as tested in a detailed computer simulation of highly confounded fMRI BOLD signal. We then implemented a massively parallelized version of the bootstrapping-based deconvolution algorithm and executed it on a high performance computer to conduct large scale (i.e., voxelwise) estimation of the neural events for a group of 17 human subjects. We show that by restricting the computation of inter-regional correlation to include only those neural events estimated with high-confidence the method appeared to have higher sensitivity for identifying the default mode network compared to a standard BOLD signal correlation analysis when compared across subjects. PMID- 26226649 TI - G protein coupled receptors as targets for next generation pesticides. AB - There is an on-going need for the discovery and development of new pesticides due to the loss of existing products through the continuing development of resistance, the desire for products with more favourable environmental and toxicological profiles and the need to implement the principles of integrated pest management. Insect G protein coupled receptors (GPCRs) have important roles in modulating biology, physiology and behaviour, including reproduction, osmoregulation, growth and development. Modifying normal receptor function by blocking or over stimulating its actions may either result in the death of a pest or disrupt its normal fitness or reproductive capacity to reduce pest populations. Hence GPCRs offer potential targets for the development of next generation pesticides providing opportunities to discover new chemistries for invertebrate pest control. Such receptors are important targets for pharmaceutical drugs, but are under-exploited by the agro-chemical industry. The octopamine receptor agonists are the only pesticides with a recognized mode of action, as described in the classification scheme developed by the Insecticide Resistance Action Committee, that act via a GPCR. The availability of sequenced insect genomes has facilitated the characterization of insect GPCRs, but the development and utilization of screening assays to identify lead compounds has been slow. Various studies using knock-down technologies or applying the native ligands and/or neuropeptide analogues to pest insects in vivo, have however demonstrated that modifying normal receptor function can have an insecticidal effect. This review presents examples of potential insect neuropeptide receptors that are potential targets for lead compound development, using case studies from three representative pest species, Tribolium castaneum, Acyrthosiphon pisum, and Drosophila suzukii. Functional analysis studies on T. castaneum suggest that GPCRs involved in growth and development (eclosion hormone, ecdysis triggering hormone and crustacean cardioacceleratory peptide receptors) as well as the dopamine-2 like, latrophilin-like, starry night, frizzled-like, methuselah-like and the smoothened receptors may be suitable pesticide targets. From in vivo studies using native ligands and peptide analogues, receptors which appear to have a role in the regulation of feeding in the pea aphid, such as the PISCF allatostatin and the various "kinin" receptors, are also potential targets. In Drosophila melanogaster various neuropeptides and their signalling pathways have been studied extensively. This may provide insights into potential pesticide targets that could be exploited in D. suzukii. Examples include the sex peptide receptor, which is involved in reproduction and host seeking behaviours, and those responsible for osmoregulation such as the diuretic hormone receptors. However the neuropeptides and their receptors in insects are often poorly characterized, especially in pest species. Although data from closely related species may be transferable (e.g. D. melanogaster to D. suzukii), peptides and receptors may have different roles in different insects, and hence a target in one insect may not be appropriate in another. Hence fundamental knowledge of the roles and functions of receptors is vital for development to proceed. PMID- 26226650 TI - The dual roles of Armigeres subalbatus prophenoloxidase V in parasite melanization and egg chorion melanization in the mosquito Ar. subalbatus. AB - Phenoloxidases (POs) play key roles in various physiological functions in insects, e.g., cuticular sclerotization, wound healing, egg tanning, cuticle formation and melanotic encapsulaction of pathogens. Previously, we identified five POs, designated As-pro-PO I-V, from the mosquito Armigeres subalbatus and demonstrated that the functions of As-pro-PO I, II and III, were associated with filarial parasite melanization, blood feeding and cuticle formation, respectively. In the present study, we delineate the dual functions of As-pro-PO V. We found that the level of As-pro-PO V mRNA in mosquitoes was significantly increased after microfilaria challenge or blood feeding, and decreased to normal level after oviposition. Knockdown of As-pro-PO V by dsRNA resulted in significant decreases in the degree of microfilaria melanization, egg chronic melanization rates and egg hatching rates in Ar. subalbatus. Further transfection and electrophoretic mobility-shift assays verified the As-pro-PO V gene might regulated by both AP-1, a putative immune-related regulatory element and CdxA, a developmental regulatory element. The binding of AP-1 and CdxA motif with mosquito nuclear extracts was significantly enhanced after microfilaria challenge and blood-feeding in Ar. subalbatus, respectively. These results indicate that As pro-PO V is a critical enzyme that is required for both an effective melanization immune response and egg chorion melanization in this mosquito. PMID- 26226652 TI - Herbivory-induced glucose transporter gene expression in the brown planthopper, Nilaparvata lugens. AB - Nilaparvata lugens, the brown planthopper (BPH) feeds on rice phloem sap, containing high amounts of sucrose as a carbon source. Nutrients such as sugars in the digestive tract are incorporated into the body cavity via transporters with substrate selectivity. Eighteen sugar transporter genes of BPH (Nlst) were reported and three transporters have been functionally characterized. However, individual characteristics of NlST members associated with sugar transport remain poorly understood. Comparative gene expression analyses using oligo-microarray and quantitative RT-PCR revealed that the sugar transporter gene Nlst16 was markedly up-regulated during BPH feeding. Expression of Nlst16 was induced 2 h after BPH feeding on rice plants. Nlst16, mainly expressed in the midgut, appears to be involved in carbohydrate incorporation from the gut cavity into the hemolymph. Nlst1 (NlHT1), the most highly expressed sugar transporter gene in the midgut was not up-regulated during BPH feeding. The biochemical function of NlST16 was shown as facilitative glucose transport along gradients. Glucose uptake activity by NlST16 was higher than that of NlST1 in the Xenopus oocyte expression system. At least two NlST members are responsible for glucose uptake in the BPH midgut, suggesting that the midgut of BPH is equipped with various types of transporters having diversified manner for sugar uptake. PMID- 26226653 TI - A gustatory stimulator. AB - BACKGROUND: In order to elicit gustatory event related potentials (gERPs) a special taste delivery system is needed which allows precise control of stimulus onset and duration. NEW METHOD: Aim of this investigation was to describe the characteristics, namely onset rise-time step and onset delay time of a recently new taste delivery system based on stepper-motor, computer-driven glass syringes, able to spray pulses of liquid solutions into the mouth. RESULTS: The measurement showed that the pulse rise time is less than 100 ms and increases with the pulse duration; the delay of the stimulus on a 12 m hose is between 55 ms and 71 ms. COMPARISON WITH EXISTING METHODS: The gustometer in examination produce a stream of pulses, constituted by a certain number of taste stimuli interleaved among a number of tasteless pulses, moreover the solution is thermos-regulated at internal body temperature. This make the technique appealing for event related procedure in neuroscience investigation related to gustatory tasks. CONCLUSION: These results of the time rise measurements confirm the suitability of this gustometer to elicit ERPs. PMID- 26226651 TI - Transcription factors, chromatin proteins and the diversification of Hemiptera. AB - Availability of complete genomes provides a means to explore the evolution of enormous developmental, morphological, and behavioral diversity among insects. Hemipterans in particular show great diversity of both morphology and life history within a single order. To better understand the role of transcription regulators in the diversification of hemipterans, using sequence profile searches and hidden Markov models we computationally analyzed transcription factors (TFs) and chromatin proteins (CPs) in the recently available Rhodnius prolixus genome along with 13 other insect and 4 non-insect arthropod genomes. We generated a comprehensive collection of TFs and CPs across arthropods including 303 distinct types of domains in TFs and 139 in CPs. This, along with the availability of two hemipteran genomes, R. prolixus and Acyrthosiphon pisum, helped us identify possible determinants for their dramatic morphological and behavioral divergence. We identified five domain families (i.e. Pipsqueak, SAZ/MADF, THAP, FLYWCH and BED finger) as having undergone differential patterns of lineage-specific expansion in hemipterans or within hemipterans relative to other insects. These expansions appear to be at least in part driven by transposons, with the DNA binding domains of transposases having provided the raw material for emergence of new TFs. Our analysis suggests that while R. prolixus probably retains a state closer to the ancestral hemipteran, A. pisum represents a highly derived state, with the emergence of asexual reproduction potentially favoring genome duplication and transposon expansion. Both hemipterans are predicted to possess active DNA methylation systems. However, in the course of their divergence, aphids seem to have expanded the ancestral hemipteran DNA methylation along with a distinctive linkage to the histone methylation system, as suggested by expansion of SET domain methylases, including those fused to methylated CpG recognition domains. Thus, differential use of DNA methylation and histone methylation might have played a role in emergence of polyphenism and cyclic parthenogenesis from the ancestral hemipteran. PMID- 26226654 TI - A multi-site array for combined local electrochemistry and electrophysiology in the non-human primate brain. AB - BACKGROUND: Currently, the primary technique employed in circuit-level study of the brain is electrophysiology, recording local field or action potentials (LFPs or APs). However most communication between neurons is chemical and the relationship between electrical activity within neurons and chemical signaling between them is not well understood in vivo, particularly for molecules that signal at least in part by non-synaptic transmission. NEW METHOD: We describe a multi-contact array and accompanying head stage circuit that together enable concurrent electrophysiological and electrochemical recording. The array is small (<200 MUm) and can be assembled into a device of arbitrary length. It is therefore well-suited for use in all major in vivo model systems in neuroscience, including non-human primates where the large brain and need for daily insertion and removal of recording devices places particularly strict demands on design. RESULTS: We present a protocol for array fabrication. We then show that a device built in the manner described can record LFPs and perform enzyme-based amperometric detection of choline in the awake macaque monkey. Comparison with existing methods Existing methods allow single mode (electrophysiology or electrochemistry) recording. This system is designed for concurrent, dual-mode recording. It is also the only system designed explicitly to meet the challenges of recording in non-human primates. CONCLUSIONS: Our system offers the possibility for conducting in vivo studies in a range of species that examine the relationship between the electrical activity of neurons and their chemical environment, with exquisite spatial and temporal precision. PMID- 26226655 TI - Methyl methacrylate embedding to study the morphology and immunohistochemistry of adult guinea pig and mouse cochleae. AB - BACKGROUND: Histological analysis of the cochlea is required to understand the physiological and pathological processes in the inner ear. In the past, many embedding techniques have been tested in the cochlea to find an optimal protocol that gives both good morphological and immunohistochemical results. Resins provide high quality cochlear morphology with reduced immunogenicity due to the higher polymerization temperature. NEW METHOD: We used Technovit 9100 New((r)), a low temperature embedding system based on methyl methacrylate, on adult guinea pig and mouse cochleae to evaluate preservation of the morphology and maintenance of the antigenicity. RESULTS: Conventional toluidine blue staining, as well as immunohistochemical staining with a set of commonly used antibodies, showed highly preserved morphology and immunogenicity of decalcified adult guinea pig and mouse cochleae. COMPARISON WITH EXISTING METHOD(S): We demonstrate both, well preserved morphology and preservation of antigenicity, superior to other embedding techniques. CONCLUSIONS: Our results showed that the Technovit 9100 New((r)) embedding system provided highly preserved morphology and immunogenicity with our protocol in adult guinea pig and mouse cochleae. PMID- 26226657 TI - Corrigendum: Electron-hole transport and photovoltaic effect in gated MoS2 Schottky junctions. PMID- 26226656 TI - Sex differences in diurnal rhythms of food intake in mice caused by gonadal hormones and complement of sex chromosomes. AB - We measured diurnal rhythms of food intake, as well as body weight and composition, while varying three major classes of sex-biasing factors: activational and organizational effects of gonadal hormones, and sex chromosome complement (SCC). Four Core Genotypes (FCG) mice, comprising XX and XY gonadal males and XX and XY gonadal females, were either gonad-intact or gonadectomized (GDX) as adults (2.5months); food intake was measured second-by-second for 7days starting 5weeks later, and body weight and composition were measured for 22weeks thereafter. Gonadal males weighed more than females. GDX increased body weight/fat of gonadal females, but increased body fat and reduced body weight of males. After GDX, XX mice had greater body weight and more fat than XY mice. In gonad-intact mice, males had greater total food intake and more meals than females during the dark phase, but females had more food intake and meals and larger meals than males during the light phase. GDX reduced overall food intake irrespective of gonad type or SCC, and eliminated differences in feeding between groups with different gonads. Diurnal phase of feeding was influenced by all three sex-biasing variables. Gonad-intact females had earlier onset and acrophase (peak) of feeding relative to males. GDX caused a phase-advance of feeding, especially in XX mice, leading to an earlier onset of feeding in GDX XX vs. XY mice, but earlier acrophase in GDX males relative to females. Gonadal hormones and SCC interact in the control of diurnal rhythms of food intake. PMID- 26226659 TI - [Guidelines for the clinical trials of antibacterial ophthalmic solution]. PMID- 26226660 TI - Want to get healthier? Get your partner involved. PMID- 26226658 TI - Evaluation of Cardiac Involvement in Children with Dengue by Serial Echocardiographic Studies. AB - BACKGROUND: Infection with dengue virus results in a wide range of clinical manifestations from dengue fever (DF), a self-limited febrile illness, to dengue hemorrhagic fever (DHF) which is characterized by plasma leakage and bleeding tendency. Although cardiac involvement has been reported in dengue, the incidence and the extent of cardiac involvement are not well defined. METHODS AND PRINCIPAL FINDINGS: We characterized the incidence and changes in cardiac function in a prospective in-patient cohort of suspected dengue cases by serial echocardiography. Plasma leakage was detected by serial chest and abdominal ultrasonography. Daily cardiac troponin-T levels were measured. One hundred and eighty one dengue cases were enrolled. On the day of enrollment, dengue cases that already developed plasma leakage had lower cardiac index (2695 (127) vs 3188 (75) (L/min/m2), p = .003) and higher left ventricular myocardial performance index (.413 (.021) vs .328 (.026), p = .021) and systemic vascular resistance (2478 (184) vs 1820 (133) (dynes.s/cm5), p = .005) compared to those without plasma leakage. Early diastolic wall motion of the left ventricle was decreased in dengue cases with plasma leakage compared to those without. Decreased left ventricular wall motility was more common in dengue patients compared to non dengue cases particularly in cases with plasma leakage. Differences in cardiac function between DF and DHF were most pronounced around the time of plasma leakage. Cardiac dysfunction was transient and did not require treatment. Transient elevated troponin-T levels were more common in DHF cases compared to DF (14.5% vs 5%, p = 0.028). CONCLUSIONS: Transient left ventricular systolic and diastolic dysfunction was common in children hospitalized with dengue and related to severity of plasma leakage. The functional abnormality spontaneously resolved without specific treatment. Cardiac structural changes including myocarditis were uncommon. PMID- 26226661 TI - Best tips to stay on your medication and stay healthy. Tried-and-true methods, plus the latest electronic reminders and gadgets. PMID- 26226662 TI - Ask the doctor. My wife says I should slow down and retire, but I hope I can work forever. What's your take? PMID- 26226663 TI - Feeling younger at heart may help you live longer. A youthful attitude may lead to better eating and exercising habits. PMID- 26226664 TI - Can you put off that knee surgery? Physical therapy and weight loss can relieve knee pain and protect your mobility. PMID- 26226665 TI - In search of a milk alternative. Soy, nut, and grain milks are available. But are they right for you? PMID- 26226666 TI - Could that leg pain be peripheral artery disease? The telltale sign is leg pain and fatigue that comes on with activity and goes away with rest. PMID- 26226667 TI - New thinking about beta blockers. If you have high blood pressure, there may be better alternatives. PMID- 26226668 TI - Final Priority; Rehabilitation Training: Vocational Rehabilitation Technical Assistance Center--Youth With Disabilities. Final priority. AB - The Assistant Secretary for Special Education and Rehabilitative Services announces a priority under the Rehabilitation Training program. The Assistant Secretary may use this priority for competitions in fiscal year (FY) 2015 and later years. This priority is designed to ensure that professionals working in State vocational rehabilitation (VR) agencies receive the technical assistance (TA) they need to provide youth with disabilities with services and supports that lead to postsecondary education and competitive integrated employment. PMID- 26226669 TI - Foreword. The Twenty-five Reports of the Study on Yusho--PCBs and Dioxin-Related Compounds. PMID- 26226670 TI - [Comparison of the prevalence of symptoms and medical histories between Yusho patients and healthy controls]. AB - Yusho disease was first reported in October 1968 in western Japan. Although a previous survey revealed that Yusho patients have suffered from various symptoms for 40 years after the outbreak of Yusho, some symptoms could be caused by aging. Therefore, we compared the prevalence of symptoms and medical histories (symptoms or patient-reported diseases) between Yusho patients and healthy controls to demonstrate the effects of Yusho on health conditions. We conducted a survey of healthy controls who had already registered to a survey company and created a dataset of symptoms and medical histories. We then merged the healthy control data with the Yusho survey data obtained from The Ministry of Health, Labour, and Welfare of Japan. Statistical analyses were performed using a chi-square analysis for the incidence of symptoms. Symptoms included in the major diagnostic criteria for Yusho, such as pigmentation and acneform eruption, were expectedly higher in the Yusho patients than in the healthy individuals. Symptoms that could be caused by aging, such as general fatigue, arthralgia, and numbness in the extremities, were also significantly higher in the Yusho patients after adjustment for age, indicating the possibility that Yusho may cause various systemic symptoms and diseases. PMID- 26226671 TI - [Anti- SSA/Ro and Anti-SSB/ La Antibodies in Patients with Yusho]. AB - To investigate chronic immune effects of polychlorinated biphenyl (PCB) and polychlorinated dibenzofuran (PCDF), anti-SSA/Ro and anti-SSB/La antibodies were studied in serum of 213 patients with Yusho and 63 control subjects in 2013. Anti SSA/Ro antibodies were found in 4.2% (9/213) of patients with Yusho and 1.6% (1/63) of control subjects. The prevalence rates of anti-SSA/Ro antibodies in Yusho patients were not associated with blood PCB concentration or blood 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) concentration. Anti-SSB/La antibodies were found in 1.4% (3/213) of patients of Yusho, but none of controls. Furthermore, high concentrations of PCB and 2,3,4,7,8-PeCDF were present in Yusho patients with anti-SSB/La antibodies. We conclude that anti-SSB/La antibody is present in patients with Yusho, and it may be associated with PCB and 2,3,4,7,8 PeCDF in the blood. PMID- 26226672 TI - [Serum Levels of Regulatory T Cell in the Yusho Patients]. AB - Dioxin and dioxin-like compounds receptor (Ahr) mainly expressed on the surface of regulatory T (Treg) cell and Th17 cell could regulate immunological functions in the Yusho patients. We prospectively analyzed data obtained in a total of 56 cases of Yusho, which include patients identified ('Nintei' ) or non-identified ( 'Minintei') or identified as a family member, at the annual health check in 2014. The number of Treg cell showed lower among identified patients compared with non identified group or family identified group (p = 0.4184 and p = 0.291, respectively). There was also a strong correlation between serum levels of neutral fat and the number of Treg cells (p = 0.0313). These results suggest that Treg cell plays a principal role in the immune response among Yusho patients. PMID- 26226673 TI - [The Effect of Maternal Exposure to Dioxins on the Level of Thyroid Hormone in Developing Pups]. AB - Maternal exposure to dioxins causes a number of developmental disorders in the offspring. Previous studies have suggested that lactational exposure to 2,3,7,8 tetrachlorodizenzo-p-dioxin (TCDD) reduces the pup level of thyroid hormone after weaning, leading to the damage to their development including neural maturation. However, the specificity for age and dioxin congeners as well as dose dependency in terms of a reduction in pup thyroid hormone remains to be clarified. To address this issue, we investigated whether TCDD or 2,3,4,7,8 pentachlorodibenzofuran (PenCDF), one of the dioxins which caused 'Yusho' incident, affects the status of thyroid hormone during the fetal and neonatal periods. Treating pregnant rats at gestational day (GD)15 with 1 MUg/kg TCDD scarcely affected the serum concentration of thyroxine, although a significant reduction by TCDD was detected at limited endpoints [GD21 and postnatal day (PND)21]. In addition, maternal exposure to TCDD (0.05-30 MUg/kg) or PenCDF (1 1,000 MUg/kg) did not have any change in the serum level of thyroxine in GD20 fetuses even at the maximum dose. Neither the expression of pituitary thyroid stimulating hormone beta (TSHbeta) nor hypothalamic thyrotropin-releasing hormone was sensitive to TCDD treatment. In pregnant dams, TCDD decreased the serum level of thyroxine at GD20 and 21, while the pituitary expression of TSHbeta was induced. These results suggest that a single administration of dioxins to pregnant rats at GD15 have little effect on the level of thyroxine in the fetuses and infants, while a reduced level of this hormone observed in the offspring at GD21 and PND21 and pregnant dams at GD20 and 21. PMID- 26226674 TI - [Bone Mineral Density in Yusho Health Examination]. AB - We examined the bone mineral density in Yusho patients. 460 subjects underwent dual-energy X-ray absorptiometry bone scans as part of the nationwide Yusho health examination in 2011. Serum levels of polychlorinated dibenzo-p-dioxin, polychlorinated dibenzofurans, and non-ortho polychlorinated biphenyls were measured using high-resolution gas chromatography and high-resolution mass spectrometry. The average age was 64.0 years in women and 63.4 in men. About one third (35%) of women (n = 89) had low bone mineral density (BMD), defined as a T score less than 70, while only 4.9% of men (n = 10) had low BMD. Serum levels of several congeners were positively associated with Z-scores in simple regression analysis. Further multivariate linear regression analysis should be required in the future. PMID- 26226675 TI - [Relationships between Half-Lives of Dioxins and SNPs in AhR among Yusho Patients]. AB - Half-lives of blood levels of 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) are varied in Yusho patients. The objective was to evaluate a relationship between half-lives of PeCDF levels and types of SNP rs10249788 of aryl hydrocarbon receptor (AHR) gene in 93 Yusho patients. Based on physical symptoms, age, sex, body mass index and other factors, we set up suitable calculation formulas to fit the actual PeCDF levels thorough rates of change in PeCDF. We found that patients with C/T SNP had longer half lives than patients with C/C and T/T SNPs. Patients with T/T SNP are known to express higher amount of AHR mRNAs. However, detailed analysis could not be carried out in T/T group due to a limited number of patients (n = 11). Further research is warranted to determine the cause of the longer half-lives in C/T patients. PMID- 26226676 TI - Metabolomics of Salivary Biomarkers in Yusho Patients. AB - Yusho patients had many symptoms, and mouth dryness was one of the important oral symptoms. Presently, some Yusho patients complain of mouth dryness. In the present study, we measured mouth dryness by using an oral moisture checking device and examined metabolites of saliva by using metabolome analysis. We found no difference between Yusho patients and controls in terms of mouth dryness. Concerning metabolomes of saliva, there were some metabolites in Yusho patients that were not in controls. PMID- 26226677 TI - [The Distribution of Dioxin Concentrations in the Blood of Yusho Patients]. AB - In 1968, the contamination of cooking oil by heat-degraded polychlorinated biphenyls (PCBs) caused a case of mass poisoning, the so-called Yusho incident. The cause of Yusho disease is thought to be ingested toxic substances, including not only PCBs but also polychlorinated dibenzofuran (PCDFs) in Kanemi rice oil. We previously measured dioxins concentrations in the blood of 854 Yusho patients by annual medical examination from 2001 to 2013. We determined the concentrations of 2,3,4,7,8-PeCDF, 1,2,3,4,7,8-HxCDF, 1,2,3,6,7,8-HxCDF and 3,3',4,4',5,5'-HxCB (#169) in the blood of Yusho patients were more than double those of normal controls. In 2012, a new Yusho criteria was established. Family members living with a Yusho patient were also certified as Yusho patients and called Yusho family cohabitant patients. In this study, we compared the distribution of 2,3,4,7,8-PeCDF concentration in the blood of Yusho patients and Yusho family cohabitant patients. It was suspected that the distribution of 2,3,4,7,8-PeCDF concentration in Yusho family cohabitant patients would be lower than that of Yusho patients. PMID- 26226678 TI - [Blood PCB Concentrations and their Tendencies Examined in Fukuoka 2011-2014 Annual Inspections for Yusho]. AB - We measured PCBs of blood of 154 people in the Yusho medical check-up from January 2011 through December 2014 and analyzed their PCB blood patterns. Eleven examinees were newly certified as Yusho patients during these 4 years. Of these 11, we identified three Yusho patients with the A pattern, five with the B pattern, and three with the BC pattern. We found no Yusho patients with the C pattern. The B pattern was found in 27 of the 154 examinees, such that the probability that an examinee with the B pattern would be certified as a Yusho patient was about 20%. Since 2012, any family members living with a Yusho patient have also been certified as Yusho patients. The number of such family cohabitants was 16, among whom the PCB pattern was uniformly the C pattern. There were 20 examinees born after 1989, and all those examinees were Yusho-suspected persons. The total PCB concentrations of this younger-age group was less than 0.5 ng/g on average and was low compared with the normal controls. PMID- 26226679 TI - A Study on Polychlorinated Biphenyls Specifically--Accumulated in Blood of Yusho Patients Collected from Medical Check-Ups in 2012. AB - In this study, we analyzed polychlorinated biphenyls (PCBs) in the blood of Yusho patients collected from medical check-ups, which were conducted in 2012. The results show that 65 PCB isomers, not including non-ortho PCBs, were detected in the blood samples, and the total concentration was 620 ng g(-1) lipid. This value was comparable to the concentration in blood samples collected in 2005, and indicated that PCB concentrations in Yusho patients remained unchanged from 2005 to 2012. Here, we focused on major and specific PCB isomers in the blood samples of Yusho patients and normal controls. Examples of the former include hexaCB-153, hexaCB-138, and heptaCB-180, which are detected in human blood, while the latter include hexaCB-156, hexaCB-157, and heptaCB-189, and are highly detected in the blood of Yusho patients. Additionally, we tried to determine why the specific isomers were highly accumulated in the blood of Yusho patients as compared to the normal controls. We therefore analyzed these isomers in the contaminated rice oil, and found that the concentrations of hexaCB-156, hexaCB-157, and heptaCB-189 were 1800, 450, and 190 ng g(-1), respectively. Notably, previous studies indicated that these isomers might not be easily metabolized in humans. Therefore, these findings demonstrated that these isomers were highly accumulated in the blood of Yusho patients. PMID- 26226680 TI - [Effect of Cynaropicrin on 2,3,4,7,8-Pentachlorodibenzofuran-induced Wasting Syndrome and Oxidative Stress]. AB - The effect of cynaropicrin that is the major component of an edible plant, artichoke (Cynara scolymus) on 2,3,4,7,8-pentachlorodibenzofuran (PenCDF)-induced toxicity in mice was studied. We evaluated the effect of cynaropicrin on the wasting syndrome and oxidative stress elicited by PenCDF. However, the PenCDF dose-response relationship on the wasting syndrome has been superficial. Therefore, we determined the dose which causes wasting syndrome in C57BL/6J mice, a responsive strain to dioxins. Since 2,3,7,8-tetrachlorodibenzo-p-dioxin (0.1 mg/kg, p.o.) induces hepatic ethoxyresorfin O-deethylase (EROD) activity in mice, we set the doses of PenCDF at 0.3, 1.0, 3.0, 5.0 and 10 mg/kg (once, p.o.) on the basis of its toxic-eqivalency factor (0.3). The wasting syndrome was evaluated by measuring the daily changes of body weight. Thiobarbituric acid-reactive substances were used as an index of oxidative stress. Of PenCDF doses examined, wasting syndrome and oxidative stress took place most markedly in 5 mg/kg. In disagreement with this, EROD activity which is the marker of the aryl hydrocarbon receptor-dependent induction of cytochrome P450 1a1 was elevated most abundantly at 0.3 mg/kg. Then, we examined the effect of cynaropicrin on the wasting syndrome and oxidative stress provoked by PenCDF at 5 mg/kg. However, this compound up to 20 mg/kg (p.o.) did not attenuate PenCDF-induced wasting syndrome. On the contray, PenCDF-induced oxidateive stress was suppressed by cynaropicrin at the highest dose (20 mg/kg), although EROD activity was increased rather than reduced by cynaropicrin at lower doses. Thus, it is suggested that cynaropicrin has an ability to reduce oxidative stress caused by PenCDF. PMID- 26226681 TI - [Metabolism of 2,2',3,4,4',5,5'-Heptachlorobiphenyl (CB180) by Animal Liver Microsomes]. AB - The in vitro metabolism of 2,2',3,4,4', 5,5'-heptachlorobiphenyl (CB180) was examined using liver microsomes of rats, guinea pigs and hamsters. Of liver microsomes from untreated animals, rats and guinea pigs produced one metabolite (M-1) with the activity of 1.2 and 18.1 pmol/hr/mg protein, respectively, but hamsters did not at all. Pretreatment of phenobarbital (PB) resulted in about 32 fold increase in rats, 4-fold increase in guinea pigs and an appearance of M-1 in hamsters (15 pmol/hr/mg protein). In addition, another metabolite (M-2) was formed only by liver microsomes of PB-treated guinea pigs. In contrast, pretreatment of 3-methylcholanthrene showed no metabolite in three animals. By comparison of the GC-MS data of the metabolites with synthesized authentic samples, M-1 and M-2 was determined to be 3'-hydroxy (OH)-CB180 and 4'-OH 2,2',3,4,5,5'-hexachlorobiphenyl (CB141), respectively. These results suggest that 3'-OH-CB180 is a major metabolite and is formed by PB-inducible cytochrome P450 (CYP2B enzymes) in animals and also guinea pigs possess much higher activity to metabolize CB180 than rats and hamsters. PMID- 26226682 TI - [Latest Findings of Yusho and Its Therapeutic Development]. AB - Yusho incident is an unprecedented mass food poisoning that occurred in the western area of Japan in 1968. It was caused by the ingestion of rice bran oil contaminated with polychlorinated biphenyls (PCBs) and various dioxins and dioxin like compounds, such as polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). The victims of Yusho have suffered from characteristic skin manifestations in company with systemic, ophthalmological, and mucosal symptoms for a long period. Since the outbreak of Yusho, the Study Group of Yusho has been conducting annual medical check-ups on Yusho victims. We describe here the latest research findings of chronic dioxin-induced toxicity to Yusho patients and the mechanisms of toxicities of dioxins through the aryl hydrocarbon receptor (AhR) pathway. High amounts of PCBs and PCDFs are still present in a number of patients with Yusho. The patients have persistent various symptoms, some of which were significantly associated with blood levels of PCBs, dioxins, or dioxin-like compounds. The adverse effects on the next generation are also found. According to the findings of recent basic studies, the biological and toxicological effects mediated by the AhR system have been becoming clear; therefore, the therapeutic interventions may be found in the near future. PMID- 26226683 TI - [Conventional and novel cardiovascular risk factors and predisposition to the development of atherosclerosis]. AB - This population-based cross-sectional study included 472 apparently healthy study participants with an increased risk of cardiovascular disease, including 300 patients with hypercholesterolemia. To assess the susceptibility to the development of atherosclerosis, an ultrasonic evaluation of common carotid arteries was used. It has been confirmed that there exists the geographical gradient of carotid intima-media thickness (cIMT), and it has been shown that this gradient is highly correlated th the known gradient of cardiovascular mortality. It was found that the combination of conventional cardiovascular risk factors can help explaining only 21% variability of cIMT, the marker of generalized atherosclerosis. It was found that a predisposition to atherosclerosis, as measured by a pathological increase in cIMT, should be due to the interaction not only conventional cardiovascular risk factors, but also to genetic and environmental factors. PMID- 26226684 TI - [Analysis of mitochondrial haplogroups in persons with subclinical atherosclerosis based on high-throughput mtDNA sequencing]. AB - Genetic predisposition plays an important role among other risk factors in multifactorial socially significant diseases such as atherosclerosis and its clinical manifestations. This pilot study was aimed to identify the relationship between the type of mitochondrial haplogroup and the risk of subclinical atherosclerosis in humans. For accurate detection of mitochondrial haplogroups, high-throughput sequencing of the mitochondrial genome using the Roche 454 technology was carried out. The results have shown that in Russian population, the belonging to haplogroup H is associated with an increased risk of atherosclerosis, but belonging to haplogroups T and U--with reduced risk. The data obtained can be used to assess individual risk of atherosclerosis and for further studies on the role of mitochondrial genome mutations in the development of atherosclerosis and its clinical manifestations. PMID- 26226685 TI - [Association of mitochondrial genome mutations with lipofibrous plaques in human aortic intima]. AB - Atherosclerosis is a basis of development for many cardiovascular diseases, which are leading causes of death among people in the 21-st century. One of possible causes of atherosclerosis may be somatic mutations of human mitochondrial genome. In order to identify mutations associated with atherosclerosis, we analyzed 42 mitochondrial mutations found in various pathologies. The subject of the study were individuals who died as a result of an accident or a sudden death. The material for the investigation were segments of intima from 7 aortas both normal and with lipofibrous plaques. DNA was isolated by a method of phenol-chloroform extraction. PCR-fragments of DNA containing the region of investigated mutations were analyzed by an original method of quantitative assessment of mitochondrial genome mutant alleles. This method was developed in our laboratory on the basis of pyrosequencing technology. Statistical data processing was performed using IBM SPSS Statistics 21.0 and by bootstrap analysis. 40 of 42 studied mutations were heteroplasmic and two were homoplasmic according to the absence of a mutant allele in atherosclerosis. The developed method of direct quantitative assessment of mitochondrial genome mutant alleles helped us to find three new mutations: 652delG, 961delC and 5132insAA. It was found that 11 of mitochondrial mutations (652insG, T3336S, C3256T, G14459A, G14846A, G15059A, 652delC, A1555G, C5178A, G13513A and G12315A), belonging to eight mitochondrial genes: rRNA 12S, tRNA - Leu (codon recognition UUR) and tRNA - Leu (codon recognition CUN), subunit 1, 2, 5 and 6 of NADH dehydrogenase and cytochrome B are potentially associated with atherosclerosis, because from 29% (2 of 7 aortas) to 86% (6/7) investigated aortas have a significant difference in the heteroplasmy level of these mutations in lipofibrous plaques compared to normal aortic intima. PMID- 26226686 TI - [Pathogenesis of the vascular consequences caused by cervical instability and their algorithm for pharmacotherapy]. AB - 256 patients with radiologic detected cervical instability were examined. This pathology may be the cause of arterial or venous vertebra-basilar disorders. We realized extensive examination the patients with the cervical instability for the pathogenic correction of vascular consequences. We founded normal blood flow only in 19.9% cases without morphology alterations the vessels of both basins. 80.1% patients had different cerebral hemodynamic disorders variations. According to our examination plan we detected the vertebra-basilar insufficiency pathogenesis and proposed medicinal correction of the cerebral instability consequences. PMID- 26226687 TI - [Dynamics of daily rhythm changes of arterial blood pressure in hypopinealism]. AB - The article presents the original data on the character of the changes in arterial blood pressure (ABP) in rabbit with hypopinealism induced by long 24 hour lighting. In experimental animals registered leveling the daily rhythm of ABP primarily because of increase this value in dark time (night, evening) and formation of arterial hypertension by 'non-dipper". PMID- 26226688 TI - [Cerebral circulation pathophisiology into pneumocephalus craniocerebral dispoportion]. AB - We included 19 patients with a different intensity postoperative pneumocephalus and an inadequate postoperative awakening. Intracranial CT excluded postoperative complications (oedema, haematoma, hidrocephalus) and diagnosed a pneumocephalus (above the frontal and temporal lobes and in the cerebral ventricular system). In two hours after operation we found systolic linear blood flow velocity (BFV syst.) decrease in the extracranial part of internal carotic artery (ICA) (p < 0.001) in patients with pneumocephalus and inadequate postoperative awakening. But in 24-48 hours after operation we diagnosed BFV syst. elevation in the ICA extracranial part (p < 0.001) and preumocephalus diminution in patients with a recovered consciousness. PMID- 26226689 TI - [The endothelium of the vessels and proxidative-antioxidative balans in pregnancy rats with endothoxinaemia]. AB - Actual problem of modern obstetrics is the infection in pregnancy which leads the deadborn, early children's death rate ind disease. In Belarus disease of newborns at specific infections for postnatal the period has made 14.1 per thousand, and death rate of 0.38 per thousand. The purpose of researches--to study a condition endothelium and activity of lipid peroxidation products at pregnant rats with endothoxinaemia. In experiments on 49 pregnancy rats with intramuscular injection of endotoxine (Lipopolysaccharide E. coli Serotype O127:B8 "Sigma") during the period placentation dysfunction development endohelium is established, that was shown more expressed in 2,3 times (p < 0.05) constriction by reaction on noradrenalin, increase in 18,3 times (p < 0.001) quantities circulating endothelium cages and decrease in 14 times (p < 0.001) the deendent endothelium vasodilatation under influence acetilcholine, to the dress increase of level of lipid peroxidation products: concentration of diene conjugates on 91% (p < 0.001), malone dialdegide--on 56% (p < 0.001), Shiff bases--on 7.9% (p < 0.05); and decrease in indicators of antioxidant protection: maintenances retinol on 29% (p < 0.05), alpha-tocopherol--on 6% (p < 0.001). PMID- 26226690 TI - [Role of activation of lipid peroxidation in the mechanisms of cardiovascular disease system under the action of heavy metals in the experiment]. AB - The main anthropogenic air pollutants are heavy metals, World Health Organization related to toxic substances hazard class 1. Penetrating into the body in different ways, metals have a strong toxic effect on all body systems, but one of the most vulnerable, due to a number of reasons, is the cardiovascular system. There are many mechanisms of pathogenic influence of xenobiotics, leading to the development of disorders of the cardiovascular system, but our attention was attracted by the ability of metals to realize their negative effects through the activation of free radical. To confirm this assumption, it was necessary to conduct a pilot study of the effect of antioxidants in long-term effect of heavy metals. As an antioxidant agent used melatonin. Investigation of the state of systemic hemodynamics is to determine the mean arterial pressure, specific peripheral vascular resistance, stroke index and cardiac index. The intensity of free radical concentration was estimated by malondialdehyde and hydroperoxides in the blood of animals. The results of experimental studies revealed that prolonged intake of heavy metals (cobalt, cadmium and mercury) leads to the development of marked hemodynamic disturbances, combined with a sharp increase in the level of lipid peroxidation products in the blood. Melatonin under intoxication by heavy metals significantly reduced hypertensive effect of heavy metals on systemic hemodynamics, which together with a reduction of lipid peroxidation processes allows us to consider the activation of lipid peroxidation one of the major pathogenic factor in the development of hemodynamic disorders in conditions of heavy metal poisoning. PMID- 26226691 TI - [Genetic features of nitric oxide generating systems predetermine the body's resistance to the development of carcinoma]. AB - Predisposition to tumors is often determined by how effectively the genotype of an individual forms an immune defense. An important factor of such protection is macrophage NO. We assumed that the body's vulnerability to the development of tumors may depend from the characteristics of the NO generating systems. The content of NO in the tumor changed by ITU, inhibitor of iNOS, c-PTIO, traps and SNP, donor NO. Production of macrophage NO were evaluated by nitrites in the culture media. iNOS was assessed using the Western blot analysis. Phenotype of macrophages was assessed using cytometry for CD labels. Life span of mice C57BL/6N with Ehrlich tumor was 25% greater than that of the C57BL/6J. Reducing the content of NO in the tumor reduced life expectancy of high-resistance to tumor subline C57BL/6N at 23%. Increase of NO increased life expectancy of low resistance subline C57BL/6J at 26%. Macrophages of C57BL/6N were 1.5 times higher contents of iNOS and NO production, as compared with macrophages of C57BL/6J. CD phenotype markers determined the macrophage phenotype C57BL/6N as M1 and C57BL/6J mice macrophage phenotype as M2. Thus, the body's vulnerability to the development of tumors may depend from the characteristics of the NO generating systems. C57BL/6J, unlike C57BL/6N does not synthesize NNT (nicotinamide nucleotide transhydrogenase) and have differences in the single nucleotide polymorphism (SNP). The important role of NO in the resistance to Carcinoma, NNT and SNP deserve attention in the development of new methods of antitumor therapy. PMID- 26226692 TI - [The effect of the biopolymer chondroitin sulfate on reparative regeneration of connective tissue]. AB - The research objective is a study of an intra-articular method of introduction of the preparation "mukosat" for stimulation of reparative regeneration of connective tissue of knee joints in rabbits with an experimental arthritis. It is ascertained that intra-articular maintenance of chondroitin sulfate (the preparation "mukosat") acts as a stimulus for reparative regeneration of connective tissue thus showing up positive changes in the status of connective tissue elements of joints: decrease in glycosaminoglycan content in blood serum and normalization of the composition of glycosaminoglycan carbohydrate component. It probably depends on stimulation of biosynthesis of autologous normal glycosaminoglycans in tissues of animal knee joints. PMID- 26226693 TI - [Characteristics of Leydig cells in the newborn posterity of female rats with chronic injury of the hepatobiliary system of various genesis]. AB - Morphological and functional features of interstitial endocrine cells (Leydig cells) in the posterity of female rats with experimental liver injury of various genesis in the neonatal period were analized. Found that in experimental rats are a reduction in the number of Leydig cells, the ratio between active and inactive endocrinocytes and as a consequence, reduction of its cell activity index. PMID- 26226694 TI - [Opportunities for pharmacological management of macrophage polarization]. AB - Macrophages play a key role in the pathogenesis of many human diseases. Both evaluation of M2/M1 macrophage ratio and discovering definite roles of macrophage phenotypes in this diseases may be used as criteria for assessment of effectiveness of treatment and for predicting prognosis of patients. Moreover, macrophage reprogramming seems to be a perspective therapeutic strategy for the diseases with inflammatory component in their pathogenesis. This review is based on articles published mainly in last five years and describes the results of the studies for some substances, most of them being used in current medical practice. This agents have been proven to have determined affection on macrophage polarization, its signal pathways, etc. Influencing macrophage reprogramming by such agents seems to be an important strategy in modern medicine. PMID- 26226695 TI - [Autoantibodies to glutamate, GABA and their receptors in epilepsy]. AB - This review discusses the pathogenic role of autoantibodies (autoAB) to excitatory and inhibitory neurotransmitters glutamate, GABA and their receptors in the pathogenesis of epilepsy. The data of clinical and experimental studies show that glutamate AMPA and NMDA- receptors autoAB and GABA receptors autoAB in high titers are highly pathogenic, causing a significant decrease of the density of the receptors and contribute the neuronal death. Discusses the results of experimental data about of the anticonvulsant action of glutamate antibodies (AT) and opposite proconvulsant effect of GABA antibodies in different models of epileptic activity. PMID- 26226696 TI - [Results of December joint plenum of Russian Scientific Society of pathophysiology and Scientific Council on general pathology and Pathophysiology. New areas of research in the pathophysiology]. AB - Contains information on the joint plenum of Russian scientific society of pathophysiology and Scientific Council on General Pathology and Pathophysiology, held 17-18 December 2014 in Moscow at the FSBSI "Institute of General Pathology and Pathophysiology". PMID- 26226697 TI - Automated external defibrillators in schools? AB - OBJECTIVE: Automated external defibrillators (AEDs) placed in public locations can save lives of cardiac arrest victims. In this paper, we try to estimate the cost-effectiveness of AED placement in Belgian schools. This would allow school policy makers to make an evidence-based decision about an on-site AED project. METHODS AND RESULTS: We developed a simple mathematical model containing literature data on the incidence of cardiac arrest with a shockable rhythm; the feasibility and effectiveness of defibrillation by on-site AEDs and the survival benefit. This was coupled to a rough estimation of the minimal costs to initiate an AED project. According to the model described above, AED projects in all Belgian schools may save 5 patients annually. A rough estimate of the minimal costs to initiate an AED project is 660 EUR per year. As there are about 6000 schools in Belgium, a national AED project in all schools would imply an annual cost of at least 3960 000 EUR, resulting in 5 lives saved. CONCLUSIONS: As our literature survey shows that AED use in schools is feasible and effective, the placement of these devices in all Belgian schools is undoubtedly to be considered. The major counter-arguments are the very low incidence and the high costs to set up a school-based AED programme. Our review may fuel the discussion about Whether or not school-based AED projects represent good value for money and should be preferred above other health care interventions. PMID- 26226698 TI - Altered expression of monocyte and dendritic cell membrane-associated antigens following coronary angiography. AB - INTRODUCTION: Coronary angiography is able to induce a systemic inflammatory response. We hypothesised that this procedure may affect monocyte and dendritic cell count and membrane-associated antigen expression. METHODS: Blood samples were obtained before and immediately after coronary angiography in twenty patients with stable angina pectoris. Cell enumeration and antigen expression levels were evaluated by flow cytometry. Plasma levels of soluble CD14 and interleukin-6 were quantified by ELISA. RESULTS: The absolute and relative numbers of circulating monocytes (Mon1, Mon2 and Mon3 subsets) and dendritic cells (myeloid and plasmacytoid subsets) were not significantly different pre versus post-angiography. Expression of CD14 on Mon1 and Mon2 decreased significantly by 12.01% (P = 0.002) and 13.01% (P=0.012), respectively. CD16 expression on Mon2 (+10.53%; P=0.017) and Mon3 (+12.58%; P<0.001) increased. CD45 expressed by monocytic and dendritic cells was lowered (-5.80% and P = 0.001, 11.49% and P < 0.001, respectively). The level of plasma IL-6 decreased significantly (P = 0.002). The reduction in sCD14 was not significant (P = 0.054). CONCLUSION: Coronary angiography leads to changes in surface expression of CD14, CD16 and CD45. These findings underline the importance of blood collection prior to the angiographic procedure when aiming to study the functional analysis of monocyte and dendritic cell numbers by flow cytometry. PMID- 26226699 TI - Determinants and impact of the natriuretic response to diuretic therapy in heart failure with reduced ejection fraction and volume overload. AB - OBJECTIVE: The objective of this study was to investigate determinants of the natriuretic response to diuretics in decompensated heart failure (HF) and the relationship with decongestion, neurohumoral activation and clinical outcome in the contemporary era of HF management. METHODS AND RESULTS: In this prospective, single-centre cohort study, consecutive patients with decompensated HF (n = 54) and left ventricular ejection fraction 45% received protocol-driven diuretic therapy until complete disappearance of congestion signs. Urine was collected during three consecutive 24-h intervals. Natriuretic response was defined as absolute natriuresis (mmol) per mg of intravenous bumetanide administered. Natriuresis was 146 mmol (76-206 mmol), 74 mmol (37-167 mmol) and 74 mmol (53-134 mmol) per mg intravenous bumetanide administered during the first, second and third 24-h interval, respectively. Diastolic blood pressure (beta = 23.048 +/- 10.788; P-value = 0.036), plasma aldosterone (beta = -25.722?11.560; P value=0.029), and combination therapy with acetazolamide (beta = 103.241 +/- 40.962; P-value = 0.014) were independent predictors of the natriuretic response. Patients with a stronger natriuretic response demonstrated more pronounced decreases in plasma NT-proBNP levels (P-value = 0.025), while a weaker response was associated with higher peak plasma aldosterone levels (P-value = 0.013) and plasma renin activity (P-value = 0.033). Natriuresis per loop diuretic dose predicted freedom from all-cause mortality or HF readmissions, independently of baseline renal function (HR 0.40, 95% CI 0.16-0.98; P-value = 0.045). CONCLUSIONS: More effective natriuresis in decompensated HF patients with reduced ejection fraction and volume overload is associated with better decongestion, less neurohumoral activation and predicts favourable clinical outcome independently from renal function per se. Acetazolamide warrants further evaluation in large prospective trials to increase the natriuretic response to loop diuretics. PMID- 26226700 TI - Subclinical arterial wall damage in patients at low to moderate cardiovascular risk. AB - AIM: The aim of this paper is to study the degree of subclinical arterial wall damage in subjects at low and moderate risk of cardiovascular death by the SCORE scale using instrumental research methods. METHODS: We enrolled 600 patients (mean age 49.0 +/- 7.1 years, 74% women) with a calculated SCORE 5%, who passed a carotid duplex ultrasonography with a measurement of the intima-media thickness (IMT) and carotid plaque (CP) severity. In the study a computer sphygmography was also performed on the subjects to determine ankle-brachial pulse wave velocity (abPWV) and an ankle-brachial index (ABI). RESULTS: We found 389 (64%) patients with subclinical signs of atherosclerosis. CPs were found in 359 patients (60%), thickened IMT in 28 patients (5%), increased abPWV in 227 patients (38%), and ABI of <0.9 in 29 patients (5%). In the patients with a thickened IMT only two had no CPs. In contrast, 92% of the patients with CPs had normal IMT. Increased abPWV was determined in 87% participants with CPs, and only in 30 subjects no CPs were found. All 29 patients with an ABI of less than 0.9 had CPs. The "presence of CP"was the most sensitive parameter in the patients included in the study, in terms of atherosclerosis determination (92%). The identification of individuals with CPs significantly increased in men over 45 years of age (in 68.4% of cases, P = 0.009), and in women over 50 (in 61.8% of cases, P = 0.001). CONCLUSION: Our data reinforces the importance of non-invasive imaging of atherosclerosis in subjects at low and moderate cardiovascular risk. The study demonstrated a high prevalence of subclinical atherosclerosis signs in patients at low to moderate risk by the SCORE scale and a high detection frequency of carotid plaques. This suggests that wider implementation of carotid ultrasound in primary care algorithms may improve risk stratification with timely initiation of preventive strategies. PMID- 26226701 TI - Smoking acutely impaired endothelial function in healthy college students. AB - OBJECTIVE: Cigarette smoking has been clearly pointed out as a risk factor for cardiovascular disease. Endothelial dysfunction contributes to the development of cardiovascular disease. Flow-mediated dilation (FMD) has been known as one of the endothelial function markers. We investigated the acute and chronic effects of smoking on endothelial function in college-aged smokers. METHODS: Eighteen smokers (mean age: 21 +/- 1 y) and 14 non-smokers (mean age: 20 +/- 1 y) were enrolled in this study. Brachial-ankle pulsed wave velocity (baPWV), systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were measured using a plethysmograph. Endothelium- dependent FMD was induced by reactive hyperaemia. High-resolution ultrasound with a 7.5-MHz linear array transducer was used to measure the diam- eter of the right brachial artery. Measurement of baPWV, SBP, DBP, HR, artery diameter, and %FMD was performed in smokers and non-smokers after 10 min bed rest, and after smoking one cigarette in the smokers. The interval between the two measurements was more than 15 minutes. RESULTS: There were no significant differences on baPWV, SBP, DBP, HR, baseline brachial artery diameter between smokers and non-smokers. Percent FMD after smoking was significantly lower than that at rest values in smokers (8.7 +/- 4.0 vs. 5.3 +/- 2.4, P < 0.005), although %FMD at rest was not significantly different between smokers and non-smokers. No other markers showed any significant differences between smokers at rest and after smoking. CONCLUSION: Even the smoking of one cigarette dramatically impaired endothelial function, although habitual cigarette smoking did not decrease FMD in young healthy smokers. PMID- 26226702 TI - Functional class and type of pulmonary hypertension determinate severity of cardiac autonomic dysfunction assessed by heart rate variability and turbulence. AB - OBJECTIVE: Heart rate variability (HRV) and turbulence (HRT) are validated methods of evaluation of cardiac autonomic nervous system (cANS) dysfunction which is associated with sudden cardiac death. There is limited data on cANS imbalance and its significance,in patients with pulmonary hypertension (PH), so we assessed HRV and especially HRT alterations in PH. METHODS AND RESULTS: Thirty three out of 41 PH patients were enrolled in the study: 22 (66.7%) with pulmonary arterial hypertension (PAH) and 11 (33.3%) with chronic thromboembolic PH (CTEPH), 11 patients were in World Health Organization Functional Class (WHO-FC) I-II, and 22 others in WHO-FC III-IV. The control group consisted of 25 healthy persons. Routine evaluations, echocardiography, right heart catheterization and 24-hour Holter monitoring with time-domain HRV and HRT evaluation were performed. Most of HRV indices and both of HRT parameters were significantly impaired in PH patients, as compared to control subjects. Abnormal HRT (turbulence onset 0.0% and/or turbulence slope 2.5 ms/RR) was found in 36.4% WHO-FC I-II and in 77.3% WHO-FC III-IV patients (P=0.05). Patients in WHO-FC III-IV or with CTEPH presented compromised HRV and HRT values when compared to patients in WHO-FC I-II or with PAH, respectively. Multivariate analysis showed that abnormal HRT occurrence in PH was influenced by higher WHO-FC only (odds ratio 5.3, 95% CI 1.4 19.9, P= 0.01). CONCLUSION: Higher WHO-FC and probably type of pulmonary hypertension (CTEPH more than PAH) determinate the severity of cANS dysfunction assessed by heart rate variability and turbulence. Potential clinical consequences of our findings need further investigations. PMID- 26226703 TI - Radiation dose of cardiac IVR x-ray systems: a comparison of present and past. AB - OBJECTIVE: Although many patients benefit greatly from fluoroscopically guided intervention (IVR) procedures such as percutaneous coronary intervention (PCI), one of the major disadvantages associated with these procedures, such as cardiac IVR, is the increased patient radiation dose. This study compared the entrance surface doses of x-ray equipment for cardiac IVR at the same seven cardiac catheterization laboratories between today and the past to determine the radiation doses of current cardiac IVR x-ray systems. METHODS AND RESULTS: This study was conducted in 2001, 2007, and 2014 at the same seven cardiac catheterization laboratories in and around Sendai City, Japan. The entrance surface doses with cineangiography and fluoroscopy were compared in 2001 (11 x ray systems), 2007, and 2014 (12 x-ray systems) using a 20-cm-thick acrylic plate and skin dose monitor. The x-ray conditions used in the measurements, including the image receptor field magnification mode and the recording speed for cineangiography and fluoroscopy, were those-normally used in the facilities performing PCI. Although presently, the entrance doses of x-ray equipment used for cardiac IVR tend to be lower than previously (fluoroscopy dose in 2001, 19.3 +/- 6.3 mGy/min; in 2014, 13.2 +/- 6.5 mGy/min), some equipment has a high radiation dose. In addition, the dose differences of the x-ray systems in 2014 were greater than those in the past (fluoroscopy dose in 2001, 3.4-fold; in 2014, 10.5-fold). CONCLUSIONS: In IVR procedures, managing the radiation dose of cardiac IVR x-ray systems is a very important issue. Periodical measurement of the radiation dose of the x-ray equipment used for both cineangiography and fluoroscopy for cardiac IVR is necessary. PMID- 26226704 TI - QRS duration shortening predicts left ventricular reverse remodelling in patients with dilated cardiomyopathy after cardiac resynchronization therapy. AB - OBJECTIVE: The relationship between the QRS duration, severity of mechanical dyssynchrony and efficacy of cardiac resynchronization therapy (CRT) is poorly understood. We determined if QRS duration shortening in patients with dilated cardiomyopathy after treatment with CRT was predictive of left ventricular (LV) reverse remodelling. METHODS: Thirty patients with dilated cardiomyopathy were enrolled. Electrocardiographic and echocardiographic recordings were obtained before and 6 months after CRT. Patients were classified as CRT responders or non responders based on their echocardiographic parameters 6 months following CRT. RESULTS: After 6 months of CRT, 9 patients (30%) were classified as non responders. Surprisingly, no significant differences in any of the preoperative metrics were found between CRT responders and non-responders. In sharp contrast, the postoperative parameters of the CRT responder group had significantly improved compared to the non-responder group. The average QRS duration of the CRT responders was significantly shorter than that of the non-responders (-37 +/- 23 ms vs. 0 +/- 23 ms; P < 0.01). The relationships between preoperative parameters, the change in QRS duration and LV end-diastolic diameter were analysed for each patient using multi-linear correlation and regression analyses. We found that the change in QRS duration positively cor- related with the change in LV endiastolic diameter (R = 0.583, P = 0.001). Furthermore, multi-linear regression analysis suggested that changes in QRS duration had a significant effect on LV end diastolic diameter (y = 9.739 + 0.272 x, P = 0.006). CONCLUSION: CRT-mediated changes in the QRS duration are predictive of LV reverse remodelling in patients with dilated cardiomyopathy. PMID- 26226705 TI - The value of aortic pulse wave velocity in predicting coronary artery disease diagnosis and severity. AB - OBJECTIVE: Aortic pulse wave velocity (AoPWV), one of the parameters showing arterial stiffness, has been investigated in different patient groups as a predictor of cardiovascular diseases. The purpose of our study is to investigate the correlation between AoPWV and coronary artery disease (CAD) and its severity. METHODS AND RESULTS: One hundred and three patients who were not diagnosed with CAD but who were scheduled to have coronary angiography (CAG) with CAD suspicion were included in the study. PWV was measured with tonometry device before CAG. Patients were divided into two groups: with or without CAD. The Gensini score of each patient was calculated in the CAD group by several independent specialists. The average age of the patients was 55.2 +/- 8.5 (range 33-73 years). CAD was confirmed in 59 patients (49%). Average PWV in the CAD group was statistically more significant than in the non-CAD group (8.6 +/- 2.0, 5.0 +/- 1.8; P < 0.001). A highly positive correlation was observed between CAD severity and PWV (r = 0.838, P = 0.001). In the CAD diagnosis, for an AoPWV cut-off value of 7.3 m/sec, the sensitivity was 83.1% and the specificity 86.4%. CONCLUSIONS: Various non invasive techniques are used in CAD prognosis. Besides being simple, these techniques are also required to show a high rate of accuracy in CAD prognosis. In this respect, AoPWV gains importance as being a non-invasive method that can be performed with a tonometry device at low cost in policlinic conditions. PMID- 26226706 TI - Galectin-3 in heart failure pathology--"another brick in the wall"? AB - Heart failure is a disease affecting millions of patients each year, and is responsible for burdening the world with high mortality rates. More concerns come from its numerous hospital readmissions (with an estimated number of 2.6 million per year which makes it one of the leading diseases responsible for national healthcare expenditures). Despite drastic improvement of therapies in recent years, heart failure remains a progressive disease. Thus, more attention has been given to finding potential biomarkers involved in the pathological mechanisms of this disease that would potentially lead to faster diagnosis and improved prognosis. One of the emerging biomarkers that has just recently come into the spotlight is galectin-3. It was associated in recent clinical trials with both the progression and severity of heart failure. Ventricular remodelling and myocardial fibrosis are essential for heart failure development and are linked to poor outcomes. An ever-growing body of evidence places galectin-3 as an important link between inflammation and fibrosis, which play a prominent role in cardiac remodelling.This review sums up the most relevant experimental and clinical studies about galectin-3 and its potential prognostic value in heart failure. The article also provides a better understanding of this molecule's involvement in heart failure pathology by modulating cardiac fibrosis. It also weighs whether the available data on galectin-3 are consistent enough to reduce readmissions and mortality while improving diagnosis and future therapies for heart failure, versus the possibility that it is simply"another brick in the wall?" PMID- 26226707 TI - Pleiotropic effects of HDL subfractions and HDL-associated enzymes on protection against coronary artery disease. AB - OBJECTIVE: High-density lipoprotein cholesterol (HDL-C) levels are inversely related to the risk of coronary artery disease (CAD). Alterations in HDL-C subclass distribution and HDL-associated enzyme activities may be more important than total HDL levels for the progression of CAD. We intended to investigate the relationship of HDL-C subclass distribution and HDL-associated enzyme activities with CAD. METHOD AND RESULTS: Our study included 101 patients with stable coronary artery disease, and 64 healthy subjects. Serum levels of HDL lipoprotein associated-phospholipase A2 (HDL-LpPLA2), paraoxonase 1 (PON1), and HDL subfraction distribution were measured. We found increased small HDL (sHDL) subfractions in patients with one-vessel disease (P < 0.001). We also found a reverse correlation between total HDL-C levels and affected vessel number (P < 0.05). Plasma HDL-Lp PLA2 enzyme level was higher in each vessel disease category compared to the control group (P < 0.001). However, PON1 enzyme activity in patients with CAD was not statically significant. Plasma sHDL, HDL-Lp PLA2 enzyme and Lp(a) were significantly different between subjects with CAD and control participants. CONCLUSIONS: We demonstrated decreased sHDL particles and a lower cardioprotective HDL-LpPLA, enzyme activity in all patient subgroups compared to controls. Measurement of total HDL-C level only may not be sufficient to predict CAD risk. PMID- 26226708 TI - Women have right ventricular infarction more frequently than men. AB - OBJECTIVE: The objective of the study was to determine whether women significantly have more frequently right ventricular infarction than men. METHODS: The study population consisted of consecutive patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous intervention. The following criteria were used for the diagnosis of right ventricular infarction: ST-segment elevation in one of the right precordial leads V4R-V6R for equal or more than 1 mm together with ST-segment elevation in at least two contiguous inferior leads. The odds ratio for the diagnosis was calculated according to gender. Searching PubMed, nine more relevant studies that used the same criteria for the diagnosis of right ventricular infarction were identified and a metanalysis was conducted. RESULTS: In our group of 517 consecutive patients with STEMI, 32 (23.5%) of 136 women and 42 (11.0%) of 381 men had RVI (odds ratio (OR) = 2.48, 95% confidence interval (CI): 1.49-4.13; P = 0.001). Two hundred and seventy-five patients had inferior STEMI and among them 32 (42.7%) of 75 women and 42 (23.1%) of 182 men, had a right ventricular infarction (OR = 2.48, 95%CI: 1.40-4.40; P= 0.002). In a meta-analysis, a total number of 4,326 patients with inferior STEMI were included. Four hundred and thirty-seven (41.4%) out of 1,056 women and 1,221 (37.3%) out of 3,270 men, had been diagnosed with RVI (OR = 1.27, 95% CI: 1.09-1.48; P = 0.021). CONCLUSION: Right ventricular infarctions occur more frequently in women than in men. PMID- 26226709 TI - Intima-media complex thickness: preliminary workup of comparative evaluation of abdominal aorta and carotid artery of small-for-gestation-age term newborns and normal size term newborns. AB - BACKGROUND: Increased intima-media thickness (IMT) has shown to be a good predictor of increased incidence of cardiovascular disease. The use of noninvasive measurement of abdominal aortic intima-media thickness (aIMT) and carotid artery intima-media thickness (cIMT) is an attractive modality to further explore and define possible intrauterine factors that may be associated with increased risk of atherosclerosis. PURPOSE: The aim of this study was to compare intima-media thickness of abdominal aorta and carotid artery in small-for gestation-age (SGA) term newborns with appropriate for gestation age (AGA or normal sized) term newborns. MATERIAL AND METHODS: We measured the intima-media thickness of the abdominal aorta (aIMT) and carotid artery (cIMT) by high resolution ultrasonography of 50 SGA and 50 AGA term newborns. RESULTS: Mean aIMT and cIMT were significantly greaterin the SGA term newborns group as compared to AGA term newborns (0.54 +/- 0.06 mm and 0.44 +/- 0.04 mm in SGA term newborns vs. 0.50 +/- 0.04 mm and 0.40 +/- 0.04 mm in AGA term newborns; P < 0.008 and P < 0.001, respectively). The significance was even more apparent after adjustment for birthweight. A negative correlation of aIMT and cIMT was seen with birthweight, Ponderal index, length and head circumference. CONCLUSION: SGA term newborns have significantly increased aortic and carotid intima-media thickness as compared to AGA term newborns. This might be associated with higher risk for atherosclerosis. Longitudinal studies are required to further enhance the possible correlation between birthweight and intima-media thickness in SGA babies. PMID- 26226710 TI - Calcified apical cardiomyopathy. PMID- 26226711 TI - Multimodality imaging of major aortapulmonary collateral arteries in type IV truncus arteriosus. PMID- 26226712 TI - Refractory coronary vasospasm: when dilatation is the solution. PMID- 26226713 TI - Multiple coronary arterial fistulas to left ventricle associated with atrial septal defect. PMID- 26226714 TI - Diffuse cardiac B-cell lymphoma presenting with pericardial effusion or mimicking hypertrophic cardiomyopathy. PMID- 26226715 TI - Sequential rupture of ventricular septum and cardiac apex. PMID- 26226716 TI - Aortic annulus rupture and transcatheter aortic valve implantation. PMID- 26226717 TI - Atorvastatin-induced dermatomyositis in a 47-year-old woman with Sjogren's syndrome. PMID- 26226718 TI - Serbian lymphoma study group: demografic characteristics of 257 patients with follicular lymphoma. AB - BACKGROUND/AIM: Follicular lymphoma (FL) is a B-cell tumor usually with indolent clinical course, yet in some cases the course of the disease can be very aggressive. The aim of the research was to determine distribution of patients into prognostic groups based on the International Prognostic Index (IPI) and Folicular Lymphoma International Prognostic Index (FLIPI) criteria, as well as to determine the importance of classifying patients into the prognostic groups, since this could potentially have the influence on selection of the treatment modality. METHODS: The retrospective study was performed on 257 patients with follicular lymphoma diagnosed between January 2000 and April 2011. RESULTS: Based on the IPI score, 153 (59.53%) patients had low risk, 57 (22.18%) low intermediate risk, 15 (5.84%) high intermediate risk, 9 (3.50%) high risk, whereas the classification of 23 patients diagnosed with FL remained with unknown risk according to the IPI. Based on the FLIPI prognostic index, 113 (43.97/6) patients had low risk, 70 (27.24%) intermediate risk and 51 (19.84%) high risk, whereas the classification of 23 (8.95%) patients remained unknown. On the basis of the FLIPI 2 prognostic index, 48 (18.68%) patients had low risk, 145 (56.42%) intermediate risk and 41 (15.95%) high risk. The classification into prognostic groups for 23 (8.95%) patients remained unknown. According to the IPI, FLIPI and FLIPI 2 there were the patients that required treatment in all the risk groups. CONCLUSION: The FLIPI and FLIPI 2 effectively identify patients at high risk, thus helping in treatment decision for each single patient. PMID- 26226719 TI - The development of the program of voluntary blood donation promotion in students population of the University of Belgrade. AB - BACKGROUND/AIM: Given that in each country students represent the most progressive population group, as of 2001, the Blood Transfusion Institute of Serbia (BTIS) has been carrying the program of voluntary blood donation promotion and education of volunteers at the University of Belgrade (UB). In 2011, the BTIS intensified all activities at the UB. The aim of this study was to present activities performed from 2001 at the Blood Donors' Motivation Department (DMD) of the BTIS related with increasing the level of awareness on voluntary blood donation in the Belgrade students' population, enhancing their motivation to become voluntary blood donors (VBDs), increasing the number of blood donations at faculties of the UB, and increasing the number of blood donations in the UB students population compared with the total number of blood units collected by BTIS in Belgrade, with the emphasis on the year 2013. METHODS: Initially, the applied methodology was based on encouraging students to donate blood through discussions and preparatory lectures, followed by organized blood drives. Appropriate selection of volunteers at each faculty was crucial. Besides their recognisable identity, they had to have remarkable communication skills and ability to positivly affect persons in their environment. The applied principle was based on retention of volunteers all through the final academic year, with the inclusion of new volunteers each year and 1,000 preparatory lectures on the annual basis. The activities were realized using two Facebook profiles, SMS messages and continuous notification of the public through the media. RESULTS: There was an increase in the average number of students in blood drives at the faculties from 2011, when the average number of the students per blood drive was 39, followed by 43 in 2012 and 46 in 2013. The number of students who donated blood in 2013 increased by 21.3% compared with 2012 data. CONCLUSION: The applied concept highly contributed to generation and retention of future VBDs willing to regularly donate blood in the coming years, with a minimum risk of transmission of transfusion transmissible diseases markers. PMID- 26226720 TI - Patients' expectation and satisfaction with complete denture before and after the therapy. AB - BACKGROUND/AIM: Difficulties in the acceptance of dentures are multifactorial including psychosocial ones. It is questionable whether the patients' satisfaction depends only on the complete denture therapy characteristics. The aim of the study was to evaluated patients' expectation and satisfaction with complete dentures before and after the treatment concerning phonetics, chewing, comfort of use and aesthetics. METHODS: Forty complete edentulous patients rated their expectation before and satisfaction after the treatment based on a questionnaire scores. Patient-related variables regarding age, gender and previous experience (whether worn complete denture or not) were also recorded. RESULTS: Patients' rating for expectations were higher than the satisfaction after treatment regarding phonetics, chewing, comfort of use and aesthetics. A negative significant correlation was shown between the items before and after the treatment rating for phonetics, chewing, comfort of use and aesthetics. No statistical correlation was found between all the evaluated aspects' (i.e., phonetics, chewing, comfort of use and aesthetics) of expectation and satisfaction, and age, gender, and previous experience except a weak negative correlation noticed between age and comfort of denture use. CONCLUSION: Patients' expectations ratings significantly exceeded their satisfactions. Expectations and satisfaction ratings were irrespective of gender and patients previous experience. PMID- 26226721 TI - Surgical site infection surveillance in orthopedic patients in the Military Medical Academy, Belgrade. AB - BACKGROUND/AIM: Active surveillance is an important component of surgical site infection (SSI) reduction strategy. The aim of this study was to analyze and compare SSI surveillance data in orthopedic patients in the Military Medical Academy (MMA), Belgrade. METHODS: A 4-year prospective cohort study was performed to identify the incidence rate and risk factors for SSI in orthopedic patients in the MMA, Belgrade. We collected data regarding patients characteristics, health care and micro-organisms isolated in SSI. The National Nosocomial Infection Surveillance (NNIS) risk index was subsequently calculated for each patient. The Centers for Disease Control and Prevention criteria were used for the diagnosis of SSI. RESULTS: Assessment of 3,867 patients after different orthopedic operations revealed SSI in 109 patients. The overall incidence rate of SSI was 2.8% with the decrease from 4.6% in 2007 to 1.6% in 2010. Using NNIS risk index for surgical procedures there were: 53.7% (2,077) patients with risk 0--the incidence rate of 1.4%; 38.9% (1,506) patients with risk 1--the incidence rate of 3.1%; 7.3% (281) patients with risk 2--the incidence rate of 11.7%; 0.1% (3) patients with risk 3--without infection within the risk. Multivariate logistic regression analysis identified 6 independent risk factors associated with SSI: contaninated or dirty wounds, smoking, preoperative infection, NNIS risk index, body mass index and the length of hospital stay. CONCLUSION: The results of our study are valuable confirmation of relations between risk factors and SSI in orthopedic patients. A decreasing incidence rate of SSI (from 4.6% to 1.6%) during a 4-year active surveillance approved its implementation as an important component of SSI reduction strategy. PMID- 26226722 TI - Association between risk factors, basal viral load, virus genotype and the degree of liver fibrosis with the response to the therapy in patients with chronic hepatitis C virus infection. AB - BACKGROUND/AIM: Hepatitis C is an important sociomedical problem worldwide due to frequent progression to chronic disease, occurrence of liver cirrhosis and hepatocellular carcinoma. Standard pegylated interferon alfa 2a plus ribavirin therapy results in resolution of infection only in 50% of patients. The aim of this study was to determine the association of various factors with response to the therapy in patients with chronic heptitis C virus (HCV) infection. Age and sex of patients, inoculation risk factors, histopathological changes in the liver, viral load and HCV genotype were analyzed. METHODS: The study included a group of 121 patients with chronic HCV infection. The treatment was carried out 24 weeks for virus genotype 2 and 3, and 48 weeks for genotype 1 and 4. The degree of histopathological changes in the liver was determined by hematoxylin and eosin staining, whereas polimerase chain reaction was used for HCV genotyping. RESULTS: In the group of non-responding patients genotype 1 was represented with 100%, while in the other groups, although predominantly present, its percentage was lower. Unresponsiveness to therapy and relapse of disease were associated with higher viral load and advanced fibrosis. Intravenous use of psychoactive substances, as a risk factor, was present in a high percentage in the group of patients with sustained response, while blood transfusion and dialysis were leading risk factors in the group of relapse responders and non responders. CONCLUSION: The results of our study showed that the treatment outcome of chronic HCV infection was associated with baseline HCV ribonucleic acid, HCV genotype, route of infection and the degree of histopathological changes in the liver. PMID- 26226723 TI - The Fracture Risk Assessment Tool (FRAX score) in subclinical hyperthyroidism. AB - BACKGROUND/AIM: The Fracture Risk Assessment Tool (FRAX score) is the 10-year estimated risk calculation tool for bone fracture that includes clinical data and hip bone mineral density measured by dual-energy x-ray absorptiometry (DXA). The aim of this cross-sectional study was to elucidate the ability of the FRAX score in discriminating between bone fracture positive and negative pre- and postmenopausal women with subclinical hyperthyroidism. METHODS: The bone mineral density (by DXA), thyroid stimulating hormone (TSH) level, free thyroxine (fT4) level, thyroid peroxidase antibodies (TPOAb) titre, osteocalcin and beta-cross laps were measured in 27 pre- and postmenopausal women with newly discovered subclinical hyperthyroidism [age 58.85 +/- 7.83 years, body mass index (BMI) 27.89 +/- 3.46 kg/m2, menopause onset in 46.88 +/- 10.21 years] and 51 matched euthyroid controls (age 59.69 +/- 5.72 years, BMI 27.68 +/- 4.66 kg/m2, menopause onset in 48.53 +/- 4.58 years). The etiology of subclinical hyperthyroisims was autoimmune thyroid disease or toxic goiter. FRAX score calculation was performed in both groups. RESULTS: In the group with subclinical hyperthyroidism the main FRAX score was significantly higher than in the controls (6.50 +/- 1.58 vs. 4.35 +/- 1.56 respectively; p = 0.015). The FRAX score for hip was also higher in the evaluated group than in the controls (1.33 +/- 3.92 vs. 0.50 +/- 0.46 respectively; p = 0.022). There was no correlations between low TSH and fracture risk (P > 0.05). The ability of the FRAX score in discriminating between bone fracture positive and negative pre- and postmenopausal female subjects (p < 0.001) is presented by the area under the curve (AUC) plotted via ROC analysis. The determined FRAX score cut-off value by this analysis was 6%, with estimated sensitivity and specificity of 95% and 75.9%, respectively. CONCLUSION: Pre- and postmenopausal women with subclinical hyperthyroidism have higher FRAX scores and thus greater risk for low-trauma hip fracture than euthyroid premenopausal women. Our results point to the use of FRAX calculator in monitoring pre- and postmenopausal women with subclinical hyperthyroidism to detect subjects with high fracture risk in order to prevent further fractures. PMID- 26226724 TI - Analysis of risk factors for occlusions of a synthetic femoropopliteal bypass graft. AB - BACKGROUND/AIM: Femoropopliteal bypass is a revascularization technique of lower extremities with excellent outcome. The great saphenous vein is the best graft material, but if it is not adequate or has been removed, synthetic grafts are an useful alternative. Graft occlusion is the most significant complication with the most serious consequences. The aim of this study was to analyse predictive factors for the synthetic femoropopliteal bypass occlusions. METHODS: This retrospective case-control study included all patients who underwent synthetic femoropopliteal bypass due to peripheral arterial occlusive disease at the Vascular Surgery Center, Clinical Center of Kragujevac, Serbia, from 2007 to 2013. The cases group were the patients with femoropopliteal graft occlusion (n = 44), with the control group consisted of the patients without such an outcome (n = 88). RESULTS: Significant effects to occlusion were: concomitant cardiovascular disease (adjustedOR 27.05; 95% CI 4.74; 154.35), a type of femoropopliteal bypass (adjustedOR 16.50; 95% CI 4.05; 67.24), previous vascular intervention (adjustedOR 4.67; 95% CI 1.20; 18.14), clinical stage of the disease (adjustedOR 3.73; 95% CI 1.94; 7.18), administration of postoperative oral anticoagulant therapy (adjustedOR 0.05; 95% CI 0.01; 0.23) and the use of angiotensin converting enzyme inhibitors (adjustedOR 0.14; 95% CI 0.03; 0.70). A significant synergism was shown for the following combinations of the observed risk factors: type of femoropopliteal bypass and cardiovascular disease, type of femoropopliteal bypass and previous vascular intervention, previous vascular intervention and cardiovascular disease, previous vascular intervention and beta blockers, cardiovascular disease and diabetes, type of femoropopliteal bypass and antiaggregant therapy, clinical stage of disease and cardiovascular disease, previous vascular intervention and antiaggregant therapy. CONCLUSION: Concomitant cardiovascular disease, below-knee femoropopliteal bypass, advanced stage of vascular disease and non-use of anticoagulant therapy and angiotensin-converting enzyme inhibitors are the significant predictors of graft occlusion after synthetic femoropopliteal bypass. Their synergistic effect determines the importance of diabetes, use of beta blockers and platelet antiaggregant therapy. PMID- 26226725 TI - Value of bacterial culture of vaginal swabs in diagnosis of vaginal infections. AB - BACKGROUND/AIM: Vaginal and cervical swab culture is still very common procedure in our country's everyday practice whereas simple and rapid diagnostic methods have been very rarely used. The aim of this study was to show that the employment of simple and rapid diagnostic tools [vaginal fluid wet mount microscopy (VFWMM), vaginal pH and potassium hydroxide (KOH) test] offers better assessment of vaginal environment than standard microbiologic culture commonly used in Serbia. METHODS: This prospective study included 505 asymptomatic pregnant women undergoing VFWMM, test with 10% KOH, determination of vaginal pH and standard culture of cervicovaginal swabs. Combining findings from the procedures was used to make diagnoses of bacterial vaginosis (BV) and vaginitis. In addition, the number of polymorphonuclear leukocytes (PMN) was determined in each sample and analyzed along with other findings. Infections with Candida albicans and Trichomonas vaginalis were confirmed or excluded by microscopic examination. RESULTS: In 36 (6%) patients cervicovaginal swab cultures retrieved several aerobes and facultative anaerobes, whereas in 52 (11%) women Candida albicans was isolated. Based on VFWMM findings and clinical criteria 96 (19%) women had BV, 19 (4%) vaginitis, and 72 (14%) candidiasis. Of 115 women with BV and vaginitis, pH 4.5 was found in 5, and of 390 with normal findings 83 (21%) had vaginal pH 4.5. Elevated numbers of PMN were found in 154 (30%) women--in 83 (54%) of them VFWMM was normal. Specificity and sensitivity of KOH test and vaginal pH determination in defining pathological vaginal flora were 95% and 81%, and 79% and 91%, respectively. CONCLUSION: Cervicovaginal swab culture is expensive but almost non informative test in clinical practice. The use of simpler and rapid methods as vaginal fluid wet mount microscopy, KOH test and vaginal pH offers better results in diagnosis, and probably in the treatment and prevention of sequels of vaginal infections. PMID- 26226726 TI - Angiogenesis: A special reference to corneal neovascularization. PMID- 26226727 TI - Does thrombolytic therapy harm or help in ST elevation myocardial infarction (STEMI) caused by the spontaneous coronary dissection? AB - INTRODUCTION: Spontaneous coronary artery dissection (SCAD) is a very rare disease with poor prognosis. It mainly affects young women free of risk factors for coronary artery disease (CAD) and women during the peripartum period. The prognosis for myocardial infarction caused by SCAD is poor, management is often difficult and guidelines still missing. CASE REPORT: We presented a woman with acute myocardial infarction of anterior wall of the left ventricle, caused by spontaneous dissection of medial segment of the left anterior descending coronary artery. We treated the patient with thrombolytic therapy and performed coronary angiography after that. Finally we decided to do nothing more. Two years later we performed coronary angiography again and founded the coronary artery normal. We also analyzed 19 cases publiched from 1996 to 2012 when coronary artery dissection had been treated with thrombolytic agent Analysis revealed only one case of 19, with complication after treating SCAD with thrombolysis. CONCLUSION: Sometimes, regarding myocardial infarction in young women with no risk factors for CAD, especially in young women in peripartum, we should think about SCAD. The presented case, like eight others, demonstrates that good clinical outcomes can be achieved with thrombolysis. In spite of all this, we still need more data to verify that thrombolysis does not have to harm the therapy for SCAD. For the time being thrombolytic therapy could be an option. PMID- 26226728 TI - Hemangioma of uterine cervix associated with high-grade squamous intraepithelial lesion. AB - INTRODUCTION: Benign, especially polypoid, lesions of the cervix are common in everyday work. Rare tumors of this region are vascular ones, particularly capillary and/or cavernous hemangiomas. Cervical hemangiomas are especially rare, usually asymptomatic and only one third of the cases is clinically manifested as vaginal bleeding, polyps, etc. CASE REPORT: We reported a 54-year-old postmenopausal female patient who had undergone conization due to high-grade squamous intraepithelial lesion (H-SIL). Microscopic analysis of slices confirmed the existence of dysplastic changes in the endocervical. epithelium and in small part in the epithelium of the gland of H-SIL type. In 2 of 15 slices, within the walls of the cervix, dilated, amplified and abnormal blood vessels lined with endothelium were observed, vaguely limited by the surrounding connective tissue of lamina propria and smooth muscle wall of the cervix. According to the pathological characteristics, the change corresponded to the hemangioma. Both changes were completely removed. CONCLUSION: In comparison with the available literature data, the presented case is the first to describe the association of hemangioma and dysplastic changes in the endocervical epithelium. Hemangioma was incidentally discovered in the histological sections of the material after the conization in a postmenopausal women. PMID- 26226729 TI - Bilateral hippocampal infarction and amnesia: A case report. AB - INTRODUCTION: The hippocampus along with other structures of the medial temporal lobe plays an important role in the process of learning and memory consolidation. Bilateral hippocampal lesions lead to persistent anterograde amnesia while unilateral damage results in milder, content-specific forms of amnesia. Hippocampus may be affected by an acute or chronic pathologic process from a wide spectrum of neurological disorders. CASE REPORT: A 61-year-old female patient with a long history of hypertension, glucose intolerance, hypercholesterolemia and depression was hospitalized for acute anterograde amnesia, which led to repeated excessive drug taking. By further examinations that included laboratory tests, electroencephalography, Doppler sonography of intra- and extracranial vessels and neurovisualization methods [multislice computed tomography (MSCT) and magnetic resonance imaging (MRI) of the brain] bilateral hippocampal ischemia that occurred at different times was detected. Cognitive and neuropsychological evaluation revealed an isolated severe damage of episodic memory with the inability of retention of new information which persisted at the control examination three months later. The assumed mechanism of occurrence of ischemia in this case could be arterioarterial embolism. CONCLUSION: Although ischemic stroke is one of the most common neurological diseases, ischemic stroke of the hippocampus is rare, the isolated bilateral presentation with clinical signs of severe amnestic syndrome in particular. Timely recognition and modern therapeutic approach could have a favorable impact on the recovery from severe neurological, cognitive deficit. It could be suggested that in patients with the clinical image of acute anterograde amnesia and vascular risk factors the MSCT examination of the brain with computed tomography perfusion and angiography is performed immediately upon hospitalization. PMID- 26226730 TI - Massive retroperitoneal hematoma as a complication of anticoagulation therapy in a patient treated in a pulmonary intensive care unit. AB - INTRODUCTION: Retroperitoneal hematoma may occur as a result of trauma, but also from rapture of arterial aneurysms (aortic or iliac), surgical complications, tumors or anticoagulation therapy. CASE REPORT: We presented a patient on permanent anticoagulation therapy. On the day of admission to our institudon, the patient had the value of his INR 5.57 which required immediate suspension of the therapy. The main symptom in this patient was pain in the right inguinal canal with propagation along the right leg, which was indicated in clinical picture of spontaneous retroperitoneal haematoma. After three days the fall of hemoglobin occurred, so the additonal diagnostics was done. A computed tomography of the abdomen was performed showing well limited, large retroperitoneal hematoma (213 x 79 x 91 mm). Transfusion of concentrated red blood cells was performed twice with satisfactory correction of hemoglobin level, and four units of fresh frozen plasma. The patient was hemodynamically stabilized and discharged after a two month long intensive care unit treatment, with the advice to use low-molecular weight heparin 2 x 0.4 mg subcutaneusly, due to persistent arrhythmia. CONCLUSION: In patients on anticoagulation therapy regular monitoring of the anticoagulant status is extremely important, because of the possibility of fatal complications development, such as retroperitoneal hematoma. PMID- 26226731 TI - Transcatheter closure of atrial septal defect in a patient with Noonan syndrome after corrective surgery. AB - INTRODUCTION: Transcatheter atrial septal defect (ASD) closure is considered to be a gold standard for patients with the suitable anatomy as compared to cardiac surgery. Reocurrence of ASD after surgical closure is a very rare late complication which can be successfully managed with transcatheter procedure. CASE REPORT: We reported a female patient with Noonan syndrome who presented with hemodinamically significant ASD 37 years after the corrective cardiac surgery. Due to numerous comorbidities which included severe kyphoscoliosis, pectus excavatum and multiple surgeries we decided to perform transcatheter closure of ASD. The procedure itself was very challenging due to the patient's short stature and heart's orientation in the chest, but was performed successfully. The subsequent follow-up was uneventful and the patient reported improvement in the symptoms. CONCLUSION: Transcatheter closure of ASD in a patient with Noonan syndrome with the history of surgically corrected ASD can be performed successfully, despite challenging chest anatomy. PMID- 26226732 TI - [Main progress on studies of pharmacological activities and clinical applications of Guizhi Fuling capsule]. AB - Guizhi Fuling capsule is a traditional Chinese medicine composed of five kinds of medicinal plants, Cinnamomi Ramulus, Poria, Moutan Cortex, Persicae Semen, and Paeoniae Radix Alba. Pharmacology studies have shown that Guizhi Fuling capsule has many activities: anti-inflammatory, analgesic, anti-tumor, regulating smooth muscle, endocrine regulation and enhancing immunity. It achieved obvious effects in the treatment of uterine fibroids, pelvic inflammatory disease, dysmenorrheal, endometriosis, ovarian cysts, breast hyperplasia and other gynecological diseases. This paper reviewed the main progress on studies of pharmacological activities and clinical applications of Guizhi Fuling capsule in recent years. PMID- 26226733 TI - [Study on anti-inflammation effect and involved mechanism of Guizhi Fuling capsule and its active complex]. AB - The aim of this study was to investigate the anti-inflammatory effect of Guizhi Fuling capsule and its active complex (consistent of 15 active compounds) on LPS induced RAW264. 7 cells. The effect of Guizhi Fuling capsule and its active complex on cell viability in RAW264. 7 cells were determined by MTT assay. The inhibitory effect of Guizhi Fuling capsule and active complex on the releasing of IL-1beta, TNF-alpha and PGE2 induced by LPS in RAW264. 7 cells was detected by ELISA assay. The expression of IL-1beta and mPGES-1 in Guizhi Fuling capsule or active complex treated RAW264. 7 cells was examined by Western blot assay. Guizhi Fuling capsule and active complex showed no significant effect on the cell viability in RAW264. 7 cells at doses range from 12.5 to 400 mg x L(-1). Compared with LPS treated group, Guizhi Fuling capsule and active complex dose dependently reduced the releasing of IL-1beta, TNF-alpha and PGE2 induced by LPS in RAW264. 7 cells. Moreover, the expression of IL-1beta and mPGES-1 was decreased after Guizhi Fuling capsule and active complex treatment, which might contribute to the inhibitory effect of Guizhi Fuling capsule in the releasing of IL-1beta, TNF alpha and PGE2. This study provided the evidence that Guizhi Fuling capsule and active complex remarkably inhibited the releasing of IL-1beta, TNF-alpha and PGE2induced by LPS in RAW264. 7 cells by reducing the expression IL-1beta and mPGES-1. This study provided an experimental basis of Guizhi Fuling capsule for the treatment of inflammation and a theoretical basis for the development of effective compounds of Guizhi Fuling capsule. PMID- 26226734 TI - [Study of effective components and molecular mechanism for Guizhi Fuling formula treatment of dysmenorrhea, pelvic inflammatory disease and uterine fibroids]. AB - In this study, the active components and potential molecular .mechanism of Guizhi Fuling formula in treatment on dysmenorrhea, pelvic inflammation, and hysteromyoma were investigated using network pharmacological methods. Sterols and pentacyclic triterpenes, with high moleculal network degree, revealed promising effects on anti-inflammatory, analgesic, anti-tumor, and immune-regulation, according to D-T network analysis. On the other hand, the targets with high degree were involved in inflammatory, coagulation, angiopoiesis, smooth muscle contraction, and cell reproduction, which showed the novel function in anti dysmenorrhea, pelvic inflammation, and hysteromyoma. Furthermore, the formula was indicated to play a key role in smooth muscle proliferation, inhibition of new vessels, circulation improvement, reduction of hormone secretion, alleviation of smooth muscle, block of arachidonic acid metabolism, and inflammation in uterus. Thus, the main mechanism of Guizhi Fuling formula was summarized. In conclusion, Guizhi Fuling formula was proven to alleviated dysmenorrhea, pelvic inflammation, and hysteromyoma by acting on multiple targets through several bioactive compounds, regulating 21 biological pathways. PMID- 26226735 TI - [Study on anti-inflammation and immunoloregulation effect of Guizhi Fuling capsule ingredients using high content screening]. AB - The present study sought to investigate the anti-inflammation and immunoloregulation effect of 17 Guizhi Fuling capsule ingredients. The anti inflammatory ingredients on LPS-induced RAW264. 7 cell injury were assessed with ELISA and immunofluorescence. The release of IL-1beta, TNF-alpha, PGE2 were detected with ELISA and the expression of COX-2 was detected with immunofluorescence. The effects of them on promoting splenic lymphocyte proliferation were assessed with MTT and Hoechst 33342 staining method. The results showed that 15 ingredients had obviously anti-inflammatory activity on LPS- induced injury and play the immunoloregulation roles. This study suggested that the 15 ingredients may be the active ingredients on pelvic infection. PMID- 26226736 TI - [Application of molecularly imprinted technology for separation of PGG from Guizhi Fuling capsule]. AB - 1,2,3,4,6-penta-O-galloyl-D-glucose (PGG) is one of the main active compounds of Guizhi Fuling capsule. Molecularly imprinted polymers (MIP) have high affinity toward template molecules synthesized by molecularly imprinted technology for its specific combined sites, which can overcome the shortcoming of traditional separation methods, such as complex operation, low efficiency, using large quantity of solvent and environmental pollution. In this paper, surface molecularly imprinted polymer (SMIP) was prepared by surface imprinting with PGG as the template molecule. Its adsorption capacity was measured by the scatchard equation. The separation of PGG from Guizhi Fuling capsule at preparatived scale was achieved with molecularly imprinted polymer as stationary phase and the purity was 90.2% by HPLC. This method can be used to prepare PGG from Guizhi Fuling capsule with large capacity and is easy to operate. It provides a new method for efficient separation and purification for other natural products. PMID- 26226737 TI - [Quality analysis of Guizhi Fuling capsule before and after application of in process quality control in pharmaceutical production]. AB - The effects of application of in-process quality control in Guizhi Fuling capsule production were evaluated by 192 batches data analysis. Using a statistical analysis method, each batch of data were to be counted to research for the difference between 96 samples adopting the technologies of in-process control or not. According to quality standards of Guizhi Fuling capsule, all measurements of the 192 batches of the drugs before and after the application of process control technology were analyzed, and they were within the rules. There was a significant difference between adopting the technologies of process control or not. Application of in-process control technology can improve the uniformity of lot-to lot for Guizhi Fuling capsule. PMID- 26226738 TI - [Different active ingredients of medicinal plant based on function differentiation of homologous gene]. AB - In the research field of quality control in Chinese medicinal materials, variation in active ingredients of medicinal plant is always the key and hot issues. With the development of high-throughput sequencing technologies and reducing cost, a large numbers of genes from medicinal plant were cloning and provide a solid foundation for further research of gene structure and its biological function, and also provides conditions for explore active ingredient variation and its quality control from the perspective of molecular pharmacognosy. This paper introduces the concept of homologous gene, gene duplication and classification. We prospect the function of duplicated genes in the role of molecular mechanism research about variation in active ingredients, aiming at providing a new way for medicinal materials quality control. PMID- 26226739 TI - [Overview of traditional Chinese medicine quality evaluation method based on overall research]. AB - The establishment of quality evaluation of traditional Chinese medicine system that not only accords with Chinese medicine function characteristics but also is recognized as international medical circles, is an arduous task in urgent need of solving the current modernization of traditional Chinese medicine in the process of internationalization. It is difficult to evaluate atraditional Chinese medicine by detection of single active components in traditional Chinesemedicinewiththe western medicine quality controlmethod due to the overall effects of traditional Chinese drugs, the components of the overall diversity, targets, and the complexity of the interaction between components of unpredictable make the Long-term since, domestic and foreign scholars continue to explore and put forward a series of quality evaluation of traditional Chinese medicine to promote the development of traditional Chinese medicine. This article summarized the related academic ideas and developments to, providea new thought and perspective for the quality control of traditional Chinese medicine. PMID- 26226740 TI - [Progresses in screening active compounds from herbal medicine by affinity chromatography]. AB - Affinity chromatography is a chromatographic method for separating molecules using the binding characteristics of the stationary phase with potential drug molecules. This method can be performed as a high throughput screening method and a chromatographic separation method to screen a variety of active drugs. This paper summarizes the history of affinity chromatography, screening technology of affinity chromatography, and application of affinity chromatography in screening bio-active compounds in herbal medicines, and then discusses its application prospects, in order to broaden applications of the affinity chromatography in drug screening. PMID- 26226742 TI - [Recent progress of potential effects and mechanisms of chlorogenic acid and its intestinal metabolites on central nervous system diseases]. AB - Chlorogenic acid displays several important roles in the therapeutic properties of many herbs, such as antioxidant activity, antibacterial, antiviral, scavenging free radicals and exciting central nervous system. Only about one-third of chlorogenic acid was absorbed in its prototype, therefore, its gut metabolites play a more important role in the therapeutic properties of chlorogenic acid. It is necessary to consider not only the bioactivities of chlorogenic acid but also its gut metabolites. This review focuses on the potential activities and mechanisms of chlorogenic acid and its gut metabolites on central nervous system diseases. PMID- 26226741 TI - [Research progress on anti-osteoporotic active ingredients and pharmacological action mechanism of traditional Chinese kidney-tonifying and bone-strengthening drugs]. AB - The therapeutic effects and mechanisms of traditional Chinese kidney-tonifying drugs in treating osteoporosis have become the focus under study. Pharmacological studies have shown that traditional Chinese kidney-tonifying drugs are promoters for the proliferation of osteoblasts, inhibitors for the activity of osteoclasts, regulators for the estrogen level and its receptor, plays important roles in promoting osteogenesis and suppressing adipogenesis of marrow mesenchymal stem cells (MSCs), modulating the function of OPG/RANK/RANKL system and the metabolism of calcium and phosphorus, as well as antioxidation. The anti-osteoporotic active ingredients and pharmacological action mechanism of traditional Chinese kidney tonifying drugs are summarized from the perspective of molecular and cell biology in this paper, so as to provide references for the study of their mechanism of anti-osteoporosis and for the development of traditional Chinese kidney-tonifying and bone-strengthening drugs. PMID- 26226743 TI - [Research of Yuanhu Zhitong prescription based on strategy of integrative pharmacology]. AB - Chinese medicinal formulae (CMF) were usually used in the clinics of traditional Chinese medicines (TCM), which were critical for modernization of Chinese medicine to shed light on the interaction between CMF and biological organisms. However, correlation between system and part, macroscopic actions and microcosmic mechanism, ADME process and pharmacologic actions were usually neglected. The put forward of integrative pharmacology provided a feasible approach to solve the problem of the fragmentation of TCM. For the past years, we applied the strategy of integrative pharmacology to study Yuanhu Zhitong prescription( YZP) systematically, and established two modes, chemical fingerprints-metabolism fingerprints-network targets and intestinal absorption-activity evaluation-data mining, to establish the interaction rule between the chemical composition and biological activity from multiple levels, such as the calculation and in vitro/vivo, which provided proof for the quality control, pharmacodynamic material basis and pharmacological action of YZP. In this paper, we summarized the related progresses of the research of YZP. PMID- 26226744 TI - [Correlation between distribution of rhizospheric microorganisms and contents of steroidal saponins of Paris polyphylla var. yunnanensis]. AB - In this paper, the varying pattern of the amount of rhizospheric microorganisms, including bacteria, actinomycetes and fungus, was observed during the cultivation of Paris polyphylla var. yunnanensis. And the correlations between number of rhizospheric microorganisms and the quality of P. polyphylla var. yunnanensis were also studied. The results showed that the rhizospheric microorganism source of P. polyphylla var. yunnanensis was rich. The distribution of rhizospheric microorganisms (soil bacteria, fungus, actinomycetes, potassium-solubilizing bacteria, inorganic phosphorus-solubilizing bacteria, organic phosphorus solubilizing bacteria) collected from different origin places existed significant difference (P < 0.05). The varying pattern for the amount of rhizospheric microorganisms was showed as following: the amount of bacteria > the amount of actinomycetes > the amount of fungus. The medicinal quality of P. polyphylla var. yunnanensis was influenced by their habits, and the increase of cultivation years caused the obvious decrease of the quality of P. polyphylla var. yunnanensis. Therefore, the increase of cultivation years will cause the variation of the soil micro-ecology flora, and decrease the nutrient absorption and the utilization of P. polyphylla var. yunnanensis, which will make the decrease of the medical quality of P. polyphylla var. yunnanensis. PMID- 26226745 TI - [Pollen viability, stigma receptivity and fruiting characteristics of botanical origin of Jinxianlian]. AB - The viability and life span of pollen were evaluated by TTC (2,3,5-triphenyl tetrazlium chloride) and the peroxidase solution, the stigma receptivity were estimated by benzidine-H2O2 method and the fruiting characteristics were investigated. The results showed that (1) Anoectochilus roxburghii and A. formosanus appeared the same up-and-down trend of the pollen viability, increased and then decreased. The storage temperature and storage time had significant impact on the pollen viability. With the extension of storage time, the pollen activity decreased. 4 degrees C refrigerator storage may be extended the pollen vitality. (2) The stigma had receptivity in 1st day and reached the highest level in the 4th day after blooming. A. roxburghii lost receptivity in the 8th day while A. formosanus lost receptivity in the 10th day after blooming. (3) The different pollination had significant impact on seed setting rate. The seed setting rate of artificial cross-pollination was higher than that of the artificial self-pollination. Collecting pollen in the 3rd day and carrying out artificial cross-pollination in the 4th day after blooming can significantly improve seed setting rate. The results provided technical assurance for A. roxburghii and A. formosanus breeding of new varieties and seed breeding. PMID- 26226746 TI - [Cloning and bioinformatics analysis of geranylgeranyl diphosphate synthase gene of Tripterygium wilfordii]. AB - A full-length cDNA of GGPPS gene from Tripterygium wilfordii suspension cells was obtained by use of RACE strategy (GeneBank: KM978333), and then analyzed by bioinformatics approaches. TwGGPPS cDNA has 1857 nucleotides and an open reading frame (ORF) encoding a protein of 514 amino acid residues. The deduced protein has isoelectric point (pI) of 7.85, a calculated molecular weight about 57.13 kD, 5 conserved domains and 2 functional domains. PSORT Prediction showed it was located at plasma membrane. Phylogenetic analysis demonstrated that TwGGPPS1 was similar to GGPPS from other species of plants. For the first time the cloning of geranylgeranyl diphosphate synthase gene from T. wilfordii was reported, it lays the foundation for further research of diterpenoids biosynthetic pathway. PMID- 26226747 TI - [Effect of water temperature, stocking density and feeding cycle on growth of juvenile Poecilobdella manillensis]. AB - The effect of water temperature, stocking density and feeding cycle on the growth of Poecilobdella manillensis juvenile was conducted P. manillensis was conducted respectively under different conditions: water temperatures(18, 22, 26, 30,34, 38 degrees C and CT), stocking density (75, 125, 200, 275, 350 individual/L) and feeding cycle(2, 4, 6, 8, 12, 16 d). After 30 days, survival rate, weight gain rate, specific growth rate were measured. There was a significant correlation between water temperature and specific growth rate (gamma = -0.066x2 + 3.543 1x 38.09, R2 = 0.837 9). Based on the regression equation, the specific growth rate of P. manillensis achieved the maximum (9.461 4) at 26.84 degrees C. And the most optimal water temperature was 26-30 degrees C. Meanwhile, the survival rates of P. manillensis was 0 at 38 degrees C in 3 d. There was significant negative correlation between density and specific growth rate (gamma = -0.005 7x + 9.197 3, R2 = 0.998 3) and between feeding cycle and specific growth rate (gamma = 0.468 2x + 10.574, R2 = 0.998 8). PMID- 26226748 TI - [Study on genetic polymorphism of Platycodon grandiflorum based on barcoding of ITS2]. AB - OBJECTIVE: ITS2 of DNA barcoding was used to study genetic polymorphism of Platycodon grandiflorum. METHOD: Total genomic DNA was isolated from P. grandiflorum. PCR was used to amplified the region of internal transcribed spacer 2 (ITS2), and PCR products were sequenced. The sequences of ITS2 were analyzed and compared by Clustal. The intraspecies genetic distance was calculated based on Kimura 2-parameter model by using MEGA 5.05. The ITS2 sequence of Codonopsis pilosula was used as the outreach value for plants of the genus, and the phylogenic tree used constructed by Neighbor-Joining (NJ) method. RESULT: The K2 P's genetic distance of all samples were ranged from 0 to 0.930. The K2-P's genetic distance of samples at the same area were ranged from 0 to 0.178. The K2 P's genetic distance of samples at different areas were ranged from 0.735 to 0.930. The analytical result showed that the degree of genetic variation were heavy in intraspecies of P. grandiflorum and significantly correlated with geographical location. CONCLUSION: The DNA barcoding of ITS2 can applied to study the intraspecific genetic diversity, it provides a reference for further development of DNA barcoding technology applications. PMID- 26226749 TI - [Quality classification standard of Scrophularia ningpoensis seedlings]. AB - The morphological indexes of the Scuophularia ningpoensis seedlings including the longth, diameter and weight were measured, clustering analysis was used to set up the standard quality grading of seedlings of S. Ningpoensis by SPSS. Field experiment was carried out to measure the indicators of plants growth and development, the yield and the quality. The results showed that the growth and yield of class I seedlings were better than those of class II and III. The content of main active ingredients was affected barely by seedlings classification. To ensure the quality, class II seedlings or above should be used for plantation. The established quality classification standard of S. ningpoensis seedlings was scientific and feasible, and provides the basis for the standardized cultivation of S. ningpoensis. PMID- 26226750 TI - [Experiment on pruning of Cistanche deserticola inoculated in artificial Haloxylon ammodendron forest]. AB - At present, the objective of cutting and pruning Cistanche deserticola is to harvest in successive years and enhance the harvesting yield and quality of C. deserticola in the process of the artificial cultivating C. deserticola. An experiment was conducted focusing on cutting and pruning C. deserticola in artificial forests of Haloxylon ammodendron drip-irrigated with saline water at the hinter-land of the Taklimakan desert, according to different growth stages and lengths. The results were following: (1) The effect of cutting on C. deserticola was similar to that of pruning, which resulted in three kinds of morphological types, not related to the bloom and size of C. deserticola. (2) The growth forms were diversified after pruning. Among them, there had sprouting new body, died or maintaining life with no sprouting, mildewed on its surface layer, etc. However, some of new bodies were sprouting from the lower part of the old body. The death rate of bloomed C. deserticola was higher than that of the underground, and the death rate of the 40 cm in stubble height for C. deserticola was higher than those with the stubble height of 20 cm and 5 cm. (3) Most of the diameter of living C. deserticola after pruning was increasing, but some of them changed little. (4) The mildew and rot of C. deserticola and the broken of the roots of the H. ammodendron and the fallen of the point of the inoculated when it was dug, which would cause the death of the C. deserticola. On the other, the yield-increasing effect and the economic benefit of the techniques of the pruning of Cistanche would need further research and evaluate. Therefore, the application of this technique needs to be cautious. PMID- 26226751 TI - [Studies on preparation by SPG membrane emulsification method and in vitro characterization of tetradrine-tashionone II(A)-PLGA composite microspheres]. AB - Tetradrine-tashionone II(A)-PLGA composite microspheres were prepared by the SPG membrane emulsification method, and the characterization of tetradrine-tashionone II(A) -PLGA composite microspheres were studied in this experiment. The results of IR, DSC and XRD showed that teradrine and tashionone II(A) in composite microspheres were highly dispersed in the PLGA with amorphous form. The results of tetradrine-tashionone II(A) -PLGA composite microspheres in vitro release experiment showed that the cumulative release amounts of tetradrine and tashionone II(A) were 6.44% and 3.60% in 24 h, and the cumulative release amounts of tetradrine and tashionone II(A) were 89.02% and 21.24% in 17 d. The process of drug in vitro release accorded with the model of Riger-Peppas. Tetradrine tashionone II(A) -PLGA composite microspheres had slow-release effect, and it could significantly reduce the burst release, prolong the therapeutic time, decrease the dosage of drugs and provide a new idea and method to prepare traditional Chinese medicine compound. PMID- 26226752 TI - A new aurone glycoside with antifungal activity from marine-derived fungus Penicillium sp. FJ-1. AB - Endophytic fungi which reside in the tissue of mangrove plants seem to play an important role in the discovery of new biologically active substances. During the course of screening for the antimicrobial metabolites from the endophytic fugus Penicillium sp. FJ-1 of mangrove plant Avicennia marina, a new aurone glycoside (1) was isolated by repeated column chromatography on silica gel and recrystallization methods. The structure of 1 was elucidated as (Z)-7,4' dimethoxy-6-hydroxy-aurone-4-O-beta-glucopyranoside, on the basis of spectroscopic analysis. Compound 1 exhibited antifungal activity against Candida sp., with the potency comparable to amphotericin B and much better than fluconazole. Compound 1 can also inhibit extracellular phospholipase secretion in a concentration-dependent manner. PMID- 26226753 TI - [Glycosides from Machilus wangchiana]. AB - Ten glycosidic compounds were isolated from an ethanol extract of Machilus wangchiana by a combination of various chromatographic techniques including column chromatography over silica gel and Sephadex LH-20 and reversed-phase flash chromatography and HPLC. Their structures were identified by spectroscopic data analysis (IR, MS, and NMR) as icariside B1 (1), boscialin-3-O-beta-D glucopyranoside (2), pisumionoside (3), isolariciresinol-9'-O-beta-D xylopyranoside (4), 5'-methoxyisolariciresinol-9'-O-beta-D-xylopyranoside (5), lyoniresinol-9'-O-beta-D-xylopyranoside (6), (E) -4-hydroxyphenylprop-7-ene 4-O beta-D-glucopyranoside (7), (E) - 4-hydroxy-3-methoxyphenylprop-7-ene 4-O-alpha-L rhamnopyranosyl-(1 --> 6) -beta-D-glucopyranoside (8), 4-hydroxy-3 methoxyphenylprop-8-ene 4-O-beta-D-xylopyraosyl-(1 --> 6) -beta-D-glucopyranoside (9), and 4-hydroxy-3,5-dimethoxyphenylprop-8-ene 4-O-alpha-L-rhamnpyranosyl-(1 - > 6)-beta-D- glucopyranoside (10), respectively. PMID- 26226754 TI - [Chemical constituents from Perovskia atriplicifolia]. AB - An investigation on the chemical constituents of the 90% EtOH extract of Perovskia atriplicifolia led to the isolation of fifteen compounds from the EtOAc fraction. Based on the detailed spectral analysis (MS, 1D and 2D NMR), as well as comparison with the literatures, the structures of compounds 1-15 were determined as cirsimaritin (1), salvigenin (2), syringaldehyde (3), vinyl caffeate (4), 2alpha, 3alpha-dihydroxyolean-12-en-28-oicacid (5), 2alpha, 3alpha-dihydroxyurs 12-en-28-oicacid (6), niga-ichigoside F1 (2alpha, 3beta, 19alpha, 23- tetrahydroxyurs - 12-en-28-oicacid- O-beta-D- glucopyranoside, 7), sericoside (8), 4-epi-niga-ichigoside F1 (2alpha, 3beta, 19alpha, 24-tetrahydroxyurs-12-en 28-oicacid O-beta-D-glucopyranoside, 9), 2alpha, 3beta, 24-trihydroxyolean-12-en 28-oicacid O-beta-D-glucopyranosyl-(1 --> 2) - beta-D-glucopyranoside (10), pruvuloside A (11), asteryunnanoside A [2alpha, 3beta, 23-trihydroxyolean-12-en 28-oicacid O-beta-D-glucopyranosyl-(1 --> 2)-beta- D- glucopyranoside,12], rosmarinic acid methyl ester (13), beta-sitosterol (14), and daucosterol (15), respectively. Compounds 1-13 were isolated from the Perovskia genus for the first time. All the compounds were obtained from P. atriplicifolia for the first time. PMID- 26226755 TI - [Fingerprint analysis of Resina Draconis from different manufactuers by UPLC coupled with chemometrics]. AB - This study is to establish an UPLC fingerprint of Resina Draconis from different manufacturers, which can provide a comprehensive evaluation for its quality control. The analysis was performed on a Phenomenex Kinetex 2.6 MU C18 100A column by agradientelution program with acetonitrile-water as mobile phase at a flow rate of 1.7 mL x min(-1). The column temperature was 40 degrees C and the detection wavelengthwas 280 nm. The fingerprints of 18 batches of Draconis Resina were further evaluated by chemometrics methods including similarity analysis (SA), hierarchical clustering analysis (HCA) and principal component analysis (PCA). As a result, there were 15 common peaks, 13 of which had been identified by LC-Q-TOF MS, and the similarity degrees of 15 batches of the samples was more than 0.9, and the samples were divided into 4 clusters by their quality difference. The method is reproducible, simple and reliablethat it can be used for quality control and evaluation of Resina Draconis from different manufacturers. PMID- 26226756 TI - [Determination of scopolin, chlorogenic acid, scopoletin, isochlorogenic acid A, isochlorogenic acid B and isochlorogenic acid C in plants of Erycibe]. AB - OBJECTIVE: An accurate and reliable analytical method for-simultaneous determination of six active components (scopolin, chlorogenic acid, scopoletin, isochlorogenic acid A, isochlorogenic acid B and isochlorogenic acid C) in plants of Erycibe was developed. METHOD: Scopolin, chlorogenic acid, scopoletin, isochlorogenic acid A, isochlorogenic acid B and isochlorogenic acid C in the samples were well separated in analytical HPLC by gradual elution with methanol 0.1% formic acid solution. The chromatographic condictions: Agilent Poroshell 120 EC-C18 column, flowing rate being 1 mL x min(-1), detecting wavelength at 345 nm. RESULT: Good linearities of scopolin, chlorogenic acid, scopoletin, isochlorogenic acid A, isochlorogenic acid B and isochlorogenic acid C were in the range of 0.026 8-2.68, 0.027 0-2.70, 0.008 1-0.81, 0.018 8-1.88, 0.017 6 1.76, 0.019 6-1.96 MUg, respectively (r > 0.999 6). The average recoveries of the six components were 98.1%, 98.7%, 100.8%, 100.4%, 99.7%, 101.1%; the relative standard deviations were 2.67%, 2.86%, 2.62%, 1.98%, 2.76%, 2.19%. CONCLUSION: The method is simple, feasible and reproducible and can be used for the quality control of plants of Erycibe. PMID- 26226757 TI - [Content of mineral elements of Gastrodia elata by principal components analysis]. AB - OBJECTIVE: To study the content of mineral elements and the principal components in Gastrodia elata. METHOD: Mineral elements were determined by ICP and the data was analyzed by SPSS. RESULT: K element has the highest content-and the average content was 15.31 g x kg(-1). The average content of N element was 8.99 g x kg( 1), followed by K element. The coefficient of variation of K and N was small, but the Mn was the biggest with 51.39%. The highly significant positive correlation was found among N, P and K . Three principal components were selected by principal components analysis to evaluate the quality of G. elata. P, B, N, K, Cu, Mn, Fe and Mg were the characteristic elements of G. elata. CONCLUSION: The content of K and N elements was higher and relatively stable. The variation of Mn content was biggest. The quality of G. elata in Guizhou and Yunnan was better from the perspective of mineral elements. PMID- 26226758 TI - [Effect of celastrol in inhibiting metastasis of lung cancer cells by influencing Akt signaling pathway and expressing integrins]. AB - Celastrol is a type of quinone methyl triterpene isolated from traditional Chinese medicine Tripterygium wilfordii, with pharmacological activities, like anti-inflammatory, immunosuppression and anti-tumor. This study focused on the effects of celastrol on adhesion, migration and invasion of lung cancer cells. The migration inhibition of lung cancer cells induced by celastrol was detected by the scratch test. The invasion inhibition of lung cancer cells induced by celastrol was measured by the transwell experiment. RT-PCR and Western blot were used to determine the effect of different concentrations of celastrol in integrin family and Akt signaling pathway in lung cancer cells. The results showed that celastrol inhibited adhesion, migration and invasion of lung cancer cells and expressions of integrins beta3, beta4, alphav and phosphorylated Akt, GSK-3beta, c-Raf, PDK1 in Akt signal pathway in a dose-dependent manner. Therefore, the study implies that Celastrol could inhibit the metastasis of lung cancer cells by suppressing Akt signaling pathway and expression of integrins. PMID- 26226759 TI - [Application of support vector machine approach in studying nephron toxicity of Chinese medicinal materials]. AB - On the basis of web databases, 111 compounds with nephrotoxicity and 90 compounds without nephrotoxicity were collected as data set of nephrotoxicity discrimination model, 39 compounds with tubular necrosis and 39 compounds without tubular necrosis were collected as data set of tubular necrosis discrimination model. The 6 122 molecular descriptors, including physicochemical, charge distribution and geometrical descriptors were calculated to characterize the molecular structure of the above-mentioned compounds. CfsSubsetEval valuation method and BestFirst-D1-N5 searching method were used to select molecular descriptors. Two models with high accuracy were built based on the support vector machine (SVM) approach, respectively. Accuracy, sensitivity, specificity and matthew's correlation coefficient of the two models were all above 70%. By using 22 nephrotoxicity compounds of Chinese medicine, the nephrotoxicity discrimination model was further verified with an accuracy of 72.73%. Using the tubular necrosis discrimination model, 10 potential compounds which can cause tubular necrosis were screened from the positive results of nephrotoxicity discrimination model, 6 of them have been verified by literatures. The results demonstrated that the discrimination models can be applied to screen nephrotoxic compounds from Chinese medicinal materials, and they also offer a new research idea for the further studies on the mechanism of nephrotoxicity. PMID- 26226760 TI - [Evaluation on dosage-based efficacy-toxicity correlation of Tripterygium wilfordii against immune inflammation in mice]. AB - OBJECTIVE: To study the anti-immune inflammation efficacy and toxicity of Tripterygium wilfordii decoction, in order to provide experimental basis for studies on its "efficacy-toxicity" correlation. METHOD: The delayed hypersensitivity model was established by dinitrofluorobenzene in mice. Different doses of T. wilfordii decoction was administered for 5 consecutive days. The ear swelling inhibition ratio and the toxic action were observed. After the final administration, the biochemical indexes of PGE2, TNF-alpha, IL-2, ALT, AST, PA, TBA, TBIL in serum were detected, and the visceral indexes of heart, liver, spleen and kidney were measured. RESULT: The DNFB-induced ear swelling could be notably inhibited by multiple oral administration of T. wilfordii decoction, with the ED50 and its 95% confidence limit of 0.34 (0.21-0.42) g x kg(-1). The contents of PGE2, TNF-alpha, IL-2 in serum decreased in a dose-dependent manner. The activities of serum AST, ALT, TBA, TBIL and the PA content reduced. CONCLUSION: T. wilfordii decoction shows a significant anti-immune inflammation efficacy within the dosage range between 0.59 and 2.34 g x kg(-1) in a dose dependent manner. With a certain hepatotoxicity, high dose (2.34-4.68 g x kg(-1)) of T. wilfordii decoction can cause substantial liver injury, with a dose dependence in liver function index. Therefore, the efficacy and toxicity of T. wilfordii is dose dependent, which provides reference for preventing adverse drug reactions in clinic and developing early-warning schemes and ensure the clinical medication safety of T. wilfordii. PMID- 26226761 TI - [Study on effect of naringenin in inhibiting migration and invasion of breast cancer cells and its molecular mechanism]. AB - OBJECTIVE: To study the effect of nadroparin in the migration of breast cancer cells MDA-MB-231 and its action mechanism. METHOD: The MTT test was adopted to observe the effect of different concentrations of naringenin on the growth capacity of breast cancer cells MDA-MB-231. Wound healing and transwell experiment analysis were conducted to detect the effect of naringenin on the migration of breast cancer cells MDA-MB-231. Western blotting was adopted to investigate the effect of naringenin on protein expressions of MDA-MB-231 cell Integrin beta3, beta1 and matrix metalloproteinase MMP-2 and MMP-9. The computer virtual docking technique was used to evaluate the combining capacity of naringenin and Integrin beta3 in vitro. RESULT: Naringenin inhibited the migration of MDA-MB-231 cells in a dose-dependent manner. In wound healing and transwell experiments, with the increase in the concentration of naringenin, the number of migrant MDA-MB-231 cells and the invasion capacity of breast cancer cells decreased. Naringenin could inhibit the protein expression of Integrin beta3 in a dose-dependent manner, but with unobvious effect on expression of Integrin beta1. Besides, naringenin could significantly inhibit the protein expressions of MMP-2 and MMP-9. The results of the computer virtual docking showed a negative value in the combining capacity between naringenin and Integrin beta3, indicating the high affinity between them. CONCLUSION: Naringenin can inhibit the growth capacity of breast cancer cells MDA-MB-231 and block the migration and invasion of breast cancer cells MDA-MB-231. Its mechanism is to down-regulate MMP-2 and MMP-9 expressions after combining with Integrin beta3. PMID- 26226762 TI - [Experimental study on efficiency of Spanishneedles Herb eye drops in treating perimenopausal xerophthalmia in rabbits]. AB - OBJECTIVE: To investigate the efficiency of Spanishneedles Herb eye drops in treating perimenopausal xerophthalmia in rabbits. METHOD: Totally 36 rabbits (36 right eyes) were ovariectomized, and 2 months later divided into three groups: the experimental group (group A, n = 12) given Spanishneedles Herb eye drops, the control group (group B, n = 12) given PBS and the model group (group C, n = 12) given no drug. The Schirmer I test (SIT), fluorescent (FL), total tear protein, diastase activity, lactoferrin and lysozyme contents and confocal scanning microscopy were performed at before the treatment and at 1 w, 2 w, 1 mo, 2 mo after the treatment. RESULT: Before the treatment, There was no significant difference in SIT, FL, total tear protein, lysozyme, lactoferrin and amylase activity between two groups. Two months later after the treatment, both the group B and the group A showed differences degrees of changes in SIT, FL, total tear protein, lysozyme, lactoferrin and amylase activity compared with that before the treatment, with statistical differences (P < 0.05); At each time point, both groups revealed statistical differences in SIT, FL, total tear protein, lysozyme, lactoferrin and amylase activity (1 < 0.05). Two months later alter the treatment, densities of basal epithelial cells and inflammatory cells in the group A were (4 122 +/-416) cells/mm2 and (339 +/- 131) cells/mm2, while that in the group B were (3 343 +/- 424) cells/mm2 and (49 +/- 17) cells/mm2, with statistical differences between them (P < 0.05). CONCLUSION: Spanishneedles Herb eye drops could effectively treat perimenopausal xerophthalmia in rabbit caused by sex hormones decline. PMID- 26226763 TI - [Effect of Jinlida on changes in expression of skeletal muscle lipid transport enzymes in fat-induced insulin resistance ApoE -/- mice]. AB - OBJECTIVE: To study the effect of Jinlida on changes in expression of skeletal muscle lipid transport enzymes in fat-induced insulin resistance ApoE -/- mice. METHOD: Eight male C57BL/6J mice were selected in the normal group (NF), 40 male ApoE -/- mice were fed for 16 weeks, divided into the model group (HF), the rosiglitazone group ( LGLT), the Jinlida low-dose group (JLDL), the Jinlida medium-dose group (JLDM), the Jinlida high-dose group (JLDH) and then orally given drugs for 8 weeks. The organization free fatty acids, BCA protein concentration determination methods were used to determine the skeletal muscle FFA content. The Real-time fluorescent quantitative reverse transcription PCR ( RT-PCR) and Western blot method were adopted to determine mRNA and protein expressions of mice fatty acids transposition enzyme (FAT/CD36), carnitine palm acyltransferase 1 (CPT1), peroxide proliferators-activated receptor alpha( PPAR alpha). RESULT: Jinlida could decrease fasting blood glucose (FBG), cholesterol (TC), triglyceride (TG), free fatty acid (FFA) and fasting insulin (FIns) and raise insulin sensitive index (ISI) in mice to varying degrees. It could also up regulate mRNA and protein expressions of CPT1 and PPARalpha, and down-regulate mRNA and protein levels of FAT/CD36. CONCLUSION: Jinlida can improve fat-induced insulin resistance ApoE -/- in mice by adjusting the changes in expression of skeletal muscle lipid transport enzymes. PMID- 26226764 TI - [Relevant studies on effect of Fuzheng Sanjie recipe in regulating immune microenvironment remodeling of TAMs in Lewis lung cancer mice]. AB - OBJECTIVE: To study the effect of Fuzheng Sanjie recipe in regulating tumor associated macrophages (TAMs) in Lewis lung cancer mice. METHOD: Efforts were made to establish the Lewis lung cancer mouse model, weigh tumors and calculate the anti-tumor rate. The immunohistochemical method was used to examine the infiltration degree of CD68 + in tumor tissues in each group. ELISA was used to examine the content of IFN-gamma, TGF-beta, IL-4, IL-13, IL-6, IL-10, IL-12, TNF alpha in mice serum. RESULT: Compared with the tumor-bearing model group, all of the other groups showed higher tumor inhibition rates, i. e. 50.28% for the DDP group, 34.37% for the TCM-preventing group and 66.76% for the Chinese and western medicine group, with statistical difference (P < 0.05), but without statistical difference in the infiltration degree of CD68+. The expressions of the IFN-gamma, IL-6, IL-12 in tumor-bearing groups were lower than that in the blank control group, but with higher contents of IL-4, IL-13, TGF-beta. Intervened with different drugs, there were significant differences in content among some relevant cytokines (P < 0.05), as well as statistical differences among the TCM prevention group, the Chinese and western medicine group and the tumor-bearing control group (P <0. 05) , but without statistical difference in TNF-alpha and IL 10 content from the tumor-bearing control group (P < 0.05). CONCLUSION: Fuzheng Sanjie recipe could reverse the immune remodeling effect and control the tumor growth by down-regulating the expressions of IL-4, IL-13, TGF-alpha in lung cancer immune microenvironment and up-regulating the expression of IFN-gamma. PMID- 26226765 TI - [Effect of Fuzheng Huayu recipe on CYP450 isozymes in normal and liver fibrosis rats]. AB - To study the effect of Fuzheng Huayu recipe (FZHY) on five types of isozymes of cytochrome P450 (CYP450) of normal and liver fibrosis rats by using the cocktail probe method. Dimethylnitrosamine ( DMN) was injected to induce the liver fibrosis model. After the tail vein injection with Cocktail probe solutions prepared with five CYP450s probe substrates (phenacetin-CYP1A2, omeprazole CYP2C9, tolbutamide-CYP2C19, dextromethorphan-CYP2D6, midazolam-CYP3A4), the plasma concentrations of the five probe substrates were determined by LC-MS/MS, and the pharmacokinetic parameters were calculated by PK solutions 2. After the oral administration with FZHY, normal rats given phenacetin, omeprazole, tolbutamide and dextromethorphan showed increase in AUC(0-t) and decrease in CL to varying degrees, indicating that FZHY obviously inhibited the activities of CYP1A2, CYP2C9, CYP2C19 and CYP2D6 in normal rats, but with no obvious effect on the activity of CYP3A4. After the oral administration with FZHY, liver fibrosis rats treated with CYP2C9 showed the significant increase in AUC(0-t) and significant decrease in Vd, hut with no obvious changes in the pharmacokinetic parameters of other four types of prove substances, suggesting that FZHY could significantly inhibit the activity of CYP2C9 in rats but had no effect on the activities of CYP1A2, CYP2C19, CYP2D6 and CYP3A4. The changes in the activity of CYP450 isozymes in liver fibrosis rats may be the reason for FZHY's different effects on CYP450 isozymes in normal and liver fibrosis rats. PMID- 26226766 TI - [Pharmacokinetics study on costunolide and dehydrocostuslactone after administration of traditional Chinese medicine Weichang'an pills]. AB - A HPLC-MS/MS multiple-reaction monitoring (MRM) quantitative analysis was made to establish a determination method for drug concentrations of costunolide (Co) and dehydrocostuslactone (De) in blood samples in the positive ion mode, with diazepam as the internal standard substance, in order to study the pharmacokinetic process of sesquiterpene lactones costunolide and dehydrocostuslactone after the oral administration of Weichang'an pills, and provide an theoretical basis for further studies on the substance basis for the anti-diarrhea effect of Weichang'an pills. In the blood samples, Co and De showed a good linearity within concentration ranges 0.700 0-769.7, 2.510-956.0 MUg x L( 1), respectively. The results of precision, stability and recovery experiences proved the stability and reliability of the plasma concentration determination method. After the oral administration, the concentrations of Co and De in plasma increased with the increase in dose, with T(max) between 10.65-12.98 h, indicating a long time to reach peak plasma concentrations; C(max) of costunolide and dehydrocostuslactone ranged between 3.750-5.450,15.34-44.52 MUg x L(-1), respectively. The in vivo adsorption of Co and De conformed to the one compartment model, with a longer time to attain the peak plasma concentrations. These results provided an experimental basis for revealing the active substance basis and clinical medication of Weichang'an pills. PMID- 26226767 TI - [Pharmacokinetic study on combined application of gastrodin and puerarin in rats]. AB - To establish a HPLC method for simultaneously determining plasma concentrations of gastrodin (Gas) and its metabolites hydroxybenzyl alcohol (HBA), puerarin (Pur) and internal standard (IS) p-hydroxyphenylethanol (Tyr) in rats and studying the pharmacokinetic process and interactions of gastrodin and puerarin after single and combined intravenous injection and oral administration. With Tyr as the internal standard, plasma samples were processed with methanol for protein precipitation, supernatant was dried with N2, and residues were re-dissolved with acetonitrile-0.05% phosphoric acid (20: 80). Chromatography was carried out on an Agilent ZORBAX SB-Aq C18 column (4.6 mm x 250 mm, 5 MUm), with acetonitrile-0.05% phosphoric acid as the gradient mobile phase for the gradient elution. The UV detector wavelength was set at 221 nm for Gas HBA and IS and 250 nm for Pur. After the single or combined administration of Gas and Pur, their plasma concentrations in rats were detected. WinNonlin 5.2 pharmacokinetic software and SPSS 17. 0 software were used to respectively calculate pharmacokinetic parameters of each group, make a statistical analysis and compare the pharmacokinetic processes of Gas and Pur after the single or combined administration. According to the results, the absolute recoveries between low, media and high concentrations of Gas, HBA and Pur and IS as well as Tyr were more than 77.20%, with a good linearity (r > 0.999 6, n = 5) for Gas, HBA and Pur within concentration ranges of 0.10-101, 0.03-7.58 and 0.05-5.98 mg xL ('1) respectively. The lower limits of quantification for Gas, HBA and Pur were 0.10, 0.03, 0.05 mg x L(-1), respectively. Their in-ra-day and inter-day precisions were less than 12% with the accuracy between 85. 1% -1 10. %. All of the three substances and IS were stable during the whole analysis process. The findings showed significant differences in the main in vivo pharmacokinetic parame-ers in rats (AUC, C.(max) T,1/2 T.(max) MRT) after the single and combined administration of Gas and Pur. Either after the oral adminis-ration or after the intravenous injection, parameters showed a lower clearance rate ( L) longer mean residence time ( RT) and higher relative bioavailability, especially after the oral administration. Specifically, the relative bioavailability of the combined oral ad-inistration of Pur was 10. 7 times of that of the single administration, while that of Gas was 1. times of that of the single administra-ion. The combined administration of Gas and Pur can promote the absorption, decrease the elimination rate and prolong the mean resi-ence time. The method is simple and accurate and can be applied in the simultaneous determination of plasma concentrations of Gas, HBA and Pur in rats and the pharmacokinetic studies. PMID- 26226768 TI - [Study on medication regularity of traditional Chinese medicines in treating attention deficit hyperactivity disorder based on data mining]. AB - In this study, efforts were made to collect 88 traditional Chinese medicine (TCM) prescriptions for treating ADHD from public literatures, establish a medication database and conduct data mining on the efficacy, properties, tastes, meridian entries and compatibility regularity of TCMs by using frequency analysis, association rules analysis and cluster analysis. The results showed 33 herbs with a high frequency (>= 10%). The top 12 frequently applied ADHD herbs were respectively Acori Tatarinowii Rhizome, Polygalae Radix, Prepared Rehmanniae Radix, Os Draconis, Glycyrrhizae Radix et Rhizome, Poria, Concha Ostreae, Testudinis Carapacis et Plastri, Paeoniae Alba Radix, Schisandrae Fructus Chinensis, Fructus Corni, Dioscoreae Rhizoma. The top seven types of frequently applied ADHD herbs by effect were respectively tonic herb, sedative herbs, livei wind calming herbs, heat clearing herbs, astringent herbs, awaking herbs and damp clearing and diuresis promoting herbs. The top three properties were warm, cold and neutral, with warm as the dominance. The top three tastes were sweetness, bitterness and acridity, with sweetness as the dominance. The top three meridian entries were liver meridian, heart meridian and kidney meridian. The association rules analysis showed commonly used herbal pairs. Polygalae Radix-Acori Tatarinowii Rhizome, Concha Ostreae-Os Draconis, Prepared Rehmanniae Radix Fructus Corni-Os Draconis. Eight highly frequent cluster prescriptions were summarized based on the cluster analysis. This study indicates that basic TCM prescriptions for treating ADHD were principally composed of tonics (nourishing liver and kidney, invigorating heart and spleen) and tranquilization, which were supplemented with herbs for calming liver, clearing heat, promoting qi circulation, promoting blood-circulation, reducing phlegm and calming endogenous wind. The combination of multiple data mining techniques can reflect the clinical medication regularity of herbs for treating ADHD in an overall and objective manner. PMID- 26226769 TI - [Preliminary study on general safe medication regularity of Chinese patent orthopedic medicines based on adverse reaction/event literature analysis]. AB - Chinese patent orthopedic medicines feature complex components, mainly including desperate and toxic herbal pieces, narrow safety window, more clinical contraindications and frequent adverse drug reaction/events (ADR/ADE). To study the general safe medication regularity of Chinese patent orthopedic medicines, define key points in the medication education and ensure rational clinical medication, the authors took 80 types of commonly used Chinese patent orthopedic medicines as the study objects, collect 237 cases from 164 ADR/ADE documents through a system retrieval strategy, make a multidimensional literature analysis to determine the common risk factors for safe and rational medication of Chinese patent orthopedic medicines and establish an ADR/ADE prevention regularity. First, in the aspect of clinical symptoms, skin allergy is the most common ADR/ADE and closely related to the toxic ingredients, particularly accumulated liver or kidney damage caused by some drugs. Second, there are three time nodes in the ADR/ADE occurrence; The ADR/ADE occurred in 30 minutes is closely related to the idiosyncrasy; the ADR/ADE occurred between several months and half a year is related to the drug-induced liver and kidney damages; The most common ADR/ADE was observed within 7 days and predictable according to the pharmacological actions; Third, toxicity is an important factor in the occurrence of ADR/ADE of Chinese patent orthopedic medicines. Fourth, emphasis shall be given to the special medication factors, such as the combination with western medicines and Chinese herbal decoctions, overdose and long-course medication and self-medical therapy. In conclusion, the general ADR/ADE prevention regularity for Chinese patent orthopedic medicines was summarized to provide supports for clinicians in safe and rational medication and give the guidance for pharmacist in medication education. PMID- 26226770 TI - [Clinical study on aconite prescriptions with incompatible herbs in different areas based on association rules and analysis on compatibility features]. AB - OBJECTIVE: To explore the current application and features of Aconite prescriptions with incompatible herbs in grade A class three hospitals in east China and central China through a clinical study and comparative analysis. METHOD: Clinical prescriptions containing Aconite with incompatible herbs were collected. Association rules were utilized to analyze the compatible features of these herbs. RESULT: This analysis found that the frequently used incompatible herba; pairs are Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma, with the support rate of 44.45%, occupying nearly half of the surveyed prescriptions; Pinelliae Rhizoma is the most frequently used herb in the two areas, with support rate up to 76.24%. Among the top 10 herbal pairs in the support rate, except for Aconiti Lateralis Radix Praeparata and Pinelliae Rhizoma, the top 10 herbs in Central China were mostly for warming the middle jiao and tonifying qi, such as Zingiberis Rhizoma, Atractylodis Macrocephalae Rhizoma and Codonopsis Radix; Whereas those in east China were mostly for activating and nourishing blood, such as Angelicae Sinensis Radix, Chuanxiong Rhizoma, and Salviae Miltiorrhizae Radix et Rhizoma. Among the top 10 herbal pairs in the support rate, except for Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma, the core herbal pairs applied in central China were mainly for resolving phlegm and warming the middle jiao, such as Pinelliae Rhizoma-Glycyrrhizae Radix et Rhizoma, Pinelliae Rhizoma-Zingiberis Rhizoma; Whereas those in east China were principally for activating blood and tonifying qi, like Atractylodis Macrocephalae Rhizoma and Pinelliae Rhizoma, Angelicae Sinensis Radix and Pinelliae Rhizoma. Among the core herbal groups in the two areas, the most frequently used herbal groups in the two areas are Aconiti Lateralis Radix Praeparata, Glycyrrhizae Radix et Rhizoma and Pinelliae Rhizoma with the support rate of 59.73%, accounting for the highest proportion among all of herbal groups. CONCLUSION: There are the combined clinical application of Aconite with incompatible herbs, mostly with Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma, but with differences in the combined application in east China and central China. PMID- 26226771 TI - [Analysis on composition and medication regularities of prescriptions treating hypochondriac pain based on traditional Chinese medicine inheritance support system inheritance support platform]. AB - To analyze the composition and medication regularities of prescriptions treating hypochondriac pain in Chinese journal full-text database (CNKI) based on the traditional Chinese medicine inheritance support system, in order to provide a reference for further research and development for new traditional Chinese medicines treating hypochondriac pain. The traditional Chinese medicine inheritance support platform software V2. 0 was used to build a prescription database of Chinese medicines treating hypochondriac pain. The software integration data mining method was used to distribute prescriptions according to "four odors", "five flavors" and "meridians" in the database and achieve frequency statistics, syndrome distribution, prescription regularity and new prescription analysis. An analysis were made for 192 prescriptions treating hypochondriac pain to determine the frequencies of medicines in prescriptions, commonly used medicine pairs and combinations and summarize 15 new prescriptions. This study indicated that the prescriptions treating hypochondriac pain in Chinese journal full-text database are mostly those for soothing liver-qi stagnation, promoting qi and activating blood, clearing heat and promoting dampness, and invigorating spleen and removing phlem, with a cold property and bitter taste, and reflect the principles of "distinguish deficiency and excess and relieving pain by smoothening meridians" in treating hypochondriac pain. PMID- 26226773 TI - [Research on collaborative innovation in traditional Chinese medicine of China based on patent cooperation network]. AB - In the situation of global completion, collaborative innovation is becoming increasingly important because its advantage in risk avoiding and innovation efficiency. In order to explore the model of collaborative innovation and its evolution in traditional Chinese medicine of China, the cooperation in traditional Chinese medicine patents of China from 1985 to 2013 has been analyzed by using the method of scientometrics and social network analysis. It is proved that, though the number of grated cooperative patents has increased sharply during the last thirty years, the degree of cooperation innovation in traditional Chinese medicine of China is still not high. Moreover, in spite of the individual subject' s leading role in the past domestic collaborative innovation in traditional Chinese medicine of China, the institutions have been more and more powerful and achieved great improvement. At last, core institutions, represented by universities have played an important role in the collaborative innovation of domestic institutions, because they are key links between many institutions and promote the transferring and diffusion of knowledge. PMID- 26226772 TI - [Effect of Tanreqing injection on immune activity of peripheral blood lymphocytes of patients with lung cancer]. AB - To investigate the effect of Tanreqing injection on immune activity of peripheral blood lymphocytes of patients with lung cancer. The peripheral blood lymphocytes of patients with lung cancer and healthy persons were separated by the density gradient centrifugation method for subsequent experiments, with those from healthy persons as the positive control. The effect of Tanreqing injection on stimulating the proliferation of lymphocytes with phytohemagglutinin (PHA) was determined by MTT method. The effect of Tanreqing injection on the lymphocyte secretions of IFN-gamma and TNF-alpha and the subset ratio of lymphocytes cultured separately or with Tanreqing injection of different concentrations were examined by ELISA and flow cytometry (FCM) respectively. In addition, the LDH release assay was used to detect the cytotoxicity of cytotoxic T cells (CTL) and natural killer cells (NK). According to the findings, all of immunological indexes of lymphocytes from patients with lung cancer were weaker than that of healthy persons, but with the obvious increases in proliferation activity and IFN gamma and TNF-alpha secretions of lymphocytes co-cultured with Tanreqing Injection (P < 0.05). Among lymphocyte subsets co-cultured with Tanreqing Injection, CD3+, CD3+ CD4+ and CD3- CD16 + 56+ cell ratios notably increased, whereas CD4+ CD25+ Treg cell ratio obviously decreased (P < 0.05). In the meantime, Tanreqing injection can markedly promote the cytotoxicities of CTL and NK (P < 0.05). In conclusion, Tanreqing injection shows a significant effect in promoting the immune activity of lymphocytes from patients with lung cancer and their anti-tumor immunity. PMID- 26226774 TI - [Construction of traditional Chinese medicine resources information spatial database]. AB - The informatization of traditional Chinese medicine resources is the basis of modern medicine. With a spatial attribute traditional Chinese medicine resources could be carried out for in-depth spatial analysis, data mining and traditional Chinese medicine resources regional industrial layout. In this paper, we took the data of Glycyrrhiza uralensis in the third national Chinese medicine resources survey as the experimental data, described the principles and structure of traditional Chinese medicine resources spatial information database. We also described the establishment of analysis model with the help of this spatial database. PMID- 26226775 TI - [Morphological diagnosis of tuberculosis under present-day conditions]. AB - The paper presents general statistical data on morbidity and mortality rates of tuberculosis, which show positive trends in recent years, with exception of those of its concurrence with HIV infection. The tasks of the morphological diagnosis of tuberculosis are divided into 4 groups: 1) to refine approaches to detecting mycobacteria in tissues; 2) to optimize the postmortem diagnosis of tuberculosis; 3) to optimize the lifetime differential diagnosis of tuberculosis and to develop methods for predicting its course; 4) to study the pathogenesis of tuberculosis from the standpoint of modern views on an infectious process. The data suggesting that the tissue forms of mycobacteria, the types of inflammatory responses, and the specific features of the pathogenesis of tuberculosis call for further investigations are given. To establish the real role of nontuberculous mycobacteria, to study the likelihood that the patient will be superinfected with other M. tuberculosis genotypes, and to elaborate a uniform (clinical, pathogenetic, and morphological) classification of tuberculosis should be also regarded as the most important tasks in its morphological examination. PMID- 26226776 TI - [Impact of preoperative drug therapy on adhesion molecule expression in colorectal cancer liver metastases]. AB - OBJECTIVE: To study E-cadherin and beta-catenin expression in colorectal cancer (CRC) liver metastases in order to assess the impact of different drug therapy regimens on the adhesive properties of tumor cells. MATERIAL AND METHODS: Intraoperative metastatic CRC samples from patients who had received preoperative cytotoxic chemotherapy or combined cytotoxic and targeted anti-VEGF (vascular endothelial growth factor) therapy were immunohistochemically examined using antibodies to E-cadherin and beta-catenin. A comparison group consisted of patients who had not received drug therapy. RESULTS: Combined therapy with cytotoxic and anti-VEGF agents was shown to result in a significant increase in the number of cases of normal membrane localization of E-cadherin as compared with control (p = 0.00043) and cytotoxic therapy-alone (p = 0.01) groups. A comparison of beta-catenin levels in three patient groups revealed no significant differences, but addition of an anti-VEGF agent caused some decrease in the number of cases of abnormal nuclear localization of the protein as compared to both the control group and the cytotoxic therapy groups. The comparison of E cadherin and beta-catenin localization in tumor cells showed that a combination of normal E-cadherin membrane localization and beta-catenin membrane-cytoplasmic expression prevailed in the combined therapy group compared to the control (p = 0.009) and cytotoxic therapy (p = 0.04) groups. CONCLUSION: The addition of a targeted anti-VEGF agent to the drug therapy of metastatic CRC has a positive impact on the cadherin-catenin complex, leading to increased intercellular contacts and suppressed beta-catenin functioning as a transcription factor that enhances tumor cell proliferation. PMID- 26226777 TI - [Clinical assessment of histological diagnostic systems for adrenocortical tumors]. AB - The Weiss scoring system encompassing 9 histological criteria for tumor grading the Weiss index (WI) and modified Weiss index (MWI), which evaluate the 5 most informative histological criteria with the exception of some inestimable signs has gained the widest acceptance for the morphological diagnosis of adrenocortical carcinoma (ACC). OBJECTIVE: To comparatively analyze the efficiency of WI and MWI in the diagnosis of ACC. SUBJECTS AND METHODS: Adrenal tumors (ACC and adenoma) from 104 patients were studied. The accuracy of WI and MWI for the diagnosis of ACC and adrenocortical adenomas was comparatively analyzed. RESULTS: The sensitivities of WI and MWI for the diagnosis of ACC were 96.8 and 91.5%, respectively. The difference was statistically insignificant (p = 0.2). CONCLUSION: MWI is less subjective, easier-to-use, and more informative for the differential diagnosis of adenomas and ACC at borderline WI values. However, there is little point in using MWI to diagnose without considering WI as MWI unreached the threshold value (3 scores) more frequently than WI in malignant tumors. PMID- 26226778 TI - [The expression of connexin 36 and some neuroglial antigens in human brain astrocytic tumors of different grades]. AB - OBJECTIVE: To reveal the expression of neuronal connexin 36 (Cx36) in gliomas and then to analyze the ratio of expression of Cx36 to that of neuroglial antigens (synaptophysin, neurofilaments, and glial fibrillary acidic protein). MATERIAL AND METHODS: Varying grade human glioma samples and tumor-adjacent tissue fragments were used for immunohistochemical examination. RESULTS: A procedure for immunohistochemical detection of Cx36 in brain tissue was tried out. It was shown that the decreased level of the examined neuronal proteins was accompanied by the impaired coexpression of synaptophysin/neurofilaments and Cx36 in the series of astrocytomas--anaplastic astrocytomas--glioblastomas. The immunohistochemical heterogeneity of glioblastomas was found. CONCLUSION: The findings suggest that it is promising to include anti-Cx36 antibodies in immunohistochemical panels when examining brain tumors. Data on the lower levels of the examined neuronal proteins, on the specific features of their distribution and impaired coexpression expand their idea on the pathogenesis of a brain tumor process and determine an area for further investigations. PMID- 26226779 TI - [Myxoinflammatory fibroblastic sarcoma: clinicopathologic and immunohistochemical analysis]. AB - OBJECTIVE: To study the specific features of myxoinflammatory fibroblastic sarcoma (MIFS), by providing clinicopathologic and immunohistochemical evaluations of neoplasms and the biological behavior of these tumors and analyzing their recurrent forms. MATERIAL AND METHODS: Ten cases of MIFS were examined with emphasis on its clinicopathological and immunohistochemical features. RESULTS: In 9 cases, the tumor involved the acral part of the extremities; in one case, it was located in the superficial tissues of the thigh. All neoplasms had a classical histological pattern of MIFS. Four cases developed local recurrences most likely due to the inadequate volume of surgical intervention. Three tumors held its original histological form, but one showed marked histologic progression. Immunohistochemically, all the tumors expressed vimentin. Some cases exhibited a positive reaction with CD68, factor XIIIa, and podoplanin. CONCLUSION: Despite altered morphological patterns, the immunoprofile of recurrent MIFS was retained. A tendency for recurrence requires that the resection margins should be meticulously investigated to exclude residual tumor. PMID- 26226780 TI - [Osteochondroma in children and adolescents]. AB - Osteochondroma is called a benign cartilage-forming tumor arising from an aberrant subperiosteal cartilage. Multiple osteochondromas syndrome (MOS) is an autosomal dominant disease, the basis for which is mutations in the EXT (EXT1 or EXT2) genes. Osteochondroma is one of the most common benign bone tumors. According to the WHO data, it is detectable in 35% of benign bone tumors and 8% of all surgically removed bone tumors. A total of 491 cases of bone tumors were analyzed in the children and adolescents diagnosed at the Department of Pathoanatomy, Russian Children's Clinical Hospital, Moscow, in 2009 to 2014. All the patients with osteochondroma were divided into 2 groups: 1) sporadic cases (n = 63) and 2) tumors included in MOS (n = 33). Both groups showed a preponderance of boys (39 boys and 24 girls in Group 1 and 21 boys and 12 girls in Group 2). Clinical, radiological, and morphological criteria for the diagnosis and differential diagnosis of osteochondromas in children and adolescents are given. PMID- 26226781 TI - [Liposarcoma of the spermatic cord]. AB - The paper reviews the literature on primary paratesticular tumors. It describes the classification, brief characteristics of liposarcomas and the morphological pattern of the tumor with an immunohistochemical profile. A clinical case of differentiated liposarcoma of the spermatic cord with myxoid and rhabdomyoblastic differentiation is depicted in a 61-year-old man. PMID- 26226782 TI - [Intravascular leiomyomatosis]. AB - Intravenous leiomyomatosis is a rare disease from a group of tumors with the indefinite grading potential. The paper describes two cases of intravenous leiomyomatosis with its detailed morphological pattern, molecular genetic findings, and a brief literature review. Losses of heterozygosity of microsatellite repeats thatwere located on chromosome 10 in 10q22.1 and common in uterine leiomyosarcomas were found in both cases. Investigations of the morphological and biological characteristics of leimyomatosis are important to clarify the key molecular mechanisms underlying the development of this nosological entity and to determine etiopathogenetic relationships between intravenous leiomyomatosis and other uterine smooth muscle neoplasms. PMID- 26226783 TI - [Role of cadherins in health and in developing breast cancer]. AB - The review gives data on the structure of cadherin cell adhesion molecules, their role in the body's development and malignant tumor progression. It describes cadherins that are considered to play the most important role in the development of a tumor process: E-, P-, and N-cadherins that belong to type I classical cadhedrins and VE-cadhedrin that does to type II cadherins. Particular emphasis is placed on the signal mechanisms with involvement of cadherins and cadherin related molecules, which are realized in the body in health and in tumor transformation of cells. PMID- 26226784 TI - [Leaders of the Medical Service Corps of Fronts and Navies in the Great Patriotic War 1941-1945 (on the occasion of the 70th anniversary of the Great Victory)]. PMID- 26226785 TI - [Professor M.N. Nikiforov is one of the founders of the Moscow School of Pathologists]. PMID- 26226786 TI - [All-Russian Scientific and Practical Conference on Current Approaches to Morphological Diagnosis of Human Neoplasms]. PMID- 26226787 TI - Government's plan to reduce access to paid parental leave (PPL). PMID- 26226788 TI - ANMF on front foot at Senate Inquiry into Temporary Work Visas (457s). PMID- 26226789 TI - Plea to support victims of domestic violence. PMID- 26226790 TI - New wristband technology streamlining patient care. PMID- 26226791 TI - New standards for midwives to prescribe scheduled meds. PMID- 26226792 TI - Online career pathways for nursing. PMID- 26226793 TI - Building nursing and midwifery voices in Parliament. PMID- 26226794 TI - Nurses working in detention centres face prison if speak out. PMID- 26226795 TI - No cents in cashing out annual leave. PMID- 26226796 TI - Reprieve for rehab unit. PMID- 26226797 TI - Disaster preparedness provided in a postgrad degree. PMID- 26226798 TI - A career in nursing and midwifery fit for a queen. PMID- 26226799 TI - Maternal risks remain higher for Indigenous women. PMID- 26226800 TI - Western Australian nurses could be given police powers. PMID- 26226801 TI - Queensland nurse and son win bid to remain in Australia. PMID- 26226802 TI - Protect nurses on frontline says ICN. PMID- 26226803 TI - New challenges in a global healthcare environment. PMID- 26226804 TI - Parliament to examine the link between migration and employment of local graduates. PMID- 26226805 TI - MISSION POSSIBLE. AUSTRALIAN NURSES AND MIDWIVES STRENGTHENING DEVELOPING COUNTRIES. PMID- 26226806 TI - Celebrating midwives creatively. PMID- 26226807 TI - Nurses--are we disaster ready? PMID- 26226808 TI - Tonnes of medicine wastage costs millions. PMID- 26226809 TI - Social media to combat youth drinking. PMID- 26226810 TI - ED increase due to ageing population. PMID- 26226811 TI - Wound ulcer recruits needed. PMID- 26226812 TI - Rationing universal healthcare. PMID- 26226813 TI - Education through Self-directed Learning. PMID- 26226814 TI - Need for improved recognition of in-hospital newborn falls. PMID- 26226815 TI - Praxis to practice: academic integrity equals professional integrity. PMID- 26226816 TI - Transition to specialty practice programs in emergency nursing. PMID- 26226817 TI - Exploring the mobile learning paradox to enable redesign of learning and teaching in the workplace. PMID- 26226818 TI - Innovating point of care education: the clinical coach. PMID- 26226819 TI - Situating clinical assessment tools within workplace learning. PMID- 26226820 TI - Teaching of safe practices to our undergraduates. PMID- 26226821 TI - Flexible education opportunities. PMID- 26226822 TI - Virtual simulation developing non-technical skills in student nurses and midwives. PMID- 26226823 TI - Using video assessments as an alternative to the Objective Structured Clinical Examination (OSCE). PMID- 26226824 TI - Advances in midwifery simulation at USC . PMID- 26226825 TI - Attracting generation Z into nursing as a career. PMID- 26226826 TI - At their mercy (letter of the month). PMID- 26226828 TI - Hospital variation in maternal complications following caesarean delivery in the United States: 2006-2012. AB - OBJECTIVE: To assess hospital variability in and patient and hospital factors associated with caesarean delivery (CD) complications. STUDY DESIGN: Population based cohort. SETTING: United States delivery admissions. POPULATION: Women who underwent a CD between 2006 and 2012. METHODS: Hospital-specific random-effects log-linear regression models were developed to account for patient, obstetric, and hospital risk factors related to a composite complication outcome including infection, haemorrhage, surgical complications and prolonged hospital stay. Between-hospital variability in rates of CD complications was also estimated. MAIN OUTCOME MEASURE: Composite complication rate. RESULTS: Among 1 339 397 women who underwent CD in 457 hospitals, 6.4% (n = 85 838) experienced a complication. The most frequent complications were haemorrhage, transfusion, length of stay >7 days, and endometritis. Complications were strongly associated with the presence of obstetric factors and pre-existing medical conditions. Complication rates were 54% higher among black (8.8%) than white (5.7%) women (P < 0.001), and were more common in teaching (8.1%) than non-teaching (5.4%) hospitals (P < 0.001). In an adjusted model, the mean complication rate was 6.7%. A small proportion of hospitals (4.8%) had a complication rate greater than twice the mean (>=13.4%). Complications were strongly associated with the presence of obstetrical factors and pre-existing medical conditions. CONCLUSIONS: CD complication rates are strongly associated with patient and obstetric factors. While CD complication rates may be a quality metric of limited utility given the low rate of complications across most hospitals, a small number of hospitals demonstrate particularly high rates of complications. Review of CD complication rates may be an important aspect of quality assurance processes for these centres. TWEETABLE ABSTRACT: A small number of hospitals demonstrate particularly high rates of caesarean complications. PMID- 26226829 TI - Issue Highlight 2015. PMID- 26226831 TI - Effect of Boric Acid Supplementation on the Expression of BDNF in African Ostrich Chick Brain. AB - The degree of brain development can be expressed by the levels of brain brain derived neurotrophic factor (BDNF). BDNF plays an irreplaceable role in the process of neuronal development, protection, and restoration. The aim of the present study was to evaluate the effects of boric acid supplementation in water on the ostrich chick neuronal development. One-day-old healthy animals were supplemented with boron in drinking water at various concentrations, and the potential effects of boric acid on brain development were tested by a series of experiments. The histological changes in brain were observed by hematoxylin and eosin (HE) staining and Nissl staining. Expression of BDNF was analyzed by immunohistochemistry, quantitative real-time PCR (QRT-PCR), and enzyme linked immunosorbent assay (ELISA). Apoptosis was evaluated with Dutp-biotin nick end labeling (TUNEL) reaction, and caspase-3 was detected with QRT-PCR. The results were as follows: (1) under the light microscope, the neuron structure was well developed with abundance of neurites and intact cell morphology when animals were fed with less than 160 mg/L of boric acid (groups II, III, IV). Adversely, when boric acid doses were higher than 320 mg/L(groups V, VI), the high-dose boric acid neuron structure was damaged with less neurites, particularly at 640 mg/L; (2) the quantity of BDNF expression in groups II, III, and IV was increased while it was decreased in groups V and VI when compared with that in group I; (3) TUNEL reaction and the caspase-3 mRNA level showed that the amount of cell apoptosis in group II, group III, and group IV were decreased, but increased in group V and group VI significantly. These results indicated that appropriate supplementation of boric acid, especially at 160 mg/L, could promote ostrich chicks' brain development by promoting the BDNF expression and reducing cell apoptosis. Conversely, high dose of boric acid particularly in 640 mg/L would damage the neuron structure of ostrich chick brain by inhibiting the BDNF expression and increasing cell apoptosis. Taken together, the 160 mg/L boric acid supplementation may be the optimal dose for the brain development of ostrich chicks. PMID- 26226832 TI - Thymoquinone Ameliorates Cadmium-Induced Nephrotoxicity, Apoptosis, and Oxidative Stress in Rats is Based on its Anti-Apoptotic and Anti-Oxidant Properties. AB - Cadmium (Cd), an environmental and industrial pollutant, generates free radicals responsible for oxidative stress. Cd can also lead to various renal toxic damage such as the proximal tubules and glomerulus dysfunction. Thymoquinone (TQ) is the main constituent of the essential oil obtained from black seeds (Nigella sativa) and has various pharmacological effects. The aim of the present study was to examine the nephroprotective, anti-oxidant, and anti-apoptotic effect of the TQ against Cd-induced nephrotoxicity. A total of 24 male Wistar albino rats were divided into three groups: control, Cd-treated, and Cd-treated with TQ; each group contain eight animals. The Cd-treated group was injected subcutaneously with CdCl2 dissolved in saline in the amount of 2 ml/kg/day for 30 days, resulting in a dosage of 1 mg/kg Cd. The rats in TQ-treated groups were given TQ (50 mg/kg body weight) once a day orally together with first Cd injection during the study period. The histopathological studies in the kidney of rats also showed that TQ markedly reduced the toxicity of Cd and preserved the normal histological architecture of the renal tissue. Immunohistochemical analysis revealed that TQ significantly decreased the Cd-induced over expression of nuclear factor-kappaB in renal tissue. Furthermore, TQ treatment resulted in decreased the number of apoptotic cells. TQ significantly suppressed lipid peroxidation, compensated deficits in the anti-oxidant defenses (reduced superoxide dismutase, glutathione peroxidase and catalase activities) in renal tissue resulted from Cd administration. These findings suggest that the nephroprotective potential of TQ in Cd toxicity might be due to its anti-oxidant and anti-apoptotic properties, which could be useful for achieving optimum effects in Cd-induced nephrotoxicity. PMID- 26226830 TI - Interferon Gamma ELISPOT Testing as a Risk-Stratifying Biomarker for Kidney Transplant Injury: Results From the CTOT-01 Multicenter Study. AB - Previous studies suggest that quantifying donor-reactive memory T cells prior to kidney transplantation by interferon gamma enzyme-linked immunosorbent spot assay (IFNgammaELISPOT) can assist in assessing risk of posttransplant allograft injury. Herein, we report an analysis of IFNgammaELISPOT results from the multicenter, Clinical Trials in Organ Transplantation-01 observational study of primary kidney transplant recipients treated with heterogeneous immunosuppression. Within the subset of 176 subjects with available IFNgammaELISPOT results, pretransplant IFNgammaELISPOT positivity surprisingly did not correlate with either the incidence of acute rejection (AR) or estimated glomerular filtration rate (eGFR) at 6- or 12-month. These unanticipated results prompted us to examine potential effect modifiers, including the use of T cell depleting, rabbit anti-thymocyte globulin (ATG). Within the no-ATG subset, IFNgammaELISPOT(neg) subjects had higher 6- and 12-month eGFRs than IFNgammaELISPOT(pos) subjects, independent of biopsy-proven AR, peak PRA, human leukocyte antigen mismatches, African-American race, donor source, and recipient age or gender. In contrast, IFNgammaELISPOT status did not correlate with posttransplant eGFR in subjects given ATG. Our data confirm an association between pretransplant IFNgammaELISPOT positivity and lower posttransplant eGFR, but only in patients who do not receive ATG induction. Controlled studies are needed to test the hypothesis that ATG induction is preferentially beneficial to transplant candidates with high frequencies of donor-reactive memory T cells. PMID- 26226833 TI - FFA-ROS-P53-mediated mitochondrial apoptosis contributes to reduction of osteoblastogenesis and bone mass in type 2 diabetes mellitus. AB - This study evaluated the association between free fatty acid (FFA), ROS generation, mitochondrial dysfunction and bone mineral density (BMD) in type 2 diabetic patients and investigated the molecular mechanism. db/db and high fat (HF)-fed mice were treated by Etomoxir, an inhibitor of CPT1, MitoQ, and PFT alpha, an inhibitor of P53. Bone metabolic factors were assessed and BMSCs were isolated and induced to osteogenic differentiation. FFA, lipid peroxidation and mtDNA copy number were correlated with BMD in T2DM patients. Etomoxir, MitoQ and PFT-alpha significantly inhibited the decrease of BMD and bone breaking strength in db/db and HF-fed mice and suppressed the reduction of BMSCs-differentiated osteoblasts. Etomoxir and MitoQ, but not PFT-alpha, inhibited the increase of mitochondrial ROS generation in db/db and HF-fed mice and osteoblasts. In addition, Etomoxir, MitoQ and PFT-alpha significantly inhibited mitochondrial dysfunction in osteoblasts. Moreover, mitochondrial apoptosis was activated in osteoblasts derived from db/db and HF-fed mice, which was inhibited by Etomoxir, MitoQ and PFT-alpha. Furthermore, mitochondrial accumulation of P53 recruited Bax and initiated molecular events of apoptotic events. These results demonstrated that fatty acid oxidation resulted in ROS generation, activating P53/Bax-mediated mitochondrial apoptosis, leading to reduction of osteogenic differentiation and bone loss in T2DM. PMID- 26226834 TI - Endothelin-1 Upregulates the Expression of High Mobility Group Box 1 in Human Bronchial Epithelial Cells. AB - Both endothelin-1 (ET-1) and high mobility group box 1 (HMGB1) reportedly are closely involved in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). In this study, we explored the regulatory effects of ET 1 on the expression of HMGB1 in human bronchial epithelial cells (HBEpCs). Primary HBEpCs were treated with ET-1 with or without transcription inhibitor actinomycin D, ETA receptor blocker BQ123, ETB receptor blocker BQ788, focal adhesion kinase (FAK) inhibitor or shRNA, or different kinase inhibitors. ET-1 increased the HMGB1 mRNA level in a statistically significant dose- and time dependent manner within 8 hours of treatment, which was reflected in the dose dependent induction of the HMGB1 protein level and the FAK activity. BQ123 and FAK inhibitor or shRNA, but not BQ788, completely abolished the promoting effect of ET-1 on the expression of HMGB1. Luciferase reporter assays revealed that neither ET-1 nor ETA nor FAK inhibition had any significant effect on the HMGB1 gene promoter activity. In the presence of the transcription inhibitor actinomycin D, the HMGB1 mRNA level markedly decreased over time, and ET-1 dose dependently rescued the HMGB1 mRNA level. This effect of ET-1 was completely abolished by BQ123 and FAK inhibitor or shRNA, but not by BQ788. In conclusion, this study provides the first evidence that ET-1 upregulates the expression of HMGB1 in HBEpCs by increasing the stability of HMGB1 mRNA via the ETA receptor by a FAK-dependent mechanism. It adds new insights into the molecular mechanisms underlying ALI/ARDS. PMID- 26226835 TI - Dramatic improvement of yellow nail syndrome with a combination of intralesional triamcinolone, fluconazole, and sinusitis management. PMID- 26226836 TI - Physiological significance of ghrelin revealed by studies using genetically engineered mouse models with modifications in the ghrelin system. AB - Ghrelin, an endogenous ligand for the growth hormone (GH) secretagogue receptor (GHS-R or ghrelin receptor), is a 28-amino acid acylated peptide mainly produced in the stomach. The pharmacological administration of ghrelin is known to exert diverse effects, such as stimulating GH secretion, promoting food intake, and increasing adiposity. In recent years, genetically engineered mouse models have provided important insights into the physiology of various hormones. In this review, we discuss current knowledge regarding the physiological significance of ghrelin on the basis of studies using genetically engineered mouse models with modifications in the ghrelin system. PMID- 26226837 TI - Low concentrations of dihydrotestosterone induce female-to-male sex reversal in the frog Pelophylax nigromaculatus. AB - Previous studies have demonstrated that some amphibian species can be sex reversed by high concentrations of androgens. Little attention has focused on the effects of androgenic endocrine-disrupting chemicals (EDCs) on amphibians. The present study aimed to investigate the effects of lower concentrations of the androgenic EDC 5alpha-dihydrotestosterone (DHT) on gonadal differentiation and development in Pelophylax nigromaculatus, a true frog distributed widely in East Asia. Tadpoles at Gosner stage 24/25 were exposed to nominal concentrations of 40 ng/L, 400 ng/L, and 4000 ng/L DHT to complete metamorphosis. In all DHT treatment groups, males and ambiguous sexes were identified based on gonadal morphology, whereas no females were found; thus, all treatment groups exhibited male-skewed ratios compared with the control group. Gonadal histological examination revealed that ambiguous sexes displayed overall testicular structure with certain ovarian characteristics, demonstrating that DHT-induced sex-ambiguous gonads were incomplete ovary-to-testis reversals (IOTTRs). The expression levels of some ovary-biased genes in the IOTTRs were significantly higher than in the control testes but lower than in the control ovaries. These results show that low concentrations of DHT induced complete or incomplete female-to-male sex reversal in P. nigromaculatus, and incomplete sex reversal retained certain ovarian characteristics not only at gonadal morphological and histological levels but also at the molecular level. They present study highlights potential risks of DHT and other androgenic EDCs for P. nigromaculatus. PMID- 26226838 TI - RADIOGRAPHIC AND ANATOMIC CHARACTERISTICS OF DORSAL HOOF WALL LAYERS IN NONLAMINITIC HORSES. AB - Early radiographic diagnosis of acute laminitis is important for treatment planning and prognosis in horses. While four histopathologic layers make up the hoof wall, only two layers are distinguished on digital radiographs of horses' hooves. Objectives of this descriptive study were to determine which macroscopic layers correspond to the two radiographically visible layers, and to describe radiographic layer measurements in a group of clinically sound Warmblood horses. Twelve ex vivo equine hooves were examined at three different levels of the dorsal hoof wall. The four macroscopic layers were variably grouped and compared with radiographic layers. Stratum externum and stratum medium represented the superficial radiographic layer while stratum internum and dermis parietis represented the deep layer. In 27 clinically sound horses (54 thoracic feet), the superficial radiographic layer represented 64.3% +/- 3.6% of the total dorsal hoof wall. Findings from this study provided baseline information for future studies of horses with acute laminitis. PMID- 26226839 TI - Class II Analphoid Chromosome in a Child with Aberrant Chromosome 7: A Rare Cytogenetic Association. AB - A neocentromere is a functional centromere that has arisen within a region not known to have a centromere. We present a case with a very rarely reported class II neocentromere formation in an aberrant chromosome 7. A 22-month-old male was referred because of dysmorphic features. Banding cytogenetics was performed, and a ring 7 and a supernumerary marker chromosome along with a normal chromosome 7 were found. In situ hybridization using a centromeric probe revealed 46 signals, of which 2 signals for chromosome 7 were observed, one on the normal and one on the ring chromosome. Further analysis using FISH revealed that the linear acentric fragment was part of the 7q region, which suggests that there could be a possible McClintock mechanism. PMID- 26226840 TI - Using a Historical Lens to Envision the Next Generation of Genomic Translation Research. AB - BACKGROUND: The past 20 years have witnessed successive and exponential advances in genomic discovery and technology, with a broad scientific imperative pushing for continual advancements. The most consistent critique of these advances is that they have vastly outpaced translation of new knowledge into improvements in public health and medicine. METHODS: We employ a historical and epistemological analysis to characterize how prevailing scientific meta-narratives have shaped the pace and priorities of research applying genomics to health promotion. We use four 'pivotal events' - the genetic characterization of Down syndrome, the launch of the Human Genome Research Project, the discovery of BRCA1, and the emergence of direct-to- consumer genetic testing - to illustrate how these scientific meta narratives have inhibited genomic translation research. RESULTS: The notion that discovery should precede translation research has over-focused translation research on the latest genetic testing platform. The idea that genetic-related research has an exceptional potential for public harm has encouraged research on worst case scenarios. The perceived competition between genetics and social determinants of health has discouraged a unified research agenda to move genomic translation forward. CONCLUSION: We make a case for creating new scientific meta narratives in which discovery and translation research agendas are envisioned as an interdependent enterprise. PMID- 26226841 TI - Loss of expression of BAP1 is a useful adjunct, which strongly supports the diagnosis of mesothelioma in effusion cytology. AB - Although most mesotheliomas present with pleural effusions, it is controversial whether mesothelioma can be diagnosed with confidence in effusion cytology. Therefore, an ancillary marker of malignant mesothelial cells applicable in effusions would be clinically valuable. BRCA-1-associated protein (BAP1) is a tumor suppressor gene, which shows biallelic inactivation in approximately half of all mesotheliomas. We investigated whether loss of BAP1 expression by immunohistochemistry can be used to support a diagnosis of mesothelioma in effusion cytology. Immunohistochemistry for BAP1 was performed on cell blocks and interpreted blinded. 43 of 75 (57%) effusions associated with confirmed mesothelioma showed negative staining with positive internal controls. Of 57 effusions considered to have atypical mesothelial cells in the absence of a definitive diagnosis of mesothelioma, 8 cases demonstrated negative staining for BAP1. On follow-up six of these patients received a definitive diagnosis of mesothelioma in the subsequent 14 months (two were lost to follow-up immediately, and mesothelioma could not be excluded). Only 5 of 100 consecutive benign effusions were interpreted as BAP1 negative. One of these patients died soon after and mesothelioma could not be excluded. On unblinded review the four other patients with apparently negative BAP1 staining but no malignancy lacked convincing positive staining in non-neoplastic cells suggesting that BAP1 immunohistochemistry may have initially been misinterpreted. 47 effusions with adenocarcinoma were BAP1 positive. We conclude that loss of BAP1 expression, while not definitive, can be used to support the diagnosis of mesothelioma in effusion cytology. We caution that interpretation of BAP1 immunohistochemistry on cell block may be difficult and that convincing positive staining in non neoplastic cells is required before atypical cells are considered negative. We also note that BAP1 loss is not a sensitive test as it occurs in only half of all mesotheliomas and cannot be used to exclude the diagnosis. PMID- 26226842 TI - Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan. AB - Enteropathy-associated T-cell lymphoma (EATL) is a rare primary T-cell lymphoma of the digestive tract. EATL is classified as either Type I, which is frequently associated with and thought to arise from celiac disease and is primarily observed in Northern Europe, and Type II, which occurs de novo and is distributed all over the world with predominance in Asia. The pathogenesis of EATL in Asia is unknown. We aimed to clarify the histological and genomic profiles of EATL in Japan in a homogeneous series of 20 cases. The cases were characterized by immunohistochemistry, high-resolution oligonucleotide microarray, and fluorescence in situ hybridization (FISH) at five different loci: 1q21.3 (CKS1B), 6q16.3 (HACE1), 7p22.3 (MAFK), 9q33.3 (PPP6C), and 9q34.3 (ASS1, CARD9) using formalin-fixed paraffin-embedded sections. The histological appearance of EATL ranged from medium- to large-sized cells in 13 cases (65%), small- to medium sized cells in five cases (25%), and medium-sized in two cases (10%). The immunophenotype was CD2(+) (60%), CD3E(+) (100%), CD4(+) (10%), CD7(+) (95%), CD8(+) (80%), CD56(+) (85%), TIA-1(+) (100%), Granzyme B(+) (25%), T-cell receptor (TCR)beta(+) (10%), TCRgamma(+) (35%), TCRgammadelta(+) (50%), and double negative for TCR (six cases, 30%). All cases were EBER(-). The genomic profile showed recurrent copy number gains of 1q32.3, 4p15.1, 5q34, 7q34, 8p11.23, 9q22.31, 9q33.2, 9q34.13, and 12p13.31, and losses of 7p14.1. FISH showed 15 patients (75%) with a gain of 9q34.3 with good correlation with array comparative genomic hybridization. EATL in Japan is characterized by non monomorphic cells with a cytotoxic CD8(+) CD56(+) phenotype similar to EATL Type II. The genomic profile is comparable to EATL of Western countries, with more similarity to Type I (gain of 1q and 5q) rather than Type II (gain of 8q24, including MYC). The 9q34.3 gain was the most frequent change confirmed by FISH irrespective of the cell origin of alphabeta-T-cells and gammadelta-T-cells. PMID- 26226843 TI - Infiltrative (sinusoidal) and hepatitic patterns of injury in acute cellular rejection in liver allograft with clinical implications. AB - Acute cellular rejection post liver transplant occurs most commonly but not exclusively in the first year. In this study, we report two patterns: sinusoidal infiltrative and hepatitic, which are not considered in the Banff system. We describe their presentation, response to Solu-Medrol, and compare these to the typical moderate-severe acute cellular rejection. Patients transplanted from 2007 to 2012 at University Health Network, who had biopsy-proven rejection in the first year, were studied. Baseline transaminases and bilirubin, time of acute cellular rejection, follow-up, and treatment responses were analyzed. A total of 407 biopsies were received, of which 77 had diagnosis of acute cellular rejection with rejection activity index 5 or above; 49 from viral hepatitis patients were excluded. Twenty-eight were included; 15/28 (54%) had typical acute cellular rejection (tACR) using Banff criteria. Six (21%) had hepatitic acute cellular rejection overlapping with typical features of acute cellular rejection; seven (25%) had infiltrative acute cellular rejection (iACR) overlapping with typical features. The iACR occurred later than the tACR (124 versus 50 days; P = 0.032) and had a higher rise in baseline aspartate aminotransferase (DeltaAST) compared with tACR (289 U/l versus 109 U/l; P=0.046). Only one out of seven patients with iACR (14 versus 40% in tACR) failed Solu-Medrol boluses and required thymoglobulin. Patients with hepatitic acute cellular rejection (hACR) had similar DeltaAST (P = 0.12) but higher bilirubinemia than typical acute cellular rejection (tACR) (160 MUmol/l versus 35 mol/l; P = 0.039) and required thymoglobulin in four out of six (67% versus 40%) instances. Patients with iACR had higher DeltaAST than tACR but better Solu-Medrol response compared with both tACR and hACR. hACR is different from plasma cell-rich late-occurring cellular rejection in its pattern but similar in its poor Solu-Medrol response. PMID- 26226844 TI - NAB2-STAT6 fusion types account for clinicopathological variations in solitary fibrous tumors. AB - Solitary fibrous tumor (SFT) is characterized by the inv12(q13q13)-derived NAB2 STAT6 fusion, which exhibits variable breakpoints and drives STAT6 nuclear expression. The implications of NAB2-STAT6 fusion variants in pathological features and clinical behavior remain to be characterized in a large cohort of SFTs. We investigated the clinicopathological correlates of this genetic hallmark and analyzed STAT6 immunoexpression in 28 intrathoracic, 37 extrathoracic, and 23 meningeal SFTs. These 88 tumors were designated as histologically nonmalignant in 75 cases and malignant in 13, including 1 dedifferentiated SFT. Eighty cases had formalin-fixed and/or fresh samples to extract assessable RNAs for RT-PCR assay, which revealed NAB2-STAT6 fusion variants comprising 12 types of junction breakpoints in 73 fusion-positive cases, with 65 (89%) falling into 3 major types. The predominant NAB2ex4-STAT6ex2 (n=33) showed constant breakpoints at the ends of involved exons, whereas the NAB2ex6-STAT6ex16 (n=16) and NAB2ex6 STAT6ex17 (n=16) might exhibit variable breakpoints and incorporate NAB2 or STAT6 intronic sequence. Including 73 fusion-positive and 7 CD34-negative SFTs, STAT6 distinctively labeled 87 (99%) SFTs in nuclei, exhibited diffuse reactivity in 73, but did not decorate 98 mimics tested. In seven fusion-negative cases, 6 were STAT6-positive, suggesting rare fusion variants not covered by RT-PCR assay. Regardless of histological subtypes, intrathoracic SFTs affected older patients (P=0.035) and tended to be larger in size (P=0.073). Compared with other variants, NAB2ex4-STAT6ex2/4 fusions were significantly predominant in the SFTs characterised by intrathoracic location (P<0.001), older age (P=0.005), decreased mitoses (P=0.0028), and multifocal or diffuse STAT6 staining (P=0.013), but not found to correlate with disease-free survival. Conclusively, STAT6 nuclear expression was distinctive in the vast majority of SFTs, including all fusion positive tumors, and exploitable as a robust diagnostics of CD34-negative cases. Despite the associations of NAB2-STAT6 fusion variants with several clincopathological factors, their prognostic relevance should be further validated in large-scale prospective studies of SFTs. PMID- 26226845 TI - Distinct methylation profiles characterize fusion-positive and fusion-negative rhabdomyosarcoma. AB - Rhabdomyosarcoma comprises two major subtypes, fusion positive (PAX3-FOXO1 or PAX7-FOXO1) and fusion negative. To investigate the significance of DNA methylation in these subtypes, we analyzed methylation profiles of 37 rhabdomyosarcoma tumors and 10 rhabdomyosarcoma cell lines, as well as 8 normal tissues. Unsupervised clustering of DNA methylation clearly distinguished the fusion-positive and fusion-negative subsets. The fusion-positive tumors showed substantially lower overall levels of methylation compared with fusion-negative tumors. Comparison with the methylation pattern of normal skeletal muscle and bone marrow indicates that fusion-negative rhabdomyosarcoma is more similar to these normal tissues compared with fusion-positive rhabdomyosarcoma, and suggests that many of the methylation differences between these subtypes arise from 'aberrant' hyper- and hypomethylation events in fusion-positive rhabdomyosarcoma. Integrative methylation and gene expression analysis revealed that methylation differences between fusion-positive and fusion-negative tumors could either be positively or negatively associated with mRNA expression. There was no significant difference in the distribution of PAX3-FOXO1-binding sites between genes with and without differential methylation. However, the finding that PAX3 FOXO1-binding sites were enriched among genes that were both differentially methylated and differentially expressed suggests that the fusion protein interacts with DNA methylation to regulate target gene expression. An 11-gene DNA methylation signature, classifying the rhabdomyosarcoma tumors into fusion positive and fusion-negative subsets, was established and validated by pyrosequencing assays. Notably, EMILIN1 (part of the 11-gene signature) showed higher methylation and lower mRNA expression in fusion-positive compared with fusion-negative tumors, and demonstrated demethylation and re-expression in multiple fusion-positive cell lines after treatment with 5-aza-2'-deoxycytidine. In conclusion, our study demonstrates that fusion-positive and fusion-negative rhabdomyosarcoma tumors possess characteristic methylation profiles that contribute to the expression differences between these fusion subtypes. These findings indicate an important relationship between fusion status and epigenetic changes in rhabdomyosarcoma, present a novel approach for ascertaining fusion status, and may identify new therapeutic targets in rhabdomyosarcoma. PMID- 26226846 TI - Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma. AB - Deficiencies in DNA mismatch repair have been associated with inferior response to 5-FU in colorectal cancer. Pancreatic ductal adenocarcinoma is similarly treated with pyrimidine analogs, yet the predictive value of mismatch repair status for response to these agents has not been examined in this malignancy. A tissue microarray with associated clinical outcome, comprising 254 resected pancreatic ductal adenocarcinoma patients was stained for four mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2). Mismatch repair deficiency and proficiency was determined by the absence or presence of uniform nuclear staining in tumor cells, respectively. Cases identified as mismatch repair deficient on the tissue microarray were confirmed by immunohistochemistry on whole slide sections. Of the 265 cases, 78 (29%) received adjuvant treatment with a pyrimidine analog and 41 (15%) showed a mismatch repair-deficient immunoprofile. Multivariable disease specific survival in the mismatch repair-proficient cohort demonstrated that adjuvant chemotherapy, regional lymph-node status, gender, and the presence of tumor budding were significant independent prognostic variables (P<=0.04); however, none of the eight clinico-pathologic covariates examined in the mismatch repair-deficient cohort were of independent prognostic significance. Univariable assessment of disease-specific survival revealed an almost identical survival profile for both treated and untreated patients with a mismatch repair-deficient profile, while treatment in the mismatch repair-proficient cohort conferred a greater than 10-month median disease-specific survival advantage over their untreated counterparts (P=0.0018). In this cohort, adjuvant chemotherapy with a pyrimidine analog conferred no survival advantage to mismatch repair-deficient pancreatic ductal adenocarcinoma patients. Mismatch repair immunoprofiling is a feasible predictive marker in pancreatic ductal adenocarcinoma patients, and further prospective evaluation of this finding is warranted. PMID- 26226848 TI - Synthetic Cannabinoids and Cathinones: Prevalence and Markets. AB - Over the past few years, the phenomenon of new designer drugs has attracted much attention. Synthetic cannabinoids and cathinones are the two main classes of these drugs. Both are potent drugs of abuse, and several cases of severe toxicity and deaths are reported. The present work is based on a systematic review of studies that have assessed the market and prevalence of synthetic cannabinoids and cathinones, and integrates pharmacological, sociological, and epidemiological aspects of these two groups of emerging synthetic drugs. The review reflects that the Internet has made synthetic cannabinoids and cathinones widely available. Furthermore, aggressive and widespread marketing, as well as the low price level of these drugs, their juridical status and their lack of detection on standard drug tests may serve as major motivations for drug use. The number of prevalence studies is small and derived from a limited number of countries. In spite of the many methodological shortcomings, some conclusions may be cautiously drawn. Taken together, the results point toward higher prevalence of use for synthetic cathinones than for synthetic cannabinoids. In the general population, the prevalence of use of synthetic cathinones is reported to be around 4% compared to figures lower than 1% for synthetic cannabinoids. Among students, the prevalence varies from 1-20% for synthetic cathinones and 2-10% for synthetic cannabinoids. Among groups with high rates of drug use, the prevalence varies between 4% to more than 60% for synthetic cathinones and around 10% for synthetic cannabinoids. PMID- 26226849 TI - Analysis of Synthetic Cannabinoids in Botanical Material: A Review of Analytical Methods and Findings. AB - Synthetic cannabinoid analogs have gained a great deal of attention from the forensic community within the last four years. The compounds found to be of most interest to forensic practitioners include those of the following series: JWH, CP, HU, AM, WIN, RCS, and most recently, XLR and UR. Structurally the HU compounds are most similar in structure to Delta9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana. The novel compounds include cyclohexylphenols, naphthoylindoles, naphthylmethylindoles, naphthylmethylindenes, benzoylindoles, naphthoylpyrroles, phenylacetylindoles, adamantoylindoles, and tetramethylcyclopropylindoles. Many of these compounds are cannabinoid receptor agonists and were originally synthesized for medical research purposes but have recently been appropriated into the illicit drug market. Their psychoactive effects, mimicking those of marijuana, as well as their indeterminate legal status, have made them popular for recreational use. Solutions of the compounds dissolved in organic solvents are sprayed onto botanical material and sold as "herbal incense" products via the Internet, and in smoke shops, convenience stores, and gas stations around the world. Many of the products are labeled "Not for human consumption" in an attempt to circumvent legislation that bans the sale and manufacture of certain compounds and their analogs for human use. The compounds that were first detected following forensic analysis of botanical materials included JWH-018, JWH-073, and CP 47,497 (C7 and C8 homologs). However, in the four years since their appearance the number of compounds has grown, and additional diverse classes of compounds have been detected. Governments worldwide have taken action in an attempt to control those compounds that have become widespread in their regions. This article discusses the history of synthetic cannabinoids and how they have been detected in the illicit drug market. It also discusses the analytical methods and techniques used by forensic scientists to analyze botanical products obtained via the Internet or from law enforcement investigations and arrests. PMID- 26226847 TI - Performance characteristics of next-generation sequencing in clinical mutation detection of colorectal cancers. AB - Activating mutations in downstream genes of the epidermal growth factor receptor (EGFR) pathway may cause anti-EGFR resistance in patients with colorectal cancers. We present performance characteristics of a next-generation sequencing assay designed to detect such mutations. In this retrospective quality assessment study, we analyzed mutation detected in the KRAS, NRAS, BRAF, and PIK3CA genes by a clinically validated next-generation sequencing assay in 310 colorectal cancer specimens. Tumor cellularity and mutant allele frequency were analyzed to identify tumor heterogeneity and mutant allele-specific imbalance. Next generation sequencing showed precise measurement of mutant allele frequencies and detected 23% of mutations with 2-20% mutant allele frequencies. Of the KRAS mutations detected, 17% were outside of codons 12 and 13. Among PIK3CA mutations, 48% were outside of codons 542, 545, and 1047. The percentage of tumors with predicted resistance to anti-EGFR therapy increased from 40% when testing for only mutations in KRAS exon 2 to 47% when testing for KRAS exons 2-4, 48% when testing for KRAS and NRAS exons 2-4, 58% when including BRAF codon 600 mutations, and 59% when adding PIK3CA exon 20 mutations. Right-sided colorectal cancers carried a higher risk of predicted anti-EGFR resistance. A concomitant KRAS mutation was detected in 51% of PIK3CA, 23% of NRAS, and 33% of kinase-impaired BRAF-mutated tumors. Lower than expected mutant allele frequency indicated tumor heterogeneity, while higher than expected mutant allele frequency indicated mutant allele-specific imbalance. Two paired neuroendocrine carcinomas and adjacent adenomas showed identical KRAS mutations, but only PIK3CA mutations in neuroendocrine carcinomas. Next-generation sequencing is a robust tool for mutation detection in clinical laboratories. It demonstrates high analytic sensitivity and broad reportable range, and it provides simultaneous detection of concomitant mutations and a quantitative measurement of mutant allele frequencies to predict tumor heterogeneity and mutant allele-specific imbalance. PMID- 26226850 TI - Forensic Analysis of Cathinones. AB - In the past decade there has been a significant increase in the popularity of synthetic cathinones in the illegal drug market. They have been easily available from Internet-based vendors as well as at "head shops" and "smart shops". The recent prominence of synthetic cathinones can be attributed to their stimulatory properties similar to those of amphetamines. This paper provides a review on the current popular cathinone derivatives, their history and prevalence in the illegal drug market, legislation of these drugs in various countries, pharmacology, toxicology, and metabolism studies, analysis of toxicology samples (blood, urine, and hair) and criminalistic samples (seized, purchased via the Internet, and synthesized). From the reviewed literature, it is concluded that the products sold as "legal highs" do not only contain cathinone but also cathinone derivatives, and adulterants such as caffeine, lidocaine, and inorganic materials. Full toxicity data is currently unavailable for this drug class and hence more research is required with regard to their analysis and metabolism. Moreover, clandestine chemists are constantly synthesizing new derivatives and hence forensic chemists often need to synthesize and characterize these drugs to confirm the identity of the seized samples. This is expensive as well as time consuming. Therefore, there is a need for national and international collaboration among forensic chemists to overcome this difficulty. PMID- 26226851 TI - Matrix Effects in the Liquid Chromatography-Tandem Mass Spectrometry Method of Analysis. AB - Matrix effects are dependent on biological fluid, ionization type, and sample preparation method. Although matrix effects are observed for both ionization types, ESI is especially susceptible, while APCI has proved to be less vulnerable. Sample preparation method has a clear influence on matrix effects as does, in particular, the choice of internal standard. When matrix effects result in severe ion suppression or enhancement of the target analyte by co-eluting residual components, they are typically located in isolated regions of the chromatogram. Postcolumn infusion and postextraction addition methods have been developed for the assessments of matrix effects. Approaches used for eliminating, minimizing, or compensating for matrix effects include improved sample preparation and chromatographic separation, sample dilution, and the utilization of internal standards. Matrix effects may not always be fully circumventable because a perfectly consistent matrix does not exist, but they can be significantly minimized and largely compensated for by various approaches, such as standard addition, matrixmatched calibration, and the use of isotopic analogs of the analytes as internal standards. PMID- 26226852 TI - Deep-Sequencing Technologies and Potential Applications in Forensic DNA Testing. AB - Development of second- and third-generation DNA sequencing technologies have enabled an increasing number of applications in different areas such as molecular diagnostics, gene therapy, monitoring food and pharmaceutical products, biosecurity, and forensics. These technologies are based on different biochemical principles such as monitoring released pyrophosphate upon incorporation of a base (pyrosequencing), fluorescence detection subsequent to reversible incorporation of a fluorescently labeled terminator base, ligation based approach wherein fluorescence of cleaved nucleotide after ligation is measured, measuring the proton released after incorporation of a base (semiconductor-based sequencing), monitoring incorporation of a nucleotide by measuring the fluorescence of the fluorophore attached to the phosphate chain of the nucleotide, and by detecting the altered charge in a protein nanopore due to released nucleotide by exonuclease cleavage of a DNA strand. Analysis of multiple DNA fragments in parallel increases the depth of coverage while decreasing labor, cost, and time, highlighting some major advantages of deep-sequencing technologies. DNA sequencing has been routinely used in the forensic laboratories for mitochondrial DNA analysis. Fragment analysis, however, is the preferred method for Short Tandem Repeat genotyping due to the cumbersome and costly nature of fi rst generation DNA sequencing methodologies. Deep-sequencing technologies have brought a new perspective to forensic DNA analysis. Studies include STR analysis to reveal hidden variation in the repeat regions, mtDNA sequencing, Single Nucleotide Polymorphism analysis, mixture resolution, and body fluid identification. Recent publications reveal that attempts are being made to expand the capability. PMID- 26226853 TI - Inferential Source Attribution from Dust: Review and Analysis. AB - The analysis of dust allows inference of exposures to geographical areas, environments, activities, and processes. This activity of inferential source attribution is distinguished from that of comparative source attribution, where the focus is on the degree of correspondence between two sources in relation to other possible sources. Review of source attribution efforts in the forensic and broader scientific literature shows that most efforts are limited in one or more of four principal ways, which are classified as: (a) methods based on attribution by direct comparison; (b) methods based on closed-set item classification; (c) analysis using restricted methods and characteristics, and (d) requirement of a large sample size. These limitations provide the context for the requirements of more generalized inferential source attribution. Occurring much more rarely, and almost exclusively in the forensic literature, are individual source attribution case reports that have a microscopical, multidisciplinary perspective. Collectively these are an excellent illustration of potential and their common features demonstrate that (a) a diversity of laboratory expertise and methodology is required in order for source attribution to be successful; (b) different tools need to be applied in different cases, and (c) a process must be in place that allows a facile choice among this diversity of tools, in response to the particular investigative problem and the specifics of the samples that are available. Alternative collaborative mechanisms are considered and recommendations are made for related research and programmatic application. PMID- 26226855 TI - National survey of emergency physicians for transient ischemic attack (TIA) risk stratification consensus and appropriate treatment for a given level of risk. AB - INTRODUCTION: Five percent of transient ischemic attack (TIA) patients have a subsequent stroke within 7 days. The Canadian TIA Score uses clinical findings to calculate the subsequent stroke risk within 7 days. Our objectives were to assess 1) anticipated use; 2) component face validity; 3) risk strata for stroke within 7 days; and 4) actions required, for a given risk for subsequent stroke. METHODS: After a rigorous development process, a survey questionnaire was administered to a random sample of 300 emergency physicians selected from those registered in a national medical directory. The surveys were distributed using a modified Dillman technique. RESULTS: From a total of 271 eligible surveys, we received 131 (48.3%) completed surveys; 96.2% of emergency physicians would use a validated Canadian TIA Score; 8 of 13 components comprising the Canadian TIA Score were rated as Very Important or Important by survey respondents. Risk categories for subsequent stroke were defined as minimal-risk: 10% risk of subsequent stroke within 7 days. CONCLUSION: A validated Canadian TIA Score will likely be used by emergency physicians. Most components of the TIA Score have high face validity. Risk strata are definable, which may allow physicians to determine immediate actions, based on subsequent stroke risk, in the emergency department. PMID- 26226854 TI - Ultrafast initiation of a neural race by impending errors. AB - KEY POINTS: The brain makes decisions by means of races between neural units representing alternative choices. In the present study, we record the eyemovements made in the Wheeless task, when a visual stimulus is followed after a short delay by another stimulus demanding a different response. The behaviour can be very precisely described as a race between three independent decision processes: one Go process for each of the responses, and a Stop process that tries to cancel the first, now erroneous, response. To explain the high success rate for cancellation that we observe, the onset time for the Stop process must be some 10-20 ms shorter than for Go. As well as extending our understanding of the dynamics of complex decision-making, this task provides a rapid, non-invasive method for quantifying disorders of higher neural function. ABSTRACT: The brain makes decisions by means of races between neural units representing alternative choices, and such models can predict behaviour in decision tasks in a precisely quantitative way. But what is less clear is how soon after the stimulus the race actually starts. In the present study, we re-visit a complex decision experiment: the Wheeless task, in which a saccadic stimulus is followed after a short delay by a second stimulus, with the subject sometimes making a saccade to the first, now inappropriate, stimulus, and sometimes going straight to the correct one. We demonstrate that a simple model with three accumulator units, two 'Go' and one 'Stop', can then account in detail for the individual responses made, as well as their timing. This complex decision-making behaviour is predicted directly for each individual subject by their performance in a simple step saccadic task, which identifies the two free parameters that are specific for each subject. By contrast to previous assumptions, we find that it is necessary for the onset time of the Stop unit to be shorter than for Go by 10-20 ms. This suggests a specifically fast mechanism for altering responses in situations where urgent action is needed to prevent an impending error. PMID- 26226856 TI - Centrifugation stress reduces the responsiveness of spermatozoa to a capacitation stimulus in in vitro-aged semen. AB - Density gradient centrifugation of semen is commonly used in many assisted reproduction techniques. Although gradients have the potential to isolate and enrich motile and viable spermatozoa, the centrifugation force presents a stress factor to cell organelles and membranes. The objective of the study was to evaluate the impact of density gradient centrifugation stress on sperm capacitation dynamics, cell stability and the ability of spermatozoa to specifically respond to bicarbonate in extended semen undergoing in vitro ageing. Extended boar semen (n = 7) was stored for 12, 24, 72 and 120 h respectively at 17 degrees C before centrifugation and incubation in variations of an in vitro capacitation medium. The number of viable, acrosome intact sperm and motility parameters as assessed by computer-assisted semen analysis did not change during storage. Kinetic changes in viability (plasma membrane integrity) and intracellular calcium levels (calcium influx) during in vitro capacitation were assessed after preparation of semen samples with both, a Percoll and a sucrose gradient centrifugation, either only Percoll, only sucrose centrifugation or no centrifugation. Changes in the viable sperm population that could be specifically attributed as a response to either bicarbonate or calcium were determined. In in vitro-aged (>12 h stored) spermatozoa, centrifugation reduced the proportion of spermatozoa which specifically responded to the capacitating stimulus bicarbonate. Concomitantly, centrifugation increased the proportion of spermatozoa responding to calcium in absence of bicarbonate, thus indicating an increased sensitivity to incubation per se. Absence of centrifugation steps during semen preparation, revealed a highly conserved ability of in vitro-aged spermatozoa to specifically respond to bicarbonate. In conclusion, density gradient centrifugation alters the physiological property of spermatozoa for controlled capacitation, which may influence the success rates of centrifuged semen in assisted reproductive technologies and confound interpretation of capacitation assays. PMID- 26226857 TI - Varicocele treatment in paediatric age: relationship between type of vein reflux, surgical technique used and outcomes. AB - Varicocele is the first andrological disease in adolescent males. The aim of this study was to report our experience with different techniques. We retrospectively analysed patients treated between January 2005 and January 2011. Inclusion criteria for the study were created. Patients were treated with different techniques based on the type of spermatic vein reflux detected on Doppler velocimetry. The following rates were considered as study endpoints: hydrocele rate, rate of relapses, rate of persistence and rate of testicular atrophy. During the study period, 522 surgical varicocelectomies were performed. Patients were treated with videolaparoscopy, open inguinal technique, subinguinal technique and one-trocar transumbilical technique. The laparoscopic and the subinguinal techniques showed a lower rate of hydrocele, and the laparoscopic technique had a lower rate of relapses. Choosing a technique based on the type of spermatic vein reflux can reduce the post-operative complications. The laparoscopic techniques had a lower rate of relapses with respect to other techniques. PMID- 26226858 TI - The effect of statins on the occurrence of peptic ulcer. AB - BACKGROUND: This study was to determine the association between the use of statins and the occurrence of peptic ulcer diseases (PUD). METHODS: Using the National Health Insurance Research Database to conduct a population-based cohort study. We identified 48,562 patients who were newly diagnosed with hyperlipidemia during the period of 1998 to 2011 and who were divided into two groups based on their use of statins. The non-statin cohort (without statin treatment, 24,139 patients) were 1:1 frequency matched with sex, age, year of diagnosis of hyperlipidemia and index-year to the statin cohort (24,423 patients). The relative risk of patients with and without statins treatment on the occurrence of PUD and concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin were analyzed using the univariable and multivariable Cox proportional hazards regression model. RESULTS: The incidence of PUD increased with age in both cohorts and female had a higher occurrence rate than male in both cohorts. Compared with the non-statin cohort, the statin cohort was associated with a significant lower risk of PUD for all age group. The concomitant use of aspirin and/or NSAIDs had higher incidence of PUD than those without in both cohorts. Analyzing the cumulative defined daily dose (DDD) of statins indicated that high dose groups (? 575 DDD) exhibited significantly decreased risk compared with non statin users. CONCLUSION: The results of the present study indicated that statins might be associated with the protection of peptic ulcer in a dose-respondent manner. PMID- 26226859 TI - Problems of older persons using a wheeled walker. AB - BACKGROUND: Wheeled walkers (WWs) are used to improve mobility and for fall prevention in older persons, but not all users are satisfied with the usability of WWs. Intelligent WWs are being developed to improve the usability. AIMS: The aim of this study was to support the development of intelligent WWs by investigating possible problems of using a WW. METHODS: This study investigated 22 geriatric in-patients (median age 82 years) with and without their WW while opening a door against the direction of walking and passing through. Other possible problems when using WWs were identified by interview. RESULTS: Walking through the door was faster without than with using the WW (8.71 versus 12.86 s, p < 0.001), while interference between door and WW was documented in 41 of 44 (93 %) cases. Backward walking performance was better when using a WW with regard to gait speed, step width and walk ratio (all p < 0.002). Most referred problems when using a WW were walking downhill (83 %) and uphill (77 %) and obstacle crossing in general (77 %). CONCLUSIONS: Problems with opening a door against the direction of walking and the optimization of downhill and uphill walking as well as obstacle crossing should be regarded when developing an intelligent WW. PMID- 26226860 TI - Femoral cortical index: an indicator of poor bone quality in patient with hip fracture. AB - BACKGROUND: Osteoporosis is a common disease in elderly, characterized by poor bone quality as a result of alterations affecting trabecular bone. However, recent studies have described also an important role of alterations of cortical bone in the physiopathology of osteoporosis. Although dual-energy X-ray absorptiometry (DXA) is a valid method to assess bone mineral density, in the presence of comorbidities real bone fragility is unable to be evaluated. The number of hip fractures is rising, especially in people over 85 years old. AIMS: The aim is to evaluate an alternative method so that it can indicate fracture risk, independent of bone mineral density (BMD). Femoral cortical index (FCI) assesses cortical bone stock using femur X-ray. METHODS: A retrospective study has been conducted on 152 patients with hip fragility fractures. FCI has been calculated on fractured femur and on the opposite side. The presence of comorbidities, osteoporosis risk factors, vitamin D levels, and BMD have been analyzed for each patient. RESULTS: Average values of FCI have been 0.42 for fractured femurs and 0.48 at the opposite side with a statistically significant difference (p = 0.002). Patients with severe hypovitaminosis D had a minor FCI compared to those with moderate deficiency (0.41 vs. 0.46, p < 0.011). 42 patients (27.6%) with osteopenic or normal BMD have presented low values of FCI. DISCUSSION AND CONCLUSION: A significant correlation among low values of FCI, comorbidities, severe hypovitaminosis D. and BMD in patients with hip fractures has been found. FCI could be a useful tool to evaluate bone fragility and to predict fracture risk even in the normal and osteopenic BMD patients. PMID- 26226861 TI - Cardiovascular Catastrophes in the Obstetric Population. AB - Pregnancy is a complex and dynamic physiologic state, in which the needs of the mother and fetus must achieve a fine balance with one another. Some of the most dreaded and deadly complications that can arise during this period affect the cardiovascular system are hypertensive emergencies (including preeclampsia and eclampsia), acute coronary syndrome, peripartum cardiomyopathy, dysrhythmias, dissection, thromboembolism, and cardiac arrest. This review provides emergency physicians, obstetricians, intensivists, and other health care providers with the most recent information on the diagnosis and management of these deadly cardiovascular complications of pregnancy. PMID- 26226862 TI - The Critically Ill Infant with Congenital Heart Disease. AB - This article presents an approach for identification of infants with congenital heart disorders. These disorders are difficult to diagnose because of the complexity and variety of cardiac malformations; additionally presentation can be complicated by age-dependent physiology. By compiling data from the history and the physical examination, the emergency physician can identify lesion category and initiate stabilization procedures. Critical congenital cardiac lesions can be classified as left-sided obstructive ductal dependent, right-sided obstructive ductal dependent, and shunting or mixing. The simplified approach categorizes infants with these lesions respectively as "pink," "blue," or "gray." The emergency provider can provide life-saving stabilization until specialized care can be obtained. PMID- 26226863 TI - Blunt Cardiac Injury. AB - Blunt cardiac injury encompasses multiple different injuries, including contusion, chamber rupture, and acute valvular disorders. Blunt cardiac injury is common and may cause significant morbidity and mortality; a high index of suspicion is needed for accurate diagnosis. Diagnostic work-up should always include electrocardiogram and cardiac enzymes, and may include echocardiography if specific disorders (ie, tamponade or valvular disorders) are suspected. Patients with myocardial contusion should be observed for 24 to 48 hours for arrhythmias. Many other significant forms of blunt cardiac injury require surgical intervention. PMID- 26226864 TI - Chameleons: Electrocardiogram Imitators of ST-Segment Elevation Myocardial Infarction. AB - The imperative for timely reperfusion therapy for patients presenting with ST segment elevation myocardial infarction (STEMI) underscores the need for clinicians to have an understanding of how to distinguish patterns of STEMI from its imitators. These imitating diagnoses may confound an evaluation, potentially delaying necessary therapy. Although numerous diagnoses may mimic STEMI, several morphologic clues may allow the physician to determine if the pattern is concerning for either STEMI or a mimicking diagnosis. Furthermore, obtaining a satisfactory history, comparing previous electrocardiograms, and assessing serial tests may provide valuable clues. PMID- 26226865 TI - Hypertensive Emergencies in the Emergency Department. AB - Hypertension affects approximately one-third of Americans. An additional 30% are unaware that they harbor the disease. Significantly increased blood pressure constitutes a hypertensive emergency that could lead to end-organ damage. When organs such as the brain, heart, or kidney are affected, an intervention that will lower the blood pressure in several hours is indicated. Several pharmacologic options are available for treatment, with intravenous antihypertensive therapy being the cornerstone, but there is no standard of care. Careful consideration of each patient's specific complaint, history, and physical examination guides the emergency physician through the treatment algorithm. PMID- 26226866 TI - Congestive Heart Failure. AB - Patients with acute decompensated heart failure are usually critically ill and require immediate treatment. However, most are not volume overloaded. Emergency department (ED) management is based on rapid initiation of noninvasive positive pressure ventilation and aggressive titration of nitrates. Afterload reduction with an angiotensin-converting enzyme inhibitor can be considered. A diuretic should not be administered before optimal preload and afterload reduction has been achieved. Short-term inotropic therapy can be considered in select patients with cardiogenic shock and acute decompensated heart failure (ADHF) who fail to respond to standard therapy. PMID- 26226867 TI - Cardiotoxicodynamics: Toxicity of Cardiovascular Xenobiotics. AB - Maintaining adequate tissue perfusion depends on a variety of factors, all of which can be influenced by xenobiotics (substances foreign to the body, including pharmaceuticals, chemicals, and natural compounds). Volume status, systemic vascular resistance, myocardial contractility, and cardiac rhythm all play a significant role in ensuring hemodynamic stability and proper cardiovascular function. Direct effects on the nervous system, the vasculature, or the heart itself as well as indirect metabolic effects may play a significant role in the development of cardiotoxicity. This article is dedicated to discussion of the disruption of cardiovascular physiology by xenobiotics. PMID- 26226868 TI - Atrial Fibrillation. AB - Atrial fibrillation (AF) is a supraventricular tachyarrhythmia that results from the chaotic depolarization of atrial tissue. AF is the most common sustained cardiac dysrhythmia and the most common dysrhythmia diagnosed in US emergency departments. All patients with AF must have their cardioembolic risk assessed, even if sinus rhythm is restored. Novel oral anticoagulants may be considered instead of vitamin K antagonists for anticoagulation in patients with nonvalvular AF. PMID- 26226869 TI - Human Immunodeficiency Virus Infection-Related Heart Disease. AB - Human immunodeficiency virus (HIV) infection and antiretroviral medications are independent risk factors for cardiovascular disease. In the pre-antiretroviral therapy (ART) era, HIV-infected patients had increased morbidity and mortality from opportunistic infections; in the post-ART era, these patients are at increased risk of chronic diseases such as acute coronary syndrome, coronary artery disease, cardiac arrhythmias, and cardiomyopathy. They may present with vague symptoms such as weakness, dyspnea, or fatigue as the initial presentation of their cardiovascular disease. An overview of the clinical presentation, workup, management, and treatment of different cardiovascular disease is provided in this article. PMID- 26226870 TI - Management of Crashing Patients with Pulmonary Hypertension. AB - Critically ill patients with pulmonary hypertension (PH) often seem well, but they can decompensate dramatically in a short time. PH has several causes, classes, and complications; but the natural progression eventually leads to right ventricular failure, which can be extraordinarily difficult to manage. The purpose of this review is to discuss the causes, signs, and symptoms of PH as well as its management strategies and emergent complications. Treatment options are often limited, so it is imperative that the emergency department physician can recognize and manage these patients in a timely fashion. PMID- 26226871 TI - Cardiogenic Shock. AB - Cardiogenic shock is the leading cause of morbidity and mortality in patients presenting with acute coronary syndrome. Although early reperfusion strategies are essential to the management of these critically ill patients, additional treatment plans are often needed to stabilize and treat the patient before reperfusion may be possible. This article discusses pharmacologic and surgical interventions, their indications and contraindications, management strategies, and treatment algorithms. PMID- 26226872 TI - Emergency Care of Patients with Pacemakers and Defibrillators. AB - Devices such as pacemakers and implantable cardioverter-defibrillators (ICDs) are commonly inserted to treat unstable cardiac rhythm disturbances. Despite the benefits of these devices on mortality and morbidity rates, patients often present to the emergency department with complaints related to device insertion or malfunction. Emergency physicians must be able to rapidly identify potential life threats caused by pacemaker malfunction, ICD firing, and complications associated with implantation of the devices. PMID- 26226873 TI - Cardiac Arrest Resuscitation. AB - Cardiac arrest is a dynamic disease that tests the multitasking and leadership abilities of emergency physicians. Providers must simultaneously manage the logistics of resuscitation while searching for the cause of cardiac arrest. The astute clinician will also realize that he or she is orchestrating only one portion of a larger series of events, each of which directly affects patient outcomes. Resuscitation science is rapidly evolving, and emergency providers must be familiar with the latest evidence and controversies surrounding resuscitative techniques. This article reviews evidence, discusses controversies, and offers strategies to provide quality cardiac arrest resuscitation. PMID- 26226875 TI - Matters of the Heart. PMID- 26226874 TI - Postcardiac Arrest Management. AB - Cardiac arrest afflicts more than 300,000 persons annually in North America alone. Advances in systematic, regimented postresuscitation care have lowered mortality and improved neurologic outcomes in select cohorts of patients over the last decade. Postcardiac arrest care now comprises its own link in the chain of survival. For most patients, high-quality postcardiac arrest care begins in the Emergency Department. This article reviews the evidence and offers treatment strategies for the key components of postcardiac arrest care. PMID- 26226876 TI - Matters of the Heart. PMID- 26226877 TI - Association between Pap smear screening and job stress in Taiwanese nurses. AB - PURPOSE: Nursing is a professional job characterized by high stress. Stress could be associated with less practice of health promoting behaviors; however, no study has investigated the relationship between job stress and health screening behaviors among nurses. This study aimed to describe the rate of Pap smears in hospital nurses and examine the effects of job stress on receiving a Pap smear. METHODS: This study was a cross-sectional survey. The study participants were 30,681 full-time female nurses who were at least 30 years of age working in 100 hospitals across Taiwan. The study participants filled out an anonymous structured questionnaire from May to July, 2011. The outcome variable was having a Pap test during the previous 3 years. The level of stress was measured by a 19 item scale, with higher scores indicating higher stress levels. RESULTS: About 62.4% of the nurses had a Pap smear during the previous three years. Each point increase in the stress score decreased the likelihood of Pap smears (OR = .997, 95% CI: .995-.999), after adjustment for participant characteristics, health status, health behaviors, and hospital characteristics. CONCLUSION: Despite more knowledge and higher accessibility, nurses were less likely to have Pap smear screening than the general population. A higher level of job stress was associated with a lower likelihood of having a Pap smear. Hospital administrators could help decrease work-related stress and improve stress adaption among nurses in order to improve their health screening behaviors. PMID- 26226878 TI - Root aquaporins contribute to whole plant water fluxes under drought stress in rice (Oryza sativa L.). AB - Aquaporin activity and root anatomy may affect root hydraulic properties under drought stress. To better understand the function of aquaporins in rice root water fluxes under drought, we studied the root hydraulic conductivity (Lpr) and root sap exudation rate (Sr) in the presence or absence of an aquaporin inhibitor (azide) under well-watered conditions and following drought stress in six diverse rice varieties. Varieties varied in Lpr and Sr under both conditions. The contribution of aquaporins to Lpr was generally high (up to 79% under well watered conditions and 85% under drought stress) and differentially regulated under drought. Aquaporin contribution to Sr increased in most varieties after drought, suggesting a crucial role for aquaporins in osmotic water fluxes during drought and recovery. Furthermore, root plasma membrane aquaporin (PIP) expression and root anatomical properties were correlated with hydraulic traits. Three chromosome regions highly correlated with hydraulic traits of the OryzaSNP panel were identified, but did not co-locate with known aquaporins. These results therefore highlight the importance of aquaporins in the rice root radial water pathway, but emphasize the complex range of additional mechanisms related to root water fluxes and drought response. PMID- 26226884 TI - Effects of Donepezil on Extrapyramidal Symptoms in Patients with Dementia with Lewy Bodies: A Secondary Pooled Analysis of Two Randomized-Controlled and Two Open-Label Long-Term Extension Studies. AB - BACKGROUND/AIMS: The aim of this study was to clarify the effects of donepezil on extrapyramidal symptoms in patients with dementia with Lewy bodies (DLB). METHODS: Using pooled datasets from phase 2 and 3, 12-week randomized, placebo controlled trials (RCT, n = 281) and 52-week open-label long-term extension trials (OLE, n = 241) of donepezil in DLB, the effects of donepezil on the incidence of extrapyramidal adverse events (AEs) and on the Unified Parkinson's Disease Rating Scale (UPDRS) part III were assessed, and potential baseline factors affecting the AEs were explored. RESULTS: The RCT analysis did not show significant differences between the placebo and active (3, 5, and 10 mg donepezil) groups in extrapyramidal AE incidence (3.8 and 6.5%, p = 0.569) and change in the UPDRS (mean +/- SD: -0.2 +/- 4.3 and -0.6 +/- 6.5, p = 0.562). In the OLE analysis (5 and 10 mg donepezil), the incidence did not increase chronologically; all AEs leading to a dose reduction or discontinuation except one were relieved. The UPDRS was unchanged for 52 weeks. An exploratory multivariate logistic regression analysis of the RCTs revealed that donepezil treatment was not a significant factor affecting the AEs. Baseline severity of parkinsonism was a predisposing factor for worsening of parkinsonism without significant interactions between donepezil and baseline severity. CONCLUSION: DLB can safely be treated with donepezil without relevant worsening of extrapyramidal symptoms, but treatment requires careful attention to symptom progression when administered to patients with relatively severe parkinsonism. PMID- 26226885 TI - Woody tissue photosynthesis in trees: salve on the wounds of drought? PMID- 26226886 TI - Reactions of allyl alcohols and boronic acids with trifluoromethanesulfonyl hypervalent iodonium ylide under copper-catalysis. AB - Trifluoromethylsulfinyl and trifluoromethylthio groups are both important substituents for pharmaceuticals, agrochemicals and functional materials. We herein report the trifluoromethylthiolation of allyl alcohols 2 with trifluoromethanesulfonyl hypervalent iodonium ylide 1 under copper catalysis to provide trifluoromethylsulfinyl compounds 3. Trifluoromethylthiolation of boronic acids 4 with 1 furnished trifluoromethylthio compounds 5. PMID- 26226887 TI - Prognostic role of the neutrophil-to-lymphocyte ratio in pancreatic cancer: a meta-analysis. AB - The relationship between the neutrophil-to-lymphocyte ratio (NLR) and tumours as a prognostic factor has been reported in many studies. In this meta-analysis, we evaluated the prognostic role of the NLR in pancreatic cancer (PC). A systematic search was performed in PubMed and Embase for relevant studies. Data from and characteristics of each study were extracted. A meta-analysis was performed to analyse the prognostic role of the NLR using the hazard ratio (HR) and 95% confidence intervals (95% CI). As a result, a total of 2035 patients in 9 cohorts were included in this meta-analysis. The pooled HR of 1.587 (95% CI: 1.411-1.785, p < 0.01) showed that patients with an elevated NLR were expected to have shorter overall survival (OS) after treatment. This meta-analysis suggests that an elevated NLR can be used as a predictor of survival in patients with pancreatic cancer. PMID- 26226888 TI - A Case of an Aortic Abscess around the Elephant Trunk. AB - A 52-year-old male patient with a history of total arch replacement using the elephant trunk technique for acute aortic dissection 4 years before visited our hospital with the chief complaint of persistent fever. Chest computed tomography (CT) suggested prosthetic vascular graft infection, which was treated surgically after chemotherapy. The first surgery consisted of debridement of an abscess around the vascular graft and in the aorta around the elephant trunk, and thoracic descending aorta replacement and vacuum-assisted closure (VAC) in view of the risk of bleeding from the peripheral region of the elephant trunk. One week later, omental filling was performed as the second step. This is a very rare case of aortic abscess around the elephant trunk that could successfully be managed by graft-conserving treatment. PMID- 26226889 TI - Road Safety Effects of Bus Rapid Transit (BRT) Systems: a Call for Evidence. AB - Road injuries are an important cause of global mortality especially in low- and middle-income countries. While these countries undergo major urban transformations, an integral part of their development has often been the implementation of mass transportation systems, including Bus Rapid Transit (BRT) systems. However, the net effect of BRT systems on road safety is still unclear, and while there is reason to believe that BRT systems improve safety, very few available empirical studies have tested this hypothesis using observational data. Furthermore, the existing evidence is mixed and sparse. This paper reviews the available literature on the links of BRT systems and road safety and calls for more research to strengthen the body of evidence on the effect of BRT systems on road safety in the future. PMID- 26226890 TI - Risk factors for autism spectrum disorder in the Thai population. AB - Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder commonly prevalent in children worldwide including Thailand. However, there are very few studies thus far addressing risk factors for ASD in Thai children. This case-control study aims to investigate whether various risk factors especially socioeconomic status, advanced parental age (age >35 years), perinatal factors, maternal autoimmune diseases, and family history of neuropsychiatric illnesses were associated with the risk of having an offspring with ASD. There were 235 children with ASD (age 8.44 +/- 3.37 years) and 235 controls (age 8.39 +/- 3.37 years) enrolled in this study. The risk of developing ASD in these children included advanced paternal age (adjusted odds ratio (AOR) = 3.49, 95 % confidence interval (CI) = 2.05-5.96), family history of neuropsychiatric illnesses particularly if such disorders came from the paternal side of the child's family (AOR = 2.87, 95 % CI = 1.29-6.39), and having unemployed mothers (AOR = 1.65, 95 % CI = 1.08-2.54). CONCLUSION: This study supports previous findings of Western countries where risk factors for ASD tend to occur in children whose fathers were of advanced paternal age and in the families with neuropsychiatric illnesses particularly if such disorders came from the paternal side of the child's family. WHAT IS KNOWN: * Family history of neuropsychiatric disorders and advanced paternal age are risk factors for ASD in the offspring previously identified in the studies in Europe and North America. What is New: * To our knowledge, this is the first study documenting risk factors for ASD in the Asian population. * Our study supports previous findings of Western countries where risk factors for ASD tend to occur in the families with neuropsychiatric illnesses particularly if such disorders came from the paternal side of the child's family. PMID- 26226891 TI - Proportional assist versus assist control ventilation in premature infants. AB - During proportional assist ventilation (PAV), the applied pressure is servo controlled based on continuous input from the infant's breathing. In addition, elastic and resistive unloading can be employed to compensate for the abnormalities in the infant's lung mechanics. The aim of this study was to test the hypothesis that in very prematurely born infants remaining ventilated beyond the first week, PAV compared to assist control ventilation (ACV) would be associated with superior oxygenation. A randomised crossover study was undertaken. Infants were studied for 4 hours each on PAV and ACV in random order; at the end of each 4-h period, the oxygenation index (OI) was calculated. Eight infants, median gestational age of 25 (range 24-33) weeks, were studied at a median of 19 (range 10-105) days. It had been intended to study 18 infants but as all the infants had superior oxygenation on PAV (p = 0.0039), the study was terminated after recruitment of eight infants. The median inspired oxygen concentration (p = 0.049), mean airway pressure (p = 0.012) and OI (p = 0.012) were all lower on PAV. CONCLUSION: These results suggest that PAV compared to ACV is advantageous in improving oxygenation for prematurely born infants with evolving or established BPD. WHAT IS KNOWN: During proportional assist ventilation (PAV), the applied pressure is servo controlled throughout each spontaneous breath. Elastic and resistive unloading can compensate for the infant's abnormalities in lung mechanics. WHAT IS NEW: In a randomised crossover study, infants with evolving/established BPD were studied on PAV and ACV each for 4 h. The oxygenation index was significantly lower on PAV in all infants studied. PMID- 26226892 TI - Riboflavin in cyclic vomiting syndrome: efficacy in three children. AB - Cyclic vomiting syndrome is an episodic disorder considered to be a migraine variant. Riboflavin is efficient in the prophylactic treatment of migraines in adults. We describe the effectiveness and tolerance of riboflavin treatment in three children with cyclic vomiting syndrome. All of them fulfilled the diagnosis criteria for cyclic vomiting syndrome. They received prophylactic monotherapy with riboflavin for at least 12 months. Excellent response and tolerability was observed. CONCLUSION: Based on clinical observation in three cases, riboflavin may be an effective and safe prophylactic treatment for children with cyclic vomiting syndrome. WHAT IS KNOWN: CVS is one of the "childhood periodic syndromes" classified as a migraine subtype by the International Headache Society. Riboflavin is currently used as a prophylactic treatment in patients with migraine. WHAT IS NEW: Riboflavin may be an effective and safe prophylactic treatment for children with CVS. Increasing doses of riboflavin and long periods of prophylaxis may be needed in some children.. PMID- 26226893 TI - Childhood adiposity: being male is a potential cardiovascular risk factor. AB - As the earliest atherosclerotic lesions begin during childhood, our aim was to correlate gender-related adiposity to classical cardiovascular risk factors in a group of children.An observational and transversal analysis was carried out in a cohort consisting of 161 children of both sexes, aged 6 to 17 years of age. Waist circumference was correlated to leptin, high-sensitivity C-reactive protein, systolic and diastolic blood pressure, plasma lipids, homeostasis model assessment-insulin resistance, and the left ventricular mass index. After adjusting for age, waist circumference in boys, compared to girls, correlated more strongly and directly to systolic (r = 0.538; p < 0.001) and diastolic blood pressure (rho = 0.401; p < 0.01), ApoB/ApoA ratio (rho = 0.515; p < 0.01), high density lipoprotein cholesterol (r = -0.441; p < 0.001), low-density lipoprotein cholesterol (rho = 0.280; p < 0.01), triglycerides (rho = 0.420; p < 0.001), homeostasis model assessment-insulin resistance (rho = 0.463; p < 0.001), and the left ventricular mass index (rho = 0.286; p < 0.01). A similar pattern was observed regarding the correlations between leptin, high-sensitivity C-reactive protein, and the above parameters (except between high-sensitivity C-reactive protein and diastolic blood pressure), and also, particularly in boys. CONCLUSION: Although increased childhood adiposity is related to a more adverse metabolic and clinical profile in both genders, males appear to have a potentially greater cardiovascular risk. WHAT IS KNOWN: Obesity is characterized by a chronic low-grade inflammatory process. WHAT IS NEW: Increased adiposity is related to a more pronounced pro-inflammatory response in boys. Childhood male adiposity is a potentially greater cardiovascular risk factor. Arterial hypertension, insulin resistance, and dyslipidemia is more strongly correlated to waist circumference in boys. PMID- 26226894 TI - Reply to the correspondence letter by J. Finsterer and S. Zarrouk-Mahjoub "Noncompaction in mitochondrial trifunctional protein deficiency due to a HADHB mutation". PMID- 26226896 TI - Synthesis of Diverse N-Substituted Muramyl Dipeptide Derivatives and Their Use in a Study of Human NOD2 Stimulation Activity. AB - A flexible synthetic strategy toward the preparation of diverse N-substituted muramyl dipeptides (N-substituted MDPs) from different protected monosaccharides is described. The synthetic MDPs include N-acetyl MDP and N-glycolyl MDP, known NOD2 ligands, and this methodology allows for structural variation at six positions, including the muramic acid, peptide, and N-substituted moieties. The capacity of these molecules to activate human NOD2 in the innate immune response was also investigated. It was found that addition of the methyl group at the C1 position of N-glycolyl MDP significantly enhanced the NOD2 stimulating activity. PMID- 26226897 TI - Quantitative study on the effect of calcium and magnesium palmitate on the formation of Pseudomonas aeruginosa biofilm. AB - Calcium palmitate and magnesium palmitate (which are major constituents of waste water) are insoluble precipitates that accumulate in bodies of water. This leads to the formation of biofilms because bacterial cells can use these fatty acid salts as a carbon source. It is important to study the formation of biofilms because they cause corrosion of pipelines and water contamination. In this study, the effect of calcium palmitate and magnesium palmitate on Pseudomonas aeruginosa biofilm formation has been evaluated. In the presence of calcium palmitate, the biofilm biomass, extracellular polysaccharide, and adhesion force were 3.45 +/- 0.06 (A590), 1810 +/- 47 MUg, and 14.5 +/- 0.9 nN, respectively. In the presence of magnesium palmitate, the biofilm biomass, extracellular polysaccharide, and adhesion force were 2.72 +/- 0.03 (A590), 1370 +/- 56 MUg, and 8.0 +/- 0.2 nN, respectively. The results suggest that biofilm biomass, extracellular polysaccharide, and adhesion force were higher in the presence of calcium palmitate. PMID- 26226895 TI - The medicinal properties and phytochemistry of plants of the genus Terminalia (Combretaceae). AB - Plants of the genus Terminalia are amongst the most widely used plants for traditional medicinal purposes worldwide. Many species are used for their antibacterial, antifungal, antiprotozoal, antiviral, antidiarrhoeal, analgesic, antimalarial, antioxidant, antiinflammatory and anticancer activities. Wound healing and cardiovascular effects have also been credited to some species. Many Terminalia species have multiple beneficial effects for multiple diseases and ailments. Indeed, the Indian species Terminalia chebula is known as the king of plants in Ayurveda due to its broad range of medicinal uses. However, apart from the reported ethnopharmacological uses of many Terminalia species, surprisingly few studies have rigorously examined this important genus for their medical properties/mechanisms and phytochemistry. This is likely due to the high tannin content common to many Terminalia species and the perception that these tannins may be responsible for much of their beneficial properties. As the complexities of tannins make them poor candidates for drug design, most interest in Terminalia species has been for their pharmacognostic and nutraceutical value and they have often been overlooked as potentials for drug discovery. However, recent reports have identified many other interesting phytochemicals and demonstrated that these may be responsible for several of the reported bioactivities of the Terminalia species used in traditional medicinal systems. The last decade has seen a large increase in the number of studies into the use of Terminalia species as therapeutic agents. Several species used in Ayurvedic medicine (Terminalia arjuna, Terminalia bellerica, Terminalia catappa, T. chebula) in particular have received much recent attention. Similarly, recent reports have also highlighted the medicinal potential of species from Africa, Australia and the Americas. The aim of this report is to summarise the recent research into the medicinal properties, phytochemistry and therapeutic mechanisms of Terminalia species and thus to highlight and direct future areas of research into the medicinal activities of this important genus. PMID- 26226898 TI - Congenital Recessive Methemoglobinemia Revealed in Adulthood: Description of a New Mutation in Cytochrome b5 Reductase Gene. AB - Methemoglobinemia can be acquired (oxidizing drugs or chemicals products) or inherited either by mutations affecting globin chains [M hemoglobins (M Hbs)] or by defects in the enzymatic system involved in the reduction of spontaneous Hb oxidation: nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase. It is encoded by the CYB5R3 gene: there are two phenotypes of autosomal recessive congenital methemoglobinemia, in type II CYB5R deficiency is generalized and affects all cells, leading to an early onset, whereas in type I, the enzyme deficiency is restricted to erythrocytes, usually discovered in infancy but not exclusively. We report a new case of methemoglobinemia discovered in a patient from Bahrain who exhibited an unknown dyspnea at the age of 37 years without trigger events or oxidizing products. We discovered a new mutation in the CYB5R3 gene: exon 9, codon 266 (delGAG) (GLU) (CYB5R3: c.726_729delGAG) in the homozygous state. Appearance of methemoglobinemia in an adult usually suggests an acquired cause but our case illustrated that it could also reveal a type I mutation of cytochrome b5 reductase. PMID- 26226900 TI - Mouse Models of Pancreatic Ductal Adenocarcinoma. AB - Only 10% to 15% of patients with pancreatic ductal adenocarcinoma (PDAC) are candidates for potentially curative surgery due to the location or spread of disease at the time of diagnosis. Despite rapid progress in the understanding of the molecular mechanisms underlying PDAC, translation to effective therapies has been modest at best. One of the key tools available for studying biology and developing more effective therapeutics is the laboratory mouse, mus musculus. This article explores new and innovative approaches to mouse modeling and how these approaches can be utilized to move the field forward. PMID- 26226899 TI - Genetics and Biology of Pancreatic Ductal Adenocarcinoma. AB - Pancreatic ductal adenocarcinoma remains a clinical challenge. Thus far, enlightenment on the downstream activities of Kras, the tumor's unique metabolic needs, and how the stroma and immune system affect it have remained untranslated to the clinical practice. Given the numbers of diverse therapies in development and a growing knowledge about how to evaluate these systems preclinically and clinically, this is expected to change significantly and for the better over the next 5 years. PMID- 26226903 TI - Diagnosis and Management of Pancreatic Cystic Neoplasms. AB - Incidentally discovered pancreatic cystic lesions are increasingly common, affecting up to 10% to 15% of patients undergoing cross-sectional imaging. Although some pancreatic cystic neoplasms harbor invasive malignancy or the potential to progress over time, a majority are benign and can be observed safely. Accurate diagnosis is key to appropriate management. Diagnosis requires a multidisciplinary and multimodal approach. This review discusses each type of pancreatic cystic neoplasm and the current data on diagnosis and treatment. PMID- 26226902 TI - Familial Pancreatic Adenocarcinoma. AB - Familial pancreatic cancer (FPC) kindreds have at least 2 first-degree relatives with pancreatic ductal adenocarcinoma. Studies of FPC have focused on the discovery of genetic cause and on the management of those at genetically high risk. Research reveals that a half dozen known hereditary syndromes or genes are associated with increased risk of developing pancreatic cancer, the most prominent of which are BRCA2 and CDKN2A. Genetic risk assessment and testing is already available. Owing to limited experience worldwide, guidance is often based on expert opinion, although all agree that research is needed to improve the shaping of options. PMID- 26226904 TI - Imaging and Endoscopic Approaches to Pancreatic Cancer. AB - Imaging and endoscopy both play important and complementary roles in the initial diagnosis, staging, monitoring, and symptomatic management of pancreatic cancer. This article provides an overview of the uses of each of the diagnostic modalities, common imaging findings, alternative considerations, and areas of ongoing work in diagnostic imaging. This article also provides details of the uses of endoscopy for diagnosis, staging, and intervention throughout the course of a patient's care. These modalities each play important roles in the complex multidisciplinary care of patients with pancreatic cancer. PMID- 26226901 TI - Epidemiology and Inherited Predisposition for Sporadic Pancreatic Adenocarcinoma. AB - Given the changing demographics of Western populations, the numbers of pancreatic cancer cases are projected to increase during the next decade. Diabetes, recent cigarette smoking, and excess body weight are the cancer's most consistent risk factors. The search for common and rare germline variants that influence risk of pancreatic cancer through genome-wide association studies and high-throughput sequencing-based studies is underway and holds the promise of increasing the knowledge of variants and genes that play a role in inherited susceptibility of this disease. Research reported in this review has advanced the understanding of pancreatic cancer. PMID- 26226905 TI - Surgery for Pancreatic Cancer. AB - Surgical resection remains the only potentially curative therapy for pancreatic cancer, despite a high rate of systemic recurrence. Because of local invasion or distant spread, a minority of patients presenting with pancreatic cancer are candidates for surgery. Although perioperative mortality is low in high-volume settings, pancreatic surgery remains associated with considerable morbidity. Minimally invasive and robotic surgical techniques are increasingly used for pancreatic resection, although not always applicable to all patients. Strategies to extend the benefits of margin-negative surgical resection to more patients include surgery with vascular resection and reconstruction for locally invasive tumors, and resection after neoadjuvant therapy. PMID- 26226907 TI - Diagnosis and Management of Borderline Resectable Pancreatic Adenocarcinoma. AB - Borderline resectable pancreatic cancer represents a subcategory of advanced cancer that is typically defined by limited involvement of the major mesenteric vasculature. Such involvement is associated with a high likelihood of microscopically incomplete resection if surgery is used as the primary therapeutic modality. Increasing data support the role of neoadjuvant therapy as part of multimodality management but there is no uniformly accepted standard of care. This review discusses, based on recent literature and the experience of the Pancreatic Tumor Study Group at The University of Texas MD Anderson Cancer Center, the classification, definition, diagnosis, and management of borderline resectable pancreatic cancer. PMID- 26226906 TI - Perioperative Therapy for Surgically Resectable Pancreatic Adenocarcinoma. AB - It is estimated that 10% to 20% of patients with pancreatic cancer present with resectable disease. Although surgery offers curative intent, the median survival after curative resection is less than 2 years. To improve clinical outcomes in this patient population, clinical studies have investigated the role of perioperative therapy, including neoadjuvant and adjuvant treatment in resectable pancreatic cancer. The role of adjuvant therapy has been well established by large randomized phase III studies, whereas benefit of the neoadjuvant approach remains inconclusive. Here, we review various treatment modalities and their clinical benefits in resectable pancreatic cancer. PMID- 26226908 TI - Treatment Approaches to Locally Advanced Pancreatic Adenocarcinoma. AB - This article focuses on the management of locally advanced pancreatic cancer, which should be treated as a distinct entity separate from metastatic disease and borderline resectable disease. Although the role, timing, and sequencing of radiation relative to systemic therapy in this disease are controversial, an emerging treatment paradigm involves induction chemotherapy, followed by consolidative chemoradiation in patients who do not progress. In addition, new chemotherapy regimens as well as novel radiosensitizers have shown promise and need to be tested further in the locally advanced setting. Advances in radiotherapy have enabled stereotactic body radiotherapy and should continue to be prospectively evaluated. PMID- 26226909 TI - Therapeutic Approaches for Metastatic Pancreatic Adenocarcinoma. AB - Since the US Food and Drug Administration's approval of gemcitabine in 1996, numerous randomized trials have investigated treatment programs to further improve the quality of life and survival of patients with advanced pancreatic cancer. After little progress over the ensuing 15 years, 2 combination treatment programs recently conferred improved survival compared with gemcitabine monotherapy in patients with metastatic pancreatic cancer: FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) and gemcitabine plus nab paclitaxel. Importantly, our understanding of the biology of pancreatic cancer continues to grow. This improved biologic understanding holds great promise for integrating new targeted and immune-modifying therapies into current treatment programs. PMID- 26226911 TI - Pancreatic Cancer. PMID- 26226910 TI - Novel Therapeutics for Pancreatic Adenocarcinoma. AB - The last decade has seen significant developments in the use of combination systemic therapy for advanced pancreatic ductal adenocarcinoma (PDAC), with median survival approaching 1 year for select patients treated with FOLFIRINOX in the metastatic setting. However, it is sobering that these developments have been achieved with the use of traditional cytotoxics rather than from successes in the more modern fields of molecularly targeted therapies or immunotherapy. This article highlights several promising therapeutic approaches to PDAC currently under clinical evaluation, including immune therapies, molecularly targeted therapies, strategies for stromal depletion, and targeted therapy for genetically selected patients. PMID- 26226912 TI - Ovarian pregnancy associated with a fresh blastocyst transfer following in vitro fertilization. AB - Ovarian pregnancy is a rare subtype of ectopic pregnancy, and its mechanisms have not been clarified. We report a case of ovarian pregnancy that supports a blastocyst migration mechanism. An infertile woman became pregnant after a single blastocyst transfer following in vitro fertilization during a fresh non-donor cycle. Transvaginal ultrasound revealed a gestational sac-like structure containing an active fetus that was located adjacent to the corpus luteum of the right ovary. Laparoscopy identified a red, swollen implantation site in the ovary, which was completely removed by wedge resection without damaging the remaining parenchyma. This case demonstrated that a fresh blastocyst transferred into the endometrial cavity migrated through the fallopian tube, implanted on an ovarian surface, and formed an ovarian pregnancy. PMID- 26226913 TI - A Rapid, Amplification-Free, and Sensitive Diagnostic Assay for Single-Step Multiplexed Fluorescence Detection of MicroRNA. AB - The importance of microRNA (miRNA) dysregulation for the development and progression of diseases and the discovery of stable miRNAs in peripheral blood have made these short-sequence nucleic acids next-generation biomarkers. Here we present a fully homogeneous multiplexed miRNA FRET assay that combines careful biophotonic design with various RNA hybridization and ligation steps. The single step, single-temperature, and amplification-free assay provides a unique combination of performance parameters compared to state-of-the-art miRNA detection technologies. Precise multiplexed quantification of miRNA-20a, -20b, and -21 at concentrations between 0.05 and 0.5 nM in a single 150 MUL sample and detection limits between 0.2 and 0.9 nM in 7.5 MUL serum samples demonstrate the feasibility of both high-throughput and point-of-care clinical diagnostics. PMID- 26226914 TI - Molecular understanding of Indian untransfused thalassemia intermedia. AB - BACKGROUND: The term thalassemia intermedia describe a form of thalassemia of intermediate severity, between the major transfusion-dependent forms of the disease and the symptomless carrier states. The phenotypic diversity of beta thalassemia results from its underlying genetic diversity. The wide clinical variability of these conditions leads to major difficulties in their management. The molecular basis of thalassemia intermedia is very heterogeneous. The clinical and hematological course of beta-thalassemia intermedia is influenced by a number of genetic factors. METHODS AND RESULTS: The main aim of the study was to evaluate the effect of globin and nonglobin genetic modifiers on clinical severity of the disease. The study group consisted of 66 homozygous patients with beta-thalassemia [40 transfusion-dependent thalassemia (TDT), 26 nontransfusion dependent thalassemia (NTDT)]. Hepatosplenomegaly was pronounced in the NTDT group. The presence of associated alpha-thalassemia was significantly higher in untransfused patients (P < 0.05). The milder beta-thalassemia mutations, such as Cap site +1 (A -> C), -88 (C -> T), and -87 (C -> G), were observed mainly in the NTDT group (9.61%) as against patients with TDT (1.25%). The cis-DNA haplotypes, motifs, or polymorphisms around the gamma-globin genes [(AT)x (T)y motif (38.4%), XmnI (76.92%)and the Agamma-delta intergenic region haplotype T (73.07%) and Pre Ggamma globin gene haplotype TAG (46.15%)] contributed significantly in amelioration of the disease severity. CONCLUSION: Our study emphasizes the complexity of genetic interactions that underlie the phenotype of beta thalassemia and highlights the importance of epistatic factors and the regulation of HbF production in beta-thalassemia syndromes. PMID- 26226915 TI - Outcomes of EVAR with the endurant stent-graft system in patients with infrarenal ruptured abdominal aortic aneurysms: Is hostile anatomy a challenging factor? AB - PURPOSE: To compare outcomes of endovascular aneurysm repair (EVAR) using the Endurant-I stent-graft system between patients who have ruptured abdominal aortic aneurysms (rAAAs) with normal and hostile anatomy. MATERIALS AND METHODS: Patients with rAAAs who underwent EVAR between January 2008 and March 2014 were included in the study. There were 21 (70%) men and 9 (30%) women with a mean age of 70 years. Multidetector computed tomography (CT) angiography findings of the rAAA were classified according to the "Classification based on CT findings," and imaging planning was performed according to the Society of Interventional Radiology Guideline. Primary outcome measures (POM) were procedure-related mortality, 30-day mortality, and survival rate at 1 year. Secondary outcome measures (SOM) were technical success, open surgical conversion, complications, survival, relationship between size-severity of the rAAA and mortality, procedure time, hospital stay. RESULTS: The periprocedural-EVAR mortality rate was 33%. The overall mortality rate without prehospital phase deaths was 40.0%. Seventy three percent of the patients with rAAAs had hostile anatomy. There were no statistically significant differences between the groups in POMs and SOMs (except mean hospital stay). Mean hospital stay was shorter in the normal anatomy group. The mortality rate was higher in patients with hematoma in both sides of the aorta and free intraperitoneal hematoma. CONCLUSION: EVAR of rAAAs with hostile anatomy is feasible and off-label use of Endurant-I endografts could be expanded. PMID- 26226916 TI - Enhanced reading time efficiency by use of automatically unfolded CT rib reformations in acute trauma. AB - Rationale of this study was to evaluate whether unfolded rib images enhance time efficiency in detection of rib fractures and time efficiency in patients with acute thoracic trauma. 51 subsequent patients with thoracic trauma underwent 64 slice computed tomography. 1mm thick axial slices were reformatted using a commercially available post-processing software application generating rotatable unfolded rib images. Diagnostic accuracy was evaluated by 3 readers and compared to multiplanar reformations of the original CT images. Reformation and evaluation times were recorded. 116 rib fractures were detected. The multiplanar reformation analysis yielded a sensitivity of 87.9%/93.9%/79.7% with a specificity of 97%/97%/82.2%, whilst the unfolded rib image analysis yielded a sensitivity of 94.8%/94.8%/92.2% and a specificity of 85.2/87.8%/82.4 (p=0.06/0.8/0.04) with high inter-observer agreement (k=0.79-0.85). The mean reading time for the multiplanar reformations was significantly longer (reader 1: 103.7 +/- 27.1s/reader 2: 81.8 +/- 40.6s/reader 3: 154.3 +/- 39.2s) than the evaluation of the unfolded rib images (19.4 +/- 4.9s/26.9 +/- 15.0s/49.9 +/- 18.7s; p<0.01). Concluding, the unfolded rib display reduces reading time for detection of rib fractures in acute thoracic trauma patients significantly and does not compromise the diagnostic accuracy significantly in experienced radiologists. However, unexperienced readers may profit from use of this display. PMID- 26226917 TI - The Dysregulation Profile in middle childhood and adolescence across reporters: factor structure, measurement invariance, and links with self-harm and suicidal ideation. AB - Recently, a phenotype of severe dysregulation, the Dysregulation Profile (DP), has been identified. DP consists of elevated scores on the Anxious/Depressed (AD), Aggressive Behavior (AGG) and Attention Problems (AP) scales of the Child Behavior Checklist (CBCL), Teacher Report Form (TRF), or Youth Self Report (YSR). A drawback in current research is that DP has been conceptualized and operationalized in different manners and research on the factor structure of DP is lacking. Therefore, we examined the factor structure of DP across multiple reporters, measurement invariance across gender, parents, and time, as well as links between DP and self-harm and suicidal ideation. Data from a large community sample were used (N = 697), covering middle childhood (Mage = 7.90, (SD = 1.16) and adolescence (Mage = 13.93, SD = 1.14). Mothers, fathers, teachers, and youth themselves reported on children's emotional and behavioral problems using the CBCL, TRF, and YSR. Results indicated that in middle childhood and in adolescence, a bifactor model with a general factor of Dysregulation alongside three specific factors of AD, AGG, and AP fitted best, compared to a second-order or one-factor model. The model showed good fit for mother, father, teacher, and youth reports and showed invariance across gender, parents and time. Youth, mother, and father reported Dysregulation was uniquely and positively related to adolescent-reported self-harm and suicidal ideation. The DP is best conceptualized as a broad dysregulation syndrome, which exists over and above anxiety/depression, aggression, and attention problems as specific problems. The bifactor model of DP explains the uniqueness and interrelatedness of these behavioral problems and can help explaining shared and non-shared etiology factors. The exclusive link between the general dysregulation factor and adolescents' self-harm and suicidal ideation further established the clinical relevance of the bifactor model. PMID- 26226919 TI - A correlation-based method for extracting subject-specific components and artifacts from group-fMRI data. AB - We present a simple but effective correlation-based method (maxCorr) for extracting subject-specific components from group-fMRI data. The method finds signal components that correlate maximally with the data set of one subject and minimally with the data sets of the other subjects. We show that such subject specific components are often related to movement and physiological noise (e.g. cardiac cycle, respiration). We further demonstrate that removing the most subject-specific components for each subject reduces the overall data variance and improves the statistical identification of true fMRI activations. We compare the performance of maxCorr with CompCor, a commonly used artifact-finding method in fMRI analysis. We show that maxCorr is less likely than CompCor to remove actual stimulus-related activity, especially when no information about the stimulus is available. MaxCorr operates without stimulus information and is therefore well suitable for analyses of fMRI experiments employing naturalistic stimuli, such as movies, where stimulus regressors are difficult to construct, and for brain decoding techniques benefiting from reduced subject-specific variance in each subject's data. PMID- 26226918 TI - ESCAP Expert Paper: New developments in the diagnosis and treatment of adolescent anorexia nervosa--a European perspective. AB - Anorexia nervosa is a potentially life-threatening disorder with a typical onset in adolescence and high rates of medical complications and psychiatric comorbidity. This article summarizes issues relating to classification in DSM-5 and presents a narrative review of key evidence-based medical and behavioral interventions for adolescent AN and subthreshold restricting eating disorders, mainly, but not exclusively published between 2012 and 2014. In addition, it systematically compares the clinical guidelines of four European countries (Germany, Spain, The Netherlands, and United Kingdom) and outlines common clinical practice, in relation to treatment settings, nutritional rehabilitation, family-oriented and individual psychotherapy, and psychopharmacological treatment. With the exception of family-based treatment, which is mainly evaluated and practiced in Anglo-American countries, the evidence base is weak, especially for medical interventions such as refeeding and pharmacological intervention. There is a need for common European research efforts, to improve the available evidence base and resulting clinical guidance. PMID- 26226920 TI - A view from the middle of the totem pole. PMID- 26226921 TI - In reply: A view from the middle of the totem pole. PMID- 26226922 TI - Early Nutrition, Health and Integrative Development in Peru. Results of an International Course promoted by the International Union of Nutritional Sciences (IUNS) through the Iberoamerican Nutrition Foundation (FINUT). PMID- 26226924 TI - Therapeutic advances in Huntington's Disease. AB - Huntington's disease is a rare hereditary degenerative disease with a wide variety of symptoms that encompass movement, cognition, and behavior. The genetic mutation that causes the disease has been known for more than 20 y, and animal models have illuminated a host of intracellular derangements that occur downstream of protein translation. A number of clinical trials targeting these metabolic consequences have failed to produce a single effective therapy, although clinical trials continue. New strategies targeting the protein at the level of transcription, translation, and posttranslational modification and aggregation engender new hope that a successful strategy will emerge, but there is much work ahead. Some of the clinical manifestations of the illness, particularly chorea, affective symptoms, and irritability, are amenable to palliative strategies, but physicians have a poor evidence base on which to select the best agents. Clinical trials since 2013 have dashed hopes that coenzyme Q10 or creatine might have disease-modifying properties but suggested other agents were safe or hinted at efficacy (cysteamine, selisistat, hydroxyquinoline) and could proceed into later-stage disease modification trials. The hunt for effective symptom relief suggested that pridopidine might be shown effective given the right outcome measure. This review summarizes recent progress in HD and highlights promising new strategies for slowing disease progression and relieving suffering in HD. PMID- 26226925 TI - Expression and regulation of androgen receptor in the mouse uterus during early pregnancy and decidualization. AB - The androgen receptor (AR) is a ligand-activated transcription factor that is important for both the male and female reproductive systems. The expression and regulation of AR in the uterine endometrium during early pregnancy and decidualization remain relatively under-investigated, so we sought to immunohistochemically examine the spatiotemporal expression of AR in mouse uteri during the peri-implantation period as well as in response to specific steroid hormones. AR protein was found in the nuclei of uterine stromal cells starting on pregnancy Days 1 and 2, with its abundance increasing on Days 3 and 4. From pregnancy Days 5 to 9, however, the expression of AR markedly declined in stromal zones of uteri. No signal was detected in the decidualized cells surrounding the site of embryo implantation; moreover, no AR immunostaining was observed in decidualized uterine cells in an artificial oil-induced model of decidualization. Progesterone significantly inhibited AR protein expression, whereas estrogen dramatically elevated AR abundance in the stroma of ovariectomized mouse uteri. Taken together, our results are the first to demonstrate that decidualization and progesterone significantly inhibited the AR protein expression in vivo, whereas estrogen increased AR protein levels in the stromal cells of mouse uteri. These responses might be advantageous for the proliferation and differentiation of uterine stroma and for embryo implantation during early pregnancy. PMID- 26226926 TI - Canal wall reconstruction and conductive hearing preservation for temporal bone paraganglioma. PMID- 26226927 TI - An enhanced Monte Carlo outlier detection method. AB - Outlier detection is crucial in building a highly predictive model. In this study, we proposed an enhanced Monte Carlo outlier detection method by establishing cross-prediction models based on determinate normal samples and analyzing the distribution of prediction errors individually for dubious samples. One simulated and three real datasets were used to illustrate and validate the performance of our method, and the results indicated that this method outperformed Monte Carlo outlier detection in outlier diagnosis. After these outliers were removed, the value of validation by Kovats retention indices and the root mean square error of prediction decreased from 3.195 to 1.655, and the average cross-validation prediction error decreased from 2.0341 to 1.2780. This method helps establish a good model by eliminating outliers. (c) 2015 Wiley Periodicals, Inc. PMID- 26226928 TI - Embolization of pulmonary arteriovenous malformations in a patient with a delayed diagnosis of hemorrhagic hereditary telangiectasia. PMID- 26226931 TI - Reaction of N-heterocyclic carbenes with chalcones leading to the synthesis of deoxy-Breslow intermediates in their oxidized form. AB - The synthesis of deoxy-Breslow intermediates in their oxidized form has been developed via the reaction of N-heterocyclic carbenes (NHCs) with chalcones. Moreover, the initial tetrahedral adduct formed from the 1,4-addition of NHCs to chalcones is also isolated. PMID- 26226929 TI - Independent sources of anisotropy in visual orientation representation: a visual and a cognitive oblique effect. AB - The representation of visual orientation is more accurate for cardinal orientations compared to oblique, and this anisotropy has been hypothesized to reflect a low-level visual process (visual, "class 1" oblique effect). The reproduction of directional and orientation information also leads to a mean error away from cardinal orientations or directions. This anisotropy has been hypothesized to reflect a high-level cognitive process of space categorization (cognitive, "class 2," oblique effect). This space categorization process would be more prominent when the visual representation of orientation degrades such as in the case of working memory with increasing cognitive load, leading to increasing magnitude of the "class 2" oblique effect, while the "class 1" oblique effect would remain unchanged. Two experiments were performed in which an array of orientation stimuli (1-4 items) was presented and then subjects had to realign a probe stimulus within the previously presented array. In the first experiment, the delay between stimulus presentation and probe varied, while in the second experiment, the stimulus presentation time varied. The variable error was larger for oblique compared to cardinal orientations in both experiments reproducing the visual "class 1" oblique effect. The mean error also reproduced the tendency away from cardinal and toward the oblique orientations in both experiments (cognitive "class 2" oblique effect). The accuracy or the reproduced orientation degraded (increasing variable error) and the cognitive "class 2" oblique effect increased with increasing memory load (number of items) in both experiments and presentation time in the second experiment. In contrast, the visual "class 1" oblique effect was not significantly modulated by any one of these experimental factors. These results confirmed the theoretical predictions for the two anisotropies in visual orientation reproduction and provided support for models proposing the categorization of orientation in visual working memory. PMID- 26226930 TI - Audio-visual synchrony and feature-selective attention co-amplify early visual processing. AB - Our brain relies on neural mechanisms of selective attention and converging sensory processing to efficiently cope with rich and unceasing multisensory inputs. One prominent assumption holds that audio-visual synchrony can act as a strong attractor for spatial attention. Here, we tested for a similar effect of audio-visual synchrony on feature-selective attention. We presented two superimposed Gabor patches that differed in colour and orientation. On each trial, participants were cued to selectively attend to one of the two patches. Over time, spatial frequencies of both patches varied sinusoidally at distinct rates (3.14 and 3.63 Hz), giving rise to pulse-like percepts. A simultaneously presented pure tone carried a frequency modulation at the pulse rate of one of the two visual stimuli to introduce audio-visual synchrony. Pulsed stimulation elicited distinct time-locked oscillatory electrophysiological brain responses. These steady-state responses were quantified in the spectral domain to examine individual stimulus processing under conditions of synchronous versus asynchronous tone presentation and when respective stimuli were attended versus unattended. We found that both, attending to the colour of a stimulus and its synchrony with the tone, enhanced its processing. Moreover, both gain effects combined linearly for attended in-sync stimuli. Our results suggest that audio visual synchrony can attract attention to specific stimulus features when stimuli overlap in space. PMID- 26226932 TI - Unilateral nipple involvement in histoid leprosy. PMID- 26226934 TI - Food Intolerance: Associations with the rs12212067 Polymorphism of FOXO3 in Crohn's Disease Patients in New Zealand. AB - BACKGROUND: Diet is known to play a major role in Crohn's disease (CD). It has also been reported that the minor G allele from the rs12212067 polymorphism (T>G) in FOXO3 is associated with milder CD. The aim of this study was to investigate the association between the rs12212067 polymorphism and food intolerances for a total of 253 foods. METHODS: Tolerances and intolerances were recorded on a self reported dietary questionnaire. Each food was scored on a 5-point ordinal scale: beneficial effects as '+ +' or '+', adverse effects as '- -' or '-', and 'makes no difference' as '='. Dietary and genotype data were available for a total of 283 CD patients. RESULTS: We identified 17 foods with beneficial effects in our study which were significantly associated with the G allele of the FOXO3 rs12212067 polymorphism. Of these, sweet potatoes had the highest reported frequency of beneficial responses. We also identified 4 foods with detrimental effects in more than 25% of our study population. These were mustard, wasabi, and raw and cooked tomatoes, which again were significantly associated with the G allele in FOXO3. CONCLUSIONS: There was strong evidence that adverse effects of mustard, wasabi, and raw and cooked tomatoes were significantly associated with the G allele of FOXO3 and that these foods should be avoided by people carrying this allele. PMID- 26226933 TI - Quantitative assessment of the upper airway in infants and children with subglottic stenosis. AB - OBJECTIVES/HYPOTHESIS: Determine whether quantitative geometric measures and a computational fluid dynamic (CFD) model derived from medical imaging of children with subglottic stenosis (SGS) can be effective diagnostic and treatment planning tools. STUDY DESIGN: Retrospective chart and imaging review in a tertiary care hospital. METHODS: Computed tomography scans (n = 17) of children with SGS were analyzed by geometric and CFD methods. Polysomnograms (n = 15) were also analyzed. Radiographic data were age/weight flow normalized and were compared to an atlas created from radiographically normal airways. Five geometric, seven CFD, and five polysomnography measures were analyzed. Statistical analysis utilized a two-sample t test with Bonferroni correction and area under the curve analysis. RESULTS: Two geometric indices (the ratio of the subglottic to midtracheal airway, the percent relative reduction of the subglottic airway) and one CFD measure (the percent relative reduction of the hydraulic diameter of the subglottic airway) were significant for determining which children with SGS received surgical intervention. Optimal cutoffs for these values were determined. Polysomnography, the respiratory effort-related arousals index, was significant only prior to Bonferroni correction for determining which children received surgical intervention. CONCLUSIONS: Geometric and CFD variables were sensitive at determining which patients with SGS received surgical intervention. Discrete quantitative assessment of the pediatric airway was performed, yielding preliminary data regarding possible objective thresholds for surgical versus nonsurgical treatment of disease. This study is limited by its small, retrospective, single-institution nature. Further studies to validate these findings and possibly optimize treatment threshold recommendations are warranted. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:1225-1231, 2016. PMID- 26226935 TI - Bovine serum albumin surface imprinted polymer fabricated by surface grafting copolymerization on zinc oxide rods and its application for protein recognition. AB - A novel bovine serum albumin (BSA) surface imprinted polymer based on ZnO rods was synthesized by surface grafting copolymerization. It exhibited an excellent recognition performance to bovine serum albumin. The adsorption capacity and imprinting factor of bovine serum albumin could reach 89.27 mg/g and 2.35, respectively. Furthermore, the fluorescence property of ZnO was used for tracing the process of protein imprinting and it implied the excellent optical sensing property of this material. More importantly, the hypothesis that the surface charge of carrier could affect the imprinting process was confirmed. That is, ZnO with positive surface charge could not only improve the recognition specificity of binding sites to template proteins (pI < 7), but also deteriorate the bindings between sites and non-template proteins (pI > 7). It was also important that the reusability of ZnO@BSA molecularly imprinted polymers was satisfactory. This implied that the poor mechanical/chemical stability of traditional zinc oxide sensors could be solved by the introduction of surface grafting copolymerization. These results revealed that the ZnO@BSA molecularly imprinted polymers are a promising optical/electrochemical sensor element. PMID- 26226936 TI - Vaccine-Derived Immunity in Children With Cancer-Analysis of Anti-Tetanus and Anti-Diphtheria Antibodies Changes after Completion of Antineoplastic Therapy. AB - BACKGROUND: Cancer survival rates and longevity of patients after therapy have significantly improved during the last decades. Thus durable protection against infections should be provided. The aim of the study was to compare the levels of vaccine-derived antibodies in children with cancer compared to those of healthy children and to investigate how therapy influences the levels of specific antibodies. PROCEDURE: A group of 40 children, diagnosed with acute lymphoblastic leukemia (ALL) or solid tumor (ST), followed in Poznan University of Medical Sciences Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation, were recruited for evaluation of humoral immunity. Antibody levels were checked before treatment and 3, 6, and 12 months after treatment. RESULTS: In patients with ALL or ST, levels of IgG against tetanus and diphtheria were significantly lower than in the control group. Among ALL patients, 9% remained negative for tetanus and diphtheria antibodies 12 months after therapy. Among patients with ST 3 months after chemotherapy, there were no protective antibodies in 12% against tetanus, and in 18% against diphtheria. All patients reconstituted immunity 6 and 12 months after therapy. CONCLUSIONS: Our data show that a considerable number of cancer patients lose immunity against diphtheria and tetanus after therapy. Compared to ST, patients with ALL lose protective antibody levels more often. Patients with ST reconstituted antibodies after the treatment cessation, while levels in ALL patients remained low. PMID- 26226937 TI - Reversible switch between the nanoporous and the nonporous state of amphiphilic block copolymer films regulated by selective swelling. AB - Switchable nanoporous films, which can repeatedly alternate their porosities, are of great interest in a diversity of fields. Currently these intelligent materials are mostly based on polyelectrolytes and their porosities can change only in relatively narrow ranges, typically under wet conditions, severely limiting their applications. Here we develop a new system, which is capable of reversibly switching between a highly porous state and a nonporous state dozens of times regulated simply by exposure to selective solvents. In this system nanopores are created or reversibly eliminated in films of a block copolymer, polystyrene-block poly(2-vinyl pyridine) (PS-b-P2VP), by exposing the films to P2VP-selective or PS selective solvents, respectively. The mechanism of the switch is based on the selective swelling of the constituent blocks in corresponding solvents, which is a nondestructive and easily controllable process enabling the repeatable and ample switch between the open and the closed state. Systematic microscopic and ellipsometric characterization methods are performed to elucidate the pore closing course induced by nonsolvents and the cycling between the pore-open and the pore-closed state up to 20 times. The affinity of the solvent for PS blocks is found to play a dominating role in determining the pore-closing process and the porosities of the pore-open films increase with the cycling numbers as a result of loose packing conditions of the polymer chains. We finally demonstrate the potential applications of these films as intelligent antireflection coatings and drug carriers. PMID- 26226939 TI - Pharmacogenetics of cutaneous flushing response to niacin/laropiprant combination in Hong Kong Chinese patients with dyslipidemia. AB - AIM: Cutaneous flushing with niacin varies between individuals and is substantially reduced by concomitant laropiprant. We investigated associations between baseline phenotypes and selected genotypes and flushing symptoms with niacin/laropiprant combination. PATIENTS & METHODS: Flushing symptoms were quantified in 196 Chinese dyslipidaemic patients treated with niacin/laropiprant, and associations with phenotypes and selected polymorphisms were analyzed. RESULTS: Moderate or severe flushing was associated with lower body mass index and the rs2279238 polymorphism in the LXRalpha on multivariate regression analysis and these factors accounted for 18.9% of the total variance. CONCLUSION: Lower body mass index and the LXRalpha polymorphism appear to be associated with flushing symptoms with niacin/laropiprant. Whether these findings can be applicable to other niacin formulations without laropiprant needs to be verified. PMID- 26226938 TI - High-Definition and Non-invasive Brain Modulation of Pain and Motor Dysfunction in Chronic TMD. AB - BACKGROUND: Temporomandibular disorders (TMD) have a high prevalence and in many patients pain and masticatory dysfunction persist despite a range of treatments. Non-invasive brain neuromodulatory methods, namely transcranial direct current stimulation (tDCS), can provide relatively long-lasting pain relief in chronic pain patients. OBJECTIVE: To define the neuromodulatory effect of five daily 2x2 motor cortex high-definition tDCS (HD-tDCS) sessions on clinical pain and motor measures in chronic TMD patients. It is predicted that M1 HD-tDCS will selectively modulate clinical measures, by showing greater analgesic after effects compared to placebo, and active treatment will increase pain free jaw movement more than placebo. METHODS: Twenty-four females with chronic myofascial TMD pain underwent five daily, 20-min sessions of active or sham 2 milliamps (mA) HD-tDCS. Measurable outcomes included pain-free mouth opening, visual analog scale (VAS), sectional sensory-discriminative pain measures tracked by a mobile application, short form of the McGill Pain Questionnaire, and the Positive and Negative Affect Schedule. Follow-up occurred at one-week and four-weeks post treatment. RESULTS: There were significant improvements for clinical pain and motor measurements in the active HD-tDCS group compared to the placebo group for: responders with pain relief above 50% in the VAS at four-week follow-up (P = 0.04); pain-free mouth opening at one-week follow-up (P < 0.01); and sectional pain area, intensity and their sum measures contralateral to putative M1 stimulation during the treatment week (P < 0.01). No changes in emotional values were shown between groups. CONCLUSION: Putative M1 stimulation by HD-tDCS selectively improved meaningful clinical sensory-discriminative pain and motor measures during stimulation, and up to four-weeks post-treatment in chronic myofascial TMD pain patients. PMID- 26226940 TI - Evaluation of renal function in patients with a main renal stone larger than 1 cm and perioperative renal functional change in minimally invasive renal stone surgery: a prospective, observational study. AB - PURPOSE: To compare the perioperative relative renal function and determine predictors of deterioration and recovery of separate renal function in patients with renal stones >10 mm and who underwent mini-percutaneous nephrolithotomy or retrograde intra-renal surgery. PATIENTS AND METHODS: A main stone >10 mm or stones growing, high-risk stone formers and extracorporeal shock-wave lithotripsy resistant stones were prospectively included in 148 patients. Patients with bilateral renal stones and anatomical deformities were excluded. Renal function was evaluated by estimated glomerular filtration rate, 99m-technetium dimercaptosuccinic acid and 99m-technetium diethylenetriamine pentaacetate prior to intervention and at postoperative 3 months. Logistic regression analyses were performed to find predictors of functional deterioration and recovery. RESULTS: The overall stone-free rate was 85.1 %. A third of patients (53/148, 35.8 %) with renal stones >10 mm showed deterioration of separate renal function. Mean renal function of operative sites showed 58.2 % (36.8 %/63.2 %) of that of contralateral sites in these patients. Abnormal separate renal function showed postoperative recovery in 31 patients (58.5 %). Three cases (5.7 %) showed deterioration of separate renal function despite no presence of remnant stones. Improvement rates of the abnormal separate renal function did not differ according to the type of surgery. The presence of hydronephrosis and three or more stones were significant predictors for renal function deterioration. Female gender and three or more stones were significantly correlated with postoperative recovery. CONCLUSIONS: Mini-percutaneous nephrolithotomy or retrograde intra renal surgery was effective and safe for renal function preservation. Patients with multiple large stones should be considered for candidates of active surgical removal. PMID- 26226941 TI - E-cadherin expression in macrophages dampens their inflammatory responsiveness in vitro, but does not modulate M2-regulated pathologies in vivo. AB - IL-4/IL-13-induced alternatively activated macrophages (M(IL-4/IL-13), AAMs or M2) are known to express E-cadherin, enabling them to engage in heterotypic cellular interactions and IL-4-driven macrophage fusion in vitro. Here we show that E-cadherin overexpression in Raw 264.7 macrophages inhibits their inflammatory response to LPS stimulation, as demonstrated by a reduced secretion of inflammatory mediators like interleukin (IL)-6, tumor necrosis factor (TNF) and nitric oxide (NO). To study the function of E-cadherin in M(IL-4/IL-13) macrophages in vivo, we generated macrophage-specific E-cadherin-deficient C57BL/6 mice. Using this new tool, we analyzed immunological parameters during two typical AAM-associated Th2-driven diseases and assessed Th2-associated granuloma formation. Although E-cadherin is strongly induced in AAMs during Taenia crassiceps helminth infections and allergic airway inflammation, its deletion in macrophages does not affect the course of both Th2 cytokine-driven diseases. Moreover, macrophage E-cadherin expression is largely redundant for granuloma formation around Schistosoma mansoni ova. Overall, we conclude that E cadherin is a valuable AAM marker which suppresses the inflammatory response when overexpressed. Yet E-cadherin deletion in macrophages does not affect M(LPS+IFNgamma) and M(IL-4) polarization in vitro, nor in vivo macrophage function, at least in the conditions tested. PMID- 26226942 TI - A case report of a solitary pancreatic metastasis of an adrenocortical carcinoma. AB - BACKGROUND: Solitary metastases to the pancreas are rare. Therefore the value of resection in curative intention remains unclear. In the literature there are several promising reports about resection of solitary metastasis to the pancreas mainly of renal origin. CASE PRESENTATION: Here we report for the first time on the surgical therapy of a 1.5 cm solitary pancreatic metastasis of an adrenocortical carcinoma. The metastasis occurred almost 6 years after resection of the primary tumor. A partial pancreatoduodenectomy was performed and postoperatively adjuvant mitotane treatment was initiated. During the follow-up of 3 years after surgery no evidence of tumor recurrence occurred. CONCLUSION: Resection of pancreatic tumors should be considered, even if the mass is suspicious for metastatic disease including recurrence of adrenocortical cancer. PMID- 26226943 TI - Extraction Kinetics of phytochemicals and antioxidant activity during black tea (Camellia sinensis L.) brewing. AB - BACKGROUND: Tea is the most consumed beverage in the world which is second only to water. Tea contains a broad spectrum of active ingredients which are responsible for its health benefits. The composition of constituents extracted to the tea brew depends on the method of preparation for its consumption. The objective of this study was to investigate the extraction kinetics of phenolic compounds, gallic acid, caffeine and catechins and the variation of antioxidant activity with time after tea brew is made. METHODS: CTC (Crush, Tear, Curl) tea manufactured in Sri Lanka was used in this study. Tea brew was prepared according to the traditional method by adding boiling water to tea leaves. The samples were collected at different time intervals. Total phenolic and flavonoid contents were determined using Folin ciocalteu and aluminium chloride methods respectively. Gallic acid, caffeine, epicatechin, epigallocatechin gallate were quantified by HPLC/UV method. Antioxidant activity was evaluated by DPPH radical scavenging and Ferric Reducing Antioxidant Power (FRAP) assays. RESULTS: Gallic acid, caffeine and catechins were extracted within a very short period. The maximum extractable polyphenols and flavanoids were achieved at 6-8 min after the tea brew is prepared. Polyphenols, flavanoids and epigallocatechin gallate showed a significant correlation (p < 0.001) with the antioxidant activity of tea. CONCLUSION: The optimum time needed to release tea constituents from CTC tea leaves is 2-8 min after tea is made. PMID- 26226945 TI - Effect of municipal solid waste incinerator types on characteristics of ashes from different air pollution control devices. AB - The purpose of this paper is to investigate the characteristics of fly and bottom ashes sampled from both fluidized bed (FB) and mass-burning (MB) municipal solid waste incinerators (MSWIs), respectively. Fly ashes from different locations at FB and MB MSWIs equipped with a cyclone, a semi-dry scrubber, and a bag filter as air pollution control devices were examined to provide the baseline information between physicochemical properties and leaching ability. Experimental results of leachability indicated that the bag filter fly ash (FB-FA(B)) from the FB incinerator meets Taiwan regulatory standards set through the toxicity characteristic leaching procedure. X-ray diffraction results revealed the presence of Cr5O12 and Pb2O3 in the cyclone fly ash (MB-FA(C)) and bag filter fly ash (MB-FA(B)), respectively, from the MB incinerator. To observe lead incorporation mechanism, mixture of simulate lead-laden waste with bed material were fired between 600 degrees C and 900 degrees C in a laboratory scale FB reactor. The results clearly demonstrate a substantial decrease in lead leaching ratio for products with an appropriate temperature. The concentration of Pb in the MB-FA(B) was 250 times that in the FB-FA(B), suggesting that incineration of MSW in FB is a good strategy for stabilizing hazardous metals. PMID- 26226944 TI - Sexual and Reproductive Health Research and Research Capacity Strengthening in Africa: Perspectives from the region. AB - Developing the capacity to effectively carry out public health research is an integral part of health systems at both the national and global levels and strengthening research capacity is recognized as an approach to better health and development in low- and middle-income countries (LMICs). Especially fields such as sexual and reproductive health (SRH) would require inter-disciplinary teams of researchers equipped with a range of methodologies to achieve this. In November 2013, as part of the International Family Planning Conference in Addis Ababa, Ethiopia, a group of African researchers came together to discuss the gaps and strategies to improve sexual and reproductive health research and research capacity strengthening in Africa. This commentary summarizes the three broad areas where the issues and proposed solutions have concentrated around: 1) Addressing research gaps that are most relevant to policies and programmes in SRH, 2) Carrying out high quality and collaborative research, and 3) Translating research findings into SRH policies and programmes. Even though the focus of the discussions was Africa, the issues and proposed solutions can also be applied to other regions facing a high burden of disease with limited resources. The time is now and these can be achieved through synergistic commitment of African and global researchers, funders and organizations. PMID- 26226946 TI - Parenchymal infiltration and lymphoma-associated membranoproliferative pattern of glomerular injury: an unusual presentation of mantle cell lymphoma. AB - Lymphomatous processes have been shown to involve the kidney by direct and paraneoplastic mechanisms. Direct injury can manifest by effacement of typical parenchymal architecture by the lymphomatous infiltrate, and indirect, paraneoplastic mechanisms have been associated with a variety of glomerular lesions. Mantle cell lymphoma (MCL) has rarely been reported to be associated with both direct infiltration and/ or paraneoplastic glomerular lesions. We describe a patient with rapidly progressive glomerulonephritis whose renal biopsy showed effacement of the renal parenchyma by MCL and a membranoproliferative pattern of glomerular injury. The patient's bone marrow was also involved by MCL, and serology revealed small M-spikes and a positive rheumatoid factor. The clinicopathologic findings were consistent with a membranoproliferative pattern of glomerular injury secondary to MCL with infiltrative destruction of renal parenchyma. This case is unusual in that MCL was diagnosed on renal biopsy, that there was a two-pronged mechanism of renal injury, and that there were two separate monoclonal immunoglobulins elaborated by the lymphoma that could be associated with the glomerular injury. Although it is uncommon to make an initial diagnosis of lymphoma from a renal biopsy, it should be recognized that patients with lymphoma might develop clinically significant renal sequelae secondary to both direct and indirect mechanisms of lymphoma-mediated nephropathy. PMID- 26226947 TI - Situs ambiguous and absence of the inferior vena cava: an extremely rare cause of femoral hemodialysis catheter dysfunction. PMID- 26226948 TI - Urinary calcium excretion in postmenopausal African American women. AB - AIM: The objective of this study was to develop a reference range for urine calcium excretion (both 24-hour and fasting) for African American women compared to White women. In addition, the variables that determine urine calcium excretion were identified. MATERIAL: Data were analyzed for baseline studies of healthy postmenopausal volunteers who participated in seven separate studies conducted at one site. METHODS: Some studies included fasting urine Ca/Cr and others 24-hour urine calcium excretion. 24-hour urine calcium was considered with and without correction for urinary creatinine excretion. Calcium was measured initially by atomic absorption spectrophotometry and more recently by an automated method (ADVIA 2400 Chemistry System). RESULTS: Participants were considered healthy based on history and physical and routine laboratory studies. Those screened who had a history of nephrolithiasis were excluded. A reference range for 24-hour urine calcium and fasting urine calcium/ creatinine was developed. Reference intervals of 11 - 197 mg/24-hour urine calcium excretion and of 0.007 - 0.222 of fasting Ca/Cr were found for African American women compared to 21 - 221 mg/24 hours and 0.019 - 0.264 in White women, respectively. Urine creatinine excretion was higher in African Americans consistent with their higher muscle mass. CONCLUSION: Urine calcium excretion is lower in postmenopausal African American than White women. The reference range developed should be considered in the diagnosis of hypocalciuric states and may also be useful in the diagnosis of hypercalciuria. PMID- 26226949 TI - Predictors of outcome for severe IgA Nephropathy in a multi-ethnic U.S. cohort. AB - BACKGROUND: Although IgA nephropathy (IgAN) is the leading cause of glomerulonephritis worldwide, there are few large cohorts representative of U.S. POPULATIONS: Prognosis remains challenging, particularly as more patients are treated with RAAS blockade and immunosuppression. METHODS: We analyzed a retrospective cohort of IgAN patients followed at Columbia University Medical Center from 1980 to 2010. We evaluated two outcomes - halving of eGFR and ESRD - using three proportional hazards models: 1) a model with only clinical parameters, 2) a model with only histopathologic parameters, and 3) a model combining clinical and histopathologic parameters. RESULTS: Of 154 patients with biopsy-proven IgAN, 126 had follow-up data available and 93 had biopsy slides re read. Median follow-up was 47 months. The cohort was 64% male, 60% white, and the average age was 34 years at diagnosis. Median (IQR) eGFR and proteinuria at diagnosis were 64.1 (38.0 - 88.7) mL/min/1.73 m2 and 2.7 (1.3 - 4.5) g/day. Over 90% of subjects were treated with RAAS blockade, and over 66% received immunosuppression. In the clinical parameters-only model, baseline eGFR and African-American race predicted both halving of eGFR and ESRD. In the histopathologic parameters-only model, no parameter significantly predicted outcome. In the combined model, baseline eGFR remained the strongest predictor of both halving of eGFR (p = 0.03) and ESRD (p = 0.001), while the presence of IgG by immunofluorescence microscopy also predicted progression to ESRD. CONCLUSION: In this diverse U.S. IgAN cohort in which the majority of patients received RAAS blockade and immunosuppression, baseline eGFR, African-American race, and co staining of IgG predicted poor outcome. PMID- 26226950 TI - Monitoring of calcineurin inhibitors by NFAT-regulated gene expression in de novo renal allograft recipients on cyclosporine A. AB - INTRODUCTION: Calcineurin inhibitors are critical-dose drugs with a narrow therapeutic range and optimal monitoring strategies are discussed in terms of safety and efficacy. A new pharmacodynamic monitoring tool - assessing the expression of nuclear factor of activated T-cells (NFAT)-regulated genes - has been established to directly measure the functional effect of cyclosporine A (CsA) in an individual patient. Until now, only sparse data on NFAT-regulated gene expression within the early post-transplant period have been available. METHOD: Altogether 80 de novo renal transplant patients were enrolled in this non interventional cohort-study. Immunosuppression consisted of interleukin (IL)-2 receptor antagonist induction, CsA, mycophenolic acid and steroids. Expression of NFAT-regulated genes (IL-2, granulocyte-macrophage colony stimulating-factor (GM CSF), interferon-gamma (IFN-gamma)) was determined by qRT-PCR (real-time reverse transcription-PCR) at CsA C0 (prior to CsA intake) and C2 (2 hours after CsA intake) at regular follow-up visits within 6 months after transplantation. RESULTS: The median age of all patients was 47.9 +/- 13.7 years (54 male). Residual NFAT-regulated gene expression showed a high interindividual variability. Inversely to reduction of CsA doses, NFAT-regulated genes increased from 1.78 +/- 1.33% to 8.04 +/- 7.36% in month 1 to month 6. Despite comparable CsA C0 levels, NFAT-regulated gene expression was significantly less inhibited in patients with treated biopsy-proven acute rejections (2.9 +/- 2.2% vs. 2.0 +/- 1.7%, p = 0.047). Patients with very low residual expression of NFAT-regulated genes were at an increased risk for early infectious episodes. Residual expression of IFN-gamma and GM-CSF genes correlated significantly with clinical outcomes. CONCLUSION: NFAT-regulated gene expression is highly inhibited in the early post-transplant period in renal allograft recipients on CsA treatment. High residual NFAT-regulated gene expression was related to acute rejection episodes and low residual expression with infectious complications. Thus, NFAT-monitoring has the potential to support pharmacokinetic monitoring during the early post transplant period. PMID- 26226951 TI - The role of type I hypersensitivity reaction and IgE-mediated mast cell activation in acute interstitial nephritis. AB - BACKGROUND: Acute interstitial nephritis (AIN) presents with acute kidney injury, with evidence of interstitial inflammation and tubulitis on histology, and the presence of fever, rash, and eosinophiluria. Although the pathogenesis of this disease is not well understood, cell-mediated immunity is thought to play a major role. We hypothesized that IgE mediated mast cell activation is also involved in the pathogenesis of renal injury in AIN. METHODS: 28 patients, with biopsy proven AIN over a 5-year period, were included in this study. Clinical data, including renal outcomes and the etiologies of AIN, were evaluated in all patients. Available tissues (renal biopsy) from 26 of the patients were stained for beta tryptase (marker for mast cell degranulation), IgE, IL-16, and CD3. A negative control for immunostaining was included. RESULTS: Samples from all 26 individuals stained positive for beta-tryptase (mean of 11.16 cells/high power field), IgE (mean average of 0.68 cells/HPF), IL-16 (28% of the interstitium), and CD3 (33% of the interstitium). Acute interstitial nephritis was due to medication in 73%, systemic disease in 15%, and unknown (idiopathic) in 12% of the cases. 86% of patients were treated with corticosteroids. 18% required acute inpatient dialysis, with 7% remaining on dialysis longterm. CONCLUSIONS: Our study suggests that IgE and mast cell activation may play a role in the pathogenesis of AIN. PMID- 26226954 TI - Using liminality to understand mothers' experiences of long-term breastfeeding: 'Betwixt and between', and 'matter out of place'. AB - Breastmilk is widely considered as the optimum nutrition source for babies and an important factor in both improving public health and reducing health inequalities. Current international/national policy supports long-term breastfeeding. UK breastfeeding initiation rates are high but rapidly decline, and the numbers breastfeeding in the second year and beyond are unknown. This study used the concept of liminality to explore the experiences of a group of women breastfeeding long-term in the United Kingdom, building on Mahon-Daly and Andrews. Over 80 breastfeeding women were included within the study, which used micro-ethnographic methods (participant observation in breastfeeding support groups, face-to-face interviews and online asynchronous interviews via email). Findings about women's experiences are congruent with the existing literature, although it is mostly dated and from outside the United Kingdom. Liminality was found to be useful in providing insight into women's experiences of long-term breastfeeding in relation to both time and place. Understanding women's experience of breastfeeding beyond current usual norms can be used to inform work with breastfeeding mothers and to encourage more women to breastfeed for longer. PMID- 26226952 TI - Autophagic digestion of Leishmania major by host macrophages is associated with differential expression of BNIP3, CTSE, and the miRNAs miR-101c, miR-129, and miR 210. AB - BACKGROUND: Autophagy participates in innate immunity by eliminating intracellular pathogens. Consequently, numerous microorganisms have developed strategies to impair the autophagic machinery in phagocytes. In the current study, interactions between Leishmania major (L. m.) and the autophagic machinery of bone marrow-derived macrophages (BMDM) were analyzed. METHODS: BMDM were generated from BALB/c mice, and the cells were infected with L. m. promastigotes. Transmission electron microscopy (TEM) and electron tomography were used to investigate the ultrastructure of BMDM and the intracellular parasites. Affymetrix chip analyses were conducted to identify autophagy-related messenger RNAs (mRNAs) and microRNAs (miRNAs). The protein expression levels of autophagy related 5 (ATG5), BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), cathepsin E (CTSE), mechanistic target of rapamycin (MTOR), microtubule associated proteins 1A/1B light chain 3B (LC3B), and ubiquitin (UB) were investigated through western blot analyses. BMDM were transfected with specific small interfering RNAs (siRNAs) against autophagy-related genes and with mimics or inhibitors of autophagy-associated miRNAs. The infection rates of BMDM were determined by light microscopy after a parasite-specific staining. RESULTS: The experiments demonstrated autophagy induction in BMDM after in vitro infection with L. m.. The results suggested a putative MTOR phosphorylation-dependent counteracting mechanism in the early infection phase and indicated that intracellular amastigotes were cleared by autophagy in BMDM in the late infection phase. Transcriptomic analyses and specific downregulation of protein expression with siRNAs suggested there is an association between the infection-specific over expression of BNIP3, as well as CTSE, and the autophagic activity of BMDM. Transfection with mimics of mmu-miR-101c and mmu-miR-129-5p, as well as with an inhibitor of mmu-miR-210-5p, demonstrated direct effects of the respective miRNAs on parasite clearance in L. m.-infected BMDM. Furthermore, Affymetrix chip analyses revealed a complex autophagy-related RNA network consisting of differentially expressed mRNAs and miRNAs in BMDM, which indicates high glycolytic and inflammatory activity in the host macrophages. CONCLUSIONS: Autophagy in L. m.-infected host macrophages is a highly regulated cellular process at both the RNA level and the protein level. Autophagy has the potential to clear parasites from the host. The results obtained from experiments with murine host macrophages could be translated in the future to develop innovative and therapeutic antileishmanial strategies for human patients. PMID- 26226955 TI - Vanishing High Mountain Glacial Archives: Challenges and Perspectives. PMID- 26226953 TI - Alberta Provincial Pediatric EnTeric Infection TEam (APPETITE): epidemiology, emerging organisms, and economics. AB - BACKGROUND: Each year in Canada there are 5 million episodes of acute gastroenteritis (AGE) with up to 70% attributed to an unidentified pathogen. Moreover, 90% of individuals with AGE do not seek care when ill, thus, burden of disease estimates are limited by under-diagnosing and under-reporting. Further, little is known about the pathogens causing AGE as the majority of episodes are attributed to an "unidentified" etiology. Our team has two main objectives: 1) to improve health through enhanced enteric pathogen identification; 2) to develop economic models incorporating pathogen burden and societal preferences to inform enteric vaccine decision making. METHODS/DESIGN: This project involves multiple stages: 1) Molecular microbiology experts will participate in a modified Delphi process designed to define criteria to aid in interpreting positive molecular enteric pathogen test results. 2) Clinical data and specimens will be collected from children aged 0-18 years, with vomiting and/or diarrhea who seek medical care in emergency departments, primary care clinics and from those who contact a provincial medical advice line but who do not seek care. Samples to be collected will include stool, rectal swabs (N = 2), and an oral swab. Specimens will be tested employing 1) stool culture; 2) in-house multiplex (N = 5) viral polymerase chain reaction (PCR) panel; and 3) multi-target (N = 15) PCR commercially available array. All participants will have follow-up data collected 14 days later to enable calculation of a Modified Vesikari Scale score and a Burden of Disease Index. Specimens will also be collected from asymptomatic children during their well child vaccination visits to a provincial public health clinic. Following the completion of the initial phases, discrete choice experiments will be conducted to enable a better understanding of societal preferences for diagnostic testing and vaccine policy. All of the results obtained will be integrated into economic models. DISCUSSION: This study is collecting novel samples (e.g., oral swabs) from previously untested groups of children (e.g., those not seeking medical care) which are then undergoing extensive molecular testing to shed a new perspective on the epidemiology of AGE. The knowledge gained will provide the broadest understanding of the epidemiology of vomiting and diarrhea of children to date. PMID- 26226956 TI - The Influence of Iron and Zinc Supplementation on the Bioavailability of Provitamin A Carotenoids from Papaya Following Consumption of a Vitamin A Deficient Diet. AB - Iron deficiency anemia, zinc and vitamin A deficiencies are serious public health problems in Cameroon, as in many developing countries. Local vegetables which are sources of provitamin A carotenoids (PACs) can be used to improve vitamin A intakes. However, traditional meals are often unable to cover zinc and iron needs. The aim of this study was to determine the bioavailability of 3 PACs (alpha-carotene, beta-carotene, and beta-cryptoxanthin) in young men, who were fed with a vitamin A-free diet and received iron and zinc supplementation. Twelve healthy participants were divided into three groups and were supplemented with elemental iron (20 mg of iron fumarate), 20 mg of zinc sulfate or iron+zinc (20 mg of iron in the morning and 20 mg of zinc in the evening) for 11 d. They were given a vitamin A- and PAC-free diet from the 6th to the 11th day, followed by a test meal containing 0.55 kg of freshly peeled papaya as a source of PACs. Blood samples were collected four times successively on the 11th day (the test meal day), at T0 (just after the test meal), after 2 h (T2), after 4 h (T4) and after 7 h (T7). Ultracentrifugation was used to isolate serum chylomicrons. Retinol appearance and PAC postprandial concentrations were determined. The supplementation with zinc, iron and iron+zinc influenced the chylomicron appearance of retinol and PACs differently as reflected by retention times and maximum absorption peaks. Iron led to highest retinol levels in the chylomicron. Zinc and iron+zinc supplements were best for optimal intact appearance of alpha carotene, beta-carotene and beta-cryptoxanthin respectively. Supplementation with iron led to the greatest bioavailability of PACs from papaya and its conversion to retinol. PMID- 26226957 TI - Exercise and a High Fat Diet Synergistically Increase the Pantothenic Acid Requirement in Rats. AB - It is thought that both exercise and dietary composition increase the utilization of, and thus the requirement for, certain water-soluble vitamins. However, there have been no studies evaluating the combined impacts of exercise and dietary composition on vitamin utilization. In this experiment, rats were fed a pantothenic acid (PaA)-restricted (0.004 g PaA-Ca/kg diet) diet containing 5% (ordinary amount of dietary fat) or 20% fat (high fat), and were forced to swim until exhaustion every other day for 22 d. PaA status was assessed by urinary excretion, which reflects body stores of water-soluble vitamins. The urinary excretion of PaA in rats fed a 5% fat diet was not affected by swimming (5% fat + non-swimming vs. 5% fat + swim; p>0.05). Excretion of PaA was decreased by the high-fat diet (5% fat + non-swim vs. 20% fat + non-swim; p<0.05) and synergistically decreased by exercise (20% fat + non-swim vs. 20% fat + swim; p<0.05). There was a significant interaction between exercise and a high-fat diet. Plasma PaA concentrations showed changes similar to those seen for urinary excretion. The experiment was then repeated using rats fed a PaA-sufficient (0.016 g PaA-Ca/kg diet) diet, and PaA excretion was again synergistically decreased by the combination of exercise and a high-fat diet (p<0.05). These results suggest that the combination of exercise and a high-fat diet synergistically increases the requirement for PaA. PMID- 26226958 TI - Chemical Synthesis of a Very Long-Chain Fatty Acid, Hexacosanoic Acid (C26:0), and the Ceramide Containing Hexacosanoic Acid. AB - Hexacosanoic acid (C26:0) (1), a very long-chain fatty acid, is related to various diseases such as adrenoleukodystrophy (ALD), adrenomyeloneuropathy (AMN) and atherosclerosis. As the level of 1 higher than the normal is related to diseases above, hexacosanoic acid (1) and the ceramide 2, which contains 1, are thought to play an important role in various tissues. Hexacosanoic acid (1) is known to be a waxy solid and to be hard to dissolve in water as well as organic solvents. Due to this physical property, it is not easy to handle hexacosanoic acid (1) in a laboratory. Therefore, efficient chemical synthesis of the compounds 1 and 2 has not been reported. Here, we report a versatile synthetic method for hexacosanoic acid (1) and the ceramide 2 containing the fatty acid 1. Synthesis of hexacosanoic acid (1) was achieved by applying the coupling of two alkyl units as a key step. Ceramide 2 was efficiently synthesized by applying the reported procedure together with hexacosanoic acid (1) synthesized here. This synthetic strategy has an advantage of getting various carbon chain length fatty acids and their ceramides by using a variety of carbon chain units. This method is also applicable for large-scale synthesis. In addition, these compounds 1 and 2 are useful for investigation of details of these compounds related to diseases such as ALD and AMN. PMID- 26226959 TI - Different Effects of Sheep- and Duck-Meat Supplemented Diets on Serum Cytokine Levels of Rats. AB - This study aimed to explore the mechanism underlying the different effects of diet supplemented with sheep- or duck-meat on serum cytokines of rats. METHODS: Male Sprague-Dawley rats were randomly divided into three groups fed on sheep meat, duck meat, or soybean, respectively. The profiles of amino acids and fatty acids of the three diets were examined, and the levels of serum cytokines in rats, including interleukin-1beta (IL-1beta), IL-2, IL-4, IL-6, IL-10 and tumor necrosis factor-alpha (TNF-alpha), were detected 30 d after feeding, using radioimmunoassay. The contents of methionine and glycine in the sheep-meat and duck-meat diets were significantly higher than those in the soybean diet. The content of saturated fatty acids in the sheep-meat diet and duck-meat diet was higher than that in soybeans, while the polyunsaturated fatty acids (PUFAs) in the duck-meat diet were highest and those in the sheep-meat diet were lowest. Serum levels of IL-2 and IL-10 in the rats of the sheep-meat and duck-meat groups were significantly higher than those in the rats of the soybean group (p<0.05). IL-10 and TNF-alpha in the rats of the sheep-meat group were higher than those in the duck-meat group. But the levels of IL-1beta and IL-6 were not significantly different among the three groups. Additionally, there were positive correlations between glycine and IL-1beta as well as glycine and IL-2, while negative correlation existed between C18:2 and TNF-alpha. Methionine, glycine and PUFAs in a diet supplemented with sheep- or duck-meat might influence the levels of serum cytokines in rats, suggesting the potential regulatory mechanism of amino acids and fatty acids from diet in immune responses. PMID- 26226960 TI - Effects of Pyrroloquinoline Quinone Disodium Salt Intake on the Serum Cholesterol Levels of Healthy Japanese Adults. AB - Pyrroloquinoline quinone (PQQ) is a water-soluble quinone compound that has a strong anti-oxidant capacity. A previous study in rats fed a PQQ-depleted diet showed that elevated levels of serum triglyceride (TG) decreased after PQQ supplementation. However, there is only one study reporting the effects of PQQ on serum lipid levels, such as those of TG and cholesterol, in humans. In this study, the effects of PQQ disodium salt (BioPQQTM) on serum TG and cholesterol levels in humans after 6 and 12 wk of treatment at an oral dosage of 20 mg/d were examined. This trial was conducted according to a randomized, placebo-controlled, double-blinded protocol. A total of 29 healthy Japanese adults, ranging from 40 to 57 y old, with normal to moderately high TG levels (110-300 mg/dL) as measured by a recent blood examination, were included in this study. In eleven volunteers out of 29, serum low-density lipoprotein cholesterol (LDL-chol) levels at baseline were high (>=140 mg/dL). After 12 wk, the mean serum TG levels had not changed; however, a marginally significant decrease in the mean LDL-chol (from 136.1 to 127.0 mg/dL) was observed in the PQQ group. In the stratification analysis of the high LDL-chol subgroup (baseline LDL-chol level >=140 mg/dL), the mean LDL-chol levels decreased significantly from the baseline values in the PQQ group compared to the placebo group. Our study findings suggest that PQQ suppressed the LDL-chol level, which is an important finding, because a high level of this lipid is a risk factor for various lifestyle-related diseases. PMID- 26226961 TI - Effects of Orally Administered Pyrroloquinoline Quinone Disodium Salt on Dry Skin Conditions in Mice and Healthy Female Subjects. AB - Pyrroloquinoline quinone (PQQ) is a coenzyme involved in the redox-cycling system. The supplemental use of PQQ has been examined based on its properties as an antioxidant and redox modulator. Although an animal study on deficiency of PQQ suggested that PQQ contributes to skin conditions, its efficacy in humans has not been reported. The present study aimed to investigate the effects of orally administered PQQ on skin moisture, viscoelasticity, and transepidermal water loss (TEWL) both in dry skin mouse models and in healthy female subjects with a subjective symptom of dry skin. In our dry skin mouse model study, oral intake of PQQ (0.0089%, w/w, in the diet for 6 wk) significantly decreased the number of mast cells in the dermis and the number of CD3+ T-cells in the epidermis. In our human study, oral intake of PQQ (20 mg/d for 8 wk) significantly inhibited the increase in TEWL on the forearm. Finally, subject questionnaires showed positive impressions for the improvement of skin conditions. These results suggest that oral intake of PQQ improves skin conditions both in female subjects with dry skin and in mice with a compromised skin barrier function. PMID- 26226963 TI - Association between Regular Exercise and Dietary Intake among Japanese Young Adults Aged 18-24 Years: A Cross-Sectional Study. AB - The aim of this study was to examine the association between regular exercise and dietary intake in Japanese young adults. A cross-sectional study was performed between May 2013 and July 2013 in universities, colleges, and technical schools located in Ibaraki, Kanagawa, Tokyo, and Nara in Japan. The final sample comprised 654 students, 473 females and 181 males, aged 18-24 y. Regular exercise and dietary intake were assessed using validated self-reported questionnaires. Logistic regression analyses were applied to examine the association between regular exercise and dietary intake. A total of 18% females and 40% males spent >=5 h per week exercising. Females who spent >=5 h per week exercising were likely to have a higher intake of fruits (odds ratio (OR), 1.84; 95% confidence interval (CI), 1.09-3.13) and a lower intake of cereals (OR, 0.57; 95% CI, 0.33 0.97) than were those who spent <1 h per week. Males who spent >=5 h per week exercising were more likely to have a higher intake of fish and shellfish (OR, 2.69; 95% CI, 1.07-6.77) than those who spent <1 h per week. In conclusions, young adults who spent >=5 h per week exercising had a higher intake of fruits among females, and a higher intake of fish and shellfish among males than those who spent <1 h per week. The present findings suggested food group intakes associated with regular exercise in Japanese young adults. PMID- 26226962 TI - Mechanisms Involved in Guiding the Preference for Fat Emulsion Differ Depending on the Concentration. AB - High-fat foods tend to be palatable and can cause addiction in mice via a reinforcing effect. However, mice showed preference for low fat concentrations that do not elicit a reinforcing effect in a two-bottle choice test with water as the alternative. This behavior indicates the possibility that the mechanism underlying fat palatability may differ depending on the dietary fat content. To address this issue, we examined the influences of the opioid system and olfactory and gustatory transductions on the intake and reinforcing effects of various concentrations of a dietary fat emulsion (Intralipid). We found that the intake and reinforcing effects of fat emulsion were reduced by the administration of an opioid receptor antagonist (naltrexone). Furthermore, the action of naltrexone was only observed at higher concentrations of fat emulsion. The intake and the reinforcing effects of fat emulsion were also reduced by olfactory and glossopharyngeal nerve transections (designated ONX and GLX, respectively). In contrast to naltrexone, the effects of ONX and GLX were mainly observed at lower concentrations of fat emulsion. These results imply that the opioid system seems to have a greater role in determining the palatability of high-fat foods unlike the contribution of olfactory and glossopharyngeal nerves. PMID- 26226964 TI - Plasma TNF-alpha Is Associated with Inflammation and Nutrition Status in Community-Dwelling Japanese Elderly. AB - Inflammation has been suggested to play an important role in age-related chronic diseases and disability, and it is associated with nutritional status including obesity and malnutrition. While numerous studies have examined the validity of inflammatory markers in the population studies in Caucasian elderly people, very little information is available for the factors affecting inflammatory markers in Asian elderly people. Among inflammatory markers frequently used for the studies of aging, tumor necrosis factor alpha (TNF-alpha) is produced mainly by macrophages, and contributes to production of interleukin-6 (IL-6) and C-reactive protein (CRP), thus directing a chronic inflammatory process in the body. In the present study, we examined the associations between plasma TNF-alpha level and several factors related to nutrition status, including BMI, albumin, and energy intake in community-dwelling Japanese elderly. We conducted a cross-sectional study of 390 men and women aged 70-86 y (average 73.5 y), who participated in health check-ups. Associations between plasma TNF-alpha levels, other clinical parameters, and lifestyle factors were analyzed using Spearman's rank correlation coefficient analysis and multiple linear regression analysis. In elderly men, plasma TNF-alpha level was positively associated with age, white blood cell count, monocyte count, plasma CRP level, serum creatinine, ureic acid, and triacylglycerol levels, and negatively associated with albumin/globulin ratio, eGFR, and serum HDL-cholesterol level. In elderly women, plasma TNF-alpha level was positively associated with age, plasma CRP level, and serum triacylglycerol level, and negatively associated with serum albumin and HDL-cholesterol levels. The results of this study suggest that plasma TNF-alpha is associated with inflammation and insulin resistance in both Japanese elderly men and women, and a prominent association of TNF-alpha with malnutrition status was observed in elderly women. PMID- 26226965 TI - The Biosynthesis of the Thiazole Moiety of Thiamin in the Archaeon Halobacterium salinarum. AB - The biosynthetic pathways of the thiazole moiety of thiamin were studied in the archaeon Halobacterium salinarum. Thiamin is generated by the union of 4-amino-5 hydroxymethyl-2-methylpyrimidine (pyrimidine) and 5-(2-hydroxyethyl)-4 methylthiazole (thiazole). The biosynthesis of thiazole is different in facultative anaerobes, aerobes and eukaryotes. In eukaryotes, the C-4, -4', -5, 5' and -5" of the thiazole is biosynthesized from nicotinamide adenine dinucleotide (NAD), with cysteine as S donor and the C-2 and N atoms of glycine. In facultative anaerobic bacteria, such as Escherichia coli, the precursors of the thiazole are the N and C-2 atoms from tyrosine and C-4, -4', -5, -5' and -5" from 1-deoxy-D-xylurose-5-phosphate, again with cysteine as S donor. In aerobic bacteria, such as Bacillus subtilis, L-tyrosine is replaced by glycine. In Archaea, known as the third domain of life, the biosynthetic pathway of thiamin has not yet been elucidated. In the present study in the archaeon H. salinarum, it was shown that both the N and C-2 from glycine are incorporated into the thiazole, rather than the N atom coming from L-tyrosine. These results show that thiazole biosynthesis in H. salinarum more closely resembles the biosynthetic pathway found in eukaryotes. PMID- 26226966 TI - Black Soybean Seed Coat Extract Prevents Hydrogen Peroxide-Mediated Cell Death via Extracellular Signal-Related Kinase Signalling in HepG2 Cells. AB - Oxidative stress reduces cell viability and contributes to disease processes. Flavonoids including anthocyanins and proanthocyanidins reportedly induce intracellular antioxidant defence systems. Thus, in this study, we examined the antioxidant effects of a commercial extract from black soybean seed coats (BE), which are rich in anthocyanin and proanthocyanidin, and investigated the associated intracellular mechanisms in HepG2 cells. HepG2 cells treated with hydrogen peroxide (HPO) showed 60% viability, whereas pretreatment with BE containing media for 2 h ameliorated HPO-mediated cell death by up to 90%. Pretreatment with BE for 2 h partially blocked HPO-mediated activation of ERK in HepG2 cells, and that for 1 h led to a 20% increase in intracellular total protein phosphatase (PP) activity, which is known to deactivate protein kinases. These results indicate that BE prevents HPO-mediated cell damage by inhibiting ERK signalling, potentially via PPs. PMID- 26226967 TI - Influence of Chronic Social Defeat Stress on Digestive System Functioning in Rats. AB - Mental disorders are caused by chronic psychosocial stress, and can cause various symptoms related to the digestive system. We focused on the conjugation of intestinal absorptive and enzymatic mechanisms between chronic social defeat stress (CSDS) model rats and healthy controls to obtain general biochemical data about the intestine of the model in this study. The small intestine was divided into three regions: proximal (PI), middle (MI), and distal (DI); mRNA expression associated with a nutrient absorption, glucose absorption activity, and activities of the digestive enzymes such as maltase, sucrase and lactase was measured. Expression of both sodium-dependent glucose transporter 1 (Sglt1) and glucose transporter 2 gene tended to be higher in the stress group compared to the control group in PI. Glucose absorption was also higher in PI of the CSDS group. Sglt1 and peptide transporter 1 gene expressions in the CSDS group were significantly higher than those in the control group in DI. Furthermore, in PI, expression of the aquaporin 1 gene was significantly higher in the CSDS group compared to the control group. Thus, absorption of some nutrients might be higher in the small intestine of the CSDS rat. PMID- 26226968 TI - Alcohol Limits and Public Safety. AB - On May 14, 2013, the National Transportation Safety Board (NTSB) recommended lowering the legal blood-alcohol limit to 0.05 g/dL for motor vehicle operators in the United States, in an effort to reduce the risk of injuries and deaths caused by a driver's alcohol impairment (NTSB/SR-13/01). This recommendation has prompted other organizations and agencies, including the National Safety Council, to evaluate and consider supporting this action. In order to determine the scientific and legal feasibility and advisability of lowering or establishing 0.05 per se laws, we examined 554 alcohol-related publications. Risk factors, instrument reliability, law enforcement, and adjudication issues were considered in this overview of the literature. The extensive scientific literature reviewed provides ample support for lowering the operation of motor vehicle alcohol limits to 0.05, and for supporting the NTSB recommendations. Research clearly demonstrates that impairment begins at very low concentrations, well below the recommended NTSB limit, and increases with concentration. Lowering the limit to 0.05 will save many lives and prevent injuries. Breath, blood, and saliva samples have proved to be accurate and reliable specimens for legal acceptability in a court of law. PMID- 26226969 TI - On-Site Detection as a Countermeasure to Chemical Warfare/Terrorism. AB - On-site monitoring and detection are necessary in the crisis and consequence management of wars and terrorism involving chemical warfare agents (CWAs) such as sarin. The analytical performance required for on-site detection is mainly determined by the fatal vapor concentration and volatility of the CWAs involved. The analytical performance for presently available on-site technologies and commercially available on-site equipment for detecting CWAs interpreted and compared in this review include: classical manual methods, photometric methods, ion mobile spectrometry, vibrational spectrometry, gas chromatography, mass spectrometry, sensors, and other methods. Some of the data evaluated were obtained from our experiments using authentic CWAs. We concluded that (a) no technologies perfectly fulfill all of the on-site detection requirements and (b) adequate on-site detection requires (i) a combination of the monitoring-tape method and ion-mobility spectrometry for point detection and (ii) a combination of the monitoring-tape method, atmospheric pressure chemical ionization mass spectrometry with counterflow introduction, and gas chromatography with a trap and special detectors for continuous monitoring. The basic properties of CWAs, the concept of on-site detection, and the sarin gas attacks in Japan as well as the forensic investigations thereof, are also explicated in this article. PMID- 26226970 TI - Pharmacology, Toxicology, and Adverse Effects of Synthetic Cannabinoid Drugs. AB - Synthetic cannabinoid drugs have become an established part of the recreational drug landscape in the United States and internationally. These drugs are manufactured in clandestine laboratories internationally and distributed in the United States in smoking mixtures, use of which produces effects very similar to use of marijuana. The adverse-effect profile of the drugs has not been studied in humans and infrequently in animal models, so much of the information about their toxicity comes from emergency department and treatment reports and forensic case studies. This review considers the discovery and characterization of the endocannabinoid system, approaches to receptor-binding studies of various synthetic cannabinoids from the first wave of naphthoylindoles (e.g., JWH-018) to the emerging adamantoylindole drugs (e.g., AKB-48), and their analogs, to evaluate the potential activity of drugs in this class. Currently employed approaches to assessing functional activity of the drugs using in vitro and in vivo models is also described, and comparisons made to the effects of THC. The physiological effects of activation of the endocannabinoid system in humans are reviewed, and the physiological effects of cannabinoid use are described. Case reports of adverse events including emergency department admissions, mental health admissions, and clinical and forensic case reports are presented in detail and discussed to summarize the current state of knowledge of adverse effects, both clinical and forensic in humans, including effects on driving ability, and tissue injury and death. The greatest weight is accorded to those reports that include toxicological confirmation of use. Finally, we discuss the current status of attempts to schedule and control the distribution of synthetic cannabinoids and the relevance of receptor binding and functional activity in this context. There is growing toxicological and pharmacological evidence of impairment, psychosis, tissue injury, and isolated deaths attributable to this emerging class of drugs. PMID- 26226971 TI - Biosocial correlates of age at menarche in a British cohort. AB - BACKGROUND: A large number of biosocial variables have been shown to associate with age at menarche, but the results are inconsistent and differentiate not only between countries but within countries as well. AIM: This study examined age at menarche in a British national cohort in relation to 21 biosocial and anthropometric variables. SUBJECTS AND METHODS: The analyses were based on 4483 girls from the British National Child Development Study (NCDS). RESULTS: The majority of girls reached menarche between 12-14 years of age. Girls from smaller families, those living in the East and South East, South West, West Midlands and Wales regions, in tied housing and uncrowded conditions, not sharing a bedroom, not having free school meals, whose families lived in households without financial problems had started menstruating earlier than their peers from families with lower socioeconomic status. However, when all the significant variables were analysed together significant associations remained only for mother's age at menarche, height and weight at 7 years, family size and tenure. CONCLUSIONS: The results of this study support the hypotheses that intra-uterine growth and conditions in early life as well as socio-economic background are associated with the timing of menarche and that greater childhood growth and better SES are related to earlier menarche. PMID- 26226972 TI - Change, stability and prediction of gross motor co-ordination in Portuguese children. AB - BACKGROUND: The knowledge about intra- and inter-individual variation can stimulate attempts at description, interpretation and prediction of motor co ordination (MC). AIM: To analyse change, stability and prediction of motor co ordination (MC) in children. SUBJECTS AND METHODS: A total of 158 children, 83 boys and 75 girls, aged 6, 7 and 8 years, were evaluated in 2006 and re-evaluated in 2012 at 12, 13 and 14 years of age. MC was assessed through the Kiphard Schilling's body co-ordination test and growth, skeletal maturity, physical fitness, fundamental motor skills (FMS), physical activity and socioeconomic status (SES) were measured and/or estimated. RESULTS: Repeated-measures MANOVA indicated that there was a significant effect of group, sex and time on a linear combination of the MC tests. Univariate tests revealed that group 3 (8-14 years) scored significantly better than group 1 (6-12 years) in all MC tests and boys performed better than girls in hopping for height and moving sideways. Scores in MC were also higher at follow-up than at baseline. Inter-age correlations for MC were between 0.15-0.74. Childhood predictors of MC were growth, physical fitness, FMS, physical activity and SES. Biological maturation did not contribute to prediction of MC. CONCLUSION: MC seemed moderately stable from childhood through adolescence and, additionally, inter-individual predictors at adolescence were growth, FMS, physical fitness, physical activity and SES. PMID- 26226973 TI - Analysis of MC4R rs17782313, POMC rs1042571, APOE-Hha1 and AGRP rs3412352 genetic variants with susceptibility to obesity risk in North Indians. AB - BACKGROUND: Obesity is a multi-factorial disorder influenced by genetic and environmental factors. The physiological pathways associated with obesity are complex and involve several genes. AIM: The aim of this survey is to evaluate the association of genetic variants of melanocortin-4-receptor (MC4R), pro opiomelanocortin (POMC), apolipoprotein E (APOE) and agouti-related protein (AGRP) with obesity in the North Indian population. METHODS: MC4R rs17782313, POMC rs1042571, APOE-Hha1 and AGRP rs3412352 polymorphisms were investigated for their association in 396 obese individuals with BMI >= 30 kg/m(2) and 300 healthy non-obese individuals with BMI < 30 kg/m(2). Genotyping was performed using Taqman probes and PCR-RFLP methods. Single locus logistic regression analysis was conducted using (SPSS), ver.19 and PLINK software Version 1.01 and high order genetic interactions associated with obesity risk were analysed using MDR software (version 2.3.0.2). RESULTS: The genotypes of MC4R rs17782313, POMC rs1042571 and APOE-Hha1 were significantly associated with obese individuals (BMI >= 30 kg/m(2)) when compared with non-obese individuals (BMI < 30 kg/m(2)). No association of AGRP rs34123523 was seen with obesity. CONCLUSIONS: The best interaction model for predicting obesity risk by MDR analysis was the three factor model including POMC (C > T), MC4R (T > C) and APOE (Hha1) polymorphisms. Genetic variants in MC4R, POMC and APOE genes might play significant roles in predisposing obesity (BMI >= 30 kg/m(2)) in the North Indian population. PMID- 26226974 TI - Predictive equations for estimating regional body composition: a validation study using DXA as criterion and associations with cardiometabolic risk factors. AB - BACKGROUND: Regional body composition can influence disease risk and simple screening methods to identify individuals at risk are still needed. AIM: To develop equations for estimating fat and lean mass distribution, using DXA as a criterion, and to compare their performance by the association with cardiometabolic risk factors (systolic and diastolic blood pressure, high-density lipoprotein cholesterol, triacylglycerides and fasting glucose). SUBJECT AND METHODS: The study was conducted among 391 adults (52% female; aged 24-64 years), randomly selected from the EPIPorto cohort, with anthropometric (skin-folds and circumferences) and DXA measures. Multiple linear regression models, by sex, were used to derive predictive equations and to investigate their performance by the associations with cardiometabolic risk factors. RESULTS: The best predicting models included circumferences and skin-folds. The final equations standard error (SEEs) ranged between 1.7-3.2% in men and 2.0-3.7% in women. Similar associations were found between regional body composition, measured by DXA or estimated by anthropometric equations, with traditional cardiometabolic risk factors, supporting the convergent validity of the equations. Additionally, it was found that central fat was associated adversely, whereas peripheral fat was favourably associated with cardiometabolic risk factors and their clustering. CONCLUSIONS: Equations combining both circumferences and skin-folds met the necessary standards for predicting regional body composition accurately, being an important tool to identify individuals with cardiometabolic risk. PMID- 26226975 TI - A diagnostic dilemma: variant Bernard-Soulier syndrome, a difficult clinical and genetic diagnosis. PMID- 26226976 TI - Quantitative Analysis of Cerebrospinal Fluid Pressure Gradients in Healthy Volunteers and Patients with Normal Pressure Hydrocephalus. AB - Magnetic resonance imaging (MRI) can depict not only anatomical information, but also physiological factors such as velocity and pressure gradient. Measurement of these physiological factors is necessary to understand the cerebrospinal fluid (CSF) environment. In this study we quantified CSF motion in various parts of the CSF space, determined changes in the CSF environment with aging, and compared CSF pressure gradient between patients with idiopathic normal pressure hydrocephalus (iNPH) and healthy elderly volunteers. Fifty-seven healthy volunteers and six iNPH patients underwent four-dimensional (4D) phase-contrast (PC) MRI. CSF motion was observed and the pressure gradient of CSF was quantified in the CSF space. In healthy volunteers, inhomogeneous CSF motion was observed whereby the pressure gradient markedly increased in the center of the skull and gradually decreased in the periphery of the skull. For example, the pressure gradient at the ventral surface of the brainstem was 6.6 times greater than that at the convexity of the cerebrum. The pressure gradient was statistically unchanged with aging. The pressure gradient of patients with iNPH was 3.2 times greater than that of healthy volunteers. The quantitative analysis of 4D-PC MRI data revealed that the pressure gradient of CSF can be used to understand the CSF environment, which is not sufficiently given by subjective impression of the anatomical image. PMID- 26226977 TI - Indications and Timings of Re-operation for Residual or Recurrent Hemifacial Spasm after Microvascular Decompression: Personal Experience and Literature Review. AB - We reviewed reports about the postoperative course of hemifacial spasm (HFS) after microvascular decompression (MVD), including in our own patients, and investigated treatment for delayed resolution or recurrence of HFS. Symptoms of HFS disappear after surgery in many patients, but spasm persists postoperatively in about 10-40%. Residual spasm also gradually decreases, with rates of 1-13% at 1 year postoperatively. However, because delayed resolution is uncommon after 1 year postoperatively, the following is advised: (1) In patients with residual spasms after 1 year postoperatively (incomplete cure) or who again experience spasm >= 1 year postoperatively (recurrence), re-operation is recommended if the spasms are worse than before MVD. (2) When re-operation is considered, preoperative magnetic resonance imaging (MRI) findings and intraoperative videos should be reviewed to ensure that no compression due to a small artery or vein was missed, and to confirm that adhesions with the prosthesis are not causing compression. If any suspicious findings are identified, the cause must be eliminated. Moreover, because of the risk of nerve injury, decompression of the distal portion of the facial nerve should be performed only in patients in whom distal compression is strongly suspected to be the cause of symptoms. (3) Cure rates after re-operation are high, but complications such as hearing impairment and facial weakness have been reported in 10-20% of cases, so surgery must be performed with great care. PMID- 26226978 TI - Posterior Cranial Vault Distraction Osteogenesis with Barrel Stave Osteotomy in the Treatment of Craniosynostosis. AB - Twenty years have passed since distraction osteogenesis was introduced into the field of craniomaxillofacial surgery, with distraction osteogenesis gradually consolidating its position for midface advancement in syndromic craniosynostosis. On the other hand, no consensus has been reached regarding its adaptation to calvarial bone. We reported that distraction osteogenesis was useful in posterior cranial vault expansion, and subsequently, similar reports have been successively observed worldwide. In posterior cranial vault distraction, intracranial capacity could be greatly expanded due to its simultaneous expansion with the scalp, with little risk of relapse because new bone is regenerated in the distraction gap. The possibility was suggested that the standard of first carrying out fronto orbital advancement (FOA) for brachycephaly observed in syndromic craniosynostosis will greatly change posterior cranial vault distraction. PMID- 26226979 TI - Limitations of Neuroendoscopic Treatment for Pediatric Hydrocephalus and Considerations from Future Perspectives. AB - Neuroendoscopy has become common in the field of pediatric neurosurgery. As an alternative procedure to cerebrospinal fluid shunt, endoscopic third ventriculostomy has been the routine surgical treatment for obstructive hydrocephalus. However, the indication is still debatable in infantile periods. The predictors of late failure and how to manage are still unknown. Recently, the remarkable results of endoscopic choroid plexus coagulation in combination with third ventriculostomy, reported from experiences in Africa, present puzzling complexity. The current data on the role of neuroendoscopic surgery for pediatric hydrocephalus is reported with discussion of its limitations and future perspectives, in this review. PMID- 26226980 TI - Evaluation of the Production and Absorption of Cerebrospinal Fluid. AB - The traditional hypothesis of cerebrospinal fluid (CSF) hydrodynamics presumes that CSF is primarily produced in the choroid plexus (CP), then flows from the ventricles into the subarachnoid spaces, and mainly reabsorbed in the arachnoid granulations. This hypothesis is necessary to reconsider in view of recent research and clinical observations. This literature review presents numerous evidence for a new hypothesis of CSF hydrodynamics-(1) A significantly strong relationship exists between the CSF and interstitial fluid (IF), (2) CSF and IF are mainly produced and absorbed in the parenchymal capillaries of the brain and spinal cord. A considerable amount of CSF and IF are also absorbed by the lymphatic system, and (3) CSF movement is not unidirectional flow. It is only local mixing and diffusion. PMID- 26226981 TI - Moist-condition Training for Cerebrovascular Anastomosis: A Practical Step after Mastering Basic Manipulations. AB - As cerebrovascular anastomosis is performed in moist conditions that may impede precise manipulations, surgeons must undergo extensive preoperative training. We developed a simple moist-condition training method. It involves placing a free floating inner platform hosting an artery from a chicken wing in an outer container filled with tap water to just below the specimen. Trainees performed anastomosis under magnification. Training sessions mimicked difficulties encountered during operations such as poor visibility of the lumen and problems handling the sutures. A retrospective comparison of 100 wet- and 100 dry condition training sessions for end-to-side anastomoses with 8 stitches showed that under moist condition the time required for the entire procedure was significantly longer (17.8 +/- 2.1 vs. 15.3 +/- 2.1 min, p < 0.01) and the incidence of wrong stitching was greater (0.38 vs. 0%, p = 0.04). In 8 cases after introducing moist-condition training, the time required in superficial temporal artery to middle cerebral artery bypass surgery was significantly shorter than 8 cases before introducing the training (32.3 +/- 5.6 min vs. 48.3 +/- 15.9 min, p = 0.01). Incidence of wrong stitches was less in cases after introducing moist-condition training (2.7 vs. 7.4%, p = 0.10). Those indicate that moist-condition training is a useful and practical step and a bridge between training for basic manipulations under dry conditions and actual surgery. PMID- 26226982 TI - A Microscopic Optically Tracking Navigation System That Uses High-resolution 3D Computer Graphics. AB - Three-dimensional (3D) computer graphics (CG) are useful for preoperative planning of neurosurgical operations. However, application of 3D CG to intraoperative navigation is not widespread because existing commercial operative navigation systems do not show 3D CG in sufficient detail. We have developed a microscopic optically tracking navigation system that uses high-resolution 3D CG. This article presents the technical details of our microscopic optically tracking navigation system. Our navigation system consists of three components: the operative microscope, registration, and the image display system. An optical tracker was attached to the microscope to monitor the position and attitude of the microscope in real time; point-pair registration was used to register the operation room coordinate system, and the image coordinate system; and the image display system showed the 3D CG image in the field-of-view of the microscope. Ten neurosurgeons (seven males, two females; mean age 32.9 years) participated in an experiment to assess the accuracy of this system using a phantom model. Accuracy of our system was compared with the commercial system. The 3D CG provided by the navigation system coincided well with the operative scene under the microscope. Target registration error for our system was 2.9 +/- 1.9 mm. Our navigation system provides a clear image of the operation position and the surrounding structures. Systems like this may reduce intraoperative complications. PMID- 26226983 TI - The Modified Concorde Position with an Intraoperative Skew Head Rotation: Technical Note. AB - The Concorde position was developed to approach pineal and cerebellar lesions with a midline suboccipital craniotomy. The neutral head position is needed to divide the occipital muscles symmetrically. The patient's head is tilted to the right and the face is turned to the right for the microscopic procedure to keep the midline of the patient's head axis straight in the surgical field for comfortable and accurate surgical manipulation. However, intraoperative repositioning of the patient's head is somewhat difficult to release the holding arm of the Sugita head holder in the original method. We found that a skew head rotation by fixing the head asymmetrically in the Sugita head holder is very quick and convenient to obtain the optimal head position both for a craniotomy and a microscopic procedure. PMID- 26226984 TI - How Do Genomes Create Novel Phenotypes? Insights from the Loss of the Worker Caste in Ant Social Parasites. AB - A central goal of biology is to uncover the genetic basis for the origin of new phenotypes. A particularly effective approach is to examine the genomic architecture of species that have secondarily lost a phenotype with respect to their close relatives. In the eusocial Hymenoptera, queens and workers have divergent phenotypes that may be produced via either expression of alternative sets of caste-specific genes and pathways or differences in expression patterns of a shared set of multifunctional genes. To distinguish between these two hypotheses, we investigated how secondary loss of the worker phenotype in workerless ant social parasites impacted genome evolution across two independent origins of social parasitism in the ant genera Pogonomyrmex and Vollenhovia. We sequenced the genomes of three social parasites and their most-closely related eusocial host species and compared gene losses in social parasites with gene expression differences between host queens and workers. Virtually all annotated genes were expressed to some degree in both castes of the host, with most shifting in queen-worker bias across developmental stages. As a result, despite >1 My of divergence from the last common ancestor that had workers, the social parasites showed strikingly little evidence of gene loss, damaging mutations, or shifts in selection regime resulting from loss of the worker caste. This suggests that regulatory changes within a multifunctional genome, rather than sequence differences, have played a predominant role in the evolution of social parasitism, and perhaps also in the many gains and losses of phenotypes in the social insects. PMID- 26226985 TI - BMD Loci Contribute to Ethnic and Developmental Differences in Skeletal Fragility across Populations: Assessment of Evolutionary Selection Pressures. AB - Bone mineral density (BMD) is a highly heritable trait used both for the diagnosis of osteoporosis in adults and to assess bone health in children. Ethnic differences in BMD have been documented, with markedly higher levels in individuals of African descent, which partially explain disparity in osteoporosis risk across populations. To date, 63 independent genetic variants have been associated with BMD in adults of Northern-European ancestry. Here, we demonstrate that at least 61 of these variants are predictive of BMD early in life by studying their compound effect within two multiethnic pediatric cohorts. Furthermore, we show that within these cohorts and across populations worldwide the frequency of those alleles associated with increased BMD is systematically elevated in individuals of Sub-Saharan African ancestry. The amount of differentiation in the BMD genetic scores among Sub-Saharan and non-Sub-Saharan populations together with neutrality tests, suggest that these allelic differences are compatible with the hypothesis of selective pressures acting on the genetic determinants of BMD. These findings constitute an explorative contribution to the role of selection on ethnic BMD differences and likely a new example of polygenic adaptation acting on a human trait. PMID- 26226986 TI - Site-Specific Amino Acid Preferences Are Mostly Conserved in Two Closely Related Protein Homologs. AB - Evolution drives changes in a protein's sequence over time. The extent to which these changes in sequence lead to shifts in the underlying preference for each amino acid at each site is an important question with implications for comparative sequence-analysis methods, such as molecular phylogenetics. To quantify the extent that site-specific amino acid preferences shift during evolution, we performed deep mutational scanning on two homologs of human influenza nucleoprotein with 94% amino acid identity. We found that only a modest fraction of sites exhibited shifts in amino acid preferences that exceeded the noise in our experiments. Furthermore, even among sites that did exhibit detectable shifts, the magnitude tended to be small relative to differences between nonhomologous proteins. Given the limited change in amino acid preferences between these close homologs, we tested whether our measurements could inform site-specific substitution models that describe the evolution of nucleoproteins from more diverse influenza viruses. We found that site-specific evolutionary models informed by our experiments greatly outperformed nonsite specific alternatives in fitting phylogenies of nucleoproteins from human, swine, equine, and avian influenza. Combining the experimental data from both homologs improved phylogenetic fit, partly because measurements in multiple genetic contexts better captured the evolutionary average of the amino acid preferences for sites with shifting preferences. Our results show that site-specific amino acid preferences are sufficiently conserved that measuring mutational effects in one protein provides information that can improve quantitative evolutionary modeling of nearby homologs. PMID- 26226987 TI - The Osteogenic Effect of Impact-Loading and Resistance Exercise on Bone Mineral Density in Middle-Aged and Older Men: A Pilot Study. AB - BACKGROUND: Regular exercise has been recommended as a potential strategy to counteract the age-related bone loss experienced by men; however, the optimal exercise prescription is not known. OBJECTIVE: To perform a pilot study to examine the osteogenic effect, safety and feasibility of a combined program of upper body resistance exercise and two doses of impact-loading exercise on bone mineral density (BMD) of middle-aged and older men. METHODS: Forty-two community dwelling men aged 50-74 years were randomly assigned to either an exercise program of combined upper body resistance exercise and either high-dose impact loading (HI; 80 jumps per session) or moderate-dose impact-loading (MOD; 40 jumps per session) or a control (CON) group. The 9-month intervention involved 4 sessions each week: 2 supervised clinic-based and 2 home-based. BMD of the lumbar spine, femoral neck, total hip, trochanter and whole body as well as lean and fat mass were assessed at baseline and 9 months by dual-energy X-ray absorptiometry. Bone turnover markers, hormone levels, physical function and muscle strength were also assessed. RESULTS: Following 9 months of training, significant differences in BMD among groups were found at the total hip (p = 0.010) and trochanter (p = 0.047) with BMD in the MOD group decreasing relative to the HI group. Although not significant, the HI group consistently preserved BMD, whereas BMD of the MOD and CON groups declined at the hip sites. Mean change for all groups at all skeletal sites was approximately within +/-1%. There was no change in bone turnover markers. There were no adverse events as a result of the intervention; however, overall attendance for the HI and MOD groups was 53% (clinic: 68%, home: 38%) and 65% (clinic: 74%, home: 55%), respectively. CONCLUSIONS: This study indicates that while impact-loading exercise can be safely undertaken in middle aged and older men, the current combined program did not elicit significant improvements in BMD. PMID- 26226988 TI - Mild Cognitive Impairment in Early Parkinson's Disease Using the Movement Disorder Society Task Force Criteria: Cross-Sectional Study in Hoehn and Yahr Stage 1. AB - BACKGROUND: Mild cognitive impairment (MCI) in Parkinson's disease (PD) is common and confers a higher risk for developing dementia. METHODS: In this cross sectional study of MCI in PD conducted at a university hospital, a comprehensive neuropsychological battery covering five domains (attention/working memory, executive, verbal, and visual memory, language, and visuospatial) was administered to 111 nondemented PD patients in Hoehn and Yahr stage 1 and to 105 healthy matched control subjects (HC). MCI was diagnosed according to level 2 of the Movement Disorder Society Task Force criteria. RESULTS: Criteria for MCI associated with PD (PD-MCI) were fulfilled by 24% of PD patients in the initial stage of the disease at the z cutoff scores of -1.5 SD in contrast to 7% of HC fulfilling criteria for MCI. Memory and visuospatial domains were the most commonly affected at -1.5 SD. PD-MCI patients mostly had a multiple-domain MCI subtype (78%). They presented a more severe bradykinesia and higher mood and apathy scores in comparison with cognitively normal PD patients. Basic motor scores predicted performance on some cognitive tests and specific cognitive-motor relationships emerged. CONCLUSIONS: MCI, predominantly of a multiple-domain subtype, was quite prevalent even in the initial stage of PD. PMID- 26226989 TI - Perception and Production of Singleton and Geminate Stops in Japanese: Implications for the Theory of Acoustic Invariance. AB - The theory of relational acoustic invariance claims that there are stable acoustic properties in speech signals that correspond to a phonological feature, and that the perception system utilizes these acoustic properties for stable perception of a phoneme. The present study examines whether such an invariance exists in native listeners' perception of Japanese singleton and geminate stops despite variability in speaking rate and word length, and whether this perception corresponds to production. Native Japanese listeners identified singleton and geminate stops in continua of 3- and 4-mora words spoken at different speaking rates. Results indicated that the perception boundary is well predicted by a linear function with two variables: durations of stop closure and the (C)V(C)CV portion (with the contrasting stops underlined) of the 3- and 4-mora words. In addition, these two variables were in a consistent relationship for both perception and production of words containing 2-4 moras. The results support the relational acoustic invariance theory. PMID- 26226990 TI - A Modified Technique for Performing Transurethral Resection of the Prostate Combined with Percutaneous Cystolithotripsy. AB - INTRODUCTION: This study aimed to determine the safety and efficacy of a modified technique for performing transurethral resection of the prostate (TURP) combined with percutaneous cystolithotripsy (PCCL). METHODS: Clinical data from 24 patients with benign prostate hyperplasia (BPH) and aggregate stone sizes >=3 cm were assessed retrospectively between June 2011 and January 2014. All stones fragmented via pneumatic lithotripter were removed. An 18-F Foley catheter was inserted into the Amplatz sheath, which was then removed from the bladder. The Foley catheter balloon was inflated with 15 ml of saline, and suprapubic traction was applied to prevent extravasation. Next, TURP was performed while a suprapubic Foley catheter provided continuous drainage. RESULTS: The mean stone size was 46.25 +/- 9.51 mm. The surgical duration for stone removal was 31.25 +/- 8.46 min. All patients were stone-free at the first month follow-up. None of the patients experienced extravasation or urethral stricture. CONCLUSIONS: PCCL is a short-duration, minimally invasive surgery that avoids urethral stricture. In the presented technique, as the drainage catheter is fixed to the dome of bladder, it is not visualized in the surgical field and remains outside of the resection area, which facilitates prostate resection. It seems to be a safe and efficient technique. PMID- 26226991 TI - Feeding Disorders in Infants and Children. PMID- 26226992 TI - Development of Suck and Swallow Mechanisms in Infants. AB - Preterm infants' hospital discharge is often delayed due to their inability to feed by mouth safely and competently. No evidence-based supported guidelines are currently available for health-care professionals caring for these infants. Available interventions advocating benefits are not readily acknowledged for lack of rigorous documentation inasmuch as any improvements may ensue from infants' normal maturation. Through research, a growing understanding of the development of nutritive sucking skills has emerged, shedding light on how and why infants may encounter oral feeding difficulties due to the immaturity of specific physiologic functions. Unfortunately, this knowledge has yet to be translated to the clinical practice to improve the diagnoses of oral feeding problems through the development of relevant assessment tools and to enhance infants' oral feeding skills through the development of efficacious preventive and therapeutic interventions. This review focuses on the maturation of the various physiologic functions implicated in the transport of a bolus from the oral cavity to the stomach. Although infants' readiness for oral feeding is deemed attained when suck, swallow, and respiration are coordinated, we do not have a clear definition of what coordination implies. We have learned that each of these functions encompasses a number of elements that mature at different times and rates. Consequently, it would appear that the proper functioning of sucking, the swallow processing, and respiration need to occur at two levels: first, the elements within each function must reach an appropriate functional maturation that can work in synchrony with each other to generate an appropriate suck, swallow process, and respiration; and second, the elements of all these distinct functions, in turn, must be able to do the same at an integrative level to ensure the safe and efficient transport of a bolus from the mouth to the stomach. PMID- 26226993 TI - Organic and Nonorganic Feeding Disorders. AB - Feeding is one of the most important interactions between caregiver and child in the first few years of life and even later on in handicapped children. Feeding disorders can present as food refusal or low quantity of food intake due to behavioral issues or underlying organic conditions. This situation concerns mostly infants and children below 6 years of age; however, feeding problems can appear also later on in life. Feeding disorders are a concern for over 10-25% of parents of otherwise healthy children below 3 years of age, but only 1-5% of infants and toddlers suffer from severe feeding problems resulting in failure to thrive. In case of premature infants or neurologically disabled children, this rate is much higher. Feeding disorders may appear as an isolated problem, mainly due to negative behaviors during feeding, or as a concomitant disorder with an underlying organic disease or structural anomaly. The newest classification also includes the feeding style presented by the caregiver (responsive, controlling, indulgent or neglectful) as a separate cause of feeding disorders. PMID- 26226994 TI - Pediatric Dysphagia: Physiology, Assessment, and Management. AB - Infancy and childhood represent a time of unparalleled physical growth and cognitive development. In order for infants and children to reach their linear and neurological growth potential, they must be able to reliably and safely consume sufficient energy and nutrients. Swallowing difficulties (dysphagia) in pediatric populations can have a detrimental effect on dietary intake and, thus, growth and development. As a result, it is imperative to accurately identify and appropriately manage dysphagia in pediatric populations. This article provides an overview of dysphagia in children, as well as common causes of childhood swallowing difficulties, populations at risk for pediatric dysphagia, techniques used to assess swallowing in pediatric patients, and the current treatment options available for infants and children with dysphagia. PMID- 26226995 TI - Behavioral Management of Feeding Disorders of Childhood. AB - Feeding disorders, characterized by suboptimal intake and/or lack of age appropriate eating habits, are common and may be seen in up to 45% of children. Feeding disorders are a significant concern to both the affected families and to the providers who treat them. Fortunately, there are well-established behavioral treatments which have been shown to be highly efficacious. This article provides an overview of behavioral assessment and treatment of pediatric feeding disorders, provides guidance in treatment planning, and provides information which may be useful in considering if additional psychological consultation may be beneficial. PMID- 26226996 TI - Estimating fermentative amino acid catabolism in the small intestine of growing pigs. AB - Fermentative catabolism (FAAC) of dietary and endogenous amino acids (AA) in the small intestine contributes to loss of AA available for protein synthesis and body maintenance functions in pigs. A continuous isotope infusion study was performed to determine whole body urea flux, urea recycling and FAAC in the small intestine of ileal-cannulated growing pigs fed a control diet (CON, 18.6% CP; n=6), a high fibre diet with 12% added pectin (HF, 17.7% CP; n = 4) or a low protein diet (LP, 13.4% CP; n = 6). (15)N-ammonium chloride and (13)C-urea were infused intragastrically and intravenously, respectively, for 4 days. Recovery of ammonia at the distal ileum was increased by feeding additional fibre when compared with the CON (P > 0.05) but was not affected by dietary protein (0.24, 0.39 and 0.14 mmol nitrogen/kg BW/day for CON, HF and LP, respectively; P < 0.05). Lowering protein intake reduced urea flux (25.3, 25.7 and 10.3 mmol nitrogen/kg BW/day; P < 0.01), urinary urea excretion (14.4, 15.0 and 6.2 mmol N/kg BW/day; P < 0.001) and urea recycling (12.1, 11.3 and 3.23 mmol nitrogen/kg BW/day; P< 0 .01) compared with CON. There was a rapid reduction in (15)N-ammonia enrichment in digesta along the small intestine suggesting rapid absorption of ammonia before the distal ileum and lack of uniformity of enrichment in the digesta ammonia pool. A two-pool model was developed to determine possible value ranges for nitrogen flux in the small intestine assuming rapid absorption of ammonia.Maximum estimated FAAC based on this model was significantly lower when dietary protein content was decreased (32.9, 33.4 and 17.4 mmol nitrogen/kg BW/day; P < 0.001). There was no impact of dietary fibre on estimates of small intestine nitrogen flux( P > 0.05)compared with CON. The two-pool model developed in the present study allows for estimation of FAAC but still has limitations. Quantifying FAAC in the small intestine of pigs, as well as other non-ruminants and humans, offers a number of challenges but warrants further investigation. PMID- 26226997 TI - Left Atrial Appendage Occlusion Device and Novel Oral Anticoagulants Versus Warfarin for Stroke Prevention in Nonvalvular Atrial Fibrillation: Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Nonvalvular atrial fibrillation is the most common arrhythmia. Patients with nonvalvular atrial fibrillation are at increased risk of stroke; therefore, we evaluated the efficacy and safety of different approaches to prevent this major complication. METHODS AND RESULTS: We conducted electronic database searches of phase III randomized controlled trials. The groups were novel oral anticoagulants, Watchman left atrial appendage occlusion device (DEVICE), and warfarin. Efficacy outcomes were stroke or systemic embolism, and all-cause mortality. Safety outcome was major bleeding and procedure-related complications. A subgroup analysis of the elderly population was done. We used random-effects model to compare pooled outcomes and tested for heterogeneity. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for each outcome. Seven randomized controlled trials (n=73,978) were included. There was a significant difference favoring novel oral anticoagulants for systemic embolism (OR, 0.84; 95% CI, 0.72-0.97; P=0.01), all-cause mortality (OR, 0.89; 95% CI, 0.84-0.94; P<0.001), and safety outcomes (OR, 0.79; 95% CI, 0.65-0.97; P=0.026) compared with warfarin. No difference was seen between DEVICE and warfarin for efficacy end points; however, DEVICE had more complications (OR, 1.85; 95% CI, 1.14-3.01; P=0.012). In the elderly (6 randomized controlled trials, n=30,699), systemic embolism was favored with novel oral anticoagulants over warfarin (OR, 0.77; 95% CI, 0.68-0.87; P<=0.001). No evidence of significant publication bias was found. CONCLUSIONS: Novel oral anticoagulants is superior to warfarin for stroke prevention in nonvalvular atrial fibrillation. This benefit was also observed in the elderly population. DEVICE is a reasonable noninferior alternative to warfarin for stroke prevention, but cautious use is essential given safety concerns. PMID- 26226998 TI - Mouse Model of Human Congenital Heart Disease: Progressive Atrioventricular Block Induced by a Heterozygous Nkx2-5 Homeodomain Missense Mutation. AB - BACKGROUND: Heterozygous human NKX2-5 homeodomain (DNA-binding domain) missense mutations are highly penetrant for varied congenital heart defects, including progressive atrioventricular (AV) block requiring pacemaker implantation. We recently replicated this genetic defect in a murine knockin model, in which we demonstrated highly penetrant, pleiotropic cardiac anomalies. In this study, we examined postnatal AV conduction in the knockin mice. METHODS AND RESULTS: A murine knockin model (Arg52Gly, Nkx2-5(+/R52G)) in a 129/Sv background was analyzed by histopathology, surface, and telemetry ECG, and in vivo electrophysiology studies, comparing with control Nkx2-5(+/+) mice at diverse postnatal stages, ranging from postnatal day 1 (P1) to 17 months. PR prolongation (first degree AV block) was present at 4 weeks, 7 months, and 17 months of age, but not at P1 in the mutant mice. Advanced AV block was also occasionally demonstrated in the mutant mice. Electrophysiology studies showed that AV nodal function and right ventricular effective refractory period were impaired in the mutant mice, whereas sinus nodal function was not affected. AV nodal size was significantly smaller in the mutant mice than their controls at 4 weeks of age, corresponding to the presence of PR prolongation, but not P1, suggesting, at least in part, that the conduction abnormalities are the result of a morphologically atrophic AV node. CONCLUSIONS: The highly penetrant and progressive AV block phenotype seen in human heterozygous missense mutations in NKX2-5 homeodomain was replicated in mice by knocking in a comparable missense mutation. PMID- 26227000 TI - Effects of Wild-Type and Mutant Forms of Atrial Natriuretic Peptide on Atrial Electrophysiology and Arrhythmogenesis. AB - BACKGROUND: Atrial natriuretic peptide (ANP) is a hormone with numerous beneficial cardiovascular effects. Recently, a mutation in the ANP gene, which results in the generation of a mutant form of ANP (mANP), was identified and shown to cause atrial fibrillation in people. The mechanism(s) through which mANP causes atrial fibrillation is unknown. Our objective was to compare the effects of wild-type ANP and mANP on atrial electrophysiology in mice and humans. METHODS AND RESULTS: Action potentials (APs), L-type Ca(2+) currents (ICa,L), and Na(+) current were recorded in atrial myocytes from wild-type or natriuretic peptide receptor C knockout (NPR-C(-/-)) mice. In mice, ANP and mANP (10-100 nmol/L) had opposing effects on atrial myocyte AP morphology and ICa,L. ANP increased AP upstroke velocity (Vmax), AP duration, and ICa,L similarly in wild-type and NPR C(-/-) myocytes. In contrast, mANP decreased Vmax, AP duration, and ICa,L, and these effects were completely absent in NPR-C(-/-) myocytes. ANP and mANP also had opposing effects on ICa,L in human atrial myocytes. In contrast, neither ANP nor mANP had any effect on Na(+) current in mouse atrial myocytes. Optical mapping studies in mice demonstrate that ANP sped electric conduction in the atria, whereas mANP did the opposite and slowed atrial conduction. Atrial pacing in the presence of mANP induced arrhythmias in 62.5% of hearts, whereas treatment with ANP completely prevented the occurrence of arrhythmias. CONCLUSIONS: These findings provide mechanistic insight into how mANP causes atrial fibrillation and demonstrate that wild-type ANP is antiarrhythmic. PMID- 26226999 TI - The HARMONY Trial: Combined Ranolazine and Dronedarone in the Management of Paroxysmal Atrial Fibrillation: Mechanistic and Therapeutic Synergism. AB - BACKGROUND: Atrial fibrillation (AF) requires arrhythmogenic changes in atrial ion channels/receptors and usually altered atrial structure. AF is commonly treated with antiarrhythmic drugs; the most effective block many ion channels/receptors. Modest efficacy, intolerance, and safety concerns limit current antiarrhythmic drugs. We hypothesized that combining agents with multiple anti-AF mechanisms at reduced individual drug doses might produce synergistic efficacy plus better tolerance/safety. METHODS AND RESULTS: HARMONY tested midrange ranolazine (750 mg BID) combined with 2 reduced dronedarone doses (150 mg BID and 225 mg BID; chosen to reduce dronedarone's negative inotropic effect see text below) over 12 weeks in 134 patients with paroxysmal AF and implanted pacemakers where AF burden (AFB) could be continuously assessed. Patients were randomized double-blind to placebo, ranolazine alone (750 mg BID), dronedarone alone (225 mg BID), or one of the combinations. Neither placebo nor either drugs alone significantly reduced AFB. Conversely, ranolazine 750 mg BID/dronedarone 225 mg BID reduced AFB by 59% versus placebo (P=0.008), whereas ranolazine 750 mg BID/dronedarone 150 mg BID reduced AFB by 43% (P=0.072). Both combinations were well tolerated. CONCLUSIONS: HARMONY showed synergistic AFB reduction by moderate dose ranolazine plus reduced dose dronedarone, with good tolerance/safety, in the population enrolled. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; Unique identifier: NCT01522651. PMID- 26227001 TI - Vitamin D-Rich Diet in Mice Modulates Erythrocyte Survival. AB - BACKGROUND/AIMS: Epidemiological evidence suggests that vitamin D deficiency is associated with anemia. The potent metabolite 1,25(OH)2 vitamin D3 [1,25(OH)2D3] activates various signaling cascades regulating a myriad of cellular functions including suicidal cell death or apoptosis. Suicidal death of erythrocytes or eryptosis is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine (PS) externalization. Stimulation of eryptosis may limit lifespan of circulating erythrocytes and thus cause anemia. In the present study, we explored the effect of a high vitamin D diet (10,000 I.U. vitamin D for 14 days) in mice on eryptosis. METHODS: Plasma concentrations of erythropoietin were estimated using an immunoassay kit, blood count using an electronic hematology particle counter, relative reticulocyte numbers using Retic-COUNT(r) reagent, PS exposure at the cell surface from annexin V binding, cell volume from forward scatter, and cytosolic Ca(2+) ([Ca(2+)]i) from Fluo3-fluorescence in FACS analysis. RESULTS: Vitamin D treatment decreased mean corpuscular volume, reticulocyte count, and plasma erythropoietin levels. Vitamin D treatment slightly but significantly decreased forward scatter but did not significantly modify spontaneous PS exposure and [Ca(2+)]i of freshly drawn erythrocytes. Vitamin D treatment augmented the stimulation of PS exposure and cell shrinkage following exposure to hyperosmotic shock (addition of 550 mM sucrose) or energy depletion (glucose removal) without significantly modifying [Ca(2+)]i. CONCLUSIONS: The present observations point to a subtle effect of exogenous vitamin D supplementation on erythrocyte survival. PMID- 26227002 TI - Is there a cognitive signature for MS-related fatigue? Response to Feinstein. PMID- 26227003 TI - Stable neuropsychiatric status in multiple sclerosis: a 3-year study. AB - Personality changes and neuropsychiatric symptoms are found in multiple sclerosis (MS), but no study has evaluated decline compared to healthy controls. This study assessed personality traits and neuropsychiatric symptoms over 3 years using the NEO Five Factor Inventory and the Neuropsychiatric Inventory. Additional metrics evaluated ambulation, manual dexterity and cognitive function. Contrary to hypothesis, patients showed no significant change in personality or neuropsychiatric status relative to controls. Patients were impaired in motor and cognitive function at baseline and follow-up, but showed only slowing in ambulation over time. The findings indicate that neuropsychiatric status is stable in MS over 3 years. PMID- 26227004 TI - Biotin and demyelinating diseases--a new connection? PMID- 26227005 TI - Length of optic nerve double inversion recovery hypersignal is associated with retinal axonal loss. AB - OBJECTIVES: To assess the association between optic nerve double inversion recovery (DIR) hypersignal length and retinal axonal loss in neuroinflammatory diseases affecting optic nerves. METHODS: We recruited patients previously affected (> 6 months) by a clinical episode of optic neuritis (ON). We had 25 multiple sclerosis (MS) patients, eight neuromyelitis optica spectrum disorder (NMOSD) patients and two patients suffering from idiopathic caused ON undergo brain magnetic resonance imaging (MRI); including a 3-dimensional (3D) DIR sequence, optical coherence tomography (OCT) examination and visual disability evaluation. Evaluation criteria were retinal thickness/volume, optic nerve DIR hypersignal length and high/low contrast vision acuity. RESULTS: In the whole cohort, we found good associations (< 0.0001) between optic nerve DIR hypersignal length, peripapillary retinal nerve fiber layer thickness, inner macular layers volumes, and visual disability. We found subclinical radiological optic nerve involvement in 38.5% of non-ON MS eyes. CONCLUSIONS: Optic nerve DIR hypersignal length may be a biomarker for retinal axonal loss, easily applicable in routine and research on new anti-inflammatory or neuroprotective drug evaluation. Detection of subclinical ON with 3D-DIR in a non-negligible proportion of MS patients argues in favor of optic nerve imaging in future OCT MS studies, in order to achieve a better understanding of retinal axonal loss in non-ON eyes. PMID- 26227006 TI - Abnormally invasive placenta-prevalence, risk factors and antenatal suspicion: results from a large population-based pregnancy cohort study in the Nordic countries. AB - OBJECTIVE: The objective was to investigate prevalence, estimate risk factors, and antenatal suspicion of abnormally invasive placenta (AIP) associated with laparotomy in women in the Nordic countries. DESIGN: Population-based cohort study. SETTING AND POPULATION: A 3-year Nordic collaboration among obstetricians to identify and report on uterine rupture, peripartum hysterectomy, excessive blood loss, and AIP from 2009 to 2012 The Nordic Obstetric Surveillance Study (NOSS). METHODS: In the NOSS study, clinicians reported AIP cases from maternity wards and the data were validated against National health registries. MAIN OUTCOME MEASURES: Prevalence, risk factors, antenatal suspicion, birth complications, and risk estimations using aggregated national data. RESULTS: A total of 205 cases of AIP in association with laparotomy were identified, representing 3.4 per 10 000 deliveries. The single most important risk factor, which was reported in 49% of all cases of AIP, was placenta praevia. The risk of AIP increased seven-fold after one prior caesarean section (CS) to 56-fold after three or more CS. Prior postpartum haemorrhage was associated with six-fold increased risk of AIP (95% confidence interval 3.7-10.9). Approximately 70% of all cases were not diagnosed antepartum. Of these, 39% had prior CS and 33% had placenta praevia. CONCLUSION: Our findings indicate that a lower CS rate in the population may be the most effective way to lower the incidence of AIP. Focused ultrasound assessment of women at high risk will likely strengthen antenatal suspicion. Prior PPH is a novel risk factor associated with an increased prevalence of AIP. TWEETABLE ABSTRACT: An ultrasound assessment in women with placenta praevia or prior CS may double the awareness for AIP. PMID- 26227007 TI - Rapidly-growing squamous cell carcinoma shortly after treatment with ingenol mebutate for actinic keratoses: report of two cases. AB - Actinic keratoses (AKs) are defined as cutaneous areas of atypical squamous transformation that are regarded as an early step in the continuum of alterations leading from normal skin to invasive and metastatic squamous cell carcinoma (SCC). AKs are classified as precancerous lesions by some authors and in situ SCC by others. The rate of evolution of a given AK to an invasive SCC has been estimated as 0.075-0.096% per lesion per year. These rates are similar to those estimated for gynaecological intraepithelial neoplasia. We describe two cases of SCC with rapid onset that developed after the application of ingenol mebutate gel for the treatment of AKs. PMID- 26227008 TI - A case of bullous scabies misdiagnosed as acquired epidermolysis bullosa. PMID- 26227009 TI - Relationship among salivary antioxidant activity, cytokines, and periodontitis: the Nagasaki Island study. AB - AIM: Antioxidant activities and cytokine levels in human body fluids are considered to be strongly associated with periodontitis. The aim of this study was to elucidate the relationship between salivary antioxidant activities against superoxide or hydroxyl radical, cytokines, and periodontal conditions through a community-based cross-sectional study conducted in Goto city, Japan. MATERIALS AND METHODS: Saliva samples were analysed for superoxide or hydroxyl radical scavenging activities and cytokine levels from 160 participants. We demonstrated that saliva contained superoxide and hydroxyl radical scavenging activities by using electron spin resonance with a spin-trapping agent. The concentrations of eight cytokines were measured using multiplex bead assays. RESULTS: There were significant differences in salivary superoxide or hydroxyl radical scavenging activity, and the levels of Interleukin-1beta, Interleukin-6, and Interleukin-8 between periodontitis classifications. Multivariate stepwise logistic regression model showed that salivary superoxide and hydroxyl radical scavenging activities were significantly associated with the classification of periodontitis. In addition, salivary superoxide scavenging activity was found to have significant association with all periodontal parameters using multiple linear regression analysis. CONCLUSIONS: These findings suggest that the evaluation of salivary antioxidant activities, as assessed by electron spin resonance, are associated with periodontitis and various clinical variables in community-dwelling participants (ClinicalTrials.gov number NCT01742728). PMID- 26227010 TI - Embolism spread in the primary xylem of Polystichum munitum: implications for water transport during seasonal drought. AB - Xylem network structure and function have been characterized for many woody plants, but less is known about fern xylem, particularly in species endemic to climates where water is a limiting resource for months at a time. We characterized seasonal variability in soil moisture and frond water status in a common perennial fern in the redwood understory of a costal California, and then investigated the consequences of drought-induced embolism on vascular function. Seasonal variability in air temperature and soil water content was minimal, and frond water potential declined slowly over the observational period. Our data show that Polystichum munitum was protected from significant drought-induced hydraulic dysfunction during this growing season because of a combination of cavitation resistant conduits (Air-seeding threshold (ASP) = -1.53 MPa; xylem pressure inducing 50% loss of hydraulic conductivity (P50 ) = -3.02 MPa) and a soil with low moisture variability. High resolution micro-computed tomography (MicroCT) imaging revealed patterns of embolism formation in vivo for the first time in ferns providing insight into the functional status of the xylem network under drought conditions. Together with stomatal conductance measurements, these data suggest that P. munitum is adapted to tolerate drier conditions than what was observed during the growing season. PMID- 26227011 TI - Cortical inhibition of laser pain and laser-evoked potentials by non-nociceptive somatosensory input. AB - Although the inhibitory action that tactile stimuli can have on pain is well documented, the precise timing of the interaction between the painful and non painful stimuli in the central nervous system is unclear. The aim of this study was to investigate this issue by measuring the timing of the amplitude modulation of laser evoked potentials (LEPs) due to conditioning non-painful stimuli. LEPs were recorded from 31 scalp electrodes in 10 healthy subjects after painful stimulation of the right arm (C6-C7 dermatomes). Non-painful electrical stimuli were applied by ring electrodes on the second and third finger of the right hand. Electrical stimuli were delivered at +50, +150, +200 and +250 ms interstimulus intervals (ISIs) after the laser pulses. LEPs obtained without any conditioning stimulation were used as a baseline. As compared to the baseline, non-painful electrical stimulation reduced the amplitude of the vertex N2/P2 LEP component and the laser pain rating when electrical stimuli followed the laser pulses only at +150 and +200 ms ISIs. As at these ISIs the collision between the non-painful and painful input is likely to take place at the cortical level, we can conclude that the late processing of painful (thermal) stimuli is partially inhibited by the processing of non-painful (cutaneous) stimuli within the cerebral cortex. Moreover, our results do not provide evidence that non-painful inputs can inhibit pain at a lower level, including the spinal cord. PMID- 26227012 TI - Novel mutation in the XPC gene: a case report of a patient with xeroderma pigmentosum. PMID- 26227013 TI - Prenatal diagnosis and follow-up of a case of branchio-oto-renal syndrome displays renal growth impairment after the second trimester. AB - Branchio-oto-renal syndrome combines branchial arch defects, hearing impairment and renal malformations or hypoplasia. Due to the high phenotypic variability, prenatal diagnosis has a limited prognostic value in mutation-positive cases. We report the first branchio-oto-renal syndrome molecular prenatal diagnosis and ultrasonographic follow-up, showing a normal renal growth until the 24th week of pregnancy, a growth deceleration during the third trimester and a renal volume recovery during the first months of life. PMID- 26227015 TI - De Novo Donor-Specific HLA Antibodies Are Associated With Rapid Loss of Graft Function Following Islet Transplantation in Type 1 Diabetes. AB - Outcomes after islet transplantation continue to improve but etiology of graft failure remains unclear. De novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) posttransplant are increasingly recognized as a negative prognostic marker. Specific temporal associations between DSA and graft function remain undefined particularly in programs undertaking multiple sequential transplants. Impact of de novo DSA on graft function over 12 months following first islet transplant was determined prospectively in consecutive recipients taking tacrolimus/mycophenolate immunosuppression at a single center. Mixed-meal tolerance test was undertaken in parallel with HLA antibody assessment pretransplant and 1-3 months posttransplant. Sixteen participants received a total of 26 islet transplants. Five (19%) grafts were associated with de novo DSA. Five (31%) recipients were affected: three post-first transplant; two post second transplant. DSA developed within 4 weeks of all sensitizing grafts and were associated with decreased stimulated C-peptide (median [interquartile range]) at 3 months posttransplant (DSA negative: 613(300-1090); DSA positive 106(34-235) pmol/L [p = 0.004]). De novo DSA directed against most recent islet transplant were absolutely associated with loss of graft function despite maintained immunosuppression at 12 months in the absence of a rescue nonsensitizing transplant. Alemtuzumab induction immunosuppression was associated with reduced incidence of de novo DSA formation (p = 0.03). PMID- 26227016 TI - Gender differences in use of prescription narcotic medications among living kidney donors. AB - Prescription narcotic use among living kidney donors is not well described. Using a unique database that integrates national registry identifiers for living kidney donors (1987-2007) in the United States with billing claims from a private health insurer (2000-2007), we identified pharmacy fills for prescription narcotic medications in periods 1-4 and >4 yr post-donation and estimated relative likelihoods of post-donation narcotic use by Cox regression. We also compared narcotic fill rates and medication possession ratios (MPRs, defined as (days of medication supplied)/(days observed)), between donors and age- and sex-matched non-donors. Overall, rates of narcotic medication fills were 32.3 and 32.4 per 100 person-years in periods 1-4 and >4 yr post-donation. After age and race adjustment, women were approximately twice as likely as men to fill a narcotic prescription in years 1-4 (adjusted hazard ratio, aHR, 2.28; 95% confidence interval, CI, 1.86-2.79) and >4 yr (aHR 1.70; 95% CI 1.50-1.93). MPRs in donors were low (<2.5% days exposed), and lower than among age- and sex-matched non donors. Prescription narcotic medication use is more common among women than men in the intermediate term after live kidney donation. Overall, total narcotic exposure is low, and lower than among non-donors from the general population. PMID- 26227017 TI - Generation of alpha1,3-galactosyltransferase and cytidine monophospho-N acetylneuraminic acid hydroxylase gene double-knockout pigs. AB - Zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) are new tools for producing gene knockout (KO) animals. The current study reports produced genetically modified pigs, in which two endogenous genes were knocked out. Porcine fibroblast cell lines were derived from homozygous alpha1,3-galactosyltransferase (GalT) KO pigs. These cells were subjected to an additional KO for the cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) gene. A pair of ZFN-encoding mRNAs targeting exon 8 of the CMAH gene was used to generate the heterozygous CMAH KO cells, from which cloned pigs were produced by somatic cell nuclear transfer (SCNT). One of the cloned pigs obtained was re-cloned after additional KO of the remaining CMAH allele using the same ZFN encoding mRNAs to generate GalT/CMAH-double homozygous KO pigs. On the other hand, the use of TALEN-encoding mRNAs targeting exon 7 of the CMAH gene resulted in efficient generation of homozygous CMAH KO cells. These cells were used for SCNT to produce cloned pigs homozygous for a double GalT/CMAH KO. These results demonstrate that the combination of TALEN-encoding mRNA, in vitro selection of the nuclear donor cells and SCNT provides a robust method for generating KO pigs. PMID- 26227018 TI - Comparison of continence outcomes of early catheter removal on postoperative day 2 and 4 after laparoscopic radical prostatectomy: a randomized controlled trial. AB - BACKGROUND: The optimal timing of catheter removal following laparoscopic radical prostatectomy (LRP) has not yet been determined. This prospective study was designed to compare the efficacy and safety of catheter removal on postoperative day (POD) 2 versus POD 4 after LRP and its impact on urinary continence outcomes. METHODS: One hundred and thirteen patients underwent LRP and were prospectively randomized into two groups: group 1 (n = 57) had the urinary catheter removed on POD 2 while group 2 (n = 56) had the catheter removed on POD 4. The urine loss ratio (ULR) was defined as the weight of urine loss in the pad divided by the daily micturition volume. Continence was defined as a pad-free status. RESULTS: No significant differences were observed in clinical features between groups 1 and 2. Acute urinary retention (AUR) after catheter removal occurred in 21 patients (18.6%) (13 (22.8%) in group 1 and 8 (14.3%) in group 2 (p = 0.244). The first-day mean ULR values were 1.16 +/- 4.95 in group 1 and 1.02 +/- 3.27 in group 2 (p = 0.870). The last-day mean ULR values were 0.57 +/- 1.60 in group 1 and 2.78 +/- 15.49 in group 2 (p = 0.353). Continence rates at 3, 6, 9, and 12 months were 21.8, 41.1, 58.0, and 71.4% in group 1 and 34.5, 66.0, 79.2, and 83.7% in group 2 (p = 0.138, 0.009, 0.024, and 0.146, respectively). In AUR cases, continence rates at 3, 6, 9, and 12 months were 0, 23.1, 38.5, and 54.5% in group 1 and 37.5, 75.0, 87.5, and 87.5% in group 2 (p = 0.017, 0.020, 0.027, and 0.127, respectively). A multivariate analysis identified AUR after catheter removal on POD 2 as the only predictive factor for incontinence 6 and 9 months after LRP (p = 0.030 and 0.018, respectively). CONCLUSIONS: Our results demonstrated that early catheter removal on POD 2 after LRP may increase the risk of incontinence. TRIAL REGISTRATION: The study was registered as Clinical trial: (UMIN000014944); registration date: 12 March 2012. PMID- 26227019 TI - Can serum isotope levels accurately measure intestinal calcium absorption compared to gold-standard methods? AB - BACKGROUND: Low fractional calcium absorption (FCA) contributes to osteoporosis but is not measured clinically, as the gold-standard method requires administration of two calcium tracers and a subsequent 24-h urine collection. We evaluated alternate methods to measure FCA, compared to the gold standard method. METHODS: We administered two stable calcium isotope tracers (~8 mg oral (44)Ca and ~3 mg intravenous (42)Ca) with breakfast to 20 fasting post-menopausal women (Cohort 1) 59 +/- 7 years old with vitamin D insufficiency. We measured subsequent calcium isotope concentrations in 24-h urine samples and serum collected 1, 3 and 5 h post tracer administration during an inpatient research stay. We assessed the candidate serum estimates in a second cohort of 9 women with similar characteristics. Methods of measuring FCA were compared using correlation coefficients and Bland-Altman tests. RESULTS: FCA estimated from a 3 h serum sample correlated highest with the levels from the 24-h urine collection (rho 0.78, p < 0.001), but explained only 58 % of the variance in FCA. The total variance explained by 3-h estimates improved to 61 % with incorporation of glomerular filtration rate (GFR). FCA estimates from the 3-h serum measurement were assessed in a second group of nine women (Cohort 2) 60 +/- 7 years old. In this cohort, however, FCA estimated by 3-h serum isotope levels did not correlate with gold-standard FCA measurements, whether determined with (rho 0.02, p = 0.97) or without GFR values (rho 0.03, p = 0.93). By contrast, FCA in Cohort 2 correlated best with 5-h serum isotope levels (rho 0.75, p = 0.02). CONCLUSIONS: We conclude that serum isotope levels correlate with true fractional calcium absorption, but do not reliably estimate FCA when analyzed using Bland-Altman tests, compared to gold-standard methods. TRIAL REGISTRATION: ClinicalTrials.gov.Identifier: NCT00933244. PMID- 26227020 TI - KCNQ channels in nociceptive cold-sensing trigeminal ganglion neurons as therapeutic targets for treating orofacial cold hyperalgesia. AB - BACKGROUND: Hyperexcitability of nociceptive afferent fibers is an underlying mechanism of neuropathic pain and ion channels involved in neuronal excitability are potentially therapeutic targets. KCNQ channels, a subfamily of voltage-gated K(+) channels mediating M-currents, play a key role in neuronal excitability. It is unknown whether KCNQ channels are involved in the excitability of nociceptive cold-sensing trigeminal afferent fibers and if so, whether they are therapeutic targets for orofacial cold hyperalgesia, an intractable trigeminal neuropathic pain. METHODS: Patch-clamp recording technique was used to study M-currents and neuronal excitability of cold-sensing trigeminal ganglion neurons. Orofacial operant behavioral assessment was performed in animals with trigeminal neuropathic pain induced by oxaliplatin or by infraorbital nerve chronic constrictive injury. RESULTS: We showed that KCNQ channels were expressed on and mediated M-currents in rat nociceptive cold-sensing trigeminal ganglion (TG) neurons. The channels were involved in setting both resting membrane potentials and rheobase for firing action potentials in these cold-sensing TG neurons. Inhibition of KCNQ channels by linopirdine significantly decreased resting membrane potentials and the rheobase of these TG neurons. Linopirdine directly induced orofacial cold hyperalgesia when the KCNQ inhibitor was subcutaneously injected into rat orofacial regions. On the other hand, retigabine, a KCNQ channel potentiator, suppressed the excitability of nociceptive cold-sensing TG neurons. We further determined whether KCNQ channel could be a therapeutic target for orofacial cold hyperalgesia. Orofacial cold hyperalgesia was induced in rats either by the administration of oxaliplatin or by infraorbital nerve chronic constrictive injury. Using the orofacial operant test, we showed that retigabine dose-dependently alleviated orofacial cold hyperalgesia in both animal models. CONCLUSION: Taken together, these findings indicate that KCNQ channel plays a significant role in controlling cold sensitivity and is a therapeutic target for alleviating trigeminal neuropathic pain that manifests orofacial cold hyperalgesia. PMID- 26227021 TI - Efficiency of pragmatic search strategies to update clinical guidelines recommendations. AB - BACKGROUND: A major challenge in updating clinical guidelines is to efficiently identify new, relevant evidence. We evaluated the efficiency and feasibility of two new approaches: the development of restrictive search strategies using PubMed Clinical Queries for MEDLINE and the use of the PLUS (McMaster Premium Literature Service) database. METHODS: We evaluated a random sample of recommendations from a national guideline development program and identified the references that would potentially trigger an update (key references) using an exhaustive approach. We designed restrictive search strategies using the minimum number of Medical Subject Headings (MeSH) terms and text words required from the original exhaustive search strategies and applying broad and narrow filters. We developed PLUS search strategies, matching Medical Subject Headings (MeSH) and Systematized Nomenclature of Medicine (SNOMED) terms with guideline topics. We compared the number of key references retrieved by these approaches with those retrieved by the exhaustive approach. RESULTS: The restrictive approach retrieved 68.1 % fewer references than the exhaustive approach (12,486 versus 39,136), and identified 89.9 % (62/69) of key references and 88 % (22/25) of recommendation updates. The use of PLUS retrieved 88.5 % fewer references than the exhaustive approach (4,486 versus 39,136) and identified substantially fewer key references (18/69, 26.1 %) and fewer recommendation updates (10/25, 40 %). CONCLUSIONS: The proposed restrictive approach is a highly efficient and feasible method to identify new evidence that triggers a recommendation update. Searching only in the PLUS database proved to be a suboptimal approach and suggests the need for topic specific tailoring. PMID- 26227022 TI - Transforming growth factor-beta increases interleukin-13 synthesis via GATA-3 transcription factor in T-lymphocytes from patients with systemic sclerosis. AB - INTRODUCTION: Transforming growth factor (TGF)-beta and interleukin (IL)-13 play a crucial role in the pathogenesis of systemic sclerosis (SSc), partly through activation of collagen production that leads to fibrosis. The aim of the present study was to determine whether TFG-beta alters IL-13 production in T lymphocytes from patients with SSc from that seen in those of healthy donors. METHODS: IL-13 mRNA and protein synthesis under TFG-beta exposure was measured in circulating T lymphocytes from healthy donors and patients with SSc and also in the Jurkat Th2 T-cell line, using quantitative real-time PCR and fluorescence-activated cell sorting analysis, respectively. The involvement of Smad and GATA-3 transcription factors was assessed by using specific inhibitors and small interfering RNA, and the binding capacity of GATA-3 to the IL-13 gene promoter was evaluated by chromatin immunoprecipitation assay. RESULTS: TGF-beta induced a significant decrease in IL-13 mRNA and protein levels in lymphocytes from healthy donors (mean [+/-SD] inhibition of 30% +/- 10% and 20% +/- 7%, respectively; p < 0.05). In contrast, TGF-beta promoted a significant increase in IL-13 mRNA levels and IL 13 synthesis by CD4(+) and CD8(+) T-cell subtypes from patients with SSc, with respective increases of 2.4 +/- 0.3-fold, 1.6 +/- 0.05-fold and 2.7 +/- 0.02 fold. The involvement of the Smad signaling pathway and upregulation of GATA-3 binding capacity on the IL-13 promoter in lymphocytes from patients with SSc contributed to the effect of TGF-beta on IL-13 production. CONCLUSIONS: These results demonstrate that TGF-beta upregulates IL-13 synthesis through GATA-3 expression in the T lymphocytes of patients with SSc, confirming that the GATA-3 transcription factor can be regarded as a novel therapeutic target in patients with SSc. PMID- 26227023 TI - Understanding recovery in the context of lived experience of personality disorders: a collaborative, qualitative research study. AB - BACKGROUND: Concepts of recovery increasingly inform the development and delivery of mental health services internationally. In the UK recent policy advocates the application of recovery concepts to the treatment of personality disorders. However diagnosis and understanding of personality disorders remains contested, challenging any assumption that mainstream recovery thinking can be directly translated into personality disorders services. METHODS: In a qualitative interview-based study understandings of recovery were explored in extended, in depth interviews with six people purposively sampled from a specialist personality disorders' service in the UK. An interpretive, collaborative approach to research was adopted in which university-, clinical- and service user (consumer) researchers were jointly involved in carrying out interviews and analysing interview data. RESULTS: Findings suggested that recovery cannot be conceptualised separately from an understanding of the lived experience of personality disorders. This experience was characterised by a complexity of ambiguous, interrelating and conflicting feelings, thoughts and actions as individuals tried to cope with tensions between internally and externally experienced worlds. Our analysis was suggestive of a process of recovering or, for some, discovering a sense of self that can safely coexist in both worlds. CONCLUSIONS: We conclude that key facilitators of recovery - positive personal relationships and wider social interaction - are also where the core vulnerabilities of individuals with lived experience of personaility disorders can lie. There is a role for personality disorders services in providing a safe space in which to develop positive relationships. Through discursive practice within the research team understandings of recovery were co-produced that responded to the lived experience of personality disorders and were of applied relevance to practitioners. PMID- 26227024 TI - Using impairment and cognitions to predict walking in osteoarthritis: A series of n-of-1 studies with an individually tailored, data-driven intervention. AB - OBJECTIVES: First, this study compares the ability of an integrated model of activity and activity limitations, the International Classification of Functioning, Disability and Health (ICF), and the Theory of Planned Behaviour (TPB) to predict walking within individuals with osteoarthritis. Second, the effectiveness of a walking intervention in these individuals is determined. DESIGN: A series of n-of-1 studies with an AB intervention design was used. METHODS: Diary methods were used to study four community-dwelling individuals with lower-limb osteoarthritis. Data on impairment symptoms (pain, pain on movement, and joint stiffness), cognitions (intention, self-efficacy, and perceived controllability), and walking (step count) were collected twice daily for 12 weeks. At 6 weeks, an individually tailored, data-driven walking intervention using action planning or a control cognition manipulation was delivered. Simulation modelling analysis examined cross-correlations and differences in baseline and intervention phase means. Post-hoc mediation analyses examined theoretical relationships and multiple regression analyses compared theoretical models. RESULTS: Cognitions, intention in particular, were better and more consistent within individual predictors of walking than impairment. The walking intervention did not increase walking in any of the three participants receiving it. The integrated model and the TPB, which recognize a predictive role for cognitions, were significant predictors of walking variance in all participants, whilst the biomedical ICF model was only predictive for one participant. CONCLUSION: Despite the lack of evidence for an individually tailored walking intervention, predictive data suggest that interventions for people with osteoarthritis that address cognitions are likely to be more effective than those that address impairment only. Further within-individual investigation, including testing mediational relationships, is warranted. STATEMENT OF CONTRIBUTION: What is already known on this subject? N-of-1 methods have been used to study within-individual predictors of walking in healthy and chronic pain populations An integrated biomedical and behavioural model of activity and activity limitations recognizes the roles of impairment and psychology (cognitions) Interventions modifying cognitions can increase physical activity in people with mobility limitations What does this study add? N-of-1 methods are suitable to study within-individual predictors of walking and interventions in osteoarthritis An integrated and a psychological model are better predictors of walking in osteoarthritis than a biomedical model There was no support for an individually tailored, data-driven walking intervention. PMID- 26227025 TI - Toxins as Weapons: A Historical Review. AB - This review article summarizes the use of toxins as weapons dating from the First World War until today, when there is a high concern of possible terrorist attacks with weapons of mass destruction. All through modern history, military programs and terrorist groups have favored toxins because of their high toxicity. However, difficulties of extraction or synthesis, as well as effective dissemination to cause a large number of casualties, have been the most important drawbacks. Special emphasis is focused on ricin and botulinum toxin, the most important toxins that have attracted the attention of military programs and terrorist groups. Other toxins like trichothecenes, saxitoxin, and Staphylococcal enterotoxin B (SEB) are also discussed. A short section about anthrax is also included: Although Bacillus anthracis is considered a biological weapon rather than a toxin weapon, it produces a toxin that is finally responsible for the anthrax disease. PMID- 26227026 TI - Acute and Long-Term Impact of Chemical Weapons: Lessons from the Iran-Iraq War. AB - Chemical weapons have given the human experience of warfare a uniquely terrifying quality that has inspired a general repugnance and led to periodic attempts to ban their use. Nevertheless, since ancient times, toxic agents have been consistently employed to kill and terrorize target populations. The evolution of these weapons is examined here in ways that may allow military, law enforcement, and scientific professionals to gain a perspective on conditions that, in the past, have motivated their use - both criminally and as a matter of national policy during military campaigns. Special emphasis is placed on the genocidal use of chemical weapons by the regime of Saddam Hussein, both against Iranians and on Kurdish citizens of his own country, during the Iran-Iraq War of 1980-88. The historical development of chemical weapons use is summarized to show how progressively better insight into biochemistry and physiology was adapted to this form of warfare. Major attributes of the most frequently used chemical agents and a description of how they affected military campaigns are explained. Portions of this review describing chemical-casualty care devote particular focus to Iranian management of neurotoxic (nerve) agent casualties due to the unique nature of this experience. Both nerve and blistering "mustard" agents were used extensively against Iranian forces. However, Iran is the only nation in history to have sustained large-scale attacks with neurotoxic weapons. For this reason, an understanding of the successes and failures of countermeasures to nerve-agent use developed by the Iranian military are particularly valuable for future civil defense and military planning. A detailed consideration of these strategies is therefore considered. Finally, the outcomes of clinical research into severe chronic disease triggered by mustard-agent exposure are examined in the context of the potential of these outcomes to determine the etiology of illness among US and Allied veterans of the 1991 Persian Gulf War. PMID- 26227027 TI - Aum Shinrikyo's Chemical and Biological Weapons: More Than Sarin. AB - The radical religious group Aum Shinrikyo was founded in Japan in the 1980s and grew rapidly in the 1990s. Aum members perpetrated a mass murder in Matsumoto City in 1994, where they used sarin as a chemical weapon to poison approximately 500 civilians. On March 20, 1995, Aum deployed sarin in an even larger terrorist attack on the Tokyo Subway System, which poisoned some 6,000 people. After the Tokyo Subway attack, the Japanese Police arrested the sect's senior members. From 2005 through 2011, 13 of these senior members were sentenced to death. In this article, aspects of Aum's chemical and biological terrorism are reviewed. Sarin production efforts by the sect are described, including how the degradation product of sarin in soil, methylphosphonic acid, enabled the detection of sarin production sites. Also, Aum's chemical-warfare agents other than sarin are described, as are its biological weapons. The author was permitted by the Japanese government to interview Dr. Tomomasa Nakagawa, one of the senior members of Aum Shinrikyo. From Dr. Nakagawa the author obtained valuable inside information about Aum's chemical and biological weapons programs. PMID- 26227028 TI - Murder by Poisons: Cases in Taiwan, 1999-2008. AB - This review summarizes the findings from a retrospective study of 17,390 forensic autopsy cases of medicolegal investigations in Taiwan during the 1999-2008 period. Among this total, 1,874 cases involved illicit drugs and 750 involved household toxic chemicals. Rarely seen toxic substances, such as cyanide, corrosive poisons, ether, etc., were found in 6.4%percent; of homicide poisoning cases. Profiling the suspects' backgrounds may play a key role in correlating unique chemicals with the suspects' homicidal behavior. PMID- 26227029 TI - Murder with Radioactive Polonium Metal. AB - The physical and biological aspects of polonium-210, one of the most hazardous radioisotopes, are summarized. Although this radioisotope is naturally occurring and rare, it received quite a bit of attention after it was used in the 2006 assassination of former Russian Intelligence member Alexander Litvinenko in London. Recent reports on the suspected murder of Yasser Arafat with polonium-210 are also discussed. PMID- 26227030 TI - Tetrodotoxin-Medicated Delay in Aconitine Toxicity: A Murder in Okinawa. AB - Aconite (wolfsbane) plants, which belong to the genus Aconitum (Ranunculaceae family), contain highly toxic alkaloids, including aconitine, mesaconitine, hypaconitine, and jesaconitine, in all of their parts. The relevance of this plant material is illustrated by the case of a Japanese female who died suddenly in 1986 and was autopsied in Okinawa by the author. The detection in 1987 of Aconitum alkaloids in her blood using gas chromatography/selected ion monitoring (GC/SIM), which was newly developed for this case, demonstrated that she had died from aconite poisoning. PMID- 26227031 TI - Forensic Analysis in the Wakayama Arsenic Case. AB - In the Wakayama poisoned curry incident in July 1998, 67 inhabitants were killed or injured by eating arsenic-laced curry at a neighborhood summer festival in Wakayama, a local city 400 km southwest of Tokyo. Heavy elements at ppm level, including arsenic, were discovered in the curry using SPring-8, a synchrotron radiation facility, as the tool for forensic analysis. This material evidence resulted in the accused being convicted and sentenced to death. Further analysis and review by other experts indicated the data presented in the trial were not enough to definitively identify the suspect as the murderer. This review highlights the potentially misinterpreted data and re-analysis truth. PMID- 26227032 TI - Management of finger gangrene caused by steal syndrome in vascular access for hemodialysis Personal experience and a brief review of the literature. AB - INTRODUCTION: Severe dialysis-associated steal syndrome (DASS) is an uncommon and severe complication after arteriovenous fistula (AVF) creation that can lead to finger gangrene and amputation. As the number of patients on hemodialysis increases in western countries the number of patients at risk for DASS will continue to rise. METHODS: We retrospectively reviewed all patients who underwent a surgical intervention for the management of DASS with finger gangrene from January 2004 to July 2013. Demographic data, pre-operative work-up, procedure details and outcomes were collected. A literature search using MEDLINE's Medical Subject Heading terms was used to identify recent articles. Cross-references from these articles were also used. RESULTS: A total of nine patients were identified. Mean age was 53 years, 67% were women. All patients presented with finger tissue loss or gangrene. Surgical procedures included AVF closure/ligation (5), distal artery ligation (DRAL) (2), distal revascularization with interval ligation (DRIL) (1), banding (1). All patients had improvement of symptoms during follow up. No major amputation occurred. CONCLUSIONS: Surgical interventions to correct DASS in patients with finger gangrene are mandatory while conservative management is not recommended. The decision for which type of procedure is made individually, according to clinical symptoms, technical findings, and patients' general state of health. PMID- 26227033 TI - Perspectives and Pitfalls in Nucleic Acids Crystallography. AB - X-ray crystallography offers precious and striking knowledge on biomolecular architectures. Although safeguards do exist to guarantee the accuracy of the structures deposited in databases, they are not always applied, leading to the spread of inaccurate data. The importance of validation reports in the publication process is emphasized. PMID- 26227034 TI - Preparation of Short 5'-Triphosphorylated Oligoribonucleotides for Crystallographic and Biochemical Studies. AB - RNA molecules participate in virtually all cellular processes ranging from transfer of hereditary information to gene expression control. In cells, many RNAs form specific interactions with proteins often using short nucleotide sequences for protein recognition. Biochemical and structural studies of such RNA protein complexes demand preparation of short RNAs. Although short RNAs can be synthesized chemically, certain proteins require monophosphate or triphosphate moieties on the 5' end of RNA. Given high cost of chemical triphosphorylation, broad application of such RNAs is impractical. In vitro transcription of RNA by DNA-dependent bacteriophage T7 RNA polymerase provides an alternative option to prepare short RNAs with different phosphorylation states as well as modifications on the 5' terminus. Here we outline the in vitro transcription methodology employed to prepare <=5-mer oligoribonucleotide for structural and biochemical applications. The chapter describes the principles of construct design, in vitro transcription and RNA purification applied for characterization of a protein that targets the 5' end of RNA. PMID- 26227035 TI - Preparation and Crystallization of Riboswitches. AB - Recent studies have revealed that the majority of biological processes are controlled by noncoding RNAs. Among many classes of noncoding RNAs, metabolite sensing segments of mRNAs called riboswitches are unique. Discovered over a decade ago in all three kingdoms of life, riboswitches specifically and directly interact with various metabolites and regulate expression of multiple genes, often associated with metabolism and transport of small molecules. Thus, riboswitches do not depend on proteins for binding to small molecules and play a role as both metabolite sensors and effectors of gene control. Riboswitches are typically located in the untranslated regions of mRNAs where they form alternative structures in the presence and absence of the ligand and modulate expression of genes through the formation of regulatory elements. To understand the mechanism of the riboswitch-driven gene control, it is important to elucidate how riboswitches interact with cognate and discriminate against non-cognate ligands. Here we outline the methodology to synthesize riboswitch RNAs and prepare riboswitch-ligand complexes for crystallographic and biochemical studies. The chapter describes how to design, prepare, and conduct crystallization screening of riboswitch-ligand complexes. The methodology was refined on crystallographic studies of several riboswitches and can be employed for other types of RNA molecules. PMID- 26227036 TI - In Vitro/In Vivo Production of tRNA for X-Ray Studies. AB - tRNAs occupy a central role in the cellular life, and they are involved in a broad range of biological processes that relies on their interaction with proteins and RNA. Crystallization and structure resolution of tRNA or/and tRNA/partner complexes can yield in valuable information on structural organizations of key elements of cellular machinery. However, crystallization of RNA, is often challenging. Here we review two methods to produce and purify tRNA in quantity and quality to perform X-ray studies. PMID- 26227037 TI - Polyacrylamide Gel Electrophoresis for Purification of Large Amounts of RNA. AB - Polyacrylamide gel electrophoresis (PAGE) constitutes a powerful technique for the efficient purification of RNA molecules dedicated to applications that require high purity levels. PAGE allows for the fractionation of RNA obtained from cell extracts, chemical or enzymatic synthesis, or modification experiments. Native or denaturing conditions can be chosen for analytical or preparative-scale separations and the nucleotide resolution can be tuned by changing the percentage and reticulation of the gel material. In this protocol, we focus on the preparation of milligram-scale amounts of ~200 nucleotides (nt) RNA molecules that were used in subsequent crystallization experiments. PMID- 26227038 TI - Use of the U1A Protein to Facilitate Crystallization and Structure Determination of Large RNAs. AB - The preparation of well-ordered crystals of RNAs with complex three-dimensional architecture can be facilitated by engineering a binding site for the spliceosomal protein U1A into a functionally and structurally dispensable stem loop of the RNA of interest. Once suitable crystals are obtained, the U1A protein, of known structure, can be employed to facilitate preparation of heavy atom or anomalously scattering atom derivatives, or as a source of partial model phases for the molecular replacement method. Here, we describe the methods for making U1A preparations suitable for cocrystallization with RNA. As an example, the cocrystallization of the tetracycline aptamer with U1A is also described. PMID- 26227040 TI - Generating Crystallographic Models of DNA Dodecamers from Structures of RNase H:DNA Complexes. AB - The DNA dodecamer 5'-d(CGCGAATTCGCG)-3' is arguably the best studied oligonucleotide and crystal structures of duplexes with this sequence account for a considerable portion of the total number of oligo-2'-deoxynucleotide structures determined over the last 30 years. The dodecamer has commonly served as a template to analyze the effects of sequence on DNA conformation, the conformational properties of chemically modified nucleotides, DNA-ligand interactions as well as water structure and DNA-cation binding. Although molecular replacement is the phasing method of choice given the large number of available models of the dodecamer, this strategy often fails as a result of conformational changes caused by chemical modification, mismatch pairs, or differing packing modes. Here, we describe an alternative approach to determine crystal structures of the dodecamer in cases where molecular replacement does not produce a solution or when crystals of the DNA alone cannot be grown. It is based on the discovery that many dodecamers of the above sequence can be readily co crystallized with Bacillus halodurans RNase H, whereby the enzyme is unable to cleave the DNA. Determination of the structure of the complex using the protein portion as the search model yields a structural model of the DNA. Provided crystals of the DNA alone are also available, the DNA model from the complex then enables phasing their structures by molecular replacement. PMID- 26227039 TI - Fab Chaperone-Assisted RNA Crystallography (Fab CARC). AB - Recent discovery of structured RNAs such as ribozymes and riboswitches shows that there is still much to learn about the structure and function of RNAs. Knowledge learned can be employed in both biochemical research and clinical applications. X ray crystallography gives unparalleled atomic-level structural detail from which functional inferences can be deduced. However, the difficulty in obtaining high quality crystals and their phasing information make it a very challenging task. RNA crystallography is particularly arduous due to several factors such as RNA's paucity of surface chemical diversity, lability, repetitive anionic backbone, and flexibility, all of which are counterproductive to crystal packing. Here we describe Fab chaperone assisted RNA crystallography (CARC), a systematic technique to increase RNA crystallography success by facilitating crystal packing as well as expediting phase determination through molecular replacement of conserved Fab domains. Major steps described in this chapter include selection of a synthetic Fab library displayed on M13 phage against a structured RNA crystallization target, ELISA for initial choice of binding Fabs, Fab expression followed by protein A affinity then cation exchange chromatography purification, final choice of Fab by binding specificity and affinity as determined by a dot blot assay, and lastly gel filtration purification of a large quantity of chosen Fabs for crystallization. PMID- 26227041 TI - Isothermal Titration Calorimetry: Assisted Crystallization of RNA-Ligand Complexes. AB - The success rate of nucleic acids/ligands co-crystallization can be significantly improved by performing preliminary biophysical analyses. Among suitable biophysical approaches, isothermal titration calorimetry (ITC) is certainly a method of choice. ITC can be used in a wide range of experimental conditions to monitor in real time the formation of the RNA- or DNA-ligand complex, with the advantage of providing in addition the complete binding profile of the interaction. Following the ITC experiment, the complex is ready to be concentrated for crystallization trials. This chapter describes a detailed experimental protocol for using ITC as a tool for monitoring RNA/small molecule binding, followed by co-crystallization. PMID- 26227042 TI - Crystallographic Data and Model Quality. AB - This article gives a consistent classification of sources of random and systematic errors in crystallographic data, and their influence on the averaged dataset obtained from a diffraction experiment. It discusses the relation between precision and accuracy and the crystallographic indicators used to estimate them, as well as topics like completeness and high-resolution cutoff. These concepts are applied in the context of presenting good practices for data processing with a widely used package, XDS. Recommendations are given for how to minimize the impact of several typical problems, like ice rings and shaded areas. Then, procedures for optimizing the processing parameters are explained. Finally, a simple graphical expression of some basic relations between data error and model error is suggested. PMID- 26227043 TI - Advanced Crystallographic Data Collection Protocols for Experimental Phasing. AB - Experimental phasing by single- or multi-wavelength anomalous dispersion (SAD or MAD) has become the most popular method of de novo macromolecular structure determination. Continuous advances at third-generation synchrotron sources have enabled the deployment of rapid data collection protocols that are capable of recording SAD or MAD data sets. However, procedural simplifications driven by the pursuit of high throughput have led to a loss of sophistication in data collection strategies, adversely affecting measurement accuracy from the viewpoint of anomalous phasing. In this chapter, we detail optimized strategies for collecting high-quality data for experimental phasing, with particular emphasis on minimizing errors from radiation damage as well as from the instrument. This chapter also emphasizes data processing for "on-the-fly" decision-making during data collection, a critical process when data quality depends directly on information gathered while at the synchrotron. PMID- 26227044 TI - Nucleic Acid Crystallography via Direct Selenium Derivatization: RNAs Modified with Se-Nucleobases. AB - Selenium-derivatized RNAs are powerful tools for structure and function studies of RNAs and their protein complexes. By taking the advantage of selenium modifications, researchers can determine novel RNA structures via convenient SAD and MAD phasing. As one of the naturally occurring tRNA modifications, 2-seleno uridine, which presents almost exclusively at the wobble position of anticodon loop in various bacterial tRNAs (Ching et al., Proc Natl Acad Sci U S A 82:347, 1985; Dunin-Horkawicz et al., Nucleic Acids Res 34:D145-D149, 2006), becomes one of the most promising modifications for crystallographic studies. Our previous studies have demonstrated many unique properties of 2-seleno-uridine, including stability (Sun et al., RNA 19:1309-1314, 2013), minimal structural perturbation (Sun et al., Nucleic Acids Res 40:5171-5179, 2012), and enhanced base-pairing fidelity (Sun et al., Nucleic Acids Res 40:5171-5179, 2012). In this protocol, we present the efficient chemical synthesis of 2-seleno-uridine triphosphate ((Se)UTP) and the facile transcription and purification of (Se)U-containing RNAs ((Se)U-RNA). PMID- 26227045 TI - Practical Radiation Damage-Induced Phasing. AB - Although crystallographers typically seek to mitigate radiation damage in macromolecular crystals, in some cases, radiation damage to specific atoms can be used to determine phases de novo. This process is called radiation damage-induced phasing or "RIP." Here, we provide a general overview of the method and a practical set of data collection and processing strategies for phasing macromolecular structures using RIP. PMID- 26227046 TI - Soaking Hexammine Cations into RNA Crystals to Obtain Derivatives for Phasing Diffraction Data. AB - Solving a novel RNA structure by x-ray crystallography requires a means to obtain initial phase estimates. This is a challenge because many of the tools available for solving protein structures are not available for RNA. We have developed a reliable means to use hexammine cations to address this challenge. The process involves engineering the RNA to introduce a reliable hexammine binding site into the structure, then soaking crystals of these RNAs with an iridium (III) or cobalt (III) compound in a "directed soaking" strategy. Diffraction data obtained from these crystals then can be used in SAD or MAD phasing. In many cases, suitable derivatives can be obtained by soaking the hexammine into RNA crystals that have not been engineered. Considerations for using this method and example protocols are presented. PMID- 26227047 TI - Using Molecular Replacement Phasing to Study the Structure and Function of RNA. AB - In recent years a wide variety of RNA molecules regulating fundamental cellular processes has been discovered. Therefore, RNA structure determination is experiencing a boost and many more RNA structures are likely to be determined in the years to come. The broader availability of experimentally determined RNA structures implies that molecular replacement (MR) will be used more and more frequently as a method for phasing future crystallographic structures. In this report we describe various aspects relative to RNA structure determination by MR. First, we describe how to select and create MR search models for nucleic acids. Second, we describe how to perform MR searches on RNA using available crystallographic software. Finally, we describe how to refine and interpret the successful MR solutions. These protocols are applicable to determine novel RNA structures as well as to establish structural-functional relationships on existing RNA structures. PMID- 26227048 TI - Helical Symmetry of Nucleic Acids: Obstacle or Help in Structure Solution? AB - Crystallographic molecular replacement method is the key tool to define an atomic structure of nucleic acids. Frequently nucleic acids are packed forming continuous helices in the crystal. This arrangement of individual molecules in "infinite" pseudo helical structures in crystal may be the reason why the molecular replacement fails to find a unique position of the search atomic model as the method requires. The Patterson function, calculated as a Fourier series with diffraction intensities, has auxiliary peaks for such a molecular packing. Those near the origin peak indicate the orientation of the helices. The coordinates of other peaks are related to the molecular position and the rotation angle between two such "infinite" helices. Thus, the peak analysis allows getting molecular position even without a search model. An intelligent selecting and averaging of the phase sets corresponding to multiple probable positions of the search model again result in a unique solution but in the form of a Fourier synthesis and not a model. This synthesis can be used then to build an atomic model as it is the case for usual phasing methods. PMID- 26227050 TI - Neutron Nucleic Acid Crystallography. AB - The hydration shells surrounding nucleic acids and hydrogen-bonding networks involving water molecules and nucleic acids are essential interactions for the structural stability and function of nucleic acids. Water molecules in the hydration shells influence various conformations of DNA and RNA by specific hydrogen-bonding networks, which often contribute to the chemical reactivity and molecular recognition of nucleic acids. However, X-ray crystallography could not provide a complete description of structural information with respect to hydrogen bonds. Indeed, X-ray crystallography is a powerful tool for determining the locations of water molecules, i.e., the location of the oxygen atom of H2O; however, it is very difficult to determine the orientation of the water molecules, i.e., the orientation of the two hydrogen atoms of H2O, because X-ray scattering from the hydrogen atom is very small.Neutron crystallography is a specialized tool for determining the positions of hydrogen atoms. Neutrons are not diffracted by electrons, but are diffracted by atomic nuclei; accordingly, neutron scattering lengths of hydrogen and its isotopes are comparable to those of non-hydrogen atoms. Therefore, neutron crystallography can determine both of the locations and orientations of water molecules. This chapter describes the current status of neutron nucleic acid crystallographic research as well as the basic principles of neutron diffraction experiments performed on nucleic acid crystals: materials, crystallization, diffraction experiments, and structure determination. PMID- 26227049 TI - RNA Structure Refinement Using the ERRASER-Phenix Pipeline. AB - The final step of RNA crystallography involves the fitting of coordinates into electron density maps. The large number of backbone atoms in RNA presents a difficult and tedious challenge, particularly when experimental density is poor. The ERRASER-Phenix pipeline can improve an initial set of RNA coordinates automatically based on a physically realistic model of atomic-level RNA interactions. The pipeline couples diffraction-based refinement in Phenix with the Rosetta-based real-space refinement protocol ERRASER (Enumerative Real-Space Refinement ASsisted by Electron density under Rosetta). The combination of ERRASER and Phenix can improve the geometrical quality of RNA crystallographic models while maintaining or improving the fit to the diffraction data (as measured by R free). Here we present a complete tutorial for running ERRASER Phenix through the Phenix GUI, from the command-line, and via an application in the Rosetta On-line Server that Includes Everyone (ROSIE). PMID- 26227051 TI - Reconstitution of Functionally Active Thermus thermophilus 30S Ribosomal Subunit from Ribosomal 16S RNA and Ribosomal Proteins. AB - In vitro reconstitution systems of ribosomal subunits from free ribosomal RNA and ribosomal proteins are helpful tool for studies on the structure, function and assembly of ribosome. Using this system mutant or modified ribosomal proteins or ribosomal RNA can be incorporated into ribosomal subunits for studying ribosome structure and function. Developing the protocol for reconstitution of 30S subunits from an extreme thermophilic bacterium Thermus thermophilus can be beneficial especially for structural studies, as proteins and nucleic acids from this organism are very stable and crystallize easier than those from mesophilic organisms. PMID- 26227052 TI - Crystallographic Studies of the Ribosomal A-Site Molecular Switches by Using Model RNA Oligomers. AB - An RNA molecular switch in the aminoacyl-tRNA decoding site (A site) of the ribosome plays a key role in the decoding process of the protein biosynthesis. The switch discriminates a single cognate-tRNA from near-cognate tRNAs by changing its conformation from "off" to "on" states and recognizing the first two base pairs of codon-anticodon mini-helix to check whether these base pairs are of the canonical Watson-Crick type or not. Aminoglycoside antibiotics specifically target the "on" state of the bacterial A-site molecular switch and disturb the fidelity of the decoding process, resulting to cell death. If it occurs in human who was given aminoglycosides, it can lead to undesirable side effects. In order to understand the molecular bases of the decoding and the antibacterial and toxic side effects of aminoglycosides, it is necessary to determine the three dimensional structures of the A-site molecular switches both in the presence and absence of aminoglycosides. This chapter focuses on methods in crystallographic studies of the A-site switches by using model RNA oligomers. The methods can be utilized in crystallographic studies of any DNA/RNA oligomers. PMID- 26227053 TI - Structure of the HCV Internal Ribosome Entry Site Subdomain IIa RNA in Complex with a Viral Translation Inhibitor. AB - The internal ribosome entry site (IRES) in the 5' untranslated region (UTR) of the hepatitis C virus (HCV) RNA genome is responsible for initiation of viral protein synthesis. The IRES RNA contains autonomously folding domains that are potential targets for antiviral translation inhibitors. Here, we describe the experimental crystal structure determination of the IRES subdomain IIa in complex with a previously discovered benzimidazole translation inhibitor. The structure of an inhibitor complex of the highly conserved IRES subdomain IIa holds promise for structure-based design of new anti-HCV drugs. PMID- 26227054 TI - Anions in Nucleic Acid Crystallography. AB - Nucleic acid crystallization buffers contain a large variety of chemicals fitting specific needs. Among them, anions are often solely considered for pH-regulating purposes and as cationic co-salts while their ability to directly bind to nucleic acid structures is rarely taken into account. Here we review current knowledge related to the use of anions in crystallization buffers along with data on their biological prevalence. Chloride ions are frequently identified in crystal structures but display low cytosolic concentrations. Hence, they are thought to be distant from nucleic acid structures in the cell. Sulfate ions are also frequently identified in crystal structures but their localization in the cell remains elusive. Nevertheless, the characterization of the binding properties of these ions is essential for better interpreting the solvent structure in crystals and consequently, avoiding mislabeling of electron densities. Furthermore, understanding the binding properties of these anions should help to get clues related to their potential effects in crowded cellular environments. PMID- 26227055 TI - Buccal adhesive nanofibers containing human growth hormone for oral mucositis. AB - Due to a lack of proper drug carriers to deliver treatments for mucositis, many cancer patients suffer from oral mucositis caused by chemotherapy and radiotherapy. We prepared a double-layered electrospun nanofibrous sheets composed of Eudragit and chitosan to accelerate the healing rate of oral mucous ulcer. Human growth hormone (hGH) and Eudragit in a mixture of dimethylacetamide and ethanol were co-electrospun to nanofibrous sheets. The electrospun fibrous mat was subsequently layered with chitosan by a dip-coating method. Chitosan layered sheets showed attenuated mass erosion while uncoated sheets were instantly melted at the physiological condition. The released hGH was trapped on the chitosan layer by the ionic interaction between positively charged chitosan and negatively charged hGH, and a large number of entrapped proteins remained on the SIS membrane due to the muco-adhesive properties of chitosan. hGH incorporated sheets significantly increased proliferation of human dermal fibroblasts. In vivo study employing oral ulcers in dogs, the ulcers dressed with chitosan-layered sheets showed enhanced wound recovery and the chitosan layers on the sheet greatly assisted prolonged recovery. Therefore, chitosan-layered Eudragit nanofibrous sheets can be potentially applied to developing muco adhesive wound dressing materials with pH-dependent drug release by adjusting the thickness of chitosan sheath on the sheets. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1396-1406, 2016. PMID- 26227056 TI - Microsurgical Decompression for Peroneal Nerve Entrapment Neuropathy. AB - Peroneal nerve entrapment neuropathy (PNEN) is one cause of numbness and pain in the lateral lower thigh and instep, and of motor weakness of the extensors of the toes and ankle. We report a less invasive surgical procedure performed under local anesthesia to treat PNEN and our preliminary outcomes. We treated 22 patients (33 legs), 7 men and 15 women, whose average age was 66 years. The mean postoperative follow-up period was 40 months. All patients complained of pain or paresthesia of the lateral aspect of affected lower thigh and instep; all manifested a Tinel-like sign at the entrapment point. As all had undergone unsuccessful conservative treatment, we performed microsurgical decompression under local anesthesia. Of 19 patients who had undergone lumbar spinal surgery (LSS), 9 suffered residual symptoms attributable to PNEN. While complete symptom abatement was obtained in the other 10 they later developed PNEN-induced new symptoms. Motor weakness of the extensors of the toes and ankle [manual muscle testing (MMT) 4/5] was observed preoperatively in 8 patients; it was relieved by microsurgical decompression. Based on self-assessments, all 22 patients were satisfied with the results of surgery. PNEN should be considered as a possible differential diagnosis in patients with L5 neuropathy due to lumbar degenerative disease, and as a causative factor of residual symptoms after LSS. PNEN can be successfully addressed by less-invasive surgery performed under local anesthesia. PMID- 26227057 TI - Neurosurgical Management of Childhood Spasticity: Functional Posterior Rhizotomy and Intrathecal Baclofen Infusion Therapy. AB - A paradigm shift is currently ongoing in the treatment of spasticity in childhood in Japan. Functional posterior rhizotomy (FPR), which was first introduced to Japan in 1996, is best indicated for children with spastic cerebral palsy, regardless of the clinical severity of spasticity. Surgery is generally carried out in the cauda equina, where the posterior root is separated from the anterior one, and neurophysiological procedures are used to judge which nerve root/rootlet should be cut. The outcome of FPR is favorable for reducing spasticity in the long-term follow-up. Intrathecal baclofen (ITB) treatment for childhood spasticity was approved in 2007 in Japan and the number of children undergoing ITB pump implantation has been gradually increasing. ITB treatment is best indicated for children with severe spasticity, especially those with dystonia, regardless of the pathological background. Since it is a surgery performed to implant foreign bodies, special attention should be paid to avoid perioperative complications such as CSF leakage, meningitis, and mechanical failure. Severely disabled children with spasticity would benefit most from ITB treatment. We would especially like to emphasize the importance of a strategic approach to the treatment of childhood spasticity. The first step is to reduce spasticity by FPR, ITB, and botulinum toxin injection. The second step is to aim for functional improvement after controlling spasticity. Traditional orthopedic surgery and neuro-rehabilitation form the second step of treatment. The combination of these treatments that allows them to complement each other is the key to a successful treatment of childhood spasticity. PMID- 26227058 TI - Molecular Biology of Pediatric Hydrocephalus and Hydrocephalus-related Diseases. AB - We are beginning to understand the molecular biology of hydrocephalus and its related diseases. X-linked hydrocephalus (XLH), holoprosencephaly (HPE), Dandy Walker malformation (DWM), and neural tube defect (NTD) can all be discussed with respect to their available molecular genetics knowledge base and its clinical applications. XLH is single gene disorder caused by mutations in the neural cell adhesion molecule-encoding L1CAM (L1) gene. Our knowledge of the molecular basis of XLH is already being applied clinically in disease diagnosis, disease classification, and prenatal diagnosis. However, the molecular mechanism underlying XLH-related hydrocephalus still needs to be clarified. Sixteen causative genes for HPE have been identified, of which mutations are most often found in SHH, ZIC2, SIX3, and TGIF. Genetic interactions, gene complexity, and the wide variety of HPE phenotypes and genotypes are topics for future study. For DWM, two important loci, 3q24, which includes the FOXC1 gene, and 6q25.3, which includes the ZIC1 and ZIC4 genes, were recently identified as causative areas. The planar cell polarity (PCP) genes CELSR1, CELSR2, VANGL1, and VANGL2 have been implicated in NTD; these genes have roles in neural tube closure and ependymal ciliary movement. PMID- 26227059 TI - MiR-345 suppresses proliferation, migration and invasion by targeting Smad1 in human prostate cancer. AB - INTRODUCTION: The roles of dysregulated microRNAs in prostate cancer metastasis are still unknown. In this study, we found that the expression of miR-345 was significantly downregulated in prostate cancer and clinical prostate cancer tissues. MATERIALS, METHODS AND RESULTS: Overexpression of miR-345 in prostate cancer cells suppressed proliferation, migration and invasion. Using nude mice model, we revealed that miR-345 inhibits the growth of prostate cancer cells in vivo and in vitro. Furthermore, we identified and validated Smad1 as a direct target of miR-345. Ectopic expression of Smad1 without its 3'-UTR rescued miR-345 induced cell migration and invasion inhibition. CONCLUSION: Taken together, our data suggest that miR-345 exerts a suppressive effect on prostate cancer proliferation, invasion and migration through downregulation of Smad1. PMID- 26227060 TI - Acute length adaptation and adjustable preload in the human detrusor. AB - AIMS: The biomechanical properties of length adaptation and adjustable preload have been previously identified in detrusor smooth muscle in animal models. This in vitro study aims to show that human detrusor smooth muscle exhibits length adaptation and adjustable preload tension which could play an important role in both overactive bladder and detrusor underactivity. METHODS: In order to demonstrate length adaptation, human detrusor smooth muscle strips are stretched and contracted beyond an optimum length and then contracted three times at the previous optimum length to determine if maximum active tension could be re established. To demonstrate adjustable preload (Tap ), human detrusor smooth muscle strips are subjected to a pre-defined loading-unloading (strain softening) sequence to reduce preload. Then, tissues are contracted and the sequence is repeated to determine if this active process restored preload. RESULTS: Nine patients (average age, 62) provide tissue: 89% are men with urothelial carcinoma and a minority (22%) also have neurogenic bladder dysfunction. In the length adaptation protocol, contractions show progressive increases in active tension (P < 0.05). In the Tap protocol, a significant amount of preload is lost to strain softening (P < 0.05) and is restored after active contraction (P = 0.50). Exposure to the rho-kinase inhibitor, H-1152, prevents the restoration of preload (P < 0.05). CONCLUSIONS: This study demonstrates that human detrusor smooth muscle displays both length adaptation and Tap . Furthermore, Tap may be regulatable through a rho-kinase pathway. These biomechanical processes may be important in the pathophysiology of both overactive bladder and detrusor underactivity. Neurourol. Urodynam. 35:792-797, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26227061 TI - Clinical utility of gadoxetate disodium-enhanced hepatic MRI for stereotactic body radiotherapy of hepatocellular carcinoma. AB - PURPOSE: To investigate the utility of gadoxetate disodium-enhanced hepatic MRI (EOB-MRI) for stereotactic body radiotherapy (SBRT) to treat hepatocellular carcinoma (HCC). MATERIALS AND METHODS: We divided 30 HCC patients who underwent SBRT into group A (no change in their Child-Pugh score 6 months post-SBRT) and group B (increased score 6 months post-SBRT). EOB-MRI was performed before and 6 months after SBRT. We calculated the liver-spleen contrast (LSC) ratio for each radiation dose area on hepatobiliary phase scans (LSCbefore using images obtained before SBRT and LSCafter using images acquired after SBRT) and the weighted LSC (W-LSC) as: [(mean LSCbefore (0-30 Gy) * liver volume (0-30 Gy) + mean LSCbefore (30 Gy-) * liver volume (30 Gy-))/total liver volume]. Then we compared the W LSC, percentage of the liver volume exposed to >20 Gy (V20), and mean liver dose in the two groups. RESULTS: The LSCafter at 48, 40, and 30 Gy to the liver was statistically lower than the unirradiated area of the liver (p < 0.01). Univariate analysis showed that only W-LSC was significantly associated with group B (p = 0.02). CONCLUSION: W-LSC was a useful parameter for predicting changes in hepatic function after SBRT. PMID- 26227062 TI - European Reference Networks and Guideline Development and Use: Challenges and Opportunities. AB - BACKGROUND: The Directive 2011/24/EU [OJEU 2011, L88/45] on the application of patient rights in cross-border health care requires the European Commission to support Member States in the development of European reference networks (ERNs). These ERNs are meant to ease the access of patients to highly specialized health care and to facilitate the cooperation at the European Union level in particular medical domains where expertise is scarce, especially in the rare disease area. METHODS: The Directive 2011/24/EU [OJEU 2011, L88/45] and the recent Commission Delegated Decision [OJEU 2014, L147/71] as well as the Implementing Decision [OJEU 2014, L147/79] require ERNs and health care providers wishing to join ERNs to have the capacity of developing good practices guidelines. RESULTS: This provision results in a number of challenges but also opportunities for Member States with respect to guideline production. Member States could consider the importance of devoting resources to build efficient systems and capacities for the development and implementation of trustworthy guidelines. Furthermore, they could adopt a cooperative approach to optimize guideline production across countries. Finally, they could promote the establishment of new research governance based on systematically identified research gaps and prioritized as well as communicated research recommendations. CONCLUSION: Member States are at a decisive point in establishing the details to ensure the transparent and effective functioning of ERNs. Producing explicit plans for the development and use of trustworthy guidelines should be an essential part of this effort. PMID- 26227063 TI - Nitrergic signalling via interstitial cells of Cajal regulates motor activity in murine colon. AB - In the enteric nervous systems, NO is released from nitrergic neurons as a major inhibitory neurotransmitter. NO acts via NO-sensitive guanylyl cyclase (NO-GC), which is found in different gastrointestinal (GI) cell types including smooth muscle cells (SMCs) and interstitial cells of Cajal (ICC). The precise mechanism of nitrergic signalling through these two cell types to regulate colonic spontaneous contractions is not fully understood yet. In the present study we investigated the impact of endogenous and exogenous NO on colonic contractile motor activity using mice lacking nitric oxide-sensitive guanylyl cyclase (NO-GC) globally and specifically in SMCs and ICC. Longitudinal smooth muscle of proximal colon from wild-type (WT) and knockout (KO) mouse strains exhibited spontaneous contractile activity ex vivo. WT and smooth muscle-specific guanylyl cyclase knockout (SMC-GCKO) colon showed an arrhythmic contractile activity with varying amplitudes and frequencies. In contrast, colon from global and ICC-specific guanylyl cyclase knockout (ICC-GCKO) animals showed a regular contractile rhythm with constant duration and amplitude of the rhythmic contractions. Nerve blockade (tetrodotoxin) or specific blockade of NO signalling (L-NAME, ODQ) did not significantly affect contractions of GCKO and ICC-GCKO colon whereas the arrhythmic contractile patterns of WT and SMC-GCKO colon were transformed into uniform motor patterns. In contrast, the response to electric field-stimulated neuronal NO release was similar in SMC-GCKO and global GCKO. In conclusion, our results indicate that basal enteric NO release acts via myenteric ICC to influence the generation of spontaneous contractions whereas the effects of elevated endogenous NO are mediated by SMCs in the murine proximal colon. PMID- 26227064 TI - Computational study enlightens the structural role of the alcohol acyltransferase DFGWG motif. AB - Alcohol acyltransferases (AAT) catalyze the esterification reaction of alcohols and acyl-CoA into esters in fruits and flowers. Despite the high divergence between AAT enzymes, two important and conserved motifs are shared: the catalytic HxxxD motif, and the DFGWG motif. The latter is proposed to play a structural role; however, its function remains unclear. The DFGWG motif is located in loop 21 and stabilized by a hydrogen bond between residues Y52 and D381. Also, this motif is distant from the HxxxD motif, and most probably without a direct role in the substrate interaction. To evaluate the role of the DFGWG motif, in silico analysis was performed in the VpAAT1 protein. Three mutants (Y52F, D381A and D381E) were evaluated. Major changes (size and shape) in the solvent channels were found, although no differences were revealed in the entire 3D structure. Molecular dynamics simulations and docking studies described unfavorable energies for interaction of the mutant proteins with different substrates, as well as unfavored ligand orientations in the solvent channel. Additionally, we examined the contribution of different energetic parameters to the total free energy of protein-ligand complexes by the MM-GBSA method. The complexes differed mainly in their van der Waals contributions and have unfavorable electrostatic interactions. VpAAT1, Y52F and D381A mutants showed a dramatic reduction in the binding capacity to several substrates, which is related to differences in electrostatic potential on the protein surfaces, suggesting that D381 from the DFGWG motif and residue Y52 play a crucial role in maintenance of the adequate solvent channel structure required for catalysis. Graphical abstract Molecular docking, molecular dynamics (MD) simulations and MM-GBSA free energy calculations were employed to obtain quantitative estimates for the binding free energies of wild type Vasconcellea pubescens alcohol acyltransferase (VpAAT1-WT) and the protein mutants. Left VpAAT1 model structure in cartoon representation showing the solvent channel in the middle of the structure. Center, right Changes in shape and structure in the solvent channel of Y52F and D381A mutant proteins, respectively, compared to WT. The results obtained reveal that the interaction between D381 and Y52 residues is important for the maintenance of solvent channel structure. PMID- 26227065 TI - Non-covalent functionalization of hexagonal boron nitride nanosheets with guanine. AB - Density functional theory (DFT) calculations were performed to analyze changes in the structural and electronic properties generated by the interaction of a single nucleobase group (guanine) with the surface of boron nitride nanosheets with hexagonal symmetry (hBNNs). Nanosheets in two contexts were tested: pristine sheets and with point defects (doped with carbon atoms). The criterion of energy minimum was used to find the ground state of the nine possible isomers generated by the hBNNs-guanine interaction. The phenomenon of physisorption is known to occur at values less than 1.0 eV; the adsorption energy results revealed that the preferential geometry was a parallel arrangement between the two partners, with van der Waals-type bonds generated for the hBNNs doped with two carbon atoms. This was the only energetically stable configuration, thus revealing a vibrational mode rather than imaginaries. Furthermore, the hBNNs/C-guanine system has a low value for work function, and therefore could be used in health applications such drug transport and delivery. The increased polarity values suggest that these nanosheets could be solubilized in common solvents used in experimental processes. PMID- 26227066 TI - Concise Review: Patient-Derived Stem Cell Research for Monogenic Disorders. AB - Monogenic disorders (MGDs) are caused by a single gene mutation and have a serious impact on human health. At present, there are no effective therapeutic methods for MGDs. Stem cell techniques provide insights into potential treatments for MGDs. With the development of patient-derived stem cells, we can begin to progressively understand the molecular mechanism of MGDs and identify new drugs for MGD treatment. Using powerful genome editing tools, such as zinc finger nucleases, transcriptional activator-like effector nucleases, and the clustered regulatory interspaced short palindromic repeat/Cas9 system, MGD-associated gene mutations can be corrected in MGD stem cells in vitro and then transplanted into MGD animal models to assess their safety and therapeutic effects. Despite the continued challenges surrounding potential pluripotent stem cell tumorigenicity and concerns regarding the genetic modification of stem cells, the extensive clinical application of MGD patient-specific stem cells will be pursued through further advances in basic research in the MGD field. In this review, we will summarize the latest progress in research into the use of patient-derived stem cells for the potential treatment of MGDs and provide predictions regarding the direction of future investigations. PMID- 26227067 TI - A mechanism for graded, dynamically routable current propagation in pulse-gated synfire chains and implications for information coding. AB - Neural oscillations can enhance feature recognition (Azouz and Gray Proceedings of the National Academy of Sciences of the United States of America, 97, 8110 8115 2000), modulate interactions between neurons (Womelsdorf et al. Science, 316, 1609-01612 2007), and improve learning and memory (Markowska et al. The Journal of Neuroscience, 15, 2063-2073 1995). Numerical studies have shown that coherent spiking can give rise to windows in time during which information transfer can be enhanced in neuronal networks (Abeles Israel Journal of Medical Sciences, 18, 83-92 1982; Lisman and Idiart Science, 267, 1512-1515 1995, Salinas and Sejnowski Nature Reviews. Neuroscience, 2, 539-550 2001). Unanswered questions are: 1) What is the transfer mechanism? And 2) how well can a transfer be executed? Here, we present a pulse-based mechanism by which a graded current amplitude may be exactly propagated from one neuronal population to another. The mechanism relies on the downstream gating of mean synaptic current amplitude from one population of neurons to another via a pulse. Because transfer is pulse based, information may be dynamically routed through a neural circuit with fixed connectivity. We demonstrate the transfer mechanism in a realistic network of spiking neurons and show that it is robust to noise in the form of pulse timing inaccuracies, random synaptic strengths and finite size effects. We also show that the mechanism is structurally robust in that it may be implemented using biologically realistic pulses. The transfer mechanism may be used as a building block for fast, complex information processing in neural circuits. We show that the mechanism naturally leads to a framework wherein neural information coding and processing can be considered as a product of linear maps under the active control of a pulse generator. Distinct control and processing components combine to form the basis for the binding, propagation, and processing of dynamically routed information within neural pathways. Using our framework, we construct example neural circuits to 1) maintain a short-term memory, 2) compute time windowed Fourier transforms, and 3) perform spatial rotations. We postulate that such circuits, with automatic and stereotyped control and processing of information, are the neural correlates of Crick and Koch's zombie modes. PMID- 26227068 TI - Sociodemographic and diagnostic characteristics of prescribing a second-line lipid-lowering medication: ezetimibe used as initial medication, switch from statins, or add-on medication. AB - OBJECTIVE: Ezetimibe is used as a second-line lipid-lowering medication (LLM) if statin therapy is not tolerated or cholesterol targets are not reached by statins alone. We aimed to investigate the impact of sociodemographic factors on ezetimibe initiation as (a) incident LLM therapy, (b) add-on therapy, and (c) switch from statins. METHODS: All individuals aged 30+ who had filled at least one prescription for either statins (N = 581.074) or ezetimibe (N = 7.932) in 2011 were followed in the nationwide Danish registries to explore LLM prescribing patterns from 1 January 2011 to end 2012. Using logistic regression analyses, the odds ratio (OR) with 95% confidence intervals (CIs) was calculated for (a) incident ezetimibe use among LLM initiators (N = 77,472), (b) ezetimibe switching by discontinuing statin users (N = 37,509), and (c) ezetimibe as add-on by non discontinuing statin users (N = 442,672). RESULTS: Women had higher odds for initiating ezetimibe than men (switch OR = 1.55; 95% CI = 1.32-1.82). While prior use of newer high-potency statins was the strongest predictor (add-on (5.56; 4.95 6.24), income was the strongest socioeconomic predictor for incident LLM use (1.33; 1.14-1.56) and switching (1.64; 1.27-2.13). Both income and education were predictors for add-on therapy, with the educational effect mediated by prior use of high-potency statins. Odds for ezetimibe prescribing were highest in myocardial infarction patients. CONCLUSION: While higher income is a predictor for switching to ezetimibe, both higher education and income are weak predictors for using ezetimibe as add-on therapy. Women and individuals with myocardial infarction are more likely to be prescribed ezetimibe than others, despite lack of evidence of ezetimibe lowering the risk of cardiovascular events. PMID- 26227069 TI - Income differences in the type of antihypertensive medicines used in ambulatory settings in Finland: a register-based study. AB - PURPOSE: The objective of this study was to explore income differences in the prevalence of moderate-to-severe hypertension, and among patients, in the use and costs of medicines. METHODS: Personal income was used to classify >=25-year-old population in quintiles (QI-QV). Patients (N = 497,560) with moderate-to-severe hypertension were identified using special refund entitlements. Medicine use and costs derived from prescription register. Direct standardisation and multivariate regression were used to adjust for demographics and comorbidities. RESULTS: Low income was associated with higher prevalence of moderate-to-severe hypertension (overall 13%). After adjusting for age, gender, residence, diabetes and coronary heart disease, nearly all patients purchased at least one antihypertensive medicine (93 vs. 96% in QI and QV). Differences in the purchased quantities were small (mean estimates 1028 vs. 1054 defined daily doses (DDDs)/patient/year in QIV and QI). High-income patients were more likely to use angiotensin receptor blockers (37 vs. 54% in QI and QV). Low-income patients were more likely to use beta-blockers (59 vs. 49%, respectively) and ACE inhibitors (35 vs. 28%, respectively). Higher income was associated with higher annual out-of-pocket costs (mean ?66 vs. ?71 in QI and QV) and reimbursements (?144 vs. ?163, respectively). CONCLUSIONS: Use of more expensive medicines contributed to higher costs among patients with higher incomes. PMID- 26227070 TI - A new Bayesian network-based approach to the analysis of sperm motility: application in the study of tench (Tinca tinca) semen. AB - In this study a Bayesian network (BN) has been built for the study of the objective motility of Tinca tinca spermatozoa (spz). Semen from eight 2-year-old sexually mature male tenchs was obtained and motility analyses were performed at 6-17, 23-34 and 40-51 s after activation, using computer-assisted sperm analysis (CASA) software. Motility parameters rendered by CASA were treated with a two step cluster analysis. Three well-defined sperm subpopulations were identified, varying the proportion of spermatozoa contained in each cluster with time and male. Cluster, cinematic and time variables were used to build the BN to study the probabilistic relationships among variables and how each variable influenced the final sperm classification into one of three predefined clusters. Both network structure and conditional probabilities were calculated based on the collected data set. Results shown that almost all the variables were directly or indirectly related to each other. By doing probabilistic inference we observed that the cluster distribution corresponded to the definition provided by the cluster analysis. Also, velocity and time variables determined the cluster to which each spermatozoon belonged with a high degree of accuracy. Thus, BNs can be applied in the study of sperm motility. The construction of a BN that include fertility data opens a new way to try to clarify the roles of motility and other sperm quality indicators in fertilization. PMID- 26227071 TI - Therapeutic advances in multiple system atrophy and progressive supranuclear palsy. AB - Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are relentlessly progressive neurodegenerative diseases leading to severe disability and ultimately death within less than 10 y. Despite increasing efforts in basic and clinical research, effective therapies for these atypical parkinsonian disorders are lacking. Although earlier small clinical studies in MSA and PSP mainly focused on symptomatic treatment, advances in the understanding of the molecular underpinnings of these diseases and in the search for biomarkers have paved the way for the first large and well-designed clinical trials aiming at disease modification. Targets of intervention in these trials have included alpha synuclein inclusion pathology in the case of MSA and tau-related mechanisms in PSP. Since 2013, four large randomized, placebo-controlled, double-blind disease modification trials have been completed and published, using rasagiline (MSA), rifampicin (MSA), tideglusib (PSP), or davunetide (PSP). All of these failed to demonstrate signal efficacy with regard to the primary outcome measures. In addition, two randomized, placebo-controlled, double-blind trials have studied the efficacy of droxidopa in the symptomatic treatment of neurogenic orthostatic hypotension, including patients with MSA, with positive results in one trial. This review summarizes the design and the outcomes of these and other smaller trials published since 2013 and attempts to highlight priority areas of future therapeutic research in MSA and PSP. (c) 2015 International Parkinson and Movement Disorder Society. PMID- 26227072 TI - Survival in Subcortical Vascular Dementia: Predictors and Comparison to Probable Alzheimer's Disease in a Tertiary Memory Clinic Population. AB - BACKGROUND: Subcortical vascular dementia (SVaD) is one of the most common dementias, after Alzheimer's disease (AD) dementia. Few survival analyses in SVaD patients have been reported. METHODS: The dates and causes of death of 146 SVaD and 725 AD patients were included. We used the Cox proportional hazards model to compare survival between SVaD and AD patients and to explore possible factors related to survival of SVaD patients. RESULTS: The median survival time after the onset of SVaD (109 months) was shorter than that recorded for AD (152 months). The most common cause of death in SVaD was stroke (47.1%). Factors associated with shorter survival in SVaD were late onset, male sex, worse baseline cognition, absence of hypertension and a family history of stroke. CONCLUSIONS: Stroke prevention may be important in SVaD treatment because 47.1% of SVaD patients died of stroke. A family history of stroke and absence of hypertension were associated with a shorter survival in SVaD, suggesting the existence of genetic or unknown risk factors. PMID- 26227073 TI - Electrochemical Label-Free Nucleotide Sensors. AB - Numerous researchers have devoted a great deal of effort over the last few decades to the development of electrochemical oligonucleotide detection techniques, owing to their advantages of simple design, inherently small dimensions, and low power requirements. Their simplicity and rapidity of detection makes label-free oligonucleotide sensors of great potential use as first-aid screening tools in the analytical field of environmental measurements and healthcare management. This review article covers label-free oligonucleotide sensors, focusing specifically on topical electrochemical techniques, including intrinsic redox reaction of bases, conductive polymers, the use of electrochemical indicators, and highly ordered probe structures. PMID- 26227074 TI - Surface Segregated AgAu Tadpole-Shaped Nanoparticles Synthesized Via a Single Step Combined Galvanic and Citrate Reduction Reaction. AB - New AgAu tadpole nanocrystals were synthesized in a one-step reaction involving simultaneous galvanic replacement between Ag nanospheres and AuCl4(-)(aq.) and AuCl4(-)(aq.) reduction to Au in the presence of citrate. The AgAu tadpoles display nodular polycrystalline hollow heads, while their undulating tails are single crystals. The unusual morphology suggests an oriented attachment growth mechanism. Remarkably, a 1 nm thick Ag layer was found to segregate so as to cover the entire surface of the tadpoles. By varying the nature of the seeds (Au NPs), double-headed Au tadpoles could also be obtained. The effect of a number of reaction parameters on product morphology were explored, leading to new insights into the growth mechanisms and surface segregation behavior involved in the synthesis of bimetallic and anisotropic nanomaterials. PMID- 26227075 TI - Benzylic C(sp(3) )?H Perfluoroalkylation of Six-Membered Heteroaromatic Compounds. AB - Successful benzylic C(sp(3) )-H trifluoromethylation, pentafluoroethylation, and heptafluoropropylation of six-membered heteroaromatic compounds were achieved as the first examples of a practical benzylic C(sp(3) )-H perfluoroalkylation. In these reactions, BF2 Cn F2n+1 (n=1-3) functioned as both a Lewis acid to activate the benzylic position and a Cn F2n+1 (n=1-3) source. The perfluoroalkylation proceeded at both terminal and internal positions of the alkyl chains. Perfluoroalkylated products were obtained in moderate to excellent yields, even on gram scale, and in a sequential procedure without isolation of the intermediates. By using this method, trifluoromethylation of a bioactive compound, as well as introduction of a CF3 group into a bioactive molecular skeleton, proceeded regioselectively. PMID- 26227076 TI - The effects of molecular collisions between the mobile phase and the solute in gas-solid chromatography. AB - In chromatographic processes, molecular collisions between the mobile phase and the solute result in the transfer of kinetic energy. Based on these interactions, the relationship between the gauge pressure of the carrier gas at the column inlet and the partition frequency of the solute is derived; consequently, the relationship between the column temperature and partition frequency can be obtained. These relationships have been experimentally validated. The change in the peak shape described herein has been successfully explained using this relationship: the partition frequency was calculated from the theoretical plate number of a tailing peak. We propose a new mechanism for peak tailing using plate theory, which states that as the number of plates increases, the symmetry of the peak increases. PMID- 26227077 TI - Otolaryngology Needs in a Free Clinic Providing Indigent Care. AB - OBJECTIVES/HYPOTHESIS: To determine the otolaryngology needs in a free clinic providing care to medically indigent patients, as perceived by the patients and health care providers. STUDY DESIGN: Cross-sectional survey. METHODS: A survey was administered to patients and health care providers of a free clinic from September 2014 through January 2015 in an urban, inner-city location. RESULTS: One hundred and thirty-seven patients (35.8% male, age 50.8 +/- 13.0 years) completed the survey. Mean household income was $29,838 +/- $10,425; 32.1% spoke English; 54.7% were employed; 10.2% had health insurance; and 37.2% had seen a primary care provider outside of the free clinic. The top three otolaryngology symptoms among patients were sleep apnea/snoring (39.4%), heartburn/reflux (30.7%), and dizziness (29.9%). Eleven health care providers (45% male, age 50.5 +/- 15.3 years, 63.6% physician, 36% nurse) completed the survey. Providers perceived the following otolaryngology complaints as the most prevalent, in descending order: cough, nasal congestion, reflux/heartburn, sore throat, and ear infection/otalgia. Providers felt that sleep apnea and hearing loss were the less common otolaryngology complaints, whereas surveyed patients indicated these symptoms with high frequency. The most requested diagnostic tool among patients and providers was chest X-rays. CONCLUSION: There are unmet otolaryngology needs in a free clinic. Medically indigent patients have significant barriers to accessing health care. Patient and provider perceptions of top otolaryngology complaints differed, but both identified access to chest X-rays as a major unmet need. Knowledge of patient perceptions may help providers elicit the breadth of otolaryngology complaints. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1321-1326, 2016. PMID- 26227078 TI - Effects of Refractive Power on Macular Thickness Measurement Using Spectral Domain Optical Coherence Tomography. AB - PURPOSE: To investigate the effects of refractive power on macular thickness measurements by spectral-domain optical coherence tomography (SD-OCT). SUBJECTS AND METHODS: For this prospective cohort study, a total of 50 eyes from 50 normal subjects with no systemic or ocular disease and no history of ocular surgery were studied from February 2014 to May 2014. We used soft contact lenses with a wide range of diopters to change the refractive power. The macular thickness of uncorrected eyes without contact lenses was measured by SD-OCT, and we compared the findings with the results of subsequent investigations in which macular thickness was measured in the presence of soft contact lenses of different diopters (-8, -4, 0, +4, and +8). We divided the patients into three groups according to the axial length (AL) and analyzed the effect of induced refraction change. The main outcome measure was macular thickness measured by OCT. RESULTS: The average age of the subjects was 28.0 +/- 3.4 years (mean +/- SD), and included 17 eyes with normal AL, 18 eyes with mid-range AL, and 15 eyes with long AL. The central macular thickness was 254.5 +/- 17.5 um for eyes without contact lenses, which was not significantly different from the measurements in the presence of plano contact lenses (254.2 +/- 18.1 um). Even with soft contact lenses of four different diopters (-8, -4, +4, and +8), central macular thickness (254.4 +/- 16.2, 253.7 +/- 17.3, 257.3 +/- 17.9, and 256.9 +/- 17.9 um, respectively) was not significantly different from that of naked eyes in each group. CONCLUSION: These results suggest that central macular thickness measured by SD-OCT is unaffected by refractive power. PMID- 26227079 TI - Exposure to colony stimulating factor 2 during preimplantation development increases postnatal growth in cattle. AB - The microenvironment of a preimplantation embryo can influence changes in development that affect postnatal phenotypes. One of the potential mediators of this effect in many species is colony-stimulating factor (CSF2), which can increase an embryo's ability to establish pregnancy after its transfer into recipients. Exposure of embryos to CSF2 during early development can also affect the pattern of development later in pregnancy in a sex-dependent manner. We therefore hypothesized that treatment of in vitro-produced embryos with CSF2 in culture would alter birth weight and postnatal growth of the resultant calf. Body weight and withers height were measured for Holstein heifer calves produced in vitro with or without 10 ng/ml CSF2 and for calves produced by artificial insemination. There were no differences in birth weight between groups; thereafter, however, calves from the CSF2-treated group experienced greater increases in body weight through 13 months of age, with only small differences in withers height. These results support the model that an embryo's postnatal characteristics can be programmed during the preimplantation period, and that CSF2 is one of the embryokines through which programming is directed. Mol. Reprod. Dev. 82: 892-897, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26227081 TI - Deep Brain Stimulation in Pathological Aggression. AB - BACKGROUND: We describe a case of deep brain stimulation in a patient with severe aggression refractory to conservative treatment. The targets of the stimulation were set bilaterally in the posteromedial hypothalamus and - in a second procedure due to its ineffectiveness - in the nucleus accumbens (NAcc) bilaterally. METHODS: In the first stage, we implanted electrodes into the posteromedial hypothalamus, after obtaining consent of the Bioethics Committee. In the early postoperative period, we observed significant improvement in the range of 50-90% in terms of quantity and quality of the attacks of aggression. After about 3 weeks, attacks of aggression started to return. Despite changes in the stimulation parameters there was no improvement. For this reason, based on the experience of surgery in patients with obsessive-compulsive disorder, Tourette syndrome and with morbid obesity, we decided to implant electrodes into the NAcc. RESULTS: After 15 months of follow-up, the patient has no aggressive behavior, with no side effects. CONCLUSIONS: Although the stimulation of the posterior-medial hypothalamus did not bring long-term benefits, its combination with bilateral stimulation of the NAcc practically freed the patient from aggressive disorders. It significantly improved the patient's quality of life. PMID- 26227080 TI - Wound-healing effect of acupuncture for treating phonotraumatic vocal pathologies: A cytokine study. AB - OBJECTIVES/HYPOTHESIS: Acupuncture is a less-invasive procedure when compared with surgical treatment for benign vocal pathologies caused by vocal overuse. This study aimed to determine the wound-healing effect of acupuncture in treating phonotraumatic vocal fold lesions. STUDY DESIGN: Two-way, mixed-model, between- and within-subjects, prospective randomized, placebo-controlled, blinded group design. METHODS: Seventeen dysphonic individuals with vocal nodules were recruited from a university clinic in Hong Kong. Each participant was randomly assigned to receive one session of either genuine or sham acupuncture. The genuine acupuncture group (n = 9) received needles puncturing nine voice-related acupoints for 30 minutes, whereas the sham acupuncture group (n = 8) received blunted needles stimulating the skin surface of the nine acupoints for the same frequency and duration. Laryngeal secretions were suctioned from the surface of the vocal folds immediately before, immediately after, and 24 hours after the acupuncture. The protein concentration levels of wound-healing-related cytokines (interleukin [IL]-1beta and IL-10) in these secretion samples were measured. RESULTS: Following acupuncture, a significant increase in the anti-inflammatory cytokine IL-10 was found in the genuine acupuncture group (n = 9) but not in the sham acupuncture group (n = 8). CONCLUSIONS: The findings showed that acupuncture of voice-related acupoints facilitated an anti-inflammatory process in phonotraumatic vocal pathologies. This could be considered as supporting evidence to consider acupuncture as a less-invasive alternative option, when compared to surgery, for treating phonotraumatic vocal pathologies. PMID- 26227082 TI - Erratum to: Cuprizone Model as a Tool for Preclinical Studies of the Efficacy of Multiple Sclerosis Diagnosis and Therapy. PMID- 26227083 TI - New Reference Values for Vitamin C Intake. AB - The German, Austrian, and Swiss nutrition societies are the editors of the 'reference values for nutrient intake'. They have revised the reference values for the intake of vitamin C and published them in February 2015. The average vitamin C requirement in healthy adults is considered to be the vitamin C amount that compensates for the metabolic losses of vitamin C, and ensures a fasting ascorbate plasma level of 50 umol/l. Based on the present data from studies with non-smoking men, metabolic losses of 50 mg/day are assumed, as well as an absorption rate of 80% and an urinary excretion of 25% of the vitamin C intake. Taking this into account, the calculated average requirement in men is 91 mg/day. Considering a coefficient of variation of 10%, a reference value (recommended intake) of 110 mg/day for men is derived. The vitamin C requirement in women as well as in children and adolescents is extrapolated from the requirement in men and in relation to their body weight. This results in a recommended intake of about 95 mg/day for adult women. Because the requirement in pregnant and lactating women is increased, higher recommended intakes are derived for them, 105 mg/day for pregnant women from the fourth month on and 125 mg/day for lactating women, respectively. For boys and girls at the age of 1 to under 15 years, there are increasing recommended intake values from 20 to 85 mg/day. For male and female adolescents, at the age of 15 to under 19 years, the recommended intake is 105 and 90 mg, respectively. As smokers have higher metabolic losses and lower plasma levels of vitamin C than non-smokers (turnover is 40% higher), the reference value for vitamin C intake is set to 135 mg/day for female smokers and 155 mg/day for male smokers. For infants in their first year of life, the reference value (estimated value) is set to 20 mg vitamin C/ day, based upon the lowest observed vitamin C intake for infants in the United Kingdom and the United States, that obviously meets the requirement in infants and that is 3 times higher than the amount necessary to prevent scurvy (7 mg/day). PMID- 26227084 TI - A topological assessment of the electronic structure of mesoionic compounds. AB - Mesoionic compounds belonging to the 1,3-oxazol-5-one, 1,3-diazole-4-thione and 1,3-thiazole-5-thione rings have been evaluated by a combination of Density Functional Theory, Quantum Theory of Atoms in Molecules, Electron Localization Function, Natural Bond Orbitals and Geodesic Electrostatic Potential Charge calculations. Atomic, bond, and ring properties have been considered to describe the electronic structure of mesoionic compounds. The results show that not only the ring type, but also the substituent groups have great influence on these properties. In addition, there is a significant and heterogeneous pi-bonding contribution throughout the mesoionic rings. Finally, we conclude that some classical conceptions of charge localization and pi-bonding contribution in these compounds are misleading or incomplete. (c) 2015 Wiley Periodicals, Inc. PMID- 26227085 TI - Vocalisation sound pattern identification in young broiler chickens. AB - In this study, we describe the monitoring of young broiler chicken vocalisation, with sound recorded and assessed at regular intervals throughout the life of the birds from day 1 to day 38, with a focus on the first week of life. We assess whether there are recognisable, and even predictable, vocalisation patterns based on frequency and sound spectrum analysis, which can be observed in birds at different ages and stages of growth within the relatively short life of the birds in commercial broiler production cycles. The experimental trials were carried out in a farm where the broiler where reared indoor, and audio recording procedures carried out over 38 days. The recordings were made using two microphones connected to a digital recorder, and the sonic data was collected in situations without disturbance of the animals beyond that created by the routine activities of the farmer. Digital files of 1 h duration were cut into short files of 10 min duration, and these sound recordings were analysed and labelled using audio analysis software. Analysis of these short sound files showed that the key vocalisation frequency and patterns changed in relation to increasing age and the weight of the broilers. Statistical analysis showed a significant correlation (P<0.001) between the frequency of vocalisation and the age of the birds. Based on the identification of specific frequencies of the sounds emitted, in relation to age and weight, it is proposed that there is potential for audio monitoring and comparison with 'anticipated' sound patterns to be used to evaluate the status of farmed broiler chicken. PMID- 26227086 TI - Acquired lymphangioma of the penis in a patient with severe phimosis. PMID- 26227087 TI - New Fixed-Dose Combinations of Fenofibrate/Simvastatin Therapy Significantly Improve the Lipid Profile of High-Risk Patients with Mixed Dyslipidemia Versus Monotherapies. AB - AIMS: Guidelines propose additional therapy to statin to treat elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDLC) in dyslipidemic patients. We evaluated the effects of new fixed-dose combinations (FDC) of fenofibrate/simvastatin on plasma lipids versus simvastatin or fenofibrate monotherapies. METHODS: Subjects with mixed dyslipidemia at high or very high cardiovascular risk on stable statin therapy for at least 3 months were included in a randomized, double-blind, active-control, parallel-group study. Patients were treated with FDC fenofibrate/simvastatin 145/20 mg or 145/40 mg, simvastatin 20 mg or 40 mg, or fenofibrate 145 mg for 12 weeks. Plasma lipids, C reactive protein, and cystatin C were measured before and after treatments. Differences in % changes were compared between FDC fenofibrate/simvastatin and monotherapies. RESULTS: Significant differences between FDC fenofibrate/simvastatin and simvastatin monotherapies were observed for the % change of TG (LS mean difference [two-sided 95% CI]: -32.2% [-38.6%, -25.8%], P < 0.001) and HDL-C (7.5% [4.7%, 10.2%], P < 0.001). A significant difference between the FDC fenofibrate/simvastatin and fenofibrate was observed for LDLC % changes (-34.7% [-40.8%, -28.5%], P < 0.001). Significant differences between FDC fenofibrate/simvastatin and their respective monotherapies were also observed for Apo B and non-HDLC % changes. The FDC were well tolerated with a similar safety profile compared with monotherapies. CONCLUSIONS: FDC fenofibrate/simvastatin are effective and well-tolerated therapies to improve the TG and HDLC profile in high risk patients with mixed dyslipidemia. PMID- 26227088 TI - Administration of Cyclosporine A in Pregnant Rats - the Effect on Blood Pressure and on the Glomerular Number in Their Offspring. AB - BACKGROUND/AIMS: Cyclosporine A (CsA) is a commonly used immunosuppressive agent. In some patients treatment with CsA has to be continued during pregnancy. The aim of the study was to assess in an experimental model whether the exposure to CsA during fetal life influences the number and volume of glomeruli, kidney function and blood pressure in the offspring. METHODS: Eight pregnant female Sprague Dawley rats were allocated to 2 treatment regimens: with CsA or solvent. Blood pressure was measured in the offspring at 7 and 11 weeks of age and albuminuria was determined at 11 weeks of age. In the kidney the number and mean volume of glomeruli was assessed using stereological methods. RESULTS: In the offspring of pregnant rats treated with CsA the number of glomeruli was significantly lower and the mean volume of glomeruli was higher when compared to the offspring of pregnant rats receiving solvent. Systolic and diastolic blood pressures as well as albuminuria were significantly higher in the offspring of mothers treated with CsA during gestation compared to the offspring from the control group. CONCLUSIONS: Exposure of rats to CsA during fetal life impairs kidney development, thus potentially predisposing to chronic kidney disease and hypertension in the adult life. PMID- 26227089 TI - See-and-treat: striking a balance between over- and under-treatment. PMID- 26227090 TI - CHILDSPLA: a collaboration between children and researchers to design and animate health states. AB - AIM: The children's health state preferences learnt from animation (CHILDSPLA) project developed an interactive application presented on a touch screen device using an animated character to collect information from children about their health. BACKGROUND: The underlying hypothesis was that health information could be directly collected from children as young as 4 years old by the use of animated characters. This paper describes in detail how children were involved in the development of the application, and recounts both the challenges and benefits of that process. A child psychologist and an animation filmmaker worked closely with children to design a character and to animate it to represent different health states. Children were recruited from a local primary school (n = 38) and a paediatric specialist hospital (n = 36). Diverse interactive activities were organized to help children give feedback and guide the design process. The activities for each session were adjusted to the children's needs, based on the experience of previous sessions. RESULTS: The character and the animations were modified according to the feedback provided by the children. CONCLUSIONS: Developing the CHILDSPLA app in collaboration with children was a worthwhile and enriching experience, despite the required iteration and extension of the design process, as it enabled us to adjust the tool to the children's needs. PMID- 26227091 TI - An invisible soil acidification: Critical role of soil carbonate and its impact on heavy metal bioavailability. AB - It is well known that carbonates inhibit heavy metals transferring from soil to plants, yet the mechanism is poorly understood. Based on the Yangtze River delta area, we investigated bioaccumulation of Ni and Cd in winter wheat as affected by the presence of carbonates in soil. This study aimed to determine the mechanism through which soil carbonates restrict transport and plant uptake of heavy metals in the wheat cropping system. The results indicate that soil carbonates critically influenced heavy metal transfer from soil to plants and presented a tipping point. Wheat grains harvested from carbonates-depleted (due to severe leaching) soils showed Ni and Cd concentrations 2-3 times higher than those of the wheat grains from carbonates-containing soils. Correspondingly, the incidence of Ni or Cd contamination in the wheat grain samples increased by about three times. With the carbonate concentration >1% in soil, uptake and bioaccumulation of Ni and Cd by winter wheat was independent with the soil pH and carbonate content. The findings suggest that soil carbonates play a critical role in heavy metal transfer from soil to plants, implying that monitoring soil carbonate may be necessary in addition to soil pH for the evaluating soil quality and food safety. PMID- 26227092 TI - Marine Sediments Remotely Unveil Long-Term Climatic Variability Over Northern Italy. AB - A deep understanding of natural decadal variability is pivotal to discuss recently observed climate trends. Paleoclimate proxies allow reconstructing natural variations before the instrumental period. Typically, regional-scale reconstructions depend on factors like dating, multi-proxy weighting and calibration, which may lead to non-robust reconstructions. Riverine records inherently integrate information about regional climate variability, partly overcoming the above mentioned limitation. The Po River provides major freshwater input to Eastern Mediterranean, as its catchment encompasses a large part of Northern Italy. Here, using historical discharge data and oceanographic measurements, we show that Po River discharge undergo robust decadal fluctuations that reach the Ionian Sea, ~1,000 km South of Po River delta, through propagating salinity anomalies. Based on this propagation, we use a high-resolution foraminiferal delta(18)O record from a sediment core in the Ionian Sea to reconstruct North Italian hydrological variability on millennial-scale for the first time. The reconstruction reveals highly significant decadal variability that persists over the last 2,000 years. Many reconstructed extremes correspond to documented catastrophic events. Our study provides the first millennial-scale reconstruction of the strength of decadal hydrological variability over Northern Italy. It paves the way to assess the persistence of large-scale circulation fingerprints on the North Italian climate. PMID- 26227093 TI - Stochasticity and Spatial Interaction Govern Stem Cell Differentiation Dynamics. AB - Stem cell differentiation underlies many fundamental processes such as development, tissue growth and regeneration, as well as disease progression. Understanding how stem cell differentiation is controlled in mixed cell populations is an important step in developing quantitative models of cell population dynamics. Here we focus on quantifying the role of cell-cell interactions in determining stem cell fate. Toward this, we monitor stem cell differentiation in adherent cultures on micropatterns and collect statistical cell fate data. Results show high cell fate variability and a bimodal probability distribution of stem cell fraction on small (80-140 MUm diameter) micropatterns. On larger (225-500 MUm diameter) micropatterns, the variability is also high but the distribution of the stem cell fraction becomes unimodal. Using a stochastic model, we analyze the differentiation dynamics and quantitatively determine the differentiation probability as a function of stem cell fraction. Results indicate that stem cells can interact and sense cellular composition in their immediate neighborhood and adjust their differentiation probability accordingly. Blocking epithelial cadherin (E-cadherin) can diminish this cell-cell contact mediated sensing. For larger micropatterns, cell motility adds a spatial dimension to the picture. Taken together, we find stochasticity and cell-cell interactions are important factors in determining cell fate in mixed cell populations. PMID- 26227094 TI - The genetic polymorphisms of POR*28 and CYP3A5*3 significantly influence the pharmacokinetics of tacrolimus in Chinese renal transplant recipients. AB - PURPOSES: The aims of this study were to assess the influence of the polymorphism of cytochrome P450 oxidoreductase (POR) as well as other relevant genes (CYP3A4, CYP3A5, ABCB1) on individual variability of tacrolimus pharmacokinetics and perform population pharmacokinetic analysis of tacrolimus in Chinese renal transplant recipients. METHODS: Tacrolimus trough whole blood concentrations and clinical details were retrospectively collected from 83 renal recipients. CYP3A4*1G, CYP3A5*3, and ABCB1 C3435T were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), POR*28 and CYP3A4*22 were genotyped by sequencing method. Population pharmacokinetic analysis was performed using NONMEM program. RESULTS: The significant influences of CYP3A5*3, CYP3A4*1G, and POR*28 polymorphisms on tacrolimus dose-adjusted trough concentrations (C0/D) were observed in 83 renal recipients. Subgroup analysis showed that POR*28 polymorphisms significantly decreased tacrolimus C0/D by 1.50 - 1.84-fold (p < 0.05) in patients who were CYP3A5 expressers (CYP3A5*1 carriers, n = 46), while similar results could not be obtained from CYP3A5 non-expressers (CYP3A5*3/*3 carriers, n = 37). Additionally, population pharmacokinetic analysis identified that the combined genotype of CYP3A5-POR was the only covariant for the apparent clearance of tacrolimus (CL/F). CONCLUSIONS: The study demonstrated that the POR*28 C>T mutation could decrease the C0/D of tacrolimus in renal recipients who were CYP3A5 expressers. The population pharmacokinetic model showed that the combined genotype of CYP3A5-POR was associated with the CL/F of tacrolimus which might provide references for personalized use of tacrolimus in clinic. PMID- 26227095 TI - QT-prolonging effects of monoclonal antibody drugs in humans: a systematic review of two literature and a public adverse event database. AB - Drug-induced prolongation of the electrocardiogram QT interval, a risk factor for ventricular arrhythmia and death, has been observed for some small drugs with masses < 1 kDa. Over the last two decades, patient exposure to large molecule monoclonal antibody drugs with masses > 40 kDa has increased dramatically; hence, the aim of this study was to systematically review the scientific literature for evidence of QT prolongation induced by these drugs. METHODS: The PubMed and Embase databases were searched for cases indicative of drug-induced QT prolongation for 28 pre-identified monoclonal antibody drugs authorized in Europe. Cases were identified by applying a standardized search string and a subsequent text search and manual review. In parallel, the public European Medicines Agency (EMA) database was searched for reported frequencies of adverse events indicative of QT prolongation. RESULTS: A valid case of drug-induced QT prolongation, caused indirectly by hypocalcaemia, could be identified for only 1 out of 28 monoclonal antibody drugs (denosumab) from the PubMed and Embase search. The EMA database showed no hits for denosumab. Considering that hypocalcaemia-mediated QT prolongation is an already-identified and labelled risk for denosumab, the current study did not identify any additional evidence of QT prolongation caused by monoclonal antibody drugs. PMID- 26227096 TI - Pharmacokinetic/pharmacodynamic research on three different infusion time regimens of linezolid in healthy Chinese volunteers. AB - OBJECTIVE: To evaluate the pharmacokinetic and pharmacodynamic (PK/PD) results of three different infusion time regimens of single doses of 600 mg linezolid in healthy Han Chinese volunteers. METHODS: We conducted a clinical trial involving 6 male and 6 female healthy Chinese volunteers. They were randomized to receive intravenous linezolid infusion (600 mg/0.5 hours, 600 mg/2 hours, or 600 mg/4 hours) in three periods with washout periods of 7 days between each dosage. Serum linezolid concentration was measured in each subject at pre-dose (at 0 hours) until 24 hours after each dose. The ratio of the area under the serum concentration-time curve (AUC) to the minimum inhibitory concentration (MIC), AUC/MIC, was adopted as the major relevant parameter. Monte Carlo simulation was used to evaluate the probability of target attainment (PTA) of these three linezolid regimens. RESULTS: One subject in 600 mg/0.5 hours regimen complained of mild pain at the injection site. No significant difference was found in pharmacokinetic parameters among the three different infusion regimens. When AUC/MIC was applied as parameter, PTA of 4 hours infusion regimen was much lower than that of the 0.5 hours and 2 hours infusion regimens (55.65% vs. 74.91% and 72.03%, respectively). Especially at higher MIC (2 MUg/mL), the PTAs of the 0.5 hours and 2 hours infusion regimens decreased to 57.2% and 50.1%, respectively, while that of the 4 hours infusion regimen dropped sharply to only 25.95%. When T>MIC was applied as a parameter, PTA of the 0.5 hours regimen was higher than 90%, while the 2 hours and 4 hours regimens remained 100%. CONCLUSION: Our findings suggest that 2 hours infusion of linezolid at a fixed dose (600 mg) regimen is appropriate to achieve the safety and efficacy against MRSA-caused infections in Chinese adults. PMID- 26227097 TI - Pioglitazone inhibits the secretion of proinflammatory cytokines and chemokines in astrocytes stimulated with lipopolysaccharide. AB - Neuroinflammation caused by the secretion of cytokines and chemokines by glial cells can promote the development of neurodegenerative disorders. The aim of this study was to explore the effects of pioglitazone (Pio), a drug that induces release of inflammatory mediators, on cytokine and chemokine secretion in astrocytes stimulated with lipopolysaccharide (LPS) to induce inflammation. Astrocytes obtained from the cerebral cortex of newborn C57BL/6 mice and grown in culture were stimulated with LPS and treated with Pio. Treatment of astrocytes with LPS significantly increased the levels of pro-inflammatory factors nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-8, but decreased the level of anti-inflammatory factors IL-4 and IL-10 (p < 0.05) compared to untreated control astrocytes. Pio treatment in LPS-stimulated astrocytes had the opposite effect, inhibiting secretion of NO, TNF-alpha, IL 1beta, IL-6, and IL-8 and enhancing IL-4 and IL-10 secretion (p < 0.05). In addition, Pio treatment suppressed the expression of pro-inflammatory chemokines Ccl20, Mcp-1, and Mip-1alpha mRNA in astrocytes stimulated with LPS (p < 0.05). These results showed that Pio can inhibit the neuroinflammatory response in LPS activated astrocytes and this response may result from the regulation of cytokine and chemokine secretion from astrocytes. PMID- 26227098 TI - Prescription patterns of psychotropic medications and use of electroconvulsive therapy in Chinese patients with dementia. AB - BACKGROUND: Little is known about psychiatric pharmacotherapy and somatic treatments in dementia in China. This study examined the prescription patterns of psychotropic medications and use of electroconvulsive therapy (ECT) in dementia patients hospitalized in a psychiatric institution in Beijing, China. METHODS: This was a retrospective chart review of 401 patients with dementia treated over a period of 7 years (2007 - 2013) in a university-affiliated psychiatric institution in Beijing. Socio-demographic and clinical data were collected from the electronic chart management system (ECMS) for discharged patients. RESULTS: Nearly all patients (96.8%) received psychotropic medications in order of frequency: second-generation antipsychotics (83.0%), benzodiazepines (77.8%), first generation antipsychotics (39.7%), antidepressants (29.7%), and mood stabilizers (24.7%). The rate of polypharmacy and ECT use was 82.0% and 3.7%, respectively. Prescription of mood stabilizers was associated with longer length of hospitalization. CONCLUSIONS: In a major psychiatric hospital in China, ECT was sporadically used in patients with dementia, while the vast majority of patients received at least one type of psychotropic medication. Factors contributing to the high use of psychopharmacological interventions in this population warrant further investigations. PMID- 26227099 TI - Single therapeutic and supratherapeutic doses of corifollitropin alfa, a sustained follicle stimulant, do not prolong the QTcF-interval in healthy postmenopausal volunteers. AB - OBJECTIVE: Corifollitropin alfa (Elonva(r)) is the first hybrid follicle stimulating hormone molecule with demonstrated sustained follicle-stimulating activity after a single subcutaneous injection. This trial evaluated if corifollitropin alfa is associated with QT/QTc prolongation and/ or proarrhythmic potential as compared to placebo in healthy post-menopausal women. MATERIALS: Participants were healthy, postmenopausal women. Study treatments were corifollitropin alfa 150 MUg, corifollitropin alfa 240 MUg, and moxifloxacin 400 mg with placebo. METHODS: This randomized, double blind, double-dummy, 4-period crossover trial compared single doses of corifollitropin alfa 150 MUg (therapeutic dose), corifollitropin alfa 240 MUg (supratherapeutic dose), and moxifloxacin 400 mg (positive control) with placebo. Corifollitropin alfa was administered on day 1 and moxifloxacin on day 2. RESULTS: The largest time matched mean QTcF difference versus placebo for the therapeutic dose of corifollitropin alfa was 1.4 ms (upper limit of 1-sided 95% confidence interval (UL 95% CI) = 3.4 ms), and for the supratherapeutic dose was 1.2 ms (UL 95% CI = 3.6 ms). CONCLUSIONS: For both the therapeutic and the supratherapeutic dose of corifollitropin alfa and at all time points, the UL 95% CI for the time matched QTcF differences compared with placebo was below 10 ms, the threshold of relevance defined by the ICH E14 guideline. Single therapeutic and supratherapeutic doses of corifollitropin alfa are not associated with clinically relevant QT/QTc-interval prolongation in healthy post-menopausal women. PMID- 26227100 TI - Posterior reversible encephalopathy syndrome and graft-versus-host disease after liver transplantation: a case report and review of the literature. AB - Case (description): A 52-year-old male patient presented with seizures on the 16th day post liver transplantation suggesting tacrolimus-associated posterior reversible encephalopathy syndrome (PRES). On the 18th day, the patient was diagnosed with graft-versus-host disease (GVHD). Calcineurin inhibitor (CNI) was stopped and the patient received 1 g methylprednisolone and 25 g immunoglobulin. However, on the 21st day, the patient's clinical condition progressively worsened and he died of multi-organ failure. GVHD could have occurred with PRES because the CNI dose was reduced. The best treatment for patients with PRES and GVHD is using immunosuppressants other than CNI. Antibody preparations and steroids could be a standard treatment. PMID- 26227101 TI - Pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol as a triple therapy in healthy volunteers. AB - OBJECTIVE: Two single-center, four-way, single-dose, crossover studies assessed the systemic exposure, systemic pharmacodynamics (PD), and safety profile of the closed triple fluticasone furoate/ umeclidinium/vilanterol (FF/UMEC/VI) therapy compared with dual therapies. These are the first studies where pharmacokinetic (PK) profile assessment was possible for this inhaled triple fixed-dose combination product. METHODS: Healthy volunteers were randomized to receive 4 consecutive inhalations (each administered as a single dose) via a single ELLIPT(r) dry powder inhaler: in study 1 (CTT116415/NCT01691547), FF/UMEC/VI at total doses of 400/500/100 MUg, FF/UMEC 400/500 MUg, UMEC/VI 500/100 MUg, or FF/VI 400/100 MUg; in study 2 (200587/NCT01894386), FF/UMEC/VI at total doses of 400/500/100 MUg or 400/250/100 MUg, FF/VI 400/100 MUg, or UMEC/VI 250/100 MUg. PK and PD parameters and safety were assessed. RESULTS: Of 88 subjects, 95% completed both studies and received all planned treatments. Total systemic exposure was similar for FF, UMEC, and VI when administered as a triple therapy compared with FF/VI and UMEC/VI. No clinically significant systemic PD findings were detected. The incidence of adverse events was low and similar across treatment arms. CONCLUSIONS: Systemic exposure to all three components of the closed triple therapy, following single-dose delivery, was similar to that seen with the dual therapies FF/VI and UMEC/VI. The delivered lung dose and safety profile of all three agents, delivered via a single inhaler, are expected to be similar to those of the dual therapies. PMID- 26227103 TI - Relation between low 50-g glucose challenge test results and small-for gestational-age infants. AB - AIM: There is no consensus opinion regarding a possible relation between low 50-g glucose challenge test (GCT) results and small-for-gestational-age infants (SGA). This study aimed to clarify the relation between low 50-g GCT results and SGA, after adjusting for potential confounding factors, using a large clinical dataset. MATERIAL AND METHODS: Our retrospective cohort study evaluated the obstetric records of women who delivered at Kofu Municipal Hospital (Japan) between January 2011 and December 2013. The exclusion criteria were gestational diabetes mellitus, diabetes in pregnancy, and GCT results of >=140 mg/dL. Based on these criteria, we included 1603 women who had undergone a GCT between 24 and 28 weeks of gestation, and divided the subjects into a low-GCT group (<=90 mg/dL) and a non-low-GCT group (91-139 mg/dL). The chi(2) -test and multivariate logistic regression analysis were used to investigate the association between low GCT results and SGA. RESULTS: The mean subject age was 30.4 +/- 5.4 years, with 45.1% nulliparity (n = 723) and 1538 (96.0%) term deliveries. The incidence of SGA was 10.7% (172/1603), and 17.9% (287/1603) of the women had low GCT results. Low GCT results were significantly associated with an increased risk of SGA (odds ratio, 1.66; 95% confidence interval, 1.14-2.42), after controlling for maternal age, pre-pregnancy maternal weight, maternal weight gain during pregnancy, and pregnancy-induced hypertension. CONCLUSION: It appears that there is a significant association between low GCT results and SGA. However, further studies are needed to explore the detailed mechanisms of this association. PMID- 26227104 TI - Michelin tire baby syndrome: a case report. PMID- 26227105 TI - Clinical Implementation of a Breast Cancer Risk Assessment Program in a Multiethnic Patient Population: Which Risk Model to Use? PMID- 26227107 TI - Emergence of methicillin-resistant coagulase-negative staphylococci resistant to linezolid with rRNA gene C2190T and G2603T mutations. AB - The aim of this article were to determinate the mechanism of linezolid resistance in coagulase-negative methicillin-resistant staphylococci from hospitals in the northeast of Brazil. We identified the isolates using VITEK((r)) 2 and MALDI-TOF. Susceptibility to antibiotics was measured by the disk-diffusion method and by Etest((r)) . Extraction of the whole genome DNA was performed, followed by screening of all the strains for the presence of mecA and cfr genes. The domain V region of 23S rRNA gene was sequenced and then aligned with a linezolid susceptible reference strain. Pulsed-field gel electrophoresis (PFGE) macro restriction analysis was performed. Three linezolid-resistant Staphylococcus hominis and two linezolid-resistant Staphylococcus epidermidis strains were analyzed. The isolates showed two point mutations in the V region of the 23S rRNA gene (C2190T and G2603T). We did not detect the cfr gene in any isolate by PCR. The S. hominis showed the same pulsotype, while the S. epidermidis did not present any genetic relation to each other. In conclusion, this study revealed three S. hominis and two S. epidermidis strains with resistance to linezolid due to a double mutation (C2190T and G2603T) in the domain V of the 23S rRNA gene. For the first time, the mutation of C2190T in S. epidermidis is described. This study also revealed the clonal spread of a S. hominis pulsotype between three public hospitals in the city of Natal, Brazil. These findings highlight the importance of continued vigilance of linezolid resistance in staphylococci. PMID- 26227106 TI - Nonchimeric HLA-Identical Renal Transplant Tolerance: Regulatory Immunophenotypic/Genomic Biomarkers. AB - We previously described early results of a nonchimeric operational tolerance protocol in human leukocyte antigen (HLA)-identical living donor renal transplants and now update these results. Recipients given alemtuzumab, tacrolimus/MPA with early sirolimus conversion were multiply infused with donor hematopoietic CD34(+) stem cells. Immunosuppression was withdrawn by 24 months. Twelve months later, operational tolerance was confirmed by rejection-free transplant biopsies. Five of the first eight enrollees were initially tolerant 1 year off immunosuppression. Biopsies of three others after total withdrawal showed Banff 1A acute cellular rejection without renal dysfunction. With longer follow-up including 5-year posttransplant biopsies, four of the five tolerant recipients remain without rejection while one developed Banff 1A without renal dysfunction. We now add seven new subjects (two operationally tolerant), and demonstrate time-dependent increases of circulating CD4(+) CD25(+++) CD127(-) FOXP3(+) Tregs versus losses of Tregs in nontolerant subjects (p < 0.001). Gene expression signatures, developed using global RNA expression profiling of sequential whole blood and protocol biopsy samples, were highly associative with operational tolerance as early as 1 year posttransplant. The blood signature was validated by an external Immune Tolerance Network data set. Our approach to nonchimeric operational HLA-identical tolerance reveals association with Treg immunophenotypes and serial gene expression profiles. PMID- 26227108 TI - An intracytoplasmic injection of deionized bovine serum albumin immediately after somatic cell nuclear transfer enhances full-term development of cloned mouse embryos. AB - In mouse somatic cell nuclear transfer (SCNT), polyvinylpyrrolidone (PVP) is typically included in the nuclear donor injection medium. However, the cytotoxicity of PVP, which is injected into the cytoplasm of oocytes, has recently become a cause of concern. In the present study, we determined whether bovine serum albumin deionized with an ion-exchange resin treatment (d-BSA) was applicable to the nuclear donor injection medium in SCNT as an alternative to PVP. The results obtained showed that d-BSA introduced into the cytoplasm of an enucleated oocyte together with a donor nucleus significantly enhanced the rate of in vitro development of cloned embryos to the blastocyst stage compared with that of a conventional nuclear injection with PVP in SCNT. We also defined the enhancing effects of d-BSA on the blastocyst formation rate when d-BSA was injected into the cytoplasm of oocytes reconstructed using the fusion method with a hemagglutinating virus of Japan envelope before oocyte activation. Furthermore, immunofluorescence experiments revealed that the injected d-BSA increased the acetylation levels of histone H3 lysine 9 and histone H4 lysine 12 in cloned pronuclear (PN) and 2-cell embryos. The injection of d-BSA before oocyte activation also increased the production of cloned mouse offspring. These results suggested that intracytoplasmic injection of d-BSA into SCNT oocytes before oocyte activation was beneficial for enhancing the in vitro and in vivo development of mouse cloned embryos through epigenetic modifications to nuclear reprogramming. PMID- 26227109 TI - Pluripotent cell derivation from male germline cells by suppression of Dmrt1 and Trp53. AB - Diploid germ cells are thought to have pluripotency potential. We recently described a method to derive pluripotent stem cells (PSCs) from cultured spermatogonial stem cells (SSCs) by depleting Trp53 and Dmrt1, both of which are known suppressors of teratomas. In this study, we used this technique to analyze the effect of this protocol in deriving PSCs from the male germline at different developmental stages. We collected primordial germ cells (PGCs), gonocytes and spermatogonia, and the cells were transduced with lentiviruses expressing short hairpin RNA against Dmrt1 and/or Trp53. We found that PGCs are highly susceptible to reprogramming induction and that only Trp53 depletion was sufficient to induce pluripotency. In contrast, gonocytes and spermatogonia were resistant to reprogramming by double knockdown of Dmrt1 and Trp53. PSCs derived from PGCs contributed to chimeras produced by blastocyst injection, but some of the embryos showed placenta-only phenotypes suggestive of epigenetic abnormalities of PGC derived PSCs. These results show that PGCs and gonocytes/spermatogonia have distinct reprogramming potential and also suggest that fresh and cultured SSCs do not necessarily have the same properties. PMID- 26227110 TI - Innovations in Training: Toward Mitigating "Eternal post-docdum" in Stem Cell Research. AB - The Networks of Centres of Excellence (NCE) is an innovative model of large-scale research networks that began in Canada in 1989, and has since been adopted by numerous countries around the globe. The Canadian Stem Cell Network (SCN), an NCE that has fostered stem cell research and innovation in Canada, has supported over 1800 trainees since its inception in 2001. In the present study we assess the impact of such a network on its research trainees professional decision-making and movements. A database populated by the SCN between the years 2001-2013 was utilized to describe trainee professional movement between sectors and geographic regions. Focus groups of SCN trainees (n = 27) were carried out and major themes and subthemes were derived from the discourse using a thematic analysis approach. We found that most SCN trainees remained in Canada and in academic positions after leaving the SCN. Trainees expressed a desire to work in environments where their scientific interests and ideas are nurtured, where funding is stable, and where supervisor mentorship is readily accessible. SCN trainees value the unique opportunities provided by the NCE, including opportunities to network with peers, to attend various workshops and to broaden their knowledge and interest base beyond science and academia. Challenges faced by postdoctoral fellows and recommendations for future NCEs are also discussed. The findings here can be used to form evidence-based recommendations for future research networks and for policy pertaining to the recruitment and retention of highly qualified personnel in stem cell research. PMID- 26227111 TI - High-level expression of human arginase I in Pichia pastoris and its immobilization on chitosan to produce L-ornithine. AB - BACKGROUND: L-ornithine (L-Orn), is an intermediate metabolite in the urea cycle that plays a significant role in humans. L-Orn can be obtained from the catalysis of L-arginine (L-Arg) by arginase. The Pichia pastoris expression system offers the possibility of generating a large amount of recombinant protein. The immobilized enzyme technology can overcome the difficulties in recovery, recycling and long-term stability that result from the use of free enzyme. METHODS: The recombinant human arginase I (ARG I) was obtained using an optimized method with the Pichia pastoris GS115 as the host strain. Chitosan paticles were cross-linked with glutaraldehyde and rinsed exhaustively. Then the expressed ARG I was immobilized on the crosslinked chitosan particles, and the enzymatic properties of both the free and immobilized enzymes were evaluated. At last, the immobilized ARG I was employed to catalyze L-Arg to L-Orn. RESULTS: The results indicated that these two states both exhibited optimal activity under the same condition of pH10 at 40 degrees C. However, the immobilized ARG I exhibited the remarkable thermal and long-term stability as well as broad adaptability to pH, suggesting its potential for wide application in future industry. After a careful analysis of its catalytic conditions, immobilized ARG I was employed to catalyze the conversion of L-Arg to L-Orn under optimal condition of 1 % glutaraldehyde, 1 mM Mn(2+), 40 degrees C, pH10 and an L-arginine (L-Arg) concentration of 200 g/L, achieving a highly converted content of 149.g/L L-Orn. CONCLUSIONS: In this work, ARG Iota was abundantly expressed, and an efficient, facile and repeatable method was developed to synthesize high-quality L-Orn. This method not only solved the problem of obtaining a large amount of arginase, but also provided a promising alternative for the future industrial production of L-Orn. PMID- 26227112 TI - Health coaching to prevent excessive gestational weight gain: A randomized controlled trial. AB - OBJECTIVES: The objectives of this study were to evaluate the efficacy of a health coaching (HC) intervention designed to prevent excessive gestational weight gain (GWG), and promote positive psychosocial and motivational outcomes in comparison with an Education Alone (EA) group. DESIGN: Randomized-controlled trial. METHODS: Two hundred and sixty-one women who were <18 weeks pregnant consented to take part. Those allocated to the HC group received a tailored HC intervention delivered by a Health Coach, whilst those in the EA group attended two education sessions. Women completed measures, including motivation, psychosocial variables, sleep quality, and knowledge, beliefs and expectations concerning GWG, at 15 weeks of gestation (Time 1) and 33 weeks of gestation (Time 2). Post-birth data were also collected at 2 months post-partum (Time 3). RESULTS: There was no intervention effect in relation to weight gained during pregnancy, rate of excessive GWG or birth outcomes. The only differences between HC and EA women were higher readiness (b = 0.29, 95% CIs = 0.03-0.55, p < .05) and the importance to achieve a healthy GWG (b = 0.27, 95% CIs = 0.02-0.52, p < .05), improved sleep quality (b = -0.22, 95% CIs = -0.44 to -0.03, p < .05), and increased knowledge for an appropriate amount of GWG that would be best for their baby's health (b = -1.75, 95% CI = -3.26 to -0.24, p < .05) reported by the HC at Time 2. CONCLUSIONS: Whilst the HC intervention was not successful in preventing excessive GWG, several implications for the design of future GWG interventions were identified, including the burden of the intervention commitment and the use of weight monitoring. STATEMENT OF CONTRIBUTION: What is already known on the subject? Designing interventions to address gestational weight gain (GWG) continues to be a challenge. To date, health behaviour change factors have not been the focus of GWG interventions. What does this study add? Our health coaching (HC) intervention did not reduce GWG more so than education alone (EA). There was an intervention effect on readiness and importance to achieve healthy GWG. Yet there were no group differences regarding confidence to achieve healthy GWG post-intervention. PMID- 26227113 TI - Usual source of care and the quality of primary care: a survey of patients in Guangdong province, China. AB - INTRODUCTION: Usual source of care (USC) refers to the provider or place a patient consults when sick or in need of medical advice. No studies have been conducted in China to compare the quality of primary care provided with or without USC. The purpose of this study was to fill this gap in the literature by examining the quality of primary care provided between those having a USC and those without. Results of the study would provide implications for policymakers in terms of improving primary care performance in China, and help guide patients in their health care seeking behaviors. METHODS: A cross-sectional survey with patients was conducted in Guangdong province of China, using the Chinese validated Primary Care Assessment Tool (PCAT). ANOVA was performed to compare the overall and ten domains of primary care quality for patients with and without USC. Multivariate analyses were used to assess the association between USC and quality of primary care attributes while controlling for sociodemographic and health care characteristics. RESULTS: The study added evidence that having a USC can provide higher quality of primary care to patients than those without a USC. Results of this study showed that the PCAT score associated with those having a USC was significantly higher than those not having a USC. Moreover, the study showed that having a usual provider of care was also independently and significantly associated with patients' satisfaction with care. CONCLUSIONS: This study added evidence that in China, patients with a USC reported higher quality of medical care experiences compared with those without a USC. The efforts to improve quality of care should include policies promoting USC. PMID- 26227114 TI - Management of renal injury in children. AB - PURPOSE: To evaluate types of trauma, other organ injuries and types and results of management in children who were admitted to our clinic because of renal trauma in the last 5 years. METHODS: Thirty one patients who were treated in our clinic for renal injury occurring after blunt abdominal trauma between January 2005-2010 were assessed retrospectively. RESULTS: The patients were aged between 1-16 (mean 8.2) years old. Twenty (64.5%) patients were boys and 11 (35.5%) were girls. The most common causes of injury were falls from height (13 patients, 41.9%). Sixteen patients (52%) had only renal injury and the others (48%) had other organ injuries. Two patients with grade III injury (20%), three patients with grade IV injury (27%) and one patient with grade V injury (100%) were operated on, although all of the patients with grade I and II injuries were managed conservatively. Twenty five patients (81%) were managed conservatively and six patients (19%) whose vital signs were not stable were operated on. CONCLUSION: Conservative management should be preferred in patients with renal injuries who are stable hemodynamically. Most renal traumas in children can be treated conservatively. Conservative management has some advantages like shorter hospitalization time, less need for blood transfusion and less morbidity and mortality than surgical management. PMID- 26227116 TI - [Not Available]. PMID- 26227115 TI - In vitro and in vivo evaluation of a shape memory polymer foam-over-wire embolization device delivered in saccular aneurysm models. AB - Current endovascular therapies for intracranial saccular aneurysms result in high recurrence rates due to poor tissue healing, coil compaction, and aneurysm growth. We propose treatment of saccular aneurysms using shape memory polymer (SMP) foam to improve clinical outcomes. SMP foam-over-wire (FOW) embolization devices were delivered to in vitro and in vivo porcine saccular aneurysm models to evaluate device efficacy, aneurysm occlusion, and acute clotting. FOW devices demonstrated effective delivery and stable implantation in vitro. In vivo porcine aneurysms were successfully occluded using FOW devices with theoretical volume occlusion values greater than 72% and rapid, stable thrombus formation. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1407 1415, 2016. PMID- 26227117 TI - [In Process Citation]. PMID- 26227118 TI - [Not Available]. PMID- 26227119 TI - [Not Available]. PMID- 26227120 TI - [Not Available]. PMID- 26227121 TI - [In Process Citation]. PMID- 26227122 TI - [In Process Citation]. PMID- 26227123 TI - [In Process Citation]. PMID- 26227124 TI - [In Process Citation]. PMID- 26227126 TI - [In Process Citation]. PMID- 26227125 TI - [In Process Citation]. PMID- 26227127 TI - [In Process Citation]. PMID- 26227128 TI - [In Process Citation]. PMID- 26227130 TI - [Percutaneous Stone Treatment Today: Standard-, Mini-, Micro-, Ultramini-PCNL]. AB - BACKGROUND: Percutaneous nephrolithotripsy (PCNL) is one of the main interventional treatment modalities for large kidney stones (> 2 cm diameter). With the implementation of miniaturised techniques the indications for PCNL have been broadened to smaller stones. Especially for urologists without emphasis on endourology it is difficult to have an overview of the growing multitude of available systems and techniques. This article describes the currently available systems for percutaneous stone treatment with their peculiarities and indications. MATERIALS AND METHODS: A PubMed-based literature search has been conducted. Relevant articles and additional manufacturers' literature have been compiled to create a summary of the different available PCNL systems. Furthermore, a brief literature review is given regarding indications, stone-free rates and complication rates of each system category. RESULTS: Several manufacturers have developed different PCNL systems with varying diameters and special features. The indications for the different systems are overlapping. Retrospective studies showed reduced complication rates (especially less bleeding and need for transfusions) but prospective randomised controlled trials on this topic are still lacking. Assessed with the criteria of evidence-based medicine, the currently available evidence does not clearly answer the question whether a miniaturisation of PCNL systems is advantageous for the patient. CONCLUSION: Invasiveness of PCNL can be reduced with the nowadays available miniaturised systems. The indication for PCNL has been broadened to small kidney stones > 1 cm diameter. PMID- 26227131 TI - [Erectile Dysfunction in Diabetic Men - Current Diagnostics and Therapy]. AB - Sexual functional dysfunctions represent a multidimensional nosological entity. Apart from the directly measurable pathophysiological parameters, psychological and dynamic partnership aspects are almost always involved. These can exert a triggering and a potentiating influence. Similarly, sociocultural factors have to be taken into account. In men the problem most frequently has a physiological focus and the main symptom within the complex of sexual difficulties, especially for diabetic patients, is erectile dysfunction. Disorders of ejaculation and orgasm may also occur. Testosterone production in men may be impaired due to obesity-related dysfunctions of the hypothalamic-pituitary-gonadal axis and this can lead to a clinically significant androgen deficit and thus also to a decline of libido. PMID- 26227132 TI - [Scrotal Mass as a Rare Initial Manifestation of Necrotising Pancreatitis]. AB - A scrotal mass as initial manifestation of necrotising pancreatitis is very rare. In addition, the diagnosis is very difficult because diseases that occur more frequently produce similar symptoms. Therefore, it is very important to think about rare entities in the differential diagnosis for testicular pain. PMID- 26227133 TI - [In Process Citation]. PMID- 26227134 TI - [In Process Citation]. PMID- 26227135 TI - Smoking cessation behavioural therapy in disadvantaged neighbourhoods: an explorative analysis of recruitment channels. AB - BACKGROUND: The optimum channel(s) used to recruit smokers living in disadvantaged neighbourhoods for smoking cessation behavioural therapy (SCBT) is unknown. This paper examines the channels through which smokers participating in a free, multi-session SCBT programme heard about and were referred to this service in a disadvantaged neighbourhood, and compares participants' characteristics and attendance between channels. METHODS: 109 participants, recruited from free SCBT courses in disadvantaged areas of two cities in the Netherlands, underwent repeated surveys. Participants were asked how they heard about the SCBT and who referred them. Participant characteristics were compared between five channels, including the General Practitioner (GP), a community organisation, word of mouth, another health professional, and media or self referred. Whether the channels through which people heard about or were referred to the service predicted attendance of >=4 sessions was investigated with logistic regression analysis. RESULTS: Over a quarter of the participants had no or primary education only, and more than half belonged to ethnic minority populations. Most participants heard through a single channel. More participants heard about (49%) and were referred to (60%) the SCBT by the (GP) than by any other channel. Factors influencing quit success, including psychosocial factors and nicotine dependence, did not differ significantly between channel through which participants heard about the SCBT. No channel significantly predicted attendance. CONCLUSION: The GP was the single most important source to both hear about and be referred to smoking cessation behavioural therapy in a disadvantaged neighbourhood. A majority of participants of low socioeconomic or ethnic minority status heard about the programme through this channel. Neither the channel through which participants heard about or were referred to the therapy influenced attendance. As such, concentrating on the channel which makes use of the existing infrastructure and which is highest yielding, the GP, would be an appropriate strategy if recruitment resources were scarce. PMID- 26227136 TI - The genetics of skin, hair, and eye color variation and its relevance to forensic pigmentation predictive tests. AB - This review examines the potential application of single nucleotide polymorphism (SNP)-based predictive tests for skin, hair, and eye color to forensic analysis in support of police investigations lacking DNA database matches or eyewitness testimony. Brief descriptions of the biology of melanogenesis and the main genes involved are presented in order to understand the basis of common pigmentation variation in humans. We outline the most recently developed forensically sensitive multiplex tests that can be applied to investigative analyses. The review also describes the biology of the SNPs with the closest associations to, and therefore the best predictors for, common variation in eye, hair, and skin pigmentation. Because pigmentation pathways are complex in their patterns, many of the better-studied human albinism traits provide insight into how pigmentation SNPs interact, control, or modify gene expression and show varying degrees of association with the key genes identified to date. These aspects of SNP action are discussed in an overview of each of the functional groups of pigmentation genes. PMID- 26227137 TI - An Improved Forensic Science Information Search. AB - Although thousands of search engines and databases are available online, finding answers to specific forensic science questions can be a challenge even to experienced Internet users. Because there is no central repository for forensic science information, and because of the sheer number of disciplines under the forensic science umbrella, forensic scientists are often unable to locate material that is relevant to their needs. The author contends that using six publicly accessible search engines and databases can produce high-quality search results. The six resources are Google, PubMed, Google Scholar, Google Books, WorldCat, and the National Criminal Justice Reference Service. Carefully selected keywords and keyword combinations, designating a keyword phrase so that the search engine will search on the phrase and not individual keywords, and prompting search engines to retrieve PDF files are among the techniques discussed. PMID- 26227138 TI - A Review of Forensic Science Management Literature. AB - The science in forensic science has received increased scrutiny in recent years, but interest in how forensic science is managed is a relatively new line of research. This paper summarizes the literature in forensic science management generally from 2009 to 2013, with some recent additions, to provide an overview of the growth of topics, results, and improvements in the management of forensic services in the public and private sectors. This review covers only the last three years or so and a version of this paper was originally produced for the 2013 Interpol Forensic Science Managers Symposium and is available at interpol.int. PMID- 26227139 TI - Acute phase proteins increase with sarcoptic mange status and severity in Iberian ibex (Capra pyrenaica, Schinz 1838). AB - Sarcoptic mange is a contagious skin disease caused by Sarcoptes scabiei, affecting both domestic and wild mammals, including the Iberian ibex (Capra pyrenaica), a medium-sized mountain ungulate almost endemic to the Iberian Peninsula. Acute phase proteins (APPs) could be an indicator of sarcoptic mange disease and severity in Iberian ibex. Serum samples from 131 healthy and sarcoptic mange-affected Iberian ibexes were collected from 2005 to 2012 in Sierra Nevada Natural Space in southern Spain. Serum alpha-1-acid glycoprotein (AGP), serum amyloid A (SAA) and haptoglobin (Hp) concentrations were quantified, and statistically significant differences according to sarcoptic mange disease and severity were assessed. Both AGP and SAA were significantly higher in the sarcoptic mange-affected ibexes than in the healthy ones as well as in the severely affected ibexes as compared to those with less than 50 % of the body surface affected. For the first time, changes in APP are reported in relation to sarcoptic mange in Iberian ibex. It is also reported for the first time that the intensity of APP increase depends on the severity of sarcoptic mange, which could be related with the pathological secondary amyloidosis, leading to organ dysfunction in severely mange-affected animals. Species and population differences in the increase of APP in response to sarcoptic mange could indicate individual and population differences in the immune capability of each population to deal with mange, population prevalence and mortality being the last indicators of such sensitivity. PMID- 26227140 TI - Sarcophaga (Liosarcophaga) tibialis Macquart 1851 (Diptera: Sarcophagidae): micromorphology of preimaginal stages of a fly of medical and veterinary interest. AB - Sarcophagids are a large family of Diptera, with a worldwide distribution. They are related to decomposing organic matter and are very interesting for health science and in forensic cases since many species produce myiasis and occur in human corpses. This family is considered difficult to study, particularly with regard to their immature stages, to which little attention has been paid. Genus Sarcophaga Meigen, 1826 is composed of species of very similar morphology, making very difficult to distinguish. Knowledge of the immature stages of this genus is important because such stages occupy the greater part of the life cycle, so that establishing a basis for their identification will increase their usefulness in systematic and applied sciences. This contribution presents a detailed study of the morphological features, both external and internal, of the preimaginal stages of Sarcophaga (Liosarcophaga) tibialis Macquart, 1851, providing a taxonomical context for the correct identification of Liosarcophaga species of forensic interest in the Iberian Peninsula. Both light and scanning electron microscopy were applied. Complete descriptions of every stage are provided and illustrated, and their usefulness for species comparison, taking into account our uneven knowledge of morphologically immature stages of this subgenus, is indicated. Features of the cephalopharyngeal skeleton, such as the shape of the mouth hook and the intermediate and basal sclerites, and external morphology, such as the pattern of spinose band and anterior and posterior spiracles, proved useful for separating species. Finally, tentative identification keys based on light microscopy observation to distinguish S. (L.) tibialis from other species of forensic interest belonging to Liosarcophaga subgenus are proposed for every immature stage. PMID- 26227141 TI - Seaweed-synthesized silver nanoparticles: an eco-friendly tool in the fight against Plasmodium falciparum and its vector Anopheles stephensi? AB - Malaria, the most widespread mosquito-borne disease, affects 350-500 million people each year. Eco-friendly control tools against malaria vectors are urgently needed. This research proposed a novel method of plant-mediated synthesis of silver nanoparticles (AgNP) using a cheap seaweed extract of Ulva lactuca, acting as a reducing and capping agent. AgNP were characterized by UV-vis spectrophotometry, Fourier transform infrared (FTIR) spectroscopy, energy dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM), and X ray diffraction (XRD). The U. lactuca extract and the green-synthesized AgNP were tested against larvae and pupae of the malaria vector Anopheles stephensi. In mosquitocidal assays, LC50 values of U. lactuca extract against A. stephensi larvae and pupae were 18.365 ppm (I instar), 23.948 ppm (II), 29.701 ppm (III), 37.517 ppm (IV), and 43.012 ppm (pupae). LC50 values of AgNP against A. stephensi were 2.111 ppm (I), 3.090 ppm (II), 4.629 ppm (III), 5.261 ppm (IV), and 6.860 ppm (pupae). Smoke toxicity experiments conducted against mosquito adults showed that U. lactuca coils evoked mortality rates comparable to the permethrin-based positive control (66, 51, and 41%, respectively). Furthermore, the antiplasmodial activity of U. lactuca extract and U. lactuca-synthesized AgNP was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. Fifty percent inhibitory concentration (IC50) values of U. lactuca were 57.26 MUg/ml (CQ-s) and 66.36 MUg/ml (CQ-r); U. lactuca-synthesized AgNP IC50 values were 76.33 MUg/ml (CQ-s) and 79.13 MUg/ml (CQ-r). Overall, our results highlighted out that U. lactuca-synthesized AgNP may be employed to develop newer and safer agents for malaria control. PMID- 26227142 TI - deFUME: Dynamic exploration of functional metagenomic sequencing data. AB - BACKGROUND: Functional metagenomic selections represent a powerful technique that is widely applied for identification of novel genes from complex metagenomic sources. However, whereas hundreds to thousands of clones can be easily generated and sequenced over a few days of experiments, analyzing the data is time consuming and constitutes a major bottleneck for experimental researchers in the field. FINDINGS: Here we present the deFUME web server, an easy-to-use web-based interface for processing, annotation and visualization of functional metagenomics sequencing data, tailored to meet the requirements of non-bioinformaticians. The web-server integrates multiple analysis steps into one single workflow: read assembly, open reading frame prediction, and annotation with BLAST, InterPro and GO classifiers. Analysis results are visualized in an online dynamic web interface. CONCLUSION: The deFUME webserver provides a fast track from raw sequence to a comprehensive visual data overview that facilitates effortless inspection of gene function, clustering and distribution. The webserver is available at cbs.dtu.dk/services/deFUME/and the source code is distributed at github.com/EvdH0/deFUME. PMID- 26227144 TI - SynLinker: an integrated system for designing linkers and synthetic fusion proteins. AB - Synthetic fusion proteins have shown great potential in various biotechnological and (bio)pharmaceutical applications. They usually contain more than two protein domains joined by a linker peptide sequence which is often selected intuitively or in ad hoc manner. Thus, we developed an integrated web-based system, SynLinker, to provide appropriate linker candidates for constructing fusion proteins. We compiled a total of 2260 linker sequences comprising of natural linkers extracted from a set of non-redundant multi-domain proteins in Protein Data Bank and artificial/empirical linkers collected from literature and patents. Multiple query interface allows users to search for the desired linker candidates based on selection criteria and their preferences. In addition, a selected linker can be combined with two domain structures which are uploaded and appended at its N and C terminals, thereby predicting a de novo structure of the fusion protein. Hence, SynLinker can serve as a systematic tool for researchers who are interested in designing synthetic fusion proteins. AVAILABILITY AND IMPLEMENTATION: SynLinker is freely available at http://bioinfo.bti.a star.edu.sg/synlinker. CONTACT: cheld@nus.edu.sg SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26227143 TI - SNPGenie: estimating evolutionary parameters to detect natural selection using pooled next-generation sequencing data. AB - New applications of next-generation sequencing technologies use pools of DNA from multiple individuals to estimate population genetic parameters. However, no publicly available tools exist to analyse single-nucleotide polymorphism (SNP) calling results directly for evolutionary parameters important in detecting natural selection, including nucleotide diversity and gene diversity. We have developed SNPGenie to fill this gap. The user submits a FASTA reference sequence(s), a Gene Transfer Format (.GTF) file with CDS information and a SNP report(s) in an increasing selection of formats. The program estimates nucleotide diversity, distance from the reference and gene diversity. Sites are flagged for multiple overlapping reading frames, and are categorized by polymorphism type: nonsynonymous, synonymous, or ambiguous. The results allow single nucleotide, single codon, sliding window, whole gene and whole genome/population analyses that aid in the detection of positive and purifying natural selection in the source population. AVAILABILITY AND IMPLEMENTATION: SNPGenie version 1.2 is a Perl program with no additional dependencies. It is free, open-source, and available for download at https://github.com/hugheslab/snpgenie. CONTACT: nelsoncw@email.sc.edu or austin@biol.sc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26227145 TI - BackCLIP: a tool to identify common background presence in PAR-CLIP datasets. AB - MOTIVATION: PAR-CLIP, a CLIP-seq protocol, derives a transcriptome wide set of binding sites for RNA-binding proteins. Even though the protocol uses stringent washing to remove experimental noise, some of it remains. A recent study measured three sets of non-specific RNA backgrounds which are present in several PAR-CLIP datasets. However, a tool to identify the presence of common background in PAR CLIP datasets is not yet available. RESULTS: We used the measured sets of non specific RNA backgrounds to build a common background set. Each element from the common background set has a score that reflects its presence in several PAR-CLIP datasets. We present a tool that uses this score to identify the amount of common backgrounds present in a PAR-CLIP dataset, and we provide the user the option to use or remove it. We used the proposed strategy in 30 PAR-CLIP datasets from nine proteins. It is possible to identify the presence of common backgrounds in a dataset and identify differences in datasets for the same protein. This method is the first step in the process of completely removing such backgrounds. AVAILABILITY: The tool was implemented in python. The common background set and the supplementary data are available at https://github.com/phrh/BackCLIP. CONTACT: phreyes@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26227146 TI - ClicO FS: an interactive web-based service of Circos. AB - : We present ClicO Free Service, an online web-service based on Circos, which provides a user-friendly, interactive web-based interface with configurable features to generate Circos circular plots. AVAILABILITY AND IMPLEMENTATION: Online web-service is freely available at http://clicofs.codoncloud.com CONTACT: : soonjoo.yap@codongenomics.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26227147 TI - Reliability and validity of urinary nerve growth factor measurement in women with lower urinary tract symptoms. AB - INTRODUCTION AND HYPOTHESIS: The validity and reliability of measurement of urinary NGF as a diagnostic biomarker in women with lower urinary tract dysfunction (LUTD) is uncertain. We aimed to evaluate both the diagnostic and discriminant validity, and the test-retest reliability of urinary NGF measurement in women with LUTD. METHODS: Urinary NGF was measured in women with LUTD (n = 205) and asymptomatic subjects (n = 31). Urinary NGF was assayed using an ELISA method and normalized against urinary creatinine. NGF/creatinine ratios were compared between symptom subgroups using Mann-Whitney U test, and between different urodynamic diagnoses using the Kruskal-Wallis test. Receiver Operator Characteristic (ROC) analysis was employed to evaluate the diagnostic performance of urinary NGF. Test-retest reliability of NGF measurement was assessed using intra-class correlation (ICC). RESULTS: Urinary NGF was significantly but non specifically increased in symptomatic patients when compared to controls (13.33 vs. 2.05 ng NGF/g Cr, P < 0.001). On multivariate logistic regression NGF was a good predictor of patients having OAB or not, however, the adjusted odds ratio only 1.006. ROC analysis demonstrated poor discriminant ability between different symptomatic groups and urodynamic groups. Using a cut off of 13.0 ng NGF/g creatinine the test provides a sensitivity of 81%, but a specificity of only 39% for overactive bladder. The assays demonstrated good test-retest reliability with ICC of 0.889. CONCLUSIONS: Although urinary NGF can be reliably assayed, and is increased in various LUTDs, it discriminates poorly between these disorders therefore has very limited potential as a biomarker. Neurourol. Urodynam. 35:944 948, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26227148 TI - Ranking treatments in frequentist network meta-analysis works without resampling methods. AB - BACKGROUND: Network meta-analysis is used to compare three or more treatments for the same condition. Within a Bayesian framework, for each treatment the probability of being best, or, more general, the probability that it has a certain rank can be derived from the posterior distributions of all treatments. The treatments can then be ranked by the surface under the cumulative ranking curve (SUCRA). For comparing treatments in a network meta-analysis, we propose a frequentist analogue to SUCRA which we call P-score that works without resampling. METHODS: P-scores are based solely on the point estimates and standard errors of the frequentist network meta-analysis estimates under normality assumption and can easily be calculated as means of one-sided p-values. They measure the mean extent of certainty that a treatment is better than the competing treatments. RESULTS: Using case studies of network meta-analysis in diabetes and depression, we demonstrate that the numerical values of SUCRA and P Score are nearly identical. CONCLUSIONS: Ranking treatments in frequentist network meta-analysis works without resampling. Like the SUCRA values, P-scores induce a ranking of all treatments that mostly follows that of the point estimates, but takes precision into account. However, neither SUCRA nor P-score offer a major advantage compared to looking at credible or confidence intervals. PMID- 26227150 TI - Does Age at Operation Influence the Short- and Long-Term Outcomes of Off-Pump Coronary Artery Bypass Grafting? AB - BACKGROUND: To investigate the relationship between age and both short- and long term outcomes of off-pump coronary bypass grafting (OPCAB). METHODS AND RESULTS: The 780 patients undergoing OPCAB were divided into 3 groups: 262 aged <65 years (young), 329 aged 65-74 years (early elderly), and 189 aged >75 years (late elderly), and retrospectively analyzed. The follow-up rate was 94.9%, and mean follow-up period was 5.6+/-3.4 years. In-hospital mortality rates were similar among the groups (0.8% in young, 1.2% in early elderly, and 1.1% in late elderly; P=0.862). In logistic regression analysis, the risk factor for predicting major complications was the New York Heart Association (NYHA) classification (odds ratio: 1.555, P=0.001), and not age. The 10-year estimated rates free from cardiac death (89.6+/-3.2, 95.0+/-2.1, and 96.5+/-2.1%, log rank, P=0.16) and cardiac events (71.8+/-3.8, 66.8+/-4.3, and 59.9+/-7.7%, P=0.61) were not significantly different among the groups. In multivariate Cox models, independent risk factors predicting cardiac events were the NYHA classification (hazard ratio (HR): 1.265, P=0.009), and ejection fraction (HR: 0.986, P=0.016), but not age (young HR: 1.0, early elderly HR: 1.276; P=0.210, late elderly HR: 0.910; P=0.707). CONCLUSIONS: Both short- and long-term cardiac outcomes of OPCAB are not influenced by age at operation. PMID- 26227149 TI - Paternal and maternal bonding styles in childhood are associated with the prevalence of chronic pain in a general adult population: the Hisayama Study. AB - BACKGROUND: Previous research has suggested that extraordinary adverse experiences during childhood, such as abuse, are possible risk factors for the development of chronic pain. However, the relationship between the perceived parental bonding style during childhood and chronic pain has been much less studied. METHODS: In this cross-sectional study, 760 community-dwelling Japanese adults were asked if they had pain that had been present for six months or more. They completed the Parental Bonding Instrument (PBI), a self-administrated questionnaire designed to assess perceived parental bonding, and the Patient Health Questionnaire-9 to assess current depressive symptoms. The PBI consists of care and overprotection subscales that are analyzed by assigning the parental bonding style to one of four quadrants: Optimal bonding (high care/low overprotection), neglectful parenting (low care/low overprotection), affectionate constraint (high care/high overprotection), and affectionless control (low care/high overprotection). Logistic regression analysis was done to estimate the contribution of the parental bonding style to the risk of chronic pain, controlling for demographic variables. RESULTS: Compared to the optimal bonding group, the odds ratios (ORs) for having chronic pain were significantly higher in the affectionless control group for paternal bonding (OR: 2.21, 95% CI: 1.50 3.27) and for maternal bonding (OR: 1.60, 95% CI: 1.09-2.36). After adjusting for depression, significance remained only for paternal bonding. CONCLUSION: The results demonstrate that the parental bonding style during childhood is associated with the prevalence of chronic pain in adults in the general population and that the association is more robust for paternal bonding than for maternal bonding. PMID- 26227151 TI - How Can We Improve Prognosis in Patients With Acute Myocardial Infarction? - Lesson From Patients Without Primary Percutaneous Coronary Intervention. PMID- 26227153 TI - In Search of 'Omics'-Based Biomarkers to Predict Risk of Frailty and Its Consequences in Older Individuals: The FRAILOMIC Initiative. AB - An increase in the number of older people experiencing disability and dependence is a critical aspect of the demographic change that will emerge within Europe due to the rise in life expectancy. In this scenario, prevention of these conditions is crucial for the well-being of older citizens and for the sustainability of our healthcare systems. Thus, the diagnosis and management of conditions like frailty, which identifies the people at the highest risk for developing those adverse outcomes, is of critical relevance. Currently, assessment of frailty relies primarily on measuring functional parameters, which have limited clinical utility. In this viewpoint article, we describe the FRAILOMIC Initiative, an international, large-scale, multi-endpoint, community- and clinic-based research study funded by the European Commission. The aim of the study is to develop validated measures, comprising both classic and 'omics-based' laboratory biomarkers, which can predict the risk of frailty, improve the accuracy of its diagnosis in clinical practice and provide a prognostic forecast on the evolution from frailty to disability. The initiative includes eight established cohorts of older adults, encompassing >75,000 subjects, most of whom (~70%) are aged >65 years. Data on function, nutritional status and exercise habits have been collected, and cardiovascular health has been evaluated at baseline. Subjects will be stratified as 'non-frail' or 'frail' using Fried's definition, all adverse outcomes of interest will be recorded and differentially expressed biomarkers associated with the risk of frailty will be identified. Genomic, proteomic and transcriptomic investigations will be carried out using array-based systems. As circulating microRNAs in plasma have been identified in the context of senescence, ageing and age-associated diseases, a miRNome-wide analysis will also be undertaken to identify a miRNA-based signature of frailty. Blood concentrations of secreted proteins known to be upregulated significantly in senescent endothelial cells and other hypothesis-driven biomarkers will be measured using ELISAs. The FRAILOMIC Initiative aims to issue a series of interim scientific reports as key results emerge. Ultimately, it is hoped that this study will contribute to the development of new clinical tools, which may help individuals to enjoy an old age that is healthier and free from disability. PMID- 26227152 TI - Rapamycin does not prevent increases in myofibrillar or mitochondrial protein synthesis following endurance exercise. AB - The present study aimed to investigate the role of the mechanistic target of rapamycin complex 1 (mTORC1) in the regulation of myofibrillar (MyoPS) and mitochondrial (MitoPS) protein synthesis following endurance exercise. Forty-two female C57BL/6 mice performed 1 h of treadmill running (18 m min(-1) ; 5 degrees grade), 1 h after i.p. administration of rapamycin (1.5 mg . kg(-1) ) or vehicle. To quantify skeletal muscle protein fractional synthesis rates, a flooding dose (50 mg . kg(-1) ) of l-[ring-(13) C6 ]phenylalanine was administered via i.p. injection. Blood and gastrocnemius muscle were collected in non-exercised control mice, as well as at 0.5, 3 and 6 h after completing exercise (n = 4 per time point). Skeletal muscle MyoPS and MitoPS were determined by measuring isotope incorporation in their respective protein pools. Activation of the mTORC1 signalling cascade was measured via direct kinase activity assay and immunoblotting, whereas genes related to mitochondrial biogenesis were measured via a quantitative RT-PCR. MyoPS increased rapidly in the vehicle group post exercise and remained elevated for 6 h, whereas this response was transiently blunted (30 min post-exercise) by rapamycin. By contrast, MitoPS was unaffected by rapamycin, and was increased over the entire post-exercise recovery period in both groups (P < 0.05). Despite rapid increases in both MyoPS and MitoPS, mTORC1 activation was suppressed in both groups post-exercise for the entire 6 h recovery period. Peroxisome proliferator activated receptor-gamma coactivator 1alpha, pyruvate dehydrogenase kinase 4 and mitochondrial transcription factor A mRNA increased post-exercise (P < 0.05) and this response was augmented by rapamycin (P < 0.05). Collectively, these data suggest that endurance exercise stimulates MyoPS and MitoPS in skeletal muscle independently of mTORC1 activation. PMID- 26227154 TI - Capsule Commentary on Flynn et al., Development and Validation of a Single-Item Screener for Self-Reporting Sexual Problems in U.S. Adults. PMID- 26227155 TI - Capsule Commentary on Blecker et al., Impact of an Intervention to Improve Weekend Hospital Care at an Academic Medical Center: An Observational Study. PMID- 26227156 TI - Capsule Commentary on Chretien et al., A Digital Ethnography of Medical Students who use Twitter for Professional Development. PMID- 26227157 TI - Capsule Commentary on Margolis et al., A Successful Multifaceted Trial to Improve Hypertension Control in Primary Care: Why did it Work? PMID- 26227159 TI - Seeing Is Believing: Alpha-Synuclein Oligomers in Parkinson's Disease Brain. PMID- 26227158 TI - In Vitro T-Cell Generation From Adult, Embryonic, and Induced Pluripotent Stem Cells: Many Roads to One Destination. AB - T lymphocytes are critical mediators of the adaptive immune system and have the capacity to serve as therapeutic agents in the areas of transplant and cancer immunotherapy. While T cells can be isolated and expanded from patients, T cells derived in vitro from both hematopoietic stem/progenitor cells (HSPCs) and human pluripotent stem cells (hPSCs) offer great potential advantages in generating a self-renewing source of T cells that can be readily genetically modified. T-cell differentiation in vivo is a complex process requiring tightly regulated signals; providing the correct signals in vitro to induce T-cell lineage commitment followed by their development into mature, functional, single positive T cells, is similarly complex. In this review, we discuss current methods for the in vitro derivation of T cells from murine and human HSPCs and hPSCs that use feeder-cell and feeder-cell-free systems. Furthermore, we explore their potential for adoption for use in T-cell-based therapies. PMID- 26227160 TI - Diagnostic accuracy of stroke volume variation measured with uncalibrated arterial waveform analysis for the prediction of fluid responsiveness in patients with impaired left ventricular function: a prospective, observational study. AB - Uncalibrated arterial waveform analysis enables dynamic preload assessment in a minimally invasive fashion. Evidence about the validity of the technique in patients with impaired left ventricular function is scarce, while adequate cardiac preload assessment would be of great value in these patients. The aim of this study was to investigate the diagnostic accuracy of stroke volume variation (SVV) measured with the FloTrac/VigileoTM system in patients with impaired left ventricular function. In this prospective, observational study, 22 patients with a left ventricular ejection fraction of 40 % or less undergoing elective coronary artery bypass grafting were included. Patients were considered fluid responsive if cardiac output increased with 15 % or more after volume loading (7 ml kg(-1) ideal body weight). The following variables were calculated: area under the receiver operating characteristics (ROC) curve, ideal cut-off value for SVV, sensitivity, specificity, positive and negative predictive values, and overall accuracy. In addition, SVV cut-off points to obtain 90 % true positive and 90 % true negative predictions were determined. ROC analysis revealed an area under the curve of 0.70 [0.47; 0.92]. The ideal SVV cut-off value was 10 %, with a corresponding sensitivity and specificity of 56 and 69 % respectively. Overall accuracy was 64 %, positive and negative predictive values were 69 and 56 % respectively. SVV values to obtain more than 90 % true positive and negative predictions were 16 and 6 % respectively. The ability of uncalibrated arterial waveform analysis SVV to predict fluid responsiveness in patients with impaired LVF was low. PMID- 26227161 TI - Continuous noninvasive cardiac output determination using the CNAP system: evaluation of a cardiac output algorithm for the analysis of volume clamp method derived pulse contour. AB - The CNAP system (CNSystems Medizintechnik AG, Graz, Austria) provides noninvasive continuous arterial pressure measurements by using the volume clamp method. Recently, an algorithm for the determination of cardiac output by pulse contour analysis of the arterial waveform recorded with the CNAP system became available. We evaluated the agreement of the continuous noninvasive cardiac output (CNCO) measurements by CNAP in comparison with cardiac output measurements invasively obtained using transpulmonary thermodilution (TDCO). In this proof-of-concept analysis we studied 38 intensive care unit patients from a previously set up database containing CNAP-derived arterial pressure data and TDCO values obtained with the PiCCO system (Pulsion Medical Systems SE, Feldkirchen, Germany). We applied the new CNCO algorithm retrospectively to the arterial pressure waveforms recorded with CNAP and compared CNCO with the corresponding TDCO values (criterion standard). Analyses were performed separately for (1) CNCO calibrated to the first TDCO (CNCO-cal) and (2) CNCO autocalibrated to biometric patient data (CNCO-auto). We did not perform an analysis of trending capabilities because the patients were hemodynamically stable. The median age and APACHE II score of the 22 male and 16 female patients was 63 years and 18 points, respectively. 18 % were mechanically ventilated and in 29 % vasopressors were administered. Mean +/- standard deviation for CNCO-cal, CNCO-auto, and TDCO was 8.1 +/- 2.7, 6.4 +/- 1.9, and 7.8 +/- 2.4 L/min, respectively. For CNCO-cal versus TDCO, Bland-Altman analysis demonstrated a mean difference of +0.2 L/min (standard deviation 1.0 L/min; 95 % limits of agreement -1.7 to +2.2 L/min, percentage error 25 %). For CNCO-auto versus TDCO, the mean difference was -1.4 L/min (standard deviation 1.8 L/min; 95 % limits of agreement -4.9 to +2.1 L/min, percentage error 45 %). This pilot analysis shows that CNCO determination is feasible in critically ill patients. A percentage error of 25 % indicates acceptable agreement between CNCO cal and TDCO. The mean difference, the standard deviation, and the percentage error between CNCO-auto and TDCO were higher than between CNCO-cal and TDCO. A hyperdynamic cardiocirculatory state in a substantial number of patients and the hemodynamic stability making trending analysis impossible are main limitations of our study. PMID- 26227162 TI - Differential expression of novel biomarkers (TLR-2, TLR-4, COX-2, and Nrf-2) of inflammation and oxidative stress in semen of leukocytospermia patients. AB - Chronic genitourinary inflammation results in Leukocytospermia (LCS), an elevated number of white blood cells (WBCs) in semen, which, in association with oxidative stress, may suppress sperm function, and manifest as male factor infertility. The current clinical diagnosis of LCS employs manual enumeration of WBCs and requires complex staining and laboratory skills or measurement of inflammatory cytokines and chemokines levels. Many patients with idiopathic infertility are asymptomatic. In search of better inflammatory markers for LCS, we evaluated expression of toll-like receptors 2 and 4 (TLR-2/4), cyclooxygenase-2 (COX-2), and nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) in semen samples of age matched infertile patients with and without LCS. We employed the usage of specific Western blot evaluation, cytokine array; immunofluorescence microscopy (IFM) followed by computer-based analysis, and other molecular approaches. As compared with non-LCS patients (n = 38), semen samples from LCS patients (n = 47) displayed significantly lower total sperm count (p < 0.01), motility (p < 0.0001), normal head count (p < 0.0001), and a significantly higher white blood cell count (p < 0.0001). Differential cytokine profiling of seminal plasma by antibody array revealed up-regulation of several pro-inflammatory chemokines in LCS samples. Western blot analysis of LCS seminal plasma (n = 15) also showed a significant increase in expression of TLR-2 (p < 0.001) and 4 (p < 0.01), COX-2 (p < 0.001), and Nrf-2 (p < 0.001) as compared with semen samples from non-LCS patients (n = 15). Computer-based objective IFM analysis of spermatozoa from LCS patients showed increased expression of TLR-4 (p < 0.001), Cox-2 (p < 0.01), and (Nrf-2) (p < 0.01). Significant differences in the subcellular localization of these proteins were evident in the sperm head and tail segments of LCS samples. Altogether, these observations suggest that TLR-2/4, COX-2, and Nrf-2 can serve as novel biomarkers of inflammation and oxidative stress. Therefore, developing a rapid assay for these biomarkers may facilitate early diagnosis and management of LCS especially in idiopathic and asymptomatic male infertility patients. PMID- 26227163 TI - Bone mineral density reduction in adolescents with systemic erythematosus lupus: association with lack of vitamin D supplementation. AB - The aim of this study is to evaluate body composition and the bone mineral density in female adolescents with juvenile systemic lupus erythematosus. Body composition (BC) and bone mineral density (BMD) were evaluated in an observational cohort study with 35 postmenarcheal adolescent females. The variables studied were as follows: current and cumulative corticosteroid dose, intake of supplements containing calcium and vitamin D, 24-h proteinuria, body mass index (BMI), and height for age (Z-score). BC was assessed using dual-energy X-ray absorptiometry (DXA) at two time points (median interval of 1.2 years). The fat mass index (FMI = fat mass in kilograms divided by the height in meters squared) and lean mass index (LMI = lean mass in kilograms divided by the height in meters squared) were calculated based on the DXA results. BMD was classified according to the International Society of Clinical Densitometry (low BMD for chronological age < -2.0 standard deviations). .The mean age of the subjects was 15.4 +/- 1.8 years. Of patients, 54.3 % were normal weight, 22.8 % were overweight, 22.8 % were obese, and 8.6 % had short stature. Low BMD for chronological age was observed in 42.8 % of patients, and 60 % were not taking vitamin D. There was no significant difference between the two time points with respect to FMI, LMI, or body mass index Z-score (ZBMI); however, BMD has decreased significantly (p = 0.011). There was an association between not taking a vitamin D supplement and decreased BMD (p = 0.027). Almost half of the patients had altered nutritional status. The BMD decrease in adolescents with juvenile systemic lupus erythematosus (JSLE) was associated with the lack of vitamin D supplementation, highlighting the importance of well-defined vitamin D supplementation protocols. PMID- 26227164 TI - Follicular helper T cells in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in the joints and other tissues. Rheumatoid factor (RF) and anticyclic citrullinated peptides (anti-CCP) are biomarkers for the evaluation of RA although their functions in the pathogenesis of RA are poorly understood. CXC chemokine receptor 5 (CXCR5)(+) T follicular helper (TFH) cells are essential for B cell maturation and antibody production. Recent studies have showed that dysregulated TFH cells are associated with the development of autoimmune diseases. This article reviews the characters and functions of TFH cells, such as their differentiation, expression, transcription factor, and B cell maturation. Meanwhile, we also discuss the possible mechanisms underlying the role of these cells in RA and potential treatments, including antibody-blocking agents, gene therapies, T cell vaccines, and T follicular regulatory (TFR) cells. Overall, we discuss the roles of TFH cells in the pathogenesis of RA and potential therapies for RA. PMID- 26227165 TI - Rheumatoid arthritis in Latin America: challenges and solutions to improve its diagnosis and treatment training for medical professionals. AB - Rheumatoid arthritis (RA) is a disease with multiple clinical manifestations and chronic complications that requires a multidisciplinary team to treat and monitor patients. This understanding between the different medical and health professionals is essential in obtaining patient well-being. This is the reason behind the assessment of the difficulties and limitations seen in Latin America in the field of rheumatology. The aim is to suggest possible mechanisms and solutions to strengthen the knowledge and understanding of the way the disease behaves and how it can be handled by doctors and medical professionals. PMID- 26227166 TI - IKBB tumor suppressive role in nasopharyngeal carcinoma via NF-kappaB-mediated signalling. AB - Tumor suppressor genes (TSGs) play a prominent role in cancer and are important in the development of nasopharyngeal carcinoma (NPC), which is endemic in Southern China as well as Southeast Asia. Apart from TSGs, aberrant signalling pathways are also commonly associated with tumor progression. Unsurprisingly, the NF-kappaB pathway is frequently associated with angiogenesis and promoting tumor growth and development. Functional complementation studies using microcell mediated chromosome transfer helped to identify IKBB as a putative TSG in NPC. IKBB, an inhibitor of NF-kappaB, has recently been shown to be inversely associated with tumor growth and metastasis via inactivation of the NF-kappaB pathway, but its suppressive role is still only poorly understood. This study takes the lead in revealing the suppressive role of IKBB in NPC. IKBB is silenced in the majority of NPC tumor tissues in all stages. Its suppressive role is substantiated by perturbation in tumor formation, cell migration and angiogenesis. Interestingly, IKBB not only affects the 'seed', but also influences the 'soil' by downregulating the transcriptional level of proangiogenic factors Rantes, Upar, IL6, and IL8. For the first time, our data establish the importance of a novel tumor suppressive IKBB gene in abrogating angiogenesis in NPC via the NF-kappaB signalling pathway, which is likely mediated by crosstalk with the Akt/Gsk3beta signalling pathway. PMID- 26227167 TI - A toolbox for multiple sclerosis lesion segmentation. AB - INTRODUCTION: Lesion segmentation plays an important role in the diagnosis and follow-up of multiple sclerosis (MS). This task is very time-consuming and subject to intra- and inter-rater variability. In this paper, we present a new tool for automated MS lesion segmentation using T1w and fluid-attenuated inversion recovery (FLAIR) images. METHODS: Our approach is based on two main steps, initial brain tissue segmentation according to the gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) performed in T1w images, followed by a second step where the lesions are segmented as outliers to the normal apparent GM brain tissue on the FLAIR image. RESULTS: The tool has been validated using data from more than 100 MS patients acquired with different scanners and at different magnetic field strengths. Quantitative evaluation provided a better performance in terms of precision while maintaining similar results on sensitivity and Dice similarity measures compared with those of other approaches. CONCLUSION: Our tool is implemented as a publicly available SPM8/12 extension that can be used by both the medical and research communities. PMID- 26227169 TI - Bilateral symmetrical basal ganglia and thalamic lesions in children: an update (2015). AB - INTRODUCTION: In children, many inherited or acquired neurological disorders may cause bilateral symmetrical signal intensity alterations in the basal ganglia and thalami. METHODS: A literature review was aimed at assisting neuroradiologists, neurologists, infectious diseases specialists, and pediatricians to provide further understanding into the clinical and neuroimaging features in pediatric patients presenting with bilateral symmetrical basal ganglia and thalamic lesions on magnetic resonance imaging (MRI). RESULTS: We discuss hypoxic-ischemic, toxic, infectious, immune-mediated, mitochondrial, metabolic, and neurodegenerative disorders affecting the basal ganglia and thalami. CONCLUSION: Recognition and correct evaluation of basal ganglia abnormalities, together with a proper neurological examination and laboratory findings, may enable the identification of each of these clinical entities and lead to earlier diagnosis. PMID- 26227168 TI - Quantitative T2, T2*, and T2' MR imaging in patients with ischemic leukoaraiosis might detect microstructural changes and cortical hypoxia. AB - INTRODUCTION: Quantitative MRI with T2, T2*, and T2' mapping has been shown to non-invasively depict microstructural changes (T2) and oxygenation status (T2* and T2') that are invisible on conventional MRI. Therefore, we aimed to assess whether T2 and T2' quantification detects cerebral (micro-)structural damage and chronic hypoxia in lesions and in normal appearing white matter (WM) and gray matter (GM) of patients with ischemic leukoaraiosis (IL). Measurements were complemented by the assessment of the cerebral blood flow (CBF) and the degree of GM and WM atrophy. METHODS: Eighteen patients with IL and 18 age-matched healthy controls were included. High-resolution, motion-corrected T2, T2*, and T2' mapping, CBF mapping (pulsed arterial spin labeling, PASL), and segmentation of GM and WM were used to depict specific changes in both groups. All parameters were compared between patients and healthy controls, using t testing. Values of p < 0.05 were accepted as statistically significant. RESULTS: Patients showed significantly increased T2 in lesions (p < 0.01) and in unaffected WM (p = 0.045) as well as significantly increased T2* in lesions (p = 0.003). A significant decrease of T2' was detected in patients in unaffected WM (p = 0.027), while no T2' changes were observed in GM (p = 0.13). Both unaffected WM and GM were significantly decreased in volume in the patient-group (p < 0.01). No differences of PASL-based CBF could be shown. CONCLUSION: Non-invasive quantitative MRI with T2, T2*, and T2' mapping might be used to detect subtle structural and metabolic changes in IL. Assessing the grade of microstructural damage and hypoxia might be helpful to monitor disease progression and to perform risk assessment. PMID- 26227170 TI - Cricothyroid joint anatomy as a predicting factor for success of cricoid-thyroid approximation in transwomen. AB - OBJECTIVES/HYPOTHESIS: Cricoid-thyroid approximation (CTA) performed to elevate the vocal pitch in transwomen fails in about one-third of the patients. The purpose of this study was to test the feasibility of predicting the likelihood of success of CTA by preoperative determination of the crico-thyroid joint (CTJ) type using three-dimensional (3-D) images derived from high-resolution computer tomography (HRCT). STUDY DESIGN: Prospective cohort study of 18 transwomen who underwent CTA at our institution. METHODS: All patients had a preoperative and a postoperative HRCT of the larynx, as well as pre- and postoperative measurements of the fundamental vocal pitch (F0 ). RESULTS: Three-dimensional images showed type A CTJs in 11 patients and type B or C CTJs in seven patients (see below for the definition of these types). Cricoid-thyroid approximation raised the F0 on average by 76 Hz in patients with type A CTJs and by 45 Hz in patients with type B/C CTJs. Moreover, CTA produced a vocal fold elongation of 17% in larynges with type A joint but only of 3% in larynges with type B/C joints. CONCLUSION: Three dimensional images allow the differentiation of type A versus type B/C CTJs but not the distinction between type B and type C CTJs. Both vocal pitch elevation and vocal fold elongation following CTA are significantly greater in patients with type A CTJs than in patients with type B/C CTJs. Based on these preliminary results, we recommend identifying the CTJ type on 3-D images and limiting CTA to patients with type A CTJs. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1380-1384, 2016. PMID- 26227171 TI - Vinylation of Unprotected Phenols Using a Biocatalytic System. AB - Readily available substituted phenols were coupled with pyruvate in buffer solution under atmospheric conditions to afford the corresponding para vinylphenol derivatives while releasing only one molecule of CO2 and water as the by-products. This transformation was achieved by designing a biocatalytic system that combines three biocatalytic steps, namely the C-C coupling of phenol and pyruvate in the presence of ammonia, which leads to the corresponding tyrosine derivative, followed by deamination and decarboxylation. The biocatalytic transformation proceeded with high regioselectivity and afforded exclusively the desired para products. This method thus represents an environmentally friendly approach for the direct vinylation of readily available 2-, 3-, or 2,3 disubstituted phenols on preparative scale (0.5 mmol) that provides vinylphenols in high yields (65-83 %). PMID- 26227172 TI - An Investigation of the Utility of the Addenbrooke's Cognitive Examination III in the Early Detection of Dementia in Memory Clinic Patients Aged over 75 Years. AB - BACKGROUND/AIMS: To examine the validity of Addenbrooke's Cognitive Examination III (ACE-III) in detecting early dementia in UK memory clinic patients aged 75-85 years. METHODS: The ACE-III was administered to 59 patients prior to diagnosis. The extent to which scores predicted the membership of the dementia or no dementia group was explored using receiver operating characteristic curve analysis and other parameters of diagnostic performance. Thirty-three participants (55.9%) were diagnosed with dementia (Alzheimer's disease = 56.3%, Alzheimer's disease with cerebrovascular disease = 31.3%, and vascular dementia = 12.5%). RESULTS: The optimal cut-off for detecting dementia was 81/100 (scores <81 indicating dementia with a sensitivity of 0.79, a specificity of 0.96, and a positive predictive value of 0.96), with superiority over published cut-offs (88/100 and 82/100) at medium and lower prevalence rates. The number of years of full-time education had a significant positive relationship to total ACE-III scores (r = 0.697, p < 0.001) for the no-dementia group. Exploratory analysis indicated that optimal cut-offs were different for higher versus lower education groups. CONCLUSIONS: The ACE-III has excellent accuracy for the detection of dementia in day-to-day clinical practice. Lower cut-offs than those specified in the index paper, and the consideration of the patients' years of full-time education may be necessary for optimal diagnostic performance. PMID- 26227173 TI - Diversified Synthesis of Furans by Coupling between Enols/1,3-Dicarbonyl Compounds and Nitroolefins: Direct Access to Dioxa[5]helicenes. AB - A versatile method for the diversified synthesis of furans and arenofurans has been developed that proceeds through K2CO3-promoted cyclization between enols/1,3 dicarbonyl compounds and nitroolefins at reflux in EtOH. This facile method has been successfully employed in the synthesis of benzotrifuran derivatives, which are useful hole-transporting materials. This procedure also provides direct access to dioxa[5]helicenes. This reaction offers a broad substrate scope, uses an inexpensive base and environmentally benign solvent, and is operationally simple. PMID- 26227174 TI - In-depth characterization of the secretome of mouse CNS cell lines by LC-MS/MS without prefractionation. AB - Microglia, astrocytes, and neurons, which have important functions in the central nervous system (CNS), communicate mutually to generate a signal through secreted proteins or small molecules, but many of which have not been identified. Because establishing a reference for the secreted proteins from CNS cells could be invaluable in examining cell-to-cell communication in the brain, we analyzed the secretome of three murine CNS cell lines without prefractionation by high resolution mass spectrometry. In this study, 2795 proteins were identified from conditioned media of the three cell lines, and 2125 proteins were annotated as secreted proteins by bioinformatics analysis. Further, approximately 500 secreted proteins were quantifiable as differentially expressed proteins by label-free quantitation. As a result, our secretome references are useful datasets for the future study of neuronal diseases. All MS data have been deposited in the ProteomeXchange with identifier PXD001597 (http://proteomecentral.proteomexchange.org/dataset/PXD001597). PMID- 26227175 TI - Effect of the Peptidic Scaffold in Copper(II) Coordination and the Redox Properties of Short Histidine-Containing Peptides. AB - A linear decapeptide containing three His and one Asp residues and a beta-turn inducing dProPro unit was synthesised. A detailed potentiometric, mass spectrometric and spectroscopic study showed that at a 1:1 ratio of CCu /Cpeptide this peptide formed a major [CuH(O(dPro)-Asp)](2+) species (pH range 5.5-7.0), in which the Cu(2+) ion was bound to the His and Asp residues in square-planar or square-pyramidal geometries. The stability constant corrected for protonated species (log K* CuH(O dPro-Asp)=9.33) is almost equal to the value obtained for the parent [CuH(O?Asp)](2+) species (log K*CuH(O-Asp) =9.28), but lower than that obtained for the cyclic [CuH(C-Asp)](2+) complex (log K*CuH(C-Asp) =10.79) previously published. Thus, the replacement of the ProGly unit by the stronger beta-turn-inducing dProPro unit did not generate a more stable copper(II) species, although the O(dPro)-Asp peptide was structured in solution, as shown by circular dichroism (CD) spectroscopy. Interestingly, the calculated value of Keff showed that this peptide behaved similarly to the O-Asp or C-Asp counterparts, depending on the pH value. The cyclic voltammetry data indicated that the most easily reducible species were [CuH(O-Asp)](2+) (E'(0) =262 mV versus a normal hydrogen electrode (NHE)) and [CuH(O(dPro)-Asp)](2+) (E'(0) =294 mV versus NHE) complexes, the peptidic scaffolds of which are open. A lower value was obtained for [CuH(C-Asp)](2+) (E'(0) =24 mV versus NHE). A different degree of non reversibility was observed for the three copper(II) complexes; this could reflect a different degree of flexibility in their respective peptidic scaffolds. PMID- 26227177 TI - Results of pediatric tympanoplasty on short-term surgical missions. AB - OBJECTIVES/HYPOTHESIS: To determine the safety and effectiveness of pediatric tympanoplasty performed on short-term international medical missions. STUDY DESIGN: Prospective observational study. METHODS: Ethiopian children who had dry or nearly dry tympanic perforations and bilateral conductive hearing losses underwent postauricular tympanoplasties with underlain temporalis fascia grafts. Pre- and postoperative air and bone audiometry was performed. Complications, graft success, hearing improvement, and dry ear at 6-month follow-up were evaluated. RESULTS: Patients were 7 to 25 years old (24 female ears, 20 male ears). The majority had subtotal perforations. Operative findings included ossicular erosions and fixation by hypertrophic mucosa. There were no major medical complications or deaths in this series. Of 44 ears, 27 had complete pre- and postoperative audiometric data. Twenty-four of 44 surgeries resulted in an intact tympanic membrane. Twelve of 44 markedly reduced the perforation. Eight of 44 grafts failed. The mean improvement in PTA was 14 dB (range = -6-45 dB). Human immunodeficiency virus (HIV)+ patients had a high rate of graft failure (3/4) and comprised 38% (3/8) of complete graft failures (P = .015). Among the 20 ears with residual perforations, 14 were dry at 6-month follow-up. Of the six ears with drainage, three were HIV+ (P = .019). CONCLUSIONS: Pediatric tympanoplasty is a safe procedure in a short-term surgical mission setting when high anesthetic and surgical standards are maintained. Surgical results were similar to those found in developing-world university hospitals, but were worse than in United States or European series. HIV+ children did worse than their HIV-/unknown peers, with a high rate of graft failure and persistent otorrhea. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1464-1469, 2016. PMID- 26227178 TI - Recurrent fusion transcripts detected by whole-transcriptome sequencing of 120 primary breast cancer samples. AB - Relatively few recurrent gene fusion events have been associated with breast cancer to date. In an effort to uncover novel fusion transcripts, we performed whole-transcriptome sequencing of 120 fresh-frozen primary breast cancer samples and five adjacent normal breast tissues using the Illumina HiSeq2000 platform. Three different fusion-detecting tools (deFuse, Chimerascan, and TopHatFusion) were used, and the results were compared. These tools detected 3,831, 6,630 and 516 fusion transcripts (FTs) overall. We primarily focused on the results obtained using the deFuse software. More FTs were identified from HER2 subtype breast cancer samples than from the luminal or triple-negative subtypes (P < 0.05). Seventy fusion candidates were selected for validation, and 32 (45.7%) were confirmed by RT-PCR and Sanger sequencing. Of the validated fusions, six were recurrent (found in 2 or more samples), three were in-frame (PRDX1-AKR1A1, TACSTD2-OMA1, and C2CD2-TFF1) and three were off-frame (CEACAM7-CEACAM6, CYP4X1 CYP4Z2P, and EEF1DP3-FRY). Notably, the novel read-through fusion, EEF1DP3-FRY, was identified and validated in 6.7% (8/120) of the breast cancer samples. This off-frame fusion results in early truncation of the FRY gene, which plays a key role in the structural integrity during mitosis. Three previously reported fusions, PPP1R1B-STARD3, MFGE8-HAPL, and ETV6-NTRK3, were detected in 8.3, 3.3, and 0.8% of the 120 samples, respectively, by both deFuse and Chimerascan. The recently reported MAGI3-AKT3 fusion was not detected in our analysis. Although future work will be needed to examine the biological significance of our new findings, we identified a number of novel fusions and confirmed some previously reported fusions. PMID- 26227179 TI - Analysis of Stereotactic Accuracy in Patients Undergoing Deep Brain Stimulation Using Nexframe and the Leksell Frame. AB - OBJECTIVE: To determine and compare the accuracy of Nexframe and the Leksell stereotactic frame in deep brain stimulation (DBS) procedures. BACKGROUND: The 'frameless' Nexframe uses bone fiducials rather than a head-mounted frame, which offers potential benefits for both the patient and the surgical team. Accuracy of lead implantation and factors affecting this accuracy are of crucial importance but have not been extensively studied for the frameless system. DESIGN/METHODS: The location of 194 (Leksell frame, n = 116; Nexframe, n = 78) DBS leads was determined on postoperative MRI. Obtained stereotactic coordinates were compared with expected intraoperative target coordinates. Resulting absolute errors in the X (medial-lateral), Y (anterior-posterior), and Z (dorsal-ventral) coordinates (x0394;X, x0394;Y, and x0394;Z) were then used to calculate the vector error (VE). The vector error describes the total error in 3-D space and represents our main outcome measure. RESULTS: The vector error (mean +/- SD) was 2.8 +/- 1.3 for Nexframe and 2.5 +/- 1.2 for the Leksell frame (p = 0.43). For Nexframe, absolute X, Y, and Z errors were 1.4 +/- 1.3, 1.7 +/- 1.2, and 1.0 +/- 0.9 mm. For the Leksell frame, the absolute X, Y, and Z errors were 1.4 +/- 1.0, 1.2 +/- 1.0, and 1.3 +/- 0.9 mm. On the anterior-posterior plane (Y coordinate), the Leksell frame was more accurate than Nexframe (p = 0.04). In contrast, Nexframe was more accurate on the dorsal-ventral plane (Z coordinate) (p = 0.04). There was no difference in accuracy between the two methods on the medial-lateral plane (X coordinate). CONCLUSION: This comparison of Nexframe and the Leksell frame shows that both techniques have equivalent overall 3-D accuracy. PMID- 26227180 TI - Role of Exercise in the Activation of Brown Adipose Tissue. AB - BACKGROUND: The energy-burning capacity of brown adipose tissue (BAT) makes it an attractive target for use in anti-obesity therapies. Moreover, due to its ability to oxidize glucose and lipids, BAT activation has been considered a potential therapy to combat type 2 diabetes and atherogenesis. SUMMARY: BAT is mainly regulated by the sympathetic nervous system (SNS); yet, recent findings have shown a group of novel activators that act independently of the stimulation of the SNS such as cardiac natriuretic peptides, irisin, interleukin-6, beta aminoisobutyric acid and fibroblast growth factor 21 that could influence BAT metabolism. Several strategies are being examined to activate and recruit BAT with no side effects. In this review, we postulate that exercise might activate and recruit human BAT through the activation of SNS, heart and skeletal muscle. KEY MESSAGES: Epidemiological and well-designed exercise-based randomized controlled studies are needed to clarify if exercise is able to activate BAT in humans. PMID- 26227181 TI - Slow-growing tumor of the nail. PMID- 26227183 TI - Solvent extraction separation of copper and zinc from MSWI fly ash leachates. AB - Fly ash from combustion of municipal solid waste (MSW) contains significant amounts of metals, some of which are valuable and some of which are potentially toxic. This type of ash is most often stabilized and landfilled which means that the metals will be difficult to reclaim at a later stage. In recent years efforts have been made to develop feasible methods to recover selected metals, such as Zn, from MSW fly ash. If this would be possible, a significant amount of valuable metals could be re-inserted in the industrial material loops. This paper describes the development and evaluation of a process for recovery of Cu and Zn from MSW combustion fly ash based on hydrochloric acid leaching followed by two solvent extraction processes, one for each metal. The separation of Cu from the acid leachate was done using an aldoxime extractant, LIX860N-I, in kerosene and a mixture of phosphine oxides, Cyanex 923, also in kerosene, was used for extraction of Zn from the Cu-depleted aqueous phase. The extraction of Cu was selective, but a significant amount of other metals, such as Fe and Pb, were co extracted together with Zn. It was shown that it is possible to decrease the contamination of Fe by using a suitable concentration of nitric acid solution for stripping or by removing the contaminating metals through cementation. The suggested process was tested for two MSW combustion fly ashes in laboratory scale experiments and gave Cu yields of 69-87% and Zn yields of 75-80% based on the contents in the ash. PMID- 26227182 TI - Developmental Changes in Genetic and Shared Environmental Contributions to Smoking Initiation and Subsequent Smoking Quantity in Adolescence and Young Adulthood. AB - BACKGROUND: Few studies examining the genetic architecture of cigarette smoking have focused on adolescents or examined developmental changes in additive genetic, shared environment, and unique environmental influences on liability to initiate cigarette smoking and quantity of cigarettes smoked. The aim of this study was to add to the literature on liability to initiate and use cigarettes during adolescence using a nationally representative sample. METHOD: Data for this study came from adolescent and young adult twin pairs (aged 14-33 years) from the National Longitudinal Study of Adolescent to Adult Health. We ran a series of developmental causal-contingent-common pathway models to examine whether additive genetic, shared, and unique environmental influences on liability to the initiation of cigarette use are shared with those on smoking quantity, and whether their contributions change across development. RESULTS: We found evidence for a developmental shift in genetic and shared environmental contributions to cigarette use. Early in adolescence, genetic and environmental influences work independently on liability to cigarette smoking initiation and quantity of cigarettes smoked, but liability to these behaviors becomes correlated as individuals age into young adulthood. CONCLUSIONS: These findings provide insight into the causal processes underlying the liability to smoke cigarettes. With age, there is greater overlap in the genetic and environmental factors that influence the initiation of cigarette smoking and quantity of cigarettes smoked. PMID- 26227184 TI - Nano-sized Mn oxides on halloysite or high surface area montmorillonite as efficient catalysts for water oxidation with cerium(iv) ammonium nitrate: support from natural sources. AB - We used halloysite, a nano-sized natural mineral, and high surface area montmorillonite as supports for nano-sized Mn oxides to synthesize efficient water-oxidising catalysts. The composites were synthesized by an easy and simple procedure, and characterized by scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, and X-ray diffraction spectrometry. Halloysite has low amounts of hydroxyl groups on its surface, thus it causes better dispersion of Mn oxides. The water-oxidising activities of these composites were also measured in the presence of cerium(iv) ammonium nitrate. Considering the low-cost, environmentally friendly precursors, simple synthesis and efficiency for water oxidation, the composites are promising catalysts in artificial photosynthetic systems. PMID- 26227185 TI - Quantitative Risk Assessment of Human Trichinellosis Caused by Consumption of Pork Meat Sausages in Argentina. AB - In Argentina, there are three known species of genus Trichinella; however, Trichinella spiralis is most commonly associated with domestic pigs and it is recognized as the main cause of human trichinellosis by the consumption of products made with raw or insufficiently cooked pork meat. In some areas of Argentina, this disease is endemic and it is thus necessary to develop a more effective programme of prevention and control. Here, we developed a quantitative risk assessment of human trichinellosis following pork meat sausage consumption, which may be used to identify the stages with greater impact on the probability of acquiring the disease. The quantitative model was designed to describe the conditions in which the meat is produced, processed, transported, stored, sold and consumed in Argentina. The model predicted a risk of human trichinellosis of 4.88 * 10(-6) and an estimated annual number of trichinellosis cases of 109. The risk of human trichinellosis was sensitive to the number of Trichinella larvae that effectively survived the storage period (r = 0.89), the average probability of infection (PPinf ) (r = 0.44) and the storage time (Storage) (r = 0.08). This model allowed assessing the impact of different factors influencing the risk of acquiring trichinellosis. The model may thus help to select possible strategies to reduce the risk in the chain of by-products of pork production. PMID- 26227187 TI - Ezetimibe and Plaque Regression: Cholesterol Lowering or Pleiotropic Effects? PMID- 26227188 TI - 10-Year Mortality Outcome of a Routine Invasive Strategy Versus a Selective Invasive Strategy in Non-ST-Segment Elevation Acute Coronary Syndrome: The British Heart Foundation RITA-3 Randomized Trial. AB - BACKGROUND: The RITA-3 (Third Randomised Intervention Treatment of Angina) trial compared outcomes of a routine early invasive strategy (coronary arteriography and myocardial revascularization, as clinically indicated) to those of a selective invasive strategy (coronary arteriography for recurrent ischemia only) in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). At a median of 5 years' follow-up, the routine invasive strategy was associated with a 24% reduction in the odds of all-cause mortality. OBJECTIVES: This study reports 10-year follow-up outcomes of the randomized cohort to determine the impact of a routine invasive strategy on longer-term mortality. METHODS: We randomized 1,810 patients with NSTEACS to receive routine invasive or selective invasive strategies. All randomized patients had annual follow-up visits up to 5 years, and mortality was documented thereafter using data from the Office of National Statistics. RESULTS: Over 10 years, there were no differences in mortality between the 2 groups (all-cause deaths in 225 [25.1%] vs. 232 patients [25.4%]: p = 0.94; and cardiovascular deaths in 135 [15.1%] vs. 147 patients [16.1%]: p = 0.65 in the routine invasive and selective invasive groups, respectively). Multivariate analysis identified several independent predictors of 10-year mortality: age, previous myocardial infarction, heart failure, smoking status, diabetes, heart rate, and ST-segment depression. A modified post-discharge Global Registry of Acute Coronary Events (GRACE) score was used to calculate an individual risk score for each patient and to form low-risk, medium-risk, and high-risk groups. Risk of death within 10 years varied markedly from 14.4 % in the low-risk group to 56.2% in the high-risk group. This mortality trend did not depend on the assigned treatment strategy. CONCLUSIONS: The advantage of reduced mortality of routine early invasive strategy seen at 5 years was attenuated during later follow-up, with no evidence of a difference in outcome at 10 years. Further trials of contemporary intervention strategies in patients with NSTEACS are warranted. (Third Randomised Intervention Treatment of Angina trial [RITA-3]; ISRCTN07752711). PMID- 26227189 TI - The Early Invasive Strategy in Acute Coronary Syndromes: Should the Guideline Recommendations Be Revisited? PMID- 26227186 TI - Impact of Dual Lipid-Lowering Strategy With Ezetimibe and Atorvastatin on Coronary Plaque Regression in Patients With Percutaneous Coronary Intervention: The Multicenter Randomized Controlled PRECISE-IVUS Trial. AB - BACKGROUND: Despite standard statin therapy, a majority of patients retain a high "residual risk" of cardiovascular events. OBJECTIVES: The aim of this study was to evaluate the effects of ezetimibe plus atorvastatin versus atorvastatin monotherapy on the lipid profile and coronary atherosclerosis in Japanese patients who underwent percutaneous coronary intervention (PCI). METHODS: This trial was a prospective, randomized, controlled, multicenter study. Eligible patients who underwent PCI were randomly assigned to atorvastatin alone or atorvastatin plus ezetimibe (10 mg) daily. Atorvastatin was uptitrated with a treatment goal of low-density lipoprotein cholesterol (LDL-C) <70 mg/dl. Serial volumetric intravascular ultrasound was performed at baseline and again at 9 to 12 months to quantify the coronary plaque response in 202 patients. RESULTS: The combination of atorvastatin/ezetimibe resulted in lower levels of LDL-C than atorvastatin monotherapy (63.2 +/- 16.3 mg/dl vs. 73.3 +/- 20.3 mg/dl; p < 0.001). For the absolute change in percent atheroma volume (PAV), the mean difference between the 2 groups (-1.538%; 95% confidence interval [CI]: -3.079% to 0.003%) did not exceed the pre-defined noninferiority margin of 3%, but the absolute change in PAV did show superiority for the dual lipid-lowering strategy (-1.4%; 95% CI: -3.4% to -0.1% vs. -0.3%; 95% CI: -1.9% to 0.9% with atorvastatin alone; p = 0.001). For PAV, a significantly greater percentage of patients who received atorvastatin/ezetimibe showed coronary plaque regression (78% vs. 58%; p = 0.004). Both strategies had acceptable side effect profiles, with a low incidence of laboratory abnormalities and cardiovascular events. CONCLUSIONS: Compared with standard statin monotherapy, the combination of statin plus ezetimibe showed greater coronary plaque regression, which might be attributed to cholesterol absorption inhibition-induced aggressive lipid lowering. (Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound [PRECISE-IVUS]; NCT01043380). PMID- 26227191 TI - Ejection Fraction Improvement After Primary Prevention Defibrillator Implantation: How Much Is Enough? PMID- 26227190 TI - Changes in Follow-Up Left Ventricular Ejection Fraction Associated With Outcomes in Primary Prevention Implantable Cardioverter-Defibrillator and Cardiac Resynchronization Therapy Device Recipients. AB - BACKGROUND: Heart failure patients with primary prevention implantable cardioverter-defibrillators (ICD) may experience an improvement in left ventricular ejection fraction (LVEF) over time. However, it is unclear how LVEF improvement affects subsequent risk for mortality and sudden cardiac death. OBJECTIVES: This study sought to assess changes in LVEF after ICD implantation and the implication of these changes on subsequent mortality and ICD shocks. METHODS: We conducted a prospective cohort study of 538 patients with repeated LVEF assessments after ICD implantation for primary prevention of sudden cardiac death. The primary endpoint was appropriate ICD shock defined as a shock for ventricular tachyarrhythmias. The secondary endpoint was all-cause mortality. RESULTS: Over a mean follow-up of 4.9 years, LVEF decreased in 13.0%, improved in 40.0%, and was unchanged in 47.0% of the patients. In the multivariate Cox models comparing patients with an improved LVEF with those with an unchanged LVEF, the hazard ratios were 0.33 (95% confidence interval: 0.18 to 0.59) for mortality and 0.29 (95% confidence interval: 0.11 to 0.78) for appropriate shock. During follow up, 25% of patients showed an improvement in LVEF to >35% and their risk of appropriate shock decreased but was not eliminated. CONCLUSIONS: Among primary prevention ICD patients, 40.0% had an improved LVEF during follow-up and 25% had LVEF improved to >35%. Changes in LVEF were inversely associated with all-cause mortality and appropriate shocks for ventricular tachyarrhythmias. In patients whose follow-up LVEF improved to >35%, the risk of an appropriate shock remained but was markedly decreased. PMID- 26227192 TI - Glycemic Control in Type 1 Diabetes and Long-Term Risk of Cardiovascular Events or Death After Coronary Artery Bypass Grafting. AB - BACKGROUND: Patients with type 1 diabetes mellitus (T1DM) have a high risk of cardiovascular events. OBJECTIVES: The aim of this study was to investigate whether preoperative hemoglobin A1c (HbA1c) levels could predict cardiovascular events or death after coronary artery bypass grafting (CABG). METHODS: This was a nationwide population-based observational cohort study that included all patients with T1DM who underwent primary isolated nonemergency CABG in Sweden between 1997 and 2012, according to the Swedish National Diabetes Register and the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) register. We calculated the crude incidence rates and 95% confidence intervals (CIs) and used Cox regression and multivariable hazard ratios (HRs) to estimate the risk of both all-cause mortality and major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, heart failure, or repeat revascularization, in relation to HbA1c levels. RESULTS: In total, 764 patients with T1DM were included. During a median follow-up of 4.7 years, 334 (44%) patients died or had MACE (incidence rate: 82 events/1,000 person-years). After multivariable adjustment, the HR (95% CI) for death or MACE in patients with HbA1c levels of 7.1% to 8.0%, 8.1% to 9.0%, 9.1% to 10.0%, and >10.0% were 1.34 (0.82 to 2.21), 1.59 (1.00 to 2.54), 1.73 (1.03 to 2.90), and 2.25 (1.29 to 3.94), respectively, compared with the reference category. When HbA1c was used as a continuous variable, the HR for a 1% increase in HbA1c level was 1.18, and the 95% CI was 1.06 to 1.32. CONCLUSIONS: In patients with T1DM, poor glycemic control before CABG was associated with increased long-term risk of death or MACE. (HeAlth-data Register sTudies of Risk and Outcomes in Cardiac Surgery [HARTROCS]; NCT02276950). PMID- 26227193 TI - The Potential of Learning Health Care Systems: The SWEDEHEART Example. PMID- 26227194 TI - Improved Detection of Cardiac Allograft Vasculopathy: A Multi-Institutional Analysis of Functional Parameters in Pediatric Heart Transplant Recipients. AB - BACKGROUND: Recent guidelines recommend assessment of systolic function and filling pressures to augment angiographic grading of cardiac allograft vasculopathy (CAV); however, no data exist on the utility of these guidelines. OBJECTIVES: The aims of this study were to evaluate whether the assessment of systolic and diastolic graft function, in addition to angiography, improves recognition of patients at high risk of graft loss and to assess the ability of adult filling-pressure thresholds to discriminate graft dysfunction in pediatric patients. METHODS: This study reviewed Pediatric Heart Transplant Study data from 1993 to 2009. Graft dysfunction was defined as significant systolic dysfunction (ejection fraction [EF] <45%) or the presence of restrictive hemodynamic features. Additional pediatric hemodynamic cutpoints of right atrial pressure (RAP) >12 mm Hg or pulmonary capillary wedge pressure (PCWP) >15 mm Hg were analyzed. RESULTS: In the study, 8,122 angiograms were performed in 3,120 patients, and 70% of patients had at least 1 angiogram. Angiographic incidence of CAV was 5%, 15%, and 28% at 2, 5, and 10 years, respectively, and most disease was mild. The presence of graft dysfunction identified patients at greater risk for graft loss even in children with mild angiographic vasculopathy (p < 0.0001). An RAP >12 mm Hg or a PCWP >15 mm Hg was sufficient to detect patients at high risk of graft loss even with mild angiographic disease. CONCLUSIONS: Patients with only mild angiographic CAV have significantly better outcomes than do patients with moderate or severe disease. The presence of an EF <45%, an RAP >12 mm Hg, or a PCWP >15 mm Hg identifies children at increased risk of graft loss even in the presence of only mild angiographic vasculopathy. PMID- 26227195 TI - Pediatric Heart Transplant Recipients and Cardiac Allograft Vasculopathy: The Importance of Hemodynamics. PMID- 26227196 TI - Calcification in Aortic Stenosis: The Skeleton Key. AB - Aortic stenosis is a common, potentially fatal condition that is set to become an increasing public health burden. Once symptoms develop, there is an inexorable deterioration with a poor prognosis. Despite this, there are no medical therapies capable of modifying disease progression, and the only available treatment is aortic valve replacement, to which not all patients are suited. Conventional teaching suggests that aortic stenosis is a degenerative condition whereby "wear and tear" leads to calcium deposition within the valve. Although mechanical stress and injury are important factors, it is becoming increasingly appreciated that aortic stenosis is instead governed by a highly complex, regulated pathological process with similarities to skeletal bone formation. This review discusses the pathophysiology of aortic stenosis with an emphasis on the emerging importance of calcification, how this can be visualized and monitored using noninvasive imaging, and how our improved knowledge may ultimately translate into novel disease-modifying treatments. PMID- 26227197 TI - Isolated Noncompaction of the Left Ventricle in Adults. AB - Isolated left ventricular noncompaction (ILVNC) is a cardiomyopathy that was first described in 1926 as a "spongy myocardium." The disorder results from intrauterine arrest of compaction of the loose interwoven meshwork of the fetal myocardial primordium and subsequent persistence of deep trabecular recesses in the myocardial wall. The classical clinical presentation is a triad of heart failure, arrhythmias, and embolic events from mural thrombi. ILVNC has been associated with several autosomal dominant, X-linked, and mitochondrial genetic mutations that are also shared among other cardiomyopathies. Over the past decade, ILVNC has been subject to intensive research, as it increases the risk for sudden cardiac death. This review focuses on the current understanding of ILVNC in adult populations and attempts to provide organized insight into the disease process, screening, diagnosis, management, role of device therapy, and prognosis. PMID- 26227198 TI - HIV and Heart Disease in Africa. PMID- 26227199 TI - A Company of Equals: Success Through Friendship in Fellowship. PMID- 26227200 TI - Impact of Secondhand Smoke Exposure on Smoking Cessation in Cardiac Patients. PMID- 26227201 TI - The Weekend Effect: Does the Type of Myocardial Infarction Impact Management and Outcomes? PMID- 26227202 TI - Reply: The Weekend Effect: Does the Type of Myocardial Infarction Impact Management and Outcomes? PMID- 26227203 TI - High Flow Velocity and Low Systolic Pressure: Compliance of the Aortic Wall or Venturi Effect Within. PMID- 26227204 TI - Reply: High Flow Velocity and Low Systolic Pressure: Compliance of the Aortic Wall or Venturi Effect Within. PMID- 26227205 TI - Erratum. PMID- 26227206 TI - Pre-activated human mesenchymal stromal cells in combination with doxorubicin synergistically enhance tumor-suppressive activity in mice. AB - BACKGROUND AIMS: Previously, we showed that human mesenchymal stromal cells (hMSCs) were activated to express tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) upon TNF-alpha stimulation, induced cell death in triple negative breast cancer (TNBC) MDA-MB-231 cells (MDA), and RNA released from apoptotic MDA further increased TRAIL expression in hMSCs. This feed-forward stimulation increased apoptosis in MDA cells. Here, we tested whether TRAIL expressing hMSCs, in combination with a sub-toxic-dose of a chemotherapy drug doxorubicin, would overcome TRAIL resistance and create synergistic effects on targeting metastatic TNBC. METHODS: To optimize conditions for the combination treatment, we (i) selected an optimal condition to activate hMSCs for TRAIL expression, (ii) selected an optimal dose of doxorubicin treatment, (iii) examined underlying mechanisms in vitro and (iv) tested the efficacy of the optimized conditions in a xenograft mouse model of human breast cancer lung metastasis. RESULTS: The results showed that DNA fragments from apoptotic MDA triggered hMSCs to increase further TRAIL expression in an absent in melanoma 2 (AIM2)-dependent manner, and thus higher TRAIL-expressing hMSCs stimulated with synthetic DNA, poly(deoxyadenylic-deoxythymidylic) acid [poly(dA:dT)], more effectively suppressed tumor progression in vivo. Furthermore, activated hMSCs increased apoptosis in MDA cells when combined with a sub-toxic dose of doxorubicin, which was mediated by up-regulating TRAIL and Fas-related pathways. When we combined the optimized conditions, pre-activated hMSCs with poly (dA:dT) synergistically reduced tumor burden even with minimal doxorubicin treatment in a xenograft mouse model of human breast cancer lung metastasis. CONCLUSIONS: These results suggest that the treatment of hMSCs with a sub-toxic dose of doxorubicin can overcome TRAIL resistance and be a potential novel therapy for TNBC metastasis treatment. PMID- 26227207 TI - Adherence and barriers to colorectal cancer screening varies among Arab Americans from different countries of origin. AB - BACKGROUND AND STUDY AIMS: Arab-Americans (ArA) in Michigan, USA had the lowest colorectal cancer screening (CRCS) in 2008 compared to the state's general population (45.6% vs. 60.8%). The adherence rate and barriers to CRCS have been identified in a previous study; however, these differences have been not examined among ArA from different countries of origin. PATIENTS AND METHODS: Community based study through a survey filled by 130 Arab-Americans aged ?50years. Demographic information and information about CRC screening knowledge were obtained. Responses were compared between the two largest population groups (Lebanese and Yemenis). RESULTS: The majority of the participants (80%) were from Lebanon (52.3%) and Yemen (27.7%). Majority of the Yemenis group have never been screened for CRC (72.2% vs. 27.9%, p<0.001). Majority of the unscreened Yemenis were males (100% vs. 63.2%, p=0.002). Both unscreened groups had similar length of residence in U.S., citizenship status, education level, health insurance and access to primary care physicians. Unscreened Lebanese had a higher family history of CRCS (31.6% vs. 0%, p=0.002). The most common reported barrier for both groups was the misconception that CRCS is not necessary (62% for Yemenis & 42% for Lebanese, p=0.197). Unscreened Yemenis were more unaware about CRCS (46% vs. 11%, p=0.002). CONCLUSION: CRC screening rates vary among Arab-Americans from different countries of origin. Physicians should consider the country of origin when recommending CRC screening to Arab-Americans. PMID- 26227208 TI - Intimate Partner Violence Detection and Care in the Veterans Health Administration: Patient and Provider Perspectives. AB - BACKGROUND: Women veterans experience high rates of intimate partner violence (IPV), with associated negative health impacts. The Veterans Health Administration (VHA) has recently developed plans to implement routine IPV screening and provide IPV-related follow-up services for VHA patients. Previous research has examined barriers and facilitators to health care provider screening for IPV. The next step is to examine patients' disclosure of IPV experiences to health care providers and effective response to such disclosures. We sought to identify VHA patients' and providers' perspectives on how to facilitate effective IPV detection and care in VHA. METHODS: We conducted semistructured, qualitative interviews with 25 female veteran patients and 15 VHA health care providers. We used an inductive approach to analyzing interview transcripts and identifying themes that constituted study findings. RESULTS: Themes fell in to two broad categories: 1) barriers to disclosure and 2) barriers to an adequate response to disclosure and providing follow-up care. Barriers to disclosure of IPV to health care providers included lack of provider inquiry, lack of comfort, and concerns about the consequences of disclosure and lack of privacy. Patients and providers both indicated a need for expanded resources to respond to IPV in VHA. CONCLUSIONS: Findings support current plans for IPV program implementation in VHA and point to recommendations for practice and implications for further research. PMID- 26227210 TI - Wavelength resolved specific optical rotations and homochiral equilibria. AB - The fundamental expressions governing specific optical rotations (SORs) of homochiral systems exhibiting monomer-dimer equilibria are presented. These equations are then utilized with the experimental measurements of wavelength resolved circular birefringence for (R)-(-)-alpha-hydroxy-beta,beta-dimethyl gamma-butyrolactone, to determine the wavelength resolved SORs of monomer and dimer components for the first time. Density functional theory predictions on the corresponding dispersion properties of monomer and dimer are found to match with experimentally determined quantities within a factor of ~2. The wavelength resolved circular birefringence in the liquid solution phase thus provides a powerful means to investigate the molecular properties involved in homochiral equilibria. PMID- 26227209 TI - The Association between Adverse Childhood Experiences and Alcohol Use during Pregnancy in a Representative Sample of Adult Women. AB - BACKGROUND: The impact of adverse childhood experiences (ACEs) on adult alcohol consumption is well-established, but little is known about the association with alcohol use during pregnancy. METHODS: Using data from the 2010 Nevada Behavioral Risk Factor Surveillance System, we assessed the relationship between ACEs and alcohol use during pregnancy in a representative sample of 1,987 adult women. An established ACEs scale was used to assess a range of childhood physical, emotional, and sexual abuse and household dysfunction (range, 0-8). Weighted logistic regression was used to assess the relationship between ACE scores and alcohol use during pregnancy after controlling for drinking before pregnancy and other covariates. RESULTS: Six percent of participants reported drinking alcohol during pregnancy. After controlling for race/ethnicity, age, employment status, smoking status, and prepregnancy alcohol use, increasing ACEs were positively associated with higher odds of alcohol use during pregnancy (1 ACE: adjusted odds ratio [AOR], 2.92; 95% CI, 1.08-7.87), (2-3 ACEs: AOR, 3.52; 95% CI, 1.46-8.48), and (>=4 ACEs: AOR, 4.79; 95% CI, 2.14-10.72). Prepregnancy drinking was also strongly associated with alcohol use during pregnancy (AOR, 11.95; 95% CI, 5.02 28.43). CONCLUSIONS: We found evidence of a dose-response relationship between ACEs and alcohol use during pregnancy that remained even after controlling for prepregnancy drinking and other covariates. Screening women of childbearing age as well as pregnant women for ACEs may be an effective way to identify and address many of the emotional, behavioral, and physical sequelae of childhood adversity. PMID- 26227211 TI - Elucidating discrepant results in a prenatal diagnosis of 48,XXY,+18 (Edwards and Klinefelter syndromes). PMID- 26227212 TI - Microprocessor-based integration of microfluidic control for the implementation of automated sensor monitoring and multithreaded optimization algorithms. AB - Microfluidic applications range from combinatorial synthesis to high throughput screening, with platforms integrating analog perfusion components, digitally controlled micro-valves and a range of sensors that demand a variety of communication protocols. Currently, discrete control units are used to regulate and monitor each component, resulting in scattered control interfaces that limit data integration and synchronization. Here, we present a microprocessor-based control unit, utilizing the MS Gadgeteer open framework that integrates all aspects of microfluidics through a high-current electronic circuit that supports and synchronizes digital and analog signals for perfusion components, pressure elements, and arbitrary sensor communication protocols using a plug-and-play interface. The control unit supports an integrated touch screen and TCP/IP interface that provides local and remote control of flow and data acquisition. To establish the ability of our control unit to integrate and synchronize complex microfluidic circuits we developed an equi-pressure combinatorial mixer. We demonstrate the generation of complex perfusion sequences, allowing the automated sampling, washing, and calibrating of an electrochemical lactate sensor continuously monitoring hepatocyte viability following exposure to the pesticide rotenone. Importantly, integration of an optical sensor allowed us to implement automated optimization protocols that require different computational challenges including: prioritized data structures in a genetic algorithm, distributed computational efforts in multiple-hill climbing searches and real-time realization of probabilistic models in simulated annealing. Our system offers a comprehensive solution for establishing optimization protocols and perfusion sequences in complex microfluidic circuits. PMID- 26227213 TI - Rapid homogeneous endothelialization of high aspect ratio microvascular networks. AB - Microvascularization of an engineered tissue construct is necessary to ensure the nourishment and viability of the hosted cells. Microvascular constructs can be created by seeding the luminal surfaces of microfluidic channel arrays with endothelial cells. However, in a conventional flow-based system, the uniformity of endothelialization of such an engineered microvascular network is constrained by mass transfer of the cells through high length-to-diameter (L/D) aspect ratio microchannels. Moreover, given the inherent limitations of the initial seeding process to generate a uniform cell coating, the large surface-area-to-volume ratio of microfluidic systems demands long culture periods for the formation of confluent cellular microconduits. In this report, we describe the design of polydimethylsiloxane (PDMS) and poly(glycerol sebacate) (PGS) microvascular constructs with reentrant microchannels that facilitates rapid, spatially homogeneous endothelial cell seeding of a high L/D (2 cm/35 MUm; > 550:1) aspect ratio microchannels. MEMS technology was employed for the fabrication of a monolithic, elastomeric, reentrant microvascular construct. Isotropic etching and PDMS micromolding yielded a near-cylindrical microvascular channel array. A 'stretch - seed - seal' operation was implemented for uniform incorporation of endothelial cells along the entire microvascular area of the construct yielding endothelialized microvascular networks in less than 24 h. The feasibility of this endothelialization strategy and the uniformity of cellularization were established using confocal microscope imaging. PMID- 26227214 TI - Mesenchymal stromal cells improve early lymphocyte recovery and T cell reconstitution after autologous hematopoietic stem cell transplantation in patients with malignant lymphomas. AB - Mesenchymal stromal cells (MSCs) possess a multi-lineage potential and immunoregulatory activities and provide a great potential in cell-based technologies. However, MSC suppressive activity raises concerns regarding the possible adverse effect of MSCs on the immune recovery. The influence of autologous MSC co-transplantation on recovery of T cell subsets in patients receiving autologous hematopoietic stem cell transplantation (AHSCT) for malignant lymphomas and multiple myeloma were characterized. Co-transplantation of MSCs improved lymphocyte recovery most effectively in patients with low input of hematopoietic stem cells or low absolute lymphocyte count in apheresis product. MSC co-transplantation improved early recovery of both memory and naive T cells with more prominent effect on naive CD4(+) T cells. Patients with MSC co transplantation showed more effective reconstitution of recent thymic emigrants. These data indicate the positive impact of MSCs on immune reconstitution and note MSC co-transplantation is feasible to optimize the outcomes of AHSCT in malignant lymphoma patients. PMID- 26227215 TI - Thermoresponsive latexes for fragrance encapsulation and release. AB - OBJECTIVE: To synthesize cross-linked latex particles protecting the encapsulated fragrance at ambient temperatures and facilitating the release of cargo at the temperature of the surface of the skin that varies in different regions of the body between 33.5 and 36.9 degrees C. Poly(stearyl acrylate) (PSA), a polymer with long crystallizable alkyl side chains (undergoes order-disorder transitions at 45 degrees C), was chosen as the main component of the polymer particles. As a result, new thermoresponsive polymer particles for fragrance encapsulation were synthesized and characterized, including assessing the performance of particles in triggered release by elevated temperature. METHODS: To obtain network domains of various crystallinity, stearyl acrylate was copolymerized with dipropylene glycol acrylate caprylate (DGAC) (comonomer) in the presence of a dipropylene glycol diacrylate sebacate (cross-linker) using the miniemulsion process. Comonomers and a cross-linker were mixed directly in a fragrance during polymerization. Fragrance release was evaluated at 25, 31, 35 and 39 degrees C to demonstrate a new material potential in personal/health care skin-related applications. RESULTS: Particles protect the fragrance from evaporation at 25 degrees C. The fragrance release rate gradually increases at 31, 35 and 39 degrees C. Two slopes were found on release plots. The first slope corresponds to a rapid fragrance release. The second slope indicates a subsequent reduction in the release rate. CONCLUSION: Crystalline-to-amorphous transition of PSA triggers the release of fragrances from cross-linked latex particles at elevated temperatures. The presence of the encapsulated fragrance, as well as the inclusion of amorphous fragments in the polymer network, reduces the particle crystallinity and enhances the release. Release profiles can be tuned by temperature and controlled by the amount of loaded fragrance and the ratio of comonomers in the feed mixture. PMID- 26227216 TI - Differences in biomass degradation between newly isolated environmental strains of Clostridium thermocellum and heterogeneity in the size of the cellulosomal scaffoldin. AB - Cellulolytic bacterial strains with high activity were isolated from cellulose degrading enrichment cultures derived from thermophilic biogas plants and environmental samples. The 16S rRNA gene sequences of the strains revealed >99.8% sequence identity and affiliation with the species Clostridium thermocellum. The strains differed in their ability to degrade crystalline cellulose, especially at an elevated temperature of up to 67 degrees C and at relatively low pH values (pH 6.5). To evaluate the influence of amino acid sequences on the discrepancies in cellulose degradation efficacy, the gene for the major cellulosomal component CelR was sequenced for all strains. The sequences were found to be almost identical (>99%). In contrast, the cellulosomal scaffoldin gene cipA showed more differences in the amino acid sequence and contained 8 or 9 cohesin modules, which indicated a different size of the cellulosome depending on the isolate. Based on MALDI-TOF MS analysis the relative abundance of important cellulosomal enzyme classes was determined. The strains with better biomass degradation properties (BC1 and NB2) had a significantly higher fraction of xylanases. PMID- 26227217 TI - Impact of body mass index on clinico-pathological parameters and outcome in patients with metastatic prostate cancer. AB - BACKGROUND: This study evaluates the correlation between body mass index (BMI) and clinicopathological parameters of metastatic prostate cancer (MPC) and its impact on survival. METHOD: During the study period, 71 MPC patients were eligible. Patients with BMI<25.0kg/m(2) were categorized as level I and patients with BMI?25.0kg/m(2) were categorized as level II. Demographic features and survival rates were evaluated by the Kaplan-Meier method and Cox proportional models. RESULTS: 31 patients belonged to level I while the rest belonged to level II with insignificant higher median follow-up duration in level II; p=0.5. In terms of age, metastasis, serum level of albumin, prostatic specific antigen, alkaline phosphatase (AKP) and Gleason score, there was no significant difference between the two levels. The cumulative survival probability in the 12th, 24th and 36th month in level I vs; level II was; 86.7%, 68.7%, 64.1% vs; 74.4%, 67.7%, 55.1%, respectively with 7 patients dead in level I compared to 14 patients dead in level II denoting a higher PC-specific death rate in the level II group. In univariate and multivariate analysis, poor prognosis was associated with increasing AKP (HR=1.0005, 95% CI, p=0.03; HR=1.001, 95% CI, p=0.03) respectively, while better prognosis was associated with no visceral metastasis (HR=0.09, 95% CI, p=0.000; HR=0.04, 95% CI, p=0.000) and increasing albumin levels (HR=0.17, 95% CI, p=0.000; HR=0.15, 95% CI, p=0.000) respectively. In multivariate analysis only, patients belonging to level I were associated with better prognosis (HR=0.17, 95% CI, p=0.02). CONCLUSION: BMI is dependent on prognostic factors in patients with MPC. PMID- 26227218 TI - miR-125/Pokemon auto-circuit contributes to the progression of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a type of human malignant tumor occurring in hepatic tissues with high mortality. Patients benefit little from current therapeutic modalities, at least partially due to the lack of complete elucidation of molecular network regulating HCC. miR-125 and Pokemon are well recognized tumor suppressor and oncogenes for HCC, respectively. However, the underlying mechanism by which the two genes exert their functions and the relationship between miR-125 and Pokemon is still unexplored yet. In this study, we found that there is an inverse association between miR-125 and Pokemon expression levels in HCC specimen and cell lines. Online database mining indicated that there are three putative mRNA recognition elements (MREs) of miR 125 within 3' untranslated region (3'UTR) of Pokemon. MREs of miR-125 confer the expression of luciferase with a miR-125-dependent fashion. The alteration in miR 125 abundance regulates the expression of Pokemon at both protein and mRNA levels. Overexpression of Pokemon is able to abrogate the inhibitory effect of miR-125 on HCC progression. Further study showed that Pokemon inhibits the expression of miR-125 by binding of recognition sites within its promoter. In conclusion, we found that there is an auto-regulatory circuit consisting of miR 125 and Pokemon, which promotes the progression of HCC and may be a promising therapeutic target in clinical HCC treatment. PMID- 26227219 TI - Identification of carcinogenic potential-associated molecular mechanisms in CD133(+) A549 cells based on microRNA profiles. AB - This study aimed to identify carcinogenic potential-related molecular mechanisms in cancer stem cells (CSCs) in lung cancer. CD133(+) and CD133(-) subpopulations were sorted from A549 cells using magnetic-activated cell sorting. The abilities to form sphere and clone, proliferate, migrate, and invade were compared between CD133(+) and CD133(-) cells, as well as drug sensitivity. Thereafter, microRNA (miRNA) profiles were performed to identify differentially expressed miRNAs between CD133(+) and CD133(-) subpopulation. Following, bioinformatic methods were used to predict target genes for differentially expressed miRNAs and perform enrichment analysis. Furthermore, the mammalian target of rapamycin (mTOR) signaling pathways and CSC property-associated signaling pathways were explored and visualized in regulatory network among competitive endogenous RNA (ceRNA), miRNA, and target gene. CD133(+) subpopulation showed greater oncogenic potential than CD133(-) subpopulation. In all, 14 differentially expressed miRNAs were obtained and enriched in 119 pathways, including five upregulated (hsa-miR-23b 3p, -23a-3p, -15b-5p, -24-3p, and -4734) and nine downregulated (hsa-miR-1246, 30b-5p, -5096, -6510-5p, has-miR-7110-5p, -7641, -3197, -7108-5p, and -6791-5p). For mTOR signaling pathway, eight differential miRNAs (hsa-miR-23b-3p, -23a-3p, 15b-5p, -24-3p, -4734, -1246, -7641, and -3197) and 39 target genes (e.g., AKT1, AKT2, PIK3CB, PIK3CG, PIK3R1, PIK3CA, and PIK3CD) were involved, as well as some ceRNAs. Besides, for CSC property-related signaling pathways, six miRNAs (hsa-miR 1246, -15b-5p, -30b-5p, -3197, -4734, and -7110-5p) were dramatically enriched in Hedgehog, Notch, and Wnt signaling pathways via regulating 108 target genes (e.g., DVL1, DVL3, WNT3A, and WNT5A). The mTOR and CSC property-associated signaling pathways may be important oncogenic molecular mechanisms in CD133(+) A549 cells. PMID- 26227220 TI - Let-7a-3 hypomethylation is associated with favorable/intermediate karyotypes but not with survival in acute myeloid leukemia. AB - Aberrant methylation of let-7a-3 promoter has been observed in various malignancies. However, the clinical relevance of let-7a-3 methylation remains poorly known in acute myeloid leukemia (AML). This study was to investigate the let-7a-3 methylation status and to explore its clinical significance in AML. let 7a-3 promoter was significantly hypomethylated in AML patients compared to controls (median 4.51 vs 0.49) (P = 0.0003). Receiver operating characteristic curve (ROC) analysis discriminated all patients or cytogenetically normal patients from controls with an areas under the ROC curve (AUC) of 0.737 or 0.783, respectively (P < 0.001). Patients with favorable/intermediate karyotypes had significantly higher let-7a-3 unmethylation than controls. Patients with DNMT3A mutations had a trend of high level of let-7a-3 unmethylation than did those with wild-type DNMT3A (median 6.76 vs 3.66, P = 0.096). There was no significant difference in overall survival between patients with and without hypomethylated let-7a-3 (median 12 vs 5 months, P = 0.103). No correlation was observed between the level of let-7a-3 expression and let-7a-3 unmethylation in AML samples (R = 0.197, P = 0.150). However, the level of let-7a-3 expression was increased in a dose-dependent manner in THP-1 line treated with 5-aza-dC, while the methylation density of let-7a-3 promoter decreased with 5-aza-dC dose. Our findings suggest that let-7a-3 hypomethylation is associated with favorable and intermediate karyotypes but not a prognostic predictor for AML patients. Let-7a-3 expression may be partially regulated by promoter methylation. PMID- 26227221 TI - GPRC5A overexpression predicted advanced biological behaviors and poor prognosis in patients with gastric cancer. AB - G protein-coupled receptor, family C, group 5, member A (GPRC5A) had received attentions for its role in carcinogenesis and prognostic values in several types of cancer. However, the functional roles of GPRC5A in gastric cancer (GC) had never been elucidated. The expression levels of GPRC5A were detected by real-time quantitative reverse transcription PCR and Western blot in GC tissues and adjacent non-tumor tissues. GPRC5A expression in tissue sections of 106 GC samples was evaluated using immunohistochemistry. The staining results were compared with clinicopathological factors and to the prognosis of GC patients. The mRNA and protein expression levels of GPRC5A in gastric cancer tissues were higher than those in adjacent non-tumor tissues. Positive GPRC5A expression was significantly correlated with larger size of primary tumor, diffuse type (Lauren's classification), deeper serosal invasion, and more lymph node metastasis. In addition, Kaplan-Meier curve analysis demonstrated that GC patients with positive GPRC5A expression had poor prognosis than those with negative GPRC5A expression. GPRC5A expression was identified as an independent factor of the overall survival in GC patients by multivariate Cox analysis. Further, the overall survival difference existed between patients with GPRC5A positive and negative groups in GC patients with lymph node metastasis. Our results suggested that elevated levels of GPRC5A played significant roles in GC progression. GPRC5A could serve as a prognostic biomarker of GC. PMID- 26227223 TI - Management of pediatric primary spontaneous pneumothorax in a tertiary hospital. PMID- 26227222 TI - Synergistic action of 5Z-7-oxozeaenol and bortezomib in inducing apoptosis of Burkitt lymphoma cell line Daudi. AB - Treatment failure in cancer chemotherapy is largely due to the toxic effects of chemotherapeutic agents on normal cells/tissues. The proteasome inhibitor bortezomib has been successfully applied to treat multiple myeloma (MM), but there are some common adverse reactions in the clinic including peripheral neuropathy (PN). The TAK1 selective inhibitor 5Z-7-oxozeaenol has been widely studied in cancer therapy. Here, we investigated the potential synergy of bortezomib and 5Z-7-oxozeaenol in Burkitt's lymphoma (BL) cell lines. Cell viability assay showed that co-treatment of bortezomib at 8 nM, representing a one-eighth concentration for growth arrest, and 5Z-7-oxozeaenol at 2 MUM, a dose that exhibited insignificant cytotoxic effects, synergistically induced apoptosis in the cell line Daudi. In parallel with the increasing dose of the bortezomib, and 5Z-7-oxozeaenol at 0.5 MUM, lower colony formation efficiencies were seen in the cell line Daudi. Western blotting analysis verified that TAK1 inhibition by 5Z-7-oxozeaenol completely blocked JNK, p38, Erk, IKK, and IkappaB phosphorylation, which was almost instantly activated by TAK1 both directly or indirectly. Both agents synergistically prevented nuclear translocation of NF kappaB, a characteristic of NF-kappaB inactivation. Moreover, a synergistic effect of bortezomib and 5Z-7-oxozeaenol on Western blotting analysis and flow cytometry was disclosed. Collectively, our results indicated that the proteasome inhibitor bortezomib and the TAK1 inhibitor 5Z-7-oxozeaenol displayed synergy on inhibiting BL cell apoptosis by inhibiting NF-kappaB activity. PMID- 26227224 TI - A case of massive hemoptysis related to a smoking-history: an acquired form of the Dieulafoy's disease? AB - The hypervascularization of the bronquial wall, secondary to chronic bronchopulmonary inflammation is a bleeding etiology in smokers, but insufficient to explain certain massive recurrent cases. We report a case of a woman with a smoking history who presented a recurrent and massive hemoptysis. A diagnostic study with laboratory tests, bronchoscopy, computed tomography and echocardiogram did not identify the etiological cause. However, bronchial arteriography showed right and left bronchial tortuous and dilated arteries and demonstrated that a bronchovascular fistula was the origin of the hemoptysis. An acquired form of the Dieulafoy's disease in this context of a smoking history might justify such findings. Bronchial arteriography as a diagnostic method should be the preferred choice rather than bronchoscopy in these cases. PMID- 26227225 TI - Ancillary findings assessed by ventilation/perfusion tomography. Impact and clinical outcome in patients with suspected pulmonary embolism. AB - Ventilation/perfusion tomography (V/P SPECT) is a recommended method for diagnosing and follow-up of pulmonary embolism (PE). Moreover, it is possible to recognize other pathologies in addition to PE, such as pneumonia, COPD and left heart failure (LHF). The objective of this prospective study was to identify frequency of ancillary findings among patients with suspected PE. Patients, material, method: 331 consecutive patients with suspected PE were examined and classified with V/P SPECT. Patients were followed up clinically and by means of other laboratory tests. RESULTS: 80 patients had a normal V/P SPECT and no clinical consequences in the follow-up. PE had 104 patients: 23 of them had also additional findings. Among the remaining 147 patients, pneumonias were shown in 82, acute in 75 patients and 7 had chronic post inflammatory state. COPD was present in 42 patients, in 3 combined with pneumonia. Sign of LHF was observed in 10: in 7 the acute LHF diagnosis was established, 3 were classified as having a chronic cardiopulmonary disease. Furthermore, in 16 patients, the V/P pattern was suggestive of a tumour. The clinical outcomes were 6 lung tumours, 3 empyema, one sarcoidosis, 2 were unclarified and 4 were lost in the follow-up. CONCLUSION: V/P SPECT identifies a high prevalence of other cardiopulmonary diseases among patients with a clinical suspicion of PE. Ancillary findings with V/P SPECT clarified patients' symptoms and had an impact on the treatment. These findings were verified by a clinical outcome by the follow-up over three months. PMID- 26227226 TI - Qualitative novelty in seventeenth-century science: Hydrostatics from Stevin to Pascal. AB - Two works on hydrostatics, by Simon Stevin in 1586 and by Blaise Pascal in 1654, are analysed and compared. The contrast between the two serves to highlight aspects of the qualitative novelty involved in changes within science in the first half of the seventeenth century. Stevin attempted to derive his theory from unproblematic postulates drawn from common sense but failed to achieve his goal insofar as he needed to incorporate assumptions involved in his engineering practice but not sanctioned by his postulates. Pascal's theory went beyond common sense by introducing a novel concept, pressure. Theoretical reflection on novel experiments was involved in the construction of the new concept and experiment also provided important evidence for the theory that deployed it. The new experimental reasoning was qualitatively different from the Euclidean style of reasoning adopted by Stevin. The fact that a conceptualization of a technical sense of pressure adequate for hydrostatics was far from obvious is evident from the work of those, such as Galileo and Descartes, who did not make significant moves in that direction. PMID- 26227227 TI - The rationale behind Pierre Duhem's natural classification. AB - The central concern of this paper is the interpretation of Duhem's attitude towards physical theory. Based on his view that the classification of experimental laws yielded by theory progressively approaches a natural classification-a classification reflecting that of underlying realities-Duhem has been construed as a realist of sorts in recent literature. Here I argue that his positive attitude towards the theoretic classification of laws had rather to do with the pragmatic rationality of the physicist. Duhem's idea of natural classification was an intuitive idea in the mind of the physicist that had to be affirmed in order to justify the physicist's pursuit of theory. PMID- 26227228 TI - Border cases between autonomy and relevance: Economic sciences in Berlin--A natural experiment. AB - The faculty of economics at today's Humboldt University in Berlin, as no other institution of economics, has witnessed three radical ruptures in its history: in 1933, National Socialism replaced the pluralism prevailing in the Weimar Republic by imposing a "German economics"; after WWII, GDR authorities replaced this NS regime by imposing a Marxist imperative, which after the fall of the wall was replaced by the Western standards of neoclassical economics. In reconstructing these three reforms, institutional history can serve as a context in which questions about the political nature of economic knowledge can be answered that remain speculative in a conceptual context. I thus present a natural experiment in the political epistemology of economics: How do economists respond to, resist, and stabilize, changing political regimes? How do economists renegotiate the autonomy of economic knowledge given changing demands as of its social task? Among others, I show that contrary to Robert Merton's old, but still widely held thesis in political epistemology-that the values of science are compatible only with democratic regimes-the totalitarian and authoritarian regimes created better conditions for methodological pluralism in economics than democratic society. PMID- 26227229 TI - A tale of three theories: Feyerabend and Popper on progress and the aim of science. AB - In this paper, three theories of progress and the aim of science are discussed: (i) the theory of progress as increasing explanatory power, advocated by Popper in The logic of scientific discovery (1935/1959); (ii) the theory of progress as approximation to the truth, introduced by Popper in Conjectures and refutations (1963); (iii) the theory of progress as a steady increase of competing alternatives, which Feyerabend put forward in the essay "Reply to criticism. Comments on Smart, Sellars and Putnam" (1965) and defended as late as the last edition of Against method (1993). It is argued that, contrary to what Feyerabend scholars have predominantly assumed, Feyerabend's changing attitude towards falsificationism-which he often advocated at the beginning of his career, and vociferously attacked in the 1970s and 1980s-must be explained by taking into account not only Feyerabend's very peculiar view of the aim of science, but also Popper's changing account of progress. PMID- 26227230 TI - Who let the demon out? Laplace and Boscovich on determinism. AB - In this paper, I compare Pierre-Simon Laplace's celebrated formulation of the principle of determinism in his 1814 Essai philosophique sur les probabilites with the formulation of the same principle offered by Roger Joseph Boscovich in his Theoria philosophiae naturalis, published 56 years earlier. This comparison discloses a striking general similarity between the two formulations of determinism as well as certain important differences. Regarding their similarities, both Boscovich's and Laplace's conceptions of determinism involve two mutually interdependent components-ontological and epistemic-and they are both intimately linked with the principles of causality and continuity. Regarding their differences, however, Boscovich's formulation of the principle of determinism turns out not only to be temporally prior to Laplace's but also-being founded on fewer metaphysical principles and more rooted in and elaborated by physical assumptions-to be more precise, complete and comprehensive than Laplace's somewhat parenthetical statement of the doctrine. A detailed analysis of these similarities and differences, so far missing in the literature on the history and philosophy of the concept of determinism, is the main goal of the present paper. PMID- 26227231 TI - Lockean superaddition and Lockean humility. AB - This paper offers a new approach to an old debate about superaddition in Locke. Did Locke claim that some objects have powers that are unrelated to their natures or real essences? The question has split commentators. Some (Wilson, Stuart, Langton) claim the answer is yes and others (Ayers, Downing, Ott) claim the answer is no. This paper argues that both of these positions may be mistaken. I show that Locke embraced a robust epistemic humility. This epistemic humility includes ignorance of the real essences of bodies, of the causal processes underlying the production of natural phenomena, and of God's method of creation. I show how this epistemic humility offers strong support for an agnostic response to the question of superaddition. Locke did not intend to claim that bodies either do or do not have properties unrelated to their real essences. Instead, his primary goal in discussing the topic was to emphasize the strict limits to human knowledge. PMID- 26227232 TI - Emergent evolutionism, determinism and unpredictability. AB - The fact that there exist in nature thoroughly deterministic systems whose future behavior cannot be predicted, no matter how advanced or fined-tune our cognitive and technical abilities turn out to be, has been well established over the last decades or so, essentially in the light of two different theoretical frameworks, namely chaos theory and (some deterministic interpretation of) quantum mechanics. The prime objective of this paper is to show that there actually exists an alternative strategy to ground the divorce between determinism and predictability, a way that is older than-and conceptually independent from-chaos theory and quantum mechanics, and which has not received much attention in the recent philosophical literature about determinism. This forgotten strategy embedded in the doctrine called "emergent evolutionism"-is nonetheless far from being a mere historical curiosity that should only draw the attention of philosophers out of their concern for comprehensiveness. It has been indeed recently revived in the works of respected scientists. PMID- 26227233 TI - Introduction: Galileo and Early Modern Philosophy. PMID- 26227234 TI - Galileo and Descartes on Copernicanism and the cause of the tides. AB - Galileo and Descartes were on the front lines of the defense of Copernicanism against theological objections that took on special importance during the seventeenth century. Galileo attempted to overcome opposition to Copernicanism within the Catholic Church by offering a demonstration of this theory that appeals to the fact that the double motion of the earth is necessary as a cause of the tides. It turns out, however, that the details of Galileo's tidal theory compromise his demonstration. Far from attempting to provide a demonstration of the earth's motion, Descartes ultimately argued that his system is compatible with the determination of the Church that the earth is at rest. Nonetheless, Descartes's account of the cause of the tides creates difficulty for this argument. PMID- 26227235 TI - Copernicus, Epicurus, Galileo, and Gassendi. AB - In his Letters on the motion impressed by a moving mover, the theory of the motion of composite bodies put forth by Gassendi is strikingly similar to Galileo's. In other of his writings, however, his description of the motion of individual atoms is understood very differently. In those places, he holds (1) that individual atoms are always in motion, even when the body that contains them is at rest, (2) that atomic motion is discontinuous although the motion of composite bodies is at least apparently continuous, and (3) that atomic motion is grounded in an intrinsic vis motrix, motive power. In contrast, composite bodies simply persist in their state of motion or rest in the absence of outside interference. Unfortunately, Gassendi neglects to explain how his accounts of atomic and composite motion fit together, and it is difficult to see how they could possibly be integrated. My goal is to explain, given this difficulty, why he accepted both the Galilean theory of the motion of composite bodies and the Epicurean theory of atomic motion. PMID- 26227236 TI - Space and motion in nature and Scripture: Galileo, Descartes, Newton. AB - In the Scholium to the Definitions in Principia mathematica, Newton departs from his main task of discussing space, time and motion by suddenly mentioning the proper method for interpreting Scripture. This is surprising, and it has long been ignored by scholars. In this paper, I argue that the Scripture passage in the Scholium is actually far from incidental: it reflects Newton's substantive concern, one evident in correspondence and manuscripts from the 1680s, that any general understanding of space, time and motion must enable readers to recognize the veracity of Biblical claims about natural phenomena, including the motion of the earth. This substantive concern sheds new light on an aspect of Newton's project in the Scholium. It also underscores Newton's originality in dealing with the famous problem of reconciling theological and philosophical conceptions of nature in the seventeenth century. PMID- 26227237 TI - Scientific progress without increasing verisimilitude: In response to Niiniluoto. AB - First, I argue that scientific progress is possible in the absence of increasing verisimilitude in science's theories. Second, I argue that increasing theoretical verisimilitude is not the central, or primary, dimension of scientific progress. Third, I defend my previous argument that unjustified changes in scientific belief may be progressive. Fourth, I illustrate how false beliefs can promote scientific progress in ways that cannot be explicated by appeal to verisimilitude. PMID- 26227238 TI - Commonalities of risk factors and biomarkers associated with the different subtypes of preterm birth. PMID- 26227239 TI - How Properties of Solid Surfaces Modulate the Nucleation of Gas Hydrate. AB - Molecular dynamics simulations were performed for CO2 dissolved in water near silica surfaces to investigate how the hydrophilicity and crystallinity of solid surfaces modulate the local structure of adjacent molecules and the nucleation of CO2 hydrates. Our simulations reveal that the hydrophilicity of solid surfaces can change the local structure of water molecules and gas distribution near liquid-solid interfaces, and thus alter the mechanism and dynamics of gas hydrate nucleation. Interestingly, we find that hydrate nucleation tends to occur more easily on relatively less hydrophilic surfaces. Different from surface hydrophilicity, surface crystallinity shows a weak effect on the local structure of adjacent water molecules and on gas hydrate nucleation. At the initial stage of gas hydrate growth, however, the structuring of molecules induced by crystalline surfaces are more ordered than that induced by amorphous solid surfaces. PMID- 26227240 TI - miR-628, a microRNA that is induced by Toll-like receptor stimulation, regulates porcine innate immune responses. AB - Mammalian innate and acquired immune responses involve a coordinated, sequential, and self limiting sequence of events controlled by positive and negative regulatory mechanism. MicroRNAs have been implicated as a negative regulator for diverse biological events including immune responses. However, the involvement of miRNAs in regulating the immune responses is just beginning to be explored. Here, we characterized the expression profiling of 375 microRNAs in porcine monocytes induced by lipopolysaccharide (LPS), and result shows that several of them are endotoxin-responsive genes. Through promoter analysis, the miR-628 was found to be a NF-kappaB dependent gene. Importantly, miR-628 was predicted to base-pair with sequences in the 3'-UTR of the myeloid differentiation protein 88 (MyD88) gene. And we found that the UTR inhibit expression of a linked reporter gene coding a key adapter molecule downstream of Toll-like receptors (TLRs), resulting in suppressing of the TLR signaling. Therefore, we not only propose a role of miR 628 in control of the TLR signaling through a negative feedback regulation loop involving down-regulation of MyD88 protein levels, but results may also contribute to rational target selection orchestrating the inflammatory responses. PMID- 26227242 TI - The Arabidopsis TAC Position Viewer: a high-resolution map of transformation competent artificial chromosome (TAC) clones aligned with the Arabidopsis thaliana Columbia-0 genome. AB - We present a high-resolution map of genomic transformation-competent artificial chromosome (TAC) clones extending over all Arabidopsis thaliana (Arabidopsis) chromosomes. The Arabidopsis genomic TAC clones have been valuable genetic tools. Previously, we constructed an Arabidopsis genomic TAC library consisting of more than 10,000 TAC clones harboring large genomic DNA fragments extending over the whole Arabidopsis genome. Here, we determined 13,577 end sequences from 6987 Arabidopsis TAC clones and mapped 5937 TAC clones to precise locations, covering approximately 90% of the Arabidopsis chromosomes. We present the large-scale data set of TAC clones with high-resolution mapping information as a Java application tool, the Arabidopsis TAC Position Viewer, which provides ready-to-go transformable genomic DNA clones corresponding to certain loci on Arabidopsis chromosomes. The TAC clone resources will accelerate genomic DNA cloning, positional walking, complementation of mutants and DNA transformation for heterologous gene expression. PMID- 26227243 TI - Electron density analysis of large (molecular and periodic) systems: A parallel implementation. AB - A parallel implementation is presented of a series of algorithms for the evaluation of several one-electron properties of large molecular and periodic (of any dimensionality) systems. The electron charge and momentum densities of the system, the electrostatic potential, X-ray structure factors, directional Compton profiles can be effectively evaluated at low computational cost along with a full topological analysis of the electron charge density (ECD) of the system according to Bader's quantum theory of atoms in molecules. The speedup of the parallelization of the different algorithms is presented. The search of all symmetry-irreducible critical points of the ECD of the crystallized crambin protein and the evaluation of all the corresponding bond paths, for instance, would require about 32 days if run in serial mode and reduces to less than 2 days when run in parallel mode over 32 processors. PMID- 26227241 TI - Genome-wide whole blood microRNAome and transcriptome analyses reveal miRNA-mRNA regulated host response to foodborne pathogen Salmonella infection in swine. AB - To understand the role of miRNAs in regulating genes involved in host response to bacterial infection and shedding of foodborne pathogens, a systematic profiling of miRNAs and mRNAs from the whole blood of pigs upon Salmonella challenge was performed. A total of 62 miRNAs were differentially expressed post infection (false discovery rate <0.1). An integrative analysis of both the differentially expressed miRNAs and mRNAs using sequence-based miRNA target prediction and negative correlation of miRNA-mRNA profiles helped identify miRNA-mRNA networks that may potentially regulate host response to Salmonella infection. From these networks, miR-214 and miR-331-3p were identified as new candidates potentially associated with Salmonella infection. An miRNA seed sequence analysis suggested that these miRNAs regulate several critical immune-related genes including SLC11A1, PIGE-108A11.3 and VAV2. We showed that challenged pigs had reduced miR 214 expression and increased miR-331-3p expression in the whole blood. Furthermore, the expression of the proposed targets of miR-214 (SLC11A1 and PIGE 108A11.3) increased while that of the proposed target of miR-331-3p (VAV2) decreased following challenge (expression changes confirmed by in vitro assays). Based on these observations, we propose potential roles for miR-214 and miR-331 3p in regulation of immune responses to Salmonella infection. PMID- 26227244 TI - Different responses of mouse islets and MIN6 pseudo-islets to metabolic stimulation: a note of caution. AB - MIN6 cells and MIN6 pseudo-islets are popular surrogates for the use of primary beta cells and islets. Even though it is generally agreed that the stimulus secretion coupling may deviate from that of beta cells or islets, direct comparisons are rare. The present side-by-side comparison of insulin secretion, cytosolic Ca(2+) concentration ([Ca(2+)] i ) and oxygen consumption rate (OCR) points out where similarities and differences exist between MIN6 cells and normal mouse beta cells. In mouse islets and MIN6 pseudo-islets depolarization by 40 mM KCl was a more robust insulinotropic stimulus than 30 mM glucose. In MIN6 pseudo islets, but not in mouse islets, the response to 30 mM glucose was much lower than to 40 mM KCl and could be suppressed by a preceding stimulation with 40 mM KCl. In MIN6 pseudo-islets, glucose was less effective to raise [Ca(2+)] i than in primary islets. In marked contrast to islets, the OCR response of MIN6 pseudo islets to 30 mM glucose was smaller than to 40 mM KCl and was further diminished by a preceding stimulation with 40 mM KCl. The same pattern was observed when MIN6 pseudo-islets were cultured in 5 mM glucose. As with insulin secretion memory effects on the OCR remained after wash-out of a stimulus. The differences between MIN6 cells and primary beta cells were generally larger in the responses to glucose than to depolarization by KCl. Thus, the use of MIN6 cells in investigations on metabolic signalling requires particular caution. PMID- 26227245 TI - A large functioning parathyroid lipoadenoma. PMID- 26227247 TI - Molecular Therapy Special Issue on Gene Editing Technologies and Applications. PMID- 26227250 TI - ASGCT and JSGT Joint Position Statement on Human Genomic Editing. PMID- 26227246 TI - Susceptibility loci for heroin and cocaine addiction in the serotonergic and adrenergic pathways in populations of different ancestry. AB - BACKGROUND: Drug addiction is influenced by genetic factors. AIM: To determine if genetic variants in the serotonergic and adrenergic pathways are associated with heroin and/or cocaine addiction. SUBJECTS & METHODS: The study examined 140 polymorphisms in 19 genes in 1855 subjects with predominantly European or African ancestries. RESULTS: A total of 38 polymorphisms (13 genes) showed nominal associations, including novel associations in S100A10 (p11) and SLC18A2 (VMAT2). The association of HTR3B SNP rs11606194 with heroin addiction in the European ancestry subgroup remained significant after correction for multiple testing (p(corrected) = 0.04). CONCLUSION: The study strengthens our previous findings of association of polymorphisms in HTR3A, HTR3B and ADRA1A. The study suggests partial overlap in genetic susceptibility between populations of different ancestry and between heroin and cocaine addiction. PMID- 26227251 TI - From Mesoderm to Mesodermatology: Bone Marrow Mesenchymal Cells Heal Skin Wounds. PMID- 26227253 TI - Driving Under the Influence of Non-Alcohol Drugs--An Update Part I: Epidemiological Studies. AB - Epidemiological studies of the association between drug use and involvement in road traffic crashes (RTCs) published from January 1998 to February 2015 have been reviewed. Cohort andpopulation studies compared RTC involvement among drug users and non-drug users, case-control studies compared drug use among RTC involved and non-RTC-involved drivers, and responsibility studies and case crossover studies were performed for RTC-involved drivers. Difficulties associated with the types of studies are discussed with a special focus on case control studies. Statistically significant associations between drug use and RTC involvement were found for benzodiazepines and z-hypnotics in 25 out of 28 studies, for cannabis in 23 out of 36 studies, for opioids in 17 out of 25 studies, for amphetamines in 8 out of 10 studies, for cocaine in 5 out of 9 studies, and for antidepressants in 9 out of 13 studies. It was a general trend among studies that did not report significant associations between the use of these drugs and increased RTC risk that they often had either poor statistical power or poor study design compared to studies that found an association. Simultaneous use of two or more psychoactive drugs was associated with higher RTC risk. Studies on the combination of alcohol and drugs have not been reviewed in this article even though this combination is known to be associated with the highest RTC risk. PMID- 26227252 TI - Dextran sulfate as a drug delivery platform for drug-coated balloons: Preparation, characterization, in vitro drug elution, and smooth muscle cell response. AB - Drug-coated balloons (DCBs) have now emerged as a promising approach to treat peripheral artery disease. However, a significant amount of drug from the balloon surface is lost during balloon tracking and results in delivering only a subtherapeutic dose of drug at the diseased site. Hence, in this study, the use of dextran sulfate (DS) polymer was investigated as a platform to control the drug release from balloons. An antiproliferative drug, paclitaxel (PAT), was incorporated into DS films (PAT-DS). The characterizations using SEM, FT-IR, and DSC showed that the films prepared were smooth and homogenous with PAT molecularly dispersed in the bulk of DS matrix in amorphous form. An investigation on the interaction of smooth muscle cells (SMCs) with control-DS and PAT-DS films showed that both films inhibited SMC growth, with a superior inhibitory effect observed for PAT-DS films. PAT-DS coatings were then produced on balloon catheters. The integrity of coatings was well-maintained when the balloons were either deflated or inflated. In this study, up to 2.2 ug/mm(2) of PAT was loaded on the balloons using the DS platform. Drug elution studies showed that only 10 to 20% of the total PAT loaded was released from the PAT-DS coated balloons during the typical time period of balloon tracking (1 min) and then ~80% of the total PAT loaded was released during the typical time period of balloon inflation and treatment (from 1 min to 4 min). Thus, this study demonstrated the use of DS as a platform to control drug delivery from balloons. (c) 2015 The Authors Journal of Biomedical Materials Research Part B: Applied Biomaterials Published by Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1416-1430, 2016. PMID- 26227254 TI - Metabolism and Disposition of Prescription Opioids: A Review. AB - Opioid analgesics are commonly prescribed for acute and chronic pain, but are subject to abuse. Consequently, toxicology testing programs are frequently implemented for both forensic and clinical applications. Understanding opioid metabolism and disposition is essential for assessing risk of toxicity and, in some cases, providing additional information regarding risk of therapeutic failure. Opioids significantly metabolized by the cytochromeP450 (CYP450) enzyme system maybe subjectto drug-drug interactions, including codeine, hydrocodone, oxycodone, fentanyl, meperidine, methadone, buprenorphine, and tramadol. CYP2D6 metabolism is polymorphic, and pharmacogenetic testing has been investigated for codeine, tramadol, oxycodone, and hydrocodone. CYP2B6 pharmacogenetic testing of methadone may reduce the risk of cardiac toxicity associated with the S enantiomer. Opioids metabolized primarily by uridine 5'-diphospho glucuronsyltransferase (UGT) enzymes include morphine, hydromorphone, dihydrocodeine, oxymorphone, levorphanol, and tapentadol. Parent and metabolite disposition is described for blood, oral fluid, and urine. Parent drug is most commonly detected in blood and oral fluid, whereas metabolites typically predominate in urine. Oral fluid/blood ratios exceed 1 for most opioids, making this an excellent alternative matrix for testing of this drug class. Metabolites of codeine, hydrocodone, and oxycodone are commercially available, and knowledge of metabolism is necessary for correct interpretation. PMID- 26227255 TI - Secretory meningioma with KLF4 K409Q mutation in collision with glioma. AB - AIMS: The simultaneous occurrence of two primary intracranial tumors is a rare event, especially if unrelated to radiotherapy or genetic disorders. We present two patients, both with two primary intracranial tumors simultaneously present at adjacent sites, in order to explore a possible mechanism of synchronous tumor formation. METHODS: We performed a molecular analysis of the K409Q mutation of the KLF4 gene, in addition to conventional immunohistochemistry. RESULTS: Preoperative gadolinium-enhanced magnetic resonance imaging revealed a necrotic mass with an irregular ring-like enhancement adjacent to a frontal meningioma in patient 1, and an infiltrative non-enhancing glial tumor with no evidence of another tumor in patient 2. Postoperative histological examination revealed the presence of two distinct tumors in both cases: secretory meningioma and glioblastoma in patient 1 and secretory meningioma and anaplastic astrocytoma in patient 2. Secretory meningiomas both showed the KLF4 K409Q mutation, while none of the glial tumors had it. CONCLUSIONS: To our knowledge, these are the first two cases reported of the simultaneous occurrence of secretory meningiomas with mutation of KLF4 in collision with a glioblastoma and an anaplastic astrocytoma, respectively. These collision tumors presumably have different molecular origins. PMID- 26227256 TI - Well-differentiated and anaplastic astroblastoma in the same patient: a case report and review of the literature. AB - Astroblastoma is a rare brain tumor occurring in children and adults, rarely in the elderly. It constitutes up to 3% of all brain tumors. We report a case of a 14-year-old girl who presented with recurrent seizures and minimal right hemiparesis. Magnetic resonance imaging (MRI) revealed a left fronto-parietal brain tumor. It was managed with subtotal resection in a local hospital. Subsequently, she was referred to Princess Nora Oncology Center for further characterization and management. Pathology slide revision revealed well differentiated astroblastoma. Upon follow up, the patient had multiple recurrences of the same tumor and emergence of a new lesion at the area of Sylvian fissure. Excision of the emerging tumor revealed anaplastic astroblastoma. Astroblastoma is a glial tumor that predominantly affects females. Its clinical progression is unpredictable, with high recurrence rate. Surgical intervention is considered the mainstay of treatment, while radiotherapy and chemotherapy effectiveness is debatable. To our knowledge, this is the first reported case of well-differentiated and anaplastic astroblastoma as two separate neoplastic lesions in the same patient with its clinical, radiological, and pathological features. PMID- 26227258 TI - Alterations in the distal colon innervation in Winnie mouse model of spontaneous chronic colitis. AB - The gastrointestinal tract is innervated by extrinsic sympathetic, parasympathetic and sensory nerve fibers as well as by intrinsic fibers from the neurons in myenteric and submucosal ganglia embedded into the gastrointestinal wall. Morphological and functional studies of intestinal innervation in animal models are important for understanding the pathophysiology of inflammatory bowel disease (IBD). The recently established Winnie mouse model of spontaneous chronic colitis caused by a point mutation in the Muc2 mucin gene develops inflammation due to a primary epithelial defect. Winnie mice display symptoms of diarrhea, ulcerations and rectal bleeding similar to those in IBD. In this study, we investigated myenteric neurons, noradrenergic, cholinergic and sensory nerve fibers in the distal colon of Winnie (Win/Win) mice compared to C57/BL6 and heterozygote littermates (Win/Wt) using histological and immunohistochemical methods. All Win/Win mice used in this study had inflammation with signs of mucosal damage, goblet cell loss, thickening of muscle and mucosal layers, and increased CD45-immunoreactivity in the distal colon. The density of sensory, cholinergic and noradrenergic fibers innervating the myenteric plexus, muscle and mucosa significantly decreased in the distal colon of Win/Win mice compared to C57/BL6 and Win/Wt mice, while the total number of myenteric neurons as well as subpopulations of cholinergic and nitrergic neurons remained unchanged. In conclusion, changes in the colon morphology and innervation found in Winnie mice have multiple similarities with changes observed in patients with ulcerative colitis. PMID- 26227257 TI - Frequencies of lymphoid T-follicular helper cells obtained longitudinally by lymph node fine-needle aspiration correlate significantly with viral load in SIV infected rhesus monkeys. AB - BACKGROUND: T-follicular helper (T(FH)) cells are an important population in lymph nodes (LNs) contributing to the generation of highly specific B cells. For SIV studies in rhesus macaques (RM), analysis of LN is necessary, but restricted due to invasive sampling. We applied the minimally invasive LN fine-needle aspiration (LN-FNA) and examined dynamics of T(FH) cells during SIV infection. MATERIALS AND METHODS: LN-FNA and LN resection were carried out on uninfected RM. Lymphocytes were analyzed by flow cytometry. Additionally, cells obtained by LN FNA over time from SIV-infected RM were analyzed. RESULTS: Percentages of lymphocyte subsets were similar in LN aspirates and whole LNs. Analysis of LN aspirates from SIV-infected RM demonstrated a decrease of CD4(+) T cells, while T(FH) cell frequencies increased over time and correlated significantly with plasma viral load. CONCLUSIONS: By applying LN-FNA, we showed that T(FH) cell expansion in chronic SIV infection is associated with viral load. PMID- 26227259 TI - A proliferation saturation index to predict radiation response and personalize radiotherapy fractionation. AB - BACKGROUND: Although altered protocols that challenge conventional radiation fractionation have been tested in prospective clinical trials, we still have limited understanding of how to select the most appropriate fractionation schedule for individual patients. Currently, the prescription of definitive radiotherapy is based on the primary site and stage, without regard to patient specific tumor or host factors that may influence outcome. We hypothesize that the proportion of radiosensitive proliferating cells is dependent on the saturation of the tumor carrying capacity. This may serve as a prognostic factor for personalized radiotherapy (RT) fractionation. METHODS: We introduce a proliferation saturation index (PSI), which is defined as the ratio of tumor volume to the host-influenced tumor carrying capacity. Carrying capacity is as a conceptual measure of the maximum volume that can be supported by the current tumor environment including oxygen and nutrient availability, immune surveillance and acidity. PSI is estimated from two temporally separated routine pre radiotherapy computed tomography scans and a deterministic logistic tumor growth model. We introduce the patient-specific pre-treatment PSI into a model of tumor growth and radiotherapy response, and fit the model to retrospective data of four non-small cell lung cancer patients treated exclusively with standard fractionation. We then simulate both a clinical trial hyperfractionation protocol and daily fractionations, with equal biologically effective dose, to compare tumor volume reduction as a function of pretreatment PSI. RESULTS: With tumor doubling time and radiosensitivity assumed constant across patients, a patient specific pretreatment PSI is sufficient to fit individual patient response data (R(2) = 0.98). PSI varies greatly between patients (coefficient of variation >128 %) and correlates inversely with radiotherapy response. For this study, our simulations suggest that only patients with intermediate PSI (0.45-0.9) are likely to truly benefit from hyperfractionation. For up to 20 % uncertainties in tumor growth rate, radiosensitivity, and noise in radiological data, the absolute estimation error of pretreatment PSI is <10 % for more than 75 % of patients. CONCLUSIONS: Routine radiological images can be used to calculate individual PSI, which may serve as a prognostic factor for radiation response. This provides a new paradigm and rationale to select personalized RT dose-fractionation. PMID- 26227260 TI - Prevalence of class 1 and 2 integrons in multi-drug resistant Escherichia coli isolated from aquaculture water in Chaharmahal Va Bakhtiari province, Iran. AB - BACKGROUND: Integrons play important role in the spread and maintenance of antimicrobial resistance among strains of Escherichia coli (E. coli) and other species of Enterobacteriaceae. This study investigated the prevalence of class 1 and 2 integrons among E. coli strains isolated from aquaculture water of fish fields in Iran. METHODS: One hundred and fifty water samples from different geographical regions in Chaharmahal Va Bakhtiari province were examined over a 2 months period. Isolation was through culture and biochemical tests. Integrons were identified through polymerase chain reaction (PCR) using oligonucleotide primers specific for class 1 and 2 integrons. Antimicrobial susceptibility testing was carried out using disc diffusion methods. RESULTS: Eighteen percent of the water samples were positive for E. coli. All the strains were multi-drug resistant; 100% to ciprofloxacin, chloramphenicol, gentamycin, ampicillin and tetracycline and least resistant to imipenem (7.2%). Ten (50%) of the most resistant strains were positive for class 1 (40%) and class 2 (10%). CONCLUSIONS: Escherichia coli in aquaculture in Iran carried integrons class 1 and 2 which could be of public health concern since they could play a role in the spread and maintenance of antimicrobial resistance among bacterial population in the region and should be constantly monitored. PMID- 26227261 TI - Design and development of indoor device for recycling of domestic vegetable scrap. AB - Since the municipal waste management and community garbage-treating systems are in vogue, there is a growing need for the waste minimization to keep our vicinity clean and green. Therefore, a feasible indoor device is designed for recycling domestic vegetable scrap by adopting the principle of soil ecosystem. To arrive at the composting process control parameters in the proposed device, the soil from landfill and quarry along with supplements namely sawdust, cow dung/yeast and the resident thermophilic bacteria are analysed. The soil parameters namely pH, electrical conductivity, Organic carbon, P, K, Fe, moisture content and the presence of thermophilic bacteria varied significantly between negative control sample (NCS) and positive control sample (PCS) and post-treatment positive control group with dried cow dung (PPC-C)-derived compost is soft-textured and homogenous. Furthermore, the double-compartment-based device would be more feasible and appealing as a recycling bin rather than as a refuse storage bin primarily due to the inclusion of dish-plantation. The standardization of composting control parameters is discussed in this article. PMID- 26227262 TI - A novel technique for bedside anorectal manometry in humans. AB - BACKGROUND: Currently, anorectal manometry (ARM), which is used to diagnose defecatory disorders and identify anal weakness in fecal incontinence (FI) is generally conducted in specialized laboratories. Our aims were to compare anorectal functions measured with high-resolution manometry (HRM) and a novel portable manometry device. METHODS: Anal pressures at rest, during squeeze, and simulated evacuation, and rectal sensation were evaluated with portable and HRM in 20 healthy women, 19 women with constipation, and 11 with FI. The relationship between anal pressures measured with portable and HRM was assessed by the concordance correlation coefficient (CCC), Bland Altman test, and paired t-tests. KEY RESULTS: Anal pressures at rest (CCC 0.45; 95% CI: 0.29, 0.58) and during squeeze (CCC 0.60; 95% CI: 0.46, 0.72) measured with portable and HRM were correlated and inversely associated with the risk of FI. During simulated evacuation, the CCC for rectal pressure (0.62; 95% CI: 0.43, 0.76) was greater than that for anal pressure (CCC 0.22; 95% CI: 0.04, 0.39) and the rectoanal gradient (CCC 0.22; 95% CI: 0.02, 0.41). Rectal sensory thresholds for first sensation, the desire to defecate, and urgency measured by portable and HRM were also significantly correlated between techniques. For several parameters, differences between portable and HRM were statistically significant and the Bland Altman test was positive. CONCLUSIONS & INFERENCES: Anorectal pressures and rectal sensation can be conveniently measured by portable manometry and are significantly correlated with high-resolution manometry. PMID- 26227263 TI - Current Trends and Future Burden of Breast Cancer Mortality in Brazil: A Population-Based Study. PMID- 26227265 TI - Colonoscopy quality indicators: from individual performance to institutional policy. PMID- 26227264 TI - Re-assessing the dimensional structure of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): empirical evidence for a shortened Brazilian version. AB - BACKGROUND: The dimensional structure, effective number of item responses and item redundancies are controversial features of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) requiring more light. The aims of the present study are to revisit the dimensional structure and propose a shorter version of the instrument. METHODS: The sample comprised 652 elderly and their informants, either attending a geriatric service of a public university clinic or enrolled in a health care provider database in Rio de Janeiro, Brazil. A Confirmatory Factor Analysis (CFA) first tested the originally proposed one dimensional structure comprised of 26 items. This was followed by sequential Exploratory Structural Equation Model (ESEM) to evaluate alternative models, in particular a bi-dimensional solution. The identification of residual correlations (RC) lead to a shortened 20-item model, which was tested further via CFA. RESULTS: The original model fitted poorly (RMSEA = 0.073; 90% CI: 0.069-0.077). Regarding the two-dimensional model, the exploratory procedure (ESEM) indicated several RCs and a lack of factor-based discriminant validity. The ensuing CFA on the one-dimensional model with freely estimated RCs showed an adequate fit (RMSEA = 0.051; 90% CI: 0.047-0.055). Addressing the identified RCs, the CFA on the abridged 20-item version also showed an adequate fit (RMSEA = 0.058; 90% CI: 0.053-0.064) and no further RCs. CONCLUSION: A one-factor dimensional structure and a reduced version with 20 locally independent items were the most tenable solution. However, although promising, this simpler structure requires further examination before it may be fully supported and recommended. PMID- 26227266 TI - Assessing mucosal healing in ulcerative colitis: the simpler, the better.... PMID- 26227267 TI - Reply to Villanacci et al. PMID- 26227268 TI - Endoscopic submucosal dissection: the best way to deal with subsquamous metaplasia? PMID- 26227269 TI - Reply to Barret et al. PMID- 26227272 TI - [Not Available]. PMID- 26227273 TI - [Not Available]. PMID- 26227274 TI - [Not Available]. PMID- 26227275 TI - Video Comment on Arthur Schmidt et al. PMID- 26227276 TI - Video Comment on Marietta Iacucci et al. PMID- 26227278 TI - Skin manifestations of primary hyperoxaluria: a case report. PMID- 26227277 TI - Fatty acid profiles and desaturase-encoding genes are different in thermo- and psychrotolerant strains of the Bacillus cereus Group. AB - BACKGROUND: The Bacillus cereus Group consists of closely-related bacteria, including pathogenic or harmless strains, and whose species can be positioned along the seven phylogenetic groups of Guinebretiere et al. (I-VII). They exhibit different growth-temperature ranges, through thermotolerant to psychrotolerant thermotypes. Among these, B. cytotoxicus is an atypical thermotolerant and food poisoning agent affiliated to group VII whose thermotolerance contrasts with the mesophilic and psychrotolerant thermotypes associated to the remaining groups I VI. To understand the role of fatty acid (FA) composition in these variable thermotypes (i.e. growth behavior vs temperatures), we report specific features differentiating the FA pattern of B. cytotoxicus (group VII) from its counterparts (groups I-VI). FINDINGS: The FA pattern of thermotolerant group VII (B. cytotoxicus) displayed several specific features. Most notably, we identified a high ratio of the branched-chain FAs iso-C15/iso-C13 (i15/i13) and the absence of the unsaturated FA (UFA) C16:1(5) consistent with the absence of ?5 desaturase DesA. Conversely, phylogenetic groups II-VI were characterized by lower i15/i13 ratios and variable proportions of C16:1(5) depending on thermotype, and presence of the DesA desaturase. In mesophilic group I, thermotype seemed to be related to an atypically high amount of C16:1(10) that may involve ?10 desaturase DesB. CONCLUSION: The levels of i15/i13 ratio, C16:1(5) and C16:1(10) UFAs were related to growth temperature variations recorded between thermotypes and/or phylogenetic groups. These FA are likely to play a role in membrane fluidity and may account for the differences in temperature tolerance observed in B. cereus Group strains. PMID- 26227280 TI - Identification of Coronary Artery Orifice to Prevent Coronary Complications in Bioprosthetic and Transcatheter Aortic Valve Replacement. AB - BACKGROUND: The aim of this study was to identify anatomical variations in coronary artery orifices among high-risk patients with a small aortic root undergoing bioprosthetic aortic valve replacement (BAVR) and transcatheter aortic valve replacement (TAVR) in order to prevent coronary orifice obstruction perioperatively. METHODS AND RESULTS: Coronary orifice and root structure were identified in 400 patients using aortic multidetector-row computed tomography (MDCT). We measured the aortic root diameter; intercommissural distances; and distance from coronary orifice to valve annulus, commissure, and sinotubular junction. We examined positional relationships between the coronary orifice and stent post, or sewing cuff of the bioprosthetic valve and leaflet of the transcatheter aortic valve. Most left coronary artery orifices were distributed near the center of the non-left and left-right commissures; right ones were relatively distributed on the non-right commissural side. Thirty-four patients (8.5%) with BAVR (coronary orifice near the commissure: 31, 7.8%; low takeoff: 5, 1.3%; and both: 2) and 39 (9.8%) with TAVR were at risk for coronary orifice obstruction. During BAVR, one-stitch rotation of the stent and one-stitch rotation with intra-annular implantation were used in near-commissure and low takeoff cases, respectively. During TAVR, percutaneous coronary intervention may be required in the height of the coronary orifice was <=10 mm from the base of the ventricle aortic junction. CONCLUSIONS: Potential coronary complications during BAVR and TAVR in high-risk patients for coronary obstruction were identified using preoperative aortic MDCT. Choice of appropriate surgical technique or valve is essential. PMID- 26227279 TI - A Phase 1 Randomized, Blinded Comparison of the Pharmacokinetics and Colonic Distribution of Three Candidate Rectal Microbicide Formulations of Tenofovir 1% Gel with Simulated Unprotected Sex (CHARM-02). AB - CHARM-02 is a crossover, double-blind, randomized trial to compare the safety and pharmacokinetics of three rectally applied tenofovir 1% gel candidate rectal microbicides of varying osmolalities: vaginal formulation (VF) (3111 mOsmol/kg), the reduced glycerin vaginal formulation (RGVF) (836 mOsmol/kg), and an isoosmolal rectal-specific formulation (RF) (479 mOsmol/kg). Participants (n = 9) received a single, 4 ml, radiolabeled dose of each gel twice, once with and once without simulated unprotected receptive anal intercourse (RAI). The safety, plasma tenofovir pharmacokinetics, colonic small molecule permeability, and SPECT/CT imaging of lower gastrointestinal distribution of drug and virus surrogate were assessed. There were no Grade 3 or 4 adverse events reported for any of the products. Overall, there were more Grade 2 adverse events in the VF group compared to RF (p = 0.006) and RGVF (p = 0.048). In the absence of simulated unprotected RAI, VF had up to 3.8-fold greater systemic tenofovir exposure, 26- to 234-fold higher colonic permeability of the drug surrogate, and 1.5- to 2-fold greater proximal migration in the colonic lumen, when compared to RF and RGVF. Similar trends were observed with simulated unprotected RAI, but most did not reach statistical significance. SPECT analysis showed 86% (standard deviation 19%) of the drug surrogate colocalized with the virus surrogate in the colonic lumen. There were no significant differences between the RGVF and RF formulation, with the exception of a higher plasma tenofovir concentration of RGVF in the absence of simulated unprotected RAI. VF had the most adverse events, highest plasma tenofovir concentrations, greater mucosal permeability of the drug surrogate, and most proximal colonic luminal migration compared to RF and RGVF formulations. There were no major differences between RF and RGVF formulations. Simultaneous assessment of toxicity, systemic and luminal pharmacokinetics, and colocalization of drug and viral surrogates substantially informs rectal microbicide product development. PMID- 26227281 TI - Osteoinductive potential of a novel biphasic calcium phosphate bone graft in comparison with autographs, xenografts, and DFDBA. AB - OBJECTIVES: Since the original description of osteoinduction in the early 20th century, the study and development of innovative biomaterials has emerged. Recently, novel synthetic bone grafts have been reported with potential to form ectopic bone in vivo. However, their full characterization in comparison with other leading bone grafts has not been investigated. The aim of this study was to determine the osteoinductive potential of bone grafts by comparing autogenous bone grafts, demineralized freeze-dried bone allografts (DFDBA), a commonly utilized natural bone mineral (NBM) from bovine origin (Bio-Oss), and a newly developed biphasic calcium phosphate (BCP). MATERIALS AND METHODS: Grafts were compared in vitro for their ability to stimulate bone marrow stromal cell (BMSC) migration, proliferation, and differentiation as assessed by quantitative real time PCR for genes coding for bone markers including Runx2, collagen I, and osteocalcin. Furthermore, bone grafts were implanted in the calf muscle of 12 beagle dogs to determine their potential to form ectopic bone in vivo. RESULTS: The in vitro results demonstrate that both autografts and DFDBA show potential for cell recruitment, whereas only autografts and BCP demonstrated the ability to differentiate BMSCs toward the osteoblast lineage. The in vivo ectopic bone model demonstrated that while NBM particles were not osteoinductive and autogenous bone grafts were resorbed quickly in vivo, ectopic bone formation was reported in DFDBA and in synthetic BCP grafts. CONCLUSION: The modifications in nanotopography and chemical composition of the newly developed BCP bone grafts significantly promoted ectopic bone formation confirming their osteoinductive potential. In conclusion, the results from this study provide evidence that synthetic bone grafts not only serve as a three-dimensional scaffold but are also able to promote osteoinduction. PMID- 26227283 TI - The interplay of stressful life events and coping skills on risk for suicidal behavior among youth students in contemporary China: a large scale cross sectional study. AB - BACKGROUND: Stressful life events are common among youth students and may induce psychological problems and even suicidal behaviors in those with poor coping skills. This study aims to assess the influence of stressful life events and coping skills on risk for suicidal behavior and to elucidate the underlying mechanism using a large sample of university students in China. METHODS: 5972 students, randomly selected from 6 universities, completed the questionnaire survey. Logistic regression analysis was performed to estimate the effect of stressful life events and coping skills on risk for suicidal behavior. Bayesian network was further adopted to probe their probabilistic relationships. RESULTS: Of the 5972 students, 7.64% reported the presence of suicidal behavior (attempt or ideation) within the past one year period. Stressful life events such as strong conflicts with classmates and a failure in study exam constituted strong risk factors for suicidal behavior. The influence of coping skills varied according to the strategies adapted toward problems with a high score of approach coping skills significantly associated with a reduced risk of suicidal behavior. The Bayesian network indicated that the probability of suicidal behavior associated with specific life events was to a large extent conditional on coping skills. For instance, a stressful experience of having strong conflicts with classmates could result in a probability of suicidal behavior of 21.25% and 15.36% respectively, for female and male students with the score of approach coping skills under the average. CONCLUSIONS: Stressful life events and deficient coping skills are strong risk factors for suicidal behavior among youth students. The results underscore the importance of prevention efforts to improve coping skills towards stressful life events. PMID- 26227284 TI - The Use of Dialectical Behavior Therapy and Prolonged Exposure to Treat Comorbid Dissociation and Self-Harm: The Case of a Client With Borderline Personality Disorder and Posttraumatic Stress Disorder. AB - There is a high rate of comorbidity between borderline personality disorder (BPD) and posttraumatic stress disorder (PTSD; Pagura et al., 2010). Preliminary studies have evaluated the treatment of PTSD in a BPD population and found positive outcomes for the integration of dialectical behavior therapy (DBT) and prolonged exposure (PE). This case study illustrates the implementation of a PE protocol into standard DBT treatment, specifically focusing on the management of self-harm and severe dissociation for a client with co-occurring PTSD and BPD. The client entered into treatment with severe and persistent dissociation and a recent history of self-harm, and the case includes consideration of two separate pauses in PTSD treatment related to elevated dissociation and self-harm behaviors. The client successfully completed the DBT PE protocol and results indicate significant improvements in PTSD symptoms as well as outcomes related to self-harm and dissociation. These findings demonstrate the efficacy of combining DBT with PE for clients with comorbid BPD and PTSD and exemplify how complex clients with BPD who present with severe dissociation and self-harm behavior can safely and successfully receive treatment for PTSD. PMID- 26227286 TI - Neurochemical and neuroendocrine correlates of overactive bladder at first demyelinating episode. AB - AIMS: Bladder dysfunction is frequent during the course of multiple sclerosis (MS), observed in up to 75% of patients. Urinary symptomatology can be a feature of the first episode of MS in a minority of cases, and most often shows characteristics of an overactive bladder (OAB), with voiding symptoms seen less frequently, often in combination with OAB. The neural control of micturition is complex, involving systems located in the brain, spinal cord, and periphery, and implicating central noradrenergic, serotonergic, and dopaminergic activities. Urinary disorders are also linked to anxiety and depression, conditions connected to hypothalamus-pituitary-adrenal axis activity. In this study we aimed to investigate neurochemical and neuroendocrine correlates of bladder dysfunction in early MS. METHODS: We included 101 patients at first demyelinating episode suggestive of MS that were drug-free at assessment. We evaluated the presence of urinary symptomatology and estimated CSF levels of the main metabolites of noradrenaline, serotonin, and dopamine, as well CSF-ACTH and serum cortisol. RESULTS: In total, 15 patients (15%) reported urinary dysfunction suggestive of OAB. Four of these had coexistent voiding symptomatology. The serotonin metabolite 5-HIAA was significantly reduced (P = 0.017) in patients with OAB syndrome, while there were no differences in the metabolites of noradrenaline (MHPG) and of dopamine (HVA). Additionally, significantly lower serum cortisol (P = 0.009) and borderline lower CSF-ACTH (P = 0.08) were found in patients with OAB. CONCLUSIONS: MS patients with OAB syndrome at the first demyelinating episode show reductions in central serotonergic activity and stress hormones. Whether the same changes persist at later disease stages remains to be investigated. Neurourol. Urodynam. 35:955-958, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26227285 TI - Contrast invariance of orientation tuning in cat primary visual cortex neurons depends on stimulus size. AB - KEY POINTS: The process of orientation tuning is an important and well characterized feature of neurons in primary visual cortex. The combination of ascending and descending circuits involved is not only relevant to understanding visual processing but the function of neocortex in general. The classic feed forward model of orientation tuning predicts a broadening effect due to increasing contrast; yet, experimental results consistently report contrast invariance. We show here that contrast invariance actually depends on stimulus size such that large stimuli extending beyond the neuron's receptive field engage circuits that promote invariance, whereas optimally sized, smaller stimuli result in contrast variance that is more in line with the classical orientation tuning model. These results illustrate the importance of optimizing stimulus parameters to best reflect the sensory pathways under study and provide new clues about different circuits that may be involved in variant and invariant response properties. ABSTRACT: Selective response to stimulus orientation is a key feature of neurons in primary visual cortex, yet the underlying mechanisms generating orientation tuning are not fully understood. The combination of feed-forward and cortical mechanisms involved is not only relevant to understanding visual processing but the function of neocortex in general. The classic feed-forward model predicts that orientation tuning should broaden considerably with increasing contrast; however, experimental results consistently report contrast invariance. We show here, in primary visual cortex of anaesthetized cats under neuromuscular blockade, that contrast invariance occurs when visual stimuli are large enough to include the extraclassical surround (ECS), which is likely to involve circuits of suppression that may not be entirely feed-forward in origin. On the other hand, when stimulus size is optimized to the classical receptive field of each neuron, the population average shows a statistically significant 40% increase in tuning width at high contrast, demonstrating that contrast variance of orientation tuning can occur. Conversely, our results also suggest that the phenomenon of contrast invariance relies in part on the presence of the ECS. Moreover, these results illustrate the importance of optimizing stimulus parameters to best reflect the neural pathways under study. PMID- 26227287 TI - Why do good people do bad things? PMID- 26227288 TI - ASHRM: Thirty five years of driving safe and trusted healthcare. PMID- 26227289 TI - Hospital and physician professional liability trends and industry topics. AB - This article summarizes the findings published in the Aon/ASHRM Hospital and Physician Professional Liability Benchmark Analysis, October 2014. The report analyzes aggregated data from hospital systems and physician groups across the United States that self-insure their professional liability exposures. Risk managers use the information to identify, measure, and better understand the risks that may affect their organizations. PMID- 26227290 TI - Effective followership: A standardized algorithm to resolve clinical conflicts and improve teamwork. AB - In healthcare, the sustained presence of hierarchy between team members has been cited as a common contributor to communication breakdowns. Hierarchy serves to accentuate either actual or perceived chains of command, which may result in team members failing to challenge decisions made by leaders, despite concerns about adverse patient outcomes. While other tools suggest improved communication, none focus specifically on communication skills for team followers, nor do they provide techniques to immediately challenge authority and escalate assertiveness at a given moment in real time. This article presents data that show one such strategy, called the Effective Followership Algorithm, offering statistically significant improvements in team communication across the professional continuum from students and residents to experienced clinicians. PMID- 26227291 TI - Maintaining the privacy of a minor's sexual orientation and gender identity in the medical environment. AB - Dealing with self-identity, sexual orientation, and gender identity is often a struggle for minors. The potential negative outcomes minors face when their sexual orientation or gender identity is disclosed to others before they have an opportunity to address it in their own time has become more evident in the media. Because of the intimate nature of the provider-patient relationship, the healthcare provider may be the first person in whom they confide. If a minor receives a positive, nonjudgmental experience from his or her provider, it will often lead to a more positive self-image, whereas a negative, judgmental experience will often result in the opposite. Critical components of their experience are a sense of trust that the provider will keep the information confidential and the healthcare setting being organized in a manner that promotes privacy. Healthcare providers play a key role in developing and projecting a safe, comfortable environment where the minor can discretely discuss issues of sexual orientation and gender identity. Establishing this environment will usually facilitate a positive therapeutic relationship between the minor and the provider. Steps healthcare providers can take to achieve trust from minor patients and ensure confidentiality of sensitive information are understanding privacy laws, making privacy a priority, getting consent, training staff, and demonstrating privacy in the environment. PMID- 26227292 TI - Of consent, informed refusal, and measles vaccination. AB - This article provides a discussion of the historic context for measles vaccination and the impact of the 2015 outbreak of measles. Seven practical risk management strategies are offered for vaccination consent. PMID- 26227293 TI - Absence of records does not prove that a visit to the ED did not occur. Price v. Port Huron Hospital. PMID- 26227294 TI - Reply: Nonmotor symptoms in subjects without evidence of dopaminergic deficits. PMID- 26227295 TI - Description of the SAGhE Cohort: A Large European Study of Mortality and Cancer Incidence Risks after Childhood Treatment with Recombinant Growth Hormone. AB - BACKGROUND: The long-term safety of growth hormone treatment is uncertain. Raised risks of death and certain cancers have been reported inconsistently, based on limited data or short-term follow-up by pharmaceutical companies. PATIENTS AND METHODS: The SAGhE (Safety and Appropriateness of Growth Hormone Treatments in Europe) study assembled cohorts of patients treated in childhood with recombinant human growth hormone (r-hGH) in 8 European countries since the first use of this treatment in 1984 and followed them for cause-specific mortality and cancer incidence. Expected rates were obtained from national and local general population data. The cohort consisted of 24,232 patients, most commonly treated for isolated growth failure (53%), Turner syndrome (13%) and growth hormone deficiency linked to neoplasia (12%). This paper describes in detail the study design, methods and data collection and discusses the strengths, biases and weaknesses consequent on this. CONCLUSION: The SAGhE cohort is the largest and longest follow-up cohort study of growth hormone-treated patients with follow-up and analysis independent of industry. It forms a major resource for investigating cancer and mortality risks in r-hGH patients. The interpretation of SAGhE results, however, will need to take account of the methods of cohort assembly and follow-up in each country. PMID- 26227296 TI - The assembly and characterisation of two structurally distinct cattle MHC class I haplotypes point to the mechanisms driving diversity. AB - In cattle, there are six classical MHC class I genes that are variably present between different haplotypes. Almost all known haplotypes contain between one and three genes, with an allele of Gene 2 present on the vast majority. However, very little is known about the sequence and therefore structure and evolutionary history of this genomic region. To address this, we have refined the MHC class I region in the Hereford cattle genome assembly and sequenced a complete A14 haplotype from a homozygous Holstein. Comparison of the two haplotypes revealed extensive variation within the MHC class Ia region, but not within the flanking regions, with each gene contained within a conserved 63- to 68-kb sequence block. This variable region appears to have undergone block gene duplication and likely deletion at regular breakpoints, suggestive of a site-specific mechanism. Phylogenetic analysis using complete gene sequences provided evidence of allelic diversification via gene conversion, with breakpoints between each of the extracellular domains that were associated with high guanine-cytosine (GC) content. Advancing our knowledge of cattle MHC class I evolution will help inform investigations of cattle genetic diversity and disease resistance. PMID- 26227297 TI - Pre-pubertal and adolescent germ cell neoplasms in Taiwan: time trends and geographic variation. AB - Evidence from our previous study suggested that the incidence of germ cell neoplasms in children and adolescents is increasing. The objectives of this analysis were to quantify this trend in patients aged 0-9 and 10-19 years (pre pubertal and adolescent groups, respectively) and compare rates in Taiwan according to geographic distribution. Germ cell neoplasm frequencies among 1267 patients aged 0-19 years spanning 1995-2009 were obtained from the population based Taiwan Cancer Registry. The incidence patterns according to sex, age, disease subgroup, and geographic distribution were analyzed. The incidence rates in the pre-pubertal and adolescent groups were 10.58 and 16.06 per million person years, respectively. The overall rates increased significantly by 3.2% annually in the adolescent group during the 15-year study period, and increased only among the males. In contrast, no change in trend was observed in the pre-pubertal group. Subgroup analysis showed significant upward trends in the incidence rates of intracranial/intraspinal and testicular germ cell tumors (GCTs) in the adolescent males and extracranial/extragonadal GCTs in the pre-pubertal boys. The most striking differences between the study population and white Americans were that the rates of testicular GCTs were 5-fold higher and 4-fold lower in the Taiwanese pre-pubertal and adolescent groups, respectively. Significantly higher rates were found in Hualien and Chiayi Counties compared with the other areas of Taiwan. The upward trend of testicular GCTs in the adolescent males is consistent with findings from Western countries. The underlying causes that led to the high rate of testicular GCTs in the pre-pubertal boys and significantly higher rates in specific counties warrant further investigation. PMID- 26227299 TI - The Reliability and Validity of the Norwegian Version of the Quality of Life in Late-Stage Dementia Scale. AB - AIM: To translate the Quality of Life in Late-Stage Dementia (QUALID) Scale into Norwegian, and to evaluate the test-retest reliability and validity of the scale. METHOD: QUALID was translated according to standardised procedures. Residents with dementia living in nursing homes were included in the study and assessed using QUALID, Cornell Scale for Depression in Dementia, Neuropsychiatric Inventory, Physical Self-Maintenance Scale and Clinical Dementia Rating Scale. RESULTS: Cronbach's alpha of QUALID was 0.79. In the reliability study, the intra class correlation was 0.83. The validity study showed a strong association between depressive symptoms and QUALID, and a moderate association between QUALID and assessments of level of functioning and agitation. CONCLUSIONS: The Norwegian version of QUALID is a reliable and valid scale for assessing quality of life in nursing home residents with dementia. PMID- 26227298 TI - Effect of sodium fluoride and stannous chloride associated with Nd:YAG laser irradiation on the progression of enamel erosion. AB - This study evaluated the progression of enamel erosion after treatment with gels containing sodium fluoride (NaF; 9047 ppm F) and stannous chloride (SnCl2; 3000 ppm Sn), associated or not with Nd:YAG laser irradiation. Sixty enamel specimens were prepared from bovine incisors and protected by a tape, leaving an exposed surface area of 4 * 1 mm. The specimens were immersed in 1 % citric acid (pH = 2.3) for 10 min to create an initial erosion lesion. After, they were randomly divided into six groups: (C) control: gel without active ingredient; (F): NaF gel; (F + Sn): NaF + SnCl2 gel; (laser): Nd:YAG laser irradiation (0.5 W; 50 mJ; ~41.66 J/cm(2); 10 Hz; 40 s); (F + laser): NaF gel + Nd:YAG; (F + Sn + laser): NaF + SnCl2 gel + Nd:YAG. All gels had pH = 4.5 and were applied for 1 min. Laser irradiation was performed after gel application. The specimens were then submitted to a 5-day erosion-remineralization cycling model using 1 % citric acid (pH = 2.3), six times per day. Enamel surface loss (SL) was analyzed by optical profilometry in the end of the cycling (in MUm). Data were analyzed by one-way ANOVA and Holm-Sidak tests (alpha = 0.05). The control and the laser groups presented the highest enamel loss (means +/- SD = 53.52 +/- 3.65 and 53.30 +/- 2.73, respectively), followed by F + Sn (44.76 +/- 2.83). The groups F (36.76 +/- 2.28), F + laser (36.25 +/- 3.59), and F + Sn + laser (39.83 +/- 4.62) showed the lowest enamel loss, with no significant difference among them (p > 0.05). In conclusion, NaF by itself or associated with SnCl2 and Nd:YAG laser was able to reduce enamel erosion progression. Nd:YAG laser alone did not show a protective effect. PMID- 26227300 TI - Nanostructured Double Perovskite Cathode With Low Sintering Temperature For Intermediate Temperature Solid Oxide Fuel Cells. AB - This study focuses on reducing the cathode polarization resistance through the use of mixed ionic electronic conductors and the optimization of cathode microstructure to increase the number of electrochemically active sites. Among the available mixed ionic electronic conductors (MIECs), the layered perovskite GdBa0.5 Sr0.5 CoFeO5+delta (GBSCF) was chosen as a cathode material for intermediate temperature solid oxide fuel cells owing to its excellent electrochemical performance and structural stability. The optimized microstructure of a GBSCF-yttria-stabilized zirconia (YSZ) composite cathode was prepared through an infiltration method with careful control of the sintering temperature to achieve high surface area, adequate porosity, and well-organized connection between nanosized particles to transfer electrons. A symmetric cell shows outstanding results, with the cathode exhibiting an area-specific resistance of 0.006 Omega cm(2) at 700 degrees C. The maximum power density of a single cell using Ce-Pd anode with a thickness of ~80 MUm electrolyte was ~0.6 W cm(-2) at 700 degrees C. PMID- 26227301 TI - Phosphoproteomic network analysis in the sea urchin Strongylocentrotus purpuratus reveals new candidates in egg activation. AB - Fertilization triggers a dynamic symphony of molecular transformations induced by a rapid rise in intracellular calcium. Most prominent are surface alterations, metabolic activation, cytoskeletal reorganization, and cell-cycle reentry. While the activation process appears to be broadly evolutionarily conserved, and protein phosphorylation is known to play a key role, the signaling networks mediating the response to fertilization are not well described. To address this gap, we performed a time course phosphoproteomic analysis of egg activation in the sea urchin Strongylocentrotus purpuratus, a system that offers biochemical tractability coupled with exquisite synchronicity. By coupling large-scale phosphopeptide enrichment with unbiased quantitative MS, we identified striking changes in global phosphoprotein patterns at 2- and 5-min postfertilization as compared to unfertilized eggs. Overall, we mapped 8796 distinct phosphosite modifications on 2833 phosphoproteins, of which 15% were differentially regulated in early egg activation. Activated kinases were identified by phosphosite mapping, while enrichment analyses revealed conserved signaling cascades not previously associated with egg activation. This work represents the most comprehensive study of signaling associated with egg activation to date, suggesting novel mechanisms that can be experimentally tested and providing a valuable resource for the broader research community. All MS data have been deposited in the ProteomeXchange with identifier PXD002239 (http://proteomecentral.proteomexchange.org/dataset/PXD002239). PMID- 26227302 TI - Facile Microwave-Assisted Solid-Phase Synthesis of Highly Fluorescent Nitrogen Sulfur-Codoped Carbon Quantum Dots for Cellular Imaging Applications. AB - Carbon quantum dots (CQDs) have recently attracted significant attention for both their fundamental science and technological applications as a new class of fluorescent zero-dimensional nanomaterials with a size below 10 nm. However, the reported methods of synthesis were generally less suitable for the large-scale production of the CQDs with high-fluorescent quantum yield (QY). In the paper, a novel one-pot microwave-assisted drying synthesis approach was presented to prepare CQDs with high QY of 61.3 % for the first time. The production yield of CQDs was 35+/-3 % in weight. The as-prepared CQDs were characterized by various techniques such as TEM, AFM, XRD, XPS, FTIR spectroscopy, UV/Vis absorption spectroscopy, and fluorescence spectroscopy. The results showed that the high QY of CQDs was largely attributed to the dual doping of nitrogen and sulphur into CQDs. Such CQDs were then used as live-cell imaging reagents due to their high QY, good water dispersibility, fine biocompatibility, high photostability, and low cytotoxicity. PMID- 26227303 TI - Clinical relevance of quality of life in laryngomalacia. AB - OBJECTIVES/HYPOTHESIS: To examine aspects of laryngomalacia and correlate findings with quality of life (QOL). STUDY DESIGN: Prospective cross-sectional study. METHODS: Seventy-two patients with laryngomalacia were examined; the mean age was 8.8 weeks. Parents answered questions from the Infant and Toddler Quality of Life Questionnaire-47 (ITQOL-SF47). Fiberoptic laryngoscopy and endoscopic examination of swallowing (FEES) were performed. The presence of laryngomalacia associated characteristics and swallowing status were recorded. Patient age, sex, presence of reflux, clinical severity, anatomical findings, and swallowing results were evaluated through logistic regression. Independent sample t tests were used to compare responses on the ITQOL-SF47. Overall laryngomalacia ITQOL SF47 scores were compared to the scores of a large healthy sample population. RESULTS: Forty-three (60%) patients had mild laryngomalacia, and 61 (85%) patients had findings suggesting gastroesophageal reflux disease. The most common abnormality was shortened aryepiglottic folds. Ten patients failed FEES. Patients with moderate laryngomalacia (chi = 7.62; P = .006) or prolapsing cuneiforms (chi = 4.79; P = .029) were more likely to fail FEES. Laryngomalacia severity impacted parental perception of their child's health (P < .05). Parents of children who demonstrated aspiration or penetration reported significant emotional impact (mean = 56.9; t = 2.74; P = .008). The mean ITQOL-SF47 scores of patients were significantly lower in certain sections than the reported general sample population. CONCLUSIONS: Epiglottal prolapse correlated with severity of laryngomalacia and cuneiform prolapse with swallowing dysfunction. Perceptions of worsening health and physical ability were related to severity of disease. Swallowing dysfunction had a significant emotional impact on parental daily life. Infants with laryngomalacia have a lower QOL LEVEL OF EVIDENCE: 3 Laryngoscope, 126:1232-1235, 2016. PMID- 26227304 TI - Free Radical Threshold Value: A New Universal Body Constant. AB - Three evolutionary sources create 'primary' reactive oxygen species (ROS) and 'secondary' lipid oxygen species (LOS), forming the human body's 'free radical ground state'. We present evidence for the existence of a universal free radical threshold value (FRTV), defining the borderline between advantageous and adverse effects of free radicals observed above the free radical ground state. Based on standard vitamin D doses, the calculated amount of ~3.5 * 10(12) rad/mg ROS/LOS tissue represents the tolerated number of free radicals in skin tissue - defined as FRTV. By means of quantitative ESR x-band spectroscopy, the FRTV was experimentally verified using ex vivo human skin irradiated with ultraviolet + visible (UV + VIS), UVB + UVA and VIS light. In addition, we investigated whether this threshold is also existent in internal organs by extending our experiment to fresh porcine liver. Based on the determination of ROS/LOS below and above the FRTV, ROS > LOS was characterized as beneficial and LOS > ROS as deleterious to the organism, respectively. Results of the experiments using porcine liver confirmed the appearance of the FRTV at radical generation ~3.5 * 10(12) rad/mg. The relation ROS/LOS before and after the FRTV was consistent with the results determined for the skin. We conclude that the FRTV, theoretically calculated and experimentally confirmed, should be considered as a new 'universal body constant'. PMID- 26227305 TI - Determinants of Postpartum Vitamin D Status in the Caucasian Mother-Offspring Pairs at a Latitude of 52 degrees N: A Cross-Sectional Study. AB - BACKGROUND: High prevalence of vitamin D deficiency in pregnancy is recorded. AIM: To establish determinants of postpartum 25-hydroxyvitamin D (25(OH)D) levels on mothers and offspring. METHODS: 25(OH)D level was measured in cord blood and maternal blood collected <=3 weeks postpartum. Maternal socioeconomic status, vitamin D intake, sun exposure during pregnancy and maternal and neonatal fat mass (FM; dual X-ray absorptiometry) were assessed within 3 weeks postpartum. RESULTS: A total of 174 mother-offspring pairs were enrolled. Maternal 25(OH)D <20 ng/ml was seen in 32 (51%) of summer and 82 (74%) of winter deliveries. Women with 25(OH)D <20 ng/ml had a 2-fold lower percentage of vitamin D intake of >=800 IU/day than women with 25(OH)D >=20 ng/ml (p = 0.02). FM (%) was comparable between groups (p > 0.05). Multiple regression analysis revealed the delivery season, prenatal vitamin D intake >=800 IU/day and duration of supplementation to be the determinants of maternal 25(OH)D level (R(2) = 0.26, p < 0.001). Maternal 25(OH)D level, season of birth and duration of maternal supplementation explained 83% of the variance in cord blood 25(OH)D level (R(2) = 0.83, p < 0.001). CONCLUSIONS: The key determinants of higher maternal vitamin D status were the summer-autumn season of delivery and prenatal use of >=800 IU/day of vitamin D. The cord blood 25(OH)D level was mainly determined by maternal 25(OH)D level and season of birth. PMID- 26227306 TI - Uncommon superficial angiomyxoma of the vulva complicated with condyloma acuminatum and Staphylococcus hominis infection: a mere example of gynecological immunocompromised district. PMID- 26227307 TI - Tackling the mental illness stigma in low- and middle-income countries: lessons learned from high-income countries and mistakes to avoid. PMID- 26227308 TI - Use of Jebsen Taylor Hand Function Test in evaluating the hand dexterity in people with Parkinson's disease. AB - OBJECTIVES: To investigate the test-retest reliability of JTT in older patients with Parkinson's disease (PD); and to compare the Jebsen Taylor Hand Function Test (JTT) scores between PD and healthy subjects. STUDY DESIGN: Cross-sectional comparative study. METHODS: Fifteen PD and fifteen healthy subjects performed the JTT and the time taken to complete the JTT was recorded. RESULTS: Test-retest reliabilities of JTT subtests and total score of both dominant and non-dominant hand were good to excellent (ICCs = 0.77-0.97) except J5 checkers which had moderate reliability. PD subjects required significantly longer time to finish subtests and the whole JTT (p < 0.05), except the subtest J1 writing of dominant hand that showed marginal significance (p = 0.059). CONCLUSION: JTT is a reliable and easily available assessment tool for assessing the hand function of PD subjects. PD subjects took a longer time to complete the JTT, suggesting that they have deficits in gross and fine functional dexterity. PMID- 26227310 TI - Improved electrochemical stability at the surface of La(0.8)Sr(0.2)CoO3 achieved by surface chemical modification. AB - The degradation of the surface chemistry on perovskite (ABO3) oxides is a critical issue for their performance in energy conversion systems such as solid oxide fuel/electrolysis cells and in splitting of H2O and CO2 to produce fuels. This degradation is typically in the form of segregation and phase separation of dopant cations from the A-site, driven by elastic and electrostatic energy minimization and kinetic demixing. In this study, deposition of Ti at the surface was found to hinder the dopant segregation and the corresponding electrochemical degradation on a promising SOFC cathode material, La(0.8)Sr(0.2)CoO3 (LSC). The surface of the LSC films was modified by Ti (denoted as LSC-T) deposited from a TiCl4 solution. The LSC and LSC-T thin films were investigated by electrochemical impedance spectroscopy, nano-probe Auger electron spectroscopy, and X-ray photoelectron spectroscopy (XPS), upon annealing at 420-530 degrees C in air up to about 90 hours. The oxygen exchange coefficient, k(q), on LSC-T cathodes was found to be up to 8 times higher than that on LSC cathodes at 530 degrees C and retained its stability. Sr-rich insulating particles formed at the surface of the annealed LSC and LSC-T films, but with significantly less coverage of such particles on the LSC-T. From this result, it appears that modification of the LSC surface with Ti reduces the segregation of the blocking Sr-rich particles at the surface, and a larger area on LSC surface (with a higher Sr doping level in the lattice) is available for the oxygen reduction reaction. The stabilization of the LSC surface through Ti-deposition can open a new route for designing surface modifications on perovskite oxide electrodes for high temperature electro- and thermo-chemical applications. PMID- 26227309 TI - Nurses' health-related behaviours: protocol for a quantitative systematic review of prevalence of tobacco smoking, physical activity, alcohol consumption and dietary habits. AB - AIM: To enumerate nurses' health-related behaviour by critically appraising studies on tobacco smoking, physical activity, alcohol consumption and dietary habits. BACKGROUND: Nurses represent the largest occupational group in healthcare systems internationally and have an established and expanding public health role. Nurses own health-related behaviour is known to impact nurses' ability and confidence to engage in health promotion, and how patients receive and respond to advice and guidance nurses' give. However, there has been no comprehensive and comparable assessment of evidence on nurses' health-related behaviours. DESIGN: Quantitative systematic review of prevalence of tobacco smoking, physical activity, alcohol consumption and dietary habits. METHODS: Systematic searches for literature published between January 2000 and February 2015 and indexed in Medical Literature Analysis and Retrieval System, Cumulative Index to Nursing and Allied Health Literature and Psychological Information. Eligibility criteria will be applied to titles and abstracts by two reviewers independently. Full text will be reviewed and the same criteria and process applied. Two reviewers will independently assess study quality guided by the Joanna Briggs Institute handbook for the systematic review of prevalence and incidence data. Discrepancies in eligibility or quality assessment will be resolved through discussion and, where required, a third reviewer. Data synthesis will be conducted and findings reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. DISCUSSION: Enumerating prevalence of nurses' health related behaviours is crucial to direct future research, inform public health policy, particularly around health promotion and to better support the nursing workforce through the development of behaviour change interventions. PROSPERO registration: CRD42015016751. PMID- 26227311 TI - Recent advances in biosensors based on enzyme inhibition. AB - Enzyme inhibitors like drugs and pollutants are closely correlated to human and environmental health, thus their monitoring is of paramount importance in analytical chemistry. Enzymatic biosensors represent cost-effective, miniaturized and easy to use devices; particularly biosensors based on enzyme inhibition are useful analytical tools for fast screening and monitoring of inhibitors. The present review will highlight the research carried out in the last 9 years (2006 2014) on biosensors based on enzyme inhibition. We underpin the recent advances focused on the investigation in new theoretical approachs and in the evaluation of biosensor performances for reversible and irreversible inhibitors. The use of nanomaterials and microfluidic systems as well as the applications of the various biosensors in real samples is critically reviewed, demonstrating that such biosensors allow the development of useful devices for a fast and reliable alarm system. PMID- 26227312 TI - Granulocyte transfusion experience in pediatric neutropenic fever: Splitted product can be an alternative? AB - The granulocyte transfusion (GTX) has been used for a long time due to uncontrolled neutropenic fever with antimicrobial agents. In some cases, the product needs to be splitted for using in the next 12 hours. The aim of this study is to evaluate the efficacy of splitted product and clinical response to GTX. In this study, 15 patients with malignancy with 19 neutropenic fever, who had received 56 GTX, were included. Seventeen of 56 GTX were splitted and used in maximum 12 hours during infections which did not respond to antibacterial and antifungal therapy in 7 days. The patients were divided in to response groups as a complete, partial and progressive. The predictive factors for response group were evaluated. GTX were well tolerated in all patients. The median granulocyte dose was 1.26 (0.38-5.22) * 10(9)/kg. Total response rate was 89.5%. The infection-related mortality rate was 10.5%. Although the granulocyte doses are the same in both of the product groups, an hour later ANC increment of primer product was higher than that of splitted product (p = 0.001). Among the products, 48.7% of primer product and 17.6% of splitted product had induced >= 1000/mm(3) ANC increment after an hour (p = 0.039). Granulocyte transfusion is safe and effective in controlling the febrile neutropenia attack. GTX should be applied in a short time to provide effective ANC increment. For now, main granulocyte product instead of splitted product should be preferred in case of uncontrolled neutropenic fever with antibacterial/antifungal agents. PMID- 26227313 TI - Trends in surgical management of urachal anomalies. AB - PURPOSE: We have noted an increasing frequency of diagnosed urachal anomalies. The purpose of this study is to evaluate this increase, as well as the outcomes of management at our institution over 10 years. METHODS: A retrospective analysis of urachal anomalies at our institution was performed. Inclusion criteria were Anomalies of Urachus (ICD 753.7) or Urinary Anomaly NOS (ICD 753.9) between January 2000 and December 2010. Exclusion criteria were having an asymptomatic urachal remnant incidentally excised. RESULTS: Eighty-five patients (49 male, 36 female) presented between 0 and 17 years of age (mean 1.5 years). Diagnoses increased from 0 in 2000 to 21 in 2010. Zero was surgically managed in 2000 while 21 were managed in 2010 (p=0.0145). Fifteen patients (17.6%) were observed with 13 (13/15, or 15.3%) resolving without complication while 2 were operated on. Average time to resolution (clinical or radiologic) was 4.9 months (Range: 0.4 12.6). A total of seventy-two patients (84.7%) underwent excision. Thirty-nine (54%) surgical cases were outpatient while 33 (46%) were admitted. Thirteen (18%) had post-operative complications. Ten (77%) of the complications were wound infections. Patients under 6 months of age accounted for 60% (6 of 10) of all wound infections and 52% (17 of 33) of hospitalizations. CONCLUSIONS: Our experience and review of the literature suggest a high complication rate with surgical management in young patients, mostly from infections and support non operative management of all non-infected urachal remnants in children. PMID- 26227314 TI - [Blood cultures in the paediatric emergency department. Guidelines and recommendations on their indications, collection, processing and interpretation]. AB - Blood culture (BC) is the gold standard when a bacteraemia is suspected, and is one of the most requested microbiological tests in paediatrics. Some changes have occurred in recent years: the introduction of new vaccines, the increasing number of patients with central vascular catheters, as well as the introduction of continuous monitoring BC systems. These changes have led to the review and update of different factors related to this technique in order to optimise its use. A practice guideline is presented with recommendations on BC, established by the Spanish Society of Paediatric Emergency Care and the Spanish Society for Paediatric Infectious Diseases. After reviewing the available scientific evidence, several recommendations for each of the following aspects are presented: BC indications in the Emergency Department, how to obtain, transport and process cultures, special situations (indications and interpretation of results in immunosuppressed patients and/or central vascular catheter carriers, indications for anaerobic BC), differentiation between bacteraemia and contamination when a BC shows bacterial growth and actions to take with a positive BC in patients with fever of unknown origin. PMID- 26227315 TI - Erratum to: Improving protein order-disorder classification using charge hydropathy plots. PMID- 26227316 TI - Surface-modified CAU-10 MOF materials as humidity sensors: impedance spectroscopic study on water uptake. AB - Metal-organic frameworks (MOFs) are crystalline microporous materials with tunable chemical and physical properties. By combining various metal clusters with different interconnecting organic linkers, the pore structure, crystallinity, as well as the surface properties can be modified. In the present work, modification of the organic linker molecules is utilized to synthesize CAU 10 type MOFs with variable affinity of the pore surface to water. In principle, this should influence the accessibility of the pores for water vapor and therefore offer a tool to control its sorption properties. For a deeper understanding we studied the water sorption characteristics and compared the results to the conductive and dielectric properties studied by impedance spectroscopy. Spectra in a wide frequency range from 1 mHz to 1 MHz were recorded. Data analysis is performed using the Havriliak-Negami model. The MOFs are also tested as sensitive layers for capacitive humidity sensing by correlating the change in permittivity of the materials with the amount of physisorbed water. Such an MOF-based sensor was tested with respect to environmental monitoring and compared to a commonly used commercial humidity sensor. PMID- 26227317 TI - Association of HO-1 and BRCA1 Is Critical for the Maintenance of Cellular Homeostasis in Prostate Cancer. AB - Prostate cancer is the second leading cause of cancer-related death in men worldwide. Many factors that participate in the development of prostate cancer promote imbalance in the redox state of the cell. Accumulation of reactive oxygen species causes injury to cell structures, ultimately leading to cancer development. The antioxidant enzyme heme oxygenase 1 (HMOX1/HO-1) is responsible for the maintenance of the cellular homeostasis, playing a critical role in the oxidative stress and the regulation of prostate cancer development and progression. In the present study, the transcriptional regulation of HO-1 was investigated in prostate cancer. Interestingly, the tumor suppressor BRCA1 binds to the HO-1 promoter and modulates HO-1, inducing its protein levels through both the increment of its promoter activity and the induction of its transcriptional activation. In addition, in vitro and in vivo analyses show that BRCA1 also controls HO-1-negative targets: MMP9, uPA, and Cyclin D1. HO-1 transcriptional regulation is also modulated by oxidative and genotoxic agents. Induction of DNA damage by mitoxantrone and etoposide repressed HO-1 transcription, whereas hydrogen peroxide and doxorubicin induced its expression. Xenograft studies showed that HO-1 regulation by doxorubicin also occurs in vivo. Immunofluorescence analysis revealed that BRCA1 overexpression and/or doxorubicin exposure induced the cytoplasmic retention of HO-1. Finally, the transcription factor NRF2 cooperates with BRCA1 protein to activate HO-1 promoter activity. In summary, these results show that the activation of BRCA1-NRF2/HO-1 axis defines a new mechanism for the maintenance of the cellular homeostasis in prostate cancer. IMPLICATIONS: Oxidative and genotoxic stress converge on HO-1 transcriptional activity through the combined actions of BRCA1 and NRF2. PMID- 26227318 TI - Introduction of a new health technology into a provincial health system: A case study of insulin pump therapy. AB - Decisions on the introduction of new non-drug health technologies into healthcare are challenging. This article describes the introduction of insulin pump therapy for type 1 diabetes in Alberta, using an Access with Evidence Development (AED) approach. The organization and implementation of the AED, its current status, and lessons learned are described. PMID- 26227319 TI - Evaluation of empiric antibiotic de-escalation in febrile neutropenia. AB - INTRODUCTION: Up until 2010, the recommended duration of empiric broad-spectrum antibiotics for febrile neutropenia was until absolute neutrophil count (ANC) recovery. An updated guideline on the use of antimicrobial agents in neutropenic patients with cancer indicates that patients who have completed an appropriate treatment course of broad-spectrum antibiotics, with resolution of signs and symptoms of infection but persistent neutropenia, can be de-escalated to oral fluoroquinolone prophylaxis until ANC recovery. METHODS: The primary objective of this retrospective investigation was to evaluate the safety and efficacy of de escalating broad-spectrum antibiotics in patients remaining neutropenic after at least 14 days of empiric broadspectrum antibiotics for febrile neutropenia compared to patients continuing broad-spectrum antibiotics until ANC recovery. RESULTS: There were 16 patients (61.5%) in the comparator group who met the primary endpoint of remaining afebrile and without escalation of antibiotics for at least 72 hours after 14 days of broad-spectrum antibiotics and 21 patients (80.7%) in the de-escalation group who met the primary endpoint of remaining afebrile and without reinitiation of broad-spectrum antibiotics for at least 72 hours after de-escalation to levofloxacin therapy (p = 0.11). Mean total duration of broad-spectrum antibiotic therapy was 23.5 +/- 1.5 days in the comparator group versus 22.2 +/- 1.43 days in the de-escalation group (p = 0.39). CONCLUSIONS: Results of this investigation indicate that broad-spectrum antibiotics can be safely de-escalated to levofloxacin prophylaxis prior to ANC recovery in select patients. This practice may decrease the duration of broad spectrum antibiotic exposure and associated complications. PMID- 26227320 TI - Anti-citrullinated protein antibodies suppress let-7a expression in monocytes from patients with rheumatoid arthritis and facilitate the inflammatory responses in rheumatoid arthritis. AB - We hypothesized that anti-citrullinated protein antibodies (ACPAs) could affect the expression of miRNAs in monocytes and contribute to the inflammatory responses in rheumatoid arthritis (RA). The expression profiles of 270 human miRNAs, co-cultured with ACPAs or human immunoglobulin G (IgG), were analyzed using real-time polymerase chain reaction. Ten miRNAs exhibited differential expression in U937 cells after co-cultured with ACPAs compared with human IgG. The expression levels of these miRNAs were investigated in monocytes from 21 ACPA positive RA patients and 13 controls. Among these miRNAs, the expression levels of let-7a was decreased in monocytes from ACPA-positive RA patients. The expression levels of let-7a showed a negative correlation with positivity of rheumatoid factor in patients sampled. We found that transfection of U937 cells with let-7a mimic suppressed K-Ras protein expression. In the ACPA-mediated signaling pathway, transfection of U937 cells with let-7a mimic suppressed the ACPA-enhanced phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK1/2), and the expression and secretion of interleukin (IL)-1beta. In conclusion, ACPA-mediated decreased let-7a expression in monocytes from ACPA-positive RA patients. Decreased let-7a expression was associated with the positivity of RF in ACPA-positive RA patients. The decreased expression of let-7a could facilitate the inflammatory pathway via enhanced ACPA mediated phosphorylation of ERK1/2 and JNK and increased expression of IL-1beta through an increase in the expression of Ras proteins. PMID- 26227321 TI - Cardiac Troponin Elevation and Outcome after Subarachnoid Hemorrhage: A Systematic Review and Meta-analysis. AB - BACKGROUND: Cardiac abnormalities frequently occur after subarachnoid hemorrhage (SAH). Cardiac troponin (cTn) is a preferred biomarker for the diagnosis of cardiac damage, and the clinical significance of cTn elevation after SAH remains controversial. This meta-analysis was performed to assess the association between cTn elevation and patient outcomes, including delayed cerebral ischemia (DCI), poor outcome (death or dependency), and death in SAH patients. METHODS: PubMed, Embase, and the Cochrane Library were searched for observational studies reporting an association between cTn elevation and outcome after SAH that were published before December 31, 2014. We extracted data regarding patient characteristics, cTn elevation, and outcome measurements (DCI, poor outcome, or death). Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Twelve studies involving 2214 patients were included in data analysis. Elevation of cTn was observed in 30% of the patients. The cTn elevation was associated with an increased risk of DCI (RR, 1.48; 95% CI, 1.23-1.79), poor outcome (RR, 1.91; 95% CI, 1.51-2.40), and death (RR, 2.53; 95% CI, 2.04-3.12). At the 3- and 12- month follow-ups, cTn elevation was associated with higher rates of DCI (RR, 1.51; 95% CI, 1.11-2.07), poor outcome (RR, 1.91; 95% CI, 1.51-2.40), and death (RR, 2.78; 95% CI, 1.80-4.29). At in-hospital follow-ups, cTn elevation was also associated with the higher rate of death (RR, 2.33; 95% CI, 1.76-3.07). CONCLUSIONS: cTn elevation in SAH patients is associated with an increased risk of DCI, poor outcome, and death after SAH. PMID- 26227322 TI - Balance and Gait Impairment in Transient Ischemic Attack and Minor Stroke. AB - BACKGROUND: There has been little research into gait and balance impairment in transient ischemic attack (TIA) and minor stroke, despite these conditions affecting large numbers of people and the potential impact on function. The aim of this study was to determine the impact of TIA and minor stroke on gait and balance. METHODS: Twelve people with TIA or minor stroke without previous gait/balance problems and 12 age- and sex-matched controls were recruited. Participants (mean age 67 years) underwent a comprehensive assessment including physiological, balance, and gait measures (clinical and computerized [NeuroCom/GAITRite]). Matched-pairs analysis was undertaken. RESULTS: Groups were similar in body mass index, vision, leg proprioception/strength, and reaction time. Cognition was worse in the TIA/minor stroke group: mean Montreal Cognitive Assessment score 22.2 versus 26.6, P = .001. People with TIA/minor stroke were significantly worse on all but one clinical test. Median scores for TIA/minor stroke versus control were as follows: Timed Up and Go (TUG), 9.4 versus 7.6 seconds, P = .019; TUG dual task, 12.3 versus 8.5 seconds, P = .012; Four Square Step Test, 10.9 versus 7.2 seconds, P = .006. Mean Step Test score for TIA/minor stroke versus control was 14.1 versus 17.7, P = .021. The TIA/minor stroke group also had significantly worse performance on computerized tests: increased turn time/sway, increased step length, slower comfortable/fast gait speeds, and greater proportion of gait cycle spent in double support. CONCLUSIONS: This study found that people with TIA/minor stroke have gait and balance dysfunction despite having no obvious physiological impairments. Intervention studies aimed at improving balance and gait in this population are needed. PMID- 26227323 TI - Effective Education Materials to Advance Stroke Awareness Without Teacher Participation in Junior High School Students. AB - BACKGROUND: Youth stroke education is promising for the spread of stroke awareness. The aim of this study was to examine whether our stroke awareness teaching materials without teacher's participation can increase student awareness to act fast on suspected stroke signs. METHODS: We used the face, arm, speech, and time (FAST) mnemonic derived from the Cincinnati Prehospital Stroke Scale. Seventy-three students of the second grade and 72 students of the third grade (age range, 13-15 years) in a junior high school were enrolled in the study. The students were divided into 2 groups: students who received a teacher's lesson (group I) and those who did not receive a teacher's lesson (group II). Students in group II watched an animated cartoon and read a Manga comic in class. All students took the educational aids home, including the Manga comic and magnetic posters printed with the FAST message. Questionnaires on stroke knowledge were examined at baseline and immediately and 3 months after receiving the intervention. RESULTS: At 3 months after the intervention, a significant improvement in understanding the FAST message was confirmed in both the groups (group I, 85%; group II, 94%). Significant increases in the knowledge of risk factors were not observed in each group. CONCLUSIONS: Our education materials include a Manga comic, an animated cartoon, and a magnetic poster, without an accompanying teacher's lesson can increase stroke awareness, including the FAST message, in junior high school students. PMID- 26227324 TI - Long QT syndrome with craniofacial, digital, and neurologic features: Is it useful to distinguish between Timothy syndrome types 1 and 2? AB - Timothy syndrome (TS) is a rare genetic condition that associates long QT syndrome, structural heart defects, dysmorphic facial features, syndactyly, seizures, developmental delay, and autism. Timothy syndrome type 1 is caused by a recurrent de novo mutation (p.Gly406Arg) in exon 8A of the L-type calcium channel gene CACNA1C. Timothy syndrome type 2 was originally reported to be associated with a more severe cardiac phenotype but without syndactyly. Timothy syndrome type 2 is caused by mutation in an alternatively spliced exon 8 of the CACNA1C gene. Other mutations in CACNA1C are also reported with long QT syndrome with and without syndromic features overlapping that described in Timothy syndrome. The purpose of this report is to describe the presentation, physical features and natural history of a 4-year-old girl with Timothy syndrome type 2 due to the recurrent p.Gly406Arg mutation in exon 8 of CACNA1C. She has similar facial features to Timothy syndrome type 1 without syndactyly. She is developmentally delayed without autism. She recently had her first episode of torsade de pointes associated with febrile illness and hypoglycemia. The findings in this case provide further information about the phenotype and natural history of CACNA1C exon 8 mutation and together with previously reported cases of Timothy syndrome question whether the clinical and molecular distinction between Timothy syndromes types 1 and 2 remains clinically useful. PMID- 26227325 TI - Reference values of amino acids and of common clinical chemistry in plasma of healthy infants aged 1 and 4 months. AB - OBJECTIVE: To compare plasma levels of amino acids and clinical chemistry parameters in healthy infants at 1 and 4 months of age and to establish corresponding reference limits. METHODS: Data of three multicenter studies assessing the safety of new infant formulas were used. During these studies infants of both age-groups were either breast-fed or received formulas of low or high protein content. All samples were analyzed centrally in the same accredited laboratory. RESULTS: Plasma was collected from 521 infants in total, 157 boys and 135 girls aged 1 month and 121 boys and 108 girls aged 4 months. At the age of 1 month, 62 infants had received exclusively breast milk, 198 exclusively formula, and 27 both; in the 4-months age group corresponding numbers were 49, 158 and 18, respectively; for 9 infants, diet was unknown. Concentrations of most amino acids and clinical chemistry parameters differed significantly between both ages. Regardless of age, most plasma amino acid levels were comparable or lower in breast-fed than in formula-fed infants whereas at 1 month of age most clinical chemistry parameters were higher. While in breast-fed infants the plasma urea concentration decreased over 4 months of age, it increased in formula-fed infants. There were significant differences between infants fed a low and high protein formula. At both ages, high protein formulas resulted in significantly higher threonine, 2-aminobutyrate, and urea concentrations. CONCLUSIONS: For clinical use, age- and diet specific reference limits in infants are warranted. PMID- 26227326 TI - Diagnosis of dermatophytosis: an evaluation of direct examination using MycetColor(r) and MycetFluo(r). AB - Dermatophytes are an important cause of superficial fungal infection. Direct examination of skin, nail, or hair samples remains essential in diagnosis, as it provides a quick response to the clinician. However, mycological analysis, including direct examination and culture, often lacks sensitivity. The use of stains or fluorochromes may enhance the performance of direct examination. We analyzed 102 samples from patients with suspected dermatophytosis in 4 different diagnostic mycology laboratories. Two reagents, MycetColor(r) and MycetFluo(r), which use Congo red and calcofluor dye, respectively, were evaluated for the direct microscopic examination of skin, hair, and nail specimens. The results were compared to those of culture and conventional direct examination. Both reagents were able to clarify the specimens and also to specifically stain fungal elements. Microscopic examination of the specimens was greatly facilitated with MycetFluo(r), which allowed a higher number of positive cases to be detected compared to the other methods. PMID- 26227327 TI - Rapid quantification of Staphylococcus aureus from endotracheal aspirates of ventilated patients: a proof-of-concept study. AB - Major concern for intubated patients is ventilator-associated pneumonia (VAP). Early detection of VAP and its causative microorganism(s) is a key challenge for clinicians. Diagnosis is based on clinical, radiological, and microbiological elements, the latter being provided 24-48h after sampling. According to practices, clinicians can sample endotracheal aspirates (ETAs) so as to check for patient colonization or perform ETA in case of VAP suspicion. In this proof-of concept study, we report the evaluation of a semiautomated molecular method to rapidly quantify Staphylococcus aureus, one of the most involved microorganisms in VAP, directly from raw ETA samples. After evaluation using artificial ETA samples, our method was applied on 40 clinical ETA samples. All S. aureus positive samples were successfully detected and quantified. Our method can provide an efficient sample preparation protocol for all raw ETA samples, combined with an accurate quantification of the bacterial load, in less than 3h 30min. PMID- 26227328 TI - First report of neonatal bacteremia caused by "Haemophilus quentini" diagnosed by 16S rRNA gene sequencing, Italy. AB - We report the first case of neonatal bacteremia caused by a "Haemophilus quentini" isolate in Italy. The isolate was differentiated from H. influenzae by 16S rRNA sequencing and was characterized by comparison with the wild-type "H. quentini" CCUG 36167. Both isolates carried substitutions in penicillin-binding protein 3 but were susceptible to aminopenicillins. PMID- 26227329 TI - [Coronary endarterectomy experience in myocardial revascularization]. AB - BACKGROUND: Coronary endarterectomy is a surgical procedure to remove atheroma plaques from the coronary arteries, with a worldwide incidence of between 3.7% 42%. 10 years' experience on this technique in our hospital is presented. MATERIAL AND METHODS: A cross-sectional descriptive study was conducted by reviewing 486 clinical records of patients subjected to myocardial revascularisation with cardiopulmonary bypass, moderate hypothermia and ante grade cardioplegia, between January 2003 and June 2013. The risk factors included were: age, gender, left-ventricular-ejection-fraction, EuroSCORE, left main coronary disease, diabetes and systemic arterial hypertension, perioperative mortality, myocardial infarction, perioperative bleeding, surgery times, mediastinitis, sternal dehiscence, and days of hospital stay. RESULTS: A total of 97 patients were included; 77 males (79.4%) and 20 females (20.6%), with a mean age of 62 +/- 8.9 years. 75.2% had arterial hypertension, 61.8% diabetes, and 46.3% both. There was left main coronary disease in 35%, and 18.5% in its equivalent (lesion > 70% in anterior descending and circumflex), 58.5% with depressed left ventricular ejection, and 11.3% was related to failed intervention. The endarterectomy of a single artery was present in 75.2%, mainly to the descending artery, average aorta-coronary bridges 3, arterial left mammary graft, 96.9%, perioperative myocardial infarction 3.09%, reoperation for bleeding 5.15%, dehiscence 3.09%, and mediastinitis 2.06%. The mean stay in the Critical Unit was 4 +/- 6 days and in hospital room 5 +/- 5 days. CONCLUSIONS: To perform coronary endarterectomy increases the morbidity rate, as described in the international literature. Increased mortality was observed in patients with EuroSCORE of intermediate and high risk, which suggests reconsidering the use of this technique in these patients. PMID- 26227330 TI - [Patient participation in decision-making within the framework of a neoliberal health system]. PMID- 26227331 TI - Reply to "Iatrogenic pneumothorax: What can we do?". PMID- 26227332 TI - Decreasing sedentary behavior by 30 minutes per day reduces cardiovascular disease risk factors in rural Americans. AB - Regular physical activity has been associated with reduced cardiovascular disease (CVD) risk factors; however, a decrease in the amount of time spent during the remainder of the day in sedentary behavior may be equally important. The aim of this study was to examine the effects of a decrease in sedentary behavior on CVD risk factors among 205 individuals living in rural Appalachia. All participants received a comprehensive CVD risk reduction life-style intervention and measurement of major CVD risk factors and physical activity levels. Participants were divided into: 1) Adopters: those who decreased their sedentary behavior by 30 min or more per day post-intervention and 2) Non-adopters: those who did not. Repeated measures analysis of variance showed a significant group by time interaction showing that Adopters had a greater reduction in body weight and BMI than Non-adopters. These findings demonstrate that decreasing sedentary behavior is important for achieving optimal body weight. PMID- 26227333 TI - The influence of music during mechanical ventilation and weaning from mechanical ventilation: A review. AB - Mechanical ventilation (MV) causes many distressing symptoms. Weaning, the gradual decrease in ventilator assistance leading to termination of MV, increases respiratory effort, which may exacerbate symptoms and prolong MV. Music, a non pharmacological intervention without side effects may benefit patients during weaning from mechanical ventilatory support. A narrative review of OVID Medline, PsychINFO, and CINAHL databases was conducted to examine the evidence for the use of music intervention in MV and MV weaning. Music intervention had a positive impact on ventilated patients; 16 quantitative and 2 qualitative studies were identified. Quantitative studies included randomized clinical trials (10), case controls (3), pilot studies (2) and a feasibility study. Evidence supports music as an effective intervention that can lesson symptoms related to MV and promote effective weaning. It has potential to reduce costs and increase patient satisfaction. However, more studies are needed to establish its use during MV weaning. PMID- 26227336 TI - Cyclic Loading Effect on Color Stability of Unshaded versus Shaded Zirconia. AB - STATEMENT OF PROBLEM: Shaded versions of dental zirconia may improve initial color matching to teeth, but might change color with cyclic mechanical loading. PURPOSE: The purpose of this study was to measure the color of unshaded and shaded zirconia dental ceramic before and after cyclic mechanical loading and calculate color differences (DeltaE). MATERIAL AND METHODS: Disk-shaped specimens (N = 30, Nobel Procera, 0.8 mm thick, 12 mm diameter) of unshaded or shaded zirconia (intrinsically shaded by small oxide modifications) were fabricated by the Nobel Biocare using standard CAD-CAM processing. Milled surfaces were polished. CIE L*a*b* values were measured (Konica Minolta spectrophotometer) before and after mechanical cycling (custom modified Leinfelder test machine, biaxial flexure loading, load = 80 N * 500,000 cycles, dry), and L*a*b* individual differences and DeltaE color differences were calculated and compared (ANOVA, p < 0.05). RESULTS: Mean L*a*b* values for the unshaded group before (U1 = 86.165, -0.887, 0.372) and after (U2 = 84.860, -0.805, 0.097) cyclic loading were compared to the shaded group before (S1 = 75.281, -0.679, 23.251) and after (S2 = 74.961, -1.233, 22.439) cyclic loading. All color variables for both unshaded and shaded groups were significantly different between before and after cyclic loading (p < .004) except for the L* value of the shaded group. The DeltaE for unshaded (1.441 +/- 0.495) versus shaded (1.252 +/- 0.363) were statistically different but clinically the change would not be detectable at this point. CONCLUSIONS: The color of the unshaded and shaded zirconia specimens was influenced by cyclic loading (p < 0.05). Color changes were detectable but small at levels up to 500,000 cycles, and remained clinically acceptable at that point. CLINICAL SIGNIFICANCE: It is important to acknowledge any possible color changes that might occur in zirconia restorations, especially in the esthetic zone. Minor color changes that are individually imperceptible to the human eye within different restorative components may be compounded to produce clinically significant color change that is not aesthetically acceptable. PMID- 26227337 TI - Generation-based life table analysis reveals manifold effects of inbreeding on the population fitness in Plutella xylostella. AB - Understanding how inbreeding affects fitness is biologically important for conservation and pest management. Despite being a worldwide pest of many economically important cruciferous crops, the influence of inbreeding on diamondback moth, Plutella xylostella (L.), populations is currently unknown. Using age-stage-specific life tables, we quantified the inbreeding effects on fitness-related traits and demographic parameters of P. xylostella. Egg hatching rate, survival and fecundity of the inbred line significantly declined compared to those of the outbred line over time. The inbred P. xylostella line showed significantly lower intrinsic rate of increase (r), net reproduction rate (R0), and finite increase rate (lambda), and increasing generation time (T). Inbreeding effects vary with developmental stages and the fitness-related traits can be profoundly affected by the duration of inbreeding. Our work provides a foundation for further studies on molecular and genetic bases of the inbreeding depression for P. xylostella. PMID- 26227335 TI - Emerging roles of lysine methylation on non-histone proteins. AB - Lysine methylation is a common posttranslational modification (PTM) of histones that is important for the epigenetic regulation of transcription and chromatin in eukaryotes. Increasing evidence demonstrates that in addition to histones, lysine methylation also occurs on various non-histone proteins, especially transcription and chromatin-regulating proteins. In this review, we will briefly describe the histone lysine methyltransferases (KMTs) that have a broad spectrum of non histone substrates. We will use p53 and nuclear receptors, especially estrogen receptor alpha, as examples to discuss the dynamic nature of non-histone protein lysine methylation, the writers, erasers, and readers of these modifications, and the crosstalk between lysine methylation and other PTMs in regulating the functions of the modified proteins. Understanding the roles of lysine methylation in normal cells and during development will shed light on the complex biology of diseases associated with the dysregulation of lysine methylation on both histones and non-histone proteins. PMID- 26227339 TI - A case of cephalomelia discovered in a baby born in Niger. AB - INTRODUCTION: Subcutaneous tumors with extra limbs are very rare, and they are considered either as fetus in fetu or fetiform teratoma. CASE REPORT: We report here the case of a 6-day-old presenting a mass extending at the level of the occipital bone. This mass is developed in the extracranial region and contains two forelimbs including hands with digits. CT shows that the squamous part of the occipital bone is involved with several defects through which a part of the cerebellum herniates. The boy was operated on and the tumor was removed. The herniated region of the cerebellum has also been removed. After surgery, the boy develops normally. CONCLUSION: This type of tumor is extremely rare and is only the second case that has been reported at this exact location. This could be the so-called cephalomelie described by Isidore Geoffroy Saint-Hilaire in a duck in his famous Treatise of Teratology (1836). The cause of this malformation is still a matter for debate. PMID- 26227338 TI - Ethmoidal meningoencephalocele and CSF leak after posthaemorrhagic ventricular dilatation in a newborn child. AB - BACKGROUND: Rhinoliquorrhoea suggests a communication between the subarachnoid space and the sinonasal tract. Clinical presentation includes clear nasal discharge, headache, pneumocephalus, meningitis or brain abscess. Cerebrospinal fluid (CSF) leaks are mostly of traumatic origin (skull base fractures), iatrogenic (secondary to endoscopic endonasal surgery) or associated with tumour aetiology. Occasionally, hydrocephalus has been the cause of rhinoliquorrhoea in adults, presumably secondary to the chronically raised intracranial pressure with skull base erosion and meningocele. To our knowledge, the association of hydrocephalus and ethmoid meningoencephalocele/CSF leak has not been previously reported in a newborn child. CASE PRESENTATION: We present the case of a 9-month old girl who was referred for rhinorrhoea. She had a history of posthaemorrhagic ventricular dilatation. Brain computed tomography (CT) and magnetic resonance imaging (MRI) showed a left ethmoidal meningoencephalocele and small ventricular size. The meningoencephalocele was surgically repaired using an intradural subfrontal approach. During the postoperative period, after the transient lumbar drain was withdrawn, she developed symptomatic hydrocephalus. Ventriculoperitoneal shunting was required. CONCLUSION: Progressive ventricular dilatation may arise from a meningoencephalocele/CSF leak in paediatric patients. Early identification and repair of the meningoencephalocele are critical to avoid development of complications. PMID- 26227334 TI - Tubulin acetylation: responsible enzymes, biological functions and human diseases. AB - Microtubules have important functions ranging from maintenance of cell morphology to subcellular transport, cellular signaling, cell migration, and formation of cell polarity. At the organismal level, microtubules are crucial for various biological processes, such as viral entry, inflammation, immunity, learning and memory in mammals. Microtubules are subject to various covalent modifications. One such modification is tubulin acetylation, which is associated with stable microtubules and conserved from protists to humans. In the past three decades, this reversible modification has been studied extensively. In mammals, its level is mainly governed by opposing actions of alpha-tubulin acetyltransferase 1 (ATAT1) and histone deacetylase 6 (HDAC6). Knockout studies of the mouse enzymes have yielded new insights into biological functions of tubulin acetylation. Abnormal levels of this modification are linked to neurological disorders, cancer, heart diseases and other pathological conditions, thereby yielding important therapeutic implications. This review summarizes related studies and concludes that tubulin acetylation is important for regulating microtubule architecture and maintaining microtubule integrity. Together with detyrosination, glutamylation and other modifications, tubulin acetylation may form a unique 'language' to regulate microtubule structure and function. PMID- 26227340 TI - A migrated knitting needle in a paediatric spine: case report. AB - PURPOSE: The aims of this study were to present migration of a sharp metal material into the spinal canal in a paediatric patient and to discuss the management of metallic foreign bodies in the spinal canal. METHODS: Patient's medical reports, radiological tests, review of intraoperative findings, and literature search were examined. RESULTS: The migration and penetration of a knitting needle in a 7-year-old-boy are presented. CONCLUSIONS: There is a significant risk of migration of penetrating foreign materials into the spinal canal. Early identification and removal of these foreign bodies retained in the spinal canal may be important even when the patient is asymptomatic. PMID- 26227341 TI - White butterflies as solar photovoltaic concentrators. AB - Man's harvesting of photovoltaic energy requires the deployment of extensive arrays of solar panels. To improve both the gathering of thermal and photovoltaic energy from the sun we have examined the concept of biomimicry in white butterflies of the family Pieridae. We tested the hypothesis that the V-shaped posture of basking white butterflies mimics the V-trough concentrator which is designed to increase solar input to photovoltaic cells. These solar concentrators improve harvesting efficiency but are both heavy and bulky, severely limiting their deployment. Here, we show that the attachment of butterfly wings to a solar cell increases its output power by 42.3%, proving that the wings are indeed highly reflective. Importantly, and relative to current concentrators, the wings improve the power to weight ratio of the overall structure 17-fold, vastly expanding their potential application. Moreover, a single mono-layer of scale cells removed from the butterflies' wings maintained this high reflectivity showing that a single layer of scale cell-like structures can also form a useful coating. As predicted, the wings increased the temperature of the butterflies' thorax dramatically, showing that the V-shaped basking posture of white butterflies has indeed evolved to increase the temperature of their flight muscles prior to take-off. PMID- 26227342 TI - Nanoscale Nitrogen Doping in Silicon by Self-Assembled Monolayers. AB - This Report presents a nitrogen-doping method by chemically forming self assembled monolayers on silicon. Van der Pauw technique, secondary-ion mass spectroscopy and low temperature Hall effect measurements are employed to characterize the nitrogen dopants. The experimental data show that the diffusion coefficient of nitrogen dopants is 3.66 * 10(-15) cm(2) s(-1), 2 orders magnitude lower than that of phosphorus dopants in silicon. It is found that less than 1% of nitrogen dopants exhibit electrical activity. The analysis of Hall effect data at low temperatures indicates that the donor energy level for nitrogen dopants is located at 189 meV below the conduction band, consistent with the literature value. PMID- 26227343 TI - Pre-referral general practitioner consultations and subsequent experience of cancer care: evidence from the English Cancer Patient Experience Survey. AB - Prolonged diagnostic intervals may negatively affect the patient experience of subsequent cancer care, but evidence about this assertion is sparse. We analysed data from 73 462 respondents to two English Cancer Patient Experience Surveys to examine whether patients with three or more (3+) pre-referral consultations were more likely to report negative experiences of subsequent care compared with patients with one or two consultations in respect of 12 a priori selected survey questions. For each of 12 experience items, logistic regression models were used, adjusting for prior consultation category, cancer site, socio-demographic case mix and response tendency (to capture potential variation in critical response tendencies between individuals). There was strong evidence (P < 0.01 for all) that patients with 3+ pre-referral consultations reported worse care experience for 10/12 questions, with adjusted odds ratios compared with patients with 1-2 consultations ranging from 1.10 (95% confidence intervals 1.03-1.17) to 1.68 (1.60-1.77), or between +1.8% and +10.6% greater percentage reporting a negative experience. Associations were stronger for processes involving primary as opposed to hospital care; and for evaluation than report items. Considering 1, 2, 3-4 and '5+' pre-referral consultations separately a 'dose-response' relationship was apparent. We conclude that there is a negative association between multiple pre diagnostic consultations with a general practitioner and the experience of subsequent cancer care. PMID- 26227344 TI - Targeted narrowband intense pulsed light on cutaneous vasculature. AB - BACKGROUND AND OBJECTIVES: Laser based therapies are the standard treatment protocol for port wine stain in the United States, but complete removal is infrequently achieved. Intense pulsed light (IPL) offers a broadband light spectrum approach as a viable treatment alternative. Previous studies suggest that IPL can be more effective in treatment of port wine stain by utilizing multiple wavelengths to selectively target different peaks in oxy- and deoxy hemoglobin. Our study objectives were to (i) determine a characteristic radiant exposure able to achieve persistent vascular shutdown with narrowband IPL irradiation, (ii) determine the degree to which narrowband IPL irradiation can achieve persistent vascular shutdown, and (iii) compare the effectiveness of narrowband IPL radiation to single wavelength pulsed dye laser (PDL) irradiation in achieving persistent vascular shutdown. STUDY DESIGN/MATERIALS AND METHODS: We utlized either single pulse or double, stacked pulses in narrowband IPL experiments, with the IPL operating over a 500-600 nm wavelength range on the rodent dorsal window chamber model. We compared the results from our narrowband IPL experiments to acquired PDL data from a previous study and determined that narrowband IPL treatments can also produce persistent vascular shutdown. We ran Monte Carlo simulations to investigate the relationship between absorbed energy, wavelength, and penetration depth. RESULTS: For single and double pulse narrowband IPL irradiation we observed (i) little to no change in blood flow, resulting in no persistent vascular shutdown, (ii) marked acute disruption in blood flow and vascular structure, followed by partial to full recovery of blood flow, also resulting in no persistent vascular shutdown, and (iii) immediate changes in blood flow and vascular structure, resulting in prolonged and complete vascular shutdown. Monte Carlo modeling resulted in a 53.2% and 69.0% higher absorbed energy distribution in the top half and the total simulated vessel when comparing the composite narrowband IPL to the 595 nm (PDL), respectively. CONCLUSIONS: Our data collectively demonstrate the potential to achieve removal of vascular lesions using a 500-600 nm range. Additionally, the narrowband IPL was tuned to optimize a specific wavelength range that can be used to treat PWS, whereas the PDL can only operate at one discrete wavelength. PMID- 26227345 TI - Cytopathology of Follicular Cell Nodules. AB - This article corresponds to a lecture delivered during the Endocrine Pathology Society symposium held in Boston on 21 March 2015 (104th USCAP meeting, March 21 27). It focuses on the importance of cytopathology in endocrine thyroid pathology and the limits and pitfalls of diagnosis in follicular cell lesions. Lights and shadows are present in each diagnostic technique: Fine needle aspiration has imposed itself as a gold standard in thyroid nodules thanks to its easiness of execution and high cost-effectiveness ratio. A milestone in this field is represented by the National Cancer Institute (NCI) Thyroid Fine Needle Aspiration (FNA) State of the State of the Science Conference hosted in October 22-23, 2007 by the NCI, followed by a series of documents published in Diagnostic Cytopathology and Cytojournal (2008) as well as in an atlas entitled: The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC): terminology and criteria (2010, Springer). "Gray" zones still remain, causing difficulties and anxiety to the cytopathologist when facing challenging cases. Each diagnostic category of TBSRTC is analyzed and discussed in a concise fashion with special emphasis on challenging cases such as atypia of undetermined significance (AUS), suspicion for follicular neoplasms (SFNs), diagnoses of papillary thyroid carcinoma (PTC) in Hashimoto thyroiditis and follicular variant of papillary carcinoma (FVPTC). Our aim was to better define and clarify the spectrum of follicular cell lesions in thyroid nodule samplings and to underline the diagnostic limits in order to avoid pitfalls. New emerging molecular biology techniques may represent useful tools in selected morphological challenging cases and lead to new therapeutic approaches in line with drug-tailored therapy and personalized medicine. PMID- 26227346 TI - Stent Fracture After Sirolimus-Eluting Stent Implantation: 8-Year Clinical Outcomes. AB - BACKGROUND: Stent fracture (SF) after sirolimus-eluting stent implantation is reported to be associated with target lesion revascularization (TLR) and stent thrombosis. We aimed to assess the clinical impact of SF at 8 years. METHODS AND RESULTS: Between 2002 and 2005, 972 patients (1795 lesions) underwent sirolimus eluting stent implantation and follow-up angiography within 1 year after index procedure. SF, defined as the complete separation of stent segments or stent struts at follow-up angiography, was observed in 105 lesions (5.8%). The study sample comprised 954 patients (1630 lesions), excluding 147 lesions undergoing TLR and 18 patients (18 lesions) who died or in whom stent thrombosis developed within 1 year after sirolimus-eluting stent implantation. The median follow-up duration was 9.1 years (the first and third quarters, 8.7 and 9.4 years). The primary end point was defined as any TLR. The 8-year cumulative rates of adverse events were estimated by Kaplan-Meier methods with P values from log-rank tests. Between patients with and without SF, there were no significant differences in the cumulative rates of all-cause death (23.5% versus 27.6%, P=0.35) and cardiac death (4.7% versus 9.1%, P=0.14), whereas patients with SF had significantly higher cumulative rates in myocardial infarction (10.1% versus 3.3%, P=0.001), very late stent thrombosis (6.8% versus 0.7%, P<0.001), any TLR (38.1% versus 10.8%, P<0.001), and clinically driven TLR (26.2% versus 6.6%, P<0.001). CONCLUSIONS: SF after sirolimus-eluting stent implantation was consistently associated with higher rates of adverse cardiac events during the 8-year follow up. PMID- 26227347 TI - Thirty-Day Readmissions After Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis in New York State. AB - BACKGROUND: Several studies have compared short-term and medium-term mortality rates for patients with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR), but no studies have compared short-term readmission rates for the 2 procedures. METHODS AND RESULTS: New York's Cardiac Surgery Reporting System was used to propensity match 617 TAVI and 1981 SAVR patients using numerous patient risk factors contained in the registry. The 389 propensity-matched pairs were then used to analyze differences in readmission rates between the 2 groups. TAVI and SAVR readmission rates were also compared for patients with a history of congestive heart failure and for patients aged >=80. Also, reasons for readmission for TAVI and SAVR patients were examined and compared. Readmission rates were not statistically different for all propensity-matched TAVI and SAVR patients (respective rates, 18.8% and 19.3%; P=0.86). After further adjustment using a logistic regression model, there was still no significant difference (adjusted odds ratio, 0.97; 95% confidence interval [0.68-1.39]). For patients aged >=80, the 30-day readmission rates were 19.9% and 22.0% (P=0.59), and when further adjusted using the logistic regression model, adjusted odds ratio=0.89 (0.55 1.45). For patients with a history of congestive heart failure, the respective rates were 22.8% and 20.4% (P=0.56), and with further adjustment, adjusted odds ratio became 1.15 (0.72-1.82). CONCLUSIONS: There are no statistically significant differences between TAVI and SAVR patients in short-term readmission rates. PMID- 26227348 TI - Decompressive hemicraniectomy for treatment of space occupying ischemic stroke after repair of type-A aortic dissection. AB - Postoperative stroke after cardiac surgery is often a lethal complication. Herein, we report on a patient who suffered space-occupying ischemic stroke after surgical treatment of type A aortic dissection. He underwent decompressive hemicraniectomy and, despite residual hemianopsia and left side flaccid hemiplegia, survived surgery and was discharged for rehabilitation. This observation suggests that early consultation with a neurosurgeon, intracranial pressure monitoring and, when indicated, decompressive hemicraniectomy should be considered in order to reduce the high mortality rate associated with ischemic stroke after cardiac surgery. PMID- 26227350 TI - Mechanical properties of human autologous tubular connective tissues (human biotubes) obtained from patients undergoing peritoneal dialysis. AB - Completely autologous in vivo tissue-engineered connective tissue tubes (Biotubes) have promise as arterial vascular grafts in animal implantation studies. In this clinical study of patients undergoing peritoneal dialysis (PD) (n = 11; age: 39-83 years), we evaluated human Biotubes' (h-Biotubes) mechanical properties to determine whether Biotubes with feasibility as vascular grafts could be formed in human bodies. We extracted PD catheters, embedded for 4-47 months, and obtained tubular connective tissues as h-Biotubes (internal diameter: 5 mm) from around the catheter' silicone tubular parts. h-Biotubes were composed mainly of collagen with smooth luminal surfaces. The average wall thickness was 278 +/- 178 MUm. No relationship was founded between the tubes' mechanical properties and patients' ages or PD catheter embedding periods statistically. However, the elastic modulus (2459 +/- 970 kPa) and tensile strength (623 +/- 314 g) of h-Biotubes were more than twice as great as those from animal Biotubes, formed from the same PD catheters by embedding in the beagle subcutaneous pouches for 1 month, or beagle arteries. The burst strength (6338 +/- 1106 mmHg) of h Biotubes was almost the same as that of the beagle thoracic or abdominal aorta. h Biotubes could be formed in humans over a 4-month embedding period, and they satisfied the mechanical requirements for application as vascular grafts. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1431 1437, 2016. PMID- 26227351 TI - [Chronic urticaria: new international guidelines]. PMID- 26227349 TI - AAV2/1 CD74 Gene Transfer Reduces beta-amyloidosis and Improves Learning and Memory in a Mouse Model of Alzheimer's Disease. AB - Modulation of the amyloid-beta (Abeta) trafficking pathway heralds a new therapeutic frontier for Alzheimer's disease (AD). As CD74 binds to the amyloid beta precursor protein (APP) and can suppresses Abeta processing, we investigated whether recombinant adeno-associated virus (AAV) delivery of CD74 could reduce Abeta production and affect disease outcomes. This idea was tested in a mouse AD model. Cotransduction of AAV-tetracycline-controlled transactivator (tTA) and AAV tet-response element (TRE)-CD74 resulted in CD74 expression, reduced Abeta production in mouse neurons containing the human APP with familial AD-linked mutations. Stereotaxic injection of AAV-TRE-GFP or CD74 into the hippocampi of an AD mouse, defined as a TgCRND8 * calmodulin-dependent protein kinase II derived promoter-tTA double-transgenic, reduced Abeta loads and pyramidal neuronal Abeta accumulation in the hippocampus. Immunofluorescent studies showed that APP colocalization with Lamp1 was increased in CD74-expressing neurons. Moreover, Morris water maze tasks demonstrated that mice treated with AAV-TRE-CD74 showed improved learning and memory compared to AAV-TRE-GFP control animals. These results support the idea that CD74-induced alteration of Abeta processing could improve AD-associated memory deficits as shown in mouse models of human disease. PMID- 26227365 TI - S1 guideline aesthetic botulinum toxin therapy. PMID- 26227366 TI - Effects of precipitation change and neighboring plants on population dynamics of Bromus tectorum. AB - Shifting precipitation patterns resulting from global climate change will influence the success of invasive plant species. In the Front Range of Colorado, Bromus tectorum (cheatgrass) and other non-native winter annuals have invaded grassland communities and are becoming more abundant. As the global climate warms, more precipitation may fall as rain rather than snow in winter, and an increase in winter rain could benefit early-growing winter annuals, such as B. tectorum, to the detriment of native species. In this study we measured the effects of simulated changes in seasonal precipitation and presence of other plant species on population growth of B. tectorum in a grassland ecosystem near Boulder, Colorado, USA. We also performed elasticity analyses to identify life transitions that were most sensitive to precipitation differences. In both study years, population growth rates were highest for B. tectorum growing in treatments receiving supplemental winter precipitation and lowest for those receiving the summer drought treatment. Survival of seedlings to flowering and seed production contributed most to population growth in all treatments. Biomass of neighboring native plants was positively correlated with reduced population growth rates of B. tectorum. However, exotic plant biomass had no effect on population growth rates. This study demonstrates how interacting effects of climate change and presence of native plants can influence the population growth of an invasive species. Overall, our results suggest that B. tectorum will become more invasive in grasslands if the seasonality of precipitation shifts towards wetter winters and allows B. tectorum to grow when competition from native species is low. PMID- 26227367 TI - Negative density-dependent mortality varies over time in a wet tropical forest, advantaging rare species, common species, or no species. AB - Although one of the most widely studied hypotheses for high tree diversity in the tropics, the Janzen-Connell hypothesis (JC), and the community compensatory trend upon which it is based, have conflicting support from prior studies. Some of this variation could arise from temporal variation in seedling survival of common and rare species. Using 10 years of data from La Selva Biological Station in Costa Rica, we analyzed annual seedling survival and found that negative density dependence (negative DD) was significantly stronger for rare species than for common species in 2 years and was significantly stronger for common species than for rare species in 4 years. This temporal variation in survival was correlated with climatic variables: in warmer and wetter years, common species had higher negative DD than rare species. The relationship between climate and variation in JC effects on seedling survival of common and rare species could have important consequences for the maintenance of tree species diversity in Central America, which is predicted to experience warmer and wetter years as global change proceeds. PMID- 26227368 TI - Frances Keesler Graham (1918-2013). PMID- 26227369 TI - Successful methodology for large-scale surveillance of severe events following influenza vaccination in Canada, 2011 and 2012. AB - In 2011 and 2012, a nationwide Canadian vaccine safety surveillance network rapidly collected safety data from healthcare workers (HCW) during the first weeks of the annual influenza vaccination campaign. This network provided the first available post-marketing safety data on seasonal influenza vaccines with information on background rates as a comparator. In 2012, these data were used to investigate a possible safety concern regarding a particular vaccine. An online questionnaire was provided to participating HCW two weeks before the annual influenza vaccination campaign for controls, and eight days after influenza vaccination for vaccinees. Control and vaccinees were requested to report health events occurring in the seven days prior to receiving the questionnaire. Control data were used to calculate background rates. HCW reporting a severe event were followed-up by telephone within 48 hours of the online report to validate the report and check on their health status. More than 22,000 vaccinated HCW were enrolled and surveyed over two seasons and > 90% reported no severe event following vaccination. Validated severe event rates were similar in vaccinated HCW and unvaccinated HCW (2.2% vs 2.3%; p < 0.70). The questionnaire was accurately completed for most reported symptoms, matched the validated report and was able to detect events of interest. Prior to the safety concern, the implicated vaccine was in use at one centre. Reassuring safety data were provided to public health authorities 48 hours after the vaccine was temporarily suspended. Data from this and similar networks can be used for rapid evaluation of vaccine safety and for safety assessment as required by the European Medicines Agency in 2015. PMID- 26227370 TI - Large and prolonged food-borne multistate hepatitis A outbreak in Europe associated with consumption of frozen berries, 2013 to 2014. AB - In May 2013, Italy declared a national outbreak of hepatitis A, which also affected several foreign tourists who had recently visited the country. Molecular investigations identified some cases as infected with an identical strain of hepatitis A virus subgenotype IA. After additional European Union/European Economic Area (EU/EEA) countries reported locally acquired and travel-related cases associated with the same outbreak, an international outbreak investigation team was convened, a European outbreak case definition was issued and harmonisation of the national epidemiological and microbiological investigations was encouraged. From January 2013 to August 2014, 1,589 hepatitis A cases were reported associated with the multistate outbreak; 1,102 (70%) of the cases were hospitalised for a median time of six days; two related deaths were reported. Epidemiological and microbiological investigations implicated mixed frozen berries as the vehicle of infection of the outbreak. In order to control the spread of the outbreak, suspected or contaminated food batches were recalled, the public was recommended to heat-treat berries, and post-exposure prophylaxis of contacts was performed. The outbreak highlighted how large food-borne hepatitis A outbreaks may affect the increasingly susceptible EU/EEA general population and how, with the growing international food trade, frozen berries are a potential high-risk food. PMID- 26227371 TI - Food-borne diseases associated with frozen berries consumption: a historical perspective, European Union, 1983 to 2013. AB - Epidemiological investigations of outbreaks of hepatitis A virus (HAV) and norovirus (NoV) infections in the European Union/European Economic Area (EU/EEA) in the last five years have highlighted frozen berries as a vehicle of infection. Given the increasing berry consumption in the EU over the last decades, we undertook a review of the existing evidence to assess the potential scale of threat associated with this product. We searched the literature and four restricted-access online platforms for outbreak/contamination events associated with consumption of frozen berries. We performed an evaluation of the sources to identify areas for improvement. The review revealed 32 independent events (i.e. outbreak, food contamination) in the period 1983-2013, of which 26 were reported after 2004. The identified pathogens were NoV, HAV and Shigella sonnei. NoV was the most common and implicated in 27 events with over 15,000 cases reported. A capture-recapture analysis was performed including three overlapping sources for the period 2005-2013. The study estimated that the event-ascertainment was 62%. Consumption of frozen berries is associated with increasing reports of NoV and HAV outbreaks and contamination events, particularly after 2003. A review of the risks associated with this product is required to inform future prevention strategies. Better integration of the available communication platforms and databases should be sought at EU/EEA level to improve monitoring, prevention and control of food-borne-related events. PMID- 26227372 TI - Authors correction for Euro Surveill. 2015;20(28). PMID- 26227373 TI - Authors correction for Euro Surveill. 2015;20(28). PMID- 26227374 TI - Reactor performance and microbial characteristics of CANON process with step-wise increasing of C/N ratio. AB - In this study, the nitrogen removal performance and microbial characteristics of completely autotrophic nitrogen removal over nitrite (CANON) process was investigated with a step-wise increasing of C/N ratio (0.5, 1, 2 and 4) in a membrane bioreactor. The microbial distribution of aerobic ammonia-oxidizing bacteria (AOB) and anaerobic AOB (AAOB) was analysed by fluorescence in situ hybridization (FISH). Results showed that the denitrification ratio rose up correspondingly with the increase of influent C/N, and nitrogen removal rate (NRR) reached the maximum when C/N was 1 due to the harmonious work of denitrification and CANON. However, NRR decreased when influent C/N was more than 2. The threshold C/N ratio of CANON process was 2.2; so the sewage with a high C/N ratio should be pretreated by combining with pre-oxidation of organics or anaerobic-energy-producing process. FISH results showed decreasing numbers of both AOB and AAOB with the addition of organics. PMID- 26227375 TI - [Not Available]. PMID- 26227376 TI - Erratum. PMID- 26227377 TI - Validation of Numerically Simulated Tissue Temperatures During Transcutaneous Recharge of Neurostimulation Systems. AB - OBJECTIVE: A research study combining numerical simulation and animal-model experiments has been performed to assess the ability of simulation to accurately calculate temperatures within living tissue during the recharge of a neuromodulation system (Restore Ultra device, Medtronic Neuromodulation, Minneapolis, MN, USA). MATERIALS AND METHODS: The experiments were carried out on a sheep with the neuromodulation implant set to depths of 0.6 cm and 2.1 cm. Temperatures were recorded on the surfaces of the implant and on the sheep skin. Finite element simulations were carried out to determine the degree to which the simulations and experiments match. Additional calculations were performed for an intermediate implant depth. RESULTS: It was found that there was excellent agreement between the simulations and the animal model for both depths. CONCLUSION: It is shown that numerical simulation using the Pennes bioheat equation is capable of predicting temperature increases within living tissues when implanted heat-generating devices are in use. The device used in the present study does not give rise to temperatures which cause concern of thermal injury or safety. The study was performed for aligned antenna and implant. PMID- 26227378 TI - [In Process Citation]. PMID- 26227379 TI - [The Impact of Psychotherapeutic or Psychiatric Pretreatment on the Mental Aptitude of Officers-to-be]. AB - In the context of the medical assessment of officers-to-be, the physical and mental aptitude of persons having revealed a psychotherapeutic or psychiatric pretreatment is frequently questioned. Generally, the fact that a person took up a specific therapy because of psychic disturbance doesn't tell anything about severeness and relevance of an underlying mental disorder. If evidence of psychiatric disease arises during the medical examination, an additional expert advice should be obtained to differentiate between mild or reversible dysfunctions and severe or chronifying psychiatric diseases. In the light of a growing social acceptance of psychotherapy, the finding of a prior psychotherapeutic or psychiatric treatment without regarding the individual background, course and prognosis cannot longer justify the exclusion from officialdom. PMID- 26227380 TI - [Management of Uninhabitable Homes - Investigation of 186 Cases of Hoarding, Domestic Neglect and Squalor in Dortmund (Germany)]. AB - OBJECTIVE: To develop an intervention concept for the management of uninhabitable homes. METHODS: Retrospective analysis of 186 cases of the community mental health service in Dortmund (Germany) presenting with a destitute situation of the domestic environment as core problem. RESULTS: All patients suffered from psychiatric illnesses, mainly from addiction (F1: 41%), psychosis (F2: 17%), depression (F3: 17%), and hoarding disorder (F63.8: 12%). Main socio-demographic characteristics of our sample are: middle age (45-65 years, 48%), male gender (73%), isolated situation (only 7% married, 84% living alone), normal schooling (only 4% without completion of schooling, 7% attended a school for special needs), after initial integration into employment nearly all patients suffered vocational disintegration (5% employed, 44% unemployment benefit, 7% welfare, 39% pension or invalidity benefit). Psychosocial interventions differed between the 4 main diagnostic groups: F1: treatment of dependence (rehab) and treatment of concomitant somatic diseases; F2: admission to a psychiatric hospital and implementation of guardianship; F3: mediation of conflicts with neighbours/landlords and implementation of guardianship; F63.8: direct practical help by members of the community mental health team and organisation of home help/waste disposal. In all diagnostic groups, acceptance of help was impaired due to social withdrawal, resistance and psychiatric symptoms. At 13%, compliance with help and interventions was lowest in the hoarder group (F1: 27%, F2: 26%, F3: 38%). Consequently, in this group the poor outcome categories "nothing accomplished" and "lost flat/eviction" were more frequent (44%, F1: 27%, F2: 26%, F3: 38%). CONCLUSIONS: Concurrent to the deterioration of the domestic situation, patients suffer vocational disintegration as well as family and social isolation. Uninhabitable homes occur in the course of various severe and chronic psychiatric diseases. They don't constitute a syndrome and they are not characteristic for one specific diagnosis. It is important to recognise the underlying psychiatric disease as diagnosis influences acceptance of help, choice of appropriate interventions, outcome and prognosis. Tab. 1 shows our suggestion for a diagnosis differentiated approach, relating appearance of the home and behaviour of the patient to diagnosis, appropriate interventions and prognosis. Hard to reach is the group of hoarders. Patients with a psychotic illness and with hoarding disorder require implementation of long-term outreach help in their homes. PMID- 26227382 TI - [Hygiene and Public Health - Significance in Medicine and Society]. AB - The presented review attempts an historical overview on the development of Public Health in Germany with special reference to the medical specialty of Hygiene. This development is put in perspective to current international developments with a special emphasis on the programmatic work in the field of Public Health of the European Union. PMID- 26227381 TI - [The Humanitarian Consultation-hour in Frankfurt am Main: Utilization by Gender, Age, Country of Origin]. AB - BACKGROUND: The humanitarian consultation-hour is a voluntary, anonymous offer provided by the City of Frankfurt am Main, which was established in December 2001. Here, people without health insurance or undocumented migrants can be treated for free. The aim of this analysis is to investigate the utilization of the consultation-hour by gender, age, country of origin and diagnosis since 2008. METHODS: The digital data documentation is available since 2008. Data from the years 2008-2013 were considered. The examination date, the date of birth, sex, country of origin, frequency of visits, diseases and medication amongst other data were examined. RESULTS: In the period from 2008 to 2013, 8,574 consultations were counted and 2,384 patients were treated during office hours. The amount of consultations has doubled between 2008 (n=673) and 2009 (n=1,154) and is rising steadily since then (1,911 visits in 2013). The majority of patients come from Africa. Since 2008, an increase of patients from Bulgaria and Romania has been recorded. Approximately two-thirds of the patients are female, one third male. One fifth of those seeking help are children and adolescents under 20 years and adults over 60 years. The most common age group is between 20-40 years old. The main diagnoses include diseases of the cardiovascular and vascular system and the musculoskeletal system, metabolic diseases (diabetes mellitus), digestive diseases and pregnancy/childbirth. CONCLUSION: The humanitarian consultation-hour is an important offer provided by the Public Health Department of the City of Frankfurt am Main and is used by a large number of people who are seeking help. In particular, people from South Eastern Europe are increasingly visiting the consultation-hour. Activities such as the humanitarian consultation-hour can take over subsidiary activities for a transitional period, however long-term structural solutions must be provided to ensure access to health care for this vulnerable group. PMID- 26227383 TI - [Detection of a Disease Cluster by the Health Authorities of Stendal District due to Campylobacter jejuni in a Nursery After the Consumption of Raw Milk]. AB - A notification from a laboratory concerning the detection of Campylobacter jejuni in a 6-year-old boy initiated the investigation carried out by the health authorities from Stendal district, in order to explain the morbidity rate caused by the germ. The day after the boy's pediatrician informed about a visit to a farm, which was confirmed by the head of the nursery. She told the health authorities about the consumption of raw milk during their visit at the farm.The following days more children fell sick. Within 10 days the total number of diseased children was 21. The health authorities asked for stool samples of the diseased children, nursery nurses and the head of the farm since raw milk presents a potential cause of infection. The health authorities together with the Saxony-Anhalt State Office for Consumer Protection conducted a retrospective cohort study. The aim was to explain the association between the exposure from raw milk consumption and the occurrence of the disease from C. jejuni. Based on a questionnaire data about the food and milk intake at the nursery and at home and about the trip to the farm were collected. 91% of the children's cohort and 86% of the adults' cohort were captured.The exposed group at risk showed a higher risk of falling ill than the group, which was not exposed. The risk factor raw milk explained the difference. Furthermore, the analysis of milk samples taken by the district veterinary office from 2 cows and from the farm's tank was able to detect the germs. The correlation of the illness, the consumption of raw milk, the detection of C. jejuni in the samples taken from the children and the samples taken from the cows was evident. Based on the case the health authorities recommended that heads of nurseries as well as heads of dairy farming in the district of Stendal needed to be advised on raw milk. Nurseries are still allowed to take trips to farms. However, raw animal derivates including milk must not be consumed. PMID- 26227384 TI - [Effectiveness of Live Attenuated Influenza Vaccines and Trivalent Inactivated Influenza Vaccines against confirmed Influenza In Children and Adolescents in Saxony-Anhalt, 2012/13]. AB - Since 2012, there are not only trivalent inactivated influenza vaccines (TIV) but also live attenuated influenza vaccines (LAIV) available for children aged 2-17 years in Germany. The Saxony-Anhalt State Office for Consumer Protection conducted a test-negative case-control-study. The aim of the study was to identify the effectiveness of LAIV and TIV against a confirmed influenza diagnosis in children and adolescents in Saxony-Anhalt in the season 2012/13. The children had nasal swabs taken, which were further diagnosed in a laboratory using the PCR method. 834 patients of 15 voluntarily participating paediatric surgeries in Saxony-Anhalt were analysed by multivariate logistic regression with STATA 12. Controlling for age group, gender and month of the disease's onset showed an effectiveness of all vaccines amongst the 2-17 years old (38% with 95% CI: 0.8-61%; p=0.046). A differentiation according to LAIV and TIV demonstrated a significant effectiveness for LAIV (84%) in children of all ages (95% CI: 45-95%, p=0.004). After stratification for age groups LAIV was proven efficient in children aged 2-6 years (90% with 95% CI: 20-99%, p=0.03), whilst it led to a non significant result in children aged 7-17 years (74% with 95% CI: -32-95%, p=0.106). There was no significant effectiveness of TIV seen in any age group.The Saxony-Anhalt State Office for Consumer Protection endorses the use of LAIV in children in accordance with the STIKO recommendations, as long as no contraindication is evident. PMID- 26227385 TI - [Hygiene in Urological Surgeries - Results of the Health Authority's Visit to all Urological Surgeries in Braunschweig]. AB - Following a patient complaint, the Health Department carried out a hygiene inspection of a urological practice in Braunschweig in February 2013. The topic of the complaint was that a patient assumed having acquired a resistant pathogen in the practice. In the subsequent visit, significant hygiene defects were found, particularly with regard to the processing of medical devices. This led to a decision to commit all urological practices in Braunschweig to hygiene inspections as part of a priority project. In retrospect, the hygiene surveys were justified. Deficiencies included inadequate preparation of medical products, procedures in practice inconsistent with hygiene plans, poor knowledge of hygiene procedures among assistant staff and doctors, lack of expertise of assistant staff and lack of hygiene risk awareness by doctors. Positive experiences were: open communication in a good atmosphere with the Practice managers, willingness to change, good cooperation between the Health Authority and the Labor Inspectorate and Physicians' Association. The claimed deficits were corrected by spring 2014 by the practice operators. The consulting expertise of the health authorities was made use of continuously. PMID- 26227386 TI - [Participation After Stroke]. PMID- 26227387 TI - Probing the nature of deficits in the 'Approximate Number System' in children with persistent Developmental Dyscalculia. AB - In the present study we examined whether children with Developmental Dyscalculia (DD) exhibit a deficit in the so-called 'Approximate Number System' (ANS). To do so, we examined a group of elementary school children who demonstrated persistent low math achievement over 4 years and compared them to typically developing (TD), aged-matched controls. The integrity of the ANS was measured using the Panamath (www.panamath.org) non-symbolic numerical discrimination test. Children with DD demonstrated imprecise ANS acuity indexed by larger Weber fraction (w) compared to TD controls. Given recent findings showing that non-symbolic numerical discrimination is affected by visual parameters, we went further and investigated whether children performed differently on trials on which number of dots and their overall area were either congruent or incongruent with each other. This analysis revealed that differences in w were only found between DD and TD children on the incongruent trials. In addition, visuo-spatial working memory strongly predicts individual differences in ANS acuity (w) during the incongruent trials. Thus the purported ANS deficit in DD can be explained by a difficulty in extracting number from an array of dots when area is anti-correlated with number. These data highlight the role of visuo-spatial working memory during the extraction process, and demonstrate that close attention needs to be paid to perceptual processes invoked by tasks thought to represent measures of the ANS. PMID- 26227388 TI - Comparative dosimetric findings using accelerated partial breast irradiation across five catheter subtypes. AB - PURPOSE: Accelerated partial breast irradiation (APBI) with balloon and strut adjusted volume implants (SAVI) show promising results with excellent tumor control and minimal toxicity. Knowing the factors that contribute to a high skin dose, rib dose, and D95 coverage may reduce toxicity, improve tumor control, and help properly predict patient outcomes following APBI. METHODS AND MATERIALS: A retrospective analysis of 594 patients treated with brachytherapy based APBI at a single institution from May 2008 to September 2014 was grouped by applicator subtype. Patients were treated to a total of 34 Gy (3.4 Gy x 10 fractions over 5 days delivered BID) targeting a planning target volume (PTV) 1.0 cm beyond the lumpectomy cavity using a high dose rate source. RESULTS: SAVI devices had the lowest statistically significant values of DmaxSkin (81.00 +/- 29.83), highest values of D90 (101.50 +/- 3.66), and D95 (96.09 +/- 4.55). SAVI-mini devices had the lowest statistically significant values of DmaxRib (77.66 +/- 32.92) and smallest V150 (18.01 +/- 3.39). Multi-lumen balloons were able to obtain the smallest V200 (5.89 +/- 2.21). Strut-based applicators were more likely to achieve a DmaxSkin and a DmaxRib less than or equal to 100 %. The effect of PTV on V150 showed a strong positive relationship (p < .001). PTV and DmaxSkin showed a weak negative relationship in multi-lumen applicators (p = .016) and SAVI-mini devices (p < .001). PTV and DmaxRib showed a weak negative relationship in multi lumen applicators (p = .009), SAVI devices (p < .001), and SAVI-mini devices (p < .001). CONCLUSION: PTV volume is strongly correlated with V150 in all devices and V200 in strut based devices. Larger PTV volumes result in greater V150 and V200, which could help predict potential risks for hotspots and resulting toxicities in these devices. PTV volume is also weakly negatively correlated with max skin dose and max rib dose, meaning that as the PTV volumes increase one can expect slightly smaller max skin and rib doses. Strut based applicators are significantly more effective in keeping skin and rib dose constraints under 125 and 100 % when compared to any balloon based applicator. PMID- 26227389 TI - Relationship of psychological and oral health statuses with self-perceived halitosis in a Jordanian population: a cross-sectional study. AB - BACKGROUND: Self-perceived halitosis could be a symptom of a psychosomatic or psychogenic disorder. The aim of this cross-sectional study was to clarify the relationship of self-perceived halitosis with psychological and oral health statuses. METHODS: One hundred participants with a history of halitosis were enrolled from a teaching hospital. They were divided into the self-perceived and suggested groups if they sensed and did not sense the malodor, respectively. Demographic and socioeconomic information, smoking status, and oral hygiene practices were noted. Complete nasal, oral, and periodontal examinations with organoleptic tests (OLTs) and N-benzoyl-DL-arginine-2-naphthylamide (BANA) tests were conducted. The participants also completed the validated Arabic version of the 90-item revised symptom checklist (SCL-90R). Data were compared by analysis of variance, chi-square test, Student's t-test, and multivariate logistic regression. RESULTS: The self-perceived group had higher OLT scores (p = 0.005) and were significantly younger (p = 0.001) than the suggested group. A significantly higher number of its participants were smokers (p = 0.004). No significant differences were observed in socioeconomic information, oral hygiene practices, oral conditions, and BANA test results. Further, no significant association was noted between self-perceived halitosis and the nine psychological dimensions of SCL-90R. CONCLUSIONS: Halitosis is a multifactorial symptom that requires multidisciplinary management. Self-reporting of the condition is unique entity and trust worthy symptom. It tends to be related to nonoral pathologies and extrinsic causes such as smoking. PMID- 26227390 TI - Emergence of human West Nile Virus infection in Sri Lanka. AB - BACKGROUND: West Nile virus (WNV) has emerged as one of the most common causes of epidemic meningoencephalitis worldwide. Most human infections are asymptomatic. However, neuroinvasive disease characterized by meningitis, encephalitis and/or acute flaccid paralysis is associated with significant morbidity and mortality. Although outbreaks have been reported in Asia, human WNV infection has not been previously reported in Sri Lanka. METHODS: Sera and cerebrospinal fluid (CSF) from 108 consecutive patients with a clinical diagnosis of encephalitis admitted to two tertiary care hospitals in Colombo, Sri Lanka were screened for WNV IgM antibody using enzyme-linked immunosorbent assay. Positive results were confirmed using plaque reduction neutralization test (PRNT). Patient data were obtained from medical records and by interviewing patients and care-givers. RESULTS: Three of the 108 patients had WNV IgM antibody in serum and one had antibody in the CSF. The presence of WNV neutralizing antibodies was confirmed in two of the three patients using PRNT. Two patients had presented with the clinical syndrome of meningoencephalitis while one had presented with encephalitis. One patient had CSF lymphocytic pleocytosis, one had neutrophilic pleocytosis while CSF cell counts were normal in one. CSF protein showed marginal increase in two patients. CONCLUSIONS: This is the first report of human WNV infection identified in patients presenting with encephalitis or meningoencephalitis in Sri Lanka. There were no clinical, routine laboratory or radiological features that were distinguishable from other infectious causes of meningoencephalitis. PMID- 26227392 TI - Left Ventricular Ejection Fraction (EF) of 55% as Cutoff for Late Transition From Heart Failure (HF) With Preserved EF to HF With Mildly Reduced EF. AB - BACKGROUND: Heart failure (HF) with preserved (HFpEF) left ventricular ejection fraction (LVEF) is a syndrome with complex pathophysiology. Little is known about changes in LVEF that occur over time in HFpEF patients. A fundamental clinical question about HFpEF is whether HFpEF is an early manifestation of HF with reduced LVEF (HFrEF). If so, which patients with HFpEF are likely to show a decline in LVEF to less than 50%? The aim of the present study was to examine longitudinal changes in LVEF in patients with HFpEF. METHODS AND RESULTS: Among 279 consecutive HFpEF patients admitted as emergencies, we examined 100 who underwent echocardiography at least 1 year after discharge. EF >50% was used as the definition of HFpEF. During a mean duration from hospitalization to follow-up echocardiography of 31.5 months, 11% of patients had LVEF <=50% (mildly reduced LVEF), known as mildly reduced (HFmrEF). The utility of LVEF during hospitalization to predict HFmrEF was assessed with receiver-operating characteristic curve analysis. A cutoff value of 55% had sensitivity of 90.9% and specificity of 97.7%. Logistic regression analysis indicated that LVEF <=55% and ischemic etiology were strong predictors of progression from HFpEF to HFmrEF (odds ratio [OR] 435, 95% confidence interval [CI] 52.65-10,614, P<0.0001 and OR 10.9, 95% CI 2.60-74.80, P=0.0007, respectively). CONCLUSIONS: The present study suggests that HFpEF patients with LVEF <=55% may progress to HFmrEF in the future. PMID- 26227391 TI - What value is the CINAHL database when searching for systematic reviews of qualitative studies? AB - BACKGROUND: The Cumulative Index to Nursing and Allied Health Literature (CINAHL) is generally thought to be a good source to search when conducting a review of qualitative evidence. Case studies have suggested that using CINAHL could be essential for reviews of qualitative studies covering topics in the nursing field, but it is unclear whether this can be extended more generally to reviews of qualitative studies in other topic areas. METHODS: We carried out a retrospective analysis of a sample of systematic reviews of qualitative studies to investigate CINAHL's potential contribution to identifying the evidence. In particular, we planned to identify the percentage of included studies available in CINAHL and the percentage of the included studies unique to the CINAHL database. After screening 58 qualitative systematic reviews identified from the Database of Abstracts of Reviews of Effects (DARE), we created a sample set of 43 reviews covering a range of topics including patient experience of both illnesses and interventions. RESULTS: For all 43 reviews (21 %) in our sample, we found that some of the included studies were available in CINAHL. For nine of these reviews, all the studies that had been included in the final synthesis were available in the CINAHL database, so it could have been possible to identify all the included studies using just this one database, while for an additional 21 reviews (49 %), 80 % or more of the included studies were available in CINAHL. Consequently, for a total of 30 reviews, or 70 % of our sample, 80 % or more of the studies could be identified using CINAHL alone. 11 reviews, where we were able to recheck all the databases used by the original review authors, had included a study that was uniquely identified from the CINAHL database. The median % of unique studies was 9.09%; while the range had a lowest value of 5.0% to the highest value of 33.0%. [corrected]. CONCLUSIONS: Assuming a rigorous search strategy was used and the records sought were accurately indexed, we could expect CINAHL to be a good source of primary studies for qualitative evidence syntheses. While we found some indication that CINAHL had the potential to provide unique studies for systematic reviews, we could only fully test this on a limited number of reviews, so we are less confident about this finding. PMID- 26227393 TI - Glycemic Variability on Continuous Glucose Monitoring System Predicts Rapid Progression of Non-Culprit Lesions in Patients With Acute Coronary Syndrome. AB - BACKGROUND: Although rapid progression (RP) of coronary artery disease (CAD) has been shown to be a powerful predictor of cardiovascular events, predictors of RP are not fully understood in patients with acute coronary syndrome (ACS). METHODS AND RESULTS: We prospectively investigated the clinical impact of glycemic variability (GV), as determined on continuous glucose monitoring system (CGMS), on RP of non-culprit lesions in 88 patients with ACS. RP was defined as >=10% diameter reduction in a pre-existing stenosis >=50%; >=30% diameter reduction in a stenosis <50%; development of a new stenosis >=30% in a previously normal segment; or progression of any stenosis to total occlusion. Patients were classified into 2 groups according to the presence (progressor, n=20) or absence (non-progressor, n=68) of RP. All patients were equipped with a CGMS during the stable phase, and mean amplitude of glycemic excursion (MAGE) was calculated as a marker of GV. Mean MAGE was significantly higher in progressors than in non progressors (55+/-19 mg/dl vs. 37+/-18 mg/dl, P<0.01). On multiple logistic regression analysis, MAGE was an independent predictor of RP (odds ratio, 1.06 per 1 mg/dl; P<0.01). CONCLUSIONS: MAGE early after the onset of ACS is a predictor of RP of non-culprit lesions. PMID- 26227394 TI - Estimating the variation, autocorrelation, and environmental sensitivity of phenotypic selection. AB - Despite considerable interest in temporal and spatial variation of phenotypic selection, very few methods allow quantifying this variation while correctly accounting for the error variance of each individual estimate. Furthermore, the available methods do not estimate the autocorrelation of phenotypic selection, which is a major determinant of eco-evolutionary dynamics in changing environments. We introduce a new method for measuring variable phenotypic selection using random regression. We rely on model selection to assess the support for stabilizing selection, and for a moving optimum that may include a trend plus (possibly autocorrelated) fluctuations. The environmental sensitivity of selection also can be estimated by including an environmental covariate. After testing our method on extensive simulations, we apply it to breeding time in a great tit population in the Netherlands. Our analysis finds support for an optimum that is well predicted by spring temperature, and occurs about 33 days before a peak in food biomass, consistent with what is known from the biology of this species. We also detect autocorrelated fluctuations in the optimum, beyond those caused by temperature and the food peak. Because our approach directly estimates parameters that appear in theoretical models, it should be particularly useful for predicting eco-evolutionary responses to environmental change. PMID- 26227395 TI - Review of Publicly-Funded Bariatric Surgery Policy in Australia-Lessons for More Comprehensive Policy Making. AB - BACKGROUND: The objective of the study was to determine the level of guidance provided by or to government health departments across different regions of Australia on publicly funded bariatric surgery. METHODS: Bariatric surgery policies and guidelines were sought from each Australian state (n = 6) and territory (n = 2) government health department and compared in relation to their origins, level of guidance on patient eligibility and priority, as well as recommendations for patient care, including follow-up surgical services. Comparison with national guidelines on bariatric surgery from Australia, the UK and USA was also made. RESULTS: Five of the eight states and territories had policies or guidelines informing practice. There was little uniformity among regional guidelines and variable consistency with national guidelines (e.g., defining obesity related comorbidity). Recommendations differed on patient eligibility, and none of the state documents mentioned re-operative bariatric or body-contouring surgery. There was limited guidance on prioritisation of eligible patients and gastric banding adjustments. Pre- and post-surgical multidisciplinary care was generally recommended. CONCLUSIONS: Policies and guidelines on publicly funded bariatric surgery are highly variable across Australia and at times inconsistent with national guidelines. Insufficient guidance exists regarding the prioritisation of eligible patients and follow-up surgical services. These findings have implications for policy, research and practice and are particularly important in health service environments with resource constraints and inequitable patient access to services. PMID- 26227396 TI - Trans-Umbilical Single Incision Laparoscopic Sleeve Gastrectomy in a Patient with Situs Inversus Totalis and Kartagener Syndrome: Video Report. AB - BACKGROUND: Single incision laparoscopic sleeve gastrectomy (SILSG) has proven to be a safe minimal invasive procedure. The umbilicus placement of the device allows the avoidance of any visible scars. Kartagener syndrome is a rare genetic disorder (1:15 000) accompanied by the combination of chronic sinusitis/bronchiectasis leading to respiratory insufficiency and situs inversus totalis (SIT) in half of the patients. SIT is a transposition of organs to the opposite side of the body and can lead to difficulties in laparoscopic surgery because of mirror image anatomy modification. METHODS: We present the case of a 52-year-old woman (122 kg; 1.58 m) with a body mass index of 49 kg/m(2) presenting SIT with chronic respiratory insufficiency as part of Kartagener syndrome. RESULTS: In this multimedia video, we present a step-by-step trans umbilical SILSG completed in SIT condition. Single site approach allows several technical advantages such as single-port placement, surgeon position as well as surgical instruments manipulation that are unchanged compared to "normal anatomy patients." These resulted in limited intra-operative difficulties. No adverse outcomes occurred during the post-operative period. CONCLUSIONS: Trans-umbilical SILSG in patients with SIT can be performed safely and in comparable conditions than in normal anatomy patients. PMID- 26227397 TI - Implant treatment planning regarding augmentation procedures: panoramic radiographs vs. cone beam computed tomography images. AB - OBJECTIVES: To evaluate the impact of cone beam computed tomography (CBCT) imaging on treatment planning regarding augmentation procedures for implant placement. MATERIAL AND METHODS: Panoramic radiographs and CBCT images of 40 patients requesting single-tooth implants in 59 sites were retrospectively analyzed by six specialists in implantology, and treatment planning was performed. Therapeutic recommendations were compared with the surgical protocol performed initially. RESULTS: Bone height estimation from panoramic radiographs yielded to higher measures and greater variability compared to CBCT. The suggested treatment plan for lateral and vertical augmentation procedures based on CBCT or panoramic radiographs coincided for 55-72% of the cases. A trend to a more invasive augmentation procedure was seen when planning was based on CBCT. Panoramic radiography revealed 57-63% (lateral) vs. 67% (vertical augmentation) congruent plans in agreement with surgery. Among the dissenting sites, there was a trend toward less invasive planning for lateral augmentation with panoramic radiographs, while vertical augmentation requirements were more frequently more invasive when based on CBCT. CONCLUSIONS: Vertical augmentation requirements can be adequately determined from panoramic radiographs. In difficult cases with a deficient lateral alveolar bone, the augmentation schedule may better be evaluated from CBCT to avoid underestimation, which occurs more frequently when based on panoramic radiographs only. However, overall, radiographic interpretation and diagnostic thinking accuracy seem to be mainly depending on the opinion of observers. PMID- 26227398 TI - Cinnamaldehyde Contributes to Insulin Sensitivity by Activating PPARdelta, PPARgamma, and RXR. AB - Cinnamon is a traditional folk herb used in Asia and has been reported to have antidiabetic effects. Our previous study showed that cinnamaldehyde (CA), a major effective compound in cinnamon, exhibited hypoglycemic and hypolipidemic effects together in db/db mice. The aim of the present study was to elucidate the molecular mechanisms of the effects of CA on the transcriptional activities of three peroxisome proliferator-activated receptors, (PPAR) alpha, delta, and gamma. We studied the effects of CA through a transient expression assay with TSA201 cells, derivatives of human embryonic kidney cell line (HEK293). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was also performed to evaluate mRNA expression levels. We show here that CA induced PPARdelta, PPARgamma and retinoid X receptor (RXR) activation. CA may activate PPARgamma in a different manner than pioglitazone, as CA selectively stimulated PPARgamma S342A mutant while pioglitazone did not. In addition, CA and L-165041 had a synergistic effect on PPARdelta activation. To gather the biological evidence that CA increases PPARs transcription, we further measured the expressions of PPARdelta and PPARgamma target genes in 3T3-L1 adipocytes. The data showed CA induced the expression of PPARdelta and PPARgamma target genes, namely aP2 and CD36, in differentiated adipocytes. As a result, PPARdelta, PPARgamma and their heterodimeric partner RXR appear to play a part in the CA action in the target tissues, thereby enhancing insulin sensitivity and fatty acid beta-oxidation and energy uncoupling in skeletal muscle and adipose tissue. PMID- 26227399 TI - (+)-Catechin Attenuates NF-kappaB Activation Through Regulation of Akt, MAPK, and AMPK Signaling Pathways in LPS-Induced BV-2 Microglial Cells. AB - (+)-Catechin is a flavanol that possesses various health and medicinal values, which include neuroprotection, anti-oxidation, antitumor and antihepatitis activities. This study investigated the modulatory effects of (+)-catechin on the lipopolysaccharides (LPS)-stimulated BV-2 cells. (+)-catechin attenuated LPS induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and inhibited microglial NO and ROS production. Additionally, (+)-catechin suppressed the production of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6, while augmenting IL-4. (+)-catechin attenuated LPS-induced nuclear factor-kappaB (NF-kappaB) p65 nuclear translocation via the inhibition of IkappaB-alpha phosphorylation. Moreover, (+)-catechin blocked the activation of Akt and its inhibition was shown to play a crucial role in LPS-induced inflammation in BV-2 microglial cells. (+)-catechin also attenuated the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK1/2), and p-38 mitogen activated protein kinases (p38 MAPK) and specific inhibitors of ERK1/2 (UO126) and p38 MAPK (SB202190) subsequently down-regulated the expression of the proinflammatory mediators iNOS and COX-2. Further mechanistic study revealed that (+)-catechin acted through the amelioration of the LPS-induced suppression of adenosine monophosphate-activated protein kinase (AMPK) activity. Taken together, our data indicate that (+)-catechin exhibits anti-inflammatory effects in BV-2 cells by suppressing the production of proinflammatory mediators and mitigation of NF kappaB through Akt, ERK, p38 MAPK, and AMPK pathways. PMID- 26227400 TI - Physiological roles for the subfornical organ: a dynamic transcriptome shaped by autonomic state. AB - The subfornical organ (SFO) is a circumventricular organ recognized for its ability to sense and integrate hydromineral and hormonal circulating fluid balance signals, information which is transmitted to central autonomic nuclei to which SFO neurons project. While the role of SFO was once synonymous with physiological responses to osmotic, volumetric and cardiovascular challenge, recent data suggest that SFO neurons also sense and integrate information from circulating signals of metabolic status. Using microarrays, we have confirmed the expression of receptors already described in the SFO, and identified many novel transcripts expressed in this circumventricular organ including receptors for many of the critical circulating energy balance signals such as adiponectin, apelin, endocannabinoids, leptin, insulin and peptide YY. This transcriptome analysis also identified SFO transcripts, the expressions of which are significantly changed by either 72 h dehydration, or 48 h starvation, compared to fed and euhydrated controls. Expression and potential roles for many of these targets are yet to be confirmed and elucidated. Subsequent validation of data for adiponectin and leptin receptors confirmed that receptors for both are expressed in the SFO, that discrete populations of neurons in this tissue are functionally responsive to these adipokines, and that such responsiveness is regulated by physiological state. Thus, transcriptomic analysis offers great promise for understanding the integrative complexity of these physiological systems, especially with development of technologies allowing description of the entire transcriptome of single, carefully phenotyped, SFO neurons. These data will ultimately elucidate mechanisms through which these uniquely positioned neurons respond to and integrate complex circulating signals. PMID- 26227401 TI - Interventions to decrease pain and anxiety in patients undergoing urodynamic testing: A randomized controlled trial. AB - AIMS: To determine if music (at 60 beats/min) or watching a pre-procedure educational video decreases pain and anxiety in women undergoing multichannel urodynamic testing compared to usual care. METHODS: Women undergoing multichannel urodynamic testing at a tertiary care center were randomized to one of three groups: usual care (UC), music (M), in which music was played throughout the urodynamic test, or video (V), in which subjects watched an informational video on the procedure prior to undergoing the test. Visual analog scales (VAS) were used to measure patient's pain and anxiety before and after the test. Demographic information was obtained and five-item Likert questionnaires were given to assess information seeking behavior, preparedness, embarrassment, and privacy. RESULTS: 98 subjects were included in this analysis. In the overall group, mean perceived pain on the pre-test VAS was significantly higher than the post-test VAS with pre test mean (SD) 47(+/-30) and post-test mean (SD) 26(+/-23), P = 0.0001. Overall the anxiety pre-test VAS was significantly greater than post-test VAS with pre test mean (SD) 46.9(+/-29) and post-test mean 17.9(+/-18), P = 0.0001. There were no differences in pain and anxiety scores between the two intervention groups and usual care. Patients who were randomized to usual care or the video arm felt more prepared for the test compared to patients who were randomized to the music arm, with (mean +/- SD): usual care (42 +/- 8), video (43 +/- 9), music (37 +/- 11), P = 0.002. CONCLUSIONS: Music and an educational video do not decrease pain or anxiety in subjects undergoing multichannel urodynamics compared to usual care. Neurourol. Urodynam. 35:975-979, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26227403 TI - Combination of sequence-defined oligoaminoamides with transferrin-polycation conjugates for receptor-targeted gene delivery. AB - BACKGROUND: Transferrin receptor (TfR), over-expressed on a majority of malignant cells, has been widely studied as a target for drug, protein and gene delivery. Both stable nucleic acid compact ability and efficient cytosol gene release capability are essential for the success of gene delivery. METHODS: In the present study, a novel nonviral TfR-targeted gene delivery system was developed based on sequence-defined cationic oligoaminoamide oligomers with endolysosomal buffer capacity and DNA binding transferrin (Tf) polycation conjugates. RESULTS: Gene transfer activities were significantly increased in a series of TfR over expressing human tumour cell lines (K562, DU145 and KB) with mixed ternary polyplexes containing Tf-conjugates and 3-arm (386 and 689) or 4-arm (577, 579 and 607) sequence-defined oligomers. Especially polyplexes containing a histidine rich 4-arm oligomer (607) and Tf-PEG-PEI achieved a 100-fold increase in gene expression compared to previously established formulations. Tf competition experiments indicate enhanced polyplex internalization via TfR as prerequisite for the high transfection activity. The additional histidines in the oligoaminoamide oligomer structure are required for more effective endolysosomal escape of the gene delivery vehicle. Polyplexes formed by first mixing pDNA with the oligomer as a cationic core, followed by the addition of the Tf-polycation conjugate for presentation at the exterior nanoparticles, exhibited the highest transfection activity. CONCLUSIONS: Utilizing the synergistic effects of Tf for receptor targeting and oligomer for packaging and endolysosomal escape, an efficient gene delivery carrier was developed. The mixed polyplex containing Tf polycation conjugates and histidinylated 4-arm oligomer with succinoyl tetraethylene pentamine or glutaroyltriethylene tetramine building blocks exhibited the highest gene transfection efficiency in TfR over-expressing human tumour cell lines. PMID- 26227405 TI - Can Parkinson's Disease Come From the Gut? PMID- 26227402 TI - Lactation and Intestinal Microbiota: How Early Diet Shapes the Infant Gut. AB - Breast milk is a multifunctional biofluid that provides nutrients along with highly diverse non-nutritive bioactive components such as antibodies, glycans, bacteria, and immunomodulatory proteins. Research over the past decade has confirmed the essential role of breast milk bioactives in the establishment a healthy intestinal microbiota within the infant. The intestinal microbiota of an exclusively breastfed baby is dominated by several species of Bifidobacteria - the most influential member of which is Bifidobacterium longum subspecies infantis (B. infantis) - and is referred to as the milk-oriented microbiome (MOM). MOM is associated with reduced risk of infection in infancy as well as a reduced risk of certain chronic illnesses in adulthood. Establishment and persistence of MOM is dependent on the selective digestion of complex sugar structures in breast milk that are otherwise indigestible to the infant by B. infantis and its relatives. This review focuses primarily on the influence of breast milk glycans and glycosylated proteins on the development of the intestinal microbiome, and how maternal phenotype may influence the development of MOM providing a framework to understand how variation in diet shapes a protective intestinal microbiome. PMID- 26227404 TI - Demographic and clinical characteristics of deaths associated with influenza A(H1N1) pdm09 in Central America and Dominican Republic 2009-2010. AB - BACKGROUND: The demographic characteristics of pandemic influenza decedents among middle and low-income tropical countries are poorly understood. We explored the demographics of persons who died with influenza A (H1N1)pdm09 infection during 2009-2010, in seven countries in the American tropics. METHODS: We used hospital based surveillance to identify laboratory-confirmed influenza deaths in Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panama and Dominican Republic. An influenza death was defined as a person who died within two weeks of a severe acute respiratory infection (SARI) defined as sudden onset of fever >38 degrees C, cough or sore-throat, and shortness of breath, or difficulty breathing requiring hospitalization, and who tested positive for influenza A (H1N1)pdm09 virus by real time polymerase chain reaction. We abstracted the demographic and clinical characteristics of the deceased from their medical records. RESULTS: During May 2009-June 2010, we identified 183 influenza deaths. Their median age was 32 years (IQR 18-46 years). One-hundred and one (55 %) were female of which 20 (20 %) were pregnant and 7 (7 %) were in postpartum. One-hundred and twelve decedents (61 %) had pre-existing medical conditions, (15 % had obesity, 13 % diabetes, 11 % asthma, 8 % metabolic disorders, 5 % chronic obstructive pulmonary disease, and 10 % neurological disorders). 65 % received oseltamivir but only 5 % received it within 48 h of symptoms onset. CONCLUSIONS: The pandemic killed young adults, pregnant women and those with pre-existing medical conditions. Most sought care too late to fully benefit from oseltamivir. We recommend countries review antiviral treatment policies for people at high risk of developing complications. PMID- 26227407 TI - Cysteine-free non-canonical C-intein for versatile protein C-terminal labeling through trans-splicing. AB - Site-specific protein labeling are powerful means of protein research and engineering; however, new and improved labeling methods are greatly needed. Split inteins catalyze a protein trans-splicing reaction that can be used for enzymatic and nearly seamless protein labeling. Non-canonical S11 split intein has been used in an earlier method of protein C-terminal labeling; however, its relatively large (~150 aa) N-intein fused to the target protein often hindered protein expression, folding, and solubility. To solve this problem, here, we have designed and demonstrated a new method of protein C-terminal labeling, by first engineering a functional non-canonical S1 split intein that has an extremely small (12 aa) N-intein and a cysteine-free C-intein. An engineered Rma DnaB S1 split intein was modified to have a cysteine-free C-intein, while still retaining its robust trans-splicing function, which permitted the C-extein in a C-precursor to have a single cysteine for easy and specific linkage with desired labeling groups. The resulting new and generally useful method has two unique advantages: (1) The extremely small (12 aa) N-intein, which must be fused to the C terminus of the target protein, is less likely to hinder the protein expression, folding, and solubility; and (2) the single cysteine in the C-extein may be readily linked to a variety of labeling or modification groups using commercially available reagents. PMID- 26227406 TI - Thirty-minute screening of antibiotic resistance genes in bacterial isolates with minimal sample preparation in static self-dispensing 64 and 384 assay cards. AB - In a clinical setting, molecular assays such as polymerase chain reaction offer a rapid means to infer or confirm identity and therapeutic decisions. Accordingly, a number of molecular assays targeting identity and antibiotic resistance (AR) genes have been developed; however, these methods can be technically complex and relatively expensive. Herein, we describe a diagnostic concept utilizing isothermal amplification technology with non-purified heat-lysed cells and self dispensing cards for testing multiple primers in parallel. This proof-of-concept study, performed with Staphylococcus aureus isolates and associated AR genes, was compared with culture-based susceptibility and quantitative PCR (qPCR). Results demonstrate reduced sample processing steps resulting in a turnaround time (starting from bacterial culture to ending in the antibiotic resistance gene profile) in less than 30 min. For antibiotics tested in which an associated AR gene was targeted on the Gene-Z card, 69% (18/26) of culture-based resistance events were positive for related AR genes. A comparison of loop-mediated isothermal amplification (LAMP) and qPCR assays targeting the same antibiotic resistance genes showed a 98.2% agreement in terms of presence and absence calls. Identity-based discrepancies between conventional (phenotypic) and molecular (genotypic) results were further resolved, and we were able to demonstrate higher accuracy in identification with the molecular analysis. PMID- 26227408 TI - Impacts and perspectives of prenyltransferases of the DMATS superfamily for use in biotechnology. AB - Prenylated compounds are ubiquitously found in nature and demonstrate interesting biological and pharmacological activities. Prenyltransferases catalyze the attachment of prenyl moieties from different prenyl donors to various acceptors and contribute significantly to the structural and biological diversity of natural products. In the last decade, significant progress has been achieved for the prenyltransferases of the dimethylallyltryptophan synthase (DMATS) superfamily. More than 40 members of these soluble enzymes are identified in microorganisms and characterized biochemically. These enzymes were also successfully used for production of a large number of prenylated derivatives. N1 , C4-, C5-, C6-, and C7-prenylated tryptophan and N1-, C2-, C3-, C4-, and C7 prenylated tryptophan-containing peptides were obtained by using DMATS enzymes as biocatalysts. Tyrosine and xanthone prenyltransferases were used for production of prenylated derivatives of their analogs. More interestingly, the members of the DMATS superfamily demonstrated intriguing substrate and catalytic promiscuity and also used structurally quite different compounds as prenyl acceptors. Prenylated hydroxynaphthalenes, flavonoids, indolocarbazoles, and acylphloroglucinols, which are typical bacterial or plant metabolites, were produced by using several fungal DMATS enzymes. Furthermore, the potential usage of these enzymes was further expanded by using natural or unnatural DMAPP analogs as well as by coexpression with other genes like NRPS and by development of whole cell biocatalyst. PMID- 26227409 TI - MoGrr1, a novel F-box protein, is involved in conidiogenesis and cell wall integrity and is critical for the full virulence of Magnaporthe oryzae. AB - The production of asexual spores plays a critical role in rice blast disease. However, the mechanisms of the genes involved in the conidiogenesis pathway are not well understood. F-box proteins are specific adaptors to E3 ubiquitin ligases that determine the fate of different substrates in ubiquitin-mediated protein degradation and play diverse roles in fungal growth regulation. Here, we identify a Saccharomyces cerevisiae Grr1 homolog, MoGrr1, in Magnaporthe oryzae. Targeted disruption of Mogrr1 resulted in defects in vegetative growth, melanin pigmentation, conidial production, and resistance to oxidative stress, and these mutants consequently exhibited attenuated virulence to host plants. Microscopy studies revealed that the inability to form conidiophores is responsible for the defect in conidiation. Although the Mogrr1 mutants could develop melanized appressoria from hyphal tips, the appressoria were unable to penetrate into plant tissues due to insufficient turgor pressure within the appressorium, thereby attenuating the virulence of the mutants. Quantitative RT-PCR results revealed significantly decreased expression of chitin synthase-encoding genes, which are involved in fungal cell wall integrity, in the Mogrr1 mutants. The Mogrr1 mutants also displayed reduced expression of central components of the MAP kinase and cAMP signaling pathways, which are required for appressorium differentiation. Furthermore, domain complementation analysis indicated that two putative protein interacting domains in MoGrr1 play essential roles during fungal development and pathogenicity. Taken together, our results suggest that MoGrr1 plays essential roles in fungal development and is required for the full virulence of M. oryzae. PMID- 26227410 TI - Unravelling glutathione conjugate catabolism in Saccharomyces cerevisiae: the role of glutathione/dipeptide transporters and vacuolar function in the release of volatile sulfur compounds 3-mercaptohexan-1-ol and 4-mercapto-4-methylpentan-2 one. AB - Sulfur-containing aroma compounds are key contributors to the flavour of a diverse range of foods and beverages, such as wine. The tropical fruit characters of Sauvignon Blanc wines are attributed to the presence of the aromatic thiols 3 mercaptohexan-1-ol (3-MH), its acetate ester 3-mercaptohexyl acetate (3-MHA), and 4-mercapto-4-methylpentan-2-one (4-MMP). These aromatic thiols are not detectable in grape juice to any significant extent but are released by yeast during alcoholic fermentation. While the processes involved in the release of 3-MH and 4 MMP from their cysteinylated precursors have been studied extensively, degradation pathways for glutathione S-conjugates (GSH-3-MH and GSH-4-MMP) have not. In this study, a candidate gene approach was taken, focusing on genes known to play a role in glutathione and glutathione-S-conjugate turnover in Saccharomyces cerevisiae. Our results confirm the role of Opt1p as the major transporter responsible for uptake of GSH-3-MH and GSH-4-MMP, and identify vacuolar Ecm38p as a key determinant of 3-MH release from GSH-3-MH. ECM38 was unimportant, on the other hand, for release of 4-MMP, and abolition of vacuolar biogenesis caused an increase in the amount of 4-MMP released. The alternative cytosolic glutathione degradation pathway was not involved in release of either thiol from their glutathionylated precursors. Finally, cycling of GSH-3-MH and/or its breakdown intermediates between the cytosol and the vacuole or extracellular space was implicated in modulation of 3-MH formation. Together, these results provide new targets for development of yeast strains that optimize release of these potent volatile sulfur compounds, and further our understanding of the processes involved in glutathione-S-conjugate turnover. PMID- 26227411 TI - Expression of a new serine protease from Crotalus durissus collilineatus venom in Pichia pastoris and functional comparison with the native enzyme. AB - Snake venom serine proteases (SVSPs) act primarily on plasma proteins related to blood clotting and are considered promising for the treatment of several hemostatic disorders. We report the heterologous expression of a serine protease from Crotalus durissus collilineatus, named collinein-1, in Pichia pastoris, as well as the enzymatic comparative characterization of the toxin in native and recombinant forms. The complementary DNA (cDNA) encoding collinein-1 was amplified from cDNA library of C. d. collilineatus venom gland and cloned into the pPICZalphaA vector. The recombinant plasmid was used to transform cells of KM71H P. pastoris. Heterologous expression was induced by methanol and yielded 56 mg of recombinant collinein-1 (rCollinein-1) per liter of culture. The native collinein-1 was purified from C. d. collilineatus venom, and its identity was confirmed by amino acid sequencing. The native and recombinant enzymes showed similar effects upon bovine fibrinogen by releasing preferentially fibrinopeptide A. Although both enzymes have induced plasma coagulation, native Colinein-1 has shown higher coagulant activity. The serine proteases were able to hydrolyze the chromogenic substrates S-2222, S-2238, and S2302. Both enzymes showed high stability on different pH and temperature, and their esterase activities were inhibited in the presence of Zn2+ and Cu2+. The serine proteases showed similar k cat/K m values in enzyme kinetics assays, suggesting no significant differences in efficiency of these proteins to hydrolyze the substrate. These results demonstrated that rCollinein-1 was expressed with functional integrity on the evaluated parameters. The success in producing a functionally active recombinant SVSP may generate perspectives to their future therapeutic applications. PMID- 26227412 TI - Pilot-scale chitin extraction from shrimp shell waste by deproteination and decalcification with bacterial enrichment cultures. AB - Extraction of chitin from mechanically pre-purified shrimp shells can be achieved by successive NaOH/HCl treatment, protease/HCl treatment or by environmentally friendly fermentation with proteolytic/lactic acid bacteria (LAB). For the last mentioned alternative, scale-up of shrimp shell chitin purification was investigated in 0.25 L (F1), 10 L (F2), and 300 L (F3) fermenters using an anaerobic, chitinase-deficient, proteolytic enrichment culture from ground meat for deproteination and a mixed culture of LAB from bio-yoghurt for decalcification. Protein removal in F1, F2, and F3 proceeded in parallel within 40 h at an efficiency of 89-91 %. Between 85 and 90 % of the calcit was removed from the shells by LAB in another 40 h in F1, F2, and F3. After deproteination of shrimp shells in F3, spent fermentation liquor was re-used for a next batch of 30 kg shrimp shells in F4 (300 L) which eliminated 85.5 % protein. The purity of the resulting chitin was comparable in F1, F2, F3, and F4. Viscosities of chitosan, obtained after chitin deacetylation and of chitin, prepared biologically or chemically in the laboratory, were much higher than those of commercially available chitin and chitosan. PMID- 26227413 TI - Characterization of a novel high-pH-tolerant laccase-like multicopper oxidase and its sequence diversity in Thioalkalivibrio sp. AB - Laccases are oxidoreductases mostly studied in fungi, while bacterial laccases remain poorly studied despite their high genetic diversity and potential for biotechnological application. Our previous bioinformatic analysis identified alkaliphilic bacterial strains Thioalkalivibrio sp. as potential sources of robust bacterial laccases that would be stable at high pH. In the present work, a gene for a laccase-like enzyme from Thioalkalivibrio sp. ALRh was cloned and expressed as a 6* His-tagged protein in Escherichia coli. The purified enzyme was a pH-tolerant laccase stable in the pH range between 2.1 and 9.9 at 20 degrees C as shown by intrinsic fluorescence emission spectrometry. It had optimal activities at pH 5.0 and pH 9.5 with the laccase substrates 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,6-dimethoxyphenol, respectively. In addition, it could oxidize several other monophenolic compounds and potassium hexacyanoferrate(II) but not tyrosine. It showed highest activity at 50 degrees C, making it suitable for prolonged incubations at this temperature. The present study shows that Thioalkalivibrio sp. encodes an active, alkaliphilic, and thermo-tolerant laccase and contributes to our understanding of the versatility of bacterial laccase-like multicopper oxidases in general. PMID- 26227414 TI - Systematic analysis of intracellular mechanisms of propanol production in the engineered Thermobifida fusca B6 strain. AB - Thermobifida fusca is a moderately thermophilic actinobacterium naturally capable of utilizing lignocellulosic biomass. The B6 strain of T. fusca was previously engineered to produce 1-propanol directly on lignocellulosic biomass by expressing a bifunctional butyraldehyde/alcohol dehydrogenase (adhE2). To characterize the intracellular mechanisms related to the accumulation of 1 propanol, the engineered B6 and wild-type (WT) strains were systematically compared by analysis of the transcriptome and intracellular metabolome during exponential growth on glucose, cellobiose, and Avicel. Of the 18 known cellulases in T. fusca, 10 cellulase genes were transcriptionally expressed on all three substrates along with three hemicellulases. Transcriptomic analysis of cellodextrin and cellulose transport revealed that Tfu_0936 (multiple sugar transport system permease) was the key enzyme regulating the uptake of sugars in T. fusca. For both WT and B6 strains, it was found that growth in oxygen-limited conditions resulted in a blocked tricarboxylic acid (TCA) cycle caused by repressed expression of Tfu_1925 (aconitate hydratase). Further, the transcriptome suggested a pathway for synthesizing succinyl-CoA: oxaloacetate to malate (by malate dehydrogenase), malate to fumarate (by fumarate hydratase), and fumarate to succinate (by succinate dehydrogenase/fumarate reductase) which was ultimately converted to succinyl-CoA by succinyl-CoA synthetase. Both the transcriptome and the intracellular metabolome confirmed that 1-propanol was produced through succinyl-CoA, L-methylmalonyl-CoA, D-methylmalonyl-CoA, and propionyl-CoA in the B6 strain. PMID- 26227415 TI - Changing maternal perceptions of healthy feeding: a novel intervention. AB - OBJECTIVE: This study sought to better understand factors influencing mothers' perceptions about healthy feeding. Additionally, a social consensus intervention was used to try to change mothers' likelihood to serve healthy foods. METHODS: Mothers saw photographs of healthy and unhealthy snacks and meals and rated them on several factors that were hypothesized to predict the likelihood of serving the foods. Then, mothers were randomly assigned to the experimental or control condition. Those in the experimental condition received social consensus information about these foods, whereas the control condition did not. The change in perceptions in the control and experimental conditions was examined. RESULTS: Mothers rated healthy meals and snacks less favourably than unhealthy meals and snacks on factors including cost, preparation time and difficulty, and child preference. Furthermore, mothers' perceptions of foods as liked by their child, easy to prepare and 'kid-friendly' predicted higher likelihood to serve those foods. Finally, mothers were more likely to describe the healthy snack as kid friendly and indicated being more likely to serve it after receiving favourable social norm information about the food. CONCLUSIONS: The use of social consensus interventions to change parents' perceptions of healthy snacks may be one means of increasing the quality of children's diets. PMID- 26227417 TI - Efficient Photochemical Synthesis of Peptide-alpha-Phenylthioesters. AB - Low yields and substantial epimerization of peptide-alpha-thioesters often compromise the overall efficiency of native chemical ligation (NCL). Peptide arylthioesters are more reactive than peptide alkylthioesters in NCL, but are also more difficult to handle due to their propensity to hydrolyze, and are therefore often generated in situ. However, pre-prepared peptide arylthioesters are required for some NCL applications. Here we present a 7-nitroindoline-based photochemical method that generates protected peptide phenylthioesters under neutral reaction conditions via their activated esters from photoreactive peptide precursors in high isolated yields, and with low levels of epimerization. This method is fully compatible with Fmoc-strategy solid-phase peptide synthesis. Global deprotection with trifluoroacetic acid furnishes peptide phenylthioesters for NCL. Photoreactive peptide precursors can also be converted into their hydrazides in two steps by this method. PMID- 26227416 TI - Imaging findings of swallowed dentures: a case series. AB - Dental prosthesis is an uncommon ingested non-food foreign body in adults. Once swallowed, it can lead to serious complications and morbidity. Hence, early localization of the offending foreign body is crucial for timely management. As the dentures are usually made up of non-metallic material and often impacted at or below the level of C7 vertebra, conventional radiograph has limited role in their evaluation. We describe the clinical history and imaging findings of swallowed partial dentures in four patients who presented to the emergency department. The dentures were localized using unenhanced CT of the neck that showed the characteristic mildly hyperdense curvilinear or irregular appearance of the dentures within the upper esophagus. Multiplanar CT reconstructions provide an orientation of the ingested denture within the esophagus, thus guiding the endoscopist. PMID- 26227418 TI - The Pudendal Nerve and Its Branches in Relation to Richter's Procedure. AB - OBJECTIVE: Variations in the branching pattern of the pudendal nerve (PN) have been described in the literature. This study investigated these variations in order to comment on a safe area for the placement of a Richter's stitch. METHODS: Richter's procedure was performed on nine unembalmed female cadavers and followed by dissection. PN dissections were done on another 20 embalmed female cadavers. Variations in the branching pattern of the PN were noted and the distance between the Richter's stitch placed and the PN/or the inferior rectal nerve (IRN) measured. RESULTS: The IRN entered the gluteal region as a separate structure in 6/29 cases. The separate IRN was found to pass between 4.1 and 14.45 mm medial to the ischial spine in 18/29 cases. In one case, the Richter's stitch was found to pierce the IRN. The distance between the stitch and the PN and/or the IRN ranged from 0 to 17.8 mm. CONCLUSIONS: To minimize the risk of nerve damage or entrapment, the Richter's stitch should be placed >20 mm from the ischial spine. This recommended area should be revised for different population groups, as variations might exist between groups. PMID- 26227420 TI - Safety of Percutaneous Ultrasound-Guided Kidney Biopsy in Patients with AA Amyloidosis. AB - BACKGROUND: Bleeding is the most frequent complication of kidney biopsy. Although bleeding risk in patients with AA amyloidosis after kidney biopsy has not been studied in a large population, AA amyloidosis has long been perceived as a risk factor for bleeding. The aim of the present study was to evaluate post-biopsy bleeding risk in patients with AA amyloidosis. METHODS: We retrospectively analyzed bleeding complications in 88 patients with AA amyloidosis and 202 controls after percutaneous kidney biopsy. All the kidney biopsies were performed under the guidance of real-time ultrasound with the use of an automated core biopsy system after a standard pre-biopsy screening protocol. Bleeding events were classified as major when transfusion of blood products or surgical or radiological intervention was required, or if the bleeding caused hypovolemic shock or death. Bleeding events that did not meet these criteria were accepted as minor. RESULTS: The incidence of post-biopsy bleeding was comparable between AA amyloidosis and control groups (5.7 vs. 5.0%, p = 0.796). Major bleeding events were observed in 3 patients from each group (p = 0.372). Selective renal angiography and embolization were applied to 2 patients from the AA amyloidosis group. One of these patients underwent colectomy and died because of infectious complications. Bleeding events were minor in 2.3% of the patients with AA amyloidosis and 3.5% of the controls (p = 0.728). CONCLUSIONS: AA amyloidosis was not associated with increased post-biopsy bleeding risk. Kidney biopsy is safe in AA amyloidosis when standard pre-biopsy screening is applied. Further data are needed to confirm these findings. PMID- 26227419 TI - 4D flow MRI and T1 -Mapping: Assessment of altered cardiac hemodynamics and extracellular volume fraction in hypertrophic cardiomyopathy. AB - PURPOSE: Hypertrophic cardiomyopathy (HCM) is associated with altered hemodynamics in the left ventricular outflow tract (LVOT) and myocardial tissue abnormalities such as fibrosis. The aim of this study was to quantify changes in LVOT 3D hemodynamics and myocardial extracellular volume fraction (ECV, measure of fibrosis) and to investigate relationships between elevated flow metrics and left ventricular (LV) tissue abnormalities. MATERIALS AND METHODS: Cardiac magnetic resonance imaging (MRI) including 4D flow (field strength = 1.5T, resolution = 2.1-4.0 * 2.1-4.0 * 2.5-3.2 mm(3) ; venc = 150-250 cm/s; TE/TR/FA = 2.2-2.5msec/4.6-4.9msec/15 degrees ) for the in vivo assessment of 3D blood flow velocities with full coverage of the LVOT was applied in 35 patients with HCM (54 +/- 15 years) and 10 age-matched healthy controls (45 +/- 14 years). In addition, pre- and postcontrast myocardial T1 -mapping (resolution = 2.3 * 1.8 mm, slice thickness = 8 mm, TE/TR-FA = 1.0-1.1msec/2.0-2.2msec/35 degrees ) of the LV (basal, mid-ventricular, apical short axis) was performed in a subgroup of 23 HCM patients. Analysis included the segmentation of the LVOT and quantification of peak systolic LVOT pressure gradients and rate of viscous energy loss EL ' as well as left ventricular ECV. RESULTS: HCM patients demonstrated significantly elevated peak systolic LVOT pressure gradients (21 +/- 16 mmHg vs. 9 +/- 2 mmHg) and energy loss EL ' (3.8 +/- 2.5 mW vs. 1.5 +/- 0.7 mW, P < 0.005) compared to controls. There was a significant relationship between increased LV fibrosis (ECV) with both elevated pressure gradients (R(2) = 0.44, P < 0.001) and energy loss EL ' (R(2) = 0.46, P < 0.001). CONCLUSIONS: The integration of 4D-flow and T1 -mapping-MRI allowed for the evaluation of tissue and flow abnormalities in HCM patients. Our findings suggest a mechanistic link between abnormal LVOT flow, increased LV loading, and adverse myocardial remodeling in HCM. PMID- 26227421 TI - Mechanochemically Reduced SiO2 by Ti Incorporation as Lithium Storage Materials. AB - This study presents a simple and effective method of reducing amorphous silica (a SiO2 ) with Ti metal through high-energy mechanical milling for improving its reactivity when used as an anode material in lithium-ion batteries. Through thermodynamic calculations, it is determined that Ti metal can easily take oxygen atoms from a-SiO2 by forming a thermodynamically stable SiO2-x /TiOx composite, meaning that electrochemically inactive a-SiO2 is partially reduced by the addition of Ti metal powder during milling. This mechanically reduced SiO2-x /TiOx composite anode exhibits a greatly improved electrochemical reactivity, with a reversible capacity of more than 700 mAh g(-1) and excellent cycle performance over 100 cycles. Furthermore, an enhancement in the mechanical and thermal stability of the composite during cycling can be mainly attributed to the in situ formation of the SiO2-x /TiOx phase. These findings provide new insight into the rational design of robust, high-capacity, Si-based anode materials, as well as their reaction mechanism. PMID- 26227422 TI - Photostable Fluorophenyl-Substituted Cyclometalated Platinum(II) Emitters for Monitoring of Molecular Oxygen in Real Time. AB - The effects of fluorophenyl substituents on the photoluminescence, redox properties, and oxygen sensing behaviors of the cyclometalated Pt(II) complexes are reported. The Pt(II) complexes with fluorophenyl substituents at the para position on the phenyl ring of 2-phenylpyridine (ppy) exhibit higher oxygen sensitivities than those at the meta position. Photodegradation tests demonstrate that the introduction of fluorophenyl substituents can strongly improve the photostability of cyclometalated Pt(II) complexes. Fast response and recovery times of oxygen sensing films are obtained in 3.0 s on going from 0% O2 to 100% O2 and in 4.0 s on going from 100% O2 to 0% O2 (95% recovery of the luminescence), respectively. The oxygen sensing films show excellent operational stability in 4000 s saturation O2/N2 cycles, which meets the requirement of monitoring molecular oxygen in real time. PMID- 26227423 TI - Risk of bias of randomized trials over time. AB - OBJECTIVES: To determine the variation in the risk of bias (RoB) of randomized controlled trials (RCTs) in time. STUDY DESIGN AND SETTING: We reviewed all included RCTs from systematic reviews (SRs) published in the issue 12 (2012) of the Cochrane Databases of Systematic Reviews. We extracted the RoB author's evaluation per domain and other RCT characteristics. Multivariate logistic regression was used to evaluate association between the presence of a low RoB according to RoB domains and other characteristics. RESULTS: We included 1,732 RCTs from 97 SRs. The rates of RCTs judged as having low and high RoB significantly increased over time, whereas the rates of unclear RoB decreased for several domains. Increased rates of low RoB were consistent when considering the type of intervention (drugs vs. others), sample size, and country income level. Multivariate logistic regression shows that RCTs published between 2006 and 2012, compared with those published before 1990, were more likely to be considered at low RoB for sequence generation (odds ratio [OR] = 3.96; 95% confidence interval [CI]: 2.29, 6.87), allocation concealment (OR = 3.56; 95% CI: 1.96, 6.46), incomplete outcome data (objective outcomes; OR = 1.89; 95% CI: 1.13, 3.15), and selective reporting (OR = 4.14; 95% CI: 2.35, 7.29) domains. CONCLUSION: RCTs have improved reporting during the last decades decreasing the uncertainty for the RoB assessment. PMID- 26227424 TI - HaploPOP: a software that improves population assignment by combining markers into haplotypes. AB - BACKGROUND: In ecology and forensics, some population assignment techniques use molecular markers to assign individuals to known groups. However, assigning individuals to known populations can be difficult if the level of genetic differentiation among populations is small. Most assignment studies handle independent markers, often by pruning markers in Linkage Disequilibrium (LD), ignoring the information contained in the correlation among markers due to LD. RESULTS: To improve the accuracy of population assignment, we present an algorithm, implemented in the HaploPOP software, that combines markers into haplotypes, without requiring independence. The algorithm is based on the Gain of Informativeness for Assignment that provides a measure to decide if a pair of markers should be combined into haplotypes, or not, in order to improve assignment. Because complete exploration of all possible solutions for constructing haplotypes is computationally prohibitive, our approach uses a greedy algorithm based on windows of fixed sizes. We evaluate the performance of HaploPOP to assign individuals to populations using a split-validation approach. We investigate both simulated SNPs data and dense genotype data from individuals from Spain and Portugal. CONCLUSIONS: Our results show that constructing haplotypes with HaploPOP can substantially reduce assignment error. The HaploPOP software is freely available as a command-line software at www.ieg.uu.se/Jakobsson/software/HaploPOP/. PMID- 26227425 TI - Laparoscopic Excision of a Pedunculated Uterine Leiomyoma in Torsion as a Cause of Acute Abdomen at 10 Weeks of Pregnancy. AB - BACKGROUND: Pregnancy outcomes after laparoscopic myomectomy are generally favorable, with a pregnancy rate that is comparable to or even higher than the rate associated with abdominal myomectomy. The purpose of this article is to present the case of a pregnant patient at 10 weeks of gestation who was submitted to successful laparoscopic myomectomy of a twisted pedunculated uterine leiomyoma. CASE REPORT: A 31 year-old Greek pregnant woman complaining about acute abdominal pain was submitted to diagnostic laparoscopy which revealed a huge twisted uterine leiomyoma. Subsequently laparoscopic myomectomy was successfully carried out. CONCLUSIONS: Laparoscopic myomectomy is a technically challenging procedure with surgeon-specific limitations. Laparoscopy during pregnancy should be performed with utmost care and it proves to be a safe and effective procedure in hands of clinicians with sufficient experience in laparoscopic surgery. PMID- 26227426 TI - Synthesis of air- and moisture-stable, storable chiral oxorhenium complexes and their application as catalysts for the enantioselective imine reduction. AB - Air-/moisture-stable, crystalline, and storable chiral salicyloxazoline based oxorhenium(V) complexes have been synthesized and their catalytic application for the asymmetric reduction of ketimines using hydrosilane as hydride source is disclosed. A broad substrate scope, high yields, and excellent enantioselectivities (up to 99 %) are attained. Furthermore, the syntheses of enantiopure alpha-amino esters, gamma- and delta-lactams, and isoindolinones have also been carried out using this methodology. Finally, the method has been applied to synthetic targets of pharmaceutical relevance, such as R-(+) salsolidine and R-(+)-crispine A. PMID- 26227428 TI - Discrimination of in vitro and in vivo digestion products of meat proteins from pork, beef, chicken, and fish. AB - In vitro digestion products of proteins were compared among beef, pork, chicken, and fish. Gastric and jejunal contents from the rats fed these meat proteins were also compared. Cooked pork, beef, chicken, and fish were homogenized and incubated with pepsin alone or followed by trypsin. The digestion products with molecular weights of less than 3000 Da were identified with MALDI-TOF-MS and nano LC-MS/MS. Gastric and jejunal contents obtained from the rats fed the four meat proteins for 7 days were also analyzed. After pepsin digestion, pork, and beef samples had a greater number of fragments in similarity than chicken and fish samples, but the in vitro digestibility was the greatest (p < 0.05) for pork and the smallest for beef samples. After trypsin digestion, the species differences were less pronounced (p > 0.05). A total of 822 and 659 peptides were identified from the in vitro and in vivo digestion products, respectively. Our results could interpret for the differences in physiological functions after the ingestion of different species of meat. PMID- 26227429 TI - Equine grass sickness in Scotland: A case-control study of environmental geochemical risk factors. AB - REASONS FOR PERFORMING STUDY: We hypothesised that the apparent geographical distribution of equine grass sickness (EGS) is partly attributable to suboptimal levels of soil macro- and trace elements in fields where EGS occurs. If proven, altering levels of particular elements could be used to reduce the risk of EGS. OBJECTIVES: To determine whether the geographical distribution of EGS cases in eastern Scotland is associated with the presence or absence of particular environmental chemical elements. STUDY DESIGN: Retrospective time-matched case control study. METHODS: This study used data for 455 geo-referenced EGS cases and 910 time-matched controls in eastern Scotland, and geo-referenced environmental geochemical data from the British Geological Survey Geochemical Baseline Survey of the Environment stream sediment (G-BASE) and the James Hutton Institute, National Soil Inventory of Scotland (NSIS) datasets. RESULTS: Multivariable statistical analyses identified clusters of three main elements associated with cases from (i) the G-BASE dataset - higher environmental Ti and lower Zn, and (ii) the NSIS dataset - higher environmental Ti and lower Cr. There was also some evidence from univariable analyses for lower Al, Cd, Cu, Ni and Pb and higher Ca, K, Mo, Na and Se environmental concentrations being associated with a case. Results were complicated by a high degree of correlation between most geochemical elements. CONCLUSIONS: The work presented here would appear to reflect soil- not horse-level risk factors for EGS, but due to the complexity of the correlations between elements, further work is required to determine whether these associations reflect causality, and consequently whether interventions to alter concentrations of particular elements in soil, or in grazing horses, could potentially reduce the risk of EGS. The effect of chemical elements on the growth of those soil microorganisms implicated in EGS aetiology also warrants further study. PMID- 26227430 TI - In response to is the OSA-18 predictive of obstructive sleep apnea: Comparison to polysomnography. PMID- 26227431 TI - Effects of Wind Chill Factor, Temperature and Other Meteorological Parameters on the Incidence of Bell's Palsy: Results Based on a Retrospective, 7-Year Long, Greek Population Study. AB - BACKGROUND: The etiology of Bell's palsy (BP), the most common type of dysfunction of the facial nerve, remains unclear despite vigorous research. Data concerning the effects of meteorological factors (MFs) on its appearance are inconclusive. The aim of our study was to examine the demographics of a convenience sample of patients with BP and to determine the effects of several MFs in the recorded number of cases per month (cpm). METHODS: We retrospectively reviewed 568 files of BP patients and concomitant data of MFs during an 84-month observation period. Information collected included age, gender, diabetic status, number of cpm (months further categorized as winter or summer), mean daily and monthly temperatures and wind speeds and monthly values of wind chill factor (WCF), a measure dependent on both temperature and wind speed. Potential correlations were estimated by univariate analyses (p = 0.05). RESULTS: Demographics were in line with previous research regarding age and diabetic status, but indicative of slight male preponderance. Summer months and mean monthly temperatures showed significant negative correlations with cpm (p = 0.002 and <0.000, respectively) and strong positive correlation with WCF (p < 0.000). CONCLUSIONS: MFs can substantially influence the possibility for BP appearance. We propose WCF as a novel, reliable estimator of the overall MF-derived risk. PMID- 26227432 TI - Personalised medicine: Development and external validation of a prognostic model for metastatic melanoma patients treated with ipilimumab. AB - PURPOSE: The purpose of this study was to set up a prognostic model for the identification of survival predictors specific for melanoma patients treated with ipilimumab. EXPERIMENTAL DESIGN: The following prospectively collected data were utilised: patient and primary tumour characteristics, relapse-free-interval, site and number of metastases, previous therapies and level of serum biomarkers (lactic dehydrogenase (LDH), C-reactive protein, beta2-microglobulin, vascular endothelial growth factor (VEGF), IL2, IL6, S-100, alkaline phosphatase (ALP), transaminases, leucocyte count, lymphocytes subpopulations). A multivariate prognostic model was developed using the Cox regression model fitted to the data of 113 consecutive metastatic patients treated with ipilimumab (3 mg/kg, q3w) at Veneto Institute of Oncology (IOV). External validation was obtained using the data of 69 and 34 patients treated at European Oncology Institute (IEO) and University of Torino (UT), respectively. RESULTS: Median survival was 8.3, 4.9 and 7.1 months from first ipilimumab administration at IOV, IEO and UT, respectively. Both higher baseline levels of LDH (Hazard Ratio [HR] v=1.36, 95% Confidence Interval [CI] 1.16-1.58, P<.001) and neutrophils (HR=1.76, 95% CI 1.41 2.10, P<.001) were associated with worse prognosis. Model performance was satisfactory both upon internal validation (Dxy=0.42) and external validation (Dxy=0.40). Serum LDH and neutrophil count discriminated patients who lived more (low neutrophils and low LDH) or less (high LDH or neutrophils) than 24 months. CONCLUSION: Serum LDH and neutrophil count were significant independent prognostic factors. This externally validated prognostic nomogram, could help clinicians to identify the patients who would benefit most from ipilimumab and consequently to improve resource allocation. These easily available biomarkers deserve further validation. PMID- 26227433 TI - Ischaemic stroke of undetermined cause. PMID- 26227434 TI - Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. AB - BACKGROUND: A third of transient ischaemic attacks (TIAs) and ischaemic strokes are of undetermined cause (ie, cryptogenic), potentially undermining secondary prevention. If these events are due to occult atheroma, the risk-factor profile and coronary prognosis should resemble that of overt large artery events. If they have a cardioembolic cause, the risk of future cardioembolic events should be increased. We aimed to assess the burden, outcome, risk factors, and long-term prognosis of cryptogenic TIA and stroke. METHODS: In a population-based study in Oxfordshire, UK, among patients with a first TIA or ischaemic stroke from April 1, 2002, to March 31, 2014, we compared cryptogenic events versus other causative subtypes according to the TOAST classification. We compared markers of atherosclerosis (ie, risk factors, coronary and peripheral arterial disease, asymptomatic carotid stenosis, and 10-year risk of acute coronary events) and of cardioembolism (ie, risk of cardioembolic stroke, systemic emboli, and new atrial fibrillation [AF] during follow-up, and minor-risk echocardiographic abnormalities and subclinical paroxysmal AF at baseline in patients with index events between 2010 and 2014). FINDINGS: Among 2555 patients, 812 (32%) had cryptogenic events (incidence of cryptogenic stroke 0.36 per 1000 population per year, 95% CI 0.23-0.49). Death or dependency at 6 months was similar after cryptogenic stroke compared with non-cardioembolic stroke (23% vs 27% for large artery and small vessel subtypes combined; p=0.26) as was the 10-year risk of recurrence (32% vs 27%; p=0.91). However, the cryptogenic group had fewer atherosclerotic risk factors than the large artery disease (p<0.0001), small vessel disease (p=0.001), and cardioembolic (p=0.008) groups. Compared with patients with large artery events, those with cryptogenic events had less hypertension (adjusted odds ratio [OR] 0.41, 95% CI 0.30-0.56; p<0.0001), diabetes (0.62, 0.43-0.90; p=0.01), peripheral vascular disease (0.27, 0.17-0.45; p<0.0001), hypercholesterolaemia (0.53, 0.40-0.70; p<0.0001), and history of smoking (0.68, 0.51-0.92; p=0.01), and compared with small vessel and cardioembolic subtypes, they had no excess risk of asymptomatic carotid disease (adjusted OR 0.64, 95% CI 0.37-1.11; p=0.11) or acute coronary events (adjusted hazard ratio [HR] 0.76, 95% CI 0.49-1.18; p=0.22) during follow-up. Compared with large artery and small vessel subtypes combined, patients with cryptogenic events also had no excess of minor-risk echocardiographic abnormalities (cryptogenic 37% vs 45%; p=0.18) or paroxysmal AF (6% vs 10%; p=0.17) at baseline or of new AF (adjusted HR 1.23, 0.78-1.95; p=0.37) or presumed cardioembolic events (1.16, 0.62-2.17; p=0.64) during follow-up. INTERPRETATION: The clinical burden of cryptogenic TIA and stroke is substantial. Although stroke recurrence rates are comparable with other subtypes, cryptogenic events have the fewest atherosclerotic markers and no excess of cardioembolic markers. FUNDING: Wellcome Trust, Wolfson Foundation, UK Stroke Association, British Heart Foundation, Dunhill Medical Trust, National Institute for Health Research, Medical Research Council, and the NIHR Oxford Biomedical Research Centre. PMID- 26227435 TI - Exhaled Carbon Dioxide and Neonatal Breathing Patterns in Preterm Infants after Birth. AB - OBJECTIVES: To examine the amount of exhaled carbon dioxide (ECO2) with different breathing patterns in spontaneously breathing preterm infants after birth. STUDY DESIGN: Preterm infants had a facemask attached to a combined carbon dioxide/flow sensor placed over their mouth and nose to record ECO2 and gas flow. A breath-by breath analysis of the first 5 minutes of the recording was performed. RESULTS: Thirty spontaneously breathing preterm infants, gestational age (mean +/- SD) 30 +/- 2 weeks and birth weight 1635 +/- 499 g were studied. ECO2 from normal breaths and slow expirations was significantly larger than with other breathing patterns (P < .001). ECO2 per breath also increased with gestational age P < .001. The expiratory hold pattern was the most prevalent breathing pattern both during the first minute of recording and overall. Breathing pattern proportions also varied by gestational age. Finally, ECO2 from the fifth minute of recording was significantly greater than that produced during the first 4 minutes of recording (P <= .029). CONCLUSIONS: ECO2 varies with different breathing patterns and increases with gestational age and over time. ECO2 may be an indicator of lung aeration and that postnatal ECO2 monitoring may be useful in preterm infants in the delivery room. PMID- 26227436 TI - Longitudinal Development of Infant Complementary Diet Diversity in 3 International Cohorts. AB - OBJECTIVES: To evaluate international differences in the development of minimum dietary diversity (MDD) between 6 and 12 months of age. STUDY DESIGN: Breastfed infants (115, 100, and 109 in Shanghai, Cincinnati, and Mexico City, respectively) were enrolled near birth and dietary intake assessed weekly by 24 hour recall of food frequency. Diet diversity per month from age 6-12 months was assessed as at least 4 of 7 food groups provided on the previous day. RESULTS: Across all cohorts, dietary diversity increased from 6 (31%) to 12 (92%) months of age. Shanghai infants were significantly more likely to achieve MDD than the other cohorts at each month of age. Meat/seafood accounted for a higher proportion of infant feeds in Shanghai compared with the other cohorts, and eggs were only fed in Shanghai, and proportional intake of dairy, grains, and fruit were highest in Cincinnati. Only 28% of Cincinnati infants fed >50% human milk achieved MDD between 6 and 12 months. CONCLUSIONS: The proportion of infants between 6 and 12 months achieving MDD was significantly higher in Shanghai than in Mexico City or Cincinnati at all ages. Of particular concern was low dietary diversity among highly breastfed Cincinnati cohort infants, suggesting a need for greater education of breastfeeding mothers about the need to introduce a diverse complementary food diet. PMID- 26227437 TI - Emotion Awareness Predicts Body Mass Index Percentile Trajectories in Youth. AB - OBJECTIVE: To examine the rate of change in body mass index (BMI) percentile across 3 years in relation to emotion identification ability and brain-based reactivity in emotional processing regions. STUDY DESIGN: A longitudinal sample of 202 youths completed 3 functional magnetic resonance imaging-based facial processing tasks and behavioral emotion differentiation tasks. We examined the rate of change in the youth's BMI percentile as a function of reactivity in emotional processing brain regions and behavioral emotion identification tasks using multilevel modeling. RESULTS: Lower correct identification of both happiness and sadness measured behaviorally predicted increases in BMI percentile across development, whereas higher correct identification of both happiness and sadness predicted decreases in BMI percentile, while controlling for children's pubertal status, sex, ethnicity, IQ score, exposure to antipsychotic medication, family income-to-needs ratio, and externalizing, internalizing, and depressive symptoms. Greater neural activation in emotional reactivity regions to sad faces also predicted increases in BMI percentile during development, also controlling for the aforementioned covariates. CONCLUSION: Our findings provide longitudinal developmental data demonstrating links between both emotion identification ability and greater neural reactivity in emotional processing regions with trajectories of BMI percentiles across childhood. PMID- 26227438 TI - More than (Double) Bubble. PMID- 26227439 TI - Neurodevelopmental Outcomes of Premature Infants Treated for Patent Ductus Arteriosus: A Population-Based Cohort Study. AB - OBJECTIVE: To compare neurodevelopmental outcomes of extremely preterm infants diagnosed with patent ductus arteriosus (PDA) who were treated medically or surgically and those who were not diagnosed with PDA or who did not undergo treatment for PDA. STUDY DESIGN: This retrospective population-based cohort study used data from a geographically defined area in New South Wales and the Australian Capital Territory served by a network of 10 neonatal intensive care units. Patients included all preterm infants born at <29 completed weeks of gestation between 1998 and 2004. Moderate/severe functional disability at 2-3 years corrected age was defined as developmental delay, cerebral palsy requiring aids, sensorineural or conductive deafness (requiring bilateral hearing aids or cochlear implant), or bilateral blindness (best visual acuity of <6/60). RESULTS: Follow-up information at age 2-3 years was available for 1473 infants (74.8%). Compared with infants not diagnosed with a PDA or who did not receive PDA treatment for PDA, those with medically treated PDA (aOR, 1.622; 95% CI, 1.199 2.196) and those with surgically treated PDA (aOR, 2.001; 95% CI, 1.126-3.556) were at significantly greater risk for adverse neurodevelopmental outcomes at age 2-3 years. CONCLUSION: Our results demonstrate that treatment for PDA may be associated with a greater risk of adverse neurodevelopmental outcome at age 2-3 years. This was particularly so among infants born at <25 weeks gestation. These results may support permissive tolerance of PDAs; however, reasons for this association remain to be elucidated through carefully designed prospective trials. PMID- 26227440 TI - Nosocomial pneumonia in non-invasive ventilation patients: incidence, characteristics, and outcomes. AB - BACKGROUND: Nosocomial pneumonia occasionally occurs in non-invasive ventilation (NIV) patients. AIM: To report the incidence, characteristics, and outcomes of nosocomial pneumonia in NIV patients. METHODS: A prospective observational study was performed in a respiratory intensive care unit (ICU). After admission, patients who received NIV for more than 48 h were enrolled. Pneumonia was considered nosocomial when it occurred after at least 48 h of NIV. FINDINGS: Between January 2012 and August 2014, we enrolled 520 NIV patients. Nosocomial pneumonia occurred in 16 patients (3.1%). The nosocomial pneumonia rate was 4.5 cases per 1000 NIV-days. The most common pathogen was Acinetobacter baumannii (81%). At the initiation of NIV, there were no differences in age, gender, diagnosis, disease severity, or arterial blood gas findings between patients with and without nosocomial pneumonia. Compared to patients without nosocomial pneumonia, nosocomial pneumonia patients had a longer duration of NIV (8.4 vs 5.0 days, P < 0.01), a longer ICU stay (10.8 vs 7.9 days, P = 0.01), a longer hospital stay (25.9 vs 15.3 days, P = 0.04), a higher intubation rate (63% vs 21%, P < 0.01), and higher hospital mortality (75% vs 25%, P < 0.01). Nosocomial pneumonia was an independent risk factor for intubation (OR: 6.74; 95% CI: 2.24 20.28) and death (7.65; 1.34-43.72). CONCLUSION: The incidence of nosocomial pneumonia in NIV patients in this population was 3.1%. Nosocomial pneumonia increased the time that NIV was required, length of ICU stay, length of hospital stay, intubation rate, and hospital mortality. PMID- 26227441 TI - Ostracism and attachment orientation: Avoidants are less affected in both individualistic and collectivistic cultures. AB - Ostracism--being excluded and ignored--is painful and threatens needs for belonging, self-esteem, control and meaningful existence. Many studies have shown that immediate responses to ostracism tend to be resistant to moderation. Once ostracized individuals are able to reflect on the experience, however, personality and situational factors moderate recovery speed and behavioural responses. Because attachment orientation is grounded in perceptions of belonging, we hypothesized that attachment orientation would moderate both immediate and delayed reactions to laboratory-induced ostracism. Participants from individualistic or collectivistic cultures were either included or ostracized in a game of Cyberball, a virtual ball-toss game. In both cultures, we found that compared to more securely attached individuals, more avoidant participants were less distressed by ostracism, but more distressed by inclusion. It is suggested that over and beyond differences in culture, individuals who avoid meaningful attachment may be less affected by ostracism. PMID- 26227442 TI - Ab initio GGA+U study of oxygen evolution and oxygen reduction electrocatalysis on the (001) surfaces of lanthanum transition metal perovskites LaBO3 (B = Cr, Mn, Fe, Co and Ni). AB - In this work, we performed density functional theory (DFT) calculations with inclusion of Hubbard U corrections for the transition metal d-electrons, to investigate stability and electrocatalytic activities of the oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) for the ABO3 (A = La; B = Cr, Mn, Fe, Co, and Ni) (001) surfaces. We showed surface binding energies of relevant ORR/OER species are coupled strongly to surface polarity and local oxidation states, giving large (~1 eV scale per adsorbate) differences in binding between (001) AO and BO2 surfaces, where the more oxidized BO2 bare surfaces in general exhibit weak coverage dependence, while the more reduced AO bare surfaces of the LaCrO3, LaMnO3, and LaFeO3 perovskites with lower d-electron filling show strong/moderate coverage dependences. We then predicted that surface coverage can play a key role in determining surface stability, and when coverage effects are included the AO and BO2(001) surfaces have either similar stability or the AO surface is more stable, as found for 1 monolayer HO* covered AO surfaces of LaCrO3 and LaFeO3 under ORR conditions and 1 monolayer O* covered LaNiO3 AO surface under OER conditions. For the (001) AO surfaces with strong coverage dependent surface adsorption, we predicted a decrease in ORR overpotential of 1-2 V with proper treatment of coverage effects as compared to those of the bare surface simulations. Our results indicated that the GGA+U method and proper treatment of coverage effects more accurately predict ORR and OER overpotentials relative to experimental values as compared to the GGA method and bare surfaces. The overall ORR activity trends vs. the LaBO3 series were predicted to be Co > Mn ~ Ni > Fe > Cr. PMID- 26227443 TI - Response to long-term growth hormone therapy in patients affected by RASopathies and growth hormone deficiency: Patterns of growth, puberty and final height data. AB - RASopathies are developmental disorders caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. Reduced growth is a common feature. Several studies generated data on growth, final height (FH), and height velocity (HV) after growth hormone (GH) treatment in patients with these disorders, particularly in Noonan syndrome, the most common RASopathy. These studies, however, refer to heterogeneous cohorts in terms of molecular information, GH status, age at start and length of therapy, and GH dosage. This work reports growth data in 88 patients affected by RASopathies with molecularly confirmed diagnosis, together with statistics on body proportions, pubertal pattern, and FH in 33, including 16 treated with GH therapy for proven GH deficiency. Thirty-three patients showed GH deficiency after pharmacological tests, and were GH-treated for an average period of 6.8 +/- 4.8 years. Before starting therapy, HV was -2.6 +/- 1.3 SDS, and mean basal IGF1 levels were -2.0 +/- 1.1 SDS. Long-term GH therapy, starting early during childhood, resulted in a positive height response compared with untreated patients (1.3 SDS in terms of height-gain), normalizing FH for Ranke standards but not for general population and Target Height. Pubertal timing negatively affected pubertal growth spurt and FH, with IGF1 standardized score increased from -2.43 to -0.27 SDS. During GH treatment, no significant change in bone age velocity, body proportions, or cardiovascular function was observed. PMID- 26227444 TI - Extension of donor lung preservation with hypothermic storage after normothermic ex vivo lung perfusion. AB - BACKGROUND: Ex vivo lung perfusion (EVLP) allows normothermic evaluation and treatment of donor lungs not currently acceptable for transplant and improves organ use. Donor lungs undergo a period of cold preservation before (cold ischemic time [CIT]-1) and after (CIT-2) EVLP. We investigated the effect of an extended CIT-2 on lung function after transplantation. METHODS: Explanted pig lungs, preserved in low-potassium dextran flush (Perfadex) at 4 degrees C for 10 hours, were subjected to 6 hours of EVLP. They were subsequently allocated to 2 groups: short CIT-2 (CIT-2 = 2 hours; n = 5), and long CIT-2 (CIT-2 = 10 hours; n = 5). In a control group (n = 6), explanted lungs were placed in cold static preservation for 24 hours without EVLP. After the total preservation period, the left lung was transplanted in all groups. RESULTS: After 4 hours of reperfusion, oxygenation function, acute lung injury score, inflammatory markers, and cell death pathway markers were similar between short and long CIT-2 groups. Both EVLP groups fared significantly better than the control group in oxygenation function (p < 0.05). CONCLUSIONS: The intervention of EVLP improved lung function after transplantation, and this was not affected by a prolonged cold static preservation time after EVLP. These results provide the basis for a practical prolonged lung preservation strategy using a combination of cold and warm preservation techniques, which may improve lung transplantation logistics and outcomes. PMID- 26227445 TI - Effects of sniffing position for tracheal intubation: a meta-analysis of randomized controlled trials. AB - BACKGROUND: The purpose of this meta-analysis was to validate the efficacy of the sniffing position in the performance of intubation with direct laryngoscopy. METHODS: We searched MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, and Web of Science. Six randomized controlled trials comprising 2759 adult participants were analyzed. The DerSimonian-Laird method was used to calculate pooled relative risk (RR) and the 95% confidence interval (CI) of Cormack-Lehane classification, Intubation Difficulty Scale, success rate of the first intubation, and weighted mean difference of intubation time. RESULTS: Compared with the other head positions, the sniffing position did not improve glottic visualization, success rate of the first intubation, or intubation time. However, the sniffing position was significantly associated with better Intubation Difficulty Scale compared with the simple head extension position. (RR,1.28; 95% CI, 1.15-1.42; p<0.0001) CONCLUSIONS: Although patients do not benefit from the sniffing position in terms of glottic visualization, success rate of the first intubation, or intubation time, the sniffing position can still be recommended as the initial head position for tracheal intubation because the sniffing position provides easier intubation conditions. PMID- 26227446 TI - Shippers and freight operators perceptions of sustainable initiatives. AB - The purpose of this paper is to document the extent to which Brazilian companies in retail channels have committed to adopting environmental sustainability measures, goals and strategies for waste disposal in the evaluation and planning of sustainable transportation. This paper also aims to examine the different viewpoints of sustainability issues and the preventive actions taken by companies in terms of controlling carbon dioxide emissions and proper disposal of tires, lubricant oils, accessories and spare parts. Finally, taking the perspective of these companies, this paper examines their difficulties in meeting environmental regulations. The research involved a survey completed by 185 representatives of different types of companies, including shippers (represented by manufacturers), LSPs (logistics service providers) and carriers. The non-linear canonical correlation was calculated to verify the opinions of these representatives from different companies regarding issues that impact on the environment, the preventive actions they adopt to reduce their environmental impact and their difficulties in meeting environmental regulations. The results show that shippers and LSPs have the same perceptions regarding these sustainability issues and preventive actions. In addition, the companies perceive high costs and the lack of training for their partners as the major challenges experienced in addressing these issues and undertaking preventive actions. Therefore they need to plan their transportation activities. PMID- 26227447 TI - Evaluation and programme planning in sustainable development. PMID- 26227448 TI - Financing global health: the poverty of nations. PMID- 26227449 TI - Ending institutionalisation of children. PMID- 26227450 TI - New guidelines for idiopathic pulmonary fibrosis. PMID- 26227451 TI - Safeguarding children and improving their care in the UK. PMID- 26227453 TI - The World Bank under Jim Kim. PMID- 26227457 TI - Signing the US Medicare Act: a long political struggle. PMID- 26227458 TI - Levi Watkins. PMID- 26227459 TI - Greek financial crisis and child mental health. PMID- 26227460 TI - Management of disease outbreak in Nepal. PMID- 26227461 TI - Is precision medicine the route to a healthy world? PMID- 26227462 TI - Polio vaccination in Pakistan. PMID- 26227463 TI - Against age discrimination. PMID- 26227464 TI - Legal preparedness and Ebola vaccines. PMID- 26227465 TI - Is crowdfunding a viable source of clinical trial research funding? PMID- 26227466 TI - Another step change for tobacco control in China? PMID- 26227467 TI - Data donation after death. PMID- 26227468 TI - Tinnitus Suppression by Intracochlear Electrical Stimulation in Single-Sided Deafness: A Prospective Clinical Trial - Part I. AB - Cochlear implantation is a viable treatment option for tinnitus, but the underlying mechanism is yet unclear. Is the tinnitus suppression due to the reversal of the assumed maladaptive neuroplasticity or is it the shift in attention from the tinnitus to environmental sounds and therefore a reduced awareness that reduces tinnitus perception? In this prospective trial, 10 patients with single-sided deafness were fitted with a cochlear implant to investigate the effect of looped intracochlear electrical stimulation (i.e. stimulation that does not encode environmental sounds) on tinnitus, in an effort to find optimal stimulation parameters. Variables under investigation were: amplitude (perceived stimulus loudness), anatomical location inside the cochlea (electrode/electrodes), amplitude modulation, polarity (cathodic/anodic first biphasic stimulation) and stimulation rate. The results suggest that tinnitus can be reduced with looped electrical stimulation, in some cases even with inaudible stimuli. The optimal stimuli for tinnitus suppression appear to be subject specific. However, medium-to-loud stimuli suppress tinnitus significantly better than soft stimuli, which partly can be explained by the masking effect. Although the long-term effects on tinnitus would still have to be investigated and will be described in part II, intracochlear electrical stimulation seems a potential treatment option for tinnitus in this population. PMID- 26227469 TI - Systematic Review of Nontumor Pediatric Auditory Brainstem Implant Outcomes. AB - OBJECTIVE: The auditory brainstem implant (ABI) was initially developed for patients with deafness as a result of neurofibromatosis type 2. ABI indications have recently extended to children with congenital deafness who are not cochlear implant candidates. Few multi-institutional outcome data exist. Herein, we aim to provide a systematic review of outcomes following implantation of the ABI in pediatric patients with nontumor diagnosis, with a focus on audiometric outcomes. DATA SOURCES: PubMed, Embase, and Cochrane. REVIEW METHODS: A systematic review of literature was performed using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) recommendations. Variables assessed included age at implantation, diagnosis, medical history, cochlear implant history, radiographic findings, ABI device implanted, surgical approach, complications, side effects, and auditory outcomes. RESULTS: The initial search identified 304 articles; 21 met inclusion criteria for a total of 162 children. The majority of these patients had cochlear nerve aplasia (63.6%, 103 of 162). Cerebrospinal fluid leak occurred in up to 8.5% of cases. Audiometric outcomes improved over time. After 5 years, almost 50% of patients reached Categories of Auditory Performance scores >4; however, patients with nonauditory disabilities did not demonstrate a similar increase in scores. CONCLUSION: ABI surgery is a reasonable option for the habilitation of deaf children who are not cochlear implant candidates. Although improvement in Categories of Auditory Performance scores was seen across studies, pediatric ABI users with nonauditory disabilities have inferior audiometric outcomes. PMID- 26227470 TI - Is MRI Necessary in the Evaluation of Pediatric Central Sleep Apnea? AB - OBJECTIVES: (1) To determine the prevalence of central nervous system (CNS) pathology identified on head magnetic resonance imaging (MRI) scans in children with central sleep apnea (CSA); (2) to assess the yield of MRI in evaluation of CSA; and (3) to identify factors that predict CNS pathology in children with CSA. STUDY DESIGN: Case series with chart review. SETTING: Tertiary children's hospital. SUBJECTS AND METHODS: A chart review was conducted over 12 years. Patients 6 months to 18 years of age who underwent head MRI for evaluation of CSA were included. CSA was diagnosed on polysomnogram as central apnea index >1. RESULTS: Forty children were included in the CSA group. Twenty-two patients were male, and the mean age was 60 +/- 41.5 months. The mean central apnea index was 3.8 +/- 1.9, while the mean obstructive apnea hypopnea index was 3.4 (interquartile range, 0.7-3.8). Eighteen percent (7 of 40) of children with CSA had evidence of CNS pathology on MRI, with the most common finding (n = 3) being arachnoid cyst. Children with CSA who had gastroesophageal reflux disease or abnormal neurologic examinations were more likely to have CNS pathology. Other factors, such as prematurity, did not improve the yield of MRI in children with CSA. CONCLUSIONS: While routine evaluation of children with elevated central apnea index by MRI is not indicated, providers should consider neuroimaging in children with CSA and abnormal neurologic examination findings or gastroesophageal reflux disease. Further research is necessary to identify other tests with improved diagnostic yield for evaluation of pediatric CSA. PMID- 26227471 TI - Hematohidrosis: insights in the pathophysiology. PMID- 26227472 TI - All eyes on the patient: the influence of oncologists' nonverbal communication on breast cancer patients' trust. AB - Trust in the oncologist is crucial for breast cancer patients. It reduces worry, enhances decision making, and stimulates adherence. Optimal nonverbal communication by the oncologist, particularly eye contact, body posture, and smiling, presumably benefits patients' trust. We were the first to experimentally examine (1) how the oncologist's nonverbal behavior influences trust, and (2) individual differences in breast cancer patients' trust. Analogue patients (APs) viewed one out of eight versions of a video vignette displaying a consultation about chemotherapy treatment. All eight versions varied only in the oncologist's amount of eye contact (consistent vs. inconsistent), body posture (forward leaning vs. varying), and smiling (occasional smiling vs. no smiling). Primary outcome was trust in the observed oncologist (Trust in Oncologist Scale). 214 APs participated. Consistent eye contact led to stronger trust (beta = -.13, p = .04). This effect was largely explained by lower educated patients, for whom the effect of consistent eye contact was stronger than for higher educated patients (beta = .18, p = .01). A forward leaning body posture did not influence trust, nor did smiling. However, if the oncologist smiled more, he was perceived as more friendly (rs = .31, p < .001) and caring (rs = .18, p = .01). Older (beta = .17, p = .01) and lower educated APs (beta = -.25, p < .001) were more trusting. Trust was weaker for more avoidantly attached APs (beta = -.16, p = .03). We experimentally demonstrated the importance of maintaining consistent eye contact for breast cancer patients' trust, especially among lower educated patients. These findings need to be translated into training for oncologists in how to optimize their nonverbal communication with breast cancer patients while simultaneously managing increased time pressure and computer use during the consultation. PMID- 26227474 TI - Increased COX-2 expression in epithelial and stromal cells of high mammographic density tissues and in a xenograft model of mammographic density. AB - Mammographic density (MD) adjusted for age and body mass index is one of the strongest known risk factors for breast cancer. Given the high attributable risk of MD for breast cancer, chemoprevention with a safe and available agent that reduces MD and breast cancer risk would be beneficial. Cox-2 has been implicated in MD-related breast cancer risk, and was increased in stromal cells in high MD tissues in one study. Our study assessed differential Cox-2 expression in epithelial and stromal cells in paired samples of high and low MD human breast tissue, and in a validated xenograft biochamber model of MD. We also examined the effects of endocrine treatment upon Cox-2 expression in high and low MD tissues in the MD xenograft model. Paired high and low MD human breast tissue samples were immunostained for Cox-2, then assessed for differential expression and staining intensity in epithelial and stromal cells. High and low MD human breast tissues were separately maintained in biochambers in mice treated with Tamoxifen, oestrogen or placebo implants, then assessed for percentage Cox-2 staining in epithelial and stromal cells. Percentage Cox-2 staining was greater for both epithelial (p = 0.01) and stromal cells (p < 0.0001) of high compared with low MD breast tissues. In high MD biochamber tissues, percentage Cox-2 staining was greater in stromal cells of oestrogen-treated versus placebo-treated tissues (p = 0.05). PMID- 26227473 TI - Proteasome inhibitors induce AMPK activation via CaMKKbeta in human breast cancer cells. AB - The purpose of present study is to examine the mechanism of the 5'-AMP-activated protein kinase (AMPK) activation induced by proteasome inhibitors. AMPK activation and ubiquitin proteasome system (UPS) inhibition have gained great attention as therapeutic strategies for the treatment of certain types of cancers. While AMPK serves as a master regulator of cellular metabolism, UPS regulates protein homeostasis. However, the relationship between these two important pathways is not very clear. We observe that proteasome inhibition leads to AMPK activation in human breast cancer cells. siRNA transfection, western blotting, qPCR, and proteasomal inhibition assays were used to study the mechanism of proteasome inhibitor-induced AMPK activation using human triple negative breast cancer, lung, and cervical cancer cell lines. We report that a variety of proteasome inhibitors activate AMPK in all the tested different cancer cell lines. Our data using liver kinase B1-deficient cancer cells suggest that proteasome inhibitor-induced AMPK activation is primarily mediated by Calcium/Calmodulin-dependent kinase kinase beta (CaMKKbeta). This hypothesis is supported by that pharmacological or genetic inhibition of CaMKKbeta leads to a decrease in proteasome inhibitor-induced AMPK activation. Additionally, the AMPK activating function of the FDA-approved proteasome inhibitor bortezomib depends on an increase in intracellular calcium levels as calcium chelation abrogates its induced AMPK activation. Finally, bortezomib-mediated upregulation in CaMKKbeta levels is due to its enhanced protein synthesis. These data suggest that proteasome inhibitors indirectly activate AMPK in human cancer cells primarily via Ca(2+)-CaMKKbeta-dependent pathway. PMID- 26227475 TI - Improving head and neck CTA with hybrid and model-based iterative reconstruction techniques. AB - AIM: To compare image quality of head and neck computed tomography angiography (CTA) reconstructed with filtered back projection (FBP), hybrid iterative reconstruction (HIR) and model-based iterative reconstruction (MIR) algorithms. MATERIALS AND METHODS: The raw data of 34 studies were simultaneously reconstructed with FBP, HIR (iDose(4), Philips Healthcare, Best, the Netherlands), and with a prototype version of a MIR algorithm (IMR, Philips Healthcare). Objective (contrast-to-noise ratio [CNR], vascular contrast, automatic vessel analysis [AVA], stenosis grade) and subjective image quality (ranking at level of the circle of Willis, carotid bifurcation, and shoulder) of the five reconstructions were compared using repeated-measures analysis of variance (ANOVA) and post-hoc analysis. RESULTS: Vascular contrast was significantly higher in both the circle of Willis and carotid bifurcation with both levels of MIR compared to the other reconstruction methods (all p<0.0001). The CNR was highest for high MIR, followed by low MIR, high HIR, mid HIR and FBP (p<0.001 except low MIR versus high HIR; p>0.33). AVA showed most complete carotids in both MIR-levels, followed by high HIR (p>0.08), mid HIR (p<0.023) and FBP (p<0.010), vertebral arteries completeness was similar (p=0.40 and p=0.06). Stenosis grade showed no significant differences (p=0.16). High HIR showed the best subjective image quality at the circle of Willis and carotid bifurcation level, followed by mid HIR. At shoulder level, low MIR and high HIR were ranked best, followed by high MIR. CONCLUSION: Objectively, MIR significantly improved the overall image quality, reduced image noise, and improved automated vessel analysis, whereas FBP showed the lowest objective image quality. Subjectively, the highest level of HIR was considered superior at the level of the circle of Willis and the carotid bifurcation, and along with the lowest level of MIR for the origins of the neck arteries at shoulder level. PMID- 26227476 TI - PPARgamma stimulates expression of L-type amino acid and taurine transporters in human placentas: the evidence of PPARgamma regulating fetal growth. AB - Placental amino acid transporters and peroxisome proliferator-activated receptors (PPARs) have been implicated to placental development and therefore regulation of fetal growth. We analyzed the correlation between the expression of amino acid transporters and PPARs and investigated whether PPARs control the expression of amino acid transporters in placentas. It was found that protein expression of PPARgamma and L-type amino acid transporter 1(LAT1) and 2 (LAT2) was decreased in small-for-gestational-age (SGA) placentas. LAT1, LAT2 and taurine transporter (TAUT) expression correlated to PPARgamma level and birth weight. In cultured placental cells, PPARgamma agonist stimulated LAT1 and LAT2 and TAUT, which was reversed by PPARgamma siRNA. PPARgamma up-regulation of LAT1 and TAUT was through specificity protein 1 (Sp-1) while stimulation of LAT2 expression was via induction of gene transcription. Our data suggest that PPARgamma, SP-1, LAT1 and LAT2 in placentas are involved in control of fetal growth. PPARgamma signaling pathway may be the therapeutic target for intrauterine growth restriction. PMID- 26227477 TI - Current State of Digital Laboratory Production Processes. PMID- 26227478 TI - Quantitative PCR detection of feline morbillivirus in cat urine samples. AB - Feline morbillivirus (FmoPV) is a new virus species and its detection is important, since correlation has been reported between FmoPV virus infection and tubulointerstitial nephritis in cats. Here, we report a real-time reverse transcription (RT)-PCR system that can detect the FmoPV L-gene sequence with more than 10-time higher sensitivity than a conventional PCR system, resulting in detection of less than 10 copies of the template DNA. The total FmoPV positive rate of urine samples from veterinary clinics and hospitals in Japan was 15.1% (25/166) using this system. This study demonstrates usefulness of the real-time RT-PCR system for detection of FmoPV for cat urine samples. PMID- 26227479 TI - Diagnostic yield of targeted next generation sequencing in various cancer types: an information-theoretic approach. AB - The information-theoretic concept of Shannon entropy can be used to quantify the information provided by a diagnostic test. We hypothesized that in tumor types with stereotyped mutational profiles, the results of NGS testing would yield lower average information than in tumors with more diverse mutations. To test this hypothesis, we estimated the entropy of NGS testing in various cancer types, using results obtained from clinical sequencing. A set of 238 tumors were subjected to clinical targeted NGS across all exons of 27 genes. There were 120 actionable variants in 109 cases, occurring in the genes KRAS, EGFR, PTEN, PIK3CA, KIT, BRAF, NRAS, IDH1, and JAK2. Sequencing results for each tumor were modeled as a dichotomized genotype (actionable mutation detected or not detected) for each of the 27 genes. Based upon the entropy of these genotypes, sequencing was most informative for colorectal cancer (3.235 bits of information/case) followed by high grade glioma (2.938 bits), lung cancer (2.197 bits), pancreatic cancer (1.339 bits), and sarcoma/STTs (1.289 bits). In the most informative cancer types, the information content of NGS was similar to surgical pathology examination (modeled at approximately 2-3 bits). Entropy provides a novel measure of utility for laboratory testing in general and for NGS in particular. This metric is, however, purely analytical and does not capture the relative clinical significance of the identified variants, which may also differ across tumor types. PMID- 26227480 TI - Mechanical properties and microstructural change of W-Y2O3 alloy under helium irradiation. AB - A wet-chemical method combined with spark plasma sintering was used to prepare a W-Y2O3 alloy. High-temperature tensile tests and nano-indentation microhardness tests were used to characterize the mechanical properties of the alloy. After He ion irradiation, fuzz and He bubbles were observed on the irradiated surface. The irradiation embrittlement was reflected by the crack indentations formed during the microhardness tests. A phase transformation from alpha-W to gamma-W was investigated by X-ray diffraction (XRD) and transmission electron microscopy (TEM). Polycrystallization and amorphization were also observed in the irradiation damage layer. The W materials tended to exhibit lattice distortion, amorphization, polycrystallization and phase transformation under He-ion irradiation. The transformation mechanism predicted by the atomic lattice model was consistent with the available experimental observations. These findings clarify the mechanism of the structural transition of W under ion irradiation and provide a clue for identifying materials with greater irradiation resistance. PMID- 26227482 TI - Comparison of patient outcomes in periarticular and intraarticular local anaesthetic infiltration techniques in total knee arthroplasty. AB - BACKGROUND: The use of local infiltration analgesia in the setting of knee arthroplasty is well established. There are no studies to date which have directly compared differences in infiltration techniques. The purpose of this study is to establish if a difference in patient outcomes exists when the infiltrate is injected into the periarticular tissues or directly into the joint. METHODS: One hundred and forty-two consecutive patients waitlisted for primary total knee arthroplasty were enrolled after primary exclusion criteria were applied. These included the following: allergy to study drugs, inability to receive spinal anaesthesia, and planned bilateral surgery. Patients were divided into two groups, a periarticular infiltration group (group A) and an intraarticular infiltration group (group B). Secondary exclusion criteria of regular opioid use, psychiatric illness, and serious medical comorbidity left a total of 47 patients in group A and 54 patients in group B. Both groups received a combination of 30 mg ketorolac, 500 MUg of adrenaline, and 300 mg of ropivacaine, and normal saline. This was either injected into the periarticular tissues during surgery (group A) or intraarticularly after closure of the wound (group B). Primary outcome measures included opioid consumption during the first 24 h postoperatively and over the total admission, and visual analogue scales (VAS) on postoperative day 1 and at discharge. Secondary measures included Oxford Knee Score, knee flexion, length of stay, haemoglobin drop, and transfusion requirement. Ethics approval was granted by the hospital review board. The trial is registered in the Australian New Zealand Clinical Trials Registry, registration ACTRN12615000488505 . RESULTS: No statistically significant differences in postoperative analgesic use were observed between the two groups. However, there was a trend toward decreased postoperative patient-controlled analgesia use in the periarticular group (mean 53.1 vs 68.3 mg morphine equivalents; p = 0.093), as well as a statistically significant reduction in postoperative visual analogue pain scores. No statistically significant differences were observed for haemoglobin drop, range of motion, or pre- to 6 week postoperative Oxford Score difference. CONCLUSIONS: Our study is the first we are aware of to directly compare a periarticular to intraarticular injection technique when using local infiltration analgesia for total knee arthroplasty. Our results show no clear statistically significant benefit with either technique. The periarticular group showed a statistically significant reduction in postoperative VAS pain scores alongside a trend in that group toward reduced overall opioid use. PMID- 26227481 TI - Modulation of influenza vaccine immune responses using an epidermal growth factor receptor kinase inhibitor. AB - Systemic use of epidermal growth factor receptor inhibitors (EGFRIs) has been shown to alter MHC expression and that of several chemokines, and to enhance immune cell recruitment into human skin. We hypothesized that EGFRIs may have value as cutaneous immune response modifiers, and determined the effects of topical application of an irreversible EGFRI on a well-established murine model of influenza vaccination. We found that a single topical application of an EGFRI led to increased levels of antibodies that inhibit influenza mediated hemagglutination and viral cytopathic effects. The topically applied EGFRI significantly enhanced the generation of vaccine-specific IL-4 and IFN-gamma producing cells within skin-draining lymph nodes as early as one week following vaccination. The EGFRI/vaccine group showed a twelve-fold reduction in detectable pulmonary viral load four days after infection as compared to the vaccine alone control group. The reduction in the lung viral titers correlated with the survival rate, which demonstrated 100% protection in the EGFRI/vaccine immunized group but only 65% protection in the mice immunized with vaccine alone. These findings are significant because they demonstrate that inhibition of defined signaling pathways within the skin using small molecule kinase inhibitors provides a novel approach to enhance immune responses to vaccines. PMID- 26227483 TI - Antimicrobial potential of the Ethiopian Thymus schimperi essential oil in comparison with others against certain fungal and bacterial species. AB - BACKGROUND: To evaluate the in vitro activities of Ethiopian Thymus schimperi with other three hydro distilled essential oils against Dermatophytes (Tricophyton spp. and Microsporum spp.) and other pathogenic micro organisms. METHODS: The studies were carried out using Agar disk diffusion method for screening the most effective essential oils and Agar dilution to determine Minimum Inhibitory Concentration (MIC) of the essential oils. RESULTS: Essential oils of T. schimperi and Cinnamomum zeylanicum were highly active against tested organisms. The MIC were in the range of 0.08 MUl/ml to 0.31 MUl/ml for T. schimperi, 0.31 MUl/ml to 0.16 MUl/ml for C. zeylanicum, 2.5 MUl/ml to1.25 MUl/ml for Citrus limon and 5 MUl/ml to 2.5 MUl/ml for Eucalyptus camaldulensis against Tricophyton spp. and Microsporum spp. T. schimperi and C. zeylanicum oils also showed antimicrobial effect against Candida albicans, Aspegilus niger, Rhodotorula rubra, Escherichia coli, Shigella spp., Bacillus spp. and Streptococci. CONCLUSIONS: The Ethiopian T. schimperi oil had pronounced antifungal and antibacterial activities against all the tested microbes. Therefore, it is required further investigation in order to identify the active compounds and their clinical applications for treatment of tested organisms. PMID- 26227484 TI - Shear wave elastography in chronic kidney disease: a pilot experience in native kidneys. AB - BACKGROUND: There currently is a need for a non-invasive measure of renal fibrosis. We aim to explore whether shear wave elastography (SWE)-derived estimates of tissue stiffness may serve as a non-invasive biomarker that can distinguish normal and abnormal renal parenchymal tissue. METHODS: Participants with CKD (by estimated GFR) and healthy volunteers underwent SWE. Renal elasticity was estimated as Young's modulus (YM) in kilopascals (kPa). Univariate Wilcoxon rank-sum tests were used. RESULTS: Twenty-five participants with CKD (median GFR 38 mL/min; quartile 1, quartile 3 28, 42) and 20 healthy controls without CKD underwent SWE performed by a single radiologist. CKD was associated with increased median YM (9.40 [5.55, 22.35] vs. 4.40 [3.68, 5.70] kPa; p = 0.002) and higher median intra-subject inter-measurement estimated YM's variability (4.27 [2.89, 9.90] vs. 1.51 [1.21, 2.05] kPa; p < 0.001). CONCLUSIONS: SWE-derived estimates of renal stiffness and intra-subject estimated stiffness variability are higher in patients with CKD than in healthy controls. Renal fibrosis is a plausible explanation for the observed difference in YM. Further studies are required to determine the relationship between YM, estimated renal stiffness, and renal fibrosis severity. PMID- 26227485 TI - Association between inflammatory potential of diet and mortality among women in the Swedish Mammography Cohort. AB - PURPOSE: Diet and dietary components have been studied previously in relation to mortality; however, little is known about the relationship between the inflammatory potential of overall diet and mortality. MATERIALS AND METHODS: We examined the association between the Dietary Inflammatory Index (DII) and mortality among 33,747 participants in the population-based Swedish Mammography Cohort. The DII score was calculated based on dietary information obtained from a self-administered food frequency questionnaire. Mortality was determined through linkage to the Swedish Cause of Death Registry through 2013. Cox proportional hazard regression was used to estimate hazard ratios (HR). During 15 years of follow-up, 7095 deaths were identified, including 1996 due to cancer, 602 of which were due to digestive-tract cancer, and 2399 due to cardiovascular disease. RESULTS: After adjusting for age, energy intake, education, alcohol intake, physical activity, BMI, and smoking status, analyses revealed a positive association between higher DII score and all-cause mortality. When used as a continuous variable (range -4.19 to 5.10), DII score was associated with all cause mortality (HRContinuous = 1.05; 95 % CI 1.01-1.09) and digestive-tract cancer mortality (HRContinuous = 1.15; 95 % CI 1.02-1.29). Comparing subjects in the highest quintile of DII (>=1.91) versus the lowest quintile (DII <= -0.67), a significant association was observed for all-cause mortality (HR = 1.25; 95 % CI 1.07-1.47, P trend = 0.003). CONCLUSION: These results indicate that a pro inflammatory diet, as indicated by higher DII score, was associated with all cause and digestive-tract cancer mortality. PMID- 26227486 TI - Met Signaling Cascade Is Amplified by the Recruitment of Phosphorylated Met to Lipid Rafts via CD24 and Leads to Drug Resistance in Endometrial Cancer Cell Lines. AB - Endometrial cancer is the most prevalent gynecologic cancer in the Western world, and the number of advanced chemotherapy-resistant cancers is increasing with the absolute increase in patients. The development of resistance to chemotherapeutic drugs by cancer cells represents a major challenge in the clinical cure of advanced and metastatic cancers. CD24 has been reported to be a marker for a poor prognosis in several tumors, and we herein examined the functions of CD24 in human endometrioid adenocarcinoma cell lines and evaluated how it contributes to cancer drug resistance. We demonstrated that CD24 was responsible for the recruitment of phosphorylated Met to the lipid raft domain of the cell membrane, resulting in amplification of the Met signaling cascade, ultimately leading endometrial cancer cells to express higher levels of ATP-binding cassette (ABC) transporters. Our findings suggest that CD24-mediated amplification of the Met cascade may contribute to the drug resistance of endometrial cancer. PMID- 26227487 TI - Cytokeratin-20 and Survivin-Expressing Circulating Tumor Cells Predict Survival in Metastatic Colorectal Cancer Patients by a Combined Immunomagnetic qRT-PCR Approach. AB - Circulating tumor cells (CTC) express epithelial and stem cell-like genes, though current approved detection methods mainly use epithelial markers. We optimized a CTC isolation method that could capture their molecular heterogeneity and predict overall survival (OS) in metastatic colorectal cancer (mCRC) patients receiving various chemotherapy regimens. We combined immunomagnetic enrichment of CD45 negative, EpCAM-positive circulating cancer cells with qRT-PCR amplification of CK20 and survivin expression in 88 mCRC patients and 20 healthy controls. We then evaluated the prognostic value of baseline CTC CK20 and survivin expression in mCRC patients. The presence of elevated CTC CK20 or survivin expression distinguished mCRC patients from controls with sufficient sensitivity (79.6%) and specificity (85%). In univariate analysis, patients with high CTC-CK20 expression (9 vs. 33.2+ months, log-rank P < 0.001) or high CTC-survivin expression (10 vs. 33.2+ months, log-rank P = 0.032) had a significantly worse median OS than those with low expression of either marker. In multivariable analysis, the high CTC CK20 group had significantly shortened OS (HR, 3.11; adjusted P = 0.01), and there was a trend toward inferior OS in the high CTC-survivin group (HR, 1.76; adjusted P = 0.099). Patients with either high CTC CK20 or survivin expression had inferior OS compared with those with low expression of both markers (HR, 4.39; 95% confidence interval, 1.56-12.35; adjusted P = 0.005). Colorectal cancer CTCs can be reliably isolated using epithelial and stem cell markers. CTC CK20 and survivin expression may effectively predict OS in mCRC patients receiving chemotherapy. PMID- 26227490 TI - Mitigating and adapting to climate change: a call to public health professionals. PMID- 26227488 TI - miR-124 Regulates the Epithelial-Restricted with Serine Box/Epidermal Growth Factor Receptor Signaling Axis in Head and Neck Squamous Cell Carcinoma. AB - Epithelial-restricted with serine box (ESX), a member of the ETS transcription factor family, is elevated and regulates EGFR in head and neck squamous cell carcinoma (HNSCC). However, the molecular mechanisms that contribute to ESX dysregulation remain to be elucidated. In this study, in silico analysis of the 3'-untranslated region (UTR) of ESX predicted two miR-124-binding sites. Delivery of miR-124 inhibited the 3'UTR ESX-driven reporter activity by 50% (P < 0.05) confirming ESX as a direct target of miR-124. Loss of miR-124 was found to be a frequent event in HNSCC. miR-124 expression was significantly depleted in the primary tumor compared with matched normal tissue in 100% (12/12) of HNSCC patients; relative mean miR-124 expression of 0.01197 and 0.00118 (P < 0.001, n = 12) in matched normal adjacent tissue and primary HNSCC tumor, respectively. Overexpression of miR-124 decreased ESX and EGFR levels in miR 124(low)/ESX(high)/EGFR(high) SCC15 HNSCC cells and reduced cell invasion, migration, proliferation, and colony formation. SCC15 cells with miR-124 restoration were less tumorigenic in vivo than miR-control SCC15 cells (70% inhibition, P < 0.01). Restoration of miR-124 in SCC15 cells enhanced the antiproliferative efficacy of the EGFR/Her2 tyrosine kinase inhibitors. Furthermore, recapitulation of EGFR in miR-124-overexpressing SCC15 cells was sufficient to completely block the antiproliferative effects of lapatinib and afatinib. Taken together, our work provides intriguing evidence that miR-124 is a novel therapeutic approach to reduce ESX/EGFR, and may be a tractable strategy to enhance the response rate of HNSCC patients to current anti-EGFR/Her2 therapies. PMID- 26227489 TI - Targeting c-MYC in Platinum-Resistant Ovarian Cancer. AB - The purpose of this study was to investigate the molecular and therapeutic effects of siRNA-mediated c-MYC silencing in cisplatin-resistant ovarian cancer. Statistical analysis of patient's data extracted from The Cancer Genome Atlas (TCGA) portal showed that the disease-free (DFS) and the overall (OS) survival were decreased in ovarian cancer patients with high c-MYC mRNA levels. Furthermore, analysis of a panel of ovarian cancer cell lines showed that c-MYC protein levels were higher in cisplatin-resistant cells when compared with their cisplatin-sensitive counterparts. In vitro cell viability, growth, cell-cycle progression, and apoptosis, as well as in vivo therapeutic effectiveness in murine xenograft models, were also assessed following siRNA-mediated c-MYC silencing in cisplatin-resistant ovarian cancer cells. Significant inhibition of cell growth and viability, cell-cycle arrest, and activation of apoptosis were observed upon siRNA-mediated c-MYC depletion. In addition, single weekly doses of c-MYC-siRNA incorporated into 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) 1,2 distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG-2000)-based nanoliposomes resulted in significant reduction in tumor growth. These findings identify c-MYC as a potential therapeutic target for ovarian cancers expressing high levels of this oncoprotein. PMID- 26227491 TI - Indications for liver surgery: laparoscopic or robotic approach. AB - Laparoscopic liver resections have been demonstrated to be safe and effective with the advantages of a shorter hospital stay, less blood loss, less adhesions and better postoperative recovery compared to open surgery. However, indications are usually confined to peripheral, small lesions, due to issues intrinsic to the approach. In the effort to overcome some of these technical limitations, robotic technology has been developed, with encouraging findings. We performed a review of the literature to assess the current indications for laparoscopic hepatic resections and to investigate the role of robotics in broadening the application of minimally invasive liver surgery. Although a paucity of data exists, especially regarding long-term oncological outcomes and specific comparisons with laparoscopy, robotics has been proved to facilitate several complex liver procedures, including parenchyma-saving resections. Thus, the number of patients who can benefit from less invasive, conservative approach is potentially increased. PMID- 26227492 TI - Erratum to: Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer. PMID- 26227494 TI - Short-term and long-term effect of diaphragm biofeedback training in gastroesophageal reflux disease: an open-label, pilot, randomized trial. AB - This study investigated the effectiveness of diaphragm biofeedback training (DBT) for patients with gastroesophageal reflux disease (GERD). A total of 40 patients with GERD treated at the Peking Union Medical College Hospital between September 2004 and July 2006 were randomized to receive DBT and rabeprazole proton pump inhibitor (PPI) or rabeprazole alone. The DBT + rabeprazole group received DBT during the 8-week initial treatment; the rabeprazole group did not. During the 6 month follow up, all patients took acid suppression according to their reflux symptoms, and the patients in the DBT + rabeprazole group were required to continue DBT. The primary outcome (used for power analysis) was the amount of acid suppression used at 6 months. Secondary outcomes were reflux symptoms, health-related quality of life (HRQL), and esophageal motility differences after the 8-week treatment compared with baseline. Acid suppression usage significantly decreased in the DBT + rabeprazole group compared with the rabeprazole group at 6 months (P < 0.05). At 8 weeks, reflux symptoms and GERD-HRQL were significantly improved in both groups (P < 0.05), without difference between them. Crural diaphragm tension (CDT) and gastroesophageal junction pressure (GEJP) significantly increased in the DBT + rabeprazole group (P < 0.05), but without change in lower esophageal sphincter (LES) pressure. There was no significant change in CDT, GEJP, and LES pressure compared with baseline in the rabeprazole group. In conclusion, long-term DBT could reduce acid suppression usage by enhancing the anti-reflux barrier, providing a non-pharmacological maintenance therapy and reducing medical costs for patients with GERD. PMID- 26227493 TI - RTN1 mediates progression of kidney disease by inducing ER stress. AB - Identification of new biomarkers and drug targets for chronic kidney disease (CKD) is required for the development of more effective therapy. Here we report an association between expression of reticulon 1 (RTN1) and severity of CKD. An isoform-specific increase in the expression of RTN1A is detected in the diseased kidneys from mice and humans, and correlates inversely with renal function in patients with diabetic nephropathy. RTN1 overexpression in renal cells induces ER stress and apoptosis, whereas RTN1 knockdown attenuates tunicamycin-induced and hyperglycaemia-induced ER stress and apoptosis. RTN1A interacts with PERK through its N-terminal and C-terminal domains, and mutation of these domains prevents this effect on ER stress. Knockdown of Rtn1a expression in vivo attenuates ER stress and renal fibrosis in mice with unilateral ureteral obstruction, and also attenuates ER stress, proteinuria, glomerular hypertrophy and mesangial expansion in diabetic mice. Together, these data indicate that RTN1A contributes to progression of kidney disease by inducing ER stress. PMID- 26227495 TI - Motor unit number index examination in dominant and non-dominant hand muscles. AB - This study investigated the effect of handedness on motor unit number index (MUNIX). Maximal hand strength, compound muscle action potential (CMAP) and voluntary surface electromyography (EMG) signals were measured bilaterally for the first dorsal interosseous (FDI) and thenar muscles in 24 right-handed and 2 left-handed healthy subjects. Mean (+/-standard error) grip and pinch forces in the dominant hand were 43.99 +/- 2.36 kg and 9.36 +/- 0.52 kg respectively, significantly larger than those in the non-dominant hand (grip: 41.37 +/- 2.29 kg, p < .001; pinch: 8.79 +/- 0.46 kg, p < .01). Examination of myoelectric parameters did not show a significant difference among the CMAP area, the MUNIX or motor unit size index (MUSIX) between the two sides in the FDI and thenar muscles. In addition, there was a lack of correlation between the strength and myoelectric parameters in regression analysis. However, strong correlations were observed between dominant and non-dominant hand muscles in both strength and myoelectric measures. Our results indicate that the population of motor units or spinal motor neurons as estimated from MUNIX may not be associated with handedness. Such findings help understand and interpret the MUNIX during its application for clinical or laboratory investigations. PMID- 26227496 TI - Validation of the Food-Linked Virtual Response task. AB - This research validates a computerized dietary selection task (Food-Linked Virtual Response or FLVR) for use in studies of food consumption. In two studies, FLVR task responses were compared with measures of health consciousness, mood, body mass index, personality, cognitive restraint toward food, and actual food selections from a buffet table. The FLVR task was associated with variables which typically predict healthy decision-making and was unrelated to mood or body mass index. Furthermore, the FLVR task predicted participants' unhealthy selections from the buffet, but not overall amount of food. The FLVR task is an inexpensive, valid, and easily administered option for assessing momentary dietary decisions. PMID- 26227497 TI - Emotional intelligence and glycemic management among type I diabetes patients. AB - Type 1 diabetes is a lifelong physical and emotional challenge. The concept of emotional intelligence may offer better understanding of personal resources facilitating management of such challenges. We therefore hypothesized that emotional intelligence will negatively associate with two measures of diabetic management: HA1c and blood sugar levels. A total of 78 young adults with type 1 diabetes mellitus reported their last HA1c test result and their blood sugar level, as well as demographics and took the audio-visual test of emotional intelligence. The results showed a negative association between emotional intelligence and HA1c and marginal results in the same direction with blood sugar levels even when controlling for demographics. PMID- 26227498 TI - Oral health knowledge and psychological determinants of oral health behavior of nursing students. AB - This survey examined the oral health knowledge and psychological determinants of oral health behavior of 1019 undergraduate and postgraduate nursing students. Overall, most of the students perceived their oral health to be average, and their flossing and dental visiting frequencies were inadequate. Moreover, the students' oral health knowledge was suboptimal, regardless of the type of study, and it was not significantly associated with oral health behavior. Binary logistic regression showed that toothbrushing self-efficacy and the type of study were both significantly associated with toothbrushing behavior. Furthermore, flossing self-efficacy and dental visiting self-efficacy were both significantly associated with flossing and dental visiting behaviors, respectively. PMID- 26227499 TI - Mechanisms involved in reproductive damage caused by gossypol in rats and protective effects of vitamin E. AB - BACKGROUND: Gossypol is a chemical present in the seeds of cotton plants (Gossypium sp.) that reduces fertility in farm animals. Vitamin E is an antioxidant and may help to protect cells and tissues against the deleterious effects of free radicals. The aim of this study was to evaluate the mechanisms of reproductive toxicity of gossypol in rats and the protective effects of vitamin E. Forty Wistar rats were used, divided into four experimental groups (n = 10): DMSO/saline + corn oil; DMSO/saline + vitamin E; gossypol + corn oil; and gossypol + vitamin E. RESULTS: Fertility was significantly reduced in male rats treated with gossypol in that a significant decrease in epididymal sperm count was observed (P < 0.05) and the number of offspring was significantly reduced in females mated with them (P < 0.05). This dysfunction was prevented by vitamin E. Gossypol caused a significant increase in the activity of the enzymes glutathione peroxidase (P < 0.01) and glutathione reductase (P < 0.01), but vitamin E did not reduce the enzyme activities (P > 0.05). The levels of reduced glutathione and pyridine nucleotides in testis homogenate were significantly reduced by gossypol (P < 0.05 and P < 0.01, respectively) and this reduction was accompanied by increased levels of oxidized glutathione (P < 0.05). Vitamin E showed a preventive effect on the changes in the levels of these substances. Gossypol significantly increased the levels of malondialdehyde (P < 0.01), a lipid peroxidation indicator, whereas treatment with vitamin E inhibited the action of the gossypol. Vitamin E prevented a decrease in mitochondrial ATP induced by gossypol (P < 0.05). CONCLUSIONS: This study suggests that the reproductive dysfunction caused by gossypol may be related to oxidative stress and mitochondrial bioenergetic damage and that treatment with vitamin E can prevent the infertility caused by the toxin. PMID- 26227501 TI - Erratum for: Gamma-Terpinene Modulates Acute Inflammatory Response in Mice. PMID- 26227502 TI - Outstanding Anti-inflammatory Potential of Selected Asteraceae Species through the Potent Dual Inhibition of Cyclooxygenase-1 and 5-Lipoxygenase. AB - Cyclooxygenase and 5-lipoxygenase are enzymes that catalyze important inflammatory pathways, suggesting that dual cyclooxygenase/lipoxygenase inhibitors should be more efficacious as anti-inflammatory medicines with lower side effects than the currently available nonsteroidal anti-inflammatory drugs. Many plants from the family Asteraceae have anti-inflammatory activities, which could be exerted by inhibiting the cyclooxygenase-1 and 5-lipoxygenase enzymes. Nevertheless, only a small number of compounds from this family have been directly evaluated for their ability to inhibit the enzymes in cell-free assays. Therefore, this study systematically evaluated 57 Asteraceae extracts in vitro in enzyme activity experiments to determine whether any of these extracts exhibit dual inhibition of cyclooxygenase-1 and 5-lipoxygenase. The chemical profiles of the extracts were obtained by the high-performance liquid chromatography ultraviolet-diode array detector method, and their major constituents were dereplicated. Of the 57 tested extracts, 13 (26.6 %, IC50 range from 0.03-36.2 ug/mL) of them displayed dual inhibition. Extracts from known anti-inflammatory herbs, food plants, and previously uninvestigated species are among the most active. Additionally, the extract action was found to be specific with IC50 values close to or below those of the standard inhibitors. Thus, the active extracts and active substances of these species are potent inhibitors acting through the mechanism of dual inhibition of cyclooxygenase-1 and 5-lipoxygenase. The extracts were prepared for this study using nontoxic extraction solvents (EtOH-H2O), requiring only a small amount of plant material to carry out the bioassays and the phytochemical analyses. In summary, this study demonstrated the potential of the investigated species as dual inhibitors, revealing their potential as pharmaceuticals or nutraceuticals. PMID- 26227503 TI - Antifungal Effect of Essential Oils against Fusarium Keratitis Isolates. AB - The present study was carried out to investigate the antifungal effects of Cinnamomum zeylanicum, Citrus limon, Juniperus communis, Eucalyptus citriodora, Gaultheria procumbens, Melaleuca alternifolia, Origanum majorana, Salvia sclarea, and Thymus vulgaris essential oils against Fusarium species, the most common etiologic agents of filamentous fungal keratitis in South India. C. zeylanicum essential oil showed strong anti-Fusarium activity, whereas all the other tested essential oils proved to be less effective. The main component of C. zeylanicum essential oil, trans-cinnamaldehyde, was also tested and showed a similar effect as the oil. The in vitro interaction between trans-cinnamaldehyde and natamycin, the first-line therapeutic agent of Fusarium keratitis, was also investigated; an enhanced fungal growth inhibition was observed when these agents were applied in combination. Light and fluorescent microscopic observations revealed that C. zeylanicum essential oil/trans-cinnamaldehyde reduces the cellular metabolism and inhibits the conidia germination. Furthermore, necrotic events were significantly more frequent in the presence of these two compounds. According to our results, C. zeylanicum essential oil/trans-cinnamaldehyde provides a promising basis to develop a novel strategy for the treatment of Fusarium keratitis. PMID- 26227504 TI - Pestalpolyols A-D, Cytotoxic Polyketides from Pestalotiopsis sp. cr013. AB - Four novel polyketides, named pestalpolyols A (1), B (2), C (3), and D (4), were isolated from solid fermentation products of Pestalotiopsis sp. cr013. Their structures were elucidated by extensive spectroscopic methods, including 1D and 2D nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry experiments, and the absolute configuration was confirmed by single crystal X-ray diffraction analysis using the anomalous scattering of Cu Kalpha radiation. The inhibitory activities of compounds 1, 2, and 4 against five human tumor lines were tested in vitro, and showed IC50 values 2.3-31.2 uM. PMID- 26227505 TI - Hsp90 Activity Modulation by Plant Secondary Metabolites. AB - Hsp90 is an evolutionarily conserved adenosine triphosphate-dependent molecular chaperone and is one of the most abundant proteins in the cells (1-3 %). Hsp90 is induced when a cell undergoes various types of environmental stresses such as heat, cold, or oxygen deprivation. It is involved in the turnover, trafficking, and activity of client proteins, including apoptotic factors, protein kinases, transcription factors, signaling proteins, and a number of oncoproteins. Most of the Hsp90 client proteins are involved in cell growth, differentiation, and survival, and include kinases, nuclear hormone receptors, transcription factors, and other proteins associated with almost all the hallmarks of cancer. Consistent with these diverse activities, genetic and biochemical studies have demonstrated the implication of Hsp90 in a range of diseases, including cancer, making this chaperone an interesting target for drug research.During the last few decades, plant secondary metabolites have been studied as a major source for lead compounds in drug discovery. Recently, several plant-derived small molecules have been discovered exhibiting inhibitory activity towards Hsp90, such as epigallocatechin gallate, gedunin, lentiginosine, celastrol, and deguelin. In this work, an overview of plant secondary metabolites interfering with Hsp90 activities is provided. PMID- 26227506 TI - [Disseminated cryptococcosis in an immunocompetent patient]. AB - Disseminated cryptococcosis is a serious opportunistic fungal infection caused by a yeast-encapsulated fungus of the genus Cryptococcus neoformans. It occurs most often in patients with a significant deficit of cellular immunity and preferentially affects the central nervous system. The skin and the lungs are the most commonly affected sites outside the neuro-subarachnoid location. We report the case of a patient apparently immunocompetent who had a disseminated cryptococcosis. The disease started with the multiple purplish skin lesions, large umbilicated on the face, groin, forearm and leg with progressively increasing volume. This symptomatology had evolved in the context of weight loss and poor general condition. The diagnosis was established by the presence of cryptococcal at the skin biopsy and cerebrospinal fluid. Research of immunosuppression common pathologies were negative. Treatment was initiated based on amphotericin B for 40 days. The patient's condition deteriorates onset of paraplegia and swallowing disorders causing death in an array of cachexia. This observation points out that disseminated cryptococcosis can occur in an immunocompetent patient. The skin lesions may be the first sign of the disease. PMID- 26227500 TI - Polycomb Group (PcG) Proteins and Human Cancers: Multifaceted Functions and Therapeutic Implications. AB - Polycomb group (PcG) proteins are transcriptional repressors that regulate several crucial developmental and physiological processes in the cell. More recently, they have been found to play important roles in human carcinogenesis and cancer development and progression. The deregulation and dysfunction of PcG proteins often lead to blocking or inappropriate activation of developmental pathways, enhancing cellular proliferation, inhibiting apoptosis, and increasing the cancer stem cell population. Genetic and molecular investigations of PcG proteins have long been focused on their PcG functions. However, PcG proteins have recently been shown to exert non-classical-Pc-functions, contributing to the regulation of diverse cellular functions. We and others have demonstrated that PcG proteins regulate the expression and function of several oncogenes and tumor suppressor genes in a PcG-independent manner, and PcG proteins are associated with the survival of patients with cancer. In this review, we summarize the recent advances in the research on PcG proteins, including both the Pc-repressive and non-classical-Pc-functions. We specifically focus on the mechanisms by which PcG proteins play roles in cancer initiation, development, and progression. Finally, we discuss the potential value of PcG proteins as molecular biomarkers for the diagnosis and prognosis of cancer, and as molecular targets for cancer therapy. PMID- 26227507 TI - Statement of the 3rd International Exercise-Associated Hyponatremia Consensus Development Conference, Carlsbad, California, 2015. PMID- 26227508 TI - Do school crossing guards make crossing roads safer? A quasi-experimental study of pedestrian-motor vehicle collisions in Toronto, Canada. AB - BACKGROUND: The presence of school crossing guards has been associated with more walking and more pedestrian-motor vehicle collisions (PMVCs) in area-level cross sectional analyses. The objectives of the study were to (1) Determine the effect on PMVC rates of newly implemented crossing guards in Toronto, Canada (2) Determine where collisions were located in relation to crossing guards throughout the city, and whether they occurred during school travel times. METHODS: School crossing guards with 50 m buffers were mapped along with police-reported child PMVCs from 2000-2011. (1) A quasi-experimental study identified all age collision counts near newly implemented guards before and after implementation, modeled using repeated measures Poisson regression adjusted for season and built environment variables. (2) A retrospective cohort study of all child PMVCS throughout the city to determine the proportions of child PMVCs which occurred during school travel times and at guard locations. RESULTS: There were 27,827 PMVCs, with 260 PMVCs at the locations of 58 newly implemented guards. Repeated measures adjusted Poisson regression found PMVCs rates remained unchanged at guard locations after implementation (IRR 1.02, 95 % CI 0.74, 1.39). There were 568 guards citywide with 1850 child PMVCs that occurred at guard locations. The majority of child PMVCs occurred outside school travel times (n = 1155, 62 %) and of those that occurred during school travel times, only 95 (13.7 %) were at a guard location. CONCLUSIONS: School crossing guards are a simple roadway modification to increase walking to school without apparent detrimental safety effects. Other more permanent interventions are necessary to address the frequency of child PMVCs occurring away from the location of crossing guards, and outside of school travel times. PMID- 26227509 TI - Global performance parameters for different pneumatic bioreactors operating with water and glycerol solution: experimental data and CFD simulation. AB - Global variables play a key role in evaluation of the performance of pneumatic bioreactors and provide criteria to assist in system selection and design. The purpose of this work was to use experimental data and computational fluid dynamics (CFD) simulations to determine the global performance parameters gas holdup ([Formula: see text]) and volumetric oxygen transfer coefficient (k L a), and conduct an analysis of liquid circulation velocity, for three different geometries of pneumatic bioreactors: bubble column, concentric-tube airlift, and split tube airlift. All the systems had 5 L working volumes and two Newtonian fluids of different viscosities were used in the experiments: distilled water and 10 cP glycerol solution. Considering the high oxygen demand in certain types of aerobic fermentations, the assays were carried out at high flow rates. In the present study, the performances of three pneumatic bioreactors with different geometries and operating with two different Newtonian fluids were compared. A new CFD modeling procedure was implemented, and the simulation results were compared with the experimental data. The findings indicated that the concentric-tube airlift design was the best choice in terms of both gas holdup and volumetric oxygen transfer coefficient. The CFD results for gas holdup were consistent with the experimental data, and indicated that k L a was strongly influenced by bubble diameter and shape. PMID- 26227511 TI - Relationships between event-related potentials and behavioral and scholastic measures of reading ability: A large-scale, cross-sectional study. AB - In the cognitive, computational, neuropsychological, and educational literatures, it is established that children approach text in unique ways, and that even adult readers can differ in the strategies they bring to reading. In the developmental event-related potential (ERP) literature, however, children with differing degrees of reading ability are, the majority of the time, placed in monolithic groups such as 'normal' and 'dyslexic' (e.g. Araujo et al., 2012) and analyzed only at the group level. This is likely done due to methodological concerns - such as low sample size or a lack of statistical power - that can make it difficult to perform analysis at the individual level. Here, we collected ERPs and behavior from > 100 children in grades pre-K-7, as they read unconnected text silently to themselves. This large sample, combined with the statistical power of the Linear Mixed Effects Regression (LMER) technique, enables us to address individual differences in ERP component effects due to reading ability at an unprecedented level of detail. Results indicate that it is possible to predict reading-related report card scores from ERP component amplitudes - especially that of the N250, a component pertaining to sublexical processing (including phonological decoding). Results also reveal relationships between behavioral measures of reading ability and ERP component effects that have previously been elusive, such as the relationship between vocabulary and N400 mean amplitude (cf. Henderson et al., 2011). We conclude that it is possible to meaningfully examine reading-related ERP effects at the single subject level in developing readers, and that this type of analysis can provide novel insights into both behavior and scholastic achievement. PMID- 26227510 TI - Detection of decomposition volatile organic compounds in soil following removal of remains from a surface deposition site. AB - PURPOSE: Cadaver-detection dogs use volatile organic compounds (VOCs) to search for human remains including those deposited on or beneath soil. Soil can act as a sink for VOCs, causing loading of decomposition VOCs in the soil following soft tissue decomposition. The objective of this study was to chemically profile decomposition VOCs from surface decomposition sites after remains were removed from their primary location. METHODS: Pig carcasses were used as human analogues and were deposited on a soil surface to decompose for 3 months. The remains were then removed from each site and VOCs were collected from the soil for 7 months thereafter and analyzed by comprehensive two-dimensional gas chromatography-time of-flight mass spectrometry (GC*GC-TOFMS). RESULTS: Decomposition VOCs diminished within 6 weeks and hydrocarbons were the most persistent compound class. Decomposition VOCs could still be detected in the soil after 7 months using Principal Component Analysis. CONCLUSIONS: This study demonstrated that the decomposition VOC profile, while detectable by GC*GC-TOFMS in the soil, was considerably reduced and altered in composition upon removal of remains. Chemical reference data is provided by this study for future investigations of canine alert behavior in scenarios involving scattered or scavenged remains. PMID- 26227512 TI - Genotypic diversity and differentiation among populations of two benthic freshwater diatoms as revealed by microsatellites. AB - Given their large population sizes and presumed high dispersal capacity, protists are expected to exhibit homogeneous population structure over large spatial scales. On the other hand, the fragmented and short-lived nature of the lentic freshwater habitats that many protists inhabit promotes strong population differentiation. We used microsatellites in two benthic freshwater diatoms, Eunotia bilunaris 'robust' and Sellaphora capitata, sampled from within a pond and connected ponds, through isolated ponds from the same region to western Europe to determine the spatial scale at which differentiation appears. Because periods of low genotypic diversity contribute to population differentiation, we also assessed genotypic diversity. While genotypic diversity was very high to maximal in most samples of both species, some had a markedly lower diversity, with up to half (Eunotia) and over 90% (Sellaphora) of the strains having the same multilocus genotype. Population differentiation showed an isolation-by distance pattern with very low standardized FST values between samples from the same or connected ponds but high values between isolated ponds, even when situated in the same region. Partial rbcL sequences in Eunotia were consistent with this pattern as isolated ponds in the same region could differ widely in haplotype composition. Populations identified by Structure corresponded to the source ponds, confirming that 'pond' is the main factor structuring these populations. We conclude that freshwater benthic diatom populations are highly fragmented on a regional scale, reflecting either less dispersal than is often assumed or reduced establishment success of immigrants, so that dispersal does not translate into gene flow. PMID- 26227513 TI - Esophagogastric junction contractility for clinical assessment in patients with GERD: a real added value? AB - BACKGROUND: The role of esophagogastric junction contractile integral (EGJ-CI) as assessed by high-resolution manometry (HRM) is unclear. We aimed to correlate the EGJ-CI with impedance-pH findings in gastro-esophageal reflux disease (GERD) patients. METHODS: Consecutive patients with GERD symptoms were enrolled. All patients underwent upper endoscopy, HRM, and impedance-pH testing. The EGJ-CI was calculated using the distal contractile integral tool box during three consecutive respiratory cycles. The value was then divided by the duration of these cycles. A value below 13 was considered as a defective EGJ-CI. We also assessed EGJ morphology, esophageal acid exposure time (AET), number of reflux episodes (NRE), and symptom association analysis (SAA). A positive impedance-pH monitoring was considered in case of abnormal AET and/or NRE and/or positive SAA. KEY RESULTS: Among 130 patients we enrolled, 91 had GERD (abnormal AET and/or elevated NRE and/or positive SAA) and 39 had functional heartburn (FH) (negative endoscopy, normal AET, normal NRE, and negative SAA). The GERD patients had a lower median value of EGJ-CI (11 [3.1-20.7] vs 22 [9.9-41], p < 0.02) compared to FH patients. Patients with a defective EGJ-CI had, more frequently, a positive impedance-pH monitoring or esophageal mucosal lesions at endoscopy (p < 0.05 and p < 0.05, respectively) than patients with a normal EGJ-CI. An EGJ-CI cut-off value of 5 mmHg cm yielded the optimal performance in identifying GERD at impedance-pH (sensitivity 89%-specificity 63%). CONCLUSIONS & INFERENCES: A defective EGJ-CI at HRM is clearly associated with evidence of GERD at impedance pH monitoring. Evaluating EGJ-CI may be useful to predict an abnormal impedance pH testing. PMID- 26227514 TI - Thriving through our professional connections. PMID- 26227515 TI - Addressing the problem of obesity. PMID- 26227516 TI - The bariatric patient: an overview of perioperative care. AB - Obesity (ie, a body mass index of >=30 kg/m(2)) is increasing in the United States. As a result, more overweight individuals are being surgically treated for weight loss, thus making it imperative for perioperative RNs to understand obesity's effects on patients' health, its contribution to significant comorbidities (eg, diabetes, cardiovascular disease, hypertension, sleep apnea, musculoskeletal issues, stroke), the perioperative care requirements (eg, specialized instruments and equipment, positioning and lifting aids), and unique needs of these patients (eg, diet, counseling). It is vital that the perioperative nurse accurately assesses the patient undergoing bariatric surgery to provide safe and appropriate nursing interventions during the perioperative continuum of care. PMID- 26227517 TI - Enhancing nursing care by understanding the bariatric patient's journey. AB - Patients who undergo obesity-related bariatric surgery seek a lasting solution to weight loss and a desire for a healthier lifestyle. Perioperative nurses should be prepared to provide sensitive, high-quality care to this population. Effective assessment and management of bariatric patients involves understanding the motivating factors for seeking bariatric surgery, such as to address the stigma and health problems associated with obesity. Nurses should be knowledgeable about expected outcomes of bariatric care, including long-term processes and lifestyle changes that patients must participate in to sustain weight loss. The informed perioperative nurse is essential to the successful treatment of bariatric patients in their journey to healthier living. PMID- 26227518 TI - Bariatric surgery: three surgical techniques, patient care, risks, and outcomes. AB - The prevalence of obesity in the United States is a serious health concern. Bariatric surgery is a recognized and accepted approach for addressing weight loss and health conditions that occur as a result of morbid or severe obesity. Lifestyle changes, dietary modifications, and regular exercise are required for optimal and lasting surgical weight loss. Perioperative care of bariatric patients requires the use of interventions that differ from those used for nonobese patients, including bariatric-specific equipment, intraoperative monitoring of blood glucose, and postoperative monitoring for respiratory compromise. This articles outlines the risks and typical outcomes associated with three common bariatric procedures-laparoscopic adjustable gastric banding, laparoscopic sleeve gastrectomy, Roux-en-Y gastric bypass-to help perioperative nurses and other health care providers successfully advise patients and monitor their care for optimal outcomes. PMID- 26227519 TI - Review of nutritional guidelines for patients undergoing bariatric surgery. AB - Health care providers often supply patients who are undergoing bariatric surgery with varying and sometimes conflicting information regarding nutrition before and after surgery. Nurses and other care providers can benefit from applying current nutritional guidelines to increase patients' understanding, compliance, nutrition, hydration, protein needs, and satisfaction. This article summarizes basic recommendations to help health care providers understand the patients' nutritional requirements and diet recommendations from two weeks before bariatric surgery to four to six weeks after surgery. PMID- 26227520 TI - The weight is over: RN first assisting techniques for laparoscopic sleeve gastrectomy. AB - Obesity-related laparoscopic sleeve gastrectomy is a common yet technically challenging bariatric procedure that requires specialized surgical knowledge and training for OR personnel. Critical components of care include an effective preoperative assessment, positioning of the patient, and operation and maintenance of laparoscopic equipment and instrumentation. The purpose of this article is to explain the steps of laparoscopic sleeve gastrectomy and illustrate principles and surgical techniques for the RN who is first assisting during the procedure. Also provided is a perioperative nursing care plan for the patient undergoing bariatric surgery, to aid perioperative nurses in understanding the sequence of events and special considerations for this patient population. PMID- 26227521 TI - Timely patient discharge from the ambulatory surgical setting. PMID- 26227522 TI - Preparing for a magnet site visit. PMID- 26227523 TI - Celebrating colleagues and their efforts to maintain a culture of safety. PMID- 26227525 TI - CYP450 drugs: expect the unexpected. PMID- 26227526 TI - The role of the nurse and the preoperative assessment in patient transitions. AB - Transitions in care in the perioperative environment are numerous and should be considered high-risk endeavors. The preoperative area is the first transition in care for a surgical patient and should be considered a critical dimension of care transition. The purposes of this study were to identify nursing's contributions to transitions in care in the perioperative environment and to identify the role of the preoperative assessment in this transition. Qualitative descriptive design was used. Focus groups were conducted with 24 nurses in a 975-bed medical center. The themes that arose in the focus groups were: (1) understanding patient vulnerabilities, (2) multidimensional communication, (3) managing patients' expectations, and (4) nursing's role in compensating for gaps. We conclude that the nurse's role in the preoperative assessment during the transition of preoperative care is that of advocate who identifies the patient's needs and risk factors that may be affected by the surgical experience. This study suggests that the nursing preoperative assessment can be useful in identifying and defining patients' risk factors not just for surgery, but for the entire perioperative care trajectory. PMID- 26227527 TI - Winning the war on surgical site infection: evidence-based preoperative interventions for total joint arthroplasty. AB - Postoperative surgical site infections (SSIs) are the most common cause of expensive and debilitating revision surgeries. The Institute for Healthcare Improvement has introduced a three-intervention package, titled Project JOINTS, which attempts to control preoperative and perioperative factors contributing to postoperative SSI in patients undergoing total joint arthroplasty (TJA). The three interventions are preoperative screening for Staphylococcus aureus, decolonizing the skin and nares, and intraoperative administration of combined antimicrobial and alcohol agents to the skin. Canton-Potsdam Hospital was an early adopter of the Project JOINTS protocol, and this quality improvement project has demonstrated a reduced SSI rate throughout the two years of implementation. Before implementation, 596 TJAs were performed with an S aureus SSI rate of 1.8%. During Project JOINTS, 305 TJAs were conducted with a significantly (P = .050) lower S aureus SSI rate of 0.66%. Thus, Project JOINTS is effective at reducing the postoperative incidence of S aureus SSIs in patients undergoing TJA. PMID- 26227528 TI - Comparing new-technology passive warming versus traditional passive warming methods for optimizing perioperative body core temperature. AB - Hypothermia puts surgical patients at risk for adverse outcomes. Traditional passive warming methods are mostly ineffective in reducing hypothermia. New technology passive warming holds promise as an effective method for promoting and sustaining normothermia throughout surgery. The purpose of this retrospective cohort study was to compare the effectiveness of new-technology passive warming with traditional methods. We measured core body temperature at anesthesia induction and at the end of surgery for patients undergoing robotic-assisted prostatectomy/hysterectomy in the lithotomy position who received either new technology passive warming (n = 30) or traditional linens and gel pads (n = 35). The traditionally warmed cohort had no change in temperature (35.9 degrees C +/- 0.6 degrees C presurgery vs 35.9 degrees C +/- 0.7 degrees C postsurgery; t = 0.47; P = .66). The intervention cohort showed a significant increase in temperature (35.75 degrees C +/- 0.52 degrees C presurgery vs 36.30 degrees C +/- 0.53 degrees C postsurgery; t = 4.64; P < .001). A repeated-measure analysis of variance adjusting for surgery duration and fluid administration confirmed the significance (F = 17.254; P < .001), suggesting that new-technology passive warming may effectively complement active warming to reduce perioperative hypothermia. PMID- 26227529 TI - Message From the Editor-in-Chief. PMID- 26227530 TI - Complete removal of infected devices and simultaneous implantation of new devices for infective endocarditis after pacemaker implantation. AB - Two cases of infective endocarditis after pacemaker implantation were reported. Complete removal of infected devices was performed under cardiopulmonary bypass, and simultaneous implantation of new devices was performed using epicardial leads and generator on the abdominal wall. The postoperative course was uneventful and recurrence was not recognized. These procedures may be suitable for the patients who depend on the pacemaker or who have repeat bacteremia with other infectious disease or conditions. PMID- 26227532 TI - Nuclear medicine training and practice in Italy. PMID- 26227531 TI - Pre-therapeutic dosimetry of normal organs and tissues of (177)Lu-PSMA-617 prostate-specific membrane antigen (PSMA) inhibitor in patients with castration resistant prostate cancer. AB - PURPOSE: (177)Lu-617-prostate-specific membrane antigen (PSMA) ligand seems to be a promising tracer for radionuclide therapy of progressive prostate cancer. However, there are no published data regarding the radiation dose given to the normal tissues. The aim of the present study was to estimate the pretreatment radiation doses in patients who will undergo radiometabolic therapy using a tracer amount of (177)Lu-labeled PSMA ligand. METHODS: The study included seven patients with progressive prostate cancer with a mean age of 63.9 +/- 3.9 years. All patients had prior PSMA positron emission tomography (PET) imaging and had intense tracer uptake at the lesions. The injected (177)Lu-PSMA-617 activity ranged from 185 to 210 MBq with a mean of 192.6 +/- 11.0 MBq. To evaluate bone marrow absorbed dose 2-cc blood samples were withdrawn in short variable times (3, 15, 30, 60, and 180 min and 24, 48, and 120 h) after injection. Whole-body images were obtained at 4, 24, 48, and 120 h post-injection (p.i.). The geometric mean of anterior and posterior counts was determined through region of interest (ROI) analysis. Attenuation correction was applied using PSMA PET/CT images. The OLINDA/EXM dosimetry program was used for curve fitting, residence time calculation, and absorbed dose calculations. RESULTS: The calculated radiation absorbed doses for each organ showed substantial variation. The highest radiation estimated doses were calculated for parotid glands and kidneys. Calculated radiation-absorbed doses per megabecquerel were 1.17 +/- 0.31 mGy for parotid glands and 0.88 +/- 0.40 mGy for kidneys. The radiation dose given to the bone marrow was significantly lower than those of kidney and parotid glands (p < 0.05). The calculated radiation dose to bone marrow was 0.03 +/- 0.01 mGy/MBq. CONCLUSION: Our first results suggested that (177)Lu-PSMA-617 therapy seems to be a safe method. The dose-limiting organ seems to be the parotid glands rather than kidneys and bone marrow. The lesion radiation doses are within acceptable ranges; however, there is a substantial individual variance so patient dosimetry seems to be mandatory. PMID- 26227533 TI - First determination of the heart-to-mediastinum ratio using cardiac dual isotope (123I-MIBG/99mTc-tetrofosmin) CZT imaging in patients with heart failure: the ADRECARD study. AB - PURPOSE: Cardiac innervation is assessed using the heart-to-mediastinum ratio (HMR) of metaiodobenzylguanidine (MIBG) on planar imaging using Anger single photon emission computed tomography (A-SPECT). The aim of the study was to determine the HMR of MIBG obtained using a CZT-based camera (D-SPECT; Spectrum Dynamics, Israel) in comparison with that obtained using conventional planar imaging. METHODS: The ADRECARD study prospectively evaluated 44 patients with heart failure. They underwent planar acquisition using the A-SPECT camera 4 h after (123)I-MIBG injection (236.4 +/- 39.7 MBq). To localize the heart using D SPECT, (99m)Tc-tetrofosmin (753 +/- 133 MBq) was administered and dual isotope acquisition was performed using the D-SPECT system. HMR was calculated using both planar A-SPECT imaging and front view D-SPECT cine data. In a phantom study, we estimated a model fitting the A-SPECT and the D-SPECT data that was further applied to correct for differences between the cameras. RESULTS: A total of 44 patients (39 men and 5 women, aged 60 +/- 11 years) with ischaemic (31 patients) and nonischaemic (13 patients) cardiomyopathy completed the study. Most patients (28 of 44) were NYHA class II, and the mean left ventricular ejection fraction was 33 +/- 7 %. The mean HMR values were 1.34 +/- 0.15 and 1.45 +/- 0.27 from A SPECT and D-SPECT, respectively (p < 0.0001). After correction, Lin's concordance correlation showed an almost perfect concordance between corrected D-SPECT HMR and A-SPECT HMR, and Bland-Altman analysis demonstrated a high agreement between the two measurements. CONCLUSION: The ADRECARD study demonstrated that determination of late HMR during cardiac MIBG imaging using dual isotope ((123)I and (99m)Tc) acquisition on a CZT camera (D-SPECT) is feasible in patients with heart failure. A linear correction based on the phantom study yielded a high agreement between (123)I MIBG HMR obtained using a CZT camera and that from conventional planar imaging. PMID- 26227534 TI - Feasibility of one-eighth time gated myocardial perfusion SPECT functional imaging using IQ-SPECT. AB - PURPOSE: IQ-SPECT, an add-on to general purpose cameras based on multifocal collimation, can reduce myocardial perfusion imaging (MPI) acquisition times to one-fourth that of standard procedures (to 12 s/view). In a phantom study, a reduction of the acquisition time to one-eighth of the standard time (to 6 s/view) was demonstrated as feasible. It remains unclear whether such a reduction could be extended to clinical practice. METHODS: Fifty patients with suspected or diagnosed CAD underwent a 2-day stress-rest (99m)Tc-sestamibi MPI protocol. Two consecutive SPECT acquisitions (6 and 12 s/view) were performed. Electrocardiogram-gated images were reconstructed with and without attenuation correction (AC). Polar maps were generated and visually scored by two blinded observers for image quality and perfusion in 17 segments. Global and regional summed stress score (SSS), summed rest score (SRS) and summed difference score (SDS) were determined. Left ventricular volumes and ejection fraction were calculated based on automated contour detection. RESULTS: Image quality was scored higher with the 12 s/view acquisition, both with and without AC. Summed scores were statistically comparable between the 6 s/view and the 12 s/view acquisition, both globally and in individual coronary territories (e.g. in images with AC, SSS were 6.6 +/- 8.3 and 6.2 +/- 8.2 with 6 s and 12 s/view, respectively, p = 0.10; SRS were 3.9 +/- 5.6 and 3.5 +/- 5.3, respectively, p = 0.19; and SDS were 2.8 +/- 5.7 and 2.6 +/- 5.7, respectively, p = 0.59). Both acquisitions allowed MPI-based diagnosis of CAD in 25 of the 50 patients (with AC). Calculated end-diastolic volume (EDV) and end-systolic volume (ESV) were modestly higher with the 6 s/view acquisition than with the 12 s/view acquisition (EDV +4.8 ml at rest and +3.7 ml after stress, p = 0.003; ESV +4.1 ml at rest and +2.6 ml after stress, p = 0.01), whereas the ejection fraction did not differ ( 1.2 % at rest, p = 0.20, and -0.9 % after stress, p = 0.27). CONCLUSION: Image quality and LV functional parameters obtained with a one-eighth acquisition time were statistically comparable to the previously validated one-fourth time protocol using IQ-SPECT. Shorter acquisition times without loss of diagnostic accuracy provide improved patient comfort and streamlined departmental efficiency. PMID- 26227535 TI - Molecular imaging of cholinergic processes in prostate cancer using 11C-donepezil and 18F-FEOBV. AB - PURPOSE: High-grade prostate cancer (PC) displays parasympathetic neoneurogenesis. We investigated the binding of two PET tracers that visualize cholinergic nerves in PC tissue using autoradiography. METHODS: Prostatectomy tissue was subjected to autoradiography with (11)C-donepezil and (18)F-FEOBV and correlated with Gleason scores (GS). Regions of interest on the autoradiograms were defined and quantified. Tracer binding in cancer tissue regions was compared with that in normal tissue. RESULTS: We included 13 patients with biopsy-verified PC. In particular, (11)C-donepezil uptake was higher in "high-grade" PC (GS >=4 + 3) than in "low-grade" PC and benign hyperplasia. (11)C-donepezil uptake ranged from a mean of 56 % higher (GS 3 + 3) to 409 % higher (GS 4 + 4), and (18)F-FEOBV uptake ranged from 67 % higher (GS 3 + 3) to 194 % higher (GS 4 + 5). The uptake of both tracers was higher in PC with a high GS than in PC with a low GS, but the difference was significant only for (11)C-donepezil (p = 0.003). CONCLUSION: Uptake of PET tracers binding to cholinergic nerves was markedly higher in PC with a high GS than in PC with a low GS. This finding implies that (11)C donepezil PET/CT may be able to differentiate between low-grade and high-grade PC. PMID- 26227536 TI - Building blocks of a fish head: Developmental and variational modularity in a complex system. AB - Evolution of the vertebrate skull is developmentally constrained by the interactions among its anatomical systems, such as the dermatocranium and the sensory system. The interaction between the dermal bones and lateral line canals has been debated for decades but their morphological integration has never been tested. An ontogenetic series of 97 juvenile and adult Amia calva (Actinopterygii) was used to describe the patterning and modularity of sensory lateral line canals and their integration with supporting cranial bones. Developmental modules were tested for the otic canal and supratemporal commissure by computing correlations in the branching sequence of groups of pores. Landmarks were digitized on 25 specimens to test a priori hypotheses of variational and developmental modularity at the level of canals and dermal bones. Branching sequence suggests a specific patterning supported by significant positive correlations in the sequence of appearance of branches between bilateral sides. Differences in patterning between the otic canal and the supratemporal commissure and tests of modularity with geometric morphometrics suggest that both canals form distinct modules. The integration between bones and canals was insufficient to detect a module. However, both components were not independent. Groups of pores tended to disappear without affecting other groups of pores suggesting that they are quasi-independent units acting as modules. This study provides evidence of a hierarchical organization for the modular sensory system that could explain variation of pattern of canals among species and their association with dermal bones. PMID- 26227537 TI - Changes in baseball batters' brain activity with increased pitch choice. AB - In baseball, one factor necessary for batters to decide whether to swing or not depends on what type of pitch is thrown. Oftentimes batters will look for their pitch (i.e., waiting for a fastball). In general, when a pitcher has many types of pitches in his arsenal, batters will have greater difficulty deciding upon the pitch thrown. Little research has been investigated the psychophysiology of a batters decision-making processes. Therefore, the primary purpose of this study was to determine how brain activation changes according to an increase in the number of alternatives (NA) available. A total of 15 male college baseball players participated in this study. The stimuli used in this experiment were video clips of a right-handed pitcher throwing fastball, curve, and slider pitches. The task was to press a button after selecting the fastball as the target stimulus from two pitch choices (fastball and curve), and then from three possibilities (fastball, curve, and slider). Functional and anatomic image scanning magnetic resonance imaging (MRI) runs took 4 and 5[Formula: see text]min, respectively. According to our analysis, the right precentral gyrus, left medial frontal gyrus, and right fusiform gyrus were activated when the NA was one. The supplementary motor areas (SMA) and primary motor cortex were activated when there were two alternatives to choose from and the inferior orbitofrontal gyrus was specifically activated with three alternatives. Contrary to our expectations, the NA was not a critical factor influencing the activation of related decision making areas when the NA was compared against one another. These findings highlight that specific brain areas related to decision making were activated as the NA increased. PMID- 26227538 TI - On the possible quantum role of serotonin in consciousness. AB - Cell membrane's fatty acids (FAs) have been carefully investigated in neurons and platelets in order to study a possible connection to psychopathologies. An important link between the FA distribution and membrane dynamics appears to emerge with the cytoskeleton dynamics. Microtubules (MTs) in particular have been implicated in some recent quantum consciousness models and analyses. The recently proposed quantum model of Craddock et al. (2014) states that MTs possess structural and functional characteristics that are consistent with collective quantum coherent excitations in the aromatic groups of their tryptophan residues. These excitations are consistent with a clocking mechanism on a sub-nanosecond scale. This mechanism and analogous phenomena in light-harvesting complexes in plants and bacteria, are induced by photons and have been touted as evidence of quantum processes in biology. A possible source of intra-cellular photons could be membrane lipid peroxidation processes, so the FA profile could then be linked to the bio-photon emission. The model presented here suggests new ways to understand the role serotonin plays in relation to FAs. In plants, tryptophan conversion of light to exciton energy can participate in the directional orientation of leaves toward sunlight. Since serotonin is structurally similar to tryptophan, in the human brain, neurons could use tryptophan to capture photons and also use serotonin to initiate movement toward the source of light. Hence, we postulate two possible new roles for serotonin: (1) as an antioxidant, in order to counter-balance the oxidative effect of FAs, and (2) to participate in quantum interactions with MTs, in the same way as anesthetics and psychoactive compounds have been recently shown to act. In this latter case, the FA profile could provide an indirect measure of serotonin levels. PMID- 26227540 TI - Urinary 5-hydroxymethyluracil and 8-oxo-7,8-dihydroguanine as potential biomarkers in patients with colorectal cancer. AB - CONTEXT: Oxidative stress linked with chronic inflammation is associated with etiology of the colorectal cancer. OBJECTIVES: To assess the diagnostic utility of urinary excretion of oxidatively modified DNA bases/nucleoside: 8-oxo-7,8 dihydroguanine (8-oxoGua), 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and 5 hydroxymethyluracil (5-hmUra). MATERIALS AND METHODS: Seventy-two healthy controls, 15 patients with adenomas and 56 colorectal cancer patients were recruited. RESULTS: The receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) for all markers tested separately was <0.7. The combination of these modifications showed better diagnostic power (AUC = 0.778 for 8-oxoGua + 8-oxodG)/5hmUra ratio). CONCLUSION: Urinary DNA modifications may reflect the oxidative stress/chronic inflammation in colorectal cancer but diagnostic performance for early-detection is moderate. PMID- 26227539 TI - The role of serotonergic mechanism in the rat prefrontal cortex for controlling the micturition reflex: An in vivo microdialysis study. AB - AIMS: To investigate the role of the PFC in the micturition reflex using an in vivo microdialysis study in rats. METHODS: Adult female Sprague-Dawley rats were used and microdyalysis in the PFC and cystometrography (CMG) were performed under consciousness and free movement in the present study. Experiment 1: Samples including extracellular neurotransmitters were collected by microdyalysis and analyzed by high performance liquid chromatography. At the same time, CMG were performed to measure intercontraction interval (ICI) and maximum voiding pressure (MVP). Experiment 2: SSRI (citalopram, 1 uM) was administered into the PFC, and microdyalysis and cystometrography (CMG) were performed simultaneously. Experiment 3: Following SSRI administration, 5-HT1A agonist (8-OH-DPAT, 300 uM), which has the effect of decreasing the level of serotonin (5-HT) in the PFC, was administered into the PFC, and microdyalysis and CMG were performed simultaneously. RESULTS: Experiment 1: Extracellular level of 5-HT in the PFC significantly increased during micturition reflex (P < 0.05), whereas levels of glutamate or dopamine were not significantly changed. Experiment 2: Local administration of SSRI in the PFC increased the 5-HT level up to approximate 600% of the basal level. It also significantly increased ICI (P < 0.05), whereas no significant change was found in MVP. Experiment 3: The extracellular level of 5 HT gradually decreased after local administration of 5-HT1A agonist, thereby ICI significantly decreased (P < 0.05). CONCLUSIONS: The results of the present study suggest that the PFC has a suppressive effect on neural control of the micturition reflex via serotonin. Neurourol. Urodynam. 35:902-907, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26227541 TI - Effects of smoking severity and moderate and severe periodontitis on serum C reactive protein levels: an age- and gender-matched retrospective cohort study. AB - BACKGROUND AND PURPOSE: C-reactive protein (CRP) which might affect cardiovascular events can be affected by chronic diseases and smoking. Since the effects of smoking dosage as well as the mutual effect of smoking and periodontitis on CRP levels have not been evaluated, we aimed to assess these. MATERIALS AND METHODS: This retrospective age- and gender-matched study was performed on 120 dental patients. Clinical attachment loss, pocket probing depth (PPD), bleeding on probing (BoP), O'Leary plaque index and serum CRP were recorded. Patients were divided into one control and five cohort groups (n = 20 each) according to smoking severity [pack years (PY) below or above 30] and periodontal condition (healthy periodontium and moderate/severe periodontitis). The effects of clinical measurements, age, gender, smoking and periodontitis on CRP were assessed using one- and two-way analyses of variance, Tukey and Bonferroni post hoc tests, and multiple linear regression (alpha = 0.05). RESULTS: CRP concentrations were 0.07255 +/- 0.009539, 0.09645 +/- 0.010625, 0.122235 +/- 0.018442, 0.3758 +/- 0.187369, 0.81595 +/- 0.0410299 and 1.8717 +/- 0.652728 mg/l, respectively, in the control (PY <= 30 with healthy periodontium), cohort 1 (PY > 30 with healthy periodontium), cohort 2 (PY <= 30 with moderate periodontitis), cohort 3 (PY > 30 with moderate periodontitis), cohort 4 (PY <= 30 with severe periodontitis) and cohort 5 (PY > 30 with severe periodontitis). The positive effects of age, smoking severity, periodontitis and PPD, on CRP increase were significant (Regression p < 0.02). BoP had a negative effect (p = 0.015). CONCLUSIONS: Clinicians should warn the patients, especially the older ones, about the effects of their gingival health and smoking on their cardiovascular condition. PMID- 26227542 TI - Disease map-based biomarker selection and pre-validation for bladder cancer diagnostic. AB - CONTEXT: Urinary biomarkers are promising as simple alternatives to cystoscopy for the diagnosis of de novo and recurrent bladder cancer. OBJECTIVE: To identify a highly sensitive and specific biomarker candidate set with potential clinical utility in bladder cancer. MATERIALS AND METHODS: Urinary biomarker concentrations were determined by ELISA. The performance of individual markers and marker combinations was assessed using ROC analysis. RESULTS: A five biomarker panel (IL8, MMP9, VEGFA, PTGS2 and EN2) was defined from the candidate set. DISCUSSION AND CONCLUSION: This panel showed a better overall performance than the best individual marker. Further validation studies are needed to evaluate its clinical utility in bladder cancer. PMID- 26227543 TI - ESAM predicts cardiovascular mortality in diabetic hemodialysis patients. AB - AIM: To assess endothelial cell selective adhesion molecule (ESAM) as predictor of cardiovascular mortality in diabetic dialysis patients (DDPs). METHODS: ESAM, clinical and laboratory parameters were assessed in 73 DDP. Cardiovascular mortality was recorded in a 2 years' prospective observational study. RESULTS: Baseline ESAM was 17.1 (10.05-24.8) ng/ml and was correlated to phosphate (r = 0.42, p = 0.008), parathormone (r = -0.36, p = 0.048), albumin (r = -0.24, p = 0.048). ESAM significantly predicted cardiovascular death in univariate [HR = 1.03, 95% CI (1.006-1.054), p = 0.01] and multivariate [HR = 1.034, 95% CI (1.003 1.066), p = 0.03] Cox analysis. Time to cardiovascular death was shorter for patients with ESAM >12.44 ng/ml, p = 0.0045. CONCLUSION: ESAM is an independent predictor of cardiovascular mortality in DDP. PMID- 26227544 TI - Genetic polymorphism of pharmacogenomic VIP variants in the Deng people from the Himalayas in Southeast Tibet. AB - Little is known about polymorphic distribution of pharmacogenes among ethnicities, including the Deng people. In this study, we recruited 100 unrelated, healthy Deng people and genotyped them with respect to 76 different single-nucleotide polymorphisms by the PharmGKB database. Our results first indicated that the polymorphic distribution of pharmacogenes of the Deng people is most similar to CHD, suggesting that Deng people have a closest genetic relationship with CHD. Our data will enrich the database of pharmacogenomics and provide a theoretical basis for safer drug administration and individualized treatment plans, promoting the development of personalized medicine. PMID- 26227546 TI - Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice. AB - BACKGROUND: Numerous studies have reported on the neuroprotective activity of estradiol, whereas the effect of the other ovarian steroid, progesterone, is much less documented. METHODS: This study sought to investigate neuroprotection with a low dose of progesterone (1 ug) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male mice to model Parkinson's disease and compare it to the effect of this steroid in intact mice (experiment 1). We also investigated if high doses of progesterone could protect dopaminergic neurons already exposed to MPTP (experiment 2). We measured progesterone effects on various dopaminergic markers [dopamine and its metabolites, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2)] and on neuroactive steroids in both plasma and the brain. RESULTS: For experiment 1, our results showed that progesterone completely prevented the effect of MPTP toxicity on dopamine concentrations, on the increase in the 3-methoxytyramine/dopamine ratio, as well as on VMAT2 specific binding in the striatum and the substantia nigra. Progesterone decreased MPTP effects on 3,4-dihydroxyphenylacetic acid concentrations and DAT-specific binding in the lateral part of the anterior striatum and in the middle striatum (medial and lateral parts). Progesterone treatment of intact mice had no effect on the markers investigated. For experiment 2, measures of dopaminergic markers in the striatum showed that 8 mg/kg of progesterone was the most effective dose to reduce MPTP effects, and more limited effects were observed with 16 mg/kg. We found that progesterone treatment increases the levels of brain progesterone itself as well as of its metabolites. CONCLUSION: Our result showed that progesterone has neuroprotective effects on dopaminergic neurons in MPTP-treated male mice. PMID- 26227545 TI - Postnatal maturation of GABAergic modulation of sensory inputs onto lateral amygdala principal neurons. AB - KEY POINTS: Throughout life, fear learning is indispensable for survival and neural plasticity in the lateral amygdala underlies this learning and storage of fear memories. During development, properties of fear learning continue to change into adulthood, but currently little is known about changes in amygdala circuits that enable these behavioural transitions. In recordings from neurons in lateral amygdala brain slices from infant up to adult mice, we show that spontaneous and evoked excitatory and inhibitory synaptic transmissions mature into adolescence. At this time, increased inhibitory activity and signalling has the ability to restrict the function of excitation by presynaptic modulation, and may thus enable precise stimulus associations to limit fear generalization from adolescence onward. Our results provide a basis for addressing plasticity mechanisms that underlie altered fear behaviour in young animals. ABSTRACT: Convergent evidence suggests that plasticity in the lateral amygdala (LA) participates in acquisition and storage of fear memory. Sensory inputs from thalamic and cortical areas activate principal neurons and local GABAergic interneurons, which provide feed-forward inhibition that tightly controls LA activity and plasticity via pre- and postsynaptic GABAA and GABAB receptors. GABAergic control is also critical during fear expression, generalization and extinction in adult animals. During rodent development, properties of fear and extinction learning continue to change into early adulthood. Currently, few studies have assessed physiological changes in amygdala circuits that may enable these behavioural transitions. To obtain first insights, we investigated changes in spontaneous and sensory input-evoked inhibition onto LA principal neurons and then focused on GABAB receptor-mediated modulation of excitatory sensory inputs in infant, juvenile, adolescent and young adult mice. We found that spontaneous and sensory-evoked inhibition increased during development. Physiological changes were accompanied by changes in dendritic morphology. While GABAB heteroreceptors were functionally expressed on sensory afferents already early in development, they could only be physiologically recruited by sensory-evoked GABA release to mediate heterosynaptic inhibition from adolescence onward. Furthermore, we found GABAB -mediated tonic inhibition of sensory inputs by ambient GABA that also emerged in adolescence. The observed increase in GABAergic drive may be a substrate for providing modulatory GABA. Our data suggest that GABAB -mediated tonic and evoked presynaptic inhibition can suppress sensory input-driven excitation in the LA to enable precise stimulus associations and limit generalization of conditioned fear from adolescence onward. PMID- 26227547 TI - Evolutionary shifts in habitat aridity predict evaporative water loss across squamate reptiles. AB - Aridity is an important determinant of species distributions, shaping both ecological and evolutionary diversity. Lizards and snakes are often abundant in deserts, suggesting a high potential for adaptation or acclimation to arid habitats. However, phylogenetic evidence indicates that squamate diversity in deserts may be more strongly tied to speciation within arid habitats than to convergent evolution following repeated colonization from mesic habitats. To assess the frequency of evolutionary transitions in habitat aridity while simultaneously testing for associated changes in water-balance physiology, we analyzed estimates of total evaporative water loss (EWL) for 120 squamate species inhabiting arid, semiarid, or mesic habitats. Phylogenetic reconstructions revealed that evolutionary transitions to and from semiarid habitats were much more common than those between arid and mesic extremes. Species from mesic habitats exhibited significantly higher EWL than those from arid habitats, while species from semiarid habitats had intermediate EWL. Phylogenetic comparative methods confirmed this association between habitat aridity and EWL despite phylogenetic signal in each. Thus, the historical colonization of arid habitats by squamates is repeatedly associated with adaptive changes in EWL. This physiological convergence, which may reflect both phenotypic plasticity and genetic adaptation, has likely contributed to the success of squamates in arid environments. PMID- 26227549 TI - A price to pay: Turkish and Northern American retaliation for threats to personal and family honor. AB - Two studies investigated retaliatory responses to actual honor threats among members of an honor culture (Turkey) and a dignity culture (northern United States). The honor threat in these studies was based on previous research which has shown that honesty is a key element of the conception of honor and that accusations of dishonesty are threatening to one's honor. In both studies, participants wrote an essay describing the role of honesty in their lives and received feedback on their essay accusing them of being dishonest (vs. neutral feedback). Turkish participants retaliated more strongly than did northern U.S. participants against the person who challenged their honesty by assigning him/her to solve more difficult tangrams over easy ones (Study 1) and by choosing sensory tasks of a higher level of intensity to complete (Study 2). Study 2 added a relational honor condition, in which participants wrote about honesty in their parents' lives and examined the role of individual differences in honor values in retaliation. Endorsement of honor values significantly predicted retaliation among Turkish participants in the relational honor attack condition, but not among northern U.S. participants. PMID- 26227548 TI - Simulated unbound structures for benchmarking of protein docking in the DOCKGROUND resource. AB - BACKGROUND: Proteins play an important role in biological processes in living organisms. Many protein functions are based on interaction with other proteins. The structural information is important for adequate description of these interactions. Sets of protein structures determined in both bound and unbound states are essential for benchmarking of the docking procedures. However, the number of such proteins in PDB is relatively small. A radical expansion of such sets is possible if the unbound structures are computationally simulated. RESULTS: The DOCKGROUND public resource provides data to improve our understanding of protein-protein interactions and to assist in the development of better tools for structural modeling of protein complexes, such as docking algorithms and scoring functions. A large set of simulated unbound protein structures was generated from the bound structures. The modeling protocol was based on 1 ns Langevin dynamics simulation. The simulated structures were validated on the ensemble of experimentally determined unbound and bound structures. The set is intended for large scale benchmarking of docking algorithms and scoring functions. CONCLUSIONS: A radical expansion of the unbound protein docking benchmark set was achieved by simulating the unbound structures. The simulated unbound structures were selected according to criteria from systematic comparison of experimentally determined bound and unbound structures. The set is publicly available at http://dockground.compbio.ku.edu. PMID- 26227550 TI - Specific Inhibition of beta-Catenin in Jeko-1 Mantle Cell Lymphoma Cell Line Decreases Proliferation and Induces Apoptosis. AB - BACKGROUND: The canonical Wnt signaling pathway has been considered as a potent oncogenic signaling in the initiation and progression of hematological malignancies. As a key regulator of the Wnt signaling pathway, the role of beta catenin in mantle cell lymphoma (MCL) pathogenesis and progression was investigated in this study. MATERIAL AND METHODS: A total of 30 MCL samples were collected from patients and were examined for the expression of beta-catenin and p-GSK3beta using immunohistochemical (IHC) staining. Further in vitro studies employed MTT and Western blot assays detecting proliferation and apoptosis related proteins in MCL cell line Jeko-1, which were transfected with beta catenin shRNA or specific inhibitor XAV939. RESULTS: Expression of beta-catenin and phosphorylated glycogen synthase kinase-3 beta (p-GSK3beta) in MCL was significantly higher than those in controlled samples. In vitro studies indicated that beta-catenin knockdown significantly inhibited cell proliferation and induced apoptosis in Jeko-1 cells. Furthermore, XAV939 induced apoptosis and growth arrest in Jeko-1 cells. Both inhibitory agents increased Bax and caspase 3 proteins, and decreased Bcl-2, c-Myc, and Cyclin D1 proteins. CONCLUSIONS: The specific inhibition of beta-catenin induces apoptosis and growth arrest, making it a potential therapeutic target against MCL. PMID- 26227552 TI - Relationship between MRI T1 rho value and histological findings of intact and radially incised menisci in microminipigs. AB - PURPOSE: To examine whether the T1 rho value reflects histological changes in menisci we analyzed the relationship between T1 rho value and histological findings in intact and radially incised menisci of pigs. MATERIALS AND METHODS: Seven microminipigs were used for this experiment. A radial incision was created and repaired in the medial meniscus, which was evaluated 4 weeks after surgery. Sagittal T1 rho mapping images were taken by 3.0T magnetic resonance imaging (MRI). The region of interest was set by dividing the meniscus into six zones (from zone 1 to zone 6). For histological evaluation of intact menisci, characteristics of each zone were determined. In incised menisci, a histological score was used to evaluate pathological change. RESULTS: In intact lateral menisci, the zone where histological findings indicated fibrocartilage showed a lower T1 rho value (34.2 +/- 2.3 msec) than hyaline-like cartilage (38.2 +/- 2.5 msec) or fibrous tissue (37.2 +/- 2.0 msec). In incised medial menisci, T1 rho values increased (about 50-90 msec) in the zone where histological findings indicated that synovial ingrowth, scar tissue formation, and degenerative changes had occurred. There were correlations between T1 rho values and histological scores in all zones (r = 0.62-0.92, P = 0.001-0.026). CONCLUSION: Zonal variations of the T1 rho value were observed in intact menisci due to varying structure in each zone. T1 rho values were correlated with histological changes such as collagen fiber organization and safranin-o stainability in incised menisci. This study supports T1 rho mapping as useful for evaluating ultrastructural composition in menisci. PMID- 26227551 TI - Capturing the Direct Binding of CFTR Correctors to CFTR by Using Click Chemistry. AB - Cystic fibrosis (CF) is a lethal genetic disease caused by the loss or dysfunction of the CF transmembrane conductance regulator (CFTR) channel. F508del is the most prevalent mutation of the CFTR gene and encodes a protein defective in folding and processing. VX-809 has been reported to facilitate the folding and trafficking of F508del-CFTR and augment its channel function. The mechanism of action of VX-809 has been poorly understood. In this study, we sought to answer a fundamental question underlying the mechanism of VX-809: does it bind CFTR directly in order to exert its action? We synthesized two VX-809 derivatives, ALK 809 and SUL-809, that possess an alkyne group and retain the rescue capacity of VX-809. By using Cu(I) -catalyzed click chemistry, we provide evidence that the VX-809 derivatives bind CFTR directly in vitro and in cells. Our findings will contribute to the elucidation of the mechanism of action of CFTR correctors and the design of more potent therapeutics to combat CF. PMID- 26227553 TI - Perspectives for Regenerative Medicine in the Treatment of Inflammatory Bowel Diseases. AB - The intestinal epithelium exerts multiple, indispensable functions to maintain the homeostasis of our body. However, this layer is frequently damaged by various gastrointestinal diseases; repair of such a damaged intestinal epithelium becomes difficult and the stem cell function gets lost or severely disrupted. Recent advances in the stem cell biology of the gastrointestinal tract have provided major breakthroughs, such as in vitro culture of intestinal stem cells (ISCs), and have also thrown light on the transplantation of those cells to repair the damaged intestinal mucosa. Based on such newly developed techniques, we are now coming close to apply them to treat various gastrointestinal diseases, including inflammatory bowel diseases (IBD). Accordingly, ISC-based therapy is currently under development for treating IBD patients, which may potentially provide benefits to those patients by the achievement of mucosal healing and the subsequent improvement of their prognosis. In this review, we would like to highlight studies that have provided information on the great advances made thus far in the research of ISCs. In addition, we would like to express some of our perspectives on the clinical use of ex-vivo-cultured ISCs in the treatment of IBD. PMID- 26227555 TI - Use of a marine microbial community as inoculum for biomethane production. AB - Marine substrates are prominent candidates for the production of biofuels, especially for biogas, which is a well-established technology that accepts different types of substrates for its production. However, the use of marine substrates in bioreactors may cause inhibition of methanogenic bacteria due to the addition of seasalts. Here, we explore a simple and economically viable way to circumvent the problem of inoculum inhibition. Based on the current knowledge of the diversity of microorganisms in marine sediments, we tested the direct use of methanogenic bacteria from an anoxic marine environment as inoculum for biomethane production. Both marine and freshwater substrates were added to this inoculum. No pretreatment (that may have enhanced methane production, but would have made the process more expensive) was applied either to the inoculum or to the substrates. For comparison, the same substrates were added to a standard inoculum (cow manure). Both the marine inoculum and cow manure produced methane by anaerobic digestion of the substrates added. The highest methane production (0.299 m(3) kg VS(-1)) was obtained by adding marine microalgae biomass (Chlorella sp. and Synechococcus sp.) to the marine inoculum. No inhibitory effects were observed due to differences in salinity between the inocula and substrates. Our results indicate the potential of using both marine inoculum and substrates for methane production. PMID- 26227554 TI - Relation between maternal antenatal anxiety and infants' weight depends on infants' sex: A longitudinal study from late gestation to 1-month post birth. AB - OBJECTIVE: To test for gender-differences in the relation between mothers' antenatal anxiety and infants' body weight during gestation, at birth, and at 1 month of age. METHODS: Two hundred and twelve randomly-recruited women were divided into two groups: Controls (n=105) and Anxious Group (n=107) based on a standard cut-off of the Beck Anxiety Inventory. Outcome measures were Fetal Weight derived from biometrics obtained from an ultrasound scan in the 3rd trimester and infants' weight at birth and at 1-month of age, both obtained from medical records. RESULTS: Multivariate analyses showed main effects of Gender on infants' birth weight (P=.001) and on infants' weight at 1-month of age (P=.004), but no main effects of Anxiety Group at any time-point. Gender x Anxiety Group interactions at all three time points (Fetal weight: P=.05; Birth weight: P=.03; 1-month of age: P=.10) reflected gender differences (males>females) among infants in the anxious group, but not among controls. Distinct trends regarding same sex comparisons across groups (Control vs. Anxiety) were in line with predictions (male controlsfemales anxious). Controlling for Postpartum Anxiety and Antenatal and Postpartum Depression in the models did not affect primary results. CONCLUSION: Gender differences in fetal and birth weight were more substantial among infants of anxious mothers than among controls due to the seemingly accelerated growth of "anxious" males and the diminution of weight among "anxious" females. PMID- 26227557 TI - The implication of irrigation in climate change impact assessment: a European wide study. AB - This study evaluates the impacts of projected climate change on irrigation requirements and yields of six crops (winter wheat, winter barley, rapeseed, grain maize, potato, and sugar beet) in Europe. Furthermore, the uncertainty deriving from consideration of irrigation, CO2 effects on crop growth and transpiration, and different climate change scenarios in climate change impact assessments is quantified. Net irrigation requirement (NIR) and yields of the six crops were simulated for a baseline (1982-2006) and three SRES scenarios (B1, B2 and A1B, 2040-2064) under rainfed and irrigated conditions, using a process-based crop model, SIMPLACE . We found that projected climate change decreased NIR of the three winter crops in northern Europe (up to 81 mm), but increased NIR of all the six crops in the Mediterranean regions (up to 182 mm yr(-1) ). Climate change increased yields of the three winter crops and sugar beet in middle and northern regions (up to 36%), but decreased their yields in Mediterranean countries (up to 81%). Consideration of CO2 effects can alter the direction of change in NIR for irrigated crops in the south and of yields for C3 crops in central and northern Europe. Constraining the model to rainfed conditions for spring crops led to a negative bias in simulating climate change impacts on yields (up to 44%), which was proportional to the irrigation ratio of the simulation unit. Impacts on NIR and yields were generally consistent across the three SRES scenarios for the majority of regions in Europe. We conclude that due to the magnitude of irrigation and CO2 effects, they should both be considered in the simulation of climate change impacts on crop production and water availability, particularly for crops and regions with a high proportion of irrigated crop area. PMID- 26227556 TI - Two-year trends in psychological outcomes after gastric bypass in adolescents with severe obesity. AB - OBJECTIVE: This study aimed to evaluate changes in mental health over 2 years in adolescents undergoing gastric bypass. METHODS: Eighty-eight adolescents (65% girls) aged 13 to 18 years were assessed at baseline and 1 and 2 years after surgery. Generic and obesity-specific questionnaires were used to evaluate outcomes in mental health, also in relation to age- and gender-specific norms. RESULTS: Symptoms of anxiety (P = 0.001), depression (P = 0.001), anger (P = 0.001), and disruptive behavior (P = 0.022) were significantly reduced at 2 years after surgery, as were obesity-related problems (P < 0.001). Self-esteem (P < 0.001), self-concept (P < 0.001), and overall mood (P = 0.025) improved significantly. Improvements were mainly observed during the first year after surgery. The second year was characterized by stabilization. Symptoms of anxiety, depression, anger, disruptive behavior, and self-concept were at normative levels after surgery. However, 19% of the adolescents had depressive symptoms in the clinical range. CONCLUSIONS: A substantial improvement in mental health in adolescents over the first 2 years after gastric bypass was found. Most adolescents had a level of mental health and self-concept similar to norms, but a marked subgroup showed substantial depressive symptoms 2 years after surgery. PMID- 26227558 TI - Power of positive thinking in quantitative proteomics. AB - Derivatization of proteins with specific isotope reagents has been widely explored for quantitative proteomics where the relative abundances of proteins present in different complex samples are compared by MS. This represents an interesting arena for innovation, where protein chemistry and MS are associated for the best of both worlds. Among the numerous reagents developed, those that introduce a permanent positive charge, such as (N-succinimidyloxycarbonylmethyl) tris(2,4,6-trimethoxyphenyl)phosphonium bromide (TMPP), increase the ionizability of their targets and thus improve the sensitivity of the approach. TMPP labeling also modifies the hydrophobicity and changes the peptide fragmentation pattern. Because TMPP reacts preferably with the N-termini of proteins and peptides, its use has been explored for proteogenomics and de novo protein sequencing. In this issue of Proteomics, Shen et al. (Proteomics 2015, 15, 2903-2909) show that accurate quantitation of proteins can be obtained with light/heavy TMPP-labeling of peptides, which can be easily prepared and desalted in a homemade C8-SCX-C8 stagetip, and then monitored by nano-LC-MS/MS analysis. Their results demonstrate enhanced sequence coverage compared with other approaches. Combined with an efficient enrichment procedure, the higher sensitivity of this "positive attitude" reagent may facilitate much deeper investigations into the quantitative proteomics of complex samples. PMID- 26227559 TI - Mean and standard deviation of reference glomerular filtration rate values in Japanese children. PMID- 26227560 TI - Autoantibodies against ganglioside GM3 are associated with narcolepsy-cataplexy developing after Pandemrix vaccination against 2009 pandemic H1N1 type influenza virus. AB - Following the mass vaccinations against pandemic influenza A/H1N1 virus in 2009, a sudden increase in juvenile onset narcolepsy with cataplexy (NC) was detected in several European countries where AS03-adjuvanted Pandemrix vaccine had been used. NC is a chronic neurological disorder characterized by excessive daytime sleepiness and cataplexy. In human NC, the hypocretin-producing neurons in the hypothalamus or the hypocretin signaling pathway are destroyed by an autoimmune reaction. Both genetic (e.g. HLA-DQB1*0602) and environmental risk factors (e.g. Pandemrix) contribute to the disease development, but the underlying and the mediating immunological mechanisms are largely unknown. Influenza virus hemagglutinin is known to bind gangliosides, which serve as host cell virus receptors. Anti-ganglioside antibodies have previously been linked to various neurological disorders, like the Guillain-Barre syndrome which may develop after infection or vaccination. Because of these links we screened sera of NC patients and controls for IgG anti-ganglioside antibodies against 11 human brain gangliosides (GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GQ1b) and a sulfatide by using a line blot assay. Samples from 173 children and adolescents were analyzed: 48 with Pandemrix-associated NC, 20 with NC without Pandemrix association, 57 Pandemrix-vaccinated and 48 unvaccinated healthy children. We found that patients with Pandemrix-associated NC had more frequently (14.6%) anti GM3 antibodies than vaccinated healthy controls (3.5%) (P = 0.047). Anti-GM3 antibodies were significantly associated with HLA-DQB1*0602 (P = 0.016) both in vaccinated NC patients and controls. In general, anti-ganglioside antibodies were more frequent in vaccinated (18.1%) than in unvaccinated (7.3%) individuals (P = 0.035). Our data suggest that autoimmunity against GM3 is a feature of Pandemrix associated NC and that autoantibodies against gangliosides were induced by Pandemrix vaccination. PMID- 26227562 TI - Vigabatrin as First-Line Treatment for Infantile Spasms Not Related to Tuberous Sclerosis Complex. AB - BACKGROUND: Infantile spasms are a rare, catastrophic, age-specific seizure disorder of infancy. Adrenocorticotropic hormone or vigabatrin have been recommended for the short-term treatment of infantile spasms by the Child Neurology Society/American Academy of Neurology practice parameter. OBJECTIVE: This retrospective study reviewed the Hospital for Sick Children's experience with the short-term efficacy of vigabatrin as first-line treatment for infantile spasms not related to tuberous sclerosis complex. METHOD: We performed a single center, retrospective analysis of all cases of newly diagnosed infantile spasms between January 2010 and September 2013. Duration of follow-up was at least 6 months from treatment initiation. RESULTS: Eighteen of the 61 infants (30%) had a clinical and electrographic response to vigabatrin therapy within 4 weeks of treatment. Of the vigabatrin responders, 2/18 (11%) relapsed. At final follow-up after initiation of vigabatrin therapy, 17/61 (27%) of the vigabatrin responders were free of all clinical seizure types. Normal development at the time of infantile spasms diagnosis was statistically associated with vigabatrin response. CONCLUSION: These findings do not support our hypothesis that vigabatrin is effective as first-line, short-term treatment of infantile spasms in non-tuberous sclerosis complex patients. However, when used in this setting, vigabatrin is most effective in children with normal development at the time of diagnosis. These findings may assist clinicians in the optimal treatment choice for children at the first presentation of infantile spasms not related to tuberous sclerosis complex. PMID- 26227563 TI - Tamoxifen Improves Final Height Prediction in Girls with McCune-Albright Syndrome: A Long Follow-Up. AB - BACKGROUND: McCune-Albright syndrome (MAS) is a genetic disorder characterized by the triad of fibrous dysplasia, skin hyperpigmentation, and autonomous hyperfunction of various endocrine organs. MAS frequently presents in females as precocious puberty (PP). Although many treatments have been proposed, the preservation of final height (FH) in these patients remains a challenge. OBJECTIVES: To evaluate the efficacy of tamoxifen in improving the FH prediction (FHP) in patients with MAS. METHOD: We retrospectively analyzed 8 female patients with MAS who presented with cafe-au-lait spots and gonadotropin-independent PP. The patients were followed for a mean period of 8.3 years (range: 3-16). RESULTS: All patients were treated with tamoxifen (10-20 mg/day) for 3-8 years (mean +/- SD: 5.75 +/- 2.05), which resulted in the cessation of vaginal bleeding and the stabilization of bone age maturation. There was a significant difference between the FHP at the beginning of treatment and at the end of treatment (145.1 +/- 8.6 cm; Z score -2.84 +/- 1.44 cm) and at the last evaluation (157.0 +/- 9.2 cm; Z score -0.85 +/- 0.54 cm; p < 0.001). CONCLUSION: Our results support a role for tamoxifen in improving the FHP in patients with MAS. PMID- 26227561 TI - Probing striatal microcircuitry to understand the functional role of cholinergic interneurons. PMID- 26227564 TI - Are Early Seizures Predictive of Epilepsy after a Stroke? Results of a Population Based Study. AB - BACKGROUND: In addition to determining the cumulative incidence and risk factors for early seizures (ES), late seizures (LS) and post stroke epilepsy (PSE), we aimed at checking if ES represented a risk factor for epilepsy and if early treatment after ES prevented the occurrence of subsequent seizures. METHODS: This study was part of a 2-year prospective community-based registry of all cerebrovascular events in the district of Udine (153,312 inhabitants), North Eastern Italy, between April 1, 2007 and March 31, 2009. People with transient ischemic attacks (TIAs) were excluded from this study. RESULTS: In all, 782 cases of stroke (79.28% ischemic, 14.83% hemorrhagic, 3.20% subarachnoid hemorrhage and 2.69% undetermined) were identified. The incidence of ES, LS and PSE was 5.10, 3.14 and 2.22%, respectively. Intracerebral hemorrhage, subarachnoid hemorrhage, stroke of undetermined origin and hyponatremia, represented risk factors for ES (p < 0.05). Among ischemic strokes, ES risk factors were hyponatremia (p = 0.024) and hemorrhagic transformation (p = 0.046). LS risk factors were younger age (p = 0.004) and cortical location of stroke (p = 0.004). Within ischemic strokes, LS risk factors were younger age (p = 0.020) and cortical location (p < 0.0001). Within intracerebral hemorrhages, the only risk factor for LS was the presence of a previous ES (p = 0.017). PSE risk factors were the same as for LS. CONCLUSIONS: All acute conditions related to the occurrence of stroke are implicated in the pathogenesis of ES, which becomes a risk factor for LS only in the setting of intracerebral hemorrhages. Therefore, early antiepileptic treatment is needed only in this situation. PMID- 26227565 TI - Abdominoplasty in Prune Belly Syndrome. AB - INTRODUCTION: Many patients with Prune Belly Syndrome (PBS) require abdominoplasty alone or in combination with correction of any urogenital abnormalities. This video presents a simplified technique with which to treat the abdominal flaccidity in PBS. METHODS: A longitudinal xypho-pubic fusiform figure is drawn on the abdomen, based on the area of skin and subcutaneous tissue to be removed. This is performed with preservation of the musculo-fascial layer and the umbilicus. A lateral elliptical single xypho-pubic line is drawn in the most lax side of the fascia, which is incised along this line. After urinary tract reconstruction and orchidopexy, closure is initiated by suturing the medial edge of the wider fascial flap laterally to the peritoneal side of the contralateral flap. Next, the now outer fascial flap is laid over the inner flap, and a buttonhole is made to expose the umbilicus. The subcutaneous tissue of the inner flap is laterally undermined to gain extra distance for the suture of the outer flap over the inner flap. The subcutaneous tissue and skin are sutured in the midline, incorporating the umbilicus. RESULTS: In a 30-year period, 43 PBS patients underwent this procedure with good cosmetic and long-term functional results. CONCLUSION: This abdominoplasty technique is simple and presents good functional and cosmetic results in PBS patients. PMID- 26227566 TI - Can AutocaptureTM Function of Permanent Pacemakers Initiate Ventricular Tachyarrhythmias? PMID- 26227567 TI - Pediatric Toxic Epidermal Necrolysis: Experience of a Tertiary Burn Center. AB - BACKGROUND: Pediatric toxic epidermal necrolysis (TEN) is a rare and potentially fatal skin disease with a multitude of causative factors and no consensus on treatment guidelines and, as a result, it has a variety of short- and long-term outcomes. We present the experience of a large specialty burn center to share our diagnostic and treatment principles. METHODS: A retrospective review from 1989 to 2010 at the Joseph M. Still Burn Center was performed to find patients with a diagnosis of Steven-Johnson syndrome (SJS) or TEN. Information was obtained on demographic and physiologic parameters such as age, race, total body surface area involved, treatments, hospital stay, and need for ventilator support. RESULTS: We identified SJS or TEN in 21 patients. Prescription drugs were the most common etiology (in 15 patients), with antibiotics as the most common causative agent. Histology confirmed the clinical diagnosis of TEN in 14 patients. Our treatment plan included a multidisciplinary team, early initiation of intravenous immunoglobulin, bronchoscopy, strict management of electrolyte and fluid balances, and meticulous surgical wound care. Mortality was 9.5%. CONCLUSION: Our experience in treating this rare but devastating disease affords us the opportunity to share the diagnostic dilemmas we faced and the treatment principles we used to treat this unique patient population successfully. PMID- 26227568 TI - Synthesis of Cembranoid Analogues through Ring-Closing Metathesis of Terpenoid Precursors: A Challenge Regarding Ring-Size Selectivity. AB - A systematic study on ring-closing metathesis with Grubbs II catalyst to cembranoid macrocycles is described. Acyclic terpenoids with a functional group X in the homoallylic position relative to an RCM active terminus and substituents R, R(1) directly attached to the other terminal double bond were prepared from geraniol derived trienes and fragments that are based on bromoalkenes and dimethyl malonate. Such terpenoids were suitable precursors, despite the presence of competing double bonds in their framework. The size of R and R(1) is crucial for successful macrocyclization. Whereas small alkyl substituents at the double bond directed the RCM towards six-membered ring formation, cross metathesis leading to dimers dominated for bulkier alkyl groups. A similar result was obtained for precursors without functional group X. In the case of unsymmetrically substituted terpenoid precursor (R = Et, R(1) = Me) with homoallylic OTBS or OMe group, the RCM could be controlled towards formation of macrocyclic cembranoids, which were isolated with excellent E-selectivity. The role of the substituents was further studied by quantum chemical calculations of simplified model substrates. Based on these results a mechanistic rationale is proposed. PMID- 26227569 TI - Barley malt increases hindgut and portal butyric acid, modulates gene expression of gut tight junction proteins and Toll-like receptors in rats fed high-fat diets, but high advanced glycation end-products partially attenuate the effects. AB - Barley malt, a product of controlled germination, has been shown to produce high levels of butyric acid in the cecum and portal serum of rats and may therefore have anti-inflammatory effects. The aim of the study was to investigate how four barley malts, caramelized and colored malts, 50-malt and 350-malt, differing in functional characteristics concerning beta-glucan content and color, affect short chain fatty acids (SCFA), barrier function and inflammation in the hindgut of rats fed high-fat diets. Male Wistar rats were given malt-supplemented high-fat diets for four weeks. Low and high-fat diets containing microcrystalline cellulose were incorporated as controls. All diets contained 70 g kg(-1) dietary fiber. The malt-fed groups were found to have had induced higher amounts of butyric and propionic acids in the hindgut and portal serum compared with controls, while cecal succinic acid only increased to a small extent. Fat increased the mRNA expression of tight junction proteins and Toll-like receptors (TLR) in the small intestine and distal colon of the rats, as well as the concentration of some amino acids in the portal plasma, but malt seemed to counteract these adverse effects to some extent. However, the high content of advanced glycation end-products (AGE) in caramelized malt tended to prohibit the positive effects on occludin in the small intestine and plasma amino acids seen with the other malt products. In conclusion, malting seems to be an interesting process for producing foods with positive health effects, but part of these effects may be destroyed if the malt contains a high content of AGE. PMID- 26227570 TI - A novel integration of three-dimensional electro-Fenton and biological activated carbon and its application in the advanced treatment of biologically pretreated Lurgi coal gasification wastewater. AB - A novel integrated process with three-dimensional electro-Fenton (3D EF) and biological activated carbon (BAC) was employed in advanced treatment of biologically pretreated Lurgi coal gasification wastewater. SAC-Fe (sludge deserved activated carbon from sewage and iron sludge) and SAC (sludge deserved activated carbon) were used in 3D EF as catalytic particle electrodes (CPEs) and in BAC as carriers respectively. Results indicated that 3D EF with SAC-Fe as CPEs represented excellent pollutants and COLOR removals as well as biodegradability improvement. The efficiency enhancement attributed to generating more H2O2 and OH. The integrated process exhibited efficient performance of COD, BOD5, total phenols, TOC, TN and COLOR removals at a much shorter retention time, with the corresponding concentrations in effluent of 31.18, 6.69, 4.29, 17.82, 13.88mg/L and <20 times, allowing discharge criteria to be met. The integrated system was efficient, cost-effective and ecological sustainable and could be a promising technology for engineering applications. PMID- 26227571 TI - Improved anaerobic digestion performance and biogas production from poultry litter after lowering its nitrogen content. AB - Poultry litter (PL) was pre-treated in order to reduce its nitrogen content and to increase the C/N ratio. The pre-treatment consisted of a first anaerobiosis phase of about 60days in order to accumulate ammonia nitrogen, followed by an ammonia stripping phase by heating the substrate at 80 degrees C for 24h. The digestion was performed with PL and pre-treated PL (TPL) after ammonia stripping as mono-substrate under four total solids loads, i.e. 5%, 10%, 15% and 20%. The TPL after ammonia stripping displayed lower ammonia (62-73%) and VFA (41-65%) concentrations compared to digesters with raw PL, while bio-methane yield increased about 8-124%. Bio-methane yields in the series with TPL after ammonia stripping were about 193, 196, 215 and 147 [Formula: see text] /kgCOD, based on the COD added, for 5%, 10%, 15% and 20% TS load, respectively. The results indicate that lowering nitrogen content using the suggested process improves bio methane yields significantly. PMID- 26227572 TI - Electro-assisted groundwater bioremediation: fundamentals, challenges and future perspectives. AB - Bioremediation is envisaged as an important way to abate groundwater contamination, but the need for chemical addition and limited bioavailability of electron donors/acceptors or contaminants hamper its application. As a promising means to enhance such processes, electrochemical system has drawn considerable attention, as it offers distinct advantages in terms of environmental benignity, controllability and treatment efficiency. Meanwhile, there are also potential risks and considerable engineering challenges for its practical application. This review provides a first comprehensive introduction of this emerging technology, discusses its potential applications and current challenges, identifies the knowledge gaps, and outlooks the future opportunities to bring it to field application. The need for a better understanding on the microbiology under electrochemical stimulation and the future requirements on process monitoring, modeling and evaluation protocols and field investigations are highlighted. PMID- 26227573 TI - Recurrent deletions and duplications of chromosome 2q11.2 and 2q13 are associated with variable outcomes. AB - Copy number variation (CNV) in the long arm of chromosome 2 has been implicated in developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), congenital anomalies, and psychiatric disorders. Here we describe 14 new subjects with recurrent deletions and duplications of chromosome 2q11.2, 2q13, and 2q11.2-2q13. Though diverse phenotypes are associated with these CNVs, some common features have emerged. Subjects with 2q11.2 deletions often exhibit DD, speech delay, and attention deficit hyperactivity disorder (ADHD), whereas those with 2q11.2 duplications have DD, gastroesophageal reflux, and short stature. Congenital heart defects (CHDs), hypotonia, dysmorphic features, and abnormal head size are common in those with 2q13 deletions. In the 2q13 duplication cohort, we report dysmorphic features, DD, and abnormal head size. Two individuals with large duplications spanning 2q11.2-2q13 have dysmorphic features, hypotonia, and DD. This compilation of clinical features associated with 2q CNVs provides information that will be useful for healthcare providers and for families of affected children. However, the reduced penetrance and variable expressivity associated with these recurrent CNVs makes genetic counseling and prediction of outcomes challenging. (c) 2015 Wiley Periodicals, Inc. PMID- 26227574 TI - Local environments of boron heteroatoms in non-crystalline layered borosilicates. AB - Boron heteroatom distributions are shown to be significantly different in two closely related layered borosilicates synthesized with subtly different alkylammonium surfactant species. The complicated order and disorder near framework boron sites in both borosilicates were characterized at the molecular level by using a combination of multi-dimensional solid-state nuclear magnetic resonance (NMR) spectroscopy techniques and first-principles calculations. Specifically, two-dimensional (2D) solid-state J-mediated (through-bond) (11)B{(29)Si} NMR analyses provide direct and local information on framework boron sites that are covalently bonded to silicon sites through bridging oxygen atoms. The resolution and identification of correlated signals from distinct (11)B-O-(29)Si site pairs reveal distinct distributions of boron heteroatoms in layered borosilicate frameworks synthesized with the different C16H33N(+)Me3 and C16H33N(+)Me2Et structure-directing surfactant species. The analyses establish that boron atoms are distributed non-selectively among different types of silicon sites in the layered C16H33N(+)Me3-directed borosilicate framework, whereas boron atoms are preferentially incorporated into incompletely condensed Q(3)-type sites in the C16H33N(+)Me2Et-directed borosilicate material. Interestingly, framework boron species appear to induce framework condensation of their next-nearest neighbor silicon sites in the C16H33N(+)Me3-directed borosilicate. By comparison, the incorporation of boron atoms is found to preserve the topology of the C16H33N(+)Me2Et-directed borosilicate frameworks. The differences in boron site distributions and local boron-induced structural transformations for the two surfactant-directed borosilicates appear to be due to different extents of cross linking of the siliceous frameworks. The molecular-level insights are supported by density functional theory (DFT) calculations, which show the distinct influences of boron atoms on the C16H33N(+)Me3- and C16H33N(+)Me2Et-directed borosilicate frameworks, consistent with the experimental observations. PMID- 26227575 TI - Prevalence of neuropathy in type 2 diabetic patients and its association with other diabetes complications: The Verona Diabetic Foot Screening Program. AB - AIMS: Somatic neuropathy is a chronic complication of diabetes. The purpose of our study was to determine prevalence and clinical variables associated with somatic neuropathy applying a simple screening method. METHODS: All outpatients with type 2 diabetes attending our diabetic clinic were offered to participate into a diabetic foot screening program, in the period January 2004-December 2012. A total of 3,591 diabetic patients (55.5% men, age 68+/-10years) underwent detection of somatic neuropathy using the Michigan Neuropathy Screening Instrument in its parts of symptoms (administering a questionnaire) and clinical assessment slightly modified (evaluating foot inspection, vibration sensation by biothesiometer, ankle reflexes). RESULTS: The prevalence of somatic neuropathy was 2.2% in men and 5.5% in women (p<0.001) when assessed by symptom questionnaire, whereas it was 30.5% in men and 30.8% (p=NS) in women when identified by clinical assessment. In subjects with somatic neuropathy macro- and microvascular complications of diabetes were significantly more common. In multivariate logistic regression analyses BMI, HbA1c and ankle/brachial index independently predicted the presence of neuropathy. CONCLUSION: The prevalence of somatic neuropathy in type 2 diabetes is nearly 30% when searched with clinical examination. Poor metabolic control, excess body weight and peripheral arteriopathy are independent markers of somatic neuropathy. PMID- 26227576 TI - Effects of personalized colorectal cancer risk information on laypersons' interest in colorectal cancer screening: The importance of individual differences. AB - OBJECTIVE: To evaluate how personalized quantitative colorectal cancer (CRC) risk information affects laypersons' interest in CRC screening, and to explore factors influencing these effects. METHODS: An online pre-post experiment was conducted in which a convenience sample (N=578) of laypersons, aged >50, were provided quantitative personalized estimates of lifetime CRC risk, calculated by the National Cancer Institute Colorectal Cancer Risk Assessment Tool (CCRAT). Self reported interest in CRC screening was measured immediately before and after CCRAT use; sociodemographic characteristics and prior CRC screening history were also assessed. Multivariable analyses assessed participants' change in interest in screening, and subgroup differences in this change. RESULTS: Personalized CRC risk information had no overall effect on CRC screening interest, but significant subgroup differences were observed. Change in screening interest was greater among individuals with recent screening (p=.015), higher model-estimated cancer risk (p=.0002), and lower baseline interest (p<.0001), with individuals at highest baseline interest demonstrating negative (not neutral) change in interest. CONCLUSION: Effects of quantitative personalized CRC risk information on laypersons' interest in CRC screening differ among individuals depending on prior screening history, estimated cancer risk, and baseline screening interest. PRACTICE IMPLICATIONS: Personalized cancer risk information has personalized effects-increasing and decreasing screening interest in different individuals. PMID- 26227577 TI - The long-term effect on mental health symptoms and patient activation of using patient feedback scales in mental health out-patient treatment. A randomised controlled trial. AB - OBJECTIVE: To investigate the long-term effect on mental health symptoms and patient activation, from using the Partners for Change Outcome Management System (PCOMS) feedback scales in out-patient mental health consultations, compared to not using feedback scales. METHODS: An open parallel-group randomised controlled trial was conducted in a mental health hospital in Norway. Eight therapists treated the intervention group, using two feedback scales, and seventeen therapists treated the treatment as usual group. RESULTS: Seventy-five patients participated. Six and twelve months after starting treatment there were no significant effects on the primary outcomes mental health symptoms or patient activation. Compared to baseline assessment the PCOMS group had significantly improved their patient activation scores after twelve months. CONCLUSION: We found no long-term effects from using the PCOMS scales on mental health symptoms or patient activation. PRACTICE IMPLICATIONS: This study shows that the use of a feedback system does not increase mental health outcomes or patient activation. PMID- 26227579 TI - From personal experience. PMID- 26227578 TI - Tools to measure health literacy among Spanish speakers: An integrative review of the literature. AB - OBJECTIVE: Health literacy measurement can help inform healthcare service delivery. The objective of this study is to identify validated tools to measure health literacy among Spanish speakers and to summarize characteristics that are relevant when selecting tools for use in clinical or research settings. METHODS: An English and Spanish search of 9 databases was conducted between October 2014 and May 2015. Inclusion criteria were peer-reviewed articles presenting initial validation and psychometric properties of a tool to measure health literacy among Spanish speaking patients. Characteristics relevant to tool selection were reviewed and presented. RESULTS: Twenty articles validating 19 instruments met inclusion criteria. Instruments were designed for use with Spanish speakers in numerous contexts and measured different health literacy skills such as reading comprehension or numeracy. Methods used to validate tools were inconsistent across instruments. CONCLUSION: Although tools have inconsistencies and inefficiencies, many can be used for assessment of health literacy among Spanish speakers. PRACTICE IMPLICATIONS: Healthcare providers, organizations, and researchers can use this review to select effective health literacy tools to indicate patient's ability to understand and use health information so that services and materials can be more appropriately tailored to Spanish speaking patients. PMID- 26227580 TI - Vancomycin-induced linear IgA bullous dermatosis demonstrating the isomorphic phenomenon. PMID- 26227581 TI - The sign of "undue contact" in the Object Use Test. PMID- 26227582 TI - Sleep not just protects memories against forgetting, it also makes them more accessible. AB - Two published datasets (Dumay & Gaskell, 2007, Psychological Science; Tamminen, Payne, Stickgold, Wamsley, & Gaskell, 2010, Journal of Neuroscience) showing a positive influence of sleep on declarative memory were re-analyzed, focusing on the "fate" of each item at the 0-h test and 12-h retest. In particular, I looked at which items were retrieved at test and "maintained" (i.e., not forgotten) at retest, and which items were not retrieved at test, but eventually "gained" at retest. This gave me separate estimates of protection against loss and memory enhancement, which the classic approach relying on net recall/recognition levels has remained blind to. In both free recall and recognition, the likelihood of maintaining an item between test and retest, like that of gaining one at retest, was higher when the retention interval was filled with nocturnal sleep, as opposed to day-time (active) wakefulness. And, in both cases, the effect of sleep was stronger on gained than maintained items. Thus, if sleep indeed protects against retroactive, unspecific interference, it also clearly promotes access to those memories initially too weak to be retrieved. These findings call for an integrated approach including both passive (cell-level) and active (systems level) consolidation, possibly unfolding in an opportunistic fashion. PMID- 26227583 TI - Omega-3 polyunsaturated fatty acids and cancer: lessons learned from clinical trials. AB - Over the past decades, extensive studies have addressed the therapeutic effects of omega-3 polyunsaturated fatty acids (omega-3 FAs) against different human diseases such as cardiovascular and neurodegenerative diseases, cancer, etc. A growing body of scientific research shows the pharmacokinetic information and safety of these natural occurring substances. Moreover, during recent years, a plethora of studies has demonstrated that omega-3 FAs possess therapeutic role against certain types of cancer. It is also known that omega-3 FAs can improve efficacy and tolerability of chemotherapy. Previous reports showed that suppression of nuclear factor-kappaB, activation of AMPK/SIRT1, modulation of cyclooxygenase (COX) activity, and up-regulation of novel anti-inflammatory lipid mediators such as protectins, maresins, and resolvins, are the main mechanisms of antineoplastic effect of omega-3 FAs. In this review, we have collected the available clinical data on the therapeutic role of omega-3 FAs against breast cancer, colorectal cancer, leukemia, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, lung cancer, head and neck cancer, as well as cancer cachexia. We also discussed the chemistry, dietary source, and bioavailability of omega-3 FAs, and the potential molecular mechanisms of anticancer and adverse effects. PMID- 26227584 TI - New advances in genitourinary cancer: evidence gathered in 2014. AB - This review provides updated information published in 2014 regarding advances and major achievements in genitourinary cancer. Sections include the best in prostate cancer, renal cancer, bladder cancer, and germ cell tumors. In the field of prostate cancer, data related to treatment approach of hormone-sensitive disease, castrate-resistant prostate cancer, mechanisms of resistance, new drugs, and molecular research are presented. In relation to renal cancer, relevant aspects in the treatment of advanced renal cell carcinoma, immunotherapy, and molecular research, including angiogenesis and von Hippel-Lindau gene, molecular biology of non-clear cell histologies, and epigenetics of clear renal cell cancer are described. New strategies in the management of muscle-invasive localized bladder cancer and metastatic disease are reported as well as salient findings of biomolecular research in urothelial cancer. Some approaches intended to improve outcomes in poor prognosis patients with metastatic germ cell cancer are also reported. Results of clinical trials in these areas are discussed. PMID- 26227585 TI - Development of bright fluorescent quadracyclic adenine analogues: TDDFT calculation supported rational design. AB - Fluorescent base analogues (FBAs) comprise a family of increasingly important molecules for the investigation of nucleic acid structure and dynamics. We recently reported the quantum chemical calculation supported development of four microenvironment sensitive analogues of the quadracyclic adenine (qA) scaffold, the qANs, with highly promising absorptive and fluorescence properties that were very well predicted by TDDFT calculations. Herein, we report on the efficient synthesis, experimental and theoretical characterization of nine novel quadracyclic adenine derivatives. The brightest derivative, 2-CNqA, displays a 13 fold increased brightness (epsilonPhiF = 4500) compared with the parent compound qA and has the additional benefit of being a virtually microenvironment insensitive fluorophore, making it a suitable candidate for nucleic acid incorporation and use in quantitative FRET and anisotropy experiments. TDDFT calculations, conducted on the nine novel qAs a posteriori, successfully describe the relative fluorescence quantum yield and brightness of all qA derivatives. This observation suggests that the TDDFT-based rational design strategy may be employed for the development of bright fluorophores built up from a common scaffold to reduce the otherwise costly and time-consuming screening process usually required to obtain useful and bright FBAs. PMID- 26227586 TI - Finding Meaning in Life Following Emergency Postpartum Hysterectomy: What Doesn't Kill Us Makes Us Stronger. AB - INTRODUCTION: Childbirth is generally perceived to be a triumphant and joyous moment in a woman's life. However, current research indicates that it can also be a time of fear, dread, and apprehension, particularly when the birth experience is traumatic. Some women attempt to seek the positives of their traumatic or unexpected childbirth experience to be able to cope with their experience. However, little attention is directed toward how women rebuild their lives and grow following traumatic birth experiences such as severe postpartum hemorrhage and emergency hysterectomy. METHODS: Twenty-one Australian women, aged 24 to 57 years, who had experienced severe postpartum hemorrhage and emergency hysterectomy were interviewed in an in-depth qualitative study about their experiences. RESULTS: Thematic analysis revealed the major theme of moving forward and 4 subthemes: appreciating life and what you have; what really counts: learning and growing; accepting it: it's just the way it is; and reframing the experience: seeking the positives All of the women found meaning following their hysterectomy, which produced a positive perspective on their lives. DISCUSSION: The way that women find meaning and cope with the trauma of having a severe postpartum hemorrhage and emergency hysterectomy is significant to their ability to move forward and live life to the fullest. Midwives and other health care providers may be in a position to provide support for women in the aftermath of severe postpartum hemorrhage and emergency hysterectomy. PMID- 26227587 TI - Immunological study of an attenuated Salmonella Typhimurium expressing ApxIA, ApxIIA, ApxIIIA and OmpA of Actinobacillus pleuropneumoniae in a mouse model. AB - Salmonella Typhimurium strain expressing the Actinobacillus pleuropneumoniae antigens, ApxIA, ApxIIA, ApxIIIA and OmpA, was previously constructed as a vaccine candidate for porcine pleuropneumonia. This strain was a live attenuated (?lon?cpxR?asd)Salmonella as a delivery host and contained a vector containing asd. An immunological study of lymphocyte proliferation, T-lymphocyte subsets and cytokines in the splenocytes of a mouse model was carried out after stimulation with the candidate Salmonella Typhimurium by intranasal inoculation. The splenic lymphocyte proliferation and the levels of IL-4, IL-6 and IL-12 of the inoculated mice were significantly increased, and the T- and B-cell populations were also elevated. Collectively, the candidate may efficiently induce the Th1- and Th2 type immune responses. PMID- 26227588 TI - Comparative Analysis of Whole-Genome Sequences of Influenza A(H1N1)pdm09 Viruses Isolated from Hospitalized and Nonhospitalized Patients Identifies Missense Mutations That Might Be Associated with Patient Hospital Admissions in Finland during 2009 to 2014. AB - Here, we report 40 new whole-genome sequences of influenza A(H1N1)pdm09 viruses isolated from Finnish patients during 2009 to 2014. A preliminary analysis of these and 186 other whole genomes of influenza A(H1N1)pdm09 viruses isolated from hospitalized and nonhospitalized patients during 2009 to 2014 in Finland revealed several viral mutations that might be associated with patient hospitalizations. PMID- 26227589 TI - Genome Sequence of a Diverse Goose Circovirus Recovered from Greylag Goose. AB - A diverse goose circovirus (GoCV) genome was recovered from a wild hunted greylag goose (Anser anser) in Poland. The genome shares 83% pairwise identity with other GoCV genomes recovered from various geese from China, Germany, and Taiwan. PMID- 26227590 TI - Virulence Factor Genes Detected in the Complete Genome Sequence of Corynebacterium uterequi DSM 45634, Isolated from the Uterus of a Maiden Mare. AB - The complete genome sequence of the type strain Corynebacterium uterequi DSM 45634 from an equine urogenital tract specimen comprises 2,419,437 bp and 2,163 protein-coding genes. Candidate virulence factors are homologs of DIP0733, DIP1281, and DIP1621 from Corynebacterium diphtheriae and of sialidase precursors from Trueperella pyogenes and Chlamydia trachomatis. PMID- 26227591 TI - Complete Genome Sequence of the Type Strain Corynebacterium testudinoris DSM 44614, Recovered from Necrotic Lesions in the Mouth of a Tortoise. AB - The complete genome sequence of the type strain Corynebacterium testudinoris DSM 44614 from the mouth of a tortoise comprises 2,721,226 bp with a mean G+C content of 63.14%. The automatic annotation of the genome sequence revealed 4 rRNA operons, 51 tRNA genes, 7 other RNA genes, and 2,561 protein-coding regions. PMID- 26227592 TI - Characterization and Sequencing of a Genotype XII Newcastle Disease Virus Isolated from a Peacock (Pavo cristatus) in Peru. AB - Here, we report the first complete sequence and biological characterization of a Newcastle disease virus (NDV) isolated from a peacock in South America (NDV/peacock/Peru/2011). This isolate, classified as genotype XII in class II, highlights the need for increased surveillance of noncommercial avian species. PMID- 26227593 TI - Draft Genome Sequence of Shiga Toxin-Producing Escherichia coli Strain D92/09. AB - Escherichia coli is suspected to be involved with Crohn's disease. Adherence and invasion to epithelial cells are properties commonly observed in these bacteria. Here, we present a draft genome sequence of E. coli D92/09, a multidrug-resistant strain, which besides showing these properties produces Shiga cytotoxin-1 and possibly other toxins. PMID- 26227594 TI - Draft Genome Sequence of the Bacteriocin-Producing Bradyrhizobium japonicum Strain FN1. AB - Bradyrhizobium japonicum strain FN1 was found to produce bacteriocin-like zones of clearing when tested against other strains of bradyrhizbia. The genome was sequenced, and several putative bacteriocin-producing genes, in addition to the expected genes involved in nodulation and nitrogen fixation, were identified. PMID- 26227595 TI - Draft Genome Sequence of Saccharomyces cerevisiae Strain NCIM3186 Used in the Production of Bioethanol from Sweet Sorghum. AB - Here, we report the draft genome sequence of Saccharomyces cerevisiae strain NCIM3186 used in bioethanol production from sweet sorghum. The size of the genome is approximately 11.9 Mb and contains 5,347 protein-coding genes. PMID- 26227596 TI - Draft Genome Sequence of Lactobacillus sp. Strain TCF032-E4, Isolated from Fermented Radish. AB - Here, we report the draft genome sequence of Lactobacillus sp. strain TCF032-E4 (= CCTCC AB2015090 = DSM 100358), isolated from a Chinese fermented radish. The total length of the 57 contigs is about 2.9 Mb, with a G+C content of 43.5 mol% and 2,797 predicted coding sequences (CDSs). PMID- 26227597 TI - Mitochondrial Genome Sequence of the Glass Sponge Oopsacas minuta. AB - We report the complete mitochondrial genome sequence of the Mediterranean glass sponge Oopsacas minuta. This 19-kb mitochondrial genome has 24 noncoding genes (22 tRNAs and 2 rRNAs) and 14 protein-encoding genes coding for 11 subunits of respiratory chain complexes and 3 ATP synthase subunits. PMID- 26227598 TI - First Complete Genome Sequence of Clostridium sporogenes DSM 795T, a Nontoxigenic Surrogate for Clostridium botulinum, Determined Using PacBio Single-Molecule Real Time Technology. AB - The first complete genome sequence of Clostridium sporogenes DSM 795(T), a nontoxigenic surrogate for Clostridium botulinum, was determined in a single contig using the PacBio single-molecule real-time technology. The genome (4,142,990 bp; G+C content, 27.98%) included 86 sets of >1,000-bp identical sequence pairs and 380 tandem repeats. PMID- 26227599 TI - Draft Genome Sequences of Five Clinical Methicillin-Resistant Staphylococcus aureus Isolates and a Methicillin-Resistant Staphylococcus epidermidis Isolate. AB - We report the complete draft genome sequences of five individually isolated strains of methicillin-resistant Staphylococcus aureus (MRSA) and a Staphylococcus epidermidis strain. These clinically important isolates have staphylococcal cassette chromosome mec type A, while Panton-Valentine leukocidin (PVL) toxin coding genes were present in MRSA isolates only. PMID- 26227600 TI - Draft Genome Sequences of Five Pseudomonas fluorescens Subclade I and II Strains, Isolated from Human Respiratory Samples. AB - We report the draft genomes of five Pseudomonas fluorescens strains, isolated from clinical samples. Phylogenetic analysis places three in subclade I and two in subclade II of the P. fluorescens species complex. The average G+C content and genomic size are 63% and 7.1 Mbp (subclade I) and 59.6% and 6.14 Mbp (subclade II), respectively. PMID- 26227601 TI - Whole-Genome Sequence of the Microcystin-Degrading Bacterium Sphingopyxis sp. Strain C-1. AB - This report describes the whole-genome sequence of an alkalitolerant microcystin degrading bacterium, Sphingopyxis sp. strain C-1, isolated from a lake in China. PMID- 26227602 TI - Draft Genome Sequence of the Lactobacillus agilis Strain Marseille. AB - We report the draft genome sequence of Lactobacillus agilis strain Marseille, isolated from stool samples of a child suffering from kwashiorkor. This strain can use two metabolic pathways allowing the assimilation of glucose and xylose. Here, we present the first draft genome of the Lactobacillus agilis species. PMID- 26227603 TI - Draft Genome Sequence of the Lactobacillus mucosae Strain Marseille. AB - Lactobacillus mucosae strain Marseille, isolated from stool samples of a child suffering from a malnutrition disorder called Kwashiorkor, produces bacteriocin and seems to have specific carbohydrate and lipid metabolisms different from those of other Lactobacillus organisms. The draft genome sequence of this strain is presented here. PMID- 26227604 TI - Isolation, Identification, Whole-Genome Sequencing, and Annotation of Four Bacillus Species, B. anthracis RIT375, B. circulans RIT379, B. altitudinis RIT380, and B. megaterium RIT381, from Internal Stem Tissue of the Insulin Plant Costus igneus. AB - Here, we report the isolation, identification, whole-genome sequencing, and annotation of four Bacillus species from internal stem tissue of the insulin plant Costus igneus, grown in Puerto Rico. The plant is of medicinal importance, as extracts from its leaves have been shown to lower blood sugar levels of hyperglycemic rats. PMID- 26227605 TI - Complete Genome Sequence of Acinetobacter baumannii CIP 70.10, a Susceptible Reference Strain for Comparative Genome Analyses. AB - The complete genome sequence for the reference strain Acinetobacter baumannii CIP 70.10 (ATCC 15151) was established. The strain was isolated in France in 1970, is susceptible to most antimicrobial compounds, and is therefore of importance for comparative genome analyses with clinical multidrug-resistant (MDR) A. baumannii strains to study resistance development and acquisition in this emerging human pathogen. PMID- 26227606 TI - Draft Genome Sequences of Human-Pathogenic Escherichia coli O26:H11 Strains Carrying the stx2 Gene Only and Circulating in France. AB - Shiga toxin-producing Escherichia coli (STEC) O26:H11 is one of the most frequent pathogens associated with diarrhea and hemolytic-uremic syndrome (HUS). In this report, we present the draft genome sequences of seven strains of STEC O26:H11 carrying the stx2a or stx2d gene only and isolated in France from HUS patients. PMID- 26227607 TI - First Complete Genome Sequence of a Salmonella enterica subsp. enterica Serovar Derby Strain Associated with Pork in France. AB - In France, Salmonella enterica subsp. enterica serovar Derby is one of the most often isolated serovars in pigs. Here, we describe the draft genome sequence of a strain isolated from a pig. This strain had the most frequent pulsed-field gel electrophoresis (PFGE) and antimicrobial patterns (S, SSU, T) usually observed in pig production in France. Those patterns have been also highlighted in human isolates. PMID- 26227608 TI - Draft Genome Sequence of Streptomyces sp. Strain PBH53, Isolated from an Urban Environment. AB - We report the draft genome sequence of Streptomyces sp. strain PBH53, a strain isolated from an urban transit station in Ottawa, Canada. The analysis of the genome using the bioinformatics tool antiSMASH showed the presence of many unique natural product biosynthetic pathways. PMID- 26227609 TI - Draft Genome Sequence of Triclosan-Resistant Cystic Fibrosis Isolate Achromobacter xylosoxidans CF304. AB - Achromobacter xylosoxidans is an emerging opportunistic pathogen. Here, we present the genome sequence of cystic fibrosis isolate CF304. Assembly resulted in 29 contigs adding up to 6.3 Mbp. This is the second genome sequence for a cystic fibrosis isolate, and little is known about the genetic basis of pathogenicity in this organism. PMID- 26227610 TI - Draft Genome Sequence of Ochrobactrum anthropi Strain W13P3, a Halotolerant Polycyclic Aromatic Hydrocarbon-Degrading Bacterium. AB - Ochrobactrum anthropi W13P3 was isolated from saline soil contaminated by polycyclic aromatic hydrocarbons (PAHs) and could degrade PAHs with 5% NaCl. We report the 5.3-Mb draft genome sequence of this strain, which is helpful for understanding the diversity of Ochrobactrum spp. and the mechanism of PAH degradation in saline environments. PMID- 26227611 TI - First Insights into the Genome of Fructobacillus sp. EFB-N1, Isolated from Honey Bee Larva Infected with European Foulbrood. AB - European foulbrood is a worldwide disease affecting the honey bee brood. Here, we report the draft genome sequence of Fructobacillus sp. EFB-N1, which was isolated from an infected honey bee larva derived from a Swiss European foulbrood outbreak. The genome consists of 68 contigs and harbors 1,629 predicted protein encoding genes. PMID- 26227612 TI - Correction for Galia et al., Genome Sequence and Annotation of a Human Infection Isolate of Escherichia coli O26:H11 Involved in a Raw Milk Cheese Outbreak. PMID- 26227613 TI - Molecular Signatures of Reduced Nerve Toxicity by CeCl3 in Phoxim-exposed Silkworm Brains. AB - CeCl3 can reduce the damage caused by OP pesticides, in this study we used the brain of silkworms to investigate the mechanism of CeCl3 effects on pesticide resistance. The results showed that phoxim treatments led to brain damages, swelling and death of neurons, chromatin condensation, and mitochondrial damage. Normal nerve conduction was severely affected by phoxim treatments, as revealed by: increases in the contents of neurotransmitters Glu, NO, and ACh by 63.65%, 61.14%, and 98.54%, respectively; decreases in the contents of 5-HT and DA by 53.19% and 43.71%, respectively; reductions in the activities of Na(+)/K(+) ATPase, Ca(2+)/Mg(2+)-ATPase, and AChE by 85.27%, 85.63%, and 85.63%, respectively; and increase in the activity of TNOS by 22.33%. CeCl3 pretreatment can significantly reduce such damages. Results of DGE and qRT-PCR indicated that CeCl3 treatments significantly upregulated the expression levels of CYP4G23, cyt b5, GSTs-sigma1, ace1, esterase-FE4, and beta-esterase 2. Overall, phoxim treatments cause nerve tissue lesions, neuron death, and nerve conduction hindrance, but CeCl3 pretreatments can promote the expression of phoxim resistance-related genes in silkworm brains to reduce phoxim-induced damages. Our study provides a potential new method to improve the resistance of silkworms against OP pesticides. PMID- 26227614 TI - DYNLT (Tctex-1) forms a tripartite complex with dynein intermediate chain and RagA, hence linking this small GTPase to the dynein motor. AB - It has been suggested that DYNLT, a dynein light chain known to bind to various cellular and viral proteins, can function as a microtubule-cargo adaptor. Recent data showed that DYNLT links the small GTPase Rab3D to microtubules and, for this to occur, the DYNLT homodimer needs to display a binding site for dynein intermediate chain together with a binding site for the small GTPase. We have analysed in detail how RagA, another small GTPase, associates to DYNLT. After narrowing down the binding site of RagA to DYNLT we could identify that a beta strand, part of the RagA G3 box involved in nucleotide binding, mediates this association. Interestingly, we show that both microtubule-associated DYNLT and cytoplasmic DYNLT are equally able to bind to the small GTPases Rab3D and RagA. Using NMR spectroscopy, we analysed the binding of dynein intermediate chain and RagA to mammalian DYNLT. Our experiments identify residues of DYNLT affected by dynein intermediate chain binding and residues affected by RagA binding, hence distinguishing the docking site for each of them. In summary, our results shed light on the mechanisms adopted by DYNLT when binding to protein cargoes that become transported alongside microtubules bound to the dynein motor. PMID- 26227615 TI - The Folding process of Human Profilin-1, a novel protein associated with familial amyotrophic lateral sclerosis. AB - Human profilin-1 is a novel protein associated with a recently discovered form of familial amyotrophic lateral sclerosis. This urges the characterization of possible conformational states, different from the fully folded state, potentially able to initiate self-assembly. Under native conditions, profilin-1 is monomeric and possesses a well-defined secondary and tertiary structure. When incubated at low pH or with high urea concentrations, profilin-1 remains monomeric but populates unfolded states exhibiting larger hydrodynamic radius and disordered structure, as assessed by dynamic light scattering, far-UV circular dichroism and intrinsic fluorescence. Refolding from the urea-unfolded state was studied at equilibrium and in real-time using a stopped-flow apparatus. The results obtained with intrinsic fluorescence and circular dichroism indicate a single phase without significant changes of the corresponding signals before the major refolding transition. However, such a transition is preceded by a burst phase with an observed increase of ANS fluorescence, which indicates the conversion into a transiently populated collapsed state possessing solvent exposed hydrophobic clusters. Kinetic analysis reveals that such state has a conformational stability comparable to that of the fully unfolded state. To our knowledge, profilin-1 is the first example of an amyloid-related protein where folding occurs in the absence of thermodynamically stable partially folded states. PMID- 26227616 TI - Meta-analysis of survival in patients with HNSCC discriminates risk depending on combined HPV and p16 status. AB - Data indicate a better prognosis for human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). HPV and p16 detection are established markers for HPV-related HNSCC. Both are accepted as survival-independent predictors. Previous studies investigating the survival in HNSCC patients depending on HPV(+/-) and p16(+/-) status consistently found discordant results with p16(-)/HPV(+) and p16(+)/HPV(-). However, no meta-analysis regarding the survival according to combined HPV/p16 status has been performed yet. The objective of this study was to discriminate the impact of combined HPV(+/-) and p16(+/-) status on survival. Data sources were identification and review of publications assessing survival of the distinct subgroups with both p16 and HPV investigated in HNSCC until February, 2015. A meta-analysis was performed to classify survival and clinical outcomes. 18 out of 397 articles (4424 patients) were eligible for the meta-analysis. The percent proportion of the subgroups was 25 % for HPV(+)/p16(+), 61.2 % for HPV(-)/p16(-), 7.1 % for HPV(-)/p16(+) and 6.8 % for HPV(+)/P16(-). The meta-analysis showed a significantly improved 5-year overall survival (OS), 5-year disease-free survival and their corresponding hazard ratio for HPV(+)/p16(+) HNSCC in comparison to HPV(-)/p16(-), HPV(+)/p16( ) and HPV(-)/p16(+). The 5-year OS of the HPV(-)/p16(+) subgroup was intermediate while HPV(+)/p16(-) and HPV(-)/p16(-) HNSCC had the shortest survival. With current therapeutic strategies, survival of patients with HNSCC is better if associated with HPV(+)/p16(+) or HPV(-)/p16(+). Clinical trials are needed to confirm the distinct survival pattern and to investigate possible differences in survival for HPV(+)/p16(-) and HPV(-)/p16(+) HNSCC. To further differentiate p16(+) HNSCC, HPV testing may be advisable. PMID- 26227617 TI - Eradication of MRSA skull base osteitis by combined treatment with antibiotics and sinonasal irrigation with sodium hypochlorite. PMID- 26227618 TI - Hybrid MR-PET in Neuroimaging. AB - Hybrid magnetic resonance (MR)-positron emission tomography (MR-PET) is a novel technology with advantages over sequential MR and PET imaging, allowing maintain full individual diagnostic performance with negligible mutual interference between the two hardware settings. Obvious synergies between MR and PET in acquisition of anatomical, functional, and molecular information for neurological diseases into one single image pave the way for establishing clear clinical indications for hybrid MR-PET as well as addressing unmet neuroimaging needs in future clinics and research. Further developments in attenuation correction, quantification, workflow, and effective MR-PET data management might unfold the full potential of integrated multimodality imaging. PMID- 26227619 TI - Essential Subcortical Tracts in Language and Reading. 3D-Tractography for Clinical Practice and Anatomic Correlation with Intraoperative Subcortical Electrostimulation. AB - Diffusion tensor imaging (DTI) and tractography provide the neurosurgeon with a valid 3D view of the white matter tracts of the brain for the presurgical planning of the treatment of lesions close to eloquent areas, this being one of the principal clinical applications of this technique. In this article, we describe through practical cases the anatomic relationships of white matter tracts that are essential for language and reading, based on DTI studies and the excellent anatomic correlation with the intraoperative subcortical map. PMID- 26227620 TI - Aneurysmal and Perianeurysmal Changes After Endovascular Treatment: from Inflammation to Microbleed. A Case Report. PMID- 26227621 TI - In Situ Biosynthesis of Fluorescent Platinum Nanoclusters: Toward Self-Bioimaging Guided Cancer Theranostics. AB - Among the noble-metal clusters, very few reports about platinum clusters were used as bioimaging probes of tumors except as a reducing catalyst. It is first established herein that the biocompatible platinum nanoclusters are spontaneously biosynthesized by cancerous cells (i.e., HepG2 (human hepatocarcinoma), A549 (lung cancer), and others) rather than noncancerous cells (i.e., L02 (human embryo liver cells)) when incubated with micromolar chloroplatinic acid solutions. These in situ biosynthesized platinum nanoclusters could be readily realized in a biological environment and emit a bright fluorescence at 460 nm, which could be further utilized to facilitate an excellent cancer-cell-killing efficiency when combined with porphyrin derivatives for photothermal treatment. This raises the possibility of providing a promising and precise bioimaging strategy for specific fluorescent self-biomarking of tumor locations and realizing fluorescence imaging-guided photothermal therapy of tumors. PMID- 26227622 TI - Delivery of large molecular protein using flat and short microneedles prepared using focused ion beam (FIB) as a skin ablation tool. AB - Many studies have been reported in the literature on the effects of various geometries and lengths of microneedles (MNs) on transdermal drug delivery using a variety of drug molecules. In particular, sharp-tipped MNs have been used to disrupt the top layer of the skin, namely, stratum corneum (SC). It has also been shown that short- and flat-tipped MNs can pierce the SC and they have the potential to increase drug permeability. However, there is little work that explores MNs as a skin ablative tool with a view to increasing skin permeability. To address this point, well-defined small patterns (size of individual pattern 10 20 MUm) on the tip of flat MN (tip radius of individual MN ~250 MUm) were created and their effects evaluated on the permeability of bovine serum albumin (BSA), which is chosen as a model drug of high molecular weight. The patterns on the tip of flat MN act as rough surfaces (e.g. like sand paper) which when applied on the surface of the skin ablate the SC layer. Focused ion beam (FIB) has been used as the fabrication technique for the MNs. The permeability data are then compared with the other data for flat- and sharp-tipped MN. The permeability data from passive diffusion experiments are used as the reference case. The exact number of MNs or patterns in the flat and patterned MN patches is not considered as important as they have not been designed to pierce the skin. However, this is an important consideration in the case of sharp MNs as they pierce and create cavities in the skin. It is found that the delivery of BSA with the fabricated flat and patterned MNs gave similar but somewhat lower drug permeation profile in comparison to the sharp MNs. Passive diffusion showed no permeation, as would be expected due to the large size of the chosen molecule. PMID- 26227623 TI - Hydrologically driven ecosystem processes determine the distribution and persistence of ecosystem-specialist predators under climate change. AB - Climate change has the capacity to alter physical and biological ecosystem processes, jeopardizing the survival of associated species. This is a particular concern in cool, wet northern peatlands that could experience warmer, drier conditions. Here we show that climate, ecosystem processes and food chains combine to influence the population performance of species in British blanket bogs. Our peatland process model accurately predicts water-table depth, which predicts abundance of craneflies (keystone invertebrates), which in turn predicts observed abundances and population persistence of three ecosystem-specialist bird species that feed on craneflies during the breeding season. Climate change projections suggest that falling water tables could cause 56-81% declines in cranefly abundance and, hence, 15-51% reductions in the abundances of these birds by 2051-2080. We conclude that physical (precipitation, temperature and topography), biophysical (evapotranspiration and desiccation of invertebrates) and ecological (food chains) processes combine to determine the distributions and survival of ecosystem-specialist predators. PMID- 26227624 TI - How to measure disease activity in eosinophilic esophagitis. AB - Activity of Eosinophilic Esophagitis (EoE) can be measured by patient reported outcomes (symptoms and quality of life) and clinician-reported outcomes (endoscopic, histologic, or biochemical alterations). Over the last years efforts have been underway to develop and validate instruments to assess EoE activity in the different domains. Such instruments are urgently needed to standardize the language of EoE activity assessment and, in so doing, to facilitate communication among various stakeholders. Such standardization will ultimately allow EoE researchers to define meaningful endpoints for use in clinical trials and observational studies, to compare the efficacy of different therapeutic modalities, and to develop algorithms in order to provide patients with the appropriate therapy. This review provides an overview of the current status of instruments that assess EoE activity in the different domains. PMID- 26227625 TI - Using information theory to identify redundancy in common laboratory tests in the intensive care unit. AB - BACKGROUND: Clinical workflow is infused with large quantities of data, particularly in areas with enhanced monitoring such as the Intensive Care Unit (ICU). Information theory can quantify the expected amounts of total and redundant information contained in a given clinical data type, and as such has the potential to inform clinicians on how to manage the vast volumes of data they are required to analyze in their daily practice. The objective of this proof-of concept study was to quantify the amounts of redundant information associated with common ICU lab tests. METHODS: We analyzed the information content of 11 laboratory test results from 29,149 adult ICU admissions in the MIMIC II database. Information theory was applied to quantify the expected amount of redundant information both between lab values from the same ICU day, and between consecutive ICU days. RESULTS: Most lab values showed a decreasing trend over time in the expected amount of novel information they contained. Platelet, blood urea nitrogen (BUN), and creatinine measurements exhibited the most amount of redundant information on days 2 and 3 compared to the previous day. The creatinine-BUN and sodium-chloride pairs had the most redundancy. CONCLUSIONS: Information theory can help identify and discourage unnecessary testing and bloodwork, and can in general be a useful data analytic technique for many medical specialties that deal with information overload. PMID- 26227626 TI - Brca1 is expressed in human microglia and is dysregulated in human and animal model of ALS. AB - BACKGROUND: There is growing evidence that microglia are key players in the pathological process of amyotrophic lateral sclerosis (ALS). It is suggested that microglia have a dual role in motoneurone degeneration through the release of both neuroprotective and neurotoxic factors. RESULTS: To identify candidate genes that may be involved in ALS pathology we have analysed at early symptomatic age (P90), the molecular signature of microglia from the lumbar region of the spinal cord of hSOD1(G93A) mice, the most widely used animal model of ALS. We first identified unique hSOD1(G93A) microglia transcriptomic profile that, in addition to more classical processes such as chemotaxis and immune response, pointed toward the potential involvement of the tumour suppressor gene breast cancer susceptibility gene 1 (Brca1). Secondly, comparison with our previous data on hSOD1(G93A) motoneurone gene profile substantiated the putative contribution of Brca1 in ALS. Finally, we established that Brca1 protein is specifically expressed in human spinal microglia and is up-regulated in ALS patients. CONCLUSIONS: Overall, our data provide new insights into the pathogenic concept of a non-cell-autonomous disease and the involvement of microglia in ALS. Importantly, the identification of Brca1 as a novel microglial marker and as possible contributor in both human and animal model of ALS may represent a valid therapeutic target. Moreover, our data points toward novel research strategies such as investigating the role of oncogenic proteins in neurodegenerative diseases. PMID- 26227627 TI - Trust behavior in Parkinson's disease: results of a trust game experiment. AB - BACKGROUND: Parkinson's Disease (PD) is a neurodegenerative disease characterized by motor symptoms, but in which behavioral and cognitive disturbances are also common. Trust, due to its pervasiveness in society, has become a major research topic in several scientific disciplines. However, empirical evidence for trust behavior in neurological patients, and specifically for movement disorders such as PD, is missing. Evidence from healthy subjects, however, indicates that three brain regions are involved in trust perceptions and behavior, namely the limbic system, basal ganglia, and frontal cortex. PD affects all these brain regions. Therefore, we hypothesized that PD patients and healthy controls show differences in trust behavior. METHODS: We conducted an experiment using the trust game, an established paradigm to investigate trust behavior in both patient and healthy populations alike, controlling for risky decision making. Twenty patients suffering from PD diagnosed according to UK PDS Brain Bank criteria and twenty healthy controls (matched for age, gender, education, and income) were recruited. We excluded those suffering from clinically relevant neuropsychiatric comorbidities. RESULTS: We found that PD patients exhibit significantly lower levels of trust than do healthy controls. Importantly, our results cannot be explained by lower levels of risk-taking. Moreover, our results indicate that the trust deficit is independent of medication, disease duration, and severity of motor symptoms. CONCLUSION: Application of a standard procedure for measuring trust behavior revealed that PD patients exhibit lower levels of trust in other humans than do healthy controls. Against this background we make a call for further research to determine the underlying pathophysiology of reduced trust in PD. PMID- 26227628 TI - [Position Paper: Significance of the Forced Vital Capacity in Idiopathic Pulmonary Fibrosis]. AB - Spirometry is a highly standardized method which allows to measure the forced vital capacity (FVC) with high precision and reproducibility. In patients with IPF FVC is directly linked to the disease process which is characterized by scaring of alveoli and shrinkage of the lungs. Consequently, there is ample evidence form clinical studies that the decline of FVC over time is consistently associated with mortality in IPF. As for the first time effective drugs for the treatment of IPF are available it becomes obvious that in studies which could demonstrate that the drug reduces FVC decline, a numerical effect on mortality was also observed, while in one study where a significant effect on FVC decline was missed, there was also no change in mortality. Based on these studies FVC decline is a validated surrogate of mortality in IPF. It is concluded that FVC decline is not only accepted as an endpoint of clinical treatment trials in IPF but is also valid as a patient related outcome parameter which should be considered for the assessment of the efficacy of an IPF drug. PMID- 26227629 TI - Dialysis-dependent acute kidney injury in children with end-stage liver disease: prevalence, dialysis modalities and outcome. AB - BACKGROUND: Acute kidney injury (AKI) is a major complication in children with hepatic failure which leads to increased morbidity and mortality. The aim of this study was to provide paediatric data on the prevalence of dialysis-dependent AKI (dAKI), the feasibility and efficacy of dialysis methods and outcome. METHODS: We conducted a retrospective analysis of 367 children listed for orthotopic liver transplantation (OLT) in our centre during the past decade. RESULTS: Data on 30 children (15 boys, 15 girls) were compiled for retrospective analysis, and data on dialysis feasibility and efficacy were available for 26 of these. Median age was 3.5 (range 0.4-17.7) years. Median MELD (Model For End-Stage Liver Disease) score was 33. dAKI was caused by hepato-renal syndrome in 16 of the 30 children. Twenty-one patients were treated with continuous veno-venous haemofiltration (CVVH), and nine patients received peritoneal dialysis (PD). Overall mortality was 77%. Mortality within the PD-group was 100 % versus 67% in the CVVH-group (p = 0.039). Urea reduction rate within the first 24 h of treatment was 12.9% in the PD group and 23.5% in the CVVH group (p = 0.019). CONCLUSIONS: Children with end stage liver disease have a high risk for dAKI associated with high mortality. CVVH is associated with better efficacy and less mortality than PD. PMID- 26227630 TI - Associations of the eNOS G894T gene polymorphism with target organ damage in children with newly diagnosed primary hypertension. AB - BACKGROUND: The endothelial nitric oxide synthase (eNOS) G894T gene polymorphism is associated with the risk of primary hypertension (PH) and vascular complications in adults with PH. METHODS: We explored the associations of the G894T polymorphism with 24-h ambulatory blood pressure, left ventricular mass (LVM), carotid intima media thickness (cIMT), urinary albumin excretion, oxidative stress and inflammatory parameters in 126 children with newly diagnosed PH and in 83 healthy children. RESULTS: Among the 126 children with PH 92 (73%) had ambulatory hypertension and 34 (27%) had severe ambulatory hypertension. Left ventricular hypertrophy (LVH) was detected in 39 (31%) patients, cIMT of >2 standard deviation scores in 21 (16.6%) patients, albuminuria of >30 mg/24 h in 18 (14.3%) patients and metabolic syndrome (MS) in 22 (17.5%) patients. The frequency of the T allele was 52.4% in the PH group and 54.2% in the control group (not significant), and in both groups the frequency of the T allele was consistent with the Hardy-Weinberg equilibrium. Compared with G allele carriers, hypertensive T allele carriers had increased cIMT (p < 0.05) and more severe albuminuria (not significant, p = 0.1); there was no difference between the groups in hypertension severity and LVM. T and G allele distribution did not differ between patients with and without metabolic syndrome. No significant correlations between the assessed parameters and the eNOS G894T gene polymorphism were found in the controls, although T allele carriers tended to have an increased cIMT (p = 0.09). CONCLUSION: The eNOS T allele is not more prevalent among hypertensive children than among healthy ones, but it is associated with early vascular damage in children with PH, independent of metabolic abnormalities. No associations between the eNOS G894T polymorphism and metabolic abnormalities were found. PMID- 26227632 TI - Mucor Thrombus. AB - BACKGROUND: To describe a rare presentation of ischemic stroke secondary to angioinvasive mucormycosis and endovascular retrieval of mycotic thrombus with stenting of the compressed vessel. SUMMARY OF CASE: We report a case of angioinvasive mucormycosis that externally compressed and invaded the internal carotid artery causing ischemic cerebral infarction. A sample of the thrombus was obtained using a stent retriever. Subsequent pathological analysis was shown to be consistent with the diagnosis of angioinvasive mucormycosis. The thrombosed and compressed segment was recanalized with the deployment of a stent. CONCLUSIONS: The endovascular placement of an expandable stent in the setting of angioinvasive mucormycosis restored good cerebral blood flow in a proximal internal carotid artery occlusion. The patient's aphasia resolved following this intervention. Artifacts of CT angiography may result in the overestimation of acute arterial occlusions. Endovascular carotid stenting may be a palliative measure in the setting of angioinvasive rhino-cerebro-orbital mucormycosis. PMID- 26227633 TI - Geographically contrasting biodiversity reductions in a widespread New Zealand seabird. AB - Unravelling prehistoric anthropogenic impacts on biodiversity represents a key challenge for biologists and archaeologists. New Zealand's endemic Stewart Island Shag (Leucocarbo chalconotus) comprises two distinct phylogeographic lineages, currently restricted to the country's south and southeast. However, fossil and archaeological remains suggest a far more widespread distribution at the time of Polynesian settlement ca. 1280 AD, encompassing much of coastal South Island. We used modern and ancient DNA, radiocarbon dating, and Bayesian modelling, to assess the impacts of human arrival on this taxon. Our analyses show that the southeast South Island (Otago) lineage was formerly widespread across coastal South Island, but experienced dramatic population extinctions, range retraction and lineage loss soon after human arrival. By comparison, the southernmost (Foveaux Strait) lineage has experienced a relatively stable demographic and biogeographic history since human arrival, retaining much of its mitochondrial diversity. Archaeological data suggest that these contrasting demographic histories (retraction vs. stability) reflect differential human impacts in mainland South Island vs. Foveaux Strait, highlighting the importance of testing for temporal and spatial variation in human-driven faunal declines. PMID- 26227631 TI - Genetic instability in the tumor microenvironment: a new look at an old neighbor. AB - The recent exponential increase in our knowledge of cellular and molecular mechanisms involved in carcinogenesis has largely failed to translate into new therapies and clinical practices. This lack of success may result in part from the fact that most studies focus on tumor cells as potential therapeutic targets and neglect the complex microenvironment that undergoes profound changes during tumor development. Furthermore, an unfortunate association of factors such as tumor genetic complexity, overestimation of biomarker and drug potentials, as well as a poor understanding of tumor microenvironment in diagnosis and prognosis leads to the current levels of treatment failure regarding a vast majority of cancer types. A growing body of evidence points to the importance of the functional diversity of immune and structural cells during tumor development. In this sense, the lack of technologies that would allow for molecular screening of individual stromal cell types poses a major challenge for the development of therapies targeting the tumor microenvironment. Progress in microenvironment genetic studies represents a formidable opportunity for the development of new selective drugs because stromal cells have lower mutation rates than malignant cells, and should prove to be good targets for therapy. PMID- 26227636 TI - Fifty-one million: A mythical number that matters. PMID- 26227634 TI - Secular trend analysis of lung cancer incidence in Sihui city, China between 1987 and 2011. AB - BACKGROUND: With industrial and econom ic development in recent decades in South China, cancer incidence may have changed due to the changing lifestyle and environment. However, the trends of lung cancer and the roles of smoking and other environmental risk factors in the development of lung cancer in rural areas of South China remain unclear. The purpose of this study was to explore the lung cancer incidence trends and the possible causes of these trends. METHODS: Joinpoint regression analysis and the age-period-cohort (APC) model were used to analyze the lung cancer incidence trends in Sihui, Guangdong province, China between 1987 and 2011, and explore the possible causes of these trends. RESULTS: A total of 2,397 lung cancer patients were involved in this study. A 3-fold increase in the incidence of lung cancer in both sexes was observed over the 25 year period. Joinpoint regression analysis showed that while the incidence continued to increase steadily in females during the entire period, a sharp acceleration was observed in males starting in 2005. The full APC model was selected to describe age, period, and birth cohort effects on lung cancer incidence trends in Sihui. The age cohorts in both sexes showed a continuously significant increase in the relative risk (RR) of lung cancer, with a peak in the eldest age group (80-84 years). The RR of lung cancer showed a fluctuating curve in both sexes. The birth cohorts identified an increased trend in both males and females; however, males had a plateau in the youngest cohorts who were born during 1955-1969. CONCLUSIONS: Increasing trends of the incidence of lung cancer in Sihui were dominated by the effects of age and birth cohorts. Social aging, smoking, and environmental changes may play important roles in such trends. PMID- 26227635 TI - The GPR55 antagonist CID16020046 protects against intestinal inflammation. AB - BACKGROUND: G protein-coupled receptor 55 (GPR55) is a lysophospholipid receptor responsive to certain cannabinoids. The role of GPR55 in inflammatory processes of the gut is largely unknown. Using the recently characterized GPR55 inhibitor CID16020046, we determined the role of GPR55 in experimental intestinal inflammation and explored possible mechanisms of action. METHODS: Colitis was induced by either 2.5% dextran sulfate sodium (DSS) supplemented in the drinking water of C57BL/6 mice or by a single intrarectal application of trinitrobenzene sulfonic acid (TNBS). KEY RESULTS: Daily application of CID16020046 (20 mg/kg) significantly reduced inflammation scores and myeloperoxidase (MPO) activity. In the DSS colitis model, levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1beta), and the expression of cyclooxygenase (Cox)-2 and signal transducer and activator of transcription 3 (STAT-3) were reduced in colon tissues while in TNBS-induced colitis, levels of Cox-2, IL-1beta and IL-6 were significantly lowered. Evaluation of leukocyte recruitment by flow cytometry indicated reduced presence of lymphocytes and macrophages in the colon following GPR55 inhibition in DSS-induced colitis. In J774A.1 mouse macrophages, inhibition of GPR55 revealed reduced migration of macrophages and decreased CD11b expression, suggesting that direct effects of CID16020046 on macrophages may have contributed to the improvement of colitis. GPR55(-/-) knockout mice showed reduced inflammation scores as compared to wild type mice in the DSS model suggesting a pro-inflammatory role in intestinal inflammation. CONCLUSIONS & INFERENCES: Pharmacological blockade of GPR55 reduces experimental intestinal inflammation by reducing leukocyte migration and activation, in particular that of macrophages. Therefore, CID16020046 represents a possible drug for the treatment of bowel inflammation. PMID- 26227637 TI - Author's response. PMID- 26227638 TI - Show, don't tell. PMID- 26227639 TI - Dentistry in the modern era. PMID- 26227640 TI - Ethical decision making. PMID- 26227641 TI - Author's response. PMID- 26227642 TI - Pregnancy outcome after in utero exposure to local anesthetics as part of dental treatment: A prospective comparative cohort study. AB - BACKGROUND: Dental treatment and use of local anesthetics during pregnancy generally are considered harmless because of lack of evidence of adverse pregnancy effects. Data on the safety of dental treatment and local anesthetics during pregnancy are scant. Dental care is often a reason for concern both among women and their health care providers. The primary objective of this study was to evaluate the rate of major anomalies after exposure to local anesthetics as part of dental care during pregnancy. METHODS: The authors performed a prospective, comparative observational study at the Israeli Teratology Information Services between 1999 and 2005. RESULTS: The authors followed 210 pregnancies exposed to dental local anesthetics (112 [53%] in the first trimester) and compared them with 794 pregnancies not exposed to teratogens. The rate of major anomalies was not significantly different between the groups (4.8% versus 3.3%, P = .300). There was no difference in the rate of miscarriages, gestational age at delivery, or birth weight. The most common types of dental treatment were endodontic treatment (43%), tooth extraction (31%), and tooth restoration (21%). Most women (63%) were not exposed to additional medications. Approximately one-half (51%) of the women were not exposed to dental radiography, and 44% were exposed to radiation, mostly bite-wing radiography. CONCLUSIONS: This study's results suggest that use of dental local anesthetics, as well as dental treatment during pregnancy, do not represent a major teratogenic risk. PRACTICAL IMPLICATIONS: There seems to be no reason to prevent pregnant women from receiving dental treatment and local anesthetics during pregnancy. PMID- 26227643 TI - Measuring quality of dental care: Caries prevention services for children. AB - BACKGROUND: The authors conducted a study to validate the following 3 evidence based, process-of-care quality measures focused on dental caries prevention for children with an elevated risk of experiencing caries: sealants for 6- to 9-year olds, sealants for 10- to 14-year-olds, and topical fluoride. METHODS: Using evidence-based guidelines, the Dental Quality Alliance developed measures for implementation with administrative data at the plan and program levels. To validate the measures, the authors used data from the Florida and Texas Medicaid programs and Children's Health Insurance Programs and from national commercial dental benefit plans. Data were extracted from 414 randomly selected dental office records to validate the use of administrative data to accurately calculate the measures. The authors also assessed statistically significant variations in overall measure performance. RESULTS: Agreement between administrative data and dental records was 95% for sealants (kappa = 0.82) and 90% for topical fluoride (kappa = 0.78). Sensitivity and specificity were 90.7% and 88.5% for topical fluoride and 77.8% and 98.8% for sealants, respectively. Variation in overall measure performance was greatest for topical fluoride (chi(2) = 5,887.1; P < .01); 18% to 37% of children with an elevated risk of experiencing caries received at least 2 topical fluoride applications during the reporting year. Although there was greater variation in performance for sealants for 6- to 9-year olds (range, 21.0-31.3%; chi(2) = 548.6; P < .01) compared with sealants for 10- to 14-year-olds (range, 8.4-11.1%; chi(2) = 22.7; P < .01), overall sealant placement rates were lower for 10- to 14-year-olds. CONCLUSIONS: These evidence based, caries prevention process-of-care quality measures can be implemented feasibly and validly using administrative claims data. PRACTICAL IMPLICATIONS: The measures can be used to assess, monitor, and improve the proportion of children with an elevated risk of experiencing dental caries who receive evidence based caries prevention services. PMID- 26227644 TI - Association between immunologic parameters, glycemic control, and postextraction complications in patients with type 2 diabetes. AB - BACKGROUND: The purpose of this study was to assess the association between metabolic control and immune dysfunction, and postoperative complications and wound healing after dental extractions in people with type 2 diabetes and control participants. METHODS: The authors performed a prospective, case-control study enrolling 53 participants with type 2 diabetes and 29 participants who did not have type 2 diabetes. Exclusion criteria included being a smoker and having teeth with periodontal pockets deeper than 4 millimeters, among others. All participants underwent an extraction of 1 erupted tooth. The investigators assessed patients' signs and symptoms at 3, 7, 21, and 60 days after surgery. The investigators measured glycemic control and immunologic profile at the time of the extraction. They compared the pattern of healing and the incidence of postextraction complications between the 2 groups. RESULTS: Even in the presence of impaired neutrophil function and poor glycemic control, we found no increase in the number of postoperative complications. There was no association between delayed wound epithelialization on postoperative day 21 and level of glycemic control, and reduced neutrophil function. On postoperative day 60, all alveolar sockets were epithelialized completely and showed no signs of infection. CONCLUSIONS: The study results suggest that type 2 diabetes per se or glycemic control is not a risk factor for experiencing postoperative complications in people undergoing dental extractions. Although people with type 2 diabetes may have impaired neutrophil function, the study results revealed that having this condition was not associated with an increased risk of experiencing postoperative complications. Additional research studies with larger sample sizes of patients who have diabetes are needed to confirm this study's findings. PRACTICAL IMPLICATIONS: The results allow clinicians to infer that people with type 2 diabetes undergoing dental extractions of erupted teeth that do not have an acute odontogenic infection should not receive antibiotic prophylaxis simply because of their diabetic status or level of glycemic control. PMID- 26227645 TI - Practice settings and dentists' job satisfaction. AB - BACKGROUND: The nature and organization of dental practice is changing. The aim of this study was to explore how job satisfaction among dentists is associated with dental practice setting. METHODS: A survey measured satisfaction with income, benefits, hours worked, clinical autonomy, work-life balance, emotional exhaustion, and overall satisfaction among dentists working in large group, small group, and solo practice settings; 2,171 dentists responded. The authors used logistic regression to measure differences in reported levels of satisfaction across practice settings. RESULTS: Dentists working in small group settings reported the most satisfaction overall. Dentists working in large group settings reported more satisfaction with income and benefits than dentists in solo practice, as well as having the least stress. CONCLUSIONS: Findings suggest possible advantages and disadvantages of working in different types of practice settings. PRACTICAL IMPLICATIONS: Dentists working in different practice settings reported differences in satisfaction. These results may help dentists decide which practice setting is best for them. PMID- 26227646 TI - Meta-analysis of the effect of an essential oil-containing mouthrinse on gingivitis and plaque. AB - BACKGROUND: Standard recommendations for oral hygiene practices have focused on mechanical methods (toothbrushing and interdental cleaning). Published evidence indicates antimicrobial mouthrinses provide oral health benefits beyond mechanical methods alone. The purpose of this meta-analysis was to evaluate the combined effectiveness of mechanical methods with essential oil-containing mouthrinses (MMEO) versus mechanical methods (MM) alone in achieving site specific, healthy gingival tissue and reducing plaque and gingivitis. TYPES OF STUDIES REVIEWED: All industry-sponsored clinical trials investigating the antigingivitis and antiplaque effects of essential oil (EO)-containing mouthrinses conducted from 1980 to 2012 were reviewed; 29 of 32 studies met the inclusion criteria of 6 months or longer duration, randomized, observer-masked, placebo-controlled, and with individual-level site-specific data. By-study treatment effects were estimated through generalized linear models for binary data and analysis of covariance for continuous data, and then combined using standard meta-analysis techniques; heterogeneity was also assessed. RESULTS: Summary odds ratios for a healthy gingival site and for a plaque-free site were, respectively, 5.0 (95% confidence interval [CI], 3.3-7.5) and 7.8 (95% CI, 5.4 11.2) for MMEO participants versus MM participants at 6 months. The summary percentage reductions in whole-mouth mean gingivitis and plaque at 6 months were 16.0 (95% CI, 11.3-20.7) and 27.7 (95% CI, 22.4-32.9), respectively. Responder analyses using aggregate individual-level data showed 44.8% of MMEO participants and 14.4% of MM participants achieved at least 50% healthy sites in their mouths at 6 months. Similarly, 36.9% of MMEO participants and 5.5% of MM participants achieved at least 50% plaque-free sites in their mouths at 6 months. CONCLUSIONS AND PRACTICAL IMPLICATIONS: This is the first meta-analysis to demonstrate the clinically significant, site-specific benefit of adjunctive EO treatment in people within a 6-month period (that is, between dental visits). PMID- 26227647 TI - A practical approach to evidence-based dentistry: VIII: How to appraise an article based on a qualitative study. AB - BACKGROUND AND OVERVIEW: Because of qualitative researchers' abilities to explore social problems and to understand the perspective of patients, qualitative research studies are useful to provide insight about patients' fears, worries, goals, and expectations related to dental care. To benefit fully from such studies, clinicians should be aware of some relevant principles of critical appraisal. In this article, the authors present one approach to critically appraise the evidence from a qualitative research study. PRACTICAL IMPLICATIONS: Critical appraisal involves assessing whether the results are credible (the selection of participants, research ethics, data collection, data analysis), what are these results, and how they can be applied in clinical practice. The authors also examined how the results could be applied to patient care in terms of offering theory, understanding the context of clinical practice, and helping clinicians understand social interactions in clinical care. By applying these principles, clinicians can consider qualitative studies when trying to achieve the best possible results for their own practices. PMID- 26227648 TI - Nonsurgical periodontal therapy to treat a case of severe periodontitis: A 12 year follow-up. AB - BACKGROUND AND OVERVIEW: This case report describes the successful treatment of a severe chronic periodontitis case by nonsurgical therapy and a strict maintenance program over a 12-year period. CASE DESCRIPTION: A 38-year-old man concerned about the protrusion of his maxillary incisors was referred for periodontal treatment. The teeth in the maxillary arch had generalized severe chronic periodontitis. Several treatment options were presented to the patient including the most aggressive, extraction of all maxillary teeth, and the most conservative, scaling and root planing. The patient opted to having the most conservative approach, even though the prognoses for the maxillary teeth were unfavorable. Therefore, he received nonsurgical therapy via scaling and root planing combined with systemic antibiotics before referral to an orthodontist to address the esthetic concerns. The maxillary dentition was treated with orthodontic therapy to retract and align the maxillary anterior segment. Periodontal maintenance (1-hour session), including subgingival instrumentation, was performed 4 times per year until the end of the 12-year follow-up period. The patient only missed 2 appointments in 12 years. Twelve years later, the results revealed that all but 1 maxillary tooth were maintained in a state of acceptable health, function, and esthetics. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Although most would agree with the initial poor prognosis of this patient's case, nonsurgical periodontal therapy was utilized with a 3-month periodontal maintenance program and demonstrated long-term success. The outcome presented in this case report may only have been possible because of patient compliance, professional experience, skill, and supervision throughout the course of treatment. PMID- 26227649 TI - Insufficient evidence exists regarding the reduction of cervical dentin hypersensitivity with surgical root coverage procedures. PMID- 26227650 TI - Solving dentistry's 'busyness' problem. PMID- 26227651 TI - How to improve staff morale. PMID- 26227652 TI - Justifiable criticism and dental amalgam. PMID- 26227653 TI - FOR THE PATIENT. Drink up!: Fluoridated water helps fight decay. PMID- 26227654 TI - Pleuropulmonary Blastoma in a Neonate Diagnosed Prenatally as Congenital Pulmonary Airway Malformation. AB - Pleuropulmonary blastoma is an extremely rare lung neoplasm exclusive to children under 5 years of age. It presents a diagnostic challenge both prenatally and in early childhood due to its similarity to benign lung cysts, which are managed differently. We present the first case, to our knowledge, of a neonate with pleuropulmonary blastoma and myelomeningocele, though prenatally diagnosed as a congenital pulmonary airway malformation. We detail the prenatal imaging that facilitated counseling and delivery management in addition to the correlating postnatal imaging. PMID- 26227655 TI - Do we reach the patients with the most problems? Baseline data from the WebCan study among survivors of head-and-neck cancer, Denmark. AB - PURPOSE: This study seeks to assess the differences in disease and socioeconomic characteristics, late effects and long-term quality of life (QoL) after head-and neck cancer (HNC) among participants and non-participants. METHODS: Five hundred sixty recurrence-free survivors treated for HNC at least 6 months previously were invited to participate in a repeated measure, controlled intervention study of computerized Patient Reported Outcome (PRO), which is provided to treating physicians at the point of care. Two hundred sixty-six consented to participate, and 292 declined; of those who declined, 103 filled in the baseline questionnaire. Late effects and QoL were evaluated on the EORTC QLQ C-30 and EORTC QLQ H&N35 and HADS questionnaires, and an empirically derived symptom list was prepared with hospital clinicians. RESULTS: Participants were younger, had a higher educational level, were more likely to cohabit, less likely to smoke, used less alcohol and were more likely to have HPV than those who declined but did not differ by gender, cancer site, stage or time since diagnosis. Participants reported significantly better QoL and functioning and less severe symptoms than those who declined participation other than filling in the baseline questionnaire. CONCLUSIONS: Late symptoms are common in HNC survivors. A wide diversity of self-reported late effects was found in this trial with participants significantly less affected than non-participants. IMPLICATIONS FOR CANCER SURVIVORS: Generalizable data on non-participation may aid in the interpretation of studies on HNC survivors in general and may have relevance for targeting recruitment and maintenance in rehabilitation and follow-up care, outside clinical trials. PMID- 26227656 TI - Altered Th17/Treg balance and dysregulated IL-1beta response influence susceptibility/resistance to experimental autoimmune arthritis. AB - This study was aimed at gaining an insight into immune mechanisms of differential susceptibility to autoimmunity of individuals sharing the same major histocompatibility complex by studying arthritis-susceptible Lewis (LEW) and arthritis-resistant Wistar Kyoto (WKY) rats (both RT.1(l)) using the adjuvant arthritis (AA) model of rheumatoid arthritis (RA). Lymph node cells (LNC) and synovium-infiltrating cells (SIC) of LEW and WKY rat subjected to an arthritogenic challenge were tested. The frequency of T helper 17 (Th17) and T regulatory (Treg) cells was determined by flow cytometry, whereas serum and spleen adherent cell (SAC)-derived supernatant were analyzed for specific cytokines and chemokines. We observed that WKY rats are not deficient in generating a Th17 response to the arthritogenic challenge in LNC (periphery); however, the Th17/Treg ratio is markedly reduced in the joint (target organ) of WKY versus LEW rats because of reduced Th17 levels therein in WKY rats. These results suggest differential and selective decrease in Th17 cell migration into the joints of WKY rats. Interestingly, serum levels of chemokines RANTES and MCP 1 were reduced in WKY rats. Furthermore, WKY rats showed reduced serum IL-1beta level in vivo but no defect in IL-1beta production by SAC in vitro, suggesting an effective in vivo regulation of IL-1beta response. We also unraveled the role of interferon-gamma (IFNgamma), which we have previously reported to be increased in WKY versus LEW rats, in regulation of IL-1beta. Thus, reduced Th17/Treg ratio in the target organ (joints) and decreased systemic IL-1beta might contribute to the AA-resistance of WKY rats; whereas the converse factors render LEW more vulnerable to AA. PMID- 26227657 TI - Thyroidectomy: Natural drainage or negative drainage? Experience with randomized single-center study. AB - AIM: The aim is to investigate, in relation to the volume of blood drained, which type drainage to use after thyroidectomy natural drainage or negative drainage. MATERIAL OF STUDY: 141 patients who underwent total thyroidectomy for multinodular thyroid disease between 22 November 2012 and 7 November 2013 were included in the present study. For the 141 patients a randomized method was used with closed circuit natural drainage (59 cases) or negative drainage (82 cases). The evaluation of the drained volume was performed 24, 48 and 72 hours following surgery. RESULTS: The amount of blood drained during the first 24 hours of the postoperative period averaged 78.59 ml in patients with a negative drain and 54.24 ml in those under natural drainage. After 48 hours, the total volume in the first group was 117.98 ml, while in the second group it was 85.18 ml. In cases where the observation was prolonged up to 72 hours, the average volume was 217 ml in the 10 cases of negative drainage and 117.5 ml in the 4 cases of natural drainage. CONCLUSION: The difference in blood volume observed between the two groups of patients with natural drainage and negative drainage, leads us to conclude that the best drainage in thyroidectomy is the natural one, diverging from the older concept of the use of negative drainage in superficial cavities. PMID- 26227658 TI - Socio-economic determinants of disease progression among HIV infected adults in Kenya. AB - BACKGROUND: Socioeconomic determinants have been shown to have an effect on the progression of HIV disease evidenced by studies carried out largely in developed countries. Knowledge of these factors could inform on prioritization of populations during scale up of highly active antiretroviral therapy (HAART) constrained health systems. The objective of this study was to identify socioeconomic correlates of HIV disease progression in an adult Kenyan population. METHODS: We analysed data from 312 HIV positive individuals, drawn from a cohort enrolled in a randomized clinical trial investigating the effectiveness of Acyclovir in the prevention of HIV transmission among serodiscordant couples. In this study we included individuals with CD4 counts >= 350 cells/mm(3) and World Health Organization (WHO), clinical stage one or two. The exposure variables measured were: - daily household income available for expenditure, age, gender, housing type and level of formal education. We used a composite outcome of disease progression to WHO clinical stage 3 or 4 or a laboratory outcome of CD4 count below 350 cells/mm(3) after two years of follow up. Logistic regression was used to determine associations of variables that were found to be significant at univariate analysis, and to control for potential confounders. RESULTS: Seventy eight (25 %) individuals reported HIV disease progression. Majority (79.9 %) were female. The median age was 30 year and 93.6 % had attained a primary level of education. Median CD4 at enrolment into the clinical trial was 564 cells/mm(3); those who had disease progression were enrolled with a significantly (p < 0.001) lower CD4 count. Daily household income available for expenditure adjusted for CD4 count at enrolment was associated significantly (p = 0.04) with HIV disease progression. Disease progression was five times more likely to occur in study subjects with daily income available for expenditure of less than US$1 compared to those with more than US$ 5 available for daily expenditure [adjusted Odds Ratio 4.6 (95 % Confidence Interval 1.4 14.4)]. Disease progression was not associated with age, gender, type of housing or level of education attained (p < 0.05). CONCLUSION: Populations with low household incomes should be considered vulnerable to disease progression and should therefore be prioritized during the scale up of HAART for treatment as prevention. PMID- 26227659 TI - An overview of the efficacy of resveratrol in the management of ischemic heart disease. AB - Ischemic heart disease is a leading cause of cardiac dysfunction and subsequent morbidity and mortality around the world. New therapies are required to complement or enhance the existing treatment regimen for the management of ischemic heart disease-related clinical complications. In this regard, compounds derived from natural sources have recently gained attention for their cardioprotective properties. In particular, the potential of food-derived compounds that exhibit medicinal properties (termed nutraceuticals) appears promising, an example being the plant polyphenol resveratrol. In the past two decades, many preclinical and a few pilot clinical studies have shown that resveratrol is beneficial in protecting against cardiovascular disease. In this short review, we will discuss current evidence on the efficacy of resveratrol in preventing or reversing deleterious effects on the heart in the setting of ischemic heart disease. PMID- 26227660 TI - Which came first: The lizard or the egg? Robustness in phylogenetic reconstruction of ancestral states. AB - Changes in parity mode between egg-laying (oviparity) and live-bearing (viviparity) have occurred repeatedly throughout vertebrate evolution. Oviparity is the ancestral amniote state, and viviparity has evolved many times independently within amniotes (especially in lizards and snakes), with possibly a few reversions to oviparity. In amniotes, the shelled egg is considered a complex structure that is unlikely to re-evolve if lost (i.e., it is an example of Dollo's Principle). However, a recent ancestral state reconstruction analysis concluded that viviparity was the ancestral state of squamate reptiles (lizards and snakes), and that oviparity re-evolved from viviparity many times throughout the evolutionary history of squamates. Here, we re-evaluate support for this provocative conclusion by testing the sensitivity of the analysis to model assumptions and estimates of squamate phylogeny. We found that the models and methods used for parity mode reconstruction are highly sensitive to the specific estimate of phylogeny used, and that the point estimate of phylogeny used to suggest that viviparity is the root state of the squamate tree is far from an optimal phylogenetic solution. The ancestral state reconstructions are also highly sensitive to model choice and specific values of model parameters. A method that is designed to account for biases in taxon sampling actually accentuates, rather than lessens, those biases with respect to ancestral state reconstructions. In contrast to recent conclusions from the same data set, we find that ancestral state reconstruction analyses provide highly equivocal support for the number and direction of transitions between oviparity and viviparity in squamates. Moreover, the reconstructions of ancestral parity state are highly dependent on the assumptions of each model. We conclude that the common ancestor of squamates was oviparous, and subsequent evolutionary transitions to viviparity were common, but reversals to oviparity were rare. The three putative reversals to oviparity with the strongest phylogenetic support occurred in the snakes Eryx jayakari and Lachesis, and the lizard, Liolaemus calchaqui. Our results emphasize that because the conclusions of ancestral state reconstruction studies are often highly sensitive to the methods and assumptions of analysis, researchers should carefully consider this sensitivity when evaluating alternative hypotheses of character-state evolution. PMID- 26227661 TI - Seeing is believing but quantifying is deciding. PMID- 26227662 TI - Popliteal sentinel lymph node involvement in melanoma patients. AB - BACKGROUND: Sentinel lymph nodes (SLN) in popliteal basins are rare, and there is controversy in literature regarding their origin, management, and outcomes. OBJECTIVES: To correlate clinical and pathological features of popliteal basin drainage and analyze the impact of popliteal lymph node drainage on survival. MATERIALS AND METHODS: Retrospective analysis of SLN biopsies performed at a single institution between 2000 and 2010. RESULTS: SLN biopsies were performed in 254 patients with melanoma in lower limbs, 247 of which were evaluated. In this group, there were 59 patients (24%) with a positive SLN. Twenty-seven cases (11%) presented with popliteal drainage, one of which lacked concurrent groin drainage. Among these 27 patients, three (11%) had popliteal metastasis, one of which had exclusive involvement of this basin. Popliteal drainage was associated with worse 5-year disease-free survival (DFS) (P = 0.028) but not 5-year overall survival (OS) (P = 0.219) in univariate analysis. In multivariate analysis, Breslow thickness, mitotic index, and positive SLN were prognostic factors for DFS. Only mitotic index correlated significantly with OS (P = 0.044). CONCLUSIONS: Popliteal drainage seems to be associated with worse prognostic features of the primary tumor. PMID- 26227663 TI - The Role of Fludrocortisone in Cognition and Mood in Patients with Primary Adrenal Insufficiency (Addison's Disease). AB - BACKGROUND: Primary adrenal insufficiency (AI) requires hormone replacement therapy with fludrocortisone and hydrocortisone stimulating glucocorticoid (GR) and mineralocorticoid receptors (MR). Evidence from animal and human studies shows that MR function is crucial for cognitive function and mood. Regarding patients with AI, very little is known about the role of MR in cognitive function and mood. METHODS: A repeated-measures within-subject design was used to determine whether cognitive function and mood are related to MR occupation in patients with AI. Intraindividually, patients were examined twice, with 1 week between testing days: once with fludrocortisone (high MR occupation) and once without fludrocortisone (low MR occupation). All patients kept their stable regimen of hydrocortisone. The assessment of cognitive function included executive function, attention, and verbal, visuospatial and working memory. Additionally, mood and blood pressure were measured. RESULTS: Verbal memory improved significantly during high MR occupation (after fludrocortisone intake) compared to low MR occupation [without fludrocortisone, t(29) = -2.1, p = 0.046]. There were trend level differences in the Number-Combination test [t(29) = -1.9, p = 0.074] and in the Stroop interference task [t(29) = -1.9, p = 0.068]. No significant differences in visuospatial and working memory were found. Furthermore, the current mood state was better during high MR occupation compared to low MR occupation [t(29) = -2.4, p = 0.023] as was diastolic blood pressure [F(2, 29) = 3.6, p = 0.07]. CONCLUSIONS: Cognitive function and mood in patients with AI depend in part on MR occupation. Because the medium effect size indicates a potential clinical significance, further studies should systematically examine which dosages of fludrocortisone are associated with optimal cognitive function and mood in AI patients. PMID- 26227664 TI - Isolated cell behavior drives the evolution of antibiotic resistance. AB - Bacterial antibiotic resistance is typically quantified by the minimum inhibitory concentration (MIC), which is defined as the minimal concentration of antibiotic that inhibits bacterial growth starting from a standard cell density. However, when antibiotic resistance is mediated by degradation, the collective inactivation of antibiotic by the bacterial population can cause the measured MIC to depend strongly on the initial cell density. In cases where this inoculum effect is strong, the relationship between MIC and bacterial fitness in the antibiotic is not well defined. Here, we demonstrate that the resistance of a single, isolated cell-which we call the single-cell MIC (scMIC)-provides a superior metric for quantifying antibiotic resistance. Unlike the MIC, we find that the scMIC predicts the direction of selection and also specifies the antibiotic concentration at which selection begins to favor new mutants. Understanding the cooperative nature of bacterial growth in antibiotics is therefore essential in predicting the evolution of antibiotic resistance. PMID- 26227665 TI - Cancer type-dependent genetic interactions between cancer driver alterations indicate plasticity of epistasis across cell types. AB - Cancers, like many diseases, are normally caused by combinations of genetic alterations rather than by changes affecting single genes. It is well established that the genetic alterations that drive cancer often interact epistatically, having greater or weaker consequences in combination than expected from their individual effects. In a stringent statistical analysis of data from > 3,000 tumors, we find that the co-occurrence and mutual exclusivity relationships between cancer driver alterations change quite extensively in different types of cancer. This cannot be accounted for by variation in tumor heterogeneity or unrecognized cancer subtypes. Rather, it suggests that how genomic alterations interact cooperatively or partially redundantly to driver cancer changes in different types of cancers. This re-wiring of epistasis across cell types is likely to be a basic feature of genetic architecture, with important implications for understanding the evolution of multicellularity and human genetic diseases. In addition, if this plasticity of epistasis across cell types is also true for synthetic lethal interactions, a synthetic lethal strategy to kill cancer cells may frequently work in one type of cancer but prove ineffective in another. PMID- 26227666 TI - White globe appearance is a novel specific endoscopic marker for gastric cancer: A prospective study. AB - BACKGROUND AND AIM: White globe appearance (WGA) is a small white lesion with a globular shape that can be identified by magnifying endoscopy with narrow-band imaging (M-NBI). WGA was recently reported as a novel endoscopic marker that can differentiate between gastric cancer (GC) and low-grade adenoma. However, the usefulness of WGA for differentiating GC from non-cancerous lesions (NC), including those of gastritis, is unknown. METHODS: To compare the prevalence of WGA in GC and NC, we carried out a prospective study of 994 patients undergoing gastroscopy. All patients were examined for target lesions that were suspected to be GC. When a target lesion was detected, the presence or absence of WGA in the lesion was evaluated using M-NBI, and all target lesions were biopsied or resected for histopathological diagnosis. Primary endpoint was a comparison of WGA prevalence in GC and NC. Secondary endpoints included WGA diagnostic performance for diagnosing GC. RESULTS: A total of 188 target lesions from 156 patients were analyzed for WGA, and histopathological diagnoses included 70 cases of GC and 118 cases of NC. WGA prevalence in GC and NC was 21.4% (15/70) and 2.5% (3/118), respectively (P < 0.001). WGA diagnostic accuracy, sensitivity, and specificity for detecting GC were 69.1%, 21.4%, and 97.5%, respectively. CONCLUSIONS: WGA prevalence in GC is significantly higher than that in NC. Because WGA is highly specific for GC, the presence of WGA is useful to diagnose GC. PMID- 26227668 TI - PNA Molecular Beacons Assembled by Post-Synthetic Click Chemistry Functionalization. AB - To avoid the tedious synthesis of functionalized peptide nucleic acid (PNA) monomers for probe development, we proposed a simple approach to modify PNA oligomers by post-synthetic on-resin click chemistry. PNA molecular beacons (MBs) were prepared by incorporation of azide-containing monomers into the oligomer by automatic solid-phase peptide synthesis and subsequent derivatization with pyrene moieties by copper-catalyzed azide-alkyne cycloaddition. Two pyrene-based quencher-free PNA molecular beacons, a stemless MB and one possessing a stem-loop structure, targeting a portion of the cystic fibrosis gene, were successfully synthesized by using this method. Fluorescence studies showed that the stem-loop MB exhibited better discrimination of changes in excimer/monomer ratios as compared to the stemless MB construct. PMID- 26227667 TI - Guanine polynucleotides are self-antigens for human natural autoantibodies and are significantly reduced in the human genome. AB - In the course of investigating anti-DNA autoantibodies, we examined IgM and IgG antibodies to poly-G and other oligonucleotides in the sera of healthy persons and those diagnosed with systemic lupus erythematosus (SLE), scleroderma (SSc), or pemphigus vulgaris (PV); we used an antigen microarray and informatic analysis. We now report that all of the 135 humans studied, irrespective of health or autoimmune disease, manifested relatively high amounts of IgG antibodies binding to the 20-mer G oligonucleotide (G20); no participants entirely lacked this reactivity. IgG antibodies to homo-nucleotides A20, C20 or T20 were present only in the sera of SLE patients who were positive for antibodies to dsDNA. The prevalence of anti-G20 antibodies led us to survey human, mouse and Drosophila melanogaster (fruit fly) genomes for runs of T20 and G20 or more: runs of T20 appear > 170,000 times compared with only 93 runs of G20 or more in the human genome; of these runs, 40 were close to brain-associated genes. Mouse and fruit fly genomes showed significantly lower T20/G20 ratios than did human genomes. Moreover, sera from both healthy and SLE mice contained relatively little or no anti-G20 antibodies; so natural anti-G20 antibodies appear to be characteristic of humans. These unexpected observations invite investigation of the immune functions of anti-G20 antibodies in human health and disease and of runs of G20 in the human genome. PMID- 26227669 TI - Prevalence of Primary Resistance of Helicobacter pylori to Clarithromycin and Levofloxacin in Southern Spain. AB - BACKGROUND: The eradication of Helicobacter pylori (HP) using clarithromycin (CLA)-based triple therapy depends on the resistance of HP to antibiotics. The Maastricht III conference recommends the implementation of locoregional surveillance programmes for primary resistance of HP to CLA. In Andalusia, there are no previous data in this respect. The aim of this study was to determine the prevalence of the primary resistance of HP to CLA and levofloxacin (LF) in southern Spain. METHODS: Multicentre cross sectional study was carried out in 6 hospitals in Andalusia. Patients of both sexes numbering 401 were included (male 48%), aged 18-80 years and naive to HP eradication. Resistance of HP to CLA (CLAr) and LF (LFr) was assessed by determining mutations by PCR: mutations of the 23S rRNA gene define CLAr and mutations of the gene gyrA define LFr. Four hundred one gastric samples were collected. CLAr was detected in 72 patients (17.9%) and LFr was detected in 56 patients (13.9%). Heteroresistance was detected for both antibiotics: CLA 37/72 (51.3%) and LF 28/56 (50%). Variability for CLAr was detected among the centres, ranging from 11.5% to 24.7% without statistical significance (p = 0.12). Female sex was related to CLAr. CONCLUSIONS: In Andalusia, there is a high rate of primary CLAr and LFr. CLA-based triple therapy should be avoided as the primary eradication regimen in this region. There is a wide variability in the rate of CLAr among centres. PMID- 26227670 TI - Indicaxanthin from Opuntia ficus-indica Crosses the Blood-Brain Barrier and Modulates Neuronal Bioelectric Activity in Rat Hippocampus at Dietary-Consistent Amounts. AB - Indicaxanthin is a bioactive and bioavailable betalain pigment from the Opuntia ficus-indica fruits. In this in vivo study, kinetic measurements showed that indicaxanthin is revealed in the rat brain within 1 h from oral administration of 2 MUmol/kg, an amount compatible with a dietary consumption of cactus pear fruits in humans. A peak (20 +/- 2.4 ng of indicaxanthin per whole brain) was measured after 2.5 h; thereafter the molecule disappeared with first order kinetics within 4 h. The potential of indicaxanthin to affect neural activities was in vivo investigated by a microiontophoretic approach. Indicaxanthin, administered in a range between 0.085 ng and 0.34 ng per neuron, dose-dependently modulated the rate of discharge of spontaneously active neurons of the hippocampus, with reduction of the discharge and related changes of latency and duration of the effect. Indicaxanthin (0.34 ng/neuron) showed inhibitory effects on glutamate induced excitation, indicating activity at the level of glutamatergic synapses. A molecular target of indicaxanthin is suggested by in silico molecular modeling of indicaxanthin with N-methyl-D-aspartate receptor (NMDAR), the most represented of the glutamate receptor family in hippocampus. Therefore, at nutritionally compatible amounts indicaxanthin (i) crosses the rat BBB and accumulates in brain; (ii) can affect the bioelectric activity of hippocampal neurons locally treated with amounts comparable with those measured in the brain; and (iii) modulates glutamate-induced neuronal excitation. The potential of dietary indicaxanthin as a natural neuromodulatory agent deserves further mechanistic and neurophysiologic investigation. PMID- 26227671 TI - Biodegradation potential of polycyclic aromatic hydrocarbons by bacteria strains enriched from Yangtze River sediments. AB - Microbial degradation is an effective method for the removal of polycyclic aromatic hydrocarbons (PAHs) compounds from polluted sediments. Surface sediments collected from Yangtze River in the downtown area of Chongqing were found to contain PAH concentrations to various different degrees. Two bacteria strains (termed PJ1 and PJ2) isolated from the sediment samples could use phenanthrene (Phe) and fluoranthene (Flu) as carbon sources for growth thereby degrading these two PAH compounds. Using 16S rDNA gene sequencing, the isolates were identified as Sphingomonas sp. and Klebsiella sp., respectively. Biodegradation assays showed that the PJ1 presented an efficient degradation capability compared to PJ2 in cultures with the initial Phe and Flu concentrations ranging from 20 to 200 mg/L. The highest rates of Phe and Flu biodegradation by PJ1 reached 74.32% and 58.18% after incubation for 15 and 30 days, respectively. This is the first report on the biodegradation potential of the bacterial from surface sediments of an industrial area upstream of the Gorge Reservoir. PMID- 26227672 TI - Complications of gastrojejunal feeding tubes in children. AB - BACKGROUND: Long-term gastrojejunal (GJ) feeding is an increasingly popular alternative to gastric fundoplication for children with pathologic reflux, particularly those with neurologic impairment. We sought to evaluate morbidity associated with GJ feeding tubes in a large population of children. MATERIALS AND METHODS: The records of all children who underwent placement of a GJ feeding tube in a large children's hospital between January 2005 and September 2013 were reviewed. Indications for GJ feedings were noted. Events including a requirement for tube replacement and intestinal complications attributable to a GJ tube that required a laparotomy were evaluated. Risk factors for morbidity were assessed. RESULTS: A total of 124 children underwent GJ tube placement at an average age of 5.0 y (2 mo-16 y). Of the total, 83 (66%) subjects were neurologically impaired and 108 (87%) had gastroesophageal reflux. Of those, 55 (44%) had undergone prior laparoscopic fundoplication. Persistent reflux symptoms occurred in 22 (17.6%). Subjects underwent an average of 2.75 tube replacements per year and those under 2 y old had almost four. Four children (3.2%) required emergent laparotomy for intestinal perforation due to a GJ tube. These subjects were significantly younger (12 mo) than those without perforations (60.6 mo, P < 0.005). CONCLUSIONS: GJ feeding tubes were associated with notable morbidity ranging from persistent reflux to dislodgement and intestinal perforation. Together with issues of inconvenience with continuous feedings, these complications should be taken into account in children and particularly infants, in whom GJ feedings are being considered as an alternative to fundoplication. PMID- 26227673 TI - Thermal injury of the recurrent laryngeal nerve by THUNDERBEAT during thyroid surgery: findings from continuous intraoperative neuromonitoring in a porcine model. AB - BACKGROUND: Recurrent laryngeal nerve (RLN) palsy is the most common and serious complication of thyroid surgery. The use of energy-based devices (EBDs) has replaced hand-tying methods in many institutions. However, EBD use proximal to the RLN presents risks related to lateral thermal spread and associated nerve damage. THUNDERBEAT (TB) is one of the most widely used EBDs. This study aimed to test the safety of TB during thyroidectomy. METHODS: Four piglets weighing 30-40 kg experienced thyroidectomy while continuous electrophysiologic monitoring (continuous intraoperative neuromonitoring) occurred, using an electromyography endotracheal tube and NIM 3.0 response system. TB was applied at various distances from the RLN, and we assessed the safety of the protocols. RESULTS: Adverse electromyography events did not occur at distances >3 mm from the RLN. Amplitude decreased at 2 mm from the RLN after 8 s. However, immediate loss of signal occurred at 1 mm from the RLN, likely due to immediate shrinkage of surrounding tissue after TB application. CONCLUSIONS: TB can be used safely at 3 mm from the RLN but must be used for <8 s at more proximal locations. This is the first report assessing the safety of TB, and findings indicate that TB should be used at least 1 mm from the RLN to avoid injury. PMID- 26227674 TI - Complications of pelvic ring fixation in patients requiring laparotomy. AB - BACKGROUND: Pelvic ring disruptions in blunt trauma are rarely an isolated finding. Many individuals needing operative pelvic fixation also require laparotomy for other injuries. Pelvic fixation can be performed by open reduction and internal fixation (ORIF) or external fixation (Ex-fix). Often when a laparotomy incision is present, ORIF is performed by extending this incision. We hypothesized ORIF performed by extending the laparotomy incision would result in higher rates of ventral hernia and wound complications versus Ex-fix. METHODS: All patients admitted from 2004-June 2014 who underwent laparotomy and pelvic fixation either by ORIF through extension of a laparotomy incision (ORIF group) or definitive Ex-fix group were identified. Injury severity score, demographics, associated injuries, and complications were collected. RESULTS: A total of 35 patients were identified who underwent laparotomy and pelvic fixation, 21 underwent Ex-fix, whereas 14 underwent ORIF through an extended laparotomy incision. There were no differences in injury severity score, demographics, associated injuries, or rate of ventral hernia. The ORIF group had more laparotomy incision infections (50.0% versus 4.8%, P < 0.01) and pelvic abscesses (42.9% versus 9.5%, P < 0.05). They required more procedures to address their complications (13 versus 5, P < 0.05). CONCLUSIONS: Individuals who have undergone laparotomy and pelvic fixation are a complex group of patients with multiple injuries. These data suggest that when surgical repair of a pelvic ring disruption is indicated and the patient has undergone laparotomy, careful consideration to the method of fixation should be given. PMID- 26227675 TI - Moderate hypothermia ameliorates enterocyte mitochondrial dysfunction in severe shock and reperfusion. AB - BACKGROUND: Hypothermia can ameliorate ischemia-reperfusion-induced intestinal injury; however, whether the therapeutic mechanism of hypothermia on hemorrhagic shock, a severe condition of ischemia-reperfusion, is associated with mitochondrial protection in enterocytes is rarely reported. We aimed to evaluate the effects of hypothermia on mitochondria after shock-induced intestinal injury. MATERIALS AND METHODS: A severe hemorrhagic shock model was constructed in Sprague-Dawley rats at induced hypothermic (32 degrees C or 34 degrees C) or normothermic temperatures (37 degrees C), followed by resuscitation with whole shed blood and Ringer lactate (15 mg/kg body weight). After 2 h, 24 rats were killed and their intestinal tissue was collected; the remaining animals were returned to the normothermic environment to observe the survival time. RESULTS: There was severe mitochondrial dysfunction in the normothermia group, as well as increased oxidative stress and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling apoptotic index. As expected, hypothermia treatment decreased mitochondrial permeability transition pore opening and restored the mitochondrial membrane potential and intracellular adenosine triphosphate content. Furthermore, hypothermia elevated mitochondrial-reduced glutathione and decreased mitochondrial malondialdehyde; consistent with the restored mitochondrial function, intestinal cell apoptosis and intestinal histopathologic injury were attenuated, the systemic inflammatory response was mitigated, and survival time was significantly prolonged. Additionally, moderate-induced hypothermia (32 degrees C) had better therapeutic effects than mild hypothermia (34 degrees C). CONCLUSIONS: The results suggest that moderate hypothermia resuscitation is an effective treatment for shock-induced intestinal injury, and its therapeutic mechanism may be related to mitochondrial protection. PMID- 26227676 TI - A treatment program for babies with esophageal atresia in Belize. AB - BACKGROUND: Children born with congenital anomalies in low- and middle-income countries often face a multitude of challenges. Access to pediatric surgical services is limited because of a lack of medical facilities, an adequate transportation system, and a lack of trained surgeons, anesthesiologists, and nurses, all of which leads to a high mortality rate. METHODS: This is a report of a 5-y collaborative effort between the World Pediatric Project, the Children's Hospital of Richmond at Virginia Commonwealth University, and multiple organizations within the country of Belize to provide care for infants born with esophageal atresia, with or without associated tracheoesophageal fistula. RESULTS: A total of six infants were transferred to our institution in Richmond, VA for operative correction of their esophageal atresia. CONCLUSIONS: Caring for infants with congenital anomalies can be challenging, especially children from low- and middle-income countries. Through collaboration between countries and nonprofit organizations, life-saving international care can be provided to children for these conditions. PMID- 26227677 TI - Metal-Doped Nitrogenated Carbon as an Efficient Catalyst for Direct CO2 Electroreduction to CO and Hydrocarbons. AB - This study explores the kinetics, mechanism, and active sites of the CO2 electroreduction reaction (CO2RR) to syngas and hydrocarbons on a class of functionalized solid carbon-based catalysts. Commercial carbon blacks were functionalized with nitrogen and Fe and/or Mn ions using pyrolysis and acid leaching. The resulting solid powder catalysts were found to be active and highly CO selective electrocatalysts in the electroreduction of CO2 to CO/H2 mixtures outperforming a low-area polycrystalline gold benchmark. Unspecific with respect to the nature of the metal, CO production is believed to occur on nitrogen functionalities in competition with hydrogen evolution. Evidence is provided that sufficiently strong interaction between CO and the metal enables the protonation of CO and the formation of hydrocarbons. Our results highlight a promising new class of low-cost, abundant electrocatalysts for synthetic fuel production from CO2 . PMID- 26227678 TI - Decellularization of bovine small intestinal submucosa and its use for the healing of a critical-sized full-thickness skin defect, alone and in combination with stem cells, in a small rodent model. AB - In this study, we initially described an efficient decellularization protocol for bovine-derived small intestinal submucosa (bSIS), involving freeze-thaw cycles, acid/base treatment and alcohol and buffer systems. We compared the efficacy of our protocol to some previously established ones, based on DNA content and SEM and histochemical analyses. DNA content was reduced by ~89.4%, significantly higher than compared protocols. The sulphated GAG content of the remaining interconnected fibrous structure was 5.738 +/- 0.207 ug/mg (55% retained). An in vitro study was performed to evaluate whether rat bone marrow mesenchymal stem cells (MSCs) could attach and survive on bSIS membranes. Our findings revealed that MSCs can preserve their viability and proliferate on bSIS for > 2 weeks in culture. We conducted in vivo applications for the treatment of an experimental rat model of critical sized (7 cm2 ) full-thickness skin defect. The wound models treated with either MSCs-seeded (1.5 * 106 cells/cm2 ) or non-seeded bSIS membranes were completely closed by week 7 without significant differences in closure time; on the other hand, the open wound control was closed at ~47% at this time point. Immunohistopathology results revealed that the group which received MSCs-seeded bSIS had less scarring at the end of the healing process and was in further stages of appendage formation in comparison with the non-seeded bSIS group. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26227680 TI - Spatial abstraction for autonomous robot navigation. AB - Optimal navigation for a simulated robot relies on a detailed map and explicit path planning, an approach problematic for real-world robots that are subject to noise and error. This paper reports on autonomous robots that rely on local spatial perception, learning, and commonsense rationales instead. Despite realistic actuator error, learned spatial abstractions form a model that supports effective travel. PMID- 26227681 TI - Microscopic Studies of Stone Alteration Products: From Field to Lab. PMID- 26227679 TI - Extracellular Matrix-Based Biohybrid Materials for Engineering Compliant, Matrix Dense Tissues. AB - An ideal tissue engineering scaffold should not only promote, but take an active role in, constructive remodeling and formation of site appropriate tissue. Extracellular matrix (ECM)-derived proteins provide unmatched cellular recognition, and therefore influence cellular response towards predicted remodeling behaviors. Materials built with only these proteins, however, can degrade rapidly or begin too weak to substitute for compliant, matrix-dense tissues. The focus of this Progress Report is on biohybrid materials that incorporate polymer components with ECM-derived proteins, to produce a substrate with desired mechanical and degradation properties, as well as actively guide tissue remodeling. Materials are described through four fabrication methods: 1) polymer and ECM-protein fibers woven together, 2) polymer and ECM proteins combined in a bilayer, 3) cell-built ECM on polymer scaffold, and 4) ECM proteins and polymers combined in a single hydrogel. Scaffolds from each fabrication method can achieve characteristics suitable for different types of tissue. In vivo testing has shown progressive remodeling in injury models, and suggests ECM based biohybrid materials promote a prohealing immune response over single component alternatives. The prohealing immune response is associated with lasting success and long term host maintenance of the implant. PMID- 26227682 TI - Porosity Structures and Capillary Migration in Granites and Limestones. PMID- 26227683 TI - Highly Ordered Hexagonal Arrays of TiO2 Nanotubes. PMID- 26227684 TI - A Study on Microstructure Characteristics of TEPs-modified Adhesives. PMID- 26227685 TI - Tensile Strength of a Brittle Epoxy Resin Reinforced with Micro Cork Particles: Effect of Size, Amount and Surface Treatment. PMID- 26227686 TI - NiTi Wires Coated by Nanomultilayers - A Solution for Self-healing? PMID- 26227687 TI - Chitosan Thin Films on Glass and Silicon Substrates. PMID- 26227688 TI - Effect of Carbon Black Nanoparticles Concentration on Mechanical Properties of an Epoxy Adhesive Cured by Dielectric Heating. PMID- 26227689 TI - Porosity... Advantage or Disadvantage? PMID- 26227690 TI - Low Energy MeV Ion Beams, Microscopy and Non-Destructive Surface Analysis of Materials. PMID- 26227691 TI - Microstructural Evaluation of Consolidated Modified SS 316L Powder. PMID- 26227692 TI - Ni/Ti and Ni/Al Laminated Composites Produced by ARB and Annealing: Microstructural Aspects. PMID- 26227693 TI - EBSD Characterization of WC-AISI304 Cemented Carbides. PMID- 26227694 TI - W-Ta Composites Consolidated by Spark Plasma Sintering. PMID- 26227695 TI - Meant to be Discovered: The Study by Microscopic Analysis of Lead-Based Pigments Alteration by a Fire. PMID- 26227696 TI - Microanalysis of Bioactive Samarium Doped Glass-Reinforced Hydroxyapatite. PMID- 26227697 TI - Corrosion Behavior of the Friction Stir Welded AZ31 Magnesium Alloy. PMID- 26227698 TI - Surface Morphology of Chitosan Films with Incorporation of Grape Pomace. PMID- 26227699 TI - Textured Potassium Sodium Niobate Ceramics Doped with Copper and Manganese. PMID- 26227700 TI - The Morphological Characterization of Anodic TiO2 Nanotube Arrays. PMID- 26227701 TI - Microstructure of Discontinuously B4C Reinforced Ti Metal Matrix Composites Processed by Hot-Pressing. PMID- 26227702 TI - Effect of Sc Additions on the Modification of Eutectic Si of As Cast Al-9wt%Si Alloy. PMID- 26227703 TI - Microstructure Evolution with Direct Current Density on Electrodeposited Copper Films. PMID- 26227704 TI - HRTEM Studies of Stress Assisted Sintered BaLa4Ti4O15. PMID- 26227705 TI - Microstructural Characterization of Metallic Parts Produced by Hot Embossing. PMID- 26227706 TI - TEM Characterization of a Mould Steel in Pre-hardened Condition and After Subsequent Heat Treatments. PMID- 26227707 TI - Microstructural Characterization of CNT/Al Nanocomposites Produced by Hot Extrusion. PMID- 26227708 TI - Microstructural Characterization of Biofunctionalized Titanium Foams. PMID- 26227709 TI - Ultrastructural Studies of the Cellular Effects of Antitumoral Compounds. PMID- 26227710 TI - Preliminary Study of a Kudoa Species (Myxosporea; Multivalvulida) Infecting the Muscle of the Freshwater Teleostean Chaetobranchopsis orbicularis (Cichlidae) in the Amazonian Fauna. PMID- 26227711 TI - Kinetics of the Metabolic and Morphological Alterations in Brown Trout Hepatic Peroxisomes Under Estradiol Influence. PMID- 26227712 TI - Is Magnetic-Activated Cell Sorting an Efficient Technique in Reducing Human Sperm DNA Fragmentation? PMID- 26227713 TI - A Microsporidian Found in the Teleost Fish Epinephelus polyphekadion from the Arabian Red Sea Coast: Ultrastructural and Phylogenetic Characterization. PMID- 26227714 TI - Ultrastructural Detection of Calcium with the Pyroantimonate Method in Cells of Marine Gastropods. PMID- 26227715 TI - Histomorphometric Evaluation of the Small Coronary Arteries in Rats Exposed to Industrial Noise. PMID- 26227716 TI - Uncovering Morphological Interferences Caused by Androgen Inputs in Peroxisomes from Primary Brown Trout Hepatocytes Using Catalase Immunofluorescence. PMID- 26227717 TI - Morphological Alterations Caused by Estrogenic and Anti-Estrogenic Signaling in Peroxisomes of Primary Brown Trout Hepatocytes - Stereological Approach Using Catalase Immunofluorescence. PMID- 26227718 TI - Effects of Ca++ and Light Exposure of 3T3 Cells in Tissue Culture. PMID- 26227719 TI - A Study of the Effects of Phonophoretic Application of Hydrocortisone on the Regeneration of Injuries to Skeletal Muscle. PMID- 26227720 TI - Administration of essential oil of tea tree (Melaleuca alternifolia) in experimental muscle injury by phonoforesis. PMID- 26227721 TI - Ethinylestradiol Exposure of Primary Culture Brown Trout Hepatocytes Induce Morphological Changes in Peroxisomes. PMID- 26227722 TI - Marine and Soil Fungi Extracts with Antiproliferative Activity Induce Morphological Alterations in Breast Cancer Cells. PMID- 26227723 TI - A New Type of Echinactinomyxon (Myxozoa), Infecting a Marine Polychaete, Heteromastus filiformis (Polychaeta: Capitellidae) In the Alvor Estuary (Portugal). PMID- 26227724 TI - Stereology of Brown Trout Liver Peroxisomes at Vitellogenesis and Pre-spawning Strengthens the Hypothesis of Their Regulation by Sex Steroids. PMID- 26227725 TI - Ultrastructure and Phylogeny of Ceratomyxa sp. (Myxosporea), a Parasite Infecting Sparus aurata (Teleostei) in a Portuguese Fish Farm. PMID- 26227726 TI - Glandular Trichomes and Biological Activities in Helichrysum italicum and H. stoechas, Two Asteraceae Species Growing Wild in Portugal. PMID- 26227727 TI - Refinement Techniques in Zebrafish Anaesthesia - Results from a Pilot Study. PMID- 26227728 TI - Integrated Analysis of Biological Samples by Imaging Flow Cytometry. PMID- 26227729 TI - Histological Changes in Stems of Pinus sylvestris Seedlings Infected with a Virulent Isolate of the Pinewood Nematode Bursaphelenchus xylophilus. PMID- 26227730 TI - A Stereological Estimation of the Nervous Ganglia Volumes and Number of Neurons in the Peppery Furrow Shell Scrobicularia plana (da Costa, 1778). PMID- 26227731 TI - Biofunctional Materials Based on Amino Cellulose Derivatives--A Nanobiotechnological Concept. AB - This feature article summarizes recent developments in the field of so-called aminodeoxy cellulose derivatives ("amino celluloses") that are applied for functional surface coating of biofunctional materials. After introducing common manufacturing methods for nanostructurized substrates (material surfaces and nanoparticles) biorelevant amino celluloses are described. It could be demonstrated that cellulose is a unique starting material for chemical modification of hydroxyl groups and the adjacent carbon atom. Amino celluloses are proved to be the modifiable polymer of choice for the biofunctionalization of material surfaces. Amino celluloses possess self assembling properties and may form monolayer composites on a variety of substrate materials. PMID- 26227732 TI - Population-Based Genetic Studies: The Search for Causative Variants in Parkinson's Disease. PMID- 26227733 TI - Risk of Cutaneous Squamous Cell Carcinoma Development in Renal Transplant Recipients Is Independent of TMC/EVER Alterations. AB - BACKGROUND: Renal transplant recipients (RTRs) have an increased risk of developing nonmelanoma skin cancer, mainly cutaneous squamous cell carcinoma (cSCC). Two genes (TMC6/EVER1 and TMC8/EVER2), mutated in epidermodysplasia verruciformis (EV) patients with an increased risk of cSCC development, contain numerous single-nucleotide polymorphisms (SNPs). AIM: To evaluate the effect of SNPs in both TMC/EVER genes on the different susceptibilities of RTRs to cSCC. METHOD: We determined the occurrence of cSCC in 105 RTRs who were transplanted at least 7 years previously and investigated the frequency of 26 SNPs within both TMC/EVER genes in severely affected (n = 16) as well as in nonaffected RTRs (n = 25). RESULTS: Our data did not indicate a significant association between any SNP genotype and risk of cSCC development in RTRs. CONCLUSION: To clarify the correlation between SNPs in both TMC genes and cSCC development in RTRs, integrated investigations of large cohorts including both RTRs and immunocompetent individuals with consideration of cSCC status, SNP genotype and human papillomavirus status might be necessary. PMID- 26227735 TI - Inflammatory myofibroblastic tumour: unexpected finding on placental examination. PMID- 26227734 TI - Patterns of Motor and Non-Motor Features in Medication-Naive Parkinsonism. AB - BACKGROUND: Parkinsonism is defined by motor features (tremor, bradykinesia, rigidity, and postural instability). Accompanying non-motor features (e.g. cognitive, autonomic, sleep disturbances) are underrecognized and undertreated. We hypothesized that clinical patterns occurring in early, medication-naive Parkinsonism are distinguished by features such as tremor, sleep, autonomic, and cognitive dysfunction. METHODS: Clinical and neuroimaging data were obtained in the Parkinson's Progression Marker Initiative. Group comparisons of Parkinsonism with dopaminergic deficits (PDD) (n = 388), controls (n = 196), and Parkinsonism with scans without evidence of dopaminergic deficits (n = 64) were done with ANOVA, chi-square, and post-hoc pairwise tests. To examine clinical patterns within the PDD group, k-means clustering was performed with non-motor or motor features, or both. RESULTS: Among PDD, 4 non-motor patterns (% of PDD) (impulsive (14.9%), sleep-autonomic (22.9%), cognitive-olfactory (18.0%), and mild (44.1%)), 4 motor patterns (tremor plus bradykinesia (56.2%), tremor without bradykinesia (16.2%), postural instability (6.7%) and no tremor (20.9%)) and 5 combined motor/non-motor patterns (tremor with bradykinesia (42.3%), tremor without bradykinesia (15.5%), no tremor and mild non-motor features (17.0%), postural instability with sleep-autonomic disturbances (6.7%) and oldest onset cognitive olfactory (18.6%)) were observed. CONCLUSIONS: To our knowledge, this is the first description of non-motor clinical patterns in early, medication-naive Parkinsonism, suggesting that such features are intrinsic to Parkinsonian disorders. PMID- 26227736 TI - Structural chromosome rearrangements in prenatal diagnosis: results from a Spanish database. PMID- 26227737 TI - Oriented nanofibrous membranes for tissue engineering applications: Electrospinning with secondary field control. AB - Electrospinning is an electrical field driven method to produce polymer fibre membranes by deposition of a charged polymer jet onto a grounded collector. Fibre alignment within these mats is usually achieved by a fast collector movement, which is not feasible for all collector geometries, such as small diameter tubes or free-form moulds. The aim of this study was to evaluate the use of charged deflector plates to apply a dynamic, alternating electrical field perpendicular to the spinning direction, in order to directly control the fibre trajectory. Different field signal types, deflector plate voltages and deflection frequency ranges have been investigated. 210 poly(E)caprolactone (PCL) membranes were electrospun. SEM images of each membrane were analysed using ImageJ. Main fibre diameter and orientation, as well as the degree of fibre alignment, were calculated, while a subset of the spun scaffolds were tested for their tensile properties. Higher deflector plate voltage amplitude resulted in a better fibre alignment. The best alignment was observed in a low deflection frequency range from 2 to 10 Hz. Mean main fibre direction was 87+/-18 degrees , relative to the deflection axis, while fibre alignment had only a minor effect on the average fibre diameter. Young's modulus and yield stress increased with the ratio of the parallel fibre component. The feasibility of the described method to achieve fibre alignment was demonstrated. However, the main fibre direction is not aligned with the deflection axis, but consistently perpendicular to it, which is also reflected in the tensile properties of spun samples. PMID- 26227738 TI - Group Prenatal Care: A Financial Perspective. AB - INTRODUCTION: Multiple studies have demonstrated improved perinatal outcomes for group prenatal care (GPC) when compared to traditional prenatal care. Benefits of GPC include lower rates of prematurity and low birth weight, fewer cesarean deliveries, improved breastfeeding outcomes and improved maternal satisfaction with care. However, the outpatient financial costs of running a GPC program are not well established. METHODS: This study involved the creation of a financial model that forecasted costs and revenues for prenatal care groups with various numbers of participants based on numerous variables, including patient population, payor mix, patient show rates, staffing mix, supply usage and overhead costs. The model was developed for use in an urban underserved practice. RESULTS: Adjusted revenue per pregnancy in this model was found to be $989.93 for traditional care and $1080.69 for GPC. Cost neutrality for GPC was achieved when each group enrolled an average of 10.652 women with an enriched staffing model or 4.801 women when groups were staffed by a single nurse and single clinician. CONCLUSIONS: Mathematical cost-benefit modeling in an urban underserved practice demonstrated that GPC can be not only financially sustainable but possibly a net income generator for the outpatient clinic. Use of this model could offer maternity care practices an important tool for demonstrating the financial practicality of GPC. PMID- 26227739 TI - Letter from Nepal, July 2015--Post-earthquake, infectious disease risks and prevention. PMID- 26227741 TI - Endothelial Function Predicts New Hospitalization due to Heart Failure Following Cardiac Resynchronization Therapy. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) has been established as a treatment for patients with chronic heart failure (HF). We tested the hypothesis that assessment of peripheral endothelial function is associated with the long term outcome of CRT and its linkage to coronary flow reserve (CFR) was also investigated. METHODS: From 2010, a total of 34 consecutive patients implanted with CRT for the treatment of advanced HF were evaluated at baseline (immediately before CRT) and 6-8 months after CRT. Endothelial function was evaluated by measurement of reactive hyperemia peripheral arterial tonometry (RH-PAT). In 24 of 34 patients, CFR was determined by transthoracic echocardiography. RESULTS: Based on the receiver-operating characteristic curves, depressed RH-PAT index (RHI) was defined as <=1.5. Accurate follow-up information during the mean of 343 +/- 120 days was obtained in 20 preserved RHI group (mean age 66 +/- 1.8 years) and 14 depressed RHI group (71 +/- 2.2 years). Kaplan-Meier survival analysis demonstrated that depressed RHI group had higher prevalence of new hospitalization due to HF progression (log-rank 5.40). Cox proportional hazards regression analysis revealed that the baseline log brain natriuretic peptide (hazard ratio 5.95) and the baseline RHI value (hazard ratio 0.066) were independently associated with the incidence of new hospitalization due to HF progression. The baseline RHI values were positively correlated with the 6-8 months change of CFR (R = 0.434, P = 0.0343). CONCLUSIONS: Our results suggest that the baseline peripheral endothelial function could predict the long-term outcome of CRT. The results also suggest that improvement of coronary microcirculation might be associated with the better baseline endothelial function. PMID- 26227740 TI - Imported malaria in pregnant women: A retrospective pooled analysis. AB - BACKGROUND: Data on imported malaria in pregnant women are scarce. METHOD: A retrospective, descriptive study of pooled data on imported malaria in pregnancy was done using data from 1991 to 2014 from 8 different collaborators in Europe, the United States and Japan. National malaria reference centres as well as specialists on this topic were asked to search their archives for cases of imported malaria in pregnancy. A total of 631 cases were collated, providing information on Plasmodium species, region of acquisition, nationality, country of residence, reason for travel, age, gestational age, prophylactic measures and treatment used, as well as on complications and outcomes in mother and child. RESULTS: Datasets from some sources were incomplete. The predominant Plasmodium species was P. falciparum (78.5% of cases). Among the 542 cases where information on the use of chemoprophylaxis was known, 464 (85.6%) did not use chemoprophylaxis. The main reason for travelling was "visiting friends and relatives" VFR (57.8%) and overall, most cases of malaria were imported from West Africa (57.4%). Severe anaemia was the most frequent complication in the mother. Data on offspring outcome were limited, but spontaneous abortion was a frequently reported foetal outcome (n = 14). A total of 50 different variants of malaria treatment regimens were reported. CONCLUSIONS: Imported cases of malaria in pregnancy are mainly P. falciparum acquired in sub-Saharan Africa. Malaria prevention and treatment in pregnant travellers is a challenge for travel medicine due to few data on medication safety and maternal and foetal outcomes. International, collaborative efforts are needed to capture standardized data on imported malaria cases in pregnant women. PMID- 26227742 TI - Inhibition of JAK2 attenuates the increase in inflammatory markers in microglia from APP/PS1 mice. AB - There is a wealth of evidence indicating that macrophages adopt distinct phenotypes when exposed to specific stimuli and, in the past few years, accumulating data suggest that microglia behave somewhat similarly. Therefore, microglia can adopt the so-called M1 or M2 phenotypes in response to interferon gamma (IFNgamma) and interleukin-4, respectively. Although it has yet to be unequivocally proven in the context of microglia, acutely activated M1 cells are probably protective, although a persistent M1 state is likely to be damaging, whereas M2 cells may be reparative and restorative. In this case, particularly because the current evidence suggests the development of a predominantly M1 state with age and in neurodegenerative diseases, it is important to identify mechanisms by which polarization of microglia can be modulated. The present findings indicate that exposure of cultured microglia to IFNgamma increased expressions of the archetypal markers of the M1 phenotype, tumour necrosis factor alpha, and inducible nitric oxide synthase, and preexposure of cells to amyloid beta (Abeta) sensitized microglia to subsequent stimulation with IFNgamma. Importantly, this synergy was also evident in microglia prepared from the brains of transgenic mice that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1, APP/PS1 mice) and are exposed to a combination of increasing concentrations of endogenous Abeta from 4 or 5 months of age and an age-related increase in IFNgamma. Significantly, the JAK2 inhibitor, TG101209, attenuated the IFNgamma-induced changes in cultured microglia and in isolated microglia prepared from APP/PS1 mice. These findings suggest that targeting JAK2 may be a potential strategy for reducing neuroinflammation in Alzheimer's disease. PMID- 26227744 TI - A Ratiometric Fluorescent Probe for Gold and Mercury Ions. AB - A fluorescent probe that displays a ratiometric fluorescence response towards gold and mercury ions has been devised. Emitting at a relatively longer wavelength, the conjugated form of the fluorescent dye transforms in the presence of the gold or mercury ions into a new dye, the molecular structure of which lacks the conjugation and consequently emits at a distinctly shorter wavelength. PMID- 26227743 TI - Hypertrophic Lichenoid Eruption in a Child Successfully Treated Using Acitretin and Surgery: A Case Report and Literature Review. AB - A 9-year-old boy presented with a history of keratotic violaceous plaques on the limbs and face for 8 years that had gradually progressed to erosive nodules on the extremities for 2 years. Several biopsies revealed hyperkeratosis, liquefactive degeneration of the basal layer, and a bandlike predominantly lymphocytic infiltrate. Based on the clinical and histologic findings, the patient was diagnosed with keratosis lichenoides chronica, a rare chronic dermatosis that is particularly uncommon in childhood. There are fewer than 20 reported cases of pediatric-onset keratosis lichenoides chronica in the current literature, with occurrence of pseudoepitheliomatous hyperplasia of primary keratosis lichenoides chronica lesions being even rarer. Here we present a unique pediatric-onset case accompanied by pseudoepitheliomatous hyperplasia that posed a significant treatment challenge to dermatologists. Significant improvement in the pseudoepitheliomatous skin lesions was achieved after treatment with oral acitretin capsules and surgical excision with skin grafting. PMID- 26227745 TI - Repeat cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent diffuse malignant peritoneal mesothelioma. AB - INTRODUCTION: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has shown to improve survival outcomes for patients with diffuse malignant peritoneal mesothelioma (DMPM). PATIENTS AND METHODS: This is a retrospective study of prospectively collected data of 44 consecutive patients with DMPM who underwent CRS and HIPEC by the same surgical team at St George Hospital in Sydney, Australia. A total of 58 operations were performed. Clinical data were divided according to the number of operation and HIPEC the patient had undergone (Group 1 = initial CRS and HIPEC; Group 2 = 2nd CRS and HIPEC; Group 3 included 3rd CRS and HIPEC; Group 4 = 4th CRS and HIPEC). A significant difference was defined as p < 0.05. RESULTS: There were no significant differences in mortality and morbidity results among the four groups. The median survival for those who only had one operation was 22 months (95% confidence interval (CI) = 0-47.2), whereas the median survival for those who had a second operation was 62 months (95% CI = 22.9-101.1). However, such a difference did not translate into a statistical significance (p = 0.141). CONCLUSION: We report an encouraging median survival of 62 months in patients who had recurrence of disease and had repeat CRS and HIPEC with similar morbidity and mortality with the initial operation. Due to the learning curve of this technique, patients with recurrent mesothelioma should be referred to specialised tertiary care centres for evaluation. Selected patients may experience prolonged survival after repeat CRS and HIPEC. PMID- 26227746 TI - Genetic analysis of SNPs in CACNA1C and ANK3 gene with schizophrenia: A comprehensive meta-analysis. AB - Recently, genome-wide association studies (GWAS), meta-analyses, and replication studies focusing on bipolar disorder (BD) have implicated the alpha-1C subunit of the L-type voltage-dependent calcium channel (CACNA1C) and ankyrin 3 (ANK3) genes in BD. Based on the hypothesis that both schizophrenia (SZ) and BD may share some common genetic risk factors, we investigated the association of CACNA1C and ANK3 with SZ using meta-analytic techniques, combining all published data up to April 2015. Nine teams, including four European decent samples and five Asian samples, contributed 14,141 cases and 30,679 controls for the analysis of CACNA1C rs1006737 and SZ. A significant difference was identified between patients and controls for the A-allele of rs1006737 in combined studies (Z = 6.02, P = 1.74E 09), in European studies (Z = 4.08, P = 4.50E-05), and in Asian studies (Z = 4.60, P = 4.22E-06). Meanwhile, for the T-allele of ANK3 rs10761482 (1,794 cases versus 1,395 controls), a significant association was observed in combined samples (Z = 2.06, P = 0.04) and in Asian samples (Z = 3.10, P = 0.002). In summary, our study provides further evidence for the positive association of CACNA1C and ANK3 with SZ. These results support the hypothesis that both SZ and BD share common genetic risk factors. Further research is needed to examine the functions of CACNA1C and ANK3, and their interacting partners in the molecular, developmental, and pathophysiological processes in SZ. PMID- 26227747 TI - Nutrient values and bioactivities of the extracts from three fern species in China: a comparative assessment. AB - Pteridium aquilinum, Osmunda cinnamomea Linn, and Athyrium multidentatum (Doll.) Ching are three fern species widely consumed as potherbs and traditional medicinal herbs in China. Nevertheless, no detailed comparative assessments of their nutrient values and bioactivities have been reported. In this paper, we examined the nutrient content of these ferns and the bioactivities of their extracts with a comparative method. The results indicated that they were nutrient dense for proteins, carbohydrates, fat and minerals. Compared with Pteridium aquilinum and Osmunda cinnamomea Linn, the extract from Athyrium multidentatum (Doll.) Ching was found to possess the strongest antioxidant activity, protective effects on biomolecules, cellular antioxidant activity, and antiproliferative effects owing to its highest total phenolic (476.52 +/- 11.26 mg GAE per g extract) and total flavonoid (924.81 +/- 4.25 mg RNE per g extract) contents. Further, Athyrium multidentatum (Doll.) Ching can lead to caspase-3 activation, poly ADP-ribose polymerase cleavage, mitochondrial membrane potential (MMP) reduction and inhibition of wound-healing in a dose-dependent manner in HepG2 cells. These results demonstrate the remarkable potential of Pteridium aquilinum, Osmunda cinnamomea Linn, and Athyrium multidentatum (Doll.) Ching as valuable sources of nutrients and natural antioxidants, and among which Athyrium multidentatum (Doll.) Ching has potential anticancer properties. PMID- 26227749 TI - Lessons from polio to Ebola. PMID- 26227748 TI - Retropharyngeal lymph node involvement in human papillomavirus-associated oropharyngeal squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to retrospectively review patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) for the presence of retropharyngeal lymph nodes (RPLNs) prior to treatment using positron emission tomography/computed tomography (PET/CT), and to determine if the presence of RPLNs is of utility in predicting outcomes. STUDY DESIGN: Retrospective review of patient data from a single institution. METHODS: Two hundred thirty patients with a diagnosis of HPV-associated OPSCC were identified from 2002 to 2013. The presence of RPLNs was determined primarily from findings on PET/CT as reviewed in a standardized fashion by two neuroradiologists. RESULTS: Of the 230 patients, 165 had pretreatment PET/CT imaging available for review. There were a total of 16 patients (9.70%) with evidence of RPLNs. Among patients positive for RPLNs pretreatment, with an average follow-up of 2 years, there was a 5.2-times greater odds of having recurrence or death (31.3% vs. 8.1%, P=.004). When T and N stage were adjusted for with multiple regression, there was no significant association between RPLN status and recurrence free survival. CONCLUSIONS: This is a unique investigation utilizing PET/CT to classify RPLN status in HPV-associated OPSCC. RPLNs were relatively common in our HPV-associated OPSCC cohort at 9.70%, at the low end of the quoted positivity of 10% to 27% in all OPSCC. A combination of PET/CT is useful in identifying RPLNs. Prospective investigation will be needed to determine the sensitivity and specificity of PET/CT in identifying RPLNs, and the precise impact of RPLNs on HPV-associated OPSCC treatment and outcomes. LEVEL OF EVIDENCE: 4. PMID- 26227750 TI - Making mandatory vaccination truly compulsory: well intentioned but ill conceived. PMID- 26227751 TI - Help from above: outer space and the fight against Ebola. PMID- 26227752 TI - Corrections. PMID- 26227753 TI - Corrections. PMID- 26227754 TI - Corrections. PMID- 26227755 TI - Tuberculosis screening programmes for migrants to low-incidence countries--the Israeli experience. PMID- 26227756 TI - Urgent need for beta-lactam-beta-lactamase inhibitors. PMID- 26227757 TI - Epidemiological profile of "Babesia venatorum". PMID- 26227758 TI - Epidemiological profile of "Babesia venatorum"--authors' reply. PMID- 26227759 TI - Travel-associated infections in Europe. PMID- 26227760 TI - Travel-associated infections in Europe. PMID- 26227761 TI - Travel-associated infections in Europe--authors' reply. PMID- 26227762 TI - Stigmatisation undermining Russia's HIV control efforts. PMID- 26227763 TI - Highlights from the 3rd ICPIC. PMID- 26227764 TI - Bringing fungal infections in from the cold. PMID- 26227767 TI - Alan Magill--aiming for a malaria-free world. PMID- 26227768 TI - Nodules on a sternotomy scar. PMID- 26227769 TI - Metal-backed glenoid implant with polyethylene insert is not a viable long-term therapeutic option. AB - BACKGROUND: The aims of this study were to determine the survival of anatomic total shoulder arthroplasty with uncemented metal-backed (MB) glenoid components with a polyethylene (PE) insert in primary osteoarthritis, to assess the reasons for revision surgery, and to identify patients and diagnostic factors that influence failure rates. METHODS: Between 1994 and 1999, 165 patients (mean age, 68 years) with primary osteoarthritis were treated with anatomic total shoulder arthroplasty using an uncemented MB/PE glenoid component. Outcomes were assessed both clinically and radiologically with a minimum of 2 years of follow-up. A prosthetic survival curve was constructed with the end point defined as either partial or complete revision, using 100% confidence intervals. RESULTS: Survival rate free of revision was 46% (100% confidence interval, 32%-54%) at 12 years. At a mean follow-up of 8.5 years (range, 2-16 years), revision was required in 61 patients (37%); 80% of shoulders undergoing revision (49 of 61) had evidence of PE wear. Glenoid loosening (because of osteolysis secondary to wear debris), soft tissue deficiency, and prosthetic instability were the most common modes of failure. Younger patients and biconcave glenoids (with posterior humeral subluxation) have a negative effect on implant survival. Proximal humerus osteolysis was significantly more frequent in shoulders with PE wear. Exchange of the PE insert (with conservation of the MB tray) was possible in only 3% of the revised shoulders. CONCLUSION: Uncemented MB glenoid resurfacing is not a viable long-term therapeutic option because of accelerated PE wear leading to early revision surgery. Conservation of the MB tray with reinsertion of a new PE insert is rarely possible because of glenoid bone loss, implant loosening, soft tissue deficiency, and prosthetic instability. Younger patients and biconcave glenoids have a negative effect on implant survival. PMID- 26227770 TI - Protective effect of exogenous nitrite in postoperative ileus. AB - BACKGROUND AND PURPOSE: As the pathogenesis of postoperative ileus (POI) involves inflammation and oxidative stress, comparable to ischaemia/reperfusion injury which can be ameliorated with nitrite, we investigated whether nitrite can protect against POI and explored the mechanisms involved. EXPERIMENTAL APPROACH: We used intestinal manipulation (IM) of the small intestine to induce POI in C57BL/6J mice. Sodium nitrite (48 nmol) was administered intravenously just before IM. Intestinal transit was assessed using fluorescent imaging. Bethanechol stimulated jejunal circular muscle contractions were measured in organ baths. Inflammatory parameters, neutrophil infiltration, inducible NOS (iNOS) activity, reactive oxygen species (ROS) levels, mitochondrial complex I activity and cGMP were measured in the intestinal muscularis. KEY RESULTS: Pre-treatment with nitrite markedly improved the delay in intestinal transit and restored the reduced intestinal contractility observed 24 h following IM. This was accompanied by reduced protein levels of TNF-alpha, IL-6 and the chemokine CCL2, along with reduced iNOS activity and ROS levels. The associated neutrophil influx at 24 h was not influenced by nitrite. IM reduced mitochondrial complex I activity and cGMP levels; treatment with nitrite increased cGMP levels. Pre-treatment with the NO scavenger carboxy-PTIO or the soluble guanylyl cyclase inhibitor ODQ abolished nitrite-induced protective effects. CONCLUSIONS AND IMPLICATIONS: Exogenous nitrite deserves further investigation as a possible treatment for POI. Nitrite induced protection of POI in mice was dependent on NO and this effect was not related to inhibition of mitochondrial complex I, but did involve activation of soluble guanylyl cyclase. PMID- 26227771 TI - Composition and variation analysis of the TCR beta-chain CDR3 repertoire in systemic lupus erythematosus using high-throughput sequencing. AB - The ability of T lymphocytes to mount an immune response against a diverse array of pathogens is primarily conveyed by the amino acid (aa) sequence of the hypervariable complementarity-determining region 3 (CDR3) segments of the T cell receptor (TCR). In this study, we used a combination of multiplex-PCR, Illumina sequencing and IMGT/HighV-QUEST for a standardized analysis of the characteristics and polymorphisms of the T-cell receptor BV complementarity determining region 3 (TCR BV CDR3) gene in peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy donors (NC). We found the distributions of CDR3, VD indel, and DJ indel lengths to be comparable between the SLE and NC groups. The degree of clonal expansion in the SLE group was significantly greater than in the NC group, and the expression levels of 10 TRbetaV segments and 6 TRbetaJ segments were also significantly different in the SLE group. Regarding public T cell responses, 3CDR3 DNA sequences and 4 aa sequences were shared by all SLE patients and may serve as biomarkers for SLE disease risk, diagnosis and/or prognosis. PMID- 26227773 TI - Benzylated and prenylated flavonoids from the root barks of Cudrania tricuspidata with pancreatic lipase inhibitory activity. AB - A new benzylated and prenylated flavonone, cudracuspiflavanone A (17) were isolated from the roots of Cudrania tricuspidata (Moraceae), together with two chromones (1-2) and fourteen flavonoids (3-16). The structures of isolated compounds were determined on the basis of spectroscopic analysis. The absolute configuration was also defined by CD analysis. Among the isolated compounds, compounds 14 and 15 inhibited pancreatic lipase activity with an IC50 value of 9.0 and 6.5 MUM, respectively. PMID- 26227772 TI - C4 phenyl aporphines with selective h5-HT(2B) receptor affinity. AB - A group of aporphine alkaloids related to (+/-)-nantenine (1) and bearing a C4 phenyl and various C1 or N-substituents, was synthesized and evaluated for affinity to h5-HT receptors. In general, unlike nantenine, the analogs lack affinity for the h5-HT(2A) receptor and other 5-HT receptors but bind selectively to the h5-HT(2B) receptor. With regards to 5-HT(2B) affinity, there appears to be a low tolerance for bulky C1 or N-substituents when the C4 phenyl moiety is present. Compound 5a had the highest 5-HT(2B) affinity of the compounds tested, was found to be an antagonist and is selective vs other CNS receptors. PMID- 26227774 TI - Enzymatic synthesis of rare sugars with L-rhamnulose-1-phosphate aldolase from Thermotoga maritima MSB8. AB - L-Rhamnulose-1-phosphate aldolase from a thermophilic source (Thermotoga maritima MSB8) (RhaDT.mari) was heterologously overexpressed in Escherichia coli and the stereoselectivity of this enzyme with or without Nus tag was investigated. We also applied this enzyme to the synthesis of rare sugars D-psicose, D-sorbose, L tagatose and L-fructose using our one-pot four-enzyme system. To the best of our knowledge, this is the first use of RhaD from a thermophilic source for rare sugar synthesis and the temperature tolerance of this enzyme paves the path for large scale fermentation. PMID- 26227775 TI - Synthesis of [11C]CX-6258 as a new PET tracer for imaging of Pim kinases in cancer. AB - The reference standard CX-6258 {(E)-5-chloro-3-((5-(3-(4-methyl-1,4-diazepane-1 carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one, 4a} and its desmethylated precursor N-desmethyl-CX-6258 {(E)-3-((5-(3-(1,4-diazepane-1 carbonyl)phenyl)furan-2-yl)methylene)-5-chloroindolin-2-one, 5} for radiolabeling were synthesized from 5-bromo-2-furaldehyde and 3-carboxybenzeneboronic acid in 3 and 4 steps with 29-49% and 24-32% overall chemical yield, respectively. The target tracer [(11)C]CX-6258 {(E)-5-chloro-3-((5-(3-(4-[(11)C]methyl-1,4 diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one, [(11)C]4a} was prepared from N-desmethyl-CX-6258 (5) with [(11)C]CH3OTf under basic condition (2N NaOH) through N-[(11)C]methylation and isolated by HPLC combined with solid phase extraction (SPE) in 40-50% radiochemical yield based on [(11)C]CO2 and decay corrected to end of bombardment (EOB) with 370-1110GBq/MUmol specific activity at EOB. PMID- 26227777 TI - New phenolic compounds from the seeds of Nigella glandulifera and their inhibitory activities against human cancer cells. AB - Four phenolic compounds, including two new ones, Nigephenol A and B (1-2), and a new natural product, Nigephenol C (3), were isolated from the seeds of Nigella glandulifera. Their structures were elucidated on the basis of spectroscopic analyses using HR-ESI-MS, 1D and 2D NMR spectra. All compounds were evaluated by MTT method for in vitro cytotoxicity against four human cancer cell lines (Bel7402, HepG2, HCT-8 and A549). The results revealed that Compounds 1-4 showed more selective activities against HepG2 cells, and that Compound 2 showed significant inhibitory effects against four human tumor cell lines with IC50 values comparable to those of 5-fluorouracil. PMID- 26227776 TI - Radiolabelling and positron emission tomography of PT70, a time-dependent inhibitor of InhA, the Mycobacterium tuberculosis enoyl-ACP reductase. AB - PT70 is a diaryl ether inhibitor of InhA, the enoyl-ACP reductase in the Mycobacterium tuberculosis fatty acid biosynthesis pathway. It has a residence time of 24 min on the target, and also shows antibacterial activity in a mouse model of tuberculosis infection. Due to the interest in studying target tissue pharmacokinetics of PT70, we developed a method to radiolabel PT70 with carbon-11 and have studied its pharmacokinetics in mice and baboons using positron emission tomography. PMID- 26227778 TI - Discovery of indolizines containing triazine moiety as new leads for the development of antitumoral agents targeting mitotic events. AB - A new family of 3-aroylindolizines bearing a dimethoxytriazine unit in their position 1 was designed, synthesized and evaluated for their ability to inhibit tubulin polymerization and cellular growth in vitro. Compound 39 was the best candidate in the current study with a GI50 value of 870 nM on SNB-75 CNS cancer cells and of 920 nM on MDA-MB-231/ATCC breast cancer cells. The standard NCI Compare results indicated that indolizine 39 may target PLK1 (polo-like kinase 1). PMID- 26227779 TI - Discovery of novel potent and selective ligands for 5-HT2A receptor with quinazoline scaffold. AB - A series of compounds with quinazoline scaffold were designed, synthesized and evaluated as novel potent 5-HT2A receptor ligands. N-(4-Chlorophenyl)-2 (piperazin-1-yl)quinazolin-4-amine (5o) has a Ki value of 14.04 +/- 0.21 nM, with a selectivity more than 10,000 fold over 5-HT1A receptors (D1 and D2-like receptors). The functional assay showed that this compound is an antagonist to 5 HT2A receptor with an IC50 value of 1.66 MUM. PMID- 26227780 TI - Phenolic 4-hydroxy and 3,5-dihydroxy derivatives of 3-phenoxyquinoxalin-2(1H)-one as potent aldose reductase inhibitors with antioxidant activity. AB - A group of novel quinoxalinone derivatives (4a-h) were prepared and investigated for their inhibitory activity against ALR2 and antioxidant activity. Most of them were found to be potent aldose reductase inhibitors with IC50 values ranging from 0.019 to 0.982 MUM. The most active compound 2-(3-(4-hydroxyphenoxy)-6-fluoro-2 oxoquinoxalin-1(2H)-yl)acetic acid (4c) also had an excellent selectivity. In addition, a number of compounds showed strong antioxidant activity and the phenolic 3,5-dihydroxyl compound 4f with 7-chloro in the quinoxalinone core was most active in scavenging the DPPH radical and suppressing lipid peroxidation. PMID- 26227781 TI - Fifty shades of yellow: a review of the xanthodermatoses. AB - The xanthodermatoses consist of a heterogeneous group of cutaneous disorders characterized by the macroscopic yellow hue seen on examination. This hue is attributable to the chemical structure of the accumulating substances within the skin or surrounding tissues. The most common culprits are lipids (cholesterol and triglycerides), elastin, and bilirubin. Exogenous sources of yellow pigment include yellow dyes (including hennas) and metal salts. This article will focus on recognition of these entities, classified in terms of morphology and the site of initial eruption, in order to support the recognition and diagnosis of these widely variable conditions. PMID- 26227782 TI - Phenotypic ASCO Characterisation of Young Patients with Ischemic Stroke in the Prospective Multicentre Observational sifap1 Study. AB - BACKGROUND: The prospective, multinational European 'Stroke in Young Fabry Patients' (sifap1) study collected 4,467 patients with acute ischemic cerebrovascular events aged 18-55 years. Initially, aetiologic subtyping was performed using the TOAST classification; however, recently the phenotypic ASCO classification was presented and might be more useful to identify stroke aetiologies in young patients with a wide set of different causes. ASCO is a classification system divided in four etiologic categories (Atherosclerosis, Small vessel disease (SVD), Cardiac embolism, Other cause) with different grades of severity (1-3) and aims to characterise patients in a more comprehensive way. METHODS: We determined the ASCO score for each patient, according to prospectively collected data using the study protocol. The distribution of aetiologies was analysed with regard to concomitant causes, cryptogenic stroke and different age groups. RESULTS: A potentially causal aetiology (grade 1) was detected in 29.3% of 4,467 patients. Merging grades 1 and 2, a suspected aetiology was found in 54.1%. In 8.6% of patients concomitant aetiologies were identified. Most common causes were cervical arterial dissection and persistent foramen ovale, but there was also a high prevalence of large artery atherosclerosis and SVD especially in older patients of this collective. About 50% of patients had more than one finding with a lower grade of evidence (grade 3). In 14% final classification of strictly cryptogenic stroke was made. CONCLUSIONS: This is the largest study to date, using the ASCO characterisation of ischemic stroke aetiologies. ASCO classification provides first evidence that many young patients presenting with acute stroke have concomitant stroke aetiologies associated with a substantial atherosclerosis risk profile. ASCO could be integrated in clinical routine and registry data banks, as well as large clinical trials to improve stroke documentation. PMID- 26227783 TI - gamma-Aminobutyric acid (GABA) administration improves action selection processes: a randomised controlled trial. AB - In order to accomplish a task goal, real-life environments require us to develop different action control strategies in order to rapidly react to fast-moving visual and auditory stimuli. When engaging in complex scenarios, it is essential to prioritise and cascade different actions. Recent studies have pointed to an important role of the gamma-aminobutyric acid (GABA)-ergic system in the neuromodulation of action cascading. In this study we assessed the specific causal role of the GABA-ergic system in modulating the efficiency of action cascading by administering 800 mg of synthetic GABA or 800 mg oral of microcrystalline cellulose (placebo). In a double-blind, randomised, between group design, 30 healthy adults performed a stop-change paradigm. Results showed that the administration of GABA, compared to placebo, increased action selection when an interruption (stop) and a change towards an alternative response were required simultaneously, and when such a change had to occur after the completion of the stop process. These findings, involving the systemic administration of synthetic GABA, provide the first evidence for a possible causal role of the GABA ergic system in modulating performance in action cascading. PMID- 26227784 TI - Discovery of Novel Inhibitors and Fluorescent Probe Targeting NAMPT. AB - Nicotinamide phosphoribosyltransferase (NAMPT) is a promising antitumor target. Novel NAMPT inhibitors with diverse chemotypes are highly desirable for development of antitumor agents. Using high throughput screening system targeting NAMPT on a chemical library of 30000 small-molecules, we found a non-fluorescent compound F671-0003 and a fluorescent compound M049-0244 with excellent in vitro activity (IC50: 85 nM and 170 nM respectively) and anti-proliferative activity against HepG2 cells. These two compounds significantly depleted cellular NAD levels. Exogenous NMN rescued their anti-proliferative activity against HepG2 cells. Structure-activity relationship study proposed a binding mode for NAMPT inhibitor F671-0003 and highlighted the importance of hydrogen bonding, hydrophobic and pi-pi interactions in inhibitor binding. Imaging study provided the evidence that fluorescent compound M049-0244 (3 MUM) significantly stained living HepG2 cells. Cellular fluorescence was further verified to be NAMPT dependent by using RNA interference and NAMPT over expression transgenic mice. Our findings provide novel antitumor lead compounds and a "first-in-class" fluorescent probe for imaging NAMPT. PMID- 26227785 TI - Distance between the Left Atrial Appendage and Mitral Annulus Evaluated by CARTO 3 Integrated Computed Tomography Imaging. AB - OBJECTIVE: To measure distances between pulmonary veins (PV) and mitral annulus (MA) using angiographic computed tomography (CT) and to compare them with the left atrial appendage-MA (LAA-MA) line. MATERIALS AND METHODS: Data from 46 catheter ablation procedures for atrial fibrillation involving 36 males, mean age 53 years, range 27-78 years, were analyzed. Three types of mitral isthmus lines were measured using angiographic CT images integrated in the CARTO 3 system (Biosense Webster): the distance between the right superior PV and MA (RSPV-MA), the right inferior PV and MA (RIPV-MA), and the left inferior PV and MA (LIPV MA). They were compared with the length of the LAA-MA line. RESULTS: The mean value of LIPV-MA was 29 +/- 11.2 mm, RIPV-MA 39 +/- 8.2 mm, and RSPV-MA 48 +/- 8.2 mm. The circumflex artery (CxA) and the coronary sinus (CS) were closest to the LIPV-MA line. Compared with the three isthmus lines, the LAA-MA was the shortest (24.7 +/- 15.6 mm), and the difference was statistically significant (p < 0.05). CONCLUSION: The angiographic CT provided detailed information regarding the anatomy of the left atrium and distances between atrial structures. The LAA MA was shorter than the other three lines with the CxA and CS situated at a distance. PMID- 26227786 TI - Personality and smoking: individual-participant meta-analysis of nine cohort studies. AB - AIMS: To investigate cross-sectional and longitudinal associations between personality and smoking, and test whether socio-demographic factors modify these associations. DESIGN: Cross-sectional and longitudinal individual-participant meta-analysis. SETTING: Nine cohort studies from Australia, Germany, the United Kingdom and the United States. PARTICIPANTS: A total of 79 757 men and women (mean age = 50.8 years). MEASUREMENTS: Personality traits of the five-factor model (extraversion, neuroticism, agreeableness, conscientiousness and openness to experience) were used as exposures. Outcomes were current smoking status (current smoker, ex-smoker and never smoker), smoking initiation, smoking relapse and smoking cessation. Associations between personality and smoking were modelled using logistic and multinomial logistic regression, and study-specific findings were combined using random-effect meta-analysis. FINDINGS: Current smoking was associated with higher extraversion [odds ratio per 1 standard deviation increase in the score: 1.16; 95% confidence interval (CI) = 1.08-1.24], higher neuroticism (1.19; 95% CI = 1.13-1.26) and lower conscientiousness (95% CI = 0.88; 0.83 0.94). Among non-smokers, smoking initiation during the follow-up period was predicted prospectively by higher extraversion (1.22; 95% CI = 1.04-1.43) and lower conscientiousness (0.80; 95% CI = 0.68-0.93), whereas higher neuroticism (1.16; 95% CI = 1.04-1.30) predicted smoking relapse among ex-smokers. Among smokers, smoking cessation was negatively associated with neuroticism (0.91; 95% CI = 0.87-0.96). Socio-demographic variables did not appear to modify the associations between personality and smoking. CONCLUSIONS: Adult smokers have higher extraversion, higher neuroticism and lower conscientiousness personality scores than non-smokers. Initiation into smoking is associated positively with higher extraversion and lower conscientiousness, while relapse to smoking among ex-smokers is associated with higher neuroticism. PMID- 26227787 TI - Allograft Anterior Cruciate Ligament Reconstruction in Patients Younger than 25 Years. AB - Purpose The purpose of this study was to evaluate the outcomes for patients younger than 25 years who had anterior cruciate ligament (ACL) reconstructions with allograft tissue. Methods A total of 52 ACL reconstructions performed with fresh-frozen, nonirradiated tibialis or Achilles allografts in active patients younger than 25 years. Outcome evaluations included the International Knee Documentation Committee (IKDC) objective and subjective forms, KT-1000 arthrometry and Lysholm. Results Forty-two patients were available for follow-up at an average follow-up of 65 months (range, 33-99 months). The average age at surgery was 17 years and 7 months (range, 11 years 10 months-24 years 8 months). Objective and subjective data were obtained from 37 patients with 1 requiring revision, and 5 patients had only subjective data. IKDC objective results were 29 A and 5-B. KT-1000 differences were 0 mm for 4 patients, 1 mm for 23, 2 mm for 8, 3 mm for 1, and > 5 mm for 1 patient. The average IKDC subjective score was 90.2 +/- 15.0 and average Lysholm score was 90.0 +/- 11. Conclusion The result of our study found that using nonirradiated Achilles or tibialis tendon allografts for ACL reconstructions in active patients younger than 25 years can achieve good outcomes, with a low rate of failure. PMID- 26227788 TI - [Comments on: Layperson warning system for cardiac arrest]. PMID- 26227789 TI - Expression of the microRNA regulators Drosha, Dicer and Ago2 in non-small cell lung carcinomas. AB - PURPOSE: MicroRNAs are evolutionarily conserved non-coding components of the transcriptome that can post-transcriptionally control gene expression. Altered microRNA expression has been found to be a common feature of several cancers, including lung carcinomas. The biogenesis and maturation of microRNAs is known to be mediated by the ribonucleases Drosha, Dicer and Ago2. The purpose of the present study was to investigate the expression and distribution of Drosha, Dicer and Ago2 in human non-small cell lung carcinomas (NSCLC) and to relate the respective expression patterns to clinocopatholical features. METHODS: We used five human NSCLC-derived cell lines and primary formalin-fixed paraffin-embedded tissue samples from 83 NSCLC patients. Drosha, Dicer and Ago2 mRNA and protein expression levels, and their sub-cellular distributions, were assessed using RT PCR, Western blotting, immunofluorescence and immunohistochemistry, respectively. RESULTS: We found that Drosha, Dicer and Ago2 were expressed in all the cell lines and primary neoplastic and non-neoplastic tissue samples tested. The intensity of the immunohistochemical staining was found to be significantly lower in stage I tumors compared to normal lung tissues. Dicer expression was found to be significantly higher in stage II compared to stage I tumors, and in stage III compared to stage II and stage I tumors. CONCLUSIONS: Our results point at a role of Drosha, Dicer and Ago2 in the development of NSCLC and suggest that Dicer may be implicated in the progression of these tumors to advanced stages. PMID- 26227790 TI - Ghrelin receptor modulates T helper cells during intestinal inflammation. AB - BACKGROUND: The orexigenic peptide ghrelin has anti-inflammatory properties in colitis, however, the mechanism of action and the immune cells targeted remain still to be elucidated. Here, we assessed the possible effect of ghrelin on T helper (Th) cells in a T cell transfer model of chronic colitis. METHODS: Disease was induced in the recombination activating gene 1 knockout mice (Rag1(-/-) ) by adoptive transfer of naive Th cells from ghrelin receptor knockout mice (GRLN-R( /-) ) or littermate wild-type (WT) mice. The course and severity of colitis was assessed by monitoring body weight, diarrhea score, histological analysis, gene expression, and flow cytometry analysis. The possible effects of ghrelin on Th cell proliferation, polarization, and apoptosis was examined in vitro. KEY RESULTS: Our data showed that Rag1(-/-) mice injected with GRLN-R(-/-) Th cells displayed increased severity of colitis compared to mice injected with WT Th cells. In addition, Rag1(-/-) mice injected with GRLN-R(-/-) Th cells had significantly higher intestinal inflammation and increased accumulation of Th1 and Th17 cells in the colon. In vitro, ghrelin directly affected proliferation of Th cells and induced apoptosis whereas it did not influence Th cell polarization. CONCLUSION & INFERENCES: Our observations suggest that ghrelin modulates Th effector cells in the gut controlling proliferation and inducing apoptosis. Our findings further support the use of ghrelin as a novel therapeutic option to treat intestinal inflammatory diseases. PMID- 26227791 TI - A Socioecological Predication Model of Posttraumatic Stress Disorder in Low Income, High-Risk Prenatal Native Hawaiian/Pacific Islander Women. AB - INTRODUCTION: Only recently has perinatal posttraumatic stress disorder (PTSD) been researched in any depth; however, the causes and consequences of this serious illness remain unclear. Most commonly, childbirth trauma and interpersonal violence have been reported as contributing factors. However, not all Native Hawaiian/Pacific Islander (NHPI) women who experience these events experience PTSD. The factors affecting PTSD are many and complex, intertwining individual, family, and community contexts. Using a socioecological framework, 3 levels of contextual variables were incorporated in this study (individual, family, and social/community). The purpose of this study was to determine the socioecological predictors associated with prenatal PTSD among NHPI. METHODS: A case-control design was used to collect retrospective data about socioecological variables from medical record data. The sample was low-income, high-risk NHPI women receiving perinatal health care at a rural community health center in Hawaii who screened positive (n = 55) or negative (n = 91) for PTSD. RESULTS: Hierarchical logistic regression was conducted to determine socioecological predictors of positive PTSD screening. Although the majority of women (66.4%) experienced some form of interpersonal violence, a constellation of significant predictor variables from all 3 levels of the model were identified: depression (individual level), lack of family support and family stress (family level), and violence (social/community level). DISCUSSION: Each of the predictor variables has been identified by other researchers as significantly affecting perinatal PTSD. However, it is because these variables occur together that a more complex picture emerges, suggesting the importance of considering multiple variables in context when identifying and caring for these women. Although additional research is needed, it is possible that the significant predictor variables could be useful in identifying women who are at higher risk for PTSD in other similar populations. PMID- 26227792 TI - Association Between Paraoxonase Gene Polymorphisms and Intracerebral Hemorrhage in a Korean Population. AB - The human paraoxonase (PON) gene family includes three members: PON1, PON2, and PON3. PON, which prevents the oxidative modification of lipoproteins, has been implicated as a potential risk factor of the cerebrovascular disease. In this study, we investigated associations between coding region single-nucleotide polymorphisms (cSNPs) of PON1, PON2, and PON3 genes and intracerebral hemorrhage (ICH) in a Korean population. Six cSNPs [rs13306698 and rs662 for PON1; rs12026 and rs7493 for PON2; rs13226149 and rs1053275 for PON3] were genotyped using direct sequencing in 145 ICH patients and 372 control subjects. Of the six cSNPs, rs12026 and rs7493, which were in complete linkage disequilibrium, were associated with ICH in log-additive (GC vs. CC vs. GG, p = 0.0008, OR = 0.53, 95 % CI = 0.36-0.78) and dominant models (GC/CC vs. GG, p = 0.0006, OR = 0.47, 95 % CI = 0.30-0.73). In addition, rs13226149 was associated with ICH in log-additive model (GA vs. AA vs. GG, p = 0.0033, OR = 0.58, 95 % CI = 0.39-0.84). In the allele frequency analysis, the C alleles of rs12026 and rs7493 and the A allele of rs13226149 were also shown to contribute to the decreased risk of ICH (p = 0.001, OR = 0.55, 95 % CI = 0.38-0.80 in rs12026 and rs7493; p = 0.003, OR = 0.58, 95 % CI = 0.40-0.83 in rs13226149). These results suggest that PON genes may be involved in the susceptibility of ICH. PMID- 26227793 TI - Neuroleptics Affect Neuropeptide S and NPSR mRNA Levels in the Rat Brain. AB - Neuropeptide S (NPS) has a multidirectional regulatory activity, especially when considered as a potent endogenous anxiolytic factor. Accumulating data suggests that neuroleptics affect peptidergic signaling in various brain structures. However, there is no information regarding the influence of treatment with antipsychotics on brain NPS expression. In the current study, we assessed the NPS and NPS receptor (NPSR) mRNA levels in the brains of rats shortly and chronically treated with chlorpromazine and olanzapine using quantitative real-time PCR. Both single-dose and long-term (4 months) olanzapine treatment led to the upregulation of NPS expression in the rat hypothalamus. It supports the hypothesis that NPS is involved in the dopamine-dependent anxiolytic actions of selected neuroleptics and possibly also in the pathophysiology of mental disorders. On the other hand, NPSR expression decreased after single-dose and chronic chlorpromazine administration in the hypothalamus, as well as after chronic olanzapine and chlorpromazine administration in the striatum and hippocampus. These results cast a new light on the pharmacology of antipsychotics and contribute to a better understanding of the mechanisms responsible for their action. Furthermore, our findings underline the complex nature of potential interactions between dopamine receptors and brain peptidergic pathways, which has potential clinical applications. PMID- 26227794 TI - Environmental Enrichment Ameliorates Neonatal Sevoflurane Exposure-Induced Cognitive and Synaptic Plasticity Impairments. AB - Early exposure to sevoflurane, an inhalation anesthetic, induces neurodegeneration in the developing brain and subsequent long-term neurobehavioral abnormalities. Here, we investigated whether an enriched environment could mitigate neonatal sevoflurane exposure-induced long-term cognitive and synaptic plasticity impairments. Male C57BL/6 mice were exposed to 3 % sevoflurane 2 h daily for 3 days from postnatal day 6 (P6) to P8. The exposed mice were randomly allocated to an enriched environment for 2 h daily between P8 and P42 or to a standard environment. Their behavior and cognition were assessed using open field (P35) and fear conditioning tests (P41-P42). Hematoxylin-eosin staining was used to study morphological changes in pyramidal neurons of hippocampal CA1 and CA3 regions. Synaptic plasticity alternations were assessed using western blotting, Golgi staining, and electrophysiological recording. We found that sevoflurane-exposed mice housed in a standard environment exhibited a reduced freezing response in the contextual test, decreased number of dendritic spines on pyramidal neurons and synaptic plasticity-related proteins in the hippocampus, and impaired long-term potentiation. However, in an enriched environment, some of these abnormities induced by repeated sevoflurane exposure. In conclusion, neonatal sevoflurane exposure-induced cognitive and synaptic plasticity impairments are ameliorated by an enriched environment. PMID- 26227795 TI - Polyphenol-rich juices reduce blood pressure measures in a randomised controlled trial in high normal and hypertensive volunteers. AB - Intake of fruits and berries may lower blood pressure (BP), most probably due to the high content of polyphenols. In the present study, we tested whether consumption of two polyphenol-rich juices could lower BP. In a randomised, double blinded, placebo-controlled trial of 12 weeks, 134 healthy individuals, aged 50 70 years, with high normal range BP (130/85-139/89 mmHg, seventy-two subjects) or stage 1-2 hypertension (140/90-179/109 mmHg, sixty-two subjects), were included. They consumed 500 ml/d of one of either (1) a commercially available polyphenol rich juice based on red grapes, cherries, chokeberries and bilberries; (2) a juice similar to (1) but enriched with polyphenol-rich extracts from blackcurrant press-residue or (3) a placebo juice (polyphenol contents 245.5, 305.2 and 76 mg/100 g, respectively). Resting BP was measured three times, with a 1 min interval, at baseline and after 6 and 12 weeks of intervention. Systolic BP significantly reduced over time (6 and 12 weeks, respectively) in the pooled juice group compared with the placebo group in the first of the three measurements, both for the whole study group (6.9 and 3.4 mmHg; P= 0.01) and even more pronounced in the hypertensive subjects when analysed separately (7.3 and 6.8 mmHg; P= 0.04). The variation in the BP measurements was significantly reduced in the pooled juice group compared with the placebo group (1.4 and 1.7 mmHg; P= 0.03). In conclusion, the present findings suggest that polyphenol-rich berry juice may contribute to a BP- and BP variability lowering effect, being more pronounced in hypertensive than in normotensive subjects. PMID- 26227796 TI - High-resolution manometry findings in symptomatic post-Nissen fundoplication patients with normal endoscopic configuration. AB - The aim of this study was to investigate high-resolution manometry (HRM) findings in symptomatic post-fundoplication patients with normal endoscopic configuration. A retrospective review of a prospectively maintained database was conducted to identify patients who underwent evaluation with HRM and endoscopy for symptom evaluation after previous fundoplication. Study period extends from September 2008 to December 2012. Only patients with complete 360 degrees fundoplication (Nissen) were included, and patients with partial fundoplication were excluded. Patients with endoscopic abnormality or patients who underwent Collis procedure were also excluded. Additionally, contrast study and 24-hour pH study if done were reviewed. Symptoms were graded using a standard questionnaire with symptoms graded on a scale of 0-3. Symptom grade 2 or 3 was considered a significant symptom. One hundred seventy-nine symptomatic patients with previous Nissen fundoplication underwent HRM and endoscopy during the study period. Of these, 136 patients were excluded (51 had recurrent hiatal hernia, 2 had disrupted fundoplication, 68 had slipped fundoplication, 10 had twisted fundoplication, 2 had esophageal stricture, and 3 had Collis procedure). Remaining forty-three patients met inclusion criteria (mean age of 56.0 +/- 14.8, 32 females).The most common symptom was dysphagia (67%). Patients with dysphagia had a significantly longer length of distal esophageal high pressure zone (HPZ) and a higher integrated relaxation pressure (IRP) than patients without dysphagia (P = 0.020, 0.049). Especially, patients who had shorter HPZ (<=2 cm) were less likely to have significant dysphagia. Twenty-three patients (53%) had heartburn. There was no significant difference in HRM findings between patients with and without heartburn. Only 4 of 28 patients with concomitant pH study showed abnormal DeMeester score (>14.7), and there was no correlation between results of pH study and lower esophageal sphincter pressure/length and IRP. Longer HPZ complex length and higher IRP as measured with HRM is associated with post-Nissen fundoplication dysphagia in patients with normal endoscopic configuration. No HRM parameters are associated with reported heartburn or a positive pH score. PMID- 26227797 TI - Molecular detection of zoonotic tick-borne pathogens from ticks collected from ruminants in four South African provinces. AB - Ticks carry and transmit a remarkable array of pathogens including bacteria, protozoa and viruses, which may be of veterinary and/or of medical significance. With little to no information regarding the presence of tick-borne zoonotic pathogens or their known vectors in southern Africa, the aim of our study was to screen for Anaplasma phagocytophilum, Borrelia burgdorferi, Coxiella burnetii, Rickettsia species and Ehrlichia ruminantium in ticks collected and identified from ruminants in the Eastern Cape, Free State, KwaZulu-Natal and Mpumalanga Provinces of South Africa. The most abundant tick species identified in this study were Rhipicephalus evertsi evertsi (40%), Rhipicephalus species (35%), Amblyomma hebraeum (10%) and Rhipicephalus decoloratus (14%). A total of 1634 ticks were collected. DNA was extracted, and samples were subjected to PCR amplification and sequencing. The overall infection rates of ticks with the target pathogens in the four Provinces were as follows: A. phagocytophilum, 7%; C. burnetii, 7%; E. ruminantium, 28%; and Rickettsia spp., 27%. The presence of B. burgdorferi could not be confirmed. The findings of this study show that zoonotic pathogens are present in ticks in the studied South African provinces. This information will aid in the epidemiology of tick-borne zoonotic diseases in the country as well as in raising awareness about such diseases in the veterinary, medical and tourism sectors, as they may be the most affected. PMID- 26227798 TI - Conformational states of the full-length glucagon receptor. AB - Class B G protein-coupled receptors are composed of an extracellular domain (ECD) and a seven-transmembrane (7TM) domain, and their signalling is regulated by peptide hormones. Using a hybrid structural biology approach together with the ECD and 7TM domain crystal structures of the glucagon receptor (GCGR), we examine the relationship between full-length receptor conformation and peptide ligand binding. Molecular dynamics (MD) and disulfide crosslinking studies suggest that apo-GCGR can adopt both an open and closed conformation associated with extensive contacts between the ECD and 7TM domain. The electron microscopy (EM) map of the full-length GCGR shows how a monoclonal antibody stabilizes the ECD and 7TM domain in an elongated conformation. Hydrogen/deuterium exchange (HDX) studies and MD simulations indicate that an open conformation is also stabilized by peptide ligand binding. The combined studies reveal the open/closed states of GCGR and suggest that glucagon binds to GCGR by a conformational selection mechanism. PMID- 26227799 TI - The SWITCH study: rationale and design of the trial. AB - Many patients do not respond to the first antipsychotic drug prescribed, but require multiple trials with different drugs before response is achieved. Current treatment guidelines vary substantially in their recommendations as to how long clinicians should wait before an antipsychotic treatment attempt should be considered as failed and the compound switched. It has, however, recently been shown that poor early response to an antipsychotic is associated with continuous poor later response in the course of the same treatment attempt. This finding suggests that patients who do experience poor early response might benefit from a switch in antipsychotic medication as early as 2 weeks after treatment initiation. In the SWITCH trial, 350 patients suffering from an acute episode of schizophrenia are randomly assigned to double-blind treatment with either olanzapine or amisulpride. The primary endpoint is symptomatic remission at week 8. Patients not experiencing at least minor response after 2 weeks are randomized again to either staying on the initially assigned drug or being switched to the alternative compound for another 6 weeks. In case early switching proves superior to maintaining treatment, time wasted for unsuccessful treatment attempts could be minimized, patients' outcomes improved, duration of hospital stays reduced, and thus overall treatment expenses saved. The current report will present the methods of the trial, focusing on various specific features which could be adopted by future studies. PMID- 26227800 TI - Assessment of left atrial volume and function in patients with psoriasis by using real time three-dimensional echocardiography. AB - BACKGROUND: Left atrial (LA) volume has been identified as a predictor of adverse cardiovascular outcomes, both in the general population and in selected clinical conditions. The aim of this study was to evaluate the effect of psoriasis on LA volume and mechanical function. METHODS: A total of 40 consecutive normotensive psoriasis patients free of any cardiovascular disease and 39 healthy volunteers were included. All participants underwent comprehensive transthoracic echocardiographic examination. LA volume and mechanical function were evaluated using real-time three-dimensional echocardiography (RT3DE). RESULTS: There were no significant differences between psoriasis and control groups with regard to conventional echocardiographic parameters. Individuals with psoriasis had a higher incidence of left ventricular diastolic dysfunction (LVDD) than the controls; nine people with psoriasis (23%) and three control individuals (8%) had LVDD (p = 0.06). With regard to the parameters obtained from RT3DE, LA maximum, LA minimum, passive stroke volume, and passive emptying fraction were significantly higher; whereas LA active emptying fraction, LA total emptying fraction, LA expansion index, and active stroke volume values were significantly lower in individuals with psoriasis compared with controls. Disease duration and Psoriasis Area of Severity Index (PASI) score correlated with the majority of volume parameters. CONCLUSION: Individuals with psoriasis had higher LA phasic volumes and impaired LA mechanical function compared with healthy controls. LA volume and functional analysis with RT3DE may facilitate recognition of subtle LA dysfunction in patients with psoriasis. PMID- 26227801 TI - The "dromedary hump" appearance. PMID- 26227802 TI - Introduction to the feature section on errors in abdominal imaging. PMID- 26227803 TI - Invasion Expansion: Time since introduction best predicts global ranges of marine invaders. AB - Strategies for managing biological invasions are often based on the premise that characteristics of invading species and the invaded environment are key predictors of the invader's distribution. Yet, for either biological traits or environmental characteristics to explain distribution, adequate time must have elapsed for species to spread to all potential habitats. We compiled and analyzed a database of natural history and ecological traits of 138 coastal marine invertebrate species, the environmental conditions at sites to which they have been introduced, and their date of first introduction. We found that time since introduction explained the largest fraction (20%) of the variability in non native range size, while traits of the species and environmental variables had significant, but minimal, influence on non-native range size. The positive relationship between time since introduction and range size indicates that non native marine invertebrate species are not at equilibrium and are still spreading, posing a major challenge for management of coastal ecosystems. PMID- 26227804 TI - Subtotal hepatectomy in swine for studying small-for-size syndrome and portal inflow modulation: is it reliable? AB - BACKGROUND: Small-for-size syndrome (SFSS) is a feared complication of extended liver resection and partial liver transplantation. Swine models of extended hepatectomy have been developed for studying SFSS and its different treatment options. Although portal inflow modulation (PIM) by splenectomy or splenic artery ligation (SAL) has been proposed in humans to prevent SFSS, such procedures have not yet been evaluated in swine. OBJECTIVES: The present study was designed to evaluate modifications in splanchnic haemodynamics yielded by extended hepatectomy with and without PIM in swine. METHODS: Nineteen animals underwent 70% hepatectomy (H70, n = 7), 90% hepatectomy (H90, n = 7) or sham laparotomy (H0, n = 5). Haemodynamic measurements were performed at baseline, after hepatectomy and after PIM by SAL and splenectomy. RESULTS: Portal vein flow increased after both H70 (273 ml/min/100 g versus 123 ml/min/100 g; P = 0.016) and H90 (543 ml/min/100 g versus 124 ml/min/100 g; P = 0.031), but the hepatic venous pressure gradient (HVPG) increased only after H90 (10.0 mmHg versus 3.7 mmHg; P = 0.016). Hepatic artery flow did not significantly decrease after either H70 or H90. In all three groups, neither splenectomy nor SAL induced any changes in splanchnic haemodynamics. CONCLUSIONS: Subtotal hepatectomy of 90% in swine is a reliable model for SFSS inducing a significant increase in HVPG. However, in view of the relevant differences between swine and human splanchnic anatomy, this model is inadequate for studying the effects of PIM by SAL and splenectomy. PMID- 26227805 TI - Failure location prediction by finite element analysis for an additive manufactured mandible implant. AB - In order to reconstruct a patient with a bone defect in the mandible, a porous scaffold attached to a plate, both in a titanium alloy, was designed and manufactured using additive manufacturing. Regrettably, the implant fractured in vivo several months after surgery. The aim of this study was to investigate the failure of the implant and show a way of predicting the mechanical properties of the implant before surgery. All computed tomography data of the patient were preprocessed to remove metallic artefacts with metal deletion technique before mandible geometry reconstruction. The three-dimensional geometry of the patient's mandible was also reconstructed, and the implant was fixed to the bone model with screws in Mimics medical imaging software. A finite element model was established from the assembly of the mandible and the implant to study stresses developed during mastication. The stress distribution in the load-bearing plate was computed, and the location of main stress concentration in the plate was determined. Comparison between the fracture region and the location of the stress concentration shows that finite element analysis could serve as a tool for optimizing the design of mandible implants. PMID- 26227806 TI - Spleen preserving laparoscopic distal pancreatectomy for treatment of pancreatic lesions. AB - AIM: Aim of this study is to evaluate the feasibility and safety of the laparoscopic approach in the treatment of distal pancreas tumors, from prospectively collected data. MATERIAL OF STUDY: From January 2003 to July 2013, 20 patients were treated by laparoscopic approach for distal pancreatic lesions. Nine patients underwent laparoscopic pancreatic tumorectomy (LPT) (Group A) for insulinoma (mean lesion diameter 1.2 cm, range, 0.5-2) and 11 patients underwent spleen preserving laparoscopic distal pancreatectomy (SP-LDP) (Group B) for ductal adenocarcinoma (pT1N0R0) (1), cystic mucinous neoplasm (5), serous cystadenoma (4) and lymphoepithelial cysts (1). RESULTS: Mean operative time was 94.3 minutes (range 80-110) for Group A and 164 minutes (range 90-240) for Group B. Intraoperative bleeding occurred in 4 cases (20%) and was easily controlled by laparoscopy. Conversion to open surgery was not required in any case. Morbidity was observed in 2 patients (18%) in Group A: pancreatic fistula (1) and peritoneal fluid collection (1); and a peritoneal fluid collection occurred in one patients (11%) in Group B. Mean hospital stay was 6.8 days (range 3-11) in Group A and 6.5 days (range 3-10) in Group B. Mortality was nil. At a mean follow up of 82 months (range 15-141) local recurrence and distant metastases were not observed. DISCUSSION: LDP is a valid treatment showing the same rate of complication to open surgery but allowing the advantages of a minimally invasive procedure. CONCLUSIONS: SP-LDP is feasible and safe for benign and malignant pancreatic lesions. PMID- 26227807 TI - The nephridial hypothesis of the gill slit origin. AB - Metameric gill slits are mysterious structures, unique for Chordata and Hemichordata, and also, perhaps, for the extinct Cambrian Calcichordata. There is a discussed hypothesis of the gill slits origin from the metameric nephridia. According to the hypothesis, the hypothetical metameric deuterostome ancestor had in each segment a pair of coelomoducts and a pair of intestinal pockets. In the anterior segments, the coelomoducts have fused with the intestinal pockets. As a result, each nephridium opened both into the gut and into the environment. Then the dissepiments and funnels reduced in all segments except the collar one. Thus, in recent enteropneusts, only the first pair of gill slits keeps the ancestral arrangement communicating at the same time with the gut, with the environment, and with the coelom of the preceding (collar) segment. In the anterior part of the branchio-genital trunk region of enteropneusts, the metameric intestinal pockets remained, as well as the metameric coelomoducts functioning as the ducts of the metameric gonads, i.e., as the gonoducts. The consequence of the hypothesis is that the metameric gill pores originate from the metameric excreting pores, and the metameric branchial sacs originate from the metameric endodermal pockets of the gut fused with the coelomoducts. The metameric gill slits by themselves correspond with metameric openings connecting the gut with metameric intestinal pockets. J. Exp. Zool. (Mol. Dev. Evol.) 324B: 647-652, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26227808 TI - Allergic contact dermatitis caused by timolol with cross-sensitivity to levobunolol. PMID- 26227810 TI - Hybrid smart mesoporous silica nanoparticles for theranostics. PMID- 26227809 TI - AduPARE1A and gemcitabine combined treatment trigger synergistic antitumor effects in pancreatic cancer through NF-kappaB mediated uPAR activation. AB - BACKGROUND: Combined treatment of oncolytic adenoviruses with chemotherapeutic agents is foreseen as a therapeutic option for cancer. Here we have investigated the potential to use gemcitabine in combination with the oncolytic adenovirus AduPARE1A to treat pancreatic cancer and evaluate the underlying mechanism. METHODS: We treated pancreatic cancer cell lines BxPC-3 and PANC-1 with AduPARE1A and gemcitabine individually or in combination and analyzed cell viability, combination index, apoptosis and viral production. We also investigated the effects of the combination on tumor growth and mice survival in two xenograft models. Furthermore, we analyzed uPAR promoter activity from different uPAR controlled adenovirus and studied NF-kappaB mediated effects. RESULTS: Synergistic cell killing from the combination AduPARE1A/Gemcitabine was observed in BxPC-3 and PANC-1 cells. Moreover, the combination treatment produced therapeutic benefits over either individual modality in two mouse models bearing orthotopic tumors, showing reduced tumor progression and significant prolonged mouse survival. Mechanistic studies showed that the synergistic cell death was not due to an increase in viral replication but occurred through an enhancement of apoptotic cell death. Gemcitabine stimulation increased the transcription of uPAR-controlled transgenes through the induction of NF-kappaB acting on the uPAR promoter. Interestingly, NF-kappaB gemcitabine-mediated induction of AduPAR adenoviruses interfered with the activation of NF-kappaB regulated genes, probably as a result of an intracellular competition for NF-kappaB DNA binding. Consequently, AduPARE1A infection sensitized cells to gemcitabine-induced apoptosis in the combined treatment. CONCLUSIONS: These data highlights the potential of the combination as a treatment modality for pancreatic cancer patients. PMID- 26227812 TI - Systematic study of the synthesis and coordination of 2-(1,2,3-triazol-4-yl) pyridine to Fe(II), Ni(II) and Zn(II); ion-induced folding into helicates, mesocates and larger architectures, and application to magnetism and self selection. AB - With its facile synthesis, the pyridine-1,2,3-triazole chelate is an attractive building block for coordination-driven self-assembly. When two such chelates are bridged by a spacer and exposed to cations of octahedral geometrical preference, they generally self-assemble into dinuclear triple-stranded structures in the solid state and in solution in the presence of non-coordinating counter-ions. In solution, a wider range of architectures may nevertheless form, depending on the nature of the spacer. A systematic study of the spacer and substitution pattern is therefore presented, which allows assessing the various factors affecting self assembly around the pyridine-1,2,3-triazole chelate, as well as the stereochemical control in these architectures. Applications to chirality, magnetism and system selection are discussed, and involve Fe(ii), Ni(ii), Zn(ii) and Cu(i) cations. PMID- 26227811 TI - Conditional inactivation of Akt three isoforms causes tau hyperphosphorylation in the brain. AB - BACKGROUND: Tau hyperphosphorylation plays a critical role in neurodegenerative diseases [EMBO Mol Med. 6:1142-60, 2014; Annu Rev Neurosci. 24:1121-59, 2001]. Recent evidence has shown that Akt is down-regulated in AD [J Pathol. 225:54-62, 2011]. However, it remained unknown which pathological process, e.g. tau pathology or neuron death, Akt may contribute to. In this study, Cre-loxP technique was employed to generate a viable Akt three isoforms conditional knockout (Akt cTKO) mouse in which total Akt levels were dramatically reduced in the adult brain. RESULTS: Significantly increased levels of tau phosphorylated (p tau) at various sites were observed in Akt cTKO mice as compared to age-matched littermate controls. Increased levels for phosphorylated GSK3alpha and phosphorylated PKA substrates were detected in Akt cTKO brains. In contrast, no significant changes on p-tau levels were found in Akt1(-/-), Akt2(-/-) or Akt3(-/ ) mice. CONCLUSIONS: Akt may regulate tau phosphorylation in the adult brain by affecting activities for PKA and GSK3alpha. PMID- 26227813 TI - Formulation optimization of a drug in adhesive transdermal analgesic patch. AB - CONTEXT: Conventional pain management approaches have limitations such as gastrointestinal side effects, frequent dosing, and difficulties in swallowing medications. Hence, to overcome these limitations, we developed a transdermal analgesic patch. OBJECTIVE: This study was designed to formulate a drug in adhesive transdermal patch with codeine (CDB) and acetaminophen (APAP) that may potentially treat moderate pain in children. MATERIALS AND METHODS: Three analgesic drugs hydrocodone bitartrate, CDB and APAP were screened by a slide crystallization study using polarized light microscope and their permeation profiles were studied using vertical Franz diffusion cells across porcine ear skin, dermatomed human skin and epidermis for 24 h, and the samples were quantified by high performance liquid chromatography. Patches used for permeation studies were prepared by dissolving sub-saturation concentration of the drug(s) in adhesive (with/without 5% w/w oleic acid [OA]), cast with a film casting knife. RESULTS AND DISCUSSION: Among the three drugs screened, CDB demonstrated the best permeation profile (660.21 ug/cm2), and shortest lag time (4.35 +/- 0.01 h), and hence was chosen for patch studies. The highest concentration of CDB in the patch at which drug does not crystallize was determined as 40% of its saturation solubility (Cs) and that of APAP was determined as 200% of its Cs. CDB standalone patch delivered 105.48 ug/cm2 of CDB, while the CDB-APAP combination patch with 5% w/w OA delivered 151.40 ug/cm2 CDB and 58.12 ug/cm2 APAP in 24 h. CONCLUSION: Drug-in-adhesive patches using CDB and APAP were developed for infants and children. Addition of OA enhanced solubility and permeation of drugs. PMID- 26227814 TI - Enhancing governance and health system accountability for people centered healthcare: an exploratory study of community scorecards in Afghanistan. AB - BACKGROUND: The premise of patient-centered care is to empower patients to become active participants in their own care and receive health services focused on their individual needs and preferences. Afghanistan has evidenced enormous gains in coverage and utilization, but the quality of care remains suboptimal, as evidenced in the balanced scorecard (BSC) performance assessments. In the United States and throughout Africa and Asia, community scorecards (CSC) have proved effective in improving accountability and responsiveness of services. This study represents the first attempt to assess CSC feasibility in a fragile context (Afghanistan) through joint engagement of service providers and community members in the design of patient-centered services with the objective of assessing impact on service delivery and perceived quality of care. METHODS: Six primary healthcare facilities were randomly selected in three provinces (Bamyan, Takhar and Nangarhar) and communities in their catchment area were selected for the study. Employing a multi-stakeholder strategy, community members and leaders, health councils, facility providers, NGO managers, and provincial directorates were engaged in a five-phase process to jointly identify structural and service delivery indicators (about 20), score performance and subsequently develop action plans for instituting improvements through participatory research methods. Three rounds of CSC assessments were conducted in each community. Over 470 community members, 34 health providers, and other provincial ministry staff participated in the performance audits. RESULTS: Structural capacity indicators including the number and cadre of service providers, particularly female providers, water and power supply, waiting rooms, essential medicines, and equipment scored low in the first round (30-50%). Provider courtesy and quality of care received high scores (>90%) throughout the study. Unrealistic community demands for ambulances and specialist doctors were mitigated by community education of entitlements described in the national standards for essential package of services. The joint interface meeting facilitated transparent dialogue between the community and providers and resulted in creative and participatory problem solving mechanisms and mobilization of resources. CONCLUSION: These results indicate the potential of the CSC as a tool for enhancing social accountability for patient-centered care. However, the process requires skilled facilitators to effectively engage communities and healthcare providers and adaptation to specific healthcare contexts. PMID- 26227815 TI - Dramatic recovery of steroid-refractory relapsed multiple sclerosis following Fingolimod discontinuation using selective immune adsorption. AB - BACKGROUND: Selective immune adsorption (SIA) is an emerging method for treating immune-mediated neurological diseases, given its superior safety profile compared to plasma exchange (PEX). However, the available literature concerning Multiple Sclerosis includes no cases of SIA applied to steroid-refractory rebound after Fingolimod discontinuation. CASE PRESENTATION: Here we report the case of a 32 year-old woman suffering from multiple sclerosis treated with Fingolimod and admitted to a Multiple Sclerosis Centre after drug discontinuation due to the occurrence of lymphopenia. During the few weeks preceding admission, the patient experienced progressive and severe neurological deterioration that did not respond to an initial cycle of pulsed high doses of intravenous 6-methyl prednisolone (IVMP). Given the ineffectiveness of a second cycle of IVMP, the patient was treated with plasma immunoadsorption, leading to dramatic functional recovery. The patient then started a neuro-rehabilitation program. About one month after the final SIA procedure the patient started Natalizumab-based therapy, while maintaining a stable neurological condition. We noted significant modification of C3/C4 complement components and total gamma globulin concentrations (IgG) during SIA. CONCLUSIONS: Our observations show that however serious, steroid-refractory neurological deterioration occurring after Fingolimod discontinuation in multiple sclerosis can be treated with selective immune adsorption therapy which thus represents a good alternative in these cases. It could be speculated that this clinical condition was associated with pattern II of demyelination, given the good response to a form of treatment that acts on autoantibodies. Thus, SIA represented an effective therapeutic strategy for this case of relapsed MS as steroid-resistent rebound post Fingolimod cessation. PMID- 26227817 TI - An overview of the current plant biostimulant legislations in different European Member States. AB - Plant biostimulants are borderline substances that play an intermediate role between plant protection products and fertilisers. At present, such substances are regulated by national laws and have different names in the various European Member States. The aim of this paper is to provide an overview on the activity of these substances and on the national laws that regulate them, as they vary considerably from one Member State to another. The greatest difficulty in terms of the correct regulatory framework for these substances is related to their heterogeneity. This situation creates uncertainties for operators, control authorities and bodies that certify and control the organic production, and strongly limits the growth of these substances. This problem will be overcome with the amendment of Regulation EC No 2003/2003 which will shortly extend its scope to the category of plant biostimulants included within the fertilising additives. PMID- 26227816 TI - The Genome of Winter Moth (Operophtera brumata) Provides a Genomic Perspective on Sexual Dimorphism and Phenology. AB - The winter moth (Operophtera brumata) belongs to one of the most species-rich families in Lepidoptera, the Geometridae (approximately 23,000 species). This family is of great economic importance as most species are herbivorous and capable of defoliating trees. Genome assembly of the winter moth allows the study of genes and gene families, such as the cytochrome P450 gene family, which is known to be vital in plant secondary metabolite detoxification and host-plant selection. It also enables exploration of the genomic basis for female brachyptery (wing reduction), a feature of sexual dimorphism in winter moth, and for seasonal timing, a trait extensively studied in this species. Here we present a reference genome for the winter moth, the first geometrid and largest sequenced Lepidopteran genome to date (638 Mb) including a set of 16,912 predicted protein coding genes. This allowed us to assess the dynamics of evolution on a genome wide scale using the P450 gene family. We also identified an expanded gene family potentially linked to female brachyptery, and annotated the genes involved in the circadian clock mechanism as main candidates for involvement in seasonal timing. The genome will contribute to Lepidopteran genomic resources and comparative genomics. In addition, the genome enhances our ability to understand the genetic and molecular basis of insect seasonal timing and thereby provides a reference for future evolutionary and population studies on the winter moth. PMID- 26227818 TI - Reviewing the Osteotropism in Neuroendocrine Tumors: The Role of Epithelial Mesenchymal Transition. AB - BACKGROUND: Neuroendocrine tumors (NETs) metastasize to the bone. However, the incidence, clinical features, management and pathogenesis of bone involvement in NET patients have been poorly investigated. METHODS: We reviewed all published reports of histologically confirmed bone metastatic NETs and explored clinical, radiological, prognostic and therapeutic characteristics in a population of 152 patients. We then evaluated immunohistochemical expression of a panel of eight epithelial-mesenchymal transition (EMT)-related factors including SNAIL, TGF beta1, CTGF, IL-11, PTHrP, EpCAM, CXCR4 and RANK in an independent cohort of 44 archival primary NETs. Biomarker expression was correlated with clinicopathological variables, including skeletal involvement, and tested for survival prediction. RESULTS: We found that 55% of NET patients with bone metastases were male, with a median age of 55 years at diagnosis. Metastases were restricted to the skeleton in 34% of the NET population, and axial and osteoblastic lesions were prevalent. NETs differently expressed proteins involved in EMT activation. High CXCR4 (p < 0.0001) and low TGF-beta1 levels (p = 0.0015) were significantly associated with increased risk of skeletal metastases, suggesting that EMT is implicated in NET osteotropism. By applying an algorithm measuring distinct immunohistochemical predictors of osteotropism on primary tumors, we were able to identify NET patients with bone metastases with a sensitivity and specificity of 91 and 100%, respectively (p < 0.0001). Patients whose primary tumors expressed CTGF (p = 0.0007) as well as the truncated form of EpCAM (p = 0.06) showed shorter survival. CONCLUSION: Although underestimated, bone metastases are a prominent feature of NETs, and the tumor expression of EMT markers at diagnosis may predict concurrent or subsequent skeleton colonization. PMID- 26227819 TI - Structural and functional correlations in a large animal model of bleomycin induced pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a severe and progressive respiratory disease with poor prognosis. Despite the positive outcomes from recent clinical trials, there is still no cure for this disease. Pre-clinical animal models are currently largely limited to small animals which have a number of shortcomings. We have previously shown that fibrosis is induced in isolated sheep lung segments 14 days after bleomycin treatment. This study aimed to determine whether bleomycin-induced fibrosis and associated functional changes persisted over a seven-week period. METHODS: Two separate lung segments in nine sheep received two challenges two weeks apart of either, 3U bleomycin (BLM), or saline (control). Lung function in these segments was assessed by a wedged bronchoscope procedure after bleomycin treatment. Lung tissue, and an ex vivo CT analysis were used to assess for the persistence of inflammation, fibrosis and collagen content in this model. RESULTS: Fibrotic changes persisted up to seven weeks in bleomycin-treated isolated lung segments (Pathology scores: bleomycin12.27 +/- 0.07 vs. saline 4.90 +/- 1.18, n = 9, p = 0.0003). Localization of bleomycin-induced injury and increased tissue density was confirmed by CT analysis (mean densitometric CT value: bleomycin -698 +/- 2.95 Hounsfield units vs. saline -898 +/- 2.5 Hounsfield units, p = 0.02). Masson's trichrome staining revealed increased connective tissue in bleomycin segments, compared to controls (% blue staining/total field area: 8.5 +/- 0.8 vs. 2.1 +/- 0.2 %, n = 9, p < 0.0001). bleomycin-treated segments were significantly less compliant from baseline at 7 weeks post treatment compared to control-treated segments (2.05 +/- 0.88 vs. 4.97 +/- 0.79 mL/cmH20, n = 9, p = 0.002). There was also a direct negative correlation between pathology scores and segmental compliance. CONCLUSIONS: We show that there is a correlation between fibrosis and correspondingly poor lung function which persist for up to seven weeks after bleomycin treatment in this large animal model of pulmonary fibrosis. PMID- 26227821 TI - The case for neuropsychoanalysis: Why a dialogue with neuroscience is necessary but not sufficient for psychoanalysis. AB - Recent advances in the cognitive, affective and social neurosciences have enabled these fields to study aspects of the mind that are central to psychoanalysis. These developments raise a number of possibilities for psychoanalysis. Can it engage the neurosciences in a productive and mutually enriching dialogue without compromising its own integrity and unique perspective? While many analysts welcome interdisciplinary exchanges with the neurosciences, termed neuropsychoanalysis, some have voiced concerns about their potentially deleterious effects on psychoanalytic theory and practice. In this paper we outline the development and aims of neuropsychoanalysis, and consider its reception in psychoanalysis and in the neurosciences. We then discuss some of the concerns raised within psychoanalysis, with particular emphasis on the epistemological foundations of neuropsychoanalysis. While this paper does not attempt to fully address the clinical applications of neuropsychoanalysis, we offer and discuss a brief case illustration in order to demonstrate that neuroscientific research findings can be used to enrich our models of the mind in ways that, in turn, may influence how analysts work with their patients. We will conclude that neuropsychoanalysis is grounded in the history of psychoanalysis, that it is part of the psychoanalytic worldview, and that it is necessary, albeit not sufficient, for the future viability of psychoanalysis. PMID- 26227820 TI - Adult-onset cerebello-brainstem dominant form of X-linked adrenoleukodystrophy presenting as multiple system atrophy: case report and literature review. AB - X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is caused by ABCD1 mutations. A cerebello-brainstem dominant form that mainly involves the cerebellum and brainstem is summarized in a review of the literature, with autopsy-confirmed cases exceedingly rare. We report a 69-year old White man who was diagnosed with this rare disorder and describe neuropathologic, ultrastructural and genetic analyses. He did not have adrenal insufficiency or a family history of X-ALD or Addison's disease. His initial symptom was temporary loss of eyesight at age 34 years. His major symptoms were chronic and progressive gait disorder, weakness in his lower extremities and spasticity, as well as autonomic failure and cerebellar ataxia suggesting possible multiple system atrophy (MSA). He also had seizures, hearing loss and sensory disturbances. His brain MRI showed no obvious atrophy or significant white matter pathology in cerebrum, brainstem or cerebellum. He died at age 69 years with a diagnosis of MSA. Microscopic analysis showed mild, patchy myelin rarefaction with perivascular clusters of PAS-positive, CD68-positive macrophages in the white matter most prominent in the cerebellum and occipital lobe, but also affecting the optic tract and internal capsule. Electron microscopy of cerebellar white matter showed cleft-like trilamellar cytoplasmic inclusions in macrophages typical of X-ALD, which prompted genetic analysis that revealed a novel ABCD1 mutation, p.R163G. Given the relatively mild pathological findings and long disease duration, it is likely that the observed pathology was the result of a slow and indolent disease process. We described a patient who had sporadic cerebello-brainstem dominant form of X-ALD with long clinical course, mild pathological findings, and an ABCD1 p.R163G substitution. We also review a total of 34 cases of adult-onset cerebello-brainstem dominant form of X-ALD. Although rare, X-ALD should be considered in the differential diagnosis of MSA. PMID- 26227822 TI - Atomic Layer Deposition of Hafnium(IV) Oxide on Graphene Oxide: Probing Interfacial Chemistry and Nucleation by using X-ray Absorption and Photoelectron Spectroscopies. AB - Interfacing graphene with metal oxides is of considerable technological importance for modulating carrier density through electrostatic gating as well as for the design of earth-abundant electrocatalysts. Herein, we probe the early stages of the atomic layer deposition (ALD) of HfO2 on graphene oxide using a combination of C and O K-edge near-edge X-ray absorption fine structure spectroscopies and X-ray photoelectron spectroscopy. Dosing with water is observed to promote defunctionalization of graphene oxide as a result of the reaction between water and hydroxyl/epoxide species, which yields carbonyl groups that further react with migratory epoxide species to release CO2 . The carboxylates formed by the reaction of carbonyl and epoxide species facilitate binding of Hf precursors to graphene oxide surfaces. The ALD process is accompanied by recovery of the pi-conjugated framework of graphene. The delineation of binding modes provides a means to rationally assemble 2D heterostructures. PMID- 26227823 TI - Targeted radionuclide therapies for pancreatic cancer. AB - Pancreatic malignancies, the fourth leading cause of cancer deaths, have an aggressive behavior with poor prognosis, resulting in a 5-year survival rate of only 4%. It is typically a silent malignancy until patients develop metastatic disease. Targeted radionuclide therapies of cancer such as radiolabeled peptides, which bind to the receptors overexpressed by cancer cells and radiolabeled antibodies to tumor-specific antigens provide a viable alternative to chemotherapy and external beam radiation of metastatic cancers. Multiple clinical trials of targeted radionuclide therapy of pancreatic cancer have been performed in the last decade and demonstrated safety and potential efficacy of radionuclide therapy for treatment of this formidable disease. Although a lot of progress has been made in treatment of pancreatic neuroendocrine tumors with radiolabeled (90)Y and (177)Lu somatostatin peptide analogs, pancreatic adenocarcinomas remain a major challenge. Novel approaches such as peptides and antibodies radiolabeled with alpha emitters, pre-targeting, bispecific antibodies and biological therapy based on the radioactive tumorlytic bacteria might offer a potential breakthrough in treatment of pancreatic adenocarcinomas. PMID- 26227824 TI - Antisense oligonucleotide targeting eukaryotic translation initiation factor 4E reduces growth and enhances chemosensitivity of non-small-cell lung cancer cells. AB - Elevated levels of eukaryotic translation initiation factor 4E (eIF4E) enhance translation of many malignancy-related proteins, such as vascular endothelial growth factor (VEGF), c-Myc and osteopontin. In non-small-cell lung cancer (NSCLC), levels of eIF4E are significantly increased compared with normal lung tissue. Here, we used an antisense oligonucleotide (ASO) to inhibit the expression of eIF4E in NSCLC cell lines. eIF4E levels were significantly reduced in a dose-dependent manner in NSCLC cells treated with eIF4E-specific ASO (4EASO) compared with control ASO. Treatment of NSCLC cells with the 4EASO resulted in decreased cap-dependent complex formation, decreased cell proliferation and increased sensitivity to gemcitabine. At the molecular level, repression of eIF4E with ASO resulted in decreased expression of the oncogenic proteins VEGF, c-Myc and osteopontin, whereas expression of beta-actin was unaffected. Based on these findings, we conclude that eIF4E-silencing therapy alone or in conjunction with chemotherapy represents a promising approach deserving of further investigation in future NSCLC clinical trials. PMID- 26227825 TI - In Vitro/In Vivo Evaluation of Dexamethasone--PAMAM Dendrimer Complexes for Retinal Drug Delivery. AB - Current treatment options for diabetic retinopathy (DR) have side effects because of invasive application and topical application does not generally result in therapeutic levels in the target tissue. Therefore, improving the drug delivery to retina, following topical administration, might be a solution to DR treatment problems. The purpose of this study was to investigate the complexation effects of poly(amidoamine) (PAMAM) dendrimers on ocular absorption of dexamethasone (DEX). Using different PAMAM generations, complex formulations were prepared and characterized. Formulations were evaluated in terms of cytotoxicity and cell permeability, as well as ex vivo transport across ocular tissues. The ocular pharmacokinetic properties of DEX formulations were studied in Sprague-Dawley rats following topical and subconjunctival applications, to evaluate the effect of PAMAM on retinal delivery of DEX. Methyl-thiazol-tetrazolium (MTT) assay indicated that all groups resulted in cell viability comparable to DEX solution (87.5%), with the cell viability being the lowest for G3 complex at 73.5%. Transport study results showed that dendrimer complexation increases DEX transport across both cornea and sclera tissues. The results of in vivo studies were also indicated that especially anionic DEX-PAMAM complex formulations have reached higher DEX concentrations in ocular tissues compared with plain DEX suspension. PMID- 26227827 TI - Catalytic wet peroxide oxidation of aniline in wastewater using copper modified SBA-15 as catalyst. AB - SBA-15 mesoporous molecular sieves modified with copper (Cu-SBA-15) were prepared by pH-adjusting hydrothermal method and characterized by X-ray diffraction, BET, transmission electron microscopy, UV-Vis and (29)Si MAS NMR. The pH of the synthesis gel has a significant effect on the amount and the dispersion of copper on SBA-15. The Cu-SBA-15(4.5) (where 4.5 denotes the pH value of the synthesis gel) modified with highly dispersed copper was used as catalyst for the oxidation of aniline by H2O2. The Cu-SBA-15(4.5) shows a higher catalytic activity compared to CuO on the surface of SBA-15. The influences of reaction conditions, such as initial pH of the aqueous solutions, temperature, as well as the dosages of H2O2 and catalyst were investigated. Under weakly alkaline aqueous solution conditions, the aniline conversion, the H2O2 decomposition and the total organic carbon (TOC) removal could be increased significantly compared to the acid conditions. The percentage of leaching Cu(2+) could be decreased from 45.0% to 3.66% when the initial pH of solution was increased from 5 to 10. The TOC removal could be enhanced with the increases of temperature, H2O2 and catalyst dosage, but the aniline conversion and H2O2 decomposition change slightly with further increasing dosage of catalyst and H2O2. At 343 K and pH 8.0, 100% aniline conversion and 66.9% TOC removal can be achieved under the conditions of 1.0 g/L catalyst and 0.05 mol/L H2O2 after 180 min. Although copper might be slightly leached from catalyst, the homogeneous Cu(2+) contribution to the whole catalytic activity is unimportant, and the highly dispersed copper on SBA-15 plays a dominant role. PMID- 26227828 TI - Hairdresser dystonia: an unusual substantia nigra hyperechogenicity. PMID- 26227829 TI - Comparison of clinical, electrophysiological, sonographic and MRI features in CIDP. AB - INTRODUCTION: We investigated the applicability of nerve ultrasound and magnetic resonance imaging (MRI) in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: We systematically examined several nerves with ultrasound and the lumbar roots and tibial nerve in the popliteal fossa of nine CIDP patients with MRI additionally to the nerve conduction studies. RESULTS: Patients with overall disability sum score (ODSS) 2-3 were characterised by normal fascicular structure in MRI and ultrasound. Patients with higher ODSS showed isolated enlarged fascicles and increased cross sectional area (CSA) of the peripheral nerves and of the diameter of the cauda equina and L5 root, whereas two of them showed atrophic fascicles in both imaging techniques. CONCLUSIONS: Nerve ultrasound and MRI findings show the same morphological fascicle alterations in peripheral nerves in correlation to ODSS. Nerve ultrasound as an affordable tool, easy and quick to perform, could replace MRI in daily routine for monitoring peripheral nerve morphology. PMID- 26227830 TI - Differentiating progressive supranuclear palsy from Parkinson's disease by MRI based dynamic cerebrospinal fluid flow. AB - OBJECTIVE: The purpose of this study was to clarify the difference between PSP and PD from the viewpoint of dynamic cerebrospinal fluid (CSF) flow focusing on the midbrain aqueduct. METHODS: Thirty-three PD patients (mean age 69.2+/-7.9) and 35 PSP patients (mean age 70.5+/-6.6) were included in this study. CSF flow was calculated by 15 images in an equidistant magnetic resonance imaging (MRI) sequence that was taken throughout a cardiac cycle. RESULTS: Absolute values of the velocity (time points of 2-6 and 12-15, *p<0.05), and the width of the CSF velocity (Vheight) (PSP, 5.1+/-2.3cm/s; PD, 6.0+/-1.6cm/s, p<0.05) effectively discriminated PSP from PD patients. On the other hand, conventional MRI measurements discriminated well the midbrain aqueduct area (Area) (PSP, 7.7+/ 2.6mm(2); PD, 5.4+/-1.8mm(2), p<0.01). Two cutoff value lines (Vheight: 4.75, Area: 5.77) of the ROC curve analysis established two areas for discriminating PSP from PD. CONCLUSION: In the present dynamic CSF flow study, it was newly found that mean velocity of each time point and Vheight showed a more significant decline in PSP than in PD patients, providing a sensitive biomarker for differentiating them. The combination of Vheight and Area could further discriminate PSP from PD patients. PMID- 26227831 TI - Single-Crystal Semiconductors with Narrow Band Gaps for Solar Water Splitting. AB - Solar water splitting provides a clean and renewable approach to produce hydrogen energy. In recent years, single-crystal semiconductors such as Si and InP with narrow band gaps have demonstrated excellent performance to drive the half reactions of water splitting through visible light due to their suitable band gaps and low bulk recombination. This Minireview describes recent research advances that successfully overcome the primary obstacles in using these semiconductors as photoelectrodes, including photocorrosion, sluggish reaction kinetics, low photovoltage, and unfavorable planar substrate surface. Surface modification strategies, such as surface protection, cocatalyst loading, surface energetics tuning, and surface texturization are highlighted as the solutions. PMID- 26227832 TI - An experimental burn wound-healing study of non-thermal atmospheric pressure microplasma jet arrays. AB - In contrast with a thermal plasma surgical instrument based on coagulative and ablative properties, low-temperature (non-thermal) non-equilibrium plasmas are known for novel medicinal effects on exposed tissue while minimizing undesirable tissue damage. In this study we demonstrated that arrays of non-thermal microplasma jet devices fabricated from a transparent polymer can efficiently inactivate fungi (Candida albicans) as well as bacteria (Escherichia coli), both in vitro and in vivo, and that this leads to a significant wound-healing effect. Microplasma jet arrays offer several advantages over conventional single-jet devices, including superior packing density, inherent scalability for larger treatment areas, unprecedented material flexibility in a plasma jet device, and the selective generation of medically relevant reactive species at higher plasma densities. The therapeutic effects of our multi-jet device were verified on second-degree burns in animal rat models. Reduction of the wound area and the histology of the wound after treatment have been investigated, and expression of interleukin (IL)-1alpha, -6 and -10 was verified to evaluate the healing effects. The consistent effectiveness of non-thermal plasma treatment has been observed especially in decreasing wound size and promoting re-epithelialization through collagen arrangement and the regulation of expression of inflammatory genes. PMID- 26227833 TI - Bioinspired Nanoparticulate Medical Glues for Minimally Invasive Tissue Repair. AB - Delivery of tissue glues through small-bore needles or trocars is critical for sealing holes, affixing medical devices, or attaching tissues together during minimally invasive surgeries. Inspired by the granule-packaged glue delivery system of sandcastle worms, a nanoparticulate formulation of a viscous hydrophobic light-activated adhesive based on poly(glycerol sebacate)-acrylate is developed. Negatively charged alginate is used to stabilize the nanoparticulate surface to significantly reduce its viscosity and to maximize injectability through small-bore needles. The nanoparticulate glues can be concentrated to ~30 w/v% dispersions in water that remain localized following injection. With the trigger of a positively charged polymer (e.g., protamine), the nanoparticulate glues can quickly assemble into a viscous glue that exhibits rheological, mechanical, and adhesive properties resembling the native poly(glycerol sebacate) acrylate based glues. This platform should be useful to enable the delivery of viscous glues to augment or replace sutures and staples during minimally invasive procedures. PMID- 26227835 TI - The Influence of Chorion Type on Health Measures at Birth and Dental Development in Australian and Dutch Twins: A Comparative Study. AB - Chorion type may significantly influence the prenatal environment of twins. This study explored the associations between chorion type and gestational age, birth weight, birth length, and the timing of emergence of the first primary tooth in two populations of twins, Australian and Dutch. Additionally, we investigated the relationship between chorion type and birth weight discordance (BWD) in order to determine whether a significant relationship existed between discordance in birth weight and discordance in the timing of emergence of the first primary tooth. The two study samples consisted of 409 Australian twin pairs and 301 Dutch twin pairs, all of European ancestry. Data were collected through a combination of questionnaires and recording charts administered to the parents and through linkage with biological databases. In the Australian sample, monozygotic monochorionic (MZMC) twins experienced the shortest mean gestation time (35 weeks), the lowest mean birth length (46 cm) and the lowest mean birth weight (2.3 kg) compared with other twin groups. For the same variables in the Dutch sample, these trends with MZMC twinning were not observed. Chorion type did not significantly affect the mean timing of emergence of the first primary tooth in either sample. Monochorionicity was found to be significantly associated with BWD in both samples, but there was a significant association between BWD in MZMC twin pairs and timing of emergence of the first primary tooth only in the Australian sample. Results from this study support previous findings that the timing of emergence of the first primary tooth is influenced strongly by genetic factors and is well protected from environmental disturbances. PMID- 26227834 TI - Macular ischemia and outcome of vitrectomy for diabetic macular edema. AB - PURPOSE: To investigate the effect of vitrectomy on the treatment of diabetic macular edema (DME) refractory to nonsurgical therapies and to determine the preoperative prognostic factors related to surgical outcomes. METHODS: Seventy seven eyes from 74 patients who had undergone vitrectomy and macular photocoagulation 2 weeks after vitrectomy for nontractional DME refractory to anti-vascular endothelial growth factor or steroid injection and/or macular grid/focal photocoagulation were included. The eyes were divided into the responsive group (group 1) and the unresponsive group (group 2) according to the postoperative changes in central subfield thickness (CST). The changes in best corrected visual acuity (BCVA) and CST were compared. Potential preoperative predictors including the size of the foveal avascular zone (FAZ) were assessed. RESULTS: In group 1 (N = 51), the mean logarithm of the minimum angle of resolution BCVAs at baseline was 0.60 +/- 0.30; 6 months after vitrectomy, 0.47 +/- 0.28 (vs. baseline, p < 0.001); 12 months after vitrectomy, 0.38 +/- 0.28 (vs. baseline, p < 0.001). However, in group 2 (N = 26), no significant change in BCVA was noted. Among the preoperative factors, only the size of the FAZ showed a significant difference between the two groups (0.45 +/- 0.17 mm(2) in group 1 vs. 0.59 +/- 0.26 mm(2) in group 2; p = 0.020). The enlarged FAZ was also significantly correlated with worse BCVA at the postoperative 6-month follow-up (r = 0.256, p = 0.025). CONCLUSIONS: Vitrectomy is an effective treatment modality for DME refractory to nonsurgical therapies, especially in cases without enlarged FAZ. Preoperative evaluation of the perfusion status of the macula seems helpful to selecting candidates for vitrectomy. PMID- 26227841 TI - Variations in reactive oxygen species between mouse strains. PMID- 26227840 TI - Detection and characterization of small insertion and deletion genetic variants in modern layer chicken genomes. AB - BACKGROUND: Small insertions and deletions (InDels) constitute the second most abundant class of genetic variants and have been found to be associated with many traits and diseases. The present study reports on the detection and characterisation of about 883 K high quality InDels from the whole-genome analysis of several modern layer chicken lines from diverse breeds. RESULTS: To reduce the error rates seen in InDel detection, this study used the consensus set from two InDel-calling packages: SAMtools and Dindel, as well as stringent post filtering criteria. By analysing sequence data from 163 chickens from 11 commercial and 5 experimental layer lines, this study detected about 883 K high quality consensus InDels with 93% validation rate and an average density of 0.78 InDels/kb over the genome. Certain chromosomes, viz, GGAZ, 16, 22 and 25 showed very low densities of InDels whereas the highest rate was observed on GGA6. In spite of the higher recombination rates on microchromosomes, the InDel density on these chromosomes was generally lower relative to macrochromosomes possibly due to their higher gene density. About 43-87% of the InDels were found to be fixed within each line. The majority of detected InDels (86%) were 1-5 bases and about 63% were non-repetitive in nature while the rest were tandem repeats of various motif types. Functional annotation identified 613 frameshift, 465 non-frameshift and 10 stop-gain/loss InDels. Apart from the frameshift and stopgain/loss InDels that are expected to affect the translation of protein sequences and their biological activity, 33% of the non-frameshift were predicted as evolutionary intolerant with potential impact on protein functions. Moreover, about 2.5% of the InDels coincided with the most-conserved elements previously mapped on the chicken genome and are likely to define functional elements. InDels potentially affecting protein function were found to be enriched for certain gene-classes e.g. those associated with cell proliferation, chromosome and Golgi organization, spermatogenesis, and muscle contraction. CONCLUSIONS: The large catalogue of InDels presented in this study along with their associated information such as functional annotation, estimated allele frequency, etc. are expected to serve as a rich resource for application in future research and breeding in the chicken. PMID- 26227842 TI - Ehrlichia-Induced Hemophagocytic Lymphohistiocytosis: A Case Series and Review of Literature. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rare potentially fatal syndrome characterized by an uncontrolled hyperinflammatory response. The secondary form of HLH is usually triggered by a causative agent. Ehrlichia chaffeensis is a rare trigger of secondary HLH. We present a case series of five adolescents and adults diagnosed with Ehrlichia-induced HLH and we discuss their clinical and laboratory findings. We also review the literature for similar cases. Between October 2003 and June 2014, we identified 76 cases of HLH in adolescents and adults, 5 of which were induced by Ehrlichia. All 5 patients had fever, cytopenias, hypertriglyceridemia, and high ferritin. Hyperferritinemia was striking with a median admission ferritin of 47,290 MUg/L (range: 2,863-85,517). In addition to the positive Ehrlichia PCR testing on peripheral blood of all patients, two patients with neurologic symptoms tested positive for E. chaffeensis in CSF specimens. Early treatment with doxycycline was effective. After a median follow up of 7.3 months, all patients were alive and none had recurrence of HLH. Clinicians should consider E. chaffeensis as a potential trigger for HLH especially in areas with tick activity. Prompt diagnosis and treatment with doxycycline are required for a better outcome. PMID- 26227843 TI - Experimental animal model to study iron overload and iron chelation and review of other such models. AB - The disorders of iron overload due to primary or secondary cause are one of the important human diseases leading to high mortality if untreated. To understand this, an animal model has been extensively studied. The source of iron administered to the mode of iron administration that can mimic the iron overload in humans has been studied. A safe and orally active iron chelator is still needed as many of the existing compounds have different types of complications and toxicity associated. Hence having a simple animal model which can be availed quickly and can be used to study various compounds for its iron chelating activity would likely to have immense utility for pharmacological studies. In this review we have shown how, using a simple procedure, a large number of small iron overloaded animals can be produced easily for various studies. PMID- 26227844 TI - Inherited and acquired thrombophilia in Indian women experiencing unexplained recurrent pregnancy loss. AB - The most frequently hypothesized cause of unexplained recurrent pregnancy loss (RPL) refers to a defective maternal haemostatic response leading to uteroplacental thrombosis. Approximately 20% women suffering from pregnancy loss (PL) are associated with autoimmune disorders and more than 50% remain idiopathic after common traditional investigations. The present study aims to investigate the prevalence of different genetic and acquired thrombophilia markers in a large series of Indian women with RPL. Such studies will help analyze the markers which pose maximum risk and help in the appropriate treatment in subsequent pregnancies. The study comprised of 587 women with no apparent etiological causes of RPL and 115 healthy women controls. p values were calculated with two tailed Fisher's exact test; statistical significance was assumed at p<0.05, 95% confidence interval. Relative risks were also calculated. Among genetic thrombophilia, the risk of PL was highest with protein S deficiency (16%, p=0.006) followed by plasminogen activator inhibitor-1 4G/4G (23%, p=0.007) polymorphism. Among acquired markers, the risk of PL was the highest in women with anti-cardiolipin antibodies (24%, p=0.0001), followed by anti-annexin V antibodies (23%, p=0.0009) and lupus anticoagulants (8%, p=0.02). Thrombophilia, inherited and acquired, is an important contributing factor in unexplained RPL and should be screened in the order of its prevalence. PMID- 26227845 TI - Castleman-Kojima disease (TAFRO syndrome) in a Caucasian patient: A rare case report and review of the literature. PMID- 26227846 TI - The JAK2V617F mutation is associated with anomalies in the frequency of monocytes, B cells, CD8+ T cells and NK cells. PMID- 26227847 TI - Increased values of the circulating PDGFbeta sustains the "withdrawal syndrome" after tyrosine kinase inhibitor discontinuation in patients affected by chronic myeloid leukemia. PMID- 26227848 TI - Factors contributing to APC-resistance in women with recurrent spontaneous miscarriages: Indian perspective. AB - Phenotypic resistance to APC is a complex mechanism associated with increased risk of venous thrombosis in women with recurrent spontaneous abortions. The primary aim of this prospective case control study was to find out the frequencies of different congenital and acquired thrombophilic factors predisposing to APC resistance and to evaluate the strength of their association with recurrent pregnancy losses. FV Leiden accounted for around 40% of all APCR positive patients and the difference in the group frequencies compared with controls, was found to be statistically significant (p=0.001). 18.33% (11/60) FV Leiden-negative APC-resistant patients had FVIII: c values exceeding 95th percentile of the control population (145IU/dL), as compared to 3% in the control group (p=0.001). Mean FVIII level in control subjects was 118+/-14.0IUdL(-), compared with 127.7+/-31.2IUdL(-) in the patient group (p=0.009). Apart from FVIII, only the anti-phospholipid antibodies showed a statistically significant association with APCR phenotype (p=0.028), unlike other thrombophilic factors such as Protein C, Protein S, FV levels, HR2 haplotype or other rarer FV variants. The strong positive association of FVL mutation, anti-phospholipid antibodies and elevated FVIII levels with APCR phenotype calls for incorporating them as first line investigations in patients with recurrent spontaneous miscarriages with APCR positivity. PMID- 26227849 TI - Hereditary hemochromatosis: The same old song. PMID- 26227850 TI - Phenotypic evaluations of -223 T>C (HBB:c.-223T>C) nucleotide substitution in the promoter region of beta-globin gene. PMID- 26227851 TI - Chemokines and relapses in childhood acute lymphoblastic leukemia: A role in migration and in resistance to antileukemic drugs. AB - We studied whether chemokines may have a role in relapses in childhood acute lymphoblastic leukemia (ALL). We compared the levels of chemokine receptors in marrow samples from 82 children with ALL at diagnosis versus 15 at relapses, and quantified the levels of chemokines in central system fluid (CSF) samples. The functional role of specific chemokines was studied in vitro and in vivo. The expression of some chemokine receptors was upregulated upon leukemic relapse, both in B- and in T-ALL, and in cases of medullary and extramedullary involvement. CXCL10 induced chemotaxis in leukemic cell lines and in primary leukemic cells, depending upon the levels of CXCR3 expression. CXCL10 specifically diminished chemotherapy-induced apoptosis on ALL cells expressing CXCR3, partially inhibiting caspase activation and maintaining the levels of the antiapoptotic protein Bcl-2. Finally, immunodeficient mice engrafted with CXCR3 expressing human leukemic cells showed decreased infiltration of marrow, spleen, and CNS after receiving a CXCR3-antagonist molecule. CXCR3 signaling in ALL may have a dual function: chemotactic for the localisation of leukemic blasts in specific niches, and it may also confer resistance to chemotherapy, enhancing the chances for relapses. PMID- 26227852 TI - Differential profile of PIP4K2A expression in hematological malignancies. AB - PIP4K2A is a lipid kinase that phosphorylates PtdIns5P, generating PtdIns4,5P2. Recently, PIP4K2A was identified as a potential target in acute myeloid leukemia cells. The objective of the present study was to investigate the PIP4K2A expression in hematological malignancies and verify the effects of PIP4K2A silencing on proliferation and survival of leukemia cell lines. PIP4K2A was found to be a cytoplasmic and nuclear protein with reduced levels in leukemia cell lines compared to normal leukocytes. PIP4K2A mRNA levels were significantly reduced in bone marrow cells from acute lymphoid leukemia (ALL) patients compared with healthy donors and in myelodysplastic syndromes (MDS) with >=5% compared with <5% bone marrow blasts. Low PIP4K2A expression (lowest tertile versus 2 higher tertiles) negatively impacted overall survival of MDS patients by univariate analysis. PIP4K2A silencing did not modulate cell proliferation, clonogenicity and apoptosis of HEL and Namalwa leukemia cells. In summary, we characterized the expression of PIP4K2A in a cohort of patients with hematological malignancies and we found that PIP4K2A mRNA expression is downregulated in RAEB-1/RAEB-2 MDS and ALL cells, and PIP4K2A silencing does not modulate cell survival in HEL and Namalwa leukemia cells. PMID- 26227853 TI - CALR mutations screening in wild type JAK2(V617F) and MPL(W515K/L) Brazilian myeloproliferative neoplasm patients. AB - Some myeloproliferative neoplasm (MPN) patients harbor JAK2(V617F) mutation, and CALR mutations were recently discovered in wild type (WT) JAK2(V617F). We evaluated the frequency and type of CALR mutations, and clinical and hematological characteristics in WT JAK2(V617F) and MPL(W515K/L) MPN patients. Sixty-five patients were included: 21 with primary myelofibrosis (PMF), 21 with myelofibrosis post-essential thrombocythemia (MPET) and 23 with essential thrombocythemia (ET). Screening for JAK2(V617F) and MPL(W515K/L) were performed using real-time PCR, while CALR mutations were analyzed by fragment analysis and Sanger sequencing. JAK2(V617F) was the most frequent mutation (54.5%) and one patient (1.5%) harbored MPL(W515L). CALR mutations were present in 38.1% of PMF, 12.5% of ET and 33.3% of MPET patients. Five types of CALR mutations were detected, among which type 1 (32.1%) and type 2 (21.4%) were found to be the most common. A novel CALR mutation in a PMF patient was found. Patients carrying CALR mutations had higher platelet count and less presence of splenomegaly than JAK2(V617F), while triple negatives had higher C-reactive protein levels than CALR mutant carriers. Screening for CALR mutations and its correlation with clinical features could be useful for the characterization of MPN patients and result in its incorporation into a new prognostic score. PMID- 26227854 TI - Targeting glutamine metabolism in myeloproliferative neoplasms. AB - JAK2(V617F) mutation can be detected in the majority of myeloproliferative neoplasm (MPN) patients. The JAK2 inhibitor Ruxolitinib is the first FDA-approved treatment for MPNs. However, its use is limited by various dose related toxicities. Here, we studied the metabolic state and glutamine metabolism of BaF3 hEPOR-JAK2V617F and BaF3-hEPOR-JAK2WT cells. We found that the JAK2(V617F)-mutant cells were associated with increased oxygen consumption rate and extracellular acidification rate than the JAK2(WT) cells and there was an increased glutamine metabolism in JAK2(V617F)-mutant cells compared to wild-type cells. Glutaminase (GLS), the key enzyme in glutamine metabolism, was upregulated in the JAK2(V617F) mutant BaF3 cells compared to the JAK2(WT) BaF3 cells. In MPN patient peripheral blood CD34+ cells, GLS expression was increased in JAK2(V617F)-mutant progenitor cells compared to JAK2 wild-type progenitor cells from the same patients and GLS levels were increased at the time of disease progression compared to at earlier time points. Moreover, GLS inhibitor increased the growth inhibitory effect of Ruxolitinib in both JAK2(V617F)-mutant cell lines and peripheral blood CD34+ cells from MPN patients. Therefore, GLS inhibitor should be further explored to enhance the therapeutic effectiveness of JAK2 inhibitor and allow the administration of lower doses of the drug to avoid its toxicity. PMID- 26227855 TI - APOBEC3G governs to ensure cellular oncogenic transformation. AB - The oncogenic potential of APOBEC3G gene was recently appreciated by the finding that revealed inhibitory influence of APOBEC3G upon micro-RNA mediated repression of the gene responsible for hepatic metastasis. Here we report for the first time that sustained APOBEC3G expression is the characteristic trait exhibited by various cancer cells of different tissue origins as well as APOBEC3G represses cellular gene coding for tumor suppressor KLF4 by binding to its mRNA. This phenomenon was paralleled by the sustained expression of the cellular SP1 which ensured overexpression of genes coding for c-myc, Bmi-1, BCL-2 and MDM2 coupled with downregulation of tumor suppressor p53 thereby creating a favorable situation for oncogenic transformation. PMID- 26227856 TI - B-cell receptor signaling in the pathogenesis of lymphoid malignancies. AB - B-cell receptor (BCR) signaling pathway plays a central role in B-lymphocyte development and initiation of humoral immunity. Recently, BCR signaling pathway has been shown as a major driver in the pathogenesis of B-cell malignancies. As a result, a vast array of BCR-associated kinases has emerged as rational therapeutic targets changing treatment paradigms in B cell malignancies. Based on high efficacy in early-stage clinical trials, there is rapid clinical development of inhibitors targeting BCR signaling pathway. Here, we describe the essential components of BCR signaling, their function in normal and pathogenic signaling and molecular effects of their inhibition in vitro and in vivo. PMID- 26227858 TI - Essential tremor and senile varieties of action tremor an evolving ART. PMID- 26227857 TI - Fluorescence assay of the interaction between hemoglobin and the cytoplasmic domain of erythrocyte membrane band 3. AB - Oxygen tension has emerged as a potent regulator of multiple erythrocyte properties, including glucose metabolism, cell volume, ATP release, and cytoskeletal organization. Because hemoglobin (Hb)(1) binds to the cytoplasmic domain of band 3 (cdb3) in an oxygen dependent manner, with deoxyHb exhibiting significantly greater affinity for cdb3 than oxyHb, the deoxyHb-cdb3 interaction has been hypothesized to constitute the molecular switch for all O2-controlled erythrocyte processes. In this study, we describe a rapid and accurate method for quantitating the interaction of deoxyHb binding to cdb3. For this purpose, enhanced green fluorescent protein (eGFP) is fused to the COOH-terminus of cdb3, and the binding of Hb to the NH2-terminus of cdb3-eGFP is quantitated by Hb mediated quenching of cdb3-eGFP fluorescence. As expected, the intensity of cdb3 eGFP fluorescence decreases only slightly following addition of oxyHb. However, upon deoxygenation of the same Hb-cdb3 solution, the fluorescence decreases dramatically (i.e. confirming that deoxyHb exhibits much greater affinity for cdb3 than oxyHb). Using this fluorescence quenching method, we not only confirm previously established characteristics of the Hb-cdb3 interaction, but also establish an assay that can be exploited to screen for inhibitors of the sickle Hb-cdb3 interaction that accelerates sickle Hb polymerization. PMID- 26227859 TI - Molecular characterization, tissue and developmental expression profiles of cryptochrome genes in wing dimorphic brown planthoppers, Nilaparvata lugens. AB - Cryptochromes (CRYs) are blue and UV light photoreceptors, known to play key roles in circadian rhythms and in the light-dependent magnetosensitivity of insects. Two novel cryptochrome genes were cloned from the brown planthopper, and were given the designations of Nlcry1 and Nlcry2, with the accession numbers KM108578 and KM108579 in GenBank. The complementary DNA sequences of Nlcry1 and Nlcry2 are 1935 bp and 2463 bp in length, and they contain an open reading frame of 1629 bp and 1872 bp, encoding amino acids of 542 and 623, with a predicted molecular weight of 62.53 kDa and 70.60 kDa, respectively. Well-conserved motifs such as DNA-photolyase and FAD-binding-7 domains were observed in Nlcry1 and Nlcry2. Phylogenetic analysis demonstrated the proteins of Nlcry1 and Nlcry2 to be clustered into the insect's cryptochrome 1 and cryptochrome 2, respectively. Quantitative polymerase chain reaction showed that the daily oscillations of messenger RNA (mRNA) expression in the head of the brown planthopper were mild for Nlcry1, and modest for Nlcry2. Throughout all developmental stages, Nlcry1 and Nlcry2 exhibited extreme fluctuations and distinctive expression profiles. Cryptochrome mRNA expression peaked immediately after adult emergence and then decreased subsequently. The tissue expression profiles of newly emerged brown planthopper adults showed higher expression levels of CRYs in the head than in the thorax or abdomen, as well as significantly higher levels of CRYs in the heads of the macropterous strain than in the heads of the brachypterous strain. Taken together, the results of our study suggest that the two cryptochrome genes characterized in the brown planthopper might be associated with developmental physiology and migration. PMID- 26227860 TI - Can piezoelectric ultrasound osteotomies result in serious noise trauma? AB - The use of ultrasound to cut bone in oral and craniofacial surgery has increased. There is concern that the application of ultrasound to the craniofacial skeleton might represent a potential hazard to the inner ear because of sound transmission by bone conduction resulting in hearing trauma. Conventional and ultrasound osteotomies were performed on human specimens of temporal bone containing an intact middle and inner ear. The equivalent sound pressure was measured with a microphone at the round window, which had been calibrated with a bone conduction audiometer. Conventional osteotomy with a rose burr resulted in maximum sound pressures of 125dB(A) consisting of major frequency components at 2100, 7600, and 9300Hz. Ultrasound osteotomy resulted in maximum sound pressures of 122dB(A) and exhibited major frequency components at around 10kHz, 20kHz, and 26.5kHz. Ultrasound osteotomies have no acoustic advantage over conventional osteotomies. Both osteotomy techniques can produce noise-induced hearing trauma, especially when applied over longer durations of time. This appears to be more relevant for ultrasound osteotomies, because the bone cutting efficiency is usually poorer than in conventional osteotomies. Surgeons should consider the risk of noise induced potential damage to the inner ear when selecting the method of osteotomy. PMID- 26227861 TI - Small Biparietal Diameter in Spinal Dysraphism: Do Not Forget the Quality Control of the Measure. PMID- 26227862 TI - Gently Does it: Ramping Is the Key to Safe and Efficient Lithotripsy. PMID- 26227863 TI - Reply to Matthew Bultitude and Pieter Le Roux's Letter to the Editor re: Jens Sonksen, Neil J. Barber, Mark J. Speakman, et al. Prospective, Randomized, Multinational Study of Prostatic Urethral Lift Versus Transurethral Resection of the Prostate: 12-month Results from the BPH6 Study. Eur Urol 2015;68:643-52. PMID- 26227864 TI - Molecular Identification of Candida Species Isolated from Onychomycosis in Shanghai, China. AB - Candida is a common cause of onychomycosis, especially for fingernail onychomycosis. In this study, two simple PCR-based assays combined with the internal transcribed spacers sequencing were performed to reveal the prevalence of Candida species including emerging species in onychomycosis, and triazole antifungal susceptibility profiles for Candida species were also evaluated. Among 210 Candida strains isolated from onychomycosis, Candida parapsilosis was the most common species (54.3%), followed by C. albicans (23.3%) and C. metapsilosis (9.5%). However, C. metapsilosis became the second leading species in toenail onychomycosis and accounted for 19.5% of Candida isolates from toenail samples. C. nivariensis, an emerging species, was firstly recovered from a toenail sample. Other emerging species such as C. orthopsilosis, C. pararugosa and C. fabryi were also identified by molecular tools. C. metapsilosis isolates exhibited significantly higher fluconazole minimum inhibitory concentrations than those exhibited by C. parapsilosis and C. albicans (P < 0.001). This study provides insight into the prevalence, distribution and susceptibility profiles of Candida species including emerging Candida species in onychomycosis. PMID- 26227865 TI - Short Tree, Long Tree, Right Tree, Wrong Tree: New Acquisition Bias Corrections for Inferring SNP Phylogenies. AB - Single nucleotide polymorphisms (SNPs) are useful markers for phylogenetic studies owing in part to their ubiquity throughout the genome and ease of collection. Restriction site associated DNA sequencing (RADseq) methods are becoming increasingly popular for SNP data collection, but an assessment of the best practises for using these data in phylogenetics is lacking. We use computer simulations, and new double digest RADseq (ddRADseq) data for the lizard family Phrynosomatidae, to investigate the accuracy of RAD loci for phylogenetic inference. We compare the two primary ways RAD loci are used during phylogenetic analysis, including the analysis of full sequences (i.e., SNPs together with invariant sites), or the analysis of SNPs on their own after excluding invariant sites. We find that using full sequences rather than just SNPs is preferable from the perspectives of branch length and topological accuracy, but not of computational time. We introduce two new acquisition bias corrections for dealing with alignments composed exclusively of SNPs, a conditional likelihood method and a reconstituted DNA approach. The conditional likelihood method conditions on the presence of variable characters only (the number of invariant sites that are unsampled but known to exist is not considered), while the reconstituted DNA approach requires the user to specify the exact number of unsampled invariant sites prior to the analysis. Under simulation, branch length biases increase with the amount of missing data for both acquisition bias correction methods, but branch length accuracy is much improved in the reconstituted DNA approach compared to the conditional likelihood approach. Phylogenetic analyses of the empirical data using concatenation or a coalescent-based species tree approach provide strong support for many of the accepted relationships among phrynosomatid lizards, suggesting that RAD loci contain useful phylogenetic signal across a range of divergence times despite the presence of missing data. Phylogenetic analysis of RAD loci requires careful attention to model assumptions, especially if downstream analyses depend on branch lengths. PMID- 26227866 TI - Contextualizing the Effectiveness of a Collaborative Care Model for Primary Care Patients with Diabetes and Depression (Teamcare): A Qualitative Assessment Using RE-AIM. AB - OBJECTIVE: We evaluated the implementation of an efficacious collaborative care model for patients with diabetes and depression in a controlled trial in 4 community-based primary care networks (PCNs) in Alberta, Canada. Similar to previous randomized trials, the nurse care manager-led TeamCare intervention demonstrated statistically significant improvements in depressive symptoms compared with usual care. We contextualized TeamCare's effectiveness by describing implementation fidelity at the organizational and patient levels. METHODS: We used the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework to evaluate TeamCare. Qualitative methods used to collect data regarding the RE-AIM dimensions of Implementation and Effectiveness included interviews with PCN staff and specialists (n=36), research team reflections (n=4) and systematic documentation. We used content analysis, and Nvivo 10 for data management. RESULTS: TeamCare was implemented as intended but with suboptimal fidelity. Deviations from the model included limited degrees of collaborative care practised within the PCNs, including varying physician participation, limited comfort in practising collaborative care and discontinuity of care managers. Despite suboptimal fidelity, respondents identified several implementation facilitators at the organizational level: training, ongoing implementation support, professional and personal qualities of the care manager and pre-existing relationships. Without knowledge of the effectiveness of the intervention in our controlled trial, respondents anticipated improved patient outcomes due to the main intervention components, including active patient follow up, specialist consultation and treat-to-target principles. CONCLUSIONS: Despite suboptimal implementation in Alberta's primary care context, TeamCare resulted in improved outcomes similar to those demonstrated in previous randomized trials. A stronger culture of collaborative care would likely have yielded greater implementation fidelity and possibly better outcomes. PMID- 26227867 TI - Hybrid Ablation in the Arms Race for the Treatment of AF. PMID- 26227868 TI - Survival and neurological status after out-of-hospital cardiac arrest in the pediatric population in Andalusia. AB - OBJECTIVE: Little is known about the evolution and long-term neurological status of pediatric patients who survive out-of-hospital cardiac arrest. Our aim is to describe long-term survival and neurological status. DESIGN: Retrospective observational study, based on the Andalusian Register of out-of-hospital Cardiac Arrest. SETTING: Pre-hospital Care. PATIENTS: The study included patients aged 0 15 years between January 2008 and December 2012. INTERVENTIONS: Patients follow up. VARIABLES: Prehospital and hospital care variables were analyzed and one-year follow-up was performed, along with a specific follow-up of survivors in June 2014. RESULTS: Of 5069 patients included in the register, 125 (2.5%) were aged <=15 years. Cardiac arrest was witnessed in 52.8% of cases and resuscitation was performed in 65.6%. The initial rhythm was shockable in 7 (5.2%) cases. Nearly half (48.8%) the patients reached the hospital alive, of whom 20% did so while receiving resuscitation maneuvers. Only 9 (7.2%) patients survived to hospital discharge; 5 showed ad integrum recovery and 4 showed significant neurological impairment. The 5 patients with complete recovery continued their long-term situation. The remaining 4 patients, although slight improvement, were maintained in situation of neurological disability. CONCLUSIONS: Survival after out-of hospital cardiac arrest in pediatric patients was low. The long-term prognosis of survivors with good neurological recovery remains, although improvement in the rest was minimal. PMID- 26227869 TI - Pedometer-determined physical activity level and change in arterial stiffness in Type 2 diabetes over 4 years. AB - AIM: To explore prospectively the correlation between the level of pedometer determined physical activity at the start of the study and the change in pulse wave velocity from baseline to 4 years later in people with Type 2 diabetes. METHODS: We analysed data from 135 men and 53 women with Type 2 diabetes, aged 54 66 years. Physical activity was measured with waist-mounted pedometers on 3 consecutive days and the numbers of steps/day at baseline were classified into four groups: <5000 steps/day, 5000-7499 steps/day, 7500-9999 steps/day and >=10 000 steps/day. Pulse wave velocity was measured using applanation tonometry over the carotid and femoral arteries at baseline and after 4 years. RESULTS: The mean (+/-sd; range) number of steps/day was 8022 (+/-3765; 956-20 921). The participants with the lowest level of physical activity had a more pronounced increase in the change in pulse wave velocity compared with the participants with the highest. When change in pulse wave velocity was analysed as a continuous variable and adjusted for sex, age, diabetes duration, HbA1c , BMI, systolic blood pressure, pulse wave velocity at baseline, beta-blocker use, statin use, unemployment, smoking and diabetes medication, the number of steps/day at baseline was significantly associated with a less steep increase in change in pulse wave velocity (P=0.005). Every 1000 extra steps at baseline corresponded to a lower increase in change in pulse wave velocity of 0.103 m/s. CONCLUSIONS: We found that a high level of pedometer-determined physical activity was associated with a slower progression of arterial stiffness over 4 years in middle-aged people with Type 2 diabetes. PMID- 26227871 TI - Use of Antimicrobial Metaphylaxis for the Control of Bovine Respiratory Disease in High-Risk Cattle. AB - Despite research and increased availability of antimicrobials, the prevalence and challenges associated with BRD in stocker and feedlot operations remain. Preconditioned calves can better handle the transition from the origin ranch to the feedlot, yet there is incentive for buyers to purchase high-risk cattle at a reduced cost, and this is influenced by the proven efficacy and availability of antimicrobial metaphylaxis. The poor sensitivity of current BRD field diagnostic methods, typical pathogenesis of BRD, and labor issues are additional reasons to use metaphylaxis. Nevertheless, practitioners should consider comprehensive and novel approaches to judiciously guide decisions on metaphylactic use of antimicrobials. PMID- 26227870 TI - Non-Uniform Sampling and J-UNIO Automation for Efficient Protein NMR Structure Determination. AB - High-resolution structure determination of small proteins in solution is one of the big assets of NMR spectroscopy in structural biology. Improvements in the efficiency of NMR structure determination by advances in NMR experiments and automation of data handling therefore attracts continued interest. Here, non uniform sampling (NUS) of 3D heteronuclear-resolved [(1)H,(1)H]-NOESY data yielded two- to three-fold savings of instrument time for structure determinations of soluble proteins. With the 152-residue protein NP_372339.1 from Staphylococcus aureus and the 71-residue protein NP_346341.1 from Streptococcus pneumonia we show that high-quality structures can be obtained with NUS NMR data, which are equally well amenable to robust automated analysis as the corresponding uniformly sampled data. PMID- 26227872 TI - Translating GWAS Into the Flow-Regulated Modulation of Lipid Mediator Signaling. PMID- 26227873 TI - CEP Is an Important and Ubiquitous Oxidation Specific Epitope Recognized by Innate Pattern Recognition Receptors. PMID- 26227874 TI - Enhanced eNOS Activation as the Fountain of Youth for Vascular Disease: Is BPIFB4 What Ponce de Leon Was Looking For? PMID- 26227876 TI - Disruption of RIP1-FADD Complexes by MicroRNA-103/107 Provokes Necrotic Cardiac Cell Death. PMID- 26227875 TI - Parkin Gone Wild: Unbridled Ubiquitination. PMID- 26227878 TI - Correction. PMID- 26227877 TI - Elizabeth McNally: A Muscular Approach. PMID- 26227879 TI - Plasma metabolic signatures reveal the regulatory effect of exercise training in db/db mice. AB - Type 2 diabetes (T2DM) is caused by a complex set of interactions between genetic modifications and life styles. This complexity creates challenges for a full understanding of the altered metabolic pathways that contribute to the development of T2DM, which needs a comprehensive metabolic analysis. Exercise training is a common therapeutic approach known to antagonize the metabolic consequences of T2DM. However, the metabolic phenotypes of exercise effected in T2DM have not been clearly characterized. Here, we present the effect of physical activity on biochemical changes in diabetic db/db mice. An untargeted metabolomics study based on liquid chromatography coupled with high resolution mass spectrometry was carried out to delineate the plasma metabolic signatures in conjunction with a multivariate statistical analysis. As a result, a total of 24 differential metabolites were identified, covering amino acids, organic acids and lipids. Three biomarkers, including lysine, creatine and uridine, were significantly reversed by exercise training in db/db diabetic mice groups compared to lean db/m+ groups. Of note, pantothenic acid and palmitoylcarnitine, which are involved in fatty acid beta-oxidation (FAO), were promoted by exercise training in diabetic mice rather than in lean mice. These findings indicated that diabetic mice might be more susceptible to exercise for energy expenditure. Together, the results might demonstrate that exercise could mitigate insulin resistance in T2DM through improving FAO and that uridine in blood might be an important indicator to reflect insulin sensitivity promoted by exercise training in T2DM mice. PMID- 26227880 TI - Normative data for rotational chair stratified by age. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study is to examine the range of vestibulo-ocular reflex (VOR) gain on rotary chair (RC) testing in subjects without ear and vestibular problems stratified by age and gender. STUDY DESIGN: Prospective cross-sectional study. METHODS: One hundred subjects ranging in age from 6 to 78 years underwent RC testing. VOR gains at frequencies ranging from 0.01 to 0.64 Hz were recorded. The PROC MIXED procedure in SAS was used to analyze differences in VOR gain between gender and the following age groups: group 1 (6-12 years), group 2 (13-17 years), group 3 (18-30 years), group 4 (31 50 years), and group 5 (>50 years). RESULTS: Twenty subjects were recruited for each of the five groups. Group 1 showed the highest average VOR gain compared to all other age groups (P < .05). There was an inverse correlation between VOR gain and age (P < .05). The lowest frequency (0.01 Hz) had the highest correlation between VOR gain and age (r = -0.425; P < .0001). CONCLUSIONS: Our study demonstrates VOR gain differences with age, especially in the preadolescent and geriatric groups. The current manufacturer-provided normative data do not serve as an accurate reference, especially for these two age groups. A larger population of all age groups should be compared to the current RC manufacturer normative values to ensure that they accurately reflect the true normative data. LEVEL OF EVIDENCE: 2. PMID- 26227881 TI - The Emotional Impact of Skin Diseases. PMID- 26227882 TI - Angiotensin II stimulation alters vasomotor response to adenosine in mouse mesenteric artery: role for A1 and A2B adenosine receptors. AB - BACKGROUND AND PURPOSE: Stimulation of the A1 adenosine receptor and angiotensin II receptor type-1 (AT1 receptor) causes vasoconstriction through activation of cytochrome P450 4A (CYP4A) and ERK1/2. Thus, we hypothesized that acute angiotensin II activation alters the vasomotor response induced by the non selective adenosine receptor agonist, NECA, in mouse mesenteric arteries (MAs). EXPERIMENTAL APPROACH: We used a Danish Myo Technology wire myograph to measure muscle tension in isolated MAs from wild type (WT), A1 receptor and A2B receptor knockout (KO) mice. Western blots were performed to determine the expression of AT1 receptors and CYP4A. KEY RESULTS: Acute exposure (15 min) to angiotensin II attenuated the NECA-dependent vasodilatation and enhanced vasoconstriction. This vasoconstrictor effect of angiotensin II in NECA-treated MAs was abolished in A1 receptor KO mice and in WT mice treated with the A1 receptor antagonist DPCPX, CYP4A inhibitor HET0016 and ERK1/2 inhibitor PD98059. In MAs from A2B receptor KO mice, the vasoconstrictor effect of angiotensin II on the NECA-induced response was shown to be dependent on A1 receptors. Furthermore, in A2B receptor KO mice, the expression of AT1 receptors and CYP4A was increased and the angiotensin II induced vasoconstriction enhanced. In addition, inhibition of KATP channels with glibenclamide significantly reduced NECA-induced vasodilatation in WT mice. CONCLUSIONS AND IMPLICATIONS: Acute angiotensin II stimulation enhanced A1 receptor-dependent vasoconstriction and inhibited A2B receptor-dependent vasodilatation, leading to a net vasoconstriction and altered vasomotor response to NECA in MAs. This interaction may be important in the regulation of BP. PMID- 26227883 TI - Absence of Dystrophin Related Protein-2 disrupts Cajal bands in a patient with Charcot-Marie-Tooth disease. AB - Using exome sequencing in an individual with Charcot-Marie-Tooth disease (CMT) we have identified a mutation in the X-linked dystrophin-related protein 2 (DRP2) gene. A 60-year-old gentleman presented to our clinic and underwent clinical, electrophysiological and skin biopsy studies. The patient had clinical features of a length dependent sensorimotor neuropathy with an age of onset of 50 years. Neurophysiology revealed prolonged latencies with intermediate conduction velocities but no conduction block or temporal dispersion. A panel of 23 disease causing genes was sequenced and ultimately was uninformative. Whole exome sequencing revealed a stop mutation in DRP2, c.805C>T (Q269*). DRP2 interacts with periaxin and dystroglycan to form the periaxin-DRP2-dystroglycan complex which plays a role in the maintenance of the well-characterized Cajal bands of myelinating Schwann cells. Skin biopsies from our patient revealed a lack of DRP2 in myelinated dermal nerves by immunofluorescence. Furthermore electron microscopy failed to identify Cajal bands in the patient's dermal myelinated axons in keeping with ultrastructural pathology seen in the Drp2 knockout mouse. Both the electrophysiologic and dermal nerve twig pathology support the interpretation that this patient's DRP2 mutation causes characteristic morphological abnormalities recapitulating the Drp2 knockout model and potentially represents a novel genetic cause of CMT. PMID- 26227884 TI - Leprosy profiles in post-elimination stage: a tertiary care hospital experience. AB - BACKGROUND: Most countries that were previously highly endemic for leprosy have achieved elimination at the national level. OBJECTIVES: To find out the pattern, prevalence, and trends of leprosy in the post-elimination stage. METHODS: A descriptive retrospective cross-sectional study was carried out using the registered records of patients attending the leprosy clinic in Chittagong Medical College Hospital between the periods 2001 and 2011. RESULTS: The new case detection rate was declining. The prevalence rate was 0.75 at the end of 2011. Of a total of 789 patients, males (74%) outnumbered the females (26%). The age of the patients in the study group ranged from 6 years to 87 years with mean age 35.58 years +/- 0.05 SEM. Paucibacillary (PB) and multibacillary (MB) cases were 314 (39.80%) and 475 (60.20%), respectively. MB percentage was increasing more among new cases in the study period, and 119 (15.08%) patients presented with grade 2 deformities. Smear positive cases were 141 (17.87%). Leprosy reaction comprised of 193 (24.46%) type 1, 68 (8.62%) type 2, and 97 (12.29%) neuritis cases. LIMITATIONS: This is a retrospective study from a single tertiary health center. CONCLUSION: MB cases with grade 2 deformities are in an upward trend, and rates of children are declining. Developing reinforced new therapies to curb reactions, deformities are very important and contact tracing, especially of children, is essential. Domiciliary treatment needs to be made available to ensure early diagnosis. PMID- 26227886 TI - Rhodium-catalyzed [5 + 2 + 1] cycloaddition of ene-vinylcyclopropanes and CO: reaction design, development, application in natural product synthesis, and inspiration for developing new reactions for synthesis of eight-membered carbocycles. AB - Practical syntheses of natural products and their analogues with eight-membered carbocyclic skeletons are important for medicinal and biological investigations. However, methods and strategies to construct the eight-membered carbocycles are limited. Therefore, developing new methods to synthesize the eight-membered carbocycles is highly desired. In this Account, we describe our development of three rhodium-catalyzed cycloadditions for the construction of the eight-membered carbocycles, which have great potential in addressing the challenges in the synthesis of medium-sized ring systems. The first reaction described in this Account is our computationally designed rhodium-catalyzed two-component [5 + 2 + 1] cycloaddition of ene-vinylcyclopropanes (ene-VCPs) and CO for the diastereoselective construction of bi- and tricyclic cyclooctenones. The design of this reaction is based on the hypothesis that the C(sp(3))-C(sp(3)) reductive elimination of the eight-membered rhodacycle intermediate generated from the rhodium-catalyzed cyclopropane cleavage and alkene insertion, giving Wender's [5 + 2] cycloadduct, is not easy. Under CO atmosphere, CO insertion may occur rapidly, converting the eight-membered rhodacycle into a nine-membered rhodacycle, which then undergoes an easy C(sp(2))-C(sp(3)) reductive elimination process and furnishes the [5 + 2 + 1] product. This hypothesis was supported by our preliminary DFT studies and also served as inspiration for the development of two [7 + 1] cycloadditions: the [7 + 1] cycloaddition of buta-1,3 dienylcyclopropanes (BDCPs) and CO for the construction of cyclooctadienones, and the benzo/[7 + 1] cycloaddition of cyclopropyl-benzocyclobutenes (CP-BCBs) and CO to synthesize the benzocyclooctenones. The efficiency of these rhodium-catalyzed cycloadditions can be revealed by the application in natural product synthesis. Two eight-membered ring-containing natural products, (+/-)-asterisca-3(15),6 diene and (+)-asteriscanolide, have been synthesized using the [5 + 2 + 1] cycloaddition as the key step. In the latter case, excellent asymmetric induction was obtained using a chiral substrate. The efficiency of the [5 + 2 + 1] reaction was further demonstrated by the synthesis of four sesquiterpene natural products, (+/-)-pentalenene, (+)-hirsutene, (+/-)-1-desoxyhypnophilin, and (+/-)-hirsutic acid C, containing linear or branched triquinane skeletons utilizing the tandem or stepwise [5 + 2 + 1] cycloaddition/aldol reaction strategy. With the success of [5 + 2 + 1] cycloaddition in natural product synthesis, application of the [7 + 1] and benzo/[7 + 1] cycloadditions in target- and function-oriented syntheses can be envisioned. PMID- 26227885 TI - Cigarette Smoking and Carotid Plaque Echodensity in the Northern Manhattan Study. AB - BACKGROUND: We sought to determine the association between cigarette smoking and carotid plaque ultrasound morphology in a multiethnic cohort. METHODS: We analyzed 1,743 stroke-free participants (mean age 65.5 +/- 8.9 years; 60% women; 18% white, 63% Hispanic, 19% black; 14% current and 38% former smokers, 48% never smoked) from the Northern Manhattan Study using an ultrasound index of plaque echodensity, the Gray-Scale Median (GSM). Echolucent plaque (low GSM) represents soft plaque and echodense (high GSM) more calcified plaque. The mean GSM weighted by plaque area for each plaque was calculated for those with multiple plaques. Quintiles of GSM were compared to no plaque. Multinomial logistic regression models were used to assess associations of cigarette smoking with GSM, adjusting for demographics and vascular risk factors. RESULTS: Among subjects with carotid plaque (58%), the mean GSM scores for quintiles 1-5 were 48, 72, 90, 105, and 128, respectively. Current smokers had over a two fold increased risk of having GSM in quintile 1 (odds ratio (OR) = 2.17; 95% confidence interval (CI), 1.34 3.52), quintile 2 (OR = 2.33; 95% CI, 1.42-3.83), quintile 4 (OR = 2.05; 95% CI, 1.19-3.51), and quintile 5 (OR = 2.13; 95% CI, 1.27-3.56) but not in quintile 3 (OR = 1.18; 95% CI, 0.67-2.10) as compared to never smokers in fully adjusted models. Former smokers had increased risk in quintile 2 (OR = 1.46; 95% CI, 1.00 2.12), quintile 3 (OR = 1.56; 95% CI, 1.09-2.24), quintile 4 (OR = 1.66; 95% CI, 1.13-2.42), and quintile 5 (OR = 1.73; 95% CI, 1.19-2.51), but not in quintile 1 (OR = 1.05; 95% CI, 0.72-1.55). CONCLUSIONS: A nonlinear, V-shaped-like relationship between current cigarette smoking and plaque echodensity was observed. Former smokers were at the highest risk for plaques in high GSM quintiles. Thus, current smokers were more likely to have either soft or calcified plaques and former smokers were at greater risk of having only echodense plaques when compared to those who have never smoked. Further research is needed to determine if plaque morphology mediates an association between smoking and clinical vascular events. PMID- 26227887 TI - TRPA1 mediates the hypothermic action of acetaminophen. AB - Acetaminophen (APAP) is an effective antipyretic and one of the most commonly used analgesic drugs. Unlike antipyretic non-steroidal anti-inflammatory drugs, APAP elicits hypothermia in addition to its antipyretic effect. Here we have examined the mechanisms responsible for the hypothermic activity of APAP. Subcutaneous, but not intrathecal, administration of APAP elicited a dose dependent decrease in body temperature in wildtype mice. Hypothermia was abolished in mice pre-treated with resiniferatoxin to destroy or defunctionalize peripheral TRPV1-expressing terminals, but resistant to inhibition of cyclo oxygenases. The hypothermic activity was independent of TRPV1 since APAP evoked hypothermia was identical in wildtype and Trpv1(-/-) mice, and not reduced by administration of a maximally effective dose of a TRPV1 antagonist. In contrast, a TRPA1 antagonist inhibited APAP induced hypothermia and APAP was without effect on body temperature in Trpa1(-/-) mice. In a model of yeast induced pyrexia, administration of APAP evoked a marked hypothermia in wildtype and Trpv1(-/-) mice, but only restored normal body temperature in Trpa1(-/-) and Trpa1(-/ )/Trpv1(-/-) mice. We conclude that TRPA1 mediates APAP evoked hypothermia. PMID- 26227888 TI - Simultaneously targeting inflammatory response and parasite sequestration in brain to treat Experimental Cerebral Malaria. AB - Malaria afflicts around 200 million people annually, with a mortality number close to 600,000. The mortality rate in Human Cerebral Malaria (HCM) is unacceptably high (15-20%), despite the availability of artemisinin-based therapy. An effective adjunct therapy is urgently needed. Experimental Cerebral Malaria (ECM) in mice manifests many of the neurological features of HCM. Migration of T cells and parasite-infected RBCs (pRBCs) into the brain are both necessary to precipitate the disease. We have been able to simultaneously target both these parameters of ECM. Curcumin alone was able to reverse all the parameters investigated in this study that govern inflammatory responses, CD8(+) T cell and pRBC sequestration into the brain and blood brain barrier (BBB) breakdown. But the animals eventually died of anemia due to parasite build-up in blood. However, arteether-curcumin (AC) combination therapy even after the onset of symptoms provided complete cure. AC treatment is a promising therapeutic option for HCM. PMID- 26227889 TI - Safety Assessment of Ethanolamides as Used in Cosmetics. AB - The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) rereviewed the safety of 28 ethanolamides and found them safe in the present practices of use and concentration when they are formulated to be nonirritating, and that these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed. Most of the ethanolamides are reported to function in cosmetics as hair-conditioning agents, skin-conditioning agents, and surfactant-foam boosters. The Panel reviewed available animal and clinical data, as well as information from previous CIR reports. PMID- 26227890 TI - Safety Assessment of Galactomannans as Used in Cosmetics. AB - The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of 16 galactomannans as used in cosmetics. These ingredients are legume polysaccharides that function mostly as hair/skin-conditioning agents and viscosity-increasing agents in cosmetic products. Their substantial molecular sizes suggest that skin penetration of these ingredients would be unlikely. The Panel concluded that these galactomannans are safe in the present practices of use and concentration described in this safety assessment. PMID- 26227891 TI - Safety Assessment of Dialkyl Malates as Used in Cosmetics. AB - The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of 6 dialkyl malate compounds used in cosmetics. These ingredients function mostly as skin-conditioning agents-emollients. The Panel reviewed relevant animal and human data related to the ingredients along with a previous safety assessment of malic acid. The similar structure, properties, functions, and uses of these ingredients enabled grouping them and using the available toxicological data to assess the safety of the entire group. The Panel concluded that these dialkyl maleate compounds are safe in the present practices of use and concentration as given in this safety assessment. PMID- 26227892 TI - Safety Assessment of Talc as Used in Cosmetics. AB - The Cosmetic Ingredient Review Expert Panel (Panel) assessed the safety of talc for use in cosmetics. The safety of talc has been the subject of much debate through the years, partly because the relationship between talc and asbestos is commonly misunderstood. Industry specifications state that cosmetic-grade talc must contain no detectable fibrous, asbestos minerals. Therefore, the large amount of available animal and clinical data the Panel relied on in assessing the safety of talc only included those studies on talc that did not contain asbestos. The Panel concluded that talc is safe for use in cosmetics in the present practices of use and concentration (some cosmetic products are entirely composed of talc). Talc should not be applied to the skin when the epidermal barrier is missing or significantly disrupted. PMID- 26227893 TI - Imaging in Glucocerebrosidase-Associated Parkinsonism: Current Status and Implications for Pathophysiology. AB - BACKGROUND: Glucocerebrosidase (GBA) mutations have been described as the most prevalent in Parkinson's disease (PD) and in Lewy body dementia, accounting for up to 7 and 13.8% of cases, respectively. To elucidate the pathophysiology of idiopathic Parkinson's disease (iPD), the pathogenic mechanisms leading to Lewy body accumulation in GBA-associated parkinsonism (GBA-PD) are a matter of current research. However, only few imaging studies, conducted on small GBA-PD patient cohorts, exist. METHODS: We provide an overview of current structural and functional imaging studies in patients with Gaucher's disease and parkinsonism and in GBA-PD patients, underlining the main differences compared to iPD. RESULTS: A limited number of PET studies have been conducted in GBA-PD, exploring brain metabolism and dopaminergic presynaptic and postsynaptic function. Moreover, structural MRI and spectroscopy studies recently evidenced the differences with iPD, aiding to understand of some peculiar aspects of iPD. Finally, new evidence from transcranial sonography confirms the technique's role in the study of GBA-PD and highlights the additional involvement of the raphe nucleus. CONCLUSIONS: Further imaging studies conducted in a broader population of early GBA-PD are warranted to characterize the disease and elucidate the pathophysiological mechanisms underlying GBA-PD and to understand GBA implications in iPD. PMID- 26227894 TI - [Health literacy of adults in Germany: Findings from the German Health Update (GEDA) study]. AB - BACKGROUND: In today's information society, health literacy (HL) is considered important for health maintenance and disease management. In this context, dealing with health information is fundamental and requires different cognitive and social skills. OBJECTIVES: The aim of this study was to investigate the distribution of HL levels in the adult population of Germany, and to identify associations with health behaviours and health status. MATERIALS AND METHODS: The analyses were based on data from the German Health Update (GEDA) study, a cross sectional survey of the German-speaking adult population of Germany, which was conducted from October 2013 to June 2014. Health literacy was assessed with the short form of the European Health Literacy Questionnaire (HLS EU-Q16), along with questions about socio-demographics, health behaviours, and health status. The HLS EU-Q16 index could be calculated for 4845 respondents. RESULTS: According to the criteria of the HLS-EU-Q16, more than half of the adults had "adequate" HL (55.8 %). Every third person (31.9 %) had "problematic" and almost every eighth person (12.3 %) had "inadequate" HL. We found significant differences in HL by educational level, but no differences in HL by sex and age group. Certain health behaviours were positively associated with health literacy. A low HL level was associated with poorer physical and mental health. CONCLUSION: The results point to a need for action to improve HL in the adult population. The strengthening of health literacy should not solely aim at the promotion of individual skills, but also give high priority to the development of health-literate settings. PMID- 26227895 TI - Gender Differences in Cardiovascular Drugs. AB - The different responses of women and men to cardiovascular drugs reflect gender specific variances in pharmacokinetic profiles and drug sensitivities coupled to inherent differences in the underlying physiology of each sex. Thus, many common cardiovascular drugs exhibit gender -specific therapeutic and adverse effects. For example, the QT interval of the electrocardiogram is longer in women compared to men, and accordingly, drugs that prolong the QT interval are more likely to cause lethal ventricular arrhythmias in female than male patients. As more clinical drug trials include women subjects, our improved knowledge base for assessing the risk/benefit ratio for cardiovascular drugs in women will enable us to consider gender as one factor in prescribing drugs and adjusting drug loading and maintenance dosages. This short review will present evidence for gender- related differences in the responses to common cardiovascular drugs including statins, antiplatelet and antithrombotic agents, beta-blockers, digoxin, vasodilator therapies, and drugs associated with the Long QT Syndrome. PMID- 26227896 TI - Women and Heart Disease; A Focus Issue. PMID- 26227897 TI - Radiation of the Drosophila nannoptera species group in Mexico. AB - The Drosophila nannoptera species group, a taxon of Mexican cactophilic flies, is an excellent model system to study the influence of abiotic and biotic factors on speciation, the genetic causes of ecological specialization and the evolution of unusual reproductive characters. However, the phylogenetic relationships in the nannoptera species group and its position within the virilis-repleta phylogeny have not been thoroughly investigated. Using a multilocus data set of gene coding regions of eight nuclear and three mitochondrial genes, we found that the four described nannoptera group species diverged rapidly, with very short internodes between divergence events. Phylogenetic analysis of repleta group lineages revealed that D. inca and D. canalinea are sister to all other repleta group species, whereas the annulimana species D. aracataca and D. pseudotalamancana are sister to the nannoptera and bromeliae species groups. Our divergence time estimates suggest that the nannoptera species group radiated following important geological events in Central America. Our results indicate that a single evolutionary transition to asymmetric genitalia and to unusual sperm storage may have occurred during evolution of the nannoptera group. PMID- 26227898 TI - Population genomics of eusocial insects: the costs of a vertebrate-like effective population size. AB - The evolution of reproductive division of labour and social life in social insects has lead to the emergence of several life-history traits and adaptations typical of larger organisms: social insect colonies can reach masses of several kilograms, they start reproducing only when they are several years old, and can live for decades. These features and the monopolization of reproduction by only one or few individuals in a colony should affect molecular evolution by reducing the effective population size. We tested this prediction by analysing genome-wide patterns of coding sequence polymorphism and divergence in eusocial vs. noneusocial insects based on newly generated RNA-seq data. We report very low amounts of genetic polymorphism and an elevated ratio of nonsynonymous to synonymous changes - a marker of the effective population size - in four distinct species of eusocial insects, which were more similar to vertebrates than to solitary insects regarding molecular evolutionary processes. Moreover, the ratio of nonsynonymous to synonymous substitutions was positively correlated with the level of social complexity across ant species. These results are fully consistent with the hypothesis of a reduced effective population size and an increased genetic load in eusocial insects, indicating that the evolution of social life has important consequences at both the genomic and population levels. PMID- 26227899 TI - Recent admixture generates heterozygosity-fitness correlations during the range expansion of an invading species. AB - Admixture, the mixing of historically isolated gene pools, can have immediate consequences for the genetic architecture of fitness traits. Admixture may be especially important for newly colonized populations, such as during range expansion and species invasions, by generating heterozygosity that can boost fitness through heterosis. Despite widespread evidence for admixture during species invasions, few studies have examined the demographic history leading to admixture, how admixture affects the heterozygosity and fitness of invasive genotypes, and whether such fitness effects are maintained through time. We address these questions using the invasive plant Silene vulgaris, which shows evidence of admixture in both its native Europe and in North America where it has invaded. Using multilocus genotype data in conjunction with approximate Bayesian computation analysis of demographic history, we showed that admixture during the invasion of North America was independent from and much younger than admixture in the native range of Europe. We tested for fitness consequences of admixture in each range and detected a significant positive heterozygosity-fitness correlation (HFC) in North America; in contrast, no HFC was present in Europe. The lack of HFC in Europe may reflect the longer time since admixture in the native range, dissipating associations between heterozygosity at markers and fitness loci. Our results support a key short-term role for admixture during the early stages of invasion by generating HFCs that carry populations past the threat of extinction from inbreeding and demographic stochasticity. PMID- 26227900 TI - When a clonal genome finds its way back to a sexual species: evidence from ongoing but rare introgression in the hybridogenetic water frog complex. AB - Besides several exceptions, asexual metazoans are usually viewed as ephemeral sinks for genomes, which become 'frozen' in clonal lineages after their emergence from ancestral sexual species. Here, we investigated whether and at what rate the asexuals are able to introgress their genomes back into the parental sexual population, thus more or less importantly affecting the gene pools of sexual species. We focused on hybridogenetic hybrids of western Palaearctic water frogs (Pelophylax esculentus), which originate through hybridization between P. ridibundus and P. lessonae, but transmit only clonal ridibundus genome into their gametes. Although usually mating with P. lessonae, P. esculentus may upon mating with P. ridibundus or another hybrid produce sexually reproducing P. ridibundus offspring with the introgressed ex-clonal genome. We compared the rate of nuclear amplified fragment length polymorphism (AFLP) and mitochondrial introgression in two types of populations, that is, those where P. ridibundus occurs in isolation and those where it lives with the hybridogens. Although significant differentiation (Phipt) between sexual and clonal ridibundus genomes suggested limited gene flow between sexuals and hybridogens, a non-negligible (~5%) proportion of P. ridibundus bore introgressed mtDNA and AFLP markers. Whereas transfer of mtDNA was exclusively unidirectional, introgression of nuclear markers was bidirectional. The proportion of introgressed P. ridibundus was highest in syntopic populations with P. esculentus, proving an ongoing and site specific interspecific genetic transfer mediated by hybridogenetic hybrids. It turns out that asexual hybrids are not just a sink for genes of sexual species, but may significantly influence the genetic architecture of their sexual counterparts. PMID- 26227901 TI - Combining large number of weak biomarkers based on AUC. AB - Combining multiple biomarkers to improve diagnosis and/or prognosis accuracy is a common practice in clinical medicine. Both parametric and non-parametric methods have been developed for finding the optimal linear combination of biomarkers to maximize the area under the receiver operating characteristic curve (AUC), primarily focusing on the setting with a small number of well-defined biomarkers. This problem becomes more challenging when the number of observations is not order of magnitude greater than the number of variables, especially when the involved biomarkers are relatively weak. Such settings are not uncommon in certain applied fields. The first aim of this paper is to empirically evaluate the performance of existing linear combination methods under such settings. The second aim is to propose a new combination method, namely, the pairwise approach, to maximize AUC. Our simulation studies demonstrated that the performance of several existing methods can become unsatisfactory as the number of markers becomes large, while the newly proposed pairwise method performs reasonably well. Furthermore, we apply all the combination methods to real datasets used for the development and validation of MammaPrint. The implication of our study for the design of optimal linear combination methods is discussed. PMID- 26227903 TI - Comparison of Abstinence and Coital Frequency Between 2 Natural Methods of Family Planning. AB - INTRODUCTION: The length of periodic abstinence, due to overestimation of the fertile phase of the menstrual cycle, is often a cause for dissatisfaction, discontinuation, and user error with natural family planning (NFP) methods. The objective of this research was to compare the length of required abstinence (ie, estimated fertility) and coital frequency between 2 NFP methods. METHODS: This was an analysis of data from a 12-month prospective comparison study in which participants were randomized into either an electronic hormonal fertility monitor (EHFM) group or a cervical mucus monitoring (CMM) group-both of which included a fertility algorithm as a double check for the beginning and end of the estimated fertile window. The number of days of estimated fertility and coitus was extracted from each menstrual cycle of data, and t tests were used to compare the means of these 2 variables between the 2 NFP methods. RESULTS: The study involved 197 women (mean [SD] age 29.7 [5.4]) who used the EHFM to estimate the fertile window and 160 women (mean [SD] age 30.4 [5.3]) who used CMM to estimate the fertile window. They produced 1,669 menstrual cycles of data. After 12 months of use, the EHFM group had statistically fewer days of estimated fertility than the CMM group (mean [SD] days, 13.25 [2.79] vs 13.68 [2.99], respectively; t = 2.07; P = .039) and significantly more coitus (mean [SD] coital acts, 4.22 [3.16] vs 4.05 [2.88], respectively; t = 1.17; P = .026). DISCUSSION: The use of the EHFM seems to provide more objectivity and confidence in self-estimating the fertile window and using nonfertile days for intercourse when avoiding pregnancy. PMID- 26227904 TI - Measuring iodine status in diverse populations. PMID- 26227902 TI - Responsiveness of clinical outcome measures in Charcot-Marie-Tooth disease. AB - BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease (CMT) is a very slowly progressive neuropathy which makes it difficult to detect disease progression over time and to assess intervention efficacy. Experience from completed clinical trials with ascorbic acid and natural history studies confirm difficulties in detecting such changes. Consequently, sensitive-to-change outcome measures (OMs) are urgently needed. METHODS: The relative responsiveness of clinical scales of the Italian-UK ascorbic acid trial (placebo arm) were assessed by using the standardized response mean (SRM), which is the ratio of the paired scores mean change over time to the standard deviation of the score change (0 is worst responsiveness). RESULTS: Little worsening of OM scores was found over 2 years. In detail, the primary OM of the trial, the CMT Neuropathy Score version 1 (CMTNSv1), showed low responsiveness (SRM 0.13). Some CMTNS items showed slightly greater responsiveness (CMT Examination Score 0.17; CMTNS Signs 0.19). Myometric assessments of handgrip and foot dorsiflexion strength were the most responsive (SRM -0.31 and -0.38, respectively). Amongst the other measures, the nine-hole peg test, which assesses upper limb functioning, showed the best sensitivity to change (SRM 0.28). CONCLUSIONS: Overall these OMs showed low or negligible responsiveness, confirming the need to improve current OMs and to develop novel ones for prognostic and interventional studies. However, handgrip and foot dorsiflexion myometry are worth retaining for future trials as they were the most responsive and are likely to be clinically relevant for patients. PMID- 26227905 TI - A Pooling Genome-Wide Association Study Combining a Pathway Analysis for Typical Sporadic Parkinson's Disease in the Han Population of Chinese Mainland. AB - Genome-wide association studies (GWAS) on sporadic Parkinson's disease (sPD) are mainly conducted in European and American populations at present, and the Han populations of Chinese mainland (HPCM) almost have not been studied yet. Here, we conducted a pooling GWAS combining a pathway analysis with 862,198 autosomal single nucleotide polymorphisms of IlluminaHumanOmniZhongHua-8 in 250 sPD and 250 controls from HPCM precluded toxicant exposure, age, and heavy coffee drinking habit interference. We revealed that among the 22 potential loci implicated, PRDM2/KIAA1026 (kgp8090149), TSG1/MANEA (kgp154172), PDE10A (kgp8130520), MDGA2 (rs9323124), ATPBD4/LOC100288892 (kgp11333367), ZFP64/TSHZ2 (kgp4156164), PAQR3/ARD1B (kgp9482779), FLJ23172/FNDC3B (kgp760898), C18orf1 (kgp348599), FLJ43860/NCRNA00051 (kgp4105983), CYP1B1/C2orf58 (kgp11353523), WNT9A/LOC728728 (rs849898), ANXA1/LOC100130911 (rs10746953), FLJ35379/LOC100132423 (kgp9550589), PLEKHN1 (kgp7172368), DMRT2/SMARCA2 (kgp10769919), ZNF396/INO80C (rs1362858), C3orf67/LOC339902 (rs6783485), LOC285194/IGSF11 (rs1879553), FGF10/MRPS30 (rs13153459), BARX1/PTPDC1 (kgp6542803), and COL5 A2 (rs11186), the peak significance was at the kgp4105983 of FLJ43860 gene in chromosome 8, the first top strongest associated locus with sPD was PRDM2 (kgp8090149) in chromosome 1, and the 24 pathways including 100 significantly associated genes were strongly associated with sPD from HPCM. The 40 genes were shared by at least two pathways. The most possible associated pathways with sPD were axon guidance, ECM-receptor interaction, neuroactive ligand-receptor interaction, tight junction, focal adhesion, gap junction, long-term depression, drug metabolism-cytochrome P450, adherens junction, endocytosis, and protein digestion and absorption. Our results indicated that these loci, pathways, and their related genes might be involved in the pathogenesis of sPD from HPCM and provided some novel evidences for further searching the genetic pathogenesis of sPD. PMID- 26227906 TI - The Role of Cdk5 in Alzheimer's Disease. AB - Alzheimer's disease (AD) is known as the most fatal chronic neurodegenerative disease in adults along with progressive loss of memory and other cognitive function disorders. Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (Cdks), is reported to intimately associate with the process of the pathogenesis of AD. Cdk5 is of vital importance in the development of CNS and neuron movements such as neuronal migration and differentiation, synaptic functions, and memory consolidation. However, when neurons suffer from pathological stimuli, Cdk5 activity becomes hyperactive and causes aberrant hyperphosphorylation of various substrates of Cdk5 like amyloid precursor protein (APP), tau and neurofilament, resulting in neurodegenerative diseases like AD. Deregulation of Cdk5 contributes to an array of pathological events in AD, ranging from formation of senile plaques and neurofibrillary tangles, synaptic damage, mitochondrial dysfunction to cell cycle reactivation as well as neuronal cell apoptosis. More importantly, an inhibition of Cdk5 activity with inhibitors such as RNA inference (RNAi) could protect from memory decline and neuronal cell loss through suppressing beta-amyloid (Abeta)-induced neurotoxicity and tauopathies. This review will briefly describe the above-mentioned possible roles of Cdk5 in the physiological and pathological mechanisms of AD, further discussing recent advances and challenges in Cdk5 as a therapeutic target. PMID- 26227907 TI - MAOA Variants and Genetic Susceptibility to Major Psychiatric Disorders. AB - Monoamine oxidase A (MAOA) is a mitochondrial enzyme involved in the metabolism of several biological amines such as dopamine, norepinephrine, and serotonin, which are important neurochemicals in the pathogenesis of major psychiatric illnesses. MAOA is regarded as a functional plausible susceptibility gene for psychiatric disorders, whereas previous hypothesis-driven association studies obtained controversial results, a reflection of small sample size, genetic heterogeneity, or true negative associations. In addition, MAOA is not analyzed in most of genome-wide association studies (GWAS) on psychiatric disorders, since it is located on Chromosome Xp11.3. Therefore, the effects of MAOA variants on genetic predisposition to psychiatric disorders remain obscure. To fill this gap, we collected psychiatric phenotypic (schizophrenia, bipolar disorder, and major depressive disorder) and genetic data in up to 18,824 individuals from diverse ethnic groups. We employed classical fixed (or random) effects inverse variance weighted methods to calculate summary odds ratios (OR) and 95 % confidence intervals (CI). We identified a synonymous SNP rs1137070 showing significant associations with major depressive disorder (p = 0.00067, OR = 1.263 for T allele) and schizophrenia (p = 0.0039, OR = 1.225 for T allele) as well as a broad spectrum of psychiatric phenotype (p = 0.000066, OR = 1.218 for T allele) in both males and females. The effect size was similar between different ethnic populations and different gender groups. Collectively, we confirmed that MAOA is a risk gene for psychiatric disorders, and our results provide useful information toward a better understanding of genetic mechanism involving MAOA underlying risk of complex psychiatric disorders. PMID- 26227908 TI - Single-center prospective study of Plummer-Vinson syndrome. AB - Post-cricoid web is an uncommon cause for dysphagia and is most frequently reported in middle-aged women. Triad of web, iron deficiency anemia (IDA), and dysphagia is known as Plummer-Vinson syndrome (PVS). Literature on PVS is very limited. Here we report the first prospective study of PVS with predefined diagnostic criteria and management plan. Adults with dysphagia or those incidentally found to have esophageal web were prospectively enrolled between July 2011 and June 2013. Participants were evaluated with hemogram, barium swallow, and esophagogastroduodenoscopy. PVS was diagnosed if a person had IDA and a post-cricoid web in barium swallow and/or endoscopy. Patients were managed with dilation using through-the-scope controlled radial expansion balloon followed by oral iron and folic acid supplementation. Thirty-seven patients (age, median [range] 40 [19-65] years; 32 [86%] women) were enrolled. Thirty-one symptomatic patients had dysphagia grade 1 (n = 12, 39%), 2 (n = 13, 42%), and 3 (n = 6, 19%) for a median (range) duration of 24 (4-324) months. Barium swallow, done in 29, showed web in 25 which were either circumferential or anterior in position. Twenty-nine (29/31, 94%) patients had complete and two had partial response after the first session of endoscopic dilatation without any complication. Dysphagia recurred in three (10%) of the 30 patients who were followed for a median (range) of 10 (1-24) months. Esophageal-web related dysphagia in patients with PVS responds favorably after single session of endoscopic dilation. PMID- 26227909 TI - Metagenomic analysis of soil fungal communities on Ulleungdo and Dokdo Islands. AB - Ulleungdo and Dokdo are volcanic islands that experience a characteristic marine climate, influenced by warm currents. The richness and diversity of the plant species, particularly vascular plants, are higher on Ulleungdo than on Dokdo. In contrast to the native plant life, little is known about the diversity of soil fungi living in the rhizosphere of these two islands. In this study, we utilized the barcoded pyrosequencing method to analyze rhizosphere soil fungi on Ulleungdo and Dokdo. In total, 768 operational taxonomic units (OTUs) were analyzed from the Ulleungdo samples, while 640 OTUs and 382 OTUs were analyzed from the Dongdo and Seodo (islets of Dokdo) samples, respectively. Species richness was considerably higher in the Ulleungdo samples than in the Dongdo and Seodo samples, while there was little difference in species diversity between the samples. The taxonomic composition analyses demonstrated that members of the phylum Basidiomycota dominated the Ulleungdo samples, whereas members of the phylum Ascomycota were predominant in the Dokdo samples. Ectomycorrhizal fungi belonging to the phylum Basidiomycota, in particular, were more abundant in the Ulleungdo samples. This finding suggests that the difference in the abundance of the ectomycorrhizal fungi in the rhizospheres of Ulleungdo and Dokdo may have been affected by species richness and diversity of the vascular plants. Our study is the first detailed report of the composition of soil fungal communities on the Ulleungdo and Dokdo islands. In addition, our findings provide a basis for understanding the ecological interactions between plants and fungi. PMID- 26227910 TI - The kinetics of Escherichia coli B growth and bacteriophage T4 multiplication in SM-1 novel minimal culture medium. AB - The aim of this study was to develop a minimal medium for the cultivation of Escherichia coli B, which could be especially suitable for the industrial propagation of bacteriophage T4. The new defined, minimal SM-1 culture medium, contains free amino acids as the only nitrogen source and enables the bacteria generation time to be prolonged and satisfactory phage titers to be achieved. The presence of organic ingredients, such as meat extracts, yeast hydrolysates, enzymatic protein hydrolysates, in a culture medium may cause problems in the case of bacteria or phage cultures for therapeutic purposes. In the present study, we introduce a new medium, together with some procedures and applications for its usage. We also present new kinetics of E. coli B growth. Some traits such as the lack of high molecular proteins, a bacterial growth comparable to that in a rich medium, and the cost effectiveness of the medium, makes it highly competitive with currently used microbiological media. The surprisingly high titers of bacteriophage T4 obtained in our experiments suggest that SM-1 medium has the potential to find a broad application in medicine, especially in infectious disease therapy, pharmacy and biotechnology. PMID- 26227911 TI - Trichopolyn VI: a new peptaibol insecticidal compound discovered using a recombinant Saccharomyces cerevisiae screening system. AB - In the course of searching for insecticides from soil microorganisms, we found that a fermentation broth of the fungus, Trichoderma brevicompactum FKI-6324, produced Trichopolyn VI, a new peptaibol, which possessed significant insecticidal potential. Spectroscopic analysis showed the compound to be a new trichopolyn I derivative. This paper describes the isolation, structure elucidation and biological activity of trichopolyn VI. PMID- 26227912 TI - Isolation of suppressors of the temperature-sensitive growth caused by a nonsense mutation in gene 1 of Bacillus subtilis phage o29 using hydroxylamine. PMID- 26227913 TI - Effect of disrupting the trichothecene efflux pump encoded by FgTri12 in the nivalenol chemotype of Fusarium graminearum. PMID- 26227914 TI - Characterization of giant spheroplasts generated from the aerobic anoxygenic photosynthetic marine bacterium Roseobacter litoralis. AB - DNA extracted from the bacterial culture used in this paper was analyzed by the massively parallel DNA sequencing. The sequence similarity search showed that most of the obtained DNA sequences were similar to those of Enterobacter genomic DNA. PCR analyses using primers to detect Enterobacter DNA showed that the original Roseobacter culture was contaminated with this bacterium. The authors recognized that the cultures used in this paper were considered as a mixture of Enterobacter and Roseobacter litoralis, and the deduced results were not well rationalized. Thus, the JGAM editorial board agreed to retract the paper. PMID- 26227915 TI - Superconductivity-induced re-entrance of the orthorhombic distortion in Ba1 xKxFe2As2. AB - Detailed knowledge of the phase diagram and the nature of the competing magnetic and superconducting phases is imperative for a deeper understanding of the physics of iron-based superconductivity. Magnetism in the iron-based superconductors is usually a stripe-type spin-density-wave, which breaks the tetragonal symmetry of the lattice, and is known to compete strongly with superconductivity. Recently, it was found that in some systems an additional spin density-wave transition occurs, which restores this tetragonal symmetry, however, its interaction with superconductivity remains unclear. Here, using thermodynamic measurements on Ba1-xKxFe2As2 single crystals, we show that the spin-density-wave phase of tetragonal symmetry competes much stronger with superconductivity than the stripe-type spin-density-wave phase, which results in a novel re-entrance of the latter at or slightly below the superconducting transition. PMID- 26227916 TI - An Unusual Case of Excavated Lung Lesion. PMID- 26227917 TI - Implementation of NCCN Palliative Care Guidelines by member institutions. AB - Increasingly, evidence suggests the integration of palliative care (PC) with standard oncologic care can yield substantial benefits. As part of an effort to improve the PC of cancer patients, the National Comprehensive Cancer Network (NCCN) has developed clinical practice guidelines for PC that promote access to quality, evidence-based PC. This study sought to characterize current implementation of the guidelines by NCCN member institutions. Institutional representatives appointed to the NCCN Palliative Care Guidelines Panel were asked to complete an online survey in the spring of 2014. The survey focused on availability of PC services, screening and referral practices for PC, PC education, and quality improvement programs. The survey was completed by representatives from 21 of 25 NCCN member institutions (84 %). A majority routinely provides PC services via interdisciplinary teams; 52 % routinely inform patients of the availability, elements, and benefits of PC. The guidelines are most often used to guide clinical practice; only 10 % reported using the guidelines to formally screen for PC needs and/or make referrals to PC specialists. Among the 62 % of institutions that screen any patients using any available criteria, when a patient screens positive for PC needs, a referral to a PC specialist is made less than half the time. Implementation of PC Guidelines is incomplete and various aspects of the guidelines, such as the recommendation to screen all patients for PC needs, are applied inconsistently. Despite this, most institutions provide PC services in a manner consistent with the guidelines. Greater implementation of the guidelines' recommendations is needed. PMID- 26227918 TI - Avoiding drainage after major hip surgery in children is a viable option: results from a retrospective comparative study. AB - PURPOSE: The use of closed-suction drainage systems to evacuate haematomas after surgical procedures is still common practice in many orthopaedic departments. However, no evidence to support the routine use of closed-suction drains in orthopaedic surgery exists. Post-operative handling and removal of the drain is particularly complicated in children. We hypothesised that the use of surgical drains in major hip procedures in children does not reduce the complication rate. METHODS: The records of 63 children undergoing 97 major hip procedures managed with closed-suction drains (centre A), and 75 children undergoing 130 major hip procedures without application of wound drains (centre B) were retrospectively reviewed in this dual-centre study. Demographic data, pre-existing conditions, surgical indications and procedures, duration of hospitalisation and complication rates were analysed. RESULTS: Children (mean age, 8.3 +/- 4 years) in both groups presented similar demographics, medical histories, surgical indications and procedures. No intra-operative complications occurred in either group. In the undrained group a significant shorter hospitalisation time was observed. Overall, there were 31 complications (31.9 %) in the drained group and 26 complications (20 %) in undrained group (p = 0.05). Applying the Clavien-Dindo grading system, both groups had mainly minor grade I and grade II complications. No differences regarding the rate of wound-related complications were observed between the two groups. CONCLUSIONS: The use of wound drains in our study cohorts has been shown to have no positive impact on complications rates after corrective osteotomies around the hip joint in children. In the light of our results and of the poor evidence of drainage use in adults, we do not recommend the routine use of drains in children undergoing orthopaedic hip procedures. PMID- 26227919 TI - Mesenchymal stem cells reside in anterior cruciate ligament remnants in situ. AB - PURPOSE: It has been reported that the anterior cruciate ligament (ACL) has certain self-healing ability after acute injury or with primary suture repair. Many studies have confirmed that a remnant preservation technique with ACL reconstruction contributes to biological augmentation for ACL healing. However, it remains unclear whether mesenchymal stem cells (MSC) reside in ACL remnants in situ. The aim of this study was to investigate the methods of culture and identification of MSC derived from the remnants of ACL rupture patients and to analyse these MSC's properties. METHODS: The cells of ACL remnants from the ACL rupture patients were isolated by the methods of enzymatic digestion and cultured in vitro to the third passage under the microscope to observe their morphology and growth status. The third passage of isolated cells was analysed for the identification of immunophenotype, osteogenic, adipogenic and chondrogenic differentiation. RESULTS: On the third to fifth days of in vitro culture, a few cells of long fusiform shape appeared and were adherent to the plastic walls. On the sixth to ninth days, cells clustered and colonies were observed. The third passage cells showed uniform cell morphology and good proliferation, with appearance of the typical surface markers of MSC, CD29, CD44, CD90 and CD105. The surface markers of CD34 and CD45 of haematopoietic stem cells were not expressed. Under appropriate conditions of in vitro culture, isolated cells could be differentiated into osteoblasts that deposit mineralised matrix and express early osteogenic markers, adipocytes that accumulate lipid droplets in cytoplasm and chondrocytes that secrete chondrogenic-specific matrix aggrecan and collagen II. Real-time polymerase chain reaction (PCR) analysis demonstrated that the specific mRNA expression of osteogenesis, adipogenesis and chondrogenesis increased significantly compared with the control groups at day zero. CONCLUSIONS: Stem cells derived in situ from the human ACL stump were successfully isolated and characterised. Those isolated cells were identified as MSC according to their adherent ability, morphology, surface markers and multilineage differentiation potential. MSC derived from ACL remnants could be a potential source of seeding cells for ligament regeneration. PMID- 26227920 TI - Synovial haemangioma of the knee: an under recognised condition. AB - BACKGROUND: Synovial haemangioma is a rare type of tumour for which only around 200 cases have been reported worldwide. It usually occurs in the female population during the second decade of life and most commonly affects the knee joint. Patients can complain of pain, recurrent knee swelling and limitation of motion. Since these lesions are uncommon and radilogical findings are nonspecific, physician awareness is low and diagnosis is often delayed, leading in turn to treatment delays and irreversible complications of the affected joint. MATERIALS AND METHODS: We report four cases of synovial haemangioma of the knee seen over a period of 20 years (1993-2013). Age at presentation ranged from six to 43 years (mean of 22.7 years) with an equal male-to-female ratio. Average duration of symptoms prior to treatment was three years--patients were often misdiagnosed and appropriate treatment was subsequently delayed. Radiographs showed moderate to severe degenerative changes. Magnetic resonance (MR) imaging revealed poorly defined intra-articular contrast-enhancing lesions, all of which were of the localised type. Three patients underwent open synovectomy and en bloc excision of the lesion; the fourth deferred surgery but continues to be monitored. Follow-up ranged from one to 11 years; all four patients are doing well, with no signs of symptom recurrence or progression. CONCLUSIONS: Synovial haemangioma is a rare but treatable condition. It should remain a differential for any patient with recurrent knee-joint symptoms. PMID- 26227921 TI - About the beginnings of orthopaedics in Timisoara. AB - The historical and geographical territory of Banat is part of present-day Romania. Timisoara's history, the capital city of Banat region, dates back to the second century B.C. Medical life in Banat was re-organised after the promulgation of the Aulic Laws in the eighteenth century. Thorough research was undertaken through historic manuscripts, old newspapers, biographies and other papers about the history of Romanian medicine. The eighteenth century witnessed the building of three hospitals in Timisoara. In that period, Banat region benefited from the expertise and professionalism of doctors who graduated and were trained mainly in Central and Western European universities. By the beginning of the twentieth century, many medical clinics or sanatoriums specialising in orthopaedics and traumatology were offering their services to the population. Banat region had many good orthopaedists, and one of them was Prof. Dr. Doc. Berceanu, who graduated from the University of Medicine Bucharest and further specialised in Paris, France. He is the founder of the Orthopaedics and Traumatology Clinic in Timisoara. PMID- 26227922 TI - Peri-articular injections of local anaesthesia can replace patient-controlled analgesia after total knee arthroplasty: a randomised controlled study. AB - PURPOSE: In recent years, there has been an increasing interest in peri-articular injections (PAI) to control post-operative pain after total knee arthroplasty (TKA). Previous studies have evaluated the effect of PAI using multimodal analgaesic protocols, but the concomitant use of patient-controlled analgesia (PCA) may has masked the genuine effects of PAI. We investigated the efficacy of PAI compared with PCA and determined whether conventional PCA can be effectively replaced with PAI after TKA. METHODS: Eighty patients undergoing unilateral TKA were randomised into two groups. The PCA group consisted of patients who used PCA after surgery, while the PAI group included patients who did not use PCA post operatively but were given PAI during surgery. We measured changes in visual analogue scale (VAS) scores, straight leg raising (SLR), range of motion (ROM) and consumption of antiemetics or analgaesics. RESULTS: Pain levels in the PAI group were significantly lower than in the PCA group during two weeks post operatively (p < 0.05).; functional recovery in the SLR test showed no difference between groups (p > 0.05).; mean ROM showed no difference; (p > 0.05) and there was no difference in the number of patients who needed additional analgaesics. However, antiemetic use was significantly lower for the PAI group (p < 0.05). CONCLUSIONS: PAI offered improved pain control and minimal side effects compared with PCA. Thus, PAI can replace conventional PCA for controlling post-operative pain after TKA. PMID- 26227923 TI - The accuracy of pre-operative imaging in the management of hepatic cysts. AB - BACKGROUND: Biliary cystic tumours (BCT) [biliary cystadenoma (BCA) and cystadenocarcinoma (BCAC)] warrant complete resection. Simple liver cysts (SLC) require fenestration when symptomatic. Distinguishing between BCT and atypical SLC with pre-operative imaging is not well studied. METHODS: All patients undergoing surgery for a pre-operative suspected SLC or BCT between 1992 and 2014 were included. Peri-operative data were retrospectively reviewed. A blind radiological review of pre-operative imaging was performed. RESULTS: Ninety-four patients underwent fenestration (n = 54) or complete excision (n = 40). Final pathology was SLC (n = 74), BCA (n = 15), BCAC (n = 2) and other primary malignancies (n = 3). A frozen section (FS) was performed in 36 patients, impacting management in 10 (27.8%) by avoiding (n = 1) or mandating a liver resection (n = 9). Frozen section results were always concordant with final pathology. Upon blind review, a solitary lesion, suspicious intracystic component, septation and biliary dilatation were associated with BCT (P < 0.05). Diagnostic sensitivity was high (87.5-100%) but specificity was poor (43.1 53.4%). The diagnostic value of imaging was most accurate when negative for BCT (negative predictive value: 92.5-100%). CONCLUSION: Radiological assessment of hepatic cysts is relatively inaccurate as SLC frequently present with concerning features. In the absence of a strong suspicion of malignancy, fenestration and FS should be considered prior to a complete resection. PMID- 26227925 TI - Primum non nocere! (First do no harm!). PMID- 26227924 TI - A microelectromechanical system artificial basilar membrane based on a piezoelectric cantilever array and its characterization using an animal model. AB - We proposed a piezoelectric artificial basilar membrane (ABM) composed of a microelectromechanical system cantilever array. The ABM mimics the tonotopy of the cochlea: frequency selectivity and mechanoelectric transduction. The fabricated ABM exhibits a clear tonotopy in an audible frequency range (2.92-12.6 kHz). Also, an animal model was used to verify the characteristics of the ABM as a front end for potential cochlear implant applications. For this, a signal processor was used to convert the piezoelectric output from the ABM to an electrical stimulus for auditory neurons. The electrical stimulus for auditory neurons was delivered through an implanted intra-cochlear electrode array. The amplitude of the electrical stimulus was modulated in the range of 0.15 to 3.5 V with incoming sound pressure levels (SPL) of 70.1 to 94.8 dB SPL. The electrical stimulus was used to elicit an electrically evoked auditory brainstem response (EABR) from deafened guinea pigs. EABRs were successfully measured and their magnitude increased upon application of acoustic stimuli from 75 to 95 dB SPL. The frequency selectivity of the ABM was estimated by measuring the magnitude of EABRs while applying sound pressure at the resonance and off-resonance frequencies of the corresponding cantilever of the selected channel. In this study, we demonstrated a novel piezoelectric ABM and verified its characteristics by measuring EABRs. PMID- 26227926 TI - Direct digital cholangioscopic visualization of suture causing a biliary anastomotic stricture. PMID- 26227927 TI - Tension capnopericardium and cardiac arrest as an unexpected adverse event of peroral endoscopic myotomy (with video). PMID- 26227928 TI - Endoscopic versus surgical resection of GI stromal tumors in the upper GI tract. AB - BACKGROUND AND AIMS: Endoscopic resection has been performed for treatment of GI stromal tumors (GISTs) in the upper GI tract. However, the therapeutic roles of the endoscopic procedure remain debatable. We aimed in this retrospective study to evaluate the feasibility and long-term follow-up results of endoscopic resection of GISTs in the upper GI tract, compared with surgery. METHODS: Between March 2005 and August 2014, 130 cases of GIST in the upper GI tract were resected. We compared baseline characteristics and clinical outcomes including R0 resection rate and recurrence rate between the endoscopy group (n = 90) and surgery group (n = 40). RESULTS: The most common location of GIST was the stomach body in the endoscopy group, whereas it was the duodenum in the surgery group (P = .001). Tumor size was significantly smaller (2.3 vs 5.1 cm; P < .001), and procedure time (51.8 +/- 36.2 vs 124.6 +/- 74.7 minutes; P < .001) and hospital stay (3.3 +/- 2.4 vs 8.3 +/- 5.4 days; P < .001) were significantly shorter in the endoscopy group than in the surgery group. The R0 resection rate was 25.6% in the endoscopy group, whereas it was 85.0% in the surgery group (P = .001), and 50.0% of resected tumors belonged to a very low-risk group in the endoscopy group, whereas 35.0% and 30.0% belonged to low-risk and high-risk in the surgery group (P = .001). However, during 45.5 months of follow-up, the recurrence rate was not significantly different between the 2 groups (2.2% vs 5.0%; P = .586). CONCLUSIONS: Endoscopic resection might be an alternative therapeutic modality for GISTs in the upper GI tract in selective cases. PMID- 26227929 TI - Vision loss: another ERCP-related adverse event, also known as isolated bilateral lateral geniculate body infarction. PMID- 26227930 TI - The evolving field of genomic biomarkers to characterize pancreatic cystic neoplasia by EUS-guided FNA. PMID- 26227932 TI - A truly visible vessel in an endoscopic submucosal dissection scare: thinking outside recommendations. PMID- 26227931 TI - Natural history of definitive diverticular hemorrhage based on stigmata of recent hemorrhage and colonoscopic Doppler blood flow monitoring for risk stratification and definitive hemostasis. AB - BACKGROUND AND AIMS: Few prospective reports describe the short-term natural history of colon diverticular hemorrhage based on stigmata of recent hemorrhage, and none include blood flow detection for risk stratification or as a guide to definitive hemostasis. Our purposes were to report the 30-day natural history of definitive diverticular hemorrhage based on stigmata and to describe Doppler probe blood flow detection as a guide to definitive hemostasis. METHODS: Different cohorts of patients with severe diverticular bleeding and stigmata on urgent colonoscopy are reported. For 30-day natural history, patients were treated medically. If severe rebleeding occurred, they had surgical or angiographic treatment. We report natural history with major stigmata (active bleeding, visible vessel, or adherent clot) and no stigmata or flat spots after clots were washed away. We also report Doppler probe detection of arterial blood flow underneath stigmata before and after hemostasis in a recent cohort. RESULTS: For natural history, patients with major stigmata treated medically had 65.8% (25/38) rebleeding rates, and 44.7% (17/38) had intervention for hemostasis. Patients with spots or clean bases had no rebleeding. A Doppler probe detected arterial blood flow in 92% of major stigmata--none after hemostasis--and there was no rebleeding. CONCLUSIONS: (1) Patients with major stigmata treated medically had high rates of rebleeding and intervention for hemostasis. (2) Patients with clean diverticula or only flat spots had no rebleeding. (3) High rates of arterial blood flow were detected under major stigmata with a Doppler probe, but with obliteration by hemostasis no rebleeding occurred. PMID- 26227933 TI - Editorial. PMID- 26227934 TI - Choreographing Compassion: A Clinical Adventure of Rhythms. AB - Compassion is a primary catalyst motivating positive human relationships, especially of those less fortunate. Our rhythms Expand-Contract of our own non verbal body joints movements and of the law of counter-balance, enable us to identify which of nine innate affects-emotions is directing the body's movements. With this reading, a trained person can synchronize choreography of these into fully authentic compassion between two or more persons. Primary references for this are the late Silvan S. Tomkins's four volumes "Affect Imagery Consciousness," and choreographers the late Rudolf Laban, Warren Lamb, Irmgard Bartenieff, and Marian Chace. Professionals, clinicians, and laity counselors can all use these. PMID- 26227935 TI - Experience of Spiritual Care in Cardiac Rehabilitation: An Interpretative Phenomenological Analysis. AB - The aim of the study was to explore the experience of spiritual care among a cardiac rehabilitation team. Spiritual care is an important dimension of providing comprehensive care, and understanding the views of health professionals is pivotal to making recommendations for caring. This study used an interpretive phenomenological approach. Semi-structured interviews were undertaken with 13 cardiac rehabilitation professionals. Seven persons participated in individual interviews and six in focus group discussions. Data were analyzed using Smith and Osborn's interpretative phenomenological analysis method. Study data were categorized into more than 150 initial themes, 12 clustered and four superordinate themes, included: 'Helping patients to obtain a meaningful sense of being', 'Providing religious/spiritual focused care', 'holistic approach to rehabilitation is needed' and 'spirituality as a neglected aspect of rehabilitation'. Participants described that they did not have sufficient training in providing spiritual care. Nurses' awareness of spiritual care meaning among a cardiac rehabilitation team is helping to respond to rehabilitation care in a holistic approach. Helping patients to get a meaningful sense of being is an important part of assisting in recovery and adjustment following an acute cardiac event. Providing clear guidelines and support for providing spiritual care in cardiac rehabilitation is required. PMID- 26227936 TI - Who Do You See? PMID- 26227937 TI - The Effects of CPE on Primary Relationships--Is It Worth Exploring? AB - Clinical Pastoral Education (CPE) can be a life transforming experience for students, but does it also transform students' primary relationships? An online survey of past CPE students at Royal Perth Hospital, Western Australia, found that--overall--CPE had a positive effect on primary relations in key areas, in particular communication, intimacy and spirituality. Recent relationships were more negatively affected. Some relationships did not survive CPE. Structural and pedagogical implications require further research. PMID- 26227938 TI - Licensed Professional Counselors' Perceptions of Pastoral Counseling in the African American Community. AB - This study utilized a phenomenological theory to evaluate the perceptions held by licensed professional counselors regarding pastoral counseling conducted in African American communities in the southeastern United States. The study was designed to build a deeper understanding of how licensed professional counselors conceptualized the African American pastor's role. To evaluate those perceptions, the researcher analyzed data collected from face-to-face interviews. The findings from this qualitative data analysis study revealed that the licensed professional counselor's perceptions of pastoral counseling are jaded by several factors that divide the two professions: lack of training, poor communications, and misconception of the level of professionalism in the church. These are just some of the results from the study. Moreover, the results of this study (a) can offer direction to pastors in selecting individual professional development goals to better prepare themselves and (b) can add perspective to the design of collaboration programs between counselors and pastors. PMID- 26227939 TI - The Willie Lomans of a Market Society: Addressing Political-Economic Sources of Suffering in Pastoral Counseling. AB - This article focuses on the culture of state-corporate capitalism as a source of psychological suffering for some people who seek the aid of pastoral counselors. An underlying premise of this article and, more particularly, the work of pastoral counseling comes from Frantz Fanon's view that the aims of psychotherapy are (a) 'to 'consciousnessize' [the patient's] unconscious, to no longer be tempted by a hallucinatory lactification', and (b) 'to enable [the patient] to choose an action with respect to the real source of the conflict, i.e., the social structure'. An aim of pastoral counseling, then, is to facilitate recognition of a person's sources of suffering so that s/he can decide how to respond. By contrast, it is argued that a pastoral counselor, in leaving a client unaware that his/her suffering is partially the result of a capitalistic culture, fosters hermeneutical mystification, and the patient is not able to choose an action directed toward a major source of his/her depression. PMID- 26227940 TI - When Violence Hits the Religious Home: Raising Awareness about Domestic Violence in Seminaries and amongst Religious Leaders. AB - The focus of this article by our research team looks specifically at the teaching of domestic violence classes in a seminary or religious context, as well as the ongoing professional education of religious leaders, such as pastors. It also considers ways to introduce therapeutic staff to the unique vulnerabilities of highly religious clients who have been abused or who act abusively. Based on data that we have collected at North American theological seminaries and in congregations, we explain some of the challenges of including instruction about domestic violence in a religious context. PMID- 26227941 TI - Truth. PMID- 26227947 TI - 'Sign of the kiss' from black henna tattoos. PMID- 26227948 TI - Green synthesis of therapeutic nanoparticles: an expanding horizon. AB - Nanotechnology continues to achieve tremendous awards in therapeutics, but the economical and ecofriendly production of nanoparticles (NPs) is still in infancy, simply due to the nanotoxicity, unprecedented health hazards and scale up issues. Green nanotechnology was introduced in the quest to mitigate such risks by utilizing natural resources as biological tool for NP synthesis. The key advantages offered by green approach include lower capital and operating expenses, reduced environmental impacts, superior biocompatibility and higher stability. In this review, we shed light on the biosynthesis of therapeutic NPs along with their numerous biomedical applications. Toxicity aspects of NPs and the impact of green approach on it, is also discussed briefly. PMID- 26227949 TI - Elucidating the structures and cooperative binding mechanism of cesium salts to the multitopic ion-pair receptor through density functional theory calculations. AB - Designing new and innovative receptors for the selective binding of radionuclides is central to nuclear waste management processes. Recently, a new multi-topic ion pair receptor was reported which binds a variety of cesium salts. Due to the large size of the receptor, quantum chemical calculations on the full ion-pair receptors are restricted, thus the binding mechanisms are not well understood at the molecular level. We have assessed the binding strengths of various cesium salts to the recently synthesized multi-topic ion-pair receptor molecule using density functional theory based calculations. Our calculations predict that the binding of cesium salts to the receptor predominantly occurs via the cooperative binding mechanism. Cesium and the anion synergistically assist each other to bind favorably inside the receptor. Energy decomposition analysis on the ion-pair complexes shows that the Cs salts are bound to the receptor mainly through electrostatic interactions with small contribution from covalent interactions for large ionic radius anions. Further, QTAIM analysis characterizes the importance of different inter-molecular interactions between the ions and the receptor inside the ion-pair complexes. The role of the crystallographic solvent molecule contributes significantly by ~10 kcal mol(-1) to the overall binding affinities which is quite significant. Further, unlike the recent molecular mechanics (MM) calculations, our calculated binding affinity trends for various Cs ion-pair complexes (CsF, CsCl and CsNO3) are now in excellent agreement with the experimental binding affinity trends. PMID- 26227946 TI - Dietary inorganic nitrate: From villain to hero in metabolic disease? AB - Historically, inorganic nitrate was believed to be an inert by-product of nitric oxide (NO) metabolism that was readily excreted by the body. Studies utilising doses of nitrate far in excess of dietary and physiological sources reported potentially toxic and carcinogenic effects of the anion. However, nitrate is a significant component of our diets, with the majority of the anion coming from green leafy vegetables, which have been consistently shown to offer protection against obesity, type 2 diabetes and metabolic diseases. The discovery of a metabolic pathway in mammals, in which nitrate is reduced to NO, via nitrite, has warranted a re-examination of the physiological role of this small molecule. Obesity, type 2 diabetes and the metabolic syndrome are associated with a decrease in NO bioavailability. Recent research suggests that the nitrate-nitrite NO pathway may be harnessed as a therapeutic to supplement circulating NO concentrations, with both anti-obesity and anti-diabetic effects, as well as improving vascular function. In this review, we examine the key studies that have led to the re-evaluation of the physiological function of inorganic nitrate, from toxic and carcinogenic metabolite, to a potentially important and beneficial agent in the treatment of metabolic disease. PMID- 26227952 TI - An overview of available crop growth and yield models for studies and assessments in agriculture. AB - The scientific community offers numerous crop models with different levels of sophistication. In such a wide range of crop models, users should have the possibility to choose the most suitable, in terms of detail, scale and representativeness, to their objectives. However, even when an appropriate choice is made, model limitations should be clarified such that modelling studies are put in the proper perspective and robust applications are achieved. This work is an overview of available models to simulate crop growth and yield. A summary matrix with more than 70 crop models is provided, storing the main model characteristics that can help users to choose the proper tool according to their purposes. Overall, we found that two main aspects of models, despite their importance, are not always clear from the published references, i.e. the versatility of the models, in terms of reliable transferability to different conditions, and the degree of complexity. Hence, the developers of models should be encouraged to pay more attention to clarifying the model limitations and limits of applicability, and users should make an effort in proper model selection, to save time often devoted to iteration of tuning steps to force an inappropriate model to be adapted to their own purpose. PMID- 26227953 TI - Cardiovascular Disease and Sleep-Disordered Breathing in Acromegaly. AB - Treatment goals in acromegaly include symptom relief, tumour control and reversal of the excess morbidity and mortality associated with the disorder. Cardiovascular complications include concentric biventricular hypertrophy and cardiomyopathy, hypertension, valvular heart disease and arrhythmias, while metabolic disturbance (insulin resistance/diabetes mellitus, dyslipidaemia) further increases the risk of cardiovascular and cerebrovascular events. Sleep disordered breathing (in the form of sleep apnoea) is also common in patients with acromegaly and may exacerbate cardiovascular dysfunction, in addition to contributing to impaired quality of life. Accordingly, and in keeping with evidence that cardiorespiratory complications in acromegaly are not automatically reversed/ameliorated simply through the attainment of 'safe' growth hormone and insulin-like growth factor 1 levels, recent guidelines have emphasised the need not only to achieve stringent biochemical control, but also to identify and independently treat these comorbidities. It is important, therefore, that patients with acromegaly are systematically screened at diagnosis, and periodically thereafter, for the common cardiovascular and respiratory manifestations and that biochemical targets do not become the only treatment goal. PMID- 26227951 TI - Identification of anti-tumour biologics using primary tumour models, 3-D phenotypic screening and image-based multi-parametric profiling. AB - BACKGROUND: Monolayer cultures of immortalised cell lines are a popular screening tool for novel anti-cancer therapeutics, but these methods can be a poor surrogate for disease states, and there is a need for drug screening platforms which are more predictive of clinical outcome. In this study, we describe a phenotypic antibody screen using three-dimensional cultures of primary cells, and image-based multi-parametric profiling in PC-3 cells, to identify anti-cancer biologics against new therapeutic targets. METHODS: ScFv Antibodies and designed ankyrin repeat proteins (DARPins) were isolated using phage display selections against primary non-small cell lung carcinoma cells. The selected molecules were screened for anti-proliferative and pro-apoptotic activity against primary cells grown in three-dimensional culture, and in an ultra-high content screen on a 3-D cultured cell line using multi-parametric profiling to detect treatment-induced phenotypic changes. The targets of molecules of interest were identified using a cell-surface membrane protein array. An anti-CUB domain containing protein 1 (CDCP1) antibody was tested for tumour growth inhibition in a patient-derived xenograft model, generated from a stage-IV non-small cell lung carcinoma, with and without cisplatin. RESULTS: Two primary non-small cell lung carcinoma cell models were established for antibody isolation and primary screening in anti proliferative and apoptosis assays. These assays identified multiple antibodies demonstrating activity in specific culture formats. A subset of the DARPins was profiled in an ultra-high content multi-parametric screen, where 300 morphological features were measured per sample. Machine learning was used to select features to classify treatment responses, then antibodies were characterised based on the phenotypes that they induced. This method co classified several DARPins that targeted CDCP1 into two sets with different phenotypes. Finally, an anti-CDCP1 antibody significantly enhanced the efficacy of cisplatin in a patient-derived NSCLC xenograft model. CONCLUSIONS: Phenotypic profiling using complex 3-D cell cultures steers hit selection towards more relevant in vivo phenotypes, and may shed light on subtle mechanistic variations in drug candidates, enabling data-driven decisions for oncology target validation. CDCP1 was identified as a potential target for cisplatin combination therapy. PMID- 26227954 TI - Ultrasonography detects early laryngeal muscle atrophy in an equine neurectomy model. AB - INTRODUCTION: A unilateral neurectomy model was used to study the relationship between histologic and ultrasonographic tissue characteristics during muscle atrophy over time. METHODS: This investigation was an in vivo experimental study in an equine model (n = 28). Mean pixel intensity of ultrasonographic images was measured, a muscle appearance grade was assigned weekly, and muscles were harvested from 4 to 32 weeks. Minimum fiber diameter, fiber density per unit area, percent collagen, percent fat, and fiber type profile were measured from muscle cryosections and correlated with the ultrasonographic parameters. RESULTS: A significant relationship was identified between collagen content, minimum fiber diameter, and ultrasonographic muscle appearance by as early as 8 weeks. There was no apparent association between fat content of muscle and the ultrasonographic appearance of atrophy before 28 weeks. CONCLUSIONS: Early muscle atrophy before fatty infiltration is detectable with ultrasound. The effect of muscle collagen content on echointensity may be mediated by reduced fiber diameter. PMID- 26227956 TI - The Quest for Polysulfides in Lithium-Sulfur Battery Electrolytes: An Operando Confocal Raman Spectroscopy Study. AB - Confocal Raman spectra of a lithium-sulfur battery electrolyte are recorded operando in a depth-of-discharge resolved manner for an electrochemical cell with a realistic electrolyte/sulfur loading ratio. The evolution of various possible polysulfides is unambiguously identified by combining Raman spectroscopy data with DFT simulations. PMID- 26227955 TI - The development of the mammalian outer and middle ear. AB - The mammalian ear is a complex structure divided into three main parts: the outer; middle; and inner ear. These parts are formed from all three germ layers and neural crest cells, which have to integrate successfully in order to form a fully functioning organ of hearing. Any defect in development of the outer and middle ear leads to conductive hearing loss, while defects in the inner ear can lead to sensorineural hearing loss. This review focuses on the development of the parts of the ear involved with sound transduction into the inner ear, and the parts largely ignored in the world of hearing research: the outer and middle ear. The published data on the embryonic origin, signalling, genetic control, development and timing of the mammalian middle and outer ear are reviewed here along with new data showing the Eustachian tube cartilage is of dual embryonic origin. The embryonic origin of some of these structures has only recently been uncovered (Science, 339, 2013, 1453; Development, 140, 2013, 4386), while the molecular mechanisms controlling the growth, structure and integration of many outer and middle ear components are hardly known. The genetic analysis of outer and middle ear development is rather limited, with a small number of genes often affecting either more than one part of the ear or having only very small effects on development. This review therefore highlights the necessity for further research into the development of outer and middle ear structures, which will be important for the understanding and treatment of conductive hearing loss. PMID- 26227957 TI - An autopsy case of frontotemporal lobar degeneration with the appearance of fused in sarcoma inclusions (basophilic inclusion body disease) clinically presenting corticobasal syndrome. AB - We describe an autopsy case of basophilic inclusion body disease (BIBD), a subtype of frontotemporal lobar degeneration (FTLD) with the appearance of fused in sarcoma (FUS) inclusions (FTLD-FUS), clinically presenting corticobasal syndrome (CBS). A 54-year-old man initially developed worsening of stuttering and right hand clumsiness. Neurological examinations revealed rigidity in the right upper and lower extremities, buccofacial apraxia, and right-side dominant limb kinetic and ideomotor apraxia. Neuroimaging showed asymmetric left-dominant brain atrophy and a cerebral blood flow reduction in the ipsilateral frontal region. At 56 years, his apraxia had advanced, and ideational apraxia was observed. Furthermore, the asymmetry in the limb-kinetic and ideomotor apraxia had disappeared, and both conditions had become bilateral. He had a new onset of aphasia. His symptoms progressed and he died 9 years after the initial symptoms. The brain weighed 955 g. Diffuse brain atrophy was most obvious in the bilateral frontotemporal regions. The atrophy of the left superior frontal and precentral gyri and bilateral basal ganglia was remarkable. Histologically, there was a marked loss of neurons with gliosis in the affected areas, where basophilic neuronal cytoplasmic inclusions were observed. The inclusions were immunoreactive for FUS, p62, and TATA-binding protein-associated factor 15 (TAF15), but not for phosphorylated tau, transactive response DNA-binding protein of 43 kDa (TDP-43), neurofilament protein, or Ewing sarcoma (EWS). From these pathological findings, this case was diagnosed as having BIBD as an FTLD-FUS variant. Spinal cord lower motor neurons were spared in number, similar to primary lateral sclerosis. Mutations in FUS were undetectable. Common background pathologies for CBS include corticobasal degeneration, Alzheimer's disease, PSP, FTLD with phosphorylated TDP 43 inclusions (FTLD-TDP), Pick's disease, Lewy body disease and CJD. However, FTLD-FUS (BIBD) has been rarely reported. Our case suggested further pathological heterogeneity in CBS than had previously been reported. It is necessary to consider FTLD-FUS (BIBD) as a background pathology for CBS in the future. PMID- 26227958 TI - Comparison of practice based research network based quality improvement technical assistance and evaluation to other ongoing quality improvement efforts for changes in agency culture. AB - BACKGROUND: Public health agencies in the USA are increasingly challenged to adopt Quality Improvement (QI) strategies to enhance performance. Many of the functional and structural barriers to effective use of QI can be found in the organizational culture of public health agencies. The purpose of this study was to assess the impact of public health practice based research network (PBRN) evaluation and technical assistance for QI interventions on the organizational culture of public health agencies in Georgia, USA. METHODS: An online survey of key informants in Georgia's districts and county health departments was used to compare perceptions of characteristics of organizational QI culture between PBRN supported QI districts and non-PBRN supported districts before and after the QI interventions. The primary outcomes of concern were number and percentage of reported increases in characteristics of QI culture as measured by key informant responses to items assessing organizational QI practices from a validated instrument on QI Collaboratives. Survey results were analyzed using Multi-level Mixed Effects Logistic Model, which accounts for clustering/nesting. RESULTS: Increases in QI organizational culture were consistent for all 10- items on a QI organizational culture survey related to: leadership support, use of data, on going QI, and team collaboration. Statistically significant odds ratios were calculated for differences in increased QI organizational culture between PBRN-QI supported districts compared to Non-PBRN supported districts for 5 of the 10 items, after adjusting for District clustering of county health departments. CONCLUSIONS: Agency culture, considered by many QI experts as the main goal of QI, is different than use of specific QI methods, such as Plan-Do-Study-Act (PDSA) cycles or root-cause analyses. The specific use of a QI method does not necessarily reflect culture change. Attempts to measure QI culture are newly emerging. This study documented significant improvements in characteristics of organizational culture and demonstrated the potential of PBRNs to support agency QI activities. PMID- 26227960 TI - T1- vs. T2-based MRI measures of spinal cord volume in healthy subjects and patients with multiple sclerosis. AB - BACKGROUND: The reliable and efficient measurement of spinal cord atrophy is of growing interest in monitoring disease progression in multiple sclerosis (MS). METHODS: We compared T1- and T2-weighted MRI for measuring cervical spinal cord volume in 31 patients with MS and 18 age-matched controls (NC) from T1-weighted gradient recalled echo and T2-weighted fast spin-echo 1.5 T axial acquisitions. The two sequences were matched on slice thickness, signal averages and voxel size. An active surface software tool determined the normalized mean cervical cord cross-sectional area. RESULTS: T1-derived cord areas were higher than T2 areas in the whole cohort (estimated mean difference = 7.03 mm(2) (8.89%); 95% Confidence Interval (CI): 5.91, 8.14; p < 0.0001) and in both groups separately. There were trends for lower spinal cord areas in MS vs. NC with both sequences. For the T1 cord area, the mean difference was 3.7 mm(2) (4.55%) (95% CI: -1.36, 8.78; p = 0.15). For the T2 cord area, the difference was larger [mean difference 4.9 mm(2) (6.52%) (95% CI: -0.83, 10.67); p = 0.091]. The T1 and T2 cord areas showed similar weak to moderate correlations with measures of clinical status and T2 spinal cord lesion volume in the MS group. Superficial spinal cord T2 lesions had no apparent confounding effect on the outlining tool. The mean intra-rater and inter-rater coefficients of variation ranged from 0.27 to 0.91% for T1- and 0.66 to 0.99% for T2-derived cord areas. CONCLUSION: T2-weighted images may prove efficient for measuring cervical spinal cord atrophy in MS, with the added advantage of lesion detectability. PMID- 26227959 TI - Non-invasive approaches to monitor EGFR-TKI treatment in non-small-cell lung cancer. AB - Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR-TKIs) are standard treatments for advanced non-small-cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. Nowadays, tumor tissues acquired by surgery or biopsy are the routine materials for EGFR mutation analysis. However, the accessibility of tumor tissues is not always satisfactory in advanced NSCLC. Moreover, a high proportion of NSCLC patients will eventually develop resistance to EGFR-TKIs. Invasive procedures, such as surgery or biopsy, are impractical to be performed repeatedly to assess the evolution of EGFR-TKI resistance. Thus, exploring some convenient and less invasive techniques to monitor EGFR-TKI treatment is urgently needed. Circulating cell-free tumor DNA (ctDNA) has a high degree of specificity to detect EGFR mutations in NSCLC. Besides, ctDNA is capable of monitoring the disease progression during EGFR-TKI treatment. Certain serum microRNAs that correlate with EGFR signaling pathway, such as miR-21 and miR-10b, have been demonstrated to be helpful in evaluating the efficiency of EGFR-TKI therapeutics. A commercialized serum-based proteomic test, named VeriStrat test, has shown an outstanding ability to predict the clinical outcome of NSCLC patients receiving EGFR-TKIs. Analysis of EGFR mutations in circulating tumor cells (CTCs) is feasible, and CTCs represent a promising material to predict EGFR-TKI-treatment efficacy and resistance. These evidences suggested that non-invasive techniques based on serum or plasma samples had a great potential for monitoring EGFR-TKI treatment in NSCLC. In this review, we summarized these non-invasive approaches and considered their possible applications in EGFR-TKI-treatment monitoring. PMID- 26227961 TI - Structural basis of the Norrin-Frizzled 4 interaction. PMID- 26227962 TI - Dendritic cells are stressed out in tumor. AB - A recently paper published in Cell reports that dendritic cells (DCs) are dysfunctional in the tumor environment. Tumor impairs DC function through induction of endoplasmic reticulum stress response and subsequent disruption of lipid metabolic homeostasis. PMID- 26227963 TI - Hyperpolarized [1-(13) C]pyruvate MRI for noninvasive examination of placental metabolism and nutrient transport: A feasibility study in pregnant guinea pigs. AB - PURPOSE: To test the feasibility of hyperpolarized [1-(13) C]pyruvate magnetic resonance imaging (MRI) for noninvasive examination of guinea pig fetoplacental metabolism and nutrient transport. MATERIALS AND METHODS: Seven pregnant guinea pigs with a total of 30 placentae and fetuses were anesthetized and scanned at 3T. T1 -weighted (1) H images were obtained from the maternal abdomen. An 80 mM solution of hyperpolarized [1-(13) C]pyruvate (hereafter referred to as pyruvate) was injected into a vein in the maternal foot. Time-resolved 3D (13) C images were acquired starting 10 seconds after the beginning of bolus injection and every 10 seconds after to 50 seconds. The pregnant guinea pigs were recovered after imaging. Regions of interest (ROIs) were drawn around the maternal heart and each placenta and fetal liver in all slices in the (1) H images. These ROIs were copied to the (13) C images and were used to calculate the sum of the pyruvate and lactate signal intensities for each organ. The signal intensities were normalized by the volume of the organ and the maximum signal in the maternal heart. RESULTS: No adverse events were observed in the pregnant guinea pigs and natural pupping occurred at term (~68 days). Pyruvate signal was observed in all 30 placentae, and lactate, a by-product of pyruvate metabolism, was also observed in all placentae. The maximum pyruvate and lactate signals in placentae occurred at 20 seconds. In addition to the observation of pyruvate and lactate signals in the placentae, both pyruvate and lactate signals were observed in all fetal livers. The maximum pyruvate and lactate signals in the fetal livers occurred at 10 seconds and 20 seconds, respectively. CONCLUSION: This work demonstrates the feasibility of using hyperpolarized [1-(13) C]pyruvate MRI to noninvasively examine fetoplacental metabolism and transport of pyruvate in guinea pigs. Hyperpolarized (13) C MRI may provide a novel method for longitudinal studies of fetoplacental abnormalities. PMID- 26227966 TI - The Slow Molecular Mobility in Amorphous Ketoprofen and Ibuprofen. AB - The slow molecular dynamics in two active pharmaceutical drugs, ketoprofen and ibuprofen, have been studied by differential scanning calorimetry (DSC) and thermally stimulated depolarization currents (TSDC). This study allowed finding the main kinetic features of the fast secondary (gamma) relaxation, of the Johari Goldstein relaxation, and of the main (glass transition) relaxation, in particular their distribution of relaxation times. The fragility index of the two glass formers was determined based on data from DSC and from TSDC. The obtained results were compared with those obtained by other experimental techniques, namely, dielectric relaxation spectroscopy. PMID- 26227965 TI - Protocadherin-1 is a glucocorticoid-responsive critical regulator of airway epithelial barrier function. AB - BACKGROUND: Impaired epithelial barrier function renders the airway vulnerable to environmental triggers associated with the pathogenesis of bronchial asthma. We investigated the influence of protocadherin-1 (PCDH1), a susceptibility gene for bronchial hyperresponsiveness, on airway epithelial barrier function. METHODS: We applied transepithelial electric resistance and dextran permeability testing to evaluate the barrier function of cultured airway epithelial cells. We studied PCDH1 function by siRNA-mediated knockdown and analyzed nasal or bronchial tissues from 16 patients with chronic rhinosinusitis (CRS) and nine patients with bronchial asthma for PCDH1 expression. RESULTS: PCDH1 was upregulated with the development of epithelial barrier function in cultured airway epithelial cells. Immunocytochemical analysis revealed that PCDH localized to cell-cell contact sites and colocalized with E-cadherin at the apical site of airway epithelial cells. PCDH1 gene knockdown disrupted both tight and adhesion junctions. Immunohistochemical analysis revealed strong PCDH1 expression in nasal and bronchial epithelial cells; however, expression decreased in inflamed tissues sampled from patients with CRS or bronchial asthma. Dexamethasone (Dex) increased the barrier function of airway epithelial cells and increased PCDH1 expression. PCDH1 gene knockdown eradicated the effect of Dex on barrier function. CONCLUSION: These results suggest that PCDH1 is important for airway function as a physical barrier, and its dysfunction is involved in the pathogenesis of allergic airway inflammation. We also suggest that glucocorticoids promotes epithelial barrier integrity by inducing PCDH1. PMID- 26227964 TI - Inhibition of the autocrine IL-6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers. AB - HER2-positive (HER2(+)) breast adenocarcinomas are a heterogeneous group in which hormone receptor (HR) status influences therapeutic decisions and patient outcome. By combining genome-wide RNAi screens with regulatory network analysis, we identified STAT3 as a critically activated master regulator of HR(-)/HER2(+) tumors, eliciting tumor dependency in these cells. Mechanistically, HR(-)/HER2(+) cells secrete high levels of the interleukin-6 (IL-6) cytokine, inducing the activation of STAT3, which in turn promotes a second autocrine stimulus to increase S100A8/9 complex (calprotectin) production and secretion. Increased calprotectin levels activate signaling pathways involved in proliferation and resistance. Importantly, we demonstrated that inhibition of the IL-6-Janus kinase 2 (JAK2)-STAT3-calprotectin axis with FDA-approved drugs, alone and in combination with HER2 inhibitors, reduced the tumorigenicity of HR(-)/HER2(+) breast cancers, opening novel targeted therapeutic opportunities. PMID- 26227967 TI - The RNA-binding protein HOS5 and serine/arginine-rich proteins RS40 and RS41 participate in miRNA biogenesis in Arabidopsis. AB - MicroRNAs are a class of small regulatory RNAs that are generated from primary miRNA (pri-miRNA) transcripts with a stem-loop structure. Accuracy of the processing of pri-miRNA into mature miRNA in plants can be enhanced by SERRATE (SE) and HYPONASTIC LEAVES 1 (HYL1). HYL1 activity is regulated by the FIERY2 (FRY2)/RNA polymerase II C-terminal domain phosphatase-like 1 (CPL1). Here, we discover that HIGH OSMOTIC STRESS GENE EXPRESSION 5 (HOS5) and two serine/arginine-rich splicing factors RS40 and RS41, previously shown to be involved in pre-mRNA splicing, affect the biogenesis of a subset of miRNA. These proteins are required for correct miRNA strand selection and the maintenance of miRNA levels. FRY2 dephosphorylates HOS5 whose phosphorylation status affects its subnuclear localization. HOS5 and the RS proteins bind both intronless and intron containing pri-miRNAs. Importantly, all of these splicing-related factors directly interact with both HYL1 and SE in nuclear splicing speckles. Our results indicate that these splicing factors are directly involved in the biogenesis of a group of miRNA. PMID- 26227969 TI - The N-terminus of RPA large subunit and its spatial position are important for the 5'->3' resection of DNA double-strand breaks. AB - The first step of homology-dependent repair of DNA double-strand breaks (DSBs) is the resection of the 5' strand to generate 3' ss-DNA. Of the two major nucleases responsible for resection, EXO1 has intrinsic 5'->3' directionality, but DNA2 does not. DNA2 acts with RecQ helicases such as the Werner syndrome protein (WRN) and the heterotrimeric eukaryotic ss-DNA binding protein RPA. We have found that the N-terminus of the RPA large subunit (RPA1N) interacts with both WRN and DNA2 and is essential for stimulating WRN's 3'->5' helicase activity and DNA2's 5'->3' ss-DNA exonuclease activity. A mutant RPA complex that lacks RPA1N is unable to support resection in Xenopus egg extracts and human cells. Furthermore, relocating RPA1N to the middle subunit but not to the small subunit causes severe defects in stimulating DNA2 and WRN and in supporting resection. Together, these findings suggest that RPA1N and its spatial position are critical for restricting the directionality of the WRN-DNA2 resection pathway. PMID- 26227968 TI - DNA sequence templates adjacent nucleosome and ORC sites at gene amplification origins in Drosophila. AB - Eukaryotic origins of DNA replication are bound by the origin recognition complex (ORC), which scaffolds assembly of a pre-replicative complex (pre-RC) that is then activated to initiate replication. Both pre-RC assembly and activation are strongly influenced by developmental changes to the epigenome, but molecular mechanisms remain incompletely defined. We have been examining the activation of origins responsible for developmental gene amplification in Drosophila. At a specific time in oogenesis, somatic follicle cells transition from genomic replication to a locus-specific replication from six amplicon origins. Previous evidence indicated that these amplicon origins are activated by nucleosome acetylation, but how this affects origin chromatin is unknown. Here, we examine nucleosome position in follicle cells using micrococcal nuclease digestion with Ilumina sequencing. The results indicate that ORC binding sites and other essential origin sequences are nucleosome-depleted regions (NDRs). Nucleosome position at the amplicons was highly similar among developmental stages during which ORC is or is not bound, indicating that being an NDR is not sufficient to specify ORC binding. Importantly, the data suggest that nucleosomes and ORC have opposite preferences for DNA sequence and structure. We propose that nucleosome hyperacetylation promotes pre-RC assembly onto adjacent DNA sequences that are disfavored by nucleosomes but favored by ORC. PMID- 26227970 TI - On the availability of microRNA-induced silencing complexes, saturation of microRNA-binding sites and stoichiometry. AB - Several authors have suggested or inferred that modest changes in microRNA expression can potentiate or impinge on their capacity to mediate gene repression, and that doing so could play a significant role in diseases. Such interpretations are based on several assumptions, namely: (i) changes in microRNA expression correlate with changes in the availability of mature, functional miRISC, (ii) changes in microRNA expression can significantly alter the stoichiometry of miRISC populations with their cognate targets, (iii) and this, in turn, can result in changes in miRISC silencing output. Here, we experimentally challenge those assumptions by quantifying and altering the availability of miRISC across several families of microRNAs. Doing so revealed a surprising fragmentation in the miRISC functional pool, striking differences in the availability of miRNA families and saturability of miRNA-mediated silencing. Furthermore, we provide direct experimental evidence that only a limited subset of miRNAs, defined by a conjuncture of expression threshold, miRISC availability and low target site abundance, is susceptible to competitive effects through microRNA-binding sites. PMID- 26227971 TI - Structure-function relationships governing activity and stability of a DNA alkylation damage repair thermostable protein. AB - Alkylated DNA-protein alkyltransferases repair alkylated DNA bases, which are among the most common DNA lesions, and are evolutionary conserved, from prokaryotes to higher eukaryotes. The human ortholog, hAGT, is involved in resistance to alkylating chemotherapy drugs. We report here on the alkylated DNA protein alkyltransferase, SsOGT, from an archaeal species living at high temperature, a condition that enhances the harmful effect of DNA alkylation. The exceptionally high stability of SsOGT gave us the unique opportunity to perform structural and biochemical analysis of a protein of this class in its post reaction form. This analysis, along with those performed on SsOGT in its ligand free and DNA-bound forms, provides insights in the structure-function relationships of the protein before, during and after DNA repair, suggesting a molecular basis for DNA recognition, catalytic activity and protein post-reaction fate, and giving hints on the mechanism of alkylation-induced inactivation of this class of proteins. PMID- 26227972 TI - Towards a comprehensive picture of alloacceptor tRNA remolding in metazoan mitochondrial genomes. AB - Remolding of tRNAs is a well-documented process in mitochondrial genomes that changes the identity of a tRNA. It involves a duplication of a tRNA gene, a mutation that changes the anticodon and the loss of the ancestral tRNA gene. The net effect is a functional tRNA that is more closely related to tRNAs of a different alloacceptor family than to tRNAs with the same anticodon in related species. Beyond being of interest for understanding mitochondrial tRNA function and evolution, tRNA remolding events can lead to artifacts in the annotation of mitogenomes and thus in studies of mitogenomic evolution. Therefore, it is important to identify and catalog these events. Here we describe novel methods to detect tRNA remolding in large-scale data sets and apply them to survey tRNA remolding throughout animal evolution. We identify several novel remolding events in addition to the ones previously mentioned in the literature. A detailed analysis of these remoldings showed that many of them are derived from ancestral events. PMID- 26227974 TI - Validation of the Conventional Resection Criteria in Patients with Hepatocellular Carcinoma in Terms of the Incidence of Posthepatectomy Liver Failure and Long Term Prognosis. AB - BACKGROUND/AIMS: Resection criteria in hepatocellular carcinoma (HCC) should be established based on the risk of posthepatectomy liver failure (PHLF) and the survival benefit from hepatectomy. This study aimed at verifying the validity of the conventional criteria regarding the incidence of PHLF and the long-term prognosis of HCC patients. METHODS: A retrospective study was performed on 265 patients who underwent major hepatectomy. Makuuchi's criteria and the future liver remnant plasma clearance rate of indocyanine green (ICGK-rem) >=0.05 criterion were evaluated. RESULTS: A total of 107 and 158 patients were within and beyond Makuuchi's criteria, respectively. Makuuchi's criteria were associated with the incidence of PHLF (p = 0.03) but not with its severity (p = 0.12). No differences in disease-free survival (DFS) or overall survival (OS) were observed between the groups (p = 0.75 and p = 0.94, respectively). Using the ICGK-rem >=0.05 criterion, 223 and 42 patients were within and beyond the criterion, respectively. ICGK-rem was correlated with both the incidence of PHLF (p = 0.002) and its severity (p = 0.03). No differences in DFS or OS were observed between the groups (p = 0.75 and p = 0.29, respectively). CONCLUSIONS: Strict criteria are likely to preclude some patients from obtaining the greater survival benefits of hepatectomy. New criteria that consider patient prognosis are needed. PMID- 26227975 TI - [Editorial. Prostheses and organ replacement]. PMID- 26227973 TI - Global identification of the genetic networks and cis-regulatory elements of the cold response in zebrafish. AB - The transcriptional programs of ectothermic teleosts are directly influenced by water temperature. However, the cis- and trans-factors governing cold responses are not well characterized. We profiled transcriptional changes in eight zebrafish tissues exposed to mildly and severely cold temperatures using RNA-Seq. A total of 1943 differentially expressed genes (DEGs) were identified, from which 34 clusters representing distinct tissue and temperature response expression patterns were derived using the k-means fuzzy clustering algorithm. The promoter regions of the clustered DEGs that demonstrated strong co-regulation were analysed for enriched cis-regulatory elements with a motif discovery program, DREME. Seventeen motifs, ten known and seven novel, were identified, which covered 23% of the DEGs. Two motifs predicted to be the binding sites for the transcription factors Bcl6 and Jun, respectively, were chosen for experimental verification, and they demonstrated the expected cold-induced and cold-repressed patterns of gene regulation. Protein interaction modeling of the network components followed by experimental validation suggested that Jun physically interacts with Bcl6 and might be a hub factor that orchestrates the cold response in zebrafish. Thus, the methodology used and the regulatory networks uncovered in this study provide a foundation for exploring the mechanisms of cold adaptation in teleosts. PMID- 26227976 TI - [The bionic hand]. AB - The loss of the upper extremity implicates a grave insult in the life of the involved person. To compensate for the loss of function different powered prosthetic devices are available. Ever since their first development 70 years ago numerous improvements in terms of size, weight and wearing comfort have been developed, but issues regarding the control of upper extremity prostheses remain. Slow grasping speed, limited grip positions and especially failure to provide a sensory feedback limit the acceptance in patients. Recent developments are aimed to allow a more intuitive control of the prosthetic device and to provide a sensory feedback to the amputee. Targeted reinnervation reassignes existing muscles to different peripheral nerves thereby enabling them to fulfill alternate functions. Implanting electrodes into muscle bellies of the forearm allows a more accurate control of the prosthesis. Promising results are being achieved by implanting nerve electrodes by establishing bilateral communication between patient and prosthesis. The following review summarizes the current developments of bionic prostheses in the upper extremity. PMID- 26227977 TI - [Knee and ankle arthroplasty - What results can be expected?]. AB - Osteoarthrits is listed number one reason for adult disability. Therefore treatment of arthritis has maximum impact for the general practitioner. Disability of knee and ankle osteoarthritis causes inability to work and loss of independence. Patients will ask their physicians about expectations after total knee or ankle arthroplasty when other treatment has failed. The satisfaction rate after knee prosthesis is 75 - 89 % and for total ankle arthroplasty even slightly higher at 79 - 97 %. This is surprising because the survival in joint registry data after knee arthroplasty is 94 % compared to ankle arthroplasty significantly less at 69 % after 10 years, when a component revision is used as endpoint. In addition, knee component revision usually means exchanging to knee revision prosthesis while at the ankle it is usually prosthetic removal and conversion to ankle fusion. This difference of satisfaction is probably caused by the fact that knee arthroplasty is a standard operation and patients have very high expectations. Key to this is realistic patient education before surgery by general practitioners and specialists about the typical postoperative course with significant pain reduction not within days but rather in the first 2 postoperative years with moderate activity allowed. Candidates for total ankle replacement must be carefully selected because the prosthesis relies on a good bone stock, stable ligaments and proper limb alignment. Unlike for the knee, none of these can currently be corrected by the ankle prosthesis itself. Patients can expect significant pain reduction, better function and a slight improved range of motion after knee and ankle prosthesis. Sports activities are possible, but should be in a low-impact area. Heavy physical work or running and jumping activities are usually not possible and surely not recommended due to increased wear. PMID- 26227978 TI - [Ventricular assist device - Possibilities of long-term mechanical circulatory support]. AB - In Switzerland 200'000 people suffer from congestive heart failure. Approximately 10'000 patients find themselves in an advanced state of the disease. When conservative treatment options are no longer available heart transplantation is the therapy of choice. Should this not be an option due to long waiting lists or medical issues assist device therapy becomes an option. Assist device therapy is separated in short-term and long-term support. Long-term support is nowadays performed with ventricular assist devices (VADs). The native heart is still in place and supported in parallel to the remaining function of the heart. The majority of patients are treated with a left ventricular assist device (LVAD). The right ventrical alone (RVAD) as well as bi-ventricular support (BiVAD) is rarely needed. The modern VADs are implantable and create a non-pulsative bloodflow. A percutaneous driveline enables energy supply and pump-control. Indication strategies for VAD implantations include bridge to transplant (short term support), bridge to candidacy and bridge to transplant. VADs become more and more a definite therapeutic option (destination therapy). VAD therapy might be a realistic alternative to organ transplantation in the near future. PMID- 26227979 TI - [Renal replacement therapies - Past, present and future]. AB - Extracorporeal renal replacement therapy is one of the most successful stories of artificial organ replacement. The current article describes the important steps in the evolution of renal replacement therapy towards modern state of the art peritoneal dialysis and hemodialysis. Open questions and possibilities for future developments are discussed. Today patients have a choice with respect to the method used to replace their failing kidney. However, in order to carefully plan and select the best possible method for a patient, he has to be seen and confronted with the various methods by a nephrologist at least six month before the necessity to start renal replacement therapy. Late referral increases mortality and the necessity for a temporary central venous access represents an additional thrombotic and infectious risk. A patient first seen by the nephrologist at the occasion of an emergeny dialysis will never have the possibility to profit from a preemptive living kidney donation. Furthermore, such patients usually stay in the center and are difficult to motivate for home or selfcare dialysis. PMID- 26227981 TI - [New strategies in living donor kidney transplantation - blood group incompatible and crossover transplantation]. AB - About 40 % of all kidney transplantations in Switzerland are from living donors. The probability of blood group incompatibility between donor and recipient is 30 %. About 10 % of recipients have preexisting HLA antibodies against their potential donors. Both risks impeded transplantation until recently. Nowadays successful protocols for blood group incompatible kidney transplantation and the possibility of crossover transplantation are available and help to overcome these risks. PMID- 26227980 TI - [A new bone anchored hemodialysis access]. AB - When classic arteriovenous fistulas or grafts fail, dialysis patients have a vital requirement for a catheter to ensure vascular access. Permanent central venous catheters penetrate the cervical and thoracic soft tissues and the skin without rigid fixation. The infection rate for such devices is high, often requiring explantation. Bone anchored hearing aids are an established treatment in patients with conductive hearing loss. The implant is firmly fixed on the temporal bone and the abutment permanently penetrates the skin. Severe infections requiring explantation are very rare. We suppose that one of the main reasons for the low complication rate is the firm fixation of the implant to the temporal bone, which minimizes the movement of the skin relative to the underlying bone. Based on the experience with implantable hearing devices we developed a percutaneous bone anchored port fixed to the skull in the region of the temporal bone. Such a bone anchored port could be a beneficial alternative to conventional central venous catheters for patients undergoing hemodialysis. In the course of the development process we investigated the individual anatomy to locate the correct implantation site with sufficient bone thickness; we studied screw stability in bone; we developed the titanium implant that houses the port system as well as the surgical tools and procedure for save implantation; we tested flow rate, leak tightness and purification on mockups; we defined the Seldinger insertion of the catheter into the internal jugular vein via a small neck incision. Our results show the technical feasibility of a temporal bone anchored port and form the basis of a now-approved clinical pilot study. PMID- 26227982 TI - [Future cardiac pacemakers - technical visions]. AB - Cardiac pacemakers are routinely used for the treatment of bradyarrhythmias. Contemporary pacemakers are reliable and allow for a patient specific programming. However, pacemaker replacements due to battery depletion are common (~25 % of all implantation procedures) and bear the risk of complications. Batteryless pacemakers may allow overcoming this limitation. To power a batteryless pacemaker, a mechanism for intracorporeal energy harvesting is required. Such a generator may consist out of subcutaneously implanted solar cells, transforming the small amount of transcutaneously available light into electrical energy. Alternatively, intravascular turbines may harvest energy from the blood flow. Energy may also be harvested from the ventricular wall motion by a dedicated mechanical clockwork converting motion into electrical energy. All these approaches have successfully been tested in vivo. Pacemaker leads constitute another Achilles heel of contemporary pacemakers. Thus, leadless devices are desired. Miniaturized pacemaker circuits and suitable energy harvesting mechanisms (incorporated in a single device) may allow catheter-based implantation of the pacemaker in the heart. Such miniaturized battery- and leadless pacemakers would combine the advantages of both approaches and overcome major limitations of today's systems. PMID- 26227983 TI - Discussion. PMID- 26227984 TI - Where do we go now? PMID- 26227985 TI - Open repair of ruptured descending thoracic and thoracoabdominal aortic aneurysms. AB - OBJECTIVE: To evaluate the results of the open repair of ruptured thoracic and thoracoabdominal aortic aneurysms. METHODS: From January 1997, a total of 100 consecutive open repairs of ruptured thoracic or thoracoabdominal aortic aneurysms were performed (43 thoracic and 57 thoracoabdominal). These patients were compared with contemporary cases that underwent repair of corresponding intact aneurysms. Propensity matching analysis was used to neutralize the differences in baseline characteristics. RESULTS: Patients with ruptured aneurysm had a significantly worse baseline clinical profile. The surgical strategy adopted was similar in intact and ruptured aneurysms, with the exception of lower use of spinal drainage, intercostal reimplantation, and associated procedures in those with rupture (P < .001 for all comparisons). In the unmatched population, in-hospital mortality was 14% in the rupture group, and 4.2% in the intact group (P = .01). The incidence of postoperative myocardial infarction, need for tracheostomy, and need for dialysis was 3%, 19%, and 11% in the rupture, and 0.8%, 5.7%, and 4.2% in the intact series (P <= .01 for all variables). Five-year survival was 47.5% for the rupture, and 59.5% for the intact series (P < .001). In the matched population, no differences in postoperative and long-term outcome were found between the rupture and intact cases. Logistic regression analysis showed that female gender, urgent/emergent operation, and preoperative hemodialysis, but not ruptured aneurysm, were predictive of in-hospital major adverse events. CONCLUSIONS: Open repair of ruptured thoracic and thoracoabdominal aortic aneurysms can be performed with a gratifying rate of success. For patients with similar preoperative comorbidities, postoperative survival is not affected by the presence of a ruptured aneurysm. PMID- 26227986 TI - Reality check in the minimally invasive world. PMID- 26227987 TI - Copper-modified covalent triazine frameworks as non-noble-metal electrocatalysts for oxygen reduction. AB - The electrochemical oxygen reduction reaction (ORR) is an important cathode reaction of various types of fuel cells. The development of electrocatalysts composed only of abundant elements is a key goal because currently only platinum is a suitable catalyst for ORR. Herein, we synthesized copper-modified covalent triazine frameworks (CTF) hybridized with carbon nanoparticles (Cu-CTF/CPs) as efficient electrocatalysts for the ORR in neutral solutions. The ORR onset potential of the synthesized Cu-CTF/CP was 810 mV versus the reversible hydrogen electrode (RHE; pH 7), the highest reported value at neutral pH for synthetic Cu based electrocatalysts. Cu-CTF/CP also displayed higher stability than a Cu-based molecular complex at neutral pH during the ORR, a property that was likely as a result of the covalently cross-linked structure of CTF. This work may provide a new platform for the synthesis of durable non-noble-metal electrocatalysts for various target reactions. PMID- 26227988 TI - Mesenchymal stem cell expression of SDF-1beta synergizes with BMP-2 to augment cell-mediated healing of critical-sized mouse calvarial defects. AB - Bone has the potential for spontaneous healing. This process, however, often fails in patients with comorbidities. Tissue engineering combining functional cells, biomaterials and osteoinductive cues may provide alternative treatment strategies. We have recently demonstrated that stromal cell-derived factor-1beta (SDF-1beta) works in concert with bone morphogenetic protein-2 (BMP-2) to potentiate osteogenic differentiation of bone marrow-derived mesenchymal stem/stromal cells (BMSCs). Here, we test the hypothesis that SDF-1beta overexpressed in Tet-Off-SDF-1beta BMSCs, delivered on acellular dermal matrix (ADM), synergistically augments BMP-2-induced healing of critical-sized mouse calvarial defects. BMSC therapies alone showed limited bone healing, which was increased with co-delivery of BMP-2. This was further enhanced in Tet-Off-SDF 1beta BMSCs + BMP-2. Only limited BMSC retention on ADM constructs was observed after 4 weeks in vivo, which was increased with BMP-2 co-delivery. In vitro cell proliferation studies showed that supplementing BMP-2 to Tet-Off BMSCs significantly increased the cell number during the first 24 h. Consequently, the increased cell numbers decreased the detectable BMP-2 levels in the medium, but increased cell-associated BMP-2. The data suggest that SDF-1beta provides synergistic effects supporting BMP-2-induced, BMSC-mediated bone formation and appears suitable for optimization of bone augmentation in combination therapy protocols. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26227990 TI - Hyposmia in SWEDD. PMID- 26227989 TI - Local Joint inflammation and histone citrullination in a murine model of the transition from preclinical autoimmunity to inflammatory arthritis. AB - OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are characteristic of rheumatoid arthritis (RA). However, their presence years before the onset of clinical RA is perplexing. Although multiple putative citrullinated antigens have been identified, no studies have demonstrated the specific capacity of these antigens to initiate inflammatory arthritis. This study was undertaken to recapitulate the transition from preclinical to clinical RA and to demonstrate the capacity of local citrullination to facilitate this transition. METHODS: We performed proteomic analysis of activated human neutrophils to identify citrullinated proteins, including those targeted as part of the RA immune response. Using enzyme-linked immunosorbent assay, we compared RA and osteoarthritis synovial fluid for levels of citrullinated histone H2B and its immune complex. Using macrophage activation assays, we assessed the effect of histone citrullination on immunostimulatory capacity and evaluated the stimulatory capacity of native and citrullinated H2B immune complexes. Finally, we assessed the potential for anti-citrullinated H2B antibodies to mediate arthritis in vivo. RESULTS: We identified robust targeting of neutrophil-derived citrullinated histones by the ACPA immune response. More than 90% of the RA patients had anti-citrullinated H2B antibodies. Histone citrullination increased innate immunostimulatory capacity, and immune complexes containing citrullinated histones activated macrophage cytokine production and propagated neutrophil activation. Finally, we demonstrated that immunization with H2B was arthritogenic, but only in the setting of underlying articular inflammation. CONCLUSION: Our findings indicate that citrullinated histones, specifically citrullinated H2B, are an antigenic target of the ACPA immune response. Furthermore, local generation of citrullinated antigen during low-grade articular inflammation provides a mechanistic model for the conversion from preclinical autoimmunity to inflammatory arthritis. PMID- 26227991 TI - Effects of Distress and Eustress on Changes in Fatigue from Waking to Working. AB - BACKGROUND: As a potential indicator of strain, fatigue is an important outcome in occupational health research. The current study examined the influence of positive (eustress) and negative (distress) work experiences on changes in fatigue from morning to at-work. It was expected that within-person changes in fatigue from waking to working would be moderated by employees' experiences of stress, pain, happiness, and meaningfulness at work. METHODS: Data on 1,195 full time working adults were collected through the Bureau of Labor Statistics' 2010 American Time Use Study (ATUS) using a day reconstruction method to assess fatigue at two time points (morning and during work) and employees' eustress and distress experiences during work. RESULTS: Multilevel modeling showed that the indicators of distress, stress and pain, predicted higher morning fatigue and stronger increases in fatigue during the workday. The indicators of eustress, happiness and meaningfulness, predicted lower fatigue at both time points but not temporal changes. CONCLUSIONS: These results contribute to understanding changes in employees' fatigue and suggest that the differential effects of distress and eustress experiences at work may be important to consider in fatigue management interventions. PMID- 26227992 TI - The Big Bluff of Amyotrophic Lateral Sclerosis Diagnosis: The Role of Neurodegenerative Disease Mimics. AB - Neurodegenerative diseases include a significant number of pathologies affecting the nervous system. Generally, the primary cause of each disease is specific; however, recently, it was shown that they may be correlated at molecular level. This aspect, together with the exhibition of similar symptoms, renders the diagnosis of these disorders difficult. Amyotrophic lateral sclerosis is one of these pathologies. Herein, we report several cases of amyotrophic lateral sclerosis misdiagnosed as a consequence of features that are common to several neurodegenerative diseases, such as Parkinson's, Huntington's and Alzheimer's disease, spinal muscular atrophy, progressive bulbar palsy, spastic paraplegia and frontotemporal dementia, and mostly with the lysosomal storage disorder GM2 gangliosidosis. Overall reports highlight that the differential diagnosis for amyotrophic lateral sclerosis should include correlated mechanisms. PMID- 26227993 TI - Baia soyae gen. nov., sp. nov., a mesophilic representative of the family Thermoactinomycetaceae, isolated from soybean root [Glycine max (L.) Merr]. AB - A mesophilic, endophytic, filamentous bacterium, designated strain NEAU-gxj18T, was isolated from soybean root [Glycine max (L.) Merr.] collected from Harbin, Heilongjiang Province, China and characterized using a polyphasic approach. Growth was observed at 20-40 degrees C (optimum 37 degrees C). Aerial mycelium was absent on all the media tested. Substrate mycelia were well-developed and formed abundant single endospores with smooth surfaces. The only menaquinone was MK-7.The diagnostic diamino acid was meso-diaminopimelic acid. The whole-cell sugars were ribose, glucose and galactose. The major fatty acids were iso-C15 : 0, C13 : 0 and iso-C17 : 0. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, one unidentified aminophospholipid and one undientified phospholipid. The DNA G+C content was 49.9 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain NEAU-gxj18T was phylogenetically related to members of the family Thermoactinomycetaceae, with the highest sequence similarity to Geothermomicrobium terrae YIM 77562T (93.35 %). On the basis of morphological and chemotaxonomic characteristics, phylogenetic analysis and characteristic patterns of 16S rRNA gene signature nucleotides, strain NEAU gxj18T represents a novel species of a new genus within the family Thermoactinomycetaceae, for which the name Baia soyae gen. nov., sp. nov. is proposed. The type strain of the type species is NEAU-gxj18T ( = CGMCC 4.7223T = DSM 46831T). PMID- 26227994 TI - RNA-sequencing elucidates the regulation of behavioural transitions associated with the mating process in honey bee queens. AB - BACKGROUND: Mating is a complex process, which is frequently associated with behavioural and physiological changes. However, understanding of the genetic underpinnings of these changes is limited. Honey bees are both a model system in behavioural genomics, and the dominant managed pollinator of human crops; consequently understanding the mating process has both pure and applied value. We used next-generation transcriptomics to probe changes in gene expression in the brains of honey bee queens, as they transition from virgin to mated reproductive status. In addition, we used CO2-narcosis, which induces oviposition without mating, to isolate the process of reproductive maturation. RESULTS: The mating process produced significant changes in the expression of vision, chemo reception, metabolic, and immune-related genes. Differential expression of these genes maps clearly onto known behavioural and physiological changes that occur during the transition from being a virgin queen to a newly-mated queen. A subset of these changes in gene expression were also detected in CO2-treated queens, as predicted from previous physiological studies. In addition, we compared our results to previous studies that used microarray techniques across a range of experimental time-points. Changes in expression of immune- and vision-related genes were common to all studies, supporting an involvement of these groups of genes in the mating process. CONCLUSIONS: Our study is an important step in understanding the molecular mechanisms regulating post-mating behavioural transitions in a natural system. The weak overlap in patterns of gene expression with previous studies demonstrates the high sensitivity of genome-wide approaches. Thus, while we build on previous microarray studies that explored post-mating changes in honey bees, the broader experimental design, use of RNA sequencing, and focus on Australian honey bees, which remain free from the devastating parasite Varroa destructor, in the current study, provide unique insights into the biology of the mating process in honey bees. PMID- 26227995 TI - Obesity Prevention in Scotland: A Policy Analysis Using the ANGELO Framework. AB - BACKGROUND: The Scottish Government's 'Route-Map Action Plan' for obesity prevention sets out 62 potential intervention policies across all stages of the life course. We used the ANGELO Framework (Analysis Grid for Environments Linked to Obesity) to assess the appropriateness and likely impact of the balance of measures being proposed. METHODS: Two assessors (JM & RJ) independently allocated a category for each intervention according to its domain (physical, economic, legislative or socio-cultural), scale (macro or micro) and predominant 'focus' (physical activity versus diet). A third assessor (RG) examined discordant allocations. RESULTS: Across the four ANGELO domains, the distribution of interventions was skewed towards socio-cultural measures (37.1%) and the physical environment (33.1%) with less emphasis on legislative or economic interventions (21.8% and 6.4% respectively). Distribution by both intervention scale and focus was more even with just over half of all policies (51.8%) at the macro-level scale and just under half (46.7%) having a dietary focus. CONCLUSION: The predominance of socio-culturally orientated interventions over their legislative and economic counterparts is at odds with the balance of international evidence on what would be most effective for obesity prevention. The ANGELO framework provides a useful tool for policy makers to monitor progress towards an appropriately balanced policy mix. PMID- 26227996 TI - Reliability and concurrent and construct validity of the Strategies for Weight Management measure for adults. AB - INTRODUCTION: This study evaluates the reliability and validity of the strategies for weight management (SWM) measure, a questionnaire that assesses weight management strategies for adults. The SWM includes 20 items that are categorized within the following subscales: (1) energy intake, (2) energy expenditure, (3) self-monitoring, and (4) self-regulation. METHODS: Baseline and 6-month data were collected from 404 overweight/obese adults (mean age=22+/-3.8 years, 68% ethnic minority) enrolled in a randomized controlled trial aiming to reduce weight by improving diet and physical activity behaviours. Reliability and validity were assessed for each subscale separately. Cronbach alpha was conducted to assess reliability. Concurrent, construct I (sensitivity to the study treatment condition), and construct II (relationship to the outcomes) validity were assessed using linear regressions with the following outcome measures: weight, self-reported diet, and weekly energy expenditure. RESULTS: All subscales showed strong internal consistency. The strength of the validity evidence depended on subscale and validity type. The strongest validity evidence was concurrent validity of the energy intake and energy expenditure subscales; construct I validity of the energy intake and self-monitoring subscales; and construct II validity of the energy intake, energy expenditure, and self-regulation subscales. CONCLUSIONS: Results indicate that the SWM can be used to assess weight management strategies among an ethnically diverse sample of adults as each subscale showed evidence of reliability and select types of validity. As validity is an accumulation of evidence over multiple studies, this study provides initial reliability and validity evidence in one population segment. PMID- 26227997 TI - r-bPiDI, an alpha6beta2* Nicotinic Receptor Antagonist, Decreases Nicotine-Evoked Dopamine Release and Nicotine Reinforcement. AB - alpha6beta2* nicotinic acetylcholine receptors (nAChRs) expressed by dopaminergic neurons mediate nicotine-evoked dopamine (DA) release and nicotine reinforcement. alpha6beta2* antagonists inhibit these effects of nicotine, such that alpha6beta2* receptors serve as therapeutic targets for nicotine addiction. The present research assessed the neuropharmacology of 1,10-bis(3-methyl-5,6 dihydropyridin-1(2H)-yl)decane (r-bPiDI), a novel small-molecule, tertiary amino analog of its parent compound, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI). bPiDI was previously shown to inhibit both nicotine-evoked DA release and the reinforcing effects of nicotine. In the current study, r-bPiDI inhibition of [(3)H]nicotine and [(3)H]methyllycaconitine binding sites was evaluated to assess interaction with the recognition binding sites on alpha4beta2* and alpha7* nAChRs, respectively. Further, r-bPiDI inhibition of nicotine-evoked DA release in vitro in the absence and presence of alpha-conotoxin MII and following chronic in vivo nicotine administration were determined. The ability of r-bPiDI to decrease nicotine self-administration and food-maintained responding was also assessed. Results show that r-bPiDI did not inhibit [(3)H]nicotine or [(3)H]methyllycaconitine binding, but potently (IC50 = 37.5 nM) inhibited nicotine-evoked DA release from superfused striatal slices obtained from either drug naive rats or from those repeatedly treated with nicotine. r-bPiDI inhibition of nicotine-evoked DA release was not different in the absence or presence of alpha-conotoxin MII, indicating that r-bPiDI acts as a potent, selective alpha6beta2* nAChR antagonist. Acute systemic administration of r-bPiDI specifically decreased nicotine self-administration by 75 %, and did not alter food-maintained responding, demonstrating greater specificity relative to bPiDI and bPiDDB, as well as the tertiary amino analog r-bPiDDB. The current work describes the discovery of r-bPiDI, a tertiary amino, alpha-conotoxin MII-like small molecule that acts as a potent and selective antagonist at alpha6beta2* nAChRs to specifically decrease nicotine self-administration in rats, thus, establishing r-bPiDI as a lead compound for development as a treatment for nicotine addiction. PMID- 26227999 TI - Litigation related to intrapartum fetal surveillance. AB - The role of intrapartum care including cardiotocography (CTG) monitoring in cases of perinatal neurological injury receives considerable debate in both clinical and medicolegal settings. The debate, however, has distracted attention from fundamental questions about the timing, mechanism, and preventability of perinatal injury. CTG tracings are used as a surrogate for asphyxia with the timing of intervention ("rescue") predicated on the presumed severity of asphyxia. Using CTG in this way has prevented intrapartum stillbirth, but it has not reduced the long-term injury in part, because, contrary to popular belief, the majority of intrapartum fetal injuries are unassociated with severe hypoxia or severe neonatal depression. This article describes the timing and mechanisms, including mechanical factors, of intrapartum perinatal injury and the benefit of using the CTG, not for the purpose of "rescue", but for identifying risk factors for fetal injury and keeping the fetus out of harm's way. PMID- 26227998 TI - Battling Alzheimer's Disease: Targeting SUMOylation-Mediated Pathways. AB - SUMO (small ubiquitin-like modifier) conjugation is a critically important control process in all eukaryotic cells, because it acts as a biochemical switch and regulates the function of hundreds of proteins in many different pathways. Although the diverse functional consequences and molecular targets of SUMOylation remain largely unknown, SUMOylation is becoming increasingly implicated in the pathophysiology of Alzheimer's disease (AD). Apart from the central SUMO-modified disease-associated proteins, such as amyloid precursor protein, amyloid beta, and tau, SUMOylation also regulates several other processes underlying AD. These are involved in inflammation, mitochondrial dynamics, synaptic transmission and plasticity, as well as in protective responses to cell stress. Herein, we review current reports on the involvement of SUMOylation in AD, and present an overview of potential SUMO targets and pathways underlying AD pathogenesis. PMID- 26228000 TI - Gender differences in the association between serum uric acid and prognosis in patients with acute coronary syndrome. AB - BACKGROUND: Increased levels of uric acid (UA) have been associated with cardiovascular disease. This association is generally stronger in women than men. However, gender differences in the prognostic value of UA in patients with acute coronary syndrome (ACS) are unknown. We investigated gender differences in the relationship between UA level and the prognosis in patients with ACS. METHOD: This was an observational analysis of patients with ACS undergoing percutaneous coronary intervention enrolled in the Ibaraki Cardiac Assessment Study (ICAS) registry. We analyzed 1380 patients (330 women, 1050 men) with ACS who had information on UA. We assessed the association between UA and the incidence of major cardiovascular adverse events (MACE), defined as all-cause death, congestive heart failure, reinfarction, and stroke. Patients were divided according to gender-specific UA quartile. RESULTS: The mean UA level in women was significantly lower than that in men (4.9mg/dl vs 5.9mg/dl, p<0.001). After a median duration of follow-up period of 437 days (interquartile range 222-801 days), MACE had occurred in 186 (13%) patients [56 (17%) events in women; 130 (12%) events in men]. Kaplan-Meier analysis for MACE-free survival demonstrated that a higher quartile of UA was associated with MACE in both women and men (p<0.001, p=0.002, respectively). Multivariate Cox regression analysis revealed that the highest quartile of UA, as compared with the lowest quartile of UA, was an independent predictor of MACE in women [hazard ratio (HR), 2.84; 95% CI, 1.19 6.77; p=0.018] but not in men (HR, 1.32; 95% CI, 0.66-2.64; p=0.422). CONCLUSIONS: An increased level of UA was associated with MACE more strongly in women than in men with ACS. These results suggest that there are gender differences in the association of UA level with the prognosis in patients with ACS. PMID- 26228001 TI - Plasma neutrophil gelatinase-associated lipocalin predicts major adverse cardiovascular events after cardiac care unit discharge. AB - BACKGROUND: Emerging acute kidney injury biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL), have a high potential for predicting worsening renal function. Acute exacerbation of renal dysfunction has a great impact on the outcomes of cardiovascular patients in critical conditions. This study aimed to evaluate whether plasma NGAL can predict the mortality and major adverse cardiovascular events (MACEs) after discharge from the cardiac care unit (CCU). METHODS: Patients who were admitted to the CCU of the Tokyo University Hospital were prospectively enrolled (101 patients). Blood and urinary markers, including the blood NGAL, brain natriuretic peptide, creatinine, cystatin C, urinary albumin, N-acetyl-beta-d-glucosaminidase, and L-type fatty acid-binding protein, were measured at CCU discharge. The primary outcome was MACEs until at least 6 months after CCU discharge. RESULTS: Thirty-five patients experienced MACEs (35%). Multivariate logistic analysis revealed that the plasma NGAL, length of CCU stay, and existence of diabetes and heart failure were independent predicting factors for MACEs. Patients with the highest NGAL at discharge (>75th percentile) showed a significantly higher risk of MACEs than those with the lowest NGAL (<25th percentile) (log-rank test; hazard ratio, 5.15; 95% confidence interval 1.84-18.20; p<0.01). CONCLUSION: Plasma NGAL at CCU discharge is a significant prognostic indicator of outcomes at 6 months in critically ill cardiac patients treated in a CCU. PMID- 26228002 TI - Importance of Ventricular Tachycardia Induction and Mapping for Patients Referred for Epicardial Ablation. AB - BACKGROUND: Many nonischemic cardiomyopathy (NICMP) patients referred for catheter ablation of ventricular tachycardia (VT) undergo an initial epicardial approach under general anesthesia (GA). However, GA may suppress inducibility and decrease tolerance of induced VT, leaving substrate modification as the sole ablation method. OBJECTIVES: Determine the utility of a strategy of initial programmed electrical stimulation (PES) under light sedation in patients referred for epicardial ablation of VT. METHODS: Of 68 NICMP patients referred for VT ablation, 25 were referred specifically for epicardial ablation. All patients underwent PES under conscious sedation, with conversion to GA and epicardial access only if VT morphology and/or endocardial mapping suggested an epicardial substrate. RESULTS: VT was induced with PES in 24 of 25 patients (mean age 52 years; 76% male; ejection fraction 38 +/- 18%). VT was hemodynamically tolerated in 63% and unstable in 38% of patients. The noninducible/unstable VT patients underwent substrate modification based on voltage and pace mapping. Of the patients with stable VT, 73% were mapped and ablated endocardially (six right ventricle, three left ventricle, one left coronary cusp, one middle cardiac vein), and 33% were successfully ablated in areas of normal endocardial voltage. After ablation, the clinical VT was noninducible in all patients. After mean follow-up of 10 months, 80% were free of implantable cardioverter defibrillator shocks or sustained VT. CONCLUSIONS: An initial approach of PES and entrainment mapping under conscious sedation is critically important for patients with NICMP referred for epicardial ablation. Empiric ablation of endocardial/epicardial scar would have missed the clinical VT in 20% of patients. PMID- 26228003 TI - [Prevalence and predictors of psychoactive substance use among men in prisons]. AB - OBJECTIVE: The use of psychoactive substances among the prison population is an important public health issue because of its magnitude and health consequences. The aim of this study was to estimate the prevalence of psychoactive substance use among the prison population and to analyse its association with sociodemographic and penitentiary factors, particularly the size of the prison. METHODS: Data were gathered using a self-administered questionnaire among 2,484 random male inmates in eight prisons of different sizes in Spain. The prevalence of psychoactive substance use with 95% confidence intervals (95% CI) during the last 6 months in prison were estimated. Prevalence ratios were used to estimate the association between psychoactive substance use and sociodemographic and penitentiary characteristics. RESULTS: The prevalence of psychoactive substance use in the past 6 months in prison was 59.9% (95% CI: 57.9-62.0). Notable among the sociodemographic variables associated with substance use were drug consumption prior to imprisonment (6.90; 95% CI: 5.51-8.65) and recidivism in prison (2.41; 95% CI: 2.04-2.85). The largest prisons showed a higher frequency of drug use than other prisons. CONCLUSIONS: A high prevalence of psychoactive substance use was found in prisons and significant differences were found according to delinquent profile and the size of the prison. PMID- 26228004 TI - Involucratustones A-C: Unprecedented Sesquiterpene Dimers Containing Multiple Contiguous Quaternary Carbons from Stahlianthus involucratus. AB - Involucratustones A-C (1-3), three cadinane dimers containing multiple contiguous quaternary carbons, were isolated from the rhizomes of Stahlianthus involucratus. Their structures were determined by a combination of NMR spectroscopy, chemical conversion, and X-ray diffraction analysis. Compounds 1 and 2 are rearranged homodimers of cadinane sesquiterpene fused with a unique fully substituted 1 oxaspiro[4.4]nonane core observed for the first time in natural products, and 3 is a novel 3',4'-seco-cadinane-dimer. Compounds 1 and 2 exhibited potent cytotoxic activities, and 3 showed notable anti-inflammatory effect. PMID- 26228005 TI - The Added Benefit of Bicycle Commuting on the Regular Amount of Physical Activity Performed. AB - INTRODUCTION: Physical inactivity is a leading cause of death and disability globally. Active transportation such as bicycling may increase physical activity levels. It is currently uncertain whether a shift from motorized transport modes to bicycle commuting leads to increased physical activity overall or substitutes other forms of physical activity. The study aims to disentangle whether bicycle commuting adds to or replaces other physical activities by comparing the physical activity performed by bicycle and motorized commuters. METHODS: Physical activity, travel behavior, health status, sociodemographic, and built environment characteristics were assessed for 752 adults, between June 2011 and May 2012, in Barcelona, Spain. Statistical analyses, performed in 2013-2014, included linear, non-linear, and mixture models to estimate disparities and the dose-response relationship between physical activity duration and commute mode. RESULTS: Regular bicycle commuters traveled by bicycle an average of 3.1 (SD=2.5) hours in the previous week. Bicycle commuting contributed positively to physical activity duration across participants (p<0.05). It amounted to 2.1 (95% CI=0.84, 3.55) hours/week extra of physical activity for bicycle commuters versus motorized commuters. Among bicycle travelers, there was a positive dose-response relationship between bicycle commuting and physical activity duration, with an average extra physical activity duration of 0.5 (95% CI=0.4, 0.6) hours/week for every additional 1 hour/week of bicycle commuting. CONCLUSIONS: Bicycle commuting likely adds to overall physical activity. The extra physical activity performed by bicycle commuters is undertaken as moderate physical activity and follows a sigmoidal dose-response relationship with bicycle duration. PMID- 26228006 TI - OMIP-029: Human NK-cell phenotypization. PMID- 26228007 TI - Contact effects and quantum interference in engineered dangling bond loops on silicon surfaces. AB - Dangling bond structures created on H-passivated silicon surfaces offer a novel platform for engineering planar nanoscale circuits, compatible with conventional semiconductor technologies. In this investigation we focus on the electronic structure and quantum transport signatures of dangling bond loops built on H passivated Si(100) surfaces contacted by carbon nanoribbons, thus leading to a two-terminal planar, nanoscale setup. The computational studies were carried out to rationalize the influence of the local atomic-scale contacts of the dangling bond system to the mesoscopic electrodes as well as the possibility of revealing quantum interference effects in the dangling bond loops. Our results reveal a strong sensitivity of the low-energy quantum transmission to the loop topology and to the atomistic details of the electrode-loop contact. Varying the length of the loop or the spatial position of at least one of the electrodes has a drastic impact on the quantum interference pattern; depending on whether constructive or destructive interference within the loop takes place, the conductance of the system can be tuned over several orders of magnitude, thus suggesting the possibility of exploiting such quantum mechanical effects in the design of two dimensional, atomic-scale electronic devices such as logic gates. PMID- 26228008 TI - Posterior auricular artery fasciocutaneous island flap: lateral temporal soft tissue reconstruction. PMID- 26228009 TI - What Constitutes an "Academic" Cardiology Practice? There Are New Models to Consider. PMID- 26228010 TI - Organizational Culture Changes Result in Improvement in Patient-Centered Outcomes: Implementation of an Integrated Recovery Pathway for Surgical Patients. AB - BACKGROUND: The goals of quality improvement are to partner with patients and loved ones to end preventable harm, continuously improve patient outcomes and experience, and eliminate waste, yet few programs have successfully worked on of all these in concert. STUDY DESIGN: We evaluated implementation of a pathway designed to improve patient outcomes, value, and experience in colorectal surgery. The pathway expanded on pre-existing comprehensive unit-based safety program infrastructure and used trust-based accountability models at each level, from senior leaders (chief financial officer and senior vice president for patient safety and quality) to frontline staff. It included preoperative education, mechanical bowel preparation with oral antibiotics, chlorhexidine bathing, multimodal analgesia with thoracic epidurals or transversus abdominus plane blocks, a restricted intravenous fluids protocol, early mobilization, and resumption of oral intake. Eleven months of pre- and post-pathway outcomes, including length of stay (LOS), National Surgical Quality Improvement Program surgical site infection (SSI), venous thromboembolism, and urinary tract infection rates, patient experience, and variable direct costs were compared. RESULTS: Three hundred ten patients underwent surgery in the baseline period, the mean LOS was 7 days, and the mean SSI rate was 18.8%. There were 330 patients who underwent surgery on the pathway, the LOS was 5 days, and the rate of SSI was 7.3%. Patient experience improved and variable direct costs decreased. CONCLUSIONS: Our trust-based accountability model, which included both senior hospital leadership and frontline providers, provided an enabling structure to rapidly implement an integrated recovery pathway and quickly improve outcomes, value, and experience of patients undergoing colorectal surgery. The study findings have significant implications for spreading surgical quality improvement work. PMID- 26228012 TI - Proposal for Standardized Tabular Reporting of Observational Surgical Studies Illustrated in a Study on Primary Repair of Bile Duct Injuries. AB - BACKGROUND: A standard format for reporting observational surgical studies does not exist. This creates difficulties in comparing studies and in performing synthesis through systematic reviews and meta-analyses. This article proposes a method called "standard tabular reporting" and illustrates its use in a case series of bile duct reconstructions for biliary injuries occurring during cholecystectomy. STUDY DESIGN: A database dealing with biliary injuries was constructed in sections. Each section was designed to be turned into a table covering one element of the subject. Whenever possible, American College of Surgeons NSQIP "Classic Variables and Definitions" were used for forming sections and tables. However, most tables are original and specific to biliary injury. The database was populated from clinical records of patients who sustained a biliary injury during cholecystectomy. RESULTS: Tables were created dealing with the following subjects: demographics, index operation, presentation, classification of injury, preoperative risk assessment, preoperative laboratory values, operative repair technique, postoperative complications, and long-term outcomes. Between 1997 and 2013, 122 primary bile duct reconstructions were performed, with 1 mortality and 47 complications. Good long-term results were obtained in 113 (92.6%) patients. No secondary surgical reconstructions have been needed. CONCLUSIONS: Presentation of data in a standard format would facilitate comparison and synthesis of observational studies on the same subject. The biliary reconstructive methods used resulted in very satisfactory outcomes. PMID- 26228011 TI - Using Human Factors and Systems Engineering to Evaluate Readmission after Complex Surgery. AB - BACKGROUND: Our objective was to use a human factors and systems engineering approach to understand contributors to surgical readmissions from a patient and provider perspective. Previous studies on readmission have neglected the patient perspective. To address this gap and to better inform intervention design, we evaluated how transitions of care relate to and influence readmission from the patient and clinician perspective using the Systems Engineering Initiative for Patient Safety (SEIPS) model. STUDY DESIGN: Patients readmitted within 30 days of discharge after complex abdominal surgery were interviewed. A focus group of inpatient clinician providers was conducted. Questions were guided by the SEIPS framework and content was analyzed. Data were collected concurrently from the medical record for a mixed-methods approach. RESULTS: Readmission occurred a median of 8 days (range 1 to 25 days) after discharge. All patients had follow-up scheduled with their surgeon, but readmission occurred before this in 72% of patients. Primary readmission diagnoses included infection, gastrointestinal complications, and dehydration. Patients (n = 18) and clinician providers (n = 6) identified a number of factors during the transition of care that may have contributed to readmission, including poor patient and caregiver understanding; inadequate discharge preparation for home care; insufficient educational process and materials, negatively affected by electronic health record design; and inadequate care team communication. CONCLUSIONS: This is the first study to use a human factors and systems engineering approach to evaluate the impact of the quality of the transition of care and its influence on readmission from the patient and clinician perspective. Important targets for future interventions include enhancing the discharge process, improving education materials, and increasing care team coordination, with the overarching theme that improved patient and caregiver understanding and engagement are essential to decrease readmission and postdischarge health care use. PMID- 26228013 TI - Association of the 2011 ACGME Resident Duty Hour Reform with Postoperative Patient Outcomes in Surgical Specialties. AB - BACKGROUND: The 2011 ACGME resident duty hour reform implemented additional restrictions to existing duty hour policies. Our objective was to determine the association between this reform and patient outcomes among several surgical specialties. STUDY DESIGN: Patients from 5 surgical specialties (neurosurgery, obstetrics/gynecology, orthopaedic surgery, urology, and vascular surgery) were identified from the American College of Surgeons NSQIP. Data from 1 year before and 2 years after the reform was implemented were obtained for teaching and nonteaching hospitals. Hospital teaching status was defined based on the percentage of operations with a resident present intraoperatively. Difference-in differences models were developed separately for each specialty and adjusted for patient demographics, comorbidities, procedural case-mix, and time trends. The association between duty hour reform and a composite measure of death or serious morbidity within 30 days of surgery was estimated for each specialty. RESULTS: The unadjusted rate of death or serious morbidity decreased during the study period in both teaching and nonteaching hospitals for all surgical specialties. In multivariable analyses, there were no significant associations between duty hour reform and the composite outcomes of death or serious morbidity in the 2 years post-reform for any surgical specialty evaluated (neurosurgery: odds ratio [OR] = 0.90; 95% CI, 0.75-1.08; p = 0.26; obstetrics/gynecology: OR = 0.96; 95% CI, 0.71-1.30; p = 0.80; orthopaedic surgery: OR = 0.95; 95% CI, 0.74-1.22; p = 0.70; urology: OR = 1.16; 95% CI, 0.89-1.51; p = 0.26; vascular surgery: OR = 1.07; 95% CI, 0.93-1.22; p = 0.35). CONCLUSIONS: Implementation of the 2011 ACGME resident duty hour reform was not associated with a significant change in patient outcomes for several surgical specialties in the 2 years after reform. PMID- 26228014 TI - Is a Colectomy Always Just a Colectomy? Additional Procedures as a Proxy for Operative Complexity. AB - BACKGROUND: Studies of surgical outcomes can be confounded by operative complexity. Complexity is difficult to assess from claims data due to the absence of established measures, but information on additional procedures is typically available. We hypothesized that analyzing same-day procedures (SDPs) would provide a useful step toward including operative complexity in risk adjustment. STUDY DESIGN: Colon resections were identified in California, Florida, and New York (2008 to 2011). Same-day procedures were categorized using 6 definitions. In hospital mortality and postoperative complications were examined. For all outcomes, we developed multivariable logistic regression models to measure the association between the SDP category and outcomes. RESULTS: Rates of SDP were 74.9% total, 69.5% surgical, 31.6% nonsurgical, 36.6% colon, 51.4% abdomen, and 34.3% other for the 215,041 colon resections examined. Mortality was associated with the inclusion of any SDP category in univariate (6.2% vs 1.7%; p < 0.001) and multivariable (odds ratio [OR] = 2.14; 95% CI, 1.99-2.30; p < 0.001) analysis. The association with mortality was high for nonsurgical (OR = 2.36; 95% CI, 2.26-2.46) and other (OR = 2.33; 95% CI, 2.23-2.43) procedures and moderate for surgical (OR = 1.45; 95% CI, 1.37-1.54) and colon (OR = 1.51; 95% CI, 1.44 1.57) procedures, but abdominal procedures were not independently associated with mortality (OR = 1.01; 95% CI, 0.97-1.06). The total number of SDPs was also associated with higher complication rates. CONCLUSIONS: The risk of complications and mortality associated with colectomy was increased among patients with SDPs and the magnitude of the association was dependent on the type and quantity of additional procedures. Information on SDPs might reflect a component of operative risk not typically captured and should be considered as a candidate variable for risk adjustment when using claims to compare outcomes across large cohorts. PMID- 26228015 TI - Improving Quality Metric Adherence to Minimally Invasive Breast Biopsy among Surgeons Within a Multihospital Health Care System. AB - BACKGROUND: Minimally invasive breast biopsy (MIBB) is the procedure of choice for diagnosing breast lesions indeterminate for malignancy. Multihospital health care systems face challenges achieving systemwide adherence to standardized guidelines among surgeons with varying practice patterns. This study tested whether providing individual feedback about surgeons' use of MIBB to diagnose breast malignancies improved quality metric adherence across a large health care organization. STUDY DESIGN: We conducted a prospective matched-pairs study to test differences (or lack of agreement) between periods before and after intervention. All analytical cases of primary breast cancer diagnosed during 2011 (period 1) and from July 2012 to June 2013 (period 2) across a multihospital health care system were reviewed for initial diagnosis by MIBB or open surgical biopsy. Open surgical biopsy was considered appropriate care only if MIBB could not be performed for reasons listed in the American Society of Breast Surgeons' quality measure for preoperative diagnosis of breast cancer. Individual and systemwide results of adherence to the MIBB metric during period 1 were sent to each surgeon in June 2012 and were later compared with period 2 results using McNemar's test of marginal homogeneity for matched binary responses. RESULTS: Forty-six surgeons were evaluated on use of MIBB to diagnose breast cancer. In period 1, metric adherence for 100% of cases was achieved by 37 surgeons, for a systemwide 100% compliance rate of 80.4%. After notification of individual performance, 44 of 46 surgeons used MIBB solely or otherwise appropriate care to diagnose breast cancer, which improved systemwide compliance to 95.7%. CONCLUSIONS: Providing individual and systemwide performance results to surgeons can increase self-awareness of practice patterns when diagnosing breast cancer, leading to standardized best-practice care across a large health care organization. PMID- 26228016 TI - Reducing Readmissions after Pancreatectomy: Limiting Complications and Coordinating the Care Continuum. AB - BACKGROUND: Recent analyses of gastrointestinal operations document that complications are a key driver of readmissions. Pancreatectomy is a high outlier with respect to readmission. This analysis sought to determine if a multifactorial approach could reduce readmissions after pancreatectomy. STUDY DESIGN: From 2007 to 2012, the number of patients readmitted by 30 days after pancreaticoduodenectomy, and distal and total pancreatectomy was measured. Steps to decrease readmissions were implemented independently at 1-year intervals; these efforts included strategies to reduce complications, creation of a Readmissions Team with a "discharge coach," increased use of home health, preferred relationships with post-acute care facilities, and the adoption of "Project RED" (Re-Engineered Discharge). The ACS NSQIP was used to track 30-day outcomes for all pancreatic resections. The University HealthSystem Consortium was used to determine length of stay index. RESULTS: Over 5 years, 1,163 patients underwent proximal (66%), distal (32%), or total pancreatectomy (2%). The observed 30-day mortality was 2.9% for the study period, and the length of stay index (observed/expected days) was 1.10. Neither varied significantly over time. However, 30-day morbidity decreased from 57% to 46%, and proportion of patients with 30-day all-cause readmissions decreased from 23.0% to 11.5% (p = 0.001). CONCLUSIONS: All-cause 30-day readmissions after pancreatectomy decreased without increasing length of stay. Efforts by surgeons to decrease complications and an increased emphasis on coordination of care may be useful for reducing readmissions. PMID- 26228017 TI - Effect of Perioperative Transfusion on Recurrence and Survival after Gastric Cancer Resection: A 7-Institution Analysis of 765 Patients from the US Gastric Cancer Collaborative. AB - BACKGROUND: The prognostic effect of perioperative blood transfusion on recurrence and survival in patients undergoing resection of gastric adenocarcinoma (GAC) remains controversial. STUDY DESIGN: All patients who underwent resection for GAC from 2000 to 2012 at the 7 institutions of the US Gastric Cancer Collaborative were identified. The effect of transfusion on recurrence-free (RFS) and overall survival (OS) in the context of adverse clinicopathologic variables was examined by univariate and multivariate regression analyses. RESULTS: Of 965 patients, 765 underwent curative intent R0 resection. Median follow-up was 44 months; 30-day mortalities were excluded. Median estimated blood loss (EBL) was 200 mL, and 168 patients (22%) received perioperative allogeneic blood transfusions. Transfused patients were less likely to receive adjuvant therapy (44% vs 56%; p = 0.01). Transfusion was associated with significantly decreased median RFS (13.5 vs 37.2 months, p < 0.001). Median OS was similarly decreased in patients receiving transfusions (18.6 vs 49.8 months, p < 0.001). On multivariate analysis, transfusion remained an independent risk factor for decreased RFS (hazard ratio [HR] 1.63; 95% CI 1.13 to 2.37; p = 0.010) and decreased OS (HR 1.79; 95% CI 1.21 to 2.67; p = 0.004), regardless of EBL or need for splenectomy. Timing (intraoperative vs postoperative) and volume of transfusion did not alter the negative prognostic effect of transfusion on survival. CONCLUSIONS: Perioperative allogeneic blood transfusion is associated with decreased RFS and OS after resection of gastric cancer, independent of adverse clinicopathologic factors. This supports the judicious use of perioperative transfusion during resection of gastric cancer. PMID- 26228018 TI - Placental hypoxia, endoplasmic reticulum stress and maternal endothelial sensitisation by sFLT1 in pre-eclampsia. AB - The human placenta is a multifunctional organ that grows and adapts to increasing fetal demand and fluctuations in the intrauterine environment. It is subjected to physiological and pathological changes in local oxygenation, both of which induce adaptive changes. In early pregnancy a low PO2 is the normal physiological state and this is not hypoxic-there is no perturbation of ATP/ADP ratios and, if the placenta is sampled very rapidly, little HIF1alpha is detected in human first trimester placental villi. Nonetheless, HIF1alpha can be increased and activated by culture. However, the placenta does show evidence of stress under pathological conditions. For example, in cases of pre-eclampsia where delivery by caesarean section is necessitated for maternal well-being before 34 weeks' gestation, placental endoplasmic reticulum stress is evident. Cases delivered >=34 weeks are indistinguishable from normal term controls. One consequence of placental stress, whether oxidative, related to the endoplasmic reticulum or immunological, is that factors are released into the maternal circulation, which affects the endothelium, leading to the maternal syndrome. Soluble FLT1 may contribute directly to this and the most likely mechanism is direct action on the maternal endothelium. sFLT1 is able to form a heterodimer with cell surface VEGF receptors and is therefore able to have a dominant negative effect (in addition to acting as a competitive inhibitor by simply binding vascular endothelial growth factor A [VEGFA] and placental growth factor [PlGF]). This leads in vitro to the sensitisation of endothelial cells to low levels of TNFalpha. PMID- 26228019 TI - Childhood bullous pemphigoid: a report of three cases in China. PMID- 26228020 TI - Foot side detection from lower lumbar spine acceleration. AB - The purpose of this paper is to present a reliable algorithm to discriminate between left/right foot contact using an accelerometer located over the lower lumbar spine. With the given accelerometer frame orientation, the side detection algorithm, based on the sign of the derivative of the sinusoidal shape obtained from the filtered mediolateral (ML) acceleration, showed 100% correct side detection for all subjects at all walking velocities. From the obtained results, it is concluded that in healthy subjects, the side of subsequent foot contact can be reliably obtained from the ML acceleration pattern of the lower lumbar spine. PMID- 26228021 TI - Gait termination in individuals with multiple sclerosis. AB - Despite the ubiquitous nature of gait impairment in multiple sclerosis (MS), there is limited information concerning the control of gait termination in individuals with MS. The purpose of this investigation was to examine planned gait termination in individuals with MS and healthy controls with and without cognitive distractors. Individuals with MS and age matched controls completed a series of gait termination tasks over a pressure sensitive walkway under non distracting and cognitively distracting conditions. As expected the MS group had a lower velocity (89.9+/-33.3 cm/s) than controls (142.8+/-22.4 cm/s) and there was a significant reduction in velocity in both groups under the cognitive distracting conditions (MS: 73.9+/-30.7 cm/s; control: 120.0+/-25.9 cm/s). Although individuals with MS walked slower, there was no difference between groups in the rate a participant failed to stop at the target (i.e. failure rate). Overall failure rate had a 10-fold increase in the cognitively distracting condition across groups. Individuals with MS were more unstable during termination. Future research examining the neuromuscular mechanisms contributing to gait termination is warranted. PMID- 26228022 TI - Dual attenuation of proteasomal and autophagic BMAL1 degradation in Clock Delta19/+ mice contributes to improved glucose homeostasis. AB - Circadian clocks orchestrate essential physiology in response to various cues, yet their mechanistic and functional plasticity remains unclear. Here, we investigated Clock(Delta19/+) heterozygous (Clk/+) mice, known to display lengthened periodicity and dampened amplitude, as a model of partially perturbed clocks. Interestingly, Clk/+ mice exhibited improved glycemic control and resistance to circadian period lengthening under high-fat diet (HFD). Furthermore, BMAL1 protein levels in Clk/+ mouse liver were upregulated compared with wild-type (WT) mice under HFD. Pharmacological and molecular studies showed that BMAL1 turnover entailed proteasomal and autophagic activities, and CLOCKDelta19 attenuated both processes. Consistent with an important role of BMAL1 in glycemic control, enhanced activation of insulin signaling was observed in Clk/+ mice relative to WT in HFD. Finally, transcriptome analysis revealed reprogramming of clock-controlled metabolic genes in Clk/+ mice. Our results demonstrate a novel role of autophagy in circadian regulation and reveal an unforeseen plasticity of circadian and metabolic networks. PMID- 26228023 TI - Posterior Circulation Ischemic Stroke Caused by Arterial Dissection: Characteristics and Predictors of Poor Outcomes. AB - BACKGROUND: Posterior circulation ischemic stroke (PCS) caused by arterial dissection (AD-PCS) was rarely discussed. The present study aimed to evaluate the clinical characteristics and predictors of poor outcomes in AD-PCS patients. METHODS: A total of 286 PCS patients were recruited from Taipei Veterans General Hospital Stroke Registry (between January 1, 2012 and February 28, 2014). Clinical/image data of recruited PCS patients were reviewed by stroke specialists who reached a consensus on the stroke etiologies. Data of AD-PCS patients were analyzed. RESULTS: Seventy-four patients (65.8 +/- 15.6 years, 56 (75.7%) men) were determined as AD-PCS. Headache and neck pain at admission were only presented in 18.9 and 6.8% of patients, respectively. The location of AD was initiated in the vertebral artery (66.2%), basilar artery (27.0%), posterior inferior cerebellar artery (5.4%) and posterior cerebral artery (1.4%). The involvement of intracranial arteries was present in the majority of patients (97.3%). Of the patients, 9.5% died, and 29.7% had poor functional outcomes (modified Rankin Scale >=4) at 3-month. Conscious change independently predicted mortality at 3 months. Quadriparesis, National Institutes of Health Stroke Scale (NIHSS) score >8 and infarct lesions involving >1 category were independent predictors for poor functional outcomes at 3 months. CONCLUSION: AD is an important etiology of PCS. Physicians should be more vigilant in recognizing AD PCS. Intracranial arteries are more important in AD-PCS; very few patients of AD PCS had dissection solely in extracranial arteries. Short-term outcomes of AD-PCS were not favorable. Conscious change, quadriparesis, NIHSS score >8 and infarct lesions involving >1 category were independent predictors for poor outcomes. Patients presenting these factors should be monitored closely. PMID- 26228024 TI - Alcohol enhances the psychostimulant and conditioning effects of mephedrone in adolescent mice; postulation of unique roles of D3 receptors and BDNF in place preference acquisition. AB - BACKGROUND AND PURPOSE: The psychostimulant mephedrone is often consumed in combination with alcohol (EtOH). This kind of drug consumption during adolescence is a matter of concern. EXPERIMENTAL APPROACH: We studied, in adolescent CD-1 mice, whether EtOH could enhance the psychostimulant (locomotor acivity) and rewarding [conditioned place preference (CPP)] effects of mephedrone. We also determined the transcriptional changes associated with a conditioning treatment with these drugs. KEY RESULTS: Mephedrone (10 mg.kg(-1)) increased locomotor activity, which was further enhanced by 40% when combined with EtOH (1 g.kg(-1)). This enhancement was blocked by haloperidol. Furthermore, mephedrone (25 mg.kg( 1)) induced CPP, which increased by 70% when administered with a dose of EtOH that was not conditioning by itself (0.75 g.kg(-1)). There was enhanced expression of the D3 dopamine receptor mRNA (Drd3) and Arpc5 in all drug-treated groups. The D3 receptor antagonist SB-277011A and the BDNF receptor antagonist ANA-12 completely prevented CPP as well as the increases in Drd3 in all groups. Accordingly, increased expression of BDNF mRNA in medial prefrontal cortex was detected at 2 and 4 h after mephedrone administration. CONCLUSIONS AND IMPLICATIONS: If translated to humans, the enhancement of mephedrone effects by ethanol could result in increased abuse liability. D3 receptors and BDNF play a key role in the establishment of CPP by mephedrone, although an accompanying increase in other synaptic plasticity-related genes may also be necessary. PMID- 26228025 TI - The Dissociation of Gefitinib Trough Concentration and Clinical Outcome in NSCLC Patients with EGFR Sensitive Mutations. AB - Gefitinib is an essential drug for NSCLC patients harboring EGFR sensitive mutations. The approved dose 250 mg/day is based on limited clinical trials, this research aims to explore the relationship between drug exposure and gefitinib response. C trough of 87 NSCLC patients harboring EGFR sensitive mutations were determined by LC-MS/MS. The median of C trough was 173.9 ng/ml (P25-P75, 130.5 231.2 ng/ml), and cutoff value 200 ng/ml was determined by X-Tile. The PFS between C trough < 200 ng/ml and C trough >= 200 ng/ml groups were not significantly different (17.3 VS 14.8 months; p = 0.258). C trough was not significantly associated with rash, diarrhea and hepatotoxicity. Non-smokers enjoyed longer PFS than smokers (18.7 VS 9.3 months; p = 0.025). The results showed that, for NSCLC patients with EGFR sensitive mutations, the PFS in lower trough concentration group were not inferior to that in higher trough concentration group and dose reduction is a rational suggestion for adjustment of dose regimen for aforementioned patients. More clinical trials are warranted to explore the precision dose schedule of gefitinib. PMID- 26228026 TI - Receptor-Interacting Protein 140 Orchestrates the Dynamics of Macrophage M1/M2 Polarization. AB - Macrophage classical (M1) versus alternative (M2) polarization is critical for the homeostatic control of innate immunity. Uncontrolled macrophage polarization is frequently implicated in diseases. This study reports a new functional role for receptor-interacting protein 140 (RIP140) in regulating this phenotypic switch. RIP140 is required for M1 activation, and its degradation is critical to LPS-induced endotoxin tolerance (ET). Here, we found that failure to establish RIP140 degradation-mediated ET prevents M2 polarization, and reducing RIP140 level facilitates an M1/M2 switch, resulting in more efficient wound healing in animal models generated with either transgenic or bone marrow transplant procedures. The M2-suppressive effect is elicited by a new function of RIP140 that, in macrophages exposed to M2 cues, is exported to cytosol, forming complexes with CAPNS1 (calpain regulatory subunit) to activate calpain 1/2, that activates PTP1B phosphatase. The activated PTP1B then reduces STAT6 phosphorylation, thereby suppressing the efficiency of M2 polarization. It is concluded that RIP140 plays dual roles in regulating the M1-M2 phenotype switch: the first, in the nucleus, is an M1 enhancer and the second, in the cytosol, is an M2 suppressor. Modulating the level and/or subcellular distribution of RIP140 can be a new therapeutic strategy for diseases where inflammatory/anti inflammatory responses are critical. PMID- 26228027 TI - [Tumor regression after neoadjuvant short-term irradiation for rectal cancer]. PMID- 26228028 TI - Sigma-1 Receptor Modulates Neuroinflammation After Traumatic Brain Injury. AB - Traumatic brain injury (TBI) remains a significant clinical problem and contributes to one-third of all injury-related deaths. Activated microglia mediated inflammatory response is a distinct characteristic underlying pathophysiology of TBI. Here, we evaluated the effect and possible mechanisms of the selective Sigma-1 receptor agonist 2-(4-morpholinethyl)-1 phenylcyclohexanecarboxylate (PRE-084) in mice TBI model. A single intraperitoneal injection 10 MUg/g PRE-084, given 15 min after TBI significantly reduced lesion volume, lessened brain edema, attenuated modified neurological severity score, increased the latency time in wire hang test, and accelerated body weight recovery. Moreover, immunohistochemical analysis with Iba1 staining showed that PRE-084 lessened microglia activation. Meanwhile, PRE-084 reduced nitrosative and oxidative stress to proteins. Thus, Sigma-1 receptors play a major role in inflammatory response after TBI and may serve as useful target for TBI treatment in the future. PMID- 26228029 TI - Complications following circumcision: Presentations to the emergency department. AB - BACKGROUND: Circumcision is the most common surgical procedure performed on boys in Australia. Patient presentations to the emergency department (ED) following circumcision are common; however, no Australian research has investigated acute care presentations. OBJECTIVES: To identify reasons for presentation to the ED after circumcision and determine whether the setting (community vs. hospital) in which the procedure had been performed has any bearing on the sequelae seen. METHODS: Retrospective chart review of children presenting with circumcision related problems to the Royal Children's Hospital, Melbourne, Australia, between 2012 and 2014. Descriptive and chi(2) analysis included sequelae of community- versus hospital-performed procedures. RESULTS: Over a 29-month period, we identified 167 children with a circumcision-related ED presentation. Mean age was 3 years. A percentage of 54.5 had been performed for non-medical, 29.9% for medical reasons and 14.4% for reasons unknown. When location was known (n = 152), 60.5% were performed in the community and 39.5% in hospital. Reasons for presentation were: bleeding (53.9%), pain (38.3%), swelling (37.1%), redness (25.7%), decreased urine output (13.8%), fever (7.2%) and pus (6%). 29.9% were diagnosed as normal healing post circumcision. Patients were admitted in 39.1% versus 15% (P = 0.001) and re-operated in 18.5% versus 1.7% (P = 0.001) after community- versus hospital-operated circumcisions. CONCLUSIONS: A range of reasons cause patients to seek help in the ED following a circumcision. Parents would have profited from better explanation of post-circumcision appearance of the penis. ED presentations after community-performed procedures required more re operations than after hospital-performed circumcisions. PMID- 26228032 TI - Asymmetric response time functions during left-/right-facing discriminations of rotated objects: The short and the long of it. AB - When deciding if a rotated object would face to the left or to the right, if imagined at the upright, mental rotation is typically assumed to be carried out through the shortest angular distance to the upright prior to determining the direction of facing. However, the response time functions for left- and right facing objects are oppositely asymmetric, which is not consistent with the standard explanation. Using Searle and Hamm's individual differences adaption of Kung and Hamm's Mixture Model, the current study compares the predicted response time functions derived when assuming that objects are rotated through the shortest route to the upright with the predicted response time functions derived when assuming that objects are rotated in the direction they face. The latter model provides a better fit to the majority of the individual data. This allows us to conclude that, when deciding if rotated objects would face to the left or to the right if imagined at the upright, mental rotation is carried out in the direction that the objects face and not necessarily in the shortest direction to the upright. By comparing results for mobile and immobile object sets we can also conclude that semantic information regarding the mobility of an object does not appear to influence the speed of mental rotation, but it does appear to influence pre-rotation processes and the likelihood of employing a mental rotation strategy. PMID- 26228031 TI - Effects of Evolocumab on Vitamin E and Steroid Hormone Levels: Results From the 52-Week, Phase 3, Double-Blind, Randomized, Placebo-Controlled DESCARTES Study. AB - RATIONALE: Vitamin E transport and steroidogenesis are closely associated with low-density lipoproteins (LDLs) metabolism, and evolocumab can lower LDL cholesterol (LDL-C) to low levels. OBJECTIVE: To determine the effects of evolocumab on vitamin E and steroid hormone levels. METHODS AND RESULTS: After titration of background lipid-lowering therapy per cardiovascular risk, 901 patients with an LDL-C >=2.0 mmol/L were randomized to 52 weeks of monthly, subcutaneous evolocumab, or placebo. Vitamin E, cortisol, adrenocorticotropic hormone, and gonadal hormones were analyzed at baseline and week 52. In a substudy (n=100), vitamin E levels were also measured in serum, LDL, high-density lipoprotein, and red blood cell membranes at baseline and week 52. Absolute vitamin E decreased in evolocumab-treated patients from baseline to week 52 by 16% but increased by 19% when normalized for cholesterol. In the substudy, vitamin E level changes from baseline to week 52 mirrored the changes in the lipid fraction, and red blood cell membrane vitamin E levels did not change. Cortisol in evolocumab-treated patients increased slightly from baseline to week 52, but adrenocorticotropic hormone and the cortisol:adrenocorticotropic hormone ratio did not change. No patient had a cortisol:adrenocorticotropic hormone ratio <3.0 (nmol/pmol). Among evolocumab-treated patients, gonadal hormones did not change from baseline to week 52. Vitamin E and steroid changes were consistent across subgroups by minimum postbaseline LDL-C <0.4 and <0.6 mmol/L. CONCLUSIONS: As expected, vitamin E levels changed similarly to lipids among patients treated for 52 weeks with evolocumab. No adverse effects were observed in steroid or gonadal hormones, even at very low LDL-C levels. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01516879. PMID- 26228030 TI - Cardiac Stem Cell Hybrids Enhance Myocardial Repair. AB - RATIONALE: Dual cell transplantation of cardiac progenitor cells (CPCs) and mesenchymal stem cells (MSCs) after infarction improves myocardial repair and performance in large animal models relative to delivery of either cell population. OBJECTIVE: To demonstrate that CardioChimeras (CCs) formed by fusion between CPCs and MSCs have enhanced reparative potential in a mouse model of myocardial infarction relative to individual stem cells or combined cell delivery. METHODS AND RESULTS: Two distinct and clonally derived CCs, CC1 and CC2, were used for this study. CCs improved left ventricular anterior wall thickness at 4 weeks post injury, but only CC1 treatment preserved anterior wall thickness at 18 weeks. Ejection fraction was enhanced at 6 weeks in CCs, and functional improvements were maintained in CCs and CPC+MSC groups at 18 weeks. Infarct size was decreased in CCs, whereas CPC+MSC and CPC parent groups remained unchanged at 12 weeks. CCs exhibited increased persistence, engraftment, and expression of early commitment markers within the border zone relative to combinatorial and individual cell population-injected groups. CCs increased capillary density and preserved cardiomyocyte size in the infarcted regions suggesting CCs role in protective paracrine secretion. CONCLUSIONS: CCs merge the application of distinct cells into a single entity for cellular therapeutic intervention in the progression of heart failure. CCs are a novel cell therapy that improves on combinatorial cell approaches to support myocardial regeneration. PMID- 26228033 TI - Survey of intimate partner violence before and during pregnancy among Japanese women. AB - AIM: Intimate partner violence (IPV) causes serious health problems, which could be life-threatening to pregnant women and their babies. Despite several IPV studies in Japan, the screening timeframe for IPV during pregnancy remains unclear. This study aimed to estimate the prevalence of IPV among Japanese women before and during pregnancy. METHODS: A survey was conducted at a hospital's outpatient clinic in Nagano, Japan, during October through December 2011 and March through July 2012. The Violence Against Women Screen (VAWS) questionnaire was distributed to 93 eligible women and 84 (89.5%) agreed to be assessed for the occurrence of IPV before and during pregnancy. RESULTS: The mean VAWS total score before pregnancy was 1.43 (standard deviation [SD] = 1.64; range, 0-7), and during pregnancy it was 0.83 (SD = 1.03; range, 0-6), and was significantly different (t = 4.98, P < 0.001). In addition, more women experienced IPV prior to pregnancy (34.9%) than during pregnancy (20.7%). All women who screened positive during pregnancy were also positive before pregnancy. Prevalence of intimate partner physical violence was 4.9% prior to pregnancy and declined to 3.7% during pregnancy. CONCLUSION: Even though the prevalence of IPV during pregnancy had decreased compared with before pregnancy, all women experiencing IPV before pregnancy continued to be victimized during pregnancy. Therefore, IPV screening questions should include IPV that had occurred a year prior. PMID- 26228034 TI - The Impact of Medicaid Expansion on Medicaid Focused Insurers in California. AB - To gain insights into the impact of Medicaid Expansion under the Affordable Care Act, this study assesses the enrollment, utilization, and financial performance measures of California Medicaid focused health insurers. The study compares these quarterly measures, during the expansion period of 2014 to the same quarterly measures in 2013 and 2012. During 2014, Medicaid focused insurers expanded enrollment, decreased inpatient days, and generated higher profit margins. PMID- 26228035 TI - Authorship Inflation in Medical Publications. AB - The number of authors per manuscript in peer-reviewed medical journals has increased substantially in the last several decades. Several reasons have been offered to explain this authorship growth, including increased researcher collaboration, honorary authorship driven by increased pressures for funding and promotion, the belief that including senior authors will facilitate publication, and the growing complexity of medical research. It is unknown, however, whether authorship has grown over time due to growing complexity of published academic articles, in which case growth could be warranted, or whether it has grown due to pressures of funding and academic promotion, which have created "authorship inflation." To answer this question, we analyzed data on authorship count, study type, and size of study population for the first 50 original articles published in each decade during 1960-2010 in 3 major medical journals. Within each type of study we considered (eg, randomized trials, observational studies, etc), average authorship rose more than 3-fold during this period. Similar growth persisted after adjustment for changes in study population sizes over time. Our findings suggest that increasing research complexity is an inadequate explanation for authorship growth. Instead, growth in authorship appears inflationary. PMID- 26228036 TI - Compression of the right iliac vein in asymptomatic subjects and patients with iliofemoral deep vein thrombosis. AB - OBJECTIVE: To evaluate right iliac vein and left iliac vein compression in asymptomatic subjects, right-sided and left-sided iliofemoral deep vein thrombosis patients. METHODS: A retrospective analysis of records and computed tomography images was conducted in 200 asymptomatic subjects (male:female, 100:100). A prospective analysis was conducted in 79 consecutive deep vein thrombosis patients (left:right deep vein thrombosis, 47:32) who had undergone contrast-enhanced computed tomography examination. The minor diameter and percentage compression of the iliac vein were evaluated. RESULTS: In asymptomatic subjects, 13.5% had right iliac vein compression >50%, 2.0% had right iliac vein compression >70%, mean compression was 23.48%; 45.0% had left iliac vein compression >50% and 17.0% had left iliac vein compression >70%, mean compression was 47.58%. Right iliac vein sandwiched between the right external iliac artery and the right internal iliac artery was the most common compression pattern (59.26%). Males had higher right iliac vein compression than the females (male:female, 26.29%:20.68%, P < 0.001). Mean percentage compression of the right iliac vein was higher in right deep vein thrombosis patients than in left deep vein thrombosis patients (right:left deep vein thrombosis, 48.54%:22.29%, P < 0.001). CONCLUSION: Similar to left iliac vein compression, right iliac vein compression was a frequent imaging finding in CT and represented a normal anatomic pattern. Right deep vein thrombosis patients had more serious right iliac vein compression than left deep vein thrombosis patients, and further research is required on the association of right iliac vein compression with right iliofemoral deep vein thrombosis. PMID- 26228037 TI - Thoracolaparoscopic dissection of esophageal lymph nodes without esophagectomy is feasible in human cadavers and safe in a porcine survival study. AB - High-risk early esophageal adenocarcinoma (i.e. submucosal invasion >500 nm, poor differentiation, and/or presence of lymphovascular invasion) is currently treated with esophagectomy with lymph node (LN) dissection given the high rates of LN metastases. However, esophagectomy is associated with substantial morbidity and mortality. Endoscopic radical resection followed by thoracolaparoscopic LN dissection without concomitant esophagectomy could be an alternative. The study aim was to evaluate the feasibility and safety of thoracolaparoscopic dissection of esophageal LNs in a preclinical setting. (i) In human cadavers, thoracolaparoscopic dissection of LNs involved in drainage of the esophagus was performed. Subsequently, esophagectomy was performed to be able to detect retained LNs. Outcome parameters included the number of dissected LNs, the number of retained LNs in the esophagectomy specimen (ES), and technical success. (ii) In swine, thoracolaparoscopic LN dissection was also performed. After the procedure, the swine survived for 28 days. Thereafter, the swine were sacrificed and esophagectomy was performed. Outcome parameters included the presence of ischemia and/or stenosis in the ES and other complications. (i) In five human cadavers, a median of 26 LNs (interquartile range 22-46) were dissected. In two ES, one retained LN was found: one high paraesophageal, one low paraesophageal. Technical success rate was 100%. (ii) None of the seven porcine ES showed signs of ischemia or stenosis. One swine died because of ventricular fibrillation during surgery; during follow up no complications were observed. Thoracolaparoscopic dissection of LNs involved in the drainage of the esophagus is feasible in human cadavers and swine. The porcine survival study suggests that the esophageal vascularity is not severely compromised by the procedure. As anatomy differs between swine and humans, safety of the procedure will have to be investigated thoroughly before applying this new technique as the treatment of choice. PMID- 26228038 TI - Effect of a high fat, high sucrose diet on the promotion of non-alcoholic fatty liver disease in male rats: the ameliorative role of three natural compounds. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease with a complex pathophysiology. The clinical features of NAFLD include obesity, insulin resistance (IR) and dyslipidemia. Consumption of a diet high in saturated fats and sucrose is an important factor in the increasing occurrence of these metabolic disorders, primarily NAFLD and IR. We sought to assess the role of a high-fat, high-sucrose (HFS) diet in the promotion of NAFLD and to evaluate the effects of quercetin (Q), berberine (BB) and o-coumaric acid (CA) on modulation of these disorders. METHODS: Fifty male rats were divided into 2 main groups as follows: group 1 comprised 10 rats fed a standard diet (SD), and group 2 comprised 40 rats fed an HFS diet for 6 weeks and then subdivided equally into 4 groups; one of these groups served as the HFS diet and each of the other three groups received daily supplementation with either Q, CA or BB for 6 weeks. RESULTS: In the present study, several metabolic disorders were induced in our laboratory animal model, as evidenced by histological and biochemical changes. These alterations included serum and hepatic dyslipidemia (i.e., increased triglyceride, total cholesterol and low-density lipoprotein levels and decreased high-density lipoprotein levels), alterations in metabolic enzyme activities (lipase, glycerol-3-phosphate dehydrogenase, and glucose-6-phosphate dehydrogenase), histological changes in the liver (micro- and macrovesicular steatosis) and the downregulation of peroxisome proliferator-activated receptor gamma (PPARgamma) in adipose tissue and the liver. Daily oral supplementation with Q, CA or BB for 6 weeks after NAFLD induction had a hypolipidemic action and modulated metabolic markers. CONCLUSION: We showed that an HFS diet is able to promote NAFLD, and our results suggest that CA and BB are promising complementary supplements that can ameliorate the metabolic disorders associated with an HFS diet; however, Q requires further investigation. PMID- 26228039 TI - Characteristics of 20 Patients with Autochthonous Acute Hepatitis E in Hokkaido, Japan: First Report of Bilateral Facial Palsy Following the Infection with Genotype 4 Hepatitis E Virus. AB - Autochthonous hepatitis E is increasingly being recognized in industrialized countries, including Japan. Although neurological abnormalities have been sporadically reported as an extrahepatic manifestation of hepatitis E virus (HEV) infection, it is rare and has not been reported in Japan. The present study aimed to characterize a total of 20 patients consecutively diagnosed with sporadic acute hepatitis E at a city hospital in Hokkaido, Japan, during 2001-2014, focusing on a patient complicated with neuropathy. Seventeen patients were infected with genotype 4 HEV, while the remaining three patients were with genotype 3 HEV. Although a 67-year-old male with severe hepatitis did not have predisposing factors associated with the development of neurological disorders, such as diabetes mellitus and the use of immunosuppressive agents, he developed bilateral peripheral facial palsy six days after admission. A neurological examination revealed the inability to smile, frown, close his eyes completely or puff out his cheeks. MRI brain scans were considered to be normal. Although it took 83 days after admission for the total bilirubin levels to normalize, his neurological symptoms resolved gradually within three weeks without any sequelae following conservative therapy. A full-length genomic analysis of the HEV strain (HE-JA30) isolated from the patient belonged to genotype 4 and was closest to that currently circulating in Hokkaido, Japan. This is the first report of HEV associated neuropathy in Japan. While all of previous reports on HEV-related neuropathy involve genotype 3 HEV, the present report is unique in that genotype 4 HEV is responsible for the neuropathy. PMID- 26228040 TI - Comparison of gene expression of the oncogenic Wnt/beta-catenin signaling pathway components in the mouse and human epididymis. AB - beta-catenin is an integral part of the Wnt signaling pathway and has been linked to tumorigenesis and multiple developmental processes. The high beta-catenin expression with low tumor incidence in the human epididymis is thus intriguing. In the present study, the beta-catenin gene and protein was found to be highly expressed in the murine caput epididymidis, and the protein mainly localized along the lateral plasma membranes of adjacent epithelial cells throughout both human and mouse epididymides. Furthermore, the adult mouse epididymis was found to express almost all the Wnt/beta-catenin signaling pathway genes that were determined previously by our group in the human organ. Despite the differences in epididymal structure, the similar location of beta-catenin and the high concordance of this pathway's components' gene expression in both the adult human and mouse epididymides make the mouse a suitable animal model for studying the anti-tumor mechanism of the epididymis. In addition, both the mRNA and protein expression of beta-catenin shared a similar spatial expression as the mRNA of Ros1, a proto-oncogene and a key developmental regulator of the initial segment of the mouse epididymis. The observations on the parallel temporal expression of beta-catenin and Ros1 during postnatal development raise the possibility that the canonical Wnt signaling pathway has an additional role in the postnatal development of mouse epididymis. PMID- 26228042 TI - One-stage dorsal lingual mucosal graft urethroplasty for the treatment of failed hypospadias repair. AB - The aim of this study was to retrospectively investigate the outcomes of patients who underwent one-stage onlay or inlay urethroplasty using a lingual mucosal graft (LMG) after failed hypospadias repairs. Inclusion criteria included a history of failed hypospadias repair, insufficiency of the local skin that made a reoperation with skin flaps difficult, and necessity of an oral mucosal graft urethroplasty. Patients were excluded if they had undergone a failed hypospadias repair using the foreskin or a multistage repair urethroplasty. Between January 2008 and December 2012, 110 patients with failed hypospadias repairs were treated in our center. Of these patients, 56 underwent a one-stage onlay or inlay urethroplasty using LMG. The median age was 21.8 years (range: 4-45 years). Of the 56 patients, one-stage onlay LMG urethroplasty was performed in 42 patients (group 1), and a modified Snodgrass technique using one-stage inlay LMG urethroplasty was performed in 14 (group 2). The median LMG urethroplasty length was 5.6 +/- 1.6 cm (range: 4-13 cm). The mean follow-up was 34.7 months (range: 10-58 months), and complications developed in 12 of 56 patients (21.4%), including urethrocutaneous fistulas in 7 (6 in group 1, 1 in group 2) and neourethral strictures in 5 (4 in group 1, 1 in group 2). The total success rate was 78.6%. Our survey suggests that one-stage onlay or inlay urethroplasty with LMG may be an effective option to treat the patients with less available skin after failed hypospadias repairs; LMG harvesting is easy and safe, irrespective of the patient's age. PMID- 26228041 TI - Reprogrammed CRISPR-Cas9 targeting the conserved regions of HPV6/11 E7 genes inhibits proliferation and induces apoptosis in E7-transformed keratinocytes. AB - The persistence infection of low-risk type (type 6 or type 11) of human papillomavirus (HPV) is the main cause of genital warts. Given the high rate of recurrence after treatment, the use of a new molecular agent is certain to be of value. The aim of this study was to achieve targeted inactivation of viral E 7 gene in keratinocytes using the reprogrammed clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) 9 system. To accomplish this, a universal CRISPR-Cas9 system for targeting both HPV6/11 E 7 genes was constructed by using a dual guide RNA vector. After transfection of the vector into E 7-transformed keratinocytes, the expression level of E 7 protein was measured using western-blot analysis and the sequence of the E 7 gene was determined using Sanger sequencing. Cell proliferation was analyzed by CCK-8 assay, and cell apoptosis was evaluated by Hoechst 33258 staining, flow cytometry analysis and ELISA assay. The results indicated that both HPV6/11 E 7 genes can be inactivated by the single CRISPR-Cas9 system. Furthermore, silencing of E 7 led to inhibition of cell proliferation and induction of apoptosis in E 7 transformed keratinocytes but not in normal keratinocytes. Our data suggested that the reprogrammed CRISPR-Cas9 system has the potential for the development of an adjuvant therapy for genital warts. PMID- 26228043 TI - A million little pieces of broken trust. AB - In April 2015, the Union Cabinet approved the Juvenile Justice (Care and Protection of Children) Bill, 2014, which proposes to bring about regressive changes in the law, that would not only be unconstitutional but also unethical. In May 2015, the Ministry of Women and Child Development introduced the Bill in the Lok Sabha, where it was passed. If the Rajya Sabha, passes the Bill and the President gives his assent to it, the youth of this country will be harmed in a manner that could break the very fabric of the nation. PMID- 26228044 TI - Trust, trustworthiness and health. AB - Trust is an essential component of good healthcare. If patients trust their physicians, then the relationship between them can be a richer and more meaningful one. The patient is more likely to feel confident and able to disclose symptoms, helping diagnosis and future care. If public health and community workers are trusted, not only is it likely that their work will be easier, in that their actions will be respected and accepted, but their advice will also be sought spontaneously. Trust, can, therefore, be thought of as something that is of benefit to all: healthcare workers, individuals and communities. Trust is, generally, something to be prized and we need to do anything we can to strengthen it. PMID- 26228045 TI - Ethics education: a priority for general practitioners in occupational medicine. AB - General practitioners (GPs) who work in occupational medicine (OM) should be trained continuously. However, it seems that ethical issues have been neglected. This cross-sectional study aimed to determine educational priorities for GPs working in OM. A total of 410 GPs who participated in OM seminars were asked to answer a number of questions related to items that they usually come across in their work. The respondents were given scores on 15 items, which pertained to their frequency of experience in OM, their felt needs regarding education in the field, and their knowledge and skills. Ethical issues were the most frequently utilised item and the area in which the felt need for education was the greatest. The knowledge of and skills in ethical issues and matters were the poorest. Ethical principles and confidentiality had the highest calculated educational priority scores. It is necessary to consider ethical issues as an educational priority for GPs working in the field of OM. PMID- 26228046 TI - Trust in the physician-patient relationship in developing healthcare settings: a quantitative exploration. AB - Trust in physicians is the patient's optimistic acceptance of vulnerability and the expectation that the physician will do what is best for his/her welfare. This study was undertaken to develop a conceptual understanding of the dimensions and determinants of trust in physicians in healthcare settings in resource-poor, developing countries. A cross-sectional household survey was conducted on a sample of 625 men and women from urban and rural areas in Tamil Nadu, India. The sample was selected using a multistage sampling method and a pre-tested structured questionnaire was utilised. The questionnaire covered the five dimensions of trust: perceived competence of the physician, assurance of treatment, confidence in the physician, loyalty towards him/her, and respect for him/her. Items covering four main factors that influence trust, ie shared identity, the physician's behaviour, personal involvement of the physician and level of comfort with him/her, were included in the questionnaire. A structural equation model was constructed with the dimensions of trust on one hand and the four factors influencing trust on the other. Trust in physicians is based more on notional constructs, such as assurance of treatment (b=0.714, p<0.001) and respect for the physician (b=0.763, p<0.001),than objective assessments, such as the physician's competence (b=0.607, p<0.001). Feeling comfortable with the physician (b=0.630, p<0.001) and the physician's communication skills (b=0.253, p<0.001) significantly influence the level of trust. The former is correlated with the personal involvement of the physician (r=0.124, p<0.001), and so is the latter (r=0.152, p<0.001). The overall model has a good statistical fit. The factors that give rise to trust in physicians vary with the sociocultural context. PMID- 26228048 TI - Trust and trust relations from the providers' perspective: the case of the healthcare system in India. AB - Commentators suggest that there is an erosion of trust in the relations between different actors in the health system in India. This paper presents the results of an exploratory study of the situation of providers in an urban setting in western India, the nature of their relations in terms of trust and what influences these relations. The data on relationships of trust were collected through interviews and focus group discussions with key informants, including public and private providers, regulators, managers and societal actors, such as patients/citizens, politicians and the media. PMID- 26228047 TI - Development and testing of a scale to measure trust in the public healthcare system. AB - Trust is an important factor in improving the performance of the healthcare system. This study aimed to develop a validated scale to measure trust in the public healthcare system. We adopted a sequential exploratory mixed study design, with developmental and testing phases. In the developmental phase, the construct of "healthcare system trust" was conceptualised and items were generated on the basis of information from a review of the literature on trust, in-depth interviews and a review of other scales. Exploratory factor analysis was employed for item reduction. In the testing phase, the reliability and validity measures were established. The face validity, content validity and construct validity of the scale were assessed. The final scale was a Likert-type scale with 23 items, 16 of which measured trust in the healthcare providers and 7, in healthcare institutions. The scale is a valid and reliable tool for measuring trust in the public healthcare system. PMID- 26228049 TI - RTI v medical ethics: some questions arising from the recent decision of the Chief Information Commissioner under the RTI Act. AB - Medical ethics attaches the utmost priority to the confidentiality of medical records. Hence, the decision of the Chief Information Commissioner (CIC) rendered on April 10, 2015 in Case No: CIC/KY/A/2014/001348SA Ms Jyoti Jeena v. PIO, Institute of Human Behaviour & Allied Science (hereinafter referred to as Jyoti Jeena), that the wife-applicant is entitled to get copies of the medical records of her estranged husband has raised many eyebrows. PMID- 26228050 TI - Treatment of chronic HCV genotype 1 coinfection. AB - Several all-oral direct-acting antiviral (DAA) combination therapies including two fixed-dose combinations (FDCs) have been recently licensed for treatment of hepatitis C virus (HCV) genotype 1 infection. Results of pivotal trials with these new compounds are now also available in human immunodeficiency virus (HIV)/HCV-coinfected patients, highlighting that, in the DAA era, differences no longer do exist in efficacy between HCV-monoinfected and HIV/HCV-coinfected patients. This review will give an overview of the key DAA-containing studies in HIV/HCV genotype 1 coinfection and give guidance on how and when these should be used in clinical practice. Simplified DAA-based and potentially interferon-free HCV therapy regimens are characterized by smaller pill burden, better tolerability, shorter treatment durations, and higher cure rates. With first pilot studies in HCV treatment-naive and treatment-experienced persons with HCV/HIV coinfection demonstrating sustained virological response rates above 95 %, interferon (IFN)-free DAA combinations should be considered the new standard of care for chronic HCV. Per both European and US treatment guidelines, HCV treatment indications and DAA drug selection in HIV-coinfected patients are no longer different from HCV-monoinfected patients as cure rates in HCV-monoinfected and HCV-coinfected patients are superimposable. Drug-drug interactions with the new DAAs and concomitant antiretroviral therapy, however, have to be checked carefully prior to selecting DAAs due to commonly shared metabolization pathways. In countries with access to the new DAAs, interferon-free DAA combination therapy for HCV genotype 1 infection is strongly recommended. Agents should be selected based upon HCV genotype and according to current guidelines. Potential drug-drug interactions between HIV antiretrovirals and HCV therapy need to be checked, and if necessary, combination antiretroviral therapy (cART) has to be adapted to the respective HCV therapy. Key Points* HCV treatment in HIV-coinfected patients is the same as in HCV-monoinfected patients as response rates under DAA in the setting of HIV coinfection have been as good as in HCV-monoinfected patients. * IFN-free DAA combinations should be considered standard of care for chronic HCV genotype 1 coinfection. * Drug-drug interactions with the new DAAs and concomitant antiretroviral therapy have to be accounted for due to shared metabolic pathways via the cytochrome p450 system and drug transporters. * Major limitations in treatment uptake are access to DAA which is increasingly driven by the cost of the medications. PMID- 26228051 TI - Intraventricular versus intravenous colistin for the treatment of extensively drug resistant Acinetobacter baumannii meningitis. AB - BACKGROUND AND PURPOSE: Reports on the safety and efficacy of intraventricularly administered (IVT) colistin for the treatment of Acinetobacter baumannii ventriculomeningitis in adults are limited and no comparative studies of IVT colistin versus intravenous (IV) therapy alone have been published. This study compared outcomes of patients with postneurosurgical ventriculomeningitis caused by extensively drug-resistant A. baumannii treated with IV colistin or IV plus IVT colistin. METHODS: In an 11-year period, information on 18 consecutive patients with extensively drug-resistant A. baumannii ventriculomeningitis was collected. Infection was defined on the basis of (i) isolation of A. baumannii from the cerebrospinal fluid (CSF); (ii) laboratory evidence of CSF infection; (iii) signs/symptoms of central nervous system (CNS) infection. Patients were divided into group 1 (nine patients, IV colistin alone) and group 2 (nine patients, IV plus IVT colistin). RESULTS: Cerebrospinal fluid sterilization was documented for 12 of 18 patients (66.6%). The CSF sterilization rate was 33.3% in group 1 and 100% in group 2 (P = 0.009). The mean time to CSF sterilization was 21 days (range 8-48). Five patients died due to A. baumannii CNS infection (all in group 1), and five deaths were unrelated to A. baumannii ventriculomeningitis. Intensive care unit mean length of stay was shorter in group 2 (20.7 vs. 41.6 days, P = 0.046). Crude relative risk ratio of cumulative incidence of persistent CNS infection in group 1 versus group 2 was 13. No cases of chemical meningitis due to intrathecal colistin administration were encountered. CONCLUSIONS: Intraventricular colistin administration is much more effective than IV therapy alone and does not seem to add further toxicity. PMID- 26228052 TI - Cardiorespiratory effects of recruitment maneuvers and positive end expiratory pressure in an experimental context of acute lung injury and pulmonary hypertension. AB - BACKGROUND: Recruitment maneuvers (RM) and positive end expiratory pressure (PEEP) are the cornerstone of the open lung strategy during ventilation, particularly during acute lung injury (ALI). However, these interventions may impact the pulmonary circulation and induce hemodynamic and respiratory effects, which in turn may be critical in case of pulmonary hypertension (PHT). We aimed to establish how ALI and PHT influence the cardiorespiratory effects of RM and PEEP. METHODS: Rabbits control or with monocrotaline-induced PHT were used. Forced oscillatory airway and tissue mechanics, effective lung volume (ELV), systemic and right ventricular hemodynamics and blood gas were assessed before and after RM, during baseline and following surfactant depletion by whole lung lavage. RESULTS: RM was more efficient in improving respiratory elastance and ELV in the surfactant-depleted lungs when PHT was concomitantly present. Moreover, the adverse changes in respiratory mechanics and ELV following ALI were lessened in the animals suffering from PHT. CONCLUSIONS: During ventilation with open lung strategy, the role of PHT in conferring protection from the adverse respiratory consequences of ALI was evidenced. This finding advocates the safety of RM and PEEP in improving elastance and advancing lung reopening in the simultaneous presence of PHT and ALI. PMID- 26228053 TI - Problems in Functioning in Patients with Chronic Musculoskeletal Pain Admitted for Multidisciplinary Rehabilitation. AB - BACKGROUND: Little is known about the extent to which improvements in various problem areas are attained after multidisciplinary rehabilitation program in patients with chronic musculoskeletal pain (CMP). AIM: To describe the pre- and postcontents of problems in functioning from the Canadian Occupational Performance Measure (COPM) in terms of the International Classification of Functioning, Disability and Health (ICF) in CMP patients following a 15-week rehabilitation program. METHODS: In all patients admitted to a rehabilitation program, the COPM was administered at admission and discharge. The problems identified at admission were linked to ICF chapters using an established linking procedure. Changes of COPM Performance/Satisfaction scores (1-10; low-high) with 95% confidence intervals (CIs) were calculated, and effect sizes (ESs) were computed. RESULTS: In total, 165 patients were included with a mean age of 44.1 (SD 12.9) years; among them, 143 (87%) were women. At admission, totally 801 problems were identified and linked to 706 unique ICF categories: 83 (12%) were related to the ICF component "Body Functions" and 621 (88%) to "Activities and Participation". ICF chapters "d4 Mobility" (124, 18%) and "d9 Community social and civic life" (143, 20%) were most frequently identified. The median changes of the COPM total scores for Performance and Satisfaction were 2.1 (95% CI 1.9 to 2.3, ES: 1.75) and 3.2 (95% CI 2.9 to 3.4, ES: 2.38). CONCLUSION: A 15-week multidisciplinary treatment program showed that most problems were seen within chapters Mobility and Community life of the ICF. The program led to significant improvements of patient reported problems, the magnitude of which was similar for all different problem areas. PMID- 26228055 TI - Direct observation of multistep energy transfer in LHCII with fifth-order 3D electronic spectroscopy. AB - During photosynthesis, sunlight is efficiently captured by light-harvesting complexes, and the excitation energy is then funneled towards the reaction centre. These photosynthetic excitation energy transfer (EET) pathways are complex and proceed in a multistep fashion. Ultrafast two-dimensional electronic spectroscopy (2DES) is an important tool to study EET processes in photosynthetic complexes. However, the multistep EET processes can only be indirectly inferred by correlating different cross peaks from a series of 2DES spectra. Here we directly observe multistep EET processes in LHCII using ultrafast fifth-order three-dimensional electronic spectroscopy (3DES). We measure cross peaks in 3DES spectra of LHCII that directly indicate energy transfer from excitons in the chlorophyll b (Chl b) manifold to the low-energy level chlorophyll a (Chl a) via mid-level Chl a energy states. This new spectroscopic technique allows scientists to move a step towards mapping the complete complex EET processes in photosynthetic systems. PMID- 26228054 TI - The frequent evolutionary birth and death of functional promoters in mouse and human. AB - Promoters are central to the regulation of gene expression. Changes in gene regulation are thought to underlie much of the adaptive diversification between species and phenotypic variation within populations. In contrast to earlier work emphasizing the importance of enhancer evolution and subtle sequence changes at promoters, we show that dramatic changes such as the complete gain and loss (collectively, turnover) of functional promoters are common. Using quantitative measures of transcription initiation in both humans and mice across 52 matched tissues, we discriminate promoter sequence gains from losses and resolve the lineage of changes. We also identify expression divergence and functional turnover between orthologous promoters, finding only the latter is associated with local sequence changes. Promoter turnover has occurred at the majority (>56%) of protein-coding genes since humans and mice diverged. Tissue-restricted promoters are the most evolutionarily volatile where retrotransposition is an important, but not the sole, source of innovation. There is considerable heterogeneity of turnover rates between promoters in different tissues, but the consistency of these in both lineages suggests that the same biological systems are similarly inclined to transcriptional rewiring. The genes affected by promoter turnover show evidence of adaptive evolution. In mice, promoters are primarily lost through deletion of the promoter containing sequence, whereas in humans, many promoters appear to be gradually decaying with weak transcriptional output and relaxed selective constraint. Our results suggest that promoter gain and loss is an important process in the evolutionary rewiring of gene regulation and may be a significant source of phenotypic diversification. PMID- 26228056 TI - Who pays for home care? A study of nationally representative data on disabled older Americans. AB - BACKGROUND: We examine who pays for services that support disabled older Americans at home. We consider both personal sources (e.g., out-of-pocket payment, family members) and publicly funded programs (e.g., Medicaid) as sources of payment for services. We examine how the funding mix for home care services is related to older people's economic resources, needs for care, and other socio demographic characteristics. METHODS: Our sample consists of 11,725 person-years from the 1989, 1994, 1999, and 2004 waves of the National Long-Term Care Survey. Two-part regression analyses were performed to model hours of care received from each payer. "Random effects" and "fixed effects" estimation yielded similar results. RESULTS: About six in ten caregivers (63%) providing home care services are paid by personal sources alone. By contrast, 28% receive payment from publicly funded programs alone, and 9% from a combination of personal and public program sources. Older people with family incomes over 75,000 dollars per year receive 8.5 more hours of home care overall than those in the lowest income category (less than 15,000 dollars). While the funding mix for home care services is strongly related to older people's economic resources, in all income groups at least 65% of services are provided by caregivers paid in whole or in part from personal sources. In fact, almost all (97%) home care received by those with family incomes over 75,000 dollars per year are financed by personal sources alone. CONCLUSIONS: We outline the implications that heavy reliance on personally financed services and economic disparities in overall services use has for disabled older Americans and their families. PMID- 26228059 TI - Synthesis of carboxylate-bridged iron-thiolate clusters from alcohols/aldehydes or carboxylate salts. AB - A series of novel carboxylate-bridged cyclopentadienyl diiron complexes [Cp*Fe(MU SEt)2(MU-eta(2)-OOCR)FeCp*][PF6] (, R = H; , R = Me; , R = Et; , R = Pr-n; , R = Ph; , R = p-Me-C6H4; , R = PhCH[double bond, length as m-dash]CH; , CH[triple bond, length as m-dash]C) were obtained from alcohols/aldehydes or sodium carboxylates at room temperature. These eight complexes were fully characterized by spectroscopy, and some of them (, , and ) were further studied by X-ray crystallography. In addition, the electrochemical properties of clusters and are also discussed. PMID- 26228058 TI - Gene expression profiling of ovarian carcinomas and prognostic analysis of outcome. AB - BACKGROUND: Ovarian cancer (OCA), the fifth leading deaths cancer to women, is famous for its low survival rate in epithelial ovarian cancer cases, which is very complicated and hard to be diagnosed from asymptomatic nature in the early stage. Thus, it is urgent to develop an effective genetic prognostic strategy. METHODS: Current study using the Database for Annotation, Visualization and Integrated Discovery tool for the generation and analysis of quantitative gene expression profiles; all the annotated gene and biochemical pathway membership realized according to shared categorical data from Pathway and Kyoto Encyclopedia of Genes and Genomes; correlation networks based on current gene screening actualize by Weighted correlation network analysis to identify therapeutic targets gene and candidate bio-markers. RESULTS: 3095 differentially expressed genes were collected from genome expression profiles of OCA patients (n = 53, 35 advanced, 8 early and 10 normal). By pathway enrichment, most genes showed contribution to cell cycle and chromosome maintenance.1073 differentially expression genes involved in the 4 dominant network modules are further generated for prognostic pattern establish, we divided a dataset with random OCA cases (n = 80) into 3 groups efficiently (p = 0.0323, 95% CIs in Kaplan-Meier). Finally, 6 prognosis related genes were selected out by COX regression analysis, TFCP2L1 related to cancer-stem cell, probably contributes to chemotherapy efficiency. CONCLUSIONS: Our study presents an integrated original model of the differentially expression genes related to ovarian cancer progressing, providing the identification of genes relevant for its pathological physiology which can potentially be new clinical markers. PMID- 26228060 TI - Dose-specific effect of simvastatin on hypoxia-induced HIF-1alpha and BACE expression in Alzheimer's disease cybrid cells. AB - BACKGROUND: Alzheimer's disease (AD) is associated with vascular risk factors; brain ischemia facilitates the pathogenesis of AD. Recent studies have suggested that the reduction of AD risk with statin was achieved by decreased amyloidogenic amyloid precursor protein. METHODS: We used mitochondrial transgenic neuronal cell (cybrid) models to investigate changes in the levels of intracellular hypoxia inducible factor 1alpha (HIF-1alpha) and beta-site amyloid precursor protein cleaving enzyme (BACE) in the presence of simvastatin. Sporadic AD (SAD) and age-matched control (CTL) cybrids were exposed to 2% O2 and incubated with 1 MUM or 10 MUM simvastatin. RESULTS: There was no significant difference between cell survival by 1 or 10 MUM simvastatin in both SAD and CTL cybrids. In the presence of 1 MUM simvastatin, intracellular levels of HIF-1alpha and BACE decreased by 40-70% in SAD, but not CTL cybrids. However, 10 MUM simvastatin increased HIF-1alpha and BACE expression in both cybrid models. CONCLUSION: Our results suggest demonstrate differential dose-dependent effects of simvastatin on HIF-1alpha and BACE in cultured Alzheimer's disease cybrid cells. PMID- 26228061 TI - Communication as a Bridge to Build a Sound Doctor-Patient/Parent Relationship. AB - Effective communication is essential to establish a good doctor-patient/parent relationship and practice high quality medicine. It is indeed the key to build confidence, faith and trust of the parents to augment the process of healing. Most parental complaints of dissatisfaction and mismanagement originate due to lack of communication or because of abrasive, cold or callous attitude of the doctor or members of the health care team and not due to lack of knowledge and skills or unsatisfactory management of the patient. The patients and parents must feel all times that they are treated with respect and dignity. We should consider patients as our clients and handle them with due confidence, humility, concern and empathy. It is important to communicate with the parents by literally coming down to their level and by maintaining an eye-to-eye contact. We should not judge, belittle or argue with the parents and handle them with due courtesy and consideration. We should be careful, tactful and diplomatic in deciding not only "what to tell the parents" but also "how to tell it". The parents should be told about the condition of the child in a simple, easy-to-understand language without any medical jargons. We should be pragmatic but honest in communicating the true medical status of the child but nevertheless try to keep the hope alive which has tremendous healing capabilities. We should not allow the technology to further dehumanize medicine and try to resurrect the declining image of the medical profession. It is desirable that all the medical and nursing colleges in the country should initiate regular education programs in the fields of social and behavioral sciences, art of communication and medical ethics for graduate and postgraduate medical and nursing students. PMID- 26228057 TI - Low-grade inflammation, diet composition and health: current research evidence and its translation. AB - The importance of chronic low-grade inflammation in the pathology of numerous age related chronic conditions is now clear. An unresolved inflammatory response is likely to be involved from the early stages of disease development. The present position paper is the most recent in a series produced by the International Life Sciences Institute's European Branch (ILSI Europe). It is co-authored by the speakers from a 2013 workshop led by the Obesity and Diabetes Task Force entitled 'Low-grade inflammation, a high-grade challenge: biomarkers and modulation by dietary strategies'. The latest research in the areas of acute and chronic inflammation and cardiometabolic, gut and cognitive health is presented along with the cellular and molecular mechanisms underlying inflammation-health/disease associations. The evidence relating diet composition and early-life nutrition to inflammatory status is reviewed. Human epidemiological and intervention data are thus far heavily reliant on the measurement of inflammatory markers in the circulation, and in particular cytokines in the fasting state, which are recognised as an insensitive and highly variable index of tissue inflammation. Potential novel kinetic and integrated approaches to capture inflammatory status in humans are discussed. Such approaches are likely to provide a more discriminating means of quantifying inflammation-health/disease associations, and the ability of diet to positively modulate inflammation and provide the much needed evidence to develop research portfolios that will inform new product development and associated health claims. PMID- 26228062 TI - Management of Retropharyngeal Node Metastases from Thyroid Carcinoma. PMID- 26228063 TI - Clinical Usefulness of 5-FU Metabolic Enzymes as Predictive Markers of Response to Chemotherapy in Colorectal Cancer. PMID- 26228064 TI - Growth Hormone Dynamics in Healthy Adults Are Related to Age and Sex and Strongly Dependent on Body Mass Index. AB - BACKGROUND: Studies on 24-hour growth hormone (GH) secretion are rare. The influences of sex, age, and adiposity are well recognized but generally derived from specific, selected subject groups, not spanning sexes, many age decades, and a range of body weights. OBJECTIVE: Our goal was to investigate GH dynamics in a group of 130 healthy adult subjects, both men and women, across 5 age decades as well as a 2.5-fold range of body mass index (BMI) values. METHODS: GH was measured by a sensitive immunofluorometric assay. Secretion parameters were quantified by automated deconvolution and relative pattern randomness by approximate entropy (ApEn). RESULTS: The median age was 40 years (range 20-77). The median BMI was 26 (range 18.3-49.8). Pulsatile 24-hour GH secretion was negatively correlated with age (p = 0.002) and BMI (p < 0.0001). Basal GH secretion negatively correlated with BMI (p = 0.003) but not with age. The sex- dependent GH secretion (greater in women) was no longer detectable after 50 years of age. Insulin-like growth factor (IGF)-1 levels were lower in women over 50 years of age compared with men of a similar age. ApEn showed an age-related increase in both sexes and was higher in premenopausal and postmenopausal women than in men of comparable age (p < 0.0001). A single fasting GH measurement is not informative of 24-hour GH secretion. CONCLUSIONS: BMI dominates the negative regulation of 24-hour GH secretion across 5 decades of age in this up till now largest cohort of healthy adults who underwent 24-hour blood sampling. Sex also impacts GH secretion before the age of 50 years as well as its regularity at all ages. Differences in serum IGF-1 partly depend on the pre- or postmenopausal state. Finally, a single GH measurement is not informative of 24-hour GH secretion. PMID- 26228065 TI - Effect of daily intake of pomegranate juice on fecal microbiota and feces metabolites from healthy volunteers. AB - SCOPE: The purpose of the study was to evaluate the effect, regarding the metabolic and microbial profile of feces, of diet supplementation of healthy adults with pomegranate juice (PJ). METHODS AND RESULTS: Twelve healthy adults were recruited to the study, which consisted of the intake of 200 mL/day of PJ during 4 weeks. Feces were collected before and after the supplementation with PJ. Metabolites (phenolic catabolites, short-chain fatty acids, and fecal steroids) and microbial profile were analyzed at baseline and at 4 weeks. Fecal phenolic metabolites, 3-phenylpropionic acid, catechol, hydroxytyrosol, and urolithin A, showed a significant increase in their concentration after supplementation with PJ. Among fecal steroids, parallel to the significant increase of cholesterol concentration, a significant decrease of coprostanol was observed. Although no significant changes in the microbiota profile were observed, different relationships between initial microbiota and the metabolites produced were found. Catechol showed positive and negative correlation with Oscillospora and Paraprevotella genera, respectively, and 3-phenylpropionic acid was positively correlated with Odoribacter genus. CONCLUSION: Inclusion of PJ in the diet did not significantly alter the gut microbiota composition in healthy adults, but the individual bacterial composition could contribute to the generation of potential health-promoting phenolic metabolites. PMID- 26228067 TI - Historic and contemporary contamination in the marine environment of Kuwait: An overview. AB - The rapid expansion of industry, along with previous pollution events linked to conflicts in the region, have led to a variety of contaminants being inadvertently or deliberately discharged into Kuwait's marine environment. These include polycyclic aromatic hydrocarbons (PAHs) and trace metals, from the petrochemical industry, and contaminated brine from the region's desalination industries. The present paper has reviewed over 60 studies that have reported the levels of contaminants, including PAHs, metals and polychlorinated biphenyls (PCBs) present in seawater, sediment and representative marine organisms. Most of the reviewed literature confirmed that while Kuwait's marine environment has been subjected to a wide array of pollution events, the actual levels of contamination remains relatively low. However, sediment contamination hotspots associated with point sources of industrial contamination, such as originating from the Shuaiba industrial area, do exist at a number of locations around the coast. PMID- 26228068 TI - Metal concentrations in demersal fish species from Santa Maria Bay, Baja California Sur, Mexico (Pacific coast). AB - Concentrations of 11 trace metals (Fe, Mn, Cr, Cu, Ni, Co, Pb, Zn, Cd, As, Hg) in 40 fish species from Santa Maria Bay, Baja California Sur, Mexico, the strategically important area for marine mammals and organisms were analyzed. Based on their concentrations the ranking of metals Fe>Zn>Ni>Cr>Mn>Pb>Cu>Co>As>Cd>Hg suggests that organism size, metabolism and feeding habits are correlated with metal concentrations. Local geological formations affect the concentrations of different metals in the aquatic environment and are subsequently transferred to fishes. The correlation analysis suggests that metabolism and nurturing habits impact the concentration of metals. Concentrations of Fe and Mn appear to be influenced by scavenging and absorption processes, which vary by species. The considerable variability in the metal concentrations obtained in different species underscores the importance of regular monitoring. PMID- 26228069 TI - Trace metals in water, sediment and bivalves of a tropical estuary, west coast of India. AB - Trace metal pollution was studied in water, sediment and three selected bivalves in Mandovi and Chapora estuaries of Goa. The trace metal in water and sediment of Mandovi was higher than in Chapora. The concentration in the tissues was in the range of 1205.2-2506.7 ppm for Paphia malabarica, 1906.2-2802.6 ppm for Perna viridis and 778.7-1607.5 ppm for Saccostrea cucullata in Mandovi estuary. Tha values for Chapora were 199.4-625.8 ppm for P. malabarica, 812.6-1220.2 for P. viridis and 392.5-418.6 ppm for S. cucullata. The anthropogenic input of metal in Mandovi estuary appears to be mainly responsible for the high accumulation of trace metals. These bivalves have potential to serve as indicator for metal contamination in seafood of Goa. PMID- 26228070 TI - Through bleaching and tsunami: Coral reef recovery in the Maldives. AB - Coral reefs are degrading worldwide, but little information exists on their previous conditions for most regions of the world. Since 1989, we have been studying the Maldives, collecting data before, during and after the bleaching and mass mortality event of 1998. As early as 1999, many newly settled colonies were recorded. Recruits shifted from a dominance of massive and encrusting corals in the early stages of recolonisation towards a dominance of Acropora and Pocillopora by 2009. Coral cover, which dropped to less than 10% after the bleaching, returned to pre-bleaching values of around 50% by 2013. The 2004 tsunami had comparatively little effect. In 2014, the coral community was similar to that existing before the bleaching. According to descriptors and metrics adopted, recovery of Maldivian coral reefs took between 6 and 15years, or may even be considered unachieved, as there are species that had not come back yet. PMID- 26228071 TI - Microbial water quality and sedimentary faecal sterols as markers of sewage contamination in Kuwait. AB - Microbial water quality and concentrations of faecal sterols in sediment have been used to assess the degree of sewage contamination in Kuwait's marine environment. A review of microbial (faecal coliform, faecal streptococci and Escherichia coli) water quality data identified temporal and spatial sources of pollution around the coastline. Results indicated that bacterial counts regularly breach regional water quality guidelines. Sediments collected from a total of 29 sites contained detectable levels of coprostanol with values ranging from 29 to 2420 ng g(-1) (dry weight). Hot spots based on faecal sterol sediment contamination were identified in Doha Bay and Sulaibikhat Bay, which are both smaller embayments of Kuwait Bay. The ratio of epicoprostanol/coprostanol indicates that a proportion of the contamination was from raw or partially treated sewage. Sewage pollution in these areas are thought to result from illegal connections and discharges from storm drains, such as that sited at Al Ghazali. PMID- 26228072 TI - Spatial distribution of some trace and major elements in sediments of the Cavado estuary (Esposende, Portugal). AB - For the first time, the occurrence and spatial distribution of several elements, including some toxic metals, have been investigated in sediments of the estuary of the Cavado River (Esposende, Portugal). The pseudo total concentrations of Al, As, Cd, Co, Cr, Cu, Fe, Mg, Mn, Ni, Pb, Sn, V and Zn in sediments collected at 24 sites covering the tidal part of the estuary were determined. According to the concentrations measured, the Cavado estuary can be considered as non contaminated. For most of the elements, the concentrations tended to be higher upstream. Only a moderate enrichment in Cr and Ni was detected in a few sites. An important decrease in concentration was observed for the most toxic metals compared to historical data reported in the literature. Several hotspots were identified, but even in those cases the amount of metals stored in the sediments does not represent a toxicological threat to living organisms. PMID- 26228073 TI - Protective Role of Sodium-Glucose Co-Transporter 2 Inhibition Against Vascular Complications in Diabetes. AB - Diabetic micro- and macroangiopathy are devastating vascular complications that could account for disabilities and high mortality rate in patients with diabetes. Indeed, diabetic nephropathy and retinopathy are the leading causes of end-stage renal failure and acquired blindness, respectively, and atherosclerotic cardiovascular diseases (CVD) accounts for about 60% of death in diabetic subjects. As a result, the average life span of diabetic patients is about 10-15 years shorter than that of non-diabetic subjects. Furthermore, tight blood glucose control might have no more than a marginal impact on CVD in general and on all-cause mortality in particular in diabetes. Therefore, therapeutic strategies that target vascular complications in diabetes need to be developed. Recently, selective inhibition of sodium-glucose co-transporter 2 (SGLT2) has been proposed as a potential therapeutic target for the treatment of patients with diabetes because of low risk of hypoglycemia and no weight gain. Because 90% of glucose filtered by the glomerulus is reabsorbed by a low-affinity/high capacity SGLT2 expressed in the S1 and S2 segments of the proximal tubule, blockade of SGLT2 promotes urinary glucose excretion and as a result improves hyperglycemia in an insulin-independent manner. Moreover, we have shown that SGLT2-mediated glucose overload to tubular cells could elicit inflammatory and pro-apoptotic reactions in this cell, being directly involved in diabetic nephropathy. In addition, several clinical studies have also shown that SGLT2 inhibitors could reduce blood pressure, body weight, and serum uric acid levels and ameliorate cardiovascular risk in patients with diabetes. This review summarizes the pathophysiological role of SGLT2 in vascular complications in diabetes and its potential therapeutic interventions. PMID- 26228074 TI - RNAseq analysis of fast skeletal muscle in restriction-fed transgenic coho salmon (Oncorhynchus kisutch): an experimental model uncoupling the growth hormone and nutritional signals regulating growth. AB - BACKGROUND: Coho salmon (Oncorhynchus kisutch) transgenic for growth hormone (Gh) express Gh in multiple tissues which results in increased appetite and continuous high growth with satiation feeding. Restricting Gh-transgenics to the same lower ration (TR) as wild-type fish (WT) results in similar growth, but with the recruitment of fewer, larger diameter, muscle skeletal fibres to reach a given body size. In order to better understand the genetic mechanisms behind these different patterns of muscle growth and to investigate how the decoupling of Gh and nutritional signals affects gene regulation we used RNA-seq to compare the fast skeletal muscle transcriptome in TR and WT coho salmon. RESULTS: Illumina sequencing of individually barcoded libraries from 6 WT and 6 TR coho salmon yielded 704,550,985 paired end reads which were used to construct 323,115 contigs containing 19,093 unique genes of which >10,000 contained >90 % of the coding sequence. Transcripts coding for 31 genes required for myoblast fusion were identified with 22 significantly downregulated in TR relative to WT fish, including 10 (vaspa, cdh15, graf1, crk, crkl, dock1, trio, plekho1a, cdc42a and dock5) associated with signaling through the cell surface protein cadherin. Nineteen out of 44 (43 %) translation initiation factors and 14 of 47 (30 %) protein chaperones were upregulated in TR relative to WT fish. CONCLUSIONS: TR coho salmon showed increased growth hormone transcripts and gene expression associated with protein synthesis and folding than WT fish even though net rates of protein accretion were similar. The uncoupling of Gh and amino acid signals likely results in additional costs of transcription associated with protein turnover in TR fish. The predicted reduction in the ionic costs of homeostasis in TR fish associated with increased fibre size were shown to involve multiple pathways regulating myotube fusion, particularly cadherin signaling. PMID- 26228075 TI - Self-Assembled Nanocomposite Organic Polymers with Aluminum and Scandium as Heterogeneous Water-Compatible Lewis Acid Catalysts. AB - While water-compatible Lewis acids have great potential as accessible and environmentally benign catalysts for various organic transformations, efficient immobilization of such Lewis acids while keeping high activity and without leaching of metals even under aqueous conditions is a challenging task. Self assembled nanocomposite catalysts of organic polymers, carbon black, aluminum reductants, and scandium salts as heterogeneous water-compatible Lewis acid catalysts are described. These catalysts could be successfully applied to various C-C bond-forming reactions without leaching of metals. Scanning transmission electron microscopy analyses revealed that the nanocomposite structure of Al and Sc was fabricated in these heterogeneous catalysts. It is noted that Al species, which are usually decomposed rapidly in the presence of water, are stabilized under aqueous conditions. PMID- 26228076 TI - Surgical resection versus ablation for hepatocellular carcinoma <= 3 cm: a population-based analysis. AB - BACKGROUND: Ablation for <= 3-cm hepatocellular carcinoma (HCC) has been demonstrated to be an effective treatment strategy. The present study sought to examine the outcomes of patients with <=3 cm HCC after ablation versus resection. METHODS: Patients treated by ablation or surgical resection for <= 3 cm T1 HCC were identified from the National Cancer Database (2002-2011). Survival outcomes were analysed according to propensity score modelling. RESULTS: A total of 2804 patients underwent ablation (n = 1984) or a resection (n = 820) for solitary HCC <= 3 cm. Patients treated with ablation as compared with a resection had a higher frequency in alpha-fetoprotein level (AFP) elevation (46.5% versus 39.1%, P < 0.01) and the presence of cirrhosis (22.2% versus 14.5%, P < 0.01). Unadjusted overall survival (OS) at 3 and 5 years was greater after a resection (67%, 55%) versus ablation (52%, 36%, P < 0.01). After propensity score matching, the improved overall survival (OS) was sustained among the resection cohort (5 year OS: 54% versus 37%, P < 0.001). In multivariable models, a resection was independently associated with an improved OS [hazard ratio (HR): 0.62, 95% confidence interval (CI): 0.48-0.81; P < 0.01]. CONCLUSION: Resection of HCC <= 3 cm results in better long-term survival as compared with ablation. Treatment strategies for small solitary HCC should emphasize a resection first approach, with ablation being reserved for patients precluded from surgery. PMID- 26228077 TI - Historical classics: Editorial. PMID- 26228078 TI - Does ulnar nerve dislocation at the elbow cause neuropathy? AB - INTRODUCTION: The role of ulnar nerve dislocation in the pathogenesis of ulnar neuropathy at the elbow (UNE) is not clear. Data exist for and against a causal relationship. METHODS: We studied UNE patients and controls divided into 4 groups consisting of 203 UNE patient arms (185 with abnormal and 18 with normal diagnostic studies) and 49 controls (10 with abnormal and 39 with normal studies). In all arms we performed neurologic examination, short-segment nerve conduction studies (SSNCS), and ultrasonography (US). The frequency of partial and complete nerve dislocation was calculated in each group. RESULTS: Dislocation tended to be more common in controls compared with UNE patients (P = 0.056). It was particularly common in controls with subclinical UNE and patients with UNE symptoms but normal diagnostic studies. CONCLUSION: Our data speak against a causal relationship between ulnar nerve dislocation and UNE. However, the findings also suggest that dislocation may cause mild ulnar nerve damage. PMID- 26228079 TI - Recruitment strategies and patient selection in clinical trials for Parkinson's disease: Going viral and keeping science and ethics at the highest standards. AB - INTRODUCTION: Enrollment of an adequate number of suitable candidates is a critical component of good quality randomized controlled trials (RCTs). Parkinson's disease (PD) is a highly heterogeneous disease and recruiting a large and homogeneous sample of patients is often challenging. Further, PD patients are often elderly, cognitively impaired and disabled, thus requiring the assistance from their caregivers for participation in RCTs. Only a limited number of studies have explored the effectiveness of recruitment strategies and PD patient selection in clinical trials. We aim to review the four crucial recruitment components of RCTs (i.e. infrastructure, nature of the research, recruiter characteristics and participant characteristics) with particular implications in PD, and to explore strategies to improve recruitment and patient selection in RCTs in PD. CONCLUSION: Movement disorders centers have a key role in managing recruitment and patient selection in RCTs in PD. Key recommendations within the infrastructure component are to improve trust and communication between patient and participant, and to consider the diversity, perceived disadvantages, and health care accessibility of the participants. Further, study designs that involve participant's opinions and considers placebo and lessebo effects are highly recommended for the nature of the research component of RCTs. Finally, a team-based approach with recruiters and participants that establishes relationships between researchers and the community and addresses ethical considerations are encouraged as part of the recruiters and participants components. Finally, we envisage a greater usage of internet-based strategies for clinical trials recruitment in PD with the goal of 'going viral' with the recruitment. PMID- 26228080 TI - Prospective study on the components of metabolic syndrome and the incidence of Parkinson's disease. AB - INTRODUCTION: Inconsistent results regarding the association between the components of metabolic syndrome and Parkinson's disease (PD) have been reported. We investigated whether the metabolic syndrome or its components, or serum total cholesterol, predict PD incidence in a prospective cohort study design. METHODS: The study was based on the Mini-Finland Health Survey including 6641 individuals aged 30-79 and free from PD at baseline (1978-1980). During 30 years of follow up, 89 incident PD cases occurred. RESULTS: After adjustment for sociodemographic and lifestyle factors, the relative risk (RR) of PD was 0.50 (95% confidence interval (CI): 0.30, 0.83) for individuals with the metabolic syndrome compared to those without. This association was especially due to elevated serum triglyceride concentration (>=1.7 vs.<1.7 mmol/L, RR = 0.52, 95%CI: 0.30-0.89, P for trend 0.02) and elevated plasma fasting glucose concentration (>=5.6 vs.<5.6 mmol/L, RR = 0.56 0.32, 0.98, P for trend 0.05). Elevated serum triglyceride and plasma fasting glucose concentration predicted lower PD risk even after excluding the first 10 years of follow-up. After this exclusion and further adjustment for other components of the metabolic syndrome, a suggestively increased PD risk was observed in overweight individuals (>=25 kg/m(2) vs.<25 kg/m(2), RR = 1.75, 95%CI: 1.00, 3.07, P for trend 0.22). Blood pressure, serum HDL cholesterol, or serum total cholesterol carried no prediction of PD risk. CONCLUSION: Elevated serum triglyceride and plasma fasting glucose concentrations predict low PD incidence whereas high BMI seems to be suggestively related to an increased PD risk. PMID- 26228083 TI - The association between fatigue and apathy in patients with either Parkinson's disease or multiple sclerosis. AB - OBJECTIVE: Fatigue and apathy are common symptoms in both multiple sclerosis (MS) and Parkinson's disease (PD). Both symptoms are considered "amotivational"- fatigue is a lack of energy to start or complete an action and apathy is a loss of interest in activities. Whether the two symptoms are related to each other is not known. The present study sought to investigate the prevalence and severity of fatigue and apathy in MS and PD, and the relationship between the two. METHODS: The Fatigue Severity Scale (FSS) and the Apathy Scale (AS) were administered to 89 consecutive PD and 73 consecutive MS subjects. RESULTS: The mean FSS score for PD subjects was 4.46 and 5.01 for MS; the average total AS score for PD was 12.4 and 12.5 for MS. Using a cutoff of >4.0 on the FSS to assess fatigue, 64% of PD subjects and 74% of MS subjects suffered from severe fatigue. Using an AS cutoff score of >14.0 to determine apathy, 57% of PD subjects and 52% of MS subjects were apathetic. There was a significant correlation between FSS score and AS score in both disorders. FSS average scores and AS total scores were significantly correlated with motor severity in PD but not in MS. Duration of disease was not correlated with either scale scores in either disorder. DISCUSSION: Results confirm that AS and FSS are correlated with each other in both disorders and that MS subjects rate their fatigue significantly higher. PMID- 26228084 TI - Trainee-therapists are not all equal: Examination of therapeutic efficiency, effectiveness and early client dropout after 12 months of clinical training. AB - OBJECTIVE: Contemporary research demonstrates the feasibility of assessing therapeutic performance of trainee-therapists through the use of objective measures of client treatment outcome. Further, significant variation between individual therapists based on their client treatment outcomes has been demonstrated. This study sets out to determine whether a reliable composite measure of therapeutic efficiency, effectiveness and early dropout can be developed and used to objectively compare trainee-therapists against each other. DESIGN AND METHODS: Treatment outcomes of 611 clients receiving treatment from 58 trainee-therapists enrolled in a professional training programme were tracked with the OQ-45.2 over a 6-year period to assess therapeutic efficiency, therapeutic effectiveness and early client dropout. RESULTS: Significant variation between trainee-therapists was observed for each index. Findings of a moderately strong correlation between therapeutic efficiency and effectiveness enabled the ranking of trainee-therapists based upon a composite measure of these indexes. A non-significant correlation was found between early client dropout and measures of therapeutic effectiveness and efficiency. CONCLUSIONS: The findings stress the importance of utilizing objective measures to track the treatment outcomes. Despite all trainee-therapists being enrolled in the same training programme, significant variation between trainee-therapists' therapeutic efficiency and effectiveness was found to exist. PRACTITIONER POINTS: Developing of potential benchmarking tools that enable trainee-therapists, supervisors and educational institutions to quickly assess therapeutic performance can become part of a holistic assessment of a trainee-therapist's clinical development. Despite an inherent optimistic belief that therapists do not cause harm, there appears to be a small and significant proportion of trainee-therapists who consistently evidence little therapeutic change. Considerable variability in trainee-therapists' therapeutic efficiency and effectiveness can exist in the one training programme. Early client dropout may not be associated with therapists' therapeutic effectiveness and efficiency. PMID- 26228081 TI - Haptoglobin phenotype modifies serum iron levels and the effect of smoking on Parkinson disease risk. AB - INTRODUCTION: Haptoglobin is a hemoglobin-binding protein that exists in three functionally different phenotypes, and haptoglobin phenotype 2-1 has previously been associated with Parkinson disease (PD) risk, with mechanisms not elucidated. Some evidence is emerging that low levels of serum iron may increase PD risk. In this study we investigated whether PD patients have lower serum iron and ferritin than controls, and whether this is dependent on haptoglobin phenotype. We also investigated the effect of Hp phenotype as a modifier of the effect of smoking on PD risk. METHODS: The study population consisted of 128 PD patients and 226 controls. Serum iron, ferritin, and haptoglobin phenotype were determined, and compared between PD cases and controls. Stratified analysis by haptoglobin phenotype was performed to determine effect of haptoglobin phenotype on serum iron parameter differences between PD cases and controls and to investigate its role in the protective effect of smoking on PD risk. RESULTS: PD cases had lower serum iron than controls (83.28 ug/100 ml vs 94.00 ug/100 ml, p 0.006), and in particular among subjects with phenotype 2-1. The protective effect of smoking on PD risk resulted stronger in subjects with phenotype 1-1 and 2-2, and weakest among subjects with phenotype 2-1. Ferritin levels were higher in PD cases than controls among subjects of White ethnicity. CONCLUSIONS: Our results report for the first time that the haptoglobin phenotype may be a contributor of iron levels abnormalities in PD patients. The mechanisms for these haptoglobin-phenotype specific effects will have to be further elucidated. PMID- 26228086 TI - Why do we need evidence-based methods in Cochrane? PMID- 26228085 TI - MicroRNA-320a acts as a tumor suppressor by targeting BCR/ABL oncogene in chronic myeloid leukemia. AB - Accumulating evidences demonstrated that the induction of epithelial-mesenchymal transition (EMT) and aberrant expression of microRNAs (miRNAs) are associated with tumorigenesis, tumor progression, metastasis and relapse in cancers, including chronic myeloid leukemia (CML). We found that miR-320a expression was reduced in K562 and in CML cancer stem cells. Moreover, we found that miR-320a inhibited K562 cell migration, invasion, proliferation and promoted apoptosis by targeting BCR/ABL oncogene. As an upstream regulator of BCR/ABL, miR-320a directly targets BCR/ABL. The enhanced expression of miR-320a inhibited the phosphorylation of PI3K, AKT and NF-kappaB; however, the expression of phosphorylated PI3K, AKT and NF-kappaB were restored by the overexpression of BCR/ABL. In K562, infected with miR-320a or transfected with SiBCR/ABL, the protein levels of fibronectin, vimentin, and N-cadherin were decreased, but the expression of E-cadherin was increased. The expression of mesenchymal markers in miR-320a-expressing cells was restored to normal levels by the restoration of BCR/ABL expression. Generally speaking, miR-320a acts as a novel tumor suppressor gene in CML and miR-320a can decrease migratory, invasive, proliferative and apoptotic behaviors, as well as CML EMT, by attenuating the expression of BCR/ABL oncogene. PMID- 26228087 TI - Quantitation of enniatins in biological samples of Wistar rats after oral administration by LC-MS/MS. AB - The emerging Fusarium mycotoxins enniatins (ENNs) have diverse biological properties, mainly due to their ionophoric activity, and represent a potential risk to human and animal health since they are commonly found in food and feed. In vivo toxicity studies are scarce and limited to the major mycotoxins. Until now, any method for the simultaneous analysis of these compounds in plasma, serum and feces from rat has been reported. A method for the extraction and determination of ENNs A, A1, B and B1 from Wistar rat samples by liquid chromatography tandem mass spectrometry has been developed. The method was successfully validated with satisfactory recoveries (70-106%), good intraday (<10%) and interday (<20%) precision, expressed as relative standard deviation, and good linearity between limits of quantitation (LOQ) and 100 times LOQ. Limits of detection (LOD) and LOQ were <=1 and <=10 ng/ml, respectively. The validated method was applied for the analysis of biological Wistar rat samples that were administered a mixture of ENNs containing 1.19, 2.16, 1.03 and 1.41 mg/kg body weight of ENN A, A1, B and B1, respectively. Blood, urine and feces samples collected every 2 h during the 8-h duration of the experiment were analyzed. The administered dose of the mixture of ENNs did not cause observable adverse effects on the animals. ENNs concentrations detected in serum and urine were below LOQs. The four ENNs were detected in feces reaching the maximum concentration at 6 h after administration. PMID- 26228088 TI - Dual fluorescent protein-based bioassay system for the detection of genotoxic chemical substances in Saccharomyces cerevisiae. AB - A new reporter system has been developed for quantifying the activity of potentially DNA-damaging substances in the yeast Saccharomyces cerevisiae. The system relies on two different reporter genes, yEGFP and DsRed-Express2, to screen for DNA-damaging chemicals. The yEGFP gene is fused to the test promoter of RNR2, whose measurable signal has a dose-dependent relationship with DNA damage. The gene encoding DsRed-Express2 is fused to a constitutive promoter of GPD, providing an internal control for normalizing cell numbers in the assay. The dual fluorescent protein assay system is performed by sequentially measuring the yEGFP and DsRed-Express2 fluorescent intensity of the same sample, with the results expressed as the ratio of yEGFP to DsRed-Express2 intensity (yEGFP/DsRed Express2). The yeast fluorescent protein reporter assay was performed in 96-well microtiter plates in the presence of different concentrations of test substances, which were then characterized. The assay was very efficient, high-throughput, and amenable to full automation. Here, we demonstrate that this system can be used as a biosensor to assess the genotoxic potential of drugs and other chemical substances. PMID- 26228089 TI - Effect of mesoporous silica nanoparticles on cell viability and markers of oxidative stress. AB - In the recent years, the use of mesoporous silica nanoparticles (MSNs) has been extended in biomedical fields such as cancer therapy, drug and gene delivery, biosensors, and enzyme immobilization. Although nanomaterials are currently being widely used in modern technology, there is a lack of information regarding to the health and environmental implications of manufactured nanomaterials. In the present study, the effects of MSNs and surface functionalized MSNs on cell viability, markers of oxidative damages (mainly intracellular reactive oxygen species (ROS) formation), and oxidative DNA damage were investigated in vitro in rat pheochromocytoma PC12 cells. Following exposure of these nanoparticles (1.95 1000 ug/mL) to PC12 cells for 12 and 24 h, no significant reduction of cell viability was observed compared with control. Moreover, ROS formation and oxidative DNA damage were not significantly changed by these nanoparticles even at high concentrations or prolong exposures. In conclusion, the results showed that neither MSNs nor functionalized MSNs exhibited any remarkable in vitro toxic properties in PC12 cells even at high concentration. PMID- 26228090 TI - Activation of protein kinase C and protein kinase D in human natural killer cells: effects of tributyltin, dibutyltin, and tetrabromobisphenol A. AB - Up to now, the ability of target cells to activate protein kinase C (PKC) and protein kinase D (PKD) (which is often a downstream target of PKC) has not been examined in natural killer (NK) lymphocytes. Here we examined whether exposure of human NK cells to lysis sensitive tumor cells activated PKC and PKD. The results of these studies show for the first time that activation of PKC and PKD occurs in response to target cell binding to NK cells. Exposure of NK cells to K562 tumor cells for 10 and 30 min increased phosphorylation/activation of both PKC and PKD by roughly 2-fold. Butyltins (tributyltin (TBT), dibutyltin (DBT)) and brominated compounds (tetrabromobisphenol A (TBBPA)) are environmental contaminants that are found in human blood. Exposures of NK cells to TBT, DBT, or TBBPA decrease NK cell lytic function in part by activating the mitogen-activated protein kinases (MAPKs) that are part of the NK lytic pathway. We established that PKC and PKD are part of the lytic pathway upstream of MAPKs and thus we investigated whether DBT, TBT, and TBBPA exposures activated PKC and PKD. TBT-activated PKC by 2-3 folds at 10 min at concentrations ranging from 50 to 300 nM while DBT caused a 1.3-fold activation at 2.5 uM at 10 min. Both TBT and DBT caused an approximately 2-fold increase in phosphorylation/activation of PKC. Exposures to TBBPA caused no statistically significant changes in either PKC or PKD activation. PMID- 26228091 TI - The Krushinsky-Molodkina rat strain: The study of audiogenic epilepsy for 65years. AB - The more recent history and main experimental data for the Krushinsky-Molodkina (KM) audiogenic rat strain are presented. The strain selection started in late 1940. Now this strain is inbred, and two new strains are maintained in a laboratory in parallel. These strains originated from KM*Wistar hybrids and were bred (starting from 2000) for no-seizure and intense audiogenic seizure phenotypes, respectively. The experimental evidences of audiogenic seizure physiology were accumulated in parallel with (and usually ahead of) data on other audiogenic-prone strains. The peculiar feature of the KM strain is its vulnerability to brain hemorrhages. Thus, the KM strain is used not only as a genetic model of seizure states, but also as a model of blood flow disturbances in the brain. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic". PMID- 26228092 TI - Apoptosis and reduced microvascular density of the lamina propria during tooth eruption in rats. AB - During tooth eruption, structural and functional changes must occur in the lamina propria to establish the eruptive pathway. In this study, we evaluate the structural changes that occur during lamina propria degradation and focus these efforts on apoptosis and microvascular density. Fragments of maxilla containing the first molars from 9-, 11-, 13- and 16-day-old rats were fixed, decalcified and embedded in paraffin. The immunohistochemical detection of vascular endothelial growth factor (VEGF), caspase-3 and MAC387 (macrophage marker), and the TUNEL method were applied to the histological molar sections. The numerical density of TUNEL-positive cells and VEGF-positive blood vessel profiles were also obtained. Data were statistically evaluated using a one-way anova with the post hoc Kruskal-Wallis or Tukey test and a significance level of P <= 0.05. Fragments of maxilla were embedded in Araldite for analysis under transmission electron microscopy (TEM). TUNEL-positive structures, fibroblasts with strongly basophilic nuclei and macrophages were observed in the lamina propria at all ages. Using TEM, we identified processes of fibroblasts or macrophages surrounding partially apoptotic cells. We found a high number of apoptotic cells in 11-, 13- and 16-day old rats. We observed VEGF-positive blood vessel profiles at all ages, but a significant decrease in the numerical density was found in 13- and 16-day-old rats compared with 9-day-old rats. Therefore, the establishment of the eruptive pathway during the mucosal penetration stage depends on cell death by apoptosis, the phagocytic activity of fibroblasts and macrophages, and a decrease in the microvasculature due to vascular cell death. These data point to the importance of vascular rearrangement and vascular neoformation during tooth eruption and the development of oral mucosa. PMID- 26228093 TI - Safe and symptomatic medicinal use of surface-functionalized Mn3O4 nanoparticles for hyperbilirubinemia treatment in mice. AB - AIM: Testing the potential of citrate-capped Mn3O4 nanoparticles (NPs) as a therapeutic agent for alternative rapid treatment of hyperbilirubinemia through direct removal of bilirubin (BR) from blood in mice. MATERIALS & METHODS: NPs were synthesized and the mechanism of BR degradation in presence and absence of biological macromolecules were characterized in vitro. To test the in vivo BR degradation ability of NPs, CCl4-intoxicated mice were intraperitoneally injected with NPs. RESULTS: We demonstrated ultrahigh efficacy of the NPs in symptomatic treatment of hyperbilirubinemia for rapid reduction of BR in mice compared with conventional medicine silymarin without any toxicological implications. CONCLUSION: These findings may pave the way for practical clinical use of the NPs as safe medication of hyperbilirubinemia in human subjects. PMID- 26228094 TI - The Effect of Small Oligomeric Protein Aggregates on the Immunogenicity of Intravenous and Subcutaneous Administered Antibodies. AB - The role of aggregates in the immunogenicity of biologics is a major concern. A recent US FDA guidance on the issue suggests that a gap in knowledge exists regarding the type and size of aggregates involved in the immunogenicity of biologics. Furthermore, the guidance suggests that current techniques cannot capture the crucial stages of protein aggregation. Using a protein unfolding model developed earlier, we generated and classified aggregates of two therapeutic antibodies based on size and conformation. The immunogenic potential of these aggregates were then tested in a murine model. Our findings show that small native-like oligomeric aggregates (<100 nm) are more immunogenic toward the native protein than monomer and large non-native aggregates in the micron-size range, irrespective of route of administration [intravenous (i.v.) vs. subcutaneous (s.c.)]. Those smaller oligomeric aggregates represented 5%-20% of the total protein concentration in the test formulations. Furthermore, in vitro data suggest that TNF-alpha production by bone marrow-derived dendritic cells could serve as a predictive marker for increased immunogenic risk of aggregates after s.c. administration. The use of orthogonal techniques such as fluorescence anisotropy and quasielastic light scattering may be useful to detect these oligomeric aggregates. PMID- 26228095 TI - Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a rare but progressive and currently incurable disease, which is characterized by vascular remodeling in association with muscularization of the arterioles, medial thickening and plexiform lesion formation. Despite our advanced understanding of the pathogenesis of PAH and the recent therapeutic advances, PAH still remains a fatal disease. In addition, the susceptibility to PAH has not yet been adequately explained. Much evidence points to the involvement of epigenetic changes in the pathogenesis of a number of human diseases including cancer, peripheral hypertension and asthma. The knowledge gained from the epigenetic study of various human diseases can also be applied to PAH. Thus, the pursuit of novel therapeutic targets via understanding the epigenetic alterations involved in the pathogenesis of PAH, such as DNA methylation, histone modification and microRNA, might be an attractive therapeutic avenue for the development of a novel and more effective treatment. This review provides a general overview of the current advances in epigenetics associated with PAH, and discusses the potential for improved treatment through understanding the role of epigenetics in the development of PAH. PMID- 26228096 TI - Short-term white matter alterations in Alzheimer's disease characterized by diffusion tensor imaging. AB - PURPOSE: To investigate whether there are any white matter changes in a 6-month follow-up of mild-moderate Alzheimer's patients using diffusion tensor imaging (DTI). MATERIALS AND METHODS: We recruited 18 mild-moderate Alzheimer's disease patients and they underwent magnetic resonance imaging (MRI) at recruitment and at 6-month follow-up. Diffusion MRI images were processed using DTI-ToolKit to create a population-based tensor template. This template was integrated with a voxel-wise and atlas-based analysis in FSL to determine the magnitude and location of change in diffusion metrics over the 6-month follow-up period. RESULTS: There were significant widespread changes in diffusion metrics across the entire white matter skeleton (P < 0.001), 95% confidence interval (CI) difference in fractional anisotropy: -0.007 (-0.011, -0.002), mean diffusivity: 0.040 (0.023, 0.058), axial diffusivity: 0.015 (0.008, 0.022), radial diffusivity: 0.012 (0.006, 0.019), as well as regions of interest in the splenium and superior longitudinal fasciculus. CONCLUSION: Our findings show that diffusion metrics are altered in a 6-month follow-up period of mild-moderate Alzheimer's patients, supporting the potential of DTI metrics to act as sensitive biomarkers for disease progression even over a relatively short time interval, and the potential utility to be applied to clinical trials of putative disease modifying therapies. PMID- 26228097 TI - Randomised clinical trial: the clinical efficacy and safety of an alginate antacid (Gaviscon Double Action) versus placebo, for decreasing upper gastrointestinal symptoms in symptomatic gastroesophageal reflux disease (GERD) in China. AB - BACKGROUND: There is a paucity of large-scale studies evaluating the clinical benefit of the Gaviscon Double Action (DA) alginate-antacid formulation for treating gastroesophageal reflux disease (GERD) symptoms. AIM: Randomised double blind placebo-controlled parallel-group study to evaluate efficacy and safety of Gaviscon DA in reducing heartburn, regurgitation and dyspepsia symptoms in individuals with mild-to-moderate GERD in China. METHODS: Participants with symptomatic GERD (n = 1107) were randomised to receive Gaviscon DA or placebo (two tablets four times daily) for seven consecutive days. The primary endpoint compared the change in Reflux Disease Questionnaire (RDQ) score for the GERD (heartburn + regurgitation) dimension between Gaviscon DA and placebo. Secondary endpoints compared the change in RDQ scores for individual heartburn, regurgitation and dyspepsia dimensions, overall treatment evaluation (OTE) scores and incidence of adverse events (AEs). RESULTS: Mean RDQ GERD scores: 2.51 for Gaviscon DA and 2.50 for placebo at baseline; 1.25 for Gaviscon DA and 1.46 for placebo post treatment. Gaviscon DA was statistically superior to placebo in reducing GERD and dyspepsia RDQ scores [least-squares mean (LSM) difference: GERD -0.21, P < 0.0001; dyspepsia -0.18, P = 0.0004], despite a substantial placebo response. The Gaviscon DA group reported more favourable overall treatment responses than the placebo group across all OTE categories (P < 0.0001). Superior relief of GERD symptoms was observed both in those with non-erosive and those with erosive reflux disease (LSM difference -0.14 [P = 0.038] and -0.29 [P < 0.0001] respectively). Incidence of AEs was similar in both groups. CONCLUSION: Gaviscon DA tablets provide effective and safe reduction in acid reflux and dyspepsia symptoms in Chinese individuals with mild-to-moderate GERD. ClinicalTrials.gov: NCT01869491. PMID- 26228098 TI - A preoperative metabolic marker of parkinsonian apathy following subthalamic nucleus stimulation. AB - BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) has been associated with the development of postoperative apathy. Debate on the causes of postoperative apathy continues, and the dominant hypothesis is that stimulation or dopaminergic drug reductions are causal in its development. We hypothesized that a preoperative predisposition to apathy also could exist. To this end, we sought to identify a preoperative metabolic pattern using [(18)]Fluorodeoxyglucose Positron Emission Tomography (PET), which could be associated with the occurrence of postoperative apathy after STN-DBS for PD. METHODS: Thirty-four patients with PD, not clinically apathetic, underwent an [(18)]Fluorodeoxyglucose-PET scan before surgery of STN-DBS, and were tested for the occurrence of apathy 1 y after surgery. Whole-brain voxel-based PET intergroup comparison (P < 0.005; corrected for the cluster) was evaluated between patients who developed apathy at 1 y and those who did not. RESULTS: Eight patients (23.5%) became apathetic after surgery. Motor improvement and decrease in dopaminergic treatment were similar in both postoperative apathy and non-apathy groups. We found a cluster of significantly greater metabolism in the postoperative apathy group within the cerebellum, brainstem (in particular ventral tegmental area), temporal lobe, insula, amygdala, lentiform nucleus, subgenual anterior cingulate, and inferior frontal gyrus. A metabolic value above 68 could discriminate patients who would develop postoperative apathy with 100% sensitivity and 88.5% specificity. CONCLUSIONS: We describe a preoperative metabolic pattern associated with the development of apathy after STN-DBS in PD. This suggests the existence of a predisposition to apathy, which may further be triggered by perioperative drug modifications. PMID- 26228099 TI - Retraction Statement. Paper by Iso et al. Entitled 'Preoperative Neutrophil-to Lymphocyte Ratio for Prognostication of Patients with Distal Bile Duct Carcinomas Undergoing Surgery' Dig Surg 2015;32:142-149. PMID- 26228103 TI - Lessons learned from yet another case of fake science. PMID- 26228100 TI - Associations between Exposure to Persistent Organic Pollutants in Childhood and Overweight up to 12 Years Later in a Low Exposed Danish Population. AB - BACKGROUND: Persistent organic pollutants (POPs) have metabolic disrupting abilities and are suggested to contribute to the obesity epidemic. We investigated whether serum concentrations of POPs at 8-10 years of age were associated with subsequent development of overweight at age 14-16 and 20-22 years. METHODS: The study was based on data from the European Youth Heart Study, Danish component (1997). Concentrations of several polychlorinated biphenyls (PCBs) and the organochlorine pesticides p,p-dichlorodiphenyldichloroethylene (DDE) and hexachlorobenzene (HCB) were measured in serum from children aged 8-10 years (n = 509). Information on BMI z-scores, waist circumference and % body fat were collected at clinical examinations at ages 8-10, 14-16 and 20-22 years. Multiple linear regression analyses were performed taking potential confounders into account. RESULTS: Overall, POP serum concentrations were low: median SigmaPCB 0.18 ug/g lipid, DDE 0.04 ug/g lipid and HCB 0.03 ug/g lipid. POPs were generally not associated with weight gain at 14-16 and 20-22 years of age, except for an inverse association among the highest exposed girls at 20-22 years of age, which might possibly be explained by multiple testing or residual confounding. CONCLUSION: This study suggests that, in a low exposed population, childhood serum concentrations of PCB, DDE, and HCB are not associated with subsequent weight gain. PMID- 26228104 TI - Use of FTA technology for detection of Trichomonas gallinae. AB - Trichomonas gallinae is the causative agent for avian trichomonosis, which can have important population implications for domestic turkeys, columbids, raptors, and various passeriformes. Continued population surveillance and genotype distribution is needed to elucidate transmission dynamics and prevalence of T. gallinae among free-ranging birds. However, obtaining live cultures for laboratory testing is logistically challenging, limiting the ability to perform surveillance and genotype investigations. In this study, we evaluated non indicating FTA Elute cards as a potential sampling storage substrate for downstream use in molecular identification of two T. gallinae isolates. Isolate concentrations of 10 or 100 trichomonads/40 MUl were inoculated onto a FTA Elute card in triplicate. At each time point (48 h, 2 weeks, and 3 weeks), DNA elution procedures were performed on the cards, and the eluents were analyzed by conventional polymerase chain reaction (PCR) using trichomonad-specific primers. Three PCR-positive samples were detected at 48 h from one isolate; however, all eluents from cards held for 2 and 3 weeks were PCR-negative. Our results suggest that use of FTA Elute cards for nucleic acid storage can lead to low PCR sensitivity of T. gallinae in low concentrations, such as those found in non clinical birds; however, more research is needed to fully evaluate the efficacy of FTA Elute cards as a diagnostic tool for T. gallinae. PMID- 26228105 TI - Polymeric Micelles of PEG-PLA Copolymer as a Carrier for Salinomycin Against Gemcitabine-Resistant Pancreatic Cancer. AB - PURPOSE: Resistance to gemcitabine in pancreatic cancer (PC) may account for the failure of conventional treatments. Recently, salinomycin (SAL) has been identified as selective inhibitor of cancer stem cells (CSCs). In our study, we aimed to deliver SAL to gemcitabine-resistant PC by the aid of poly ethylene glycol-b-poly lactic acid (PEG-b-PLA) polymeric micelles (PMs). METHODS: SAL loaded PMs were prepared and investigated in terms of pharmaceutical properties. MTT and Annexin V/PI assays were used to study cell proliferation and apoptosis in AsPC-1 cells in response to treatment with SAL micellar formulations. Alterations in CSC phenotype, invasion strength, and mRNA expression of epithelial mesenchymal transition (EMT) markers were also determined in the treated cells. In vivo antitumor study was performed in Balb/c AsPC-1 xenograft mice. RESULTS: PM formulations of SAL were prepared in suitable size and loading traits. In gemcitabine-resistant AsPC-1 cells, SAL was found to significantly increase cell mortality and apoptosis. It was also observed that SAL micellar formulations inhibited invasion and harnessed EMT in spite of induced expression of Snail. The in vivo antitumor experiment showed significant tumor eradication and the highest survival probability in mice treated with SAL PMs. CONCLUSIONS: The obtained results showed the efficacy of SAL nano-formulation against PC tumor cells. PMID- 26228106 TI - Loss-of-Function SOX10 Mutation in a Patient with Kallmann Syndrome, Hearing Loss, and Iris Hypopigmentation. AB - BACKGROUND: Kallmann syndrome (KS) is a clinically and genetically heterogeneous disorder consisting of hypogonadotropic hypogonadism and anosmia. KS is occasionally associated with deafness. Recently, mutations in SOX10, a well-known causative gene of Waardenburg syndrome (WS) characterized by deafness, skin/hair/iris hypopigmentation, Hirschsprung disease, and neurological defects, have been identified in a few patients with KS and deafness. However, the current understanding of the clinical consequences of SOX10 mutations remains fragmentary. CASE REPORT: A Japanese male patient presented with sensory deafness, blue irises, and anosmia, but no hair/skin hypopigmentation, Hirschsprung disease, or neurological abnormalities. He showed no pubertal sex development at 15.1 years of age. Blood examinations revealed low levels of FSH and testosterone. RESULTS: Molecular analysis detected a de novo p.Leu145Pro mutation in SOX10, which has previously been reported in a patient with WS and Hirschsprung disease. The mutation was predicted to be probably damaging. The mutant protein barely exerted in vitro transactivating activity. CONCLUSIONS: These results highlight the significance of SOX10 haploinsufficiency as a genetic cause of KS with deafness. Importantly, our data imply that the same SOX10 mutations can underlie both typical WS and KS with deafness without skin/hair hypopigmentation, Hirschsprung disease, or neurological defects. PMID- 26228107 TI - Transarterial Therapy for Primary Liver Carcinomas: A Crack in the Armor? PMID- 26228108 TI - Diameter of Solid Tumor Component Alone Should be Used to Establish T Stage in Lung Adenocarcinoma. AB - PURPOSE: The computed tomographic (CT) appearance of so-called ground glass components within lung adenocarcinomas correlate with noninvasive tumor histology, and solid radiographic components correlate with invasive histology. We hypothesized that T stage might be more accurately applied by considering the solid component nodule diameter rather than total nodule diameter. METHODS: We identified 74 patients with a solitary lung adenocarcinoma who underwent resection without receiving neoadjuvant therapy. Maximum total diameter and solid diameter of the nodules were measured on CT scans performed within 3 months of surgery. Cox proportional hazard modeling and Kaplan-Meier analyses were performed to determine whether total nodule diameter or solid component diameter was more predictive of overall survival. RESULTS: Thirty-three patients (45 %) had a solid nodule and 41 patients (55 %) had a part-solid nodule. Most patients were white (59 %) and female (69 %), and 42 % had never smoked. Seventy-four percent underwent lobectomy and 23 % sublobar resection. Sixty-six percent had pathologic stage I disease, 22 % stage II, and 12 % stage IIIA. Mean +/- SD total and solid nodule diameters were 32.1 +/- 17.5 and 24.8 +/- 18.0 mm, respectively (p = 0.01). Among patients with part-solid nodules, multivariate modeling incorporating significant univariate predictors of survival (age, gender, procedure, N descriptor) revealed that maximum solid diameter was associated with overall survival (hazard ratio 1.4, p = 0.01), while maximum total diameter was not. CONCLUSIONS: In a largely non-Asian cohort undergoing resection for adenocarcinoma, radiographic diameter of the solid component of a part-solid lesion on CT predicts overall survival better than total lesion diameter. These data provide further evidence to support altering the T descriptor for lung adenocarcinoma for part-solid nodules. PMID- 26228110 TI - [The feasibility of screening for COPD and asthma in the general population]. AB - INTRODUCTION: There are very few surveys devoted to the prevalence of asthma and COPD in the general population. The Motorola Health System has been developed to make such surveys easier. OBJECTIVES: The main objective was to assess the acceptability and efficacy of the Motorola Health system in collecting health data at home in the context of an epidemiological study of respiratory health. The secondary objective was to determine whether a home-based survey would lead to a higher participation rate than a hospital-based survey. METHODS: Four hundred and eighty-three individuals were selected from the electoral rolls of the 15th district of Marseille and randomly divided into two groups: home-based and hospital-based. The protocol included a questionnaire, several measurements: height, weight, blood pressure, spirometry and pulse oxymetry, and blood sampling. All data were transferred to a portable computer. RESULTS: Data acquisition and transfer worked well. Among the 232 subjects from the home-based survey, 62 (26.7%) participated, whereas only 36 (14.3%) of the 251 subjects from the hospital-based group did so (P<0.001). In an additional telephone survey, participants (13.6%) and non-participants (11.0%) had the same (P<0.9) prevalence of asthma. CONCLUSION: The Motorola Health System allowed accurate data acquisition and transfer in the context of an epidemiological survey of respiratory health. A home-based survey gave a higher participation rate than a hospital-based one. PMID- 26228109 TI - Prognostic Impact of Peritumoral IL-17-Positive Cells and IL-17 Axis in Patients with Intrahepatic Cholangiocarcinoma. AB - BACKGROUND: Development of cancer has been linked to inflammatory cytokines such as interleukin (IL)-6 and IL-17. In this study, we assessed the expression of these cytokines in intrahepatic cholangiocarcinoma (ICC) and determined their correlation to the survival probability. METHODS: A total of 72 consecutive patients who underwent curative resection of ICC at Osaka University Hospital from March 1998 to November 2014 were enrolled. Immunohistochemical analysis was performed for IL-17 and its receptor A (IL-17RA), as well as IL-6. Enzyme-linked immunosorbent assay (ELISA) was performed for preoperative plasma levels of IL-6 and IL-17 in 32 patients with ICC. RESULTS: Immunohistochemical analysis showed that the IL-6(high) (n = 34) and IL-17RA(high) (n = 29) groups had significantly worse disease-free survival (DFS) than IL-6(low) (n = 38) and IL-17RA(low) (n = 43) groups, respectively. Although IL-17(+) cells were abundant in the intratumoral area, patients with high peritumoral, but not intratumoral, IL-17(+) cells (n = 28) corresponded with a significantly lower overall survival (OS) and DFS (OS, p = 0.023; DFS, p = 0.026) than those with low group. Moreover, multivariate Cox proportional hazards analysis revealed that IL-6, peritumoral IL 17(+), and IL-17RA are independent prognostic factors for DFS (p = 0.023, p = 0.0088, p = 0.039, respectively). In addition, high preoperative plasma levels of IL-6 in patients with ICC corresponded with significantly lower DFS (p = 0.002). CONCLUSIONS: Our data suggested that IL-6, peritumoral IL-17(+) cells, and IL 17RA expression are postoperative useful markers for predicting recurrence in patients with ICC. PMID- 26228111 TI - Imbalance between proliferation and in vitro apoptosis rates predicts progression in chronic lymphocytic leukemia. PMID- 26228112 TI - Gold nanorods as a theranostic platform for in vitro and in vivo imaging and photothermal therapy of inflammatory macrophages. AB - Inflammatory macrophages play pivotal roles in the development of atherosclerosis. Theranostics, a promising approach for local imaging and photothermal therapy of inflammatory macrophages, has drawn increasing attention in biomedical research. In this study, gold nanorods (Au NRs) were synthesized, and their in vitro photothermal effects on the macrophage cell line (Ana-1 cells) under 808 nm near infrared reflection (NIR) were investigated by the CCK8 assay, calcein AM/PI staining, flow cytometry, transmission electron microscopy (TEM), silver staining and in vitro micro-computed tomography (CT) imaging. These Au NRs were then applied to an apolipoprotein E knockout (Apo E) mouse model to evaluate their effects on in vivo CT imaging and their effectiveness as for the subsequent photothermal therapy of macrophages in femoral artery restenosis under 808 nm laser irradiation. In vitro photothermal ablation treatment using Au NRs exhibited a significant cell-killing efficacy of macrophages, even at relatively low concentrations of Au NRs and low NIR powers. In addition, the in vivo results demonstrated that the Au NRs are effective for in vivo imaging and photothermal therapy of inflammatory macrophages in femoral artery restenosis. This study shows that Au nanorods are a promising theranostic platform for the diagnosis and photothermal therapy of inflammation-associated diseases. PMID- 26228115 TI - A tale of two states. PMID- 26228113 TI - Determination of the coenzyme Q10 status in a large Caucasian study population. AB - Coenzyme Q10 (CoQ10 ) exists in a reduced (ubiquinol) and an oxidized (ubiquinone) form in all human tissues and functions, amongst others, in the respiratory chain, redox-cycles, and gene expression. As the status of CoQ10 is an important risk factor for several diseases, here we determined the CoQ10 status (ubiquinol, ubiquinone) in a large Caucasian study population (n = 1,911). The study population covers a wide age range (age: 18-83 years, 43.4% men), has information available on more than 10 measured clinical phenotypes, more than 30 diseases (presence vs. absence), about 30 biomarkers, and comprehensive genetic information including whole-genome SNP typing (>891,000 SNPs). The major aim of this long-term resource in CoQ10 research is the comprehensive analysis of the CoQ10 status with respect to integrated health parameters (i.e., fat metabolism, inflammation), disease-related biomarkers (i.e., liver enzymes, marker for heart failure), common diseases (i.e., neuropathy, myocardial infarction), and genetic risk in humans. Based on disease status, biomarkers, and genetic variants, our cohort is also useful to perform Mendelian randomisation approaches. In conclusion, the present study population is a promising resource to gain deeper insight into CoQ10 status in human health and disease. PMID- 26228114 TI - Do otolaryngology residency applicants relocate for training? AB - OBJECTIVES/HYPOTHESIS: To determine whether there is an association between the geographic location of an applicant's undergraduate school, medical school, and residency program among matched otolaryngology residency applicants. STUDY DESIGN: Observational. METHODS: Otolaryngology residency program applications to our institution from 2009 to 2013 were analyzed. The geographic location of each applicant's undergraduate education and medical education were collected. Online public records were queried to determine the residency program location of matched applicants. Applicants who did not match or who attended medical school outside the United States were excluded. Metro area, state, and region were determined according to US Census Bureau definitions. RESULTS: From 2009 to 2013, 1,089 (78%) of 1,405 applicants who matched into otolaryngology residency applied to our institution. The number of subjects who attended medical school and residency in the same geographic region was 241 (22%) for metropolitan area, 305 (28%) for state, and 436 (40%) for region. There was no difference in geographic location retention by gender or couples match status of the subject. United States Medical Licensing Exam step 1 scores correlated with an increased likelihood of subjects staying within the same geographic region (P = .03). CONCLUSIONS: Most otolaryngology applicants leave their previous geographic area to attend residency. Based on these data, the authors recommend against giving weight to geography as a factor when inviting applicants to interview. LEVEL OF EVIDENCE: NA. PMID- 26228117 TI - PLANETARY SCIENCE. Comet lander's scientific harvest may be its last. PMID- 26228118 TI - BIOPHYSICS. Tiny built-in lasers light up living cells. PMID- 26228119 TI - INFECTIOUS DISEASES. Risk of 'leaky' vaccines debated. PMID- 26228120 TI - SCIENCE AND THE LAW. Forensic labs explore blind testing to prevent errors. PMID- 26228121 TI - Q&A. Former head of China's genome powerhouse starts new chapter. PMID- 26228122 TI - NEUROSCIENCE. Alzheimer's amyloid theory gets modest boost. PMID- 26228123 TI - Cosmic convergence. PMID- 26228124 TI - Setting the bar. PMID- 26228125 TI - ROBOTICS. Two leaps forward for robot locomotion. PMID- 26228126 TI - ORGANIC CATALYSIS. A leap ahead for activating C-H bonds. PMID- 26228127 TI - PLANETARY SCIENCE. Ancient planetary dynamos, take two. PMID- 26228128 TI - CANCER. A p53-regulated immune checkpoint relevant to cancer. PMID- 26228129 TI - WATER. What scale for water governance? PMID- 26228130 TI - WATER. Fresh water goes global. PMID- 26228131 TI - WATER. Local perspectives on water. PMID- 26228132 TI - BIODIVERSITY. Averting a North American biodiversity crisis. PMID- 26228133 TI - Science in Congress: Good-faith debate. PMID- 26228134 TI - Science in Congress: Unnecessary conflict. PMID- 26228135 TI - Science in Congress: Deceptive statistics. PMID- 26228136 TI - Science in Congress: Deceptive statistics-Response. PMID- 26228137 TI - INSECT PHYLOGENOMICS. Comment on "Phylogenomics resolves the timing and pattern of insect evolution". AB - Misof et al. (Reports, 7 November 2014, p. 763) used a genome-scale data set to estimate the relationships among insect orders and the time scale of their evolution. Here, we reanalyze their data and show that their method has led to systematic underestimation of the evolutionary time scale. We find that key insect groups evolved up to 100 million years earlier than inferred in their study. PMID- 26228138 TI - INSECT PHYLOGENOMICS. Response to Comment on "Phylogenomics resolves the timing and pattern of insect evolution". AB - Tong et al. comment on the accuracy of the dating analysis presented in our work on the phylogeny of insects and provide a reanalysis of our data. They replace log-normal priors with uniform priors and add a "roachoid" fossil as a calibration point. Although the reanalysis provides an interesting alternative viewpoint, we maintain that our choices were appropriate. PMID- 26228139 TI - Philae's first look. Philae's First Days on the Comet. Introduction. PMID- 26228141 TI - HEAVY FERMIONS. Strange metal without magnetic criticality. AB - A fundamental challenge to our current understanding of metals is the observation of qualitative departures from Fermi liquid behavior. The standard view attributes such non-Fermi liquid phenomena to the scattering of electrons off quantum critical fluctuations of an underlying order parameter. Although the possibility of non-Fermi liquid behavior isolated from the border of magnetism has long been speculated, no experimental confirmation has been made. Here, we report on the observation of a strange metal region away from a magnetic instability in an ultrapure single crystal. In particular, we show that the heavy fermion superconductor beta-YbAlB4 forms a possible phase with strange metallic behavior across an extensive pressure regime, distinctly separated from a high pressure magnetic quantum phase transition by a Fermi liquid phase. PMID- 26228140 TI - METABOLISM. S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. AB - The association between inflammation and endoplasmic reticulum (ER) stress has been observed in many diseases. However, if and how chronic inflammation regulates the unfolded protein response (UPR) and alters ER homeostasis in general, or in the context of chronic disease, remains unknown. Here, we show that, in the setting of obesity, inflammatory input through increased inducible nitric oxide synthase (iNOS) activity causes S-nitrosylation of a key UPR regulator, IRE1alpha, which leads to a progressive decline in hepatic IRE1alpha mediated XBP1 splicing activity in both genetic (ob/ob) and dietary (high-fat diet-induced) models of obesity. Finally, in obese mice with liver-specific IRE1alpha deficiency, reconstitution of IRE1alpha expression with a nitrosylation resistant variant restored IRE1alpha-mediated XBP1 splicing and improved glucose homeostasis in vivo. Taken together, these data describe a mechanism by which inflammatory pathways compromise UPR function through iNOS-mediated S nitrosylation of IRE1alpha, which contributes to defective IRE1alpha activity, impaired ER function, and prolonged ER stress in obesity. PMID- 26228142 TI - REACTION DYNAMICS. Spectroscopic observation of resonances in the F + H2 reaction. AB - Photodetachment spectroscopy of the FH2(-) and FD2(-) anions allows for the direct observation of reactive resonances in the benchmark reaction F + H2 -> HF + H. Using cooled anion precursors and a high-resolution electron spectrometer, we observe several narrow peaks not seen in previous experiments. Theoretical calculations, based on a highly accurate F + H2 potential energy surface, convincingly assign these peaks to resonances associated with quasibound states in the HF + H and DF + D product arrangements and with a quasibound state in the transition state region of the F + H2 reaction. The calculations also reveal quasibound states in the reactant arrangement, which have yet to be resolved experimentally. PMID- 26228143 TI - BORON CATALYSIS. Metal-free catalytic C-H bond activation and borylation of heteroarenes. AB - Transition metal complexes are efficient catalysts for the C-H bond functionalization of heteroarenes to generate useful products for the pharmaceutical and agricultural industries. However, the costly need to remove potentially toxic trace metals from the end products has prompted great interest in developing metal-free catalysts that can mimic metallic systems. We demonstrated that the borane (1-TMP-2-BH2-C6H4)2 (TMP, 2,2,6,6 tetramethylpiperidine) can activate the C-H bonds of heteroarenes and catalyze the borylation of furans, pyrroles, and electron-rich thiophenes. The selectivities complement those observed with most transition metal catalysts reported for this transformation. PMID- 26228144 TI - BIOMECHANICS. Jumping on water: Surface tension-dominated jumping of water striders and robotic insects. AB - Jumping on water is a unique locomotion mode found in semi-aquatic arthropods, such as water striders. To reproduce this feat in a surface tension-dominant jumping robot, we elucidated the hydrodynamics involved and applied them to develop a bio-inspired impulsive mechanism that maximizes momentum transfer to water. We found that water striders rotate the curved tips of their legs inward at a relatively low descending velocity with a force just below that required to break the water surface (144 millinewtons/meter). We built a 68-milligram at scale jumping robotic insect and verified that it jumps on water with maximum momentum transfer. The results suggest an understanding of the hydrodynamic phenomena used by semi-aquatic arthropods during water jumping and prescribe a method for reproducing these capabilities in artificial systems. PMID- 26228145 TI - PALEOMAGNETISM. A Hadean to Paleoarchean geodynamo recorded by single zircon crystals. AB - Knowing when the geodynamo started is important for understanding the evolution of the core, the atmosphere, and life on Earth. We report full-vector paleointensity measurements of Archean to Hadean zircons bearing magnetic inclusions from the Jack Hills conglomerate (Western Australia) to reconstruct the early geodynamo history. Data from zircons between 3.3 billion and 4.2 billion years old record magnetic fields varying between 1.0 and 0.12 times recent equatorial field strengths. A Hadean geomagnetic field requires a core mantle heat flow exceeding the adiabatic value and is suggestive of plate tectonics and/or advective magmatic heat transport. The existence of a terrestrial magnetic field before the Late Heavy Bombardment is supported by terrestrial nitrogen isotopic evidence and implies that early atmospheric evolution on both Earth and Mars was regulated by dynamo behavior. PMID- 26228146 TI - NANOELECTRONICS. Epitaxial growth of a monolayer WSe2-MoS2 lateral p-n junction with an atomically sharp interface. AB - Two-dimensional transition metal dichalcogenides (TMDCs) such as molybdenum sulfide MoS2 and tungsten sulfide WSe2 have potential applications in electronics because they exhibit high on-off current ratios and distinctive electro-optical properties. Spatially connected TMDC lateral heterojunctions are key components for constructing monolayer p-n rectifying diodes, light-emitting diodes, photovoltaic devices, and bipolar junction transistors. However, such structures are not readily prepared via the layer-stacking techniques, and direct growth favors the thermodynamically preferred TMDC alloys. We report the two-step epitaxial growth of lateral WSe2-MoS2 heterojunction, where the edge of WSe2 induces the epitaxial MoS2 growth despite a large lattice mismatch. The epitaxial growth process offers a controllable method to obtain lateral heterojunction with an atomically sharp interface. PMID- 26228147 TI - FOREST ECOLOGY. Pervasive drought legacies in forest ecosystems and their implications for carbon cycle models. AB - The impacts of climate extremes on terrestrial ecosystems are poorly understood but important for predicting carbon cycle feedbacks to climate change. Coupled climate-carbon cycle models typically assume that vegetation recovery from extreme drought is immediate and complete, which conflicts with the understanding of basic plant physiology. We examined the recovery of stem growth in trees after severe drought at 1338 forest sites across the globe, comprising 49,339 site years, and compared the results with simulated recovery in climate-vegetation models. We found pervasive and substantial "legacy effects" of reduced growth and incomplete recovery for 1 to 4 years after severe drought. Legacy effects were most prevalent in dry ecosystems, among Pinaceae, and among species with low hydraulic safety margins. In contrast, limited or no legacy effects after drought were simulated by current climate-vegetation models. Our results highlight hysteresis in ecosystem-level carbon cycling and delayed recovery from climate extremes. PMID- 26228150 TI - Why not have a life? PMID- 26228149 TI - PLANT EVOLUTION. Convergent evolution of strigolactone perception enabled host detection in parasitic plants. AB - Obligate parasitic plants in the Orobanchaceae germinate after sensing plant hormones, strigolactones, exuded from host roots. In Arabidopsis thaliana, the alpha/beta-hydrolase D14 acts as a strigolactone receptor that controls shoot branching, whereas its ancestral paralog, KAI2, mediates karrikin-specific germination responses. We observed that KAI2, but not D14, is present at higher copy numbers in parasitic species than in nonparasitic relatives. KAI2 paralogs in parasites are distributed into three phylogenetic clades. The fastest-evolving clade, KAI2d, contains the majority of KAI2 paralogs. Homology models predict that the ligand-binding pockets of KAI2d resemble D14. KAI2d transgenes confer strigolactone-specific germination responses to Arabidopsis thaliana. Thus, the KAI2 paralogs D14 and KAI2d underwent convergent evolution of strigolactone recognition, respectively enabling developmental responses to strigolactones in angiosperms and host detection in parasites. PMID- 26228148 TI - ACTIN-DIRECTED TOXIN. ACD toxin-produced actin oligomers poison formin-controlled actin polymerization. AB - The actin cross-linking domain (ACD) is an actin-specific toxin produced by several pathogens, including life-threatening spp. of Vibrio cholerae, Vibrio vulnificus, and Aeromonas hydrophila. Actin cross-linking by ACD is thought to lead to slow cytoskeleton failure owing to a gradual sequestration of actin in the form of nonfunctional oligomers. Here, we found that ACD converted cytoplasmic actin into highly toxic oligomers that potently "poisoned" the ability of major actin assembly proteins, formins, to sustain actin polymerization. Thus, ACD can target the most abundant cellular protein by using actin oligomers as secondary toxins to efficiently subvert cellular functions of actin while functioning at very low doses. PMID- 26228151 TI - COMETARY SCIENCE. The structure of the regolith on 67P/Churyumov-Gerasimenko from ROLIS descent imaging. AB - The structure of the upper layer of a comet is a product of its surface activity. The Rosetta Lander Imaging System (ROLIS) on board Philae acquired close-range images of the Agilkia site during its descent onto comet 67P/Churyumov Gerasimenko. These images reveal a photometrically uniform surface covered by regolith composed of debris and blocks ranging in size from centimeters to 5 meters. At the highest resolution of 1 centimeter per pixel, the surface appears granular, with no apparent deposits of unresolved sand-sized particles. The thickness of the regolith varies across the imaged field from 0 to 1 to 2 meters. The presence of aeolian-like features resembling wind tails hints at regolith mobilization and erosion processes. Modeling suggests that abrasion driven by airfall-induced particle "splashing" is responsible for the observed formations. PMID- 26228152 TI - COMETARY SCIENCE. Thermal and mechanical properties of the near-surface layers of comet 67P/Churyumov-Gerasimenko. AB - Thermal and mechanical material properties determine comet evolution and even solar system formation because comets are considered remnant volatile-rich planetesimals. Using data from the Multipurpose Sensors for Surface and Sub Surface Science (MUPUS) instrument package gathered at the Philae landing site Abydos on comet 67P/Churyumov-Gerasimenko, we found the diurnal temperature to vary between 90 and 130 K. The surface emissivity was 0.97, and the local thermal inertia was 85 +/- 35 J m(-2) K(-1)s(-1/2). The MUPUS thermal probe did not fully penetrate the near-surface layers, suggesting a local resistance of the ground to penetration of >4 megapascals, equivalent to >2 megapascal uniaxial compressive strength. A sintered near-surface microporous dust-ice layer with a porosity of 30 to 65% is consistent with the data. PMID- 26228153 TI - COMETARY SCIENCE. Properties of the 67P/Churyumov-Gerasimenko interior revealed by CONSERT radar. AB - The Philae lander provides a unique opportunity to investigate the internal structure of a comet nucleus, providing information about its formation and evolution in the early solar system. We present Comet Nucleus Sounding Experiment by Radiowave Transmission (CONSERT) measurements of the interior of Comet 67P/Churyumov-Gerasimenko. From the propagation time and form of the signals, the upper part of the "head" of 67P is fairly homogeneous on a spatial scale of tens of meters. CONSERT also reduced the size of the uncertainty of Philae's final landing site down to approximately 21 by 34 square meters. The average permittivity is about 1.27, suggesting that this region has a volumetric dust/ice ratio of 0.4 to 2.6 and a porosity of 75 to 85%. The dust component may be comparable to that of carbonaceous chondrites. PMID- 26228154 TI - COMETARY SCIENCE. 67P/Churyumov-Gerasimenko surface properties as derived from CIVA panoramic images. AB - The structure and composition of cometary constituents, down to their microscopic scale, are critical witnesses of the processes and ingredients that drove the formation and evolution of planetary bodies toward their present diversity. On board Rosetta's lander Philae, the Comet Infrared and Visible Analyser (CIVA) experiment took a series of images to characterize the surface materials surrounding the lander on comet 67P/Churyumov-Gerasimenko. Images were collected twice: just after touchdown, and after Philae finally came to rest, where it acquired a full panorama. These images reveal a fractured surface with complex structure and a variety of grain scales and albedos, possibly constituting pristine cometary material. PMID- 26228155 TI - COMETARY SCIENCE. CHO-bearing organic compounds at the surface of 67P/Churyumov Gerasimenko revealed by Ptolemy. AB - The surface and subsurface of comets preserve material from the formation of the solar system. The properties of cometary material thus provide insight into the physical and chemical conditions during their formation. We present mass spectra taken by the Ptolemy instrument 20 minutes after the initial touchdown of the Philae lander on the surface of comet 67P/Churyumov-Gerasimenko. Regular mass distributions indicate the presence of a sequence of compounds with additional CH2- and -O- groups (mass/charge ratios 14 and 16, respectively). Similarities with the detected coma species of comet Halley suggest the presence of a radiation-induced polymer at the surface. Ptolemy measurements also indicate an apparent absence of aromatic compounds such as benzene, a lack of sulfur-bearing species, and very low concentrations of nitrogenous material. PMID- 26228156 TI - COMETARY SCIENCE. Organic compounds on comet 67P/Churyumov-Gerasimenko revealed by COSAC mass spectrometry. AB - Comets harbor the most pristine material in our solar system in the form of ice, dust, silicates, and refractory organic material with some interstellar heritage. The evolved gas analyzer Cometary Sampling and Composition (COSAC) experiment aboard Rosetta's Philae lander was designed for in situ analysis of organic molecules on comet 67P/Churyumov-Gerasimenko. Twenty-five minutes after Philae's initial comet touchdown, the COSAC mass spectrometer took a spectrum in sniffing mode, which displayed a suite of 16 organic compounds, including many nitrogen bearing species but no sulfur-bearing species, and four compounds-methyl isocyanate, acetone, propionaldehyde, and acetamide-that had not previously been reported in comets. PMID- 26228157 TI - CRYSTAL GROWTH. Crystallization by particle attachment in synthetic, biogenic, and geologic environments. AB - Field and laboratory observations show that crystals commonly form by the addition and attachment of particles that range from multi-ion complexes to fully formed nanoparticles. The particles involved in these nonclassical pathways to crystallization are diverse, in contrast to classical models that consider only the addition of monomeric chemical species. We review progress toward understanding crystal growth by particle-attachment processes and show that multiple pathways result from the interplay of free-energy landscapes and reaction dynamics. Much remains unknown about the fundamental aspects, particularly the relationships between solution structure, interfacial forces, and particle motion. Developing a predictive description that connects molecular details to ensemble behavior will require revisiting long-standing interpretations of crystal formation in synthetic systems, biominerals, and patterns of mineralization in natural environments. PMID- 26228158 TI - COMETARY SCIENCE. The landing(s) of Philae and inferences about comet surface mechanical properties. AB - The Philae lander, part of the Rosetta mission to investigate comet 67P/Churyumov Gerasimenko, was delivered to the cometary surface in November 2014. Here we report the precise circumstances of the multiple landings of Philae, including the bouncing trajectory and rebound parameters, based on engineering data in conjunction with operational instrument data. These data also provide information on the mechanical properties (strength and layering) of the comet surface. The first touchdown site, Agilkia, appears to have a granular soft surface (with a compressive strength of 1 kilopascal) at least ~20 cm thick, possibly on top of a more rigid layer. The final landing site, Abydos, has a hard surface. PMID- 26228161 TI - Tattoo-induced psoriasis. PMID- 26228160 TI - Survivin is not an independent prognostic factor for patients with upper tract urothelial carcinoma: a multi-institutional study. AB - OBJECTIVE: Several small single-center studies have reported conflicting results on the prognostic value of survivin expression in upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy. We attempted to validate the prognostic utility of survivin using a large multi-institutional cohort. MATERIAL AND METHODS: Survivin expression was evaluated by immunohistochemistry in tumor tissue from 732 patients with unilateral, sporadic UTUC treated with radical nephroureterectomy between 1990 and 2008 at 7 centers. Survivin expression was considered altered when at least 10% of the tumor cells stained positive. Associations of altered survivin expression with recurrence-free survival (RFS) and cancer-specific survival (CSS) were evaluated using Cox proportional hazards regression models. RESULTS: Altered survivin expression was observed in 288 (39.3%) tumors and was associated with more advanced pathological tumor stages (P<0.001), lymph node metastases (P<0.001), lymphovascular invasion (P<0.001), tumor necrosis (P = 0.027), and tumor architecture (P<0.001). Median follow-up was 35 (16-64) months. There were 191 (25.4%) patients who experienced disease recurrence, and 165 patients (21.9%) died of the disease. In the univariable analysis, altered survivin expression was significantly associated with worse RFS and CSS (each P<0.001); however, altered survivin expression did not achieve independent predictive status on multivariable models (P = 0.24 and P = 0.53). Similarly, survivin was not independently associated with outcomes in subgroup analyses, including patients with high-grade tumors. CONCLUSIONS: In UTUC, altered survivin expression is associated with worse clinicopathological features and worse RFS and CSS. However, it does not appear to be independently associated with cancer outcomes when considering standard prognostic factors. PMID- 26228159 TI - Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53. AB - The inefficient clearance of dying cells can lead to abnormal immune responses, such as unresolved inflammation and autoimmune conditions. We show that tumor suppressor p53 controls signaling-mediated phagocytosis of apoptotic cells through its target, Death Domain1alpha (DD1alpha), which suggests that p53 promotes both the proapoptotic pathway and postapoptotic events. DD1alpha appears to function as an engulfment ligand or receptor that engages in homophilic intermolecular interaction at intercellular junctions of apoptotic cells and macrophages, unlike other typical scavenger receptors that recognize phosphatidylserine on the surface of dead cells. DD1alpha-deficient mice showed in vivo defects in clearing dying cells, which led to multiple organ damage indicative of immune dysfunction. p53-induced expression of DD1alpha thus prevents persistence of cell corpses and ensures efficient generation of precise immune responses. PMID- 26228162 TI - Individual differences in hedonic experience: Further evidence for the construct validity of the ACIPS. AB - We conducted three investigations to examine the convergent and discriminant validity of the Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS; Gooding and Pflum, Psychiatry Research, 2014). In Study One, we used Mechanical Turk to individually administer the ACIPS to a diverse group of community adults aged 25-69. Reports of greater social/interpersonal pleasure was associated with greater sense of interpersonal connectedness with others, higher need to belong, and less likelihood of reporting anxiety during social interactions. In Studies Two and Three, participants were tested in group settings. Studies with undergraduate participants indicated that ACIPS scores are associated with measures of prosocial interactions and sociability as well as measures of anhedonia. Despite differences in testing conditions (i.e., online vs. paper administration) and heterogeneity in the samples in terms of educational level, geographical location, and age, the ACIPS demonstrated good convergent and discriminant validity. Taken together, these studies add to the increasing body of evidence for the construct validity of the ACIPS. PMID- 26228163 TI - The Mental Health Literacy Scale (MHLS): A new scale-based measure of mental health literacy. AB - Although Mental Health Literacy (MHL) has been a topic of substantial interest, measurement of this concept using a scale-based measure has been limited, including a lack of psychometric and methodologically robust scale-based measures of MHL. This study developed a new scale-based measure of MHL, the Mental Health Literacy Scale (MHLS), which assesses all attributes of MHL. Construction of the MHLS was done over three key stages, including measure development, pilot testing and assessment of psychometrics and methodological quality. The resulting measure is a 35 item, univariate scale that is easily administered and scored. Results showed significant differences in scores between mental health professionals and a community sample, as well as individuals with greater experience with mental health, and a significant positive relationship with help-seeking intentions. The MHLS also demonstrated good internal and test-retest reliability. Evaluation of the methodological quality of the MHLS indicated that it has substantial methodological advantages in comparison to existing scale-based measures of MHL. The MHLS can be used in assessing individual and population level differences in MHL and in determining the impact of programmes designed to improve MHL. PMID- 26228165 TI - Patients with mild Alzheimer's disease produced shorter outgoing saccades when reading sentences. AB - In the present work we analyzed forward saccades of thirty five elderly subjects (Controls) and of thirty five mild Alzheimer's disease (AD) during reading regular and high-predictable sentences. While they read, their eye movements were recorded. The pattern of forward saccade amplitudes as a function of word predictability was clearly longer in Controls. Our results suggest that Controls might use stored information of words for enhancing their reading performance. Further, cloze predictability increased outgoing saccades amplitudes, as this increase stronger in high-predictable sentences. Quite the contrary, patients with mild AD evidenced reduced forward saccades even at early stages of the disease. This reduction might reveal impairments in brain areas such as those corresponding to working memory, memory retrieval, and semantic memory functions that are already present at early stages of AD. Our findings might be relevant for expanding the options for the early detection and monitoring of in the early stages of AD. Furthermore, eye movements during reading could provide a new tool for measuring a drug's impact on patient's behavior. PMID- 26228164 TI - Course of symptom change during anxiety treatment: Reductions in anxiety and depression in patients completing the Coordinated Anxiety Learning and Management program. AB - When treating anxious patients with co-occurring depression, research demonstrates that both types of symptoms independently improve. The current analyses examined how reductions in anxiety and depression may be interrelated both during treatment, as well as over time following treatment. Participants were 503 individuals with one or more DSM-IV anxiety disorders who completed a collaborative care anxiety management program. Anxiety and depression were assessed at each treatment session (i.e., session by session data) and also at 6, 12, and 18-month post-baseline assessments (i.e., long-term outcomes data). Mediation analyses examined changes in symptoms in session by session data and long-term outcomes data. Anxiety and depression changed reciprocally in session by session data; change in anxiety mediated change in depression to a greater extent than vice versa. In the long-term outcomes data, change in anxiety mediated change in depression. However, the reverse mediation model of the long term outcomes period revealed that accounting for changes in depression altered the effect of time on anxiety. Thus, temporal change during active treatment may share similarities with those related to maintaining gains after treatment, although differences arose in the reverse mediation models. Limitations of the methodology and implications of anxiety treatment for depression outcomes are discussed. PMID- 26228166 TI - Toward improved diagnosis of HIT. PMID- 26228167 TI - Upfront CyBorD in AL amyloidosis. PMID- 26228168 TI - Wipping p53 into subservience in B-cell development. PMID- 26228169 TI - TSLPR: a new CAR in the showroom for B-ALL. PMID- 26228170 TI - Pharmacologic control of chromatin looping. PMID- 26228171 TI - Polymerized fibrin activates glycoprotein VI. PMID- 26228173 TI - [Autoimmune skin diseases]. PMID- 26228172 TI - [Contact allergies in the German workforce : Data of the IVDK network from 2003 2013]. AB - BACKGROUND: In Germany, occupational skin diseases rank first in the occupational skin disease statistics for many years. Especially, occupationally acquired contact allergies as well as multi-sensitization are the most important predictors for a poor prognosis and persistent eczema. OBJECTIVES: To update the spectrum and sensitization frequencies of most frequent allergens from the standard series in Germany in patients with occupationally acquired type IV sensitizations in general and within different occupational groups. METHODS: Data of all employed patients (age range: 16-68 years, n = 14234) patch tested between 2003 and 2013 in the German Departments of the Information Network of Departments of Dermatology (IVDK) and diagnosed occupationally acquired contact dermatitis after patch testing were analyzed. The control group was composed of all other patients (n = 31706) within the same time frame, in which occupationally acquired allergic contact dermatitis was negated explicitly. RESULTS: The prevalence Ratio (PR; indicating risk) was significantly increased for: Thiuram-mix (PR 5.63 95 %CI 4.97-6.4), zinkdiethyldithiocarbamate (PR 6.22 95 %CI 4.76-8.22), mercaptobenzothiazole (MBT) (PR 3.88 95 %CI 3.09-4.89), mercapto-mix without MBT (PR 3.23 95 %CI 2.59-4.03), N-isopropyl-N'-phenyl-p-phenylene diamine (IPPD) (PR 2.3195 %CI 1.87-2.86), epoxy resin (PR 2.82 95 %CI 2.45-3.25), chloromethylisothiazolinone/methylisothiazolinone (MCI/MI) (PR 2.19 95 %CI 1.97 2.42) and compositae mix II (PR 2.05 95 %CI 1.45-2.89). They were the predominant occupational allergens and were at least associated with a doubled risk (PR >= 2.0) for acquiring occupationally allergic contact dermatitis. The highest risk increase was identified in employees in the health services, in agriculture, metal industry, food and service industry as well as building trades CONCLUSIONS: A limited number of occupationally relevant allergens cause the majority of sensitizations in the workforce, if standard series allergens are concerned. Data analysis of national and international contact allergy data bases provide valuable information on sensitization rates and profiles in skin risk occupations to implement targeted prevention strategies. To diagnose occupational allergic contact dermatitis in individual cases additional testing of occupation related patch test series as well as patients' own products is commonly inevitable. PMID- 26228174 TI - Paraquat Poisoning Followed by Toxic Epidermal Necrolysis: A Report of Two Cases and Published Work Review. AB - Toxic epidermal necrolysis (TEN) is a life-threatening, typically drug-induced, mucocutaneous disease. Whether paraquat, one of the most widely used herbicides, could induce TEN is not known. We describe 2 paraquat-poisoned patients with TEN. Both patients presented erythema after hospital discharge following initial paraquat poisoning and then developed a widespread eruption of diffuse erythema on almost the whole body, with bullae, epidermal necrosis and sloughing. They were successfully treated with intravenous immunoglobulin and methylprednisolone. These clinical features were consistent with TEN caused by medications with a high risk to induce Stevens-Johnson syndrome/TEN. Moreover, it is suggested that both skin exposure and ingestion of paraquat could induce TEN. To our knowledge, this is the first case report of TEN related to paraquat poisoning. PMID- 26228175 TI - Discriminative Learning for Automatic Staging of Placental Maturity via Multi layer Fisher Vector. AB - Currently, placental maturity is performed using subjective evaluation, which can be unreliable as it is highly dependent on the observations and experiences of clinicians. To address this problem, this paper proposes a method to automatically stage placenta maturity from B-mode ultrasound (US) images based on dense sampling and novel feature descriptors. Specifically, our proposed method first densely extracts features with a regular grid based on dense sampling instead of a few unreliable interest points. Followed by, these features are clustered using generative Gaussian mixture model (GMM) to obtain high order statistics of the features. The clustering representatives (i.e., cluster means) are encoded by Fisher vector (FV) for staging accuracy enhancement. Differing from the previous studies, a multi-layer FV is investigated to exploit the spatial information rather than the single layer FV. Experimental results show that the proposed method with the dense FV has achieved an area under the receiver of characteristics (AUC) of 96.77%, sensitivity and specificity of 98.04% and 93.75% for the placental maturity staging, respectively. Our experimental results also demonstrate that the dense feature outperforms the traditional sparse feature for placental maturity staging. PMID- 26228177 TI - Direct and protective effects of single or combined addition of vincristine and epsilon-viniferin on human HepG2 cellular oxidative stress markers in vitro. AB - The objective of this study is to examine the direct effects of low doses and high doses of epsilon-viniferin, a substance known to be an antioxidant, and vincristine sulphate, a chemotherapeutic agent, alone and in combination [epsilon viniferin + vincristine] on HepG2 cell strain, as well as evaluate oxidative stress after incubation periods of 3, 6, and 24 h. Direct effect was determined right after the incubation period; however, for protective effect, antioxidant protection response was determined after the treatment for 1 h with 500 MUM H2O2, which is an oxidative stressor. For this purpose, superoxide dismutase was determined for enzyme activity, and lipid hydroperoxide (LPO) and reduced glutathione concentrations were studied as indicators of oxidative stress. Results show that low [3.63 uM vincristine + 3.75 uM epsilon-viniferin] and high [11.25 uM vincristine + 15.8 uM epsilon-viniferin] doses of combination groups showed similar direct antioxidant effect on LPO levels as protective when compared to the H2O2 control group (p < 0.05). Superoxide dismutase enzyme showed a direct antioxidant effect in low and high dose combination groups. In addition, when the incubation period was increased to 24 h, a protective effect was observed in both dose groups (p < 0.05). Reduced glutathione activities showed a direct effect in the low dose combination group, and a protective effect in both the low and high doses in the 24 h. These results show that combined usage of drugs in HepG2 cell strain possesses a protective effect against exogenically produced oxidative stress conditions. PMID- 26228179 TI - Installing logic gates in permeability controllable polyelectrolyte-carbon nitride films for detecting proteases and nucleases. AB - Proteases and nucleases are enzymes heavily involved in many important biological processes, such as cancer initiation, progression, and metastasis; hence, they are indicative of potential diagnostic biomarkers. Here, we demonstrate a new label free and sensitive electrochemiluminescent (ECL) sensing strategy for protease and nuclease assays that utilize target-triggered desorption of programmable polyelectrolyte films assembled on graphite-like carbon nitride (g C3N4) film to regulate the diffusion flux of a coreactant. Furthermore, we have built Boolean logic gates OR and AND into the polyelectrolyte films, capable of simultaneously sensing proteases and nucleases in a complicated system by breaking it into simple functions. The developed intelligent permeability controlled enzyme sensor may prove valuable in future medical diagnostics. PMID- 26228176 TI - Combining citrulline with atorvastatin preserves glucose homeostasis in a murine model of diet-induced obesity. AB - BACKGROUND AND PURPOSE: NO is a crucial regulator of energy and lipid metabolism, whose homeostasis is compromised during obesity. Combination of citrulline and atorvastatin potentiated NO production in vitro. Here we have assessed the effects of this combination in mice with diet-induced obesity (DIO). EXPERIMENTAL APPROACH: C57BL/6J male mice were given a standard diet (control) or a high fat high sucrose diet (DIO) for 8 weeks. DIO mice were then treated with DIO alone, DIO with citrulline, DIO with atorvastatin or DIO with citrulline and atorvastatin (DIOcit-stat) for 3 weeks. Thereafter, body composition, glucose tolerance, insulin sensitivity and liver fat metabolism were measured. KEY RESULTS: DIOcit-stat mice showed lower body weight, fat mass and epididymal fat depots compared with other DIO groups. Unlike other DIO groups, glucose tolerance and insulin sensitivity of DIOcit-stat, along with blood glucose and insulin concentrations in response to feeding, were restored to control values. Refeeding induced changes in liver lipogenic activity were also reduced in DIOcit-stat mice compared with those of DIO animals. This was associated with decreased gene expression of the transcription factor SREBP-1, liver X receptor alpha, ChREBP and of target lipogenic enzymes in the liver of DIOcit-stat mice compared with those of other DIO groups. CONCLUSIONS AND IMPLICATIONS: The citrulline atorvastatin combination prevented fat mass accumulation and maintained glucose homeostasis in DIO mice. Furthermore, it potentiated inhibition of hepatic de novo lipogenesis activity. This combination has potential for preservation of glucose homeostasis in patients receiving statin therapy. PMID- 26228178 TI - Effect of CPP-ACP Paste on Enamel Carious Lesion of Primary Upper Anterior Teeth Assessed by Quantitative Light-Induced Fluorescence: A One-Year Clinical Trial. AB - The purpose of this clinical trial was to evaluate the effect of 1 year of daily application of 10% w/v CPP-ACP (casein phosphopeptide-amorphous calcium phosphate) paste in addition to regular toothbrushing with fluoridated toothpaste on the remineralization of enamel carious lesions in preschool children using quantitative light-induced fluorescence (QLF). A total of 103 Thai children (aged 2(1)/2-3(1)/2 years) with high caries risk who had at least 1 enamel carious lesion (ICDAS 1-3) on the labial surface of the upper anterior teeth were assigned to receive either CPP-ACP paste (n = 53) or placebo control (n = 50) following toothbrushing with fluoridated toothpaste after lunch at school. QLF measurement was performed at baseline, 6 months and 1 year. At 1 year, a significant reduction in fluorescence loss (DeltaF), lesion area and lesion volume (DeltaQ; p <= 0.001) of the lesions were found over time in both groups. However, no significant difference was observed between the groups (p = 0.79, 0.98 and 0.88, respectively). There was no statistically significant difference between the odds of DeltaQ transition to a stage of regression or arrest compared with progression from baseline to 1 year between the two groups (OR = 1.03, 95% CI 0.31-3.39). The daily application of 10% w/v CPP-ACP paste on a school day for 1 year resulted in no improvement of enamel carious lesion remineralization in the primary upper anterior teeth as assessed by QLF. The lesion improvement was not superior to remineralization from regular toothbrushing with fluoridated toothpaste alone in these children. PMID- 26228180 TI - Influence of electric current pulses on the solidification of Cu-Bi-Sn immiscible alloys. AB - Continuous solidification experiments were carried out with Cu-Bi-Sn alloys under the effects of Electric Current Pulses (ECPs). A model describing the microstructure evolution was developed. The formation of the microstructure in the continuously solidified alloys was calculated. The calculations demonstrated that ECPs mainly affect the solidification process through changing the energy barrier for the nucleation of the minority phase droplets (MPDs). When the matrix liquid has a lower electric conductivity compared to the MPD, the ECPs lead to a decrease in the energy barrier for the nucleation of the MPDs which then promote the formation of a finely dispersed microstructure. When the matrix liquid has a higher electric conductivity compared to the MPD, the ECPs cause an increase in the energy barrier for the nucleation and lead to the formation of a phase segregated microstructure. PMID- 26228181 TI - Advocacy skills in resident doctors. AB - BACKGROUND: The objective of this project was to study whether a standardised patient clinical encounter learning exercise improved an Obstetrics and Gynaecology (OBGYN) resident's ability to perform patient advocacy, a systems based practice skill. METHODS: Case-control study: each of the 12 residents functioned as their own control. Additionally, aggregate data from the programme was reviewed. RESULTS: Twelve residents from a mid-sized OBGYN residency programme performed a standardised patient clinical encounter exercise in March of 2014. As demonstrated by the Assessment for Professional Behavior (APB) 360 degrees evaluation, the overall total scores for the programme on patient advocacy improved, with statistical significance, when analysed by the signed ranked test. Additionally, the residents' self-identified capability to perform advocacy improved after the programme, with statistical significance, when analysed by the signed rank test. CONCLUSIONS: A standardised patient clinical encounter, used as a learning exercise, can demonstrate meaningful improvement in the advocacy skills of a resident doctor. PMID- 26228182 TI - ROC residuals in signal-detection models of recognition memory. AB - A long-standing debate in the recognition-memory literature concerns which model provides the best account. Prominent candidates in this debate are the unequal variance signal detection model (UVSD), the dual-process model (DPSD), and two versions of the mixture model (MSD). The present work evaluates a recently proposed ROC-based method for comparing these models (Dede, Squire, & Wixted, Neuropsychologia, 54, 51-56, 2014). This method consists of evaluating the pattern of residuals produced by each model's best fits to ROC data. Previous results showed that the DPSD produced systematic residuals while the UVSD did not, a difference that was interpreted as evidence for the superiority of the latter model. Using a linear mixed model (LMM), we evaluated each model's residuals for 883 individual ROCs. LMM results revealed the presence of systematic residuals in all candidate models, indicating a general failure of these models to capture some of the regularities found in the data. We discuss different ways that current signal detection models can be modified or extended in order to meet the challenge that these systematic residuals represent. PMID- 26228183 TI - Visuospatial cueing by self-caused features: Orienting of attention and action outcome associative learning. AB - The effect of a salient visual feature in orienting spatial attention was examined as a function of the learned association between the visual feature and the observer's action. During an initial acquisition phase, participants learned that two keypress actions consistently produced red and green visual cues. Next, in a test phase, participants' actions continued to result in singletons, but their color could be either congruent or incongruent with the learned action color associations. Furthermore, the color singletons now functioned as valid or invalid spatial cues in a visual search, in which participants looked for a tilted line ("/" or "?") among distractors ("X"s). The results showed that an action-congruent color was more effective as a valid cue in the search task (increased benefit), but less effective as an invalid cue (reduced cost). We discuss our findings in terms of both an inhibition account and a preactivation account of action-driven sensory bias, and argue in favor of the preactivation account. PMID- 26228184 TI - Effect of gestational age and blood glucose on C-peptide excretion rate and clearance in neonates. AB - AIMS: The aim of this study was to measure urinary C-peptide concentrations, and then calculate C-peptide clearance (Cl), and excretion rate (UER) in neonates. In addition, the effect of gestational age (GA) and blood glucose levels (BGL) on C peptide UER were investigated. METHODS: Insulin concentrations in plasma and C peptide concentrations were measured in plasma and urine, in 20 neonates. Chemiluminescent immunoassays were used for insulin and C-peptide measurements, with urine diluted to 40% with bovine serum albumin 1% in phosphate buffered saline. Urine volume and time of collection were recorded and used to calculate UER and Cl. RESULTS: The mean Cl of C-peptide was 0.309 +/- 0.329 mL/min/kg, and UER was 0.0329 +/- 0.0342 pmol/min/kg. Correlations between Cl or UER and GA were not significant (P > 0.05). No significant correlation was shown between Cl or UER and BGL (P > 0.05). CONCLUSIONS: Both Cl and UER were highly variable in neonates, but were not correlated with GA. Additionally, BGL did not appear to affect C-peptide UER and Cl. As GA and BGL did not appear to affect Cl and UER, urinary C-peptide may provide a non-invasive method of measuring insulin production in neonates. PMID- 26228185 TI - A study of sacral anthropometry to determine S1 screw placement for spinal lumbosacral fixation in the Korean population. AB - PURPOSE: 1. To investigate the incidence of closed-type PSIS in the Korean population. 2. To categorize the morphological features of Korean sacrum. 3. To measure the safe marginal length and angle for screw fixation considering the PSIS and course of the external iliac vein, using a Korean sacrum model. METHODS: We performed our study in 160 sacra including the pelvic ring obtained from 80 Korean cadavers. The bony measurements were obtained by performing 1-mm computed tomography cuts from the L5 lumbar vertebra to the pelvic ring and excluding other structures. We evaluated the incidence of anatomic variation of the PSIS and measured the safe marginal length and angle for screw fixation considering the PSIS and course of the external iliac vein, using a Korean sacrum model. RESULTS: Our study showed that the closed type of PSIS is more frequent in males than in females. The optimal angle for screw fixation is 16.91 +/- 6.85 ( degrees ), while the left side S1 pedicle insertion angle is 16.00 +/- 6.20 ( degrees ). The average Korean optimal screw length is 58.35 +/- 14.90 (cm) for the right side and 55.89 +/- 16.16 (cm) for the left side. CONCLUSION: With reference to these parameters, the optimal screw length and angle can be chosen and bicortical anteromedial screw fixation can be easily and safely performed. PMID- 26228186 TI - Nontraumatic spinal subdural hematoma complicating direct factor Xa inhibitor treatment (rivaroxaban): a challenging management. AB - PURPOSE: We report on a 72-year-old male patient who developed a nontraumatic spinal subdural hematoma (SSDH) during rivaroxaban therapy, a relatively new orally administered direct factor Xa inhibitor. CASE DESCRIPTION: The patient sustained a sudden onset of interscapular pain, followed by gait impairment and paraplegia. Magnetic resonance imaging (MRI) of the spine demonstrated SSDH from T6 to T8. Laboratory tests revealed a high rivaroxaban level, associated with a major hemorrhagic risk. Surgery was, therefore, performed the following morning, after normalization of coagulation parameters. CONCLUSION: Determining the time of safe surgery remains challenging when hemorrhagic complications happen with direct factor Xa inhibitor, especially when neurological prognosis is engaged. Spinal subdural hematoma has not previously been reported following rivaroxaban therapy. PMID- 26228187 TI - The presence of stem cells in potential stem cell niches of the intervertebral disc region: an in vitro study on rats. AB - PURPOSE: The potential of stem cell niches (SCNs) in the intervertebral disc (IVD) region, which may be of great significance in the regeneration process, was recently proposed. To the best of our knowledge, no previous in vitro study has examined the characteristics of stem cells derived from the potential SCN of IVD (ISN). Therefore, increasing knowledge on ISN-derived stem cells (ISN-SCs) may provide a greater understanding of IVD degeneration and regeneration processes. We aimed to demonstrate the existence of ISN-SCs and to compare their characteristics with bone marrow mesenchymal stem cells (BMSCs) in vitro. METHODS: Sprague-Dawley rats (male, 10-week-old) were used in this study. ISN tissues were separated by ophthalmic surgical instruments under a dissecting microscope according to the anatomical areas. BMSCs and cells isolated from the ISN tissues were cultured and expanded in vitro. Passage 4 populations were used for further analysis with respect to colony-forming ability, cellular immunophenotype, cell cycle, stem cell-related gene expression, and proliferation and multipotential differentiation capacities. RESULTS: In general, both of ISN SCs and mesenchymal stromal cells (MSCs) met the minimal criteria for the definition of multipotent mesenchymal stromal cells, including adherence to plastic, specific surface antigen expression, and multipotent differentiation potential. Especially, ISN-SCs even showed greater potential of osteogenesis and chondrogenesis. The ISN-SCs also expressed stem cell-related genes that were comparable to those of BMSCs, and had colony-forming and self-renewal abilities. CONCLUSIONS: To the best of our knowledge, this is the first in vitro study aimed towards determining the existence and characteristics of ISN-SCs, which belong to the MSC family and with greater osteogenic and chondrogenic abilities than BMSCs according to our data. This finding may be of great significance for additional studies that investigate the migration of ISN-SCs into the IVD, and may provide a new perspective on different biological approaches for IVD self-regeneration. PMID- 26228189 TI - Up close and personal with low-molecular-weight heparins (LMWHs). PMID- 26228188 TI - Pancreatic beta-cell imaging in humans: fiction or option? AB - Diabetes mellitus is a growing worldwide epidemic disease, currently affecting 1 in 12 adults. Treatment of disease complications typically consumes ~10% of healthcare budgets in developed societies. Whilst immune-mediated destruction of insulin-secreting pancreatic beta cells is responsible for Type 1 diabetes, both the loss and dysfunction of these cells underly the more prevalent Type 2 diabetes. The establishment of robust drug development programmes aimed at beta cell restoration is still hampered by the absence of means to measure beta-cell mass prospectively in vivo, an approach which would provide new opportunities for understanding disease mechanisms and ultimately assigning personalized treatments. In the present review, we describe the progress towards this goal achieved by the Innovative Medicines Initiative in Diabetes, a collaborative public-private consortium supported by the European Commission and by dedicated resources of pharmaceutical companies. We compare several of the available imaging methods and molecular targets and provide suggestions as to the likeliest to lead to tractable approaches. Furthermore, we discuss the simultaneous development of animal models that can be used to measure subtle changes in beta cell mass, a prerequisite for validating the clinical potential of the different imaging tracers. PMID- 26228190 TI - Review on immunotherapy in airway allergen sensitised patients. AB - Allergen immunotherapy is a more than 100-year-old treatment in particular for birch pollen, grass pollen, house dust mite and cat dander sensitised allergic patients. The mechanism of allergen-specific immunotherapy is complex. Different hypotheses have been postulated to explain the mode of action, such as a decrease of the number of tissue mast cells, eosinophils and basophils, an increase of IgG4 and IgA synthesis, a shift from Th2 to Th1 cells and an increase in the number and function of IL-10 producing T-regulatory cells (T-reg). All these immunological effects may contribute to immune tolerance and long-term changes in the immune system. The efficacy and safety of subcutaneous (SCIT) and sublingual immunotherapy (SLIT) with pollen and house dust mite have been investigated in many trials, meta-analyses and reviews. Nowadays grass pollen SLIT and SCIT, and birch pollen and house dust mite SCIT are implemented in clinical practice to treat therapy-resistant patients. However, the treatment is not effective for all patients and often not without side effects. Therefore, the development of new, safer and more effective immunotherapies is needed. These are approached along novel routes, including improved administration, combined treatment with immune response modifiers, fusion with immune response modifiers, allergen coupled to adjuvants and reconstruction of natural extracts with multiple recombinant allergens or with modified allergens. These developments are promising, but more research is required to implement them in clinical practice. PMID- 26228191 TI - Anticoagulation with dalteparin and nadroparin in nocturnal haemodialysis. AB - BACKGROUND: Low-molecular-weight heparins (LMWHs) are increasingly used as anticoagulant during haemodialysis. The aim of this study is to establish the efficiency and duration of anticoagulation with dalteparin and nadroparin administration in patients treated with nocturnal haemodialysis. METHODS: All patients were treated with nocturnal in-centre haemodialysis, 3-4 times a week. Anticoagulation was obtained with dalteparin (n = 15) or nadroparin (n = 10). Anti-factor- Xa activity was measured during a midweek dialysis session at t = 0, 4 and 8 hours. RESULTS: The LMWH dose necessary to prevent extracorporeal circuit clotting was higher for dalteparin than for nadroparin. In the dalteparin group, anti-Xa activity was almost negligible at the start of dialysis whereas most patients on nadroparin still had anti-Xa activity at the start of dialysis (0.08 (IQR 0.05-0.11) IU/ml), reflecting the effect of previous LMWH administration. After eight hours of dialysis, median anti-factor-Xa activity was 0.49 (IQR 0.22 0.57) after dalteparin and 0.69 (IQR 0.55- .83) after nadroparin (p = 0.01). When a target range of 0.2-0.6 IU/ml was applied, the present dosing method led to over-anticoagulation in more than half of the patients. CONCLUSION: Administration of two doses of LMWH is an effective method of anticoagulation in nocturnal, eight-hour haemodialysis. With two doses of dalteparin, a larger proportion of patients reached but did not exceed target levels of anticoagulation, compared with two doses of nadroparin. Nadroparin caused prolonged anti-Xa activity with measurable anticoagulation up to the next dialysis session. The measurement of anti-Xa activity is advocated for dose assessment of LMWH, when LMWH is used as anticoagulant during nocturnal haemodialysis. PMID- 26228192 TI - Do patients with newly diagnosed type 2 diabetes have impaired physical fitness, and energy expenditures? AB - BACKGROUND: The disease-related components such as physical fitness and daily energy expenditure may change in each progressive period of type 2 diabetes. The purpose of this study was to compare the maximal aerobic capacity (VO2 max), muscle strength, trunk flexibility, total energy expenditure, daily physical activity, resting metabolic rate (RMR), body composition, and body fat distribution in newly diagnosed type 2 diabetic patients with those of healthy controls. METHODS: Eighty patients (40 male, 40 female) with type 2 diabetes and 80 (40 male, 40 female) controls were included in this study. All participants completed the measurements. RESULTS: It was determined that the VO2 max, muscle strength, daily number of steps, and total energy expenditure were lower, and the body fat percentage, and central obesity were higher in male and female type 2 diabetic patients, when compared with the controls. In addition, the lean body mass was decreased in male diabetic patients, compared with the controls. The fasting plasma glucose showed negative correlations with the maximal aerobic capacity, daily number of steps, and muscle strength in the patients in both genders. RMR and trunk flexibility values were not significantly different between the patients and the controls in either gender. CONCLUSION: We suggest that using exercise intervention especially comprised of strength training and aerobic activities, including not only daily slow activities but also moderate to vigorous activities, as a lifestyle modification in newly diagnosed type 2 diabetic patients might be helpful for the development of earlier and more successful illness management strategies. PMID- 26228193 TI - Immunosuppressive therapy in patients with IgA nephropathy. AB - BACKGROUND: There is limited evidence to support cytotoxic therapy in patients with IgA nephropathy and renal insufficiency. We studied the effect of cytotoxic therapy in patients with IgA nephropathy and renal insufficiency, and evaluated possible predictors of response. METHODS: Retrospective analysis of patients with IgA nephropathy who received immunosuppressive therapy. The primary outcome measure was progression of renal disease, defined as an increase in serum creatinine levels of >= 50% or development of end-stage renal disease. RESULTS: From 1996 to 2008, 19 patients with biopsy-proven IgA nephropathy were treated with cytotoxic agents and prednisone because of renal insufficiency and/ or severe proteinuria. Characteristics of patients at the start of therapy: age 42±11 years, serum creatinine 208 (96-490) MUmol/l, estimated glomerular filtration rate (eGFR) 33 (12-65) ml/min/1.73 m2, and protein- creatinine ratio 3.8 (0.6-18.2) g/10 mmol. Follow-up after initiation of therapy was 35 (7-133) months. Ten patients had progressive renal disease, whereas eGFR was stable in nine. Serum creatinine levels and proteinuria at the start of treatment were not significantly different between responders and non- responders. Proteinuria response at six months after start of therapy proved a good predictor: proteinuria decreased by >= 50% and/or reached levels below 1 g/day in 8/9 responders. In contrast, proteinuria decreased by more than 50% and reached levels < 1 g/day in only 3/10 non-responders (p < 0.01). CONCLUSION: Prolonged immunosuppressive therapy with cytotoxic agents and prednisone may benefit a subgroup of patients with progressive IgA nephropathy. A reduction of proteinuria >= 50% to levels below 1 g/day within six months predicts a favourable long-term response. PMID- 26228194 TI - Myelopathy in systemic lupus erythematosus: a case report and a review of the literature. AB - Myelopathy, a severe condition characterised by paraparesis, sensory deficits and sphincter dysfunction, is one of the neuropsychiatric manifestations that have been described in patients with systemic lupus erythematosus (SLE). SLE associated myelopathy may confront clinicians with a challenging decision-making process due to the broad differential diagnosis, the lack of disease-specific findings, and the urgency to initiate immunosuppressive therapy early in the course of the disease to favourably affect outcome. PMID- 26228195 TI - Horner's syndrome in a patient presenting with chest pain. AB - An altered mental status and peripheral nerve dysfunction are alarming signs in a patient presenting with chest pain. If complicated by acute myocardial infarction, this raises the suspicion of aortic dissection and warrants immediate CT angiography. We report a dramatic case of chest pain in a 79-year-old man with somnolence and Horner's syndrome, subsequently complicated by myocardial infarction. Autopsy demonstrated a type A aortic dissection involving the carotid arteries and the right coronary artery. PMID- 26228196 TI - Melioidosis and renal failure in a Dutch man after a trip to Gambia. AB - Melioidosis is due to Burkholderia pseudomallei and is known to be endemic in South-East Asia, while epidemiology of disease in Sub-Saharan Africa is still unclear. Prompt recognition of infection is crucial for adequate antibiotic treatment. Infection can lead to visceral abcesses and awareness of this complication is important for proper management. PMID- 26228197 TI - A 29-year-old woman with multiple pulmonary masses. Synovial sarcoma. PMID- 26228199 TI - A 7-year-old boy with fever, rash and coughing. Erythema multiforme (EM) major. PMID- 26228201 TI - Survival after intoxication with inhaled methanol. PMID- 26228202 TI - Lung ultrasound: the need of an adequate training for the next generation of internists. PMID- 26228203 TI - Response to the letter of Trovato et al. PMID- 26228204 TI - Esophagogastric junctional adenocarcinoma originating from endoscopically unrecognizable Barrett's epithelium. PMID- 26228205 TI - Virtual Reality Training with Cognitive Load Improves Walking Function in Chronic Stroke Patients. AB - Virtual reality training is considered as an effective intervention method of stroke patients, and the virtual reality system for therapeutic rehabilitation has emphasized the cognitive factors to improve walking function. The purpose of current study was to investigate the effect of virtual reality training with cognitive load (VRTCL) on walking function of chronic stroke. Chronic stroke patients were randomly assigned to the VRTCL group (11 patients, including 5 men; mean age, 60.0 years; post-stroke duration, 273.9 days) or control group (11 patients, including 2 men; mean age, 58.6 years; post-stroke duration, 263.9 days). All subjects participated in the standard rehabilitation program that consisted of physical and occupational therapies. In addition, VRTCL group participated in the VRTCL for 4 weeks (30 min per day and five times a week), while those in the control group participated in virtual reality treadmill training. Walking function under single (walking alone) and dual task (walking with cognitive tasks) conditions was assessed using an electrical walkway system. After the 4-week intervention, under both single and dual task conditions, significant improvement on walking function was observed in VRTCL and control groups (P < 0.05). In addition, in the dual task condition, greater improvement on walking function was observed in the VRTCL group, compared with the control group (P < 0.05). These findings demonstrated the efficacy of VRTCL on the walking function under the dual task condition. Therefore, we suggest that VRTCL may be an effective method for the achievement of independent walking in chronic stroke patients. PMID- 26228206 TI - The MEK1/2 Inhibitor Pimasertib Enhances Gemcitabine Efficacy in Pancreatic Cancer Models by Altering Ribonucleotide Reductase Subunit-1 (RRM1). AB - PURPOSE: Gemcitabine, a nucleoside analogue, is an important treatment for locally advanced and metastatic pancreatic ductal adenocarcinoma (PDAC) but provides only modest survival benefit. Targeting downstream effectors of the RAS/ERK signaling pathway by direct inhibition of MEK1/2 proteins is a promising therapeutic strategy, as aberrant activation of this pathway occurs frequently in PDAC. In this study, the ability of pimasertib, a selective allosteric MEK1/2 inhibitor, to enhance gemcitabine efficacy was tested and the molecular mechanism of their interaction was investigated. EXPERIMENTAL DESIGN: Cell survival and apoptosis were assessed by MTT and Caspase 3/7 Glo assays in human pancreatic cancer cell lines. Protein expression was detected by immunoblotting. The in vivo sensitivity of gemcitabine with pimasertib was evaluated in an orthotopic model of pancreatic tumor. RESULTS: Synergistic activity was observed when gemcitabine was combined sequentially with pimasertib, in human pancreatic cancer cells. In particular, pimasertib reduced ribonucleotide reductase subunit 1 (RRM1) protein, and this was associated with sensitivity to gemcitabine. Pretreatment with MG132 impaired reduction of RRM1 protein induced by pimasertib, suggesting that RRM1 is degraded posttranslationally. Immunoprecipitation indicated enhanced MDM2 mediated polyubiquitination of RRM1 through Lys-48-mediated linkage following pimasertib treatment, an effect mediated, in part, by AKT. Finally, the combination treatment with pimasertib and gemcitabine caused significant tumor growth delays in an orthotopic pancreatic cancer model, with RRM1 downregulation in pimasertib-treated mice. CONCLUSIONS: These results confirm an important role of RRM1 in gemcitabine response and indicate MEK as a potential target to sensitize gemcitabine therapy for PDAC. Clin Cancer Res; 21(24); 5563-77. (c)2015 AACR. PMID- 26228207 TI - Prevalence of the Metabolic Syndrome Among Employees in Northeast China. AB - BACKGROUND: The metabolic syndrome is a clustering of metabolic abnormalities and has been associated with increased risk of type 2 diabetes mellitus and cardiovascular disease. This study aimed to estimate the prevalence of the metabolic syndrome among employees in Northeast China. METHODS: Totally, 33,149 employees who received health screening in the International Health Promotion Center in the First Hospital of Jilin University were enrolled. Height, weight, waist circumference, blood pressure, fasting plasma glucose, triglyceride, high density lipoprotein, and low-density lipoprotein were recorded. Three definitions for the metabolic syndrome were applied, revised National Cholesterol Education Program's Adult Treatment Panel III (NCEP ATP III) criteria, the International Diabetes Federation (IDF) criteria, and the Chinese Diabetes Society (CDS) criteria. RESULTS: Overall, the age-standardized prevalence of the metabolic syndrome was 22.9%, 20.6%, and 15.3% based on definitions of revised NCEP ATP III criteria, the IDF criteria, and the CDS criteria, respectively. Men had higher age-standardized prevalence than women in all three definitions (P < 0.05). The prevalence was 27.1%, 24.5%, and 20.4% for men; 17.1%, 15.4%, and 8.3% for women, respectively. The most common metabolic component with the metabolic syndrome was overweight (54.7% of men had an elevated body mass index, and 35.9% of women had central obesity). CONCLUSIONS: A large proportion of employees among Northeast China have the metabolic syndrome. These findings place emphasis on the need to develop aggressive lifestyle modification for patients with the metabolic syndrome and population level strategies for the prevention, detection, and treatment of cardiovascular risk. PMID- 26228208 TI - Comparison of C50 for Propofol-remifentanil Target-controlled Infusion and Bispectral Index at Loss of Consciousness and Response to Painful Stimulus in Elderly and Young Patients. AB - BACKGROUND: In this prospective randomized study, we compared the predicted blood and effect-site C 50 for propofol and remifentanil target-controlled infusion (TCI) and the bispectral index (BIS) values at loss of consciousness (LOC) and response to a standard noxious painful stimulus (LOS) in elderly and young patients, respectively. We hypothesized that the elderly patients will require lower target concentration of both propofol and remifentanil at above two clinical end-points. METHODS: There were 80 American Society of Anesthesiologists (ASA) physical status I-II unpremedicated patients enrolled in this study, they were divided into elderly group (age >=65 years, n = 40) and young group (aged 18 64 years, n = 40). Propofol was initially given to a predicted blood concentration of 1.2 MUg/ml and thereafter increased by 0.3 MUg/ml every 30 s until Observer's Assessment of Alertness and Sedation score was 1. The propofol level was kept constant, and remifentanil was given to provide a predict blood concentration of 2.0 ng/ml, and then increased by 0.3 ng/ml every 30 s until loss of response to a tetanic stimulus. BIS (version 3.22, BIS Quattro sensor) was also recorded. RESULTS: In elderly group, the propofol effect-site C 50 at LOC of was 1.5 (1.4-1.6) MUg/ml, was significantly lower than that of young group, which was 2.2 (2.1-2.3) MUg/ml, the remifentanil effect-site C 50 at LOS was 3.5 (3.3 3.7) ng/ml in elderly patients, was similar with 3.7 (3.6-3.8) ng/ml in young patients. Fifty percent of patients lost consciousness at a BIS value of 57.3 (56.4-58.1), was similar with that of young group, which was 55.2 (54.0-56.3). CONCLUSION: In elderly patients, the predicted blood and effect-site concentrations of propofol at LOC were lower than that of young patients. At same sedation status, predicted blood and effect-site concentrations of remifentanil required at LOS were similar in elderly and young patients. BIS were not affected by age. Low-propofol/high-opioid may be optional TCI strategy for elderly patients. PMID- 26228209 TI - Fractional Flow Reserve Guided Percutaneous Coronary Intervention Improves Clinical Outcome with Reduced Cost in Contemporary Clinical Practice. AB - BACKGROUND: Fractional flow reserve (FFR) is currently considered as the gold standard for evaluating the functional significance of coronary stenosis. However, its potential benefits in real-world practice remain unknown in China. This study aimed to test the hypothesis that the use of FFR is associated with improved outcome and reduced cost in Chinese real-world clinical practice. METHODS: A retrospective cohort study was carried out using the database of Second Affiliated Hospital of Zhejiang University, a tertiary and high-volume center in China. Clinical events were compared using the Cox proportional hazards model during a median follow-up of 13 months. RESULTS: The study cohort consisted of 366 consecutive patients referred for coronary revascularization with adjunct FFR and 366 matched controls, from 2010 to 2014. Major adverse cardiac events (MACEs) (death, myocardial infarction, repeated revascularization, or hospitalization for angina) at 4 years were found in 12.0% of angiography-guided patients and 4.9% in the FFR-guided group (P < 0.001). The mean number of implanted stents was significantly lower in FFR treated subjects (0.52 +/- 0.82 stents) compared with the angiography-guided group (0.93 +/- 0.96 stents) (P < 0.001). No difference in overall costs at initial hospitalization was observed between angiography-guided percutaneous coronary intervention (PCI) compared with FFR-guided PCI (RMB 33,000 Yuan, range: RMB 7393-44,700 Yuan) versus RMB 21,200 Yuan (RMB 19,100-47,100 Yuan) (P = 0.54). However, costs for MACEs during follow up were significantly reduced in the FFR-guided arm (P < 0.001). CONCLUSIONS: In the contemporary clinical practice, FFR-guided PCI is associated with decreased use of stents, improved clinical outcome, and reduced costs, compared with angiography-guided PCI. PMID- 26228210 TI - Serum Gamma-glutamyl Transferase Concentration Within the Reference Range is Related to the Coronary Heart Disease Risk Prediction in Korean Men: Analysis of the Korea National Health and Nutrition Examination Survey (V-1, 2010 and V-2, 2011). AB - BACKGROUND: Limited data exist on the association of serum gamma-glutamyl transferase (GGT) level within the reference range with the increased risk of coronary heart disease (CHD) prediction in men. The study examined the association between serum GGT concentration within the reference range and the CHD risk prediction in Korean men. METHODS: The study employed data from Korean National Health and Nutrition Examination Survey (V-1, 2010 and V-2, 2011) where a total of 1301 individuals were analyzed. A 10-year CHD risk prediction was computed using the Framingham Risk Score (FRS) modified by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III). RESULTS: Positive correlations were established between log-transformed GGT concentration and FRS (r = 0.237, P < 0.001). After adjustment of body mass index, the amount of alcohol intake and low-density lipoprotein-cholesterol, the odds ratio (95% confidence interval) for intermediate risk and beyond of 10-year CHD prediction (10-year risk >=10%) with lowest quartile of participants was 1.21 (0.78-1.87) for second quartiles, 1.39 (0.88-2.21) for third quartiles and 2.03 (1.23-3.34) for highest quartiles. CONCLUSIONS: Higher serum GGT within its reference range was significantly correlated with a 10-year CHD risk prediction estimation using NCEP ATP III in Korean men. PMID- 26228211 TI - Use of Platelet Indices for Determining Illness Severity and Predicting Prognosis in Critically Ill Patients. AB - BACKGROUND: Decreased platelet (PLT) count is one of the independent risk factors for mortality in intensive care unit (ICU) patients. This study was to investigate the relationship between PLT indices and illness severity and their performances in predicting hospital mortality. METHODS: Adult patients who admitted to ICU of Changzheng Hospital from January 2011 to September 2012 and met inclusion criteria were included in this study. Univariate analysis was used to identify potential independent risk factors for mortality. Multiple logistic regression analysis was used to calculate adjusted odds ratio for mortality in patients with normal or abnormal PLT indices. The relationship between PLT indices and illness severity were assessed by the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores or sequential organ failure assessment (SOFA) scores in patients with normal and abnormal PLT indices. The performances of PLT indices in predicting mortality were assessed by receiver operating curves and diagnostic parameters. The survival curves between patients with normal and abnormal PLT indices were compared using Kaplan-Meier method. RESULTS: From January 2011 to September 2012, 261 of 361 patients (204 survivors and 57 nonsurvivors) met the inclusion criteria. After adjustment for clinical variables, PLT count <100 * 10 12 /L (P = 0.011), plateletcrit (PCT) <0.108 (P = 0.002), mean platelet volume (MPV) >11.3 fL (P = 0.023) and platelet distribution width (PDW) percentage >17% (P = 0.009) were identified as independent risk factors for mortality. The APACHE II and SOFA scores were 14.0 (9.0-20.0) and 7.0 (5.0-10.5) in the "low PLT" tertile, 13.0 (8.0-16.0) and 7.0 (4.0-11.0) in the "low PCT" tertile, 14.0 (9.3-19.0) and 7.0 (4.0-9.8) in the "high MPV" tertile, 14.0 (10.5-20.0) and 7.0 (5.0-11.0) in the "high PDW" tertile, all of which were higher than those in patients with normal indices. Patients with decreased PLT and PCT values (all P < 0.001), or increased MPV and PDW values (P = 0.007 and 0.003, respectively) had shortened length of survival than those with normal PLT indices. CONCLUSIONS: Patients with abnormally low PLT count, high MPV value, and high PDW value were associated with more severe illness and had higher risk of death as compared to patients with normal PLT indices. PMID- 26228212 TI - Quantitative Detection of ID4 Gene Aberrant Methylation in the Differentiation of Myelodysplastic Syndrome from Aplastic Anemia. AB - BACKGROUND: The diagnosis of myelodysplastic syndrome (MDS), especially hypoplastic MDS, and MDS with low blast counts or normal karyotype may be problematic. This study characterized ID4 gene methylation in patients with MDS and aplastic anemia (AA). METHODS: The methylation status of ID4 was analyzed by bisulfite sequencing polymerase chain reaction (PCR) and quantitative real-time methylation-specific PCR (MethyLight PCR) in 100 patients with MDS and 31 patients with AA. RESULTS: The MDS group had a higher ID4 gene methylation positivity rate (22.22%) and higher methylation levels (0.21 [0-3.79]) than the AA group (P < 0.05). Furthermore, there were significant differences between the hypoplastic MDS and AA groups, the MDS with low blast count and the AA groups, and the MDS with normal karyotype and the AA groups. The combination of genetic and epigenetic markers was used in much more patients with MDS (62.5% [35/56]) than the use of genetic markers only (51.79% [29/56]). CONCLUSIONS: These results showed that the detection of ID4 methylation positivity rates and levels could be a useful biomarker for MDS diagnosis. PMID- 26228213 TI - Analyses of Potential Predictive Markers and Response to Targeted Therapy in Patients with Advanced Clear-cell Renal Cell Carcinoma. AB - BACKGROUND: Vascular endothelial growth factor-targeted agents are standard treatments in advanced clear-cell renal cell carcinoma (ccRCC), but biomarkers of activity are lacking. The aim of this study was to investigate the association of Von Hippel-Lindau (VHL) gene status, vascular endothelial growth factor receptor (VEGFR) or stem cell factor receptor (KIT) expression, and their relationships with characteristics and clinical outcome of advanced ccRCC. METHODS: A total of 59 patients who received targeted treatment with sunitinib or pazopanib were evaluated for determination at Cancer Hospital and Institute, Chinese Academy of Medical Sciences between January 2010 and November 2012. Paraffin-embedded tumor samples were collected and status of the VHL gene and expression of VEGFR and KIT were determined by VHL sequence analysis and immunohistochemistry. Clinical pathological features were collected and efficacy such as response rate and Median progression-free survival (PFS) and overall survival (OS) were calculated and then compared based on expression status. The Chi-square test, the Kaplan Meier method, and the Lon-rank test were used for statistical analyses. RESULTS: Of 59 patients, objective responses were observed in 28 patients (47.5%). The median PFS was 13.8 months and median OS was 39.9 months. There was an improved PFS in patients with the following clinical features: Male gender, number of metastatic sites 2 or less, VEGFR-2 positive or KIT positive. Eleven patients (18.6%) had evidence of VHL mutation, with an objective response rate of 45.5%, which showed no difference with patients with no VHL mutation (47.9%). VHL mutation status did not correlate with either overall response rate (P = 0.938) or PFS (P = 0.277). The PFS was 17.6 months and 22.2 months in VEGFR-2 positive patients and KIT positive patients, respectively, which was significantly longer than that of VEGFR-2 or KIT negative patients (P = 0.026 and P = 0.043). CONCLUSION: VHL mutation status could not predict the efficacy of sunitinib or pazopanib. Further investigation of VHL/VEGFR pathway components is needed. PMID- 26228214 TI - Glycemic Variation in Tumor Patients with Total Parenteral Nutrition. AB - BACKGROUND: Hyperglycemia is associated with poor clinical outcomes and mortality in several patients. However, studies evaluating hyperglycemia variation in tumor patients receiving total parenteral nutrition (TPN) are scarce. The aim of this study was to assess the relationship between glycemia and tumor kinds with TPN by monitoring glycemic variation in tumor patients. METHODS: This retrospective clinical trial selected 312 patients with various cancer types, whose unique nutrition treatment was TPN during the monitoring period. All patients had blood glucose (BG) values assessed at least six times daily during the TPN infusion. The glycemic variation before and after TPN was set as the indicator to evaluate the factors influencing BG. RESULTS: The clinical trial lasted 7.5 +/- 3.0 days adjusted for age, gender, family cancer history and blood types. There were six cancer types: Hepatic carcinoma (HC, 21.8%), rectal carcinoma (17.3%), colon carcinoma (CC, 14.7%), gastric carcinoma (29.8%), pancreatic carcinoma (11.5%), and duodenal carcinoma (DC, 4.8%). The patients were divided into diabetes and nondiabetes groups. No statistical differences in TPN glucose content between diabetes and nondiabetes groups were found; however, the tumor types affected by BG values were obvious. With increasing BG values, DC, HC and CC were more represented than other tumor types in this sequence in diabetic individuals, as well as in the nondiabetic group. BG was inclined to be more easily influenced in the nondiabetes group. Other factors did not impact BG values, including gender, body mass index, and TPN infusion duration time. CONCLUSIONS: When tumor patients are treated with TPN, BG levels should be monitored according to different types of tumors, besides differentiating diabetes or nondiabetes patients. Special BG control is needed for DC, HC and CC in both diabetic and nondiabetic patients. If BG overtly increases, positive measurements are needed to control BG values. The ClinicalTrials.gov ID is NCT02024321. PMID- 26228215 TI - Study of Individual Characteristic Abdominal Wall Thickness Based on Magnetic Anchored Surgical Instruments. AB - BACKGROUND: Magnetic anchored surgical instruments (MASI), relying on magnetic force, can break through the limitations of the single port approach in dexterity. Individual characteristic abdominal wall thickness (ICAWT) deeply influences magnetic force that determines the safety of MASI. The purpose of this study was to research the abdominal wall characteristics in MASI applied environment to find ICAWT, and then construct an artful method to predict ICAWT, resulting in better safety and feasibility for MASI. METHODS: For MASI, ICAWT is referred to the thickness of thickest point in the applied environment. We determined ICAWT through finding the thickest point in computed tomography scans. We also investigated the traits of abdominal wall thickness to discover the factor that can be used to predict ICAWT. RESULTS: Abdominal wall at C point in the middle third lumbar vertebra plane (L3) is the thickest during chosen points. Fat layer thickness plays a more important role in abdominal wall thickness than muscle layer thickness. "BMI-ICAWT" curve was obtained based on abdominal wall thickness of C point in L3 plane, and the expression was as follow: f(x) = P1 * x 2 + P2 * x + P3, where P1 = 0.03916 (0.01776, 0.06056), P2 = 1.098 (0.03197, 2.164), P3 = -18.52 (-31.64, -5.412), R-square: 0.99. CONCLUSIONS: Abdominal wall thickness of C point at L3 could be regarded as ICAWT. BMI could be a reliable predictor of ICAWT. In the light of "BMI-ICAWT" curve, we may conveniently predict ICAWT by BMI, resulting a better safety and feasibility for MASI. PMID- 26228216 TI - Clinical Study of 224 Patients with Hypertriglyceridemia Pancreatitis. AB - BACKGROUND: Hypertriglyceridemia (HTG) is the most common etiology of acute pancreatitis (AP) after alcohol and gallstone-induced disease. Elevation of serum triglyceride (TG) levels to >= 1000 mg/dl in a patient with AP strongly indicates HTG as the cause. The absolute risk of pancreatitis based on serum TG <= 1000 mg/dl has not been clearly defined. The aims of this study were to address the role of elevated TG levels between 500 and 1000 mg/dl in the clinical course of HTG pancreatitis (HTGP); and assess the relationship between the level of serum TG and disease severity. METHODS: A total of 224 HTGP patients between 2007 and 2011 were divided into two subgroups. Totally, 122 patients in Group A had serum TG >1000 mg/dl; 102 patients in Group B had maximal TG levels between 500 and 1000 mg/dl accompanied by lactescent serum; 100 patients with biliary AP and 99 patients with alcoholic AP hospitalized during the study period were enrolled as controls. The clinical and biochemical data were analyzed. RESULTS: The clinical presentation of HTG-induced pancreatitis was similar to other causes. Severe form of AP in Group A was higher than Group B (chi2 = 4.002, P = 0.045). The severity with HTGP was significantly higher as compared to biliary AP (chi2 = 33.533, P = 0.000) and alcoholic AP (chi2 = 7.179, P = 0.007). Systemic complications with HTGP were significantly higher than biliary AP (chi2 = 58.763, P = 0.000). CONCLUSIONS: The study demonstrated that TG level >= 500 mg/dl should raise a high degree of suspicion, especially if no other etiology of AP is apparent. The severity of HTGP seems to correlate directly with TG level. HTGP seems be more severe than other causes of AP. PMID- 26228217 TI - Association between Polymorphism of Interleukin-23 Receptor and Hashimoto's Thyroiditis in Chinese Han Population of Shandong. AB - OBJECTIVE: The interleukin-23 receptor (IL-23R) has been shown to be associated with autoimmune diseases in many different populations. This study aimed to investigate the association between IL-23R gene polymorphism and susceptibility to Hashimoto's thyroiditis (HT) in Chinese Han population of Shandong. METHODS: A case-control cohort study was performed in 145 HT patients from First People's Hospital of Jining between February 2010 to October 2013 and 150 healthy controls. Two single nucleotide polymorphisms located in the promoter region of IL-23R gene (rs17375018 and rs7517847) were examined by polymerase chain reaction restriction fragment length polymorphism analysis. Hardy-Weinberg equilibrium was performed using the Chi-square test. Genotype frequencies were estimated by direct counting, and allele and genotype frequencies between patients and controls were analyzed by the Chi-square test. RESULTS: The rs17375018 GG genotype and the G allele were significantly increased in HT patients compared with healthy controls (P = 0.034 and P = 0.013, respectively). No association was identified between HT patients and healthy controls in rs7517847. CONCLUSION: The study demonstrated that polymorphism of IL-23R gene rs17375018 is highly associated with HT in Chinese Han population of Shandong, suggesting that IL-23R gene polymorphism (rs17375018 G) may play a critical role in susceptibility to HT. PMID- 26228218 TI - Comparison of Functional and Radiological Outcomes Between Two Posterior Approaches in the Treatment of Multilevel Cervical Spondylotic Myelopathy. AB - BACKGROUND: Posterior cervical decompression is an accepted treatment for multilevel cervical spondylotic myelopathy (CSM). Each posterior technique has its own advantages and disadvantages. In the present study, we compared the functional and radiological outcomes of expansive hemilaminectomy and laminoplasty with mini titanium plate in the treatment of multilevel CSM. METHODS: Forty-four patients with multilevel CSM treated with posterior cervical surgery in Department of Orthopedic Surgery, Beijing Army General Hospital from March 2011 to June 2012 were enrolled in this retrospective study. Patients were divided into two groups by surgical procedure: Laminoplasty (Group L) and hemilaminectomy (Group H). Perioperative parameters including age, sex, duration of symptoms, operative duration, and intraoperative blood loss were recorded and compared. Spinal canal area, calculated using AutoCAD (r) software(Autodesk Inc., San Rafael, CA, USA), and neurological improvement, evaluated with Japanese Orthopedic Association score, were also compared. RESULTS: Neurological improvement did not differ significantly between groups. Group H had a significantly shorter operative duration and significantly less blood loss. Mean expansion ratio was significantly greater in Group L (77.83 +/- 6.41%) than in Group H (62.72 +/- 3.86%) (P < 0.01). CONCLUSIONS: Both surgical approaches are safe and effective in treating multilevel CSM. Laminoplasty provides a greater degree of enlargement of the spinal canal, whereas expansive hemilaminectomy has the advantages of shorter operative duration and less intraoperative blood loss. PMID- 26228219 TI - Early Outcomes of Primary Total Hip Arthroplasty for Osteonecrosis of the Femoral Head in Patients with Human Immunodeficiency Virus in China. AB - BACKGROUND: Studies have reported that patients with human immunodeficiency virus (HIV) have a high incidence of osteonecrosis of the femoral head (ONFH). Total hip arthroplasty (THA) is an effective management of ONFH. However, little data exist regarding the use of THA for the HIV patients with ONFH in China. This study reviewed the outcomes of HIV-positive patients who underwent THA for ONFH, compared with HIV-negative individuals. METHODS: The patients who underwent THA for ONFH from September 2012 to September 2014 in Beijing Ditan Hospital, Capital Medical University were retrospectively studied. Twenty-eight HIV-positive patients and 35 HIV-negative patients underwent 48 THAs and 45 THAs with cementless components, respectively. Medical records and follow-up data were reviewed. Harris Hip Score (HHS) was applied to evaluate the pain and function of the hips before and after THA. Complications such as wound healing, surgical site infection, deep venous thrombosis, pulmonary embolism, sepsis, mortality, and complications from the prosthesis were reviewed. The operation time, blood loss, and hospital stay were compared between the two groups. RESULTS: The mean follow up period was 19.5 +/- 5.8 months (ranging from 6 to 30 months). The mean age of the HIV-positive patients with osteonecrosis at the time of surgery was 35 years old, which was significantly lower than that of the HIV-negative group (42 years old) (P < 0.05). The HIV-positive patients underwent surgery a mean of 2.5 years after their original symptoms, which was significantly shorter than the HIV negatives' (mean 4 years) (P < 0.05). Among HIV-positive patients, the prevalence of being male and rate of bilateral procedures were significantly higher than those in the HIV-negative group (P < 0.05). The operation time in HIV-positive patients was significantly longer than that in HIV-negative patients (P < 0.05). There were no significant differences in blood loss or hospital stay between the two groups (P > 0.05). The HHSs of two groups significantly improved after THAs (P < 0.05), without significant difference between two groups. No wound complication, sepsis, mortality, prosthesis complication, and occupational exposure occurred, except for two cases of heterotopic ossification and one case of humeral head necrosis. CONCLUSIONS: ONFH is more likely to occur bilaterally in younger HIV-positive males. The development of osteonecrosis seems faster in HIV-positive patients than in HIV-negative patients. This should be cautionary for asymptomatic HIV-positive patients with low viral RNA level and in the primary HIV stage. Despite longer operation times in the HIV-positive patients than in the HIV-negative patients, THA is still a safe and efficient approach to treat ONFH in HIV-positive patients. The incidence of complications is much lower than previously reported. However, the long-term follow-up is needed. PMID- 26228220 TI - Outcomes of Adults with Acute Lymphoblastic Leukemia After Autologous Hematopoietic Stem Cell Transplantation and the Significance of Pretransplantation Minimal Residual Disease: Analysis from a Single Center of China. AB - BACKGROUND: The postremission therapies for adult patients generally contain consolidation chemotherapy, allogeneic hematopoietic stem cell transplantation and autologous hematopoietic stem cell transplantation (auto-HSCT). Because of the various results from different centers, the optimal therapy for adult acute lymphoblastic leukemia (ALL) patients is still uncertain. This study aimed to better understand predictive factors and role of auto-HSCT in the postremission therapy for adult ALL patients. METHODS: The outcomes of 135 adult patients with ALL, who received the first auto-HSCT in Hematopoietic Stem Cell Transplantation Center of Blood Diseases Hospital, Chinese Academy of Medical Sciences from January 1, 1994 to February 28, 2014, were retrospectively analyzed. Survival curves were estimated using the Kaplan-Meier method and simultaneous effects of multiple covariates were estimated with the Cox model. RESULTS: Overall survival (OS) and disease-free survival (DFS) at 5 years for the whole cohort were 59.1 +/ 4.5% and 59.0 +/- 4.4%, respectively. The cumulative nonrelapse mortality and relapse rate at 5 years were 4.5 +/- 0.03% and 36.6 +/- 0.19%. For both OS and DFS, acute T-cell lymphoblastic leukemia, high lactate dehydrogenase (LDH) at diagnosis, blast cell proportion >=5% on the 15 th day of induction therapy, and extramedullary infiltration before HSCT were the poor prognosis factors. In addition, age >=35 years predicted poor DFS. Only T-ALL and high LDH were the independent undesirable factors associated with OS and DFS in Cox regression model. For 44 patients who had results of pretransplantation minimal residual disease (MRD), positive MRD (MRD >=0.01%) indicated poor OS (P = 0.044) and DFS (P = 0.008). Furthermore, for the standard risk group, the patients with negative MRD (MRD <0.01%) had better results (OS at 18 months was 90.0 +/- 9.5%, while for the patients with positive MRD OS was 50.0 +/- 35.4%, P = 0.003; DFS at 18 months was 90.0 +/- 9.5%, while for the positive MRD group DFS was 0%, P < 0.001). CONCLUSIONS: This study confirmed that auto-HSCT combined with posttransplantation maintenance chemotherapy could be an option for adult ALL patients and pretransplantation MRD may play a significant role in the direction of therapy for adult ALL patients. PMID- 26228221 TI - Prostatic Arterial Embolization with Small Sized Particles for the Treatment of Lower Urinary Tract Symptoms Due to Large Benign Prostatic Hyperplasia: Preliminary Results. AB - BACKGROUND: The clinical failure after prostatic artery embolization (PAE) with conventional particles was relatively high, in treatment for lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). We reported the results of PAE with combined polyvinyl alcohol particles 50 MUm and 100 MUm in size as a primary treatment in 24 patients with severe LUTS secondary to large BPH. METHODS: From July 2012 to June 2014, we performed PAE in 24 patients (65-85 years, mean 74.5 years) with severe LUTS due to large BPH (>=80 cm 3 ) and refractory to medical therapy. Embolization was performed using combination of 50 MUm and 100 MUm in particles size. Clinical follow-up was performed using the International Prostate Symptom Score (IPSS), quality of life (QoL), peak urinary flow (Q max ), postvoid residual (PVR) volume, the International Index of Erectile Function (IIEF), prostatic specific antigen (PSA), and prostatic volume measured by magnetic resonance imaging at 1, 3, 6, and every 6-month thereafter. Technical success was defined when PAE was completed in at least one pelvic side. Clinical success was defined as the improvement of both symptoms and QoL. A Student's t-test for paired samples was used. RESULTS: PAE was technically successful in 22 patients (92%). Bilateral PAE was performed in 19 (86%) patients and unilateral in 3 (14%) patients. Follow-up data were available for 22 patients observed for mean of 14 months. The clinical improvement at 1, 3, 6, and 12-month was 91%, 91%, 88%, and 83%, respectively. At 6-month follow-up, the mean IPSS, QoL, PVR, and Q max were from 27 to 8 (P = 0.001), from 4.5 to 2.0 (P = 0.002), from 140.0 ml to 55.0 ml (P = 0.002), and from 6.0 ml/s to 13.0 ml/s (P = 0.001), respectively. The mean prostate volume decreased from 110 cm 3 to 67.0 cm 3 (mean reduction of 39.1%; P = 0.001). The PSA and IIEF improvements after PAE did not differ from pre-PAE significantly. No major adverse events were noted. CONCLUSIONS: The combination of 50 MUm and 100 MUm particles for PAE is a safe and effective treatment method for patients with severe LUTS due to large BPH, which further improves the clinical results of PAE. PMID- 26228222 TI - Ranibizumab Plus Combined Surgery for Treatment of Neovascular Glaucoma with Vitreous Hemorrhage. AB - BACKGROUND: Neovascular glaucoma (NVG) is a refractory glaucoma. The management of NVG is very difficult, and it is more difficult when combined with vitreous hemorrhage. The aim of this study was to investigate the effects of ranibizumab plus combined surgery for NVG with vitreous hemorrhage. METHODS: A total of 26 eyes of 26 NVG patients with vitreous hemorrhage were recruited in this study. The patients aged from 36 to 63 years with a mean age of 51.97 +/- 7.60 years. The mean intraocular pressure (IOP) was 46.38 +/- 5.75 mmHg (1 mmHg = 0.133 kPa) while being treated with the maximum medical therapy. The mean best-corrected visual acuities converted to logarithm of the minimum angle of resolution (logMAR BCVA) was 2.62 +/- 0.43. All the patients underwent intravitreal injection of 0.5 mg (0.05 ml) ranibizumab combined with pars plana vitrectomy (PPV), pars plana lensectomy (PPL) with a preserved anterior capsule, panretinal photocoagulation (PRP), and trabeculectomy (intravitreal ranibizumab [IVR] + PPV + PPL + PRP + trabeculectomy). The IOP and logMAR BCVA were the main outcome measures in this study. RESULTS: The follow-up period was 12 months. The mean postoperative IOPs were 26.38 +/- 3.75 mmHg, 21.36 +/- 3.32 mmHg, 18.57 +/- 3.21 mmHg, and 16.68 +/- 2.96 mmHg, respectively at 7 days, 1 month, 3 months, and 12 months after PPV + PPL + PRP + trabeculectomy. At the last follow-up, the mean IOP was significantly lower than the preoperative one (t = 6.612, P = 0.001). At 7 days, 1 month, 3 months, and 12 months after PPV + PPL + PRP + trabeculectomy, the mean logMAR BCVA were 1.30 +/- 0.36, 1.29 +/- 0.37, 1.29 +/- 0.39, and 1.26 +/- 0.29, respectively. At the last follow-up, the mean logMAR BCVA was significantly improved, and the difference was statistically significant compared with preoperative one (t = 6.133, P = 0.002). The logMAR BCVA improved in 22 eyes (84.62%), and remained stable in 4 eyes (15.38%). The neovascularization in the iris and the angle regressed significantly in all patients 7 days after ranibizumab injection. No serious complications occurred during 12 months of the study. CONCLUSIONS: IVR + PPV + PPL + PRP + trabeculectomy can control IOP well and improve BCVA without severe complication for NVG patients with vitreous hemorrhage. PMID- 26228223 TI - The Number of Positive Pelvic Lymph Nodes and Multiple Groups of Pelvic Lymph Node Metastasis Influence Prognosis in Stage IA-IIB Cervical Squamous Cell Carcinoma. AB - BACKGROUND: Pelvic lymph node metastasis (LNM) is an important prognostic factor in cervical cancer. Cervical squamous cell carcinoma accounts for approximately 75-80% of all cervical cancers. Analyses of the effects of the number of positive lymph nodes (LNs), unilateral versus bilateral pelvic LNM and a single group versus multiple groups of pelvic LNM on survival and recurrence of cervical squamous cell carcinoma are still lacking. The study aimed to analyze the effects of the number of positive pelvic LNs and a single group versus multiple groups of pelvic LNM on survival and recurrence. METHODS: We performed a retrospective review of 296 patients diagnosed with Stage IA-IIB cervical squamous cell carcinoma who received extensive/sub-extensive hysterectomy with pelvic lymphadenectomy/pelvic LN sampling at Peking University People's Hospital from November 2004 to July 2013. Ten clinicopathological variables were evaluated as risk factors for pelvic LNM: Age at diagnosis, gravidity, clinical stage, histological grade, tumor diameter, lymph-vascular space involvement (LVSI), depth of cervical stromal invasion, uterine invasion, parametrial invasion, and neoadjuvant chemotherapy. RESULTS: The incidence of pelvic LNM was 20.27% (60/296 cases). Pelvic LNM (P = 0.00) was significantly correlated with recurrence. Pelvic LNM (P = 0.00), the number of positive pelvic LNs (P = 0.04) and a single group versus multiple groups of pelvic LNM (P = 0.03) had a significant influence on survival. Multivariate analysis revealed that LVSI (P = 0.00), depth of cervical stromal invasion (P = 0.00) and parametrial invasion (P = 0.03) were independently associated with pelvic LNM. CONCLUSIONS: Patients with pelvic LNM had a higher recurrence rate and poor survival outcomes. Furthermore, more than 2 positive pelvic LNs and multiple groups of pelvic LNM appeared to identify patients with worse survival outcomes in node-positive IA-IIB cervical squamous cell carcinoma. LVSI, parametrial invasion, and depth of cervical stromal invasion were identified as independent clinicopathological risk factors for pelvic LNM. PMID- 26228224 TI - Quantification of Adventitial Vasa Vasorum Vascularization in Double-injury Restenotic Arteries. AB - BACKGROUND: Accumulating evidence indicates a potential role of adventitial vasa vasorum (VV) dysfunction in the pathophysiology of restenosis. However, characterization of VV vascularization in restenotic arteries with primary lesions is still missing. In this study, we quantitatively evaluated the response of adventitial VV to vascular injury resulting from balloon angioplasty in diseased arteries. METHODS: Primary atherosclerotic-like lesions were induced by the placement of an absorbable thread surrounding the carotid artery of New Zealand rabbits. Four weeks following double-injury induced that was induced by secondary balloon dilation, three-dimensional patterns of adventitial VV were reconstructed; the number, density, and endothelial surface of VV were quantified using micro-computed tomography. Histology and immunohistochemistry were performed in order to examine the development of intimal hyperplasia. RESULTS: Results from our study suggest that double injured arteries have a greater number of VV, increased luminal surface, and an elevation in the intima/media ratio (I/M), along with an accumulation of macrophages and smooth muscle cells in the intima, as compared to sham or single injury arteries. I/M and the number of VV were positively correlated (R2 = 0.82, P < 0.001). CONCLUSIONS: Extensive adventitial VV neovascularization occurs in injured arteries after balloon angioplasty, which is associated with intimal hyperplasia. Quantitative assessment of adventitial VV response may provide insight into the basic biological process of postangioplasty restenosis. PMID- 26228225 TI - Stroke-like Migraine Attacks after Radiation Therapy Syndrome. AB - OBJECTIVE: To summarize the clinical presentation, pathogenesis, neuroimaging, treatment, and outcome of stroke-like migraine attacks after radiation therapy (SMART) syndrome, and to propose diagnostic criteria for this disorder. DATA SOURCES: We searched the PubMed database for articles in English published from 1995 to 2015 using the terms of "stroke-like AND migraine AND radiation." Reference lists of the identified articles and reviews were used to retrieve additional articles. STUDY SELECTION: Data and articles related to late-onset effects of cerebral radiation were selected and reviewed. RESULTS: SMART is a rare condition that involves complex migraines with focal neurologic deficits following cranial irradiation for central nervous system malignancies. The recovery, which ranges from hours to days to weeks, can be partial or complete. We propose the following diagnostic criteria for SMART: (1) Remote history of therapeutic external beam cranial irradiation for malignancy; (2) prolonged, reversible clinical manifestations mostly years after irradiation, which may include migraine, seizures, hemiparesis, hemisensory deficits, visuospatial defect, aphasia, confusion and so on; (3) reversible, transient, unilateral cortical gadolinium enhancement correlative abnormal T2 and fluid-attenuated inversion recovery signal of the affected cerebral region; (4) eventual complete or partial recovery, the length of duration of recovery ranging from hours to days to weeks; (5) no evidence of residual or recurrent tumor; (6) not attributable to another disease. To date, no specific treatment has been identified for this syndrome. CONCLUSIONS: SMART is an extremely rare delayed complication of brain irradiation. However, improvements in cancer survival rates have resulted in a rise in its frequency. Hence, awareness and recognition of the syndrome is important to make a rapid diagnosis and avoid aggressive interventions such as brain biopsy and cerebral angiography. PMID- 26228226 TI - Consensus of Chinese Specialists on Diagnosis and Treatment of Resistant Hypertension. PMID- 26228227 TI - Technique of Tubularized Bladder Mucosa Method for Treating Recurrent Vesicoureteral Reflux. PMID- 26228228 TI - Utility of Tissue Similarity Maps Based on Relative Cerebral Blood Volume for Grading Gliomas as Validated by Histological Results. PMID- 26228229 TI - Retaining Chorda Tympani Nerve Integrity During Cochlear Implant Surgery. PMID- 26228230 TI - Scedosporium Apiospermum Infection after Near-drowning. PMID- 26228231 TI - Foreign Body Reaction After Cochlear Implantation: A Case Report. PMID- 26228232 TI - Relief Effect of Bevacizumab on Severe Edema Induced by Re-irradiation in Brain Tumor Patients. PMID- 26228233 TI - Adventitial Vasa Vasorum: A Potential Therapeutic Target But Yet a Long Way to Go. PMID- 26228234 TI - Twitter Social Media is an Effective Tool for Breast Cancer Patient Education and Support: Patient-Reported Outcomes by Survey. AB - BACKGROUND: Despite reported benefits, many women do not attend breast cancer support groups. Abundant online resources for support exist, but information regarding the effectiveness of participation is lacking. We report the results of a Twitter breast cancer support community participant survey. OBJECTIVE: The aim was to determine the effectiveness of social media as a tool for breast cancer patient education and decreasing anxiety. METHODS: The Breast Cancer Social Media Twitter support community (#BCSM) began in July 2011. Institutional review board approval with a waiver of informed consent was obtained for a deidentified survey that was posted for 2 weeks on Twitter and on the #BCSM blog and Facebook page. RESULTS: There were 206 respondents to the survey. In all, 92.7% (191/206) were female. Respondents reported increased knowledge about breast cancer in the following domains: overall knowledge (80.9%, 153/189), survivorship (85.7%, 162/189), metastatic breast cancer (79.4%, 150/189), cancer types and biology (70.9%, 134/189), clinical trials and research (66.1%, 125/189), treatment options (55.6%, 105/189), breast imaging (56.6%, 107/189), genetic testing and risk assessment (53.9%, 102/189), and radiotherapy (43.4%, 82/189). Participation led 31.2% (59/189) to seek a second opinion or bring additional information to the attention of their treatment team and 71.9% (136/189) reported plans to increase their outreach and advocacy efforts as a result of participation. Levels of reported anxiety before and after participation were analyzed: 29 of 43 (67%) patients who initially reported "high or extreme" anxiety reported "low or no" anxiety after participation (P<.001). Also, no patients initially reporting low or no anxiety before participation reported an increase to high or extreme anxiety after participation. CONCLUSIONS: This study demonstrates that breast cancer patients' perceived knowledge increases and their anxiety decreases by participation in a Twitter social media support group. PMID- 26228235 TI - Central iliac arteriovenous anastomosis for hypertension: targeting mechanical aspects of the circulation. AB - Raised blood pressure is the leading attributable risk factor for global morbidity and mortality. Real world data demonstrates that half of treated patients are at elevated cardiovascular risk because of inadequately controlled BP. In addition to pharmacotherapy, certain interventional strategies to reduce blood pressure and cardiovascular risk in hypertension can be considered according to international guidelines. One of the newer technologies entering this field is a proprietary arteriovenous coupler device that forms a fixed flow arteriovenous conduit in the central vasculature. In this review, we examine the development of and rationale for the creation of a central arteriovenous anastomosis in patients with hypertension and review the proposed mechanisms by which it may ameliorate hypertension. We critically review the clinical trial evidence base to date and postulate on future therapeutic directions. PMID- 26228236 TI - The brain-derived neurotrophic factor Val66Met polymorphism and degeneration of the corticospinal tract after stroke: a diffusion tensor imaging study. AB - BACKGROUND AND PURPOSE: A common single nucleotide polymorphism, Val66Met, in the human brain-derived neurotrophic factor (BDNF) gene has a potential role in the pathogenesis and treatment of stroke. The relevance of the BDNF Val66Met polymorphism to long-term stroke outcomes was examined, specifically with respect to changes in corticospinal integrity. METHODS: Thirty-five stroke patients with unilateral motor weakness were genotyped within 2 weeks after onset (T1), and changes in the integrity of the ipsilesional corticospinal tract (CST) as well as alterations in motor function at 1 month (T2) and 3 months after onset (T3) were tracked. RESULTS: On the basis of the Fugl-Meyer assessment upper extremity score, carriers of the Met allele (Val/Met and Met/Met) showed poorer motor outcomes at T2 and T3 compared to carriers of only the Val allele (Val/Val). For both BDNF allele types, patients exhibited characteristic degeneration of the CST compared to healthy controls. There were no differences between the two genotypes with respect to time-dependent changes in diffusion-tensor-imaging-derived parameters of the CST. However, the two groups showed different relationships between motor outcomes and directional diffusivities according to the elapsed time after onset. Poorer motor function was associated with lower axial diffusivity values for the Val/Val genotype group in the sub-acute phase (T1 and T2) but with higher radial diffusivity values for the Val/Met and Met/Met genotype group in the early chronic phase (T3). CONCLUSIONS: Motor recovery in stroke patients may be affected by the BDNF Val66Met polymorphism, possibly through its effects on distinct pathological processes underlying corticospinal degeneration. PMID- 26228237 TI - Factors affecting stigma toward suicide and depression: A Korean nationwide study. AB - BACKGROUND: Suicide attempts and depression are considerably misunderstood by Korean society. Studies regarding factors should provide basic information concerning the factors that should be considered when examining stigmatization. AIM: This study aimed to investigate sociodemographic factors related to the social stigma toward people with a history of suicide attempts or depression in a Korean nationwide community sample. METHOD: Face-to-face interviews were conducted with participants selected via a multi-stage cluster sampling method; 779 respondents completed Link's Perceived Devaluation and Discrimination (PDD) scale to assess the social stigma they attached to suicide attempts, and another 743 completed PDD scale to assess the social stigma they attached to depression. Multiple regression analysis, including socioeconomic and psychiatric variables, was performed to identify the factors predictive of social stigma. RESULTS: Results of multiple regressions revealed that age (beta = .12, p = .018), sex (beta = .08, p = .038), years of education (beta = -.31, p = .006) and history of suicide attempts (beta = -.11, p = .009) significantly predicted the degree of stigma toward people who had made suicide attempts, whereas age (beta = .15, p = .003) and education (beta = -.40, p = .001) also predicted the social stigma toward people with depression, sex and history of a depressive episode did not. CONCLUSION: Older men with less education and no experience with suicide perceived suicide attempts more negatively. Similarly, older people with less education placed a greater stigma on people suffering from depression. These results suggest that greater access to higher education may reduce stigma toward people with mental illness. PMID- 26228238 TI - The Fear-avoidance Components Scale (FACS): Development and Psychometric Evaluation of a New Measure of Pain-related Fear Avoidance. AB - Pain-related fear avoidance (FA), a common problem for patients with painful medical conditions, involves pain-related catastrophizing cognitions, hypervigilance, and avoidance behaviors, which can ultimately lead to decreased functioning, depression, and disability. Several patient-reported instruments have been developed to measure FA, but they have been criticized for limited construct validity, inadequate item specificity, lack of cutoff scores, and missing important FA components. The Fear-Avoidance Components Scale (FACS) is a new patient-reported measure designed to comprehensively evaluate FA in patients with painful medical conditions. It combines important components of FA found in prior FA scales, while trying to correct some of their deficiencies, within a framework of the most current FA model. Psychometric evaluation of the FACS found high internal consistency (alpha = 0.92) and high test/retest reliability (r = 0.90-0.94, P < 0.01). FACS scores differentiated between 2 separate chronic pain patient samples and a nonpatient comparison group. When clinically relevant severity levels were created, FACS severity scores were highly associated with FA related patient-reported psychosocial and objective lifting performance variables. These results suggest that the FACS is a psychometrically strong and reliable measure that can help healthcare providers assess FA-related barriers to function and recovery. PMID- 26228239 TI - Histopathologic tumor spreading in primary ovarian cancer with modified posterior exenteration. AB - BACKGROUND: To achieve optimal cytoreduction for advanced-stage ovarian cancer, modified posterior exenteration is the most frequently performed bowel surgery. We assessed the extents of tumor spreading in the rectosigmoid wall and pelvic side wall in modified posterior exenteration specimens during primary debulking surgery (PDS) and interval debulking surgery (IDS) following neoadjuvant chemotherapy, and compared the validity of selecting this surgical procedure in the patients undergoing PDS with that in the patients undergoing IDS. METHODS: Clinicopathological data from consecutive patients who had undergone a modified posterior exenteration for primary ovarian, tubal, and peritoneal cancer at our institution between April 2008 and March 2013 was retrospectively reviewed. RESULTS: A total of 75 patients (38 in PDS and 37 in IDS) were included in this study. Tumor involvement of the rectosigmoid was histopathologically confirmed in 65% of the specimens. Though the extent of tumor spreading in the rectosigmoid was deeper in PDS than in IDS, the frequency of tumor involvement of the rectosigmoid in patients who had undergone modified posterior exenteration during PDS was equivalent to that in the IDS group. Lateral tumor spreading to the side wall(s) was histopathologically confirmed in 53% of the patients in whom a pelvic side wall resection had been performed. CONCLUSIONS: During both PDS and IDS for ovarian cancer presenting with tumor involvement of the cul-de-sac, close inspection and palpation by gynecologic oncologists may enable the extent of tumor spreading in the pelvis to be estimated, enabling valid decisions as to whether an en bloc resection of the pelvic tumors together with the rectosigmoid and the pelvic side wall might or might not be appropriate. PMID- 26228241 TI - On generalized fixed sequence procedures for controlling the FWER. AB - Testing a sequence of pre-ordered hypotheses to decide which of these can be rejected or accepted while controlling the familywise error rate (FWER) is of importance in many scientific studies such as clinical trials. In this paper, we first introduce a generalized fixed sequence procedure whose critical values are defined by using a function of the numbers of rejections and acceptances, and which allows follow-up hypotheses to be tested even if some earlier hypotheses are not rejected. We then construct the least favorable configuration for this generalized fixed sequence procedure and present a sufficient condition for the FWER control under arbitrary dependence. Based on the condition, we develop three new generalized fixed sequence procedures controlling the FWER under arbitrary dependence. We also prove that each generalized fixed sequence procedure can be described as a specific closed testing procedure. Through simulation studies and a clinical trial example, we compare the power performance of these proposed procedures with those of the existing FWER controlling procedures. Finally, when the pairwise joint distributions of the true null p-values are known, we further improve these procedures by incorporating pairwise correlation information while maintaining the control of the FWER. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26228242 TI - Relationship between Sloan-Kettering virus expression and mammalian follicular development. AB - Sloan-Kettering virus gene, a product of a cellular proto-oncogene c-Ski is a unique nuclear pro-oncoprotein and belongs to the Ski/Sno proto-oncogene family. The aim of the present study was to locate Ski protein in rat ovaries in order to find insights into the possible involvement of Ski in follicular development. First, expression of c-Ski mRNA in the ovaries of adult female rats was confirmed by RT-PCR. Then, ovaries obtained on the day of estrus were subjected to immunohistochemical analysis for Ski and proliferating cell nuclear antigen (PCNA) in combination with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). RT-PCR and in situ hybridization revealed that c-Ski mRNA was expressed in the ovaries of the adult rat on the day of estrous and localized mainly in the granulose cells. Ski was expressed in granulosa cells that were positive for TUNEL, but negative for PCNA, regardless of the shape and size of follicles. Expression of Ski in TUNEL-positive granulosa cells, but not in PCNA-positive granulosa cells, was also verified in rats having atretic follicles with double staining. These results indicate that Ski is profoundly expressed in the granulosa cells of atretic follicles, but not in growing follicles. Based on the present findings, Ski may play a role in the apoptosis of granulosa cells during follicular atresia. PMID- 26228240 TI - PTEN mediates Notch-dependent stalk cell arrest in angiogenesis. AB - Coordinated activity of VEGF and Notch signals guides the endothelial cell (EC) specification into tip and stalk cells during angiogenesis. Notch activation in stalk cells leads to proliferation arrest via an unknown mechanism. By using gain and loss-of-function gene-targeting approaches, here we show that PTEN is crucial for blocking stalk cell proliferation downstream of Notch, and this is critical for mouse vessel development. Endothelial deletion of PTEN results in vascular hyperplasia due to a failure to mediate Notch-induced proliferation arrest. Conversely, overexpression of PTEN reduces vascular density and abrogates the increase in EC proliferation induced by Notch blockade. PTEN is a lipid/protein phosphatase that also has nuclear phosphatase-independent functions. We show that both the catalytic and non-catalytic APC/C-Fzr1/Cdh1 mediated activities of PTEN are required for stalk cells' proliferative arrest. These findings define a Notch-PTEN signalling axis as an orchestrator of vessel density and implicate the PTEN-APC/C-Fzr1/Cdh1 hub in angiogenesis. PMID- 26228243 TI - Diagnostic and prognostic utility of mid-expiratory flow rate in older community dwelling persons with respiratory symptoms, but without chronic obstructive pulmonary disease. AB - BACKGROUND: The maximal expiratory flow at 50 % of the forced vital capacity (MEF50) is the flow where half of forced vital capacity (FVC) remains to be exhaled. A reduced MEF50 has been suggested as a surrogate marker of small airways disease. The diagnostic and prognostic utility of this easy to assess spirometric variable in persons with respiratory symptoms, but without COPD is unclear. METHODS: We used data from the UHFO-COPD cohort in which 405 community dwelling persons aged 65 years or over, and a general practitioner's diagnosis of chronic obstructive pulmonary disease (COPD) underwent pulmonary function testing and echocardiography. In total 161 patients had no COPD according to the spirometric GOLD criteria. We considered MEF50 as reduced if < 60 % of predicted. RESULTS: Of the 161 patients without COPD (mean age 72 +/- 5.7 years; 35 % male; follow-up 4.5 +/- 1.1 years), 61 (37.9 %) had a reduced MEF50. They were older, had more pack-years of smoking, more respiratory symptoms, and used more frequently inhaled medication than the remaining 100 subjects. A reduced MEF50 was nearly twice as often associated with newly detected heart failure (HF) at assessment (29.5 % vs. 15.6 %, p = 0.045). In age-and sex-adjusted Cox regression analysis, a reduced MEF50 was significantly associated with episodes of acute bronchitis (hazard ratio 2.54 95 % confidence interval (1.26; 5.13) P = 0.009), and in trend with pneumonia (2.14 (0.98; 4.69) P = 0.06) and hospitalizations for pulmonary reasons (2.28 (0.93; 5.62) P = 0.07). CONCLUSIONS: In older community dwelling persons with pulmonary symptoms but without COPD, a reduced MEF50 may help to uncover unrecognized HF, and identify those at a higher risk for episodes of acute bronchitis, pneumonia and hospitalizations for pulmonary reasons. Echocardiography and close follow-up should be considered in these patients. PMID- 26228244 TI - Growth and optical properties of Cu2ZnSnS4 decorated reduced graphene oxide nanocomposites. AB - Cu2ZnSnS4 (CZTS) nanoparticles were synthesized by the precursor injection method using oleylamine as a solvent. Preliminary characterization indicated that the synthesized nanoparticles belonged to the kesterite structure with a bulged sphere-like morphology. Reduced graphene oxide (rGO) was synthesized by an improved Hummers method and was used for nanoparticle functionalization. CZTS nanocrystals were decorated on rGO by two different methods. One was oleylamine based nanoparticle functionalization, and the other was in situ nanoparticle growth. Transmission electron microscopy analysis of CZTS-functionalized rGO showed that the synthesized nanoparticles were uniformly spread on the surface of rGO sheets. Single phase CZTS nanoparticles were grown on rGO without any impurity phase in the in situ growth. Tuned absorption of the pure CZTS was observed by the decoration of CZTS nanoparticles on the surface of rGO in the visible and UV regions. PMID- 26228245 TI - Predicting mortality in sick African children: the FEAST Paediatric Emergency Triage (PET) Score. AB - BACKGROUND: Mortality in paediatric emergency care units in Africa often occurs within the first 24 h of admission and remains high. Alongside effective triage systems, a practical clinical bedside risk score to identify those at greatest risk could contribute to reducing mortality. METHODS: Data collected during the Fluid As Expansive Supportive Therapy (FEAST) trial, a multi-centre trial involving 3,170 severely ill African children, were analysed to identify clinical and laboratory prognostic factors for mortality. Multivariable Cox regression was used to build a model in this derivation dataset based on clinical parameters that could be quickly and easily assessed at the bedside. A score developed from the model coefficients was externally validated in two admissions datasets from Kilifi District Hospital, Kenya, and compared to published risk scores using Area Under the Receiver Operating Curve (AUROC) and Hosmer-Lemeshow tests. The Net Reclassification Index (NRI) was used to identify additional laboratory prognostic factors. RESULTS: A risk score using 8 clinical variables (temperature, heart rate, capillary refill time, conscious level, severe pallor, respiratory distress, lung crepitations, and weak pulse volume) was developed. The score ranged from 0-10 and had an AUROC of 0.82 (95 % CI, 0.77-0.87) in the FEAST trial derivation set. In the independent validation datasets, the score had an AUROC of 0.77 (95 % CI, 0.72-0.82) amongst admissions to a paediatric high dependency ward and 0.86 (95 % CI, 0.82-0.89) amongst general paediatric admissions. This discriminative ability was similar to, or better than other risk scores in the validation datasets. NRI identified lactate, blood urea nitrogen, and pH to be important prognostic laboratory variables that could add information to the clinical score. CONCLUSIONS: Eight clinical prognostic factors that could be rapidly assessed by healthcare staff for triage were combined to create the FEAST Paediatric Emergency Triage (PET) score and externally validated. The score discriminated those at highest risk of fatal outcome at the point of hospital admission and compared well to other published risk scores. Further laboratory tests were also identified as prognostic factors which could be added if resources were available or as indices of severity for comparison between centres in future research studies. PMID- 26228246 TI - Imaging Features of Radiofrequency Ablation with Heat-Deployed Liposomal Doxorubicin in Hepatic Tumors. AB - INTRODUCTION: The imaging features of unresectable hepatic malignancies in patients who underwent radiofrequency ablation (RFA) in combination with lyso thermosensitive liposomal doxorubicin (LTLD) were determined. MATERIALS AND METHODS: A phase I dose escalation study combining RFA with LTLD was performed with peri- and post- procedural CT and MRI. Imaging features were analyzed and measured in terms of ablative zone size and surrounding penumbra size. The dynamic imaging appearance was described qualitatively immediately following the procedure and at 1-month follow-up. The control group receiving liver RFA without LTLD was compared to the study group in terms of imaging features and post ablative zone size dynamics at follow-up. RESULTS: Post-treatment scans of hepatic lesions treated with RFA and LTLD have distinctive imaging characteristics when compared to those treated with RFA alone. The addition of LTLD resulted in a regular or smooth enhancing rim on T1W MRI which often correlated with increased attenuation on CT. The LTLD-treated ablation zones were stable or enlarged at follow-up four weeks later in 69% of study subjects as opposed to conventional RFA where the ablation zone underwent involution compared to imaging acquired immediately after the procedure. CONCLUSION: The imaging features following RFA with LTLD were different from those after standard RFA and can mimic residual or recurrent tumor. Knowledge of the subtle findings between the two groups can help avoid misinterpretation and proper identification of treatment failure in this setting. Increased size of the LTLD-treated ablation zone after RFA suggests the ongoing drug-induced biological effects. PMID- 26228247 TI - Reciprocity on Demand : Sharing and Exchanging Food in Northwestern Namibia. AB - Two competing models concerning food transfers prominent in the anthropological literature conceptualize such transfers either as sharing or as exchange. Sharing is understood as situational transactions formed through demands and unconditional giving, whereas reciprocal exchange is understood in terms of networking and keeping score. I propose that the picture is more complicated than these classifications suggests. Drawing on data collected in Northwestern Namibia, I show that sharing and reciprocal exchange are dynamically interrelated in actual food transfers. As a local norm, people can demand food from anyone, and they are typically given food in response to a demand. However, in practice, food transfer networks emerge (N = 62) that are highly reciprocal and fit the exchange model much better. Although the sharing norm makes no restrictions on whom to ask, in practice people often turn to their neighbors. Interpersonal dynamics account for why some of those ties become strongly reciprocal and others do not. Under these circumstances, unconditional sharing, a norm that has been viewed as an alternative to exchange, can lead to reciprocity via reciprocity on demand. PMID- 26228248 TI - Electrochemical Skin Conductance in Diabetic Kidney Disease. AB - BACKGROUND: There is a need to identify patients with diabetic kidney disease (DKD) using noninvasive, cost-effective screening tests. Sudoscan(r), a device using electrochemical skin conductance (ESC) to measure sweat gland dysfunction, is valuable for detecting peripheral neuropathy. ESC was tested for association with DKD (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2)) in 383 type 2 diabetes mellitus (T2D)-affected patients; diagnostic thresholds were determined in 540 patients. METHODS: Relationships between ESC with eGFR and urine albumin:creatinine ratio (UACR) were assessed in 202 European Americans and 181 African Americans with T2D. RESULTS: In 92 European American DKD cases and 110 T2D non-nephropathy controls, respectively, mean (SD) ages were 69 (9.7) and 61 (10.8) years, hemoglobin A1c (HbA1c) 7.4 (1.2) and 7.4 (1.3)%, eGFR 29.6 (12.2) and 87.8 (14.2) ml/min/1.73 m(2), and UACR 1,214 (1,705) and 7.5 (5.8) mg/g. In 57 African American cases and 124 controls, respectively, mean (SD) ages were 64.0 (11.9) and 59.5 (9.7) years, HbA1c 7.4 (1.3) and 7.5 (1.7)%, eGFR 29.6 (13.3) and 90.2 (16.2) ml/min/1.73 m(2), and UACR 1,172 (1,564) and 7.8 (7.1) mg/g. Mean (SD) ESC (MUS) was lower in cases than controls (European Americans: case/control hands 49.5 (18.5)/62.3 (16.2); feet 62.1 (17.9)/73.6 (13.8), both p < 1.3 * 10(-6); African Americans: case/control hands 39.8 (19.0)/48.5 (17.1); feet 53.2 (21.3)/63.5 (19.4), both p <= 0.01). Adjusting for age, sex, body mass index and HbA1c, hands and feet ESC associated with eGFR <60 ml/min/1.73 m(2) (p <= 7.2 * 10(-3)), UACR >30 mg/g (p <= 7.0 * 10(-3)), UACR >300 mg/g (p <= 8.1 * 10(-3)), and continuous traits eGFR and UACR (both p <= 5.0 * 10(-9)). HbA1c values were not useful for risk stratification. CONCLUSIONS: ESC measured using Sudoscan(r) is strongly associated with DKD in African Americans and European Americans. ESC is a useful screening test to identify DKD in patients with T2D. PMID- 26228249 TI - Retinoic acid has the potential to suppress endometriosis development. AB - BACKGROUND: Despite endometriosis is common estrogen dependent disease afflicting women in reproductive age, the pathogenesis has not been fully elucidated. Retinoic acid has various functions in cells as biologic modulator, and aberrant retinoid metabolism seems to be involved in the lesions of endometriosis. In order to evaluate the potential of all-trans retinoic acid (ATRA) for therapeutic treatment, a transcriptome analysis and estradiol measurements in cultured endometriotic cells and tissues were conducted. METHODS: The mRNA expression levels in ATRA-treated endometriotic stromal cells (ESC) isolated from ovarian endometrial cysts (OEC) were investigated. Estradiol production in OEC tissues was also investigated. RESULTS: In the isolated ESC culture supplemented with ATRA for four days, total RNA was extracted followed by a transcriptome analysis using GeneChip. Forty-nine genes were upregulated and four genes were down regulated by the ATRA treatment. Many upregulated genes were associated with the negative regulation of cellular proliferation. In addition, ATRA treatment decreased the mRNA expression of 17-beta-dehydrogenase 2 (HSD17B2) which converts estradiol into estrone in a dose-dependent manner, and the ELISA measurements indicated that estradiol production in the OEC tissue was inhibited by ATRA treatment. CONCLUSIONS: Retinoic acid has the potential to suppress endometriosis development. PMID- 26228250 TI - Constructing an episode of care from acute hospitalization records for studying effects of timing of hip fracture surgery. AB - Episodes of care defined by the event of hip fracture surgery are widely used for the assessment of surgical wait times and outcomes. However, this approach does not consider nonoperative deaths, implying that survival time begins at the time of procedure. This approach makes treatment effect implicitly conditional on surviving to treatment. The purpose of this article is to describe a novel conceptual framework for constructing an episode of hip fracture care to fully evaluate the incidence of adverse events related to time after admission for hip fracture. This admission-based approach enables the assessment of the full harm of delay by including deaths while waiting for surgery, not just deaths after surgery. Some patients wait until their conditions are optimized for surgery, whereas others have to wait until surgical service becomes available. We provide definitions, linkage rules, and algorithms to capture all hip fracture patients and events other than surgery. Finally, we discuss data elements for stratifying patients according to administrative factors for delay to allow researchers and policymakers to determine who will benefit most from expedited access to surgery. PMID- 26228251 TI - Procyanidin B2 attenuates neurological deficits and blood-brain barrier disruption in a rat model of cerebral ischemia. AB - SCOPE: Disruption of the blood-brain barrier (BBB) is a major pathogenic mechanism of neurological dysfunction and death after ischemic stroke. The aim of our study was to investigate the effect of procyanidin B2 (PB), a bioactive food compound, on BBB disruption induced by ischemic stroke and explore the underlying mechanism. METHODS AND RESULTS: PB was administrated intragastrically once a day starting at 3 h after transient middle cerebral artery occlusion (MCAO). PB treatment significantly decreased the infarction volume, brain edema, and neurological deficits after MCAO. PB prevented BBB disruption against ischemic stroke, as indicated by the reduction of Evans blue leakage and IgG levels. These results were also corroborated by immunofluorescence staining and Western blot analysis of ZO-1. Additionally, levels of reactive oxygen species and malondialdehyde were lessened in the ipsilateral ischemic area of brain by PB. The activities of antioxidant enzymes were elevated. Meanwhile, PB reversed the suppression of NF-E2-related factor nuclear translocation, and increased the protein expression of HO-1, GSTalpha, and NQO1 in the ipsilateral ischemic area of brain. CONCLUSION: PB attenuates neurological deficits and BBB disruption in a rat model of cerebral ischemia, and the neuroprotection of PB is associated with activation of NF-E2-related factor pathway. PMID- 26228254 TI - [Ambulatory blood pressure, chronotherapy of hypertension and glaucoma]. PMID- 26228255 TI - [Neurocysticercosis]. PMID- 26228256 TI - [Multifocal skeletal tuberculosis simulating a soft-tissue sarcoma]. PMID- 26228253 TI - Physical activity, depressed mood and pregnancy worries in European obese pregnant women: results from the DALI study. AB - BACKGROUND: The purpose of this study was to examine the association between mental health status (i.e. depressed mood and pregnancy-related worries) and objectively measured physical activity levels in obese pregnant women from seven European countries. METHODS: Baseline data from the vitamin D and lifestyle intervention for the prevention of gestational diabetes mellitus (DALI) study were used. Time spent in moderate-to-vigorous physical activity (MVPA) and sedentary behaviour was measured with accelerometers. Depressed mood was measured with the WHO well-being index (WHO-5) and pregnancy-related worries with the Cambridge Worry Scale (CWS). In addition, socio-demographic characteristics, lifestyle factors, and perceptions and attitude regarding weight management and physical activity were measured. Linear regression analyses were performed to assess the association of mental health status with MVPA and sedentary behaviour. RESULTS: A total of 98 obese pregnant women from Austria, Belgium, Ireland, Italy, Poland, Spain and the Netherlands were included. Women had a mean age of 31.6 +/- 5.8 years, a pre-pregnancy BMI of 34.1 +/- 4.3 kg/m(2), and were on average 15.4 +/- 2.8 weeks pregnant. WHO-5 scores indicative of depressed mood (<50) were reported by 27.1 % of the women and most frequently endorsed pregnancy related worries pertained to own and the baby's health. Women with good well being spent 85% more time in MVPA compared to women with a depressed mood (P = 0.03). No differences in MVPA levels were found for women with no, some, or many pregnancy worries. Depressed mood and pregnancy-related worries were not associated with sedentary behaviour. CONCLUSIONS: These findings suggest that in pregnant women who are obese, a depressed mood, but not pregnancy-related worries, may be associated with less physical activity. The combined risk of poor mental health and low physical activity levels makes women vulnerable for pregnancy complications. Whether a depressed mood may be a barrier for improving physical activity warrants further study. PMID- 26228257 TI - [Skin infection by community-acquired methicillin resistant Staphylococcus aureus with familial transmission]. PMID- 26228258 TI - [Rheumatoid arthritis at present]. PMID- 26228259 TI - The Cleavage of a C-C Bond in Cyclobutylanilines by Visible-Light Photoredox Catalysis: Development of a [4+2] Annulation Method. AB - We report the first example of an intermolecular [4+2] annulation of cyclobutylanilines with alkynes enabled by visible-light photocatalysis. Monocyclic and bicyclic cyclobutylanilines successfully undergo the annulation with terminal and internal alkynes to generate a wide variety of amine substituted cyclohexenes including new hydrindan and decalin derivatives with good to excellent diastereoselectivity. The reaction is overall redox neutral with perfect atom economy. PMID- 26228260 TI - Ankle muscle strength influence on muscle activation during dynamic and static ankle training modalities. AB - Muscle weakness is considered a risk factor for ankle injury. Balance training and barefoot running have been used in an attempt to strengthen the muscles crossing the ankle. It is expected that training tasks that successfully strengthen the ankle would elicit increased muscular activity. However, it is unknown how an individual's ankle strength will influence the muscle activity used during a given task. Twenty-six participants performed dynamic (shod, barefoot running) and static tasks (squat on ground, squat on (r)Bosu Ball) believed to strengthen the muscles surrounding the ankle. Electromyographic signals of the tibialis anterior, peroneus longus, gastrocnemius lateralis (GL) and gastrocnemius medialis (GM) were recorded and analysed using a non-linearly scaled wavelet analysis. Participants were divided into a strong group and a weak group according to their isometric plantar-flexion torque. The weak group required more relative GL and GM muscle activity during each training task compared to the strong group. No difference was observed between shod and barefoot running. There was a significant effect of training task on muscle activation level for the weak group. Differences in ankle strength had a significant impact on muscle activation. PMID- 26228261 TI - Reply. PMID- 26228263 TI - Rechargeable magnesium-ion battery based on a TiSe2-cathode with d-p orbital hybridized electronic structure. AB - Rechargeable ion-batteries, in which ions such as Li(+) carry charges between electrodes, have been contributing to the improvement of power-source performance in a wide variety of mobile electronic devices. Among them, Mg-ion batteries are recently attracting attention due to possible low cost and safety, which are realized by abundant natural resources and stability of Mg in the atmosphere. However, only a few materials have been known to work as rechargeable cathodes for Mg-ion batteries, owing to strong electrostatic interaction between Mg(2+) and the host lattice. Here we demonstrate rechargeable performance of Mg-ion batteries at ambient temperature by selecting TiSe2 as a model cathode by focusing on electronic structure. Charge delocalization of electrons in a metal ligand unit through d-p orbital hybridization is suggested as a possible key factor to realize reversible intercalation of Mg(2+) into TiSe2. The viewpoint from the electronic structure proposed in this study might pave a new way to design electrode materials for multivalent-ion batteries. PMID- 26228262 TI - Assessment of the reporting of quality and outcome measures in hepatic resections: a call for 90-day reporting in all hepatectomy series. AB - BACKGROUND: The aim of this paper is to assess the current state of quality and outcomes measures being reported for hepatic resections in the recent literature. METHODS: Medline and PubMed databases were searched for English language articles published between 1 January 2002 and 30 April 2013. Two examiners reviewed each article and relevant citations for appropriateness of inclusion, which excluded papers of liver donor hepatic resections, repeat hepatectomies or meta-analyses. Data were extracted and summarized by two examiners for analysis. RESULTS: Fifty five studies were identified with suitable reporting to assess peri-operative mortality in hepatic resections. In only 35% (19/55) of the studies was the follow-up time explicitly stated, and in 47% (26/55) of studies peri-operative mortality was limited to in-hospital or 30 days. The time period in which complications were captured was not explicitly stated in 19 out of 28 studies. The remaining studies only captured complications within 30 days of the index operation (8/28). There was a paucity of quality literature addressing truly patient-centred outcomes. CONCLUSION: Quality outcomes after a hepatic resection are inconsistently reported in the literature. Quality outcome studies for a hepatectomy should report mortality and morbidity at a minimum of 90 days after surgery. PMID- 26228264 TI - Walking is a Feasible Physical Activity for People with Rheumatoid Arthritis: A Feasibility Randomized Controlled Trial. AB - BACKGROUND: Exercise has been recognized as important in the management of rheumatoid arthritis (RA). Walking is a low-cost and low-impact activity, requiring little supervision. It requires no specialist training, is suited to a variety of environments and is inherently a clinically meaningful measure of independence. The aim of the present study was to determine whether a designed walking programme for people with RA successfully facilitated regular physical activity in participants, without detriment to pain levels. METHODS: Thirty-three people with RA were recruited from Dunedin Hospital rheumatology outpatient clinics and enrolled in a walking randomized controlled trial (RCT) feasibility study. Participants were randomly allocated to the walking intervention (n = 11) or control (n = 22) groups. Control participants received a nutrition education session, and the walking intervention group received instructions on a walking route with three loops, to be completed 3-4 times per week. The walking route shape was designed so that the length of the walk could be tailored by participants. Both groups were assessed at baseline and six weeks later. The primary outcome measures were feasibility, acceptability and safety. The principal secondary outcome was change in walking speed after the intervention. Additional outcome measures were a step-up test, activity limitations (on the Health Assessment Questionnaire), global well-being (on the European Quality of Life Questionnaire), self-efficacy for managing arthritis symptoms, self-efficacy for physical activity, daily pedometer readings and a daily visual analogue scale for pain. RESULTS: Participants successfully completed the walk for the suggested frequency, indicating feasibility and acceptability. There were no reported adverse effects of participation and the walking intervention group did not have higher daily pain levels than the control group, indicating safety. The walking intervention group showed a pattern of improvements in self-efficacy and global well-being; no changes in these outcomes were noted in the control group. No outcome measure showed statistically significant between-group differences. CONCLUSIONS: Walking appears to be a feasible, acceptable and safe intervention for people with RA. These findings inform the design and power requirements of larger trials of structured walking interventions. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26228265 TI - Genetic screening in sudden cardiac death in the young can save future lives. AB - BACKGROUND: Autopsy of sudden cardiac death (SCD) in the young shows a structurally and histologically normal heart in about one third of cases. Sudden death in these cases is believed to be attributed in a high percentage to inherited arrhythmogenic diseases. The purpose of this study was to investigate the value of performing post-mortem genetic analysis for autopsy-negative sudden unexplained death (SUD) in 1 to 35 year olds. METHODS AND RESULTS: From January 2009 to December 2011, samples from 15 cases suffering SUD were referred to the Department of Clinical Genetics, Umea University Hospital, Sweden, for molecular genetic evaluation. PCR and bidirectional Sanger sequencing of genes important for long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome type 1 (BrS1), and catecholaminergic polymorphic ventricular tachycardia (CPVT) (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RYR2) was performed. Multiplex ligation-dependent probe amplification (MLPA) was used to detect large deletions or duplications in the LQTS genes. Six pathogenic sequence variants (four LQTS and two CPVT) were discovered in 15 SUD cases (40%). Ten first-degree family members were found to be mutation carriers (seven LQTS and three CPVT). CONCLUSION: Cardiac ion channel genetic testing in autopsy-negative sudden death victims has a high diagnostic yield, with identification of the disease in 40 of families. First-degree family members should be offered predictive testing, clinical evaluation, and treatment with the ultimate goal to prevent sudden death. PMID- 26228266 TI - Interventions for waterpipe smoking cessation. AB - BACKGROUND: Waterpipe tobacco smoking is a traditional method of tobacco use, especially in the Eastern Mediterranean Region (EMR), but its use is now spreading worldwide. Recent epidemiological data, for example, show that waterpipe smoking has become the most prevalent tobacco use method among adolescents in the EMR, and the second most prevalent in the US. Waterpipes are used socially, often being shared between friends or family at home, or in dedicated bars and cafes that provide waterpipes to patrons. Because the smoke passes through a reservoir of water, waterpipe tobacco smoking is perceived as being less harmful than other methods of tobacco use. At least in some cultures, women and girls are more likely to use a waterpipe than to use other forms of tobacco, and it is popular among younger smokers. Accumulating evidence suggests that some waterpipe smokers become addicted, have difficulty quitting, and experience similar health risks as cigarette smokers. OBJECTIVES: To evaluate the effectiveness of tobacco cessation interventions for waterpipe users. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Review Group specialized register in June 2015. We also searched MEDLINE, EMBASE, PsycINFO and CINAHL , using variant terms and spellings ('waterpipe' or 'narghile' or 'arghile' or 'shisha' or 'goza' or 'narkeela' or 'hookah' or 'hubble bubble'). We searched for trials, published or unpublished, in any language, and especially in regions where waterpipe use is widespread. SELECTION CRITERIA: We sought randomized, quasi-randomized or cluster-randomized controlled trials of smoking cessation interventions for waterpipe smokers of any age or gender. The primary outcome of interest was abstinence from tobacco use, measured at six months post-cessation or longer, regardless of whether abstinence was biochemically verified. We included interventions that were pharmacological (for example, nicotine replacement therapy (NRT) or bupropion) or behavioural, or both, and could be directed at individual waterpipe users or at groups of users. We only included tobacco cessation interventions, and did not consider trials of prevention of uptake. DATA COLLECTION AND ANALYSIS: Two review authors assessed abstracts of the studies retrieved by the search strategy, for possible inclusion in the review. We retrieved full-text articles for all abstracts that any of the authors believed might be suitable. Two review authors then extracted data and assessed trial quality independently in accordance with standard Cochrane Collaboration methodologies. We aimed to pool groups of studies that we considered to be sufficiently similar, provided there was no evidence of substantial statistical heterogeneity, and aimed to estimate a pooled risk ratio (RR) using the Mantel Haenszel fixed-effect method. Where meta-analysis was not possible, we presented summary and descriptive statistics. MAIN RESULTS: Our search retrieved 1311 unique citations, of which 1289 were excluded after title and abstract screening. Of the remaining 22, we excluded 19 because they were empirical studies that were not randomized, quasi-randomized or cluster-randomized controlled trials (n = 12), because they were review articles (n = 3), because they described protocols only (n = 2), they were conducted among cigarette smokers only (n = 1), or they had only a three-month follow-up (n = 1).We identified three controlled trials which tested cessation interventions for waterpipe smokers. Studies were carried out in Egypt (Mohlman 2013), Pakistan (Dogar 2014), and the US (Lipkus 2011). One was a randomized controlled trial and two were cluster-randomized trials. Two studies tested individual-level interventions, and one tested a community-level intervention. Two studies included only behavioural interventions, and one study (Dogar 2014) included two intervention groups: one behavioural, and the other behavioural with bupropion. The Lipkus and Mohlman studies delivered waterpipe specific interventions, and the Dogar study delivered a non-specific tobacco intervention. Due to study variation we did not pool results, and intervention effects are reported descriptively. Compared to control groups, waterpipe smoking cessation rates were higher in the intervention groups in all three studies, with a significant difference in two studies. For the Dogar study, the RRs for waterpipe smoking abstinence at 25 weeks among waterpipe-only smokers were 2.2 (95% confidence interval (CI) 1.3 to 3.8; 180 participants) in the behavioural group, and 2.5 (95% CI 1.3 to 4.7; 84 participants) in the behavioural plus bupropion group. In our analysis we have combined both groups, to give a RR of 2.28 (95% CI 1.36 to 3.83; 200 participants). The Mohlman study delivered a RR in male waterpipe-smokers at one year in favour of the intervention of 3.25 (95% CI 1.19 to 8.89). AUTHORS' CONCLUSIONS: Although the literature on waterpipe cessation interventions remains sparse, the reviewed studies provide a basis for developing interventions in this area. The lack of statistically significant effects in one of the three studies is not unexpected, given the small and pilot nature of the studies. The studies highlight important design and content issues that need to be considered for future cessation trials in waterpipe smokers. These include building on the vast experience developed in the study of smoking cessation interventions in cigarette smokers, whilst including components and assessment tools that address the specific aspects of waterpipe smoking, such as its social dimension, unique experiences, and cues. PMID- 26228269 TI - Empedobacter stercoris sp. nov., isolated from an input sample of a biogas plant. AB - Two Gram-stain-negative, rod-shaped bacteria, strains 990B6_12ER2AT and 994B6_12ER2A, were isolated during microbiological analysis of a mixed manure sample which was used as input material for a German biogas plant. Phylogenetic identification based on nearly full-length 16S rRNA gene sequences placed the isolates into the family Flavobacteriaceae within the phylum Bacteroidetes. Strains 990B6_12ER2AT and 994B6_12ER2A shared identical 16S rRNA gene sequences and showed highest 16S rRNA gene sequence similarity to the type strains of Empedobacter falsenii (97.3 %) and Empedobacter brevis (96.8 %).The major cellular fatty acids of strains 990B6_12ER2AT and 994B6_12ER2A were iso-C15 : 0, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and iso-C17 : 0 3-OH.The polyamine pattern contained predominantly sym-homospermidine and the quinone system was menaquinone MK-6. Major polar lipids were phosphatidylethanolamine, one unidentified aminolipid and one unidentified polar lipid not containing an amino residue, a phosphate residue or a sugar moiety. In addition, moderate to minor amounts of several unidentified lipids were detected. The DNA G+C content was 31.7 and 29.0 mol%, for strains 990B6_12ER2AT and 994B6_12ER2A, respectively. On the basis of phylogenetic, chemotaxonomic and physiological analysis we propose a novel species of the genus Empedobacter, Empedobacter stercoris sp. nov. (type strain 990B6_12ER2AT = CIP 110833T = LMG 28501T). PMID- 26228268 TI - Genome-wide association study revealed a promising region and candidate genes for eggshell quality in an F2 resource population. AB - BACKGROUND: Eggshell is subject to quality loss with aging process of laying hens, and damaged eggshells result in economic losses of eggs. However, the genetic architecture underlying the dynamic eggshell quality remains elusive. Here, we measured eggshell quality traits, including eggshell weight (ESW), eggshell thickness (EST) and eggshell strength (ESS) at 11 time points from onset of laying to 72 weeks of age and conducted comprehensive genome-wide association studies (GWAS) in 1534 F2 hens derived from reciprocal crosses between White Leghorn (WL) and Dongxiang chickens (DX). RESULTS: ESWs at all ages exhibited moderate SNP-based heritability estimates (0.30 ~ 0.46), while the estimates for EST (0.21 ~ 0.31) and ESS (0.20 ~ 0.27) were relatively low. Eleven independent univariate genome-wide screens for each trait totally identified 1059, 1026 and 1356 significant associations with ESW, EST and ESS, respectively. Most significant loci were in a region spanning from 57.3 to 71.4 Mb of chromosome 1 (GGA1), which together account for 8.4 ~ 16.5% of the phenotypic variance for ESW from 32 to 72 weeks of age, 4.1 ~ 6.9% and 2.95 ~ 16.1% for EST and ESS from 40 to 72 weeks of age. According to linkage disequilibrium (LD) and conditional analysis, the significant SNPs in this region were in extremely strong linkage disequilibrium status. Ultimately, two missense SNPs in GGA1 and one in GGA4 were considered as promising loci on three independent genes including ITPR2, PIK3C2G, and NCAPG. The homozygotes of advantageously effective alleles on PIK3C2G and ITPR2 possessed the best eggshell quality and could partly counteract the negative effect of aging process. NCAPG had certain effect on eggshell quality for young hens. CONCLUSIONS: Identification of the promising region as well as potential candidate genes will greatly advance our understanding of the genetic basis underlying dynamic eggshell quality and has the practical significance in breeding program for the improvement of eggshell quality, especially at the later part of laying cycle. PMID- 26228270 TI - Comparative study of the primary cilia in thyrocytes of adult mammals. AB - Since their discovery in different human tissues by Zimmermann in 1898, primary cilia have been found in the vast majority of cell types in vertebrates. Primary cilia are considered to be cellular antennae that occupy an ideal cellular location for the interpretation of information both from the environment and from other cells. To date, in mammalian thyroid gland, primary cilia have been found in the thyrocytes of humans and dogs (fetuses and adults) and in rat embryos. The present study investigated whether the existence of this organelle in follicular cells is a general event in the postnatal thyroid gland of different mammals, using both immunolabeling by immunofluorescence and electron microscopy. Furthermore, we aimed to analyse the presence of primary cilia in various thyroid cell lines. According to our results, primary cilia are present in the adult thyroid gland of most mammal species we studied (human, pig, guinea pig and rabbit), usually as a single copy per follicular cell. Strikingly, they were not found in rat or mouse thyroid tissues. Similarly, cilia were also observed in all human thyroid cell lines tested, both normal and neoplastic follicular cells, but not in cultured thyrocytes of rat origin. We hypothesize that primary cilia could be involved in the regulation of normal thyroid function through specific signaling pathways. Nevertheless, further studies are needed to shed light on the permanence of these organelles in the thyroid gland of most species during postnatal life. PMID- 26228271 TI - Two-photon microscopy of a Flt1 peptide-hyaluronate conjugate. AB - AIM: Two-photon microscopy was performed to visualize ocular distribution of Flt1 peptide-hyaluronate (HA) conjugate micelles for eye drop treatment of corneal neovascularization. MATERIALS & METHODS: Flt1 peptide-HA conjugate micelles were topically administered to the eye for two-photon microscopy and antiangiogenic effect assessment after silver nitrate cauterization. RESULTS: In vivo two-photon microscopy revealed that Flt1 peptide-HA conjugate micelles were absorbed and remained on the corneal epithelia with an increased residence time, facilitating the corneal delivery of carboxyfluorescein succinimidyl ester (CFSE) as a model drug. Furthermore, repeated eye drops of Flt1 peptide-HA conjugate micelles showed comparable therapeutic effect to the subconjunctival injection on the corneal neovascularization. DISCUSSION & CONCLUSION: We confirmed the feasibility of Flt1 peptide-HA conjugate micelles for eye drop treatment of corneal neovascularization. PMID- 26228272 TI - Metabolomics-Inspired Insight into Developmental, Environmental and Genetic Aspects of Tomato Fruit Chemical Composition and Quality. AB - Tomato was one of the first plant species to be evaluated using metabolomics and remains one of the best characterized, with tomato fruit being both an important source of nutrition in the human diet and a valuable model system for the development of fleshy fruits. Additionally, given the broad habitat range of members of the tomato clade and the extensive use of exotic germplasm in tomato genetic research, it represents an excellent genetic model system for understanding both metabolism per se and the importance of various metabolites in conferring stress tolerance. This review summarizes technical approaches used to characterize the tomato metabolome to date and details insights into metabolic pathway structure and regulation that have been obtained via analysis of tissue samples taken under different developmental or environmental circumstance as well as following genetic perturbation. Particular attention is paid to compounds of importance for nutrition or the shelf-life of tomatoes. We propose furthermore how metabolomics information can be coupled to the burgeoning wealth of genome sequence data from the tomato clade to enhance further our understanding of (i) the shifts in metabolic regulation occurring during development and (ii) specialization of metabolism within the tomato clade as a consequence of either adaptive evolution or domestication. PMID- 26228273 TI - Identification and Analysis of Medicago truncatula Auxin Transporter Gene Families Uncover their Roles in Responses to Sinorhizobium meliloti Infection. AB - Auxin transport plays a pivotal role in the interaction between legume species and nitrogen-fixing bacteria to form symbioses. Auxin influx carriers auxin resistant 1/like aux 1 (AUX/LAX), efflux carriers pin-formed (PIN) and efflux/conditional P-glycoprotein (PGP/ABCB) are three major protein families participating in auxin polar transport. We used the latest Medicago truncatula genome sequence to characterize and analyze the M. truncatula LAX (MtLAX), M. truncatula PIN (MtPIN) and M. truncatula ABCB (MtABCB) families. Transient expression experiments indicated that three representative auxin transporters (MtLAX3, MtPIN7 and MtABCB1) showed cell plasma membrane localizations. The expression of most MtLAX, MtPIN and MtABCB genes was up-regulated in the roots and was down-regulated in the shoots by Sinorhizobium meliloti infection in the wild type (WT). However, the expression of these genes was down-regulated in both the roots and shoots of an infection-resistant mutant, dmi3. The different expression patterns between the WT and the mutant roots indicated that auxin relocation may be involved in rhizobial infection responses. Furthermore, IAA contents were significantly up-regulated in the shoots and down-regulated in the roots after Sinorhizobium meliloti infection in the WT. Inoculation of roots with rhizobia may reduce the auxin loading from shoots to roots by inhibiting the expression of most auxin transporter genes. However, the rate of change of gene expression and IAA contents in the dmi3 mutant were obviously lower than in the WT. The identification and expression analysis of auxin transporter genes helps us to understand the roles of auxin in the regulation of nodule formation in M. truncatula. PMID- 26228274 TI - Short-term outcomes in adult cardiac surgery in the use of del Nido cardioplegia solution. AB - OBJECTIVES: Del Nido cardioplegia in adult cardiac surgery has not been studied although it has been in common use as a "single" dose cardioplegia in pediatric heart surgery. We retrospectively assessed the short-term (in-hospital) clinical outcomes of patients undergoing aortic valve replacement (AVR) using del Nido cardioplegia solution, comparing it to conventional multi-dose whole blood cardioplegia. METHODS: We switched our cardioplegia protocol from conventional whole blood cardioplegia exclusively to del Nido solution in May 2011. In 2011, 240 consecutive patients underwent isolated AVR. One hundred and seventy-eight of them were operated on with the use of del Nido cardioplegia (del Nido group) and whole blood cardioplegia (conventional group) was used in the other 62 patients. Isolated AVR was chosen as a cohort because of its relative simplicity and the similarity of surgical techniques among surgeons. Propensity-score matching identified 54 matched pairs for analysis. RESULTS: The retrograde cardioplegia technique was used in 19 cases (35.2%) in the del Nido group and 52 cases (96.3%) in the conventional group (p<0.001). Mean cardiopulmonary bypass time and mean aortic cross-clamp time were significantly shorter in the del Nido group compared to the conventional group: 71 +/- 16 min vs. 84 +/- 28 min (p<0.01), 52 +/- 14 min vs. 60 +/- 16 min (p<0.01), respectively. Postoperative inotropic support was required in 11 patients (20.4 %) in the del Nido group and 13 patients (24.1 %) in the conventional group (p=0.82) with no statistical difference. No patient required a postoperative intra-aortic balloon pump and in-hospital mortality was 0% in both groups. There was no significant difference in postoperative complications between the two groups. CONCLUSIONS: Short-term outcomes in adult cardiac surgery using del Nido solution were acceptable and comparable to conventional multi-dose whole blood cardioplegia. The del Nido cardioplegia technique was associated with shortened cross-clamp times and less frequent utilization of the retrograde cardioplegia delivery technique. PMID- 26228275 TI - Systemic oxidant/antioxidant balance in human abdominal aortic aneurysm. AB - The aim of this study was to evaluate the oxidant-antioxidant balance in patients with abdominal aortic aneurysms (AAA). Forty-two consecutive patients with AAA and 46 control subjects were included. Total oxidant status (TOS) and total antioxidant status (TAS) levels were measured and the oxidative stress index (OSI) value determined. Serum TOS and OSI values in patients with AAA were higher than those in the controls (p < 0.001, p < 0.001, respectively). There was a positive correlation between abdominal aortic diameters, serum TOS levels (r = 0.592, p < 0.001) and OSI values (r = 0.598, p < 0.001). A cut-off value of 17.68 umol H2O2equivalent/L for TOS was associated with 86% sensitivity and 83% specificity and a cut-off value of 1.77 for OSI was associated with 86% sensitivity and 81% specificity for predicting AAA. Systemic oxidative imbalance develops in patients with AAA, particularly as a result of an increase in TOS. PMID- 26228276 TI - A prospective randomized trial comparing the clinical effectiveness and biocompatibility of heparin-coated circuits and PMEA-coated circuits in pediatric cardiopulmonary bypass. AB - OBJECT: We compared the clinical effectiveness and biocompatibility of poly-2 methoxyethyl acrylate (PMEA)-coated and heparin-coated cardiopulmonary bypass (CPB) circuits in a prospective pediatric trial. METHODS: Infants randomly received heparin-coated (n=7) or PMEA-coated (n=7) circuits in elective pediatric cardiac surgery with CPB for ventricular septum defects. Clinical and hematologic variables, respiratory indices and hemodynamic changes were analyzed perioperatively. RESULTS: Demographic and clinical variables were similar in both groups. Leukocyte counts were significantly lower 5 minutes after CPB in the PMEA group than the heparin group. Hemodynamic data showed that PMEA caused hypotension within 5 minutes of CPB. The respiratory index was significantly higher immediately after CPB and 1 hour after transfer to the intensive care unit (ICU) in the PMEA group, as were levels of C-reactive protein 24 hours after transfer to the ICU. CONCLUSION: Our study shows that PMEA-coated circuits, unlike heparin-coated circuits, cause transient leukopenia during pediatric CPB and, perhaps, systemic inflammatory respiratory syndrome after pediatric CPB. PMID- 26228277 TI - Bacille Calmette-Guerin can induce cellular apoptosis of urothelial cancer directly through toll-like receptor 7 activation. AB - Immunotherapy using bacille Calmette-Guerin (BCG) instillation is the mainstay treatment modality for superficial urothelial cancer (UC) through toll-like receptor (TLR) activation of cognitive immune response. We investigated the roles of TLR7 in the activation of apoptosis in UC cells after BCG treatment. The in vitro cytotoxicity effect of BCG on UC cells was measured by a modified 3-(4,5 dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium assay. Expressions of TLR7 mRNA and protein in native UC cells prior to and after BCG treatment were analyzed using real-time quantitative polymerase chain reaction and western blot methods. Phagocytotic processes after BCG treatment in UC cells were observed microscopically using a specific immunostain, subsequent cellular apoptosis related signals induced by TLR7 were analyzed by western blot. Low-grade UC cells, TSGH8301, showed significant cellular death (4.23-fold higher than the high-grade UC cells T24 and J82) when treated with BCG and the BCG cytotoxicity was displayed in a dose-time-dependent manner. TSGH8301 cells had the highest content of TLR7 mRNA, 7.2- and 4.5-fold higher than that of T24 and J82 cells, respectively. TLR7 protein expression was also significantly increased in TSGH8301 cells. Phagocytosis-related markers, including beclin 1, ATG2, and LC3, were increased when TSGH8301 cells were treated by BCG. Interleukin-1 receptor associated kinases 2 and 4 were also increased markedly in TSGH8301 cells. On the contrary, cellular apoptosis of TSGH8301 cells decreased by 34% when TLR7 activation was suppressed by the TLR antagonist IRS661 after BCG treatment. Our findings suggest that well differentiated TCC cells have higher expression of TLR7 and BCG can drive cellular death of TCC cells directly via TLR7 activation and related apoptotic pathway. PMID- 26228278 TI - Reversal of P-glycoprotein overexpression by Ginkgo biloba extract in the brains of pentylenetetrazole-kindled and phenytoin-treated mice. AB - The purpose of this study was to investigate the combined effects of Ginkgo biloba extract and phenytoin (PHT) sodium as a dose regimen simulating the clinical treatment of patients with epilepsy, on P-glycoprotein (P-GP) overexpression in a pentylenetetrazole-kindled mouse model of epilepsy. Epilepsy was induced by intraperitoneal administration of pentylenetetrazole (40 mg/kg) for 7 days followed by intragastric administration of PHT (40 mg/kg) for 14 days. Thirty mice that developed seizures were randomly divided into three groups and administered PHT as well as the following treatments: saline (negative control); verapamil (20 mg/kg, positive control); and G. biloba (30 mg/kg). Seizure severity was recorded 30 minutes after treatment on Day 4 of drug administration, after which the mice were euthanized, and their brains isolated. Western blots and immunohistochemistry were performed to analyze the expression of P-GP and caspase-3, respectively, in the brain tissue. High-performance liquid chromatography was used to measure the concentrations of PHT in the brains of the treated mice. After 4 consecutive days of treatment, the seizure severity in the mice in the G. biloba extract group was more significantly reduced than the seizure severity in the saline control group, and a significant difference was observed between the G. biloba extract and verapamil control groups (p < 0.05). P GP expression in the brain more significantly decreased in the mice treated with G. biloba extract and verapamil than it did in the saline-treated control group (p < 0.05). Compared with the saline-treated control group, the mice treated with G. biloba extract and verapamil showed significantly increased brain PHT concentrations (p < 0.05). Furthermore, caspase-3 expression in the brain tissue of the G. biloba extract group was significantly lower than that in the vehicle control group (p < 0.05); this finding demonstrated the neuroprotective effects of G. biloba. Therefore, this study showed that treatment with G. biloba extract in combination with PHT prevented the upregulation of P-GP expression in mice. Moreover, G. biloba extract decreased seizure severity in pentylenetetrazole kindled/PHT-treated mice through a mechanism that might be related to the reduction of P-GP expression in the brain. PMID- 26228279 TI - Renal sympathetic denervation prevents the development of pulmonary arterial hypertension and cardiac dysfunction in dogs. AB - The renin-angiotensin-aldosterone system is activated in pulmonary arterial hypertension (PAH) patients, and this activation may have long-term negative effects on the progression of PAH. The purpose of this study was to evaluate the effects of transcatheter renal sympathetic denervation (RSD) on the development of pulmonary arterial hypertension and cardiac dysfunction in dogs using two dimensional speckle tracking imaging. Twenty-two dogs were randomly divided into three groups: control group (n = 7), PAH group (n = 8), and PAH + RSD group (n = 7). All dogs were assessed using two-dimensional speckle tracking imaging. The ventricular strain, ventricular synchrony, left ventricular (LV) twist, and torsion rate were analyzed to evaluate cardiac function. After 8 weeks, the right ventricular lateral longitudinal strain and the septum longitudinal strain were reduced in the PAH group compared with the control group (p < 0.001). However, these values were significantly restored in the PAH + RSD group compared with the PAH group (p < 0.01). The degree of LV and RV dyssynchrony was significantly higher in the PAH group compared with the control group (p < 0.001), but the degree of LV and RV dyssynchrony was significantly lower in the PAH + RSD group compared to the PAH group (p < 0.01). The LV twist was significantly restored in the PAH + RSD group compared to the PAH group (p < 0.01). Similarly, the rotation rate was markedly decreased in the PAH group, and strikingly improved in the PAH + RSD group (p < 0.01). These results indicate that RSD prevents the development of PAH and cardiac dysfunction in dogs. PMID- 26228280 TI - Radiofrequency ablation assisted by real-time virtual sonography for hepatocellular carcinoma inconspicuous under sonography and high-risk locations. AB - Radiofrequency ablation (RFA) is an effective and real-time targeting modality for small hepatocellular carcinomas (HCCs). However, mistargeting may occur when the target tumor is confused with cirrhotic nodules or because of the poor conspicuity of the index tumor under ultrasonography (US). Real-time virtual sonography (RVS) can provide the same reconstruction computed tomography images as US images. The aim of this study is to investigate the usefulness of RVS assisted RFA for HCCs that are inconspicuous or conspicuous under US. A total of 21 patients with 28 HCC tumors-divided into US inconspicuous and high-risk subgroup (3 tumors in 3 patients), US inconspicuous and nonhigh-risk subgroup (5 tumors in 4 patients), US conspicuous and high-risk subgroup (16 tumors in 14 patients), and US conspicuous and nonhigh-risk subgroup (4 tumors in 3 patients) underwent RVS-assisted RFA between May 2012 and June 2014 in our institution. The mean diameter of the nodules was 2.0 +/- 1.1 cm. The results showed that the complete ablation rate is 87.5% (7/8) in the US undetectable group and 75% (15/20) in the US detectable group. A comparison between six tumors with incomplete ablation and 22 tumors with complete ablation showed higher alpha fetoprotein level (mean, 1912 ng/mL vs. 112 ng/mL) and larger tumor size (mean diameter, 26 mm vs. 16 mm) in the incomplete ablation nodules (both p < 0.05). In conclusion, RVS-assisted RFA is useful for tumors that are difficult to detect under conventional US and may also be useful for tumors in high-risk locations because it may prevent complication induced by mistargeting. PMID- 26228281 TI - Posterior pole asymmetry analysis and retinal thickness measurements in young relatives of glaucoma patients. AB - The presence of a family history of glaucoma is a known risk factor for primary open-angle glaucoma (POAG) in middle-aged and older individuals. In this study, our aim was to demonstrate possible early glaucomatous alterations in young first and second-degree relatives of POAG patients by spectral-domain optical coherence tomography. A total of 104 participants (52 relatives of POAG patients and 52 healthy individuals) were recruited in this cross-sectional study. All the participants were between 17 years and 45 years of age. All eyes underwent testing with spectral-domain optical coherence tomography. Peripapillary retinal nerve fiber layer thickness, hemifield macular thickness, macular ganglion cell complex thickness, posterior pole asymmetry analysis, and retinal arteriolar caliber measurements were taken for comparison between the study and control groups. The mean peripapillary retinal nerve fiber layer thickness was 104.9 +/- 8.8 MUm in the study group and 105.6 +/- 7.4 MUm in the control group (p = 0.68). Although whole macular thickness measurements were higher in the control group when compared with the study group (p = 0.008), the macular ganglion cell complex thickness was similar in both groups (p = 0.87). The posterior pole asymmetry analysis revealed no statistically significant difference between the groups in the aspect of consecutive black squares (p = 0.79). The mean retinal arteriolar caliber was 85.9 +/- 4.8 MUm in the study group and 86.0 +/- 5.0 MUm in the control group (p = 0.90). In conclusion, young relatives of POAG patients do not show characteristic glaucomatous damage when compared with the controls. PMID- 26228282 TI - Evaluation of the effects of serum iron levels on lacrimal gland secretion. AB - In our study we aimed to demonstrate the relationship between the serum iron levels, and tears quality and quantity in term newborns. This study was conducted at a single institution between March 2013 and May 2013. A total of 46 newborns were prospectively enrolled. Serum iron levels were measured via the umbilical cord blood. Infants were divided into two groups according to their serum iron levels. Group A, serum iron level <=70 MUg/dL (n = 27) and Group B, serum iron level > 70 MUg/dL (n = 19). The evaluation of the osmolarity was tested by using the TearLab Osmolarity System (TearLab Co, San Diego, CA, USA). The assessment of quantity was performed by using Schirmer I test. Osmolarity testing and Schirmer I test (with/without anesthesia) were performed bilaterally on the 1(st) day of life by an ophthalmologist. The outcomes of Schirmer I and tear osmolarity showed no statistically significant difference between right and left eyes of any infant in the groups. Moreover, there was no statistical difference between sexes in these two groups. Osmolarity was found to have a moderate negative correlation coefficient with serum iron level (r = -0.4, p < 0.01). Furthermore, there was a high positive correlation between Schirmer I with anesthesia and serum iron levels (r = 0.7, p < 0.01). We observed that the quality and quantity of the tears was lower in term newborns with lower serum iron levels than healthy newborns. These results indicate that low serum iron level could affect lacrimal gland functions. PMID- 26228283 TI - Assessment of intra-interobserver reliability of the sonographic optic nerve sheath diameter measurement. AB - Diagnosis and measuring the level of increase in intracranial pressure (ICP) is critical, especially for the management of trauma patients in the emergency department and intensive care unit. However, measurements are operator-dependent as in all of the sonographic diagnoses. The aim of this study is to assess the operator variations in the measurement of optic nerve sheath diameter (ONSD). There were four emergency medicine specialists involved in the study. Each had at least 1 year of experience of ultrasound scans and performed at least 25 prior ocular scans examining the ONSD. Two measurements were made 1 week apart from both axial and longitudinal planes. Sixty healthy adults were involved in the study and every investigator obtained four measurements from each. Intra interobserver reliabilities were tested. The investigators performed 60 ocular ultrasounds on individual healthy adults and obtained two measurements in axial and longitudinal planes 1 week apart. Therefore, 960 measurements were analyzed. The levels of compatibilities for most of the measurements were found at acceptable levels statistically. However, it is not possible to say that there was a perfect compatibility among the sonographers according to the previously conducted reliability studies of ultrasound measurements. According to our results, it is hard to say that sonographic measurement of the ONSD is a highly reliable method both in longitudinal and transverse planes. PMID- 26228284 TI - Acute antibody-mediated rejection with graft loss during anti-tuberculosis therapy in kidney transplantation. PMID- 26228285 TI - Recurrent lupus mesenteric vasculitis leading to gastrointestinal perforation and sepsis. PMID- 26228286 TI - Extremely rare cause of obstructive jaundice: Non-neoplastic, noninfectious lymphadenitis. PMID- 26228287 TI - Effective Remote Loading of Doxorubicin into DPPC/Poloxamer 188 Hybrid Liposome to Retain Thermosensitive Property and the Assessment of Carrier-Based Acute Cytotoxicity for Pulmonary Administration. AB - Functional liposome administration via the pulmonary route is of interest to treat pulmonary diseases, including cancer. Here, a block copolymer used as a medical additive, Poloxamer 188 (P188), was incorporated into liposome membranes, and the thermosensitive characteristics of the DPPC/P188 hybrid liposomes were assessed. An increase in P188 incorporation in DPPC liposomes enhanced the release of calcein, a fluorescence marker, from liposomes at 42 degrees C in vitro; calcein release was significantly slower at 37 degrees C. The lipid composition was optimal at a DPPC/P188 ratio of 3:0.4 (molar ratio). DPPC/P188 liposomes did not exhibit in vitro cytotoxicity against A549 cells and Raw 264.7 cells used as models of pulmonary cells or trigger in vivo acute inflammation as determined by the secretion of tumor necrosis factor alpha. Next, an anticancer drug, doxorubicin (DOX), was loaded with approximately 90% efficiency into DPPC/P188 liposomes using a remote-loading method and a DOX-phospholipid ratio of 1:20 (w/w). The interior buffer of liposome has remarkably changed DOX release at 42 degrees C. DOX released from DPPC/P188 liposomes at 42 degrees C exhibited cytotoxic effects toward A549 cells comparable with free DOX solution. These results suggest that a DOX-loaded DPPC/P188 liposome formulation administered via the pulmonary route may be useful for treating lung cancer. PMID- 26228289 TI - Certification figures and their accuracy. PMID- 26228290 TI - Response to: 'Comment on Gas tamponade combined with laser photocoagulation therapy for congenital optic disc pit maculopathy'. PMID- 26228288 TI - The stereotypical molecular cascade in neovascular age-related macular degeneration: the role of dynamic reciprocity. AB - This review summarises our current understanding of the molecular basis of subretinal neovascularisation (SRNV) in age-related macular degeneration (AMD). The term neovascular AMD (NVAMD) is derived from the dominant early clinical features of haemorrhage, fluid, and lipid in the subretinal space (SRS) and the historical role of fluorescein angiography in detecting the presence of NV tissue. However, at the cellular level, SRNV resembles an aberrant but stereotypical tissue repair response that incorporates both an early inflammatory phase and a late fibrotic phase in addition to the neovascular (NV) component that dominates the early clinical presentation. This review will seek not only to highlight the important molecules involved in each of these components but to demonstrate that the development of SRNV has its origins in the earliest events in non-NV AMD pathogenesis. Current evidence suggests that this early-stage pathogenesis is characterised by complement-mediated immune dysregulation, leading to a state of chronic inflammation in the retinal pigment epithelium/Bruch's membrane/choriocapillaris complex. These initial events can be seamlessly and inextricably linked to late-stage development of SRNV in AMD by the process of dynamic reciprocity (DyR), the ongoing bidirectional communication between cells, and their surrounding matrix. Moreover, this correlation between disease onset and eventual outcome is reflected in the temporal and spatial correlation between chronic inflammation, NV, and fibrosis within the reparative microenvironment of the SRS. In summary, the downstream consequences of the earliest dysfunctional molecular events in AMD can result in the late-stage entity we recognize clinically as SRNV and is characterized by a spectrum of predictable, related, and stereotypical processes referred to as DyR. PMID- 26228291 TI - Month-6 primary outcomes of the READ-3 study (Ranibizumab for Edema of the mAcula in Diabetes-Protocol 3 with high dose). AB - PURPOSE: To compare 2.0 mg ranibizumab (RBZ) injections with 0.5 mg RBZ for eyes with center-involved diabetic macular edema (DME) and a central subfield thickness (CFT) of >=250 MUm on time-domain optical coherence tomography.DesignRandomized, controlled, multicenter clinical trial. METHODS: Eligible eyes were randomized in a 1:1 ratio to 0.5 mg (n=77) or 2.0 mg (n=75) RBZ. Study eyes received 6-monthly injections.Main outcome measuresThe primary outcome measure was the mean change in best corrected visual acuity (BCVA) at month 6. Secondary outcomes included the incidence and severity of systemic and ocular adverse events and the mean change in CFT from baseline. RESULTS: In all, 152 eyes (152 patients) were randomized in the study. At month 6, the mean improvement from baseline BCVA was +9.43 letters in the 0.5 mg RBZ group and +7.01 letters in the 2.0 mg RBZ group (P=0.161). At month 6, one death occurred in the 0.5 mg RBZ group and three deaths in the 2.0 mg RBZ group, all due to myocardial infarction in subjects with a prior history of heart disease. Mean CFT was reduced by 168.58 MUm in the 0.5 mg RBZ group and by 159.70 MUm in the 2.0 mg RBZ group (P=0.708). CONCLUSIONS: There was no statistically significant difference in the mean number of letters gained between the 0.5 and 2.0 mg RBZ groups through month 6. In this DME study population, high-dose RBZ does not appear to provide additional benefit over 0.5 mg RBZ. PMID- 26228292 TI - Lens parameters as predictors of intraocular pressure changes after phacoemulsification. AB - PURPOSE: To evaluate intraocular pressure (IOP) change after cataract surgery in non-glaucomatous eyes with narrow and open angles (OAs) and its relation to novel lens parameters measured by anterior segment optical coherence tomography (AS OCT). SETTING: University affiliated hospital, Farabi Eye Hospital, Tehran, Iran. DESIGN: Prospective interventional case series. METHODS: In this prospective study, 85 non-glaucomatous eyes underwent phacoemulsification and lens implantation. Thirty-nine eyes had OAs and 46 eyes had narrow angles (NAs). IOP and biometric parameters were measured by AS-OCT preoperatively and 3 months after surgery. Change in IOP and its relation to biometric parameters, including lens vault (LV), anterior vault (AV), defined as the sum of the LV and the ACD, and relative LV (rLV), defined as the ratio of the LV to the AV, were evaluated. The main outcome measure was degree of IOP change after phacoemulsification. RESULTS: Of the 85 patients included in the analysis, 35 were male and 50 were female with an overall mean age of 62.2 +/- 8.9 years. The average IOP reduction was -4.95 +/- 2.26 mm Hg, from a preoperative mean of 17.12 +/- 2.47 mm Hg, at 3 months after cataract surgery. The amount of IOP reduction was significantly greater in the NA compared with the OA group. In multivariate linear regression analysis, preoperative IOP and AV were significantly associated with IOP decrease (all <= 0.03). CONCLUSION: Cataract surgery results in IOP reduction in both OA and NA eyes. The amount of IOP reduction is related to AV. PMID- 26228293 TI - Comment on 'Gas tamponade combined with laser photocoagulation therapy for congenital optic disc pit maculopathy'. PMID- 26228294 TI - A convenient screening method to differentiate phenolic skin whitening tyrosinase inhibitors from leukoderma-inducing phenols. AB - BACKGROUND: Tyrosinase is able to oxidize a great number of phenols and catechols to form ortho-quinones. Ortho-quinones are highly reactive compounds that exert cytotoxicity through binding with thiol enzymes and the production of reactive oxygen species. Certain phenolic (and catecholic) compounds are known to induce contact/occupational leukoderma through activation to ortho-quinones. OBJECTIVE: We report a convenient screening method to follow the oxidation of those leukoderma-inducing phenols by mushroom tyrosinase. METHODS: Oxidation of phenolic compounds by mushroom tyrosinase was followed periodically by UV-vis spectrophotometry. The production of ortho-quinones were confirmed by their absorptions around 400-420 nm. HPLC analysis after reduction with NaBH4 detected the corresponding catechols. RESULTS: Leukoderma-inducing phenols, rhododendrol, raspberry ketone, 4-methoxyphenol, 4-benzyloxyphenol, 4-tert-butylphenol, and 4 tert-butylcatechol, were readily oxidized by mushroom tyrosinase to form ortho quinones. On the other hand, phenolic skin whitening tyrosinase inhibitors, ellagic acid, 4-n-butylresorcinol, potassium 4-methoxysalicylate, and 2,2' dihydroxy-5,5'-di-n-propylbiphenyl, were not oxidized by mushroom tyrosinase, while arbutin was only slowly oxidized. CONCLUSION: This study has provided a convenient screening method to differentiate phenolic skin whitening tyrosinase inhibitors from leukoderma-inducing phenols. A common chemical feature of the latter group of compounds is that they are readily oxidized by tyrosinase to form reactive ortho-quinone species. The present results point out the necessity that tyrosinase inhibitors should also be examined as substrates if they are phenolic compounds. PMID- 26228295 TI - Parental Body Mass Index, Gestational Weight Gain, and Risk of Macrosomia: a Population-Based Case-Control Study in China. AB - BACKGROUND: The prevalence of macrosomia has risen markedly worldwide, including in China, during the past two decades. Few epidemiological studies, however, have investigated the risk factors for macrosomia in China. This study was designed to investigate the associations between parental anthropometric characteristics, gestational weight gain (GWG), and risk of macrosomia in China. METHODS: This population-based, case-control study in Wuhan, China, included a total of 6341 subjects (870 cases and 5471 controls). Multivariable logistic regression was conducted to calculate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Mothers or fathers who were overweight or obese before pregnancy had an elevated risk of giving birth to a macrosomic infant compared with their normal weight counterparts. Women with GWG above the Institute of Medicine (IOM) recommendation had an adjusted OR of 6.09 [95% CI 5.04, 7.35] for delivering a macrosomic infant compared with women who had GWG within the IOM recommendation. When stratified by maternal pre-pregnancy body mass index (BMI), women who were underweight or normal weight before pregnancy were observed to have a higher risk of macrosomia birth associated with greater GWG. CONCLUSIONS: Parental pre pregnancy overweight/obesity and excessive GWG during pregnancy were highly associated with macrosomia. The association with GWG was most pronounced in mothers who had a normal or underweight pre-pregnancy BMI. Weight control efforts before pregnancy for mothers and fathers as well as control of maternal gain during pregnancy may reduce the risk of macrosomia. PMID- 26228296 TI - Reply to letter to the editor 'Independent application of MoCA/MMSE conversion' by Armstrong et al. PMID- 26228297 TI - Effect of Tri-Staple Technology and Slow Firing on Secure Stapling Using an Endoscopic Linear Stapler. AB - AIM: To evaluate the effect of Tri-staple technology and slow firing using the Endo-GIA endoscopic linear stapler. METHODS: The cardiac and pyloric portions of porcine stomachs were divided using the endoscopic linear stapler with different reload types. A total of 8 min of waiting time was employed during firing in the slow-firing group and no waiting time was employed in the normal-firing group. The shape of the staples was then evaluated. The length of the staple line and serosal laceration was also determined. RESULTS: There was a moderate negative correlation between tissue thickness and secure staple formation. Tri-staple reloads (purple, black) offered more secure staple formation compared with Universal green reload. Although slow firing enhanced secure staple formation, its effect was greater when using green reload, compared with Tri-staple reloads. Significantly shorter staple line length and longer serosal laceration was observed in the thick tissue. Although the cartridge type did not influence lengths of the staple line or serosal laceration, both were better in the slow firing group. CONCLUSIONS: Tri-staple reloads offered more secure staple formation compared with the Universal reload. Although slow firing improved staple line shortening and serosal laceration, its effect on secure stapling was relatively small when using Tri-staple reloads. PMID- 26228298 TI - Quantification of metamorphopsia using the MacuFlow test before and after vitreoretinal surgery. AB - BACKGROUND AND OBJECTIVE: This pilot study evaluated the clinical utility of the MacuFlow software in measuring metamorphopsia prior to and following surgery in patients with vitreoretinal diseases. PATIENTS AND METHODS: Four patients with vitreoretinal disorders causing metamorphopsia were included in this pilot study. Visual acuity (VA), optical coherence tomography and MacuFlow scores were recorded prior to and following surgical intervention. RESULTS: The mean preoperative VA was 0.59 +/- 0.09 logMAR, central macular thickness 491.2 +/- 41.3 um and calculated macular volume 8.99 +/-1.47 mm(3). These parameters improved postoperatively to a mean VA of 0.30 +/- 0.22 logMAR, central macular thickness of 372.8 +/- 85.4 um and macular volume of 7.94 +/- 1.34 mm(3) but did not reach statistical significance. The mean preoperative MacuFlow score was 14.02 +/- 8.21, which significantly improved postoperatively to 5.4 +/- 3.13 (p = 0.045). CONCLUSIONS: This is the first study to demonstrate the clinical utility of MacuFlow for the quantification of metamorphopsia and its improvement or resolution following surgery. This simple method may be a valuable addition for the clinical assessment and monitoring of patients with retinal diseases causing metamorphopsia. PMID- 26228299 TI - An effective combination of sanger and next generation sequencing in diagnostics of primary ciliary dyskinesia. AB - BACKGROUND: Primary ciliary dyskinesia (PCD) is a multigenic autosomal recessive condition affecting respiratory tract and other organs where ciliary motility is required. The extent of its genetic heterogeneity is remarkable. The aim of the study was to develop a cost-effective pipeline for genetic diagnostics using a combination of Sanger and next generation sequencing (NGS). MATERIALS AND METHODS: Data and samples of 33 families with 38 affected subjects with PCD diagnosed in childhood were collected over the territory of the Czech Republic. A panel of 18 PCD causative or candidate genes was implemented into an Illumina TruSeq Custom Amplicon NGS assay, and three ancestral mutations in SPAG1 were screened by conventional Sanger sequencing, which was also used for the confirmation of the NGS results and for the analysis of familial segregation. RESULTS: The causative gene was DNAH5 in 11/33 (33%) probands, SPAG1 in 8/33 (24%), and DNAI1, CCDC40, LRRC6 in one family each. If the high proportion of subjects with bi-allelic ancestral mutations in SPAG1 is corroborated in other Caucasian populations, a simple Sanger sequencing test for these three mutations may serve as an effective pre-screening step, being followed by an NGS panel for other, much larger, PCD genes. CONCLUSIONS: We present a combination of Sanger sequencing with an NGS panel for known and candidate PCD genes, implemented in a moderate-size national collection of patients. This strategy has proven to be cost-effective, rapid and reliable, and was able to detect the causative gene in two thirds of our PCD patients. PMID- 26228300 TI - Genetic linkage facilitates cloning of Ert-m regulating plant architecture in barley and identified a strong candidate of Ant1 involved in anthocyanin biosynthesis. AB - The erectoides-m anthocyanin-less 1 (ert-m ant1) double mutants are among the very few examples of induced double mutants in barley. From phenotypic observations of mutant plants it is known that the Ert-m gene product regulates plant architecture whereas the Ant1 gene product is involved in anthocyanin biosynthesis. We used a near-isogenic line of the cultivar Bowman, BW316 (ert m.34), to create four F2-mapping populations by crosses to the barley cultivars Barke, Morex, Bowman and Quench. We phenotyped and genotyped 460 plants, allowing the ert-m mutation to be mapped to an interval of 4.7 cM on the short arm of barley chromosome 7H. Bioinformatic searches identified 21 candidate gene models in the mapped region. One gene was orthologous to a regulator of Arabidopsis thaliana plant architecture, ERECTA, encoding a leucine-rich repeat receptor-like kinase. Sequencing of HvERECTA in barley ert-m mutant accessions identified severe DNA changes in 15 mutants, including full gene deletions in ert-m.40 and ert-m.64. Both deletions, additionally causing anthocyanin deficiency, were found to stretch over a large region including two putative candidate genes for the anthocyanin biosynthesis locus Ant1. Analyses of ert-m and ant1 single- and double-deletion mutants suggest Ant1 as a closely linked gene encoding a R2R3 myeloblastosis transcription factor. PMID- 26228301 TI - Foxp3(+) regulatory T cells are expanded in severe atopic dermatitis patients. AB - Regulatory T cells (Tregs) are known to play critical roles in homeostasis and immune responses in the skin. Whether Treg frequencies are altered in atopic dermatitis (AD) patients has been addressed by several studies, leading to conflicting results. The detection of Tregs by FOXP3 expression may lead to false positive results as activated T cells without regulatory function may transiently upregulate this transcription factor. In contrast, measurement of the DNA methylation status of a region within the FOXP3 locus that is selectively demethylated only in bona fide Tregs (Treg-specific demethylated region, TSDR) represents a reliable method to quantify Tregs. Here, we measured circulating Treg frequencies of adult patients and detected a positive correlation with disease severity. Subsequent surface marker analysis revealed higher frequencies of CD45RA(+) CCR7(-) tissue-homing Tregs in the patient group with a tendency of reduced expression of CD39 compared with healthy donors, a marker for the highly suppressive TREM subtype. PMID- 26228302 TI - New perspectives on the mutated NGLY1 enigma. AB - The enzyme N-glycanase 1 (NGLY1) is considered a component of the endoplasmic reticulum-associated degradation (ERAD) machinery and clinical manifestations of its dysfunction include global developmental delay, a movement disorder, peripheral neuropathy, liver disorders, microcephaly, diminished reflexes and seizures. Although several mutations in NGLY1 have been identified, the relation between the defected protein and the above described pathologies is yet unknown. We hypothesised that NGLY1 failure to degrade certain proteins may result in their accumulation and overexpression and used a systems biology approach to identify proteins that may be affected by NGLY1 deficiency. Genes that interact with the NGLY1 gene according to BioGRID database of physical and genetic interactions were analysed with STRING Protein-Protein interaction database. Network analysis identified FAF1 (Fas-Associated Factor 1), an apoptosis potentiating protein, as a possible degradation substrate of NGLY1. Examination of normal tissue microarrays demonstrated that FAF1-to-NGLY1 ratio is maximal (more than 3:1) in skeletal muscle and brain tissues microarrays. This evidence may explain the pathologies in brain and muscle tissues of patients with mutated NGLY1. To test this hypothesis, laboratory studies that will assess if FAF1 protein is overexpressed in tissues of patients with mutated NGLY1 are required. PMID- 26228303 TI - EDUCATION AND IMAGING. Hepatobiliary and Pancreatic: Post-transplant recurrence of fibrolamellar hepatocellular carcinoma in lung and pancreas. PMID- 26228304 TI - Temperament and risk for exercise dependence: results of a pilot study in female patients with eating disorders compared to elite athletes. AB - BACKGROUND: The present pilot study investigated the relationship between temperament and the risk for exercise dependence (EXD). SAMPLING AND METHODS: A total of 32 female patients with eating disorders (potentially at risk for secondary EXD) and 29 female elite athletes without eating disturbances (potentially at risk for primary EXD) answered the Eating Disorder Examination Questionnaire (EDE-Q), the Exercise Dependence Scale-German version (EDS-G), the Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) scales, and the effortful control subscale of the Adult Temperament Questionnaire (ATQ-EC). RESULTS: There were significant positive correlations of the EDS-G with the BIS in women with an eating disorder and with the BAS in elite athletes. No significant association was found between the EDS-G and effortful control. CONCLUSIONS: The results indicate that the risk for EXD is associated with avoidance tendencies in women with eating disorders and with approach tendencies in elite athletes. Implications for secondary and primary EXD are discussed. PMID- 26228305 TI - Engineering the defect state and reducibility of ceria based nanoparticles for improved anti-oxidation performance. AB - Due to their excellent anti-oxidation performance, CeO2 nanoparticles receive wide attention in pharmacological application. Deep understanding of the anti oxidation mechanism of CeO2 nanoparticles is extremely important to develop potent CeO2 nanomaterials for anti-oxidation application. Here, we report a detailed study on the anti-oxidation process of CeO2 nanoparticles. The valence state and coordination structure of Ce are characterized before and after the addition of H2O2 to understand the anti-oxidation mechanism of CeO2 nanoparticles. Adsorbed peroxide species are detected during the anti-oxidation process, which are responsible for the red-shifted UV-vis absorption spectra of CeO2 nanoparticles. Furthermore, the coordination number of Ce in the first coordination shell slightly increased after the addition of H2O2. On the basis of these experimental results, the reactivity of coordination sites for peroxide species is considered to play a key role in the anti-oxidation performance of CeO2 nanoparticles. Furthermore, we present a robust method to engineer the anti oxidation performance of CeO2 nanoparticles through the modification of the defect state and reducibility by doping with Gd(3+). Improved anti-oxidation performance is also observed in cell culture, where the biocompatible CeO2-based nanoparticles can protect INS-1 cells from oxidative stress induced by H2O2, suggesting the potential application of CeO2 nanoparticles in the treatment of diabetes. PMID- 26228306 TI - Nursing students' attitudes toward statistics: Effect of a biostatistics course and association with examination performance. AB - BACKGROUND: Although statistical knowledge and skills are necessary for promoting evidence-based practice, health sciences students have expressed anxiety about statistics courses, which may hinder their learning of statistical concepts. OBJECTIVES: To evaluate the effects of a biostatistics course on nursing students' attitudes toward statistics and to explore the association between these attitudes and their performance in the course examination. DESIGN: One group quasi-experimental pre-test/post-test design. SETTING AND PARTICIPANTS: Undergraduate nursing students of the fifth or higher semester of studies, who attended a biostatistics course. METHODS: Participants were asked to complete the pre-test and post-test forms of The Survey of Attitudes Toward Statistics (SATS) 36 scale at the beginning and end of the course respectively. Pre-test and post test scale scores were compared, while correlations between post-test scores and participants' examination performance were estimated. RESULTS: Among 156 participants, post-test scores of the overall SATS-36 scale and of the Affect, Cognitive Competence, Interest and Effort components were significantly higher than pre-test ones, indicating that the course was followed by more positive attitudes toward statistics. Among 104 students who participated in the examination, higher post-test scores of the overall SATS-36 scale and of the Affect, Difficulty, Interest and Effort components were significantly but weakly correlated with higher examination performance. CONCLUSIONS: Students' attitudes toward statistics can be improved through appropriate biostatistics courses, while positive attitudes contribute to higher course achievements and possibly to improved statistical skills in later professional life. PMID- 26228307 TI - Selective oxidative stress and cholesterol metabolism in lipid-metabolizing cell classes: Distinct regulatory roles for pro-oxidants and antioxidants. AB - Atherogenesis is associated with macrophage cholesterol and oxidized lipids accumulation and foam cell formation. However, two other major lipid-metabolizing cell classes, namely intestinal and liver cells, are also associated with atherogenesis. This study demonstrates that manipulations of cellular oxidative stress (by fatty acids, glucose, low-density lipoprotein, angiotensin II, polyphenolic antioxidants, or the glutathione/paraoxonase 1 systems) have some similar, but also some different effects on cholesterol metabolism in macrophages (J774A.1) versus intestinal cells (HT-29) versus liver cells (HuH7). Cellular oxidative stress was ~3.5-folds higher in both intestinal and liver cells versus macrophages. In intestinal cells or liver cells versus macrophages, the cholesterol biosynthesis rate was increased by 9- or 15-fold, respectively. In both macrophages and intestinal cells C-18:1 and C-18:2 but not C-18:0, fatty acids significantly increased oxidative stress, whereas in liver cells oxidative stress was significantly decreased by all three fatty acids. In liver cells, trans C-18:1 versus cis C-18:1, unlike intestinal cells or macrophages, significantly increased cellular oxidative stress and cellular cholesterol biosynthesis rate. Pomegranate juice (PJ), red wine, or their phenolics gallic acids or quercetin significantly reduced cellular oxidation mostly in macrophages. Recombinant PON1 significantly decreased macrophage (but not the other cells) oxidative stress by ~30%. We conclude that cellular atherogenesis research should look at atherogenicity, not only in macrophages but also in intestinal and liver cells, to advance our understanding of the complicated mechanisms behind atherogenesis. (c) 2015 BioFactors, 41(4):273-288, 2015. PMID- 26228308 TI - Does Combined Use of the J-tip(r) and Buzzy(r) Device Decrease the Pain of Venipuncture in a Pediatric Population? AB - BACKGROUND: Both the J-tip(r) (a needle-free device for subcutaneous delivery of lidocaine) and the Buzzy(r) (a cooled, vibrating device to employ gate control to minimize procedural pain) have shown some efficacy in diminishing the pain of venipuncture. PURPOSE: To develop an optimal protocol for pre-venipuncture/IV start pain management by investigating the impact of adding the use of Buzzy(r) prior to the use of the J-tip(r). PROCEDURES: Pediatric emergency department patients aged 1 month to 21 years were prospectively enrolled in Phase 1 (J tip(r) only) then Phase 2 (Buzzy(r)+J-tip(r)) for analgesia prior to venipuncture or IV start. Age-appropriate pain scale scores were collected for the subsequent procedure, as well the administration of lidocaine via J-tip(r). MAIN FINDINGS: With the combined intervention (phase 2), 14.2% of patients had a pain scale score >3 with venipuncture and 16.1% had a pain scale score >3 with application of the J-tip(r) itself. With no intervention for pain relief, 71% of patients experienced a pain scale score >3 for venipuncture. With the J-tip(r) alone (phase 1), 21% had a pain scale score >3 with venipuncture and 22.3% had a pain scale score >3 with application of the J-tip(r) itself. CONCLUSIONS: Patients receiving either intervention reported lower scores on pain scales during venipuncture or IV start than the no analgesia group. The combined intervention did not yield a significant decrease in scores on pain scale scores over the J tip(r) alone. PMID- 26228309 TI - The Role of Health Advocacy in Transitions from Pediatric to Adult Care for Children with Special Health Care Needs: Bridging Families, Provider and Community Services. AB - BACKGROUND: Youth and young adults with special healthcare needs (YASHCN) experience challenges during transition from pediatric to adult care. Prior studies have not examined how community and healthcare resources can work together to assist YASHCN in transitioning from child-focused care and services to adult-oriented providers. OBJECTIVE: The aim of this study was to develop a theoretical understanding of how family, healthcare providers and community supports can assist YASHCN during the transition from pediatric to adult healthcare and services. DESIGN/METHODS: We conducted 41 semi-structured interviews with YASHCN aged 16-25, their family members and healthcare and community providers. We focused our interviews on support mechanisms, both within the traditional healthcare system, and those available in the community. Using grounded theory methods, we performed a multi-step analysis process. RESULTS: The theoretical code "Transition Advocacy" was developed from the data. This theoretical perspective arose from three major categories, which were developed in the analysis: "Fighting for healthcare", "Obtaining resources", and "Getting ready to transition". Transition Advocacy consists of the presence of, or need for, a healthcare "advocate" who did or can assist the YASHCN with the healthcare transition, particularly to navigate complex health or community services. The "advocate" role was performed by family members, healthcare or agency professionals, or sometimes the YASHCN themselves. If advocates were identified, youth were more likely to obtain needed services. CONCLUSIONS: Parents, health providers, and community agencies are potentially well-poised to assist transitioning YASHCN. Efforts to encourage development of strong advocacy skills will facilitate better transitions for YASHCN. PMID- 26228311 TI - Evolutionary patterns in Antarctic marine invertebrates: an update on molecular studies. PMID- 26228310 TI - Uncharted Territory: Systematic Review of Providers' Roles, Understanding, and Views Pertaining to Health Care Transition. AB - BACKGROUND: Health care transition (HCT) for adolescents and emerging adults (AEA) with special health care needs is an emerging field of interdisciplinary field of practice and research that is based upon an intergenerational approach involving care coordination between pediatric and adult systems of health care. Informed understanding of the state of the HCT science pertaining to this group of providers is needed in order to develop and implement service programs that will meet the comprehensive needs of AEA with special health care needs. METHODS: The authors conducted a systematic review of the literature on the transition from child to adult care for adolescents and emerging adults (AEA) with special health care needs from 2004 to 2013. Fifty-five articles were selected for this review. An adaptation of the PRISMA guidelines was applied because all studies in this review used descriptive designs. RESULTS: Findings revealed lack of evidence due to the limitations of the research designs and methodology of the studies included in this systematic review. Study findings were categorized the following four types: adult provider competency, provider perspectives, provider attitudes, and HCT service models. The discipline of medicine was predominant; interdisciplinary frameworks based upon integrated care were not reported. Few studies included samples of adult providers. CONCLUSIONS: Empirical-based data are lacking pertaining to the role of providers involved in this specialty area of practice. Evidence is hampered by the limitations of the lack of rigorous research designs and methodology. PMID- 26228312 TI - Evolutionary volatile Cysteines and protein disorder in the fast evolving tunicate Oikopleura dioica. AB - Cysteine (Cys) is regarded as the most conservative amino acid in nature, something that does not occur in the tunicate Oikopleura dioica, where this amino acid is one of the fastest evolving. In this work we analyze some of the causes of this intriguing absence of conservation. Considering the well-known stabilizing role of Cys, it was first investigated whether the lack of conservation was accompanied by an increase in intrinsic protein disorder. In contrast to expectations, it was found that O. dioica is the chordate that has the lowest levels of intrinsic disorder, while vertebrates (represented by Bos taurus) contain the most disordered proteins. Oikopleura proteins are shorter than their homologs in other Chordates (Ciona and B. taurus proteins are respectively 11% and 18% longer). This process of protein shortening was more intense in intrinsic disordered regions. As a result proteins became not only shorter but also more compact. It is also reported here that the conservation/divergence behavior of Cys depends on whether they are located in ordered or disordered regions. In the four species analyzed, disordered Cys are majorly (> 75%) not conserved at all. Ordered Cys instead, are much more free to diverge in Oikopleura than in the other chordates. We hypothesize that the preferential deletion of disordered regions resulted in a decreased protein disorder and a direct elimination (by deletion) of many ancestral Cys. Besides, the alterations (shortening or complete elimination) of some disordered regions (loops/random coils) probably promoted further Cys evolutionary volatility, because some ancestral Cys (and other amino acids which play a role in stability like Trp) located outside deleted regions became redundant due to the loss of their stabilizing partners. PMID- 26228313 TI - Characterization of retentive capacity of the subpericranial pocket in cochlear implants with and without a pedestal. AB - OBJECTIVES/HYPOTHESIS: To quantify the retentive capacity (RC) of the subpericranial pocket (SpP) in children undergoing cochlear implantation (CI) and measure improvements in RC with the addition of a pedestal to the device base. Retention of a CI in an SpP relies on the integrity of surrounding tissues to determine device position and resist movement from external forces. We hypothesize that device position can be controlled and resistance to movement can be improved with placement of a small pedestal on the base of the CI receiver stimulator. STUDY DESIGN: Analysis of prospectively assembled data. METHODS: Ninety-seven patients (145 devices) underwent CI (48 bilateral, 49 unilateral). Intraoperatively, a force gauge measured the displacement force on a template Nucleus 5 (Cochlear Corporation, Sydney, Australia) implant placed in an SpP prior to routine suture fixation of a standard device. In 47 patients (64 devices), displacement forces were also measured for a custom template Nucleus 5 implant with pedestal. RESULTS: Average RC of the SpP for the standard device was 5.59 N +/- 2.73 standard deviation (SD), which increased to 9.401 N +/- 4.6267 SD with a pedestaled device. Resistance to displacement decreased significantly across trials in both groups (P <.0001). Retentive capacity of the SpP increased significantly with the addition of a pedestaled device (P < .0001). The interaction between device and trial was also found to be significant (P = .05). CONCLUSIONS: The RC of the SpP in children and the ability to resist device migration in the absence of fixation may improve with the addition of a pedestal attached to the device. LEVEL OF EVIDENCE: 2b. Laryngoscope, 126:1175-1179, 2016. PMID- 26228314 TI - Kinking of a Superior Mesenteric Artery Stent due to Contraction of the Abdominal Wall. PMID- 26228315 TI - Our experience with a severe case of aplasia cutis congenita with a large skull defect. PMID- 26228316 TI - Enigmatic Translocator protein (TSPO) and cellular stress regulation. AB - Translocator proteins (TSPOs) are conserved, ubiquitous membrane proteins identified initially as benzodiazepine-binding proteins in mammalian cells. Recent genetic and biochemical studies have challenged the accepted model that TSPOs are essential and required for steroidogenesis in animal cells. Instead, evidence from different kingdoms of life suggests that TSPOs are encoded by nonessential genes that are temporally upregulated in cells encountering conditions of oxidative stress, including inflammation and tissue injury. Here we discuss how TSPOs may be involved in complex homeostasis signaling mechanisms. We suggest that the main physiological role of TSPOs may be to modulate oxidative stress, irrespective of the cell type or subcellular localization, in part through the subtle regulation of tetrapyrrole metabolism. PMID- 26228317 TI - [Iron deficiency anemia and anemia of chronic disorders]. AB - Hypochromic-microcytic anemias are characterized by a hemoglobin deficiency of the erythrocytes. The main reason for the insufficient hemoglobin synthesis is, with exception of thalassemia and a few other rare conditions, primarily a disorder of iron metabolism. Differential diagnostic considerations are focused on iron deficiency anemia, with approximately 80% the most common form of anemia worldwide. Iron deficiency anemia shows a particularly high prevalence in developing countries, but is also in industrialized Western countries the most common cause of anemia. Infants, toddlers, premenopausal or pregnant women, and elderly people are at particularly high risk of iron deficiency anemia. The most important differential diagnosis for iron deficiency anemia is the anemia of chronic disorders (ACD). This anemia is caused by a disturbance of iron utilization (functional iron deficiency), in which iron absorption and iron release, as a nonspecific defense mechanism, is blocked to restrict iron availability for the inflammatory process but also withhold iron from the erythropoiesis. ACD is not rare, but plays a significant role in hospitalized patients and in the elderly. The differentiation between ACD and iron deficiency anemia is highly important from a clinical point of view, due to different types of further management. The cause for iron deficiency should be clarified in each case, whereas the etiology for ACD is often obvious. The standard treatment of iron deficiency anemia is oral iron supplementation. Intravenous iron application is reserved for problem patients. The best treatment for ACD is the elimination of the underlying chronic disorder. In case of persistent ACD, red blood cell transfusions, erythropoietin, and intravenous iron are used therapeutically. PMID- 26228318 TI - Association of Single Nucleotide Polymorphisms in the CYP19A1 Gene with Female Pattern Hair Loss in a Chinese Population. AB - BACKGROUND: It has been suggested that the single nucleotide polymorphism (SNP) of the CYP19A1 gene encoding aromatase may affect the development of female pattern hair loss (FPHL). OBJECTIVE: Our aim was to investigate the association of CYP19A1 gene SNPs with FPHL in a Chinese population. METHODS: Two hundred Chinese Han patients with FPHL and 200 controls were enrolled into our study. SNaPshot technology was used to detect CYP19A1 gene candidate SNPs. RESULTS: The allele frequencies and distributions of rs6493497 and rs7176005 were significantly different between FPHL and control subjects (p < 0.001 and p < 0.001 vs. p < 0.001 and p = 0.003). CONCLUSION: The rs6493497 and rs7176005 SNPs of the CYP19A1 gene may be genetic markers that influence the risk of FPHL in this Chinese population. PMID- 26228319 TI - A new pathogenetic explanation of human chiari malformations. PMID- 26228320 TI - Prevalence and types of androgenetic alopecia in north Anatolian population: A community-based study. AB - OBJECTIVE: To determine the prevalence and pattern of androgenetic alopecia in Turkey and to compare the results with different regions. METHODS: The community based study was carried out from September 2012 to June 2013 across all the 12 districts of Tokat province of Turkey. Individuals 20-years-old or older were included, and more than two first-degree relatives were excluded. Dermatological examination of all the subjects was performed by dermatologists. The degree of androgenetic alopecia was classified according to the Hamilton-Norwood and Ludwig classifications. RESULTS: Of the 2322 volunteers, 1288(55.46%) were women and 1034(44.53%) were men. Overall mean age was 47.3+/-15.3 years (range: 20-87 years). Androgenetic alopecia was detected in 740(31.8%) subjects; 247(19.17%) women and 493(47.6%) men. CONCLUSIONS: The prevalence of androgenetic alopecia in Turkish society was higher than Asian and African communities; and similar to the rate in European societies hair-loss. PMID- 26228321 TI - The effects of implementing a nutritional support algorithm in critically ill medical patients. AB - OBJECTIVE: To determine the effect of the enteral nutrition algorithm on nutritional support in critically ill medical patients. METHODS: The quasi experimental study was conducted at a medical Intensive Care Unit of a university hospital in central Anatolia region in Turkey from June to December 2008. The patients were divided into two equal groups: the historical group was fed in routine clinical applications, while the study group was fed according to the enteral nutritional algorithm. Prior to collecting data, nurses were trained interactively about enteral nutrition and the nutritional support algorithm. The nutrition of the study group was directed by the nurses. Data were recorded during 3 days of care. SPSS 22 was used for statistical analysis. RESULTS: The 40 patients in the study were divided into two equal groups of 20(50%) each. The energy intake of study group was 62% of the prescribed energy requirement on the 1st, 68.5% on the 2nd and 63% on the 3rd day, whereas in the historical group 38%, 56.5% and 60% of the prescribed energy requirement were met. The consumed energy of the historical group on the 1st 2nd and 3rd day was significantly different (p=0.020). In the study group, serum total protein and albumin levels decreased significantly (p<0.05), but pre-albumin and fasting blood glucose levels were not changed on the 1st and 4th day. In the historical group, any of the serum parameters did not change. Enteral nutrition-induced complications, duration of stay in intensive care unit were not significantly different between the groups (p>0.05). CONCLUSIONS: The use of standard algorithms for enteral nutrition may be an effective way to meet the nutritional requirements of patients. PMID- 26228322 TI - Evaluation of postoperative antibiotics after non-perforated appendectomy. AB - OBJECTIVE: To evaluate the role of postoperative antibiotics in reducing surgical site infections after appendectomy for non-perforated appendicitis. METHODS: The randomised controlled trial was conducted at Khyber Teaching Hospital, Peshawar, Pakistan, from November 11, 2012, to May 30, 2014, and comprised patients of emergency appendectomy for non-perforated appendicitis who were divided into groups A and B. Group A received a single dose of cefuroxime sodium and metronidazole half-an-hour before induction, while Group B received one more dose of the same antibiotics postoperatively. Both groups were followed for 6 weeks. SPSS 20 was used for statistical analysis. RESULTS: Of the 390 patients in the study, 192(49.2%) were in Group A and 198(50.7%) in Group B. Number of surgical site infections was 15(7.8%) in Group A and 18(9.1%) in Group B (p=0.65). Mean hospital stay of 3.32+/-0.4 days and 3.59+/-0.46 days was observed for Group A and B, respectively, (p<0.001). CONCLUSIONS: A single pre-operative dose of cefuroxime and metronidazole had the same efficacy in preventing surgical site infections in cases of non-perforated appendicitis as when the same regimen was repeated post-operatively. PMID- 26228323 TI - Monoamine Oxidase A gene polymorphisms and self reported aggressive behaviour in a Pakistani ethnic group. AB - OBJECTIVE: To investigate the association of monoamine oxidase Agene polymorphisms with aggression. METHODS: The study was conducted in an ethnic community in Lahore, Pakistan, from August 2008 to December 2009 on the basis of data that was collected through a questionnaire between August 2004 and September 2005. It analysed 10 single nucleotide polymorphisms of monoamine oxidase A in unrelated males from the same ethnic background who were administered a Punjabi translation of the Buss and Perry aggression questionnaire. SPSS 13 was used for statistical analysis. RESULTS: Of the total 133 haplotypes studied, 52(39%) were Haplotype A, 58(43.6%) B, 8(6%) C, 3(2.3%) D, 9(6.8%) E and 3(2.3%) F. The six haplotypes were analysed for association with scores of the four subscales of the aggression questionnaire and multivariate analysis of variance showed no significant differences (p>0.05 each) in the error variances of the total scores and scores for three of the sub-scales across the haplotypes. The variance was significantly different only for the anger sub-scale (p<0.05). CONCLUSIONS: The association of an extended haplotype with low levels of self-reported aggression in this study should assist in characterisation of functional variants responsible for non-aggressive behaviour in male subjects. PMID- 26228324 TI - Frequency of using non-prescribed medication in Majmaah city, Saudi Arabia -- A cross sectional study. AB - OBJECTIVE: To determine the frequency of using non-prescribed medication in a Saudi Arabian city. METHODS: The cross-sectional study was conducted in Majmaah city, Saudi Arabia, from January to May 2014, and comprised adults of either gender. For data collection, a questionnaire was designed and its reliability was checked by Cronbach Alpha. SPSS 20 was used for statistical analysis. RESULTS: Of the 390 respondents 276(70.8%) were males, while 114(29.2%) were females. The overall mean age was 29.90+/-11.56 years (range: 18-83 years). Of the total, 363(93.1%) were using non-prescribed medication; and 148(37.9%) said they were using the drugs as they had experienced similar symptoms before and they knew the treatment. Public pharmacies were the main source for obtaining non-prescribed medication for 163(41.8%) subjects. Gender and use of non-prescribed medication was significantly associated (p<0.05). CONCLUSIONS: The frequency of using non prescribed medication in Majmaah city was high. Pain-killers, antibiotics and antipyretics were the most used non-prescribed medications. Male respondents used non-prescribed medication more than the females. PMID- 26228325 TI - Asymmetric dimethylarginine in experimental breast cancer; action of Vitamin C and E. AB - OBJECTIVE: To investigate the arginase-nitric oxide synthase paradox through asymmetric dimethylarginine, symmetric dimethylarginine and nitric oxide levels, and to see the effect of antioxidant vitamins on this mechanism of cancer action. METHODS: The animal-based study was conducted at Trakya University, Turkey, in 2008, and comprised mice that were divided into five equal groups. Group 1 had healthy controls, while in the other four groups breast cancer was induced. Group 2 received saline solution, group 3 received 200 mg/kg/day vitamin C (tumour +vit C), group 4 received 300 mg/kg/day vitamin E (tumour +vitE) and group 5 received both 200 mg/kg/day vitamin C and 300 mg/kg/day vitamin E (tumour +vit C+vit E) for 15 days intra-peritoneally.Arginine, asymmetric dimethylarginine, symmetric dimethylarginine and nitric oxide levels were determined in each group. RESULTS: The 50 mice in the study were divided into five groups of 10(20%) each. Plasma arginine levels were significantly decreased, asymmetric dimethylarginine and symmetric dimethylarginine levels were increased, while plasma nitric oxide level was significantly decreased in group 2. There was no statistically significant difference in treatment groups for all parameters (p>0.05 each). CONCLUSIONS: Understanding of the mechanism may help to develop new anti-cancer agents. PMID- 26228326 TI - Microhardness of heat cure acrylic resin after treatment with disinfectants. AB - OBJECTIVE: To evaluate the effect of disinfectants and distilled water on the micro-hardness of heat cure acrylic resins. METHODS: The case-control study was conducted at Dr. Ishrat-ul-Ebad Khan Institute of Oral Health Sciences, Dow University of Health Sciences, and Nadirshaw Edulji Dinshaw University of Engineering and Technology, Karachi, from April to October 2011. Specimens were fabricated from heat cure acrylic resin material and they were divided into four equal groups. Group 1 was evaluated at baseline and was taken as the control group. Group 2 was immersed in distilled water for 20 minutes, Group 3 in1% sodium hypochlorite for 20 minutes, and Group 4 in 2% alkaline gluteraldehyde for 10 minutes. All specimens were polished, stored in distilled water for 24 hours prior to experiment. All the specimens were immersed twice daily for a total of 60 days after which they were tested for Vickers micro-hardness test. Statistical analysis was conducted with one-way analysis of variance and Tukey post hoc test (a=0.05). RESULTS: There were 72 specimens divided into four groups of 18(25%) each. Statistically significant differences were found among all groups (p<0.0001). The storage medium had an effect on the micro-hardness of heat cure acrylic resins. Group 4 showed the most reduction in the hardness value which was followed by Group 3. CONCLUSIONS: The hardness of heat cure acrylic resin was affected by disinfectants. PMID- 26228327 TI - Status of oxidant, antioxidantand serum enzymes in thalassaemic children receiving multiple blood transfusions. AB - OBJECTIVE: To determine the levels of oxidant, antioxidant and serum enzymes in thalassaemic children receiving multiple blood transfusions. METHODS: The case control study was done from February to August 2012, and comprised thalassaemic children receiving multiple blood transfusions at Allied Hospital, Ali Zeb Foundation, and the Thalassaemia Centre in Hilal-e-Ahmar Hospital, Faisalabad, Pakistan. Healthy subjects were also screened for any related disease condition that could prejudice the results. Blood samples were analysed for the values of total oxidant status, total antioxidant capacity, serum malondialdehyde, catalase, paraoxonase, arylesterase, glutathione peroxidase and ceruloplasmin. RESULTS: There were 180 children in the study; 90(50%) cases and 90(50%) controls. Of the cases, 48(53.3%) were under-weight while the weight of 42(46.7%) was in the normal range. The values of total oxidant status and total antioxidant capacity were significantly (p<0.01) higher in thalassaemic children compared to normal values. Serum malondialdehyde and catalase levels were also considerably elevated (p<0.05), suggesting the increased activity of these enzymes. However, the concentrations of serum paraoxonase, arylesterase, glutathione peroxidase were significantly (p<0.01) lower in cases than the controls, displaying diminished activities during multiple blood transfusions in these patients. CONCLUSIONS: Multiple blood transfusions disconcert the levels of oxidants, antioxidants and serum enzymes of thalassaemic children. Oxidative damage is seen because of the increased iron overload in these patients. Hence, regular evaluation of oxidant and antioxidant status should be monitored in thalassaemic patients during initial few years of life. PMID- 26228328 TI - Comparison of semi-continuous and interrupted suture techniques for mitral valve replacement. AB - OBJECTIVE: To compare the efficacy of semi-continuous technique and interrupted suture technique for mitral valve replacement in early post-operative period. METHODS: The randomised prospective study was conducted at Chaudhry Pervaiz Elahi Institute of Cardiology, Multan, Pakistan, from December 2012 to December 2014 The patients were divided into two equal groups: Group I patients underwent semi continuous technique for mitral valve replacement, and Group II underwent interrupted technique. Data was analysed using SPSS 16. RESULTS: The 100 patients were divided into two equal groups of 50(50%) each. There was no significant difference in terms of age, gender and pre-operative echocardiographic characteristics (p>0.05 each). Total bypass and cross-clamp times were significantly higher in Group II (p<0.0001 and p<0.0001). The incidence of peri prosthetic leakage was low in Group II compared to Group I but it was not significantly different (p=0.64). CONCLUSIONS: Semi-continuous technique was found to be a safe and reliable method of mitral valve replacement. PMID- 26228329 TI - Producing financially literate medical graduates -- a national need for a brighter Pakistan. AB - OBJECTIVE: To compare the awareness of financial wellness between male and female medical students. METHODS: The cross-sectional questionnaire-based survey was conducted from February to December 2011 and comprised first year medical students belonging to different medical colleges of Karachi. Students from both genders, aged 19-24 years, belonging to all ethnic groups willing to participate were included. A close-ended questionnaire evaluated aspects of financial wellness, using four-point Likert's scale: never, sometimes, mostly, and always from 0 to 4. Besides, factor analysis was performed to investigate common financial wellness among the participants. RESULTS: Of the total 800 students approached, complete responses were received from 736(92%); 210(28.5%) boys and 526(71.5%) girls. The mean financial wellness score of boys was 8.60+/-3.04 and that of the girls was 7.61+/-3.12 (p<0.0005). Greater number of boys 93(44%) set both short- and long-term financial goals compared to 180(36%) girls (p=0.03). Besides, 218(42%) girls confined themselves to the budget compared to 81(39%) boys (p>0.05). More boys 71(34%) were spendthrift (p<0.0001) and 57(27%) preferred to keep their savings in bank accounts compared to the girls (p<0.0001). Overall, boys were better in financial security wellness compared to the girls (p=0.001). CONCLUSIONS: Male medical students exhibited awareness of financial wellness better than girls. PMID- 26228330 TI - Evaluation of vascular endothelial growth factors A, C and D as indicators of lymphangiogenesis and angiogenesis in invasive and non-invasive urothelial carcinoma bladder. AB - OBJECTIVE: To study the immunohistochemical expression of vascular endothelial growth factors in urothelial tumours of bladder and its possible association with tumour characteristics and microvessel density. METHODS: The cross-sectional descriptive study was conducted at the Histopathology Department of the Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from July 2011 to December 2012, and comprised cases of non-invasive and invasive urothelial tumours of the bladder. The microvessel density and expression of vascular endothelial growth factors A, C, D were evaluated by immunohistochemistry. Specimens of transurethral bladder biopsies and surgical resection were examined. The cases were classified into non-invasive (stage pTa ) and invasive groups as well as low grade and high-grade groups. The presence of in-situ component was evaluated in each category. To assess the microvessel density, highly vascularised foci ('hot spots') after immuno-staining with CD34 were quantified for number of vessels per square millimetre and for vascular surface area density. No distinction was made between lymphatic and blood vessels. Vascular endothelial growth factor staining was scored semi-quantitatively. RESULTS: The study examined 100 histopathology specimens, including 90(90%) transurethral bladder biopsies and 10(10%) surgical resection specimens of bladder. There were 45(45%) non-invasive (stage pTa) cases and 55(55%) invasive (stage pT1-4) cases. Besides, there were 43(43%) low-grade (grades 1 and 2) cases, and 57(57%) high-grade (grade 3) cases. Vascular endothelial growth factors A, C and D staining scores showed positive association with stage (p=0.02;p<0.01; p<0.01)and grade (p=0.007;p=0.004; p=0.002) of the tumour. Tumours with in-situ component showed association with number of vessels per square millimetre (p<0.01) and vascular surface area density (p=0.02). CONCLUSIONS: Parameters like vascular endothelial growth factor and microvessel density need to be studied further for selection of cases with potential for targeted therapy. PMID- 26228331 TI - What are the coping strategies gynaecologists employ to meet with stressful situations? AB - OBJECTIVE: To explore the correlation of stress and coping strategies among gynaecologists. METHODS: The cross-sectional study was conducted at Jinnah, Ganga Ram and Mayo Hospitals, Lahore, from 10th January 2014 to 30th June 2014 and comprised gynaecologists at public-sector hospital with work experience ranging from 5 to 30 years. Demographic Information Form, Perceived Stress Scale and Cope Scale were employed to collect data. Descriptive statistics were used to express stress and coping strategies. RESULTS: The mean age of the 200 respondents was 35.6+/-7.98 years (range: 25-59 years). Their mean experience was 15.5+/-2.65 years (range: 5 to 27 years). Overall, 52(26%) were experiencing mild stress, 82(41%) moderate stress and 66(33%) severe stress. Significant positive correlation was found of stress with problem-focused coping strategies like active coping, planning, instrumental social support, acceptance and positive reframing (p<0.05 each), and demographic factors like age, marital status, monthly income, working shifts, number of dependents, working hours, nature of job and family system (p<0.05 each)gynaecologist. Active coping, planning, instrumental social support, acceptance and positive reframing (p<0.05 each) were significant predicting strategies of stress. Monthly income, working shifts, working hours and nature of job (p<0.05 each) were significant predictors of stress among gynaecologists. CONCLUSIONS: The findings will contribute to knowledge about coping strategies employed by gynaecologists and variables that predict stress among gynaecologists. PMID- 26228332 TI - Malignant head and neck tumours in Radiology Department JPMC Karachi -- a tertiary care experience. AB - OBJECTIVE: To study age, gender and sites of malignant head and neck tumours on contrast-enhanced computed tomography and to elucidate its role. METHODS: The retrospective study was conducted at the Jinnah Postgraduate Medical Centre, Karachi, and comprised data of patients with histologically proven malignant head and neck tumours reporting from February 2013 to February 2014. Contrast enhanced computed tomography with puffed cheek technique was done in cases of oral cancer, while routine contrast computed tomography was done in cases of other head and neck tumours. SPSS 19 was used for statistical analysis. RESULTS: A total of 100 biopsy-proven cases of malignant tumours comprised the study sample. The male: female ratio was 1.5:1 with an overall mean age of 46.4+/-16-76 years. . The most common histopathologically proven tumour was squamous cell carcinoma affecting oral mucosa 43(43%), followed by larynx 27(27%) and pharynx 10(10%) . CONCLUSIONS: Oral squamous cell carcinoma was the commonest tumour. Compute tomography scan with puffed cheek technique played a beneficial role in locating the site of primary tumour. PMID- 26228333 TI - Laparoscopic versus open repair of para-umbilical hernia. Is it a good alternative? AB - OBJECTIVE: To compare the experience of laparoscopic repair of para-umbilical hernia with conventional open repair in terms of operative time, pre- and post operative complications, total hospital stay, post-operative pain, morbidity, mortality and cosmesis. METHODS: The prospective, randomized study was conducted at Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan, and two private hospitals from June 2011 to June 2013, and comprised patients who were admitted with para-umbilical hernias of different sizes during the study period. The patients were divided into two groups. Group A underwent laparoscopic surgery, while Group B had conventional mesh repair. Variables studied included duration of surgery, operative and post-operative complications, morbidity and mortality. SPSS 20 was used for statistical analysis. RESULTS: Of the 337 patients in the study, 200(59.34%) were at the Liaquat University Hospital, while remaining 137(40.65%) patients were operated in two private hospitals. The overall mean age of the study sample was 42.18+/-9.789 years (range: 23-73). There were 68(20.18%) males and 269(79.82%) females. There were 166(49.26%) patients in Group A and 171(50.74%) Group B. The operative time was comparatively longer in Group A (p<0.001) especially in the first 30 operations. The laparoscopic approach was associated with a comparatively low incidence of operative and post-operative complications, reduced duration of hospital stay and cosmetically better results (p<0.05). There was no mortality in this series. CONCLUSIONS: Laparoscopic para-umbilical hernia repair, though a new technique, gave promising results compared to open conventional technique. However, there is a long way to go before coming to a consensus. PMID- 26228334 TI - Low prevalence of asthma among textile workers in Karachi, Pakistan. AB - OBJECTIVE: To determine the prevalence of asthma in textile workers through post bronchodilator spirometry and to compare the differences in prevalence based on different criteria used to assess asthma. METHODS: The cross-sectional study was conducted between July and December 2013 in Karachi, Pakistan, and comprised workers from15 textile mills in the city and its outskirts. Asthma and associated respiratory symptoms were assessed using the American Thoracic Society Division of Lung Diseases Questionnaire, and post-bronchodilator spirometry. SPSS 19 was used for statistical analysis. RESULTS: Among the 372 workers in the study, asthma was found in 19(5%) as diagnosed on post-bronchodilator spirometry. The prevalence of self-reported and physician-diagnosed asthma was 15(4%) and 8(2%) respectively. Work in the spinning section, age >=38 years, duration of work >=10 years in textile industry, history of smoking, and >=10 pack years of smoking were found to be important predictors of asthma. CONCLUSIONS: Textile industry workers had low prevalence of asthma, assessed through post-bronchodilator spirometry, compared to estimates for the general population. This could possibly be due to some protective effect of endotoxin exposure although further evaluation with better exposure assessment is warranted. PMID- 26228335 TI - Diagnostic validity of ultrasonography in thyroid nodules. AB - OBJECTIVE: To determine the diagnostic validity of thyroid ultrasound in differentiating between benign and malignant thyroid nodules. METHODS: The cross sectional study was conducted at Aga Khan University Hospital, Karachi, from August 2011 to January 2013, and comprised all patients of either gender with thyroid nodules referred for ultrasound thyroid and fine needle aspiration cytology. Ultrasonography was performed by radiologists and ultrasound parameters were assessed and compared with cytology results in all nodules. Diagnostic validity of each ultrasound feature was calculated. RESULTS: Of the 101 patients, 81(80%) were female. The overall mean age was 43+/-13 years (range: 15-73 years). On histocytopathology, 96(95%) nodules were benign and 5(4.9%) were malignant. The sensitivity and specificity of ultrasound features in predicting malignancy were calcification 80% and 68%; hypoechogenecity 80% and 52%; ill-defined lobulated margin 40% and 96%; solid 80% and 40%; taller than wider 50% and 63%. Each ultrasound feature had negative predictive value ranging from 95% to 98% in malignant nodules. CONCLUSIONS: Identification of calcification, hypoechogenecity and solid with ill-defined margins in a thyroid nodule on ultrasound was helpful in suspecting thyroid malignancy and warranted urgent diagnostic fine needle aspiration cytology. PMID- 26228336 TI - Comparison of fluorescence microscopy and Ziehl-Neelsen technique in diagnosis of tuberculosis in paediatric patients. AB - Early diagnosis of tuberculosis is very important for therapeutic reasons and to control the spread of infection. The purpose of this study was to compare the efficacy of fluorescence (FL) microscopy in comparison to Ziehl-Neelsen (ZN) staining. A total of 103 samples were collected from paediatric tuberculosis (TB) suspects and processed using Petroff's method. The smears were subjected to ZN and FL staining for the detection of acid-fast bacilli (AFB). Positive smears were graded according to scale of International Union Against Tuberculosis and Lung Disease and World Health Organisation (IUATLD/WHO). Out of 103 pulmonary and extra-pulmonary samples, 7(6.8%) were positive for AFB on the ZN method, while the positivity increased to 9(8.7%) on the FL method. Two positive samples were missed on ZN staining which were found to be positive with FL microscopy; thus overall positivity increased by 2/9 (22.22%) by FL microscopy over the conventional ZN method. The difference in case detection was found to be statistically significant (p<0.00). FL technique has a better diagnostic value and is less time-consuming compared to ZN in diagnosing tuberculosis in paediatric patients. PMID- 26228337 TI - Reciprocal benefit to senior and junior peers: An outcome of a pilot research workshop at medical university. AB - A study was planned to explore and evaluate the role of senior peers in the learning process of their juniors during a Research Methodology workshop, and to assess educational advantages for seniors in leading roles. Twenty medical students participated with 15 juniors (1st to 3rd year) and 5 seniors (final/fourth year) divided into 5 groups with one senior student each at Foundation University Medical College, Islamabad, Pakistan. The seniors supervised and engaged the groups to develop research questions, formulate objectives, review literature, outline study designs, develop study tools/questionnaire and finally shape their projects in synopsis. Overall advantages to both juniors and seniors through this peer-assisted learning model were assessed by feedback proformas with open and closed-ended questions. Senior peers' facilitation was effective in the learning process of junior peers. Senior peers also gained academic benefit by exercising their leadership qualities through teaching and maintaining group dynamics. PMID- 26228338 TI - Time to declare ophthalmology an independent discipline by initiating Bachelor of Ophthalmic Surgery programme. AB - Medical education, associated with lengthy, exhaustive pathways requisite of time, energy and efforts, restrain an individual from pursuing a career in medicine. Most students enrol in medical colleges under the influence of their family members, and only some strive to seek medicine as their own ambition. Medical students confront a number of problems in memorising huge amount of data and the various strategies are integrated in MBBS curriculum from time to time. After MBBS programme, most graduates tend to abandon studies, some migrate abroad, a few continue as general physicians and even fewer strive to get registered for postgraduate specialisation. This results in suboptimal supply of medical workforce. Inconsideration of the current ophthalmologist work ratio and growing demand for eye care services, an initiative is put forward to introduce Bachelors of Ophthalmic Surgery programme similar to Bachelor of Dental Surgery. Such initiative may facilitate effective learning, enable command in a particular area and encourage more individuals to pursue a career in ophthalmology. Using a questionnaire to undergraduate medical students, medical professors and ophthalmologists were surveyed to evaluate the efficacy of the proposed initiative. The results threw a mixed response. PMID- 26228339 TI - Unusual presentation with polymenorrhagia and markedly high 17-hydroxy progesterone levels in a lady with Non-Classic Congenital Adrenal Hyperplasia. AB - Congenital adrenal hyperplasia is generally associated with oligo-amenorrhea, and its presentation with polymenorrhagia is rare. Here we present a case of an Asian female who presented with polymenorrhagia since menarche, increased body hair growth and enlargement of clitoris for 7-8 years. Examination revealed a normal Body Mass Index, moderate hirsutism, Tanner 5 breasts and significant clitoromegaly. Serum testosterone and 17-hydroxyprogesterone levels were elevated. Ultrasonography revealed normal adrenal glands and polycystic ovaries. adrenocorticotropic hormone stimulation test uncovered borderline cortisol deficiency. Oral dexamethasone was commenced and six months later, she showed improvement though there was no change in hirsutism or clitoromegaly. The case is unique because it presented with polymenorrhagia. Also, such phenomenally high 17 hydroxyprogesterone levels are not expected in non-classic congenital adrenal hyperplasia. PMID- 26228340 TI - Ampullary carcinoid tumour presenting with extrahepatic biliary obstruction. AB - Carcinoid tumours are slow growing tumours, derived from enterochromaffin cells located in the crypts of Lieberkuhn, which is part of neuroendocrine system. A 36 year-old female patient presented in surgical clinic with complaints of progressively increasing yellowish discolouration of her eyes and pruritis for 6 months. She was deeply jaundiced with a soft and non-tender abdomen. Diagnostic work-up revealed obstructive jaundice secondary to ampullary growth, while computed tomography revealed a small intraluminal lower common bile duct mass. Endoscopic ultrasound showed thickened duodenum at ampulla of Vater. Pancreaticoduodenectomy (Whipple's procedure) with pancreaticojejunostomy, hepaticojejunostomy and gastrojejunostomy was done. Pathological examination of the resected specimen revealed carcinoid tumour. Postoperative course of patient was unremarkable and she is doing well after surgery. PMID- 26228341 TI - Unique side effects of interferon. AB - Interferon-alpha, a potent mediator of host immune response, has immunomodulatory properties in addition to its antiviral effects. A wide spectrum of autoimmune diseases can occur in patients treated with interferon-alpha for chronic hepatitis B and D, of which clinical systemic lupus erythematosus (SLE) accounts for less than 1% and hypothyroidism for 2-4 %. We report herein a case of a 16 year-old male who developed antinuclear antibody (ANA)-negative SLE and hypothyroidism after treatment with interferon-alpha for chronic hepatitis. High index of suspicion is therefore necessary in all patients treated with interferon for early diagnosis and treatment. PMID- 26228342 TI - A novel mutation, IVS2-2AgG, associated with acute intermittent porphyria in a Chinese family. AB - Porphyria is a group of disorders caused by the accumulation of porphyrin and porphyrin precursors due to the abnormalities in certain enzymes that normally participate in the production of haem. We report a case of a woman with severe menstruation-related abdominal pain, hyponatraemia, and psychiatric symptoms. Excessive porphobilinogen was found in her urine. A new mutation in intron 2 (IVS2-2Ag->G), which had never previously been reported in patients with porphyria or in healthy Chinese population, was identified in the heterozygous state in the patient and her mother. PMID- 26228344 TI - Good clinical sense in diabetology. AB - This article defines and explains the concept of good clinical sense. It defines good clinical sense as "the presence of sensory faculties, their usage and interpretation, by which one is able to practice good clinical medicine". Good clinical sense differs from good clinical practice (GCP) and good clinical acumen. It encompasses all steps of the clinical, diagnostic and therapeutic process, and encourages diligent practice of clinical medicine. Good clinical sense is integral to the practice of diabetology. PMID- 26228343 TI - Huge carcinoid tumour causing complete obstruction of the left main bronchus and destruction of left lung. AB - Carcinoid tumours arise from the neuroendocrine cells of the bronchial epithelium known as Kulchitsky cells and comprise 4% of all lung malignancies. We report a case of a 16- year-old male who presented with a 1-month history of fever, cough, left-side chest pain and shortness of breath. Chest X -ray showed loss of lung volume on the left side with cystic spaces and air fluid levels. Computed tomography scan chest demonstrated a homogenous mass extending into the left main bronchus causing its complete obstruction along with extensive bronchiectatic changes in the left lung. Bronchoscopy and bronchial biopsy confirmed the diagnosis of typical carcinoid tumour. A pneumonectomy was performed. This case is unusual due to the large size of the tumour, its location and associated destruction of the entire left lung. PMID- 26228345 TI - Cardiovascular risk management in diabetes in primary care. AB - This communication describes simple targets and interventions, aimed at cardiovascular risk reduction in diabetes mellitus, which are feasible at primary care level. It summarizes therapeutic goals and strategies for management of high blood pressure, dyslipidaemia, and anti-platelet therapy. PMID- 26228346 TI - Crossing the ethical boundaries. PMID- 26228347 TI - Role of pelvic X-ray in blunt trauma patients -- A university hospital experience in Oman. AB - OBJECTIVE: To confirm the safety of the advanced trauma life support algorithm by comparing the incidence of pelvic fractures diagnosed by pelvic X-ray and computed tomography and to evaluate the need of pelvic X-ray in the management of haemodynamically stable polytrauma patients in whom computed tomography is deemed necessary. METHODS: The prospective study was conducted at Sultan Qaboos University, Muscat, Oman, from January to December 2012, and comprised stable blunt trauma patients treated according to advanced trauma life support guidelines. All the patients underwent pelvic X-ray on presentation and later had computed tomography scan of abdomen and pelvis. Radiology reports were filed by the on-call radiologist prospectively. The reports were reviewed retrospectively. Data was analysed using SPSS 19. RESULTS: Of the 67 patients, 59(88%) were male and 8(12%) were females. The overall mean age was 32.09+/-12.28 years (range: 14 77 years) Pelvic X-rays showed no fracture in 62(92.5%) cases compared to 55(82.1%) scans. All cases that were positive on pelvic X-ray were detected by scan. Pelvic X-ray revealed only 4(6%) patients as having only pelvic fracture and 1(1.5%) as femoral head fracture. Computed tomography scan was able to detect 6(9%) pelvic fractures, 2(3%) femoral fractures and 4(6%) lumbar fractures. CONCLUSIONS: Computed tomography scan was found to be superior in detecting pelvic, femoral and lumbar fractures. PMID- 26228348 TI - Propranolol decreases retention of fear memory by modulating the stability of surface glutamate receptor GluA1 subunits in the lateral amygdala. AB - BACKGROUND AND PURPOSE: Posttraumatic stress disorder (PTSD) is a mental disorder with enhanced retention of fear memory and has profound impact on quality of life for millions of people worldwide. The beta-adrenoceptor antagonist propranolol has been used in preclinical and clinical studies for the treatment of PTSD, but the mechanisms underlying its potential efficacy on fear memory retention remain to be elucidated. EXPERIMENTAL APPROACH: We investigated the action of propranolol on the retention of conditioned fear memory, the surface expression of glutamate receptor GluA1 subunits of AMPA receptors and synaptic adaptation in the lateral amygdala (LA) of rats. KEY RESULTS: Propranolol attenuated reactivation-induced strengthening of fear retention while reducing enhanced surface expression of GluA1 subunits and restoring the impaired long-term depression in LA. These effects of propranolol were mediated by antagonizing reactivation-induced enhancement of adrenergic signalling, which activates PKA and calcium/calmodulin-dependent protein kinase II and then regulates the trafficking of AMPA receptors via phosphorylation of GluA1 subunits at the C terminus. Both i.p. injection and intra-amygdala infusion of propranolol attenuated reactivation-induced enhancement of fear retention. CONCLUSIONS AND IMPLICATIONS: Reactivation strengthens fear retention by increasing the level of noradrenaline and promotes the surface expression of GluA1 subunits and the excitatory synaptic transmission in LA. These findings uncover one mechanism underlying the efficiency of propranolol on retention of fear memories and suggest that beta-adrenoceptor antagonists, which act centrally, may be more suitable for the treatment of PTSD. PMID- 26228350 TI - Tooth Surface Level Caries Progression in the Primary Dentition among Preschool Children. AB - The objective of this paper is to describe primary tooth surface level caries progression, over 2 years, based on the severity of the caries lesions. Data were collected from 790 low-income African-American preschool children in Detroit, Mich., USA. The caregivers of the children (aged 0-5 years) completed interviews and the dyad of child-caregiver completed dental examinations in 2002-2004 (baseline) and in 2004-2005 (follow-up). Caries were measured using the International Caries Detection and Assessment System (ICDAS). The caries status of tooth surfaces was classified into initial (ICDAS 1-2), moderate (ICDAS 3-4) and extensive (ICDAS 5-6) stages. Counts of tooth surfaces with progression, by baseline caries severity level, were used to compute rate ratios (RRs) relative to sound stages. RRs were also computed for type of tooth surfaces and frequency of intake of soda consumption at baseline. After adjusting for confounders, caries progression was more likely to occur in tooth surfaces with any baseline caries relative to sound surfaces. For surfaces with initial caries, the rate of progression to moderate caries was 9.6 times higher than that of sound surfaces. Surfaces with initial and moderate caries progressed to extensive caries 6.1 and 20.6 times, respectively, relative to sound surfaces. Baseline soda consumption was not associated with the RR of caries progression. In conclusion, the staging of caries identifies different progression risks and significant emphasis should be placed on secondary prevention of initial lesions as well as on primary prevention. PMID- 26228349 TI - Hair elements and healthy aging: a cross-sectional study in Hainan Island, China. AB - Healthy aging is considered as the core issue of aging population. Centenarians are a symbol of healthy aging. Concentration of elements in hair is an indicator of micronutrient status, which can affect the human health. In the present study, we investigated element concentrations in the scalp hair of 255 healthy centenarians from Hainan Island, China. The pattern of intergenerational transmission of elements and the effects of confounders such as sex, age, education level, smoking habits, alcohol intake, and frequency of hospitalization on hair element concentrations were assessed. For most elements, the load in hair increased significantly through intergenerational transmission (i.e., centenarians < children < grandchildren). Our results also demonstrated that female centenarians had significantly higher concentrations of Ca, Mg, Mn, Se, and Sr but lower levels of Cr and P. The Mn level was statistically significantly lower in the primary studies group. Alcohol intake was positively associated with Cd and Na levels, whereas smoking habits showed no significant effect on all the elements. Furthermore, the frequency of hospitalization was significantly positively associated with Cd, Cu, and Pb concentration. Moreover, our analysis suggested that adequate concentrations of Fe and Se might increase the life span of centenarians, whereas excessive concentrations of P and Pb were harmful to health and reduced life span. These results imply that element concentrations could be manipulated as a therapeutic modality in geriatric disease. They might also provide reference values for diseased subjects, allowing improved diagnoses and more effective therapies, which might support effective policies on health and aging. PMID- 26228351 TI - Efficient two-photon fluorescent probe with red emission for imaging of thiophenols in living cells and tissues. AB - Thiophenols, a class of highly toxic and pollutant compounds, are widely used in industrial production. Some aliphatic thiols play important roles in living organisms. Therefore, the development of efficient methods to discriminate thiophenols from aliphatic thiols is of great importance. Although several one photon fluorescent probes have been reported for thiophenols, two-photon fluorescent probes are more favorable for biological imaging due to its low background fluorescence, deep penetration depth, and so on. In this work, a two photon fluorescent probe for thiophenols, termed NpRb1, has been developed for the first time by employing 2,4-dinitrobenzene-sulfonate (DNBS) as a recognition unit (also a fluorescence quencher) and a naphthalene-BODIPY-based through-bond energy transfer (TBET) cassette as a fluorescent reporter. The TBET system consists of a D-pi-A structured two-photon naphthalene fluorophore and a red emitting BODIPY. It displayed highly energy transfer efficiency (93.5%), large pseudo-Stokes shifts upon one-photon excitation, and red fluorescence emission (lambdaem = 586 nm), which is highly desirable for bioimaging applications. The probe exhibited a 163-fold thiophenol-triggered two-photon excited fluorescence enhancement at 586 nm. It showed a high selectivity and excellent sensitivity to thiophenols, with a detection limit of 4.9 nM. Moreover, it was successfully applied for practical detection of thiophenol in water samples with a good recovery, two-photon imaging of thiophenol in living cells, and tissues with tissue-imaging depths of 90-220 MUm, demonstrating its practical application in environmental samples and biological systems. PMID- 26228352 TI - Trade-off between allocation to reproductive ramets and rhizome buds in Carex brevicuspis populations along a small-scale elevational gradient. AB - The trade-off between allocation to sexual and clonal reproduction in clonal plants is influenced by a variety of environmental factors; however, it has rarely been examined under field conditions. In this study, we investigated the trade-off between two modes of reproduction in Carex brevicuspis C. B. Clarke across a small-scale elevational gradient (21-27 m a.s.l.) at the Dongting Lake wetlands, China. The proportion of biomass allocated to and the density of reproductive ramets were higher at low than at intermediate and high elevations. In contrast, the proportion of biomass allocated to and the density of rhizome buds were lower at low than at intermediate and high elevations. Redundancy analysis showed that sexual reproduction was positively correlated with soil moisture content, soil organic matter, total phosphorus, and pH, and negatively correlated with elevation and ramet density. Our findings suggested that allocation to sexual reproduction is favored in disturbed habitats with fertile soils, whereas allocation to vegetative propagation is favored in stable and competitive habitats. Trade-off between allocation to sexual reproduction and vegetative propagation along an elevational gradient might be a reproductive strategy of C. brevicuspis to adapt to the water level fluctuations in wetland habitats. PMID- 26228353 TI - Identification of genes coding for putative wax ester synthase/diacylglycerol acyltransferase enzymes in terrestrial and marine environments. AB - Synthesis of neutral lipids such as triacylglycerols (TAG) and wax esters (WE) is catalyzed in bacteria by wax ester synthase/diacylglycerol acyltransferase enzymes (WS/DGAT). We investigated the diversity of genes encoding this enzyme in contrasting natural environments from Patagonia (Argentina). The content of petroleum hydrocarbons in samples collected from oil-producing areas was measured. PCR-based analysis covered WS/DGAT occurrence in marine sediments and soil. No product was obtained in seawater samples. All clones retrieved from marine sediments affiliated with gammaproteobacterial sequences and within them, most phylotypes formed a unique cluster related to putative WS/DGAT belonging to marine OM60 clade. In contrast, soils samples contained phylotypes only related to actinomycetes. Among them, phylotypes affiliated with representatives largely or recently reported as oleaginous bacteria, as well as with others considered as possible lipid-accumulating bacteria based on the analysis of their annotated genomes. Our study shows for the first time that the environment could contain a higher variety of ws/dgat than that reported from bacterial isolates. The results of this study highlight the relevance of the environment in a natural process such as the synthesis and accumulation of neutral lipids. Particularly, both marine sediments and soil may serve as a useful source for novel WS/DGAT with biotechnological interest. PMID- 26228354 TI - Hyperglycaemic hyperosmolar syndrome in children: Patient characteristics, diagnostic delays and associated complications. AB - AIMS: The aim of this study was to describe the demographical and clinical characteristics, diagnostic difficulties, and morbidity and mortality in children with hyperglycaemic hyperosmolar syndrome (HHS). METHODS: Retrospective cross section descriptive study of children (<18 years of age) at an urban, tertiary, academic Children's Hospital diagnosed with HHS from January 2002 to December 2011. RESULTS: Six patients met inclusion criteria for the diagnosis of HHS. Age ranged from 6 to 16 years with 4 (67%) patients younger than 13 years. Four (67%) patients were women and 5 (83%) were African-American. Body mass index (BMI)-for age percentile was >97% in four (67%) patients. Three (60%) of five patients seen as outpatients were misdiagnosed, two cases were seen twice before an accurate diagnosis of HHS was made. There was one (17%) death. Complications included three patients with acute renal failure, one patient with seizures, and one patient with rhabdomyolysis and compartment syndrome leading to below the knee amputation. Malignant hyperthermia and ventricular arrhythmias occurred in the patient who expired. Three of the five patients who had autoantibody tests had positive results and were diagnosed with type 1 diabetes mellitus. CONCLUSIONS: Characteristics of children with HSS are variable for age, gender and BMI-for-age percentile and not predominately limited to obese male adolescent African American. Delay in diagnosis is common and morbidity and mortality in paediatric HHS are significant. The subsequent diagnosis of patients presenting with HHS includes type 1 and 2 diabetes mellitus. PMID- 26228355 TI - Screening and surveillance for occupational cholangiocarcinoma in workers exposed to organic solvents. AB - PURPOSE: This study aimed to establish an efficient strategy for screening and surveillance for occupational cholangiocarcinoma. METHODS: We evaluated the consecutive changes in laboratory findings during regular health examinations and in abdominal ultrasonography findings before the diagnosis of occupational cholangiocarcinoma in nine patients. The results of laboratory tests and abdominal ultrasonography at the time of diagnosis were also examined. RESULTS: In all patients, the serum gamma-glutamyl transpeptidase (gamma-GTP) activity increased several years before the diagnosis of cholangiocarcinoma. The serum alanine aminotransferase (ALT) activity also increased several years before the diagnosis, following an increase in the serum aspartate aminotransferase (AST) activity in most patients. Abdominal ultrasonography before the diagnosis revealed regional dilatation of the bile ducts, which continued to enlarge. At the time of diagnosis, the gamma-GTP, AST, and ALT activities were increased in nine, seven, and seven patients, respectively. The regional dilatation of bile ducts without tumor-induced stenosis, dilated bile ducts due to tumor-induced stenosis, space-occupying lesions, and/or lymph node swelling were observed. The serum concentrations of carbohydrate antigen 19-9 (CA 19-9) and/or carcinoembryonic antigen (CEA) were increased in all patients. CONCLUSIONS: Regular health examinations with a combination of ultrasonography and laboratory tests including the gamma-GTP, AST, ALT, CA 19-9, and CEA levels are useful for screening and surveillance for occupational cholangiocarcinoma. PMID- 26228357 TI - Participants with Treated Hyperlipidemia may be More Health Conscious. PMID- 26228358 TI - Combining different therapeutic interventions in eosinophilic esophagitis may lead to unreplicable and misleading results. PMID- 26228356 TI - A role for exercise after bariatric surgery? AB - Obesity predisposes an individual to develop numerous comorbidities, including type 2 diabetes, and represents a major healthcare issue in many countries worldwide. Bariatric surgery can be an effective treatment option, resulting in profound weight loss and improvements in metabolic health; however, not all patients achieve similar weight loss or metabolic improvements. Exercise is an excellent way to improve health, with well-characterized physiological and psychological benefits. In the present paper we review the evidence to determine whether there may be a role for exercise as a complementary adjunct therapy to bariatric surgery. Objectively measured physical activity data indicate that most patients who undergo bariatric surgery do not exercise enough to reap the health benefits of exercise. While there is a dearth of data on the effects of exercise on weight loss and weight loss maintenance after surgery, evidence from studies of caloric restriction and exercise suggest that similar adjunctive benefits may be extended to patients who perform exercise after bariatric surgery. Recent evidence from exercise interventions after bariatric surgery suggests that exercise may provide further improvements in metabolic health compared with surgery-induced weight loss alone. Additional randomized controlled exercise trials are now needed as the next step to more clearly define the potential for exercise to provide additional health benefits after bariatric surgery. This valuable evidence will inform clinical practice regarding much-needed guidelines for exercise after bariatric surgery. PMID- 26228359 TI - ERCP for common bile duct stone extraction: Sphincterotomy, balloon dilation, or both? PMID- 26228360 TI - Selecting the optimum first-line treatment for H. pylori eradication. PMID- 26228361 TI - A Saudi Gastroenterology association position statement on the use of tumor necrosis factor-alfa antagonists for the treatment of inflammatory bowel disease. AB - The objective of this position statement from the Saudi Gastroenterology Association is to guide gastroenterologists on the use of tumor necrosis factor alfa (TNF-alpha) antagonists for the treatment of the idiopathic inflammatory bowel diseases, Crohn's disease, and ulcerative colitis. In this article, we summarize the relevant literature regarding the safety and efficacy of TNF-alpha antagonists, highlight relevant safety concerns specific to the environment in Saudi Arabia, and provide specific recommendations for the use of these agents. PMID- 26228362 TI - Framework for interpretation of trypsin-antitrypsin imbalance and genetic heterogeneity in pancreatitis. AB - Early intracellular premature trypsinogen activation was interpreted as the key initiator of pancreatitis. When the balance in the homeostasis of trypsin and antitrypsin system is disequilibrated, elevated aggressive enzymes directly attack the pancreatic tissue, which leads to pancreatic destruction and inflammation. However, trypsin alone is not enough to cause complications in pancreatitis, which may play a crucial role in modulating signaling events in the initial phase of the disease. NFkappaB activation is the major inflammatory pathway involved in the occurrence and development of pancreatitis and it can be induced by intrapancreatic activation of trypsinogen. Synthesis of trypsinogen occurs in endoplasmic reticulum (ER), and ER stress is an important early acinar cell event. Components of ER stress response are known to be able to trigger cell death as well as NFkappaB signaling cascade. The strongest evidence supporting the trypsin-centered theory is that gene mutations, which lead to the generation of more trypsin, or reduce the activity of trypsin inhibitors or trypsin degradation, are associated with pancreatitis. Thus, trypsin-antitrypsin imbalance may be the first step leading to pancreatic autodigestion and inducing other pathways. Continued experimental studies are necessary to determine the specific relationships between trypsin-antitrypsin imbalance and genetic heterogeneity in pancreatitis. In this article, we review the latest advances that contributed to the understanding of the basic mechanisms behind the occurrence and development of pancreatitis with a focus on the interpretation of trypsin-antitrypsin imbalance and their relationships with other inflammation pathways. We additionally highlight genetic predispositions to pancreatitis and possible mechanisms associated with them. PMID- 26228363 TI - The impact of Clostridum difficile on surgical rate among ulcerative colitis patients: A systemic review and meta-analysis. AB - There is growing recognition of the impact of Clostridum difficile infection (CDI) on patients with inflammatory bowel disease. Clostridium difficile infection causes greater morbidity and mortality. This study aimed to evaluate the impact of C. difficile on surgical risk among ulcerative colitis (UC) patients. We searched the following databases: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, ACP Journal Club, DARE, CMR, and HTA. Studies were included if fulfilled the following criteria: (1) Cohort or case control studies, which involved a comparison group that lacked CDI, (2) Patients were given a primary diagnosis of UC, (3) Comorbidity of CDI was evaluated by enzyme immunoassay of stool for C. difficile toxin A and B or C. difficile stool culture, (4) Studies evaluated surgical rate, and (5) Studies reported an estimate of odds ratio, accompanied by a corresponding measure of uncertainty. Five studies with 2380 patients fulfilled the inclusion criteria. Overall, meta analysis showed that UC with CDI patients had a significant higher surgical rate than patients with UC alone. (OR=1.76, 95% CI=1.36-2.28). C. difficile infection increased the surgical rate in UC patients. However, results should be interpreted with caution, given the limitations of this stud. PMID- 26228365 TI - Prospective trial in Saudi Arabia comparing the 14-day standard triple therapy with the 10-day sequential therapy for treatment of Helicobacter pylori infection. AB - BACKGROUND/AIMS: Treatment success for Helicobacter pylori infection in Saudi Arabia is relatively unexplored. This prospective study compared the efficacy of sequential versus standard triple therapy in curing H. pylori infections. PATIENTS AND METHODS: Eligible patients underwent upper endoscopy at a single center in Saudi Arabia from October 2011 to February 2014. Patients who tested positive for H. pylori infection were randomly assigned to sequential therapy or standard triple therapy. Sequential treatment: Esomeprazole (20 mg bid for 10 days), amoxicillin (1000 mg for 5 days), then clarithromycin 500 mg and tinidazole 500 mg; both bid for 5 days. Standard triple treatment: Esomeprazole 20 mg, clarithromycin 500 mg, and amoxicillin 1000 mg each bid for 14 days. After 6 weeks of treatment, patients were tested for cure using a validated urea breath test. Application of the E-test determined susceptibility of H. pylori to different antibiotics. RESULTS: Of the 115 patients who received sequential therapy, 93 completed treatment. In the triple-therapy arm, 103 of 117 patients completed treatment. The eradication rate was 58/93 (62.3%) with sequential therapy and 69/102 (67.6%) with standard triple therapy, P = 0.44. Risk ratio was 0.92 (95% CI; 0.75-1.13), and number needed to treat was 19. Overall primary resistance: Metronidazole (48.5%), clarithromycin (23.3%), amoxicillin (14.8%), levofloxacin (11.1%), and tetracycline (2.3%). Mild adverse events occurred in 35 and 17 patients in the sequential and standard therapy groups, respectively. CONCLUSION: Sequential and standard triple therapies were similarly effective at eradicating H. pylori in two-thirds of Saudi patients. Metronidazole and clarithromycin resistance to H. pylori strains was common. PMID- 26228364 TI - Superiority of 10-mm-wide balloon over 8-mm-wide balloon in papillary dilation for bile duct stones: A matched cohort study. AB - BACKGROUND/AIMS: Endoscopic papillary balloon dilation (EPBD) is a possible alternative to endoscopic sphincterotomy (EST) for common bile duct (CBD) stones. To date, 10- and 8-mm EPBD have not been fully compared. PATIENTS AND METHODS: Patients who underwent EPBD for CBD stones at two Japanese tertiary care centers between May 1994 and January 2014 were identified. Matched pairs with 10- and 8 mm EPBD were generated. Short- and long-term outcomes were compared between the two groups. RESULTS: A total of 869 patients were identified (61 and 808 patients for 10- and 8-mm EPBD, respectively), and 61 well-balanced pairs were generated. The rate of complete stone removal within a single session was higher in the 10 mm EPBD group than in the 8-mm EPBD group (69% vs. 44%, P < 0.001), and use of lithotripsy was less frequent in the 10-mm EPBD group (23% vs. 56%, P < 0.001). The rates of post-ERCP pancreatitis were similar between the 10- and 8-mm EPBD groups (11% vs. 8%). Cumulative biliary complication-free rates were not statistically different between the two groups: 88% [95% confidence interval (CI): 79-97%] and 94% (95% CI: 88-100%) at 1 year and 69% (95% CI: 56-85%) and 80% (95% CI: 69-93%) at 2 years in the 10- and 8-mm EPBD groups, respectively. In the 10-mm EPBD group, ascending cholangitis was not observed, and pneumobilia was found in 5% of cases during the follow-up period. CONCLUSIONS: EPBD using a 10-mm balloon for CBD stones is safe and more effective than 8-mm EPBD. The sphincter function is highly preserved after 10-mm EPBD. PMID- 26228366 TI - The expression of hepatic carboxypeptidase E is decreased in patients with cholesterol gallstone. AB - BACKGROUND/AIMS: Decreased carboxypeptidase E (CPE) expression is associated with numerous pathophysiological conditions. This study aimed to investigate the potential function of hepatic CPE in cholesterol gallstone formation. PATIENTS AND METHODS: Patients with cholesterol gallstone (CGS group) and patients without cholesterol gallstones (non-CGS group) were enrolled. The serum total cholesterol, triglyceride, and biliary composition were analyzed. Eight liver samples from two patients without CGS and six patients with CGS were subjected to cDNA microarray analysis. Hepatic CPE expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemical analysis. Plasma CCK level was measured by ELISA. RESULTS: cDNA microarray identified CPE as a gene downregulated in the CGS group. RT-PCR showed that CPE mRNA level was lower in CGS group than in control (P < 0.05, t test). Moreover, Western blot and immunohistochemistry analysis showed that CPE protein level was significantly lower in CGS group than in the control group. In addition, plasma CCK level was lower in CGS group than in the control group. A positive correlation was found between serum CCK level and hepatic CPE mRNA level (r2 = 0.713, P = 0.003). CONCLUSIONS: Down-expression of liver CPE may reduce the secretion of serum CCK and contribute to the formation of cholesterol gallstone. PMID- 26228367 TI - Nonalcoholic fatty liver disease progression in rats is accelerated by splenic regulation of liver PTEN/AKT. AB - BACKGROUND/AIM: The spleen has been reported to participate in the development of nonalcoholic fatty liver disease (NAFLD), but the mechanism has not been fully characterized. This study aims to elucidate how the spleen affects the development of NAFLD in a rat model. MATERIALS AND METHODS: Following either splenectomy or sham operation, male Sprague-Dawley (SD) rats were fed a high-fat diet to drive the development of NAFLD; animals fed a normal diet were used as controls. Two months after surgery, livers and blood samples were collected. Serum lipids were measured; liver histology, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) gene expression, and the ratio of pAkt/Akt were determined. RESULTS: Splenectomy increased serum lipids, except triglyceride (TG) and high-density lipoprotein (HDL), in animals fed either a high-fat or normal diet. Furthermore, splenectomy significantly accelerated hepatic steatosis. Western blot analysis and real-time polymerase chain reaction showed splenectomy induced significant downregulation of PTEN expression and a high ratio of pAkt/Akt in the livers. CONCLUSIONS: The spleen appears to play a role in the development of NAFLD, via a mechanism involving downregulation of hepatic PTEN expression. PMID- 26228368 TI - Bactericidal permeability increasing protein gene polymorphism is associated with inflammatory bowel diseases in the Turkish population. AB - BACKGROUND/AIMS: Inflammatory bowel disease, a chronic inflammatory disease with unknown etiology, affects the small and large bowel at different levels. It is increasingly considered that innate immune system may have a central position in the pathogenesis of the disease. As a part of the innate immune system, bactericidal permeability increasing protein has an important role in the recognition and neutralization of gram-negative bacteria. The aim of our study was to investigate the involvement of bactericidal permeability increasing protein gene polymorphism (bactericidal permeability increasing protein Lys216Glu) in inflammatory bowel disease in a large group of Turkish patients. PATIENTS AND METHODS: The present study included 528 inflammatory bowel disease patients, 224 with Crohn's disease and 304 with ulcerative colitis, and 339 healthy controls. RESULTS: Bactericidal permeability increasing protein Lys216Glu polymorphism was found to be associated with both Crohn's disease and ulcerative colitis (P = 0.0001). The frequency of the Glu/Glu genotype was significantly lower in patients using steroids and in those with steroid dependence (P = 0.012, OR, 0.80; 95% confidence interval [CI]: 0.68-0.94; P = 0.0286, OR, 0.75; 95% CI: 0.66-0.86, respectively). There was no other association between bactericidal permeability increasing protein gene polymorphism and phenotypes of inflammatory bowel disease. CONCLUSIONS: Bactericidal permeability increasing protein Lys216Glu polymorphism is associated with both Crohn's disease and ulcerative colitis. This is the first study reporting the association of bactericidal permeability increasing protein gene polymorphism with steroid use and dependence in Crohn's disease. PMID- 26228369 TI - Predictors of sustained virologic response after discontinuation of nucleos(t)ide analog treatment for chronic hepatitis B. AB - BACKGROUND/AIMS: The aim of this study was to identify the predictors for relapse after discontinuation of oral nucleos(t)ide analog treatment for chronic hepatitis B (CHB). PATIENTS AND METHODS: We evaluated patients who were receiving long-term, regular antiviral therapy with nucleos(t)ide analogs, and subsequently achieved the discontinuation criteria from the Asia-Pacific guideline. After they voluntarily discontinued the drug therapy, data were prospectively collected to observe the potential virologic relapse, and the parameters that predicted recurrence were analyzed. RESULTS: Sixty-five patients met the inclusion criteria, and were included in this study. Twenty-eight patients relapsed, and the accumulative recurrence rates at the 3-month, 6-month, and 1-year follow-ups were 13.85%, 32.31%, and 49.23%, respectively. There was no difference in the accumulative recurrence rate 12 months after discontinuation among patients who were positive or negative for the hepatitis B e antigen (HBeAg) before they received the medication. Logistic regression analysis revealed that the time to complete response, age at discontinuation, and HBsAg levels at discontinuation affected the rate of relapse. CONCLUSIONS: Among patients who received orally administrated nucleos(t)ide analogs, serum levels of HBsAg, age at discontinuation, and the time to complete response might be used as a guide to discontinue treatment. Among younger patients, those with low serum HBsAg levels, and those with an earlier complete response, the risk of relapse is lower and discontinuation is much safer. PMID- 26228370 TI - The international normalized ratio does not reflect bleeding risk in esophageal variceal hemorrhage. AB - BACKGROUND/AIMS: The international normalized ratio (INR) has not been validated as a predictor of bleeding risk in cirrhotics. The aim of this study was to determine whether elevation in the INR correlated with risk of esophageal variceal hemorrhage and whether correction of the INR prior to endoscopic therapy affects failure to control bleeding. PATIENTS AND METHODS: Patient records were retrospectively reviewed from January 1, 2000 to December 31, 2010. Cases were cirrhotics admitted to the hospital due to bleeding esophageal varices. Controls were cirrhotics with a history of non-bleeding esophageal varices admitted with ascites or encephalopathy. All variceal bleeders were treated with octreotide, antibiotics, and band ligation. Failure to control bleeding was defined according to the Baveno V criteria. RESULTS: We analyzed 74 cases and 74 controls. The mean INR at presentation was lower in those with bleeding varices compared to non bleeders (1.61 vs 1.74, P = 0.03). Those with bleeding varices had higher serum sodium (136.1 vs 133.8, P = 0.02), lower hemoglobin (9.59 vs 11.0, P < 0.001), and lower total bilirubin (2.47 vs 5.50, P < 0.001). Multivariable logistic regression showed total bilirubin to inversely correlate with bleeding (OR = 0.74). Bleeders received a mean of 1.14 units of fresh frozen plasma (FFP) prior to endoscopy (range 0-11 units). Of the 14 patients (20%) with failure to control bleeding, median INR (1.8 vs 1.5, P = 0.02) and median units of FFP transfused (2 vs 0, P = 0.01) were higher than those with hemostasis after the initial endoscopy. CONCLUSIONS: The INR reflects liver dysfunction, not bleeding risk. Correction of INR with FFP has little effect on hemostasis. PMID- 26228371 TI - Noninvasive methods to diagnose NAFLD. PMID- 26228372 TI - Ribavirin-free treatment may soon be a reality. PMID- 26228373 TI - Hepatitis C position statement: Taking a stand and standing by it. PMID- 26228374 TI - Doxorubicin-loaded drug-eluting beads versus conventional transarterial chemoembolization for nonresectable hepatocellular carcinoma: Erratum. PMID- 26228375 TI - Cardiovascular Risk and Its Associated Factors in Health Care Workers in Colombia: A Study Protocol. AB - BACKGROUND: Cardiovascular diseases are the leading cause of mortality worldwide, for this reason, they are a public health problem. In Colombia, cardiovascular diseases are the main cause of mortality, having a death rate of 152 deaths per 100,000 population. There are 80% of these cardiovascular events that are considered avoidable. OBJECTIVE: The objective of the study is to determine the prevalence of the cardiovascular risk and its associated factors among the institution's workers in order to design and implement interventions in the work environment which may achieve a decrease in such risk. METHODS: An analytical cross-sectional study was designed to determine the cardiovascular risk and its associated factors among workers of a high complexity health care institution. A self-applied survey will be conducted considering sociodemographic aspects, physical activity, diet, alcohol consumption, smoking, level of perceived stress, and personal and family history. In a second appointment, a physical examination will be made, as well as anthropometric measurements and blood pressure determination. Also, blood samples for evaluating total and high density lipoprotein cholesterol, triglycerides, and fasting blood sugar will be taken. A ten-year global risk for cardiovascular disease will be determined using the Framingham score. A descriptive analysis of the population's characteristics and a stratified analysis by sex, age, and occupation will be made. Bivariate and multivariate analysis will be made using logistic regression models to evaluate the association between cardiovascular risk and the independent variables. The research protocol was approved by the Scientific and Technical Committee and the Ethics Committee on Research of the Fundacion Cardiovascular de Colombia. RESULTS: The protocol has already received funding and the enrollment phase will begin in the coming months. CONCLUSIONS: The results of this study will give the foundation for the design, implementation, and evaluation of a program based on promoting healthy lifestyles, such as performing regular physical activity and healthy food intake in order to avoid and/or control the cardiovascular risk in the workers of a high complexity health care institution. PMID- 26228376 TI - Psychopathological comorbidities in medication-overuse headache: a multicentre clinical study. AB - BACKGROUND AND PURPOSE: In medication-overuse headache (MOH) patients, the presence of psychopathological disturbances may be a predictor of relapse and poor response to treatment. This multicentre study aimed to assess the occurrence of psychopathological disorders in MOH patients by comparing the incidence of psychopathological disturbances with episodic migraine (EM) patients and healthy controls (HC). METHODS: The psychopathological assessment of patients and HC involved the administrations of the Beck Depression Inventory, the Beck Anxiety Inventory, the Modified Mini International Neuropsychiatric Interview (M-MINI), the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Leeds Dependence Questionnaire. RESULTS: The MOH, EM and HC groups (88, 129 and 102 subjects, respectively) differed significantly from each other for the presence of moderate/severe anxiety, whereas mood disorder and depression were revealed in similar proportions for both MOH and EM patients. By stratifying the M-MINI questionnaire results according to the number of psychiatric disorders, it was found that MOH patients had a more complex profile of psychiatric comorbidity. Furthermore, clinically relevant obsessive-compulsive disturbances for abused drugs assessed by Y-BOCS appeared to be more represented in the MOH group, whilst the prevalence of this trait in the EM group was comparable to that of HC (12.5%, 0.8% and 0%, respectively). CONCLUSIONS: Our study indicates the multiple presence of psychopathological comorbidities in patients with MOH. In light of this, it is recommended that the assessment of the psychopathological profile be included in an evaluation of MOH patients, allowing the clinician to more rapidly start an appropriate behavioural treatment, which would greatly improve MOH management. PMID- 26228378 TI - Single-atom electron energy loss spectroscopy of light elements. AB - Light elements such as alkali metal (lithium, sodium) or halogen (fluorine, chlorine) are present in various substances and indeed play significant roles in our life. Although atomic behaviours of these elements are often a key to resolve chemical or biological activities, they are hardly visible in transmission electron microscope because of their smaller scattering power and higher knock-on probability. Here we propose a concept for detecting light atoms encaged in a nanospace by means of electron energy loss spectroscopy using inelastically scattered electrons. In this method, we demonstrate the single-atom detection of lithium, fluorine, sodium and chlorine with near-atomic precision, which is limited by the incident probe size, signal delocalization and atomic movement in nanospace. Moreover, chemical shifts of lithium K-edge have been successfully identified with various atomic configurations in one-dimensional lithium compounds. PMID- 26228377 TI - The Neurobiological Grounding of Persistent Stuttering: from Structure to Function. AB - Neuroimaging and transcranial magnetic stimulation provide insights into the neuronal mechanisms underlying speech disfluencies in chronic persistent stuttering. In the present paper, the goal is not to provide an exhaustive review of existing literature, but rather to highlight robust findings. We, therefore, conducted a meta-analysis of diffusion tensor imaging studies which have recently implicated disrupted white matter connectivity in stuttering. A reduction of fractional anisotropy in persistent stuttering has been reported at several different loci. Our meta-analysis revealed consistent deficits in the left dorsal stream and in the interhemispheric connections between the sensorimotor cortices. In addition, recent fMRI meta-analyses link stuttering to reduced left fronto parieto-temporal activation while greater fluency is associated with boosted co activations of right fronto-parieto-temporal areas. However, the physiological foundation of these irregularities is not accessible with MRI. Complementary, transcranial magnetic stimulation (TMS) reveals local excitatory and inhibitory regulation of cortical dynamics. Applied to a speech motor area, TMS revealed reduced speech-planning-related neuronal dynamics at the level of the primary motor cortex in stuttering. Together, this review provides a focused view of the neurobiology of stuttering to date and may guide the rational design of future research. This future needs to account for the perpetual dynamic interactions between auditory, somatosensory, and speech motor circuits that shape fluent speech. PMID- 26228379 TI - Lenalidomide and secondary acute lymphoblastic leukemia: a case series. AB - Lenalidomide is often used in the maintenance setting for multiple myeloma and has been linked to the development of secondary primary malignancies. The mechanism of lenalidomide causing secondary malignancies has not been fully elucidated, but case reports and phase 3 trials have captured this uncommon occurrence. A case series describing development of secondary acute lymphoblastic leukemia in patients receiving lenalidomide maintenance therapy is presented. Based on data published in the literature thus far and commonalities among patients in this case series, secondary acute lymphoblastic leukemia is likely duration related rather than dose related. Increased cognizance of this secondary malignancy will allow for a more accurate characterization of its true incidence. Regimens for acute lymphoblastic leukemia can be used for management of secondary acute lymphoblastic leukemia with plan for stem cell transplantation. Further studies are needed to identify risk factors for development of secondary malignancy and the best management approach for these patients. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26228380 TI - Drastic increases in overweight and obesity from 1981 to 2010 and related risk factors: results from the Barbados Children's Health and Nutrition Study. AB - OBJECTIVE: To examine overweight and obesity (OWOB), changes in prevalence and potential risk factors in Barbadian children. DESIGN: A cross-section of students were weighed and measured. The WHO BMI-for-age growth references (BAZ), the International Obesity Task Force cut-offs and the US Centers for Disease Control and Prevention growth percentiles were used to determine OWOB prevalence. Harvard weight-for-height-for-age growth standards were used to estimate differences in OWOB prevalence from 1981 to 2010. Samples of parents and students were interviewed to describe correlates of OWOB. SETTING: Barbados. SUBJECTS: Public school students (n 580) in class 3. RESULTS: Based on WHO BAZ, the overall prevalence of OWOB was 34.8 % (95 % CI 30.9, 38.7 %). A trend of higher OWOB prevalence was seen for girls across cut-offs, with significant sex differences noted using the International Obesity Task Force cut-offs. According to Harvard growth standards, OWOB has increased dramatically, from 8.52 % to 32.5 %. Children were more likely to be OWOB when annual household income was below BBD 9000 (OR=2.69; 95 % CI 1.21, 5.99). Eating dinner with the family every night was associated with a lower prevalence of OWOB (OR=0.56; 95 % CI 0.36, 0.87). CONCLUSIONS: The sharp increase of OWOB rates in Barbados warrants attention. Sex disparities in OWOB prevalence may emerge at a young age. Promoting family meals may be a feasible option for OWOB prevention. Understanding familial and sociodemographic factors influencing OWOB will be useful in planning successful intervention or prevention programmes in Barbados. PMID- 26228381 TI - Synthesis, structure and reactivity of a donor-stabilised silylene with a bulky bidentate benzamidinato ligand. AB - The novel donor-stabilised silylene was prepared in a four-step synthesis, starting from bis(2,6-diisopropylphenyl)carbodiimide (Dipp-N[double bond, length as m-dash]C[double bond, length as m-dash]N-Dipp), and its reactivity was studied in a series of oxidative addition reactions and a nucleophilic substitution reaction. The three-coordinate silicon(ii) complex contains the bulky bidentate amidinato ligand Dipp-NC(Ph)N-Dipp(-) and a dimethylamido ligand. Treatment of with N2O afforded the dinuclear five-coordinate silicon(iv) complex (SiO2N3 skeletons), and the reaction with S8 yielded the dinuclear four-coordinate silicon(iv) complex (SiS2N2 skeletons). Treatment of with Se and Te afforded the respective four-coordinate silicon(iv) complexes (SiSeN3 skeleton) and (SiTeN3 skeleton), which contain an Si[double bond, length as m-dash]Se and Si[double bond, length as m-dash]Te double bond, respectively. The reaction of with the silyl azide Me3SiN3 yielded the four-coordinate silicon(iv) complex (SiN4 skeleton) with an Si[double bond, length as m-dash]N double bond, whereas the reaction with the alkyl azide PhSCH2N3 gave the four-coordinate silicon(iv) complex (SiSN3 skeleton), the first silicon(iv) complex with an unsubstituted methyleneamido ligand. The reaction of with [Fe(CO)5] afforded the four coordinate silicon(ii) complex (SiFeN3 skeleton) with an Si-Fe bond. Compounds (and the precursors and (five-coordinate silicon(iv) complexes with an SiCl3N2 and SiCl2N3 skeleton, respectively) in the synthesis of ) were characterised by elemental analyses, crystal structure analyses and multinuclear NMR spectroscopic studies in the solid state and in solution. PMID- 26228382 TI - Evaluation of morphology of the nasopalatine canal using cone-beam computed tomography in a subgroup of Turkish adult population. AB - PURPOSE: The aim of the study was to evaluate the anatomy and morphology of the nasopalatine canal (NPC) using cone-beam computed tomography (CBCT) and to determine variations of the NPC in relation to age, gender, and status of edentulism of anterior maxilla. METHODS: Patients scheduled for CBCT imaging for further radiographic evaluation of the maxilla with various reasons were consecutively enrolled in this study. Reformatted sagittal and coronal slices were analyzed with regard to dimensions and anatomic characteristics of the NPC. The correlation of age, gender, and status of edentulism of anterior maxilla with all the variables were evaluated. RESULTS: The study comprised 157 subjects with a mean age of 49.64 years. The analysis of the diameter of the incisive foramen revealed a mean of 4.48 mm whereas the diameter of the palatine foramen revealed a mean of 2.88 mm. The mean length of NPC was 10.87 mm and found significantly longer in males and patients with anterior teeth. In terms of incisive foramen and palatine foramen diameter, there was not any significant difference between males and females and between patients with and without anterior teeth (p > 0.05). CONCLUSION: There was relationship between the gender of the patients and the length of the NPC, with significantly lower mean values in females. This result suggests that careful analysis of anatomical structures by taking into consideration some variables would aid the clinician in performing a safer surgical intervention and prevent possible complications. CNCT scanning prior to implant surgery specifically in edentulous patients with severely atrophic maxillae might be a good diagnostic tool to guide the clinician for a safer and predictable procedure. PMID- 26228384 TI - Correction of differential renal function for asymmetric renal area ratio in unilateral hydronephrosis. AB - OBJECTIVE: Children with unilateral hydronephrosis are followed up with anteroposterior pelvic diameter (APD), hydronephrosis grade, mercaptoacetyltriglycine (MAG-3) drainage pattern and differential renal function (DRF). Indeterminate drainage preserved DRF in higher grades of hydronephrosis, in some situations, complicating the decision-making process. Due to an asymmetric renal area ratio, falsely negative DRF estimations can result in missed optimal surgery times. This study was designed to assess whether correcting the DRF estimation according to kidney area could reflect the clinical situation of a hydronephrotic kidney better than a classical DRF calculation, concurrently with the hydronephrosis grade, APD and MAG-3 drainage pattern. MATERIALS AND METHODS: We reviewed the MAG-3, dimercaptosuccinic acid (DMSA) scans and ultrasonography (US) of 23 children (6 girls, 17 boys, mean age: 29 +/- 50 months) with unilateral hydronephrosis. MAG-3 and DMSA scans were performed within 3 months (mean 25.4 +/- 30.7 days). The closest US findings (mean 41.5 +/- 28.2 days) were used. DMSA DRF estimations were obtained using the geometric mean method. Secondary calculations were performed to correct the counts (the total counts divided by the number of pixels in ROI) according to kidney area. The renogram patterns of patients were evaluated and separated into subgroups. The visual assessment of DMSA scans was noted and the hydronephrotic kidney was classified in comparison to the normal contralateral kidney's uptake. The correlations of the DRF values of classical and area-corrected methods with MAG-3 renogram patterns, the visual classification of DMSA scan, the hydronephrosis grade and the APD were assessed. RESULTS: DRF estimations of two methods were statistically different (p: 0.001). The categories of 12 hydronephrotic kidneys were changed. There were no correlations between classical DRF estimations and the hydronephrosis grade, APD, visual classification of the DMSA scan and uptake evaluation. The DRF distributions according to MAG-3 drainage patterns were not different. Area-corrected DRF estimations correlated with all: with an increasing hydronephrosis grade and APD, DRF estimations decreased and MAG-3 drainage patterns worsened. A decrease in DRF (< 45 %) was determined when APD was >= 10 mm. When APD was >= 26 mm, a reduction of DRF below 40 % was determined. CONCLUSION: Our results suggest that correcting DRF estimation for asymmetric renal area ratio in unilateral hydronephrosis can be more robust than the classical method, especially for higher grades of hydronephrotic kidneys, under equivocal circumstances. PMID- 26228383 TI - Morphometrics of the human thumb metacarpal bone: interest for developing an osseointegrated prosthesis. AB - INTRODUCTION: Amputation of the thumb presents a serious insult to the hand and diminished quality of life for a patient physically, vocationally, and possibly psychologically. The aim of this study was to define the geometry of the thumb metacarpal in order to help create a standardized set of transcutaneous osseointegrated prostheses to treat patients who have suffered amputation of the thumb at the level of the metacarpophalangeal joint. MATERIALS AND METHODS: A total of 80 metacarpals from 46 cadavers were studied. All soft tissues were removed and the thumb metacarpals were imaged using computed tomography. Three dimensional models were constructed using images from the coronal, sagittal, and axial planes. Using HyperMeshTM CAD software, the bones were analyzed for overall length, radius of curvature, medullary canal diameter, cortical thickness, and distance to the isthmus, defined as the narrowest portion of the intramedullary canal. RESULTS: The average length of the first metacarpal was 47.6 mm (+/-3.3 mm, 39.2-56.9 mm). The average radius of curvature was 55.5 mm (+/-10.7 mm, 33 78.9 mm). Inner bone diameter, measured in two axes, was 10.5 mm (+/-1.3 mm, 5.4 18.7 mm) for the major axis and 7.7 mm (+/-0.9 mm, 4.3-17.8 mm) for the minor axis. The average cortical thickness was 1.4 mm (+/-0.3 mm, 0.7-3.1 mm). The distance to the center of the isthmus from the distal end had an average length of 21.3 mm (+/-1.9 mm, 17-25 mm). CONCLUSIONS: Using these findings a standardized set of intramedullary stems can be developed as a base for a transcutaneous osseointegrated prosthesis, helping to create a reliable method for treating patients with amputated thumbs. PMID- 26228385 TI - Pre-Transplant Weight Loss and Survival after Kidney Transplantation. AB - BACKGROUND/AIMS: We examined post-transplant survival among obese kidney candidates who were temporarily designated waitlist inactive (status 7) due to their weight. METHODS: Using OPTN/United Network for Organ Sharing data, patient and graft survival of adult status 7 recipients with a registration body mass index (BMI) >=30 kg/m(2) (n = 328) were compared to all others (controls; n = 74,066). Status 7 recipients were then matched to controls to assess whether pre transplant weight loss was associated with a survival benefit. RESULTS: Median BMI at registration (38 vs. 27 kg/m(2), p < 0.001) and transplant (36 vs. 27 kg/m(2), p < 0.001) and reduction in BMI while waitlisted (-5.0 vs. 0.0%, p < 0.001) were higher among status 7 than controls. Patient (status 7: 87.3%; control: 89.3%; p = 0.90) and graft survival (status 7: 82.9%; control: 81.6%; p = 0.75) were similar over 4 years. There was no association between status 7 and mortality (HR 0.96, 95% CI 0.59-1.57) or graft loss (HR 0.95, 95% CI 0.66-1.38) in the overall population nor between matched status 7 recipients and controls (patient survival: 86.0 vs. 87.5%, p = 0.20; graft survival: 82.6 vs. 77.2%, p = 0.61). CONCLUSION: Among obese status 7 kidney candidates previously considered too obese for transplant, patient and graft survival were comparable to the general transplant population. No difference in survival was observed with pre transplant weight loss. PMID- 26228386 TI - General design approach and practical realization of decoupling matrices for parallel transmission coils. AB - PURPOSE: In a coupled parallel transmit (pTx) array, the power delivered to a channel is partially distributed to other channels because of coupling. This power is dissipated in circulators resulting in a significant reduction in power efficiency. In this study, a technique for designing robust decoupling matrices interfaced between the RF amplifiers and the coils is proposed. The decoupling matrices ensure that most forward power is delivered to the load without loss of encoding capabilities of the pTx array. THEORY AND METHODS: The decoupling condition requires that the impedance matrix seen by the power amplifiers is a diagonal matrix whose entries match the characteristic impedance of the power amplifiers. In this work, the impedance matrix of the coupled coils is diagonalized by a successive multiplication by its eigenvectors. A general design procedure and software are developed to generate automatically the hardware that implements diagonalization using passive components. RESULTS: The general design method is demonstrated by decoupling two example parallel transmit arrays. Our decoupling matrices achieve better than -20 db decoupling in both cases. CONCLUSION: A robust framework for designing decoupling matrices for pTx arrays is presented and validated. The proposed decoupling strategy theoretically scales to any arbitrary number of channels. Magn Reson Med 76:329-339, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26228388 TI - Evidence for CVD 103-HgR as an effective single-dose oral cholera vaccine. AB - We propose the ideal oral cholera vaccine (OCV) should be an inexpensive, single, oral dose that rapidly confers immunity for a long duration, and is well tolerated by individuals vulnerable to cholera. Vaccine trials in industrialized countries of a single oral dose of 5 * 10(8) colony forming units (CFU) of the live, attenuated cholera strain CVD 103-HgR have shown 88-97% serum vibriocidal antibody seroconversion rates, a correlate of protection and documented vaccine efficacy of >=80% using volunteer challenge studies with wild-type cholera. For individuals of developing countries, a 5 * 10(9) CFU dose of CVD 103-HgR is necessary to elicit similar antibody responses. Presently, a reformulation of CVD 103-HgR is in late-stage clinical development for prospective US FDA licensure; making a cholera vaccine for US travelers potentially accessible in 2016. The availability of CVD 103-HgR should be a welcome addition to the currently available OCVs. PMID- 26228387 TI - Phytoestrogens and risk of prostate cancer: a meta-analysis of observational studies. AB - BACKGROUND: Epidemiologic studies have reported various results relating phytoestrogens to prostate cancer (PCa). The aim of this study was to provide a comprehensive meta-analysis on the extent of the possible association between phytoestrogens (including consumption and serum concentration) and the risk of PCa. METHODS: Eligible studies were retrieved via both computer searches and review of references. The summary relative risk ratio (RR) or odds ratio (OR) and 95% confidence interval (CI) were calculated with random effects models. RESULTS: A total of 11 studies (2 cohort and 9 case-control studies) on phytoestrogen intake and 8 studies on serum concentration were included in the meta-analysis. The pooled odds ratio (OR) showed a significant influence of the highest phytoestrogens consumption (OR 0.80, 95% CI 0.70-0.91) and serum concentration (OR 0.83, 95% CI 0.70-0.99) on the risk of PCa. In stratified analysis, high genistein and daidzein intake and increased serum concentration of enterolactone were associated with a significant reduced risk of PCa. However, no significant associations were observed for isoflavone intake, lignans intake, or serum concentrations of genistein, daidzein, or equol. CONCLUSIONS: The overall current literature suggests that phytoestrogen intake is associated with a decreased risk of PCa, especially genistein and daidzein intake. Increased serum concentration of enterolactone was also associated with a significant reduced risk of PCa. Further efforts should be made to clarify the underlying biological mechanisms. PMID- 26228389 TI - Liquid transmission characteristics of padding bandages under pressure. AB - Padding is an essential component in a multilayer compression bandaging system, used inside the compression bandage through which substantial amount of pressure is exerted on the limb of patient for treatment of venous leg ulcers. As a result, the liquid transmission behavior of padding is also critical in managing body fluids or sweat exuded from the affected limb, reducing the excessive moisture build-up around the wound and thereby ensuring comfort to and hence a better compliance from the patients. This study investigates the in-plane fluid transport characteristics of needle-punched nonwoven padding bandages. It first reviewed the existing studies related to the problems, and discussed their limits and possible improvements in dealing with complex fluid transport issues in textile porous media. The measurement of fluid transport under different pressure levels was then done using a newly designed apparatus capable of simultaneously tracing the liquid in-plane spreading along different directions, and obtaining several transport characteristics of a testing sample, e.g. the liquid flow anisotropy, the rate of movement, the area of wet surface with time, etc. Also the effects of several important factors, such as the levels of pressure applied, the specimen bulk density, and needling density of the padding products, have been experimentally investigated. In addition, based on an extended Lucas Washburn theory, we calculated the liquid flow distance, both instantaneous speed and a more useful time-averaged speed v(av) at any given direction, and also defined a flow anisotropy index I(A) as a convenient parameter to represent the material flow anisotropy. The applications of v(av) and I(A) to actual samples have demonstrated the usefulness of these parameters in characterizing the flow nature and behavior of the materials. PMID- 26228390 TI - Study protocol for a randomised controlled trial evaluating the efficacy of a telehealth program--management of asthma with supportive telehealth of respiratory function in pregnancy (MASTERY(c)). AB - BACKGROUND: Telehealth has the potential to improve asthma management through regular monitoring of lung function and/or asthma symptoms by health professionals in conjunction with feedback to patients. Although the benefits of telehealth for improving asthma management have been extensively studied, the feasibility of telehealth for supporting asthma management in pregnant women has not been investigated. This study aims to evaluate the use of telehealth for remotely monitoring lung function and optimising asthma control during pregnancy. METHODS: A randomised controlled trial comparing usual care with a telehealth program (MASTERY(c)) has been conducted. The intervention comprised a mobile application - Breathe-easy(c) supported by a Bluetooth-enabled handheld device (COPD-6(r)), which was used for self-monitoring of lung function (FEV1, FEV6) twice daily, and recording asthma symptoms and medication usage weekly; and a written asthma action plan (WAAP). The primary outcome measure is change in asthma control measured using the Asthma Control Questionnaire (ACQ). Secondary outcomes include changes in mini-Asthma Quality of Life Questionnaire (mAQLQ) score, lung function, asthma-related health visits, days off work/study, and oral corticosteroid use. Outcome data were collected at baseline, 3 months and 6 months by a research assistant masked to group allocation. Maternal and neonatal outcomes were also collected post-partum. DISCUSSION: This is the first study to evaluate the application of telehealth to optimize asthma management in pregnant women. If effective, this telehealth program could improve asthma self-management by pregnant women which may reduce the maternal and fetal risks of poorly controlled asthma during pregnancy. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN 12613000800729 ) 17 July 2013. PMID- 26228392 TI - Multi-Compartmental Hydrogel Microparticles Fabricated by Combination of Sequential Electrospinning and Photopatterning. AB - Multi-compartmental non-spherical hydrogel microparticles were fabricated by combining electrospinning and photopatterning. Sequential electrospinning produced multi-layered fiber matrices with different composition in which each layer became a compartment of the particle. Photopatterning of the hydrogel in the presence of the multi-layered fiber matrix generated multi-compartmental microparticles with different vertical functionalities. While the shapes of the hydrogel microparticles were determined by the design of the photomask, the chemical properties and size of each compartment were independently controlled by changing the molecules incorporated into each fiber matrix and the electrospinning times, respectively. The resultant multi-compartmental hydrogel microparticles could carry out not only the release of different growth factors with independent kinetics but also binding of multiple targets at different compartments. PMID- 26228391 TI - Joint association between birth weight at term and later life adherence to a healthy lifestyle with risk of hypertension: a prospective cohort study. AB - BACKGROUND: Low birth weight and unhealthy lifestyles in adulthood have been independently associated with an elevated risk of hypertension. However, no study has examined the joint effects of these factors on incidence of hypertension. METHODS: We followed 52,114 women from the Nurses' Health Study II without hypercholesterolemia, diabetes, cardiovascular disease, cancer, prehypertension, and hypertension at baseline (1991-2011). Women born preterm, of a multiple pregnancy, or who were missing birth weight data were excluded. Unhealthy adulthood lifestyle was defined by compiling status scores of body mass index, physical activity, alcohol consumption, the Dietary Approaches to Stop Hypertension diet, and the use of non-narcotic analgesics. RESULTS: We documented 12,588 incident cases of hypertension during 20 years of follow-up. The risk of hypertension associated with a combination of low birth weight at term and unhealthy lifestyle factors (RR, 1.95; 95 % CI, 1.83-2.07) was more than the addition of the risk associated with each individual factor, indicating a significant interaction on an additive scale (P interaction <0.001). The proportions of the association attributable to lower term birth weight alone, unhealthy lifestyle alone, and their joint effect were 23.9 % (95 % CI, 16.6 31.2), 63.7 % (95 % CI, 60.4-66.9), and 12.5 % (95 % CI, 9.87-15.0), respectively. The population-attributable-risk for the combined adulthood unhealthy lifestyle and low birth weight at term was 66.3 % (95 % CI, 56.9-74.0). CONCLUSION: The majority of cases of hypertension could be prevented by the adoption of a healthier lifestyle, though some cases may depend on simultaneous improvement of both prenatal and postnatal factors. PMID- 26228393 TI - The antidepressant-like effect of vagus nerve stimulation is mediated through the locus coeruleus. AB - It has been shown that vagus nerve stimulation (VNS) has an antidepressant-like effect in the forced swim test. The mechanism of action underlying this effect is incompletely understood, but there is evidence suggesting that the locus coeruleus (LC) may play an important role. In this study, noradrenergic LC neurons were selectively lesioned to test their involvement in the antidepressant like effect of VNS in the forced swim test. Forced swim test behavior was assessed in rats that were subjected to VNS or sham treatment. In half of the VNS treated animals, the noradrenergic neurons from the LC were lesioned using the selective neurotoxin DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride], yielding three experimental arms: sham, VNS and DSP-4-VNS (n = 8 per group). Furthermore, the open field test was performed to evaluate locomotor activity. A dopamine-beta-hydroxylase immunostaining was performed to confirm lesioning of noradrenergic LC neurons. VNS significantly reduced the percentage of immobility time in the forced swim test compared to sham treatment (median: 56%, interquartile range: 41% vs. median: 75%, interquartile range: 12%). This antidepressant-like effect of VNS could not be demonstrated in the DSP-4-VNS group (median: 79%, interquartile range: 33%). Locomotor activity in the open field test was not different between the three treatment arms. The absence of hippocampal dopamine-beta-hydroxylase immunostaining in the DSP-4-treated rats confirmed the lesioning of noradrenergic neurons originating from the brainstem LC. The results of this study demonstrate that the noradrenergic neurons from the LC play an important role in the antidepressant-like effect of VNS. PMID- 26228394 TI - A randomized study of cognitive remediation for forensic and mental health patients with schizophrenia. AB - Cognitive remediation has proven efficacy for improving neurocognition in people with schizophrenia. The current study evaluated the benefits of cognitive remediation on neurocognition, functioning, psychotic symptoms, and aggression in a sample of forensic and mental health patients. Care recipients with schizophrenia or schizoaffective disorder (N = 78) receiving services in the forensic and mental health units of a state hospital were randomized to participate in cognitive remediation versus computer games control activities. Participants' neurocognition, functional capacity, experiential recovery, psychotic symptoms, and aggression incidents were assessed at baseline and posttreatment. Cognitive remediation was associated with improvements in several neurocognitive domains and circumscribed domains of functional capacity. People assigned to cognitive remediation experiences greater reductions in negative symptoms, agitation/excitement, and verbal and physical aggression. In addition to improving neurocognition in long-term hospitalized forensic and mental health patients, cognitive remediation may enhance efforts at reducing negative symptoms, emotion dysregulation, and aggression incidents. Forensic settings may represent a new frontier for the clinical dissemination of cognitive remediation. PMID- 26228395 TI - Latent profile analyses of posttraumatic stress disorder, depression and generalized anxiety disorder symptoms in trauma-exposed soldiers. AB - Posttraumatic stress disorder (PTSD) is comorbid with major depressive disorder (MDD; Kessler et al., 1995) and generalized anxiety disorder (GAD; Brown et al., 2001). We aimed to (1) assess discrete patterns of post-trauma PTSD-depression GAD symptoms using latent profile analyses (LPAs), and (2) assess covariates (gender, income, education, age) in defining the best fitting class solution. The PTSD Checklist (assessing PTSD symptoms), GAD-7 scale (assessing GAD symptoms), and Patient Health Questionnaire-9 (assessing depression) were administered to 1266 trauma-exposed Ohio National Guard soldiers. Results indicated three discrete subgroups based on symptom patterns with mild (class 1), moderate (class 2) and severe (class 3) levels of symptomatology. Classes differed in symptom severity rather than symptom type. Income and education significantly predicted class 1 versus class 3 membership, and class 2 versus class 3. In conclusion, there is heterogeneity regarding severity of PTSD-depression-GAD symptomatology among trauma-exposed soldiers, with income and education predictive of class membership. PMID- 26228396 TI - Acute high frequency stimulation of the prefrontal cortex or nucleus accumbens does not increase hippocampal neurogenesis in rats. AB - To date, the effects of deep brain stimulation (DBS) on hippocampal neurogenesis have been mainly characterized in the context of memory. Acute stimulation (i.e. for 1 h) of either the entorhinal cortex or the anterior thalamus increases both cell proliferation and survival. We investigate whether stimulation applied to targets being considered for the treatment of depression, namely the ventromedial prefrontal cortex (vmPFC) or nucleus accumbens (Acb), also increases hippocampal neurogenesis in rodents. Rats were treated with vmPFC or Acb DBS for 1 h at different settings. 5'-bromo-2'deoxyuridine (BrdU) was injected three days following stimulation onset and animals were sacrificed 24 h or 28 days later. Overall, we found that neither vmPFC nor Acb DBS increased hippocampal neurogenesis. In summary, the delivery of acute stimulation into targets homologous to those used in human depression trials does not increase hippocampal neurogenesis. PMID- 26228397 TI - Longitudinal assessment of gender differences in the development of PTSD among US military personnel deployed in support of the operations in Iraq and Afghanistan. AB - Divergent findings from previous research examining gender differences in the development of posttraumatic stress disorder (PTSD) among US military members deployed to the operations in Iraq or Afghanistan (recent operations) prompted this study utilizing a matching approach to examine whether risk for new-onset PTSD and PTSD severity scores differed by gender. US military members from the Millennium Cohort Study deployed in support of the recent operations were followed for approximately 7 years from baseline through 2 follow-up periods between 2001 and 2008. Propensity score matching was used to match 1 male to each female using demographic, military, and behavioral factors including baseline sexual assault. Analyses were stratified by combat experience defined as reporting at least one of five exposures during follow-up. Outcome measures included a positive screen for PTSD and severity scores measured by the PTSD Patient Checklist-Civilian Version. Discrete-time survival analysis quantified the association between gender and incident PTSD. Among 4684 matched subjects (2342 women and men), 6.7% of women and 6.1% of men developed PTSD during follow up. Results showed no significant gender differences for the likelihood of developing PTSD or for PTSD severity scores among women and men who reported combat experience and among those who did not. This study is the first of its kind to match a large population of male and female service members on important baseline characteristics including sexual assault. Findings suggest that while combat deployed personnel develop PTSD, women do not have a significantly different risk for developing PTSD than men after experiencing combat. PMID- 26228399 TI - What's in a delayed bathyphase? PMID- 26228398 TI - Connectome signatures of neurocognitive abnormalities in euthymic bipolar I disorder. AB - OBJECTIVES: Connectomics have allowed researchers to study integrative patterns of neural connectivity in humans. Yet, it is unclear how connectomics may elucidate structure-function relationships in bipolar I disorder (BPI). Expanding on our previous structural connectome study, here we used an overlapping sample with additional psychometric and fMRI data to relate structural connectome properties to both fMRI signals and cognitive performance. METHODS: 42 subjects completed a neuropsychological (NP) battery covering domains of processing speed, verbal memory, working memory, and cognitive flexibility. 32 subjects also had fMRI data performing a Go/NoGo task. RESULTS: Bipolar participants had lower NP performance across all domains, but only working memory reached statistical significance. In BPI participants, processing speed was significantly associated with both white matter integrity (WMI) in the corpus callosum and interhemispheric network integration. Mediation models further revealed that the relationship between interhemispheric integration and processing speed was mediated by WMI, and processing speed mediated the relationship between WMI and working memory. Bipolar subjects had significantly decreased BA47 activation during NoGo vs. Go. Significant predictors of BA47 fMRI activations during the Go/NoGo task were its nodal path length (left hemisphere) and its nodal clustering coefficient (right hemisphere). CONCLUSIONS: This study suggests that structural connectome changes underlie abnormalities in fMRI activation and cognitive performance in euthymic BPI subjects. Results support that BA47 structural connectome changes may be a trait marker for BPI. Future studies are needed to determine if these "connectome signatures" may also confer a biological risk and/or serve as predictors of relapse. PMID- 26228400 TI - Assessment of DNA damage and repair efficiency in drug naive schizophrenia using comet assay. AB - The etiology of schizophrenia continues to be confounding and elusive. Some knowledge gaps exist in the neurodegenerative theory of schizophrenia. Oxidative DNA damage and repair deficits are relevant to the mechanisms of neurodegeneration but have not been studied in drug naive schizophrenia. The present study used the comet assay technique to study the extent of DNA damage in circulating peripheral lymphocytes of patients with drug naive schizophrenia (n = 40) along with an age and gender matched control group (n = 40). We also assessed the DNA repair efficiency in cases following incubation in a nutrient medium. All the assayed comet parameters demonstrated significantly greater baseline DNA damage in cases in comparison to the controls except for head diameter (p < 0.001 for all significant results, p = 0.32 for head diameter). Gender, age and duration of illness (p = 0.21, 0.69 and 0.12 respectively for tail length) did not influence any of the parameters significantly. Significant decrease was noted in the comet tail length and percentage of DNA in comet tail (p < 0.001 for both) in cases following incubation suggesting that the DNA repair machinery was preserved. No difference in DNA repair efficiency was noted between the genders (p = 0.23 for tail length). Our findings confirm the presence of significant baseline DNA damage in schizophrenia even prior to the initiation of anti psychotic treatment. Additionally, intact genomic repair efficiency was noted in this group as a whole. These results provide some evidence for oxidative DNA damage as molecular link underpinning neurodegeneration in drug naive schizophrenia. PMID- 26228401 TI - Is risk-taking propensity a familial vulnerability factor for alcohol use? An examination in two independent samples. AB - Research indicates that increased risk-taking propensity (RTP) is associated with higher alcohol use. There is also some evidence to suggest that it is not just a state factor or 'scar,' but instead a vulnerability factor. If this is the case, increased RTP should be evident in healthy individuals that are at risk for alcohol use. To date, few studies have examined whether RTP is a familial vulnerability factor and thus, the aim of the current study was to test whether RTP aggregates within families and if increased RTP is evident in biological family members at risk for alcohol use. Sample 1 included 87 biological, adult sibling pairs and Sample 2 included 111 biological mother and adolescent dyads (total N = 396). All participants completed a behavioral measure of RTP and were assessed for alcohol use. Results in both samples were strikingly consistent. In Sample 1, RTP was correlated among siblings and greater frequency of proband alcohol use predicted greater sibling RTP, over and above sibling alcohol use. In Sample 2, RTP was correlated among mothers and their offspring and greater maternal alcohol use problems predicted greater adolescent RTP over and above adolescent substance use. Together, these findings suggest that RTP may be a familial vulnerability factor for alcohol use as it aggregates within families and is increased in relatives of individuals with higher levels of alcohol use. PMID- 26228402 TI - Plasma linoleic acid partially mediates the association of bipolar disorder on self-reported mental health scales. AB - We have shown that bipolar individuals have reduced quality diets, including lower intake of polyunsaturated fatty acids (PUFA). We have also reported reduced plasma levels of the n-6 PUFA, linoleic acid (LA), and the n-3 PUFA, eicosapentaenoic acid (EPA) in bipolar subjects. In the current analysis we hypothesized that LA and EPA plasma levels would mediate lower self-reported mental health and life functioning scores in bipolar subjects. In a cross sectional study, we collected a 7-day diet record in bipolar (n = 56) and control subjects (n = 46) followed by a fasted blood draw. We used structured equation modeling path analysis to test for mediating effects of dietary intake and plasma levels of LA and EPA on self-reported mental health questionnaire scores, including the Life Functioning Questionnaire (LFQ), the Patient Health Questionnaire (PHQ9), and the Short Form Health Survey (SF12), extracting the mental health component summary score (SF12-MH). We adjusted for age, gender, psychiatric medication use, body mass index (BMI), and total caloric intake as covariates with bipolar disorder as the primary predictor. We found a significant path association from bipolar disorder to lower plasma LA levels (p = 0.03) and significant paths from plasma LA to PHQ9 (p = 0.05), LFQ (p = 0.01) and SF12-MH (p = 0.05) scores, such that lower plasma LA predicted worse outcomes. We found no significant paths from plasma EPA levels to any of the outcome measures. These findings suggest that plasma LA levels partially mediate the effect of bipolar disorder on self-reported measures of mental health and life functioning. PMID- 26228403 TI - Assessing measures of suicidal ideation in clinical trials with a rapid-acting antidepressant. AB - Rapid reduction of suicidal thoughts is critical for treating suicidal patients. Clinical trials evaluating these treatments require appropriate measurement. Key methodological issues include: 1) the use of single or multi-item assessments, and 2) evaluating whether suicidal ideation measures can track rapid change over time. The current study presents data from two randomized, placebo-controlled, crossover clinical trials evaluating ketamine in individuals with treatment resistant depression (n = 60). Participants were assessed for suicidal thoughts using the Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), and Scale for Suicidal Ideation (SSI) at eight time points over three days. Assessments were compared using correlational analyses and effect sizes at 230 min and three days after ketamine infusion. Linear mixed models evaluated change in ideation across all time points. The HAM-D and MADRS suicide items demonstrated correlations of r > .80 with the first five items of the SSI (SSI5). On linear mixed models, an effect for ketamine was found for the HAM-D, MADRS, BDI items, and SSI5 (p < .001), but not for the full SSI (p = .88), which suggests a limited ability to assess change over time in patients with low levels of suicidal thoughts. Taken together, the results suggest that repeated suicidal assessments over minutes to days appear to detect improvement in suicidal thoughts after ketamine infusion compared to placebo. The MADRS suicide item, BDI suicide item, and SSI5 may be particularly sensitive to rapid changes in suicidal thoughts. PMID- 26228404 TI - Disturbed sleep as risk factor for the subsequent onset of bipolar disorder--Data from a 10-year prospective-longitudinal study among adolescents and young adults. AB - There is ample data suggesting that individuals with bipolar disorder more frequently suffer from disturbed sleep even when euthymic. Since sleep is a process that is crucial for affective homeostasis, disturbed sleep in healthy individuals may be a risk factor for the subsequent onset of bipolar disorder. Utilizing data from a large cohort of adolescents and young adults, this study tests the hypothesis that disturbed sleep constitutes a risk factor for the later onset of bipolar disorder. A representative community sample of N = 3021 adolescents and young adults (baseline age 14-24) was assessed using the standardized Composite International Diagnostic Interview and followed-up prospectively up to 3 times over up to 10 years. Disturbed sleep at baseline was quantified utilizing the corresponding items from the self-report inventory SCL 90-R. The compound value (insomnia-score) as an ordinal parameter for the severity of sleep disturbances was used to assess associations with the incidence of bipolar disorder among participants free of major mental disorder at baseline (N = 1943) using odds ratios (OR) from logistic regressions. Analyses were adjusted for age, gender, parental mood disorder and lifetime alcohol or cannabis dependence. Poor sleep quality significantly increased the risk for the subsequent development of bipolar disorder (OR = 1.75; p = 0.001). Regarding individual sleep items, trouble falling asleep and early morning awakening were predictive for the subsequent onset of bipolar disorder. Disturbed sleep in persons otherwise free of major mental disorders appears to confer an increased risk for the subsequent onset of bipolar disorder. PMID- 26228405 TI - Corticosteroid receptor genes and childhood neglect influence susceptibility to crack/cocaine addiction and response to detoxification treatment. AB - The aim of this study was to analyze hypotheses-driven gene-environment and gene gene interactions in smoked (crack) cocaine addiction by evaluating childhood neglect and polymorphisms in mineralocorticoid and glucocorticoid receptor genes (NR3C2 and NR3C1, respectively). One hundred thirty-nine crack/cocaine-addicted women who completed 3 weeks of follow-up during early abstinence composed our sample. Childhood adversities were assessed using the Childhood Trauma Questionnaire (CTQ), and withdrawal symptoms were assessed using the Cocaine Selective Severity Assessment (CSSA) scale. Conditional logistic regression with counterfactuals and generalized estimating equation modeling were used to test gene-environment and gene-gene interactions. We found an interaction between the rs5522-Val allele and childhood physical neglect, which altered the risk of crack/cocaine addiction (Odds ratio = 4.0, P = 0.001). Moreover, a NR3C2-NR3C1 interaction (P = 0.002) was found modulating the severity of crack/cocaine withdrawal symptoms. In the post hoc analysis, concomitant carriers of the NR3C2 rs5522-Val and NR3C1 rs6198-G alleles showed lower overall severity scores when compared to other genotype groups (P-values <= 0.035). This gene-environment interaction is consistent with epidemiological and human experimental findings demonstrating a strong relationship between early life stress and the hypothalamic-pituitary-adrenal (HPA) axis dysregulation in cocaine addiction. Additionally, this study extended in crack/cocaine addiction the findings previously reported for tobacco smoking involving an interaction between NR3C2 and NR3C1 genes. PMID- 26228406 TI - Subcortical volumes differentiate Major Depressive Disorder, Bipolar Disorder, and remitted Major Depressive Disorder. AB - Subcortical gray matter regions have been implicated in mood disorders, including Major Depressive Disorder (MDD) and Bipolar Disorder (BD). It is unclear, however, whether or how these regions differ among mood disorders and whether such abnormalities are state- or trait-like. In this study, we examined differences in subcortical gray matter volumes among euthymic BD, MDD, remitted MDD (RMD), and healthy (CTL) individuals. Using automated gray matter segmentation of T1-weighted MRI images, we estimated volumes of 16 major subcortical gray matter structures in 40 BD, 57 MDD, 35 RMD, and 61 CTL individuals. We used multivariate analysis of variance to examine group differences in these structures, and support vector machines (SVMs) to assess individual-by-individual classification. Analyses yielded significant group differences for caudate (p = 0.029) and ventral diencephalon (VD) volumes (p = 0.003). For the caudate, both the BD (p = 0.004) and the MDD (p = 0.037) participants had smaller volumes than did the CTL participants. For the VD, the MDD participants had larger volumes than did the BD and CTL participants (ps < 0.005). SVM distinguished MDD from BD with 59.5% accuracy. These findings indicate that mood disorders are characterized by anomalies in subcortical gray matter volumes and that the caudate and VD contribute uniquely to differential affective pathology. Identifying abnormalities in subcortical gray matter may prove useful for the prevention, diagnosis, and treatment of mood disorders. PMID- 26228408 TI - Internet versus face-to-face group cognitive-behavioral therapy for fibromyalgia: A randomized control trial. AB - BACKGROUND: The aim of this study was to explore the effectiveness of Internet delivered cognitive-behavioral therapy (iCBT) in treating fibromyalgia (FM) compared with an identical protocol using conventional group face-to-face CBT. METHODS: Sixty participants were assigned to either (a) the waiting list group, (b) the CBT group, or (c) the iCBT group. The groups were assessed at baseline, after 10 weeks of treatment, and at 3-, 6-, and 12-month follow-ups. The primary outcome measured was the impact of FM on daily functioning, as measured by the Fibromyalgia Impact Questionnaire (FIQ). The secondary outcomes were psychological distress, depression, and cognitive variables, including self efficacy, catastrophizing, and coping strategies. RESULTS: In post-treatment, only the CBT group showed improvement in the primary outcome. The CBT and iCBT groups both demonstrated improvement in psychological distress, depression, catastrophizing, and utilizing relaxation as a coping strategy. The iCBT group showed an improvement in self-efficacy that was not obtained in the CBT group. CBT and iCBT were dissimilar in efficacy at follow-up. The iCBT group members improved their post-treatment scores at their 6- and 12-month follow-ups. At the 12-month follow-up, the iCBT group showed improvement over their primary outcome and catastrophizing post-treatment scores. A similar effect of CBT was expected, but the positive results observed at the post-treatment assessment were not maintained at follow-up. CONCLUSIONS: The results suggest that some factors, such as self-efficacy or catastrophizing, could be enhanced by iCBT. Specific characteristics of iCBT may potentiate the social support needed to improve treatment adherence. PMID- 26228409 TI - Early identification of treatment non-response utilizing the Patient Health Questionnaire (PHQ-9). AB - BACKGROUND: Treatment non-response among high-risk, psychiatric patients exposes those suffering to suicidal risk as well as persistent social and occupational difficulties. Strategies for identification of treatment non-response are limited. AIMS: Diagnostic efficiency of a self-report, cross-cutting symptom measure was assessed as a marker of treatment non-response. METHOD: 835 inpatients at a specialist psychiatric hospital completed the Patient Health Questionnaire - Depression (PHQ-9) at admission and every two weeks during hospitalization. RESULTS: For patients admitted with severe depression (PHQ-9 >= 20), results indicated good accuracy of 2-week PHQ-9 change score in identifying treatment non-response (AUC = 0.80, SE = 0.04, p < .0001; sensitivity = 85%; specificity = 73%; OR = 14.91). CONCLUSIONS: The search for predictors of non response to psychiatric treatment has a long and generally unfulfilled history. The PHQ-9 change score holds promise as a cost-effective test with comparable diagnostic characteristics to other medical tests. PMID- 26228407 TI - Development of a clinician-administered National Institutes of Health-Brief Fatigue Inventory: A measure of fatigue in the context of depressive disorders. AB - OBJECTIVE: Fatigue is a complex, multidimensional condition. Although it is often associated with depression, it is not known whether it has a distinct network from depression or whether it can be clinically evaluated, separately. This study describes preliminary findings in the development of a brief, clinician administered instrument to measure fatigue in the context of depressive disorders using items from existing clinician-administered depression and mania scales. METHODS: Based on items from prior fatigue measurements, items were selected from the Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale, and Structured Interview Guide for HDRS with Atypical Depression. The final items composed the NIH-Brief Fatigue Inventory (NIH-BFI). Responses from 89 depressed adults collected pre- and post antidepressant therapy (ADT) determined the reliability and consistency of the NIH-BFI using Cronbach's alpha and principal components analysis (PCA). Correlations of the NIH-BFI and fatigue items from other scales before and after ADT explored validity. RESULTS: The 7-item NIH-BFI had Cronbach alphas ranging from 0.81 to 0.88 and PCA indicating a single dimension. The NIH-BFI score was strongly correlated (r = 0.73, p < 0.001) with fatigue items from Beck Depression Index, with MADRS without fatigue items (r = 0.77, p < 0.001), and HDRS without fatigue items (pre: r = 0.69, p < 0.001). CONCLUSIONS: Preliminary findings show support for internal consistency reliability and validity of the NIH-BFI, a clinician-administered measure of fatigue. Further testing in other clinical populations is recommended to obtain additional information on reliability and validity. The NIH-BFI provides a method for clinician-rated fatigue that may be a separate from depression. PMID- 26228410 TI - Suicide risk in Iraq and Afghanistan veterans with mental health problems in VA care. AB - Suicide rates among U.S. military personnel and veterans are a public health concern, and those with mental health conditions are at particular risk. We examined demographic, military, temporal, and diagnostic associations with suicidality in veterans. We conducted a population-based, retrospective cohort study of all Iraq and Afghanistan war veterans who screened positive for posttraumatic stress disorder (PTSD) and/or depression, received a suicide risk assessment, and endorsed hopelessness about the present or future after their last deployment and between January 1, 2010 and June 29, 2014 (N = 45,741). We used bivariate and multivariate logistic regression analyses to examine variables associated with having endorsed suicidal thoughts and a plan. Multiple factors were associated with suicidality outcomes, including longer time from last deployment to screening (proxy for time to seeking VA care), an alcohol use disorder diagnosis, further distance from VA (rurality), and being active duty during military service. Hispanic veterans were at decreased risk of having suicidal ideation and a plan, compared to their white counterparts. In high-risk veterans, some of the strongest associations with suicidality were with modifiable risk factors, including time to VA care and alcohol use disorder diagnoses. Promising avenues for suicide prevention efforts can include early engagement/intervention strategies with a focus on amelioration of high-risk drinking. PMID- 26228412 TI - Initial test of an emotional avoidance model of restriction in anorexia nervosa using ecological momentary assessment. AB - It has been hypothesized that restrictive eating allows individuals with anorexia nervosa (AN) to avoid contact with negative emotions; however, this presumption has not been directly tested. In this study, we conducted an initial investigation examining whether restrictive eating serves an emotional avoidance function among individuals with AN. Females with AN (n = 118) reported on negative and positive affect, anxiety/tension, and eating behaviors at multiple time points daily over a 2-week period using ecological momentary assessment methodology. Affective patterns were compared using generalized estimating equation models between days in which participants reported either: (1) relatively high restriction (without binge eating); (2) relatively low restriction (without binge eating); (3) binge eating; or (4) no restriction or binge eating. We hypothesized that, if restriction were functioning to avoid negative affect, average negative affect and anxiety/tension, as well as average negative and positive affect lability, would be lower and average positive affect would be higher on days characterized by high levels of restriction compared to other eating patterns. Contrary to hypotheses: (1) average negative affect, anxiety/tension, and positive affect were not significantly different between days characterized by high restriction and those characterized by low or no restriction; (2) Negative affect and anxiety/tension lability were higher on days characterized by high restriction compared to no restriction or binge eating days; (3) Anxiety/tension lability was higher on days characterized by high versus low levels of restriction. This patterns of findings does not support an avoidance model of restrictive eating for individuals with AN. PMID- 26228411 TI - Examining gene-environment interactions in comorbid depressive and disruptive behavior disorders using a Bayesian approach. AB - OBJECTIVE: The objective of this study was to apply a Bayesian statistical analytic approach that minimizes multiple testing problems to explore the combined effects of chronic low familial support and variants in 12 candidate genes on risk for a common and debilitating childhood mental health condition. METHOD: Bayesian mixture modeling was used to examine gene by environment interactions among genetic variants and environmental factors (family support) associated in previous studies with the occurrence of comorbid depression and disruptive behavior disorders youth, using a sample of 255 children. RESULTS: One main effect, variants in the oxytocin receptor (OXTR, rs53576) was associated with increased risk for comorbid disorders. Two significant gene * environment and one signification gene * gene interactions emerged. Variants in the nicotinic acetylcholine receptor alpha5 subunit (CHRNA5, rs16969968) and in the glucocorticoid receptor chaperone protein FK506 binding protein 5 (FKBP5, rs4713902) interacted with chronic low family support in association with child mental health status. One gene * gene interaction, 5-HTTLPR variant of the serotonin transporter (SERT/SLC6A4) in combination with MU opioid receptor (OPRM1, rs1799971) was associated with comorbid depression and conduct problems. CONCLUSIONS: Results indicate that Bayesian modeling is a feasible strategy for conducting behavioral genetics research. This approach, combined with an optimized genetic selection strategy (Vrieze et al., 2012), revealed genetic variants involved in stress regulation (FKBP5, SERT * OPMR), social bonding (OXTR), and nicotine responsivity (CHRNA5) in predicting comorbid status. PMID- 26228414 TI - Antidepressant dose and treatment response in bipolar depression: Reanalysis of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) data. AB - The aim of this study is to evaluate whether an adjunct antidepressant therapy at a higher dose to a mood stabilizer would make a difference in the treatment of bipolar depression. This is a post-hoc analysis of the data from the randomized treatment for acute depression of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), in which patients with bipolar depression were randomly assigned to treatment with a mood stabilizer plus adjunctive antidepressant drugs or placebo. According to the highest dose received in the course of treatment, the subjects were divided into one of the following three groups: high-dose, low-dose and placebo groups. The primary and secondary outcomes were durable recovery (which was operationally defined as eight consecutive weeks with 0.7) and had small changes in stable patients (d < 0.2). The good metric properties of the Spanish PROMIS Depression measures provide further evidence of their adequacy for monitoring depression levels of patients in clinical settings. This double check of quality (within countries and populations) supports the ability of PROMIS measures for guaranteeing fair comparisons across languages and countries in specific clinical populations. PMID- 26228415 TI - Phosphorus magnetic resonance spectroscopy studies in schizophrenia. AB - Phosphorus magnetic resonance spectroscopy ((31)P MRS) allows in vivo quantification of phosphorus metabolites that are considered to be related to membrane turnover and energy metabolism. In schizophrenia (SZ), (31)P MRS studies found several abnormalities in different brain regions suggesting that alterations in these pathways may be contributing to the pathophysiology. In this paper, we systematically reviewed the (31)P MRS studies in SZ published to date by taking patient characteristics, medication status and brain regions into account. Publications written in English were searched on http://www.ncbi.nlm.nih.gov/pubmed/, by using the keywords 'phosphomonoester', 'phosphodiester', 'ATP', 'phosphocreatine', 'phosphocholine', 'phosphoethanolamine','glycerophosphocholine', 'glycerophosphoethanolamine', 'pH', 'schizophrenia', and 'MRS'. Studies that measured (31)P metabolites in SZ patients were included. This search identified 52 studies. Reduced PME and elevated PDE reported in earlier studies were not replicated in several subsequent studies. One relatively consistent pattern was a decrease in PDE in chronic patients in the subcortical structures. There were no consistent patterns for the comparison of energy related phosphorus metabolites between patients and controls. Also, no consistent pattern emerged in studies seeking relationship between (31)P metabolites and antipsychotic use and other clinical variables. Despite emerging patterns, methodological heterogeneities and shortcomings in this literature likely obscure consistent patterns among studies. We conclude with recommendations to improve study designs and (31)P MRS methods in future studies. We also stress the significance of probing into the dynamic changes in energy metabolism, as this approach reveals abnormalities that are not visible to steady-state measurements. PMID- 26228416 TI - The Danieli Inventory of Multigenerational Legacies of Trauma, Part I: Survivors' posttrauma adaptational styles in their children's eyes. AB - A comprehensive valid behavioral measure for assessing multidimensional multigenerational impacts of massive trauma has been missing thus far. We describe the development of the Posttrauma Adaptational Styles questionnaire (Part I of the three-part Danieli Inventory of Multigenerational Legacies of Trauma), a self-report questionnaire of Holocaust survivors' children's perceptions of each parent and their own upbringing (60 items per parent). The items were based on literature and cognitive interviewing of 18 survivors' offspring. A web-based convenience sample survey was designed in English and Hebrew and completed by 482 adult children (M age = 59; 67% women) of Holocaust survivors. Exploratory factor analyses were conducted by using maximum likelihood extraction with Geomin rotation to examine the factor structure of the original 70 items for each parent. Conducted hierarchically, the analysis yielded three higher-order factors reflecting intensities of victim, numb, and fighter styles. The 30-item Victim Style Scale (alpha = .92-.93) and 18-item Numb Style Scale (alpha = .89) had excellent internal consistency; the consistency of the 12-item Fighter Style Scale (alpha = .69-.70) was more modest. English-Hebrew analyses suggested good-to-excellent congruence in factor structure (phi = .87-.99). Further research is needed to evaluate the validity of the measure in other samples and populations. PMID- 26228417 TI - Different stress-related gene expression in depression and suicide. AB - OBJECTIVE: Suicide occurs in some, but not all depressed patients. So far, it remains unknown whether the studied stress-related candidate genes change in depression, suicide or both. The prefrontal cortex (PFC) is involved in, among other things, impulse control and inhibitory behavior and plays an important role in both suicide and depression. METHODS: We have employed qPCR to study 124 anterior cingulate cortex (ACC) and dorsolateral PFC (DLPFC) brain samples, obtained from two brain banks, from: i) young depressed patients (average age 43 years) who committed suicide (MDD-S) and depressed patients who died from causes other than suicide (MDD-NS) and from ii) elderly depressed patients (average age 75 years) who did not commit suicide (DEP). Both cohorts were individually matched with non-psychiatric non-suicide control subjects. We determined the transcript levels of hypothalamic-pituitary-adrenal axis-regulating molecules (corticotropin-releasing hormone (CRH), CRH receptors, CRH binding protein, mineralocorticoid receptor/glucocorticoid receptor), transcription factors that regulate CRH expression, CRH-stimulating cytokines, chaperone proteins, retinoid signaling, brain-derived neurotrophic factor and tropomyosin-related kinase B, cytochrome proteins, nitric oxide synthase (NOS) and monoamines. RESULTS: In the MDD-S group, expression levels of CRH and neuronal NOS-interacting DHHC domain containing protein with dendritic mRNA (NIDD) were increased. Other changes were only present in the DEP group, i.e. decreased NIDD, and increased and 5 hydroxytryptamine receptor 1A (5-HT1A) expression levels. Changes were found to be more pronounced in the anterior cingulate cortex than in the dorsolateral PFC. CONCLUSION: Depressed patients who committed suicide have different gene expression patterns than depressed patients who died of causes other than suicide. PMID- 26228418 TI - Risk of depressive disorders in women undergoing hysterectomy: A population-based follow-up study. AB - OBJECTIVE: The objective of this study was to assess the risk of depressive disorders in women who underwent hysterectomy in Taiwan. METHODS: A retrospective study was conducted in a matched cohort of cases using the National Health Insurance Research Database of Taiwan. Database records from 1689 women who underwent hysterectomy between 2001 and 2005 were included in this study. A control group matched for age and physical comorbidity was selected from the same database (n = 6752). For all cases, medical records were tracked until the end of 2009 to identify whether a depressive disorder was diagnosed during the follow-up period. The hazard ratio (HR) for depression during the observation period was analyzed using multivariable Cox proportional-hazards models, adjusted for age, physical comorbidities, and other socioeconomic factors. RESULTS: The HR for depression was 1.78 times higher for the group that underwent hysterectomy than for the control group (adjusted HR = 1.78; 95% CI = 1.46-2.18, p < 0.001). In addition, HR for major depressive disorder in women who underwent hysterectomy was significantly higher (1.84 times) than for the control group (adjusted HR = 1.84; 95% CI = 1.23-2.74, p < 0.01). CONCLUSIONS: Our study revealed that, in Taiwan, women who underwent hysterectomy had an increased risk of developing depression. Longitudinal studies to follow-up the psychological outcomes in Taiwanese women who underwent hysterectomy will be necessary to confirm our findings. PMID- 26228419 TI - First-degree relatives of suicide completers may have impaired decision-making but functional cognitive control. AB - BACKGROUND: The heritability of suicide is well established. Transmission of risk appears to follow traits more than disorders like depression. In the present project, we aimed at investigating the potential for transmission of cognitive deficits previously observed in suicide attempters, specifically impaired decision-making and cognitive control. METHODS: Seventeen healthy first-degree relatives of suicide completers with no personal history of suicidal act were compared to 18 first-degree relatives of individuals with major depressive disorder but no family history of suicidal act, and 19 healthy controls. Decision making was assessed with the Iowa Gambling Task, and cognitive control with the Stroop Task, the Hayling Sentence Completion Test, and the Trail-Making Test. RESULTS: Both suicide and depressed relatives showed lower gambling task net scores than healthy controls. However, there were trends toward lower learning abilities in suicide than depressed relatives (interaction: p = 0.07), with more risky choices at the end of the test. Suicide relatives also showed a higher number of self-corrected errors relative to the total number of errors in the Stroop colour test compared to both control groups, with no difference in interference scores. There was no group-difference for any other cognitive tests. CONCLUSION: Our findings suggest that decision-making impairment may be found in healthy relatives of suicides and represent a cognitive endophenotype of suicidal behaviour. Normal cognitive control (or self-corrected deficits) may protect relatives against suicidal acts. Impairments in value-based and control processes may, therefore, be part of the suicide vulnerability and represent potential targets of preventative interventions. PMID- 26228420 TI - Intramuscular olanzapine for agitated patients: A systematic review and meta analysis of randomized controlled trials. AB - We performed an updated systematic review and meta-analysis of randomized controlled trials (RCTs) of intramuscular (IM)-olanzapine (OLA-IM) versus controls in agitated patients. The risk ratio, number-needed-to-treat/harm, and standardized mean difference based on a random effects model were calculated. We identified 13 RCTs (19 comparisons) as follows: 7 comparisons with 1059 patients for OLA-IM versus placebo; 5 comparisons with 613 patients for OLA-IM versus haloperidol (HAL)-IM; 2 comparisons with 108 patients for OLA-IM versus ziprasidone (ZIP)-IM; 2 comparisons with 110 patients for OLA-IM versus HAL-IM plus midazolam; and 3 comparisons with 412 patients for OLA-IM versus HAL-IM plus promethazine, 2 comparisons with 355 patients for OLA-IM versus lorazepam-IM (LOR IM); and 1 comparison with 67 patients for OLA-IM versus HAL-IM plus LOR-IM. OLA IM was superior to placebo in both Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) and Agitation-Calmness Evaluation Scale (ACES) scores 2 h after first injection, and had a comparable side effect profile, including over sedation, extrapyramidal symptoms, akathisia, and anticholinergic use. While there was no significant difference in PANSS-EC scores after 2 h between OLA-IM and HAL-IM, OLA-IM outperformed HAL-IM in ACES after 2 h. Compared with HAL-IM, OLA-IM was associated with fewer side effects, including anticholinergic use, akathisia, extrapyramidal symptoms, and dystonia, and marginally less QT prolongation compared with HAL-IM. Based on our findings, OLA-IM is preferable to HAL-IM for the treatment of agitated patients. However, comparator data for ZIP IM, LOR-IM and HAL-IM combination therapy were insufficient. PMID- 26228421 TI - Oxidative stress in drug naive first episode psychosis and antioxidant effects of risperidone. AB - BACKGROUND: Schizophrenia is accompanied by increased lipid peroxidation and nitric oxide (NO) levels and by lowered antioxidant levels. However, the effect of antipsychotic agents on these processes remains unclear. The objective of this study is to determine the oxidative stress (OS) status in drug naive first episode psychotic patients (FEP) compared to healthy controls and to delineate the effects of risperidone on these biomarkers. METHODS: 51 drug naive FEP patients and 61 healthy controls were enrolled; FEP patients were reassessed 11 weeks after risperidone treatment. Three OS biomarkers, i.e. lipid hydroperoxides - LOOH, NO metabolites - NOx, and advanced oxidation protein products - AOPP, and two antioxidant biomarkers, i.e. total radical-trapping antioxidant parameter - TRAP, and paraoxonase 1 - PON1, were measured. The Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS) were used to measure symptoms severity. RESULTS: Significantly lower PON1 activity and increased TRAP values were found in FEP patients. There were no significant associations between any of the OS/antioxidant biomarkers and clinical data. Risperidone treatment significantly increased PON1 activity and decreased LOOH levels. These effects of risperidone were not significantly associated with the clinical response and risperidone dosage. DISCUSSION: Changes in antioxidant profile, but not in lipid or protein oxidation or increased NO production, were found in drug-naive FEP. Risperidone may have antioxidant effects by lowering lipid peroxidation and increasing the antioxidant defenses against lipid peroxidation related to PON1. None of the biomarkers predicted treatment outcome. PMID- 26228423 TI - Ketamine vs other anesthetic agents for electroconvulsive therapy (ECT) in major depression. PMID- 26228422 TI - Elucidating X chromosome influences on Attention Deficit Hyperactivity Disorder and executive function. AB - OBJECTIVE: To identify distinct behavioral and cognitive profiles associated with ADHD in Turner syndrome (TS), relative to idiopathic ADHD and neurotypical controls, in order to elucidate X-linked influences contributing to ADHD. METHODS: We used a multilevel-model approach to compare 49 girls with TS to 37 neurotypical females, aged 5-12, on established measures of behavior (BASC-2) and neurocognitive function (NEPSY). We further compared girls with TS to BASC-2 and NEPSY age-matched reference data obtained from children with idiopathic ADHD. RESULTS: Within the TS group, 51% scored at or above the "at-risk" range for ADHD associated behaviors on the BASC-2 (TS/+ADHD). The BASC-2 behavioral profile in this TS/+ADHD-subgroup was comparable to a reference group of boys with ADHD with respect to attentional problems and hyperactivity. However, the TS/+ADHD-subgroup had significantly higher hyperactivity scores relative to a reference sample of girls with ADHD (p = 0.016). The behavioral profile in TS was associated with significantly lower attention and executive function scores on the NEPSY relative to neurotypical controls (p = 0.015); but was comparable to scores from a reference sample of children with idiopathic ADHD. Deficits in attention and executive function were not observed in girls with TS having low levels of ADHD associated behavior (TS/-ADHD). CONCLUSIONS: ADHD-associated behavioral and cognitive problems in TS are prevalent and comparable in severity to those found in children with idiopathic ADHD. The ADHD phenotype in TS also appears relatively independent of cognitive features typically associated with TS, like visuospatial weaknesses. These findings suggest that X-linked haploinsufficiency and downstream biological effects contribute to increased risk for ADHD. PMID- 26228424 TI - Brain volume reduction predicts weight development in adolescent patients with anorexia nervosa. AB - BACKGROUND: Acute anorexia nervosa (AN) is associated with marked brain volume loss potentially leading to neuropsychological deficits. However, the mechanisms leading to this brain volume loss and its influencing factors are poorly understood and the clinical relevance of these brain alterations for the outcome of these AN-patients is yet unknown. METHODS: Brain volumes of 56 female adolescent AN inpatients and 50 healthy controls (HCs) were measured using MRI scans. Multiple linear regression analyses were used to determine the impact of body weight at admission, prior weight loss, age of onset and illness duration on volume loss at admission and to analyse the association of brain volume reduction with body weight at a 1-year follow-up (N = 25). RESULTS: Cortical and subcortical grey matter (GM) and cortical white matter (WM) but not cerebellar GM or WM were associated with low weight at admission. Amount of weight loss, age of onset and illness duration did not independently correlate with any volume changes. Prediction of age-adjusted standardized body mass index (BMI-SDS) at 1 year follow-up could be significantly improved from 34% of variance explained by age and BMI-SDS at admission to 47.5-53% after adding cortical WM, cerebellar GM or WM at time of admission. CONCLUSION: Whereas cortical GM changes appear to be an unspecific reflection of current body weight ("state marker"), cortical WM and cerebellar volume losses seem to indicate a longer-term risk (trait or "scar" of the illness), which appear to be important for the prediction of weight rehabilitation and long-term outcome. PMID- 26228425 TI - Repetitive Transcranial Magnetic Stimulation (rTMS) improves symptoms and reduces clinical illness in patients suffering from OCD--Results from a single-blind, randomized clinical trial with sham cross-over condition. AB - OBJECTIVES: Both psychotherapeutic and psychopharmacological methods are used in the treatment of patients suffering from obsessive-compulsive disorders (OCD), and both with encouraging but also mixed results. Here, we tested the hypothesis that repetitive Transcranial Magnetic Stimulation (rTMS) improves symptoms and reduces illness severity in patients suffering from treatment-resistant OCD. METHODS: A total of 21 patients (57% females; mean age: M = 35.8 years) suffering from treatment-resistant OCD were randomly assigned either to an rTMS-first-sham second, or a sham-first-rTMS-second condition. Treatment sessions lasted for 4 weeks with five sessions per week, each of about 50 min duration. Symptoms were assessed via both self- and expert-ratings. RESULTS: Both self- and expert reported symptom severity reduced in the rTMS condition as compared to the sham condition. Full- and partial responses were observed in the rTMS-condition, but not in the sham-condition. CONCLUSIONS: The pattern of results from this single blind, sham- and cross-over design suggests that rTMS is a successful intervention for patients suffering from treatment-resistant OCD. PMID- 26228426 TI - The (in)consistency of changes in brain macrostructure in male paedophiles: A combined T1-weighted and diffusion tensor imaging study. AB - Thus far, four studies have used magnetic resonance imaging (MRI) to test for differences in brain structure between paedophilic (i.e. sexually attracted to pre-pubescent children) and teleiophilic (i.e. sexually attracted to adults) men, revealing divergent results. To re-examine this issue, we acquired high resolution structural T1-weighted and diffusion MRI scans of the brain in 24 paedophilic and 32 teleiophilic men. We performed voxel-based morphometry (VBM) of the T1-weighted images and tract-based spatial statistics (TBSS) of the diffusion tensor imaging data to search for grey and white matter differences between groups. In contrast to previous studies, less than half of the individuals in our paedophilic group had a record of sexual offences against children, as subjects were partially recruited from two outpatient facilities of a child sexual abuse prevention project for self-acknowledged paedophiles. After adjustment for multiple comparisons and controlling for important confounding factors, we did not find any significant grey or white matter differences between the paedophilic and teleiophilic subjects. Together with the inconsistencies in the literature, these results argue against consistent structural differences at the macroanatomical scale between paedophiles and teleiophiles. PMID- 26228427 TI - Social cognition, social competence, negative symptoms and social outcomes: Inter relationships in people with schizophrenia. AB - Social deficits are common in people with schizophrenia and the treatment of deficits in social competence has been a long-time treatment strategy. However, negative symptoms and social cognitive deficits also contribute to social dysfunction. In this study, we examined the correlations between everyday social outcomes, a performance based measure of social competence, and performance on 8 different social cognition tests in 179 patients with schizophrenia. Social cognition, social competence, and motivation-related negative symptoms accounted for 32% of the variance in real-world social outcomes. In addition, two different social cognition tests, along with expression-related negative symptoms accounted for 32% of the variance in performance-based assessments of social competence. These data suggest that negative symptoms exert an important influence on social outcomes and social competence, but not social cognition, and that social cognition and social competence exert separable influences on real-world social outcomes. Improving social outcomes seems to require a multi-faceted approach which considers social cognition, social competence, and negative symptoms. PMID- 26228428 TI - The amino acid transporter SLC6A15 is a regulator of hippocampal neurochemistry and behavior. AB - Although mental disorders as major depression are highly prevalent worldwide their underlying causes remain elusive. Despite the high heritability of depression and a clear genetic contribution to the disease, the identification of genetic risk factors for depression has been very difficult. The first published candidate to reach genome-wide significance in depression was SLC6A15, a neuronal amino acid transporter. With a reported 1,42 fold increased risk of suffering from depression associated with a single nucleotide polymorphism (SNP) in a regulatory region of SLC6A15, the polymorphism was also found to affect hippocampal morphology, integrity, and hippocampus-dependent memory. However, the function of SLC6A15 in the brain is so far largely unknown. To address this question, we investigated if alterations in SLC6A15 expression, either using a full knockout or a targeted hippocampal overexpression, affect hippocampal neurochemistry and consequently behavior. We could show that a lack of SLC6A15 reduced hippocampal tissue levels of proline and other neutral amino acids. In parallel, we observed a decreased overall availability of tissue glutamate and glutamine, while at the same time the basal tone of extracellular glutamate in the hippocampus was increased. By contrast, SLC6A15 overexpression increased glutamate/glutamine tissue concentrations. These neurochemical alterations could be linked to behavioral abnormalities in sensorimotor gating, a key translational endophenotype relevant for many psychiatric disorders. Overall, our data supports SLC6A15 as a crucial factor controlling amino acid content in the hippocampus, thereby likely interfering with glutamatergic transmission and behavior. These findings emphasize SLC6A15 as pivotal risk factor for vulnerability to psychiatric diseases. PMID- 26228429 TI - A systematic review of randomised control trials on the effects of yoga on stress measures and mood. AB - Stress related disorders such as depression and anxiety are leading sources of disability worldwide, and current treatment methods such as conventional antidepressant medications are not beneficial for all individuals. There is evidence that yoga has mood-enhancing properties possibly related to its inhibitory effects on physiological stress and inflammation, which are frequently associated with affective disorders. However the biological mechanisms via which yoga exerts its therapeutic mood-modulating effects are largely unknown. This systematic review investigates the effects of yoga on sympathetic nervous system and hypothalamic pituitary adrenal axis regulation measures. It focuses on studies collecting physiological parameters such as blood pressure, heart rate, cortisol, peripheral cytokine expression and/or structural and functional brain measures in regions involved in stress and mood regulation. Overall the 25 randomised control studies discussed provide preliminary evidence to suggest that yoga practice leads to better regulation of the sympathetic nervous system and hypothalamic-pituitary-adrenal system, as well as a decrease in depressive and anxious symptoms in a range of populations. Further research is warranted to confirm these preliminary findings and facilitate implementation in clinical settings. PMID- 26228430 TI - Social Anxiety and Friendship Quality over Time. AB - High social anxiety in adults is associated with self-report of impaired friendship quality, but not necessarily with impairment reported by friends. Further, prospective prediction of social anxiety and friendship quality over time has not been tested among adults. We therefore examined friendship quality and social anxiety prospectively in 126 young adults (67 primary participants and 59 friends, aged 17-22 years); the primary participants were screened to be extreme groups to increase power and relevance to clinical samples (i.e., they were recruited based on having very high or very low social interaction anxiety). The prospective relationships between friendship quality and social anxiety were then tested using an Actor-Partner Interdependence Model. Friendship quality prospectively predicted social anxiety over time within each individual in the friendship, such that higher friendship quality at Time 1 predicted lower social anxiety approximately 6 months later at Time 2. Social anxiety did not predict friendship quality. Although the results support the view that social anxiety and friendship quality have an important causal relationship, the results run counter to the assumption that high social anxiety causes poor friendship quality. Interventions to increase friendship quality merit further consideration. PMID- 26228431 TI - The National NeuroAIDS Tissue Consortium (NNTC) Database: an integrated database for HIV-related studies. AB - We herein present the National NeuroAIDS Tissue Consortium-Data Coordinating Center (NNTC-DCC) database, which is the only available database for neuroAIDS studies that contains data in an integrated, standardized form. This database has been created in conjunction with the NNTC, which provides human tissue and biofluid samples to individual researchers to conduct studies focused on neuroAIDS. The database contains experimental datasets from 1206 subjects for the following categories (which are further broken down into subcategories): gene expression, genotype, proteins, endo-exo-chemicals, morphometrics and other (miscellaneous) data. The database also contains a wide variety of downloadable data and metadata for 95 HIV-related studies covering 170 assays from 61 principal investigators. The data represent 76 tissue types, 25 measurement types, and 38 technology types, and reaches a total of 33,017,407 data points. We used the ISA platform to create the database and develop a searchable web interface for querying the data. A gene search tool is also available, which searches for NCBI GEO datasets associated with selected genes. The database is manually curated with many user-friendly features, and is cross-linked to the NCBI, HUGO and PubMed databases. A free registration is required for qualified users to access the database. PMID- 26228432 TI - OCDB: a database collecting genes, miRNAs and drugs for obsessive-compulsive disorder. AB - Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive and unwilling thoughts (obsessions) giving rise to anxiety. The patients feel obliged to perform a behavior (compulsions) induced by the obsessions. The World Health Organization ranks OCD as one of the 10 most disabling medical conditions. In the class of Anxiety Disorders, OCD is a pathology that shows an hereditary component. Consequently, an online resource collecting and integrating scientific discoveries and genetic evidence about OCD would be helpful to improve the current knowledge on this disorder. We have developed a manually curated database, OCD Database (OCDB), collecting the relations between candidate genes in OCD, microRNAs (miRNAs) involved in the pathophysiology of OCD and drugs used in its treatments. We have screened articles from PubMed and MEDLINE. For each gene, the bibliographic references with a brief description of the gene and the experimental conditions are shown. The database also lists the polymorphisms within genes and its chromosomal regions. OCDB data is enriched with both validated and predicted miRNA-target and drug-target information. The transcription factors regulations, which are also included, are taken from David and TransmiR. Moreover, a scoring function ranks the relevance of data in the OCDB context. The database is also integrated with the main online resources (PubMed, Entrez-gene, HGNC, dbSNP, DrugBank, miRBase, PubChem, Kegg, Disease-ontology and ChEBI). The web interface has been developed using phpMyAdmin and Bootstrap software. This allows (i) to browse data by category and (ii) to navigate in the database by searching genes, miRNAs, drugs, SNPs, regions, drug targets and articles. The data can be exported in textual format as well as the whole database in.sql or tabular format. OCDB is an essential resource to support genome-wide analysis, genetic and pharmacological studies. It also facilitates the evaluation of genetic data in OCD and the detection of alternative treatments. PMID- 26228433 TI - Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial) - a randomized, multidisciplinary, multinational phase III trial. AB - BACKGROUND: Despite complete resection, disease-free survival (DFS) of patients with cholangiocarcinoma (CCA) is less than 65 % after one year and not more than 35 % after three years. For muscle invasive gallbladder carcinoma (GBCA), prognosis is even worse, with an overall survival (OS) of only 30 % after three years. Thus, evaluation of adjuvant chemotherapy in biliary tract cancer in a large randomized trial is warranted. METHODS/DESIGN: ACTICCA-1 is a randomized, multidisciplinary, multinational phase III investigator initiated trial. With respect to data obtained in the ABC-02 trial, we selected the combination of gemcitabine and cisplatin for 24 weeks as investigational treatment. Based on adjuvant trials in pancreatic cancer with comparable postoperative recovery time, inclusion of patients within a maximum interval of 16 weeks between surgery and start of chemotherapy was stipulated. Due to the different prognosis and treatment susceptibility of muscle invasive carcinoma, two separate cohorts (CCA and GBCA) were included to capture the potentially different treatment effects. Randomization is stratified for lymph node status for both cohorts and localization for CCA. The primary endpoint is DFS and secondary endpoints include OS, safety and tolerability of chemotherapy, quality of life, and patterns of disease recurrence. For CCA, adjuvant chemotherapy should increase DFS 24 months post-surgery from 40 to 55 % to be considered relevant. With a power of 80 % and a significance level of 5 %, 271 evaluable study patients have to be followed for 24-28 months to observe 166 events. For GBCA, chemotherapy should increase DFS 24 months post-surgery from 35 to 55 % to be of relevance; thus, 154 evaluable study patients have to be monitored for 24-28 months to observe 90 events. In both cohorts, randomization will be 1:1 with chemotherapy for 24 weeks and imaging every twelve weeks. In 2014, the study was initiated in Germany and in The Netherlands (funded by the Deutsche Krebshilfe, the Dutch Cancer Society, and supported by medac GmbH). Sites in Australia, Denmark, and the United Kingdom (funded by Cancer Research UK) are joining 2015. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov ( NCT02170090 ) and the European Clinical Trials Database (2012-005078-70). Registration date is 06/18/2014. PMID- 26228434 TI - Pediatric endoscopic ear surgery in clinical practice: Lessons learned and early outcomes. AB - OBJECTIVES/HYPOTHESIS: Only a few reports describe the outcomes following endoscopic ear surgery (EES) in children for chronic ear disease. We differentiate between transcanal endoscopic ear surgery (TEES), where the case is performed with only endoscopic visualization, from non-TEES, where the endoscope is not used at all or used as an adjunct to the microscope. We hypothesize that EES is an effective approach to manage middle ear pathology using a transcanal approach in most cases, and can be incorporated into a pediatric otology practice with a neutral or positive effect on outcomes. Lessons learned during this process are analyzed and discussed. STUDY DESIGN: Single-institution, retrospective chart review of outcomes following TEES and non-TEES in children from January 1, 2013 through July 1, 2014. METHODS: Procedures included tympanoplasty, ossiculoplasty, and cholesteatoma resection. Primary outcome measures included closure rate of tympanic membrane perforations, audiometric outcomes, and complications. Surgical times were reported as secondary measures. RESULTS: Ninety-four patients underwent 121 middle ear procedures. TEES was performed in 51/121 of cases (42.1%). Comparison of TEES versus non-TEES cases showed no significant difference in rate of tympanoplasty closure (P > .99). The mean pure-tone improvement following TEES tympanoplasty was -7.8 dB versus -1.33 dB for non-TEES cases (P = .03). Surgical times were similar between groups. CONCLUSIONS: EES techniques were readily incorporated into a pediatric otology practice. A standardized EES classification system is useful for analyzing utilization patterns and results across institutions. Tympanic membrane closure rates and hearing outcomes were similar in TEES and non-TEES cases. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:732-738, 2016. PMID- 26228435 TI - The relationship between nociceptive brain activity, spinal reflex withdrawal and behaviour in newborn infants. AB - Measuring infant pain is complicated by their inability to describe the experience. While nociceptive brain activity, reflex withdrawal and facial grimacing have been characterised, the relationship between these activity patterns has not been examined. As cortical and spinally mediated activity is developmentally regulated, it cannot be assumed that they are predictive of one another in the immature nervous system. Here, using a new experimental paradigm, we characterise the nociceptive-specific brain activity, spinal reflex withdrawal and behavioural activity following graded intensity noxious stimulation and clinical heel lancing in 30 term infants. We show that nociceptive-specific brain activity and nociceptive reflex withdrawal are graded with stimulus intensity (p < 0.001), significantly correlated (r = 0.53, p = 0.001) and elicited at an intensity that does not evoke changes in clinical pain scores (p = 0.55). The strong correlation between reflex withdrawal and nociceptive brain activity suggests that movement of the limb away from a noxious stimulus is a sensitive indication of nociceptive brain activity in term infants. This could underpin the development of new clinical pain assessment measures. PMID- 26228436 TI - A new chromosome was born: comparative chromosome painting in Boechera. AB - Comparative chromosome painting is a powerful tool to study the evolution of chromosomes and genomes. Analyzing karyotype evolution in cruciferous plants highlights the origin of aberrant chromosomes in apomictic Boechera and further establishes the cruciferous plants as important model system for our understanding of plant chromosome and genome evolution. PMID- 26228437 TI - Let's change deep tendon reflex to muscle stretch reflex. PMID- 26228438 TI - Successful treatment of secondary graft failure following unrelated cord blood transplant with hematopoietic growth factors in a pediatric patient with Fanconi anemia. AB - Graft failure following allogeneic HCT in Fanconi anemia is associated with significant mortality. Retransplantation may be considered; however, the limited toxicity profile of HGFs also makes them an option for the treatment of graft failure. We describe a five-yr-old female diagnosed with Fanconi anemia and marrow failure treated with HCT. The course was complicated by secondary graft failure treated successfully with HGFs including G-CSF, EPO, and romiplostim. The outcome could be related to the intervention, but could also be the natural course of recovery, including recovering from a recent CMV infection treated with ganciclovir. We found the use of HGFs to be an effective and safe alternative to the potential complications as well as morbidity and mortality associated with the use of retransplantation. PMID- 26228439 TI - Refractive correction and myopia progression. PMID- 26228440 TI - Properties of electrically evoked potentials activated by optic nerve stimulation with penetrating electrodes of different modes in rabbits. AB - PURPOSE: To investigate the effect of different stimulation modes on cortical electrically evoked potentials (EEPs) by intraorbital optic nerve (ON) stimulation with penetrating electrodes. METHODS: A stimulating electrode array with three electrodes arranged linearly was inserted into the ON along its axis. EEPs were recorded using a 4 * 4 silver-ball electrode array in response to monopolar and bipolar stimulation mode, respectively. RESULTS: The simultaneous monopolar stimulation mode had a lower threshold than the individual monopolar stimulation mode, but elicited smaller cortical response when a fixed charge was injected. The threshold of the bipolar stimulation mode was comparable to that of individual monopolar stimulation mode. The response to the smaller spacing (150 MUm) bipolar stimulation mode was similar in amplitude to that of the individual monopolar stimulation mode, but spread wider. The larger spacing (500 MUm) bipolar stimulation mode elicited stronger and wider response than the individual monopolar stimulation mode. For the individual monopolar stimulation mode, stimulation with different electrodes can be differentiated even when the spacing of the two electrodes was 150 MUm. CONCLUSIONS: For ON stimulation with penetrating electrodes, the monopolar stimulation mode could induce more localized cortical responses than the bipolar stimulation mode with comparable threshold and had a high stimulation selectivity. These findings may provide valuable information for the design of stimulation strategy of the penetrative ON visual prosthesis. PMID- 26228442 TI - Assessment of the antidiabetic and antilipidemic properties of Bacillus subtilis SPB1 biosurfactant in alloxan-induced diabetic rats. AB - The present study aimed to scrutinize the potential of Bacillus subtilis SPB1biosurfactant, orally administered, for preventing diabetic complications in rats. The findings revealed that, Bacillus subtilis biosurfactant was an effective reducer of alpha-amylase activity in the plasma. Moreover, this supplement helped protect the beta-cells from death and damage. Both the inhibitory action of SPB1 biosurfactant on alpha-amylase and the protection of the pancreas' beta-cells lead to a decrease of the blood glucose levels, consequently antihyperglycemic effect. Interestingly, this lipopeptide biosurfactant modulated key enzyme related to hyperlipidemia as lipase; which leads to the regulation of the lipid profile in serum by the delay in the absorption of LDL-cholesterol and triglycerides, and a significant increase in HDL-cholesterol. Histological analyses also showed that it exerted a protective action on the pancreases and efficiently preserved the liver-kidney functions of diabetic rats, evidenced by significant decreases in aspartate transaminase, alanine transaminase, gamma-glytamyl transpeptidase and lactate deshydrogenase activities in the plasma, as well as in the creatinine and urea contents. Overall, the present study demonstrated that the hypoglycemic and antilipidemic activities exhibited by Bacillus subtilis biosurfactant were effective enough to alleviate induced diabetes in experimental rats. Therefore, SPB1biosurfactant could be considered as a potential strong candidate for the treatment and prevention of diabetes. PMID- 26228441 TI - Dexamethasone intravitreal implant (Ozurdex(r)) for pediatric uveitis. AB - PURPOSE: The purpose of this study was to investigate the safety and effectiveness of an intravitreally injected dexamethasone-containing implant (Ozurdex((r))) in the treatment of uveitis in children. METHODS: The study group included ten patients (14 eyes) aged 6.5-15 years (mean age 12 years) with intermediate or posterior uveitis who were treated with the Ozurdex implant at two tertiary medical centers between 2009 and 2014, following an insufficient response to standard uveitis therapy. All were followed for at least 6 months (mean 12.2 +/- 4.9 months). Clinical data before and after treatment were collected retrospectively from the medical files. Outcome measures were best corrected visual acuity, vitreous haze, and macular thickness. Ocular complications were documented. RESULTS: Visual acuity improved in 12 eyes (86 %) and intraocular inflammation decreased in 13 eyes (93 %) from 1 week to 3 months after the first injection. Macular edema decreased in all eyes from 1 month to 3 months after the first injection. Five patients underwent repeated injections because of an increase in macular thickness at 3-6 month follow-up. Complications included cataract progression in one patient after one injection and cataract formation in two patients after two injections, and an elevation in intraocular pressure in two patients who responded well to topical treatment. CONCLUSIONS: Both single and repeated injections of a dexamethasone-containing implant are safe and effective for the treatment of noninfectious intermediate and posterior uveitis in children. The duration of the beneficial effect may be limited. More data are required to establish the safety profile of the implant in the pediatric age group. PMID- 26228444 TI - Comment on: Reduction of surgical site infections after laparoscopic gastric bypass with circular gastrojejunostomy. PMID- 26228445 TI - Comment on: Resident education in robotic-assisted vertical sleeve gastrectomy: outcomes and cost-analysis of 411 consecutive cases. PMID- 26228446 TI - Electrocardiogram changes and wall motion abnormalities in the acute phase of Tako-Tsubo syndrome. AB - BACKGROUND: The Tako-Tsubo syndrome is still rarely diagnosed in patients presenting with symptoms of acute myocardial ischaemia. It is accompanied by wall motion abnormalities of the left ventricle but significant narrowings or occlusions of epicardial coronary arteries are absent. We investigated a potential relationship between electrocardiogram (ECG) changes, wall motion abnormalities and gender influence of Tako-Tsubo syndrome in an Austrian cohort of Tako-Tsubo syndrome patients. METHODS AND RESULTS: We were recently able to describe four different anatomical types of Tako-Tsubo syndrome in 153 patients of the Austrian Tako-Tsubo syndrome registry. In the present retrospective analysis we investigated ischaemia-related changes in the first diagnostic ECG for the different types of Tako-Tsubo syndrome: the apical and the combined apical-midventricular type showed most frequently a ST elevation (41.1% and 35.3%), whereas the midventricular type of Tako-Tsubo syndrome was more often accompanied by T wave inversion (60%). ECG changes in relation to the Tako-Tsubo syndrome type were similar in women and men. There was no difference in the prevalence of clinical complications among patients presenting with ST elevation or left bundle branch block (14.5%) compared with patients without ST elevation (10.4%) (p=0.476). CONCLUSION: Patients with Tako-Tsubo syndrome show characteristic ECG changes in the first diagnostic ECG which are associated to some extent with the anatomical type of Tako-Tsubo syndrome, but these ECG changes were not related to clinical outcome. PMID- 26228447 TI - Tpeak-to-Tend/QT is an independent predictor of early ventricular arrhythmias and arrhythmic death in anterior ST elevation myocardial infarction patients. AB - BACKGROUND: The aim of our study was to analyse the markers of transmural dispersion of ventricular repolarization, especially Tpeak-to-Tend and Tpeak-to Tend /QT ratio, in patients with anterior ST elevation myocardial infarction on admission and to evaluate their association with in-hospital life-threatening arrhythmias and mortality. METHODS AND RESULTS: A total of 223 consecutive patients with anterior wall ST elevation myocardial infarction admitted to our Division of Cardiology between January 2010 and December 2012 were prospectively evaluated. A standard electrocardiogram was obtained on admission and then analysed. The primary end point was constituted by in-hospital ventricular arrhythmias and arrhythmic death. At univariate analysis heart rate (odds ratio = 1.03; 95% confidence intervals 1.006-1.05; p=0.001), maximal ST elevation (odds ratio =1.25; 95% confidence intervals 1.10-1.43; p=0.0001), QTc Bazett (odds ratio = 1.01; 95% confidence intervals 1.006-1.02; p=0.002), QT dispersion (odds ratio = 1.02; 95% confidence intervals 1.002-1.04; p=0.02) and both Tpeak-to-Tend and Tpeak-to-Tend/QT (odds ratio = 1.02; 95% confidence intervals 1.01-1.03; p<0.0001 and OR = 1.07; 95% confidence intervals 1.03-1.11; p<0.0001 respectively) were significantly associated with ventricular arrhythmias and arrhythmic mortality. Of note, Tpeak-to-Tend /QT remained a predictor of early ventricular arrhythmias and arrhythmic death (odds ratio = 1.04; 95% confidence intervals 1.003 - 1.10; p=0.03) independently from heart rate and maximal ST elevation. Receiver operating characteristic curve analysis showed that Tpeak-to Tend /QT values <0.31 had a predictive negative value of 92% for the prediction of the composite outcome. CONCLUSIONS: Tpeak-to-Tend /QT was an independent predictor of early ventricular arrhythmias and arrhythmic mortality in patients with anterior ST elevation myocardial infarction. Especially, Tpeak-to-Tend /QT <0.31 may identify a subgroup of ST elevation myocardial infarction patients with low risk of early arrhythmias and arrhythmic death. PMID- 26228448 TI - Impact of chronic kidney disease on long-term ischemic and bleeding outcomes in medically managed patients with acute coronary syndromes: Insights from the TRILOGY ACS Trial. AB - AIMS: We aimed to study the relationship of chronic kidney disease stages with long-term ischemic and bleeding outcomes in medically managed acute coronary syndrome patients and the influence of more potent antiplatelet therapies on platelet reactivity by chronic kidney disease stage. METHODS AND RESULTS: We estimated creatinine clearance for 8953 medically managed acute coronary syndrome patients enrolled in the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial. Patients were classified by chronic kidney disease stage: normal renal function/mild (creatinine clearance >60 mL/min); moderate (creatinine clearance 30-60 mL/min); severe (creatinine clearance <30 mL/min). Kaplan-Meier event rates through 30 months were evaluated for ischemic (cardiovascular death, myocardial infarction or stroke; primary end point) and bleeding (Global Use of Strategies to Open Occluded Coronary Arteries and Thrombolysis In Myocardial Infarction bleeding) outcomes by chronic kidney disease stage and treatment allocation (prasugrel vs. clopidogrel) within each stage. Adjusted hazard ratios (95% confidence intervals) for moderate and for severe chronic kidney disease vs. normal/mild chronic kidney disease were estimated. Platelet reactivity at 30 days was assessed in a subset of patients (n = 1947). The majority of patients were in the normal/mild chronic kidney disease group (67%), followed by moderate chronic kidney disease (29%) and severe chronic kidney disease (4%). The incidence of ischemic and bleeding outcomes increased sharply across chronic kidney disease stages and no significant treatment interactions were observed. The adjusted risk of the primary end point increased across chronic kidney disease stages (moderate vs. normal/mild: hazard ratio 1.26; 95% confidence interval 1.09-1.46; severe vs. normal/mild: hazard ratio 1.60; 95% confidence interval 1.25-2.04). Platelet reactivity was lower in patients treated with prasugrel compared with clopidogrel, across all three chronic kidney disease stages. CONCLUSIONS: Among medically managed acute coronary syndrome patients, the long-term risks of ischemic and bleeding outcomes increased markedly with worse chronic kidney disease stages. Despite lower platelet reactivity of prasugrel compared with clopidogrel, no treatment interactions for ischemic and bleeding outcomes were observed. PMID- 26228449 TI - Heart failure in patients with diabetes undergoing primary percutaneous coronary intervention. AB - INTRODUCTION: Diabetes mellitus is associated with increased risk after acute coronary syndromes. Primary percutaneous coronary intervention is the most effective method of reperfusion for acute ST-elevation myocardial infarction and can limit the ischaemic damage to the left ventricle. However, there are few data on the impact of diabetes mellitus on the risk of heart failure following primary percutaneous coronary intervention. METHODS: We studied 958 ST-elevation myocardial infarction patients treated with primary percutaneous coronary intervention, of whom 263 (27.5%) had diabetes mellitus, with 67 (7.0%) treated with insulin. The primary end points of the study were re-admission for heart failure. Secondary end points were all-cause mortality and recurrent infarctions. The follow-up period was 5 years after hospital discharge. RESULTS: The cumulative incidence of re-admission for heart failure was 8.4%, 15.2% and 26.7% in patients without diabetes mellitus, non-insulin-treated and insulin-treated diabetes mellitus, respectively. Compared with patients without diabetes mellitus, the adjusted hazard ratio for heart failure was 1.95 (95% confidence intervals 1.30-2.93) and 3.09 (95% confidence intervals 1.71-5.60) in non-insulin treated and insulin-treated diabetes mellitus, respectively. The corresponding hazard ratios for mortality were 1.03 (95% confidence intervals 0.68-1.55) and 2.04 (95% confidence intervals 1.22-3.42), respectively. There was a J-shaped association between fasting glucose levels in the acute phase and risk of mortality (P=0.0001) and a direct association with heart failure (P=0.03). CONCLUSION: Despite modern treatment of ST-elevation myocardial infarction and high levels of guideline-based medical care, diabetes mellitus had an independent adverse effect on the risk of re-admissions for heart failure, which was particularly high among insulin-treated patients. PMID- 26228450 TI - Structures of the Alzheimer's Wild-Type Abeta1-40 Dimer from Atomistic Simulations. AB - We have studied the dimer of amyloid beta peptide Abeta of 40 residues by means of all-atom replica exchange molecular dynamics. The Abeta-dimers have been found to be the smallest toxic species in Alzheimer's disease, but their inherent flexibilities have precluded structural characterization by experimental methods. Though the 24-MUs-scale simulation reveals a mean secondary structure of 18% beta strand and 10% alpha helix, we find transient configurations with an unstructured N-terminus and multiple beta-hairpins spanning residues 17-21 and 30-36, but the antiparallel and perpendicular peptide orientations are preferred over the parallel organization. Short-lived conformational states also consist of all alpha topologies, and one compact peptide with beta-sheet structure stabilized by a rather extended peptide with alpha-helical content. Overall, this first all atom study provides insights into the equilibrium structure of the Abeta1-40 dimer in aqueous solution, opening a new avenue for a comprehensive understanding of the impact of pathogenic and protective mutations in early-stage Alzheimer's disease on a molecular level. PMID- 26228451 TI - Intelligence, Attention, and Behavioral Outcomes in Internationally Adopted Girls with a History of Institutionalization. AB - OBJECTIVE: The aim of this study was to investigate the association of neurocognitive functioning with internalizing and externalizing problems and school and social competence in children adopted internationally. METHOD: Participants included girls between the ages of 6-12 years who were internationally adopted from China (n = 32) or Eastern Europe (n = 25) and a control group of never-adopted girls (n = 25). Children completed the Vocabulary and Matrix Reasoning subtests from the Wechsler Abbreviated Scale of Intelligence and the Score! and Sky Search subtests from the Test of Everyday Attention for Children. Parents completed the Child Behavior Checklist and the Home and Community Social Behavior Scales. RESULTS: Compared to the controls, the Eastern European group evidenced significantly more problems with externalizing behaviors and school and social competence and poorer performance on measures of verbal intelligence, perceptual reasoning, and auditory attention. More internalizing problems were reported in the Chinese group compared to the controls. Using generalized linear regression, interaction terms were examined to determine whether the associations of neurocognitive functioning with behavior varied across groups. Eastern European group status was associated with more externalizing problems and poorer school and social competence, irrespective of neurocognitive test performance. In the Chinese group, poorer auditory attention was associated with more problems with social competence. CONCLUSIONS: Neurocognitive functioning may be related to behavior in children adopted internationally. Knowledge about neurocognitive functioning may further our understanding of the impact of early institutionalization on post-adoption behavior. PMID- 26228456 TI - Characterization of Human Duodenal Fluids in Fasted and Fed State Conditions. AB - This work provides an elaborate characterization of human intestinal fluids (HIF) collected in fasted- and fed-state conditions. HIF from 20 healthy volunteers (10 M/F) were aspirated by intubation near the ligament of Treitz in a time-dependent manner (10-min intervals) and characterized for pH, bile salts, phospholipids, cholesterol, triacylglycerides (TAG), diacylglycerides (DAG), monoacylglycerides (MAG), free fatty acids (FFA), pancreatic lipase, phospholipase A2, and nonspecific esterase activity. For almost all parameters, a food-induced effect was observed. Results were characterized by a high variability, as illustrated by the broad ranges observed for each parameter: pH (fasted: 3.4-8.3; fed: 4.7-7.1), bile salts (fasted: 0.03-36.18 mM; fed: 0.74-86.14 mM), phospholipids (fasted: 0.01-6.33 mM; fed: 0.16-14.39 mM), cholesterol (fasted: 0-0.48 mM; fed: 0-3.29 mM), TAG (fed: 0-6.76 mg/mL), DAG (fed: 0-3.64 mg/mL), MAG (fasted: 0-1.09 mg/mL; fed: 0-11.36 mg/mL), FFA (fasted: 0-3.86 mg/mL; fed: 0.53-15.0 mg/mL), pancreatic lipase (fasted: 26-86 g/mL; fed: 146-415 g/mL), phospholipase A2 (fasted: 3-6 ng/mL; fed: 4.3-27.7 ng/mL), and nonspecific esterase activity (fasted: 270-4900 U/mL; fed: 430-4655 U/mL). This comprehensive overview may serve as reference data for physiologically based pharmacokinetic modeling and the optimization of biorelevant simulated intestinal fluids for the use in in vitro dissolution, solubility, and permeability profiling. PMID- 26228457 TI - Ingested Salmonella enterica, Cronobacter sakazakii, Escherichia coli O157:H7, and Listeria monocytogenes: transmission dynamics from adult house flies to their eggs and first filial (F1) generation adults. AB - BACKGROUND: The mechanical transmission of pathogenic bacteria by synanthropic filth flies is widely recognized. While many studies report the fate and the temporospatial distribution of ingested foodborne bacteria by filth flies, there is little evidence about the transmission dynamics of ingested foodborne bacteria by adult house flies (Musca domestica) to their progeny. In this study, we fed parental house fly adults with food contaminated with low, medium, and high concentrations of Salmonella enterica, Cronobacter sakazakii, Escherichia coli O157:H7, and Listeria monocytogenes and evaluated the probability of transmission of these pathogens to house fly eggs and the surface and the alimentary canal of their first filial (F1) generation adults. RESULTS: All foodborne pathogens were present in samples containing pooled house fly eggs. The probability of transmission was higher after parental house flies ingested food containing medium bacterial loads. Cronobacter sakazakii was 16, 6, and 3 times more likely to be transmitted to house fly eggs than S. enterica, E. coli O157:H7, and L. monocytogenes, respectively. Only S. enterica and C. sakazakii were transmitted to F1 generation adults and their presence was 2.4 times more likely on their body surfaces than in their alimentary canals. The highest probabilities of finding S. enterica (60 %) and C. sakazakii (28 %) on newly emerged F1 adults were observed after parental house flies ingested food containing medium and high levels of these pathogens, respectively. CONCLUSION: Our study demonstrates that adult house flies that fed from food contaminated with various levels of foodborne bacteria were able to transmit those pathogens to their eggs and some were further transmitted to newly emerged F1 generation adults, enhancing the vector potential of these insects. Understanding the type of associations that synanthropic filth flies establish with foodborne pathogens will help to elucidate transmission mechanisms and possible ways to mitigate the spread of foodborne pathogens. PMID- 26228458 TI - Obesity risk in rural, urban and rural-to-urban migrants: prospective results of the PERU MIGRANT study. AB - BACKGROUND: Although migration and urbanization have been linked with higher obesity rates, especially in low-resource settings, prospective information about the magnitude of these effects is lacking. We estimated the risk of obesity and central obesity among rural subjects, rural-to-urban migrants and urban subjects. METHODS: Prospective data from the PERU MIGRANT Study were analyzed. Baseline data were collected in 2007-2008 and participants re-contacted in 2012-2013. At follow-up, outcomes were obesity and central obesity measured by body mass index and waist circumference. At baseline, the primary exposure was demographic group: rural, rural-to-urban migrant and urban. Other exposures included an assets index and educational attainment. Cumulative incidence, incidence ratio (IR) and 95% confidence intervals (95% CI) for obesity and central obesity were estimated with Poisson regression models. RESULTS: At baseline, mean age (+/-s.d.) was 47.9 (+/ 12.0) years, and 53.0% were females. Rural subjects comprised 20.2% of the total sample, whereas 59.7% were rural-to-urban migrants and 20.1% were urban dwellers. A total of 3598 and 2174 person-years were analyzed for obesity and central obesity outcomes, respectively. At baseline, the prevalence of obesity and central obesity was 20.0 and 52.5%. In multivariable models, migrant and urban groups had an 8- to 9.5-fold higher IR of obesity compared with the rural group (IR migrants=8.19, 95% CI=2.72-24.67; IR urban=9.51, 95% CI=2.74-33.01). For central obesity, there was a higher IR only among the migrant group (IR=1.95; 95% CI=1.22-3.13). Assets index was associated with a higher IR of central obesity (IR top versus bottom tertile 1.45, 95% CI=1.03-2.06). CONCLUSIONS: Peruvian urban individuals and rural-to-urban migrants show a higher incidence of obesity compared with their rural counterparts. Given the ongoing urbanization occurring in middle-income countries, the rapid development of increased obesity risk by rural-to-urban migrants suggests that measures to reduce obesity should be a priority for this group. PMID- 26228459 TI - Anti-inflammatory properties of bone morphogenetic protein 4 in human adipocytes. AB - BACKGROUND: Obesity is characterized by increased adipocyte number and size as well as white adipose tissue (WAT) inflammation, which is fundamental for the development of insulin resistance and type-2 diabetes. These processes, regulated by various endocrine, paracrine and autocrine factors, are extensively studied with the hope to interfere and to inhibit weight gain and related complications in obese patients. Recent data suggest an important role of bone morphogenic protein 4 (BMP4) in the regulation of adipogenesis and development of obesity. BMP4 is a growth factor of the transforming growth factor-beta superfamily. Initially, BMPs were identified as inducers of ectopic bone formation. It is now apparent, however, that these proteins have different pleiotropic developmental actions and including playing a role in white adipogenesis. METHODS AND RESULTS: Here, we demonstrate that the expression of BMP4 in human WAT is negatively correlated to body mass index and to the expression of pro-inflammatory cytokines. In vitro, BMP4 expression in cultured human adipocytes is upregulated after induction of differentiation. Cells treated with exogenous BMP4 increased peroxisome proliferator-activated receptor gamma (PPARgamma) expression and significantly reduced the expression of pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-alpha) and monocyte chemoattractant protein 1. TNF-alpha treatment of fully differentiated adipocytes resulted in downregulation of the expression of adipogenic genes and elevated expression of pro-inflammatory cytokines. Exogenous BMP4 addition significantly reduced the negative effect of TNF-alpha on the expression profile of adipocytes. Finally, treatment of human adipocytes with exogenous BMP4 reduced the adipocytes' chemoattractant potential and the migration of monocytes toward adipocyte-conditioned medium. CONCLUSIONS: These results indicate that BMP4 is an important anti-inflammatory molecule, which may act through PPARgamma and reduces TNF-alpha-mediated pro-inflammatory cytokine production in human adipocytes. Through its anti-inflammatory potential, BMP4 may serve as a protective factor for inflammation-related diseases such as insulin-tolerance or type-2 diabetes. PMID- 26228460 TI - Transfer of liraglutide from blood to cerebrospinal fluid is minimal in patients with type 2 diabetes. AB - Treatment with liraglutide leads to weight loss. We investigated whether blood-to cerebrospinal fluid (CSF) transfer of liraglutide occurs, and if so, whether it associates with clinical weight loss following liraglutide treatment in humans. We performed lumbar puncture and blood sampling in eight patients with type 2 diabetes (mean (range)): age 63 (54-79) years; actual body weight: 90 (75-118) kg treated with 1.8 mg liraglutide for 14 (5-22) months and with a treatment-induced weight loss of 8.4 (7-11) kg. We measured liraglutide in plasma and CSF with a radioimmunoassay specific for the N-terminus of the GLP-1 moiety of liraglutide. Mean plasma liraglutide was 31 (range: 21-63) nmol l(-1). The mean CSF liraglutide concentration was 6.5 (range: 0.9-13.9) pmol l(-1). Ratio of CSF: plasma-liraglutide concentrations was 0.02 (range: 0.07-0.002)% and plasma liraglutide did not correlate with CSF-liraglutide levels (P=0.67). Body weight loss tended to correlate with plasma-liraglutide levels (P=0.06), but not with CSF-liraglutide levels (P=0.69). In conclusion, we measured very low concentrations of liraglutide in CSF, and the levels of CSF liraglutide did not correlate with the actual clinical weight loss in these patients. The amount of liraglutide in plasma tended to correlate with the clinical weight loss. PMID- 26228461 TI - Gut fat signaling and appetite control with special emphasis on the effect of thylakoids from spinach on eating behavior. AB - The metabolic controls of eating are embedded in a neural system that permits an interaction with the environment. The result is an integrated adaptive response that coordinates the internal milieu with the prevailing environment. Securing adequate amounts of fat and optimizing its storage and use has an evolutionary basis. By generating neuronal and endocrine feedback signals, behavior and metabolism could then adapt to fluctuations in food availability. However, in modern society, foods that appeal to the palate are neither in shortage nor are they difficult to procure. These foods can activate brain reward circuitry beyond their evolved 'survival advantage' limits. Many foods high in fat invoke an undeniably pleasurable sensation and could excessively stimulate the brain's reward pathways leading to overeating. However, the high appeal and potential for being eaten in excess notwithstanding, fat has the added distinction of inducing powerful signals in the gut that are transduced to the brain and result in the regulation of appetite. Fatty acids are sensed by G-protein-coupled receptors on enteroendocrine cells which trigger the release of peptides involved in appetite regulation. Lipid sensing may also occur through the fatty acid translocase, CD 36, on enterocytes. Additionally, fat can activate dopaminergic systems affecting reward, to promote an inhibition over eating. Prolonging the presence of fats in the gastrointestinal lumen permits the activation of signaling mechanisms. Thylakoids, found within the chloroplasts of plants, are flattened disc-like membranous vesicles in which the light-dependent reactions of photosynthesis occur. By interacting with lipids and delaying fat digestion, thylakoid membranes promote the release of peptides involved in appetite regulation and may influence the reward system. This review explores gut lipid sensing and signaling in the context of appetite regulation. The effects of thylakoid membranes on eating behavior are also reviewed. PMID- 26228462 TI - Pioglitazone treatment increases food intake and decreases energy expenditure partially via hypothalamic adiponectin/adipoR1/AMPK pathway. AB - INTRODUCTION: Thiazolidinediones (TZDs) enhanced body weight (BW) partially by increased adipogenesis and hyperphagia. Neuronal PPARgamma knockout mice on high fat diet (HFD) are leaner because of enhanced leptin response, although it could be secondary to their leanness. Thus, it still is an open question how TZDs may alter energy balance. Multiple factors regulate food intake (FI) and energy expenditure (EE), including anorexigenic hormones as insulin and leptin. Nonetheless, elevated hypothalamic AMPK activity increases FI and TZDs increase AMPK activity in muscle cells. Thus, the aim of the present study was to investigate whether Pioglitazone (PIO) treatment alters hypothalamic insulin and leptin action/signaling, AMPK phosphorylation, and whether these alterations may be implicated in the regulation of FI and EE. METHODS: Swiss mice on HFD (2 months) received PIO (25 mg kg(-1) per day-gavage) or vehicle for 14 days. AMPK and AdipoR1 were inhibited via Intracerebroventricular injections using Compound C (CompC) and small interference RNA (siRNA), respectively. Western blot, real time PCR and CLAMS were done. RESULTS: PIO treatment increased BW, adiposity, FI, NPY mRNA and decreased POMC mRNA expression and EE in HFD mice. Despite higher adiposity, PIO treatment improved insulin sensitivity, glucose tolerance, decreased insulin and increased adiponectin serum levels. This result was associated with, improved insulin and leptin action/signaling, decreased alpha2AMPK(Ser491) phosphorylation and elevated Acetyl-CoA carboxylase and AMPK(Thr172) phosphorylation in hypothalamus. The inhibition of hypothalamic AMPK with CompC was associated with decreased adiposity, FI, NPY mRNA and EE in PIO treated mice. The reduced expression of hypothalamic AdipoR1 with siRNA concomitantly with PIO treatment reverted PIO induced obesity development, suggesting that adiponectin may be involved in this effect. CONCLUSIONS: These results demonstrated that PIO, despite improving insulin/leptin action in hypothalamus, increases FI and decreases EE, partially, by activating hypothalamic adiponectin/AdipoR1/AMPK axis. Suggesting a novel mechanism in the hypothalamus by which TZDs increase BW. PMID- 26228463 TI - Halorussus amylolyticus sp. nov., isolated from an inland salt lake. AB - A halophilic archaeal strain, YC93T, was isolated from Yuncheng salt lake in Shanxi Province, China. Cells were pleomorphic rods, stained Gram-negative and formed light-red-pigmented colonies on agar plates. Strain YC93T was able to grow at 25-50 degrees C (optimum 37 degrees C), with 1.4-4.8 M NaCl (optimum 2.0 M), with 0-1.0 M MgCl2 (optimum 0.05 M) and at pH 6.0-9.5 (optimum pH 7.0). Cells lysed in distilled water and the minimal NaCl concentration to prevent cell lysis was 8 % (w/v). 16S rRNA gene sequence analysis revealed that strain YC93T had two dissimilar 16S rRNA genes both of which were phylogenetically related to those of the two recognized members of the genus Halorussus (93.0-95.3 % similarity). The rpoB' gene of strain YC93T was phylogenetically related to the corresponding gene of Halorussus rarus TBN4T (91.3 % similarity) and Halorussus ruber YC25T (90.5 %). The major polar lipids were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, phosphatidylglycerol sulfate and five glycolipids chromatographically identical to those of Halorussus rarus CGMCC 1.10122T. The DNA G+C content of strain YC93T was 64.6 mol%. The phenotypic, chemotaxonomic and phylogenetic properties suggested that strain YC93T represents a novel species of the genus Halorussus, for which the name Halorussus amylolyticus sp. nov. is proposed. The type strain is YC93T ( = CGMCC 1.12126T = JCM 18367T). PMID- 26228464 TI - Limited sampling strategies for therapeutic drug monitoring of amikacin and kanamycin in patients with multidrug-resistant tuberculosis. AB - Amikacin and kanamycin are considered important and effective drugs in the treatment of multidrug-resistant tuberculosis (MDR-TB). Unfortunately, the incidence of toxicity is high and is related to elevated drug exposure. In order to achieve a balance between efficacy and toxicity, a population pharmacokinetic (PPK) model may help to optimise drug exposure. Patients with MDR-TB who had received amikacin or kanamycin as part of their treatment and who had routinely received therapeutic drug monitoring were evaluated. A PPK model was developed and subsequently validated. Using this model, a limited sampling model was developed. Eleven patients receiving amikacin and nine patients receiving kanamycin were included in this study. The median observed 24-h area under the concentration-time curve (AUC0-24h) was 77.2 mg h/L [interquartile range (IQR) 64.7-96.2 mg h/L] for amikacin and 64.1 mg h/L (IQR 55.6-92.1 mg h/L) for kanamycin. The PPK model was developed and validated using n-1 cross-validation. A robust population model was developed that is suitable for predicting the AUC0 24h of amikacin and kanamycin. This model, in combination with the limited sampling strategy developed, can be used in daily routine to guide dosing but also to assess AUC0-24h in phase 3 studies. PMID- 26228465 TI - Teicoplanin use in adult patients with haematological malignancy: Exploring relationships between dose, trough concentrations, efficacy and nephrotoxicity. AB - In 2010, our hospital introduced a higher target teicoplanin trough concentration of >=20 mg/L by Day 3 for haematological malignancy patients. This study aimed to explore whether target trough concentrations were achieved, to identify factors associated with trough concentrations attained, and to assess clinical efficacy with teicoplanin treatments and nephrotoxicity. This was a retrospective, single centre, cohort study of 172 teicoplanin treatments in 104 adults with haematological malignancy. Mixed-effects regression was used to evaluate factors affecting trough concentrations, and logistic regression was used to assess the relationship between trough concentrations and treatment outcomes. Nephrotoxicity was assessed using the RIFLE criteria. Considerable variability in trough concentrations was observed, with trough concentrations >=20 mg/L rarely achieved early in therapy. A mixed-effects regression model explaining 52% of the variation in trough concentrations was developed. Dose and day of therapy were positively associated with trough concentration, whilst estimated renal function and, interestingly, acute myeloid leukaemia diagnosis were negatively associated (P<0.05). Results suggested a positive relationship between trough concentration and the likelihood of a favourable outcome for coagulase-negative staphylococcal central line-associated bloodstream infections. Elucidation of a specific target concentration requires further investigation. Teicoplanin was well tolerated renally. Findings suggest a risk of underexposure if conventional teicoplanin doses are used in haematological malignancy patients. Given the variability in trough concentrations observed, the identified factors affecting trough concentrations attained and the suggested link with clinical outcome, individualised initial dosing followed by therapeutic drug monitoring is recommended to ensure early adequate exposure in this vulnerable patient group. PMID- 26228467 TI - From the Editors. PMID- 26228466 TI - A randomized controlled bicenter trial of yoga for patients with colorectal cancer. AB - OBJECTIVE: The aim of this trial was to evaluate the effects of yoga on health related quality of life in patients with colorectal cancer. METHODS: Patients with non-metastatic colorectal cancer were randomly assigned to a 10-week yoga intervention (90 min once weekly) or a waitlist control group. Primary outcome measure was disease-specific quality of life (Functional Assessment of Cancer Therapy - Colorectal [FACT-C]) at week 10. Secondary outcome measures included FACT-C subscales: spiritual well-being (FACT - Spirituality); fatigue (FACT - Fatigue); sleep disturbances (Pittsburgh Sleep Quality Inventory); depression and anxiety (Hospital Anxiety and Depression Scale); body awareness (Scale of Body Connection); and body-efficacy expectations (Body-Efficacy Expectations Scale). Outcomes were assessed at week 10 and week 22 after randomization. RESULTS: Fifty four patients (mean age 68.3 +/- 9.7 years) were randomized to yoga (n = 27; attrition rate 22.2%) and control group (n = 27; attrition rate 18.5%). Patients in the yoga group attended a mean of 5.3 +/- 4.0 yoga classes. No significant group differences for the FACT-C total score were found. Group differences were found for emotional well-being at week 22 (? = 1.59; 95% CI = 0.27,2.90; p = 0.019), sleep disturbances at week 22 (? = -1.08; 95% CI = -2.13, -0.03; p = 0.043), anxiety at week 10 (? = -1.14; 95% CI = -2.20, -0.09; p = 0.043), and depression at week 10 (? = -1.34; 95% CI = -2.61, -0.8; p = 0.038). No serious adverse events occurred in the yoga group, while liver metastases were diagnosed in one patient in the control group. CONCLUSION: This randomized trial found no effects of yoga on health-related quality of life in patients with colorectal cancer. Given the high attrition rate and low intervention adherence, no definite conclusions can be drawn from this trial. PMID- 26228468 TI - Advanced imaging approaches for regenerative medicine: Emerging technologies for monitoring stem cell fate in vitro and in vivo. AB - The future of regenerative medicine relies on our ability to control stem cell fate in order to produce functional tissues. Stem cells are the preferred cell source for tissue engineering endeavors and regenerative medicine therapies due to their high potency and capacity for expansion. However, their potency also makes them very difficult to control, as they are in a constant state of flux. Therefore, in order to advance research in regenerative medicine, it is necessary to be able to monitor cell state and phenotype both in vitro and in vivo. This review will detail the imaging technologies currently in use to monitor stem cell phenotype, migration, and differentiation. In addition to providing examples of the most recent work in this area, we will also discuss the future of imaging technologies for regenerative medicine, and how current imaging modalities might be utilized to image specific cell functionality in order to track stem cell fate. The research area of imaging stem cells is progressing toward identifying mature and differentiating cells not only by phenotypic markers, but also by visualizing cell function. Many of the cutting-edge modalities detailed in this review have the potential to be harnessed toward this goal. PMID- 26228469 TI - Diagnostic Yield of Venous Thrombosis and Pulmonary Embolism by Combined CT Venography and Pulmonary Angiography in Patients with Cryptogenic Stroke and Patent Foramen Ovale. AB - BACKGROUND: Paradoxical embolism via a patent foramen ovale (PFO) has been suggested as a potential stroke mechanism. Combined CT venography and pulmonary angiography (CVPA) is a simple, validated and accurate technique to diagnose deep venous thrombosis (DVT) or pulmonary embolism (PE). We sought to assess the prevalence of DVT or PE among patients with PFO and cryptogenic stroke (CS) by CVPA. METHODS: Patients were identified retrospectively from a clinical registry of consecutive patients with stroke admitted to our Stroke Unit. The following criteria were required for inclusion in this study: CS, PFO identified by transthoracic echography using contrast medium and CVPA performed during the hospitalization following stroke. RESULTS: A total of 114 patients with PFO underwent a CVPA within 7 days (interquartile range 4-9) from stroke symptom onset. On cerebral imaging, 11% had multiple infarcts. CVPA documented deep vein thrombosis (DVT) in 10 patients (8.8%) and PE in 5 patients (4.4%), that is, a total of 12 patients with prevalence of 10.5% (95% CI 5.5-17.7). Patients with PE DVT had higher D-dimers and C reactive protein level than patients without PE-DVT (p < 0.05). CONCLUSION: CVPA may be used by the stroke team in the work-up of suspected paradoxical embolism among cryptogenic ischemic stroke patients with PFO. PMID- 26228470 TI - Threshold levels of visual field and acuity loss related to significant decreases in the quality of life and emotional states of patients with retinitis pigmentosa. AB - INTRODUCTION: Retinitis pigmentosa (RP) is an inherited retinal disorder, characterized by photoreceptor degeneration inducing progressive vision loss. This study evaluates its impact on quality of life (QOL) and emotional states of patients affected by RP. METHODS: A cross-sectional study was conducted on 60 RP patients diagnosed with rod-cone dystrophy and on 20 control subjects. The RP population has been divided into 3 groups according to visual field (VF) and visual acuity (VA) impairments. Concurrently, scores of self-reported QOL (25 item National Eye Institute Visual Functioning Questionnaire) and of the Hospital Anxiety and Depression Scale for anxiety/depression assessments were collected. RESULTS: For the QOL composite score, we noticed consistent differences between all VF and VA affected groups and their control group. We also found significant differences between both the most affected VF group (VF1: OVF <20 degrees ) and VA group (VA1: VA <0.3) compared to other VF and VA groups. For anxiety/depression scores, consistent differences have been found between the control group and VF1 and VA1, respectively. CONCLUSIONS: This work determines that, for RP patients, a significant QOL and emotional state deterioration correlates with a residual VF diameter below 20 degrees and a VA lower than 0.3. It introduces, for the first time, thresholds to be used in visual restoration or visual preservation therapies to improve QOL of RP patients. PMID- 26228471 TI - The internationalization voyage of Zoological Research. PMID- 26228474 TI - The breeding biology of Red-Whiskered Bulbul (Pycnonotus jocosus) in Xishuangbanna, southwest China. AB - To fill the gap in breeding biology information about the Red-Whiskered Bulbul (Pycnonotus jocosus), in 2013, we studied the breeding biology of this species in Xishuangbanna, southwest China. The breeding began from February and continued until early August. The breeding strategy of P. jocosus was more flexible and their nests were only built in cultivated landscapes, whereas, no nest building in native tropical rain forest was found. Small open cup nests were built on 50 different plant species, and at heights ranging from 2.1+/-0.6 m above the ground (n=102). The mean clutch size was 2.53+/-0.51 eggs (n=40) and the mean egg mass was 2.81+/-0.25 g (n=60). The average incubation period was 11.1+/-0.5 days (n=14), and the average nestling period was 11.0+/-0.8 days (n=31). The overall nest success was 34.22%.The hatching and fledging showed either asynchrony or synchrony. Invertebrate food decreased with nestling age, whereas, plant food increased with nestling age. Moreover, distinct parental roles of the parents in nestling period were found. Compared with other passerine species, P. jocosus spent less time in incubating (58%). The clutch size, incubation and nestling period of the P. jocosus in southwest China were different from those of the P. jocosus in India. PMID- 26228473 TI - Population genetic studies in the genomic sequencing era. AB - Recent advances in high-throughput sequencing technologies have revolutionized the field of population genetics. Data now routinely contain genomic level polymorphism information, and the low cost of DNA sequencing enables researchers to investigate tens of thousands of subjects at a time. This provides an unprecedented opportunity to address fundamental evolutionary questions, while posing challenges on traditional population genetic theories and methods. This review provides an overview of the recent methodological developments in the field of population genetics, specifically methods used to infer ancient population history and investigate natural selection using large-sample, large scale genetic data. Several open questions are also discussed at the end of the review. PMID- 26228475 TI - Effects of frugivorous birds on seed retention time and germination in Xishuangbanna, southwest China. AB - The dispersal of many plants depends on transportation by birds as seed dispersers. The birds play an important role in long distance seed dispersal and may also affect seed germination. However, for plants who have many bird dispersers, the influence of dominant and non-dominant dispersers on retention time (dispersal distance) and germination remains poorly understood. In this study, we performed experiments with captive frugivorous birds and fruiting plant species to study the effects of dominant and non-dominant dispersers on seed retention time (SRT) and germination (seed germination percentage and germination speed). Our study showed a great interspecific variation in the effects of frugivorous birds on both SRT and germination. Some birds enhance the germination of a given plant species, but others do not. Generally, the dominant visitors improved the seed germination and performed longer seed retention time. PMID- 26228476 TI - Extraction and identification of membrane proteins from black widow spider eggs. AB - The eggs of oviparous animals are storehouses of maternal proteins required for embryonic development. Identification and molecular characterization of such proteins will provide much insight into the regulation of embryonic development. We previously analyzed soluble proteins in the eggs of the black widow spider (Latrodectus tredecimguttatus), and report here on the extraction and mass spectrometric identification of the egg membrane proteins. Comparison of different lysis solutions indicated that the highest extraction of the membrane proteins was achieved with 3%-4% sodium laurate in 40 mmol/L Tris-HCl buffer containing 4% CHAPS and 2% DTT (pH 7.4). SDS-PAGE combined with nLC-MS/MS identified 39 proteins with membrane-localization annotation, including those with structural, catalytic, and regulatory activities. Nearly half of the identified membrane proteins were metabolic enzymes involved in various cellular processes, particularly energy metabolism and biosynthesis, suggesting that relevant metabolic processes were active during the embryonic development of the eggs. Several identified cell membrane proteins were involved in the special structure formation and function of the egg cell membranes. The present proteomic analysis of the egg membrane proteins provides new insight into the molecular mechanisms of spider embryonic development. PMID- 26228477 TI - Nostalgia-Evoked Inspiration: Mediating Mechanisms and Motivational Implications. AB - Six studies examined the nostalgia-inspiration link and its motivational implications. In Study 1, nostalgia proneness was positively associated with inspiration frequency and intensity. In Studies 2 and 3, the recollection of nostalgic (vs. ordinary) experiences increased both general inspiration and specific inspiration to engage in exploratory activities. In Study 4, serial mediational analyses supported a model in which nostalgia increases social connectedness, which subsequently fosters self-esteem, which then boosts inspiration. In Study 5, a rigorous evaluation of this serial mediational model (with a novel nostalgia induction controlling for positive affect) reinforced the idea that nostalgia-elicited social connectedness increases self-esteem, which then heightens inspiration. Study 6 extended the serial mediational model by demonstrating that nostalgia-evoked inspiration predicts goal pursuit (intentions to pursue an important goal). Nostalgia spawns inspiration via social connectedness and attendant self-esteem. In turn, nostalgia-evoked inspiration bolsters motivation. PMID- 26228478 TI - Why Small is Too Small a Term: Prevention Science for Health Disparities, Culturally Distinct Groups, and Community-Level Intervention. AB - Implications of the Advancing Small Sample Prevention Science Special Section are discussed. Efficiency and precision are inadequately considered in many current prevention-science methodological approaches. As a result, design and analytic practices pose difficulties for the study of contextual factors in prevention, which often involve small samples. Four primary conclusions can be drawn from the Special Section. First, contemporary statistical and measurement approaches provide a number of underutilized opportunities to maximize power. These strategies maximize efficiencies by optimizing design and resource allocation parameters, allowing for the detection of effects with small samples. Second, several alternative research designs provide both rigor and further optimize efficiencies through more complete use of available information, allowing study of important questions in prevention science for which only small samples may be accessible. Third, mixed methods hold promise for enhancing the utility of qualitative data in studies with small samples. Finally, Bayesian analytic approaches, through their use of prior information, allow for even greater efficiencies in work with small samples, and through their introduction in the routines of mainstream software packages, hold particular promise as an emergent methodology in prevention research. PMID- 26228480 TI - Applying a Family-Level Economic Strengthening Intervention to Improve Education and Health-Related Outcomes of School-Going AIDS-Orphaned Children: Lessons from a Randomized Experiment in Southern Uganda. AB - Children comprise the largest proportion of the population in sub-Saharan Africa. Of these, millions are orphaned. Orphanhood increases the likelihood of growing up in poverty, dropping out of school, and becoming infected with HIV. Therefore, programs aimed at securing a healthy developmental trajectory for these orphaned children are desperately needed. We conducted a two-arm cluster-randomized controlled trial to evaluate the effectiveness of a family-level economic strengthening intervention with regard to school attendance, school grades, and self-esteem in AIDS-orphaned adolescents aged 12-16 years from 10 public rural primary schools in southern Uganda. Children were randomly assigned to receive usual care (counseling, school uniforms, school lunch, notebooks, and textbooks), "bolstered" with mentorship from a near-peer (control condition, n = 167), or to receive bolstered usual care plus a family-level economic strengthening intervention in the form of a matched Child Savings Account (Suubi-Maka treatment arm, n = 179). The two groups did not differ at baseline, but 24 months later, children in the Suubi-Maka treatment arm reported significantly better educational outcomes, lower levels of hopelessness, and higher levels of self concept compared to participants in the control condition. Our study contributes to the ongoing debate on how to address the developmental impacts of the increasing numbers of orphaned and vulnerable children and adolescents in sub Saharan Africa, especially those affected by HIV/AIDS. Our findings indicate that innovative family-level economic strengthening programs, over and above bolstered usual care that includes psychosocial interventions for young people, may have positive developmental impacts related to education, health, and psychosocial functioning. PMID- 26228472 TI - Why do we study animal toxins? AB - Venom (toxins) is an important trait evolved along the evolutionary tree of animals. Our knowledges on venoms, such as their origins and loss, the biological relevance and the coevolutionary patterns with other organisms are greatly helpful in understanding many fundamental biological questions, i.e., the environmental adaptation and survival competition, the evolution shaped development and balance of venoms, and the sophisticated correlations among venom, immunity, body power, intelligence, their genetic basis, inherent association, as well as the cost-benefit and trade-offs of biological economy. Lethal animal envenomation can be found worldwide. However, from foe to friend, toxin studies have led lots of important discoveries and exciting avenues in deciphering and fighting human diseases, including the works awarded the Nobel Prize and lots of key clinic therapeutics. According to our survey, so far, only less than 0.1% of the toxins of the venomous animals in China have been explored. We emphasize on the similarities shared by venom and immune systems, as well as the studies of toxin knowledge-based physiological toxin-like proteins/peptides (TLPs). We propose the natural pairing hypothesis. Evolution links toxins with humans. Our mission is to find out the right natural pairings and interactions of our body elements with toxins, and with endogenous toxin-like molecules. Although, in nature, toxins may endanger human lives, but from a philosophical point of view, knowing them well is an effective way to better understand ourselves. So, this is why we study toxins. PMID- 26228479 TI - Alcohol Sales to Youth: Data from Rural Communities Within the Cherokee Nation. AB - Access to alcohol among individuals under 21 years of age continues to be a public health concern with approximately 5000 youth deaths attributable to alcohol each year (US Department of Health and Human Services 2007). To date, there is no research on youth access to alcohol from commercial sources within rural communities with large populations of Native American families. We evaluated commercial access to alcohol by underage-appearing female confederates in 4 rural towns within the Cherokee Nation, a non-reservation tribal jurisdiction that includes a high proportion of Native Americans embedded within a predominately White population. Alcohol purchase attempts were conducted approximately every 4 weeks on 10 occasions for a total of 997 alcohol purchase attempts. In addition to purchase attempt outcome, we collected data on characteristics of the outlets and clerks. Alcohol was sold to confederates without use of age identification on 23 % of all purchase attempts. Across repeated attempts, 76 % of outlets sold alcohol to a confederate at least once. Males and younger clerks were more likely to sell alcohol to the confederates. Grocery stores and gas stations were more likely to sell alcohol to the confederate than liquor stores, but this effect was no longer significant once seller age was accounted for in a multivariable model. Three out of 4 outlets sold alcohol to young-appearing buyers at least once across repeated attempts. Results reinforce the continuing need for regular enforcement of laws against selling alcohol to minors. PMID- 26228481 TI - Outcomes of Open Dorsal Wrist Ganglion Excision in Active-Duty Military Personnel. AB - PURPOSE: To examine the most common presenting complaints of active-duty service members with isolated dorsal wrist ganglions and to determine the rate of return to unrestricted duty after open excision. METHODS: Surgical records at 2 military facilities were screened to identify male and female active duty service members undergoing isolated open excision of dorsal wrist ganglions from January 1, 2006 to January 1, 2014. Electronic medical records and service disability databases were searched to identify the most common presenting symptoms and to determine whether patients returned to unrestricted active duty after surgery. Postoperative outcomes examined were pain persisting greater than 4 weeks after surgery, stiffness requiring formal occupational therapy treatment, surgical wound complications, and recurrence. RESULTS: A total of 125 active duty military personnel (Army, 54; Navy, 43; and Marine Corps, 28) met criteria for inclusion. Mean follow-up was 45 months. Fifteen percent (8 of 54) of the Army personnel were given permanent waivers from performing push-ups owing to persistent pain and stiffness. Pain persisting greater than 4 weeks after surgery was an independent predictor of eventual need for a permanent push-up waiver. The overall recurrence incidence was 9%. No demographic or perioperative factors were associated with recurrence. CONCLUSIONS: Patients whose occupation or activities require forceful wrist extension should be counseled on the considerable risk of residual pain and functional limitations that may occur after open dorsal wrist ganglion excision. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26228482 TI - Sublingual allergen immunotherapy in HIV-positive patients. AB - HIV infection is a relative contraindication for allergic immunotherapy (AIT). In the last decade, highly active antiretroviral therapy (HAART) has improved the immune function and life expectancy in HIV-infected patients whose respiratory allergic incidence is similar to the general population. We evaluated the safety and clinical effectiveness of sublingual immunotherapy in a group of grass pollen allergic HAART-treated HIV-positive patients. Thirteen patients received sublingual immunotherapy (SLIT) tablet (Oralair, Stallergenes(c)) and symptomatic therapy and were compared with nine patients receiving symptomatic therapy alone. Clinical benefits were evaluated by the analysis of total combined score (TCS), sum of symptom-medication score, and a quality of life (QoL) questionnaire. HIV viral load and peripheral TCD4 lymphocytes were analyzed at the beginning and at the end of the study. Clinical efficacy data showed a significant improvement in SLIT-treated patients compared to controls (TCS: P = 0.0001; QoL: P = 0.03). We did not observe any significant alteration of TCD4 cell counts and viral load (VL) in both groups. Our preliminary data showed that SLIT therapy in viro immunological controlled HAART treated HIV positive patients was efficacious, safe and well tolerated. PMID- 26228484 TI - Preclinical activity of the repurposed drug auranofin in classical Hodgkin lymphoma. PMID- 26228485 TI - Cytokinesis failure in RhoA-deficient mouse erythroblasts involves actomyosin and midbody dysregulation and triggers p53 activation. AB - RhoA GTPase has been shown in vitro in cell lines and in vivo in nonmammalian organisms to regulate cell division, particularly during cytokinesis and abscission, when 2 daughter cells partition through coordinated actomyosin and microtubule machineries. To investigate the role of this GTPase in the rapidly proliferating mammalian erythroid lineage, we developed a mouse model with erythroid-specific deletion of RhoA. This model was proved embryonic lethal as a result of severe anemia by embryonic day 16.5 (E16.5). The primitive red blood cells were enlarged, poikilocytic, and frequently multinucleated, but were able to sustain life despite experiencing cytokinesis failure. In contrast, definitive erythropoiesis failed and the mice died by E16.5, with profound reduction of maturing erythroblast populations within the fetal liver. RhoA was required to activate myosin-regulatory light chain and localized at the site of the midbody formation in dividing wild-type erythroblasts. Cytokinesis failure caused by RhoA deficiency resulted in p53 activation and p21-transcriptional upregulation with associated cell-cycle arrest, increased DNA damage, and cell death. Our findings demonstrate the role of RhoA as a critical regulator for efficient erythroblast proliferation and the p53 pathway as a powerful quality control mechanism in erythropoiesis. PMID- 26228483 TI - Mice expressing a mutant form of fibrinogen that cannot support fibrin formation exhibit compromised antimicrobial host defense. AB - Fibrin(ogen) is central to hemostasis and thrombosis and also contributes to multiple physiologic and pathologic processes beyond coagulation. However, the precise contribution of soluble fibrinogen vs insoluble fibrin matrices to vascular integrity, tissue repair, inflammation, and disease has been undefined and unapproachable. To establish the means to distinguish fibrinogen- and fibrin dependent processes in vivo, Fib(AEK) mice were generated that carry normal levels of circulating fibrinogen but lack the capacity for fibrin polymer formation due to a germ-line mutation in the Aalpha chain thrombin cleavage site. Homozygous Fib(AEK) mice developed to term and exhibited postnatal survival superior to that of fibrinogen-deficient mice. Unlike fibrinogen-deficient mice, platelet-rich plasma from Fib(AEK) mice supported normal platelet aggregation in vitro, highlighting that fibrinogen(AEK) retains the functional capacity to support interactions with platelets. Thrombin failed to release fibrinopeptide-A from fibrinogen(AEK) and failed to induce polymer formation with Fib(AEK) plasma or purified fibrinogen(AEK) in 37 degrees C mixtures regardless of incubation time. Fib(AEK) mice displayed both an absence of fibrin polymer formation following liver injury, as assessed by electron microscopy, and a failure to generate stable occlusive thrombi following FeCl3 injury of carotid arteries. Fib(AEK) mice exhibited a profound impediment in Staphylococcus aureus clearance following intraperitoneal infection similar to fibrinogen-deficient mice, yet Fib(AEK) mice displayed a significant infection dose-dependent survival advantage over fibrinogen-deficient mice following peritonitis challenge. Collectively, these findings establish for the first time that fibrin polymer is the molecular form critical for antimicrobial mechanisms while simultaneously highlighting biologically meaningful contributions and functions of the soluble molecule. PMID- 26228487 TI - The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis. AB - The JAK2 c.1849G>T (p.V617F) mutation leads to constitutive activation of Janus kinase (JAK)2 and contributes to dysregulated JAK signaling in myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). In the phase 3 Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment-I trial, patients with MF, post-PV MF, or post-ET MF achieved significant reductions in splenomegaly and improvements in symptoms with ruxolitinib vs placebo at week 24. This long-term follow-up analysis was performed to determine whether ruxolitinib therapy altered the JAK2p.V617F allele burden in JAK2p.V617F-positive patients. Assessments at baseline and weeks 24, 48, 120, 144, 168, and 216 demonstrated reductions in allele burden from baseline with ruxolitinib treatment that correlated with spleen volume reductions. Of 236 JAK2p.V617F-positive patients analyzed, 20 achieved partial and 6 achieved complete molecular responses, with median times to response of 22.2 and 27.5 months, respectively. Allele burden reductions were greater in patients with shorter disease duration, which suggests a potential benefit of earlier treatment. This trial was registered at www.clinicaltrials.gov as #NCT00952289. PMID- 26228488 TI - Analysis of Shear-Induced Platelet Aggregation and Breakup. AB - To better understand the mechanisms leading to the formation of thrombi of hazardous sizes in the bulk of the blood, we have developed a kinetic model of shear-induced platelet aggregation (SIPA). In our model, shear rate regulates a mass-conservative population balance equation which computes the aggregation and disaggregation of platelets in a cluster mass distribution. Aggregation is modeled by the Smoluchowski coagulation equation, and disaggregation is incorporated using the aggregate breakup model of Pandya and Spielman. Previous experimental data for SIPA have been correlated with a special case of this model where only the two-body collision of free platelets was considered. However, the two-body collision theory is oblivious to the steady-state condition, and it required the use of a shear-dependent aggregation efficiency parameter to fit it to experimental data. Our method not only predicts steady states but also correlates with literature data without employing a shear-dependent aggregation efficiency. PMID- 26228486 TI - Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma. AB - Early-stage cutaneous T-cell lymphoma (CTCL) is a skin-limited lymphoma with no cure aside from stem cell transplantation. Twelve patients with stage IA-IIA CTCL were treated in a phase 1 trial of 0.03% and 0.06% topical resiquimod gel, a Toll like receptor 7/8 agonist. Treated lesions significantly improved in 75% of patients and 30% had clearing of all treated lesions. Resiquimod also induced regression of untreated lesions. Ninety-two percent of patients had more than a 50% improvement in body surface area involvement by the modified Severity Weighted Assessment Tool analysis and 2 patients experienced complete clearing of disease. Four of 5 patients with folliculotropic disease also improved significantly. Adverse effects were minor and largely skin limited. T-cell receptor sequencing and flow cytometry studies of T cells from treated lesions demonstrated decreased clonal malignant T cells in 90% of patients and complete eradication of malignant T cells in 30%. High responses were associated with recruitment and expansion of benign T-cell clones in treated skin, increased skin T-cell effector functions, and a trend toward increased natural killer cell functions. In patients with complete or near eradication of malignant T cells, residual clinical inflammation was associated with cytokine production by benign T cells. Fifty percent of patients had increased activation of circulating dendritic cells, consistent with a systemic response to therapy. In summary, topical resiquimod is safe and effective in early-stage CTCL and the first topical therapy to our knowledge that can induce clearance of untreated lesions and complete remissions in some patients. This trial was registered at www.clinicaltrials.gov as #NCT813320. PMID- 26228489 TI - Waist Circumference as a Predictor of Failure of Sonographic Estimation of Fetal Birth Weight. AB - OBJECTIVE: Several factors may interfere with the success of fetal birth weight (BW) prediction. In this study we tried to determine the most probable factors that may lead to unsuccessful BW estimation. METHODS: 200 consecutive pregnancies between 34 and 41 weeks of gestation were enrolled for the study. All subjects underwent sonographic fetal BW estimation before membrane rupture or engagement of presented part. Sonography was performed by the same sonographer blinded to the study design. Failure of estimation was determined when deviation was found to be >15%. RESULTS: Both amniotic fluid index (AUC = 0.768, p < 0.001) and maternal waist circumference (AUC = 0.698, p = 0.004) were significant predictors for failure of estimation. Optimal cut-off values were 80 mm for amniotic fluid index (77% sensitivity, 65% specificity) and 105 cm for maternal waist circumference (70% sensitivity, 61% specificity). The number of pregnancies with anteriorly located placenta was significantly higher in the group with failed estimation (12/20 vs. 39/180, p = 0.001). CONCLUSION: Amniotic fluid volume, body mass index, maternal waist circumference and placental location may all cause failure of fetal weight estimation and may need to be adjusted. Moreover, our results indicate that waist circumference may be a more reliable predictor of failure of fetal weight estimation compared to body mass index. PMID- 26228490 TI - An ordered and porous N-doped carbon dot-sensitized Bi2O3 inverse opal with enhanced photoelectrochemical performance and photocatalytic activity. AB - A novel ordered porous Bi2O3 inverse opal structure (IOS) was prepared using a polystyrene (PS) photonic crystal as the template for the first time. Nitrogen doped carbon dots (N-CDs) were chosen to sensitize the as-prepared Bi2O3 IOS for improving photoelectrochemical performance and photocatalytic activity. The photocurrent density of the fabricated N-CDs/Bi2O3 IOS with favorable visible light absorption properties can achieve 0.75 mA cm(-2), which significantly enhanced performance two-, seven-, and thirty-fold compared with that of the CDs/Bi2O3 IOS, Bi2O3 IOS, and Bi2O3 nanoparticles (NPs), respectively. The N CDs/Bi2O3 IOS also has increased photocatalytic activity for the decolorization of Rhodamine B (RhB), 4 times higher than Bi2O3 NPs. The above performance enhancement of N-CDs/Bi2O3 IOS is caused by the synergistic effect of N-CDs sensitization and the highly ordered IOS, which make it a promising material to be used in clean energy, solar cells, potential applications in water purification and so on. PMID- 26228491 TI - Range of Hip Joint Motion in Developmental Dysplasia of the Hip Patients Following Total Hip Arthroplasty With the Surgical Technique Using the Concept of Combined Anteversion: A Study of Crowe I and II Patients. AB - The combined anteversion surgical technique has been proposed and used in clinical practice. To more objectively evaluate the feasibility of this surgical technique using combined anteversion concept for DDH patients, we studied 34 DDH patients (40 hips) in this research. Every patient underwent pelvic CT scans before and after surgery and the HHSs were recorded. Optimal range of joint motion was measured using a three-dimensional reconstruction technique and a dynamic measurement technique. The results revealed that joint function met the requirements of daily life and the range of motion was not over-limited by impingement between the prosthesis and the skeleton. Moreover, the combined anteversion was found to be the most critical parameter in this study. PMID- 26228492 TI - Russula subnigricans Poisoning: From Gastrointestinal Symptoms to Rhabdomyolysis. AB - Wild mushroom poisoning is often reported to cause acute liver or renal failure. However, acute rhabdomyolysis caused by wild mushroom poisoning has rarely been reported. We describe 7 patients of 1 family with Russula subnigricans Hongo poisoning. Their clinical manifestations varied from gastrointestinal symptoms to rhabdomyolysis, with 1 fatality. Our report provides supporting evidence that rhabdomyolysis may result from ingestion of R subnigricans mushrooms. A key to survival for patients with rhabdomyolysis caused by R subnigricans poisoning may be early recognition and intensive supportive care. PMID- 26228493 TI - Effectiveness of mandibular advancement appliances in treating obstructive sleep apnea syndrome: A systematic review. AB - OBJECTIVES/HYPOTHESIS: Mandibular advancement devices are an alternative to continuous positive airway pressure for patients with mild or moderate obstructive sleep apnea/hypopnea syndrome (OSAHS). The main aim of this review was to assess the effectiveness of different devices in treating OSAHS, based on polysomnographic measurements such as the apnea/hypopnea index (AHI) and oxygen saturation, and on changes in the upper airway and improvements in the most common symptoms: snoring and somnolence. Their adverse effects were also noted. STUDY DESIGN: Systematic review. METHODS: Following an exhaustive search in the Medline, Scopus, and Cochrane Library databases, 22 articles published in the past 10 years met the quality and inclusion criteria. RESULTS: Using mandibular advancement devices during the hours of sleep helps to prevent snoring and excessive daytime sleepiness, reduce the AHI significantly, and bring about beneficial changes in the upper airway. Adjustable and custom-made mandibular advancement devices give better results than fixed and prefabricated appliances. Monobloc devices give rise to more adverse events, although these are generally mild and transient. CONCLUSIONS: Mandibular advancement devices increase the area of the airway. They bring the soft palate, tongue, and hyoid bone forward and activate the masseter and submental muscles, preventing closure. All these effects reduce the AHI, increase the oxygen saturation, and improve the main symptoms of OSAHS. LEVEL OF EVIDENCE: NA. PMID- 26228495 TI - A novel and effortless technique for application of lower limb backslabs. PMID- 26228494 TI - Treatment patterns for older veterans with localized prostate cancer. AB - OBJECTIVE: Concerns about over-treatment have led to practice guidelines discouraging active treatment of prostate cancer (PCa) in men with limited life expectancies and/or low-risk tumors. We evaluated treatment patterns for older veterans with localized PCa, particularly those with low-risk features. METHODS: We used VA Cancer Registry data to identify men aged 65+ diagnosed with clinically localized PCa between January 1st, 2003 and December 31st, 2008. We obtained baseline data on demographics, tumor characteristics, comorbidities, and initial treatment within 6 months of diagnosis: radical prostatectomy, radiotherapy, primary androgen-deprivation therapy (PADT), or no active treatment. National VA surveys provided facility data, including academic affiliation, availability of oncologic specialists, and distance to radiotherapy facilities. Multinomial regression analyses determined associations between patient and facility characteristics and cancer treatment for men with localized (stage=3, and 33% had low-risk tumors. Overall, 39% received radiotherapy, 6% surgery, 20% PADT, and 35% no active treatment. For those with low-risk cancers, older men (RR=0.36, 95% CI 0.30-0.43) and sicker men (RR=0.75, 95% CI 0.62-0.90) were less likely to receive surgery or radiotherapy versus no active treatment. Over time, more of these men received no active treatment (from 41% to 57%, P<0.001) while fewer received PADT (from 11% to 4%, P<0.001). CONCLUSION: VA treatment patterns followed evidence-based guidelines against treating older and sicker men with surgery or radiotherapy, for decreasing use of PADT, and for increasingly withholding active treatment, particularly for men with low-risk PCa. PMID- 26228496 TI - Effectiveness of hyaluronic acid in post-tonsillectomy pain relief and wound healing: a prospective, double-blind, controlled clinical study. AB - OBJECTIVES: To find the effectiveness of hyaluronic acid in post-tonsillectomy pain relief and wound healing. METHODS: Fifty patients were included in this prospective, double-blind, controlled clinical study (20 males, 30 females mean age of 13.56 years). Hyaluronic acid was applied to one side and the other side was used as a control during tonsillectomy. Therefore, the same patient evaluated and scored the post-tonsillectomy pain, excluding individual bias. RESULTS: Results indicated that patients had significantly lower pain scores for hyaluronic acid treated side (p<0.001). At the end of two weeks follow-up period, the wound in the hyaluronic acid side was almost completely healed, indicating that the healing was faster with hyaluronic acid compared to control side (p<0.001). CONCLUSION: Hyaluronic acid could be recommended as an effective treatment for the management of post-tonsillectomy pain and wound healing. PMID- 26228498 TI - [Gunshot and stab wounds: Combination of clinical and forensic medical data]. PMID- 26228497 TI - The microbiome of otitis media with effusion in Indigenous Australian children. AB - INTRODUCTION: Indigenous Australian children have a high prevalence of otitis media with effusion (OME) and associated conductive hearing loss. Only three microbiological studies of middle ear fluid (MEF) from Indigenous Australian children with OME have been reported. All of these were reliant on culture or species-specific PCR assays. The aim of this study was to characterise the middle ear fluid (MEF), adenoid and nasopharyngeal (NP) microbiomes of Indigenous Australian children, using culture-independent 16S rRNA gene sequencing. METHODS: MEF, NP swabs and adenoid specimens were collected from 11 children in the Alice Springs region of Central Australia. Bacterial communities in these specimens were characterised using 16S rRNA gene sequencing. RESULTS: The microbiota in MEF samples were dominated (>50% relative abundance) by operational taxonomic units (OTUs) consistent with Alloiococcus otitidis (6/11), Haemophilus influenzae (3/11) or Streptococcus sp. (specifically, Mitis group streptococci which includes Streptococcus pneumoniae) (1/11). Anatomical site selectivity was indicated by the presence of a single conserved Haemophilus OTU in 7/11 MEF samples. In comparison, there were ten distinct Haemophilus OTUs observed across the NP and adenoid samples. Despite significant differences between the MEF and NP/adenoid microbiomes, Streptococcus sp., H. influenzae and Moraxella catarrhalis OTUs were common to all sample types. Co-occurrence of classical otopathogens in paired MEF and NP/Adenoid samples is consistent with earlier culture-based studies. CONCLUSION: These data highlight the need to further assess H. influenzae traits important in otitis media and to understand the role of canal flora, especially A. otitidis, in populations with a high prevalence of tympanic membrane perforation. PMID- 26228499 TI - Advantages of Recombinant Follicle-Stimulating Hormone over Human Menopausal Gonadotropin in Intrauterine Insemination: A Randomized Clinical Trial in Polycystic Ovary Syndrome-Associated Infertility. AB - BACKGROUND: Various gonadotropin preparations have been used for ovarian stimulation in intrauterine insemination (IUI). The purpose of the current study was to compare human menopausal gonadotropin (hMG) and recombinant follicle stimulating hormone (rFSH) combined with clomiphene citrate (CC) in IUI cycles for polycystic ovary syndrome-associated infertility. METHODS: In this prospective trial, couples prepared for IUI cycles were randomly allocated either to receive CC and rFSH (group A, n = 132) or CC and hMG (group B, n = 144) for ovarian stimulation. Outcomes including rates of clinical pregnancy, miscarriage, ovarian hyperstimulation syndrome, multiple pregnancy, cancellation and live birth were compared. RESULTS: The duration of gonadotropin therapy was shorter and total doses of gonadotropins was lower in the rFSH group. The number of stimulated follicles reaching >17 mm diameter was comparable between groups, but the mean follicular diameter was significantly higher in the rFSH group. The endometrium was also significantly thicker at the time of human chorionic gonadotropin administration in the rFSH group. However, pregnancy outcomes, including the rates of clinical pregnancy, ongoing pregnancy, live birth, miscarriage, ovarian hyperstimulation syndrome and cancellation, were similar between groups. CONCLUSION: IUI cycles in which rFSH is administered may result in shorter duration of treatment, a lower total gonadotropin dose and better follicular and endometrial characteristics on the day of human chorionic gonadotropin injection. (c) 2015 S. Karger AG, Basel. PMID- 26228500 TI - New and emerging concepts in managing and preventing community-associated methicillin-resistant Staphylococcus aureus infections. AB - Methicillin-resistant Staphylococcus aureus (MRSA) infections occurring within communities are increasing and can affect healthy individuals who have had little to no experience with hospital or healthcare settings (community-associated MRSA, CA-MRSA). CA-MRSA infections have multiple presentations which can make diagnosis and timely treatment difficult yet often manifest as a skin and soft tissue infection (SSTI) requiring dermatological intervention. There is emerging evidence of multiple environmental sources of bacteria that may contribute to recurrence. As with other infections, preventing transmission and recurrence depends on adherence to hand-washing and personal hygiene practices. Pharmaceutical intervention should be culture- rather than empirically-guided. The goal of this review is to provide dermatologists with a brief summary of the diagnostic features of CA-MRSA infections and updated strategies for management and prevention of transmission and recurrence of CA-MRSA infections, infections likely to present to dermatology offices. PMID- 26228502 TI - [Large scale nursing competitions for a permanent job: a symptom of lack of strategies on nurses?]. PMID- 26228501 TI - New acyloxy nitroso compounds with improved water solubility and nitroxyl (HNO) release kinetics and inhibitors of platelet aggregation. AB - New acyloxy nitroso compounds, 4-nitrosotetrahydro-2H-pyran-4-yl 2,2,2 trichloroacetate and 4-nitrosotetrahydro-2H-pyran-4-yl 2,2-dichloropropanoate were prepared. These compounds release HNO under neutral conditions with half lives between 50 and 120min, identifying these HNO donors as kinetically intermediate to the much slower acetate derivative and the faster trifluoroacetic acid derivative. These compounds or HNO-derived from these compounds react with thiols, including glutathione, thiol-containing enzymes and heme-containing proteins in a similar fashion to other acyloxy nitroso compounds. HNO released from these acyloxy nitroso compounds inhibits activated platelet aggregation. These acyloxy nitroso compounds augment the range of release for this group of HNO donors and should be valuable tools in the further study of HNO biology. PMID- 26228503 TI - [The natural story of a mega selection for nurses: a case study]. AB - INTRODUCTION: In the Italian National Health Service, it has been documented recently a new phenomenon called 'mega-selection' where thousands of newly graduates submit their application and compete for the few positions available. However, scarce scientific information is available on mega - selections and their outcomes. OBJECTIVES: To evaluate the nurses candidates profile attending the public selections, the factors affecting their likelihood of success and the duration of the entire selection process. METHODS: Administrative data of the public selection of nurses performed by 4-health trusts in Friuli Venezia Giulia (Italy) has been obtained: the number and characteristics of the candidates admitted, as well as of those who passed the competition. RESULTS: Over 3.901 applications, 3.880 candidates were admitted to the selection; only 1.690 (43.3%) attended the public selection, 417 (10.6%) passed the first examination and 217 (7%) passed the competition (7%). The winners were, on average, 27 years old, graduated from approximately 1.5 years, lived and obtained their nursing degree in the northern Italian regions. CONCLUSIONS: With the hiring freezing documented in recent years in the health sector, a large number of candidates are expected in the public selections; however a limited number succeed in the selection process. Some recommendations are proposed to streamline the public selection process. PMID- 26228504 TI - [Pre-analytical errors in blood sampling: an observational study on specimen collection technique and laboratory results]. AB - INTRODUCTION: Around 60-70% of diagnostic and therapeutic decisions are based on blood exams. Several errors occur during the pre-analytic phase. AIMS: of this study were: to describe nurses' behaviours in blood specimen collection; to describe prevalence and type of pre-analytical errors; to assess the association between pre-analytical errors and occurrence of unsuitable specimens. METHODS: An observational cross-sectional study was conducted by means of a structured form based on up-to-date clinical recommendations. A researcher observed nurses' behaviors during 172 blood sampling procedures in medical, surgical and emergency care settings. Unsuitable procedures were registered. RESULTS: Most behaviours were correct, however some significantly diverged from recommended practices: active and passive patient identification; respect of antiseptic solution's drying time; rapid removal of tourniquet when blood started flowing. The prevalence of unsuitable specimen reports was significantly higher when the procedure involved a small calibre vein (RP: 0.19; IC95% 0.04 - 0.98; p = 0.03) and when blood drawing was difficult (RP; 3.83; IC95% 1.63 - 9.01; p <0.001). CONCLUSIONS: The pre-analytical phase is important for the diagnostic process and safety of patients. Although some factors - as patients' characteristics - are non-modifiable, some nurses' behaviours could be improved to reduce risk of pre analytical errors. Further studies are needed to clarify the associations between pre-analytical errors and laboratory outcomes. PMID- 26228505 TI - [Can a blood sample for diagnostic exams be drawn from a peripheral venous catheter?]. AB - INTRODUCTION: Often the blood sample in patients exposed to serial blood exams is taken from the venous cannula (PVC) to avoid a second venipuncture. AIM: To assess whether blood draws from PVCs are more haemolized than those drawn from phlebotomy, and if the blood drawn from a cannula interferes with the test results. METHODS: A bibliographic search was conducted in PubMed, Cinhal and Ovid, with the following key words: Peripheral Catheter, Blood Specimen Collection, Blood Sample, Haemolysis, 19 articles were identified (including 2 meta analyses), selecting the articles involving emergency departments. RESULTS: The meta-analyses agree on the lower risk for haemolysis in blood drawn from a needle: risk reduction of 84% (RR=0.16, IC 95% 0.11-0.24) (Heyer et al); the blood draw from PVC increased the risk for hemolysis of 7% (RR 1.07 IC 95% 1.06 1.08, p<0.001) (Lippi et al). Manual aspiration reduces the risk for hemolysis compared to the vacutainer equipment. However, the results of tests drawn from PVC are not significantly different compared to the classical phlebotomy. CONCLUSIONS: Blood draws from PVC bear an higher risk for heamolysis but can be safely used for most diagnostic exams, with the exception of blood gase. PMID- 26228506 TI - [Should nurses be managed by doctors or nurses?]. AB - A recent verdict of the administrative court of Lazio Region abrogated a Decree that originally stated that nurse managers (and not the head of the medical department) should be responsible for the management of the nursing personnel, and that had set up the premises for the Nursing Departments. The verdict contrasts with a previous pronouncement of the same court (same members, same president) that supported the wards organized by intensity of care and run by nurses. The organization should be flexible and be shaped not by power struggles but by patients needs: while patients in acute care require mostly medical interventions, chronic patients require more educational and nursing interventions. The verdict is the occasion for reflections on the never ending contrasts between doctors and nurse, that often move to the background patients' priorities and care. PMID- 26228507 TI - [Ordinary life stories?]. AB - Very often simple and well known measures, if correctly implemented, are able to control problems, reduce infections and improve the quality of care. Most of these measures are (independent) nursing interventions. Two experiences related to infection control practices - for the reduction of central venous catheter infections in intensive care units and urinary tract infections in a nursing home show, once again, the invaluable nurses' role and contribution to patients safety and care. PMID- 26228508 TI - [In Process Citation]. AB - The encyclical letter of Papa Francesco on an integral ecology (with its universal, not religious or catholic approach to the theme) includes a very comprehensive "care" of the world. It appears to be of specific interest and relevance for an innovative understanding of the role of the nursing profession, which crosses also frequently the fragile victims of the violations of the "human ecology", and which is called to be among the actors of active promotion of fundamental rights to life. PMID- 26228509 TI - Macrolides increase the expression of 11beta-hydroxysteroid dehydrogenase 1 in human sinonasal epithelium, contributing to glucocorticoid activation in sinonasal mucosa. AB - BACKGROUND AND PURPOSE: The anti-inflammatory and immunomodulatory effects of macrolides include the ability to decrease mucus secretion and inhibit inflammatory mediators in chronic rhinosinusitis. Nevertheless, their mechanisms of action remain to be determined. Here we have investigated the effects of macrolide antibiotics (clarithromycin, azithromycin and josamycin; representating the 14-, 15- and 16-membered macrolides) on endogenous steroids in human sinonasal epithelial cells and mouse nasal mucosa. EXPERIMENTAL APPROACH: The effects of macrolides on the expression of steroid-converting enzymes [11beta hydroxysteroid dehydrogenase (11beta-HSD1 and 11beta-HSD2)], steroid-synthesizing enzymes (3beta-HSD, CYP21, CYP11B1 and CYP11A1) and cortisol levels were assessed in cultured human epithelial cells. In control and adrenalectomized mice , these enzymes and corticosterone levels were evaluated in nasal mucosa and serum after administration of macrolides. KEY RESULTS: The expression levels of 3beta-HSD, CYP21, 11beta-HSD1 and CYP11B1 increased in human epithelial cells treated with clarithromycin and azithromycin, whereas the expression levels of 11beta-HSD2 and CYP11A1 were not affected. Josamycin had no effects on the expression of these enzymes. Cortisol levels increased in epithelial cells treated with clarithromycin or azithromycin. The expression of 3beta-HSD, CYP11A1, CYP21, CYP11B1 and 11beta-HSD1 was upregulated in nasal mucosa of mice treated with clarithromycin or azithromycin, but not in adrenalectomized mice. CONCLUSIONS AND IMPLICATIONS: This study provides evidence that 14- and 15-membered macrolide antibiotics may affect the expression of steroid-synthesizing and steroid converting enzymes in human sinonasal epithelial cells and mouse nasal mucosa, increasing the endogenous cortisol levels in sinonasal mucosa. PMID- 26228510 TI - Effect of 1-Minute Fluoride Treatment on Potential Virulence and Viability of a Cariogenic Biofilm. AB - Fluoride is a well-studied and widely used agent for the prevention of dental caries. Although dental caries is strongly related to cariogenic biofilms, the effect of brief fluoride treatment on the virulence properties of biofilms has not been well studied. This study evaluated the effect of a 1-min fluoride treatment on the virulence properties and viability of cariogenic biofilms, using a Streptococcus mutans biofilm model. For this study, 46-hour-old S. mutans biofilms were formed on saliva-coated hydroxyapatite discs and were treated with fluoride (0, 30, 300, 1,000, and 2,000 ppm F(-)) for 1 min. Viability and changes in acidogenicity, aciduricity and extracellular polysaccharide (EPS) formation of the biofilms were analyzed using biochemical and microbiological methods (pH drop, H(+) permeability, acid killing, and bacterial colony-forming unit assays). Laser scanning confocal fluorescence microscopy study was also performed. After the 1-min fluoride treatment, acidogenicity, aciduricity, and EPS formation of 46 hour-old S. mutans biofilms were significantly reduced when treated with concentrations >=300 ppm F(-). The antivirulence activities of the 1-min fluoride treatment increased in a concentration-dependent pattern. However, the 1-min fluoride treatments did not affect viability, biovolume, and microcolony appearance of biofilm bacteria, even at high concentrations. These results suggest that the brief treatment with fluoride at concentrations >=300 ppm F(-) is an effective measure for controlling cariogenic biofilms. PMID- 26228511 TI - Gnathostoma spinigerum Mitochondrial Genome Sequence: a Novel Gene Arrangement and its Phylogenetic Position within the Class Chromadorea. AB - Human gnathostomiasis is an emerging food-borne parasitic disease caused by nematodes in the genus Gnathostoma. In spite of their significance as pathogens, these parasites remain poorly understood at the molecular level. In the present study, we sequenced the mitochondrial (mt) genome of G. spinigerum, which infects a range of definitive hosts including dogs, cats, tigers, leopards and humans. The mt genome of G. spinigerum is 14,079 bp in size and shows substantial changes in gene order compared to other nematodes studied to date. Phylogenetic analyses of mt genome sequences by Bayesian inference (BI) revealed that the infraorder Gnathostomatomorpha (represented by G. spinigerum) is closely related to the infraorder Ascaridomorpha. G. spinigerum is the first species from the infraorder Gnathostomatomorpha for which a complete mt genome has been sequenced. The new data will help understand the evolution, population genetics and systematics of this medically important group of parasites. PMID- 26228513 TI - Dorsum sellae and bilateral temporal bone fracture associated with bilateral abducens and facial nerve palsy: letter to the editor. PMID- 26228512 TI - pLR-HL: A Novel Amphibian Bowman-Birk-type Trypsin Inhibitor from the Skin Secretion of the Broad-folded Frog, Hylarana latouchii. AB - In this study, we report a novel heptadecapeptide (LIGGCWTKSIPPKPCLV) of the pLR/ranacyclin family, named pLR-HL, whose structure was deduced from its biosynthetic precursor-encoding cDNA cloned from the skin secretion-derived cDNA library of the broad-folded frog, Hylarana latouchii, by employing a 'shotgun' cloning technique. It contains a disulphide loop between Cys(5) and Cys(15) which is consistent with Bowman-Birk-type protease inhibitors. The primary structure of pLR-HL deduced from the cDNA sequence was confirmed by fractionating the skin secretion using reverse-phase HPLC and subsequent analysis using MALDI-TOF mass spectrometry and LC/MS/MS fragmentation sequencing. On the basis of the establishment of unequivocal amino acid sequence, a synthetic replicate was synthesized by solid-phase Fmoc chemistry, and it displayed a moderately potent trypsin inhibition with a Ki of 143 nm. The substitution of Lys-8 by Phe (Phe(8) pLR-HL) resulted in abolition of trypsin inhibition but generation of modest inhibition on chymotrypsin with a Ki of 2.141 MUm. Additionally, both the disulphide loops of pLR-HL and Phe(8) -pLR-HL were synthesized and tested. Both of the catalytic loops retained similar inhibitory potencies towards trypsin or chymotrypsin in comparison with the original intact molecules. Thus, the replacement of reactive site residues could alter the specificity of these protease inhibitors, while the canonical reactive loop alone can independently constitute biologically active moiety. PMID- 26228514 TI - Intraoperative electrical stimulation of the cortex reveals the speech area missed by extraoperative stimulation because of epicortical hematoma. PMID- 26228515 TI - Effects of intravenous immunoglobulin therapy on behavior deficits and functions in sepsis model. AB - BACKGROUND: We aim to demonstrate behavioral alterations in a sepsis model using intravenous (IV) immunoglobulin G (IgG) and immunoglobulins enriched with IgA and IgM (IgGAM). METHODS: We divided 48 Wistar albino rats into five groups: control group, sham-operated group (only antibiotic treatment), cecal ligation and puncture (CLP) group (CLP plus antibiotic treatment), IgG group (250 mg/kg IV IgG) and IgGAM group (250 mg/kg IV IgGAM). Intravenous immunoglobulins were given 5 min after the CLP procedure. Experimental animals put into three behavioral tasks 10, 30 and 60 days after the surgery; to evaluate the locomotor activity, an open field test was performed, elevated plus maze test was used to measure anxiety levels, and depressive state was assessed by forced swimming test. The effects of therapy which were acquired from the results of these tests were used to estimate the behavioral changes after CLP. RESULTS: The mortality rate of 50% in the septic rats decreased to 30 and 20% with the administration of IgG and IgGAM, respectively. Significant changes on locomotor activity and depressive like behavior were reported in the sepsis group; on the other hand, the treatment with immunoglobulins reduced the symptoms. Treatment with immunoglobulins attenuated the sepsis-related anxiogenic-like responses. Behavioral alterations returned to normal on day 60 in all groups. CONCLUSIONS: Sepsis caused deterioration on behavioral parameters. Immunoglobulin treatments alleviated the symptoms of functional disturbances and caused early reversal of behavioral deficits in septic animals. PMID- 26228516 TI - Randomized controlled trial comparing esophageal dilation to no dilation among adults with esophageal eosinophilia and dysphagia. AB - The role of esophageal dilation in patients with esophageal eosinophilia with dysphagia remains unknown. The practice of dilation is currently based on center preferences and expert opinion. The aim of this study is to determine if, and to what extent, dysphagia improves in response to initial esophageal dilation followed by standard medical therapies. We conducted a randomized, blinded, controlled trial evaluating adult patients with dysphagia and newly diagnosed esophageal eosinophilia from 2008 to 2013. Patients were randomized to dilation or no dilation at time of endoscopy and blinded to dilation status. Endoscopic features were graded as major and minor. Subsequent to randomization and endoscopy, all patients received fluticasone and dexlansoprazole for 2 months. The primary study outcome was reduction in overall dysphagia score, assessed at 30 and 60 days post-intervention. Patients with severe strictures (less than 7-mm esophageal diameter) were excluded from the study. Thirty-one patients were randomized and completed the protocol: 17 randomized to dilation and 14 to no dilation. Both groups were similar with regard to gender, age, eosinophil density, endoscopic score, and baseline dysphagia score. The population exhibited moderate to severe dysphagia and moderate esophageal stricturing at baseline. Overall, there was a significant (P < 0.001) but similar reduction in mean dysphagia score at 30 and 60 days post-randomization compared with baseline in both groups. No significant difference in dysphagia scores between treatment groups after 30 (P = 0.93) or 60 (P = 0.21) days post-intervention was observed. Esophageal dilation did not result in additional improvement in dysphagia score compared with treatment with proton pump inhibitor and fluticasone alone. In patients with symptomatic esophageal eosinophilia without severe stricture, dilation does not appear to be a necessary initial treatment strategy. PMID- 26228517 TI - Job characteristics and musculoskeletal pain among shift workers of a poultry processing plant in Southern Brazil. AB - OBJECTIVES: The purpose of this study was to evaluate the association between job characteristics and musculoskeletal pain among shift workers employed at a 24 hour poultry processing plant in Southern Brazil. METHODS: This was a cross sectional study of 1,103 production line workers aged 18-52 years. The job characteristics of interest were shift (day/night), shift duration, and plant sector ambient temperature. Musculoskeletal pain was defined as self-reported occupational-related pain in the upper or lower extremities and trunk, occurring often or always, during the last 12 months. RESULTS: The mean (SD) participant age was 30.8 (8.5) years, and 65.7% of participants were women. The prevalence of musculoskeletal pain was greater among female participants than male participants. After adjustment for job characteristics and potential confounders, the prevalence ratios (PR) of lower extremity musculoskeletal pain among female workers employed in extreme-temperature conditions those working the night shift, and those who had been working longer on the same shift were 1.75 (95% CI 1.12, 2.71), 1.69 (95% CI 1.05, 2.70), and 1.64 (95% CI 1.03, 2.62), respectively. In male workers, only extreme-temperature conditions showed a significant association with lower extremity musculoskeletal pain (PR=2.17; 95% CI 1.12, 4.22) after adjustment analysis. CONCLUSIONS: These findings suggest a need for implementation of measures to mitigate the damage caused by nighttime work and by working under extreme temperature conditions, especially among female shift workers, such as changing positions frequently during work and implementation of rest breaks and a workplace exercise program, so as to improve worker quality of life. PMID- 26228518 TI - Occupational injuries of teachers and educational staff at special schools with multiple and severely handicapped children in Rhineland-Palatinate (Germany): results of a cross-sectional study. AB - OBJECTIVES: The present study aimed to describe the prevalence, type, and influencing factors of occupational injuries of staff working at special schools with multiple and severely handicapped pupils in Southwestern Germany. METHODS: This cross-sectional study was carried out between August 2010 and August 2012 at 13 special schools with focus on motoric and/or holistic development of handicapped pupils in Rhineland-Palatinate (Germany). Participants were interviewed using a written questionnaire. RESULTS: There were 395 participants (response proportion: 59.7%) in our study, with 390 being eligible for statistical analysis. Respondents were on average 45 years old and mainly female (86.9%). The 12-month injury prevalence was 16.9%. Joint dislocations, sprains, and torn ligaments (41.6%) were the main types of injuries. Pupils (59.8%) and auxiliary equipment (12.2%) were identified as the main causes of injury by the respondents. Multivariable logistic regression analysis showed that washing pupils (using auxiliary equipment) (aOR, 3.93; 95% CI, 1.66-9.31) and daily physical strain due to unexpected conduct of pupils (aOR, 3.70; 95% CI, 1.20 11.37) were the main influencing factors for an occupational injury. CONCLUSIONS: Almost one in five persons suffered an occupational injury in the previous 12 months. Nursing activities, including close contact with pupils, were identified as the most important factors for an injury. In order to prevent injuries at special schools, a multifaceted approach is necessary. This includes sufficient supply of auxiliary devices including proper technical maintenance. Furthermore, regular participation in training for manual handling of heavy loads and schooling on the technical use of auxiliary devices should be encouraged. PMID- 26228519 TI - Sickness absence among young employees: trends from 2002 to 2013. AB - OBJECTIVES: Young adults entering employment are a key group in extending work careers, but there is a lack of research on trends in work ability among young employees. Prolonged sickness absence (SA) constitutes a risk for permanent work disability. We examined 12-year trends in SA spells among young female and male municipal employees. METHODS: The data were obtained from the employers' registers in the City of Helsinki, Finland. The data included employees aged 18 24, 25-29, 30-34, and 35-54 from 2002 to 2013 (the average number for each year was 31,600). Self-certified (1-3 days) and medically certified intermediate (4-14 days) and long (15+ days) SAs were examined. Joinpoint regression models were used to identify major changes in SA trends. RESULTS: Younger employees had more short SAs but fewer long SAs than older employees. During the study period, SAs of almost any length first increased and later decreased among both genders, except for young men. The turning points for short SA were in 2007-2011 among younger and older employees. In intermediate and long SAs the respective turning points were in 2008-2009 and 2005-2009. Women had more SAs in all categories. CONCLUSIONS: Age is related to the length of absences. Given the relatively low chronic morbidity among younger employees, it is likely that reasons other than ill health account for increased SA. More evidence on factors behind the changing trends is needed in order to reduce SA and extend the working careers of young people. PMID- 26228520 TI - Long working hours and sleep problems among public junior high school teachers in Japan. AB - OBJECTIVES: Long working hours may impact human health. In Japan, teachers tend to work long hours. From 2002 to 2012, the number of leaves of absence due to diseases other than mental disorders, or mental disorders among public school teachers increased by 1.3 times (from 2,616 to 3,381), or 1.8 times (from 2,687 to 4,960), respectively. The present study aimed to investigate the association between long working hours and sleep problems among public school teachers. METHODS: This cross-sectional study was conducted from mid-July to September 2013 in Hokkaido Prefecture, Japan. Questionnaires were distributed to 1,245 teachers in public junior high schools. Information about basic characteristics including working hours, and responses to the Pittsburgh Sleep Quality Index were collected anonymously. Multiple logistic regression analysis was used to calculate odds ratios (ORs) for the association between long working hours and sleep problems separately by sex. RESULTS: The response rate was 44.8% (n=558). After excluding ineligible responses, the final sample comprised 515 teachers (335 males and 180 females). Sleep problems was identified in 41.5% of males and 44.4% of females. Our results showed a significantly increased risk of sleep problems in males working >60 hours per week (OR 2.05 [95% CI 1.01-4.30]) compared with those working <=40 hours per week. No significant association was found in females. CONCLUSIONS: There is a significant association between long working hours and sleep problems in male teachers. Reducing working hours may contribute to a reduction in sleep problems. PMID- 26228521 TI - Early prognostication markers in cardiac arrest patients treated with hypothermia. AB - BACKGROUND AND PURPOSE: Established prognostication markers, such as clinical findings, electroencephalography (EEG) and biochemical markers, used by clinicians to predict neurological outcome after cardiac arrest (CA) are altered under therapeutic hypothermia (TH) conditions and their validity remains uncertain. METHODS: MEDLINE and Embase were searched for evidence on the current standards for neurological outcome prediction for out-of-hospital CA patients treated with TH and the validity of a wide range of prognostication markers. Relevant studies that suggested one or several established biomarkers and multimodal approaches for prognostication are included and reviewed. RESULTS: Whilst the prognostic accuracy of various tests after TH has been questioned, pupillary light reflexes and somatosensory evoked potentials are still strongly associated with negative outcome for early prognostication. Increasingly, EEG background activity has also been identified as a valid predictor for outcome after 72 h after CA and a preferred prognostic method in clinical settings. Neuroimaging techniques, such as magnetic resonance imaging and computed tomography, can identify functional and structural brain injury but are not readily available at the patient's bedside because of limited availability and high costs. CONCLUSIONS: A multimodal algorithm composed of neurological examination, EEG-based quantitative testing and somatosensory evoked potentials, in conjunction with newer magnetic resonance imaging sequences, if available, holds promise for accurate prognostication in CA patients treated with TH. In order to avoid premature withdrawal of care, prognostication should be performed more than 72 h after CA. PMID- 26228522 TI - Sarcopenia and the Common Mental Disorders: a Potential Regulatory Role of Skeletal Muscle on Brain Function? AB - While it is understood that body composition impacts on physical conditions, such as diabetes and cardiovascular disease, it is only now apparent that body composition might play a role in the genesis of common mental disorders, depression and anxiety. Sarcopenia occurs in ageing and comprises a progressive decline in muscle mass, strength and function, leading to frailty, decreased independence and poorer quality of life. This review presents an emerging body of evidence to support the hypothesis that shared pathophysiological pathways for sarcopenia and the common mental disorders constitute links between skeletal muscle and brain function. Contracting skeletal muscle secretes neurotrophic factors that are known to play a role in mood and anxiety, and have the dual role of nourishing neuronal growth and differentiation, while protecting the size and number of motor units in skeletal muscle. Furthermore, skeletal muscle activity has important immune and redox effects that impact behaviour and reduce muscle catabolism. PMID- 26228523 TI - A molecular understanding of D-homoestrone-induced G2/M cell cycle arrest in HeLa human cervical carcinoma cells. AB - 2-Methoxyestradiol (ME), one of the most widely investigated A-ring-modified metabolites of estrone, exerts significant anticancer activity on numerous cancer cell lines. Its pharmacological actions, including cell cycle arrest, microtubule disruption and pro-apoptotic activity, have already been described in detail. The currently tested D-ring-modified analogue of estrone, D-homoestrone, selectively inhibits cervical cancer cell proliferation and induces a G2/M phase cell cycle blockade, resulting in the development of apoptosis. The question arose of whether the difference in the chemical structures of these analogues can influence the mechanism of anticancer action. The aim of the present study was therefore to elucidate the molecular contributors of intracellular processes induced by D-homoestrone in HeLa cells. Apoptosis triggered by D-homoestrone develops through activation of the intrinsic pathway, as demonstrated by determination of the activities of caspase-8 and -9. It was revealed that D homoestrone-treated HeLa cells are not able to enter mitosis because the cyclin dependent kinase 1-cyclin B complex loses its activity, resulting in the decreased inactivation of stathmin and a concomitant disturbance of microtubule formation. However, unlike 2-ME, D-homoestrone does not exert a direct effect on tubulin polymerization. These results led to the conclusion that the D homoestrone-triggered intracellular processes resulting in a cell cycle arrest and apoptosis in HeLa cells differ from those in the case of 2-ME. This may be regarded as an alternative mechanism of action among steroidal anticancer compounds. PMID- 26228524 TI - Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and 'Schizophrenia-Like Behaviors' in Mice. AB - Rasd2 is a thyroid hormone target gene, which encodes for a GTP-binding protein enriched in the striatum where, among other functions, it modulates dopaminergic neurotransmission. Here we report that human RASD2 mRNA is abundant in putamen, but it also occurs in the cerebral cortex, with a distinctive expression pattern that differs from that present in rodents. Consistent with its localization, we found that a genetic variation in RASD2 (rs6518956) affects postmortem prefrontal mRNA expression in healthy humans and is associated with phenotypes of relevance to schizophrenia, including prefrontal and striatal grey matter volume and physiology during working memory, as measured with magnetic resonance imaging. Interestingly, quantitative real-time PCR analysis indicated that RASD2 mRNA is slightly reduced in postmortem prefrontal cortex of patients with schizophrenia. In the attempt to uncover the neurobiological substrates associated with Rasd2 activity, we used knockout mice to analyze the in vivo influence of this G protein on the prepulse inhibition of the startle response and psychotomimetic drug-related behavioral response. Data showed that Rasd2 mutants display deficits in basal prepulse inhibition that, in turn, exacerbate gating disruption under psychotomimetic drug challenge. Furthermore, we documented that lack of Rasd2 strikingly enhances the behavioral sensitivity to motor stimulation elicited by amphetamine and phencyclidine. Based on animal model data, along with the finding that RASD2 influences prefronto-striatal phenotypes in healthy humans, we suggest that genetic mutation or reduced levels of this G-protein might have a role in cerebral circuitry dysfunction underpinning exaggerated psychotomimetic drugs responses and development of specific biological phenotypes linked to schizophrenia. PMID- 26228526 TI - Adherence to the Australian dietary guidelines during pregnancy: evidence from a national study. AB - OBJECTIVE: To assess dietary intake of pregnant women against the Australian Dietary Guidelines with respect to the Five Food Group recommendations and determine predictors of adherence to the recommendations. DESIGN: Cross-sectional web-based survey. Data were analysed using descriptive statistics and logistic regression. SETTING: Pregnant women living in Australia. A national sample was recruited using an online panel provider and a South Australian sample was recruited through the antenatal clinic of a large public maternity hospital. SUBJECTS: A total of 857 pregnant women. RESULTS: Fifty-six per cent, 29% and less than 10% of women met the recommendations for the fruit, dairy and other core food groups, respectively. None of the women met the recommendations for all Five Food Groups. Women who were born overseas and who were less physically active pre-pregnancy were less likely to adhere to the fruit and dairy recommendations. Women who smoked during pregnancy, were overweight pre-pregnancy and had lower household incomes were also less likely to meet the fruit recommendations; and women living in metropolitan areas were less likely to meet the vegetable recommendations. Sixty-one per cent believed their diet during this pregnancy was healthy. CONCLUSIONS: The majority of pregnant women in Australia perceive their diets to be healthy yet they do not consume the recommended daily servings from the Five Food Groups. Intervention strategies are warranted, particularly those that increase women's ability to evaluate their diet and also encourage positive dietary changes. These strategies may increase adoption of dietary guidelines and optimise pregnancy and other long-term health outcomes. PMID- 26228525 TI - Long-term follow-up of imatinib plus combination chemotherapy in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. AB - The effects of imatinib plus chemotherapy were assessed in 87 patients with newly diagnosed Philadelphia chromosome-positive (Ph(+) ) acute lymphoblastic leukemia (ALL). Imatinib was administered continuously, starting from the eighth day of remission induction chemotherapy, then through five courses of consolidation or until allogeneic hematopoietic cell transplantation (HCT). Patients who were not transplanted were maintained on imatinib for 2 years. Eighty-two patients (94.3%) achieved complete remission (CR). Among these 82 CR patients, 40 experienced recurrence of leukemia. The 5-year relapse free survival (RFS) rate and overall survival (OS) rates were 39.0% and 33.4%, respectively. In total, 56 patients underwent allogeneic HCT in first CR. The 5-year cumulative incidence of relapse and OS rate of them were 59.1% and 52.6%, respectively. Six of seven patients who were maintained on imatinib after completion of consolidation relapsed and the median time of RFS was 40.7 months. In total patient, cumulative molecular CR rate was 88.5% and median time of molecular CR duration was 13 months. Initial imatinib dose intensity was significantly associated with median CR duration (P < 0.0001), and overall survival (P = 0.002). During the initial phase of treatment of patients with Ph(+) ALL, it is important to maintain imatinib dose intensity. PMID- 26228527 TI - Low-temperature synthesis of homogeneous solid solutions of scheelite-structured Ca1-xSrxWO4 and Sr1-xBaxWO4 nanocrystals. AB - A series of compositionally complex scheelite-structured nanocrystals of the formula A1-xAWO4 (A = Ca, Sr, Ba) have been prepared under benign synthesis conditions using the vapor diffusion sol-gel method. Discrete nanocrystals with sub-20 nm mean diameters were obtained after kinetically controlled hydrolysis and polycondensation at room temperature, followed by composition-dependent thermal aging at or below 60 degrees C. Rietveld analysis of X-ray diffraction data and Raman spectroscopy verified the synthesis of continuous and phase-pure nanocrystal solid solutions across the entire composition space for A1-xAWO4, where 0 <= x <= 1. Elemental analysis by X-ray photoelectron and inductively coupled plasma-atomic emission spectroscopies demonstrated excellent agreement between the nominal and experimentally determined elemental stoichiometries, while energy dispersive X-ray spectroscopy illustrated good spatial elemental homogeneity within these nanocrystals synthesized under benign conditions. PMID- 26228528 TI - Inhibition of ovarian cancer cell growth by a novel TAK1 inhibitor LYTAK1. AB - PURPOSE: Transforming growth factor-beta-activating kinase 1 (TAK1) has been implicated in promoting ovarian cancer progression. Here, we evaluated the anti ovarian cancer effect of LYTAK1, a novel and specific TAK1 inhibitor. METHODS: Established or primary human ovarian cancer cells were treated with LYTAK1, and its cytotoxicity and underlying mechanisms were analyzed using in vitro and in vivo assays. RESULTS: We demonstrated that LYTAK1 blocked TAK1-nuclear factor kappa B activation, and potently inhibited growth of established (SKOV3, CaOV3 and A2780 lines) or primary (patient-derived) human ovarian cancer cells, where TAK1 was over-expressed and over-activated. While the normal ovarian epithelial cells (IOSE-80), with low TAK1 expression, were minimally affected by the same LYTAK1 treatment. In ovarian cancer cells, LYTAK1 mainly induced necrosis (but not apoptosis), which was associated with mitochondrial permeability transition pore (mPTP) opening, the latter was evidenced by mitochondrial membrane potential reduction. Inhibition of mPTP, either by its inhibitor sanglifehrin A or cyclosporine A, as well as by siRNA-mediated knockdown of cyclophilin-D or voltage-dependent anion channel, attenuated LYTAK1-induced necrosis and cytotoxicity in ovarian cancer cells. In vivo, LYTAK1 oral administration suppressed growth of SKOV3 xenografts in nude mice, and its activity could be further enhanced by co-treatment of paclitaxel (Taxol). CONCLUSIONS: These data reveal the therapeutic potential of LYTAK1 as an agent targeting the pro oncogenic TAK1 in ovarian cancer. PMID- 26228529 TI - Immunosuppressive properties of Wharton's jelly-derived mesenchymal stromal cells in vitro. AB - Recent studies have reported that mesenchymal stromal cells (MSCs) migrate to areas of inflammation and suppress adverse immune reactions. Bone marrow (BM) derived MSCs have been successfully used in patients with acute graft versus host disease (GVHD), but the harvesting of BM carries certain risks for the donor. To circumvent these, we obtained MSCs from Wharton's jelly (WJ) derived from umbilical cord and investigated their potential for immunosuppression. In a mixed lymphocyte reaction (MLR), responder T cell proliferation triggered by allogeneic dendritic cells was inhibited efficiently by WJ-MSCs derived from the same donor of responder cells or those from a third party donor. These inhibitory effects were reversed in a dose-dependent manner in the presence of 1-methyl-DL tryptophan, an inhibitor of the soluble factor indoleamine 2, 3-dioxygenase (IDO). Immunosuppression by WJ-MSCs was also attenuated by blocking cell-cell contact between WJ-MSCs and responder T cells using a Transwell chamber. Moreover, IDO gene expression was induced in both WJ- and BM-MSCs by inflammatory cytokine IFN-gamma, but HLA-DR was expressed in BM-MSCs and not in WJ-MSCs upon stimulation by a relatively low concentration of IFN-gamma. These results indicate that WJ-MSCs exert their immunosuppressive effects by cell-cell contact with activated T cells and in part through IDO, and suggest the need for cells rather than soluble factors secreted from MSCs to achieve immunosuppressive therapy in severe cases of GVHD. PMID- 26228530 TI - TOWERS: T-One with Enhanced Robustness and Speed. AB - PURPOSE: A new T1 mapping method is proposed that is accurate, rapid, and robust to motion. Considering these features, the method is dubbed "T-One with Enhanced Robustness and Speed (TOWERS)." METHODS: TOWERS is composed of inversion recovery (IR) and saturation recovery (SR) acquisitions. In the IR acquisitions, a slice reordering scheme is used to sample all slices in an efficient manner, whereas the SR acquisitions serve as references for motion estimation. Furthermore, as opposed to the usual way of running generalized autocalibrating partially parallel acquisitions (GRAPPA) calibration only once at the beginning, GRAPPA coefficients are updated in the middle and at the end, and are later used for retrospectively correcting for motion artifacts. Finally, sub-voxel magnetization tracking is deployed to account for motion-induced signal evolution changes. RESULTS: Whole-brain T1 mapping data with a spatial resolution of 1.56 * 1.56 * 2.00 mm can be collected within 2.5 min. TOWERS and the gold-standard IR method agree well in phantom, while high reproducibility is achieved in vivo. High quality T1 maps in the presence of severe motion show the robustness of the method. CONCLUSION: The proposed method, TOWERS, is shown to be rapid, accurate, and robust. Multiple GRAPPA calibrations and sub-voxel magnetization tracking make TOWERS unique. Magn Reson Med 76:118-126, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26228531 TI - Human papillomavirus infection and p16 overexpression in oropharyngeal squamous cell carcinoma: a case series from 2010 to 2014. AB - AIM: Human papillomavirus (HPV) associated oropharyngeal squamous cell carcinomas (OPSCC) show better prognosis and response to therapy. We evaluated HPV-DNA prevalence, p16 overexpression and HPV-attributable fraction in recent consecutive OPSCCs. MATERIALS & METHODS: 140 OPSCCs were analyzed for HPV-DNA using the INNO-LiPA assay and p16 overexpression using CINtec(r) Histology kit. RESULTS: HPV-DNA prevalence was 40.7%, and was significantly higher in basaloid and nonkeratinizing SCCs, but similar in tonsillar and base of tongue SCCs. Moreover, 98.0% of the HPV-positive OPSCCs overexpressed p16, compared with 12.3% of the HPV-negative cases (p < 0.0001). Based on HPV-DNA and p16 double positivity, 39.8% of the cases were HPV related. CONCLUSION: The high estimate of the HPV-attributable fraction suggests that a substantial proportion of OPSCC patients may be managed less intensively. PMID- 26228532 TI - Serum Potassium, End-Stage Renal Disease and Mortality in Chronic Kidney Disease. AB - BACKGROUND/AIMS: Hypokalemia and hyperkalemia are often noted in chronic kidney disease (CKD) patients, but their impact on mortality and end-stage renal disease (ESRD) is less well understood. We aimed at studying the associations between potassium disorders, and mortality and progression to ESRD in a CKD population. METHODS: Using our electronic health record-based CKD registry, 36,359 patients with eGFR <60 ml/min/1.73 m(2) and potassium levels measured from January 1, 2005 to September 15, 2009 were identified. We examined factors associated with hypokalemia (<3.5 mmol/l) and hyperkalemia (>5.0 mmol/l) using logistic regression models and associations between serum potassium levels (both as continuous and categorical variables) and all-cause mortality or ESRD using Cox proportional hazards models. RESULTS: Serum potassium <3.5 mmol/l was noted among 3% and >5.0 mmol/l among 11% of the study population. In the multivariable logistic regression analysis, lower eGFR, diabetes and use of ACE inhibitors or Angiotensin-Receptor Blockers were associated with higher odds of having hyperkalemia. Heart failure and African American race were factors associated with higher odds of hypokalemia. After adjustment for covariates including kidney function, serum potassium <4.0 and >5.0 mmol/l were significantly associated with increased mortality risk, but there was no increased risk for progression to ESRD. Time-dependent repeated measures analysis confirmed these findings. When potassium was examined as a continuous variable, there was a U-shaped association between serum potassium levels and mortality. CONCLUSION: In patients with stage 3-4 CKD, serum potassium levels <4.0 and >5.0 mmol/l are associated with higher mortality but not with ESRD. PMID- 26228533 TI - Gingerols and shogaols: Important nutraceutical principles from ginger. AB - Gingerols are the major pungent compounds present in the rhizomes of ginger (Zingiber officinale Roscoe) and are renowned for their contribution to human health and nutrition. Medicinal properties of ginger, including the alleviation of nausea, arthritis and pain, have been associated with the gingerols. Gingerol analogues are thermally labile and easily undergo dehydration reactions to form the corresponding shogaols, which impart the characteristic pungent taste to dried ginger. Both gingerols and shogaols exhibit a host of biological activities, ranging from anticancer, anti-oxidant, antimicrobial, anti inflammatory and anti-allergic to various central nervous system activities. Shogaols are important biomarkers used for the quality control of many ginger containing products, due to their diverse biological activities. In this review, a large body of available knowledge on the biosynthesis, chemical synthesis and pharmacological activities, as well as on the structure-activity relationships of various gingerols and shogaols, have been collated, coherently summarised and discussed. The manuscript highlights convincing evidence indicating that these phenolic compounds could serve as important lead molecules for the development of therapeutic agents to treat various life-threatening human diseases, particularly cancer. Inclusion of ginger or ginger extracts in nutraceutical formulations could provide valuable protection against diabetes, cardiac and hepatic disorders. PMID- 26228534 TI - A Single Enzyme Transforms a Carboxylic Acid into a Nitrile through an Amide Intermediate. AB - The biosynthesis of nitriles is known to occur through specialized pathways involving multiple enzymes; however, in bacterial and archeal biosynthesis of 7 deazapurines, a single enzyme, ToyM, catalyzes the conversion of the carboxylic acid containing 7-carboxy-7-deazaguanine (CDG) into its corresponding nitrile, 7 cyano-7-deazaguanine (preQ0 ). The mechanism of this unusual direct transformation was shown to proceed via the adenylation of CDG, which activates it to form the newly discovered amide intermediate 7-amido-7-deazaguanine (ADG). This is subsequently dehydrated to form the nitrile in a process that consumes a second equivalent of ATP. The authentic amide intermediate is shown to be chemically and kinetically competent. The ability of ToyM to activate two different substrates, an acid and an amide, accounts for this unprecedented one enzyme catalysis of nitrile synthesis, and the differential rates of these two half reactions suggest that this catalytic ability is derived from an amide synthetase that gained a new function. PMID- 26228535 TI - Prolactin-producing pituitary adenoma with atypical spindle cell morphology: a case report. AB - Reported herein is a 25-year-old woman who was treated for a large and highly atypical prolactin-producing pituitary adenoma. On presentation, she exhibited right hemiparesis and left-sided visual loss, associated with amenorrhea. A massive (>5 cm) intra- and suprasellar lesion was seen on imaging, and her serum prolactin level was 4408 ng/ml. The patient received dopamine agonist treatment preoperatively for 4 weeks. To resect the tumor, a two-stage excision was required. Histologically, the specimen was composed of polygonal or spindle cells showing marked nuclear pleomorphism and/or multinucleation. Fibrosis was also focally conspicuous. Differential diagnoses included pituitary adenoma, pituitary carcinoma, pituicytoma, paraganglioma, spindle cell oncocytoma, and meningioma. Immunohistochemically, the tumor cells were positive for prolactin, chromogranin A, and synaptophysin, but were negative for glial fibrillary acidic protein, S 100 protein, epithelial membrane antigen, and vimentin. No apparent cerebrospinal or systemic metastases are found. Ultimately, prolactin-producing pituitary adenoma was diagnosed. Our case highlights the difficulty in definitively diagnosing an unusual prolactin-producing adenoma based on histopathology alone and the importance of referring to clinical information and immunohistochemical findings when deriving the diagnosis. PMID- 26228536 TI - Interpersonal Problems, Mindfulness, and Therapy Outcome in an Acceptance-Based Behavior Therapy for Generalized Anxiety Disorder. AB - OBJECTIVE: To better understand the role interpersonal problems play in response to two treatments for generalized anxiety disorder (GAD); an acceptance-based behavior therapy (ABBT) and applied relaxation (AR), and to examine how the development of mindfulness may be related to change in interpersonal problems over treatment and at follow-up. METHOD: Eighty-one individuals diagnosed with GAD (65.4% female, 80.2% identified as white, average age 32.92) were randomized to receive 16 sessions of either ABBT or AR. GAD severity, interpersonal problems, and mindfulness were measured at pre-treatment, post-treatment, 6-month follow-up, and 12-month follow-up. RESULTS: Mixed effect regression models did not reveal any significant effects of pre-treatment interpersonal problems on GAD severity over treatment. After controlling for post-treatment GAD severity, remaining post-treatment interpersonal problems predicted 6- but not 12-month GAD severity. Participants in both conditions experienced a large decrease in interpersonal problems over treatment. Increases in mindfulness over treatment and through follow-up were associated with decreases in interpersonal problems, even when accounting for reductions in overall GAD severity. CONCLUSIONS: Interpersonal problems may be an important target of treatment in GAD, even if pre-treatment interpersonal problems are not predictive of outcome. Developing mindfulness in individuals with GAD may help ameliorate interpersonal difficulties among this population. PMID- 26228537 TI - The disease-modifying effect of dehydroepiandrosterone in different stages of experimentally induced osteoarthritis: a histomorphometric study. AB - BACKGROUND: Osteoarthritis (OA) is likely to become an increasing burden in the coming decades. Various agents have been developed to slow the progression of OA, and are collectively known as 'disease-modifying drugs', however, there is still little reliable evidence that such agents will be successful. Dehydroepiandrosterone (DHEA), a sex hormone precursor, has been recently proven as protective agent against OA, but the exact mechanism is still unkown. In the current study, the effects of weekly intra-articular injections of DHEA in preventing the progression of existing cartilage degeneration in an OA rabbit model were evaluated. The aim of the current study is to demonstrate the feature of its disease-modifying efficacy during OA progression. METHODS: Thirty male New Zealand white rabbits were used in this study. An anterior cruciate ligament transection (ACLT) model was used to create a progressive OA model in twenty rabbits. The animals were treated with DHEA or a placebo and were necropsied at 9 and 16 weeks. Ten rabbits receiving sham operations served as controls. The articular cartilage of the medial femoral condyle (MFC), lateral femoral condyle (LFC), medial tibial plateau (MTP) and lateral tibial plateau (LTP) was evaluated macroscopically and histologically. RESULTS: In the joints of the sham-operated rabbits, few histological changes were detected on the articular surfaces of the femoral condyles and tibial plateaus. ACLT obviously induced erosive changes on the cartilage surfaces. Compared to the placebo group, the macroscopic and Mankin score analyses demonstrated that the DHEA treatment markedly reduced the cartilage lesions and delayed cartilage degeneration in the four regions of the knee at 9 weeks after operation (macroscopic score: MFC P = 0.013; LFC P = 0.048; MTP P = 0.045; LTP P = 0.02, Mankin score: MFC P = 0.012; LFC P = 0.034; MTP P = 0.016; LTP P = 0.002). At 16 weeks, DHEA demonstrated chondroprotective effects on the lateral compartment of the knee compared to the placebo group, whereas the cartilage degeneration at the medial compartment of the knee did not differ among the groups (macroscopic score: LFC P = 0.046; LTP = 0.034, Mankin score: LFC P = 0.005; LTP P = 0.002). CONCLUSION: The disease-modifying efficacy of DHEA aganist OA is time-specific and site-dependent. DHEA could be used as a disease-modifying strategy to limit the progression of OA, especially in the middle stage. PMID- 26228538 TI - Disposition of cimicoxib in plasma and milk of whelping bitches and in their puppies. AB - BACKGROUND: Caesarean section of bitches is a well recognized painful condition in dogs and it can be classified as a soft tissue surgery. Cimicoxib, a newly registered NSAID in European Union has a claim for the relief of pain in peri operative conditions. However, in case of caesarean section, the main concerns of using NSAIDs are the transfer of the drugs into milk and its impact on the suckling pups. Thus, the aim of the present work was to evaluate the transfer of cimicoxib into the milk of 6 lactating bitches after a single oral administration of the drug on day 0 (just after whelping) and on day 28 at the target dose of 2 mg/kg. Another aim of the study was to evaluate the transfer of the drug from the milk into the suckling pups. Blood and milk samples were collected from the bitches after each administration on day 0 and day 28 and blood samples were drawn from the pups after suckling on day 28. RESULTS: All bitches whelped without any complication and gave birth to 38 pups. After administration on D0, the mean observed plasma Cmax in bitches was 0.5323 MUg/mL and the mean area under the concentration-time curve extrapolated to the infinity, AUCINF, was 2.411 MUg.h/mL. After administration on D28, only AUCINF was significantly higher with a value of 3.747 MUg.h/mL. In milk, after administration on D0, the mean observed Cmax was 0.9974 MUg/mL and the mean area under the concentration-time curve until the last measurable time point, AUClast, was 4.205 MUg.h/mL. Out of 24 sampled pups on D28, only 2 animals had a sample with very low cimicoxib concentrations slightly above the limit of quantification (0.01 MUg/mL). CONCLUSION: The presented data show that cimicoxib given by oral route to lactating bitches at a single dose of 2 mg/kg had a high transfer rate into the milk with a milk to plasma ratio of 1.7 to 1.9. The transfer rate to the suckling pups was low and no clinical abnormalities were detected in both bitches and pups. PMID- 26228539 TI - Mirtazapine toxicity in cats: retrospective study of 84 cases (2006-2011). AB - Objectives Mirtazapine is commonly used in veterinary medicine at doses of 1.88 or 3.75 mg as an appetite stimulant. The objectives of this study were to determine the most common adverse effects reported and the dose associated with these signs. Methods Records of cats with mirtazapine exposure (2006-2011) were obtained from the American Society for the Prevention of Cruelty to Animals' Animal Poison Control Center. The following parameters were recorded: signalment, weight, outcome, agent ingested, amount ingested, route of exposure, clinical signs observed, intended of use, onset time of signs and duration of signs. Results The 10 most commonly observed adverse effects reported in 84 cats exposed to mirtazapine included vocalization (56.0% of cats; mean dose 2.56 mg/kg), agitation (31.0%; 2.57 mg/kg), vomiting (26.2%; 2.92 mg/kg), abnormal gait/ataxia (16.7%; 2.87 mg/kg), restlessness (14.3%; 3.55 mg/kg), tremors/trembling (14.3%; 2.43 mg/kg), hypersalivation (13.0%; 2.89 mg/kg), tachypnea (11.9%; 3.28 mg/kg), tachycardia (10.7%; 3.04 mg/kg) and lethargy (10.7%; 2.69 mg/kg). Fifty-nine (70.2%) cases were considered accidental ingestions and 25 (29.8%) cases were given mirtazapine as prescribed. The doses associated with signs of toxicity were 15.00 mg (40 cats), 3.75 mg (25 cats), 7.50 mg (four cats), 30.00 mg (one cat), 18.75 mg (one cat), 11.25 mg (one cat), 5.80 mg (one cat) and 1.88 mg (one cat). For cats with available information, the onset of clinical signs ranged from 15 mins to 3 h, and time to resolution of clinical signs ranged from 12-48 h. Conclusions and relevance The greater number of adverse effects at 3.75 mg rather than 1.88 mg suggests that the latter may be a more appropriate starting dose for stimulating appetite while limiting toxicity. The benefit of dispensing exact doses of mirtazapine is implied given the likelihood of accidental administration of a full tablet (15 mg) and the resulting toxicity. PMID- 26228540 TI - Internal to external jugular vein bypass allowing for simultaneous bilateral radical neck dissection. AB - OBJECTIVES/HYPOTHESIS: The goal of the study was to determine the role of internal jugular vein (IJV) to external jugular vein (EJV) bypass grafting in the setting of bilateral radical neck dissection with IJV sacrifice. STUDY DESIGN: The study group consisted of eight patients who underwent bilateral radical neck dissection with IJV sacrifice. Demographic and oncologic parameters were defined for each patient, including age, gender, and pathology. Patients were monitored and evaluated for potential effects of increased intracranial pressure (ICP). Doppler ultrasonic evaluation was performed to assess patency of the site of anastamoses. RESULTS: In all, six patients underwent unilateral bypass grafting, whereas two patients underwent bilateral bypass grafts. Average age at time of surgery was 68.2 (range 56-71). Postoperatively, no sequelae of increased ICP were noted. Follow-up ultrasonic evaluation revealed patent vessels in all patients. CONCLUSION: We presently report on the use of EJV-to-IJV bypass grafting for all patients undergoing bilateral radical neck dissection for extensive neck disease. LEVEL OF EVIDENCE: 4. PMID- 26228543 TI - Visual performance of single vision and multifocal contact lenses in non presbyopic myopic eyes. AB - PURPOSE: To assess visual performance of single vision and multifocal soft contact lenses. METHODS: At baseline, forty-four myopic participants (aged 18-35 years) were fitted bilaterally with a control lens (AirOptix Aqua). At the four follow-up visits, a total of 16 study lenses (5 single vision, 11 multifocal lenses) were fitted contralaterally. After 1h of lens wear, participants rated (scale 1-10) vision clarity (distance, intermediate and near), magnitude of ghosting at distance, comfort during head movement, and overall comfort. Distance high contrast visual acuity (HCVA), central refraction and higher order aberrations, and contact lens centration were measured. RESULTS: For single vision lenses, vision ratings were not significantly different to the control (p>0.005). The control outperformed Acuvue Oasys, Clariti Monthly and Night and Day in HCVA (mean VA: -0.10 +/- 0.07 logMAR, p<0.005). Most refraction and higher order aberration measures were not different between lenses. The Night and Day lens showed greatest differences compared to the control, i.e., C[4, 0] was more positive (p<0.005) at distance (Delta=0.019 MUm) and near (Delta=0.028 MUm). For multifocal lenses, the majority of vision ratings (84%) were better with the control (p<0.005). HCVA was better with the control (p<0.005). Proclear Multifocal lenses showed greatest differences for M, C[3, -1] and C[4, 0] at distance and near, and were inferiorly de-centered (p<0.005). CONCLUSION: Design differences between single vision lenses had a small impact on visual performance. Lenses featuring multifocality decreased visual performance, in particular when power variations across the optic zone were large and/or the lens was significantly de-centered. PMID- 26228542 TI - A novel cytosporone 3-Heptyl-4,6-dihydroxy-3H-isobenzofuran-1-one: synthesis; toxicological, apoptotic and immunomodulatory properties; and potentiation of mutagenic damage. AB - BACKGROUND: A large number of studies are attempting to identify alternative products from natural sources or synthesized compounds that effectively interact with cancer cells without causing adverse effects on healthy cells. Resorcinolic lipids are a class of bioactive compounds that possess anticancer activity and are able to interact with the lipid bilayer. Therefore, the objective of this study was to synthesize a novel resorcinolic lipid and test its biological proprieties. METHODS: We aimed to synthesize a novel resorcinolic lipid belonging to the class of cytosporones, AMS049 (3-Heptyl-4,6-dihydroxy-3H-isobenzofuran-1 one) and to evaluate the toxicity of two concentrations of this lipid (7.5 and 10 mg/kg) by determining its genotoxic, mutagenic, immunomodulatory, and apoptotic effects, as well as any biochemical and histopathological alterations in mice treated with cyclophosphamide. The results were analyzed by ANOVA followed by the Tukey test A . level of significance of p < 0.05 was adopted. RESULTS: The new cytosporone AMS049 was synthesized in only three steps and in satisfactory yields. The results indicate that the compound is neither genotoxic nor mutagenic and does not alter biochemical parameters. The histological alterations observed in the liver and kidneys did not compromise the function of these organs. Histology of the spleen suggested immunomodulation, although no changes were observed in splenic phagocytosis or differential blood cell count. The results also show that AMS049 potentiates the mutagenic effect of the chemotherapy drug cyclophosphamide and that the combination induces apoptosis. CONCLUSION: These facts indicate a potential therapeutic application of this novel cytosporone as an important chemotherapeutic adjuvant. PMID- 26228544 TI - dissectHMMER: a HMMER-based score dissection framework that statistically evaluates fold-critical sequence segments for domain fold similarity. AB - BACKGROUND: Annotation transfer for function and structure within the sequence homology concept essentially requires protein sequence similarity for the secondary structural blocks forming the fold of a protein. A simplistic similarity approach in the case of non-globular segments (coiled coils, low complexity regions, transmembrane regions, long loops, etc.) is not justified and a pertinent source for mistaken homologies. The latter is either due to positional sequence conservation as a result of a very simple, physically induced pattern or integral sequence properties that are critical for function. Furthermore, against the backdrop that the number of well-studied proteins continues to grow at a slow rate, it necessitates for a search methodology to dive deeper into the sequence similarity space to connect the unknown sequences to the well-studied ones, albeit more distant, for biological function postulations. RESULTS: Based on our previous work of dissecting the hidden markov model (HMMER) based similarity score into fold-critical and the non-globular contributions to improve homology inference, we propose a framework-dissectHMMER, that identifies more fold-related domain hits from standard HMMER searches. Subsequent statistical stratification of the fold-related hits into cohorts of functionally-related domains allows for the function postulation of the query sequence. Briefly, the technical problems as to how to recognize non-globular parts in the domain model, resolve contradictory HMMER2/HMMER3 results and evaluate fold-related domain hits for homology, are addressed in this work. The framework is benchmarked against a set of SCOP-to-Pfam domain models. Despite being a sequence-to-profile method, dissectHMMER performs favorably against a profile-to-profile based method-HHsuite/HHsearch. Examples of function annotation using dissectHMMER, including the function discovery of an uncharacterized membrane protein Q9K8K1_BACHD (WP_010899149.1) as a lactose/H+ symporter, are presented. Finally, dissectHMMER webserver is made publicly available at http://dissecthmmer.bii.a-star.edu.sg . CONCLUSIONS: The proposed framework dissectHMMER, is faithful to the original inception of the sequence homology concept while improving upon the existing HMMER search tool through the rescue of statistically evaluated false-negative yet fold-related domain hits to the query sequence. Overall, this translates into an opportunity for any novel protein sequence to be functionally characterized. PMID- 26228545 TI - Draft genome of the most devastating insect pest of coffee worldwide: the coffee berry borer, Hypothenemus hampei. AB - The coffee berry borer, Hypothenemus hampei, is the most economically important insect pest of coffee worldwide. We present an analysis of the draft genome of the coffee berry borer, the third genome for a Coleopteran species. The genome size is ca. 163 Mb with 19,222 predicted protein-coding genes. Analysis was focused on genes involved in primary digestion as well as gene families involved in detoxification of plant defense molecules and insecticides, such as carboxylesterases, cytochrome P450, gluthathione S-transferases, ATP-binding cassette transporters, and a gene that confers resistance to the insecticide dieldrin. A broad range of enzymes capable of degrading complex polysaccharides were identified. We also evaluated the pathogen defense system and found homologs to antimicrobial genes reported in the Drosophila genome. Ten cases of horizontal gene transfer were identified with evidence for expression, integration into the H. hampei genome, and phylogenetic evidence that the sequences are more closely related to bacterial rather than eukaryotic genes. The draft genome analysis broadly expands our knowledge on the biology of a devastating tropical insect pest and suggests new pest management strategies. PMID- 26228546 TI - Minimal symptoms in McArdle disease: A real PYGM genotype effect? PMID- 26228547 TI - CrossTalk proposal: 5-HT is necessary for peristalsis. PMID- 26228548 TI - CrossTalk opposing view: 5-HT is not necessary for peristalsis. PMID- 26228549 TI - Rebuttal from Terence K. Smith and Michael D. Gershon. PMID- 26228550 TI - Rebuttal from Nick J. Spencer, Tiong Cheng Sia, Simon J Brookes, Marcello Costa and Damien J. Keating. PMID- 26228551 TI - Intracellular Ca(2+) handling and myofibrillar Ca(2+) sensitivity are defective in single muscle fibres of aged humans. PMID- 26228552 TI - A new look at structures and mechanisms regulating endoplasmic/sarcoplasmic reticulum Ca(2+) release in health and disease. PMID- 26228554 TI - Triadin regulation of the ryanodine receptor complex. AB - The calcium release complex is the major player in excitation-contraction coupling, both in cardiac and skeletal muscle. The core of the complex is the ryanodine receptor, and triadin is a regulating protein. Nevertheless, the precise function of triadin is only partially understood. Besides its function in the anchoring of calsequestrin at the triad/dyad, our recent results allow us to propose hypotheses on new triadin scaffolding functions, based on the studies performed using different models, from triadin knockout mice to human patients, and expression in non-muscle cells, taking into account the presence of multiple triadin isoforms. PMID- 26228553 TI - New and notable ion-channels in the sarcoplasmic/endoplasmic reticulum: do they support the process of intracellular Ca2+ release? AB - Intracellular Ca(2+) release through ryanodine receptor (RyR) and inositol trisphosphate receptor (IP3 R) channels is supported by a complex network of additional proteins that are located in or near the Ca(2+) release sites. In this review, we focus, not on RyR/IP3 R, but on other ion-channels that are known to be present in the sarcoplasmic/endoplasmic reticulum (ER/SR) membranes. We review their putative physiological roles and the evidence suggesting that they may support the process of intracellular Ca(2+) release, either indirectly by manipulating ionic fluxes across the ER/SR membrane or by directly interacting with a Ca(2+) -release channel. These channels rarely receive scientific attention because of the general lack of information regarding their biochemical and/or electrophysiological characteristics makes it difficult to predict their physiological roles and their impact on SR Ca(2+) fluxes. We discuss the possible role of SR K(+) channels and, in parallel, detail the known biochemical and biophysical properties of the trimeric intracellular cation (TRIC) proteins and their possible biological and pathophysiological roles in ER/SR Ca(2+) release. We summarise what is known regarding Cl(-) channels in the ER/SR and the non selective cation channels or putative 'Ca(2+) leak channels', including mitsugumin23 (MG23), pannexins, presenilins and the transient receptor potential (TRP) channels that are distributed across ER/SR membranes but which have not yet been fully characterised functionally. PMID- 26228555 TI - Letter to the Editor. PMID- 26228556 TI - Reply from Lars Larsson, Nicola Cacciani and Barry Dworkin. PMID- 26228557 TI - Pathology of oak-wisteria powdery mildew. AB - The relationship between oak and wisteria powdery mildew, the reason artificial infection of Wisteria sinensis was difficult, and the identity of the pathogen were investigated. Inoculations of detached leaves of Quercus robur with Erysiphe alphitoides from either W. sinensis or Q. robur were successful. Wisteria floribunda was completely and W. sinensis partially resistant. Isolates from wisteria and oak had similar pathogenicities and matching DNA profiles and hence not separable into formae speciales. Instead, oak mildew now includes wisteria and possibly Sorbaria as hosts. On non-host Brassica and cellulose acetate, conidial germ tube development ceased after formation of terminal appressoria. Only Q. robur supported visible lesions. W. sinensis supported fewer colony forming hyphae (CFH) per conidium and smaller hyphal appressoria. Failure to form visible lesions was due to prevention or termination of CFH and not to inhibition of conidial germination or to a host's hypersensitive reaction. Absorption of antifungal compounds via appressoria from maturing host tissue is discussed. The pathogen's DNA ITS region indicated an identification of Erysiphe alphitoides sensu lato, since some isolates did not completely match E. alphitoides sensu stricto. To rapidly indicate susceptibility, a microscopic examination of young leaves 48 h post inoculation is recommended. PMID- 26228558 TI - Serine proteases activity is important for the interaction of nematophagous fungus Duddingtonia flagrans with infective larvae of trichostrongylides and free living nematodes Panagrellus spp. AB - The nematode-trapping fungus Duddingtonia flagrans has been studied as a possible control method for gastrointestinal nematodes of livestock animals. These fungi capture and infect the nematode by cuticle penetration, immobilization, and digestion of the internal contents. It has been suggested that this sequence of events occurs by a combination of physical and enzymatical activities. The aim of this study was to investigate the participation of proteolytic enzymatic activity during the interaction of the nematophagous fungus D. flagrans with infective larvae of trichostrongylides and the free-living nematode Panagrellus spp. Protease inhibitors used interfered in the predatory activity of D. flagrans. However, only PMSF significantly reduced the mean number of Panagrellus spp. captured by D. flagrans in comparison with the control. The experiment with fluorogenic substrate showed that maximum urokinase activity during the interaction of the fungus with the infective larvae of trichostrongylides or Panagrellus spp. occurred within 7 or 1 h of incubation, respectively. The protease activity, especially of the serine class, may be important during the interaction between the fungus and nematodes. PMID- 26228560 TI - Hydrothermal time models for conidial germination and mycelial growth of the seed pathogen Pyrenophora semeniperda. AB - Population-based threshold models using hydrothermal time (HTT) have been widely used to model seed germination. We used HTT to model conidial germination and mycelial growth for the seed pathogen Pyrenophora semeniperda in a novel approach to understanding its interactions with host seeds. Germination time courses and mycelial growth rates for P.semeniperda were measured on PDA amended to achieve a series of five water potentials (ca. 0 to -6 MPa) at six constant temperatures (5 30 degrees C). Conidial germination was described with alternative population based models using constant or variable base and maximum temperature and water potential parameters. Mycelial growth was modeled as a continuous, linear process with constant base temperature and base water potential. Models based on HTT showed reasonable fit to germination and growth rate data sets. The best-fit conidial germination model (R(2) = 0.859) was based on variable base and maximum temperature as a function of water potential. The good fit of the linear mycelial growth model (R(2) = 0.916) demonstrated the utility of HTT for modeling continuous as well as population-based processes. HTT modeling may be a useful approach to the quantification of germination and growth processes in a wide range of filamentous fungi. PMID- 26228561 TI - A new anaerobic fungus (Oontomyces anksri gen. nov., sp. nov.) from the digestive tract of the Indian camel (Camelus dromedarius). AB - Two cultures of anaerobic fungi were isolated from the forestomach of an Indian camel (Camelus dromedarius). Phylogenetic analysis using both the internal transcribed spacer (ITS) and large-subunit (LSU) regions of the rRNA locus demonstrated that these isolates were identical and formed a distinct clade within the anaerobic fungi (phylum Neocallimastigomycota). Morphological examination showed that these fungi formed monocentric thalli with filamentous rhizoids and uniflagellate zoospores, broadly similar to members of the genus Piromyces. However, distinctive morphological features were observed, notably the pinching of the cytoplasm in the sporangiophore and the formation of intercalary rhizoidal swellings. Since genetic analyses demonstrated this fungus was only distantly related to Piromyces spp. and closer to the polycentric Anaeromyces clade, we have assigned it to a new genus and species Oontomyces anksri gen. nov., sp. nov. Interrogation of the GenBank database identified several closely related ITS sequences, which were all environmental sequences obtained from camels, raising the possibility that this fungus may be specific to camelids. PMID- 26228563 TI - H2O2 plays an important role in the lifestyle of Colletotrichum gloeosporioides during interaction with cowpea [Vigna unguiculata (L.) Walp]. AB - Plant-fungus interactions usually generate H(2)O(2) in the infected plant tissue. H(2)O(2) has a direct antimicrobial effect and is involved in the cross-linking of cell walls, signaling, induction of gene expression, hypersensitive cell death and induced systemic acquired resistance. This has raised the hypothesis that H(2)O(2) manipulation by pharmacological compounds could alter the lifestyle of Colletotrichum gloeosporioides during interaction with the BR-3-Tracuateua cowpea genotype. The primary leaves of cowpea were excised, infiltrated with salicylic acid (SA), glucose oxidase + glucose (GO/G), catalase (CAT) or diphenyliodonium chloride (DPI), followed by spore inoculation on the adaxial leaf surface. SA or GO/G-treated plantlets showed increased H(2)O(2) accumulation and lipid peroxidation. The fungus used a subcuticular, intramural necrotrophic strategy, and developed secondary hyphae associated with the quick spread and rapid killing of host cells. However, CAT or DPI-treated leaves exhibited decreased H(2)O(2) concentration and lipid peroxidation and the fungus developed intracellular hemibiotrophic infection with vesicles, in addition to primary and secondary hyphal formation. These results suggest that H(2)O(2) plays an important role in the cowpea (C. gloeosporioides) pathosystem given that it affected fungal lifestyle during interaction. PMID- 26228559 TI - Revisiting the taxonomy of Phanerochaete (Polyporales, Basidiomycota) using a four gene dataset and extensive ITS sampling. AB - We amplified RPB1, RPB2, and the ITS and LSU ribosomal genes from species mostly in the phlebioid clade, focusing heavily in phanerochaetoid taxa. We performed Maximum Likelihood and Bayesian analyses for different combinations of datasets. Our results provide a strongly supported phylogenetic picture of the phlebioid clade, representing 89 species in the four genes analyses, of which 49 represent phanerochaetoid taxa. Phanerochaete sensu lato is polyphyletic and distributed across nine lineages in the phlebioid clade. Six of these lineages are associated to already described genera, while we describe the new genus Phaeophlebiopsis to accommodate Phlebiopsis-like species in one of the remaining lineages. We also propose three taxonomic transfers and describe nine new species, with four of those species currently placed in Phanerochaete sanguinea or Phanerochaete velutina. Finally, the placement of Leptoporus mollis along with other potential brown-rot species in the phlebioid clade suggests that, in addition to the Antrodia clade, brown-rot fungi may have evolved more than once in Polyporales. PMID- 26228562 TI - Chemodiversity and biodiversity of fungi associated with the pine weevil Hylobius abietis. AB - The pine weevil Hylobius abietis is a severe pest of conifer seedlings in reforestation areas. Weevils lay eggs in the root bark or in the soil near roots of recently dead trees and cover the eggs with frass (feces combined with chewed bark), possibly to avoid conspecific egg predation. The aim of the present investigation focused on isolation, identification, and volatile production of fungi from pine-weevil feces and frass. Fungi were isolated from weevil frass and feces separately, followed by identification based on ITS sequencing. Fifty-nine isolates belonging to the genera Penicillium, Ophiostoma, Mucor, Leptographium, Eucasphaeria, Rhizosphaera, Debaryomyces, and Candida were identified. Volatile organic compounds (VOCs) produced by the fungal community and fungal isolates cultured on weevil-frass broth were identified by SPME-GCMS. Major VOCs emitted from the fungal community and pure isolates were species- and strain specific and included isopentylalcohol, styrene, 3-octanone, 6-protoilludene, methyl salicylate, 3-methylanisole, 2-methoxyphenol, and phenol. Some of these are known to influence the orientation of pine weevils when tested among highly attractive newly planted conifer seedlings. PMID- 26228564 TI - Proteomic Approach to Identify Nuclear Proteins in Wheat Grain. AB - The nuclear proteome of the grain of the two cultivated wheat species Triticum aestivum (hexaploid wheat; genomes A, B, and D) and T. monococcum (diploid wheat; genome A) was analyzed in two early stages of development using shotgun-based proteomics. A procedure was optimized to purify nuclei, and an improved protein sample preparation was developed to efficiently remove nonprotein substances (starch and nucleic acids). A total of 797 proteins corresponding to 528 unique proteins were identified, 36% of which were classified in functional groups related to DNA and RNA metabolism. A large number (107 proteins) of unknown functions and hypothetical proteins were also found. Some identified proteins may be multifunctional and may present multiple localizations. On the basis of the MS/MS analysis, 368 proteins were present in the two species, and in two stages of development, some qualitative differences between species and stages of development were also found. All of these data illustrate the dynamic function of the grain nucleus in the early stages of development. PMID- 26228565 TI - The voice of the next generation. PMID- 26228566 TI - Neuroimaging of psychotherapy for obsessive-compulsive disorder: A systematic review. AB - The symptoms of obsessive-compulsive disorder (OCD) include intrusive thoughts, compulsive behavior, anxiety, and cognitive inflexibility, which are associated with dysfunction in dorsal and ventral corticostriato-thalamocortical (CSTC) circuits. Psychotherapy involving exposure and response prevention has been established as an effective treatment for the affective symptoms, but the impact on the underlying neural circuits is not clear. This systematic review used the Medline, Embase, and PsychINFO databases to investigate how successful therapy may affect neural substrates of OCD. Sixteen studies measuring neural changes after therapy were included in the review. The studies indicate that dysfunctions in neural function and structure are partly reversible and state-dependent for affective symptoms, which may also apply to cognitive symptoms. This is supported by post-treatment decreases of symptoms and activity in the ventral circuits during symptom provocation, as well as mainly increased activity in dorsal circuits during cognitive processing. These effects appear to be common to both psychotherapy and medication approaches. Although neural findings were not consistent across all studies, these findings indicate that people with OCD may experience functional, symptomatic, and neural recovery after successful treatment. PMID- 26228567 TI - Neural correlates associated with symptom provocation in pediatric obsessive compulsive disorder after a single session of sham-controlled repetitive transcranial magnetic stimulation. AB - Treatments for pediatric obsessive-compulsive disorder (OCD) could be enhanced if the physiological changes engendered by treatment were known. This study examined neural correlates of a provocation task in youth with OCD, before and after sham controlled repetitive transcranial magnetic stimulation (rTMS). We hypothesized that rTMS to the right dorsolateral prefrontal cortex would inhibit activity in cortico-striato-thalamic (CST) circuits associated with OCD to a greater extent than sham rTMS. After baseline (Time 1) functional magnetic resonance imaging (fMRI) during a provocation task, subjects received one session of either fMRI guided sham (SG; n=8) or active (AG; n=10) 1-Hz rTMS over the rDLPFC for 30min. During rTMS, subjects were presented with personalized images that evoked OCD related anxiety. Following stimulation, fMRI and the provocation task were repeated (Time 2). Contrary to our prediction for the provocation task, the AG was associated with no changes in BOLD response from Times 1 to 2. In contrast, the SG had a significant increase at Time 2 in BOLD response in the right inferior frontal gyrus and right putamen, which persisted after adjusting for age, gender, and time to scanner as covariates. This study provides an initial framework for TMS interrogation of the CST circuit in pediatric OCD. PMID- 26228569 TI - Imaging upregulated brain arachidonic acid metabolism in HIV-1 transgenic rats. AB - This article has been retracted by the Editors in Chief at the request of the author Stanley I Rapoport following the finding of the National Institutes of Health that Dr Mireille Basselin engaged in research misconduct by fabricating data in Figure 4A-C and Figure 5B. None of the other authors are implicated in any way. PMID- 26228568 TI - Factor structure of a combined measure of major depressive disorder and male depression in prostate cancer patients. PMID- 26228570 TI - Methanosalsum natronophilum sp. nov., and Methanocalculus alkaliphilus sp. nov., haloalkaliphilic methanogens from hypersaline soda lakes. AB - Two groups of haloalkaliphilic methanogenic archaea were dominating in enrichments from hypersaline soda lake sediments at pH 10. At moderate salt concentrations with formate or H2 as electron donor, methanogens belonging to the genus Methanocalculus were enriched, while at high salt concentrations with methylated substrates, a group related to Methanosalsum zhilinae was dominating. For both groups, several pure cultures were obtained including the type strains AMF2T for the Methanocalculus group and AME2T for the Methanosalsum group. The Methanocalculus group is characterized by lithoheterotrophic growth with either formate (preferable substrate) or H2 at moderate salinity up to 1.5-2 M total Na+ and obligate alkaliphilic growth with an optimum at pH 9.5. According to phylogenetic analysis, the group also includes closely related strains isolated previously from the low-salt alkaline Lonar Lake. The novel Methanosalsum group is characterized by high salt tolerance (up to 3.5 M total Na+) and obligate alkaliphilic growth with an optimum at pH 9.5. It has a typical methylotrophic substrate profile, utilizing methanol, methylamines and dimethyl sulfide (at low concentrations) as methanogenic substrates. On the basis of physiological and phylogenetic data, it is proposed that the two groups of soda lake methanogenic isolates are assigned into two novel species, Methanocalculus alkaliphilus sp. nov. (type strain AMF2T = DSM 24457T = UNIQEM U859T) and Methanosalsum natronophilum sp. nov. (type strain AME2T = DSM 24634T = NBRC 110091T). PMID- 26228571 TI - The ubiquitin ligase Mdm2 controls oligodendrocyte maturation by intertwining mTOR with G protein-coupled receptor kinase 2 in the regulation of GPR17 receptor desensitization. AB - During oligodendrocyte precursor cell (OPC) differentiation, defective control of the membrane receptor GPR17 has been suggested to block cell maturation and impair remyelination under demyelinating conditions. After the immature oligodendrocyte stage, to enable cells to complete maturation, GPR17 is physiologically down-regulated via phosphorylation/desensitization by G protein coupled receptor kinases (GRKs); conversely, GRKs are regulated by the "mammalian target of rapamycin" mTOR. However, how GRKs and mTOR are connected to each other in modulating GPR17 function and oligodendrogenesis has remained elusive. Here we show, for the first time, a role for Murine double minute 2 (Mdm2), a ligase previously involved in ubiquitination/degradation of the onco-suppressor p53 protein. In maturing OPCs, both rapamycin and Nutlin-3, a small molecule inhibitor of Mdm2-p53 interactions, increased GRK2 sequestration by Mdm2, leading to impaired GPR17 down-regulation and OPC maturation block. Thus, Mdm2 intertwines mTOR with GRK2 in regulating GPR17 and oligodendrogenesis and represents a novel actor in myelination. PMID- 26228573 TI - Bioreactor control improves bioprocess performance. AB - The performance of bioreactors is not only determined by productivity but also by process quality, which is mainly determined by variances in the process variables. As fluctuations in these quantities directly affect the variability in the product properties, combatting distortions is the main task of practical quality assurance. The straightforward way of reducing this variability is keeping the product formation process tightly under control. Purpose of this keynote is to show that there is enough evidence in literature showing that the performance of the fermentation processes can significantly be improved by feedback control. Most of the currently used open loop control procedures can be replaced by relatively simple feedback techniques. It is shown by practical examples that such a retrofitting does not require significant changes in the well-established equipment. Feedback techniques are best in assuring high reproducibility of the industrial cultivation processes and thus in assuring the quality of their products. Many developments in supervising and controlling industrial fermentations can directly be taken over in manufacturing processes. Even simple feedback controllers can efficiently improve the product quality. It's the time now that manufacturers follow the developments in most other industries and improve process quality by automatic feedback control. PMID- 26228574 TI - Improving Research Practice in Rat Orthotopic and Partial Orthotopic Liver Transplantation: A Review, Recommendation, and Publication Guide. AB - BACKGROUND: Due to a worldwide shortage of donor organs for liver transplantation, alternative approaches, such as split and living donor liver transplantations, were introduced to increase the donor pool and reduce mortality on liver transplant waiting lists. Numerous details concerning the mechanisms and pathophysiology of liver regeneration, small-for-size syndrome, rejection, and tolerance in partial liver transplantation facilitated the development of various animal models. The high number of preclinical animal studies contributed enormously to our understanding of many clinical aspects of living donor and partial liver transplantations. SUMMARY: Microsurgical rat models of partial orthotopic liver transplantation are well established and widely used. Nevertheless, several issues regarding this procedure are controversial, not clarified, or not yet properly standardized (graft rearterialization, size reduction techniques, etc.). The major aim of this literature review is to give the reader a current overview of rat orthotopic liver transplantation models with a special focus on partial liver transplantation. The aspects of model evolution, microsurgical training, and different technical problems are analyzed and discussed in detail. Our further aim in this paper is to elaborate a detailed publication guide in order to improve the quality of reporting in the field of rat liver transplantation according to the ARRIVE guidelines and the 3R principle. Key Messages: Partial orthotopic liver transplantation in rats is an indispensable, reliable, and cost-efficient model for transplantation research. A certain consensus on different technical issues and a significant improvement in scientific reporting are essential to improve transparency and comparability in this field as well as to foster refinement. PMID- 26228572 TI - Prevalence and diversity of Salmonella enterica in water, fish and lettuce in Ouagadougou, Burkina Faso. AB - BACKGROUND: This study investigated the prevalence, serotypes and antimicrobial sensitivity patterns of Salmonella enterica in environment in Ouagadougou, Burkina Faso. A total of 476 samples, consisting of 36 samples of tap water, 51 samples of well water, 87 samples of channel water, 44 samples of reservoir water, 238 samples of fish, and 20 samples of lettuce were examined using standard bacteriological procedures for Salmonella. RESULTS: Salmonella were isolated from 98 samples. Salmonella were rare in drinking water, since they were not found at all from the tap water, and only in 2 % of well water. Salmonella were more common in the water of reservoir of Tanghin (15 %), reservoir of Yamtenga (20 %), and in the water channels in the city (from 20 to 31 %). Salmonella were commonly isolated from the fish (24 %) caught from the reservoir of Tanghin and from the lettuce (50 %) irrigated with water from Tanghin. The Salmonella isolates were found to represent 50 different serotypes. The 11 most common serotypes were Salmonella Bredeney and S. Colindale (both 8.2 %), S. Muenster (6.1 %), S. Korlebu (5.1 %), S. Eastbourne and S. Poona (both 4.1 %), and S. Agona, S. Derby, S. Drac, S. Senftenberg, S. Waycross (each 3.1 %), accounting for 51.3 % of all the isolates. In general, the Salmonella strains were sensitive to the antimicrobials tested, but two strains were resistant to streptomycin and many more intermediate to streptomycin or sulphonamide. CONCLUSION: This study highlights the common prevalence of Salmonella and the high diversity of Salmonella serotypes in aquatic environment in Ouagadougou, Burkina Faso. Therefore, various human activities linked to water and consumption of water-related products, such as fish and lettuce, can lead to human Salmonella infections. PMID- 26228575 TI - Hyperactivation to pleasant interoceptive stimuli characterizes the transition to stimulant addiction. AB - AIMS: Altered interoception, how the brain processes afferents from the body, may contribute to the urge to take drugs, and subsequently, the development of addiction. Although chronic stimulant dependent individuals exhibit attenuated brain responses to pleasant interoceptive stimuli, it is unclear whether this deficit exists early-on in the process of transition to stimulant addiction. METHODS: To this end, we compared problem stimulant users (PSU; n=18), desisted stimulant users (DSU; n=15), and stimulant naive comparison subjects (CTL; n=15) during functional magnetic resonance imaging (fMRI) while they anticipated and experienced pleasant soft touch (slow brushstroke to the palm and forearm). RESULTS: Groups did not differ in behavioral performance or visual analog scale ratings of soft touch stimuli. fMRI results indicated that PSU exhibited greater right anterior insula, left inferior frontal gyrus, and right superior frontal gyrus activation than DSU and CTL during the anticipation and experience of soft touch. Moreover, during the experience of soft touch, PSU demonstrated higher bilateral precentral gyrus/middle insula and right posterior temporal gyrus activation than DSU and CTL. CONCLUSIONS: In contrast to chronic stimulant dependence, individuals who have recently developed stimulant use disorders show exaggerated neural processing of pleasant interoceptive stimuli. Thus, increased processing of body-relevant information signaling pleasant touch in those individuals who develop problem use may be a predictive interoceptive biomarker. However, future investigations will need to determine whether the combination of probing pleasant interoception using neuroimaging is sufficiently sensitive and specific to help identify individuals at high risk for future problem use. PMID- 26228576 TI - Development of a new benazepril hydrochloride chewable tablet and evaluation of its bioequivalence for treatment of heart failure in dogs. AB - The aim of the study was to develop a new chewable benazepril hydrochloride(BH) tablet, investigate its physical properties, and evaluate its bioequivalence with the branded formulation (Fortekor). A corrective agent was included in the formula to improve its palatability and convenience for administration to dogs. The tablet remained stable in light, heat, and humidity tests, and its physical properties such as hardness, uniformity of content, and dissolution rate were highly consistent with the technical standards. After single and repeated administrations to eight beagles and single dose to 14 mongrel dogs (0.5 mg/kg p.o.), plasma BH and its active metabolite, benazeprilat (BZ), were detected. There was no significant difference in the major pharmacokinetic parameters (Cmax , Tmax, and AUC0-24) between the two formulations. The 90% confidence intervals calculated for the ratios of area under the time-concentration curve (AUC0-24) were 92.4-116.3% for BH and 89.9-102.3% for BZ, within the accepted range for bioequivalence of 80-125%. The results showed our new chewable tablet is bioequivalent to the commercial product and suitable for addition to the benazepril product family for the treatment of heart failure in dogs. PMID- 26228577 TI - Diagnostic accuracy of sperm DNA degradation index (DDSi) as a potential noninvasive biomarker to identify men with varicocele-associated infertility. AB - PURPOSE: Varicocele is a frequent cause of impaired testicular function that has been associated with increased levels of sperm DNA fragmentation (SDF). Sperm with degraded DNA (DDS), as observed using the sperm chromatin dispersion (SCD) test, represent a subpopulation of spermatozoa with extensive DNA and nuclear protein damage. The aim of this work was to determine the usefulness of sperm DNA degradation index (DDSi) as a novel noninvasive biomarker to identify infertile men with varicocele. METHODS: A total of 593 semen samples obtained from men attending infertility clinics were analyzed for SDF and DDS with the SCD test. These samples were classified as: (1) fertile donors; (2) infertile patients with least two failed assisted reproduction cycles; (3) leukocytospermia; (4) Chlamydia trachomatis infection; (5) testicular cancer, and (6) infertile men with varicocele. The DDSi was obtained by determining the proportion of DDS in the whole sperm population presenting with fragmented DNA. The diagnostic accuracy of DDSi was evaluated by correlation coefficient and receiver operating characteristics analyses. RESULTS: A positive correlation (r >= 0.52) was observed between the SDF and the frequency of degraded sperm in all patient groups. The sperm DNA degradation index (DDSi) was at least twice as higher in infertile men with varicocele (mean: 0.54) compared with other clinical conditions and fertile donors (means ranging from 0.02 to 0.21; P < 0.0001). A DDSi >= 0.33 identified patients with varicocele with 94 % accuracy. CONCLUSION: Although DDS is not pathognomonic of varicocele, the DDSi is a useful noninvasive biomaker to identify infertile individuals with varicocele when examining sperm DNA damage during a routine semen analysis. This finding may alert practitioners and laboratories performing semen analysis that in the presence of an abnormal DDSi it is likely that a given patient has varicocele. It is therefore strongly recommended that such patients be referred to urologists in order to undergo a full andrological examination and be properly counseled. PMID- 26228578 TI - Attitudes Toward Collaboration Among Practitioners in Newly Established Medical Homes: A Survey of Nurses, General Practitioners, and Specialists. AB - The objective was to evaluate the attitudes toward collaboration of nurses, general practitioners (GPs), and specialists practicing in newly established Medical Homes (MHs) in Parma Local Health Authority (LHA), Emilia-Romagna region, Italy. The 15-item Jefferson Scale of Attitudes Toward Physician-Nurse Collaboration was administered electronically to 172 physicians (66 GPs, 106 specialists) and 113 nurses practicing in 12 MHs. In all, 191 surveys (45 GPs, 59 specialists, 87 nurses) were completed (67% response rate). The mean total score among nurses (51.5, standard deviation [SD] = 3.7) reflected a significantly (P < .01) more positive attitude toward collaboration compared with GPs (47.8, SD = 4.6) and specialists (45.3, SD = 7.7). Discrepancies in attitudes are concerning because conflicting perceptions of professional roles may impede a successful transition to integrated care within MHs in Parma LHA. Internationally, further research into understanding interprofessional relationships within MHs is needed to inform policy and build a necessary culture of team-based care. PMID- 26228579 TI - Implementing High-Performance Teams: Strengths of a Standard Communication Tool in Neurosurgery. PMID- 26228580 TI - Management of Coronary Artery Disease in Patients With Descending Thoracic Aortic Aneurysms. AB - BACKGROUND: The combination of descending aortic aneurysm (DAA) with concomitant coronary artery disease (CAD) is associated with increased morbidity and mortality. We review the surgical management for patients with this combined disease. METHODS: From January 2000 to January 2014, we performed 268 elective surgeries on the descending or thoracoabdominal aorta. Sixty-six patients (24.7%) had significant CAD. Indications for aortic intervention included thoracoabdominal aortic aneurysm (TAAA) in 28 (42.4%), DAA in 36 (54.5%), and coarctation and ulcer in one each. Fifty-two (78.8%) patients had prior CAD, with remote coronary intervention in 32 (48.5%). RESULTS: Sixteen (24.2%) patients required coronary intervention prior to aortic surgery, percutaneous coronary intervention in three and coronary artery bypass grafting (CABG) in 13 (six off pump). We used the right internal thoracic artery (ITA) because of vulnerability of the left ITA during DAA clamping; the left ITA as a free graft or in situ when disease was distant to the left subclavian artery; and off-pump CABG to avoid manipulation and embolization. Mean duration between coronary intervention and aortic surgery was 37.2 days. There was no mortality or major adverse cardiac events (MACE) following coronary intervention or during interim to aortic surgery. There were two (3%) cardiac mortalities following DAA/TAAA repair. CONCLUSION: CAD is common among patients with DAA/TAAA. We recommend aggressive evaluation and prior treatment of CAD to minimize perioperative MACE. PMID- 26228581 TI - Outcome in Multiple Myeloma Patients Eligible for Stem Cell Transplantation: A Single-Center Experience. AB - Autologous hematopoietic stem cell transplantation (ASCT) is the standard of care for selected patients with multiple myeloma (MM). Many data exist on ASCT in the era of novel agents. We retrospectively analyzed 189 patients (108 males and 81 females) with biopsy-proven MM, who had received ASCT after induction therapy with either conventional chemotherapy alone or in combination with novel agents at our department. The outcomes of both groups and the risk factors for shorter survival were investigated. The most commonly used induction chemotherapy prior to ASCT was VAD (vincristine, doxorubicin and dexamethasone, 42%), followed by PAD (bortezomib, doxorubicin and dexamethasone, 21%). One-hundred and twenty-nine patients (68%) received cyclophosphamide-recombinant human granulocyte colony stimulating factor for stem cell mobilization. No differences were observed for progression-free survival in terms of the number of transplanted CD34+ cells (p = 0.261). A trend in improved overall survival (OS) was seen for the use of novel agents when compared to conventional chemotherapy (164.3 vs. 82.0 months; p = 0.046). The International Staging System stages had a significant (p = 0.036) impact on OS. The novel agents improved OS in our patients with MM undergoing ASCT when compared to conventional chemotherapy regimens. The number of transplanted CD34+ cells had no significant impact on hematopoietic reconstitution. PMID- 26228582 TI - Quantitative nanoscale electrostatics of viruses. AB - Electrostatics is one of the fundamental driving forces of the interaction between biomolecules in solution. In particular, the recognition events between viruses and host cells are dominated by both specific and non-specific interactions and the electric charge of viral particles determines the electrostatic force component of the latter. Here we probe the charge of individual viruses in liquid milieu by measuring the electrostatic force between a viral particle and the Atomic Force Microscope tip. The force spectroscopy data of co-adsorbed phi29 bacteriophage proheads and mature virions, adenovirus and minute virus of mice capsids is utilized for obtaining the corresponding density of charge for each virus. The systematic differences of the density of charge between the viral particles are consistent with the theoretical predictions obtained from X-ray structural data. Our results show that the density of charge is a distinguishing characteristic of each virus, depending crucially on the nature of the viral capsid and the presence/absence of the genetic material. PMID- 26228583 TI - Obituary: Professor Moritz Konerding (1960-2015). PMID- 26228585 TI - Standardized binomial models for risk or prevalence ratios and differences. AB - BACKGROUND: Epidemiologists often analyse binary outcomes in cohort and cross sectional studies using multivariable logistic regression models, yielding estimates of adjusted odds ratios. It is widely known that the odds ratio closely approximates the risk or prevalence ratio when the outcome is rare, and it does not do so when the outcome is common. Consequently, investigators may decide to directly estimate the risk or prevalence ratio using a log binomial regression model. METHODS: We describe the use of a marginal structural binomial regression model to estimate standardized risk or prevalence ratios and differences. We illustrate the proposed approach using data from a cohort study of coronary heart disease status in Evans County, Georgia, USA. RESULTS: The approach reduces problems with model convergence typical of log binomial regression by shifting all explanatory variables except the exposures of primary interest from the linear predictor of the outcome regression model to a model for the standardization weights. The approach also facilitates evaluation of departures from additivity in the joint effects of two exposures. CONCLUSIONS: Epidemiologists should consider reporting standardized risk or prevalence ratios and differences in cohort and cross-sectional studies. These are readily-obtained using the SAS, Stata and R statistical software packages. The proposed approach estimates the exposure effect in the total population. PMID- 26228586 TI - Obstetric referrals from a rural clinic to a community hospital in Honduras. AB - OBJECTIVES: referrals between health care facilities are important in low resource settings, particularly in maternal and child health, to transfer pregnant patients to the appropriate level of obstetric care. Our aim was to characterise the obstetrical referrals from a rural clinic to a community referral hospital in Honduras, to identify barriers in effective transport/referral, and to describe subsequent patient outcomes. METHODS: we performed a descriptive retrospective study of patients referred during a 9-month period. We reviewed patient charts to review diagnosis, referral, and treatment times at both sites to understand the continuity of care. RESULTS: ninety-two pregnant patients were referred from the rural clinic to the community hospital. Twenty six pregnant patients (28%) did not have complete and accurate medical records and were excluded from the study. The remaining 66 patients were our study population. Of the 66 patients, 54 (82%) received antenatal care with an average of 5.5+/-2.4 visits. The most common diagnoses requiring referral were non-reassuring fetal status, hypertensive disorders of pregnancy, and preterm labour. The time spent in the rural clinic until transfer was 7.35+/-8.60 hours, and transport times were 4.42+/-1.07 hours. Of the 66 women transferred, 24 (36%) had different primary diagnoses and 16 (24%) had additional diagnoses after evaluation in the community hospital, whereas the remaining 26 (40%) had diagnoses that remained the same. No system was in place to give feedback to the referring clinic doctors regarding their primary diagnoses. CONCLUSIONS: our results demonstrate challenges seen in obstetric transport from a rural clinic to a community hospital in Honduras. Further research is needed for reform of emergency obstetric care management, targeting both healthcare personnel and medical referral infrastructure. The example of Honduras can be taken to motivate change in other resource-limited areas. PMID- 26228587 TI - Eight decades of mortality in an English high-security hospital. AB - BACKGROUND: Psychiatric patients are known to have poorer physical health than the general population and to have premature mortality, but the impact of institutional care on the physical health of patients is less clear. AIMS: This study aimed to compare mortality rates and causes of death between a high security psychiatric hospital cohort and the general population in England for the periods 1920-1961 and 1972-2000. METHOD: Data were obtained from various clinical and non-clinical archives and death certificates. Standardised mortality ratios were calculated for all causes of patient death for each International Classification of Diseases, 10th Edition category. RESULTS: Mortality rates of men ever resident in Rampton Hospital were similar to those of men in the general population, but women in Rampton Hospital had nearly twice the national death rate. Younger men in the latest time period (1972-2000), however, had a higher mortality rate. Higher mortality rates in the hospital than in the general population were accounted for by infectious and parasitic diseases as well as diseases of the nervous system; rates of neoplasms and diseases of the blood and of circulatory or respiratory diseases were lower among the patients. CLINICAL IMPLICATIONS: Specific-cause mortality rates were compatible with our working hypothesis that the hospital could in some ways pose risks and in other ways be protective. Morbidity and causes of premature death may be environment-specific, so recognition of the types of illness linked to premature death among high security hospital patients could inform improvements in the physical health of long-stay patients. Further longitudinal studies should be undertaken to monitor trends and inform changes needed to reduce premature mortality. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26228584 TI - Low frequency of cigarette smoking and the risk of head and neck cancer in the INHANCE consortium pooled analysis. AB - BACKGROUND: Cigarette smoking is a major risk factor for head and neck cancer (HNC). To our knowledge, low cigarette smoking (<10 cigarettes per day) has not been extensively investigated in fine categories or among never alcohol drinkers. METHODS: We conducted a pooled analysis of individual participant data from 23 independent case-control studies including 19 660 HNC cases and 25 566 controls. After exclusion of subjects using other tobacco products including cigars, pipes, snuffed or chewed tobacco and straw cigarettes (tobacco product used in Brazil), as well as subjects smoking more than 10 cigarettes per day, 4093 HNC cases and 13 416 controls were included in the analysis. The lifetime average frequency of cigarette consumption was categorized as follows: never cigarette users, >0-3, >3 5, >5-10 cigarettes per day. RESULTS: Smoking >0-3 cigarettes per day was associated with a 50% increased risk of HNC in the study population [odds ratio (OR) = 1.52, 95% confidence interval (CI): (1.21, 1.90). Smoking >3-5 cigarettes per day was associated in each subgroup from OR = 2.01 (95% CI: 1.22, 3.31) among never alcohol drinkers to OR = 2.74 (95% CI: 2.01, 3.74) among women and in each cancer site, particularly laryngeal cancer (OR = 3.48, 95% CI: 2.40, 5.05). However, the observed increased risk of HNC for low smoking frequency was not found among smokers with smoking duration shorter than 20 years. CONCLUSION: Our results suggest a public health message that low frequency of cigarette consumption contributes to the development of HNC. However, smoking duration seems to play at least an equal or a stronger role in the development of HNC. PMID- 26228588 TI - Autonomous Ovarian Cysts in Prepubertal Girls. How Aggressive Should We Be? A Review of the Literature. AB - STUDY OBJECTIVE: Precocious pseudopuberty in girls occurs as a result of peripheral estrogen production, most commonly through an autonomous ovarian cyst or in patients with McCune Albright syndrome. Current management is either conservative or surgical. The aim of this study was to identify available literature on presentation, course and treatment of such cases. DESIGN: We performed a medline literature search using the key words 'ovarian autonomous cyst' and 'pseudopuberty'. We included articles published in English, from 1980 to date relating to females aged 2 to 8 years. We excluded papers on other endocrine conditions resulting in premature puberty. OUTCOME MEASURES: Type of management, time of resolution, recurrence, progression to Central Precocious Puberty and McCune Albright Syndrome. RESULTS: We identified 9 articles referring to 26 cases of autonomous ovarian cysts. All patients had suppressed LHRH testing and had simple ovarian cysts producing estradiol. Median age of patients was 5 years (range 2.2-8) and size of cyst was 41.5mm (9-60). Ten patients underwent cystectomy or oophorectomy, three were given cyproterone acetate and 13 were managed conservatively. Nine of 13 patients that were managed conservatively and two of those that had a cystectomy had a recurrence. There were three cases that progressed to central precocious puberty (CPP) and one case that was then identified to have McCune Albright (MCA) syndrome. One further case with multiple recurrences was given long term treatment with letrozole. CONCLUSION: We conclude that although a conservative approach should always be proposed in the first instance, one should be aware of the risk of recurrence and progression to CPP or MCA. Antiestrogen treatment appears promising; however data comparing it with surgical options and particularly long term consequences with regards to future reproductive outcomes are not available. PMID- 26228590 TI - Black men in England are twice as likely to get prostate cancer as white men, study shows. PMID- 26228589 TI - REMODEL larger cohort with long-term outcomes and meta-analysis of standalone balloon dilation studies. AB - OBJECTIVES/HYPOTHESIS: To provide the final results from the REMODEL (randomized evaluation of maxillary antrostomy versus ostial dilation efficacy through long term follow-up) full-study cohorts and perform meta-analyses of standalone balloon sinus dilation studies to explore long-term outcomes in a large patient sample. STUDY DESIGN: Randomized controlled trial and meta-analysis. METHODS: Final outcomes from the REMODEL randomized trial, including a larger cohort of 135 patients treated with functional endoscopic sinus surgery (FESS) or in-office balloon dilation, were evaluated. One hundred thirty patients had 12-month data, 66 had 18-month data, and 25 had 24-month data. In addition, a meta-analysis evaluated outcomes from six studies including 358 standalone balloon dilation patients with up to 24 months follow-up. RESULTS: Outcomes out to 2 years from the REMODEL full-study cohort are consistent with 6-month and 12-month outcomes. In the meta-analysis of standalone balloon dilation studies, technical success is 97.5%, and mean 20-item Sino-Nasal Outcomes Test scores are significantly and clinically improved at all time points (P < .0001). There are significant reductions (P < .0001) in work/school days missed, homebound days, physician/nurse visits, acute infections, and antibiotic prescriptions. Mean recovery time is 1.4 days. Comparison of 12-month symptom improvements and revision rates between the REMODEL FESS arm (n = 59), REMODEL balloon dilation arm (n = 71), and pooled single-arm standalone balloon dilation studies (n = 243) demonstrated no statistical difference. CONCLUSIONS: All outcomes are comparable between FESS and balloon dilation at all time points from 6 months to 24 months. Balloon dilation produces faster recovery, less postoperative pain, and fewer debridements than FESS. There is significant, durable benefit in a large series of 358 patients undergoing standalone balloon dilation. PMID- 26228591 TI - Group music interventions for dementia-associated anxiety: A systematic review. AB - OBJECTIVE: This systematic review examines the few published studies using group music interventions to reduce dementia-associated anxiety, the delivery of such interventions, and proposes changes to nursing curriculum for the future. DESIGN: Literature review. METHODS: All quantitative studies from 1989 to 2014 were searched in CINAHL and PubMed databases. Only published articles written in English were included. Studies excluded were reviews, non-human subjects, reports, expert opinions, subject age less than 65, papers that were theoretical or philosophical in nature, individual music interventions, case studies, studies without quantification of changes to anxiety, and those consisting of less than three subjects. Components of each study are analyzed and compared to examine the risk for bias. RESULTS: Eight articles met the inclusion criteria for review. Subject dementia severity ranged from mild to severe among studies reviewed. Intervention delivery and group sizes varied among studies. Seven reported decreases to anxiety after a group music intervention. CONCLUSIONS: Group music interventions to treat dementia-associated anxiety is a promising treatment. However, the small number of studies and the large variety in methods and definitions limit our ability to draw conclusions. It appears that group size, age of persons with dementia and standardization of the best times for treatment to effect anxiety decreases all deserve further investigation. In addition, few studies have been conducted in the United States. In sum, while credit is due to the nurses and music therapists who pioneered the idea in nursing care, consideration of patient safety and improvements in music intervention delivery training from a healthcare perspective are needed. Finally, more research investigating resident safety and the growth of nursing roles within various types of facilities where anxiety is highest, is necessary. PMID- 26228592 TI - [Eye lens radiation exposure during ureteroscopy with and without a face protection shield: Investigations on a phantom model]. AB - BACKGROUND AND OBJECTIVES: Eye lens radiation exposure during radiologically guided endoscopic procedures may result in radiation-induced cataracts; therefore, we investigated the ocular radiation exposure during ureteroscopy on a phantom model. MATERIALS AND METHODS: Using an Alderson phantom model and eye lens dosimeters, we measured the ocular radiation exposure depending on the number of X-ray images and on the duration of fluoroscopic imaging. The measurements were done with and without using a face protection shield. RESULTS: We could demonstrate that a significant ocular radiation exposure can occur, depending on the number of X-ray images and on the duration time of fluoroscopy. Eye lens doses up to 0.025 mSv were recorded even using modern digital X-ray systems. Using face protection shields this ocular radiation exposure can be reduced to a minimum. CONCLUSION: The International Commission on Radiological Protection (ICRP) recommendations of a mean eye lens dosage of 20 mSv/year may be exceeded during repeated ureteroscopy by a high volume surgeon. Using a face protection shield, the eye lens dose during ureteroscopy could be reduced to a minimum in a phantom model. Further investigations will show whether these results can be transferred to real life ureteroscopic procedures. PMID- 26228593 TI - [Urinary diversion with continent umbilical stoma: Which techniques are suitable for which patients?]. AB - BACKGROUND: Continent cutaneous diversions play a secondary role even in many centers for urinary diversion. The result is that knowledge about, indications and operation technique does not exist in many clinics. RESULTS: The general complication rates of the various forms of urinary diversion are not significantly different. There is no quality of life study showing a significant advantage for either form of urinary diversion. The functional results of neobladders in females with up to 70% hypercontinence are worse than in men, resulting in 2.4-fold more continent urinary diversions in men compared to women. The complication rates of the various forms of continent cutaneous pouches are different. CONCLUSION: Continent cutaneous pouches are an option for all patients with non-existing or functionally unusable urethra and as primary indication in all women with bladder cancer, consulting in very good quality of life and perfect body image. Age (<75 years), manual skills and psychological ability are selection criteria. As far as the results and complication rates are concerned the ileocecal pouch with an appendix umbilical stoma is the best option. In cases of non-existing appendix, alternatives are a neoappendix, serosal lined tapered ileum and ileal invagination nipple. PMID- 26228594 TI - A new option for the reconstruction of orbital floor defects with heterologous cortical bone. AB - BACKGROUND: The orbital floor is one of the most frequently injured areas of the maxillofacial skeleton during facial trauma. A retrospective analysis of patients who have undergone treatment of orbital floor fractures with heterologous cortical bone is presented. METHODS: This retrospective study was carried out with 21 patients over a period of 4 years between 2010 and 2014. All patients with a traumatic orbital floor defect who underwent reconstruction with heterologous cortical bone were included. The operations were carried out under general anesthesia for all patients. A subciliary incision was used in 20 patients and an infraorbital approach was used in one patient. All patients underwent follow-up examinations clinically as well as radiologically, at 1, 3, 6 and 12 months postoperatively. Computed tomographic scans were taken at the postoperative 6th month, and at the first postoperative year if needed. RESULTS: Preoperatively, the physical examination revealed diplopia in 17 patients (80.9%), gaze restriction in 14 patients (66.6%), enophthalmos in six patients (28.5%), and infraorbital nerve paresthesia in two patients (9.5%). None of the patients showed impaired visual acuity preoperatively or postoperatively. Diplopia and gaze restriction resolved postoperatively in all of the patients. All patients had a negative intraoperative forced duction test demonstrating free globe movement. Enophthalmos showed complete resolution in the postoperative period. In one of the two patients with preoperative infraorbital nerve paresthesia, this resolved at the postoperative fifth month. Scleral show appeared in six patients but resolved completely within 3-8 weeks with massage. There was no graft extrusion, resorption or displacement during the follow-up period. CONCLUSIONS: Tecnoss Semi Soft Lamina is a good alternative for the reconstruction of blowout fractures due to its plasticity and biocompatible structure. Without donor site morbidity, it is a safe and appropriate heterologous bone graft material for maxillofacial applications such as orbital floor reconstruction. We cannot recommend its use for near-total, wide orbital floor defects as it may not provide enough support in such circumstances. PMID- 26228595 TI - Cardiopulmonary Bypass Decreases Activation of the Signal Transducer and Activator of Transcription 3 (STAT3) Pathway in Diabetic Human Myocardium. AB - BACKGROUND: Cardiopulmonary bypass (CPB) is associated with increased myocardial oxidative stress and apoptosis in diabetic patients. A mechanistic understanding of this relationship could have therapeutic value. To establish a possible mechanism, we compared the activation of the cardioprotective signal transducer and activator of transcription 3 (STAT3) pathway between patients with uncontrolled diabetes (UD) and nondiabetic (ND) patients. METHODS: Right atrial tissue and serum were collected before and after CPB from 80 patients, 39 ND and 41 UD (HbA1c >= 6.5), undergoing cardiac operations. The samples were evaluated with Western blotting, immunohistochemistry, and microarray. RESULTS: On Western blot, leptin levels were significantly increased in ND post-CPB (p < 0.05). Compared with ND, the expression of Janus kinase 2 and phosphorylation (p-) of STAT3 was significantly decreased in UD (p < 0.05). The apoptotic proteins p Bc12/Bc12 and caspase 3 were significantly increased (p < 0.05), antiapoptotic proteins Mcl-1, Bcl-2, and p-Akt were significantly decreased (p < 0.05) in UD compared with ND. The microarray data suggested significantly increased expression of interleukin-6 R, proapoptotic p-STAT1, caspase 9, and decreased expression of Bc12 and protein inhibitor of activated STAT1 antiapoptotic genes (p = 0.05) in the UD patients. The oxidative stress marker nuclear factor-kappaB was significantly higher (p < 0.05) in UD patients post-CPB compared with the pre CPB value, but was decreased, albeit insignificantly, in ND patients post-CPB. CONCLUSIONS: Compared with ND, UD myocardium demonstrated attenuation of the cardioprotective STAT3 pathway. Identification of this mechanism offers a possible target for therapeutic modulation. PMID- 26228596 TI - The Subclavian Intraaortic Balloon Pump: A Compelling Bridge Device for Advanced Heart Failure. AB - BACKGROUND: A subclavian intraaortic balloon pump (SC-IABP) can help to optimize patients with advanced congestive heart failure as a bridge to definitive therapy. We retrospectively reviewed our experience to assess the application and safety of this technique. METHODS: We studied 88 patients with decompensated advanced congestive heart failure who received SC-IABP placement between January 2011 and December 2014. The SC-IABP was placed through a graft in the subclavian artery. The intended therapeutic goals for SC-IABP were bridge to transplant (n = 61), mechanical circulatory support (n = 21), or recovery (n = 6). Success was defined as stroke-free survival, achievement of therapeutic goal, and maintenance or improvement in renal function, hemodynamics, and physical conditioning through ambulation and rehabilitation. RESULTS: Eighty patients were successfully bridged to the next therapy (transplant 93.4%, mechanical circulatory support 95.3%, recovery 50%). There was no mortality related to SC-IABP placement. Duration of SC-IABP support was 4 to 135 days (median 21). Failure was attributed to escalation of support (n = 5), stroke (n = 2), and sepsis (n = 1). Mean pulmonary artery pressure significantly improved from 33 +/- 11 mm Hg to 28 +/- 8 mm Hg (p < 0.05). Eighty-four patients (95.5%) ambulated more than 3 times a day. Two minute step test demonstrated significant improvement, from 50 +/- 9 steps to 90 +/- 23 steps (n = 16, p < 0.001). Specific complications of SC-IABP included exchange/repositioning (n = 26, 29.5%), subclavian artery thrombosis (n = 1, 1.1%), and reexploration for hematoma (n = 4, 4.5%) and infection (n = 2, 2.3%). No distal thromboembolic events were observed. CONCLUSIONS: The SC-IABP provided excellent hemodynamic support with minimal morbidity and mortality, allowed for extensive rehabilitation, and permitted more than 90% of patients to receive their intended therapy. Therefore, SC-IABP is a compelling bridge device for patients with advanced congestive heart failure. PMID- 26228597 TI - Dilated Cardiomyopathy: Normalized Multiparametric Myocardial Strain Predicts Contractile Recovery. AB - BACKGROUND: Left ventricular contractile injury in dilated cardiomyopathy (DCM) may occur in a consistently heterogeneous distribution, suggesting that early injury sentinel regions may have prognostic significance. Heightened surveillance of these regions with high-resolution contractile metrics may predict recovery in DCM. METHODS: Multiple three-dimensional strain parameters were calculated at each of 15,300 left ventricular grid points from systolic displacement data obtained from cardiac magnetic resonance imaging in 124 test subjects. In 24 DCM patients, Z-scores for two strain parameters at each grid point were calculated by comparison of patient-specific strain values to respective point-specific mean and standard deviation values from a normal human strain database (n = 100). Multiparametric strain Z-scores were averaged over six left ventricular regions at basilar, mid, and apical levels (18 subregions). Patients with DCM were stratified into three groups on the basis of a blinded review of clinical contractile recovery (complete, n = 7; incomplete, n = 7; none, n = 10). RESULTS: Basilar-septal subregions were consistently heavily injured. Basilar-septal Z scores were significantly larger (worse) than those for the rest of the left ventricle (2.73 +/- 1.27 versus 2.22 +/- 0.83; p = 0.011) and lateral wall (2.73 +/- 1.27 versus 1.44 +/- 0.72; p < 0.001). All patients with sentinel region average multiparametric strain Z-scores less than two standard deviations (n = 6) experienced complete recovery, whereas 17 of 18 DCM patients with Z-scores greater than two standard deviations experienced incomplete or no contractile recovery. CONCLUSIONS: Contractile injury in DCM is heterogeneous, with basilar septal regions injured more than lateral regions. The targeting of early-injury sentinel regions for heightened surveillance with high-resolution metrics of microregional contractile function may accurately predict recovery on medical therapy. A two standard deviation Z-score threshold may predict contractile recovery. PMID- 26228599 TI - Surgical Innovation: Lessons From the Pragmatic Philosophical School. PMID- 26228598 TI - Restrictive Mitral Annuloplasty Does Not Limit Exercise Capacity. AB - BACKGROUND: Restrictive mitral annuloplasty is the preferred method of treating secondary mitral regurgitation. The use of small annuloplasty rings to reduce the high recurrence rates may result in mitral stenosis. METHODS: Thirty-six patients who underwent restrictive mitral annuloplasty with Carpentier-Edwards classic 26 size ring underwent exercise echocardiography and ergospirometry. Resting catecholamines and N-terminal pro brain natriuretic peptide (NT-proBNP) levels were measured. RESULTS: At the time of study, the median time from operation was 16.6 months (interquartile range, 8.5 to 43.3 months). Left ventricular end systolic volume index (LVESVI) was 67 mL/m(2) (interquartile range, 25 to 92 mL/m(2)), and ejection fraction (EF) was 38.8% (interquartile range, 28.3% to 59.0%). Mitral gradients were higher at the leaflet tips than at the annular level. Continuous wave (CW) Doppler gradients at rest were 3.4 mmHg (interquartile range, 2.4 to 4.9 mmHg) mean and 9.5 mmHg (interquartile range, 7.0 to 14.7 mmHg) maximal. On exertion, they increased to 6.8 mmHg (interquartile range, 5.4 to 8.8 mmHg) (p = 0.001) and 19.7 mmHg (interquartile range, 12.8 to 23.3 mmHg) (p = 0.001), respectively. Maximal VO2 was 18.2 mL/kg/min (interquartile range, 16.3 to 21.5 mL/kg/min), VE/VCO2 slope was 31.1 (interquartile range, 26 to 34). Epinephrine level was 0.024 ng/mL (interquartile range, 0.0098 to 0.043 ng/mL), norepinephrine was 0.61 ng/mL (interquartile range, 0.41 to 0.95 ng/mL), and NT-proBNP was 303 pg/mL (interquartile range, 155 to 553 pg/mL). Maximal VO2 negatively correlated with resting norepinephrine level (r = -0.50, p = 0.003). VE/VCO2 slope positively correlated with NT-proBNP (r = 0.36, p = 0.004) and epinephrine (r = 0.36, p = 0.04) levels and with LV volumes (r = 0.51, p = 0.006) and was negatively correlated with LVEF (r = -0.52, p = 0.004). Neither maximal VO2 nor VE/VCO2 slope correlated with the highest mean (r = 0.24, p = 0.2, and r = -0.20, p = 0.3, respectively) and maximal (r = 0.13, p = 0.5, r = -0.20, p = 0.3, respectively) mitral gradients on exertion. CONCLUSIONS: Restrictive mitral annuloplasty for secondary mitral regurgitation does result in a degree of mitral stenosis; however, primary heart disease seems more important for patient's exercise performance than the mitral stenosis resulting from using an undersized ring. PMID- 26228600 TI - Bilateral Versus Single Internal Mammary Artery Grafting in the Elderly: Long Term Survival Benefit. AB - BACKGROUND: Extensive evidence documents a survival benefit for bilateral internal mammary artery (BIMA) grafting compared with single internal mammary artery (SIMA) grafting for patients with advanced coronary artery disease. However, controversy continues to exist regarding the incremental benefit of broadly applied BIMA grafting in elderly patients. METHODS: Retrospective analysis was conducted of 4,503 consecutive isolated coronary artery bypass grafting operations (SIMA, n = 2,340 and BIMA, n = 2,163) performed from 1972 to 1994. Multivariate analysis was used to created propensity score-matched groups of SIMA (n = 1,063) and BIMA (n = 1,063) to compare patients 65 years of age and older, and 70 years of age and older (n = 612), with similar baseline characteristics. Survival status was obtained by periodic follow-up, query of the US National Death Index, and other Internet searches, and was 99.6% complete. RESULTS: The propensity score-matched groups experienced similar perioperative mortality and morbidity. Survival benefits were found for BIMA versus SIMA grafting across both age categories. Actuarial curves after 23,593 patient-years of follow-up (mean BIMA = 11.7 years; 6 weeks to 33.1 years; mean SIMA = 10.5 years; 6 weeks to 30.7 years) demonstrated improved long-term survival for BIMA versus SIMA patients at 12 years (51.0 +/- 1.5% versus 39.0 +/- 1.5%) and at 24 years (3.5 +/- 0.7% versus 4.5 +/- 0.7%; p < 0.001). Similarly, in matched groups of patients age 70 and older, overall survival was also enhanced with BIMA grafting (p = 0.005). CONCLUSIONS: Advanced age should not be a contraindication for BIMA grafting. Long-term follow-up clearly demonstrates that BIMA grafting when broadly applied in elderly patients results in improved long-term survival over SIMA grafting. PMID- 26228602 TI - Retention Rate of Electromagnetic Navigation Bronchoscopic Placed Fiducial Markers for Lung Radiosurgery. AB - BACKGROUND: Radiosurgery is becoming an increasingly used modality for the medically inoperable early stage lung cancer patient. The optimal fiducial marker with respect to retention rate has yet to be identified. METHODS: We retrospectively reviewed our experience with electromagnetic navigational bronchoscopic fiducial marker placement in preparation for stereotactic radiosurgery. RESULTS: Forty-eight patients, treated between 2010 and January 2013, were retrospectively reviewed. All patients had a diagnosis of early stage lung cancer. Comparison of initial fiducial placement procedure data with imaging at the time of treatment was accomplished for all patients in this data set. Fiducial retention rates were as follow: VortX coil fiducials were retained in 59 of 61 (96.7%) cases; two-band fiducials were retained in 24 of 33 (72.7%) of instances; and gold seed fiducials were retained in 23 of 33 (69.7%) of cases. Retention was statistically superior when comparing the VortX coil with the two band fiducial or the gold seed (p = 0.004 and p = 0.0001). Anatomic location by lobe was analyzed, but no statistically significant differences were observed. CONCLUSIONS: The VortX coil fiducial marker showed a statistically significant increase in retention rate compared with gold seeds or two-band fiducials. This may translate to cost savings through placing fewer markers per patient as retention is high. PMID- 26228601 TI - Multidisciplinary Treatment for Stage IIIA Non-Small Cell Lung Cancer: Does Institution Type Matter? AB - BACKGROUND: Improved survival of patients with early-stage non-small cell lung cancer (NSCLC) undergoing resection at high-volume centers has been reported. However, the effect of institution is unclear in stage IIIA NSCLC, where a variety of neoadjuvant and adjuvant therapies are used. METHODS: Treatment and outcomes data of clinical stage IIIA NSCLC patients undergoing resection as part of multimodality therapy was obtained from the National Cancer Database. Multivariable regression models were fitted to evaluate variables influencing 30 day mortality and overall survival. RESULTS: From 1998 to 2010, 11,492 clinical stage IIIA patients underwent resection at community centers, and 7,743 patients received resection at academic centers. Academic center patients were more likely to be younger, female, non-Caucasian, have a lower Charlson-Deyo comorbidity score, and to receive neoadjuvant chemotherapy (49.6% vs 40.6%; all p < 0.001). Higher 30-day mortality was associated with increasing age, male gender, preoperative radiotherapy, and pneumonectomy. Patients undergoing operations at academic centers experienced lower 30-day mortality (3.3% vs 4.5%; odds ratio, 0.75; 95% confidence interval [CI], 0.60 to 0.93; p < 0.001). Decreased long-term survival was associated with increasing age, male gender, higher Charlson-Deyo comorbidity score, and larger tumors. Neoadjuvant chemotherapy (hazard ratio, 0.66; 95% CI, 0.62 to 0.70), surgical intervention at an academic center (hazard ratio, 0.92; 95% CI, 0.88 to 0.97), and lobectomy (hazard ratio, 0.72; 95% CI, 0.67 to 0.77) were associated with improved overall survival. CONCLUSIONS: Stage IIIA NSCLC patients undergoing resection at academic centers had lower 30-day mortality and increased overall survival compared with patients treated at community centers, possibly due to higher patient volume and an increased rate of neoadjuvant chemotherapy. PMID- 26228603 TI - Reported Outcome After Valve-Sparing Aortic Root Replacement for Aortic Root Aneurysm: A Systematic Review and Meta-Analysis. AB - Valve-sparing aortic root techniques have progressively gained ground in the treatment of aortic root aneurysm and aortic insufficiency. By avoiding anticoagulation therapy they offer a good alternative to composite graft replacement. This systematic review describes the reported outcome of valve sparing aortic root replacement, focusing on the remodeling and reimplantation technique. A systematic literature search on the characteristics of and outcomes after valve-sparing aortic root replacement revealed 1,659 articles. The inclusion criteria were a focus on valve-sparing aortic root replacement in adults with aortic root aneurysm, presentation of survival data, and inclusion of at least 30 patients. Data were pooled by inverse variance weighting and analyzed by linear regression. Of 1,659 articles published between January 1, 2000, and January 1, 2014, 31 were included (n = 4,777 patients). The mean age at operation was 51 +/- 14.7 years, and 14% of patients had a bicuspid aortic valve. The reimplantation technique was used in 72% and remodeling in 27% (1% other). No clinical advantage in terms of survival and reoperation of one technique over the other was found. Cusp repair was performed in 33%. Pooled early mortality was 2% (n = 103). During follow-up (21,716 patient-years), 262 patients died (survival 92%), and 228 (5%) underwent reoperation, mainly valve replacement. Major adverse valve-related events were low (1.66% patient-years). Preoperative severe aortic valve regurgitation showed a trend toward higher reoperation rate. Remodeling and reimplantation techniques show comparable survival and valve durability results, providing a valid alternative to composite valve replacement. The heterogeneity in the data underlines the need for a collaborative effort to standardize outcome reporting. PMID- 26228604 TI - Changes in Risk Profile Over Time in the Population of a Pediatric Heart Transplant Program. AB - BACKGROUND: Single-center data on pediatric heart transplantation spanning long time frames is sparse. We attempted to analyze how risk profile and pediatric heart transplant survival outcomes at a large center changed over time. METHODS: We divided 320 pediatric heart transplants done at Stanford University between 1974 and 2014 into three groups by era: the first 20 years (95 transplants), the subsequent 10 years (87 transplants), and the most recent 10 years (138 transplants). Differences in age at transplant, indication, mechanical support, and survival were analyzed. RESULTS: Follow-up was 100% complete. Average age at time of transplantation was 10.4 years, 11.9 years, and 5.6 years in eras 1, 2, and 3, respectively. The percentage of infants who received transplants by era was 21%, 7%, and 18%, respectively. The indication of end-stage congenital heart disease vs cardiomyopathy was 24%, 22%, and 49%, respectively. Only 1 patient (1%) was on mechanical support at transplant in era 1 compared with 15% in era 2 and 30% in era 3. Overall survival was 72% at 5 years and 57% at 10 years. Long term survival increased significantly with each subsequent era. Patients with cardiomyopathy generally had a survival advantage over those with congenital heart disease. CONCLUSIONS: The risk profile of pediatric transplant patients in our institution has increased over time. In the last 10 years, median age has decreased and ventricular assist device support has increased dramatically. Transplantation for end-stage congenital heart disease is increasingly common. Despite this, long-term survival has significantly and consistently improved. PMID- 26228605 TI - Prolonged White Matter Inflammation After Cardiopulmonary Bypass and Circulatory Arrest in a Juvenile Porcine Model. AB - BACKGROUND: White matter (WM) injury is common after neonatal cardiopulmonary bypass (CPB). We have demonstrated that the inflammatory response to CPB is an important mechanism of WM injury. Microglia are brain-specific immune cells that respond to inflammation and can exacerbate injury. We hypothesized that microglia activation contributes to WM injury caused by CPB. METHODS: Juvenile piglets were randomly assigned to 1 of 3 CPB-induced brain insults (1, no-CPB; 2, full-flow CPB; 3, CPB and circulatory arrest). Neurobehavioral tests were performed. Animals were sacrificed 3 days or 4 weeks postoperatively. Microglia and proliferating cells were immunohistologically identified. Seven analyzed WM regions were further categorized into 3 fiber connections (1, commissural; 2, projection; 3, association fibers). RESULTS: Microglia numbers significantly increased on day 3 after CPB and circulatory arrest, but not after full-flow CPB. Fiber categories did not affect these changes. On post-CPB week 4, proliferating cell number, blood leukocyte number, interleukin (IL)-6 levels, and neurologic scores had normalized. However, both full-flow CPB and CPB and circulatory arrest displayed significant increases in the microglia number compared with control. Thus brain-specific inflammation after CPB persists despite no changes in systemic biomarkers. Microglia number was significantly different among fiber categories, being highest in association and lowest in commissural connections. Thus there was a WM fiber-dependent microglia reaction to CPB. CONCLUSIONS: This study demonstrates prolonged microglia activation in WM after CPB. This brain specific inflammatory response is systemically silent. It is connection fiber dependent which may impact specific connectivity deficits observed after CPB. Controlling microglia activation after CPB is a potential therapeutic intervention to limit neurologic deficits after CPB. PMID- 26228606 TI - Sonographic Features of Endobronchial Ultrasonography Predict Intrathoracic Lymph Node Metastasis in Lung Cancer Patients. AB - BACKGROUND: Intrathoracic lymph node sampling by endobronchial ultrasonography guided transbronchial needle aspiration (EBUS-TBNA) has become a standard of care in staging lung cancer. This study aimed to assess the efficacy of utilizing the individual sonographic features of lymph nodes for predicting metastasis in lung cancer patients. METHODS: From January 2010 to May 2012, we retrospectively studied 459 metastatic lymph nodes in 298 lung cancer patients and 176 reactive lymph nodes in 90 patients with nonspecific inflammation. Digital videos of the lymph nodes were obtained during EBUS-TBNA and categorized according to the following characteristics: size, shape, margin, central hilar structure, echogenicity, necrosis sign, matting, calcification, and vascular patterns. The sonographic findings were compared with the final pathology results and clinical follow-up. RESULTS: Multivariate analysis revealed five independent predictive factors for lymph node metastasis: long axis, round shape, absence of central hilar structure, presence of matting, and nonhilar vascular pattern perfusion. An aggregate score system based on the odds ratio was developed and reduced the criteria to four factors: presence of matting, nonhilar vascular pattern perfusion, absence of central hilar structure, and round shape. It showed at least two of four independent predictive factors could obtain the best performance for predicting metastatic lymph nodes and yield a high sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of 93.03%, 55.68%, 84.55%, 75.38%, and 82.68%, respectively. CONCLUSIONS: Sonographic features of the EBUS images can differentiate metastatic from reactive lymph nodes, so it may help predict intrathoracic lymph nodes metastasis in lung cancer patients. PMID- 26228607 TI - [The DAPT study]. PMID- 26228608 TI - [Treatment of the thoracic and abdominal aorta: what the new European guidelines explain and what the experience has taught us]. PMID- 26228609 TI - [An increase of infective endocarditis cases in England seen with concomitant reduction in antibiotic prophylaxis since the implementation of NICE guidelines in 2008: possible explanations]. AB - Dayer and colleagues recently reported in The Lancet an increased incidence of infective endocarditis in England since 2008, year of NICE guideline on the restriction of antibiotic prophylaxis. They observed a concomitant decrease in the use of antibiotic prophylaxis. The temporal link between reduction of prophylaxis prescribing and increase of infective endocarditis raises the question of whether there is a causal association. In view of this observation, should we rethink antibiotic prophylaxis to prevent infective endocarditis? PMID- 26228610 TI - [Coronary artery aneurysms]. AB - Coronary artery aneurysms are defined as coronary dilations as greater than 1.5 times the largest diameter of the adjacent coronary segment. They are a relatively rare finding on coronary angiography, with prevalence ranging from 0.3% to 5% depending on case series. The identification of a coronary artery aneurysm is often a dilemma for both the clinician and the interventionist in terms of diagnosis, treatment and follow-up. This review summarizes the etiologic, pathogenetic, clinical and therapeutic aspects of coronary artery aneurysms in the light of the latest research on this topic. PMID- 26228611 TI - [Primary prevention of sudden cardiac death through a wearable cardioverter defibrillator]. AB - Nowadays, the implantable cardioverter-defibrillator is the gold standard for the prevention of sudden cardiac death due to tachyarrhythmias. However, its use is not free from short and long-term risks. In the last years, the wearable cardioverter-defibrillator (WCD) has become a widespread option for patients who need a safe and reversible protection against ventricular tachyarrhythmias. Notwithstanding this, its everyday application is restricted by several limitations, including the risk of inappropriate shocks, the device size and the need for strict compliance of both patients and caregivers. In this review, we report the most relevant literature data on WCD usage along with the main fields of applications and future perspectives. PMID- 26228612 TI - [Italian cardiologists and tobacco smoking. A survey on the prevalence and knowledge of smoking and strategies for smoking cessation in a cohort of Italian cardiologists]. AB - BACKGROUND: Tobacco use is the single most preventable cause of death. Its cessation is the most cost-effective strategy for reducing long-term cardiovascular morbidity and mortality. Although both healthcare professionals and the general population are aware of the detrimental effects of smoking on health, more than 25% of Italians are current smokers. Recent surveys showed that almost 50% of smoker patients relapse to smoke after having been discharged for acute coronary syndrome. Physicians who smoke may be a barrier for effective cessation interventions. Thus, it is important to assess cardiologists' attitude toward smoking habits and the implementation of smoking cessation programs. METHODS: The survey "Italian cardiologists and smoking habits" has been held in 2013 during the 44 degrees National Congress of the Italian Association of Hospital Cardiologists (ANMCO) to assess cardiologists' smoking status, their level of knowledge about smoking cessation interventions and their involvement in the management of smoking cessation. Out of more than 1200 cardiologists attending the ANMCO congress, 610 subjects (aged 51 +/- 11 years) answered an anonymous 35-item questionnaire; they were asked to declare their smoking status (9.5% current smokers). RESULTS: Among doctors who attended the survey, 58% correctly indicated smoking as an addiction and 45% regularly advised their patients to stop smoking. The majority of cardiologists (93%) reported a positive attitude toward smoking cessation strategies, 62% of them thought that cardiologists themselves should treat smoking dependence, though specific tools (70%) and education for the management of smoking cessation are lacking (66%). Two thirds of the entire sample of ANMCO cardiologists declared their willingness to participate in specialized educational programs. CONCLUSIONS: More than a half of Italian cardiologists are aware that smoking is an addiction. Although they feel themselves yet inadequate toward this approach, they are favorable to implement their own knowledge and skills toward smoking cessation. PMID- 26228613 TI - [ST-elevation acute myocardial infarction with a coronary artery aneurysm as the culprit lesion]. AB - The incidence of coronary artery aneurysms (CAA) in the general population ranges from 0.3% to 5.3%. Although CAA may cause thrombus formation or undergo progressive expansion with subsequent rupture, their natural history remains largely unknown. Appropriate treatment, including percutaneous, surgical or conservative management, may be challenging, particularly in acute settings. We describe the acute management of two patients with ST-elevation myocardial infarction where CAA was identified as the culprit lesion. PMID- 26228614 TI - [The conundrum of therapeutic management in acute myocardial infarction complicated by endoventricular thrombosis: moving between different risks]. AB - Coronary artery disease is a rare entity in young patients and accurate assessment of its prevalence is difficult. Although coronary artery disease is frequently a silent process, it may also acutely present with myocardial infarction (MI). One of the most feared complications of MI is left ventricular thrombus formation. Transthoracic echocardiography is recommended for all patients with MI, and cardiac magnetic resonance should be considered because of its higher sensitivity if thrombus cannot clearly be demonstrated. The optimal treatment is based on anticoagulant therapy that should be started early and maintained for 3-4 months after the index event. We report the case of a 35-year old male patient with anterior MI, complicated by left ventricular thrombus formation, extensive edema, microvascular obstruction and hemorrhagic core of the apical septum on cardiac magnetic resonance assessment. PMID- 26228615 TI - [Implementation of post-resuscitation care in adult cardiac arrest patients - Experts' opinion]. AB - Current evidence on post-resuscitation care suffers from important knowledge gaps on new treatments and prognostication, mainly because of the lack of large multicenter randomized trials. However, optimization of post-resuscitation care is crucial, and the establishment of a treatment easy to be accepted and implemented locally, based on currently available evidence, is advisable. The present article is a multisociety experts' opinion on post-cardiac arrest that aims (i) to provide schematic and clear suggestions on therapeutic interventions to be delivered following resuscitation from cardiac arrest, so as to implement local protocols with a standardized post-resuscitation care; (ii) to suggest post resuscitation therapeutic interventions that may result in improved survival with good neurological recovery, intended as a Cerebral Performance Category (CPC) score of 1-2; and finally (iii) to propose a pragmatic and schematic approach to post-resuscitation care for rapid initiation of intensive treatments (i.e. temperature management). The suggestions reported in this document are intended for adult patients resuscitated from both out-of-hospital and in-hospital cardiac arrest. They should be considered solely as an experts' opinion aimed to improve post-cardiac arrest care and they do not represent an official national guideline. PMID- 26228616 TI - A case of Bannayan-Riley-Ruvalcaba syndrome. A new clinical finding and brief review. PMID- 26228617 TI - Angiokeratomas Scroti Associated with Angiokeratomas of the Eyelids: Coincidence or One Entity? A Case Report and Review of the Literature. AB - We describe a unique patient with multiple angiokeratomas on both upper eyelids and on the scrotum. We review the literature and discuss the pathogenetic relationship. Angiokeratomas are described as vascular lesions, which are defined histologically as one or several dilated blood vessel(s) covered by a keratotic layer. They are usually divided into 5 groups: angiokeratoma of Mibelli, Fordyce's angiokeratoma, angiokeratoma corporis diffusum, angiokeratoma circumscriptum naeviforme and solitary angiokeratoma. Angiokeratomas of the eyelid are a very rare finding in the literature, whereas they appear more frequently on the scrotum. The aim of this report is to present a new case of angiokeratomas on the eyelids combined with angiokeratomas of the scrotum. The clinical manifestation and the aetiology of angiokeratomas vary among the subtypes. While the pathogenesis in Fordyce's angiokeratoma seems to be based on increased venous pressure, the cause of angiokeratomas of the eyelids remains to be discussed. PMID- 26228618 TI - Hearing Where the Eyes See: Children Use an Irrelevant Visual Cue When Localizing Sounds. AB - To reduce sensory uncertainty, humans combine cues from multiple senses. However, in everyday life, many co-occurring cues are irrelevant to the task at hand. How do humans know which cues to ignore? And does this ability change with development? This study shows the ability to ignore cross-modal irrelevant information develops late in childhood. Participants performed a sound discrimination task, with or without an irrelevant visual flash, presented synchronously in front of them. Adults ignored the irrelevant visual information, while 7- to 10-year-olds' responses were biased toward the flash location. The findings show that acquiring mature cue combination mechanisms is a multifaceted process that includes learning to ignore irrelevant cues, as well as to optimally combine relevant cues. PMID- 26228619 TI - Monitoring land cover changes in Isfahan Province, Iran using Landsat satellite data. AB - Changes in land cover and land use reveal the effects of natural and human processes on the Earth's surface. These changes are predicted to exert the greatest environmental impacts in the upcoming decades. The purpose of the present study was to monitor land cover changes using Multispectral Scanner Sensor (MSS) and multitemporal Landsat Thematic Mapper (TM) data from the counties of Isfahan Province, Iran, during 1975, 1990, and 2010. The maximum likelihood supervised classification method was applied to map land cover. Postclassification change detection technique was also used to produce change images through cross-tabulation. Classification results were improved using ancillary data, visual interpretation, and local knowledge about the area. The overall accuracy of land cover change maps ranged from 88 to 90.6%. Kappa coefficients associated with the classification were 0.81 for 1975, 0.84 for 1990, and 0.85 for 2010 images. This study monitored changes related to conversion of agricultural land to impervious surfaces, undeveloped land to agricultural land, agricultural land to impervious surfaces, and undeveloped land to impervious surfaces. The analyses of land cover changes during the study period revealed the significant development of impervious surfaces in counties of Isfahan Province as a result of population growth, traffic conditions, and industrialization. The image classification indicated that agricultural lands increased from 2520.96 km(2) in 1975 to 4103.85 km(2) in 2010. These land cover changes were evaluated in different counties of Isfahan Province. PMID- 26228620 TI - Spatial and temporal variations of the particulate size distribution and chemical composition over Ibadan, Nigeria. AB - Spatial and temporal variation of suspended particulate matter was measured in Ibadan, Nigeria during the raining and dry months of 2013 and 2014, respectively. Six different locations were considered, reflecting city-spread, population density, lifestyle, and vehicular- and industrial-related activities. Elemental characterisation of the samples were carried out using energy dispersive x-ray fluorescence (ED-XRF) spectroscopy, while the black carbon content was determined using an optical transmissometer. Backward trajectory analysis indicated that most air mass was of maritime origin except on few occasions that suggested the Sahara desert origin. Average PM2.5/PM10 ratio for the entire sampling period was 0.32 +/- 0.04. This is slightly lower than the reported values in the coastal city of Lagos, partly because of more adequately paved and better road networks resulting in lower dust re-suspension and/or there are relatively finer fraction particulates from other sources, which might include marine, industrial, and secondary emission-related sources. Black carbon showed predominance in the fine fractions and was, majorly, of traffic origin. Major enriched elements of concern are S, Zn, As, and Pb aside from those of sea origin. Refuse burning was observed to be the principal source of Pb and Zn in all the sites except one, which showed major industrial-related activities source. This study will provide data for future measurement and modelling works as well as providing a benchmark for relevant agencies for policy making on setting emission standards for the country. PMID- 26228621 TI - Sealant versus Fluoride in Primary Molars of Kindergarten Children Regularly Receiving Fluoride Varnish: One-Year Randomized Clinical Trial Follow-Up. AB - OBJECTIVES: The objectives of this study were to measure the caries preventive effect of sealants applied to occlusal surfaces of primary molars compared to fluoride varnish applications, and to assess the retention rate of sealants after 1 year. METHODS: 147 first-grade pupils from two kindergarten schools in Kuwait, whose parents gave their written consent, were included. The children were examined by one dentist using the International Caries Detection and Assessment System. After the examination, sealants and fluoride varnish were applied on the selected occlusal surfaces of primary molars by another dentist. The jaw quadrant for intervention was selected randomly; molars on the contralateral side of the mouth received the contralateral intervention. Examinations and intervention were provided on the school premises in the mobile dental unit with a portable spotlight. Moisture was controlled by cotton rolls, suction and air drying. The follow-up examinations were conducted after 1 year. All children received fluoride varnish before and 6 months after the intervention. RESULTS: From 267 matched pairs of occlusal surfaces of primary molars, varnished surfaces were significantly more likely to develop new caries lesions than the sealed ones (odds ratio = 2.92; 95% confidence interval = 1.82-4.71) during the 1-year follow up. The majority (73.0%) of the sealants were completely retained and 15.1% partially. CONCLUSIONS: Sealing fissures seems to be better in preventing occlusal caries lesions in primary molars than applying only fluoride varnish. After 1 year, the majority of sealants were retained sound. PMID- 26228622 TI - RD-1 encoded EspJ protein gets phosphorylated prior to affect the growth and intracellular survival of mycobacteria. AB - Mycobacterium tuberculosis (MTB) synchronizes a number of processes and controls a series of events to subvert host defense mechanisms for the sake of residing inside macrophages. Besides these, MTB also possesses a wide range of signal enzyme systems, including eleven serine threonine protein kinases (STPKs). The present study describes STPK modulated modification in one of the hypothetical proteins of the RD1 region; EspJ (ESX-1 secretion associated protein), which is predicted to be involved in virulence of MTB. We have employed knock-out MTB, and M. bovis BCG as a surrogate strain to elaborate the consequence of the phosphorylation of EspJ. The molecular and mass spectrometric analyses in this study, confirmed EspJ as one of the substrates of STPKs. The ectopic expression of phosphoablative mutants of espJ in M. bovis BCG also articulated the effect of phosphorylation on the growth and in survival of mycobacteria. Importantly, the level of phosphorylation of EspJ also differed between pathogenic H37 Rv (Rv) and non pathogenic H37 Ra (Ra) strains of MTB. This further suggested that to a certain extent, the STPKs mediated phosphorylation may be accountable, in determining the growth and in intra-cellular survival of mycobacteria. PMID- 26228623 TI - Structural and Kinetic Insights into the "Ceftazidimase" Behavior of the Extended Spectrum beta-Lactamase CTX-M-96. AB - Diversification of the CTX-M beta-lactamases led to the emergence of variants responsible for decreased susceptibility to ceftazidime, like the Asp240Gly harboring "ceftazidimases". We solved the crystallographic structure of the Asp240Gly variant CTX-M-96 at 1.2 A and evaluated the role of Asp240 in the activity toward oxyimino-cephalosporins through simulated models and kinetics. There seem to be subtle changes in the conformation of the active site cavity of CTX-M-96, compared to enzyme variants harboring the Asp240, and these small rearrangements could be due to localized shifts in the environment of the beta3 strand. According to the crystallographic evidence, CTX-M-96 presents a "compact" active site, which in spite of its reduced cavity seems to allow the proper interaction with oxyimino-cephalosporins, as suggested by simulated models. The term "ceftazidimases" that is currently applied for the Asp240Gly-harboring CTX-M variants should be used carefully. Structural differences between CTX-M harboring the Asp240Gly mutation (and also probably others like those at Pro167) do not seem to be conclusive to determine the "ceftazidimase" behavior observed in vivo, which is in turn partially supported by the mild improvement in the catalytic efficiency toward ceftazidime by CTX-M-96 and similar enzymes, compared to "parental" Asp240-harboring variants. In addition, it is observed that alterations in OmpF expression could act synergistically with CTX-M-96 for yielding clinical resistance toward ceftazidime. We therefore propose that the observed resistance in vivo is due to the sum of synergic mechanisms, and the term "cefotaximases associated with ceftazidime resistance" could be conveniently used to describe CTX-M harboring the Asp240Gly substitution. PMID- 26228624 TI - Syndrome diagnosis with single-nucleotide polymorphism (SNP) microarray. PMID- 26228625 TI - Short-latency afferent inhibition in patients with Parkinson's disease and freezing of gait. AB - Freezing of gait (FOG) is one of the most common gait disturbances in patients with Parkinson's disease (PD). Recently, a PET study has documented that PD patients with FOG display cholinergic deficits selectively driven by nucleus basalis of Meynert (nbM)-neocortical denervation and not by peduncolopontine nucleus (PPN)-thalamic degeneration. Short-latency afferent inhibition (SAI) is a neurophysiological technique that allows evaluating major cholinergic sources in the central nervous system in vivo. We sought to determine whether central cholinergic circuits, evaluated by means of SAI testing, are impaired in patients with PD with FOG (FOG+) as compared to those without (FOG-). SAI and neuropsychological data were collected in 14 FOG+ and 10 FOG-. SAI was also performed in 11 healthy control subjects. Demographic, clinical, and cognitive data were compared by using non-parametric tests. Parametric tests were used to compare electrophysiological results among groups. FOG+ and FOG- had similar SAI without significant differences with controls (p = 0.207). None of the PD patients had SAI values outside the normal range (>72 %). FOG+ presented poorer executive and visuospatial performances as compared to FOG-. Despite the presence of cognitive deficits, SAI failed to detect any significant decrease of cholinergic activity in FOG+. However, nbM-related cholinergic dysfunction cannot be ruled out. In fact, integrity or even increased activation of PPN-related cholinergic circuits may mask an eventual nbM dysfunction thus resulting in normal SAI findings. Indeed, selective PPN cholinergic neurons sparing maybe a distinctive features of FOG. Alternatively or complementary, FOG pathophysiology is underpinned by non-cholinergic neurotransmitters dysfunction. PMID- 26228627 TI - Reliability of assessing lifestyle and trigger factors in patients with migraine- findings from the PAMINA study. AB - BACKGROUND AND PURPOSE: Numerous lifestyle factors are blamed for triggering migraine attacks. The reliability of assessing these factors retrospectively is unknown. Therefore, retrospective and prospective assessments of lifestyle in general and of migraine triggers in particular were compared in patients with migraine. METHODS: At baseline, the patients filled in two questionnaires covering the previous 90 days. Thereafter they kept a prospective 90-day diary. Questionnaires and diary included the same set of 45 factors. In the first questionnaire the patients assessed their lifestyle, in the second they rated for each factor the likelihood of triggering a migraine attack, and in the diary they recorded the daily presence of these factors irrespective of headache. Five categories were used for comparing frequencies in questionnaire and diary, defining agreement as identical categories in diary and questionnaire, minor disagreement and major disagreement as overestimation or underestimation by one category and two or more categories, respectively. RESULTS: In all, 327 patients (283 women, age 41.9 +/- 12.1 years) who recorded 28,325 patient days were included. Calculating for each factor the percentage of patients with major disagreement the mean proportion was larger for trigger factors than for lifestyle (38.7% +/- 6.6% vs. 16.9% +/- 6.4%, P < 0.001). The proportion of factors showing major disagreement in more than 20% of the patients was 8.8% for lifestyle but 94.1% for trigger factors (P < 0.001). CONCLUSION: Comparing questionnaire and diary assessments of lifestyle and trigger factors in patients with migraine shows that questionnaire assessment of lifestyle is reliable, whereas trigger factors are overestimated and/or underestimated in retrospective questionnaires. PMID- 26228626 TI - A prospective study on blood Abeta levels and the cognitive function of patients with hemodialysis: a potential therapeutic strategy for Alzheimer's disease. AB - To obtain the proof of concept of a novel therapy for Alzheimer's disease (AD), we conducted two prospective studies with hemodialysis patients who had amyloid beta protein (Abeta) removed from their blood three times a week. One major pathological change in the brain associated with AD is Abeta deposition, mainly 40 amino acids Abeta1-40 and 42 amino acids Abeta1-42. Impaired Abeta clearance is proposed to be one cause of increased Abeta in the AD brain. Thus, we hypothesized that an extracorporeal removal system of Abeta from the blood may remove brain Abeta and be a useful therapeutic strategy for AD. In the first prospective study, plasma Abeta levels and the cognitive function of 30 hemodialysis patients (65-76 years old) were evaluated at baseline as well as 18 or 36 months after. Although plasma Abeta1-40 levels either decreased or remained unchanged, levels of Abeta1-42 either remained unchanged or increased at the second time point. Mini-Mental State Examination scores of most subjects increased or were maintained at the second time point. Abeta1-40 influx into the blood correlated with MMSE at the second time point. In the second prospective study, five patients (51-84 years old) with renal failure were evaluated before and after the initiation of hemodialysis. Plasma Abeta levels decreased, while cognitive function improved after initiating blood Abeta removal. Therefore, long term hemodialysis, which effectively removes blood Abeta, might alter Abeta influx and help maintain cognitive function. PMID- 26228628 TI - Pharmacokinetics and Brain Distribution and Metabolite Identification of Coptisine, a Protoberberine Alkaloid with Therapeutic Potential for CNS Disorders, in Rats. AB - Coptisine (COP), a protoberberine alkaloid (PBA) from Chinese medicinal plants (such as family Berberidaceae), may be useful for improving central nervous system disorders. However, its pharmacokinetics, disposition and metabolism are not well defined. In the present study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for the analysis of COP in biological samples. To better understand its in vivo pharmacological activities, COP concentrations in rat plasma were determined after oral (50 mg/kg) and intravenous administration (10 mg/kg). For the brain distribution study, the concentration of COP in five different regions was examined after intravenous administration at 10 mg/kg. Pharmacokinetic parameters from the COP concentration time profiles in plasma and brain, and the brain-to-plasma coefficient (Kp, brain) were calculated by non-compartmental analysis. The metabolites of COP in rats in vivo and in vitro (urine, bile, liver microsomes and intestinal bacteria incubation) were also identified. Seventeen metabolites, including 11 unconjugated metabolites formed by hydroxylation, hydrogenation, demethylation, dehydrogenation, demethylation, and 6 glucuronide and sulfate conjugates were identified for the first time. The results suggested that COP had low oral bioavailability of 8.9% and a short (plasma) half-life (T1/2=0.71 h) in rats. After intravenous administration, it quickly crossed the blood-brain barrier, accumulating at higher concentrations and then was slowly eliminated from different brain regions. Moreover, COP was transformed into metabolites through multiple metabolic pathways in vivo and in vitro. These results should help to promote further research on COP and contribute to clarifying the metabolic pathways of PBAs. PMID- 26228629 TI - Dietary Deficiency of Calcium and/or Iron, an Age-Related Risk Factor for Renal Accumulation of Cadmium in Mice. AB - The major route of cadmium (Cd) intake by non-smokers is through food ingestion. Cd is a non-essential metal absorbed through one or more transporters of essential metal ions. Expression of these transporters is affected by nutritional status. To investigate the risk factors for Cd toxicity, the effects of deficiency of essential metals on hepatic and renal accumulation of Cd were studied in mice of different ages. Mice were administered a control diet or one of the essential metal-deficient diets, administered Cd by gavage for 6 weeks, and killed; then, Cd accumulation was evaluated. Iron deficiency (FeDF) or calcium deficiency (CaDF) resulted in remarkable increases in hepatic and renal Cd accumulation compared with control-diet mice and other essential metal deficient mice. Cd accumulation in hepatic and renal tissue was increased significantly at all ages tested in FeDF and CaDF mice. Renal Cd concentrations were higher in 4-week-old mice than in 8- and 25-week-old mice. Increase in intestinal mRNA expression of calcium transporter (CaT)1, divalent metal ion transporter-1, and metallothionein (MT)1 was also higher in 4-week-old mice than in other mice. Renal accumulation of Cd showed strong correlation with intestinal mRNA expression of CaT1 and MT1. These data suggest that CaDF and FeDF at younger ages can be a risk factor for Cd toxicity. PMID- 26228630 TI - Mangiferin Inhibits Renal Urate Reabsorption by Modulating Urate Transporters in Experimental Hyperuricemia. AB - Mangiferin, a natural glucosyl xanthone from the leaves of Mangifera indica L., was previously shown to exert potent hypouricemic effects associated with inhibition of the activity of xanthine dehydrogenase/oxidase. The present study aimed to evaluate its uricosuric effect and possible molecular mechanisms underlying the renal urate transporters responsible for urate reabsorption in vivo. Mangiferin (1.5-24.0 mg/kg) was administered intragastrically to hyperuricemic mice and rats induced by the intraperitoneal injection of uric acid and potassium oxonate, respectively. The uricosuric effect was evaluated by determining the serum and urinary urate levels as well as fractional excretion of uric acid (FEUA). The mRNA and protein levels of renal urate-anion transporter 1 (URAT1), organic anion transporter 10 (OAT10), glucose transporter 9 (GLUT9), and PDZ domain-containing protein (PDZK1) were analyzed. The administration of mangiferin significantly decreased the serum urate levels in hyperuricemic mice in a dose- and time-dependent manner. In hyperuricemic rats, mangiferin also reduced the serum urate levels and increased the urinary urate levels and FEUA. These results indicate that mangiferin has uricosuric effects. Further examination showed that mangiferin markedly inhibited the mRNA and protein expression of renal URAT1, OAT10, and GLUT9 in hyperuricemic rats, but did not interfere with PDZK1 expression. Taken together, these findings suggest that mangiferin promotes urate excretion by the kidney, which may be related to the inhibition of urate reabsorption via downregulation of renal urate transporters. PMID- 26228632 TI - Innate lymphoid cells in graft-versus-host disease. AB - Innate lymphoid cells (ILC) are lymphocytes lacking rearranged antigen receptors such as those expressed by T and B cells. ILC are important effector and regulatory cells of the innate immune system, controlling lymphoid organogenesis, tissue inflammation, and homeostasis. The family of ILC consists of cytotoxic NK cells and the more recently described noncytotoxic group 1, 2, and 3 ILC. The classification of noncytotoxic ILC-in many aspects-mirrors that of T helper cells, which is based on the expression of master transcription factors and signature cytokines specific for each subset. The IL-22 producing RORgammat(+) ILC3 subset was recently found to be critical in the prevention of intestinal graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (HCT) via strengthening the intestinal mucosal barrier. In this review, we summarize the current view of the immunological functions of human noncytotoxic ILC subsets and discuss the potentially beneficial features of IL-22 producing ILC3 in improving allo-HCT efficacy by attenuating susceptibility to GVHD. In addition, we explore the possibility of other ILC subsets playing a role in GVHD. PMID- 26228631 TI - Big opportunities for small molecules in immuno-oncology. AB - The regulatory approval of ipilimumab (Yervoy) in 2011 ushered in a new era of cancer immunotherapies with durable clinical effects. Most of these breakthrough medicines are monoclonal antibodies that block protein-protein interactions between T cell checkpoint receptors and their cognate ligands. In addition, genetically engineered autologous T cell therapies have also recently demonstrated significant clinical responses in haematological cancers. Conspicuously missing from this class of therapies are traditional small-molecule drugs, which have previously served as the backbone of targeted cancer therapies. Modulating the immune system through a small-molecule approach offers several unique advantages that are complementary to, and potentially synergistic with, biologic modalities. This Review highlights immuno-oncology pathways and mechanisms that can be best or solely targeted by small-molecule medicines. Agents aimed at these mechanisms--modulation of the immune response, trafficking to the tumour microenvironment and cellular infiltration--are poised to significantly extend the scope of immuno-oncology applications and enhance the opportunities for combination with tumour-targeted agents and biologic immunotherapies. PMID- 26228633 TI - Mediators and mechanisms of heat shock protein 70 based cytoprotection in obstructive nephropathy. AB - Urinary heat shock protein 70 (Hsp70) is rapidly increased in patients with clinical acute kidney injury, indicating that it constitutes a component of the endogenous stress response to renal injury. Moreover, experimental models have demonstrated that Hsp70 activation is associated with the cytoprotective actions of several drugs following obstruction, including nitric oxide (NO) donors, geranylgeranylacetone, vitamin D, and rosuvastatin. Discrete and synergistic effects of the biological activities of Hsp70 may explain its cytoprotective role in obstructive nephropathy. Basic studies point to a combination of effects including inhibition of apoptosis and inflammation, repair of damaged proteins, prevention of unfolded protein aggregation, targeting of damaged protein for degradation, and cytoskeletal stabilization as primary effectors of Hsp70 action. This review summarizes our understanding of how the biological actions of Hsp70 may affect renal cytoprotection in the context of obstructive injury. The potential of Hsp70 to be of central importance to the mechanism of action of various drugs that modify the genesis of experimental obstructive nephropathy is considered. PMID- 26228635 TI - High Prevalence and Genetic Diversity of Campylobacter jejuni in Wild Crows and Pigeons. AB - The occurrence, seasonal variation and genetic diversity of Campylobacter spp. in pigeons and crows over a 1-year period were evaluated. Campylobacter spp. were isolated from 166 (34.6 %) out of 480 wild bird faecal samples. The occurrence of Campylobacter spp. in faecal samples was higher among crows (39.2 %) than pigeons (30.0 %), (P < 0.05). Campylobacter jejuni was the most common species detected among wild bird faecal samples (98.2 %). Meanwhile, Campylobacter coli prevalence in wild bird faecal samples was low-6 %. The Simpson's diversity index of C. jejuni flaA RFLP types was lower in pigeons (D = 0.88) compared with C. jejuni isolates detected in crows (D = 0.97). Obtained results revealed that C. jejuni are widely prevalent among crows and pigeons, indicating these wild birds as potential infection sources to humans. Further studies are required to determine crows and pigeons role in zoonotic transmission of Campylobacter. PMID- 26228634 TI - Selenoproteins and heat shock proteins play important roles in immunosuppression in the bursa of Fabricius of chickens with selenium deficiency. AB - Selenium (Se) is necessary for the immune system in chicken and mediates its physiological functions through selenoproteins. Heat shock proteins (Hsps) are indispensable for maintaining normal cell function and for directing the immune response. The aim of the present study was to investigate the effects of Se deficiency on the messenger ribonucleic acid (mRNA) expression levels of selenoproteins and Hsps as well as immune functions in the chicken bursa of Fabricius. Two groups of chickens, namely the control and Se-deficient (L group) groups, were reared for 55 days. The chickens were offered a basal diet, which contained 0.15 mg Se/kg in the diet fed to the control group and 0.033 mg Se/kg in the diet fed to the L group. We performed real-time quantitative polymerase chain reaction to detect the mRNA expression levels of selenoproteins and Hsps on days 15, 25, 35, 45 and 55. Western blotting was used to determine the protein expression levels of Hsps on days 35, 45 and 55, and immune functions were assessed through an enzyme-linked immunosorbent assay on days 15, 35, and 55. The data showed that the mRNA expression levels of selenoproteins, such as Txnrd1, Txnrd2, Txnrd3, Dio1, Dio2, Dio3, GPx1, GPx2, GPx3 GPx4, Sepp1, Selo, Sel-15, Sepx1, Sels, Seli, Selu, Selh, and SPS2, were significantly lower (P < 0.05) in the L group compared with the control group. Additionally, the mRNA and protein expression levels of Hsps (Hsp27, Hsp40, Hsp60, Hsp70, and Hsp90) were also significantly higher (P < 0.05) in the L group. The expression levels of IL-2, IL 6, IL-8, IL-10, IL-17, IL-1beta, IFN-alpha, IFN-beta, and IFN-gamma were significantly lower (P < 0.05) and TNF-alpha was significantly higher (P < 0.05) in the L group compared with the control group. Our results show that immunosuppression was accompanied by a downregulation of mRNA expression levels of selenoproteins and an upregulation of the Hsp mRNA expression levels. Thus, Se deficiency causes defects in the chicken bursa of Fabricius, and selenoproteins and Hsps play important roles in immunosuppression in the bursa of Fabricius of chickens with Se deficiency. PMID- 26228637 TI - Enhancement of white-light-emission from single-phase Sr5(PO4)3F:Eu(2+),Mn(2+) phosphors for near-UV white LEDs. AB - A series of single-phase broadband white-light-emitting Sr5(PO4)3F:Eu(2+),Mn(2+) phosphors were prepared by a solid state reaction. The luminescence property, and the crystal and electronic structures of the fluorophosphates were studied by photoluminescence analysis, XRD Rietveld refinement and density functional theory calculation (DFT), respectively. Under near ultraviolet excitation in the 250 to 430 nm wavelength range, the phosphors exhibit two emission bands centered at 440 and 556 nm, caused by the Eu(2+) and Mn(2+) ions. By altering the relative ratios of Eu(2+) and Mn(2+) in the compounds, the emission color could be modulated from blue to white. The efficient energy transfer from the Eu(2+) to Mn(2+) ions could be ascribed to the well crystallized host lattice and the facile substitution of Eu(2+) and Mn(2+) for Sr(2+) sites due to similar ionic radii. A series of fluxes were investigated to improve the photoluminescence intensity. When KCl was used as flux in the synthesis, the photoluminescence intensity of Sr5(PO4)3F:Eu(2+),Mn(2+) was enhanced by 85% compared with no fluxes added. These results demonstrate that the single-phase Sr5(PO4)3F:Eu(2+),Mn(2+) with enhanced luminescence efficiency could be promising as a near UV-convertible direct white light-emitting phosphor for WLED applications. PMID- 26228636 TI - An alternative way of understanding exit, voice and loyalty: the case of informal payments for health care in Israel. AB - This study examines Hirschman's model of exit, voice and loyalty with regard to informal payments in the Israeli healthcare system. Based on a national survey, we investigate the extent of "black" payments, its characteristics and its correlated factors. We find that informal payments do exist in Israel-although it seems that there has been a decline in the phenomenon. Contrary to the literature, we find no relationship between the option of voice or dissatisfaction with healthcare services and informal payments. However, we do find a negative correlation between trust and the use of such payments. This finding is consistent with Hirschman's insight that a lack of loyalty may lead people to strategies of exit. We suggest that given the fact that health care in Israel is a public service, the exit option may actually be a quasi-exit behavior. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26228638 TI - Increased morbidity during long-term follow-up of survivors of thrombotic thrombocytopenic purpura. PMID- 26228639 TI - Are 24 h urinary sodium excretion and sodium:potassium independently associated with obesity in Chinese adults? AB - OBJECTIVE: To examine the association of 24 h urinary Na excretion and Na:K with obesity in Chinese adults. DESIGN: Population-based cross-sectional study using a four-stage stratified sampling strategy. SETTING: Shandong Province, China. SUBJECTS: Chinese adults (n 1906) aged 18-69 years who provided complete 24 h urine samples. RESULTS: Odds of obesity increased significantly across increasing quartiles of urinary Na excretion (1.00, 1.54, 1.69 and 2.52, respectively, for overweight; 1.00, 1.20, 1.50, and 2.03, respectively, for obesity; 1.00, 1.44, 1.85 and 2.53, respectively, for abdominal obesity (assessed by waist circumference); and 1.00, 1.28, 1.44 and 1.75, respectively, for abdominal obesity (assessed by waist-to-height ratio); P for linear trend <0.001 for all). In addition, odds of abdominal obesity, but not odds of overweight and obesity, increased significantly with successive Na:K quartiles. Additionally, for each increment in urinary Na excretion of 100 mmol, odds of overweight, obesity, abdominal obesity (by waist circumference) and abdominal obesity (by waist-to height ratio) increased significantly by 46 %, 39 %, 55 % and 33 %, respectively. Similarly, with a 1 sd increase in Na:K, odds of abdominal obesity (by waist circumference) and abdominal obesity (by waist-to-height ratio) increased significantly by 12 % and 15 %, respectively. CONCLUSIONS: These findings suggest that 24 h urinary Na excretion and Na:K might be important risk factors for obesity in Chinese adults. PMID- 26228640 TI - Antimicrobial activity and resistance selection of different bioglass S53P4 formulations against multidrug resistant strains. AB - AIMS: This study aimed to evaluate the antimicrobial activity of two different formulations of bioglass BAG-S53P4 against multiresistant microorganisms involved in bone infections, and the capability of bioglass to select for resistance. METHODS: Antibacterial activity was evaluated by means of killing curves. The ability to select for resistant bacteria was evaluated by subculturing microorganisms in serial dilutions of bioglass. Scanning electron microscope acquisitions were conducted to evaluate bioglass-induced morphology changes. RESULTS: BAG-S53P4 formulations display a high antimicrobial activity and do not seem to select for resistance. Scanning electron microscopy analysis showed cell shrinkage and membrane damage after exposure to bioglass. CONCLUSIONS: BAG-S53P4 has a significant potential as bone substitute for the treatment of infections caused by multiresistant microorganisms. PMID- 26228642 TI - Stem Cell Approaches to Intervertebral Disc Regeneration: Obstacles from the Disc Microenvironment. AB - Intervertebral disc (IVD) degeneration results in segmental instability and irritates neural compressive symptoms, such as low back pain and motor deficiency. The transplanting of stem cell into degenerative discs has attracted increasing clinical attention, as a new and proven approach to alleviating disc degeneration and to relieving discogenic pains. Aside from supplementation with stem cells, the IVD itself already contains a pool of stem and progenitor cells. Since the resident disc stem cells are incapable of reversing the pathologic changes that occur during aging and disc degeneration, it has been debated as to whether transplanted stem cells are capable of providing an efficient and durable therapeutic effect, even though there have been positive outcomes in both animal models and in clinical trials. This review aims to decipher the interactions between the stem cell and the disc microenvironment. Within their new niches in the IVD, the exogenous stem cell shows metabolic adaptation to the low-glucose supply, hypoxia, and compressive loadings, but demonstrates little tolerance to the disc-like acidity and hypertonicity. Similarly, the survival of endogenous stem cells is threatened as well by the harsh disc microenvironment, which may exhaust the stem cell resources and restrict the self-repair capacity of a degenerating IVD. To eliminate the intrinsic obstacles within the stressful disc niches, stem cells should be delivered with an injectable scaffold that provides both survival and mechanical support. Quick healing or concretion of the injection injuries, which minimizes stem cell leakage and disturbance to disc homeostasis, is of equal importance toward achieving efficient stem cell-based disc regeneration. PMID- 26228641 TI - Expression of adiponectin, chemerin and visfatin in plasma and different tissues during a laying season in turkeys. AB - BACKGROUND: In mammals, adipose tissue is able to secrete various hormones called adipokines including adiponectin (ADP), chemerin (Chem) and visfatin (Visf) which are involved in controlling energy metabolism as well as reproductive functions. Visf receptor is still unknown whereas ADP and Chem mainly act through AdipoR1, AdipoR2 and CMKLR1 and GPR1 receptors, respectively. No studies have yet demonstrated the presence of these three adipokines in peripheral tissues, ovarian cells or turkey plasma. Here, we investigated the expression (mRNA and protein) of ADP, Chem, Visf and their receptors in peripheral tissues and ovarian cells (granulosa and theca cells) from hierarchical follicles. Furthermore, we determined the plasma profile of ADP, Visf and Chem at different physiological stages: start, peak and end of the laying period in Meleagris gallopavo turkeys. This data was correlated with the metabolic data (plasma glucose, triglycerides, cholesterol and phospholipids). METHODS: Tissue and ovarian cells mRNA and protein expression levels were determined by RT-qPCR and immunoblot, respectively. Plasma adipokines were measured by chicken ELISA and immunoblotting. RESULTS: In turkeys, Chem is mainly expressed in the liver while ADP and Visf are mainly expressed in the abdominal adipose tissue and pectoral muscles,respectively. As in mammals, AdipoR1 and AdipoR2 expression levels (mRNA and protein) are highly present in muscle and liver, respectively, whereas the mRNA expression of CMKLR1 and GPR1 is ubiquitous. In ovarian cells, ADP, Visf, Chem and their receptors are more highly expressed in theca cells than in granulosa cells excepted for AdipoR1. Furthermore, we found that plasma levels of ADP, Chem and Visf were reduced at the end of the laying period compared to the start of this period. At the plasma levels, the levels of these adipokines are strongly negatively correlated with glucose and only plasma Chem is negatively correlated with cholesterol, triglycerides and phospholipids. CONCLUSIONS: In turkeys, ADP, Visf and Chem and their receptors are expressed in peripheral tissues and ovarian cells. Plasma concentration of ADP, Visf and Chem decrease at the end of laying period and only plasma Chem is negatively correlated with levels of cholesterol, triglycerides and phospholipids levels during the entire laying period. PMID- 26228643 TI - Prognostic factors for abatacept retention in patients who received at least one prior biologic agent: an interim analysis from the observational, prospective ACTION study. AB - BACKGROUND: The emergence of new therapies for the treatment of rheumatoid arthritis (RA), the paucity of head-to-head studies, and the heterogeneous nature of responses to current biologics highlight the need for the identification of prognostic factors for treatment response and retention in clinical practice. Prognostic factors for patient retention have not been explored thoroughly despite data for abatacept and other biologics being available from national registries. Real-world data from the ACTION study may supplement the findings of randomized controlled trials and show how abatacept is used in clinical practice. The aim of this interim analysis was to identify prognostic factors for abatacept retention in patients with RA who received at least one prior biologic agent. METHODS: A large, international, non-interventional cohort of patients with moderate-to-severe RA who initiated intravenous abatacept in Canada and Europe (May 2008-January 2011) enrolled in the ACTION study. Potential prognostic factors for retention in this interim analysis (data cut-off February 2012; including patients from Canada, Germany, Greece, and Italy) were baseline demographics and disease characteristics, medical history, and previous and concomitant medication. Clinically relevant variables with p <= 0.20 in univariate analysis and no collinearity were entered into a Cox proportional hazards regression model, adjusted for clustered data. Variables with p <= 0.10 were retained in the final model (backward selection). RESULTS: The multivariate model included 834 patients. Anti-cyclic citrullinated peptide (CCP) antibody positivity (hazard ratio [95% confidence interval]: 0.55 [0.40, 0.75], p < 0.001), failure of <2 prior anti-tumor necrosis factors (TNFs) (0.71 [0.56, 0.90], p = 0.005 versus >=2 prior anti-TNFs), and cardiovascular comorbidity at abatacept initiation (0.48 [0.28, 0.83], p = 0.009) were associated with lower risk of abatacept discontinuation. Patients in Greece and Italy were less likely to discontinue abatacept than patients in Germany and Canada (Greece: 0.30 [0.16, 0.58]; Italy: 0.50 [0.33, 0.76]; Canada: 1.04 [0.78, 1.40], p < 0.001 versus Germany). CONCLUSIONS: Real-world prognostic factors for abatacept retention include anti-CCP positivity and fewer prior anti-TNF failures. Differences in retention rates between countries may reflect differences in healthcare systems. The finding that abatacept has potential advantages in patients with cardiovascular comorbidities needs to be confirmed in further research. PMID- 26228644 TI - Low Bone Turnover in Chronic Kidney Disease Is Associated with Decreased VEGF-A Expression and Osteoblast Differentiation. AB - BACKGROUND: Low turnover bone (low bone formation rates (BFRs)) with decreased osteoblast number is common in patients with chronic kidney disease (CKD) and attributed to 'over-suppression' of the parathyroid hormone (PTH) despite supra physiologic levels. An alternative hypothesis is abnormal osteoblast differentiation, resulting in low BFRs due to reduced VEGF-A. METHODS: We analyzed the expression of VEGF-A and mesenchymal stem cell (MSC) differentiation factors in freshly isolated bone marrow (BM) cells, and in BM cell-derived MSC in rats with different levels of BFRs and PTH (modulated by calcium and zoledronic acid). The regulators of VEGF in MSC were also determined. RESULTS: VEGF-A expression was reduced in the BM cells from CKD vs. normal animals (p < 0.02). In BM-derived MSC from CKD, there were decreased osteoblast transcription factors and mineralization. In CKD animals, the BM VEGF-A expression was positively correlated with BFR (r = 0.80, p < 0.001). Reducing BFRs in CKD animals led to reductions in VEGF-A expression and osteoblast transcription factors regardless of the PTH level. We therefore examined other regulators of VEGF-A and found decreased expression of hypoxia-inducible factor-1alpha and the master transcription factor of antioxidants nuclear factor (erythroid-derived 2)-like 2 in CKD animals with low PTH. CONCLUSION: Low BFRs in CKD are associated with a basal decrease in VEGF-A expression in BM that may be driven by altered hypoxia and oxidative stress. PMID- 26228645 TI - Propranolol and venlafaxine for vestibular migraine prophylaxis: A randomized controlled trial. AB - OBJECTIVES/HYPOTHESIS: We compared the effectiveness of venlafaxine and propranolol for the prophylaxis of vestibular migraine (VM). STUDY DESIGN: Prospective, randomized, controlled clinical trial. METHODS: Sixty-four subjects with definite VM were enrolled. The subjects were randomly assigned to receive propranolol (group P, n = 33) or venlafaxine (group V, n = 31) for VM prophylaxis. Dizziness Handicap Inventory (DHI) scores, the Vertigo Severity Score (VSS), and the number of vertiginous attacks were recorded before and 4 months after treatment. The Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) scores were also recorded to monitor the resolution of psychiatric symptoms. RESULTS: At 4 months after treatment, the DHI total score decreased from 55.8 +/- 2.7 to 31.3 +/- 3.7 and from 50.9 +/- 2.5 to 19.9 +/- 2.9 (P < .001), the mean number of total vertiginous attacks decreased from 12.6 +/- 1.8 to 1.9 +/- 0.7 and from 12.2 +/- 1.8 to 2.6 +/- 1.1 (P < .001), and VSS decreased from 7.3 +/- 0.3 to 2.1 +/- 0.4 and from 7.9 +/- 0.3 to 1.8 +/- 0.5 (P < .001) in groups P and V, respectively. However, the treatment effects were similar in both groups (P > .05). BAI scores significantly decreased in both groups, whereas BDI scores decreased only in group V. CONCLUSIONS: This study provided evidence that venlafaxine and propranolol show equal effectiveness as prophylactic drugs for ameliorating vertiginous symptoms in VM patients. However, venlafaxine may be superior to propranolol in ameliorating depressive symptoms. PMID- 26228646 TI - Interplay between ultrastructural findings and atherothrombotic complications in type 2 diabetes mellitus. AB - Accelerated atherosclerosis is the main underlying factor contributing to the high risk of atherothrombotic events in patients with diabetes mellitus and atherothrombotic complications are the main cause of mortality. Like with many bodily systems, pathology is observed when the normal processes are exaggerated or uncontrolled. This applies to the processes of coagulation and thrombosis as well. In diabetes, in fact, the balance between prothrombotic and fibrinolytic factors is impaired and thus the scale is tipped towards a prothrombotic and hypofibrinolytic milieu, which in association with the vascular changes accompanying plaque formation and ruptures, increases the prevalence of ischaemic events such as angina and myocardial infarction. Apart from traditional, modifiable risk factors for cardiovascular disease like hypertension, smoking, elevated cholesterol; rheological properties, endogenous fibrinolysis and impaired platelet activity are rapidly gaining significance in the pathogenesis of atherosclerosis especially in diabetic subjects. Blood clot formation represents the last step in the athero-thrombotic process, and the structure of the fibrin network has a role in determining predisposition to cardiovascular disease. It is no surprise that just like platelets and fibrin networks, erythrocytes have been shown to play a role in coagulation as well. This is in striking contrast to their traditional physiological role of oxygen transport. In fact, emerging evidence suggests that erythrocytes enhance functional coagulation properties and platelet aggregation. Among the spectrum of haematological abnormalities in diabetes, erythrocyte aggregation and decreased deformability of erythrocytes predominate. More importantly, they are implicated in the pathogenesis of microvascular complications of diabetes. The morphology of platelets, fibrin networks and erythrocytes are thus essential role players in unravelling the pathogenesis of cardiovascular complications in diabetic subjects. PMID- 26228648 TI - X-ray Radiation-Controlled NO-Release for On-Demand Depth-Independent Hypoxic Radiosensitization. AB - Multifunctional stimuli-responsive nanotheranostic systems are highly desirable for realizing simultaneous biomedical imaging and on-demand therapy with minimized adverse effects. Herein, we present the construction of an intelligent X-ray-controlled NO-releasing upconversion nanotheranostic system (termed as PEG USMSs-SNO) by engineering UCNPs with S-nitrosothiol (R-SNO)-grafted mesoporous silica. The PEG-USMSs-SNO is designed to respond sensitively to X-ray radiation for breaking down the S-N bond of SNO to release NO, which leads to X-ray dose controlled NO release for on-demand hypoxic radiosensitization besides upconversion luminescent imaging through UCNPs in vitro and in vivo. Thanks to the high live-body permeability of X-ray, our developed PEG-USMSs-SNO may provide a new technique for achieving depth-independent controlled NO release and positioned radiotherapy enhancement against deep-seated solid tumors. PMID- 26228647 TI - Colchicine--Update on mechanisms of action and therapeutic uses. AB - OBJECTIVES: To review the literature and provide an update on the mechanisms of action and therapeutic uses of oral colchicine in arthritis and inflammatory conditions. METHODS: We performed PubMed database searches through June 2014 for relevant studies in the English literature published since the last update of colchicine in 2008. Searches encompassed colchicine mechanisms of action and clinical applications in medical conditions. A total of 381 articles were reviewed. RESULTS: The primary mechanism of action of colchicine is tubulin disruption. This leads to subsequent down regulation of multiple inflammatory pathways and modulation of innate immunity. Newly described mechanisms include various inhibitory effects on macrophages including the inhibition of the NACHT LRRPYD-containing protein 3 (NALP3) inflammasome, inhibition of pore formation activated by purinergic receptors P2X7 and P2X2, and stimulation of dendritic cell maturation and antigen presentation. Colchicine also has anti-fibrotic activities and various effects on endothelial function. The therapeutic use of colchicine has extended beyond gouty arthritis and familial Mediterranean fever, to osteoarthritis, pericarditis, and atherosclerosis. CONCLUSION: Further understanding of the mechanisms of action underlying the therapeutic efficacy of colchicine will lead to its potential use in a variety of conditions. PMID- 26228651 TI - Educational technology "Anatomy and Vital Signs": Evaluation study of content, appearance and usability. AB - BACKGROUND: The use of new technology has recently grown considerably as an increasing number of college students using Internet. In nursing education, the personal computer and the Internet facilitate teaching theoretical and practical knowledge. OBJECTIVES: Evaluate an educational technology known as "Anatomy and Vital Signs" with respect to content, appearance and usability. METHOD: This was a first stage evaluation-by specialists to verify content and functioning, prior to a second validation as to learning by students. A methodological study in which instructional technologists (11 participants) and nursing specialists (17 participants) used the technology in an unguided manner and completed three questionnaires. The evaluation was measured by the difference between disagreement and agreement for each statement in the questionnaires. RESULTS: Most of the items were positively evaluated at a level higher than 70% by most of the evaluators except for the following usability criteria: grouping by shape, minimum actions and user control, which did not attain the 70% agreement level among instructional technologists. CONCLUSION: The evaluation was useful to improve the technology and guarantee suitable product for nursing education. It may be a reliable educational tool for nursing education that applies technological resources. PMID- 26228650 TI - Problem list completeness in electronic health records: A multi-site study and assessment of success factors. AB - OBJECTIVE: To assess problem list completeness using an objective measure across a range of sites, and to identify success factors for problem list completeness. METHODS: We conducted a retrospective analysis of electronic health record data and interviews at ten healthcare organizations within the United States, United Kingdom, and Argentina who use a variety of electronic health record systems: four self-developed and six commercial. At each site, we assessed the proportion of patients who have diabetes recorded on their problem list out of all patients with a hemoglobin A1c elevation>=7.0%, which is diagnostic of diabetes. We then conducted interviews with informatics leaders at the four highest performing sites to determine factors associated with success. Finally, we surveyed all the sites about common practices implemented at the top performing sites to determine whether there was an association between problem list management practices and problem list completeness. RESULTS: Problem list completeness across the ten sites ranged from 60.2% to 99.4%, with a mean of 78.2%. Financial incentives, problem-oriented charting, gap reporting, shared responsibility, links to billing codes, and organizational culture were identified as success factors at the four hospitals with problem list completeness at or near 90.0%. DISCUSSION: Incomplete problem lists represent a global data integrity problem that could compromise quality of care and put patients at risk. There was a wide range of problem list completeness across the healthcare facilities. Nevertheless, some facilities have achieved high levels of problem list completeness, and it is important to better understand the factors that contribute to success to improve patient safety. CONCLUSION: Problem list completeness varies substantially across healthcare facilities. In our review of EHR systems at ten healthcare facilities, we identified six success factors which may be useful for healthcare organizations seeking to improve the quality of their problem list documentation: financial incentives, problem oriented charting, gap reporting, shared responsibility, links to billing codes, and organizational culture. PMID- 26228652 TI - Information system technologies' role in augmenting dermatologists' knowledge of prescription medication costs. AB - OBJECTIVES: Despite the recent rising costs of once affordable dermatologic prescription medications, a survey measuring dermatologists' attitudes, beliefs, and knowledge of the cost of drugs they commonly prescribe has not been conducted. Awareness of drug costs is hindered by a lack of access to data about the prices of medicines. No surveys of physicians have addressed this issue by proposing new information system technologies that augment prescription medication price transparency and measuring how receptive physicians are to using these novel solutions in their daily clinical practice. Our research aims to investigate these topics with a survey of physicians in dermatology. METHODS: Members of the North Carolina Dermatology Association were contacted through their electronic mailing list and asked to take an online survey. The survey asked several questions about dermatologists' attitudes and beliefs about drug costs. To measure their knowledge of prescription medications, the National Average Drug Acquisition Cost was used as an authoritative price that was compared to the survey takers' price estimates of drugs commonly used in dermatology. Physicians' willingness to use four distinct information system technologies that increase drug price transparency was also assessed. RESULTS: Dermatologists believe drug costs are an important factor in patient care and believe access to price information would allow them to provide a higher quality of care. Dermatologists' knowledge of the costs of medicines they commonly prescribe is poor, but they want to utilize information system technologies that increase access to drug pricing information. CONCLUSIONS: There is an unmet demand for information system technologies which increase price transparency of medications in dermatology. Physicians and IT professionals have the opportunity to create novel information systems that can be utilized to help guide cost conscious clinical decision making. PMID- 26228653 TI - Opportunistic infections complicating solid organ transplantation with alemtuzumab induction. AB - Opportunistic infections remain a common complication of solid organ transplantation. Despite significant changes in immunosuppression and infectious diseases prophylaxis, data are limited on the contemporary epidemiology and outcomes of opportunistic infections. Alemtuzumab, a potent lymphocyte-depleting antibody, has been used with increased frequency in solid organ transplant recipients in the last decade. A literature review was performed to summarize the current understanding of the epidemiology, risk factors, and outcomes of opportunistic infections complicating solid organ transplantation with and without alemtuzumab induction therapy. Areas where data are limited regarding opportunistic infections in solid organ transplantation with alemtuzumab induction are indicated. PMID- 26228654 TI - De novo hepatic steatosis drives atherogenic risk in liver transplantation recipients. AB - Nonalcoholic fatty liver disease is associated with cardiovascular disease (CVD) in the general population. Despite a high prevalence of de novo hepatic steatosis after liver transplantation (LT), there are no data exploring the association between hepatic steatosis after LT and atherogenic risk. The aim of the study was to explore the impact of hepatic steatosis on serum atherogenic markers in liver transplantation recipients (LTRs). Biomarkers of CVD risk were compared in 89 LTRs with no known history of dyslipidemia, ischemic heart disease, or graft cirrhosis. To avoid potential confounders, LTRs on oral hypoglycemic agents, exogenous insulin, corticosteroids, or lipid-lowering therapy were excluded. Only patients for whom histological assessment was available after LT were included in the study. Thirty-five LTRs had de novo hepatic steatosis after LT, whereas 54 did not. Both cohorts were similar with regards to age, sex, ethnicity, and follow-up from LT. Additionally, the traditional lipid profile was similar between the 2 cohorts. LTRs with hepatic steatosis had higher serum concentrations of small-dense low-density lipoprotein cholesterol (sdLDL-C; 34.8 +/- 16.9 versus 22.7 +/- 11.2 mg/dL; P < 0.001), sdLDL-C to low-density lipoprotein cholesterol ratio (32.6 +/- 11.6 versus 24.6 +/- 10.2; P < 0.01), small-dense low-density lipoprotein particle concentration (sdLDL-P; 770 +/- 440 versus 486 +/- 402 nmol/L; P < 0.01), very low density lipoprotein particle concentration (VLDL-P; 7.90 +/- 7.91 versus 3.86 +/- 3.18 nmol/L; P < 0.01), and very low density lipoprotein size (VLDL-size; 51.9 +/- 6.4 versus 48.7 +/- 6.3 nm; P = 0.06). LTRs with hepatic steatosis had higher serum insulin concentrations (27.8 +/- 41.8 versus 11.7 +/- 7.8 uU/mL; P < 0.01) but similar fasting glucose and hemoglobin A1c. Steatosis grade was directly related to sdLDL C, sdLDL-P, insulin, VLDL-P, and VLDL-size. In multivariate analysis, the association between steatosis grade and sdLDL-C (beta = 0.03; P = 0.029), VLDL size (beta = 0.316; P = 0.04), and low-density lipoprotein particle size (beta = 0.27; P = 0.05) was independent of sex, body mass index, age, diabetes mellitus, time from transplant, and indication for LT. In conclusion, de novo hepatic steatosis after LT is associated with atherogenic lipoproteins and independent of traditional CVD risk factors. PMID- 26228655 TI - XAB2 tagSNPs contribute to non-small cell lung cancer susceptibility in Chinese population. AB - BACKGROUND: XPA-binding protein 2 (XAB2) interacts with Cockayne syndrome complementation group A (CSA), group B (CSB) and RNA polymerase II to initiate nucleotide excision repair. This study aims to evaluate the association of XAB2 genetic variants with the risk of non-small cell lung cancer (NSCLC) using a tagging approach. METHODS: A hospital-based case-control study was conducted in 470 patients with NSCLC and 470 controls in Chinese population. Totally, 5 tag single nucleotide polymorphisms (SNPs) in XAB2 gene were selected by Haploview software using Hapmap database. Genotyping was performed using iPlex Gold Genotyping Asssy and Sequenom MassArray. Unconditional logistic regression was conducted to estimate odd ratios (ORs) and 95 % confidence intervals (95 % CI). RESULTS: Unconditional logistic regression analysis showed that the XAB2 genotype with rs794078 AA or at least one rs4134816 C allele were associated with the decreased risk of NSCLC with OR (95 % CI) of 0.12 (0.03-0.54) and 0.46 (0.26 0.84). When stratified by gender, we found that the subjects carrying rs4134816 CC or CT genotype had a decreased risk for developing NSCLC among males with OR (95 % CI) of 0.39 (0.18-0.82), but not among females. In age stratification analysis, we found that younger subjects (age <= 60) with at least one C allele had a decreased risk of NSCLC with OR (95 % CI) of 0.35 (0.17-0.74), but older subjects didn't. We didn't find that XAB2 4134816 C > T variant effect on the risk of NSCLC when stratified by smoking status. The environmental factors, such as age, sex and smoking had no effect on the risk of NSCLC related to XAB2 genotypes at other polymorphic sites. CONCLUSIONS: The XAB2 tagSNPs (rs794078 and rs4134816) were significantly associated with the risk of NSCLC in Chinese population, which supports the XAB2 plays a significant role in the development of NSCLC. PMID- 26228656 TI - Insulin-degrading enzyme prevents alpha-synuclein fibril formation in a nonproteolytical manner. AB - The insulin-degrading enzyme (IDE) degrades amyloidogenic proteins such as Amyloid beta (Alphabeta) and Islet Amyloid Polypeptide (IAPP), i.e. peptides associated with Alzheimer's disease and type 2 diabetes, respectively. In addition to the protease activity normally associated with IDE function an additional activity involving the formation of stable, irreversible complexes with both Alphabeta and alpha-synuclein, an amyloidogenic protein involved in Parkinson's disease, was recently proposed. Here, we have investigated the functional consequences of IDE-alpha-synuclein interactions in vitro. We demonstrate that IDE in a nonproteolytic manner and at sub-stoichiometric ratios efficiently inhibits alpha-synuclein fibril formation by binding to alpha synuclein oligomers making them inert to amyloid formation. Moreover, we show that, within a defined range of alpha-synuclein concentrations, interaction with alpha-synuclein oligomers increases IDE's proteolytic activity on a fluorogenic substrate. We propose that the outcomes of IDE-alpha-synuclein interactions, i.e. protection against alpha-synuclein amyloid formation and stimulated IDE protease activity, may be protective in vivo. PMID- 26228657 TI - Evaluation of root canal sealer filling quality using a single-cone technique in oval shaped canals: An In vitro Micro-CT study. AB - The aim of this study was to evaluate and compare the presence of voids in oval root canals filled with different root canal sealers (EndoSequence BC Sealer, Smartpaste bio, ActiV GP) and to compare those with root canals filled with AH Plus sealer using micro-CT. In total, 40 freshly extracted human single-root maxillary premolars were used. Specimens instrumented with the EndoSequence NiTi rotary instrument were assigned randomly into four groups. In each group, root canals were filled with single-cone gutta-percha and one of the tested sealers. Each specimen was then scanned using micro-CT at a voxel resolution of 13.47 MUm. Proportions of sections with voids in cross-sectional images and void volumes for each sealer were calculated in the apical, middle, and coronal thirds. Differences according to root canal sealers were evaluated statistically using the Kruskal-Wallis test and the Mann-Whitney U-test at a significance level of 5%. The analysis showed a decrease in void formation in the apical third, with a significant difference between the apical and coronal thirds among bioceramic sealers, ActiV GP, and AH Plus (p < 0.05) but no significant difference between the apical and middle thirds or between the middle and coronal thirds was found for the sealers tested (p > 0.05). All root canal sealers tested resulted in voids. The bioceramic sealers (EndoSequence BC Sealer, Smartpaste bio) produced similar voids which had the fewest in the apical third of root canals among the sealers tested which can be related due to root canal anatomy variations. PMID- 26228658 TI - Linking NHS data for pediatric pharmacovigilance: Results of a Delphi survey. AB - BACKGROUND: Adverse drug events are a major cause of patient safety incidents. Current systems of pharmacovigilance under-report adverse drug reactions (ADRs), especially in children, leading to delays in their identification. This is of particular concern, as children especially have an increased vulnerability to ADRs. OBJECTIVES: The objective was to seek consensus among healthcare professionals (HCPs) about barriers and facilitators to the linkage of routinely collected health data for pediatric pharmacovigilance in Scotland. METHODS: A Delphi survey was conducted with a random sample of HCPs including nurses, pharmacists and doctors, working in primary or secondary care, in Scotland. Participants were identified from sampling frames of the target professionals such as an NHS workforce list for general practitioners and recruited by postal invitation. A total of 819 HCPs were invited to take part. Those agreeing to participate were given the option of completing the questionnaires online or as hard copy. Reminders were sent twice at a fortnightly interval. Questions content included description of professional role as well as testing for the willingness to support the proposed project and was informed by the Theoretical Domains Framework of Behavior Change (TDF) and earlier qualitative work. Three Delphi rounds were administered, including a first round for item generation. RESULTS: 121 of those invited agreed to take part (15%). The first round of the Delphi study included 21 open questions and generated over a 1000 individual statements from 61 participants that returned the questionnaires (50.4%). These were rationalized to 149 items for the second round in which participants rated their views on the importance (or not) of each item on a 9-point Likert scale (strongly disagree - strongly agree). After the third round, there was consensus on items that focused on professional standards, and practical requirements, overall there was support for data linkage and a multi-professional approach. CONCLUSIONS: It would be acceptable to stakeholders to introduce a data linkage system for pharmacovigilance as long as identified concerns are addressed. Concerns included adherence to current professional, legal and ethical standards, as well resolving practical issues. PMID- 26228659 TI - Oxidative stress and insulin resistance in policemen working shifts. AB - PURPOSE: Shift work is a work schedule involving irregular or unusual hours, compared to those of a normal daytime work schedule. In developed countries, night shift work is very common. In several cities of our country, 12/24 shift system is implemented in police organization. While night shift work composes half of the 20 shift in a month, in ergonomic shift system, an alternative shift schedule, shift work can be performed in three shifts in a day. In this study, we aimed to investigate the effects of 12/24 shift work system on insulin resistance and oxidative stress and systemic inflammation. METHODS: Two hundred and four 12/24 shift workers (age 44.3 +/- 5.6 years) and 193 ergonomic shift workers (age 42.6 +/- 5.5 years) were included to study. Serum oxidized LDL (ox-LDL), neutrophil gelatinase lipocalin-2 (NGAL) as oxidative stress markers, glucose, insulin, ferritin, high-sensitive C-reactive protein (hsCRP) and erythrocyte sedimentation rate values were measured. Homeostasis model assessment for insulin resistance (HOMA-IR) was calculated to evaluate insulin resistance. RESULTS: Serum ox-LDL, HOMA-IR, hsCRP and NGAL levels in 12/24 shift system were found to be significantly higher compared with ergonomic shift workers (p < 0.0001, p = 0.02, p = 0.03, p = 0.02, respectively). When evaluated all subjects, weak but significant correlation was found between HOMA-IR with ox-LDL (r = 0.12, p = 0.01), hsCRP (r = 0.17, p = 0.001) and ferritin (r = 0.15, r = 0.003). Also in 12/24 shift work group, there were significant correlations between HOMA-IR with hsCRP (r = 0.17, p = 0.01) and ferritin (r = 0.25, p = 0.0001). CONCLUSION: It may be concluded that 12/24 shift system might give rise to insulin resistance and oxidative stress. Additionally, workers in this system may under risk of systemic inflammatory response. Working hours must be arranged in accordance with the physiological rhythm. PMID- 26228660 TI - Optimally weighted L(2) distance for functional data. AB - Many techniques of functional data analysis require choosing a measure of distance between functions, with the most common choice being L2 distance. In this article we show that using a weighted L2 distance, with a judiciously chosen weight function, can improve the performance of various statistical methods for functional data, including k-medoids clustering, nonparametric classification, and permutation testing. Assuming a quadratically penalized (e.g., spline) basis representation for the functional data, we consider three nontrivial weight functions: design density weights, inverse-variance weights, and a new weight function that minimizes the coefficient of variation of the resulting squared distance by means of an efficient iterative procedure. The benefits of weighting, in particular with the proposed weight function, are demonstrated both in simulation studies and in applications to the Berkeley growth data and a functional magnetic resonance imaging data set. PMID- 26228661 TI - Changes in the radiological depth correlate with dosimetric deterioration in particle therapy for stage I NSCLC patients under high frequency jet ventilation. AB - BACKGROUND: Particle dose distributions are highly sensitive to anatomy changes in the beam path, which may lead to substantial dosimetric deviations. Robust planning and dedicated image guidance together with strategies for online decision making to counteract dosimetric deterioration are thus mandatory. We aimed to develop methods to quantify anatomical discrepancies as depicted by repeated computed tomography (CT) imaging and to test whether they can predict deviations in target coverage. MATERIAL AND METHODS: Dedicated software tools allowed for voxel-based calculations of changes in the water equivalent path length (WEPL) in beam directions. We prepared proton and carbon ion plans with different coplanar beam angle settings on a series of lung cancer patients, for which planning and localization CT scans under high frequency jet ventilation (HFJV) for tumor fixation were performed. We investigated the reproducibility of target coverage between the optimized and recalculated treatment plans. We then studied how different raster scan and planning settings influence the robustness. Finally, we carried out a systematic analysis of the variations in the WEPL along different coplanar beam angles to find beam directions, which could minimize such variations. RESULTS: The Spearman's correlations for the GTV DeltaV95 and DeltaV98 with the DeltaWEPL for the proton plans with a 0 degrees and -45 degrees two-field configuration were 0.701 (p = 0.02) and 0.719 (p = 0.08), respectively. For beam configurations 0 degrees and -90 degrees , or 0 degrees and + 45 degrees , with lower DeltaWEPL, the correlations were no significant. The same trends were observed for the carbon ion plans. Increased beam spot overlap reduced dosimetric deterioration in case of large DeltaWEPL. CONCLUSION: Software tools for fast online analysis of WEPL changes might help supporting clinical decision making of image guidance. Raster scan and treatment planning settings can help to compensate for anatomical deviations. PMID- 26228662 TI - Postoperative changes in bone metabolism and bone mineral density in Japanese patients with acromegaly: a 3-year prospective study. AB - Growth hormone and insulin-like growth factor-I play important roles in regulating bone metabolism and bone mineral density in adulthood. However, the effect of excess growth hormone on bone metabolism and bone mineral density is not fully understood. Here, we investigated the long-term changes in bone metabolism and bone mineral density after a rapid decline in growth hormone levels due to transsphenoidal surgery in acromegalic patients. Eighteen acromegalic patients (10 males and 8 females) who underwent transsphenoidal surgery were enrolled in this prospective study. Bone formation marker (serum bone alkaline phosphatase), bone resorption marker (urinary type I collagen cross linked N-telopeptide), and bone mineral density were measured before surgery and at 3 months, 1 year, and 3 years after transsphenoidal surgery. While both serum bone alkaline phosphatase and urinary type I collagen cross-linked N-telopeptide levels decreased significantly after surgery, serum bone alkaline phosphatase/urinary type I collagen cross-linked N-telopeptide ratio was significantly increased at 3 months and 3 years after surgery. Bone mineral density did not change markedly after surgery. In conclusion, the rapid decline in growth hormone levels following transsphenoidal surgery had no marked effect on bone mineral density for up to 3 years, despite significant changes in levels of bone turnover makers post-surgery. PMID- 26228663 TI - Blocking and Blending: Different Assembly Models of Cyclodextrin and Sodium Caseinate at the Oil/Water Interface. AB - The stability of cyclodextrin (CD)-based emulsions is attributed to the formation of a solid film of oil-CD complexes at the oil/water interface. However, competitive interactions between CDs and other components at the interface still need to be understood. Here we develop two different routes that allow the incorporation of a model protein (sodium caseinate, SC) into emulsions based on beta-CD. One route is the components adsorbed simultaneously from a mixed solution to the oil/water interface (route I), and the other is SC was added to a previously established CD-stabilized interface (route II). The adsorption mechanism of beta-CD modified by SC at the oil/water interface is investigated by rheological and optical methods. Strong sensitivity of the rheological behavior to the routes is indicated by both steady-state and small-deformation oscillatory experiments. Possible beta-CD/SC interaction models at the interface are proposed. In route I, the protein, due to its higher affinity for the interface, adsorbs strongly at the interface with blocking of the adsorption of beta-CD and formation of oil-CD complexes. In route II, the protein penetrates and blends into the preadsorbed layer of oil-CD complexes already formed at the interface. The revelation of interfacial assembly is expected to help better understand CD based emulsions in natural systems and improve their designs in engineering applications. PMID- 26228664 TI - From the Editor: The Akira Endo Award. Foreword. PMID- 26228665 TI - JCL Roundtable: Gender differences in risk reduction with lifestyle changes. AB - The first efforts to uncover the causes of cardiovascular disease focused on the behavioral, now called lifestyle habits of populations. Diet, exercise, and smoking were recognized as important issues with strong relationships in community-based observational studies such as the Seven Countries study, the Framingham Heart Study, and the Western Electric Study in Chicago. The first meaningful intervention in the United States was the dietary recommendations made by the American Heart Association in 1963 and the Surgeon General's Report on Smoking and Health in 1964. The American public listened and a very large change occurred in food consumption data and cigarette smoking over the next decade. These changes were mainly focused on men because the incidence of myocardial infarction was much higher in middle aged and older men than women. As smoking prevalence has decreased in men and increased in women and the population has aged, the differences in major vascular events have virtually disappeared. Women still enjoy a longer period of low rates but eventually the incidence rates approach those of men. As we constantly attempt to demonstrate ways of reducing risk by improved lifestyle it behooves us to re-evaluate the potential differences in gender response and adjust our expectations accordingly as clinicians. PMID- 26228666 TI - The low-density lipoprotein hypothesis: Proven again with the Improved Reduction of Outcomes: Vytorin Efficacy International Trial. PMID- 26228667 TI - The risk of cardiovascular events with increased apolipoprotein CIII: A systematic review and meta-analysis. AB - BACKGROUND: Apolipoprotein CIII (apoC-III) is an atherogenic protein found on HDL, VLDL and LDL. OBJECTIVE: The objective of this study is to review the literature on the association of blood apoC-III level with cardiovascular events and the dose-response relationship for this association. METHODS AND RESULTS: MEDLINE, EMBASE, BIOSIS, CINAHL, Clinicaltrials.gov, grey-literature sources, contact with investigators, and reference lists of studies, without language restrictions, were reviewed. Twelve studies (5 retrospective and 7 prospective) with a total of 3163 cases of cardiovascular events met inclusion criteria for this systematic review. The pooled standardized mean difference showed significantly higher levels of apoC-III in the non-HDL fraction of plasma (representing apoC-III in VLDL and LDL) in those with cardiovascular disease compared with controls; no difference for apoC-III levels in HDL; and, a trend toward higher total plasma apoC-III in the cases. Pooled risk estimates from the meta-analysis were 2.48 (1.48-4.32; non-HDL apoC-III), 1.09 (0.65-1.82; HDL apoC III), and 1.33 (1.07-1.66; total apoC-III) for a cardiovascular event with a 5 mg/dL increase in apoC-III. CONCLUSIONS: The current body of literature includes several methodologically sound studies that together provide consistent evidence for an association of cardiovascular events with blood apoC-III level in total plasma or in VLDL and LDL. More data are needed to determine importance of levels of apoC-III in specific lipoproteins for cardiovascular risk assessment and management and to elucidate the interaction between triglycerides and apoC-III in relation to risk of cardiovascular disease. PMID- 26228668 TI - Lipid phenotypes at the extremes of high-density lipoprotein cholesterol: The very large database of lipids-9. AB - BACKGROUND: Low serum levels of high-density lipoprotein cholesterol (HDL-C) are an important risk factor for atherosclerotic disease. To date, therapeutically raising HDL-C has not been shown to impact risk for cardiovascular events. OBJECTIVE: We aim to characterize lipid parameters at the extremes of HDL-C. METHODS: We examined cholesterol profiles from 1,350,908 US adults and children from the Very Large Database of Lipids who were clinically referred for advanced lipoprotein testing from 2009 to 2011. We categorized patients into HDL-C percentile categories (<0.1th, 0.1th-<1st, 1st-5th, 25th-75th, 95th-99th, >99th 99.9th, and >99.9th). Within these groups, we examined HDL-C subclasses, low density lipoprotein cholesterol (LDL-C), LDL and very-low density lipoprotein densities, non-HDL-C, triglycerides (TG), very-low density lipoprotein cholesterol, and remnant lipoprotein cholesterol (RLP-C), as well as prevalence of Fredrickson-Levy dyslipidemias. RESULTS: Extremely low HDL-C percentiles were associated with increased LDL density, TG, and especially RLP-C. Very high HDL-C levels (>= 92 mg/dL) showed increasing HDL2-C/HDL3-C ratio and very low levels of RLP-C and triglyceride-rich lipoproteins. Type IV dyslipidemia had the highest prevalence among classical dyslipidemia and was the most frequent at extremely low HDL-C percentiles. CONCLUSIONS: These findings demonstrate a high prevalence of elevated triglyceride-rich lipoprotein levels and increased LDL density in patients with extremely low HDL-C levels. The relative contributions of these various changes in lipid profiles of patients with low HDL-C to cardiovascular risk need to be further scrutinized to more fully establish if low HDL-C is truly an independent risk factor for coronary heart disease or simply reflects detrimental shifts in the levels of atherogenic lipoproteins. PMID- 26228669 TI - Clinical characteristics of Japanese patients with severe hypertriglyceridemia. AB - BACKGROUND: Although of interest, few data exist on the clinical characteristics of Japanese patients with an extremely high triglyceride level (>= 1000 mg/dL). OBJECTIVE: We assessed the clinical characteristics of Japanese patients with an extremely high triglyceride level. METHODS: We investigated the presence of coronary artery disease, history of pancreatitis, the presence of fatty liver, and the potential causes of elevated triglyceride in Japanese subjects with an extremely high level of fasting triglyceride (>= 1000 mg/dL) among 70,368 subjects whose serum triglyceride was measured for any reason at Kanazawa University Hospital from April 2004 to March 2014. RESULTS: We identified 215 (0.31%) subjects (mean age, 46 years; male, 170, mean body mass index, 25 kg/m(2)) with severe hypertriglyceridemia. Among them, 4 (1.9%) subjects were classified as type I, 97 (45.1%) subjects were type IV, and 114 (53.0%) subjects were type V hyperlipidemia, according to Fredrickson's classification. Among 215 subjects, 116 subjects (54.0%) drank alcohol, 58 (27.0%) showed heavy intake (>= 60 g/d), and 64 (29.8%) subjects had diabetes. In total, 59 (27.4%) subjects had transient severe hypertriglyceridemia caused by corticosteroids (N = 19), antidepressant (N = 18), l-asparaginase and steroids for acute lymphoid leukemia (N = 15), hormone replacement therapy for breast cancer (N = 9), beta-blocker (N = 5), hypothyroidism (N = 4), pregnancy (N = 4), and panhypopituitarism (N = 2). As many as 119 (55.3%) subjects exhibited fatty liver. Moreover, 12 (5.6%) and 17 (7.9%) subjects had a history of pancreatitis and coronary artery disease, respectively. CONCLUSIONS: A variety of situations can cause severe hypertriglyceridemia. We suggest that potential secondary causes should be carefully assessed for such patients. PMID- 26228670 TI - Residual dyslipidemia according to low-density lipoprotein cholesterol, non-high density lipoprotein cholesterol, and apolipoprotein B among statin-treated US adults: National Health and Nutrition Examination Survey 2009-2010. AB - BACKGROUND: Despite being on treatment, many persons with dyslipidemia still have suboptimal lipid levels and still experience cardiovascular disease (CVD) events. OBJECTIVE: We examined the extent of residual dyslipidemia in terms of low density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apoB), in the US population, despite treatment with statin therapy. METHODS: We evaluated the attainment of LDL-C, non-HDL-C, and apoB targets in statin-treated subjects in the National Health and Nutrition Examination Survey 2009-2010. We report on percentage of individuals who attained goal and the mean distance from goal. LDL-C goals were set at <70 mg/dL for those with coronary heart disease, <100 mg/dL for those with other CVDs, diabetes, chronic kidney disease or >20% 10-year CVD risk, <130 mg/dL for those with 10% to 20% 10-year CVD risk or 2+ risk factors, and <160 mg/dL in those with <10% 10 year CVD risk or no more than 1 risk factor. Goals for non-HDL-C were 30 mg/dL higher than corresponding LDL-C goals, and goals of apoB were set to correspond with the same percentile of each LDL-C goal. RESULTS: Of the 5995 US adults aged >= 18 years surveyed, 463 (7.7%) were identified as being on a statin-based therapy. Overall, 64% of statin users were at goal for LDL-C, 63% were at goal for non-HDL-C, but only 52% were at goal for apoB. Of those who did not reach goal, 41%, 29%, and 39% were 30% or more from goal for LDL-C, non-HDL-C, and apoB, respectively. Non-Hispanic blacks and those with CVD or diabetes had the highest proportions that were not at goal for LDL-C, non-HDL-C, and apoB. Among those at goal for non-HDL-C, 50% of those with CHD and 33% of other high risk adults were not at ApoB goals. CONCLUSIONS: Despite statin treatment, many persons continue to have residual dyslipidemia with LDL-C, non-HDL-C, and/or apoB levels not being at recommended levels. PMID- 26228672 TI - Additive effects of plant sterols supplementation in addition to different lipid lowering regimens. AB - OBJECTIVE: Plant sterol (PS) supplementation has been widely used alone or combined with lipid-lowering therapies (LLTs) to reduce low-density lipoprotein (LDL) cholesterol. The effects of PS added to high-intensity LLT are less reported, especially regarding the effects on cholesterol synthesis and absorption. METHODS: A prospective, randomized, open-label study, with parallel arms and blinded end points was designed to evaluate the effects of addition of PS to LLT on LDL cholesterol, markers of cholesterol synthesis, and absorption. Eighty-six patients of both genders were submitted to a 4-wk run-in period with atorvastatin 10 mg (baseline). Following, subjects received atorvastatin 40 mg, ezetimibe 10 mg, or combination of both drugs for another 4-wk period (phase I). In phase II, capsules containing 2.0 g of PSs were added to previous assigned treatments for 4 wk. Lipids, apolipoproteins, plasma campesterol, beta sitosterol, and desmosterol levels were assayed at all time points. Within and between-group analyses were performed. RESULTS: Compared with baseline, atorvastatin 40 mg reduced total and LDL cholesterol (3% and 22%, respectively, P < .05), increased beta-sitosterol, campesterol/cholesterol, and beta sitosterol/cholesterol ratios (39%, 47%, and 32%, respectively, P < .05); ezetimibe 10 mg reduced campesterol and campesterol/cholesterol ratio (67% and 70%, respectively, P < .05), and the combined therapy decreased total and LDL cholesterol (22% and 38%, respectively, P < .05), campesterol, beta-sitosterol, and campesterol/cholesterol ratio (54%, 40%, and 27%, P < .05). Addition of PS further reduced total and LDL cholesterol by ~ 7.7 and 6.5%, respectively, in the atorvastatin therapy group and 5.0 and 4.0% in the combined therapy group (P < .05, for all), with no further effects in absorption or synthesis markers. CONCLUSIONS: PS added to LLT can further improve lipid profile, without additional effects on intestinal sterol absorption or synthesis. PMID- 26228671 TI - Monocyte subset distribution in patients with stable atherosclerosis and elevated levels of lipoprotein(a). AB - BACKGROUND: Lipoprotein(a) (Lp(a)) is a proatherogenic plasma lipoprotein currently established as an independent risk factor for the development of atherosclerotic disease and as a predictor for acute thrombotic complications. In addition, Lp(a) is the major carrier of proinflammatory oxidized phospholipids (OxPL). Today, atherosclerosis is considered to be an inflammatory disease of the vessel wall in which monocytes and monocyte-derived macrophages are crucially involved. Circulating monocytes can be divided according to their surface expression pattern of CD14 and CD16 into at least 3 subsets with distinct inflammatory and atherogenic potential. OBJECTIVE: The aim of this study was to examine whether elevated levels of Lp(a) and OxPL on apolipoprotein B-100 containing lipoproteins (OxPL/apoB) are associated with changes in monocyte subset distribution. METHODS: We included 90 patients with stable coronary artery disease. Lp(a) and OxPL/apoB were measured, and monocyte subsets were identified as classical monocytes (CMs; CD14++CD16-), intermediate monocytes (IMs; CD14++CD16+), and nonclassical monocytes (NCMs; CD14+CD16++) by flow cytometry. RESULTS: In patients with elevated levels of Lp(a) (>50 mg/dL), monocyte subset distribution was skewed toward an increase in the proportion of IM (7.0 +/- 3.8% vs 5.2 +/- 3.0%; P = .026), whereas CM (82.6 +/- 6.5% vs 82.0 +/- 6.8%; P = .73) and NCM (10.5 +/- 5.3 vs 12.8 +/- 6.0; P = .10) were not significantly different. This association was independent of clinical risk factors, choice of statin treatment regime, and inflammatory markers. In addition, OxPL/apoB was higher in patients with elevated Lp(a) and correlated with IM but not CM and NCM. CONCLUSIONS: In conclusion, we provide a potential link between elevated levels of Lp(a) and a proatherogenic distribution of monocyte subtypes in patients with stable atherosclerotic disease. PMID- 26228673 TI - High-density lipoprotein cholesterol, a protective or a risk factor for developing coronary heart disease? Tehran Lipid and Glucose Study. AB - BACKGROUND: Recently, there are controversial findings on protective effect of high-density lipoprotein cholesterol (HDL-C) against coronary heart disease (CHD) in some population. OBJECTIVE: We aim to determine the effect of HDL-C on CHD in premenopausal and postmenopausal women. METHODS: Between February 1999 and August 2001, 3778 women aged 30 to 74 y, free of clinical cardiovascular diseases, were recruited and followed up to March 2010. HDL-C and other CHD risk factors were measured at baseline. Using multivariable Cox proportional hazard model, the adjusted hazard ratio was calculated. RESULTS: During a median follow-up of 9.6 y, a total of 228 new CHD events occurred. In postmenopausal women, the adjusted hazard ratio for each standard deviation increase in HDL-C was 0.76 (95% confidence interval, 0.63-0.92). Among premenopausal women, a time varying model was fitted; the adjusted hazard ratio for each standard deviation increase of HDL C among 30-year-old women was 2.67 (95% confidence interval, 0.98-7.29) but decreased by 5% for each year increase of age. CONCLUSIONS: Different effects of HDL-C in premenopausal and postmenopausal women were identified. During premenopausal period, the hazard of CHD increased by any increase of HDL-C level, but the amount of this increment gradually decreased over time, whereas during postmenopausal period, the hazard of CHD was inversely associated with HDL-C level. PMID- 26228674 TI - Medical nutrition therapy is the essential cornerstone for effective treatment of "refractory" severe hypertriglyceridemia regardless of pharmaceutical treatment: Evidence from a Lipid Management Program. AB - BACKGROUND: Patients with refractory severe hypertriglyceridemia are at risk of pancreatitis and cardiovascular disease. The role of individualized nutrition therapy in these patients independent of pharmaceutical treatment has not been documented. OBJECTIVE: To document the effect of nutrition intervention on severe hypertriglyceridemia regardless of medication status or prior nutrition counseling. METHODS: Outcomes of new patients with triglycerides >= 500 mg/dL presenting to a Lipid Management Program over a 6-year period were tracked. Patients received comprehensive laboratory assessment, nutrition assessment, and initiation of an individualized diet intervention before seeing the lipidologist. Clinical and behavioral outcomes were recorded. RESULTS: In all, 168 patients (117 men; mean age, 49.03 +/- 11.22 years; body mass index, 32.61 +/- 5.85 kg/m(2); 110 (65.5%) on lipid-lowering medications) returned for assessment of nutrition intervention. Triglycerides were reduced from median (interquartile range) 961.5 (611.5-1785.3) to 493.0 (337-736.3) mg/dL (P < .0001 for log transformation of triglycerides). There was no difference in median percentage reduction in triglycerides after nutrition intervention between those not on lipid-lowering medication, on a fibric acid derivative, on other lipid-lowering medication, or on a combination of lipid-lowering medications (P = .376) in a median (interquartile range) of 5 (3-7) weeks. Effect was independent of prior nutrition counseling (P = .260). Reported percentage fat in the diet at second visit correlated with log-transformed triglycerides achieved, independent of initial triglycerides level (r = 0.290; P = .001). CONCLUSIONS: Individualized nutrition therapy results in changes in eating behavior and reductions in triglyceride levels in patients with refractory severe hypertriglyceridemia independent of lipid-lowering medication(s) and prior nutrition counseling. PMID- 26228675 TI - Fenofibrate lowers atypical sphingolipids in plasma of dyslipidemic patients: A novel approach for treating diabetic neuropathy? AB - BACKGROUND: The condensation of palmitoyl-CoA and L-Serine is the first step in the de novo formation of sphingolipids and catalyzed by the serine palmitoyltransferase (SPT). Besides other acyl-CoAs the SPT can also metabolize L alanine and glycine, which forms an atypical category of neurotoxic 1-deoxy sphingolipids (1-deoxySL). Several mutations in SPT are associated with pathologically increased 1-deoxySL levels, which cause the inherited sensory neuropathy HSAN1. 1-DeoxySL levels are also elevated in individuals with the metabolic syndrome and diabetes mellitus type II and seem to be involved in the pathology of the diabetic neuropathy. OBJECTIVE: In previous studies, we observed a strong correlation between plasma 1-deoxySLs and triglycerides (TGs). We were therefore interested whether lowering plasma TG levels also affects plasma sphingolipid and in particular, 1-deoxySL levels. METHODS: Sixty-six patients with dyslipidemia were treated for 6 wk with the TG-lowering drug fenofibrate (160 mg/d) or extended-release niacin (0.5 g/d for 3 wk, then 1 g/d) with 4 wk of washout between treatments. The sphingoid base profile was analyzed by liquid chromatography-mass spectrometry (LC-MS) before and after each treatment block. RESULTS: Fenofibrate significantly lowered 1-deoxySLs and other atypical sphingoid bases (P < .001) but had no effect on the typical sphingolipids. In contrast, extended-release niacin had no effect on 1-deoxySL levels although both treatments lowered plasma TG levels. CONCLUSIONS: The lowering of plasma 1 deoxySL levels by fenofibrate in dyslipidemic patients might be a novel therapeutic approach in the prevention and treatment of diabetic neuropathy. PMID- 26228676 TI - Low- and high-density lipoprotein subclasses in subjects with nonalcoholic fatty liver disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is associated with increased cardiometabolic risk. Although dyslipidemia represents a key factor in this disease, its impact on serum levels of distinct lipoprotein subfractions is largely unknown. OBJECTIVE: To assess the full low-density lipoprotein (LDL) and high-density lipoprotein (HDL) profiles in patients with NAFLD. METHODS: Seven LDL and 10 HDL subfractions were assessed by gel electrophoresis (Lipoprint, Quantimetrix Corporation, USA) in men with biopsy proven NAFLD (simple steatosis [n = 17, age, 34 +/- 7 years] and nonalcoholic steatohepatitis [NASH; n = 24, age, 32 +/- 6 years]). Exclusion criteria included robust alcohol consumption, infection with hepatitis B or C virus, body mass index >= 40 kg/m(2), diabetes mellitus, and hypertension. RESULTS: Compared with simple steatosis, NASH patients had similar body mass index, homeostasis model assessment of insulin resistance index and plasma lipids, with increased levels of both aspartate aminotransferase and alanine transaminase. NASH subjects had lower levels of larger LDL1 (10 +/- 4 vs 13 +/- 4%, P = .010) and increased smaller LDL3 and LDL4 particles (9 +/- 5 vs 5 +/- 5%, P = .017 and 3 +/- 3 vs 1 +/- 2%, P = .012, respectively). No changes were found in the HDL subclass profile. By multiple regression analysis, we found that NASH was associated only with increased levels of LDL3 (P = .0470). CONCLUSIONS: The increased levels of small, dense LDL3 and LDL4 in NASH may help to at least partly explain the increased risk for atherosclerosis and cardiovascular diseases in these patients. PMID- 26228677 TI - Treatment decision making for adolescents with familial hypercholesterolemia: Role of family history and past experiences. AB - BACKGROUND: Adolescents and young adults (AYAs) with familial hypercholesterolemia (FH) are at high risk for underdiagnosis and inadequate treatment. Yet, little is known about the factors that influence the medical decision making of AYAs with FH and their families. OBJECTIVE: This study explores how family medical history, family narratives of medical experiences, and AYA medical experiences together function as "experiential evidence" and influence screening and treatment decisions. METHODS: Twenty-four parents and AYAs affected by FH from a pediatric preventive cardiology practice responded to a survey and a semistructured qualitative interview. Transcribed interviews were analyzed using a modified grounded theory approach. Study design, instruments, and interpretation of results were informed by a 20-member stakeholder panel. RESULTS: AYAs and parents reported extensive personal and family experiences with cholesterol and cardiovascular conditions and treatments, sometimes distinct from FH, which were used as evidence to inform their own perceptions of FH risk and treatment. This experiential evidence impacted perceptions of: (1) hereditary risk for FH diagnoses, (2) risk for future cardiovascular disease, (3) risks associated with treatments, and (4) capacity to comply with recommended treatments. Although experiences of family members initially informed screening and treatment decisions, the subsequent personal experiences of AYAs led to new experiential evidence that informed future decisions. CONCLUSIONS: Family cardiovascular history related to and distinct from FH influenced screening and treatment decisions of AYAs and parents affected by FH. Additional clinical assessment of personal and family medical experiences may enhance understanding of the decision-making processes among AYAs and ultimately improve adherence to screening and treatment recommendations. PMID- 26228678 TI - Successful reintroduction of statin therapy after statin-associated rhabdomyolysis. AB - The case report demonstrates the successful use of an alternative statin after a statin-related episode of rhabdomyolysis. Statin-associated rhabdomyolysis is a serious adverse event with a very low incidence and is considered the most severe of the muscle-related side effects of the statins. Rechallenge with statins is not a recommended practice after rhabdomyolysis. The patient experienced a myocardial infarct 1 y after the episode of rhabdomyolysis. He used alternative lipid-lowering therapy for 2 y. His low-density lipoprotein cholesterol was not meeting typical secondary prevention targets. An alternative statin was introduced and the patient has been followed for 4 years without recurrence of the rhabdomyolysis. This case suggests it may be time to reconsider the accepted practice of permanently avoiding statin therapy after rhabdomyolysis. PMID- 26228680 TI - Symmetrical lipomatosis of the tongue: Case report and literature review. AB - Multiple symmetric lipomatosis is rare and characterized by diffuse growth and nonencapsulated lipomas. It is usually found in the posterior neck and upper trunk, and the entity is known as "benign symmetric lipomatosis," "Madelung disease," and "Launois-Bensaude syndrome." Symmetric lipomatosis of the tongue was first described by Desmond and is an extremely rare condition. A 74-year-old man complained of painless tongue swelling and difficulty speaking. Clinical findings revealed no tumor masses on the trunk, limbs, or head and neck region. Intraoral findings included soft yellowish masses with a smooth surface without erosions on the side of the tongue bilaterally. They were 30 mm in diameter. An incisional biopsy was taken from the mass, and the lipoma was diagnosed. The bilateral tongue lesions were resected under general anesthesia. Intraoperative findings revealed adipose tissues interspersed with lingual muscles and no capsulation. The lesion was finally diagnosed as symmetric lipomatosis of the tongue based on clinical findings and radiological and histologic examination. PMID- 26228679 TI - Statin desensitization in a patient with probable familial hypercholesterolemia. AB - PROBLEM OVERVIEW: With cardiovascular disease being the leading cause of morbidity and mortality in the United States, cholesterol-lowering medications have become a prominent focus of medical management and cardiovascular risk reduction, including the use of statins making them the most widely prescribed class of medications in the United States and are the cornerstone of management of hyperlipidemia. This case report describes a 29-year-old female with probable familial hypercholesterolemia (FH) who had allergic reactions to statin therapy on two separate occasions. She required statin therapy based on her elevated carotid intima media thickness test, historic LDL-C >= 190 mg/dL, elevated Lp(a), and family history significant for premature coronary heart disease. In this report, we document a case of successful oral desensitization to rosuvastatin and propose a replicable statin desensitization protocol. MAJOR MANAGEMENT: The patient was admitted for rosuvastatin desensitization following predetermined protocols, utilizing an interdisciplinary team, and monitored for 24 hours following completion of administration prior to discharge. She successfully completed desensitization to rosuvastatin 10mg by mouth daily without anaphylactic reaction. She continued to tolerate rosuvastatin 10mg daily through most recent follow-up, and with this addition, significant improvement in lipid levels was achieved. CONCLUSION: This case report presented a patient with probable FH who was previously intolerant to other statin therapies that underwent successful desensitization to rosuvastatin with subsequent achievement of therapy goals. PMID- 26228681 TI - Treating homozygous familial hypercholesterolemia in a real-world setting: Experiences with lomitapide. AB - Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by markedly elevated plasma levels of low-density lipoprotein cholesterol (LDL-C). Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor approved as an adjunct to other lipid-lowering therapies (LLTs), with or without lipoprotein apheresis (LA), for the treatment of adult HoFH. Diet with <20% calories from fat is required. Due to a varying genetic and phenotypic profile of patients with HoFH, individual patients may respond to therapy differently; therefore examining individual cases in a 'real-world' setting provides valuable information on the effective day-to-day management of HoFH cases. Four HoFH cases were selected for analysis and discussion: a 20-year-old female compound heterozygote; a 62-year old female homozygote; a 42-year-old female compound heterozygote; and a 36-year-old male homozygote. Each patient was commenced on lomitapide according to the prescribed protocol and subjected to routine follow-up. All four patients experienced clinically meaningful reductions in LDL-C levels of 35-73%. Three of the patients had evidence of steatosis or mildly elevated liver function tests) before lomitapide was started, but effects of lomitapide on hepatic function were not universal. Three of the patients experienced gastrointestinal adverse events, but were managed with appropriate dietary control. Lomitapide is an effective adjunct LLT in the management of patients with HoFH, with or without LA. Real-world use of lomitapide has a side effect profile consistent with clinical trials and one that can be managed by adherence to recommendations on dose escalation, dietary modification and dietary supplements. PMID- 26228682 TI - Inhibiting amyloid beta-protein assembly: Size-activity relationships among grape seed-derived polyphenols. AB - Epidemiological evidence that red wine consumption negatively correlates with risk of Alzheimer's disease has led to experimental studies demonstrating that grape seed extracts inhibit the aggregation and oligomerization of Abeta in vitro and ameliorate neuropathology and behavioral deficits in a mouse model of Alzheimer's disease. The active agent in the extracts is a mixed population of polyphenolic compounds. To evaluate the relative potency of each of these compounds, HPLC was used to fractionate the mixture into monomers, dimers, and oligomers. Each fraction was analyzed for its effect on Abeta conformational dynamics (circular dichroism), oligomerization (zero-length photochemical cross linking), aggregation kinetics (Thioflavin T fluorescence), and morphology (electron microscopy). The relative activities of each fraction were determined on the basis of molar concentration (mol/L) or mass concentration (g/L). When molar concentration, the number concentration of each polyphenolic compound, was considered, the oligomer fraction was the most potent inhibitor of Abeta oligomerization and aggregation. However, when mass concentration, the number concentration of phenolic groups, was considered, monomers were the most potent inhibitors. To understand these ostensibly contradictory results, a model of polyphenol:Abeta complexation was developed. This model, which was found to be consistent with published X-ray crystallographic studies, offers an explanation for the effects of functional group polyvalency on inhibitor activity. Our data emphasize the importance of an in-depth understanding of the mechanism(s) underlying 'concentration dependence' in inhibitor systems involving polyfunctional agents. PMID- 26228683 TI - Lesions of the paraventricular nucleus of the thalamus differentially affect sign and goal-tracking conditioned responses. AB - Recently, evidence has emerged suggesting a role for the paraventricular nucleus of the thalamus (PVT) in the processing of reward-associated cues. However, the specific role of the PVT in these processes has yet to be elucidated. Here we use an animal model that captures individual variation in response to discrete reward associated cues to further assess the role of the PVT in stimulus-reward learning. When rats are exposed to a Pavlovian conditioning paradigm, wherein a discrete cue predicts food reward, two distinct conditioned responses emerge. Some rats, termed sign-trackers, approach and manipulate the cue, whereas others, termed goal-trackers, approach the location of reward delivery upon cue presentation. For both sign- and goal-trackers the cue is a predictor, but only for sign-trackers is it also an incentive stimulus. We investigated the role of the PVT in the acquisition and expression of these conditioned responses using an excitotoxic lesion. Results indicate that PVT lesions prior to acquisition amplify the differences between phenotypes - increasing sign-tracking and attenuating goal-tracking behavior. Lesions of the PVT after rats had acquired their respective conditioned responses also attenuated the expression of the goal tracking response, and increased the sign-tracking response, but did so selectively in goal-trackers. These results suggest that the PVT acts to suppress the attribution of incentive salience to reward cues, as disruption of the functional activity within this structure enhances the tendency to sign-track. PMID- 26228684 TI - De-DUFing the DUFs: Deciphering distant evolutionary relationships of Domains of Unknown Function using sensitive homology detection methods. AB - BACKGROUND: In the post-genomic era where sequences are being determined at a rapid rate, we are highly reliant on computational methods for their tentative biochemical characterization. The Pfam database currently contains 3,786 families corresponding to "Domains of Unknown Function" (DUF) or "Uncharacterized Protein Family" (UPF), of which 3,087 families have no reported three-dimensional structure, constituting almost one-fourth of the known protein families in search for both structure and function. RESULTS: We applied a 'computational structural genomics' approach using five state-of-the-art remote similarity detection methods to detect the relationship between uncharacterized DUFs and domain families of known structures. The association with a structural domain family could serve as a start point in elucidating the function of a DUF. Amongst these five methods, searches in SCOP-NrichD database have been applied for the first time. Predictions were classified into high, medium and low- confidence based on the consensus of results from various approaches and also annotated with enzyme and Gene ontology terms. 614 uncharacterized DUFs could be associated with a known structural domain, of which high confidence predictions, involving at least four methods, were made for 54 families. These structure-function relationships for the 614 DUF families can be accessed on-line at http://proline.biochem.iisc.ernet.in/RHD_DUFS/ . For potential enzymes in this set, we assessed their compatibility with the associated fold and performed detailed structural and functional annotation by examining alignments and extent of conservation of functional residues. Detailed discussion is provided for interesting assignments for DUF3050, DUF1636, DUF1572, DUF2092 and DUF659. CONCLUSIONS: This study provides insights into the structure and potential function for nearly 20 % of the DUFs. Use of different computational approaches enables us to reliably recognize distant relationships, especially when they converge to a common assignment because the methods are often complementary. We observe that while pointers to the structural domain can offer the right clues to the function of a protein, recognition of its precise functional role is still 'non-trivial' with many DUF domains conserving only some of the critical residues. It is not clear whether these are functional vestiges or instances involving alternate substrates and interacting partners. PMID- 26228685 TI - Treating recalcitrant verruca vulgaris in a pediatric patient with H2 blocker: An easy alternative approach. PMID- 26228686 TI - Randomized study of different approaches for catheter-directed thrombolysis for lower-extremity acute deep venous thrombosis. AB - BACKGROUND/PURPOSE: To investigate the feasibility, effectiveness, and complications of catheter-directed thrombolysis (CDT) using three different approaches for acute lower-extremity deep venous thrombosis (DVT). METHODS: A total of 106 patients with acute DVT were enrolled in this study. Forty-one patients received CDT through the small saphenous vein (Group A), 35 through the great saphenous vein (Group B), and 30 through the popliteal vein (Group C). Iliac vein balloon dilation and stenting was performed in 65 cases. RESULTS: The vascular approach route was not statistically related to limb edema reduction rates (Groups A, B, and C: 82.3 +/- 7.6% vs. 81.6 +/- 6.0% vs. 83.9 +/- 6.1%), nor to thrombolysis rates (63.5 +/- 7.7% vs. 66.9 +/- 8.4% vs. 66.1 +/- 2.7%). The procedure was significantly shorter for Groups B and C. No significant difference was found between Groups B and C. Most complications occurred in Group A. The complication rate in Group B was the lowest. Eighty-eight patients were followed up for 7-24 months. Of these, 78 were pain-free and without limb edema; six showed rethrombosis. CONCLUSION: CDT is an effective method to manage acute DVT. Of the three routes tested, the small saphenous vein route was associated with more frequent complications. Great saphenous vein catheterization was more effective because of its lower complication rate. PMID- 26228687 TI - Hepatitis C virus infection in Taiwan: Past, present, and future. PMID- 26228688 TI - Novel Marmoset Cytochrome P450 2C19 in Livers Efficiently Metabolizes Human P450 2C9 and 2C19 Substrates, S-Warfarin, Tolbutamide, Flurbiprofen, and Omeprazole. AB - The common marmoset (Callithrix jacchus), a small New World monkey, has the potential for use in human drug development due to its evolutionary closeness to humans. Four novel cDNAs, encoding cytochrome P450 (P450) 2C18, 2C19, 2C58, and 2C76, were cloned from marmoset livers to characterize P450 2C molecular properties, including previously reported P450 2C8. The deduced amino acid sequence showed high sequence identities (>86%) with those of human P450 2Cs, except for marmoset P450 2C76, which has a low sequence identity (~70%) with any human P450 2Cs. Phylogenetic analysis showed that marmoset P450 2Cs were more closely clustered with those of humans and macaques than other species investigated. Quantitative polymerase chain reaction analysis showed that all of the marmoset P450 2C mRNAs were predominantly expressed in liver as opposed to the other tissues tested. Marmoset P450 2C proteins were detected in liver by immunoblotting using antibodies against human P450 2Cs. Among marmoset P450 2Cs heterologously expressed in Escherichia coli, marmoset P450 2C19 efficiently catalyzed human P450 2C substrates, S-warfarin, diclofenac, tolbutamide, flurbiprofen, and omeprazole. Marmoset P450 2C19 had high Vmax and low Km values for S-warfarin 7-hydroxylation that were comparable to those in human liver microsomes, indicating warfarin stereoselectivity similar to findings in humans. Faster in vivo S-warfarin clearance than R-warfarin after intravenous administration of racemic warfarin (0.2 mg/kg) to marmosets was consistent with the in vitro kinetic parameters. These results indicated that marmoset P450 2C enzymes had functional characteristics similar to those of humans, and that P450 2C-dependent metabolic properties are likewise similar between marmosets and humans. PMID- 26228689 TI - Evolutionary Conservation of the Early Axon Scaffold in the Vertebrate Brain. AB - The early axon scaffold is the first axonal structure to appear in the rostral brain of vertebrates, paving the way for later, more complex connections. Several early axon scaffold components are conserved between all vertebrates; most notably two main ventral longitudinal tracts, the tract of the postoptic commissure and the medial longitudinal fascicle. While the overall structure is remarkably similar, differences both in the organization and the development of the early tracts are apparent. This review will bring together extensive data from the last 25 years in different vertebrates and for the first time, the timing and anatomy of these early tracts have been directly compared. Representatives of major vertebrate clades, including cat shark, Xenopus, chick, and mouse embryos, will be compared using immunohistochemistry staining based on previous results. There is still confusion over the nomenclature and homology of these tracts which this review will aim to address. The discussion here is relevant both for understanding the evolution of the early axon scaffold and for future studies into the molecular regulation of its formation. PMID- 26228690 TI - Stem cell divisions and cancer. PMID- 26228691 TI - Integration of ultrasonography course in the students' curriculum. Is it always useful? PMID- 26228692 TI - Detailed Anatomical Orientations for Certain Types of Morphometric Measurements Can Be Determined Automatically With Geometric Algorithms. AB - Morphometric datasets only convey useful information about variation when measurement landmarks and relevant anatomical axes are clearly defined. We propose that anatomical axes of 3D digital models of bones can be standardized prior to measurement using an algorithm that automatically finds a universal geometric alignment among sampled bones. As a case study, we use teeth of "prosimian" primates. In this sample, equivalent occlusal planes are determined automatically using the R-package auto3dgm. The area of projection into the occlusal plane for each tooth is the measurement of interest. This area is used in computation of a shape metric called relief index (RFI), the natural log of the square root of crown area divided by the square root of occlusal plane projection area. We compare mean and variance parameters of area and RFI values computed from these automatically orientated tooth models with values computed from manually orientated tooth models. According to our results, the manual and automated approaches yield extremely similar mean and variance parameters. The only differences that plausibly modify interpretations of biological meaning slightly favor the automated treatment because a greater proportion of differences among subsamples in the automated treatment are correlated with dietary differences. We conclude that-at least for dental topographic metrics automated alignment recovers a variance pattern that has meaning similar to previously published datasets based on manual data collection. Therefore, future applications of dental topography can take advantage of automatic alignment to increase objectivity and repeatability. PMID- 26228693 TI - Pedigree-Free Descent-Based Gene Mapping from Population Samples. AB - Segments of the genome inherited from a common ancestor by related individuals are said to be identical by descent (IBD). Modern genetic marker data provide information to infer such segments among multiple related members of a population, even when pedigree relationships are unknown. Previous methods have been proposed for the detection of pairwise IBD, but the computation of probabilities of trait data under many trait models requires an IBD estimate jointly consistent among individuals and slowly varying across genome locations; we refer to such an estimate as an 'IBD graph'. In this paper, we develop a novel method that builds IBD graphs sequentially among related individuals from a population sample using either phased or unphased genetic marker data. We show how IBD graphs realized conditionally on marker data provide a form of linkage mapping score, analogous to a LOD score, and propose a permutation approach to normalize this mapping score. Using a simulated quantitative trait dependent on the (unobserved) genotype at a major locus, we apply the approach to two samples containing both closely and remotely related individuals, among whom there are complex patterns of IBD. We compare the results of our approach with an alternate approach based on the estimation of local kinship. We show that pairwise estimates derived from a joint IBD graph give significant improvements in LOD score estimation over estimates derived from an intrinsically pairwise approach. PMID- 26228694 TI - Procognitive Compounds Promote Neurite Outgrowth. AB - BACKGROUND/AIMS: To this date, the only available drugs for treating Alzheimer's disease are cognitive enhancers, which may improve the cognitive function of patients for a few years while the disease continues to progress. As such, there are intense investigations to develop disease-modifying drugs to suppress progressive neurodegeneration. METHODS: In this study, a range of procognitive compounds are tested in a primary neuronal culture to determine their relative potential for promoting neuritogenesis. RESULTS: We report that donepezil, memantine, dimebon, Pre-084 and 4-IBP are neuritogenic while tacrine, rosemarinic acid, memoquin and a BACE1 inhibitor suppress neurite outgrowth of neurons. CONCLUSIONS: The results of this study indicate that some procognitive compounds may possess a disease-modifying potential. PMID- 26228696 TI - Pharmacokinetics studies of enrofloxacin injectable in situ forming gel in dogs. AB - The objective of this study was to evaluate the pharmacokinetic characteristics of enrofloxacin (ENR) injectable in situ gel we developed in dogs following a single intramuscular (i.m.) administration. Twelve healthy dogs were randomly divided into two groups (six dogs per group), then administrated a single 20 mg/kg body weight (b.w.) ENR injectable in situ gel and a single 5 mg/kg b.w. ENR conventional injection, respectively. High-performance liquid chromatography (HPLC) was used to determine ENR plasma concentrations. The pharmacokinetic parameters of ENR injectable in situ gel and conventional injection in dogs are as follows: MRT (mean residence time) (45.59 +/- 14.05) h verse (11.40 +/- 1.64) h, AUC (area under the blood concentration vs. time curve) (28.66 +/- 15.41) MUg.h/mL verse (11.06 +/- 3.90) MUg.h/mL, cmax (maximal concentration) (1.59 +/- 0.35) MUg/mL verse (1.46 +/- 0.07) MUg/mL, tmax (time needed to reach cmax ) (1.25 +/- 1.37) h verse (1.40 +/- 0.55) h, t1/2lambdaz (terminal elimination half life) (40.27 +/- 17.79) h verse (10.32 +/- 0.97) h. The results demonstrated that the in situ forming gel system could increase dosing interval of ENR and thus reduced dosing frequency during long-term treatment. Therefore, the ENR injectable in situ gel seems to be worth popularizing in veterinary clinical application. PMID- 26228695 TI - Variability in gene cassette patterns of class 1 and 2 integrons associated with multi drug resistance patterns in Staphylococcus aureus clinical isolates in Tehran-Iran. AB - BACKGROUND: To investigate antibiotic resistance, the occurrence and distribution of class 1 and 2 integrons in multidrug- resistant Staphylococcus aureus isolates from hospitals in Tehran, Iran. The isolates were examined for susceptibility to antimicrobial agents. The mecA gene, class 1 and 2 integrons were detected by PCR. Integrase positive strains were further analysed for the presence of resistance gene cassettes using specific primers and were sequenced. RESULTS: Among 139 S.aureus isolates, 109 (78.4 %) and 112 (80.5 %) strains were considered as multidrug resistant and mecA positive, respectively. Class 1 integrons and internal variable regions were found in 72.6 % (101/139) and 97 % (98/101) and class 2 integrons and variable regions also in 35.2 % (49/139) and 65.3 % (32/49) of S.aureus clinical isolates, respectively. Twelve distinct cassette arrays were found, containing genes encoding resistance to beta-lactams, aminoglycosides, streptothricin, trimethoprim, chloramphenicol,a putative glucose dehydrogenase precursor and a protein with unknown function. Gene cassette arrays aadB, aadA2 and dhfrA1-sat2-aadA1 were common in S.aureus isolates. We detected a completely new gene cassettes which contained aadB, oxa2, aacA4, orfD-aacA4 catB8, aadB-catB3, orfD-aacA4 and aadB-aadA1-cmlA6 of class 1 and dhfrA1-sat2 aadA1, dhfrA11, dhfrA1-sat2 of class 2 integrons. CONCLUSIONS: This is the first study to report carriage of class 1 and 2 integrons and associated gene cassettes among in S.aureus isolates from Iran. PMID- 26228697 TI - Intraoperative Molecular Imaging of Lung Adenocarcinoma Can Identify Residual Tumor Cells at the Surgical Margins. AB - PURPOSE: During lung surgery, identification of surgical margins is challenging. We hypothesized that molecular imaging with a fluorescent probe to pulmonary adenocarcinomas could enhance residual tumor during resection. PROCEDURES: Mice with flank tumors received a contrast agent targeting folate receptor alpha. Optimal dose and time of injection was established. Margin detection was compared using traditional methods versus molecular imaging. A pilot study was then performed in three humans with lung adenocarcinoma. RESULTS: The peak tumor-to background ratio (TBR) of murine tumors was 3.9. Fluorescence peaked at 2 h and was not improved beyond 0.1 mg/kg. Traditional inspection identified 30% of mice with positive margins. Molecular imaging identified an additional 50% of residual tumor deposits (p < 0.05). The fluorescent probe visually enhanced all human tumors with a mean TBR of 3.5. CONCLUSIONS: Molecular imaging is an important adjunct to traditional inspection to identify surgical margins after tumor resection. PMID- 26228698 TI - Factors associated with improved outcomes following proximal row carpectomy: a long-term outcome study of 144 patients. AB - We conducted a review of 144 consecutive patients who underwent proximal row carpectomy from 1967 to 2010 for the diagnosis of wrist arthritis. At a mean follow-up of 13.4 years, patients experienced good pain relief with preservation (but not improvement) of wrist motion. A total of 17 patients (12%) required revision surgery at an average of 44.6 months. Improved pain, function, and survival outcomes were seen in those who underwent proximal row carpectomy after the age of 40, had a preoperative diagnosis of Kienbock's disease, who underwent a concomitant neurectomy procedure, patients who were non-labourers, and patients who underwent surgery after 1990. Although 45% of patients developed moderate to severe radiocapitate arthrosis postoperatively, these findings did not correlate with clinical outcomes or risk of revision surgery. Patients with type II lunate and type II and III capitate shapes had higher rates of postoperative radiocapitate arthrosis. LEVEL OF EVIDENCE: III, Prognostic. PMID- 26228699 TI - Implantation of a denaturated cellulose adhesion barrier after plate osteosynthesis of finger proximal phalangeal fractures: results of a randomized controlled trial. AB - Adhesions after osteosynthesis of finger proximal phalangeal fractures often cause stiffness. To minimize adhesions, the use of an adhesion barrier has been proposed. The results until now have not been convincing. The aim of this prospective randomized trial was to evaluate the use of an adhesion barrier. The trial included any isolated, closed proximal phalangeal fracture needing plate osteosynthesis. The patients were randomized into two groups: with or without application of the adhesion barrier. The outcomes we measured were finger ranges of motion and DASH score at 6 weeks and 6 months post-operatively. A total of 42 patients (42 fingers) entered the study; 37 completed the study. The key baseline characteristics were comparable. At 6 weeks there was a trend favouring the adhesion barrier that disappeared at 6 months. Overall the results do not support the use of this device. PMID- 26228701 TI - Bioprosthetic Mitral Transcatheter Transapical Valve-in-Valve Implantation for Mitral Stenosis in an End-Stage Renal Disease Patient. AB - Transcatheter mitral valve-in-valve implantation (TMVIV) is an option for patients with mitral prosthetic valve dysfunction who are at high risk for surgical valve replacement. Efficacy and safety of TMVIV is at its infancy. We report a high-risk symptomatic dialysis-dependent end-stage renal disease patient with severe bioprosthetic mitral valve stenosis who had TMVIV performed successfully. PMID- 26228700 TI - How the lumbrical muscle contributes to placing the fingertip in space: a three dimensional cadaveric study to assess fingertip trajectory and metacarpophalangeal joint balancing. AB - Three-dimensional fingertip trajectory was examined under different force levels of the lumbrical muscle to clarify the function of the lumbrical muscle in free index finger motion. The metacarpophalangeal joint balancing effect of the lumbrical muscle in the thumb-up position was also examined. The motions of the finger bones were recorded during simulated contraction of flexor digitorum profundus when different forces (0.000-1.960 N) were applied to the lumbrical muscle in cadaveric specimens. The greater the force with which the lumbrical muscle was pulled, the larger the arc formed by the fingertip, and the greater the rebalancing influence on the metacarpophalangeal joint. This result indicates that the lumbrical muscle functions simultaneously to enlarge the fingertip trajectory and to balance the metacarpophalangeal joint against gravity in the axial plane. A 0.980 N force was ideal for maximal finger movement. The lumbrical muscle rebalanced the metacarpophalangeal joint against gravity in the thumb-up position with a force ?0.980 N. PMID- 26228702 TI - Achiral, acyclic nucleic acids: synthesis and biophysical studies of a possible prebiotic polymer. AB - The search for prebiotic, nucleic acid precursors is, at its best, a speculative undertaking. Given the complex structure of RNA, it is not very likely that RNA was the first information system in the universe and thus finding possible precursor/s i.e. pre-RNA remains an open challenge. We, in this paper, have tried to construct nucleic acid polymers with a simple acyclic, achiral backbone. Such a linear, achiral backbone may have been formed from simple monomers that may have existed in the "prebiotic soup". We have shown that such polymers are capable of identifying the complementary "other self" and thus forming a potential system for information storage and transmission. This study thus involves investigation of nucleic acid analogues with a modified backbone that are likely to have formed in the prebiotic setting. PMID- 26228703 TI - [The Application of Bryophyllum pinnatum Preparations in Obstetrics and Gynaecology - a Multicenter, Prospective Observational Study]. AB - BACKGROUND: Bryophyllum pinnatum has been introduced in anthroposophic medicine in Europe and is nowadays also widely used in conventional medicine. The aim of this study was to assess the prescriptions in the field of gynaecology and obstetrics in Switzerland and to document potential effects and possible adverse events of B. pinnatum. PATIENTS AND METHODS: Private practices and clinics for obstetrics and gynaecology were asked to document each prescription of B. pinnatum for their female patients during 31 months with an online questionnaire. RESULTS: At the University Hospital Zurich, at the Cantonal Hospital Winterthur as well as at 2 private practices, a total of 174 women and 208 prescriptions of B. pinnatum were recorded (several prescriptions per patient were possible). Most of the patients were pregnant (87%). B. pinnatum was prescribed as a tocolytic agent to 83% of all patients and to 95% of all pregnant patients and showed a good or a very good effectiveness. Further, 14% of the patients received B. pinnatum for sedation against their restlessness during the day and 5% for sedation against sleep problems. A decrease of the restlessness was achieved for these 2 indications. 13% of the patients suffered from a hyperactive bladder and in two-thirds of them the effectiveness of the treatment with B. pinnatum was classified as very good. In 92% of the cases, Bryophyllum 50% chewable tablets were prescribed. CONCLUSIONS: In conventional gynaecology and obstetrics, B. pinnatum is predominantly prescribed for pregnant women in case of prematurel abour, against restlessness and for hyperactive bladder. B. pinnatum showed a good effectiveness with a high benefit in the treatment of hyperactivity associated health problems. PMID- 26228704 TI - Systematic viewing in radiology: seeing more, missing less? AB - To prevent radiologists from overlooking lesions, radiology textbooks recommend "systematic viewing," a technique whereby anatomical areas are inspected in a fixed order. This would ensure complete inspection (full coverage) of the image and, in turn, improve diagnostic performance. To test this assumption, two experiments were performed. Both experiments investigated the relationship between systematic viewing, coverage, and diagnostic performance. Additionally, the first investigated whether systematic viewing increases with expertise; the second investigated whether novices benefit from full-coverage or systematic viewing training. In Experiment 1, 11 students, ten residents, and nine radiologists inspected five chest radiographs. Experiment 2 had 75 students undergo a training in either systematic, full-coverage (without being systematic) or non-systematic viewing. Eye movements and diagnostic performance were measured throughout both experiments. In Experiment 1, no significant correlations were found between systematic viewing and coverage, r = -.10, p = .62, and coverage and performance, r = -.06, p = .74. Experts were significantly more systematic than students F2,25 = 4.35, p = .02. In Experiment 2, significant correlations were found between systematic viewing and coverage, r = -.35, p < .01, but not between coverage and performance, r = .13, p = .31. Participants in the full coverage training performed worse compared with both other groups, which did not differ between them, F2,71 = 3.95, p = .02. In conclusion, the data question the assumption that systematic viewing leads to increased coverage, and, consequently, to improved performance. Experts inspected cases more systematically, but students did not benefit from systematic viewing training. PMID- 26228705 TI - Team communication amongst clinical teachers in a formal meeting of post graduate medical training. AB - The importance of team communication, or more specifically speaking up, for safeguarding quality of patient care is increasingly being endorsed in research findings. However, little is known about speaking up of clinical teachers in postgraduate medical training. In order to determine how clinical teachers demonstrate speaking up in formal teaching team meetings and what factors influence this, the authors carried out an exploratory study based on ethnographic principles. The authors selected 12 teaching teams and observed, audio recorded and analysed the data. Subsequently, during an interview, the program directors reflected on speaking up of those clinical teachers present during the meeting. Finally, the authors analysed iteratively all data, using a template analysis, based on Edmondson's behaviours of speaking up. The study was conducted from October 2013 to July 2014 and ten teams participated. During the teaching team meetings, the clinical teachers exhibited most of the behaviours of speaking up. "Sharing information" strongly resembles providing information and "talking about mistakes" occurs in a general sense and without commitment of improvement activities. "Asking questions" was often displayed by closed questions and at times several questions simultaneously. The authors identified factors that influence speaking up by clinical teachers: relational, cultural, and professional. The clinical teachers exhibit speaking up, but there is only limited awareness to discuss problems or mistakes and the discussion centred mainly on the question of blame. It is important to take into account the factors that influence speaking up, in order to stimulate open communication during the teaching team meetings. PMID- 26228707 TI - Two Cases of Cerebrovascular Accidents in Neonates With Incontinentia Pigmenti. PMID- 26228708 TI - Spasmus Nutans: More Than Meets the Eye. PMID- 26228706 TI - The influence of speed and grade on wheelchair propulsion hand pattern. AB - BACKGROUND: The hand pattern used during manual wheelchair propulsion (i.e., full cycle hand path) can provide insight into an individual's propulsion technique. However, previous analyses of hand patterns have been limited by their focus on a single propulsion condition and reliance on subjective qualitative characterization methods. The purpose of this study was to develop a set of objective quantitative parameters to characterize hand patterns and determine the influence of propulsion speed and grade of incline on the patterns preferred by manual wheelchair users. METHODS: Kinematic and kinetic data were collected from 170 experienced manual wheelchair users on an ergometer during three conditions: level propulsion at their self-selected speed, level propulsion at their fastest comfortable speed and graded propulsion (8%) at their level self-selected speed. Hand patterns were quantified using a set of objective parameters, and differences across conditions were identified. FINDINGS: Increased propulsion speed resulted in a shift away from under-rim hand patterns. Increased grade of incline resulted in the hand remaining near the handrim throughout the cycle. INTERPRETATION: Manual wheelchair users change their hand pattern based on task specific constraints and goals. Further work is needed to investigate how differences between hand patterns influence upper extremity demand and potentially lead to the development of overuse injuries and pain. PMID- 26228709 TI - Prefabricated auricular cartilage radial forearm free flap reconstruction for cricoid chondrosarcoma. AB - This case describes a subtotal cricoid cartilage defect reconstructed with a prefabricated composite free flap. A 61-year-old man with a chondrosarcoma of the cricoid cartilage required a subtotal cricoidectomy. The resulting defect was successfully reconstructed with a two-stage prefabricated radial forearm free flap utilizing auricular cartilage. Our case further adds to the evidence that prefabricated flaps are reliable in airway reconstruction. Additionally, this provides another option for laryngeal preservation in patients with laryngeal chondrosarcoma. PMID- 26228710 TI - Serum biochemical, blood gas and antioxidant status in search and rescue dogs before and after simulated fieldwork. AB - The aim of the study was to assess the physiological and antioxidant status before and after a 4 h search and rescue field exercise, with handlers, under warm-weather conditions performing activities compared to a control group of similarly trained dogs at rest. Serum chemistry demonstrated a decrease in serum sodium (Na) and potassium (K) in both exercising and control groups, however only Na was decreased significantly (P < 0.05) after exercise and hematocrits (HCTs) remained unchanged. The exercise group demonstrated significantly decreased serum phosphorus (P) and magnesium (Mg) compared to pre-exercise values, as did the control group (P < 0.025). There was also a significant increase in creatinine kinase concentrations in the exercise groups (P < 0.025). Serum non-esterified fatty acids were increased only in the exercise group after exercise, suggesting fat mobilization to produce energy. The mean total serum antioxidant potential in searching dogs was no different from the pre- and post-exercise values in the control dogs. Serum vitamin E concentrations did not differ between the two groups, with a decreasing trend in both groups. There was a modest decrease in serum uric acid in the control group, while there was a significant rise after exercise in the searching group (P < 0.01). Multiple changes in serum chemistry, HCTs and blood gases were documented in this study, and were similar to those observed after other endurance activities. The lack of hemoconcentration in this field search exercise suggested that even in extreme environmental conditions (heat and humidity), dogs with access to water do not experience significant dehydration or diminished antioxidant status. PMID- 26228711 TI - Treatment of advanced oesophagogastric cancer with FOLFOX-4 regimen followed by leucovorin/bolus and continuous infusion 5-FU as maintenance chemotherapy in patients aged >= 75 years with impaired performance status. AB - OBJECTIVES: To evaluate the efficacy and safety of FOLFOX-4 combination chemotherapy, followed by leucovorin (LV)/bolus and continuous infusion 5 fluorouracil (5-FU) as maintenance chemotherapy in elderly (>= 75 years) patients with advanced oesophagogastric cancer with impaired performance status (PS). MATERIALS AND METHODS: Patients with a PS score >1 were included in this study. PS evaluations were performed by a geriatrician and two medical oncologists. FOLFOX-4 consisted of oxaliplatin concurrently with LV/bolus and continuous infusion 5-FU every 2 weeks. After a maximum of six FOLFOX-4 cycles, patients with no evidence of disease progression received maintenance treatment with LV/bolus and continuous infusion 5-FU every 2 weeks until disease progression or unacceptable toxicity. RESULTS: Thirty-eight patients were enrolled in this study. Of these, 32 (84.2%) patients had a PS score of 2 and six (15.7%) patients had a PS score of 3. After completion of FOLFOX-4, 18 (47.3%) patients achieved a partial response and 14 (36.8%) patients had stable disease. Thirty-two patients (84.2%) received maintenance chemotherapy for a median of eight cycles (range one to 26 cycles). The 6-month disease-control rate was 47.3% [95% confidence interval (CI) 30.9-64.1]. The median progression-free survival was 5.9 months (95% CI 4.7-6.8) and the median overall survival was 9.6 months (95% CI 8.1 11.7). Grade 3 neutropenia occurred in six patients (15.7%), and Grade 3 anaemia and thrombocytopenia occurred in two patients (5.2%). CONCLUSION: FOLFOX-4 followed by LV/bolus and continuous infusion 5-FU as maintenance chemotherapy seems to be an active and well-tolerated first-line treatment strategy for elderly patients with advanced oesophagogastric cancer and impaired PS. PMID- 26228712 TI - Development of a bilayer ring system for achieving high strain in commercial rheometers. AB - Mechanical stimulation of cell cultures has been shown be an effective means of enhancing ECM production. ECM produced from vocal fold fibroblast cultures has the potential for therapeutic use for vocal fold repair. However, current bioreactor designs generally fail to produce physiological relevant frequency and strain values. Here we present an approach for using commercial oscillatory rheometers and an elastic ring bilayer system to produce physiologically relevant strain values at frequencies in the range of 20-100 Hz. We demonstrate the ability to target specific strain and frequency values by manipulating system parameters, and also show that it is possible to maintain high oscillatory strains for extended periods of time. Such a system could be used to mechanically stimulate cell cultures contained within gel carrier systems and has the potential to be extended to other applications requiring high strains at low frequencies. PMID- 26228713 TI - Friction coefficient and effective interference at the implant-bone interface. AB - Although the contact pressure increases during implantation of a wedge-shaped implant, friction coefficients tend to be measured under constant contact pressure, as endorsed in standard procedures. Abrasion and plastic deformation of the bone during implantation are rarely reported, although they define the effective interference, by reducing the nominal interference between implant and bone cavity. In this study radial forces were analysed during simulated implantation and explantation of angled porous and polished implant surfaces against trabecular bone specimens, to determine the corresponding friction coefficients. Permanent deformation was also analysed to determine the effective interference after implantation. For the most porous surface tested, the friction coefficient initially increased with increasing normal contact stress during implantation and then decreased at higher contact stresses. For a less porous surface, the friction coefficient increased continually with normal contact stress during implantation but did not reach the peak magnitude measured for the rougher surface. Friction coefficients for the polished surface were independent of normal contact stress and much lower than for the porous surfaces. Friction coefficients were slightly lower for pull-out than for push-in for the porous surfaces but not for the polished surface. The effective interference was as little as 30% of the nominal interference for the porous surfaces. The determined variation in friction coefficient with radial contact force, as well as the loss of interference during implantation will enable a more accurate representation of implant press-fitting for simulations. PMID- 26228714 TI - Effects of home-based bench step exercise on inflammatory cytokines and lipid profiles in elderly Japanese females: A randomized controlled trial. AB - PURPOSE: The purpose of the current study was to investigate the effects of a 12 week home-based bench step exercise program on inflammatory cytokines and lipid profiles in elderly females. METHODS: Sixty-two postmenopausal females (65-85 years of age) were randomized to either the bench step exercise group (n=31) or the control group (n=31). The subjects in the bench step exercise group were instructed to perform bench step exercises at the exercise intensity corresponding to lactate threshold (LT), three times per day 10-20 min each session, for a goal of >=140 min/week at home for 12 weeks. At baseline and 12 weeks, circulating levels of nine inflammatory cytokines (high-molecular-weight adiponectin, interleukin-4 [IL-4], IL-5, IL-6, IL-8, IL-15, tumor necrosis factor alpha [TNF-alpha], TNF-beta and interferon-gamma [IFN-gamma]) and serum lipids including high-density lipoprotein cholesterol (HDL-C) were measured. RESULTS: The bench step training at the LT significantly increased HDL-C levels and decreased IFN-gamma concentrations in the subjects with lower (< 63 mg/dL) baseline HDL-C levels (p<0.05). The change in IFN-gamma inversely correlated with the change in HDL-C in the exercise group (rho=-0.56, p<0.01), whereas this association was not observed in the control group. Additionally, principal component analysis-derived index of what we called "inflammatory status factor" was inversely associated with the changes in HDL-C in the exercise group. CONCLUSION: The bench step exercise-induced reduction in the IFN-gamma levels may partially explain the degree of improvement in the HDL-C levels with the exercise program. PMID- 26228716 TI - Machine that combines radiotherapy with MRI scanner will undergo trials next year. PMID- 26228715 TI - Oral health related quality of life and it's related factors of stroke patients at home in Korea. AB - OBJECTIVE: Due to physical impairments of stroke patients oral health tends to deteriorate, which may have an impact on the oral health-related quality of life (OHRQoL). Therefore, the aim of this study was to evaluate the OHRQoL and analyze its related factors among stroke patients cared for at home in Korea. METHODS: OHRQoL of 549 stroke patients aged over 50 who received care at home was assessed by Oral Health Impact Profile-14 (OHIP-14) in a City, Korea, from May to June 2009. Trained researchers and five nurses conducted interviews with patients or caregivers in their homes using structured questionnaires. Demographic, general health, stroke, and oral health related variables were surveyed. Statistically, t test, an analysis of variance (ANOVA), and multiple regression analyses were used to evaluate the relationship between OHRQoL and various covariates. RESULTS: Mean of total OHIP-14 score was 35.7 +/- 10.0. Age, activity of daily living (ADL) (p<0.001), subjective general and oral health status (p<0.001), degree of disability (p<0.001), frequency of tooth brushing (p<0.001), use of dental floss (p<0.01), missing teeth, and use of denture (p<0.001) showed significant association with the OHIP-14 scores. In multiple regression analyses, ADL, frequency of tooth brushing per day, subjective general status, and oral health status were identified as significant factors with the OHIP-14 scores in stroke patients who received care at home. CONCLUSION: Among strong patients who received care at home, participants who had more severe physical disability, poorer oral hygiene and more missing teeth showed poorer OHRQoL. PMID- 26228717 TI - Regular peaks and troughs in the Australian incidence of childhood type 1 diabetes mellitus (2000-2011). AB - AIMS/HYPOTHESIS: The aim of this study was to determine the incidence and incidence rate trends for type 1 diabetes mellitus in children aged 0-14 years, Australia-wide, from 2000 to 2011. METHODS: Cases of type 1 diabetes mellitus diagnosed in 0- to 14-year-olds were identified from the National (insulin treated) Diabetes Register, with a 97% ascertainment rate. Annual age standardised, sex- and age-specific incidences were calculated and Poisson regression was used to analyse the incidence by calendar year, sex and age at diagnosis. Non-linear temporal trends were analysed using sine and cosine functions applied to Poisson regression models for 3, 4, 5, 6 and 7 year cycles, and the Akaike information criterion was used to assess goodness of fit. RESULTS: A total of 11,575 cases (6,049 boys and 5,526 girls) of childhood type 1 diabetes mellitus were registered between 2000 and 2011, giving a mean incidence of 23.6 per 100,000 person-years (95% CI 23.2, 24.0). The mean incidence was 4.9% (95% CI 1.1%, 8.8%) higher in boys than in girls. Compared with 0- to 4-year-olds, the mean incidence was 65% higher in 5- to 9-year-olds and 208% higher in 10- to 14 year-olds. A 5 year cyclical variation in incidence was observed overall, in both sexes and in all age groups. An average annual increase in incidence was observed only in the 10- to 14-year-old age group (increase of 1.2% per year [95% CI 0.4%, 2.1%]). CONCLUSIONS/INTERPRETATION: A sinusoidal pattern was observed in the incidence rate trend of childhood type 1 diabetes mellitus in Australia. The 5 yearly peaks and troughs in incidence rate trends observed Australia-wide corroborate findings previously reported for Western Australia and require further investigation. PMID- 26228718 TI - Aquaporin-deficient mutant of Synechocystis is sensitive to salt and high-light stress. AB - Cyanobacterial aquaporins play an important role in the regulation of various physiological functions: cell volume control, osmotic stress responses, gas exchange. We employed the AqpZ-deficient mutant of Synechocystis to study the role of aquaporins in responses to salt (NaCl) and high light stress. Electron microscopy and paramagnetic resonance revealed that AqpZ-deficient cells are unable to efficiently regulate the cytoplasmic volume under salt stress. Both photosystems (PSII and, especially, PSI) of these cells are more sensitive to NaCl and to high light. Thus, AqpZ of Synechocystis participates in regulation of the photosynthetic activity of PSI and PSII under salt and high-light stress. Our results demonstrate that AqpZ might be necessary for the repair of PSII and PSI after photodamage. PMID- 26228719 TI - Extending helicopter operations to meet future integrated transportation needs. AB - Helicopters have the potential to be an integral part of the future transport system. They offer a means of rapid transit in an overly populated transport environment. However, one of the biggest limitations on rotary wing flight is their inability to fly in degraded visual conditions in the critical phases of approach and landing. This paper presents a study that developed and evaluated a Head up Display (HUD) to assist rotary wing pilots by extending landing to degraded visual conditions. The HUD was developed with the assistance of the Cognitive Work Analysis method as an approach for analysing the cognitive work of landing the helicopter. The HUD was tested in a fixed based flight simulator with qualified helicopter pilots. A qualitative analysis to assess situation awareness and workload found that the HUD enabled safe landing in degraded conditions whilst simultaneously enhancing situation awareness and reducing workload. Continued development in this area has the potential to extend the operational capability of helicopters in the future. PMID- 26228720 TI - [Conflicts of interest: should we lower our guard?]. AB - Conflicts of interest affect the scientific communication and information: their effects on the physician's prescribing behavior have been frequently studied and clearly documented. Recently, the New England Journal of Medicine published a series of papers questioning the radical positions on this topic, asking to reconsider the most intransigent approach, so that it may be possible a productive collaboration between academic medicine and pharmaceutical industry, in the interest of the patient. The papers published in the New England Journal of Medicine confirm the difficulties experienced by the biomedical journals: the support of the industry is essential and most of the authors and referees has ties with pharmaceutical or biotech companies. The debate among the various stakeholders is vital but should be open and transparent, with the aim to restore credibility to all the parties concerned: academic medicine, pharmaceutical industry and scientific publishers. PMID- 26228721 TI - [Individual response to treatment: from Withering to contemporary medicine]. AB - This is an essay dealing with the 1785 cohort study by William Withering (the "account"), in which he reported the results of the treatment with foxglove (Digitalis purpurea) in 163 patients suffering from various forms of hydropsy (water retention). Withering reported the results of all patients, and classified them into responders and non-responders. He identified the responders as suffering from heart failure. In the 18th century, medical treatments were judged as successful if they complied with the criteria a priori of the theory of the four humors, and not on the patient's response to the treatment. Withering was the first not only to compare the patient's conditions before and after treatment, but also to identify the individual clinical characteristics of the patients who responded. In modern medicine, drugs are released on the market and approved for use after what is known as "population-derived clinical research", principally randomized controlled trials, and guidelines. More than 200 years ago, Withering anticipated the current and growing trend towards individual responses to treatment, and personalized medicine. PMID- 26228722 TI - [Palliative care in neurology]. AB - Palliative care in neurology is characterized by the need of taking into account some distinguishing features which supplement and often differ from the general palliative approach to cancer or to severe organ failures. Such position is emphasized by a new concept of palliative assistance which is not limited to the "end of life" stage, as it was the traditional one, but is applied along the entire course of progressive, life-limiting, and disabling conditions. There are various reasons accounting for a differentiation of palliative care in neurology and for the development of specific expertise; the long duration of the advanced stages of many neurological diseases and the distinguishing features of some clinical problems (cognitive disorders, psychic disorders, etc.), in addition to the deterioration of some general aspects (nutrition, etc.), make the general criteria adopted for cancer, severe respiratory, hepatic or renal failures and heart failure inadequate. The neurological diseases which could benefit from the development of a specific palliative approach are dementia, cerebrovascular diseases, movement disorders, neuromuscular diseases, severe traumatic brain injury, brain cancers and multiple sclerosis, as well as less frequent conditions. The growing literature on palliative care in neurology provides evidence of the neurological community's increasing interest in taking care of the advanced and terminal stages of nervous system diseases, thus encouraging research, training and updating in such direction. This document aims to underline the specific neurological requirements concerning the palliative assistance. PMID- 26228723 TI - [Synergy between radiotherapy and immunotherapy in the treatment of advanced malignancies: recent evidences of a new challenge in oncology]. AB - Radiotherapy remains a cornerstone of oncological treatment modalities for many types of tumors. Recently, preliminary studies have evidenced that ionizing radiations delivered by High Tech Linear Accelerators may increase the effectiveness of patients' antitumor immunoresponse in the clinical setting even at distant sites. Radiations may awake the dormant antitumor T-cells by promoting also an "abscopal effect", i.e. the control of metastasis outside the irradiated tumor site. These emerging findings have stimulated the design of combinations of high tech radiotherapy with new immunotherapies in order to obtain a synergy against biologically aggressive cancers. In preclinical model and clinical trials radiotherapy has been widely associated with citokines, peptides, immunoagonists and mainly with immune checkpoint inhibitors to counteract the function of CTLA-4 or Programmed-Death-1 receptors or PD-L1/L2 ligands. In this review the complex biological processes induced by radiotherapy on immunosystem are briefly explained. Although several trials are still ongoing, the preliminary interesting results obtained by this innovative radio-immunotherapy synergy to control advanced malignancies are reported and discussed. PMID- 26228724 TI - [Considerations on the use of WhatsApp in physician-patient communication and relationship]. AB - WhatsApp is an instant messaging application developed in 2009 and quickly spread among users of all ages, for personal relationships, as entertainment, as an aid to the study and as a virtual place of contact with their group. The international scientific literature on the use of this application in the health sector, identified by the major database on-line reports only a small number of publications. Although its impact in the clinical setting has been poorly investigated, WhatsApp is among the most widely used communication tools, which may also be valuable in favoring the communication and relationship between patients and physicians. Healthcare providers should be trained to use modern web based communication systems with accurate assessment of indications and contraindications. In particular, virtual means should be prevented from replacing real interactions. PMID- 26228725 TI - [Benign prostatic hyperplasia related content on YouTube: unregulated and concerning]. AB - INTRODUCTION: Information derived from social media sources is being used to save lives and take vital life altering decisions. You Tube is one of the most widely used social media for seeking medical information. Quality of information available to patients and medical professionals on YouTube with regards to benign prostatic hyperplasia (BPH), a common urological condition, w.as assessed. MATERIALS AND METHODS: First 1 00 videos results on BPH were analysed by three independent observers and graded based on the quality of information provided using an indigenous grading system of five points ranging from not useful to Informative for the Medical Professional. Correlation of this score with rank, number of views and "likes" was performed. Source of videos was identified along with analysis of comments. RESULTS: A large proportion of videos (63%) was found to be irrelevant to the search, projected wrong facts or provided very basic . information about prostate and the disease. A small but significant number of videos contained useful and relevant information. Only a handful of videos were useful for the urologist and adequate to guide the patient. A negative correlation between the quality of videos and their ranking on search was observed. CONCLUSIONS: YouTube offers very few high quality resources for patients and physicians. There is a significant negative correlation between useful videos and higher ranks in search results, but no correlation with number of views and likes. The first video in such results should be issued by a governing body that serves as the gold standard for patients and physicians. PMID- 26228726 TI - [To communicate with who doesn't communicate: an "unexplained" fever in an elderly woman with Alzheimer's dementia at an advanced stage]. AB - Fever of unknown origin is per se a -diagnostic challenge. In elderly patients with advanced Alzheimer disease the impairment of verbal communication adds another critical element. We describe the clinical case of an elderly woman in which fever, proved secondary to Horton disease, was accompanied by manifestations misinterpreted as behavioral disorders. PMID- 26228727 TI - [Tenderly mad. Can mental suffering ever be "tender"?]. PMID- 26228728 TI - Recurrent reactive angioendotheliomatosis in pregnancy: a case report. PMID- 26228729 TI - Tobacco and psychosis: Not quite a smoking gun. PMID- 26228730 TI - Clinical practice guidelines for eating disorders - Comments from the front line. PMID- 26228731 TI - Speaking Out and Being Heard Residents' Committees in Quebec's Residential Long Term Care Centre. AB - Residents' councils in Quebec's residential and long-term care centres have the mandate to promote the improvement of living conditions for residents, to assess their level of satisfaction, and to defend their rights. Based on two studies on the autonomy of councils, we examined how committees can express themselves on topics other than those the management is already aware of, to reveal various previously unknown aspects of the services, and to voice unexpressed concerns. We are especially interested in what makes management receptive, or not, to what the committee members say. The councils' ability to express them selves is, in fact, inseparable from its capacity to listen to the management teams, and we seek to determine the conditions required to perform this dual capacity. PMID- 26228732 TI - Effect of Lesion Baseline Severity and Mineral Distribution on Remineralization and Progression of Human and Bovine Dentin Caries Lesions. AB - The aims of this laboratory study were to compare the effects of lesion baseline severity, mineral distribution and substrate on remineralization and progression of caries lesions created in root dentin. Lesions were formed in dentin specimens prepared from human and bovine dentin using three protocols, each utilizing three demineralization periods to create lesions of different mineral distributions (subsurface, moderate softening, extreme softening) and severity within each lesion type. Lesions were then either remineralized or demineralized further and analyzed using transverse microradiography. At lesion baseline, no differences were found between human and bovine dentin for integrated mineral loss (x0394;Z). Differences in mineral distribution between lesion types were apparent. Human dentin lesions were more prone to secondary demineralization (x0394;x0394;Z) than bovine dentin lesions, although there were no differences in x0394;L. Likewise, smaller lesions were more susceptible to secondary demineralization than larger ones. Subsurface lesions were more acid-resistant than moderately and extremely softened lesions. After remineralization, differences between human and bovine dentin lesions were not apparent for x0394;x0394;Z although bovine dentin lesions showed greater reduction in lesion depth L. For lesion types, responsiveness to remineralization (x0394;x0394;Z) was in the order extremely softened>moderately softened>subsurface. More demineralized lesions exhibited greater remineralization than shallower ones. In summary, some differences exist between human and bovine dentin and their relative responsiveness to de- and remineralization. These differences, however, were overshadowed by the effects of lesion baseline mineral distribution and severity. Thus, bovine dentin appears to be a suitable substitute for human dentin in mechanistic root caries studies. PMID- 26228733 TI - Novel Holistic Approaches for Overcoming Therapy Resistance in Pancreatic and Colon Cancers. AB - Gastrointestinal (GI) cancers, such as of the colon and pancreas, are highly resistant to both standard and targeted therapeutics. Therapy-resistant and heterogeneous GI cancers harbor highly complex signaling networks (the resistome) that resist apoptotic programming. Commonly used gemcitabine or platinum-based regimens fail to induce meaningful (i.e. disease-reversing) perturbations in the resistome, resulting in high rates of treatment failure. The GI cancer resistance networks are, in part, due to interactions between parallel signaling and aberrantly expressed microRNAs (miRNAs) that collectively promote the development and survival of drug-resistant cancer stem cells with epithelial-to-mesenchymal transition (EMT) characteristics. The lack of understanding of the resistance networks associated with this subpopulation of cells as well as reductionist, single protein-/pathway-targeted approaches have made 'effective drug design' a difficult task. We propose that the successful design of novel therapeutic regimens to target drug-resistant GI tumors is only possible if network-based drug avenues and agents, in particular 'natural agents' with no known toxicity, are correctly identified. Natural agents (dietary agents or their synthetic derivatives) can individually alter miRNA profiles, suppress EMT pathways and eliminate cancer stem-like cells that derive from pancreatic cancer and colon cancer, by partially targeting multiple yet meaningful networks within the GI cancer resistome. However, the efficacy of these agents as combinations (e.g. consumed in the diet) against this resistome has never been studied. This short review article provides an overview of the different challenges involved in the understanding of the GI resistome, and how novel computational biology can help in the design of effective therapies to overcome resistance. PMID- 26228735 TI - Claudin expression in follicle-associated epithelium of rat Peyer's patches defines a major restriction of the paracellular pathway. AB - AIM: Members of the tight junction protein family of claudins have been demonstrated to specifically determine paracellular permeability of the intestinal epithelium. In small intestinal mucosa, which is generally considered to be a leaky epithelium, Peyer's patches are a primary part of the immune system. The aim of this study was to analyse the tight junctional barrier of follicle-associated epithelium covering Peyer's patches (lymphoid follicles). METHODS: Employing small intestinal tissue specimens of male Wistar rats, electrophysiological analyses including the Ussing chamber technique, marker flux measurements and one-path impedance spectroscopy were performed. Morphometry of HE-stained tissue sections was taken into account. Claudin expression and localization was analysed by immunoblotting and confocal laser scanning immunofluorescence microscopy. RESULTS: Almost twofold higher parameters of epithelial and transepithelial tissue resistance and a markedly lower permeability for the paracellular permeability markers 4 and 20 kDa FITC-dextran were detected in follicle-associated epithelium compared to neighbouring villous epithelium. Analysis of claudin expression and localization revealed a stronger expression of major sealing proteins in follicle-associated epithelium, including claudin-1, claudin-4, claudin-5 and claudin-8. Therefore, the specific expression and localization of claudins is in accordance with barrier properties of follicle associated epithelium vs. neighbouring villous epithelium. CONCLUSION: We demonstrate that follicle-associated epithelium is specialized to ensure maximum restriction of the epithelial paracellular pathway in Peyer's patches by selective sealing of tight junctions. This results in an exclusive transcellular pathway of epithelial cells as the limiting and mandatory route for a controlled presentation of antigens to the underlying lymphocytes under physiological conditions. PMID- 26228734 TI - Investigation of temperature-dependent photoluminescence in multi-quantum wells. AB - Photoluminescence (PL) is a nondestructive and powerful method to investigate carrier recombination and transport characteristics in semiconductor materials. In this study, the temperature dependences of photoluminescence of GaAs-AlxGa1 xAs multi-quantum wells samples with and without p-n junction were measured under both resonant and non-resonant excitation modes. An obvious increase of photoluminescence(PL) intensity as the rising of temperature in low temperature range (T < 50 K), is observed only for GaAs-AlxGa1-xAs quantum wells sample with p-n junction under non-resonant excitation. The origin of the anomalous increase of integrated PL intensity proved to be associated with the enhancement of carrier drifting because of the increase of carrier mobility in the temperature range from 15 K to 100 K. For non-resonant excitation, carriers supplied from the barriers will influence the temperature dependence of integrated PL intensity of quantum wells, which makes the traditional methods to acquire photoluminescence characters from the temperature dependence of integrated PL intensity unavailable. For resonant excitation, carriers are generated only in the wells and the temperature dependence of integrated PL intensity is very suitable to analysis the photoluminescence characters of quantum wells. PMID- 26228736 TI - Analgesic Effect of Ilex paraguariensis Extract on Postoperative and Neuropathic Pain in Rats. AB - Ilex paraguariensis, known as "Yerba Mate," is an herb used in a beverage that is widely consumed in southern Latin American countries. Furthermore, it has been traditionally used to treat depression, and as an analgesic to manage both nerve pain and headache. The pain-related experimental evidence regarding the analgesic effects of Mate is unclear. Therefore, this study was designed to investigate whether Mate extract exhibits analgesic effects in both the plantar incision and spared nerve injury (SNI) models in rats. We tested the mechanical withdrawal threshold (MWT) using von Frey filaments. We also tested pain-related behavior using ultrasonic vocalization (USV). Neuropeptide Y (NPY) and pain-related cytokines were also determined in the dorsal root ganglia in a rat model of SNI. Our results showed that oral administration of Mate extract significantly increased MWT values, and reduced the number of 22-27 kHz USVs 24 h after the plantar incision operation. Moreover, after 15 d of continuous treatment with Mate extract, the SNI-induced hypersensitivity, cytokine levels, and NPY expression were significantly reduced compared to the corresponding findings in the control group. These results suggest that the intake of Mate extract has potential as a treatment for both postoperative pain and neuropathic pain. PMID- 26228737 TI - Longitudinal evaluation, acceptability and long-term retention of knowledge on a horizontally integrated organic and functional systems course. AB - Undergraduate medical education is moving from traditional disciplinary basic science courses into more integrated curricula. Integration models based on organ systems originated in the 1950s, but few longitudinal studies have evaluated their effectiveness. This article outlines the development and implementation of the Organic and Functional Systems (OFS) courses at the University of Minho in Portugal, using evidence collected over 10 years. It describes the organization of content, student academic performance and acceptability of the courses, the evaluation of preparedness for future courses and the retention of knowledge on basic sciences. Students consistently rated the OFS courses highly. Physician tutors in subsequent clinical attachments considered that students were appropriately prepared. Performance in the International Foundations of Medicine examination of a self-selected sample of students revealed similar performances in basic science items after the last OFS course and 4 years later, at the moment of graduation. In conclusion, the organizational and pedagogical approaches of the OFS courses achieve high acceptability by students and result in positive outcomes in terms of preparedness for subsequent training and long-term retention of basic science knowledge. PMID- 26228738 TI - Beyond work-hour restrictions: a qualitative study of residents' subjective workload. AB - INTRODUCTION: Following the introduction of work-hour restrictions, residents' workload has become an important theme in postgraduate training. The efficacy of restrictions on workload, however, remains controversial, as most research has only examined objective workload. The purpose of this study was to explore the less clearly understood component of subjective workload and, in particular, the factors that influenced residents' subjective workload. METHOD: This study was conducted in Japan at three community teaching hospitals. We recruited a convenience sample of 31 junior residents in seven focus groups at the three sites. Audio-recorded and transcribed data were read iteratively and analyzed thematically, identifying, analyzing and reporting themes within the data and developing an interpretive synthesis of the topic. RESULTS: Seven factors influenced residents' subjective workload: (1) interaction within the professional community, (2) feedback from patients, (3) being in control, (4) professional development, (5) private life, (6) interest and (7) protected free time. DISCUSSION AND CONCLUSION: Our findings indicate that residents who have good interaction with colleagues and patients, are competent enough to control their work, experience personal development through working, have greater interest in their work, and have fulfilling private lives will have the least subjective workload. PMID- 26228739 TI - PdEPF1 regulates water-use efficiency and drought tolerance by modulating stomatal density in poplar. AB - Water deficiency is a critical environmental condition that is seriously reducing global plant production. Improved water-use efficiency (WUE) and drought tolerance are effective strategies to address this problem. In this study, PdEPF1, a member of the EPIDERMAL PATTERNING FACTOR (EPF) family, was isolated from the fast-growing poplar clone NE-19 [Populus nigra * (Populus deltoides * Populus nigra)]. Significantly, higher PdEPF1 levels were detected after induction by dehydration and abscisic acid. To explore the biological functions of PdEPF1, transgenic triploid white poplars (Populus tomentosa 'YiXianCiZhu B385') overexpressing PdEPF1 were constructed. PdEPF1 overexpression resulted in increased water deficit tolerance and greater WUE. We confirmed that the transgenic lines with greater instantaneous WUE had approximately 30% lower transpiration but equivalent CO2 assimilation. Lower transpiration was associated with a 28% reduction in abaxial stomatal density. PdEPF1 overexpression not only strongly enhanced WUE, but also greatly improved drought tolerance, as measured by the leaf relative water content and water potential, under limited water conditions. In addition, the growth of these oxPdEPF1 plants was less adversely affected by reduced water availability than plants with a higher stomatal density, indicating that plants with a low stomatal density may be well suited to grow in water-scarce environments. Taken together, our data suggest that PdEPF1 improves WUE and confers drought tolerance in poplar; thus, it could be used to breed drought-tolerant plants with increased production under conditions of water deficiency. PMID- 26228740 TI - The role of the bi-compartmental stem cell niche in delaying cancer. AB - In recent years, by using modern imaging techniques, scientists have found evidence of collaboration between different types of stem cells (SCs), and proposed a bi-compartmental organization of the SC niche. Here we create a class of stochastic models to simulate the dynamics of such a heterogeneous SC niche. We consider two SC groups: the border compartment, S1, is in direct contact with transit-amplifying (TA) cells, and the central compartment, S2, is hierarchically upstream from S1. The S1 SCs differentiate or divide asymmetrically when the tissue needs TA cells. Both groups proliferate when the tissue requires SCs (thus maintaining homeostasis). There is an influx of S2 cells into the border compartment, either by migration, or by proliferation. We examine this model in the context of double-hit mutant generation, which is a rate-limiting step in the development of many cancers. We discover that this type of a cooperative pattern in the stem niche with two compartments leads to a significantly smaller rate of double-hit mutant production compared with a homogeneous, one-compartmental SC niche. Furthermore, the minimum probability of double-hit mutant generation corresponds to purely symmetric division of SCs, consistent with the literature. Finally, the optimal architecture (which minimizes the rate of double-hit mutant production) requires a large proliferation rate of S1 cells along with a small, but non-zero, proliferation rate of S2 cells. This result is remarkably similar to the niche structure described recently by several authors, where one of the two SC compartments was found more actively engaged in tissue homeostasis and turnover, while the other was characterized by higher levels of quiescence (but contributed strongly to injury recovery). Both numerical and analytical results are presented. PMID- 26228741 TI - Protecting Ideas: Ethical and Legal Considerations When a Grant's Principal Investigator Changes. AB - Ethical issues related the responsible conduct of research involve questions concerning the rights and obligations of investigators to propose, design, implement, and publish research. When a principal investigator (PI) transfers institutions during a grant cycle, financial and recognition issues need to be addressed to preserve all parties' obligations and best interests in a mutually beneficial way. Although grants often transfer with the PI, sometimes they do not. Maintaining a grant at an institution after the PI leaves does not negate the grantee institution's obligation to recognize the PI's original ideas, contributions, and potential rights to some forms of expression and compensation. Issues include maintaining a role for the PI in determining how to take credit for, share and publish results that involve his or her original ideas. Ascribing proper credit can become a thorny issue. This paper provides a framework for addressing situations and disagreements that may occur when a new PI continues the work after the original PI transfers. Included are suggestions for proactively developing institutional mechanisms that address such issues. Considerations include how to develop solutions that comply with the responsible conduct of research, equitably resolve claims regarding reporting of results, and avoid the possibility of plagiarism. PMID- 26228742 TI - Value of routine ultrasound in detecting early joint changes in children with haemophilia using the 'Haemophilia Early Arthropathy Detection with UltraSound' protocol. AB - INTRODUCTION: Patients with haemophilia tend to bleed in large joints even during prophylactic replacement therapy. Detection of early blood-induced joint changes may improve monitoring of treatment. The aim of this study was to explore the value of routine ultrasound in detecting early joint abnormalities in children with haemophilia on prophylaxis. METHODS: Sixty-four joints in 32 children with haemophilia were examined by one operator using the Haemophilia Early Arthropathy Detection with UltraSound protocol during annual multidisciplinary follow-up. Based on reported bleeding, the joint with the highest risk of blood-induced joint damage and the contralateral joint were examined. At the same day, clinical function was assessed according to the Haemophilia Joint Health Score (HJHS). RESULTS: Median age was 11.5 years (range = 5.5-16.4). Out of the 64 examined joints, one ankle was excluded because of previous surgery. Median lifetime joint bleeds/joint was three (interquartile ranges = 1-5). Clinical function of most joints was perfect: only 7/49 joints with reported bleeds scored positive due to swelling, muscle atrophy and/or range of motion loss (HJHS range = 1-2 points). Ultrasound showed abnormalities in 5/49 joints with reported bleeding, and 4/5 showed positive HJHS scores. Ultrasound abnormalities were present in 1/56 joints (1.8%, CI: 0.1-9.6%) without loss of clinical function. CONCLUSION: Ultrasound abnormalities were found during routine evaluation of joints in children with haemophilia on prophylaxis. Most joints with ultrasound abnormalities showed low HJHS scores too. Ultrasound could be used to evaluate whether minimal losses of clinical function might be caused by anatomical changes. PMID- 26228743 TI - Acute Neurological Illness in a Kidney Transplant Recipient Following Infection With Enterovirus-D68: An Emerging Infection? AB - We report the first case of enterovirus-D68 infection in an adult living-donor kidney transplant recipient who developed rapidly progressive bulbar weakness and acute flaccid limb paralysis following an upper respiratory infection. We present a 45-year-old gentleman who underwent pre-emptive living-donor kidney transplantation for IgA nephropathy. Eight weeks following transplantation, he developed an acute respiratory illness from enterovirus/rhinovirus that was detectable in nasopharyngeal (NP) swabs. Within 24 h of onset of respiratory symptoms, the patient developed binocular diplopia which rapidly progressed to multiple cranial nerve dysfunctions (acute bulbar syndrome) over the next 24 h. Within the next 48 h, asymmetric flaccid paralysis of the left arm and urinary retention developed. While his neurological symptoms were evolving, the Centers for Disease Control reported that the enterovirus strain from the NP swabs was, in fact, Enterovirus-D68 (EV-D68). Magnetic resonance imaging of the brain demonstrated unique gray matter and anterior horn cell changes in the midbrain and spinal cord, respectively. Constellation of these neurological symptoms and signs was suggestive for postinfectious encephalomyelitis (acute disseminated encephalomyelitis [ADEM]) from EV-D68. Treatment based on the principles of ADEM included intensive physical therapy and other supportive measures, which resulted in a steady albeit slow improvement in his left arm and bulbar weakness, while maintaining stable allograft function. PMID- 26228744 TI - Genome plasticity in filamentous plant pathogens contributes to the emergence of novel effectors and their cellular processes in the host. AB - Plant diseases cause extensive yield loss of crops worldwide, and secretory 'warfare' occurs between plants and pathogenic organisms all the time. Filamentous plant pathogens have evolved the ability to manipulate host processes and facilitate colonization through secreting effectors inside plant cells. The stresses from hosts and environment can drive the genome dynamics of plant pathogens. Remarkable advances in plant pathology have been made owing to these adaptable genome regions of several lineages of filamentous phytopathogens. Characterization new effectors and interaction analyses between pathogens and plants have provided molecular insights into the plant pathways perturbed during the infection process. In this mini-review, we highlight promising approaches of identifying novel effectors based on the genome plasticity. We also discuss the interaction mechanisms between plants and their filamentous pathogens and outline the possibilities of effector gene expression under epigenetic control that will be future directions for research. PMID- 26228745 TI - Appendectomy may delay Parkinson's disease Onset. AB - BACKGROUND: Alpha-synuclein (alpha-Syn) is particularly abundant in the vermiform appendix, which makes this structure an anatomical candidate for the initiation of Parkinson's disease (PD) pathology. We hypothesized that history of appendectomy might affect PD clinical onset. METHODS: A total of 295 PD patients enrolled in a comprehensive observational study were asked about past history of appendectomy. Cox's regression, with a time-dependent covariate, explored the effects of appendectomy on age at PD onset. RESULTS: Thirty-four patients (11.5%) had appendectomy before PD onset. There was no significant effect of appendectomy on age at PD onset for the entire cohort (P = 0.153). However, among patients with late onset (>=55 years), we found evidence that those with past appendectomy had more years of life without PD symptoms than patients without appendectomy (P = 0.040). No association was found for the young-onset group (P = 0.663). CONCLUSIONS: An apparent relationship was observed between appendectomy and PD onset in the late PD cohort. PMID- 26228747 TI - NCI-MATCH trial pushes cancer umbrella trial paradigm. PMID- 26228746 TI - Glutamine-Loaded Liposomes: Preliminary Investigation, Characterization, and Evaluation of Neutrophil Viability. AB - Glutamine has received attention due to its ability to ameliorate the immune system response. Once conventional liposomes are readily recognized and captured by immune system cells, the encapsulation of glutamine into those nanosystems could be an alternative to reduce glutamine dosage and target then to neutrophils. Our goals were to nanoencapsulate glutamine into conventional liposomes (Gln-L), develop an analytical high-performance liquid chromatography (HPLC) method for its quantification, and evaluate the viability of neutrophils treated with Gln-L. Liposomes were prepared using the thin-film hydration technique followed by sonication and characterized according to pH, mean size, zeta potential, and drug encapsulation efficiency (EE%). We also aimed to study the effect of liposomal constituent concentrations on liposomal characteristics. The viability of neutrophils was assessed using flow cytometry after intraperitoneal administration of free glutamine (Gln), Gln-L, unloaded-liposome (UL), and saline solution as control (C) in healthy Wistar rats. The selected liposomal formulation had a mean vesicle size of 114.65 +/- 1.82 nm with a polydispersity index of 0.30 +/- 0.00, a positive surface charge of 36.30 +/- 1.38 mV, and an EE% of 39.49 +/- 0.74%. The developed chromatographic method was efficient for the quantification of encapsulated glutamine, with a retention time at 3.8 min. A greater viability was observed in the group treated with glutamine encapsulated compared to the control group (17%), although neutrophils remain viable in all groups. Thus, glutamine encapsulated into liposomes was able to increase the number of viable neutrophils at low doses, thereby representing a promising strategy for the treatment of immunodeficiency conditions. PMID- 26228748 TI - Bacteriophage therapies re-enter clinical trials. PMID- 26228752 TI - Pierre Meulien. PMID- 26228753 TI - Target validation: Genetic information adds supporting weight. PMID- 26228756 TI - Inflammatory diseases: Adding insult to allergy. PMID- 26228760 TI - Infant sleep and feeding patterns are associated with maternal sleep, stress, and depressed mood in women with a history of major depressive disorder (MDD). AB - Our goal was to examine associations of infant sleep and feeding patterns with maternal sleep and mood among women at risk for postpartum depression. Participants were 30 women (age +/- SD = 28.3 +/- 5.1 years) with a history of MDD (but not in a mood episode at enrollment) who completed daily sleep diaries, wore wrist actigraphs to estimate sleep, and had their mood assessed with the Hamilton Depression Rating Scale (HAM-D-17) during four separate weeks of the perinatal period (33 weeks pregnancy and weeks 2, 6, and 16 postpartum). They logged their infants' sleep and feeding behaviors daily and reported postnatal stress on the Childcare Stress Inventory (CSI) at week 16. Mothers' actigraphically estimated sleep showed associations with infant sleep and feeding patterns only at postpartum week 2. Shorter duration of the longest infant-sleep bout was associated with shorter maternal sleep duration (p = .02) and lower sleep efficiency (p = .04), and maternal sleep efficiency was negatively associated with the number of infant-sleep bouts (p = .008) and duration of infant feeding (p = .008). Neither infant sleep nor feeding was associated with maternal sleep at 6 or 16 weeks, but more disturbed infant sleep and more frequent feeding at 6 weeks were associated with higher HAM-D scores at 6 and 16 weeks and higher CSI scores. Sleep in the mother-infant dyad is most tightly linked in the early postpartum weeks, but mothers continue to experience disturbed sleep and infant sleep and feeding behaviors continue to be associated with mothers' depressive symptoms and stress ratings as long as 16 weeks postpartum. These data imply that interventions designed to improve maternal sleep and postpartum mood should include both mothers and infants because improving infant sleep alone is not likely to improve maternal sleep, and poor infant sleep is linked to postpartum depression and stress. PMID- 26228761 TI - The addition of bromine and iodine to palladacyclopentadienyl complexes bearing bidentate heteroditopic P-N spectator ligands derived from differently substituted quinolinic frames. The unexpected evolution of the reaction. AB - We have synthesized two palladacyclopentadienyl derivatives bearing bidentate ligands heteroditopic 8-(diphenylphosphino)quinoline or 8-(diphenylphosphino)-2 methylquinoline. We have reacted the palladacyclopentadienyl complexes with Br2 and I2 to gain clues on the formation mechanism of the corresponding sigma butadienyl derivatives. We were able to obtain the pure sigma-butadienyl derivative only in the case of Br2 reacting with the palladacyclopentadienyl complex bearing the unsubstituted quinoline. However, an equilibrium mixture of the sigma-butadienyl and a novel zwitterionic species was obtained when the same complex reacts with I2. Furthermore, we have obtained exclusively an unprecedented zwitterionic complex when I2 reacts with the palladacyclopentadienyl complex bearing the substituted quinoline and a different ratio of an equilibrium mixture of sigma-butadienyl and the zwitterionic species when the latter derivative reacts with Br2. The solid state structures of one sigma-butadienyl complex and of the two novel zwitterionic derivatives were determined and an interpretation of the observed reactivity based on kinetic data and a computational study has been suggested. PMID- 26228762 TI - BMI, eating habits and sleep in relation to salivary counts of mutans streptococci in children - the IDEFICS Sweden study. AB - OBJECTIVE: The objective of the present study was to investigate the association between salivary counts of mutans streptococci (MS) and children's weight status, while considering associated covariates. MS ferments carbohydrates from the diet and contributes to caries by lowering the pH in dental plaque. In adults, high counts of MS in saliva have been associated with overweight, but this has not been shown in children. DESIGN: Cross-sectional study investigating salivary counts of MS, BMI Z-score, waist circumference, meal frequency, sugar propensity and sleep duration, in children. SETTING: West Sweden. SUBJECTS: Children (n 271) aged 4-11 years. RESULTS: Medium-high counts of MS were positively associated with higher BMI Z-score (OR=1.6; 95% CI 1.1, 2.3). Positive associations were also found between medium-high counts of MS and more frequent meals per day (OR=1.5; 95% CI 1.1, 2.2), greater percentage of sugar-rich foods consumed (OR=1.1; 95% CI 1.0, 1.3) and female sex (OR=2.4; 95% CI 1.1, 5.4). A negative association was found between medium-high counts of MS and longer sleep duration (OR=0.5; 95% CI 0.3, 1.0). CONCLUSIONS: BMI Z-score was associated with counts of MS. Promoting adequate sleep duration and limiting the intake frequency of sugar rich foods and beverages could provide multiple benefits in public health interventions aimed at reducing dental caries and childhood overweight. PMID- 26228759 TI - Combination cancer immunotherapy and new immunomodulatory targets. AB - Targeting immune checkpoints such as programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has achieved noteworthy benefit in multiple cancers by blocking immunoinhibitory signals and enabling patients to produce an effective antitumour response. Inhibitors of CTLA4, PD1 or PDL1 administered as single agents have resulted in durable tumour regression in some patients, and combinations of PD1 and CTLA4 inhibitors may enhance antitumour benefit. Numerous additional immunomodulatory pathways as well as inhibitory factors expressed or secreted by myeloid and stromal cells in the tumour microenvironment are potential targets for synergizing with immune checkpoint blockade. Given the breadth of potential targets in the immune system, critical questions to address include which combinations should move forward in development and which patients will benefit from these treatments. This Review discusses the leading drug targets that are expressed on tumour cells and in the tumour microenvironment that allow enhancement of the antitumour immune response. PMID- 26228764 TI - Impact of the HITECH Act on physicians' adoption of electronic health records. AB - BACKGROUND AND OBJECTIVE: The Health Information Technology for Economic and Clinical Health (HITECH) Act has distributed billions of dollars to physicians as incentives for adopting certified electronic health records (EHRs) through the meaningful use (MU) program ultimately aimed at improving healthcare outcomes. The authors examine the extent to which the MU program impacted the EHR adoption curve that existed prior to the Act. METHODS: Bass and Gamma Shifted Gompertz (G/SG) diffusion models of the adoption of "Any" and "Basic" EHR systems in physicians' offices using consistent data series covering 2001-2013 and 2006 2013, respectively, are estimated to determine if adoption was stimulated during either a PrePay (2009-2010) period of subsidy anticipation or a PostPay (2011 2013) period when payments were actually made. RESULTS: Adoption of Any EHR system may have increased by as much as 7 percentage points above the level predicted in the absence of the MU subsidies. This estimate, however, lacks statistical significance and becomes smaller or negative under alternative model specifications. No substantial effects are found for Basic systems. The models suggest that adoption was largely driven by "imitation" effects (q-coefficient) as physicians mimic their peers' technology use or respond to mandates. Small and often insignificant "innovation" effects (p-coefficient) are found suggesting little enthusiasm by physicians who are leaders in technology adoption. CONCLUSION: The authors find weak evidence of the impact of the MU program on EHR uptake. This is consistent with reports that many current EHR systems reduce physician productivity, lack data sharing capabilities, and need to incorporate other key interoperability features (e.g., application program interfaces). PMID- 26228763 TI - Extramedullary hematopoiesis is associated with lower cardiac iron loading in chronically transfused thalassemia patients. AB - The aim of this study was to evaluate, in a large cohort of chronically transfused patients, whether the presence of extramedullary hematopoiesis (EMH) accounts for the typical patterns of cardiac iron distribution and/or cardiac function parameters. We retrospectively selected 1,266 thalassemia major patients who had undergone regular transfusions (611 men and 655 women; mean age: 31.3 +/- 8.9 years, range: 4.2-66.6 years) and were consecutively enrolled within the Myocardial Iron Overload in Thalassemia network. The presence of EMH was evaluated based on steady-state free precession sequences; cardiac and liver iron overloads were quantified using a multiecho T2* approach; cardiac function parameters and pulmonary diameter were quantified using the steady-state free precession sequences; and myocardial fibrosis was evaluated using the late gadolinium enhancement technique. EMH was detected in 167 (13.2%) patients. The EMH+ patients had significantly lower cardiac iron overload than that of the EMH- patients (P = 0.003). The patterns of cardiac iron distribution were significantly different in the EMH+ and EMH- patients (P < 0.0001), with a higher prevalence of patients with no myocardial iron overload and heterogeneous myocardial iron overload and no significant global heart iron in the EMH+ group EMH+ patients had a significantly higher left ventricle mass index (P = 0.001) and a significantly higher pulmonary artery diameter (P = 0.002). In conclusion, in regularly transfused thalassemia patients, EMH was common and was associated with a thalassemia intermedia-like pattern of cardiac iron deposition despite regular transfusion therapy. PMID- 26228765 TI - An in silico method to identify computer-based protocols worthy of clinical study: An insulin infusion protocol use case. AB - OBJECTIVE: Develop an efficient non-clinical method for identifying promising computer-based protocols for clinical study. An in silico comparison can provide information that informs the decision to proceed to a clinical trial. The authors compared two existing computer-based insulin infusion protocols: eProtocol insulin from Utah, USA, and Glucosafe from Denmark. MATERIALS AND METHODS: The authors used eProtocol-insulin to manage intensive care unit (ICU) hyperglycemia with intravenous (IV) insulin from 2004 to 2010. Recommendations accepted by the bedside clinicians directly link the subsequent blood glucose values to eProtocol insulin recommendations and provide a unique clinical database. The authors retrospectively compared in silico 18,984 eProtocol-insulin continuous IV insulin infusion rate recommendations from 408 ICU patients with those of Glucosafe, the candidate computer-based protocol. The subsequent blood glucose measurement value (low, on target, high) was used to identify if the insulin recommendation was too high, on target, or too low. RESULTS: Glucosafe consistently provided more favorable continuous IV insulin infusion rate recommendations than eProtocol insulin for on target (64% of comparisons), low (80% of comparisons), or high (70% of comparisons) blood glucose. Aggregated eProtocol-insulin and Glucosafe continuous IV insulin infusion rates were clinically similar though statistically significantly different (Wilcoxon signed rank test P = .01). In contrast, when stratified by low, on target, or high subsequent blood glucose measurement, insulin infusion rates from eProtocol-insulin and Glucosafe were statistically significantly different (Wilcoxon signed rank test, P < .001), and clinically different. DISCUSSION: This in silico comparison appears to be an efficient nonclinical method for identifying promising computer-based protocols. CONCLUSION: Preclinical in silico comparison analytical framework allows rapid and inexpensive identification of computer-based protocol care strategies that justify expensive and burdensome clinical trials. PMID- 26228767 TI - Fosmidomycin as an antimalarial drug: a meta-analysis of clinical trials. AB - With first indications of resistance against artemisinin compounds, the development of novel alternative antimalarials remains an urgent need. One candidate is fosmidomycin (Fos), a phosphonic acid derivative. This PRISMA guideline-adhering and PROSPERO-registered systematic review and meta-analysis provides an overview of the state-of-the-art of the clinical development of Fos as an antimalarial. Pooling six clinical trials of Fos against uncomplicated malaria in African children yielded an overall day 28 cure rate of 85% (95% CI: 71-98%); a parasite clearance time of 39 h; and a fever clearance time of 30 h. In four adult cohorts, the corresponding values were 70% (95% CI: 40-100%), 49 and 42 h, respectively. Data suggest that besides the partner drug, formulation determines efficacy. We advocate further clinical development of Fos combinations. PROSPERO registration number: CRD42014013688. PMID- 26228766 TI - Integrating community-based participatory research and informatics approaches to improve the engagement and health of underserved populations. AB - OBJECTIVE: We compare 5 health informatics research projects that applied community-based participatory research (CBPR) approaches with the goal of extending existing CBPR principles to address issues specific to health informatics research. MATERIALS AND METHODS: We conducted a cross-case analysis of 5 diverse case studies with 1 common element: integration of CBPR approaches into health informatics research. After reviewing publications and other case related materials, all coauthors engaged in collaborative discussions focused on CBPR. Researchers mapped each case to an existing CBPR framework, examined each case individually for success factors and barriers, and identified common patterns across cases. RESULTS: Benefits of applying CBPR approaches to health informatics research across the cases included the following: developing more relevant research with wider impact, greater engagement with diverse populations, improved internal validity, more rapid translation of research into action, and the development of people. Challenges of applying CBPR to health informatics research included requirements to develop strong, sustainable academic-community partnerships and mismatches related to cultural and temporal factors. Several technology-related challenges, including needs to define ownership of technology outputs and to build technical capacity with community partners, also emerged from our analysis. Finally, we created several principles that extended an existing CBPR framework to specifically address health informatics research requirements. CONCLUSIONS: Our cross-case analysis yielded valuable insights regarding CBPR implementation in health informatics research and identified valuable lessons useful for future CBPR-based research. The benefits of applying CBPR approaches can be significant, particularly in engaging populations that are typically underserved by health care and in designing patient-facing technology. PMID- 26228768 TI - Rolling circle replication for engineering drug delivery carriers. PMID- 26228769 TI - Gene therapy with nonviral poly(epsilon-caprolactone) nanoparticles. PMID- 26228770 TI - A pharmaceutics perspective on drug delivery to the nail: recent advances and challenges. PMID- 26228771 TI - Suppression of the reticuloendothelial system using lambda-carrageenan to prolong the circulation of gold nanoparticles. AB - AIM: Gold nanoparticles are employed for imaging and treatment of surgically inaccessible tumors owing to their inherent optical absorption and ability to extravasate through intravenous distribution. These nanoparticles are cleared from the blood by the reticuloendothelial system (RES) as expected given their size. MATERIALS & METHODS: This study demonstrates the effects of RES blockade through the intravenous administration of lambda-carrageenan, resulting in a decrease in the median clearance rate from 18.9 (95% CrI: 15.9-22.6) to 11.2 (95% CrI: 8.8-13.9) MUl/min and an increase in nanoparticle circulation half-life t(1/2)( = 264 +/- 73 vs 160 +/- 22 min; p < 0.01). RESULTS: This 59.3% decrease in clearance is greater than the 15% previously reported for liposomes [ 1 ]. CONCLUSION: The primary benefit of nontoxic RES blockade is to increase the circulation time, where traditional particle modification is ineffective or impractical. PMID- 26228772 TI - Effects of lipid composition on the properties of doxorubicin-loaded liposomes. AB - BACKGROUND: The liposomal lipid composition of doxorubicin-loaded liposome likely will influence its pharmacological activity. Results & methodology: We prepared 18 formulations of doxorubicin-loaded liposomes in which the lipid composition was varied. It was indicated that the intracellular uptake of doxorubicin is the primary property of doxorubicin-loaded liposome that affects its cytotoxicity in vitro. Furthermore, the release rate of doxorubicin from liposome and the biological activity of the lipid itself also affected the cytotoxicity. SUMMARY: These findings provide an insight into how lipid composition influences the cytotoxicity of the doxorubicin-loaded liposomes. Our results provide valuable information that should help to enhance the therapeutic efficacy of liposomal anticancer drug products by optimizing their formulations. PMID- 26228774 TI - Recent developments in silicones for topical and transdermal drug delivery. AB - Silicones have been used in medicines, cosmetics and medical devices for over 60 years. Polydimethylsiloxanes are polymers that are typically used either as an active in oral drug products or as excipients in topical and transdermal drug products. Inherent characteristics like hydrophobicity, adhesion and aesthetics allow silicones to offer function and performance to drug products. Recent technologies like swollen crosslinked silicone elastomer blend networks, sugar siloxanes, amphiphilic resin linear polymers and silicone hybrid pressure sensitive adhesives promise potential performance advantages and improved drug delivery efficacy. This article presents a review of recent silicone material developments focusing on their function as excipients influencing drug delivery in topical and transdermal systems. PMID- 26228775 TI - Challenges and new strategies for therapeutic peptide delivery to the CNS. AB - Therapeutic peptides represent a largely untapped resource in medicine today, especially in the central nervous system. Despite their ease of design and remarkably high target specificity, it is difficult to deliver them beyond the blood-brain barrier or into the required intracellular compartments. In addition, the instability of these peptides in vivo precludes their use to combat the symptoms of numerous neurological disorders including Alzheimer's disease and spinocerebellar ataxia. In this review, we aim to characterize recent advances in the delivery of therapeutic peptides to the central nervous system past the blood brain barrier and discuss the advantages and disadvantages of the examined methods as well as explore new potential directions. PMID- 26228776 TI - Chitosan coatings to control release and target tissues for therapeutic delivery. AB - The natural biopolymer chitosan has versatile applications in therapeutic delivery. Coating drug delivery matrices or biomaterials with chitosan offers several advantages in drug delivery, including control of drug release, slowing degradation rate and improving biocompatibility. Advanced uses of chitosan in coating form include targeting drug delivery vehicles to specific tissue as well as providing a stimulus-controlled release response. The present review summarizes the current applications of chitosan coatings in the context of different biomaterial delivery technologies, as well as future directions of chitosan coatings for drug delivery technologies under development. PMID- 26228777 TI - Emerging therapeutic delivery capabilities and challenges utilizing enzyme/protein packaged bacterial vesicles. AB - Nanoparticle-based therapeutics are poised to play a critical role in treating disease. These complex multifunctional drug delivery vehicles provide for the passive and active targeted delivery of numerous small molecule, peptide and protein-derived pharmaceuticals. This article will first discuss some of the current state of the art nanoparticle classes (dendrimers, lipid-based, polymeric and inorganic), highlighting benefits/drawbacks associated with their implementation. We will then discuss an emerging class of nanoparticle therapeutics, bacterial outer membrane vesicles, that can provide many of the nanoparticle benefits while simplifying assembly. Through molecular biology techniques; outer membrane vesicle hijacking potentially allows for stringent control over nanoparticle production allowing for targeted protein packaged nanoparticles to be fully synthesized by bacteria. PMID- 26228778 TI - A path analysis study of retention of healthcare professionals in urban India using health information technology. AB - BACKGROUND: Healthcare information technology (HIT) applications are being ubiquitously adopted globally and have been indicated to have effects on certain dimensions of recruitment and retention of healthcare professionals. Retention of healthcare professionals is affected by their job satisfaction (JS), commitment to the organization and intention to stay (ITS) that are interlinked with each other and influenced by many factors related to job, personal, organization, etc. The objectives of the current study were to determine if HIT was one among the factors and, if so, propose a probable retention model that incorporates implementation and use of HIT as a strategy. METHODS: This was a cross-sectional survey study covering 20 hospitals from urban areas of India. The sample (n = 586) consisted of doctors, nurses, paramedics and hospital administrators. Data was collected through a structured questionnaire. Factors affecting job satisfaction were determined. Technology acceptance by the healthcare professionals was also determined. Interactions between the factors were predicted using a path analysis model. RESULTS: The overall satisfaction rate of the respondents was 51 %. Based on factor analysis method, 10 factors were identified for JS and 9 factors for ITS. Availability and use of information technology was one factor that affected JS. The need for implementing technology influenced ITS through work environment and career growth. Also, the study indicated that nearly 70 % of the respondents had awareness of HIT, but only 40 % used them. The importance of providing training for HIT applications was stressed by many respondents. CONCLUSION: The results are in agreement with literature studies exploring job satisfaction and retention among healthcare professionals. Our study documented a relatively medium level of job satisfaction among the healthcare professionals in the urban area. Information technology was found to be one among the factors that can plausibly influence their job satisfaction and intention to stay. Based on the results of the study, a retention strategy has been suggested that utilizes implementation of HIT and provision of training to influence the retention of healthcare workers. PMID- 26228773 TI - Delivery of drugs bound to erythrocytes: new avenues for an old intravascular carrier. AB - For several decades, researchers have used erythrocytes for drug delivery of a wide variety of therapeutics in order to improve their pharmacokinetics, biodistribution, controlled release and pharmacodynamics. Approaches include encapsulation of drugs within erythrocytes, as well as coupling of drugs onto the red cell surface. This review focuses on the latter approach, and examines the delivery of red blood cell (RBC)-surface-bound anti-inflammatory, anti-thrombotic and anti-microbial agents, as well as RBC carriage of nanoparticles. Herein, we discuss the progress that has been made in surface loading approaches, and address in depth the issues relevant to surface loading of RBC, including intrinsic features of erythrocyte membranes, immune considerations, potential surface targets and techniques for the production of affinity ligands. PMID- 26228779 TI - Metal backed fixed-bearing unicondylar knee arthroplasties using minimal invasive surgery: a promising outcome analysis of 132 cases. AB - BACKGROUND: Unicondylar knee arthroplasty (UKA) is a well-established treatment for isolated osteoarthritis (OA) of the medial knee compartment. Aim of this retrospective study was to evaluate the early clinical and radiological outcomes of a consecutive series of patients treated with medial metal backed fixed bearing UKA. Furthermore, the influence of the component orientation on the outcome was analyzed. METHODS: From 09/2006 to 11/2010 106 patients (132 knees; 69 +/- 9 years) were treated using a metal backed fixed-bearing UKA with a MIS approach. All patients underwent a standardized clinical and radiological follow up at 6 weeks, 1, 2 and 5 years. Mean follow-up was 3.4 +/- 1.0 years. Two patients (three UKAs) deceased and two patients (two UKAs) were lost to follow up. Three different survival analyses were performed using three different endpoints defining failure: (a) revision with exchange of any UKA component (b) aseptic loosening and (c), a worst case scenario, where it was assumed that all progressive radiolucencies would lead to aseptic loosening and thus these were additionally counted. Clinical outcome was assessed using the American knee society score (AKS) and the Oxford knee score (OKS). Radiographic analysis was done according to the American Knee Society Evaluation and Scoring System adapted for UKA and correlated with the AKS and OKS. RESULTS: Five UKAs (3.8 %) were revised to total knee arthroplasties (TKAs) after a median of 25 (10-33) months. Five year survival was 95.2, 97.5 and 87.7% for the aforementioned endpoints. At final follow-up the median AKS knee score was 99 (50-100) points and the median AKS function score was 100 (60-100) points. The median OKS was 43 (8-48) points. Clinical outcome was independent of the component orientation. CONCLUSION: Fixed bearing UKA showed excellent clinical and radiological results at up to 5 years follow-up. Outcome was independent of component orientation. PMID- 26228780 TI - The ISPD Cardiovascular and Metabolic Guideline for Adults Treated with Peritoneal Dialysis. PMID- 26228781 TI - Staphylococcus aureus Infections: Adipocytes Join the Fight. PMID- 26228782 TI - ISPD Cardiovascular and Metabolic Guidelines in Adult Peritoneal Dialysis Patients Part I - Assessment and Management of Various Cardiovascular Risk Factors. AB - Cardiovascular disease contributes significantly to the adverse clinical outcomes of peritoneal dialysis (PD) patients. Numerous cardiovascular risk factors play important roles in the development of various cardiovascular complications. Of these, loss of residual renal function is regarded as one of the key cardiovascular risk factors and is associated with an increased mortality and cardiovascular death. It is also recognized that PD solutions may incur significant adverse metabolic effects in PD patients. The International Society for Peritoneal Dialysis (ISPD) commissioned a global workgroup in 2012 to formulate a series of recommendations regarding lifestyle modification, assessment and management of various cardiovascular risk factors, as well as management of the various cardiovascular complications including coronary artery disease, heart failure, arrhythmia (specifically atrial fibrillation), cerebrovascular disease, peripheral arterial disease and sudden cardiac death, to be published in 2 guideline documents. This publication forms the first part of the guideline documents and includes recommendations on assessment and management of various cardiovascular risk factors. The documents are intended to serve as a global clinical practice guideline for clinicians who look after PD patients. The ISPD workgroup also identifies areas where evidence is lacking and further research is needed. PMID- 26228784 TI - Malfunction of Peritoneal Catheters by Proliferation of Vascularized Fibrous Tissue. PMID- 26228783 TI - ISPD Cardiovascular and Metabolic Guidelines in Adult Peritoneal Dialysis Patients Part II - Management of Various Cardiovascular Complications. AB - Cardiovascular mortality has remained high in patients on peritoneal dialysis (PD) due to the high prevalence of various cardiovascular complications including coronary artery disease, left ventricular hypertrophy and dysfunction, heart failure, arrhythmia (especially atrial fibrillation), cerebrovascular disease, and peripheral arterial disease. In addition, nearly a quarter of PD patients develop sudden cardiac death as the terminal life event. Thus, it is essential to identify effective treatment that may lower cardiovascular mortality and improve survival of PD patients. The International Society for Peritoneal Dialysis (ISPD) commissioned a global workgroup in 2012 to formulate a series of recommendation statements regarding lifestyle modification, assessment and management of various cardiovascular risk factors, and management of the various cardiovascular complications to be published in 2 guideline documents. This publication forms the second part of the guideline documents and includes recommendation statements on the management of various cardiovascular complications in adult chronic PD patients. The documents are intended to serve as a global clinical practice guideline for clinicians who look after PD patients. We also define areas where evidence is clearly deficient and make suggestions for future research in each specific area. PMID- 26228785 TI - Serum Concentrations of p-Cresyl Sulfate and Indoxyl Sulfate, but Not Inflammatory Markers, Increase in Incident Peritoneal Dialysis Patients in Parallel with Loss of Residual Renal Function. PMID- 26228786 TI - Molecular characterization of HCMV-specific immune responses: Parallels between CD8(+) T cells, CD4(+) T cells, and NK cells. AB - CD8(+) T cells are important for immunity against human cytomegalovirus (HCMV). The HCMV-specific CD8(+) T-cell response is characterized by the accumulation of terminally differentiated effector cells that have downregulated the costimulatory molecules CD27 and CD28. These HCMV-specific CD8(+) T cells maintain high levels of cytotoxic molecules such as granzyme B and rapidly produce the inflammatory cytokine IFN-gamma upon activation. Remarkably, HCMV specific CD8(+) T cells are able to persist long term as fully functional effector cells, suggesting a unique differentiation pathway that is distinct from the formation of memory CD8(+) T cells after infection with acute viruses. In this review, we aim to highlight the most recent developments in HCMV-specific CD8(+) T-cell differentiation, maintenance, tissue distribution, metabolism and function. HCMV also induces the differentiation of effector CD4(+) T cells and NK cells, which share characteristics with HCMV-specific CD8(+) T cells. We propose that the overlap in differentiation of NK cells, CD4(+) and CD8(+) T cells after HCMV infection may be regulated by a shared transcriptional machinery. A better understanding of the molecular framework of HCMV-specific CD8(+) T-cell responses may benefit vaccine design, as these cells uniquely combine the capacity to rapidly respond to infection with long-term survival. PMID- 26228787 TI - A prescription for sustaining community engagement in malaria elimination on Aneityum Island, Vanuatu: an application of Health Empowerment Theory. AB - BACKGROUND: Community engagement has contributed to disease control and elimination in many countries. Community engagement in malaria elimination (ME) on Aneityum Island has been sustained since its introduction in the early 1990s. Capacity developed within this population has led to a health empowered community response. Health Empowerment Theory (HET) can account for the innovative community actions and capacity development efforts taken to realize and sustain meaningful changes in well-being. This study used the HET framework to investigate participant perceptions of ME efforts on the island focusing on two HET elements, personal and social-contextual resources. The purpose of this study was to explore the role of empowerment as a critical element of community engagement. METHODS: Six focus group discussions, ten key informant interviews and 17 in-depth interviews were conducted in July 2012 on Aneityum. Both deductive and inductive approaches to qualitative content analysis were used to identify themes, which were condensed, coded and classified based on the HET elements above. RESULTS: Awareness and use of personal and social-contextual resources played an important role in ME efforts. Most participants shared their knowledge to prevent malaria reintroduction. Many participants reported their skills needed for behavioral maintenance, problem-solving or leadership. Participants who perceived a threat took preventive actions even in the dry season. Community leaders focused on second generation capacity development. A local health coalition provided ME services. Members of networks were sources of information and assistance. Face-to-face was the preferred method of communication. Barriers to engagement (e.g., financial difficulties, health literacy issues and underdeveloped infrastructure) were minimized through active collaboration and mutual assistance. CONCLUSIONS: In the community engagement continuum, health empowerment develops incrementally overtime as people gain their knowledge and skills, form coalitions and develop collaborative networks (social capital) to make decisions and take action for change. Community engagement, which facilitates local personal and social-contextual resource development, has potential for ME and multilevel empowerment through community based capacity development processes. These self-empowered communities have written and will continue to write a 'prescription' for sustaining high levels of engagement. PMID- 26228789 TI - Pro-Apoptotic Effects of Plasma from Patients with Cardiorenal Syndrome on Human Tubular Cells. AB - BACKGROUND: The pathophysiology of Cardiorenal Syndrome Type 1 (CRS1) is widely studied, although the mechanisms by which renal tubular epithelial cells (TECs) cease to proliferate and embark upon terminal differentiation, following the initial insult of heart failure (HF), remain a key target. This study seeks to provide insight into the pathophysiological pathways in CRS1; we evaluated in vitro the effects of CRS1 plasma on TECs. METHODS: We enrolled 40 acute HF patients and 15 controls (CTR) without HF or acute kidney injury (AKI). Ten out of 40 HF patients exhibited AKI at the time of admission for HF or developed AKI during hospitalization and were classified as CRS1. In vitro, cell viability, DNA fragmentation and caspase-3 levels were investigated in TECs incubated with HF, CRS1, and CTR plasma. We assessed inflammatory cytokines and NGAL expression at the gene and protein levels. RESULTS: We observed a marked pro-apoptotic activity and a significantly increased in vitro level of apoptosis in TECs incubated with plasma from CRS1 patients compared to HF and CTR (p < 0.01). In the CRS1 group, the mRNA expression of IL-6, IL-18 and NGAL resulted significantly higher in TECs incubated with CRS1 plasma compared with those incubated with plasma from HF and CTR (p < 0.01). IL-6, IL-18, NGAL, and RANTES levels were significantly higher in TECs supernatant incubated with CRS1 plasma compared with HF patients and CTR plasma (p < 0.01). CONCLUSION: In vitro exposure to plasma from CRS1 patients altered the expression profile of TECs characterized by increases in proinflammatory mediators, release of tubular damage markers, and apoptosis. PMID- 26228788 TI - Neoplastic transformation of porcine mammary epithelial cells in vitro and tumor formation in vivo. AB - BACKGROUND: The mammary glands of pigs share many functional and morphological similarities with the breasts of humans, raising the potential of their utility for research into the mechanisms underlying normal mammary function and breast carcinogenesis. Here we sought to establish a model for the efficient manipulation and transformation of porcine mammary epithelial cells (pMEC) in vitro and tumor growth in vivo. METHODS: We utilized a vector encoding the red florescent protein tdTomato to transduce populations of pMEC from Yorkshire Hampshire crossbred female pigs in vitro and in vivo. Populations of primary pMEC were then separated by FACS using markers to distinguish epithelial cells (CD140a ) from stromal cells (CD140a+), with or without further enrichment for basal and luminal progenitor cells (CD49f+). These separated pMEC populations were transduced by lentivirus encoding murine polyomavirus T antigens (Tag) and tdTomato and engrafted to orthotopic or ectopic sites in immunodeficient NOD.Cg Prkdc (scid) Il2rg (tm1Wjl) /SzJ (NSG) mice. RESULTS: We demonstrated that lentivirus effectively transduces pMEC in vitro and in vivo. We further established that lentivirus can be used for oncogenic-transformation of pMEC ex vivo for generating mammary tumors in vivo. Oncogenic transformation was confirmed in vitro by anchorage-independent growth, increased cell proliferation, and expression of CDKN2A, cyclin A2 and p53 alongside decreased phosphorylation of Rb. Moreover, Tag-transformed CD140a- and CD140a-CD49f + pMECs developed site specific tumors of differing histopathologies in vivo. CONCLUSIONS: Herein we establish a model for the transduction and oncogenic transformation of pMEC. This is the first report describing a porcine model of mammary epithelial cell tumorigenesis that can be applied to the study of human breast cancers. PMID- 26228790 TI - Combination of quantitative analysis and chemometric analysis for the quality evaluation of three different frankincenses by ultra high performance liquid chromatography and quadrupole time of flight mass spectrometry. AB - Frankincense has gained increasing attention in the pharmaceutical industry because of its pharmacologically active components such as boswellic acids. However, the identity and overall quality evaluation of three different frankincense species in different Pharmacopeias and the literature have less been reported. In this paper, quantitative analysis and chemometric evaluation were established and applied for the quality control of frankincense. Meanwhile, quantitative and chemometric analysis could be conducted under the same analytical conditions. In total 55 samples from four habitats (three species) of frankincense were collected and six boswellic acids were chosen for quantitative analysis. Chemometric analyses such as similarity analysis, hierarchical cluster analysis, and principal component analysis were used to identify frankincense of three species to reveal the correlation between its components and species. In addition, 12 chromatographic peaks have been tentatively identified explored by reference substances and quadrupole time-of-flight mass spectrometry. The results indicated that the total boswellic acid profiles of three species of frankincense are similar and their fingerprints can be used to differentiate between them. PMID- 26228791 TI - Serial peripheral nerve ultrasound in Guillain-Barre syndrome. AB - OBJECTIVE: To assess the longitudinal changes of nerve ultrasound in Guillain Barre syndrome (GBS) patients. METHODS: We prospectively recruited 17 GBS patients and 17 age and gender-matched controls. Serial studies of their nerve conduction parameters and nerve ultrasound, documenting the cross-sectional areas (CSA), were performed at admission and repeated at several time points throughout disease course. RESULTS: Serial nerve ultrasound revealed significantly enlarged CSA in median, ulnar and sural nerves within the first 3 weeks of disease onset. Longitudinal evaluation revealed an improvement in the nerve CSA with time, reaching significance in the ulnar and sural nerves after 12 weeks. There was no significant difference between the demyelinating and axonal subtypes. There was also no significant correlation found between nerve CSA and neurophysiological parameters or changes in nerve CSA and muscle strength. CONCLUSION: In GBS, serial studies of peripheral nerve ultrasound CSA are helpful to detect a gradual improvement in the nerve size. SIGNIFICANCE: Serial nerve ultrasound studies could serve as a useful tool in demonstrating nerve recovery in GBS. PMID- 26228792 TI - Sinonasal malignancies: A population-based analysis of site-specific incidence and survival. AB - OBJECTIVES/HYPOTHESIS: Sinonasal malignancies vary in behavior according to histology and anatomical location. Incidence, survival, and optimal treatment for these lesions are thus uncertain in various cases. Our objective was to utilize a national population-based registry to identify the most common sinonasal histopathologies by anatomical site, and subsequently analyze the data by incidence trends, survival rates, patient demographics, and treatment modalities. STUDY DESIGN: Retrospective analysis of the United States National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry. METHODS: The SEER database was examined for patients diagnosed with sinonasal malignancies between 1973 and 2011. Data were stratified according to anatomical site, incidence, survival, histology, staging, and patient demographics. Therapy-based outcomes were analyzed for cases from 1983 to 2011. RESULTS: A total of 13,295 patients were identified, with an incidence of 0.83 per 100,000 people. Males comprised 58.6% of cases. Whites represented 81.5% of cases, while blacks comprised 8.7%. Squamous cell carcinoma was the most common histology (41.9%) across all sites of the sinonasal tract. The most common anatomical site of malignancy was the nasal cavity (45.7%), and least common was the frontal sinus (1.2%). For single sites, 5-year disease-specific survival (DSS) was highest for nasal cavity tumors (67.1%) and lowest for overlapping sinus malignancies (37.6%). The overall 5-year DSS for all sinonasal malignancies was 53.7%. CONCLUSION: Sinonasal malignancies are rare entities with poor overall prognosis. By anatomical site, prognosis is best for nasal cavity cancers and worst for overlapping lesions. LEVEL OF EVIDENCE: 4. PMID- 26228794 TI - Circulating irisin is lower in gestational diabetes mellitus. AB - Irisin is a newly identified myokine. Several studies have reported irisin concentrations in patients with gestational diabetes mellitus (GDM), but because of smaller sample sizes, the data from previous reports showed a wide range in serum/plasma irisin. Therefore, the present investigation is designed to summarize a precise confidence interval of circulating irisin in participants with GDM from a cross-sectional study in Chinese population and a meta-analysis for validation. Serum irisin was tested in patients with GDM and healthy controls (newly diagnosed cases: 61 and matched controls: 61) in the cross-sectional study. The two groups of participants were matched for age and pregnancy duration. Furthermore, we did a comprehensive meta-analysis to confirm whether serum/plasma irisin differs between participants with GDM and controls. Articles reported "circulating irisin and GDM" in Medline, PubMed, and EMBase were obtained, with the key word "myokine" or "irisin". The comparison was analyzed by Review Manager 5.2. In the cross-sectional investigation, serum irisin showed a significant lower level in the GDM patients, compared with that in the control group. In the meta-analysis study, the summarized results of the present 5 studies in which 632 participants were included indicated that there was a lower level irisin of -58.68 ng/mL [95% confidence interval (CI)](-113.42, -3.93, P=0.04) in GDM patients than in the control group. The present cross-sectional investigation and meta-analysis is the first to show significant lower circulating irisin in subjects with GDM. PMID- 26228793 TI - Glass is a Viable Substrate for Precision Force Microscopy of Membrane Proteins. AB - Though ubiquitous in optical microscopy, glass has long been overlooked as a specimen supporting surface for high resolution atomic force microscopy (AFM) investigations due to its roughness. Using bacteriorhodopsin from Halobacterium salinarum and the translocon SecYEG from Escherichia coli, we demonstrate that faithful images of 2D crystalline and non-crystalline membrane proteins in lipid bilayers can be obtained on microscope cover glass following a straight-forward cleaning procedure. Direct comparison between AFM data obtained on glass and on mica substrates show no major differences in image fidelity. Repeated association of the ATPase SecA with the cytoplasmic protrusion of SecYEG demonstrates that the translocon remains competent for binding after tens of minutes of continuous AFM imaging. This opens the door for precision long-timescale investigations of the active translocase in near-native conditions and, more generally, for integration of high resolution biological AFM with many powerful optical techniques that require non-birefringent substrates. PMID- 26228795 TI - Resveratrol improved the spatial learning and memory in subclinical hypothyroidism rat induced by hemi-thyroid electrocauterization. AB - The major purpose of this study was to investigate the effect of resveratrol (RES) on the spatial learning and memory ability in subclinical hypothyroidism (SCH) rat model and the potential mechanism. A SCH rat model was induced by hemi thyroid electrocauterization and the activity of hypothalamus-pituitary-thyroid (HPT) axis was detected. The spatial learning and memory ability was tested using Morris water maze (MWM) and Y-maze. The protein expressions of synaptotagmin-1 (syt-1) and brain-derived neurotrophic factor (BDNF) in the hippocampus were measured via western blot. The results showed that SCH rat model was successfully duplicated. The SCH rats showed impaired learning and memory in the behavioral tests. However, these changes were reversed by the treatment of RES (15mg/kg) and levothyroxine (LT4). Moreover, RES treated rats exhibited reduced plasma TSH level and hypothalamic thyrotropin releasing hormone (TRH) mRNA expression, which suggested that the imbalance of HPT axis in the SCH rats could be reversed by RES treatment. Furthermore, RES treatment up-regulated the protein levels of syt-1 and BDNF in hippocampus. These findings indicated an amelioration effect of RES on the spatial learning and memory in the SCH rats, the mechanism of which might be involved with its ability of modifying the hyperactive HPT axis and up regulating the hippocampal hypo-expression of syt-1 and BDNF. PMID- 26228796 TI - Dose response signal detection under model uncertainty. AB - We investigate likelihood ratio contrast tests for dose response signal detection under model uncertainty, when several competing regression models are available to describe the dose response relationship. The proposed approach uses the complete structure of the regression models, but does not require knowledge of the parameters of the competing models. Standard likelihood ratio test theory is applicable in linear models as well as in nonlinear regression models with identifiable parameters. However, for many commonly used nonlinear dose response models the regression parameters are not identifiable under the null hypothesis of no dose response and standard arguments cannot be used to obtain critical values. We thus derive the asymptotic distribution of likelihood ratio contrast tests in regression models with a lack of identifiability and use this result to simulate the quantiles based on Gaussian processes. The new method is illustrated with a real data example and compared to existing procedures using theoretical investigations as well as simulations. PMID- 26228797 TI - Descriptive epidemiology of birth defects thought to arise by new mutation. AB - BACKGROUND: The current study is the first to examine the association of a broad range of sociodemographic factors with conditions thought to arise most of the time by de novo mutation. METHODS: Data were taken from 1999 to 2009 from the Texas Birth Defects Registry (TBDR), a statewide active surveillance program. We used Poisson regression to generate crude and adjusted measures of association; the latter included models with all variables and with a parsimonious subset of variables. RESULTS: There were 1694 cases with any of the phenotypes in the panel, 1100 cases in a subpanel with >=90% of cases thought to arise de novo, 523 with chromosomal deletion disorders, and 243 with imprinting disorders. In the most parsimonious models, there was an increasing time trend in all groups except imprinting (p <= 0.01). Plurality (twins, triplets, etc.) was associated with greater risk of all groups except chromosomal deletions (p <= 0.01). Parental age showed strong trends with all groups; paternal age was most important for the total and imprinting groups (p <= 0.0001), and maternal age for the others (p <= 0.04). De novo mutation phenotypes were more prevalent among offspring of fathers who are non-Hispanic White compared with some other race/ethnic groups. CONCLUSION: This study suggests that birth defects arising by new mutation may be more prevalent among offspring of older parents and in plural births. The increasing time pattern and race/ethnic pattern may be related to greater use of or access to genetic tests. This approach to mutation epidemiology seems feasible for birth defects registries to consider. PMID- 26228798 TI - An Enantioselective Synthesis of Spirobilactams through Copper-Catalyzed Intramolecular Double N-Arylation and Phase Separation. AB - Spirobicyclic structures are versatile building blocks for functional chiral molecules. An enantioselective synthesis of chiral spirobilactams via a copper catalyzed double N-arylation was developed. Amplification of solution ee by in situ precipitation of the racemate was observed with this method and enantioenriched spirobilactams were obtained with excellent ee values through simple solid-solution phase separation. PMID- 26228800 TI - What's new in heart failure in the patient with type 2 diabetes? AB - Type 2 diabetes mellitus (T2DM) is considered an independent risk factor of heart failure (HF). It has been observed that diabetics have a higher risk of heart failure than non-diabetics. However, many aspects are still unknown; for example, the existence of a particular myocardiopathy common to T2DM, the pathogenesis of the HF associated with T2DM that is still not sufficiently clear, its role in the prognosis of HF, or the influence of anti-diabetic treatments on the outcome of the HF. An attempt is made in this review to summarise all those findings that have been published in the past 5 years as regards this interesting question, placing special emphasis on those questions still unresolved. PMID- 26228799 TI - Computational modeling of Adelta-fiber-mediated nociceptive detection of electrocutaneous stimulation. AB - Sensitization is an example of malfunctioning of the nociceptive pathway in either the peripheral or central nervous system. Using quantitative sensory testing, one can only infer sensitization, but not determine the defective subsystem. The states of the subsystems may be characterized using computational modeling together with experimental data. Here, we develop a neurophysiologically plausible model replicating experimental observations from a psychophysical human subject study. We study the effects of single temporal stimulus parameters on detection thresholds corresponding to a 0.5 detection probability. To model peripheral activation and central processing, we adapt a stochastic drift diffusion model and a probabilistic hazard model to our experimental setting without reaction times. We retain six lumped parameters in both models characterizing peripheral and central mechanisms. Both models have similar psychophysical functions, but the hazard model is computationally more efficient. The model-based effects of temporal stimulus parameters on detection thresholds are consistent with those from human subject data. PMID- 26228801 TI - Triptans attenuate circadian responses to light. AB - Daily exposure to light synchronizes the circadian clock, located in the suprachiasmatic nucleus (SCN), to external day/night cycles. These responses to light can be modified by serotonergic drugs, such as serotonin 5HT1B receptor agonists. Triptans are specific 5HT1B agonists prescribed to treat migraines. Here, we examined the effects of two triptans (zolmitriptan and sumatriptan) on photic phase resetting in Syrian hamsters. Pre-treatment with intra-SCN sumatriptan significantly attenuates, and at higher doses completely blocks, phase advances to light during the late night. Pre-treatment with systemic zolmitriptan significantly attenuates both light-induced phase advances and phase delays. Neither of these drugs, nor their vehicles, causes phase shifts on their own. Pre-treatment with zolmitriptan also significantly reduces the expression of light-induced c-fos in the SCN. Neither zolmitriptan nor vehicle alone induces significant c-fos expression in the SCN. Finally, pre-treatment with zolmitriptan does not attenuate phase shifts to intra-SCN N-methyl-d-aspartate injections, indicating that the mechanism of action for zolmitriptan is likely to be through activation of presynaptic 5HT1B receptors on retinal terminals, thereby decreasing light-induced neurotransmitter release. As triptans are commercially available medications, there is potential for their use in blocking unwanted photic phase shifting during shift-work or jet-lag. Additionally, triptans may also affect the circadian clock in patients receiving them regularly for migraines. Finally, our results may hint at the mechanism by which triptans can alleviate the photophobia that frequently accompanies migraines, namely by activating 5HT1B receptors on retinal terminals elsewhere in the brain, and thereby diminishing visually-evoked neurotransmitter signalling in those areas. PMID- 26228802 TI - Seminal Corynebacterium strains in infertile men with and without leucocytospermia. AB - This study aimed to identify seminal Corynebacterium strains in infertile men with and without leucocytospermia. Semen samples from 60 infertile men were allocated into two equal groups: semen samples with leucocytospermia and semen samples without leucocytospermia. Semen culture for Corynebacterium species was carried out on Columbia agar medium confirmed by Gram-stained film and biochemical tests followed by analytical profile index biotyping and antibiotic susceptibility. Bacterial isolates were detected in 20/60 semen cultures (33.3%) as Corynebacteria, Staphylococci, Alpha haemolytic streptococci and E. coli. In all, 12/60 (20%) had Corynebacterium positive semen culture, whereas C. seminal was the major isolated species followed by C. amycolatum, C. jekium and C. urealyticum. There was nonsignificant difference between patients with/without Corynebacterium positive culture regarding sperm concentration and normal sperm morphology; however, in positive cultures sperm motility was significantly lower compared with negative cultures. Antimicrobial sensitivity among Corynebacteria strains was highest for vancomycin, rifampicin then imipenem, ampicillin + sulbactam, ciprofloxacin. It is concluded that positive semen cultures for different Corynebacteria species were demonstrated in infertile men, whereas Corynebacterium seminale was the most common isolated species. Vancomycin, rifampicin then imipenem and ampicillin + sulbactam are recommended as sensitive antibiotics. PMID- 26228803 TI - [Nager syndrome associated with tetralogy of Fallot: A frequent association?]. AB - Nager syndrome belongs to a heterogeneous group of disorders involving abnormal development of the extremities, face, and jaw: acrofacial dysostosis (AFD). Fewer than 100 cases of Nager syndrome have been reported to date. Recently, mutations in the 1q21.2 region of the SF3B4 gene (splicing factor 3B subunit 4), which encodes a spliceosomal protein (SAP49) involved in the assembly of the spliceosomal complex U2SNP, have been demonstrated in patients with Nager syndrome. We report the case of a child who had a characteristic association (Pierre Robin sequence, bilateral and symmetrical malar hypoplasia, absent thumbs) clinically diagnosed as Nager syndrome. This child also presented tetralogy of Fallot. This combination is unusual; only two other cases have been described. The karyotype and the CGH-array were normal. After the description in 2012 of several mutations in the SF3B4 gene (1q21.2) in Nager syndrome, a genetic search for our patient revealed the mutation c.1229delC. In 2013, other authors showed the presence of these same mutations in the majority of their patients diagnosed as Nager syndrome. The haploinsufficiency of the SF3B4 region seems to be the major cause of Nager syndrome. PMID- 26228804 TI - [Fall from a scooter]. PMID- 26228806 TI - [Cholestatic jaundice induced by Epstein-Barr virus infection]. PMID- 26228807 TI - [Consent in children: Practical situations (part 2)]. AB - Ethical and regulatory documents frame informed consent in pediatric research; their application is obligatory but may be complex. In this specific context, pediatric investigators have a central ethical role to play to ensure the strict respect of regulatory and ethical requirements adapted to the French legal, social, and cultural context as well as good clinical practices. This article attempts to shed light on the considerations that can allow researchers to come to terms with industrial and institutional demands while responding to the needs of patients, particularly in the domain of pediatric research. PMID- 26228808 TI - [Anxiety disorders in type 1 neurofibromatosis: A case report]. AB - BACKGROUND: Neurofibromatosis type 1 (NF1), also known as Von Recklinghausen disease, is one of the most frequent human genetic diseases, with a prevalence of one case in 3000 births, an autosomal dominant mode of inheritance, and a high rate of new mutations. NF1 has markedly variable clinical expression, with manifestations ranging from mild lesions to several complications and functional impairment. The complications are age-specific. Psychiatric disorders are more frequent in NF1 than in the general population, especially in children. They include dysthymia, depressive mood, anxiety, and personality disorders. Bipolar mood disorders or schizophrenia are rather rare. The majority of studies have focused on physical health and neurocognitive function in NF1, whereas psychiatric disorders associated with this disease remain unclear and poorly documented. This report is based on a clinical case and discusses the relationship between neurofibromatosis type 1 and psychiatric disorders, particularly anxiety disorders. PRESENTATION OF CASE: This case concerns a 13 year-old girl, the first child of healthy and non-consanguineous parents. The patient's history showed normal psychomotor and psychoaffective development. Her father and paternal grandmother had isolated cafe-au-lait spots. In June 2013, a subcutaneous mass appeared in her right thigh. She consulted a neurologist and was explored. The physical examination revealed signs of NF1. She had cafe-au lait spots on the trunk and extremities, and a neurofibroma in the right thigh. Bilateral ophthalmic examination revealed multiple Lish nodules. After 1 month, a psychiatric consultation was requested for sad mood and night terrors. Obsessive compulsive disorder and generalized anxiety disorder were diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. CONCLUSIONS: The current psychiatric literature does not provide full explanations of anxiety symptoms associated with NF1. Some authors have tried to explain the link between NF1 and psychiatric disorders, and several etiopathogenic hypotheses have been discussed. In our case, a concomitant diagnosis of NF1 and anxiety disorders was made at the age of 13. However, anxiety symptoms started to appear before age 4; they increased gradually and occupied the foreground. This would strengthen the hypothesis of genetic determinism in NF1 patients. The question that arises is: is it a fortuitous association of psychiatric disorders and NF1 or are they psychiatric manifestations induced by a multisystem disease? More detailed investigations are necessary to clarify the etiopathogenic and psychopathological mechanisms that would cause psychiatric comorbidity associated with NF1. PMID- 26228809 TI - [Neonatal purpura fulminans without sepsis due to a severe congenital protein C deficiency]. AB - Severe congenital protein C deficiency is a rare life-threatening coagulopathy. In the early hours of life, the neonate presents with extensive purpura fulminans and substantial skin necrosis contrasting with a preserved general state and a negative infectious exam. Disseminated intravascular coagulation sets in secondarily. Prenatal outset of thrombotic events is a rare situation that worsens the prognosis, especially protein C replacement in utero is not available. We report a case of a male newborn of consanguineous parents who were asymptomatic carriers of heterozygous protein C deficiency. This infant presented prenatal ventricular hemorrhage with hydrocephalus and rapidly extensive postnatal skin necrosis that was not regressive in spite of fresh frozen plasma administrated after 24h of life. Prenatal diagnosis, early recognition, and urgent therapy with protein C replacement and anticoagulant treatment are crucial to improve the prognosis, avoid further damage after delivery, and prevent the devastating consequences of severe protein C deficiency. PMID- 26228810 TI - [Apparent life-threatening events and sudden unexpected death in infancy: Two different entities]. AB - Most infant apparent life-threatening events (ALTEs) are minor with spontaneously favorable prognosis. Frequent etiologies are gastroesophageal reflux, obstructive apneas, respiratory infections, and breath-holding spells. Some rare but potentially serious causes must be discussed. Diagnosis is usually guided by careful questioning of the parents and repeated clinical examinations. A few complementary examinations are systematically needed and their performance is increased if they are oriented by clinical aspects. Hospitalization is usual for monitoring, further etiological investigation, and management of parental anxiety. ALTE and sudden unexpected death in infancy (SUDI) etiologies are often different. SUDI is called sudden unexplained death in infancy if it remains unexplained after investigation including autopsy. The annual incidence in France fell sharply after prevention campaigns in the 1990s, and now is about 400 SUDI, including 250 unexplained SUDI. The main guidelines of prevention are back sleeping, cessation of smoking during and after pregnancy, securing the bed and bedding, prevention of hyperthermia, and avoidance of dangerous factors of bed sharing. In the future, infants with particular vulnerabilities may be identified. The Haute Autorite de sante (French National Authority for Health) has published guidelines to support SUDI, standardize procedures, and improve our understanding of the causes of death. PMID- 26228811 TI - [Legal aspects of consent in children (Part 1)]. AB - In pediatric research, the patient is legally a minor and therefore protected by law. Research can only be conducted after parental consent and patient assent have been obtained. In this context, this review discusses the historical events and documents related to all ethical precautions and obligations. It also underlines that physicians shall respect all legal measures, but that individual involvement must comply with ethical standards while taking into account issues particular to pediatric research related to parental consent and child assent to clinical trials. PMID- 26228812 TI - Inhibiting MEK in MAPK pathway-activated myeloma. PMID- 26228814 TI - IDH1 and IDH2 mutations in myelodysplastic syndromes and role in disease progression. PMID- 26228815 TI - Morphogenesis of the lymphatic vasculature: A focus on new progenitors and cellular mechanisms important for constructing lymphatic vessels. AB - Lymphatic vessels serve crucial roles in the regulation of tissue fluid homeostasis, dietary lipid absorption and immune cell trafficking. Defects in lymphatic vessel morphogenesis and function have been associated with lymphedema, obesity, hypertension and tumour metastasis. Morphogenetic events important for construction of the lymphatic vasculature during development include the specification and emergence of lymphatic endothelial progenitor cells, their differentiation and assembly into interconnected vessels and vascular remodeling, ultimately giving rise to a functional vascular network. Despite the embryonic origins of lymphatic endothelial progenitor cells being long debated, work performed over the last decade had overwhelmingly supported at least a great majority of progenitor cells arising from the venous vasculature. Here, we review the most recent advances in the field of lymphatic vessel morphogenesis, with a focus on studies that have identified novel sources of embryonic lymphatic endothelial progenitor cells, together with the cellular mechanisms by which lymphatic vessels are initially assembled. PMID- 26228816 TI - "Those who have dissected or inspected many [bodies] have at least learnt to doubt; while others who are ignorant of anatomy and do not take the trouble to attend it are in no doubt at all". PMID- 26228813 TI - Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. AB - Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR cGVHD that should be validated in a prospective trial. PMID- 26228817 TI - High-resolution microendoscope imaging of inverted papilloma and normal sinonasal mucosa: evaluation of interobserver concordance. AB - BACKGROUND: High-resolution microendoscopy (HRME) enables real-time imaging of epithelial tissue. The utility of this novel imaging modality for inverted papilloma has not been previously described. This study examines the ability of otolaryngologists to differentiate between images of inverted papilloma and normal sinonasal mucosa obtained with a HRME. METHODS: Inverted papilloma and normal sinonasal mucosa specimens were stained with a contrast agent, proflavine. HRME images were subsequently captured. Histopathological diagnosis was obtained for each sample. Quality-controlled images were used to assemble a training set. After reviewing the training images, 6 otolaryngologists without prior HRME experience reviewed and classified test images. RESULTS: Five samples of inverted papilloma and 2 normal sinonasal mucosa samples were collected. Four representative images from each specimen were used for the 28-image test set. The mean accuracy among all reviewers was 89.9% (95% confidence interval [CI], 84.3% to 94.0%). The sensitivity to correctly identify inverted papilloma was 86.7% (95% CI, 79.2% to 92.2%), and the specificity was 92.9% (95% CI, 89.0% to 100.0%). The Fleiss kappa interrater reliability score was 0.80 (95% CI, 0.70 to 0.89). CONCLUSION: Inverted papilloma and normal sinonasal mucosa have distinct HRME imaging characteristics. Otolaryngologists can be successfully trained to distinguish between inverted papilloma and normal sinonasal mucosa. HRME is a feasible tool for identification of inverted papilloma. By conducting future in vivo trials, HRME potentially may enable real-time surgical margin determination during surgical excision of inverted papilloma. PMID- 26228818 TI - Skin changes in primary psychiatric disorders. AB - Primary psychiatric disorders where skin changes appear most frequently include: delusions of parasitosis, body dysmorphic disorder, neurotic excoriations, dermatitis artefacta, and trichotillomania. In all these diseases the primary pathologic condition is of psychiatric nature, and the skin changes are secondary and self-induced. In this review we wanted to present the epidemiology, clinical pictures, and treatment options for these disorders. These patients are more frequently seen in dermatology clinics, as they may be unwilling to acknowledge a psychiatric basis for their psychical symptoms. If we want the treatment to be effective and timely, it is important for the dermatologist to understand the underlying psychopathology of these conditions. Treatment should be gradual. An initially supportive, nonconfrontational, empathic approach to the patient is indicated. Immediate confrontation regarding the suspicion that the patient's lesions are self-induced can be counterproductive in that the patient will often refuse treatment. Frequent visits and symptomatic topical treatments are useful in the beginning. The goal is to establish a trusting and supportive enough relationship with the patient so that he or she will accept a psychiatric referral to explore the complex personality and behavioral issues that often underlie these conditions. PMID- 26228820 TI - Association between single nucleotide polymorphisms of the interleukin-4 gene and atopic dermatitis. AB - Atopic dermatitis (AD) is an inflammatory skin disease in which both genetic and environmental factors seem to be involved. Several studies investigated the association of certain genetic factors with AD in different ethnic groups, but conflicting data were obtained. This study was performed to check the possible association between single nucleotide polymorphisms (SNPs) of interleukin 4 (IL 4) and the IL-4 receptor alpha chain (IL-4Ralpha) and AD in a group of Iranian patients. The allele and genotype frequencies of genes encoding for IL-4 and IL 4Ralpha were investigated in 89 patients with AD in comparison with 139 healthy controls, using methods based on polymerase chain reaction sequence-specific primers. The most frequent alleles of IL-4 in patients were T at -1098 (P<0.001, odds ratio (OR)=2.35), C at -590 (P<0.001, OR=4.84) and C at -33 (P=0.002, OR=2.08). The most frequent genotypes of IL-4 in patients were TT, CC, and CC at positions -1098 (P<0.001, OR=3.59), -590 (P<0.001, OR=31.25) and -33 (P<0.001, OR=3.46), respectively. We found a significant lower frequency of GT at -1098 GT, TC at -590, and TC at -33 in patients. There were no statistically significant differences in the frequency of alleles and genotypes of IL-4Ralpha gene at position +1902. A strong positive association was seen between TCC haplotype and AD (68% in patients vs. 23.4% in controls, P<0.001, OR=8.91). We detected a significantly lower frequency of TTC, GCC, and TTT haplotypes (P<0.001, OR=0.02, P<0.001, OR=0.40, P<0.001, OR=0.39, respectively) in patients compared to controls. A significant association between the polymorphisms of the IL-4 gene promoter at positions -1098, -590, and -33 and AD was detected in the Iranian population. PMID- 26228819 TI - Evolution of melanocytic nevi under vemurafenib, followed by combination therapy with dabrafenib and trametinib for metastatic melanoma. AB - Treatment of advanced melanoma with selective BRAF and MEK inhibitors is associated with a series of mucocutaneous side effects, among which morphological changes in preexisting nevi and the development of new melanocytic lesions, both benign and malignant. Objective was to describe the changes observed in melanocytic nevi under vemurafenib therapy, followed by combination therapy with dabrafenib and trametinib for metastatic melanoma. The melanocytic lesions of a 51-year-old Caucasian male patient diagnosed with stage IV melanoma were monitored both clinically and dermoscopically throughout vemurafenib, followed by combined treatment with dabrafenib and trametinib. The 65 monitored nevi presented different behaviors under vemurafenib treatment: 18 reticular nevi, 9 reticular-homogenous nevi, 3 reticular-globular nevi, and 2 globular nevi showed a diffuse decrease in pigmentation. Ten reticular nevi remained unchanged, while the rest of the nevi, independent of the dermoscopic pattern, presented a gradual increase in pigmentation. On the other hand, under dabrafenib and trametinib treatment 57 of these nevi showed gradual decrease in pigmentation and central involution, while 7 reticular nevi and 1 globular nevus remained unchanged; none of the monitored nevi increased in pigmentation nor presented new globules following this combination therapy. Systematic total body skin examination is mandatory in patients receiving BRAF inhibitors. The divergent course of melanocytic nevi during vemurafenib vs. dabrafenib and trametinib therapy remains to be elucidated by further research. PMID- 26228821 TI - Lymphedema after breast and gynecological cancer - a frequent, chronic, disabling condition in cancer survivors. AB - The goal of our study was to determine clinical characteristics of women cancer survivors treated for secondary lymphedema, the time from cancer treatment to the development of lymphedema, and the effect of therapy on reduction of lymphedema and occurrence of erysipelas. We performed a retrospective study of women with secondary lymphedema after breast cancer (BR) and gynecological (cervical, uterine, ovarian, vulvar) cancers (GYN) treated at our Department from 2004 to 2010. The average time from cancer treatment to the development of lymphedema in our patients was 2.2 and 4.75 years in the BR and GYN groups, respectively, ranging from within days after the procedure to as long as 31 years. The duration of lymphedema in our patients before they first received appropriate therapy was on average 4.1 and 2.65 years in the BR and GYN groups, respectively. In our series, untreated lymphedema was a strong predisposing risk factor for erysipelas, whereas no cases of erysipelas were noticed after the establishment of therapy. Compression therapy was shown to be an effective measure to reduce lymphedema. The duration of required initial decongesting therapy with short stretch elastic bandages was longer in patients with more long-standing edema. Lymphedema may first appear several years after the cancer procedure. Our findings emphasize the need for awareness of lymphedema as a possible long-term iatrogenic complication in cancer survivors to avoid a delay in diagnosis and therapy. Physicians in care of cancer survivors should actively look for lymphedema. Untreated lymphedema is a strong predisposing risk factor for erysipelas. PMID- 26228822 TI - Prevalence and antifungal susceptibility patterns of dermatophytes isolated from patients with neoplastic diseases: a case control study. AB - Patients with neoplasia who are severely immunocompromised have a higher risk of fungal infections. There are limited data in the literature regarding the frequency of dermatophyte infections and efficacy of antifungals in patients with malignancies. Objective was assessment of the incidence of dermatophyte infections and antifungal susceptibility, determination of dermatophyte species isolated from patients with neoplastic diseases. 138 patients diagnosed with various malignancies and 160 immunocompetent patients who were referred to the Department of Dermatology in Brasov, Romania, for suspicion of dermatophyte infections were included in the study. Nail clippings or skin scrapings were examined by direct microscopy and cultures in Sabouraud agar medium. Susceptibility tests for antifungals were conducted in vitro using a method of broth microdilution. Infections with dermatophytes were identified in 30.4% of patients with neoplastic diseases and in 29.37% in the control group. There was a significantly higher frequency of dermatophyte infections in patients with hematologic malignancies (52%) compared to those with solid cancers (25.66%) (P=0.01). The clinical aspects of dermatophyte infections in patients with neoplastic diseases were not different from those of patients without cancer; though in some cases the infections were more extensive. There were no statistically significant differences between mean values of minimum inhibitory concentration of antifungals compared with controls. Terbinafine had the highest antidermatophyte activity for all tested dermatophyte species isolated from patients with neoplastic diseases. There were no differences in frequency of dermatophyte infections and antifungal susceptibility to dermatophytes between patients with neoplastic diseases and immunocompetent patients. PMID- 26228823 TI - Clinico-pathological features of patients with melanoma and positive sentinel lymph node biopsy: a single institution experience. AB - Sentinel lymph node biopsy (SLNB) is an established method for the assessment of tumor aggressiveness in patients with primary cutaneous melanoma (PCM). To improve the criteria for the selection of SLNB candidates, the aim of our study was to determine clinico-pathohistological parameters that can serve as predictors of metastatic progression. We retrospectively evaluated all available clinico-pathohistological parameters in 844 patients with PCM diagnosed between January 1, 2005 and December 31, 2010. SLNB was conducted in 484 (57.3%) patients, 122 (14.5%) of whom had a positive node. The association between predictors and SLNB outcomes (positive SLNB and metastatic development) was tested using logistic regression analysis. The main predictors of positive SLNB were Breslow thickness (adjusted odds ratio (AOR)=1.22; 95% confidence interval (CI)=1.11-1.33), Clark levels (AOR=1.78; 95% CI=1.31-2.40), ulceration (AOR=3.1; 95% CI=1.65-5.81), microsatellitosis, gender, and tumor localization. The predictors of metastatic spread were Breslow thickness (AOR=1,69; 95% CI=1.51 1.89), Clark level (AOR=3.59; 95% CI=2.79-4.62), nodular type of melanoma (AOR=8.21; 95% CI=1.70-39.53), ulceration, mitotic rate, microsatellitosis, gender, and tumor localization. It seems that these parameters should be taken into consideration when selecting patients for SLNB since tumor thickness is not a sufficient predictor of SLNB outcome, particularly in case of very thin lesions. PMID- 26228824 TI - Pigmented Bowen's disease of the genitalia masquerading as malignant melanoma. AB - Pigmented Bowen's disease is a rare subtype of in situ squamous cell carcinoma of the skin and mucosa, with a potential risk of invasion and metastasis. It is universally accepted that human papillomavirus (HPV) is the cause of genital Bowen's disease. Herein we report an unusual case of pigmented Bowen's disease of the genital area that clinically simulated malignant melanoma. Accurate diagnosis could only be established after histological examination. Polymerase chain reaction (PCR) analysis showed that the lesion harbored HPV 16 DNA. Although pigmented Bowen's disease is rare, it should be considered in the differential diagnosis of all pigmented lesions of the genitalia. This case report highlights the necessity of biopsy and histopathological examination for every suspicious cutaneous lesion. PMID- 26228825 TI - Myeloid sarcoma of the skin in a patient with myelodysplastic syndrome. AB - We report the case of a 76-year-old woman who presented with asymptomatic extensive erythematous. Firm plaques were noted over the right cheek. Complete blood count was normal, as was a peripheral smear. An excision biopsy taken from the cheek showed infiltration of the dermis and hypodermis with atypical cells which were strongly positive for human leukocyte antigen (HLA-DR) and lysozyme and were moderately myeloperoxidase (MPO) enzyme. The results of immunohistochemical staining for CD34, CD117, CD3, CD4, CD8, CD20, CD23, CD56, and ALK-1 were negative. Bone marrow analysis indicated myelodysplastic syndrome RAEB 1 while cytogenetic finding showed tetrasomy 8. It was recommended that the patient undergo local radiotherapy of skin lesions, but she refused and was lost to follow-up. PMID- 26228826 TI - Stasis papillomatosis with cardiac complications and vein insufficiency. AB - We report the case of a 73-year-old man with massive swelling of the lower extremities, with a chronic and rather uncommon form of stasis dermatitis - stasis papillomatosis. The patient was also diagnosed with severe heart failure, including dilated cardiomyopathy, hypothyroidism that required a substantial dose of exogenous tyrosine, microcytic and megaloblastic anemia, iron deficiency, and type 2 diabetes. The cause of stasis dermatitis lesions is not completely understood. It may be caused by the allergic reaction to some epidermal protein antigen formation or chronic damage to the dermal-epidermal barrier that makes the skin more sensitive to irritants or trauma. It has, however, been suggested that the term stasis dermatitis should be used to refer only to cases caused by chronic venous insufficiency, which belongs to a group of lifestyle diseases and affects both women and men more and more frequently. PMID- 26228827 TI - Subcutaneous cavernous angiolipoma: a new soft-tissue entity. PMID- 26228828 TI - Persistent pruritic eruptions in adult-onset Still's disease: additional histopathological findings. PMID- 26228829 TI - Photodynamic therapy for nonmelanoma skin cancer of the genital area: our experience. PMID- 26228830 TI - Superficial morphea of the lips and gingiva. PMID- 26228831 TI - Nonvenereal sclerosing lymphangitis of the penis. PMID- 26228832 TI - Buccal Cytome Biomarkers and Their Association with Plasma Folate, Vitamin B12 and Homocysteine in Alzheimer's Disease. AB - BACKGROUND/AIMS: Alzheimer's disease (AD) is an irreversible neurodegenerative disorder and is the commonest form of dementia. One aim of this study was to determine whether AD individuals have altered plasma folate, vitamin B12 and homocysteine (Hcy) levels compared to controls. The other aim was to investigate correlations between B vitamins and buccal biomarkers to test whether they are influenced by B vitamin status. METHODS: Folate, vitamin B12 and Hcy were measured using ARCHITECT(r) and AxSYM(r) assays. Genomic stability was measured using the buccal micronucleus cytome assay. RESULTS: The area under the receiver operating characteristic curve for AD basal cells was 0.96 (p < 0.0001), for karyorrhectic cells 0.88 (p < 0.0001) and for basal and karyorrhectic cells 0.91 (p < 0.0001). Hcy was significantly increased (p = 0.0003) compared to controls. Plasma vitamin B12 in controls showed a positive correlation with pyknosis (r = 0.5365, p = 0.004), karyolysis (r = 0.5447, p = 0.004) and condensed chromatin (r = 0.5238, p = 0.006). Plasma vitamin B12 in AD cases showed a positive correlation with micronuclei (r = 0.3552, p = 0.04) and basal cells (r = 0.3448, p = 0.04), whilst plasma Hcy showed a negative correlation with karyorrhectic cells (r = -0.4107, p = 0.01). CONCLUSIONS: Hcy was significantly increased in AD cases relative to controls. The lower frequency of basal cells and karyorrhectic cells observed in AD cases may be explained by lower vitamin B12 and higher Hcy levels, respectively. PMID- 26228833 TI - The EP3 Agonist Sulprostone Enhances Platelet Adhesion But Not Thrombus Formation Under Flow Conditions. AB - Platelets express the EP2, EP3 and EP4 receptors. Prostaglandin (PG) E2 has a biphasic effect on platelets. Low concentrations of PGE2 enhance platelet aggregation through the activation of the EP3 receptors, while at high concentrations it attenuates aggregation via the EP4 receptor. Consequently, EP3 receptor inhibition was shown to inhibit artherothrombosis, but had no influence on bleeding time in vivo. In this study, we investigated the role of the EP3 receptor in adhesion and thrombus formation under flow conditions in vitro. The EP3 agonist sulprostone caused an increase in the adhesion of washed platelets to fibrinogen as well as to collagen under low shear stress, an effect that was blocked by the EP3 antagonist L-798106. In contrast, when whole blood was perfused over collagen-coated surfaces, sulprostone did not enhance binding and thrombus formation of platelets on collagen; at high concentrations it even attenuated this response. We conclude that in more physiological models of thrombus formation, the role for EP3 receptors is limited, indirectly suggesting that the primary action of PGE2 in haemostasis might be an inhibitory one. PMID- 26228834 TI - Interactions between nutritional approaches and defences against microbial diseases in small ruminants. AB - Objective of this review is to discuss the role of small ruminant diet in the defence of these animals against microbial diseases, in relation to different experimental approaches and various stressors acting on animals. The effects of various diets in immune reactions and animal defences are presented. Also, effects in relation to the species studied and the type of stressors acting on animals are discussed. Evidence is provided about the significance of the diet in enhancing immune responses of small ruminants during specific conditions, e.g., around parturition, during lactation, as well as in growing lambs or kids. PMID- 26228835 TI - A retrospective study on equine herpesvirus type-1 associated myeloencephalopathy in France (2008-2011). AB - Diagnosis of equine herpesvirus-1 associated myeloencephalopathy (EHM) can be troublesome, but early recognition and knowledge of risk factors are essential for prevention and control. The objectives for this study are to (1) describe EHM in France, (2) improve clinical recognition, (3) identify risk factors. Through epidemiosurveillance of acute neurological cases (all considered to be potentially infectious cases) in France (2008-2011), 26 EHM cases were identified and 29 EHM negative control cases. EHM cases were described and compared to controls with univariate, multivariate and classification and regression tree analysis. EHM cases had a 46% fatality rate and were frequently isolated cases. Most showed ataxia, paresis and a cauda equina syndrome, yet presence of other neurological signs was variable. Statistical analysis identified the following variables to be significantly associated to EHM compared to controls: introduction of a new horse to the herd, cauda equina syndrome, larger herd size, saddle horses and month of occurrence. The presence of many isolated cases, and less typical and variable clinical presentations emphasize the difficulty in diagnosing EHM. Nevertheless, history and clinical examination of acute neurological cases can be valuable in recognizing EHM early as well in order to select those cases that need further laboratory testing and infection control measures. Moreover, with a different study format and geographic location, risk factors were found to be similar to previous studies, therefore strengthening their significance to the spread of EHM. PMID- 26228836 TI - The implausibility of 'usual care' in an open system: sedation and weaning practices in Paediatric Intensive Care Units (PICUs) in the United Kingdom (UK). AB - BACKGROUND: The power of the randomised controlled trial depends upon its capacity to operate in a closed system whereby the intervention is the only causal force acting upon the experimental group and absent in the control group, permitting a valid assessment of intervention efficacy. Conversely, clinical arenas are open systems where factors relating to context, resources, interpretation and actions of individuals will affect implementation and effectiveness of interventions. Consequently, the comparator (usual care) can be difficult to define and variable in multi-centre trials. Hence outcomes cannot be understood without considering usual care and factors that may affect implementation and impact on the intervention. METHODS: Using a fieldwork approach, we describe PICU context, 'usual' practice in sedation and weaning from mechanical ventilation, and factors affecting implementation prior to designing a trial involving a sedation and ventilation weaning intervention. We collected data from 23 UK PICUs between June and November 2014 using observation, individual and multi-disciplinary group interviews with staff. RESULTS: Pain and sedation practices were broadly similar in terms of drug usage and assessment tools. Sedation protocols linking assessment to appropriate titration of sedatives and sedation holds were rarely used (9% and 4% of PICUs respectively). Ventilator weaning was primarily a medical-led process with 39% of PICUs engaging senior nurses in the process: weaning protocols were rarely used (9% of PICUs). Weaning methods were variably based on clinician preference. No formal criteria or use of spontaneous breathing trials were used to test weaning readiness. Seventeen PICUs (74%) had prior engagement in multi-centre trials, but limited research nurse availability. Barriers to previous trial implementation were intervention complexity, lack of belief in the evidence and inadequate training. Facilitating factors were senior staff buy-in and dedicated research nurse provision. CONCLUSIONS: We examined and identified contextual and organisational factors that may impact on the implementation of our intervention. We found usual practice relating to sedation, analgesia and ventilator weaning broadly similar, yet distinctively different from our proposed intervention, providing assurance in our ability to evaluate intervention effects. The data will enable us to develop an implementation plan; considering these factors we can more fully understand their impact on study outcomes. PMID- 26228837 TI - Evaluation of tizanidine as a marker of canine CYP1A2 activity. AB - The dog CYP1A2 enzyme is likely an important contributor to the metabolism of veterinary drugs. Dog CYP1A2 is expressed in liver, plus it is inducible and polymorphic, creating the potential for intersubject differences in pharmacokinetics. Hence, the ability to probe dog CYP1A2 activity and inhibition is relevant toward veterinary drug development and drug-drug interaction assessment. Previous studies have relied on human probes with questionable specificity for CYP1A2, so it was hypothesized that recombinant CYP1A2 could be used to find a specific CYP1A2 substrate. Intrinsic clearance experiments demonstrated that tizanidine was a substrate of CYP1A2. Profiling of tizanidine metabolites generated by CYP1A2 identified the imidazole metabolite that was detectable in dog plasma. The imidazole metabolite was subsequently used to evaluate tizanidine as a CYP1A2 probe. Co-administration of the CYP1A inhibitor enrofloxacin with tizanidine significantly decreased (30%; n = 3) the formation of the imidazole metabolite vs. control experiments. As enrofloxacin is a weak inhibitor, further studies are required to confirm the sensitivity of tizanidine as an in vivo probe. However, tizanidine may be a more selective CYP1A2 probe than phenacetin when conducting in vitro studies due to the presence of other phenacetin-metabolizing enzymes in dog liver microsomes. PMID- 26228838 TI - Prostanoid-mediated contractions of the carotid artery become Nox2-independent with aging. AB - Aging is a major risk factor for carotid artery disease that may lead to stroke and dementia. Vascular effects associated with aging include increased vasomotor tone, as well as enhanced contractility to endothelial vasoconstrictor prostanoids and reduced nitric oxide (NO) bioactivity partly due to increased oxidative stress. We hypothesized that vascular NADPH oxidase (Nox)-derived superoxide may be involved in prostanoid- and NO-related functional aging. NO mediated relaxations and prostanoid-mediated contractions to acetylcholine as well as phenylephrine-dependent contractions were investigated in the carotid artery from young (4 months) and aged mice (24 months). Gene expression of Nox subunits and endothelial NO synthase (eNOS) was determined in the carotid artery and aorta. In young mice, the thromboxane-prostanoid receptor antagonist SQ 29,548 fully blocked acetylcholine-induced contractions while reducing responses to phenylephrine by 75 %. The Nox2-targeted inhibitor Nox2ds-tat and the superoxide scavenger tempol reduced acetylcholine-stimulated, prostanoid-mediated contractions by 85 and 75 %, respectively, and phenylephrine-dependent contractions by 45 %. Unexpectedly, in aged mice, the substantial Nox2-dependent component of acetylcholine- and phenylephrine-induced, prostanoid-mediated contractions was abolished. In addition, endothelium-dependent, NO-mediated relaxations were impaired with aging. The expression of Nox subunits was greater in the aorta compared with the carotid artery, in which Nox1 was undetectable. eNOS gene expression was reduced in the aorta of aged compared to young mice. In conclusion, aging decreases prostanoid-mediated contractility in the carotid artery involving a loss of Nox2 activity and is associated with impaired endothelium-dependent, NO-mediated relaxation. These findings may contribute to a better understanding of the pathophysiology of carotid artery disease and the aging process. PMID- 26228839 TI - Association between cognition and gene polymorphisms involved in thrombosis and haemostasis. AB - An association between blood markers of thrombosis and haemostasis and cognitive decline has been described. These results may be confounded by lifestyle and environmental factors. We used a Mendelian randomisation approach to describe the association between thrombosis/haemostasis genotypes and cognition. We studied the genetic variants (single nucleotide polymorphisms) of circulating markers of thrombosis and haemostasis. Our chosen blood factors and associated polymorphisms were D-dimer [rs12029080], fibrinogen [rs1800789], plasminogen activator inhibitor [rs2227631], and von Willebrand factor [rs1063857]. We described association with multidomain cognitive test scores using data from the Scottish Family Health Study. Cognitive data were analysed for individual tests and combined to give a general cognitive factor. In 20,288 subjects, we found no evidence of association between cognitive function (individual tests and combined scores) and any of the above-mentioned single nucleotide polymorphisms. Lower scores on cognitive measures were associated with increasing age, socioeconomic deprivation, blood pressure, waist-hip ratio, smoking, and vascular comorbidity (all p < 0.001). In a post hoc sensitivity analysis restricted to those aged over 50 years, there was still no signal of association. Our data add to our understanding of determinants of cognition but are not definitive; the variation in blood levels explained by SNPs was modest and our sample size may have been insufficient to detect a modest association. PMID- 26228840 TI - Ruthenium-catalyzed cyclization of N-carbamoyl indolines with alkynes: an efficient route to pyrroloquinolinones. AB - A regioselective synthesis of substituted pyrroloquinolinones via a ruthenium catalyzed oxidative cyclization of substituted N-carbamoyl indolines with alkynes is described. The cyclization reaction was compatible with various symmetrical and unsymmetrical alkynes including substituted propiolates. Later, we performed the aromatization of pyrroloquinolinones into indole derivatives in the presence of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). PMID- 26228841 TI - A Fine Balance: Developing Clinical Practice Guidelines in Areas Where Evidence is Lacking. AB - Over the last 15 years, numerous clinical practice guidelines have been developed by clinicians driven by national societies and funders of healthcare services. Writing and publication of guidelines have been refined such that a transparent and robust process has evolved. The main purpose of clinical practice guidelines is to provide healthcare professionals with evidence-based recommendations to assist clinical decision-making and reduce variability in clinical practice: this benefits patients and the healthcare system. When evidence is abundant and robust, guideline development is relatively straightforward. However, in areas where evidence is lacking, there is a tension between providing advice based on expert opinion while maintaining a clinical equipoise that will facilitate the design and execution of clinical trials, so that new information is gained, and that will ultimately inform care . In this commentary, we explore these problems and suggest an alternative approach to the development of clinical guidance in areas where evidence is lacking. PMID- 26228842 TI - Umezawaea endophytica sp. nov., isolated from tobacco root samples. AB - Two Gram-staining positive, aerobic and non-motile actinomycete strains, designated YIM 2047X(T) and YIM 2047D, were isolated from tobacco root samples collected from Shiling county, Yunnan province, South-West China. The isolates grew at 15-40 degrees C, pH 6.0-8.0 and 0-4.5 % NaCl (w/v). The whole-cell hydrolysates contained meso-diaminopimelic acid, galactose, mannose, ribose and rhamnose. The polar lipids detected were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylinositol and phosphatidylinositol mannoside. The major cellar fatty acids identified were iso-C14:0, iso-C15:0, anteiso-C15:0, iso-C16:0, C16:0, C17:1 omega8c and C17:0. MK-9 (H4) was the predominant menaquinone. The genomic DNA G+C contents were 73.4 and 74.2 mol%, respectively. These chemotaxonomic data, together with their morphological properties, were consistent with the assignment of the two strains to the genus Umezawaea. They showed highest similarities to Umezawaea tangerina JCM 10302(T) on phylogenetic analysis of their 16S rRNA gene sequences and were found to form a coherent cluster. However, the DNA-DNA hybridization values of YIM 2047X(T) and YIM 2047D with U. tangerina JCM 10302(T) were 46.5 +/- 3.1 and 57.5 +/- 1.6 %, respectively; while the reassociation value between themselves was 80.4 +/- 2.3 %. The results of physiological and biochemical tests allowed the two new isolates to be differentiated phenotypically from the recognized strain U. tangerina JCM 10302(T). On the basis of results from this polyphasic study, the strains were characterized as a novel species of the genus Umezawaea, for which the name Umezawaea endophytica sp. nov. is proposed. The type strain is YIM 2047X(T) (=KCTC 39538(T) = CPCC 204132(T)). PMID- 26228843 TI - Acute megakaryocytic leukemia: What have we learned. AB - Acute megakaryocytic leukemia (AMegL) is a biologically heterogenous subtype of acute myeloid leukemia (AML) that arises from megakaryocytes. Improvements in the accuracy of diagnosing AMegL as well as interest in the molecular analysis of leukemias have led to an increased amount of data available on this rare AML subtype. In this review, we will analyze the diverse molecular features unique to AMegL and how they have influenced the development of novel treatment strategies, including polyploidization. The review will also consider the data available on clinical outcomes in AMegL and how it is a poor individual prognostic factor for AML. Finally, the role of allogeneic hematopoietic stem cell transplant in AMegL will be explored. PMID- 26228844 TI - Obesity--a risk factor for postoperative complications in general surgery? AB - BACKGROUND: Obesity is generally believed to be a risk factor for the development of postoperative complications. Although being obese is associated with medical hazards, recent literature shows no convincing data to support this assumption. Moreover a paradox between body mass index and survival is described. This study was designed to determine influence of body mass index on postoperative complications and long-term survival after surgery. METHODS: A single-centre prospective analysis of postoperative complications in 4293 patients undergoing general surgery was conducted, with a median follow-up time of 6.3 years. We analyzed the impact of bodyweight on postoperative morbidity and mortality, using univariate and multivariate regression models. RESULTS: The obese had more concomitant diseases, increased risk of wound infection, greater intraoperative blood loss and a longer operation time. Being underweight was associated with a higher risk of complications, although not significant in adjusted analysis. Multivariate regression analysis demonstrated that underweight patients had worse outcome (HR 2.1; 95 % CI 1.4-3.0), whereas being overweight (HR 0.6; 95 % CI 0.5 0.8) or obese (HR 0.7; 95 % CI 0.6-0.9) was associated with improved survival. CONCLUSION: Obesity alone is a significant risk factor for wound infection, more surgical blood loss and a longer operation time. Being obese is associated with improved long-term survival, validating the obesity paradox. We also found that complication and mortality rates are significantly worse for underweight patients. Our findings suggest that a tendency to regard obesity as a major risk factor in general surgery is not justified. It is the underweight patient who is most at risk of major postoperative complications, including long-term mortality. PMID- 26228845 TI - Development of a novel larynx pacemaker multichannel array electrode: In vivo animal analysis. AB - OBJECTIVES/HYPOTHESIS: Electrical stimulation of posterior cricoarytenoid muscle offers a physiological approach to retain the function of the paralyzed larynx muscle after paralysis. The aim of this study was to develop and evaluate a durable, biocompatible, and atraumatic array electrode for inclusion in a larynx pacemaker. In addition to developing the electrode array, an evaluation methodology using in vivo multichannel electromyography was assessed. STUDY DESIGN: In vivo test procedures for material evaluation: an animal model. METHODS: Over the research period, 42 array electrodes representing nine different prototypes were implanted in the triceps brachii muscle of 21 rats. Biocompatibility and atraumatic functions were evaluated via observation. Electrode function and durability were determined by comparison of daily electromyographic measurements of the muscle activity of the front leg (triceps brachii muscle) during locomotion. RESULTS: The used animal model demonstrated electrode material problems that could not be material evaluation from in vitro tests alone. Through use of this in vivo method, it was found that an array tip that is durable, biocompatible, and atraumatic should consist of many small electrode plates cast in flexible silicone. The connecting wires to the individual electrode plates should be Litz wire, which consists of multiple strands. CONCLUSIONS: The here demonstrated in vivo test method was a suitable animal model for designing and evaluating electrodes to be further developed for inclusion in human implants. LEVEL OF EVIDENCE: N/A. PMID- 26228846 TI - Is it possible to diagnose Rett syndrome before classical symptoms become obvious? Review of 24 Danish cases born between 2003 and 2012. AB - BACKGROUND/PURPOSE: Rett syndrome (RTT) is a neurodevelopmental disorder that affects mainly females; it results in multiple disabilities and carries a risk of medical comorbidities. Early diagnosis is important to help establish the best treatment opportunities and preventive care in order to slow down the progression of symptoms. We wanted to test our hypothesis that it is possible to diagnose RTT before the classical symptoms become obvious. METHODS: We analysed development and symptoms before and at the time of the RTT diagnosis, as well as the symptoms that triggered MECP2 mutation analysis, in a cohort of girls with RTT born in Denmark between 2003 and 2012. RESULTS: Twenty-four girls were included, and 87.5% of these girls were diagnosed when the classical RTT symptoms were recognized. However, parents were concerned about their daughters between 3 and 58 months prior to the RTT diagnosis, and they felt that the professionals did not share their concern in the beginning. When reviewing medical files and questionnaires, we noted that the majority of girls did have combinations of concerning symptoms such as developmental delay and a collection of subtle signs such as autistic traits, placidity, floppiness with suspicion of muscular or mitochondrial diseases, hair pulling, teeth grinding, development of incontinence and problems with initiating movements. CONCLUSION: We conclude that many individuals with MECP2 mutation exhibit characteristics that should raise suspicion for RTT, prior to evolution of the core clinical criteria. As RTT is a rare disease, it is of importance to constantly educate clinicians for heightened awareness of RTT. PMID- 26228847 TI - Coronary Artery Dominance and Long-term Prognosis in Patients With ST-segment Elevation Myocardial Infarction Treated With Primary Angioplasty. AB - INTRODUCTION AND OBJECTIVES: The long-term prognostic significance of coronary artery dominance pattern in patients with ST-segment elevation myocardial infarction is poorly characterized. We investigated the prognosis of such patients according to whether they had right dominance, left dominance, or codominance. METHODS: This was a retrospective study of 767 patients, who were admitted to hospital between 2007 and 2012 with ST-segment elevation myocardial infarction and treated with primary percutaneous coronary intervention. We determined the effect of the coronary dominance pattern on all-cause mortality and readmission for infarction, adjusting for mortality as a competing event. RESULTS: A total of 80.9% of patients had right coronary dominance, and 8.6% had left coronary dominance. Over 40.8 months' [interquartile range, 21.9-58.3 months] follow-up, 118 (15.4%) deaths were recorded, of which 39 (5.1%) were in hospital. Mortality for right dominance, left dominance, and codominance was 7.1%, 36.4%, and 13.8% (P ? .001), respectively. Cause of death was cardiovascular in 7.1%, 21.2%, and 2.4%. On Cox multivariate analysis, left dominance was significantly associated with mortality (hazard ratio = 1.76; P = .02). Taking "coronary dominance" into account in prediction of risk of death improved the discrimination and calibration capacity of GRACE (Global Registry of Acute Coronary Events) scoring. At follow-up, 9.3% (71 patients) had reinfarction. On multivariate analysis, left dominance was an independent predictor of reinfarction (subhazard ratio = 2.06; P = .01). CONCLUSIONS: In ST segment elevation myocardial infarction treated with primary percutaneous coronary intervention, left coronary artery dominance confers a higher risk of death and reinfarction than right coronary artery dominance, and should be included in prognostic stratification. PMID- 26228848 TI - Factors Contributing to the Low Rate of Surgical Coronary Revascularization in Spain. Are We Following the Recommendations? Response. PMID- 26228849 TI - Rapid chiral separation of atenolol, metoprolol, propranolol and the zwitterionic metoprolol acid using supercritical fluid chromatography-tandem mass spectrometry - Application to wetland microcosms. AB - A method for enantiomeric separation of the three beta-blocking agents atenolol, metoprolol, propranolol and the zwitterionic metoprolol acid, a major metabolite of both metoprolol and in environmental matrices also atenolol, has been developed. By use of supercritical fluid chromatography and the polysaccharide based Chiralpak((r)) IB-3, all four compounds were simultaneously enantiomerically separated (Rs>1.5) within 8min. Detection was performed using tandem mass spectrometry, and to avoid isobaric interference between the co eluting metoprolol and metoprolol acid, the achiral column Acquity((r)) UPC(2) BEH 2-EP was attached ahead of to the chiral column. Carbon dioxide with 18% methanol containing 0.5% (v/v) of the additives trifluoroacetic acid and ammonia in a 2:1 molar ratio were used as mobile phase. A post column make-up flow (0.3mL/min) of methanol containing 0.1% (v/v) formic acid was used to enhance the positive electrospray ionization. Detection was carried out using a triple quadrupole mass spectrometer operating in the selected reaction monitoring mode, using one transition per analyte and internal standard. The method was successfully applied for monitoring the enantiomeric fraction change over time in a laboratory scale wetland degradation study. It showed good precision, recovery, sensitivity and low effect of the sample matrix. PMID- 26228850 TI - Determination of phthalate esters in environmental water by magnetic Zeolitic Imidazolate Framework-8 solid-phase extraction coupled with high-performance liquid chromatography. AB - In this study, the magnetic Zeolitic Imidazolate Framework-8 (ZIF-8) microspheres were successfully synthesized and applied as an effective sorbent for preconcentration of several typical phthalate esters (PAEs) from environmental water samples. Firstly, the solvothermal treatment method was used for preparation of Fe3O4 nanoparticles. Then, mercaptoacetic acid (MAA) was served as the functionalized chemical to modify Fe3O4 nanoparticles. The Fe3O4@ZIF-8 core shell microspheres were synthesized through coating the MAA-capped Fe3O4 nanoparticles with ZIF-8. By coupling magnetic solid-phase extraction (MSPE) with high-performance liquid chromatography (HPLC), a reliable, sensitive and cost effective method for simultaneous determination of five main PAEs including dimethyl phthalate (DMP), diethyl phthalate (DEP), di-n-butyl phthalate (DBP), benzyl butyl phthalate (BBP), and dioctyl phthalate (DOP) was developed. Good linearity was observed in the range of 1.0-100.0MUg/L. The limits of detection (S/N=3) and limits of quantification (S/N=10) were in the range of 0.08-0.24 and 0.3-0.8MUg/L, respectively. The relative standard deviations were less than 5.5% and the accuracies of the method for the PAEs were in the range from 85.6% to 103.6%. Finally, the Fe3O4@ZIF-8 was successfully applied for rapid extraction of trace amounts of PAEs in environmental water samples. PMID- 26228851 TI - Capillary electrophoresis of sialylated oligosaccharides in milk from different species. AB - Oligosaccharides are relevant components of human milk, which have been quite well studied for their pre-biotic effect and their capacity in stimulating the immune system. Since oligosaccharides from milk of non-human mammals received so far less attention, the aim of this work was the application of capillary electrophoresis (CE) for the analysis of sialylated oligosaccharides in cow, goat and equine (mare and donkey) milk to possibly identify potential sources of oligosaccharides to use as health promoting ingredients in functional foods. Human milk was used as reference milk. A recent CE technique was applied to resolve and quantify 3-sialyllactose (3-SL), 6-sialyllactose (6-SL) and disialyl lacto-N-tetraose (DSLNT). Analysis of non-human milk samples confirmed differences among species and individuals: DSLNT, which was the most abundant compound in human milk (455-805MUg/mL) was missing in most of the samples. In most cases, 3-SL showed to be the most concentrated of the quantified analytes, with values ranging from 12 to 77MUg/mL. PMID- 26228852 TI - Robust naphthyl methacrylate monolithic column for high performance liquid chromatography of a wide range of solutes. AB - An organic monolithic column based on the co-polymerization of 2-naphthyl methacrylate (NAPM) as the functional monomer and trimethylolpropane trimethacrylate (TRIM) as the crosslinker was introduced for high performance reversed-phase liquid chromatography (RPC). The co-polymerization was performed in situ in a stainless steel column of 4.6mm i.d. in the presence of a ternary porogen consisting of 1-dodecanol and cyclohexanol. This monolithic column (referred to as naphthyl methacrylate monolithic column or NMM column) showed high mechanical stability at relatively high mobile phase flow velocity indicating that the column has excellent hydrodynamic characteristics. To characterize the NMM column, different probe molecules including alkyl benzenes, and aniline, benzene, toluene and phenol derivatives were chromatographed on the column and the results in terms of k, selectivity and plate counts were compared to those obtained on an octadecyl silica (ODS) column in order to assess the presence of pi-pi and hydrophobic interactions on the NMM column under otherwise the same elution conditions. The NMM column offered additional pi-pi interactions with aromatic molecules in addition to hydrophobic interactions under RPC elution conditions. Run-to-run and column-to-column reproducibility of solute k values were evaluated, and percent relative standard deviation of <1% and ~2-3.5%, respectively, were obtained. Six standard proteins were readily separated on the NMM column using shallow (30min at 1.0mL/min), steep (10min at 1.0mL/min) and ultra steep (1min at 3.0mL/min) linear gradient elution at increasing ACN concentration in the mobile phase using a 10cm*4.6mm i.d. column in case of shallow and steep linear gradients and a 3cm*4.6mm i.d. column for ultra steep linear gradient. PMID- 26228853 TI - Sum of ranking differences to rank stationary phases used in packed column supercritical fluid chromatography. AB - The identification of a suitable stationary phase in supercritical fluid chromatography (SFC) is a major source of difficulty for those with little experience in this technique. Several protocols have been suggested for column classification in high-performance liquid chromatography (HPLC), gas chromatography (GC), and SFC. However, none of the proposed classification schemes received general acceptance. A fair way to compare columns was proposed with the sum of ranking differences (SRD). In this project, we used the retention data obtained for 86 test compounds with varied polarity and structure, analyzed on 71 different stationary phases encompassing the full range in polarity of commercial packed columns currently available to the SFC chromatographer, with a single set of mobile phase and operating conditions (carbon dioxide-methanol mobile phase, 25 degrees C, 150bar outlet pressure, 3ml/min). First, a reference column was selected and the 70 remaining columns were ranked based on this reference column and the retention data obtained on the 86 analytes. As these analytes previously served for the calculation of linear solvation energy relationships (LSER) on the 71 columns, SRD ranks were compared to LSER methodology. Finally, an external comparison based on the analysis of 10 other analytes (UV filters) related the observed selectivity to SRD ranking. Comparison of elution orders of the UV filters to the SRD rankings is highly supportive of the adequacy of SRD methodology to select similar and dissimilar columns. PMID- 26228855 TI - End-of-life care practices of critical care nurses: A national cross-sectional survey. AB - BACKGROUND: The critical care context presents important opportunities for nurses to deliver skilled, comprehensive care to patients at the end of life and their families. Limited research has identified the actual end-of-life care practices of critical care nurses. OBJECTIVE: To identify the end-of-life care practices of critical care nurses. DESIGN: A national cross-sectional online survey. METHODS: The survey was distributed to members of an Australian critical care nursing association and 392 critical care nurses (response rate 25%) completed the survey. Exploratory factor analysis using principal axis factoring with oblique rotation was undertaken on survey responses to identify the domains of end-of life care practice. Descriptive statistics were calculated for individual survey items. RESULTS: Exploratory factor analysis identified six domains of end-of-life care practice: information sharing, environmental modification, emotional support, patient and family centred decision-making, symptom management and spiritual support. Descriptive statistics identified a high level of engagement in information sharing and environmental modification practices and less frequent engagement in items from the emotional support and symptom management practice areas. CONCLUSIONS: The findings of this study identified domains of end-of-life care practice, and critical care nurse engagement in these practices. The findings highlight future training and practice development opportunities, including the need for experiential learning targeting the emotional support practice domain. Further research is needed to enhance knowledge of symptom management practices during the provision of end-of-life care to inform and improve practice in this area. PMID- 26228854 TI - Factorial structure of complicated grief: associations with loss-related traumatic events and psychosocial impacts of mass conflict amongst West Papuan refugees. AB - INTRODUCTION: Definitions of complicated grief vary across diagnostic systems, being represented as persistent complex bereavement (PCB) in DSM-5 and prolonged grief disorder (PGD) in the proposed revision of the ICD system. A past study in a high-income country has identified a six-factor structure for complicated grief, but there are no data testing this or any other model across cultures. The present study reports findings from a survey amongst West Papuan refugees (n = 230, response rate = 92 %) residing in Port Moresby, Papua New Guinea. MATERIALS AND METHODS: We applied culturally adapted measures of conflict-related traumatic event (TEs) (drawing specifically on domains of conflict and loss), symptoms of complicated grief adapted and modified to the culture, and a multidimensional psychosocial index of the broader effects of conflict and displacement. RESULTS: Confirmatory factor analysis yielded a single higher order construct of complicated grief comprising six factors of yearning/preoccupation; shock/disbelief; anger/negative appraisal; behavioural change; estrangement from others/impairment; and a novel dimension of confusion/diminished identity. In contrast, our analysis failed to support DSM or ICD models of PCB or PGD. A Multiple Indicators Multiple Causes (MIMIC) model revealed that traumatic loss and the sense of injustice each were associated with the unitary construct of complicated grief and its subdomains of yearning/preoccupation; shock/disbelief; anger/negative appraisal (exclusive to injustice); and estrangement from others/social impairment (exclusive to TE domain of conflict and loss). CONCLUSIONS: Conflict and loss associated with feelings of injustice may be especially pathogenic in generating the anger/negative appraisal component of complicated grief amongst refugees. PMID- 26228856 TI - [The value of time in cancer patients]. AB - In medicine time is one of the main dimensions used in order to assess the efficacy of a cure. In oncology we measure either the advantage obtained with a treatment or the clinical course of a cancer as time intervals or survival benefit. In the last years we can describe life expectancy in many solid tumors following therapy, not only in terms of median survival, but also in terms of 3-5 years survival. Additional life time, that given by novel drugs, is now a real experience in some solid tumors allowing a reflection on its value and meaning in the personal perception of patients as well in an absolute perspective. The concept of time deformation in physics suggests a metaphorical similarity with rediscovery of the authentic sense of life in an increasing number of patients affected by cancer who experience a significant life prolongation. PMID- 26228857 TI - [Meat consumption reduction policies: benefits for climate change mitigation and health]. AB - Agricultural food production substantially contributes to green house gas (GHG) emissions worldwide and 80% of the agricultural emissions arise from the livestock sector, in particular from ruminants. Meat consumption is generally above dietary recommendations in many countries, including Italy, and it is increasing in developing countries. Although meat is a source of essential nutrients, it provides large amounts of saturated fat, which is a known risk factor for obesity and for several diseases such as stroke, breast cancer and colon cancer. Dietary changes, with lower intake of red and processed meat, are likely to be beneficial for improving health and for the environment by reducing emissions of GHG. Data on meat consumption in Italy among adults, referred to the last ten years, shows heterogeneity among regions, with the highest consumption in the North-western regions and generally with higher consumption among males. We describe meat consumption distribution worldwide, in Europe and Italy. An assessment of the potential environmental and health co-benefits considering different reduction scenarios of red meat consumption in Italy is provided. Dietary changes can substantially lower GHG and coordinated actions are needed across public health and other sectors to promote healthy, low-emission diets. PMID- 26228858 TI - [Models in the management of long-term life]. AB - The number of cancer survivors is progressively increasing. Despite the significant progress in the cancer therapies, we are facing the emerging concern of the late side effects and/or psycosocial problems that require diversified follow-up. Healthcare models supporting the oncological patient's needs should be established to improve the quality of life after the diagnosis of oncological disease. Several care models have been proposed - mainly focused on the pediatric population - although further research is needed to optimize the programs. Furthermore, the heterogeneity in existing survivorship care should be addressed: the individual patient characteristics and risk factors (histology, treatment received, age, performance status, comorbidities, lifestyle, behavior risk) should be considered. An efficient cooperation between the General practitioner and the Oncologic team is needed. PMID- 26228859 TI - [Early breast cancer in pre-menopausal women and endocrine treatment: which factors impact on decision-making process?]. AB - Incidence of breast cancer (BC), particularly in younger women, has increased in last decade. About forty percent of all BC are observed in women under the age of 50 years and, accordingly, in pre-menopausal women. Luminal-like is the most common subtype. Pre-menopausal status is associated with clinical, social and psychological issues that must be addressed as part of oncology care to guarantee the best global health outcomes after treatment. This review aims to answer the most common questions on endocrine treatment in pre-menopausal women. In particular, it focuses on the decision-making process that drives the choice about ovarian function suppression, use of aromatase inhibitors, and duration of therapy. PMID- 26228860 TI - [Cancer genetic counseling and quality of life: the effect of coping strategies and psychopathological symptoms during pre-test genetic counseling]. AB - The cancer genetic counseling (CGC) identifies genetic mutations for hereditary neoplastic diseases, but little is known on its psychological effects on subjects. METHODS: The present study involved women who underwent genetic counseling for breast or ovarian cancer: 19 unaffected, 43 current patients, and 28 past patients. The aim of the study was to examine the relation between coping strategies and the quality of life during genetic counseling before testing, considering the effects of psychopathological symptoms and the health status. RESULTS: Results showed that the use of avoidance strategies led to a decrease in quality of life, and that this relationship was entirely mediated by the intensity of psychopathological symptoms, while the health status did not show any effect on it. CONCLUSIONS: The study, which is the first in Italy, suggests the importance of assessing coping strategies in subjects who undergo the CGO to identify individuals who are at risk of decrease of psychological well-being. Indeed, psychological counselling improving coping strategies could preserve the psychological well-being of individuals. PMID- 26228861 TI - [Rehabilitation pathway after knee arthroplasty with mega prosthesis in osteosarcoma]. AB - INTRODUCTION: The knee is the most frequent location for osteosarcoma (60%). Until 30 years ago patients with osteosarcoma were treated with an amputation of the affected limb; today 85% of these cases are treated with a "Limb Salvage" procedure, through replacement of the affected bone with a mega prosthesis implant. AIM: To measure functional recovery of patients with a knee mega prosthesis and how rehabilitation impacts on quality of life (QOL); another aim is to define rehabilitation guidelines to manage these patients in the rehabilitation pathway. METHODS: A sample of outpatients with knee mega prosthesis were selected in the follow-up orthopedic oncology surgery between march and may 2013. We measured the functional outcome using the multidimensional standardized Musculoskeletal Tumor Society scale (MSTS) that gives a score (0-5) for each of 7 items: pain, range of motion, stability, deformity, strength, functional activity, emotional acceptance. RESULTS: The sample included 28 outpatients. The median MSTS score was 29 (min 19, max 33) equal to 83%. Only 14 patients (50%) followed a correct rehabilitation path after surgery. DISCUSSION: 21 cases got "excellent" outcomes and 3 "good" (based on MSTS classification). In few cases (n 4) the outcome was "fairly good", related to necessity of a prosthesis surgical revision based on instability of implant (because of usage). Quadricep strength is the item that most affects the final score. There is a statistically significant correlation between high scores and patients who have recently undergone surgery. We found higher scores in patients that followed a physiotherapy program after surgery: the difference was statistically significant. CONCLUSIONS: Mega-prosthesis implants give satisfactory functional outcomes. These outcomes keep high score in time. It is recommended to follow the guidelines described in the purposed rehabilitation program. PMID- 26228862 TI - [18F-FDG PET/CT in ocular and orbital abnormalities not only neopastic: comparison with traditional imaging]. AB - Orbital and ocular neoplasms are rare tumors that could be benign or malign, primary or metastatic. Abnormalities within the orbit present a challenge in evaluation for imaging, both for morphologic examinations (ME) as weel as computed tomography (CT) and magnetic resonance (MR) and [18F]-2-deoxy-D-glucose Positron emission tomography/computed tomography (18F-FDG PET/CT). The aim of our study was evaluate 18F-FDG PET/CT role in orbital abnormalities, comparing it with CT and MR. MATERIALS AND METHODS: A retrospective analysis of 67 patients (pts) (34 males and 33 females; mean age 59.91 years old) who performed 18F-FDG PET/CT for orbital and ocular abnormalities was performed. Comparison between 18F FDG PET/CT and ME was performed by Cohen's K also within the most representative hystologic subtypes. RESULTS: 18F-FDG PET/CT resulted positive in 19/67 pts. 47/67 pts performed ME (27/47 performed CT and 20/27 MR) within 20 days before 18F-FDG PET/CT and concordance was very poor (K=0.154). Considering 27/47 pts who performed CT, concordance was very poor (K=0.100). Considering the 20/47 pts who performed MR concordance was poor (K=0.266). Considering 19/47 pts with primary ocular NHL concordance resulted poor (K=0.269). Considering 6/47 pts with primary ocular melanoma concordance resulted very poor (K=0.182). In 9/47 pts with metastases diagnosis, concordance was absent (K=-0.189). CONCLUSIONS: CT and MR are ME that permit the evaluation of the orbital region even with limits related to the difficulties of the region. 18F-FDG PET/CT is a sensitive tecnique for several malignancies. The low concordance among 18F-FDG PET/CT and ME suggests their complementary role, then to associate 18F-FDG PET/CT even for the whole body evaluation. PMID- 26228863 TI - [Non-AIDS-associated cancer disorders. A novel scenario after over thirty years from HIV discovery? Clinical experience and literature appraisal]. AB - INTRODUCTION: Both natural history and epidemiological trend of HIV infection have been deeply modified by the introduction of highly active antiretroviral therapy (HAART), around twenty years ago. METHODS: However, despite a rapid drop of the incidence of the large majority of opportunistic infections, a slow, but continued increase of malignancies occurred, with particular evidence focused on cancers which are not strictly related to the definition of full blown AIDS (the so called non-AIDS-defining malignancies). RESULTS: The unique clinical occurrence of HIV infection complicated by even four non-AIDS-defining cancers prompted us to re-discuss the epidemiology and the possible pathogenesis, the clinical presentation, and the differential diagnosis of this pathologic presentation. CONCLUSIONS: On the ground of our experience in this field, and the available literature evidences, we discuss how this clinical occurrence is acting on HIV infection presentation during the HAART era of the third millennium. These changes need broad scale studies, and promise relevant consequences on etiopathogenetic, prevention, therapeutic, and management aspects of HIV disease in the next future. PMID- 26228864 TI - [Current approaches to the first-line treatment of clear-cell renal cell carcinoma]. AB - The medical treatment of renal cell carcinoma has been revolutionized in recent years, thanks to translation of our increasingly accurate knowledge on the molecular pathogenesis of this tumor, and of its clear cell histology in particular, into an accelerated drug development, and then into everyday's clinical practice. In this review, starting with the pathogenesis of clear cell renal cell carcinoma, we shall address the results of the clinical trials that led to the registration of seven targeted agents for this disease once orphan of active treatments, taking into account the different prognostic groups in which the patients suffering from it can be divided. Finally, we shall discuss the complex and controversial issue of the ideal timing to start a systemic treatment, a critical and still highly debated topic. All major international guidelines agree on the standard first line therapeutic options, which are represented by sunitinib, bevacizumab (associated with interferon-alpha) and pazopanib for patients with good or intermediate risk features, and temsirolimus for poor-risk patients. All these agents proved able to prolong progression-free survival within randomized phase III trials. The use of an observation period, before starting a systemic treatment, seems also reasonable, at least in the more indolent tumors and in patients with a better prognosis, even if the topic is still controversial. Finally, the individualization of therapy and the proper conduct of the same is essential for a successful outcome of the treatment. PMID- 26228865 TI - [Late complete response after long remission from treatment with FOLFIRI aflibercept for metastatic colorectal cancer after progression to FOLFOX bevacizumab]. AB - We report a case of a 59 years old man affected by an adenocarcinoma of the rectum RAS wild type with synchronous liver metastases, diagnosed on October, 2011. The patient underwent a left hemicolectomy with left hepatic lobectomy. In view of the recurrence of the disease from 18.01.2012 to 13.7.2012 we practiced first line chemotherapy with FOLFOX plus bevacizumab for 12 total cycles, obtaining a complete response, so the patient underwent clinical follow-up controls that proved negative until January, 2013, when, following the appearance of pain in the pelvis to the left, a total body PET with 18FDG was performed that documented the presence of bone metastases (left hemipelvis), confirmed histologically. Therefore from 03.18.2013 to 29.03.2013 the patient underwent a left ischium radiotherapy (for a total of 30 Gy). On May, 2013, a CT scan showed a progression of disease in the liver and so the patient started a II line chemotherapy with FOLFIRI and aflibercept, treatment still ongoing. At 46 months after diagnosis, the patient is in good general condition, presenting a complete response of the disease, demonstrated by a total body CT scan, performed in April 2015, completely negative. PMID- 26228866 TI - Standing for healthier lives--literally. PMID- 26228867 TI - Replacing sitting time with standing or stepping: associations with cardio metabolic risk biomarkers. AB - AIMS: While excessive sitting time is related adversely to cardio-metabolic health, it is unknown whether standing is a suitable replacement activity or whether ambulatory movement is required. Using isotemporal substitution analyses, we modelled cross-sectional associations with cardio-metabolic risk biomarkers of reallocating time (2 h/day) from sitting to standing or to stepping. METHODS AND RESULTS: A subsample of participants from the 2011/12 Australian Diabetes, Obesity, and Lifestyle Study wore the posture-based activPAL3 monitor [36-80 years (mean 57.9, SD 9.9 years); 57% women; n = 698 with data]. Associations of activPAL3-derived mean daily time sitting/lying (sitting), standing and stepping with body mass index (BMI), waist circumference, blood pressure, HbA1c, fasting glucose and lipids (high-density lipoprotein-, HDL, and low-density lipoprotein cholesterol, total/HDL-cholesterol ratio, and triglycerides), and 2-h plasma glucose were examined. Adjusted for relevant confounders, sitting-to-standing reallocations were only significantly (P < 0.05) associated with approximately 2% lower fasting plasma glucose, 11% lower triglycerides, 6% lower total/HDL cholesterol ratio, and 0.06 mmol/L higher HDL-cholesterol per 2 h/day. Sitting-to stepping reallocations were only significantly associated with approximately 11% lower BMI, 7.5 cm lower waist circumference, 11% lower 2-h plasma glucose, 14% lower triglycerides, and 0.10 mmol/L higher HDL-cholesterol per 2 h/ day, while standing-to-stepping reallocations were only significantly associated with ~10% lower BMI, 7 cm lower waist circumference, and 11% lower 2-h plasma glucose. CONCLUSION: Findings suggested that sitting-reduction strategies targeting increased standing, stepping, or both, may benefit cardio-metabolic health. Standing is a simple alternative to sitting, and requires further examination in prospective and intervention studies. PMID- 26228868 TI - Quality of life: a research gap in teledermatology. AB - An important outcome in healthcare, and in particular for dermatologic healthcare, is quality of life. Whereas the literature is well represented by quality of life assessments in dermatology, very little information is available that specifically addresses teledermatology's impact on quality of life. This gap in our knowledge of teledermatology is noteworthy precisely because of the importance that quality of life plays in dermatologic disease and healthcare delivery. The goal of this review is to briefly outline the concept of quality of life and its importance to dermatology, describe the different type of instruments that are used to assess quality of life, and to review studies that implemented teledermatology interventions and made quality of life assessments. The available literature has shown that teledermatology interventions do result in improved quality of life, and those changes correlate with improvements in disease severity and clinical course. Integrating quality of life assessments in future evaluations of teledermatology interventions would be valuable to provide a more comprehensive depiction of teledermatology's impact on patients receiving dermatology care via telemedicine. PMID- 26228869 TI - Ectopic extramammary Paget's disease on the head: case report and literature review. PMID- 26228870 TI - Life and Health: A Value in Itself for Human Beings? AB - The presence of a human being/organism--a living human 'whole', with the defining tendency to promote its own welfare--has value in itself, as do the functions which compose it. Life is inseparable from health, since without some degree of healthy functionality (if not in all cases active functioning) the living whole would not exist. The value of life differs both within a single life (in different periods or possible situations) and between lives (lives that vary in length, health or even physical maturity are not all equally fulfilled). As with any other form of human flourishing, the value of life-and-health must be distinguished from the moral importance of human beings: less fulfilled means not less important morally, but more in need of being fulfilled. That said, to say that life and health has value is not to say exactly what-if anything-that value requires by way of active promotion at a given time. Many factors must be taken into account in making health care decisions, even if the worth of all lives, and the dignity of all human beings, must in every case be acknowledged. PMID- 26228871 TI - Application of Plant Extracts for the Prevention of Dental Erosion: An in situ/in vitro Study. AB - OBJECTIVES: Antiadherent and antibacterial effects of certain plant extracts have been proven to be beneficial in preventive dentistry. In the present in situ/in vitro crossover study, the impact of plant extracts rich in polyphenols on the erosion-protective properties of the in situ pellicle was evaluated. METHODS: Individual splints were prepared for 12 subjects for intraoral exposure of bovine enamel specimens. Following formation of a 1-min pellicle, watery plant extracts (leaves of the wild form of Ribes nigrum, the wild form of Origanum as well as a combination of both) were administered for 10 min in situ. Alternatively, a mouth rinse with fluorides (Elmex Kariesschutz) was performed for 1 min. After further oral exposure for 19/28 min, respectively, slabs were removed and incubated with HCl in vitro over 120 s (pH 2, 2.3, 3). The resulting calcium and phosphate release was quantified photometrically. Slabs with and without a 30-min in situ pellicle served as controls. The modification of pellicle ultrastructure was evaluated by transmission electron microscopy (TEM). RESULTS: Plant extracts modulated the erosion-protective properties of the native in situ pellicle in all test groups in a pH-dependent manner. The combination of R. nigrum leaves and Origanum enhanced the protective properties of the pellicle at all pH values; the administration of this preparation was comparable, yet superior, to the effect of the fluoridated mouth rinse. TEM images indicated that rinsing with R. nigrum leaves/Origanum yielded a distinctly thicker and more electron-dense pellicle. CONCLUSION: The combination of certain plant extracts offers a novel approach to the complementary prevention of dental erosion. PMID- 26228872 TI - An indica rice genotype showed a similar yield enhancement to that of hybrid rice under free air carbon dioxide enrichment. AB - Although the rice growth response to FACE (free-air CO2 enrichment) has been widely studied and is considered important within the scientific community, few studies have attempted to examine the effects of FACE on the yield of indica rice, which is typically the parent of indica hybrids in China. The effects of FACE on the yield, yield components, biomass, N uptake and leaf photosynthesis of Yangdao 6 Hao (an indica rice) in China were examined over 2 years. The grain yield increased over 30%, the panicle number increased 12.4% on average, and the spikelet number per panicle also showed an average increase of 8.2% at elevated CO2. FACE caused a significant enhancement in both the filled spikelet percentage (+5.9%) and the individual grain weight (+3.0%). Compared with three prior FACE studies on rice, a similar enhancement of yield in hybrid indica was shown under FACE, with much a higher value than for the japonica rice cultivar (approximately + 13%) because of indica's stronger sink generation and N uptake capacity, which help coordinate the C/N balance to avoid photosynthetic acclimation. The high enhancement of the indica rice yield under FACE holds promise for improved cultivar selection for future food security. PMID- 26228873 TI - Atrial Tachycardias After Atrial Fibrillation Ablation Manifest Different Waveform Characteristics: Implications for Characterizing Tachycardias. AB - INTRODUCTION: Atrial fibrillation (AF) ablation patients often manifest atrial tachycardias (AT) with atypical ECG morphologies that preclude accurate localization and mechanism. Diagnostic maneuvers used to define ATs during electrophysiology studies can be limited by tachycardia termination or transformation. Additional methods of characterizing post-AF ablation ATs are required. METHODS AND RESULTS: We evaluated the utility of noninvasive ECG signal analytics in postablation AF patients for the following features: (1) Localization of ATs (i.e., right vs. left atrium), and (2) Identification of common left AT mechanisms (i.e., focal vs. macroreentrant). Atrial waveforms from the surface ECG were used to analyze (1) spectral organization, including dominant amplitude (DA) and mean spectral profile (MP), and (2) temporospatial variability, using temporospatial correlation coefficients. We studied 94 ATs in 71 patients who had undergone prior pulmonary vein isolation for AF and returned for a second ablation: (1) right atrial cavotricuspid-isthmus dependent (CTI) ATs (n = 21); (2) left atrial macroreentrant ATs (n = 41) and focal ATs (n = 32). Right CTI ATs manifested higher DAs and lower MPs than left ATs, indicative of greater stability and less complexity in the frequency spectrum. Left macroreentrant ATs possessed higher temporospatial organization than left focal ATs. CONCLUSIONS: Noninvasively recorded atrial waveform signal analyses show that right ATs possess more stable activation properties than left ATs, and left macroreentrant ATs manifest higher temporospatial organization than left focal ATs. Further prospective analyses evaluating the role these novel ECG-derived tools can play to help localize and identify mechanisms of common ATs in AF ablation patients are warranted. PMID- 26228874 TI - Chemotherapy does not improve quality of life in cancer patients at end of life, US study finds. PMID- 26228876 TI - Computerized Angiographic Occlusion Rating for Ruptured Clipped Aneurysms is Superior to Subjective Occlusion Rating. AB - BACKGROUND AND PURPOSE: The computerized occlusion rating to estimate angiographic occlusion of embolized aneurysms is superior to the subjective occlusion rating. In this study, we compared the 2 methods in the analysis of aneurysms clipped after subarachnoid hemorrhage. MATERIALS AND METHODS: The pre- and postoperative angiographic images (DSA) of 95 selected patients were analyzed and stratified in 4 grades (grade 0 for 100%, grade I for <99%-90%, grade II for <89%-70%, grade III for <70% occlusion) by using the subjective (angiographic) occlusion rating and the computerized (angiographic) occlusion rating. For the subjective occlusion rating, the occlusion rate was estimated; for the computerized occlusion rating, the "occluded" and "nonoccluded" aneurysm areas were automatically calculated in square millimeters after outlining the ideal occlusion line. RESULTS: With the subjective occlusion rating, 75 (78.9%), 12 (12.6%), 7 (7.4%), and 1 (1.1%) and with the computerized occlusion rating 45 (47.4%), 24 (25.3%), 20 (21.0%), and 6 (6.3%) patients had aneurysms stratified to grades 0, I, II and III, respectively. The interobserver variation was significant with the subjective occlusion rating but not with the computerized occlusion rating. The subjective occlusion rating overestimated aneurysm occlusion in 30 (31.6%) patients. Mean values were the following: subjective occlusion rating of 97.5 +/- 6.3% and computerized occlusion rating of 93.5 +/- 9.7%; P = < .001. No patient rebled, and 4 patients underwent retreatment during 36 +/- 38.9 months; the predictive value (log-rank, Kaplan-Meier) of the subjective and computerized occlusion ratings with respect to retreatment was highly significant for both methods (subjective occlusion rating: chi(2), 29.65; P < .001; computerized occlusion rating: chi(2), 35.57, P < .001). CONCLUSIONS: The 2 methods showed remarkable differences in the estimation of the angiographic occlusion rates of clipped aneurysms. The clearly lower interobserver variation of the computerized versus subjective occlusion rating may indicate a superiority of the computerized occlusion rating. PMID- 26228877 TI - Carotid Webs and Recurrent Ischemic Strokes in the Era of CT Angiography. AB - BACKGROUND AND PURPOSE: Carotid webs may cause recurrent ischemic stroke. We describe the prevalence, demographics, clinical presentation, imaging features, histopathology, and stroke risk associated with this under-recognized lesion. MATERIALS AND METHODS: A carotid web was defined on CTA as a thin intraluminal filling defect along the posterior wall of the carotid bulb just beyond the carotid bifurcation on oblique sagittal section CTA that was seen as a septum on axial CTA. Using a prospective case series from April 2013 to April 2014, we describe the demographics, spectrum of imaging features on CTA, and histopathology of these carotid webs. From a retrospective analysis of patients at our center from May 2012 to April 2013 who had a baseline head and neck CTA followed by a brain MR imaging within 1-2 days of the CTA, we determine the period prevalence of carotid webs and the prevalence of ipsilateral stroke on imaging. RESULTS: In the prospective series, the mean age was 50 years (range, 41 55 years); 5/7 patients were women. Recurrent stroke was seen in 5/7 (71.4%) patients with the carotid web; time to recurrence ranged from 1 to 97 months. Histopathology suggested a high probability of fibromuscular dysplasia. In the retrospective series, carotid webs were seen in 7/576 patients for a hospital based-period prevalence of 1.2% (95% CI, 0.4%-2.5%). Two of these 7 patients had acute stroke in the vascular territory of the carotid web. CONCLUSIONS: A carotid web may contribute to recurrent ischemic stroke in patients with no other determined stroke mechanism. Intimal variant fibromuscular dysplasia is the pathologic diagnosis in most cases. The prevalence of carotid web is low, while the optimal management strategy remains unknown. PMID- 26228878 TI - Ultra-High-Field MRI Visualization of Cortical Multiple Sclerosis Lesions with T2 and T2*: A Postmortem MRI and Histopathology Study. AB - BACKGROUND AND PURPOSE: At 7T MR imaging, T2*-weighted gradient echo has been shown to provide high-resolution anatomic images of gray matter lesions. However, few studies have verified T2*WI lesions histopathologically or compared them with more standard techniques at ultra-high-field strength. This study aimed to determine the sensitivity of T2WI and T2*WI sequences for detecting cortical GM lesions in MS. MATERIALS AND METHODS: At 7T, 2D multiecho spin-echo T2WI and 3D gradient-echo T2*WI were acquired from 27 formalin-fixed coronal hemispheric brain sections of 15 patients and 4 healthy controls. Proteolipid-stained tissue sections (8 MUm) were matched to the corresponding MR images, and lesions were manually scored on both MR imaging sequences (blinded to histopathology) and tissue sections (blinded to MR imaging). The sensitivity of MR imaging sequences for GM lesion types and white matter lesions was calculated. An unblinded retrospective scoring was also performed. RESULTS: If all cortical GM lesions were taken into account, the T2WI sequence detected slightly more lesions than the T2*WI sequence: 28% and 16%, respectively (P = .054). This difference disappeared when only intracortical lesions were considered. When histopathologic information (type, location) was revealed to the reader, the sensitivity went up to 84% (T2WI) and 85% (T2*WI) (not significant). Furthermore, the false-positive rate was 8.6% for the T2WI and 10.5% for the T2*WI sequence. CONCLUSIONS: There is no strong advantage of the T2*WI sequence compared with a conventional T2WI sequence in the detection of cortical lesions at 7T. Retrospectively, a high percentage of lesions could be detected with both sequences. However, many lesions are still missed prospectively. This could possibly be minimized with better a priori observer training. PMID- 26228879 TI - RNA-Sequencing Analysis of Messenger RNA/MicroRNA in a Rabbit Aneurysm Model Identifies Pathways and Genes of Interest. AB - BACKGROUND AND PURPOSE: Rabbit aneurysm models are used for the testing of embolization devices and elucidating the mechanisms of human intracranial aneurysm growth and healing. We used RNA-sequencing technology to identify genes relevant to induced rabbit aneurysm biology and to identify genes and pathways of potential clinical interest. This process included sequencing microRNAs, which are important regulatory noncoding RNAs. MATERIALS AND METHODS: Elastase-induced saccular aneurysms were created at the origin of the right common carotid artery in 6 rabbits. Messenger RNA and microRNA were isolated from the aneurysm and from the control left common carotid artery at 12 weeks and processed by using RNA sequencing technology. The results from RNA sequencing were analyzed by using the Ingenuity Pathway Analysis tool. RESULTS: A total of 9396 genes were analyzed by using RNA sequencing, 648 (6.9%) of which were found to be significantly differentially expressed between the aneurysms and control tissues (P < .05; false-discovery rate, <0.01; fold change, >2 or <.5). Of these genes, 614 were mapped successfully, 143 were down-regulated, and 471 were up-regulated in the aneurysms as compared with controls. Using the same criteria for significance, 3 microRNAs were identified as down-regulated and 5 were identified as up regulated. Pathway analysis associated these genes with inflammatory response, cellular migration, and coagulation, among other functions and pathologies. CONCLUSIONS: RNA-sequencing analysis of rabbit aneurysms revealed differential regulation of some key pathways, including inflammation and antigen presentation. ANKRD1 and TACR1 were identified as genes of interest in the regulation of matrix metalloproteinases. PMID- 26228880 TI - White Matter Development is Potentially Influenced in Adolescents with Vertically Transmitted HIV Infections: A Tract-Based Spatial Statistics Study. AB - BACKGROUND AND PURPOSE: Convergent evidence indicates that HIV is associated with abnormal WM microstructure in adults. However, little is known about whether HIV affects WM development in adolescents. In this study, we used DTI to investigate the integrity of WM microstructure in adolescents with vertically transmitted HIV infections. MATERIALS AND METHODS: Fifteen HIV-positive adolescents with vertically transmitted infections and 26 HIV-negative controls participated in this study. Whole-brain analysis of fractional anisotropy was performed by Tract Based Spatial Statistics to localize abnormal WM regions between groups. VOI analysis was further performed to explore the changes in diffusivity indices in the regions with fractional anisotropy alterations. Correlation analyses were used to assess the relationship between fractional anisotropy alterations and clinical measures within the HIV-positive group. RESULTS: Relative to HIV negative controls, HIV-positive adolescents demonstrated significantly reduced fractional anisotropy in the corpus callosum, superior and posterior corona radiata, frontal and parietal WM, pre-/postcentral gyrus, and superior longitudinal fasciculus. In the affected regions, fractional anisotropy reductions were caused by an increase in radial diffusivity, and no changes were observed in axial diffusivity. Moreover, fractional anisotropy values in the bilateral frontal WM were negatively correlated with the duration of highly active antiretroviral therapy and were positively associated with the age at onset of highly active antiretroviral therapy. CONCLUSIONS: These findings suggest that early HIV infections may affect WM development, especially in the frontal WM, corpus callosum, and corona radiata in adolescents, which may be associated with hypomyelination and demyelination. Moreover, WM integrity may serve as a potential new treatment target. PMID- 26228881 TI - Hyperintense Vessels on T2-PROPELLER-FLAIR in Patients with Acute MCA Stroke: Prediction of Arterial Stenosis and Perfusion Abnormality. AB - BACKGROUND AND PURPOSE: Fluid-attenuated inversion recovery hyperintense vessels in stroke represent leptomeningeal collateral flow. We presumed that FLAIR hyperintense vessels would be more closely associated with arterial stenosis and perfusion abnormality in ischemic stroke on T2-PROPELLER-FLAIR than on T2-FLAIR. MATERIALS AND METHODS: We retrospectively reviewed 35 patients with middle cerebral territorial infarction who underwent MR imaging. FLAIR hyperintense vessel scores were graded according to the number of segments with FLAIR hyperintense vessels in the MCA ASPECTS areas. We compared the predictability of FLAIR hyperintense vessels between T2-PROPELLER-FLAIR and T2-FLAIR for large artery stenosis. The interagreement between perfusion abnormality and FLAIR hyperintense vessels was assessed. In subgroup analysis (9 patients with MCA horizontal segment occlusion), the association of FLAIR hyperintense vessels with ischemic lesion volume and perfusion abnormality volume was evaluated. RESULTS: FLAIR hyperintense vessel scores were significantly higher on T2-PROPELLER-FLAIR than on T2-FLAIR (3.50 +/- 2.79 versus 1.21 +/- 1.47, P < .01), and the sensitivity for large-artery stenosis was significantly improved on T2-PROPELLER FLAIR (93% versus 68%, P = .03). FLAIR hyperintense vessels on T2-PROPELLER-FLAIR were more closely associated with perfusion abnormalities than they were on T2 FLAIR (kappa = 0.64 and kappa = 0.27, respectively). In subgroup analysis, FLAIR hyperintense vessels were positively correlated with ischemic lesion volume on T2 FLAIR, while the mismatch of FLAIR hyperintense vessels between the 2 sequences was negatively correlated with ischemic lesion volume (P = .01). CONCLUSIONS: In MCA stroke, FLAIR hyperintense vessels were more prominent on T2-PROPELLER-FLAIR compared with T2-FLAIR. In addition, FLAIR hyperintense vessels on T2-PROPELLER FLAIR have a significantly higher sensitivity for predicting large-artery stenosis than they do on T2-FLAIR. Moreover, the areas showing FLAIR hyperintense vessels on T2-PROPELLER-FLAIR were more closely associated with perfusion abnormality than those on T2-FLAIR. PMID- 26228882 TI - WEB-DL Endovascular Treatment of Wide-Neck Bifurcation Aneurysms: Long-Term Results in a European Series. AB - BACKGROUND AND PURPOSE: Flow disruption with the WEB-DL device has been used safely for the treatment of wide-neck bifurcation aneurysms. The stability of aneurysm occlusion after this treatment was evaluated in the short and midterm, but not in the long term. This retrospective multicenter European study is the continuation of an already published series dealing with short- and midterm anatomic results and analyzes long-term data in patients treated with the WEB-DL. MATERIALS AND METHODS: Twelve European neurointerventional centers initially participated in the study. In addition to data collected for the initial publication, images obtained at long-term follow-up were collected and independently analyzed by the same experienced interventional neuroradiologist. RESULTS: Of the initial 45 patients, 26 (20 women and 6 men; 35-73 years of age; mean, 55.2 +/- 10.6 years; median, 55.5 years) with 26 aneurysms treated with the WEB-DL device had long-term follow-up (median, 27.4 months). Three of 26 patients (11.5%) were retreated between short- and midterm follow-up, and none, between mid- and long-term follow-up. Long-term aneurysm occlusion in the 19 patients treated with the WEB only and not retreated during follow-up was complete occlusion in 13/19 patients (68.4%), including aneurysms with opacification of the proximal recess in 9/19 patients (47.4%), neck remnant in 3/19 patients (15.8%), and aneurysm remnant in 3/19 patients (15.8%). In all patients (100.0%), aneurysm occlusion was stable between midterm and long-term follow-up. CONCLUSIONS: The results suggest that WEB treatment of wide-neck bifurcation aneurysms offers long-term stable occlusion. PMID- 26228883 TI - Correlation of Asymmetry Indices Measured by Arterial Spin-Labeling MR Imaging and SPECT in Patients with Crossed Cerebellar Diaschisis. AB - BACKGROUND AND PURPOSE: Crossed cerebellar diaschisis, not only a secondary result of supratentorial infarction but also an indicator of clinical outcomes, has frequently been reported on PET and SPECT but has been rarely described with arterial spin-labeling MR imaging. The purpose of this study was to determine the ability of arterial spin-labeling MR imaging to evaluate crossed cerebellar diaschisis compared with that of SPECT. To our knowledge, this is the first study to validate arterial spin-labeling in crossed cerebellar diaschisis by using SPECT as a reference standard. MATERIALS AND METHODS: This study included 16 patients in whom crossed cerebellar diaschisis was shown on SPECT and 10 control subjects in whom crossed cerebellar diaschisis was not shown on SPECT. During the qualitative analysis, asymmetric cerebellar perfusion on arterial spin-labeling was divided into 1 of the following 3 grades by 2 blinded observers: the affected cerebellum was isointense compared with the unaffected cerebellum (grade I), it was slightly hypointense (grade II), or it was markedly hypointense (grade III). In the quantitative analysis, asymmetry indices were calculated by using SPECT and arterial spin-labeling images. For statistical analysis, kappa statistics, the interobserver correlation coefficient, the independent t test, Pearson correlation, and linear regression analysis were used. RESULTS: Almost all the diagnoses of crossed cerebellar diaschisis on SPECT were noted on arterial spin labeling in both qualitative and quantitative analyses with good interobserver agreement (kappa = 0.961; interobserver correlation coefficient, 0.806). The mean asymmetry index of arterial spin-labeling (26.06 +/- 9.00) was significantly larger than that for SPECT (15.28 +/- 5.34; P < .001). There was a significant positive correlation between the asymmetry indices obtained for SPECT and those for arterial spin-labeling (r = 0.77 [95% CI, 0.443-0.916]; P < .001). The relationship of asymmetry indices between SPECT and arterial spin-labeling (x, y) was calculated as y = 6.2131 + 1.2986x (R(2) = 0.592; P < .001). CONCLUSIONS: Arterial spin-labeling can be a noninvasive alternative to SPECT for evaluating crossed cerebellar diaschisis. PMID- 26228884 TI - Early Quantification of Hematoma Hounsfield Units on Noncontrast CT in Acute Intraventricular Hemorrhage Predicts Ventricular Clearance after Intraventricular Thrombolysis. AB - BACKGROUND AND PURPOSE: Thrombolytic efficacy of intraventricular rtPA for acute intraventricular hemorrhage may depend on hematoma composition. We assessed whether hematoma Hounsfield unit quantification informs intraventricular hemorrhage clearance after intraventricular rtPA. MATERIALS AND METHODS: Serial NCCT was performed on 52 patients who received intraventricular rtPA as part of the Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage trial and 12 controls with intraventricular hemorrhage, but no rtPA treatment. A blinded investigator calculated Hounsfield unit values for intraventricular hemorrhage volumes on admission (t0), days 3-4 (t1), and days 6 9 (t2). Controls were matched uniquely to 12 rtPA-treated patients for comparison. RESULTS: Median intraventricular hemorrhage volume on admission for patients treated with intraventricular rtPA was 31.9 mL (interquartile range, 34.1 mL), and it decreased to 4.9 mL (interquartile range, 14.5 mL) (t2). Mean (+/-standard error of the mean) Hounsfield unit for intraventricular hemorrhage was 52.1 (0.59) at t0 and decreased significantly to 50.1 (0.63) (t1), and to 45.1 (0.71) (t2). Total intraventricular hemorrhage Hounsfield unit count was significantly correlated with intraventricular hemorrhage volume at all time points (t0: P = .002; t1: P < .001; t2: P < .001). On serologic and CSF analysis at t0, only higher CSF protein was positively correlated with intraventricular hemorrhage Hounsfield units (P = .03). In 24 matched patients treated with rtPA and controls, total intraventricular hemorrhage Hounsfield units were significantly lower in patients treated with rtPA at t2 (P = .02). Higher Hounsfield unit quantification of fourth ventricle hematomas independently predicted slower clearance of this ventricle (95% CI, 0.02-0.14; P = .02), along with higher intraventricular hemorrhage volume (95% CI, 0.02-0.41; P = .03) and lower CSF protein levels (95% CI, -0.003 to -0.002; P < .001). CONCLUSIONS: Intraventricular hemorrhage Hounsfield unit counts decrease significantly in the acute phase and to a greater extent with intraventricular rtPA treatment. Intraventricular hemorrhage Hounsfield units are correlated significantly with CSF protein and not with serum erythrocyte or platelet concentrations. Hounsfield unit counts may reflect intraventricular hemorrhage clot composition and rtPA sensitivity. PMID- 26228885 TI - Accuracy of Preoperative Imaging in Detecting Nodal Extracapsular Spread in Oral Cavity Squamous Cell Carcinoma. AB - BACKGROUND AND PURPOSE: The increasing impact of diagnosing extracapsular spread by using imaging, especially in patients with oropharyngeal squamous cell carcinoma, highlights the need to rigorously evaluate the diagnostic accuracy of imaging. Previous analysis suggested 62.5%-80.9% sensitivity and 60%-72.7% specificity. Our goals were to evaluate the accuracy of imaging in diagnosing extracapsular spread in a cohort of patients with oral cavity squamous cell carcinoma (pathologic confirmation of extracapsular spread routinely available), as a proxy for oropharyngeal squamous cell carcinoma, and to independently assess the reliability of imaging features (radiographic lymph node necrosis, irregular borders/stranding, gross invasion, and/or node size) in predicting pathologically proven extracapsular spread. MATERIALS AND METHODS: One hundred eleven consecutive patients with untreated oral cavity squamous cell carcinoma and available preoperative imaging and subsequent lymph node dissection were studied. Two neuroradiologists blinded to pathologically proven extracapsular spread status and previous radiology reports independently reviewed all images to evaluate the largest suspicious lymph node along the expected drainage pathway. Radiologic results were correlated with pathologic results from the neck dissections. RESULTS: Of 111 patients, 29 had radiographically determined extracapsular spread. Pathologic examination revealed that 28 of 111 (25%) had pathologically proven extracapsular spread. Imaging sensitivity and specificity for extracapsular spread were 68% and 88%, respectively. Radiographs were positive for lymph node necrosis in 84% of the patients in the pathology-proven extracapsular spread group and negative in only 7% of those in the pathologically proven extracapsular spread-negative group. On logistic regression analysis, necrosis (P = .001), irregular borders (P = .055), and gross invasion (P = .068) were independently correlated with pathologically proven extracapsular spread. CONCLUSIONS: Although the specificity of cross-sectional imaging for extracapsular spread was high, the sensitivity was low. Combined logistic regression analysis found that the presence of necrosis was the best radiologic predictor of pathologically proven extracapsular spread, and irregular borders and gross invasion were nearly independently significant. PMID- 26228886 TI - Comparison of the Diagnostic Accuracy of DSC- and Dynamic Contrast-Enhanced MRI in the Preoperative Grading of Astrocytomas. AB - BACKGROUND AND PURPOSE: Dynamic contrast-enhanced MR imaging parameters can be biased by poor measurement of the vascular input function. We have compared the diagnostic accuracy of dynamic contrast-enhanced MR imaging by using a phase derived vascular input function and "bookend" T1 measurements with DSC MR imaging for preoperative grading of astrocytomas. MATERIALS AND METHODS: This prospective study included 48 patients with a new pathologic diagnosis of an astrocytoma. Preoperative MR imaging was performed at 3T, which included 2 injections of 5-mL gadobutrol for dynamic contrast-enhanced and DSC MR imaging. During dynamic contrast-enhanced MR imaging, both magnitude and phase images were acquired to estimate plasma volume obtained from phase-derived vascular input function (Vp_Phi) and volume transfer constant obtained from phase-derived vascular input function (K(trans)_Phi) as well as plasma volume obtained from magnitude-derived vascular input function (Vp_SI) and volume transfer constant obtained from magnitude-derived vascular input function (K(trans)_SI). From DSC MR imaging, corrected relative CBV was computed. Four ROIs were placed over the solid part of the tumor, and the highest value among the ROIs was recorded. A Mann-Whitney U test was used to test for difference between grades. Diagnostic accuracy was assessed by using receiver operating characteristic analysis. RESULTS: Vp_ Phi and K(trans)_Phi values were lower for grade II compared with grade III astrocytomas (P < .05). Vp_SI and K(trans)_SI were not significantly different between grade II and grade III astrocytomas (P = .08-0.15). Relative CBV and dynamic contrast-enhanced MR imaging parameters except for K(trans)_SI were lower for grade III compared with grade IV (P <= .05). In differentiating low- and high grade astrocytomas, we found no statistically significant difference in diagnostic accuracy between relative CBV and dynamic contrast-enhanced MR imaging parameters. CONCLUSIONS: In the preoperative grading of astrocytomas, the diagnostic accuracy of dynamic contrast-enhanced MR imaging parameters is similar to that of relative CBV. PMID- 26228887 TI - HydroCoils Are Associated with Lower Angiographic Recurrence Rates Than Are Bare Platinum Coils in Treatment of "Difficult-to-Treat" Aneurysms: A Post Hoc Subgroup Analysis of the HELPS Trial. AB - BACKGROUND AND PURPOSE: The HydroCoil Endovascular Aneurysm Occlusion and Packing Study was a randomized controlled trial that compared HydroCoils to bare platinum coils. Using data from this trial, we performed a subgroup analysis of angiographic and clinical outcomes of patients with "difficult-to-treat" aneurysms, defined as irregularly shaped and/or having a dome-to-neck ratio of <1.5. MATERIALS AND METHODS: Separate subgroup analyses comparing outcomes of treatment with HydroCoils to that of bare platinum coils were performed for the following: 1) irregularly shaped aneurysms, 2) regularly shaped aneurysms, 3) aneurysms with a dome-to-neck ratio of <1.5, and 4) aneurysms with a dome-to-neck ratio of >=1.5. For each subgroup analysis, the following outcomes were studied at the last follow-up (3-18 months): 1) any recurrence, 2) major recurrence, 3) re-treatment, and 4) an mRS score of <=2. Multivariate logistic regression analysis was performed to determine if the HydroCoil was independently associated with improved outcomes in these subgroups. RESULTS: Among the patients with an irregularly shaped aneurysm, the HydroCoil was associated with lower major recurrence rates than the bare platinum coils (17 of 66 [26%] vs 30 of 69 [44%], respectively; P = .046). Among the patients with an aneurysm with a small dome-to neck ratio, the HydroCoil was associated with lower major recurrence rates than the bare platinum coils (18 of 73 [24.7%] vs 32 of 76 [42.1%], respectively; P = .02). No difference in major recurrence was seen between HydroCoils and bare platinum coils for regularly shaped aneurysms (42 of 152 [27.6%] vs 52 of 162 [32.1%], respectively; P = .39) or aneurysms with a large dome-to-neck ratio (41 of 145 [28.3%] vs 50 of 155 [32.3%], respectively; P = .53). CONCLUSIONS: This unplanned post hoc subgroup analysis found that HydroCoils are associated with improved angiographic outcomes in the treatment of irregularly shaped aneurysms and aneurysms with a dome-to-neck ratio of <1.5. Because this was a post hoc analysis, these results are not reliable and absolutely should not alter clinical practice but, rather, may inform the design of future randomized controlled trials. PMID- 26228888 TI - Cerebral Microbleeds in Patients with Dementia with Lewy Bodies and Parkinson Disease Dementia. AB - BACKGROUND AND PURPOSE: The burden of amyloid beta is greater in patients with dementia with Lewy bodies than in those with Parkinson disease dementia, and an increased amyloid beta load is closely related to a higher incidence of cerebral microbleeds. Here, we investigated the prevalence and topography of cerebral microbleeds in patients with dementia with Lewy bodies and those with Parkinson disease dementia to examine whether cerebral microbleeds are more prevalent in patients with dementia with Lewy bodies than in those with Parkinson disease dementia. MATERIALS AND METHODS: The study population consisted of 42 patients with dementia with Lewy bodies, 88 patients with Parkinson disease dementia, and 35 controls who underwent brain MR imaging with gradient recalled-echo. Cerebral microbleeds were classified as deep, lobar, or infratentorial. RESULTS: The frequency of cerebral microbleeds was significantly greater in patients with dementia with Lewy bodies (45.2%) than in those with Parkinson disease dementia (26.1%) or in healthy controls (17.1%; P = .017). Lobar cerebral microbleeds were observed more frequently in the dementia with Lewy bodies group (40.5%) than in the Parkinson disease dementia (17%; P = .004) or healthy control (8.6%; P = .001) group, whereas the frequencies of deep and infratentorial cerebral microbleeds did not differ among the 3 groups. Logistic regression analyses revealed that, compared with the healthy control group, the dementia with Lewy bodies group was significantly associated with the presence of lobar cerebral microbleeds after adjusting for age, sex, nonlobar cerebral microbleeds, white matter hyperintensities, and other vascular risk factors (odds ratio, 4.39 [95% CI, 1.27-15.25]). However, compared with the healthy control group, the Parkinson disease dementia group was not significantly associated with lobar cerebral microbleeds. CONCLUSIONS: This study showed that patients with dementia with Lewy bodies had a greater burden of cerebral microbleeds and exhibited a lobar predominance of cerebral microbleeds than did patients with Parkinson disease dementia. PMID- 26228890 TI - Cortical Activation Through Passive-Motion Functional MRI. AB - BACKGROUND AND PURPOSE: Functional brain mapping is an important technique for neurosurgical planning, particularly for patients with tumors or epilepsy; however, mapping has traditionally involved invasive techniques. Existing noninvasive techniques require patient compliance and may not be suitable for young children. We performed a retrospective review of our experience with passive-motion functional MR imaging in anesthetized patients to determine the diagnostic yield of this technique. MATERIALS AND METHODS: A retrospective review of patients undergoing passive-motion fMRI under general anesthesia at a single institution over a 2.5-year period was performed. Clinical records were evaluated to determine the indication for fMRI, the ability to detect cortical activation, and, if present, the location of cortical activation. RESULTS: We identified 62 studies in 56 patients in this time period. The most common indication for fMRI was epilepsy/seizures. Passive-motion fMRI identified upper-extremity cortical activation in 105 of 119 (88%) limbs evaluated, of which 90 (86%) activations were in an orthotopic location. Lower-extremity cortical activation was identified in 86 of 118 (73%) limbs evaluated, of which 73 (85%) activations were in an orthotopic location. CONCLUSIONS: Passive-motion fMRI was successful in identifying cortical activation in most of the patients. This tool can be implemented easily and can aid in surgical planning for children with tumors or candidates for epilepsy surgery, particularly those who may be too young to comply with existing noninvasive functional measures. PMID- 26228891 TI - Wall Mechanical Properties and Hemodynamics of Unruptured Intracranial Aneurysms. AB - BACKGROUND AND PURPOSE: Aneurysm progression and rupture is thought to be governed by progressive degradation and weakening of the wall in response to abnormal hemodynamics. Our goal was to investigate the relationship between the intra-aneurysmal hemodynamic conditions and wall mechanical properties in human aneurysms. MATERIALS AND METHODS: A total of 8 unruptured aneurysms were analyzed. Computational fluid dynamics models were constructed from preoperative 3D rotational angiography images. The aneurysms were clipped, and the domes were resected and mechanically tested to failure with a uniaxial testing system under multiphoton microscopy. Linear regression analysis was performed to explore possible correlations between hemodynamic quantities and the failure characteristics and stiffness of the wall. RESULTS: The ultimate strain was correlated negatively to aneurysm inflow rate (P = .021), mean velocity (P = .025), and mean wall shear stress (P = .039). It was also correlated negatively to inflow concentration, oscillatory shear index, and measures of the complexity and instability of the flow; however, these trends did not reach statistical significance. The wall stiffness at high strains was correlated positively to inflow rate (P = .014), mean velocity (P = .008), inflow concentration (P = .04), flow instability (P = .006), flow complexity (P = .019), wall shear stress (P = .002), and oscillatory shear index (P = .004). CONCLUSIONS: In a study of 8 unruptured intracranial aneurysms, ultimate strain was correlated negatively with aneurysm inflow rate, mean velocity, and mean wall shear stress. Wall stiffness was correlated positively with aneurysm inflow rate, mean velocity, wall shear stress, flow complexity and stability, and oscillatory shear index. These trends and the impact of hemodynamics on wall structure and mechanical properties should be investigated further in larger studies. PMID- 26228893 TI - Elecsys((r)) AMH Assay: A Review in Anti-Mullerian Hormone Quantification and Assessment of Ovarian Reserve. AB - The Elecsys((r)) AMH assay is an in vitro, fully automated assay indicated for the quantification of anti-Mullerian hormone (AMH) in human serum/lithium-plasma, which (in conjunction with other clinical and laboratory findings) can help to determine ovarian reserve. The assay is highly sensitive and precise, with a broad linear range, and correlates well with manual AMH assays and transvaginal sonographic assessment of antral follicle count, but has the benefit of being less variable. The Elecsys((r)) AMH assay also has a shorter testing time than some other AMH assays and was shown to provide a reproducible measure of ovarian reserve in women of reproductive age in a large prospective cohort study, demonstrating its usefulness in this setting. PMID- 26228892 TI - Outcome Differences between Intra-Arterial Iso- and Low-Osmolality Iodinated Radiographic Contrast Media in the Interventional Management of Stroke III Trial. AB - BACKGROUND AND PURPOSE: Intracarotid arterial infusion of nonionic, low-osmolal iohexol contrast medium has been associated with increased intracranial hemorrhage in a rat middle cerebral artery occlusion model compared with saline infusion. Iso-osmolal iodixanol (290 mOsm/kg H2O) infusion demonstrated smaller infarcts and less intracranial hemorrhage compared with low-osmolal iopamidol and saline. No studies comparing iodinated radiographic contrast media in human stroke have been performed, to our knowledge. We hypothesized that low-osmolal contrast media may be associated with worse outcomes compared with iodixanol in the Interventional Management of Stroke III Trial (IMS III). MATERIALS AND METHODS: We reviewed prospective iodinated radiographic contrast media data for 133 M1 occlusions treated with endovascular therapy. We compared 5 prespecified efficacy and safety end points (mRS 0-2 outcome, modified TICI 2b-3 reperfusion, asymptomatic and symptomatic intracranial hemorrhage, and mortality) between those receiving iodixanol (n = 31) or low-osmolal contrast media (n = 102). Variables imbalanced between iodinated radiographic contrast media types or associated with outcome were considered potential covariates for the adjusted models. In addition to the iodinated radiographic contrast media type, final covariates were those selected by using the stepwise method in a logistic regression model. Adjusted relative risks were then estimated by using a log-link regression model. RESULTS: Of baseline or endovascular therapy variables potentially linked to outcome, prior antiplatelet agent use was more common and microcatheter iodinated radiographic contrast media injections were fewer with iodixanol. Relative risk point estimates are in favor of iodixanol for the 5 prespecified end points with M1 occlusion. The percentage of risk differences are numerically greater for microcatheter injections with iodixanol. CONCLUSIONS: While data favoring the use of iso-osmolal iodixanol for reperfusion of M1 occlusion following IV rtPA are inconclusive, potential pathophysiologic mechanisms suggesting clinical benefit warrant further investigation. PMID- 26228894 TI - Prostaglandin E-mediated molecular mechanisms driving remodeling of the ductus arteriosus. AB - The ductus arteriosus (DA), a fetal arterial connection between the pulmonary arteries and aorta, normally closes after birth. Persistent DA patency usually has life-threatening consequences. In certain DA-dependent congenital heart diseases, however, patient survival depends on maintaining DA patency. Complete closure of the DA involves both functional closure, induced by muscle contraction, and anatomical closure, achieved through morphological and molecular remodeling. Anatomical closure of the DA is associated with the formation of intimal thickening, which is characterized by deposition of extracellular matrix in the subendothelial region, sparse elastic fiber formation, and migration of medial smooth muscle cells into the subendothelial space. In addition, fetal molecular remodeling that is suitable for postnatal muscle contraction has been observed in the DA. After the second trimester, high concentration of prostaglandin E2 (PGE2) causes the DA to dilate through the remainder of the fetal period. Emerging evidence from studies using pharmacological approaches and genetically modified mice suggests that, in addition to its vasodilatory effect, this chronic exposure to PGE2 promotes DA-specific anatomical and molecular remodeling through EP4, one of four receptor subtypes for PGE2. Signals that are downstream of PGE2-EP4, such as cyclic AMP (cAMP)-protein kinase A (PKA), exchange protein activated by cAMP (Epac), phospholipase C, and Wnt/beta-catenin, may be involved in the regulation of intimal thickening, elastogenesis, and contraction-related genes. Understanding the physiological role of PGE2 in DA remodeling could enable more effective regulation of PDA, both in isolation and in the context of congenital cardiac anomalies. PMID- 26228895 TI - Trial of labour in twin pregnancies: a retrospective cohort study. AB - OBJECTIVE: To assess the success rate of vaginal delivery among women with twin pregnancies; the Twin Birth Study has shown that vaginal delivery and caesarean section are equally safe for twin delivery but >40% of the planned vaginal delivery group delivered by caesarean section. DESIGN: A retrospective cohort study. SETTING: A tertiary medical centre. POPULATION: A total of 2194 women with twin pregnancies not complicated with very low birthweight. METHODS: Planned mode of delivery was documented in the woman's electronic record upon entering the delivery room. Information regarding maternal age at delivery, parity, gestational age, presentation, previous history of caesarean delivery, birthweight and Apgar score was collected from the obstetric electronic charts. MAIN OUTCOME MEASURED: Rate of vaginal twin delivery. RESULTS: Of the 2194 women included, 1311 twin pregnancies had planned caesarean delivery and 883 underwent a trial of labour. Of the 883 women who underwent a trial of labour, the rate of vaginal delivery was 86.9%, whereas the rates of caesarean delivery and combined vaginal-caesarean delivery were 11.1% and 2.0%, respectively. Presentation of second twin, gestational age and maternal age did affect the chances of success. Nulliparity [odds ratio (OR) 2.38, 95% confidence interval (95% CI) 1.4-4.05], Foley induction of labour (OR 2.33, 95% CI 1.38-3.91) and body mass index >30 kg/m(2) (OR 1.76, 95% CI 1.03-3) were independent risk factors for caesarean delivery. CONCLUSIONS: The rate of vaginal delivery among women with twin pregnancies who undergo labour can be high, especially in women who laboured spontaneously and have delivered before. TWEETABLE ABSTRACT: The rate of vaginal delivery of twins can be high, especially in women who have delivered before. PMID- 26228896 TI - Editorial-Measuring Satisfaction: Can It Be Done? PMID- 26228898 TI - Percutaneous transluminal aortic valve implantation for severe aortic valve stenosis in a patient with severe haemophilia A. PMID- 26228897 TI - Pathogen Stimulation History Impacts Donor-Specific CD8(+) T Cell Susceptibility to Costimulation/Integrin Blockade-Based Therapy. AB - Recent studies have shown that the quantity of donor-reactive memory T cells is an important factor in determining the relative heterologous immunity barrier posed during transplantation. Here, we hypothesized that the quality of T cell memory also potently influences the response to costimulation blockade-based immunosuppression. Using a murine skin graft model of CD8(+) memory T cell mediated costimulation blockade resistance, we elicited donor-reactive memory T cells using three distinct types of pathogen infections. Strikingly, we observed differential efficacy of a costimulation and integrin blockade regimen based on the type of pathogen used to elicit the donor-reactive memory T cell response. Intriguingly, the most immunosuppression-sensitive memory T cell populations were composed primarily of central memory cells that possessed greater recall potential, exhibited a less differentiated phenotype, and contained more multi cytokine producers. These data, therefore, demonstrate that the memory T cell barrier is dependent on the specific type of pathogen infection via which the donor-reactive memory T cells are elicited, and suggest that the immune stimulation history of a given transplant patient may profoundly influence the relative barrier posed by heterologous immunity during transplantation. PMID- 26228899 TI - MRI-guidance in percutaneous core decompression of osteonecrosis of the femoral head. AB - OBJECTIVES: The purpose of this study was to evaluate the usefulness of MRI guidance for core decompression of avascular necrosis of the femoral head. MATERIALS AND METHODS: Twelve MRI-guided core decompressions were performed on patients with different stages of avascular necrosis of the femoral head. The patients were asked to evaluate their pain and their ability to function before and after the procedure and imaging findings were reviewed respectively. RESULTS: Technical success in reaching the target was 100 % without complications. Mean duration of the procedure itself was 54 min. All patients with ARCO stage 1 osteonecrosis experienced clinical benefit and pathological MRI findings were seen to diminish. Patients with more advanced disease gained less, if any, benefit and total hip arthroplasty was eventually performed on four patients. CONCLUSIONS: MRI-guidance seems technically feasible, accurate and safe for core decompression of avascular necrosis of the femoral head. Patients with early stage osteonecrosis may benefit from the procedure. KEY POINTS: * MRI is a useful guidance method for minimally invasive musculoskeletal interventions. * Bone drilling seems beneficial at early stages of avascular necrosis. * MRI-guidance is safe and accurate for bone drilling. PMID- 26228900 TI - Quantitative susceptibility mapping in patients with systemic lupus erythematosus: detection of abnormalities in normal-appearing basal ganglia. AB - OBJECTIVES: To evaluate whether quantitative susceptibility mapping (QSM) can be employed to detect abnormalities within normal-appearing basal ganglia on conventional MRI in patients with neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: For 33 SLE patients (13 NPSLE and 20 non-NPSLE patients) and 23 age/sex-matched controls, two radiologists independently measured the mean QSM and R2* values in various brain structures that appeared to be normal on conventional MR images. These values in each brain structure were compared among the two SLE groups and controls. RESULTS: Regarding the putamen, the NPSLE patients showed significantly higher QSM values than the non-NPSLE patients and controls (p < 0.05). For the lateral globus pallidus, both SLE groups showed significantly higher QSM values than the controls (p < 0.05). The R2* values were not significantly different between both SLE groups. The NPSLE patients showed a significant correlation between the mean QSM values in putamen and the disease duration (r = 0.63, p < 0.05). For the interobserver agreement, the QSM value was superior to the R2* value (0.690 vs. 0.446, Kendall W value). CONCLUSIONS: QSM can be used to identify increased susceptibility of the basal ganglia appearing to be normal on conventional MR images in NPSLE patients. KEY POINTS: * QSM values in the putamen are significantly higher in NPSLE than non-NPSLE. * NPSLE patients show correlation between QSM values in the putamen and disease duration. * QSM is more sensitive than R2* mapping for detecting subtle changes. PMID- 26228901 TI - Longitudinal study of the substantia nigra in Parkinson disease: A high-field (1) H-MR spectroscopy imaging study. AB - INTRODUCTION: The value of biomarkers in early diagnosis and development of therapeutics in Parkinson's disease (PD) is well established. METHODS: We used proton magnetic resonance spectroscopy in a prospective, longitudinal study of 23 patients with early PD, naive to dopaminergic therapy, and six age-matched healthy controls to examine the temporal changes in metabolic profile of substantia nigra over a period of 3 months. RESULTS: N-acetyl aspartate to creatine ratio at month 3 was compared with baseline values in the PD and control groups, as well as the side-to-side difference of the ratio at baseline. By month 3, n-acetyl aspartate to creatine ratio had decreased by 4.4% in patients with PD (P = 0.024), without a concomitant change in healthy controls. The side-to-side asymmetry was significantly higher in the PD group (16.7%) vs. healthy controls (1.6%, P = 0.0024). CONCLUSION: Estimation of change in the n-acetyl aspartate to creatine ratio appears to be a fast, quantifiable, and reliable marker of dopaminergic neuronal viability in PD. PMID- 26228889 TI - Cerebral Microbleeds, CSF p-Tau, and Cognitive Decline: Significance of Anatomic Distribution. AB - BACKGROUND AND PURPOSE: Cerebral microbleeds are associated with aging, hypertension, and Alzheimer disease. Microbleeds in a lobar distribution are believed to reflect underlying amyloid angiopathy, whereas microbleeds in the deep gray matter and infratentorial brain are commonly seen with hypertension. However, it is unknown how microbleeds in either distribution are related to Alzheimer pathogenesis. The purpose of this analysis was to test whether lobar and deep gray/infratentorial microbleeds demonstrate differential associations with CSF amyloid-beta and phosphorylated tau 181 protein levels and longitudinal cognitive decline. MATERIALS AND METHODS: A total of 626 subjects (151 cognitively normal, 389 with mild cognitive impairment, and 86 with Alzheimer disease) from the Alzheimer's Disease Neuroimaging Initiative who had undergone 3T MR imaging and lumbar puncture were included in the analysis. The number and location of microbleeds were assessed visually. Associations between lobar or deep gray/infratentorial microbleeds with CSF amyloid-beta levels, abnormal CSF phosphorylated tau 181 protein levels, and longitudinal cognitive decline were assessed by using ordinary least-squares, logistic, and mixed-effects regression models while adjusting for covariates. RESULTS: Having >=3 lobar microbleeds was associated with lower levels of CSF amyloid-beta (P = .001). After adjusting for CSF amyloid-beta level, lobar microbleeds were independently associated with a higher likelihood of having an abnormal CSF phosphorylated tau 181 protein level (P = .004). Lobar microbleeds were associated with accelerated longitudinal cognitive decline (P = .007). Deep gray/infratentorial microbleeds revealed no significant associations. CONCLUSIONS: The distribution of microbleeds revealed different associations with amyloid-beta and phosphorylated tau 181 protein levels and cognition. Lobar and deep gray/infratentorial microbleeds should be considered separately with regard to Alzheimer disease pathogenesis. PMID- 26228902 TI - Erratum to: Intestinal necrosis due to norovirus enteritis. AB - Erratum to: Clin J Gastroenterol (2015) 8:10-13,DOI 10.1007/s12328-014-0540-0. The name of the third author should be given as Hiroki Imaoka, not Yuhki Imaoka. PMID- 26228903 TI - Inflammation: NETting a one-two punch. PMID- 26228906 TI - The impact of thiol peroxidases on redox regulation. AB - The biology of glutathione peroxidases and peroxiredoxins is reviewed with emphasis on their role in metabolic regulation. Apart from their obvious function in balancing oxidative challenge, these thiol peroxidases are not only implicated in orchestrating the adaptive response to oxidative stress, but also in regulating signaling triggered by hormones, growth factors and cytokines. The mechanisms presently discussed comprise dampening of redox-sensitive regulatory processes by elimination of hydroperoxides, suppression of lipoxygenase activity, committing suicide to save H2O2 for signaling, direct binding to receptors or regulatory proteins in a peroxidase activity-independent manner, or acting as sensors for hydroperoxides and as transducers of oxidant signals. The various mechanistic proposals are discussed in the light of kinetic data, which unfortunately are scarce. Taking into account pivotal criteria of a meaningful regulatory circuit, kinetic plausibility and specificity, the mechanistic concepts implying a direct sensor/transducer function of the thiol peroxidases appear most appealing. With rate constants for the reaction with hydroperoxide of 105-108 M- 1 s- 1, thiol peroxidases are qualified as kinetically preferred hydroperoxide sensors, and the ability of the oxidized enzymes to react with defined protein thiols lends specificity to the transduction process. The versatility of thiol peroxidases, however, allows multiple ways of interaction with regulatory pathways. PMID- 26228905 TI - Synthesis and characterization of tritium labeled N-((R)-1-((S)-4-(4 chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3 sulfamoylbenzamide. AB - N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1 oxobutan-2-yl)-3-sulfamoylbenzamide is a potent C-C chemokine receptor 1 (CCR1) antagonist. The compound, possessing benzamide functionality, successfully underwent tritium/hydrogen (T/H) exchange with an organoiridium catalyst (Crabtree's catalyst). The labeling pattern in the product was studied with liquid chromatography-mass spectrometry, time-of-flight mass spectrometry, and (3) H-NMR. Overall, multiple labeled species were identified. In addition to the anticipated incorporation of tritium in the benzamide moiety, tritium labeling was observed in the valine portion of the molecule including substitution at its chiral carbon. Using authentic standards, liquid chromatography analysis of the labeled compound showed complete retention of stereochemical configuration. PMID- 26228904 TI - Relationship between toothpastes properties and patient-reported discomfort: crossover study. AB - OBJECTIVES: This study aims to correlate patient-reported reactions with in vitro analyses of the pH, abrasive quality, and cytotoxicity of four toothpastes. MATERIALS AND METHODS: One hundred twenty-one patients received non-identified samples of toothpaste to be used for 6 days and answered a questionnaire about their sensations. In vitro analysis: the pH of toothpastes was measured with a pH meter. The abrasivity of toothpastes was evaluated against composite resin specimens (n = 10). A toothbrushing machine was used to simulate wear, which was indirectly measured by mass loss using a scale. Cell culture media conditioned with toothpaste were used to assess the cytotoxicity. Confluent cells were kept in contact with the conditioned media or control for 24 h. The cell viability was measured using the 3-(bromide, 4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium (MTT)-reduction assay. The obtained data on the pH, weight loss, and cell viability were compared by ANOVA/Tukey's tests (p < 0.05). RESULTS: With the exception of the bleaching effect paste, the Oral B(r) paste produced the highest frequencies of irritation reports, tooth sensitivity, taste discomfort, and texture discomfort in the clinical study; patients also reported rougher teeth, soft tissue peeling, dry mouth, thrush, tingling, and taste changes in response to this paste. The in vitro analysis demonstrated that Oral B(r) had the lowest pH, the highest abrasivity, and produced the lowest cell viability (p < 0.01). CONCLUSION: Results suggest that low pH toothpastes that are highly abrasive and cytotoxic may cause undesirable reactions in patients. CLINICAL RELEVANCE: Toothpaste's properties should be well known for indication to patient therefore minimizing discomfort reports. PMID- 26228907 TI - A Call for Canadian Pediatric Emergency Guidelines--As Certain As Motherhood? PMID- 26228908 TI - Iron nanotube-silica composite (ZVI-S-PCAT modified silica composite) preparation, characterization and application as a recyclable catalytic system for 5-membered ring organic transformations. AB - Iron nanotube silica composite have been synthesized and studied through particle size analysis, FTIR, SEM-EDX, TEM, XRD, UV, VSM, TGA-DTA and XPS techniques. The application of nanoframeworks as sustainable recyclable catalytic systems has been observed for azole cyclic ring organic transformations. The good reaction yields and characterization through (1)H NMR, (13)C NMR and mass analysis support the performance of the nanoframeworks. We also present here the synthesis of two novel compounds. Also the prepared nanoframework has been observed to show soft magnetism which provides a scope to be used in sensing devices. PMID- 26228909 TI - Bone Regeneration Using Hydroxyapatite Sponge Scaffolds with In Vivo Deposited Extracellular Matrix. AB - There is currently an increased interest in studying the extracellular matrix (ECM) and its potential applications for tissue engineering and regenerative medicine. The ECM plays an important role by providing adhesive substrates to cells during migration, morphogenesis, differentiation, and homeostasis by signaling biochemical and biomechanical cues to cells. In this study, the ECM was incorporated into hydroxyapatite by implanting sponge replica scaffolds in subcutaneous pockets in rats, and the implants were tested for bone regeneration potential. The resulting scaffolds were characterized using scanning electron microscopy, confocal microscopy, DNA and RNA quantification, tissue staining, energy dispersive X-ray spectroscopy analysis, compressive strength testing, porosity, and pore size distribution analysis using bare scaffolds as a control reference. Biocompatibility was assessed using MC3T3-E1 preosteoblast cells and in vivo studies were carried out by implanting decellularized scaffolds in 11 mm radial defects in New Zealand rabbits for 4 and 8 weeks to determine the effect of the in vivo deposited ECM. Material characterization indicated that a 2-week decellularized scaffold was the best among the samples, with an evenly distributed ECM visible on hematoxylin and eosin-stained tissue sections, a compressive strength of 2.53 +/- 0.68 MPa, a porosity of 58.08 +/- 3.32% and a pore size distribution range of 10-150 MUm. In vivo results showed no severe inflammation, with increased cell infiltration followed by dense matrix deposition after 4 weeks and new bone formation at 8 weeks. The results indicate that incorporation of an in vivo deposited ECM into ceramic scaffolds can potentially improve bone regeneration. PMID- 26228910 TI - Improved conversion of cinnamaldehyde derivatives to diol compounds via a pyruvate decarboxylase-dependent mechanism in budding yeast. AB - Cinnamaldehyde is stereospecifically converted to (2S,3R) 5-phenylpent-4-ene-2,3 diol, an important starting material for the synthesis of biologically active compounds, by the budding yeast Saccharomyces cerevisiae. Immobilization of the yeast in calcium alginate capsules suppressed the formation of by-products and increased accumulation of the diol compounds. The mechanism of cinnamaldehyde conversion was investigated by using recombinant strains of Escherichia coli and S. cerevisiae carrying the pyruvate decarboxylase gene PDC1. As a result, condensation of the substrate with acetaldehyde was enhanced by PDC and flow to the diol product was altered. PMID- 26228911 TI - Feminization of the medical workforce in low-income settings; findings from surveys in three African capital cities. AB - BACKGROUND: Women represent an increasingly growing share of the medical workforce in high-income countries, with abundant research focusing on reasons and implications of the phenomenon. Little evidence is available from low- and middle-income countries, which is odd given the possible repercussion this may have for the local supply of medical services and, ultimately, for attaining universal health coverage. METHODS: Drawing from secondary analysis of primary survey data, this paper analyses the proportion and characteristics of female physicians in Bissau, Maputo and Praia, with the objective of gaining insights on the extent and features of the feminization of the medical workforce in low- and middle-income settings. We used descriptive statistics, parametric and non parametric test to compare groups and explore associations between different variables. Zero-inflated and generalized linear models were employed to analyse the number of hours worked in the private and public sector by male and female physicians. RESULTS AND DISCUSSION: We show that although female physicians do not represent yet the majority of the medical workforce, feminization of the profession is under way in the three locations analysed, as women are presently over-represented in younger age groups. Female doctors distribute unevenly across medical specialties in the three cities and are absent from traditionally male dominated ones such as surgery, orthopaedics and stomatology. Our data also show that they engage as much as their male peers in private practice, although overall they dedicate fewer hours to the profession, particularly in the public sector. CONCLUSIONS: While more research is needed to understand how this phenomenon affects rural areas in a broader range of locations, our work shows the value of exploring the differences between female and male physicians' engagement with the profession in order to anticipate the impact of such feminization on national health systems and workforces in low- and middle-income countries. PMID- 26228912 TI - Fingerprint analysis, multi-component quantitation, and antioxidant activity for the quality evaluation of Salvia miltiorrhiza var. alba by high-performance liquid chromatography and chemometrics. AB - Salvia miltiorrhiza Bge. var. alba C.Y. Wu and H.W. Li has wide prospects in clinical practice. A useful comprehensive method was developed for the quality evaluation of S. miltiorrhiza var. alba by three quantitative parameters: high performance liquid chromatography fingerprint, ten-component contents, and antioxidant activity. The established method was validated for linearity, precision, repeatability, stability, and recovery. Principal components analysis and hierarchical clustering analysis were both used to evaluate the quality of the samples from different origins. The results showed that there were category discrepancies in quality of S. miltiorrhiza var. alba samples according to the three quantitative parameters. Multivariate linear regression was adopted to explore the relationship between components and antioxidant activity. Three constituents, namely, danshensu, rosmarinic acid, and salvianolic acid B, significantly correlated with antioxidant activity, and were successfully elucidated by the optimized multivariate linear regression model. The combined use of high-performance liquid chromatography fingerprint analysis, simultaneous multicomponent quantitative analysis, and antioxidant activity for the quality evaluation of S. miltiorrhiza var. alba is a reliable, comprehensive, and promising approach, which might provide a valuable reference for other herbal products in general to improve their quality control. PMID- 26228913 TI - Methane-rich saline attenuates ischemia/reperfusion injury of abdominal skin flaps in rats via regulating apoptosis level. AB - BACKGROUND: In plastic surgery, skin damage induced by ischemia/reperfusion (I/R) is a multifactorial process that often occurs. Methane gas has been reported to be a new therapeutic gas for attenuating I/R injury. In this study, we assessed the effects of methane-rich saline (MRS) in regulating apoptosis on skin flap I/R injury. METHODS: Male Sprague-Dawley rats, 6-8 weeks old, were divided randomly into three groups: one sham surgery group (SH) and two surgery groups. After undergoing 6 h of I/R management of an abdominal skin flap, surgery groups were treated with physiological saline (I/R-P) or methane-rich saline (I/R-M). On the 3rd postoperative day, a laser Doppler flowmeter was used to measure flap blood supply, and hematoxylin and eosin (H&E) staining was used to observe morphological changes. TdT-mediated dUTP-X nick end labeling (TUNEL) staining was also used to observe early apoptosis and is presented as the percentage of TUNEL positive cells. Moreover, pASK-1, pJNK, Bcl-2 and Bax were detected by immunohistochemical technology. Caspase-3 activity was also measured to evaluate the effects of MRS. RESULTS: Compared to the I/R-P group, the flaps in the I/R-M group presented a larger survival area and better blood perfusion with less inflammatory infiltration and cell apoptosis, a higher expression of Bcl-2, a lower expression of pASK-1, pJNK and Bax, and a lower caspase-3 activity. CONCLUSION: According to the results, MRS attenuated I/R injury by regulating apoptosis and has the potential to be applied as a new therapy for improving skin flap survival. PMID- 26228915 TI - Measuring windows of selection for anti-malarial drug treatments. AB - BACKGROUND: The long half-lives of malaria 'partner' drugs are a potent force selecting for drug resistance. Clinical trials can quantify this effect by estimating a window of selection (WoS), defined as the amount of time post treatment when drug levels are sufficiently high that resistant parasites can re establish an infection while preventing drug-sensitive parasites from establishing viable infections. METHODS: The ability of clinical data to accurately estimate the true WoS was investigated using standard pharmacokinetic pharmacodynamic models for three widely used malaria drugs: artemether lumefantrine (AR-LF), artesunate-mefloquine (AS-MQ) and dihydroartemisinin piperaquine (DHA-PPQ). Estimates of the clinical WoS either (1) ignored all new infections occurring after the 63-day follow-up period, as is currently done in clinical trials, or, (2) recognized that all individuals would eventually be re infected and arbitrarily assigned them a new infection day. RESULTS: The results suggest current methods of estimating the clinical WoS underestimate the true WoS by as much as 9 days for AR-LF, 33 days for AS-MQ and 7 days for DHA-PPQ. The new method of estimating clinical WoS (i.e., retaining all individuals in the analysis) was significantly better at estimating the true WoS for AR-LF and AS MQ. CONCLUSIONS: Previous studies, based on clinically observed WoS, have probably underestimated the 'true' WoS and hence the role of drugs with long half lives in driving resistance. This has important policy implications: high levels of drug use are inevitable in mass drug administration programmes and intermittent preventative treatment programmes and the analysis herein suggests these policies will be far more potent drivers of resistance than previously thought. PMID- 26228916 TI - The Interface Between Violence, Disability, and Poverty: Stories From a Developing Country. AB - People with disabilities are vulnerable to multiple forms of violence in their everyday lives, including structural violence, deprivation, and physical, emotional, and sexual exploitation. Despite increasing reports of violence against people with disabilities, little is known about this phenomenon, especially in the context of poverty. Furthermore, the various types of violence have traditionally been studied in isolation, which has led to a limited understanding of the nature and persistence of violence in society, and has affected our understanding of the relationship between different forms of violence. In this article, we explore the relationship between violence, disability, and poverty among people living in a rural area of South Africa. Thirty adults with a variety of disabilities living in 12 rural villages in the Mpumalanga Province of South Africa participated in the study. Each of the participants was provided with an opportunity to tell their life story. Narrative inquiry and participant observation were used to explore the ways in which violence pervades the participants' everyday experiences. Results were analyzed using thematic analysis and suggest that in the context of poverty, it is impossible to separate the experience of disability from the experience of violence. Structural violence was shown to underpin all other forms of interpersonal violence, making persons with disabilities vulnerable to additional forms of exploitation, and serve to further isolate people with disabilities from society, compromising both health and human rights. The findings suggest that an understanding of contextual factors is fundamental to understanding the relationship between violence and disability. PMID- 26228917 TI - The Dark Figure of Stalking: Examining Law Enforcement Response. AB - Despite the growing body of scholarship on stalking victimization, the criminal justice system's response has been substantially understudied. Although scholars consider stalking to be a significant issue, its prevalence is not echoed in official data representing stalking arrests and convictions. The disparity between prevalence estimates and official data reinforces a "dark figure" of stalking that warrants further examination. To develop a better understanding of underreporting and/or underrecording, this exploratory study used official data from the Houston Police Department to examine police response to stalking. Findings indicated that, compared with other interpersonal crimes, incidents of stalking are dramatically underrecorded. Over an 8-year period, there were a total of 3,756 stalking calls for service, 66 stalking-related incident reports, and only 12 arrests for stalking. However, not one of the stalking calls for service generated a stalking-related incident report nor an arrest for stalking. Of the stalking calls for service that did generate an incident report, the large majority of the reports were classified as either harassment or a violation of a protective order. Furthermore, incident reports and arrests for stalking generally emerged from calls for service for harassment or terroristic threats. Implications for research and policy are discussed. PMID- 26228914 TI - The Nature of Self-Regulatory Fatigue and "Ego Depletion": Lessons From Physical Fatigue. AB - Self-regulation requires overriding a dominant response and leads to temporary self-regulatory fatigue. Existing theories of the nature and causes of self regulatory fatigue highlight physiological substrates such as glucose, or psychological processes such as motivation, but these explanations are incomplete on their own. Historically, theories of physical fatigue demonstrate a similar pattern of useful but incomplete explanations, as recent views of physical fatigue emphasize the roles of both physiological and psychological factors. In addition to accounting for multiple inputs, these newer views also explain how fatigue can occur even in the presence of sufficient resources. Examining these newer theories of physical fatigue can serve as a foundation on which to build a more comprehensive understanding of self-regulatory fatigue that integrates possible neurobiological underpinnings of physical and self-regulatory fatigue, and suggests the possible function of self-regulatory fatigue. PMID- 26228918 TI - The Association Between Weapon Carrying and Health Risk Behaviors Among Adolescent Students in Bangkok, Thailand. AB - Carrying weapons is a significant social and public health problem worldwide, especially among adolescents. The present study examined the association between weapon carrying and related risk behaviors among Thai adolescents. A cross sectional study of 2,588 high school and vocational school students aged 11 to 19 years from 26 schools in Bangkok, Thailand, was conducted in 2014. This study found that 7.8% of youth reported having carried a weapon in the past 12 months. The high prevalence of weapon carrying was reported by male students, and males were more likely to have reported carrying a weapon than females. The association between weapon carrying and the health risk behaviors like drinking, smoking, any drug use, and physical fighting were significant with higher odds of weapon carrying in all models. Among males, weapon carrying was related to drinking and smoking, any drug use, physical fighting, and school type. Among females, suicidal thoughts were significantly related along with drinking and smoking, any drug use, and physical fighting. Having a mother who used substances was significant only among females. These data could be used for further interventions about weapon carrying to reduce violence. PMID- 26228919 TI - Main and Moderating Influence of Temperament Traits on the Association Between Intimate Partner Violence and Trauma Symptoms. AB - Trauma symptoms are common among survivors of intimate partner violence (IPV), although not all women who experience IPV develop trauma symptoms. One of the factors that may influence whether women develop trauma symptoms upon exposure to IPV is temperament. In this study, we examined the main and moderating effects of temperament traits (constraint, negative emotionality, and positive emotionality) on the association between IPV and trauma symptoms in a sample of young adult women ( N = 654) using a Bayesian approach to multiple linear regression to address significant non-normality in the data. Our results indicated that each temperament trait incrementally predicted trauma symptoms over and above the effects of IPV and other negative life events. Results further indicated that both negative emotionality and constraint moderated the influence of IPV on trauma symptoms such that IPV was positively associated with trauma symptoms at high levels of these traits but not at low levels. However, these effects differed depending on the type of violence experienced (physical, sexual, or psychological). These results extend previous research on the influence of temperament traits to the context of IPV; this underscores the importance of incorporating temperament in the study of IPV, as well as in the study of traumatic stress more generally. PMID- 26228920 TI - Familial risk of pediatric chronic rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: To determine the risk of chronic rhinosinusitis (CRS) in relatives of children with a diagnosis of CRS. STUDY DESIGN: Retrospective observational cohort study with population-based matched controls. METHODS: A unique genealogical database linked to medical records was used to identify subjects <=12 years old with a diagnosis of CRS from 1996 to 2011. The familial recurrence risks of CRS in first- through fifth-degree relatives of probands were calculated using Cox models and compared to controls randomly selected from the Utah population and matched 10:1 on sex and birth year. RESULTS: We identified 496 pediatric patients with CRS. Siblings of patients with CRS demonstrated a 57.5-fold increased risk (P < 10(-8) ) of also having pediatric CRS. First cousins had a 9.0-fold increased risk (P < 10(-3) ) and second cousins had a 2.9 fold increased risk (P = .002) of pediatric CRS. First-degree relatives, second degree relatives, and first cousins of pediatric cases demonstrated a significant increased risk of having adult CRS. Parents of probands demonstrated a 5.6-fold increased risk (P < 10(-15) ). Fifty-five probands had one affected parent versus three probands with two affected parents. CONCLUSIONS: In the largest population study to date of children with CRS, a significant familial risk is confirmed. Parents of probands were also at increased risk, although it was much more likely for one parent to be affected than both, suggesting a genetic component of the disease. Further understanding of the genetic basis of CRS and its interplay with environmental factors could clarify the etiology and lead to more effective targeted treatments. LEVEL OF EVIDENCE: 3b Laryngoscope, 126:739-745, 2016. PMID- 26228922 TI - A Computational Model of Innate Directional Selectivity Refined by Visual Experience. AB - The mammalian visual system has been extensively studied since Hubel and Wiesel's work on cortical feature maps in the 1960s. Feature maps representing the cortical neurons' ocular dominance, orientation and direction preferences have been well explored experimentally and computationally. The predominant view has been that direction selectivity (DS) in particular, is a feature entirely dependent upon visual experience and as such does not exist prior to eye opening (EO). However, recent experimental work has shown that there is in fact a DS bias already present at EO. In the current work we use a computational model to reproduce the main results of this experimental work and show that the DS bias present at EO could arise purely from the cortical architecture without any explicit coding for DS and prior to any self-organising process facilitated by spontaneous activity or training. We explore how this latent DS (and its corresponding cortical map) is refined by training and that the time-course of development exhibits similar features to those seen in the experimental study. In particular we show that the specific cortical connectivity or 'proto architecture' is required for DS to mature rapidly and correctly with visual experience. PMID- 26228921 TI - Adenosine A2b receptor promotes progression of human oral cancer. AB - BACKGROUND: Adenosine A2b receptor (ADORA2B) encodes an adenosine receptor that is a member of the G protein-coupled receptor superfamily. This integral membrane protein stimulates adenylate cyclase activity in the presence of adenosine. Little is known about the relevance of ADORA2B to human malignancy including oral squamous cell carcinoma (OSCC). We aimed to characterize the expression state and function of ADORA2B in OSCC. METHODS: The ADORA2B expression levels in nine OSCC derived cells were analyzed by quantitative reverse transcriptase-polymerase chain reaction and immunoblotting analyses. Using an ADORA2B knockdown model, we assessed cellular proliferation and expression of hypoxia-inducible factor1alpha (HIF-1alpha). We examined the adenosine receptor expression profile under both normoxic and hypoxic conditions in the OSCC-derived cells. In addition to in vitro data, the clinical correlation between the ADORA2B expression levels in primary OSCCs (n = 100 patients) and the clinicopathological status by immunohistochemistry (IHC) also was evaluated. RESULTS: ADORA2B mRNA and protein were up-regulated significantly (p < 0.05) in seven OSCC-derived cells compared with human normal oral keratinocytes. Suppression of ADORA2B expression with shRNA significantly (p < 0.05) inhibited cellular proliferation compared with the control cells. HIF-1alpha also was down-regulated in ADORA2B knockdown OSCC cells. During hypoxia, ADORA2B expression was induced significantly (p < 0.05) in the mRNA and protein after 24 hours of incubation in OSCC-derived cells. IHC showed that ADORA2B expression in primary OSCCs was significantly (p < 0.05) greater than in the normal oral counterparts and that ADORA2B-positive OSCCs were correlated closely (p < 0.05) with tumoral size. CONCLUSION: Our results suggested that ADORA2B controls cellular proliferation via HIF-1alpha activation, indicating that ADORA2B may be a key regulator of tumoral progression in OSCCs. PMID- 26228923 TI - Interactive effects of CYP3A4, CYP3A5, MDR1 and NR1I2 polymorphisms on tracrolimus trough concentrations in early postrenal transplant recipients. AB - AIMS: To evaluate the influences of CYP3A4, CYP3A5, MDR1 and NR1I2 polymorphisms on tacrolimus concentration in early postrenal transplant recipients. PATIENTS & METHODS: A total of 159 patients were included, dose-adjusted tacrolimus trough concentration on day 7 after transplantation (C0D7/D) was calculated and 10 SNPs in four genes were genotyped. RESULTS: CYP3A5*3 explained 32.8% of variability of tacrolimus C0D7/D. CYP3A4*1G, MDR1 1236-2677-3435 diplotype and NR1I2 -25385C > T explained 21.4% of variability of tacrolimus C0D7/D in CYP3A5 nonexpressers. CONCLUSION: CYP3A5*3 was the predominant determinant affecting tacrolimus concentration. Genotyping of CYP3A4/MDR1/NR1I2 polymorphisms may be helpful for better guiding tacrolimus dosing in CYP3A5 nonexpressers. PMID- 26228925 TI - Assessment of Fundamental Movement Skills in Childhood Cancer Patients. AB - BACKGROUND: The improved treatment protocols and subsequent improved survival rates among childhood cancer patients have shifted the focus toward the long-term consequences arising from cancer treatment. Children who have completed cancer treatment are at a greater risk of delayed development, diminished functioning, disability, compromised fundamental movement skill (FMS) attainment, and long term chronic health conditions. The aim of the study was to compare FMS of childhood cancer patients with an aged matched healthy reference group. METHODS: Pediatric cancer patients aged 5-8 years (n = 26; median age 6.91 years), who completed cancer treatment (<5 years) at the Sydney Children's Hospital, were assessed performing seven key FMS: sprint, side gallop, vertical jump, catch, over-arm throw, kick, and leap. Results were compared to the reference group (n = 430; 6.56 years). RESULTS: Childhood cancer patients scored significantly lower on three out of seven FMS tests when compared to the reference group. These results equated to a significantly lower overall score for FMS. CONCLUSIONS: This study highlighted the significant deficits in FMS within pediatric patients having completed cancer treatment. In order to reduce the occurrence of significant FMS deficits in this population, FMS interventions may be warranted to assist in recovery from childhood cancer, prevent late effects, and improve the quality of life in survivors of childhood cancer. PMID- 26228924 TI - Molecular mechanisms of hypoxia-inducible factor-induced pulmonary arterial smooth muscle cell alterations in pulmonary hypertension. AB - Oxygen (O2) is essential for the viability and function of most metazoan organisms and thus is closely monitored at both the organismal and the cellular levels. However, alveoli often encounter decreased O2 levels (hypoxia), leading to activation of physiological or pathophysiological responses in the pulmonary arteries. Such changes are achieved by activation of transcription factors. The hypoxia-inducible factors (HIFs) are the most prominent hypoxia-regulated transcription factors in this regard. HIFs bind to hypoxia-response elements (HREs) in the promoter region of target genes, whose expression and translation allows the organism, amongst other factors, to cope with decreased environmental O2 partial pressure (pO2). However, prolonged HIF activation can contribute to major structural alterations, especially in the lung, resulting in the development of pulmonary hypertension (PH). PH is characterized by a rise in pulmonary arterial pressure associated with pulmonary arterial remodelling, concomitant with a reduced intravascular lumen area. Patients with PH develop right heart hypertrophy and eventually die from right heart failure. Thus, understanding the molecular mechanisms of HIF regulation in PH is critical for the identification of novel therapeutic strategies. This review addresses the relationship of hypoxia and the HIF system with pulmonary arterial dysfunction in PH. We particularly focus on the cellular and molecular mechanisms underlying the HIF-driven pathophysiological processes. PMID- 26228926 TI - Unacylated ghrelin restores insulin and autophagic signaling in skeletal muscle of diabetic mice. AB - Impairment of insulin signaling in skeletal muscle detrimentally affects insulin stimulated disposal of glucose. Restoration of insulin signaling in skeletal muscle is important as muscle is one of the major sites for disposal of blood glucose. Recently, unacylated ghrelin (UnAG) has received attention in diabetic research due to its favorable actions on improving glucose tolerance, glycemic control, and insulin sensitivity. The investigation of UnAG has entered phase Ib clinical trial in type 2 diabetes and phase II clinical trial in hyperphagia in Prader-Willi syndrome. Nonetheless, the precise mechanisms responsible for the anti-diabetic actions of UnAG remain incompletely understood. In this study, we examined the effects of UnAG on restoring the impaired insulin signaling in skeletal muscle of db/db diabetic mice. Our results demonstrated that UnAG effectively restored the impaired insulin signaling in diabetic muscle. UnAG decreased insulin receptor substrate (IRS) phosphorylation, increased protein kinase B (Akt) phosphorylation, and, hence, suppressed mTOR signaling. Consequently, UnAG enhanced Glut4 localization and increased PDH activity in the diabetic skeletal muscle. Intriguingly, our data indicated that UnAG normalized the suppressed autophagic signaling in diabetic muscle. In conclusion, our findings illustrated that UnAG restored the impaired insulin and autophagic signaling in skeletal muscle of diabetic mice, which are valuable to understand the underlying mechanisms of the anti-diabetic action of UnAG at peripheral skeletal muscle level. PMID- 26228927 TI - Beyond static structures: Putting forth REMD as a tool to solve problems in computational organic chemistry. AB - Computational studies of organic systems are frequently limited to static pictures that closely align with textbook style presentations of reaction mechanisms and isomerization processes. Of course, in reality chemical systems are dynamic entities where a multitude of molecular conformations exists on incredibly complex potential energy surfaces (PES). Here, we borrow a computational technique originally conceived to be used in the context of biological simulations, together with empirical force fields, and apply it to organic chemical problems. Replica-exchange molecular dynamics (REMD) permits thorough exploration of the PES. We combined REMD with density functional tight binding (DFTB), thereby establishing the level of accuracy necessary to analyze small molecular systems. Through the study of four prototypical problems: isomer identification, reaction mechanisms, temperature-dependent rotational processes, and catalysis, we reveal new insights and chemistry that likely would be missed using static electronic structure computations. The REMD-DFTB methodology at the heart of this study is powered by i-PI, which efficiently handles the interface between the DFTB and REMD codes. PMID- 26228928 TI - Novel Triazolopyrimidine-Derived Cannabinoid Receptor 2 Agonists as Potential Treatment for Inflammatory Kidney Diseases. AB - The cannabinoid receptor 2 (CB2) system is described to modulate various pathological conditions, including inflammation and fibrosis. A series of new heterocyclic small-molecule CB2 receptor agonists were identified from a high throughput screen. Lead optimization gave access to novel, highly potent, and selective (over CB1) triazolopyrimidine derivatives. A preliminary structure activity relationship was established, and physicochemical properties in this compound class were significantly improved toward better solubility, lipophilicity, and microsomal stability. An optimized triazolopyrimidine derivative, (3S)-1-[5-tert-butyl-3-[(1-cyclopropyltetrazol-5 yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol (39), was tested in a kidney ischemia-reperfusion model, in which it showed efficacy at a dose of 10 mg kg(-1) (p.o.). A significant depletion of the three measured kidney markers indicated a protective role of CB2 receptor activation toward inflammatory kidney damage. Compound 39 was also protective in a model of renal fibrosis. Oral treatment with 39 at 3 mg kg(-1) per day significantly decreased the amount of fibrosis by ~ 40% which was induced by unilateral ureter obstruction. PMID- 26228930 TI - Death due to obstruction of the upper airways caused by edema of the laryngeal mucosa in the course of hereditary angioedema. AB - A rare case of death of a young man due to airway obstruction in the course of angioedema (Quincke's edema). Type I hereditary angioedema due to C1 esterase inhibitor deficiency had been diagnosed in the man while he was alive. The information concerning the man's health state was given in the Public Prosecutor's decision ordering medico legal autopsy, which was extremely helpful in recognizing the cause of death. PMID- 26228929 TI - Providers' Note-Writing Practices for Post-traumatic Stress Disorder at Five United States Veterans Affairs Facilities. AB - The capacity of electronic health records (EHRs) to capture desired information depends on the practices of health care providers. These practices have not been well studied in relation to post-traumatic stress disorder (PTSD). This qualitative study investigated how providers write EHR notes on PTSD through 38 interviews with providers working at five Veterans Affairs (VA) hospitals across the United States of America. Two overarching themes were prominent in the results. Providers used progress notes primarily to remember and access details for direct patient care, but only rarely for care coordination. Providers infrequently recorded information not judged to directly contribute to improved care, sometimes deliberately omitting information perceived to jeopardize patients' access to, or quality of, care. Omitted information frequently included sexual or non-military trauma. Understanding providers' thought processes can help clinicians be aware of the limitations of EHR notes as a tool for learning the histories of new patients. Similarly, researchers relying on EHR data for PTSD research should be aware of likely areas of missing data. PMID- 26228931 TI - Characterization of repolarization in Brugada syndrome patients during exercise testing: Dynamic angle evaluation. AB - BACKGROUND: A new ECG criterion has been studied in Brugada syndrome (BrS) at rest to differentiate type 2 and incomplete right bundle branch block (IRBBB). METHODS: We assessed this criterion during exercise comparing BrS (46 patients) and IRBBB (17 patients). A beta angle was measured from lead V1 between the upslope of S-wave and the downslope of the r'-wave. RESULTS: Beta angle was significantly larger in BrS at rest (58+/-24 degrees vs 25+/-15 degrees , p<0.001), exercise (47+/-26 degrees vs 15+/-11 degrees , p<0.001), and recovery (46+/-24 degrees vs 21+/-12 degrees , p<0.001) with a reduction in angle at exercise compared to rest. There was a significant rebound in angle at recovery in the control group to (p<0.001); no such rebound was observed in the BrS group (p=NS). CONCLUSION: Beta angle study at rest and its evolution at exercise could help discriminate BrS patients from healthy subjects. PMID- 26228932 TI - Choosing among possible persons: The ethics of prenatal selection in the postgenomic age. AB - The "spectre of eugenics" is often raised about various current reproductive practices that imply a form of choice between future possible persons. Some of these practices are linked to genetic technologies such as pre-implantation genetic diagnosis, others merely entail the choice of a procreator having specific traits, such as in artificial insemination with donor. The weight and limits of this reproof of eugenics are examined, with special attention to the conceptual problems resulting from confusing choices involving virtual persons with the selection of existing persons. PMID- 26228933 TI - Medical treatments of the future: Between animality and artifice. AB - Medical treatments are behavioural phenomena developed through acculturation, but dating back to our animal ancestors. Medical treatments, and indeed other cultural phenomena, have been extensively developed in certain human societies, triggering risks that could affect the future of mankind. Excessive modification of the physical animal function of the human body, which has matured harmoniously over millions of years of biological evolution, may change the very nature of the human being. Respect for the animal nature of the human being stands as a key safeguard when considering medical treatments for the future. PMID- 26228934 TI - Is the relative increase in income inequality related to tooth loss in middle aged adults? AB - OBJECTIVES: To assess whether Brazilian middle-aged adults living in cities that experienced a relative increase on income inequality were more likely to have severe tooth loss and lack a functional dentition. METHODS: Data on Brazilian adults aged 35-44 years from state capitals and Federal District from the 2010 Brazilian Oral Health Survey (SBBrasil 2010) were analyzed. Clinically assessed tooth loss outcomes were severe tooth loss (<9 remaining natural teeth) and lack of functional dentition (<21 natural teeth). Income inequality was assessed by Gini Index in 1991, 2000, and 2003 using tertiles of distribution. Variation in Gini Index was assessed by changes in the tertiles distribution between years. Multilevel logistic regression models were used to estimate odds ratios (ORs) and 95 percent confidence intervals (95 percent CI) between variation in income inequality and tooth loss outcomes adjusting for individual socio-demographic characteristics. RESULTS: Prevalence of severe tooth loss and lack of functional dentition was 4.8 percent and 21.2 percent, respectively. Individuals living in cities with moderate and high increase in income inequality between 1991 and 2003 were more likely to have severe tooth loss and lack a functional dentition in 2010 compared with those living in cities with stable income inequality in the same period. Relationships between low family income and both tooth loss outcomes were significantly attenuated by relative increases in income inequality. CONCLUSIONS: Relative increases in income inequality were significantly associated with severe tooth loss and lack of a functional dentition in Brazilian middle-aged adults. PMID- 26228935 TI - Emerging Opportunities for Pharmacy in Advancing Healthcare. PMID- 26228937 TI - Oral Ribavirin for the Treatment of Noninfluenza Respiratory Viral Infections: A Systematic Review. AB - OBJECTIVE: To review clinical outcomes data for patients treated with oral ribavirin for noninfluenza respiratory viral infections (NIRVIs). DATA SOURCES: MEDLINE, EMBASE, and PubMed Central (1972 to June 1, 2015) were queried with the following search term combinations: "Oral" AND "ribavirin" AND ("respiratory syncytial virus" OR "metapneumovirus" OR "parainfluenza" OR "coronavirus" OR "rhinovirus" OR "enterovirus" OR "adenovirus"). STUDY SELECTION AND DATA EXTRACTION: Included studies must have characterized the clinical outcomes of a cohort of patients treated with oral ribavirin for symptomatic NIRVIs. Case reports and series with <5 cases, conference abstracts, and articles written in languages other than English were excluded. DATA SYNTHESIS: Of the 1256 unique reports, 15 met inclusion criteria: 12 retrospective, 3 prospective, and 3 comparative with untreated control groups. All studies except for 2 Middle East respiratory syndrome coronavirus (MERS-CoV) studies were in immunocompromised patients (9 malignancy/stem cell transplant, 4 lung transplant). The mortality rate ranged from 0% to 31% in malignancy/stem cell transplant recipients treated with oral ribavirin, and 1/108 (0.9%) ribavirin-treated lung transplant recipients died at 30 days. Three studies (one each for malignancy, lung transplant, and MERS-CoV) suggested a clinical outcomes benefit with oral ribavirin compared with supportive care alone; however, the nonrandomized design precludes efficacy determination. Hemolysis was the most common adverse reaction, occurring in 14% (54/375) of patients. Ribavirin was discontinued in 4% of patients secondary to adverse reactions. CONCLUSIONS: Oral ribavirin should be considered for the treatment of NIRVI in immunocompromised adults (malignancy/stem cell transplant or lung transplant) or adults with MERS-CoV. PMID- 26228936 TI - Anticholinergic Use and Recurrent Falls in Community-Dwelling Older Adults: Findings From the Health ABC Study. AB - BACKGROUND: Although it is generally accepted that anticholinergic use may lead to a fall, results from studies assessing the association between anticholinergic use and falls are mixed. In addition, direct evidence of an association between use of anticholinergic medications and recurrent falls among community-dwelling elders is not available. OBJECTIVE: To assess the association between anticholinergic use across multiple anticholinergic subclasses, including over the-counter medications, and recurrent falls. METHODS: This was a longitudinal analysis of 2948 participants, with data collected via interview at year 1 from the Health, Aging and Body Composition study and followed through year 7 (1997 2004). Self-reported use of anticholinergic medication was identified at years 1, 2, 3, 5, and 6 as defined by the list from the 2015 American Geriatrics Society Beers Criteria. Dosage and duration were also examined. The main outcome was recurrent falls (>=2) in an ensuing 12-month period from each medication data collection. RESULTS: Using multivariable generalized estimating equation models, controlling for demographic, health status/behaviors, and access-to-care factors, a 34% increase in likelihood of recurrent falls in anticholinergic users (adjusted odds ratio = 1.34; 95% CI = 0.93-1.93) was observed, but the results were not statistically significant; similar results were found with higher doses and longer duration of use. CONCLUSION: Increased point estimates suggest an association of anticholinergic use with recurrent falls, but the associations did not reach statistical significance. Future studies are needed for more definitive evidence and to examine other measures of anticholinergic burden and associations with more intermediate adverse effects such as cognitive function. PMID- 26228938 TI - Skin Hyperpigmentation and Melanonychia From Chronic Doxycycline Use. PMID- 26228939 TI - Influence of Methylphenidate on the Frequency of Stuttering: A Randomized Controlled Trial. AB - BACKGROUND: Recently, a case report described a decrease in frequency of stuttering after intake of methylphenidate (MPH). OBJECTIVE: This study was undertaken to investigate if this effect could again be reproduced in a population of young healthy male adult persons with developmental stuttering. METHODS: A double-blind randomized crossover trial, with a 2-week washout period, including 15 Dutch-speaking young healthy persons with developmental stuttering, assessed the effects of a single dose of 20 mg MPH compared with placebo on stuttering. Dependent and 1-sample t tests were used to detect significant differences. The end point was the number of stutter moments and self-perceived improvement. RESULTS: MPH yielded a significant decrease in the number of stutter moments when reading and speaking (P = 0.002), which was not the case with placebo (P = 0.090). There was a significant improvement from baseline after intake of MPH as compared with placebo (P = 0.003). Self-perceived improvement with MPH was not significantly better as compared with placebo (P = 0.28). CONCLUSIONS: This study showed that the participants had an objective statistically significant decrease in the frequency of stuttering with MPH, and this was not the case with placebo. This was also the case for a reduction in stutter moments when reading out loud and speaking spontaneously. However, this result was not subjectively perceived by the participants. PMID- 26228941 TI - Multilingual event extraction for epidemic detection. AB - OBJECTIVE: This paper presents a multilingual news surveillance system applied to tele-epidemiology. It has been shown that multilingual approaches improve timeliness in detection of epidemic events across the globe, eliminating the wait for local news to be translated into major languages. We present here a system to extract epidemic events in potentially any language, provided a Wikipedia seed for common disease names exists. METHODS: The Daniel system presented herein relies on properties that are common to news writing (the journalistic genre), the most useful being repetition and saliency. Wikipedia is used to screen common disease names to be matched with repeated characters strings. Language variations, such as declensions, are handled by processing text at the character level, rather than at the word level. This additionally makes it possible to handle various writing systems in a similar fashion. MATERIAL: As no multilingual ground truth existed to evaluate the Daniel system, we built a multilingual corpus from the Web, and collected annotations from native speakers of Chinese, English, Greek, Polish and Russian, with no connection or interest in the Daniel system. This data set is available online freely, and can be used for the evaluation of other event extraction systems. RESULTS: Experiments for 5 languages out of 17 tested are detailed in this paper: Chinese, English, Greek, Polish and Russian. The Daniel system achieves an average F-measure of 82% in these 5 languages. It reaches 87% on BEcorpus, the state-of-the-art corpus in English, slightly below top-performing systems, which are tailored with numerous language-specific resources. The consistent performance of Daniel on multiple languages is an important contribution to the reactivity and the coverage of epidemiological event detection systems. CONCLUSIONS: Most event extraction systems rely on extensive resources that are language-specific. While their sophistication induces excellent results (over 90% precision and recall), it restricts their coverage in terms of languages and geographic areas. In contrast, in order to detect epidemic events in any language, the Daniel system only requires a list of a few hundreds of disease names and locations, which can actually be acquired automatically. The system can perform consistently well on any language, with precision and recall around 82% on average, according to this paper's evaluation. Daniel's character-based approach is especially interesting for morphologically-rich and low-resourced languages. The lack of resources to be exploited and the state of the art string matching algorithms imply that Daniel can process thousands of documents per minute on a simple laptop. In the context of epidemic surveillance, reactivity and geographic coverage are of primary importance, since no one knows where the next event will strike, and therefore in what vernacular language it will first be reported. By being able to process any language, the Daniel system offers unique coverage for poorly endowed languages, and can complete state of the art techniques for major languages. PMID- 26228940 TI - Proteotoxic stress and ageing triggers the loss of redox homeostasis across cellular compartments. AB - The cellular proteostasis network integrates the protein folding and clearance machineries in multiple sub-cellular compartments of the eukaryotic cell. The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins. A distinctive feature of the ER is its tightly controlled redox homeostasis necessary for the formation of inter- and intra-molecular disulphide bonds. Employing genetically encoded in vivo sensors reporting on the redox state in an organelle-specific manner, we show in the nematode Caenorhabditis elegans that the redox state of the ER is subject to profound changes during worm lifetime. In young animals, the ER is oxidizing and this shifts towards reducing conditions during ageing, whereas in the cytosol the redox state becomes more oxidizing with age. Likewise, the redox state in the cytosol and the ER change in an opposing manner in response to proteotoxic challenges in C. elegans and in HeLa cells revealing conservation of redox homeostasis. Moreover, we show that organelle redox homeostasis is regulated across tissues within C. elegans providing a new measure for organismal fitness. PMID- 26228942 TI - Functional evaluation of peripheral nerve regeneration and target reinnervation in animal models: a critical overview. AB - Peripheral nerve injuries usually lead to severe loss of motor, sensory and autonomic functions in the patients. Due to the complex requirements for adequate axonal regeneration, functional recovery is often poorly achieved. Experimental models are useful to investigate the mechanisms related to axonal regeneration and tissue reinnervation, and to test new therapeutic strategies to improve functional recovery. Therefore, objective and reliable evaluation methods should be applied for the assessment of regeneration and function restitution after nerve injury in animal models. This review gives an overview of the most useful methods to assess nerve regeneration, target reinnervation and recovery of complex sensory and motor functions, their values and limitations. The selection of methods has to be adequate to the main objective of the research study, either enhancement of axonal regeneration, improving regeneration and reinnervation of target organs by different types of nerve fibres, or increasing recovery of complex sensory and motor functions. It is generally recommended to use more than one functional method for each purpose, and also to perform morphological studies of the injured nerve and the reinnervated targets. PMID- 26228943 TI - A. Stephen K. Hashmi. PMID- 26228944 TI - Natural (13) C distribution in oil palm (Elaeis guineensis Jacq.) and consequences for allocation pattern. AB - Oil palm has now become one of the most important crops, palm oil representing nearly 25% of global plant oil consumption. Many studies have thus addressed oil palm ecophysiology and photosynthesis-based models of carbon allocation have been used. However, there is a lack of experimental data on carbon fixation and redistribution within palm trees, and important C-sinks have not been fully characterized yet. Here, we carried out extensive measurement of natural (13) C abundance (delta(13) C) in oil palm tissues, including fruits at different maturation stages. We find a (13) C-enrichment in heterotrophic organs compared to mature leaves, with roots being the most (13) C-enriched. The delta(13) C in fruits decreased during maturation, reflecting the accumulation in (13) C depleted lipids. We further used observed delta(13) C values to compute plausible carbon fluxes using a steady-state model of (13) C-distribution including metabolic isotope effects ((12) v/(13) v). The results suggest that fruits represent a major respiratory loss (~39% of total tree respiration) and that sink organs such as fruits are fed by sucrose from leaves. That is, glucose appears to be a quantitatively important compound in palm tissues, but computations indicate that it is involved in dynamic starch metabolism rather that C-exchange between organs. PMID- 26228945 TI - Exact confidence intervals for the relative risk and the odds ratio. AB - For comparison of proportions, there are three commonly used measurements: the difference, the relative risk, and the odds ratio. Significant effort has been spent on exact confidence intervals for the difference. In this article, we focus on the relative risk and the odds ratio when data are collected from a matched pairs design or a two-arm independent binomial experiment. Exact one-sided and two-sided confidence intervals are proposed for each configuration of two measurements and two types of data. The one-sided intervals are constructed using an inductive order, they are the smallest under the order, and are admissible under the set inclusion criterion. The two-sided intervals are the intersection of two one-sided intervals. R codes are developed to implement the intervals. Supplementary materials for this article are available online. PMID- 26228946 TI - Prominent Canadian researcher loses libel case against documentary makers. PMID- 26228947 TI - Synthesis of globular precursors. AB - o-Carborane (C2 B10 H12 ) was adapted to perform as the core of globular macromolecules, dendrons or dendrimers. To meet this objective, precisely defined substitution patterns of terminal olefin groups on the carborane framework were subjected to Heck cross-coupling reactions or hydroboration leading to hydroxyl terminated arms. These led to new terminal groups (chloro, bromo, and tosyl leaving groups, organic acid, and azide) that permitted ester production, click chemistry, and oxonium ring opening to be performed as examples of reactions that demonstrate the wide possibilities of the globular icosahedral carboranes to produce new dendritic or dendrimer-like structures. Polyanionic species were obtained in high yield through the ring-opening reaction of cyclic oxonium compound [3,3'-Co(8-C4 H8 O2 -1,2-C2 B9 H10 )(1',2'-C2 B9 H11 )] by using terminal hydroxyl groups as nucleophiles. These new polyanionic compounds that contain multiple metallacarborane clusters at their periphery may prove useful as new classes of compounds for boron neutron capture therapy with enhanced water solubility and as cores to make a new class of high-boron globular macromolecules. PMID- 26228948 TI - A new open door for endoscopic ultrasound (EUS); the colon. PMID- 26228949 TI - Echoendoscopic characterization of the human colon. AB - PURPOSE: To characterize colon and rectum walls, pericolic and perirectal spaces, using endoscopic ultrasonography miniprobes. METHODS: Sixty individuals (50% males), aged 18-80, were included. Using 12 and 20 MHz endoscopic ultrasonography miniprobes, all different colon segments (ascending, transverse, descending, sigmoid) and rectum were evaluated according to the number and thickness of the different layers in intestinal wall, to the presence and (largest) diameter of vessels in the submucosa and of peri-intestinal nodes. RESULTS: The 20 MHz miniprobe identified a higher number of layers than the 12 MHz miniprobe, with medians of 7 and 5 respectively (p < 0.001). The rectal wall (p = 0.001), its muscularis propria (p < 0.001) and mucosa (p = 0.01) were significantly thicker than the different segments of the colon, which had no significant differences between them. Patients aged 41-60 presented thicker colonic wall and muscularis propria in descending (p = 0.001 and p = 0.004) and rectum (p = 0.01 and p = 0.01). Submucosal vessels were identified in 30% of individuals in descending and rectum, and in 12% in ascending. Adenopathies were observed in 9% of the colon segments and 5% in rectum. CONCLUSIONS: A higher frequency enabled the identification of a higher number of layers. Rectal wall is thicker than the one from all the segments of the colon and there are no differences between these, namely in the ascending colon. Moreover, periintestinal adenopathies were rarely identified but present in asymptomatic individuals. All together, these results describe for the first time features which are relevant during staging and therapeutic management of colonic lesions. PMID- 26228950 TI - [Validation of the Glasgow-Blatchford Scoring System to predict mortality in patients with upper gastrointestinal bleeding in a hospital of Lima, Peru (June 2012-December 2013)]. AB - BACKGROUND AND AIM: Upper gastrointestinal bleeding is a major cause of hospitalization and the most prevalent emergency worldwide, with a mortality rate of up to 14%. In Peru, there have not been any studies on the use of the Glasgow Blatchford Scoring System to predict mortality in upper gastrointestinal bleeding. The aim of this study is to perform an external validation of the Glasgow-Blatchford Scoring System and to establish the best cutoff for predicting mortality in upper gastrointestinal bleeding in a hospital of Lima, Peru. METHODS: This was a longitudinal, retrospective, analytical validation study, with data from patients with a clinical and endoscopic diagnosis of upper gastrointestinal bleeding treated at the Gastrointestinal Hemorrhage Unit of the Hospital Nacional Edgardo Rebagliati Martins between June 2012 and December 2013. We calculated the area under the curve for the receiver operating characteristic of the Glasgow-Blatchford Scoring System to predict mortality with a 95% confidence interval. RESULTS: A total of 339 records were analyzed. 57.5% were male and the mean age (standard deviation) was 67.0 (15.7) years. The median of the Glasgow-Blatchford Scoring System obtained in the population was 12. The ROC analysis for death gave an area under the curve of 0.59 (95% CI 0.5-0.7). Stratifying by type of upper gastrointestinal bleeding resulted in an area under the curve of 0.66 (95% CI 0.53-0.78) for non-variceal type. CONCLUSIONS: In this population, the Glasgow-Blatchford Scoring System has no diagnostic validity for predicting mortality. PMID- 26228951 TI - [Sphincterotomy plus large balloon dilation versus sphincterotomy alone for the extraction of complex lithiasis: A prospective analysis]. AB - BACKGROUND AND PURPOSE: Mid-size sphincterotomy associated with large balloon dilation is an alternative to wide sphincterotomy to remove complex lithiases. However, which of the two techniques is most effective remains unclear. Hence, we conducted this study to compare both methods prospectively. METHOD: Since January 2012 until March 2014, 133 consecutive patients with complex stones were included. Group A underwent mid-size sphincterotomy associated with large balloon dilation and group B underwent wide sphincterotomy alone. Success rates were assessed for: Extraction of stones, ductal patency rate, the use of mechanical lithotripsy, dose, time and dose per radioscopy area as well as procedure-related complications. RESULTS: Group A comprised 44 patients and group B comprised 69 patients. Overall success rate for extraction was 86.4% in group A and 70% in group B (p = 0.069). In giant lithiasis, effective extraction was 89.3% in group A and 58.6% in group B (p = 0.019). Use of mechanical lithotripsy was 15.9% and 30.4%, respectively (p = 0.142). Total radiotherapy dose was 39.8 mGy vs. 26.2 mGy, respectively (p = 0.134). Complications occurred in 6.8% and 5.5% of the procedures in each group, without significant differences among them (p = 0.856). CONCLUSION: Sphincterotomy plus large balloon dilation is more effective and equally safe than conventional sphincterotomy for the management of giant main bile duct lithiasis. PMID- 26228952 TI - [Hilar bile duct tumors: Endoscopic or percutaneous drainage? A prospective analysis]. AB - BACKGROUND AND OBJECTIVE: Both the endoscopic and the percutaneous approach are widely accepted for the drainage of hilar tumors. Our primary objective was to report on the effectiveness and complications of these procedures. METHODS: Prospective observational analysis of the endoscopic and/or percutaneous management of all hilar tumors treated at a referral hospital from October 2011 until October 2014. Group A included patients treated endoscopically and group B included patients treated with percutaneous drainage. The following variables were assessed: Effective biliary drainage rate, survival time and complications. RESULTS: Group A comprised 40 patients and group B, 22 patients. Overall success rate in achieving effective biliary drainage was 85% in group A and 90.9% in group B (p = 0.78). Five patients required a combined approach. In group A, the rate of effective drainage in patients with Bismuth IV-type tumors was 58.3%, while it was 81.8% in patients in group B (p = 0.44). There was no difference in mean survival between both groups. For group A, complication rate was 11.5%, whereas it was 2.94% for group B (p = 0.41). CONCLUSIONS: Endoscopic and percutaneous biliary drainage are both effective methods for the palliative treatment of patients with hilar tumors. However, for Bismuth IV-type strictures, percutaneous drainage proved to be safer and more effective. PMID- 26228953 TI - [Diagnosis agreement between capsule endoscopy and double-balloon enteroscopy in obscure gastrointestinal bleeding at a referral center]. AB - BACKGROUND AND AIM: Capsule endoscopy and double balloon enteroscopy are well recognized procedures in obscure gastrointestinal bleeding, with many factors that may influence their diagnosis yield. The aim of the present study was to characterize the degree of agreement between both techniques with focus on the type of lesion in a large cohort of patients at a referral center. MATERIAL AND METHOD: One thousand two hundred and nine capsules were administered in 1,078 patients and 381 enteroscopies were performed in 361 patients with obscure gastrointestinal bleeding from 2004 to 2014. RESULTS: Both procedures were carried out in 332 patients (mean age: 65.22 +/- 15.41, 183 men) and they have a similar diagnosis yield (70.5% vs. 69.6%, p = 0.9). Overall enteroscopy diagnosis yield was higher within patients with a previous positive capsule endoscopy (79.3% vs. 27.9%, p < 0.001). The degree of agreement was very good for polyps (0.89 [95% CI: 0.78-0.99]), good for vascular lesions (0.66 [95% CI: 0.55-0.77]) and tumors(0.66 [95% CI: 0.55-0.76]) and moderate for ulcers (0.56 [95% CI: 0.46 0.67]). Diverticula (0.39 [95% CI: 0.29-0.5]) achieved a fair agreement. The results of CE and DBE differed in 73 patients (22%). CONCLUSIONS: The present study confirms that although overall diagnostic yield by capsule endoscopy and double-balloon enteroscopy is similar, there are many factors which can modify these values, mainly the type of lesion. PMID- 26228954 TI - Management of fundic varices. Endoscopic aspects. PMID- 26228955 TI - Intestinal intussusception as an atypical presentation of celiac disease. PMID- 26228956 TI - [Overt obscure gastrointestinal bleeding secondary to small bowel gastrointestinal stromal tumor diagnosed by videocapsule endoscopy]. PMID- 26228958 TI - [Sedation in digestive endoscopy]. PMID- 26228957 TI - Fanconi syndrome and chronic renal failure in a chronic hepatitis B monoinfected patient treated with tenofovir. AB - Tenofovir disoproxil fumarate (TDF) is one of the first-line treatment options in chronic hepatitis B (CHB). Despite its efficacy in suppressing viral load and a high resistance barrier, long life maintenance therapy is required. Registration studies demonstrated TDF to be a safe drug. However, post-marketing experience reported cases of serious nephrotoxicity associated with hypophosphatemia, osteomalacia and, even more recently, Fanconi syndrome associated with TDF therapy in CHB monoinfected patients.Here the authors report a case of a 40 year old male, with a CHB monoinfection, that, three years after TDF therapy, developed a progressive chronic kidney disease with a serious hypophosphatemia and a secondary osteomalacia that was manifested by bone pain and multiple bone fractures. Further investigational analyses unveiled a proximal renal tubular dysfunction, which fulfilled most of the diagnostic criteria for a Fanconi syndrome. After TDF withdrawal and oral supplementation with phosphate and calcitriol, his renal function stabilized (despite not returning to normal), proximal renal tubular dysfunction abnormalities resolved as well as osteomalacia. In conclusion, physicians should be aware that, in CHB monoinfected patients under TDF therapy, serious renal damage is possible and preventable by timely monitoring serum creatinine and phosphate. PMID- 26228959 TI - Abdominal primary extra-gastrointestinal stromal tumor (E-GIST). A cytologic diagnosis in ascitic fluid. PMID- 26228960 TI - [Extrahepatic shunt. Unusual cause of hepatic encephalopathy]. PMID- 26228961 TI - [Retrorectal tumors - A diagnostic-therapeutic challenge]. PMID- 26228962 TI - [BAX as a susceptibility factor in hereditary non polyposis colorectal cancer]. PMID- 26228963 TI - [Gastrointestinal manifestations in Cowden syndrome. Screening recommendations]. PMID- 26228964 TI - [Gastric adenocarcinoma associated with Helicobacter pylori in the pediatric setting]. PMID- 26228965 TI - Congenital optic tract hypoplasia. AB - We report a case of isolated unilateral optic tract hypoplasia, described only twice previously. Bilateral optic disk hypoplasia was seen ophthalmoscopically and visual field studies showed an incongruous right homonymous hemianopia. Magnetic resonance imaging showed bilateral hypoplasia of both optic nerves and the left optic tract. Spectral domain optical coherence tomography mapping correlated well with the visual field studies. PMID- 26228966 TI - Enlarging corneoscleral cyst in a 2-year-old girl. AB - Cysts rarely develop within the cornea or sclera of children with no previous history of trauma or surgery. Primary corneoscleral cysts may arise from proliferation of anomalously situated epithelial or endothelial cells. We report the case of a 2-year-old girl with a primary enlarging cyst situated at the limbus of her left eye. Optical coherence tomography was used to determine whether there was any communication between the cyst and the anterior chamber and to help plan appropriate management. PMID- 26228967 TI - Therapeutic effect of atropine 1% in children with low myopia. AB - PURPOSE: To evaluate the efficacy of topical atropine 1% in promoting unaided visual acuity, reducing myopia, and slowing the progression of ocular axial elongation in Chinese children with low myopia. METHODS: Children with low myopia were randomly assigned to one of two groups, receiving either atropine 1% (treatment group) or placebo eyedrops (control group) once nightly for 1 year. After instillation of 3 drops of cyclopentolate 1%, unaided visual acuity, cycloplegic refraction, and ocular axial length were tested and recorded at baseline (2 weeks after atropine or vehicle eyedrops), 3 months, 6 months, 9 months, and 1 year. RESULTS: A total of 132 children 7-12 years of age with a refractive error of spherical equivalent -0.50 D to -2.00 were included. After 1 year, the mean unaided visual acuity in the treatment group was 0.31 +/- 0.16 logMAR; in the control group, 0.66 +/- 0.15 logMAR, (P < 0.0001). After treatment for 1 year, there was a decrease of 0.32 +/- 0.22 D from baseline in the treatment group and an increase of -0.85 +/- 0.31 D in the control group (P < 0.0001). The axial elongation in the treatment group was -0.03 +/- 0.07 mm; in the control group, 0.32 +/- 0.15 mm (P < 0.0001). CONCLUSIONS: In this study cohort, topical atropine1% reduced the degree of low myopia and slowed the progression of ocular axial elongation in children. PMID- 26228968 TI - The Sino-Nasal Outcome Test-22 as a tool to identify chronic rhinosinusitis in adults with cystic fibrosis. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is becoming increasingly prevalent in adults with cystic fibrosis (CF), as the median age of survival rises for these individuals. Delayed identification of CRS may contribute to worsening health related quality of life and increased treatment burden. Our objective was to investigate the utility of the 22-item Sino-Nasal Outcome Test (SNOT-22) as a tool to identify CRS in adults with CF. METHODS: In this cross-sectional study, participants were sampled from an adult-specific CF clinic in Vancouver, Canada, between September 2013 and April 2014. CRS was determined by use of standardized diagnostic guidelines. Participants completed the SNOT-22 and medical charts were reviewed for additional predictor variables. Logistic regression was used to compare the SNOT-22 as a univariable predictor variable to a multivariable prediction model, in order to best differentiate CRS and non-CRS participants. RESULTS: Ninety-three of 101 adults provided written informed consent. The prevalence of CRS was 56.3% (95% confidence interval [CI], 45.9% to 66.3%). Individuals with CRS reported significantly higher SNOT-22 scores than non-CRS participants (mean difference: 13.9; 95% CI, 6.1 to 21.7). The optimal SNOT-22 score to differentiate CRS was 21 out of 110 (sensitivity: 76%, specificity: 61%, positive predictive value: 71%, likelihood ratio: 1.9). CONCLUSION: Compared to the current diagnostic gold standard, SNOT-22 scores greater than 21 sufficiently identified adults with CF presenting with concomitant CRS. The SNOT-22 is a simple instrument that can easily be implemented in adult CF clinics to assist care providers identify individuals requiring more detailed assessment or referral to a sinus clinic. PMID- 26228969 TI - A new approach to delineating lymph node target volumes for post-operative radiotherapy in gastric cancer: A phase II trial. AB - PURPOSE: In the context of gastric cancer, lymph node target volume delineation for post-operative radiotherapy is currently built on the traditional system of dividing the stomach and 2-D treatment methods. Here, we have proposed a new delineation approach with irradiation indications for lymph node stations. Its safety and efficacy were evaluated in a phase II clinical trial. MATERIALS AND METHODS: Fifty-four gastric cancer patients with D2 lymph node dissection received 2 cycles of FOLFOX4. They subsequently received concurrent chemoradiotherapy (45 Gy at 1.8 Gy per fraction, 5 fractions per week for 5 weeks) with a 5-fluorouracil/leucovorin regimen, followed by 4 additional FOLFOX4 cycles. The target volume included the remnant stomach, anastomosis site, tumor bed, and regional lymph nodes selected through our new approach by taking gastric arteries as references. RESULTS: The most common grade 3-4 adverse event was neutropenia (14.8%). Neutropenia, anemia, and nausea were common grade 1-2 toxicities. No treatment-related deaths occurred during treatment. The 3-year overall, disease-free, and locoregional recurrence-free survival rates were 81.6%, 70.2%, and 91.1%, respectively. Eight patients developed peritoneal or distant metastases. CONCLUSIONS: Using our new approach and irradiation indications, delineation of the target volume of post-operative lymph node stations was feasible and well tolerated after D2 resection in patients with gastric cancer. PMID- 26228970 TI - Mapping of failures after radiochemotherapy in patients with non-metastatic esophageal cancer: A posteriori analysis of the dose distribution in the sites of loco-regional relapse. AB - BACKGROUND AND PURPOSE: We aimed to evaluate the patterns of loco-regional failure (LRF) after exclusive chemoradiotherapy (eCRT) for esophageal cancer with respect to planned dose and/or the incidental (unplanned) dose outside target volumes. MATERIALS AND METHODS: Co-image registration of CT or (18)F-FDG PET-CT at the time of failure (tf) and at the time of CRT (t0) was performed in 34 patients with LRF. Dosimetric parameters with regard to local failure (LF), nodal failure (NF) and involved nodal stations (NS) were derived. RESULTS: Twenty-two patients (64.7%) had LF, the majority of which (95.5%) were located at the epicenter of the GTV of the primary tumor. The mean doses recalculated to the NS at tf were more likely to be lower than the planned dose delivered to the PTV at t0: Dmean=33.9 +/- 20.8 Gy vs 52.2 +/- 8.5 Gy (p=0.0009), D95%=27.5 +/- 21 Gy vs 46.1 +/- 4.8 Gy (p=0.004). Among the 12 patients with NF outside the elective nodal irradiation (ENI) volume, Dmean of NS outside the ENI was significantly lower (19.4 +/- 21.4 Gy) than the Dmean of NS with failure within the ENI (45.1 +/- 6.1 Gy, p=0.01). CONCLUSION: Loco-regional failure after exclusive chemoradiotherapy for esophageal cancer may be due to an inadequately low dose. PMID- 26228971 TI - Radiotherapy for GIST progressing during or after tyrosine kinase inhibitor therapy: A prospective study. AB - PURPOSE: Gastrointestinal stromal tumor (GIST) has been considered radiation resistant, and radiotherapy is recommended only for palliation of bone metastases in current treatment guidelines. No registered prospective trial has evaluated GIST responsiveness to radiotherapy. PATIENTS AND METHODS: Patients with GIST progressing at intra-abdominal sites or the liver were entered to this prospective Phase II multicenter study (identifier NCT00515931). Metastases were treated with external beam radiotherapy using either conformal 3D planning or intensity modulated radiotherapy and conventional fractionation to a cumulative planning target volume dose of approximately 40 Gy. Systemic therapy was maintained unaltered during the study. RESULTS: Of the 25 patients entered, 19 were on concomitant tyrosine kinase inhibitor therapy, most often imatinib. Two (8%) patients achieved partial remission, 20 (80%) had stable target lesion size for ?3 months after radiotherapy with a median duration of stabilization of 16 months, and 3 (12%) progressed. The median time to radiotherapy target lesion progression was 4-fold longer than the median time to GIST progression at any site (16 versus 4 months). Radiotherapy was generally well tolerated. CONCLUSIONS: Responses to radiotherapy were infrequent, but most patients had durable stabilization of the target lesions. GIST patients with soft tissue metastases benefit frequently from radiotherapy. PMID- 26228972 TI - Inhibition of hyperactivity and impulsivity by carbonic anhydrase inhibitors in spontaneously hypertensive rats, an animal model of ADHD. AB - RATIONALE: Dysregulation of noradrenergic and dopaminergic systems is involved in the pathology of attention deficit hyperactivity disorder (ADHD). Carbonic anhydrase (CA) has been reported to affect monoamine transmission in the central nervous system. OBJECTIVES: The aim of this study is to investigate the effect of CA inhibitors on the hyperactivity and impulsivity of the spontaneously hypertensive rat (SHR), which is currently the best-validated animal model of ADHD. METHODS: SHRs and Wistar Kyoto rats at 6 to 8 weeks of age were pretreated with intraperitoneal injections of acetazolamide and methazolamide, both carbonic anhydrase inhibitors, before the behavior tests. The open-field locomotion test and the electro-foot shock aversive water drinking test were then applied to quantify their hyperactivity and impulsivity, respectively. The Morris water maze test, on the other hand, monitored their spatial learning. RESULTS: Acetazolamide and methazolamide significantly inhibited the hyperactivity of SHRs but had no effects in Wistar Kyoto rats. Acetazolamide also inhibited the impulsivity of SHRs. Low doses of acetazolamide had the greater inhibitory effects on the hyperactivity and impulsivity, but did not impair the spatial learning of SHRs. CONCLUSIONS: This is the first study to show that carbonic anhydrase inhibitors can strain-specifically antagonize the hyperactivity and impulsivity of SHRs. Under a low dose of acetazolamide, there was no cognition impairment in SHRs. Carbonic anhydrase inhibitors may be the novel drugs for treatment for patients with ADHD. PMID- 26228973 TI - Metal-free cycloaddition to synthesize naphtho[2,3-d][1,2,3]triazole-4,9-diones. AB - A metal-free domino [3 + 2] cycloaddition is reported to construct naphtho[2,3 d][1,2,3]triazole-4,9-dione derivatives and provide an alternative approach to the azide-alkyne cycloadditions. The key features are easily available starting materials, mild reaction conditions, a good atom economy, eco-friendly characteristics and a broad substrate scope with high yields. PMID- 26228974 TI - Types of approximation for probabilistic cognition: Sampling and variational. AB - A basic challenge for probabilistic models of cognition is explaining how probabilistically correct solutions are approximated by the limited brain, and how to explain mismatches with human behavior. An emerging approach to solving this problem is to use the same approximation algorithms that were been developed in computer science and statistics for working with complex probabilistic models. Two types of approximation algorithms have been used for this purpose: sampling algorithms, such as importance sampling and Markov chain Monte Carlo, and variational algorithms, such as mean-field approximations and assumed density filtering. Here I briefly review this work, outlining how the algorithms work, how they can explain behavioral biases, and how they might be implemented in the brain. There are characteristic differences between how these two types of approximation are applied in brain and behavior, which points to how they could be combined in future research. PMID- 26228976 TI - Cut, copy, move, delete: The study of human interferon genes reveal multiple mechanisms underlying their evolution in amniotes. AB - Interferons (IFNs) are rapidly evolving cytokines released when viral infections are detected in cells. Previous research suggests that genes encoding IFNs and their receptors duplicated extensively throughout vertebrate evolution. We present molecular genetic evidence that supports the use of nonallelic homologous recombination (NAHR) to expand select IFN genes during amniote evolution. The duplication of long regions of genome (encompassing at least one functional IFN gene) followed by the insertion of this genome fragment near its parent's location, is commonly observed in many amniote genomes. Duplicates inserted away from duplication hotspots are not as frequently perturbed with new duplicates, and tend to survive long periods of evolution, sometimes becoming new IFN subtypes. Although most duplicates are inserted parallel to and near the original sequence, the insertion of the Kelch-like 9 gene within the Type I IFN locus of placental mammals promoted antiparallel insertion of gene duplicates between the Kelch-like 9 and IFN-epsilon loci. Genetic exchange between highly similar Type I gene duplicates as well as between Type III IFN gene duplicates homogenized their diversification. Oddly, Type III IFN genes migrated long distances throughout the genome more frequently than did Type I IFN genes. The inter-chromosomal movement of Type I IFN genes in amniotes correlated with complete intron loss in their gene structure, and repeatedly occurred with occasional Type III IFN genes. PMID- 26228975 TI - Suberoylanilide Hydroxamic Acid, an Inhibitor of Histone Deacetylase, Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes. AB - Here, we explored the effects of suberoylanilide hydroxamic acid (SAHA) on the viability and apoptosis of rheumatoid arthritis of fibroblast-like synoviocytes (rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS)). FLS obtained from RA patients were treated with SAHA. SAHA significantly inhibited the viability of RA FLS in a concentration-dependent manner up to 5 MUM. SAHA-treated FLS showed a significant increase in the percentage of apoptosis and the expression and activity of caspase-3 and higher intracellular ROS levels. N-acetyl-l-cysteine (NAC) pretreatment significantly attenuated SAHA-induced apoptosis, decreasing the percentage of apoptosis by about 60 %. A significant decline in phosphorylated IkappaBalpha and nuclear factor kappa B (NF-kappaB) p65 and concomitant increase in total IkappaBalpha were shown in SAHA-treated FLS. Additionally, the levels of anti-apoptotic Bcl-2 proteins (Bcl-xL and Mcl-1) were significantly reduced by SAHA. Collectively, SAHA induces apoptosis of RA FLS, at least partially, through generation of ROS and suppression of NF-kappaB activation and Bcl-xL and Mcl-1 expression. PMID- 26228977 TI - [Ethics and Bioethics in Gastroenterology and the great technologic development]. PMID- 26228978 TI - [Cultural adaptation and psychometric validation of the health-related quality of life questionnaire EORTC QLQ STO-22 for patients with gastric cancer in Peru]. AB - OBJECTIVE: To validate the health-related quality of life questionnaire EORTC QLQ STO-22 for patients with gastric cancer in Peru, evaluating cultural and psychometric characteristics. MATERIALS AND METHODS: The first phase consisted in measure the content and appearance validity. In the second phase, the questionnaire was applied to patients diagnosed with gastric cancer and the internal consistency, test-retest reliability, convergent validity, discriminant validity and criterion validity was determined. RESULTS: After performing the content and appearance validity the questions/items 31 and 39 were changed. The global Cronbach's I+/- was 0.90 and I+/- coefficients greater than 0.7 in the multi-item subscales was obtained. The test-retest reliability showed an overall correlation of 0.924. When analyzing the convergent and discriminant validity, the values of Pearson's "r" were higher between an item and its own subscale, than the same item with other multi-item sub-scales. The criterion validity of the EORTC QLQ STO-22 compared with the EORTC QLQ C-30 showed a positive correlation of 0.727 with items evaluating symptomatology, and a negative correlation of -0.587 when comparing with functional status items, both statistically significant. CONCLUSION: The modified questionnaire EORTC QLQ STO 22 meets the reliability and validity criteria for assessing the quality of life in patients with gastric cancer in Peru. PMID- 26228979 TI - Correlacion entre sintomas gastrointestinales funcionales y la histopatologia de la mucosa gastrica, incluyendo la infeccion por Helicobacter pylori, en Lima, Peru. AB - OBJECTIVE: This study aims to investigate the relationship between functional gastrointestinal disorders and histopathology characteristics, including H. pylori infection, of gastric mucosa, at Cayetano Heredia National Hospital, Lima Peru, in 2013. MATERIALS AND METHODS: 112 patients were interviewed prospectively between June and July 2013 in the gastroenterology service. Dyspepsia, irritable bowel syndrome, and postprandial distress syndrome were characterized using the Rome III Survey. RESULTS: Pathology results were determined by gastric biopsies obtained by endoscopy. Of the patients interviewed, biopsy results were obtained for 101. 22.8% had atrophy, 24.8% had intestinal metaplasia, 57.4% presented with H pylori. CONCLUSIONS: Using chi-square analysis, no statistically significant relationship could be identified between clinical presentation and biopsy results. PMID- 26228980 TI - [Effect of Capsicum annum L (pucunucho, aji mono) in gastric ulcer experimentally induced in rats]. AB - OBJECTIVE: To examine the effects of the Capsicum annum L lyophilized fruit extract in experimentally-induced gastric ulcer in rats. MATERIALS AND METHODS: We used the model of indomethacin gastric ulcer-induced and the gastric ulcer model induced by pylorus ligation in rats. The rats were divided in five treatment groups as follow: G1: Distilled water 1 ml/Kg; G2: Ranitidine 50 mg/kg, G3: Capsicum 10mg/kg, G4: Capsicum 100 mg/kg, G5: Capsicum 1000 mg/kg. RESULTS: The results of the first model showed an ulcer inhibition of 60,4% and 66,7% using the doses of Capsicum at 10 mg/kg and 100 mg/kg, respectively. The results of the second model showed that neither the pH nor the volume of the gastric content were modified by the administered extract (p >0.05); however, by using the doses of Capsicum at 100 mg/kg and 1000 mg/kg, there was clearly an ulcer inhibition of 75.59% and 81.63% respectively, which were even greater than the inhibition obtained by ranitidine (75.51%). CONCLUSIONS: Therefore, in this experiment we demonstrated that the Capsicum annum L lyophilized fruit extract has a gastroprotective effect in experimentally-induced gastric ulcer in rats. PMID- 26228981 TI - [Clinical-radiological characteristics and explore the association between therapeutic success in patients undergoing ERCP and age in Cayetano Heredia Hospital, Lima, Peru]. AB - OBJECTIVE: To compare the clinical-radiological characteristics and explore the association between therapeutic success in patients undergoing ERCP and age in Cayetano Heredia Hospital, Lima, Peru. MATERIALS AND METHODS: Retrospective, descriptive study based on the review of records of patients undergoing ERCP between the years 2008 to 2014. These were divided into two groups: greater than or equal to 60 years (group 1) and less than 60 years (group 2). Indications of ERCP, radiological finding, therapeutic success, diagnostic and complications were documented. RESULTS: A total of 450 patients were studied, the group 1 consisting of 164 and group 2 of 286 patients. The most frequent indication for ERCP in both groups was choledocholithiasis. The most common radiological finding in both groups was bile duct dilatation (p=0.155). The most common diagnosis was choledocholithiasis in both groups, predominantly in group 2. We achieved a complete cleaning of the bile duct in 185(78.75%) patients with choledocholithiasis, finding more patients in group 2 (p=0.008) (OR=0.46; CI 95%: 0.25-0.87). The most frequent complication was pancreatitis in both groups (p=0.01). CONCLUSIONS: Choledocholithiasis and pancreatitis were the diagnosis and the most frequent complication. We found that the therapeutic success in patients who presented choledocholithiasis is associated with an age less than 60 years. PMID- 26228982 TI - [Severe hypertriglyceridemia induced acute pancreatitis: a case report and review of the literature]. AB - Hypertriglyceridemia-induced acute pancreatitis occurs in about 1-4% of the cases. It is the third leading cause of pancreatitis after biliary and alcoholic etiology. Hypertriglyceridemia can be caused by primary causes, lipid metabolism disorders and secondary causes. A 32 year old man, born in Huancayo, with a history of diabetes mellitus type 2, severe mixed dyslipidemia with primary hypertriglyceridemia, was admitted to emergency with 10 days of abdominal pain with moderate intensity in epigastrium and left hypochondrium spreading to dorsal region after intake of high-fat meal. 24 hours before admission, pain exacerbates increasing intensity and causing nausea and bilious vomits. Therefore, all laboratory examinations are carried out resulting in hypertriglyceridemia-induced acute pancreatitis. For that reason, an adequate clinical history physical examination associated with laboratory and image examinations are important to consider hypertriglyceridemia as part of the etiology of acute pancreatitis. PMID- 26228983 TI - [Gastrosplenic fistula secondary to gastric adenocarcinoma]. AB - We present a case report of a patient with spontaneous gastro-splenic fistula due to gastric adenocarcinoma associated with Streptococcus anginosus bacteriemia and fatal outcome. PMID- 26228985 TI - [Acute pancreatitis in childhood by choledocal stone in a choledocal cyst. Case report]. AB - Acute pancreatitis is a known complication of choledochal cysts. It is associated with changes in the biliopancreatic junction and with intra-cystic gallstones. We describe a case of pancreatitis and biliary obstruction caused by choledochal cyst type IVa complicated with obstruction by biliary stones in a 2 year old infant. PMID- 26228986 TI - [Hypercalcemia-induced pancreatitis in a patient with parathyroid adenoma and thyroid papillary carcinoma]. AB - Acute pancreatitis due to hypercalcemia secondary to primary hyperparathyroidism is a rare aetiology. We present a female patient with pancreatitis; with prior cholecystectomy, no alcohol usage or dyslipidemia. Laboratory studies showed, serum calcium 17.93 mg/dL and iPTH 441 pg/ml. Neck CT showed multinodular goiter and a parathyroid nodule. The patient underwent surgery after which serum Ca and PTH decreased. Biopsy showed follicular variant papillary thyroid carcinoma. This report discusses possible theories of association between parathyroid adenoma and hypercalcemic pancreatitis and describes the association with follicular variant papillary thyroid carcinoma, not previously described. PMID- 26228987 TI - Chemical and Physical Characteristics of Doxorubicin Hydrochloride Drug-Doped Salmon DNA Thin Films. AB - Double-stranded salmon DNA (SDNA) was doped with doxorubicin hydrochloride drug molecules (DOX) to determine the binding between DOX and SDNA, and DOX optimum doping concentration in SDNA. SDNA thin films were prepared with various concentrations of DOX by drop-casting on oxygen plasma treated glass and quartz substrates. Fourier transform infrared (FTIR) spectroscopy was employed to investigate the binding sites for DOX in SDNA, and electrical and photoluminescence (PL) analyses were used to determine the optimum doping concentration of DOX. The FTIR spectra showed that up to a concentration of 30 MUM of DOX, there was a tendency for binding with a periodic orientation via intercalation between nucleosides. The current and PL intensity increased as the DOX concentration increased up to 30 MUM, and then as the concentration of DOX further increased, we observed a decrease in current as well as PL quenching. Finally, the optical band gap and second band onset of the transmittance spectra were analyzed to further verify the DOX binding and optimum doping concentration into SDNA thin films as a function of the DOX concentration. PMID- 26228988 TI - The economic impact of vocal attrition in public school teachers in Miami-Dade County. AB - OBJECTIVES/HYPOTHESIS: Teachers are a known at-risk population for voice disorders. The prevalence and risk factors for voice disorders have been well studied in this population, but little is known about the associated economic cost. The purpose of this study is to assess the economic impact of voice dysfunction in teachers and understand the difference between the cost of absenteeism and presenteeism as a direct result of voice dysfunction. STUDY DESIGN: Cross-sectional analysis via self-administered online questionnaire. METHODS: A total of 14,256 public school teachers from Miami-Dade County, Florida, were asked to participate. Questions were formatted based on the previously validated Work Productivity and Activity Impairment: Specific Health Problem questionnaire adapted for hoarseness and voice disorders. Additional demographic questions were included in the questionnaire. RESULTS: A total of 961 questionnaire responses were received. The demographic characteristics of respondents closely matched known statistics for public school teachers in Miami Dade County. Economic calculations were performed for each questionnaire respondent and summed for all respondents to avoid bias. Per week, absenteeism related costs were $25,000, whereas presenteeism-related costs were approximately $300,000. These figures were used to extrapolate annual cost. Per year, absenteeism-related costs were $1 million, whereas presenteeism-related costs were approximately $12 million. CONCLUSION: The economic impact of voice dysfunction on the teaching profession is enormous. With the above calculations only including lost wages and decreased productivity, the actual figures may in fact be larger (cost of substitute teachers, impact on nonwork activities, etc.). Research investigating preventative measures for voice dysfunction in teachers is necessary to reduce this costly issue. LEVEL OF EVIDENCE: 2C. Laryngoscope, 126:665-671, 2016. PMID- 26228989 TI - Developmental staging models in bipolar disorder. AB - The previous contribution of Duffy and colleagues suggests that a chain of behavioral events starting during childhood precedes the development of full blown bipolar disorder. In this vein, the recent contribution of Keown-Stoneman and colleagues brings a new perspective to the study of prodromal symptoms of bipolar disorder. PMID- 26228990 TI - Differences in Pornography Use Among Couples: Associations with Satisfaction, Stability, and Relationship Processes. AB - The present study utilized a sample of 1755 adult couples in heterosexual romantic relationships to examine how different patterns of pornography use between romantic partners may be associated with relationship outcomes. While pornography use has been generally associated with some negative and some positive couple outcomes, no study has yet explored how differences between partners may uniquely be associated with relationship well-being. Results suggested that greater discrepancies between partners in pornography use were related to less relationship satisfaction, less stability, less positive communication, and more relational aggression. Mediation analyses suggested that greater pornography use discrepancies were primarily associated with elevated levels of male relational aggression, lower female sexual desire, and less positive communication for both partners which then predicted lower relational satisfaction and stability for both partners. Results generally suggest that discrepancies in pornography use at the couple level are related to negative couple outcomes. Specifically, pornography differences may alter specific couple interaction processes which, in turn, may influence relationship satisfaction and stability. Implications for scholars and clinicians interested in how pornography use is associated with couple process are discussed. PMID- 26228991 TI - Men with Sexual Problems and Their Partners: Findings from the International Survey of Relationships. AB - Epidemiologic studies of sexual function problems in men have focused on the individual male and related sociodemographic characteristics, individual risk factors and lifestyle concomitants, or medical comorbidities. Insufficient attention has been given to the role of sexual and relationship satisfaction and, more particularly, to the perspective of the couple as causes or correlates of sexual problems in men or women. Previously, we reported results of the first large, multi-national study of sexual satisfaction and relationship happiness in 1,009 midlife and older couples in five countries (Brazil, Germany, Japan, Spain, U.S.). For the present study, we examined, within each problem, the association of four major sexual problems in men (loss of sexual desire, erectile problems, premature ejaculation, delayed/absent orgasm) and multiple problems, with male and female partners' assessments of physical intimacy, sexual satisfaction, and relationship happiness, as well as associations with well-known health and psychosocial correlates of sexual problems in men. Sexual problem rates of men in our survey were generally similar to rates observed in past surveys in the general population, and similar risk factors (age, relationship duration, overall health) were associated with lack of desire, anorgasmia, or erection difficulties in our sample. As in previous surveys, there were few correlates of premature ejaculation. As predicted, men with one or more sexual problems reported decreased relationship happiness as well as decreased sexual satisfaction compared to men without sexual problems. Moreover, female partners of men with sexual problems had reduced relationship happiness and sexual satisfaction, although these latter outcomes were less affected in the women than the men. The association of men's sexual problems with men's and women's satisfaction and relationship happiness were modest, as these couples in long-term, committed relationships were notable for their relatively high levels of physical affection and relationship happiness. PMID- 26228992 TI - The Temporal Stability of Lack of Sexual Attraction Across Young Adulthood. AB - There is a large and growing literature on the stability of sexual orientation across the lifespan. However, virtually no studies have been conducted on the longitudinal stability of any dimension of asexuality. Here I utilized Kinsey scale-type data from Wave III and Wave IV of the Add Health survey to measure the stability of indicating "not sexually attracted to either males or females" in a forced-choice, Kinsey-type scale and during the time participants were moving through early adulthood (18-26 years in Wave III and 24-32 years in Wave IV). I found that, for the most part, individuals who reported no sexual attraction in Wave III were not the same individuals who reported no sexual attraction in Wave IV, with only three out of the 25 in Wave III who indicated no sexual attraction going on to do the same in Wave IV. This inter-wave consistency was lower than it was for other sexual minorities. However, indicating no sexual attraction in one wave was still a statistically significant predictor of indicating no sexual attraction in the other wave, as was refusing to answer or indicating the "don't know" option in the other wave. These findings do not necessarily denote change in sexual attraction across waves; the fact that not answering the question in one wave was a significant predictor of indicating no sexual attraction in the other wave provides quantitative evidence for the ambiguities involved in sexual identities when sexuality is taken for granted in the broader culture. This ambiguity affects the operationalization and quantification of asexuality. PMID- 26228993 TI - Preliminary results after upper cervical chiropractic care in patients with chronic cerebro-spinal venous insufficiency and multiple sclerosis. AB - PURPOSE: The aim of the study is to evaluate the clinical and X-ray results of the Upper Cervical Chiropractic care through the specific adjustments (corrections) of C1-C2 on patients with chronic venous cerebral-spinal insufficiency (CCSVI) and multiple sclerosis (MS). METHOD: We studied a sample of 77 patients before and after the Upper Cervical Chiropractic care, and we analyzed: A) The change of the X-ray parameters; B) The clinical results using a new set of questions. The protocol of the C1- C2 upper Cervical Chiropractic treatment, specific for these patients, lasts four months. From a haemodynamic point of view we divided the patients in 3 types: Type 1 - purely vascular with intravenous alterations; Type 2 - "mechanical" with of external venous compressions; Type 3 - mixed. RESULTS: We found an improvement in all kinds of subluxations after the treatment with respect to the pre-treatment X-ray evaluation, with a significant statistical difference. The differences between the clinical symptoms before and after the specific treatment of C1-C2 are statistically significant with p<0.001 according to the CHI-Square test revised by Yates. CONCLUSIONS: The preliminary X-ray and clinical improvements of the Upper Cervical Chiropractic corrections on C1- C2 on these patients with CCSVI and MS encourage us to continue with our studies. We believe that the Upper Cervical correction on C1-C2 could be the main non-invasive treatment of the CCSVI mechanical type in patients with MS. Further studies are required to evaluate the correlation between the Upper Cervical Chiropractic correction on C1 C2 on the cerebral venous drainage and the cerebro-spinal fluid. PMID- 26228994 TI - Multivariate logistic regression analysis of postoperative complications and risk model establishment of gastrectomy for gastric cancer: A single-center cohort report. AB - BACKGROUND: Reporting of surgical complications is common, but few provide information about the severity and estimate risk factors of complications. If have, but lack of specificity. METHODS: We retrospectively analyzed data on 2795 gastric cancer patients underwent surgical procedure at the Affiliated Hospital of Qingdao University between June 2007 and June 2012, established multivariate logistic regression model to predictive risk factors related to the postoperative complications according to the Clavien-Dindo classification system. RESULTS: Twenty-four out of 86 variables were identified statistically significant in univariate logistic regression analysis, 11 significant variables entered multivariate analysis were employed to produce the risk model. Liver cirrhosis, diabetes mellitus, Child classification, invasion of neighboring organs, combined resection, introperative transfusion, Billroth II anastomosis of reconstruction, malnutrition, surgical volume of surgeons, operating time and age were independent risk factors for postoperative complications after gastrectomy. Based on logistic regression equation, p=Exp?BiXi / (1+Exp?BiXi), multivariate logistic regression predictive model that calculated the risk of postoperative morbidity was developed, p = 1/(1 + e((4.810-1.287X1-0.504X2-0.500X3-0.474X4-0.405X5 0.318X6-0.316X7-0.305X8-0.278X9-0.255X10-0.138X11))). The accuracy, sensitivity and specificity of the model to predict the postoperative complications were 86.7%, 76.2% and 88.6%, respectively. CONCLUSIONS: This risk model based on Clavien-Dindo grading severity of complications system and logistic regression analysis can predict severe morbidity specific to an individual patient's risk factors, estimate patients' risks and benefits of gastric surgery as an accurate decision-making tool and may serve as a template for the development of risk models for other surgical groups. PMID- 26228995 TI - Dopant and excitation wavelength dependent color-tunable white light-emitting Ln(3+):Y2WO6 materials (Ln(3+) = Sm, Eu, Tb, Dy). AB - Microstructured Y2WO6 materials were prepared in a hydrothermal synthesis in the presence of glycerol, which was employed as both a solvent and a structure directing agent, after which they were heat treated at 1100 degrees C. These materials, similar to other previously reported Y2WO6 as well as other rare-earth tungstate structures, showed interesting luminescence properties. Six Ln(3+) doped or co-doped samples, which showed white light emission, are described in this paper. It was observed that the doping ion(s)/doping percentage, heat treatment of the material, as well as the chosen excitation wavelength could be used to tune the emission color of the samples to obtain white light with a warmer or colder undertone. The luminescence lifetimes, quantum yields, CIE coordinates and correlated color temperatures for these samples were determined. Additionally, for the co-doped Y2WO6 samples the energy transfer mechanisms were proposed because a significant change in the luminescence properties was observed after heat treatment. This can be linked to the conversion from distorted tungstate groups in the precursor material to regular tungstate groups in the heat treated material. PMID- 26228996 TI - The invisibility of men in South African violence prevention policy: national prioritization, male vulnerability, and framing prevention. AB - BACKGROUND: South Africa has a significant violence problem. The exposure of girls and women to interpersonal violence is widespread, and the victimization of men, especially to severe and homicidal forms of aggression, is of considerable concern, with male homicide eight times the global rate. In the last two decades, there have been a plethora of South African policies to promote safety. However, indications suggest that the policy response to violence is not coherently formulated, comprehensive, or evenly implemented. OBJECTIVE: This study examines selected South African national legislative instruments in terms of their framing and definition of violence and its typology, vulnerable populations, and prevention. DESIGN: This study comprises a directed content analysis of selected legislative documents from South African ministries mandated to prevent violence and its consequences or tasked with the prevention of key contributors to violence. Documents were selected using an electronic keyword search method and analyzed independently by two researchers. RESULTS: The legislative documents recognized the high levels of violence, confirmed the prioritization of selected vulnerable groups, especially women, children, disabled persons, and rural populations, and above all drew on criminological perspectives to emphasize tertiary prevention interventions. There is a policy focus on the protection and support of victims and the prosecution of perpetrators, but near absent recognition of men as victims. CONCLUSIONS: There is a need to broaden the policy framework from primarily criminological and prosecutorial perspectives to include public health contributions. It is likewise important to enlarge the conceptions of vulnerability to include men alongside other vulnerable groups. These measures are important for shaping and resourcing prevention decisions and strengthening primary prevention approaches to violence. PMID- 26228997 TI - Decelerating Mature Adipocyte Dedifferentiation by Media Composition. AB - The establishment of adipose tissue test systems is still a major challenge in the investigation of cellular and molecular interactions responsible for the pathogenesis of inflammatory diseases involving adipose tissue. Mature adipocytes are mainly involved in these pathologies, but rarely used in vitro, due to the lack of an appropriate culture medium which inhibits dedifferentiation and maintains adipocyte functionality. In our study, we showed that Dulbecco's Modified Eagle's Medium/Ham's F-12 with 10% fetal calf serum (FCS) reported for the culture of mature adipocytes favors dedifferentiation, which was accompanied by a high glycerol release, a decreasing release of leptin, and a low expression of the adipocyte marker perilipin A, but high expression of CD73 after 21 days. Optimized media containing FCS, biotin, pantothenate, insulin, and dexamethasone decelerated the dedifferentiation process. These cells showed a lower lipolysis rate, a high level of leptin release, as well as a high expression of perilipin A. CD73-positive dedifferentiated fat cells were only found in low quantity. In this work, we showed that mature adipocytes when cultured under optimized conditions could be highly valuable for adipose tissue engineering in vitro. PMID- 26228998 TI - Bolus intravenous 0.9% saline, but not 4% albumin or 5% glucose, causes interstitial pulmonary edema in healthy subjects. AB - Rapid intravenous (iv) infusion of 0.9% saline alters respiratory mechanics in healthy subjects. However, the relative cardiovascular and respiratory effects of bolus iv crystalloid vs. colloid are unknown. Six healthy male volunteers were given 30 ml/kg iv 0.9% saline, 4% albumin, and 5% glucose at a rate of 100 ml/min on 3 separate days in a double-blinded, randomized crossover study. Impulse oscillometry, spirometry, lung volumes, diffusing capacity (DLCO), and blood samples were measured before and after fluid administration. Lung ultrasound B line score (indicating interstitial pulmonary edema) and Doppler echocardiography indices of cardiac preload were measured before, midway, immediately after, and 1 h after fluid administration. Infusion of 0.9% saline increased small airway resistance at 5 Hz (P = 0.04) and lung ultrasound B-line score (P = 0.01) without changes in Doppler echocardiography measures of preload. In contrast, 4% albumin increased DLCO, decreased lung volumes, and increased the Doppler echocardiography mitral E velocity (P = 0.001) and E-to-lateral/septal e' ratio, estimated blood volume, and N-terminal pro B-type natriuretic peptide (P = 0.01) but not lung ultrasound B-line score, consistent with increased pulmonary blood volume without interstitial pulmonary edema. There were no significant changes with 5% glucose. Plasma angiopoietin-2 concentration increased only after 0.9% saline (P = 0.001), suggesting an inflammatory mechanism associated with edema formation. In healthy subjects, 0.9% saline and 4% albumin have differential pulmonary effects not attributable to passive fluid filtration. This may reflect either different effects of these fluids on active signaling in the pulmonary circulation or a protective effect of albumin. PMID- 26228999 TI - Effects of chronic hypergravity: from adaptive to deleterious responses in growing mouse skeleton. AB - One of the most important but least studied environmental factors playing a major role in bone physiology is gravity. While the knowledge of deleterious effects of microgravity on the skeleton is expanding, little is known about hypergravity and its osteogenic potential. Centrifugation was used to assess effects of 21-day continuous 2- or 3-g acceleration on femur and L2-vertebra of 7-wk-old male C57BL/6 mice. Under 3 g, body mass growth slowed down, and deleterious skeletal effects were found (P < 0.05 compared with control): cortical thinning, osteoclasts surface increase (+41% in femur, +20% in vertebra), and bone formation rate decrease (-34% in femur, -38% in vertebra). A 2-g centrifugation did not reduce body mass and improved trabecular volume (+18% in femur, +13% in vertebra) and microarchitecture (+32% connectivity density in femur, +9% trabecular thickness in vertebra, P < 0.05 compared with control). Centrifugation at 2 g also decreased osteoclast surfaces (-36% in femur, -16% in vertebra) and increased the extent of mineralized surfaces (+31% in femur, +48% in vertebra, P < 0.05 compare to control). Quantitative immunohistochemistry revealed an increase of dentin matrix acidic phosphoprotein 1 (DMP1) and decrease of sclerostin (+60% and -35% respectively, P < 0.001 compared with control) in the femur cortex of 2-g mice. In the distal femur metaphysis, the number and volume of blood vessels increased by 22 and 44%, respectively (P < 0.05 compared with control). In conclusion, the effects of continuous hypergravity were bone compartment-specific and depended on the gravity level, with a threshold between beneficial 2-g and deleterious 3-g effects. PMID- 26229000 TI - Sleep at high altitude: guesses and facts. AB - Lowlanders commonly report a poor sleep quality during the first few nights after arriving at high altitude. Polysomnographic studies reveal that reductions in slow wave sleep are the most consistent altitude-induced changes in sleep structure identified by visual scoring. Quantitative spectral analyses of the sleep electroencephalogram have confirmed an altitude-related reduction in the low-frequency power (0.8-4.6 Hz). Although some studies suggest an increase in arousals from sleep at high altitude, this is not a consistent finding. Whether sleep instability at high altitude is triggered by periodic breathing or vice versa is still uncertain. Overnight changes in slow wave-derived encephalographic measures of neuronal synchronization in healthy subjects were less pronounced at moderately high (2,590 m) compared with low altitude (490 m), and this was associated with a decline in sleep-related memory consolidation. Correspondingly, exacerbation of breathing and sleep disturbances experienced by lowlanders with obstructive sleep apnea during a stay at 2,590 m was associated with poor performance in driving simulator tests. These findings suggest that altitude related alterations in sleep may adversely affect daytime performance. Despite recent advances in our understanding of sleep at altitude, further research is required to better establish the role of gender and age in alterations of sleep at different altitudes, to determine the influence of acclimatization and of altitude-related illness, and to uncover the characteristics of sleep in highlanders that may serve as a study paradigm of sleep in patients exposed to chronic hypoxia due to cardiorespiratory disease. PMID- 26229001 TI - Exploring new concepts in the management of heart failure with preserved ejection fraction: is exercise the key for improving treatment? PMID- 26229002 TI - High-intensity interval training attenuates endothelial dysfunction in a Dahl salt-sensitive rat model of heart failure with preserved ejection fraction. AB - Heart failure patients with preserved left ventricular ejection fraction (HFpEF) have endothelial dysfunction, but the underlying molecular mechanisms remain unknown. In addition, whether exercise training improves endothelial function in HFpEF is still controversial. The present study therefore aimed to determine the functional and molecular alterations in the endothelium associated with HFpEF, while further assessing the effects of high-intensity interval training (HIT). Female Dahl salt-sensitive rats were randomized for 28 wk into the following groups: 1) control: fed 0.3% NaCl; 2) HFpEF: fed 8% NaCl; and 3) HFpEF + HIT: animals fed 8% NaCl and HIT treadmill exercise. Echocardiography and invasive hemodynamic measurements were used to assess diastolic dysfunction. Endothelial function of the aorta was measured in vitro. Expression of endothelial nitric oxide synthase (eNOS), nicotinamide adenine dinucleotide phosphate-oxidase [NAD(P)H oxidase], and advanced glycation end product (AGE)-modified proteins were quantified by Western blot, and zymography quantified matrix metalloproteinase (MMP) activity. In this model of HFpEF, endothelium-dependent and -independent vasodilation was impaired. However, this was prevented by HIT. In HFpEF protein expression of eNOS was reduced by 47%, but MMP-2 and MMP-9 activity was elevated by 186 and 68%. The expression of AGE-modified proteins was increased by 106%. All of these changes were prevented by HIT. Endothelial function was impaired in this model of HFpEF, which was associated with reduced expression of eNOS, increased MMP activity, and increased AGE-modified proteins. HIT was able to attenuate both these functional and molecular alterations. These findings therefore suggest HFpEF induces endothelial dysfunction, but this is reversible by HIT. PMID- 26229003 TI - Validation of optical voltage reporting by the genetically encoded voltage indicator VSFP-Butterfly from cortical layer 2/3 pyramidal neurons in mouse brain slices. AB - Understanding how behavior emerges from brain electrical activity is one of the ultimate goals of neuroscience. To achieve this goal we require methods for large scale recording of the electrical activity of specific neuronal circuits. A very promising approach is to use optical reporting of membrane voltage transients, particularly if the voltage reporter is genetically targeted to specific neuronal populations. Targeting in this way allows population signals to be recorded and interpreted without blindness to neuronal diversity. Here, we evaluated the voltage-sensitive fluorescent protein, VSFP Butterfly 2.1, a genetically encoded voltage indicator (GEVI), for monitoring electrical activity of layer 2/3 cortical pyramidal neurons in mouse brain slices. Standard widefield fluorescence and two-photon imaging revealed robust, high signal-to-noise ratio read-outs of membrane voltage transients that are predominantly synaptic in nature and can be resolved as discrete areas of synaptically connected layer 2/3 neurons. We find that targeted expression of this GEVI in the cortex provides a flexible and promising tool for the analysis of L2/3 cortical network function. PMID- 26229004 TI - Differential miRNA expression in inherently high- and low-active inbred mice. AB - Despite established health benefits of regular exercise, the majority of Americans do not meet the recommended levels of physical activity. While it is known that voluntary activity levels are largely heritable, the genetic mechanisms that regulate activity are not well understood. MicroRNAs (miRNAs) are small non-coding RNAs that inhibit transcription by binding to a target gene, inhibiting protein production. The purpose of this study was to investigate differential miRNA expression between inherently high- (C57L/J) and low- (C3H/HeJ) active inbred mice in soleus, extensor digitorum longus (EDL), and nucleus accumbens tissues. Expression was initially determined by miRNA microarray analysis, and selected miRNAs were validated by qRT-PCR. Expression of 13 miRNAs varied between strains in the nucleus accumbens, 20 in soleus, and eight in EDL, by microarray analysis. Two miRNAs were validated by qRT-PCR in the nucleus accumbens; miR-466 was downregulated (~4 fold; P < 0.0004), and miR-342 5p was upregulated (~115 fold; P < 0.0001) in high-active mice. MiR-466 was downregulated (~5 fold; P < 0.0001) in the soleus of high-active mice as well. Interestingly, miR-466 is one of several miRNA families with sequence located in intron 10 of Sfmbt2; miRNAs at this locus are thought to drive imprinting of this gene. "Pathways in cancer" and "TGFbeta signaling" were the most significant pathways of putative target genes in both the soleus and nucleus accumbens. Our results are the first to consider differential miRNA expression between high- and low-active mice, and suggest that miRNAs may play a role in regulation of physical activity. PMID- 26229005 TI - Regulation of cardiac cellular bioenergetics: mechanisms and consequences. AB - The regulation of cardiac cellular bioenergetics is critical for maintaining normal cell function, yet the nature of this regulation is not fully understood. Different mechanisms have been proposed to explain how mitochondrial ATP production is regulated to match changing cellular energy demand while metabolite concentrations are maintained. We have developed an integrated mathematical model of cardiac cellular bioenergetics, electrophysiology, and mechanics to test whether stimulation of the dehydrogenase flux by Ca(2+) or Pi, or stimulation of complex III by Pi can increase the rate of mitochondrial ATP production above that determined by substrate availability (ADP and Pi). Using the model, we show that, under physiological conditions the rate of mitochondrial ATP production can match varying demand through substrate availability alone; that ATP production rate is not limited by the supply of reducing equivalents in the form of NADH, as a result of Ca(2+) or Pi activation of the dehydrogenases; and that ATP production rate is sensitive to feedback activation of complex III by Pi. We then investigate the mechanistic implications on cytosolic ion homeostasis and force production by simulating the concentrations of cytosolic Ca(2+), Na(+) and K(+), and activity of the key ATPases, SERCA pump, Na(+)/K(+) pump and actin-myosin ATPase, in response to increasing cellular energy demand. We find that feedback regulation of mitochondrial complex III by Pi improves the coupling between energy demand and mitochondrial ATP production and stabilizes cytosolic ADP and Pi concentrations. This subsequently leads to stabilized cytosolic ionic concentrations and consequentially reduced energetic cost from cellular ATPases. PMID- 26229007 TI - WASM 2015 editorial. PMID- 26229006 TI - Neuromuscular electrical stimulation leads to physiological gains enhancing postural balance in the pre-frail elderly. AB - Physiological aging leads to a progressive weakening of muscles and tendons, thereby disturbing the ability to control postural balance and consequently increasing exposure to the risks of falls. Here, we introduce a simple and easy to-use neuromuscular electrical stimulation (NMES) training paradigm designed to alleviate the postural control deficit in the elderly, the first hallmarks of which present as functional impairment. Nine pre-frail older women living in a long-term care facility performed 4 weeks of NMES training on their plantarflexor muscles, and seven nontrained, non-frail older women living at home participated in this study as controls. Participants were asked to perform maximal voluntary contractions (MVC) during isometric plantarflexion in a lying position. Musculo tendinous (MT) stiffness was assessed before and after the NMES training by measuring the displacement of the MT junction and related tendon force during MVC. In a standing position, the limit of stability (LoS) performance was determined through the maximal forward displacement of the center of foot pressure, and related postural sway parameters were computed around the LoS time gap, a high force requiring task. The NMES training induced an increase in MVC, MT stiffness, and LoS. It significantly changed the dynamics of postural balance as a function of the tendon property changes. The study outcomes, together with a multivariate analysis of investigated variables, highlighted the benefits of NMES as a potential tool in combating neuromuscular weakening in the elderly. The presented training-based strategy is valuable in alleviating some of the adverse functional consequences of aging by directly acting on intrinsic biomechanical and muscular properties whose improvements are immediately transferable into a functional context. PMID- 26229008 TI - Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice. AB - Chronic pancreatitis (CP) is a devastating disease with no treatments. Experimental models have been developed to reproduce the parenchyma and inflammatory responses typical of human CP. For the present study, one objective was to assess and compare the effects of pancreatic duct ligation (PDL) to those of repetitive cerulein (Cer)-induced CP in mice on pancreatic production of bone morphogenetic protein-2 (BMP2), apelin, and parathyroid hormone-related protein (PTHrP). A second objective was to determine the extent of cross talk among pancreatic BMP2, apelin, and PTHrP signaling systems. We focused on BMP2, apelin, and PTHrP since these factors regulate the inflammation-fibrosis cascade during pancreatitis. Findings showed that PDL- and Cer-induced CP resulted in significant elevations in expression and peptide/protein levels of pancreatic BMP2, apelin, and PTHrP. In vivo mouse and in vitro pancreatic cell culture experiments demonstrated that BMP2 stimulated pancreatic apelin expression whereas apelin expression was inhibited by PTHrP exposure. Apelin or BMP2 exposure inhibited PTHrP expression, and PTHrP stimulated upregulation of gremlin, an endogenous inhibitor of BMP2 activity. Transforming growth factor beta (TGF-beta) stimulated PTHrP expression. Together, findings demonstrated that PDL- and Cer-induced CP resulted in increased production of the pancreatic BMP2, apelin, and PTHrP signaling systems and that significant cross talk occurred among pancreatic BMP2, apelin, and PTHrP. These results together with previous findings imply that these factors interact via a pancreatic network to regulate the inflammation-fibrosis cascade during CP. More importantly, this network communicated with TGF-beta, a key effector of pancreatic pathophysiology. This novel network may be amenable to pharmacologic manipulations during CP in humans. PMID- 26229010 TI - Polarizing news? Representations of threat and efficacy in leading US newspapers' coverage of climate change. AB - This study examines non-editorial news coverage in leading US newspapers as a source of ideological differences on climate change. A quantitative content analysis compared how the threat of climate change and efficacy for actions to address it were represented in climate change coverage across The New York Times, The Wall Street Journal, The Washington Post, and USA Today between 2006 and 2011. Results show that The Wall Street Journal was least likely to discuss the impacts of and threat posed by climate change and most likely to include negative efficacy information and use conflict and negative economic framing when discussing actions to address climate change. The inclusion of positive efficacy information was similar across newspapers. Also, across all newspapers, climate impacts and actions to address climate change were more likely to be discussed separately than together in the same article. Implications for public engagement and ideological polarization are discussed. PMID- 26229009 TI - Suppression of fibrogenic signaling in hepatic stellate cells by Twist1-dependent microRNA-214 expression: Role of exosomes in horizontal transfer of Twist1. AB - A hallmark of liver fibrosis is the activation of hepatic stellate cells (HSC), which results in their production of fibrotic molecules, a process that is largely regulated by connective tissue growth factor (CCN2). CCN2 is increasingly expressed during HSC activation because of diminished expression of microRNA-214 (miR-214), a product of dynamin 3 opposite strand (DNM3os) that directly suppresses CCN2 mRNA. We show that an E-box in the miR-214 promoter binds the basic helix-loop-helix transcription factor, Twist1, which drives miR-214 expression and results in CCN2 suppression. Twist1 expression was suppressed in HSC of fibrotic livers or in cultured HSC undergoing activation in vitro or after treatment with ethanol. Furthermore, Twist1 decreasingly interacted with DNM3os as HSC underwent activation in vitro. Nanovesicular exosomes secreted by quiescent but not activated HSC contained high levels of Twist1, thus reflecting the suppression of cellular Twist1 during HSC activation. Exosomal Twist1 was intercellularly shuttled between HSC and stimulated expression of miR-214 in the recipient cells, causing expression of CCN2 and its downstream effectors to be suppressed. Additionally, the miR-214 E-box in HSC was also regulated by hepatocyte-derived exosomes, showing that functional transfer of exosomal Twist1 occurs between different cell types. Finally, the levels of Twist1, miR-214, or CCN2 in circulating exosomes from fibrotic mice reflected fibrosis-induced changes in the liver itself, highlighting the potential utility of these and other constituents in serum exosomes as novel circulating biomarkers for liver fibrosis. These findings reveal a unique function for cellular or exosomal Twist1 in CCN2-dependent fibrogenesis. PMID- 26229011 TI - Metamaterial Absorbers for Infrared Detection of Molecular Self-Assembled Monolayers. AB - The emerging field of plasmonic metamaterials has introduced new degree of freedom to manipulate optical field from nano to macroscopic scale, offering an attractive platform for sensing applications. So far, metamaterial sensor concepts, however, have focused on hot-spot engineering to improve the near-field enhancement, rather than fully exploiting tailored material properties. Here, we present a novel spectroscopic technique based on the metamaterial infrared (IR) absorber allowing for a low-background detection scheme as well as significant plasmonic enhancement. Specifically, we experimentally demonstrate the resonant coupling of plasmonic modes of a metamaterial absorber and IR vibrational modes of a molecular self-assembled monolayer. The metamaterial consisting of an array of Au/MgF2/Au structures exhibits an anomalous absorption at ~ 3000 cm(-1), which spectrally overlaps with C-H stretching vibrational modes. Symmetric/asymmetric C H stretching modes of a 16-Mercaptohexadecanoic acid monolayer are clearly observed as Fano-like anti-resonance peaks within a broad plasmonic absorption of the metamaterial. Spectral analysis using Fano line-shape fitting reveals the underlying resonant interference in plasmon-molecular coupled systems. Our metamaterial approach achieves the attomole sensitivity with a large signal-to noise ratio in the far-field measurement, thus may open up new avenues for realizing ultrasensitive IR inspection technologies. PMID- 26229012 TI - Point-of-care molecular diagnostic devices: an overview. AB - Point-of-care molecular diagnostic devices are a rapidly expanding market. A variety of technologies are being developed for DNA detection and amplification, mostly aiming to detect pathogens. Of the two devices for detection of human genetic variations, both focus on CYP2C19 and have obtained regulatory approval. Most other devices have not obtained US FDA approval and are still undergoing clinical trials. Most, if not all, devices in development require equipment to which disposable test cartridges are placed. Thus, they may not fulfill FDA's definition of being 'simple'. There is a clear need to develop completely disposable devices that do not require equipment maintenance, and to detect other genetic variants predictive of disease susceptibility and drug response. PMID- 26229013 TI - Calcium Metabolism Profile in Rat Inner Ear Indicated by MRI After Tympanic Medial Wall Administration of Manganese Chloride. AB - OBJECTIVES: To evaluate the efficacy of the novel method for the targeted delivery of Mn(++) to the inner ear and monitor calcium metabolism activity in the inner ear. MATERIALS AND METHODS: Dynamic signal changes of Mn(++) in the rat inner ear were followed using T1-weighted magnetic resonance imaging (MRI) after administration of 2.5 ul MnCl2(500 mM) to the medial wall of the middle ear cavity. RESULTS: Mn(++) passed through both the oval and round windows and distributed in the perilymphatic compartments, where it formed bright sharp lines along the fluid-cellular borders 12 minutes post administration and entered the endolymph sufficiently after 45 minutes. After 6 hours, the distribution of Mn(++) shifted from a fluid-dominant pattern to a cell-dominant pattern. Mn(++) concentrated in the area of the basilar membrane, periphery process, and soma of the spiral ganglion on day 2; became more distinguishable on day 4; declined on day 8; and remained detectable for 16 days post administration. CONCLUSIONS: The novel targeted delivery method efficiently introduced Mn(++) into the inner ear. The dynamic distribution pattern of Mn(++) in the inner ear shown by MRI indicates that this method can be used to monitor calcium metabolism activity in the inner ear. PMID- 26229014 TI - If you don't want it, neither do I: Social influences on children's choices. AB - To what extent does knowing what others like influence children's valuation of objects? The current study examined the effect of having observed another person's choices on children's decisions about objects. Specifically, we asked whether children consider what the other person does not choose. In the first of three conditions, 4-year-olds watched as an experimenter looked inside two boxes and then selected the box containing the object she liked best. Children were then asked to choose between the remaining box (that the experimenter did not take) and a neutral box (that replaced the chosen box). Children tended to select the neutral box, suggesting that they had devalued the box the experimenter did not choose. However, in the second condition, when the experimenter chose a box without first looking inside--and thus was ignorant of the contents--children chose randomly. The third condition revealed that children continued to select the neutral box even when the experimenter who made the initial choice was not present. This indicates that children's valuation of the rejected option changed rather than their choices being solely influenced by the social dynamics of the situation (e.g., reluctance to choose the box with the option the experimenter knowingly rejected while in the presence of that experimenter). Taken together, these findings suggest that by 4 years of age, children's own choices--and values -are influenced by observing others' informed choices, including what they do not choose. The findings provide new insight into the potential role of social influence in children's developing preferences. PMID- 26229015 TI - Virtual endoscopy--a new assessment tool in difficult airway management. AB - Preemptive mapping of the airway is a useful adjunct to conventional clinical assessments when airway management planning for patients with complex head and neck pathology. Nasendoscopy is frequently used for this purpose but is also invasive and poorly tolerated in a subset of patients and, even in expert hands, may not allow complete visualization of the glottis and subglottic structures. We present a novel tool for difficult airway management planning in the form of virtual endoscopy by applying free online OsiriX software to head and neck computed tomographic scans to generate a "fly-through" airway reconstruction. To highlight how well virtual endoscopy correlates to conventional fibreoscopy, we compare both of these assessment tools in 3 patients with glottic, subglottic, and multilevel airway pathologies. Virtual endoscopy represents a unique, noninvasive, safe, and accurate airway assessment and educational resource, which warrants further exploration. PMID- 26229016 TI - Effects of nutritional status and cognitive ability on olfactory function in geriatric patients. AB - OBJECTIVE: The aim of this study was to investigate the prevalence of olfactory dysfunction and evaluate the relationship between olfactory function and nutritional status, comorbidity, and the results of a neurocognitive test in geriatric patients who do not suffer from neurodegenerative disease. MATERIALS AND METHODS: A total of 45 patients who visited the Geriatric Health Center of Chungnam National University Hospital were enrolled in this study. Olfactory function was assessed using a Korean Version of Sniffin' Stick Test II. Cognitive status of all participants was assessed with the MMSE-K (Korean version of the Mini-Mental State Examination). Nutritional status was assessed with body mass index, Mini-Nutritional Assessment (MNA), and serum total protein and albumin. RESULTS: A total of 45 participants were enrolled in this study. Of these subjects, 28 were men and 17 were women, with a mean age of 71.7+/-5.16 years. Nine (20%) were normosmia, 13 (28.9%) were hyposmia, and 23 (51.1%) were anosmia. Thirty-six patients (80%) suffered from olfactory dysfunction (anosmia or hyposmia). MMSE score showed significant correlation with MNA score. There were significant negative correlations between age and total TDI (threshold, discrimination, and identification) score, discrimination score, identification score, and MMSE score. MMSE score showed significant correlation with discrimination score and identification score. However, MNA score did not show any significant correlation with olfactory function test results. CONCLUSION: Although olfactory function was not influenced by nutritional status, abilities of discrimination and identification of odors were associated with cognitive function in geriatric patients. PMID- 26229017 TI - Can tissue adhesives and platelet-rich plasma prevent pharyngocutaneous fistula formation? AB - OBJECTIVE: One of the frequently encountered disorders of wound healing following laryngectomy is pharyngocutaneous fistula. However, although studies have been performed with the aim of prevention of pharyngocutaneous fistulae, there are very few studies with tissue adhesives and platelet-rich plasma. In this study, our aim was to investigate the histopathologic changes in wound healing caused by various tissue adhesives and platelet-rich plasma, together with their effects on prevention of pharyngocutaneous fistula. METHODS: 40 male rats were randomly divided into five groups: control, platelet-rich plasma, fibrin tissue adhesive, protein-based albumin glutaraldehyde and synthetic tissue adhesive groups. The pharyngotomy procedure was performed and was sutured. Except the control group, tissue adhesives and platelet-rich plasma were applied. Then, the skin was sutured. On the seventh day, the rats were sacrificed. The skin was opened and pharyngotomy site was assessed in terms of fistulae. The pharyngeal suture line was evaluated histopathologically by using Ehrlich Hunt scale. RESULTS: Inflammatory infiltration was found to be higher in "platelet-rich plasma" group than "fibrin tissue adhesive" and "synthetic tissue adhesive" groups. The fibroblastic activity of "platelet-rich plasma", "fibrin tissue adhesive" and "protein-based albumin glutaraldehyde" groups was higher than the control group. The positive changes created by platelet-rich plasma and fibrin tissue adhesive at the histopathologic level were found together with no detected fistula. Among the study groups, there was no statistical difference for pharyngeal fistula development. This result may be obtained by the small number of animal experiments. CONCLUSION: These results shed light on the suggestion that platelet rich plasma and fibrin tissue adhesive can be used in clinical studies to prevent pharyngocutaneous fistula. PMID- 26229018 TI - Doctors' leaders call for warning system for GP burnout. PMID- 26229019 TI - Rejoinder to Discussions on: Deductive derivation and turing-computerization of semiparametric efficient estimation. PMID- 26229020 TI - Cribriform morphology predicts upstaging after radical prostatectomy in patients with Gleason score 3 + 4 = 7 prostate cancer at transrectal ultrasound (TRUS) guided needle biopsy. AB - Selected patients with transrectal ultrasound (TRUS)-guided biopsies containing Gleason score 3 + 4 = 7 prostate cancer (PCa) may be considered candidates for active surveillance (AS). The purpose of this study was to determine if there are features that predict PCa upstaging and/or upgrading after radical prostatectomy (RP) in patients with Gleason score 3 + 4 = 7 PCa diagnosed on TRUS-guided biopsies. We searched our institution's database for patients with Gleason score 3 + 4 = 7 PCa diagnosed on TRUS-guided biopsy who underwent subsequent RP between January 2010 and January 2015. Two blinded genitourinary pathologists independently reviewed and assessed the following on biopsies: (a) nuclear size, nucleolar size and distribution of macronucleoli of PCa, which were subjectively graded using a semi-quantitative scale from 1 to 3, and (b) PCa with cribriform morphology and the size of cribriform disease. Patient age, serum prostate specific antigen (PSA) and PSA density (PSAD) were also recorded. The Gleason score and stage (presence or absence of organ-confined disease (OCD)) were retrieved from RP reports. Comparisons were performed between groups using the chi-square test and Spearman correlation. One hundred and four patients were identified to have met inclusion criteria. The mean age was 63 (+/-6.1) years. Mean PSA and PSAD at diagnosis were 7.5 (+/-4.2) and 0.25 (+/-0.15) ng/mL, respectively. Gleason scores were upgraded to greater than 3 + 4 = 7 in 26.9 % (28/104) of patients, and 44.2 % (46/104) of patients had no OCD after RP. There was no correlation between age, PSA, PSAD or percent of biopsies with Gleason pattern 4 for either Gleason score upgrading or absence of OCD at the time of RP (p > 0.05). Thirty patients had cribriform morphology on TRUS-guided biopsy of which 60 % (18/30) had no OCD at RP (p = 0.04) while 36.7 % (11/30) were upgraded to Gleason score >=3 + 4 = 7 after RP (p = 0.15). There was no association between nuclear size, nucleolar size and/or distribution of macronucleoli with upgrading and/or absence of OCD (p > 0.05). The size of cribriform pattern was not associated with the absence of OCD (p = 0.43) or Gleason score upgrade (p = 0.28). A proportion of patients with Gleason score 3 + 4 = 7 PCa at needle biopsy do not have OCD or are upgraded to higher Gleason scores after RP. In our study, patients with Gleason score 3 + 4 = 7 PCa with the presence of cribriform pattern 4 had a significantly increased chance of being found to have no OCD at the time of RP. There were no clinical or pathologic parameters at the time of TRUS-guided biopsy that identified risk factors for Gleason score upgrading at RP in this study. Cribriform morphology detected on biopsy in patients with Gleason score 3 + 4 = 7 PCa is associated with tumour upstaging after RP and may be considered a contraindication to active surveillance. PMID- 26229023 TI - A critical review of recent progress in analytical laser-induced breakdown spectroscopy. AB - Laser-induced breakdown spectroscopy (LIBS) has become an established analytical atomic spectrometry technique and is valued for its very compelling set of advantageous analytical and technical characteristics. It is a rapid, versatile, non-contact technique, which is capable of providing qualitative and quantitative analytical information for practically any sample, in a virtually non-destructive way, without any substantial sample preparation. The instrumentation is simple, robust, compact, and even enables remote analysis. This review attempts to give a critical overview of the diverse progress of the field, focusing on the results of the last five years. The advancement of LIBS instrumentation and data evaluation is discussed in detail and selected results of some prominent applications are also described. PMID- 26229022 TI - National transparency assessment of Kuwait's pharmaceutical sector. AB - OBJECTIVES: Corruption is one of several factors that may hinder the access to pharmaceuticals. Since Kuwait has the highest per-capita spending on pharmaceuticals in the region, we wanted to evaluate the level of transparency in its pharmaceutical sector using an established assessment tool adapted by the World Health Organization. METHODS: Standardized questionnaires were conducted via semi-structured interviews with key informants to measure the level of transparency in eight functions of the public pharmaceutical sector. RESULTS: The scores for the degree of vulnerability to corruption reflected marginal to moderate venerability to corruption for most pharmaceutical sectors. The perceived strengths included availability of appropriate laws, the presence of clear standard operating procedures, and the use of an efficient registration/distribution system. Weaknesses included lack of conflict of interest guidelines and written terms of reference, absence of pharmacoeconomic studies, and inconsistencies in law enforcement. CONCLUSIONS: Findings reveal that few functions of Kuwait pharmaceutical sector remain fairly vulnerable to corruption. However, the willingness of Kuwait Ministry of Health to adopt the assessment study and the acknowledgement of the weaknesses of current processes of the pharmaceutical sector may assist to achieve a transparent pharmaceutical system in the near future. PMID- 26229021 TI - The presence of high-risk human papillomavirus (HPV) E6/E7 mRNA transcripts in a subset of sinonasal carcinomas is evidence of involvement of HPV in its etiopathogenesis. AB - The aim of the study was to investigate prevalence of high-risk human papillomavirus (HR-HPV) infection in sinonasal carcinomas by immunohistochemistry, in situ hybridization, and polymerase chain reaction, detecting p16(INK4a) protein (p16) expression and presence of both HPV DNA and HPV E6/E7 messenger RNA (mRNA). The study comprised 47 males and 26 females, aged 23-83 years (median 62 years), mostly (67 %) with a squamous cell carcinoma (SCC). Of the tumors, 53 % arose in the nasal cavity, 42 % in the maxillary sinus, and 5 % in the ethmoid complex. The follow-up period ranged 1-241 months (median 19 months). HPV16, HPV18, or HPV35 were detected in 18/73 (25 %) tumors, 17 SCCs, and 1 small cell neuroendocrine carcinoma. There was a strong correlation between results of HPV detection methods and p16 expression (p < 0.005). HPV-positive SCCs occurred more frequently in smokers (p = 0.04) and were more frequently p16-positive (p < 0.0001) and nonkeratinizing (p = 0.02), the latter occurring more commonly in nasal cavity (p = 0.025). Median survival for HPV-positive SCC patients was 30 months, while for HPV-negative SCC patients was 14 months (p = 0.23). In summary, we confirm that HR-HPV is actively involved in the etiopathogenesis of a significant subset of sinonasal SCCs. p16 may be used as a reliable surrogate marker for determination of HPV status also in sinonasal SCCs. Although we observed a trend toward better overall survival in HPV-positive SCCs, the prognostic impact of HPV status in sinonasal carcinomas needs to be elucidated by further studies. PMID- 26229024 TI - Direct characterization of polyurethanes and additives by atmospheric solid analysis probe with time-of-flight mass spectrometry (ASAP-TOF-MS). AB - Because of the wide range of formulations, polyurethanes (PURs) are among the most used copolymers. According to their applications, the nature and concentration of the monomers, as well as the additives, are adjusted. As copolymer, this material is difficult to characterize directly by mass spectrometry without sample pretreatment. In this work, atmospheric solid analysis probe mass spectrometry (ASAP-MS) is used to characterize model and commercial PURs with different formulations. Application of a temperature gradient over the ASAP probe allows a soft vaporization of all sample components: additives are detected at lower gas temperature, whereas the polymer is detected at higher gas temperature. Thus, a temporal separation of the molecules as a function of their volatilization and/or degradation temperature is observed. The vaporized products are identified by ASAP thanks to pyrolysis, but also by low energy source fragmentation observed during the analysis. Thus, complete analysis of PURs with only a single time-of-flight (TOF) mass analyzer is realized. The ability of ASAP-MS for differentiation of different chemical structures of PURs (polyester and polyether based PURs) is demonstrated; the main advantage of this technique being that the analysis is performed in one step, directly on the crude polymer. PMID- 26229026 TI - Analysis of trans-2,6-difluoro-4'-(N,N-dimethylamino)stilbene (DFS) in biological samples by liquid chromatography-tandem mass spectrometry: metabolite identification and pharmacokinetics. AB - The metabolism of a promising antineoplastic agent, trans-2,6-difluoro-4'-(N,N dimethylamino)stilbene (DFS), was studied in mouse, rat, and human liver microsomes using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with the multiple reaction monitoring-information-dependent acquisition-enhanced product ion scan (MRM-IDA-EPI) method. Ten putative metabolites were identified and the structures of four metabolites were confirmed using authentic standards. Since trans-2,6-difluoro-4'-(N-methylamino)stilbene (DMDFS, M1) was present in all species as metabolite and displayed in vitro growth inhibition superior to DFS, its pharmacokinetic profiles were examined in Sprague-Dawley rats using DFS as a comparator. A reliable LC-MS/MS multiple reaction monitoring (MRM) method was subsequently developed and validated for the simultaneous quantification of both DFS and DMDFS in rat plasma for this purpose. Upon intravenous administration (4 mg/kg), DFS had a moderate clearance (Cl = 62.7 +/- 23.2 mL/min/kg), terminal elimination half-life (t 1/2 lambdaZ = 299 +/- 73 min), and mean transit time (MTT = 123 +/- 14 min) with demethylation metabolism accounting for about 10 % of its total clearance. DMDFS possessed an intravenous pharmacokinetic profile similar to DFS. During oral dosing (10 mg/kg) where both DFS and DMDFS were absorbed rapidly, the oral bioavailability of DFS was approximately 2-fold greater than that of DMDFS (DFS: F = 42.1 +/- 12.8 %; DMDFS: F = 18.7 +/- 3.9 %). Interestingly, the DMDFS exposure after oral dosing of DFS (10 mg/kg) was comparable to that after oral administration of DMDFS (10 mg/kg) alone. As DFS displayed potent anticancer activities and excellent pharmacokinetic profiles, it appears to be a favorable candidate for further pharmaceutical development. PMID- 26229025 TI - Heavy chain single-domain antibodies to detect native human soluble epoxide hydrolase. AB - The soluble epoxide hydrolase (sEH) is a potential pharmacological target for treating hypertension, vascular inflammation, pain, cancer, and other diseases. However, there is not a simple, inexpensive, and reliable method to estimate levels of active sEH in tissues. Toward developing such an assay, a polyclonal variable domain of heavy chain antibody (VHH) sandwich immunoassay was developed. Ten VHHs, which are highly selective for native human sEH, were isolated from a phage-displayed library. The ten VHHs have no significant cross-reactivity with human microsomal epoxide hydrolase, rat and mouse sEH, and denatured human sEH. There is a high correlation between protein levels of the sEH determined by the enzyme-linked immunosorbent assay (ELISA) and the catalytic activity of the enzyme in S9 fractions of human tissues (liver, kidney, and lung). The VHH-based ELISA appears to be a new reliable method for monitoring the sEH and may be useful as a diagnostic tool for diseases influenced by sEH. This study also demonstrates the broad utility of VHH in biochemical and pharmacological research. PMID- 26229027 TI - Spatially resolved investigation of systemic and contact pesticides in plant material by desorption electrospray ionization mass spectrometry imaging (DESI MSI). AB - Distribution of pesticides both on the surface of leaves and in cross sections of plant stem and leaves was investigated using desorption electrospray ionization mass spectrometry imaging (DESI-MSI) with a spatial resolution of 50-100 MUm. Two commercially available insecticide sprays containing different contact pesticides were applied onto leaves of Cotoneaster horizontalis, and the distributions of all active ingredients were directly analyzed. The first spray contained pyrethrins and rapeseed oil, both known as natural insecticides. Each component showed an inhomogeneous spreading throughout the leaf, based on substance polarity and solubility. The second spray contained the synthetic insecticides imidacloprid and methiocarb. Imidacloprid accumulated on the border of the leaf, while methiocarb was distributed more homogenously. In order to investigate the incorporation of a systemically acting pesticide into Kalanchoe blossfeldiana, a commercially available insecticide tablet containing dimethoate was spiked to the soil of the plant. Cross sections of the stem and leaf were obtained 25 and 60 days after application. Dimethoate was mainly detected in the transport system of the plant after 25 days, while it was found to be homogenously distributed in a leaf section after 60 days. PMID- 26229028 TI - Simultaneous enzymatic hydrolysis and extraction of endocrine-disrupting chemicals in fish bile using polyethersulfone polymer. AB - This study describes a new method for the simultaneous extraction and enzymatic hydrolysis of alkylphenols, estrogens, bisphenol-A and phthalate metabolite (mono 2-ethylhexyl ester, MEHP) in fish bile using polyethersulfone (PES) polymer as sorptive material. Parameters affecting the hydrolysis (enzyme amount) and extraction (nature of polymeric material, PES desorption solvent nature and time, PES amount and time profile) were optimised. The optimum conditions were fixed as: 5 PES tubes (1.5 cm length * 0.7 mm o.d.) were added to a vessel with 100 MUL of sample, 800 MUL of ultrapure water, 1.5 mL phosphate buffer (0.1 mol L(-1), pH 6) and 200 MUL of beta-glucuronidase (1000 U mL(-1)) enzyme and the mixture was stirred at 37 degrees C and 550 rpm for 3 h. Quantitative results were obtained after desorption of PES material using 500 MUL of ethyl acetate. The extracts were reconstituted in 250 MUL of methanol and analysed by liquid chromatography tandem mass spectrometry, obtaining apparent recoveries in the range of 73-134 % using deuterated compounds surrogates corrections. Relative standard deviations below 27 % were obtained for all target analytes and the method detection limits (MDLs) were in low nanograms per mililliter level for all the studied compounds, except in the case of MEHP which was detected at higher concentration levels (ng MUL(-1)) in bile samples that do not allow its MDL determination. Bisphenol A (MDL-10.8 ng mL(-1)), diethylstilbestrol (MDL-1.4 ng mL(-1)) and MEHP (975-2604 ng mL(-1)) were detected in grey mullets captured nearby the wastewater treatment plant of Gernika (Biosphere Reserve of Urdaibai). PMID- 26229029 TI - Characterization of Dickeya and Pectobacterium species by capillary electrophoretic techniques and MALDI-TOF MS. AB - Dickeya and Pectobacterium species represent an important group of broad-host range phytopathogens responsible for blackleg and soft rot diseases on numerous plants including many economically important plants. Although these species are commonly detected using cultural, serological, and molecular methods, these methods are sometimes insufficient to classify the bacteria correctly. On that account, this study was undertaken to investigate the feasibility of three individual analytical techniques, capillary zone electrophoresis (CZE), capillary isoelectric focusing (CIEF), and matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MALDI-TOF MS), for reliable classification of Dickeya and Pectobacterium species. Forty-three strains, representing different Dickeya and Pectobacterium species, namely Dickeya dianthicola, Dickeya dadantii, Dickeya dieffenbachiae, Dickeya chrysanthemi, Dickeya zeae, Dickeya paradisiaca, Dickeya solani, Pectobacterium carotovorum, and Pectobacterium atrosepticum, were selected for this purpose. Furthermore, the selected bacteria included one strain which could not be classified using traditional microbiological methods. Characterization of the bacteria was based on different pI values (CIEF), migration velocities (CZE), or specific mass fingerprints (MALDI-TOF MS) of intact cells. All the examined strains, including the undetermined bacterium, were characterized and classified correctly into respective species. MALDI-TOF MS provided the most reliable results in this respect. PMID- 26229030 TI - Optimization and single-laboratory validation of a method for the determination of flavonolignans in milk thistle seeds by high-performance liquid chromatography with ultraviolet detection. AB - Seeds of milk thistle, Silybum marianum (L.) Gaertn., are used for treatment and prevention of liver disorders and were identified as a high priority ingredient requiring a validated analytical method. An AOAC International expert panel reviewed existing methods and made recommendations concerning method optimization prior to validation. A series of extraction and separation studies were undertaken on the selected method for determining flavonolignans from milk thistle seeds and finished products to address the review panel recommendations. Once optimized, a single-laboratory validation study was conducted. The method was assessed for repeatability, accuracy, selectivity, LOD, LOQ, analyte stability, and linearity. Flavonolignan content ranged from 1.40 to 52.86% in raw materials and dry finished products and ranged from 36.16 to 1570.7 MUg/mL in liquid tinctures. Repeatability for the individual flavonolignans in raw materials and finished products ranged from 1.03 to 9.88% RSDr, with HorRat values between 0.21 and 1.55. Calibration curves for all flavonolignan concentrations had correlation coefficients of >99.8%. The LODs for the flavonolignans ranged from 0.20 to 0.48 MUg/mL at 288 nm. Based on the results of this single-laboratory validation, this method is suitable for the quantitation of the six major flavonolignans in milk thistle raw materials and finished products, as well as multicomponent products containing dandelion, schizandra berry, and artichoke extracts. It is recommended that this method be adopted as First Action Official Method status by AOAC International. PMID- 26229031 TI - Capillary electrophoresis of biomolecules. PMID- 26229032 TI - Autoimmune polyendocrine syndrome and thrombocytosis. AB - We describe a woman aged 37 years, affected with Hashimoto's thyroiditis, detected since the age of 17, with gonadic insufficiency with anti-ovarian antibodies since the age of 22 years and Addison's disease since 24 years old. At that moment, the diagnosis of autoimmune polyendocrine syndrome (APS) was made. Concomitant to this diagnosis, thrombocytosis was detected and aetiological assessment revealed an atrophy of the spleen. Differential diagnoses of APS and hyposplenism will be discussed. We will look at a possible association between these two pathologies. Indeed, asplenism is found in approximately 20% of adults affected by type 1 APS, also called auto-immune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome. The most likely aetiology for this atrophy of the spleen is a destruction of auto-immunological origin. However, in our patient, the search for a mutation of the autoimmune regulator (AIRE) gene proved negative. This mutation is commonly, but not systematically, present in type 1 APS. A type 2 APS should then be considered. PMID- 26229033 TI - Synthesis of fully protected, reverse N-prenylated (2S,3R)-3-hydroxytryptophan, a unique building block of the cyclomarins. AB - Reverse N-prenylated 3-hydroxytryptophan, the rather exotic amino acid of the cyclomarins, is obtained in enantio- and diastereomerically pure and fully protected form by a combination of a highly stereoselective addition of a zincated indole toward protected serinal and subsequent palladium-catalyzed N prenylation. PMID- 26229034 TI - The emerging role of the androgen receptor in bladder cancer. AB - Men are three to four times more likely to get bladder cancer than women. The gender disparity characterizing bladder cancer diagnoses has been investigated. One hypothesis is that androgen receptor (AR) signaling is involved in the etiology and progression of this disease. Although bladder cancer is not typically described as an endocrine-related malignancy, it has become increasingly clear that AR signaling plays a role in bladder tumors. This review summarizes current findings regarding the role of the AR in bladder cancer. We discuss work demonstrating AR expression in bladder cancer and its role in promoting formation and progression of tumors. Additionally, we discuss the therapeutic potential of targeting the AR in this disease. PMID- 26229035 TI - Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy. AB - The orphan nuclear receptor 4A1 (NR4A1) is overexpressed in mammary tumors and breast cancer cell lines. The functional activity of this receptor was investigated by RNA interference with oligonucleotides targeted to NR4A1 (siNR4A1) and by treatment with NR4A1 antagonists. Breast cancer cells were treated with NR4A1 antagonists or transfected with siNR4A. Effects on cell proliferation and apoptosis as well as specific genes associated with these responses were investigated in MCF-7, SKBR3, and MDA-MB-231 cells, and in athymic nude mice bearing MDA-MB-231 cells as xenografts. Transfection of MCF-7, MDA-MB 231, and SKBR3 breast cancer cells with siNR4A1 decreased cell proliferation and induced apoptosis in these cell lines. Transfection of breast cancer cells with siNR4A1 also decreased expression of Sp-regulated genes including survivin, bcl 2, and epidermal growth factor receptor, inhibited mTOR signaling in MCF-7 cells that express WT p53, and activated oxidative and endoplasmic reticulum stress through downregulation of thioredoxin domain-containing 5 and isocitrate dehydrogenase 1. 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) are NR4A1 ligands that act as NR4A1 antagonists. Treatment with selected analogs also inhibited breast cancer cell and tumor growth and induced apoptosis. The effects of C-DIM/NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. Results with siNR4A1 or C-DIMs/NR4A1 antagonists in breast cancer cells and tumors were similar to those previously reported in pancreatic, lung, and colon cancer cells. They demonstrate the potential clinical applications of NR4A1 antagonists in patients with tumors that overexpress this receptor. PMID- 26229037 TI - Distillery effluent as a liquid fertilizer: a win-win option for sustainable agriculture. AB - A promising approach to recycle the residual distillery waste as a potential liquid fertilizer has been discussed in this paper. Field studies were conducted on Brassica compestris to assess the potential of the diluted post- methanated distillery effluent. The results indicated that there was not much variation in pH, conductivity and nitrate of soil, whereas total dissolved solids, conductivity, nitrate and chemical oxygen demand of the well water increased slightly but well within the permissible limit. However, there was a significant increase in the plant biomass, diameter of the shoot and root, area of leaf, as well as number and length of pods and root hairs. The hydrophilic colloids of the seed increased significantly (p < .01) and the yield of mustard seeds was increased by 30% as compared to the conventional fertilizer. The carbohydrate, chlorophyll and ascorbic acid content of the leaf, stem and root were also analysed and its morpho- physiological significance is also presented in this paper. PMID- 26229036 TI - Computed tomography-based high-risk coronary plaque score to predict acute coronary syndrome among patients with acute chest pain--Results from the ROMICAT II trial. AB - BACKGROUND: Coronary computed tomography angiography (CTA) can be used to detect and quantitatively assess high-risk plaque features. OBJECTIVE: To validate the ROMICAT score, which was derived using semi-automated quantitative measurements of high-risk plaque features, for the prediction of ACS. MATERIAL AND METHODS: We performed quantitative plaque analysis in 260 patients who presented to the emergency department with suspected ACS in the ROMICAT II trial. The readers used a semi-automated software (QAngio, Medis medical imaging systems BV) to measure high-risk plaque features (volume of <60HU plaque, remodeling index, spotty calcium, plaque length) and diameter stenosis in all plaques. We calculated a ROMICAT score, which was derived from the ROMICAT I study and applied to the ROMICAT II trial. The primary outcome of the study was diagnosis of an ACS during the index hospitalization. RESULTS: Patient characteristics (age 57 +/- 8 vs. 56 +/- 8 years, cardiovascular risk factors) were not different between those with and without ACS (prevalence of ACS 7.8%). There were more men in the ACS group (84% vs. 59%, p = 0.005). When applying the ROMICAT score derived from the ROMICAT I trial to the patient population of the ROMICAT II trial, the ROMICAT score (OR 2.9, 95% CI 1.4-6.0, p = 0.003) was a predictor of ACS after adjusting for gender and >= 50% stenosis. The AUC of the model containing ROMICAT score, gender, and >= 50% stenosis was 0.91 (95% CI 0.86-0.96) and was better than with a model that included only gender and >= 50% stenosis (AUC 0.85, 95%CI 0.77-0.92; p = 0.002). CONCLUSIONS: The ROMICAT score derived from semi-automated quantitative measurements of high-risk plaque features was an independent predictor of ACS during the index hospitalization and was incremental to gender and presence of >= 50% stenosis. PMID- 26229038 TI - Volumetric evaluation of fat resorption after breast lipofilling. AB - INTRODUCTION: The fat transfer or the lipofilling is a technique that had a major impact on the breast surgery results. We have been using this technique since 1998 as an adjuvant in breast reconstruction. The transferred fat is partially resorbed in the first three months after fat grafting. Literature shows that fat resorption varies from 30 to 80% and the experimental studies register a variation between 50 and 90%. The difficulty of the lipomodeling consists in anticipating the fat resorption rate in order to obtain breast symmetry. The purpose of this article is to evaluate the resorption rate of the transferred fat in the reconstructed breast by means of volumetric imaging 3 months after fat grafting. MATERIAL AND METHODS: A prospective study was undertaken including breast reconstructions with total autologous latissimus dorsi. All the surgical procedures have been done by the same surgeon (1st author). It focused on the second stage of breast reconstruction: the lipofilling. We registered the average harvested volumes, the volumes obtained after centrifugation and the transferred volumes for every reconstructed breast. The intramuscular volume in the reconstructed breast was measured by volumetric imaging on the third day after lipofilling (D3) and three months after lipofilling (M3). The volumetry was performed by using an after treatment console SIEMENS (SOMATOM definition AS 2*64 barettes). The average intramuscular volume was registered at D3 and M3. The average volume difference was calculated in order to obtain the exact resorption rate. RESULTS: This prospective study was undertaken on 32 reconstructed breasts by total autologous latissimus dorsi flap. The average age was 52 years, the average BMI was 24.7 kg/m(2). The average harvested fat volume for the breast lipofilling was 560 cc and the volume obtained after centrifugation was evaluated at about 371 cc, the average fat volume transferred being 291 cc. The volumetric study showed that intramuscular volume at D3 was measured at 284 cc and at M3 about 223 cc, of a resorption intramuscular rate of 21.5%. CONCLUSION: In our study, the rate of resorption of the fat transferred to the muscle in the reconstructed breast was measured at 21.5%. The low resorption rate found in our study, lower than those in the literature, sustains the supposition that the muscle is an excellent receiving matrix for the fat tissue. In order to obtain this percentage, a learning curve is necessary. Once acquired, this technique produces a major improvement of the breast surgery results. PMID- 26229040 TI - Possible Affective Switch Associated With Intravenous Ketamine Treatment in a Patient With Bipolar I Disorder. PMID- 26229042 TI - Field-induced slow relaxation of magnetization in a pentacoordinate Co(II) compound [Co(phen)(DMSO)Cl2]. AB - The static and dynamic magnetic properties of a pentacoordinate [Co(phen)(DMSO)Cl2] compound (phen = 1,10'-phenanthroline, DMSO = dimethyl sulfoxide) were thoroughly studied by experimental (SQUID magnetometry and HF-EPR spectroscopy) and theoretical methods (DFT and CASSCF calculations). It has been found from temperature/field-dependent magnetization measurements that the studied compound possesses a large and negative magnetic anisotropy (D = -17(1) cm(-1)) with large rhombicity (E/D = 0.24(5)), and these experimental results are in agreement with ab initio calculations (D = -17.7 cm(-1), E/D = 0.31). Interdoublet resonances were not observed in the HF-EPR measurements, but the large rhombicity was confirmed (DEPR = -17.7 cm(-1) (fixed from CASSCF calculations), E/DEPR = 0.33). A frequency dependent out-of-phase susceptibility signal was observed only in a non-zero static magnetic field (B = 0.1 T) and the following parameters of slow-relaxation of magnetisation were derived from the experimental data: either the energy of spin reversal barrier, Ueff = 10.4 K, and the relaxation time, tau0 = 5.69 * 10(-9) s using the Debye model, or Ueff = 21.4 40.3 K and tau0 = 0.248-58.3 * 10(-9) based on a simplified model. PMID- 26229039 TI - Pituitary Adenylate Cyclase-Activating Polypeptide Disrupts Motivation, Social Interaction, and Attention in Male Sprague Dawley Rats. AB - BACKGROUND: Severe or prolonged stress can trigger psychiatric illnesses including mood and anxiety disorders. Recent work indicates that pituitary adenylate cyclase-activating polypeptide (PACAP) plays an important role in regulating stress effects. In rodents, exogenous PACAP administration can produce persistent elevations in the acoustic startle response, which may reflect anxiety like signs including hypervigilance. We investigated whether PACAP causes acute or persistent alterations in behaviors that reflect other core features of mood and anxiety disorders (motivation, social interaction, and attention). METHODS: Using male Sprague Dawley rats, we examined if PACAP (.25-1.0 ug, intracerebroventricular infusion) affects motivation as measured in the intracranial self-stimulation test. We also examined if PACAP alters interactions with a conspecific in the social interaction test. Finally, we examined if PACAP affects performance in the 5-choice serial reaction time task, which quantifies attention and error processing. RESULTS: Dose-dependent disruptions in motivation, social interaction, and attention were produced by PACAP, as reflected by increases in reward thresholds, decreases in social behaviors, and decreases in correct responses and alterations in posterror accuracy. Behavior normalized quickly in the intracranial self-stimulation and 5-choice serial reaction time task tests but remained dysregulated in the social interaction test. Effects on attention were attenuated by the corticotropin-releasing factor receptor-1 antagonist antalarmin but not the kappa opioid receptor antagonist JDTic. CONCLUSIONS: Our findings suggest that PACAP affects numerous domains often dysregulated in mood and anxiety disorders, but that individual signs depend on brain substrates that are at least partially independent. This work may help to devise therapeutics that mitigate specific signs of these disorders. PMID- 26229043 TI - Imaging flow cytometry. PMID- 26229044 TI - Acute effects of Kinesio taping on muscle strength and fatigue in the forearm of tennis players. AB - OBJECTIVES: To explore the immediate effects of Kinesio taping applied over the wrist extensors and flexors on muscle strength and endurance during isometric and isokinetic muscle actions. DESIGN: The study had a single-blinded, placebo control, and randomized design. METHODS: Fourteen trained male volunteers were required to complete 5s isometric maximal voluntary contractions and 50 consecutive maximal concentric wrist extension and flexion repetitions at each of two angular speeds (60 degrees /s and 210 degrees /s) in three taping conditions: Kinesio taping (KT), placebo taping (PT), and no taping (NT). RESULTS: KT did not improve peak moment, peak power, average power, and total work for wrist extensors and flexors in the isometric and isokinetic contractions. However, KT showed a 13% decrease in work fatigue of the wrist flexors compare to NT (p=0.014) at 60 degrees /s. Furthermore, a 20% decrease was also observed in the rate of decline of moment (k) of the wrist flexors in KT compared to NT (p=0.007), and the k in PT was also significantly lower in magnitude compared to NT (p=0.035). Moreover, there was also a trend in terms of magnitudes for kKT=10-year outcomes of 2 postoperative regimens after Achilles tendon rupture repair: early weightbearing with early mobilization versus early weightbearing with early immobilization in tension. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 50 patients with acute Achilles tendon ruptures were randomized postoperatively to receive either early movement of the ankle between neutral and plantar flexion in a brace for 6 weeks (group 1) or Achilles tendon immobilization in tension using a below-knee cast with the ankle in a neutral position for 6 weeks (group 2). Patients were assessed at 3, 6, and 14 months and 11 years postoperatively. RESULTS: There were 37 patients (74%) evaluated at a mean (+/-SD) of 11.0 +/- 0.9 years. The mean Leppilahti score was 92.9 +/- 5.6 in group 1 and 93.6 +/- 7.2 in group 2 (P = .68). The mean isokinetic plantar flexion peak torque deficits or average work deficits in plantar flexion showed no differences between the groups with any angular velocity. Isokinetic strength changed minimally between 1 and 11 years compared with the unaffected ankle, but a mean deficit of 5% in peak torque and mean deficit of 8% in average work were still present after 11 years. On the contrary, isometric plantar flexion strength recovered significantly, with only a 2.4% difference at 11-year follow-up. CONCLUSION: After the 11-year follow-up, early mobilization and immobilization in tension after Achilles rupture repair resulted in similar clinical outcomes and isokinetic strengths. Regardless of patient satisfaction with the operative treatment, calf muscle strength did not recover normally even at 11-year follow-up. PMID- 26229049 TI - Bariatric surgery. PMID- 26229050 TI - Pollen Tube Discharge Completes the Process of Synergid Degeneration That Is Initiated by Pollen Tube-Synergid Interaction in Arabidopsis. AB - In flowering plant reproduction, pollen tube reception is the signaling system that results in pollen tube discharge, synergid degeneration, and successful delivery of male gametes (two sperm cells) to the site where they can fuse with female gametes (egg cell and central cell). Some molecules required for this complex and essential signaling exchange have been identified; however, fundamental questions about the nature of the interactions between the pollen tube and the synergid cells remain to be clarified. Here, we monitor pollen tube arrival, pollen tube discharge, and synergid degeneration in Arabidopsis (Arabidopsis thaliana) wild type and in male and female gametophytic mutants that disrupt development and function of the gametophytes. By combining assays used previously to study these interactions and an assay that facilitates simultaneous analysis of pollen tube discharge and synergid degeneration, we find that synergid degeneration could be initiated without pollen tube discharge. Our data support the hypothesis that pollen tube-synergid contact, or signaling via secreted molecules, initiates receptive synergid degeneration. We also find that when pollen tubes successfully burst, they always discharge into a degenerated synergid. In addition to this pollen tube-dependent promotion of synergid degeneration, we also show that a basal developmental pathway mediates synergid degeneration in the absence of pollination. Our results are consistent with the model that a complex set of interactions between the pollen tube and synergid cells promote receptive synergid degeneration. PMID- 26229052 TI - Men, Masculinities, and Hemophilia. AB - Hemophilia is a congenital bleeding disorder that predominantly affects men. Home intravenous replacement of missing clotting factor is the most effective treatment; however, the uptake of preventative treatment (also known as prophylaxis) varies among men with hemophilia. The purpose of the current qualitative study was to describe the connections between masculinities and men's (n = 11) experiences of hemophilia across varying age groups. The inductively derived findings revealed bleed-related joint pain as the primary prompt for men to treat or seek medical help. Many men reported experiencing a high number of bleed-related injuries in adolescence, particularly in high school, oftentimes as a result of engaging in idealized masculine physical activities. Though the limitations imposed by hemophilia were contested by most men early on in their lives, as men grow older more conservative approaches were employed both in terms of treatment and activity to reduce the potential for residual bleed-related disabilities. Overall, the results indicate that men with hemophilia may benefit from peer and professional education about recognition, prevention, and optimal treatment of bleeds. Furthermore, masculine ideals act as important context in which men navigate hemophilia management practices and may facilitate contesting or conceding behaviors. Masculine ideals of strength and control may be garnered to facilitate optimal hemophilia management practices. PMID- 26229051 TI - A Critical Role of Lyst-Interacting Protein5, a Positive Regulator of Multivesicular Body Biogenesis, in Plant Responses to Heat and Salt Stresses. AB - Multivesicular bodies (MVBs) are unique endosomes containing vesicles in the lumen and play critical roles in many cellular processes. We have recently shown that Arabidopsis (Arabidopsis thaliana) Lyst-Interacting Protein5 (LIP5), a positive regulator of the Suppressor of K(+) Transport Growth Defect1 (SKD1) AAA ATPase in MVB biogenesis, is a critical target of the mitogen-activated protein kinases MPK3 and MPK6 and plays an important role in the plant immune system. In this study, we report that the LIP5-regulated MVB pathway also plays a critical role in plant responses to abiotic stresses. Disruption of LIP5 causes compromised tolerance to both heat and salt stresses. The critical role of LIP5 in plant tolerance to abiotic stresses is dependent on its ability to interact with Suppressor of K(+) Transport Growth Defect1. When compared with wild-type plants, lip5 mutants accumulate increased levels of ubiquitinated protein aggregates and NaCl under heat and salt stresses, respectively. Further analysis using fluorescent dye and MVB markers reveals that abiotic stress increases the formation of endocytic vesicles and MVBs in a largely LIP5-dependent manner. LIP5 is also required for the salt-induced increase of intracellular reactive oxygen species, which have been implicated in signaling of salt stress responses. Basal levels of LIP5 phosphorylation by MPKs and the stability of LIP5 are elevated by salt stress, and mutation of MPK phosphorylation sites in LIP5 reduces the stability and compromises the ability to complement the lip5 salt-sensitive mutant phenotype. These results collectively indicate that the MVB pathway is positively regulated by pathogen/stress-responsive MPK3/6 through LIP5 phosphorylation and plays a critical role in broad plant responses to biotic and abiotic stresses. PMID- 26229053 TI - A Bourdieusian Analysis of U.S. Military Culture Ground in the Mental Help Seeking Literature. AB - This theoretical treatise uses the scientific literature concerning help seeking for mental illness among those with a background in the U.S. military to posit a more complex definition of military culture. The help-seeking literature is used to illustrate how hegemonic masculinity, when situated in the military field, informs the decision to seek formal treatment for mental illness among those men with a background in the U.S. military. These analyses advocate for a nuanced, multidimensional, and situated definition of U.S. military culture that emphasizes the way in which institutional structures and social relations of power intersect with individual values, beliefs, and motivations to inform and structure health-related practices. PMID- 26229054 TI - The trouble with Martin O'Meara. AB - OBJECTIVE: The objective of this article is to highlight the pitfalls of translating historical cases of wartime psychiatric trauma into modern post traumatic stress disorder (PTSD). METHOD: We examined all available primary sources relating to the case of Martin O'Meara VC (1885-1935). RESULTS: We found that O'Meara's symptoms are not consistent with a diagnosis of PTSD. CONCLUSIONS: It is more likely that O'Meara developed a form of schizoaffective disorder, or long-lasting trauma-induced psychosis, after World War I. PMID- 26229055 TI - Performance of the Maze Navigation Test in a sample of older New Zealanders. AB - OBJECTIVE: It is often difficult to assess the driving performance of people with mild dementia. The Maze Navigation Test (MNT) was developed in the USA and has been shown to predict driving performance. The aim of this study is to evaluate how the MNT is performed against three commonly used bedside cognitive screening tools and compare our findings with the US population. METHODS: A convenience sample of 42 cognitively intact older people (age >=65) completed the MNT, Mini Mental State Examination, the revised Addenbrooke's Cognitive Examination and the Trail Making Tests. RESULTS: The mean MNT completion time was 307.6 (SD=85.6) and 444.5 (SD=157.3) for the 65-74 years and 75-84 years age group, respectively. Pearson's product-moment correlations were strongest with the Trail Making Test Part B (r=0.602). CONCLUSIONS: The findings of this study were comparable with the initial US data. The MNT is an easy-to-administer bedside cognitive screening tool. Further validation studies using the MNT and driving performance are warranted. PMID- 26229056 TI - Genome-wide association between Six4, MyoD, and the histone demethylase Utx during myogenesis. AB - Adult skeletal muscles can regenerate after injury, due to the presence of satellite cells, a quiescent population of myogenic progenitor cells. Once activated, satellite cells repair the muscle damage by undergoing myogenic differentiation. The myogenic regulatory factors (MRFs) coordinate the process of progenitor differentiation in cooperation with other families of transcription factors (TFs). The Six1 and Six4 homeodomain TFs are expressed in developing and adult muscle and Six1 is critical for embryonic and adult myogenesis. However, the lack of a muscle developmental phenotype in Six4-null mice, which has been attributed to compensation by other Six family members, has discouraged further assessment of the role of Six4 during adult muscle regeneration. By employing genome-wide approaches to address the function of Six4 during adult skeletal myogenesis, we have identified a core set of muscle genes coordinately regulated in adult muscle precursors by Six4 and the MRF MyoD. Throughout the genome of differentiating adult myoblasts, the cooperation between Six4 and MyoD is associated with chromatin repressive mark removal by Utx, a demethylase of histone H3 trimethylated at lysine 27. Among the genes coordinately regulated by Six4 and MyoD are several genes critical for proper in vivo muscle regeneration, implicating a role of Six4 in this process. Using in vivo RNA interference of Six4, we expose an uncompensated function of this TF during muscle regeneration. Together, our results reveal a role for Six4 during adult muscle regeneration and suggest a widespread mechanism of cooperation between Six4 and MyoD. PMID- 26229058 TI - Inquiry will examine transgender people's access to healthcare. PMID- 26229057 TI - Kinesin family 17 (osmotic avoidance abnormal-3) is dispensable for photoreceptor morphology and function. AB - In Caenorhabditis elegans, homodimeric [kinesin family (KIF) 17, osmotic avoidance abnormal-3 (OSM-3)] and heterotrimeric (KIF3) kinesin-2 motors are required to establish sensory cilia by intraflagellar transport (IFT) where KIF3 and KIF17 cooperate to build the axoneme core and KIF17 builds the distal segments. However, the function of KIF17 in vertebrates is unresolved. We expressed full-length and motorless KIF17 constructs in mouse rod photoreceptors using adeno-associated virus in Xenopus laevis rod photoreceptors using a transgene and in ciliated IMCD3 cells. We found that tagged KIF17 localized along the rod outer segment axoneme when expressed in mouse and X. laevis photoreceptors, whereas KIF3A was restricted to the proximal axoneme. Motorless KIF3A and KIF17 mutants caused photoreceptor degeneration, likely through dominant negative effects on IFT. KIF17 mutant lacking the motor domain translocated to nuclei after exposure of a C-terminal nuclear localization signal. Germ-line deletion of Kif17 in mouse did not affect photoreceptor function. A rod-specific Kif3/Kif17 double knockout mouse demonstrated that KIF17 and KIF3 do not act synergistically and did not prevent rhodopsin trafficking to rod outer segments. In summary, the nematode model of KIF3/KIF17 cooperation apparently does not apply to mouse photoreceptors in which the photosensory cilium is built exclusively by KIF3. PMID- 26229059 TI - An Integrative Review of Enablement in Primary Health Care. AB - OBJECTIVES: To review how enablement is conceptualized and practiced in primary health care and to explore the factors that influence patient enablement in this setting. METHOD: A narrative integrative literature review was undertaken. RESULTS: Twenty-four articles specifically relating to enablement in primary health care were identified. Three literature reviews, 4 qualitative studies, and 17 quantitative studies were included in the analysis. CONCLUSIONS: In the primary health care setting, the concept of enablement is well defined as an outcome measure of quality. The literature exploring the practice of enablement is sparse, but 2 randomized controlled trials suggest enablement is linked to better outcomes for patients with asthma and diabetes. Primary factors influencing enablement included the practitioners' open communication style, the degree to which the practitioner is patient centered, and longer consultations. Other factors found to be associated with enablement were the presenting health issue, general state of health, ethnicity, the patient's own coping strategies and degree of independence, and socioeconomic status. The association between enablement and patients' expectations and satisfaction is less clear. The majority of research on enablement was carried out among general practitioners. Further research into the degree to which patients are enabled by a wider range of health care providers is needed. Additional qualitative research would provide a deeper understanding of the attributes of enablement in the primary health care setting. PMID- 26229060 TI - Left gastric artery aneurysm rupture: a rare cause of retroperitoneal bleeding: a case report. AB - INTRODUCTION: Visceral artery aneurysms are very rare. Patients usually present as emergency secondary to the sudden rupture of the aneurysm or as an incidental finding on ultrasound, MRI or abdominal computed tomography. Among these, splenic artery aneurysms are the most common ones accounting for 60% of all splanchnic aneurysms and gastric and gastroepiploic aneurysms account for only about 4%. CASE PRESENTATION: We present a 61-year-old Caucasian male previously fit and well, presenting with sudden onset epigastric pain due to retroperitoneal haemorrhage secondary to ruptured left gastric artery aneurysm. Apart from a tender epigastrium, there were no other obvious signs elicited on abdominal examination. He had persistent tachycardia and haemoglobin drop from 10 g/dl to 6.7 g/dl. He underwent a contrast computed tomography which identified the ruptured left gastric artery. The aneurysm was controlled successfully with coil embolisation of the left gastric artery. At three-month follow-up, there was no evidence of the aneurysm. CONCLUSION: Clinical presentations that do not correlate with examination finding should prompt immediate extensive investigation. The aid of contrast computed tomography and minimally invasive radiological interventional is the key to a fruitful outcome for this very rare entity. PMID- 26229061 TI - Audit of preoperative localisation of tumor with tattoo for patients undergoing laparoscopic colorectal surgery. AB - BACKGROUND: Preoperative localisation of tumour is an essential requirement in laparoscopic colorectal surgery. Since the introduction of laparoscopic colorectal resections in NGH in February 2010, the difficulties of tumour localisation at the time of surgery without tattoo have been highlighted. Furthermore, endoscopic documentation of site of tattoo with respect to the tumour can be inconsistent and at times misleading or difficult to interpret. Tattooing guidelines should be simple to follow and consistent for all lesions irrespective of the location of the tumour. The recommendations were to place at least three spots of tattoo one mucosal fold distal to the lesion and clearly document site of tattoo with respect to tumour in the endoscopy report. METHOD: We identified 100 patients undergoing elective laparoscopic colorectal cancer resections over a two-year period. Data were collected regarding presence of tattoo preoperatively as documented in the colonoscopy report and subsequently the visibility of the tattoo at time of laparoscopy and its accuracy in relation to the tumour. Abdominoperineal resections and emergency colorectal operations were excluded. RESULTS: Only 59% of the patients had a visible and accurate tattoo. In 17% of the patients, the tattoo was not visible at all, although it was documented in the endoscopy report that it had been administered. In 4% of patients, it was visible but inaccurately placed. In 20% of the patients, there were no tattoos at all, necessitating on table endoscopy and intraoperative specimen analysis to confirm that the tumour/lesion was within the resection specimen. DISCUSSION: Preoperative tumour localisation is extremely important to correctly identify the site of tumour or lesion at laparoscopy. A standardised departmental protocol should be implemented by all endoscopists to place three spots of tattoo one mucosal fold distal to any significant lesions found. Failure to tattoo lesions/cancers preoperatively can lead to intraoperative delays and potential harm to patients from on-table endoscopy. PMID- 26229063 TI - India's AIDS programmes shrink after government cuts spending. PMID- 26229062 TI - The Core Extrusion Schema-Revised: Hiding Oneself Predicts Severity of Social Interaction Anxiety. AB - Cognitive behavioral models of social anxiety disorder (SAD) suggest that fear of negative evaluation is a core fear or vulnerability for SAD. However, why negative evaluation is feared is not fully understood. It is possible that core beliefs contribute to the relationship between fear of negative evaluation and SAD. One of these beliefs may be a core extrusion schema: a constellation of beliefs that one's true self will be rejected by others and therefore one should hide one's true self. In the current study (N = 699), we extended research on the Core Extrusion Schema and created a shortened and revised version of the measure called the Core Extrusion Schema-Revised The Core Extrusion Schema-Revised demonstrated good factor fit for its two subscales (Hidden Self and Rejection of the True Self) and was invariant across gender and ethnicity. The Hidden Self subscale demonstrated excellent incremental validity within the full sample as well as in participants diagnosed with generalized SAD. Specifically, the Hidden Self subscale may help explain severity of social interaction anxiety. This measure could be used with individuals diagnosed with generalized SAD to design exposures targeting these core beliefs. PMID- 26229064 TI - Heterogeneity of clonal patterns among patches of kudzu, Pueraria montana var. lobata, an invasive plant. AB - BACKGROUND AND AIMS: Viny species are among the most serious invasive plants, and better knowledge of how vines grow to dominate landscapes is needed. Patches may contain a single genotype (i.e. genet), a competitively dominant genet or many independent but interacting genets, yet the clonal structure of vining species is often not apparent. Molecular markers can discriminate among the genetic identities of entwined vines to reveal the number and spatial distribution of genets. This study investigated how genets are spatially distributed within and among discrete patches of the invasive vine kudzu, Pueraria montana var. lobata, in the United States. It was expected that ramets of genets would be spatially clustered within patches, and that an increase in the number of genets within a patch would be associated with a decrease in the average size of each genet. METHODS: Six discrete kudzu patches were sampled across 2 years, and 1257 samples were genotyped at 21 polymorphic allozyme loci. Variation in genotypic and genetic diversity among patches was quantified and patterns of genet interdigitation were analysed. KEY RESULTS: Substantial genotypic and genetic variation occurred within and among patches. As few as ten overlapping genets spanned up to 68 m(2) in one patch, while >90 % of samples were genetically unique in another patch. Genotypic diversity within patches increased as mean clone size decreased, although spatially widespread genets did not preclude interdigitation. Eight genets were shared across >=2 patches, suggesting that vegetative dispersal can occur among patches. CONCLUSIONS: Genetically unique kudzu vines are highly interdigitated. Multiple vegetative propagules have become established in spatially discrete patches, probably through the movement of highway construction or maintenance machinery. The results suggest that common methods for controlling invasive vines (e.g. mowing) may inadvertently increase genotypic diversity. Thus, understanding vine architecture and growth has practical implications. PMID- 26229065 TI - The compounding effects of high pollen limitation, selfing rates and inbreeding depression leave a New Zealand tree with few viable offspring. AB - BACKGROUND AND AIMS: Interactions between species are especially sensitive to environmental changes. The interaction between plants and pollinators is of particular interest given the potential current global decline in pollinators. Reduced pollinator services can be compensated for in some plant species by self pollination. However, if inbreeding depression is high, selfed progeny could die prior to reaching adulthood, leading to cryptic recruitment failure. METHODS: To examine this scenario, pollinator abundance, pollen limitation, selfing rates and inbreeding depression were examined in 12 populations of varying disturbance levels in Sophora microphylla (Fabaceae), an endemic New Zealand tree species. KEY RESULTS: High pollen limitation was found in all populations (average of 58 % reduction in seed production, nine populations), together with high selfing rates (61 % of offspring selfed, six populations) and high inbreeding depression (selfed offspring 86 % less fit, six populations). Pollen limitation was associated with lower visitation rates by the two endemic bird pollinators. CONCLUSIONS: The results suggest that for these populations, over half of the seeds produced are genetically doomed. This reduction in the fitness of progeny due to reduced pollinator service is probably important to population dynamics of other New Zealand species. More broadly, the results suggest that measures of seed production or seedling densities may be a gross overestimate of the effective offspring production. This could lead to cryptic recruitment failure, i.e. a decline in successful reproduction despite high progeny production. Given the global extent of pollinator declines, cryptic recruitment failure may be widespread. PMID- 26229067 TI - Metacognitive Reading and Study Strategies and Academic Achievement of University Students With and Without a History of Reading Difficulties. AB - University students who report a history of reading difficulties have been demonstrated to have poorer word reading and reading comprehension skills than their peers; yet, without a diagnosed learning disability, these students do not have access to the same support services, potentially placing them at academic risk. This study provides a comprehensive investigation of first-year academic achievement for students with a history of reading difficulties (n = 244) compared to students with no such history (n = 603). We also examine reported use of metacognitive reading and study strategies and their relations with GPA. Results indicate that students with a history of reading difficulties earn lower GPA and successfully complete fewer credits compared to students with no history of reading difficulty. These patterns varied somewhat by faculty of study. Students with a history of reading difficulties also reported lower scores across multiple metacognitive reading and study strategy scales, yet these scores were not associated with their academic performance. Together, these results demonstrate the importance of identifying students with a history of reading difficulties and that commonly used study strategy inventories have limited value in predicting their academic success. PMID- 26229066 TI - Nitric oxide is required for the auxin-induced activation of NADPH-dependent thioredoxin reductase and protein denitrosylation during root growth responses in arabidopsis. AB - BACKGROUND AND AIMS: Auxin is the main phytohormone controlling root development in plants. This study uses pharmacological and genetic approaches to examine the role of auxin and nitric oxide (NO) in the activation of NADPH-dependent thioredoxin reductase (NTR), and the effect that this activity has on root growth responses in Arabidopsis thaliana. METHODS: Arabidopsis seedlings were treated with auxin with or without the NTR inhibitors auranofin (ANF) and 1-chloro-2, 4 dinitrobenzene (DNCB). NTR activity, lateral root (LR) formation and S nitrosothiol content were measured in roots. Protein S-nitrosylation was analysed by the biotin switch method in wild-type arabidopsis and in the double mutant ntra ntrb. KEY RESULTS: The auxin-mediated induction of NTR activity is inhibited by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3 oxide (CPTIO), suggesting that NO is downstream of auxin in this regulatory pathway. The NTR inhibitors ANF and DNCB prevent auxin-mediated activation of NTR and LR formation. Moreover, ANF and DNCB also inhibit auxin-induced DR5 : : GUS and BA3 : : GUS gene expression, suggesting that the auxin signalling pathway is compromised without full NTR activity. Treatment of roots with ANF and DNCB increases total nitrosothiols (SNO) content and protein S-nitrosylation, suggesting a role of the NTR-thioredoxin (Trx)-redox system in protein denitrosylation. In agreement with these results, the level of S-nitrosylated proteins is increased in the arabidopsis double mutant ntra ntrb as compared with the wild-type. CONCLUSIONS: The results support for the idea that NTR is involved in protein denitrosylation during auxin-mediated root development. The fact that a high NO concentration induces NTR activity suggests that a feedback mechanism to control massive and unregulated protein S-nitrosylation could be operating in plant cells. PMID- 26229068 TI - A two-week regimen of high-dose integrase inhibitors does not cause nephrotoxicity in mice. AB - BACKGROUND: The integrase inhibitors, raltegravir and dolutegravir, are nucleoside reverse transcriptase inhibitor-sparing agents which may be used as part of first-line antiretroviral therapy for HIV. These drugs inhibit creatinine secretion through organic cation transporters, thus elevating serum creatinine without affecting glomerular filtration. We sought to determine whether subtle signs of nephrotoxicity could be observed in mice administered a two-week regimen of high-dose integrase inhibitors. METHODS: C57BL/6 mice were fed standard water (CTRL, n = 6), raltegravir-containing water (40 mg/kg/day, n = 6), or dolutegravir-containing water (2.7 mg/kg/day, n = 6) for two weeks and sacrificed. Endpoints were assessed including urine microalbumin, kidney injury molecule-1 renal tissue gene expression, renal histopathology, serum creatinine, and blood urea nitrogen. RESULTS: The results are NOT consistent with a direct nephrotoxic effect of the integrase inhibitors in mice. Serum creatinine was significantly elevated in raltegravir and dolutegravir mice (p < 0.05) compared to control (raltegravir = 0.25 mg/dl, dolutegravir = 0.30 mg/dl versus CTRL = 0.17 mg/dl). Blood urea nitrogen, cystatin C, and urine microalbumin were unchanged. Kidney injury molecule-1 tissue expression in raltegravir and dolutegravir groups was nonsignificantly elevated compared to control (1.2-fold compared to control). Renal histopathology by periodic acid-Schiff staining failed to reveal glomerular or tubular renal injury in any group. CONCLUSION: These studies are consistent with integrase inhibitors competitively inhibiting creatinine secretion. While no evidence of direct nephrotoxicity was observed after two weeks of high-dose drug administration, additional studies may be performed to understand whether these drugs lead to chronic nephropathy. PMID- 26229069 TI - Characterization of a spermine/spermidine transport system reveals a novel DNA sequence duplication in Neisseria gonorrhoeae. AB - During infection, Neisseria gonorrhoeae, the causative agent of the sexually transmitted disease gonorrhea, comes into contact with numerous host compounds including polyamines (e.g. spermine and spermidine). Here, we show that spermine and spermidine concentrations in the growth medium decrease to undetectable levels in the presence of gonococci over time, but not when proteins of the putative polyamine transport system are lost due to mutation. We propose that gonococci have a functional and sole polyamine transport system (PotFGHI) that specifically imports spermine and spermidine. Bioinformatics and molecular analyses showed that the transporter's potGHI genes are organized as an operon while the gene encoding the necessary cognate periplasmic polyamine-binding protein (PotF) is located elsewhere on the chromosome. Interestingly, within the potGHI locus, we identified a novel duplicated sequence, which we term the Pot Gene-Associated-Duplication-Element, present in variable copy numbers in different gonococcal strains that was likely formed from the 5(') and 3(') ends of the coding sequences of the tandemly linked potH and potG genes, respectively. PMID- 26229070 TI - Conserved and divergent functions of RcrRPQ in Streptococcus gordonii and S. mutans. AB - In the dental caries pathogen Streptococcus mutans, an MarR-like transcriptional regulator (RcrR), two ABC efflux pumps (RcrPQ) and two effector peptides encoded in the rcrRPQ operon provide molecular connections between stress tolerance, (p)ppGpp metabolism and genetic competence. Here, we examined the role of RcrRPQ in the oral commensal S. gordonii. Unlike in S. mutans, introduction of polar or non-polar rcrR mutations into S. gordonii elicited no significant changes in transformation efficiency. However, S. gordonii rcrR mutants were markedly impaired in their ability to grow in the presence of hydrogen peroxide, paraquat, low pH or elevated temperature. Sensitivity to paraquat could also be conferred by mutation of cysteine residues that are present in the RcrR protein of S. gordonii, but not in S. mutans RcrR. Thus, stress tolerance is a conserved function of RcrRPQ in a commensal and pathogenic streptococcus, but the study reveals additional differences in regulation of genetic competence development between S. mutans and S. gordonii. PMID- 26229071 TI - Efficacy of interventions used by physiotherapists for patients with headache and migraine-systematic review and meta-analysis. AB - AIM: We aimed to conduct a systematic review evaluating the effectiveness of interventions used by physiotherapists on the intensity, frequency and duration of migraine, tension-type (TTH) and cervicogenic headache (CGH). METHODS: We performed a systematic search of electronic databases and a hand search for controlled trials. A risk of bias analysis was conducted using the Cochrane risk of bias tool (RoB). Meta-analyses present the combined mean effects; sensitivity analyses evaluate the influence of methodological quality. RESULTS: Of 77 eligible trials, 26 were included in the RoB assessment. Twenty trials were included in meta-analyses. Nineteen out of 26 trials had a high RoB in >1 domain. Meta-analyses of all trials indicated a reduction of TTH ( ITALIC! p < 0.0001; mean reduction -1.11 on a 0-10 visual analog scale (VAS); 95% CI -1.64 to -0.57) and CGH ( ITALIC! p = 0.0002; mean reduction -2.52 on a 0-10 VAS; 95% CI -3.86 to -1.19) pain intensity, CGH frequency ( ITALIC! p < 0.00001; mean reduction -1.34 days per month; 95% CI -1.40 to -1.28), and migraine ( ITALIC! p = 0.0001; mean reduction -22.39 hours without relief; 95% CI -33.90 to -10.88) and CGH ( ITALIC! p < 0.00001; mean reduction -1.68 hours per day; 95% CI -2.09 to -1.26) duration. Excluding high RoB trials increased the effect sizes and reached additional statistical significance for migraine pain intensity ( ITALIC! p < 0.00001; mean reduction -1.94 on a 0-10 VAS; 95% CI -2.61 to -1.27) and frequency ( ITALIC! p < 0.00001; mean reduction -9.07 days per month; 95% CI -9.52 to -8.62). DISCUSSION: Results suggest a statistically significant reduction in the intensity, frequency and duration of migraine, TTH and CGH. Pain reduction and reduction in CGH frequency do not reach clinically relevant effect sizes. Small sample sizes, inadequate use of headache classification, and other methodological shortcomings reduce the confidence in these results. Methodologically sound, randomized controlled trials with adequate sample sizes are required to provide information on whether and which physiotherapy approach is effective. According to Grading of Recommendations Assessment, Development and Evaluation (GRADE), the current level of evidence is low. PMID- 26229072 TI - Disparities in mental health among adolescents with and without impairments. AB - AIM: To analyse whether there are differences in mental health among adolescents with and without various kinds of impairments, taking into account the number of impairments and gender. METHODS: Data from the study Life & Health - Young People conducted in a Swedish county in 2011 was used. The survey included all students in grades 7 (13-14 years) and 9 (15-16 years) in compulsory school and grade 2 (17-18 years) in upper secondary school; there were 7793 respondents (81.0%). The students answered a questionnaire anonymously during school hours. Various measures of mental health were assessed in the groups: hard of hearing, visual impairment, motor impairment, difficulties in reading/writing/dyslexia, attention deficit hyperactive disorder/attention deficit disorder, other impairment, no impairment. RESULTS: Of the studied impairments, difficulties in reading/writing/dyslexia are the most common (6.3%), followed by hard of hearing (5.4%). To have at least one impairment is more common among boys (18.2%) than girls (15.4%). In the impairment group, 21.5% have multiple impairments. Adolescents with impairments have worse mental health than those without, and those with multiple impairments have particularly higher odds ratio to have worse mental health. There are also differences in mental health between number and various kinds of impairments and between girls and boys. CONCLUSION: Adolescents with impairments, particularly girls and those with multiple impairments, have considerably worse mental health than others. These inequalities in health are an immense challenge, not only for those directly involved with the impaired: they affect everyone involved with the goal health equity for the whole population. PMID- 26229073 TI - Life course models of economic stress and poor mental health in mid-adulthood: Results from the prospective Northern Swedish Cohort. AB - AIM: The aim was to analyse the association between economic stress during youth and adulthood, and poor mental health through life course models of (1) accumulation of risk and (2) sensitive period. METHODS: The study was based on the Northern Sweden Cohort, a 26-year prospective cohort (N = 1010 in 2007; 94% of those participating in 1981 still alive) ranging from adolescence to middle age. Economic stress was measured at age 16, 21, 30 and 42 years. Two life course models of accumulation of risk and sensitive period were analysed using ordinal regression with internalized symptoms of mental health as outcome. RESULTS: Exposure of economic stress at several life course periods was associated with higher odds of internalized mental health symptoms for both women and men, which supports the accumulated risk model. No support for a sensitive period was found for the whole sample. For men, however, adolescence appears to be a sensitive period during which the exposure to economic stress has negative mental health consequences later in life independently of economic stress at other ages. CONCLUSION: This study confirms that the duration of economic stress between adolescence and middle age is important for mental health. In addition, the results give some indication of a sensitive period of exposure to economic stress during adolescence for men, although more research is needed to confirm possible gender differences. PMID- 26229074 TI - Quality in sickness certificates in a Swedish social security system perspective. AB - AIM: In Sweden, the information in the sickness certificate is crucially important for the sick-listed person as well as for the Swedish Social Insurance Agency and the sick-listed person's employer. The certificate is used as the basis for deciding whether a person is entitled to sickness benefits. Further, it communicates information significant for the return-to-work process. The aim of the study was to evaluate the quality of sickness certificates issued in primary health care and examine if the patients' or physicians' gender influences the information in the sickness certificate. METHODS: An insurance specialist at the Swedish Social Insurance Agency assessed the quality of the stated information in a sample of 323 certificates issued by 146 different general practitioners at 29 different primary health care centres in northern Sweden. RESULTS: Thirty-four percent of the certificates did not contain sufficient information requested. The areas of the certificates in need of supplementary information were mainly the descriptions of impairment of body function and activity limitation. More certificates issued for women than certificates issued for men lacked the required information. Full-time sick leave was more often prescribed for male patients than for female. Significant differences between certificates issued for women and certificates issued for men appeared in the group of musculoskeletal diseases. No differences in quality aspects connected to physicians' gender were found. CONCLUSION: Our study indicates a need for increased knowledge about the descriptions of functioning for sick-listed persons; more cooperation between health professionals in primary health care and a better gender awareness in health care encounters. PMID- 26229075 TI - If forest dynamics in Canada's west are driven mainly by competition, why did they change? Half-century evidence says: Climate change. PMID- 26229076 TI - Reply to Price et al.: An inconvenient truth about the long-term forest change in western Canada: Competition is the primary driving force. PMID- 26229077 TI - Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype. AB - Triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancer but is responsible for a disproportionate share of morbidity and mortality because of its aggressive characteristics and lack of targeted therapies. Chemotherapy induces enrichment of breast cancer stem cells (BCSCs), which are responsible for tumor recurrence and metastasis. Here, we demonstrate that chemotherapy induces the expression of the cystine transporter xCT and the regulatory subunit of glutamate-cysteine ligase (GCLM) in a hypoxia-inducible factor (HIF)-1-dependent manner, leading to increased intracellular glutathione levels, which inhibit mitogen-activated protein kinase kinase (MEK) activity through copper chelation. Loss of MEK-ERK signaling causes FoxO3 nuclear translocation and transcriptional activation of the gene encoding the pluripotency factor Nanog, which is required for enrichment of BCSCs. Inhibition of xCT, GCLM, FoxO3, or Nanog blocks chemotherapy-induced enrichment of BCSCs and impairs tumor initiation. These results suggest that, in combination with chemotherapy, targeting BCSCs by inhibiting HIF-1-regulated glutathione synthesis may improve outcome in TNBC. PMID- 26229079 TI - Seeing is believing: Ras dimers observed in live cells. PMID- 26229078 TI - An inhibitor persistently decreased enteric methane emission from dairy cows with no negative effect on milk production. AB - A quarter of all anthropogenic methane emissions in the United States are from enteric fermentation, primarily from ruminant livestock. This study was undertaken to test the effect of a methane inhibitor, 3-nitrooxypropanol (3NOP), on enteric methane emission in lactating Holstein cows. An experiment was conducted using 48 cows in a randomized block design with a 2-wk covariate period and a 12-wk data collection period. Feed intake, milk production, and fiber digestibility were not affected by the inhibitor. Milk protein and lactose yields were increased by 3NOP. Rumen methane emission was linearly decreased by 3NOP, averaging about 30% lower than the control. Methane emission per unit of feed dry matter intake or per unit of energy-corrected milk were also about 30% less for the 3NOP-treated cows. On average, the body weight gain of 3NOP-treated cows was 80% greater than control cows during the 12-wk experiment. The experiment demonstrated that the methane inhibitor 3NOP, applied at 40 to 80 mg/kg feed dry matter, decreased methane emissions from high-producing dairy cows by 30% and increased body weight gain without negatively affecting feed intake or milk production and composition. The inhibitory effect persisted over 12 wk of treatment, thus offering an effective methane mitigation practice for the livestock industries. PMID- 26229080 TI - A Child With Nephrotic Syndrome and Abdominal Pain. PMID- 26229081 TI - Automated biological sulphate reduction: a review on mathematical models, monitoring and bioprocess control. AB - In the sulphate-reducing process, bioprocess control can be used to regulate the competition between microbial groups, to optimize the input of the electron donor and/or to maximize or minimize the production of sulphide. As shown in this review, modelling and monitoring are important tools in the development and application of a bioprocess control strategy. Pre-eminent literature on modelling, monitoring and control of sulphate-reducing processes is reviewed. This paper firstly reviews existing mathematical models for sulphate reduction, focusing on models for biofilms, microbial competition, inhibition and bioreactor dynamics. Secondly, a summary of process monitoring strategies is presented. Special attention is given to in situ sensors for sulphate, sulphide and electron donor concentrations as well as for biomass activity and composition. Finally, the state of the art of the bioprocess control strategies in biological sulphate reduction processes is overviewed. PMID- 26229082 TI - What Is Insufficient about Validation? PMID- 26229083 TI - Validation Is Necessary but Insufficient. PMID- 26229085 TI - Dependence and independence: Structure and inference. AB - Evaluations of relationships between pairs of variables, including testing for independence, are increasingly important. Erich Leo Lehmann noted that "the study of the power and efficiency of tests of independence is complicated by the difficulty of defining natural classes of alternatives to the hypothesis of independence." This paper presents a general review, discussion and comparison of classical and novel tests of independence. We investigate a broad spectrum of dependence structures with/without random effects, including those that are well addressed in both the applied and the theoretical scientific literatures as well as scenarios when the classical tests of independence may break down completely. Motivated by practical considerations, the impact of random effects in dependence structures are studied in the additive and multiplicative forms. A novel index of dependence is proposed based on the area under the Kendall plot. In conjunction with the scatterplot and the Kendall plot, the proposed method provides a comprehensive presentation of the data in terms of graphing and conceptualizing the dependence. We also present a graphical methodology based on heat maps to effectively compare the powers of various tests. Practical examples illustrate the use of various tests of independence and the graphical representations of dependence structures. PMID- 26229084 TI - Decision Aids: The Effect of Labeling Options on Patient Choices and Decision Making. AB - BACKGROUND: Conscious and unconscious biases can influence how people interpret new information and make decisions. Current standards for creating decision aids, however, do not address this issue. METHOD: Using a 2*2 factorial design, we developed surveys that contained a decision scenario (involving a choice between aspirin or a statin drug to lower risk of heart attack) and a decision aid. Each aid presented identical information about reduction in heart attack risk and likelihood of a major side effect. They differed in whether the options were labeled and the amount of decisional guidance: information only (a balance sheet) versus information plus values clarification (a multicriteria decision analysis). We sent the surveys to members of 2 Internet survey panels. After using the decision aid, participants indicated their preferred medication. Those using a multicriteria decision aid also judged differences in the comparative outcome data provided for the 2 options and the relative importance of achieving benefits versus avoiding risks in making the decision. RESULTS: The study sample size was 536. Participants using decision aids with unlabeled options were more likely to choose a statin: 56% versus 25% (P < 0.001). The type of decision aid made no difference. This effect persisted after adjustment for differences in survey company, age, gender, education level, health literacy, and numeracy. Participants using unlabeled decision aids were also more likely to interpret the data presented as favoring a statin with regard to both treatment benefits and risk of side effects (P <= 0.01). There were no significant differences in decision priorities (P = 0.21). CONCLUSION: Identifying the options in patient decision aids can influence patient preferences and change how they interpret comparative outcome data. PMID- 26229086 TI - Circulating miR-33a and miR-33b are up-regulated in familial hypercholesterolaemia in paediatric age. AB - Hypercholesterolaemia is one of the major causes of CVD (cardiovascular disease). It is associated with enhanced oxidative stress, leading to increased lipid peroxidation which in turn determines endothelial dysfunction and susceptibility to coronary vasoconstriction and atherosclerosis. Different miRNAs are involved in the pathogenesis of CVD and play an important role in inflammatory process control, therefore, together with atherogenic factors, they can stimulate atherosclerotic degeneration of the vessel walls of arteries. miR-33a and miR-33b play a pivotal role in a variety of biological processes including cholesterol homoeostasis, HDL (high-density lipoprotein)-cholesterol formation, fatty acid oxidation and insulin signalling. Our study aimed to determine whether circulating miR-33a and miR-33b expression was altered in familial hypercholesterolaemic children. Total RNA was extracted from plasma, and miR-33a and miR-33b were measured by quantitative real-time PCR. We found that miR-33a and miR-33b were significantly up-regulated in the plasma of 28 hypercholesterolaemic children compared with 25 healthy subjects (4.49+/-0.27 fold increase, P<0.001, and 3.21+/-0.39-fold increase, P<0.05 respectively), and for both miRNAs, a positive correlation with total cholesterol, LDL (low-density lipoprotein)-cholesterol, LDL-cholesterol/HDL-cholesterol ratio, apolipoprotein B, CRP (C-reactive protein) and glycaemia was found. OLS (ordinary least squares) regression analysis revealed that miR-33a was significantly affected by the presence of FH (familial hypercholesterolaemia), glycaemia and CRP (P<0.001, P<0.05 and P<0.05 respectively). The same analysis showed that miR-33b was significantly related to FH and CRP (P<0.05 and P<0.05 respectively). Although it is only explorative, the present study could be the first to point to the use of miR-33a and miR-33b as early biomarkers for cholesterol levels in childhood, once validated in independent larger cohorts. PMID- 26229087 TI - The efficacy of ceritinib in patients with ALK-positive non-small cell lung cancer. AB - Research over the last decade has determined that the gene rearrangement involving the anaplastic lymphoma kinase (ALK) gene is an oncogenic driver in approximately 5% of patients with non-small cell lung carcinoma (NSCLC). This review describes the discovery of the ALK translocation, development of ALK directed therapy, and acquired resistance to ALK directed therapy with a focus on the clinical data and efficacy of the most recently approved ALK inhibitor, ceritinib. PMID- 26229088 TI - Proposal for a standardised inter-professional undergraduate curriculum in preventive cardiology. PMID- 26229089 TI - Prediction of the effect of atrasentan on renal and heart failure outcomes based on short-term changes in multiple risk markers. AB - BACKGROUND: A recent phase II clinical trial (Reducing Residual Albuminuria in Subjects with Diabetes and Nephropathy with AtRasentan trial and an identical trial in Japan (RADAR/JAPAN)) showed that the endothelin A receptor antagonist atrasentan lowers albuminuria, blood pressure, cholesterol, hemoglobin, and increases body weight in patients with type 2 diabetes and nephropathy. We previously developed an algorithm, the Parameter Response Efficacy (PRE) score, which translates short-term drug effects into predictions of long-term effects on clinical outcomes. DESIGN: We used the PRE score on data from the RADAR/JAPAN study to predict the effect of atrasentan on renal and heart failure outcomes. METHODS: We performed a post-hoc analysis of the RADAR/JAPAN randomized clinical trials in which 211 patients with type-2 diabetes and nephropathy were randomly assigned to atrasentan 0.75 mg/day, 1.25 mg/day, or placebo. A PRE score was developed in a background set of completed clinical trials using multivariate Cox models. The score was applied to baseline and week-12 risk marker levels of RADAR/JAPAN participants, to predict atrasentan effects on clinical outcomes. Outcomes were defined as doubling serum creatinine or end-stage renal disease and hospitalization for heart failure. RESULTS: The PRE score predicted renal risk changes of -23% and -30% for atrasentan 0.75 and 1.25 mg/day, respectively. PRE scores also predicted a small non-significant increase in heart failure risk for atrasentan 0.75 and 1.25 mg/day (+2% vs. +7%). Selecting patients with >30% albuminuria reduction from baseline (responders) improved renal outcome to almost 50% risk reduction, whereas non-responders showed no renal benefit. CONCLUSIONS: Based on the RADAR/JAPAN study, with short-term changes in risk markers, atrasentan is expected to decrease renal risk without increased risk of heart failure. Within this population albuminuria responders appear to contribute to the predicted improvements, whereas non-responders showed no benefit. The ongoing hard outcome trial (SONAR) in type 2 diabetic patients with >30% albuminuria reduction to atrasentan will allow us to assess the validity of these predictions. PMID- 26229090 TI - Detection of Enhancer-Associated Rearrangements Reveals Mechanisms of Oncogene Dysregulation in B-cell Lymphoma. AB - B-cell lymphomas frequently contain genomic rearrangements that lead to oncogene activation by heterologous distal regulatory elements. We used a novel approach called "pinpointing enhancer-associated rearrangements by chromatin immunoprecipitation," or PEAR-ChIP, to simultaneously map enhancer activity and proximal rearrangements in lymphoma cell lines and patient biopsies. This method detects rearrangements involving known cancer genes, including CCND1, BCL2, MYC, PDCD1LG2, NOTCH1, CIITA, and SGK1, as well as novel enhancer duplication events of likely oncogenic significance. We identify lymphoma subtype-specific enhancers in the MYC locus that are silenced in lymphomas with MYC-activating rearrangements and are associated with germline polymorphisms that alter lymphoma risk. We show that BCL6-locus enhancers are acetylated by the BCL6-activating transcription factor MEF2B, and can undergo genomic duplication, or target the MYC promoter for activation in the context of a "pseudo-double-hit" t(3;8)(q27;q24) rearrangement linking the BCL6 and MYC loci. Our work provides novel insights regarding enhancer-driven oncogene activation in lymphoma. SIGNIFICANCE: We demonstrate a novel approach for simultaneous detection of genomic rearrangements and enhancer activity in tumor biopsies. We identify novel mechanisms of enhancer-driven regulation of the oncogenes MYC and BCL6, and show that the BCL6 locus can serve as an enhancer donor in an "enhancer hijacking" translocation. PMID- 26229096 TI - Choice of New Oral Anticoagulant Agents Versus Vitamin K Antagonists in Atrial Fibrillation: FANTASIIA Study. AB - INTRODUCTION: Atrial fibrillation (AF) is associated with an increased risk of thromboembolic events. Many patients with AF receive chronic anticoagulation, either with vitamin K antagonists (VKAs) or with non-VKA oral anticoagulants (NOACs). We sought to analyze variables associated with prescription of NOAC. METHODS: Patients with AF under anticoagulation treatment were prospectively recruited in this observational registry. The sample comprised 1290 patients under chronic anticoagulation for AF, 994 received VKA (77.1%) and 296 NOAC (22.9%). Univariate and multivariate analyses were performed to identify variables associated with use of NOAC. RESULTS: Mean age was 73.8 +/- 9.4 years, and 42.5% of the patients were women. The CHA2DS2-VASc score was 0 in 4.9% of the population, 1 in 24.1%, and >=2 in 71% (median = 4, interquartile range = 2). Variables associated with NOAC treatment were major bleeding (odds ratio [OR] = 3.36; confidence interval [CI] 95%: 1.73-6.51; P < .001), hemorrhagic stroke (OR = 3.19; CI 95% 1.00-10.15, P = .049), university education (OR = 2.44; CI 95%: 1.55-3.84; P < .001), high diastolic blood pressure (OR = 1.02; CI 95%: 1.00 1.03; P = .006), and higher glomerular filtration rate (OR 1.01, CI 95% 1.00 1.01; P = .01). And variables associated with VKA use were history of cancer (OR = 0.46; CI 95%: 0.25-0.85; P = .013) and bradyarrhythmia (OR = 0.40; CI 95% 0.19 0.85; P = .020). CONCLUSION: Medical and social variables were associated with prescription of NOAC. Major bleeding, hemorrhagic stroke, university education, and higher glomerular filtration rate were more frequent among patients under NOAC. On the contrary, patients with history of cancer or bradyarrhythmias more frequently received VKA. PMID- 26229097 TI - Formaldehyde exposure inhibits the expression of mammalian target of rapamycin in rat testis. AB - Formaldehyde (FA), a ubiquitous environmental pollutant, has long been suspected of causing adverse male reproductive effects. However, the molecular and cellular mechanisms underlying this phenomenon remain elusive. The overall aim of this study is to clarify the role of mammalian target of rapamycin (mTOR) in male reproductive injuries induced by FA exposure, by which we can further understand the molecular mechanism of FA male reproductive toxicity. In this study, immunohistochemistry, Western blotting, and reverse transcription polymerase chain reaction analysis were used to detect the expression of mTOR molecule in testicular tissues. We found that FA exposure inhibits the expression of mTOR in a dose-dependent manner. Combined with our earlier finding, we found the decreasing expression of mTOR in testicular tissue were consistent with the changes of testicular structure and autophagy levels. In summary, our data suggested that mTOR molecule might be involved in male reproductive injuries induced by FA exposure. PMID- 26229098 TI - Differential expression of metallothionein-1 and cytochrome p450-2a5 (cyp2a5) in mice in response to lead acetate exposure and industrial effluents in Ibadan, Nigeria. AB - Metallothionein-1 ( MT-1), cytochrome P450-2A ( CYP2a) and other genes are involved in the detoxification of xenobiotics such as heavy metals and toxins. Changes in their expression precede overt toxic effects and can serve as a marker for exposure to pollutants. We used a mouse experimental system and quantitative reverse transcription polymerase chain reaction to determine changes in gene expression and the direction of change, in response to exposure to lead acetate (LA) and waste water (WW) from an industrial area in Ibadan. MT-1 and CYP2a5 genes were quickly and highly induced at different exposure periods and concentrations. MT-1 was mostly downregulated by the LA exposure, but upregulated by several folds on exposure to WW. CYP2a5 expression was mostly downregulated with LA exposure. The optimum expression of MT-1 and CYP2a5 genes induced by both LA and WW was at 48 h. We conclude that rapid assays to determine the direction of change in the expression of MT-1 and CYP2a5 could be a fast and reliable method in developing countries for screening humans exposed to pollutants from industrial waste. PMID- 26229099 TI - Positive and Negative Allosteric Modulation of an alpha1beta3gamma2 gamma Aminobutyric Acid Type A (GABAA) Receptor by Binding to a Site in the Transmembrane Domain at the gamma+-beta- Interface. AB - In the process of developing safer general anesthetics, isomers of anesthetic ethers and barbiturates have been discovered that act as convulsants and inhibitors of gamma-aminobutyric acid type A receptors (GABAARs) rather than potentiators. It is unknown whether these convulsants act as negative allosteric modulators by binding to the intersubunit anesthetic-binding sites in the GABAAR transmembrane domain (Chiara, D. C., Jayakar, S. S., Zhou, X., Zhang, X., Savechenkov, P. Y., Bruzik, K. S., Miller, K. W., and Cohen, J. B. (2013) J. Biol. Chem. 288, 19343-19357) or to known convulsant sites in the ion channel or extracellular domains. Here, we show that S-1-methyl-5-propyl-5-(m trifluoromethyl-diazirynylphenyl) barbituric acid (S-mTFD-MPPB), a photoreactive analog of the convulsant barbiturate S-MPPB, inhibits alpha1beta3gamma2 but potentiates alpha1beta3 GABAAR responses. In the alpha1beta3gamma2 GABAAR, S-mTFD MPPB binds in the transmembrane domain with high affinity to the gamma(+)-beta(-) subunit interface site with negative energetic coupling to GABA binding in the extracellular domain at the beta(+)-alpha(-) subunit interfaces. GABA inhibits S [(3)H]mTFD-MPPB photolabeling of gamma2Ser-280 (gammaM2-15') in this site. In contrast, within the same site GABA enhances photolabeling of beta3Met-227 in betaM1 by an anesthetic barbiturate, R-[(3)H]methyl-5-allyl-5-(m-trifluoromethyl diazirynylphenyl)barbituric acid (mTFD-MPAB), which differs from S-mTFD-MPPB in structure only by chirality and two hydrogens (propyl versus allyl). S-mTFD-MPPB and R-mTFD-MPAB are predicted to bind in different orientations at the gamma(+) beta(-) site, based upon the distance in GABAAR homology models between gamma2Ser 280 and beta3Met-227. These results provide an explanation for S-mTFD-MPPB inhibition of alpha1beta3gamma2 GABAAR function and provide a first demonstration that an intersubunit-binding site in the GABAAR transmembrane domain binds negative and positive allosteric modulators. PMID- 26229100 TI - Phosphorylation of Tyrosine 1070 at the GluN2B Subunit Is Regulated by Synaptic Activity and Critical for Surface Expression of N-Methyl-D-aspartate (NMDA) Receptors. AB - The number and subunit composition of synaptic N-methyl-d-aspartate receptors (NMDARs) play critical roles in synaptic plasticity, learning, and memory and are implicated in neurological disorders. Tyrosine phosphorylation provides a powerful means of regulating NMDAR function, but the underling mechanism remains elusive. In this study we identified a tyrosine site on the GluN2B subunit, Tyr 1070, which was phosphorylated by a proto-oncogene tyrosine-protein (Fyn) kinase and critical for the surface expression of GluN2B-containing NMDARs. The phosphorylation of GluN2B at Tyr-1070 was required for binding of Fyn kinase to GluN2B, which up-regulated the phosphorylation of GluN2B at Tyr-1472. Moreover, our results revealed that the phosphorylation change of GluN2B at Tyr-1070 accompanied the Tyr-1472 phosphorylation and Fyn associated with GluN2B in synaptic plasticity induced by both chemical and contextual fear learning. Taken together, our findings provide a new mechanism for regulating the surface expression of NMDARs with implications for synaptic plasticity. PMID- 26229101 TI - Identification of Novel 14-3-3 Residues That Are Critical for Isoform-specific Interaction with GluN2C to Regulate N-Methyl-D-aspartate (NMDA) Receptor Trafficking. AB - The 14-3-3 family of proteins is widely distributed in the CNS where they are major regulators of essential neuronal functions. There are seven known mammalian 14-3-3 isoforms (zeta,, tau, epsilon, eta, beta, and sigma), which generally function as adaptor proteins. Previously, we have demonstrated that 14-3-3epsilon isoform dynamically regulates forward trafficking of GluN2C-containing NMDA receptors (NMDARs) in cerebellar granule neurons, that when expressed on the surface, promotes neuronal survival following NMDA-induced excitotoxicity. Here, we report 14-3-3 isoform-specific binding and functional regulation of GluN2C. In particular, we show that GluN2C C-terminal domain (CTD) binds to all 14-3-3 isoforms except 14-3-3sigma, and binding is dependent on GluN2C serine 1096 phosphorylation. Co-expression of 14-3-3 (zeta and epsilon) and GluN1/GluN2C promotes the forward delivery of receptors to the cell surface. We further identify novel residues serine 145, tyrosine 178, and cysteine 189 on alpha helices 6, 7, and 8, respectively, within zeta-isoform as part of the GluN2C binding motif and independent of the canonical peptide binding groove. Mutation of these conserved residues abolishes GluN2C binding and has no functional effect on GluN2C trafficking. Reciprocal mutation of alanine 145, histidine 180, and isoleucine 191 on 14-3-3sigma isoform promotes GluN2C binding and surface expression. Moreover, inhibiting endogenous 14-3-3 using a high-affinity peptide inhibitor, difopein, greatly diminishes GluN2C surface expression. Together, these findings highlight the isoform-specific structural and functional differences within the 14-3-3 family of proteins, which determine GluN2C binding and its essential role in targeting the receptor to the cell surface to facilitate glutamatergic neurotransmission. PMID- 26229103 TI - An antisense RNA-mediated mechanism eliminates a meiosis-specific copper regulated transcript in mitotic cells. AB - Sense and antisense transcripts produced from convergent gene pairs could interfere with the expression of either partner gene. In Schizosaccharomyces pombe, we found that the iss1(+) gene produces two transcript isoforms, including a long antisense mRNA that is complementary to the meiotic cum1(+) sense transcript, inhibiting cum1(+) expression in vegetative cells. Inhibition of cum1(+) transcription was not at the level of its initiation because fusion of the cum1(+) promoter to the lacZ gene showed that activation of the reporter gene occurs in response to low copper conditions. Further analysis showed that the transcription factor Cuf1 and conserved copper-signaling elements (CuSEs) are required for induction of cum1(+)-lacZ transcription under copper deficiency. Insertion of a multipartite polyadenylation signal immediately downstream of iss1(+) led to the exclusive production of a shorter iss1(+) mRNA isoform, thereby allowing accumulation of cum1(+) sense mRNA in copper-limited vegetative cells. This finding suggested that the long iss1(+) antisense mRNA could pair with cum1(+) sense mRNA, thereby producing double-stranded RNA molecules that could induce RNAi. We consistently found that mutant strains for RNAi (dcr1Delta, ago1Delta, rdp1Delta, and clr4Delta) are defective in selectively eliminating cum1(+) sense transcript in the G1 phase of the cell cycle. Taken together, these results describe the first example of a copper-regulated meiotic gene repressed by an antisense transcription mechanism in vegetative cells. PMID- 26229102 TI - Cystic Fibrosis Transmembrane Conductance Regulator (CFTR): CLOSED AND OPEN STATE CHANNEL MODELS. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette (ABC) transporter superfamily. CFTR controls the flow of anions through the apical membrane of epithelia. Dysfunctional CFTR causes the common lethal genetic disease cystic fibrosis. Transitions between open and closed states of CFTR are regulated by ATP binding and hydrolysis on the cytosolic nucleotide binding domains, which are coupled with the transmembrane (TM) domains forming the pathway for anion permeation. Lack of structural data hampers a global understanding of CFTR and thus the development of "rational" approaches directly targeting defective CFTR. In this work, we explored possible conformational states of the CFTR gating cycle by means of homology modeling. As templates, we used structures of homologous ABC transporters, namely TM(287-288), ABC-B10, McjD, and Sav1866. In the light of published experimental results, structural analysis of the transmembrane cavity suggests that the TM(287-288) based CFTR model could correspond to a commonly occupied closed state, whereas the McjD-based model could represent an open state. The models capture the important role played by Phe-337 as a filter/gating residue and provide structural information on the conformational transition from closed to open channel. PMID- 26229104 TI - Mechanism of Fine-tuning pH Sensors in Proprotein Convertases: IDENTIFICATION OF A pH-SENSING HISTIDINE PAIR IN THE PROPEPTIDE OF PROPROTEIN CONVERTASE 1/3. AB - The propeptides of proprotein convertases (PCs) regulate activation of cognate protease domains by sensing pH of their organellar compartments as they transit the secretory pathway. Earlier experimental work identified a conserved histidine encoded pH sensor within the propeptide of the canonical PC, furin. To date, whether protonation of this conserved histidine is solely responsible for PC activation has remained unclear because of the observation that various PC paralogues are activated at different organellar pH values. To ascertain additional determinants of PC activation, we analyzed PC1/3, a paralogue of furin that is activated at a pH of ~5.4. Using biophysical, biochemical, and cell-based methods, we mimicked the protonation status of various histidines within the propeptide of PC1/3 and examined how such alterations can modulate pH-dependent protease activation. Our results indicate that whereas the conserved histidine plays a crucial role in pH sensing and activation of this protease an additional histidine acts as a "gatekeeper" that fine-tunes the sensitivity of the PC1/3 propeptide to facilitate the release inhibition at higher proton concentrations when compared with furin. Coupled with earlier analyses that highlighted the enrichment of the amino acid histidine within propeptides of secreted eukaryotic proteases, our work elucidates how secreted proteases have evolved to exploit the pH of the secretory pathway by altering the spatial juxtaposition of titratable groups to regulate their activity in a spatiotemporal fashion. PMID- 26229105 TI - Regulation of Ergothioneine Biosynthesis and Its Effect on Mycobacterium tuberculosis Growth and Infectivity. AB - Ergothioneine (EGT) is synthesized in mycobacteria, but limited knowledge exists regarding its synthesis, physiological role, and regulation. We have identified Rv3701c from Mycobacterium tuberculosis to encode for EgtD, a required histidine methyltransferase that catalyzes first biosynthesis step in EGT biosynthesis. EgtD was found to be phosphorylated by the serine/threonine protein kinase PknD. PknD phosphorylates EgtD both in vitro and in a cell-based system on Thr(213). The phosphomimetic (T213E) but not the phosphoablative (T213A) mutant of EgtD failed to restore EGT synthesis in a DeltaegtD mutant. The findings together with observed elevated levels of EGT in a pknD transposon mutant during in vitro growth suggests that EgtD phosphorylation by PknD negatively regulates EGT biosynthesis. We further showed that EGT is required in a nutrient-starved model of persistence and is needed for long term infection of murine macrophages. PMID- 26229106 TI - Codon-Anticodon Recognition in the Bacillus subtilis glyQS T Box Riboswitch: RNA DEPENDENT CODON SELECTION OUTSIDE THE RIBOSOME. AB - Many amino acid-related genes in Gram-positive bacteria are regulated by the T box riboswitch. The leader RNA of genes in the T box family controls the expression of downstream genes by monitoring the aminoacylation status of the cognate tRNA. Previous studies identified a three-nucleotide codon, termed the "Specifier Sequence," in the riboswitch that corresponds to the amino acid identity of the downstream genes. Pairing of the Specifier Sequence with the anticodon of the cognate tRNA is the primary determinant of specific tRNA recognition. This interaction mimics codon-anticodon pairing in translation but occurs in the absence of the ribosome. The goal of the current study was to determine the effect of a full range of mismatches for comparison with codon recognition in translation. Mutations were individually introduced into the Specifier Sequence of the glyQS leader RNA and tRNA(Gly) anticodon to test the effect of all possible pairing combinations on tRNA binding affinity and antitermination efficiency. The functional role of the conserved purine 3' of the Specifier Sequence was also verifiedin this study. We found that substitutions at the Specifier Sequence resulted in reduced binding, the magnitude of which correlates well with the predicted stability of the RNA-RNA pairing. However, the tolerance for specific mismatches in antitermination was generally different from that during decoding, which reveals a unique tRNA recognition pattern in the T box antitermination system. PMID- 26229107 TI - The oncoprotein HBXIP modulates the feedback loop of MDM2/p53 to enhance the growth of breast cancer. AB - MDM2 and p53 form a negative feedback loop, in which p53 as a transcription factor positively regulates MDM2 and MDM2 negatively regulates tumor suppressor p53 through promoting its degradation. However, the mechanism of the feedback loop is poorly understood in cancers. We had reported previously that the oncoprotein hepatitis B X-interacting protein (HBXIP) is a key oncoprotein in the development of cancer. Thus, we supposed that HBXIP might be involved in the event. Here, we observed that the expression levels of HBXIP were positively correlated to those of MDM2 in clinical breast cancer tissues. Interestingly, HBXIP was able to up-regulate MDM2 at the levels of mRNA and protein in MCF-7 breast cancer cells. Mechanically, HBXIP increased the promoter activities of MDM2 through directly binding to p53 in the P2 promoter of MDM2. Strikingly, we identified that the acetyltransferase p300 was recruited by HBXIP to p53 in the promoter of MDM2. Moreover, we validated that HBXIP enhanced the p53 degradation mediated by MDM2. Functionally, the knockdown of HBXIP or/and p300 inhibited the proliferation of breast cancer cells in vitro, and the depletion of MDM2 or overexpression of p53 significantly blocked the HBXIP-promoted growth of breast cancer in vitro and in vivo. Thus, we concluded that highly expressed HBXIP accelerates the MDM2-mediated degradation of p53 in breast cancer through modulating the feedback loop of MDM2/p53, resulting in the fast growth of breast cancer cells. Our findings provide new insights into the mechanism of the acceleration of the MDM2/p53 feedback loop in the development of cancer. PMID- 26229108 TI - Molecular Insights into Inhibition of the Methylated Histone-Plant Homeodomain Complexes by Calixarenes. AB - Plant homeodomain (PHD) finger-containing proteins are implicated in fundamental biological processes, including transcriptional activation and repression, DNA damage repair, cell differentiation, and survival. The PHD finger functions as an epigenetic reader that binds to posttranslationally modified or unmodified histone H3 tails, recruiting catalytic writers and erasers and other components of the epigenetic machinery to chromatin. Despite the critical role of the histone-PHD interaction in normal and pathological processes, selective inhibitors of this association have not been well developed. Here we demonstrate that macrocyclic calixarenes can disrupt binding of PHD fingers to methylated lysine 4 of histone H3 in vitro and in vivo. The inhibitory activity relies on differences in binding affinities of the PHD fingers for H3K4me and the methylation state of the histone ligand, whereas the composition of the aromatic H3K4me-binding site of the PHD fingers appears to have no effect. Our approach provides a novel tool for studying the biological roles of methyllysine readers in epigenetic signaling. PMID- 26229109 TI - Does adding mobilization to stretching improve outcomes for people with frozen shoulder? A randomized controlled clinical trial. AB - OBJECTIVE: To assess the effectiveness of joint mobilization combined with stretching exercises in patients with frozen shoulder. DESIGN: A randomized controlled clinical pilot trial. SETTING: Department of Orthopedics and Traumatology. SUBJECTS: Thirty patients with frozen shoulder. INTERVENTION: All participants were randomly assigned to one of two treatment groups: joint mobilization and stretching versus stretching exercises alone. Both groups performed a home exercise program and were treated for six weeks (18 sessions). MAIN MEASURES: The primary outcome measures for functional assessment were the Disabilities of the Arm, Shoulder and Hand score and the Constant score. The secondary outcome measures were pain level, as evaluated with a visual analog scale, and range of motion, as measured using a conventional goniometer. Patients were assessed before treatment, at the end of the treatment, and after one year as follow-up. RESULTS: Two-by-two repeated-measures ANOVA with Bonferroni corrections revealed significant increases in abduction (91.9 degrees [CI: 86.1 96.7] to 172.8 degrees [CI: 169.7-175.5]), external rotation (28.1 degrees [CI: 22.2-34.2] to 77.7 degrees [CI: 70.3-83.0]) and Constant score (39.1 [CI: 35.3 42.6] to 80.5 [75.3-86.6]) at the one-year follow-up in the joint mobilization combined with stretching exercise group, whereas the group performing stretching exercise alone did not show such changes. CONCLUSION: In the treatment of patients with frozen shoulder, joint mobilization combined with stretching exercises is better than stretching exercise alone in terms of external rotation, abduction range of motion and function score. PMID- 26229110 TI - Descriptions of memory rehabilitation group interventions for neurological conditions: a systematic review. AB - OBJECTIVE: To establish what aspects of group-based cognitive rehabilitation for memory problems are reported, and to develop a checklist for authors, which may to improve reporting of these interventions in future studies. DATA SOURCES: A systematic search was conducted on Web of Knowledge, CINAHL, MEDLINE, AMED, EMBASE and PsycINFO electronic databases (last search: 01/05/2015). REVIEW METHODS: Articles were included if the sample were adults with a neurological disorder, the intervention was group-based cognitive rehabilitation for memory problems, and if the study was a randomised controlled trial. Articles were independently screened for inclusion and data extracted by two researchers, with the third researcher arbitrating any disputes. RESULTS: Fourteen studies were included in this review. The reporting of certain aspects of an intervention was found to be poor, particularly in relation to: duration of the programme (6 of 14 studies did not report), the development of the intervention (7 of 14 studies did not discuss), and the content and structure of intervention (7 of the 14 studies did not provide details). CONCLUSION: This review found that the overall reporting of memory rehabilitation content and format is poor. Refinement and adaption of pre-existing checklists to capture aspects of cognitive rehabilitation programmes may help authors when reporting complex interventions. A draft checklist is provided that could be refined and validated in further research. PMID- 26229112 TI - QUANTUM GASES. Observation of many-body localization of interacting fermions in a quasirandom optical lattice. AB - Many-body localization (MBL), the disorder-induced localization of interacting particles, signals a breakdown of conventional thermodynamics because MBL systems do not thermalize and show nonergodic time evolution. We experimentally observed this nonergodic evolution for interacting fermions in a one-dimensional quasirandom optical lattice and identified the MBL transition through the relaxation dynamics of an initially prepared charge density wave. For sufficiently weak disorder, the time evolution appears ergodic and thermalizing, erasing all initial ordering, whereas above a critical disorder strength, a substantial portion of the initial ordering persists. The critical disorder value shows a distinctive dependence on the interaction strength, which is in agreement with numerical simulations. Our experiment paves the way to further detailed studies of MBL, such as in noncorrelated disorder or higher dimensions. PMID- 26229111 TI - Characterization of Aes nuclear foci in colorectal cancer cells. AB - Amino-terminal enhancer of split (Aes) is a member of Groucho/Transducin-like enhancer (TLE) family. Aes is a recently found metastasis suppressor of colorectal cancer (CRC) that inhibits Notch signalling, and forms nuclear foci together with TLE1. Although some Notch-associated proteins are known to form subnuclear bodies, little is known regarding the dynamics or functions of these structures. Here, we show that Aes nuclear foci in CRC observed under an electron microscope are in a rather amorphous structure, lacking surrounding membrane. Investigation of their behaviour during the cell cycle by time-lapse cinematography showed that Aes nuclear foci dissolve during mitosis and reassemble after completion of cytokinesis. We have also found that heat shock cognate 70 (HSC70) is an essential component of Aes foci. Pharmacological inhibition of the HSC70 ATPase activity with VER155008 reduces Aes focus formation. These results provide insight into the understanding of Aes-mediated inhibition of Notch signalling. PMID- 26229113 TI - BIOSAFETY. Safeguarding gene drive experiments in the laboratory. PMID- 26229115 TI - Transmission of innate immune signaling by packaging of cGAMP in viral particles. AB - Infected cells detect viruses through a variety of receptors that initiate cell intrinsic innate defense responses. Cyclic guanosine monophosphate (GMP) adenosine monophosphate (AMP) synthase (cGAS) is a cytosolic sensor for many DNA viruses and HIV-1. In response to cytosolic viral DNA, cGAS synthesizes the second messenger 2'3'-cyclic GMP-AMP (cGAMP), which activates antiviral signaling pathways. We show that in cells producing virus, cGAS-synthesized cGAMP can be packaged in viral particles and extracellular vesicles. Viral particles efficiently delivered cGAMP to target cells. cGAMP transfer by viral particles to dendritic cells activated innate immunity and antiviral defenses. Finally, we show that cell-free murine cytomegalovirus and Modified Vaccinia Ankara virus contained cGAMP. Thus, transfer of cGAMP by viruses may represent a defense mechanism to propagate immune responses to uninfected target cells. PMID- 26229118 TI - Introductory paragraph. PMID- 26229114 TI - HIV-1 VACCINES. Diversion of HIV-1 vaccine-induced immunity by gp41-microbiota cross-reactive antibodies. AB - An HIV-1 DNA prime vaccine, with a recombinant adenovirus type 5 (rAd5) boost, failed to protect from HIV-1 acquisition. We studied the nature of the vaccine induced antibody (Ab) response to HIV-1 envelope (Env). HIV-1-reactive plasma Ab titers were higher to Env gp41 than to gp120, and repertoire analysis demonstrated that 93% of HIV-1-reactive Abs from memory B cells responded to Env gp41. Vaccine-induced gp41-reactive monoclonal antibodies were non-neutralizing and frequently polyreactive with host and environmental antigens, including intestinal microbiota (IM). Next-generation sequencing of an immunoglobulin heavy chain variable region repertoire before vaccination revealed an Env-IM cross reactive Ab that was clonally related to a subsequent vaccine-induced gp41 reactive Ab. Thus, HIV-1 Env DNA-rAd5 vaccine induced a dominant IM-polyreactive, non-neutralizing gp41-reactive Ab repertoire response that was associated with no vaccine efficacy. PMID- 26229116 TI - Growth dynamics of gut microbiota in health and disease inferred from single metagenomic samples. AB - Metagenomic sequencing increased our understanding of the role of the microbiome in health and disease, yet it only provides a snapshot of a highly dynamic ecosystem. Here, we show that the pattern of metagenomic sequencing read coverage for different microbial genomes contains a single trough and a single peak, the latter coinciding with the bacterial origin of replication. Furthermore, the ratio of sequencing coverage between the peak and trough provides a quantitative measure of a species' growth rate. We demonstrate this in vitro and in vivo, under different growth conditions, and in complex bacterial communities. For several bacterial species, peak-to-trough coverage ratios, but not relative abundances, correlated with the manifestation of inflammatory bowel disease and type II diabetes. PMID- 26229117 TI - Viruses transfer the antiviral second messenger cGAMP between cells. AB - Cyclic GMP-AMP synthase (cGAS) detects cytosolic DNA during virus infection and induces an antiviral state. cGAS signals by synthesis of a second messenger, cyclic GMP-AMP (cGAMP), which activates stimulator of interferon genes (STING). We show that cGAMP is incorporated into viral particles, including lentivirus and herpesvirus virions, when these are produced in cGAS-expressing cells. Virions transferred cGAMP to newly infected cells and triggered a STING-dependent antiviral program. These effects were independent of exosomes and viral nucleic acids. Our results reveal a way by which a signal for innate immunity is transferred between cells, potentially accelerating and broadening antiviral responses. Moreover, infection of dendritic cells with cGAMP-loaded lentiviruses enhanced their activation. Loading viral vectors with cGAMP therefore holds promise for vaccine development. PMID- 26229119 TI - Adaptive intervention design in mobile health: Intervention design and development in the Cell Phone Intervention for You trial. AB - BACKGROUND/AIMS: The obesity epidemic has spread to young adults, and obesity is a significant risk factor for cardiovascular disease. The prominence and increasing functionality of mobile phones may provide an opportunity to deliver longitudinal and scalable weight management interventions in young adults. The aim of this article is to describe the design and development of the intervention tested in the Cell Phone Intervention for You study and to highlight the importance of adaptive intervention design that made it possible. The Cell Phone Intervention for You study was a National Heart, Lung, and Blood Institute sponsored, controlled, 24-month randomized clinical trial comparing two active interventions to a usual-care control group. Participants were 365 overweight or obese (body mass index>=25 kg/m2) young adults. METHODS: Both active interventions were designed based on social cognitive theory and incorporated techniques for behavioral self-management and motivational enhancement. Initial intervention development occurred during a 1-year formative phase utilizing focus groups and iterative, participatory design. During the intervention testing, adaptive intervention design, where an intervention is updated or extended throughout a trial while assuring the delivery of exactly the same intervention to each cohort, was employed. The adaptive intervention design strategy distributed technical work and allowed introduction of novel components in phases intended to help promote and sustain participant engagement. Adaptive intervention design was made possible by exploiting the mobile phone's remote data capabilities so that adoption of particular application components could be continuously monitored and components subsequently added or updated remotely. RESULTS: The cell phone intervention was delivered almost entirely via cell phone and was always-present, proactive, and interactive-providing passive and active reminders, frequent opportunities for knowledge dissemination, and multiple tools for self-tracking and receiving tailored feedback. The intervention changed over 2 years to promote and sustain engagement. The personal coaching intervention, alternatively, was primarily personal coaching with trained coaches based on a proven intervention, enhanced with a mobile application, but where all interactions with the technology were participant-initiated. CONCLUSION: The complexity and length of the technology-based randomized clinical trial created challenges in engagement and technology adaptation, which were generally discovered using novel remote monitoring technology and addressed using the adaptive intervention design. Investigators should plan to develop tools and procedures that explicitly support continuous remote monitoring of interventions to support adaptive intervention design in long-term, technology-based studies, as well as developing the interventions themselves. PMID- 26229120 TI - Anti-CD20 Therapy Acts via FcgammaRIIIA to Diminish Responsiveness of Human Natural Killer Cells. AB - Natural killer (NK) immune cells mediate antibody-dependent cellular cytotoxicity (ADCC) by aggregating FcgammaRIIIA/CD16, contributing significantly to the therapeutic effect of CD20 monoclonal antibodies (mAb). In this study, we show that CD16 ligation on primary human NK cells by the anti-CD20 mAb rituximab or ofatumumab stably impairs the spontaneous cytotoxic response attributable to cross-tolerance of several unrelated NK-activating receptors (including NKG2D, DNAM-1, NKp46, and 2B4). Similar effects were obtained from NK cells isolated from patients with chronic lymphocytic leukemia in an autologous setting. NK cells rendered hyporesponsive in this manner were deficient in the ability of these cross-tolerized receptors to phosphorylate effector signaling molecules critical for NK cytotoxicity, including SLP-76, PLCgamma2, and Vav1. These effects were associated with long-lasting recruitment of the tyrosine phosphatase SHP-1 to the CD16 receptor complex. Notably, pharmacologic inhibition of SHP-1 with sodium stibogluconate counteracted CD20 mAb-induced NK hyporesponsiveness, unveiling an unrecognized role for CD16 as a bifunctional receptor capable of engendering long-lasting NK cell inhibitory signals. Our work defines a novel mechanism of immune exhaustion induced by CD20 mAb in human NK cells, with potentially negative implications in CD20 mAb-treated patients where NK cells are partly responsible for clinical efficacy. PMID- 26229121 TI - Prodding the Beast: Assessing the Impact of Treatment-Induced Metastasis. AB - The arsenal of treatments for most cancers fit broadly into the categories of surgery, chemotherapy, radiation, and targeted therapy. All represent proven and successful strategies, yet each can trigger local (tumor) and systemic (host) processes that elicit unwanted, often opposing, influences on cancer growth. Under certain conditions, nearly all cancer treatments can facilitate metastatic spread, often in parallel (and sometimes in clear contrast) with tumor reducing benefits. The paradox of treatment-induced metastasis (TIM) is not new. Supporting preclinical studies span decades, but are often overlooked. With recent evidence of prometastatic effects following treatment with targeted agents blocking the tumor microenvironment, a closer inspection of this literature is warranted. The TIM phenomena may diminish the impact of effective therapies and play a critical role in eventual resistance. Alternatively, it may simply exemplify the gap between animal and human studies, and therefore have little impact for patient disease and treatment. This review will focus on the preclinical model systems used to evaluate TIM and explore the mechanisms that influence overall treatment efficacy. Understanding the role of TIM in established and emerging drug treatment strategies may help provide rationales for future drug combination approaches with antimetastatic agents to improve outcomes and reduce resistance. PMID- 26229122 TI - 2015 Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adults. AB - These guidelines are intended for use by infectious disease specialists, orthopedic surgeons, neurosurgeons, radiologists, and other healthcare professionals who care for patients with native vertebral osteomyelitis (NVO). They include evidence and opinion-based recommendations for the diagnosis and management of patients with NVO treated with antimicrobial therapy, with or without surgical intervention. PMID- 26229124 TI - Rhytidectomy Utilizing Bidirectional Self-Retaining Sutures: The Bidirectional Lift and the Extended Bidirectional Lift. AB - This article outlines a new rhytidectomy technique, developed by the author, that utilizes bidirectional self-retaining (barbed) sutures for superficial musculoaponeurotic system (SMAS) plication and, in some instances, skin closures. Short-scar and traditional versions of the procedure are presented, and the history of purse-string SMAS plication and the advantages for using self retaining sutures in this application are discussed. PMID- 26229125 TI - Complications Associated With the Use of Autologous Costal Cartilage in Rhinoplasty: A Systematic Review. AB - BACKGROUND: Autologous costal cartilage grafts are common in rhinoplasty. To date, no formal systematic review of complications associated with autologous costal cartilage grafting in rhinoplasty exists. OBJECTIVES: The authors review current literature to examine the rates of donor and recipient site complications associated with autologous costal cartilage in rhinoplasty. METHODS: Databases (EMBASE, PubMed, MEDLINE, and Cochrane Database of Systematic Reviews) and references of pertinent articles were searched between January 1980 to July 2014 to find studies evaluating rates of complications with autologous costal cartilage grafting in rhinoplasty. These studies were then screened with specific inclusion/exclusion criteria, and data were extracted from included studies and pooled for analysis. RESULTS: A total of 21 eligible studies were included. Pooled donor site complication incidence was pneumothorax (0.1%), pleural tear (0.6%), infection (0.6%), seroma (0.6%), scar-related problems (2.9%), and severe donor site pain (0.2%). Pooled recipient site complications were as follows: warping (5.2%), infection (2.5%), displacement/extrusion (0.6%), graft fracture (0.2%), and graft resorption (0.9%). CONCLUSIONS: Autologous costal rhinoplasty remains a safe procedure, but is associated with not insignificant rates of minor recipient site complications, such as warping. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 26229127 TI - Commentary on: Histologic, Molecular, and Clinical Evaluation of Explanted Breast Prostheses, Capsules, and Acellular Dermal Matrices for Bacteria. PMID- 26229126 TI - Histologic, Molecular, and Clinical Evaluation of Explanted Breast Prostheses, Capsules, and Acellular Dermal Matrices for Bacteria. AB - BACKGROUND: Subclinical infections, manifest as biofilms, are considered an important cause of capsular contracture. Acellular dermal matrices (ADMs) are frequently used in revision surgery to prevent recurrent capsular contractures. OBJECTIVE: We sought to identify an association between capsular contracture and biofilm formation on breast prostheses, capsules, and ADMs in a tissue expander/implant (TE/I) exchange clinical paradigm. METHODS: Biopsies of the prosthesis, capsule, and ADM from patients (N = 26) undergoing TE/I exchange for permanent breast implant were evaluated for subclinical infection. Capsular contracture was quantified with Baker Grade and intramammary pressure. Biofilm formation was evaluated with specialized cultures, rtPCR, bacterial taxonomy, live:dead staining, and scanning electron microscopy (SEM). Collagen distribution, capsular histology, and ADM remodeling were quantified following fluorescent and light microscopy. RESULTS: Prosthetic devices were implanted from 91 to 1115 days. Intramammary pressure increased with Baker Grade. Of 26 patients evaluated, one patient had a positive culture and one patient demonstrated convincing evidence of biofilm morphology on SEM. Following PCR amplification 5 samples randomly selected for 16S rRNA gene sequencing demonstrated an abundance of suborder Micrococcineae, consistent with contamination. CONCLUSIONS: Our data suggest that bacterial biofilms likely contribute to a proportion, but not all diagnosed capsular contractures. Biofilm formation does not appear to differ significantly between ADMs or capsules. While capsular contracture remains an incompletely understood but common problem in breast implant surgery, advances in imaging, diagnostic, and molecular techniques can now provide more sophisticated insights into the pathophysiology of capsular contracture. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 26229128 TI - Lipomodeling: An Innovative Approach to Global Volumetric Rejuvenation of the Hand. AB - BACKGROUND: Rejuvenation of the hand, particularly the dorsum, has garnered increased attention because of its unique aesthetic importance. Various methods have been advocated for achieving optimal aesthetic results. OBJECTIVES: The authors describe their experience applying lipotransfer to total hand rejuvenation, including rejuvenation of the radial and ulnar aspects of the fingers. METHODS: The authors conducted a retrospective review of 22 women who underwent global hand rejuvenation by lipotransfer. Aesthetic outcomes were assessed objectively by serial photography and subjectively by patient self assessments. RESULTS: No major postoperative complications were observed. Of 22 patients, 21 indicated that they were "satisfied" or "very satisfied" with the procedure. Plastic surgeons noted improvement in the aesthetic appearance of the hands after treatment. CONCLUSIONS: Global hand rejuvenation should aim to restore volume and reduce skin laxity to reverse the signs of extrinsic aging. The fingers represent almost 50% of the length of the hand and should be included in treatments to achieve optimal aesthetic outcomes. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 26229129 TI - Commentary on: The Fountain of Stem Cell-Based Youth? Online Portrayals of Anti Aging Stem Cell Technologies. PMID- 26229130 TI - Analysis of Cosmetic Topics on the Plastic Surgery In-Service Training Exam. AB - BACKGROUND: The Plastic Surgery In-Service Training Exam (PSITE) is a multiple choice examination taken by plastic surgery trainees to provide an assessment of plastic surgery knowledge. OBJECTIVE: The purpose of this study was to evaluate cosmetic questions and determine overlap with national procedural data. METHODS: Digital syllabi of six consecutive PSITE administrations (2008-2013) were analyzed for cosmetic surgery topics. Questions were classified by taxonomy, focus, anatomy, and procedure. Answer references were tabulated by source. Relationships between tested material and national procedural volume were assessed via Pearson correlation. RESULTS: 301 questions addressed cosmetic topics (26% of all questions) and 20 required image interpretations (7%). Question-stem taxonomy favored decision-making (40%) and recall (37%) skills over interpretation (23%, P < .001). Answers focused on treatments/outcomes (67%) over pathology/anatomy (20%) and diagnoses (13%, P < .001). Tested procedures were largely surgical (85%) and focused on the breast (25%), body (18%), nose (13%), and eye (10%). The most common surgeries were breast augmentation (12%), rhinoplasty (11%), blepharoplasty (10%), and body contouring (6%). Minimally invasive procedures were lasers (5%), neuromodulators (4%), and fillers (3%). Plastic and Reconstructive Surgery (58%), Clinics in Plastic Surgery (7%), and Aesthetic Surgery Journal (6%) were the most cited journals, with a median 5-year publication lag. There was poor correlation between PSITE content and procedural volume data (r(2) = 0.138, P = .539). CONCLUSIONS: Plastic surgeons receive routine evaluation of cosmetic surgery knowledge. These data may help optimize clinical and didactic experiences for training in cosmetic surgery. PMID- 26229131 TI - Commentary on: Analysis of Cosmetic Topics on the Plastic Surgery In-Service Training Exam. PMID- 26229133 TI - Development and Validation of a Clinical Assessment Tool for Platysmal Banding in Cervicomental Aesthetics of the Female Neck. AB - BACKGROUND: In facial aesthetics, grading systems are useful tools for planning aesthetic procedures. One key component of rejuvenation--the anterior neck--has been relatively overlooked. In the 1980s, criteria were established for the appearance of a youthful neck. Considering the significant contribution of the anterior neck to the aesthetics of the lower face, updated and more extensive clinical evaluation tools are critical to successful execution and measurement of rejuvenation. A validated assessment scale has yet to be created for platysmal banding, one component of the anterior neck that significantly contributes to the aesthetics. OBJECTIVES: The purpose of this study was to establish a validated platysmal banding scale for clinical application. METHODS: Three-dimensional standardized photographs from over 100 volunteer patients of various ages and ethnicities were analyzed to develop a five-point scale for platysmal banding. The scale was validated by a group of academic and nonacademic attending plastic surgeons as well as senior level plastic surgery residents then analyzed through a two stage process to ensure both interrater and intrarater validity. RESULTS: We measured the Intraclass Correlation Coefficients (ICC) for the interrater reliability. ICCs ranged from moderate to excellent agreement. Cronbach's alpha, which represents intrarater reliability, was also calculated for the same sample with all results being good to excellent. CONCLUSIONS: This study established a validated scale to assess the degree of platysmal banding in the female neck. This grading system has potential application in the preprocedure planning for patients considering face and neck rejuvenation to address platysmal banding. PMID- 26229134 TI - Ptosis: An Underestimated Complication after Autologous Fat Injection into the Upper Eyelid. AB - BACKGROUND: Autologous fat injection into the upper eyelid is a commonly used technique in plastic surgery for volume restoration. However, ptosis, as one of the potential complications of the procedure, has been less well-discussed than other complications. OBJECTIVE: To present five cases of ptosis after autologous fat injection for the correction of sunken eyelid deformity and explore its causes. METHODS: In this retrospective, non-comparative, and interventional case series, we identified five patients with ptosis. All patients had a history of previous autologous fat injection into the upper eyelid, performed by different plastic surgeons. Preoperative, intraoperative, and postoperative photographs were taken to analyze the causes of ptosis. RESULTS: Five patients developed ptosis after autologous fat injection for upper eyelid augmentation and were referred to our group for treatment. Three of the patients had received two injections of autologous fat each. Grafted fat removal with or without levator aponeurosis advancement was required in all five cases. CONCLUSIONS: Ptosis can develop following autologous fat injection into the upper eyelid. Surgeons should be aware of this complication, which rarely manifests during the procedure itself. Techniques for performing autologous fat injection and knowledge of upper eyelid anatomy should be refined to avoid postprocedural ptosis. LEVEL OF EVIDENCE: 5 Risk. PMID- 26229135 TI - Nipple Reduction With the Chullo-Hat Technique. AB - BACKGROUND: Although various techniques of nipple reduction have been described in the literature, many are difficult to design or have unreliable outcomes. For men, as well as women who do not plan to breastfeed, it is not necessary to apply a complicated technique that protects the lactiferous ducts. OBJECTIVES: The authors introduce a simple technique for nipple reduction that has achieved consistent, reproducible results. METHODS: The desired nipple length is marked, and a chullo-hat excision pattern is drawn. After infiltration of a local anesthetic solution around the nipple, excision of the excess nipple tissue is performed, comprising 2 triangular flaps. The remaining 2 pillars are approximated with 5-0 Nylon simple interrupted sutures. However, the wound is not completely closed in the central area of the nipple, which promotes the drainage of discharge. RESULTS: Fifty-three women (106 nipples) underwent this surgery between December 2009 and December 2013. The follow-up period ranged from 6 months to 2 years (mean, 10 months). No major complications occurred, and the scars were very inconspicuous. The postoperative appearance of nipples was consistently similar in size and shape. CONCLUSIONS: This simple technique was safe and effective in nipples of different sizes. The results were reliable and consistent with expectations. Although this study included only women, the authors believe that outcomes would be successful in men as well. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 26229136 TI - Silicone Breast Implant Skewered by a Ventriculoperitoneal Shunt with Secondary Cerebrospinal Fluid Pseudocyst. PMID- 26229138 TI - Trimethylamine N-Oxide as a Novel Therapeutic Target in CKD. PMID- 26229137 TI - Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden. AB - Trimethlyamine-N-oxide (TMAO) was recently identified as a promoter of atherosclerosis. Patients with CKD exhibit accelerated development of atherosclerosis; however, no studies have explored the relationship between TMAO and atherosclerosis formation in this group. This study measured serum concentrations and urinary excretion of TMAO in a CKD cohort (n=104), identified the effect of renal transplant on serum TMAO concentration in a subset of these patients (n=6), and explored the cross-sectional relationship between serum TMAO and coronary atherosclerosis burden in a separate CKD cohort (n=220) undergoing coronary angiography. Additional exploratory analyses examined the relationship between baseline serum TMAO and long-term survival after coronary angiography. Serum TMAO concentrations demonstrated a strong inverse association with eGFR (r(2)=0.31, P<0.001). TMAO concentrations were markedly higher in patients receiving dialysis (median [interquartile range], 94.4 MUM [54.8-133.0 MUM] for dialysis-dependent patients versus 3.3 MUM [3.1-6.0 MUM] for healthy controls; P<0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min-max] 71.2 MUM [29.2-189.7 MUM] pretransplant versus 11.4 MUM [8.9-20.2 MUM] post-transplant; P=0.03). TMAO concentration was an independent predictor for coronary atherosclerosis burden (P=0.02) and predicted long-term mortality independent of traditional cardiac risk factors (hazard ratio, 1.26 per 10 MUM increment in TMAO concentration; 95% confidence interval, 1.13 to 1.40; P<0.001). In conclusion, serum TMAO concentrations substantially increase with decrements in kidney function, and this effect is reversed by renal transplantation. Increased TMAO concentrations correlate with coronary atherosclerosis burden and may associate with long-term mortality in patients with CKD undergoing coronary angiography. PMID- 26229139 TI - BMP9 Induces Cord Blood-Derived Endothelial Progenitor Cell Differentiation and Ischemic Neovascularization via ALK1. AB - OBJECTIVE: Modulating endothelial progenitor cells (EPCs) is essential for therapeutic angiogenesis, and thus various clinical trials involving EPCs are ongoing. However, the identification of environmental conditions and development of optimal methods are required to accelerate EPC-driven vasculogenesis. APPROACH AND RESULTS: We evaluated gene expression profiles of cord blood-derived EPCs and endothelial cells to identify the key factors in EPC->endothelial cell differentiation and to show that transforming growth factor-beta family members contribute to EPC differentiation. The expression levels of activin receptor-like kinase 1 (ALK1) and its high-affinity ligand, bone morphogenetic protein 9 (BMP9) were markedly changed in EPC->endothelial cell differentiation. Interestingly, BMP9 induced EPC->endothelial cell differentiation and EPC incorporation into vessel-like structures by acting on ALK1 expressed on EPCs in vitro. BMP9 also induced neovascularization in mice with hindlimb ischemia by increasing vessel formation and the incorporation of EPCs into vessels. Conversely, neovascularization was impaired when ALK1 signaling was blocked. Furthermore, EPCs exposed to either short- or long-term BMP9 stimulation demonstrated these functions in EPC-mediated neovascularization. CONCLUSIONS: Collectively, our results indicated that BMP9/ALK1 augmented vasculogenesis and angiogenesis, and thereby enhanced neovascularization. Thus, we suggest that BMP9/ALK1 may improve the efficacy of EPC-based therapies for treating ischemic diseases. PMID- 26229140 TI - Targeted Knockdown of Hepatic SOAT2 With Antisense Oligonucleotides Stabilizes Atherosclerotic Plaque in ApoB100-only LDLr-/- Mice. AB - OBJECTIVE: To test the hypothesis that the attenuation of cholesterol oleate packaging into apoB-containing lipoproteins will arrest progression of pre existing atherosclerotic lesions. APPROACH AND RESULTS: Atherosclerosis was induced in apoB-100 only, LDLr(-/-) mice by feeding a diet enriched in cis monounsaturated fatty acids for 24 weeks. A subset of mice was then euthanized to quantify the extent of atherosclerosis. The remaining mice were continued on the same diet (controls) or assigned to the following treatments for 16 weeks: (1) a diet enriched in n-3 polyunsaturated fatty acids, (2) the cis-monounsaturated fatty acid diet plus biweekly injections of an antisense oligonucleotide specific to hepatic sterol-O-acyltransferase 2 (SOAT2); or (3) the cis-monounsaturated fatty acid diet and biweekly injections of a nontargeting hepatic antisense oligonucleotide. Extent of atherosclerotic lesions in the aorta was monitored morphometrically in vivo with magnetic resonance imaging and ex vivo histologically and immunochemically. Hepatic knockdown of SOAT2 via antisense oligonucleotide treatment arrested lesion growth and stabilized lesions. CONCLUSIONS: Hepatic knockdown of SOAT2 in apoB100-only, LDLr(-/-) mice resulted in remodeling of aortic atherosclerotic lesions into a stable phenotype, suggesting SOAT2 is a viable target for the treatment of atherosclerosis. PMID- 26229141 TI - 18F-FDG PET Is an Early Predictor of Overall Survival in Suspected Atypical Parkinsonism. AB - Early prognostic stratification is desirable in patients with suspected atypical parkinsonian syndromes (APSs) for optimal treatment and counseling. We investigated the prognostic value of imaging disease-specific metabolism patterns with 18F-FDG PET compared with that of clinical diagnosis. METHODS: Seventy-eight patients with suspected APS at study inclusion underwent a follow-up of up to 5.9 y after prospective 18F-FDG PET imaging. Survival data were analyzed by Kaplan Meier and Cox regression analyses according to diagnostic classifications provided by 18F-FDG PET at baseline and clinical diagnoses after a median follow up of 1 y after PET. RESULTS: Forty-four of 78 patients were alive 4.7+/-0.6 y after PET. Patients diagnosed with an APS by PET or 1-y clinical follow-up showed a significantly shorter median survival time (4.1 y, age-adjusted hazard ratios [HRs]=3.8 for both classifiers) than those diagnosed with Lewy-body diseases (LBDs; majority Parkinson disease [PD]; median survival time not reached). Subgroup classifications of progressive supranuclear palsy/corticobasal degeneration (PSP/CBD) or multiple-system atrophy (MSA) by PET and clinical follow-up were associated with significantly shorter survival than PD. Age adjusted mortality was significantly increased for PSP/CBD (HR=5.2) and MSA (HR=5.6) classified by PET, but for PSP/CBD only when diagnosed by clinical follow-up (HR=4.5). Patients with a PET pattern suggestive of PD with dementia/dementia with Lewy bodies (PDD/DLB) exhibited a trend toward shorter survival than those with PD (P=0.07), whereas patients classified as PDD/DLB by clinical follow-up did not (P=0.65). CONCLUSION: 18F-FDG PET is an early predictor of survival in patients with clinically suspected APS. Detection of cortical or subcortical hypometabolism by 18F-FDG PET is an unfavorable predictor. Risk stratification by 18F-FDG PET appears to be at least as predictive as the 1-y follow-up clinical diagnosis. This finding strongly supports the early inclusion of PET imaging in patient care. PMID- 26229142 TI - Quantification, Variability, and Reproducibility of Basal Skeletal Muscle Glucose Uptake in Healthy Humans Using 18F-FDG PET/CT. AB - The quantification and variability of skeletal muscle glucose utilization (SMGU) in healthy subjects under basal (low insulin) conditions are poorly known. This information is essential early in clinical drug development to effectively interrogate novel pharmacologic interventions that modulate glucose uptake. The aim of this study was to determine test-retest characteristics and variability of SMGU within and between healthy subjects under basal conditions. Furthermore, different kinetic modeling strategies were evaluated to find the best-fitting model to assess SMGU studied by 18F-FDG. METHODS: Six healthy male volunteers underwent 2 dynamic 18F-FDG PET/CT scans with an interval of 24 h. Subjects were admitted to the clinical unit to minimize variability in daily activities and food intake and restrict physical activity. 18F-FDG PET/CT scans of gluteal and quadriceps muscle area were obtained with arterial input. Regions of interest were drawn over the muscle area to obtain time-activity curves and standardized uptake values (SUVs) between 60 and 90 min. Spectral analysis of the data and kinetic modeling was performed using 2-tissue-irreversible (2T3K), 2-tissue reversible, and 3-tissue-sequential-irreversible (3T5KS) models. Reproducibility was assessed by intraclass correlation coefficients (ICCs) and within-subject coefficient of variation (WSCV). RESULTS: SUVs in gluteal and quadriceps areas were 0.56+/-0.09 and 0.64+/-0.07. ICCs (with 90% confidence intervals in parentheses) were 0.88 (0.64-0.96) and 0.96 (0.82-0.99), respectively, for gluteal and quadriceps muscles, and WSCV for gluteal and quadriceps muscles was 2.2% and 3.6%, respectively. The rate of glucose uptake into muscle was 0.0016+/ 0.0004 mL/mL?min, with an ICC of 0.94 (0.93-0.95) and WSCV of 6.6% for the 3T5KS model, whereas an ICC of 0.98 (0.92-1.00) and WSCV of 2.8% was obtained for the 2T3K model. 3T5KS demonstrated the best fit to the measured experimental points. CONCLUSION: Minimal variability in skeletal muscle glucose uptake was observed under basal conditions in healthy subjects. SUV measurements and rate of glucose uptake values were reproducible, with an average WSCV of less than 5%. Compared with SUV, the 3-tissue model adds information about kinetics between blood, intra and intercellular compartments, and phosphorylation that may highlight the exact mechanisms of metabolic changes after pharmacologic intervention. PMID- 26229143 TI - Current Status of Nuclear Medicine Practice in Latin America and the Caribbean. AB - The practice of nuclear medicine (NM) in the Latin American and Caribbean region has experienced important growth in the last decade. However, there is great heterogeneity among countries regarding the availability of technology and human resources. According to data collected through June 2014 by the International Atomic Energy Agency (IAEA), the total number of gamma cameras in the region is 1,231, with an average of 2.16 per million inhabitants. Over 90% of the equipment is SPECT cameras; 7.6% of which have hybrid technology. There are 161 operating PET or PET/CT cameras in 12 member states, representing a rate of 0.3 per million people. Most NM centers belong to the private health system and are in capitals or major cities. Only 4 countries have the capability of assembling 99Mo-99mTc generators, and 2 countries produce 99mTc from nuclear reactors. Cold kits are produced in some countries, and therapeutic agents are mostly imported from outside the region. There are 35 operative cyclotrons. In relation to human resources: there is 1 physician per gamma camera, 1.6 technologists per gamma camera, 0.1 medical physicist per center, and approximately 0.1 radiochemist or radiopharmacist per center. Nearly 94% of the procedures are diagnostic. PET studies represent about 4% of the total. The future of NM in the Latin American and Caribbean region is promising, with great potential and possibilities. Some of the most important factors driving the region toward greater homogeneity in the availability and application of NM, and bridging the gaps between countries, are clinician awareness of the importance of NM in managing diseases prevalent in the region, increased building of capacity, continuous and strong support from international organizations such as the IAEA through national and regional projects, and strong public-private partnerships and government commitment. PMID- 26229144 TI - Estimation of Tumor Volumes by 11C-MeAIB and 18F-FDG PET in an Orthotopic Glioblastoma Rat Model. AB - Brain tumor volume assessment is a major challenge. Molecular imaging using PET may be a promising option because it reflects the biologically active cells. We compared the agreement between PET- and histology-derived tumor volumes in an orthotopic glioblastoma rat model with a noninfiltrating (U87MG) and an infiltrating (T87) tumor phenotype using 2 different radiotracers, 2 different image reconstruction algorithms, parametric imaging, and 2 different image segmentation techniques. METHODS: Rats with U87MG- and T87-derived glioblastomas were continuously scanned with PET for 1 h starting immediately after the injection of 11C-methylaminoisobutyric acid (11C-MeAIB). One hour later, 18F-FDG was injected, followed by a 3-h dynamic PET scan. Images were reconstructed using 2-dimensional ordered-subsets expectation maximization and 3-dimensional maximum a posteriori probability (MAP3D) algorithms. In addition, a parametric image, encompassing the entire tumor kinetics in a single image, was calculated on the basis of the 11C-MeAIB images. All reconstructed images were segmented by fixed thresholding of maximum voxel intensity (VImax) and mean background intensity. The agreement between PET- and histology-derived tumor volumes and intra- and interobserver agreement of the PET-derived volumes were evaluated using Bland Altman plots. RESULTS: By PET, the mean U87MG tumor volume was 35.0 mm3 using 18F FDG and 34.1 mm3 with 11C-MeAIB, compared with 33.7 mm3 by histology. Corresponding T87 tumor volumes were 122.1 mm3 using 18F-FDG, 118.3 mm3 with 11C MeAIB, and 125.4 mm3 by histology. None of these volumes were significantly different. The best agreement between PET- and histology-derived U87MG tumor volumes was achieved with 11C-MeAIB, MAP3D reconstruction, and fixed thresholding of VImax. The intra- and interobserver agreement was high using this method. For T87 tumors, the best agreement between PET- and histology-derived volumes was obtained using 18F-FDG, MAP3D reconstruction, and fixed thresholding of mean background intensity. The agreement using 11C-MeAIB, parametric imaging, and fixed thresholding of VImax was slightly inferior, but the intra- and interobserver agreement was clearly superior. CONCLUSION: Estimation of tumor volume by PET of noninfiltrating brain tumors was accurate and reproducible. In contrast, tumor volume estimation by PET of infiltrating brain tumors was difficult and hard to reproduce. On the basis of our results, PET evaluation of highly infiltrating brain tumors should be further developed. PMID- 26229145 TI - Impact of Image Reconstruction Settings on Texture Features in 18F-FDG PET. AB - Evaluation of tumor heterogeneity based on texture parameters has recently attracted much interest in the PET imaging community. However, the impact of reconstruction settings on texture parameters is unclear, especially relating to time-of-flight and point-spread function modeling. Their effects on 55 texture features (TFs) and 6 features based on first-order statistics (FOS) were investigated. Standardized uptake value (SUV) measures were also evaluated as peak SUV (SUVpeak), maximum SUV, and mean SUV (SUVmean). METHODS: This study retrospectively recruited 20 patients with lesions in the lung who underwent whole-body (18)F-FDG PET/CT. The coefficient of variation (COV) of each feature across different reconstructions was calculated. RESULTS: SUVpeak, SUVmean, 18 TFs, and 1 FOS were the most robust (COV <= 5%) whereas skewness, cluster shade, and zone percentage were the least robust (COV > 20%) with respect to reconstruction algorithms using default settings. Heterogeneity parameters had different sensitivities to iteration number. Twenty-four parameters including SUVpeak and SUVmean exhibited variation with a COV less than 5%; 28 parameters, including maximum SUV, showed variation with a COV in the range of 5%-10%. In addition, skewness, cluster shade, and zone percentage were the most sensitive to iteration number. In terms of sensitivity to full width at half maximum (FWHM), 15 TFs and 1 FOS had the best performance with a COV less than 5%, whereas SUVpeak and SUVmean had a COV between 5% and 10%. Grid size had the largest impact on image features, which was demonstrated by only 11 features, including SUVpeak and SUVmean, having a COV less than 10%. CONCLUSION: Different image features have different sensitivities to reconstruction settings. Iteration number and FWHM of the gaussian filter have a similar impact on the image features. Grid size has a larger impact on the features than iteration number and FWHM. The features that exhibited large variations such as skewness in FOS, cluster shade, and zone percentage should be used with caution. The entropy in FOS, difference entropy, inverse difference normalized, inverse difference moment normalized, low gray-level run emphasis, high gray-level run emphasis, and low gray-level zone emphasis are the most robust features. PMID- 26229146 TI - Use of a Single 11C-Meta-Hydroxyephedrine Scan for Assessing Flow-Innervation Mismatches in Patients with Ischemic Cardiomyopathy. AB - Mismatch between areas of reduced myocardial blood flow (MBF) and reduced myocardial innervation (defect areas) may be used to estimate the risk for ventricular arrhythmias. The presence of a mismatch zone can be derived using a combined protocol consisting of both an MBF scan and an (11)C-meta hydroxyephedrine ((11)C-HED) scan. The rate of influx from blood to myocardium (K1) of (11)C-HED is proportional to MBF and can potentially be used as an index for defining MBF defects. The aim of this study was to assess whether K1 derived from an (11)C-HED scan can be used as an index of MBF, potentially allowing for an assessment of MBF-innervation mismatch areas from a single (11)C-HED scan. METHODS: Seventeen patients with known ischemic cardiomyopathy underwent dynamic (15)O-water and (11)C-HED scans. Discrete arterial blood samples were taken during (11)C-HED scans for metabolite correction of the image-derived input function. (11)C-HED influx rate was obtained using a single-tissue-compartment model and compared with transmural MBF (MBFT), defined as MBF as measured with (15)O-water multiplied by perfusable tissue fraction. Defect sizes were obtained from parametric K1 and MBFT images, using 50% of a remote control segment as the cutoff value. RESULTS: There was a significant correlation between MBFT and K1 (y = 0.40x + 0.05 mL.g(-1).min(-1), r = 0.80, P < 0.001), although K1 was significantly lower than MBFT (slope of the regression line significantly different from 1, P < 0.001). Correlation between MBFT and K1 defect sizes was high (y = 0.89x + 1.38%, r = 0.95, P < 0.001), with no significant difference in mean defect size based on K1 or MBFT (20.9% +/- 11.3% and 20.1% +/- 10.7% for MBFT and K1, respectively, P = 0.41). CONCLUSION: (11)C-HED influx rate K1 can be used as an alternative to a separate MBF scan for assessing mismatch areas between MBF and myocardial innervation. PMID- 26229147 TI - Promising New 18F-Labeled Tracers for PET Myocardial Perfusion Imaging. PMID- 26229148 TI - Results of a Prospective Multicenter International Atomic Energy Agency Sentinel Node Trial on the Value of SPECT/CT Over Planar Imaging in Various Malignancies. AB - We aimed to assess the additional value of SPECT/CT over planar lymphoscintigraphy (PI) in sentinel node (SN) detection in malignancies with different lymphatic drainage such as breast cancer, melanoma, and pelvic tumors. METHODS: From 2010 to 2013, 1,508 patients were recruited in a multicenter study: 1,182 breast cancer, 262 melanoma, and 64 pelvic malignancies (prostate, cervix, penis, vulva). PI was followed by SPECT/CT 1-3 h after injection of (99m)Tc colloid particles. Surgery was performed the same or next day. RESULTS: Significantly more SNs were detected by SPECT/CT for breast cancer (2,165 vs. 1,892), melanoma (602 vs. 532), and pelvic cancer (195 vs. 138), all P < 0.001. The drainage basin mismatch between PI and SPECT/CT was 16.5% for breast cancer, 11.1% for melanoma, and 51.6% for pelvic cancers. Surgical adjustment was 17% for breast cancer, 37% for melanoma, and 65.6% for pelvic cancer. CONCLUSION: SPECT/CT detected more SNs and changed the drainage territory, leading to surgical adjustments in a considerable number of patients in all malignancies studied but especially in the pelvic cancer group because of this group's deep lymphatic drainage. We recommend SPECT/CT in all breast cancer patients with no SN visualized on PI, all patients with melanoma of the head and neck or trunk, all patients with pelvic malignancies, and those breast cancer and melanoma patients with unexpected drainage on PI. PMID- 26229150 TI - Bronchoalveolar galactomannan in invasive pulmonary aspergillosis: a prospective study in pediatric patients. AB - BACKGROUND: Elevations in the number of immunocompromised patients in the past decade has lead to progressive increase in the incidence of Invasive Pulmonary Aspergillosis (IPA) among children; however, early diagnosis remains a challenge. Detection of galactomannan (GM) in the bronchoalveolar lavage (BAL) fluid appears to possess higher sensitivity and specificity than serum in immunocompromised adult patients but, it rarely has been investigated in pediatric patients. METHODS: We performed a prospective case-control study to evaluate the efficacy of BAL GM in immunocompromised pediatric patients. Cases were subjects fulfilling the host factor criteria as defined by the EORTC/MSG and met established definitions for proven or probable IPA. Control group was patients with possible IPA in whom diagnoses other than IPA were confirmed and patients without risk factors of IPA who underwent bronchoscopy for other diagnostic purpose. Galactomannan testing was performed on BAL fluid samples using platelia Aspergillus seroassay. RESULTS: Sixteen cases of IPA (4 proven, 12 probable) and 54 controls (6 possible IPA and 48 no IPA) were documented according to EORTC/MSG definitions. The sensitivity and positive predictive values of BAL GM using an OD index of >=0.5 were 87.5% and 93.33% respectively. We found seven cases of IPA with negative serum GM while their BAL GM was positive. CONCLUSION: We found high diagnostic value of BAL GM in immunocompromised pediatric patients with IPA. The lower OD index is necessary in children to avoid missing the cases of IPA in children. PMID- 26229149 TI - Proteomic Analysis Reveals Distinct Metabolic Differences Between Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) and Macrophage Colony Stimulating Factor (M-CSF) Grown Macrophages Derived from Murine Bone Marrow Cells. AB - Macrophages are crucial in controlling infectious agents and tissue homeostasis. Macrophages require a wide range of functional capabilities in order to fulfill distinct roles in our body, one being rapid and robust immune responses. To gain insight into macrophage plasticity and the key regulatory protein networks governing their specific functions, we performed quantitative analyses of the proteome and phosphoproteome of murine primary GM-CSF and M-CSF grown bone marrow derived macrophages (GM-BMMs and M-BMMs, respectively) using the latest isobaric tag based tandem mass tag (TMT) labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Strikingly, metabolic processes emerged as a major difference between these macrophages. Specifically, GM-BMMs show significant enrichment of proteins involving glycolysis, the mevalonate pathway, and nitrogen compound biosynthesis. This evidence of enhanced glycolytic capability in GM-BMMs is particularly significant regarding their pro-inflammatory responses, because increased production of cytokines upon LPS stimulation in GM-BMMs depends on their acute glycolytic capacity. In contrast, M-BMMs up-regulate proteins involved in endocytosis, which correlates with a tendency toward homeostatic functions such as scavenging cellular debris. Together, our data describes a proteomic network that underlies the pro-inflammatory actions of GM-BMMs as well as the homeostatic functions of M-BMMs. PMID- 26229151 TI - Cryptococcus neoformans in the respiratory tract of squirrels, Callosciurus finlaysonii (Rodentia, Sciuridae). AB - Cryptococcosis is a fungal disease acquired from the environment, for which animals may serve as sentinels for human exposure. The occurrence of Cryptococcus spp. in the respiratory tract of 125 squirrels, Callosciurus finlaysonii, trapped in Southern Italy, was assessed. Upon examination of nasal swabs and lung tissue from each individual, a total of 13 (10.4%) animals scored positive for yeasts, 7 for Cryptococcus neoformans (C.n.) (5.6%) and 6 for other yeasts (4.8%). C.n. was isolated from the nostrils and lungs, with a high population size in nostrils. Two C.n. molecular types, VNI and VNIV, were identified, with C.n. var. grubii VNI the most prevalent. Phylogenetic analyses of ITS+ and URA5 sequences revealed that C.n. isolates were genetically similar to isolates from a range of geographical areas and hosts. Results suggest that C.n. can colonize or infect the respiratory tract of C. finlaysonii. The high occurrence and level of colonization of nasal cavities might be an indicator of environmental exposure to high levels of airborne microorganism. The close phylogenetic relationship of C.n. strains from squirrels with those from human and other animal hosts suggests a potential role for these animals as "sentinels" for human exposure. PMID- 26229152 TI - Environmental sampling reveals that Pythium insidiosum is ubiquitous and genetically diverse in North Central Florida. AB - Pythiosis is a deadly disease of horses, dogs, and other mammals, including humans, in tropical and subtropical regions. In the United States, the disease has been reported in the Southeast as well as in the temperate North and the dry Southwest. The causal agent of pythiosis is Pythium insidiosum, one of few mammalian pathogens in the fungus-like Oomycetes. P. insidiosum has not been studied in the environment in the United States. Given anecdotal reports of pythiosis in Gainesville, Florida dogs, we hypothesized that warm standing water in lakes and ponds in North Central Florida is suitable habitat for P. insidiosum. We sampled 19 lakes or ponds to examine the environmental distribution of P. insidiosum and to determine which of the three previously described genetic clusters of P. insidiosum are present. We found P. insidiosum in 11 of the sampled lakes and ponds. Sequencing of the ITS region separated isolates into three genetic clusters, including a distinct group previously represented by a single isolate from South Carolina. AFLP genotyping of isolates showed genetic variation in Cluster I, which is the group associated with the majority of characterized clinical isolates from the Americas. Our results indicate that animal exposure to P. insidiosum in North Central Florida is common. This study provides the first evidence that P. insidiosum may be more widely distributed in freshwater lakes and ponds in the Southeastern United States than previously appreciated. PMID- 26229153 TI - Epidemiology and risk factors for nosocomial Non-Candida albicans candidemia in adult patients at a tertiary care hospital in North China. AB - Nosocomial candidemia extends the length of hospital stay, increases the costs of medical care, and is associated with a high mortality rate. Epidemiological data that assist in the choice of initial therapy may help to improve the prognosis. The present study was undertaken to investigate the epidemiology of nosocomial candidemia and identify risk factors for nosocomial candidemia caused by C. albicans and non-albicans Candida species (NAC). A retrospective chart review was undertaken to analyze cases of nosocomial candidemia treated at the Beijing Friendship Hospital between January 2008 and December 2012. All cases of candidemia were identified using the previously published criteria. Among 106 patients analyzed, 53.8% had nosocomial candidemia caused by NAC. Candida albicans was the most common causative agent, accounting for 46.2% of all cases, followed by C. glabrata (25.5%), C. tropicalis (15.1%), C. parapsilosis (10.4%) and C. Krusei (0.9%). Comparison of nosocomial C. albicans and NAC candidemia by multivariate logistic regression showed that factors independently associated with nosocomial NAC candidemia included exposure to azole agents (odds ratio [OR]: 3.359; 95% confidence interval [CI]: 1.136-10.154; P = .031) and artificial surgical implants (OR: 37.519; 95% CI: 2.5-562.998; P = .009). A significant risk factor for nosocomial C. albicans candidemia was cancer surgery (OR: 0.075; 95% CI: 0.013-0.437; P = .004). Clinical and epidemiological differences in the risk factors between nosocomial candidemia caused by C. albicans and NAC should be considered when selecting an initial antifungal regimen for the treatment of adult patients. This should be undertaken before the availability of species identification and/or antifungal susceptibility results. PMID- 26229154 TI - Assembly of hair bundles, an amazing problem for cell biology. AB - The hair bundle--the sensory organelle of inner-ear hair cells of vertebrates- exemplifies the ability of a cell to assemble complex, elegant structures. Proper construction of the bundle is required for proper mechanotransduction in response to external forces and to transmit information about sound and movement. Bundles contain tightly controlled numbers of actin-filled stereocilia, which are arranged in defined rows of precise heights. Indeed, many deafness mutations that disable hair-cell cytoskeletal proteins also disrupt bundles. Bundle assembly is a tractable problem in molecular and cellular systems biology; the sequence of structural changes in stereocilia is known, and a modest number of proteins may be involved. PMID- 26229155 TI - Prophylactic antibiotics in orthopedic surgery: Controversial issues in its use. PMID- 26229156 TI - Percutaneous vertebroplasty and percutaneous balloon kyphoplasty for osteoporotic vertebral compression fracture: A metaanalysis. AB - BACKGROUND: Osteoporotic vertebral compression fracture (OVCF) is the most common complication of osteoporosis, however, debate persists over which procedure of percutaneous vertebroplasty (PVP) or balloon kyphoplasty (BKP) is a better treatment. We performed a metaanalysis of prospective, randomized controlled and clinical controlled trials of PVP and BKP to determine the efficacy and safety for the treatment of OVCFs to reach a relatively conclusive answer. MATERIALS AND METHODS: We searched computerized databases comparing efficacy and safety of PVP and BKP in osteoporotic vertebral compression fractures. These reports included pain relief, functional capacity (Oswestry disability index [ODI] score), anterior vertebral body height (AVBH), kyphotic angle and complications (i.e. cement leakage, incident fractures). Studies were assessed for methodological bias and potential reasons for heterogeneity were explored. RESULTS: As of March 15, 2013, a PubMed search resulted in 761 articles, of which eleven studies encompassing 789 patients, met the inclusion criteria. The average length of followup is 17 months and 4.6% patients were lost to followup. Results of metaanalysis indicated that BKP is more effective for short term pain relief. In addition, BKP is more effective to restore the AVBH (anterior vertebral body height), ODI and kyphotic angle of OVCFs. Moreover, BKP need more polymethylmethacrylate amount. CONCLUSIONS: In terms of better effectiveness of BKP procedure, we believe BKP to be superior over PVP for the treatment of osteoporotic VCFs. PMID- 26229157 TI - Safe corridors for K-wiring in phalangeal fractures. AB - BACKGROUND: Unstable phalangeal fractures are commonly treated with K-wire fixation. Operative fixation must be used judiciously and with the expectation that the ultimate outcome should be better than the outcome after nonoperative management. It is necessary to achieve a stable fracture fixation and early mobilization. In order to achieve this goal, one should closely understand the safe portals/corridors in hand for K-wire entry for fractures of the phalanges. Safe corridors were defined and tested using a pilot cadaveric and a clinical case study by assessing the outcome. MATERIALS AND METHODS: In our prospective case series, 50 patients with 64 phalangeal fractures were treated with closed reduction and K-wires were inserted through safe portals identified by a pilot cadaveric study. On table active finger movement test was done and the results were analyed using radiology, disabilities of the arm, shoulder, and hand (DASH) score and total active motion (TAM). In our study, little finger (n = 28) was the most commonly involved digit. In fracture pattern, transverse (n = 20) and spiral (n = 20) types were common. Proximal phalanx (n = 38) was commonly involved and the common site being the base of the phalanx (n = 28). RESULTS: 47 (95%) patients had excellent TAM and the mean postoperative DASH score was 58.05. All patients achieved excellent and good scores proving the importance of the safe corridor concept. CONCLUSION: K-wiring through the safe corridor has proved to yield the best clinical results because of least tethering of soft tissues as evidenced by performing "on-table active finger movement test" at the time of surgery. We strongly recommend K-wiring through safe portals in all phalangeal fractures. PMID- 26229158 TI - Prophylactic corticosteroid injection in ulnar wrist pain in distal radius fracture. AB - BACKGROUND: Ulnar sided wrist pain is one of the most common complications of distal radius fractures. The simplest method for decreasing pain for this affliction is corticosteroid injection. The present study was designed to assess the effect of corticosteroid injection in the prevention of ulnar sided wrist pain. MATERIALS AND METHODS: In this clinical trial patients with distal radius fractures scheduled for closed reduction and percutaneous pin fixation were divided into control and corticosteroid groups. In the corticosteroid group, the patient received a single betamethasone injection in the dorsoulnar side of the wrist before reduction, while the control group received placebo. The patients were to be followed for at least 6 months. RESULTS: 82 patients were followed for 6 months. At the end of the 3 months followup the difference between the two groups about the number of individuals without ulnar sided wrist pain was statistically significant (P = 0.038), so that less patients in the control group were painless, while this was not the case in the 6 months followup (P = 0.507), but in the both time frames the mean grip power, visual analog pain score and the disabilities of the arm, shoulder and hand (DASH) score showed statistically significant difference between the two groups, so that the corticosteroid groups demonstrated greater power grip and less scores in pain and DASH (P < 0.05). CONCLUSION: Based on the findings of the present study it seems that prophylactic corticosteroid injection will be associated with a decrease in the severity of wrist pain in patients with acute distal radius fractures. With regard to the decrease in the number of painless individuals, it seems that the decrease is not persistent. Overall the need for a study with longer followup is obvious. PMID- 26229159 TI - Cast index in predicting outcome of proximal pediatric forearm fractures. AB - BACKGROUND: Many pediatric forearm fractures can be treated in plaster following closed reduction. The cast index (CI, a ratio of anteroposterior to lateral internal diameters of the cast at the fracture site) is a simple, reliable marker of quality of molding and a CI of >0.8 correlates with increased risk of redisplacement. Previously, CI has been applied to all forearm fractures. We hypothesize that an acceptable CI is more difficult to achieve and does not predict outcome in fractures of the proximal forearm. MATERIALS AND METHODS: Seventynine cases of pediatric forearm fractures initially treated by manipulation alone over a year were included in this retrospective radiographic analysis. The CI was calculated from the post manipulation radiographs. All fractures were divided as either proximal or distal half forearm based on the location of the radius fracture. Subsequent radiographs were reviewed to assess redisplacement and reoperation. RESULTS: The mean CI was 0.77. Remanipulation was required in five cases (6%), all distal half fractures - mean CI 0.79. CI was higher in proximal half forearm fractures (0.83 vs. 0.76, P = 0.006), nonetheless these fractures did not re-displace more than distal fractures. CONCLUSION: Cast index is useful in predicting redisplacement of manipulated distal forearm fractures. We found that in proximal half forearm fractures it is difficult to achieve a CI of <0.8, but increased CI does not predict loss of position in these fractures. We therefore discourage the use of CI in proximal half forearm fractures. PMID- 26229160 TI - Subungual glomus tumors of the hand: Treated by transungual excision. AB - BACKGROUND: Glomus tumors are benign hamartomas arising from the glomus body, mostly occurring in the subungual region of the digits. A triad of excruciating pain, localized tenderness and cold sensitivity is the key to diagnosing these tumors. Two surgical approaches are described in the literature for excision of subungual glomus tumors-transungual and periungual. We reviewed retrospectively the results of subungual glomus tumors of the hand treated by transungual excision. MATERIALS AND METHODS: Twelve patients (9 females and 3 males) with histopathologically confirmed subungual glomus tumors of the hand were treated by transungual excision at our institute. The mean age of the patients was 40.5 years (range 28-63 years). All patients presented with pain in the nail bed and cold sensitivity. A bluish-brown discoloration was present in 6 patients. Love's pin test was positive in all and Hildreth's test was positive in 8 patients. The mean duration of followup was 38 months (range 8-72 months). RESULTS: All patients had complete pain relief. There was no new nail deformity and no recurrence till last followup. One patient had deformity of the nail preoperatively due to previous surgery, which persisted after excision of the tumor. All of them returned to their preoperative occupation and regained full function of the hand. CONCLUSIONS: The transungual approach provides good access to the entire lesion and facilitates complete excision. Contrary to reported literature, we did not find the development of any new nail deformity with this approach. PMID- 26229161 TI - Outcome of humeral shaft fractures treated by functional cast brace. AB - BACKGROUND: Functional brace application for isolated humeral shaft fracture persistently yields good results. Nonunion though uncommon involves usually the proximal third shaft fractures. Instead of polyethylene bivalve functional brace four plaster sleeves wrapped and molded with little more proximal extension expected to prevent nonunion of proximal third fractures. Periodic compressibility of the cast is likely to yield a better result. This can be applied on the 1(st) day of the presentation as an outpatient basis. Comprehensive objective scoring system befitting for fracture humeral shaft is a need. MATERIALS AND METHODS: Sixty six (male = 40, female = 26) unilateral humeral shaft fractures of mean age 34.4 years (range 11-75 years) involving 38 left and 28 right hands were included in this study during April 2008 to December 2012. Fractures involved proximal (n = 18), mid (n = 35) and distal (n = 13) of humerus. Transverse, oblique, comminuted and spiral orientations in 18, 35 and 13 patients respectively. One had segmental fracture and three had a pathological fracture with cystic bone lesion. Mechanisms of injuries as identified in this study were road traffic accidents 57.6% (n = 38), fall 37.9% (n = 25). 12.1% (n = 8) had radial nerve palsy 7.6% (n = 5) had Type I open fracture. Four plaster strips of 12 layers and 5-7.5 cm broad depending on the girth of arm were prepared. Arm was then wrapped with single layer compressed cotton. Lateral and medial strips were applied and then after molding anterior and posterior strips were applied in such a way that permits full elbow range of motion and partial abduction of the shoulder. Care was taken to prevent adherence of one strip with other except in the proximal end. Limb was then put in loose collar and cuff sling intermittently allowing active motion of the elbow ROM and pendular movement of the shoulder. Weekly tightening of the cast by fresh layers of bandage over the existing cast brace continued. RESULTS: The results were assessed using 100 point scoring system where union allotted 30 points and 60 points allotted for angulations (10), elbow motion (10), shoulder abduction (10), shortening (5), rotation (5), absence of infection (10), absence of nerve palsy during treatment (10). Remaining 10 points were allotted for five items with two points each. They were the absence of skin sore, absence of vascular problem, absence of reflex sympathetic dystrophy (RSD), recovery of paralyzed nerve during injury and recovery of paralyzed nerve during treatment. Results were considered excellent with 90 and above, good with 80-89, fair with 70-79 and poor below 70 point. Results at 6 months were excellent in 43.94% (n = 29), good in 42.42% (n = 28), fair in 9.1% (n = 6), poor in 4.55% (n = 3). Union took place in 98.48% (n = 65) with an average of 10.3 weeks (range 6-16 weeks). 87.5% (n = 7) paralyzed radial nerve recovered. All wounds healed. Four patients had transient skin problem. One patient with mid shaft fracture had nonunion due to the muscle interposition. CONCLUSION: Modified functional cast brace is one of the options in treatment for humeral shaft fractures as it can be applied on the 1(st) day of the presentation in most of the situations. Simple objective scoring system was useful particularly in uneducated patients. PMID- 26229162 TI - Mid term results of Pemberton pericapsular osteotomy. AB - BACKGROUND: Treatment for developmental dysplasia of the hip (DDH) varies according to the age of the patient. For children under 3 months, the preferred treatment is Pavlik bandaging and/or dynamic hip orthosis;for children of 3-18 months (with/without arthrography), closed and open reductions (ORs) are most common; and for children 18 months and older, pelvic osteotomies are used. Radiological and functional outcomes of patients between 16 months and 7 years of age who underwent Pemberton pericapsular osteotomy (PPO) were evaluated. MATERIALS AND METHODS: Twelve patients with developmental dysplasia of the hip (DDH) received treatment on 14 hips between 2001 and 2006. All patients with DDH had PPO as pelvic osteotomy. PPO was done solely in 3 hips, PPO and open reduction (OR) in and OR + PPO + femoral shortening in 6. The average age was 39.85 months (range 16-83 months). All had 1-stage surgery. Acetabular index (AI) and the grade of displacement were determined according to Tonnis'. Center-edge (CE) angle was evaluated. Clinical evaluations were made as described by McKay, radiological assessments by Severin's criteria and femoral head avascular necrosis measurements by Kalamchi-MacEwen's criteria. Average followup periods were 83.35 months (range 48-115 months). RESULTS: Preoperative and postoperative average AI levels were 41.92 degrees (range 30-50 degrees ) and 19,5 degrees (range 5-34 degrees ), respectively (P < 0.001). According to Severin's classification, 11 (78.57%) patients were Ia, 1 (7.14%) was Ib, 1 (7.14%) was II and 1 (7.14%) was III. According to Kalamchi-McEven criteria, 12 (85.71%) patients were type I, 2 (14.28%) patients were type II. CE postoperatively was measured as 24.24 degrees (range 12-41 degrees ). Clinically (McKay), the functional results in 13 (92.85%) patients were very good (I) and in 1 (7.14%) was good (II). CONCLUSIONS: Functional and radiological mid term outcomes were found to be comparable in most of the patients with DDH undergoing PPO between the ages of 16 months and 7 years. PMID- 26229163 TI - Vertical pelvic ring displacement in pelvic ring injury: Measurements in pelvic outlet radiograph and in cadavers. AB - BACKGROUND: Vertical pelvic ring displacement (VPRD) is a serious injury and needs assessment. Pelvic outlet radiographs are routinely taken. However, relationship of radiographic and actual VPRD is still in question. Thus, measurement of VPRD from pelvic radiographs was studied. MATERIALS AND METHODS: 2 dry pelvic bones and 1 sacrum from same cadaver was reconstructed to be the pelvic ring. Five specimens were enrolled. 10, 20 and 30 mm vertical displacement of right pelvic bone was performed at levels of sacroiliac joint and pubic symphysis for representing right VPRD. Then, the pelvis was set sacral inclination at 60 degrees from X-ray table for outlet and anteroposterior pelvic radiographs. Right VPRD was measured by referring to superior most pelvic articular surface of both sacroiliac joints and sacral long axis. Radiographic VPRD and actual displacement were analyzed by Pearson correlation coefficient at more than 0.90 for the strong correlation and strongly significant simple regression analysis was set at P < 0.01. RESULTS: Radiographic VPRD from outlet and anteroposterior pelvic views at 10 mm actual displacement were 20.12 +/- 1.98 and 4.08 +/- 3.76 mm, at 20 mm were 40.31 +/- 1.97 and 9.94 +/- 7.27 mm and at 30 mm were 58.56 +/- 2.53 and 11.29 +/- 2.89 mm. Statistical analyses showed that radiographic VPRD from pelvic outlet view is 1.95 times of actual displacement with strong correlation at 0.992 coefficient and strongly significant regression analysis (P < 0.001) with 0.984 of R (2) value. Whereas, the measurement from anteroposterior pelvic radiograph was not strongly significant. CONCLUSION: Pelvic outlet radiograph provides efficient measurement of VPRD with 2 times of actual displacement. PMID- 26229164 TI - Outcome of limb reconstruction system in open tibial diaphyseal fractures. AB - BACKGROUND: Management of open tibial diaphyseal fractures with bone loss is a matter of debate. The treatment options range from external fixators, nailing, ring fixators or grafting with or without plastic reconstruction. All the procedures have their own set of complications, like acute docking problems, shortening, difficulty in soft tissue management, chronic infection, increased morbidity, multiple surgeries, longer hospital stay, mal union, nonunion and higher patient dissatisfaction. We evaluated the outcome of the limb reconstruction system (LRS) in the treatment of open fractures of tibial diaphysis with bone loss as a definative mode of treatment to achieve union, as well as limb lengthening, simultaneously. MATERIALS AND METHODS: Thirty open fractures of tibial diaphysis with bone loss of at least 4 cm or more with a mean age 32.5 years were treated by using the LRS after debridement. Distraction osteogenesis at rate of 1 mm/day was done away from the fracture site to maintain the limb length. On the approximation of fracture ends, the dynamized LRS was left for further 15-20 weeks and patient was mobilized with weight bearing to achieve union. Functional assessment was done by Association for the Study and Application of the Methods of Illizarov (ASAMI) criteria. RESULTS: Mean followup period was 15 months. The mean bone loss was 5.5 cm (range 4-9 cm). The mean duration of bone transport was 13 weeks (range 8-30 weeks) with a mean time for LRS in place was 44 weeks (range 24-51 weeks). The mean implant index was 56.4 days/cm. Mean union time was 52 weeks (range 31-60 weeks) with mean union index of 74.5 days/cm. Bony results as per the ASAMI scoring were excellent in 76% (19/25), good in 12% (3/25) and fair in 4% (1/25) with union in all except 2 patients, which showed poor results (8%) with only 2 patients having leg length discrepancy more than 2.5 cm. Functional results were excellent in 84% (21/25), good in 8% (2/25), fair in 8% (2/25). Pin tract infection was seen in 5 cases, out of which 4 being superficial, which healed to dressings and antibiotics. One patient had a deep infection which required frame removal. CONCLUSION: Limb reconstruction system proved to be an effective modality of treatment in cases of open fractures of the tibia with bone loss as definite modality of treatment for damage control as well as for achieving union and lengthening, simultaneously, with the advantage of early union with attainment of limb length, simple surgical technique, minimal invasive, high patient compliance, easy wound management, lesser hospitalization and the lower rate of complications like infection, deformity or shortening. PMID- 26229165 TI - Outcome of intertrochanteric fractures treated by intramedullary nail with two integrated lag screws: A study in Asian population. AB - BACKGROUND: The incidence of intertrochanteric fracture has increased during recent years as life expectancy has also increased. Currently, orthopedic surgeons use various fixation methods for intertrochanteric fractures like, intramedullary (IM) nailing or dynamic hip screws and plates. The intramedullary (IM) nail with two integrated lag screws has been used recently in intertrochanteric fractures to overcome Z-affect phenomenon. However, no study is available in an Asian population. This prospective study was undertaken to document the clinical and radiologic outcomes of the IM nail with two integrated lag screws and its limitations in Asian patients. MATERIALS AND METHODS: Osteosynthesis was performed using InterTAN nail in 100 patients with an intertrochanteric fractures followed up for at least 1 year after surgery. We evaluated the recovery rates to prefracture status, time to bony union and the incidence of complications. RESULTS: Seventy four patients were available for at least 1 year followup examinations. Forty-five patients (60.8%) recovered prefracture status. Mean time to bony union was 18.3 +/- 8.6 weeks. Intraoperative technical problems related to an unavoidable superior positioning of the lag screw occurred in five cases. Postoperative complications requiring reoperation occurred in three patients; two cases of varus collapse with cut out and one case of periprosthetic fracture. CONCLUSIONS: The IM nail with two integrated lag screws showed favorable outcomes in Asian patients with an intertrochanteric fracture even though several complications that were not previously reported with this nail were found. The proper selection of patients and careful insertion of two lag screws should be mandatory in Asian patients. PMID- 26229166 TI - Cementless arthroplasty with a distal femoral shortening for the treatment of Crowe type IV developmental hip dysplasia. AB - BACKGROUND: Severe developmental dysplasia of the hip is a surgical challenge. The purpose of this study is to describe the cementless arthroplasty with a distal femoral shortening osteotomy for Crowe type IV developmental hip dysplasia and to report the results of this technique. MATERIALS AND METHODS: 12 patients (2 male and 10 female) of Crowe type IV developmental hip dysplasia operated between January 2005 and December 2010 were included in the study. All had undergone cementless arthroplasty with a distal femoral shortening osteotomy. Acetabular cup was placed at the level of the anatomical position in all the hips. The clinical outcomes were assessed and radiographs were reviewed to evaluate treatment effects. RESULTS: The mean followup for the 12 hips was 52 months (range 36-82 months). The mean Harris hip score improved from 41 points (range 28-54) preoperatively to 85 points (range 79-92) at the final followup. The mean length of bone removed was 30 mm (range 25-40 mm). All the osteotomies healed in a mean time of 13 weeks (range 10-16 weeks). There were no neurovascular injuries, pulmonary embolism or no infections. CONCLUSION: Our study suggests that cementless arthroplasty with a distal femoral shortening is a safe and effective procedure for severe developmental dysplasia of the hip. PMID- 26229167 TI - Short term results of cementless total hip arthroplasty in sicklers. AB - BACKGROUND: Sickle cell (SC) disease leading to endarteritis induces skeletal changes in the form of osteitis, sclerosis of femoral canal and osteonecrosis of the femoral head. All these make total hip arthroplasty (THA) difficult and prolonged. There is increased risk of infection, SC crisis and increased complication rate. Our paper aims to highlight preoperative, intraoperative and postoperative hurdles encountered in performing THA in sicklers and the short term outcome using cementless implants. MATERIALS AND METHODS: Thirty-nine patients with SC disease, who had osteonecrosis of the femoral head, were operated between 2007 and 2011. The mean age of patients was 22 years (range 13 49 years). There were twenty eight females and 11 males. Bilateral cementless total hip replacement (THR) was performed in 11 patients (22 hips) and in the rest unilateral (28 hips). Preoperative and postoperative modified Harris hip score was evaluated. The average followup was 3.8 years (range 2-6 years). RESULTS: The average operating time was 96 min (range 88-148 min). The average blood loss was 880 ml (range 650-1200 ml). The average intraoperative blood transfused was 2.3 units (range 2-5 units). All patients showed an improvement in Harris hip score from 42 points preoperatively to 92 points at latest followup. Intraoperatively, one patient had a periprosthetic fracture. Six patients developed acute SC crisis and were managed in intensive care unit. Three patients developed wound hematoma. Three patients developed limb length discrepancy less than 1 cm. None had early or late dislocations, infection, heterotopic ossification, sciatic nerve palsy and aseptic loosening. CONCLUSION: THA in sicklers involves considerable challenge for the orthopedic surgeon. Management requires a multidisciplinary approach involving the anesthetist, hematologist and the orthopedic surgeon. Contrary to previous reports, THA in sicklers now has a predictable outcome especially with the use of cementless implants. PMID- 26229168 TI - Robot assisted navigated drilling for percutaneous pedicle screw placement: A preliminary animal study. AB - BACKGROUND: There is much more radiation exposure to the surgeons during minimally invasive pedicle screws placement. In order to ease the surgeon's hand eye coordination and to reduce the iatrogenic radiation injury to the surgeons, a robot assisted percutaneous pedicle screw placement is useful. This study assesses the feasibility and clinical value of robot assisted navigated drilling for pedicle screw placement and the results thus achieved formed the basis for the development of a new robot for pedicle screw fixation surgery. MATERIALS AND METHODS: Preoperative computed tomography (CT) of eight bovine lumbar spines (L1 L5) in axial plane were captured for each vertebra, the entry points and trajectories of the screws were preoperatively planned. On the basis of preoperative CT scans and intraoperative fluoroscopy, we aligned the robot drill to the desired entry point and trajectory, as dictated by the surgeon's preoperative plan. Eight bovine lumbar spines were inserted 80 K-wires using the spine robot system. The time for system registration and pedicle drilling, fluoroscopy times were measured and recorded. Postoperative CT scans were used to assess the position of the K-wires. RESULTS: Assisted by spine robot system, the average time for system registration was (343.4 +/- 18.4) s, the average time for procedure of drilling one pedicle screw trajectory was (89.5 +/- 6.1) s, times of fluoroscopy for drilling one pedicle screw were (2.9 +/- 0.8) times. Overall, 12 (15.0%) of the 80 K-wires violated the pedicle wall. Four screws (5.0%) were medial to the pedicle and 8 (10.5%) were lateral. The number of K-wires wholly within the pedicle were 68 (85%). CONCLUSIONS: The preliminary study supports the view that computer assisted pedicle screw fixation using spinal robot is feasible and the robot can decrease the intraoperative fluoroscopy time during the minimally invasive pedicle screw fixation surgery. As spine robotic surgery is still in its infancy, further research in this field is worthwhile especially the accuracy of spine robot system should be improved. PMID- 26229169 TI - Outcome of percutaneous balloon kyphoplasty in vertebral compression fractures. AB - BACKGROUND: Incidence of vertebral compression fractures (VCFs) is increasing due to increase in human life expectancy and prevalence of osteoporosis. Vertebroplasty had been traditional treatment for pain, but it neither attempts to restore vertebral body height nor eliminates spinal deformity and is associated with a high rate of cement leakage. Balloon kyphoplasty involves introduction of inflatable balloon into the fractured body of vertebra for elevation of the end-plates prior to fixation of the fracture with bone cement. This study evaluates short term functional and radiological outcomes of balloon kyphoplasty. The secondary aim is to explore short-term complications of the procedure. MATERIALS AND METHODS: A retrospective study of 199 kyphoplasty procedures in 135 patients from March 2009 to March 2012 were evaluated with short form-36 (SF-36) score, visual analogue scale (VAS), detailed neurological and radiological evaluations. The mean followup was 18 months (range 12-20 months). Statistical analysis including paired sample t-test was done with statistical package for social sciences. RESULTS: Statistically significant improvements in SF-36 (from 34.29 to 48.53, an improvement of 14.24, standard deviation (SD) - 20.08 P < 0.0001), VAS (drop of 4.49, from 6.74 to 2.24, SD - 1.44, P < 0.0001), percentage restoration of lost vertebral height (from 30.62% to 16.19%, improvement of 14.43%, SD - 15.37, P < 0.0001) and kyphotic angle correction (from 17.41 degrees to 10.59 degrees , improvement of 6.82, SD - 7.26 degrees , P < 0.0001) were noted postoperatively. Six patients had cement embolism, 65 had cement leak and three had adjacent level fracture which required repeat kyphoplasty later. One patient with history of ischemic heart disease had cardiac arrest during the procedure. No patients had neurological deterioration in the followup period. CONCLUSIONS: Kyphoplasty is a safe and effective treatment for VCFs. It improves physical function, reduces pain and corrects kyphotic deformity. PMID- 26229170 TI - Cervical pedicle screw fixation at C6 and C7: A cadaveric study. AB - BACKGROUND: Cervical pedicle screw fixation is an effective method for treating traumatic and non traumatic injuries. But many studies have reported higher incidence of cervical pedicle penetration, so many research efforts have aimed at improving the accuracy of cervical screw fixation. Most of the anatomical studies on cervical pedicle screw placement previously published focused on the measurements of anatomical parameters, the entry point of pedicle screw is vague. We preliminarily designed a C3, C4 and C5 pedicle screw fixation method that had clear entry point and clinical cases confirmed that this method is feasible and safe. So we did this study of cervical pedicle screw fixation for C6 and C7 vertebrae. MATERIALS AND METHODS: Fifteen cervical vertebrae specimens were prepared and bilateral pedicle screws were manually inserted into C6 and C7. The intersection of the horizontal line through the midpoint of the transverse process root and the vertical line through the intersection of the posterolateral and posterior planes of the isthmus was the entry point. The screws were inserted along the axis of the pedicle, with the screw axis coinciding with the pedicle. The pedicle was truncated axially and sagittally along the trajectory and the narrowest pedicular height (PH), pedicular width (PW), overall length of the screw channel (LSC), transverse angle (E) and vertical angle (F) were measured. RESULTS: In C6, the PW and PH were 6.12 +/- 0.78 and 7.48 +/- 0.81 mm, respectively. In C7, the PW and PH were 6.85 +/- 0.73 and 8.03 +/- 0.38 mm, respectively. The LSC was 30.83 +/- 0.91 mm. Two E angles were identified, namely E1 and E2 and their values were 89.61 +/- 1.24 and 59.71 +/- 1.10 degrees , respectively. Meanwhile, F averaged 75.86 +/- 1.12 degrees . CONCLUSION: The intersection of the horizontal line through the midpoint of the transverse process root and vertical line through the intersection of the posterolateral and posterior planes of the isthmus can be used as an entry point for C6 and C7 pedicle screw fixation. The screws should be inserted at 60 or 90 degrees with the posterolateral isthmus in the horizontal plane and at 75 degrees with the posterior isthmus in the sagittal plane. The LSC should not exceed 30 mm. PMID- 26229171 TI - Anterior D-rod and titanium mesh fixation for acute mid-lumbar burst fracture with incomplete neurologic deficits: A prospective study of 56 consecutive patients. AB - BACKGROUND: Anterior decompression and reconstruction have gained wide acceptance as viable alternatives for unstable mid-lumbar burst fracture, but there are no mid and long term prospective studies regarding clinical and radiologic results of mid-lumbar burst fractures. MATERIALS AND METHODS: An Institutional Review Board-approved prospective study of 56 consecutive patients of mid-lumbar burst fractures with a load-sharing score of 7 or more treated with anterior plating was carried out. All patients were evaluated for radiologic and clinical outcomes. The fusion status, spinal canal compromise, segmental kyphotic angle (SKA), vertebral body height loss (VBHL), and adjacent segment degeneration was examined for radiologic outcome, whereas the American Spinal Injury Association scale, the visual analog scale (VAS), and the employment status were used for clinical evaluation. RESULTS: The patients underwent clinical and radiologic followup for at least 5 years after the surgery. At the last followup, there was no case of internal fixation failure, adjacent segment degeneration, and other complications. Interbody fusion was achieved in all cases. The average fusion time was 4.5 months. No patient suffered neurological deterioration and the average neurologic recovery was 1.3 grades on final observation. Based on VAS pain scores, canal compromise, percentage of VBHL and SKA, the difference was statistically significant between the preoperative period and postoperative or final followup (P < 0.05). Results at postoperative and final followup were better than the preoperative period. However, the difference was not significant between postoperative and final followup (P > 0.05). Thirty-four patients who were employed before the injury returned to work after the operation, 15 had changed to less strenuous work. CONCLUSION: Good mid term clinicoradiological results of anterior decompression with D-rod and titanium mesh fixation for suitable patients with mid-lumbar burst fractures with incomplete neurologic deficits can be achieved. The incident rate of complications was low. D-rod is a reliable implant and has some potential advantages in L4 vertebral fractures. PMID- 26229172 TI - Nine toes; Mirror Foot Deformity. AB - Mirror foot is a very rare congenital anomaly, with only a few papers presenting definitive treatment for this entity. There are limited management recommendations. Most cases are treated before walking age. In our case, there were no associated developmental defects of the leg. The child underwent complex rays resection with medial foot reconstruction. After 7.5 years of followup, definitive surgical treatment was performed with satisfactory cosmetic and functional outcome. PMID- 26229173 TI - Multifocal bilateral xanthogranulomatous osteomyelitis. AB - Xanthogranulomatous osteomyelitis is a rare chronic inflammatory disorder which clinically resembles bone tumor. It is characterized histologically by the presence of a large number of foamy histiocytes admixed with lymphocytes and plasma cells. Xanthogranulomatous inflammation can involve any organ, with kidneys and gall bladder being the worst affected. Only anecdotal cases of osteomyelitis have been reported in the past with scant medical literature. However, all the earlier reported cases, except one, were unifocal lesions. The authors present a case of multifocal xanthogranulomatous osteomyelitis involving the left medial malleoli, left talus and the right cuboid bones. PMID- 26229174 TI - Stem cell therapy in spinal trauma: Does it have scientific validity? PMID- 26229175 TI - Author's reply. PMID- 26229176 TI - Erratum: Bipolar hip arthroplasty for avascular necrosis of femoral head in young adults: Erratum. AB - [This corrects the article on p. 329 in vol. 49, PMID: 26015634.]. PMID- 26229177 TI - Erratum: Results of reconstruction of massive irreparable rotator cuff tears using a fascia lata allograft: Erratum. AB - [This corrects the article on p. 304 in vol. 49, PMID: 26015630.]. PMID- 26229178 TI - Data sets on pensions and health: Data collection and sharing for policy design. AB - A growing number of countries are developing or reforming pension and health policies in response to population ageing and to enhance the welfare of their citizens. The adoption of different policies by different countries has resulted in several natural experiments. These offer unusual opportunities to examine the effects of varying policies on health and retirement, individual and family behaviour, and well-being. Realizing these opportunities requires harmonized data collection efforts. An increasing number of countries have agreed to provide data harmonized with the Health and Retirement Study in the United States. This article discusses these data sets, including their key parameters of pension and health status, research designs, samples, and response rates. It also discusses the opportunities they offer for cross-national studies and their implications for policy evaluation and development. PMID- 26229180 TI - Lack of toilets and safe water in health-care facilities. PMID- 26229181 TI - WHO's first global health treaty: 10 years in force. PMID- 26229182 TI - Food safety in a globalized world. PMID- 26229184 TI - Rapid Ebola tests hold promise. AB - New rapid diagnostic tests for Ebola may help Guinea, Liberia and Sierra Leone reach zero cases and allow routine health services to resume. Fiona Fleck reports. PMID- 26229185 TI - What to do about resistant bacteria in the food-chain? AB - This year's World Health Day is on food safety. The mass use of antibiotics in animal husbandry is contaminating the food supply with resistant bacteria, causing difficult-to-treat infections while reducing the power of antibiotics to cure human infections. Antoine Andremont talks to Fiona Fleck. PMID- 26229186 TI - Antibiotic prescription behaviours in Lao People's Democratic Republic: a knowledge, attitude and practice survey. AB - OBJECTIVE: To assess the antibiotic prescribing practices of doctors working in the Lao People's Democratic Republic and their knowledge of local antibiotic resistance patterns. METHODS: Doctors attending morning meetings in 25 public hospitals in four provinces were asked to complete a knowledge, attitude and practice survey. The questionnaire contained 43 multiple choice questions that the doctor answered at the time of the meeting. FINDINGS: The response rate was 83.4% (386/463). Two hundred and seventy doctors (59.8%) declared that they had insufficient information about antibiotics. Only 14.0% (54/386) recognized the possibility of cephalosporin cross-resistance in methicillin-resistant Staphylococcus aureus. Most participants had no information about local antibiotic resistance for Salmonella Typhi (211/385, 54.8%) and hospital-acquired pneumonia (253/384, 65.9%). Unnecessary antibiotic prescriptions were considered as harmless by 115 participants and 148 considered locally-available generic antibiotics to be of poor quality. Nearly three-quarters (280/386) of participants agreed that it was difficult to select the correct antibiotics. Most participants (373/386) welcomed educational programmes on antibiotic prescribing and 65.0% (249/383) preferred local over international antibiotic guidelines. CONCLUSION: Doctors in the Lao People's Democratic Republic seem to favour antibiotic prescribing interventions. Health authorities should consider a capacity building programme that incorporates antibiotic prescribing and hospital infection control. PMID- 26229187 TI - Data-driven methods for imputing national-level incidence in global burden of disease studies. AB - OBJECTIVE: To develop transparent and reproducible methods for imputing missing data on disease incidence at national-level for the year 2005. METHODS: We compared several models for imputing missing country-level incidence rates for two foodborne diseases - congenital toxoplasmosis and aflatoxin-related hepatocellular carcinoma. Missing values were assumed to be missing at random. Predictor variables were selected using least absolute shrinkage and selection operator regression. We compared the predictive performance of naive extrapolation approaches and Bayesian random and mixed-effects regression models. Leave-one-out cross-validation was used to evaluate model accuracy. FINDINGS: The predictive accuracy of the Bayesian mixed-effects models was significantly better than that of the naive extrapolation method for one of the two disease models. However, Bayesian mixed-effects models produced wider prediction intervals for both data sets. CONCLUSION: Several approaches are available for imputing missing data at national level. Strengths of a hierarchical regression approach for this type of task are the ability to derive estimates from other similar countries, transparency, computational efficiency and ease of interpretation. The inclusion of informative covariates may improve model performance, but results should be appraised carefully. PMID- 26229188 TI - The Global Drug Facility as an intervention in the market for tuberculosis drugs. AB - OBJECTIVE: To investigate funding for the Global Drug Facility since 2001 and to analyse the facility's influence on the price of high-quality tuberculosis drugs. METHODS: Data on the price of tuberculosis drugs were obtained from the Global Drug Facility for 2001 to 2012 and, for the private sector in 15 countries, from IMS Health for 2002 to 2012. Data on funding of the facility were also collected. FINDINGS: Quality-assured tuberculosis drugs supplied by the Global Drug Facility were generally priced lower than drugs purchased in the private sector. In 2012, just three manufacturers accounted for 29.9 million United Stated dollars (US$) of US$ 44.5 million by value of first-line drugs supplied. The Global Fund to Fight AIDS, Tuberculosis and Malaria provided 73% (US$ 32.5 million of US$ 44.5 million) and 89% (US$ 57.8 million of US $65.2 million) of funds for first- and second-line drugs, respectively. Between 2010 and 2012, the facility's market share of second-line tuberculosis drugs increased from 26.1% to 42.9%, while prices decreased by as much as 24% (from US$ 1231 to US$ 939). Conversely, the facility's market share of first-line drugs fell from 37.2% to 19.2% during this time, while prices increased from US$ 9.53 to US$ 10.2. CONCLUSION: The price of tuberculosis drugs supplied through the facility was generally less than that on the private market. However, to realize its full potential and meet the needs of more tuberculosis patients, the facility requires more diverse and stable public funding and greater flexibility to participate in the private market. PMID- 26229189 TI - Nurse versus physician-provision of early medical abortion in Mexico: a randomized controlled non-inferiority trial. AB - OBJECTIVE: To examine the effectiveness, safety, and acceptability of nurse provision of early medical abortion compared to physicians at three facilities in Mexico City. METHODS: We conducted a randomized non-inferiority trial on the provision of medical abortion and contraceptive counselling by physicians or nurses. The participants were pregnant women seeking abortion at a gestational duration of 70 days or less. The medical abortion regimen was 200 mg of oral mifepristone taken on-site followed by 800 MUg of misoprostol self-administered buccally at home 24 hours later. Women were instructed to return to the clinic for follow-up 7-15 days later. We did an intention-to-treat analysis for risk differences between physicians' and nurses' provision for completion and the need for surgical intervention. FINDINGS: Of 1017 eligible women, 884 women were included in the intention-to-treat analysis, 450 in the physician-provision arm and 434 in the nurse-provision arm. Women who completed medical abortion, without the need for surgical intervention, were 98.4% (443/450) for physicians' provision and 97.9% (425/434) for nurses' provision. The risk difference between the group was 0.5% (95% confidence interval, CI: -1.2% to 2.3%). There were no differences between providers for examined gestational duration or women's contraceptive method uptake. Both types of providers were rated by the women as highly acceptable. CONCLUSION: Nurses' provision of medical abortion is as safe, acceptable and effective as provision by physicians in this setting. Authorizing nurses to provide medical abortion can help to meet the demand for safe abortion services. PMID- 26229191 TI - Midterm review of national health plans: an example from the United Republic of Tanzania. AB - In the health sector, planning and resource allocation at country level are mainly guided by national plans. For each such plan, a midterm review of progress is important for policy-makers since the review can inform the second half of the plan's implementation and provide a situation analysis on which the subsequent plan can be based. The review should include a comprehensive analysis using recent data - from surveys, facility and administrative databases - and global health estimates. Any midterm analysis of progress is best conducted by a team comprising representatives of government agencies, independent national institutions and global health organizations. Here we present an example of such a review, done in 2013 in the United Republic of Tanzania. Compared to similar countries, the results of this midterm review showed good progress in all health indicators except skilled birth attendance. PMID- 26229190 TI - Inequities in postnatal care in low- and middle-income countries: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the socioeconomic, geographical and demographic inequities in the use of postnatal health-care services in low- and middle-income countries. METHODS: We searched Medline, Embase and Cochrane Central databases and grey literature for experimental, quasi-experimental and observational studies that had been conducted in low- and middle-income countries. We summarized the relevant studies qualitatively and performed meta-analyses of the use of postnatal care services according to selected indicators of socioeconomic status and residence in an urban or rural setting. FINDINGS: A total of 36 studies were included in the narrative synthesis and 10 of them were used for the meta analyses. Compared with women in the lowest quintile of socioeconomic status, the pooled odds ratios for use of postnatal care by women in the second, third, fourth and fifth quintiles were: 1.14 (95% confidence interval, CI : 0.96-1.34), 1.32 (95% CI: 1.12-1.55), 1.60 (95% CI: 1.30-1.98) and 2.27 (95% CI: 1.75-2.93) respectively. Compared to women living in rural settings, the pooled odds ratio for the use of postnatal care by women living in urban settings was 1.36 (95% CI: 1.01-1.81). A qualitative assessment of the relevant published data also indicated that use of postnatal care services increased with increasing level of education. CONCLUSION: In low- and middle-income countries, use of postnatal care services remains highly inequitable and varies markedly with socioeconomic status and between urban and rural residents. PMID- 26229192 TI - Reducing the price of treatment for multidrug-resistant tuberculosis through the Global Drug Facility. AB - PROBLEM: Many countries have limited experience of securing the best prices for drugs and have little negotiating power. This is particularly true for the complex, lengthy and expensive regimens used to treat multidrug-resistant tuberculosis. APPROACH: The Stop TB Partnership's Global Drug Facility is dedicated to improving worldwide access to antituberculosis medicines and diagnostic techniques that meet international quality standards. LOCAL SETTING: The Global Drug Facility is able to secure price reductions through competitive tendering among prequalified drug manufacturers and by consolidating orders to achieve large purchase volumes. Consolidating the market in this way increases the incentives for suppliers of quality-assured medicines. RELEVANT CHANGES: In 2013 the Global Drug Facility reduced the price of the second-line drugs it supplies for multidrug-resistant tuberculosis: the overall cost of the longest and most expensive treatment regimen for a patient decreased by 26% - from 7890 United States dollars (US$) in 2011 to US$ 5822 in 2013. LESSONS LEARNT: The price of treatment for multidrug-resistant tuberculosis supplied by the Global Drug Facility was reduced by consolidating orders to achieve large purchase volumes, by international, competitive bidding and by the existence of donor funded medicine stockpiles. The rise in the number of suppliers of internationally quality-assured drugs was also important. The savings achieved from lower drug costs could be used to increase the number of patients on high quality treatment. PMID- 26229193 TI - Tough decisions on essential medicines in 2015. PMID- 26229194 TI - Corrigendum. PMID- 26229196 TI - Measuring self-reported HIV status in bio-behavioural surveys. PMID- 26229198 TI - Hubs to spread technology and save lives. AB - The patent on an expensive preventive treatment for respiratory syncytial virus infections expires this year. A WHO technology transfer hub in the Netherlands aims to help developing countries make the drug themselves. Gary Humphreys reports. PMID- 26229199 TI - Keeping the living well. AB - Few people have done so much to put health research for developing countries on the international agenda. Ade Lucas talks to Fiona Fleck. PMID- 26229200 TI - The healthy food environment policy index: findings of an expert panel in New Zealand. AB - OBJECTIVE: To assess government actions to improve the healthiness of food environments in New Zealand, based on the healthy food environment policy index. METHODS: A panel of 52 public health experts rated the extent of government implementation against international best practice for 42 indicators of food environment policy and infrastructure support. Their ratings were informed by documented evidence, validated by government officials and international benchmarks. FINDINGS: There was a high level of implementation for some indicators: providing ingredient lists and nutrient declarations and regulating health claims on packaged foods; transparency in policy development; monitoring prevalence of noncommunicable diseases and monitoring risk factors for noncommunicable diseases. There was very little, if any implementation of the following indicators: restrictions on unhealthy food marketing to children; fiscal and food retail policies and protection of national food environments within trade agreements. Interrater reliability was 0.78 (95% confidence interval, CI: 0.76-0.79). Based on the implementation gaps, the experts recommended 34 actions, and prioritized seven of these. CONCLUSION: The healthy food environment policy index provides a useful set of indicators that can focus attention on where government action is needed. It is anticipated that this policy index will increase accountability of governments, stimulate government action and support civil society advocacy efforts. PMID- 26229201 TI - Injury-related mortality in South Africa: a retrospective descriptive study of postmortem investigations. AB - OBJECTIVE: To investigate injury-related mortality in South Africa using a nationally representative sample and compare the results with previous estimates. METHODS: We conducted a retrospective descriptive study of medico-legal postmortem investigation data from mortuaries using a multistage random sample, stratified by urban and non-urban areas and mortuary size. We calculated age specific and age-standardized mortality rates for external causes of death. FINDINGS: Postmortem reports revealed 52,493 injury-related deaths in 2009 (95% confidence interval, CI: 46,930-58,057). Almost half (25,499) were intentionally inflicted. Age-standardized mortality rates per 100,000 population were as follows: all injuries: 109.0 (95% CI: 97.1-121.0); homicide 38.4 (95% CI: 33.8 43.0; suicide 13.4 (95% CI: 11.6-15.2) and road-traffic injury 36.1 (95% CI: 30.9 41.3). Using postmortem reports, we found more than three times as many deaths from homicide and road-traffic injury than had been recorded by vital registration for this period. The homicide rate was similar to the estimate for South Africa from a global analysis, but road-traffic and suicide rates were almost fourfold higher. CONCLUSION: This is the first nationally representative sample of injury-related mortality in South Africa. It provides more accurate estimates and cause-specific profiles that are not available from other sources. PMID- 26229202 TI - Surveys of measles vaccination coverage in eastern and southern Africa: a review of quality and methods used. AB - OBJECTIVE: To assess the methods used in the evaluation of measles vaccination coverage, identify quality concerns and provide recommendations for improvement. METHODS: We reviewed surveys that were conducted to evaluate supplementary measles immunization activities in eastern and southern Africa during 2012 and 2013. We investigated the organization(s) undertaking each survey, survey design, sample size, the numbers of study clusters and children per study cluster, recording of immunizations and methods of analysis. We documented sampling methods at the level of clusters, households and individual children. We also assessed the length of training for field teams at national and regional levels, the composition of teams and the supervision provided. FINDINGS: The surveys were conducted in Comoros, Eritrea, Ethiopia, Kenya, Lesotho, Malawi, Mozambique, Namibia, Rwanda, Swaziland, Uganda, Zambia and Zimbabwe. Of the 13 reports we reviewed, there were weaknesses in 10 of them for ethical clearance, 9 for sample size calculation, 6 for sampling methods, 12 for training structures, 13 for supervision structures and 11 for data analysis. CONCLUSION: We recommend improvements in the documentation of routine and supplementary immunization, via home-based vaccination cards or other records. For surveys conducted after supplementary immunization, a standard protocol is required. Finally, we recommend that standards be developed for report templates and for the technical review of protocols and reports. This would ensure that the results of vaccination coverage surveys are accurate, comparable, reliable and valuable for programme improvement. PMID- 26229203 TI - A multimedia consent tool for research participants in the Gambia: a randomized controlled trial. AB - OBJECTIVE: To assess the effectiveness of a multimedia informed consent tool for adults participating in a clinical trial in the Gambia. METHODS: Adults eligible for inclusion in a malaria treatment trial (n = 311) were randomized to receive information needed for informed consent using either a multimedia tool (intervention arm) or a standard procedure (control arm). A computerized, audio questionnaire was used to assess participants' comprehension of informed consent. This was done immediately after consent had been obtained (at day 0) and at subsequent follow-up visits (days 7, 14, 21 and 28). The acceptability and ease of use of the multimedia tool were assessed in focus groups. FINDINGS: On day 0, the median comprehension score in the intervention arm was 64% compared with 40% in the control arm (P = 0.042). The difference remained significant at all follow up visits. Poorer comprehension was independently associated with female sex (odds ratio, OR: 0.29; 95% confidence interval, CI: 0.12-0.70) and residing in Jahaly rather than Basse province (OR: 0.33; 95% CI: 0.13-0.82). There was no significant independent association with educational level. The risk that a participant's comprehension score would drop to half of the initial value was lower in the intervention arm (hazard ratio 0.22, 95% CI: 0.16-0.31). Overall, 70% (42/60) of focus group participants from the intervention arm found the multimedia tool clear and easy to understand. CONCLUSION: A multimedia informed consent tool significantly improved comprehension and retention of consent information by research participants with low levels of literacy. PMID- 26229204 TI - Estimates of alcohol-related oesophageal cancer burden in Japan: systematic review and meta-analyses. AB - OBJECTIVE: To refine estimates of the burden of alcohol-related oesophageal cancer in Japan. METHODS: We searched PubMed for published reviews and original studies on alcohol intake, aldehyde dehydrogenase polymorphisms, and risk for oesophageal cancer in Japan, published before 2014. We conducted random-effects meta-analyses, including subgroup analyses by aldehyde dehydrogenase variants. We estimated deaths and loss of disability-adjusted life years (DALYs) from oesophageal cancer using exposure distributions for alcohol based on age, sex and relative risks per unit of exposure. FINDINGS: We identified 14 relevant studies. Three cohort studies and four case-control studies had dose-response data. Evidence from cohort studies showed that people who consumed the equivalent of 100 g/day of pure alcohol had an 11.71 fold, (95% confidence interval, CI: 2.67 51.32) risk of oesophageal cancer compared to those who never consumed alcohol. Evidence from case-control studies showed that the increase in risk was 33.11 fold (95% CI: 8.15-134.43) in the population at large. The difference by study design is explained by the 159 fold (95% CI: 27.2-938.2) risk among those with an inactive aldehyde dehydrogenase enzyme variant. Applying these dose-response estimates to the national profile of alcohol intake yielded 5279 oesophageal cancer deaths and 102,988 DALYs lost - almost double the estimates produced by the most recent global burden of disease exercise. CONCLUSION: Use of global dose response data results in an underestimate of the burden of disease from oesophageal cancer in Japan. Where possible, national burden of disease studies should use results from the population concerned. PMID- 26229205 TI - Strategies to increase the demand for childhood vaccination in low- and middle income countries: a systematic review and meta-analysis. AB - OBJECTIVE: To investigate which strategies to increase demand for vaccination are effective in increasing child vaccine coverage in low- and middle-income countries. METHODS: We searched MEDLINE, EMBASE, Cochrane library, POPLINE, ECONLIT, CINAHL, LILACS, BDSP, Web of Science and Scopus databases for relevant studies, published in English, French, German, Hindi, Portuguese and Spanish up to 25 March 2014. We included studies of interventions intended to increase demand for routine childhood vaccination. Studies were eligible if conducted in low- and middle-income countries and employing a randomized controlled trial, non randomized controlled trial, controlled before-and-after or interrupted time series design. We estimated risk of bias using Cochrane collaboration guidelines and performed random-effects meta-analysis. FINDINGS: We identified 11 studies comprising four randomized controlled trials, six cluster randomized controlled trials and one controlled before-and-after study published in English between 1996 and 2013. Participants were generally parents of young children exposed to an eligible intervention. Six studies demonstrated low risk of bias and five studies had moderate to high risk of bias. We conducted a pooled analysis considering all 11 studies, with data from 11,512 participants. Demand-side interventions were associated with significantly higher receipt of vaccines, relative risk (RR): 1.30, (95% confidence interval, CI: 1.17-1.44). Subgroup analyses also demonstrated significant effects of seven education and knowledge translation studies, RR: 1.40 (95% CI: 1.20-1.63) and of four studies which used incentives, RR: 1.28 (95% CI: 1.12-1.45). CONCLUSION: Demand-side interventions lead to significant gains in child vaccination coverage in low- and middle-income countries. Educational approaches and use of incentives were both effective strategies. PMID- 26229206 TI - Onsite training of doctors, midwives and nurses in obstetric emergencies, Zimbabwe. AB - PROBLEM: In Zimbabwe, many health facilities are not able to manage serious obstetric complications. Staff most commonly identified inadequate training as the greatest barrier to preventing avoidable maternal deaths. APPROACH: We established an onsite obstetric emergencies training programme for maternity staff in the Mpilo Central Hospital. We trained 12 local staff to become trainers and provided them with the equipment and resources needed for the course. The trainers held one-day courses for 299 staff at the hospital. LOCAL SETTING: Maternal mortality in Zimbabwe has increased from 555 to 960 per 100,000 pregnant women from 2006 to 2011 and 47% of the deaths are believed to be avoidable. Most obstetric emergencies trainings are held off-site, away from the clinical area, for a limited number of staff. RELEVANT CHANGES: Following an in-hospital train the-trainers course, 90% (138/153) of maternity staff were trained locally within the first year, with 299 hospital staff trained to date. Local system changes included: the introduction of a labour ward board, emergency boxes, colour-coded early warning observation charts and a maternity dashboard. In this hospital, these changes have been associated with a 34% reduction in hospital maternal mortality from 67 maternal deaths per 9078 births (0.74%) in 2011 compared with 48 maternal deaths per 9884 births (0.49%) in 2014. LESSONS LEARNT: Introducing obstetric emergencies training and tools was feasible onsite, improved clinical practice, was sustained by local staff and associated with improved clinical outcomes. Further work to study the implementation and effect of this intervention at scale is required. PMID- 26229207 TI - Routine feedback of test results to participants in clinic- and survey-based surveillance of HIV. AB - Surveillance for human immunodeficiency virus (HIV) in low- and middle-income countries started in the 1980s. However, the questions of whether the results of HIV tests should be given to participants, and if so how, has still not been resolved. In the absence of effective treatment, it was considered acceptable to withhold results from HIV-positive participants. However, when antiretroviral treatment is available, some argue for beneficence - that it is the researcher's duty to return the test results to all those who provide samples for surveillance. The corollary is that only participants who wish to receive their test results would be eligible to participate in surveys. Others argue for autonomy - that to obtain a more representative result for the general population, surveys should not exclude participants who do not wish to receive their test results. This round table discussion takes a closer look at those two arguments. We believe that the global community should work towards routine feedback of HIV surveillance while ensuring that participants receive and understand their test results. PMID- 26229208 TI - Understanding why people participate in HIV surveillance. PMID- 26229209 TI - Accurate information as a tool to decrease HIV test refusals in research studies. PMID- 26229210 TI - The asbestos paradox: global gaps in the translational science of disease prevention. PMID- 26229211 TI - Genetics and Epigenetics of Eating Disorders. PMID- 26229212 TI - Distinguishing Bereavement from Depression in DSM-5: Evidence from Longitudinal Epidemiologic Surveys. AB - Following the earlier versions of the diagnostic manual, the DSM-IV set a higher symptom and duration threshold for the diagnosis of major depression in individuals who have experienced recent bereavement-the bereavement exclusion criterion. This criterion excludes a diagnosis of major depression among those whose symptoms persist for less than two months, as long as they do not have marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation. The DSM-5 committee, however, has proposed to remove this criterion from the upcoming DSM-5. The committee's decision was based on reviews of past literature. However, few past studies directly compared DSM-excluded bereavement-related depression to other major depressive disorder in representative population samples and had adequate power to detect differences. The results of these studies, therefore, did not provide strong evidence for the validity of bereavement exclusion. In this paper, we review three recently published analyses based on large epidemiologic samples that found significant differences between those with bereavement-excluded episodes and episodes meeting major depression criteria with regard to short-term risk of future depressive episodes, psychiatric comorbidity and other clinical and socio-demographic characteristics. In follow-ups ranging from 1 to 3 years, individuals with bereavement-excluded depressive episodes were significantly less likely to experience new episodes than those who met criteria for depression, and were not more likely to experience future episodes than those without any past history of depression. The findings from these new studies support the validity of the DSM-IV bereavement exclusion criterion and argue for preserving it in the new edition of the manual. PMID- 26229213 TI - Response Styles to Positive Affect and Depression: Concurrent and Prospective Associations in a Community Sample. AB - We examined the concurrent and prospective relations between response styles to positive affect and depression in a community sample. Participants (n = 345) completed self-report measures of current and past depressive episodes, depressive symptoms, anhedonia, and responses to positive affect (including dampening and positive rumination) at two time points, with a 5-month interval. Higher levels of dampening responses to positive affect were related to higher concurrent levels of depressive symptoms. The tendency to positively ruminate on positive affect was negatively related to concurrent anhedonic symptoms. When controlling for current depressive symptomatology, formerly depressed individuals had a higher tendency to dampen positive affect than never-depressed controls, and did not differ from a currently depressed group. Dampening responses did not predict depressive symptoms prospectively, but lower levels of (self-focused) positive rumination did predict higher levels of future anhedonic symptoms. Results indicate that not only currently but also formerly depressed individuals engage in dysfunctional (dampening) strategies in response to positive affect. It is possible that currently as well as formerly depressed individuals might benefit from interventions that are directed at the remediation of disturbed regulation of positive affect. However, our prospective results make clear that more research is needed to examine the precise conditions under which dampening would be a detrimental (and positive rumination a beneficial) response style in the course of depression. PMID- 26229214 TI - Valence stabilization of polyvalent ions during gamma irradiation of their aqueous solutions by sacrificial protection. III-Valence stabilization of Fe(II) ions by organic additives. AB - Valence stabilization of polyvalent ions in gamma irradiated aqueous solutions is sometimes necessary in some chemical operations. In previous publications, valence stabilization of some polyvalent ions in solution upon gamma irradiation was achieved by using inorganic additives capable of interacting with the oxidizing or reducing species formed during water radiolysis. The results showed that the nature and duration of valence stabilization of Fe(II) depend on the concentration of the inorganic additives used. In the present work, a series of some organic additives has been used to investigate their capability in inducing valence stabilization of polyvalent iron ions, taken as an indicator, in aqueous acidic solutions when subjected to extended gamma irradiation. The results showed that the efficiency of valence stabilization depends on the amount and chemical structure of the organic additive used. PMID- 26229215 TI - Polonium 210Po activities in human blood of patients with ischaemic heart disease from Gdansk in Poland. AB - The determination of polonium 210Po in human blood samples is presented and discussed in this paper. The human blood samples were collected from patients of Medical University of Gdansk with ischaemic heart disease (morbus ischaemicus cordis, MIC). The polonium concentrations in analyzed human blood samples are very differentiated. 210Po is of particular interest in public health and although is present in the environment in extremely low amounts, it is easily bioaccumulated to the human body. The study shows that the amount of 210Po that is incorporated into the human body depends on the food habits and some difference in its levels could be observed between smokers and non-smokers. PMID- 26229217 TI - Estimation of the committed radiation dose resulting from gamma radionuclides ingested with food. AB - The objective of the study was to estimate the value of the radiation dose absorbed in consequence of consumption of popular food products for individual age groups. Potatoes, corn and sugar beet were selected for the study. Edible parts of these plants were collected in experimental fields of the KWS Lochow Polska Sp. z o.o. seeding company in Kondratowice (Poland). On the basis of the obtained study results, it can be stated that in consequence of consumption of the selected food products, people may receive increased doses from both natural and artificial radioactive isotopes. The doses calculated for several age groups do not show any health hazards in consequence of consumption of the tested food. One of the determined radionuclides was 137Cs; however, its presence in the absorbed dose is lower than the doses from natural radioactive isotopes, in particular 40K. PMID- 26229216 TI - 241Pu in the biggest Polish rivers. AB - In the paper the results of 241Pu activity concentration determination in the biggest Polish rivers are presented. The analysis of more than 100 river water samples showed the Vistula and the Odra as well as three Pomeranian Rivers are important sources of 241Pu in the southern Baltic Sea. There were differences in 241Pu activities depending on season and sampling site and the plutonium contamination came mainly from the global atmospheric fallout as well as the Chernobyl accident, which is confirmed by plutonium activity ratios of 241Pu/239+240Pu and 238Pu/239+240Pu. PMID- 26229218 TI - The application of selected radionuclides for monitoring of the D-D reactions produced by dense plasma-focus device. AB - The dense plasma focus (DPF) device-DPF-1000U which is operated at the Institute of Plasma Physics and Laser Microfusion is the largest that type plasma experiment in the world. The plasma that is formed in large plasma experiments is characterized by vast numbers of parameters. All of them need to be monitored. A neutron activation method occupies a high position among others plasma diagnostic methods. The above method is off-line, remote, and an integrated one. The plasma which has enough temperature to bring about nuclear fusion reactions is always a strong source of neutrons that leave the reactions area and take along energy and important information on plasma parameters and properties as well. Silver as activated material is used as an effective way of neutrons measurement, especially when they are emitted in the form of short pulses like as it happens from the plasma produced in Dense Plasma-Focus devices. Other elements such as beryllium and yttrium are newly introduced and currently tested at the Institute of Plasma Physics and Laser Microfusion to use them in suitable activation neutron detectors. Some specially designed massive indium samples have been recently adopted for angular neutrons distribution measurements (vertical and horizontal) and have been used in the recent plasma experiment conducted on the DPF-1000U device. This choice was substantiated by relatively long half-lives of the neutron induced isotopes and the threshold character of the 115In(n,n')115mIn nuclear reaction. PMID- 26229219 TI - Analytical method for total chromium and nickel in urine using an inductively coupled plasma-universal cell technology-mass spectrometer (ICP-UCT-MS) in kinetic energy discrimination (KED) mode. AB - Biomonitoring and emergency response measurements are an important aspect of the Division of Laboratory Sciences of the National Center for Environmental Health, Centers for Disease Control and Prevention (CDC). The continuing advancement in instrumentation allows for enhancements to existing analytical methods. Prior to this work, chromium and nickel were analyzed on a sector field inductively coupled plasma-mass spectrometer (SF-ICP-MS). This type of instrumentation provides the necessary sensitivity, selectivity, accuracy, and precision but due to the higher complexity of instrumentation and operation, it is not preferred for routine high throughput biomonitoring needs. Instead a quadrupole based method has been developed on a PerkinElmer NexIONTM 300D ICP-MS. The instrument is operated using 6.0 mL min-1 helium as the collision cell gas and in kinetic energy discrimination mode, interferences are successfully removed for the analysis of 52Cr (40Ar12C and 35Cl16O1H) and 60Ni (44Ca16O). The limits of detection are 0.162 MUg L-1 Cr and 0.248 MUg L-1 Ni. Method accuracy using NIST SRM 2668 level 1 (1.08 MUg L-1 Cr and 2.31MUg L-1 Ni) and level 2 (27.7 MUg L-1 Cr and 115 MUg L-1 Ni) was within the 95% confidence intervals reported in the NIST certificate. Among-run precision is less than 10% RSDs (N = 20) for in house quality control and NIST SRM urine samples. While the limits of detection (LOD) for the new quadrupole ICP-UCT-MS with KED method are similar to the SF-ICP-MS method, better measurement precision is observed for the quadrupole method. The new method presented provides fast, accurate, and more precise results on a less complex and more robust ICP-MS platform. PMID- 26229220 TI - Image-based Material Decomposition with a General Volume Constraint for Photon Counting CT. AB - Photon-counting CT (PCCT) potentially offers both improved dose efficiency and material decomposition capabilities relative to CT systems using energy integrating detectors. With respect to material decomposition, both projection based and image-based methods have been proposed, most of which require accurate a priori information regarding the shape of the x-ray spectra and the response of the detectors. Additionally, projection-based methods require access to projection data. These data can be difficult to obtain, since spectra, detector response, and projection data formats are proprietary information. Further, some published image-based, 3-material decomposition methods require a volume conservation assumption, which is often violated in solutions. We have developed an image-based material decomposition method that can overcome those limitations. We introduced a general condition on volume constraint that does not require the volume to be conserved in a mixture. An empirical calibration can be performed with various concentrations of basis materials. The material decomposition method was applied to images acquired from a prototype whole-body PCCT scanner. The results showed good agreement between the estimation and known mass concentration values. Factors affecting the performance of material decomposition, such as energy threshold configuration and volume conservation constraint, were also investigated. Changes in accuracy of the mass concentration estimates were demonstrated for four different energy configurations and when volume conservation was assumed. PMID- 26229221 TI - Hemostatic Parameters according to Renal Function and Time after Transplantation in Brazilian Renal Transplanted Patients. AB - Kidney transplantation is the key for patients with end-stage renal disease, improving quality of life and longer survival. However, kidney transplant triggers an intense inflammatory response and alters the hemostatic system, but the pathophysiological mechanisms of these changes are not completely understood. The aim of this cross-sectional cohort study was to investigate hemostatic biomarkers in Brazilian renal transplanted patients according to renal function and time after transplantation. A total of 159 renal transplanted patients were enrolled and D-Dimer (D-Di), Thrombomodulin (TM), von Willebrand Factor (VWF), and ADAMTS13 plasma levels were assessed by ELISA. An increase of D-Di was observed in patients with higher levels of creatinine. ADAMTS13 levels were associated with creatinine plasma levels and D-Di levels with Glomerular Filtration Rate. These results suggested that D-Di and ADAMTS13 can be promising markers to estimate renal function. ADAMTS13 should be investigated throughout the posttransplant time to clarify the participation of this enzyme in glomerular filtration and acceptance or rejection of the graft in Brazilian transplanted patients. PMID- 26229222 TI - An overview of disease surveillance and notification system in Nigeria and the roles of clinicians in disease outbreak prevention and control. AB - While outbreaks of infectious diseases have long presented a public health challenge, especially in developing countries like Nigeria; within recent years, the frequency of such outbreaks has risen tremendously. Furthermore, with the recent outbreaks of emerging and re-emerging infectious diseases such as Ebola virus disease and other epidemic prone diseases in Nigeria demanding immediate public health action, there is a need to strengthen the existing notifiable disease surveillance and notification system with increased clinicians' involvement in timely reporting of notifiable diseases to designated public health authorities for prompt public health action. Hence, this paper provides the opportunity to increase awareness among clinicians on the importance of immediate reporting of notifiable diseases and intensify engagement of clinicians in disease notification activities by describing various notifiable diseases in Nigeria using their surveillance case definition, outlines the reporting channel for notifying these diseases and highlights the roles of clinicians in the current disease surveillance and notification network for early disease outbreak detection and public health response in Nigeria. PMID- 26229223 TI - BAX/BCL-2 mRNA and protein expression in human breast MCF-7 cells exposed to drug vehicles-methanol and dimethyl sulfoxide (DMSO) for 24 hrs. AB - BACKGROUND: Methanol and DMSO are commonly used as carrier solvents for lipophilic chemicals in in-vitro experiments. However, very little information is available regarding the effects of these solvents on the expression of pro and anti-apoptotic genes and proteins. MATERIALS AND METHODS: In this study, we examined the cytotoxic effects of methanol and dimethylsulfoxide at 0.5% (final concentrations recommended for in-vitro toxicity assays) on human breast cancer MCF-7 cells. We also investigated the effects of these solvents on the mRNA and immunocytochemical expression of apoptotic proteins BAX and BCL-2. RESULTS: The results of neutral red cell viability assay showed that methanol and DMSO concentrations of 0.5% exhibited no cytotoxic effects on MCF-7 cells following a 24 hour exposure. Gene expression and Immunofluorescence results showed that methanol but not DMSO reduced the expression of the BAX pro-apoptotic protein, while both solvents did not alter the expression of the BCL-2 oncoprotein. CONCLUSION: Our results suggest that while methanol concentrations at 0.5% may be appropriate for in vitro toxicity studies in human breast cancer MCF-7 cells, it could alter the results of gene and protein expression experiments. PMID- 26229224 TI - Haematopoietic stem cell transplantation in Nigerian sickle cell anaemia children patients. AB - BACKGROUND: Sickle cell anaemia (SCA) remains associated with high risks of morbidity and early death. Children with SCA are at high risk for ischaemic stroke and transient ischaemic attacks, secondary to intracranial arteriopathy involving carotid and cerebral arteries. Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative treatment for SCA. We report our experience with transplantation in a group of patients with the Black African variant of SCA. PATIENTS AND METHODS: This study included 31 consecutive SCA patients who underwent bone marrow transplantation from human leukocyte antigen (HLA)-identical sibling donors between 2010 and 2014 following a myeloablative conditioning regimen. RESULTS: The median patient age was 10 years (range 2-17 years). Before transplantation, 14 patients had recurrent, painful, vaso occlusive crisis; ten patients had recurrent painful crisis in association with acute chest syndrome; three patients experienced ischaemic stroke and recurrent vaso-occlusive crisis; two patients experienced ischaemic stroke; one patient exhibited leukocytosis; and one patient exhibited priapism. Of the 31 patients, 28 survived without sickle cell disease, with Lansky/Karnofsky scores of 100. All surviving patients remained free of any SCA-related events after transplantation. CONCLUSION: The protocols used for the preparation to the transplant in thalassaemia are very effective also in the other severe haemoglobinopathy as in the sickle cell anaemia with 90% disease free survival. Today, if a SCA patient has a HLA identical family member, the cellular gene therapy through the transplantation of the allogeneic haemopoietic cell should be performed. Tomorrow, hopefully, the autologous genetically corrected stem cell will break down the wall of the immunological incompatibility. PMID- 26229225 TI - Caesarean section and perinatal outcomes in a sub-urban tertiary hospital in North-West Nigeria. AB - OBJECTIVES: This study was undertaken to review the caesarean section rate and perinatal mortality in Federal Medical Centre, Birnin Kudu from 1(st) January 2010 to 31st December, 2012. MATERIALS AND METHODS: This was a retrospective study involving review of 580 case files. Ethical clearance was obtained. The records of labour ward, neonatal intensive care unit (ICU) and operating theatre were use. Information extracted includes age, parity, booking status, total deliveries, indications for caesarean section and perinatal outcome from 1(st) January 2010 to 31(st) December 2012 at Federal Medical Centre, Birnin Kudu. The data obtained was analysed using SPSS version 17.0 statistical software (Chicago, Il, USA). Absolute numbers and simple percentages were used to describe categorical variables. Association between caesarean section and perinatal mortality was determined using Pearson's Coefficient of correlation and student t test. P - value < 0.05 was considered statistically significant. RESULT: This study reported a caesarean section rate of 17.69 % and a perinatal mortality rate of 165.6 per 1000. Majority of the babies (78.2%) were within normal weight. The mean age of the women was 25.9 +/- 6.2 years and mean parity was 4 +/- 3. Majority of them were uneducated and unemployed. Obstructed labour was the commonest indication for emergency caesarean section accounting for 31.7% of caesarean sections and foetal distress was the least at 2.6 %. Two or more previous caesarean section was the commonest indication for elective caesarean section (17.1%) and bad obstetrics history the least indication (1.4%). There is a weak positive correlation (r = 0.35) between caesarean section rate and perinatal mortality and this association was not statistically significant (P = 0.12). CONCLUSION: Caesarean section and perinatal mortality rates in the present study are comparatively high. Absence of significant correlation means that a high caesarean section rate is not likely to improve perinatal outcomes in babies of normal weight; therefore the caesarean section rate in this centre should be reduced. Measures to reduce perinatal mortality such as skilled attendant in labour and training of medical staff in neonatal resuscitation should be adopted. PMID- 26229226 TI - Predictors of breast self-examination as cancer prevention practice among women of reproductive age-group in a rural town in Nigeria. AB - BACKGROUND: Early detection of breast cancer plays an important role in decreasing its morbidity and mortality. This study therefore examines the factors influencing breast self-examination (BSE) awareness and practices among women in Ogun state, Western Nigeria. MATERIALS AND METHODS: This analytical cross sectional study was conducted between 22 April and 13 May 2013 using a semi- structured questionnaire. A multi-stage cluster sampling technique was used to select one participant per household into the study. RESULTS: A total of 495 women were interviewed in this study, the mean age of the respondents was 36.45 +/- 5.12 years. About half (58.2%) of respondents have heard of BSE and 24.4% have ever perform BSE. Only 5.3% of our respondents perform BSE regularly (monthly) as recommended. Barrier to non-performance of BSE were perception of not being at risk (47.6%), lack of knowledge of how to perform BSE (47.6%). Only 18.5% of respondents have ever had their breast examined by physicians for lump and all of them had continued to perform BSE afterwards. The only predictor of awareness and practice of breast self-examination was tertiary level of education [odds ratio (OR) = 1.43 cumulative incidence (CI) = 1.12-2.18]. CONCLUSION: The study shows level of education, smoking habits and history of breast exam by health professional and were the factors found associated with BSE practice. Training on BSE should be given to women especially during antenatal care in order to increase the practice of BSE thus averting the severe morbidity and mortality of breast cancer in developing countries. PMID- 26229227 TI - Maternal renal artery Doppler sonographic changes in pregnancy-induced hypertension in South West Nigeria. AB - BACKGROUND: To evaluate the renal arterial hemodynamic changes caused by pregnancy-induced hypertension using Doppler ultrasonography. MATERIALS AND METHODS: Eighty (80) subjects with pregnancy-induced hypertension (PIH) and 160 controls (80 pregnant normotensive women and 80 healthy, non-pregnant women) underwent triplex renal sonography prospectively to determine their renal volumes and right renal artery Doppler indices. RESULTS: The peak systolic velocity, end diastolic velocity, pulsatility index, systolic/diastolic ratio and acceleration time were respectively significantly higher in the PIH group (68.67 cm/s, 21.55 cm/s, 1.23, 3.38, 123.2 ms) than the pregnant, normotensive group (65.19 cm/s, 20.27 cm/s, 0.88, 3.35, 61.14 ms) and healthy, non-pregnant group (52.06 cm/s, 18.27 cm/s, 0.84, 2.90, 68.48 ms). Resistivity index was also increased in the PIH group, but this was not statistically significant. Conversely, the systolic acceleration was significantly lower in the PIH group (6.06 m/s(2)) compared to the pregnant, normotensive group (11.82 m/s(2)) and healthy, non-pregnant group (8.26 m/s(2)). The right renal volume of the PIH group (132.76 cm(3)) was significantly higher that of the pregnant, normotensive group (125.29 cm(3)) and healthy, non-pregnant group (91.66 cm(3)). The same pattern was observed in the left renal volume which was 168.78 cm(3), 164.95 cm(3) and 113.80 cm(3) in the study groups, respectively. CONCLUSION: Renal Doppler ultrasound is clinically relevant in the diagnosis and follow-up of renal complications in patients with pregnancy-induced hypertension. PMID- 26229228 TI - The effect of hospital infection control policy on the prevalence of surgical site infection in a tertiary hospital in South-South Nigeria. AB - BACKGROUND: Surgical site infections (SSIs) are a significant cause of morbidity, emotional stress and financial cost to the affected patients and health care institutions; and infection control policy has been shown to reduce the burden of SSIs in several health care institutions. This study assessed the effects of the implementation of the policy on the prevalence of SSI in the University of Port Harcourt Teaching Hospital, Nigeria. PATIENTS AND METHODS: A review of the records of all Caesarean sections carried out in the hospital, before and 2 years after the implementation of the infection control policy was conducted. Data collected include the number and characteristics of the patients that had Caesarean section in the hospital during the period and those that developed SSI while on admission. RESULTS: The proportion of patients with SSI decreased from 13.33% to 10.34%, 2 years after the implementation of the policy (P-value = 0.18). The implementation of the policy did not also result in any statistically significant change in the nature of the wound infection (P-value = 0.230), in the schedule of the operations (P-value = 0.93) and in the other predisposing factors of the infections (P-value = 0.72); except for the significant decrease in the infection rate among the un-booked patients (P-value = 0.032). CONCLUSION: The implementation of the policy led to a small decrease in SSI, due to the non implementation of some important aspects of the WHO policy. The introduction of surveillance activities, continuous practice reinforcing communications and environmental sanitation are recommended to further decrease the prevalence of SSI in the hospital. PMID- 26229229 TI - Denture care practice among patients attending the prosthetic clinic in a Nigerian teaching hospital. AB - BACKGROUND: Good denture care practice by individuals using Removable Partial Denture (RPD) is an important component of oral health measures. An assessment of denture care practice of such individuals by dental care practitioners is necessary. OBJECTIVE: To evaluate the denture care practice among prosthetics patients attending a tertiary Hospital Dental Centre in Nigeria. MATERIALS AND METHODS: An interviewer administered questionnaire was used to obtain information from RPD wearers that were willing to participate. The questionnaire assessed among other things, patients' bio-data, frequency, techniques and device used for cleaning their dentures. Data was analyzed using Chi-square test (P < 0.05). RESULTS: One hundred and ninety eight denture wearers consisting of 100 (50.5%) males and 98 (49.5%) females participated in the study. Majority 110 (55.6%) cleaned their dentures once daily and toothbrush and pastes were used by 105 (53%) of the participants. More than 70% of the respondents removed their dentures at night. One hundred and sixty-six (83.8%) visited the dentist only when they needed treatment. There was a statistical significant relationship between frequency and technique of cleaning denture, and denture cleanliness (P < 0.05). CONCLUSION: This study shows that once daily cleaning of dentures and cleaning the denture with rest of the teeth are ineffective in prevention of plaque accumulation. PMID- 26229230 TI - Adolescents with sickle cell anaemia: Experience in a private tertiary hospital serving a tertiary institution. AB - BACKGROUND: Many adolescents with sickle cell disease (SCD) have adjustment difficulties in the transition period from paediatric care to the adult system because they find themselves in unfamiliar waters where they have to learn to manage themselves. The aim of this study is to evaluate the prevalent crises and morbidities associated with SCD in adolescents in Babcock University Teaching Hospital (BUTH), to also assess the level of knowledge of these adolescents about SCD and to determine their emotional response to the disease. MATERIALS AND METHODS: This was a retrospective review of case notes of adolescents with sickle cell anaemia that were seen in BUTH, from May 2013 to April 2014. Data extracted from the case notes was entered into a Microsoft (MS) Excel and analysed using descriptive statistics. Results were presented in tables. RESULTS: A total of 50 subjects were seen in the department during this study period. Vaso-occlusive crises in the form of bone pains (93.1%) were the commonest crises encountered. Associated morbidities were malaria 34 (85%), tonsilitis 1 (2.5%), pneumonia 1 (2.5%), leg ulcer 1 (2.5%), azotaemia 1 (2.5%) and subarachnoid haemorrhage 2 (5%). Majority (88%) had adequate knowledge about general health maintenance while knowledge on nutrition and appropriate analgesia use is still inadequate. Eleven (22%) had symptoms of depression, four (8%) had suicidal ideation while one (2%) had a history of attempted suicide. CONCLUSION: This study emphasizes the importance of psychosocial intervention as part of a comprehensive health management for people with SCD. PMID- 26229231 TI - Relationship of blood pressure with some cardiovascular disease risk factors in a rural population of Plateau State, North Central Nigeria. AB - BACKGROUND: Hypertension is associated with certain cardiovascular disease (CVD) risk factors which vary from one place to the other depending on community sophistication. We decided to obtain the situation as it affects this rural Nigerian community to be in an evidence-based position to initiate individual and group prevention strategies. DESIGN: Cross-sectional population survey. MATERIALS AND METHODS: We surveyed for CVD risk factors among subjects 15 years and above in this rural community using a questionnaire requesting personal, medical and anthropometric information. One in three of them were randomly assigned to laboratory investigations. RESULTS: Of the 840 subjects studied, 25% were males. The population mean age was 45.5 (18.2) standard deviation (SD), with 1.8% smokers and 4.1% using alcohol. Systolic blood pressure (SBP) correlated with age, body mass index (BMI), total cholesterol (TC) and uric acid (UA); while diastolic blood pressure (DBP) correlated with age, BMI, TC, UA and atherogenic index (AI). SBP and DBP improved with exercise but not salt intake. The local seasonings used in cooking had no impact on blood pressure. CONCLUSION: To reduce cardiovascular morbidity in this and probably other rural sub-Saharan African communities, BMI, TC, UA and salt intake in diet should be targeted for reduction. Physical activity should be encouraged. Interestingly, these fall into the sphere of healthy lifestyle which should be encouraged and re-inforced. PMID- 26229232 TI - A five year audit of mammography in a tertiary hospital, North Central Nigeria. AB - BACKGROUND: Breast imaging plays a vital role in the multidisciplinary approach to management of breast disease. A baseline data is apt and necessary for collaborative studies. MATERIALS AND METHODS: This is a prospective descriptive study carried out between January 2009 and December 2013 at our institution. Patients who had breast imaging were recruited into the study. Film-screen mammograms were acquired with a General Electric (GE) Senographe DMR machine. Breast ultrasound done using an Aloka Prosound SSD-350+ ultrasound machine equipped with linear and curvilinear 7.5-10 MHz transducer. Findings were categorized using the ACR-BIRADS (American college of Radiologists-Breast imaging reporting and data system). Data was collated and analysed using social statistical package (SPSS) version 17. RESULT: The mammograms of 824 patients were evaluated during this study period. Their age ranged from 40-85 years with a mean age of 50.9 +/- 8.1 years. Eight hundred and sixteen (99%) were females and eight (1%) were males. The commonest clinical indication was breast lump (23.9%). The commonest density pattern was BIRADS 2-scattered fibroglandular pattern (43.9%). Mammograms were normal in 266 (32.3%) and positive in 558 (67.7%). The final BIRADS assessment showed BIRADS 0, 1, 2, 3, 4, 5 and 6 constituted 6.6%, 30.1%, 29.7%, 22.2%, 5.9%, 5.0% and 0.5% respectively. CONCLUSION: The level of awareness of breast cancer is quite high with the positive mammographic yield emphasizing the value of a multidisciplinary approach in the management of breast diseases. PMID- 26229233 TI - Plasmodium falciparum parasitaemia among booked parturients who received two doses of sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment in pregnancy (IPTp) in a tertiary health facility Southeast Nigeria. AB - BACKGROUND: Malaria is preventable but has contributed significantly to maternal morbidity and mortality in our environment. Malaria parasitaemia during pregnancy is mostly asymptomatic, untreated but with complications. AIM: A follow-up study aimed at determining plasmodium falciparum parasitaemia and associated complications among booked parturient who had intermittent preventive treatment with sulfadoxine-pyrimethamine (SP) compared with another study among unbooked parturients who did not take SP for intermittent preventive treatment in pregnancy (IPTp). MATERIALS AND METHODS: This study was conducted in the labour ward complex of Federal Teaching Hospital, Abakaliki from March to May 2012. Five hundred booked parturients at term that received two doses of SP were consecutively recruited. A structured data collection sheet was administered to each parturient. Thick and thin blood films were prepared for quantification and speciation of parasitaemia, respectively. The haemoglobin concentration and birth weights were determined. Analysis was done with the Statistical Package for the Social Sciences (SPSS) software with level of significance at P value < 0.05. RESULTS: The prevalence of malaria parasitaemia in the study was 59.6%. The mean age of parturients was 28.7 (5.5). The highest prevalence of malaria parasitaemia, 92% was found among the parturients aged <=19 years. The association between age and parasitaemia was significant (x(2) = 16.496, P = 0.000). The median parity was 1.0 (3.0). The highest prevalence of asymptomatic parasitaemia, 65.5% was noted among the nulliparous parturients. The association between parity and parasitaemia was significant (x(2) = 11.551, P = 0.003). Majority of the parturients were of high social class. Those of the lowest social class (class 5) had the highest prevalence (80%) of parasitaemia. The association between social class and parasitaemia was significant (x(2) = 9.131, P = 0.003). Prevalence of anaemia in the study was 14%. The non-parasitaemic and parasitaemic parturients had mean haemoglobin concentrations of 12.7 g/dl and 10.4 g/dl, respectively. There was significant association between haemoglobin concentration and parasitaemia (x(2) = 39.143, P = 0.000). The prevalence of low birth weight was 3.0%. The relationship between birth weight and parasitaemia was significant (x(2) = 2.535, P = 0.000). CONCLUSION: The was reduction in asymptomatic malaria parasitaemia compared to parturients who had no SP though the prevalence was still high showing possibly increasing resistance to SP but the treatment was still very effective in reducing anaemia and low birth weight associated with malaria in pregnancy. PMID- 26229234 TI - Role of ultrasound-guided percutaneous antegrade pyelography in malignant obstructive uropathy: A Nigerian experience. AB - Ultrasound-guided percutaneous nephrostomy of the renal pelvis is a technique that is widely acceptable especially when contrast media is introduced in the procedure of antegrade pyelography. It is a relatively safe procedure that effectively improves renal function in obstructed kidneys. It can be performed in most cases as an alternative to retrograde pyelography. We present our experience and its role in obstructive uropathy due to malignancy. PMID- 26229235 TI - Who plays the major role in fatal injuries by motorcycle in developing countries? PMID- 26229236 TI - Amyloid beta Enhances Typical Rodent Behavior While It Impairs Contextual Memory Consolidation. AB - Alzheimer's disease (AD) is associated with an early hippocampal dysfunction, which is likely induced by an increase in soluble amyloid beta peptide (Abeta). This hippocampal failure contributes to the initial memory deficits observed both in patients and in AD animal models and possibly to the deterioration in activities of daily living (ADL). One typical rodent behavior that has been proposed as a hippocampus-dependent assessment model of ADL in mice and rats is burrowing. Despite the fact that AD transgenic mice show some evidence of reduced burrowing, it has not been yet determined whether or not Abeta can affect this typical rodent behavior and whether this alteration correlates with the well known Abeta-induced memory impairment. Thus, the purpose of this study was to test whether or not Abeta affects burrowing while inducing hippocampus-dependent memory impairment. Surprisingly, our results show that intrahippocampal application of Abeta increases burrowing while inducing memory impairment. We consider that this Abeta-induced increase in burrowing might be associated with a mild anxiety state, which was revealed by increased freezing behavior in the open field, and conclude that Abeta-induced hippocampal dysfunction is reflected in the impairment of ADL and memory, through mechanisms yet to be determined. PMID- 26229237 TI - CD4+ROR gamma t++ and Tregs in a Mouse Model of Diet-Induced Nonalcoholic Steatohepatitis. AB - BACKGROUND AND AIMS: Inflammatory mediators that cross-talk in different metabolically active organs are thought to play a crucial role in the pathogenesis of Nonalcoholic Steatohepatitis (NASH). This study was aimed at investigating the CD4+RORgammat+ T-helper cells and their counterpart, the CD4+CD25+FOXP3+ regulatory T cells in the liver, subcutaneous adipose tissue (SAT), and abdominal adipose tissue (AAT) in a high fat diet (HFD) mouse model. METHODS: C57BL6 mice were fed a HFD or a normal diet (ND). Liver enzymes, metabolic parameters, and liver histology were assessed. The expression of CD4+RORgammat+ cells and regulatory T cells in different organs (blood, liver, AAT, and SAT) were analyzed by flow cytometry. Cytokine and adipokine tissue expression were studied by RT-PCR. RESULTS: Mice fed a HFD developed NASH and metabolic alterations compared to normal diet. CD4+RORgammat++ cells were significantly increased in the liver and the AAT while an increase of regulatory T cells was observed in the SAT of mice fed HFD compared to ND. Inflammatory cytokines were also upregulated. CONCLUSIONS: CD4+RORgammat++ cells and regulatory T cells are altered in NASH with a site-specific pattern and correlate with the severity of the disease. These site-specific differences are associated with increased cytokine expression. PMID- 26229238 TI - Relation of Biomarkers of Inflammation and Oxidative Stress with Hypertension Occurrence in Lone Atrial Fibrillation. AB - We compared plasma levels of biomarkers of inflammation (CRP) and oxidation (oxLDL), determined at study inclusion in lone atrial fibrillation (LAF) patients (48.6 +/- 11.5 years; 74.0% men) and sinus rhythm controls (49.7 +/- 9.3 years; 72.7% men, P > 0.05), and investigated the association of baseline CRP and oxLDL levels with the risk for vascular disease (VD) development (hypertension, cerebrovascular disease, coronary/peripheral artery disease, and pulmonary embolism) during prospective follow-up. Baseline CRP (1.2 [0.7-1.9] mg/L versus 1.1 [0.7-1.6] mg/L) and oxLDL levels (66.3 +/- 21.2 U/L versus 57.1 +/- 14.6 U/L) were higher in LAF patients (both P < 0.05). Following a median of 36 months, incident VD occurred in 14 (28.0%) LAF patients, all of whom developed arterial hypertension, and in 5 (11.4%) controls (hypertension, n = 4; coronary artery disease, n = 1), P < 0.05. LAF patients developed VD more frequently and at a younger age. Both CRP (HR, 2.54; 95% CI, 1.26-5.12; P = 0.009) and oxLDL (HR, 2.24; 95% CI, 1.14-4.40; P = 0.019) were multivariate predictors of incident hypertension in LAF patients, but not in the controls. Further research should clarify clinical relevance of investigated biomarkers for risk stratification and treatment of LAF patients. PMID- 26229239 TI - The Transcription Factor ZNF395 Is Required for the Maximal Hypoxic Induction of Proinflammatory Cytokines in U87-MG Cells. AB - Hypoxia activates the expression of proangiogenic and survival promoting factors as well as proinflammatory cytokines that support tissue inflammation. Hypoxia and inflammation are associated with tumor progression. The identification of the factors participating in the hypoxia associated inflammation is essential to develop strategies to control tumor hypoxia. The transcription factor ZNF395 was found to be overexpressed in various tumors including glioblastomas particularly in the network of a hypoxic response pointing to a functional role of ZNF395. On the other hand, ZNF395 was suggested to have tumor suppressor activities which may rely on its repression of proinflammatory factors. To address these conflictive observations, we investigated the role of ZNF395 in the expression of proinflammatory cytokines in the astrocytoma cell line U87-MG under hypoxia. We show that ZNF395 is a target gene of the hypoxia inducible factor HIF-1alpha. By gene expression analysis, RT-PCR and ELISA, we demonstrated that the siRNA mediated suppression of ZNF395 impairs the hypoxic induction of IL-1beta, IL-6, IL-8, and LIF in U87-MG cells. At ambient oxygen concentrations, ZNF395 had no enhancing effect, indicating that this transcriptional activation by ZNF395 is restricted to hypoxic conditions. Our results suggest that ZNF395 contributes to hypoxia associated inflammation by superactivating proinflammatory cytokines. PMID- 26229240 TI - Gestation Related Gene Expression of the Endocannabinoid Pathway in Rat Placenta. AB - Mammalian placentation is a vital facet of the development of a healthy and viable offspring. Throughout gestation the placenta changes to accommodate, provide for, and meet the demands of a growing fetus. Gestational gene expression is a crucial part of placenta development. The endocannabinoid pathway is activated in the placenta and decidual tissues throughout pregnancy and aberrant endocannabinoid signaling during the period of placental development has been associated with pregnancy disorders. In this study, the gene expression of eight endocannabinoid system enzymes was investigated throughout gestation. Rat placentae were obtained at E14.25, E15.25, E17.25, and E20, RNA was extracted, and microarray was performed. Gene expression of enzymes Faah, Mgll, Plcd4, Pld1, Nat1, Daglalpha, and Ptgs2 was studied (cohort 1, microarray). Biological replication of the results was performed by qPCR (cohort 2). Four genes showed differential expression (Mgll, Plcd4, Ptgs2, and Pld1), from mid to late gestation. Genes positively associated with gestational age were Ptgs2, Mgll, and Pld1, while Plcd4 was downregulated. This is the first comprehensive study that has investigated endocannabinoid pathway gene expression during rat pregnancy. This study provides the framework for future studies that investigate the role of endocannabinoid system during pregnancy. PMID- 26229241 TI - Early Foundations for Mathematics Learning and Their Relations to Learning Disabilities. AB - Children's quantitative competencies upon entry into school can have lifelong consequences. Children who start behind generally stay behind, and mathematical skills at school completion influence employment prospects and wages in adulthood. I review the current debate over whether early quantitative learning is supported by (a) an inherent system for representing approximate magnitudes, (b) an attentional-control system that enables explicit processing of quantitative symbols, such as Arabic numerals, or (c) the logical problem-solving abilities that facilitate learning of the relations among numerals. Studies of children with mathematical learning disabilities and difficulties have suggested that each of these competencies may be involved, but to different degrees and at different points in the learning process. Clarifying how and when these competencies facilitate early quantitative learning and developing interventions to address their impact on children have the potential to yield substantial benefits for individuals and for society. PMID- 26229242 TI - Evaluation of the relationship between fungal infection, neutrophil leukocytes and macrophages in cervicovaginal smears: Light microscopic examination. AB - BACKGROUND: Right after opportunistic fungi become pathogenic, they face immune system cells including macrophages and neutrophil leukocytes. Although the relationship between fungi and immune cells are being widely studied by using animal models and culture techniques, cervicovaginal smears have not been used to evaluate this interaction yet. AIM: The aim of this study was to investigate the interactions between fungal infection, macrophages and neutrophil leukocytes in cervicovaginal smear. MATERIALS AND METHODS: Papanicolaou-stained cervicovaginal smears from 2307 women, aged between 18 and 73 years, were examined by light microscopy. Periodic acid-Schiff stain was also used to confirm the presence of fungal cell walls. RESULTS: Fungal infections were detected in 239 of 2307 patients (10.4%), and these cases were taken as the study group. Cases without any infectious agents (n = 1800, 78%) were considered as the control group. When the study and control groups were statistically compared in view of macrophages and neutrophil leukocytes, a significant relationship between presence of fungal infection, macrophages and neutrophil leukocytes was detected (P < 0.05). Furthermore, macrophages and neutrophil leukocytes were found to work against the fungal infection together (P < 0.05). Additionally, when the relationship between the existence of yeast or filamentous forms and these immune cells were evaluated, a significant correlation was not found (P > 0.05). CONCLUSIONS: Our findings indicate that macrophages and neutrophils may play a determining role in host defense against fungal infection together, but neither yeast nor filamentous forms affect the presence of neutrophil leukocytes and macrophages. As a result of this, both yeast and filamentous forms may have pathogenic effects. PMID- 26229243 TI - The role of collecting bladder wash fluid before biopsy procedure to help the cytological diagnosis of residual tumor. AB - BACKGROUND: Urinary cytology has low sensitivity and specificity in urinary neoplasm. AIM: We planned to assess whether the examination of bladder washing before biopsy (WBB) plays a role in better cytologic diagnosis of bladder wash fluid collected after biopsy procedure (WAB) in papillary urothelial neoplasms. MATERIALS AND METHODS: We included 36 patients with papillary lesion of bladder. Prior to the biopsy, the bladder is washed and fluid is collected for cytology; later transurethral resection (TUR) is performed, then bladders are washed again and the fluid is separately collected for cytology. Both fluids were centrifuged and stained with May-Grunwald Giemsa (MGG). First the WAB slides were evaluated and diagnosed. After evaluation of the WBB slides, the WAB slides were rediagnosed. Presence of cellularity, papillary structure, fusiform cells, background bleeding, and cytolysis in WBB and WAB were evaluated separately. RESULTS: We determined that 31 WBB samples were hypercellular, and 12 of them remained as hypercellular in WAB. Papillary structures were observed in 20 WBB samples; and in one WAB cytology. In 29 cases where no fusiform cells are identified in WBB, 22 showed fusiform cells in WAB. Cytolysis in WABs was noted in 15 cases whose WBBs did not show cytolysis. The decrease in cellularity, papillary structure (P < 0.001, both), cytolysis (P = 0.008), and fusiform cells (P < 0.001) were statistically significant. After seeing the WBB slides, we reevaluated the WAB slides. Out of the eight out of 36 (22.2%) samples diagnosed with degeneration previously, five (62.5%) samples were rediagnosed as benign, two (25%) as cytologic atypia which favor reactive, and one (12.5%) as malignant. CONCLUSION: Due to the better quality, initial evaluation of WBB may help more effective diagnoses of WAB slides. PMID- 26229244 TI - Comparative study of cytology and immunocytochemistry with trucut biopsy and immunohistochemistry in diagnosis of localized lung lesions: A prospective study. AB - BACKGROUND: Percutaneous lung biopsy is now a common procedure in pulmonary medicine, and several different techniques are in use. The most common has been the use of a fine needle under computed tomography (CT) guidance combined with the trucut needle for histology. AIM: To evaluate the efficacy of fine needle aspiration cytology (FNAC) and immunocytochemistry in comparison with trucut biopsy and immunohistochemistry in patients with localized intrathoracic lesions suspicious for malignancy. MATERIALS AND METHODS: Eighty patients with localized mass lesions in the lung on imaging (chest radiograph/CT) were selected for this study over a period of 1 year. FNAC was carried out by a 22 G spinal needle after localization of the mass in the CT scan followed by guided trucut biopsy. Immunocytochemistry and immunohistochemistry were performed as and when required. RESULTS: The mean age of our study population was 57.6 years and the M:F ratio was 4.2:1. Majority of the lesions were peripheral and in the right lung. Adenocarcinoma was most prevalent (49%), followed by squamous cell carcinoma and small cell carcinoma. Cyto-histopathological concordance was seen in 60 cases (75%). The highest rate of concordance was seen in small cell carcinoma (83.3%). The overall sensitivity of FNAC in distinguishing malignant lung lesions from benign lesions was 84.2% and the specificity was 100%. The sensitivity of cytology in diagnosing small cell carcinoma was 83.3% and of non-small cell carcinoma was 65.38%. Immunocytochemistry was carried out in 34 cases, all of which were followed by immunohistochemistry. Cyto-histopathological concordance was noted in 31 of these cases (91.2%). We used the standard panel of four markers (cytokeratin-7, thyroid transcription factor-1, p63 and CD56) for all selected cases. CONCLUSION: Cytology along with immunocytochemistry is highly effective in diagnosing and categorizing lung neoplasms, producing comparable results to trucut biopsy and immunohistochemistry. PMID- 26229245 TI - Histopathology-like categories based on endometrial imprint cytology in dysfunctional uterine bleeding. AB - BACKGROUND: Cytology of the endometrium is an underused technique in diagnostic pathology. It has been used in the past for endometrial hyperplasia and carcinoma. Only few studies have used cytology in the diagnosis of dysfunctional uterine bleeding (DUB). Endometrial imprint cytology has been rarely used except for application of immunocytochemistry in diagnosis of endometrial carcinoma. AIM: The present study was conducted to evaluate whether it is possible to assign histopathology-like diagnosis by imprint cytology and also to evaluate its usefulness in the assessment of patients of dysfunctional uterine bleeding of low clinical suspicion. MATERIALS AND METHODS: Imprint smears were made from 93 curettage materials during a study of DUB. Blinded analysis of imprint smears was performed by using McKenzie's criteria and some criteria devised for the requirements of this study. Results of cytology were correlated with histopathology. Statistical analysis was carried out by GraphpadInStat Demo. RESULTS: Majority of the patterns classifiable in histopathology could also be classified in this study on imprint cytology. The overall sensitivity and specificity of cytology in the detection of endometrial patterns in DUB patients were 91.23% and 83.87%, respectively, although the sensitivities and specificities differ according to the phase of endometrium. CONCLUSION: Histopathology-like categories can be assigned on imprint smears in the diagnosis of DUB. Endometrial imprint cytology can be helpful in centers where histopathology laboratories are not available and even in well-established institutes. It is possible to improve the sensitivity and specificity with better imprinting techniques. PMID- 26229246 TI - Genotoxic and cytotoxic effects of X-ray on buccal epithelial cells following panoramic radiography: A pediatric study. AB - BACKGROUND: Ionizing radiation is a potent mutagenic agent capable of inducing both mutation and chromosomal aberrations. Non-lethal doses of ionizing radiation may induce genomic instability favoring carcinogenesis. In spite of their mutagenic potential, this kind of radiation is an important tool for diagnosis of the disease and is used in medical and dental practice. It has been believed that the number of micronucleus and increased frequency of other nuclear alterations, including karyorrhexis, condensed chromatin and pyknosis, are related to the increasing effects of carcinogens. Many approaches and techniques have been developed for the monitoring of human populations exposed to various mutagens, but the analysis of micronuclei (MN) has become a standard approach for the assessment of chromosomal damage in human populations. AIM: To assess the effects of radiation exposure from panoramic radiography on the buccal epithelial cells (BECs) of pediatric patients. MATERIALS AND METHODS: The study included 20 pediatric patients who had to undergo panoramic radiography for further dental treatment. Exfoliated BECs were obtained and examined immediately before and 10 days after radiation exposure. The cells were stained using rapid Papanicolaou (PAP) kit. Evaluation for MN and nuclear alterations was carried out by an oral pathologist and data were statistically analyzed using the "t" test. RESULTS: The mean number of MN in the BECs before exposure of pediatric patients to panoramic radiography was 4.25 and after exposure was 4.40. This difference was not found to be statistically significant (P < 0.0001). However, the mean nuclear alterations of 8.70 and 15.75 before and after exposure were statistically significant (P < 0.0001). CONCLUSION: Panoramic radiographs can induce cytotoxicity but not genotoxic effects in buccal mucosal cells. Hence, dental radiographs should be prescribed only when deemed indispensable. PMID- 26229247 TI - Cytomorphometric analysis of keratinized round cells in human oral carcinoma. AB - AIM: During the present investigation, two types of keratinized round cells (KRCs), large keratinized round cells (LKRCs) and small keratinized round cells (SKRCs), were observed in the exfoliated buccal smears of oral cancer patients. Therefore, the aim of the present study was to determine the practical utility of KRCs during difficult diagnosis and in the early detection of oral squamous cell carcinoma (OSCC) through cytomorphometric analysis. MATERIALS AND METHODS: In a hospital-based case control study, exfoliated scrape smears were collected from 136 patients clinically diagnosed as suffering from pre-cancerous lesions and OSCC and a parallel set of 136 samples were also collected from non-addicted and non-cancerous healthy individuals from different regions of Odisha, and this was considered as the control group. Wet-fixed smears were stained by adopting Papanicolaou's staining protocol and counter-stained with Giemsa's solution. One thousand cells were screened and keratinized round cells along with other cytological atypia were scored. Cytomorphometry was carried out using a computer assisted Cat Cam 1.30 (1.3 Mega Pixel) microscope camera. The findings were statistically analyzed and interpreted with respect to oral sites, age groups and sexes. RESULTS: Cytomorphometrically, the nucleus to cytoplasmic ratio of the LKRCs was 1:4.7 in males and 1:4.3 in females, and in SKRCs it was calculated to be 1:4.6 in males and 1:5.2 in females. CONCLUSION: Cellular keratinization, hyperchromasia and increased N/C ratios in both LKRCs and SKRCs indicates the state of malignancy and thus the present finding has a practical value in early detection and diagnosis of OSCC patients. PMID- 26229248 TI - Comparison of honey with ethanol as an oral cytological fixative: A pilot study. AB - INTRODUCTION: The fixation of cytological smears using ethanol is the gold standard. But, there exists a quench to search a new alternative for it due to it being expensive, carcinogenic and not freely available. Honey has various properties, like dehydrant, anti-bacterial and antioxidant. The use of honey as a preservative in funerary practices is well documented. A thorough search in the literature did not reveal any matter for the utility of honey as a fixative in cytological smear, but its use in histopathology is well recognized. AIMS: To analyze the efficacy of cytological smears fixed in ethanol and 20% unprocessed honey and to compare the efficacy between the two fixatives. MATERIALS AND METHODS: The study group comprised of 30 normal healthy individuals who willingly gave written consent. Prior to the collection of buccal cells, subjects were asked to rinse their mouth with water. Buccal cells were collected using a wooden ice cream stick. Two smears were collected from each subject. One smear was fixed in ethanol and the other was fixed in unprocessed 20% honey. The slides were washed in tap water for about 30 s, following which they were subjected to the conventional Papanicolaou staining procedure. The slides thus fixed were evaluated separately for ethanol and honey. The cytoplasmic and nuclear details were scored for 50 cells in each slide. Data were statistically analyzed using the chi-square test and P < 0.05 was considered statistically significant. RESULTS: Ninety percent of the ethanol-fixed (EF) smears were adequately fixed as compared with the honey-fixed (HF) smears, which were 80% adequate. The P-value obtained was 0.47 and the data were statistically insignificant. CONCLUSION: Both EF and HF smears were at par with each other, and honey can be safely used as a substitute to ethanol. PMID- 26229249 TI - Greater auricular nerve masquerading as lymph node. AB - Hansen's disease is on the verge of being eliminated from India and often missed by clinicians due to low index of suspicion. We present an unusual case in which greater auricular nerve thickening masqueraded as enlarged lymph node in the neck. The patient was referred for fine needle aspiration cytology, which revealed epithelioid cell granulomas suggestive of Hansen's disease. Further clinical examination and investigations including the skin biopsy confirmed the disease, highlighting the role of pathologist in the management of such unusual presentation of a common disease. PMID- 26229250 TI - Cutaneous metastases of prostatic adenocarcinoma. AB - Prostatic adenocarcinoma (PA) is a common visceral malignancy of elderly men. Cutaneous metastasis of PA is rare. The incidence is <1%. A 55-year-old man presented with urinary symptoms and multiple cutaneous nodules around suprapubic region, inner aspect of both thighs and scrotum. Fine-needle aspiration cytology (FNAC) of cutaneous nodules was suggestive of metastatic adenocarcinoma. Skin and prostatic biopsies confirmed the cytological diagnosis. Serum level of prostate specific antigen was raised. Total prostatectomy revealed adenocarcinoma of Gleason's score 7 (3 + 4). Though rare, cutaneous metastases of PA must be known to cytopathologists. Meticulously performed FNAC in such cases may help in early diagnosis. PMID- 26229251 TI - Urinary filariasis masquerading as the bladder tumor: A case report with cyto histological correlation. AB - Filariasis is a prevalent parasitic infection of lymphatic frequently seen in tropical countries. It has been reported in cytological samples from various sites; however, presence of microfilaria in smears from the urine sample is an uncommon finding. We describe an interesting and unusual case of elderly female who presented with achylous hematuria and an exophytic mass lesion in urinary bladder on computed tomography scan suspected of neoplastic mass lesion; however diagnosed as urinary filariasis on urine cytology and bladder biopsy. PMID- 26229252 TI - Report of a case of primary breast lymphoma highlighting the importance of fine needle aspiration cytology as an initial diagnostic tool. AB - Primary non-Hodgkin lymphoma of breast is a rare pathology, representing 0.5% of malignant breast tumors. We report a case of 52 year old female presenting with a large painful mass in left breast with ipsilateral axillary lymph node diagnosed on fine needle aspiration cytology as non-Hodgkin's lymphoma. Breast lymphoma should be differentiated from other breast malignancies because of the differences in their treatment modalities. When breast lymphoma presents as a lump with axillary node, it clinically mimics breast carcinoma. Ultrasonogram and mammogram shows no characteristic features that can distinguish it from other breast malignancy. In such cases, FNAC becomes an important diagnostic tool that can differentiate PBL from other breast malignancy and avoid unnecessary surgery. PMID- 26229253 TI - Cytological diagnosis of syringocystadenoma papilliferum a rare adnexal tumor. AB - Syringocystadenoma papilliferum is an uncommon benign adnexal tumor occurring most commonly on scalp and face. The clinical presentation varies from nodular swelling to ulcerated lesions. The lesion was on a rare site (eyebrow) was diagnosed cytologically. PMID- 26229254 TI - Transthoracic fine-needle aspiration cytology of non-invasive, low-grade urothelial carcinoma with lung metastasis: A case report with review of the literature. AB - Radiological analyses in a 61-year-old patient being followed since 2005 for low grade, non-invasive urothelial carcinoma (UC) (Ta) revealed a 5-cm pleural-based mass in the lower lobe of the right lung for which a subsequent transthoracic fine-needle aspiration cytology was performed. Upon observing the carcinoma cells consistent with UC metastasis, systemic chemotherapy was commenced. The patient underwent a metastatectomy based on the thoracic computerized tomography scan performed on the 4(th) month of treatment, which revealed notable regression. The resected tumor was morphologically similar to cells seen in the transthoracic fine-needle aspiration and was immunohistochemically positive for p63, uroplakin, thrombomodulin, CK7 and CK20 at varying degrees but was negative for TTF-1. We report a case of metastatic UC of the lung in a patient who had had a low-grade superficial UC of the urinary bladder and we discuss the cytopathological features of this rare entity in light of the literature. PMID- 26229255 TI - Cytological diagnosis of small cell osteosarcoma of the bone. AB - Small cell osteosarcoma (OS) is a rare histological variant of OS that poses unique diagnostic difficulties. We present a case of a 10-year-old child who underwent fine needle aspiration cytology (FNAC) from a mass in the right thigh. The cytological findings were those of a malignant small round cell tumor, closest to small cell OS. The FNAC findings were confirmed on histopathology. PMID- 26229256 TI - Intra-operative cytodiagnosis of primary ovarian choriocarcinoma with Ki67 immunoexpression. AB - Primary ovarian choriocarcinoma is a rare neoplasm that can be gestational and non-gestational in origin. It accounts for one in 369 million pregnancies. Both types present with similar clinical, histomorphological and ultrastructural findings. But, it is essential to differentiate the two because the gestational type has a better clinical course and responds to single-agent chemotherapy. Usually, the gestational ovarian choriocarcinoma is metastatic from uterine choriocarcinoma and follows antecedent pregnancy and is seen in females of 40 years or older. DNA polymorphism analysis showing the presence of paternal genes in the tumor establishes the gestational origin of choriocarcinoma. We present the intra-operative cytological findings of a case of primary ovarian choriocarcinoma in a 25-year-old lady arising from ectopic pregnancy with Ki67 immunostain. PMID- 26229257 TI - Disseminated histoplasmosis in an immunocompetent haweli dweller: A diagnosis and follow-up by endoscopic ultrasound-guided fine-needle aspiration. AB - Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is nowadays widespread minimally invasive procedure for diagnosing a large number of benign as well as malignant lesions. We report a case of a 62-year-old immunocompetent elderly male, who presented with high-grade fever, hepatosplenomegaly and mediastinal and intra-abdominal lymph nodes. He was residing in an old haweli with bats infestation. EUS-FNA of the subcarinal and the preaortic lymph node clinched the diagnosis. A rapid on-site evaluation of the cytology material revealed organisms conforming to the morphology of Histoplasma capsulatum. The patient was immediately started on amphotericin B and itraconazole and responded well. In this case, we found the role of EUS-FNA not only in diagnosis, but also in the follow-up of the patient. PMID- 26229258 TI - Keep it short and simple, please!! PMID- 26229260 TI - A great visionary and versatile legend. PMID- 26229259 TI - Hand in hand! PMID- 26229261 TI - A tribute to Dr. Lalit M. Guglani. PMID- 26229262 TI - Antioxidants in periodontitis and diabetes. PMID- 26229263 TI - Authors, authorship order, the moving finger writes. AB - There has been a phenomenal increase in the number of research papers with multiple authors. Increasing academic pressures and halo around individuals with prolific publications have made many aspirants to claim authorship. Increasing number of authors has brought its own issues of author credits, disputes, rivalry, and a degree of unwelcome scramble for credit sharing. Many unresolved issues about authorship and various guidelines and admonitions are more often infringed than adhered to. The position of the first and last author seem to be well recognized in medical and dental journals, but the fate of middle authors is left to guessing and often of inconsequential importance. Most of these issues, as well as fraud, misconduct in medical research publications, have been discussed amply but too of no avail. It is comforting to know that except for small shouts and whispers, dental research has been relatively free from scams and frauds. The complacency, however, needs to be tempered with constant vigil against fraud, falsification and fabrication of research reports. Honest authorship, vigilant editors, robust peer review, and a discerning readership are the sine qua non for a good research paper. Academic institutions and selection committees should be concentrating on the quality of research papers and not enamored of their number. PMID- 26229264 TI - Comparative evaluation of enamel abrasivity by toothbrush and velcro: An in vitro scanning electron microscope study. AB - CONTEXT: Plaque control has been shown to be pivotal in maintaining the optimal periodontal health. Mechanical plaque control is the most popular option for establishing the optimal oral health. Toothbrushes have been the novel tool for mechanical cleansing. However, the abrasive potential of the toothbrushes on the enamel surface is an area in gray. AIMS: The aim of this in vitro study is to evaluate the abrasivity of the toothbrush versus the velcro fasteners. MATERIALS AND METHODS: The mounted teeth of both the groups were subjected to abrasion test, and the tooth surfaces were observed for the possible abrasions from the oscillating strokes (toothbrush) and frictional contacts (hook and loop velcro) and examined under the scanning electron microscope. RESULTS: Comparative assessment of both velcro (hook and loop) and toothbrush bristles did not reveal any evidence of abrasion on the tooth specimens. CONCLUSIONS: Veclro fasteners are safe and qualitatively at par to the manual toothbrush for their efficacy and efficiency in teeth cleansing. PMID- 26229265 TI - Comparative in vitro SEM study of a novel root canal irrigant-MTAD and conventional root biomodifiers on periodontally involved human teeth. AB - BACKGROUND: Smear layer removal and collagen fiber exposure may improve regeneration which can be accomplished by use of root biomodifiers. These enhance the degree of connective tissue attachment to denuded roots. The objective of this in vitro study was to evaluate and compare novel root canal irrigant and other root biomodifiers for smear layer removal on periodontally involved human teeth. MATERIALS AND METHODS: Forty human teeth were collected and stored in saline. After scaling and root planing, two samples were obtained from each tooth. Thus, a total of 80 dentin blocks were randomly divided into four groups: Mixture of tetracycline, acid and detergent (MTAD), tetracycline hydrochloride (TTC HCl), citric acid (CA), and ethylenediaminetetraacetic acid (EDTA). The agents were applied for 3 min by active burnishing. Immediately following treatment, the specimens were rinsed, dehydrated, fixed and prepared for scanning electron microscope and were examined at * 3500 magnification. Sampaio's index was evaluated by the previously trained blind examiner using photomicrographs. Groups were compared using analysis of variance followed by Tukey's post-hoc test. RESULTS: Mixture of tetracycline, acid, and detergent is most efficacious in removing the smear layer and showed statistically significant dentinal tubules opening, followed by EDTA, TTC HCl, and CA. CONCLUSION: Mixture of tetracycline, acid and detergent and conventional root biomodifiers used in the study alters the dentin surface by smear layer removal and exposure of dentinal tubules. Hence, MTAD as a root biomodifier may have a significant role in periodontal regeneration. PMID- 26229266 TI - Mechanical properties of resin glass fiber-reinforced abutment in comparison to titanium abutment. AB - PURPOSE: So far, definitive implant abutments have been performed with high elastic modulus materials, which prevented any type of shock absorption of the chewing loads and as a consequence, the protection of the bone-fixture interface. This is particularly the case when the esthetic restorative material chosen is ceramic rather than composite resin. The adoption of an anisotropic abutment, characterized by an elastic deformability, could allow decreasing the impulse of chewing forces transmitted to the crestal bone. MATERIALS AND METHODS: According to research protocol, the mechanical resistance to cyclical load was evaluated in a tooth-colored fiber-reinforced abutment (TCFRA) prototype and compared to that of a titanium abutment (TA), thus eight TCFRAs and eight TAs were adhesively cemented on as many titanium implants. The swinging that the two types of abutments showed during the application of sinusoidal load was also analyzed. RESULTS: In the TA group, both fracture and deformation occurred in 12.5% of samples while debonding 62.5%. In the TCFRA group, only debonding was present in 37.5% of samples. In comparison to the TAs, the TCFRAs exhibited a greater swinging during the application of sinusoidal load. In the TA group, the extrusion prevailed, whereas in the TCFRA group, the intrusion was more frequent. CONCLUSION: The greater elasticity of TCFRA to the flexural load allows absorbing part of the transversal load applied on the fixture during the chewing function, thus reducing the stress on the bone-implant interface. PMID- 26229267 TI - New portable system for dental plaque measurement using a digital single-lens reflex camera and image analysis: Study of reliability and validation. AB - BACKGROUND: The quantification of the dental plaque (DP) by indices has limitations: They depend on the subjective operator's evaluation and are measured in an ordinal scale. The purpose of this study was to develop and evaluate a method to measure DP in a proportional scale. MATERIALS AND METHODS: A portable photographic positioning device (PPPD) was designed and added to a photographic digital single-lens reflex camera. Seventeen subjects participated in this study, after DP disclosure with the erythrosine, their incisors, and a calibration scale ware photographed by two operators in duplicate, re-positioning the PPPD among each acquisition. A third operator registered the Quigley-Hein modified by Turesky DP index (Q-H/TPI). After tooth brushing, the same operators repeated the photographs and the Q-H/TPI. The image analysis system (IAS) technique allowed the measurement in mm(2) of the vestibular total tooth area and the area with DP. RESULTS: The reliability was determined with the intra-class correlation coefficient that was 0.9936 (P < 0.05) for the intra-operator repeatability and 0.9931 (P < 0.05) for inter-operator reproducibility. The validity was assessed using the Spearman's correlation coefficient that indicated a strong positive correlation with the Q-H/TPI r s = 0.84 (P < 0.01). The sensitivity of the IAS was evaluated with two sample sizes, only the IAS was able to detect significant differences (P < 0.05) with the sample of smaller size (n = 8). CONCLUSIONS: Image analysis system showed to be a reliable and valid method to measure the quantity of DP in a proportional scale, allowing a more powerful statistical analysis, thus facilitating trials with a smaller sample size. PMID- 26229268 TI - Evaluation of accuracy of cone beam computed tomography for measurement of periodontal defects: A clinical study. AB - AIMS: The aim of the present study was to evaluate the accuracy of Cone Beam Computed Tomography (CBCT) measurements of alveolar bone defects caused due to periodontal disease, by comparing it with actual surgical measurements which is the gold standard. MATERIALS AND METHODS: Hundred periodontal bone defects in fifteen patients suffering from periodontitis and scheduled for flap surgery were included in the study. On the day of surgery prior to anesthesia, CBCT of the quadrant to be operated was taken. After reflection of the flap, clinical measurements of periodontal defect were made using a reamer and digital vernier caliper. The measurements taken during surgery were then compared to the measurements done with CBCT and subjected to statistical analysis using the Pearson's correlation test. RESULTS: Overall there was a very high correlation of 0.988 between the surgical and CBCT measurements. In case of type of defects the correlation was higher in horizontal defects as compared to vertical defects. CONCLUSIONS: CBCT is highly accurate in measurement of periodontal defects and proves to be a very useful tool in periodontal diagnosis and treatment assessment. PMID- 26229269 TI - Validity of ridge mapping and cone beam computed tomography in dental implant therapy. AB - AIM: The purpose of this study was to compare the validity of alveolar ridge measurements obtained with ridge mapping (RM) technique against cone beam computed tomography (CBCT) measurements. MATERIALS AND METHODS: Twenty partially edentulous patients were recruited for implant placement in the Clinic of San Martin de Porres University. For all the measurements, a vacuum-formed stent was fabricated for each subject. A buccal and lingual point was made in the stent to provide a reference of measurement for each implant site. RM measurements with the stent were obtained before and after surgical flap reflection. Two calibrated observers made the CBCT images measurements. T-test was used for the statistical analysis. Values <0.05 were considered statistically significant. Also, specificity and sensibility of CBCT and RM were compared. Intra-class correlation coefficient (ICC)_ was measure between CBCT measurements. RESULTS: A total of 62 implants sites were evaluated. No statistical significant differences were obtained with CBCT and RM measurements (P = 0,207). Detecting proper buccal lingual ridge, the sensitivity and specificity were 59% and 91% for RM while CBCT obtained 92% of sensitivity and 94% of specificity. Concordance was found "good" (ICC 0.82). CONCLUSION: Both methods provide valid measurements. Even though, we found diagnostic limitations in the RM, it demonstrated to be a useful method for its exactitude, low cost, the immediate result and no need of radiation. CBCT was recommended when the bone ridge width and height were in the less than ideal for conventional dental implant placement. PMID- 26229270 TI - Relationship between depression and chronic periodontitis. AB - BACKGROUND: Periodontitis is a chronic, multifactorial, polymicrobial disease causing inflammation in the supporting structures of the teeth. There is a plethora of nonoral risk factors which can be quoted to aid in the development of chronic periodontitis. According to WHO, depression is a common mental disorder that presents with depressed mood, loss of interest or pleasure, feelings of guilt, disturbed sleep or appetite, low energy and poor concentration. Depression is associated with negligent oral health care and another mechanism proposed disturbance in the hypothalamic-pituitary axis system and hypothalamic-pituitary thyroid system, which can affect the periodontal status by affecting the immune system. AIM: The aim of this study was to assess the association between periodontal clinical parameters and depression rating. MATERIALS AND METHODS: The study design is a case-control study with 35 patients each in case and control group. The periodontal parameters taken for measurement were probing depth and clinical attachment loss. Depression was calculated using Beck's depression scale. STATISTICAL ANALYSIS: The statistical analysis was performed by means of SPSS software (SPSS Inc., Chicago, IL, USA; version 17.0 under windows 2000). Student's t-test was used to determine the relationship between the clinical periodontal parameters and depression. RESULTS: Self-reported scoring of depression by using Beck's depression inventory has shown that periodontal patients had a significantly higher total depression score than normal controls. CONCLUSION: This study reveals that there is a direct correlation between the severity of periodontal disease and the severity of depression in patients. PMID- 26229271 TI - Oral and salivary changes in patients with chronic kidney disease: A clinical and biochemical study. AB - BACKGROUND: Both chronic kidney disease (CKD) and its treatment can affect a wide range of tissues and systems. It directly or indirectly affects flow, concentrations and composition of saliva. Hemodialysis can effectively minimize most of these complications to some extent. AIMS: The main aim of this study was to know the salivary content of sodium, potassium, calcium, urea, bicarbonate and oral manifestations in patients with CKD. MATERIALS AND METHODS: For this study, 50 patients diagnosed with CKD and 50 systemically and periodontally healthy individuals were subjected to a detailed general and intraoral examination. Whole un-stimulated saliva samples of all the selected subjects were collected and subjected to calcium (Ca), phosphorous (P), sodium (Na), potassium (K), bicarbonate and urea analysis. STATISTICAL ANALYSIS USED: Paired t-test, Mann Whitney test. RESULTS: Among 50 study subjects, 26 subjects had reduced salivary flow in the range of 0.1-0.4 ml/min. Intraoral examination of the study subjects revealed pallor, increased deposition of calculus, bleeding gums, metallic taste, hypoplasia of teeth and fissured tongue. There was a significant difference between healthy and prehemodialysis patients in the salivary sodium, potassium, calcium, phosphorus, urea levels and the difference was insignificant in relation to bicarbonate levels. CONCLUSIONS: Alterations in salivary calcium, phosphorous, urea, sodium, potassium levels were significantly higher in the study groups when compared to control groups and the difference was insignificant in relation to bicarbonate level. The increased levels in dialysis patients correlated with renal disease severity. PMID- 26229272 TI - Exploring association between sleep deprivation and chronic periodontitis: A pilot study. AB - BACKGROUND: Sleep deprivation has become a global phenomenon, and epidemiologic data indicate that short sleep duration adversely impacts human physical health. Underlying mechanisms involve modulation of immune-inflammatory mechanisms. These changes might contribute to potentiation of destructive periodontal disease. Therefore, the present study aimed to assess if there is an association of sleep deprivation with chronic periodontal diseases. MATERIALS AND METHODS: Sixty subjects were categorized into 3 groups (n = 20 each) viz. clinically healthy, gingivitis and periodontitis. Periodontal status of subjects was assessed by gingival index and pocket probing depth. All the study subjects were administered Pittsburgh Sleep Quality Index (PSQI) questionnaire for the assessment of sleep deprivation. RESULTS: Present investigation revealed that mean PSQI was highest in the periodontitis group as compared to other two groups and the difference among three groups was statistically significant. CONCLUSION: The present study with preliminary results suggestive of the association of sleep deprivation with severity of periodontal disease, definitely calls on for future studies with larger samples. PMID- 26229273 TI - Prevalence of gingival overgrowth induced by antihypertensive drugs: A hospital based study. AB - BACKGROUND: Gingival overgrowth (GO) is a known side-effect of calcium channel blockers. Although there have been several case reports, few studies have examined the prevalence of nifedipine, diltiazem, and amlodipine. This study was conducted to determine the prevalence and risk factors for GO in patients treated with calcium channel blockers. MATERIALS AND METHODS: A cross-sectional study was conducted in out patient Department of Medicine, Government Medical College, Calicut. 133 patients taking antihypertensives were examined for the presence of GO using two different indices: Vertical GO in 6 points around each tooth and horizontal Miranda-Brunet index in the interdental area. Gingival index (GI), plaque index, and probing depth were also evaluated. RESULTS: The frequency of GO was significantly higher in nifedipine-treated cases than other drug groups. Frequency of GO was 75% for nifedipine, 31.4% for amlodipine and 25% for amlodipine + metoprolol. Higher gingival, plaque and calculus were observed in patients taking calcium channel blockers. Among the possible risk factors, only the GI showed a significant correlation with GO. CONCLUSIONS: Patients taking antihypertensives had poor oral hygiene. Patients taking nifedipine showed a higher frequency of GO. Gingival inflammation acts as a predisposing factor. PMID- 26229274 TI - Periodontal health status of transport workers of a union territory in India: A cross-sectional study. AB - BACKGROUND: Periodontal disease is one of the most prevalent dental diseases, which affects the adult population of the world, varying only in degree from mild to severe. Transport industry is considered an important pillar for socioeconomic development of any nation. The present study was carried out to assess the periodontal health status of transport workers working in Chandigarh Transport Undertaking (CTU) buses, Chandigarh (Union territory). MATERIALS AND METHODS: A cross-sectional study was conducted on all available CTU workers at all three bus depots. The data were recorded on a modified WHO format (1997). A total of 998 subjects were included for community periodontal index (CPI) and attachment loss computations after doing necessary exclusions. Periodontal status was evaluated using CPI. RESULTS: About 8.13% of the subjects had healthy periodontium while maximum subjects (73.2%) had a score 2 (calculus) as evaluated by CPI. 3.4% (12) of the subjects belonging to upper middle class had deep pockets as compared to 1.9% (10) of the subjects in the lower middle class. None of the subjects in the upper high, high, and upper middle socioeconomic status (SES) category had a loss of attachment score 4. 25.9% of the postgraduates had a CPI score of 0 whereas 0.7% high school subjects had a loss of attachment score 4. CONCLUSION: Advanced periodontal disease (CPI score, 4) affected small number of subjects with maximum subjects (73%) having a CPI score of 2. There was statistically significant association of SES and education level with the CPI score and loss of attachment level. PMID- 26229275 TI - Attitudes of dental professionals toward tobacco use. AB - BACKGROUND: The habit of tobacco consumption has plagued all nations from time immemorial. While tobacco use is decreasing in many developed countries, it is increasing in developing countries like India. Health care professionals have a key role to play to motivate and advise tobacco users to quit. AIM: The aim was to assess the attitudes and practice of dental professionals in Mumbai and Navi Mumbai toward tobacco cessation and the potential barriers faced. MATERIALS AND METHODS: Questionnaire-based survey was conducted with 500 dental surgeons in Mumbai and Navi Mumbai. The questionnaire contained close-ended questions and assessed the smoking status of the professional, whether they impart tobacco cessation advice to their patients, whether the professional is trained for basic intervention, whether they would be eager to undergo training and also the potential barriers encountered by the professional. STATISTICAL ANALYSIS USED: The SPSS version 17 was used. Frequencies and percentages were used to determine distributions of the responses for each of the variables. Chi-square test was used for analysis. RESULTS: It was observed that the majority of dental clinicians do not use tobacco and although 93% believed that it is the role of the dental professional to offer advice, 21% do not. Potential barriers reported were: Little chance of success, lack of training, lack of time, lack of remuneration, and the possibility of losing patients. CONCLUSIONS: Dental professionals must expand their horizon and armamentarium to tobacco intervention strategies inclusive of their regular preventive and therapeutic treatment modalities. Furthermore, the dental institutions (schools) should include tobacco intervention in the curriculum, but it should not be just theoretical knowledge rather it must have a practical component. PMID- 26229276 TI - A survey on acquaintance, orientation and behavior of general medical practitioners toward periodontal diseases. AB - BACKGROUND: An association between oral conditions such as periodontal diseases and systemic conditions is noted. As such, periodontal disease is associated with an increased risk of systemic illnesses such as cardiovascular disease, diabetes, adverse pregnancy outcome, atherosclerosis, stroke and hospital acquired pneumonia. The concept of diagnosing and treating a potential patient to minimize the deleterious effects of this chronic infectious and inflammatory condition on systemic conditions represents both an unprecedented challenge and opportunity to our profession. Keeping this in view, the present survey was designed to evaluate the acquaintance, orientation and behavior of general medical practitioners; concerning the effects of periodontal disease on systemic health. MATERIALS AND METHODS: A typed questionnaire carrying four sets of questions was distributed among general medical practitioners of seven different government and private medical colleges and hospitals. Questionnaire was developed to assess the acquaintance, orientation and behavior of general medical practitioners toward periodontal disease. RESULTS: Most of the respondents have knowledge regarding the signs and symptoms of periodontal disease and its association with cardiovascular disease. However, majority of them do not know about the potential effect of periodontal disease on other organ systems. CONCLUSION: General medical practitioners have inadequate knowledge regarding periodontal diseases. Hence, oral health related training should be an integral part of the medical curriculum. PMID- 26229277 TI - Oral pulse or hyaline ring granuloma: A case report and a brief review. AB - Pulse or hyaline ring granulomas are rare but are well-defined oral and extraoral lesions due to implantation of the cellulose moiety of plant foods in contrast starch components. A unique form as reactive gingival growth showing histologic features of oral pulse or hyaline ring granuloma (OPHRG) which had resulted from implantation of food particles of plant or vegetable origin into the periodontium has been illustrated. Such a presentation is attributable to compromised periodontal health and poor oral hygiene favoring the implantation of food particles has been described here along with a literature update on OPHRG. PMID- 26229278 TI - Recurrent peripheral cemento-ossifying fibroma. AB - Peripheral cement-ossifying fibroma (PCOF) is a rare osteogenic neoplasm that ordinarily presents as an epulis-like growth. It frequently occurs in maxillary anterior region in teenagers and young adults. We report a case of PCOF in a 42 year-old male, which was previously surgically excised and recurred after a period of 2 years. PCOF should be considered in the differential diagnosis of reactive hyperplastic lesions originating from gingiva. Hence, early diagnosis with proper surgical excision and aggressive curettage of the adjacent tissues is essential for prevention of recurrence. PMID- 26229279 TI - Carotid type of Eagle's syndrome. AB - Eyes don't see what mind does not know. It is important for a clinician to refresh his knowledge frequently to recognize some of the conditions that one may come across rarely no matter how insignificant the condition may seem. Especially in a dental outpatient department setting, individuals may complain of varied symptoms which the clinician, often tends to correlate to one of the oral diseases. We present a case of Eagle's syndrome with vague clinical presentation which could have easily gone undiagnosed if not for the application of simple diagnostic procedures and aids like Orthopantamogram (OPG). PMID- 26229280 TI - Traumatic impaction of foreign body in the mucobuccal fold of lower anterior region in the oral cavity: A chance finding. AB - Foreign bodies may be ingested, inserted or deposited in the oral cavity. Iatrogenic foreign bodies such as impression material, amalgam, broken instruments, needles etc., are commonly encountered. These foreign bodies are generally symptomatic and show signs of inflammation pain and purulent discharge. An unusual case of asymptomatic traumatic foreign body (stone) impacted in the lower anterior region due to an accident 3 years back, which was diagnosed during routine oral examination is reported. PMID- 26229281 TI - Management of hereditary gingival fibromatosis: A 2 years follow-up case report. AB - Hereditary gingival fibromatosis (HGF) is a rare hereditary condition characterized by slow, progressive, nonhemorrhagic, fibrous enlargement of gingiva due to increase in sub-mucosal connective tissue component. This paper presents a case report of an 18-year-old female suffering from HGF with positive family history. Her 42-year-old mother also have enlargement of the gums. After through clinical examination of both the patients, routine blood investigation was advised. All the investigations were within normal physiological limits of both the patients. Surgical excision of enlarged gingival tissue was planned after meticulous scaling and root planing. Patients were recalled 1 week after surgery. Postoperative healing were good and desired crown lengthening was achieved with significant improvement in speech and masticatory problems in both the patients. There was no recurrence of the disease even after 2 years follow up. PMID- 26229282 TI - Periodontal plastic procedure for the management of the residual gingival defect after excision of an epulis. AB - Dentinal hypersensitivity and unesthetic appearance are common findings after excision of an epulis due to exposure of root and underlying bone. The simultaneous placement of subepithelial connective tissue grafting after excision of the lesion seems to be viable surgical option in such cases. Furthermore, this will avoid second surgical procedure for the management of the residual gingival defect. PMID- 26229283 TI - Endodontic and periodontal management of a severely affected maxillary lateral incisor having combined mucosal fenestration and palatogingival groove. AB - Mucosal fenestrations, wherein the tooth root apices are clinically discernible in the oral cavity subsequent to loss of overlying alveolar bone and mucosa, are rare pathologic entities. Palato gingival grooves- anatomic aberrations are also infrequent occurrences that notoriously predispose to periodontal pathologies of varying extent. Both conditions independently are known to popularly affect maxillary lateral incisors. Coexistent fenestration defect and palato gingival groove in the same tooth is extremely rare and undoubtedly is a perfect combination to precipitate severe endodontic-periodontal consequences. In this report, a 34-year-old patient presented to the dental department with complaint of esthetics in relation to exposed root of right maxillary lateral incisor. On closer inspection, a palato gingival groove in addition to fenestration defect was evident on the root surface along with a periodontal pocket of >5 mm. An interdisciplinary treatment was instituted which included endodontic treatment followed by root end resection, osseous bone graft placement and guided tissue regeneration procedures for repair of mucosal fenestration defect. Debridement of the palatal pocket, with saucerization of the groove and restoration with glass ionomer cement were simultaneously employed to correct the palatal defect. PMID- 26229284 TI - Surgical management of the bilateral maxillary buccal exostosis. AB - Buccal exostosis is benign, broad-based surface masses of the outer or facial aspect of the maxilla and less commonly, the mandible. They begin to develop in early adulthood and may very slowly enlarge over the years. A 24-year-old female presented with gingival enlargement on the buccal aspect of both the quadrants of the maxillary arch. The overgrowth was a cosmetic problem for the patient. The etiology of the overgrowth remains unclear though the provisional diagnosis indicates toward a bony enlargement, which was confirmed with the help of transgingival probing. The bony enlargement was treated with resective osseous surgery. The following paper presents a rare case of the bilateral maxillary buccal exostosis and its successful management. PMID- 26229285 TI - Modified lip repositioning: A surgical approach to treat the gummy smile. AB - Gummy smile has been an esthetic concern for many patients. This clinical report describes a successful surgical coverage obtained by modified lip repositioning, thus surgically treating the gummy smile. The technique was performed to limit the retraction of elevator muscles (e.g., zygomaticus minor, orbicularis oris, leviator anguli oris and levator labi oris.) The technique is fulfilled by removing two strips of mucosa from maxillary buccal vestibule on both the sides leaving the frenum untouched and creating a partial thickness flap between mucogingival junction and upper lip musculature, and suturing the lip mucosa with mucogingival junction, resulting in a narrow vestibule and restricted muscle pull, thereby reducing gingival display. This technique is different from the conventional surgical lip repositioning as labial frenum is left untouched over here as it helps in maintain Litton the midline for lip repositioning and reduces the morbidity associated with it. PMID- 26229286 TI - HgsDb: Haplogroups Database to understand migration and molecular risk assessment. AB - HgsDb, a database is developed to organize the data under a single platform to facilitate easy access for researcher to get information on migration and molecular risk assessment. In past, human beings migrate from one place to other over the globe in search of food and better habitat, where they got adapted. These adaptations are visible in the form of change in color, facial pattern, average height, eye shape, hair texture, etc. This leads to origin of different race of human being. The adaptations are remarkable when move from equator to either poles. There are hundreds of different haplogroups reported on both maternal and paternal sites. This database provides overview of seventy-six major Haplogroup of mt-DNA and Y-DNA with their sub classes supplemented with structural information of individual Haplogroup responsible for various factor such molecular risk assessment, migration and origin. They help genealogist to gain deep insight information about their maternal and paternal patterns. , we had collected data from open source such as National Center for Biotechnology (NCBI), to develop this database for providing information, which Will helps the medical biology, molecular biology, genealogy and for designing personalized medicine. AVAILABILITY: www.gbpec.ac.in/research/HgsDb/. PMID- 26229287 TI - MapRepeat: an approach for effective assembly of repetitive regions in prokaryotic genomes. AB - The newest technologies for DNA sequencing have led to the determination of the primary structure of the genomes of organisms, mainly prokaryotes, with high efficiency and at lower costs. However, the presence of regions with repetitive sequences, in addition to the short reads produced by the Next-Generation Sequencing (NGS) platforms, created a lot of difficulty in reconstructing the original genome in silico. Thus, even today, genome assembly continues to be one of the major challenges in bioinformatics specifically when repetitive sequences are considered. In this paper, we present an approach to assemble repetitive regions in prokaryotic genomes. Our methodology enables (i) the identification of these regions through visual tools, (ii) the characterization of sequences on the extremities of gaps and (iii) the extraction of consensus sequences based on mapping of raw data to a reference genome. We also present a case study on the assembly of regions that encode ribosomal RNAs (rRNA) in the genome of Corynebacterium ulcerans FRC11, in order to show the efficiency of the strategies presented here. The proposed methods and tools will help in finishing genome assemblies, besides reducing the running time and associated costs. AVAILABILITY: All scripts are available at http://github.com/dcbmariano/maprepeat. PMID- 26229288 TI - Molecular docking based screening of GABA (A) receptor inhibitors from plant derivatives. AB - The present antipsychotic drugs have known to show serious concerns like extra pyramidal side effects therefore, pursuit for novel antipsychotic GABAnergic drugs has lately focused on the folkloric medicine from plant derivatives as better treatment option of schizophrenia. The present study centers to identify potential inhibitors of plant origin for GABA receptor through in silico approaches. Three compound datasets were undertaken in the study. The first set consisted of seven compounds which included Magnolol, Honokiol and other plant derivatives. The second set consisted of 16 derivatives of N-diarylalkenyl piperidinecarboxylic acid synthesized by Zheng et al., 2006. The third dataset had thirty two compounds which were Magnolol and Honokiol analogues synthesized by Fuchs et al., 2014. All the compounds were docked at the allosteric site of the GABA (A) receptor. The compounds were further tested for ADMET and biological activity. We observed Honokiol and its derivatives demonstrated superior druglike properties than any compound undertaken in the study. Further, compound 61 [2-(4 methoxyphenyl)-4-propylphenol] of dataset three - a synthetic derivative of honokiol had better profile than its parent compound. In a possible attempt to identify compound with even better efficacious compound than 61, virtual screening was performed, 135 compounds akin to compound 61 were retrieved. Interestingly none of the 135 compounds showed better druggable properties than compound 61. Our in silico pharmacological profiling of compounds is in coherence and is complemented by the findings of Fuchs et al, which also revealed compound 61 to be the good potentiator of GABA receptor. ABBREVIATIONS: GABA (A) R - Gamma Amino Butyric Acid Receptor, subtype A, GPCR - G Protein Coupled Receptor, OPLS - Optimized Potentials for Liquid Simulations, PDB - Protein Data Bank, PLP - Piece wise Linear Potential, T.E.S.T - Toxicity Estimation Software Tool, TCM - Traditional Chinese Medicine. PMID- 26229289 TI - Detection of G-type density in promoter sequence of colon cancer oncogenes and tumor suppressor genes. AB - The guanine rich locations are present in human genome. Previous studies have shown that the presence of G rich sequences and motifs may be significant for gene activity and function. We decided to focus our interest to identify G rich motifs in promoters of oncogenes and tumor suppressor genes. We used a set of 100 most common oncogenes and tumor suppressor genes (TSG) for this analysis. We collected 600nt long promoters with -500 and +100 TSS (transcription start site) from the oncogenes and TSG set. Using a computer program, we calculated the G densities using numbers and locations of G forms with 100nt moving widow. We included G numbers from 2 to 7 guanines. Analysis shows that G density increases from -500 to +100 and more from TSS. G density is found to be maximum within /+100 of TSS. The results of G densities were compared with the expression data of the selected oncogenes and tumor suppressor genes in patients with colon cancer (n=174). PMID- 26229290 TI - Implication from the predicted docked interaction of sigma H and exploration of its interaction with RNA polymerase in Mycobacterium tuberculosis. AB - M. tuberculosis is adapted to remain active in the extreme environmental condition due to the presence of atypical sigma factors commonly called extra cytoplasmic function (ECF) sigma factors. Among the 13 sigma factors of M. tuberculosis, 10 are regarded as the ECF sigma factor that exerts their attributes in various stress response. Therefore it is of interest to describe the structural prediction of one of the ECF sigma factors, sigma H (SigH), involved in oxidative and heat stress having interaction with the beta' subunit of M. tuberculosis. RNA polymerase (Mtb-RNAP). The model of Mtb-SigH was build using the commercial package of Discovery Studio version 2.5 from Accelerys (San Diego, CA, USA) containing the inbuilt MODELER module and that of beta' subunit of Mtb-RNAP using Phyre Server. Further, the protein models were docked using the fully automated web tool ClusPro (cluspro.bu.edu/login.php). Mtb-SigH is a triple helical structure having a putative DNA-binding site and the beta' subunit of MtbRNAP consists of 18-beta sheets and 22 helices. The SigH-Mtb-RNAP beta' interaction studies showed that Arg26, Gln19 andAsp18, residues of SigH protein are involved in binding with Arg137, Gln140, Arg152, Asn133 and Asp144 of beta' subunit of Mtb-RNAP. The predicted model helps to explore the molecular mechanism in the control of gene regulation with a novel unique target for potential new generation inhibitor. PMID- 26229291 TI - Insight into the mechanism of lipids binding and uptake by CD36 receptor. AB - The membrane protein CD36 is a member of the class B scavenger receptor family. It plays a crucial role in some cardiovascular pathologies and metabolic diseases. Studying the mechanism of action of CD36 receptor is limited due to the absence of its tridimensional crystallized structure. The molecular docking method has allowed us to perform various simulation of the CD36 receptor interaction with their ligands involved in the development of some diseases. In this work, we predicted a tridimensional structure model of CD36 extracellular domain. In addition, we have achieved several tests of rigid and flexible docking by acting on residues proposed in previous experimental researches as essential in fixing of LFCAs. Furthermore, we have acted on regions that appear a key binding site of LFCAs. The physicoc hemical evaluation indicated the reliability of the proposed CD36 structure used for different molecular docking tests. Based on the docking outcome, we were able to propose the different steps of the mechanism allowing the interaction of fatty acids on CD36 receptor and their penetration into the cell cytoplasm. The obtained results and taking in consideration CD36 receptor as a therapeutic target will help us to suggest the mechanism by which an antagonist may inhibit this receptor by acting on its extracellular domain. PMID- 26229292 TI - Molecular Docking studies of FKBP12-mTOR inhibitors using binding predictions. AB - Mammalian target of rapamycin (mTOR) is a key regulator of cell growth, proliferation and angiogenesis. mTOR signaling is frequently hyper activated in a broad spectrum of human cancers thereby making it a potential drug target. The current drugs available have been successful in inhibiting the mTOR signaling, nevertheless, show low oral bioavailability and suboptimal solubility. Considering the narrow therapeutic window of the available inhibitors, through computational approaches, the present study pursues to identify a compound with optimal oral bioavailability and better solubility properties in addition ensuing high affinity between FKBP12 and FRB domain of mTOR. Current mTOR inhibitors; Everolimus, Temsirolimus Deforolimus and Echinomycin served as parent molecules for similarity search with a threshold of 95%. The query molecules and respective similar molecules were docked at the binding cleft of FKBP12 protein. Aided by MolDock algorithm, high affinity compounds against FKBP12 were retrieved. Patch Dock supervised protein-protein interactions were established between FRB domain of mTOR and ligand (query and similar) bound and free states of FKBP12. All the similar compounds thus retrieved showed better solubility properties and enabled better complex formation of mTOR and FKBP12. In particular Everolimus similar compound PubChem ID: 57284959 showed appreciable drugs like properties bestowed with better solubility higher oral bioavailability. In addition this compound brought about enhanced interaction between FKBP12 and FRB domain of mTOR. In the study, we report Everolimus similar compound PubChem ID: 57284959 to be potential inhibitor for mTOR pathway which can overcome the affinity and solubility concerns of current mTOR drugs. ABBREVIATIONS: mTOR - Mammalian Target of Rapamycin, FRB domain - FKBP12-rapamycin associated protein, FKBP12 - FK506 binding protein 12, OPLS - Optimized Potentials for Liquid Simulations, Akt - RAC alpha serine/threonine-protein kinase, PI3K - phosphatidylinositide 3-kinases. PMID- 26229293 TI - Computer aided gene mining for gingerol biosynthesis. AB - Inspite of the large body of genomic data obtained from the transcriptome of Zingiber officinale, very few studies have focused on the identification and characterization of miRNAs in gingerol biosynthesis. Zingiber officinale transcriptome was analyzed using EST dataset (38169 total) deposited in public domains. In this paper computational functional annotation of the available ESTs and identification of genes which play a significant role in gingerol biosynthesis are described. Zingiber officinale transcriptome was analyzed using EST dataset (38169 total) from ncbi. ESTs were clustered and assembled, resulting in 8624 contigs and 8821 singletons. Assembled dataset was then submitted to the EST functional annotation workflow including blast, gene ontology (go) analysis, and pathway enrichment by kyoto encyclopedia of genes and genomes (kegg) and interproscan. The unigene datasets were further exploited to identify simple sequence repeats that enable linkage mapping. A total of 409 simple sequence repeats were identified from the contigs. Furthermore we examined the existence of novel miRNAs from the ESTs in rhizome, root and leaf tissues. EST analysis revealed the presence of single hypothetical miRNA in rhizome tissue. The hypothetical miRNA is warranted to play an important role in controlling genes involved in gingerol biosynthesis and hence demands experimental validation. The assembly and associated information of transcriptome data provides a comprehensive functional and evolutionary characterization of genomics of Zingiber officinale. As an effort to make the genomic and transcriptomic data widely available to the public domain, the results were integrated into a web based Ginger EST database which is freely accessible at http://www.kaubic.in/gingerest/. PMID- 26229294 TI - What's new in emergencies, trauma and shock? Traumatic Brain Injury Research in India: Getting shape, taking momentum. PMID- 26229295 TI - An epidemiological study of traumatic brain injury cases in a trauma centre of New Delhi (India). AB - BACKGROUND: Trauma is one of the leading causes of death and disability in Indian population. AIM: To correlate various variables like epidemiology, clinical status, severity of TBI & associated co-morbid conditions and its outcome. SETTINGS AND DESIGN: This study involved retrospective collection, prospective management and follow up of 796 cases of TBI admitted to the neurosurgery department of a tertiary care hospital in New Delhi during one year study duration. MATERIALS AND METHODS: All the relevant variables recorded and analyzed with Glasgow Outcome Scale (GOS) in 6 months into 3 groups i.e. group 1 (GOS 1/Dead), group 2 (GOS-2&3/Bad) and group 3- (GOS-3&4/good). STATISTICAL ANALYSIS: Compiled data collected, analyzed and difference between two proportions was analyzed using Chi Square test. RESULTS: This study included 791 cases with 569 (72%) males and 222 (28%) females with average age of 24 years. Fall from height was the main cause of TBI (56%) followed by road traffic injury (RTI) (36%). Majority (61%) patients reached the hospital within 6 hours of injury out of which 27% patients were unconscious. As per Glasgow coma scale mild, moderate & severe grade of TBI was seen in 62%, 22% &16% cases respectively. Radiological examination of other body parts revealed injuries in 11% cases. Only 11% cases required surgical management, rest was managed conservatively. Good outcome noted in 80% cases and 20% cases expired. Average duration of hospital stay was 5 days. According to multivariate analysis, the factors which correlated with poor prognosis are presence of radiological injuries to other body parts, GCS, abnormal cranial nerve examination, abnormal plantar and abnormal pupillary reflex. (P < 0.05). CONCLUSION: TBI predominantly affects young male population and most of these are preventable. Early transportation to the hospital and first aid results in good outcome. Mortality increases with the severity of TBI and associated injuries therefore multimodality approach in polytrauma is essential. PMID- 26229296 TI - "Occult" rib fractures diagnosed on computed tomography scan only are still a risk factor for solid organ injury. AB - INTRODUCTION: Prior to the widespread use of computed tomography (CT) scan imaging, lower rib fractures diagnosed on chest X-rays (CXRs) were considered a risk factor for abdominal solid organ injury (ASOI). However, CXRs miss about 50% of the rib fractures that are detected on CT scans. We hypothesized that these "occult" rib fractures would not be predictive for ASOI. MATERIALS AND METHODS: Retrospective review of a level I trauma center's database identified all adult blunt trauma patients (n = 11,170) over a 5-year period. Data were abstracted for demographics, injury severity score, presence of ASOI, extremity, pelvic and spine fractures as well as presence and location of rib fractures. RESULTS: Rib fractures correlated with the presence of ASOI, regardless of whether they were diagnosed by CXR or CT scan alone (P < 0.01). Middle (3-7) and lower (8-12) rib fractures, especially, correlated with the presence of ipsilateral ASOI (P < 0.0001). DISCUSSION: Although CT scan detects more rib fractures than CXR, rib fractures remain a marker for increased likelihood of ASOI regardless of the modality by which they are diagnosed. Patients with rib fractures also have a greater incidence of spine and pelvic fractures. As the trauma community debates moving away from routine whole-body CT imaging towards a more selective approach, these results suggest that any clinical suspicion of rib fractures, despite a negative CXR, may warrant further investigation. PMID- 26229297 TI - Insulin treatment before resuscitation following hemorrhagic shock improves cardiac contractility and protects the myocardium in the isolated rat heart. AB - BACKGROUND: Insulin has been shown to exert positive inotropic effects in several in vivo ex vivo models and in human hearts. Resuscitation following hemorrhagic shock results in myocardial contractile dysfunction. However, the optimal timing for treatment with insulin for the cardioprotection effects is unclear. OBJECTIVES: The objective of this study was to test the hypothesis that treatment with insulin before resuscitation provides better cardioprotection than treatment with insulin after resuscitation. MATERIALS AND METHODS: Rats were assigned to 3 experimental groups (n = 6 per group): (1) Hemorrhagic shock and resuscitation, (2) hemorrhagic shock resuscitated then treated with insulin and (3) hemorrhagic shock treated with insulin before resuscitation. Rats were hemorrhaged for 60 min to rach mean arterial blood pressure of 40 mmHg. Rats were resuscitated in vivo by reinfusion of the shedded blood to restore normotension and monitored for 60 min. Rats were treated or not with insulin 200 MUU/g body weight intramuscularly either before or after resuscitation. The maximum of the left ventricular developed pressure (+dP/dt) was measured for 60 min in the isolated perfused hearts using the Langendorff method. Blood samples were obtained for measurements of tumor necrosis factor-alpha (TNF-alpha). RESULTS: Treatment with insulin before resuscitation following hemorrhagic shock significantly elevated max dP/dt compared with insulin treatment after resuscitation and the untreated group. TNF alpha levels were lower in the insulin treatment before resuscitation compared to the treatment after resuscitation and the untreated group. CONCLUSION: Insulin treatment before resuscitation following hemorrhagic shock provides better cardiac protection than treatment with insulin after resuscitation, as evidenced by the improved myocardial contractility, preservation of myocardial structure. The mechanism of cardiac protection involves decrease in the inflammatory response to shock by lowering the levels of TNF. PMID- 26229298 TI - Ultrasound guided Deep Vein cannulation: "Perpendicular Insertion Technique (PIT)", an edge over "Conventional Insertion Technique (CIT)". AB - INTRODUCTION: The use of ultrasound imaging before or during vascular cannulation greatly improves first-pass success and reduces complications, but this skill must then be combined with manual dexterity to perform the three dimensional (3D) procedure of placing a catheter into the deep veins while analyzing the 2D images. Hence this study is an attempt to still decrease the above mentioned limitation of guided deep vein cannulation by slight modification in the insertion technique. AIMS AND OBJECTIVES: Aims to compare the ultrasound guided deep vein cannulation by conventional insertion technique(CIT) v/s ultrasound guided perpendicular insertion technique (PIT). Main comparison parameters here are number of attempts required, time taken for successful insertion, vessel counter puncture, arterial puncture and other known mechanical complications of deep venous cannulation. MATERIAL AND METHOD: Prospective, non randomized cross sectional study, done over 200 patients in two arms. Data-analysed by epi2k and state-9 software. RESULTS: Total number of insertions were 64 by CIT v/s 136 by the PIT. Mean of number of attempts required were 1.918 with the CIT v/s 1.106 for the PIT method. Mean of time of cannulation was 78.62 + 18 sec with CIT while it was 66.98 + 12 sec for PIT and this was statistically significant(P = 0.041). Incidence of vessel counter-puncture was much lower in PIT as compared to CIT (6.1 % v/s 16.2%). 5.9% cannulation done by CIT had arterial puncture v/s 0.8% with the PIT. Not a single episode of any other mechanical complications with either of the method. CONCLUSION: USG guided perpendicular method is less time consuming, less number of attempts are required and there are less chances of arterial picture or vessel counter puncture. PMID- 26229299 TI - Patterns and outcomes of traumatic neck injuries: A population-based observational study. AB - OBJECTIVES: We aimed to analyze the pattern and outcome of traumatic neck injury (TNI) in a small population. MATERIALS AND METHODS: It is a retrospective analysis of all TNI patients who were admitted to the trauma center between 2008 and 2012. Patients' demographics, details of TNI, associated injuries, hospital course, and mortality were analyzed. RESULTS: A total of 51 TNI cases were included revealing an overall incidence of 0.61/100,000 population. The mean age was 31 +/- 9 years. The most frequent mechanism of injury was motor vehicle crash (29.4%) followed by stab (17.6%), machinery injury (17.6%), fall (9.8%), and assault (7.8%). Larynx, thyroid gland, trachea, jugular veins, and carotid were the commonly injured structures. The majority of cases had Zone II TNI whereas isolated injury was observed in 11 cases. TNI were mainly presented with active bleeding (38%), hypovolemic shock (16%) and respiratory distress (16%). Surgical interventions mainly included simple repair and closure (53%), vein ligation (12%), repair of major arteries (4%), tracheal repair (6%), larynx and hypopharynx repair (4%), and repair of parotid gland (2%). Neck exploration was performed in 88%, and emergency tracheostomy was required in 18% of cases. Overall mortality rate was 11.8%, of which five patients had associated injuries, and one had isolated TNI. CONCLUSION: TNI are not frequent but represent an alarming serious entity in Qatar. Patients with persistent signs of major injuries should undergo early operative interventions. Moreover, the effective injury prevention program should be developed to minimize these preventable injuries in the majority of cases. PMID- 26229300 TI - Pyruvate dose response studies targeting the vital signs following hemorrhagic shock. AB - OBJECTIVES: To determine the optimal effective dose of sodium pyruvate in maintaining the vital signs following hemorrhagic shock (HS) in rats. MATERIALS AND METHODS: Anesthetized, male Sprague-Dawley rats underwent computer-controlled HS for 30 minute followed by fluid resuscitation with either hypertonic saline, or sodium pyruvate solutions of 0.5 M, 1.0 M, 2.0 M, and 4.0 M at a rate of 5ml/kg/h (60 minute) and subsequent blood infusion (60 minute). The results were compared with sham and non- resuscitated groups. The animals were continuously monitored for mean arterial pressure, systolic and diastolic pressure, heart rate, pulse pressure, temperature, shock index and Kerdo index (KI). RESULTS: The Sham group remained stable throughout the experiment. Non-resuscitated HS animals did not survive for the entire experiment due to non-viable vital signs and poor shock and KI. All fluids were effective in normalizing the vital signs when shed blood was used adjunctively. Sodium pyruvate 2.0 M was most effective, and 4.0 M solution was least effective in improving the vital signs after HS. CONCLUSIONS: Future studies should be directed to use 2.0 M sodium pyruvate adjuvant for resuscitation on multiorgan failure and survival rate in HS. PMID- 26229301 TI - Ultrasound visualization of a pleural adhesion. AB - A group of multidisciplinary sonologists conduct weekly Intensive Care Unit (ICU) rounds consisting of ultrasound examinations on select patients recommended by the critical care staff. This image was acquired on a 51-year-old male in the ICU with known valve vegetations, and a pleural adhesion was incidentally discovered on ultrasound. PMID- 26229302 TI - Penetrating injury from high-speed motor vehicle collision. AB - We present the case history of a post motor vehicle crash victim with lower extremity fractures and decreased blood flow. Emergent Angipgraphy revealed a foreign body which was later operated and removed. The case emphasizes that High speed motor vehicle accidents commonly lead to penetrating injury from objects within and outside of the vehicle. PMID- 26229303 TI - Presence of rash in a catastrophic condition. PMID- 26229304 TI - Application of a scoring instrument to predict intracerebral hemorrhage and outcome after thrombolysis for acute ischemic stroke. PMID- 26229305 TI - An unexpected complication of sneezing: Blow-out orbital fracture. PMID- 26229306 TI - Sagittal sinus thrombosis in puerperium. PMID- 26229307 TI - Rare case of pure medial subtalar dislocation: Conservative treatment and 32 months follow-up. PMID- 26229308 TI - Acid ingestion in pediatric population; negligence to be compensated with lifelong morbidity. PMID- 26229309 TI - Polytrauma patient with through and through penetrating rod in abdomen: Timing and team is of utmost importance in emergency management. PMID- 26229310 TI - The Qur'an and the development of rational thinking Urology Annals April-June 2015 | Vol 7 | Issue 2. PMID- 26229311 TI - Alteration in the etiology of penile fracture in the Middle East and Central Asia regions in the last decade; a literature review. AB - Penile fracture is a well-recognized, relatively uncommon medical condition and its etiology differs according to geographic area. In this review article, we evaluated literature reported in the past decade, aiming to verify whether there has been any change in the etiology of this condition. A literature review was done for studies published in the past 10 years and focusing on the etiology of penile fracture. Inclusion criteria comprised articles in English language, of sample size more than 10 patients and originating from the Middle East and Central Asia. Data relating to the studied population, etiology of penile fracture, clinical presentation, investigations, management, and outcome was analyzed. One thousand six hundred and twenty-nine patients from 21 original articles were included in the study. The mean age +/- standard deviation of the patients was 33.3 +/- 3.23 years. Etiologies of penile fracture were vigorous sexual intercourse, manual bending of erect penis, vigorous masturbation, rolling over in bed and blunt trauma in 41%, 29%, 10%, 14% and 6% patients, respectively. Treatment choices were surgery and conservative, in 1580 (95%), 83 (5%) patients, respectively. A higher incidence of complications was found in conservatively treated patients. As a conclusion, in the last 10 years, vigorous sexual intercourse was the commonest etiology of penile fracture in the Middle East and Central Asia regions. Surgery remains the preferred treatment option for patients diagnosed with penile fracture. PMID- 26229312 TI - Laparoendoscopic single site surgery versus conventional laparoscopy for transperitoneal pyeloplasty: A systematic review and meta-analysis. AB - We aimed to review studies comparing the outcomes of the laparoendoscopic single site (LESS) pyeloplasty with those of conventional laparoscopic pyeloplasty (CLP). A systematic review of the literature was performed according to the PRISMA (preferred reporting items for systematic reviews and meta-analysis) criteria. The methodological quality of the studies was rated according validated scales. The level of evidence (LE) was reported as described by the Oxford criteria. Preoperative demographic parameters and perioperative outcomes between the two surgical techniques were assessed. A meta-analysis of the included studies was performed. A total of 5 studies were elected for the analysis, including 164 cases, 70 (42.6%) of them being LESS and 94 (57.4%) being CLP. Four studies were observational retrospective comparative studies (LE: 3a-4); one was a prospective randomized controlled trial (LE: 2b). There was no significant difference in age, body mass index, gender, side and presence of the crossing vessel, between the groups. There was no significant difference regarding the operative time (weight mean difference [WMD]: -7.02; 95% confidence interval [CI]: -71.82-57.79; P = 0.83) and length of hospital stay (WMD: 0.04; 95% CI: 0.11-0.20; P = 0.58), whereas the estimated blood loss was statistically lower for LESS (WMD: -16.83; 95% CI: -31.79--1.87; P = 0.03). The postoperative use of analgesic favored the LESS group but without reaching statistical significance (WMD: -7.52; 95% CI: -17.56-2.53; P = 0.14). In conclusion, LESS pyeloplasty offers comparable surgical and functional outcomes to CLP while providing the potential advantages of less blood loss and lower analgesic requirement. Thus, despite being more technically challenging, LESS pyeloplasty can be regarded as a minimally invasive approach for patients seeking fewer incisional scars. PMID- 26229313 TI - Laparoscopic simple prostatectomy: A reasonable option for large prostatic adenomas. AB - AIM OF THE STUDY: In this work, surgical technique followed by two academic departments on laparoscopic simple prostatectomy (LSP) of large prostatic adenomas is being described. MATERIALS AND METHODS: The initial cumulative experience from 11 patients with lower urinary tract symptoms of benign prostatic hyperplasia origin subjected to LSP is being presented. RESULTS: All cases had prostatic adenomas greater than 80 ml. Mean operation time was 99.5 min (values from 70 to 150 min) and mean blood loss was 205 ml (values from 100 to 300 ml). Blood transfusion was deemed necessary in one case. Bladder catheter was removed successfully on postoperative day 5 in all cases. No significant postoperative complication was noted. At a 3 months follow-up a significant decrease in International Prostate Symptom Score (IPSS) was evident in all patients (mean IPSS 27.7 vs. 15.3 preoperative vs. postoperative accordingly). CONCLUSIONS: According to our data and similarly to the rest of the LSP literature, laparoscopic excision of voluminous prostatic adenomas is a feasible and safe procedure. Nevertheless, further investigation including a larger number of patients and long-term follow-up is deemed necessary before making definite conclusions regarding the approach. PMID- 26229314 TI - Penile lichen sclerosus: An urologist's nightmare! - A single center experience. AB - PURPOSE: Penile lichen sclerosus (LS) is a nagging condition and its progression result in devastating urinary and sexual problems and reduction in the quality-of life. This study has been carried out to present our experience about this disease with simultaneous review of the available literature. MATERIALS AND METHODS: This retrospective study has been done at a tertiary care center of eastern India. The data of 306 patients affected with LS were analyzed for clinical presentation, physical examination, investigations, and treatment offered. RESULTS: Presenting symptoms were non-specific. The prepuce was most commonly involved location followed by glans and meatus. Urethral involvement was not isolated as the primary site. Circumcision was done in 237 patients, while 63 patients underwent meatotomy. Thirty-six of 39 cases of LS induced stricture were treated with buccal mucosal graft (BMG) either in one stage or in two stages. CONCLUSION: LS varies from being a highly aggressive disease of the penis and anterior urethra to a burnt out condition affecting just the meatus and surrounding glans. Early diagnosis and treatment are required to prevent its complication and associated morbidity. Management depends on the anatomical location of lesion, extent of involvement, rapidity of progression and its severity. Use of BMG in LS induced urethral stricture has shown encouraging results. PMID- 26229315 TI - Penile lichen sclerosus: An enigmatic and challenging disease. PMID- 26229316 TI - Comparison between the use of 99% ethanol and 3% polidocanol in percutaneous echoguided sclerotherapy treatment of simple renal cysts. AB - AIM: In this study, we compared and valued efficacy and safety of percutaneous echoguided sclerotherapy (PES) using 3% polidocanol with that using 99% ethanol in the treatment of patients with simple renal cysts. MATERIALS AND METHODS: PES was performed for 65 simple renal cysts. Under ultrasonographic guidance the cyst was punctured using an 18 gauge needle. Sclerotherapy was performed with ethanol in 55% (36/65) of cases and with polidocanol in the remaining 45% (29/65). Patients were followed up with an ultrasound examination at 4 months, 8 months, and then at yearly intervals. A reduction of 50% or greater in cyst diameter was considered successful. RESULTS: The median followup period for the ethanol and polidocanol groups was 24.6 and 22.8 months, respectively. The successful outcome ratio of the polidocanol group was significantly higher (90% vs. 61%, respectively) than the one of the ethanol group (P = 0.003). The partial regression of the ethanol and polidocanol groups were 6% versus 7%, respectively. The failure ratio of the polidocanol group was significantly lower (3% vs. 33%, respectively) than that of the ethanol group (P = 0.004). Neither infectious complications nor hyperthermia occurred in all treated cases. However, these methods are not completely free from symptoms. All these symptoms disappeared few hours after the procedure. CONCLUSIONS: Polidocanol is a safe and effective sclerosing agent for renal cysts, with superior clinical results than ethanol. Therefore, polidocanol can be an alternative to ethanol in sclerotherapy of renal cysts. PMID- 26229317 TI - Current practice of prostate biopsy in Australia and New Zealand: A survey. AB - INTRODUCTION: Prostate biopsy remains the gold standard for prostate cancer diagnosis. The field of prostate biopsy is undergoing a rapid change. This study aims to provide a snapshot of the current practice of prostate biopsy in the Urological Society of Australia and New Zealand (USANZ). MATERIALS AND METHODS: A 31-question multiple-choice survey was constructed using a web-based provider and was distributed to 644 members of USANZ. The questionnaire addressed various aspects of prostate biopsy. Questionnaire results were collated and the data were analyzed statistically. RESULTS: 150 completed surveys were returned, with a response rate of 23.3%: 84.5% of those completing the survey were consultant urologists and 68% were working in a metropolitan setting. 98.6% of clinicians used prophylactic antibiotics before prostate biopsy, most commonly a quinolone. 30.6% had used intravenous (IV) carbapenems at least once. Peri-prostatic local anesthetic (LA) infiltration was used by 39.9% of clinicians with 73% using IV sedation or general anesthetic (GA). 38.4% of clinicians reported performing TPT biopsy of the prostate and 19.6% of clinicians had ordered a MRI of the prostate prior to an initial biopsy with 10.2% routinely ordering a MRI of the prostate before repeat biopsy. CONCLUSION: Frequent prophylactic use of carbapenems suggests concern amongst clinicians about sepsis with quinolone-resistant bacteria. Almost 75% of TRUS biopsies were performed under IV sedation or GA indicating a heavy demand of health resources. TPT biopsy was used commonly and there was significant use of multiparametric MRI prior to prostate biopsy. PMID- 26229319 TI - Ketamine versus magnesium sulfate with caudal bupivacaine block in pediatric inguinoscrotal surgery: A prospective randomized observer-blinded study. AB - INTRODUCTION: Possible approaches for postoperative analgesia after pediatric inguinoscrotal surgery are caudal block by bupivacaine/ketamine (BK) and bupivacaine/magnesium sulfate (BM). AIM: The purpose of the following study is to compare the analgesic efficacy and safety of ketamine and magnesium sulfate in combination with bupivacaine for caudal blockade in pediatric patients after inguinoscrotal operations. MATERIALS AND METHODS: Patients randomly received one of the two solutions for caudal epidural injection after induction of general anesthesia. Group-BK: Were given a mixture of 0.25% bupivacaine and 0.5 mg/kg of ketamine. Group-BM: Were given a mixture of 0.25% bupivacaine and 50 mg magnesium sulfate. Postoperatively, a blinded post-anesthesia care unit nurse assessed the quality of analgesia with a visual pain analog scale (VPAS). Significant pain is defined as one that has a VAPS of >=3. RESULTS: Forty American Society of Anesthesiologists I-II children (20 in each group) completed the study. The two groups were comparable regards age, sex, body mass index, anesthesia and surgery durations, recovery time and sevoflurane concentration. The mean duration of caudal analgesia +/- standard deviation was 462 +/- 17.2 min versus 398.05 +/- 12.9 min for BK and BM groups, receptively (P < 0.001). Supplemental rectal paracetamol within 12 h postoperatively were 15% for BK group versus 25% for BM (P = 0.05). Four patients in BK group only experienced postoperative nausea and vomiting (P = 0.053). CONCLUSION: Caudal administration of BK is efficient and safe for pediatric inguinoscrotal operations with longer postoperative analgesia than BM sulfate. PMID- 26229318 TI - The effect of spinal cord-injury level on the outcome of neurogenic bladder treatment using OnabotulinumtoxinA. AB - AIM: The aim was to report the effectiveness and safety OnabotulinumtoxinA (Botox, Allergan, Inc., Irvine, CA, USA) intradetrusor injections in spinal cord injured (SCI) patients with refractory neurogenic detrusor overactivity. And to assess the result based on SCI level. MATERIALS AND METHODS: We reviewed the chart of 103 patients with neurogenic bladder secondary to SCI at the rehab center who received OnabotulinumtoxinA in our Neurourology Department for treatment of lower urinary tract symptoms between January 2007 and December 2013. All patients had a clinical examination, urinalysis, and an urodynamic study at baseline and 3 months after treatment as well as a visual analogue scale (VAS; range scale: 0-10) and a bladder diary checked for 3 days. 300 IU of OnabotulinumtoxinA, detrusor muscle injections were performed in 30 sites under cystoscopic guidance. Outcome measures included frequency of urge urinary incontinence collected by bladder diaries; changes in urodynamic parameters such as maximum cystometric bladder capacity, reflex volume, maximum detrusor pressure; side-effects; antimuscarinic drug consumption and quality of life (QOL) measured with VAS. RESULTS: The study includes 32 female and 71 male with a mean patient age of 29 years (range: 18-56 year). The effect of Botox injection on bladder function was observed within 1-2 week after treatment. The urodynamic parameters were improved significantly after treatment compared with baseline values. There were significant reductions in the frequencies of incontinence episodes after treatment as seen in the voiding diary. A significant improvement in patient satisfaction was found after treatment which was expressed on the VAS assessment, with an improvement of the mean of 3 points. Patients with thoracic and lumbar injury have better result compare to cervical injury patients. The earliest recurrence of clinical symptoms was at 10 weeks. Overall, the mean duration of symptomatic improvement was 8 (2.5-21) months. CONCLUSION: Intradetrusor onabotulinumtoxinA injections are an effective and well-tolerated treatment for neurogenic overactive bladder that will increase patient satisfaction and improve QOL with persisted clinical efficacy for more than 8 months. PMID- 26229320 TI - Management of renal cell carcinoma presenting as inflammatory renal mass. AB - INTRODUCTION: Renal cell carcinoma (RCC) can have a wide spectrum of clinical presentations. In the immunocompromised patient fever and an inflammatory renal mass can harbor RCC. MATERIALS AND METHODS: We reviewed the charts of patients who were managed at our department during 1998-2008 as renal abscess or perinephric collection. Renal ultrasound and subsequently abdominal CT was done. Medical treatment in the form of antibiotics, control of diabetes and drainage was done. Percutaneous or open biopsy, pus cultures, and histopathology were used to guide therapy. With a positive biopsy radical surgery was considered, while with a negative result a follow up CT was planned. RESULTS: We identified 11 patients who had high fever, a renal abscess (in 4), or a suspicious mass with perinephric collection (in 7), and were eventually diagnosed to have RCC. Mean patient age was 66 years (53-82). 8 patients had uncontrolled diabetes. Five patients had a percutaneous drainage biopsy; of those two had a positive histopathology, the other three patients had a persistent enhancing mass on follow-up CT scan. Of this group three patients underwent radical nephrectomy. Another five patients had open drainage and biopsy, four patients had very poor performance status. One patient had radical surgery without the need for biopsy. CONCLUSION: In the elderly and immunocompromised patient renal cancer may present as renal abscess or perinephric collection. Histopathology and bacteriology are the mainstay of diagnosis. If biopsy was negative, follow up should include a CT scan to exclude any residual enhancing masses. PMID- 26229321 TI - Role of transrectal sectional sonography (TRSS) in management of prostatic abscesses. AB - AIM: The aim of this study was to assess the effectiveness of transrectal sectional sonography (TRSS) in the diagnosis and treatment of prostatic abscess. MATERIALS AND METHODS: Eighteen patients with prostatic abscesEs were the material of the present study. The criteria of abscess collection within the prostate gland and the periprostatic tissues were confirmed by TRSS, which guided the aspiration in all patients. RESULTS: Diagnosis and transperineal needle aspiration of prostatic abscesses were successful in all cases. After the second puncture procedure, recurrence noted in 2 (11.1%) out of 18 patients, who were further subjected to transurethral deroofing under TRSS vision. The amount of pus drained ranged between 3.6 and 29.3 mL (mean: 15.1 mLSD +/- 1.5), compatible with the estimated volume by virtual organ computer-aided analysis three-dimensional measurements. The most frequently involved organism was Escherichia coli. All patients received intravenous antibiotics (third generation cephalosporin) after the midstream urine analysis and further proper antibiotics, according to the aspirated pus culture and sensitivity. CONCLUSIONS: Transrectal sectional sonography could be a more reliable method in the diagnosis of prostatic abscesses. It can provide precise needle-guides into the best drainage location of the abscess cavity and justify transurethral unroofing if persistent recurrence is there. PMID- 26229322 TI - Three different anesthesia techniques for a comfortable prostate biopsy. AB - AIM: In this paper, we aimed to compare the efficacy of three different anesthesia techniques applied in 90 cases of which transrectal ultrasound (TRUS) guided prostate biopsies were taken. MATERIALS AND METHODS: Between February 2012 and July 2012, TRUS-guided 16 core biopsies were taken from 90 patients who comply the study criteria. Patients were randomly divided into three groups each of which consists of 30 individuals. Group 1: Was applied periprostatic block anesthesia; Group 2: Was administered intrarectal lidocaine gel; Group 3: Was applied pudendal block. Visual analog scale (VAS) of patients in groups was evaluated. RESULTS: There was no statistically significant difference between the mean ages, prostate-specific antigen values of three groups. Although pain ratings of Groups 2 and 3 were high, no significant difference was present between each other (P > 0.05). In Groups 1 and 2, the difference between VASs was significant. In the group where periprostatic block was applied, pain ratings were significantly low compared with the other two groups (P = 0.0001). DISCUSSION: Enabling pain and discomfort control in patients is very important during TRUS-guided prostate biopsy. In our study, we observed that the periprostatic block enables more comfortable compared with patient groups with intrarectal lidocaine gel and pudendal block and better reduction in pain scores. PMID- 26229323 TI - Tadalafil once daily and intralesional verapamil injection: A new therapeutic direction in Peyronie's disease. AB - INTRODUCTION: The aim of this study was to evaluate the combination of intralesional verapamil injection (IVI) therapy with and tadalafil in men affected by Peyronie's disease (PD). MATERIALS AND METHODS: In this study, 59 patients diagnosed with PD, were divided into three groups. Group A (GA) counted 23 patients treated with IVI; Group B (GB) treated 19 patients with tadalafil 5 mg once a day, and Group C (GC) treated 17 patients with IVI and tadalafil for 3 months. There were assessed at baseline and follow-up: Erectile function, presence and severity of painful erections, penile plaque size and penile curvature degree. RESULTS: After 3 months pain resolved completely in 57% cases of GA, 61% of GB and 76% of GC; the final mean curvature degree further decreased in all groups without statistically significant differences; mean plaque size remained stable in GA: 1.57 versus 1.59 at baseline (P = 0.364) and GB: 1.51 versus 1.52 at baseline (P = 0,265), while a further decrease was evident in GC: 1.46 versus 1.58 at baseline (P = 0.03). Mean International Index of Erectile Function-5 score further improved significantly in the group treated with verapamil plus tadalafil: 23.1 versus 14.4 of GA and 18.2 of GB (P <= 0.01). CONCLUSIONS: The association of IVI and tadalafil showed better pain control while reducing penile curvature and erectile function, improving the quality of life. PMID- 26229324 TI - Role of Vitamin C and E supplementation in reduction of serum level of renal injury marker following shock wave lithotripsy: Prospective single centre experience. AB - INTRODUCTION: Shock wave lithotripsy has become first line treatment modality for renal calculi due to its noninvasiveness. However, the destructive forces like dispersion of cavitation bubbles can cause trauma to thin-walled vessels and renal parenchyma during fragmentation of the stones. Antioxidants are our first line of defense against oxidative stress. The aim of this study was to investigate whether oral administration of Vitamin C and E help in a reduction of the serum level of inflammatory mediator by serial measurement of high sensitivity C-reactive protein (hs-CRP) and by this reduction in the risk of renal damage. PATIENTS AND METHODS: A total of 107 subjects were recruited in three groups. Group A served as a control group, and Group B and Group C received oral medication of Vitamin E 800 mg/day and Vitamin C 1000 mg/day respectively, start from 2 days prior the lithotripsy and continued for total 7 days. The level of hs-CRP was used as a mediator of the inflammatory response following lithotripsy and thus for long term renal injury. Serum level of hs-CRP was measured on 2 days prior the lithotripsy and day 2, 7 and 28 after the lithotripsy. RESULTS: Patients who were given either Vitamin C or Vitamin E showed a significant reduction of serum level of hs-CRP when compared to control the group. CONCLUSION: Oral administration of Vitamin C and E helps in reduction of serum levels of the inflammatory marker for acute renal injury and thus they can be useful in minimizing the kidney injury following lithotripsy for renal stone disease. PMID- 26229325 TI - Highest risk of symptomatic venous thromboembolic events after radical cystectomy occurs in patients with obesity or nonurothelial cancers. AB - CONTEXT: Venous thromboembolism (VTE) is a common cause of postoperative morbidity and mortality in cystectomy patients. AIMS: The aim of this study is to identify variables associated with risk of developing deep venous thrombosis (DVT) or pulmonary embolism (PE) within 90 days after radical cystectomy (RC). SETTING AND DESIGN: Retrospective chart review of patients undergoing RC from 2004 to 2011 at the University of Wisconsin. SUBJECTS AND METHODS: Clinical variables collected for all RC patients. All patients received mechanical prophylaxis, and routine heparin prophylaxis began in 2010. STATISTICAL ANALYSIS USED: Univariate and multivariate analyses were used to evaluate VTE association with known risk factors. RESULTS: A total of 241 patients were identified with median age of 67.1 (interquartile range: 57.8-74.3) years. Body mass index (BMI) was >=30 in 36.8% of patients. Median blood loss was 950 (600-1500) mL and 157/241 (65.2%) patients received a blood transfusion. CONCLUSIONS: Patients with BMI >=30 or nonurothelial cancer are at highest risk for postoperative VTE and should be considered for extended heparin prophylaxis. PMID- 26229326 TI - LESS living donor nephrectomy: Surgical technique and results. AB - PURPOSE: We present the findings of 50 patients undergoing pure trans-umbilical laparo-endoscopic single-site surgery (LESS) living donor nephrectomy (LDN), between February 2010 and May 2014. MATERIALS AND METHODS: Laparo-endoscopic single-site surgery LDN was performed through an umbilical incision. Different trocars were used, namely Gelpoint (Applied Miotadical, Rancho Santa Margarita, CA) SILS port (Covidien, Hamilton, Bermuda), R-port (Olympus Surgical, Orangeburg, NY) and standard trocars, inserted through the same skin incision but using separate fascial punctures. The standard laparoscopic technique was employed. The kidney was pre-entrapped in a retrieval bag and extracted trans umbilically. Data were collected prospectively including questionnaires containing patient reported oral pain medication duration and time to recovery. RESULTS: LESS LDN was successful in all patients. Mean warm ischemia time was 6.2 min (3-15), mean procedure time was 233.2 min (172-300), and hospitalization stay was 3.94 days (3-7) with a visual analogue pain score at discharge of 1.32 (0-3). No intraoperative complications occurred. The mean time of oral pain medication was 8.72 days (1-20) and final scar length was 4.06 cm (3-5). Each allograft was functional. CONCLUSION: Although challenging, trans-umbilical LESS LDN seems to be feasible and safe. Hence, LESS has the potential to improve cosmetic results and decrease morbidity. PMID- 26229327 TI - How do we know what damage a safe intervention has in the long-term: Considering the risk of extra-corporeal shockwave lithotripsy and the onset of diabetes mellitus. PMID- 26229328 TI - A clever technique for placement of a urinary catheter over a wire. AB - OBJECTIVE: The objective was to present a straightforward, step-by-step reproducible technique for placement of a guide-wire into any type of urethral catheter, thereby offering a means of access similar to that of a council-tip in a situation that may require a different type of catheter guided over a wire. MATERIALS AND METHODS: Using a shielded intravenous catheter inserted into the eyelet of a urinary catheter and through the distal tip, a "counsel-tip" can be created in any size or type of catheter. Once transurethral bladder access has been achieved with a hydrophilic guide-wire, this technique will allow unrestricted use of catheters placed over a wire facilitating guided catheterization. RESULTS: Urethral catheters of different types and sizes are easily advanced into the bladder with wire-guidance; catheterization is improved in the setting of difficult urethral catheterization (DUC). Cost analysis demonstrates benefit overuse of traditional council-tip catheter. CONCLUSION: Placing urinary catheters over a wire is standard practice for urologists, however, use of this technique gives the freedom of performing wire-guided catheterization in more situations than a council-tip allows. This technique facilitates successful transurethral catheterization over wire in the setting of DUC for all catheter types and styles aiding in urologic management of patients at a cost benefit to the health care system. PMID- 26229329 TI - Effect of obesity on International Prostate Symptom Score and prostate volume. AB - AIM: The aim of this study was to investigate the relationship between obesity and lower urinary tract symptoms and prostate volume in patients who underwent prostate biopsies. MATERIALS AND METHODS: Between December 2008 and November 2009, transrectal ultrasound-guided prostate biopsy was performed on patients who had elevated prostate-specific antigen levels or abnormal digital rectal examination findings. A total of 211 patients were included in this study. Prostate volumes, International Prostate Symptom Score (IPSS) values, and the patient's height and weight were all recorded during the biopsy. Body mass index (BMI) <18.5 was determined as underweight, 18.5-23.0 normal, 23.0-27.5 overweight, and >27.5 obese. RESULTS: The mean age of the patients was 68.0 +/- 6.3 years, and the mean BMI was 28.0 +/- 4.9 kg/m(2). The mean prostate volume of the normal, overweight, and obese groups was 30, 50, and 70 ml, respectively. The positive and statistically significant correlation between BMI and prostate volume was determined (P < 0.001). According to BMI, the mean IPSS was 8.0, 16.5, and 20.0 in the groups, respectively. Similarly, a statistically positive correlation between BMI and IPSS was demonstrated (P < 0.001). CONCLUSIONS: As the result of a rise in BMI, prostate volumes and IPSS increase in patients. Prostate volume and IPSS decrease due to weight loss, and hence that fewer urinary symptoms occur, and the quality-of-life of patients may increase. PMID- 26229330 TI - Extensive nephroureteric calcification presenting with renal failure: A rare case report. AB - The diagnosis of renal Tuberculosis (TB) can be hypothesized in the setting of non-specific bacterial cystitis associated with a therapeutic failure or a urinalysis with a persistent leukocyturia and absence of bacteriuria. Renal TB is an important cause of kidney disease, mainly in tropical areas of the globe, which can lead to end-stage renal disease if not diagnosed early and treated correctly. We report a case of a 58 year man with a past history of pulmonary TB treated for six months with extensive nephroureteric calcification presenting with renal failure. PMID- 26229331 TI - A rare case report of bilateral testicular masses as an initial manifestation of systemic sarcoidosis. AB - Sarcoidosis is an idiopathic, systemic disease that rarely involves the genitourinary tract. Here, we present a case of a 40-year-old male presented with bilateral scrotal swelling. The scrotal ultrasound showed multiple echogenic masses bilaterally ranging between 3 mm and 15 mm involving both testicles. Enlarged retroperitoneal lymph nodes were detected on the abdominal computed tomography (CT). Surgical exploration of the testes with a frozen section analysis of the left testicular mass was carried out, and it revealed noncaseating granulomas. CT scan of the chest revealed the classic bilateral hilar and mediastinal lymphadenopathy with reticulonodular infiltrates. The final pathological diagnosis was systemic sarcoidosis with bilateral testicular involvement. Treatment with high-dose corticosteroids resulted in complete resolution of the testicular mass and a significant decrease in the size of the hilar, mediastinal, and retroperitoneal lymphadenopathy. PMID- 26229332 TI - A unique case of a serous borderline tumor of the paratestis. AB - Serous borderline tumors of the paratestis are histologically identical to their ovarian counterparts and hypothesized to arise from Mullerian metaplasia of the tunica vaginalis. They are exceedingly rare with many cases probably going clinically unnoticed. We present a case of serous borderline tumor of the paratestis, with, to the best of our knowledge, the first published sonographic and magnetic resonance (MR) images of this entity. It was successfully treated with partial orchiectomy with no disease recurrence after one-and-a-half years. PMID- 26229333 TI - Chromophobe renal cell carcinoma of the kidney with neuroendocrine differentiation: A case report with review of literature. AB - Chromophobe renal cell carcinoma (chRCC) is a distinctive type of malignant kidney tumor characterized by large cells with defined cell membrane. Primary renal neuroendocrine tumors (NET) are rare with morphology similar to NET at other sites. There are few case reports describing the coexistence of these 2 neoplasms within the same tumor mass. We describe a case of chRCC with neuroendocrine features in a 70-year-old male patient who presented with hematuria and right flank pain. The histological and immunohistochemical features of both components were characteristic with no overlapping features. The neuroendocrine element was associated with nodal metastasis. PMID- 26229334 TI - Sustained systemic response paralleled with ovarian metastasis progression by sunitinib in metastatic renal cell carcinoma: Is this an anti-angiogenic potentiation of cancer? AB - Metastatic renal cell cancer is associated with poor prognosis and survival and is resistant to conventional chemotherapy. Therapeutic targeting of molecular pathways for tumor angiogenesis and other specific activation mechanisms offers improved tumor response and prolonged survival. A 48-year-old, female patient presented with large right renal mass with features suggesting of renal cell cancer without metastasis on contrast enhanced computed tomography (CT). Right radical nephrectomy was done. After 9 months of surgery, she got metastasis in lung, liver and ovary. The patient received sunitinib via an expanded access program. After eight 6-week cycles of sunitinib, a reassessment CT scan confirmed an excellent partial response with the almost complete disappearance (90%) of liver and lung metastasis but the adnexal mass had increased in size (>10 times) and the possibility was thought of second malignancy. Excision of the mass performed. Histopathology of the mass depicted metastatic renal cell cancer. There is possibility of a 'site-specific anti-angiogenic potentiation mechanism' of malignancy in relation to sunitinib based upon the preclinical studies, in reference to the index case. Regression of one site with concurrent progression is possible. The exact mechanism of site-specific response, especially organ specific progression by vascular endothelial growth factor inhibitors in metastatic renal cell cancer warrants further study. PMID- 26229335 TI - Malignant priapism: Penile metastasis originating on a primary prostate adenocarcinoma. AB - Malignant priapism is a definition invented in 1938 by Peacock, defined as a persistent erection, not related with sexual activity, caused by cavernous sinus and associated venous systems invasion with malignant cells. Penile secondary lesions are rare entities. Primary locations are usually the pelvic cavity organs, namely the prostate and the bladder as the most common ones. Priapism as a first manifestation of these kinds of lesions is even rarer. The aim was to present a 52-year-old patient harboring a penile metastasis that originated in the primary prostate adenocarcinoma, manifesting itself as a "common" priapism. The patient referred to the emergency room presenting with a priapism and nodules at the coronal sulcus, without previous similar episodes. His evolution until properly diagnosed was catastrophic with multiple lymph nodes, bone and organ involvement, and with his demise soon after from serious bleeding and congestive heart failure, almost 2 months after he first came to the emergency room. We review the literature concerning malignant priapism, diagnosis, and current treatment and survival perspectives. PMID- 26229336 TI - Robotic approach to vaginal atresia repair in an adolescent girl. AB - A 9-year-old girl presented to us, after failed perineal approach for vaginal atresia, with abdominal pain. She was thoroughly evaluated and contrast enhanced computed tomographic was done, which revealed absence of lower 1/3(rd) of vagina with normal uterus, fallopian tubes and ovaries. There was no associated anomaly. She was successfully managed by a combined robotic and perineal approach. Follow up after 6 and 12 months revealed large capacious vagina with healthy mucocutaneous junction. PMID- 26229337 TI - Cavernous hemangioma of the glans penis. AB - Cavernous hemangioma of the glans penis is a very rare lesion, and only a few cases are reported in the literature. Urologists are in a dilemma to treat such lesion with cosmetic and to obtain good functional outcome. Here, we report a case of cavernous hemangioma of the glans penis in a 22-year-old boy with a successful outcome by intralesional sclerotherapy with 3% sodium tetradecyl sulfate with a review of the literature on the subject. PMID- 26229338 TI - Paraganglioma of urinary bladder. AB - Paraganglioma of the urinary bladder are tumors of chromaffin tissue originating from the sympathetic innervations of the urinary bladder wall and are extremely rare. Being functional, in most of the cases they are recognized by their characteristic presentation of hypertensive crisis and postmicturition syncope. A silent presentation of a bladder paraganglioma is very unusual but quite dangerous as they are easily misdiagnosed and adequate peri-operative attention is not provided. Here, we are presenting one such silent paraganglioma in adult women who presented with only a single episode of hematuria and severe hypertensive crisis occur during its trans-urethral resection. PMID- 26229339 TI - Long-standing hemospermia in a patient with megacava associated to a circumaortic renal vein. AB - Hemospermia may have a broad range of functional and organic causes. It is defined as the presence of blood in seminal fluid and usually tends to resolve spontaneously within a few weeks. We present the case of a patient with a 10-year history of hemospermia associated with megacava and circumaortic renal vein. The diagnosis, treatment, and evolution of the condition are reported. Vascular anomalies are rare causes of chronic hemospermia, and the one described in our patient may constitute the first case reported in the literature. PMID- 26229340 TI - Synchronous bilateral ureteric metastasis from gastric cancer. AB - Distant metastasis to the ureters is uncommon. Moreover, isolated ureteric metastasis from gastric cancer is extremely rare and only sporadically reported. It indicates an advanced stage and carrier a very poor prognosis. We describe a case of synchronous bilateral ureteric metastasis from stomach adenocarcinoma after gastrectomy and chemoradiation. To our knowledge, it is the first case published in the literature with such presentation. PMID- 26229341 TI - Bladder paraganglioma with renal agenesis: A possible new association and its implications in the light of REarranged in transfection gene genetics. AB - Pheochromocytoma/paraganglioma and renal agenesis are commonly reported conditions. Their coexistence, however, is rare, with few cases reported. We report the case of a 21-year-old male who presented with painless hematuria. He was found to have congenital absent right kidney along with bladder mass on imaging. Examination including blood pressure was normal. He underwent cystoscopy that showed a solid looking tumor on the anterior wall. Paraganglioma was suspected due to intraoperative rise in blood pressure during resection and was confirmed on histopathology. Subsequently after work up and preoperative alpha blockade, patient underwent partial cystectomy and excision of the paravesical mass. Histopathology showed paraganglioma confined to bladder wall with surgical margins free and a paravesical mass that was seminal vesicle cyst. On follow-up, patient is normotensive and asymptomatic. This coexistence of paraganglioma and renal agenesis may have a common genetic mechanism in the form of REarranged in Transfection (RET) gene mutation. This is a well-characterized gene, mutations of which are known to be associated with both conditions. Current knowledge of the role of RET gene in both conditions is reviewed to put forth RET mutation as the possible common underlying genetic mechanism along with possible clinical implications of the combination. PMID- 26229342 TI - Lupus cystitis presenting with urinary symptoms. AB - We present a case of a young woman presenting with irritative lower urinary tract symptoms and microscopic hematuria who was diagnosed with systemic lupus erythematosus (SLE). Abdominal ultrasound revealed bilateral hydronephrosis and a thickened bladder wall. Cystoscopic evaluation revealed severe diffuse inflammation, erythema and hemorrhage at the trigone with punctate extensions to the bladder base. She was treated with prednisone and mycophenolate mofetil with improvements in her symptoms and ultrasound findings. Lupus cystitis is a rare manifestation of SLE. PMID- 26229343 TI - Antiarthritic activity of a polyherbal formulation against Freund's complete adjuvant induced arthritis in Female Wistar rats. AB - OBJECTIVES: To formulate a polyherbal formulation and evaluate its antiarthritic activity against Freund's complete adjuvant induced arthritis in Female Wistar rats. MATERIALS AND METHODS: Glycosmis pentaphylla, Tridax procumbens, and Mangifera indica are well-known plants available throughout India and they are commonly used for the treatment of various diseases including arthritis. The polyherbal formulation was formulated using the ethanol extracts of the stem bark of G. pentaphylla , whole plant of T. procumbens, and leaves of M. indica. The polyherbal formulation contains the ethanol extracts of G. pentaphylla, T. procumbens, and M. indica in the ratio of 2:2:1. The quality of the finished product was evaluated as per the World Health Organization's guidelines for the quality control of herbal materials. Arthritis was induced in female Wistar rats using Freund's complete adjuvant (FCA), and the antiarthritic effect of polyherbal formulation was studied at doses of 250 and 500 mg/kg. The effects were compared with those of indomethacin (10 mg/kg). At the end of the study, blood samples were collected for biochemical and hematological analysis. The radiological examination was carried out before terminating the study. RESULTS: Polyherbal formulation showed significant antiarthritic activity at 250 and 500 mg/kg, respectively, and this effect was comparable with that of indomethacin. The antiarthritic activity of polyherbal formulation is supported by biochemical and hematological analysis. CONCLUSION: The polyherbal formulation showed signinicant antiarthritic activity against FCA-induced arthritis in female Wistar rats. PMID- 26229344 TI - Causality assessment of adverse drug reaction in Pulmonology Department of a Tertiary Care Hospital. AB - BACKGROUND: Adverse drug reaction (ADR) is considered to be the sixth leading cause of death. The incidence rate estimates approximately 2% of hospital admissions are due to ADRs. OBJECTIVE: To monitor ADRs in Pulmonology department of a tertiary care hospital patient with pulmonary diseases in an inpatient department of pulmonology. MATERIALS AND METHODS: A prospective, single centered, observational and open labeled study was carried out in Princess Esra Hospital. The patient population was broadly divided into four categories based on diagnosis - chronic obstructive pulmonary disease, Infections, Asthma and Others. Suspected ADRs were reported, analyzed, and causality assessment was carried out using Naranjo's algorithm scale. RESULTS: A total of 302 patients were observed, of which 98 patients experienced ADRs, which accounted for 32.23% of the incidence and totally 160 ADEs were observed. Adult Patients were found to have higher incidence (32.09%) while the incidence rate was slightly greater in geriatric patients (32.39%). The highest incidence of ADEs were found in others group (78.57%). Majority of ADRs were suspected to be due to theophylline (19.39%). Gastrointestinal system (38.75%) was the most common organ system affected due to ADRs. Drug was withdrawn in 12 patients, and specific treatment was administered to 32 patients in view of clinical status. Specific treatment for the management of suspected reaction was administered in 32.65% of ADR reports. CONCLUSION: A relatively high incidence of adverse drug events (32.2%) have been recorded which shows that not only Geriatric patients, but also adults are more susceptible to adverse drug effects. A number of drugs in combination were used, and ADEs often get multiplied. Careful therapeutic monitoring and dose individualization is necessary. PMID- 26229345 TI - In vitro activity of levofloxacin against lower respiratory tract pathogens. AB - BACKGROUND: Considerable morbidity and mortality are associated with lower respiratory tract infections (LRTIs) that put a considerable strain on the health budget. Selection of appropriate antibiotics as empirical therapy maximizes positive patient outcomes, and that depends on regular surveillance of infective agents and their antibiograms, which vary according to the geographical areas. AIM: The aim was to study the drug susceptibility pattern of the isolated pathogens of the respiratory tract infections. SETTINGS AND DESIGN: Retrospective study for a period of 1-year 3 months from January 2013 to March 2014 at a Tertiary Care Hospital. MATERIALS AND METHODS: Eleven hundred and eighty-four sputum samples from both outdoor and indoor patients with symptoms of LRTI were processed, and antibiotic sensitivity test was done to commonly used antibiotics. Descriptive statistics was used to analyze the data. RESULTS: Among 502 quality sputum samples, 312 (62.15%) samples showed growth of pathogenic bacteria. The most common pathogens were Klebsiella spp. (38.14%), Moraxella spp. (16.02%), Streptococcus pneumoniae (14.10%), Pseudomonas spp. (9.93%), S. aureus (9.29%). It was found that the overall susceptibility pattern was <50% for amoxicillin, amoxicillin-clavulanic acid, cefuroxime, cotrimoxazole and erythromycin whereas for cefotaxime, cefixime, and cefoperazone-sulbactum it was 60.08%, 51.59%, 69.04%, respectively. The susceptibility to ciprofloxacin, ofloxacin, and levofloxacin were 66.67%, 70.19% and 83.33%, respectively. CONCLUSION: Klebsiella spp. was the most common LRTI pathogen. There was limited activity of amoxicillin, amoxicillin-clavulanic acid, cefuroxime, cotrimoxazole and erythromycin for the treatment of LRTI whereas levofloxacin, (being an oral drug with good compliance) had good activity against respiratory pathogens and could be used for empiric treatment in LRTI. PMID- 26229346 TI - Sociodemographic profile and pattern of opioid abuse among patients presenting to a de-addiction centre in tertiary care Hospital of Kashmir. AB - BACKGROUND: The substances abuse has become one of the major public health problems of present society. Recently there has been an increase in the incidence of substance abuse including that of opioids throughout the world. The proper assessment of the current trends and pattern of opioid abuse can be helpful in more effective intervention of this menace. MATERIALS AND METHODS: To find out various socio-demographic variables and pattern of opioid abuse, a predevised questionnaire was administered to 200 opioid patients who presented to de addiction center for treatment. RESULTS: Majority of the participants (75%) were of young age group (20-30 years) and the mean age of subjects was 27.6 years. More than half of participants (55%) were abusing the opioid substances for < 3 years followed by 30% of the abusers who were using the opioids for 4-6 years. Oral route was the most common route(35%)of substance administration followed by chasing(13%) and intravenous(11%) routes. Diverted pharmaceuticals emerged as one of the common substances of abuse, and peer pressure was found to be the main reason to start substance abuse. CONCLUSION: A comprehensive preventive program targeting young adults needs to be formulated and strict laws against sales of diverted pharmaceuticals to be implemented. PMID- 26229347 TI - Cold agglutinin disease in sepsis: A rare entity. AB - Cold agglutinin disease (CAgD) is a type of autoimmune hemolytic anemia which generally occurs in adults and is characterized by the presence of IgM antibodies directed against polysaccharide antigens on red blood cell surface. A 16-year-old male, having clinical picture of sepsis and anemia, presented to the Emergency Department of our Institute in an Hemodynamically unstable condition. Investigation profile revealed hemolysis due to CAgD, which responded to corticosteroids, antibiotics and supportive treatment. This case highlights the importance of recognizing this entity in such type of cases presenting with sepsis and anemia. PMID- 26229348 TI - Acute pancreatitis in the use of canagliflozin: A rare side-effect of the novel therapy for type 2 diabetes mellitus. AB - Canagliflozin (Invokana) is an innovative treatment for type 2 diabetes mellitus (DM) approved in a new class acknowledged as sodium-glucose co-transporter 2 inhibitors. Acute pancreatitis is a very rare side effect with an incidence <1%. a 50-year-old white male with DM type 2 presented to the emergency department with acute onset of abdominal pain after 4 days treatment with canagliflozin. He was successfully diagnosed with diabetic ketoacidosis induced by acute pancreatitis. Canagliflozin was discontinued. His diabetic ketoacidosis was improved after aggressive intravenous fluid along with intravenous insulin infusion. Our case demonstrates very rare but serious side effect, acute pancreatitis in the use of canagliflozin. As the utility of canagliflozin expands, physicians must be aware of this potentially fatal adverse effect. More specific details on potential candidates for this novel therapy are urgently needed. PMID- 26229350 TI - A review of injection and antibiotic use at primary health care (public and private) centers in Africa. AB - We conducted a review to study antibiotic and injections use at primary care centers (PHCs) within the World Health Organization African region. This was part of a larger study on prescribing indicators at PHCs within the region. We analyzed antibiotic and injection use reported in studies published between 1993 and June 2013, which were identified through searches conducted in PubMed, Scopus, Web of science, Africa-Wide NiPAD, Africa Journals Online, Google Scholar, and International Network for Rational Use of Drugs bibliography databases. Sub-group analysis was carried out for private and public centers. Data were retrieved from 18 studies in 6 countries involving 21,283 patient encounters across 338 PHCs. The percentage of patient encounters with antibiotics prescribed was 51.5% (IQR 41.1-63.3%). The percentage of patient encounters which resulted in the prescription of an injection was 36.8% (IQR 20.7-57.6%). Injection use rate at private facilities was 38% (IQR 19.1-42.7) while that of the public was 32.3% (IQR 20.6-57.6). Rate of antibiotic prescribing at public centers was 49.7% (IQR 51.1-75.7) and that of private facilities 57.6 (IQR 39.0 69.5). The percentage use of injections and antibiotics is high in Africa. The excessive use of antibiotics and injections are particularly more problematic in private than public facilities. Further research is needed to understand fully the underlying factors for the observed patterns and ways of improving medicines use. PMID- 26229349 TI - Clinical pharmacists: The major support to Indian healthcare system in near future. AB - Pharmacy practice is still in the initial stages of development in India, but launching of Doctor of Pharmacy (PharmD) study program has brought serious discussions about clinical pharmacy in the country. As the profession is in budding stage in the country, the patients, physicians, nurses, other healthcare providers, recruiters in pharmaceutical industries, prospective students, and their parents have numerous questions about this profession and study course. The objective of this article is to create awareness about clinical pharmacy services (CPS) and to introduce the role of clinical pharmacists (CPs). After reading this article, one will know about the usefulness of CPs in the Indian healthcare system against the current flaws in the system. The article describes the role of CPs in the hospitals, in research, in pharmaceutical/contract research companies, in community service and it also tells about the related myths and facts. Prospective job opportunities for CPs, present challenges and the possible solutions are elaborated as well. In conclusion, CPs are going to be the major support to the Indian healthcare system in near future; the reasons being (1) CPS are beneficial in many ways to improve healthcare; CPS have already proved their importance in western countries (2) India was never officially and efficiently exposed to CPS; so launching of CPS shall revolutionize the country's healthcare scenario. PMID- 26229351 TI - The use of psychotropic substances among students: The prevalence, factor association, and abuse. AB - This detailed review analyzed the previously published studies related to the prevalence of psychotropic substances use, associated factors, and the misuse of the psychotropics among students. A comprehensive literature search covering six databases was performed. References from published articles and reports were extracted. This helped in identifying the available information on the use of psychotropic drugs. A total of 16 articles were included in this review. There is an upsurge of using psychotropics with the preceding years. More students are exposed to the risk of using psychotropic substances due to the multiple factors like stress, increased academic workload, etc. The misuse is found to be common with prescribed psychotropic substances. Students need to be aware of the bad outcomes of using psychotropic substances. Participation of every stakeholder to curb this menace needs to be emphasized. More extensive studies are required to know about the increasing prevalence, factors, and misuse of psychotropics. PMID- 26229354 TI - Nationwide survey on barriers for dental research in India. AB - OBJECTIVE: Research in the dental field is progressing at mightier speed worldwide, but an unfortunately representation of India at this platform is negligible. The present study was undertaken to unearth the barriers for dental research among dental professionals in Indian scenario. MATERIALS AND METHODS: A cross-sectional questionnaire study was conducted on 1514 participant's (Master of Dental Surgery and Bachelor of Dental Surgery staff) and postgraduates in 40 dental colleges of India selected by multistage random sampling. The response rate was 75.7%. The survey was undertaken from July 2013 to December 2013. The survey instrument was 24-item, investigator developed, self-structured, close ended, and self-administered questionnaire grouped into four categories that are, institutional/departmental support related barriers, financial/training support related barriers, time-related barriers, and general barriers. RESULTS: Among all respondents 47.23% informed that they are administrative and educational work rather than research work as (P < 0.001). Overall 57.53% of study participants reported lack of administrative and technical support for research work as (P < 0.001). Overall 64.9% reported meager college funding was the barrier (P < 0.001). Overall 61.5% respondents reported lack of time to do research work due to clinical and teaching responsibilities (P < 0.001) was the barrier for research. Largely 80.25% agreed that, the lack of documentation and record maintenance are an obvious barrier for research (P < 0.001). CONCLUSIONS: Present study unearths certain barriers for research in an Indian scenario, which includes administrative overburden, lack of funds, and lack of documentation of the dental data. Governing authorities of dentistry in India have to make major interventions to make research non-intensive environment to research-friendly environment. PMID- 26229353 TI - Physiologically active hydrogel (in situ gel) of sparfloxacin and its evaluation for ocular retention using gamma scintigraphy. AB - OBJECTIVE: Due to the structure and physiological barrier of eye, only 1% of instilled dose is available for action on the corneal surface. In this work, we developed and evaluated chitosan (pH sensitive) and gellan gum (ion sensitive) in situ gel of sparfloxacin to improve precorneal residence time. MATERIALS AND METHODS: A protocol for radiolabeling of sparfloxacin with Tc-99m was optimized to study the ocular retention using gamma scintigraphy technique. RESULTS: The clear formulation was developed. In vitro release showed a sustained and prolonged release compared to plain eye drop solution. Dynamic and static gamma scintigraphy showed better retention than plain eye drops. The ocular tolerance test (hen's egg test-chorioallantoic membrane test and infra-red study) showed that the formulation is nonirritant and can be used as ocular vehicle. CONCLUSION: Radiolabel protocol for sparfloxacin was successfully developed and evaluated on ocular retention studies of developed in situ gel. The developed in situ gel is non irritant and can go further with clinical evaluation. PMID- 26229352 TI - Applications of regenerative medicine in organ transplantation. AB - A worldwide shortage of organs for clinical implantation establishes the need to bring forward and test new technologies that will help in solving the problem. The concepts of regenerative medicine hold the potential for augmenting organ function or repairing damaged organ or allowing regeneration of deteriorated organs and tissue. Researchers are exploring possible regenerative medicine applications in organ transplantation so that coming together of the two fields can benefit each other. The present review discusses the strategies that are being implemented to regenerate or bio-engineer human organs for clinical purposes. It also highlights the limitations of the regenerative medicine that needs to be addressed to explore full potential of the field. A web-based research on MEDLINE was done using keywords "regenerative medicine," "tissue engineering," "bio-engineered organs," "decellularized scaffold" and "three dimensional printing." This review screened about 170 articles to get the desired knowledge update. PMID- 26229355 TI - Lifetime and 5 years risk of breast cancer and attributable risk factor according to Gail model in Iranian women. AB - INTRODUCTION: Breast cancer is the most commonly diagnosed cancers in women worldwide and in Iran. It is expected to account for 29% of all new cancers in women at 2015. This study aimed to assess the 5 years and lifetime risk of breast cancer according to Gail model, and to evaluate the effect of other additional risk factors on the Gail risk. MATERIALS AND METHODS: A cross sectional study conducted on 296 women aged more than 34-year-old in Qom, Center of Iran. Breast Cancer Risk Assessment Tool calculated the Gail risk for each subject. Data were analyzed by paired t-test, independent t-test, and analysis of variance in bivariate approach to evaluate the effect of each factor on Gail risk. Multiple linear regression models with stepwise method were used to predict the effect of each variable on the Gail risk. RESULTS: The mean age of the participants was 47.8 +/- 8.8-year-old and 47% have Fars ethnicity. The 5 years and lifetime risk was 0.37 +/- 0.18 and 4.48 +/- 0.925%, respectively. It was lower than the average risk in same race and age women (P < 0.001). Being single, positive family history of breast cancer, positive history of biopsy, and radiotherapy as well as using nonhormonal contraceptives were related to higher lifetime risk (P < 0.05). Moreover, a significant direct correlation observed between lifetime risk and body mass index, age of first live birth, and menarche age. While an inversely correlation observed between lifetimes risk of breast cancer and total month of breast feeding duration and age. CONCLUSION: Based on our results, the 5 years and lifetime risk of breast cancer according to Gail model was lower than the same race and age. Moreover, by comparison with national epidemiologic indicators about morbidity and mortality of breast cancer, it seems that the Gail model overestimate the risk of breast cancer in Iranian women. PMID- 26229356 TI - In-silico gene co-expression network analysis in Paracoccidioides brasiliensis with reference to haloacid dehalogenase superfamily hydrolase gene. AB - CONTEXT: Paracoccidioides brasiliensis, a dimorphic fungus is the causative agent of paracoccidioidomycosis, a disease globally affecting millions of people. The haloacid dehalogenase (HAD) superfamily hydrolases enzyme in the fungi, in particular, is known to be responsible in the pathogenesis by adhering to the tissue. Hence, identification of novel drug targets is essential. AIMS: In-silico based identification of co-expressed genes along with HAD superfamily hydrolase in P. brasiliensis during the morphogenesis from mycelium to yeast to identify possible genes as drug targets. MATERIALS AND METHODS: In total, four datasets were retrieved from the NCBI-gene expression omnibus (GEO) database, each containing 4340 genes, followed by gene filtration expression of the data set. Further co-expression (CE) study was performed individually and then a combination these genes were visualized in the Cytoscape 2. 8.3. STATISTICAL ANALYSIS USED: Mean and standard deviation value of the HAD superfamily hydrolase gene was obtained from the expression data and this value was subsequently used for the CE calculation purpose by selecting specific correlation power and filtering threshold. RESULTS: The 23 genes that were thus obtained are common with respect to the HAD superfamily hydrolase gene. A significant network was selected from the Cytoscape network visualization that contains total 7 genes out of which 5 genes, which do not have significant protein hits, obtained from gene annotation of the expressed sequence tags by BLAST X. For all the protein PSI BLAST was performed against human genome to find the homology. CONCLUSIONS: The gene co-expression network was obtained with respect to HAD superfamily dehalogenase gene in P. Brasiliensis. PMID- 26229357 TI - Is Greulich and Pyle standards of skeletal maturation applicable for age estimation in South Indian Andhra children? AB - INTRODUCTION: Now-a-day age determination has gained importance for various forensic and legal reasons. Skeletal age (SA) of a test population can be estimated by comparing with established standards of Greulich and Pyle (G-P). As this atlas has been prepared using data from upper-class children born between 1917 and 1942 in the USA and the applicability of these standards to contemporary populations has yet to be tested on Andhra children living in India. Hence, this study was aimed to assess the reliability of bone age calculated by G-P atlas in estimation of age in selected population. MATERIALS AND METHODS: A total of 660 children (330 girls, 330 boys) between ages 9 and 20 years were randomly selected from outpatient Department of Oral Medicine in GITAM Dental College, Andhra Pradesh. Digital hand-wrist radiographs were obtained and assessed for SA using G P atlas and the difference between estimated SA and chronological age (CA) were compared with paired t-test and Wilcoxon signed rank test. RESULTS: G-P method underestimated the SA by 0.23 +/- 1.53 years for boys and overestimated SA by 0.02 +/- 2 years in girls and mild underestimation was noted in the total sample of about 0.1 +/- 1.78 years. Spearman rank test showed significant correlation between SA and CA (r = 0.86; P < 0.001). CONCLUSION: This study concluded that G P standards were reliable in assessing age in South Indian Andhra children of age 9-20 years with unknown CA. PMID- 26229358 TI - Assessment of treatment interruption among pulmonary tuberculosis patients: A cross-sectional study. AB - BACKGROUND: Multi-drug resistant tuberculosis (TB) is a rising peril of the TB control in India caused mostly by incomplete treatment. AIM: The aim was to assess the treatment interruption among pulmonary TB (PTB) patients. MATERIALS AND METHODS: A cross-sectional study was carried out for a period of 9 months among PTB patients. Patients admitted with active pulmonary Koch's and history of anti-TB treatment (ATT) for 1-month or more from any source and who returns to treatment after not taking ATT consecutively for 2 months or more were included in the study. The data were collected from the patients or their caretakers to obtain the source of treatment given previously before default, number of treatment interruptions, phase and reasons for treatment interruption treatment. RESULTS: A total of 107 defaulters were identified during the study period. In the present study, 62.6% of the patients interrupted treatment only once, 55.34% of the patient's early continuation (3-4 months) treatment, and 47.66% of the patient's only one reason for the treatment interruptions during the course of the treatment. The most common reason for the treatment interruptions were felt well with TB treatment (29.53%) followed by side effects (16.06%), lack of money (8.29%), and other reasons. CONCLUSION: The study revealed that most of the defaulters were in the age group between 35 and 60 years, male gender, illiterates, daily wage labor, and married. The treatment interruptions were minimized by putting the efforts to improve direct supervision; pretreatment counseling and retrieve treatment interrupters were recommended. PMID- 26229359 TI - Electronic solutions for combating counterfeit drugs. AB - INTRODUCTION: The problem of counterfeiting of drugs is assuming alarming proportions and is getting difficult to combat due to its trans-national character. It is undermining the faith of people on health care system. Therefore, there is a need to adopt zero tolerance approach to combat the problem. THE WAY FORWARD: There are many solutions available which are being adopted in piece meal manner by individual manufacturers. However, for wholesalers and resellers it is getting difficult to maintain multiple solutions. Therefore, there is a need to adopt a unified solution preferably with the help of the government. CONCLUSIONS: This paper discusses the available solutions, their shortcomings and proposes a comprehensive solution where at each level in the supply chain the authenticity is verified preferable linking it with Unique identification. PMID- 26229360 TI - Combinational effect of resveratrol and atorvastatin on isoproterenol-induced cardiac hypertrophy in rats. AB - INTRODUCTION: Resveratrol is a natural polyphenol present mainly in grapes. It has been shown to offer strong cardio protection in animal models due to its ability to correct lipid peroxidation and maintain antioxidants level. Atorvastatin, a HMG-CoA reductase inhibitor, lowers cholesterol level and is commonly prescribed to heart patients. Our aim in this study was to see the combination effect of these two drugs against Isoproterenol-induced cardiac hypertrophy in rats. MATERIALS AND METHODS: Wister Albino rats were treated with resveratrol (20 mg/kg/day, p.o), atorvastatin (20 mg/kg/day, p.o) and in combination (resveratrol [10 mg/kg/day, p.o] + atorvastatin [10 mg/kg/day, p.o]) for a period of 25 days and from 15(th) till 25(th) day Isoproterenol (5 mg/kg/day, s.c) was co-administered to rats to induce cardiac hypertrophy. RESULTS: A significant increase in creatine kinase, lactate dehydrogenase, aspartate transaminase and lipid peroxidation with the significant decrease in reduced glutathione, superoxide dismutase and catalase were observed in Isoproterenol treated rats. Resveratrol, atorvastatin and their combination significantly reversed the effect. The histopathological studies and myocardial infarct size evaluation also confirmed the protection. CONCLUSION: Comparing the data we came to this conclusion that atorvastatin although showed the protection along all the parameters, the extent of protection offered by resveratrol alone and in combination were more effective. Hence, it can be concluded that resveratrol, an herbal nutritional supplement, alone and in combination is better against cardiac hypertrophy. PMID- 26229361 TI - Perspective: Does personalized medicine hold the future for medicine? PMID- 26229362 TI - Surface Roughness of Composite Resins after Simulated Toothbrushing with Different Dentifrices. AB - BACKGROUND: The aim of the study was to evaluate, in vitro, the surface roughness of two composite resins submitted to simulated toothbrushing with three different dentifrices. MATERIALS AND METHODS: Totally, 36 samples of Z350XT and 36 samples of Empress Direct were built and randomly divided into three groups (n = 12) according to the dentifrice used (Oral-B Pro-Health Whitening [OBW], Colgate Sensitive Pro-Relief [CS], Colgate Total Clean Mint 12 [CT12]). The samples were submitted to 5,000, 10,000 or 20,000 cycles of simulated toothbrushing. After each simulated period, the surface roughness of the samples was measured using a roughness tester. RESULTS: According to three-way analysis of variance, dentifrice (P = 0.044) and brushing time (P = 0.000) were significant. The composite resin was not significant (P = 0.381) and the interaction among the factors was not significant (P > 0.05). The mean values of the surface roughness (um) followed by the same letter represent no statistical difference by Tukey's post-hoc test (P <0.05): Dentifrice: CT12 = 0.269(a); CS Pro- Relief = 0.300(ab); OBW = 0.390(b). Brushing time: Baseline = 0,046a; 5,000 cycles = 0.297(b); 10,000 cycles = 0.354(b); 20,000 cycles = 0.584(c). CONCLUSION: Z350 XT and Empress Direct presented similar surface roughness after all cycles of simulated toothbrushing. The higher the brushing time, the higher the surface roughness of composite resins. The dentifrice OBW caused a higher surface roughness in both composite resins. PMID- 26229363 TI - Nanoleakage of Class V Resin Restorations Using Two Nanofilled Adhesive Systems. AB - BACKGROUND: This study was carried out to evaluate the nanoleakage of two types of nanofilled adhesive systems in Class V composite resin restorations. MATERIALS AND METHODS: Totally 60 human premolars were randomly assigned to two groups (n = 30). Standardized round Class V cavities (enamel and dentin margins) were prepared. A total-etch (N-Bond total etch) (Ivoclar Vivadent) and self-etching (N Bond self-etch) (Ivoclar Vivadent) adhesive system were evaluated. The cavities were restored incrementally with nanohybird composite resin (Tetric N-Ceram). The teeth were sectioned into a series of 1 mm thick beams then they were immersed in the prepared ammoniacal silver nitrate tracer solution for 24 h in a black photo film container to ensure total darkness. The beams were then rinsed with distilled water, and immersed in photo-developing solution for eight hours then they were subjected to the nanoleakage evaluation. The specimens were analyzed in the environmental scanning electron operated with backscattered electron mode at *1000 magnification. RESULTS: Self-etch adhesive recorded higher nanoleakage % mean value than the total-etch adhesive. The difference in nanoleakage % mean values between total and self-etch adhesive was statistically significant. CONCLUSION: The self-etch adhesive had statistically significant higher nanoleakage mean values than the total-etch adhesive. PMID- 26229365 TI - Comparison of Shear Bond Strength of New Self-etching Primer with Conventional Self-etching Primers: An In-vitro Study. AB - BACKGROUND: In the past few years, there has been a major research drive to increase bond strength between dental materials and dental hard tissue and to reduce the associated demineralization around fixed orthodontic appliances. Thus, a recent approach is to incorporate an antibacterial agent into the primer to reduce the demineralization and enhance bond strength. The objective of this study was: (1) To evaluate the shear bond strength of orthodontic preadjusted edgewise appliance brackets bonded to extracted premolar teeth with antimicrobial self-etch primer (Reliance self-etching primer, Clearfil Protect Bond) and self etching primer without antimicrobial agent (Clearfil SE bond). (2) To compare the mean shear bond strength values of the tested materials to conventional self etching primer Transbond Plus. MATERIALS AND METHODS: A total of 125 extracted human premolar teeth were randomly divided into five groups of 25 teeth each. Each sample was embedded in an acrylic block of polymethyl meth acrylate resin till coronal portion. Instron testing machine model LR LOYD 50 K was used for testing the shear bond strength of individual samples. RESULTS: The results of the study showed that all five groups had adequate clinically acceptable bond strength. In intergroup comparison, there was statistically significant difference in bond strength of Reliance self-etching primer, Promt L pop, Clearfil Protect Bond, clearfil SE bond and Transbond Plus. CONCLUSION: Reliance self-etching primer showed highest bond strength, followed by Clearfil Protect Bond, clearfil SE bond, and Transbond Plus. Clearfil Protect Bond primer containing methacryloxy dodecyl pyridium bromide have been demonstrated to kill Streptococcus mutans within a short time of contact and also exhibits an inhibitory effect on the growth of bacteria on its surface. PMID- 26229364 TI - Comparing the Accuracy of Three Different Impression Materials in Making Duplicate Dies. AB - BACKGROUND: Marginal adaptation is very important in cast restorations. Maladaptation leads to plaque retention, reduction of mechanical and esthetic properties. The aim of this study was to evaluate the precision of three different impression materials (including: Additional silicone [AS] and condensational silicone [CS] and polyether [PE]) for duplicating master dies. MATERIALS AND METHODS: Three master dies from an acrylic tooth model-with supragingival and shoulder finishing line was made by using PE: Impergum, CS: Speedex, and AS: Panasil separately. The Ni-Cr copings were prepared from master dies separately. They were placed on the acrylic model and the mean marginal difference was recorded by using a stereomicroscope. Then 30 duplicate test dies were made by using the same impression materials and the marginal gaps were recorded. The comparison was done by one-way ANOVA and SPSS software (Version 13) at a significant level of 0.05. RESULTS: The mean marginal difference of four walls from Impergum (38.56 um) was the lowest than Speedex (38.92 um) and Panasil (38.24 um). The Impergum had the highest capability in making duplicate dies (P > 0.05). CONCLUSION: The Impergum impression material manifested the highest capability in making a better marginal adaptation of duplicate dies but further studies are needed to make a precise decision. PMID- 26229366 TI - Effect of Post Material and Length on Fracture Resistance of Endodontically Treated Premolars: An In-Vitro Study. AB - BACKGROUND: Endodontically treated teeth with posts are more prone to fracture. Hence, the purpose of this study was to investigate the in-vitro fracture resistance of devitalized teeth and mode of failure restored with posts of different materials and different lengths. MATERIALS AND METHODS: Sixty freshly extracted human mandibular premolars were endodontically treated and then restored with 1 of 2 prefabricated posts: Stainless-steel (SS) and glass-fiber (fiber posts [FP]) with intraradicular lengths of 4, 5 or 10 mm (n = 10). Following core restoration, a static compressive load was applied perpendicular to the long-axis of the teeth. Initial failure of each specimen was recorded in Newton. The mode of failure was also determined radiographically. The data were analyzed using two-way ANOVA and Tukey's post-hoc analysis with Bonferroni adjustment. RESULTS: Analysis indicated significant differences (P < 0.001) among the groups. Among the SS posts, SS/7 (246 N) exhibited the highest failure load and SS/4 (122 N) the lowest. FP/10 (140.5 N) exhibited the highest failure load among the FP and FP/4 (68.5 N) the lowest. SS posts showed post pull out, followed by core fracture while FP showed core debonding, followed by core fracture as the primary mode of failure. CONCLUSION: Fracture resistance of the teeth proportionately increased with increase in the length of FP while it decreased with that of metal post. SS posts showed greater fracture resistance than FP when 90 degrees load was applied. PMID- 26229367 TI - Comparison of Galvanic Currents Generated Between Different Combinations of Orthodontic Brackets and Archwires Using Potentiostat: An In Vitro Study. AB - BACKGROUND: Technological advances in wire selection and bracket design have led to improved treatment efficiency and allowed longer time intervals between appliance adjustments. The wires remain in the mouth for a longer duration and are subjected to electrochemical reactions, mechanical forces of mastication and generalized wear. These cause different types of corrosion. This study was done to compare the galvanic currents generated between different combinations of brackets and archwires commonly used in orthodontic practices. MATERIALS AND METHODS: The materials used for the study included different commercially available orthodontic archwires and brackets. The galvanic current generated by individual materials and different combinations of these materials was tested and compared. The orthodontic archwires used were 0.019" * 0.025" heat-activated nickel-titanium (3M Unitek), 0.019" * 0.025" beta-titanium (3M Unitek) and 0.019" * 0.025" stainless steel (3M Unitek). The orthodontic brackets used were 0.022" MBT laser-cut (Victory Series, 3M Unitek) and metal-injection molded (Leone Company) maxillary central incisor brackets respectively. The ligature wire used for ligation was 0.009" stainless steel ligature (HP Company). The galvanic current for individual archwires, brackets, and the different bracket-archwire ligature combinations was measured by using a Potentiostat machine. The data were generated using the Linear Sweep Voltammetry and OriginPro 8.5 Graphing and Data Analysis Softwares. The study was conducted in two phases. Phase I comprised of five groups for open circuit potential (OCP) and galvanic current (I), whereas Phase II comprised of six groups for galvanic current alone. RESULTS: Mean, standard deviation and range were computed for the OCP and galvanic current (I) values obtained. Results were subjected to statistical analysis through ANOVA. In Phase I, higher mean OCP was recorded in stainless steel archwire, followed by beta-titanium archwire, heat-activated nickel titanium archwire, laser-cut bracket and metal-injection molded bracket, respectively. The difference in mean OCP recorded among the groups was found to be statistically significant in aerated phosphate buffered saline solution. The galvanic current (I) for metal injection molded stainless steel brackets showed significantly higher values than all the other materials. Phase II results suggested that, in the couples formed by the archwire-bracket-ligature combinations, the bracket had more important contribution to the total galvanic current generated, since there were significant differences between galvanic current among the 2 brackets tested but not among the 3 wires. The galvanic current of the metal-injection molded bracket was significantly higher than that of laser-cut bracket. Highest mean current (I) was recorded in metal-injection molded bracket when used with heat-activated nickel titanium archwire while lowest mean current (I) was recorded in laser-cut bracket when used with beta-titanium archwire. CONCLUSION: The present study concluded that the bracket emerged to be the most important factor in determining the galvanic current (I). Higher mean current (I) was recorded in metal-injection molded bracket compared to laser-cut bracket. Among the three archwires, higher mean current (I) was recorded in heat-activated nickel-titanium, followed by stainless-steel and beta-titanium respectively. When coupled together; highest mean current (I) was recorded in metal-injection molded bracket when used with heat-activated nickel titanium archwire while lowest mean current (I) was recorded in laser-cut bracket when used with beta-titanium archwire. PMID- 26229368 TI - Effect of Desensitising Laser Treatment on the Bond Strength of Full Metal Crowns: An In Vitro Comparative Study. AB - BACKGROUND: Dentinal hypersensitivity is a very common complaint of patients undergoing crown and bridge restorations on vital teeth. Of the many desensitizing agents used to counter this issue, desensitizing laser treatment is emerging as one of the most successful treatment modality. However, the dentinal changes brought about by the desensitizing laser application could affect the bond strength of luting cements. MATERIALS AND METHODS: Freshly extracted 48 maxillary first premolars, which were intact and morphologically similar were selected for the study. The specimens were divided into two groups, an untreated the control group and a desensitizing laser-treated group, which were exposed to Erbium, Chromium: Yttrium, Selenium, Galium, Garnet laser at 0.5 W potency for 15 s. Each of the above two groups were again randomly divided into two subgroups, on to which full veneer metal crowns, which were custom fabricated were luted using glass-ionomer and resin luting cements, respectively. Tensile bond strength of the luting cements was evaluated with the help of a Universal Testing Machine. Statistical analysis of the values were done using descriptive, independent samples' test, and two-way ANOVA test. RESULTS: The tensile bond strength of crowns luted on desensitizing laser treated specimens using self-adhesive resin cement showed a marginal increase in bond strength though it was not statistically significant. CONCLUSION: The self-adhesive resin cements could be recommended as the luting agent of choice for desensitizing laser treated abutment teeth, as it showed better bond strength. PMID- 26229369 TI - Bacterial Biofilm Removal Using Static and Passive Ultrasonic Irrigation. AB - BACKGROUND: The aim of the present study was to evaluate the efficiency of two irrigating techniques - static and dynamic (passive ultrasonic instrumentation) irrigation in the elimination of bacterial biofilm. MATERIALS AND METHODS: Forty extracted human permanent maxillary central incisors teeth with straight roots and single canals, were randomly allocated to two groups for static irrigation and passive ultrasonic irrigation (PUI). The root canal irrigant used was 2.5 % sodium hypochlorite. The root canals were prepared to tip sizes (20, 40) and tapers (0.04, 0.08). Using system GT instruments (Dentsply Malliefer, Switerzland). The teeth were split longitudinally into two, stained collagen was applied to the canal surfaces and the tooth reassembled for static and PUI. Digital images of the canal surface were taken before and after irrigation with 9, 18, 27 and 37 mL solution. The digital images were analyzed using ImageJ software (National Institute of Health, USA) to quantify residual canal coverage by the stained collagen. The data were analyzed using linear regression models and subjected to statistical analysis. RESULTS: The mean percentage of canal surface with residual collagen increased with the coronal level of canal, decrease in apical size and taper of canal preparation and decrease in the volume of the irrigant. There was less residual collagen after PUI compared with static irrigation. The canal surface facing the open side port of the needle had less residual collagen after irrigation than the opposing surface. CONCLUSION: The stained collagen biomolecular film could not be removed completely either by passive ultrasonic instrumentation or static irrigation. The PUI was found to be more effective in the removal of collagen, especially in the apical part of the root canal. PMID- 26229370 TI - Establishing Cephalometric Norms using Sagittal and Vertical Occlusal Cephalometric Analysis of Pancherz for Dakshina Kannada Children. AB - BACKGROUND: The purpose of this study was to establish norms for the sagittal occlusal (SO) and vertical occlusal (VO) cephalometric analyses of Pancherz for Dakshina Kannada children and to analyze and compare the difference between boys and girls of same age group (10-14 years). MATERIALS AND METHODS: Two hundred and sixty-three (132 boys and 131 girls) children of Dakshina Kannada were included in this study. Lateral cephalometric radiographs of children belonging to the age group of 10-14 years were taken. Dental lateral cephalometric radiographs were obtained and these cephalometric radiographs were then manually traced. All the parameters considered in the Pancherz analysis were considered while establishing the norms for Dakshina Kannada children. RESULTS: Statistically significant sex differences were found for 9 of 11 parameters in the sagittal occlusal analysis, and 10 of 10 in the Vertical occlusal analysis. CONCLUSIONS: For the sagittal and Vertical occlusal analyses of Pancherz a separate sex-specific standards are needed for Dakshina Kannada children. PMID- 26229371 TI - Comparison of Shear Bond Strength of Three Self-etching Adhesives: An In-Vitro Study. AB - BACKGROUND: The aim of the study was to determine and compare the shear bond strength of brackets bonded with Adper Promt self-etching adhesive (3M ESPE), Xeno III self-etching adhesive (DENSPLY), Transbond plus self-etching adhesive (3M) with that of conversional bonding procedure, and to calculate the adhesive remnant index (ARI). MATERIALS AND METHODS: Totally, 60 maxillary premolar teeth were collected, and divided into Group I (Blue): TransbondTM XT primer, Group II (Purple): AdperTM PromptTM self-etching adhesive, Group III (Orange): Xeno III(r) self-etching adhesive, Group IV (Pink): TranbondTM Plus self-etching adhesive. RESULTS: The results of the study showed there was no statistical significance in the shear bond strength according to an analysis of variance (P = 0.207) of the four groups. The mean shear bond strength of Groups I, II, III, IV were 14.56 +/- 2.97 Megapascals (MPa), 12.62 +/- 2.48 MPa, 13.27 +/- 3.16, and 12.64 +/- 2.56, respectively. Chi-square comparison for the ARI indicated that there was a significant difference (P = 0.003) between the groups. CONCLUSION: All the four self-etching adhesives showed clinically acceptable mean shear bond strength. The ARI score showed a self-etching adhesive the debonding occurred more within the adhesive interface leaving less composite adhesive on the tooth surface making it easy to clean up. PMID- 26229372 TI - Evaluation of Micro-organism in Ligated Metal and Self-ligating Brackets using Scanning Electron Microscopy: An In Vivo Study. AB - BACKGROUND: The objective of the study was to determine the sites of plaque accumulation and to compare the plaque accumulated with metal and self-ligating orthodontic brackets in order to know which bracket type had a higher plaque retaining capacity. MATERIALS AND METHODS: The study was done on 20 subjects who were scheduled for orthodontic treatment including extraction of four premolars and fixed orthodontic appliances. Mesh-backed edgewise metal brackets ligated with steel ligatures and self-ligating brackets were bonded to the premolars to be extracted using composite (Transbond XT, 3M). The subjects were told to continue their normal oral hygiene regimen. Teeth were extracted at 1, 2, and 3 weeks after bracket bonding. Plaque attached to the buccal surfaces was stained using plaque disclosing agent. The teeth were then immersed in fixative containing 4% formaldehyde and 1% glutaraldehyde in phosphate buffer for 24 h, followed by 0.1 M phosphate buffer for 12 h. The specimens were then mounted on aluminum stubs, and sputter coated with gold prior to Scanning electron microscopy examination. RESULTS: The results showed that increased retention of plaque in metal brackets ligated with steel ligatures and comparatively less in self-ligating brackets at the base of the brackets. CONCLUSIONS: This study highlights that higher retention of plaque in metal brackets ligated with steel ligatures and comparatively less plaque retention in self-ligating brackets. Excess composite around the bracket base is the critical site of plaque accumulation associated with fixed appliances due to its rough surface texture. PMID- 26229373 TI - Evaluation of the Effect of Surface Polishing, Oral Beverages and Food Colorants on Color Stability and Surface Roughness of Nanocomposite Resins. AB - BACKGROUND: It is beyond doubt that finishing and polishing of a composite restoration enhance its esthetics and, is also essential for the health of the periodontium. A variety of instruments are commonly used for finishing and polishing tooth-colored restorative materials Thus, it is important to understand which type of surface finishing treatments would significantly affect the staining and surface irregularities of the composite resin restoration. Still one of the properties of the composite resins that have to pass the test of time is its color stability. In modern day dentistry, a large emphasis is laid over esthetics. Hence, it is important to understand the various agents capable of adversely affecting the esthetics of a restoration due to its staining capacity. Thus, the aim of this in vitro study was to evaluate the effect of surface polishing, oral beverages and food colorants on the color stability and surface roughness of nanocomposite resins. MATERIALS AND METHODS: 90 Disks of nanocomposites resin (Filtek Z350 XT) measuring 8 mm in diameter and 2 mm in thickness were fabricated using a custom made silicon mold. Pre-polishing surface roughness (Ra1) of all the 90 samples were measured using a Surface Profilometer. The nano-composite disks were then randomly divided into 3 groups with 30 samples in each group. Group I: CONTROL GROUP: The samples were not subjected to any polishing procedures. Group II: Sof-Lex group: Samples subjected to polishing using different grits of Sof-Lex disks. Group III: Diamond polishing paste group: Samples were subjected with a polishing paste consisting of diamond particles. Following polishing procedures, the surface roughness of all samples were measured again to obtain change in surface roughness due to polishing procedures (Ra2), pre immersion spectrophotometric value (DeltaE1) was also recorded for baseline color of the samples. The samples were then divided into subgroups (A, B, C, D, E), by including every first sample in Subgroup A, second in Subgroup B, third in Subgroup C, fourth in Subgroup D, and fifth in Subgroup E. Each was immersed in the respective test solution for 10 min, twice a day for 30 days. Group A - Tea, Group B - Coffee, Group C - Cola, Group D - Turmeric, Group E - Control (artificial saliva). Post immersion profilometric value was recorded to evaluate roughness bought about by the solutions (Ra3) and spectrophotometric value was recorded to evaluate the color change in samples (DeltaE2). Results were statistically analyzed using ANOVA. RESULTS: Higher mean roughness (Ra2-Ra1) value was recorded in Sof-Lex, followed by Diamond polishing paste and Control group. Comparison of surface roughness caused due to beverages and food colorant solution showed subgroup C (Coca Cola) increased surface roughness in all groups (Group I, II, III). Subgroup D (Turmeric) had the highest discoloration potential (P < 0001) in all groups, followed by coffee, tea, coca-cola and artificial saliva. Sof-Lex polishing System showed most color stability. CONCLUSION: Polishing procedures significantly roughen the surface of the restoration compared to the unpolished Mylar controls. One-step polishing system (diamond polishing paste) produces a smoother surface compared to a multi-step system (Sof Lex polishing disks). Turmeric solution caused maximum staining of the samples, to a visually perceptible level. PMID- 26229374 TI - Microleakage in Resin Composite Restoration following Antimicrobial Pre treatments with 2% Chlorhexidine and Clearfil Protect Bond. AB - AIM: To evaluate microleakage in resin composite restorations after antimicrobial pre - treatments. MATERIALS AND METHODS: Forty freshly extracted non carious human premolars were procured. In all forty premolar specimens, class V preparation of standard dimension were prepared and were randomly divided into three experimental and one control group. In all control and experimental groups the class V preparations were restored with FILTEK Z350 composite restorative material. The experimental groups included different self etching primers and 2% Chlorhexidine gluconate. The control group included Xeno III and no antimicrobial pre-treatment was done for the control group. Thereafter these specimens were thermocycled, dried and sealed with nail varnish, leaving 1mm around the restoration and immersed in 0.5% basic fuchsin for 24 hours and then the specimens were subjected for microleakage evaluation. The results were statistically analyzed by Kruskal Wallis Test and Mann Whitney 'U' test. RESULTS: Results indicate that group II (2% chlorhexidine gluconate group) had the minimum mean value (15.05) and group III(Clearfil protect Bond group) and IV(control group) had the maximum mean microleakage at the enamel margin (23.00). At the gingival margin the lowest mean microleakage values were obtained with group I (Clearfil SE bond group) and group II (2% chlorhexidine gluconate) (20.25) and highest with group III and group IV (20.85). The difference was not statistically significant both at the enamel margin and the dentin margin (p>0.05). INTERPRETATION & CONCLUSIONS: Within the limitations of this in-vitro study, we conclude that: None of the materials tested in this study completely eliminated microleakage at the enamel and at the gingival margin.All of the tested materials provided better sealing at the enamel margin than at the gingival margin. PMID- 26229375 TI - Assessment of the Risk Factors for Oro-Dental Injuries to Occur during General Anesthesia and Measures taken by Anesthesiologist to Prevent them. AB - BACKGROUND AND AIM: Anesthesiologist gain access to the airway passage orally with the help of laryngoscope. Dental trauma can occur during different steps in anesthesia. The aim of the study is to evaluate the risk factor for dental trauma perioperatively and to look for the preventive measures mostly employed by the anesthesiologist to prevent dental insult. MATERIALS AND METHODS: The present study involved 40 anesthetists working in private hospitals using simple random sampling. They were asked to answer a questionnaire designed to look for the risk factors that makes tooth most prone for injury and find out the measures that anesthesiologists follow to prevent such injuries to occur. Codes were placed for the obtained data and Medcalc statistical package was used for analysis. RESULTS: Injuries mostly occur during intubation with a laryngoscope in patients where there is limited visibility to the hypopharynx. Maxillary left central incisor was mostly affected. Some anesthetists used plastic blades or curved blades to prevent such injury. CONCLUSION: Patient with poor dentition and history of difficult intubation should be sent for pre-operative dental evaluation to prevent dental injuries. PMID- 26229376 TI - Clinical Evaluation of Different Pre-impression Preparation Procedures of Dental Arch. AB - BACKGROUND: Bubbles and voids on the occlusal surface impede the actual intercuspation and pre-impression preparation aims to reduce the incidence of air bubbles and voids as well as influences the quality of occlusal reproduction and actual clinical intercuspation in the articulator. The study was undertaken to determine the influence of different pre-impression preparation procedures of antagonistic dental arch on the quality of the occlusal reproduction of the teeth in irreversible hydrocolloid impressions and to determine most reliable pre impression preparation method to reduce the incidence of air bubbles. MATERIALS AND METHODS: A total of 20 subjects were selected having full complement of mandibular teeth from second molar to second molar with well demarcated cusp height. 200 impressions were made with irreversible hydrocolloid material. The impressions were divided into five groups of 40 impressions each and each group had one specific type of pre-impression preparation. All the impressions were poured in die stone. A stereomicroscope with graduated eyepiece was used to count the number of bubbles on the occlusal surface of premolars and molars. The mean and standard deviations were calculated for each group. Mann-Whitney U-test was applied to find the significant difference between different groups. RESULTS: Least bubbles were found in the group in which oral cavity was dried by saliva ejector and fluid hydrocolloid was finger painted onto the occlusal surfaces immediately before the placement of impression tray in the mouth. CONCLUSION: It was found that finger painting the tooth surfaces with fluid hydrocolloid immediately before the placement of loaded impression tray in the mouth was the most reliable method. The oral cavity can be cleared more easily of excess saliva by vacuum suction rather than by use of an astringent solution. PMID- 26229377 TI - Evaluation of Lactobacillus and Streptococcus mutans by Addition of Probiotics in the form of Curd in the Diet. AB - BACKGROUND: Probiotics are defined as live microorganisms which when taken in adequate amounts provide a health benefit on the host. They have been used to improve gastrointestinal health, and their popularity has prompted increased interest for their role in the promotion of oral health also. The study was undertaken to evaluate the influence of diet alteration on oral microflora with the addition of probiotics in the form of curd in the diet. MATERIALS AND METHODS: Sample pool included total 20 children, 15 in experimental group; who were given curd containing probiotic bacteria in their diet daily and 5 children in control group; who were contradicted of food containing probiotics. All the children were followed for over a period of 1-year. A pre and post quantitative analysis of Streptococcus mutans and Lactobacilli were done in the saliva of both active and control groups, and caries score was recorded. STATISTICAL ANALYSIS USED: The data thus compiled were statistically evaluated using Chi-square test and Pearson correlation on SPSS software version 14. RESULTS: In experimental group, 87% children showed decrease and 7% showed increase in S. mutans count (P = 0.83), whereas 67% showed increase and 7% decrease in Lactobacilli count (P = 0.002) after 1-year of follow-up. CONCLUSIONS: Probiotics are upcoming as an intriguing field in oral health. Efforts should be made to increase the knowledge of the general dental practitioners with this facet of oral disease therapy and promote the implementation of the concept of "food rather than medicine." PMID- 26229378 TI - Evaluation of Anti-Inflammatory Effects of Curcumin Gel as an Adjunct to Scaling and Root Planing: A Clinical Study. AB - BACKGROUND: Complete removal of irritants is not possible with mechanical therapy alone. Adjunctive use of systemic administration of antibiotics results in the distribution of drug throughout the body, which can give rise to toxicity. Curcumin (diferuloylmethane), a constituent of Curcuma longa plant, which possess antioxidant, anti-inflammatory, anti-carcinogenic, anti-microbial, anti-hyper algesic and hypocholesterolemic properties. The aim of the present study is to compare the effects of the curcumin gel as an adjunct to subgingival scaling and root planning with the effect achieved using subgingival scaling and root planning alone. MATERIALS AND METHODS: Thirty patients either male or female with chronic localized or generalized periodontitis aged between 25 and 60 years with pocket depth of 5-7 mm affecting at least two nonadjacent sites were included. In the experimental site scaling and root planning was performed, followed by placement of the curcumin gel and periodontal pack application. In the control site, subgingival scaling alone was performed followed by periodontal pack application. Parameters included were: Plaque index (PI), gingival index (GI), probing depth (PD) and clinical attachment loss. These parameters were recorded on day 0, 30 and 45 days. RESULTS: Significant reduction in mean was observed in PI, GI, PD and gain in clinical attachment level were demonstrated in both the groups from baseline to 45 days. However, statistical significant reduction was observed in PI at baseline and 30(th) day and GI at 30(th) day. CONCLUSION: Curcumin can be effectively used along with scaling and root planning. Future research is required to determine the long-term effects of curcumin on a large sample of subjects. PMID- 26229379 TI - Evaluation of Prevalence and Severity of Malocclusion in South Travancore Population. AB - BACKGROUND: Assess prevalence and severity of malocclus ion in 12 - 16 year old population of Travancore using IOTN index. Tertiary care setting, with the study being conducted in the Dept of Orthodontics at PMS Dental College & the samples being collected from four different dental health care centres. Study design is descriptive study. MATERIALS AND METHODS: 120 pre- treatment study models of patients aged 12-16 yrs were collected, 30 each from four dental health centres spread across the state. These casts were subjected to three stages of screening based on IOTN index to arrive at the prevalence and severity of malocclusion in the targeted group. Kappa statistics and stratified kappa statistics. RESULTS: Results of the study showed that the prevalence of malocclusion and treatment need was 53.3%. CONCLUSIONS: The prevalence of orthodontic treatment need in South Kerala was found to be 53.3%. PMID- 26229380 TI - Knowledge and Perceptions Regarding Nicotine Replacement Therapy among Dental Students in Karnataka. AB - BACKGROUND: Organized dentistry has recognized the role of oral health professionals in discouraging tobacco use. Unexplored level of knowledge regarding the benefits and prescription of nicotine replacement therapy (NRT) have aroused interest among us which initiated us to assess the knowledge and perception of dental students toward NRT among various dental colleges in Karnataka, South India. MATERIALS AND METHODS: A questionnaire survey was done among 16 selected colleges in Karnataka. It was distributed for 3(rd) year, final year, and interns. The study group provided answers to 14 item close-ended questionnaire. The first dimension obtained information on sex, age, course and year of study, and other dimension on forms in which NRT's are supplied, effectiveness of NRT's, side effects of NRT's, rate of success of NRT's, electronic cigars, and recommendations of NRT's. Statistical analysis was done using frequency distribution of responses. RESULTS: A total of 1984 undergraduate students from Dental Colleges in Karnataka responded to the questionnaire. Most of the students were unaware about NRT term and its forms. Most of the students were aware about the effectiveness of NRT's (54%) for the rescue of the smokers to quit and felt transdermal patch (42%) could be the most effective way for smokers to quit followed by chewing gums, respectively. More than half of the respondents (53.5%) were unaware of E-cigar's and also felt that NRT's and Counseling cumulatively can contribute for cessation of the tobacco habit. CONCLUSION: A large proportion of dental students in this part of the country were unaware about NRT. PMID- 26229381 TI - Effect of Tetracycline Hydrochloride and Spiramycin Sub Gingival Irrigation with Pulsated Jet Irrigator in Chronic Periodontitis Patients: A Clinical Study. AB - BACKGROUND: The present study is designed to evaluate the clinical effects of pulsated subgingival irrigation with tetracycline and spiramycin. MATERIALS AND METHODS: Ten patient diagnosed chronic periodontitis were included in the present study. Each patient is assigned to be irrigated with saline (placebo) (Group A), tetracycline HCl at 0.5% concentration (Group B), and 0.5% spiramycin (Group C). Scaling and root planing (SC/RP) was recorded as Group D. Plaque index, gingival index, gingival bleeding index, probing pocket depth were assessed on pre irrigation (day 0), and at days 7, 14, 21, 28, and 35 day. RESULTS: The results showed that subgingival irrigation with 0.5% tetracycline and spiramycin produced a significant reduction in clinical parameters compared to the control, while SC/RP was showed better improvement. CONCLUSION: The result of this study suggested that subgingival irrigation of tetracycline and spiramycin play a beneficial role in the management of chronic periodontitis patients. PMID- 26229382 TI - Oral Hygiene Levels in Children of Tribal Population of Eastern Ghats: An Epidemiological Study. AB - BACKGROUND: Oral hygiene has been given due importance since ages. Different cultures have been using different methods for the maintenance of good oral hygiene. The study was done to find out the oral hygiene levels in children of tribal population and to correlate the brushing methods used and the oral hygiene levels. METHODOLOGY: A total of 5129 children of 5-12 years age (boys 2778, girls 2351) were checked for the simplified oral hygiene index in the study. RESULTS: The overall oral hygiene status of 1267 girls and 1348 boys was fair, whereas 821 girls and 937 boys was good and 263 girls and 493 boys was poor. It has been shown that fair oral hygiene practices were being followed by the children. CONCLUSION: Children using twigs and other materials for oral hygiene had nearly equally good oral hygiene when compared to the tooth brush and tooth paste, though children using toothbrush and tooth paste had slightly better oral hygiene. PMID- 26229383 TI - Evaluation of Sealing Ability of Biodentine as Retrograde Filling Material by Using two Different Manipulation Methods: An In Vitro Study. AB - BACKGROUND: The study was aimed to evaluate the microleakage of Biodentine using two different manipulation methods by dye penetration. MATERIALS AND METHODS: A total of 60 single-rooted human maxillary permanent teeth were cleaned and obturated with gutta-percha using lateral condensation method. Standardized root end cavities were prepared after apical resection. All teeth were divided randomly into two groups of 30 specimens and were filled with Biodentine by trituration and hand manipulation methods. The samples were coated with varnish and immersed in 1% methylene blue dye for 72 h. Then the teeth were sectioned longitudinally and observed under a stereomicroscope. The depth of dye penetration was measured in millimeters. RESULTS: There was highly statistical significant difference observed between Group I and Group II (P < 0.001) when dye penetration scores were compared. CONCLUSION: More microleakage was seen when Biodentine was manually manipulated as compared to machine trituration. PMID- 26229384 TI - Detection of Acid Fast Bacilli in Saliva using Papanicolaou Stain Induced Fluorescence Method Versus Fluorochrome Staining: An Evaluative Study. AB - BACKGROUND: Fifty years after effective chemotherapy, tuberculosis (TB) still remains leading infectious cause of adult mortality. The aim of present study was to evaluate diagnostic utility of papanicolaou (Pap) stain induced fluorescence microscopic examination of salivary smears in the diagnosis of pulmonary TB. MATERIALS AND METHODS: Cross-sectional study of 100 individuals clinically suspected of suffering from active pulmonary TB. Control group - 50 individuals are suffering from any pulmonary disease other than TB such as pneumonia or bronchiogenic carcinoma. Fluorescence microscopic examination of two salivary smears stained by Pap stain and auramine-rhodamine (A-R) stain respectively for each patient. Ziehl-Neelsen stained sputum smear examined under the light microscope for each patient. Culture was done in all the patients for microbiological confirmation. McNemar's Chi-square analysis, Kappa test, and Z test. RESULTS: The sensitivities of the three staining methods using culture as a reference method were 93.02%, 88.37% and 87.20% for Pap, A-R and Ziehl-Neelson respectively. CONCLUSION: Pap-induced fluorescence of salivary smears is a safe, reliable and rapid method, which can prove as a valuable diagnostic tool for diagnosis of TB. PMID- 26229385 TI - Rehabilitation of an Orbital Defect: A Simplified Technique. AB - Loss of tissue, whether congenital or traumatic or resulting from malignancy or radical surgery, is accompanied by esthetic and psychologic effects. This loss is more pronounced when the affected part is the eye and all orbital contents, resulting in gross mutilation. Success in maxillofacial prosthetics depends on the full cognizance of the principles that underlie facial harmony, color matching, anchorage and retention, weight bearing and leverage, durability and strength of materials used, tissue compatibility and tolerance. The restoration of orbital defects presents a challenge in maxillofacial prosthetics. Many variations exist in techniques and materials for fabricating orbital prostheses. Careful positioning of the ocular portion of the orbital prosthesis is one of the requirements for a successful esthetic result. A change of this position, which may occur during fabrication or may be due to distortion of the prosthetic housing or loss of retention of the prosthesis, may result in an unsatisfactory appearance. This article presents a simplified technique for fabricating an orbital prosthesis. PMID- 26229386 TI - A Rare Case of Apical Root Resorption during Orthodontic Treatment of Patient with Multiple Aplasia. AB - External apical root resorption is an adverse effect of orthodontic treatment. It reduces the length of root and breaks the integrity of teeth and dental arch. Orthodontics is the only dental specialty that clinically uses the inflammatory process to correct the mal-aligned teeth. Hence, it is necessary to know the risk factors of root resorption and do everything to reduce the rate of root resorption. Hence, all predisposing factors which are systemic as well as local should be considered before treatment begins. This case report describes the incidence of root resorption following orthodontic treatment and the teeth affected in the patient with multiple aplasia. PMID- 26229387 TI - Dentofacial Asymmetries: Challenging Diagnosis and Treatment Planning. AB - Dentofacial asymmetry is quite common and when sufficiently severe can require surgical orthodontic intervention. Asymmetries can be classified according to the structures involved into skeletal, dental and functional. In diagnosing asymmetries, a thorough clinical examination and radiographic survey are essential to determine the extent of soft tissue, skeletal, dental and functional involvement. Dental asymmetries, as well as a variety of functional deviations, can be managed orthodontically, whereas significant structural facial asymmetries require a comprehensive orthodontic and orthognathic management. With less severe dental, skeletal and soft tissue deviations the advisability of treatment should be carefully considered. The following article also contains a case report highlighting the importance of proper diagnosis in treatment plan for management of dentofacial asymmetry. PMID- 26229388 TI - Pseudoepitheliomatous Hyperplasia: Relevance in Oral Pathology. AB - Pseudoepitheliomatous hyperplasia (PEH), a neglected entity by oral pathologist possesses utmost importance in the field of research. Of all the investigative challenges, PEH, a reactive epithelial proliferation is seen secondary to lesions with infectious, inflammatory, reactive, and degenerative origin. Small sized samples, incomplete excision, improper orientation, and dense inflammatory changes render diagnostic confront to the oral pathologist in exclusion of frankly invasive malignant lesions like squamous cell carcinoma from lesions exhibiting PEH. The diagnosis can occasionally be difficult as they mimic other lesions also, on clinic-pathological assessment. Thus, this article gives an insight regarding the various concepts of etiopathogenesis, histopathology, differential diagnosis, and malignant potential of PEH. A combined effort of a clinician and pathologist benefits every patient to rule out malignancy and render appropriate treatment as the only local conservative approach is essential to remove PEH associated lesions. PMID- 26229390 TI - Role of Mycoplasma in the Initiation and Progression of Oral Cancer. PMID- 26229389 TI - Periodontal Disease: A Possible Risk-Factor for Adverse Pregnancy Outcome. AB - Bacterial invasion in subgingival sites especially of gram-negative organisms are initiators for periodontal diseases. The periodontal pathogens with persistent inflammation lead to destruction of periodontium. In recent years, periodontal diseases have been associated with a number of systemic diseases such as rheumatoid arthritis, cardiovascular-disease, diabetes mellitus, chronic respiratory diseases and adverse pregnancy outcomes including pre-term low-birth weight (PLBW) and pre-eclampsia. The factors like low socio-economic status, mother's age, race, multiple births, tobacco and drug-abuse may be found to increase risk of adverse pregnancy outcome. However, the same are less correlated with PLBW cases. Even the invasion of both aerobic and anerobic may lead to inflammation of gastrointestinal tract and vagina hence contributing to PLBW. The biological mechanism involved between PLBW and Maternal periodontitis is the translocation of chemical mediators of inflammation. Pre-eclampsia is one of the commonest cause of both maternal and fetal morbidity as it is characterized by hypertension and hyperprotenuria. Improving periodontal health before or during pregnancy may prevent or reduce the occurrences of these adverse pregnancy outcomes and, therefore, reduce the maternal and perinatal morbidity and mortality. Hence, this article is an attempt to review the relationship between periodontal condition and altered pregnancy outcome. PMID- 26229391 TI - Gastrointestinal cancers in the era of theranostics: Updates and future perspectives. AB - Theranostics are one of the practical aspects of personalized medicine. This concept was designed to describe a material combining diagnosis, treatment and follow up of a disease. It evolved and included molecular targeting and nanotechnologies that incorporate both diagnosis and therapeutics. In this editorial, we are presenting briefly the concept and evolution of theranostics, highlighting many applications of theranostics in daily practice and discussing future perspectives and aspects of this model in gastro-intestincal cancers. PMID- 26229392 TI - Current and future treatments for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) represents a unique challenge for physicians and patients. There is no definitively curative treatment. Rather, many treatment and management modalities exist with differing advantages and disadvantages. Both current guidelines and individual patient concerns must be taken into account in order to properly manage HCC. In addition, quality of life issues are particularly complex in patients with HCC and these concerns must also be factored into treatment strategies. Thus, considering all the options and their various pros and cons can quickly become complex for both clinicians and patients. In this review, we systematically discuss the current treatment modalities available for HCC, detailing relevant clinical data, risks and rewards and overall outcomes for each approach. Surgical options discussed include resection, transplantation and ablation. We also discuss the radiation modalities: conformal radiotherapy, yttrium 90 microspheres and proton and heavy ion radiotherapy. The biologic agent Sorafenib is discussed as a promising new approach, and recent clinical trials are reviewed. We then detail currently described molecular pathways implicated in the initiation and progression of HCC, and we explore the potential of each pathway as an avenue for drug exploitation. We hope this comprehensive and forward-looking review enables both clinicians and patients to understand various options and thereby make more informed decisions regarding this disease. PMID- 26229393 TI - Hepatitis C virus comes for dinner: How the hepatitis C virus interferes with autophagy. AB - Autophagy is a highly-regulated, conserved cellular process for the degradation of intracellular components in lysosomes to maintain the energetic balance of the cell. It is a pro-survival mechanism that plays an important role during development, differentiation, apoptosis, ageing and innate and adaptive immune response. Besides, autophagy has been described to be involved in the development of various human diseases, e.g., chronic liver diseases and the development of hepatocellular carcinoma. The hepatitis C virus (HCV) is a major cause of chronic liver diseases. It has recently been described that HCV, like other RNA viruses, hijacks the autophagic machinery to improve its replication. However, the mechanisms underlying its activation are conflicting. HCV replication and assembly occurs at the so-called membranous web that consists of lipid droplets and rearranged endoplasmic reticulum-derived membranes including single-, double- and multi-membrane vesicles. The double-membrane vesicles have been identified to contain NS3, NS5A, viral RNA and the autophagosomal marker microtubule-associated protein 1 light chain 3, corroborating the involvement of the autophagic pathway in the HCV life-cycle. In this review, we will highlight the crosstalk of the autophagosomal compartment with different steps of the HCV life-cycle and address its implications on favoring the survival of infected hepatocytes. PMID- 26229394 TI - Gastroesophageal reflux and congenital gastrointestinal malformations. AB - Although the outcome of newborns with surgical congenital diseases (e.g., diaphragmatic hernia; esophageal atresia; omphalocele; gastroschisis) has improved rapidly with recent advances in perinatal intensive care and surgery, infant survivors often require intensive treatment after birth, have prolonged hospitalizations, and, after discharge, may have long-term sequelae including gastro-intestinal comorbidities, above all, gastroesophageal reflux (GER). This condition involves the involuntary retrograde passage of gastric contents into the esophagus, with or without regurgitation or vomiting. It is a well-recognized condition, typical of infants, with an incidence of 85%, which usually resolves after physiological maturation of the lower esophageal sphincter and lengthening of the intra-abdominal esophagus, in the first few months after birth. Although the exact cause of abnormal esophageal function in congenital defects is not clearly understood, it has been hypothesized that common (increased intra abdominal pressure after closure of the abdominal defect) and/or specific (e.g., motility disturbance of the upper gastrointestinal tract, damage of esophageal peristaltic pump) pathological mechanisms may play a role in the etiology of GER in patients with birth defects. Improvement of knowledge could positively impact the long-term prognosis of patients with surgical congenital diseases. The present manuscript provides a literature review focused on pathological and clinical characteristics of GER in patients who have undergone surgical treatment for congenital abdominal malformations. PMID- 26229395 TI - Alcohol liver disease: A review of current therapeutic approaches to achieve long term abstinence. AB - Harmful alcohol drinking may lead to significant damage on any organ or system of the body. Alcoholic liver disease (ALD) is the most prevalent cause of advanced liver disease in Europe. In ALD, only alcohol abstinence was associated with a better long-term survival. Therefore, current effective therapeutic strategy should be oriented towards achieving alcohol abstinence or a significant reduction in alcohol consumption. Screening all primary care patients to detect those cases with alcohol abuse has been proposed as population-wide preventive intervention in primary care. It has been suggested that in patients with mild alcohol use disorder the best approach is brief intervention in the primary care setting with the ultimate goal being abstinence, whereas patients with moderate to-severe alcohol use disorder must be referred to specialized care where detoxification and medical treatment of alcohol dependence must be undertaken. PMID- 26229396 TI - Circulating RNAs as new biomarkers for detecting pancreatic cancer. AB - Pancreatic cancer remains difficult to treat and has a high mortality rate. It is difficult to diagnose early, mainly due to the lack of screening imaging modalities and specific biomarkers. Consequently, it is important to develop biomarkers that enable the detection of early stage tumors. Emerging evidence is accumulating that tumor cells release substantial amounts of RNA into the bloodstream that strongly resist RNases in the blood and are present at sufficient levels for quantitative analyses. These circulating RNAs are upregulated in the serum and plasma of cancer patients, including those with pancreatic cancer, compared with healthy controls. The majority of RNA biomarker studies have assessed circulating microRNAs (miRs), which are often tissue specific. There are few reports of the tumor-specific upregulation of other types of small non-coding RNAs (ncRNAs), such as small nucleolar RNAs and Piwi interacting RNAs. Long ncRNAs (lncRNAs), such as HOTAIR and MALAT1, in the serum/plasma of pancreatic cancer patients have also been reported as diagnostic and prognostic markers. Among tissue-derived RNAs, some miRs show increased expression even in pre-cancerous tissues, and their expression profiles may allow for the discrimination between a chronic inflammatory state and carcinoma. Additionally, some miRs and lncRNAs have been reported with significant alterations in expression according to disease progression, and they may thus represent potential candidate diagnostic or prognostic biomarkers that may be used to evaluate patients once detection methods in peripheral blood are well established. Furthermore, recent innovations in high-throughput sequencing techniques have enabled the discovery of unannotated tumor-associated ncRNAs and tumor-specific alternative splicing as novel and specific biomarkers of cancers. Although much work is required to clarify the release mechanism, origin of tumor specific circulating RNAs, and selectivity of carrier complexes, and technical advances must also be achieved, such as creating a consensus normalization protocol for quantitative data analysis, circulating RNAs are largely unexplored and might represent novel clinical biomarkers. PMID- 26229398 TI - MicroRNA expression in hepatitis C virus-related malignancies: A brief review. AB - Not only is chronic hepatitis C virus (HCV) infection a major public health problem, but also it can cause hepatocellular carcinoma and, more rarely, non Hodgkin's lymphoma. These characteristics mean that HCV is the only virus infecting humans that is able to cause two different cancers. The fine pathogenetic and molecular mechanisms by which HCV induces these two malignancies are not completely clear. In the last decade, it has been shown that microRNAs (miRNAs), a class of 21-23-nucleotide molecules modulating post-transcriptional gene expression, make an important contribution to the pathogenesis of several cancers and are also considered highly promising biomarkers. Here, we briefly describe the current knowledge about microRNAs' involvement in HCV-related molecular oncogenesis. We decided to focus our attention on studies fully conducted on ex vivo samples with this specific etiology, and on cultured cell lines partially or completely expressing the HCV genome. Some of the results reported in this review are controversial, possibly because of methodological issues, differences in sampling size and features, and ethnicity of patients. What is certain is that miRNAs play a remarkable role in regulating gene expression during oncogenetic processes and in viral infection. A clear understanding of their effects is fundamental to elucidating the mechanisms underlying virus-induced malignancies. PMID- 26229399 TI - Association of hepatocyte-derived growth factor receptor/caudal type homeobox 2 co-expression with mucosal regeneration in active ulcerative colitis. AB - AIM: To characterize the regeneration-associated stem cell-related phenotype of hepatocyte-derived growth factor receptor (HGFR)-expressing cells in active ulcerative colitis (UC). METHODS: On the whole 38 peripheral blood samples and 38 colonic biopsy samples from 18 patients with histologically proven active UC and 20 healthy control subjects were collected. After preparing tissue microarrays and blood smears HGFR, caudal type homeobox 2 (CDX2), prominin-1 (CD133) and Musashi-1 conventional and double fluorescent immunolabelings were performed. Immunostained samples were digitalized using high-resolution Mirax Desk instrument, and analyzed with the Mirax TMA Module software. For semiquantitative counting of immunopositive lamina propria (LP) cells 5 fields of view were counted at magnification * 200 in each sample core, then mean +/- SD were determined. In case of peripheral blood smears, 30 fields of view with 100 MUm diameter were evaluated in every sample and the number of immunopositive cells (mean +/- SD) was determined. Using 337 nm UVA Laser MicroDissection system at least 5000 subepithelial cells from the lamina propria were collected. Gene expression analysis of HGFR, CDX2, CD133, leucine-rich repeat-containing G protein coupled receptor 5 (Lgr5), Musashi-1 and cytokeratin 20 (CK20) were performed in both laser-microdisscted samples and blood samples by using real time reverse transcription polymerase chain reaction (RT-PCR). RESULTS: By performing conventional and double fluorescent immunolabelings confirmed by RT PCR, higher number of HGFR (blood: 6.7 +/- 1.22 vs 38.5 +/- 3.18; LP: 2.25 +/- 0.85 vs 9.22 +/- 0.65; P < 0.05), CDX2 (blood: 0 vs 0.94 +/- 0.64; LP: 0.75 +/- 0.55 vs 2.11 +/- 0.75; P < 0.05), CD133 (blood: 1.1 +/- 0.72 vs 8.3 +/- 1.08; LP: 11.1 +/- 0.85 vs 26.28 +/- 1.71; P < 0.05) and Musashi-1 (blood and LP: 0 vs scattered) positive cells were detected in blood and lamina propria of UC samples as compared to controls. HGFR/CDX2 (blood: 0 vs 1 +/- 0.59; LP: 0.8 +/- 0.69 vs 2.06 +/- 0.72, P < 0.05) and Musashi-1/CDX2 (blood and LP: 0 vs scattered) co expressions were found in blood and lamina propria of UC samples. HGFR/CD133 and CD133/CDX2 co-expressions appeared only in UC lamina propria samples. CDX2, Lgr5 and Musashi-1 expressions in UC blood samples were not accompanied by CK20 mRNA expression. CONCLUSION: In active UC, a portion of circulating HGFR-expressing cells are committed to the epithelial lineage, and may participate in mucosal regeneration by undergoing mesenchymal-to-epithelial transition. PMID- 26229400 TI - Restraint stress induces and exacerbates intestinal inflammation in interleukin 10 deficient mice. AB - AIM: To investigate the effects of restraint stress on chronic colitis in interleukin (IL)-10 deficient (IL-10(-/-)) mice. METHODS: The first experiment compared the effect of restraint stress on the development of intestinal inflammation in wild-type and IL-10(-/-) mice. Both wild-type and IL-10(-/-) mice were physically restrained in a well-ventilated, 50 cm(3) conical polypropylene tube for 2 h per day for three consecutive days. The second experiment was performed to assess the effect of restraint stress on exacerbation of colitis induced by piroxicam in IL-10(-/-) mice. The IL-10(-/-) mice were exposed to restraint stress for 2 h per day for 3 consecutive days, and then treated with piroxicam for 4 d at a dose of 200 ppm administered in the rodent chow. RESULTS: In the first experiment, none of the wild-type mice with or without restraint stress showed clinical and histopathological abnormality in the gut. However, IL 10(-/-) mice exposed to restraint stress exhibited histologically significant intestinal inflammation as compared to those without restraint stress. In the second experiment, restraint stress significantly reduced body weight and increased the severity of intestinal inflammation assessed by histopathologic grading in IL-10(-/-) mice. Colonic IL12p40 mRNA expression was strongly increased in mice exposed to restraint stress. CONCLUSION: This novel animal model could be useful in future study of psychological stress in the pathogenesis of inflammatory bowel disease. PMID- 26229401 TI - Overexpression of chaperonin containing TCP1, subunit 3 predicts poor prognosis in hepatocellular carcinoma. AB - AIM: To investigate the value of chaperonin containing TCP1, subunit 3 (CCT3) to predict the prognosis of patients with hepatocellular carcinoma (HCC) and determine its function in HCC progression. METHODS: CCT3 expression levels were examined in human non-cancerous liver tissues and a variety of HCC cell lines by quantitative real-time PCR and immunoblotting. CCT3 expression was suppressed by small interfering RNA. The effects of reducing CCT3 expression in HCC cells were tested. The 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay, cell counting experiment, cell cycle assay, apoptosis assay and invasion assay were employed to evaluate cell functions in vitro. Immunohistochemistry was performed on HCC specimens. In addition, CCT3 expression in HCC specimens was also assessed at the protein and mRNA level. Associations between clinicopathological characteristics and prognosis were analyzed, along with the possible mechanisms involved in CCT3's function in HCC progression. RESULTS: The expression levels of CCT3 mRNA and protein were upregulated in HCC cell lines in contrast to adjacent non-cancerous tissues. Reducing CCT3 expression not only suppressed cell proliferation in cell counts, MTT assay, cell cycle assay and induced cell apoptosis (P < 0.05 vs negative control), but also inhibited the tumor cell invasion capacity in vitro (P < 0.01 vs negative control). Overexpression of CCT3 in the nuclei of cancer cells in HCC specimens (58 of 104 patients, 55.8%) was associated with poor prognosis in HCC patients (3-year survival rate, 55.5% vs 84.2%, P = 0.020) after hepatectomy. Mechanistic analyses showed that signal transducer and activator of transcription 3 (STAT3) activation was decreased even when stimulated by interleukin-6 after knocking down CCT3 in the HepG2 cell line. CONCLUSION: Overexpression of CCT3 in the nuclei of cancerous cells is associated with HCC progression. CCT3 may be a target that affects the activation of STAT3 in HCC. PMID- 26229397 TI - Benign liver tumors in pediatric patients - Review with emphasis on imaging features. AB - Benign hepatic tumors are commonly observed in adults, but rarely reported in children. The reasons for this remain speculative and the exact data concerning the incidence of these lesions are lacking. Benign hepatic tumors represent a diverse group of epithelial and mesenchymal tumors. In pediatric patients, most benign focal liver lesions are inborn and may grow like the rest of the body. Knowledge of pediatric liver diseases and their imaging appearances is essential in order to make an appropriate differential diagnosis. Selection of the appropriate imaging test is challenging, since it depends on a number of age related factors. This paper will discuss the most frequently encountered benign liver tumors in children (infantile hepatic hemangioendothelioma, mesenchymal hamartoma, focal nodular hyperplasia, nodular regenerative hyperplasia, and hepatocellular adenoma), as well as a comparison to the current knowledge regarding such tumors in adult patients. The current emphasis is on imaging features, which are helpful not only for the initial diagnosis, but also for pre- and post-treatment evaluation and follow-up. In addition, future perspectives of contrast-enhanced ultrasound (CEUS) in pediatric patients are highlighted, with descriptions of enhancement patterns for each lesion being discussed. The role of advanced imaging tests such as CEUS and magnetic resonance imaging, which allow for non-invasive assessment of liver tumors, is of utmost importance in pediatric patients, especially when repeated imaging tests are needed and radiation exposure should be avoided. PMID- 26229402 TI - Linked PNPLA3 polymorphisms confer susceptibility to nonalcoholic steatohepatitis and decreased viral load in chronic hepatitis B. AB - AIM: To investigate the association of PNPLA3 polymorphisms with concurrent chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD). METHODS: A cohort of Han patients with biopsy-proven CHB, with or without NAFLD (CHB group, n = 51; CHB + NAFLD group, n = 57), and normal controls (normal group, n = 47) were recruited from Northern (Tianjin), Central (Shanghai), and Southern (Zhangzhou) China. Their PNPLA3 polymorphisms were genotyped by gene sequencing. The association between PNPLA3 polymorphisms and susceptibility to NAFLD, and clinical characteristics of NAFLD were evaluated on the basis of physical indices, liver function tests, glycolipid metabolism, and histopathologic scoring. The association of PNPLA3 polymorphisms and hepatitis B virus (HBV) load was determined by the serum level of HBV DNA. RESULTS: After adjusting for age, sex, and body mass index, we found that four linked single nucleotide polymorphisms (SNPs) of PNPLA3, including the rs738409 G allele (CHB + NAFLD group vs CHB group: odds ratio [OR] = 2.77, 95% confidence interval [CI]: 1.18 6.54; P = 0.02), rs3747206 T allele (CHB + NAFLD group vs CHB group: OR = 2.77, 95%CI: 1.18-6.54; P = 0.02), rs4823173 A allele (CHB + NAFLD group vs CHB group: OR = 2.73, 95%CI: 1.16-6.44; P = 0.02), and rs2072906 G allele (CHB + NAFLD group vs CHB group: OR = 3.05, 95%CI: 1.28-7.26; P = 0.01), conferred high risk to NAFLD in CHB patients. In patients with both CHB and NAFLD, these genotypes of PNPLA3 polymorphisms were associated with increased susceptibility to nonalcoholic steatohepatitis (NASH) (NAFLD activity score >= 3; P = 0.01-0.03) and liver fibrosis (> 1 Metavir grading; P = 0.01-0.04). As compared to those with C/C and C/G at rs738409, C/C and C/T at rs3747206, G/G and G/A at rs4823173, and A/A and A/G at rs2072906, patients in the CHB + NAFLD group with G/G at rs738409, T/T at rs3747206, A/A at rs4823173, and G/G at rs2072906 showed significantly lower serum levels of HBV DNA (P < 0.01-0.05). CONCLUSION: Four linked SNPs of PNPLA3 (rs738409, rs3747206, rs4823173, and rs2072906) are correlated with susceptibility to NAFLD, NASH, liver fibrosis, and HBV dynamics in CHB patients. PMID- 26229403 TI - TLR4 upregulates CBS expression through NF-kappaB activation in a rat model of irritable bowel syndrome with chronic visceral hypersensitivity. AB - AIM: To investigate the roles of toll-like receptor 4 (TLR4) and nuclear factor (NF)-kappaB on cystathionine beta synthetase (CBS) expression and visceral hypersensitivity in rats. METHODS: This study used 1-7-wk-old male Sprague-Dawley rats. Western blot analysis was employed to measure the expression of TLR4, NF kappaB and the endogenous hydrogen sulfide-producing enzyme CBS in colon dorsal root ganglia (DRG) from control and "irritable bowel syndrome" rats induced by neonatal colonic inflammation (NCI). Colon-specific DRG neurons were labeled with Dil and acutely dissociated to measure excitability with patch-clamp techniques. Immunofluorescence was employed to determine the co-expression of TLR4, NF-kappaB and CBS in DiI-labeled DRG neurons. RESULTS: NCI significantly upregulated the expression of TLR4 in colon-related DRGs (0.34 +/- 0.12 vs 0.72 +/- 0.02 for the control and NCI groups, respectively, P < 0.05). Intrathecal administration of the TLR4-selective inhibitor CLI-095 significantly enhanced the colorectal distention threshold of NCI rats. CLI-095 treatment also markedly reversed the hyperexcitability of colon-specific DRG neurons and reduced the expression of CBS (1.7 +/- 0.1 vs 1.1 +/- 0.04, P < 0.05) and of the NF-kappaB subunit p65 (0.8 +/- 0.1 vs 0.5 +/- 0.1, P < 0.05). Furthermore, the NF-kappaB-selective inhibitor pyrrolidine dithiocarbamate (PDTC) significantly reduced the upregulation of CBS (1.0 +/- 0.1 vs 0.6 +/- 0.1, P < 0.05) and attenuated visceral hypersensitivity in the NCI rats. In vitro, incubation of cultured DRG neurons with the TLR4 agonist lipopolysaccharide significantly enhanced the expression of p65 (control vs 8 h: 0.9 +/- 0.1 vs 1.3 +/- 0.1; control vs 12 h: 0.9 +/- 0.1 vs 1.3 +/- 0.1, P < 0.05; control vs 24 h: 0.9 +/- 0.1 vs 1.6 +/- 0.1, P < 0.01) and CBS (control vs 12 h: 1.0 +/- 0.1 vs 2.2 +/- 0.4; control vs 24 h: 1.0 +/- 0.1 vs 2.6 +/- 0.1, P < 0.05), whereas the inhibition of p65 via pre-incubation with PDTC significantly reversed the upregulation of CBS expression (1.2 +/- 0.1 vs 0.6 +/- 0.0, P < 0.01). CONCLUSION: Our results suggest that the activation of TLR4 by NCI upregulates CBS expression, which is mediated by the NF-kappaB signaling pathway, thus contributing to visceral hypersensitivity. PMID- 26229404 TI - Newly designed "pieced" stent in a rabbit model of benign esophageal stricture. AB - AIM: To investigate a newly designed stent and its dilatation effect in a rabbit model of benign esophageal stricture. METHODS: Thirty-four New Zealand white rabbits underwent a corrosive injury in the middle esophagus for esophageal stricture formation. Thirty rabbits with a successful formation of esophageal strictures were randomly allocated into two groups. The control group (n = 15) was implanted with a conventional stent, and the study group (n = 15) was implanted with a detachable "pieced" stent. The study stent (30 mm in length, 10 mm in diameter) was composed of three covered metallic pieces connected by surgical suture lines. The stent was collapsed by pulling the suture lines out of the mesh. Two weeks after stricture formation, endoscopic placement of a conventional stent or the new stent was performed. Endoscopic extraction was carried out four weeks later. The extraction rate, ease of extraction, migration, complications, and survival were evaluated. RESULTS: Stent migration occurred in 3/15 (20%) animals in the control group and 2/15 (13%) animals in the study group; the difference between the two groups was not statistically significant. At the end of four weeks, the remaining stents were successfully extracted with the endoscope in 100% (11/11) of the animals in the study group, and 60% (6/10) of the animals in the control group; this difference was statistically significant (P < 0.05). There was no difference in the mean number of follow-up days between the control and study groups (25.33 vs 25.85). Minor bleeding was reported in five cases in the study group and four in the control group. There were no severe complications directly associated with stent implantation or extraction in either of the two groups. CONCLUSION: In this experimental protocol of benign esophageal strictures, the novel "pieced" stent demonstrated a superior removal rate with a similar migration rate compared to a conventional stent. PMID- 26229405 TI - Clinical characteristics of Helicobacter pylori-negative drug-negative peptic ulcer bleeding. AB - AIM: To investigate the clinical characteristics and outcomes of idiopathic Helicobacter pylori (H. pylori)-negative and drug-negative] peptic ulcer bleeding (PUB). METHODS: A consecutive series of patients who experienced PUB between 2006 and 2012 was retrospectively analyzed. A total of 232 patients were enrolled in this study. The patients were divided into four groups according to the etiologies of PUB: idiopathic, H. pylori-associated, drug-induced and combined (H. pylori-associated and drug-induced) types. We compared the clinical characteristics and outcomes between the groups. When the silver stain or rapid urease tests were H. pylori-negative, we obtained an additional biopsy specimen by endoscopic re-examination and performed an H. pylori antibody test 6-8 wk after the initial endoscopic examination. For a diagnosis of idiopathic PUB, a negative result of an H. pylori antibody test was confirmed. In all cases, re bleeding was confirmed by endoscopic examination. For the risk assessment, the Blatchford and the Rockall scores were calculated for all patients. RESULTS: For PUB, the frequency of H. pylori infection was 59.5% (138/232), whereas the frequency of idiopathic cases was 8.6% (20/232). When idiopathic PUB was compared to H. pylori-associated PUB, the idiopathic PUB group showed a higher rate of re bleeding after initial hemostasis during the hospital stay (30% vs 7.4%, P = 0.02). When idiopathic PUB was compared to drug-induced PUB, the patients in the idiopathic PUB group showed a higher rate of re-bleeding after initial hemostasis upon admission (30% vs 2.7%, P < 0.01). When drug-induced PUB was compared to H. pylori-associated PUB, the patients in the drug-induced PUB were older (68.49 +/- 14.76 years vs 47.83 +/- 15.15 years, P < 0.01) and showed a higher proportion of gastric ulcer (77% vs 49%, P < 0.01). However, the Blatchford and the Rockall scores were not significantly different between the two groups. Among the patients who experienced drug-induced PUB, no significant differences were found with respect to clinical characteristics, irrespective of H. pylori infection. CONCLUSION: Idiopathic PUB has unique clinical characteristics such as re bleeding after initial hemostasis upon admission. Therefore, these patients need to undergo close surveillance upon admission. PMID- 26229406 TI - Aggressive surgical resection does not improve survival in operable esophageal squamous cell carcinoma with N2-3 status. AB - AIM: To investigate the influence of nodal status on response and clarify the optimal treatment for operable esophageal squamous cell carcinoma (OSCC). METHODS: We retrospectively analyzed 1490 OSCC patients who underwent transthoracic esophagectomy and lymphadenectomy between December 1996 and December 2009 at the Sun Yat-sen University Cancer Center. The surgical approach and the number of resected lymph nodes (LNs) were considered in the assessment of surgery. Patients were classified according to their nodal statuses (N0 vs N1 vs N2-3). Overall survival was defined as the time from the date of death or final follow-up. Survival analysis was performed using the Kaplan-Meier method and differences between curves were assessed by the log-rank test. Univariate and multivariate Cox regression analyses were used to identify factors associated with prognosis. Statistical significance was assumed at a P < 0.05. RESULTS: With a median time from surgery to the last censoring date for the entire cohort of 72.2 mo, a total of 631 patients were still alive at the last follow-up and the median survival time was 35.5 mo. The surgical approach (left transthoracic vs Ivor-Lewis/tri-incisional) was verified as independent prognostic significance in patients with N0 or N1 status, but not in those with N2-3 status. Similar results were also observed with the number of resected LNs (<= 14 vs >= 15). Compared with surgery alone, combined therapy achieved better outcomes in patients with N1 or N2-3 status, but not in those with N0 status. For those with N2-3 status, neither the surgical approach nor the number of resected LNs reached significance by univariate analysis, with unadjusted HRs of 0.826 (95%CI: 0.644-1.058) and 0.849 (95%CI: 0.668-1.078), respectively, and aggressiveness of surgery did not influence the outcome; the longest survival was observed in those patients who received the combined therapy. CONCLUSION: Combined therapy has a positive role in OSCC with LN metastasis, and aggressive surgical resection does not improve survival in patients with N2-3 status. PMID- 26229407 TI - Hepatitis B surface antigen levels of cessation of nucleos(t)ide analogs associated with virological relapse in hepatitis B surface antigen-negative chronic hepatitis B patients. AB - AIM: To investigate the virological relapse rate in hepatitis B e antigen (HBeAg) negative patients after antiviral therapy discontinuation and analyze the factors associated with virological relapse. METHODS: Among patients diagnosed with chronic hepatitis B infection between May 2005 and July 2010, 204 were eligible for analysis. The Kaplan-Meier method and log-rank test were used to calculate the cumulative rate of relapse and compare cumulative relapse rates between groups. The Cox proportional hazards regression model was used to evaluate the predictive factor of virological relapse. RESULTS: The 2 and 1 year cumulative risks of virological relapse after antiviral therapy discontinuation were 79.41% (162/204) and 43.82% (71/162), respectively. Multivariate analysis revealed that only post treatment hepatitis B surface antigen (HBsAg) level was associated with virological relapse (P = 0.011). The cumulative risk of virological relapse was higher in the patients with HBsAg levels >= 1500 IU/L than in those with HBsAg levels < 1500 IU/L (P = 0.0013). The area under the curve was 0.603 (P = 0.033). The cutoff HBsAg value for predicting virological relapse was 1443 IU/L. CONCLUSION: We found that the virological relapse rate remained high after antiviral therapy discontinuation in the HBeAg-negative patients and that the post treatment HBsAg levels predicted virological relapse. PMID- 26229408 TI - Boceprevir early-access for advanced-fibrosis/cirrhosis in Asia-Pacific hepatitis C virus genotype 1 non-responders/relapsers. AB - AIM: To examined the efficacy and safety of treatment with boceprevir, PEGylated interferon and ribavirin (PR) in hepatitis C virus genotype 1 (HCVGT1) PR treatment-failures in Asia. METHODS: The Boceprevir Named-Patient Program provided boceprevir to HCVGT1 PR treatment-failures. Participating physicians were invited to contribute data from their patients: baseline characteristics, on treatment responses, sustained virological response at week 12 (SVR12), and safety were collected and analysed. Multivariate analysis was performed to determine predictors of response. RESULTS: 150 patients were enrolled from Australia, Malaysia, Singapore and Thailand (Asians = 86, Caucasians = 63). Overall SVR12 was 61% (Asians = 59.3%, Caucasians = 63.5%). SVR12 was higher in relapsers (78%) compared with non-responders (34%). On-treatment responses predicted SVR, with undetectable HCVRNA at week 4, 8 and 12 leading to SVR12s of 100%, 87%, and 82% respectively, and detectable HCVRNA at week 4, 8 and 12, leading to SVR12s of 58%, 22% and 6% respectively. Asian patients were similar to Caucasian patients with regards to on-treatment responses. Patients with cirrhosis (n = 69) also behaved in the same manner with regards to on-treatment responses. Those with the IL28B CC genotype (80%) had higher SVRs than those with the CT/TT (56%) genotype (P = 0.010). Multivariate analysis showed that TW8 and TW12 responses were independent predictors of SVR. Serious adverse events occurred in 18.6%: sepsis (2%), decompensation (2.7%) and blood transfusion (14%). Discontinuations occurred in 30.7%, with 18.6% fulfilling stopping rules. CONCLUSION: Boceprevir can be used successfully in PR treatment failures with a SVR12 > 80% if they have good on-treatment responses; however, discontinuations occurred in 30% because of virological failure or adverse events. PMID- 26229409 TI - Current state of laparoscopic parastomal hernia repair: A meta-analysis. AB - AIM: To evaluate the efficacy and safety of the laparoscopic approaches for parastomal hernia repair reported in the literature. METHODS: A systematic review of PubMed and MEDLINE databases was conducted using various combination of the following keywords: stoma repair, laparoscopic, parastomal, and hernia. Case reports, studies with less than 5 patients, and articles not written in English were excluded. Eligible studies were further scrutinized with the 2011 levels of evidence from the Oxford Centre for Evidence-Based Medicine. Two authors reviewed and analyzed each study. If there was any discrepancy between scores, the study in question was referred to another author. A meta -analysis was performed using both random and fixed-effect models. Publication bias was evaluated using Begg's funnel plot and Egger's regression test. The primary outcome analyzed was recurrence of parastomal hernia. Secondary outcomes were mesh infection, surgical site infection, obstruction requiring reoperation, death, and other complications. Studies were grouped by operative technique where indicated. Except for recurrence, most postoperative morbidities were reported for the overall cohort and not by approach so they were analyzed across approach. RESULTS: Fifteen articles with a total of 469 patients were deemed eligible for review. Most postoperative morbidities were reported for the overall cohort, and not by approach. The overall postoperative morbidity rate was 1.8% (95%CI: 0.8 3.2), and there was no difference between techniques. The most common postoperative complication was surgical site infection, which was seen in 3.8% (95%CI: 2.3-5.7). Infected mesh was observed in 1.7% (95%CI: 0.7-3.1), and obstruction requiring reoperation also occurred in 1.7% (95%CI: 0.7-3.0). Other complications such as ileus, pneumonia, or urinary tract infection were noted in 16.6% (95%CI: 11.9-22.1). Eighty-one recurrences were reported overall for a recurrence rate of 17.4% (95%CI: 9.5-26.9). The recurrence rate was 10.2% (95%CI: 3.9-19.0) for the modified laparoscopic Sugarbaker approach, whereas the recurrence rate was 27.9% (95%CI: 12.3-46.9) for the keyhole approach. There were no intraoperative mortalities reported and six mortalities during the postoperative course. CONCLUSION: Laparoscopic intraperitoneal mesh repair is safe and effective for treating parastomal hernia. A modified Sugarbaker approach appears to provide the best outcomes. PMID- 26229410 TI - Screening for pancreatic cancer in familial high-risk individuals: A systematic review. AB - AIM: To analyze the benefits and harms of pancreatic cancer screening in familial high-risk individuals (HRIs). METHODS: Studies were identified by searching PubMed, EBSCO, ClinicalTrials.gov and the Cochrane database from database inception to June 2014. We also obtained papers from the reference lists of pertinent studies and systematic reviews. English-language trials and observational studies were searched. The key words used as search terms were "screening" and "surveillance". Cost-effectiveness, diagnostic rate, survival rate, mortality and adverse events were the outcomes of interest. Age, sex, lifestyle and other confounding factors were also considered. However, anticipating only a few of these studies, we also included observational studies with or without control groups. We also included studies concerning the anxiety associated with pancreatic cancer risk and other psychological changes in familial HRIs. We extracted details on study design, objectives, population characteristics, inclusion criteria, year of enrollment, method of screening, adjusted and unadjusted mortality, cost-effectiveness and adverse events from the included studies. Studies were assessed using the Reporting of Observational studies in Epidemiology (STROBE) checklist. RESULTS: Sixteen studies on pancreatic cancer screening were included. Five studies included control groups, nine were observational studies without control groups, and the other two studies investigated the worry associated with pancreatic cancer risk. We found that pancreatic cancer screening resulted in a high curative resection rate (60% vs 25%, P = 0.011), longer median survival time (14.5 mo vs 4 mo, P < 0.001), and higher 3-year survival rate (20% vs 15.0%, P = 0.624). We also found that familial HRIs had a higher diagnostic rate of pancreatic tumors than controls (34% vs 7.2%, P < 0.001). In patients who underwent regular physical examinations, more stage I pancreatic cancers were observed (19% vs 2.6%, P = 0.001). In addition, endoscopic ultrasonography, which was the main means of detection, diagnosed 64.3% of pancreatic cancers. In comparison, endoscopic retrograde cannulation of the pancreas, magnetic resonance imaging, and computed tomography diagnosed 28.6%, 42.9%, and 21.4%, respectively. For mass lesions, instant surgery was recommended because of the beneficial effects of post operative chemotherapy. However, in patients with intraductal papillary mucinous neoplasms, we did not find a significant difference in outcome between surgery and follow-up without treatment. Moreover, pancreatic cancer screening in familial HRIs had a greater perceived risk of pancreatic cancer (P < 0.0001), higher levels of anxiety regarding pancreatic cancer (P < 0.0001), and increased economic burden. CONCLUSION: Pancreatic cancer screening in familial HRIs is associated with a higher detection rate and longer survival, although screening may influence psychological function and increase the economic burden. PMID- 26229412 TI - Autologous bone marrow transplantation in decompensated liver: Systematic review and meta-analysis. AB - AIM: To evaluate the efficacy of autologous bone marrow mononuclear cell transplantation in decompensated liver disease. METHODS: Medline, EMBASE, PubMed, Science Direct, and the Cochrane Library were searched for relevant studies. Retrospective case-control studies were included along with randomized clinical trials. Meta-analysis was performed in line with recommendations from the Cochrane Collaboration software review manager. Heterogeneity was assessed using a random-effects model. RESULTS: Four randomized controlled trials and four retrospective studies were included. Cell transplantation increased serum albumin level by 1.96 g/L (95%CI: 0.74-3.17; P = 0.002], 2.55 g/L (95%CI: 0.32-4.79; P = 0.03), and 3.65 g/L (95%CI: 0.76-6.54; P = 0.01) after 1, 3, and 6 mo, respectively. Patients who had undergone cell transplantation also had a lower level of total bilirubin [mean difference (MD): -1.37 mg/dL; 95%CI: -2.68-( 0.06); P = 0.04] after 6 mo. This decreased after 1 year when compared to standard treatment (MD: -1.26; 95%CI: -2.48-(-0.03); P = 0.04]. A temporary decrease in alanine transaminase and aspartate transaminase were significant in the cell transplantation group. However, after 6 mo treatment, patients who had undergone cell transplantation had a slightly longer prothrombin time (MD: 5.66 s, 95%CI: 0.04-11.28; P = 0.05). Changes in the model for end-stage liver disease score and Child-Pugh score were not statistically significant. CONCLUSION: Autologous bone marrow transplantation showed some benefits in patients with decompensated liver disease. However, further studies are still needed to verify its role in clinical treatment for end-stage liver disease. PMID- 26229411 TI - Correlation of human epidermal growth factor receptor protein expression and colorectal cancer. AB - AIM: To investigate the correlation between human epidermal growth factor receptor (HER-2) protein expression and colorectal cancer (CRC) using a case control study and meta-analysis. METHODS: Tumor tissue specimens from 162 CRC patients were selected for the case group. Fifty cases were randomly selected, and normal CRC tissue at least 10 cm away from the tumor margins of these cases was used to generate the control group. The expression of the HER-2 protein in the 162 CRC tissue samples and the 50 adjacent normal mucosa tissue samples was detected via immunohistochemistry. The experimental data were analyzed using SPSS 18.0 software, and R software version 3.1.0 was utilized for further verification. RESULTS: The expression of HER-2 protein in the 162 CRC tissue samples was significantly higher than in the normal tissue specimens. The data showed that the expression of HER-2 in CRC was related to the Dukes' stage, the depth of invasion and lymph node metastasis. The HER-2-positive patients had lower 3- and 5-year OS rates than the HER-2-negative patients, but there was no significant difference. However, there was a statistically significant difference in the 3- and 5-year disease-free survival (DFS) rates of HER-2-positive and HER 2-negative patients. The results of the meta-analysis showed that the expression of HER-2 in CRC patients was statistically significantly increased over that of healthy people. The 3-year DFS rate in HER-2-positive patients was markedly lower than that in HER-2-negative patients. CONCLUSION: Down-regulation of HER-2 expression might be a dependable strategy for CRC therapy. PMID- 26229413 TI - Interleukin-18 genetic polymorphisms contribute differentially to the susceptibility to Crohn's disease. AB - AIM: To investigate the correlation between interleukin-18 (IL-18) gene polymorphisms and the risk of developing Crohn's disease (CD). METHODS: The PubMed, CISCOM, CINAHL, Web of Science, EBSCO, Cochrane Library, MEDLINE, EMBASE and CBM databases were searched without any language restrictions using combinations of keywords relating to CD and IL-18 for relevant articles published before November 1(st), 2013. Screening of the published studies retrieved from searches was based on our stringent inclusion and exclusion criteria and resulted in seven eligible studies for meta-analysis. A meta-analysis was conducted using a random-effects model with STATA 12.0 software. Crude odds ratios (ORs) with 95% confidence intervals (95%CI) were calculated. RESULTS: Seven case-control studies, with a total of 1930 CD cases and 1930 healthy subjects, met our inclusion criteria. The results of our meta-analysis indicated that the IL-18 rs1946518 A>C and rs187238 G>C polymorphisms may correlate with an increased risk of CD under five genetic models (all P < 0.05). Furthermore, we observed positive associations between the IL-18 rs360718 A>C polymorphism and CD risk under three genetic models (C allele vs A allele: OR = 2.03, 95%CI: 1.20-3.43, P = 0.008; CC vs AA+AC: OR = 2.39, 95%CI: 1.2-4.43, P = 0.006; CC vs AC: OR = 2.31, 95%CI: 1.22 4.38, P = 0.010). However, such associations were not found for the IL-18 rs917997 C>T, codon 35 A>C and rs1946519 G>T polymorphisms (all P > 0.05). A subgroup analysis was conducted to investigate the effect of ethnicity on an individual's susceptibility to CD. Our results revealed positive correlations between IL-18 genetic polymorphisms and an increased risk of CD among Asians and Africans (all P < 0.05), but not among Caucasians (all P > 0.05). CONCLUSION: This meta-analysis indicated that the IL-18 rs1946518 A>C, rs187238 G>C and rs360718 A>C polymorphisms may contribute to susceptibility to CD, especially among Asians and Africans. These polymorphisms are known to reduce IL-18 mRNA and protein levels. PMID- 26229414 TI - Conservative reconstruction using stents as salvage therapy for disruption of esophago-gastric anastomosis. AB - Esophagectomy with extended lymphadenectomy and gastric conduit reconstruction is a radical procedure for the treatment of esophageal cancer that is associated with a high morbidity rate. Gastric conduit necrosis is a fatal complication that occurs in 2% of patients. Conventionally, two-stage salvage surgery consisting of removal of the necrotic gastric conduit followed by reconstruction has been performed; however, this procedure has a high morbidity rate. We describe a 61 year-old man who underwent minimally invasive esophagectomy complicated by slowly progressive gastric conduit necrosis associated with complete neck drainage and a stable overall condition. There was a 2 cm gap in the anastomosis. Because there was no evidence of residual gastric conduit necrosis, a removable, covered self expanding metal stent (SEMS) was inserted to bridge the anastomosis. The stent was fixed to the patient's ear with silk thread through the lasso on its proximal end to prevent migration. Eight weeks after insertion, the stent was removed easily without any associated complications. The anastomotic defect was completely bridged with granulation tissue, showing progressive epithelialization without leakage or stenosis. The patient was discharged home in good general health. This is the first report of the successful conservative management of esophago-gastric conduit anastomosis disruption with SEMS placement. PMID- 26229416 TI - Liminality in Ontario's long-term care facilities: Private companions' care work in the space 'betwixt and between'. AB - Nursing, personal care, food and cleaning are publicly funded in Ontario's long term care facilities, but under-staffing usually renders all but the most basic of personal preferences superfluous. This individualization of responsibility for more personalized care has resulted in more families providing more care and opting to hire private, private companion care. With direct payment of companions becoming a growing but largely invisible facet of care, exploring companion's roles is important. Using a six site rapid ethnographic study in long-term care facilities (i.e. observations, documents and key informant interviews (n=167)), this paper argues that private companions occupy a liminal space between policy, family and market, and their role within institutions and in private homes may be the missing link in the care work chain in the sense that it can at once be classified as formal and informal and draws on their own and others paid and unpaid labour. PMID- 26229417 TI - Piecewise Linear Slope Estimation. AB - This paper presents a method for directly estimating slope values in a noisy piecewise linear function. By imposing a Markov structure on the sequence of slopes, piecewise linear fitting is posed as a maximum a posteriori estimation problem. A dynamic program efficiently solves this by traversing a linearly growing trellis. The alternating maximization algorithm (a kind of pseudo-EM method) is used to estimate the model parameters from data and its convergence behavior is analyzed. Ultrasound shear wave imaging is presented as a primary application. The algorithm is general enough for applicability in other fields, as suggested by an application to the estimation of shifts in financial interest rate data. PMID- 26229415 TI - Hepatic inflammatory pseudotumor presenting in an 8-year-old boy: A case report and review of literature. AB - Hepatic inflammatory pseudotumors are uncommon benign lesions. Accurately diagnosing hepatic inflammatory pseudotumor can be very challenging because the clinical presentation and radiological appearances are nonspecific and cannot be certainly distinguished from malignant neoplastic processes. Herein, we present a case of hepatic IPT in an 8-year-old boy who presented to clinic with a 3-mo history of a tender hepatic mass, fever of unknown origin, and 9-kg weight loss. The physical examination was notable for tender hepatomegaly. Laboratory investigations were notable for a normal hepatic profile and elevated erythrocyte sedimentation rate and C-reactive protein. A T2-attenuated magnetic resonance imaging scan of the abdomen showed a 4.7 cm * 4.7 cm * 6.6 cm, contrast enhancing, hyper-intense, well-defined lesion involving the right hepatic lobe. In view of the unremitting symptoms, tender hepatomegaly, thrombosed right hepatic vein, nonspecific radiological findings, and high suspicion of a deep seated underlying infection or malignancy, a right hepatic lobectomy was recommended. Microscopically, the hepatic lesion exhibited a mixture of inflammatory cells (histiocytes, plasma cells, mature lymphocytes, and occasional multinucleated giant cells) in a background of dense fibrous tissue. Immunohistochemically, the cells stained negative for SMA, ALK-1, CD-21 and CD 23, diffusely positive for CD-68, and focally positive for IgG4. The final histopathological diagnosis was consistent with hepatic IPT. At the postoperative 4-mo follow-up, the patient was asymptomatic without radiological evidence of recurrence. PMID- 26229418 TI - EVALUATION OF SMOKE AND GAS SENSOR RESPONSES FOR FIRES OF COMMON MINE COMBUSTIBLES. AB - Experiments were conducted to evaluate the response characteristics of commercially available gas, smoke, and flame sensors to fires of common combustible mine materials. The experiments were conducted in the large-scale Fire gallery located at the National Institute for Occupational Safety and Health (NIOSH) Lake Lynn Laboratory (LLL) in Fairchance, PA, using Ponderosa Pine, Red Oak, Douglas-fir, high and low volatile coals, PVC and SBR conveyor belt, No. 2 diesel fuel, and diesel exhaust. All the experiments (except those using No. 2 diesel fuel and the diesel exhaust tests) were conducted in a similar manner, with combustible materials heated rapidly by electrical strip heaters producing smoldering fires that quickly transitioned into flaming fires. The sensors included a diffusion-type carbon monoxide (CO) sensor, photoelectric- and ionization-type smoke sensors, a video smoke/flame detector, and an optical flame detector. Simultaneous measurements were obtained for average gas concentrations, smoke mass concentrations, and smoke optical densities in order to quantify the levels of combustion products at the alert and alarm times of the sensors. Because the required sensor alarm levels are 10 ppm and 0.044 m-1 optical density for CO and smoke sensors, respectively, the different sensor alarms are compared to the time at which the CO and smoke reached these alarm levels (1). In addition, the potential impact of using smoke sensors that have met the performance standards from accredited testing laboratories is also evaluated using the response of an Underwriters' Laboratory (UL)-approved combination photoelectric/ionization smoke detector. The results are discussed relative to fire sensor needs that can have a positive impact on mine fire safety. PMID- 26229419 TI - Single-Port Laparoscopic Cholecystectomy for Gall Bladder Polyps. AB - BACKGROUND AND OBJECTIVES: Single-port laparoscopic cholecystectomy (SPLC) was introduced to improve patients' postoperative quality of life and cosmesis over the conventional approach (CLC). The purpose of this case-control study was to compare the outcome of SPLC with that of CLC in a specific disease: gall bladder (GB) polyps. METHODS: Eligible for the study were all patients with GB polyps who underwent laparoscopic cholecystectomy between June 1, 2009, and June 30, 2011. The 112 patients studied (56 each for SPLC and CLC) were matched by using a propensity score that included gender, age, body mass index (BMI), American Society of Anesthesiologists (ASA) score, history of previous abdominal operation, and pathology outcome. To avoid selection bias caused by the surgeon's choice (often dependent on the degree of inflammation) and to investigate the efficacy of SPLC for a single disease, GB polyps, we excluded patients with acute or chronic cholecystitis. RESULTS: Characteristics of the patients matched by a propensity score between SPLC and CLC showed no significant difference. Incidentally detected malignancy was in postoperative pathology in cases in both groups. Although operative time was shorter for SPLC, there was no significant difference in time between the 2 groups. There were 3 open conversions in the CLC group, and an additional port was used in the SPLC group. There was no difference between the groups in hospital stay and postoperative complications. CONCLUSION: In the management of GB polyps, the operative results of SPLC are comparable to those of CLC. We conclude that SPLC is as safe as CLC and has the potential for greater cosmetic satisfaction for patients than CLC. Further trials for objective appraisal of cosmetic outcomes are needed. PMID- 26229420 TI - Transition From Hand-Assisted to Pure Laparoscopic Donor Nephrectomy. AB - BACKGROUND AND OBJECTIVES: We compared perioperative donor outcomes and early graft function of hand-assisted laparoscopic donor nephrectomy (HALDN) and pure laparoscopic donor nephrectomy (PLDN) performed by a single surgeon, to define the feasibility of technical transition from HALDN to PLDN. METHODS: From October 1, 2012, through June 30, 2014, 60 donor nephrectomies were performed by a single surgeon who lacked experience with laparoscopic renal surgery: the first 30 by HALDN and the last 30 by PLDN. Operative and convalescence parameters were compared, as were intra- and postoperative complications within 90 days according to the Satava and Clavien-Dindo classifications, respectively. Binary logistic regression analysis was used to estimate the association of baseline characteristics with complications. RESULTS: Baseline characteristics were similar in the 2 groups, except for American Society of Anesthesiologists score II (10.0% vs 43.3%; P = .007). All procedures were completed as planned. All operative and convalescence parameters of donors and graft outcomes were similar in the 2 groups, as were overall rates of intraoperative (43.3% vs 36.7%, P = .598) and postoperative (86.7% vs 70.0%; P = .209) complications. No factor was significantly predictive of intraoperative complications, whereas sex (female vs male, odds ratio, 0.183; P = .029) and learning curve (odds ratio, 0.602; P = .036) were significant determinants of postoperative complication. CONCLUSION: The technical transition from HALDN to PLDN does not involve a steep learning curve for surgeons less experienced with laparoscopic renal surgery and maintains similar perioperative donor and graft outcomes. PMID- 26229421 TI - Needlescopic Surgery Versus Single-port Laparoscopy for Inguinal Hernia. AB - BACKGROUND AND OBJECTIVES: In recent years, 2 modifications of laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair-needlescopic (nTAPP) surgery and single-port (sTAPP) surgery-have greatly improved patient outcomes over traditional approaches. For a comparison of these 2 modifications, we sought to investigate and compare the extent of surgical trauma and postoperative consequences for the abdominal wall in these two procedures. METHODS: In a retrospective study, 50 nTAPP and 35 sTAPP procedures occurring at a community hospital from November 1, 2009, through July 31, 2012 were reviewed. Intraoperative data, including length of the umbilical skin incision and operative time, were recorded. A follow-up evaluation included investigation of hernia recurrence, postoperative pain, abdominal wall mobility, cosmetic satisfaction, and period of sick leave. RESULTS: The mean umbilical skin incision was 13 +/- 4 mm in nTAPP vs 27 +/- 3 mm in sTAPP (P < .001). The nTAPP procedure required less operating time than the sTAPP procedure (54.8 +/- 16.9 minutes vs 85.9 +/- 19.7 minutes; P < .001). The mean immediate postoperative pain score on the visual analog scale was 2.7 +/- 2.1 in the nTAPP group and 4.4 +/- 1.9 in the sTAPP group (P = .016). In addition, patients who underwent nTAPP had a shorter period of sick leave (11.2 +/- 8.4 days vs 24.1 +/- 20.1 days; P = .02). At the follow-up evaluation after approximately 30 months, abdominal wall mobility and cosmetic satisfaction were equally positive, with no hernia recurrence. CONCLUSION: In patients with uncomplicated inguinal hernia, the nTAPP procedure, with less surgical trauma and operating time, has distinct advantages in reduction of immediate postoperative pain and sick leave time. PMID- 26229422 TI - Interannual Survival of Myotis lucifugus (Chiroptera: Vespertilionidae) near the Epicenter of White-Nose Syndrome. AB - Reduced populations of Myotis lucifugus (Little Brown Myotis) devastated by white nose syndrome (WNS) persist in eastern North America. Between 2009 and 2013, we recaptured 113 marked individuals that survived between 1 and 6 winters in New England since the arrival of WNS. We also observed signs of reproductive success in 57 recaptured bats. PMID- 26229423 TI - Long-term outcomes in patients undergoing vitrectomy for retinal detachment due to viral retinitis. AB - PURPOSE: To determine the outcomes in patients with rhegmatogenous retinal detachment (RRD) secondary to viral retinitis. PATIENTS AND METHODS: This was a retrospective, consecutive, noncomparative, interventional case series of 12 eyes in ten patients with RRD secondary to viral retinitis. Results of vitreous or aqueous biopsy, effect of antiviral therapeutics, time to retinal detachment, course of visual acuity, and anatomic and surgical outcomes were investigated. RESULTS: There were 1,259 cases of RRD during the study period, with 12 cases of RRD secondary to viral retinitis (prevalence of 0.95%). Follow-up was available for a mean period of 4.4 years. Varicella zoster virus was detected in six eyes, herpes simplex virus in two eyes, and cytomegalovirus in two eyes. Eight patients were treated with oral valacyclovir and two patients with intravenous acyclovir. Lack of optic nerve involvement correlated with improved final visual acuity of 20/100 or greater. Pars plana vitrectomy (n=12), silicone-oil tamponade (n=11), and scleral buckling (n=10) provided successful anatomic retinal reattachment in all cases, with no recurrent retinal detachment and no cases of hypotony during the follow-up period. CONCLUSION: Varicella zoster virus was the most frequent cause of viral retinitis, and lack of optic nerve involvement was predictive of a favorable visual acuity prognosis. Vitrectomy with silicone-oil tamponade and scleral buckle placement provided stable anatomical outcomes. PMID- 26229424 TI - Clinical experience with fixed bimonthly aflibercept dosing in treatment experienced patients with neovascular age-related macular degeneration. AB - PURPOSE: To evaluate the durability of fixed bimonthly dosing of intravitreal aflibercept for neovascular age-related macular degeneration. METHODS: Records of 16 patients were retrospectively reviewed. Patients received three initial 2.0 mg monthly doses of aflibercept then 8-weekly doses according to the product label. Best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study [ETDRS] letters), central macular thickness, fluid on optical coherence tomography, and pigment epithelial detachment (PED) were measured. RESULTS: Prior to starting aflibercept, 13 patients had subretinal fluid (SRF), five had intraretinal fluid (IRF), four had PED, and baseline visual acuity (VA) was 62 approximate ETDRS letters. Following the monthly dosing, seven patients had no improvement or decreased VA, ten patients still had SRF/IRF, and PED had worsened in one patient. At Visit 4, an average of 6.8 weeks after Visit 3, VA had decreased in seven patients, SRF/IRF had increased in 12 patients, and PED had returned in all patients who initially responded. Based on the presence of fluid after the initial monthly injections, 12 patients could not be extended to fixed bimonthly dosing. CONCLUSION: This study adds to the growing body of evidence on the need for flexible dosing schedules for the personalized treatment of neovascular age related macular degeneration. PMID- 26229425 TI - Postcataract endophthalmitis prophylaxis using irrigation, incision hydration, and eye pressurization with vancomycin. AB - PURPOSE: This study aimed to determine whether switching from balanced salt solution (BSS) to vancomycin 20 g/mL BSS for incision hydration and eye pressurization reduces the rate of postcataract endophthalmitis. METHODS: This was a patient safety/quality improvement project, including all patients undergoing cataract surgery at the Kaiser Permanente Colorado Ophthalmology Department from January 2002 to December 2014. Throughout the study, patients received vancomycin 20 MUg/mL in the irrigating solution. During the baseline period from 2002 to 2005, surgeons pressurized eyes and hydrated incisions with plain BSS. During the intervention period from 2006 through 2014, surgeons switched from BSS to the vancomycin/BSS irrigating solution for eye pressurization and incision hydration. RESULTS: A total of 57,263 cataract operations were performed by 24 surgeons at seven surgical centers: 12,400 in the baseline period and 44,863 in the intervention period. The rate of post-cataract endophthalmitis declined significantly from 5/12,400 (rate: 0.4/1,000) in the baseline period to 1/44,863 (rate: 0.022/1,000) during the intervention period (odds ratio [OR]: 18.1, 95% confidence interval [CI]: 2.11-154.9; chi (2)=13.5, P=0.00024). Accounting for an estimated 2.05-fold risk reduction due to confounding variables, the risk reduction attributed to the intervention remained significant: (adjusted OR: 8.78, 95% CI: 1.73-44.5; chi (2)=10.06, P=0.0015). Since 2009, we have not experienced any cases of postcataract endophthalmitis after 32,753 operations. CONCLUSION: We experienced a significant reduction in postcataract endophthalmitis when we switched from BSS to the vancomycin/BSS irrigating solution for incision hydration and eye pressurization. The pharmacokinetics profile indicates that this switch was important for effective prophylaxis. PMID- 26229426 TI - Micropulse diode laser trabeculoplasty in Nigerian patients. AB - INTRODUCTION: The term micropulse laser trabeculoplasty suggests that only a fraction of the laser power is applied to the trabeculum to effect pressure lowering. It has not yet been exclusively used in Negroes, and we wish to report on our experience in Nigerian patients. METHODS: The study design is a retrospective chart review of our patients at the Rachel Eye Center in Abuja. The 810 diode Optos FastPulse laser was used to apply 34 cycles of treatment to 30 eyes of 16 individuals. Patients were selected based on the failure of maximal medical therapy. One patient had two extra rounds of treatment, while two patients were treated in only one eye. The pressure change at 1 hour after the treatment was analyzed. Patients were followed up for a mean period of 160 days with continuous monitoring of pressure changes. Patients' original therapy was not disturbed. RESULTS: Postlaser immediate drop in intraocular pressure (IOP) averaged 3.2 mmHg (CI 1.6-4.7, P<0.0001) representing 17.2% drop from baseline prelaser IOP. The drop in IOP was sustained over varying periods, from a few weeks to several months. There was a temporary spike in three instances. No serious side effects were noted. CONCLUSION: Micropulse diode laser trabeculoplasty is a useful adjunct in the management of open-angle glaucoma in Nigerians. This corroborates the findings of other researchers in western populations. PMID- 26229427 TI - Refractive index and its impact on pseudophakic dysphotopsia. AB - PURPOSE: It has been shown that the biggest dissatisfier for uncomplicated cataract surgery patients is pseudophakic dysphotopsia (PD). While edge design of an intraocular lens (IOL) impacts this problem, refractive index is still controversial as to its impact. This retrospective cohort study was designed to determine the role of increasing refractive index in PD. PATIENTS AND METHODS: This study was conducted at the John A. Moran Eye Center, University of Utah, USA. A retrospective chart review identified patients who received one of two hydrophobic acrylic single piece IOLs (AcrySof WF SP [SN60WF] or Tecnis SP [ZCB00]), which differed mainly by refractive index (1.55 versus 1.47). Eighty seven patients who had received implantation of a one-piece hydrophobic acrylic IOL were enrolled. Patients were included if the surgery had been uncomplicated and took place at least a year before study participation. All eligible patients had 20/20 best corrected vision, without any disease known to impact visual quality. In addition to conducting a record review, the enrolled patients were surveyed for PD, using a modified National Eye Institute Visual Function questionnaire, as well as for overall satisfaction with visual quality. RESULTS: Statistical analysis demonstrated no difference between the two cohorts regarding PD, general visual function, and overall visual satisfaction. CONCLUSION: The study suggests that with the two IOLs assessed, increasing the refractive index does not increase incidence of PD or decrease overall visual satisfaction. PMID- 26229428 TI - Posterior corneal curvature changes following Refractive Small Incision Lenticule Extraction. AB - PURPOSE: To compare the posterior corneal curvature changes, in terms of corneal power and asphercity, following Refractive Small Incision Lenticule Extraction (ReLEx SMILE) procedure for low, moderate, and high myopia. METHODS: This retrospective, non randomized, comparative, interventional trial; included 52 eyes of 26 patients, divided in three groups: low myopia (myopia <=3 D [diopters] spherical equivalent [SE]), moderate myopia (myopia >3 D and <6 D SE), and high myopia (myopia >=6 D SE). All patients were treated for myopia and myopic astigmatism using ReLEx SMILE. The eyes were examined pre-operatively and 3 months post-operatively using SCHWIND SIRIUS, a three-dimensional rotating Scheimpflug camera with a Placido disc topographer to assess corneal changes with regard to keratometric power and asphericity of the cornea. RESULTS: A statistically significant increase in mean keratometric power in the 3, 5, and 7 mm zones of the posterior corneal surface compared with its pre-ReLEx SMILE value was detected after 3 months in the moderate myopia group (pre-operative [pre-op] 6.14+/-0.23, post-operative [post-op] -6.29+/-0.22, P<0.001) and high myopia group (pre-op -6.19+/-0.16, post-op -6.4+/-0.18, P<0.001), but there was no significant change in keratometric power of the posterior surface in the low myopia group (pre-op -5.87+/-0.17, post-op -6.06+/-0.29, P=0.143). Asphericity (Q value) of the posterior surface changed significantly (P<0.001) after ReLEx SMILE in the moderate myopia group in the 3, 5, and 7 mm zones, and in the high myopia group in the 3 and 7 mm zones; but there was no significant change in the Q-value in the low myopia group in all three zones (pre-op 0.23+/-0.43, post-op -0.40+/ 0.71, P=0.170), and in the high myopia group in the 5 mm zone (P=0.228). CONCLUSION: ReLEx SMILE causes significant changes in posterior corneal keratometric power and asphericity in moderate and high myopia, but the effect is subtle and insignificant in low myopia. PMID- 26229429 TI - Erratum: The efficacy and safety of add-on 0.1% brimonidine tartrate preserved with sodium chlorite in on-treatment Japanese normal-tension glaucoma patients [Corrigendum]. AB - [This corrects the article on p. 1681 in vol. 8, PMID: 25214761.]. PMID- 26229430 TI - Comparison of cumulative dissipated energy between the Infiniti and Centurion phacoemulsification systems. AB - PURPOSE: To compare cumulative dissipated energy between two phacoemulsification machines. SETTING: An ambulatory surgical center, Honolulu, Hawaii, USA. DESIGN: Retrospective chart review. METHODS: A total of 2,077 consecutive cases of cataract extraction by phacoemulsification performed by five surgeons from November 2012 to November 2014 were included in the study; 1,021 consecutive cases were performed using the Infiniti Vision System, followed by 1,056 consecutive cases performed using the Centurion Vision System. RESULTS: The Centurion phacoemulsification system required less energy to remove a cataractous lens with an adjusted average energy reduction of 38% (5.09 percent-seconds) (P<0.001) across all surgeons in comparison to the Infiniti phacoemulsification system. The reduction in cumulative dissipated energy was statistically significant for each surgeon, with a range of 29%-45% (2.25-12.54 percent seconds) (P=0.005-<0.001). Cumulative dissipated energy for both the Infiniti and Centurion systems varied directly with patient age, increasing an average of 2.38 percent-seconds/10 years. CONCLUSION: The Centurion phacoemulsification system required less energy to remove a cataractous lens in comparison to the Infiniti phacoemulsification system. PMID- 26229431 TI - Relationship between progression of visual field defect and intraocular pressure in primary open-angle glaucoma. AB - PURPOSE: To analyze the relationship between intraocular pressure (IOP) and the progression of visual field defects in Japanese primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG) patients. PATIENTS AND METHODS: The subjects of the study were patients undergoing treatment for POAG or NTG who had performed visual field tests at least ten times with a Humphrey field analyzer (Swedish interactive thresholding algorithm standard, C30-2 program). The progression of visual field defects was defined by a significantly negative value of the mean deviation slope at the final visual field test during the follow-up period. The relationships between the progression of visual field defects and IOP, as well as other clinical factors, were retrospectively analyzed. RESULTS: A total of 156 eyes of 156 patients were included in the analysis. Significant progression of visual field defects was observed in 70 eyes of 70 patients (44.9%), while no significant progression was evident in 86 eyes of 86 patients (55.1%). The eyes with visual field defect progression had significantly lower baseline IOP (P<0.05), as well as significantly lower IOP reduction rate (P<0.01). The standard deviation of IOP values during follow-up was significantly greater in the eyes with visual field defect progression than in eyes without (P<0.05). CONCLUSION: Reducing IOP is thought to be useful for Japanese POAG or NTG patients to suppress the progression of visual field defects. In NTG, IOP management should take into account not only achieving the target IOP, but also minimizing the fluctuation of IOP during follow-up period. PMID- 26229432 TI - Relationship between UGT1A1*6/*28 polymorphisms and severe toxicities in Chinese patients with pancreatic or biliary tract cancer treated with irinotecan containing regimens. AB - PURPOSE: The aim of this retrospective study was to investigate the relationship between UGT1A1 polymorphisms and toxicities in Chinese patients with pancreatic or biliary tract cancer receiving irinotecan-containing regimens as the second- or third-line chemotherapy. PATIENTS AND METHODS: A total of 36 patients with unresectable pancreatic cancer and 12 patients with unresectable biliary tract cancer were included. Approximately 33 patients were treated with FOLFIRI regimen, a chemotherapy regimen, where FOL stands for folinic acid, F for fluorouracil, and IRI for irinotecan (irinotecan 180 mg/m(2) at day 1, CF 200 mg/m(2) at day 1-2, 5-FU 400 mg/m(2) at day 1-2, followed by continuous infusion of 5-FU 600 mg/m(2) for 22 hours at day 1-2, every 2 weeks). The other 15 patients were treated with irinotecan monotherapy (180 mg/m(2), every 2 weeks). UGT1A1*6/*28 polymorphisms were detected by direct sequencing. RESULTS: The frequencies of GG, GA, AA genotypes for UGT1A1*6 were 70.8% (n=34), 25.0% (n=12), and 4.2% (n=2), respectively. And those of TA6/TA6, TA6/TA7, TA7/TA7 for UGT1A1*28 were 79.2% (n=38), 18.8% (n=9), and 2.0% (n=1), respectively. A total of 22 patients (45.8%) had grade III-IV neutropenia, and six patients (12.5%) experienced grade III-IV diarrhea. The incidence of grade III-IV neutropenia in patients with UGT1A1*6 GA or AA genotype was 71.4%, which was significantly higher than that with GG genotype (35.3%, P=0.022). No relationship was found between grade III-IV neutropenia and UGT1A1*28 polymorphism. The statistical analysis between grade III-IV diarrhea and UGT1A1*6/*28 polymorphisms was not conducted in view of the limited number of patients. CONCLUSION: In Chinese patients with pancreatic or biliary tract cancer administered irinotecan containing regimens, those with UGT1A1*6 variant may have a high risk of severe neutropenia. PMID- 26229433 TI - The efficacy and safety of pemetrexed-based doublet therapy compared to pemetrexed alone for the second-line treatment of advanced non-small-cell lung cancer: an updated meta-analysis. AB - BACKGROUND: Pemetrexed is currently recommended as the second-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). However, it is unclear whether pemetrexed-based doublet therapy improves treatment efficacy and safety. Thus, this meta-analysis was performed to resolve this controversial question. METHODS: Electronic databases, including PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant articles before April 2015. Hazard ratios (HRs) were used to estimate overall survival (OS) and progression-free survival (PFS), and odds ratios (ORs) were used to analyze the overall response rate (ORR) and grade >=3 toxicities. Subgroup analysis, sensitivity analysis, and publication bias were also evaluated. RESULTS: A total of 2,519 patients from ten randomized controlled trials were included. Compared to pemetrexed alone, PFS and ORR significantly improved in the pemetrexed-based doublet group (HR, 0.86; 95% CI [confidence interval], 0.75-0.99; P=0.038; and OR, 1.98; 95% CI, 1.25-3.12; P=0.003, respectively). However, no statistically significant differences in OS were observed between groups (HR, 0.92; 95% CI, 0.83-1.02; P=0.132). In addition, subgroup analyses indicated that improved OS was only observed in nonsquamous NSCLC patients who received the combination of pemetrexed and erlotinib. An increasing incidence of grade >=3 neutropenia and thrombocytopenia was observed in the pemetrexed-based doublet group. CONCLUSION: Among patients with advanced NSCLC, pemetrexed-based doublet treatment tended to be associated with improved PFS, ORR, and increased toxicity, but not OS. PMID- 26229434 TI - Mechanisms underlying probucol-induced hERG-channel deficiency. AB - The hERG gene encodes the pore-forming alpha-subunit of the rapidly activating delayed rectifier potassium channel (I Kr), which is important for cardiac repolarization. Reduction of I hERG due to genetic mutations or drug interferences causes long QT syndrome, leading to life-threatening cardiac arrhythmias (torsades de pointes) or sudden death. Probucol is a cholesterol lowering drug that could reduce hERG current by decreasing plasma membrane hERG protein expression and eventually cause long QT syndrome. Here, we investigated the mechanisms of probucol effects on I hERG and hERG-channel expression. Our data demonstrated that probucol reduces SGK1 expression, known as SGK isoform, in a concentration-dependent manner, resulting in downregulation of phosphorylated E3 ubiquitin ligase Nedd4-2 expression, but not the total level of Nedd4-2. As a result, the hERG protein reduces, due to the enhanced ubiquitination level. On the contrary, carbachol could enhance the phosphorylation level of Nedd4-2 as an alternative to SGK1, and thus rescue the ubiquitin-mediated degradation of hERG channels caused by probucol. These discoveries provide a novel mechanism of probucol-induced hERG-channel deficiency, and imply that carbachol or its analog may serve as potential therapeutic compounds for the handling of probucol cardiotoxicity. PMID- 26229436 TI - Clinicopathological significance of matrix metalloproteinase-7 protein expression in esophageal cancer: a meta-analysis. AB - BACKGROUND: The MMP-7 basement membrane and extracellular matrix may be essential for tumor invasion and metastasis, and the results presented herein showed a relationship between MMP-7 expression and esophageal cancer (EC). However, its clinicopathological value for EC patients remains inconsistent. To clarify their associations, a meta-analysis of the relevant published literature was conducted. MATERIALS AND METHODS: Databases including PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, and Google Scholar were electronically searched. Only those studies analyzing MMP-7 expression in EC patients with regard to series of different demographic variables and clinicopathological stages (TNM stage, differentiation and invasion grade, and lymph-node [LN] metastasis) were eligible for inclusion. Summary odds ratios (ORs) were pooled in accordance with the random-effect model. RESULTS: Fourteen clinical cohort studies (tumor samples =935) were incorporated into the current meta-analysis. Results revealed that increased MMP-7 expression in EC patients was positively correlated to TNM stage III-IV (OR 3.04, 95% confidence interval [CI] 1.43-6.46; P=0.004). Similar connections were also detected in the differentiation grade, invasion grade, and LN metastasis (all P<0.05). Country-stratified analysis yielded significant association of elevated MMP-7 expression with EC in the People's Republic of China (PRC) under both TNM III-IV versus I-II and differentiation low versus high comparisons (TNM stage, OR 2.01, 95% CI 1.55 2.59, P<0.001; differentiation grade, OR 1.32, 95% CI 1.11-1.57, P=0.002). With regard to invasion grade and LN metastasis, significant association was observed in all the experimental subgroups (all P-values [PRC and Japan] were lower than 0.05). CONCLUSION: These data showed an obvious connection between MMP-7 and TNM stages, differentiation grade, invasive grade, and LN metastasis of EC, indicating that overexpression of MMP-7 may be a suitable diagnostic biomarker for variation in EC clinicopathological features. PMID- 26229435 TI - Targeting brain cells with glutathione-modulated nanoliposomes: in vitro and in vivo study. AB - BACKGROUND: The blood-brain barrier prevents many drug moieties from reaching the central nervous system. Therefore, glutathione-modulated nanoliposomes have been engineered to enhance the targeting of flucytosine to the brain. METHODS: Glutathione-modulated nanoliposomes were prepared by thin-film hydration technique and evaluated in the primary brain cells of rats. Lecithin, cholesterol, and span 65 were mixed at 1:1:1 molar ratio. The molar percentage of PEGylated glutathione varied from 0 mol% to 0.75 mol%. The cellular binding and the uptake of the targeted liposomes were both monitored by epifluorescent microscope and flow cytometry techniques. A biodistribution and a pharmacokinetic study of flucytosine and flucytosine-loaded glutathione-modulated liposomes was carried out to evaluate the in vivo brain-targeting efficiency. RESULTS: The size of glutathione-modulated nanoliposomes was <100 nm and the zeta potential was more than -65 mV. The cumulative release reached 70% for certain formulations. The cellular uptake increased as molar percent of glutathione increased to reach the maximum at 0.75 mol%. The uptake of the targeted liposomes by brain cells of the rats was three times greater than that of the nontargeted liposomes. An in vivo study showed that the relative efficiency was 2.632+/-0.089 and the concentration efficiency was 1.590+/-0.049, and also, the drug-targeting index was 3.670+/-0.824. CONCLUSION: Overall, these results revealed that glutathione PEGylated nanoliposomes enhance the effective delivery of flucytosine to brain and could become a promising new therapeutic option for the treatment of the brain infections. PMID- 26229437 TI - Escherichia coli Nissle 1917 bacterial ghosts retain crucial surface properties and express chlamydial antigen: an imaging study of a delivery system for the ocular surface. AB - To target chronic inflammatory ocular surface diseases, a drug delivery platform is needed that is safe, possesses immunomodulatory properties, and can be used either for drug delivery, or as a foreign antigen carrier. A new therapeutic approach that we have previously proposed uses nonliving bacterial ghosts (BGs) as a carrier-delivery system which can be engineered to carry foreign antigens and/or be loaded with therapeutic drugs. The parent strain chosen for development of our BG delivery system is the probiotic Escherichia coli strain Nissle 1917 (EcN), whose intrinsic properties trigger the innate immune system with the flagella and fimbriae used to attach and stimulate epithelial cells. In previous studies, we have shown that EcN BGs are safe for the ocular surface route, but evidence that EcN BGs retain flagella and fimbriae after transformation, has never been visually confirmed. In this study, we used different visualization techniques to determine whether flagella and fimbriae are retained on EcN BGs engineered either for drug delivery or as a foreign antigen carrier. We have also shown by immunoelectron microscopy that EcN retains two foreign antigens after processing to become EcN BGs. Furthermore, we demonstrated that BGs derived from EcN and expressing a foreign antigen attachment to conjunctival epithelial cells in vitro without causing reduced cell viability. These results are an important step in constructing a delivery system based on a nonliving probiotic that is suitable for use in ocular surface diseases pairing immunomodulation and targeted delivery. PMID- 26229438 TI - Bu-Shen-Ning-Xin decoction: inhibition of osteoclastogenesis by abrogation of the RANKL-induced NFATc1 and NF-kappaB signaling pathways via selective estrogen receptor alpha. AB - INTRODUCTION: Bu-Shen-Ning-Xin decoction (BSNXD) is a traditional Chinese medicinal composition that has been used as a remedy for postmenopausal osteoporosis, but the mechanisms affecting bone metabolism are not fully understood. PURPOSE: We investigated the molecular mechanism and signaling pathway underlying the effect of BSNXD on osteoclastogenesis. MATERIALS AND METHODS: A postmenopausal osteoporosis animal model generated by ovariectomy was administered BSNXD and drug-derived serum was prepared. An enzyme immunoassay was conducted to measure the 17-beta-estradiol (E2) concentration in the drug-derived serum. Bone marrow-derived monocyte/macrophage precursor cells were treated with drug-derived serum, and tartrate-resistance acid phosphatase staining was conducted to observe osteoclastogenesis. A bone resorption assay was performed to analyze the effect on osteoclastic resorptive function. Real-time PCR, flow cytometry, Western blotting, transfection, and luciferase assays were conducted to explore the related mechanism. RESULTS: E2 was not elevated in BSNXD-derived serum. BSNXD-derived serum suppressed receptor activation of nuclear factor kappaB ligand (RANKL)-activated osteoclastogenesis in a dose-dependent manner; this effect could be reversed by estrogen receptor alpha antagonist methyl piperidino-pyrazole. The serum suppressed RANKL-induced NF-kappaB transcription and inhibited the accumulation of nuclear factor of activated T-cells, cytoplasmic 1 in osteoclast precursor cells; the inhibitory effect was abolished by methyl-piperidino-pyrazole but not the estrogen receptor beta antagonist or androgen receptor antagonist. CONCLUSION: These results collectively suggest that administration of BSNXD presents inhibitory effects on osteoclast differentiation by abrogating the RANKL-induced nuclear factor of activated T-cells, cytoplasmic 1 and NF-kappaB signaling pathways downstream of estrogen receptor alpha, thereby contributing to the inhibitory effect on bone resorption. PMID- 26229439 TI - Design, development, drug-likeness, and molecular docking studies of novel piperidin-4-imine derivatives as antitubercular agents. AB - Tuberculosis remains one of the major grievous diseases worldwide. The emergence of resistance to antituberculosis drugs emphasize the necessity to discover new therapeutic agents for preferential tuberculosis therapy. In this study, various novel 1-(1H-benzimidazol-2-ylmethyl) piperidin-4-imine derivatives were developed and checked for favorable pharmacokinetic parameters based on drug-likeness explained by Lipinski's rule of five. All 20 of the novel chemical entities were found to possess a favorable pharmacokinetic profile since they were not violating Lipinski's rule of five. The title compounds were also synthesized, characterized, and tested for ex vivo antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294). The results revealed that four compounds (2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene] hydrazinecarbothioamide, 2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]-N hydroxy-hydrazinecarbo-thioamide, 1-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4 ylidene]guanidine, and 2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4 ylidene]hydrazinecarboxamide) were the most potent (minimum inhibitory concentration 6.25 ug/mL) antitubercular agents, with less toxicity (selectivity index more than 10). The molecules were also subjected to three-dimensional molecular docking on the crystal structure of enoyl-acyl carrier protein (EACP) reductase enzyme (code 1ZID, Protein Data Bank), which represents a good prediction of the interactions between the molecules and EACP reductase with minimum binding energy. PMID- 26229440 TI - Colon-targeted delivery of budesonide using dual pH- and time-dependent polymeric nanoparticles for colitis therapy. AB - Single pH-dependent drug delivery systems have been widely used for colon targeted delivery, but their efficiency is often hampered by the variation in gut pH. To overcome the limitation of single pH-dependent delivery systems, in this study, we developed and evaluated the therapeutic potential of budesonide-loaded dual pH/time-dependent nanoparticles (NPs) for the treatment of colitis. Eudragit FS30D was used as a pH-dependent polymer, and Eudragit RS100 as a time-dependent controlled release polymer. Single pH-dependent NPs (pH_NPs), single time dependent NPs (Time_NPs), and dual pH/time-dependent NPs (pH/Time_NPs) were prepared using the oil-in-water emulsion method. The physicochemical properties and drug release profiles of these NPs in gastrointestinal (GI) tract conditions were investigated. The therapeutic potential and in vivo distribution of the NPs were evaluated in a dextran sulfate sodium (DSS)-induced colitis mice model. The pH/Time_NPs prevented a burst drug release in acidic pH conditions and showed sustained release at a colonic pH. The in vivo distribution study in the mice GI tract demonstrated that pH/Time_NPs were more efficiently delivered to the inflamed colon than pH_NPs were. Compared to the single pH_NPs-treated group, the pH/Time_NPs-treated group showed increased body weight and colon length and markedly decreased disease activity index, colon weight/length ratios, histological damage, and inflammatory cell infiltration in colon tissue. Our results demonstrate that the dual pH/time-dependent NPs are an effective oral colon-targeted delivery system for colitis therapy. PMID- 26229441 TI - Adjunctive therapies to reduce thrombotic events in patients with a history of myocardial infarction: role of vorapaxar. AB - Acute myocardial infarction (AMI) is generally attributed to coronary atherothrombotic disease. Platelet activation is essential for thrombus formation and is thus an important target for pharmacological intervention to prevent and treat AMI. Despite contemporary treatment with dual antiplatelet therapy, including acetylsalicylic acid and adenosine diphosphate receptor antagonists, patients with prior AMI remain at increased risk of future thrombotic events. This has stimulated the search for more potent antithrombotic agents. Among these is the oral protease-activated receptor-1 antagonist vorapaxar, which represents a new oral antiplatelet agent to reduce thrombotic risk in patients with atherothrombotic disease. The TRACER and the TRA 2 degrees P-TIMI 50 trials concluded that vorapaxar in addition to standard therapy reduced ischemic adverse cardiac events. A remarkable benefit was observed in patients with stable atherosclerotic disease, particularly those with a previous history of AMI. Although favorable effects were seen in reduction of adverse cardiac events, this was associated with excess major and intracranial bleeding, particularly in patients at high risk of bleeding and those with a history of stroke or transient ischemic attack. Currently, the lack of a reliable individualized risk stratification tool to assess patients for thrombotic and bleeding tendencies in order to identify those who might gain most net clinical benefit has led to limited use of vorapaxar in clinical practice. Vorapaxar may find a niche as an adjunct to standard care in patients at high risk of thrombotic events and who are at low risk of bleeding. PMID- 26229443 TI - A new recombinant factor VIII: from genetics to clinical use. PMID- 26229442 TI - Developments in managing severe chronic pain: role of oxycodone-naloxone extended release. AB - Chronic pain is a highly disabling condition, which can significantly reduce patients' quality of life. Prevalence of moderate and severe chronic pain is high in the general population, and it increases significantly in patients with advanced cancer and older than 65 years. Guidelines for the management of chronic pain recommend opioids for the treatment of moderate-to-severe pain in patients whose pain is not responsive to initial therapies with paracetamol and/or nonsteroidal anti-inflammatory drugs. Despite their analgesic efficacy being well recognized, adverse events can affect daily functioning and patient quality of life. Opioid-induced constipation (OIC) occurs in 40% of opioid-treated patients. Laxatives are the most common drugs used to prevent and treat OIC. Laxatives do not address the underlying mechanisms of OIC; for this reason, they are not really effective in OIC treatment. Naloxone is an opioid receptor antagonist with low systemic bioavailability. When administered orally, naloxone antagonizes the opioid receptors in the gut wall, while its extensive first-pass hepatic metabolism ensures the lack of antagonist influence on the central-mediated analgesic effect of the opioids. A prolonged-release formulation consisting of oxycodone and naloxone in a 2:1 ratio was developed trying to reduce the incidence of OIC maintaining the analgesic effect compared with use of the sole oxycodone. This review includes evidence related to use of oxycodone and naloxone in the long-term management of chronic non-cancer pain and OIC. PMID- 26229444 TI - Navigating into the binding pockets of the HER family protein kinases: discovery of novel EGFR inhibitor as antitumor agent. AB - The epidermal growth factor receptor (EGFR) family has been validated as a successful antitumor drug target for decades. Known EGFR inhibitors were exposed to distinct drug resistance against the various EGFR mutants within non-small cell lung cancer (NSCLC), particularly the T790M mutation. Although so far a number of studies have been reported on the development of third-generation EGFR inhibitors for overcoming the resistance issue, the design procedure largely depends on the intuition of medicinal chemists. Here we retrospectively make a detailed analysis of the 42 EGFR family protein crystal complexes deposited in the Protein Data Bank (PDB). Based on the analysis of inhibitor binding modes in the kinase catalytic cleft, we identified a potent EGFR inhibitor (compound A-10) against drug-resistant EGFR through fragment-based drug design. This compound showed at least 30-fold more potency against EGFR T790M than the two control molecules erlotinib and gefitinib in vitro. Moreover, it could exhibit potent HER2 inhibitory activities as well as tumor growth inhibitory activity. Molecular docking studies revealed a structural basis for the increased potency and mutant selectivity of this compound. Compound A-10 may be selected as a promising candidate in further preclinical studies. In addition, our findings could provide a powerful strategy to identify novel selective kinase inhibitors on the basis of detailed kinase-ligand interaction space in the PDB. PMID- 26229445 TI - The brain signature of paracetamol in healthy volunteers: a double-blind randomized trial. AB - BACKGROUND: Paracetamol's (APAP) mechanism of action suggests the implication of supraspinal structures but no neuroimaging study has been performed in humans. METHODS AND RESULTS: This randomized, double-blind, crossover, placebo-controlled trial in 17 healthy volunteers (NCT01562704) aimed to evaluate how APAP modulates pain-evoked functional magnetic resonance imaging signals. We used behavioral measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli with APAP or placebo administration. Region-of interest analysis revealed that activity in response to noxious stimulation diminished with APAP compared to placebo in prefrontal cortices, insula, thalami, anterior cingulate cortex, and periaqueductal gray matter. CONCLUSION: These findings suggest an inhibitory effect of APAP on spinothalamic tracts leading to a decreased activation of higher structures, and a top-down influence on descending inhibition. Further binding and connectivity studies are needed to evaluate how APAP modulates pain, especially in the context of repeated administration to patients with pain. PMID- 26229446 TI - Functional magnetic resonance imaging is a powerful approach to probing the mechanism of action of therapeutic drugs that act on the central nervous system. PMID- 26229447 TI - Dendrimer-coupled sonophoresis-mediated transdermal drug-delivery system for diclofenac. AB - The purpose of the present study was to develop a novel transdermal drug-delivery system comprising a polyamidoamine dendrimer coupled with sonophoresis to enhance the permeation of diclofenac (DF) through the skin. The novel transdermal drug delivery system was developed by using a statistical Plackett-Burman design. Hairless male Wistar rat skin was used for the DF-permeation study. Coupling media concentration, ultrasound-application time, duty cycle, distance from probe to skin, and a third-generation polyamidoamine-dendrimer concentration were selected as independent variables, while in vitro drug release was selected as a dependent variable. Independent variables were found to be statistically significant (P<0.05). DF gel without dendrimer and ultrasound treatment to skin (passive delivery, run 13) showed 56.69 ug/cm(2) cumulative drug permeated through the skin, while the DF-dendrimer gel without sonophoresis treatment (run 14) showed 257.3 ug/cm(2) cumulative drug permeated through the skin after 24 hours. However, when the same gel was applied to sonophoresis-treated skin, drastic permeation enhancement was observed. In the case of run 3, the cumulative drug that permeated through the skin was 935.21 ug/cm(2). It was concluded that dendrimer-coupled sonophoresis-mediated transdermal drug delivery system has the potential to enhance the permeation of DF through the skin. PMID- 26229448 TI - Aterofisiol((r)) in carotid plaque evolution. AB - BACKGROUND: In patients with carotid stenosis, the risk of plaque rupture is related to the composition of the atherosclerotic plaque rather than to its magnitude. In this regard, we evaluated the effects of a supplement, Aterofisiol,((r)) containing omega-3 (EPA [eicosapen acid] DHA [docosahexaenoic acid]), vitamin K2, vitamin B6, vitamin B12, oligomeric proanthocyanidins (OPC) and resveratrol on the composition of atherosclerotic plaque and on neurological symptoms in patients with carotid stenosis undergoing carotid endarterectomy. METHODS: The study was randomized, prospective, and double-blinded. Eligible patients were of both sexes, with carotid stenosis >70% who underwent endarterectomy. Enrolled patients were randomly allocated to receive either one tablet of acetylsalicylic acid 100 mg (Cardioaspirin((r))) + one tablet of Aterofisiol every 24 hours or one tablet of Cardioaspirin + one tablet of placebo every 24 hours. Each treatment was started 30 days before the surgery and was stopped 5 days before the surgery. The plaques were removed "en bloc" using standard surgical technique. RESULTS: During the study period, 214 patients (135 men and 79 women) were enrolled for intent-to-treat and randomized in two groups: Group A: 107 patients (68 men and 39 women) were treated with Cardioaspirin + Aterofisiol. Group B: 107 patients (67 men and 40 women) were treated with Cardioaspirin + placebo. At the end of the study, 202 patients participated fully (103 patients in Group A and 99 patients in Group B), making up the protocol evaluation population (94.4%). The mean lipid content of removed plaques was significantly lower (P<0.05) in Group A. We recorded a significantly lower incidence of neurological symptoms in Group A in comparison with Group B (P<0.05). CONCLUSION: In the study, Aterofisiol showed to be effective in reducing the amounts of cholesterol and lipids in the plaques and in reducing adverse neurological events in the study group with respect to controls. PMID- 26229449 TI - Association of neutrophil/lymphocyte ratio with obstructive coronary artery disease and coronary artery calcium score detected by multislice computed tomography in type 2 diabetes mellitus patients. AB - OBJECTIVE: The aim of the present study was to investigate the association of neutrophil/lymphocyte ratio (NLR) with coronary artery calcium score (CACS) and obstructive coronary artery disease (CAD) detected by multislice computed tomography (MSCT) angiography in type 2 diabetes mellitus (T2DM) patients. METHODS: Two hundred and ninety-two T2DM patients, who were either asymptomatic or symptomatic (but noncharacteristic) for coronary artery disease (CAD) and underwent MSCT angiography in our clinic between May 2009 and June 2014, were enrolled. All patients were divided into two groups according to their mean NLR values. Patients with NLR <=2.05 were assigned to Group 1 and patients with NLR >2.05 were assigned to Group 2. The association of NLR with CACS and obstructive CAD, which were detected by MSCT angiography, was investigated in T2DM patients. RESULTS: According to the Agatston scoring method, the mean CACS was 129.5+/ 209.8 Au in Group 1 and 290.3+/-399.6 Au in Group 2 (P<0.001). Obstructive CAD was detected in 40 (26.8%) patients in Group 1 and in 56 (39.2%) patients in Group 2 (P<0.05, P<0.021). CONCLUSION: The rate of obstructive CAD was significantly higher in the T2DM patients with NLR >2.05 than that in the T2DM patients with NLR <=2.05. In addition, the CACS was also significantly higher in the T2DM patients with NLR >2.05 than that in the T2DM patients with NLR <=2.05. PMID- 26229450 TI - Development of an unsupportive social interaction scale for patients with diabetes. AB - OBJECTIVES: The positive aspects of social support and its impact on health have been studied extensively. However, there may also be negative effects of social environments on the diabetic patient. This study developed and validated a new diabetic unsupportive social interaction scale (USIS), including two subscales: interference and insensitivity. METHODS: A list of 22 items depicting unsupportive interactions associated with management of diabetes was developed. A telephone survey was administered to 764 Israelis with diabetes. The questionnaire included the USIS and questions about social networks, social support, health behaviors, and health. The characteristics, validity, and reliability of the scale were tested. RESULTS: A principal component analysis was performed for extraction of two factors describing unsupportive social interaction concepts: interference and insensitivity. Cronbach's alpha for the full 15-item scale was 0.84, indicating internal consistency. The two subscales were calculated to have Cronbach's alphas of 0.85 and 0.73, respectively. The USIS showed construct validity as it was associated with social support, some measures of social networks, subjective measures of health, and health behaviors. Arabs, older respondents, those defining themselves as more religious, and the less educated reported higher rates of unsupportive interactions. CONCLUSION: This study suggests a new concept of unsupportive interactions including interference and insensitivity. These unsupportive interactions may adversely affect patients' ability to adhere to treatment and may undermine their health in various ways. Identifying these problems may enable clinicians to help patients cope with their unsupportive environments. PMID- 26229451 TI - Patient willingness for repeat screening and preference for CT colonography and optical colonoscopy in ACRIN 6664: the National CT Colonography trial. AB - BACKGROUND: Current American Cancer Society recommendations for colon cancer screening include optical colonoscopy every 10 years or computed tomography colonography (CTC) every 5 years. Bowel preparation (BP) is currently required for both screening modalities. PURPOSE: To compare ACRIN 6664: the National CT Colonography Trial (NCTCT) participant experiences with CTC and optical colonoscopy (OC), procedure preference, and willingness to return for each procedure. MATERIALS AND METHODS: Participants from fifteen NCTCT sites, who underwent CTC followed by OC under sedation, were invited to complete questionnaires 2 weeks postexam, asking about procedure preference, physical discomfort, and embarrassment experienced and whether that discomfort and embarrassment was better or worse than expected during BP, CTC, and OC, as well as willingness to return for repeat CTC and OC at different time intervals. RESULTS: A total of 2,310 of 2,600 patients (89%) returned their questionnaires. Of patients reporting a preference, 1,058 (46.6%) preferred CTC, 569 (25.0%) preferred OC, and 626 (27.6%) reported no preference. Participant-reported discomfort worse than expected differed significantly between CTC (32.9%) and OC (5.0%) (P<0.001). About 79.3% were willing to be screened again with CTC in 5 years, and 96.6% with OC in 10 years. Discomfort and embarrassment worse than expected with OC were associated with increased intention to adhere with CTC in the future. Conversely, embarrassment experienced during CTC and discomfort worse than expected on CTC were associated with increased intention to adhere with OC in the future. CONCLUSION: While a larger proportion of participants indicated that they preferred CTC to OC, willingness to undergo repeat CTC compared to OC was limited by unanticipated exam discomfort and embarrassment and CTC's shorter screening interval. PMID- 26229452 TI - Oral treatment with herbal formula B307 alleviates cardiac failure in aging R6/2 mice with Huntington's disease via suppressing oxidative stress, inflammation, and apoptosis. AB - Cardiac failure is often observed in aging patients with Huntington's disease (HD). However, conventional pharmacological treatments for cardiac failure in HD patients have rarely been studied. Chinese herbal medicines, especially combined herbal formulas, have been widely used to treat cardiac dysfunctions over the centuries. Thus, we assess whether oral treatment with herbal formula B307 can alleviate cardiac failure in transgenic mice with HD. After oral B307 or vehicle treatment for 2 weeks, cardiac function and cardiomyocytes in 12-week-old male R6/2 HD mice and their wild-type littermate controls (WT) were examined and then compared via echocardiography, immunohistochemistry, and Western blotting. We found that cardiac performance in aging R6/2 HD mice had significantly deteriorated in comparison with their WT (P<0.01). Cardiac expressions of superoxide dismutase 2 (SOD2) and B-cell lymphoma 2 (Bcl-2) in aging R6/2 HD mice were significantly lower than their WT (P<0.01), but cardiac expressions of tumor necrosis factor alpha (TNF-alpha), neurotrophin-3 (3-NT), 4-hydroxynonenal (4 HNE), Bcl-2-associated X protein (Bax), calpain, caspase 12, caspase 9, and caspase 3 of aging R6/2 HD mice were significantly higher than their WT (P<0.05). Furthermore, we found that cardiac performance in aging R6/2 HD mice had significantly improved under oral B307 treatment (P<0.05). Cardiac expressions of SOD2 and Bcl-2 of aging R6/2 HD mice were significantly higher under oral B307 treatment (P<0.01), but cardiac expressions of TNF-alpha, 3-NT, 4-HNE, Bax, calpain, caspase 12, caspase 9, and caspase 3 of aging R6/2 HD mice were significantly reduced under oral B307 treatment (P<0.05). Oral B307 treatment may briefly alleviate cardiac failure in aging HD R6/2 mice via suppressing cardiac oxidative stress, inflammation, and apoptosis. We suggested that the herbal formula B307 may be further developed as a potential health supplement for ameliorating cardiac failure associated with aging. PMID- 26229453 TI - On the utility of within-participant research design when working with patients with neurocognitive disorders. AB - Within-participant research designs are frequently used within the field of behavior analysis to document changes in behavior before, during, and after treatment. The purpose of the present article is to show the utility of within participant research designs when working with older adults with neurocognitive disorders. The reason for advocating for these types of experimental designs is that they provide valid information about whether the changes that are observed in the dependent variable are caused by manipulations of the independent variable, or whether the change may be due to other variables. We provide examples from published papers where within-participant research design has been used with patients with neurocognitive disorders. The examples vary somewhat, demonstrating possible applications. It is our suggestion that the within participant research design may be used more often with the targeted client group than is documented in the literature at the current date. PMID- 26229454 TI - A stewardship intervention program for safe medication management and use of antidiabetic drugs. AB - BACKGROUND: Diabetes patients are complex due to considerations of polypharmacy, multimorbidities, medication adherence, dietary habits, health literacy, socioeconomic status, and cultural factors. Meanwhile, insulin and oral hypoglycemic agents are high-alert medications. Therefore it is necessary to require a multidisciplinary team's integrated endeavors to enhance safe medication management and use of antidiabetic drugs. METHODS: A 5-year stewardship intervention program, including organizational measures and quality improvement activities in storage, prescription, dispensing, administration, and monitoring, was performed in the Second Affiliated Hospital of Zhejiang University, People's Republic of China, a 3,200-bed hospital with 3.5 million outpatient visits annually. RESULTS: The Second Affiliated Hospital of Zhejiang University has obtained a 100% implementation rate of standard storage of antidiabetic drugs in the Pharmacy and wards since August 2012. A zero occurrence of dispensing errors related to highly "look-alike" and "sound-alike" NovoMix 30((r)) (biphasic insulin aspart) and NovoRapid((r)) (insulin aspart) has been achieved since October 2011. Insulin injection accuracy among ward nurses significantly increased from 82% (first quarter 2011) to 96% (fourth quarter 2011) (P<0.05). The number of medication administration errors related to insulin continuously decreased from 20 (2011) to six (2014). The occurrence rate of hypoglycemia in non-endocrinology ward diabetes inpatients during 2011-2013 was significantly less than that in 2010 (5.03%-5.53% versus 8.27%) (P<0.01). Percentage of correct management of hypoglycemia by nurses increased from 41.5% (April 2014) to 67.2% (August 2014) (P<0.01). The percentage of outpatient diabetes patients receiving standard insulin injection education increased from 80% (April 2012) to 95.2% (October 2012) (P<0.05). Insulin injection techniques among diabetes outpatients who started to receive insulin were better than indicated in data from two questionnaire surveys in the literature, including the percentage checking injection sites prior to injection (85.6%), priming before injection (98.1%), rotation of injecting sites (98.1%), remixing before use (94.5%), keeping the pen needle under the skin for >10 seconds (99.4%), and using the pen needle only once (88.7%). On-site inspection indicated of great improvement in the percentage of drug-related problems in the antidiabetes regimen between the first and second quarter of 2014 (1.08% versus 0.28%) (P<0.05). CONCLUSION: Quality improvements in safe medication management and use of antidiabetic drugs can be achieved by multidisciplinary collaboration among pharmacists, nurses, physicians, and information engineers. PMID- 26229455 TI - Self-reported alcohol intake and risk of acute exacerbations of chronic obstructive pulmonary disease: a prospective cohort study. AB - OBJECTIVE: To evaluate the relationship between alcohol consumption and the risk of acute exacerbation of COPD (AECOPD). METHODS AND MEASUREMENTS: We conducted a secondary analysis of data previously collected in a large, multicenter trial of daily azithromycin in COPD. To analyze the relationship between amount of baseline self-reported alcohol consumption in the past 12 months and subsequent AECOPD, we categorized the subjects as minimal (<1 drink/month), light-to moderate (1-60 drinks/month), or heavy alcohol users (>60 drinks/month). The primary outcome was time to first AECOPD and the secondary outcome was AECOPD rate during the 1-year study period. RESULTS: Of the 1,142 enrolled participants, 1,082 completed baseline alcohol questionnaires and were included in this analysis. Six hundred and forty-five participants reported minimal alcohol intake, 363 reported light-to-moderate intake, and 74 reported heavy intake. There were no statistically significant differences in median time to first AECOPD among minimal (195 days), light-to-moderate (241 days), and heavy drinkers (288 days) (P=0.11). The mean crude rate of AECOPD did not significantly differ between minimal (1.62 events per year) and light-to-moderate (1.44 events per year) (P=0.095), or heavy drinkers (1.68 events per year) (P=0.796). There were no significant differences in hazard ratios for AECOPD after adjustment for multiple covariates. CONCLUSION: Among persons with COPD at high risk of exacerbation, we found no significant relationship between self-reported baseline alcohol intake and subsequent exacerbations. The number of patients reporting heavy alcohol intake was small and further study is needed to determine the effect of heavy alcohol intake on AECOPD risk. PMID- 26229456 TI - Characteristics of prevalent and new COPD cases in Greece: the GOLDEN study. AB - BACKGROUND: Greece has one of the highest rates of smoking and chronic obstructive pulmonary disease (COPD) in Europe. AIM: The study aimed to record both the disease characteristics among a sample of Greek COPD patients and the nationwide rates of newly diagnosed COPD cases. METHODS: In this noninterventional, epidemiological cross-sectional study, a representative nationwide sample of 45 respiratory centers provided data on the following: 1) the demographic and clinical characteristics of COPD patients and 2) newly diagnosed COPD cases monitored over a period of 6 months by each physician. RESULTS: Data from 6,125 COPD patients were collected. Advanced age (median age: 68 years), male predominance (71.3%), largely overweight status with median body mass index (BMI) =27.5 kg/m(2), high percentage of current and ex-smokers (89.8%), and presence of comorbidities (81.9%) were evident in the sample. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 criteria, majority of the COPD patients had moderate or severe airflow limitation (61%). Severity of airflow limitation was significantly associated with older age, male sex, obesity, ex-smoking status, and presence of comorbidity (all P-values <0.001). A total of 61.3% of the patients received medication, mostly bronchodilators (64.4%) and fixed-dose combinations of long-acting beta2 agonists and inhaled corticosteroids (39.9%), while 35.9% reported taking medication on demand. The majority (81.1%) of patients reported a preference for fewer inhalations of their bronchodilator therapy. Based on the mixed-effect Poisson model, the rate of newly diagnosed COPD cases was estimated to be 18.2% (95% confidence interval: 14.9-22.3) per pulmonologist/3 months. Of those newly diagnosed, the majority of patients had mild or moderate airflow limitation (78.2%). CONCLUSION: The Greek Obstructive Lung Disease Epidemiology and health ecoNomics study reflected the real-life profile of COPD patients and provided evidence on the profile of new COPD cases in Greece. Various demographic factors were delineated, which can assist in designing more effective diagnostic and management strategies for COPD in Greece. PMID- 26229457 TI - Clinical role of dual bronchodilation with an indacaterol-glycopyrronium combination in the management of COPD: its impact on patient-related outcomes and quality of life. AB - Chronic obstructive pulmonary disease (COPD) is the result of persistent and progressive pathologic abnormalities in the small airways, most often associated with alveolar loss. Smoking cessation is the most effective intervention to slow down the progression of COPD. Long-acting inhaled bronchodilators are prescribed for the symptomatic relief at any stage of disease severity. For patients whose COPD cannot be not sufficiently controlled with long-acting bronchodilator monotherapy, international guidelines suggest the possibility of associating a long-acting beta2 agonist (LABA) with a long-acting muscarinic antagonist (LAMA), ie, dual bronchodilation. This is not a new concept as the combination of short acting agents has been popular in the past. In recent years, several fixed-dose combinations containing a LAMA and a LABA in a single inhaler have been approved by regulatory authorities in several countries. Among the new LAMA/LABA combinations, the fixed-dose combination of indacaterol 110 ug/glycopyrronium 50 ug (QVA149) has been shown in a series of clinical trials to be as safe as the single components and placebo, and more effective than placebo and the single components with regard to lung function, symptoms, and patient-oriented outcomes. Furthermore, QVA149 achieved better bronchodilation than salmeterol 50 ug/fluticasone 500 ug twice daily. Compared with tiotropium, a well-recognized treatment for COPD, the percentage of patients that exceed the minimal clinical important difference for dyspnea and health-related quality of life measurements was superior with QVA149. Other patient-oriented outcomes, such as daily symptoms, night-time awakening, and use of rescue medication consistently favored QVA149. Finally, QVA149 was significantly superior to LAMAs for reducing all types of exacerbation. In conclusion, several years after introduction of dual bronchodilation, the fixed-dose combination of indacaterol 110 ug/glycopyrronium 50 ug in a single inhaler for once-daily administration via the Breezhaler device (QVA149) has been demonstrated to be a safe and effective treatment for COPD patients. PMID- 26229458 TI - Constant-load exercise decreases the serum concentration of myeloperoxidase in healthy smokers and smokers with COPD. AB - There is an ongoing demand for easily accessible biomarkers related to pathophysiological processes in chronic obstructive pulmonary disease (COPD). Short-term intense exercise is known to increase the peripheral blood levels of cytokines. Therefore, we tested the potential and the repeatability of an exercise challenge to amplify seven serum biomarkers (interleukin 6 [IL6], C reactive protein [CRP], myeloperoxidase [MPO], leukotriene B4, soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and von Willebrand factor [VWF]) in smokers with and without COPD. Twenty-three smokers with moderate COPD (GOLD 2) and 23 sex- and age-matched healthy smokers underwent up to 30-minute submaximal, constant-load exercise (75% of maximum work load) on two occasions separated by 4 weeks (second challenge n=19/20). Serum samples were obtained before, 5 minutes after the start, at the end of exercise (maximum 30 minutes or until exhaustion), and after additional 20 minutes of rest. The median (interquartile range) exercise time until exhaustion in the two challenges was 10.0 (4.0) minutes and 10.0 (8.0) minutes in smokers with COPD and 22.0 (16.0) minutes and 26.5 (14.5) minutes in healthy smokers. The exercise challenge significantly increased the serum concentrations of IL6 and VWF, but decreased the concentrations of MPO. Healthy smokers showed a significantly greater increase (at the end of exercise compared to before exercise) in IL6 (P=0.01) and a larger decline (P=0.03) in MPO. The overall profile of the serum markers during the exercise challenge was shown to be repeatable in the second challenge. In summary, intense load exercise is capable of changing the concentration of inflammatory and endothelial function markers. Especially, the decline in the level of MPO, a marker closely related to cardiovascular risk, appears to be of clinical interest, as the exercise-induced decline might be related to the beneficial effects of physical activity in general. PMID- 26229459 TI - Is dynamometry able to infer the risk of muscle mass loss in patients with COPD? AB - INTRODUCTION: Sarcopenia is characterized by a progressive and generalized decrease of strength and muscle mass. Muscle mass loss is prevalent in patients with chronic obstructive pulmonary disease (COPD) as a result of both the disease and aging. Some methods have been proposed to assess body composition (and therefore identify muscle mass loss) in this population. Despite the high accuracy of some methods, they require sophisticated and costly equipment. AIM: The purpose of this study was to infer the occurrence of muscle mass loss measured by a sophisticated method (dual energy X-ray absorptiometry [DEXA]) using a more simple and affordable equipment (dynamometer). METHODS: Fifty-seven stable subjects with COPD were evaluated for anthropometric characteristics, lung function, functional exercise capacity, body composition, and peripheral muscle strength. A binary logistic regression model verified whether knee-extension strength (measured by dynamometry) could infer muscle mass loss (from DEXA). RESULTS: Patients with decreased knee-extension strength were 5.93 times more likely to have muscle mass loss, regardless of sex, disease stage, and functional exercise capacity (P=0.045). CONCLUSION: Knee-extension dynamometry was able to infer muscle mass loss in patients with COPD. PMID- 26229460 TI - Smoking duration, respiratory symptoms, and COPD in adults aged >=45 years with a smoking history. AB - BACKGROUND: The purpose of this study was to assess the relationship of smoking duration with respiratory symptoms and history of chronic obstructive pulmonary disease (COPD) in the South Carolina Behavioral Risk Factor Surveillance System survey in 2012. METHODS: Data from 4,135 adults aged >=45 years with a smoking history were analyzed using multivariable logistic regression that accounted for sex, age, race/ethnicity, education, and current smoking status, as well as the complex sampling design. RESULTS: The distribution of smoking duration ranged from 19.2% (1-9 years) to 36.2% (>=30 years). Among 1,454 respondents who had smoked for >=30 years, 58.3% were current smokers, 25.0% had frequent productive cough, 11.2% had frequent shortness of breath, 16.7% strongly agreed that shortness of breath affected physical activity, and 25.6% had been diagnosed with COPD. Prevalence of COPD and each respiratory symptom was lower among former smokers who quit >=10 years earlier compared with current smokers. Smoking duration had a linear relationship with COPD (P<0.001) and all three respiratory symptoms (P<0.001) after adjusting for smoking status and other covariates. While COPD prevalence increased with prolonged smoking duration in both men and women, women had a higher age-adjusted prevalence of COPD in the 1-9 years, 20-29 years, and >=30 years duration periods. CONCLUSION: These state population data confirm that prolonged tobacco use is associated with respiratory symptoms and COPD after controlling for current smoking behavior. PMID- 26229461 TI - Validation of an administrative claims-based diagnostic code for pneumonia in a US-based commercially insured COPD population. AB - OBJECTIVE: To estimate the accuracy of claims-based pneumonia diagnoses in COPD patients using clinical information in medical records as the reference standard. METHODS: Selecting from a repository containing members' data from 14 regional United States health plans, this validation study identified pneumonia diagnoses within a group of patients initiating treatment for COPD between March 1, 2009 and March 31, 2012. Patients with >=1 claim for pneumonia (International Classification of Diseases Version 9-CM code 480.xx-486.xx) were identified during the 12 months following treatment initiation. A subset of 800 patients was randomly selected to abstract medical record data (paper based and electronic) for a target sample of 400 patients, to estimate validity within 5% margin of error. Positive predictive value (PPV) was calculated for the claims diagnosis of pneumonia relative to the reference standard, defined as a documented diagnosis in the medical record. RESULTS: A total of 388 records were reviewed; 311 included a documented pneumonia diagnosis, indicating 80.2% (95% confidence interval [CI]: 75.8% to 84.0%) of claims-identified pneumonia diagnoses were validated by the medical charts. Claims-based diagnoses in inpatient or emergency departments (n=185) had greater PPV versus outpatient settings (n=203), 87.6% (95% CI: 81.9%-92.0%) versus 73.4% (95% CI: 66.8%-79.3%), respectively. Claims diagnoses verified with paper-based charts had similar PPV as the overall study sample, 80.2% (95% CI: 71.1%-87.5%), and higher PPV than those linked to electronic medical records, 73.3% (95% CI: 65.5%-80.2%). Combined paper-based and electronic records had a higher PPV, 87.6% (95% CI: 80.9%-92.6%). CONCLUSION: Administrative claims data indicating a diagnosis of pneumonia in COPD patients are supported by medical records. The accuracy of a medical record diagnosis of pneumonia remains unknown. With increased use of claims data in medical research, COPD researchers can study pneumonia with confidence that claims data are a valid tool when studying the safety of COPD therapies that could potentially lead to increased pneumonia susceptibility or severity. PMID- 26229462 TI - Effect of liposomal fluidity on skin permeation of sodium fluorescein entrapped in liposomes. AB - The purpose of this study was to investigate the effect of ultradeformable liposome components, Tween 20 and terpenes, on vesicle fluidity. The fluidity was evaluated by electron spin resonance spectroscopy using 5-doxyl stearic acid and 16-doxyl stearic acid as spin labels for phospholipid bilayer fluidity at the C5 atom of the acyl chain near the polar head group (hydrophilic region) and the C16 atom of the acyl chain (lipophilic region), respectively. The electron spin resonance study revealed that Tween 20 increased the fluidity at the C5 atom of the acyl chain, whereas terpenes increased the fluidity at the C16 atom of the acyl chain of the phospholipid bilayer. The increase in liposomal fluidity resulted in the increased skin penetration of sodium fluorescein. Confocal laser scanning microscopy showed that ultradeformable liposomes with terpenes increase the skin penetration of sodium fluorescein by enhancing hair follicle penetration. PMID- 26229463 TI - Increased osteoblast function in vitro and in vivo through surface nanostructuring by ultrasonic shot peening. AB - Surface topography has significant influence on good and fast osseointegration of biomedical implants. In this work, ultrasonic shot peening was conducted to modify titanium to produce nanograined (NG) surface. Its ability to induce new bone formation was evaluated using an in vivo animal model. We demonstrated that the NG surface enhanced osteoblast adhesion, proliferation, differentiation, and mineralization in in vitro experiments compared to coarse-grained titanium surface. Push-out test, histological observations, fluorescent labeling, and histomorphometrical analysis consistently indicated that the NG surfaces developed have the higher osseointegration than coarse-grained surfaces. Those results suggest that ultrasonic shot peening has the potential for future use as a surface modification method in biomedical application. PMID- 26229465 TI - Undetactable levels of genotoxicity of SiO2 nanoparticles in in vitro and in vivo tests [Erratum]. PMID- 26229464 TI - Preparation and tumor cell model based biobehavioral evaluation of the nanocarrier system using partially reduced graphene oxide functionalized by surfactant. AB - BACKGROUND: Currently, surfactant-functionalized nanomaterials are tending toward development of novel tumor-targeted drug carriers to overcome multidrug resistance in cancer therapy. Now, investigating the biocompatibility and uptake mechanism of specific drug delivery systems is a growing trend, but usually a troublesome issue, in simple pharmaceutical research. METHODS: We first reported the partially reduced graphene oxide modified with poly(sodium 4 styrenesulfonate) (PSS) as a nanocarrier system. Then, the nanocarrier was characterized by atomic force microscope, scanning electron microscope, high resolution transmission electron microscope, ultraviolet-visible (UV-vis) spectroscopy, Fourier transform infrared spectroscopy, X-Ray powder diffraction, and Raman spectroscopy. Epirubicin (EPI) was attached to PSSG via pi-pi stacking, hydrogen bonding, and physical absorption to form conjugates of PSSG-EPI. The adsorption and desorption profiles, cytotoxicity coupled with drug accumulation, and uptake of PSSG and PSSG-EPI were evaluated. Finally, the subcellular behaviors, distribution, and biological fate of the drug delivery system were explored by confocal laser scanning microscope using direct fluorescence colocalization imaging and transmission electron microscopy. RESULTS: The partially reduced graphene oxide sheets functionalized by surfactant exhibit good dispersibility. Moreover, due to much less carboxyl groups retained on the edge of PSSG sheets, the nanocarriers exhibit biocompatibility in vitro. The obtained PSSG shows a high drug-loading capacity of 2.22 mg/mg. The complexes of PSSG-EPI can be transferred to lysosomes in 2 hours through endocytosis, then the drug is released in the cytoplasm in 8 hours, and ultimately EPI is delivered into cell nucleus to exhibit medicinal effects in 1 day. CONCLUSION: The comprehensive exploration of the biological uptake mechanism of functional graphene-mediated tumor cell targeting model provides a typical protocol for evaluation of drug delivery system and will benefit the discovery of new surfactant-modified nanocarriers in nanomedicine. PMID- 26229466 TI - Immobilization of collagen peptide on dialdehyde bacterial cellulose nanofibers via covalent bonds for tissue engineering and regeneration. AB - Bacterial cellulose (BC) is an alternative nanostructured biomaterial to be utilized for a wide range of biomedical applications. Because of its low bioactivity, which restricted its practical application, collagen and collagen hydrolysate were usually composited into BC. It is necessary to develop a new method to generate covalent bonds between collagen and cellulose to improve the immobilization of collagen on BC. This study describes a facile dialdehyde BC/collagen peptide nanocomposite. BC was oxidized into dialdehyde bacterial cellulose (DBC) by regioselective oxidation, and then composited with collagen peptide (Col-p) via covalent bonds to form Schiff's base type compounds, which was demonstrated by the results of microstructures, contact angle, Col-p content, and peptide-binding ratio. The peptide-binding ratio was further affected by the degree of oxidation, pH value, and zeta potential. In vitro desorption measurement of Col-p suggested a controlled release mechanism of the nanocomposite. Cell tests indicated that the prepared DBC/Col-p composite was bioactive and suitable for cell adhesion and attachment. This work demonstrates that the DBC/Col-p composite is a promising material for tissue engineering and regeneration. PMID- 26229467 TI - Study of magnetic silk fibroin nanoparticles for massage-like transdermal drug delivery. AB - A synergistic approach by the combination of magnetic nanoparticles with an alternating magnetic field for transdermal drug delivery was investigated. Methotrexate-loaded silk fibroin magnetic nanoparticles were prepared using suspension-enhanced dispersion by supercritical CO2. The physiochemical properties of the magnetic nanoparticles were characterized. In vitro studies on drug permeation across skin were performed under different magnetic fields in comparison with passive diffusion. The permeation flux enhancement factor was found to increase under a stationary magnetic field, while an alternating magnetic field enhanced drug permeation more effectively; the combination of stationary and alternating magnetic fields, which has a massage-like effect on the skin, achieved the best result. The mechanistic studies using attenuated total reflection Fourier-transform infrared spectroscopy demonstrate that an alternating magnetic field can change the ordered structure of the stratum corneum lipid bilayers from the gel to the lipid-crystalline state, which can increase the fluidity of the stratum corneum lipids, thus enhancing skin penetration. Compared with the other groups, the fluorescence signal with a bigger area detected in deeper regions of the skin also reveals that the simulated massage could enhance the drug permeation across the skin by increasing the follicular transport. The combination of magnetic nanoparticles with stationary/alternating magnetic fields has potential for effective massage-like transdermal drug delivery. PMID- 26229468 TI - Styrene maleic acid micelles as a nanocarrier system for oral anticancer drug delivery - dual uptake through enterocytes and M-cells. AB - Drug delivery systems could potentially overcome low bioavailability and gastrointestinal toxicity, which are the major challenges for the development of oral anticancer drugs. Herein, we demonstrate the ability of styrene maleic acid (SMA) nanomicelles encapsulating epirubicin to traverse in vitro and ex vivo models of the intestinal epithelium without affecting the tissue integrity. Further, SMA micelles encapsulating a fluorescent dye dioctadecyl-3,3,3',3' tetramethylindocarbocyanine perchlorate (DiI) showed twofold higher accumulation in the liver and spleen, 15-fold higher accumulation in the tumor, and sixfold higher accumulation in the lung as compared with the free DiI, following oral administration in a mice xenograft breast cancer model. Additionally, SMA micelles showed colocalization with microfold (M)-cells and accumulation in Peyer's patches, which together confirms the M-cell mediated uptake and transport of SMA micelles. Our results indicate that SMA micelles, showing dual uptake by enterocytes and M-cells, are a potential tool for safe oral anticancer drug delivery. PMID- 26229469 TI - Reducible chimeric polypeptide consisting of octa-D-arginine and tetra-L histidine peptides as an efficient gene delivery vector. AB - Cationic oligopeptide as a nonviral gene delivery vector has aroused much research interest recently, but its further application is limited by its low transfection efficiency. In the present study, we have created a high-efficiency gene vector by using octa-D-arginine and tetra-L-histidine to form a disulfide cross-linked chimeric polypeptide and used this vector to deliver the therapeutic gene tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) to see whether the gene could be transferred and could exert antitumor effects in vitro and in vivo. The result showed that the newly designed vector was able to condense DNA into nanosized polyplexes effectively, thus facilitating its transmembrane transport, promoting its endosomal escape, and finally enabling degradation within the cell. Our study has demonstrated that this chimeric polypeptide is an effective gene carrier in cancer therapy. PMID- 26229470 TI - Disconnection of the hippocampus and amygdala associated with lesion load in relapsing-remitting multiple sclerosis: a structural and functional connectivity study. AB - BACKGROUND AND PURPOSE: Little is known about the functional and structural connectivity (FC and SC) of the hippocampus and amygdala, which are two important structures involved in cognitive processes, or their involvement in relapsing remitting multiple sclerosis (RRMS). In this study, we aimed to examine the connectivity of white-matter (WM) tracts and the synchrony of intrinsic neuronal activity in outer regions connected with the hippocampus or amygdala in RRMS patients. PATIENTS AND METHODS: Twenty-three RRMS patients and 23 healthy subjects participated in this study. Diffusion tensor probabilistic tractography was used to examine the SC, the FC correlation coefficient (FC-CC) and combined FC strength (FCS), which was derived from the resting-state functional magnetic resonance imaging used to examine the FC, of the connection between the hippocampus or the amygdala and other regions, and the correlations of these connections with clinical markers. RESULTS: Compared with healthy subjects, the RRMS patients showed significantly decreased SC and increased FCS of the bilateral hippocampus, and left amygdala. Their slightly increased FC-CC was positively correlated with WM tract damage in the right hippocampus (rho=0.57, P=0.005); an increased FCS was also positively correlated with WM tract damage in the right amygdala. A relationship was observed between the WM lesion load and SC alterations, including the lg(N tracts) of the right hippocampus (rho=-0.68, P<0.05), lg(N tracts) (rho=-0.69, P<0.05), and fractional anisotropy (rho=-0.68, P<0.05) and radial diffusivity of the left hippocampus (rho=0.45, P<0.05). A relationship between WM lesion load and FCS of the left amygdale was also observed. CONCLUSION: The concurrent increased functional connections and demyelination-related structural disconnectivity between the hippocampus or amygdala and other regions in RRMS suggest that the functional-structural relationships require further investigation. PMID- 26229471 TI - Individual correlates of self-stigma in patients with anxiety disorders with and without comorbidities. AB - BACKGROUND: A number of psychiatric patients experience stigma connected to prejudices about mental disorders. It has been shown that stigma is most harmful when it is internalized. Most of the studies were performed on individuals either with psychoses or with mood disorders, and hence, there are almost no studies with other diagnostic categories. The goals of this research were to identify factors that are significantly related to self-stigma in patients with anxiety disorders and to suggest possible models of causality for these relationships. METHODS: A total of 109 patients with anxiety disorders and possible comorbid depressive or personality disorders, who were admitted to the psychotherapeutic department participated in this study. All patients completed several psychodiagnostic methods, ie, the Internalized Stigma of Mental Illness Scale, Temperament and Character Inventory-Revised Version, Adult Dispositional Hope Scale, Dissociative Experiences Scale, Beck Anxiety Inventory, Beck Depression Inventory-Second Edition, and Clinical Global Impression (also completed by the senior psychiatrist). RESULTS: The overall level of self-stigma was positively associated with a comorbid personality disorder, more severe symptomatology, more intense symptoms of anxiety and depression, and higher levels of dissociation and harm avoidance. Self-stigma was negatively related to hope, reward dependence, persistence, self-directedness, and cooperativeness. Multiple regression analysis showed that the most significant factors connected to self-stigma are harm avoidance, the intensity of depressive symptoms, and self-directedness. Two models of causality were proposed and validated. It seems that the tendency to dissociate in stress increases the probability of development of self-stigma, and this relationship is entirely mediated by avoidance of harm. Conversely, self directedness lowers the probability of occurrence of self-stigma, and this effect is partly mediated by hope. CONCLUSION: Patients with anxiety disorders accompanied with or without comorbid depressive or personality disorders may suffer from self-stigma. Individuals with greater sensitivity to rejection and other socially aversive stimuli are prone to the development of self-stigma. Other personality factors, such as hopeful thinking and self-acceptance serve as factors promoting resilience concerning self-stigma. PMID- 26229472 TI - Acute multiple focal neuropathies and delayed postanoxic encephalopathy after alcohol intoxication. AB - Acute-onset alcohol-associated neuropathy is only occasionally reported, and delayed postanoxic encephalopathy is rare. Here, we report a male who developed acute multiple focal neuropathies and later delayed postanoxic encephalopathy after alcohol intoxication. He had hypoxia and rhabdomyolysis, presenting with acute renal failure initially, and cardiopulmonary support, including mechanical ventilation, led to improvement of the patient at the acute stage. He suffered from bilateral hand numbness and mild weakness of the right lower limb thereafter. Nerve-conduction study revealed no pickup of compound muscle action potential or sensory nerve action potential in the bilateral ulnar nerve, but showed attenuated amplitude of compound muscle action potential in the right femoral nerve. Multiple focal neuropathies were suspected, and he received outpatient rehabilitation after being discharged. However, the patient developed gradual onset of weakness in four limbs and cognitive impairment 23 days after the hypoxia event. Brain computed tomography showed low attenuation over bilateral globus pallidus, and brain magnetic resonance imaging disclosed diffuse increased signal intensity on T 2-weighted images and fluid-attenuated inversion recovery in bilateral white matter. He was admitted again under the impression of delayed postanoxic brain injury. Supportive treatment and active rehabilitation were given. He had gradual improvement in motor and functional status after rehabilitation. He could walk with festinating gait under supervision, and needed only minimal assistance in performing activities of daily living approximately 1 year later. PMID- 26229473 TI - Effects of maintenance lithium treatment on serum parathyroid hormone and calcium levels: a retrospective longitudinal naturalistic study. AB - OBJECTIVE: The aim of this retrospective longitudinal naturalistic study was to evaluate the effects of maintenance lithium treatment on parathyroid hormone (PTH) and calcium levels. METHODS: A retrospective longitudinal naturalistic study design was used. Data were collected from the database of a tertiary psychiatric center covering the years 2010-2014. Included were bipolar patients who had never been exposed to lithium and had lithium started, and who had PTH, and total and ionized calcium levels available before and during lithium treatment. Paired t-tests were used to analyze changes in PTH and calcium levels. Linear regressions were performed, with mean lithium level and duration of lithium exposure as independent variables and change in PTH levels as dependent variable. RESULTS: A total 31 patients were included. The mean duration of lithium treatment was 18.6+/-11.4 months. PTH levels significantly increased during lithium treatment (+13.55+/-14.20 pg/mL); the rate of hyperparathyroidism was 12.9%. Neither total nor ionized calcium increased from baseline to follow up; none of our patients developed hypercalcemia. Linear regressions analyses did not show an effect of duration of lithium exposure or mean lithium level on PTH levels. CONCLUSION: Lithium-associated stimulation of parathyroid function is more common than assumed to date. Among parameters to be evaluated prior to lithium implementation, calcium and PTH should be added. PMID- 26229474 TI - Markers of neurodevelopmental impairments in early-onset psychosis. AB - BACKGROUND: The aim of this study was to assess the association between the clinical and neurobiological markers of neurodevelopmental impairments and early onset schizophrenia spectrum psychosis. METHODS: A sample of 36 patients with early-onset schizophrenia spectrum psychosis was compared to a control sample of 36 patients with migraine. We assessed early childhood neurodevelopmental milestones using a modified version of the General Developmental Scale, general intellectual ability using the Wechsler Intelligence Scale for Children-Revised or Leiter International Performance Scale-Revised for patients with speech and language abnormalities, and neurological soft signs with specific regard to subtle motor impairment. RESULTS: Subjects with early-onset psychosis had a higher rate of impaired social development (P=0.001), learning difficulties (P=0.04), enuresis (P=0.0008), a lower intelligence quotient (P<0.001), and subtle motor impairments (P=0.005) than control subjects. CONCLUSION: We suggest that neurodevelopment in early-onset psychosis is characterized by a global impairment of functional and adaptive skills that manifests from early childhood, rather than a delay or limitation in language and motor development. The current evidence is based on a small sample and should be investigated in larger samples in future research. PMID- 26229475 TI - Sudden loss of the deep brain stimulation effect with high impedance without macroscopic fracture: a case report and review of the published literature. AB - The number of deep brain stimulation (DBS) hardware complications has increased during the past decade. In cases of abnormally high lead impedance with no evidence of a macroscopic fracture, optimal treatment options have not yet been established. Here, we present the case of a 49-year-old woman with a 12-year history of Parkinson's disease who received bilateral subthalamic nucleus DBS in March 2006. The patient showed good control of parkinsonism until December 24, 2010, when she awoke with abrupt worsening of parkinsonian symptoms. At telemetric testing, lead impedances were found at >2,000 Omega in all four leads on the left side. Fracture of a lead or an extension wire was suspected. However, radiological screening and palpation revealed no macroscopic fracture. In June 2011, the implantable pulse generator (IPG) was changed under local anesthesia without any complications. Postoperatively, her parkinsonism immediately improved to the previous level, and the lead impedance readings by telemetry were also normalized. The disconnection of the neurostimulator connector block and the hybrid circuit board of the IPG was confirmed by destructive analysis. The present report illustrates that a staged approach that starts with simple IPG replacement can be an option for some cases of acute DBS effect loss with high impedance, when radiological findings are normal, thereby sparing the intact electrodes and extension wires. PMID- 26229477 TI - Paliperidone extended-release tablets in Chinese patients with schizophrenia: meta-analysis of randomized controlled trials. AB - BACKGROUND: Previous meta-analyses have compared paliperidone extended-release (ER) tablets with other antipsychotics, but none have involved Chinese patients or studies from People's Republic of China. Further, the results of these meta analyses may not be applicable to Chinese patients. In the present study, we evaluated the efficacy, safety, and acceptability of paliperidone ER compared with other second-generation antipsychotics (SGAs) for Chinese patients with schizophrenia. METHODS: Randomized controlled studies of paliperidone ER and other SGAs as oral monotherapy in the acute phase treatment of schizophrenia were retrieved from Medline, Embase, and the Cochrane Library (CENTRAL), as well as from Chinese databases including the China National Knowledge Infrastructure, Wanfang, and VIP Information/Chinese Scientific Journals Database. We pooled data on response rates, chance of withdrawal due to adverse events, probability of adverse events, and odds of withdrawal for any reason. RESULTS: Fifty randomized controlled trials were identified. The response rate for paliperidone ER was significantly higher than that of other pooled SGAs (risk ratio [RR] 0.83, 95% confidence interval [CI] 0.72-0.96) and ziprasidone (RR 0.57, 95% CI 0.39-0.82). Paliperidone ER significantly reduced the chance of withdrawal due to adverse events and the chance of any adverse events compared with other pooled SGAs (RR 0.32, 95% CI 0.17-0.58 and RR 0.88, 95% CI 0.79-0.97) and risperidone (RR 0.31, 95% CI 0.14-0.67 and RR 0.70, 95% CI 0.57-0.86). The incidence of extrapyramidal symptoms on paliperidone ER was comparable with other pooled SGAs (RR 0.94, 95% CI 0.66-1.35) and significantly lower than that of risperidone (RR 0.56, 0.41 0.77) but higher than that of olanzapine (RR 1.88, 95% CI 1.05-3.36). Paliperidone ER was superior to other pooled SGAs (RR 0.32, 95% CI 0.21-0.49 and RR 0.50, 95% CI 0.35-0.72) and olanzapine (RR 0.23, 95% CI 0.15-0.33 and RR 0.33, 95% CI 0.23-0.47) as far as weight gain and somnolence were concerned. Further, prolactin-related adverse events caused by paliperidone ER were comparable with other pooled SGAs (RR 1.30, 95% CI 0.73-2.33), but outnumbered those caused by olanzapine (RR 7.53, 95% CI 2.05-27.71). CONCLUSION: Paliperidone ER is efficacious, safe, and well accepted when compared with other pooled SGAs for the treatment of Chinese patients with schizophrenia. PMID- 26229476 TI - Altered blood oxygen level-dependent signal variability in chronic post-traumatic stress disorder during symptom provocation. AB - BACKGROUND: Recent research suggests that variability in brain signal provides important information about brain function in health and disease. However, it is unknown whether blood oxygen level-dependent (BOLD) signal variability is altered in post-traumatic stress disorder (PTSD). We aimed to identify the BOLD signal variability changes of PTSD patients during symptom provocation and compare the brain patterns of BOLD signal variability with those of brain activation. METHODS: Twelve PTSD patients and 14 age-matched controls, who all experienced a mining accident, underwent clinical assessment as well as fMRI scanning while viewing trauma-related and neutral pictures. BOLD signal variability and brain activation were respectively examined with standard deviation (SD) and general linear model analysis, and compared between the PTSD and control groups. Multiple regression analyses were conducted to explore the association between PTSD symptom severity and these two brain measures across all subjects as well as in the PTSD group. RESULTS: PTSD patients showed increased activation in the middle occipital gyrus compared with controls, and an inverse correlation was found between PTSD symptom severity and brain activation in the hippocampus and anterior cingulate cortex/medial prefrontal cortex. Brain variability analysis revealed increased SD in the insula, anterior cingulate cortex/medial prefrontal cortex, and vermis, and decreased SD in the parahippocapal gyrus, dorsolateral prefrontal cortex, somatosensory cortex, and striatum. Importantly, SD alterations in several regions were found in both traumatic and neutral conditions and were stratified by PTSD symptom severity. CONCLUSION: BOLD signal variability may be a reliable and sensitive biomarker of PTSD, and combining brain activation and brain variability analysis may provide complementary insight into the neural basis of this disorder. PMID- 26229478 TI - Transmural dispersion of repolarization and atrial electromechanical coupling: complementary indices for quantifying cardiac electrical heterogeneity in patients with conversion disorder. PMID- 26229479 TI - Treatment of degloving injury involving multiple fingers with combined abdominal superficial fascial flap, dorsalis pedis flap, dorsal toe flap, and toe-web flap. AB - BACKGROUND: Our aim was to summarize the treatment of degloving injury involving multiple fingers using combined abdominal superficial fascial flap, dorsalis pedis flap, dorsal toe flap, and toe-web flap. PATIENTS AND METHODS: Each degloved finger was debrided under microscopic guidance and embedded in the superficial layer of the abdominal fascia. The abdominal skin was sutured to the skin on the back and side of the hand to promote circumferential healing. After removal, the only remaining injured region was on the flexor surface, and this was repaired by multiple dorsal toe flaps, toe-web flaps, and dorsalis pedis flaps to provide blood vessels and sensory nerves. All fingers had proper flap thickness 3-6 months after surgery, and required only lateral Z-plasty modification with web deepening and widening to narrow the fingers and extend their relative length. RESULTS: We completed flap-graft and finger narrowing for 25 fingers in eight patients. Abdominal skin flaps and dorsal toe flaps were grafted, and resulted in both firmness and softness, providing finger flexibility. The dorsal toe flap provided good blood circulation and sensory nerves, and was used to cover the finger-flexor surface to regain sensation and stability when holding objects. During the 1-8 years of follow-up, sensation on the finger-flexor side recovered to the S3-4 level, and patient satisfaction based on the Michigan Hand Outcomes Questionnaire was 4-5. Flap ulcers or bone/tendon necrosis were not observed. CONCLUSION: Treatment of degloving injury involving multiple fingers with combined abdominal superficial fascial flap, dorsalis pedis flap, dorsal toe flap, and toe-web flap was effective and reliable. PMID- 26229480 TI - Hypoglycemia hospitalization frequency in patients with type 2 diabetes mellitus: a comparison of dipeptidyl peptidase 4 inhibitors and insulin secretagogues using the French health insurance database. AB - AIM: We aimed to compare the frequency of severe hypoglycemia leading to hospitalization (HH) and emergency visits (EV) for any cause in patients with type 2 diabetes mellitus exposed to dipeptidyl peptidase 4 (DPP4) inhibitors (DPP4-i) versus those exposed to insulin secretagogues (IS; sulfonylureas or glinides). METHODS: Data were extracted from the EGB (Echantillon Generaliste des Beneficiaires) database, comprising a representative sample of ~1% of patients registered in the French National Health Insurance System (~600,000 patients). Type 2 diabetes mellitus patients exposed to regimens containing either a DPP4-i (excluding treatment with IS, insulin, or glucagon-like peptide 1 analog) or IS (excluding treatment with insulin and any incretin therapy) between 2009 and 2012 were selected. HH and EV during the exposure periods were identified in both cohorts. A similar analysis was conducted considering vildagliptin alone versus IS. Comparative analyses adjusting for covariates within the model (subjects matched for key characteristics) and using multinomial regression models were performed. RESULTS: Overall, 7,152 patients exposed to any DPP4-i and 1,440 patients exposed to vildagliptin were compared to 10,019 patients exposed to IS. Eight patients (0.11%) from the DPP4-i cohort and none from the vildagliptin cohort (0.0%) were hospitalized for hypoglycemia versus 130 patients (1.30%) from the IS cohort (138 hospitalizations) (P=0.02 and P<0.0001, respectively). Crude rates of HH/1,000 patient-years were 1.4 (95% CI: 0.7; 2.4) in the DPP4-i cohort, 0.0 in the vildagliptin cohort (95% CI: 0.0; 4.0), versus 5.6 (95% CI, 4.7; 6.6) in the IS cohort (P<0.0001). After adjustments, rates per 1,000 patient-years of HH were 1.4 (95% CI: 0.7; 2.4) with DPP4-i versus 7.5 (95% CI: 6.0; 9.2) with IS (P<0.0001), and 0.0 (95% CI: 0.0; 4.0) with vildagliptin versus 13.6 (95% CI: 10.4; 17.5) with IS (P<0.0001). Adjusted EV rates were also significantly lower with all DPP4-i or with vildagliptin, as compared to IS (P<0.0001). Consistent results were found when considering only treatment initiations for all compared cohorts. CONCLUSION: HH and EV were significantly less frequent in patients exposed to any DPP4-i or to vildagliptin versus IS. These real-life data should be considered in the benefit/risk evaluation of the drugs. PMID- 26229481 TI - The eXtraordinarY Kids Clinic: an interdisciplinary model of care for children and adolescents with sex chromosome aneuploidy. AB - PURPOSE: Individuals with sex chromosome aneuploidies (SCAs) are born with an atypical number of X and/or Y chromosomes, and present with a range of medical, developmental, educational, behavioral, and psychological concerns. Rates of SCA diagnoses in infants and children are increasing, and there is a need for specialized interdisciplinary care to address associated risks. The eXtraordinarY Kids Clinic was established to provide comprehensive and experienced care for children and adolescents with SCA, with an interdisciplinary team composed of developmental-behavioral pediatrics, endocrinology, genetic counseling, child psychology, pediatric neuropsychology, speech-language pathology, occupational therapy, nursing, and social work. The clinic model includes an interdisciplinary approach to care, where assessment results by each discipline are integrated to develop unified diagnostic impressions and treatment plans individualized for each patient. Additional objectives of the eXtraordinarY Kids Clinic program include prenatal genetic counseling, research, education, family support, and advocacy. METHODS: Satisfaction surveys were distributed to 496 patients, and responses were received from 168 unique patients. RESULTS: Satisfaction with the overall clinic visit was ranked as "very satisfied" in 85%, and as "satisfied" in another 9.8%. Results further demonstrate specific benefits from the clinic experience, the importance of a knowledgeable clinic coordinator, and support the need for similar clinics across the country. Three case examples of the interdisciplinary approach to assessment and treatment are included. PMID- 26229482 TI - Comparison of dynamic contrast-enhanced magnetic resonance imaging with T2 weighted imaging for preoperative staging of early endometrial carcinoma. AB - PURPOSE: This study aimed to compare dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with T2-weighted imaging (T2WI) for the preoperative staging of early endometrial carcinoma. METHODS: This retrospective study included 22 subjects with early endometrial carcinoma who underwent 3.0 T MRI examination prior to hysterectomy. DCE-MRI and T2WI were evaluated for the preoperative staging of endometrial carcinoma. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of DCE-MRI and T2WI were assessed and compared using the revised International Federation of Gynecology and Obstetrics surgical staging guidelines (2009) as the reference standard. RESULTS: Out of the 22 cases of endometrial carcinoma, the use of the reference standard method led to the staging of 14 as IA and eight as IB. The sensitivity, specificity, PPV, NPV, and accuracy of DCE-MRI for preoperative staging were 100% (95% confidence interval: 0.73-1.0), 62.5% (95% CI: 0.26-0.90), 82.4% (95% CI: 0.56-0.95), 100% (95% CI: 0.46-1.0), and 86.4%, respectively, and these values were 85.7% (95% CI: 0.56-0.97), 75% (95% CI: 0.36-0.96), 85.7% (95% CI: 0.56-0.97), 75% (95% CI: 0.36-0.96), and 81.8%, respectively, for T2WI. Thus, the sensitivity and accuracy of DCE-MRI were greater than those of T2WI for preoperative endometrial carcinoma staging. CONCLUSION: DCE-MRI was more sensitive but less specific than T2WI for the preoperative staging of early endometrial carcinoma. DCE-MRI may serve as a useful and reliable tool for the preoperative assessment of endometrial carcinoma. PMID- 26229483 TI - IL-2 -330T/G polymorphism and cancer risk: a meta-analysis. AB - PURPOSE: Some studies have investigated the association of IL-2 -330T/G (rs2069762) polymorphism with cancer risk, but the previous results were conflicting and had relatively low statistical power. Thus, we performed a meta analysis to derive a more precise estimation of the association between IL-2 330T/G polymorphism and cancer risk. METHODS: A literature search was performed systematically using electronic databases. The odds ratio (OR) with 95% confidence interval (CI) was used to estimate the pooled effect. RESULTS: A total of ten studies including 3,060 cases and 3,435 controls were involved in this meta-analysis. The results indicated that IL-2 -330T/G polymorphism was significantly associated with cancer risk ([OR =2.03, 95% CI =1.40-2.95] for GG vs TT; [OR =1.37, 95% CI =1.11-1.69] for GT vs TT; [OR =1.46, 95% CI =1.18-1.81] for [GG + GT] vs TT; [OR =1.66, 95% CI =1.24-2.23] for GG vs [GT + TT]; and [OR =1.35, 95% CI =1.16-1.57] for G vs T). In the subgroup analysis according to cancer type, significant association was found in lymphoma ([OR =1.46, 95% CI =1.11-1.91] for GT vs TT; [OR =1.58, 95% CI =1.22-2.05] for [GG + GT] vs TT; [OR =1.84, 95% CI =1.22-2.77] for GG vs [GT + TT]) and other cancers, but not in gastric cancer. In the subgroup analysis by ethnicity, the significant risk was found among Asians, but not among Europeans. CONCLUSION: This meta-analysis suggests that IL-2 -330T/G polymorphism has an increased risk of cancer in Asians. However, further detailed studies are still required to confirm our findings. PMID- 26229486 TI - MTA1 promotes proliferation and invasion in human gastric cancer cells. AB - Although metastasis-associated protein 1 (MTA1) has been widely linked to tumor metastasis, the relevant mechanisms remain to be elucidated, especially in gastric cancer. The aim of this study was to examine whether the MTA1 gene is associated with the process of proliferation and invasion by regulating several molecular targets in gastric cancer. MTA1 expression in 61 gastric cancer tissue and adjacent noncancerous tissues was analyzed by immunohistochemistry. The prognostic value of MTA1 for overall survival and disease-free survival was determined by Kaplan-Meier estimates, and the significance of differences between curves was evaluated by the log-rank test. Furthermore, overexpression of MTA1 in SGC7901 and BGC823 cells promoted cell cycle progression, cell adhesion, and cell invasion. Our study found that MTA1 is overexpressed in gastric cancers, which contributes to malignant cell growth by facilitating cell cycle progression through upregulation of cyclin D1 and accelerates the migration and invasion of human gastric cancer cells by regulating expression of fibronectin and MMP2/MMP9. Taken together, MTA1 was involved in the pathogenesis of gastric cancer and might be a candidate therapeutic target in gastric cancer. PMID- 26229484 TI - Volasertib for AML: clinical use and patient consideration. AB - Acute myeloid leukemia (AML) is a disease diagnosed mostly in patients >65 years of age. Despite its heterogeneous nature, the different types of AMLs are still managed by standard induction chemotherapy for those who can tolerate it in the beginning. For the elderly and infirm patients, however, this approach leads to unacceptably high induction mortality rate. This article reviews past and current efforts searching for low-intensiveness treatments for the elderly and infirm patients who cannot tolerate the standard induction regimen. Volasertib, currently in Phase III clinical trials in combination with cytarabine, is reviewed as a promising agent for this patient population with AML, from the viewpoints of potential compliance and efficacy. PMID- 26229485 TI - miR-32 functions as a tumor suppressor and directly targets SOX9 in human non small cell lung cancer. AB - PURPOSE: MicroRNA-32 (miR-32) is dysregulated in certain human malignancies and correlates with tumor progression. However, its expression and function in non small cell lung cancer (NSCLC) remain unclear. Thus, the aim of this study was to explore the effects of miR-32 expression on NSCLC tumorigenesis and development. METHODS: Using real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR), we detected miR-32 expression in NSCLC cell lines and primary tumor tissues. The association of miR-32 expression with clinicopathological factors and prognosis was also analyzed. Then, the effects of miR-32 expression on the biological behavior of NSCLC cells were investigated. Finally, the potential regulatory effect of miR-32 on SOX9 expression was confirmed. RESULTS: miR-32 expression levels were significantly downregulated in NSCLC compared with the corresponding noncancerous lung tissues (P<0.001). In addition, decreased miR 32 expression was significantly associated with lymph node metastasis (P=0.002), advanced tumor/nodes/metastasis (TNM) classification stages (P<0.001), and shorter overall survival (P<0.001). Multivariate regression analysis corroborated that downregulated miR-32 expression was an independent unfavorable prognostic factor for NSCLC patients. In vitro studies demonstrated that miR-32 overexpression reduced A549 cell proliferation, migration, and invasion, and promoted apoptosis. Furthermore, SOX9 was confirmed as a direct target of miR-32, using a luciferase reporter assay. CONCLUSION: These findings indicate that miR 32 may act as a tumor suppressor in NSCLC and could serve as a novel therapeutic agent for miR-based therapy. PMID- 26229487 TI - Identification of the key genes connected with plasma cells of multiple myeloma using expression profiles. AB - OBJECTIVE: To uncover the potential regulatory mechanisms of the relevant genes that contribute to the prognosis and prevention of multiple myeloma (MM). METHODS: Microarray data (GSE13591) were downloaded, including five plasma cell samples from normal donors and 133 plasma cell samples from MM patients. Differentially expressed genes (DEGs) were identified by Student's t-test. Functional enrichment analysis was performed for DEGs using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Transcription factors and tumor-associated genes were also explored by mapping genes in the TRANSFAC, the tumor suppressor gene (TSGene), and tumor-associated gene (TAG) databases. A protein-protein interaction (PPI) network and PPI subnetworks were constructed by Cytoscape software using the Search Tool for the Retrieval of Interacting Genes (STRING) database. RESULTS: A total of 63 DEGs (42 downregulated, 21 upregulated) were identified. Functional enrichment analysis showed that HLA-DRB1 and VCAM1 might be involved in the positive regulation of immune system processes, and HLA-DRB1 might be related to the intestinal immune network for IgA production pathway. The genes CEBPD, JUND, and ATF3 were identified as transcription factors. The top ten nodal genes in the PPI network were revealed including HLA-DRB1, VCAM1, and TFRC. In addition, genes in the PPI subnetwork, such as HLA-DRB1 and VCAM1, were enriched in the cell adhesion molecules pathway, whereas CD4 and TFRC were both enriched in the hematopoietic cell pathway. CONCLUSION: Several crucial genes correlated to MM were identified, including CD4, HLA-DRB1, TFRC, and VCAM1, which might exert their roles in MM progression via immune-mediated pathways. There might be certain regulatory correlations between HLA-DRB1, CD4, and TFRC. PMID- 26229488 TI - Upregulation of nucleostemin in colorectal cancer and its effects on cell malignancy. AB - OBJECTIVE: Nucleostemin (NS) is a new protein localized in the nucleolus of most stem cells and tumor cells, which regulates their self-renewal and cell cycle progression. The aim of this study was to investigate the expression of NS in colorectal cancer (CRC) and the effects of NS knockdown in the Sw620 cell line to provide basis for clinical target therapy. METHODS: NS expression in 372 patients with CRC and 367 normal participants was assessed using immunohistochemistry. The expression level of NS gene was evaluated by polymerase chain reaction. Then, the relationship among NS expression, clinicopathological features, and prognosis was analyzed. Silencing of NS expression was achieved by using NS-specific small interfering RNAs. The viability and growth rate of Sw620 cells were determined by proliferation and invasion assays. Cell cycle distribution of the cells was analyzed by flow cytometry. RESULTS: High NS expression was positively related with node metastasis, distant metastasis, and TNM stage. In Kaplan-Meier survival analysis, patients with low NS expression always had significantly longer survival time than those with high expression. Moreover, our results showed that knockdown of NS expression inhibited proliferation and viability of Sw620 cells in a time-dependent manner. Cell cycle studies revealed that NS depletion resulted in G1 cell cycle arrest at short times of transfection (24 hours), followed with apoptosis at longer times (48 hours and 72 hours), suggesting that post-G1 arrest apoptosis occurred in Sw620 cells. CONCLUSION: Overall, these results point to the essential role of NS in Sw620 cells; thus, this gene might be considered a promising target for treatment of CRC. PMID- 26229489 TI - Diffuse anterior retinoblastoma: current concepts. AB - Diffuse anterior retinoblastoma is a rare variant of retinoblastoma seeding in the area of the vitreous base and anterior chamber. Patients with diffuse anterior retinoblastoma are older than those with the classical types, with the mean age being 6.1 years. The original cells of diffuse anterior retinoblastoma are supposed to be cone precursor. Patients most commonly present with pseudouveitis, pseudohypopyon, and increased intraocular pressure. The retina under fundus examination is likely to be normal, and the clinical features mimic the inflammation progress, which can often lead to misdiagnosis. The published diffuse anterior retinoblastoma cases were diagnosed after fine-needle aspiration biopsy running the potential risk of inducing metastasis. The most common treatment for diffuse anterior retinoblastoma is enucleation followed by systematic chemotherapy according to the patient's presentation and clinical course. This review summarizes the recent advances in etiology (including tumorigenesis and cell origin), pathology, diagnosis, differential diagnosis, and new treatment. The challenges of early diagnosis and prospects are also discussed. PMID- 26229490 TI - Expression of PD-1 by CD4(+)CD25(+)CD127(low) Treg cells in the peripheral blood of lung cancer patients. PMID- 26229491 TI - Association between GSTP1 polymorphisms and prognosis of osteosarcoma in patients treated with chemotherapy: a meta-analysis. AB - OBJECTIVE: The aim of this study was to evaluate the relationship between GSTP1 polymorphisms and prognosis of osteosarcoma in patients treated with chemotherapy, by performing a meta-analysis. METHODS: The studies of effects of GSTP1 gene polymorphisms on osteosarcoma survival after chemotherapy were collected. STATA (version 12.0) was used to perform data synthesis. RESULTS: Six studies involving 898 participants were included. A meta-analysis was performed on studies in GSTP1 313A>G(rs1695) assessing the association between tumor response and the polymorphisms in GSTP1 (AA vs AG, AA vs GG), the pooled odds ratios (ORs) were 2.06 (95% confidence interval [CI]: 1.48-2.86, P=0.628, I (2)=0.0%). There was significant association between the polymorphisms in GSTP1 (AA vs AG, AA vs GG) and the events that happened, the pooled ORs were 1.86 (95% CI: 1.14-3.06, P=0.034, I (2)=58.6%), and there was significant association between the polymorphisms in GSTP1 (AA vs AG, AA vs GG) and survival times (overall survival and progression-free survival) in osteosarcoma patients treated with chemotherapy, and the pooled ORs were 2.14 (95% CI: 1.51-3.04, P=0.675, I (2)=0.0%) and 2.77 (95% CI: 1.56-4.91, P=0.347, I (2)=9.3%), respectively. Two studies assessed the association of polymorphisms in GSTP1 I105V (IIe/IIe vs IIe/Val, IIe/IIe vs Val/Val) with overall survival in human osteosarcoma. The pooled ORs were 1.20 (95% CI: 0.64-2.27, P=0.010, I (2)=73.5%). The study showed an insignificant difference in overall survival for the polymorphisms in GSTP1 (IIe/IIe vs IIe/Val, IIe/IIe vs Val/Val). CONCLUSION: This meta-analysis indicated that GSTP1 polymorphisms might influence osteosarcoma risk and suggests that GSTP1 polymorphisms may be an important risk factor for osteosarcoma. PMID- 26229492 TI - Expression of ARs in triple negative breast cancer tumors: a potential prognostic factor? AB - BACKGROUND/AIM: In light of the controversial published literature, this study aims to examine the potential prognostic role of AR immunohistochemical expression in triple negative breast cancer (TNBC). PATIENTS AND METHODS: Ninety patients with TNBC were included in this study; the associations between AR expression (Allred score), clinicopathological variables (stage, grade, histological subtype, tumor size, nodal status, age at diagnosis, Ki67 expression, and p53 expression), and overall survival were evaluated. RESULTS: AR expression was not associated with stage, grade, histological subtype, tumor size, nodal status, age at diagnosis, Ki67 expression, and p53 expression. AR immunopositivity was not associated with overall survival either at the univariate or at the multivariate Cox regression analysis (multivariate hazard ratio =0.66, 95% confidence interval: 0.26-1.70, P=0.393). CONCLUSION: AR expression does not seem to play a prognostic role in TNBC. PMID- 26229494 TI - Retrospective analysis of drug utilization, health care resource use, and costs associated with IFN therapy for adjuvant treatment of malignant melanoma. AB - BACKGROUND: This study examines real-world drug utilization patterns, health care resource use, and costs among patients receiving adjuvant treatment with IFN versus patients receiving no treatment ("observation") for malignant melanoma following surgery. METHODS: A retrospective cohort study was conducted using administrative claims from Truven Health Analytics (MarketScan((r))) to identify all adjuvant melanoma patients (aged >=18 years) diagnosed between June 2007 and June 2011 who had a lymph node dissection (ie, index surgery) and were treated with IFN or subsequently observed. Health care resource use and costs of services were converted to 2012 US dollars and were evaluated and compared using multivariable regression. RESULTS: Of 1,999 eligible subjects with melanoma surgery claims, 179 (9.0%) were treated with IFN and 1,820 (91.0%) were observed. The median duration (days) and number of doses of IFN therapy were 73 and 36, respectively. Among IFN-treated patients, only 10.6% completed >=80% of maintenance therapy. The total average cost for patients treated with IFN was US$60,755+/-$3,972 (n=179); significantly higher than for patients undergoing observation ($31,641+/-$2,471; P<0.0001). Similar trends were observed when evaluating total cost components, including melanoma-related and non-melanoma related medical costs. Among the melanoma-related medical costs, outpatient services, including office visits and laboratory testing, represented between 33% and 53% of total costs and demonstrated the largest difference between IFN treated and observation patients. Outpatient service costs for IFN-treated patients were $32,414+/-$2,498, over three times greater than those for observation patients ($10,556+/-$1,128; P<0.0001). CONCLUSION: The majority of adjuvant melanoma patients in this study was treated with observation versus IFN treatment. Among those who attempted IFN treatment, most could not complete the recommended course of therapy. Health care costs were significantly greater for patients treated with IFN, with the greatest differences being for melanoma related medical cost components. These findings illustrate the significant economic burden borne by adjuvant melanoma patients and their health insurers. PMID- 26229493 TI - Stinging insect allergy: current perspectives on venom immunotherapy. AB - Systemic allergic reactions to insect stings affect up to 5% of the population during their lifetime, and up to 32% of beekeepers. Such reactions can be fatal, albeit very rarely, and fear of a further systemic reaction (SR) can lead to significant anxiety and quality of life impairment. A recent Cochrane systematic review confirmed that venom immunotherapy (VIT) is an effective treatment for people who have had a systemic allergic reaction to an insect sting. VIT reduces risk of a further SR (relative risk 0.10, 95% confidence interval 0.03-0.28), but VIT also reduces risk of a future large local reaction, and significantly improves disease-specific quality of life. However, health economic analysis showed that VIT is generally not cost effective for preventing future SRs; most people are stung infrequently, most SRs resolve without long-term consequences, and a fatal outcome is extremely rare. VIT only becomes cost effective if one is stung frequently (eg, beekeepers) or if quality of life improvement is considered. Thus, for most people with insect sting allergy, anxiety and quality of life impairment should be the overriding consideration when making treatment decisions, highlighting the importance of a patient-centered approach. Areas which need to be explored in future research include efforts to improve the safety and convenience of VIT such as the use of sublingual immunotherapy; quality of life effects of venom allergy in children and adolescents as well as their parents; and the optimal duration of treatment. PMID- 26229495 TI - Health and economic outcomes associated with uncontrolled surgical bleeding: a retrospective analysis of the Premier Perspectives Database. AB - BACKGROUND: Bleeding remains a common occurrence in surgery. Data describing the burden of difficult-to-control bleeding and topical absorbable hemostat use are sparse. This study was conducted to estimate the clinical and economic impact that remains associated with uncontrolled surgical bleeding, even when hemostats are used during surgery. METHODS: This US retrospective analysis used the Premier Perspectives Database. Hospital discharges from 2012 were used to identify patients treated with hemostats during eight surgery types. Patients were included if they were >=18 years, had an inpatient hospitalization with one of the eight surgeries, and received a hemostat on the day of surgery. Patients were stratified by procedure and presence or absence of major bleeding (uncontrolled) despite hemostat use. Outcomes were all-cause hospitalization costs, hemostat costs, length of stay, reoperation, and surgery-related complications (eg, mortality). Statistical significance was tested through chi-square or t-tests. Multivariate analyses were conducted for all-cause costs and length of stay using analysis of covariance. RESULTS: Among 25,048 procedures, major bleeding events occurred in 14,251 cases. Despite treatment with hemostats, major bleeding occurred in 32%-68% of cases. All-cause costs were significantly higher in patients with uncontrolled bleeding despite hemostat use versus controlled bleeding (US$24,203-$61,323 [uncontrolled], US$14,420-$45,593 [controlled]; P<0.001). Hemostat costs were significantly greater in the uncontrolled bleeding cohort for all surgery types except cystectomy and pancreatic surgery. Reoperation and mortality rates were significantly higher in the uncontrolled bleeding cohort in all surgical procedures except cystectomy and radical hysterectomy. CONCLUSION: Uncontrolled intraoperative bleeding despite hemostat use is prevalent and associated with significantly higher hospital costs and worse clinical outcomes across several surgical procedures compared to controlled bleeding. There is an unmet need for newer hemostats that can more effectively control bleeding, improve outcomes, and reduce hospital resource use. PMID- 26229496 TI - Type 2 diabetes mellitus development programs in the new regulatory environment with cardiovascular safety requirements. AB - For type 2 diabetes mellitus treatment and clinical development, proper evaluation of cardiovascular risk has been required by regulatory agencies (eg, the US Food and Drug Administration) since cardiovascular safety is very important in this patient population. The US Food and Drug Administration issued general guidelines for cardiovascular safety evaluation that outlined the requirements considered adequate for cardiovascular safety evaluation. However, there are multiple options to obtain the data and fulfill these requirements. In this paper, we outline the potential pathways and challenges in various aspects of cardiovascular safety evaluation in type 2 diabetes clinical development, including study design, populations, and endpoints. Specifically, we discuss some challenges in statistical analysis which have implications for the design, implementation, and interpretation of these outcome studies. PMID- 26229497 TI - The humanistic and economic burden associated with increasing body mass index in the EU5. AB - OBJECTIVES: This study evaluated the association of body mass index (BMI) with health-related quality of life (HRQoL), health utilities, health care resource utilization, productivity, activity impairment, and the associated costs. METHODS: Results were from the 2013 EU5 (France, Germany, Italy, Spain, UK) National Health and Wellness Survey, a nationally representative, online survey of respondents aged >=18 years. Analyses focused on normal weight (BMI >=18.5 kg/m(2) and BMI <25 kg/m(2)), overweight (BMI >=25 kg/m(2) and BMI <30 kg/m(2)), Obese Class (OC) I (BMI >=30 kg/m(2) and BMI <35 kg/m(2)), OC II (BMI >=35 kg/m(2) and BMI <40 kg/m(2)), and OC III (BMI >=40 kg/m(2)) respondents. Outcomes included HRQoL (Short Form [SF]-36v2), health utilities (SF-six dimension [6D]), productivity loss (Work Productivity and Activity Impairment questionnaire), and resource utilization (provider visits, emergency room visits, and hospitalizations) in the past 6 months. Direct and indirect costs were estimated from the literature. Generalized linear regression models predicted outcomes as a function of BMI, adjusting for covariates (age, sex, comorbidities). RESULTS: Among 58,364 respondents, 46.9% were normal weight, 34.5% were overweight, 12.5% were OC I, 4.0% were OC II, and 2.1% were OC III. Metabolic comorbidities increased as BMI increased. After adjustments, all three OC respondents exhibited significantly lower HRQoL than normal weight respondents. Health utilities (normal weight: 0.720; overweight: 0.718; OC I: 0.703; OC II: 0.683; OC III: 0.662) declined with an increase in BMI (all P<0.05 vs normal). Among employed respondents (57.7%), overall work impairment increased as BMI increased. Normal (vs all OCs) had lower activity impairment and fewer provider visits, lower indirect costs (normal weight: ?7,974; overweight: ?7,825; OC I: ?8,465; OC II: ?9,394; OC III: ?10,437), and lower total direct costs (normal weight: ?516; overweight: ?553; OC I: ?583; OC II: ?605; OC III: ?717), all P<0.05. CONCLUSION: Increased BMI was associated with worse HRQoL, greater comorbidities, higher direct and indirect costs, and worse health utilities. Weight management may improve patient outcomes. PMID- 26229498 TI - Highly efficient and compatible shampoo for use after hair transplant. AB - BACKGROUND: Sensitive or hyperreactive skin is a common condition defined by prickling, burning, pain, and pruritus. Although this skin problem was initially described on the face, the scalp is often affected. A sensitive scalp can react with irritation to harsh surfactants or other additives which are often present in shampoos. For this reason, we developed a new rinse-off hypertolerant shampoo specifically designed for the hypersensitive and problematic scalp. METHODS: The shampoo formulation is based on an extremely mild surfactant system and contains bisabolol, an anti-irritant and anti-inflammatory ingredient of chamomile. The shampoo is free of additives such as perfumes, silicones, colorants, parabens, paraffins, and betaine. Since skin can remain in a hyperreactive state after wounding, the status after hair transplantation was chosen as a model system to test the shampoo. Scalp condition and compatibility of each volunteer were analyzed by a plastic surgeon directly after hair transplant and after stitch removal. The plastic surgeons also rated whether they would recommend the further use of the test shampoo. Additionally, volunteers completed a self-assessment questionnaire. RESULTS: Following hair transplantation, regular use of the shampoo resulted in a significant reduction in the extent of scabbing and erythema. This was confirmed by dermatological scalp examinations performed by the plastic surgeon as well as in volunteers' self-assessments. The plastic surgeon highly recommended the further use of the test shampoo after hair transplant to all study participants. CONCLUSION: Application of the test shampoo demonstrated excellent skin compatibility and product efficacy after hair transplant. The test shampoo significantly reduced the extent of scabs and erythema. Therefore, the shampoo is ideally suited for use after hair transplantation and for the treatment of sensitive scalp. The excellent skin compatibility is because of the mild surfactant system, the calming ingredient bisabolol, and the absence of potentially irritating ingredients. PMID- 26229499 TI - Impact of switching from mycophenolate mofetil to enteric-coated mycophenolate sodium on gastrointestinal side effects in patients with autoimmune disease: a Phase III, open-label, single-arm, multicenter study. AB - BACKGROUND: The purpose of this study was to assess changes in gastrointestinal symptom severity in patients with autoimmune disease who were switched from mycophenolate mofetil to enteric-coated mycophenolate sodium (EC-MPS). METHODS: In this national, explorative, single-arm study, 111 patients were enrolled and switched to equimolar EC-MPS at baseline. The primary endpoint was change in the Gastrointestinal Symptom Rating Scale (GSRS) total score after 6-8 weeks of treatment (Visit 2). The optional follow-up visit was 6-12 weeks after completion of the study (Visit 2). Secondary endpoints were changes in GSRS subscale score; changes in gastrointestinal-related quality of life measured by the Gastrointestinal Quality of Life Index (GIQLI); and general health-related quality of life (HRQoL) measured by Psychological General Well-Being Index and assessment of overall treatment effect (OTE). Change was evaluated by paired t tests. RESULTS: At Visit 2, the mean +/- standard deviation GSRS total score improved from 2.28+/-1.13 to 2.02+/-0.93 points. The change (-0.28+/-0.92 points, P=0.002) was statistically significant. The change at the follow-up visit ( 0.36+/-0.94 points, P=0.001) was statistically significant and more than the minimal clinical important difference. GSRS subscores showed statistically significant and clinically relevant improvement for abdominal pain (-0.51+/-1.2 points, P<0.001) and indigestion (-0.42+/-1.33 points, P=0.002). Overall GIQLI score showed significant improvement from baseline to Visit 2 (-5.8+/-18.6 points, P=0.002). Per OTE, improvement was reported in 44.1% and 34.2% patients as rated by physicians and patients, respectively. The majority of patients (55%) reported OTE-HRQoL as unchanged. Diarrhea and nausea were the commonly reported adverse events. CONCLUSION: Patients switched to EC-MPS experienced less gastrointestinal symptom burden and showed improvement in HRQoL. PMID- 26229500 TI - Alstrom syndrome: current perspectives. AB - Alstrom syndrome (ALMS) is a rare genetic disorder that has been included in the ciliopathies group, in the last few years. Ciliopathies are a growing group of diseases associated with defects in ciliary structure and function. The development of more powerful genetic approaches has been replaced the strategies to follow for getting a successful molecular diagnosis for these patients, especially for those without the typical ALMS phenotype. In an effort to deepen the understanding of the pathogenesis of ALMS disease, much work has been done, in order to establish the biological implication of ALMS1 protein, which is still being elucidated. In addition to its role in ciliary function and structure maintenance, this protein has been implicated in intracellular trafficking, regulation of cilia signaling pathways, and cellular differentiation, among others. All these progresses will lead to identifying therapeutic targets, thus opening the way to future personalized therapies for human ciliopathies. PMID- 26229501 TI - In silico ordinary differential equation/partial differential equation hemodialysis model estimates methadone removal during dialysis. AB - BACKGROUND: There is a need to have a model to study methadone's losses during hemodialysis to provide informed methadone dose recommendations for the practitioner. AIM: To build a one-dimensional (1-D), hollow-fiber geometry, ordinary differential equation (ODE) and partial differential equation (PDE) countercurrent hemodialyzer model (ODE/PDE model). METHODOLOGY: We conducted a cross-sectional study in silico that evaluated eleven hemodialysis patients. Patients received a ceiling dose of methadone hydrochloride 30 mg/day. Outcome measures included: the total amount of methadone removed during dialysis; methadone's overall intradialytic mass transfer rate coefficient, km ; and, methadone's removal rate, j ME. Each metric was measured at dialysate flow rates of 250 mL/min and 800 mL/min. RESULTS: The ODE/PDE model revealed a significant increase in the change of methadone's mass transfer with increased dialysate flow rate, %Deltakm =18.56, P=0.02, N=11. The total amount of methadone mass transferred across the dialyzer membrane with high dialysate flow rate significantly increased (0.042+/-0.016 versus 0.052+/-0.019 mg/kg, P=0.02, N=11). This was accompanied by a small significant increase in methadone's mass transfer rate (0.113+/-0.002 versus 0.014+/-0.002 mg/kg/h, P=0.02, N=11). The ODE/PDE model accurately predicted methadone's removal during dialysis. The absolute value of the prediction errors for methadone's extraction and throughput were less than 2%. CONCLUSION: ODE/PDE modeling of methadone's hemodialysis is a new approach to study methadone's removal, in particular, and opioid removal, in general, in patients with end-stage renal disease on hemodialysis. ODE/PDE modeling accurately quantified the fundamental phenomena of methadone's mass transfer during hemodialysis. This methodology may lead to development of optimally designed intradialytic opioid treatment protocols, and allow dynamic monitoring of outflow plasma opioid concentrations for model predictive control during dialysis in humans. PMID- 26229502 TI - The influence of repeated pain stimulation on the emotional aspect of pain: a preliminary study in healthy volunteers. AB - PURPOSE: Pain is a multidimensional experience with sensory-discriminative, cognitive-evaluative, and affective-motivational components. Emotional factors, such as unpleasantness or anxiety, are known to have influence on pain in humans. Repeated painful stimulation has been reported to reduce subjective pain intensity. Nevertheless, there is little evidence of the influence of such stimulation on the emotional factors of pain. The aim of this study was to evaluate the influence of repeated painful stimulation on the experience of unpleasantness and anxiety. MATERIALS AND METHODS: Eight subjects (six females, two males) volunteered to participate in this study. Subjects received repeated painful stimulation for 3 consecutive days each instance lasting 6 seconds, 60 times per day, on the medial side of the forearm of the nondominant hand. We examined the following items to evaluate changes of responses to painful stimulation: pain thresholds, pain tolerance levels, pain intensities, unpleasantness, and anxiety. Furthermore, pain thresholds and pain tolerance levels were compared between different sites on the ipsilateral and contralateral forearms. RESULTS: No immediate or chronological changes in pain thresholds or pain tolerance levels were observed. Pain intensities were reduced significantly over the 3-day experimental period (P<0.05). On the other hand, there was no great change in unpleasantness during the 3-day period. Anxiety was increased significantly after the painful stimulation compared with that without the painful stimulation and before day 1 of the stimulation (P<0.05). CONCLUSION: These results suggest that repeated painful stimulation may result in habituation to pain intensities but not habituation to emotional factors. PMID- 26229503 TI - Optical imaging for breast cancer prescreening. AB - Breast cancer prescreening is carried out prior to the gold standard screening using X-ray mammography and/or ultrasound. Prescreening is typically carried out using clinical breast examination (CBE) or self-breast examinations (SBEs). Since CBE and SBE have high false-positive rates, there is a need for a low-cost, noninvasive, non-radiative, and portable imaging modality that can be used as a prescreening tool to complement CBE/SBE. This review focuses on the various hand held optical imaging devices that have been developed and applied toward early stage breast cancer detection or as a prescreening tool via phantom, in vivo, and breast cancer imaging studies. Apart from the various optical devices developed by different research groups, a wide-field fiber-free near-infrared optical scanner has been developed for transillumination-based breast imaging in our Optical Imaging Laboratory. Preliminary in vivo studies on normal breast tissues, with absorption-contrasted targets placed in the intramammary fold, detected targets as deep as 8.8 cm. Future work involves in vivo imaging studies on breast cancer subjects and comparison with the gold standard X-ray mammography approach. PMID- 26229504 TI - Prevalence of bone metastases and bone-targeting agent use among solid tumor patients in the United States. AB - PURPOSE: Patients with bone metastases are at an increased risk of experiencing morbidity due to bone complications, and bone-targeting agents (BTA) are indicated for the prevention of these complications. Population-based estimates of the prevalence of bone metastases associated with solid tumors, and current treatment patterns for these patients, are limited. This study was undertaken to estimate the prevalence of bone metastases from solid tumors and to describe recent trends in the use of BTA in the US. METHODS: We estimated the prevalence of bone metastases in the US in 2012 using data from Medicare fee-for-service and PharMetrics Plus, a large commercial claims database. We evaluated the proportion of patients with bone metastases who were treated with BTA in 2012, timing of initiation of BTA relative to bone metastasis diagnosis, and persistence on BTA, overall and by primary tumor type and treatment. RESULTS: There were ~330,000 (168,063 Medicare fee-for-service; 162,239 other) patients aged >=18 years living with solid tumors and bone metastases in 2012. BTA were used by 43% (Commercial) to 47% (Medicare) of patients in 2012, with the greatest use among breast cancer patients. Over half (Medicare: 57%; Commercial: 53%) of BTA-treated patients initiated BTA after experiencing a bone complication. CONCLUSION: Of the estimated 330,000 solid tumor patients living with bone metastases in the US in 2012, many may have received less than optimal care to prevent bone complications during the calendar year. PMID- 26229505 TI - Existing data sources for clinical epidemiology: the Danish Patient Compensation Association database. AB - Any patient in the Danish health care system who experiences a treatment injury can make a compensation claim to the Danish Patient Compensation Association (DPCA) free of charge. The aim of this paper is to describe the DPCA database as a source of data for epidemiological research. Data to DPCA are collected prospectively on all claims and include information on patient factors and health records, system factors, and administrative data. Approval of claims is based on injury due to the principle of treatment below experienced specialist standard or intolerable, unexpected extensiveness of injury. Average processing time of a compensation claim is 6-8 months. Data collection is nationwide and started in 1992. The patient's central registration system number, a unique personal identifier, allows for data linkage to other registries such as the Danish National Patient Registry. The DPCA data are accessible for research following data usage permission and make it possible to analyze all claims or specific subgroups to identify predictors, outcomes, etc. DPCA data have until now been used only in few studies but could be a useful data source in future studies of health care-related injuries. PMID- 26229506 TI - Drug utilization in selected health facilities of South West Shoa Zone, Oromia Region, Ethiopia. AB - BACKGROUND: Sustaining the availability and rational use of safe and effective drugs is a major problem in developing countries. Irrational drug use affects quality of health care more than accessibility of drugs. OBJECTIVE: To assess drug utilization in selected health facilities of South West Shoa Zone, Oromia Region, Ethiopia. METHODS: A cross-sectional study was conducted in selected health facilities of South West Shoa Zone from January 21-28, 2012 by using structured questionnaires. RESULTS: Of 50 prescribers and 30 dispensers, 58% and 83.3% were males, respectively. The result showed that majority of prescribers agreed on availability of essential drugs (72%) and had access to up-to-date drug information (76%). However, 43.3% of dispensers didn't get access to up-to-date drug information. 86% and 88% of prescribers note cost of drugs and stick to standard treatment guidelines of Ethiopia during prescription, respectively. All drug dispensers check the name of the drug (100%), age of the patient (90%), the dosage form of drug (96.7%), the route of administration (90%), the duration of therapy (86.7%), and frequency of administration (86.7%) for prescription papers. CONCLUSION: In general, drug utilization at the study sites was found to be good, although there are major deviations from the concept of rational drug use. PMID- 26229507 TI - Cardiovascular effects of hormone therapy for prostate cancer. AB - Androgen deprivation therapy (ADT) has been the mainstay of treatment for advanced prostate cancer for decades, and has been shown to control disease and improve symptoms. In addition, for men with high-risk localized or locally advanced prostate cancer, short-course ADT in combination with radiotherapy improves survival. There is evidence that ADT increases cardiovascular risk, particularly in men with preexisting cardiovascular disease. This increased risk may apply even with short-course ADT. In an individual patient, the benefits of ADT should be balanced against the risk, and patients who require ADT should have risk factors for cardiovascular disease optimized. There is some evidence to suggest that more contemporary methods of delivering ADT may reduce cardiovascular risk. PMID- 26229508 TI - Maternal ophthalmic artery Doppler velocimetry in pre-eclampsia in Southwestern Nigeria. AB - BACKGROUND: Pre-eclampsia (PE) poses a serious challenge to maternal and fetal health in Africa. It is associated with hemodynamic changes that may affect the internal carotid/ophthalmic artery circulation with consequent neuro-ophthalmic manifestations. Ophthalmic artery Doppler (OAD) ultrasound is an important tool that can be used to detect hemodynamic changes in PE and monitor its severity. In this study, we evaluated hemodynamic changes on OAD ultrasound in the ophthalmic arteries of pre-eclamptic women and compared these with values in healthy pregnant women. METHODS: OAD parameters, such as, peak systolic velocity, peak diastolic velocity, end diastolic velocity, pulsatility index, and peak ratio, were measured on transorbital triplex ultrasound scan with a 7-10 MHz multifrequency linear transducer in 42 consenting pre-eclamptic patients and 41 pregnant controls matched for maternal age, gestational age, and parity at the Department of Radiology, University College Hospital, Ibadan. Univariate, bivariate, and receiver operating characteristic curve data analyses were performed. P<0.05 was considered to be statistically significant. RESULTS: Mean resistivity index, pulsatility index, and peak systolic velocity were significantly lower in pre-eclamptic patients than in the controls. Mean peak diastolic velocity, end diastolic velocity, and peak ratio were significantly higher in the pre-eclamptic group. The receiver operating characteristic curve showed that the resistivity index (sensitivity 75%, specificity 77.8%) could distinguish mild from severe PE while the peak ratio (sensitivity 90.5%, specificity 81.3%) could accurately detect PE. CONCLUSION: OAD ultrasound can be used to monitor patients with PE for early detection of progression to severe forms before cerebral complications develop. OAD screening of patients at high risk for PE can also detect early changes of hemodynamic derangement. PMID- 26229510 TI - Acute macular edema following intracorporeal prostaglandin injection for erectile dysfunction. AB - PURPOSE: We aimed to describe the first case of macular edema following intracorporeal injection of alprostadil, a prostaglandin E1. METHODS: This was a retrospective case report followed with optical coherence tomography, fundus photos, and fluorescein angiography images. RESULTS: A patient developed bilateral cystoid macular edema following intracorporeal injection of alprostadil, a prostaglandin E1 for treatment of erectile dysfunction. The edema resolved following treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, with subsequent recovery in visual acuity. DISCUSSION: Systemic prostaglandin administration can cause macular edema and vision loss, indicating that elevated systemic prostaglandin levels may affect visual function. This has potential implications for other systemic disorders and treatments that could affect macular function. PMID- 26229511 TI - Cyanoacrylate tissue glue for wound repair in early posttrabeculectomy conjunctival bleb leak: a case series. AB - We demonstrated a noninvasive management of early bleb leak following trabeculectomy using cyanoacrylate tissue glue (CATG). Three patients who underwent augmented trabeculectomy with mitomycin C with early bleb leak between January 2009 and June 2010 were reviewed. Case 1 and Case 2 exhibited bleb leak on postoperative Day 1 and Case 3 showed leak on follow-up at postoperative Day 7. Case 1 was successfully sealed with CATG at postoperative Day 3, after failed pressure padding and bandage contact lens. Case 2 was successfully sealed with CATG at postoperative Day 3, after failed pressure padding and conjunctiva flap resuturing. In Case 3, the leaking conjunctival flap was managed with combined techniques of resuturing and applying CATG at postoperative Day 9, after failed pressure padding. During leakage, the intraocular pressure was low (6-8 mmHg) in all three cases, with shallow anterior chamber depth and absence of other complications such as choroidal detachment, hypotony maculopathy, or endophthalmitis. Foreign body sensation was the main complaint following the procedure. No clinical allergy reaction was documented. CATG may serve as a potential adjunctive and effective method in the management of posttrabeculectomy early bleb leak. PMID- 26229509 TI - From bladder to systemic syndrome: concept and treatment evolution of interstitial cystitis. AB - Interstitial cystitis, presently known as bladder pain syndrome, has been recognized for over a century but is still far from being understood. Its etiology is unknown and the syndrome probably harbors different diseases. Autoimmune dysfunction, urothelial leakage, infection, central and peripheral nervous system dysfunction, genetic disease, childhood trauma/abuse, and subsequent stress response system dysregulation might be implicated. Management is slowly evolving from a solo act by the end-organ specialist to a team approach based on new typing and phenotyping of the disease. However, oral and invasive treatments are still largely aimed at the bladder and are based on currently proposed pathophysiologic mechanisms. Future research will better define the disease, permitting individualization of treatment. PMID- 26229512 TI - Combination immunotherapy in the treatment of chronic bilateral panuveitis and uveitic glaucoma during acute dengue fever infection in the Caribbean. AB - BACKGROUND: Ocular manifestations of the dengue fever virus include bilateral panuveitis that can occur after the acute systemic infection has resolved. In most reported cases, the inflammation resolves with topical or systemic steroid therapy. We report a case of chronic, refractory bilateral panuveitis and uveitic glaucoma that began during the acute phase of the systemic infection and required treatment with oral steroids, multiple steroid-sparing agents, and surgical therapy for glaucoma. FINDINGS: A 22-year-old male with acute systemic dengue fever presented with bilateral pain and decreased vision. Clinical examination revealed bilateral panuveitis with elevated intraocular pressures. Management required oral steroids, mycophenolate mofetil, cyclosporine, and bilateral glaucoma valve implantation. CONCLUSION: This case highlights the fact that dengue-associated panuveitis can begin in the acute stage of systemic infection and persist long after convalescence with progression to chronic bilateral panuveitis and uveitic glaucoma. Dengue-associated chronic panuveitis with uveitic glaucoma may be effectively managed with a combination of steroid-sparing oral immunosuppression and glaucoma surgery. This is, to our knowledge, the first case of bilateral refractory dengue-associated panuveitis from the Caribbean treated with combination steroid-sparing oral immunosuppression and bilateral glaucoma valve implantation. PMID- 26229513 TI - Cybersecurity vulnerabilities in medical devices: a complex environment and multifaceted problem. AB - The increased connectivity to existing computer networks has exposed medical devices to cybersecurity vulnerabilities from which they were previously shielded. For the prevention of cybersecurity incidents, it is important to recognize the complexity of the operational environment as well as to catalog the technical vulnerabilities. Cybersecurity protection is not just a technical issue; it is a richer and more intricate problem to solve. A review of the factors that contribute to such a potentially insecure environment, together with the identification of the vulnerabilities, is important for understanding why these vulnerabilities persist and what the solution space should look like. This multifaceted problem must be viewed from a systemic perspective if adequate protection is to be put in place and patient safety concerns addressed. This requires technical controls, governance, resilience measures, consolidated reporting, context expertise, regulation, and standards. It is evident that a coordinated, proactive approach to address this complex challenge is essential. In the interim, patient safety is under threat. PMID- 26229515 TI - Evaluation of performance quality of an advanced scope physiotherapy role in a hospital emergency department. AB - BACKGROUND: Physiotherapists working in advanced and extended scope roles internationally make a difference to workflow, performance targets, and patient satisfaction in areas traditionally served by medicine and nursing. AIM: To assess the impact of an advanced scope of practice physiotherapist (ASoP-PT) service in a large Australian hospital emergency department (ED) by measuring national service and triage category indicators, patient and staff satisfaction. METHODS: Consecutive patients consulting the ASoP-PT were recruited over 53 weeks following service inception. Descriptions of ASoP-PT activities and patients were collected. Performance was assessed against national ED indicators for length of stay and wait. Patient and staff perspectives were assessed independently by semi structured interviews. The physiotherapist was formally trained to extended scope of practice including competency in medicines, prescription and application. The legislation prevented him from applying these skills, therefore he worked in an ASoP-PT role in ED. RESULTS: The ASoP-PT treated on average, 72 patients per month in ten shifts per fortnight, consulting patients aged from 1 to 88 years. Patients largely presented with musculoskeletal problems in triage Categories 4 and 5. There were shorter length of wait and length of stay, when the ASoP-PT was on shift. However overall compliance with national performance targets was similar with and without the ASoP-PT. Staff and patient satisfaction was high, particularly valuing the ASoP-PT's expertise in musculoskeletal injuries. CONCLUSION: The ASoP-PT performed at least as well as other ED health care providers in meeting national triage targets. Had the legislation permitted his independent prescription of medicines, the ASoP-PT could have worked in an extended scope role, and his performance in meeting targets may have been better. PMID- 26229514 TI - Cognitive-behavioral therapy for obsessive-compulsive disorder: access to treatment, prediction of long-term outcome with neuroimaging. AB - This article reviews issues related to a major challenge to the field for obsessive-compulsive disorder (OCD): improving access to cognitive-behavioral therapy (CBT). Patient-related barriers to access include the stigma of OCD and reluctance to take on the demands of CBT. Patient-external factors include the shortage of trained CBT therapists and the high costs of CBT. The second half of the review focuses on one partial, yet plausible aid to improve access - prediction of long-term response to CBT, particularly using neuroimaging methods. Recent pilot data are presented revealing a potential for pretreatment resting state functional magnetic resonance imaging and magnetic resonance spectroscopy of the brain to forecast OCD symptom severity up to 1 year after completing CBT. PMID- 26229516 TI - Are junior doctors competent in providing effective feedback to medical students? PMID- 26229517 TI - Predictions for the leptonic Dirac CP violation phase: a systematic phenomenological analysis. AB - We derive predictions for the Dirac phase [Formula: see text] present in the [Formula: see text] unitary neutrino mixing matrix [Formula: see text], where [Formula: see text] and [Formula: see text] are [Formula: see text] unitary matrices which arise from the diagonalisation, respectively, of the charged lepton and the neutrino mass matrices. We consider forms of [Formula: see text] and [Formula: see text] allowing us to express [Formula: see text] as a function of three neutrino mixing angles, present in U, and the angles contained in [Formula: see text]. We consider several forms of [Formula: see text] determined by, or associated with, symmetries, tri-bimaximal, bimaximal, etc., for which the angles in [Formula: see text] are fixed. For each of these forms and forms of [Formula: see text] allowing one to reproduce the measured values of the neutrino mixing angles, we construct the likelihood function for [Formula: see text], using (i) the latest results of the global fit analysis of neutrino oscillation data, and (ii) the prospective sensitivities on the neutrino mixing angles. Our results, in particular, confirm the conclusion, reached in earlier similar studies, that the measurement of the Dirac phase in the neutrino mixing matrix, together with an improvement of the precision on the mixing angles, can provide unique information as regards the possible existence of symmetry in the lepton sector. PMID- 26229518 TI - Rationale for a New Direction in Foster Youth Substance Use Disorder Prevention. AB - BACKGROUND: Of the 463,000 children residing in United States foster care, 29,000 annually exit the system because they have "aged out," are thus dropped from supportive services, and become responsible for their own housing, finances, and health needs. Given histories of maltreatment, housing instability, and parental substance use, youth preparing to exit care are at substantial risk of developing substance use disorders. Unfortunately, access to services is often limited, both before and after exit from care. METHODS: With the goal of developing a relevant substance use intervention for these youth, focus groups were conducted with foster care staff, administrators, and parents to assess the feasibility of potential approaches. RESULTS: Participants identified several population specific barriers to delivering adapted intervention models developed for normative populations. They expressed concerns about foster youth developing, then quickly ending, relationships with interventionists, as well as admitting to substance use, given foster care program sanctions for such behavior. Group members stressed the importance of tailoring interventions, using creative, motivational procedures. CONCLUSIONS: Foster youth seem to encounter unique barriers to receiving adequate care. In light of these results, a novel, engaging approach to overcoming these barriers is also presented. PMID- 26229519 TI - When care situations evoke difficult emotions in nursing staff members: an ethnographic study in two Norwegian nursing homes. AB - BACKGROUND: Caring practice in nursing homes is a complex topic, especially the challenges of meeting the basic needs of residents when their behaviour evokes difficult emotions. Cognitive and physical changes related to aging and disability can contribute to behaviours considered to be unacceptable. For example, resident behaviours such as spitting, making a mess with food or grinding teeth are behaviours that most people do not want to see, hear or experience. The aim of this study was to gain a deeper understanding of how nursing home staff members deal with such behaviours in care situations. METHODS: This article draws on ethnographic data to describe how nursing home staff members manage unpleasant resident behaviours. The study was based on two long term units in two Norwegian public nursing homes. The Region's Medical Ethics Committee and the Norwegian Social Science Data Services granted approval. In total, 45 participants (37 nursing aides and eight nurses) agreed to participate in this study. Ten of the participants were interviewed at the end of the field study. RESULTS: This study indicates that nursing home staff members experience difficult emotions related to some residents' behaviours. However, they found these feelings difficult to express and rarely verbalized them openly. In addition, they were characterized by a strong obligation to help all residents, despite their own feelings. Therefore, it appears that an inner struggle occurs as a part of everyday practice. CONCLUSIONS: Despite these difficult emotions, nursing staff members believed that they needed to manage their responses and continued to offer good care to all residents. These findings extend our understanding of this unarticulated part of nursing home practice. PMID- 26229520 TI - Protein Mobility Shifts Contribute to Gel Electrophoresis Liquid Chromatography Analysis. AB - Profiling of cellular and subcellular proteomes by liquid chromatography with tandem mass spectrometry (MS) after fractionation by SDS-PAGE is referred to as GeLC (gel electrophoresis liquid chromatography)-MS. The GeLC approach decreases complexity within individual MS analyses by size fractionation with SDS-PAGE. SDS PAGE is considered an excellent fractionation technique for intact proteins because of good resolution for proteins of all sizes, isoelectric points, and hydrophobicities. Additional information derived from the mobility of the intact proteins is available after an SDS-PAGE fractionation, but that information is usually not incorporated into the proteomic analysis. Any chemical or proteolytic modification of a protein that changes the mobility of that protein in the gel can be detected. The ability of SDS-PAGE to resolve proteins with chemical modifications has not been widely utilized within profiling experiments. In this work, we examined the ability of the GeLC-MS approach to help identify proteins that were modified after a small hairpin RNA-dependent knockdown in an experiment using stable isotope labeling by amino acids in cell culture-based quantitation. PMID- 26229522 TI - Principles of Use of Biostatistics in Research. AB - Collecting, analyzing, and interpreting data are essential components of biomedical research and require biostatistics. Doing various statistical tests has been made easy by sophisticated computer software. It is important for the investigator and the interpreting clinician to understand the basics of biostatistics for two reasons. The first is to choose the right statistical test for the computer to perform based on the nature of data derived from one's own research. The second is to understand if an analysis was performed appropriately during review and interpretation of others' research. This article reviews the choice of an appropriate parametric or nonparametric statistical test based on type of variable and distribution of data. Evaluation of diagnostic tests is covered with illustrations and tables. PMID- 26229523 TI - High-performance metabolic profiling with dual chromatography-Fourier-transform mass spectrometry (DC-FTMS) for study of the exposome. AB - Studies of gene-environment (G * E) interactions require effective characterization of all environmental exposures from conception to death, termed the exposome. The exposome includes environmental exposures that impact health. Improved metabolic profiling methods are needed to characterize these exposures for use in personalized medicine. In the present study, we compared the analytic capability of dual chromatography-Fourier-transform mass spectrometry (DC-FTMS) to previously used liquid chromatography-FTMS (LC-FTMS) analysis for high throughput, top-down metabolic profiling. For DC-FTMS, we combined data from sequential LC-FTMS analyses using reverse phase (C18) chromatography and anion exchange (AE) chromatography. Each analysis was performed with electrospray ionization in the positive ion mode and detection from m/z 85 to 850. Run time for each column was 10 min with gradient elution; 10 ul extracts of plasma from humans and common marmosets were used for analysis. In comparison to analysis with the AE column alone, addition of the second LC-FTMS analysis with the C18 column increased m/z feature detection by 23-36%, yielding a total number of features up to 7,000 for individual samples. Approximately 50% of the m/z matched to known chemicals in metabolomic databases, and 23% of the m/z were common to analyses on both columns. Database matches included insecticides, herbicides, flame retardants, and plasticizers. Modularity clustering algorithms applied to MS-data showed the ability to detection clusters and ion interactions. DC-FTMS thus provides improved capability for high-performance metabolic profiling of the exposome and development of personalized medicine. PMID- 26229524 TI - Geographic trends of tobacco-related cancers in Cyprus. AB - BACKGROUND: Causal relationships have been previously established between smoking and various cancers. In Cyprus, 39 % of men and 14 % of women reported daily smoking in 2008. The objective of this study was to compare the incidence of tobacco-related cancers to all other cancers by district and rural-urban classification to understand the impact of tobacco in Cyprus. METHODS: Data on lung, urinary bladder, oral, pharyngeal, head/neck, and laryngeal cancers were obtained from the Cyprus Cancer Registry (1998-2008). There were 3,635 patients with tobacco-related cancers and 18,780 with non-tobacco cancers. Univariate analysis comparing tobacco-related cancers and all other cancers were conducted with regards to age at diagnosis, age groups, sex, smoking status, disease stage, and rural/urban status, with a p-value of 0.05 considered significant. Smoking prevalence, lung cancer, and bladder cancer rates of Cyprus were also compared to a number of other European countries. RESULTS: Patients with tobacco-related cancers were older than those with non-tobacco cancers (mean age 67.2 +/- 12.4 vs. 62.4 +/- 17.1, p < 0.0001). Among those with tobacco-related cancers, 80.1 % were male compared to 45.4 % males with other cancer types. The proportion of ever smokers was higher among males compared to females in urban and rural districts. Sub-districts 41 (Age Adjusted Rate (AAR) 41.9, 95 % CI: 35.7-48.1), 60 (AAR 40.3, 95 % CI: 35.2-45.3), and 50 (AAR 36.3, 95 % CI: 33.8-38.7) had the highest rates of tobacco-related cancers. The overall tobacco-related cancer rate was the highest among males in urban districts (AAR 60.8, 95 % CI: 58.2-63.5). Among tobacco-related cancers, lung cancer had the highest overall AAR (17.9 per 100,000) while head and neck cancer had the lowest overall AAR (5.3 per 100,000). Additionally, even though Cypriot males aged 65-69 years old exhibited higher smoking prevalence than other European countries, the overall lung and bladder cancer rates were lower in Cyprus. CONCLUSION: Despite the high proportion of smokers in Cyprus, cancer rates are low compared to other countries. Future in depth measurements of relevant risk factors and smoking exposure can help understand this phenomenon and provide insights for cancer prevention. PMID- 26229525 TI - A checklist of the scorpions of Ecuador (Arachnida: Scorpiones), with notes on the distribution and medical significance of some species. AB - Ecuador harbors one of the most diverse Neotropical scorpion faunas, hereby updated to 47 species contained within eight genera and five families, which inhabits the "Costa" (n = 17), "Sierra" (n = 34), "Oriente" (n = 16) and "Insular" (n = 2) biogeographical regions, corresponding to the western coastal, Andean, Amazonian, and the Galapagos archipelago regions, respectively. The genus Tityus Koch, in the family Buthidae, responsible for severe/fatal accidents elsewhere in northern South America and the Amazonia, is represented in Ecuador by 16 species, including T. asthenes, which has caused fatalities in Colombia and Panama, and now in the Ecuadorian provinces of Morona Santiago and Sucumbios. Underestimation of the medical significance of scorpion envenoming in Ecuador arises from the fact that Centruroides margaritatus (Gervais) (family Buthidae) and Teuthraustes atramentarius Simon (family Chactidae), whose venoms show low toxicity towards vertebrates, frequently envenom humans in the highly populated Guayas and Pichincha provinces. This work also updates the local scorpion faunal endemicity (74.5 %) and its geographical distribution, and reviews available medical/biochemical information on each species in the light of the increasing problem of scorpionism in the country. A proposal is hereby put forward to classify the Ecuadorian scorpions based on their potential medical importance. PMID- 26229526 TI - A Novel Mittag-Leffler Kernel Based Hybrid Fault Diagnosis Method for Wheeled Robot Driving System. AB - The wheeled robots have been successfully applied in many aspects, such as industrial handling vehicles, and wheeled service robots. To improve the safety and reliability of wheeled robots, this paper presents a novel hybrid fault diagnosis framework based on Mittag-Leffler kernel (ML-kernel) support vector machine (SVM) and Dempster-Shafer (D-S) fusion. Using sensor data sampled under different running conditions, the proposed approach initially establishes multiple principal component analysis (PCA) models for fault feature extraction. The fault feature vectors are then applied to train the probabilistic SVM (PSVM) classifiers that arrive at a preliminary fault diagnosis. To improve the accuracy of preliminary results, a novel ML-kernel based PSVM classifier is proposed in this paper, and the positive definiteness of the ML-kernel is proved as well. The basic probability assignments (BPAs) are defined based on the preliminary fault diagnosis results and their confidence values. Eventually, the final fault diagnosis result is archived by the fusion of the BPAs. Experimental results show that the proposed framework not only is capable of detecting and identifying the faults in the robot driving system, but also has better performance in stability and diagnosis accuracy compared with the traditional methods. PMID- 26229527 TI - LogDet Rank Minimization with Application to Subspace Clustering. AB - Low-rank matrix is desired in many machine learning and computer vision problems. Most of the recent studies use the nuclear norm as a convex surrogate of the rank operator. However, all singular values are simply added together by the nuclear norm, and thus the rank may not be well approximated in practical problems. In this paper, we propose using a log-determinant (LogDet) function as a smooth and closer, though nonconvex, approximation to rank for obtaining a low-rank representation in subspace clustering. Augmented Lagrange multipliers strategy is applied to iteratively optimize the LogDet-based nonconvex objective function on potentially large-scale data. By making use of the angular information of principal directions of the resultant low-rank representation, an affinity graph matrix is constructed for spectral clustering. Experimental results on motion segmentation and face clustering data demonstrate that the proposed method often outperforms state-of-the-art subspace clustering algorithms. PMID- 26229528 TI - MELD Score Is Not Related to Spontaneous Bacterial Peritonitis. AB - This study investigates the correlation between SBP and repeated paracentesis, and its relation to MELD score, in cirrhotic patients with refractory ascites in an outpatient setting. Through the data base, 148 cirrhotic patients were prospectively included in the study with refractory ascites undergoing relief paracentesis from March 2012 to March 2013. Demographics data, etiology of liver disease, MELD score, and inscription on the waiting list for liver transplantation were analyzed. The ascites removed was analyzed through cellular count and culture for the diagnosis of spontaneous bacterial peritonitis. The cirrhotic patients underwent a total of 854 paracentesis procedures in the ambulatory setting during the study period. Eighty-one patients (54%) were on the waiting list for liver transplantation. Patients on the liver transplant list had higher associated costs due to a higher total number of outpatient paracentesis procedures (394.7 +/- 512.3 versus 291.7 +/- 384.7) and a higher volume drained per procedure (6.5 +/- 8.5 versus 4.8 +/- 6.4). There were 28 episodes of SBP (3.3%) diagnosed in 24 patients. In conclusion, the prevalence of asymptomatic SBP in cirrhotic patients with refractory ascites undergoing repeated paracentesis is low. MELD score is not related to spontaneous bacterial peritonitis. PMID- 26229529 TI - Clinical Efficacy of Various Diagnostic Tests for Small Bowel Tumors and Clinical Features of Tumors Missed by Capsule Endoscopy. AB - Background. We aimed to evaluate the efficacy of various diagnostic tools such as computerized tomography (CT), small bowel follow-through (SBFT), and capsule endoscopy (CE) in diagnosing small bowel tumors (SBTs). Additionally, we aimed to evaluate the clinical features of SBTs missed by CE. Methods. We retrospectively studied 79 patients with histologically proven SBT. Clinical data were analyzed with particular attention to the efficacy of CT, SBFT, and CE in detecting SBT preoperatively. We also analyzed the clinical features of SBTs missed by CE. Results. The most common symptoms of SBT were bleeding (43%) and abdominal pain (13.9%). Diagnostic yields were as follows: CT detected 55.8% of proven SBTs; SBFT, 46.1%; and CE, 83.3%. The sensitivity for detecting SBTs was 40.4% for CT, 43.9% for SBFT, and 79.6% for CE. Two patients with nondiagnostic but suspicious findings on CE and seven patients with negative findings on CE were eventually found to have SBT. These nine patients were eventually diagnosed with gastrointestinal stromal tumor (4), small polyps (3), inflammatory fibroid polyp (1), and adenocarcinoma (1). These tumors were located in the proximal jejunum (5), middle jejunum (1), distal jejunum (1), and proximal ileum (1). Conclusion. CE is more efficacious than CT or SBFT for detecting SBTs. However, significant tumors may go undetected with CE, particularly when located in the proximal jejunum. PMID- 26229530 TI - Narrow-Band Imaging Magnifying Endoscopy versus Lugol Chromoendoscopy with Pink Color Sign Assessment in the Diagnosis of Superficial Esophageal Squamous Neoplasms: A Randomised Noninferiority Trial. AB - Previous studies have shown the high diagnostic accuracy of narrow-band imaging magnifying endoscopy (NBI-ME) and Lugol chromoendoscopy with pink-color sign assessment (LCE-PS) for superficial esophageal squamous cell carcinoma (SESCC). However, there has been no controlled trial comparing these two diagnostic techniques. We conducted a randomized noninferiority trial to compare the diagnostic accuracy of NBI-ME and LCE-PS. We recruited patients with, or with a history of, squamous cell carcinoma in the head and neck region or in the esophagus. They were randomly assigned to either NBI-ME or LCE-PS. When lesions > 5 mm in diameter were found as brownish areas on NBI or as Lugol-voiding lesions (LVL), they were evaluated to determine whether they are SESCC on the basis of the findings of NBI-ME or PS in the LVL. NBI-ME and LCE-PS were completed in 147 patients each. There was no significant difference in all diagnostic values between the two techniques. Compared with LCE-PS, NBI-ME showed a significantly shorter examination time but a larger number of misdiagnosed lesions especially in patients with many irregularly shaped multiform LVLs. Compared with LCE-PS, NBI-ME might be similarly accurate and less invasive, but less reliable in patients with many LVLs, in the diagnosis of SESCC. PMID- 26229531 TI - Consequence of Menin Deficiency in Mouse Adipocytes Derived by In Vitro Differentiation. AB - Lipoma in patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome is a type of benign fat-cell tumor that has biallelic inactivation of MEN1 that encodes menin and could serve as a model to investigate normal and pathologic fat cell (adipocyte) proliferation and function. The role of menin and its target genes in adipocytes is not known. We used in vitro differentiation to derive matched normal and menin-deficient adipocytes from wild type (WT) and menin-null (Men1-KO) mouse embryonic stem cells (mESCs), respectively, or 3T3-L1 cells without or with menin knockdown to investigate cell size, lipid content, and gene expression changes. Adipocytes derived from Men1-KO mESCs or after menin knockdown in 3T3-L1 cells showed a 1.5-1.7-fold increase in fat-cell size. Global gene expression analysis of mESC-derived adipocytes showed that lack of menin downregulated the expression of many differentially methylated genes including the tumor suppressor long noncoding RNA Meg3 but upregulated gene expression from the prolactin gene family locus. Our results show that menin deficiency leads to fat-cell hypertrophy and provide model systems that could be used to study the regulation of fat-cell size. PMID- 26229532 TI - Role of Vitamin D in Osteoarthritis: Molecular, Cellular, and Clinical Perspectives. AB - Osteoarthritis is a debilitating and degenerative disease which affects millions of people worldwide. The causes and mechanisms of osteoarthritis remain to be fully understood. Vitamin D has been hypothesised to play essential roles in a number of diseases including osteoarthritis. Many cell types within osteoarthritic joints appear to experience negative effects often at increased sensitivity to vitamin D. These findings contrast clinical research which has identified vitamin D deficiency to have a worryingly high prevalence among osteoarthritis patients. Randomised-controlled trial is considered to be the most rigorous way of determining the effects of vitamin D supplementation on the development of osteoarthritis. Studies into the effects of low vitamin D levels on pain and joint function have to date yielded controversial results. Due to the apparent conflicting effects of vitamin D in knee osteoarthritis, further research is required to fully elucidate its role in the development and progression of the disease as well as assess the efficacy and safety of vitamin D supplementation as a therapeutic strategy. PMID- 26229533 TI - Isolated Subclinical Hyperthyrotropinemia in Obese Children: Does Levothyroxine (LT4) Improve Weight Reduction during Combined Behavioral Therapy? AB - Objective. The study aim was to analyze whether anthropometrical parameters and TSH values in obese children with isolated subclinical hypothyroidism (IsHT) treated with levothyroxine (LT4) and weight reduction program differ from those managed by dietary and behavior counselling only. Material and Methods. 51 obese children with IsHT, who were treated according to the same weight reduction program, were retrospectively analyzed. They were divided into two groups: Group 1, n = 26, and Group 2, n = 25, without or with LT4 therapy, respectively. Changes in anthropometrical (delta BMI z-score) and hormonal (delta TSH) status were analyzed at the first follow-up visit. Results. In both groups significant decrease of TSH and BMI z-score values were noted. TSH normalized in 80.9% of children from Group 1 versus 90.5% from Group 2, p = NS. Delta BMI z-score was insignificantly higher in Group 1 compared to Group 2. Delta TSH was significantly related to initial TSH level in children treated by lifestyle intervention program only. Conclusions. In obese children with sHT dietary behavioral management intervention contributed to reduction of body mass index, irrespective of levothyroxine use. This finding suggests that moderately elevated levels of TSH are a consequence rather than cause of overweight and pharmacological treatment should be avoided. PMID- 26229534 TI - Effect of Advanced Glycation End Products on Human Thyroglobulin's Antigenicity as Identified by the Use of Sera from Patients with Hashimoto's Thyroiditis and Gestational Diabetes Mellitus. AB - Advanced glycation end products (AGEs) are formed on proteins after exposure to high concentrations of glucose and modify protein's immunogenicity. Herein, we investigated whether the modification of thyroglobulin (Tg) by AGEs influences its antigenicity and immunogenicity. Human Tg was incubated in vitro with increasing concentrations of D-glucose-6-phosphate in order to produce Tgs with different AGE content (AGE-Tg). Native Tg and AGE-Tgs were used in ELISA to assess the serum antibody reactivity of two patient groups, pregnant women with gestational diabetes (GDM), and patients with Hashimoto's thyroiditis (HT). We produced in vitro AGE-Tg with low and high AGE content, 13 and 49 AGE units/mg Tg, respectively. All HT patients' sera presented the same antibody reactivity profile against native Tg and AGE-Tgs, indicating that the modification of Tg by AGEs did not alter its antigenicity. Similarly, the GDM patients' sera did not discriminate among the two forms of Tg, native or artificially glycated, suggesting that the modification of Tg by AGEs might not alter its immunogenicity. The modification of Tg by AGEs has no obvious effect on neither its antigenicity nor, most likely, its immunogenicity. It seems that other Tg modifications might account for the production of aTgAbs in patients with GDM. PMID- 26229535 TI - Mycobiota and Natural Incidence of Aflatoxins, Ochratoxin A, and Citrinin in Indian Spices Confirmed by LC-MS/MS. AB - Nine different Indian spices (red chilli, black pepper, turmeric, coriander, cumin, fennel, caraway, fenugreek, and dry ginger) commonly cultivated and highly used in India were analysed for natural occurrence of toxigenic mycoflora and aflatoxins (AFs), ochratoxin A (OTA), and citrinin (CTN) contamination. Aspergillus flavus and Aspergillus niger were the most dominant species isolated from all types of spices. Red chilli samples were highly contaminated with aflatoxins (85.4%) followed by dry ginger (77.7%). 56% Aspergillus flavus from red chilli and 45% Aspergillus ochraceus from black pepper were toxigenic and produced aflatoxins and ochratoxin A, respectively. Qualitative detection and quantitative detection of mycotoxins in spices were analyzed by ELISA and further confirmed by LC-MS/MS. Penicillium citrinum produced citrinin in red chilli, black pepper, coriander, cumin, fenugreek, and dry ginger samples. The highest amount of AFs was found in red chilli (219.6 ng/g), OTA was in black pepper (154.1 ng/g), and CTN was in dry ginger samples (85.1 ng/g). The results of this study suggest that the spices are susceptible substrate for growth of mycotoxigenic fungi and further mycotoxin production. This is the first report of natural occurrence of citrinin in black pepper and dry ginger from India. PMID- 26229536 TI - Lupus-Associated Pulmonary Arterial Hypertension: Variable Course and Importance of Prompt Recognition. AB - We describe a critically ill young woman with systemic lupus erythematosus (SLE) presenting with circulatory shock, multiorgan dysfunction, and elevated right sided heart pressures. She was found to have recurrent acute severe pulmonary arterial hypertension (PAH) in the setting of an SLE flare. Our report highlights the variable course that SLE-associated PAH can take in the same patient and the implications of this for instituting the most effective treatment approach with each episode. This report also highlights the potential for SLE-associated PAH to present with life-threatening symptoms requiring critical care level interventions. We also describe evidence-based therapies, which can result in significant improvement in symptoms, function, and long-term outcomes. PMID- 26229537 TI - Intravascular Hemolysis and Septicemia due to Clostridium perfringens Emphysematous Cholecystitis and Hepatic Abscesses. AB - Context. Clostridium perfringens septicemia is often associated with translocation from the gastrointestinal or gastrourinary tract and occurs in patients who have malignancy or are immunocompromised. Clostridium perfringens septicemia is usually fatal without early identification, source control, and antibiotics. Case. We present a case of a 65-year-old female with Clostridium perfringens septicemia secondary to emphysematous cholecystitis, with progression to hepatic abscesses. Conclusion. Septicemia secondary to Clostridium perfringens is generally fatal if not detected early. Source control with surgery or percutaneous drainage and early antibiotic therapy is imperative. Hyperbaric oxygen therapy may reduce mortality. Clinicians caring for patients with sepsis and intravascular hemolysis must have Clostridium perfringens septicemia on their differential diagnosis with a low threshold for starting antibiotics and pursuing source of infection. PMID- 26229538 TI - Exercise-Induced Pulmonary Edema in a Triathlon. AB - Introduction. Family physicians have more opportunities to attend athletic competitions as medical staff at first-aid centers because of the increasing popularity of endurance sports. Case. A 38-year-old man who participated in a triathlon race experienced difficulty in breathing after swimming and was moved to a first-aid center. His initial oxygen saturation was 82% and a thoracic computed tomography scan showed bilateral ground glass opacity in the peripheral lungs. His diagnosis was noncardiogenic pulmonary edema associated with exercise or swimming: exercise-induced pulmonary edema (EIPE) or swimming-induced pulmonary edema (SIPE). Treatment with furosemide and corticosteroid relieved his symptoms of pulmonary edema. Discussion. Noncardiogenic pulmonary edema associated with endurance sports is not common, but knowledge about EIPE/SIPE or neurogenic pulmonary edema associated with hyponatremia, which is called Ayus Arieff syndrome, is crucial. Knowledge and caution for possible risk factors, such as exposure to cold water or overhydration, are essential for both medical staff and endurance athletes. Conclusion. To determine the presence of pulmonary edema associated with strenuous exercise, oxygen saturation should be used as a screening tool at a first-aid center. To avoid risks for EIPE/SIPE, knowledge about these diseases is essential for medical staff and for athletes who perform extreme exercise. PMID- 26229539 TI - In Vitro Differentiation Potential of Human Placenta Derived Cells into Skin Cells. AB - Skin autografting is the most viable and aesthetic technique for treatment of extensive burns; however, this practice has potential limitations. Harvesting cells from neonatal sources (such as placental tissue) is a simple, inexpensive, and noninvasive procedure. In the current study authors sought to evaluate in vitro potential of human placenta derived stem cells to develop into skin-like cells. After extensive washing, amniotic membrane and umbilical cord tissue were separated to harvest amniotic epithelial cells (AECs) and umbilical cord mesenchymal stem cells (UC-MSCs), respectively. Both types of cells were characterized for the expression of embryonic lineage markers and their growth characteristics were determined. AECs and UC-MSCs were induced to differentiate into keratinocytes-like and dermal fibroblasts-like cells, respectively. After induction, morphological changes were detected by microscopy. The differentiation potential was further assessed using immunostaining and RT-PCR analyses. AECs were positive for cytokeratins and E-Cadherin while UC-MSCs were positive for fibroblast specific makers. AECs differentiated into keratinocytes-like cells showed positive expression of keratinocyte specific cytokeratins, involucrin, and loricrin. UC-MSCs differentiated into dermal fibroblast-like cells indicated expression of collagen type 3, desmin, FGF-7, fibroblast activation protein alpha, procollagen-1, and vimentin. In conclusion, placenta is a potential source of cells to develop into skin-like cells. PMID- 26229540 TI - Exposure Perception as a Key Indicator of Risk Perception and Acceptance of Sources of Radio Frequency Electromagnetic Fields. AB - The presented survey was conducted in six European countries as an online study. A total of 2454 subjects participated. Two main research questions were investigated: firstly, how does the cognitive, moral, and affective framing of radio frequency electromagnetic field (RF EMF) exposure perception influence RF EMF risk perception? Secondly, can the deployment of mobile phone base stations have greater acceptance with RF EMF exposure reduction? The findings with respect to the first question clearly indicated that the cognitive framed exposure perception is the main determinant of RF EMF risk perception. The concomitant sensitivity to exposure strength offers an opportunity to improve the acceptance of base stations by exposure reduction. A linear regression analysis supported this assumption: in a fictional test situation, exposure reduction improved the acceptance of base stations, operationalized as the requested distance of the base station from one's own home. Furthermore, subjects with high RF EMF risk perception were most sensitive to exposure reduction. On average, a 70% exposure reduction reduced the requested distance from about 2000 meters to 1000 meters. The consequences for risk communication are discussed. PMID- 26229541 TI - The in vitro Effect of Irrigants with Low Surface Tension on Enterococcus faecalis. AB - INTRODUCTION: Due to the complex anatomy of the root canal system and high surface tension of common root canal irrigants (RCI), conducting an investigation on RCIs containing surfactants is a priority. The aim of this in vitro study was to verify the antibacterial potential of RCI with low surface tension in root canals infected with Enterococcus faecalis (E. faecalis). METHODS AND MATERIALS: Thirty-five extracted human maxillary anterior teeth were prepared and inoculated with E. faecalis for 60 days. After root canal preparation, the teeth were randomly divided to one positive and one negative control groups and 5 experimental groups: Hypoclean/Tetraclean NA, Hypoclean, Tetraclean, NaOCl/Tetraclean and NaOCl. Bacterial growth was observed by turbidity of culture medium and then measured using a UV spectrophotometer. Data were analyzed in three time intervals (pre-instrumentation and, 20 min and 72 h after canal preparation) using the ANOVA and post hoc Tukey's tests. The level of significance was set at 0.05. RESULTS: The results indicated the presence of E. faecalis in all post-irrigation samples irrespective of the RCI. However, the optical densities in both post-irrigation periods showed bacterial reduction and significant differences between groups. CONCLUSION: RCI with low surface tension showed antibacterial potential in E. faecalis infected roots. PMID- 26229543 TI - Antidepressant-Like and Antioxidant Effects of Plinia trunciflora in Mice. AB - The jaboticaba tree, Plinia trunciflora (O. Berg) Kausel, is popularly named "jabuticabeira" in Brazil and is used in folk medicine to treat diabetes and chronic inflammation of the tonsils, but studies evaluating the central effects of this species are limited. This study evaluated the antidepressant-like and antioxidant effects of P. trunciflora (PT) aqueous extract, in which five different anthocyanins were identified. PT showed significant ferric-reduction power and DPPH radical scavenging activity in vitro and reduced lipid peroxidation both in vitro and ex vivo. At the behavioural level, PT (400 and 800 mg/kg, i.p.) dose-dependently reduced immobility time in the tail suspension test in Swiss male mice. The identification of bioactive compounds accompanied by the in vitro and ex vivo antioxidant activity of PT suggests that these activities might be related to the antidepressant-like activity of P. trunciflora. PMID- 26229542 TI - Huaier Aqueous Extract Induces Hepatocellular Carcinoma Cells Arrest in S Phase via JNK Signaling Pathway. AB - Huaier aqueous extract, the main active constituent of Huaier proteoglycan, has antihepatocarcinoma activity in experimental and clinical settings. However, the potential and associated antihepatoma mechanisms of Huaier extract are not yet fully understood. Therefore, in this study, we aimed to elucidate the inhibitory proliferation effect of Huaier extract on apoptosis and cycle of HepG2 and Bel 7402 cells. Our data demonstrated that incubation with Huaier extract resulted in a marked decrease in cell viability dose-dependently. Flow cytometric analysis showed that a 48 h treatment of Huaier extract caused cell apoptosis. Typical apoptotic nucleus alterations were observed with fluorescence microscope after Hoechst staining. Immunoblot analysis further demonstrated that Huaier extract activated caspase 3 and PARP. Additionally, Huaier extract inhibited the activity of p-ERK, p-p38, and p-JNK in terms of MAPK. Furthermore, Huaier extract induced HCC cells arrest in S phase and decreased the cycle related protein expression of beta-catenin and cyclin D1. Studies with JNK specific inhibitor, SP600125, showed that Huaier extract induced S phase arrest and decreased beta-catenin and cyclin D1 expression via JNK signaling pathway. In conclusion, we verify that Huaier extract causes cell apoptosis and induces hepatocellular carcinoma cells arrest in S phase via JNK pathway, which advances our understanding on the molecular mechanisms of Huaier extract in hepatocarcinoma management. PMID- 26229545 TI - Research of Herb-Partitioned Moxibustion for Primary Dysmenorrhea Patients Based on the LC-MS Metabonomics. AB - Objective. To explore the efficacy and mechanism of primary dysmenorrhea patients were treated with herb-partitioned moxibustion through metabonomics. Methods. 20 patients with primary dysmenorrhea were randomized into two groups, separately treated with herb-partitioned moxibustion at CV8 (shenque) and acupuncture at SP6 (sanyinjiao). After three menstrual cycles' treatment, the intensity of menstrual pain using VAS and the changes of metabolites of plasma using LC-MS were observed. Results. The VAS of two groups decreased with different descending range. Herb-partitioned moxibustion upregulated 20alpha-dihydroprogesterone, pregnenolone, prostaglandin E2 and gamma-aminobutyric acid and downregulated the content of estrone and prostaglandin H2, while acupuncture upregulated pregnenolone and 20alpha-dihydroprogesterone and downregulated 2-methoxyestradiol 3-methylether, 15-hydroxyeicosatrienoic acid and 6-keto-prostaglandin. Discussion. It was effective in relieving the abdominal pain by these two therapies. Herb-partitioned moxibustion is superior to acupuncture for primary dysmenorrhea, which could be related to regulating the endocrine hormone. PMID- 26229544 TI - A Study on Effect of Electroacupuncture on Gene Expression in Hypothalamus of Rats with Stress-Induced Prehypertension Based on Gene Chip Technology. AB - Objective. To explore the effect of electroacupuncture (EA) on gene expression in the hypothalamus of rats with stress-induced prehypertension and try to reveal its biological mechanism with gene chip technology. Methods. The stress-induced hypertensive rat model was prepared by combining electric foot-shocks with generated noise. Molding cycle lasted for 14 days and EA intervention was applied on model + EA group during model preparation. Rat Gene 2.0 Array technology was used for the determination of gene expression profiles and the screened key genes were verified by real-time fluorescence quantitative PCR method. Results. Compared with the blank group, 234 genes were upregulated and 73 were downregulated in the model group. Compared with the model group, 110 genes were upregulated and 273 genes were downregulated in model + EA group. The PCR results of the key genes including HSPB1, P2RX4, PPP1R14A, and TH are consistent with that of gene chip test. Conclusion. EA could significantly lower blood pressure of stress-induced prehypertension rats and affect its gene expression profile in hypothalamus. Genes and their signal transduction pathway that related to the contraction of vascular smooth muscle, concentration of Ca(2+), and excitability of sympathetic nerve may be involved in EA's antihypertensive mechanism. PMID- 26229546 TI - Neuroprotective Activity of Coptisine from Coptis chinensis (Franch). AB - Coptis chinensis rhizomes (CR) are one important ingredient of traditional Chinese herbal formulas such as San-Huang-Xie-Xin-Tang which is used for treatment of cardiovascular and neurodegenerative diseases. Recent studies suggest that the extract of CR might be a potential therapeutic agent for amelioration of neurological disorders associated with oxidative stress. In the present study we aimed at revealing the main active compound(s) of the CR extract and at investigating the mechanism of action. Four main alkaloids of the CR extract (berberine, coptisine, jatrorrhizine, and palmatine) were selected for this study. Results showed that out of those alkaloids only pretreatment with coptisine significantly attenuated tert-butylhydroperoxide induced reduction of cell viability, increased rate of apoptosis, and declined mitochondrial membrane potential. Elisa assay and quantitative real-time PCR analyses revealed that thioredoxin-interacting protein (TXNIP) gene expression was downregulated by coptisine, which could explain the neuroprotective effect, hypothetically, by strengthening the thioredoxin defense system against oxidative stress and attenuation of apoptosis signal-regulating kinase (Ask1) mediated apoptotic signaling. A comparison between coptisine and CR extract identified coptisine as the main single component responsible for the neuroprotective effect. Based on the results the CR extract and coptisine are promising candidate agents for prevention or improvement of diabetic neuropathy and neurodegenerative disorders. PMID- 26229547 TI - Antioxidant and Antiproliferative Activities of the Essential Oils from Thymbra capitata and Thymus Species Grown in Portugal. AB - The antioxidant and antiproliferative activities of the essential oils from Thymbra capitata and Thymus species grown in Portugal were evaluated. Thymbra and Thymus essential oils were grouped into two clusters: Cluster I in which carvacrol, thymol, p-cymene, alpha-terpineol, and gamma-terpinene dominated and Cluster II in which thymol and carvacrol were absent and the main constituent was linalool. The ability for scavenging ABTS(*+) and peroxyl free radicals as well as for preventing the growth of THP-1 leukemia cells was better in essential oils with the highest contents of thymol and carvacrol. These results show the importance of these two terpene-phenolic compounds as antioxidants and cytotoxic agents against THP-1 cells. PMID- 26229548 TI - Community assessment of tropical tree biomass: challenges and opportunities for REDD. AB - BACKGROUND: REDD+ programs rely on accurate forest carbon monitoring. Several REDD+ projects have recently shown that local communities can monitor above ground biomass as well as external professionals, but at lower costs. However, the precision and accuracy of carbon monitoring conducted by local communities have rarely been assessed in the tropics. The aim of this study was to investigate different sources of error in tree biomass measurements conducted by community monitors and determine the effect on biomass estimates. Furthermore, we explored the potential of local ecological knowledge to assess wood density and botanical identification of trees. RESULTS: Community monitors were able to measure tree DBH accurately, but some large errors were found in girth measurements of large and odd-shaped trees. Monitors with experience from the logging industry performed better than monitors without previous experience. Indeed, only experienced monitors were able to discriminate trees with low wood densities. Local ecological knowledge did not allow consistent tree identification across monitors. CONCLUSION: Future REDD+ programmes may benefit from the systematic training of local monitors in tree DBH measurement, with special attention given to large and odd-shaped trees. A better understanding of traditional classification systems and concepts is required for local tree identifications and wood density estimates to become useful in monitoring of biomass and tree diversity. PMID- 26229549 TI - Stem cell-derived erythrocytes as upcoming players in blood transfusion. AB - BACKGROUND: Blood transfusion is current standard-of-care for genetic forms of anemia that would be otherwise lethal and allows implementation of aggressive cytotoxic/surgical therapies developed for numerous types of cancer. In developed countries the blood supply is adequate and sporadically even in excess. However, difficulties exist in finding blood with rare phenotypes to treat alloimmunized patients and the progressive ageing of the human population predicts that blood will become scarce by 2050. These considerations establish the need for the development of techniques to generate cultured red blood cell (cRBCs) as transfusion products. MATERIALS AND METHODS: Recent progress in cell culture techniques is revolutionizing organ replacement therapies. Two new disciplines, cell therapy and tissue engineering, have been developed to generate in vitro therapeutic products for a variety of applications ranging from skin grafts to organ-function repairs. It is currently believed that these advances will eventually allow ex-vivo production of various cell types in numbers so great that, in the case of red cells, would be clinically adequate for transfusion. RESULTS: Proof-of-principle in animal models indicate that cRBCs generated from murine embryonic stem cells protect mice from lethal anemia. Conditions to generate small amounts of clinical grade cRBCs have been established and the first-in-man administration of autologous cRBCs perfomed. The results of this trial indicate that cRBCs survive in vivo at least as long as their natural counterpart. DISCUSSION: These ground-breaking reports have raised great excitement for clinical evaluation of cRBCs for transfusion. However, skepticism still persist that production of cRBCs in numbers sufficient for transfusion will ever be possible. This paper will discuss diagnostic and clinical goals pursuable with numbers of cRBCs that may be generated with current technology. CONCLUSION: We are confident that development of relevant clinical goals achievable with current technologies will not only improve clinical care in transfusion medicine but will also foster studies to overcome scientific and technical barriers that render transfusion with cRBCs of the general population impractical today. PMID- 26229550 TI - Vascular injuries of the extremities are a major challenge in a third world country. AB - BACKGROUND: Traumatic vascular injuries of the extremities are a major challenge especially in the third world countries. These injuries are mostly due to poor traffic laws, street crimes, firearms and blast associated injuries. We therefore would like to share our 10 years of experience in dealing with vascular injuries in Pakistan. METHODS: This was a retrospective observational study conducted in the department of vascular surgery of Liaquat National Hospital, Karachi, Pakistan. Patients' records were retrieved from the department and were reviewed. Cases with vascular injuries of upper and lower limb that presented with signs of salvageable limb and presented within 12 hours of injury were included in the study. Patients with more than 12 hours of presentation and in whom primary amputation was done, were excluded from the study. RESULTS: There were 328 patients who presented with vascular injuries of the extremities that fell in the inclusion criteria. Limb salvage rate was 41 %, whereas 30-days perioperative mortality was 5.48 %. The major cause of limb loss was delay in presentation of more than 8 h of injury. Major vessels involved were popliteal artery (41.76 %), followed by femoral artery (27.43 %). CONCLUSION: Vascular injuries are becoming a major contributor of limb loss in third world countries due to violence, terrorism and unavailability of vascular facilities. This morbidity can be reduced by improving law and order situation, evolving an effective emergency ambulatory system and with better training and provision of vascular services in remote areas so that the delay factor can be reduced. PMID- 26229551 TI - The complex pattern of epigenomic variation between natural yeast strains at single-nucleosome resolution. AB - BACKGROUND: Epigenomic studies on humans and model species have revealed substantial inter-individual variation in histone modification profiles. However, the pattern of this variation has not been precisely characterized, particularly regarding which genomic features are enriched for variability and whether distinct histone marks co-vary synergistically. Yeast allows us to investigate intra-species variation at high resolution while avoiding other sources of variation, such as cell type or subtype. RESULTS: We profiled histone marks H3K4me3, H3K9ac, H3K14ac, H4K12ac and H3K4me1 in three unrelated wild strains of Saccharomyces cerevisiae at single-nucleosome resolution and analyzed inter strain differences statistically. All five marks varied significantly at specific loci, but to different extents. The number of nucleosomes varying for a given mark between two strains ranged from 20 to several thousands; +1 nucleosomes were significantly less subject to variation. Genes with highly evolvable or responsive expression showed higher variability; however, the variation pattern could not be explained by known transcriptional differences between the strains. Synergistic variation of distinct marks was not systematic, with surprising differences between functionally related H3K9ac and H3K14ac. Interestingly, H3K14ac differences that persisted through transient hyperacetylation were supported by H3K4me3 differences, suggesting stabilization via cross talk. CONCLUSIONS: Quantitative variation of histone marks among S. cerevisiae strains is abundant and complex. Its relation to functional characteristics is modular and seems modest, with partial association with gene expression divergences, differences between functionally related marks and partial co-variation between marks that may confer stability. Thus, the specific context of studies, such as which precise marks, individuals and genomic loci are investigated, is primordial in population epigenomics studies. The complexity found in this pilot survey in yeast suggests that high complexity can be anticipated among higher eukaryotes, including humans. PMID- 26229552 TI - Phenotype-driven strategies for exome prioritization of human Mendelian disease genes. AB - Whole exome sequencing has altered the way in which rare diseases are diagnosed and disease genes identified. Hundreds of novel disease-associated genes have been characterized by whole exome sequencing in the past five years, yet the identification of disease-causing mutations is often challenging because of the large number of rare variants that are being revealed. Gene prioritization aims to rank the most probable candidate genes towards the top of a list of potentially pathogenic variants. A promising new approach involves the computational comparison of the phenotypic abnormalities of the individual being investigated with those previously associated with human diseases or genetically modified model organisms. In this review, we compare and contrast the strengths and weaknesses of current phenotype-driven computational algorithms, including Phevor, Phen-Gen, eXtasy and two algorithms developed by our groups called PhenIX and Exomiser. Computational phenotype analysis can substantially improve the performance of exome analysis pipelines. PMID- 26229553 TI - Emergency medical genomes: a breakthrough application of precision medicine. AB - Today there exist two medical applications where relatively strong evidence exists to support the broad adoption of genome-informed precision medicine. These are the differential diagnosis of single gene diseases and genotype-based selection of patients for targeted cancer therapies. However, despite the availability of the $1000 genome and $700 exome for research, there is as yet little broad uptake of genomic medicine, even in these applications. Significant impediments to mainstream adoption exist, including unavailability in many institutions, lack of scalability in others, a dearth of physician understanding of interpreted genome or exome results or knowledge of how to translate consequent precision medicine care plans, and a lack of test reimbursement. In short, genomic medicine lacks a breakthrough application. Rapid genome sequencing of acutely ill infants with suspected genetic diseases (STATseq) may become that application when scaled to dozens of trios per day without loss of timeliness or accuracy. Also critical for broad adoption is embedding STATseq in software for timely patient ascertainment, augmented intelligence for interpretation, explanation of results for generalist physicians, and dynamic precision medicine decision support. PMID- 26229554 TI - So rare we need to hunt for them: reframing the ethical debate on incidental findings. AB - Incidental findings are the subject of intense ethical debate in medical genomic research. Every human genome contains a number of potentially disease-causing alterations that may be detected during comprehensive genetic analyses to investigate a specific condition. Yet available evidence shows that the frequency of incidental findings in research is much lower than expected. In this Opinion, we argue that the reason for the low level of incidental findings is that the filtering techniques and methods that are applied during the routine handling of genomic data remove these alterations. As incidental findings are systematically filtered out, it is now time to evaluate whether the ethical debate is focused on the right issues. We conclude that the key question is whether to deliberately target and search for disease-causing variations outside the indication that has originally led to the genetic analysis, for instance by using positive lists and algorithms. PMID- 26229555 TI - Identifying type 2 diabetes risk classification systems and recommendations for review of podiatric care in an Australian Aboriginal health clinic. AB - BACKGROUND: There are several risk classification systems developed to facilitate diabetic foot assessments and prioritise diabetes patients for foot prevention services according to risk factors. Utilisation of both The University of Texas Diabetic Foot Risk Classification System (UTDFRCS) and The National Evidence Based Guideline on Prevention, Identification and Management of Foot Complications in Diabetes (Part of the Guidelines on Management of Type 2 Diabetes), allows guidance for the podiatrist in terms of review timeframes for future assessments and treatment. The aim of this clinical audit was to classify Aboriginal type 2 diabetes subjects' risk status according to UTDFRCS and identify if evidence based standards are being met for podiatry services at the Albury-Wodonga Aboriginal Health Service in New South Wales, Australia. METHODS: A retrospective clinical audit over a twenty six month period was undertaken at the Albury-Wodonga Aboriginal Health Service, New South Wales. This is a primary health care facility that started podiatry services in August 2011. The primary variables of interest were the UTDFRCS for each subject and whether those participants met or did not meet the National Evidence-Based Guideline for review appointment timeframes. Other variables of interest include age, gender, duration of diabetes, occasions of visits and cancelled and failure to attend appointments to the podiatry service over the data collection period. RESULTS: There was excellent overall adherence (94 %) of this sample population (n = 729) to the National Evidence-Based Guideline for podiatric review timeframes according to their risk status. Males were reported to be less likely to comply with the review timeframes compared to women. There was no association between risk status and age (OR = 1.04, p = 0.11), duration of diabetes (OR = 1.03, p = 0.71) or gender (OR = 0.77, p = 0.67). CONCLUSIONS: Regular foot examinations aid in stratifying patients according to risk status, guiding podiatry interventions to reduce the likelihood of ulceration and amputation. This primary health care setting has achieved podiatric evidence based standards for Aboriginal people with type 2 diabetes, demonstrated by acceptable timeframes for review appointments. PMID- 26229556 TI - Postperfusion lung syndrome: Respiratory mechanics, respiratory indices and biomarkers. AB - Postperfusion lung syndrome is rare but lethal. Secondary inflammatory response was the popularly accepted theory for the underlying etiology. Respiratory index (RI) and arterial oxygen tension/fractional inspired oxygen can be reliable indices for the diagnosis of this syndrome as X-ray appearance is always insignificant at the early stage of the onset. Evaluations of extravascular lung water content and pulmonary compliance are also helpful in the definite diagnosis. Multiorgan failure and triple acid-base disturbances that might develop secondary to postperfusion lung syndrome are responsible for the poor prognosis and increased mortality rather than postperfusion lung syndrome itself. Mechanical ventilation with low tidal volume (TV) and proper positive end expiratory pressure can be an effective treatment strategy. Use of ulinastatin and propofol may benefit the patients through different mechanisms. PMID- 26229557 TI - Auscultation of the respiratory system. AB - Auscultation of the lung is an important part of the respiratory examination and is helpful in diagnosing various respiratory disorders. Auscultation assesses airflow through the trachea-bronchial tree. It is important to distinguish normal respiratory sounds from abnormal ones for example crackles, wheezes, and pleural rub in order to make correct diagnosis. It is necessary to understand the underlying pathophysiology of various lung sounds generation for better understanding of disease processes. Bedside teaching should be strengthened in order to avoid erosion in this age old procedure in the era of technological explosion. PMID- 26229558 TI - Overweight-mortality paradox and impact of six-minute walk distance in lung transplantation. AB - Overweight-mortality paradox and impact of six-minute walk distance (SMWD) in lung transplantation. BACKGROUND: The objective of this study was to examine combined prognostic influence of body mass index (BMI) and SMWD on mortality in lung transplant recipients. METHODS: Consecutive isolated lung transplant recipients were identified. Preoperative BMI and SMWD data were collected. The cohort was followed for all-cause mortality. RESULTS: The study included 324 lung transplant recipients with mean age of 57 +/- 13 years and 58% were male (27% obstructive, 3% vascular, 6% cystic fibrosis, and 64% with restrictive lung diseases). In the total cohort; 37% had normal BMI, 10% were underweight, 33% were overweight, and 20% were obese. The median SMWD was 700 feet. The lower SMWDgroup was defined as the patients who had SMWD <237 feet as determined by receiver operating characteristic (ROC). Based on this definition, 66 patients (20%) had lower SMWD. There were 71 deaths during a median follow-up of 2.3 years. In multivariate analysis, both BMI and SMWD were independently associated with death. Being overweight was associated with reduced mortality risk (hazard ratio (HR) 0.50, P = 0.042) compared to the normal BMI group, and this was primarily driven by early mortality posttransplant. This paradoxical overweight mortality relationship remained significant in the lower SMWD group (HR 0.075, P = 0.018), but not in the higher SMWD group (P = 0.552). CONCLUSION: In lung transplant recipients under lung allocation score (LAS) era, pretransplant BMI and SMWD were independent predictors for mortality after the transplant. The lowest mortality risk was noted in a group of transplant recipients identified as overweight; whereas, being underweight or obese was associated with increased mortality. PMID- 26229559 TI - Prevalence and risk factors of asymptomatic bronchiectasis in patients with rheumatoid arthritis at a tertiary care center in Saudi Arabia. AB - INTRODUCTION AND OBJECTIVES: Bronchiectasis is a pulmonary manifestation that often occurs in individuals with rheumatoid arthritis (RA). Nevertheless, the prevalence of bronchiectasis in RA patients and predictors of its development/progression remain ill-defined. Our objective was to investigate the prevalence of bronchiectasis in a group of RA patients and examine possible clinical or biochemical risk factors that might contribute to its development. METHODS: This was an observational study analyzing 100 RA patients with no pulmonary symptoms selected from King Abdulaziz University Hospital in the Western region of Saudi Arabia from October 2013 to 2014. Demographic, clinical and laboratory information were collected for all patients. Diagnosis was based on the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification system, and disease activity was assessed using the 28-Joint Disease Activity Score Index with C-reactive protein; high resolution computed tomography chest scans were performed. The prevalence of bronchiectasis was recorded and its association with different risk factors was examined using standard statistical methods. RESULTS: All 100 patients fulfilled the ACR and EULAR classification criteria for RA diagnosis. Their mean age was 51.05 +/- 13.5 years, disease duration was 6.19 +/- 6.4 years and disease activity index was 4 +/- 1.3 (moderate activity). A total of 35 (35%) patients developed bronchiectasis. Notably, we observed significant positive associations of bronchiectasis with age, disease duration and male gender (P < 0.001, P = 0.006, P = 0.028, respectively). CONCLUSIONS: Asymptomatic bronchiectasis represents a common complication in moderately active RA patients within the Western Region of Saudi Arabia. Furthermore, several predictors of bronchiectasis development were identified, which can contribute to effective risk stratification in RA patients. Further prospective studies are needed to detect the prognosis of asymptomatic bronchiectasis in RA patients. PMID- 26229560 TI - Management of malignant pleural effusion by an indwelling pleural catheter: A cost-efficiency analysis. AB - BACKGROUND: For patients that are expected to survive for longer, the risk of complications combined with the need for more vacuum drainage bottles have become barriers to the placement of indwelling pleural catheter (IPC), since these could increase costs. OBJETIVES: The objective of the current article is to determine the cost and efficiency of treating malignant pleural effusion (MPE) with IPC in Spanish hospitals. METHODS: We compared the cost associated with the use of IPC per outpatient and per inpatient. We analyzed the number of consultations, length of hospital stay, and outcome of the procedure. RESULTS: Fifty-five patients were recruited. Spontaneous pleurodesis was achieved in 34.4% of the cases. Post catheterization complications were observed in 7.2%. Supplementary procedures were unnecessary and 87.7% of the patients reported improved dyspnea. In 64.9% of the cases, the IPCs were inserted during hospitalization with a median hospitalization time of 4 days (1-7.5). There were differences in the number of visits with more consultations being observed in the outpatient group. There was no difference in the number of vacuum drainage bottles used. The complications supposed a cost increase of ?1045.6 per outpatient and ?432.54 per inpatient. The overall average cost of treatment per outpatient was ?3310.2 and ?5450.3 per inpatient. CONCLUSIONS: The treatment with IPC was effective, safe, without need of any more procedures and led to improved dyspnea in more than 85% of the patients. The cost is lower in the outpatient group, although complications represent an increased cost in both groups. PMID- 26229561 TI - Incidence of tuberculosis and immunological profile of TB/HIV co-infected patients in Nigeria. AB - BACKGROUND: We obtained estimates of the incidence of tuberculosis (TB) among patients receiving HIV Treatment. We also modeled the relationship between incident TB and change in CD4 count over the follow-up period. METHODS: We analyzed the incidence of TB over 10 years from initiation of HIV treatment among 345 HIV treatment-naive persons, who were enrolled in a cohort in Kano, Nigeria. We used Generalized Estimating Equation [GEE] to identify determinants of TB incidence and model the relationship between the occurrences of TB with change in CD4 count over the follow-up period. We created Kaplan-Meier curves stratified by anti-retroviral therapy (ART) treatment failure status to examine the effect of first line ART treatment failure on occurrence of TB. RESULT: During the 10-year period, 47(13.62%) had TB [incidence was 7.43 per (1,000) person year)]. It is associated with decreasing age (OR = 0.98), female gender (OR = 0.83), being on first line ART other than AZT (OR = 0.87), poor adherence (OR = 1.25), change in ART regimen (OR = 2.3) and ART treatment failure (OR = 1.51). Odds of TB occurrence was also associated with CD4 increment at 10 years (OR = 0.99). Those with TB/HIV co-infection tend to have statistically significant shorter time to failing first line ART regimen compared to those with HIV infection alone. CONCLUSION: There was high incidence of TB in the studied HIV cohort with a deleterious effect on the outcome of ART treatment. There is need for early TB screening and re-screening among all HIV patients. PMID- 26229562 TI - Prevalence of restless legs syndrome and associated risk factors among middle aged Saudi population. AB - BACKGROUND AND AIM: The prevalence of restless legs syndrome (RLS) in the general population ranges from 5 to 15%; however, locally, such data are scarce. The aim of this study was to estimate the prevalence of RLS in the middle-aged Saudi population. METHODS: This was a cross-sectional study that was conducted from February 2013 to June 2013 in Jeddah, Saudi Arabia. The target study population was Saudi school employees. Saudi employees aged 30-60 years were randomly selected and interviewed individually. Trained interviewers completed the Wisconsin Sleep Questionnaire, questions about demographics, the Epworth Sleepiness Scale to measure daytime sleepiness, and questions regarding symptoms of RLS based on the criteria defined by the International Restless Legs Syndrome Study Group (IRLSSG). RESULTS: This survey revealed that 8.4% (95% confidence interval (CI): (7.35-9.45)) of the 2,682 participants (62.5% of them were males) had RLS. There was no age effect on the prevalence of RLS. RLS was found to be significantly associated with other sleep disorders, including excessive daytime sleepiness and habitual snoring. A univariate analysis revealed significant correlation of many factors with the RLS, including gender, consanguinity, snoring, diabetes, hypertension, asthma, chronic bronchitis, and smoking. However, when a multivariate logistic regression analysis performed, RLS continued to be associated with male gender, diabetes, asthma, and habitual snoring only. CONCLUSION: The prevalence of RLS is 8.4%, which is within the range reported by Western studies. However, unlike findings of most studies, RLS significantly affects males more than females. In addition, snoring, asthma, and consanguinity are potential new risk factors for RLS. PMID- 26229563 TI - Correlation between pentraxin-3 and endothelial dysfunction in obstructive sleep apnea syndrome. AB - BACKGROUND AND AIM: Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for cardiovascular disease. Recent studies showed endothelial dysfunction and pentraxin-3 both of an early marker for development of cardiovascular disease. The aim of the study was to evaluate the relationship between severity of OSAS and endothelial dysfunction and inflammatory markers including pentraxin-3 and high-sensitivity C-reactive protein (hs-CRP). METHODS: This was a cross-sectional study in which patients who had undergone a polysomnographic study for diagnosis of OSAS were recruited. Included patients were grouped according to apnea-hypopnea index (AHI) as mild (AHI between 5 and 14.9) and moderate-severe OSAS (AHI ? 15). Patients with AHI < 5 served as control group. Endothelial function was evaluated by flow-mediated dilatation (FMD). Serum pentraxin-3 and hs-CRP levels were measured. RESULTS: Eighty-three patients enrolled for the study. We found a significant increment in pentraxin-3 and hs-CRP levels and a significant decrement in FMD as the severity of OSAS increased. There was a negative correlation between FMD and AHI, pentraxin, and hs-CRP. CONCLUSION: OSAS patients have significantly elevated pentraxin-3 levels and endothelial dysfunction. Furthermore, both pentraxin-3 and endothelial dysfunction were independently associated with severity of OSAS defined by AHI. PMID- 26229564 TI - Saudi experience in the management of pulmonary arterial hypertension; the outcome of PAH therapy with the exclusion of chronic parenteral prostacyclin. AB - AIMS: The purpose of this study is to present our center's experience in managing patients with pulmonary arterial hypertension (PAH). The main objective is to describe patients' management profile and treatment outcome. METHODS: This study presents the results from a single pulmonary hypertension (PH) specialized center in Saudi Arabia. Both incidence and prevalence cases are included. We have previously reported the clinical and physiological characteristics at the time of diagnosis for this cohort of patients. In this study, we describe the clinical management and the outcome of therapy in the same cohort, who were prospectively followed for a mean of 22 months. RESULTS: A total of 107 patients were identified as having PAH. At the time of enrollment, 56.1% of patients were in modified New York Heart Association functional class (NYHA FC) III and 16.8% were in IV. Phosphdiesterase-5 inhibitor was the most commonly used target therapy (82.2%) followed by endothelin receptors antagonist (74.4%). Only five patients (4.7%) were candidate to use calcium channel blockers. Seventy-nine patients (73.8 %) received a combination nonparenteral target therapy. Thirty-one patients (28.9%) died during the follow-up period. Modified NYHA FC III and IV patients, portopulmonary hypertension, heritable PAH, and PAH associated with connective tissue diseases had the highest mortality rate (P < 0.001). CONCLUSION: Our patients are detected at advanced stage of the disease, and thus the mortality is still unacceptably high. Advanced functional class at presentation and certain disease subgroups are associated with increased mortality. PMID- 26229565 TI - Amyloidosis involving the respiratory system: 5-year's experience of a multi disciplinary group's activity. AB - Amyloidosis may involve the respiratory system with different clinical radiological-functional patterns which are not always easy to be recognized. A good level of knowledge of the disease, an active integration of the pulmonologist within a multidisciplinary setting and a high level of clinical suspicion are necessary for an early diagnosis of respiratory amyloidosis. The aim of this retrospective study was to evaluate the number and the patterns of amyloidosis involving the respiratory system. We searched the cases of amyloidosis among patients attending the multidisciplinary rare and diffuse lung disease outpatients' clinic of Pulmonology Unit of the Hospital of Arezzo from 2007 to 2012. Among the 298 patients evaluated during the study period, we identified three cases of amyloidosis with involvement of the respiratory system, associated or not with other extra-thoracic localizations, whose diagnosis was histo-pathologically confirmed after the pulmonologist, the radiologist, and the pathologist evaluation. Our experience of a multidisciplinary team confirms that intra-thoracic amyloidosis is an uncommon disorder, representing 1.0% of the cases of rare and diffuse lung diseases referred to our center. The diagnosis of the disease is not always easy and quick as the amyloidosis may involve different parts of the respiratory system (airways, pleura, parenchyma). It is therefore recommended to remind this orphan disease in the differential diagnosis of the wide clinical scenarios the pulmonologist may intercept in clinical practice. PMID- 26229566 TI - Recurrent intrathoracic solitary fibrous tumor: Remarkable response to radiotherapy. PMID- 26229567 TI - Is fludeoxyglucose-fluorodeoxyglucose-positron emission tomography/computed tomography ((18)F-FDG-PET/CT) really useless in staging pulmonary carcinoid tumors and in discriminating histological subtypes? Controversial points and future perspectives. PMID- 26229568 TI - Re-emerging Middle East respiratory syndrome coronavirus: The hibernating bat hypothesis. PMID- 26229569 TI - Bocavirus viremia. PMID- 26229570 TI - Erratum: Factors associated with poor asthma control in the outpatient clinic setting: Erratum. AB - [This corrects the article on p. 100 in vol. 10, PMID: 25829960.]. PMID- 26229571 TI - Face scanning and spontaneous emotion preference in Cornelia de Lange syndrome and Rubinstein-Taybi syndrome. AB - BACKGROUND: Existing literature suggests differences in face scanning in individuals with different socio-behavioural characteristics. Cornelia de Lange syndrome (CdLS) and Rubinstein-Taybi syndrome (RTS) are two genetically defined neurodevelopmental disorders with unique profiles of social behaviour. METHODS: Here, we examine eye gaze to the eye and mouth regions of neutrally expressive faces, as well as the spontaneous visual preference for happy and disgusted facial expressions compared to neutral faces, in individuals with CdLS versus RTS. RESULTS: Results indicate that the amount of time spent looking at the eye and mouth regions of faces was similar in 15 individuals with CdLS and 17 individuals with RTS. Both participant groups also showed a similar pattern of spontaneous visual preference for emotions. CONCLUSIONS: These results provide insight into two rare, genetically defined neurodevelopmental disorders that have been reported to exhibit contrasting socio-behavioural characteristics and suggest that differences in social behaviour may not be sufficient to predict attention to the eye region of faces. These results also suggest that differences in the social behaviours of these two groups may be cognitively mediated rather than subcortically mediated. PMID- 26229572 TI - G Protein-Coupled Estrogen Receptor (GPER) Agonist Dual Binding Mode Analyses toward Understanding of its Activation Mechanism: A Comparative Homology Modeling Approach. AB - G protein-coupled estrogen receptor (GPER) has been shown to be important in several disease states such as estrogen sensitive cancers. While several selective ligands have been identified for the receptor, little is known about how they interact with GPER and how their structures influence their activity. Specifically, within one series of ligands, whose structure varied only at one position, the replacement of a hydrogen atom with an acetyl group changed a potent antagonist into a potent agonist. In this study, two GPER homology models were constructed based on the x-ray crystal structures of both the active and inactive beta2-adrenergic receptors (beta2AR) in an effort to characterize the differences of binding modes between agonists and antagonists to the receptor, and to understand their activity in relation to their structures. The knowledge attained in this study is expected to provide valuable information on GPER ligands structure activity relationship to benefit future rational design of potent agonists and antagonists of the receptor for potential therapeutic applications. PMID- 26229573 TI - Evolution of a Biosynthetic Temporary Skin Substitute: A Preliminary Study. AB - OBJECTIVE: To compare PermeaDerm to first temporary biosynthetic skin substitute (Biobrane, cleared by the Food and Drug Administration in 1979). METHODS: Different temporary skin substitutes (Biobrane, PermeaDerm, and PermeaDerm derivatives) were tested for physical differences, impact on healing wounds, inflammatory response, and ability to allow adequate growth of dermal fibroblasts and mesenchymal stem cells without accumulation of excessive scar-forming myofibroblasts. Proliferation of fibroblasts and stem cells on various skin substitutes was measured, and myofibroblast marker accumulation was evaluated by the expression of alpha-smooth muscle actin and fibronectin. Fibroblast migration was measured by tracking viable cells with MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] dye. RESULTS: In vivo testing shows PermeaDerm works well as a temporary skin substitute, performing better than Biobrane with respect to inflammation and fluid accumulation. Tissue culture techniques revealed that cells on PermeaDerm grow in a more uniform fashion and migrated to a greater extent than cells on Biobrane. Furthermore, cells grown in the presence of PermeaDerm expressed lower levels of the myofibroblast markers alpha-smooth muscle actin and fibronectin than cells grown on Biobrane. CONCLUSION: PermeaDerm with variable porosity possesses all attributes and properties known to be important for a successful temporary skin substitute and enables the clinician to control porosity from essentially zero to what the wound requires. The ability of the clinician to minimize wound desiccation without fluid accumulation is related to the reduction of punctate scarring. PMID- 26229574 TI - Nevus Sebaceus of Jadassohn. PMID- 26229575 TI - Invasive Squamous Cell Carcinoma of the Scalp. PMID- 26229576 TI - Complications After Primary Breast Augmentation: Capsular Contracture. PMID- 26229577 TI - Omental Flap for Thoracic Aortic Graft Infection. PMID- 26229579 TI - Heterozygosis deficit of polymorphic markers linked to the beta-globin gene cluster region in the Iranian population. AB - OBJECTIVES: Iran is considered as one of the high-prevalence areas for beta thalassemia with a rate of about 10% carrier frequency. Molecular diagnosis of the disease is performed both by direct sequencing and indirectly by the use of polymorphic markers present in the beta globin gene cluster. However, to date there is no reliable information on the application of the markers in the Iranian population. Here we report the results of an extended molecular analysis of five RFLP markers, XmnI, HindIIIA, HindIIIG, RsaI and HinfI, located within the beta globin gene cluster region in four subpopulations of Iran. MATERIALS AND METHODS: A total of 552 blood samples taken from the Iranian subpopulations including Isfahan, Chaharmahal-O-Bakhtiari, Khuzestan and Hormozgan were genotyped using PCR-RFLP and sequencing. The allele frequency, the expected and observed heterozygosity, and Shannon's information index (I) of these markers were calculated. RESULTS: Distribution of the allele frequencies for XmnI, HindIIIA, HindIIIG, RsaI and HinfI polymorphic markers did not differ significantly among the subpopulations examined. Overall observed heterozygosity ranged from 0.1706 for HindIIIA to 0.4484 for RsaI. The Shannon index was <1 for all the polymorphic markers in the populations studied. The data indicated that heterozygosity of these markers was low in the Iranian population. CONCLUSION: The results suggested that genotyping of these markers is not informative enough once used as single markers for prenatal diagnosis and carrier detection of beta-thalassemia in the Iranian population. However, haplotyping of these markers may provide more useful data in linkage analysis and prenatal diagnosis as well as carrier detections for beta-thalassemia in Iranians. PMID- 26229578 TI - High Potency of a Novel Resveratrol Derivative, 3,3',4,4'-Tetrahydroxy-trans stilbene, against Ovarian Cancer Is Associated with an Oxidative Stress-Mediated Imbalance between DNA Damage Accumulation and Repair. AB - We explored the effect of a new resveratrol (RVT) derivative, 3,3',4,4' tetrahydroxy-trans-stilbene (3,3',4,4'-THS), on viability, apoptosis, proliferation, and senescence of three representative lines of ovarian cancer cells, that is, A2780, OVCAR-3, and SKOV-3, in vitro. In addition, the mechanistic aspects of 3,3',4,4'-THS activity, including cell redox homeostasis (the production of reactive oxygen species, activity of enzymatic antioxidants, and magnitude of DNA damage accumulation and repair), and the activity of caspases (3, 8, and 9) and p38 MAPK were examined. The study showed that 3,3',4,4'-THS affects cancer cell viability much more efficiently than its parent drug. This effect coincided with increased generation of reactive oxygen species, downregulated activity of superoxide dismutase and catalase, and excessive accumulation of 8-hydroxy-2'-deoxyguanosine and its insufficient repair due to decreased expression of DNA glycosylase I. Cytotoxicity elicited by 3,3',4,4'-THS was related to increased incidence of apoptosis, which was mediated by caspases 3 and 9. Moreover, 3,3',4,4'-THS inhibited cancer cell proliferation and accelerated senescence, which was accompanied by the activation of p38 MAPK. Collectively, our findings indicate that 3,3',4,4'-THS may constitute a valuable tool in the fight against ovarian malignancy and that the anticancer capabilities of this stilbene proceed in an oxidative stress-dependent mechanism. PMID- 26229580 TI - Coronectomy of Deeply Impacted Lower Third Molar: Incidence of Outcomes and Complications after One Year Follow-Up. AB - OBJECTIVES: The purpose of present study was to assess the surgical management of impacted third molar with proximity to the inferior alveolar nerve and complications associated with coronectomy in a series of patients undergoing third molar surgery. MATERIAL AND METHODS: The position of the mandibular canal in relation to the mandibular third molar region and mandibular foramen in the front part of the mandible (i.e., third molar in close proximity to the inferior alveolar nerve [IAN] or not) was identified on panoramic radiographs of patients scheduled for third molar extraction. RESULTS: Close proximity to the IAN was observed in 64 patients (35 females, 29 males) with an impacted mandibular third molar. Coronectomy was performed in these patients. The most common complication was tooth migration away from the mandibular canal (n = 14), followed by root exposure (n = 5). Re-operation to remove the root was performed in cases with periapical infection and root exposure. CONCLUSIONS: The results indicate that coronectomy can be considered a reasonable and safe treatment alternative for patients who demonstrate elevated risk for injury to the inferior alveolar nerve with removal of the third molars. Coronectomy did not increase the incidence of damage to the inferior alveolar nerve and would be safer than complete extraction in situations in which the root of the mandibular third molar overlaps or is in close proximity to the mandibular canal. PMID- 26229581 TI - Stability after Cleft Maxillary Distraction Osteogenesis or Conventional Orthognathic Surgery. AB - OBJECTIVES: To compare stability of maxillary advancements in patients with cleft lip and palate following distraction osteogenesis or orthognathic surgery. MATERIAL AND METHODS: INCLUSION CRITERIA: 1) cleft lip and palate, 2) advancement > 8 mm. Eleven patients comprised the distraction osteogenesis group (DOG). Seven patients comprised the orthognathic treatment group (CONVG). Skeletal and soft tissue points were traced on lateral cephalograms: T1 (preoperatively), T2 (after surgery), T3 (follow-up). Group differences were analyzed using Students t-test. RESULTS: At T1-T2, advancement of 6.98 mm (P = 0.002) was observed in DOG. Horizontal overjet increased 11.62 mm (P = 0.001). A point-nasion-B point (ANB) angle increased 8.82 degrees (P = 0.001). Aesthetic plane to upper lip was reduced 5.44 mm (P = 0.017) and the naso-labial angle increased 16.6 degrees (P = 0.001). Vertical overbite (VOB) increased 2.27 mm (P = 0.021). In T2-T3, no significant changes were observed in DOG. In T1-T2, horizontal overjet increased 8.45 mm (P = 0.02). The ANB angle, 9.33 degrees (P = 0.009) in CONVG. At T2-T3, VOB increased, 2.35 mm (P = 0.046), and the ANB angle reduced, 3.83 degrees (P = 0.003). In T2-T3, no parameters changed in CONVG. At follow-up (T3), VOB increased in CONVG compared with DOG, (P = 0.01). Vertical position of A point differed between the groups (P = 0.04). No significant intergroup differences between soft tissue parameters occurred. CONCLUSIONS: Distraction osteogenesis resulted in a stable position of the maxilla and movement upwards in vertical plane, however in case of orthognathic treatment sagittal relapse and a continued postoperatively downward movement was registered. PMID- 26229582 TI - Cyclooxygenase-2 and Ki67 Expression in Oral Leukoplakia: a Clinicopathological Study. AB - OBJECTIVES: Oral leukoplakia is a precancerous lesion of the oral mucosa. The upregulation of Ki67 and cyclooxygenase-2 has been reported in both dysplastic and non-dysplastic tissues. The aim of this clinicopathological study was to investigate the prognostic value of Ki67 and cyclooxygenase-2 expression for oral leukoplakia. MATERIAL AND METHODS: A total of 50 samples were investigated and the study group consisted of 30 oral leukoplakia samples. Samples of 10 intact oral mucosa and 10 squamous cell carcinoma were included as negative and positive control groups, respectively. Epithelial dysplasia was defined as oral intraepithelial neoplasia (OIN) and classified into subgroups 1 - 3. Tissue samples were assessed immunohistochemically for Ki67 and cyclooxygenase-2 expression. Clinicopathological correlations of oral leukoplakia patients were also investigated. RESULTS: All OIN 3 patients were non-smokers (P < 0.05), and homogeneous oral leukoplakia lesions also presented OIN. Both cyclooxygenase-2 and Ki67 expression increased with the severity of lesions, which defined different subgroups (P < 0.05), except there was no significant difference between the hyperkeratosis and OIN groups for Ki67 expression. CONCLUSIONS: Cyclooxygenase-2 and Ki67 expression may have a prognostic value for the malignant transformation of oral leukoplakia. PMID- 26229583 TI - Expression of cdk4 and p16 in Oral Lichen Planus. AB - OBJECTIVES: The purpose of this study was to evaluate the expression of cdk4 and p16, the proteins implicated in hyperproliferation and arrest in oral lichen planus and to compare their expression in erosive and non-erosive oral lichen planus and with normal mucosa and oral squamous cell carcinoma. MATERIAL AND METHODS: Analysis of cdk4 and p16 expression was done in 43 erosive oral lichen planus (EOLP) and 17 non-erosive oral lichen planus (NOLP) cases, 10 normal mucosa and 10 oral squamous cell carcinoma (OSCC) cases with immunohistochemistry. RESULTS: This study demonstrated a significantly increased expression of cytoplasmic cdk4 (80% cases, cells stained - 19.6%), and cytoplasmic p16 (68.3% cases, cells stained - 16.4%) in oral lichen planus (OLP) compared to normal mucosa. cdk4 was much higher in OSCC in both cytoplasm and nuclei compared to normal mucosa. Also, while comparing OLP with positive control, significant difference was noted for cdk4 and p16, with expression being more in OSCC. While comparing EOLP with NOLP; significant differences were seen for cdk4 cytoplasmic staining only, for number of cases with positive staining as well as number of cells stained. CONCLUSIONS: Overexpression of cytoplasmic cdk4 and p16 was registered in oral lichen planus, however considerably lower than in squamous cell carcinoma. Erosive oral lichen planus demonstrated overexpression of cytoplasmic cdk4 and premalignant nature compared to non-erosive lesion. Therefore there is an obvious possibility for cytoplasmic expression of cdk4 and p16 to predict malignant potential of oral lichen planus lesions. PMID- 26229584 TI - Management of Intraosseous Vascular Malformations of the Jaws in Children and Adolescents: Report of 6 Cases and Literature Review. AB - BACKGROUND: Intraosseous vascular malformations represent a rare clinical entity of the facial skeleton. The purpose of the current study was to present our experience in a Greek paediatric population and propose guidelines for the treatment of these jaws anomalies in children and adolescents. METHODS: A retrospective study (from 2009 to 2014) was performed to investigate the features and management of the intraosseous vascular anomalies in a Greek paediatric population. RESULTS: Six patients aged between 6 and 14 years were treated for intraosseous vascular malformations (4 venous and 2 arteriovenous) of the jaws. Five lesions were located in the mandible and one in the maxilla. In four lesions with pronounced vascularity superselective angiography, followed by embolization was performed. Individualized surgical treatment, depending on the size and vascularity of the lesions was applied in 4 patients. CONCLUSIONS: The intraosseous vascular malformations of the jaws may escape diagnosis in paediatric patients. A multidisciplinary approach is important for their safe and efficient treatment. Embolization is recommended for extended high-flow lesions, either preoperatively or as a first-line treatment, when surgery is not feasible without significant morbidity. PMID- 26229585 TI - Improving the Sequence Ontology terminology for genomic variant annotation. AB - BACKGROUND: The Genome Variant Format (GVF) uses the Sequence Ontology (SO) to enable detailed annotation of sequence variation. The annotation includes SO terms for the type of sequence alteration, the genomic features that are changed and the effect of the alteration. The SO maintains and updates the specification and provides the underlying ontologicial structure. METHODS: A requirements analysis was undertaken to gather terms missing in the SO release at the time, but needed to adequately describe the effects of sequence alteration on a set of variant genomic annotations. We have extended and remodeled the SO to include and define all terms that describe the effect of variation upon reference genomic features in the Ensembl variation databases. RESULTS: The new terminology was used to annotate the human reference genome with a set of variants from both COSMIC and dbSNP. A GVF file containing 170,853 sequence alterations was generated using the SO terminology to annotate the kinds of alteration, the effect of the alteration and the reference feature changed. There are four kinds of alteration and 24 kinds of effect seen in this dataset. (Ensembl Variation annotates 34 different SO consequence terms: http://www.ensembl.org/info/docs/variation/predicted_data.html). CONCLUSIONS: We explain the updates to the Sequence Ontology to describe the effect of variation on existing reference features. We have provided a set of annotations using this terminology, and the well defined GVF specification. We have also provided a provisional exploration of this large annotation dataset. PMID- 26229586 TI - Palladium-Catalyzed Cross-Coupling of alpha-Bromocarbonyls and Allylic Alcohols for the Synthesis of alpha-Aryl Dicarbonyl Compounds. AB - The palladium-catalyzed coupling of olefins and organohalides is a versatile approach for synthesizing complex molecules from simple starting materials. We have developed a palladium-catalyzed coupling of alpha-bromocarbonyl compounds with allylic alcohols for the generation of acyclic aryl-substituted dicarbonyl compounds. The reaction proceeds via a tandem olefin insertion of an alpha-acyl radical followed by a 1,2-aryl migration. In addition to providing preliminary evidence for a free radical mediated mechanism, we demonstrate unprecedented levels of 1,3-stereoinduction for the 1,2-migration step. PMID- 26229587 TI - Rh-Catalyzed Decarbonylation of Conjugated Ynones via Carbon-Alkyne Bond Activation: Reaction Scope and Mechanistic Exploration via DFT Calculations. AB - In this full article, detailed development of a catalytic decarbonylation of conjugated monoynones to synthesize disubstituted alkynes is described. The reaction scope and limitation has been thoroughly investigated, and a broad range of functional groups including heterocycles were compatible under the catalytic conditions. Mechanistic exploration via DFT calculations has also been executed. Through the computational study, a proposed catalytic mechanism has been carefully evaluated. These efforts are expected to serve as an important exploratory study for developing catalytic alkyne-transfer reactions via carbon alkyne bond activation. PMID- 26229588 TI - Exogenous hydrogen sulfide restores cardioprotection of ischemic post conditioning via inhibition of mPTP opening in the aging cardiomyocytes. AB - The physiological and pathological roles of hydrogen sulfide (H2S) in the regulation of cardiovascular functions have been recognized. H2S protects against the hypoxia/reoxygenation (H/R)-induced injury and apoptosis of cardiomyocytes, and ischemic post-conditioning (PC) plays an important role in cardioprotection from H/R injury in neonatal cardiomyocytes but not in aging cardiomyocytes. Whether H2S is involved in the recovery of PC-induced cardioprotection in aging cardiomyocytes is unclear. In the present study, we found that both H/R and PC decreased cystathionine-gamma-lyase (CSE) expression and the production rate of H2S. Supplementation of NaHS protected against H/R-induced apoptosis, the expression of cleaved caspase-3 and cleaved caspase-9, the release of cytochrome c (Cyt c), and mPTP opening. The addition of NaHS also counteracted the reduction of cell viability caused by H/R and increased the phosphorylation of ERK1/2, PI3K, Akt, GSK-3beta and mitochondrial membrane potential. Additionally, NaHS increased Bcl-2 expression, promoted PKC-epsilon translocation to the cell membrane, and activated mitochondrial ATP-sensitive K channels (mitoKATP). PC alone did not provide cardioprotection in H/R-treated aging cardiomyocytes, which was significantly restored by the supplementation of NaHS. In conclusion, our results suggest that exogenous H2S restores PC-induced cardioprotection via the inhibition of mPTP opening by the activation of the ERK1/2-GSK-3beta, PI3K-Akt GSK-3beta and PKC-epsilon-mitoKATP pathways in aging cardiomyocytes. These findings provide a novel target for the treatment of aging ischemic cardiomyopathy. PMID- 26229589 TI - Depressive-like history alters persistent pain behavior in rats: Opposite contribution of frontal cortex and amygdala implied. AB - Numerous studies have shown that pain perception is strongly influenced by depression. However, very few studies have examined whether pain perception is altered in the remission period of depression, and what role the fronto-limbic circuits may play in the behavioral changes associated with remission. Using an unpredictable chronic mild stress (UCMS) animal model of depression, the present study investigated pain-related behaviors in rats with prior exposure to a UCMS stimulus. The gamma-aminobutyric acid (GABA)A receptor agonist muscimol was microinjected bilaterally into the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) to examine the modulation of pain by these brain regions in the recovery state. Rats with a depression-like history displayed increased ongoing pain behavior in the formalin test, although their thermal pain thresholds were unchanged. Intra-BLA muscimol during the recovery phase dramatically decreased formalin-induced pain behavior and also significantly increased rats' sucrose preference. By contrast, in the mPFC, muscimol produced the opposite effect, suggesting different, perhaps opposing, roles of the BLA and mPFC in mediating the influence of prior UCMS exposure on pain perception. Taken together, these results demonstrated that a depressive experience may cause long term alterations in limbic circuit excitability and thus lead to long-lasting changes in pain perception. PMID- 25767695 TI - Open peer review at four STEM journals: an observational overview. AB - Open peer review, peer review where authors' and reviewers' identities are disclosed to one another, is a growing trend in scholarly publishing. Through observation of four journals in STEM disciplines, PLOS One, Atmospheric Chemistry & Physics, PeerJ, and F1000Research, an observational overview is conducted. The overview relies on defined characteristics of open peer review. Results show that despite differing open peer review implementations, each journal retains editorial involvement in scholarly publishing. Further, the analysis shows that only one of these implementations is fully transparent in its peer review and decision making process. Finally, the overview contends that journals should clearly outline peer review and editorial processes in order to allow for open peer review to be better understood and adopted by authors, reviewers, editors, and readers of science communications. PMID- 25949804 TI - Finding small molecules for the 'next Ebola'. AB - The current Ebola virus epidemic may provide some suggestions of how we can better prepare for the next pathogen outbreak. We propose several cost effective steps that could be taken that would impact the discovery and use of small molecule therapeutics including: 1. text mine the literature, 2. patent assignees and/or inventors should openly declare their relevant filings, 3. reagents and assays could be commoditized, 4. using manual curation to enhance database links, 5. engage database and curation teams, 6. consider open science approaches, 7. adapt the "box" model for shareable reference compounds, and 8. involve the physician's perspective. PMID- 25949805 TI - Digital teaching tools and global learning communities. AB - In 2009, we started a project to support the teaching and learning of university level plant sciences, called Teaching Tools in Plant Biology. Articles in this series are published by the plant science journal, The Plant Cell (published by the American Society of Plant Biologists). Five years on, we investigated how the published materials are being used through an analysis of the Google Analytics pageviews distribution and through a user survey. Our results suggest that this project has had a broad, global impact in supporting higher education, and also that the materials are used differently by individuals in terms of their role (instructor, independent learner, student) and geographical location. We also report on our ongoing efforts to develop a global learning community that encourages discussion and resource sharing. PMID- 26229594 TI - Deeply sequenced metagenome and metatranscriptome of a biogas-producing microbial community from an agricultural production-scale biogas plant. AB - BACKGROUND: The production of biogas takes place under anaerobic conditions and involves microbial decomposition of organic matter. Most of the participating microbes are still unknown and non-cultivable. Accordingly, shotgun metagenome sequencing currently is the method of choice to obtain insights into community composition and the genetic repertoire. FINDINGS: Here, we report on the deeply sequenced metagenome and metatranscriptome of a complex biogas-producing microbial community from an agricultural production-scale biogas plant. We assembled the metagenome and, as an example application, show that we reconstructed most genes involved in the methane metabolism, a key pathway involving methanogenesis performed by methanogenic Archaea. This result indicates that there is sufficient sequencing coverage for most downstream analyses. CONCLUSIONS: Sequenced at least one order of magnitude deeper than previous studies, our metagenome data will enable new insights into community composition and the genetic potential of important community members. Moreover, mapping of transcripts to reconstructed genome sequences will enable the identification of active metabolic pathways in target organisms. PMID- 26229595 TI - Missense mutation in the PTEN promoter of a patient with hemifacial hyperplasia. AB - The cellular mechanisms involved in the asymmetric facial overgrowth syndrome, hemifacial hyperplasia (HFH), are not well understood. This study was conducted to compare primary cell cultures from hyperplastic and normal HFH bone for cellular and molecular differences. Primary cultures developed from biopsies of a patient with isolated HFH showed a twofold difference in cell size and cell number between hyperplastic and normal bone. Microarray data suggested a 40% suppression of PTEN (phosphatase-tensin homolog) transcripts. Sequencing of the PTEN gene and promoter identified novel C/G missense mutation (position -1053) in the regulatory region of the PTEN promoter. Western blots of downstream pathway components showed an increase in PKBa/Akt1 phosphorylation and TOR (target of rapamcyin) signal. Sirolimus, an inhibitor of TOR, when added to overgrowth cells reversed the cell size, cell number and total protein differences between hyperplastic and normal cells. In cases of facial overgrowth, which involve PTEN/Akt/TOR dysregulation, sirolimus could be used for limiting cell overgrowth. PMID- 26229593 TI - The Role of Hydroxyl Channel in Defining Selected Physicochemical Peculiarities Exhibited by Hydroxyapatite. AB - Mysteries surrounding the most important mineral for the vertebrate biology, hydroxyapatite, are many. Perhaps the Greek root of its name, alphapialphataualphao, meaning 'to deceive' and given to its mineral form by the early gem collectors who confused it with more precious stones, is still applicable today, though in a different connotation, descriptive of a number of physicochemical peculiarities exhibited by it. Comparable to water as the epitome of peculiarities in the realm of liquids, hydroxyapatite can serve as a paradigm for peculiarities in the world of solids. Ten of the peculiar properties of hydroxyapatite are sketched in this review piece, ranging from (i) the crystal lattice flexibility to (ii) notorious surface layer instability to (iii) finite piezoelectricity, pyroelectricity and conductivity to protons to (iv) accelerated growth and improved osteoconductivity in the electromagnetic fields to (v) high nucleation rate at low supersaturations and low crystal growth rate at high supersaturations to (vi) higher bioactivity and resorbability of biological apatite compared to the synthetic ones, and beyond. An attempt has been made to explain this array of curious characteristics by referring to a particular element of the crystal structure of hydroxyapatite: the hydroxyl ion channel extending in the direction of the c-axis, through a crystallographic column created by the overlapping calcium ion triangles. PMID- 26229596 TI - Adult Tph2 knockout mice without brain serotonin have moderately elevated spine trabecular bone but moderately low cortical bone thickness. AB - Disruption of serotonin synthesis in neurons and the periphery by knockout (KO) of mouse genes for tryptophan hydroxylases (peripheral Tph1 and neuronal Tph2) has been claimed to decrease (Tph2 KO) and increase (Tph1 KO) bone mass. In this report, adult male and female Tph2 KO mice were observed to have elevated spine trabecular bone. Female Tph2 KO mice have reduced midshaft femur cortical bone thickness. Bone mass was normal in male and female Tph1 KO mice examined as part of a Tph1/Tph2 double knockout (DKO) mouse cohort. PMID- 26229597 TI - The vocabulary of microbiome research: a proposal. AB - The advancement of DNA/RNA, proteins, and metabolite analytical platforms, combined with increased computing technologies, has transformed the field of microbial community analysis. This transformation is evident by the exponential increase in the number of publications describing the composition and structure, and sometimes function, of the microbial communities inhabiting the human body. This rapid evolution of the field has been accompanied by confusion in the vocabulary used to describe different aspects of these communities and their environments. The misuse of terms such as microbiome, microbiota, metabolomic, and metagenome and metagenomics among others has contributed to misunderstanding of many study results by the scientific community and the general public alike. A few review articles have previously defined those terms, but mainly as sidebars, and no clear definitions or use cases have been published. In this editorial, we aim to propose clear definitions of each of these terms, which we would implore scientists in the field to adopt and perfect. PMID- 26229598 TI - Erratum to: Stability of operational taxonomic units: an important but neglected property for analyzing microbial diversity. AB - [This corrects the article DOI: 10.1186/s40168-015-0081-x.]. PMID- 26229599 TI - The burden of mental health in lymphatic filariasis. AB - BACKGROUND: Neglected Tropical Diseases (NTDs) afflict around one billion individuals in the poorest parts of the world with many more at risk. Lymphatic filariasis is one of the most prevalent of the infections and causes significant morbidity in those who suffer the clinical conditions, particularly lymphedema and hydrocele. Depressive illness has been recognised as a prevalent disability in those with the disease because of the stigmatising nature of the condition. No estimates of the burden of depressive illness of any neglected tropical disease have been undertaken to date despite the recognition that such diseases have major consequences for mental health not only for patients but also their caregivers. METHODS: We developed a mathematical model to calculate the burden of Disability- Adjusted Life Years (DALY) attributable to depressive illness in lymphatic filariasis and that of their caregivers using standard methods for calculating DALYs. Estimates of numbers with clinical disease was based on published estimates in 2012 and the numbers with depressive illness from the available literature. RESULTS: We calculated that the burden of depressive illness in filariasis patients was 5.09 million disability-adjusted life years (DALYs) and 229,537 DALYs attributable to their caregivers. These figures are around twice that of 2.78 million DALYs attributed to filariasis by the Global Burden of Disease study of 2010. CONCLUSIONS: Lymphatic filariasis and other neglected tropical diseases, notably Buruli Ulcer, cutaneous leishmaniasis, leprosy, yaws, onchocerciasis and trachoma cause significant co morbidity associated with mental illness in patients. Studies to assess the prevalence of the burden of this co-morbidity should be incorporated into any future assessment of the Global Burden of neglected tropical diseases. The prevalence of depressive illness in caregivers who support those who suffer from these conditions is required. Such assessments are critical for neglected tropical diseases which have such a huge global prevalence and thus will contribute a significant burden of co-morbidity attributable to mental illness. PMID- 26229600 TI - Journal of Medical Radiation Sciences - a joint journal between Australia and New Zealand. PMID- 26229601 TI - Magnetic resonance microscopy of prostate tissue: How basic science can inform clinical imaging development. AB - This commentary outlines how magnetic resonance imaging (MRI) microscopy studies of prostate tissue samples and whole organs have shed light on a number of clinical imaging mysteries and may enable more effective development of new clinical imaging methods. PMID- 26229602 TI - Developing radiographer roles in the context of advanced and consultant practice. AB - Skill-mix initiatives have provided opportunities for radiographers to develop roles and achieve their potential, thus contributing to radiographer retention rates and increased job satisfaction. This reflective article explores two radiographic roles within an interprofessional context including the implications for confidence, competence, and future sustainability. These were reporting roles which extended into two modalities, one into bone densitometry and another into ultrasound. This article discusses how successful skill mix can benefit the individual, their department, and NHS organization and that role expansion can develop a more dynamic and resourceful workforce with transferability of skills and attributes. PMID- 26229603 TI - Whole breast and excision cavity radiotherapy plan comparison: Conformal radiotherapy with sequential boost versus intensity-modulated radiation therapy with a simultaneously integrated boost. AB - INTRODUCTION: A comparative study was conducted comparing the difference between (1) conformal radiotherapy (CRT) to the whole breast with sequential boost excision cavity plans and (2) intensity-modulated radiation therapy (IMRT) to the whole breast with simultaneously integrated boost to the excision cavity. The computed tomography (CT) data sets of 25 breast cancer patients were used and the results analysed to determine if either planning method produced superior plans. METHODS: CT data sets from 25 past breast cancer patients were planned using (1) CRT prescribed to 50 Gy in 25 fractions (Fx) to the whole-breast planning target volume (PTV) and 10 Gy in 5Fx to the excision cavity and (2) IMRT prescribed to 60 Gy in 25Fx, with 60 Gy delivered to the excision cavity PTV and 50 Gy delivered to the whole-breast PTV, treated simultaneously. In total, 50 plans were created, with each plan evaluated by PTV coverage using conformity indices, plan maximum dose, lung dose, and heart maximum dose for patients with left-side lesions. RESULTS: CRT plans delivered the lowest plan maximum doses in 56% of cases (average CRT = 6314.34 cGy, IMRT = 6371.52 cGy). They also delivered the lowest mean lung dose in 68% of cases (average CRT = 1206.64 cGy, IMRT = 1288.37 cGy) and V20 in 88% of cases (average CRT = 20.03%, IMRT = 21.73%) and V30 doses in 92% of cases (average CRT = 16.82%, IMRT = 17.97%). IMRT created more conformal plans, using both conformity index and conformation number, in every instance, and lower heart maximum doses in 78.6% of cases (average CRT = 5295.26 cGy, IMRT = 5209.87 cGy). CONCLUSION: IMRT plans produced superior dose conformity and shorter treatment duration, but a slightly higher planning maximum and increased lung doses. IMRT plans are also faster to treat on a daily basis, with shorter fractionation. PMID- 26229604 TI - A snapshot of radiation therapy techniques and technology in Queensland: An aid to mapping undergraduate curriculum. AB - INTRODUCTION: Undergraduate students studying the Bachelor of Radiation Therapy at Queensland University of Technology (QUT) attend clinical placements in a number of department sites across Queensland. To ensure that the curriculum prepares students for the most common treatments and current techniques in use in these departments, a curriculum matching exercise was performed. METHODS: A cross sectional census was performed on a pre-determined "Snapshot" date in 2012. This was undertaken by the clinical education staff in each department who used a standardized proforma to count the number of patients as well as prescription, equipment, and technique data for a list of tumour site categories. This information was combined into aggregate anonymized data. RESULTS: All 12 Queensland radiation therapy clinical sites participated in the Snapshot data collection exercise to produce a comprehensive overview of clinical practice on the chosen day. A total of 59 different tumour sites were treated on the chosen day and as expected the most common treatment sites were prostate and breast, comprising 46% of patients treated. Data analysis also indicated that intensity modulated radiotherapy (IMRT) use is relatively high with 19.6% of patients receiving IMRT treatment on the chosen day. Both IMRT and image-guided radiotherapy (IGRT) indications matched recommendations from the evidence. CONCLUSION: The Snapshot method proved to be a feasible and efficient method of gathering useful data to inform curriculum matching. Frequency of IMRT use in Queensland matches or possibly exceeds that indicated in the literature. It is recommended that future repetition of the study be undertaken in order to monitor trends in referral patterns and new technology implementation. PMID- 26229605 TI - Mammographic screening for breast cancer: A review. AB - In 2011, BreastScreen Australia celebrated 20 years of mammographic screening for breast cancer in Australia. There has been a reduction in mortality from breast cancer over the last two decades, coincident with mammographic screening. However, there are concerns that mammographic screening may result in overdiagnosis of breast cancer and that the reduction in mortality from breast cancer is the result of better treatment rather than screening. This article reviews the evidence on which mammographic screening for breast cancer is based, considers the issue of overdiagnosis of breast cancer by screening mammography, and assesses the role of screening mammography in the reduction in breast cancer mortality seen over the last two decades. PMID- 26229606 TI - Radiotherapy in the management of early breast cancer. AB - Radiotherapy is an indispensible part of the management of all stages of breast cancer. In this article, the common indications for radiotherapy in the management of early breast cancer (stages 0, I, and II) are reviewed, including whole-breast radiotherapy as part of breast-conserving treatment for early invasive breast cancer and pre-invasive disease of ductal carcinoma in situ, post mastectomy radiotherapy, locoregional radiotherapy, and partial breast irradiation. Key clinical studies that underpin our current practice are discussed briefly. PMID- 26229607 TI - Action research in radiography: What it is and how it can be conducted. AB - Action research is a form of research that investigates and describes a social or work situation with the aim of achieving a change which results in improvement. This article emphasizes the potential for action research to be a useful research method in radiography. A search was conducted to determine the extent to which action research has been utilized in radiography. Although action research has been used in a number of health-care settings, there are no published examples of action research being utilized in a clinical medical imaging department. Action research is discussed in detail, along with an example guide for an action research study. Action research has been identified as a useful way to affect change, to involve radiographers in the research process, and to introduce evidence-based practice to radiography. PMID- 26229608 TI - A retrospective comparison of smart prep and test bolus multi-detector CT pulmonary angiography protocols. AB - INTRODUCTION: Optimal arterial opacification is crucial in imaging the pulmonary arteries using computed tomography (CT). This poses the challenge of precisely timing data acquisition to coincide with the transit of the contrast bolus through the pulmonary vasculature. The aim of this quality assurance exercise was to investigate if a change in CT pulmonary angiography (CTPA) scanning protocol resulted in improved opacification of the pulmonary arteries. Comparison was made between the smart prep protocol (SPP) and the test bolus protocol (TBP) for opacification in the pulmonary trunk. METHODS: A total of 160 CTPA examinations (80 using each protocol) performed between January 2010 and February 2011 were assessed retrospectively. CT attenuation coefficients were measured in Hounsfield Units (HU) using regions of interest at the level of the pulmonary trunk. The average pixel value, standard deviation (SD), maximum, and minimum were recorded. For each of these variables a mean value was then calculated and compared for these two CTPA protocols. RESULTS: Minimum opacification of 200 HU was achieved in 98% of the TBP sample but only 90% of the SPP sample. The average CT attenuation over the pulmonary trunk for the SPP was 329 (SD = +/-21) HU, whereas for the TBP it was 396 (SD = +/-22) HU (P = 0.0017). The TBP also recorded higher maximum (P = 0.0024) and minimum (P = 0.0039) levels of opacification. CONCLUSION: This study has found that a TBP resulted in significantly better opacification of the pulmonary trunk than the SPP. PMID- 26229609 TI - Use of (99m)Tc 2-methoxyisobutyl isonitrile in minimally invasive radioguided surgery in patients with primary hyperparathyroidism: A narrative review of the current literature. AB - The use of technetium-99m 2-methoxyisobutyl isonitrile ((99m)Tc MIBI) for assistance in minimally invasive radioguided surgery (MIRS) is growing in popularity as a safe, effective, and proficient technique used for parathyroidectomy in primary hyperparathyroidism (PHPT) treatment. Previously, the preferred treatment for PHPT was bilateral neck exploration (BNE), a very invasive, costly, and lengthy procedure. However, as a large majority (80-85% of cases of PHPT) are attributed to a single parathyroid adenoma (PA), a simpler more direct technique such as MIRS is a far better option. The following article is an exploration of the current literature concerning varied protocols utilizing (99m)Tc MIBI for assistance in MIRS for patients undergoing treatment of PHPT. This technique boasts many advantageous outcomes for patients suffering from PHPT. These include a reduction in cost, operating time, and patient recovery; less evidence of post-surgical hypocalcaemia, less pain, and complications; superior cosmetic results; same-day discharge; and the possibility of local anaesthesia which is particularly beneficial in elderly patients. Better outcomes for patients with deep or ectopic PAs, reduced intra-operative complications, and improved cosmetic outcomes for patients who have previously undergone thyroid and/or parathyroid surgery are also advantageous. Of the literature reviewed it was also found that no patients suffered any major surgical complications such as laryngeal nerve palsy or permanent hypoparathyroidism using (99m)Tc MIBI for assistance in MIRS. PMID- 26229610 TI - Novel utilization of 3D technology and the hybrid operating theatre: Peri operative assessment of posterior sterno-clavicular dislocation using cone beam CT. AB - A patient with a medial and posterior dislocation of the right sterno-clavicular (SC) joint and displacement of the trachea and brachiocephalic artery by the medial head of the clavicle underwent general anaesthetic in the operating theatre for an open reduction procedure. The surgeon initially attempted a closed reduction, but this required imaging to check SC alignment. The patient was transferred to an adjacent hybrid operating theatre for imaging. Cone beam computed tomography (CBCT) was performed, which successfully demonstrated a significant reduction in the dislocation of the SC joint. The trachea and brachiocephalic artery were no longer compressed or displaced. This case study demonstrates an alternative to the patient being transferred to the medical imaging department for multi-slice CT. It also describes a novel use of the hybrid operating theatre and its CBCT capabilities. PMID- 26229611 TI - Cherry-picking of evidence fails to accurately show extent of overdiagnosis: Mammographic screening harms understated. PMID- 26229612 TI - Letter in response to "Cherry-picking of evidence fails to accurately show extent of overdiagnosis: Mammographic screening harms understated". PMID- 26229613 TI - Is digital health technology empowering patients? PMID- 26229614 TI - Intensity modulated radiation therapy versus volumetric intensity modulated arc therapy. PMID- 26229615 TI - A retrospective planning analysis comparing intensity modulated radiation therapy (IMRT) to volumetric modulated arc therapy (VMAT) using two optimization algorithms for the treatment of early-stage prostate cancer. AB - INTRODUCTION: The primary aim of this study is to compare intensity modulated radiation therapy (IMRT) to volumetric modulated arc therapy (VMAT) for the radical treatment of prostate cancer using version 10.0 (v10.0) of Varian Medical Systems, RapidArc radiation oncology system. Particular focus was placed on plan quality and the implications on departmental resources. The secondary objective was to compare the results in v10.0 to the preceding version 8.6 (v8.6). METHODS: Twenty prostate cancer cases were retrospectively planned using v10.0 of Varian's Eclipse and RapidArc software. Three planning techniques were performed: a 5 field IMRT, VMAT using one arc (VMAT-1A), and VMAT with two arcs (VMAT-2A). Plan quality was assessed by examining homogeneity, conformity, the number of monitor units (MUs) utilized, and dose to the organs at risk (OAR). Resource implications were assessed by examining planning and treatment times. The results obtained using v10.0 were also compared to those previously reported by our group for v8.6. RESULTS: In v10.0, each technique was able to produce a dose distribution that achieved the departmental planning guidelines. The IMRT plans were produced faster than VMAT plans and displayed improved homogeneity. The VMAT plans provided better conformity to the target volume, improved dose to the OAR, and required fewer MUs. Treatments using VMAT-1A were significantly faster than both IMRT and VMAT-2A. Comparison between versions 8.6 and 10.0 revealed that in the newer version, VMAT planning was significantly faster and the quality of the VMAT dose distributions produced were of a better quality. CONCLUSION: VMAT (v10.0) using one or two arcs provides an acceptable alternative to IMRT for the treatment of prostate cancer. VMAT-1A has the greatest impact on reducing treatment time. PMID- 26229616 TI - An evaluation of author productivity in international radiography journals 2004 2011. AB - INTRODUCTION: Radiography, the allied health profession, has changed beyond recognition over the last century; however, in academic terms radiography is a relatively young profession. It is therefore still establishing its professional knowledge base. This article uses peer-review author productivity distribution to evaluate its scholarly maturity. METHODS: Four peer-reviewed journals in medical radiation sciences were examined over an 8-year period (2004-2011) and author productivity was compared to Lotka's law. Further analysis of the most prolific authors provided an evaluation of their characteristics. RESULTS: The 1306 unique authors contributed 835 articles during the study period. Of these, 1012 (77.5%) contributed only one article to the journals studied, with an inverse power relationship of author productivity. At the 0.1 level of significance, radiography does not fit Lotka's law (n = -2.334; c = 0.712; D max = 0.0627; Critical threshold = 0.0337). There was a significant correlation between the most prolific authors and collaboration (P = 0.002), although variation was noted in author discipline and location. CONCLUSIONS: The results of this study add to the discussion of radiography scholarship and demonstrate that the radiography authors have similar productivity distribution to other professions, but do not follow Lotka's law. PMID- 26229617 TI - An exploration of the feasibility of radiation therapist participation in treatment reviews. AB - INTRODUCTION: As radiation oncologists' (ROs') workload has increased over time, treatment review clinics have become recognized as an area of RO practice into which radiation therapist (RT) practice could extend. There has been limited utilization of RTs in this role in Australia and a paucity of data on the acceptability and opinions regarding RTs practising in this role in an Australian context. The purpose of this audit was to investigate the feasibility of RT participation in review clinics at Calvary Mater Newcastle. METHODS: Feasibility was determined by two methods: an audit of 200 treatment reviews to determine medical intervention (MI) levels required and a survey of 80 clinical staff to explore attitudes towards RT participation in clinics. RESULTS: Medical intervention was required in 59% (n = 118) of observed reviews, with the lowest being for breast (33%) and prostate (28%) cancers. MI peaked at 73% between fractions 16-20 and was lowest early and late in the treatment period at 48%. There were 60 responses to the staff survey. All but one respondent agreed that RTs would be willing to participate in treatment review clinics, but all five consultant ROs indicated they would not be willing to delegate reviews to RTs. CONCLUSIONS: Neither feasibility measure reached acceptable levels to recommend RT participation in treatment review clinics. Further investigation and RT education are required to help meet the future RO workforce shortfall. As MI rates are lowest for breast and prostate cancer RT participation could be targeted to these clinics. PMID- 26229618 TI - Tips for writing a case report for the novice author. AB - A case report is a description of important scientific observations that are missed or undetectable in clinical trials. This includes a rare or unusual clinical condition, a previously unreported or unrecognized disease, unusual side effects to therapy or response to treatment, and unique use of imaging modalities or diagnostic tests to assist diagnosis of a disease. Generally, a case report should be short and focussed, with its main components being the abstract, introduction, case description, and discussion. This article discusses the essential components of a case report, with the aim of providing guidelines and tips to novice authors to improve their writing skills. PMID- 26229620 TI - Investigating the experiences of New Zealand MRI technologists: Exploring intra orbital metallic foreign body safety practices. AB - INTRODUCTION: Qualitative research is lacking regarding the experiences of magnetic resonance imaging (MRI) technologists and their involvement in workplace safety practices. This article provides a gateway to explore, describe and document experiences of MRI technologists in New Zealand (NZ) pertaining to intra orbital metallic foreign body (IMFB) safety practices. METHODS: This phenomenological study describes the experiences of seven MRI technologists all with a minimum of 5 years' NZ work experience in MRI. The MRI technologists were interviewed face-to-face regarding their professional IMFB workplace experiences in order to explore historical, current and potential issues. RESULTS: Findings demonstrated that aspects of organization and administration are fundamentally important to MRI technologists. Varying levels of education and knowledge, as well as experience and skills gained, have significantly impacted on MRI technologists' level of confidence and control in IMFB practices. Participants' descriptions of their experiences in practice regarding decision-making capabilities further highlight the complexity of these themes. A model was developed to demonstrate the interrelated nature of the themes and the complexity of the situation in totality. CONCLUSIONS: Findings of this study have provided insight into the experiences of MRI technologists pertaining to IMFB safety practices and highlighted inconsistencies. It is hoped that these findings will contribute to and improve the level of understanding of MRI technologists and the practices and protocols involved in IMFB safety screening. The scarcity of available literature regarding IMFB safety practices highlights that more research is required to investigate additional aspects that could improve MRI technologists' experiences. PMID- 26229619 TI - Retrospective evaluation of exposure index (EI) values from plain radiographs reveals important considerations for quality improvement. AB - INTRODUCTION: Following X-ray exposure, radiographers receive immediate feedback on detector exposure in the form of the exposure index (EI). PURPOSE: To identify whether radiographers are meeting manufacturer-recommended EI (MREI) ranges for routine chest, abdomen and pelvis X-ray examinations under a variety of conditions and to examine factors affecting the EI. METHODS: Data on 5000 adult X ray examinations including the following variables were collected: examination parameters, EI values, patient gender, date of birth, date and time of examination, grid usage and the presence of implant or prosthesis. Descriptive statistics were used to summarize each data set and the Mann-Whitney U test was used to determine significant differences, with P < 0.05 indicating significance for all tests. RESULTS: Most examinations demonstrated EI values that were outside the MREI ranges, with significantly higher median EI values recorded for female patient radiographs than those for male patients for all manufacturers, indicating higher detector exposures for all units except for Philips digital radiography (DR), where increased EI values indicate lower exposure (P = 0.01). Median EI values for out of hours radiography were also significantly higher compared with normal working hours for all technologies (P <= 0.02). Significantly higher median EI values were demonstrated for Philips DR chest X rays without as compared to those with the employment of a grid (P = 0.03), while significantly lower median EI values were recorded for Carestream Health computed radiography (CR) chest X-rays when an implant or prosthesis was present (P = 0.02). CONCLUSIONS: Non-adherence to MREIs has been demonstrated with EI value discrepancies being dependent on patient gender, time/day of exposure, grid usage and the presence of an implant or prosthesis. Retrospective evaluation of EI databases is a valuable tool to assess the need of quality improvement in routine DR. PMID- 26229621 TI - Retrospective evaluation of dosimetric quality for prostate carcinomas treated with 3D conformal, intensity modulated and volumetric modulated arc radiotherapy. AB - INTRODUCTION: This study examines and compares the dosimetric quality of radiotherapy treatment plans for prostate carcinoma across a cohort of 163 patients treated across five centres: 83 treated with three-dimensional conformal radiotherapy (3DCRT), 33 treated with intensity modulated radiotherapy (IMRT) and 47 treated with volumetric modulated arc therapy (VMAT). METHODS: Treatment plan quality was evaluated in terms of target dose homogeneity and organs at risk (OAR), through the use of a set of dose metrics. These included the mean, maximum and minimum doses; the homogeneity and conformity indices for the target volumes; and a selection of dose coverage values that were relevant to each OAR. Statistical significance was evaluated using two-tailed Welch's T-tests. The Monte Carlo DICOM ToolKit software was adapted to permit the evaluation of dose metrics from DICOM data exported from a commercial radiotherapy treatment planning system. RESULTS: The 3DCRT treatment plans offered greater planning target volume dose homogeneity than the other two treatment modalities. The IMRT and VMAT plans offered greater dose reduction in the OAR: with increased compliance with recommended OAR dose constraints, compared to conventional 3DCRT treatments. When compared to each other, IMRT and VMAT did not provide significantly different treatment plan quality for like-sized tumour volumes. CONCLUSIONS: This study indicates that IMRT and VMAT have provided similar dosimetric quality, which is superior to the dosimetric quality achieved with 3DCRT. PMID- 26229622 TI - Evaluating the dosimetric effect of treatment-induced changes in virally mediated head and neck cancer patients. AB - INTRODUCTION: Patients with virally mediated head and neck cancer (VMHNC) often present with advanced nodal disease that is highly radioresponsive as demonstrated by tumour and nodal regression during treatment. The resultant changes may impact on the planned dose distribution and so adversely affect the therapeutic ratio. The aim of this study was to evaluate the dosimetric effect of treatment-induced anatomical changes in VMHNC patients who had undergone a replan. METHODS: Thirteen patients with virally mediated oropharyngeal or nasopharyngeal cancer who presented for definitive radiotherapy between 2005 and 2010 and who had a replan generated were investigated. The dosimetric effect of anatomical changes was quantified by comparing dose-volume histograms (DVH) of primary and nodal gross target volumes and organs at risk (OAR), including spinal cord and parotid glands, from the original plan and a comparison plan. RESULTS: Eleven three-dimensional conformal radiation therapy (3DCRT) and two intensity modulated radiation therapy (IMRT) plans were evaluated. Dose to the spinal cord and brainstem increased by 4.1% and 2.6%, respectively. Mean dose to the parotid glands also increased by 3.5%. In contrast, the dose received by 98% of the primary and nodal gross tumour volumes decreased by 0.15% and 0.3%, respectively, when comparing the initial treatment plan to the comparison plan. CONCLUSION: In this study, treatment-induced anatomical changes had the greatest impact on OAR dose with negligible effect on the dose to nodal gross tumour volumes. In the era of IMRT, accounting for treatment-induced anatomical changes is important as focus is placed on minimizing the acute and long-term side effects of treatment. PMID- 26229623 TI - Carcinoma of the anal canal: Intensity modulated radiation therapy (IMRT) versus three-dimensional conformal radiation therapy (3DCRT). AB - INTRODUCTION: Patients with anal canal carcinoma treated with standard conformal radiotherapy frequently experience severe acute and late toxicity reactions to the treatment area. Roohipour et al. (Dis Colon Rectum 2008; 51: 147-53) stated a patient's tolerance of chemoradiation to be an important prediction of treatment success. A new intensity modulated radiation therapy (IMRT) technique for anal carcinoma cases has been developed at the Andrew Love Cancer Centre aimed at reducing radiation to surrounding healthy tissue. METHODS: A same-subject repeated measures design was used for this study, where five anal carcinoma cases at the Andrew Love Cancer Centre were selected. Conformal and IMRT plans were generated and dosimetric evaluations were performed. Each plan was prescribed a total of 54 Gray (Gy) over a course of 30 fractions to the primary site. RESULTS: The IMRT plans resulted in improved dosimetry to the planning target volume (PTV) and reduction in radiation to the critical structures (bladder, external genitalia and femoral heads). Statistically there was no difference between the IMRT and conformal plans in the dose to the small and large bowel; however, the bowel IMRT dose-volume histogram (DVH) doses were consistently lower. CONCLUSION: The IMRT plans were superior to the conformal plans with improved dose conformity and reduced radiation to the surrounding healthy tissue. Anecdotally it was found that patients tolerated the IMRT treatment better than the three-dimensional (3D) conformal radiation therapy. This study describes and compares the planning techniques. PMID- 26229624 TI - Research papers by radiographers and radiation therapists: An Australian perspective. PMID- 26229625 TI - Erratum: Radiation therapy advanced practice - commentary. PMID- 26229626 TI - Erratum: Implementation of extended scope of practice. PMID- 26229627 TI - Erratum: Response to letters to the editor regarding 'feasibility of radiation therapist-performed treatment reviews'. PMID- 26229629 TI - Target volume delineation and margins in the management of lung cancers in the era of image guided radiation therapy. PMID- 26229630 TI - Relationship of computed tomography perfusion and positron emission tomography to tumour progression in malignant glioma. AB - IntroductionThis study aimed to explore the potential for computed tomography (CT) perfusion and 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting sites of future progressive tumour on a voxel-by-voxel basis after radiotherapy and chemotherapy. MethodsTen patients underwent pre-radiotherapy magnetic resonance (MR), FDG-PET and CT perfusion near the end of radiotherapy and repeated post-radiotherapy follow-up MR scans. The relationships between these images and tumour progression were assessed using logistic regression. Cross-validation with receiver operating characteristic (ROC) analysis was used to assess the value of these images in predicting sites of tumour progression. ResultsPre-radiotherapy MR-defined gross tumour; near-end-of-radiotherapy CT defined enhancing lesion; CT perfusion blood flow (BF), blood volume (BV) and permeability-surface area (PS) product; FDG-PET standard uptake value (SUV); and SUV:BF showed significant associations with tumour progression on follow-up MR imaging (P < 0.0001). The mean sensitivity (+/-standard deviation), specificity and area under the ROC curve (AUC) of PS were 0.64 +/- 0.15, 0.74 +/- 0.07 and 0.72 +/- 0.12 respectively. This mean AUC was higher than that of the pre radiotherapy MR-defined gross tumour and near-end-of-radiotherapy CT-defined enhancing lesion (both AUCs = 0.6 +/- 0.1, P <= 0.03). The multivariate model using BF, BV, PS and SUV had a mean AUC of 0.8 +/- 0.1, but this was not significantly higher than the PS only model. ConclusionPS is the single best predictor of tumour progression when compared to other parameters, but voxel based prediction based on logistic regression had modest sensitivity and specificity. PMID- 26229631 TI - Establishing advanced practice for medical imaging in New Zealand. AB - IntroductionThis article presents the outcome and recommendations following the second stage of a role development project conducted on behalf of the New Zealand Institute of Medical Radiation Technology (NZIMRT). The study sought to support the development of profiles and criteria that may be used to formulate Advanced Scopes of Practice for the profession. It commenced in 2011, following on from initial research that occurred between 2005 and 2008 investigating role development and a possible career structure for medical radiation technologists (MRTs) in New Zealand (NZ). MethodsThe study sought to support the development of profiles and criteria that could be used to develop Advanced Scopes of Practice for the profession through inviting 12 specialist medical imaging groups in NZ to participate in a survey. ResultsFindings showed strong agreement on potential profiles and on generic criteria within them; however, there was less agreement on specific skills criteria within specialist areas. ConclusionsThe authors recommend that one Advanced Scope of Practice be developed for Medical Imaging, with the establishment of generic and specialist criteria. Systems for approval of the overall criteria package for any individual Advanced Practitioner (AP) profile, audit and continuing professional development requirements need to be established by the Medical Radiation Technologists Board (MRTB) to meet the local needs of clinical departments. It is further recommended that the NZIMRT and MRTB promote and support the need for an AP pathway for medical imaging in NZ. PMID- 26229632 TI - Assessment of work-integrated learning: comparison of the usage of a grading rubric by supervising radiographers and teachers. AB - IntroductionProfessional work-integrated learning (WIL) that integrates the academic experience with off-campus professional experience placements is an integral part of many tertiary courses. Issues with the reliability and validity of assessment grades in these placements suggest that there is a need to strengthen the level of academic rigour of placements in these programmes. This study aims to compare the attitudes to the usage of assessment rubrics of radiographers supervising medical imaging students and teachers supervising pre service teachers. MethodsWIL placement assessment practices in two programmes, pre-service teacher training (Avondale College of Higher Education, NSW) and medical diagnostic radiography (Faculty of Health Sciences, University of Sydney, NSW), were compared with a view to comparing assessment strategies across these two different educational domains. Educators (course coordinators) responsible for teaching professional development placements of teacher trainees and diagnostic radiography students developed a standards-based grading rubric designed to guide assessment of students' work during WIL placement by assessors. After ~12 months of implementation of the rubrics, assessors' reaction to the effectiveness and usefulness of the grading rubric was determined using a specially created survey form. Data were collected over the period from March to June 2011. Quantitative and qualitative data found that assessors in both programmes considered the grading rubric to be a vital tool in the assessment process, though teacher supervisors were more positive about the benefits of its use than the radiographer supervisors. ResultsBenefits of the grading rubric included accuracy and consistency of grading, ability to identify specific areas of desired development and facilitation of the provision of supervisor feedback. The use of assessment grading rubrics is of benefit to assessors in WIL placements from two very different teaching programmes. ConclusionRadiographers appear to need more training in the rubric's use, whereas teachers are found to generally use it appropriately. There are implications drawn from this finding that are applicable to health science and medical education in general. PMID- 26229633 TI - The effect of image-guided radiation therapy on the margin between the clinical target volume and planning target volume in lung cancer. AB - IntroductionThis study aimed to evaluate the effect of image-guided radiation therapy (IGRT) on the margin between the clinical target volume (CTV) and planning target volume (PTV) in lung cancer. MethodsThe CTV and PTV margin were determined in three dimensions by four radiation oncologists using a standard method in 10 lung cancer patients, and compared to consensus values. Transfer error was measured using a rigid phantom containing gold markers. Systematic error ([Formula: see text]) and random error ([Formula: see text]) set up errors were calculated in three dimensions from pre-treatment and post-treatment cone beam CT scans. Finally, the margin between the CTV and PTV was corrected for set up error and calculated. ResultsThe margins between the CTV and PTV with IGRT (and without IGRT) were 0.88 cm (0.96 cm), 0.99 cm (1.08 cm) and 1.28 cm (1.82 cm) in the anterior and posterior (AP), left and right (LR) and superior and inferior (SI) directions, respectively. Images from two other patients verified the validity of the corrected margin. The target delineation errors of the radiation oncologists are considered to be the largest compared with the set up errors. The application of IGRT reduced the set up errors and the margins between CTV and PTV. ConclusionsThe delineation errors of radiation oncologists are the most important factor to consider for the margin between CTV and PTV for lung cancer. IGRT can reduce the margins by reducing the set up errors, especially in the SI direction. Further research is required to assess whether the reduction in the margin is solely based on set up errors. PMID- 26229634 TI - Establishing radiation therapy advanced practice in New Zealand. AB - INTRODUCTION: Advanced practice (AP) is of increasing interest to many radiation therapists (RTs) both nationally and internationally. In New Zealand, initial research (2005-2008) showed strong support for the development of an AP role for medical radiation technologists (MRTs). Here, we report on a nationwide survey in which RTs validated and prioritised nine AP profiles for future development. METHODS: All registered RTs in New Zealand (n = 260) were invited to take part in a survey in December 2011; 73 of whom returned a complete response. RESULTS: RTs supported the implementation of AP roles in New Zealand and the requirement of a Master's degree qualification to underpin clinical knowledge. Most RTs endorsed the criteria attributed to each of the nine proposed AP profiles. The study identified that activities may qualify as either advanced practice or standard practice depending on the department. All participants agreed that an advanced practitioner should be a leader in the field, able to initiate and facilitate future developments within as well as outside this specific role. Acceptance of the AP roles by RTs and other health professionals as well as the availability of resources for successful implementation, were concerns expressed by some RTs. CONCLUSION: The authors recommend (1) the development of one scope of practice titled 'advanced practitioner' with generic and specialist criteria for each profile as the future career pathway, (2) promotion and support for the AP pathway by the New Zealand Institute of Medical Radiation Technology and the New Zealand Medical Radiation Technologists Board. PMID- 26229635 TI - Factors influencing radiation therapy student clinical placement satisfaction. AB - INTRODUCTION: Radiation therapy students at Queensland University of Technology (QUT) attend clinical placements at five different clinical departments with varying resources and support strategies. This study aimed to determine the relative availability and perceived importance of different factors affecting student support while on clinical placement. The purpose of the research was to inform development of future support mechanisms to enhance radiation therapy students' experience on clinical placement. METHODS: This study used anonymous Likert-style surveys to gather data from years 1 and 2 radiation therapy students from QUT and clinical educators from Queensland relating to availability and importance of support mechanisms during clinical placements in a semester. RESULTS: The study findings demonstrated student satisfaction with clinical support and suggested that level of support on placement influenced student employment choices. Staff support was perceived as more important than physical resources; particularly access to a named mentor, a clinical educator and weekly formative feedback. Both students and educators highlighted the impact of time pressures. CONCLUSIONS: The support offered to radiation therapy students by clinical staff is more highly valued than physical resources or models of placement support. Protected time and acknowledgement of the importance of clinical education roles are both invaluable. Joint investment in mentor support by both universities and clinical departments is crucial for facilitation of effective clinical learning. PMID- 26229636 TI - Australian radiation therapy - Part two: Reflections of the past, the present, the future. AB - INTRODUCTION: Documentation on the history of Australian radiotherapy is limited. This study provides radiation therapists' (RTs) perspectives of the people, workplace, and work practices in Australian radiotherapy centres from 1960 onwards. It provides a follow-up to our previous study: Australian radiation therapy: An overview - Part one, which outlines the history and development of radiotherapy from conception until present day. METHODS: Four focus groups were conducted on separate occasions in 2010, one in South Australia and three in Victoria, Australia. Participants who worked in radiotherapy were purposively selected to ensure a range of experience, age, and years of work. RESULTS: From a RT perspective, radiotherapy has evolved from a physically demanding 'hands-on' work environment, often with unpleasant sights and smells of disease, to a more technology-driven workplace. CONCLUSION: Understanding these changes and their subsequent effects on the role of Australian RTs will assist future directions in advanced role development. PMID- 26229637 TI - Letter in response to 'Research papers by radiographers and radiation therapists: An Australian perspective'. PMID- 26229638 TI - Creating our future: conformity or change? PMID- 26229639 TI - Radiographer reporting. PMID- 26229640 TI - A survey of radiographers' confidence and self-perceived accuracy in frontline image interpretation and their continuing educational preferences. AB - INTRODUCTION: The provision of a written comment on traumatic abnormalities of the musculoskeletal system detected by radiographers can assist referrers and may improve patient management, but the practice has not been widely adopted outside the United Kingdom. The purpose of this study was to investigate Australian radiographers' perceptions of their readiness for practice in a radiographer commenting system and their educational preferences in relation to two different delivery formats of image interpretation education, intensive and non-intensive. METHODS: A cross-sectional web-based questionnaire was implemented between August and September 2012. Participants included radiographers with experience working in emergency settings at four Australian metropolitan hospitals. Conventional descriptive statistics, frequency histograms, and thematic analysis were undertaken. A Wilcoxon signed-rank test examined whether a difference in preference ratings between intensive and non-intensive education delivery was evident. RESULTS: The questionnaire was completed by 73 radiographers (68% response rate). Radiographers reported higher confidence and self-perceived accuracy to detect traumatic abnormalities than to describe traumatic abnormalities of the musculoskeletal system. Radiographers frequently reported high desirability ratings for both the intensive and the non-intensive education delivery, no difference in desirability ratings for these two formats was evident (z = 1.66, P = 0.11). CONCLUSIONS: Some Australian radiographers perceive they are not ready to practise in a frontline radiographer commenting system. Overall, radiographers indicated mixed preferences for image interpretation education delivered via intensive and non-intensive formats. Further research, preferably randomised trials, investigating the effectiveness of intensive and non-intensive education formats of image interpretation education for radiographers is warranted. PMID- 26229641 TI - A phenomenological study to explore the experiences of Ugandan women that have undergone transvaginal ultrasound. AB - INTRODUCTION: Transvaginal ultrasound (TVUS) is an important examination of the female pelvis that involves the transducer being inserted into the vagina to obtain more detailed images of the pelvic organs. Unfortunately, this examination has received mixed experiences from the women who have undergone it. This study set out to explore the lived experiences of Ugandan women who have undergone TVUS. METHODS: It was a phenomenological exploratory study involving 20 women in Uganda that had previously undergone TVUS. Data were collected using in-depth individual interviews. The responses from the women were audio-recorded and later transcribed. Thematic analysis was used to interpret and make meaning of the data collected. RESULTS: Analysis of data revealed mostly negative experiences of the women who were included in this study. Key words from the participating women that illustrated the negative experiences included: fear, vulnerability, guilt, anxiety and embarrassment. It was also observed that these initial negative experiences are likely to reduce the women's acceptability and compliance to TVUS even when it is needed for better clinical management. Data were categorised into the following three thematic areas: (1) broken communication, (2) anxiety and discomfort and (3) cultural influence. CONCLUSION: Women in this study portrayed negative experiences of undergoing TVUS. Key suggestions like informed consent are recommended to improve compliance of the women to this type of procedure. PMID- 26229642 TI - Volumetric modulated arc therapy versus step-and-shoot intensity modulated radiation therapy in the treatment of large nerve perineural spread to the skull base: a comparative dosimetric planning study. AB - INTRODUCTION: Cutaneous squamous cell carcinoma with large nerve perineural (LNPN) infiltration of the base of skull is a radiotherapeutic challenge given the complex target volumes to nearby organs at risk (OAR). A comparative planning study was undertaken to evaluate dosimetric differences between volumetric modulated arc therapy (VMAT) versus intensity modulated radiation therapy (IMRT) in the treatment of LNPN. METHODS: Five consecutive patients previously treated with IMRT for LNPN were selected. VMAT plans were generated for each case using the same planning target volumes (PTV), dose prescriptions and OAR constraints as IMRT. Comparative parameters used to assess target volume coverage, conformity and homogeneity included V95 of the PTV (volume encompassed by the 95% isodose), conformity index (CI) and homogeneity index (HI). In addition, OAR maximum point doses, V20, V30, non-target tissue (NTT) point max doses, NTT volume above reference dose, monitor units (MU) were compared. RESULTS: IMRT and VMAT plans generated were comparable for CI (P = 0.12) and HI (P = 0.89). VMAT plans achieved better V95 (P = < 0.001) and reduced V20 and V30 by 652 cubic centimetres (cc) (28.5%) and 425.7 cc (29.1%), respectively. VMAT increased MU delivered by 18% without a corresponding increase in NTT dose. CONCLUSION: Compared with IMRT plans for LNPN, VMAT achieved comparable HI and CI. PMID- 26229643 TI - Comparing four volumetric modulated arc therapy beam arrangements for the treatment of early-stage prostate cancer. AB - INTRODUCTION: This study compared four different volumetric modulated arc therapy (VMAT) beam arrangements for the treatment of early-stage prostate cancer examining plan quality and the impact on a radiotherapy department's resources. METHODS: Twenty prostate cases were retrospectively planned using four VMAT beam arrangements (1) a partial arc (PA), (2) one arc (1A), (3) one arc plus a partial arc (1A + PA) and (4) two arcs (2A). The quality of the dose distributions generated were compared by examining the overall plan quality, the homogeneity and conformity to the planning target volume (PTV), the number of monitor units and the dose delivered to the organs at risk. Departmental resources were considered by recording the planning time and beam delivery time. RESULTS: Each technique produced a plan of similar quality that was considered adequate for treatment; though some differences were noted. The 1A, 1A + PA and 2A plans demonstrated a better conformity to the PTV which correlated to improved sparing of the rectum in the 60-70 Gy range for the 1A + PA and 2A techniques. The time needed to generate the plans was different for each technique ranging from 13.1 min for 1A + PA to 17.8 min for 1A. The PA beam delivery time was fastest with a mean time of 0.9 min. Beam-on times then increased with an increase in the number of arcs up to an average of 2.2 min for the 2A technique. CONCLUSION: Which VMAT technique is best suited for clinical implementation for the treatment of prostate cancer may be dictated by the individual patient and the availability of departmental resources. PMID- 26229644 TI - How do Medical Radiation Science educators keep up with the [clinical] Joneses? AB - INTRODUCTION: Medical radiation science (MRS) disciplines include medical imaging, radiation therapy and nuclear medicine. These allied health fields are technology driven and evolving rapidly with regard to imaging and treatment techniques within the clinical environment. This research aims to identify the activities academics are currently participating in to maintain clinical currency and offer strategies to support academics to connect with an ever-changing clinical environment. METHODS: A cross-sectional designed survey was sampled across the nine Australian universities where MRS programmes are offered. The survey targeted academic teaching staff that were working in MRS programmes at the time of distribution (n ~ 90). Enablers and barriers to maintaining clinical currency as well as support to participate in continuing professional development were rated by the respondents. Descriptive statistics were used to analyse quantitative data, and free-text comment responses were collated and themed. RESULTS: There were 38 responses to the survey (42%) and all three disciplines were represented. Responses highlighted activities valued by academics as contributing to their knowledge of current practice and as resources to inform their teaching. Positive elements included participating in clinical work and research, attending clinical sites and training days and attending scientific meetings. Common barriers identified by academics in this area were time constraints, workload allocation and employer/financial support. CONCLUSION: This research has identified that Australian MRS academics participate in a broad range of activities to inform their teaching and maintain knowledge of contemporary clinical practice. A connection with the clinical world is valued highly by academics, however, access and support to maintain that link is often a difficulty and as a result for MRS teaching staff keeping up with the clinical [MRS] Joneses is often a challenge. PMID- 26229645 TI - Digital radiography exposure indices: A review. AB - Digital radiography (DR) technologies have the advantage of a wide dynamic range compared to their film-screen predecessors, however, this poses a potential for increased patient exposure if left unchecked. Manufacturers have developed the exposure index (EI) to counter this, which provides radiographers with feedback on the exposure reaching the detector. As these EIs were manufacturer-specific, a wide variety of EIs existed. To offset this, the international standardised EI has been developed by the International Electrotechnical Commission (IEC) and the American Association of Physicists in Medicine (AAPM). The purpose of this article is to explore the current literature relating to EIs, beginning with the historical development of the EI, the development of the standardised EI and an exploration of common themes and studies as evidenced in the research literature. It is anticipated that this review will provide radiographers with a useful guide to understanding EIs, their application in clinical practice, limitations and suggestions for further research. PMID- 26229646 TI - Protecting the radiation-damaged skin from friction: a mini review. AB - Radiation-induced skin reactions are an unavoidable side effect of external beam radiation therapy, particularly in areas prone to friction and excess moisture such as the axilla, head and neck region, perineum and skin folds. Clinical studies investigating interventions for preventing or managing these reactions have largely focussed on formulations with moisturising, anti-inflammatory, anti microbial and wound healing properties. However, none of these interventions has emerged as a consistent candidate for best practice. Much less emphasis has been placed on evaluating ways to protect the radiation-damaged skin from friction and excess moisture. This mini review analyses the clinical evidence for barrier products that form a protective layer by adhering very closely to the skin folds and do not cause further trauma to the radiation-damaged skin upon removal. A database search identified only two types of barrier products that fitted these criteria and these were tested in two case series and six controlled clinical trials. Friction protection was most effective when the interventions were used from the start of treatment and continued for several weeks after completion of treatment. Soft silicone dressings (Mepilex Lite and Mepitel Film) and Cavilon No Sting Barrier Film, but not Cavilon Moisturizing Barrier Cream, decreased skin reaction severity, most likely due to differences in formulation and skin build up properties. It seems that prophylactic use of friction protection of areas at risk could be a worthwhile addition to routine care of radiation-damaged skin. PMID- 26229647 TI - Ochrobactrum anthropi induced retropharyngeal abscess with mediastinal extension complicating airway obstruction: a case report. AB - Retropharyngeal abscess with involvement of mediastinal abscess represents an uncommon complication of upper respiratory tract infections. We report a case presenting with a large retropharyngeal abscess with airway obstruction as the primary presenting symptom. Contrast-enhanced CT showed a large retropharyngeal abscess in the neck with extension to the upper and posterior mediastinal spaces. The abscess was surgically excised with 200 cc pus drained from the neck and mediastinal regions. We describe this case to assist physicians in making the difficult diagnosis when confronting a patient with airway obstruction, as early recognition of retropharyngeal abscess permits emergent airway management. PMID- 26229648 TI - Reflections on the current status of commercial automated segmentation systems in clinical practice. PMID- 26229649 TI - Radiation dose in coronary angiography and intervention: initial results from the establishment of a multi-centre diagnostic reference level in Queensland public hospitals. AB - INTRODUCTION: Radiation dose to patients undergoing invasive coronary angiography (ICA) is relatively high. Guidelines suggest that a local benchmark or diagnostic reference level (DRL) be established for these procedures. This study sought to create a DRL for ICA procedures in Queensland public hospitals. METHODS: Data were collected for all Cardiac Catheter Laboratories in Queensland public hospitals. Data were collected for diagnostic coronary angiography (CA) and single-vessel percutaneous intervention (PCI) procedures. Dose area product (P KA), skin surface entrance dose (K AR), fluoroscopy time (FT), and patient height and weight were collected for 3 months. The DRL was set from the 75th percentile of the P KA. RESULTS: 2590 patients were included in the CA group where the median FT was 3.5 min (inter-quartile range = 2.3-6.1). Median K AR = 581 mGy (374-876). Median P KA = 3908 uGym(2) (2489-5865) DRL = 5865 uGym(2). 947 patients were included in the PCI group where median FT was 11.2 min (7.7-17.4). Median K AR = 1501 mGy (928-2224). Median P KA = 8736 uGym(2) (5449-12,900) DRL = 12,900 uGym(2). CONCLUSION: This study established a benchmark for radiation dose for diagnostic and interventional coronary angiography in Queensland public facilities. PMID- 26229650 TI - Factors influencing the development and implementation of advanced radiographer practice in Australia - a qualitative study using an interpretative phenomenological approach. AB - INTRODUCTION: The purpose of this study was to explore the factors influencing the implementation or the lack of implementation of advanced practitioner role in Australia. METHODS: This study uses an interpretative phenomenological approach to explore the in-depth real life issues, which surround the advanced practitioner as a solution to radiologist workforce shortages in Australia. Research participants are radiographers, radiation therapists and health managers registered with the Australian Institute of Radiography (AIR) and holding senior professional and AIR Board positions with knowledge of current advanced practice. RESULTS: In total, seven interviews were conducted revealing education, governance, technical, people issues, change management, government, costs and timing as critical factors influencing advanced practice in Australia. CONCLUSIONS: Seven participants in this study perceived an advanced practice role might have major benefits and a positive impact on the immediate and long-term management of patients. Another finding is the greater respect and appreciation of each other's roles and expertise within the multidisciplinary healthcare team. Engagement is required of the critical stakeholders that have been identified as 'blockers' (radiologists, health departments) as well as identified allies (e.g. emergency clinicians, supportive radiologists, patient advocacy groups). The research supports that the AIR has a role to play for the professional identity of radiographers and shaping the advanced practice role in Australia. PMID- 26229651 TI - Evaluation of atlas-based auto-segmentation software in prostate cancer patients. AB - INTRODUCTION: The performance and limitations of an atlas-based auto-segmentation software package (ABAS; Elekta Inc.) was evaluated using male pelvic anatomy as the area of interest. METHODS: Contours from 10 prostate patients were selected to create atlases in ABAS. The contoured regions of interest were created manually to align with published guidelines and included the prostate, bladder, rectum, femoral heads and external patient contour. Twenty-four clinically treated prostate patients were auto-contoured using a randomised selection of two, four, six, eight or ten atlases. The concordance between the manually drawn and computer-generated contours were evaluated statistically using Pearson's product-moment correlation coefficient (r) and clinically in a validated qualitative evaluation. In the latter evaluation, six radiation therapists classified the degree of agreement for each structure using seven clinically appropriate categories. RESULTS: The ABAS software generated clinically acceptable contours for the bladder, rectum, femoral heads and external patient contour. For these structures, ABAS-generated volumes were highly correlated with 'as treated' volumes, manually drawn; for four atlases, for example, bladder r = 0.988 (P < 0.001), rectum r = 0.739 (P < 0.001) and left femoral head r = 0.560 (P < 0.001). Poorest results were seen for the prostate (r = 0.401, P < 0.05) (four atlases); however this was attributed to the comparison prostate volume being contoured on magnetic resonance imaging (MRI) rather than computed tomography (CT) data. For all structures, increasing the number of atlases did not consistently improve accuracy. CONCLUSIONS: ABAS-generated contours are clinically useful for a range of structures in the male pelvis. Clinically appropriate volumes were created, but editing of some contours was inevitably required. The ideal number of atlases to improve generated automatic contours is yet to be determined. PMID- 26229652 TI - The development and evaluation of a medical imaging training immersive environment. AB - INTRODUCTION: A novel realistic 3D virtual reality (VR) application has been developed to allow medical imaging students at Queensland University of Technology to practice radiographic techniques independently outside the usual radiography laboratory. METHODS: A flexible agile development methodology was used to create the software rapidly and effectively. A 3D gaming environment and realistic models were used to engender presence in the software while tutor determined gold standards enabled students to compare their performance and learn in a problem-based learning pedagogy. RESULTS: Students reported high levels of satisfaction and perceived value and the software enabled up to 40 concurrent users to prepare for clinical practice. Student feedback also indicated that they found 3D to be of limited value in the desktop version compared to the usual 2D approach. A randomised comparison between groups receiving software-based and traditional practice measured performance in a formative role play with real equipment. The results of this work indicated superior performance with the equipment for the VR trained students (P = 0.0366) and confirmed the value of VR for enhancing 3D equipment-based problem-solving skills. CONCLUSIONS: Students practising projection techniques virtually performed better at role play assessments than students practising in a traditional radiography laboratory only. The application particularly helped with 3D equipment configuration, suggesting that teaching 3D problem solving is an ideal use of such medical equipment simulators. Ongoing development work aims to establish the role of VR software in preparing students for clinical practice with a range of medical imaging equipment. PMID- 26229653 TI - Definition and visualisation of regions of interest in post-prostatectomy image guided intensity modulated radiotherapy. AB - INTRODUCTION: Standard post-prostatectomy radiotherapy (PPRT) image verification uses bony anatomy alignment. However, the prostate bed (PB) moves independently of bony anatomy. Cone beam computed tomography (CBCT) can be used to soft tissue match, so radiation therapists (RTs) must understand pelvic anatomy and PPRT clinical target volumes (CTV). The aims of this study are to define regions of interest (ROI) to be used in soft tissue matching image guidance and determine their visibility on planning CT (PCT) and CBCT. METHODS: Published CTV guidelines were used to select ROIs. The PCT scans (n = 23) and CBCT scans (n = 105) of 23 post-prostatectomy patients were reviewed. Details on ROI identification were recorded. RESULTS: Eighteen patients had surgical clips. All ROIs were identified on PCTs at least 90% of the time apart from mesorectal fascia (MF) (87%) due to superior image quality. When surgical clips are present, the seminal vesicle bed (SVB) was only seen in 2.3% of CBCTs and MF was unidentifiable. Most other structures were well identified on CBCT. The anterior rectal wall (ARW) was identified in 81.4% of images and penile bulb (PB) in 68.6%. In the absence of surgical clips, the MF and SVB were always identified; the ARW was identified in 89.5% of CBCTs and PB in 73.7%. CONCLUSIONS: Surgical clips should be used as ROIs when present to define SVB and MF. In the absence of clips, SVB, MF and ARW can be used. RTs must have a strong knowledge of soft tissue anatomy and PPRT CTV to ensure coverage and enable soft tissue matching. PMID- 26229654 TI - Patient-based radiographic exposure factor selection: a systematic review. AB - INTRODUCTION: Digital technology has wider exposure latitude and post-processing algorithms which can mask the evidence of underexposure and overexposure. Underexposure produces noisy, grainy images which can impede diagnosis and overexposure results in a greater radiation dose to the patient. These exposure errors can result from inaccurate adjustment of exposure factors in response to changes in patient thickness. This study aims to identify all published radiographic exposure adaptation systems which have been, or are being, used in general radiography and discuss their applicability to digital systems. METHODS: Studies in EMBASE, MEDLINE, CINAHL and SCOPUS were systematically reviewed. Some of the search terms used were exposure adaptation, exposure selection, exposure technique, 25% rule, 15% rule, DuPontTM Bit System and radiography. A manual journal-specific search was also conducted in The Radiographer and Radiologic Technology. Studies were included if they demonstrated a system of altering exposure factors to compensate for variations in patients for general radiography. Studies were excluded if they focused on finding optimal exposures for an 'average' patient or focused on the relationship between exposure factors and dose. RESULTS: The database search uncovered 11 articles and the journal specific search uncovered 13 articles discussing systems of exposure adaptation. They can be categorised as simple one-step guidelines, comprehensive charts and computer programs. CONCLUSION: Only two papers assessed the efficacy of exposure adjustment systems. No literature compares the efficacy of exposure adaptations system for film/screen radiography with digital radiography technology nor is there literature on a digital specific exposure adaptation system. PMID- 26229655 TI - A paediatric X-ray exposure chart. AB - The aim of this review was to develop a radiographic optimisation strategy to make use of digital radiography (DR) and needle phosphor computerised radiography (CR) detectors, in order to lower radiation dose and improve image quality for paediatrics. This review was based on evidence-based practice, of which a component was a review of the relevant literature. The resulting exposure chart was developed with two distinct groups of exposure optimisation strategies - body exposures (for head, trunk, humerus, femur) and distal extremity exposures (elbow to finger, knee to toe). Exposure variables manipulated included kilovoltage peak (kVp), target detector exposure and milli-ampere-seconds (mAs), automatic exposure control (AEC), additional beam filtration, and use of antiscatter grid. Mean dose area product (DAP) reductions of up to 83% for anterior-posterior (AP)/posterior-anterior (PA) abdomen projections were recorded postoptimisation due to manipulation of multiple-exposure variables. For body exposures, the target EI and detector exposure, and thus the required mAs were typically 20% less postoptimisation. Image quality for some distal extremity exposures was improved by lowering kVp and increasing mAs around constant entrance skin dose. It is recommended that purchasing digital X-ray equipment with high detective quantum efficiency detectors, and then optimising the exposure chart for use with these detectors is of high importance for sites performing paediatric imaging. Multiple-exposure variables may need to be manipulated to achieve optimal outcomes. PMID- 26229656 TI - Beyond cancer treatment - a review of total lymphoid irradiation for heart and lung transplant recipients. AB - Immunosuppressive drugs used in the management of heart and lung transplants have a large monetary and quality of life cost due to their side effects. Total lymphoid irradiation (TLI) is one method of minimising the need for or replacing post-operative immunosuppressive drugs. A literature review was conducted on electronic databases using defined search terms. The aim was to establish the indications for the use of TLI, its advantages and disadvantages and the weaknesses associated with the methods used in related research. Eight articles were located that focused on TLI usage in combating organ rejection. These studies identified that the use of TLI resulted in a reduction in early rejection. One study reported a drop in rejection episodes from 0.46 to 0.14 episodes per patient per month once the TLI was complete. While the short-term prognosis is excellent, the long-term outlook is less positive with an increased risk of organ rejection and myelodysplasia 3.5 years post-TLI. This review reminds us that radiation therapy (RT) is not exclusively indicated for cancer treatment. While TLI cannot replace immunosuppressive drug therapy, it can offer a treatment option for people that cannot tolerate immunosuppressive drugs, or when conventional anti-rejection treatment is no longer viable. Reported long term complications suggest that TLI should be used with caution. However, this modality should not be overlooked in cases of chronic rejection. Further research is required to establish the efficacy of RT in the treatment of transplant patients who are unsuitable for drug-based anti-rejection therapies. PMID- 26229657 TI - Intensity-modulated radiation therapy to bilateral lower limb extremities concurrently: a planning case study. AB - Non-melanomatous skin cancers represent 80% of all newly diagnosed cancers in Australia with basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) being the most common. A previously healthy 71-year-old woman presented with widespread and tender superficial skin cancers on the lower bilateral limbs. External beam radiation therapy through the use of intensity-modulated radiation therapy (IMRT) was employed as the treatment modality of choice as this technique provides conformal dose distribution to a three-dimensional treatment volume while reducing toxicity to surrounding tissues. The patient was prescribed a dose of 60 Gy to the planning target volume (PTV) with 1.0 cm bolus over the ventral surface of each limb. The beam arrangement consisted of six treatment fields that avoided entry and exit through the contralateral limb. The treatment plans met the International Commission on Radiation Units and Measurements (ICRU) guidelines and produced highly conformal dosimetric results. Skin toxicity was measured against the National Cancer Institute: Common Terminology Criteria for Adverse Events (NCI: CTCAE) version 3. A well-tolerated treatment was delivered with excellent results given the initial extent of the disease. This case study has demonstrated the feasibility and effectiveness of IMRT for skin cancers as an alternative to surgery and traditional superficial radiation therapy, utilising a complex PTV of the extremities for patients with similar presentations. PMID- 26229660 TI - Rolling out radioguided occult lesion localisation for breast tumours. PMID- 26229661 TI - What is the best way to support patients undergoing radiation therapy? PMID- 26229662 TI - Radioguided localisation of impalpable breast lesions using 99m-Technetium macroaggregated albumin: Lessons learnt during introduction of a new technique to guide preoperative localisation. AB - INTRODUCTION: Preoperative wire-guided localisation (WGL) of impalpable breast lesions is widely used but can be technically difficult. Risks include wire migration, inaccurate placement, and inadequate surgical margins. Research shows that radioguided occult lesion localisation (ROLL) is quicker, easier, and can improve surgical and cosmetic outcomes. An audited introduction of ROLL was conducted to validate the technique as a feasible alternative to WGL. METHODS: Fifty patients with single impalpable lesions and biopsy proven malignancy or indeterminate histology underwent WGL followed by intralesional radiopharmaceutical injection of 99m-Technetium macroaggregated albumin. Postprocedural mammography was performed to demonstrate wire position, and scintigraphy to evaluate radiopharmaceutical migration. Lymphoscintigraphy and intraoperative sentinel node biopsy were performed if indicated, followed by lesion localisation and excision using a gamma probe. Specimen imaging was performed, with immediate reexcision for visibly inadequate margins. RESULTS: Accurate localisation was achieved in 86% of patients with ROLL compared to 72% with WGL. All lesions were successfully removed, with clear margins in 71.8% of malignant lesions. Reexcision and intraoperative sentinel node localisation rates were equivalent to preaudit figures for WGL. ROLL was easy to perform and problems were infrequent. Inaccurate radiopharmaceutical placement necessitating WGL occurred in four patients. Minor radiopharmaceutical migration was common, but precluded using ROLL in only two cases. CONCLUSIONS: ROLL is effective, simple, inexpensive, and easily learnt; however, preoperative confirmation of correct radiopharmaceutical placement using mammography and the gamma probe is important to help ensure successful lesion removal. Insertion of a backup hookwire is recommended during the initial introduction of ROLL. PMID- 26229663 TI - Evaluation of radiographers' mammography screen-reading accuracy in Australia. AB - INTRODUCTION: This study aimed to evaluate the accuracy of radiographers' screen reading mammograms. Currently, radiologist workforce shortages may be compromising the BreastScreen Australia screening program goal to detect early breast cancer. The solution to a similar problem in the United Kingdom has successfully encouraged radiographers to take on the role as one of two screen readers. Prior to consideration of this strategy in Australia, educational and experiential differences between radiographers in the United Kingdom and Australia emphasise the need for an investigation of Australian radiographers' screen-reading accuracy. METHODS: Ten radiographers employed by the Westmead Breast Cancer Institute with a range of radiographic (median = 28 years), mammographic (median = 13 years) and BreastScreen (median = 8 years) experience were recruited to blindly and independently screen-read an image test set of 500 mammograms, without formal training. The radiographers indicated the presence of an abnormality using BI-RADS(r). Accuracy was determined by comparison with the gold standard of known outcomes of pathology results, interval matching and client 6-year follow-up. RESULTS: Individual sensitivity and specificity levels ranged between 76.0% and 92.0%, and 74.8% and 96.2% respectively. Pooled screen reader accuracy across the radiographers estimated sensitivity as 82.2% and specificity as 89.5%. Areas under the reading operating characteristic curve ranged between 0.842 and 0.923. CONCLUSIONS: This sample of radiographers in an Australian setting have adequate accuracy levels when screen-reading mammograms. It is expected that with formal screen-reading training, accuracy levels will improve, and with support, radiographers have the potential to be one of the two screen-readers in the BreastScreen Australia program, contributing to timeliness and improved program outcomes. PMID- 26229664 TI - Evaluating radiographers' diagnostic accuracy in screen-reading mammograms: what constitutes a quality study? AB - INTRODUCTION: The aim of this study was to first evaluate the quality of studies investigating the diagnostic accuracy of radiographers as mammogram screen readers and then to develop an adapted tool for determining the quality of screen reading studies. METHODS: A literature search was used to identify relevant studies and a quality evaluation tool constructed by combining the criteria for quality of Whiting, Rutjes, Dinnes et al. and Brealey and Westwood. This constructed tool was then applied to the studies and subsequently adapted specifically for use in evaluating quality in studies investigating diagnostic accuracy of screen-readers. RESULTS: Eleven studies were identified and the constructed tool applied to evaluate quality. This evaluation resulted in the identification of quality issues with the studies such as potential for bias, applicability of results, study conduct, reporting of the study and observer characteristics. An assessment of the applicability and relevance of the tool for this area of research resulted in adaptations to the criteria and the development of a tool specifically for evaluating diagnostic accuracy in screen-reading. CONCLUSIONS: This tool, with further refinement and rigorous validation can make a significant contribution to promoting well-designed studies in this important area of research and practice. PMID- 26229665 TI - Imaging dose in breast radiotherapy: does breast size affect the dose to the organs at risk and the risk of secondary cancer to the contralateral breast? AB - INTRODUCTION: Correct target positioning is crucial for accurate dose delivery in breast radiotherapy resulting in utilisation of daily imaging. However, the radiation dose from daily imaging is associated with increased probability of secondary induced cancer. The aim of this study was to quantify doses associated with three imaging modalities and investigate the correlation of dose and varying breast size in breast radiotherapy. METHODS: Planning computed tomography (CT) data sets of 30 breast cancer patients were utilised to simulate the dose received by various organs from a megavoltage computed tomography (MV-CT), megavoltage electronic portal image (MV-EPI) and megavoltage cone-beam computed tomography (MV-CBCT). The mean dose to organs adjacent to the target volume (contralateral breast, lungs, spinal cord and heart) were analysed. Pearson correlation analysis was performed to determine the relationship between imaging dose and primary breast volume and the lifetime attributable risk (LAR) of induced secondary cancer was calculated for the contralateral breast. RESULTS: The highest contralateral breast mean dose was from the MV-CBCT (1.79 Gy), followed by MV-EPI (0.22 Gy) and MV-CT (0.11 Gy). A similar trend was found for all organs at risk (OAR) analysed. The primary breast volume inversely correlated with the contralateral breast dose for all three imaging modalities. As the primary breast volume increases, the likelihood of a patient developing a radiation-induced secondary cancer to the contralateral breast decreases. MV-CBCT showed a stronger relationship between breast size and LAR of developing a radiation-induced contralateral breast cancer in comparison with the MV-CT and MV EPI. CONCLUSIONS: For breast patients, imaging dose to OAR depends on imaging modality and treated breast size. When considering the use of imaging during breast radiotherapy, the patient's breast size and contralateral breast dose should be taken into account. PMID- 26229666 TI - Quantifying intra- and inter-fractional motion in breast radiotherapy. AB - INTRODUCTION: The magnitude of intra- and inter-fractional variation in the set up of breast cancer patients treated with tangential megavoltage photon beams was investigated using an electronic portal imaging device (EPID). METHODS: Daily cine-EPID images were captured during delivery of the tangential fields for ten breast cancer patients treated in the supine position. Measurements collected from each image included the central lung distance (CLD), central flash distance (CFD), superior axial measurement (SAM) and the inferior axial measurement (IAM). The variation of motion within a fraction (intra-fraction) and the variation between fractions (inter-fraction) was analysed to quantify set up variation and motion due to respiration. RESULTS: Altogether 3775 EPID images were collected from 10 patients. The effect of respiratory motion during treatment was <0.1 cm standard deviation (SD) in the anterior-posterior (AP) direction. The inter fraction movement caused by variations in daily set up was larger at 0.28 cm SD in the AP direction. Superior-inferior (SI) variation was more difficult to summarise and proved unreliable as the measurements were taken to an ambiguous point on the images. It was difficult to discern true SI movement from that implicated by AP movement. CONCLUSION: There is minimal intra-fractional chest wall motion due to respiration during treatment. Inter-fractional variation was larger, however, on average it remained within departmental tolerance (0.5 cm) for set up variations. This review of our current breast technique provides confidence in the feasibility of utilising advanced treatment techniques (field in-field, intensity modulated radiotherapy or volumetric modulated arc therapy) following a review of the current imaging protocol. PMID- 26229667 TI - Expanding the indications for MRI in the diagnosis and treatment of breast cancer: what is best practice? AB - Breast magnetic resonance imaging (MRI) now has an accepted place in screening younger women at high risk of breast cancer, and is increasingly used in a number of other settings including assessment of response to neo-adjuvant therapy and local staging of cancer. Although the evidence for its general use in these settings is very limited, in highly selected patients, especially where discordance with conventional measurements occurs, MRI can have a place in assessing extent of disease, both whether operable and how operable, and guiding surgery. These scenarios and future indications and alternative technologies are explored in this paper. PMID- 26229668 TI - The role of general nuclear medicine in breast cancer. AB - The rising incidence of breast cancer worldwide has prompted many improvements to current care. Routine nuclear medicine is a major contributor to a full gamut of clinical studies such as early lesion detection and stratification; guiding, monitoring, and predicting response to therapy; and monitoring progression, recurrence or metastases. Developments in instrumentation such as the high resolution dedicated breast device coupled with the diagnostic versatility of conventional cameras have reinserted nuclear medicine as a valuable tool in the broader clinical setting. This review outlines the role of general nuclear medicine, concluding that targeted radiopharmaceuticals and versatile instrumentation position nuclear medicine as a powerful modality for patients with breast cancer. PMID- 26229669 TI - The cardiac dose-sparing benefits of deep inspiration breath-hold in left breast irradiation: a systematic review. AB - INTRODUCTION: Despite technical advancements in breast radiation therapy, cardiac structures are still subject to significant levels of irradiation. As the use of adjuvant radiation therapy after breast-conserving surgery continues to improve survival for early breast cancer patients, the associated radiation-induced cardiac toxicities become increasingly relevant. Our primary aim was to evaluate the cardiac-sparing benefits of the deep inspiration breath-hold (DIBH) technique. METHODS: An electronic literature search of the PubMed database from 1966 to July 2014 was used to identify articles published in English relating to the dosimetric benefits of DIBH. Studies comparing the mean heart dose of DIBH and free breathing treatment plans for left breast cancer patients were eligible to be included in the review. Studies evaluating the reproducibility and stability of the DIBH technique were also reviewed. RESULTS: Ten studies provided data on the benefits of DIBH during left breast irradiation. From these studies, DIBH reduced the mean heart dose by up to 3.4 Gy when compared to a free breathing approach. Four studies reported that the DIBH technique was stable and reproducible on a daily basis. According to current estimates of the excess cardiac toxicity associated with radiation therapy, a 3.4 Gy reduction in mean heart dose is equivalent to a 13.6% reduction in the projected increase in risk of heart disease. CONCLUSION: DIBH is a reproducible and stable technique for left breast irradiation showing significant promise in reducing the late cardiac toxicities associated with radiation therapy. PMID- 26229671 TI - Finding my own voice through the breast cancer journey: humour, sadness and smurfs. PMID- 26229670 TI - Review of deep inspiration breath-hold techniques for the treatment of breast cancer. AB - Radiation treatment to the left breast is associated with increased cardiac morbidity and mortality. The deep inspiration breath-hold technique (DIBH) can decrease radiation dose delivered to the heart and this may facilitate the treatment of the internal mammary chain nodes. The aim of this review is to critically analyse the literature available in relation to breath-hold methods, implementation, utilisation, patient compliance, planning methods and treatment verification of the DIBH technique. Despite variation in the literature regarding the DIBH delivery method, patient coaching, visual feedback mechanisms and treatment verification, all methods of DIBH delivery reduce radiation dose to the heart. Further research is required to determine optimum protocols for patient training and treatment verification to ensure the technique is delivered successfully. PMID- 26229672 TI - The trouble with apparent diffusion coefficient papers. PMID- 26229673 TI - Using the apparent diffusion coefficient to identifying MGMT promoter methylation status early in glioblastoma: importance of analytical method. AB - INTRODUCTION: Accurate knowledge of O(6)-methylguanine methyltransferase (MGMT) gene promoter subtype in patients with glioblastoma (GBM) is important for treatment. However, this test is not always available. Pre-operative diffusion MRI (dMRI) can be used to probe tumour biology using the apparent diffusion coefficient (ADC); however, its ability to act as a surrogate to predict MGMT status has shown mixed results. We investigated whether this was due to variations in the method used to analyse ADC. METHODS: We undertook a retrospective study of 32 patients with GBM who had MGMT status measured. Matching pre-operative MRI data were used to calculate the ADC within contrast enhancing regions of tumour. The relationship between ADC and MGMT was examined using two published ADC methods. RESULTS: A strong trend between a measure of 'minimum ADC' and methylation status was seen. An elevated minimum ADC was more likely in the methylated compared to the unmethylated MGMT group (U = 56, P = 0.0561). In contrast, utilising a two-mixture model histogram approach, a significant reduction in mean measure of the 'low ADC' component within the histogram was associated with an MGMT promoter methylation subtype (P < 0.0246). CONCLUSION: This study shows that within the same patient cohort, the method selected to analyse ADC measures has a significant bearing on the use of that metric as a surrogate marker of MGMT status. Thus for dMRI data to be clinically useful, consistent methods of data analysis need to be established prior to establishing any relationship with genetic or epigenetic profiling. PMID- 26229674 TI - Dose planning objectives in anal canal cancer IMRT: the TROG ANROTAT experience. AB - INTRODUCTION: Intensity modulated radiotherapy (IMRT) is ideal for anal canal cancer (ACC), delivering high doses to irregular tumour volumes whilst minimising dose to surrounding normal tissues. Establishing achievable dose objectives is a challenge. The purpose of this paper was to utilise data collected in the Assessment of New Radiation Oncology Treatments and Technologies (ANROTAT) project to evaluate the feasibility of ACC IMRT dose planning objectives employed in the Australian situation. METHODS: Ten Australian centres were randomly allocated three data sets from 15 non-identifiable computed tomography data sets representing a range of disease stages and gender. Each data set was planned by two different centres, producing 30 plans. All tumour and organ at risk (OAR) contours, prescription and dose constraint details were provided. Dose-volume histograms (DVHs) for each plan were analysed to evaluate the feasibility of dose planning objectives provided. RESULTS: All dose planning objectives for the bone marrow (BM) and femoral heads were achieved. Median planned doses exceeded one or more objectives for bowel, external genitalia and bladder. This reached statistical significance for bowel V30 (P = 0.04), V45 (P < 0.001), V50 (P < 0.001), external genitalia V20 (P < 0.001) and bladder V35 (P < 0.001), V40 (P = 0.01). Gender was found to be the only significant factor in the likelihood of achieving the bowel V50 (P = 0.03) and BM V30 constraints (P = 0.04). CONCLUSION: The dose planning objectives used in the ANROTAT project provide a good starting point for ACC IMRT planning. To facilitate clinical implementation, it is important to prioritise OAR objectives and recognise factors that affect the achievability of these objectives. PMID- 26229675 TI - Evaluation of the dosimetric impact of applying flattening filter-free beams in intensity-modulated radiotherapy for early-stage upper thoracic carcinoma of oesophagus. AB - INTRODUCTION: Flattening filter-free (FFF) radiation beams have recently become clinically available on modern linear accelerators in radiation therapy. This study aimed to evaluate the dosimetric impact of using FFF beams in intensity modulated radiotherapy (IMRT) for early-stage upper thoracic oesophageal cancer. METHODS: Eleven patients with primary stage upper thoracic oesophageal cancer were recruited. For each patient, two IMRT plans were computed using conventional beams (Con-P) and FFF beams (FFF-P), respectively. Both plans employed a five beam arrangement and were prescribed with 64 Gy to (planning target volume) PTV1 and 54 Gy to PTV2 in 32 fractions using 6 MV photons. The dose parameters of the target volumes and organs at risks (OARs), and treatment parameters including the monitor units (MU) and treatment time (TT) for Con-P and FFF-P were recorded and compared. RESULTS: The mean D 5 of PTV1 and PTV2 were higher in FFF-P than Con-P by 0.4 Gy and 0.3 Gy, respectively. For the OARs, all the dose parameters did not show significant difference between the two plans except the mean V 5 and V 10 of the lung in which the FFF-P was lower (46.7% vs. 47.3% and 39.1% vs. 39.6%, respectively). FFF-P required 54% more MU but 18.4% less irradiation time when compared to Con-P. CONCLUSION: The target volume and OARs dose distributions between the two plans were comparable. However, FFF-P was more effective in sparing the lung from low dose and reduced the mean TT compared with Con-P. Long term clinical studies are suggested to evaluate the radiobiological effects of FFF beams. PMID- 26229676 TI - Evaluation of a performance appraisal framework for radiation therapists in planning and simulation. AB - INTRODUCTION: Constantly evolving technology and techniques within radiation therapy require practitioners to maintain a continuous approach to professional development and training. Systems of performance appraisal and adoption of regular feedback mechanisms are vital to support this development yet frequently lack structure and rely on informal peer support. METHODS: A Radiation Therapy Performance Appraisal Framework (RT-PAF) for radiation therapists in planning and simulation was developed to define expectations of practice and promote a supportive and objective culture of performance and skills appraisal. Evaluation of the framework was conducted via an anonymous online survey tool. Nine peer reviewers and fourteen recipients provided feedback on its effectiveness and the challenges and limitations of the approach. RESULTS: Findings from the evaluation were positive and suggested that both groups gained benefit from and expressed a strong interest in embedding the approach more routinely. Respondents identified common challenges related to the limited ability to implement suggested development strategies; this was strongly associated with time and rostering issues. CONCLUSIONS: This framework successfully defined expectations for practice and provided a fair and objective feedback process that focussed on skills development. It empowered staff to maintain their skills and reach their professional potential. Management support, particularly in regard to provision of protected time was highlighted as critical to the framework's ongoing success. The demonstrated benefits arising in terms of staff satisfaction and development highlight the importance of this commitment to the modern radiation therapy workforce. PMID- 26229677 TI - Neuroimaging in adult penetrating brain injury: a guide for radiographers. AB - Penetrating brain injuries (PBI) are a medical emergency, often resulting in complex damage and high mortality rates. Neuroimaging is essential to evaluate the location and extent of injuries, and to manage them accordingly. Currently, a myriad of imaging modalities are included in the diagnostic workup for adult PBI, including skull radiography, computed tomography (CT), magnetic resonance imaging (MRI) and angiography, with each modality providing their own particular benefits. This literature review explores the current modalities available for investigating PBI and aims to assist in decision making for the appropriate use of diagnostic imaging when presented with an adult PBI. Based on the current literature, the authors have developed an imaging pathway for adult penetrating brain injury that functions as both a learning tool and reference guide for radiographers and other health professionals. Currently, CT is recommended as the imaging modality of choice for the initial assessment of PBI patients, while MRI is important in the sub-acute setting where it aids prognosis prediction and rehabilitation planning, Additional follow-up imaging, such as angiography, should be dependent upon clinical findings. PMID- 26229678 TI - Obese patients and radiography literature: what do we know about a big issue? AB - Obesity is a global health issue with obese patients requiring specialised diagnosis, treatment and care through the health service. The practical and social difficulties associated with medical imaging of obese patients are an increasingly common problem and it is currently unknown how student and qualified radiographers perceive and respond to these challenges. By better understanding challenges presented in providing quality imaging and care of imaging obese patients, education for both qualified and student radiographers can be enhanced. Radiographers are heavily reliant on visual and tactile senses to locate the position of anatomical structures for diagnostic imaging and determine radiation exposure through a delicate consideration of dose, image quality and anatomical attenuation. However, obese patients require modifications to routine radiographic practice in terms of movement/assisted positioning, equipment capabilities to take increased weight or coverage. These patients may also be subject to compromised radiological diagnosis through poor visualisation of structures. In this paper, the professional and educational literature was narratively reviewed to assess gaps in the evidence base related to the skill and care knowledge for obese patients. Literature was sourced relating to discrete radiographic considerations such as the technical factors of imaging obese patients, exposure and the impact of obesity on imaging departments' service provisions. The recent literature (post-2000 to coincide with the sharp increase in global obesity) on the perceptions of health professionals and student health practitioners has also been explored because there are no specific radiographer studies to report. By understanding the research in similar fields, we may identify what common attitudes qualified and student radiographer's hold and what challenges, technical and care related, can be prepared for. PMID- 26229679 TI - A review of stereotactic body radiotherapy - is volumetric modulated arc therapy the answer? AB - Stereotactic body radiotherapy (SBRT) is a high precision radiotherapy technique used for the treatment of small to moderate extra-cranial tumours. Early studies utilising SBRT have shown favourable outcomes. However, major disadvantages of static field SBRT include long treatment times and toxicity complications. Volumetric modulated arc therapy (VMAT) and intensity modulated radiotherapy (IMRT) may potentially mitigate these disadvantages. This review aims to assess the feasibility of emerging VMAT and IMRT-based SBRT treatment techniques and qualify which offers the best outcome for patients, whilst identifying any emerging and advantageous SBRT planning trends. A review and synthesis of data from current literature up to September 2013 was conducted on EMBASE, Medline, PubMed, Science Direct, Proquest central, Google Scholar and the Cochrane Database of Systematic reviews. Only full text papers comparing VMAT and or IMRT and or Static SBRT were included. Ten papers were identified that evaluated the results of VMAT/IMRT SBRT. Five related to medically inoperable stage 1 and 2 non small-cell lung cancer (NSCLC), three to spinal metastasis, one related to abdominal lymph node malignancies, with the final one looking at pancreatic adenocarcinoma. Overall treatment times with VMAT were reduced by 66-70% for lung, 46-58% for spine, 42% and 21% for lymph node and pancreatic metastasis respectively, planning constraints were met with several studies showing improved organs at risk sparing with IMRT/VMAT to static SBRT. Both IMRT and VMAT were able to meet all planning constraints in the studies reviewed, with VMAT offering the greatest treatment efficiency. Early clinical outcomes with VMAT and IMRT SBRT have demonstrated excellent local control and favourable survival outcomes. PMID- 26229680 TI - Regional cancer centre demonstrates voluntary conformity with the national Radiation Oncology Practice Standards. AB - Radiation Oncology Practice Standards have been developed over the last 10 years and were published for use in Australia in 2011. Although the majority of the radiation oncology community supports the implementation of the standards, there has been no mechanism for uniform assessment or governance. North Coast Cancer Institute's public radiation oncology service is provided across three main service centres on the north coast of NSW. With a strong focus on quality management, we embraced the opportunity to demonstrate conformity with the Radiation Oncology Practice Standards. The Local Health District's Clinical Governance units were engaged to perform assessments of our conformity with the standards and this was signed off as complete on 16 December 2013. The process of demonstrating conformity with the Radiation Oncology Practice Standards has enhanced the culture of quality in our centres. We have demonstrated that self assessment utilising trained auditors is a viable method for centres to demonstrate conformity. National implementation of the Radiation Oncology Practice Standards will benefit individual centres and the broader radiation oncology community to improve the service delivered to our patients. PMID- 26229681 TI - Placement of a peripherally inserted central catheter into the azygous vein. AB - Peripherally inserted central catheters (PICC) are used for a variety of infusion therapies. They are indicated in patients requiring long-term venous access. Incorrect positioning of the insertion of a PICC line is one of the known complications when inserting the device in clinical practice. Radiographers once performing imaging will commonly check if the tip of a PICC has entered the superior vena cava. This case study will report on a lesser known incorrect placement of a PICC line into the azygous vein and how this can be detected on radiographic imaging. This outcome for the patient can be detrimental as it has an increased risk of perforation, thrombus, and fistula formation. PMID- 26229682 TI - Intracystic mural nodules of the breast: benign versus malignant; a multidisciplinary imaging and management approach. AB - This case report illustrates the presence of intracystic mural nodules within the breast, a benign proliferative disorder associated with the fibrocystic spectrum: papillary apocrine metaplasia. The aim of this paper is to provide a comprehensive understanding of the physical and histological attributes of benign intracystic mural nodules, and the ability to distinguish these from a malignant papilloma and carcinoma. Also, the technical and patient considerations, as well as the appropriate imaging and interventional methods required to ensure correct patient management pathway are discussed, extending into an analysis of the psychological effects felt by patients undergoing assessment. PMID- 26229683 TI - Comparison of Oncentra(r) Brachy IPSA and graphical optimisation techniques: a case study of HDR brachytherapy head and neck and prostate plans. AB - There are a number of different dwell positions and time optimisation options available in the Oncentra(r) Brachy (Elekta Brachytherapy Solutions, Veenendaal, The Netherlands) brachytherapy treatment planning system. The purpose of this case study was to compare graphical (GRO) and inverse planning by simulated annealing (IPSA) optimisation techniques for interstitial head and neck (HN) and prostate plans considering dosimetry, modelled radiobiology outcome and planning time. Four retrospective brachytherapy patients were chosen for this study, two recurrent HN and two prostatic boosts. Manual GRO and IPSA plans were generated for each patient. Plans were compared using dose-volume histograms (DVH) and dose coverage metrics including; conformity index (CI), homogeneity index (HI) and conformity number (CN). Logit and relative seriality models were used to calculate tumour control probability (TCP) and normal tissue complication probability (NTCP). Approximate planning time was also recorded. There was no significant difference between GRO and IPSA in terms of dose metrics with mean CI of 1.30 and 1.57 (P > 0.05) respectively. IPSA achieved an average HN TCP of 0.32 versus 0.12 for GRO while for prostate there was no significant difference. Mean GRO planning times were greater than 75 min while average IPSA planning times were less than 10 min. Planning times for IPSA were greatly reduced compared to GRO and plans were dosimetrically similar. For this reason, IPSA makes for a useful planning tool in HN and prostate brachytherapy. PMID- 26229684 TI - 'Rolling out radioguided occult lesion localisation for breast tumours': moving from ROLL to ROLLIS. PMID- 26229685 TI - Implementation of continuous renal replacement therapy with regional citrate anticoagulation on a surgical and trauma intensive care unit: impact on clinical and economic aspects-an observational study. AB - BACKGROUND: Regional citrate anticoagulation (RCA) is being increasingly used during continuous renal replacement therapy (CRRT) in intensive care units as an alternative to systemic heparin anticoagulation. However, due to its availability in a variety of solutions and dialysis systems, RCA is still considered a complex intervention, possibly leading to confusion and pitfalls in everyday practice. We therefore tested retrospectively if the introduction of RCA as a new anticoagulation strategy for CRRT was feasible and had not negatively impacted efficacy, safety, metabolic stability, filter lifetime, and cost-effectiveness compared to well-established systemic heparin. METHODS: This observational, retrospective study was performed on a non-cardiac surgical and trauma intensive care unit (ICU) in a university hospital. All charts of patients receiving one of the CRRT techniques from May 2006 to April 2010 were reviewed. The first 60 consecutive patients receiving CRRT with regional citrate anticoagulation after its implementation in February 2008 (continuous veno-venous haemodialysis, Multifiltrate(r) with integrated CiCa(r) system, AV 1000 S(r) filter, n = 60) were included in the study. The last 50 consecutive patients with systemic heparin anticoagulation therapy (continuous veno-venous haemodiafiltration, PRISMAFLEX(r), AN69(r) filter, n = 50), treated immediately before the introduction of RCA, were used as a historic control group. RESULTS: Both treatment modalities were effective in terms of uraemia control. Patients in the citrate group presented with significantly higher pH levels, lower ionized calcium levels, and higher sodium levels compared with the heparin treated group, however, without notable adverse clinical events. Interestingly, mean circuit lifetime was significantly longer in the citrate group (48.6 +/- 24.2 h vs. 18.8 +/- 13.5 h; p < 0.0001). Both treatment modalities were cost-effective. CONCLUSIONS: Our results suggest that the implementation of regional citrate anticoagulation was safe and effective. Due to the retrospective design of the study and inherent limitations therein concerning several baseline parameters, i.e. different filters, modes of dialysis, and flow parameters not having been standardized, we were unable to draw a causative effect relationship. Nonetheless, our results warrant further study. PMID- 26229687 TI - Repeatability of Perimacular Ganglion Cell Complex Analysis with Spectral-Domain Optical Coherence Tomography. AB - Purpose. To assess the repeatability of spectral-domain optical coherence tomography to measure macular and perimacular ganglion cell complex thicknesses and compare retinal ganglion cell parameters between algorithms. Methods. Ninety two nonglaucomatous eyes from 92 participants underwent macular and perimacular ganglion cell complex thickness measurement using OCT-HS100 Glaucoma 3D algorithm and these measurements were repeated for 34 subjects. All subjects also had macular ganglion cell-inner plexiform layer thickness measured by Cirrus HD-OCT Ganglion Cell Analysis algorithm. Intraclass correlation coefficient and Pearson's correlation analyses were performed. Results. Subfields of both macular and perimacular ganglion cell complex thicknesses had high intraclass correlation coefficient values between 0.979 (95% confidence interval [CI]: 0.958-0.989) and 0.981 (95% CI: 0.963, 0.991) and between 0.70 (95% CI: 0.481-0.838) and 0.987 (95% CI: 0.956-0.989), respectively. The overall average ganglion cell complex and macular average ganglion cell-inner plexiform layer thicknesses were strongly correlated (r = 0.83, P < 0.001). Conclusions. The assessment of macular and perimacular retinal ganglion cell parameters by OCT-HS100 Glaucoma 3D algorithm is highly repeatable, and strongly correlates to retinal ganglion cell parameters assessed by Ganglion Cell Analysis algorithm. A comprehensive evaluation of retinal ganglion cells may be possible with OCT-HS100. PMID- 26229686 TI - Early outgrowth pro-angiogenic cell number and function do not correlate with left ventricular structure and function in conventional hemodialysis patients: a cross-sectional study. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is commonly found in chronic dialysis (CD) recipients, and is associated with impaired microvascular cardiac perfusion and heart failure. In response to LVH and cardiac ischemia, early outgrowth pro-angiogenic cellS(EPCs) mobilize from the bone marrow to facilitate angiogenesis and endothelial repair. In the general population, EPC number and function correlate inversely with cardiovascular risk. In end-stage renal disease (ESRD), EPC number and function are generally reduced. OBJECTIVES: To test whether left ventricular abnormalities retain their potent ability to promote EPC reparative responses in the setting of ESRD. DESIGN: Cross-sectional study. SETTING: St. Michael's Hospital, Toronto, Ontario, Canada. PATIENTS: 47 prevalent chronic dialysis recipients. MEASUREMENTS: (1) circulating CD34(+) and CD133(+) EPC number, (2) cultured EPC migratory ability, in vitro differentiation potential, and apoptosis rate, and (3) cardiac magnetic resonance-measured LV mass, volume and ejection fraction. METHODS: Bivariate correlation analysis was performed with Spearman's rho test. RESULTS: Of the 47 patients (mean age: 54 +/- 13 years), the mean delivered urea reduction was 74 +/- 10 %. Mean LV mass was 123 +/- 38 g. Circulating CD34(+) and CD133(+) EPCs represented 0.14 % (IQR: 0.05 - 0.29 %) and 0.05 % (IQR: 0.01 - 0.10 %) of peripheral blood mononuclear cells. There were no significant correlations between any EPC parameter and measures of LV mass or ejection fraction. LIMITATIONS: Lack of a non-ESRD control population, and the inability to measure all parameters of EPC function due to limitations in blood sampling. Our inability to measure cardiac VEGF expression prevented an assessment of changes in cardiac EPC mobilization signals. CONCLUSIONS: These data suggest that in ESRD, the reparative EPC response to cardiac hypertrophy may be blunted. Further investigation of the effects of uremia on EPC physiology and its relationship to cardiac injury are required. PMID- 26229688 TI - Risk Factors for Premenopausal Breast Cancer in Bangladesh. AB - Background. The incidence of premenopausal breast cancer is rising throughout South Asia. Our objective was to determine the role of risk factors associated with Westernization for premenopausal breast cancer in Bangladesh. Methods. We conducted a matched case-control study between January 1, 2007, and December 31, 2010, at four hospitals in Bangladesh. Cases were premenopausal women diagnosed with invasive breast cancer. Controls were premenopausal women with no personal history of breast cancer. Logistic regression was used to calculate the odds ratios (OR) for breast cancer. Results. We identified 129 age-matched pairs. The mean age of breast cancer diagnosis was 37.5 years. Each year decrease in the age of menarche significantly increased the risk of breast cancer (OR = 1.67, 95% CI 1.09-2.56, P = 0.02). The risk was also increased with a current body mass index of >=25 kg/m(2) (OR = 5.24, 95% CI 1.10-24.9, P = 0.04). Age at first childbirth, parity, and breastfeeding were not significantly associated with premenopausal breast cancer risk (P > 0.05). Conclusions. Age at menarche and adult weight gain were associated with premenopausal breast cancer risk. Other factors associated with Westernization may not be relevant to premenopausal breast cancer risk in Bangladesh. PMID- 26229690 TI - Evolution of Apparent Diffusion Coefficient and Fractional Anisotropy in the Cerebrum of Asphyxiated Newborns Treated with Hypothermia over the First Month of Life. AB - The objective of this study was to assess the evolution of diffusion-weighted imaging (DWI) and diffusion-tensor imaging (DTI) over the first month of life in asphyxiated newborns treated with hypothermia and to compare it with that of healthy newborns. Asphyxiated newborns treated with hypothermia were enrolled prospectively; and the presence and extent of brain injury were scored on each MRI. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were measured in the basal ganglia, in the white matter and in the cortical grey matter. Sixty-one asphyxiated newborns treated with hypothermia had a total of 126 ADC and FA maps. Asphyxiated newborns developing brain injury eventually had significantly decreased ADC values on days 2-3 of life and decreased FA values around day 10 and 1 month of life compared with those not developing brain injury. Despite hypothermia treatment, asphyxiated newborns may develop brain injury that still can be detected with advanced neuroimaging techniques such as DWI and DTI as early as days 2-3 of life. A study of ADC and FA values over time may aid in the understanding of how brain injury develops in these newborns despite hypothermia treatment. PMID- 26229691 TI - Change of Neural Connectivity of the Red Nucleus in Patients with Striatocapsular Hemorrhage: A Diffusion Tensor Tractography Study. AB - The red nucleus (RN) is involved in motor control and it is known to have potential to compensate for injury of the corticospinal tract (CST). We investigated the change of connectivity of the RN (RNc) and its relation to motor function in patients with striatocapsular hemorrhage. Thirty-five chronic patients with striatocapsular hemorrhage were recruited. Motricity Index (MI), Modified Brunnstrom Classification (MBC), and Functional Ambulation Category (FAC) were measured for motor function. The probabilistic tractography method was used for evaluation of the RNc. Fractional anisotropy (FA), mean diffusivity (MD), and tract volume (TV) of the RNc were measured. FA and TV ratios of the RNc in patients with discontinuation of the affected CST were significantly higher than those of patients with preserved integrity of the CST in the affected hemisphere (p < 0.05). TV ratio of the RNc showed significant negative correlation with upper MI (weak correlation, r = -0.35), total MI (weak correlation, r = -0.34), and MBC (moderate correlation, r = -0.43), respectively (p < 0.05). We found that the neural structure of the RNc was relatively increased in the unaffected hemisphere compared with the affected hemisphere in patients with more severe injury of the CST. PMID- 26229692 TI - Right Breast Mastectomy and Reconstruction with Tissue Expander under Thoracic Paravertebral Blocks in a 12-Week Parturient. AB - Paravertebral blocks are becoming increasingly utilized for breast surgery with studies showing improved postoperative pain control, decreased need for opioids, and less nausea and vomiting. We describe the anesthetic management of an otherwise healthy woman who was 12 weeks pregnant presenting for treatment of her breast cancer. For patients undergoing breast mastectomy and reconstruction with tissue expanders, paravertebral blocks offer an anesthetic alternative when general anesthesia is not desired. PMID- 26229693 TI - A Large Intra-Abdominal Hiatal Hernia as a Rare Cause of Dyspnea. AB - Giant hiatal hernias, generally seen at advanced ages, can rarely cause cardiac symptoms such as dyspnea and chest pain. Here, we aimed to present a case with a large hiatal hernia that largely protruded to intrathoracic cavity and caused dyspnea, particularly at postprandial period, by compressing the left atrium and right pulmonary vein. We considered presenting this case as large hiatal hernia is a rare, intra-abdominal cause of dyspnea. PMID- 26229694 TI - Facial Swelling as a Primary Manifestation of Multiple Myeloma. AB - Facial swellings are commonly encountered in the dental office, the cause of which could range from a congenital etiology to an acquired one or it may even be a manifestation of an underlying systemic disease. The clinician must have a thorough knowledge of the various clinical and imaging manifestations and the sites of occurrence of the various conditions to arrive at the appropriate diagnosis. Facial swellings can be classified into different groups which include acute swellings with inflammation, nonprogressive swellings, and slowly or rapidly progressive swellings. The various imaging modalities like CT and MRI are useful for assessing the extent of the swelling as well as evaluating the soft tissue and osseous involvement of the swelling. Multiple myeloma represents clonal proliferation of plasma cells and is a condition in which a facial swelling might be present, though not common. This paper reports a case of a patient with a unilateral facial swelling, which on investigation led to a diagnosis of multiple myeloma. PMID- 26229689 TI - Neural Plasticity in Multiple Sclerosis: The Functional and Molecular Background. AB - Multiple sclerosis is an autoimmune neurodegenerative disorder resulting in motor dysfunction and cognitive decline. The inflammatory and neurodegenerative changes seen in the brains of MS patients lead to progressive disability and increasing brain atrophy. The most common type of MS is characterized by episodes of clinical exacerbations and remissions. This suggests the presence of compensating mechanisms for accumulating damage. Apart from the widely known repair mechanisms like remyelination, another important phenomenon is neuronal plasticity. Initially, neuroplasticity was connected with the developmental stages of life; however, there is now growing evidence confirming that structural and functional reorganization occurs throughout our lifetime. Several functional studies, utilizing such techniques as fMRI, TBS, or MRS, have provided valuable data about the presence of neuronal plasticity in MS patients. CNS ability to compensate for neuronal damage is most evident in RR-MS; however it has been shown that brain plasticity is also preserved in patients with substantial brain damage. Regardless of the numerous studies, the molecular background of neuronal plasticity in MS is still not well understood. Several factors, like IL-1beta, BDNF, PDGF, or CB1Rs, have been implicated in functional recovery from the acute phase of MS and are thus considered as potential therapeutic targets. PMID- 26229695 TI - Full Mouth Reconstruction of a Bruxer with Severely Worn Dentition: A Clinical Report. AB - Tooth wear is attributed to several factors many of which often remain unidentified. Management of tooth wear is challenging in preventive and restorative dentistry. Correct assessment of occlusal vertical dimension, interocclusal rest space, and centric relation records are critical for successful treatment. In order to evaluate different treatment modalities and select the treatment of choice some information can be obtained from study casts and diagnostic wax-up. In order to achieve a predictable and desirable result, a systematic approach may be helpful. This paper describes the full mouth rehabilitation of a 36-year-old bruxer with severely worn dentition and other dental problems such as unfavorable restorations. A diagnostic work-up was performed and provisional restorations were made; then, they were clinically evaluated and adjusted based on the criteria dictating esthetics, phonetics, and vertical dimension. After endodontic therapy, clinical crown lengthening was performed. Two short implants were inserted in the posterior mandible. Custom cast dowel cores and metal-ceramic restorations were fabricated and a full occlusal splint was used to protect the restorations. We ensured stable contacts on all teeth with equal intensity in centric relation and anterior guidance in accord with functional jaw movements. PMID- 26229696 TI - Toxic Effects of Rhamnus alaternus: A Rare Case Report. AB - In Tunisia, there are about 478 species of plants commonly used in folk medicine. Medicinal plants and herbal remedies used are responsible for 2% of intoxications listed by Tunisian National Poison Center. Most cases are related to confusion between edible plants and toxic plants lookalikes or to an excessive consumption of therapeutic plants. We report the case of a 58-year-old man admitted to the Emergency Department of the Regional Hospital of Zaghouan (Tunisia), with renal failure and rhabdomyolysis. The patient reported having daily consumption of a homemade tea based on Mediterranean Buckthorn roots, during the last 6 months to treat type 2 diabetes. The aim of this work was to establish an association between the consumption of the herbal remedy and the occurrence of both renal failure and rhabdomyolysis. No similar cases have been reported in recent literature. PMID- 26229697 TI - Hyperandrogenism-Insulin Resistance-Acanthosis Nigricans Syndrome. AB - Introduction. Female hyperandrogenism is a frequent motive of consultation. It is revealed by hirsutism, acne or seborrhea, and disorders in menstruation cycle combined or not with virilisation signs. Several etiologies are incriminated but the hyperandrogenism-insulin resistance-acanthosis nigricans syndrome is rare. Observation. A 20-year-old girl, having had a five-year-old secondary amenorrhea. The exam revealed a patient, normotensive with a body mass index at 30 kg/m(2) and a waist measurement of 120 cm, a severe hirsutism assessed to be 29 according to Ferriman Gallwey scale, virilisation signs of male morphotype, clitoridic hypertrophy and frontal alopecia, and an acanthosis nigricans behind the neck, in the armpits and elbows. The assessment carried out revealed testosteronemia at 1.28 ng/mL, which is more than twice the upper norm of the laboratory. Imaging studies were negative for both ovarian and adrenal masses. The retained diagnosis is HAIR-AN syndrome probably related to ovarian hyperthecosis and she was provided with androcur 50 mg/day and estradiol pills 2 mg/day and under hygiene dietetic conditions. Conclusion. This case proves that HAIR-AN syndrome could be responsible for severe hyperandrogenism with virilisation signs. It must be retained after discarding the tumoral causes and when there are signs of insulin resistance. PMID- 26229698 TI - Neonatal Acute Megakaryoblastic Leukemia Presenting with Leukemia Cutis and Multiple Intracranial Lesions Successfully Treated with Unrelated Cord Blood Transplantation. AB - Neonatal acute megakaryoblastic leukemia (AMKL) without Down syndrome (DS) is an extremely rare disorder. We report of a one-day-old male infant without DS who developed AMKL with leukemia cutis and right facial nerve palsy. Magnetic resonance imaging of the patient's brain revealed multiple intracranial tumors. A biopsy specimen of the skin lesion was suggestive of AMKL, but the bone marrow leukemic cells were less than 5% of the marrow nucleated cells. The skin and intracranial lesions had spontaneously regressed within one and a half months, but the patient's anemia and thrombocytopenia gradually worsened and the leukemic cells in the bone marrow gradually increased to more than 20% of the nucleated cells. In addition, multiple intracranial lesions reappeared at 72 days of life. We diagnosed the patient with AMKL, and chemotherapy followed by unrelated cord blood transplantation after a reduced-intensity conditioning regimen resulted in sustained complete remission. At present, the patient is well, and he has demonstrated normal development for five years. PMID- 26229699 TI - Presentation of Complex Homozygous Allele in ABCA4 Gene in a Patient with Retinitis Pigmentosa. AB - Retinitis pigmentosa is a degenerative retinal disease characterized by progressive photoreceptor damage, which causes loss of peripheral and night vision and the development of tunnel vision and may result in loss of central vision. This study describes a patient with retinitis pigmentosa caused by a mutation in the ABCA4 gene with complex allele c.1622T>C, p.L541P; c.3113C>T, p.A1038V in homozygous state. PMID- 26229700 TI - Chronic Exertional Compartment Syndrome in a High School Soccer Player. AB - Chronic exertional compartment syndrome (CECS) is a relatively rare condition that affects young adult athletes and often causes them to present to the emergency department. If left untreated, those who continue to compete at high levels may experience debilitating leg pain. Physicians may have difficulty differentiating CECS from other syndromes of the lower leg such as medial tibial stress syndrome, stress fractures, and popliteal artery entrapment. The gold standard for diagnosing CECS is intramuscular compartment pressure monitoring before and/or after 10 minutes of exercise. Some patients may choose to stop participation in sports in order to relieve their pain, which otherwise does not respond well to nonoperative treatments. In patients who wish to continue to participate in sports and live an active life, fasciotomy provides relief in 80% or more. The typical athlete can return to training in about 8 weeks. This is a case of a high school soccer player who stopped competing due to chronic exertional compartment syndrome. She had a fascial hernia, resting intramuscular pressure of 30 mmHg, and postexercise intramuscular pressure of 99 mmHg. Following fasciotomy she experienced considerable life improvement and is once again training and playing soccer without symptoms. PMID- 26229701 TI - Netherton Syndrome in a Neonate with Possible Growth Hormone Deficiency and Transient Hyperaldosteronism. AB - Netherton syndrome, a rare autosomal recessive genetic disorder, is classified as an ichthyosiform syndrome. In this report we present the case of a neonate with erythroderma shortly after birth, accompanied by severe hypernatremia, recurrent infections, transient hyperaldosteronism, and signs of growth hormone (GH) deficiency. DNA molecular analysis in the SPINK5 gene revealed heterozygosity in our index patient for 238insG and 2468delA frameshift mutations in exons 4 and 26, respectively, in the maternal allele and 1431-12G>A splice-site mutation in intron 15 in the paternal allele as well as the missense variation E420K in homozygous state. Combination of the identified mutations along with transient hyperaldosteronism and possible GH deficiency have not been described before. Accordingly, the importance of early multidisciplinary approach is highlighted, in order to reach accurate diagnosis, initiate prompt treatment, and ensure survival with fewer disease complications. PMID- 26229702 TI - Are Aortic Stent Grafts Safe in Pregnancy? AB - Aortic stent grafts are increasingly used to treat aortic aneurysms and also other aortic pathologies. The safety of aortic stent grafts in pregnancy has never been studied or reported. We report on two cases of aortic stent grafts in pregnant women and discuss the effect of pregnancy on these aortic stent grafts. PMID- 26229703 TI - Severe Rhabdomyolysis without Systemic Involvement: A Rare Case of Idiopathic Eosinophilic Polymyositis. AB - Introduction. Eosinophilic polymyositis (EPM) is a rare cause of rhabdomyolysis characterized by eosinophilic infiltrates in the muscle. We describe the case of a young patient with eosinophilic polymyositis causing isolated severe rhabdomyolysis without systemic involvement. Case Presentation. A 22-year-old Haitian female with no past medical history presented with progressive generalized muscle aches without precipitating factors. Examination of the extremities revealed diffuse muscle tenderness. Laboratory findings demonstrated peripheral eosinophilia and high creatinine phosphokinase (CPK) and transaminase levels. Workup for the common causes of rhabdomyolysis were negative. Her CPK continued to rise to greater than 100,000 units/L so a muscle biopsy was performed which showed widespread eosinophilic infiltrate consistent with eosinophilic polymyositis. She was started on high dose systemic corticosteroids with improvement of her symptoms, eosinophilia, and CPK level. Discussion. This case illustrates a systematic workup of rhabdomyolysis in the presence of peripheral eosinophilia. Many differential diagnoses must be considered before establishing a diagnosis of idiopathic eosinophilic polymyositis. To our knowledge, our case of eosinophilic polymyositis is unique as it presented with severe rhabdomyolysis without another organ involvement. Clinicians should maintain a high index of suspicion for this physically debilitating disease to aid in prompt diagnosis. PMID- 26229704 TI - Achalasia in Pregnancy: Botulinum Toxin A Injection of Lower Esophageal Sphincter. AB - Background. Achalasia, a rare esophageal motility disorder that may cause malnutrition during pregnancy, can result in fetal and maternal morbidity and mortality. Many medical treatment regimens are contraindicated or not tolerated during pregnancy, and surgery is generally avoided due to potential risks to the fetus. Case Report. Severe, medically refractory achalasia in a 23-year-old pregnant woman that caused malnutrition was successfully managed by administering a botulinum toxin A injection to the lower esophageal sphincter. The injection was performed at approximately 14 weeks' gestation and the patient reported clinically significant relief from dysphagia. She gained weight and ultimately delivered a healthy baby girl at term, but her symptoms returned a few months postpartum. She underwent a second treatment of botulinum toxin A injection, but it offered only one month of relief. Roughly eight months after delivery, the patient underwent a laparoscopic extended Heller myotomy and Dor fundoplication. The patient resumed a normal diet one week postoperatively, and her baby has had no complications. Conclusion. This is only the second reported case of botulinum toxin A injection being used to treat achalasia in pregnancy. This treatment proved to be a safe temporary alternative without the risks of surgery and anesthesia during pregnancy. PMID- 26229705 TI - Gastric Cancer in the Excluded Stomach 10 Years after Gastric Bypass. AB - According to the Brazilian health authorities, around 2,000 new cases of gastric cancer emerge in Brazil per year (Instituto Nacional de Cancer Jose Alencar Gomes da Silva, 2014). Indeed, gastric cancer constitutes the second most common cause of cancer-related mortality worldwide and 95% of such malignancies are adenocarcinomas (De Roover et al., 2006, and Clark et al., 2006). Roux-en-Y gastric bypass (RYGB) is a procedure frequently employed in bariatric surgery but restricted access to the excluded stomach means that discovery of gastric lesions is difficult, and diagnosis and treatment may be delayed. We report herein a case of gastric adenocarcinoma in the excluded stomach of a patient submitted to RYGB with the purpose of illustrating the difficulty of diagnosing and treating this rare condition. PMID- 26229706 TI - Huge Pyogenic Granuloma of the Penis. AB - Pyogenic granulomas are benign vascular disorders of the skin and mucose membranes, generally developed by trauma and irritation. The lesions are generally small. They are most commonly seen in the skin and oral mucosa and rarely seen on penis. We present the case of a huge pyogenic granuloma on the penis. PMID- 26229707 TI - Corrigendum to "Changes in Vowel Articulation with Subthalamic Nucleus Deep Brain Stimulation in Dysarthric Speakers with Parkinson's Disease". AB - [This corrects the article DOI: 10.1155/2014/487035.]. PMID- 26229708 TI - Validation of the Official Slovak Version of the Unified Dyskinesia Rating Scale (UDysRS). AB - After successful clinimetric testing of the Unified Dyskinesia Rating Scale (UDysRS), a program for translation and validation of non-English versions of the UDysRS was initiated. The aim of this study was to validate and confirm the factor structure of the Slovak translation of the UDysRS. We examined 251 patients with Parkinson's disease and dyskinesia using the Slovak version of the UDysRS. The average age of our sample was 65.2 +/- 9.2 years and average disease duration was 10.9 +/- 5.0 years. Slovak data were compared using confirmatory factor analysis with the Spanish data. To be designated as the official Slovak UDysRS translation, the comparative fit index (CFI) had to be >=0.90 relative to the Spanish language version. Exploratory factor analysis was performed to explore the underlying factor structure without the constraint of a prespecified factor structure. For all four parts of the Slovak UDysRS, the CFI, in comparison with the Spanish language factor structure, was >=0.98. Isolated differences in the factor structure of the Slovak UDysRS were identified by exploratory factor analysis compared with the Spanish version. The Slovak version of the UDysRS was designated as an official non-English translation and can be downloaded from the website of the International Parkinson and Movement Disorder Society. PMID- 26229710 TI - Hygiene Practices among Workers in Local Eateries of Orolu Community in South Western Nigeria. AB - BACKGROUND: Activities of local food premises and monitoring of food handlers are usually not regulated. AIM: The objective of this study was to determine food hygiene (FH) practices among food handlers in rural communities in South Western Nigeria. SUBJECTS AND METHODS: Descriptive cross-sectional study was carried out among 235 food handlers; data collection was by interviewer administered questionnaires. Using the SPSS software, multivariate analysis in two separate models was done to explore the predictors of correct knowledge and good hygiene practices. The model fit was assessed as good using the Hosmer and Lemeshow test. RESULTS: Mean age of respondents was 31.8 (10.8) years. Of the respondents (134) that had training, 17.2% (23/134) had formal training, and 82.8% (111/134) had apprenticeship; about 31.5% (74/235) of respondents maintained a good level of hygiene in their practices. Significant predictors of correct knowledge were found to be being trained (significant 0.01, odds ratio [OR] 2.4, 95% confidence interval [CI] 1.2-4.8) and receiving the training as an apprentice (significant 0.01, OR - referent group); or in a formal setting (significant 0.01, OR 3.3, 95% CI 1.6-7.0) and having no formal education (significant 0.04, OR - reference group). CONCLUSION: Good knowledge and attitude but low level of good practices toward FH characterized food handlers under study. PMID- 26229709 TI - Impacted Mandibular Third Molars: Review of Literature and a Proposal of a Combined Clinical and Radiological Classification. AB - Tooth impaction is a pathological situation where a tooth fails to attain its normal functional position. Impacted third molars are commonly encountered in routine dental practice. The impaction rate is higher for third molars when compared with other teeth. The mandibular third molar impaction is said to be due to the inadequate space between the distal of the second mandibular molar and the anterior border of the ascending ramus of the mandible. Impacted teeth may remain asymptomatic or may be associated with various pathologies such as caries, pericoronitis, cysts, tumors, and also root resorption of the adjacent tooth. Even though various classifications exist in the literature, none of those address the combined clinical and radiologic assessment of the impacted third molar. Literature search using the advanced features of various databases such as PubMed, Scopus, Embase, Google Scholar, Directory of Open Access Journals and Cochrane electronic databases was carried out. Keywords like impaction, mandibular third molar, impacted mandibular third molar, complications, anatomy, inferior alveolar nerve injury, lingual nerve injury were used to search the databases. A total of 826 articles were screened, and 50 articles were included in the review which was obtained from 1980 to February 2015. In the present paper, the authors have proposed a classification based on clinical and radiological assessment of the impacted mandibular third molar. PMID- 26229711 TI - Characterization of Escherichia coli Phylogenetic Groups Associated with Extraintestinal Infections in South Indian Population. AB - BACKGROUND: Escherichia coli strains mainly fall into four phylogenetic groups (A, B1, B2, and D) and that virulent extra-intestinal strains mainly belong to groups B2 and D. AIM: The aim was to determine the association between phylogenetic groups of E. coli causing extraintestinal infections (ExPEC) regarding the site of infection, expression of virulence factors, antimicrobial resistance patterns, and clinical outcome. This descriptive study was carried out in a multi-specialty Tertiary Care Hospital. MATERIALS AND METHODS: A total of 300 E. coli causing ExPEC were studied. Triplex polymerase chain reaction was used to classify the phylogenetic groups; hemolysin production was assessed on sheep blood agar and biofilm production in a microtiter plate assay. Production of extended spectrum of beta-lactamase (ESBLs) was detected by combination disk method; AmpC was detected by AmpC disk test, Carbapenemase production was detected by modified Hodge test and metallo-beta-lactamase by metallo-beta lactamases (MBL) E-test. RESULTS: Of 300 isolates, 61/300 (20%) belonged to phylogroup A, 27/300 (9%) to phylogroup B1, 104/300 (35%) were B2 and 108/300 (36%) belonged to group D, respectively. Phylogroups B2 and D were the most predominant groups in urinary tract infection and sepsis. Prognoses were better in infections with group A and B1 isolates, and relapses and death were common in infections with B2 and D. Expression of biofilm was greatest in B1 and hemolysin in group B2. Group A and B1 showed higher resistance to ciprofloxacin and were most frequent beta-lactamase (ESBL, AmpC, Carbapenemase and MBL) producers. CONCLUSIONS: Phylogenetic group B2 and D were predominant in ExPEC and exhibited least antimicrobial resistance among the groups. Resistance to multiple antibiotics was most prevalent in group A and B1. Regular monitoring of antimicrobial susceptibility in commensal strains is essential as they might transfer the property of antimicrobial resistance to pathogenic strains. PMID- 26229712 TI - Perception of Simulation-based Learning among Medical Students in South India. AB - BACKGROUND: Traditional methods of educating medical students are no longer sufficient in the current era largely influenced by multimedia. Simulation-based techniques may play a pivotal role in bridging this educational gap. AIM: This study was conducted to explore the perception of medical students towards simulation based learning (SBL). SUBJECTS AND METHODS: This cross-sectional study was conducted in May 2013 in a private medical college in Mangalore, Karnataka, India. A total of 247 participants from fourth, sixth, eighth semester and internship were chosen by convenience sampling method. Attitudinal data on perception towards SBL were collected using a self-administered questionnaire with responses in a 5-point Likert's scale. RESULTS: The mean age of students was 21.3 (standard deviation 1.9) years, and males constituted 55.5% (137/247). Most participants 72.5% (179/247) had favorable perceptions of SBL, with scores of92 118 out of a possible 118 points. Favorable perception towards SBL was seen significantly more among female students (P = 0.04) and senior MBBS students of sixth and eighth semesters (P = 0.05). Nearly, all students (90.7%; 224/247) agreed that simulation supports the development of clinical skills. As many as 29.6% (73/247) agreed that real patients might be replaced with simulated patients in practical examinations. CONCLUSION: SBL was perceived as favorable by a large number of participants in this study indicating a bright prospect for its implementation in the medical curriculum. PMID- 26229713 TI - Why are Children Still Being Infected with HIV? Impact of an Integrated Public Health and Clinical Practice Intervention on Mother-to-Child HIV Transmission in Las Vegas, Nevada, 2007-2012. AB - BACKGROUND: During a 9 months period, September 2005 through June 2006, Nevada documented six cases of pediatric HIV acquired through mother-to-child transmission. Subsequently, a community-based approach to the care of women and children living with or exposed to HIV was implemented. SUBJECTS AND METHODS: A detailed review of mother-infant pairs where HIV transmission occurred was performed to identify missed opportunities for prevention of mother-to-child HIV transmission. An intervention program was developed and implemented using the six step process. Data were collected prospectively over a 6 years period (2007-2012) and were evaluated for six core outcomes measures: (1) adequacy of prenatal care (2) HIV diagnoses of expectant mothers prior to delivery (3) appropriate use of antiretroviral (ARV) therapy before delivery (4) appropriate use of cesarean section for delivery (5) adequacy of zidovudine prophylaxis to newborn (6) HIV transmission rate. RESULTS: Twenty-six infants were born to HIV-infected mothers from July 2005 to June 2006 with 6 documented infections. One hundred and five infants were born to HIV infected mothers from January 2007 to December 2012. Postimplementation, adequacy of prenatal care increased from 58% (15/26) to 85% (89/105); appropriate use of ARV therapy before delivery increased from 73% (19/26) to 86% (90/105); cesarean section as the method for delivery increased from 62% (16/26) to 74% (78/105); adequacy of zidovudine prophylaxis to newborn increased from 54% (14/26) to 87% (91/105). HIV transmission rate dropped from 23% (6/26) to 0%. CONCLUSION: Integrating public health and clinical services in the care of HIV-infected pregnant women and exposed infants leads to better coordination of care and improved quality of care. PMID- 26229714 TI - Influence of Intensity and Duration of Yoga on Anxiety and Depression Scores Associated with Chronic Illness. AB - BACKGROUND: Chronic illness is commonly associated with anxiety and depression. Both anxiety and depression respond to yoga. However, there is no report on the association between the intensity and duration of yoga practice with the benefits seen. AIM: The present study was intended to determine whether the daily duration of yoga practice and the duration of experience in months would predict anxiety and depression, associated with chronic illness. SUBJECTS AND METHODS: Seven hundred and sixty-three volunteers with ages between 14 and 86 years (group mean age standard deviation, 50.2 [14.2]) who attended a 7 day residential yoga camp in the north of India were included in this cross-sectional study. All participants had chronic illnesses, which were under control with treatment, and which were categorized and are detailed. Participants were assessed for state anxiety scores using State-Trait Anxiety Inventory and for anxiety with hospital anxiety and depression scale (HADS-A), and depression was assessed using HADS-D scores of the HADS. Linear multiple regression analyses were performed using PASW SPSS version 18.0 (Armonk, New York, U.S.) to determine how the daily and monthly duration of yoga practice could influence state anxiety, hospital anxiety and depression of the participants. RESULTS: Yoga practice in months and the time spent practicing yoga each day significantly predict the level of state anxiety (P < 0.001, P = 0.03) and HAD-A (P < 0.01, P < 0.01). The duration of yoga practice in months alone was a significant predictor of the HAD-D (P < 0.01). CONCLUSIONS: The results suggest that the duration of yoga practice in months and daily practice in minutes predict anxiety associated with chronic illness. In contrast the duration of yoga practice in months alone, predicted depression scores. PMID- 26229715 TI - Awareness, Practices and Treatment Seeking Behavior of Type 2 Diabetes Mellitus Patients in Delhi. AB - BACKGROUND: Type 2 diabetes mellitus is a multisystem disorder that is associated with number of complications. Patient's awareness and practices are crucial components in reducing the burden of diseases and its complications. AIM: To assess patient's knowledge about their disease and its complications, practices, treatment seeking behavior and average expenditure incurred by its management. SUBJECTS AND METHODS: A community based cross-sectional study was conducted in rural and urban slum areas of Delhi selecting a total of 98 diabetic patients diagnosed during the two community surveys and interviewed using pretested and predesigned questionnaire. Data were analyzed using SPSS software, version 17 (Chicago II, USA). Chi-square, fisher or Mann-Whitney tests were used for test of significance and considered statistically significant at P < 0.05. RESULTS: Of 98 participants, 31.6% (31/98) were from urban slum area, and 68.4% (67/98) were from the rural area. In both urban and rural areas, majority were Hindu, married, literate and unemployed. Significantly less subjects (61.3%, 19/31) of urban slum area than of rural area (85.1%, 57/67) could name at least one complication of DM (P < 0.01, odds ratio [OR] =3.6, 95% confidence interval [CI] =1.3-9.6). Majority of participants in both urban slum and rural area have knowledge about at least one component of management but significantly lesser in urban (83.9%, 26/31) than rural area (97.0%, 65/67) were reported (P = 0.02, OR = 6.2, 95% CI = 1.1-34.2). Significantly more subjects (29.0%, 9/31) in urban slum area than rural areas (7.5%, 5/67) reported that they were not taking any treatment for DM (P < 0.01, OR = 0.2, 95% CI = 0.1-0.6). In urban area, 32.2% (10/31) patients told that it is a burden on their family while in rural area 44.7% (30/67) of the patients told that they have to squeeze money from the family expenditure to afford drugs. CONCLUSION: Patients need to be made aware of the asymptomatic phase of DM and its long term complications. At the same time, efforts should be made to sensitize them about the importance of taking regular treatment and management. PMID- 26229716 TI - Vulvovaginal Candidiasis in Aminu Kano Teaching Hospital, North-West Nigeria: Hospital-Based Epidemiological Study. AB - BACKGROUND: Vulvovaginal candidiasis (VVC) remains a common problem worldwide and the role of douching as a predisposing factor is unclear. AIM: This study was undertaken to highlight the prevalence and predisposing factors of VVC in North west Nigeria. SUBJECTS AND METHODS: This was a prospective study done at Aminu Kano Teaching Hospital (AKTH), North-west. AKTH is a 500-bed tertiary hospital located in Kano, the most populous state in Nigeria. Ethical clearance was obtained. Three hundred patients with VVC were recruited from the gynecologic and general outpatients' clinics of AKTH. Research structured questionnaires were used to obtain sociodemographic and clinical information. The data obtained were analyzed using SPSS version 16.0 statistical software (SPSS Inc., Chicago IL, USA). Frequency, mean and simple percentages were used to analyze data. RESULT: Candida albicans was the most frequent cause of the positive high vaginal swabs constituting 84.5% (316/374) while Proteus vulgaris was the least frequent cause constituting 0.53% (2/374). Fifty-three percent (143/270) of those with VVC were aged 26-35 years; the married were 80% (216/270) and those who were unmarried were 20% (54/270). Douching was the commonest predisposing factor occurring in 42.5% (115/270) of cases. CONCLUSION: VVC was the most prevalent cause of vaginosis in North-west Nigeria, and douching was the commonest predisposing factor. PMID- 26229717 TI - Prevalence and Predictors of Erectile Dysfunctions among Men on Antiretroviral Therapy in South-western Nigeria. AB - BACKGROUND: Erectile dysfunctions (EDs) are common presentations among men on anti-retroviral therapy, many of who had a course to discontinue anti-retroviral drugs or search for alternative treatments. AIM: This study assessed the prevalence and predictors of ED among men on anti-retro viral therapies (ART) in a Nigerian population. SUBJECTS AND METHODS: It was a descriptive cross-sectional survey among 234 HIV-positive men on anti-retroviral therapy selected using stratified sampling method after excluding for co-morbidities. Research instrument was semi-structured interviewer administered questionnaire, and data were analyzed using the SPSS software version 17.0 (Chicago IL, USA), while binary logistic regression and Chi-square test were used to demonstrate association between selected categorical variable. RESULTS: Mean age of respondents was 37.1 (1.6) years, 85.6% have not missed their medications, self reported adherence was reported as good among 213 [(90.8%) 213/234], though calculated adherence was 90% among as many as 201 [(85.6%) 201/234]. Pattern of EDs revealed weak erection among 42 [(37.8%) 42/111], 15 [(13.5%) 15/111] said they could no longer achieve erection, 33 [(29.7%) 33/111] said they could not maintain erections, while 27 [(24.3%) 27/111] presented with loss of libido. Delayed and premature ejaculations were reported among 24 [(21.6%) 24/111] and 8 [(7.2%) 8/111] respectively. About 14% (33/234) of respondents said that anti retroviral drugs could have caused their ED while 78% (183/234) said it should not. A statistically significant association exists between having weak erections and age above 65 years and calculated the adherence <95%, while none exists between having weak erections and missing pills. CONCLUSION: Anti-retroviral drugs are common causes of EDs. Concerns of clients should always be addressed most especially issues that may compromise adherence. PMID- 26229718 TI - Lipid and Some Other Cardiovascular Risk Factors Assessment in a Rural Community in Eastern Nigeria. AB - BACKGROUND: Continuous re-evaluation of modifiable cardiovascular risk factors (cardiovascular diseases [CVDs]) in developing nations is imperative as it lays foundation for early preventive/intervention measures at grass root level to improve/prevent CVD morbidity and mortality in those nations where health indices still score below the standard. AIM: The aim was to assess CVD risk factors as a continuous re-evaluation of these may underscore the need for early intervention measures at grass root level. SUBJECTS AND METHODS: A total of 257 apparently healthy inhabitants aged 18-85 years were recruited in a rural community in South Eastern Nigeria by convenient sampling. Blood pressure, waist circumference and blood lipid analysis were done procedurally and data analyzed using SPSS 16.0 statistical software. RESULTS: The males were older (59.41 [5.22]) than the females (53.31 [16.90]). 69.2% (133/192) were low level farmers, retirees and dependents. Total cholesterol (TC), low density lipoprotein (LDL), and risk predictive index were higher in females while triglyceride (TG), high density lipoprotein and very LDL (VLDL) were higher in males. The middle aged and elderly respectively had higher TG and VLDL compared to the young. Aside hypertriglyceridemia, all lipid abnormalities were higher in females than males both singly (high TC: 28.9% [35/121] vs. 16.9% [12/71]; high LDL cholesterol: 52.0% [63/121] vs. 31.0% [22/71]) and in combination hypercholesterolemia with hypertriglyceridemia (42.9% [52/121] vs. 36.6% [26/71]). "Multiple risk factors" also occurred more in females with seeming further increase in older age. CONCLUSION: The chances of a female having CVD after menopause seemed to outweigh that of the male. CVD preventive measures should be focused at the primary/community level as a means to curtailing the increasing morbidity and eventual mortality from CVDs. PMID- 26229719 TI - Possible Hematological Changes Associated with Acute Gastroenteritis among Kindergarten Children in Gaza. AB - BACKGROUND: Gastroenteritis is considered one of the leading causes of morbidity and mortality in children especially in developing countries. It is a major childhood problem in Gaza and one of the most common etiologic agents of iron deficiency anemia (IDA). AIM: This study was conducted to investigate possible changes in blood parameters that are associated with gastroenteritis infection among kindergarten children in Gaza. SUBJECTS AND METHODS: A cross-sectional case control study was performed including kindergarten children suffering from gastroenteritis and matched healthy control group. Types of etiological agents were identified using standard microbiological and serological procedures. Blood samples were collected for estimation of complete blood count and for determination of serum iron, total iron binding capacity (TIBC), and transferrin saturation. Independent sample t-test was used for comparisons and performed using SPSS software version 17(Chicago Illinois USA). RESULTS: The prevalence of enteric pathogens among cases (88.5% [85/96]) was significantly higher than in asymptomatic controls (11.1% [6/54]). The most common enteric pathogens isolated were Entamoeba histolytica (28% [42/91]) and Giardia lamblia (26.7% [40/91]). Blood tests revealed that 21.8% (21/96) of cases and 14.8% (8/54) of controls had IDA, which were not significantly different. Meanwhile, a significant difference was found between the TIBC and hemoglobin in cases compared to controls. CONCLUSION: This study indicates that gastroenteritis infection could be considered as a common health problem in kindergarten children in Gaza, and it is possibly associated with changes in hemoglobin concentration and TIBC. PMID- 26229720 TI - Expression of Podoplanin in Different Grades of Oral Squamous Cell Carcinoma. AB - BACKGROUND: The expression of podoplanin is up-regulated in a number of different human cancers, including squamous cell carcinoma of the oral cavity and its relationship with tumor invasion raises the possibility that podoplanin expression could be used as a biomarker for diagnosis and prognosis. AIM: The aim of the present study is to evaluate the expression of podoplanin in different grades of squamous cell carcinoma (SCC) and to correlate the expression of podoplanin with relevant clinical features such as age, sex, site and associated habits. MATERIALS AND METHODS: Retrospective study was carried on formalin fixed, paraffin embedded blocks of oral SCC (OSCC) from the archives of Department of Oral and Maxillofacial Pathology, Vishnu Dental College, Bhimavaram. Thirty diagnosed cases were included, of which 10 were well-differentiated SCC (WDSCC) (n = 10), 10 moderately DSCC and 10 poorly DSCC. Demographics including age, sex, gender and associated habit history, were recorded. Immunohistochemical staining was done with podoplanin anti D2-40 antibody, for all the cases of OSCC and assessed qualitatively. The data obtained were tabulated and subjected to statistical analysis. RESULTS: In the present study, 27 cases of SCC showed podoplanin expression and remaining three cases showed no expression. The scoring criterion suggested by Yuan et al. was followed for semi-quantitative assessment. OSCC, seven cases presented weak expression (Immunoreactive score [IRS] 0-3), 15 presented moderate expression (IRS Score 4-7) and 5 presented high expression (IRS Score > 8). The assessment of podoplanin expression in the cytoplasm, the membrane and the cytoplasm and membrane (both) of tumor cells showed overall high positivity in the cytoplasmic followed by both and the membrane. CONCLUSION: Podoplanin could be a potent biomarker in assessing the cytoplasm/membrane staining of tumor cells. Furthermore, a high level of podoplanin expression is suggestive of high frequency of lymph node metastasis and immature status in the differentiation process of OSCC. PMID- 26229722 TI - Ulcerative Colitis Prone to Delayed Diagnosis in a Nigerian Population: Case Series. AB - Inflammatory bowel disease is an emerging disease burden in the developing world. In Nigeria there is a persisting perception among physicians that it is a very rare disease, and publications on it are sparse. Early manifestations of ulcerative colitis (UC) are therefore likely to be missed at many health institutions. This publication aims to contribute to the growing literature on UC among Nigerians. We present 3 cases of UC that were diagnosed at very late stages. It took a range of 2-7 years for the diagnosis to be made from onset of symptoms. UC was confirmed in the first patient after bowel resection for massive gastrointestinal haemorrhage. The other two had colonoscopy and biopsy for confirmation. An increased awareness about UC is necessary in Nigerian population, because the condition may be commoner than hitherto thought. Provision of colonoscopy services to a wider population will assist in early discovery of this disease. PMID- 26229721 TI - Audit of Childbirth Emergency Referrals by Trained Traditional Birth Attendants in Enugu, Southeast, Nigeria. AB - BACKGROUND: The essence of training traditional birth attendants (TBAs) is to attend to women in uncomplicated labor and to refer them immediately to hospitals when complications develop. AIM: The aim was to audit childbirth emergency referrals by trained TBAs to a specialist hospital in Enugu, Nigeria. SUBJECTS AND METHODS: A retrospective study of 205 childbirth emergencies referred to Semino Hospital and Maternity (SHM), Enugu by trained TBAs from August 1, 2011 to January 31, 2014. Data analysis was descriptive and inferential at 95% confidence level. RESULTS: Most of the patients (185/205, 90.2%) were married and (100/205, 48.8%) had earlier booked for antenatal care in formal health facilities. There were obstetric danger signs or previous bad obstetric histories (pregnancies with unfavorable outcome) in 110 (110/205, 53.7%) women on admission at SHM. One hundred and fifteen (115/205, 56.1%) women walked into the hospital by themselves while 50 (50/205, 24.39%) could not walk. The fetal heart sounds were normal in 94 (94/205, 45.6%), abnormal in 65 (65/205, 31.8%) and absent in 42 (42/205, 20.4%) of the women on admission. Five healthy babies were delivered by the TBAs before referring their mothers. Delays of more than 12 h had occurred in 155 (155/205, 76.6%) of the women before referrals. Prolonged labor (100/205, 48.8%), obstructed labor (40/205, 19.5%), attempted vaginal birth after previous cesarean delivery (40/205, 19.5%) and malpresentation (30/205, 14.6%) were the common indications for referrals. The maternal mortality and perinatal mortality ratios were 610/100,000 live births and 228/1000 total births respectively. CONCLUSION: Delays at TBA centers are common before referral and most patients are referred in poor clinical state. Further training and re-training of the TBAs with more emphasis on recognition of obstetric danger signs and bad obstetric histories may help in screening high-risk patients for prompt referral to hospitals before complications develop. PMID- 26229723 TI - Candidiasis, A Rare Cause of Gastric Perforation: A Case Report and Review of Literature. AB - Fungi are unusually rare causes of gastric perforation, with most cases of gastric perforation occurring as complications of peptic ulcer disease (PUD), nonsteroidal anti-inflammatory drugs (NSAIDs) and gastric neoplasms. Here, we report the case of a 70-year-old Nigerian male who presented with severe epigastric pain, with no associated history of PUD, NSAIDs use or gastric neoplasm. An emergency exploratory laparotomy was performed and a gastric perforation was discovered and repaired. Histopathological examination of the gastric perforation edge biopsy revealed an intense Candida growth consisting of numerous fungal spores and hyphae invading and destroying the gastric wall. He was subsequently treated with fluconazole antifungal and discharged home after an uneventful postoperative period. PMID- 26229724 TI - Multiple Unerupted Permanent Teeth Associated with Noonan Syndrome. AB - The present report describes a case of Noonan's syndrome from a dental viewpoint. Noonan syndrome is an autosomal dominant multisystem disorder. Congenital heart deformities, short stature, thoracic deformities, short neck with webbing, hypertelorism, and malocclusions are some of the frequently observed clinical features. Atypical dental anomalies such as multiple unerupted permanent teeth, multiple submerged and retained deciduous teeth, and supernumerary teeth were found in the present case. Oral prophylaxis and preventive resin restorations were done following which the supernumerary teeth were extracted. 54, 55, 64, 65, 74, 75 and 84 were extracted after orthodontic consultation to facilitate the eruption of permanent teeth. The patient is undergoing fixed orthodontic therapy for forced eruption of unerupted permanent teeth. General dentists should correlate dental anomalies with other systemic features in the diagnosis of such syndromes because of the variability in presentation and the need for multidisciplinary care. PMID- 26229725 TI - Cerebral Malaria Complicated by Blindness, Deafness and Extrapyramidal Tract Manifestation. AB - Cerebral malaria is a severe manifestation of a parasitic infection caused by Plasmodium falciparum. The sequelae of this disease such as blindness, deafness, loss of motor function could be emotionally traumatic and physically disabling. We, therefore, present this case of an 8-year-old boy who presented with high grade intermittent fever associated with multiple convulsions and prolonged coma. He regained consciousness after 12 days of treatment with intravenous quinine but was found to have blindness, sensory-neural deafness and extrapyramidal sign. This extrapyramidal sign regressed following treatment with chlorpromazine. He also regained his sight and auditory function before he was discharged though not completely. This report is aimed at emphasizing these rare complications of cerebral malaria as well as reminding clinicians working in malaria endemic areas of the world on the need for early diagnosis and prompt treatment. PMID- 26229726 TI - Ethical Issues in Deep Brain Stimulation Research for Treatment-Resistant Depression: Focus on Risk and Consent. AB - Deep brain stimulation (DBS) is currently in pivotal trials as an intervention for treatment-resistant depression (TRD). Although offering hope for TRD, DBS also provokes ethical concerns-particularly about decision-making capacity of people with depression-among bioethicists, investigators, institutional review boards, and the public. Here, we examine this critical issue of informed consent for DBS research using available evidence regarding decision-making capacity and depression. Further, we explore the implications of the nature of TRD as well as that of the intervention (invasive brain surgery) for informed consent. Based on these analyses, we argue that additional safeguards specific to DBS research for TRD, beyond those that might be used in any higher risk study, are not supported by available empirical evidence. We nevertheless underscore the limited data on such invasive procedures in severely ill psychiatric patients and advocate a research agenda for the systematic study of ethical issues raised by these research endeavors. PMID- 26229727 TI - Epirubicin-[Anti-HER2/neu] Synthesized with an Epirubicin-(C13-imino)-EMCS Analog: Anti-Neoplastic Activity against Chemotherapeutic-Resistant SKBr-3 Mammary Carcinoma in Combination with Organic Selenium. AB - PURPOSE: Discover the anti-neoplastic efficacy of epirubicin-(C13-imino)-[anti HER2/neu] against chemotherapeutic-resistant SKBr-3 mammary carcinoma and delineate the capacity of selenium to enhance it's cytotoxic anti-neoplastic potency. METHODS: In molar excess, EMCH was combined with epirubicin to create a covalent epirubicin-(C13-imino)-EMCH-maleimide intermediate with sulfhydryl reactive properties. Monoclonal immunoglobulin selective for HER2/neu was then thiolated with 2-iminothiolane at the terminal epsilon-amine group of lysine residues. The sulfhydryl-reactive epirubicin-(C13-imino)-EMCH intermediate was then combined with thiolated anti-HER2/neu monoclonal immunoglobulin. Western blot analysis was utilized to characterize the molecular weight profiles while binding of epirubicin-(C13-imino)-[anti-HER2/neu] to membrane receptors was determined by cell-ELISA utilizing populations of SKBr-3 mammary carcinoma that highly over-expresses HER2/neu complexes. Anti-neoplastic potency of epirubicin (C13-imino)-[anti-HER2/neu] between the epirubicin-equivalent concentrations of 10-12 M and 10-7 M was determined by vitality staining analysis with and without the presence of selenium (5 MUM). RESULTS: Epiribucin-(C13-imino)-[anti-HER2/neu] between epirubicin-equivalent concentrations of 10-8 M to 10-7 M consistently evoked higher anti-neoplastic potency than "free" non-conjugated epirubicin which corresponded with previous investigations utilizing epirubicin-(C3-amide)-[anti HER2/neu] and epirubicin-(C3-amide)-[anti-EGFR]. Selenium at 5 mM consistently enhanced the cytotoxic anti-neoplastic potency of epirubicin-(C13-imino)-[anti HER2/neu] at epirubicin equivalent concentrations (10-12 to 10-7 M). CONCLUSIONS: Epirubicin-(C13-imino)-[anti-HER2/neu] is more potent than epirubicin against chemotherapeutic-resistant SKBr-3 mammary carcinoma and selenium enhances epirubicin-(C13-imino)-[anti-HER2/neu] potency. The methodology applied for synthesizing epirubicin-(C13-imino)-[anti-HER2/neu] is relatively time convenient and has low instrumentation requirements. PMID- 26229729 TI - Needle Steering in Biological Tissue using Ultrasound-based Online Curvature Estimation. AB - Percutaneous needle insertions are commonly performed for diagnostic and therapeutic purposes. Accurate placement of the needle tip is important to the success of many needle procedures. The current needle steering systems depend on needle-tissue-specific data, such as maximum curvature, that is unavailable prior to an interventional procedure. In this paper, we present a novel three dimensional adaptive steering method for flexible bevel-tipped needles that is capable of performing accurate tip placement without previous knowledge about needle curvature. The method steers the needle by integrating duty-cycled needle steering, online curvature estimation, ultrasound-based needle tracking, and sampling-based motion planning. The needle curvature estimation is performed online and used to adapt the path and duty cycling. We evaluated the method using experiments in a homogenous gelatin phantom, a two-layer gelatin phantom, and a biological tissue phantom composed of a gelatin layer and in vitro chicken tissue. In all experiments, virtual obstacles and targets move in order to represent the disturbances that might occur due to tissue deformation and physiological processes. The average targeting error using our new adaptive method is 40% lower than using the conventional non-adaptive duty-cycled needle steering method. PMID- 26229728 TI - Gendered Pathways: Violent Childhood Maltreatment, Sex Exchange, and Drug Use. AB - OBJECTIVE: Recent work has emphasized the role of violent victimization, along with risky contexts like sex exchange, in pathways to problems of externalizing and substance use in women. Nonetheless, few studies have empirically tested gender differences involving the roles of adversity factors (e.g., childhood violent maltreatment, sex exchange) in drug use patterns. The present study tested a model of gender differences in relationships between childhood physical and sexual abuse, sex exchange, and two indicators of drug use: engagement and symptoms of disorder. METHOD: We recruited an ethnically-diverse sample of 304 (130 women) adults with recent histories of violence and/or drug use, who completed a substance use diagnostic interview, the Childhood Trauma Questionnaire, and a sex exchange questionnaire. RESULTS: First, structural equation modeling revealed that childhood sexual and physical abuse were related to increased drug engagement in women and men, respectively, above the influence of early childhood contextual variables (e.g., neighborhood, family) and age. Second, sexual abuse was related to sex exchange, which in turn was related to drug use symptoms in women but not men. CONCLUSIONS: These data provide empirical support for distinct trauma-related pathways to drug use problems in men and women, which has implications for gendered explanations and prevention approaches. PMID- 26229730 TI - Craniocervical junction tuberculosis: Usual pathology at an unusual site. AB - BACKGROUND: Tuberculosis (TB) of the craniocervical junction is rare even where the condition is endemic. It poses problems in both diagnosis and management if not managed in time it may cause life-threatening complications. CASE DESCRIPTION: An 18-year-old male patient presented with pain in the nape of the neck since 12 months duration which was not improving with medication. After magnetic resonance imaging of cervical spine, he was diagnosed as craniocervical junction TB. We did a transoral decompression of abscess with biopsy along with posterior decompression of cord and occipitocervical fusion. Biopsy of pathological material came as TB. He was advised for anti-tubercular therapy for 18 months. CONCLUSION: Although craniocervical junction TB is a rare disease, the outcome of treatment is good. Antituberculous drug therapy remains the mainstay of treatment after confirming the diagnosis. The surgical management options include transoral decompression with or without posterior fusion, depending upon the presence and persistence of atlantoaxial instability. PMID- 26229731 TI - Ethical and methodological considerations on conducting clinical research in poor and low-income countries: Viewpoint of the authors of the BEST TRIP ICP randomized trial in Latin America. PMID- 26229732 TI - Strategy for endovascular coil embolization of a penetrating vertebral artery injury. AB - BACKGROUND: Penetrating vertebral artery injuries (VAIs) are even rarer than carotid artery injuries. For anatomical reasons, the surgical management of VAI is difficult, and endovascular management often yields a good outcome. We report our strategy for the endovascular treatment of a patient with a penetrating VAI at the V2 segment of the left vertebral artery. CASE DESCRIPTION: In a fall on a large rake, a 76-year-old man was stabbed in the left neck by three tines. Although he manifested no neurological deficits, computed tomography (CT) suggested penetrating VAI. Digital subtraction angiography confirmed VAI and extravasation, and he underwent endovascular coil embolization. Two microcatheters, inserted proximal and distal to the injury sites, were used for successful endovascular coil embolization. Postoperative magnetic resonance imaging - and single photon emission CT studies denied cerebral infarction and a decrease in cerebral perfusion. The patient exhibited no neurological deficits and was able to leave the hospital on foot. CONCLUSION: This is the rare documentation of a patient whose penetrating VAI was treated by simultaneous coil embolization and foreign body removal. Imaging studies confirmed the patency and perfusion of the intracranial artery. Our treatment strategy produced a good outcome in this unusual patient. PMID- 26229733 TI - The odontoid process invagination in normal subjects, Chiari malformation and Basilar invagination patients: Pathophysiologic correlations with angular craniometry. AB - BACKGROUND: Craniometric studies have shown that both Chiari malformation (CM) and basilar invagination (BI) belong to a spectrum of malformations. A more precise method to differentiate between these types of CVJM is desirable. The Chamberlain's line violation (CLV) is the most common method to identify BI. The authors sought to clarify the real importance of CLV in the spectrum of craniovertebral junction malformations (CVJM) and to identify possible pathophysiological relationships. METHODS: We evaluated the CLV in a sample of CVJM, BI, CM patients and a control group of normal subjects and correlated their data with craniocervical angular craniometry. RESULTS: A total of 97 subjects were studied: 32 normal subjects, 41 CM patients, 9 basilar invagination type 1 (BI1) patients, and 15 basilar invagination type 2 (BI2) patients. The mean CLV violation in the groups were: The control group, 0.16 +/- 0.45 cm; the CM group, 0.32 +/- 0.48 cm; the BI1 group, 1.35 +/- 0.5 cm; and the BI2 group, 1.98 +/- 0.18 cm. There was strong correlation between CLV and Boogard's angle (R = 0.82, P = 0.000) and the clivus canal angle (R = 0.7, P = 0.000). CONCLUSIONS: CM's CLV is discrete and similar to the normal subjects. BI1 and BI2 presented with at least of 0.95 cm CLV and these violations were strongly correlated with a primary cranial angulation (clivus horizontalization) and an acute clivus canal angle (a secondary craniocervical angle). PMID- 26229734 TI - High-Activity Iron Catalysts for the Hydrogenation of Hindered, Unfunctionalized Alkenes. AB - The activity of aryl-substituted bis(imino)pyridine and bis(arylimidazol-2 ylidene)pyridine iron dinitrogen complexes has been evaluated in a series of catalytic olefin hydrogenation reactions. In general, more electron donating chelates with smaller 2,6-aryl substituents produce more active iron hydrogenation catalysts. Establishment of this structure-activity relationship has produced base metal catalysts that exhibit high turnover frequencies for the hydrogenation of unfunctionalized, tri- and tetrasubstituted alkenes, one of the most challenging substrate classes for homogenous hydrogenation catalysts. PMID- 26229735 TI - Anti-apoptotic Effects of Bone Marrow on Human Islets: A Preliminary Report. AB - Apoptosis is one of the major factors contributing to the failure of human islet transplantation. Contributors to islet apoptosis exist in both the pre transplantation and post transplantation stages. Factors include the islet isolation process, deterioration in vitro prior to transplantation, and immune rejection post transplantation. Previous studies have demonstrated that co cultured bone marrow cells with human islets not only significantly enhanced the longevity of human islets but also maintained function. We hypothesized that the protective effects of bone marrow cells on human islets are through mechanisms related to preventing apoptosis. This study observed the levels of inflammatory factors such as interleukin-1beta (IL-1beta), the release of extracellular ATP in vitro, and expression levels of P2X7 ATP receptor (P2X7R), all of which lead to the occurrence of apoptosis in human islets. When human islets were co-cultured with human bone marrow, there was a reduction in the rate of apoptosis correlated with the reduction in inflammatory factors, extra cellular ATP accumulation, and ATP receptor P2X7R expression versus human islets cultured alone. These results suggest that co-culturing bone marrow cells with human islets inhibits inflammation and reduces apoptosis, thus protecting islets from self deterioration. PMID- 26229736 TI - A Review of Ethnicity, Culture, and Acculturation Among Asian Caregivers of Older Adults (2000-2012). AB - This review identified domains of care experiences among studies of Chinese, Filipino, Japanese, Korean, and Vietnamese caregivers in the United States and Canada between 2000 and 2012. Using a narrative approach, 46 peer-reviewed journal articles were found through electronic databases and references. Considering caregivers' assimilation to host countries, attention was given to their culture, socioeconomic resources, immigrant status, filial responsibility, generation, and acculturation. Three primary domains were identified across subgroups. The caregivers' experiences domain was a strong sense of filial responsibility and its varied effects on caregiving experience; in the cultural values domain, reciprocity, and familism. In the acculturation domain, caregivers' generations influenced their experiences. Because our society is rapidly changing demographically and culturally, studies of older adults and their caregivers that are not only inclusive of all racial/ethnic groups but also sensitive to specific racial/ethnic and cultural subgroup differences are necessary to inform policy and practice. PMID- 26229738 TI - Diving into Data: Planning a Research Data Management Event. PMID- 26229737 TI - Viscosity of ring polymer melts. AB - We have measured the linear rheology of critically purified ring polyisoprenes, polystyrenes and polyethyleneoxides of different molar masses. The ratio of the zero-shear viscosities of linear polymer melts eta0,linear to their ring counterparts eta0,ring at isofrictional conditions is discussed as function of the number of entanglements Z. In the unentangled regime eta0,linear/eta0,ring is virtually constant, consistent with the earlier data, atomistic simulations, and the theoretical expectation eta0,linear/eta0,ring=2. In the entanglement regime, the Z-dependence of rings viscosity is much weaker than that of linear polymers, in qualitative agreement with predictions from scaling theory and simulations. The power-law extracted from the available experimental data in the rather limited range 175 years. Guidelines recommend that older women be informed of the uncertainty of benefit and potential for harm, especially for women with short life expectancy. However, few older women are informed of harms of screening and many with short life expectancy are screened. Therefore, we aim to test whether a mammography screening decision aid (DA) for women >75 years affects their use of mammography, particularly for women with <10 year life expectancy. METHODS/DESIGN: The DA is a self-administered pamphlet that includes information on screening outcomes, tailored information on breast cancer risk, health, life expectancy, and competing mortality risks, and includes a values clarification exercise. We are conducting a large cluster randomized controlled trial (RCT) of the DA with the primary care provider (PCP) as the unit of randomization to evaluate its efficacy. We plan to recruit 550 women 75-89 years from 100 PCPs to receive either the mammography DA or a pamphlet on home safety for older adults (control arm) before a visit with their PCP, depending on their PCP's randomization assignment. The primary outcome is receipt of mammography screening assessed through chart abstraction. Secondary outcomes include effect of the DA on older women's screening intentions, knowledge, and decisional conflict, and on documented discussions about mammography by their PCPs. We will recruit women from 5 Boston-based primary care practices (3 community-based internal medicine practices and 2 academic practices), and 2 North Carolina-based academic primary care practices. DISCUSSION: It is essential that we test the DA in a large RCT to determine if it is efficacious and to substantiate the need for broad translation into clinical practice. Our DA has the potential to improve health care utilization and care in a manner dictated by patient preferences. PMID- 26229744 TI - Analysis of paired end Pol II ChIP-seq and short capped RNA-seq in MCF-7 cells. AB - While a role of promoter-proximal RNA Polymerase II (Pol II) pausing in regulation of eukaryotic gene expression is implied, the mechanisms and dynamics of this process are poorly understood. We performed genome-wide analysis of short capped RNAs (scRNAs) and Pol II chromatin immunoprecipitation sequencing (ChIP seq) in human breast cancer MCF-7 cells to better understand Pol II pausing (Samarakkody, A., Abbas, A., Scheidegger, A., Warns, J., Nnoli, O., Jokinen, B., Zarns, K., Kubat, B., Dhasarathy, A. and Nechaev, S. (2015) RNA polymerase II pausing can be retained or acquired during activation of genes involved in the epithelial to mesenchymal transition. Nucleic Acids Res43, 3938-3949). The data are available at the NCBI Gene Expression Omnibus under accession number GSE67041. For both ChIP and scRNA samples, we used paired end sequencing on the Illumina MiSeq instrument. For ChIP-seq, the use of paired end sequencing allowed us to avoid ambiguities in center-read definition. For scRNA seq, this allowed us to identify both the 5'-end and the 3'-end in the same run that represent, respectively, the transcription start sites and the locations of Pol II pausing. The sharpening of Pol II ChIP-seqmetagene profiles when aligned against 5'-ends of scRNAs indicates that these RNAs can be used to define the start sites for the majority of mRNA transcription events. PMID- 26229743 TI - Melatonin modulates endoplasmic reticulum stress and Akt/GSK3-beta signaling pathway in a rat model of renal warm ischemia reperfusion. AB - Melatonin (Mel) is widely used to attenuate ischemia/reperfusion (I/R) injury in several organs. Nevertheless, the underlying mechanisms remain unclear. This study was conducted to explore the effect of Mel on endoplasmic reticulum (ER) stress, Akt and MAPK cascades after renal warm I/R. Eighteen Wistar rats were randomized into three groups: Sham, I/R, and Mel + I/R. The ischemia period was 60 min followed by 120 min of reperfusion. Mel (10 mg/kg) was administrated 30 min prior to ischemia. The creatinine clearance, MDA, LDH levels, and histopathological changes were evaluated. In addition, Western blot was performed to study ER stress and its downstream apoptosis as well as phosphorylation of Akt, GSK-3beta, VDAC, ERK, and P38. Mel decreased cytolysis and lipid peroxidation and improved renal function and morphology compared to I/R group. Parallely, it significantly reduced the ER stress parameters including GRP 78, p PERK, XBP 1, ATF 6, CHOP, and JNK. Simultaneously, p-Akt level was significantly enhanced and its target molecules GSK-3beta and VDAC were inhibited. Furthermore, the ERK and P38 phosphorylation were evidently augmented after Mel administration in comparison to I/R group. In conclusion, Mel improves the recovery of renal function by decreasing ER stress and stimulating Akt pathway after renal I/R injury. PMID- 26229745 TI - Accreditation - A solution for problems or a fresh problem? PMID- 26229746 TI - Medical writing on an accelerated path in India. AB - The medical writing industry is on an upwards growth path in India. This is probably driven by an increasing urgency to have high-quality documents authored to support timely drug approvals, complemented by the realization that the competencies required are available in emerging geographies such as India. This article reviews the business landscape and the opportunities and challenges associated with outsourcing medical writing work India. It also analyzes the core competencies that a medical writer should possess and enlists various associations supporting learning in this domain. PMID- 26229747 TI - Regulating off-label drug use in India: The arena for concern. AB - Off-label use of drugs is relatively common in medical practice, even if it's often not supported by strong scientific evidence. Off-label use of medicine not only involves physicians and pharmaceutical companies, but regulatory agencies and patients as well. Therapeutic options might get restricted without off-label prescribing in some patient population. Off-label uses can be useful to patients with an orphan disease where sometimes it can be the only available treatment. Permitting the promotion of drugs for off-label uses may be appropriate in instances in which a drug can improve the quality (e.g., same or better outcomes at lower cost). Although many controversies exist, experts generally agree that further efforts are needed to increase access to suitable off-label drugs for patients with rare and other diseases. However, they also concur that potential inappropriate promotion, as well as possibly dangerous prescribing practices for these drugs, should be prevented. Proponents argue that the key benefit of allowing manufacturers to distribute off-label information is that it allows more data to be readily available to physicians, enabling them to make better treatment decisions. PMID- 26229748 TI - Patient centric approach for clinical trials: Current trend and new opportunities. AB - The clinical research industry today is undergoing a major facelift. Companies are continuously looking to adopt and implement effective and innovative ways to accelerate drug launches in the market. Companies today are more open and do not view patients as mere "subjects" who generate data, - but as informed collaborators whose participation is "core" to the overall success of trials leading to the emergence of the concept of "patient-centric trials." This paper is intended to highlight the current trends and new opportunities that can be seen in industry -indicative of crucial role patients today play in their own health care using technology, social media and self education. PMID- 26229749 TI - Reporting of pre-enrolment screening with randomized clinical trials: A small item that could impact a big difference. AB - INTRODUCTION: Randomized controlled trials (RCTs), when conducted using ethical and transparent methods, become the ultimate standard for producing evidence based knowledge in the field of medical research. We sought to determine the proportion of RCTs in which the number of screened patients is reported, and also to ascertain what predicted efficient screening (i.e., a high number of screened participants being enrolled). MATERIALS AND METHODS: Thirty-five RCTs from the Journals Clinical Infectious Diseases and The Lancet Infectious Diseases were reviewed from the time period of January 2012 to July 2013 using standardised criteria. RESULTS: From the 35 RCTs, 9 of 35 (26%) did not report the number of patients screened prior to recruitment. From the 26 studies that reported this screening figure, 10,215 (47%; range: 2-98%) of the screened participants (21,862) were subsequently enrolled. About 18.3% of those screened and not enrolled, met inclusion and exclusion criteria yet did not wish to participate in an RCT. Studies performed in developed countries and pediatric populations were more likely to have low rates of enrolment compared with the screened population although there was no statistical significance to these associations (P = 0.2 for both variables). CONCLUSION: Many reports of RCTs do not report screening figures, even though these add useful information about the feasibility of future trials. PMID- 26229750 TI - A study of knowledge, attitudes, and practice of dental doctors about adverse drug reaction reporting in a teaching hospital in India. AB - OBJECTIVE: The aim was to investigate the knowledge, attitudes, and practice of dental doctors about adverse drug reaction (ADR) reporting. MATERIALS AND METHODS: In a cross-sectional study, questionnaire was administered to 95 dental doctors working in a teaching dental hospital attached to a medical college with an ADR monitoring center (AMC). STATISTICAL ANALYSIS USED: Descriptive statistics were used to analyze responses. The association of knowledge and attitude with respect to position of dentists was analyzed with Chi-square test. RESULTS: The response rate and spontaneous reporting rate was found to be 61.0% and 13.7%, respectively. Important factors contributing to under reporting of ADRs include lack of awareness about AMC in the institute (81.0%) and pharmacovigilance program (72.4%), complacency (67.2%), lack of training to identify ADRs (65.5%), fear factor (63.7%), lethargy (58.6%), lack of risk perception of over the counter product related ADR (39.6%), inadequate risk perception of nonallopathic and herbal medicines (31%), indifference (27.5%) and concern that report may be wrong (27.5%). No significant difference in knowledge and attitudes of doctors with respect to position was found except for reporting of ADRs of newly marketed drugs and serious reactions to established product (P < 0.05). CONCLUSION: The deficiencies in knowledge and attitudes appear to be the underlying factor for under reporting by dental practitioners. It should be addressed urgently in order to increase spontaneous reporting by them. PMID- 26229751 TI - Cost-effectiveness analysis of three different combinations of inhalers for severe and very severe chronic obstructive pulmonary disease patients at a tertiary care teaching hospital of South India. AB - BACKGROUND: This study aims at simplifying the practical patient management and offers some general indications for pharmacotherapeutic choice by the implementation of (Global Initiative for Chronic Lung Disease) guidelines. This study was designed to evaluate the clinical and economic consequences of salmeterol/fluticasone (SF), formoterol/budesonide (FB), and formoterol/fluticasone (FF) in severe and very severe chronic obstructive pulmonary disease (COPD) patients. OBJECTIVES: The aim was to find out the most cost-effective drug combination between the three combinations (SF/FB/FF) in COPD patients. MATERIALS AND METHODS: A prospective observational comparative study (cost-effectiveness analysis), in which 90 severe (30 <= forced expiratory volume in 1 s [FEV1] <50% predicted) and very severe (FEV1 < 30% predicted) COPD patients (outpatients/inpatients) who are prescribed with any one of the following combinations (SF/FB/FF) were selected. In our study, we have divided 90 COPD patients into three groups (Group I, Group II, and Group III) each group consisting of 30 patients. Group I was prescribed with medication SF, Group II with medication FB, and Group III with medication FF. We used five different parameters such as spirometry test (mean FEV1 initial and final visit), number of symptom-free days (SFDs), number of moderate and severe exacerbations, Number of days of hospitalization and direct, indirect, and total cost to assess the cost effectiveness of SF/FB/FF. Comparison of cost and effects was done during the period of 6 months of using SF/FB/FF. RESULTS: The average FEV1 for Group I, Group II, and Group III subjects at initial visit was 33.47%, 33.73%, and 33.20% and was increased to 36.60%, 35.8%, and 33.4%, respectively. A 3% increment in FEV1 was reported for Group I subjects (SF) and was highly significant statistically (t = -8.833, P = 0.000) at 95% CI. For Group II subjects (FB), a 2% increment in FEV1 was reported and was highly significant statistically (t = 9.001, P = 0.000) at 95% CI. For Group III (FF) subjects 0.2% increment in FEV1. The overall mean total cost for Group I, Group II, and Group III subjects during the 6 months period was found to be Rs. 29,725/-, Rs. 32,602/- and Rs. 37,155/-. Incremental cost-effectiveness of FB versus SF was Rs. 37,781/- per avoided exacerbation and Rs. 661/-per SFD. CONCLUSION: This study highlights the favorable therapeutic performance of combined inhaled bronchodilators and corticosteroids (SF/FB/FF), thus suggesting that healthcare costs would be also affected positively. Results from our study showed that SF and FB were the most effective strategies in the treatment of COPD, with a slight clinical superiority of SF. The FF strategy was not much effective (i.e. associated with fewer outcomes and higher costs). PMID- 26229752 TI - Consent for audio-video recording of informed consent process in rural South India. AB - INTRODUCTION AND OBJECTIVES: In recent times, audio-video (A-V) recording of consent process for all the study subjects entering a clinical trial has been made mandatory. A-V recording of informed consent process is a big challenge due to confidentiality and the sociocultural environment in India. It is important to find out the acceptability for A-V recording of the consent process and reasons for refusal, if any to address this new challenge. MATERIALS AND METHODS: A descriptive survey was done among 150 residents of a rural community of South India. Acceptability for A-V recording of consent process was assessed among those who had given the informed written consent for participation in the study. An attempt to find the factors determining the refusal was also made. RESULTS: More than one-third (34%) of the study subjects refused to give consent for A-V recording of consent process. Not interested in recording or don't like to be recorded (39%) were the most common reasons to refuse for A-V recording of consent process. The refusal was higher among female and younger age-group adult subjects. Socioeconomic status was not found to be significantly associated with refusal to consent for A-V recording. CONCLUSION: Refusal for A-V recording of consent process is high in the South Indian rural population. Before any major clinical trial, particularly a field trial, an assessment of consent for A-V recording would be helpful in recruitment of study subjects. PMID- 26229753 TI - Comparative evaluation of efficacy and safety of combination of metformin vidagliptin versus metfromin-glimepiride in most frequently used doses in patients of type 2 diabetes mellitus with inadequately controlled metformin monotherapy-A randomised open label study. AB - AIM AND OBJECTIVE: The aim was to evaluate and compare the efficacy and safety of combinations of metformin-vidagliptin (MF-VG) and metfromin-glimepiride (MF-GP) in type 2 diabetes mellitus (T2DM) patients. MATERIALS AND METHODS: A comparative randomized open-label trial was conducted on patients with uncomplicated T2DM, on treatment with MF for 4 months out of which on maximum tolerated dose of MF (1000 2500 mg/day) for 4 weeks, glycosylated Haemoglobin [HbA1c]) >=6.5%, fasting blood glucose (FBG) >=126 mg/dl and post prandial glucose (PPG) >=200 mg/dl were included in the study. Patients were randomized to receive MF (500 mg BD) + VG (50 mg BD) or MF (500 mg BD) + GP (2 mg BD). RESULTS: Both the groups caused significant decline in blood glucose levels both FBG as well as PPG levels (P < 0.01). HbA1c was also reduced significantly in both groups at 12 weeks (P < 0.01). Total serum cholesterol, triglycerides, low-density lipoprotein and very low-density lipoprotein decreased significantly, whereas high-density lipoprotein levels increased significantly from baseline levels in both the groups (P < 0.01). Intergroup comparison failed to demonstrate any statistical difference on all of above parameters. Both weight and body mass index did not alter statistically from baseline in either of the groups as well as demonstrated no difference statistically on comparison (P > 0.05). At the end of the study, both liver functions tests and renal functions tests remained unaltered statistically and within normal clinical range in both the groups (P > 0.05). However, hypoglycemia and other adverse events were numerically more in MF + GP group. CONCLUSION: Both the regimens on comparison revealed similar efficacy and safety thereby failing to prove superiority over each other. PMID- 26229754 TI - Common pitfalls in statistical analysis: Clinical versus statistical significance. AB - In clinical research, study results, which are statistically significant are often interpreted as being clinically important. While statistical significance indicates the reliability of the study results, clinical significance reflects its impact on clinical practice. The third article in this series exploring pitfalls in statistical analysis clarifies the importance of differentiating between statistical significance and clinical significance. PMID- 26229755 TI - Good pharmacovigilance practice: Need of the hour from pharmaceutical companies. PMID- 26229757 TI - Effects of dexmedetomidine and clonidine as propofol adjuvants on intra-operative hemodynamics and recovery profiles in patients undergoing laparoscopic cholecystectomy: A prospective randomized comparative study. AB - CONTEXT: Alpha-2 (alpha2) adrenergic receptor agonists, clonidine and dexmedetomidine, are widely used as adjuvants during anesthesia for analgesic, sedative, sympatholytic, and cardiovascular stabilizing effects. AIMS: We compared effects of clonidine and dexmedetomidine (as propofol adjuvants) on intra-operative hemodynamics, recovery time, and postoperative cognitive function impairment. SUBJECTS AND METHODS: Forty-five American Society of Anesthesiologists I and II patients, scheduled for laparoscopic cholecystectomy were divided into three groups (n = 15). Group C patients received bolus of clonidine 3 MUg/kg followed by a continuous infusion; Group D patients received dexemedetomidine 1 MUg/kg and a continuous infusion; and Group P patients received a bolus of normal saline followed by an infusion. Intra-operative mean arterial pressure (MAP) and pulse rate (PR) were measured throughout the surgery. Bispectral index was maintained at 55 +/- 5 by titrating propofol infusion rate. The time between the interruption of anesthesia and eye opening (recovery time) was measured. Cognitive function was assessed using short mental status questionnaire at 15, 30, 45, and 60 min postoperatively. RESULTS: The sympathetic response to laryngoscopy and extubation on MAP and PR were significantly reduced with the use of clonidine and dexmedetomidine (P < 0.05). The recovery was delayed (P < 0.05) with both the drug combinations and it was more pronounced with dexmedetomidine (P < 0.05). Dexmedetomidine group showed cognitive impairment in a postoperative period lasting up to an hour. CONCLUSIONS: When co administered with propofol, both clonidine, and dexmedetomidine attenuate sympathetic response to laryngoscopy and extubation but cause delay in the recovery from anesthesia. Dexmedetomidine causes impairment of postoperative cognitive functions. PMID- 26229756 TI - Advances in diagnostic interventional pulmonology. AB - The recent advances in diagnostic pulmonary procedures have revolutionized the evaluation of abnormal thoracic findings including lung nodules and masses, mediastinal lymphadenopathy, and pleural diseases. Bronchoscopies with endobronchial ultrasonography and electromagnetic navigation are examples of new technology that has significantly improved the specificity and sensitivity of these procedures in diagnosis and staging of lung cancer without the need for more invasive procedures. This report describes the different diagnostic pulmonary interventions providing a description of the procedures, their indications, diagnostic yield and drawback. PMID- 26229758 TI - Antimicrobial resistance of bacterial isolates from respiratory secretions of ventilated patients in a multi-specialty hospital. AB - CONTEXT: Ventilator-associated pneumonia (VAP) is a common nosocomial infection occurring in intensive care unit (ICU) settings. VAP occurs due to interplay of three factors - impaired host defense, access of large numbers of pathogenic bacteria to the lower respiratory tract and the virulence of the organism. Knowledge of colonizing microbial flora and their antibiogram in ventilated patients is of great importance in timely institution of empirical therapy, so that mortality and morbidity due to VAP can be reduced. SUBJECTS AND METHODS: A prospective study was performed over a period of 6 months in a multi-specialty hospital to determine the various pathogens in respiratory secretions and to determine the prevalence of multidrug resistance (MDR). RESULTS: Pseudomonas aeruginosa (26%), Acinetobacter (26%), Klebsiella pneumoniae (26%), followed by Escherichia coli (15%), Staphylococcus aureus (6%) and Citrobacter spp. (1.5%) were the common pathogens isolated in our study. In all, 72.73% (48/66) bacterial isolates were isolated from medical ICU, while 25.76% (17/66) were isolated from surgical ICU. Only one strain (Acinetobacter) was isolated from pediatric ICU. Fifty-seven (86.36%) of the 66 pathogens in our study were MDR. CONCLUSION: There is increasing colonization of pathogenic bacteria in ventilated patients admitted in ICUs, which are predominantly MDR. These colonizers may cause infection resulting in VAP. Judicious use of antibiotics, guided by local antibiotic resistance profile coupled with strict infection control practices alongside application of VAP bundle are important measures to prevent these pathogens from causing VAP in ICU patients. PMID- 26229759 TI - Brainstem auditory evoked potential in clinical hypothyroidism. AB - OBJECTIVES: The association of hypothyroidism with impairment of hearing is known to occur. It may be of any kind i. e., conductive, sensorineural or mixed. The aim of this study is to assess auditory pathway by brainstem auditory evoked potential (BAEP) in newly diagnosed patients of clinical hypothyroidism and healthy sex- and age-matched controls. MATERIALS AND METHODS: The study included 25 healthy age- and sex-matched controls (Group I) and 25 patients of newly diagnosed clinical hypothyroidism (Group II). The recording was taken by using RMS EMG EP MK2 equipment. STATISTICAL ANALYSIS USED: Unpaired Student's t test. RESULTS: There was a significant increase in wave IV (5.16 +/- 0.85 ms) and wave V (6.17 +/- 0.89 ms) latencies of right ear BAEP of Group II in comparison to wave IV (4.66 +/- 0.39 ms) and wave V (5.49 +/- 0.26 ms) of Group I. Wave V of left ear BAEP of Group II was also prolonged (6 +/- 0.61 ms) in comparison to Group I (5.47 +/- 0.35 ms). There was a significant difference in inter-peak latencies IPL I -V (4.44 +/- 0.66 ms) and IPL III -V (2.2 +/- 0.5 ms) of right ear BAEP of Group II in comparison to IPL I -V (3.94 +/- 0.31 ms) and IPL III -V (1.84 +/- 0.34 ms) of Group I. A significant prolongation was also found of IPL I -V (4.36 +/- 0.59 ms) and IPL III -V (2.2 +/- 0.42 ms) of left ear BAEP of Group II in comparison to IPL I -V (3.89 +/- 0.3 ms) and IPL III -V (1.85 +/- 0.3 ms) of Group I. CONCLUSION: Prolongation of wave IV and V along with inter-peak latencies in BAEP of both ears suggests that central auditory pathway is affected significantly in clinical hypothyroid patients. PMID- 26229760 TI - Visceral adipose tissue influences on coronary artery calcification at young and middle-age groups using computed tomography angiography. AB - PURPOSE: The purpose of the study was to evaluate the impact of excessive visceral adipose tissue (VAT) on subclinical coronary atherosclerosis and coronary artery calcifications (CAC) in young and middle-age groups using multislice computed tomography. METHODS: This study is a single center, cross sectional study. Eligible patients (n = 159), who under the age of 61 years, with chest pain and mild to moderate probability to have coronary artery disease (CAD) were enrolled. Coronary calcium score and epicardial adipose tissue (EAT) were measured at the level of the left main coronary artery while VAT was measured at the level of the iliac crest. RESULTS: The average age was (48 +/- 8 years). The mean VAT was (38 +/- 21 cm(2)) with no significant difference between men and women (38 +/- 22 vs. 37 +/- 19 P = 0.8) respectively. Student's t-test analysis showed significantly higher VAT in patients with detectable CAC than patients with no CAC (48 +/- 24 vs. 33 +/- 18 P = 0.00002), respectively. Univariate regression analysis showed that VAT and EAT, are strong predictor for CAC (hazard ratio [HR] 1.034, 95% confidence interval [CI: 1.016-1.052]. P <0.001 and [HR] 1.344, 95% CI: [1.129-1.601] P = 0.001), respectively. CONCLUSION: Excessive VAT is significantly associated with positive CAC. VAT can strongly predict subclinical CAD in individuals at young and middle-age groups. PMID- 26229761 TI - Rapid-onset obesity, hypoventilation, hypothalamic dysfunction, autonomic dysregulation syndrome. AB - Rapid-onset obesity with hypoventilation, hypothalamic dysfunction and autonomic dysregulation syndrome is a rare disorder that presents with rapidly evolving obesity with several endocrine disorders during early childhood. We present here a documented case of a 6-year-old Syrian girl with the characteristic symptoms of rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation, associated with an abdominal mass (mature ganglioneuroma). PMID- 26229762 TI - Tenofovir induced lichenoid drug eruption. AB - Cutaneous adverse reactions are a common complication of anti-retroviral therapy. Tenofovir is a newer anti-retroviral drug belonging to the nucleotide reverse transcriptase inhibitor group. Systemic adverse effects like nausea, vomiting, diarrhea, hepatotoxicity and renal toxicity are common with tenofovir but cutaneous adverse effects are rare. Lichenoid drug eruptions are a common adverse effect seen with a large variety of drugs including antimalarials, antihypertensives, nonsteroidal anti-inflammatory drugs and diuretics. Lichenoid drug eruption is a rare cutaneous adverse effect of tenofovir with only a single case reported till date. Here, we report a case of tenofovir induced lichenoid drug eruption in a 54-year-old human immunodeficiency virus affected male who presented with generalized lichenoid eruption after 6 weeks of initiation of tenofovir and complete clearance on cessation of the drug. PMID- 26229763 TI - Ascending pharyngeal artery arising from a hypoplastic internal carotid artery. AB - Normal vascular variants often have clinical/surgical significance and can be misinterpreted for pathology. We report a case ascending pharyngeal artery arising from a hypoplastic internal carotid artery. We provide clues to differentiate between dysgenesis and disease/thrombosis of the internal carotid artery. PMID- 26229764 TI - The path toward editorial quality. PMID- 26229765 TI - Current concepts on the sagittal balance and classification of spondylolysis and spondylolisthesis. AB - Treatment of spondylolysis and spondylolisthesis remains a challenge for orthopaedic surgeons, neurosurgeons and paediatrics. In spondylolisthesis, it has been clearly demonstrated over the past decade that spino-pelvic morphology is abnormal and that it can be associated to an abnormal sacro-pelvic orientation as well as to a disturbed global sagittal balance of spine. This article presents the SDSG (Spinal Deformity Study Group) classification of lumbosacral spondylolisthesis. The proper treatment of spondylolisthesis is dependent on recognizing the type of slip, sacro-pelvic balance and overall sagittal balance and its natural history. Although a number of clinical radiographic features have been identified as risk factors, their role as primary causative factors or secondary adaptative changes is not clear. The conservative treatment of adult isthmic spondylolisthesis results in good outcome in the majority of cases. Of those patients who fail conservative treatment, success with surgery is quite good, with significant improvement in neurologic function in those patients with deficits, as well as improvement in patients with back pain. PMID- 26229766 TI - Level of evidence of knee surgery in national journal. AB - Select the studies related to knee surgery in the orthopedic literature published by Acta Ortopedica Brasileira (AOB) and the Revista Brasileira de Ortopedia (RBO) and classify them according to the levels of evidence. We selected all studies published from 2000 to 2011 related to knee surgery in AOB and RBO. The following categorization was adopted: level 1: systematic review; level 2: clinical trial; level 3: cohort studies and case-control; level 4: number of cases; level 5: narrative review and others. We found in the national literature selected 255 studies related to knee surgery. In the Southeast were developed 212 articles (83.1%), 30 publications in the South (11.7%), Northeast 5 (2%), North and Central West 2 jobs each (0.8%). Four work performed in other country (1.6%). The most common issue was the anterior cruciate ligament in 58 studies (22.7%) and arthroplasty in 55 studies (21.5%). Most studies presented evidence level IV (27.8%) and V (50.2%). The national scientific production related to knee surgery presents itself expanding with predominant expression in the Southeast. Most studies related to knee surgery published in national journals have low level evidence and focuses on the approach of the anterior cruciate ligament and arthroplasty. PMID- 26229767 TI - Analysis of using antirotational device on cephalomedullary nail for proximal femoral fractures. AB - OBJECTIVE: To analyze the influence of femoral neck diameter in the positioning of the sliding screw in cefalomedulares nails for treatment of unstable transtrochanteric fractures. METHODS: Prospectively throughout 2011, patients with unstable fractures transtrochanteric undergoing osteosynthesis with cephalomedullary nail using antirotacional device. They were evaluated for sex, age and fracture classification according to Tronzo. Through digital radiographs angle reduction, tip apex distance (TAD), stem diameter and measures between the positioning of the screws and the limits of the cervix were measured. RESULTS: Of the 58 patients, 42 (72.4%) were female and 16 (27.6%) were male. 33 patients were classified as Tronzo III (56.9%), 6 patients as Tronzo IV (10.4%) and 19 as Tronzo V (19.8%). The majority were in between the eighth and ninth decade of life. The average reduction in the angle was 130.05 degrees for females and 129.4 degrees for males. The TAD average was 19.7 mm for females and 21.6 for males. The average diameter of the neck and head vary with statistical significance between men and women. In 19 patients the placement of the sliding bolt can be optimal. If the ideal positioning was not possible, the mean displacement for non-infringement of higher cortical neck was 4.06 mm. CONCLUSION: The optimal placement would not be possible for the majority of the population, for the average diameter of the neck of the sample. PMID- 26229768 TI - Results of open reduction and internal fixation of severe fractures of the proximal humerus in elderly patients. AB - OBJECTIVE: To evaluate clinical and radiological results with open reduction and internal fixation of severe fractures of the proximal humerus in the patients over the age of 60 years. METHODS: Between June 1992 and February 2011, 21 patients with FGEPU over the age of 60 years were treated by open reduction and internal fixation at the Group of Shoulder and Elbow Department of Orthopaedics and Traumatology of Santa Casa de Sao Paulo Medical School. 18 patients were reviewed. RESULTS: Two patients had excellent results, 12 good, three regular and one bad. Therefore, we find that 77.7% of these had good and excellent results. All patients were satisfied with the treatment and only three patients did not return to previous activities. Mean postoperative mobilities were 122 degrees elevation (90-150 degrees ), 39 lateral rotation (20-60 degrees ) and medial rotation of T11 (T5 to sacro iliac joint). CONCLUSION: Open reduction and internal fixation of FGEPU may also be indicated for elderly patients and obtained 77.7% of good and excellent results. Statistically (p < 0.05), the anatomical reduction of the fracture was found to be important for obtaining good results. PMID- 26229769 TI - Evaluation of surgical treatment of Dupuytren's disease by modified open palm technique. AB - OBJECTIVE: to assess the surgical technique using the modified palm open technique for the treatment of severe contractions of Dupuytren's disease. METHODS: over a period of four years, 16 patients underwent surgical treatment, and in its entirety belonged to stages III and IV of the classification proposed by Tubiana et al. We performed measurements of the extension deficit of the metacarpophalangeal joints, proximal and distal interphalangeal in preoperative, postoperative (3 months) and late postoperative period (5-8 years). Angles greater than 30 degrees metacarpophalangeal joints and 15 degrees proximal interphalangeal the results were considered surgical recurrence. RESULTS: there was obtained an average of 6.3 degrees at the metacarpophalangeal joint, 13.8 degrees in the proximal interphalangeal and distal interphalangeal at 1.9 degrees . CONCLUSION: the modified open palm technique is an effective method in the surgical treatment of severe contractures in Dupuytren's disease. PMID- 26229770 TI - Results evaluation of the use of intra-articular sodium hyaluronate in the post operative knee arthroscopy. AB - OBJECTIVE: to evaluate the efficacy of hyaluronic acid in the post-operative of knee arthroscopy. METHODS: we have evaluated 49 patients undergoing arthroscopic procedure with the use of intra-articular hyaluronic acid (Group 1) and 49 patients undergoing arthroscopic procedure without the use of hyaluronic acid (Group 2). Patients were evaluated based on the Visual Analogue Scale, household analgesia, assessment of the Range of Motion with a goniometer, and the Lysholm questionnaire. RESULTS: there were no substantial adverse effects on either group. CONCLUSION: the use of hyaluronic acid in the post-operative of knee arthroscopy is justified due/because it leads to a decrease in pain in the early stage, enabling faster recovery of the patient. PMID- 26229771 TI - Blood transfusion in hip arthroplasty: a laboratory hematic curve must be the single predictor of the need for transfusion? AB - OBJECTIVE: to determine whether the laboratory hematic curve must be the single predictor of postoperative blood transfusion in total hip arthroplasty. METHODS: the laboratory blood samples of 78 consecutive patients undergoing total hip arthroplasty was analyzed during five distinct moments: one preoperative and four postoperative. There was a count of hemoglobin, hematocrit and platelets of the patients samples. Other catalogued variables ascertain possible risk factors related to transfusional practice. They characterized the anthropometric, behavioral and co morbidities data in this population. The study subjects were divided and categorized into two groups: those who received blood transfusion during or after surgery (Group 1, G1), and those who did not accomplish blood transfusion (Group 2, G2). Transfusion rules were lead by guidelines of American Academy of Anesthesiology and the British Society of Hematology. RESULTS: a total of 27 (34.6%) patients received blood transfusions. The curves of hemoglobin, hematocrit and platelet transfusions between G1 and G2 were similar (p > 0.05). None of the analyzed risk factors modified the rate of transfusion rate in their analysis with p value > 0.05, except the race. The sum of clinical co morbidities associated with patients in G1 was a median of 3 (95% CI 2.29-3.40), while in G2 the median was 2 (95% CI 1.90-2.61) with p = 0.09. CONCLUSION: the curve in red blood cells has limited reliability when used as sole parameter. The existence of tolerant patients hematimetric curve variations assumes that their assessments of clinical, functional evaluation and co-morbidities are parameters that should influence the decision to transfusion red blood cells. PMID- 26229772 TI - Clinical and radiographic medium-term evaluation on patients with developmental dysplasia of the hip, who were submitted to open reduction, capsuloplasty and Salter osteotomy. AB - OBJECTIVE: to evaluate the clinical and radiographic medium-term results from surgical treatment of developmental dysplasia through open reduction, Salter et al.'s osteotomy and capsuloplasty. METHODS: 13 patients were evaluated, 13 hips treated surgically by the proposed technique between 2004 and 2011. A clinical and radiographic evaluation was conducted by Dutoit et al. and Severin et al. criteria, respectively. RESULTS: the acetabular preoperative index for the 13 surgically treated hips ranged from 27 degrees to 50 degrees (average of 36), and after surgical correction to 18.5 degrees (10-28 degrees ), so that the evaluations of preoperative and postoperative acetabular indexes showed up significant statistic reduction (p < 0.05). Regarding the postoperative clinical evaluation, it was found: nine excellent hips (69.2%), three good ones (23.1%), no fair hips (0%) and a poor one (7.7%). In radiographic evaluation, it was found: six excellent hips (46.1%), three good ones (23.1%), no fair hips (0%) and four poor ones (30.8%). Therefore, favorable results were obtained (92.3%), with grouped hips with excellent and good ratings as satisfactory and with fair and bad ratings as unsatisfactory. It is also important to notice that there was no significance among occurrence of complications, the patient's age, the time of surgery and the preoperative acetabular index (p > 0.05). As complications occurred, it was found that three subluxations and a subluxation associated with avascular necrosis of the femoral head. CONCLUSION: open reduction, Salter et al.'s osteotomy and capsuloplasty are seen to be a viable option for the treatment of developmental dysplasia of the hip, according to clinical and radiological medium-term evaluations. PMID- 26229773 TI - Tibiotalocalcaneal arthrodesis with retrograde intramedullary nailing: 29 patients' clinical and functional evaluation. AB - OBJECTIVE: To evaluate clinically and functionally the pos-operative results of patients submitted to tibiotalocalcaneal arthrodesis for the treatment of traumatic arthropathy and neuropathy. METHODS: Retrospective study of 29 patients undergoing ankle arthrodesis with intramedullary retrograde nail. All patients were evaluated for fusion time, AOFAS and VAS scores, satisfaction, and complications of surgery. The mean follow-up was 36 months (range 6-60 months). RESULTS: The union rate was 82%, and the consolidation occurred on average at 16 weeks (10-24 weeks). The pos-operative AOFAS score improved in 65.5% (average of 57.7 on neurological cases and 75.7 on cases pos-traumatic) and VAS score improved 94.1% (average of 2.3 on neurological cases and 4,2 on post-traumatic cases), and 86% of patients were satisfied with the procedure performed. Complications occurred in 11 patients (38%), including pseudoarthrosis (17.24%), infection (17.24%), material failure (13.8%) and fracture (13.8%). CONCLUSION: Tibiotalocalcaneal arthrodesis with retrograde intramedullary nail proved to be a good option for saving the ankle joint, with improvement of clinical and functional scores (AOFAS = 65.5% and VAS = 94.1%). PMID- 26229774 TI - Effect of hyaluronic acids as chondroprotective in experimental model of osteoarthrosis. AB - OBJECTIVE: to analyze the effects of hyaluronic acid of different molecular weights in an experimental model of osteoarthritis in rabbits. METHODS: forty four male California rabbits were divided randomly into three groups and underwent resection of the anterior cruciate ligament in his right knee. After three weeks of the surgical procedure began three weekly intra-articular injections of hyaluronic acid native (Polireumin((r)))-PR, hyaluronic acid branched chain (Synvisc((r)))-S and 0.9% saline-P. All animals were sacrificed after twelve weeks of surgery and tibial plateau infiltrated the knees were dissected. Histological cartilage of the support areas of the tibial plateaus were stained with Alcian Blue pH 1.0, Alcian Blue pH = 2.5 and toluidine blue for research on the amount of proteoglycans. The intensity of staining was quantified on a Zeiss microscope apparatus Imager Z2 MetaSystems and analyzed by software MetaferMsearch. RESULTS: the effect of chondroprotetor hyaluronic acids used in the study was confirmed when compared to the control group, but the comparison made between them, there was no statistically significant difference regarding chondroprotetion. CONCLUSION: the hyaluronic acids tested had chondroprotective effect, with no statistical difference with regard to the different molecular weights. PMID- 26229775 TI - Total arthroplasty in displaced dysplastic hips with acetabular reconstruction and femoral shortening - technical note. AB - To describe a new procedure of total hip replacement in patient with severe developmental dysplasia of the left hip, using technique of acetabular reconstruction with autogenous bone grafts and subtrochanteric shortening femoral osteotomy. Total hip replacement done in January of 2003. The Eftekhar's classification was used and included type D, neglected dislocations. Bone graft incorporated in acetabular shelf and femoral osteotomy. Our contribution is the use of an Allis plate to better fix acetabular grafts, avoiding loosening, and cerclage around bone graft in femoral osteotomy site, which diminish pseudoarthrosis risk. This technique shows efficiency, allowing immediately resolution for this case with pain and range of motion of hip improvement. It also allows the acetabular dysplasia reconstruction, equalization of the limb length (without elevated risk of neurovascular lesion) and repairs the normal hip biomechanics due to the correction of the hip's center of rotation. PMID- 26229776 TI - Lipoma arborescens of the knee: a case report. AB - Case report of a female patient of 26 years who complained of pain and recurrent episodes of joint swelling in his left knee about 10 years ago. After anamnesis, physical examination and radiographic imaging and magnetic resonance were diagnosed with arborescent lipoma of the knee, and the patient underwent arthroscopic treatment for resection of the lesion. Postoperatively the patient was referred to physical therapy rehabilitation with good evolution. PMID- 26229777 TI - Necrotizing fasciitis after internal fixation of fracture of femoral trochanteric. AB - Necrotizing fasciitis is a rare and potentially lethal soft tissue infection. We report a case of trochanteric femur fracture in a patient who underwent fracture fixation and developed necrotizing fasciitis. A literature review on the topic will be addressed. PMID- 26229778 TI - Osteoid osteoma of the acromion simulating acromioclavicular pain. AB - The osteoid osteoma is a benign bone tumour that usually presents with nocturnal pain in young adults, relieved by rest and anti-inflammatories. It can affect any bone; however, their occurrence is rare in the acromion. The authors describe a case of osteoid osteoma located in the acromion, with symptoms that simulated acromion claviculararthrosis. The diagnosis was made by CT scan and treatment was excision of the nidus through arthroscopy. The diagnosis was confirmed by histopathology. In the outpatient segment, the patient remained asymptomatic, with complete recovery of function of the affected limb. PMID- 26229779 TI - Compartment syndrome after tibial plateau fracture. AB - Fractures of the tibial plateau are relatively rare, representing around 1.2% of all fractures. The tibia, due to its subcutaneous location and poor muscle coverage, is exposed and suffers large numbers of traumas, not only fractures, but also crush injuries and severe bruising, among others, which at any given moment, could lead compartment syndrome in the patient. The case is reported of a 58-year-old patient who, following a tibial plateau fracture, presented compartment syndrome of the leg and was submitted to decompressive fasciotomy of the four right compartments. After osteosynthesis with internal fixation of the tibial plateau using an L-plate, the patient again developed compartment syndrome. PMID- 26229780 TI - Nodular fasciitis in finger simulating soft tissue malignancy. AB - Nodular fasciitis (NF) is a rare fibroblastic proliferative lesion, characterized clinically as a solitary mass of hardened and slightly painful on palpation, fast growing and no gender preference. The objective of this study is to report the case of a patient with NF in third finger of left hand, describe the findings of plain radiography, computed tomography and magnetic resonance imaging and correlate with the literature. Since the diagnosis of NF is a challenge, being necessary to conciliate the clinical, radiological and pathological. PMID- 26229781 TI - Open anterior dislocation of the hip in an adult: a case report and review of literature. AB - Open anterior hip dislocation is a rare condition and results from high-energy trauma. Ten cases of open anterior dislocation have been described in the literature so far. Its rarity is due to the inherent stability of the joint, its deep position in the pelvis, with strong ligaments and bulky muscles around the articulation. Several factors influence the prognosis, such as the degree of compounding, the associated soft tissue injuries, the age of the patient and, mainly, the delay in reduction. The main complications are: arthrosis of the hip, with incidence of 50% of cases, when associated with fractures of the femoral head; and osteonecrosis of the femoral head, with incidence between 1.7 and 40% (in closed anterior dislocation). Because of the rarity and the potential disability of this lesion, we report a case in a 46-year-old man, involved in an automobile accident. The hip was reduced (anterior superior dislocation) in the first three hours of the trauma. The patient was kept non-weight bearing until sixth week, with complete weight bearing after 10th week. After one year follow up, the functional result was poor (Harris Hip Score: 52), probably because of the associated labral tear, but without signs of osteonecrosis of the femoral head in magnetic resonance imaging. PMID- 26229782 TI - The anterolateral ligament of the knee - Visibility on magnetic resonance imaging. PMID- 26229783 TI - What makes us accept the way we work? Maybe the pleasure of practicing medicine! PMID- 26229785 TI - Trauma to the nail complex. AB - OBJECTIVE: to analyze the results from surgical intervention to treat trauma of the nail complex. METHODS: we retrospectively reviewed a series of 94 consecutive patients with trauma of the nail complex who were treated between 2000 and 2009. In 42 patients, nail bed suturing was performed. In 27 patients, nail bed suturing was performed subsequent to osteosynthesis of the distal phalanx. In 15, immediate grafting was performed, and in 10, late-stage grafting of the nail bed. The growth, size and shape of the nail were evaluated in comparison with the contralateral finger. The results were obtained by summing scores and classifying them as good, fair or poor. RESULTS: the results were considered to be good particularly in the patients who underwent nail bed suturing or nail bed suturing with osteosynthesis of the distal phalanx. Patients who underwent immediate or late-stage nail grafting had poor results. CONCLUSION: trauma of the nail complex without loss of substance presented better results than did deferred treatment for reconstruction of the nail complex. PMID- 26229786 TI - Intra-focal reduction and percutaneous fixation of neck fractures of the fifth metacarpal: description of surgical technique. AB - OBJECTIVE: to demonstrate a surgical technique for treating neck fractures of the fifth metacarpal, by means of reduction through intra-focal manipulation and percutaneous fixation using Kirschner wires, with the aims of making it easier to achieve and maintain the reduction during the operation and enabling reduction of these fractures even if a fibrous callus has formed. METHODS: a series of ten patients with neck fractures of the fifth metacarpal presenting palmar angles greater than 30 degrees underwent the surgical technique described, as examples, and their results were evaluated through postoperative radiographs and clinical examinations. RESULTS: all the patients achieved reductions that were close to anatomical and evolved to consolidation of the fracture in the position obtained. CONCLUSION: the surgical technique described is effective, easy to carry out, minimally invasive and low-cost, thereby enabling adequate clinical and radiographic reduction, even in subacute fractures already presenting a fibrous callus. PMID- 26229784 TI - Current possibilities for hip arthroplasty. AB - Hip arthroscopy has been popularized over the last decade and, with technical advances regarding imaging diagnostics, understanding of the physiopathology or surgical techniques, several applications have been described. Both arthroscopy for intra-articular conditions and endoscopy for extra-articular procedures can be used in diagnosing or treating different conditions. This updated article has the objective of presenting the various current possibilities for hip arthroscopy. PMID- 26229787 TI - Transtrochanteric fractures: evaluation of data between hospital admission and discharge. AB - OBJECTIVE: to evaluate the data obtained from patients with transtrochanteric fractures who were attended at a tertiary-level trauma referral hospital, between admission and discharge, gathered prospectively by means of the SINPE((c)) software. METHODS: 109 consecutive patients who were admitted between April 2011 and January 2012 were evaluated using an electronic storage and analysis database in SINPE((c)). The data were gathered prospectively, including evaluations on personal information about the patients, history-taking, fracture classification (Evans-Jensen, AO/OTA and Tronzo), treatment and discharge. RESULTS: the sample was composed of 43 men and 66 women. Their ages ranged from 20 to 105 years, with a mean of 69 years. Falling was the trauma mechanism for 92 patients and traffic accidents for 17. The most prevalent chronic diseases were systemic arterial hypertension and diabetes mellitus. According to the AO/OTA classification, the commonest fracture type was 31 A1. According to the Tronzo classification, type III was commonest. The fracture was fixed by means of a cephalomedullary nail in 64 cases and a sliding screw-plate in 44 cases. One fracture was fixed with a 95 degrees screw-plate. Seven patients presented some form of clinical complication and three died during the hospital stay. All the patients who were discharged were instructed to only partially bear weight on the repair. CONCLUSION: through SINPE((c)), it was possible to evaluate the personal information, history-taking, classification, treatment and discharge of patients with transtrochanteric fractures, from hospital admission to discharge. PMID- 26229788 TI - Functional evaluation of patients with injury of the distal insertion of the biceps brachii muscle treated surgically. AB - OBJECTIVE: to functionally evaluate patients with injury of the distal insertion of the biceps brachii muscle that was treated surgically. METHODS: between April 2002 and June 2011, 15 elbows of 14 patients underwent surgical treatment performed by the Shoulder and Elbow Surgery Group, Department of Orthopedics and Traumatology, School of Medical Sciences, Santa Casa de Sao Paulo. The minimum follow-up was six months, with a mean of 28 months. The patients' ages ranged from 28 to 62 years, with a mean age of 40 years. All the patients were male and the dominant arm was affected in 64.2%. The clinical evaluation on the results was conducted using the criteria of the American Medical Association (AMA), as modified by Bruce, with evaluation of the joint range of motion (flexion extension and pronosupination), the presence of pain and the patient's degree of satisfaction. RESULTS: from the AMA criteria, as modified by Bruce, we obtained 100% satisfactory results, of which 85.7% were considered to be excellent and 14.3% good. We observed that when distal injuries of the biceps brachii muscle affected young and active patients, surgical treatment was a good option. PMID- 26229789 TI - Evaluation of treatment for camptodactyly: retrospective analysis on 40 fingers. AB - OBJECTIVE: to retrospectively assess the results from cases treated in the hand surgery service, starting from a preestablished protocol; and to conduct a critical analysis on the results achieved, with separation of the cases into their respective subgroups. METHODS: twenty-three patients and a total of 40 fingers were evaluated between January 2004 and December 2011. We correlated the altered anatomical structures found in the cases that underwent the surgical procedure and its results, with regard to both conservative and surgical treatment, emphasizing the main indications. RESULTS: the results were analyzed using the Sierget method of the Mayo Clinic. CONCLUSION: we observed that the cases of camptodactyly of the little finger alone in the flexible form (>60 degrees ) that underwent surgical treatment uniformly presented excellent results. In the rigid forms, our observations indicated that there were benefits comprising gains of extension and correction of the deformity. However, the range of motion with active flexion in the proximal interphalangeal joint was always partial. With evolution over time, some cases presented some loss of the gain previously achieved, which corroborates the need for continual vigilance during the follow-up, with systematic use of braces until the final phase of skeletal growth. PMID- 26229790 TI - Preoperative planning of primary total hip arthroplasty using conventional radiographs. AB - OBJECTIVE: the objective of this study was to present an analog method for preoperative planning of primary total hip arthroplasty procedures based on measuring the components by overlaying the transparencies of the prosthesis on the preoperative radiographs and checking the accuracy, both for predicting the size of the acetabular and femoral components used and for restoring the offset and correcting the dysmetria. METHODS: between March 2005 and July 2009, 56 primary total hip arthroplasty procedures performed on 56 patients at the Mario Covas State Hospital in Santo Andre were analyzed. The measurements on the femoral and acetabular components obtained through planning were compared with those that were used in the surgery. The offsets measured through the preoperative planning were compared with those measured on the postoperative radiographs. Dysmetria was evaluated before and after the operation. RESULTS: accuracy of 78.6% (p < 0.001) in predicting the size of the acetabular component and 82.2% (p < 0.001) in predicting the femoral nail was observed. The offsets measured through preoperative planning were statistically similar to the offsets measured on the postoperative radiographs. After the operation, we observed absolute equalization in 48.2% of the cases. In 87.5%, the dysmetria was less than or equal to 1 cm and in 69.6%, it was less than or equal to 0.5 cm. CONCLUSIONS: the accuracy was 78.6% and 82.2%, respectively, for the acetabular and femoral components. The offsets that were planned preoperatively were statistically similar to those measured on postoperative radiographs. We found absolute equalization in 48.2% of the cases. PMID- 26229791 TI - Total knee arthroplasty with computer-assisted navigation: an analysis of 200 cases. AB - OBJECTIVE: to evaluate the results from surgery with computer-assisted navigation in cases of total knee arthroplasty. METHOD: a total of 196 patients who underwent total knee arthroplasty with computer-assisted navigation were evaluated. The extension and flexion spaces (gaps) were evaluated during the operation and the alignment after the operation was assessed. The Knee Society Score (KSS) questionnaire for assessing patient's function was applied preoperatively and postoperatively after a mean follow-up of 22 months. RESULTS: in all, 86.7% of the patients presented good alignment of the mechanical axis (less than 3 degrees of varus or valgus in relation to the mechanical axis) and 96.4% of the patients presented balanced flexion and extension gaps. Before the operation, 97% of the patients presented poor or insufficient KSS, but after the operation, 77.6% presented good or excellent KSS. CONCLUSION: the navigation system made it possible to achieve aligned and balanced implants, with notable functional improvement among the patients. It was found to be useful in assessing, understanding and improving knowledge in relation to performing arthroplasty procedures. PMID- 26229792 TI - Revision of unicompartmental knee arthroplasty: implants used and causes of failure. AB - OBJECTIVE: to determine the causes of unicondylar knee arthroplasty failures, as well as identify the implants used and the need of bone grafting in patients undergoing revision UKA in Center of Knee Surgery at the Instituto Nacional de Traumatologia e Ortopedia (INTO) in the period between January 1990 and January 2013. METHODS: a retrospective analysis of the medical documentation and imaging, determining the cause of failure of UKA and the time of its occurrence, as well as prosthetic components implanted during the review and the need for bone grafting. RESULTS: in this study, 27 UKA failures in 26 patients were included. Collapse of one or more components was the main cause of failure, occurring in 33% of patients. Aseptic failure was identified in 30% of cases, progression of osteoarthrosis in 15%, infection and pain 7% each, and osteolysis and polyethylene failure in 4% each. Early failure occurred in 41% of all revisions of UKA and late failure in 59%. 23 patients have undergone revision of UK. CONCLUSION: in 35% of revisions the use of bone grafting was needed in tibial area; in 3 cases we needed allograft from Tissue Bank. We did not use metal increase in any of the revision. In one patient we used implant constraint for instability. PMID- 26229793 TI - Radiological analysis on femoral tunnel positioning between isometric and anatomical reconstructions of the anterior cruciate ligament. AB - OBJECTIVE: the aim of this study was to radiologically evaluate the femoral tunnel position in anterior cruciate ligament (ACL) reconstructions using the isometric and anatomical techniques. METHODS: a prospective analytical study was conducted on patients undergoing ACL reconstruction by means of the isometric and anatomical techniques, using grafts from the knee flexor tendons or patellar tendon. Twenty-eight patients were recruited during the immediate postoperative period, at the knee surgery outpatient clinic of FCMMG-HUSJ. Radiographs of the operated knee were produced in anteroposterior (AP) view with the patient standing on both feet and in lateral view with 30 degrees of flexion. The lines were traced out and the distances and angles were measured on the lateral radiograph to evaluate the sagittal plane. The distance from the center of the screw to the posterior cortical bone of the lateral condyle was measured and divided by the Blumensaat line. In relation to the height of the screw, the distance from the center of the screw to the joint surface of the lateral condyle of the knee was measured. On the AP radiograph, evaluating the coronal plane, the angle between the anatomical axis of the femur and a line traced at the center of the screw was measured. RESULTS: with regard to the p measurement (posteriorization of the interference screw), the tests showed that the p-value (0.4213) was greater than the significance level used (0.05); the null hypothesis was not rejected and it could be stated that there was no statistically significant difference between the anatomical and isometric techniques. With regard to the H measurement (height of the screw in relation to the lower cortical bone of the knee), the p-value observed (0.0006) was less than the significance level used (0.05); the null hypothesis was rejected and it could be stated that there was a statistically significant difference between the anatomical and isometric techniques. It can be concluded that the latter difference occurred because the isometric technique generated greater values for the H measurement than the anatomical technique. With regard to the MED variable (position of the screw on the AP radiograph), the observed p-value (0.000) was less than the significance level (5%); the null hypothesis was rejected and it could be stated with 95% confidence that there was a significant difference between the anatomical and isometric techniques. CONCLUSIONS: there were statistically significant differences in the radiological evaluations of the femoral tunnel, both in the sagittal and in the coronal plane, between the ACL reconstruction techniques. PMID- 26229794 TI - Clinical and functional evaluation of forefoot reconstruction in patients with rheumatoid arthritis. AB - OBJECTIVE: to evaluate the long-term results from reconstruction of the forefoot in patients with rheumatoid arthritis who underwent arthrodesis of the metatarsophalangeal joint of the hallux, resection arthroplasty of the heads of the lateral metatarsals and correction of the deformities of the smaller toes through arthrodesis of the proximal interphalangeal joint or closed manipulation. METHODS: seventeen patients (27 feet) who underwent forefoot reconstruction surgery by means of arthrodesis of the first metatarsophalangeal joint, resection of the heads of the lateral metatarsals and correction of the deformities of the smaller toes, were studied retrospectively. The mean follow-up was 68 months (12 148 months); the mean age was 52 years (range: 20-75 months); and four patients were male and 13 were female. RESULTS: the results were classified as excellent in 17 feet, good in two, fair in four and poor in two. The mean score on the AOFAS scale was 70 points; 21 feet (78%) were found to be asymptomatic; and six feet (22%) presented some type of symptom. Three feet presented pseudarthrosis, and one of these successfully underwent revision of the arthrodesis. There was no significant difference in scoring on the AOFAS scale or in the consolidation rate, between using a plate and screws and using Kirschner wires for fixation of the arthrodesis. CONCLUSION: arthrodesis of the first metatarsophalangeal joint with resection arthroplasty on the heads of the lateral metatarsals and correction of the deformities of the smaller toes, which was used in forefoot reconstruction in rheumatoid patients, showed good long-term results with a high satisfaction rate among the patients and clinical-functional improvement. PMID- 26229795 TI - Do computed tomography and its 3D reconstruction increase the reproducibility of classifications of fractures of the proximal extremity of the humerus? AB - OBJECTIVE: to determine whether 3D reconstruction images from computed tomography (CT) increase the inter and intraobserver agreement of the Neer and Arbeitsgemeinschaft fur Osteosynthesefragen (AO) classification systems. METHODS: radiographic images and tomographic images with 3D reconstruction were obtained in three shoulder positions and were analyzed on two occasions by four independent observers. RESULTS: the radiographic evaluation demonstrated that using CT improved the inter and intraobserver agreement of the Neer classification. This was not seen with the AO classification, in which CT was only shown to increase the interobserver agreement. CONCLUSION: use of 3D CT allows better evaluation of fractures with regard to their component parts and their displacements, but nevertheless the intraobserver agreement presented is less than ideal. PMID- 26229796 TI - Functional evaluation of arthroscopic repair of rotator cuff injuries in patients with pseudoparalysis. AB - OBJECTIVE: to evaluate the functional result from arthroscopic repair of rotator cuff injuries in patients with pseudoparalysis, defined as incapacity to actively raise the arm above 90 degrees , while complete passive elevation was possible. METHODS: we reevaluated 38 patients with a mean follow-up of 51 months (minimum of 24). We analyzed the pseudoparalysis reversion rate and the functional result obtained. RESULTS: according to the assessment criteria of the University of California in Los Angeles (UCLA), 31 (82%) patients had good and excellent results, two (5%) had fair results and five (13%) had poor results. The mean active elevation went from 39 degrees before the operation to 139 degrees after the operation (p < 0.05); the mean active lateral rotation went from 30 degrees to 48 degrees (p < 0.05) and the mean active medial rotation went from level L3 to T12 (p < 0.05). CONCLUSION: arthroscopic repair of rotator cuff injuries produced good and excellent results in 82% of the cases and a statistically significant improvement of active range of motion, with reversion of the pseudoparalysis in 97.4% of the cases. It is therefore a good treatment option. PMID- 26229797 TI - Fasciocutaneous flaps for covering foot and ankle injuries. AB - OBJECTIVE: to present some cases from our service and to confirm that sural and lateral supramalleolar flaps are good options for covering the soft tissues of the foot and ankle. METHODS: twenty-two flaps were constructed in 21 patients of ages ranging from 15 to 72 years. Male patients predominated (66.6%) and in 47.6% of the cases the injury resulted from accidents involving motorcycles. RESULTS: among the 22 flaps, 12 were sural and 10 were lateral supramalleolar; in one case, two flaps were used. In all the cases, the injuries were successfully covered and the patients recovered well. During the postoperative follow-up, the commonest complication was epidermolysis, occurring in eight cases (three in a sural flap and five in a supramalleolar flap), among which two cases progressed to distal necrosis of the flap (one sural and the other supramalleolar). One patient wanted the flap reviewed for esthetic reasons. CONCLUSIONS: sural and supramalleolar flaps are very reliable. They preserve the main trunk arteries, are quickly dissected, have low hospital cost, enable coverage of extensive areas, present esthetically acceptable damage to the donor area and do not impair motor function. PMID- 26229798 TI - Evaluation of spinopelvic balance among patients undergoing surgical treatment for lumbar disk hernia. AB - OBJECTIVE: to evaluate spinopelvic balance using the pelvic incidence, sacral slope and pelvic tilt among patients with lumbar disk hernias who underwent surgical treatment. METHODS: thirty patients at the spinal services of Hospital Santa Casa de Misericordia de Vitoria and Hospital Vila Velha were evaluated by measuring their spinopelvic balance from the angles of pelvic tilt, sacral slope and pelvic incidence, with their respective means, on simple lateral-view lumbopelvic radiographs that needed to encompass the lumbar spine, sacrum and proximal third of the femur. RESULTS: the spinopelvic balance measurements obtained from the mean angles of the population studied, for pelvic incidence, sacral slope and pelvic tilt, were 45 degrees , 36.9 degrees and 8.1 degrees , respectively. The confidence interval for the mean pelvic incidence was from 41.9 to 48.1 (95% CI), thus including a reference value that characterized it as low, for an asymptomatic population, thus confirming that the sample was extracted from a population with this characteristic. CONCLUSION: among these patients with lumbar disk hernias who underwent surgical treatment, the average spinopelvic balance was found to have pelvic incidence lower than what has been reported in the literature for an asymptomatic population. PMID- 26229799 TI - Quality-of-life assessment among patients undergoing total knee arthroplasty in Manaus. AB - OBJECTIVE: this study had the aim of assessing the quality of life among patients undergoing total knee arthroplasty (TKA). For this, the SF-36 and WOMAC questionnaires respectively were used to make comparisons with preoperative values. METHODS: a prospective observational cohort study was conducted, with blinded analysis on the results from 107 TKAs in 99 patients, between June 2010 and October 2011. The present study included 55 knees/patients, among whom 73% were female and 27% were male. The patients' mean age was 68 years. The SF-36 and WOMAC questionnaires (which have been validated for the Portuguese language) were applied immediately before and six months after the surgical procedure. RESULTS: the statistical and graphical analyses indicated that the variables presented normal distribution. From the data, it was seen that all the indices underwent positive changes after the surgery. CONCLUSIONS: despite the initial morbidity, TKA is a very successful form of treatment for severe osteoarthritis of the knee (i.e. more than two joint compartments affected and/or Ahlback classification greater than 3), from a functional point of view, with improvement of the patients' quality of life, as confirmed in the present study. This study presented evidence level IV (description of case series), with analysis on the results, without a comparative study. PMID- 26229800 TI - Fixation of an osteochondral fragment after acute patellar dislocation in an immature skeleton. AB - Fixation of an osteochondral fracture after acute patellar dislocation is an infrequent form of treatment. Likewise, the location of this fragment in the lateral region of the lateral femoral condyle, functioning as a free body, is uncommon. The aim of this study was to present a case of osteochondral fracture of the patella at an unusual site, along with the therapy used and the clinical follow-up. PMID- 26229802 TI - There is no consensus that overcomes common sense. PMID- 26229801 TI - Patellar osteochondroma: case report. AB - The aim was to report on a rare case of patellar osteochondroma. A 60-year-old man presented a tumor on his left patella that had developed over a 10-year period, which is a rare occurrence, considering the patient's age and the site at which the tumor appeared. The clinical condition comprised mild pain and the presence of a mass, without limitation of flexion-extension or any neurovascular deficit. The tumor dimensions were 8 cm longitudinally * 6 cm transversally * 3 cm anteroposteriorly. It was hardened and was adhering to the patellar bone plane. On radiographs and tomographic scans, we observed areas of greater density corresponding to bone and other less dense areas that could correspond to slow growing cartilage, with irregularities on the patellofemoral joint surface. Simple resection of the tumor was performed, and the anatomopathological examination confirmed that it was a patellar osteochondroma. Osteochondroma, or osteocartilaginous exostosis, includes a large proportion of the benign bone tumors. It results from cell alterations that trigger unregulated production of spongy bone. It is basically treated by means of surgical removal of the tumor mass. This is not essential, but is recommended in order to avoid lesions caused by contiguity and the risk of malignant transformation. PMID- 26229803 TI - Talalgia: plantar fasciitis. AB - Plantar fasciitis is a very common painful syndrome, but its exact etiology still remains obscure. The diagnosis is essentially clinical, based on history-taking and physical examination. Complementary laboratory tests and imaging examinations may be useful for differential diagnoses. The treatment is essentially conservative, with a high success rate (around 90%). The essence of the conservative treatment is the home-based program of exercises to stretch the plantar fascia. Indications for surgical treatment are only made when the symptoms persist without significant improvement, after at least six months of conservative treatment supervised directly by the doctor. PMID- 26229805 TI - Exposure of the surgical team to ionizing radiation during orthopedic surgical procedures. AB - OBJECTIVE: the aim of this study was to assess the degree of exposure of the orthopedic surgical team to fluoroscopic ionizing radiation. METHODS: the ionizing radiation to which the orthopedic surgical team (R1, R2 and R3) was exposed was assayed using thermoluminescent dosimeters that were distributed in target anatomical regions (regions with and without protection using a lead apron). This was done during 45 hip osteosynthesis procedures to treat transtrochanteric fractures that were classified as 31-A2.1 (AO). RESULTS: the radioactive dose received by R3 was 6.33 mSv, R2 4.51 mSv and R3 1.99 mSv (p = 0.33). The thyroid region received 0.86 mSv of radiation, the thoracic region 1.24 mSv and the gonadal region 2.15 mSv (p = 0.25). There was no record of radiation at the dosimeters located below the biosafety protectors or on the team members' backs. CONCLUSIONS: the members of the surgical team who were located closest to the fluoroscope received greater radiation doses than those located further away. The anatomical regions located below the waistline were the ones that received most ionizing radiation. These results emphasize the importance of using biosafety devices, since these are effective in preventing radiation from reaching the vital organs of the medical team. PMID- 26229804 TI - Randomized clinical trial on percutaneous minimally invasive osteosynthesis of fractures of the distal extremity of the radius. AB - OBJECTIVES: the purpose of this study was to compare the postoperative radiological and clinical outcomes with minimally invasive percutaneous osteosynthesis using three implants: volar locking plate, intramedullary nail system and nonbridging external fixator for distal radius fractures. METHODS: forty-eight patients (A group, 16; B group 16; C group 16) underwent minimally invasive percutaneous osteosynthesis of reductible and unstable displaced (Type IIB by Rayhack Classification) distal radius fractures. In B group intramedullary nail system was used, in A group the patients were treated with volar locking plate and in C group the patients were treated by nonbridging external fixator from January 2011 to December 2012. The mean follow-up period was 12 months. Radiologic parameters, range of motion, grip strength, and disability of the arm, shoulder, and hand score were evaluated at each examination (3rd and 6th week, and 12th months). The visual analog scale of wrist pain and complications were assessed at the final follow-up. RESULTS: the groups did not differ significantly in radiological outcomes after 12 months, but the clinical results, VAS scale and dash score in group A (volar locking plate) and B (nail intramedullary) were statistically significantly better than that of C group (nonbridging external fixator). One patient underwent an osteosynthesis with nail intramedullary and another with external fixator (C group) developed persistent pain near the site of the superficial radial nerve because of the distal's screw and pins, respectively. CONCLUSION: in clinical parameters, significant differences in outcomes were found between groups A and B after six weeks versus C group. PMID- 26229806 TI - Return to sport after surgical treatment for pubalgia among professional soccer players. AB - OBJECTIVE: to evaluate the return to sport after surgical treatment for pubalgia among 30 professional soccer players and describe the surgical technique used. METHOD: this case series was evaluated by means of a questionnaire and physical examination on 30 male professional soccer players of mean age 24.4 years (range: 18-30). The mean duration of the symptoms was 18.6 months (range: 13-28). The diagnosis was made through clinical investigation, special maneuvers and complementary examinations, by the same examiner. All the patients underwent surgical treatment after conservative treatment failed; all procedures were performed by the same surgeon using the same technique. Nonparametric comparisons were made to investigate the time taken to recover after the surgery, for the patients to return to their sport. RESULTS: five patients evolved with hematoma, with the need to remove the stitches three weeks after the operation because of a small dehiscence at the site of the operative wound. The wound healed completely in all these cases by five weeks after the surgery. Four patients presented dysuria in the first week, but improved in the second postoperative week. The mean time taken to return to training was around eight weeks (range: seven-nine). All the players returned to competitive soccer practice within 16 weeks. When asked about their degree of satisfaction after the operation (satisfied or dissatisfied), taking into consideration their return to the sport, there was 100% satisfaction, and they returned to professional practice at the same competitive level as before the injury. This degree of satisfaction continued to the last assessment, which was made after 36 months of postoperative follow-up. CONCLUSION: the surgical technique presented in this case series, with trapezoidal resection of the pubic symphysis in association with bilateral partial tenotomy of the long adductor, was a fast and effective procedure with a low rate of postoperative complications. It was shown to be an excellent treatment option for refractory cases, with a return to sports activity among professional soccer players. PMID- 26229807 TI - Correlation between the result from arthroscopic reconstruction of the anterior cruciate ligament of the knee and the return to sports activity. AB - OBJECTIVE: To evaluate the return to pre-injury sports activity in a group of patients who underwent anterior cruciate ligament (ACL) reconstruction, in relation to age, sex, body mass index (BMI) and associations with upper-limb fractures. METHODS: A group of 265 patients who underwent ACL reconstruction using an ipsilateral graft from the thigh flexor tendons, between July 2000 and November 2007, was analyzed. RESULTS: A total of 176 patients was evaluated after a mean period of 34.95 +/- 18.8 months (median: 31 months) (interquartile range: 20-48 months). The minimum evaluation period was 12 months and the maximum was 87 months. The number of patients who returned to their sports activity prior to tearing the ACL was 121/176 (68.8%). Patients under 30 years of age more frequently returned to sports activity and this was considered significant: p = 0.016; odds ratio, OR = 0.44 (95% confidence interval, CI: 0.22-0.86). Returning to previous sports activity more frequently was not considered significant for male sex (p = 0.273), individuals with BMI < 25 (p = 0.280) or patients with an ACL injury unrelated to an initial traumatic episode with upper-limb fracturing (p = 0.353). CONCLUSIONS: The rate of return to the sports activity prior to ACL injury was 68.8%. It was found that patients under the age of 30 years had a significantly greater rate of return to sports activity after the surgery. In relation to sex, BMI and association with an initial traumatic episode of upper limb fracturing, there was no statistical difference in the return to sports activity. PMID- 26229808 TI - Use of a trabecular metal cone made of tantalum, to treat bone defects during revision knee arthroplasty. AB - OBJECTIVES: the aim of this study was to evaluate the surgical technique and determine the initial results, with a minimum follow-up of two years, from total knee arthroplasty revisions in which trabecular metal cones made of tantalum were used at the Knee Surgery Center of the National Institute of Traumatology and Orthopedics (INTO) or at the authors' private clinic between July 2008 and December 2010. METHODS: ten patients were included in the study prospectively, through clinical and radiographic evaluations. RESULTS: seven patients presented evolution without complications relating to the tantalum cones used. Five of these patients said that they did not have any pain and all of them were able to walk without needing crutches. In all the cases, we observed that osseointegration of the tantalum cones had occurred. No migration or loosening of the implants was observed, nor was osteolysis. CONCLUSION: use of trabecular metal cones made of tantalum for treating AORI type II or II bone defects was capable of providing efficient structural support to the prosthetic revision implants, in evaluations with a short follow-up. PMID- 26229809 TI - Reconstruction of the anterior cruciate ligament in skeletally immature patients: an individualized approach. AB - OBJECTIVE: to evaluate a series of skeletally immature patients who underwent three surgical techniques for anterior cruciate ligament (ACL) reconstruction according to each patient's growth potential. METHODS: a series of 23 skeletally immature patients who underwent ACL reconstruction surgery at ages ranging from 7 to 15 years was evaluated prospectively. The surgical technique was individualized according to the Tanner sexual maturity score. The surgical techniques used were transphyseal reconstruction, partial transphyseal reconstruction and extraphyseal reconstruction. Four patients underwent the extraphyseal technique, seven the partial transphyseal technique and twelve the full transphyseal technique, on the ACL. The postoperative evaluation was based on the Lysholm score, clinical analysis on the knee and the presence of angular deformity or dysmetria of the lower limb. RESULTS: the mean Lysholm score was 96.34 (+/-2.53). None of the patients presented differences in length and/or clinical or radiographic misalignment abnormality of the lower limbs. CONCLUSION: ACL reconstruction using flexor tendon grafts in skeletally immature patients provided satisfactory functional results. Use of individualized surgical techniques according to growth potential did not give rise to physeal lesions capable of causing length discrepancies or misalignments of the lower limbs, even in patients with high growth potential. PMID- 26229810 TI - Evaluation of the results from proximal fixation of uncemented conical femoral components in Dorr type C femurs. AB - OBJECTIVE: To evaluate the results from proximal fixation of uncemented conical femoral components in patients with a type C proximal femur and compare them with the results obtained from type A and B femurs. METHODS: This was a retrospective study on 87 patients with 90 uncemented total hip arthroplasty procedures. Three patients (three hips) were excluded because their follow-up lasted for less than two years. The follow-up ranged from 2 to 4.3 years and the mean was 2.8 years. The Bicontact femoral implant model was used. The preoperative radiographs were evaluated, the femurs were classified as Dorr types A, B or C and the cortical indices were measured. The patients were evaluated clinically by means of the Harris Hip Score (HHS), before the surgery and at the last follow-up. The sequences of postoperative radiographs were compared regarding stability, complications and any signs of osseointegration of the femoral prosthesis. RESULTS: Among the 87 hips with follow-up greater than two years, 32 femurs were type A (37%), 37 type B (42%) and 18 type C (21%). Before the operation, the mean HHS was 39.4 for types A and B and 38.8 for type C. At the last follow-up, the mean HHS was 89.8 for types A and B and 86 for type C. None of the 87 femoral components had been revised by the time of the last follow-up; all of them were considered stable. In 86 cases, the radiographs showed signs of osseointegration. CONCLUSION: There were no significant differences in the clinical results or in the fixation (and osseointegration) of conical uncemented femoral prostheses with proximal porosity, among femurs with different types of femoral morphology according to the Dorr classification. This conclusion may vary if another implant model were to be used. PMID- 26229811 TI - Association between trochanteric bursitis, osteoarthrosis and total hip arthroplasty. AB - OBJECTIVE: this was an epidemiological study on trochanteric bursitis at the time of performing total hip arthroplasty. METHODS: sixty-two sequential patients who underwent total hip arthroplasty due to osteoarthrosis, without any previous history of trochanteric bursitis, were evaluated. The bursas were collected and evaluated histologically. RESULTS: there were 35 female patients (56.5%) and 27 male patients (43.5%), with a mean age of 65 years (+/-11). Trochanteric bursitis was conformed histologically in nine patients (14.5%), of whom six were female (66.7%) and three were male (33.3%). CONCLUSIONS: 14.5% of the bursas analyzed presented inflammation at the time that the primary total hip arthroplasty due to osteoarthrosis was performed, and the majority of the cases of bursitis were detected in female patients. PMID- 26229812 TI - Evaluation of the results from surgical treatment of the terrible triad of the elbow. AB - OBJECTIVE: to evaluate the results from surgical treatment of the terrible triad of the elbow (fracture of the radial head, fracture of the coronoid process and elbow dislocation) and its complications. METHODS: between August 2002 and August 2010, 15 patients (15 elbows) with the terrible triad were treated by the Shoulder and Elbow Group of the Department of Orthopedics and Traumatology, School of Medical Sciences, Santa Casa de Sao Paulo. Nine (60%) were male and six (40%) were female; their ages ranged from 21 to 66 years, with a mean of 41 years. With the exception of one case that underwent arthroscopic surgery, all the patients underwent open surgery. The fracture of the coronoid process was fixed in 10 patients (66.7%). The fracture of the radial head was treated by means of internal osteosynthesis in 11 cases (73.3%); in three cases (20%), the radial head was resected; and in one case, only the fragment of the fracture was resected. The collateral ligaments, except for one case, were repaired whenever they were found to be injured; ten cases (66.7%) of medial collateral injury and 15 (100%) of lateral collateral injury were found. The mean length of the postoperative follow-up was 62 months, with a minimum of 12 months. The postoperative evaluation was done by means of the Bruce score. RESULTS: more than 80% of the patients recovered their functional ranges of motion but, according to the Bruce score, only 26% of the patients achieved results that were considered satisfactory. CONCLUSION: despite the unsatisfactory results, the functional ranges of motion and elbow function could be restored. PMID- 26229813 TI - Reverse arthroplasty of the shoulder for treating rotator cuff arthropathy. AB - OBJECTIVE: to present a retrospective analysis on the clinical-functional results and complications among patients with rotator cuff arthropathy (RCA) who underwent reverse arthroplasty of the shoulder. METHODS: patients with a diagnosis of RCA associated with pseudoparalysis of anterior elevation who underwent reverse arthroplasty of the shoulder with a minimum follow-up of one year were selected. RESULTS: preoperative information was gathered from our shoulder and elbow arthroplasty register, comprising age, sex, laterality, history of previous procedures, Constant's functional scores and the preoperative range of motion as described in the protocol of the American Academy of Shoulder and Elbow Surgery (ASES). After a mean follow-up of 44 months, 17 patients (94%) were satisfied with the result from the procedure. CONCLUSION: reverse arthroplasty for treating RCA in patients with pseudoparalysis of the shoulder was shown to be effective in achieving a statistically significant improvement in range of motion regarding anterior flexion and abduction. However, in this series, there was no improvement in range of motion regarding external and internal rotation. Reverse arthroplasty is a procedure that reestablishes shoulder joint function in patients who previously did not present any therapeutic possibilities. PMID- 26229815 TI - Evaluation of surgical treatments for leprosy sequelae using the Salsa and Dash scales. AB - OBJECTIVE: to compare the SALSA and risk awareness scales with the DASH scale in assessments on leprosy surgery. METHOD: before the operation and 90 days afterwards, we applied the tests to 14 patients (11 females and three males) of ages from 28 to 67 years, who were operated between November 2011 and May 2012. RESULTS: the patients were evaluated after the operation using the SALSA and DASH scales, to measure their relationships and results. CONCLUSION: despite the small sample, this study showed that there were similar relationships of results between the SALSA/risk awareness and DASH scales. PMID- 26229814 TI - Degree of thoracic kyphosis and peak torque of trunk flexors and extensors among healthy women. AB - OBJECTIVE: The aim of this study was to analyze the effects of aging on the degree of thoracic kyphosis and peak torque of the trunk flexor and extensor muscles among women without a densitometric diagnosis of osteoporosis. METHODS: Thirty women were selected to make up three groups: young women (n = 10; 24.60 +/ 2.27 years of age); adults (n = 10; 43.50 +/- 2.88); and elderly women (n = 10; 62.40 +/- 2.67). Bone mineral density (BMD), degree of thoracic kyphosis and peak torque of the trunk flexors and extensors were evaluated. Differences between the groups were evaluated using the Kruskal-Wallis ANOVA and Mann-Whitney U tests. Pearson's correlation coefficient was used to assess correlations between the variables. The significance level was taken to be 5% (p <= 0.05). RESULTS: The elderly group presented a greater degree of thoracic kyphosis (p = 0.009) and lower peak torque of the trunk flexors and extensors than the young group. The adult group presented lower peak torque of the trunk than the young group. A negative correlation was observed between age and peak torque of the trunk flexors and extensors (p <= 0.001), and a positive correlation between age and the degree of thoracic kyphosis (r = 0.58; p <= 0.001). The elderly group presented higher values for the eccentric/concentric ratio of the peak torque for flexors (p = 0.03) and extensors (p = 0.02). CONCLUSION: This study suggests that physiological aging may be associated with a greater degree of thoracic kyphosis and lower muscle strength of the trunk flexors and extensors. Moreover, the elderly women showed a relative capacity for preservation of eccentric strength. PMID- 26229816 TI - Translation and cultural adaptation of the Hip Outcome Score to the Portuguese language. AB - OBJECTIVE: to translate the Hip Outcome Score clinical evaluation questionnaire into Portuguese and culturally adapt it for Brazil. METHODS: the Hip Outcome Score questionnaire was translated into Portuguese following the methodology consisting of the steps of translation, back-translation, pretesting and final translation. RESULTS: the pretesting was applied to 30 patients with hip pain without arthrosis. In the domain relating to activities of daily living, there were no difficulties in comprehending the translated questionnaire. In presenting the final translation of the questionnaire, all the questions were understood by more than 85% of the individuals. CONCLUSION: the Hip Outcome Score questionnaire was translated and adapted to the Portuguese language and can be used in clinical evaluation on the hip. Additional studies are underway with the objective of evaluating the reproducibility and validity of the Brazilian translation. PMID- 26229817 TI - Ameloblastoma: a clinical and therapeutic analysis on six cases. AB - Ameloblastomas are odontogenic tumors that are locally invasive and slow-growing. Their etiology is still not well defined, but the forms of treatment have been widely discussed because of the possibility of tumor recurrence and postoperative complications. In this study, six patients who were diagnosed with ameloblastoma in the mandibular region and were treated in the Department of Orthopedics and Traumatology of Hospital das Clinicas, Federal University of Goias, between 1958 and 1963, were evaluated. The radiological, clinical and therapeutic characteristics were evaluated. There was no predominance regarding gender in the sample studied. The symptoms most often presented by the patients were pain and tumor formation. The radiological characteristics with greatest incidence were multilocular lesions and the treatment used for all the patients was radical surgery. There was no recurrence over the minimum follow-up period of one year and six months. PMID- 26229818 TI - Avulsion fracture of the iliac crest in a child. AB - Avulsion fractures of the apophysis of the iliac crest have rare incidence and are little known. In this article, we report the case of an 11-year-old female patient who presented this injury after indirect trauma. From careful radiographic analysis, an avulsion fracture of the iliac crest was identified. It was decided to use nonsurgical treatment comprising analgesia and load restriction. This case report emphasizes the importance of suspecting avulsion fractures in cases of low-energy trauma, and also guides the treatment, so as to prevent functional deficit and deformities. PMID- 26229819 TI - Solitary ischial osteochondroma: an unusual cause of sciatic pain: case report. AB - The aim was to report on a rare case of osteochondroma of the left ischium, which evolved with compression of the sciatic nerve, thus causing sciatic pain in the homolateral lower limb. The patient was female and presented sciatic pain that was treated clinically for one year. However, the pain evolved with increasing intensity and worsened with hip movement. This was associated with diminished motor force and paresthesia of the homolateral lower limb. Radiological investigation of the region showed a bone lesion in the external portion of the left ischium, in the path of the sciatic nerve. Tomographic reconstruction showed cortical continuity with the bone of origin, i.e., a pattern characteristic of osteochondroma. En-bloc resection of the lesion was performed using the Kocher Langerbeck route, and the anatomopathological analysis proved that it was an osteochondroma. The patient's neurological symptoms improved and, after two months of follow-up, she remained asymptomatic and without any signs of recurrence. Since osteochondroma is the commonest benign bone tumor, it should be taken into consideration in the diagnostic investigation of compressive tumor lesions that could affect the sciatic nerve. PMID- 26229820 TI - Donato D'Angelo - a pioneer. PMID- 26229821 TI - Turco's injury: diagnosis and treatment. AB - The aim of this study was to alert doctors to the existence of Turco's injury and discus the existing treatments that have been described in the worldwide literature. A bibliographic survey of Lisfranc's injury and Turco's injury covering from 1985 to 2013 was conducted in the SciELO and PubMed databases. Among the 193 articles, those relating to bone-ligament injuries of the Lisfranc joint and high-energy trauma were excluded, as were the case reports. The patients selected were professional or amateur athletes who solely presented a ligament injury to the Lisfranc joint (Turco's injury), which was diagnosed from the history, physical examination, radiographs and magnetic resonance images. Non athletic patients and those with associated bone injuries were excluded (10). According to the injury classification, the patients were treated by means of either an open or a closed procedure and then a standard rehabilitation protocol. Out of the 10 patients, five underwent conservative treatment and five underwent surgical treatment using different techniques and synthesis materials. We obtained two poor results, one satisfactory, five good and two excellent. We conclude that the correct diagnosis has a direct influence on the treatment and on the final result obtained, and that lack of knowledge of this injury is the main factor responsible for underdiagnosing Turco's injury. There is a need for randomized prospective studies comparing the types of synthesis and evolution of treated cases, in order to define the best treatment for this injury. PMID- 26229822 TI - Terrible triad of the elbow: influence of radial head treatment. AB - OBJECTIVE: to test the null hypothesis that patients with the terrible triad of the elbow (dislocation together with fractures of the radial head and coronoid process) who are treated with open reduction and internal fixation of the radial head have final results that are comparable with those of patients treated with arthroplasty or partial resection of the radial head. METHODS: twenty-six patients with the terrible triad of the elbow who were operated by a single surgeon were evaluated on average 23 months after the surgery (range: 16-36 months). There were 17 men and nine women of mean age 41 +/- 13.4 years. The fractures of the radial head were treated by means of osteosynthesis (12 patients), arthroplasty (nine) or resection of a small fragment or no treatment (five). Fixation of the coronoid process/anterior capsule was performed in 21 patients. The lateral ligament complex (LLC) was repaired in all the patients, while the medial ligament complex (MLC) was repaired in three patients whose elbows remained unstable after treatment for the radial head and LLC, but without fixation of the coronoid process. RESULTS: the mean final range of flexion and extension was 112 degrees . The mean pronation was 70 degrees and supination, 6 degrees . The mean DASH score (Disabilities of the Arm, Shoulder & Hand) was 12 and mean MEPI (Mayo Elbow Performance Index) was 87. According to the MEPI scores, 21 patients (80%) had good and excellent results. There was no statistically significant difference in the results between the patients who underwent fixation of the radial head and those who underwent arthroplasty or resection of a small fragment. CONCLUSION: there was no difference between the patients treated with arthroplasty of the radial head and those treated with other techniques. PMID- 26229823 TI - Epidemiological study on talus fractures. AB - OBJECTIVE: to analyze the characteristics of patients with talus fractures and the injuries that they present. METHODS: retrospective analysis on patients hospitalized in the Institute of Orthopedics and Traumatology, Hospital das Clinicas, School of Medicine of the University of Sao Paulo, between 2006 and 2011, with talus fractures. Patient profile parameters, risk factors, fracture characteristics, treatment data and acute complications were analyzed. RESULTS: analysis on 23 cases showed that men were more affected than women, with a ratio of 4.8:1. The most frequent trauma mechanism was traffic accidents, followed by falls from a height. The most frequent type of fracture was at the neck of the talus, with 17 cases. Among the 23 cases, seven had peritalar dislocation at the time of presentation, four had exposed fractures and 11 presented other associated fractures. The mean length of time between the trauma and the definitive treatment was six days, while the mean length of hospital stay was 11 days. Three patients presented acute postoperative complications. CONCLUSION: talus fractures occurred most commonly in the region of the talar neck and most frequently in young males who suffered high-energy trauma. In almost half of the cases, there were other associated fractures. The length of hospital stay was 11 days. PMID- 26229824 TI - Correct use of safety belts and child restraint devices in cars among children in Goiania. AB - OBJECTIVE: to conduct an observational study, by means of campaigns, regarding the use of child restraint devices in cars in Goiania. METHODS: this was a cross sectional study using a convenience sample built up as cases arose. The data were gathered into an Excel spreadsheet and were analyzed descriptively and statistically (SPSS 16.0), using chi-square and taking p < 0.05 as significant. RESULTS: in 2006, 410 cars were evaluated, and in 2010, 544 cars were evaluated. Around 85% of the occupants were using seat belts correctly at both times (p = 0.650). In 2006, it was observed that a total of 273 passengers were occupying the rear seats, while in 2010 there were 226. Among these, 178 and 170 were using seat belts, respectively, i.e. 65.2% and 75.22% (p = 0.001). In 2006, five children were occupying the front seat without using the seat belt, while in 2010, this number was 42 (p < 0.001). In 2010, it was observed that 458 vehicles were transporting children on the rear seats, and this was being done correctly in 214 vehicles, i.e. 46.72%. In 2006, of the 410 vehicles analyzed, only 90 of them (21.95%) were transporting children correctly (p < 0.001). In addition, there was a difference in the variables within the year evaluated, in which transportation done correctly in the front seat was much more frequent than transportation done correctly in the rear seats, in both years (p < 0.001). Cars transported one to four children, while vans transported one to nine children. In 2006, one van transporting children irregularly was observed, while in 2010 it was done correctly in all cases. CONCLUSION: comparing these two years (2006 and 2010) in which data were gathered, we can conclude that changes in behavior among drivers in Goiania have begun, with regard to safety when transporting children in vehicles, with an improvement of 25% (p < 0.001). A large part of this has come through changes in knowledge among this segment of the population, through campaigns that have been carried out, including through the media, and because of legal obligations. PMID- 26229825 TI - Analysis on the results from percutaneous extensor osteotomy of the distal femur in patients with amyoplasia. AB - OBJECTIVE: to review the medical files of 19 patients with a diagnosis of amyoplasia, who underwent percutaneous extensor osteotomy of the distal femur to correct deformities in whom the knees were fixed in flexion. METHODS: we analyzed 37 osteotomy procedures on 35 knees that presented an initial deformity in which the knees were fixed in flexion at 33.8 degrees . All of these knees underwent percutaneous extensor osteotomy of the distal femur and were followed up for a mean period of 73.7 months. RESULTS: we observed recurrence of the deformity in 29 osteotomy cases, i.e. in 78.4% of them. The mean recurrence velocity of the deformity was 0.69 degrees /month. CONCLUSION: percutaneous extensor osteotomy of the distal femur provided sufficient correction of deformities in which the knee was fixed in flexion in these amyoplasia cases, but there was a significant degree of recurrence among the patients analyzed. PMID- 26229826 TI - Bilateral developmental dysplasia of the hip treated with open reduction and Salter osteotomy: analysis on the radiographic results. AB - OBJECTIVES: to evaluate the radiographic results from patients with bilateral developmental dysplasia of the hip (DDH) who underwent surgical treatment by means of open reduction and Salter osteotomy, with or without associated femoral shortening as described by Ombredanne. METHODS: this was a retrospective descriptive study in which 21 patients with bilateral DDH (42 hips) were analyzed. They were treated at Hospital Infantil Joana de Gusmao (HIJG), with operations between August 1997 and October 2009. To evaluate the radiographic results, the acetabular index and the Wiberg center-edge angle were measured, and the Severin and Kalamchi-MacEwen classifications were used. Descriptive and parametric statistical analyses were used to evaluate the data. RESULTS: we did not observe any statistically significant difference in analyzing the radiographic parameters, making comparisons regarding the side affected, the order of the procedures and whether femoral shortening was performed, although there was a significant difference between them from before to after the operation. CONCLUSION: open reduction in association with iliac osteotomy as described by Salter presented significant improvements in the radiographic parameters analyzed, comparing the pre- and postoperative values. This improvement occurred independently of whether Ombredanne femoral shortening was performed. The most prevalent complication in the study group was avascular necrosis of the femoral head. PMID- 26229827 TI - Focal treatment of spasticity using botulinum toxin A in cerebral palsy cases of GMFCS level V: evaluation of adverse effects. AB - OBJECTIVE: To report on the experience of injections of botulinum toxin A (BTA) in a series of patients with cerebral palsy of Gross Motor Function Classification System (GMFCS) level V. METHODS: This was a retrospective case series study on 33 patients with cerebral palsy of GMFCS level V who received 89 sessions of BTA application (of which 84 were Botox((r)) and five were other presentations), in which the basic aim was to look for adverse effects. RESULTS: The mean number of application sessions per patient was three, and the mean age at the time of each injection was 4 + 6 years (range: 1.6-13 years). The muscles that most frequently received injections were the gastrocnemius, hamstrings, hip adductors, biceps brachii and finger flexors. The mean total dose was 193 U and the mean dose per weight was 12.5 U/kg. Only one patient received anesthesia for the injections and no sedation was used in any case. No local or systemic adverse effects were observed within the minimum follow-up of one month. CONCLUSION: The absence of adverse effects in our series was probably related to the use of low doses and absence of sedation or anesthesia. According to our data, BTA can be safely used for patients with cerebral palsy of GMFCS level V, using low doses and preferably without sedation or anesthesia. PMID- 26229828 TI - Evaluation of the fixation of the trabecular metal wedge in patients undergoing revision of total hip arthroplasty. AB - OBJECTIVE: this study aimed to evaluate the fixation of the trabecular metal wedge in patients undergoing revision of total hip arthroplasty. METHODS: twenty three cases with minimum grading of Paprosky II-B that were operated between July 2008 and February 2013 were evaluated. These cases were evaluated based on radiographs before the operation, immediately after the operation and later on after the operation. Loss of fixation was defined as a change in the abduction angle of the component greater than 10 degrees or any mobilization greater than 6 mm. RESULTS: it was found that there was 100% fixation of the acetabula after a mean of 29.5 months. One case underwent removal of the implanted components due to infection. CONCLUSIONS: there is still no consensus regarding the best option for reconstructing hips with bone loss. However, revision using a trabecular metal wedge has presented excellent short- and medium-term results. This qualifies it as an important tool for achieving a fixed and stable acetabular component. PMID- 26229829 TI - Posterior cruciate ligament reconstruction by means of tibial tunnel: anatomical study on cadavers for tunnel positioning. AB - OBJECTIVE: to determine the reference points for the exit of the tibial guidewire in relation to the posterior cortical bone of the tibia. METHODS: sixteen knees from fresh cadavers were used for this study. Using a viewing device and a guide marked out in millimeters, three guidewires were passed through the tibia at 0, 10 and 15 mm distally in relation to the posterior crest of the tibia. Dissections were performed and the region of the center of the tibial insertion of the posterior cruciate ligament (PCL) was determined in each knee. The distances between the center of the tibial insertion of the PCL and the posterior tibial border (CB) and between the center of the tibial insertion of the PCL and wires 1, 2 and 3 (CW1, CW2 and CW3) were measured. RESULTS: in the dissected knees, we found the center of the tibial insertion of the PCL at 1.09 +/- 0.06 cm from the posterior tibial border. The distances between the wires 1, 2 and 3 and the center of the tibial insertion of the PCL were respectively 1.01 +/- 0.08, 0.09 +/- 0.05 and 0.5 +/- 0.05 cm. CONCLUSION: the guidewire exit point 10 mm distal in relation to the posterior crest of the tibia was the best position for attempting to reproduce the anatomical center of the PCL. PMID- 26229830 TI - Radiographic analysis of factors predisposing toward tendon tears in the knee extensor mechanism. AB - OBJECTIVES: to review radiographs of patients who suffered tendon tears of the knee extensor apparatus and observe alterations that might be factors predisposing toward this type of injury. METHODS: we retrospectively analyzed 60 cases of injury to the knee extensor mechanism that were treated surgically at the Miguel Couto Municipal Hospital between March 2004 and March 2011. Four patients were excluded due to poor quality of the examination. RESULTS: of the 56 patients evaluated, 23 were considered to be normal and 33 presented radiographic alterations. Among these, eight (24.3%) presented suprapatellar osteophytes alone; seven (21.2%), infrapatellar calcification; seven (21.2%), suprapatellar calcification; six (18.2%), supra- and infrapatellar osteophytes; and five (15.1%), infrapatellar osteophytes alone. CONCLUSION: radiographic alterations were frequently observed in patients with extensor mechanism tears. PMID- 26229831 TI - Influence of corticoids on healing of the rotator cuff of rats - biomechanical study. AB - OBJECTIVE: to compare healing strength of the infraspinatus tendon of rats with corticoid inoculation, regarding maximum tension, maximum force and rupture force, after injury and experimental repair. METHODS: a total of 60 Wistar rats were subjected to tenotomy of the infraspinatus tendon, which was then sutured. Before the surgery, they were divided into a control group (C) inoculated with serum and a study group (S) inoculated with corticoids over the tendon. After repair, the rats were sacrificed in groups of 10 individuals in the control group and 10 in the study group at the times of one week (C1 and S1), three weeks (C3 and S3) and five weeks (C5 and S5). The rats were dissected, separating out the infraspinatus tendon with the humerus. The study specimens were subjected to a traction test, with evaluation of the maximum tension (kgf/cm(2)), maximum force (kgf) and rupture force (kgf), comparing the study group with the respective control groups. RESULTS: among the rats sacrificed one week after the procedure, we observed greater maximum tension in group C1 than in group S1. The variables of maximum force (kgf) and rupture force did not differ statistically between the groups investigated. In the same way, among the rats sacrificed three weeks after the procedure, group C3 only showed greater maximum tension than group S3 (p = 0.007), and the other variables did not present differences. Among the rats sacrificed five weeks after the procedure (C5 and S5), none of the parameters studied presented statistical differences. CONCLUSION: we concluded that corticoid diminished the resistance to maximum tension in the groups sacrificed one and three weeks after the procedure, in comparison with the respective control groups. The other parameters did not show differences between the study and control groups. PMID- 26229832 TI - Prevalence of microbiological markers in bone tissue from live and cadaver donors in the musculoskeletal tissue bank of Passo Fundo. AB - OBJECTIVE: To conduct an epidemiological analysis on the main microbiological markers in bone tissue that was processed at the musculoskeletal tissue bank of Hospital Sao Vicente de Paulo, in Passo Fundo, between August 2007 and October 2011. METHODS: Between August 2007 and October 2011, 202 musculoskeletal tissue samples were collected for the tissue bank. Among these, 159 samples were from living donor patients and 43 were from cadaver donors. The following serological tests were requested: hepatitis B, hepatitis C, syphilis, cytomegalovirus, Chagas disease, toxoplasmosis, HIV and HTLV. RESULTS: Among the 159 living donors, 103 (64.75%) were men and 56 (35.25%) were women. The patients' mean age was 59.35 +/ 8.87 years. Out of this total, 76 tissue samples (47.8%) from donors were rejected. There was no difference in the number of rejections in relation to sex (p = 0.135) or age (p = 0.523). The main cause of rejection was serologically positive findings for the hepatitis B virus, which was responsible for 48 rejections (63.15%). Among the 43 cadaver donors, the mean age was 37.84 +/- 10.32 years. Of these, 27 (62.8%) were men and 16 (37.2%) were women. Six of the samples collected from cadaver donors were rejected (13.9%), and the main cause of rejection was serologically positive findings for the hepatitis C virus, which was responsible for three cases (50%). There was no significant difference in the number of rejections in relation to sex (p = 0.21) or age (p = 0.252). CONCLUSION: There were a greater number of rejections of tissues from living donors (47.8%) than from cadaver donors (13.9%). Among the living donors, the main cause of rejection was the presence of serologically positive findings of the hepatitis B virus, while among the cadaver donors, it was due to the hepatitis C virus. PMID- 26229833 TI - Transport accidents among children and adolescents at the emergency service of a teaching hospital in the southern zone of the city of Sao Paulo. AB - OBJECTIVE: to describe the victim profile and circumstances of transport accidents involving children and adolescents who were attended at a teaching hospital in the southern zone of the city of Sao Paulo. METHODS: this was an individual observational case series study among patients up to the age of 19 years who were attended at a hospital in the southern zone of the city of Sao Paulo, state of Sao Paulo, Brazil, due to traffic accidents. The files notifying suspected or confirmed cases of violence and accidents (SIVVA files) covering January to December 2012 were analyzed. RESULTS: among the 149 cases notified, 64.4% related to males and 35.6% to females. The transport accidents were predominantly among males, irrespective of age. The main injury diagnoses were superficial head trauma (24.8%) followed by multiple non-specified trauma (36.4%), in both sexes. CONCLUSION: transport accidents among children and adolescents occurred more often among males. The main transport accidents among the children and adolescents attended as emergency cases were caused by motor vehicles and motorcycles. Among the accident victims, the largest proportion was attended because of being run over. PMID- 26229835 TI - Garre's sclerosing osteomyelitis: case report. AB - The aim of this study was to report on a rare case of Garre's sclerosing osteomyelitis. The patient was a 54-year-old woman with a history of treatment for lupus using corticoids for 20 years, and for osteoporosis using alendronate for five years. She presented edema and developed a limitation of left knee movement one year earlier, with mild effusion and pain on metaphyseal palpation, but without fever. She was in a good general state, without local secretion. Images of her knee showed trabecular osteolysis of the distal metaphysis of the femur and a periosteal reaction in both proximal tibias and both distal femurs, compatible with chronic osteomyelitis of low virulence and slow progression. Magnetic resonance imaging showed T2 hypersignal in the femur and tibia. Curettage was performed on the left distal femur, with release of secretion, but this was negative on culturing. A biopsy showed chronic infection and inflammation, fibrosis, xanthogranulomatous reaction and foci of suppuration. Antibiotic therapy was administered for six months. The etiology was not clarified: bacterial infection was suspected, but culturing was generally negative. The chronic process was maintained by low-virulence infection or even after treatment. The differential diagnoses were fibrous dysplasia, syphilis, pustulosis palmoplantaris, rectocolitis, Crohn's disease, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) and Paget's disease. The unifocal diseases were osteoid osteoma, Ewing's disease, osteosarcoma and eosinophilic granuloma. PMID- 26229834 TI - Surgical results from treating children with syndactyly through the collective effort system at "SOS Hand Recife" between 2005 and 2009. AB - OBJECTIVE: to evaluate the results from and parents' satisfaction with treatment for children with syndactyly who were operated at the "SOS Hand Recife" hospital between 2005 and 2009. METHODS: data for assessing the results were gathered from the patients' medical files. The subjective scores, which were ascertained prospectively, were as follows: greater than or equal to 9, good result; between 6 and 8, fair result; less than 6, poor result. The results were analyzed statistically. This study was approved by the institution's ethics committee. RESULTS: among the 35 cases, 21 (60%) consisted of simple syndactyly and 14 (40%) were complex; 22 (62.8%) were boys and 13 (37.1%) were girls. The complex cases were predominantly among males. The main complications were infection (11.4%), bleeding (11.4%) and pain (8.6%). There were more complications in the complex cases (42.8%) than in the simple cases (33.3%). The mean scores from the parents' subjective evaluations were as follows: 7.6 for esthetics (7.7 in simple cases and 7.3 in complex cases; 8.2 for function (8.6 in simple cases and 7.6 in complex cases); 8.3 for the parents' general satisfaction level (8.6 in simple cases and 8.0 in complex cases); and 85.7% of the parents would recommend the surgery to others while 14.5% would not. A strong association was observed between the specialist's objective assessment and the scores given by the parents (p < 0.05). CONCLUSION: the surgical results from treating syndactyly presented differences between the simple and complex types, even though the parents' esthetic evaluations and satisfaction were similar. PMID- 26229836 TI - Lumbar stenosis: clinical case. AB - Lumbar stenosis is an increasingly common pathological condition that is becoming more frequent with increasing mean life expectancy, with high costs for society. It has many causes, among which degenerative, neoplastic and traumatic causes stand out. Most of the patients respond well to conservative therapy. Surgical treatment is reserved for patients who present symptoms after implementation of conservative measures. Here, a case of severe stenosis of the lumbar spine at several levels, in a female patient with pathological and surgical antecedents in the lumbar spine, is presented. The patient underwent two different decompression techniques within the same operation. PMID- 26229837 TI - Calcaneal chondrosarcoma: a case report. AB - The objective was to report on a rare case of chondrosarcoma of the bones of the foot, and specifically the calcaneus. The patient was a 30-year-old woman with a complaint of painless nodulation on the lateral face of the calcaneus, which she had had for around eight years, which then started to present significant pain. Radiography showed a tumor with imprecise limits, compromising the calcaneus, talus and lateral malleolus. The lesion had a destructive, aggressive and osteolytic appearance, with invasion of the surrounding soft tissues and the presence of points of calcification. Amputation was performed in the middle third of the right lower leg, with a histological diagnosis of chondrosarcoma. The case evolved with local recurrence of the tumor formation and subsequent amputation in the middle third of the right thigh. One year after the second amputation, the patient evolved with metastasis from the chondrosarcoma in soft tissues throughout the body and in the lungs, and she died one year and ten months after the diagnosis was made. Chondrosarcomas that involve the calcaneus are rare in young adults, with few reports in the literature. For this reason, the present report becomes important in that it shows that even though this is a rare condition, it is present in our environment. Early investigation is essential, especially by means of imaging examinations, with the aim of diminishing the chances of malignant transformation and consequent complications, so as to avoid death. PMID- 26229838 TI - Surgical features of Trevor's disease of the patella. AB - The aim of this study was to describe surgical features of resection of hemimelic epiphyseal dysplasia of the patella. We already described the clinical and imaging features in another article. The patient was a six-year-old boy with a tumor in his right knee measuring 12 cm longitudinally and 6 cm transversally, which was adhering to the patella and had been slowly growing for two years. Biopsy findings were suggestive of a benign osteochondromatous lesion, without a defined diagnosis. Imaging examinations such as radiography and tomography showed areas of bone formation and radiotransparent areas, while magnetic resonance imaging showed areas of hypo and hypersignal in T1 and T2, of estimated size 8.5 cm longitudinally and 6 cm transversally. The tumor growth was surgically resected and curettage was performed on the epiphyseal nucleus of ossification of the upper and medial centers of the patella, with good patellar remodeling and normal development. The patient did not present any recurrence of the lesion up to the time of reaching skeletal maturity. PMID- 26229840 TI - Continuing medical education, a nice problem. PMID- 26229839 TI - Concept of healing of recurrent shoulder dislocation. AB - This paper presents the main surgical techniques applied in the treatment of anterior recurrent shoulder dislocation, aiming the achievement of the normality of articulate movements. This was obtained by combining distinct surgical procedures, which allowed the recovery of a complete functional capacity of the shoulder, without jeopardizing the normality of movement, something that has not been recorded in the case of the tense sutures of the surgical procedures of Putti-Platt, Bankart, Latarjet, Dickson-O'Dell and others. The careful review of the methods applied supports the conclusion that recurrent shoulder dislocation can be cured, since cure has been obtained in 97% of the treated cases. However, some degree of limitation in the shoulder movement has been observed in most of the treated cases. Our main goal was to achieve a complete shoulder functional recovery, by treating simultaneously all of the anatomical-pathological lesions, without considering the so-called essential lesions. The period of post-operatory immobilization only last for the healing of soft parts; this takes place in a position of neutral shoulder rotation, since the use of vascular bone graft eliminates the need for long time immobilization, due to the shoulder stabilization provided by rigid fixation of the coracoid at the glenoid edge, as in the Latarjet's technique. Our procedure, used since 1959, comprises the association of several techniques, which has permitted shoulder healing without movement limitation. That was because of the tension reduction in the sutures of the subescapularis, capsule, and coracobraquialis muscles. PMID- 26229841 TI - Carpal tunnel syndrome - Part I (anatomy, physiology, etiology and diagnosis). AB - Carpal tunnel syndrome (CTS) is defined by compression of the median nerve in the wrist. It is the commonest of the compressive syndromes and its most frequent cause is idiopathic. Even though spontaneous regression is possible, the general rule is that the symptoms will worsen. The diagnosis is primarily clinical, from the symptoms and provocative tests. Electroneuromyographic examination may be recommended before the operation or in cases of occupational illnesses. PMID- 26229843 TI - Comparative study between physical examination, electroneuromyography and ultrasonography in diagnosing carpal tunnel syndrome. AB - OBJECTIVE: To evaluate the sensitivity of electromyography and ultrasonography in diagnosing carpal tunnel syndrome (CTS), in comparison with physical examination, which is considered to be the gold standard. METHODS: In this cross-sectional study, the medical files of 56 patients with 70 hands affected by CTS who were attended between March 2010 and June 2012 were reviewed. The study included patients with a clinical diagnosis of CTS. The sensitivity of the complementary examinations was analyzed and compared with physical examination. RESULTS: Nocturnal symptoms were found in 96.4%, thenar atrophy in 62.5% and abnormal sense of touch in 50%. The sensitivities found were: ultrasonography, 67.1% (95% CI: 55.7%-78.6%); an association of physical examination tests, 95.7% (95% CI: 90.0%-100%); and electromyography, 98.6% (95% CI: 95.7%-100%). The presence of atrophy, abnormalities of the sense of touch and longer-duration symptoms increased the sensitivity of ultrasonography and physical examination. CONCLUSION: The sensitivity of ultrasonography for CTS was lower than that of electromyography and physical examination. PMID- 26229842 TI - Carpal tunnel syndrome - Part II (treatment). AB - The treatments for non-deficit forms of carpal tunnel syndrome (CTS) are corticoid infiltration and/or a nighttime immobilization brace. Surgical treatment, which includes sectioning the retinaculum of the flexors (retinaculotomy), is indicated in cases of resistance to conservative treatment in deficit forms or, more frequently, in acute forms. In minimally invasive techniques (endoscopy and mini-open), and even though the learning curve is longer, it seems that functional recovery occurs earlier than in the classical surgery, but with identical long-term results. The choice depends on the surgeon, patient, severity, etiology and availability of material. The results are satisfactory in close to 90% of the cases. Recovery of strength requires four to six months after regression of the pain of pillar pain type. This surgery has the reputation of being benign and has a complication rate of 0.2-0.5%. PMID- 26229844 TI - Use of adrenalin with lidocaine in hand surgery. AB - OBJECTIVE: Because of the received wisdom within our setting that claims that local anesthesia should not be used with adrenalin in hand surgery; we conducted a study using lidocaine with adrenalin, to demonstrate its safety, utility and efficacy. METHODS: We conducted a prospective study in which, in wrist, hand and finger surgery performed from July 2012 onwards, we used local anesthesia comprising a 1% lidocaine solution with adrenalin at 1:100,000. We evaluated the quantity of bleeding, systemic alterations, signs of arterial deficit and complications, among other parameters. We described the infiltration techniques for specific procedures individually. RESULTS: We operated on 41 patients and chose to describe separately the raising of a lateral microsurgical flap on the arm, which was done without excessive bleeding and within the usual length of time. In only three cases was there excessive bleeding or use of bipolar tweezers. No systemic alterations were observed by the anesthesiologists or any complications relating to ischemia and necrosis in the wounds or in the fingers, and use of tourniquets was not necessary in any case. CONCLUSIONS: Use of lidocaine with adrenalin in hand surgery was shown to be a safe local anesthetic technique, without complications relating to necrosis. It provided efficient exsanguination of the surgical field and made it possible to perform the surgical procedures without using a pneumatic tourniquet, thereby avoiding its risks and benefiting the patient through lower sedation. PMID- 26229845 TI - Body mass index as a prognostic factor for fracturing of the proximal extremity of the femur: a case-control study. AB - OBJECTIVES: To compare the body mass index (BMI) of patients with fractures in the proximal extremity of the femur with the BMI of patients without any previous history of fractures. METHODS: We investigated patients of both sexes, aged 65 years or over, who were admitted to Hospital Independencia, Hospital Beneficencia Portuguesa or ULBRA University Hospital, between December 2007 and December 2010, with histories of low-energy trauma such as falling from a standing position. These individuals were compared with patients of the same age but without any history of fracturing of the proximal extremity of the femur (n = 89), who were attended at the geriatrics outpatient clinic of the Sociedade Porto-Alegrense de Auxilio aos Necessitados (SPAAN). RESULTS: The age group of the patients with fractures in the proximal extremity of the femur ranged from 65 to 96 years (mean: 77.58). The main type of fracture was trochanteric (47; 62.2%), followed by femoral neck fractures (27; 36%). Among the patients who presented on fracturing the proximal extremity of the femur, 12% had low weight, 62.7% normal weight, 24% overweight, and 1.3% obesity. Among the patients without any history of fractures, 5.6% presented low weight, 43.8% normal weight, 33.7% overweight, and 9.8% obesity. It was observed that the patients with fractures in the proximal extremity of the femur (n = 75) presented a mean BMI of 22.6, while the patients without fractures presented a mean BMI of 25.5. CONCLUSION: The patients in the group with fractures were significantly taller than those in the group without fractures and presented significantly lower BMI than those in the group without fractures. PMID- 26229846 TI - Densitometric study of the clavicle: bone mineral density explains the laterality of the fractures. AB - INTRODUCTION: Epidemiological studies have shown laterality in clavicle fractures, such that the left side is more frequently fractured. The present study had the aim of evaluating whether the clavicle on the dominant side is denser and thus explaining the greater incidence of fractures on the non-dominant side. MATERIALS AND METHODS: This was a descriptive study on 52 healthy patients, who were classified according to age, sex and whether the dominant or non dominant side was affected. RESULTS: The participants comprised 28 women (53.8%) and 24 men (46.2%). Regarding the dominant side, 30 were right-handed (57.7%) and 22 were left-handed (42.3%). The mean age was 25 years. In this study, it could be seen that the non-dominant side had greater bone mass than the dominant side. It was also observed that the bone density was greater in the middle and distal thirds on the non-dominant side, with a statistically significant difference. In the women, the density was also greater on the non-dominant side; this difference was not significant in relation to the dominant side, but there were significant differences between the middle thirds (p < 0.001) and the distal thirds (p < 0.006). CONCLUSION: Variations in bone density, toward higher and lower bone mass, may have been responsible for the fractures. According to the findings from this study, fractures occur more in the middle third of the non-dominant clavicle, as a result of greater bone mineral mass, which gives rise to lower flexibility and fractures in the region. PMID- 26229848 TI - Evaluation of the quality of life after vertebroplasty to treat compressive osteoporotic fractures. AB - OBJECTIVE: with increasing life expectancy around the world, fractures due to osteoporosis have become more common and the expenditure for treating them has also increased. The aim here was to evaluate the improvement in pain and quality of life among patients with compressive osteoporotic vertebral fractures undergoing vertebroplasty. METHODS: eighteen patients with 27 fractured vertebrae underwent vertebroplasty and were evaluated using the Oswestry 2.0 limitations questionnaire before the operation and 24 h and six months after the operation. RESULTS: there was a 75% improvement in pain and quality of life, going from a mean preoperative Oswestry of 40% to 10% 24 h after the operation and 9% six months after the operation (p <= 0.05). CONCLUSION: vertebroplasty is effective in managing compressive osteoporotic vertebral fractures, with improvement in pain and quality of life in the immediate postoperative period and over the medium term. PMID- 26229847 TI - Do patients lose weight after total hip arthroplasty? AB - OBJECTIVE: To investigate the effect of total hip arthroplasty (THA) on body mass index (BMI), from before to after the operation. METHODS: 100 patients who underwent THA were retrospectively analyzed. They were stratified according to BMI, as proposed by the World Health Organization (WHO). RESULTS: There were 48 male patients and 52 female patients. Their mean age was 63.8 +/- 13.5 years. The mean follow-up was 24.6 +/- 0.6 months. The men had a mean preoperative BMI of 28.4 +/- 3.6 kg/m(2) and the women, 27.5 +/- 5.0 kg/m(2). The mean postoperative BMI was 28.9 +/- 0.7 kg/m(2) for the men and 27.8 +/- 0.7 kg/m(2) for the women. There was a general mean increase in BMI of 0.4 kg/m(2). The BMI increased both in patients with normal weight and in those who were overweight, but it decreased slightly in patients who were obese. BMI remained unchanged in the majority of the patients (73%). CONCLUSION: The improvement in mobility achieved through THA did not promote any reduction in anthropometric measurements in the majority of the patients. PMID- 26229849 TI - Prevention of lower-limb lesions and reduction of morbidity in diabetic patients. AB - OBJECTIVE: To assess the impact of a diabetic foot outpatient clinic on reducing the morbidity of this disease, with emphasis on lower-limb lesions. METHODS: This was a prospective observational study with a target population of 30 cases out of a total of 77 patients in the diabetic foot outpatient clinic. The inclusion criterion was that data relating to laboratory tests, clinical examinations, neuropathic and vascular tests and the elbow-arm index needed to be available from all the patients, with repetition after 18 months of follow-up, so as to analyze their evolution. The statistical analysis was done using the McNemar chi square test for dependent samples. RESULTS: The patients' mean age was 61 years. All of them had type 2 diabetes mellitus (DM), which had started 14.5 years previously, on average, and 20% had neuropathies. After 18 months, there was no change in the frequency of lesions in diabetes target organs (p = 1.000) or in the neuropathy rate (p = 1.000). However, there were significant improvements in neuropathic symptoms, from 70% to 36.7% (p = 0.035), and in peripheral arterial disease, from 73.3% to 46.7% (p = 0.021). There was also a decrease in ulcers from 13.3% to 10% (p = 1.000). CONCLUSIONS: Creation of specialized outpatient clinics for prevention of diabetic foot is a viable investment, which has low cost compared with the high costs generated through the complications from this disease. This approach noticeably improves the patients' quality of life, with reduction of morbidity. PMID- 26229850 TI - Comparison of the results from simple radiography, from before to after Salter osteotomy, in patients with Legg-Calve-Perthes disease. AB - OBJECTIVES: To determine whether the clinical variables and preoperative classification of patients with Legg-Calve-Perthes disease (LCPD) who undergo Salter osteotomy correlate with the radiographic result at the time of skeletal maturity. METHODS: In this retrospective cohort study, 47 individuals with LCPD who were treated using Salter osteotomy (1984-2004) were evaluated. The patients were evaluated according to sex, skin color, side affected and age at which osteotomy was performed. The preoperative radiographs were analyzed in accordance with the classifications of Waldenstrom, Catterall, Laredo and Herring. The radiographs obtained at the time of skeletal maturity were classified using the Stulberg method. RESULTS: The mean age at the time of surgical treatment was 82.87 months (6.9 years). The age presented a statistically significant correlation with the Stulberg grades at skeletal maturity (p < 0.001). Patients over the age of 6.12 years tended to present less favorable results. The variables of sex, skin color and side affected did not present any statistically significant correlation with the prognosis (p = 0.425; p = 0.467; p = 0.551, respectively). Only the Laredo classification presented a statistically significant correlation with the final result given by the Stulberg classification (p = 0.001). The other classifications used (Waldenstrom, Catterall and Herring) did not present any correlation between the time at which surgery was indicated and the postoperative result. CONCLUSIONS: The age at which the patients underwent surgical treatment and the Laredo classification groups were the only variables that presented significant correlations with the Stulberg classification. PMID- 26229851 TI - Anatomical study of the posterior cruciate ligament with the knee flexed at 90 degrees . AB - OBJECTIVE: To study the anatomy of the posterior cruciate ligament (PCL) and define anatomical parameters with the knee flexed at 90 degrees . METHODS: Eight knees from cadavers were dissected in order to make measurements from the center of the anterolateral band to the roof (AL1), from the center of the anterolateral band to the anterior cartilage (AL2), from the center of the posteromedial band to the roof (PM1), from the center of the posteromedial band to the anterior cartilage (PM2), from the center of the tibial insertion to the medial region of the tibia (TIM), from the center of the tibial insertion to the lateral region of the tibia (TIL), from the center of the medial insertion to the medial meniscus (IMM) and the width of the origin of the PCL (WO). To obtain the results from each anatomical structure, the means and standard deviations of the measurements were calculated. RESULTS: The measurements in millimeters that were found were AL1, 6.2; AL2, 4.9; PM1, 11.7; PM2, 5.5; TIM, 32.5; TIL, 40.6; IMM, 9.4; and WO, 32.5. CONCLUSIONS: The PCL has an extensive origin. The center of the anterolateral band is 6 mm from the roof and 5 mm from the anterior cartilage of the knee. The tibial insertion is slightly medial and 10 mm distal to the posterior cornu of the medial meniscus. PMID- 26229852 TI - Reconstruction of the medial patellofemoral ligament in cases of acute traumatic dislocation of the patella: current perspectives and trends in Brazil. AB - OBJECTIVE: To evaluate the approaches and procedures used by knee surgeons in Brazil for treating medial patellofemoral lesions (MPFL) of the knee in cases of acute traumatic dislocation of the patella. MATERIALS AND METHODS: A questionnaire comprising 15 closed questions on topics relating to treating MPFL of the knee following acute dislocation of the patella was used. It was applied to Brazilian knee surgeons during the three days of the 44th Brazilian Congress of Orthopedics and Traumatology, in 2012. RESULTS: 106 knee surgeons completely filled out the questionnaire and formed part of the sample analyzed. Most of them were from the southeastern region of Brazil. The majority (57%) reported that they perform fewer than five MPFL reconstruction procedures per year. Indication of non-surgical treatment after a first episode of acute dislocation of the patella was preferred and done by 93.4% of the sample. Only 9.1% of the participants reported that they had never observed postoperative complications. Intraoperative radioscopy was used routinely by 48%. The professionals who did not use this tool to determine the point of ligament fixation in the femur did not have a statistically greater number of postoperative complications than those who used it (p > 0.05). CONCLUSIONS: There are clear evolutionary trends in treatments and rehabilitation for acute dislocation of the patella due to MPFL, in Brazil. However, further prospective controlled studies are needed in order to evaluate the clinical and scientific benefit of these trends. PMID- 26229853 TI - Total knee arthroplasty: indication of blood transfusion according to hematimetric variation and clinical symptoms of hypoperfusion. AB - OBJECTIVE: To analyze the relationship between hematimetric variation and the presence of clinical symptoms of hypoperfusion for indicating blood transfusion in patients undergoing total knee arthroplasty. METHODS: A retrospective analysis was conducted on data gathered from the medical files of 55 patients with a diagnosis of gonarthrosis, who underwent total knee arthroplasty at a hospital orthopedics and traumatology service between February 2011 and December 2012. The patients studied presented unilateral joint degeneration and fitted into the indications for surgical treatment. All the patients underwent a preoperative cardiological evaluation, presenting a pattern of ASA I-III and absence of blood dyscrasia, and preoperative hemoglobin measurements were made. However, no minimum hematimetric value was established for the surgical treatment; there were only clinical criteria for blood perfusion. RESULTS: Among the 55 patients, 35 were female and 20 were male, and the mean age was 68 years. Six patients underwent homologous blood transfusion, because of their clinical condition of tissue hypoperfusion, persistent hypotension, loss of consciousness, sweating and coercible vomiting. They presented postoperative hemoglobin of 7.5-8.8 g/dL. CONCLUSION: For patients with falls in hemoglobin counts greater than 20% and values lower than 9 g/dL after the surgery, there is a possible need for blood transfusion, which should only be indicated when accompanied by major symptoms of tissue hypoperfusion. PMID- 26229854 TI - Description of an evaluation system for knee kinematics in ligament lesions, by means of optical tracking and 3D tomography. AB - OBJECTIVE: To describe and demonstrate the viability of a method for evaluating knee kinematics, by means of a continuous passive motion (CPM) machine, before and after anterior cruciate ligament (ACL) injury. METHODS: This study was conducted on a knee from a cadaver, in a mechanical pivot-shift simulator, with evaluations using optical tracking, and also using computed tomography. RESULTS: This study demonstrated the viability of a protocol for measuring the rotation and translation of the knee, using reproducible and objective tools (error < 0.2 mm). The mechanized provocation system of the pivot-shift test was independent of the examiner and always allowed the same angular velocity and traction of 20 N throughout the movement. CONCLUSION: The clinical relevance of this method lies in making inferences about the in vivo behavior of a knee with an ACL injury and providing greater methodological quality in future studies for measuring surgical techniques with grafts in relatively close positions. PMID- 26229855 TI - Quality of life after total knee arthroplasty: systematic review. AB - OBJECTIVE: To review the literature on quality of life among patients who underwent total knee arthroplasty (TKA) and assess the impact of various associated factors. METHODS: this was a systematic review of the literature in the Medline, Embase, Lilacs and SciELO databases, using the terms: TKA (total knee arthroplasty); TKR (total knee replacement); quality of life; and outcomes. There were no restrictions regarding study design. RESULTS: 31 articles addressing this topic using various quality-of-life evaluation protocols were selected. SF-36/SF-12, WOMAC and Oxford were the ones most frequently used. The studies made it possible to define that TKA is capable of making an overall improvement in patients' quality of life. Pain and function are among the most important predictors of improvement in quality of life, even when function remains inferior to that of healthy patients. CONCLUSION: The factors associated negatively were obesity, advanced age, comorbidities, persistence of pain after the procedure and a lengthy wait for surgery. PMID- 26229856 TI - Use of the semitendinosus tendon for foot and ankle tendon reconstructions. AB - OBJECTIVE: To demonstrate the results obtained from foot and ankle tendon reconstructions using the tendon of the semitendinosus muscle. The clinical results, the patient's degree of satisfaction and complications in the graft donor and recipient areas were evaluated. METHODS: This was a retrospective study in which the medical files of 38 patients who underwent this surgical procedure between 2006 and 2010 were surveyed. The functional results from this technique, the complications in the donor and recipient areas and the patients' degree of satisfaction were evaluated. RESULTS: Three patients presented complications in the recipient area (skin necrosis); one patient showed complications in the donor area (pain and insensitivity); and all patients had satisfactory functional results, with complete range of motion. CONCLUSION: The semitendinosus muscle is a good option for treatments for foot and ankle tendon injuries. PMID- 26229857 TI - Proposal for a new clinical test for diagnosing lateral hip snapping. AB - Lateral hip snapping is a nosological entity that is often unknown to many orthopedists and even to some hip surgery specialists. It comprises palpable and/or audible snapping on the lateral face of the hip that is sometimes painful, caused by muscle-tendon friction on the greater trochanter during flexion and extension of the coxofemoral joint. In the following, we describe a new test for diagnosing lateral hip snapping, which is eminently clinical. PMID- 26229858 TI - Charcot neuroarthropathy: realignment of diabetic foot by means of osteosynthesis using intramedullary screws - case report. AB - Diabetes mellitus is a serious disease that affects a large portion of the population. Charcot neuroarthropathy is one of its major complications and can lead to osteoarticular deformities, functional incapacity, ulcers and ankle and foot infections. Realignment of the foot by means of arthrodesis presents a high rate of implant failure due to weight-bearing on an insensitive foot. The aim of this report was to describe successful use of intramedullary osteosynthesis with compression screws to stabilize the deformed foot, in a diabetic patient with neuroarthropathy. PMID- 26229859 TI - Bilateral spontaneous fracturing of the femoral neck in a patient with renal osteodystrophy. AB - We report a case of bilateral fracturing of the femoral neck in a patient with renal osteodystrophy who was treated by means of osteosynthesis. In this type of patient, there is a need to remain watchful for the possibility of occurrences of spontaneous fracturing of the femoral neck, even if the initial radiographic examination is normal. PMID- 26229860 TI - Pelvic pseudotumor following total hip arthroplasty - case report. AB - Loosening is a well-known complication of total hip arthroplasty. The accumulation of detritus resulting from mechanical wear forms inflammatory cells that have the function of phagocytizing this debris. Over the long term, these cells may give rise to a local granulomatous reaction. Here, we present a report on a case of pelvic pseudotumor subsequent to total hip arthroplasty, which is considered rare in the literature. The patient was a 48-year-old black man who started to be followed up medically eight months earlier because of uncharacteristic abdominal pains, dysuria and pollakiuria. He had undergone left total hip arthroplasty 17 years previously. Through clinical investigation and complementary examinations, an extra-articular granulomatous mass was diagnosed, constituting a pelvic pseudotumor. PMID- 26229861 TI - Safe surgery for all. PMID- 26229862 TI - Osteochondroma: ignore or investigate? AB - Osteochondromas are bone protuberances surrounded by a cartilage layer. They generally affect the extremities of the long bones in an immature skeleton and deform them. They usually occur singly, but a multiple form of presentation may be found. They have a very characteristic appearance and are easily diagnosed. However, an atypical site (in the axial skeleton) and/or malignant transformation of the lesion may sometimes make it difficult to identify osteochondromas immediately by means of radiographic examination. In these cases, imaging examinations that are more refined are necessary. Although osteochondromas do not directly affect these patients' life expectancy, certain complications may occur, with varying degrees of severity. PMID- 26229863 TI - Cartilage lesions and ankle osteoarthrosis: review of the literature and treatment algorithm. AB - The main etiology of ankle osteoarthrosis is post-traumatic and its prevalence is highest among young individuals. Thus, this disease has a great socioeconomic impact and gives rise to significant losses of patients' quality of life. The objective of its treatment is to eliminate pain and keep patients active. Therefore, the treatment should be staged according to the degree of degenerative evolution, etiology, joint location, systemic condition, bone quality, lower-limb alignment, ligament stability and age. The treatment algorithm is divided into non-surgical therapeutic methods and options for surgical treatment. Joint preservation, joint replacement and arthrodesis surgical procedures have precise indications. This article presents a review on this topic and a proposal for a treatment algorithm for this disease. PMID- 26229864 TI - Muscle injury: current perspectives and trends in Brazil. AB - OBJECTIVE: To evaluate the management, procedures and perspectives of sports physicians and orthopedists in Brazil with regard to diagnosing and treating muscle injuries. METHODS: A questionnaire containing 20 questions relating to the topic of muscle injury was applied to sports physicians and orthopedists during the Second Brazilian Congress of Arthroscopy and Sports Traumatology, in 2013. RESULTS: Completely answered questionnaires were received from 168 sports physicians and orthopedists. Doctors from all regions of Brazil with a mean of 11 years of experience of treating muscle injuries were interviewed. Lower limbs were affected in 97% of the cases, particularly the quadriceps, adductor and sural triceps. The injury occurred during the eccentric phase in 62% of the interviews; 39% underwent ultrasound examination and 37% magnetic resonance imaging (MRI) for the injury to be diagnosed. Medication, rest and cryotherapy during the acute phase (87.5%) and medication, rest and physiotherapy during treatment of the injury (56%) were the prevalent options. The criteria for returning to sports were very subjective and disparate among the options presented, and most of the interviewees had already used some therapy that was adjuvant to traditional methods. CONCLUSION: The number of muscle injuries treated per year was greater than 30, independent of whether in the public or private sector. These injuries occurred mainly at the muscle-tendon junction, in the lower limbs and during the eccentric phase of muscle contraction. Ultrasound was the examination most performed, while MRI was considered ideal. For most of the interviewees, the preferred treatment involved rest, medication and physiotherapy. In addition, 52% believed that platelet-rich plasma was an efficient treatment and 42% said that they had already used it. PMID- 26229865 TI - Evaluation of the reproducibility of the Tronzo classification for intertrochanteric fractures of the femur. AB - OBJECTIVE: To evaluate the inter-observer reproducibility of the Tronzo classification for transtrochanteric fractures using the kappa concordance coefficient (kappa). METHODS: Twenty radiographic images in anteroposterior view on hips with transtrochanteric fractures of the femur were used. These were classified by 12 observers using the Tronzo method. The images were presented in sequence and a questionnaire containing all the options of the Tronzo classification was filled out, along with a simplified classification using Tronzo divisions into two groups (stable and unstable). The data were analyzed by means of the kappa concordance test. RESULTS: The following kappa indices were found: for images with stable fractures (Tronzo 1 and 2), 0.11; for images with unstable fractures (Tronzo 3, 3 variant, 4 and 5), 0.52; and for the complete classification, 0.44 (moderate concordance). In turn, the simplified classification did not increase the concordance rates. CONCLUSION: The Tronzo classification is unsuitable for clinical practice. We suggest that another system should be used or created for this type of fracture. PMID- 26229866 TI - Analysis on the mechanical resistance of fixation of femoral neck fractures in synthetic bone, using the dynamic hip system and an anti-rotation screw. AB - OBJECTIVE: To statistically analyze the results obtained from biomechanical tests on fixation of femoral neck fractures of Pauwels III type, in synthetic bone, using the dynamic hip system with an anti-rotation screw, versus a control group. METHODS: Ten synthetic bones from a Brazilian manufacturer (model C1010) were used and divided into two groups: test and control. In the test group, fixation of an osteotomy was performed with 70 degrees of inclination at the level of the femoral neck, using DHS with an anti-rotation screw. The resistance of this fixation was evaluated, along with its rotational deviation at 5 mm of displacement (phase 1) and at 10 mm of displacement (phase 2), which was considered to be failure of synthesis. In the control group, the models were tested in their entirety until femoral neck fracturing occurred. RESULTS: The test values in the test group (samples 1-5) in phase 1 were: 1512 N, 1439 N, 1205 N, 1251 N and 1273 N, respectively (mean = 1336 N; standard deviation [SD] = 132 N). The rotational deviations were: 4.90 degrees , 3.27 degrees , 2.62 degrees , 0.66 degrees and 0.66 degrees , respectively (mean = 2.42 degrees ; SD = 1.81 degrees ). In phase 2, we obtained: 2064 N, 1895 N, 1682 N, 1713 N and 1354 N, respectively (mean = 1742 N; SD = 265 N). The failure loading values in the control group were: 1544 N, 1110 N, 1359 N, 1194 N and 1437 N, respectively (mean = 1329 N; SD = 177 N). The statistical analysis using the Mann-Whitney test showed that the test group presented maximum loading at a displacement of 10 mm, i.e. significantly greater than the failure loading of the control group (p = 0.047). CONCLUSION: The mechanical resistance of the test group was significantly greater than that of the control group. PMID- 26229867 TI - Importance of radiological studies by means of computed tomography for managing fractures of the tibial plateau. AB - OBJECTIVES: To evaluate the concordance among knee surgery specialists regarding the classification and surgical technique indicated in cases of tibial plateau fracture, using conventional radiographs and computed tomography. METHODS: Forty four patients with fractures of the tibial plateau shown on radiographic and tomographic images were selected. These were evaluated by specialists at two different times, with an interval of seven days. On the first occasion, the specialists only had access to the radiographs, while on the second occasion they had access to both radiographs and computed tomography images. Their concordance was evaluated by means of the kappa coefficient. RESULTS: The interobserver reliability of the Schatzker classification on the first occasion was 0.36 and on the second occasion, 0.35. This was considered to present low reproducibility. In evaluating the intra-observer reproducibility of this classification, the mean kappa index was 0.42, which was classified as moderate. From evaluating the choice of surgical access, the inter-observer reliability was 0.55 on the first occasion and 0.50 on the second, which was considered to present moderate reproducibility. Evaluation on the implant chosen showed that the interobserver reliability was 0.01 on the first occasion and -0.06 on the second, which was considered to be poor and discordant. In evaluating the classification of the three columns, the inter-observer reproducibility was 0.47 (p < 0.0001), which was classified as moderate concordance. CONCLUSION: Use of computed tomography did not present any improvement in the inter-observer concordance, using the Schatzker classification, and did not produce any change in the preoperative planning. PMID- 26229868 TI - Accidents involving motorcyclists and cyclists in the municipality of Sao Paulo: characterization and trends. AB - OBJECTIVE: To describe the characteristics of motorcycle and bicycle accident victims, according to notifications of suspected and confirmed accidents that have occurred in the municipality of Sao Paulo. METHOD: This was a descriptive epidemiological study. It covered all accidents (12,924) that occurred involving motorcycles (11,366) and bicycles (1558) between January 2011 and October 2013. Data in the Health Department's information system for surveillance of violence and accidents (SIVVA) was surveyed. RESULTS: Motorcycle accidents accounted for 52.1% of the cases notified and bicycles, 7.1%. Males predominated in both types of accidents: 81.6% and 80.6%, respectively. In the motorcycle accidents, the predominant age group among the victims was from 20 to 24 years. Both types of accidents occurred during the daytime (7:00-18:00 h): 37.4% and 27.0% respectively. Among the motorcycle accidents, the driver had been using alcohol in 3% and it was not possible to identify whether this had occurred in 67%. CONCLUSIONS: Public policies prioritizing financial and human resources applied toward reducing these types of accidents need to be brought in. PMID- 26229869 TI - Proprioceptive deficit in individuals with unilateral tearing of the anterior cruciate ligament after active evaluation of the sense of joint position. AB - OBJECTIVE: To ascertain whether the proprioceptive deficit in the sense of joint position continues to be present when patients with a limb presenting a deficient anterior cruciate ligament (ACL) are assessed by testing their active reproduction of joint position, in comparison with the contralateral limb. METHODS: Twenty patients with unilateral ACL tearing participated in the study. Their active reproduction of joint position in the limb with the deficient ACL and in the healthy contralateral limb was tested. Meta-positions of 20% and 50% of the maximum joint range of motion were used. Proprioceptive performance was determined through the values of the absolute error, variable error and constant error. RESULTS: Significant differences in absolute error were found at both of the positions evaluated, and in constant error at 50% of the maximum joint range of motion. CONCLUSION: When evaluated in terms of absolute error, the proprioceptive deficit continues to be present even when an active evaluation of the sense of joint position is made. Consequently, this sense involves activity of both intramuscular and tendon receptors. PMID- 26229870 TI - Proprioceptive deficit in patients with complete tearing of the anterior cruciate ligament. AB - OBJECTIVE: To investigate the existence of proprioceptive deficits between the injured limb and the uninjured (i.e. contralateral normal) limb, in individuals who suffered complete tearing of the anterior cruciate ligament (ACL), using a strength reproduction test. METHODS: Sixteen patients with complete tearing of the ACL participated in the study. A voluntary maximum isometric strength test was performed, with reproduction of the muscle strength in the limb with complete tearing of the ACL and the healthy contralateral limb, with the knee flexed at 60 degrees . The meta-intensity was used for the procedure of 20% of the voluntary maximum isometric strength. The proprioceptive performance was determined by means of absolute error, variable error and constant error values. RESULTS: Significant differences were found between the control group and ACL group for the variables of absolute error (p = 0.05) and constant error (p = 0.01). No difference was found in relation to variable error (p = 0.83). CONCLUSION: Our data corroborate the hypothesis that there is a proprioceptive deficit in subjects with complete tearing of the ACL in an injured limb, in comparison with the uninjured limb, during evaluation of the sense of strength. This deficit can be explained in terms of partial or total loss of the mechanoreceptors of the ACL. PMID- 26229871 TI - Reconstruction of the anterior cruciate ligament by means of an anteromedial portal and femoral fixation using Rigidfix. AB - OBJECTIVE: To evaluate a series of patients who underwent surgery for reconstruction of the anterior cruciate ligament with flexor tendons, by means of the anteromedial transportal technique using Rigidfix for femoral fixation, and to analyze the positioning of the pins by means of tomography. METHODS: Thirty two patients were included in the study. The clinical evaluation was done using the Lysholm, subjective IKDC and Rolimeter. All of them underwent computed tomography with 3D reconstruction in order to evaluate the entry point and positioning of the Rigidfix pins in relation to the joint cartilage of the lateral condyle of the femur. RESULTS: The mean Lysholm score obtained was 87.81 and the subjective IKDC was 83.72. Among the 32 patients evaluated, 43% returned to activities that were considered to be very vigorous, 9% vigorous, 37.5% moderate and 12.5% light. In 16 patients (50%), the distal entry point of the Rigidfix pin was located outside of the cartilage (extracartilage); in seven (21.87%), the distal pin injured the joint cartilage (intracartilage); and in nine (28.12%), it was at the border of the lateral condyle of the femur. CONCLUSION: The patients who underwent ACL reconstruction by means of the anteromedial transportal using the Rigidfix system presented satisfactory clinical results over the length of follow-up evaluated. However, the risk of lesions of the joint cartilage from the distal Rigidfix pin needs to be taken into consideration when the technique via an anteromedial portal is used. Further studies with larger numbers of patients and longer follow-up times should be conducted for better evaluation. PMID- 26229872 TI - Importance of anatomically locating the infrapatellar branch of the saphenous nerve in reconstructing the anterior cruciate ligament using flexor tendons. AB - OBJECTIVE: To describe the path of the infrapatellar branch of the saphenous nerve (IBSN) using the medial joint line, anterior tibial tuberosity (ATT), tibial collateral ligament and a horizontal line parallel to the medial joint line that passes over the ATT, as reference points, in order to help surgeons to diminish the likelihood of injuring this nerve branch during reconstruction of the anterior cruciate ligament (ACL) using flexor tendons. METHODS: Ten frozen knees that originated from amputations were examined. Through anatomical dissection performed with the specimens flexed, we sought to find the IBSN, from its most medial and proximal portion to its most lateral and distal portion. Following this, the anatomical specimens were photographed and, using the ImageJ software, we determined the distance from the IBSN to the medial joint line and to a lower horizontal line going through the ATT and parallel to the first line. We also measured the angle of the direction of the path of the nerve branch in relation to this lower line. RESULTS: The mean angle of the path of the nerve branch in relation to the lower horizontal line was 17.50 +/- 6.17 degrees . The mean distance from the IBSN to the medial joint line was 2.61 +/- 0.59 cm and from the IBSN to the lower horizontal line, 1.44 +/- 0.51 cm. CONCLUSION: The IBSN was found in all the knees studied. In three knees, we found a second branch proximal to the first one. The direction of its path was always from proximal and medial to distal and lateral. The IBSN was always proximal and medial to the ATT and distal to the medial joint line. The medial angle between its direction and a horizontal line going through the ATT was 17.50 +/- 6.17 degrees . PMID- 26229873 TI - Biomechanical evaluation between the modified Mason-Allen stitch and the locked double-tie stitch on the infraspinatus of sheep. AB - OBJECTIVES: To evaluate and compare the in vitro biomechanical results from two stitches: the Mason-Allen stitch, as modified by Habermeyer; and the locked double-tie stitch developed at our service, on tendons of the infraspinatus muscle of sheep. METHODS: Twenty tendons from the infraspinatus muscle of sheep were randomly divided into two groups: LDT, on which the locked double-tie stitch was performed; and MA, with the modified Mason-Allen stitch. The evaluation was performed in the mechanics laboratory, using a standard test machine with unidirectional traction, constant velocity of 20 mm per second and a 500 N load cell, without force cycling. RESULTS: We observed that LDT was superior to MA, for the force needed to form spaces of both 5 mm (p = 0.01) and 10 mm (p = 0.002) and also for the maximum traction resistance (p = 0.003). CONCLUSION: We confirmed our hypothesis that LDT stitches are superior to MA stitches from a biomechanical point of view. This is a further stitching option for surgeons, when fragile and poorly vascularized tendons need to be sutured, and it improves the quality of fixation without increasing the "strangulation" and, consequently, the ischemic area. PMID- 26229874 TI - Analysis on the acromial curvature and its relationships with the subacromial space and types of acromion. AB - OBJECTIVE: To correlate the acromial curvature, using the angles proposed, with the subacromial space and types of acromion. METHODS: Ninety scapulas were studied. The acromia were classified as types I, II or III. The acromial curvature was analyzed by means of the alpha, beta and theta angles. We also measured the distance between the anteroinferior extremity of the acromion and the supraglenoid tubercle (DA). The scapulas were grouped in relation to sex and age. The angles proposed were analyzed in relation to each type of acromion and also in relation to the measurements of the distance DA. RESULTS: Out of the total number of acromia, 39 (43.3%) were type I, 43 (47.7%) type II and eight (9%) type III. The mean ages for each type of acromion (I-III) were 45.6, 55.2 and 51.1 years, respectively. The proportions of the different types of acromion varied in relation to sex and age. The evaluations on the mean beta angle (p = 0.008) and theta angle (p = 0.028), with comparisons in relation to each type of acromion and measurements of the distance DA (p = 0.037), were shown to be statistically significant. CONCLUSION: The angles proposed in our study can be used for morphometric analysis on the acromion, especially regarding its curvature, and can contribute towards studies on diseases of the shoulder and aid in surgical planning and analysis of the acromial slope, by means of radiography or magnetic resonance. PMID- 26229876 TI - Cubital compressive neuropathy in the elbow: in situ neurolysis versus anterior transposition - comparative study. AB - OBJECTIVE: To compare the results from two of the most commonly used surgical techniques: in situ decompression and subcutaneous transposition. The processes of patients treated surgically in a public university hospital between January 2004 and December 2011 were reviewed. Cases of proximal compression of the nerve, angular deformity of the elbow and systemic diseases associated with non compressive neuropathy were excluded. METHODS: Ninety-seven cases were included (96 patients). According to the modified McGowan score, 14.4% of the patients presented grade Ia, 27.8% grade II, 26.8% grade IIb and 30.9% grade III. In situ neurolysis of the cubital was performed in 64 cases and subcutaneous anterior transposition in 33. RESULTS: According to the modified Wilson and Knout score, the results were excellent in 49.5%, good in 18.6%, only satisfactory in 17.5% and poor in 14.4%. In comparing the two techniques, we observed similar numbers of excellent and good results. Grades IIb and III were associated with more results that were less satisfactory or poor, independent of the surgical technique. CONCLUSION: Both techniques were shown to be efficient and safe for treating cubital tunnel syndrome. PMID- 26229875 TI - Profile of collagen gene expression in the glenohumeral capsule of patients with traumatic anterior instability of the shoulder. AB - OBJECTIVE: To evaluate the expression of the genes COL1A1, COL1A2, COL3A1 and COL5A1 in the glenohumeral capsule of patients with traumatic anterior instability of the shoulder. METHODS: Samples from the glenohumeral capsule of 18 patients with traumatic anterior instability of the shoulder were evaluated. Male patients with a positive grip test and a Bankart lesion seen on magnetic resonance imaging were included. All the patients had suffered more than one episode of shoulder dislocation. Samples were collected from the injured glenohumeral capsule (anteroinferior region) and from the macroscopically unaffected region (anterosuperior region) of each patient. The expression of collagen genes was evaluated using the polymerase chain reaction after reverse transcription with quantitative analysis (qRT-PCR). RESULTS: The expression of COL1A1, COL1A2 and COL3A1 did not differ between the two regions of the shoulder capsule. However, it was observed that the expression of COL5A1 was significantly lower in the anteroinferior region than in the anterosuperior region (median +/- interquartile range: 0.057 +/- 0.052 vs. 0.155 +/- 0.398; p = 0.028) of the glenohumeral capsule. CONCLUSION: The affected region of the glenohumeral capsule in patients with shoulder instability presented reduced expression of COL5A1. PMID- 26229877 TI - Surgical treatment for myelodysplastic clubfoot. AB - OBJECTIVE: To analyze the results from surgical treatment of 69 cases of clubfoot in 43 patients with myelodysplasia according to clinical and radiographic criteria, at our institution between 1984 and 2004. METHODS: This was a retrospective study involving analysis of medical files, radiographs and consultations relating to patients who underwent surgical correction of clubfoot. The surgical technique consisted of radical posteromedial and lateral release with or without associated talectomy. RESULTS: The patients' mean age at the time of the surgery was four years and two months, and the mean length of postoperative follow-up was seven years and two months. Satisfactory results were achieved in 73.9% of the feet and unsatisfactory results in 26.1% (p < 0.0001). CONCLUSION: Residual deformity in the immediate postoperative period was associated with unsatisfactory results. Opening of the Kite (talocalcaneal) angle in feet that only underwent posteromedial and lateral release, along with appropriate positioning of the calcaneus in cases that underwent talectomy, was the radiographic parameter that correlated with satisfactory results. PMID- 26229878 TI - Prevalence of nonspecific lumbar pain and associated factors among adolescents in Uruguaiana, state of Rio Grande do Sul. AB - OBJECTIVE: To identify the prevalence of nonspecific lumbar pain and associated factors among adolescents in Uruguaiana, state of Rio Grande do Sul. METHODS: This was a cross-sectional school-based study conducted among adolescents aged 10 17 years who were enrolled in the day shift of the municipal and state educational systems of Uruguaiana. This study evaluated 1455 adolescents. The data-gathering procedures involved two stages. Firstly, a questionnaire on sociodemographic indicators, behavioral patterns and habits of the daily routine and history of nonspecific lumbar pain was applied. Subsequently, height, body mass, flexibility and abdominal strength/resistance measurements were evaluated. To analyze the data, univariate, bivariate and multivariable methods were used and the significance level was taken to be 5% for all the tests. RESULTS: The prevalence of lumbar pain among the adolescents evaluated was 16.1%. Grouped according to sex, the prevalence among males was 10.5% and among females, 21.6%. The variables of sex, body mass index, abdominal strength/resistance and physical activity level presented statistically significant associations with nonspecific lumbar pain. In the adjusted analysis, sex (OR = 2.36; p < 0.001), age (OR = 1.14; p < 0.001) and body mass index (OR = 1.44; p = 0.029) maintained significance in the final model. CONCLUSIONS: Female adolescents of older age and who presented overweight or obesity had higher chances of developing nonspecific lumbar pain. PMID- 26229879 TI - Dominance of foreign citations in Brazilian orthopedics journals. AB - OBJECTIVE: To evaluate whether there is any preference for citing journals from other countries to the detriment of Brazilian journals, in three Brazilian orthopedics journals. METHODS: All the references of articles published in 2011 by the journals Acta Ortopedica Brasileira, Coluna/Columna and Revista Brasileira de Ortopedia were evaluated to as certain how many of these came from Brazilian journals and how many from foreign journals. RESULTS: 3813 references distributed among 187 articles were analyzed. Out of this total, 306 (8.02%) were from Brazilian journals. There was no difference between the three journals analyzed. There were 76 articles (40.64%) without any citations of articles in Brazilian journals and only two articles (1%) cited more Brazilian articles than articles published elsewhere. CONCLUSION: There is a need for Brazilian researchers to cite articles from Brazilian journals more often. PMID- 26229880 TI - Pre-tibial synovial cyst after reconstruction of the anterior cruciate ligament: case report. AB - Arthroscopic reconstruction of the anterior cruciate ligament has been modernized through new surgical techniques and new materials. When tibial fixation is performed using an absorbable screw, complications may occur, such as formation of a pre-tibial cyst. The case described here is about a patient who presented an anteromedial synovial cyst in his right knee, three years after having undergone ACL reconstruction. The patient did not present any pain nor any complaints other than a mass that progressively increased in size, worsened after physical activities. Imaging examinations were requested: simple radiography of the knee and magnetic resonance. Anteromedial imaging of the knee showed a mass with well delimited borders and internal fluid content, suggestive of a synovial cyst, with communication with the joint cavity through the tibial tunnel, without presenting enlargement or absorption of the bone tunnel. The cyst was surgically resected and the tibial tunnel occlusion was performed using a bone plug. The diagnosis of a synovial cyst was subsequently confirmed through the results from the anatomopathological examination. The patient presented good clinical evolution, with disappearance of the symptoms and a return to physical activities. PMID- 26229881 TI - Knee osteoarthrosis secondary to ochronosis - clinical case. AB - Alkaptonuria is a rare metabolic disease in which a deficiency of the enzyme homogentisate dioxygenase causes an accumulation of homogentisic acid. Ochronosis consists of excessive deposition of homogentisic acid in the connective tissue and presents as a chestnut brown or black pigmentation. With aging, the accumulation of pigments from homogentisic acid in the joints causes osteoarthrosis. There is no specific treatment for the disease and the approach is symptomatic. Arthroplasty is the solution for severe cases of osteoarthrosis caused by this pathological condition and presents results comparable to those from patients with primary osteoarthrosis. Here, the case of a 67-year-old patient who underwent several arthroplasty procedures because of osteoarthrosis caused by this rare pathological condition is presented. The last surgical intervention consisted of total right knee arthroplasty. PMID- 26229882 TI - Bone mineral density evaluation among patients with neuromuscular scoliosis secondary to cerebral palsy. AB - OBJECTIVE: To evaluate bone mineral density among patients with neuromuscular scoliosis secondary to quadriplegic cerebral palsy. METHODS: This was a descriptive prospective study in which both bone densitometric and anthropometric data were evaluated. The inclusion criteria used were that the patients should present quadriplegic cerebral palsy, be confined to a wheelchair, be between 10 and 20 years of age and present neuromuscular scoliosis. RESULTS: We evaluated 31 patients (20 females) with a mean age of 14.2 years. Their mean biceps circumference, calf circumference and body mass index were 19.4 cm, 18.6 cm and 16.9 kg/m(2), respectively. The mean standard deviation from bone densitometry was -3.2 (z-score), which characterizes osteoporosis. CONCLUSION: There is high incidence of osteoporosis in patients with neuromuscular scoliosis secondary to quadriplegic cerebral palsy. PMID- 26229883 TI - Total hip arthroplasty using a posterior minimally invasive approach - results after six years. AB - OBJECTIVE: To evaluate the medium-term clinical-functional results (minimum follow-up of six years) from total uncemented hip arthroplasty performed by means of a posterior minimally invasive access, in comparison with the traditional right lateral access. METHODS: In a comparative prospective study, 224 adult patients underwent elective total hip arthroplasty due to a diagnosis of primary or secondary osteoarthrosis. A group of 103 patients with posterior minimally invasive access was compared with a group of 121 patients with the traditional right lateral access. The mean length of follow-up among the patients of this sample was 7.2 years. We evaluated the clinical-functional and radiographic results and occurrences of loosening, along with any complications that occurred, with a minimum follow-up of six years. RESULTS: The clinical-functional analyses before the surgical procedure and six years afterwards were similar in the two groups (p = 0.88 and p = 0.55). One patient in the minimally invasive group underwent revision of the acetabular component and two patients in the control group underwent the same procedure (p = 0.46). The Trendelenburg clinical test, which showed weakness of the hip abductor musculature, was present in five patients operated using the traditional lateral route and absent in all those who underwent the minimally invasive procedure (p = 0.06). There was no difference regarding the radiographic parameters obtained, either in acetabular or in femoral positioning (p = 0.32 and p = 0.58). CONCLUSIONS: The medium-term clinical and radiographic results and the complication rates were similar between the patients who underwent total hip arthroplasty by means of the posterior minimally invasive access and those with the traditional lateral access. PMID- 26229884 TI - Bankart arthroscopic procedure: comparative study on use of double or single thread anchors after a 2-year follow-up. AB - OBJECTIVE: To compare the use of anchors with double and single-thread loading in the single-row Bankart arthroscopic procedure. METHODS: 252 patients (258 shoulders) underwent Bankart arthroscopic surgery with evaluation after a minimum follow-up of 2 years. They underwent repairs either using anchors with single loading of a high-resistance non-absorbable braided thread (206 shoulders; group AS) or using double loading of thread with the same characteristics (52 shoulders; group AD). The patients were evaluated using the UCLA and Carter-Rowe scales. The patients' return to sports activity and recurrences were also compared. RESULTS: There was no significant difference between the groups regarding the surgical failure rate (group AS 5.8%; group AD 7.7%; p = 0.62). Group AS presented a better mean Carter-Rowe score (group AS 94.4; group AD 88.6; p < 0.05) and greater return to the same sports level (group AS 79.1; group AD 72.1; p < 0.05). CONCLUSION: Use of anchors with double thread loading did not show any clinical advantage for arthroscopic repair of traumatic anterior shoulder instability, in relation to use of single-thread anchors, over a 2-year follow-up. PMID- 26229886 TI - Plasma cytokine expression after lower-limb compression in rats. AB - OBJECTIVES: Muscle injury due to crushing (muscle compression injury) is associated with systemic manifestations known as crush syndrome. A systemic inflammatory reaction may also be triggered by isolated muscle injury. The aim of this study was to investigate the plasma levels of interleukins (IL) 1, 6 and 10 and tumor necrosis factor alpha (TNF-alpha), which are markers for possible systemic inflammatory reactions, after isolated muscle injury resulting from lower-limb compression in rats. METHODS: Male Wistar rats were subjected to 1 h of compression of their lower limbs by means of a rubber band. The plasma levels of IL 1, 6 and 10 and TNF-alpha were measured 1, 2 and 4 h after the rats were released from compression. RESULTS: The plasma levels of IL 10 decreased in relation to those of the other groups, with a statistically significant difference (p < 0.05). The method used did not detect the presence of IL 1, IL 6 or TNF-alpha. CONCLUSION: Our results demonstrated that the changes in plasma levels of IL 10 that were found may have been a sign of the presence of circulating interleukins in this model of lower-limb compression in rats. PMID- 26229885 TI - Histomorphometry of the organic matrix of the femur in ovariectomized rats treated with sodium alendronate. AB - OBJECTIVE: To evaluate the effect of two different concentrations of sodium alendronate on the quantity of organic matrix in the femur of rats with estrogen suppression caused by ovariectomy. METHODS: Sixty-days-old Wistar rats (Rattus norvegicus) were subjected to bilateral laparotomy to remove the ovaries. The animals were divided into a control group, in which they only underwent laparotomy; an ovariectomized group (OVX); an ovariectomized group treated with 1 mg/kg of alendronate (OVX 1 mg); and an ovariectomized group treated with 2 mg/kg of alendronate (OVX 2 mg). The rats received alendronate twice a week for 90 days. The left femur was then removed, fixed and processed for embedding in paraffin. Semi-serial sections stained with hematoxylin and eosin were used to determine the area occupied by organic bone matrix, by means of image analysis software. The animals' weights were obtained at the beginning and end of the experiment. RESULTS: The ovariectomized animals and those treated with 1 mg/kg of alendronate presented significant increases in body weight (p < 0.05), in comparison with the control group. Histomorphometric analysis revealed that in the animals treated with 2 mg/kg of alendronate, the area (MUm(2)) occupied by organic matrix (1,81,900 +/- 18,130) was similar (p > 0.05) to that of the non ovariectomized control animals (2,04,800 +/- 9590), which indicates that this medication had a preventive effect with regard to bone mass loss. CONCLUSION: The higher concentration of the medication, administered twice a week for 90 days, was more effective than the dose of 1 mg/kg over the same period. PMID- 26229887 TI - Spontaneous dislocation of the polyethylene component following knee revision arthroplasty: case report. AB - Dislocation of the polyethylene component in knee arthroplasty is a rare complication. The main triggering factor is failure of the locking mechanism, which may result from technical errors of insertion, trauma or even implant failure. Here, a case of dislocation of the polyethylene component from the tibial base, nine years after revision arthroplasty, is reported. It is believed that this is the first such case reported in the Brazilian literature. PMID- 26229888 TI - CBOT: our constant challenge. PMID- 26229889 TI - Shockwave treatment for musculoskeletal diseases and bone consolidation: qualitative analysis of the literature. AB - Shockwave treatment is an option within orthopedics. The exact mechanism through which shockwaves function for treating musculoskeletal diseases is unknown. The aim of this study was to make a qualitative analysis on the effectiveness of shockwave treatment among patients with musculoskeletal pathological conditions and pseudarthrosis. Searches were conducted in the Cochrane Library, Medline and Lilacs databases. Thirty-nine studies that reported using shockwave treatment for musculoskeletal diseases were found. Their results varied greatly, as did the types of protocol used. The studies that evaluated the effectiveness of shockwave treatment for lateral epicondylitis, shoulder tendinopathy, knee osteoarthrosis, femoral head osteonecrosis and trochanteric bursitis reported inconsistent results for most of their patients. Those that evaluated patients with calcifying tendinopathy, plantar fasciitis, Achilles tendinopathy, patellar tendinopathy and pseudarthrosis showed benefits. Shockwave treatment is a safe and non-invasive method for chronic cases in which conventional techniques have been unsatisfactory and should be used in association with other treatment methods for tendinopathy. Further quality studies are needed. PMID- 26229890 TI - Partial tearing of the anterior cruciate ligament: diagnosis and treatment. AB - Partial tears of the anterior cruciate ligament (ACL) are common and represent 10 27% of the total. The main reasons for attending to cases of non-torn bundles are biomechanical, vascular and proprioceptive. Continued presence of the bundle also serves as protection during the healing process. There is controversy regarding the definition of these injuries, which is based on anatomy, clinical examination, translation measurements, imaging examinations and arthroscopy. The way in which it is treated will depend on the existing laxity and instability. Conservative treatment is optional for cases without instability, with a focus on motor rehabilitation. Surgical treatment is a challenge, since it requires correct positioning of the bone tunnels and conservation of the remnants of the torn bundle. The pivot shift test under anesthesia, the magnetic resonance findings, the previous level and type of sports activity and the arthroscopic appearance and mechanical properties of the remnants will aid the orthopedist in the decision-making process between conservative treatment, surgical treatment with strengthening of the native ACL (selective reconstruction) and classical (anatomical) reconstruction. PMID- 26229891 TI - Radiographic study on the anatomical characteristics of the proximal femur in Brazilian adults. AB - OBJECTIVE: To ascertain the geometry of the femur in the Brazilian population by means of a radiographic study and to correlate the values with regard to sex and right/left side. METHODS: Five hundred anteroposterior radiographs of the pelvis of skeletally mature patients (250 of each sex) who did not present any osteoarthrosis, fractures or tumoral or infectious lesions were analyzed. The length and width of the femoral neck, length of the femoral axis, neck-shaft angle and femoral offset were measured. RESULTS: The following means were observed: 36.54 mm for the length of the femoral neck; 37.48 mm for the width of the femoral neck; 108.42 mm for the length of the femoral axis; 130.47 degrees for the neck-shaft angle; and 44.4 mm for the femoral offset. CONCLUSION: The mean values for the main measurements on the proximal femur in Brazilians differed from those of previous studies. It could also be shown that there was a statistically significant mean difference between men and women for all the variables, both on the left and on the right side, and that the men had greater means than the women. PMID- 26229892 TI - Treatment of two-part fractures of the surgical neck of the humerus using a locked metaphyseal intramedullary nail proximally with angular stability. AB - OBJECTIVES: To evaluate the functional results from patients with surgical neck fractures treated with a locked metaphyseal intramedullary nail and angular stability. METHODS: Twenty-two patients between the ages of 21 and 69 years were evaluated prospectively between January 2010 and January 2011. Their time taken for consolidation, age, sex, complications and functional results were correlated using the modified protocol of the University of California at Los Angeles (UCLA). RESULTS: The mean time taken for consolidation was 9.26 weeks +/- confidence interval (CI) of 0.40 weeks. One case (4.5%) did not become consolidated. There were no cases of infection. There was one case (4.5%) of adhesive capsulitis with good evolution through clinical treatment. Five patients (22.7%) presented occasional mild pain and one case (4.5%) reported medium intensity pain associated with the subacromial impact of the implant. The mean score on the modified UCLA scale was 30.4 +/- CI 1.6 points, obtained at the end of 12 weeks of evaluation: 18 cases (81.8%) with "excellent" and "good" scores, three cases (13.6%) with "fair" scores and one case (4.5%) with a "poor" score. CONCLUSION: In the group of patients evaluated, treatment of two-part surgical neck fractures by means of a locked metaphyseal intramedullary nail and angular stability demonstrated satisfactory functional results and a low complication rate, similar to what is seen in the literature. PMID- 26229893 TI - Is there a difference in the positioning of sliding screws between stable and unstable extracapsular fractures? AB - OBJECTIVE: To analyze the tip-apex distance (TAD), cervicodiaphyseal angle and Garden angle in stable and unstable extracapsular fractures of the femur treated with a plate and sliding screw. METHOD: Hip radiographs in anteroposterior (AP) and lateral view on 117 patients were evaluated. The fractures were classified as stable or unstable, using the AO classification, and the reduction achieved was assessed in accordance with the following criteria: TAD > 3 cm; Garden alignment index (AP) < 160 degrees ; and AP cervicodiaphyseal varus angle < 125 degrees . When two or more criteria were present, the quality of the osteosynthesis was classified as "not ideal". RESULTS: The patients with unstable fractures presented AP cervicodiaphyseal angles that were significantly greater (p = 0.05) than in those with stable fractures. The patients with unstable fractures presented lateral cervicodiaphyseal angles that were significantly smaller (p = 0.05) than in those with stable fractures. There were no significant differences in the remainder of the criteria evaluated. CONCLUSION: This study did not find any significant differences in the measurements evaluated, except in relation to the cervicodiaphyseal angle. Satisfactory reduction was achieved both for the stable and for the unstable fractures, when we used a plate and sliding screw to treat proximal extracapsular fractures of the femur. PMID- 26229894 TI - Cost-effectiveness of surgical treatment for hip fractures among the elderly in Brazil. AB - OBJECTIVES: To estimate the cost per quality-adjusted life-year (QALY) focusing on the length of time between trauma and surgery. METHODS: A retrospective cohort with systematic sampling was conducted among all the patients who were admitted to the study hospital through the Brazilian National Health System (SUS) over a three-year period. Two treatment strategies were compared: early treatment, if the patient was operated up to the fourth day; and late treatment, if this was done after the fourth day. The cost was the direct medical cost from the point of view of SUS, which was gathered from the management system, from the SUS table of procedures, medications and implant material costs (SIGTAP), to account for the costs associated with the hospital, medical fees and implants used. The outcome of usefulness was measured indirectly by means of EuroQOL-5D, which is an instrument used worldwide, and these measurements were transformed into usefulness by means of the standard rules of the Regional Planning and Development Center of Minas Gerais (CEDEPLAR) of 2013. RESULTS: The sample included 110 patients: 27 in the early group and 83 in the late group. The confounding variables of age, gender, anesthetic risk (ASA), fracture type and surgery type were controlled for. The samples were shown to be homogenous with regard to these variables. The cost per QALY of the early strategy was R$ 5,129.42 and the cost of the late strategy was R$ 8,444.50. CONCLUSION: The early strategy was highly favorable in relation to the late strategy in this study. PMID- 26229895 TI - Femoropatellar radiographic alterations in cases of anterior cruciate ligament failure. AB - OBJECTIVE: To make a comparative analysis on three femoropatellar radiographic parameters, between knees with chronic failure of the anterior cruciate ligament (ACL) and normal knees. METHODS: Thirty volunteer patients with a diagnosis of unilateral isolated chronic ACL injury for more than one year and a normal contralateral knee were selected. Digital radiographs were produced for all the patients, on both knees in absolute lateral view at 30 degrees of flexion, with and without load-bearing on one leg, and in axial view of the patella at 30 degrees . The Caton-Deschamps patellar height index, Merchant patellar congruence angle and Laurin lateral patellar tilt angle were measured on the radiographs obtained from the normal knees and knees with ACL injuries, and comparative analysis was performed between these two groups. RESULTS: The patellar height was statistically significantly lower (p < 0.001) in the knees with ACL failure than in the normal knees, both on radiographs without loading and on those with single foot loading. The Merchant patellar congruence angle was significantly smaller (p < 0.001) in the normal knees and the lateral patellar tilt angle was smaller (p < 0.001) in the knees with ACL failure. CONCLUSION: Chronic ACL failure gave rise to a statistically significant change in the femoropatellar radiographic values studied (p < 0.001). Knees with injuries to this ligament presented lower patellar height values, greater tilt and lateral displacement of the patella, in relation to the femoral trochlea, in comparison with the normal contralateral knees. PMID- 26229896 TI - Comparison of grafts for anatomical reconstruction of the ACL: patellar versus semitendinosus/gracilis. AB - OBJECTIVE: To compare the functional results from surgical treatment for anatomical reconstruction of the anterior cruciate ligament (ACL) with a single band, using two types of autologous grafts. METHODS: Twenty-seven patients who underwent anatomical reconstruction of the ACL by means of the Chambat technique were evaluated prospectively. They were divided into two groups: A, with 14 patients, using grafts from flexor tendons; and B, with 13 patients, using grafts from the patellar tendon. In both groups, fixation was performed using an absorbable interference screw. RESULTS: Based on the Lysholm score, group A presented a mean score of 71.6 in the first month, while B presented 75. At the end of the sixth month, both groups presented 96.6. Evaluation of the total IKDC showed that in the first month, the majority of the patients, both in group A (85.7%) and in group B (76.9%), presented a knee assessment that was close to normal. In the sixth month, 92.9% of group A had normal presentations, and 100% of group B. CONCLUSION: According to the Lysholm functional evaluation and the IKDC subjective assessment, there was no statistically significant difference in the results between the groups, and the results were better in the sixth month. PMID- 26229897 TI - Functional result relating to the positioning of the graft in anterior cruciate ligament reconstruction. AB - OBJECTIVE: To ascertain the coronal angles for the femoral and tibial tunnels that provide the best postoperative result from anterior cruciate ligament (ACL) reconstruction surgery, through assessing the variables of the IKDC and Lysholm Tegner questionnaires and the hop test. METHODS: Sixteen patients with a single unilateral ACL injury who underwent this surgery between 24 and 36 months earlier were evaluated. They were divided into four groups in which the tibial and femoral tunnel angles were greater than or less than 65 degrees in the coronal plane. RESULTS: The results demonstrated that a more vertical angle for the tibial tunnel (72 degrees ) and a more horizontal angle for the femoral tunnel (60 degrees ), with valgus alignment of 12 degrees correlated with the best values for the variables studied. This may indicate that the long-term results from this surgery are excellent. CONCLUSION: A more horizontal femoral angle and a more vertical tibial angle produced better assessments in the tests that were applied and in the functional results evaluated. PMID- 26229898 TI - Immediate postoperative pain level from lumbar arthrodesis following epidural infiltration of morphine sulfate. AB - OBJECTIVE: To evaluate the pain level in patients treated with epidural infusion of morphine sulfate in a single dose, after a surgical procedure to perform lumber arthrodesis. METHODS: Forty patients underwent posterolateral lumbar arthrodesis or intersomatic lumbar arthrodesis via a posterior route at one, two or three levels. They were prospectively randomized into two groups of 20. In the first group (study group), 2 mg of morphine sulfate diluted in 10 mL of physiological serum was infiltrated into the epidural space, through the laminectomy area. The second group (controls) did not receive analgesia. The patients were asked about their pain levels before and after the operation, using a visual analog scale (VAS). RESULTS: It was found that the patients presented a significant diminution of pain as shown by the VAS. From before to after the operation, it decreased by an average of 4.7 points (p = 0.0001), which corresponded to 53.2% (p = 0.0001). CONCLUSION: Application of 2 mg of morphine sulfate in a single epidural dose was shown to be a good technique for pain therapy following lumbar spinal surgery. PMID- 26229899 TI - Comparative analysis on arthroscopic sutures of large and extensive rotator cuff injuries in relation to the degree of osteopenia. AB - OBJECTIVE: To analyze the results from arthroscopic suturing of large and extensive rotator cuff injuries, according to the patient's degree of osteopenia. METHOD: 138 patients who underwent arthroscopic suturing of large and extensive rotator cuff injuries between 2003 and 2011 were analyzed. Those operated from October 2008 onwards formed a prospective cohort, while the remainder formed a retrospective cohort. Also from October 2008 onwards, bone densitometry evaluation was requested at the time of the surgical treatment. For the patients operated before this date, densitometry examinations performed up to two years before or after the surgical treatment were investigated. The patients were divided into three groups. Those with osteoporosis formed group 1 (n = 16); those with osteopenia, group 2 (n = 33); and normal individuals, group 3 (n = 55). RESULTS: In analyzing the University of California at Los Angeles (UCLA) scores of group 3 and comparing them with group 2, no statistically significant difference was seen (p = 0.070). Analysis on group 3 in comparison with group 1 showed a statistically significant difference (p = 0.027). CONCLUSION: The results from arthroscopic suturing of large and extensive rotator cuff injuries seem to be influenced by the patient's bone mineral density, as assessed using bone densitometry. PMID- 26229900 TI - Result from arthroscopic surgical treatment of renewed tearing of the rotator cuff of the shoulder. AB - OBJECTIVES: To evaluate function among patients with postoperative recurrence of rotator cuff injuries that was treated arthroscopically (case series) and compare this with function in patients without recurrence (control group); and to compare function among patients with recurrence of rotator cuff injuries that were greater than and smaller than 3 cm. METHODS: This was a retrospective evaluation of patients who underwent arthroscopic revision of rotator cuff injuries using the ASES, Constant & Murley and UCLA scores and a visual analog pain scale, in comparison with patients in a control group who underwent primary rotator cuff repair. RESULTS: The size of the rotator cuff injury recurrence had a statistically significant influence on the result from the arthroscopic surgical treatment. The functional scores showed worse results than those from the first procedure. CONCLUSION: Arthroscopic surgical treatment of renewed tearing of rotator cuff injuries showed worse functional scores than those from primary repair of the injury. PMID- 26229901 TI - Axillary artery lesion secondary to fracturing of the proximal third of the humerus: case report. AB - Lesions of the axillary artery are rare in patients with fracturing of the proximal third of the humerus and may have greatly varying clinical manifestations. They are responsible for 15% and 20% of upper-limb artery injuries and the commonest mechanism is a fall to the ground, which accounts for 79% of such injuries. In some cases, the signs only appear later on. It is important to bear this association in mind, so as to make an early diagnosis and avoid serious complications. We report on a case of traumatic injury of the axillary artery secondary to fracturing of the proximal third of the humerus in an 84-year-old patient, with late evolution of clinical signs of ischemia in the limb affected. The aim here was to discuss the diagnostic difficulties and treatment. PMID- 26229902 TI - Tumor formation in Hoffa's infrapatellar fat: Case report. AB - Although tumors or pseudotumoral lesions are rare in the infrapatellar fat, they may affect it. Osteochondroma is the commonest benign bone tumor. However, extraskeletal presentations are rare. There are three extraskeletal variants of osteochondroma: synovial chondromatosis, para-articular chondroma and soft-tissue chondroma. We present a case of a single intra-articular lesion in the area of Hoffa's fat, in a 78-year-old female patient with a complaint of progressive knee pain associated with severe arthrosis. From the clinical and radiological findings, the diagnosis was para-articular osteochondroma. However, the histopathological findings, after excision of the lesion, showed that this was synovial chondromatosis secondary to osteoarthrosis. PMID- 26229903 TI - The RBO turns 50 and gets a present. PMID- 26229904 TI - Advances in treating exposed fractures. AB - The management of exposed fractures has been discussed since ancient times and remains of great interest to present-day orthopedics and traumatology. These injuries are still a challenge. Infection and nonunion are feared complications. Aspects of the diagnosis, classification and initial management are discussed here. Early administration of antibiotics, surgical cleaning and meticulous debridement are essential. The systemic conditions of patients with multiple trauma and the local conditions of the limb affected need to be taken into consideration. Early skeletal stabilization is necessary. Definitive fixation should be considered when possible and provisional fixation methods should be used when necessary. Early closure should be the aim, and flaps can be used for this purpose. PMID- 26229905 TI - Pseudoaneurysm after arthroscopic procedure in the knee. AB - The aim of this study was to review all cases of pseudoaneurysm in the literature, in predominantly arthroscopic procedures on the knee, and to report on a case of pseudoaneurysm that we treated. A bibliographic search was conducted for scientific articles published in Brazilian and foreign periodicals over the last 23 years. Forty-seven cases were found, in 40 articles. In addition to these 47 cases, there was the case that we treated, which was also included in the data. Among the operations that progressed with formation of a pseudoaneurysm, 60% were cases of meniscal injuries and 23%, anterior cruciate ligament injuries. In 46% of the cases, the artery affected with the popliteal, and in 21%, the inferomedial genicular artery. The commonest clinical symptom was pain (37%), followed by pulsating tumor (31%), edema of the calf (12%) and hemarthrosis (11%). The median time taken to make the diagnosis was 11 days, but it ranged from one day to 10 weeks after the procedure. Although rare, pseudoaneurysms are a risk that is inherent to arthroscopic surgery. All patients should be made aware of the vascular risks, even in small-scale procedures. PMID- 26229906 TI - Fractures of the distal clavicle: comparison between two surgical treatment methods. AB - OBJECTIVE: To compare the clinical and radiographic results from osteosynthesis of fractures of the lateral third of the clavicle, using two methods: T plates or anchors together with Kirschner wires. METHODS: Fifteen patients of mean age 34.3 years (range: 19-57) and mean follow-up 22.7 months (range: 14-32) were evaluated. In nine cases, a T plate was used; and in six cases, coracoclavicular fixation was used with anchors in the coracoid process and Kirschner wires through the acromioclavicular joint. The evaluation included the Constant score, personal satisfaction and radiographic assessment. RESULTS: Both types of treatment achieved consolidation in all cases. Group 1 presented a higher Constant score (83.4) than that of Group 2 (76.4) (p = 0.029). Neither of the techniques presented any severe complications, and mild complications were only observed in Group 2 (80%), mostly consisting of migration of the Kirschner wire and superficial infection. CONCLUSION: Surgical treatment of fractures of the distal clavicle using T plates provided the same consolidation rate as shown by coracoclavicular fixation with anchors in the coracoid process and Kirschner wires through the acromioclavicular joint, and better clinical results. LEVEL OF EVIDENCE: Level III evidence was obtained. Comparative retrospective study and therapeutic study were performed. PMID- 26229907 TI - Evaluation of the results from surgical treatment of fractures of the lateral extremity of the clavicle, using the double ligature technique. AB - OBJECTIVE: To evaluate the incidence of consolidation in surgical treatment of fractures of the lateral extremity of the clavicle using the double subcoracoid ligature technique, with nonabsorbable No. 5 thread. METHODS: Between May 1993 and June 2013, the Shoulder and Elbow Group of our service surgically treated 116 patients (116 shoulders) with fractures of the lateral extremity of the clavicle. Among these, we were able to reassess 65 cases. The surgical technique used consisted of double subcoracoid ligature with two nonabsorbable threads. In two patients classified as type III, we had to combine this technique with use of an interfragmentary screw for fixation of the intra-articular portion of the acromioclavicular joint. RESULTS: We achieved fracture consolidation in 90%. Fourteen cases (21%) evolved with major complications: four cases of pseudarthrosis, five of adhesive capsulitis, two of delayed consolidation and three of loss of reduction. Two cases (3%) evolved with minor complications of skin granuloma. CONCLUSION: The double ligature technique for fractures of the lateral extremity of the clavicle promotes the stabilization needed for consolidation to take place, without the need for synthesis using metal components. It avoids reoperation for the synthesis material to be removed. Moreover, it is a low-cost procedure with good reproducibility and preservation of the acromioclavicular joint. PMID- 26229908 TI - Results from surgical treatment of Morel-Lavallee lesions: prospective cohort study. AB - OBJECTIVE: To present the results from early diagnosis and delayed surgical treatment of a cohort of patients who were diagnosed with Morel-Lavallee lesions. METHODS: Between January 2006 and December 2013, we performed delayed surgical debridement on Morel-Lavallee lesions, after delimitation of the local tissue necrosis, followed by closure through second intention and/or use of grafts/flaps. RESULTS: All the patients evolved with complete closure of the lesion after the delayed debridement, granulation of the operative wound and primary suturing or construction of pedunculated flaps. Three patients (50%) evolved with deep infectious processes due to the successive operative procedures. CONCLUSION: Whatever the treatment methods used are, they should be performed in a radical manner. If not, the patient will be at risk of evolution to septicemia and death. PMID- 26229909 TI - Associations of vitamin D deficiency with postoperative gait and mortality among patients with fractures of the proximal femur. AB - OBJECTIVE: To assess whether serum vitamin D concentration is associated with gait status and mortality among patients with fractures of the proximal femur, six months after suffering the fracture. METHODS: Consecutive patients aged >=65 years with fractures of the proximal femur, who were admitted to the orthopedics and traumatology ward of our service between January and December 2011, were prospectively evaluated. Clinical, radiological, epidemiological and laboratory analyses were performed, including vitamin D. The patients underwent surgery and were followed up as outpatients, with return visits 15, 30, 60 and 180 days after discharge, at which the outcomes of gait and mortality were evaluated. RESULTS: Eighty-eight patients were evaluated. Two of them were excluded because they presented oncological fractures. Thus, 86 patients of mean age 80.2 +/- 7.3 years were studied. In relation to serum vitamin D, the mean was 27.8 +/- 14.5 ng/mL, and 33.7% of the patients presented deficiency of this vitamin. In relation to gait, univariate and multivariate logistic regression showed that vitamin D deficiency was not associated with gait recovery, even after adjustment for gender, age and type of fracture (OR: 1.463; 95% CI: 0.524-4.088; p = 0.469). Regarding mortality, Cox regression analysis showed that vitamin D deficiency was not related to its occurrence within six months, even in multivariate analysis (HR: 0.627; 95% CI: 0.180-2.191; p = 0.465). CONCLUSION: Serum vitamin D concentration was not related to gait status and/or mortality among patients with fractures of the proximal femur, six months after suffering the fracture. PMID- 26229910 TI - Trochlear dysplasia and patellar instability in patients with Down syndrome. AB - OBJECTIVE: To analyze occurrences of trochlear dysplasia in patients with Down syndrome in the presence and absence of femoropatellar instability. METHODS: Eleven knees with stable patellae and thirteen with unstable patellae in patients with Down syndrome were compared. Radiographs were produced to evaluate patellar height, trochlear angle and femoropatellar congruence angle. RESULTS: The prevalence ratio for a high patella between the unstable and the stable patients was 1.01 using the Insall-Salvati index and 0.68 using the Caton-Deschamps index. For an abnormal congruence angle, the prevalence ratio was 2.04. An increased congruence angle was only found in four cases, all presenting instability. CONCLUSIONS: Trochlear dysplasia was only found in cases of instability. The trochlear groove angle and the femoropatellar congruence angle correlated with the presence of patellar instability. PMID- 26229911 TI - Anatomical reference point for harvesting a flexor graft during arthroscopic reconstruction of the anterior cruciate ligament. AB - OBJECTIVES: To evaluate the prevalence of a vascular network adjacent to the insertion of the pes anserinus, so that it could be used as an anatomical reference point to facilitate harvesting flexor grafts for arthroscopic reconstruction of the anterior cruciate ligament (ACL). METHODS: Thirty patients with ACL tears who were going to undergo ACL reconstruction using the tendons of the semitendinosus and gracilis muscles as grafts were selected randomly. During the harvesting of these tendons, the presence or absence of this anatomical reference point was noted. RESULTS: All the patients presented a vascular network of greater or lesser diameter. CONCLUSION: The vascular network seems to be a good reference point during harvesting of the tendons of the semitendinosus and gracilis muscles, for facilitating graft harvesting. PMID- 26229912 TI - Alignment of the tibial component in total knee arthroplasty procedures using an intramedullary or extramedullary guide: double-blind randomized prospective study. AB - OBJECTIVES: To evaluate the results obtained through using an intramedullary or extramedullary guide for sectioning the tibia in total knee arthroplasty procedures, with a view to identifying the accuracy of these guides and whether one might be superior to the other. METHODS: This was a randomized double-blind prospective study on 41 total knee arthroplasty procedures performed between August 2011 and March 2012. The angle between the base of the tibial component and the mechanical axis of the tibia was measured during the immediate postoperative period by means of radiography in anteroposterior view on the tibia that encompassed the knee and ankle. RESULTS: There was no demographic difference between the two groups evaluated. The mean alignment of the tibial component in the patients of group A (intramedullary) was 90.3 degrees (range: 84-97 degrees ). In group B (extramedullary), it was 88.5 degrees (range: 83-94 degrees ). CONCLUSION: In our study, we did not find any difference regarding the precision or accuracy of either of the guides. Some patients present an absolute or relative contraindication against using one or other of the guides. However, for the other cases, neither of the guides was superior to the other one. PMID- 26229913 TI - Biomechanical analysis on transverse tibial fixation in anterior cruciate ligament reconstructions. AB - OBJECTIVE: To verify whether the combination of tibial cross pin fixation and femoral screw fixation presents biomechanical advantages when compared to femoral cross pin fixation and tibial screw fixation for the reconstruction of the anterior cruciate ligament (ACL). METHODS: Thirty-eight porcine knees and bovine extensor digitorum tendons were used as the graft materials. The tests were performed in three groups: (1) standard, used fourteen knees, and the grafts were fixated with the combination of femoral cross pin and a tibial screw; (2) inverted, used fourteen knees with an inverted combination of tibial cross pin and a femoral screw; (3) control, ten control tests performed with intact ACL. After the grafts fixation, all the knees were subjected to tensile testing to determine yield strength and ultimate strength. RESULTS: There was no statistically significant difference in survival techniques in regard to strength, yield load and tension. There was a higher survival compared in the standard curves of yield stress (p < 0.05). CONCLUSION: There is no biomechanical advantage, observed in animal models testing, in the combination of tibial cross pin fixation and femoral screw when compared to femoral cross pin fixation and tibial screw. PMID- 26229914 TI - Neuromuscular efficiency of the vastus lateralis and biceps femoris muscles in individuals with anterior cruciate ligament injuries. AB - OBJECTIVE: To analyze strength and integrated electromyography (IEMG) data in order to determine the neuromuscular efficiency (NME) of the vastus lateralis (VL) and biceps femoris (BF) muscles in patients with anterior cruciate ligament (ACL) injuries, during the preoperative and postoperative periods; and to compare the injured limb at these two times, using the non-operated limb as a control. METHODS: EMG data and BF and VL strength data were collected during three maximum isometric contractions in knee flexion and extension movements. The assessment protocol was applied before the operation and two months after the operation, and the NME of the BF and VL muscles was obtained. RESULTS: There was no difference in the NME of the VL muscle from before to after the operation. On the other hand, the NME of the BF in the non-operated limb was found to have increased, two months after the surgery. CONCLUSIONS: The NME provides a good estimate of muscle function because it is directly related to muscle strength and capacity for activation. However, the results indicated that two months after the ACL reconstruction procedure, at the time when loading in the open kinetic chain within rehabilitation protocols is usually started, the neuromuscular efficiency of the VL and BF had still not been reestablished. PMID- 26229915 TI - Platelet-rich plasma (PRP) applied during total knee arthroplasty. AB - OBJECTIVE: To evaluate the efficacy of platelet-rich plasma regarding healing, pain and hemostasis after total knee arthroplasty, by means of a blinded randomized controlled and blinded clinical study. METHODS: Forty patients who were going to undergo implantation of a total knee prosthesis were selected and randomized. In 20 of these patients, platelet-rich plasma was applied before the joint capsule was closed. The hemoglobin (mg/dL) and hematocrit (%) levels were assayed before the operation and 24 and 48 h afterwards. The Womac questionnaire and a verbal pain scale were applied and knee range of motion measurements were made up to the second postoperative month. The statistical analysis compared the results with the aim of determining whether there were any differences between the groups at each of the evaluation times. RESULTS: The hemoglobin (mg/dL) and hematocrit (%) measurements made before the operation and 24 and 48 h afterwards did not show any significant differences between the groups (p > 0.05). The Womac questionnaire and the range of motion measured before the operation and up to the first two months also did not show any statistical differences between the groups (p > 0.05). The pain evaluation using the verbal scale showed that there was an advantage for the group that received platelet-rich plasma, 24 h, 48 h, one week, three weeks and two months after the operation (p < 0.05). CONCLUSIONS: In the manner in which the platelet-rich plasma was used, it was not shown to be effective for reducing bleeding or improving knee function after arthroplasty, in comparison with the controls. There was an advantage on the postoperative verbal pain scale. PMID- 26229916 TI - Acromioclavicular dislocation: postoperative evaluation of the coracoclavicular ligaments using magnetic resonance. AB - OBJECTIVE: To radiologically evaluate the healing of the coracoclavicular ligaments after surgical treatment for acromioclavicular dislocation. METHODS: Ten patients who had undergone surgical treatment for acromioclavicular dislocation via a posterosuperior route at least one year earlier were invited to return for radiological assessment using magnetic resonance. This evaluation was done by means of analogy with the scale described in the literature for studying the healing of the anterior cruciate ligament of the knee and for measuring the healed coracoclavicular ligaments. RESULTS: A scar structure of fibrous appearance had formed in 100% of the cases. In 50% of the cases, the images of this structure had a good appearance, while the other 50% were deficient. CONCLUSION: Late postoperative evaluation using magnetic resonance, on patients who had been treated for acute acromioclavicular dislocation using a posterosuperior route in the shoulder, showed that the coracoclavicular ligaments had healed in 100% of the cases, but that this healing was deficient in 50%. PMID- 26229917 TI - Long-term functional evaluation of videoarthroscopic treatment of partial injuries of the rotator cuff. AB - OBJECTIVE: To compare the functional results from high and low-grade isolated partial lesions of the supraspinatus tendon of bursal and articular types, after arthroscopic treatment. METHODS: Sixty-four patients with isolated partial lesions of the supraspinatus tendon were evaluated. The mean length of follow-up was 76 months (range: 29-193). The mean age was 59 years (range: 36-82). The dominant side was affected in 44 patients (68.8%). There were 35 bursal lesions (54.7%) and 29 articular lesions (45.3%). We used the Ellman classification and characterized the lesions as low or high-grade according to whether they affected less than or more than 50% of the tendon thickness, respectively. Debridement was performed in 15 patients (23.5%), repair without completing the lesion in 11 (17%) and repair after completing the lesion in 38 (59.5%). The functional assessments on the patients were done using the Constant & Murley and UCLA scores. RESULTS: The mean Constant & Murley score among the patients with bursal lesions was 82.64 +/- 6.98 (range: 59.3-99) and among those with articular lesions, 83.57 +/- 7.58 (range: 66-95), while the mean UCLA score in the bursal lesions was 33.37 +/- 2.85 (range: 21-35) and in the articular lesions, 32.83 +/- 2.95 (range: 22-35). CONCLUSION: Videoarthroscopic treatment of partial lesions of the rotator cuff presents good or excellent results when the low-grade lesions are debrided and the high-grade lesions are completed and repaired. These results are maintained over the long term, with a high satisfaction rate and few complications. PMID- 26229918 TI - Preliminary analysis on the MD-4((r)) plasma-sprayed titanium acetabular component. AB - OBJECTIVES: To evaluate the short-term performance of a type of implant manufactured in Brazil. METHODS: This study analyzed a cohort of 60 patients who underwent implantation of MD-4((r)) acetabular components during primary hip arthroplasty procedures performed between January 1, 2010, and August 1, 2012. The patients were studied retrospectively with regard to clinical behavior, stability and radiological osseointegration. The patients were followed up for a minimum of 12 months and a maximum of 42 months (mean: 27) and were evaluated by means of the Harris Hip Score, SF-36 questionnaire and serial conventional radiographs. RESULTS: All the components were radiologically stable, without evidence of migration or progressive radiolucency lines. On average, the Harris Hip Score evolved from 36.1 to 92.1 (p < 0.001) and the SF-36 showed significant increases in all its domains (p < 0.001). No differences were observed among patients with osteoarthrosis, osteonecrosis, hip dysplasia or other conditions. CONCLUSIONS: The short-term results showed clinical and radiological signs of stability and osseointegration of the implants, which may represent a predictive factor regarding medium-term survival of this acetabular component. PMID- 26229919 TI - Evaluation of the anterolateral ligament of the knee by means of magnetic resonance examination. AB - OBJECTIVE: To evaluate the presence of the anterolateral ligament (ALL) of the knee in magnetic resonance imaging (MRI) examinations. METHODS: Thirty-three MRI examinations on patients' knees that were done because of indications unrelated to ligament instability or trauma were evaluated. T1-weighted images in the sagittal plane and T2-weighted images with fat saturation in the axial, sagittal and coronal planes were obtained. The images were evaluated by two radiologists with experience of musculoskeletal pathological conditions. In assessing ligament visibility, we divided the analysis into three portions of the ligament: from its origin in the femur to its point of bifurcation; from the bifurcation to the meniscal insertion; and from the bifurcation to the tibial insertion. The capacity to view the ligament in each of its portions and overall was taken to be a dichotomous categorical variable (yes or no). RESULTS: The ALL was viewed with signal characteristics similar to those of the other ligament structures of the knee, with T2 hyposignal with fat saturation. The main plane in which the ligament was viewed was the coronal plane. Some portion of the ligament was viewed clearly in 27 knees (81.8%). The meniscal portion was evident in 25 knees (75.7%), the femoral portion in 23 (69.6%) and the tibial portion in 13 (39.3%). The three portions were viewed together in 11 knees (33.3%). CONCLUSION: The anterolateral ligament of the knee is best viewed in sequences in the coronal plane. The ligament was completely characterized in 33.3% of the cases. The meniscal portion was the part most easily identified and the tibial portion was the part least encountered. PMID- 26229920 TI - Comparison of the efficacy of transforaminal and interlaminar radicular block techniques for treating lumbar disk hernia. AB - OBJECTIVE: To compare the interlaminar and transforaminal block techniques with regard to the state of pain and presence or absence of complications. METHOD: This was a randomized double-blind prospective study of descriptive and comparative nature, on 40 patients of both sexes who presented lumbar sciatic pain due to central-lateral or foraminal disk hernias. The patients had failed to respond to 20 physiotherapy sessions, but did not present instability, as diagnosed in dynamic radiographic examinations. The type of block to be used was determined by means of a draw: transforaminal (group 1; 20 patients) or interlaminar (group 2; 20 patients). RESULTS: Forty patients were evaluated (17 males), with a mean age of 49 years. There was a significant improvement in the state of pain in all patients who underwent radicular block using both techniques, although the transforaminal technique presented better results than the interlaminar technique. CONCLUSION: Both techniques were effective for pain relief and presented low complication rates, but the transforaminal technique was more effective than the interlaminar technique. PMID- 26229921 TI - Use of tranexamic acid for controlling bleeding in thoracolumbar scoliosis surgery with posterior instrumentation. AB - OBJECTIVE: Scoliosis surgery involves major blood loss and frequently requires blood transfusion. The cost and risks involved in using allogeneic blood have motivated investigation of methods capable of reducing patients' bleeding during operations. One of these methods is to use antifibrinolytic drugs, and tranexamic acid is among these. The aim of this study was to assess the use of this drug for controlling bleeding in surgery to treat idiopathic scoliosis. METHODS: This was a retrospective study in which the medical files of 40 patients who underwent thoracolumbar arthrodesis by means of a posterior route were analyzed. Of these cases, 21 used tranexamic acid and were placed in the test group. The others were placed in the control group. The mean volumes of bleeding during and after the operation and the need for blood transfusion were compared between the two groups. RESULTS: The group that used tranexamic acid had significantly less bleeding during the operation than the control group. There was no significant difference between the groups regarding postoperative bleeding and the need for blood transfusion. CONCLUSIONS: Tranexamic acid was effective in reducing bleeding during the operation, as demonstrated in other studies. The correlation between its use and the reduction in the need for blood transfusion is multifactorial and could not be established in this study. We believe that tranexamic acid may be a useful resource and that it deserves greater attention in randomized double-blind prospective series, with proper control over variables that directly influence blood loss. PMID- 26229922 TI - Effects of long-term administration of omeprazole on bone mineral density and the mechanical properties of the bone. AB - OBJECTIVES: Epidemiological studies have shown a relationship between long-term use of proton pump inhibitors and bone metabolism. However, this relationship has not yet become established. The aim of the present study was to analyze the mechanical properties and bone mineral density (BMD) of rats that were subjected to long-term omeprazole use. METHODS: Fifty Wistar rats weighing between 200 and 240 g were divided equally into five groups: OMP300 (omeprazole intake at a dose of 300 MUmoL/kg/day); OMP200 (200 MUmoL/kg/day); OMP40 (40 MUmoL/kg/day); OMP10 (10 MUmoL/kg/day); and Cont (control group; intake of dilution vehicle). The solutions were administered for 90 consecutive days. After the rats had been sacrificed, their BMD, the mechanical properties of the dissected femurs and their serum Ca++ levels were analyzed. RESULTS: The BMD of the OMP300 group was lower than that of the controls (p = 0.006). There was no difference on comparing the OMP200, OMP40 and OMP10 groups with the controls. The maximum strength and rigidity of the femur did not differ in the experimental groups in comparison with the controls. The OMP300 group had a statistically lower serum Ca++ concentration than that of the controls (p = 0.049), but the other groups did not show any difference in relation to the controls. CONCLUSION: Daily intake of 300 MUmoL/kg/day of omeprazole decreased the BMD of the femur, but without changes to the rigidity and strength of the femur in adult rats. PMID- 26229923 TI - Gorham's disease: clinical case. AB - Gorham's disease, also known as idiopathic massive osteolysis, is a rare pathological condition characterized by vascular proliferation that results in destruction and reabsorption of the bone matrix, of unknown etiology. It was first described by Jackson in 1838, but it was Gorham and Stout, in 1955, who defined this disease as a specific entity. It has variable clinical presentation and generally has progressive behavior. Controversy continues regarding the treatment and there is no standard treatment. This pathological condition generally presents a favorable prognosis. Here, a case of Gorham's disease with involvement of the left hip is presented, in a male patient without relevant antecedents. PMID- 26229925 TI - RBO print or eletronic? PMID- 26229924 TI - Hip arthroscopy. AB - Hip arthroscopy is a safe method for treating a variety of pathological conditions that were unknown until a decade ago. Femoroacetabular impingement is the commonest of these pathological conditions and the one with the best results when treated early on. The instruments and surgical technique for hip arthroscopy continue to evolve. New indications for hip arthroscopy has been studied as the ligamentum teres injuries, capsular repair in instabilities, dissection of the sciatic nerve and repair of gluteal muscles tears (injuries to the hip rotator cuff), although still with debatable reproducibility. The complication rate is low, and ever-better results with fewer complications should be expected with the progression of the learning curve. PMID- 26229926 TI - Hip salvage surgery in cerebral palsy cases: a systematic review. AB - Imbalance and muscle spasticity, in association with coxa valga and persistent femoral anteversion, compromises hip development in cases of cerebral palsy and may result in chronic pain and even dislocation. Some of these hips undergo salvage surgery because of the severe impact of their abnormalities in these patients' quality of life. We conducted a systematic review of the literature to compare the results from the main hip salvage techniques applied to these individuals. The literature search focused on studies that evaluated results from hip salvage surgery in cases of cerebral palsy, published from 1970 to 2011, which are present in the Embase, Medline, PubMed, Cochrane Library and SciELO databases. Although the results were not statistically comparable, this systematic review demonstrates that hip salvage surgery should be indicated after individual evaluation on each patient, due to the wide spectrum of presentations of cerebral palsy. Therefore, it seems that no surgical technique is superior to any other. Rather, there are different indications. PMID- 26229927 TI - Effect of methylprednisolone use on the rotator cuff in rats: biomechanical and histological study. AB - OBJECTIVE: To evaluate the influence of treatment with different doses of methylprednisolone on the mechanical resistance and possible histological alterations of the rotator cuff tendon in rats. METHODS: Male Wistar rats were divided randomly into four treatment groups: sham, vehicle or 0.6 mg/kg or 6.0 mg/kg of methylprednisolone. Changes to mechanical resistance (in N) and histological parameters (fibrillar appearance, presence of collagen, edema and vascular proliferation) of the rotator cuff tendon were evaluated. The analyses were conducted after administration of one treatment (24 h afterwards), two treatments (7 days afterward) or three treatments (14 days afterwards), into the subacromial space. RESULTS: Seven and fourteen days after the treatments were started, it was found that in a dose-dependent manner, methylprednisolone reduced the mechanical resistance of the rotator cuff tendon (p < 0.05 in relation to the vehicle group). Modifications to the histological parameters were observed on the 7th and 14th days after the first infiltration, especially regarding the presence of collagen and vascular proliferation, for the dose of 0.6 mg/kg of methylprednisolone, and also regarding the presence of collagen, edema and vascular proliferation for the dose of 6.0 mg/kg of corticoid. CONCLUSION: The results obtained demonstrated a relationship between methylprednisolone use through infiltration into the subacromial space and reduction of the mechanical resistance of and histological modifications to the rotator cuff tendon in rats. PMID- 26229928 TI - Reproducibility of the AO/ASIF and Gartland classifications for supracondylar fractures of the humerus in children. AB - OBJECTIVE: To evaluate the reproducibility of the radiographic classifications of Gartland and the Association for Osteosynthesis/Association for the Study of Internal Fixation (AO/ASIF) for supracondylar fractures of the humerus in children. METHODS: On two occasions, 50 radiographs in anteroposterior and lateral views were evaluated by three pediatric orthopedists in accordance with the Gartland and AO/ASIF pediatric classifications. Their responses were subjected to statistical analysis consisting of calculation of the kappa coefficient to assess the intra- and interobserver concordance, in both classifications. RESULTS: The strength of the intraobserver concordance was high or near perfect for the three examiners in the two classification systems. The strength of the interobserver concordance was high in the two systems, with kappa coefficients of 0.756 for the Gartland classification and 0.766 for the AO/ASIF classification. CONCLUSION: The Gartland and AO/ASIF classification systems showed similar reproducibility and performance. High strength of concordance was seen in the intra- and interobserver analyses. PMID- 26229929 TI - Safety zone for surgical access in the middle third of the clavicle: study on cadavers. AB - OBJECTIVE: The aim of this study was to establish a neurovascular safety zone for surgical access in the middle third of the clavicle, by means of dissection on cadavers. METHODS: Twenty shoulders were dissected in 10 cadavers, with deep dissection of the middle third of the clavicle. The following structures were identified: subclavian vein, upper trunk of the brachial plexus (anterior and posterior divisions) and suprascapular nerve. These structures were marked out in order to measure their distances from the most proximal point of the middle third of the clavicle. RESULTS: The mean distances from the middle third of the clavicle to the suprascapular nerve, subclavian vein, upper trunk, anterior division of the upper trunk and posterior division of the upper trunk were respectively, for the right side: 15.92 cm, 10.77 cm, 23.68 cm, 14.60 cm and 15.42 cm; and for the left side: 12.69 cm; 9.82 cm; 22.19 cm; 12.16 cm and 13.46 cm. CONCLUSION: There was a statistical difference in the distances to the suprascapular nerve and anterior division of the upper trunk, in comparing between the right and left sides. The closest neurovascular structures to the middle third of the clavicle were the suprascapular nerve and subclavian vein. PMID- 26229930 TI - Use of risedronate for consolidation and callus formation in Colles fractures in postmenopausal women: SOLID study. AB - OBJECTIVE: This open, randomized and blinded parallel-group multicenter study evaluated the efficacy of Actonel((r)) (35 mg) plus calcium/vitamin D versus calcium/vitamin D alone for preserving bone mineral density (BMD) in postmenopausal women with Colles fractures. METHODS: Patients with a Colles fracture for seven days were randomized to receive either Actonel((r)) (35 mg) once a week plus calcium/vitamin D (ACD group) or calcium/vitamin D alone (CD group). The patients were evaluated after 90 and 180 days of treatment. RESULTS: 59 ACD patients and 56 CD patients completed all the evaluations. At the end of the study, the BMD of the radius at the fracture location showed a negative change in the CD group (32.8%). The loss of BMD in the ACD group (20.8%) was slightly less than that in the CD group. There was a difference in the proportions of patients with BMD losses at the end of the study period in the two treatment groups, in favor of the ACD group, although this was not statistically significant. There was no significant difference in radiological identification of callus formation between the treatment groups. In the majority of the patients, the callus could be radiologically identified after 90 days. CONCLUSION: Postmenopausal women with Colles fractures who received risedronate sodium plus calcium/vitamin D did not show any significant difference in BMD loss in forearm fractures, in comparison with those who received calcium/vitamin D alone. Risedronate presented a tendency toward a protective effect regarding BMD loss due to immobilization. The time taken for fracture consolidation to be achieved was unaffected. PMID- 26229931 TI - Comparative radiographic analysis on the anatomical axis in knee osteoarthritis cases: inter and intraobserver evaluation. AB - OBJECTIVE: To make a comparative inter and intraobserver analysis on measurements of the anatomical axis between panoramic radiographs of the lower limbs in anteroposterior (AP) view with bipedal weight-bearing, on short film. METHODS: An accuracy study comparing radiographic measurements on 47 knees of patients attending the knee surgery outpatient clinic due to osteoarthritis. The radiographic evaluation used was as standardized for the total knee arthroplasty program, including panoramic AP views of the lower limbs and short radiographs of the knees in AP and lateral views, all with bipedal weight-bearing. Following this, the anatomical axis of the lower limbs or the femorotibial angle was measured by five independent examiners on the panoramic and short AP radiographs; three of the examiners were considered to be more experienced and two, less experienced. All the measurements were made again by the same examiners after an interval of not less than 15 days. The statistical analysis was performed using the intraclass correlation coefficient, in order to evaluate the inter and intraobserver concordance of the anatomical axis measurements. RESULTS: From the statistical analysis, it was observed that there was strongly significant concordance between the anatomical axis measurements on the panoramic and short radiographs, for all the five examiners and for both measurements. CONCLUSIONS: Under the conditions studied, short radiographs were equivalent to panoramic radiographs for evaluating the anatomical axis of the lower limbs in patients with advanced osteoarthritis. The measurements used also showed high rates of inter and intraobserver concordance and reproducibility. PMID- 26229932 TI - Total knee arthroplasty with mobile tibial weight-bearing: clinical evaluation after a minimum of five years of postoperative follow-up. AB - OBJECTIVE: To evaluate the medium and long term results from total knee arthroplasty with rotating tibial weight-bearing. METHODS: Between January 2000 and July 2007, 162 patients underwent total knee arthroplasty with mobile tibial weight-bearing. Among these, 96 were evaluated in a previous study with a mean follow-up of 4 years. In the present study, the same group was invited back for reassessment and the results were analyzed. Sixty-nine patients responded to this call (79 knees), and they were evaluated in accordance with the Knee Society Rating System (KSRS), after a mean follow-up of 8 years and 8 months (ranging from 5.5 and 13 years). RESULTS: A mean KSRS score of 74.41 points was obtained, with good or excellent results. CONCLUSION: The medium and long-term results from total knee arthroplasty with mobile tibial weight-bearing were good, and a mean score of 74.41 points in the Knee Society Clinical Rating System was attained. PMID- 26229933 TI - Distal femoral cut in total knee arthroplasty in a Brazilian population. AB - OBJECTIVE: To determine the ideal angle for making the distal femoral cut in total knee arthroplasty in a Brazilian population. METHODS: Panoramic radiographs of the lower limbs bearing weight from 79 patients (57 women and 22 men) were studied, totaling 107 knees with an indication for total knee arthroplasty. The femoral anatomical axis, femoral mechanical axis and cervical-diaphyseal angle were traced out. The angle of the femoral cut was determined from the meeting point between the femoral anatomical and mechanical axes. The ideal degree of femoral valgus was compared between men and women and between knees presenting varus and valgus alignment of the lower limb. The ideal distal femoral cut was also correlated with the cervical-diaphyseal angle. RESULTS: The ideal femoral valgus angle ranged from 4.2 to 8.6 degrees, with a mean of 6.3 degrees. There was no statistically significant difference in the distal femoral cut between patients with coronal varus and valgus alignment (p = 0.180). Comparing men and women, there was no statistically significant difference regarding the ideal femoral valgus between the groups (p = 0.057). The cervical-diaphyseal angle presented an inverse relationship with the distal femoral cut. CONCLUSIONS: The mean angle between the femoral mechanical and anatomical axes was 6.3 degree. Neither preoperative coronal alignment nor sex had any influence on the distal femoral cut. The cervical-diaphyseal angle presented an inverse relationship with the distal femoral cut. PMID- 26229934 TI - Reconstruction of the anterior cruciate ligament: comparison of analgesia using intrathecal morphine, intra-articular morphine and intra-articular levobupivacaine. AB - OBJECTIVE: To compare the analgesic effect of intra-articular administration of morphine and levobupivacaine (separately or in combination) with intrathecal administration of morphine in patients undergoing anterior cruciate ligament (ACL) reconstruction using autologous grafts from the patellar tendon. METHODS: This was a retrospective analysis on data gathered from the medical files of 60 patients aged 20 to 50 years who underwent knee video arthroscopy for ACL reconstruction. The patients were divided into four groups of 15 individuals (A, B, C and D) according to the agent administered into the joint and around the incision: 20 mL of saline solution with 5 mg of morphine in A; 20 mL of 0.5% levobupivacaine solution in B; 10 mL of solution with 2.5 mg of morphine plus 10 mL of 0.5% levobupivacaine solution in C; and morphine administered intrathecally in D. RESULTS: All the groups presented low pain scores during the first 12 h after the surgery. Groups B and C presented significantly greater pain scores than shown by group D (control), 24 h after the surgery. There was no statistical difference in pain scores between group A and group D. CONCLUSION: The patients in group A presented analgesia comparable to that of the patients in group D, whereas the procedure of group C was no capable of reproducing the analgesic effect observed in group D, as observed 24 h after the surgery. Further studies are needed in order to show the exact mechanism of action, along with the ideal dose and concentration for applying opioids to joints. PMID- 26229935 TI - Evaluation of the results from arthroscopic surgical treatment of rotator cuff injuries in patients aged 65 years and over. AB - OBJECTIVES: To evaluate the results from arthroscopic surgical treatment of rotator cuff injuries in patients aged 65 years and over. METHODS: Between 1998 and 2009, 168 patients underwent operations. Five cases were excluded. The remaining 163 patients were stratified according to their age group: 65-69 years (49.1%), 70-74 (26.4%) and 75 years and over (24.5%). Their mean age was 71 years (range: 65-83). There were 63 male patients (38.7%). The mean length of time with pain, from the onset of symptoms to the surgery, was 23 months (range: 2 days to 240 months). Sixty-two patients (38%) reported histories of trauma and 26 (16%) reported that their pain worsened through exertion. RESULTS: From the UCLA criteria, 80.4% of the results were excellent, 16% good, 1.8% fair and 1.8% poor. Complications occurred in 11%. The final clinical result did not show any correlation with age progression, injury size or tendons affected. However, there was a significant association (p < 0.001) between the presence of trauma and larger injuries. The length of time between the onset of symptoms and the surgical procedure had a significant relationship (p < 0.027) with the postoperative results: the longer this time was, the worse the results were. CONCLUSION: Arthroscopic treatment of rotator cuff injuries in patients aged 65 years and over presented excellent and good results in 96.4% of the cases, according to the UCLA assessment, with a low complication rate. Advanced age did not show any influence on the postoperative clinical evolution, but the earlier the surgical treatment was instituted, the better the results were. PMID- 26229936 TI - Functional evaluation of arthroscopic treatment of SLAP lesions through the O'Brien portal. AB - OBJECTIVE: To evaluate the functional results from arthroscopic repair of SLAP lesions through the portal described by O'Brien. METHODS: A retrospective evaluation was conducted on 19 shoulders in 18 patients who underwent arthroscopic repair of SLAP lesions through the O'Brien portal between November 2007 and January 2012. RESULTS: Nineteen shoulders in 18 patients were evaluated: 16 male patients (84.2%) and three female patients (15.7%). The patients' ages ranged from 27 to 40 years (mean of 34.3 years). There were 12 patients (63.1%) with injuries on the right shoulder, six (31.5%) with injuries on the left shoulder and one (5.2%) with bilateral injury. In relation to dominance, 13 patients (68.4%) presented the injury on the dominant limb and five (26.3%) were affected on the non-dominant limb. We observed that nine cases (47.3%) had SLAP lesions alone and 10 cases (52.6%) were related to glenohumeral instability. There was one case (5.2%) of recurrence of glenohumeral dislocation, but this patient chose not to undergo a new surgical intervention. According to the UCLA and ASES scales translated and adapted to the Portuguese language, 96% of the results were good or excellent. CONCLUSION: The approach for treating SLAP lesions through the portal described by O'Brien et al. is easy to reproduce, with a high rate of good and excellent results and a low complication rate. PMID- 26229937 TI - Rotator cuff injury in patients over the age of 65 years: evaluation of function, integrity and strength. AB - OBJECTIVE: To retrospectively evaluate the results from patients who underwent arthroscopic treatment for rotator cuff injuries, among those aged over 65 years, observing integrity, function and strength. METHODS: Thirty-five shoulders were operated between July 2005 and July 2010, and 28 shoulders were re-evaluated regarding elevation strength and external rotation, using a digital dynamometer. Integrity was evaluated by means of ultrasound examinations. The patients, whose mean age was 70.54 years (ranging from 65 to 82 years), were followed up for a minimum of 26 months and mean of 51.18 months (ranging from 26 to 82 months). To evaluate function, the UCLA score, the Simple Shoulder Test (SST) and a visual analog scale (VAS) for pain were used. RESULTS: In analyzing the ultrasound scans, it was observed that the integrity of the rotator cuff was maintained in 75% of the cases at the end of the follow-up, along with the improvement in the UCLA score, which evolved from 17.46 to 32.39, i.e. excellent and good results in 89.28%. The mean SST and VAS indices were 9.86 and 1.5 respectively. CONCLUSION: Arthroscopic surgery to repair rotator cuff injuries in patients over the age of 65 years leads to improved function and pain relief, with maintenance of the integrity of the repair. The data on muscle strength were inconclusive. PMID- 26229938 TI - Low-term results from non-conventional partial arthroplasty for treating rotator cuff arthroplasthy. AB - OBJECTIVE: To evaluate the evolution of the functional results from CTA((r)) hemiarthroplasty for surgically treating degenerative arthroplathy of the rotator cuff, with a mean follow-up of 5.4 years. METHODS: Eighteen patients who underwent CTA((r)) partial arthroplasty to treat degenerative arthroplathy of the rotator cuff between April 2007 and June 2009 were reevaluated, with minimum and mean follow-ups of 4.6 years and 5.4 years, respectively. Pre and postoperative parameters for functionality and patient satisfaction were used (functional scale of the University of California in Los Angeles, UCLA). All the patients underwent prior conservative treatment for 6 months and underwent surgical treatment because of the absence of satisfactory results. Patients were excluded if they presented any of the following: previous shoulder surgery; pseudoparalysis; insufficiency of the coracoacromial arch (type 2 B in Seebauer's classification); neurological lesions; or insufficiency of the deltoid muscle and the subscapularis muscle. RESULTS: With a mean follow-up of 5.4 years, 14 patients considered that they were satisfied with the surgery (78%); the mean range of joint motion for active elevation improved from 55.8 degrees before the operation to 82.0 degrees after the operation; the mean external rotation improved from 18.9 degrees before the operation to 27.3 degrees after the operation; and the mean medial rotation remained at the level of the third lumbar vertebra. The mean UCLA score after the mean follow-up of 5.4 years was 23.94 and this was an improvement in comparison with the preoperative mean and the mean 1 year after the operation. CONCLUSION: The functional results from CTA((r)) hemiarthroplasty for treating rotator cuff arthroplasty in selected patients remained satisfactory after a mean follow-up of 5.4 years. PMID- 26229939 TI - Analysis on the serum levels of the biomarker CTX-II in professional indoor soccer players over the course of one season. AB - OBJECTIVE: The aim of this study was to analyze the blood serum levels of CTX-II in professional indoor soccer players, at three different times during one season: at the start of the pre-season, four months later (a time that marks the middle of the season) and at the end of the season. METHODS: Fourteen male soccer players of mean age 19 years were included. Blood samples of 3 mL were collected from each individual. The samples were analyzed by means of Elisa tests. RESULTS: There was a significant increase in the serum level of CTX-II in the indoor soccer players, from the beginning to the end of the season (p < 0.01). CONCLUSION: These data suggest that joint degradation had occurred in these soccer players, by the end of this period. It is evident that further studies are needed, with methodological rigor, so as to make an effective contribution toward precise elucidation of the etiology of this osteoarthritis and its relationship with the biomarkers, as a tool for early diagnosis. PMID- 26229940 TI - Parsonage-Turner syndrome. AB - OBJECTIVE: To describe the clinical, electrophysiological and imaging findings from Parsonage-Turner syndrome and evaluate the results from conservative treatment. METHODS: Eight cases were studied between February 2010 and February 2012, with a minimum follow-up of one year (mean of 14 months). All the patients answered a clinical questionnaire and underwent functional evaluation using the Constant and Murley score. After clinical suspicion was raised, an electromyography examination was performed to confirm the diagnosis. RESULTS: Eight patients (mean age of 29 years) were evaluated. The right side was affected in 70% of the cases, and the dominant side in 80% of the cases. All the patients reported that their shoulder pain had started suddenly, lasting from one to five days in six cases and up to 15 days in two cases. In three cases, severe atrophy of the deltoid muscle was observed. Hypotrophy of the supraspinatus and infraspinatus muscles was observed in three cases. A winged scapula was observed in the two remaining cases. Electromyography demonstrated involvement of the long thoracic nerve in these last two cases and confirmed the involvement of the axillary and suprascapular nerves in the remaining six cases. The mean score on the Constant and Murley scale was 96 at the end of the conservative treatment with non-steroidal anti-inflammatory drugs and physiotherapy. Six of the eight patients presented good recovery of muscle strength. CONCLUSIONS: In the majority of the cases, the functional recovery was good, although muscle strength was not completely restored in some of them. PMID- 26229941 TI - Radiographic study on the tibial insertion of the posterior cruciate ligament. AB - OBJECTIVE: To establish the radiographic distances from posterior cruciate ligament (PCL) tibial insertions centers to the lateral and medial tibial cortex in the anteroposterior view, and from these centers to the PCL facet most proximal point on the lateral view, in order to guide anatomical tunnels drilling in PCL reconstruction and for tunnel positioning postoperative analysis. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty cadaver knees were evaluated. The PCL's bundles tibial insertions were identified and marked out using metal tags, and the knees were radiographed. On these radiographs, the bundles insertion sites center location relative to the tibial mediolateral measure, and the distances from the most proximal PCL facet point to the bundle's insertion were determined. All measures were calculated using the ImageJ software. RESULTS: On the anteroposterior radiographs, the mean distance from the anterolateral (AL) bundle insertion center to the medial tibial edge was 40.68 +/ 4.10 mm; the mean distance from the posteromedial (PM) bundle insertion center to the medial tibial edge was 38.74 +/- 4.40 mm. On the lateral radiographs, the mean distances from the PCL facet most proximal point to AL and PM bundles insertion centers were 5.49 +/- 1.29 mm and 10.53 +/- 2.17 mm respectively. CONCLUSIONS: It was possible to establish a radiographic pattern for PCL tibial bundles insertions, which may be useful for intraoperative tunnels locations control and for postoperative tunnels positions analysis. PMID- 26229942 TI - Popliteal artery injury during posterior cruciate ligament reconstruction. AB - This study reports a case of popliteal artery injury during arthroscopic reconstruction of the posterior cruciate ligament. The evolution of the injury is described and comments are made regarding the anatomy of this artery and potential risks of this surgical technique. This study had the aims of alerting the medical community, especially knee surgeons, regarding a severe surgical complication and discussing the ways of preventing it. PMID- 26229943 TI - Bryan and Morrey type IV intra-articular fracture of the distal extremity of the humerus treated surgically with anterior access: case report. AB - Within the context of elbow-level trauma, fractures with a coronal line at the distal extremity of the humerus are rare and result from indirect axial trauma with the arm extended. These are difficult-to-treat intra-articular fractures, since they require stable anatomical reduction in order to maintain joint congruence and diminish complications such as stiffness. This paper reports a case that occurred in a young man who suffered a fall from a ladder that resulted in a Bryan and Morrey type IV intra-articular fracture of the humerus. The injury was treated surgically by means of an anterior access, using osteosynthesis with two Herbert screws that were inserted from anterior to posterior. PMID- 26229944 TI - Fracture of the proximal extremity of the tibia after anterior cruciate ligament reconstruction: case report. AB - We report a rare condition that has been little described in the literature: a fracture of the proximal extremity of the tibia after anterior cruciate ligament reconstruction using an autologous patellar bone-tendon graft. In this report, we discuss the factors that predisposed toward this episode, the treatment and the evolution of the case after the surgical treatment. PMID- 26229945 TI - Effect of cleft lip palate repair on craniofacial growth. AB - OBJECTIVE: The aim of this cross-sectional study was to compare craniofacial growth among operated and unoperated unilateral cleft lip and palate non syndromic subjects. MATERIALS AND METHODS: A sample of 180 subjects of Indian origin was selected. Of them, 90 were operated, and 90 were unoperated complete unilateral cleft lip and palate individuals. The subjects were divided into three age groups of 3-5, 8-10, and 20-25 years comprised of 30 patients in each group. The following measurements were evaluated: Angle and length of the cranial base; maxillary spatial positioning and length; mandibular spatial positioning; morphology and length; maxillomandibular relationship. Comparative analysis of the means between the groups was performed with Student's t-test at the significance levels of 5%. The ANOVA test has been performed to test the effect of time. RESULTS: No significant differences were observed between the measurements that represented the angle and length of the cranial base of unoperated and the operated patients (P>0.05). There was statistically significant decrease (P?0.05) in the maxillary length (Co-A; 69.00 mm in 3-5 years, 68.33 mm in 8-10 years, and 67.17 mm in 20-25 years age group), and SNA angle (74.83 degrees in 3-5 years, 74.17 degrees in 8-10 years and 73.17 degrees in 20-25 years age group) in operated group. No significant difference noticed on cephalometric values of the mandible, except Ar-Go-Me angle (P?0.05), which showed vertical growth pattern in unoperated patients (132.50 degrees in 3-5 years, 132.00 degrees I 8-10 years and 138.33 degrees in 20-25 years age group). CONCLUSION: Lip and palate repair has a significant influence on the maxilla and resulting in retarded growth of maxilla, which causes midface deficiency beyond acceptable sagittal limits. The Gonial angle showed vertical growth pattern in unoperated patients, but the cranial base angle and length of unoperated and the operated patients were similar. PMID- 26229946 TI - Evaluating the effect of laser irradiation on bone regeneration in midpalatal suture concurrent to rapid palatal expansion in rats. AB - BACKGROUND: Rapid palatal expansion is one of the most important orthopedic treatments that correct the dental and palatal constriction. Stability of the changes partly depend on the rapidity of new bone formation in affected sutures after expansion. The purpose of this study was to investigate the effect of laser irradiation on the healing of midpalatal suture concurrent to the expansion of midpalatal suture in rats. MATERIALS AND METHODS: A total of 78 male Sprague rats in seven groups were evaluated: A control group of six rats without any treatments and three experimental groups of 24 which underwent palatal expansion for different time periods (7, 14, and 30 days), and each divided into two groups of with and without laser irradiation. Laser therapy was done by gallium-aluminum arsenide diode laser with 810 nm wavelength and 4 J/cm(2) irradiation in days 0, 2, 4, 6, 8, 10, 12, 14 in 4 points (1 labial and 3 palatal points). After sacrificing, the sections were evaluated by histomorphometric and quantitative analysis and results were statistically investigated by independent samples t test. RESULTS: The results in 7 days, 14 days, and 30 days show that laser therapy can increase the rate of osteogenesis in palatal suture during rapid palatal expansion but the differences in 7 days groups were not significant (P = 0.117) while in 14 days groups (P = 0.032) and 30 days groups were significant (P = 0.001). Most of effectiveness of low-power laser was seen between 14 and 30 days while the laser therapy was stopped. CONCLUSION: These findings suggest that low-level laser irradiation can increase and accelerate bone regeneration in the midpalatal suture after rapid palatal expansion, hence, reduce retention time. PMID- 26229947 TI - Effect of tooth bleaching on orthodontic stainless steel bracket bond strength. AB - OBJECTIVES: The objective was to assess the shear bond strength (SBS) of composite resins on stainless steel brackets immediately bonded to previously bleached teeth with 35% hydrogen peroxide and to compare the neutralization effect of various antioxidant agents on the bond strength after bleaching. MATERIALS AND METHODS: One hundred sound human maxillary premolars were used for the study. Teeth were divided into 5 groups (n = 20); Group 1 (control), Group 2 (bleach treatment), Group 3 (sodium ascorbate treatment), Group 4 (tocopherol acetate treatment), and Group 5 (retinol acetate treatment). Teeth in Group 3, 4, and 5 were treated as in Group 2, but after that and before bleaching received treatment with sodium ascorbate, tocopherol acetate, and retinol acetate, respectively. Subsequently, teeth were bonded with stainless steel brackets (Ormco) using 3M Transbond XT. After 24 h, each specimen was loaded into a universal testing machine to determine the SBS at debonding. The data were exposed to the analysis of variance, Bonferroni, and Weibull Analysis. RESULT: There significant SBS difference (P = 0.000, F = 32.125) between various groups. Group 1 had the highest SBS (12.182 +/- 1.41 MPa) and Group 2 the least SBS (6.182 +/- 1.49 MPa). Significant SBS differences observed between Group 1 and 2; Group 2 and 3; Group 2 and 4; and Group 2 and 5 (P = 0.000). There was no significant SBS difference between Group 1 and 3; Group 1 and 4; and Group 3 and 4 (P = 1.000). Bonferroni results also indicated that there was a significant difference between Group 1 and 5 (P = 0.002); Group 3 and 5 (P = 0.144); and between Group 4 and 5 (P = 0.008). Weibull analysis indicated that bond strength for a 90% probability of failure, which was highest for Group 1 (13.99 MPa) and lowest for Group 2 (8.49 MPa). CONCLUSION: The in-vitro study showed that bleaching with 35% hydrogen peroxide reduced the SBS significantly and this could be effectively reversed by the application of 10% sodium ascorbate, 10% tocopherol acetate, or 10% retinol acetate. Thus, treatment of bleached teeth with antioxidants can be a good clinical option for bonding immediately after bleaching. PMID- 26229948 TI - Bolton tooth size ratio among Sudanese Population sample: A preliminary study. AB - BACKGROUND: The study of the mesiodistal size, the morphology of teeth and dental arch may play an important role in clinical dentistry, as well as other sciences such as Forensic Dentistry and Anthropology. AIMS: The aims of the present study were to establish tooth-size ratio in Sudanese sample with Class I normal occlusion, to compare the tooth-size ratio between the present study and Bolton's study and between genders. MATERIALS AND METHODS: The sample consisted of dental casts of 60 subjects (30 males and 30 females). Bolton formula was used to compute the overall and anterior ratio. The correlation coefficient between the anterior ratio and overall ratio was tested, and Student's t-test was used to compare tooth-size ratios between males and females, and between the present study and Bolton's result. RESULTS: The results of the overall and anterior ratio was relatively similar to the mean values reported by Bolton, and there were no statistically significant differences between the mean values of the anterior ratio and the overall ratio between males and females. The correlation coefficient was (r = 0.79). CONCLUSIONS: The result obtained was similar to the Caucasian race. However, the reality indicates that the Sudanese population consisted of different racial groups; therefore, the firm conclusion is difficult to draw. Since this sample is not representative for the Sudanese population, hence, a further study with a large sample collected from the different parts of the Sudan is required. PMID- 26229949 TI - Bolton ratio in a North Indian population with different malocclusions. AB - OBJECTIVE: The objective was to evaluate the Bolton ratio in a North Indian population in Lucknow with different malocclusion. MATERIALS AND METHODS: Totally, 110 study cast [Age: Female (14.2 +/- 1.5 years, Male (13.9 +/- 2.3 years)] were taken from the patients undergoing orthodontic treatment and Subjects were divided into three groups: Group I (Angle's Class I, n = 40), Group II (Angle's Class II, n = 50) and Group III (Angle's Class III, n = 20) according Angle's classification of malocclusion. The mesiodistal widths of all maxillary and mandibular teeth from right first molar to left first molar were measured with a digital caliper to calculate the Bolton ratio. The readings were then used to compute the anterior and total Bolton ratios. ANOVA and Tukey's test were used for the statistical analysis. RESULTS: A mean total Bolton ratio of 91.36 +/- 2.13 and a mean anterior Bolton ratio of 78.14 +/- 4.09 were found for the sample, Significantly higher mean anterior tooth ratios were found for Group II (Angle's Class II) patients (P < 0.01). All other ratios were within close range of Bolton's norms. CONCLUSIONS: Angle's Class II patients showed a tendency toward wider mesiodistal widths of teeth in the mandibular anterior region or smaller tooth sizes in the maxillary anterior region. PMID- 26229950 TI - Differences in dentofacial characteristics of Class I malocclusion between Saudi and Japanese adult females. AB - OBJECTIVES: The objective was to compare dentofacial characteristics of Class I malocclusion in Saudi and Japanese adult females. MATERIALS AND METHODS: Lateral cephalograms of 50 Saudi adult female and 50 Japanese adult female (18-35-year old) were obtained. All patients were skeletal Class I, angle Class I malocclusion, arch length discrepancy (-10-10 mm), overjet (1-5 mm), overbite (1 5 mm), absence of congenital anomalies, or significant facial asymmetries or congenitally missing tooth other than the 3(rd) molar and absence of temporomandibular joint problems. Patient cephalograms were traced and digitized. 16 angular measurements and 13 linear measurements of facial form were used. RESULTS: A comparison of the vertical dimension showed that the Saudi females had a significantly larger gonial angle, a significantly larger facial angle and longer lower face height compared to the Japanese females. Dentally, Saudi females had more protruded incisors with increased distances of the posterior teeth to the palatal plane. For the soft tissue dimension, the Saudi subjects had a significantly more prominent nose, retruded lip and a more protruded chin compared with Japanese. CONCLUSIONS: There were significant differences in dentofacial morphology between Saudi and Japanese adult females. Both Asian countries have distinct cephalometric features, which should be considered as a reference in treating patients of varying ethnic backgrounds to optimize the final results. PMID- 26229951 TI - Modified serial extraction treatment in a patient with congenitally missing lower second premolars. AB - Serial extraction is a sequential plan of premature removal of one or more deciduous teeth in order to improve the alignment of permanent teeth and then removal of permanent teeth to maintain the proper ratio between tooth size and arch size. The aim of this case report was to present a case treated successfully with a modified serial extraction protocol in the lower arch because the patient had congenitally missing lower second premolars with severe crowding. The treatment consisted of selective removal of the deciduous mandibular teeth only (C, D, and E) and no permanent premolar removal. However, the space of the missing second premolars was utilized to resolve the anterior crowding along with the spontaneous closure of the extra spaces by physiologic movement of the permanent mandibular teeth. Whereas in the upper arch conventional serial extraction was performed. PMID- 26229952 TI - Prevalence and Diagnostic Approach to Sleep Apnea in Hemodialysis Patients: A Population Study. AB - BACKGROUND: Previous observations found a high prevalence of obstructive sleep apnea (OSA) in the hemodialysis population, but the best diagnostic approach remains undefined. We assessed OSA prevalence and performance of available screening tools to propose a specific diagnostic algorithm. METHODS: 104 patients from 6 Swiss hemodialysis centers underwent polygraphy and completed 3 OSA screening scores: STOP-BANG, Berlin's Questionnaire, and Adjusted Neck Circumference. The OSA predictors were identified on a derivation population and used to develop the diagnostic algorithm, which was validated on an independent population. RESULTS: We found 56% OSA prevalence (AHI >= 15/h), which was largely underdiagnosed. Screening scores showed poor performance for OSA screening (ROC areas 0.538 [SE 0.093] to 0.655 [SE 0.083]). Age, neck circumference, and time on renal replacement therapy were the best predictors of OSA and were used to develop a screening algorithm, with higher discriminatory performance than classical screening tools (ROC area 0.831 [0.066]). CONCLUSIONS: Our study confirms the high OSA prevalence and highlights the low diagnosis rate of this treatable cardiovascular risk factor in the hemodialysis population. Considering the poor performance of OSA screening tools, we propose and validate a specific algorithm to identify hemodialysis patients at risk for OSA for whom further sleep investigations should be considered. PMID- 26229953 TI - Determination of Elemental Composition of Malabar spinach, Lettuce, Spinach, Hyacinth Bean, and Cauliflower Vegetables Using Proton Induced X-Ray Emission Technique at Savar Subdistrict in Bangladesh. AB - The concentrations of 18 different elements (K, Ca, Fe, Cl, P, Zn, S, Mn, Ti, Cr, Rb, Co, Br, Sr, Ru, Si, Ni, and Cu) were analyzed in five selected vegetables through Proton Induced X-ray Emission (PIXE) technique. The objective of this study was to provide updated information on concentrations of elements in vegetables available in the local markets at Savar subdistrict in Bangladesh. These elements were found in varying concentrations in the studied vegetables. The results also indicated that P, Cl, K, Ca, Mn, Fe, and Zn were found in all vegetables. Overall, K and Ca exhibited the highest concentrations. Cu and Ni exhibited the lowest concentrations in vegetables. The necessity of these elements was also evaluated, based on the established limits of regulatory standards. The findings of this study suggest that the consumption of these vegetables is not completely free of health risks. PMID- 26229954 TI - Results from the Registry of Atrial Fibrillation (AFABE): Gap between Undiagnosed and Registered Atrial Fibrillation in Adults--Ineffectiveness of Oral Anticoagulation Treatment with VKA. AB - OBJECTIVE: This study aimed to examine the effectiveness of the use of oral anticoagulation (OAC) medication, recommended by national guidelines for stroke prevention but reportedly underused in AF patients with moderate to high stroke risk. METHOD: A multicentre and cross-sectional study of undiagnosed AF among out of-hospital patients over 60 years old was carried out, visiting 3,638 patients at primary health centres or at home for AF diagnosis using the IDC-10 classification. The main outcome measures were CHA2DS2VASC, HAS-BLED scores, cardiovascular comorbidity, pharmacological information, TTR, and SAMe-TT2R2 scores. RESULTS: The main findings were undiagnosed AF in 26.44% of cases; 31.04% registered with AF but not using OAC despite 95.6% having a CHA2DS2VASC >= 2 score; a risk of bleeding in important subgroups using OAC without indication (37.50% CHA2DS2VASC < 2 score); the use of OAC with TTR < 60% (33.1%), of whom 47.6% had a HAS-BLED score >=3. Thus, 35.4% of the expected AF prevalence achieved an optimal time in the therapeutic range. CONCLUSIONS: The expected AF prevalence was 10.9% (n 5267), but the registered prevalence was 7.5% (n 3638). Only 35.04% (CI = 95%, 33.7-36.3) of AF patients treated with vitamin K antagonists (VKAs) achieve the goal of TTR > 60%. PMID- 26229955 TI - RLN2 Is a Positive Regulator of AKT-2-Induced Gene Expression Required for Osteosarcoma Cells Invasion and Chemoresistance. AB - The aim of the study was to determine the effect of H2 relaxin (RLN2) on invasion, migration, and chemosensitivity to cisplatin in human osteosarcoma U2 OS and MG-63 cells and then to investigate the effect of RLN2 on the AKT/NF kappaB signaling pathway. The expression of RLN2, p-AKT (Ser473), and p-ERK1/2 (Phospho-Thr202/Tyr204) proteins was detected by western blot in OS tissues from 21 patients with pulmonary metastatic disease, and the correlation between RLN2 and p-AKT or RLN2 and p-ERK1/2 expression was investigated. RLN2 expression was inhibited by RLN2 siRNA transfection in the MG-63 cells. RLN2 was overexpressed in the U2-OS cells by treatment with recombinant relaxin. The results showed that positive relation was found between RLN2 and p-AKT expression in tissues of OS. Silencing RLN2 inhibited cell migratory and invasive ability and angiogenesis formation and increased the chemosensitivity to cisplatin in MG-63 cells. RLN2 overexpression promoted migratory and invasive ability and angiogenesis and increased the chemoresistance to cisplatin in U2-OS cells. Silencing RLN2 inhibited the activity of AKT/NF-kappaB signaling pathway in MG-63 cells, and vice versa. Blockage of both pathways by specific inhibitors abrogated RLN2 induced survival and invasion of OS cells, and vice versa. Our results indicated RLN2 confers to migratory and invasive ability, angiogenesis, and chemoresistance to cisplatin via modulating the AKT/NF-kappaB signaling pathway in vitro. PMID- 26229956 TI - Surgical Treatment of Concomitant Atrial Fibrillation: Focus onto Atrial Contractility. AB - BACKGROUND: Maze procedure aims at restoring sinus rhythm (SR) and atrial contractility (AC). This study evaluated multiple aspects of AC recovery and their relationship with SR regain after ablation. METHODS: 122 mitral and fibrillating patients underwent radiofrequency Maze. Rhythm check and echocardiographic control of biatrial contractility were performed at 3, 6, 12, and 24 months postoperatively. A multivariate Cox analysis of risk factors for absence of AC recuperation was applied. RESULTS: At 2-years follow-up, SR was achieved in 79% of patients. SR-AC coexistence increased from 76% until 98%, while biatrial contraction detection augmented from 84 to 98% at late stage. Shorter preoperative arrhythmia duration was the only common predictor of SR-AC restoring, while pulmonary artery pressure (PAP) negatively influenced AC recuperation. Early AC restoration favored future freedom from arrhythmia recurrence. Minor LA dimensions correlated with improved future A/E value and vice versa. Right atrial (RA) contractility restoring favored better left ventricular (LV) performance and volumes. CONCLUSIONS: SR and left AC are two interrelated Maze objectives. Factors associated with arrhythmia "chronic state" (PAP and arrhythmia duration) are negative predictors of procedural success. Our results suggest an association between postoperative LA dimensions and "kick" restoring and an influence of RA contraction onto LV function. PMID- 26229957 TI - Big Data Analytics in Healthcare. AB - The rapidly expanding field of big data analytics has started to play a pivotal role in the evolution of healthcare practices and research. It has provided tools to accumulate, manage, analyze, and assimilate large volumes of disparate, structured, and unstructured data produced by current healthcare systems. Big data analytics has been recently applied towards aiding the process of care delivery and disease exploration. However, the adoption rate and research development in this space is still hindered by some fundamental problems inherent within the big data paradigm. In this paper, we discuss some of these major challenges with a focus on three upcoming and promising areas of medical research: image, signal, and genomics based analytics. Recent research which targets utilization of large volumes of medical data while combining multimodal data from disparate sources is discussed. Potential areas of research within this field which have the ability to provide meaningful impact on healthcare delivery are also examined. PMID- 26229958 TI - Atorvastatin Treatment for Atrial Fibrillation Reduces Serum High-Sensitivity C Reactive Protein Levels. AB - We investigated whether serum hs-CRP levels predict the efficacy of atrial fibrillation (AF) treated with atorvastatin. Bibliographic databases were exhaustively searched for studies relevant to the research topic. Newcastle Ottawa Scale (NOS) criteria, combined with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS), were applied for study quality assessment. Our meta analysis identified seven cohort studies (2006~2013), providing information on the change in serum hs-CRP levels in AF patients receiving atorvastatin therapy. After atorvastatin treatment, hs-CRP level in AF patients decreased significantly (SMD = 1.02, 95% CI: 0.58-1.47, P < 0.001). Subgroup analysis by country and hs CRP detection methods suggested a negative relationship between atorvastatin treatment and hs-CRP levels among Chinese AF patients (SMD = 1.34, 95% CI: 1.00 1.69, P < 0.001) and by using ELISA method (SMD = 1.11, 95% CI: 0.51-1.71, P < 0.001), but not among Turkish population and using INA method (all P > 0.05). Egger's test showed no publication bias (P = 0.450). hs-CRP was clearly lowered in AF patients treated with atorvastatin, which may be helpful in the choice of statin agents for AF treatment. However, longer follow-ups are necessary to assess the clinical value of lowering hs-CRP in the clinical setting of AF treatment outcomes. PMID- 26229959 TI - Evaluation of Single-Impact-Induced Cartilage Degeneration by Optical Coherence Tomography. AB - Posttraumatic osteoarthritis constitutes a major cause of disability in our increasingly elderly population. Unfortunately, current imaging modalities are too insensitive to detect early degenerative changes of this disease. Optical coherence tomography (OCT) is a promising nondestructive imaging technique that allows surface and subsurface imaging of cartilage, at near-histological resolution, and is principally applicable in vivo during arthroscopy. Thirty-four macroscopically normal human cartilage-bone samples obtained from total joint replacements were subjected to standardized single impacts in vitro (range: 0.25 J to 0.98 J). 3D OCT measurements of impact area and adjacent tissue were performed prior to impaction, directly after impaction, and 1, 4, and 8 days later. OCT images were assessed qualitatively (DJD classification) and quantitatively using established parameters (OII, Optical Irregularity Index; OHI, Optical Homogeneity Index; OAI, Optical Attenuation Index) and compared to corresponding histological sections. While OAI and OHI scores were not significantly changed in response to low- or moderate-impact energies, high impact energies significantly increased mean DJD grades (histology and OCT) and OII scores. In conclusion, OCT-based parameterization and quantification are able to reliably detect loss of cartilage surface integrity after high-energy traumatic insults and hold potential to be used for clinical screening of early osteoarthritis. PMID- 26229960 TI - Chronotropic Modulation of the Source-Sink Relationship of Sinoatrial-Atrial Impulse Conduction and Its Significance to Initiation of AF: A One-Dimensional Model Study. AB - Initiation and maintenance of atrial fibrillation (AF) is often associated with pharmacologically or pathologically induced bradycardic states. Even drugs specifically developed in order to counteract cardiac arrhythmias often combine their action with bradycardia and, in turn, with development of AF, via still largely unknown mechanisms. This study aims to simulate action potential (AP) conduction between sinoatrial node (SAN) and atrial cells, either arranged in cell pairs or in a one-dimensional strand, where the relative amount of SAN membrane is made varying, in turn, with junctional resistance. The source-sink relationship between the two membrane types is studied in control conditions and under different simulated chronotropic interventions, in order to define a safety factor for pacemaker-to-atrial AP conduction (SASF) for each treatment. Whereas antiarrhythmic-like interventions which involve downregulation of calcium channels or of calcium handling decrease SASF, the simulation of Ivabradine administration does so to a lesser extent. Particularly interesting is the increase of SASF observed when downregulation G Kr, which simulates the administration of class III antiarrhythmic agents and is likely sustained by an increase in I CaL. Also, the increase in SASF is accompanied by a decreased conduction delay and a better entrainment of repolarization, which is significant to anti-AF strategies. PMID- 26229961 TI - An Integrated Approach Using Spatial Analysis to Study the Risk Factors for Leishmaniasis in Area of Recent Transmission. AB - Some epidemiological aspects of leishmaniasis in the municipality of Formiga, Brazil, an important touristic site, were evaluated. Those included phlebotomine sand fly vectors, canine infection, and geoprocessing analysis for determining critical transmission areas. Sand flies (224 insects) belonging to ten different species were captured. The most captured species included Lutzomyia longipalpis (35.3%), Lutzomyia cortelezzii (33.5%), and Lutzomyia whitmani (18.3%). A significant correlation between sand fly densities and climatic conditions was detected. Serological diagnosis (DPP and ELISA) was performed in 570 dogs indicating a prevalence of 5.8%. After sequencing the main species circulating in the area were Leishmania infantum and Leishmania braziliensis. Spatial analysis demonstrated that vegetation and hydrography may be related to sand fly distribution and infected dogs. The municipality of Formiga has proven leishmaniasis vectors and infected dogs indicating the circulation of the parasite in the city. Correlation of those data with environmental and human cases has identified the critical areas for control interventions (south, northeast, and northwest). In conclusion, there is current transmission of visceral and canine human cases and the city is on the risk for the appearance of cutaneous cases. PMID- 26229962 TI - Cyclic Tensile Strain Induces Tenogenic Differentiation of Tendon-Derived Stem Cells in Bioreactor Culture. AB - Different loading regimens of cyclic tensile strain impose different effects on cell proliferation and tenogenic differentiation of TDSCs in three-dimensional (3D) culture in vitro, which has been little reported in previous literatures. In this study we assessed the efficacy of TDSCs in a poly(L-lactide-co-epsilon caprolactone)/collagen (P(LLA-CL)/Col) scaffold under mechanical stimulation in the custom-designed 3D tensile bioreactor, which revealed that cyclic tensile strain with different frequencies (0.3 Hz, 0.5 Hz, and 1.0 Hz) and amplitudes (2%, 4%, and 8%) had no influence on TDSC viability, while it had different effects on the proliferation and the expression of type I collagen, tenascin-C, tenomodulin, and scleraxis of TDSCs, which was most obvious at 0.5 Hz frequency with the same amplitude and at 4% amplitude with the same frequency. Moreover, signaling pathway from microarray analysis revealed that reduced extracellular matrix (ECM) receptor interaction signaling initiated the tendon genius switch. Cyclic tensile strain highly upregulated genes encoding regulators of NPM1 and COPS5 transcriptional activities as well as MYC related transcriptional factors, which contributed to cell proliferation and differentiation. In particular, the transcriptome analysis provided certain new insights on the molecular and signaling networks for TDSCs loaded in these conditions. PMID- 26229963 TI - Impact of Dabigatran versus Phenprocoumon on ADP Induced Platelet Aggregation in Patients with Atrial Fibrillation with or without Concomitant Clopidogrel Therapy (the Dabi-ADP-1 and Dabi-ADP-2 Trials). AB - BACKGROUND: A relevant number of patients receive triple therapy with clopidogrel, aspirin, and oral anticoagulation. Clopidogrel's efficacy on ADP induced platelet function may be influenced by concomitant antithrombotic therapies. Data regarding the effect of dabigatran on platelet function is limited to in vitro studies and healthy individuals. METHODS: The "Dabi-ADP-1" and "Dabi-ADP-2" trials randomized patients with atrial fibrillation to either dabigatran or phenprocoumon for a 2-week period. In Dabi-ADP-1 (n = 70) patients with clopidogrel therapy were excluded and in Dabi-ADP-2 (n = 46) patients had to be treated concomitantly with clopidogrel. The primary endpoint was ADP-induced platelet aggregation between dabigatran and phenprocoumon at 14 days. Secondary endpoints were ADPtest HS-, TRAP-, and COL-induced platelet aggregation. RESULTS: There was no significant difference regarding the primary endpoint between both groups in either trial (Dabi-ADP-1: Dabigatran: 846 [650-983] AU * min versus phenprocoumon: 839 [666-1039] AU * min, P = 0.90 and Dabi-ADP-2: 326 [268-462] versus 350 [214-535], P = 0.70) or regarding the secondary endpoints, ADPtest HS , TRAP-, and COL-induced platelet aggregation. CONCLUSION: Dabigatran as compared to phenprocoumon has no impact on ADP-induced platelet aggregation in atrial fibrillation patients neither with nor without concomitant clopidogrel therapy. PMID- 26229964 TI - Atrial Fibrillation and Fibrosis: Beyond the Cardiomyocyte Centric View. AB - Atrial fibrillation (AF) associated with fibrosis is characterized by the appearance of interstitial myofibroblasts. These cells are responsible for the uncontrolled deposition of the extracellular matrix, which pathologically separate cardiomyocyte bundles. The enhanced fibrosis is thought to contribute to arrhythmias "indirectly" because a collagenous septum is a passive substrate for propagation, resulting in impulse conduction block and/or zigzag conduction. However, the emerging results demonstrate that myofibroblasts in vitro also promote arrhythmogenesis due to direct implications upon cardiomyocyte electrophysiology. This electrical interference may be considered beneficial as it resolves any conduction blocks; however, the passive properties of myofibroblasts might cause a delay in impulse propagation, thus promoting AF due to discontinuous slow conduction. Moreover, low-polarized myofibroblasts reduce, via cell-density dependence, the fast driving inward current for cardiac impulse conduction, therefore resulting in arrhythmogenic uniformly slow propagation. Critically, the subsequent reduction in cardiomyocytes resting membrane potential in vitro significantly increases the likelihood of ectopic activity. Myofibroblast densities and the degree of coupling at cellular border zones also impact upon this likelihood. By considering future in vivo studies, which identify myofibroblasts "per se" as a novel targets for cardiac arrhythmias, this review aims to describe the implications of noncardiomyocyte view in the context of AF. PMID- 26229965 TI - Heartbeat Cycle Length Detection by a Ballistocardiographic Sensor in Atrial Fibrillation and Sinus Rhythm. AB - BACKGROUND: Heart rate monitoring is especially interesting in patients with atrial fibrillation (AF) and is routinely performed by ECG. A ballistocardiography (BCG) foil is an unobtrusive sensor for mechanical vibrations. We tested the correlation of heartbeat cycle length detection by a novel algorithm for a BCG foil to an ECG in AF and sinus rhythm (SR). METHODS: In 22 patients we obtained BCG and synchronized ECG recordings before and after cardioversion and examined the correlation between heartbeat characteristics. RESULTS: We analyzed a total of 4317 heartbeats during AF and 2445 during SR with a correlation between ECG and BCG during AF of r = 0.70 (95% CI 0.68-0.71, P < 0.0001) and r = 0.75 (95% CI 0.73-0.77, P < 0.0001) during SR. By adding a quality index, artifacts could be reduced and the correlation increased for AF to 0.76 (95% CI 0.74-0.77, P < 0.0001, n = 3468) and for SR to 0.85 (95% CI 0.83 0.86, P < 0.0001, n = 2176). CONCLUSION: Heartbeat cycle length measurement by our novel algorithm for BCG foil is feasible during SR and AF, offering new possibilities of unobtrusive heart rate monitoring. This trial is registered with IRB registration number EK205/11. This trial is registered with clinical trials registration number NCT01779674. PMID- 26229966 TI - Diagnosing Paroxysmal Atrial Fibrillation: Are Biomarkers the Solution to This Elusive Arrhythmia? AB - Atrial fibrillation (AF) is the commonest sustained arrhythmia globally and results in significantly increased morbidity and mortality including a fivefold risk of stroke. Paroxysmal atrial fibrillation (PAF) constitutes approximately half of all AF cases and is thought to represent an early stage of the disease. This intermittent form of atrial arrhythmia can be a challenge to identify and as a result many affected individuals are not prescribed appropriate antithrombotic therapy and hence are at risk of stroke and thromboembolism. Despite these adverse outcomes there have been relatively few diagnostic advances in the field since the introduction of the Holter monitor in 1949. This review aims to establish the available evidence for electrophysiological, molecular, and morphological biomarkers to improve the detection of PAF with reference to the underlying mechanisms for the condition. PMID- 26229967 TI - Clinical, Psychopathological, and Personality Characteristics Associated with ADHD among Individuals Seeking Treatment for Gambling Disorder. AB - OBJECTIVES: (1) To assess the current presence of ADHD symptoms among patients seeking treatment for gambling disorder; (2) to explore clinical and sociodemographic differences between patients who score high and low on the measure of ADHD symptoms; (3) to analyze whether the presence of ADHD symptoms is associated with more severe psychopathology and with specific personality traits; (4) to analyze the mediating role of ADHD symptoms in the relationship between novelty seeking and gambling severity. METHOD: A total of 354 consecutive patients were administered an extensive battery assessing gambling behavior, psychopathology, and personality traits. RESULTS: Male and female gamblers did not differ significantly in their mean scores on the ADHD measure. However, younger participants aged 18-35 scored higher. Higher ADHD scores were also associated with greater severity of gambling disorder and more general psychopathology. Regarding personality traits, high persistence and self directedness were negatively related to ADHD scores, while in women alone a positive correlation was found between ADHD scores and scores on harm avoidance and self-transcendence. CONCLUSION: The presence of ADHD symptoms in both male and female gambling disorder patients may act as an indicator of the severity of gambling, general psychopathology, and dysfunctional personality traits. PMID- 26229968 TI - Rat Models of Diet-Induced Obesity and High Fat/Low Dose Streptozotocin Type 2 Diabetes: Effect of Reversal of High Fat Diet Compared to Treatment with Enalapril or Menhaden Oil on Glucose Utilization and Neuropathic Endpoints. AB - We examined whether reversal of high fat diet, stimulating weight loss, compared to two treatments previously shown to have beneficial effects, could improve glucose utilization and peripheral neuropathy in animal models of obesity and type 2 diabetes. Rats were fed a high fat diet and treated with a low dose of streptozotocin to create models of diet induced obesity or type 2 diabetes, respectively. Afterwards, rats were transferred to a normal diet or treated with enalapril or dietary enrichment with menhaden oil for 12 weeks. Obesity and to a greater extent type 2 diabetes were associated with impaired glucose utilization and peripheral neuropathy. Placing obese rats on a normal diet improved glucose utilization. Steatosis but not peripheral neuropathy was improved after placing obese or diabetic rats on a normal diet. Treating obese and diabetic rats with enalapril or a menhaden oil enriched diet generally improved peripheral neuropathy endpoints. In summary, dietary improvement with weight loss in obese or type 2 diabetic rats was not sufficient to correct peripheral neuropathy. These results further stress the need for discovery of a comprehensive treatment for peripheral neuropathy. PMID- 26229969 TI - Mild Type 2 Diabetes Mellitus Reduces the Susceptibility of the Heart to Ischemia/Reperfusion Injury: Identification of Underlying Gene Expression Changes. AB - Despite clinical studies indicating that diabetic hearts are more sensitive to ischemia/reperfusion injury, experimental data is contradictory. Although mild diabetes prior to ischemia/reperfusion may induce a myocardial adaptation, further research is still needed. Nondiabetic Wistar (W) and type 2 diabetic Goto Kakizaki (GK) rats (16-week-old) underwent 45 min occlusion of the left anterior descending coronary artery and 24 h reperfusion. The plasma glucose level was significantly higher in diabetic rats compared to the nondiabetics. Diabetes mellitus was associated with ventricular hypertrophy and increased interstitial fibrosis. Inducing myocardial infarction increased the glucose levels in diabetic compared to nondiabetic rats. Furthermore, the infarct size was smaller in GK rats than in the control group. Systolic and diastolic functions were impaired in W + MI and did not reach statistical significance in GK + MI animals compared to the corresponding controls. Among the 125 genes surveyed, 35 genes showed a significant change in expression in GK + MI compared to W + MI rats. Short-term diabetes promotes compensatory mechanisms that may provide cardioprotection against ischemia/reperfusion injury, at least in part, by increased antioxidants and the upregulation of the prosurvival PI3K/Akt pathway, by the downregulation of apoptotic genes, proinflammatory cytokine TNF-alpha, profibrogenic TGF-beta, and hypertrophic marker alpha-actin-1. PMID- 26229970 TI - Activation-Inactivation Cycling of Rab35 and ARF6 Is Required for Phagocytosis of Zymosan in RAW264 Macrophages. AB - Phagocytosis of zymosan by phagocytes is a widely used model of microbial recognition by the innate immune system. Live-cell imaging showed that fluorescent protein-fused Rab35 accumulated in the membranes of phagocytic cups and then dissociated from the membranes of newly formed phagosomes. By our novel pull-down assay for Rab35 activity, we found that Rab35 is deactivated immediately after zymosan internalization into the cells. Phagosome formation was inhibited in cells expressing the GDP- or GTP-locked Rab35 mutant. Moreover, the simultaneous expression of ACAP2-a Rab35 effector protein-with GTP-locked Rab35 or the expression of plasma membrane-targeted ACAP2 showed a marked inhibitory effect on phagocytosis through ARF6 inactivation by the GAP activity of ACAP2. ARF6, a substrate for ACAP2, was also localized on the phagocytic cups and dissociated from the membranes of internalized phagosomes. In support of the microscopic observations, ARF6-GTP pull-down experiments showed that ARF6 is transiently activated during phagosome formation. Furthermore, the expression of GDP- or GTP-locked ARF6 mutants also suppresses the uptake of zymosan. These data suggest that the activation-inactivation cycles of Rab35 and ARF6 are required for the uptake of zymosan and that ACAP2 is an important component that links Rab35/ARF6 signaling during phagocytosis of zymosan. PMID- 26229972 TI - Generation of a stable packaging cell line producing high-titer PPT-deleted integration-deficient lentiviral vectors. AB - The risk of insertional mutagenesis inherent to all integrating exogenous expression cassettes was the impetus for the development of various integration defective lentiviral vector (IDLV) systems. These systems were successfully employed in a plethora of preclinical applications, underscoring their clinical potential. However, current production of IDLVs by transient plasmid transfection is not optimal for large-scale production of clinical grade vectors. Here, we describe the development of the first tetracycline-inducible stable IDLV packaging cell line comprising the D64E integrase mutant and the VSV-G envelope protein. A conditional self-inactivating (cSIN) vector and a novel polypurine tract (PPT)-deleted vector were incorporated into the newly developed stable packaging cell line by transduction and stable transfection, respectively. High titer (~10(7) infectious units (IU)/ml) cSIN vectors were routinely generated. Furthermore, screening of single-cell clones stably transfected with PPT-deleted vector DNA resulted in the identification of highly efficient producer cell lines generating IDLV titers higher than 10(8) IU/mL, which upon concentration increased to 10(10) IU/ml. IDLVs generated by stable producer lines efficiently transduce CNS tissues of rodents. Overall, the availability of high-titer IDLV lentivirus packaging cell line described here will significantly facilitate IDLV based basic science research, as well as preclinical and clinical applications. PMID- 26229974 TI - A Content Analysis of Electronic Cigarette Portrayal in Newspapers. AB - OBJECTIVE: To determine how electronic cigarettes (e-cigarettes) are portrayed in newspaper informative articles and opinion pieces. METHODS: A content analysis was conducted on 450 articles published in the United States from 1997 to mid 2014 and obtained by a Newsbank search. The articles were reliably coded for overall frame, type of article, first topic and main topics addressed. RESULTS: The article topics have changed over time and suggest significant differences between news articles and opinion pieces. Informative articles focused on e cigarette regulation, while opinion pieces highlighted their increasing popularity and perceived health benefits. CONCLUSIONS: This content analysis uncovered significant interest in e-cigarettes, particularly in their regulation. The FDA should consider public perceptions of e-cigarettes when developing regulations. PMID- 26229973 TI - NeuroCa: integrated framework for systematic analysis of spatiotemporal neuronal activity patterns from large-scale optical recording data. AB - Optical recording facilitates monitoring the activity of a large neural network at the cellular scale, but the analysis and interpretation of the collected data remain challenging. Here, we present a MATLAB-based toolbox, named NeuroCa, for the automated processing and quantitative analysis of large-scale calcium imaging data. Our tool includes several computational algorithms to extract the calcium spike trains of individual neurons from the calcium imaging data in an automatic fashion. Two algorithms were developed to decompose the imaging data into the activity of individual cells and subsequently detect calcium spikes from each neuronal signal. Applying our method to dense networks in dissociated cultures, we were able to obtain the calcium spike trains of [Formula: see text] neurons in a few minutes. Further analyses using these data permitted the quantification of neuronal responses to chemical stimuli as well as functional mapping of spatiotemporal patterns in neuronal firing within the spontaneous, synchronous activity of a large network. These results demonstrate that our method not only automates time-consuming, labor-intensive tasks in the analysis of neural data obtained using optical recording techniques but also provides a systematic way to visualize and quantify the collective dynamics of a network in terms of its cellular elements. PMID- 26229971 TI - Regulation of Dendritic Cell Function in Inflammation. AB - Dendritic cells (DC) are professional antigen presenting cells and link the innate and adaptive immune system. During steady state immune surveillance in skin, DC act as sentinels against commensals and invading pathogens. Under pathological skin conditions, inflammatory cytokines, secreted by surrounding keratinocytes, dermal fibroblasts, and immune cells, influence the activation and maturation of different DC populations including Langerhans cells (LC) and dermal DC. In this review we address critical differences in human DC subtypes during inflammatory settings compared to steady state. We also highlight the functional characteristics of human DC subsets in inflammatory skin environments and skin diseases including psoriasis and atopic dermatitis. Understanding the complex immunoregulatory role of distinct DC subsets in inflamed human skin will be a key element in developing novel strategies in anti-inflammatory therapy. PMID- 26229977 TI - Effect of Environmental Factors on Germination and Emergence of Invasive Rumex confertus in Central Europe. AB - Rumex confertus is a biennial species native to Eastern Europe and Asia, where it thrives on meadow-steppes and glades in forest-steppe. This species has increased its range rapidly within central Europe, yet its biology is not well understood, which has led to poorly timed management. Effects of temperature, light, sodium chloride (NaCl), hydrogen ion concentration (pH), potassium nitrate (KNO3), and polyethylene glycol 6000 on seed germination were examined. Seedling emergence was examined for seeds sown at different depths in sand-filled pots. Seeds of R. confertus were nondormant at maturity. The germination percentage and rate of germination were significantly higher in light than in darkness. Secondary dormancy was induced in these seeds by 12 weeks of dark incubation at 4 degrees C. The seeds of R. confertus undergo a seasonal dormancy cycle with deep dormancy in winter and early spring and a low level of dormancy in early autumn. Germination decreased as soil salinity increased. NO3(-) increased the percentage and rate of germination in the studied species. Decrease in seedling emergence from the seeds buried at >0.5 cm may be due to deficiency of light. From our experiments, we conclude that the weed R. confertus normally becomes established in vegetation gaps or due to disturbance of the uppermost soil layer during the growing season through the germination of seeds originating from a long-lived seed bank. PMID- 26229978 TI - A Dynamic Recommender System for Improved Web Usage Mining and CRM Using Swarm Intelligence. AB - In modern days, to enrich e-business, the websites are personalized for each user by understanding their interests and behavior. The main challenges of online usage data are information overload and their dynamic nature. In this paper, to address these issues, a WebBluegillRecom-annealing dynamic recommender system that uses web usage mining techniques in tandem with software agents developed for providing dynamic recommendations to users that can be used for customizing a website is proposed. The proposed WebBluegillRecom-annealing dynamic recommender uses swarm intelligence from the foraging behavior of a bluegill fish. It overcomes the information overload by handling dynamic behaviors of users. Our dynamic recommender system was compared against traditional collaborative filtering systems. The results show that the proposed system has higher precision, coverage, F1 measure, and scalability than the traditional collaborative filtering systems. Moreover, the recommendations given by our system overcome the overspecialization problem by including variety in recommendations. PMID- 26229979 TI - Study of Microstructure and Mechanical Properties Effects on Workpiece Quality in Sheet Metal Extrusion Process. AB - Sheet metal extrusion is a metal forming process in which the movement of a punch penetrates a sheet metal surface and it flows through a die orifice; the extruded parts can be deflected to have an extrusion cavity and protrusion on the opposite side. Therefore, this process results in a narrow region of highly localized plastic deformation due to the formation and microstructure effect on the work piece. This research investigated the characteristics of the material-flow behavior during the formation and its effect on the microstructure of the extruded sheet metal using the finite element method (FEM). The actual parts and FEM simulation model were developed using a blank material made from AISI-1045 steel with a thickness of 5 mm; the material's behavior was determined subject to the punch penetration depths of 20%, 40%, 60%, and 80% of the sheet thickness. The results indicated the formation and microstructure effects on the sheet metal extrusion parts and defects. Namely, when increasing penetration, narrowing the die orifice the material flows through, the material was formed by extruding, and defects were visibility, and the microstructure of the material's grains' size was flat and very fine. Extrusion defects were not found in the control material flow. The region of highly localized plastic deformation affected the material gain and mechanical properties. The FEM simulation results agreed with the experimental results. Moreover, FEM could be investigated as a tool to decrease the cost and time in trial and error procedures. PMID- 26229976 TI - Racial/ethnic disparities in sleep health and health care: importance of the sociocultural context. PMID- 26229975 TI - How genetic errors in GPCRs affect their function: Possible therapeutic strategies. AB - Activating and inactivating mutations in numerous human G protein-coupled receptors (GPCRs) are associated with a wide range of disease phenotypes. Here we use several class A GPCRs with a particularly large set of identified disease associated mutations, many of which were biochemically characterized, along with known GPCR structures and current models of GPCR activation, to understand the molecular mechanisms yielding pathological phenotypes. Based on this mechanistic understanding we also propose different therapeutic approaches, both conventional, using small molecule ligands, and novel, involving gene therapy. PMID- 26229980 TI - Modeling Bone Marrow Progenitor Cell Differentiation and Susceptibility to HIV-1 Infection. AB - Human immunodeficiency virus type 1 (HIV-1) infection of the monocytic lineage is involved in the pathologic events associated with AIDS and HIV-1-associated dementia (HAD). Hematopoietic progenitor cells (HPCs) within the bone marrow are refractile to HIV-1 infection, while their progeny of the monocyte-macrophage lineage are susceptible. Previous studies, using phorbol-myristate-acetate (PMA) as a differentiating agent, have suggested that the CD34+/CD38+ TF-1 cell line may be used as one model to study the differentiation processes of HPCs. In the present study, medium that has been conditioned by PMA-treated TF-1 cells but is devoid of any traces of PMA, was utilized to induce differentiation of TF-1 cells. The conditioned medium (CM) from this bone marrow-derived cell population is enriched with respect to numerous cytokines and induces differentiation and activation of TF-1 cells, as indicated by changes in the expression of CD34, CD38, and CD69 cell surface molecules. Furthermore, treatment with CM was also shown to induce the expression of CCR5 and CXCR4, while maintaining the expression of CD4, which was ultimately correlated with increased susceptibility to HIV-1. Additionally, the activation of the TF-1 cells was shown to lead to increased LTR activity, with specificity protein (Sp) and nuclear factor kappa light-chain-enhancer of activated B cells) NF-kappaB factors playing a crucial role in HIV-1 long terminal repeat (LTR)-mediated transcription and possibly overall TF-1 permissivity. Interleukin (IL)-1beta, which is elevated in the CM, recapitulates some of the CM effects. In summary, these studies suggest that the TF-1 cell line could serve as a model to study the susceptibility of bone marrow progenitor cells to HIV-1 infection. PMID- 26229981 TI - The matrikine N-alpha-PGP couples extracellular matrix fragmentation to endothelial permeability. AB - The compartmentalization and transport of proteins and solutes across the endothelium is a critical biologic function altered during inflammation and disease, leading to pathology in multiple disorders. The impact of tissue damage and subsequent extracellular matrix (ECM) fragmentation in regulating this process is unknown. We demonstrate that the collagen-derived matrikine acetylated proline-glycine-proline (N-alpha-PGP) serves as a critical regulator of endothelial permeability. N-alpha-PGP activates human endothelial cells via CXC chemokine receptor 2 (CXCR2), triggering monolayer permeability through a discrete intracellular signaling pathway. In vivo, N-alpha-PGP induces local vascular leak after subcutaneous administration and pulmonary vascular permeability after systemic administration. Furthermore, neutralization of N alpha-PGP attenuates lipopolysaccharide-induced lung leak. Finally, we demonstrate that plasma from patients with acute respiratory distress syndrome (ARDS) induces VE-cadherin phosphorylation in human endothelial cells, and this activation is attenuated by N-alpha-PGP blockade with a concomitant improvement in endothelial monolayer impedance. These results identify N-alpha-PGP as a novel ECM-derived matrikine regulating paracellular permeability during inflammatory disease and demonstrate the potential to target this ligand in various disorders characterized by excessive matrix turnover and vascular leak such as ARDS. PMID- 26229983 TI - Activation of GTP hydrolysis in mRNA-tRNA translocation by elongation factor G. AB - During protein synthesis, elongation of the polypeptide chain by each amino acid is followed by a translocation step in which mRNA and transfer RNA (tRNA) are advanced by one codon. This crucial step is catalyzed by elongation factor G (EF G), a guanosine triphosphatase (GTPase), and accompanied by a rotation between the two ribosomal subunits. A mutant of EF-G, H91A, renders the factor impaired in guanosine triphosphate (GTP) hydrolysis and thereby stabilizes it on the ribosome. We use cryogenic electron microscopy (cryo-EM) at near-atomic resolution to investigate two complexes formed by EF-G H91A in its GTP state with the ribosome, distinguished by the presence or absence of the intersubunit rotation. Comparison of these two structures argues in favor of a direct role of the conserved histidine in the switch II loop of EF-G in GTPase activation, and explains why GTP hydrolysis cannot proceed with EF-G bound to the unrotated form of the ribosome. PMID- 26229982 TI - The microbiome of uncontacted Amerindians. AB - Most studies of the human microbiome have focused on westernized people with life style practices that decrease microbial survival and transmission, or on traditional societies that are currently in transition to westernization. We characterize the fecal, oral, and skin bacterial microbiome and resistome of members of an isolated Yanomami Amerindian village with no documented previous contact with Western people. These Yanomami harbor a microbiome with the highest diversity of bacteria and genetic functions ever reported in a human group. Despite their isolation, presumably for >11,000 years since their ancestors arrived in South America, and no known exposure to antibiotics, they harbor bacteria that carry functional antibiotic resistance (AR) genes, including those that confer resistance to synthetic antibiotics and are syntenic with mobilization elements. These results suggest that westernization significantly affects human microbiome diversity and that functional AR genes appear to be a feature of the human microbiome even in the absence of exposure to commercial antibiotics. AR genes are likely poised for mobilization and enrichment upon exposure to pharmacological levels of antibiotics. Our findings emphasize the need for extensive characterization of the function of the microbiome and resistome in remote nonwesternized populations before globalization of modern practices affects potentially beneficial bacteria harbored in the human body. PMID- 26229984 TI - Transplantability of a circadian clock to a noncircadian organism. AB - Circadian oscillators are posttranslationally regulated and affect gene expression in autotrophic cyanobacteria. Oscillations are controlled by phosphorylation of the KaiC protein, which is modulated by the KaiA and KaiB proteins. However, it remains unclear how time information is transmitted to transcriptional output. We show reconstruction of the KaiABC oscillator in the noncircadian bacterium Escherichia coli. This orthogonal system shows circadian oscillations in KaiC phosphorylation and in a synthetic transcriptional reporter. Coexpression of KaiABC with additional native cyanobacterial components demonstrates a minimally sufficient set of proteins for transcriptional output from a native cyanobacterial promoter in E. coli. Together, these results demonstrate that a circadian oscillator is transplantable to a heterologous organism for reductive study as well as wide-ranging applications. PMID- 26229985 TI - Personality & Earnings Lost: The Economic Costs of Work Cut Back Days Due to Physical and Mental Health. AB - Personality traits have emerged as significant contributors to physical and mental health, as well as various economic outcomes including income. Few studies have explored whether personality is related to the frequency of days lost on the job due to physical or mental health issues, and the subsequent economic losses as a result. The current study bridged the health, economic, and personality variables to determine whether personality was associated with earnings lost due to work cut back days from poor physical or mental health. We found, both concurrently and over a 10 year follow up, that high neuroticism and low openness were associated with more earnings lost due to mental health, while low extraversion was associated with more earnings lost due to physical health. These findings are interpreted in light of the effects that personality may have on an individual's career and financial outcomes, and the economic effects of untreated physical and mental health problems. PMID- 26229986 TI - Analysis of mass-limited mixtures using supercritical-fluid chromatography and microcoil NMR. AB - A protocol is presented for offline microfluidic NMR analysis hyphenated with supercritical chromatographic separation. The method demonstrates quantitative detection with good sensitivity. Typical sample amounts of 10 nanomoles can be detected in a fast and cost-effective manner. PMID- 26229987 TI - Single molecular recognition force spectroscopy study of a DNA aptamer with the target epithelial cell adhesion molecule. AB - The epithelial cell adhesion molecule (EpCAM) is a tumor-specific antigen for malignancies of the epithelialis lineage. In this study the interaction between the DNA-based EpCAM aptamer (SYL3C) and EpCAM was explored using single molecular recognition force spectroscopy (SMFS). The capability of aptamer SYL3C to recognize the EpCAM protein and the kinetic parameters were investigated. PMID- 26229988 TI - Naked-eye nanobiosensor for therapeutic drug monitoring of methotrexate. AB - Sensing of methotrexate at clinically-relevant concentrations was achieved with a plasmon-coupling assay. In this assay, free methotrexate and folic acid Au nanoparticles competed for human dihydrofolate reductase (hDHFR)-functionalized Au nanoparticles (Au NP). The hDHFR-functionalized Au NPs were immobilized on a small glass sensor inserted in a portable 4-channel LSPR reader. This allowed rapid (minutes) and sensitive (nanomolar range) measurement of methotrexate concentration by means of total internal reflection plasmonic spectroscopy. The large bathochromic shifts of the plasmon-coupling assay led to striking colour changes visible to the naked eye for methotrexate at clinically-relevant concentrations. The results demonstrate the potential for therapeutic drug monitoring of a widely used chemotherapy agent, as assessed with the naked eye. PMID- 26229989 TI - Visualization of film-forming polymer particles with a liquid cell technique in a transmission electron microscope. AB - One of the long-standing challenges in studying structure-property relationships in latex films is to directly characterize the size and morphology of the corresponding polymer particles, especially the particles with low film formation temperatures. Here we present an in situ transmission electron microscopy (TEM) study that allows characterization of film-forming latex particles in solution. Liquid cell TEM provides the opportunity to image latexes with a range of particle sizes and glass transition temperatures. Together with a staining technique, it can also be used as a tool to characterize the internal structure of particles in solution. PMID- 26229990 TI - Catalytic oxidation of alkanes by a (salen)osmium(VI) nitrido complex using H2O2 as the terminal oxidant. AB - The osmium(VI) nitrido complex, [Os(VI)(N)(L)(CH3OH)](+) (1, L = N,N' bis(salicylidene)-o-cyclohexyldiamine dianion) is an efficient catalyst for the oxidation of alkanes under ambient conditions using H2O2 as the oxidant. Alkanes are oxidized to the corresponding alcohols and ketones, with yields up to 75% and turnover numbers up to 2230. Experimental and computational studies are consistent with a mechanism that involves O-atom transfer from H2O2 to [Os(VI)(N)(L)](+) to generate an [Os(VIII)(N)(O)(L)](+) active intermediate. PMID- 26229991 TI - Control of the photoluminescence properties of single-walled carbon nanotubes by alkylation and subsequent thermal treatment. AB - Dibutylated single-walled carbon nanotubes (Bu-SWNTs-Bu) with varying degrees of functionalization were prepared by two-step reductive alkylation and subsequent thermal treatment. A new photoluminescence peak at around 1240 nm was observed and increased drastically after the thermal treatment. The results indicate that thermally treated Bu-SWNTs-Bu are promising NIR photoluminescent materials. PMID- 26229992 TI - Hydroxylated carbon nanotube enhanced sulfur cathodes for improved electrochemical performance of lithium-sulfur batteries. AB - Hydroxylated multi-walled carbon nanotubes were introduced into sulfur cathodes to utilize the hydrophilic attraction between the OH group and polysulfides as well as to increase the utilization of sulfur. This approach shows a promising strategy for diminishing the polysulfides shuttling behavior and improving the electrochemical performance of lithium-sulfur batteries. PMID- 26229993 TI - A novel quaternary solid solution photo-absorber material for photoelectrochemical hydrogen generation. AB - We report a novel quaternary solid solution (Ag-Cu-Sb-S or ACSS) serving as a photo-absorber material in the photoelectrochemical field for the first time, and ZnO/ACSS nanoarrays exhibited a photocurrent density of 4.45 mA cm(-2). The research indicates that ZnO/ACSS composite structures have enormous potential in PEC hydrogen generation systems. PMID- 26229994 TI - A highly enantioselective Mannich reaction of aldehydes with cyclic N-acyliminium ions by synergistic catalysis. AB - Matched combinations of Bronsted or Lewis acids with suitable pro-electrophiles and secondary amine organocatalysts enable the novel enantioselective syntheses of carbamoyl dihydroquinoline and tetrahydropyridine derivatives with concomitant formation of two stereocenters. A short formal asymmetric synthesis of (2R,2'R) threo-methylphenidate (Ritalin) is also described. PMID- 26229995 TI - Ionic liquids enhance the electrochemical CO2 reduction catalyzed by MoO2. AB - Several imidazolium-based ionic liquids significantly enhance the activity of MoO2 for electrochemical reduction of CO2. The overpotential of CO2 reduction is as low as 40 mV. The ionic liquids act as both electrolytes and co-catalysts, which not only leads to lower overpotentials, but also alters the product selectivity. PMID- 26229996 TI - Tuning the structural asymmetries of three-dimensional gold nanorod assemblies. AB - A series of 3D AuNR dimers and trimers were fabricated under the guidance of DNA origami. By tuning the size, number and spatial configuration of AuNRs, their structural and componential asymmetries were rationally designed. Circular dichroism measurements showed that the resultant plasmonic chiroptical activities of these nanorod assemblies can be precisely tailored. PMID- 26229997 TI - Thermochromic and solvatochromic properties of Lindqvist polyoxometalates. AB - The thermochromic and solvatochromic properties of Lindqvist metal oxide clusters [V(x)M(6-x)O19](n-) (x = 0, 1, 2, M = Mo, W) are reported. The cluster anions show pronounced changes of their electronic structure depending on their chemical environment (e.g. solvent polarity, temperature). These are rationalized using experimental and theoretical methods. A combined density functional theory and (51)V-NMR study suggests that temperature-dependent changes in the structural dynamics of the metal oxide framework are the underlying cause for the observed thermochromism. The results might open new avenues for the design of molecular optical sensors. PMID- 26229998 TI - Erratum. PMID- 26229999 TI - Sir Donald Ross, pioneer aortic valve surgeon. AB - Tribute to Sir Donald Ross by David Wheatley, as read by Robert Kleinloog, President, Society of Cardiothoracic Surgeons of South Africa at the Annual Congress of the South African Heart Association 19 October 2014. PMID- 26230000 TI - Plans of the British Cardiovascular Society to seek patients' views on research may aid research grant applications. AB - Priorities for unanswered questions concerning major areas of cardiovascular disease are being sought by the British Cardiovascular Society, using the methods of the James Lind Alliance, which involves clinicians and patients in an equal partnership, reports Barry Shurlock PhD. PMID- 26230001 TI - Dr Hector Bueno reviews the proposed criteria of the German Society of Cardiology for the Establishment of Chest Pain Units in their 2014 update. PMID- 26230002 TI - Author Response. PMID- 26230003 TI - Author Response. PMID- 26230004 TI - Targeting the Effect of VEGF in Diabetic Macular Edema. PMID- 26230005 TI - Tropical protection. PMID- 26230006 TI - Professor Kerstin Lundstrom, Swedish University of Agricultural Sciences, Uppsala, 1946-2015. PMID- 26230007 TI - Extramural work: To serve or not to serve. PMID- 26230008 TI - The electronic cigarette: a wolf in sheep's clothing. AB - The American Heart Association warned from the potential of electronic cigarettes to renormalize smoking in public and the International Respiratory Societies demanded regulation of all nicotine products as medicines or tobacco products. This review summarizes the results of studies on hazards of e-cigarette use, which has increased dramatically and may be the real threat for the achievements in tobacco control of the past 20 years. PMID- 26230009 TI - Bacterial scissors to edit human embryos? AB - A recently discovered gene editing tool raises the possibility of precisely targeted changes to human genes, even in the germline. The nascent debate over the ethics and limitations of its use has already been overtaken by events. Is this a whole new Pandora's box for bioethics? PMID- 26230010 TI - The promise and peril of intensive-site-based ecological research: insights from the Hubbard Brook ecosystem study. AB - Ecological research is increasingly concentrated at particular locations or sites. This trend reflects a variety of advantages of intensive, site-based research, but also raises important questions about the nature of such spatially delimited research: how well does site based research represent broader areas, and does it constrain scientific discovery? We provide an overview of these issues with a particular focus on one prominent intensive research site: the Hubbard Brook Experimental Forest (HBEF), New Hampshire, USA. Among the key features of intensive sites are: long-term, archived data sets that provide a context for new discoveries and the elucidation of ecological mechanisms; the capacity to constrain inputs and parameters, and to validate models of complex ecological processes; and the intellectual cross-fertilization among disciplines in ecological and environmental sciences. The feasibility of scaling up ecological observations from intensive sites depends upon both the phenomenon of interest and the characteristics of the site. An evaluation of deviation metrics for the HBEF illustrates that, in some respects, including sensitivity and recovery of streams and trees from acid deposition, this site is representative of the Northern Forest region, of which HBEF is a part. However, the mountainous terrain and lack of significant agricultural legacy make the HBEF among the least disturbed sites in the Northern Forest region. Its relatively cool, wet climate contributes to high stream flow compared to other sites. These similarities and differences between the HBEF and the region can profoundly influence ecological patterns and processes and potentially limit the generality of observations at this and other intensive sites. Indeed, the difficulty of scaling up may be greatest for ecological phenomena that are sensitive to historical disturbance and that exhibit the greatest spatiotemporal variation, such as denitrification in soils and the dynamics of bird communities. Our research shows that end member sites for some processes often provide important insights into the behavior of inherently heterogeneous ecological processes. In the current era of rapid environmental and biological change, key ecological responses at intensive sites will reflect both specific local drivers and regional trends. PMID- 26230011 TI - A biophysical basis for patchy mortality during heat waves. AB - Extreme heat events cause patchy mortality in many habitats. We examine biophysical mechanisms responsible for patchy mortality in beds of the competitively dominant ecosystem engineer, the marine mussel Mytilus californianus, on the west coast of the United States. We used a biophysical model to predict daily fluctuations in body temperature at sites from southern California to Washington and used results of laboratory experiments on thermal tolerance to determine mortality rates from body temperature. In our model, we varied the rate of thermal conduction within mussel beds and found that this factor can account for large differences in body temperature and consequent mortality during heat waves. Mussel beds provide structural habitat for other species and increase local biodiversity, but, as sessile organisms, they are particularly vulnerable to extreme weather conditions. Identifying critical biophysical mechanisms related to mortality and ecological performance will improve our ability to predict the effects of climate change on these vulnerable ecosystems. PMID- 26230012 TI - How far away is the next basket of eggs? Spatial memory and perceived cues shape aggregation patterns in a leaf beetle. AB - Gregarious organisms need to handle the trade-off between increasing food competition and the positive effects of group living, and this is particularly important for ovipositing females. We hypothesized that insect females consider how many conspecifics previously visited a host plant. In a no-choice assay, we show that the gregarious blue willow leaf beetle (Phratora vulgatissima) laid the most eggs and the largest clutches on plants where a sequence of few individual females was released, compared to plants where one or many different females were repeatedly released. Therefore, this species is more sensitive to the indirectly perceived number of conspecifics than the directly perceived number of eggs on a plant. We further hypothesized that females adjust their own intra-plant egg clutch distribution to that of conspecifics and discovered a new behavioral component, i.e., the modulation of distances between clutches. Females adjusted these distances in ways indicating the use of spatial memory, because the largest distance increases were observed on plants with their own clutches, compared to plants with clutches from conspecifics. However, adjustment of aggregation level and distance between clutches occurred only on a suitable, and not on an unsuitable, Salix genotype. We conclude that both behaviors should reduce competition between sibling and non-sibling larvae. PMID- 26230013 TI - Resource pulses can alleviate the biodiversity-invasion relationship in soil microbial communities. AB - The roles of species richness, resource use, and resource availability are central to many hypotheses explaining the diversity-invasion phenomenon but are generally not investigated together. Here, we created a large diversity gradient of soil microbial communities by either assembling communities of pure bacterial strains or removing the diversity of a natural soil. Using data on the resource use capacities of the soil communities and an invader that were gathered from 71 carbon sources, we quantified the niches available to both constituents by using the metrics community niche and remaining niche available to the invader. A strong positive relationship between species richness and community niche across both experiments indicated the presence of resource complementarity. Moreover, community niche and the remaining niche available to the invader predicted invader abundance well. This suggested that increased competition in communities of higher diversity limits community invasibility and underscored the importance of resource availability as a key mechanism through which diversity hinders invasions. As a proof of principle, we subjected selected invaded communities to a resource pulse, which progressively uncoupled the link between soil microbial diversity and invasion and allowed the invader to rebound after nearly being eliminated in some communities. Our results thus show that (1) resource competition suppresses invasion, (2) biodiversity increases resource competition and decreases invasion through niche preemption, and (3) resource pulses that cannot be fully used, even by diverse communities, are favorable to invasion. PMID- 26230014 TI - Fungal symbiosis and precipitation alter traits and dune building by the ecosystem engineer, Ammophila breviligulata. AB - Ecosystem engineer species influence their community and ecosystem by creating or altering the physical structure of habitats. The function of ecosystem engineers is variable and can depend on both abiotic and biotic factors. Here we make use of a primary successional system to evaluate the direct and interactive effects of climate change (precipitation) and fungal endophyte symbiosis on population traits and ecosystem function of the ecosystem engineering grass species, Ammophila breviligulata. We manipulated endophyte presence in A. breviligulata in combination with rain-out shelters and rainfall additions in a factorial field experiment established in 2010 on Lake Michigan sand dunes. We monitored plant traits, survival, growth, and sexual reproduction of A. breviligulata from 2010 2013, and quantified ecosystem engineering as the sand accumulation rate. Presence of the endophyte in A. breviligulata increased vegetative growth by up to 19%, and reduced sexual reproduction by up to 46% across all precipitation treatments. Precipitation was a less significant factor than endophyte colonization for A. breviligulata growth. Reduced precipitation increased average leaf number per tiller but had no other effects on plant traits. Changes in A. breviligulata traits corresponded to increases in sand accumulation in plots with the endophyte as well as in plots with reduced precipitation. Sand accumulation is a key ecosystem function in these primary successional habitats, and so microbial symbiosis in this ecosystem engineer could lead to direct effects on the value of these dune habitats for humans. PMID- 26230015 TI - Nonlinear responses in salt marsh functioning to increased nitrogen addition. AB - Salt marshes provide storm protection to shorelines, sequester carbon (C), and mitigate coastal eutrophication. These valuable coastal ecosystems are confronted with increasing nitrogen (N) inputs from anthropogenic sources, such as agricultural runoff, wastewater, and atmospheric deposition. To inform predictions of salt marsh functioning and sustainability in the future, we characterized the response of a variety of plant, microbial, and sediment responses to a seven-level gradient of N addition in three Californian salt marshes after 7 and 14 months of N addition. The marshes showed variable responses to the experimental N gradient that can be grouped as neutral (root biomass, sediment respiration, potential carbon mineralization, and potential net nitrification), linear (increasing methane flux, decreasing potential net N mineralization, and increasing sediment inorganic N), and nonlinear (saturating aboveground plant biomass and leaf N content, and exponentially increasing sediment inorganic and organic N). The three salt marshes showed quantitative differences in most ecosystem properties and processes rates; however, the form of the response curves to N addition were generally consistent across the three marshes, indicating that the responses observed may be applicable to other marshes in the region. Only for sediment properties (inorganic and organic N pool) did the shape of the response differ significantly between marshes. Overall, the study suggests salt marshes are limited in their ability to sequester C and N with future increases in N, even without further losses in marsh area. PMID- 26230016 TI - Environmental conditions during early life accelerate the rate of senescence in a short-lived passerine bird. AB - Environmental conditions experienced in early life may shape subsequent phenotypic traits including life history. We investigated how predation risk caused by domestic cats (Felis silvestris catus) and local breeding density affected patterns of reproductive and survival senescence in Barn Swallows (Hirundo rustica) breeding semicolonially in Denmark. We recorded the abundance of cats and the number of breeding pairs at 39 breeding sites during 24 years and related these to age-specific survival rate and reproductive senescence to test predictions of the life history theory of senescence. We found evidence for actuarial senescence for the first time in this species. Survival rate increased until reaching a plateau in midlife and then decreased later. We also found that survival rate was higher for males than females. Local breeding density or predation risk did not affect survival as predicted by theory. Barn Swallows with short lives did not invest more in reproduction in early life, inconsistent with expectations for trade-offs between reproduction and survival as theory suggests. However, we found that the rate of reproductive decline during senescence was steeper for individuals exposed to intense competition, and predation pressure accelerated the rate of reproductive senescence, but only in sites with many breeding pairs. These latter results are in accordance with one of the predictions suggested by the life history theory of aging. These results emphasize the importance of considering intraspecific competition and interspecific interactions such as predation when analyzing reproductive and actuarial senescence. PMID- 26230017 TI - Genotype variation in bark texture drives lichen community assembly across multiple environments. AB - A major goal of community genetics is to understand the influence of genetic variation within a species on ecological communities. Although well-documented for some organisms, additional research is necessary to understand the relative and interactive effects of genotype and environment on biodiversity, identify mechanisms through which tree genotype influences communities, and connect this emerging field with existing themes in ecology. We employ an underutilized but ecologically significant group of organisms, epiphytic bark lichens, to understand the relative importance of Populus angustifolia (narrowleaf cottonwood) genotype and environment on associated organisms within the context of community assembly and host ontogeny. Several key findings emerged. (1) In a single common garden, tree genotype explained 18-33% and 51% of the variation in lichen community variables and rough bark cover, respectively. (2) Across replicated common gardens, tree genotype affected lichen species richness, total lichen cover, lichen species composition, and rough bark cover, whereas environment only influenced composition and there were no genotype by environment interactions. (3) Rough bark cover was positively correlated with total lichen cover and richness, and was associated with a shift in species composition; these patterns occurred with variation in rough bark cover among tree genotypes of the same age in common gardens and with increasing rough bark cover along a -40 year tree age gradient in a natural riparian stand. (4) In a common garden, 20-year old parent trees with smooth bark had poorly developed lichen communities, similar to their 10-year-old ramets (root suckers) growing in close proximity, while parent trees with high rough bark cover had more developed communities than their ramets. These findings indicate that epiphytic lichens are influenced by host genotype, an effect that is robust across divergent environments. Furthermore, the response to tree genotype is likely the result of genetic variation in the timing of the ontogenetic shift from smooth to rough bark allowing communities on some genotypes to assemble faster than those on other genotypes. Organisms outside the typical sphere of community genetics, such as lichens, can help address critical issues and connect plant genotype effects to long-established streams of biological research, such as ontogeny and community assembly. PMID- 26230018 TI - Linking environmental filtering and disequilibrium to biogeography with a community climate framework. AB - We present a framework to measure the strength of environmental filtering and disequilibrium of the species composition of a local community across time, relative to past, current, and future climates. We demonstrate the framework by measuring the impact of climate change on New World forests, integrating data for climate niches of more than 14000 species, community composition of 471 New World forest plots, and observed climate across the most recent glacial-interglacial interval. We show that a majority of communities have species compositions that are strongly filtered and are more in equilibrium with current climate than random samples from the regional pool. Variation in the level of current community disequilibrium can be predicted from Last Glacial Maximum climate and will increase with near-future climate change. PMID- 26230019 TI - Warming tolerance across insect ontogeny: influence of joint shifts in microclimates and thermal limits. AB - The impact of warming on the persistence and distribution of ectotherms is often forecasted from their warming tolerance, inferred as the difference between their upper thermal limit and macroclimate temperature. Ectotherms, however, are thermally adapted to their microclimates, which can deviate substantially from macroscale conditions. Ignoring microclimates can therefore bias estimates of warming tolerance. We compared warming tolerance of an insect across its ontogeny when calculated from macro- and microclimate temperatures. We used a heat balance model to predict experienced microclimate temperatures from macroclimate, and we measured thermal limits for several life stages. The model shows a concomitant increase in microclimate temperatures and thermal limits across insect ontogeny, despite the fact that they all share the same macroclimate. Consequently, warming tolerance; as estimated from microclimate temperature, remained constant across ontogeny. When calculated from macroclimate temperature, however, warming tolerance was overestimated by 7-10 degrees C, depending on the life stage. Therefore, errors are expected when predicting persistence and distribution shifts of ectotherms in changing climates using macroclimate rather than microclimate. PMID- 26230020 TI - Trophic phylogenetics: evolutionary influences on body size, feeding, and species associations in grassland arthropods. AB - Contemporary animal-plant interactions such as herbivory are widely understood to be shaped by evolutionary history. Yet questions remain about the role of plant phylogenetic diversity in generating and maintaining herbivore diversity, and whether evolutionary relatedness of producers might predict the composition of consumer communities. We tested for evidence of evolutionary associations among arthropods and the plants on which they were found, using phylogenetic analysis of naturally occurring arthropod assemblages sampled from a plant-diversity manipulation experiment. Considering phylogenetic relationships among more than 900 arthropod consumer taxa and 29 plant species in the experiment, we addressed several interrelated questions. First, our results support the hypothesis that arthropod functional traits such as body size and trophic role are phylogenetically conserved in community ecological samples. Second, herbivores tended to cooccur with closer phylogenetic relatives than would be expected at random, whereas predators and parasitoids did not show phylogenetic association patterns. Consumer specialization, as measured by association through time with monocultures of particular host plant species, showed significant phylogenetic signal, although the. strength of this association varied among plant species. Polycultures of phylogenetically dissimilar plant species supported more phylogenetically dissimilar consumer communities than did phylogenetically similar polycultures. Finally, we separated the effects of plant species richness and relatedness in predicting the phylogenetic distribution of the arthropod assemblages in this experiment. The phylogenetic diversity of plant communities predicted the phylogenetic diversity of herbivore communities even after accounting for plant species richness. The phylogenetic diversity of secondary consumers differed by guild, with predator phylogenetic diversity responding to herbivore relatedness, while parasitoid phylogenetic diversity was driven by plant relatedness. Evolutionary associations between plants and their consumers are apparent in plots only meters apart in a single field, indicating a strong role for host-plant phylogenetic diversity in sustaining landscape consumer biodiversity. PMID- 26230021 TI - Similar plastic responses to elevated temperature among different-sized brook trout populations. AB - The potential influence of population size on the magnitude of phenotypic plasticity, a key factor in adaptation to environmental change, has rarely been studied. Conventionally, small populations might exhibit consistently lower plasticity than large populations if small population habitats are generally poor in quality and if genetic diversity underpinning plasticity is lost as population size is reduced. Alternatively, small populations might exhibit (1) consistently higher plasticity as a response to the increased environmental variation that can accompany habitat fragment size reduction or (2) greater variability in plasticity, as fragmentation can increase variability in habitat types. We explored these alternatives by investigating plasticity to increasing temperature in a common garden experiment using eight fragmented populations of brook trout varying nearly 50-fold in census size (179-8416) and 10-fold in effective number of breeders (18-135). Across six early-life-history traits and three temperatures, we found almost no evidence for differences in either the magnitude or variability of plasticity in relation to population size, despite that one temperature represented an extreme climate warming scenario. The documentation of similar plastic responses of small and large populations suggests that phenotypic plasticity is not reduced as population size decreases, and that even very small populations of some species might have the ability to respond to climate change. PMID- 26230022 TI - Wave action modifies the effects of consumer diversity and warming on algal assemblages. AB - To understand the consequences of biodiversity loss, it is necessary to test how biodiversity-ecosystem functioning relationships may vary with predicted environmental change. In particular, our understanding will be advanced by studies addressing the interactive effects of multiple stressors on the role of biodiversity across trophic levels. Predicted increases in wave disturbance and ocean warming, together with climate-driven range shifts of key consumer species, are likely to have profound impacts on the dynamics of coastal marine communities. We tested whether wave action and temperature modified the effects of gastropod grazer diversity (Patella vulgata, Littorina littorea, and Gibbula umbilicalis) on algal assemblages in experimental rock pools. The presence or absence of L. littorea appeared to drive changes in microalgal and macroalgal biomass and macroalgal assemblage structure. Macroalgal biomass also decreased with increasing grazer species richness, but only when wave action was enhanced. Further, independently of grazer diversity, wave action and temperature had interactive effects on macroalgal assemblage structure. Warming also led to a reversal of grazer-macroalgal interaction strengths from negative to positive, but only when there was no wave action. Our results show that hydrodynamic disturbance can exacerbate the effects of changing consumer diversity, and may also disrupt the influence of other environmental stressors on key consumer resource interactions. These findings suggest that the combined effects of anticipated abiotic and biotic change on the functioning of coastal marine ecosystems, although difficult to predict, may be substantial. PMID- 26230023 TI - Drivers of observed biotic homogenization in pine barrens of central Wisconsin. AB - Fire suppression throughout the 20th century greatly altered plant communities in fire-dominated systems across North America. Our ability to assess these effects over the long-term, however, is handicapped by the paucity of baseline data. Here, we used detailed baseline data from the 1950s to track changes in the over- and understory composition of pine-barrens vegetation growing on sandy, glacial lake-bed sediments in central Wisconsin. We expected fire suppression to favor succession to closed-canopy conditions, leading to decreases in shade-intolerant and fire-adapted species and consequent reductions in alpha and gamma diversity. We also expected beta diversity to decline due to increases in shade-tolerant, fire-sensitive, and exotic species. In fact, fire suppression has greatly altered the structure and composition of these pine-barrens communities over the past 54 years. Woody, wind-pollinated, and shade-tolerant species all increased in richness and abundance, as expected, with succession following fire suppression. Contrary to expectations, local and regional species richness increased by 12% and 26%, respectively, while Shannon beta diversity declined 24.1%. Increases in canopy coverage and number of native species appear to have driven this biotic homogenization. In contrast, increases in exotic species in our study did not promote biotic homogenization, reflecting their relative rarity across sites. Our findings highlight the key role fire plays in shaping the assembly of these pine barrens communities. PMID- 26230024 TI - Differences in beta diversity between exotic and native grasslands vary with scale along a latitudinal gradient. AB - Biodiversity can be partitioned into alpha, beta, and gamma components, and beta diversity is not as clearly understood. Biotic homogenization predicts that exotic species should lower beta diversity at global and continental scales, but it is still unclear how exotic species impact beta diversity at smaller scales. Exotic species could theoretically increase or decrease beta diversity relative to natives depending on many factors, including abiotic conditions, community assembly history, management, dispersal rates of species, and connectivity among patches. We sampled plant species abundances in 42 novel, exotic- and native dominated (remnant) grasslands across a latitudinal gradient in the tallgrass prairie region, and tested whether exotic and native grasslands differed in beta diversity at three scales: across sites within the entire biome, across sites within regions, and across locations within sites. Exotic-dominated grasslands differed from native-dominated grasslands in beta diversity at all scales, but the direction of the difference changed from positive to negative as scales went from large to small. Contrary to expectations, exotic-dominated grasslands had higher beta diversity than native-dominated grasslands at the largest scale considered. This occurred because the identity of dominant exotic species varied across the latitudinal gradient, with many exotic grassland pairs exhibiting zero similarity, whereas native-dominated grasslands differed more gradually with distance. Beta diversity among sites within a region was variable, with exotic dominated grasslands having 29% higher beta diversity than native grasslands in the south and 33% lower beta diversity in the north. Within sites, beta diversity was 26% lower in exotic-dominated than native grasslands. Our results provide evidence that different regional identities and abundances of exotics, and lack of connectivity in fragmented landscapes can alter beta diversity in unexpected ways across spatial scales. PMID- 26230025 TI - Apparent competition and native consumers exacerbate the strong competitive effect of an exotic plant species. AB - Direct and indirect effects can play a key role in invasions, but experiments evaluating both are rare. We examined the roles of direct competition and apparent competition by exotic Amur honeysuckle (Lonicera maackii) by manipulating (1) L. maackii vegetation, (2) presence of L. maackii fruits, and (3) access to plants by small mammals and deer. Direct competition with L. maackii reduced the abundance and richness of native and exotic species, and native consumers significantly reduced the abundance and richness of native species. Although effects of direct competition and consumption were more pervasive, richness of native plants was also reduced through apparent competition, as small-mammal consumers reduced richness only when L. maackii fruits were present. Our experiment reveals the multiple, interactive pathways that affect the success and impact of an invasive exotic plant: exotic plants may directly benefit from reduced attack by native consumers, may directly exert strong competitive effects on native plants, and may also benefit from apparent competition. PMID- 26230026 TI - Mechanisms underlying local functional and phylogenetic beta diversity in two temperate forests. AB - Although trait information has been widely used to explore underlying mechanisms of forest community structure, most studies have focused on local patterns of phylogenetic or functional alpha diversity. Investigations of functional beta diversity, on the other hand, have not been conducted at local scales in a spatially explicit way. In this study, we provide a powerful methodology based on recent advances in spatial point pattern analysis using fully mapped data of large and small trees in two large temperate forest plots. This approach allowed us to assess the relative importance of different ecological processes and mechanisms for explaining patterns of local phylogenetic and functional beta diversity. For both forests and size classes, we found a clear hierarchy of scales: habitat filtering accounted for patterns of phylogenetic and functional beta diversity at larger distances (150-250 m), dispersal limitation accounted for the observed decline in beta diversity at distances below 150 m, and species interactions explained small departures from functional and phylogenetic beta diversity at the immediate plant-neighborhood scale (below 20 m). Thus, both habitat filtering and dispersal limitation influenced the observed patterns in phylogenetic and functional beta diversity at local scales. This result contrasts with a previous study from the same forests, where dispersal limitation alone approximated the observed species beta diversity for distances up to 250 m. In addition, species interactions were relatively unimportant for predicting phylogenetic and functional beta diversity. Our analysis suggests that phylogenetic and functional beta diversity can provide insights into the mechanisms of local community assembly that are missed by studies focusing exclusively on species beta diversity. PMID- 26230027 TI - Dispersal strength influences zooplankton co-occurrence patterns in experimental mesocosms. AB - Negative co-occurrence patterns are intriguing because they may reflect the outcome of interspecific interactions and therefore signal how competition shapes communities. However, other factors also contribute to these patterns. For example, theoretical studies as well as two survey-based studies have all suggested that dispersal may also impact these patterns. While natural communities commonly have nonrandom patterns of negative co-occurrence, understanding how different processes drive these patterns requires further research. We tested the influence of dispersal on co-occurrence patterns using a zooplankton mesocosm experiment with four different dispersal treatments varying in the number of dispersers delivered into mesocosms on regular intervals. Our dispersal treatments were intended to adjust the relative importance of dispersal and competition experienced within mesocosms (i.e., high dispersal results in a relatively low influence of competition on species composition and vice versa). Higher dispersal translated into increased zooplankton species richness and inter mesocosm compositional similarity, and also changed species occupancy patterns such that species occurrences were more even across mesocosms in higher-dispersal treatments. Dispersal treatments also differed markedly in species co-occurrence patterns. Negative co-occurrence patterns were significant for all but the lowest dispersal treatment, peaked in the intermediate-dispersal treatments, and declined in the highest-dispersal treatment. Stability analyses illustrate that co-occurrence differences are robust to the exclusion of any single mesocosm in null model analyses. Dispersal treatments did not significantly differ with respect to abiotic variation, which has been recognized as a potential driver of negative co-occurrence patterns. These results suggest that not only can dispersal influence patterns of negative co-occurrence via changes to species richness and distribution (occupancy patterns among mesocosms), but the degree to which they do so varies nonlinearly with the strength of dispersal. Critically, because negative co-occurrence patterns were nonsignificant when the contribution of dispersal was lowest, it is possible that dispersal contributes strongly to many observed patterns of negative co-occurrence. Consequently, great care should be taken prior to interpreting significant co-occurrence tests as a product of species interactions. PMID- 26230028 TI - Combining mesocosm and field experiments to predict invasive plant performance: a hierarchical Bayesian approach. AB - Invasive plant fecundity underlies propagule pressure and ultimately range expansion. Predicting fecundity across large spatial scales, from regions to landscapes, is critical for understanding invasion dynamics and optimizing management. However, to accurately predict fecundity and other demographic processes, improved models that scale individual plant responses to abiotic drivers across heterogeneous environments are needed. Here we combine two experimental data sets to predict fecundity of a widespread and problematic invasive grass over large spatial scales. First, we analyzed seed production as a function of plant biomass in a small-scale mesocosm experiment with manipulated light levels. Then, in a field introduction experiment, we tracked plant performance across 21 common garden sites that differed widely in available light and other factors. We jointly analyzed these data using a Bayesian hierarchical model (BHM) framework to predict fecundity as a function of light in the field. Our analysis reveals that the invasive species is likely to produce sufficient seed to overwhelm establishment resistance, even in deeply shaded environments, and is likely seed-limited across much of its range. Finally, we extend this framework to address the general problem of how to scale up plant demographic processes and analyze the factors that control plant distribution and abundance at large scales. PMID- 26230029 TI - Temporal dynamics of a commensal network of cavity-nesting vertebrates: increased diversity during an insect outbreak. AB - Network analysis offers insight into the structure and function of ecological communities, but little is known about how empirical networks change over time during perturbations. "Nest webs" are commensal networks that link secondary cavity-nesting vertebrates (e.g., bluebirds, ducks, and squirrels, which depend on tree cavities for nesting) with the excavators (e.g., woodpeckers) that produce cavities. In central British Columbia, Canada, Northern Flicker (Colaptes auratus) is considered a keystone excavator, providing most cavities for secondary cavity-nesters. However, roles of species in the network, and overall network architecture, are expected to vary with population fluctuations. Many excavator species increased in abundance in association with a pulse of food (adult and larval beetles) during an outbreak of mountain pine beetle (Dendroctonus ponderosae), which peaked in 2003-2004. We studied nest-web dynamics from 1998 to 2011 to determine how network architecture changed during this resource pulse. Cavity availability increased at the onset of the beetle outbreak and peaked in 2005. During and after the outbreak, secondary cavity nesters increased their use of cavities made by five species of beetle-eating excavators, and decreased their use of flicker cavities. We found low link turnover, with 74% of links conserved from year to year. Nevertheless, the network increased in evenness and diversity of interactions, and declined slightly in nestedness and niche overlap. These patterns remained evident seven years after the beetle outbreak, suggesting a legacy effect. In contrast to previous snapshot studies of nest webs, our dynamic approach reveals how the role of each cavity producer, and thus quantitative network architecture, can vary over time. The increase in interaction diversity with the beetle outbreak adds to growing evidence that insect outbreaks can increase components of biodiversity in forest ecosystems at various temporal scales. The observed changes in (quantitative) network architecture contrast with the relatively stable (qualitative) architecture of empirical mutualistic networks that have been studied to date. However, they are consistent with recent theory on the importance of population fluctuations in driving network architecture. Our results support the view that models should allow for the possibility of rewiring (species switching partners) to avoid overestimation of secondary extinction risk. PMID- 26230030 TI - The diversity and abundance of North American bird assemblages fail to track changing productivity. AB - Plant biomass or productivity and the species richness of birds are associated across a range of spatial scales. Species-energy theory is generally assumed to explain these correlations. If true, bird richness should also track productivity temporally, and there should be spatial and temporal relationships between productivity and both bird abundance and bird richness. Using the summer normalized difference vegetation index (NDVI) for 1982-2006 and the North American Breeding Bird Survey, we evaluated the response of avian richness and abundance to interannual changes in plant biomass or productivity. We found positive spatial relationships between richness and NDVI for all 25 years. Temporally, however, richness and NDVI were positively associated at 1579 survey sites and negatively associated at 1627 sites (mean r2 = 0.09). Further, total abundance and NDVI were unrelated spatially (r2 values spanning < 0.01 and 0.03) and weakly related temporally (mean r2 = 0.10). We found no evidence that productivity drives bird richness beyond the spatial correlations, and neither prediction arising from species-energy theory was confirmed. Spatial relationships between productivity and bird richness may thus be largely spurious, arising via covariance between plant biomass or productivity and vegetation structural complexity, and the latter may be driving bird communities. This is consistent with the MacArthurs' classic hypothesis that the vertical profile of foliage drives bird species diversity. PMID- 26230031 TI - Biogeography of a plant invasion: plant-herbivore interactions. AB - Theory predicts that native plant species should exhibit latitudinal gradients in the strength of their interactions with herbivores. We hypothesize that if an invasive plant species exhibits a different latitudinal gradient in response to herbivores (e.g., a nonparallel gradient), it can create large-scale heterogeneities in community resistance/susceptibility to the invasive species. We conducted a study of latitudinal variation in the strength of herbivory and defenses of native genotypes of Phragmites australis in North America (NA) and Europe (EU) and European invasive genotypes in NA. Within NA, we tested whether (1) invasive genotypes are better defended and suffer less herbivory than co occurring native genotypes, (2) herbivory and defenses of native P. australis decreases with increasing latitude; and (3) invasive genotypes exhibit either no latitudinal gradient, or a nonparallel latitudinal gradient in herbivory and defenses compared to native genotypes. For the European genotypes, we tested two additional hypotheses: (4) defenses, nutritional condition, and herbivory would differ between the native (EU) and invasive ranges (NA) and (5) latitudinal gradients in defenses and herbivory would be similar between ranges. Within NA, chewing damage, internal stem-feeding incidence, and aphid abundance were 650%, 300%, and 70% lower, respectively, on invasive than native P. australis genotypes. Genotypes in NA also differed in nutritional condition (percent N, C:N ratio), but there was little support for invasive genotypes being better defended than native genotypes. For the European genotypes, herbivory was significantly lower in the invaded than native range, supporting the enemy-release hypothesis. Defense levels (leaf toughness and total phenolics) and tissue percent C and percent N were higher in the invaded than native range for European genotypes. Overall, latitudinal gradients in P. australis nutritional condition, defenses, and herbivory were common. Interestingly, chewing damage and stem-feeder incidence decreased with latitude for native P. australis genotypes in NA and EU, but no latitudinal gradients in response to herbivores were evident for invasive genotypes in NA. Nonparallel latitudinal gradients in herbivory between invasive and native P. australis suggest that the community may be more susceptible to invasion at lower than at higher latitudes. Our study points to the need for invasion biology to include a biogeographic perspective. PMID- 26230032 TI - The interplay of adult and larval time constraints shapes species differences in larval life history. AB - In animals with a complex life cycle, larval life-history plasticity is likely shaped by the interplay of selective factors in both larval and adult stages. A wide interspecific variation in responses to larval time constraints imposed by seasonality has been documented. Few studies have addressed differences among closely related species in the evolutionary trajectories of age and size at metamorphosis and their link with larval growth rate under time constraints. None have considered how species-specific length of the reproductive season affects larval developmental responses to time constraints. We tested in four Coenagrion damselfly species whether species with a longer reproductive season, facing a smaller threat of missing out on reproduction, react less to larval time constraints and pre-winter food shortage by accelerating development rate and growth rate, and therefore pay less physiological costs. All species increased development and growth rates under larval time constraints. The magnitude of this increase negatively correlated across species with the length of the reproductive season. Under larval time constraints, only the species exhibiting the longest reproductive season suffered a delayed emergence and a reduced investment in energy storage, yet also showed an increased immune function. Under a longer reproductive season, evolution may favor compensation for larval constraints after metamorphosis. Growth rate was accelerated after pre-winter food shortage to the same extent across species; effects on age and mass at emergence also did not differ among species. Time constraints associated with the length of the reproductive season may predictably contribute to species differences in their response to time constraints imposed in the larval stage. Our study adds empirical proof that the interplay of selective factors in the larval and adult stages may determine life-history plasticity with regard to larval time constraints. PMID- 26230033 TI - Microbial stoichiometry overrides biomass as a regulator of soil carbon and nitrogen cycling. AB - Understanding the role of soil microbial communities in coupled carbon and nitrogen cycles has become an area of great interest as we strive to understand how global change will influence ecosystem function. In this endeavor, microbially explicit decomposition models are being adopted because they include microbial stoichiometry- and biomass-mediated mechanisms that may be important in shaping ecosystem response to environmental change. Yet there has been a dearth of empirical tests to verify the predictions of these models and hence identify potential improvements. We measured the response of soil microbes to multiple rates of carbon and nitrogen amendment in experimental microcosms, and used the respiration and nitrogen mineralization responses to assess a well-established, single-pool, microbial decomposition model. The model generally predicted the empirical trends in carbon and nitrogen fluxes, but failed to predict the empirical trends in microbial biomass. Further examination of this discontinuity indicated that the model successfully predicted carbon and nitrogen cycling because stoichiometry overrode microbial biomass as a regulator of cycling rates. Stoichiometric control meant that the addition of carbon generally increased respiration and decreased nitrogen mineralization, whereas nitrogen had the opposite effects. Biomass only assumed importance as a control on cycling rates when stoichiometric ratios of resource inputs were a close match to those of the microbial biomass. Our work highlights the need to advance our understanding of the stoichiometric demands of microbial biomass in order to better understand biogeochemical cycles in the face of changing organic- and inorganic-matter inputs to terrestrial ecosystems. PMID- 26230034 TI - A new perspective on trait differences between native and invasive exotic plants: comment. PMID- 26230035 TI - A new perspective on trait differences between native and invasive exotic plants: reply. PMID- 26230037 TI - Thiol/disulfide homeostasis in asphalt workers. AB - The aim of this study was to investigate thiol/disulfide homeostasis in asphalt workers who are exposed to polycyclic aromatic hydrocarbons occupationally. The study was carried out in 34 nonsmoker asphalt workers. Additionally, 35 healthy nonsmoker volunteers were recruited as control group. Thiol and disulfide concentrations were determined using the novel automated measurement method. Levels of urinary 1-OH-pyrene were analyzed by liquid chromatography. Disulfide/thiol ratio was significantly higher in exposed group (p = .034). Also, a positive correlation was detected between disulfide/thiol ratio and 1-OH-pyrene values (r = .249, p = .036). Thiol/disulfide homeostasis was found to be disturbed in asphalt workers. The novel test used in this study may be useful for evaluating the oxidative status in polycyclic aromatic hydrocarbon (PAH) exposure. PMID- 26230038 TI - Applying ISO 16840-2 Standard to differentiate impact force dissipation characteristics of selection of commercial wheelchair cushions. AB - Results from applying the International Organization for Standardization (ISO) 16840-2 test method for determining the impact damping characteristics of 35 wheelchair cushions plus a high resilience (HR70) polyurethane reference foam sample are reported. The generation of impact forces when a wheelchair user either transfers onto a cushion or the wheelchair encounters rough terrain or bumps down a step can endanger the viability of tissues, especially if these forces occur repeatedly. The results demonstrate significant differences in the impact force dissipation characteristics of different cushion products but do not reliably identify differences in performance that can be attributed to descriptive information about cushion composition alone. Instead, these results demonstrate that the materials, proprietary design, and construction features of wheelchair cushions in combination dictate impact force dissipation properties. The results of a cluster analysis are used to generate a model that can be used to compare the impact damping properties obtained from the ISO 16840-2 test method with those of a range of cushions and the reference cushion. Manufacturers will therefore be able to provide users and clinicians with information about the impact force dissipation properties of the cushions that will enable them to make more informed product choices for achieving improved comfort and to protect skin integrity. PMID- 26230040 TI - Janko Kersnik (1960-2015). PMID- 26230039 TI - Change in calculated cardiovascular risk due to guideline revision: A cross sectional study in the Netherlands. AB - BACKGROUND: Guidelines and accompanying risk charts concerning cardiovascular risk management (CVRM) are regularly revised worldwide. OBJECTIVE: To evaluate whether revision of the Dutch CVRM guideline has led to the reclassification of patients and, accordingly, to changes in drug recommendations. METHODS: All medical records (year 2011) of patients aged 40-65 years with no history of cardiovascular disease (CVD) but using antihypertensive and/or lipid-lowering drugs, were selected from the Registration Network of General Practices associated with Leiden University Medical Center. Multiple imputation techniques for missing determinants were used. The individual cardiovascular risk was calculated and the resulting drug recommendation was assessed according to both the 2006 and 2012 versions of the guideline. RESULTS: In total, 2075 patients were selected, of whom 1248 fulfilled the guideline criteria (systolic blood pressure 115-180 mmHg and total cholesterol/high-density-lipoprotein-cholesterol ratio 3.5-8). According to the 2012 guideline, 58.2% of the patients had low risk and 249 patients (20.0%) shifted to a different risk category. For 150 of these patients (12.0%), this category shift implied a shift in drug recommendation. The probability of shifting in drug recommendation increased with increasing age, cholesterol level, and blood pressure, and by being male. CONCLUSION: Guideline revision may have important implications: based on identical values for risk factors, according to the latest revision of the Dutch CVRM guideline 20% of patients shifted in risk category and 12% of the patients shifted in drug recommendation. PMID- 26230042 TI - Treatment with human immunoglobulin G improves the early disease course in a mouse model of Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a severe hereditary myopathy. Standard treatment by glucocorticosteroids is limited because of numerous side effects. The aim of this study was to test immunomodulation by human immunoglobulin G (IgG) as treatment in the experimental mouse model (mdx) of DMD. 2 g/kg human IgG compared to human albumin was injected intraperitoneally in mdx mice at the age of 3 and 7 weeks. Advanced voluntary wheel running parameters were recorded continuously. At the age of 11 weeks, animals were killed so that blood, diaphragm, and lower limb muscles could be removed for quantitative PCR, histological analysis and ex vivo muscle contraction tests. IgG compared to albumin significantly improved the voluntary running performance and reduced muscle fatigability in an ex vivo muscle contraction test. Upon IgG treatment, serum creatine kinase values were diminished and mRNA expression levels of relevant inflammatory markers were reduced in the diaphragm and limb muscles. Macrophage infiltration and myopathic damage were significantly ameliorated in the quadriceps muscle. Collectively, this study demonstrates that, in the early disease course of mdx mice, human IgG improves the running performance and diminishes myopathic damage and inflammation in the muscle. Therefore, IgG may be a promising approach for treatment of DMD. Two monthly intraperitoneal injections of human immunoglobulin G (IgG) improved the early 11-week disease phase of mdx mice. Voluntary running was improved and serum levels of creatine kinase were diminished. In the skeletal muscle, myopathic damage was ameliorated and key inflammatory markers such as mRNA expression of SPP1 and infiltration by macrophages were reduced. The study suggests that IgG could be explored as a potential treatment option for Duchenne muscular dystrophy and that pre-clinical long-term studies should be helpful. PMID- 26230044 TI - Carotid Endarterectomy Surgical Simulation Model Using a Bovine Placenta Vessel. AB - BACKGROUND: Carotid endarterectomy (CEA) is a common, well-developed surgical procedure. Although surgical simulation is gaining in importance for residency training, CEA practice opportunities for surgical residents are limited. OBJECTIVE: To describe a new haptic CEA model. METHODS: Six bovine placentas were used to create the model. Each placenta provided about 6 large arterial and venous bifurcations. In total, 36 large-vessel bifurcations were dissected and prepared for the CEA simulation. Bovine placenta vessels were arranged to simulate the common carotid artery (CCA), internal carotid artery (ICA), and external carotid artery (ECA). The diameters and wall thicknesses were measured and compared with human CCA, ICA, and ECA parameters. RESULTS: All bovine placentas provided vessels suitable for modeling carotid artery bifurcations and CEA training. Mean +/- SD diameters of simulated CCAs, ECAs, and ICAs were 11.2 +/- 1.8, 4.3 +/- 0.5, and 9.8 +/- 3.0 mm, respectively, from nondilated veins and 8.7 +/- 1.4, 4.4 +/- 1.3, and 7.2 +/- 1.7 mm, respectively, from nondilated arteries. Mean vessel wall thicknesses were 2.0 +/- 0.6 mm for arteries and 1.4 +/- 0.5 mm for veins. Placental vessel tissue had dimensions and handling characteristics similar to those of human carotid arteries. The CEA procedure and its subtasks, including vessel-tissue preparation and surgical skills performance, could be reproduced with high fidelity. CONCLUSION: A bovine placenta training model for CEA is inexpensive and readily available and closely resembles human carotid arteries. The model can provide a convenient and valuable simulation and practice addition for vascular surgery training. PMID- 26230046 TI - How to Design Tobacco Prevention and Control Games for Youth and Adolescents: A Qualitative Analysis of Expert Interviews. AB - OBJECTIVE: Games for health, including digital videogames and gaming-based approaches, are increasingly being used in health promotion research and practice. Recently published research has shown that videogames have significant potential to promote healthy behaviors among youth and adolescents. Yet, there is a lack of available evidence-based resources to guide practitioners on the integration of games into tobacco prevention and smoking cessation interventions. To address this gap, expert researchers and game developers were interviewed to further define games for health, explore the current research, and provide recommendations for developing, evaluating, and promoting effective anti-tobacco games. MATERIALS AND METHODS: Nationally recognized experts on game development, games for health, tobacco, and health behavior were asked to participate. A qualitative analysis of 25 in-depth individual interviews using a constant comparative approach for emerging themes was conducted. RESULTS: Main themes that emerged from the data analysis included the following: (1) the current state of games for health research to facilitate health behavior change, (2) strategies for how to develop and evaluate games for quality and impact, and (3) recommendations for how to effectively design tobacco prevention and smoking cessation educational videogames that engage youth and adolescents. CONCLUSIONS: The synthesized findings identified through these expert interviews offer stakeholders strategies for how to incorporate games for health within their current and future work. Specific recommendations are presented for developers and researchers to consider when developing and evaluating videogames for tobacco prevention and smoking cessation targeted at youth and adolescents. PMID- 26230045 TI - Microparticles Impair Hypotensive Cerebrovasodilation and Cause Hippocampal Neuronal Cell Injury after Traumatic Brain Injury. AB - Endothelin-1 (ET-1), tissue plasminogen activator (tPA), and extracellular signal regulated kinases-mitogen activated protein kinase (ERK-MAPK) are mediators of impaired cerebral hemodynamics after fluid percussion brain injury (FPI) in piglets. Microparticles (MPs) are released into the circulation from a variety of cells during stress, are pro-thrombotic and pro-inflammatory, and may be lysed with polyethylene glycol telomere B (PEG-TB). We hypothesized that MPs released after traumatic brain injury impair hypotensive cerebrovasodilation and that PEG TB protects the vascular response via MP lysis, and we investigated the relationship between MPs, tPA, ET-1, and ERK-MAPK in that process. FPI was induced in piglets equipped with a closed cranial window. Animals received PEG-TB or saline (vehicle) 30-minutes post-injury. Serum and cerebrospinal fluid (CSF) were sampled and pial arteries were measured pre- and post-injury. MPs were quantified by flow cytometry. CSF samples were analyzed with enzyme-linked immunosorbent assay. MP levels, vasodilatory responses, and CSF signaling assays were similar in all animals prior to injury and treatment. After injury, MP levels were elevated in the serum of vehicle but not in PEG-TB-treated animals. Pial artery dilation in response to hypotension was impaired after injury but protected in PEG-TB-treated animals. After injury, CSF levels of tPA, ET-1, and ERK-MAPK were all elevated, but not in PEG-TB-treated animals. PEG-TB-treated animals also showed reduction in neuronal injury in CA1 and CA3 hippocampus, compared with control animals. These results show that serum MP levels are elevated after FPI and lead to impaired hypotensive cerebrovasodilation via over expression of tPA, ET-1, and ERK-MAPK. Treatment with PEG-TB after injury reduces MP levels and protects hypotensive cerebrovasodilation and limits hippocampal neuronal cell injury. PMID- 26230047 TI - Snapshot prediction of carbon productivity, carbon and protein content in a Southern Ocean diatom using FTIR spectroscopy. AB - Diatoms, an important group of phytoplankton, bloom annually in the Southern Ocean, covering thousands of square kilometers and dominating the region's phytoplankton communities. In their role as the major food source to marine grazers, diatoms supply carbon, nutrients and energy to the Southern Ocean food web. Prevailing environmental conditions influence diatom phenotypic traits (for example, photophysiology, macromolecular composition and morphology), which in turn affect the transfer of energy, carbon and nutrients to grazers and higher trophic levels, as well as oceanic biogeochemical cycles. The paucity of phenotypic data on Southern Ocean phytoplankton limits our understanding of the ecosystem and how it may respond to future environmental change. Here we used a novel approach to create a 'snapshot' of cell phenotype. Using mass spectrometry, we measured nitrogen (a proxy for protein), total carbon and carbon-13 enrichment (carbon productivity), then used this data to build spectroscopy-based predictive models. The models were used to provide phenotypic data for samples from a third sample set. Importantly, this approach enabled the first ever rate determination of carbon productivity from a single time point, circumventing the need for time series measurements. This study showed that Chaetoceros simplex was less productive and had lower protein and carbon content during short-term periods of high salinity. Applying this new phenomics approach to natural phytoplankton samples could provide valuable insight into understanding phytoplankton productivity and function in the marine system. PMID- 26230048 TI - Diverse, rare microbial taxa responded to the Deepwater Horizon deep-sea hydrocarbon plume. AB - The Deepwater Horizon (DWH) oil well blowout generated an enormous plume of dispersed hydrocarbons that substantially altered the Gulf of Mexico's deep-sea microbial community. A significant enrichment of distinct microbial populations was observed, yet, little is known about the abundance and richness of specific microbial ecotypes involved in gas, oil and dispersant biodegradation in the wake of oil spills. Here, we document a previously unrecognized diversity of closely related taxa affiliating with Cycloclasticus, Colwellia and Oceanospirillaceae and describe their spatio-temporal distribution in the Gulf's deepwater, in close proximity to the discharge site and at increasing distance from it, before, during and after the discharge. A highly sensitive, computational method (oligotyping) applied to a data set generated from 454-tag pyrosequencing of bacterial 16S ribosomal RNA gene V4-V6 regions, enabled the detection of population dynamics at the sub-operational taxonomic unit level (0.2% sequence similarity). The biogeochemical signature of the deep-sea samples was assessed via total cell counts, concentrations of short-chain alkanes (C1-C5), nutrients, (colored) dissolved organic and inorganic carbon, as well as methane oxidation rates. Statistical analysis elucidated environmental factors that shaped ecologically relevant dynamics of oligotypes, which likely represent distinct ecotypes. Major hydrocarbon degraders, adapted to the slow-diffusive natural hydrocarbon seepage in the Gulf of Mexico, appeared unable to cope with the conditions encountered during the DWH spill or were outcompeted. In contrast, diverse, rare taxa increased rapidly in abundance, underscoring the importance of specialized sub-populations and potential ecotypes during massive deep-sea oil discharges and perhaps other large-scale perturbations. PMID- 26230050 TI - Anterior Loop of the Mandibular Canal-A Source of Possible Complications. AB - INTRODUCTION: Recognizing the radiographic position of the mental foramina is not sufficient to avoid complications during dental implant surgery. In many cases, the inferior alveolar nerve extends mesially as an "anterior loop" (AL). The aim of this study was to investigate the prevalence and spatial extension of the AL on computed tomography (CT). MATERIALS AND METHODS: Thirty-seven human mandibles from an anatomical collection underwent CT analysis. Cross-sectional views and panoramic reconstructions were obtained. Prevalence and length of the AL were investigated. RESULTS: Recognition of the AL on CT was 100%. Prevalence of the AL was 97.3% (n = 36). AL mean length was 2.26 mm (maximum: 7.0 mm). CONCLUSION: Recognition of the AL on CT scans (100%) is higher compared with data in literature for detection on panoramic radiographs (38.2%). To avoid complications, it is important to detect the AL presence and its mesial extension from the mental foramen. Safety distance of at least 2 mm from the mesial extend of the AL is recommended. Therefore, 3D imaging techniques are advised for loops which courses are not clearly identifiable on panoramic radiographs. PMID- 26230049 TI - The cyanobacterium Mastigocladus fulfills the nitrogen demand of a terrestrial hot spring microbial mat. AB - Cyanobacteria from Subsection V (Stigonematales) are important components of microbial mats in non-acidic terrestrial hot springs. Despite their diazotrophic nature (N2 fixers), their impact on the nitrogen cycle in such extreme ecosystems remains unknown. Here, we surveyed the identity and activity of diazotrophic cyanobacteria in the neutral hot spring of Porcelana (Northern Patagonia, Chile) during 2009 and 2011-2013. We used 16S rRNA and the nifH gene to analyze the distribution and diversity of diazotrophic cyanobacteria. Our results demonstrate the dominance of the heterocystous genus Mastigocladus (Stigonematales) along the entire temperature gradient of the hot spring (69-38 degrees C). In situ nitrogenase activity (acetylene reduction), nitrogen fixation rates (cellular uptake of (15)N2) and nifH transcription levels in the microbial mats showed that nitrogen fixation and nifH mRNA expression were light-dependent. Nitrogen fixation activities were detected at temperatures ranging from 58 degrees C to 46 degrees C, with maximum daily rates of 600 nmol C2H4 cm(-2) per day and 94.1 nmol N cm(-2) per day. These activity patterns strongly suggest a heterocystous cyanobacterial origin and reveal a correlation between nitrogenase activity and nifH gene expression during diurnal cycles in thermal microbial mats. N and C fixation in the mats contributed ~3 g N m(-2) per year and 27 g C m(-2) per year, suggesting that these vital demands are fully met by the diazotrophic and photoautotrophic capacities of the cyanobacteria in the Porcelana hot spring. PMID- 26230052 TI - Cell outer membrane mimetic chitosan nanoparticles: preparation, characterization and cytotoxicity. AB - A negatively charged copolymer poly (MPC-co-AMPS) of 2-methacryloyloxyethyl phosphorylcholine (MPC) and 2-acrylamide-2-methyl propane sulfonic acid (AMPS) was designed and synthesized. Chitosan nanoparticles with cell outer membrane mimetic structure were prepared by electrostatic interaction between the sulfonic acid groups of poly (MPC-co-AMPS) and the protonated amino groups of chitosan. Effects of factors on influencing the particle size, distribution, and stability were investigated. The experimental results showed that cell membrane mimetic chitosan nanoparticles with controllable and homogeneous size ranged from 100 to 300 nm were prepared at the concentration of 0.1-2.0 mg/mL and the charge ratio of 0.5-1.1. Chitosan nanoparticles prepared can exist stably for more than 45 days when placed at 4 degrees C and pH < 7.5. The cytotoxicity of the chitosan nanoparticles reduced significantly after surface modification with cell membrane mimetic structure, meeting the basic requirements of biomedical materials. The results suggest cell membrane mimetic chitosan nanoparticles prepared with polyanion and polycation obtain good biological compatibility and immune stealth ability, which has important academic significance and great application prospects. PMID- 26230053 TI - Simultaneous quantitation of acetylsalicylic acid and clopidogrel along with their metabolites in human plasma using liquid chromatography tandem mass spectrometry. AB - The interest in therapeutic drug monitoring has increased over the last few years. Inter- and intra-patient variability in pharmacokinetics, plasma concentration related toxicity and success of therapy have stressed the need of frequent therapeutic drug monitoring of the drugs. A sensitive, selective and rapid liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous quantification of acetylsalicylic acid (aspirin), salicylic acid, clopidogrel and carboxylic acid metabolite of clopidogrel in human plasma. The chromatographic separations were achieved on Waters Symmetry Shield(TM) C18 column (150 * 4.6 mm, 5 um) using 3.5 mm ammonium acetate (pH 3.5)-acetonitrile (10:90, v/v) as mobile phase at a flow rate of 0.75 mL/min. The present method was successfully applied for therapeutic drug monitoring of aspirin and clopidogrel in 67 patients with coronary artery disease. PMID- 26230054 TI - Rare Presentations of Epstein-Barr Virus--Associated Smooth Muscle Tumor in Children. AB - Epstein-Barr virus (EBV) has oncogenic potential and has been implicated in the etiology of a wide range of malignancies. Certain EBV-driven neoplasms, such as smooth muscle tumors (SMTs), manifest typically in immunocompromised patients. In children, these neoplasms have been encountered in the setting of primary immune disorders, specifically severe combined and common variable immunodeficiency syndromes. Human immunodeficiency virus infection and posttransplant immunosuppression, in particular liver and kidney transplantation, likewise increase the risk in the pediatric population. The location of these neoplasms appears related to the type of immunodeficiency: in acquired immunodeficiency syndrome they are frequently located intracranially or intraspinally, whereas after transplant they usually involve the liver or lung. We report 2 distinct cases of EBV-related SMT, unique through their coassociated immunosuppressive state or location: the 1st occurred in a patient with immunodeficiency secondary to NEMO gene mutation following hematopoietic stem cell transplantation; the 2nd developed in the orbit after heart transplant. PMID- 26230056 TI - Cardiovascular implantable electronic device infections: associated risk factors and prevention. AB - Infections of cardiovascular implantable electric devices (CIED) are a burden on patients and healthcare systems and should be prevented. The most frequent pathogens are coagulase-negative staphylococci and Staphylococcus aureus. The most important risk factors for CIED infections are diabetes mellitus, renal and heart failure, corticosteroid use, oral anticoagulation, fever within 24 hours before the procedure and leucocytosis, implantable cardioverter defibrillator compared with pacemaker, especially in the case of Staphylococcus aureus bacteraemia, lack of antibiotic prophylaxis, and postoperative haematoma and other wound complications. Other important risk factors are history of prior procedures and previous CIED infections, number of leads, use of povidone-iodine compared with chlorhexidine-alcohol, and centres and operators with a low volume of implants. To prevent CIED infections, patients undergoing CIED procedures and appropriate devices should be carefully selected, and interventions should be performed by trained operators. Antibiotic prophylaxis should be administered, and skin antisepsis should be done with chlorhexidine-alcohol. Oral anticoagulation should be continued during CIED procedures in high-risk patients for thromboembolism, instead of bridging with heparin. Early reintervention in cases of haematoma or lead dislodgement should be avoided. The implementation of infection prevention programmes reduces infection rates. More randomised controlled studies are needed to evaluate prevention strategies, especially skin preparation and antibiotic prophylaxis with glycopeptides. PMID- 26230055 TI - Cholesterol hydroperoxides as substrates for cholesterol-metabolizing cytochrome P450 enzymes and alternative sources of 25-hydroxycholesterol and other oxysterols. AB - The interaction of the primary autoxidation products of cholesterol, namely 25- and 20xi-hydroperoxides, with the four principal cholesterol-metabolizing cytochrome P450 enzymes is reported. Addition of cholesterol 25-hydroperoxide to the enzymes CYP27A1 and CYP11A1 induced well-defined spectral changes while generating 25-hydroxycholesterol as the major product. The 20xi-hydroperoxides induced spectral shifts in CYP27A1 and CYP11A1 but glycol metabolites were detected only with CYP11A1. CYP7A1 and CYP46A1 failed to give metabolites with any of the hydroperoxides. A P450 hydroperoxide-shunt reaction is proposed, where the hydroperoxides serve as both donor for reduced oxygen and substrate. CYP27A1 was shown to mediate the reduction of cholesterol 25-hydroperoxide to 25 hydroxycholesterol, a role of potential significance for cholesterol-rich tissues with high oxidative stress. CYP27A1 may participate in the removal of harmful autoxidation products in these tissues, while providing a complementary source of 25-hydroxycholesterol, a modulator of immune cell function and mediator of viral cell entry. PMID- 26230057 TI - The impact of executive function on response to cognitive behavioral therapy in late-life depression. AB - OBJECTIVE: Late-life depression (LLD) is a common and debilitating condition among older adults. Cognitive behavioral therapy (CBT) has strong empirical support for the treatment of depression in all ages, including in LLD. In teaching patients to identify, monitor, and challenge negative patterns in their thinking, CBT for LLD relies heavily on cognitive processes and, in particular, executive functioning, such as planning, sequencing, organizing, and selectively inhibiting information. It may be that the effectiveness of CBT lies in its ability to train these cognitive areas. METHODS: Participants with LLD completed a comprehensive neuropsychological battery before enrolling in CBT. The current study examined the relationship between neuropsychological function prior to treatment and response to CBT. RESULTS: When using three baseline measures of executive functioning that quantify set shifting, cognitive flexibility, and response inhibition to predict treatment response, only baseline Wisconsin Card Sort Task performance was associated with a significant drop in depression symptoms after CBT. Specifically, worse performance on the Wisconsin Card Sort Task was associated with better treatment response. CONCLUSIONS: These results suggest that CBT, which teaches cognitive techniques for improving psychiatric symptoms, may be especially beneficial in LLD if relative weaknesses in specific areas of executive functioning are present. PMID- 26230059 TI - [77-year-old female with hyponatremia, pruritus and papulous exanthema]. PMID- 26230062 TI - [30-year old man with ST-segment elevation after blunt thoracic trauma]. PMID- 26230063 TI - [Rheumatology: from symptom to diagnosis: early diagnosis - early medical intervention]. PMID- 26230064 TI - [Differential diagnosis of polyarthritis]. PMID- 26230065 TI - [Mono- or oligoarthritis and inflammatory backpain]. PMID- 26230066 TI - [Fever, skin changes, myalgia--from early symptom to diagnosis]. AB - New clinical symptoms in the context of rheumatic inflammatory system diseases require the exact knowledge of the anamnestic symptom-characteristic. Fever, skin changes and myalgia are frequent and unspecific symptoms that need a particularly broad-based interdisciplinary approach to identify potential causes. The attending physician can thereby avoid unnecessary, expensive and somewhat stressful tests. This article is intended to give important advice for everyday practice in step-wise diagnostics. PMID- 26230067 TI - [Inspection of the corpse]. AB - In Germany the postmortem examination has to be performed by a physician. It has to include the determination of at least one sign of death, a statement about the time and cause of death and the distinction between a "death by natural causes" in the sense of the law and its opposite. PMID- 26230068 TI - [Cranial nerve palsies: ganglioside autoantibodies indicating an immunoneuropathy]. AB - BACKGROUND: Cranial neuropathies are not infrequent and need a broad differential diagnostic approach. Etiologically autoimmune processes have to be considered. METHOD: In five patients with cranial neuropathy (in two cases lesion of the abducens nerve, in one case bilateral facial palsy, in one case abducens, facial and bilateral vestibular lesion, in one case bilateral glossopharyngeal lesion) IgG and IgM autoantibodies directed against most relevant gangliosides were quantitatively analyzed (Buhlmann Laboratories AG, Schonenbuch, Switzerland). All patients underwent lumbar puncture and cranial imaging. RESULTS: Trauma, tumor, elevated intracranial pressure and vascular lesion could be excluded. In one patient varicella infection as a cofactor was probable, in the remaining patients direct infection could be excluded. In one patient a prominent cyto-albumin dissociation of the CSF was found. In all patients autoantibodies directed against gangliosides were detected with positive antibodies against GD1a and GD1b in all patients. Prior to the cranial neuropathy one patient reported an infection of the upper airway and one reported an infection of the gastrointestinal tract. One patient was treated with steroids and one patient with intravenous immunoglobulin, the other patients were been carefully observed. All patients recovered well. CONCLUSION: Autoimmune processes with positive autoantibodies directed against gangliosides can be found in cranial neuropathy. Based on these observations an immunomodulating therapy should be considered. PMID- 26230069 TI - [Athlete's heart and hypertrophic cardiomyopathy: contribution on clinical and morphologic differentiation]. AB - Hypertrophic cardiomyopathy (HCM) is a complex genetic disorder usually diagnosed in a young adult population. The diagnosis is based on echocardiographic identification of left ventricular hypertrophy, associated with a non-dilated hyperdynamic chamber in the absence of another cardiac or systemic disorder. The differentiation between HCM and physiological left ventricular hypertrophy (athlete's heart) is essential: HCM is the main cause of exercise-induced sudden cardiac death in the young and especially in young athletes with overlapping features in Athlete's Heart or HCM. Differentiation between physiological left ventricular hypertrophy and HCM is challenging. Echocardiography allows detailed assessment of left ventricular structure and function which is fundamental. Additional genetic studies for identification of the broad HCM phenotype can be necessary to differentiate between Athlete's Heart and HCM. PMID- 26230070 TI - [Differential diagnosis "non-cardiac chest pain"]. AB - Non cardiac chest pain (NCCP) are recurrent angina pectoris like pain without evidence of coronary heart diesease in conventional diagnostic evaluation. The prevalence of NCCP is up to 70% and may be detected in this order at all levels of the medical health care system (general practitioner, emergency department, chest pain unit, coronary care). Reduction of quality of life in NCCP is comparable, partially even higher compared to cardiac chest pain. Reasons for psychological strain are symptom recurrence in app. 50%, nonspecific diagnosis with resulting uncertainty and insufficient integration of other medical disciplines in diagnostic work-up. Managing of patients with NCCP has to be interdisciplinary because non cardiac causes of chest pain may be found frequently. This are musculosceletal in app. 40%, gastrointestinal in app. 20%, psychiatric in app. 10% and pulmonary and mediastinal diseases in app. 5% of cases. Also gastroenterological expertise is required because here gastroesophageal reflux disease (GERD) in app. 60%, hypercontractile esophageal motility disorders with nutcracker, jackhammer esophagus or distal esophageal spasmus or achalasia in app. 20% and other esophageal alterations (e. g. infectious esophageal inflammation, drug-induced ulcer, rings, webs, eosinophilic esophagits) in app. 30% of cases may be detected as cause of chest pain may. This implicates that regular interdisciplinary round wards and interdisciplinary management of chest pain units are mandatory. PMID- 26230071 TI - [Working conditions of physicians in hospitals--A comparison of specialties in German hospitals (iCept-Study)]. AB - BACKGROUND: In the context of the iCept-Study several medical specialties have been examined for their stress related working conditions. This study contrasts the different medical specialties. METHODS: The iCept-Study was designed as a web based survey in which altogether 7.090 respondents took part. The published data concerning the iCept-Study was systematically analyzed focusing on distress and job satisfaction. RESULTS: 53,9% of respondents showed unfavorable working conditions with an ER/JDC-Ratio > 1 (distress). Especially surgical specialties showed a higher prevalence: The odds ratio of surgery to anesthesiology was at 1,59 (95%-CI: 1,35|1,86; p < 0,001). On the other hand specialties like occupational medicine showed a lower prevalence in comparison with the average: The odds ratio was here at 0,37 (95%CI: 0,19|0,71; p < 0,01). Furthermore 55,8% of respondents stated that they were very satisfied with their job. CONSEQUENCES: Surgical specialties encountered distress the most. Moreover there was a positive correlation between high job satisfaction and lack of distress evident. Therefore it seems that distress and job satisfaction are two dependent characteristics of a changing work environment. Especially surgical specialties need to catch up with today's demand of improved working conditions and thus reducing distress and increasing satisfaction. PMID- 26230072 TI - ["Do-not-rescuscitate"--Results of introducing a standardized order sheet on documentation quality]. AB - INTRODUCTION: DNR orders have been used internationally since the 1970 s. Despite the growing importance of patient preference in German law, there is little data on DNR orders in Germany Methods: The prevalence of DNR orders was assessed on the hospital wards. Healthcare were asked about their experiences and opinions in two polls. The charts of all deceased patients were reviewed for DNR notes for 9 month before and after introduction of the new DNR order sheets. RESULTS: The prevalence of DNR orders remained constant at 8% of patients. In 12,4% of these DNR status was not known by the nursing staff. After introduction of the order sheet, the percentage of orders with comprehensive documentation increased from 5.9 to 65.4% of orders (p < 0.001). In the polls the healthcare workers saw a significant improvement in information content of DNR orders after introduction of the new order sheets. The chart review documented an improved documentation of DNR status going up from 28.8 to 40.8% of deceased patients (p < 0.001). The fraction of comprehensive orders increased from 32% to 84.6% (p < 0.001). CONCLUSION: INTRODUCTION of DNR order sheets in a German hospital lead to objective improvements in the quality of end-of life care documentation while the prevalence of DNR orders remained unchanged. PMID- 26230073 TI - Design, testing and modelling of a novel robotic system for trans-oesophageal ultrasound. AB - BACKGROUND: Trans-oesophageal echocardiography (TOE) has been widely utilized for cardiac disease diagnosis and interventional procedure guidance. However, the TOE operator is required to manually manipulate the probe, often for long periods of time and sometimes in an X-ray environment where there is exposure to ionizing radiation. METHODS: A novel robotic manipulation system for remote control of commercial TOE probes has been developed and tested. The system has four degrees of freedom (DOFs) and is characterized by a kinematic model. The accuracy of the model and the error propagation were analysed. RESULTS: The prototype system was shown to exhibit the required function in terms of the mechanical reliability and range of motion. The forward kinematic model can accurately predict the trajectory of the probe tip movement. The average point-to-point errors were 2.60 mm and 3.55 degrees . CONCLUSIONS: Robotic assistance provided by the proposed system may improve the TOE operating environment. The proposed forward kinematic model can be further employed for automatic control. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26230075 TI - Impact of Roasting on Identification of Hazelnut (Corylus avellana L.) Origin: A Chemometric Approach. AB - Hazelnuts belonging to different cultivars or cultivated in different geographic areas can be differentiated by their chemical profile; however, the roasting process may affect the composition of raw hazelnuts, thus compromising the possibility to identify their origin in processed foods. In this work, we characterized raw and roasted hazelnuts (Tonda Gentile Trilobata, TGT, from Italy and from Chile, Tonda di Giffoni from Italy, and Tombul from Turkey), as well as hazelnuts isolated from commercial products, with the aim to discriminate their cultivar and origin. The chemometric evaluation of selected chemical parameters (proximate composition, fatty acids, total polyphenols, antioxidant activity, and protein fingerprint by SDS-PAGE) permitted us to identify hazelnuts belonging to different cultivars and, concerning TGT samples, their different geographic origin. Also commercial samples containing Piedmontese TGT hazelnuts were correctly assigned to TGT cluster. In conclusion, even if the roasting process modifies the composition of roasted hazelnuts, this preliminary model study suggests that the identification of their origin is still possible. PMID- 26230074 TI - Phenotypic assays to identify agents that induce reactive gliosis: a counter screen to prioritize compounds for preclinical animal studies. AB - Astrocyte phenotypes change in a process called reactive gliosis after traumatic central nervous system (CNS) injury. Astrogliosis is characterized by expansion of the glial fibrillary acidic protein (GFAP) cytoskeleton, adoption of stellate morphologies, and differential expression of some extracellular matrix molecules. The astrocytic response immediately after injury is beneficial, but in the chronic injury phase, reactive astrocytes produce inhibitory factors (i.e., chondroitin sulfate proteoglycans [CSPGs]) that limit the regrowth of injured axons. There are no drugs that promote axon regeneration or functional recovery after CNS trauma in humans. To develop novel therapeutics for the injured CNS, we screened various libraries in a phenotypic assay to identify compounds that promote neurite outgrowth. However, the effects these compounds have on astrocytes are unknown. Specifically, we were interested in whether compounds could alter astrocytes in a manner that mimics the glial reaction to injury. To test this hypothesis, we developed cell-based phenotypic bioassays to measure changes in (1) GFAP morphology/localization and (2) CSPG expression/immunoreactivity from primary astrocyte cultures. These assays were optimized for six-point dose-response experiments in 96-well plates. The GFAP morphology assay is suitable for counter-screening with a Z-factor of 0.44+/-0.03 (mean+/-standard error of the mean; N=3 biological replicates). The CSPG assay is reproducible and informative, but does not satisfy common metrics for a "screenable" assay. As proof of principle, we tested a small set of hit compounds from our neurite outgrowth bioassay and identified one that can enhance axon growth without exacerbating the deleterious characteristics of reactive gliosis. PMID- 26230076 TI - Photoinduced One-Electron Oxidation of Benzyl Methyl Sulfides in Acetonitrile: Time-Resolved Spectroscopic Evidence for a Thionium Ion Intermediate. AB - The photo-oxidation of 4-methoxybenzyl methyl sulfide (1a), benzyl methyl sulfide (1b), and 4-cyanobenzyl methyl sulfide (1c) has been investigated in the presence of N-methoxy phenanthridinium hexafluorophosphate (MeOP(+)PF6(-)) under nitrogen in CH3CN. The steady-state photolysis experiments showed for the investigated sulfides exclusively the formation of the corresponding benzaldehyde as the oxidation product, reasonably due to a deprotonation of the sulfide radical cations. Photo-oxidation of 1a-1c occurs through an electron transfer process. Indeed, laser flash photolysis measurements showed an efficient formation of sulfide radical cations, detected in their dimeric form [(4-X-C6H4CH2SCH3)2(+*)] at ~520 nm. At longer delay times, the absorption of the dimer radical cation was replaced by an absorption band assigned to the (alpha-thio)benzyl cation (thionium ion, lambdamax = 420-400 nm), formed by oxidation of the benzyl radical and not by that of the (alpha-thiomethyl)benzyl radical, as expected if a Calpha H bond cleavage is operative. This finding highlights a particular stability of this kind of cation never reported before, even though its involvement in one electron oxidation mechanisms of various sulfides has already been invoked. Density functional theory calculations allowed identification of a significant charge and spin delocalization involving both the phenyl ring and the sulfur atom of the radical cations. PMID- 26230077 TI - Links between the Crystal and Electronic Structure in the New Family of Unconventional Superconductors A2Cr3As3 (A = K, Rb, Cs). AB - The electronic structure of a new family of superconductors is examined through density functional theory calculations. In contrast with other quasi-1D superconductors, these phases exhibit a relatively complex electronic structure and the Fermi surface contains both 1D and 3D components. It is shown that cations have an almost nil influence on the electronic structure. The absence of a structural Peierls modulation is discussed, and the differences with the structurally related M2Mo6Se6 (M = Tl, In, ...) superconductors are stressed. The large electron mass renormalization and the lack of clear correlation between N(EF) and Tc suggest the existence of strong electron correlations and an unconventional origin of the superconductivity. PMID- 26230078 TI - Development of a High-Throughput and Miniaturized Cytokinesis-Block Micronucleus Assay for Use as a Biological Dosimetry Population Triage Tool. AB - Biodosimetry is an essential tool for providing timely assessments of radiation exposure. For a large mass-casualty event involving exposure to ionizing radiation, it is of utmost importance to rapidly provide dose information for medical treatment. The well-established cytokinesis-block micronucleus (CBMN) assay is a validated method for biodosimetry. However, the need for an accelerated sample processing is required for the CBMN assay to be a suitable population triage tool. We report here on the development of a high-throughput and miniaturized version of the CMBN assay for accelerated sample processing. PMID- 26230080 TI - Introgression between invasive and native blue mussels (genus Mytilus) in the central California hybrid zone. AB - The ecological and genetic factors determining the extent of introgression between species in secondary contact zones remain poorly understood. Here, we investigate the relative importance of isolating barriers and the demographic expansion of invasive Mytilus galloprovincialis on the magnitude and the direction of introgression with the native Mytilus trossulus in a hybrid zone in central California. We use double-digest restriction-site-associated DNA sequencing (ddRADseq) to genotype 1337 randomly selected single nucleotide polymorphisms and accurately distinguish early and advanced generation hybrids for the first time in the central California Mytilus spp. hybrid zone. Weak levels of introgression were observed in both directions but were slightly more prevalent from the native M. trossulus into the invasive M. galloprovincialis. Few early and advanced backcrossed individuals were observed across the hybrid zone confirming the presence of strong barriers to interbreeding. Heterogeneous patterns of admixture across the zone of contact were consistent with the colonization history of M. galloprovincialis with more extensive introgression in northern localities furthest away from the putative site of introduction in southern California. These observations reinforce the importance of dynamic spatial and demographic expansions in determining patterns of introgression between close congeners, even in those with high dispersal potential and well developed reproductive barriers. Our results suggest that the threat posed by invasive M. galloprovincialis is more ecological than genetic as it has displaced, and continues to displace the native M. trossulus from much of central and southern California. PMID- 26230079 TI - Global Metabolomic Identification of Long-Term Dose-Dependent Urinary Biomarkers in Nonhuman Primates Exposed to Ionizing Radiation. AB - Due to concerns surrounding potential large-scale radiological events, there is a need to determine robust radiation signatures for the rapid identification of exposed individuals, which can then be used to guide the development of compact field deployable instruments to assess individual dose. Metabolomics provides a technology to process easily accessible biofluids and determine rigorous quantitative radiation biomarkers with mass spectrometry (MS) platforms. While multiple studies have utilized murine models to determine radiation biomarkers, limited studies have profiled nonhuman primate (NHP) metabolic radiation signatures. In addition, these studies have concentrated on short-term biomarkers (i.e., <72 h). The current study addresses the need for biomarkers beyond 72 h using a NHP model. Urine samples were collected at 7 days postirradiation (2, 4, 6, 7 and 10 Gy) and processed with ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight (QTOF) MS, acquiring global metabolomic radiation signatures. Multivariate data analysis revealed clear separation between control and irradiated groups. Thirteen biomarkers exhibiting a dose response were validated with tandem MS. There was significantly higher excretion of l carnitine, l-acetylcarnitine, xanthine and xanthosine in males versus females. Metabolites validated in this study suggest perturbation of several pathways including fatty acid beta oxidation, tryptophan metabolism, purine catabolism, taurine metabolism and steroid hormone biosynthesis. In this novel study we detected long-term biomarkers in a NHP model after exposure to radiation and demonstrate differences between sexes using UPLC-QTOF-MS-based metabolomics technology. PMID- 26230081 TI - F11R mRNA expression and promoter polymorphisms in patients with rheumatoid arthritis. AB - AIM: Although F11 receptor (F11R), also named junctional adhesion molecular A (JAM-A), participates in leukocyte migration, its role in autoimmune diseases has not been specifically disclosed. In this study, we examined the association of F11R expression with the development and clinical manifestations of rheumatoid arthritis (RA). METHOD: RNA from peripheral blood mononuclear cells (PBMCs) and DNA from the peripheral blood in RA patients and a healthy control group were extracted. F11R messenger RNA (mRNA) expression was determined by quantitative real-time polymerase chain reaction. The F11R polymorphisms were determined by the TaqMan genotyping assay. RESULTS: There was more F11R mRNA expression in the PBMCs of RA patients than those of the control group (P = 0.018). In F11R promoter -688 A > C, C carriers have lower titers of the anticyclic citrullinated peptide (anti-CCP) antibodies (P = 0.002) and fewer positive rates of Schirmer's tests (P = 0.009). The effect is independent of the existence of HLA-DR4. Different genotypes in F11R promoter -688 A > C and -436 A > G do not lead to changes of the gene expression in RA patients. CONCLUSION: RA patients have higher mRNA expression of F11R. In RA patients, F11R -688 C may be a protective factor for the development of anti-CCP antibodies and positive rates of Schirmer's tests. PMID- 26230082 TI - Decreasing Proportion of Recent Infections among Newly Diagnosed HIV-1 Cases in Switzerland, 2008 to 2013 Based on Line-Immunoassay-Based Algorithms. AB - BACKGROUND: HIV surveillance requires monitoring of new HIV diagnoses and differentiation of incident and older infections. In 2008, Switzerland implemented a system for monitoring incident HIV infections based on the results of a line immunoassay (Inno-Lia) mandatorily conducted for HIV confirmation and type differentiation (HIV-1, HIV-2) of all newly diagnosed patients. Based on this system, we assessed the proportion of incident HIV infection among newly diagnosed cases in Switzerland during 2008-2013. METHODS AND RESULTS: Inno-Lia antibody reaction patterns recorded in anonymous HIV notifications to the federal health authority were classified by 10 published algorithms into incident (up to 12 months) or older infections. Utilizing these data, annual incident infection estimates were obtained in two ways, (i) based on the diagnostic performance of the algorithms and utilizing the relationship 'incident = true incident + false incident', (ii) based on the window-periods of the algorithms and utilizing the relationship 'Prevalence = Incidence x Duration'. From 2008-2013, 3'851 HIV notifications were received. Adult HIV-1 infections amounted to 3'809 cases, and 3'636 of them (95.5%) contained Inno-Lia data. Incident infection totals calculated were similar for the performance- and window-based methods, amounting on average to 1'755 (95% confidence interval, 1588-1923) and 1'790 cases (95% CI, 1679-1900), respectively. More than half of these were among men who had sex with men. Both methods showed a continuous decline of annual incident infections 2008 2013, totaling -59.5% and -50.2%, respectively. The decline of incident infections continued even in 2012, when a 15% increase in HIV notifications had been observed. This increase was entirely due to older infections. Overall declines 2008-2013 were of similar extent among the major transmission groups. CONCLUSIONS: Inno-Lia based incident HIV-1 infection surveillance proved useful and reliable. It represents a free, additional public health benefit of the use of this relatively costly test for HIV confirmation and type differentiation. PMID- 26230083 TI - Cardiac Dysregulation and Myocardial Injury in a 6-Hydroxydopamine-Induced Rat Model of Sympathetic Denervation. AB - BACKGROUND: Cardiac sympathetic denervation is found in various cardiac pathologies; however, its relationship with myocardial injury has not been thoroughly investigated. METHODS: Twenty-four rats were assigned to the normal control group (NC), sympathectomy control group (SC), and a sympathectomy plus mecobalamin group (SM). Sympathectomy was induced by injection of 6-OHDA, after which, the destruction and distribution of sympathetic and vagal nerve in the left ventricle (LV) myocardial tissue were determined by immunofluorescence and ELISA. Heart rate variability (HRV), ECG and echocardiography, and assays for myocardial enzymes in serum before and after sympathectomy were examined. Morphologic changes in the LV by HE staining and transmission electron microscope were used to estimate levels of myocardial injury and concentrations of inflammatory cytokines were used to reflect the inflammatory reaction. RESULTS: Injection of 6-OHDA decreased NE (933.1 +/- 179 ng/L for SC vs. 3418.1+/- 443.6 ng/L for NC, P < 0.01) and increased NGF (479.4+/- 56.5 ng/mL for SC vs. 315.85 +/- 28.6 ng/mL for NC, P < 0.01) concentrations. TH expression was reduced, while ChAT expression showed no change. Sympathectomy caused decreased HRV and abnormal ECG and echocardiography results, and histopathologic examinations showed myocardial injury and increased collagen deposition as well as inflammatory cell infiltration in the cardiac tissue of rats in the SC and SM groups. However, all pathologic changes in the SM group were less severe compared to those in the SC group. CONCLUSIONS: Chemical sympathectomy with administration of 6-OHDA caused dysregulation of the cardiac autonomic nervous system and myocardial injuries. Mecobalamin alleviated inflammatory and myocardial damage by protecting myocardial sympathetic nerves. PMID- 26230084 TI - Corp Regulates P53 in Drosophila melanogaster via a Negative Feedback Loop. AB - The tumor suppressor P53 is a critical mediator of the apoptotic response to DNA double-strand breaks through the transcriptional activation of pro-apoptotic genes. This mechanism is evolutionarily conserved from mammals to lower invertebrates, including Drosophila melanogaster. P53 also transcriptionally induces its primary negative regulator, Mdm2, which has not been found in Drosophila. In this study we identified the Drosophila gene companion of reaper (corp) as a gene whose overexpression promotes survival of cells with DNA damage in the soma but reduces their survival in the germline. These disparate effects are shared by p53 mutants, suggesting that Corp may be a negative regulator of P53. Confirming this supposition, we found that corp negatively regulates P53 protein level. It has been previously shown that P53 transcriptionally activates corp; thus, Corp produces a negative feedback loop on P53. We further found that Drosophila Corp shares a protein motif with vertebrate Mdm2 in a region that mediates the Mdm2:P53 physical interaction. In Corp, this motif mediates physical interaction with Drosophila P53. Our findings implicate Corp as a functional analog of vertebrate Mdm2 in flies. PMID- 26230085 TI - Acceptance of Home-Based Chlamydia Genital and Anorectal Testing Using Short Message Service (SMS) in Previously Tested Young People and Their Social and Sexual Networks. AB - BACKGROUND: Control strategies for Chlamydia trachomatis (CT) are most effective when targeting people at highest risk. We assessed test acceptance of home collection test kits offered by short messaging services (SMS) texts, in high risk young people, i.e. those who had previously tested CT positive (positive indices), or negative reporting more than 3 sex partners (negative indices), and their sexual and social networks. METHODS: Young (16 to 25 years old) heterosexuals who previously tested positive (n=536) or negative (n=536) in our STI clinic received, 3 to 20 months after their initial screening, an SMS inviting them to re-test. They were offered a free home-collection test kit including a genital (men and women) and anorectal (women only) test, and a test kit to pass on to a friend or sex partner (peer). SMS reminders were sent in case of non-response. We assessed proportions of tests requested and returned, peers tested, and positivity. Associations with the individual's initial screening result and other factors were explored using logistic regression. RESULTS: Of 1072 people invited to retest, 34.4% (n=369) requested a test. Of these, 55.8% (n=206) retested. Overall, retest participation was higher in positive (22%) than in negative indices (16%) (p<0.001); it was also higher in women and in those aged >22 years. Positivity was 13% and 7% in positive and negative indices, respectively. One in 3 retesters also had a peer tested. Of tested peers (n=87), 84% were friends, 31% were first-time testers, and 7% tested positive. CONCLUSION: Acceptance of a relatively low-cost strategy for genital and anorectal testing, i.e. using SMS and home-collection test kits, was highest in individuals who previously tested CT positive suggesting that implementation for this group may be considered. By further including a peer-led testing component, undetected CT positives can be identified in the social networks surrounding a high-risk individual. PMID- 26230086 TI - Understanding Fear of Opportunism in Global Prize-Based Science Contests: Evidence for Gender and Age Differences. AB - Global prize-based science contests have great potential for tapping into diverse knowledge on a global scale and overcoming important scientific challenges. A necessary step for knowledge to be utilized in these contests is for that knowledge to be disclosed. Knowledge disclosure, however, is paradoxical in nature: in order for the value of knowledge to be assessed, inventors must disclose their knowledge, but then the person who receives that knowledge does so at no cost and may use it opportunistically. This risk of potential opportunistic behavior in turn makes the inventor fearful of disclosing knowledge, and this is a major psychological barrier to knowledge disclosure. In this project, we investigated this fear of opportunism in global prize-based science contests by surveying 630 contest participants in the InnoCentive online platform for science contests. We found that participants in these science contests experience fear of opportunism to varying degrees, and that women and older participants have significantly less fear of disclosing their scientific knowledge. Our findings highlight the importance of taking differences in such fears into account when designing global prize-based contests so that the potential of the contests for reaching solutions to important and challenging problems can be used more effectively. PMID- 26230087 TI - In Vivo Measurement of Mesokinesis in Gekko gecko: The Role of Cranial Kinesis during Gape Display, Feeding and Biting. AB - Cranial kinesis refers to movements of skeletal sub-units relative to one another at mobile sutures within the skull. The presence and functional significance of cranial kinesis has been investigated in various vertebrates, with much of our understanding coming from comparative studies and manipulation of ligamentous specimens. Drawing on these studies, cranial kinesis in lizards has been modeled as a four-bar linkage system involving streptostyly (rotation of the quadrate), hypokinesis (dorsoventral flexion and extension of the palato-maxillary sub unit), mesokinesis (dorsoventral flexion and extension of the snout at the fronto parietal suture) and metakinesis (sliding movements between parietal and supraocciptal bones). In vivo studies, although limited, suggest that cranial kinesis serves an important role during routine behaviors such as feeding. Here, we use X-ray Reconstruction Of Moving Morphology to further quantify mesokinesis in vivo in Gekko gecko during three routine behaviors: gape display, biting and post-ingestion feeding. During gape display, the snout rotates dorsally above rest position, with mesokinesis accounting for a 10% increase in maximum gape over that achieved solely by the depression of the lower jaw. During defensive biting, the snout rotates ventrally below rest position to participate in gape closure. Finally, ventroflexion of the snout also occurs during post-ingestion feeding, accounting for 42% of gape closure during intra-oral transport, 86% during puncture-crushing, and 61% during pharyngeal packing. Mesokinesis thus appears to facilitate prey puncturing by allowing the snout to rotate ventrally so that the upper teeth pierce the prey item, thus limiting the need for large movements of the lower jaw. This is suggested to maintain a firm grip on the prey and reduce the possibility of prey escape. More generally, this study demonstrates that mesokinesis is a key component of defensive biting and gape display behaviors, as well as post-ingestion feeding, all of which are linked to organismal fitness. PMID- 26230088 TI - Pseudomonas aeruginosa DesB Promotes Staphylococcus aureus Growth Inhibition in Coculture by Controlling the Synthesis of HAQs. AB - Pseudomonas aeruginosa is a pathogen that can cause serious infections and usually coexists with other pathogens, such as Staphylococcus aureus. Virulence factors are important for maintaining a presence of the organisms in these multispecies environments, and DesB plays an important role in P. aeruginosa virulence. Therefore, we investigated the effect of DesB on S. aureus reduction under competitive situation. Liquid cultures of P. aeruginosa wild type (WT) and its desB mutant were spotted on agar plates containing S. aureus, and the size of the clear zones was compared. In addition, interbacterial competition between P. aeruginosa and S. aureus was observed over time during planktonic coculture. The transcriptional profiles of the WT and desB mutant were compared by qRT-PCR and microarray to determine the role of DesB in S. aureus reduction at the molecular level. As a result, the clear zone was smaller for the desB mutant than for P. aeruginosa PAO1 (WT), and in planktonic coculture, the number of S. aureus cells was reduced in the desB mutant. qRT-PCR and microarray revealed that the expression of MvfR-controlled pqsA-E and phnAB operons was significantly decreased, but the mexEF-oprN operon was highly expressed. The results indicate that intracellular levels of 4-hydroxy-2-heptylquinoline (HHQ), a ligand of MvfR, are reduced due to MexEF-OprN-mediated efflux in desB mutant, resulting in the decrease of MvfR binding to pqsA-E promoter and the reduction of 4-hydroxy-2 alkylquinolines (HAQs) synthesis. Overexpression of mexEF-oprN operon in desB mutant was phenotypically confirmed by observing significantly increased resistance to chloramphenicol. In conclusion, these results suggest that DesB plays a role in the inhibition of S. aureus growth by controlling HAQ synthesis. PMID- 26230089 TI - Working position influences the biomechanical demands on the lower back during dental hygiene. AB - This investigation monitored the biomechanical demands on the lower back during simulated dental hygiene work. A total of 19 female, registered dental hygienists performed 30 continuous minutes of manual scaling (plaque removal) of a manikin's teeth while seated. We monitored the working location and orientation of the dental hygienists, with respect to the manikin, along with their spine kinematics, spine extensor muscle activities and seat pressure, throughout the 30 min. A clock representation was used to express the working location. The location significantly influenced the dental hygienists' pelvic orientation with respect to the manikin, spine posture, erector muscle activity and pressure distribution. Findings from this study suggest that the prevalence of lower back pain amongst dental hygienists may be directly related to low-level tonic activity of the spine's extensor musculature, and the combined flexed and axially rotated spine postures. Practitioner Summary: Low back pain (LBP) is prevalent in dental hygienists, yet occupational demand on the low back has not been investigated. Posture, muscle activity and seat pressure were monitored. Combined spine rotation and flexion, and tonic activity of the extensor musculature may be related to LBP in dental hygienists. PMID- 26230090 TI - Withaferin A Induces Cell Death Selectively in Androgen-Independent Prostate Cancer Cells but Not in Normal Fibroblast Cells. AB - Withaferin A (WA), a major bioactive component of the Indian herb Withania somnifera, induces cell death (apoptosis/necrosis) in multiple types of tumor cells, but the molecular mechanism underlying this cytotoxicity remains elusive. We report here that 2 MUM WA induced cell death selectively in androgen insensitive PC-3 and DU-145 prostate adenocarcinoma cells, whereas its toxicity was less severe in androgen-sensitive LNCaP prostate adenocarcinoma cells and normal human fibroblasts (TIG-1 and KD). WA also killed PC-3 cells in spheroid forming medium. DNA microarray analysis revealed that WA significantly increased mRNA levels of c-Fos and 11 heat-shock proteins (HSPs) in PC-3 and DU-145, but not in LNCaP and TIG-1. Western analysis revealed increased expression of c-Fos and reduced expression of the anti-apoptotic protein c-FLIP(L). Expression of HSPs such as HSPA6 and Hsp70 was conspicuously elevated; however, because siRNA mediated depletion of HSF-1, an HSP-inducing transcription factor, reduced PC-3 cell viability, it is likely that these heat-shock genes were involved in protecting against cell death. Moreover, WA induced generation of reactive oxygen species (ROS) in PC-3 and DU-145, but not in normal fibroblasts. Immunocytochemistry and immuno-electron microscopy revealed that WA disrupted the vimentin cytoskeleton, possibly inducing the ROS generation, c-Fos expression and c-FLIP(L) suppression. These observations suggest that multiple events followed by disruption of the vimentin cytoskeleton play pivotal roles in WA-mediated cell death. PMID- 26230092 TI - Experimental Barley Flour Production in 12,500-Year-Old Rock-Cut Mortars in Southwestern Asia. AB - Experimental archaeology at a Natufian site in the Southern Levant documents for the first time the use of 12,500-year-old rock-cut mortars for producing wild barley flour, some 2,000 to 3,000 years before cereal cultivation. Our reconstruction involved processing wild barley on the prehistoric threshing floor, followed by use of the conical mortars (a common feature in Natufian sites), thereby demonstrating the efficient peeling and milling of hulled grains. This discovery complements nearly 80 years of investigations suggesting that the Natufians regularly harvested almost-ripe wild cereals using sickles hafted with flint blades. Sickles had been replicated in the past and tested in the field for harvesting cereals, thusly obtaining the characteristic sheen along the edge of the hafted flint blades as found in Natufian remnants. Here we report that Natufian wide and narrow conical mortars enabled the processing of wild barley for making the groats and fine flour that provided considerable quantities of nourishment. Dishes in the Early Natufian (15,000-13,500 CalBP) were groat meals and porridge and subsequently, in the Late Natufian (13,500-11,700 CalBP), we suggest that unleavened bread made from fine flour was added. These food preparing techniques widened the dietary breadth of the sedentary Natufian hunter gatherers, paving the way to the emergence of farming communities, the hallmark of the Neolithic Revolution. PMID- 26230091 TI - IL-25 and IL-33 Contribute to Development of Eosinophilic Airway Inflammation in Epicutaneously Antigen-Sensitized Mice. AB - BACKGROUND: IL-25, IL-33 and TSLP are produced predominantly by epithelial cells and are known to induce Th2-type cytokines. Th2-type cytokines are involved not only in host defense against nematodes, but also in the development of Th2-type allergic diseases. TSLP was reported to be crucial for development of allergic airway inflammation in mice after inhalation of allergens to which they had been sensitized epicutaneously (EC) beforehand. However, the roles of IL-25 and IL-33 in the setting remain unclear. METHODS: Mice deficient in IL-25 and IL-33 were sensitized EC with ovalbumin (OVA) and then challenged intranasally with OVA. Airway inflammation, the number of inflammatory cells in bronchoalveolar lavage fluids (BALFs) and airway hyperresponsiveness (AHR) in the mice were determined, respectively, by histological analysis, with a hemocytometer, and by using plethysmograph chambers with a ventilator. Expression of mRNA in the skin and lungs was determined by quantitative PCR, while the BALF levels of myeloperoxidase (MPO) and eosinophil peroxidase (EPO) and the serum levels of IgE were determined by ELISA. RESULTS: Normal OVA-specific Th2- and Th17-cell responses of lymph nodes and spleens were observed in IL-25-deficient (IL-25-/-) and IL-33-/- mice after EC sensitization with OVA. Nevertheless, the number of eosinophils, but not neutrophils, in the BALFs, and the levels of Th2 cytokines, but not Th17 cytokines, in the lungs were significantly decreased in the IL-25-/- and IL-33-/- mice pre-sensitized EC with OVA, followed by inhalation of OVA, whereas their levels of AHR and OVA-specific serum IgE were normal. CONCLUSIONS: Both IL-25 and IL-33 are critical for induction of Th2-type cytokine-mediated allergic airway eosinophilia, but not Th17-type cytokine-mediated airway neutrophilia, at the local sites of lungs in the challenge phase of mice sensitized EC with OVA. They do not affect OVA-specific T-cell induction in the sensitization phase. PMID- 26230093 TI - Genetic Evaluation of Dual-Purpose Buffaloes (Bubalus bubalis) in Colombia Using Principal Component Analysis. AB - Genealogy and productive information of 48621 dual-purpose buffaloes born in Colombia between years 1996 and 2014 was used. The following traits were assessed using one-trait models: milk yield at 270 days (MY270), age at first calving (AFC), weaning weight (WW), and weights at the following ages: first year (W12), 18 months (W18), and 2 years (W24). Direct additive genetic and residual random effects were included in all the traits. Maternal permanent environmental and maternal additive genetic effects were included for WW and W12. The fixed effects were: contemporary group (for all traits), sex (for WW, W12, W18, and W24), parity (for WW, W12, and MY270). Age was included as covariate for WW, W12, W18 and W24. Principal component analysis (PCA) was conducted using the genetic values of 133 breeding males whose breeding-value reliability was higher than 50% for all the traits in order to define the number of principal components (PC) which would explain most of the variation. The highest heritabilities were for W18 and MY270, and the lowest for AFC; with 0.53, 0.23, and 0.17, respectively. The first three PCs represented 66% of the total variance. Correlation of the first PC with meat production traits was higher than 0.73, and it was -0.38 with AFC. Correlations of the second PC with maternal genetic component traits for WW and W12 were above 0.75. The third PC had 0.84 correlation with MY270. PCA is an alternative approach for analyzing traits in dual-purpose buffaloes and reduces the dimension of the traits. PMID- 26230094 TI - A Mechanistic Assessment of the Discordance between Normal Serum Alanine Aminotransferase Levels and Altered Liver Histology in Chronic Hepatitis B. AB - To understand the mechanisms underlying the discordance between normal serum alanine aminotransferase (ALT) levels and significant alterations in liver histology of chronic hepatitis B virus (HBV) infection with persistent normal ALT (PNALT) or minimally elevated ALT. A total of 300 treatment-naive chronic HBV infected patients with PNALT (ALT <= upper limit of normal [ULN, 40 U/ml]) or minimally elevated ALT (1-2*ULN) were retrospectively enrolled. All patients underwent liver biopsy and histological changes were analyzed along with biochemical and HBV markers. Among 300 participants, 177 were HBeAg-positive and 123 HBeAg-negative. Significant histologic abnormalities were found in 42.9% (76/177) and 52.8% (65/123) of HBeAg-positive and HBeAg-negative patients, respectively. Significant fibrosis, which is a marker of prior injury, was more frequently detected than significant necroinflammation (suggesting active liver injury) in both HBeAg-positive and -negative groups, suggesting that liver injury occurred intermittently in our cohort. No significant differences were noticed in the percentage of patients with severe fibrosis between HBeAg-positive and negative phases or between ages 30 and 40 and over 40, suggesting that the fibrosis was possibly carried over from an early phase. Finally, lowering ALT ULN (30 U/L for men, 19 U/L for women) alone was not adequate to increase the sensitivity of ALT detection of liver injury. However, the study was limited to a small sample size of 13 HBeAg-positive patients with ALT in the revised normal range. We detected significant liver pathology in almost 50% of chronic HBV infected patients with PNALT (ALT <= 40 U/ml) or minimally elevated ALT. We postulated that small-scale intermittent liver injury was possibly responsible for the discordance between normal serum ALT and significant liver changes in our cohort. PMID- 26230095 TI - Circulating miRNAs: Potential Novel Biomarkers for Hepatopathology Progression and Diagnosis of Schistosomiasis Japonica in Two Murine Models. AB - BACKGROUND: Schistosomiasis remains a major public health issue, with an estimated 230 million people infected worldwide. Novel tools for early diagnosis and surveillance of schistosomiasis are currently needed. Elevated levels of circulating microRNAs (miRNAs) are commonly associated with the initiation and progression of human disease pathology. Hence, serum miRNAs are emerging as promising biomarkers for the diagnosis of a variety of human diseases. This study investigated circulating host miRNAs commonly associated with liver diseases and schistosome parasite-derived miRNAs during the progression of hepatic schistosomiasis japonica in two murine models. METHODOLOGY/PRINCIPAL FINDINGS: Two mouse strains (C57BL/6 and BALB/c) were infected with a low dosage of Schistosoma japonicum cercariae. The dynamic patterns of hepatopathology, the serum levels of liver injury-related enzymes and the serum circulating miRNAs (both host and parasite-derived) levels were then assessed in the progression of schistosomiasis japonica. For the first time, an inverse correlation between the severity of hepatocyte necrosis and the level of liver fibrosis was revealed during S. japonicum infection in BALB/c, but not in C57BL/6 mice. The inconsistent levels of the host circulating miRNAs, miR-122, miR-21 and miR-34a in serum were confirmed in the two murine models during infection, which limits their potential value as individual diagnostic biomarkers for schistosomiasis. However, their serum levels in combination may serve as a novel biomarker to mirror the hepatic immune responses induced in the mammalian host during schistosome infection and the degree of hepatopathology. Further, two circulating parasite-specific miRNAs, sja-miR-277 and sja-miR-3479-3p, were shown to have potential as diagnostic markers for schistosomiasis japonica. CONCLUSIONS/SIGNIFICANCE: We provide the first evidence for the potential of utilizing circulating host miRNAs to indicate different immune responses and the severity of hepatopathology outcomes induced in two murine strains infected with S. japonicum. This study also establishes a basis for the early and cell-free diagnosis of schistosomiasis by targeting circulating schistosome parasite derived miRNAs. PMID- 26230096 TI - A Single RNaseIII Domain Protein from Entamoeba histolytica Has dsRNA Cleavage Activity and Can Help Mediate RNAi Gene Silencing in a Heterologous System. AB - Dicer enzymes process double-stranded RNA (dsRNA) into small RNAs that target gene silencing through the RNA interference (RNAi) pathway. Dicer enzymes are complex, multi-domain RNaseIII proteins, however structural minimalism of this protein has recently emerged in parasitic and fungal systems. The most minimal Dicer, Saccharomyces castellii Dicer1, has a single RNaseIII domain and two double stranded RNA binding domains. In the protozoan parasite Entamoeba histolytica 27nt small RNAs are abundant and mediate silencing, yet no canonical Dicer enzyme has been identified. Although EhRNaseIII does not exhibit robust dsRNA cleavage in vitro, it can process dsRNA in the RNAi-negative background of Saccharomyces cerevisiae, and in conjunction with S. castellii Argonaute1 can partially reconstitute the RNAi pathway. Thus, although EhRNaseIII lacks the domain architecture of canonical or minimal Dicer enzymes, it has dsRNA processing activity that contributes to gene silencing via RNAi. Our data advance the understanding of small RNA biogenesis in Entamoeba as well as broaden the spectrum of non-canonical Dicer enzymes that contribute to the RNAi pathway. PMID- 26230097 TI - The Accuracy of p16/Ki-67 and HPV Test in the Detection of CIN2/3 in Women Diagnosed with ASC-US or LSIL. AB - The objective of this study was to compare the accuracies of double staining for p16/Ki-67 and the molecular test for high-risk HPV (hr-HPV) to identify high grade cervical intraepithelial neoplasia (CIN2/CIN3) in women with cervical cytology of atypical squamous cells of undetermined significance (ASC-US) and low grade squamous intraepithelial lesion (LSIL). Data were collected from 201 women who underwent cervical cytology screening in the Barretos Cancer Hospital and their results were categorized as ASC-US (n=96) or LSIL (n=105). All patients underwent colposcopy with or without cervical biopsy for diagnosis of CIN2/CIN3. The hr-HPV test (Cobas 4800 test) and immunocytochemistry were performed to detect biomarkers p16/Ki-67 (CINtec PLUS test). Two samples (1 ASC-US/1 LSIL) were excluded from the analysis due to inconclusive results of the histologic examination. There were 8 cases of CIN2/CIN3 among 95 women with ASC-US (8.4%), and 23 cases of CIN2/CIN3 among 104 women with LSIL (22.1%). In the group of women with ASC-US, the sensitivity and specificity in diagnosing CIN2/CIN3 were 87.5% and 79.5% for the HPV test and 62.5% and 93.1% for p16/Ki-67. Among women with LSIL, the sensitivity and specificity in the diagnosis of CIN2/CIN3 were 87% and 34.7% for the HPV test and 69.6% and 75.3% for immunocytochemistry. Superior performance was observed for p16/Ki-67 double staining, especially among women under 30 for whom the test had an area under the ROC curve of 0.762 (p<0.001). Both p16/Ki-67 double staining and the hr-HPV DNA test had similar performance in predicting high-grade cervical intraepithelial neoplasia among women with ASC-US. The best performance was observed in women aged >30 years. In younger women (<=30 years) with LSIL, p16/Ki-67 had greater accuracy in identifying precursor lesions. Among women >30 years diagnosed with LSIL, the two methods showed similar performance. PMID- 26230098 TI - Correction: Plasma Hsp90 Level as a Marker of Early Acute Lymphoblastic Leukemia Engraftment and Progression in Mice. AB - [This corrects the article DOI: 10.1371/journal.pone.0129298.]. PMID- 26230100 TI - Talking About Patients in Front of Them. PMID- 26230101 TI - Part II - Brown University's Program in Liberal Medical Education (PLME): Medical Exchange Programs; Student Research. PMID- 26230099 TI - Systems Modeling of Interactions between Mucosal Immunity and the Gut Microbiome during Clostridium difficile Infection. AB - Clostridium difficile infections are associated with the use of broad-spectrum antibiotics and result in an exuberant inflammatory response, leading to nosocomial diarrhea, colitis and even death. To better understand the dynamics of mucosal immunity during C. difficile infection from initiation through expansion to resolution, we built a computational model of the mucosal immune response to the bacterium. The model was calibrated using data from a mouse model of C. difficile infection. The model demonstrates a crucial role of T helper 17 (Th17) effector responses in the colonic lamina propria and luminal commensal bacteria populations in the clearance of C. difficile and colonic pathology, whereas regulatory T (Treg) cells responses are associated with the recovery phase. In addition, the production of anti-microbial peptides by inflamed epithelial cells and activated neutrophils in response to C. difficile infection inhibit the re growth of beneficial commensal bacterial species. Computational simulations suggest that the removal of neutrophil and epithelial cell derived anti-microbial inhibitions, separately and together, on commensal bacterial regrowth promote recovery and minimize colonic inflammatory pathology. Simulation results predict a decrease in colonic inflammatory markers, such as neutrophilic influx and Th17 cells in the colonic lamina propria, and length of infection with accelerated commensal bacteria re-growth through altered anti-microbial inhibition. Computational modeling provides novel insights on the therapeutic value of repopulating the colonic microbiome and inducing regulatory mucosal immune responses during C. difficile infection. Thus, modeling mucosal immunity-gut microbiota interactions has the potential to guide the development of targeted fecal transplantation therapies in the context of precision medicine interventions. PMID- 26230102 TI - Traditional Chinese Medicine Program in Hangzhou, Zhejiang, China: Summer 2013 Reflection. PMID- 26230103 TI - As Far as the East is from the West: Exchange Experiences in Traditional Chinese Medicine. PMID- 26230104 TI - Understanding Patient Perspective. PMID- 26230105 TI - At the Children's Hospital in Hangzhou. PMID- 26230106 TI - Society and Infant Genital Reassignment Surgery: Past, Present, and Future. PMID- 26230108 TI - Radiographic Evaluation of the Carpometacarpal Joint in Early Stage Osteoarthritis Severity and Joint Laxity. PMID- 26230109 TI - HIV Testing for At-Risk Adolescents at Rhode Island Hospital. AB - Early detection of HIV has great potential to reduce transmission, especially when newly diagnosed individuals are treated early. Early treatment and suppression of viral loads is known to effectively attenuate HIV transmission. However, little is known about whether persons at high risk for HIV are being appropriately tested during healthcare encounters according to national guidelines. Specifically, the at-risk adolescent population may be under tested and are not routinely monitored by state-level surveillance system. This study reviewed HIV testing rates for at-risk adolescents from 2005-2012 at the main tertiary care and pediatric center in Rhode Island. While the absolute number of HIV tests for at-risk adolescents continued to increase, the HIV testing rates for this population decreased during the seven year period. Increasing awareness of HIV testing for patients, their families, and physicians may improve the HIV testing rate among at-risk adolescents in Rhode Island. PMID- 26230110 TI - Delayed Diagnosis of Subdural Empyema in a Septic Child. AB - The prompt identification of sepsis in children is challenging, but once sepsis is identified, initiation of care and determination of proper disposition may be insufficient to ensure optimal outcomes. The best opportunity for full recovery also requires rapid identification and treatment of the infectious source. Acute bacterial sinusitis is common in the pediatric population, and although intracranial complications of sinusitis are rare, they are associated with significant morbidity and mortality. History and physical examination may be imperfectly sensitive for the presence of acute bacterial sinusitis and its intracranial complications. We present a case of pediatric sepsis in which the diagnosis of intracranial extension of bacterial sinusitis was not made during the first phase of care and describe complications that followed. Emergency physicians should consider subdural empyema in patients presenting with fever, nausea and headache with worrisome vital signs and laboratory values suggestive of a severe infection. PMID- 26230111 TI - Dyspnea and Chest Pain in a 45-Year-Old Woman. PMID- 26230112 TI - Rhode Island Violent Death Reporting System, 2004-2013. PMID- 26230113 TI - Low temperature syntheses and reactivity of Cu2O2 active-site models. AB - Nature's facility with dioxygen outmatches modern chemistry in the oxidation and oxygenation of materials and substrates for biosynthesis and cellular metabolism. The Earth's most abundant naturally occurring oxidant is-frankly-poorly understood and controlled, and thus underused. Copper-based enzyme metallocofactors are ubiquitous to the efficient consumption of dioxygen by all domains of life. Over the last several decades, we have joined many research groups in the study of copper- and dioxygen-dependent enzymes through close investigation of synthetically derived, small-molecule active-site analogs. Simple copper-dioxygen clusters bearing structural and spectroscopic similarity to dioxygen-activating enzymes can be probed for their fundamental geometrical, electronic, and reactive properties using the tools available to inorganic and synthetic chemistry. Our exploration of the copper-dioxygen arena has sustained product evaluation of the key dynamics and reactivity of binuclear Cu2O2 compounds. Almost exclusively operating at low temperatures, from -78 degrees C to solution characterization even at -125 degrees C, we have identified numerous compounds supported by simple and easily accessed, low molecular weight ligands chiefly families of bidentate diamine chelates. We have found that by stripping away complexity in comparison to extended protein tertiary structures or sophisticated, multinucleating architectures, we can experimentally manipulate activated compounds and open pathways of reactivity toward exogenous substrates that both inform on and extend fundamental mechanisms of oxygenase enzymes. Our recent successes have advanced understanding of the tyrosinase enzyme, and related hemocyanin and NspF, and the copper membrane monooxygenases, specifically particulate methane monooxygenase (pMMO) and ammonia monooxygenase (AMO). Tyrosinase, ubiquitously distributed throughout life, is fundamental to the copper-based oxidation of phenols and the production of chromophores by dedicated biosynthesis or incidental oxidative browning. The copper membrane monooxygenases are comparatively new entrants to the copper-dioxygen field. While pMMO mediates the synthetically tantalizing transformation of methane to methanol, AMO catalyzes the first metabolic step in deriving chemical energy from ammonia-a reaction massively represented on a global scale and a critical component of chemical homeostasis on Earth. In this Account, we begin by introduction of the synthetic copper-dioxygen chemistry field, from techniques to the differential coordination of dioxygen with copper. Then, we describe the unambiguous self assembly of an oxygenated tyrosinase mimic from basic constituents (copper, dioxygen, and monodentate-imidazole histidine analogs) and the resulting emergence of intrinsic reactivity, free of any influence due to the protein environment. Next, we discuss the first catalytic oxidation of phenol through a fully characterized tyrosinase mimic, derived from molecular oxygen, and its application to substrates unreactive in the native enzyme system. Finally, we detail evidence for chemical plausibility of dioxygen activation in pMMO (and AMO) through a high-valent species and the thermodynamic criteria that beg introduction of the Cu(III) state to biological redox catalysis. PMID- 26230114 TI - Type 1 Diabetes Prone NOD Mice Have Diminished Cxcr1 mRNA Expression in Polymorphonuclear Neutrophils and CD4+ T Lymphocytes. AB - In humans, CXCR1 and CXCR2 are two homologous proteins that bind ELR+ chemokines. Both receptors play fundamental roles in neutrophil functions such as migration and reactive oxygen species production. Mouse Cxcr1 and Cxcr2 genes are located in an insulin-dependent diabetes genetic susceptibility locus. The non obese diabetic (NOD) mouse is a spontaneous well-described animal model for insulin dependent type 1 diabetes. In this disease, insulin deficiency results from the destruction of insulin-producing beta cells by autoreactive T lymphocytes. This slow-progressing disease is dependent on both environmental and genetic factors. Here, we report descriptive data about the Cxcr1 gene in NOD mice. We demonstrate decreased expression of mRNA for Cxcr1 in neutrophils and CD4+ lymphocytes isolated from NOD mice compared to other strains, related to reduced NOD Cxcr1 gene promoter activity. Looking for Cxcr1 protein, we next analyze the membrane proteome of murine neutrophils by mass spectrometry. Although Cxcr2 protein is clearly found in murine neutrophils, we did not find evidence of Cxcr1 peptides using this method. Nevertheless, in view of recently-published experimental data obtained in NOD mice, we argue for possible Cxcr1 involvement in type 1 diabetes pathogenesis. PMID- 26230116 TI - Evaluation of motion platform embedded with dual belt treadmill instrumented with two force plates. AB - Motek Medical's Computer Aided Rehabilitation Environment (CAREN)-Extended system is a virtual environment primarily used in physical rehabilitation and biomechanical research. This virtual environment consists of a 180 degree projection screen used to display a virtual scene, a 12-camera motion capture system, and a six degree of freedom actuated platform equipped with a dual-belt treadmill and two force plates. The goal of this article was to investigate the performance characteristics associated with a "treadmill-motion platform" configuration and how system operation can affect the data collected. Platform static and dynamic characteristics were evaluated by translating or rotating the platform over progressively larger distances and comparing input and measured values. Treadmill belt speed was assessed with and without a person walking on the platform and at different orientations. Force plate measurements were examined when the treadmill was in operation, during ambulation, and over time to observe the baseline drift. Platform acceleration was dependent on the distance travelled and system settings. Treadmill speed variability was greatest at faster speeds. Force plate measurements were affected by platform and treadmill operation, contralateral impact forces during gait, and baseline drift. Knowledge of performance characteristics and their effect on outcome data is crucial for effective design of CAREN research protocols and rehabilitation scenarios. PMID- 26230115 TI - The European Hare (Lepus europaeus): A Picky Herbivore Searching for Plant Parts Rich in Fat. AB - European hares of both sexes rely on fat reserves, particularly during the reproduc-tive season. Therefore, hares should select dietary plants rich in fat and energy. However, hares also require essential polyunsaturated fatty acids (PUFA) such as linoleic acid (LA) and alpha-linolenic acid (ALA) to reproduce and survive. Although hares are able to absorb PUFA selectively in their gastrointestinal tract, it is unknown whether this mechanism is sufficient to guarantee PUFA supply. Thus, diet selection may involve a trade-off between a preference for energy versus a preference for crucial nutrients, namely PUFA. We compared plant and nutrient availability and use by hares in an arable landscape in Austria over three years. We found that European hares selected their diet for high energy content (crude fat and crude protein), and avoided crude fibre. There was no evidence of a preference for plants rich in LA and ALA. We conclude that fat is the limiting resource for this herbivorous mammal, whereas levels of LA and ALA in forage are sufficiently high to meet daily requirements, especially since their uptake is enhanced by physiological mechanisms. Animals selected several plant taxa all year round, and preferences did not simply correlate with crude fat content. Hence, European hares might not only select for plant taxa rich in fat, but also for high-fat parts of preferred plant taxa. As hares preferred weeds/grasses and various crop types while avoiding cereals, we suggest that promoting heterogeneous habitats with high crop diversity and set-asides may help stop the decline of European hares throughout Europe. PMID- 26230118 TI - Host response to Brucella infection: review and future perspective. AB - Brucellosis is a zoonotic and contagious infectious disease caused by infection with Brucella species. The infecting brucellae are capable of causing a devastating multi-organ disease in humans with serious health complications. The pathogenesis of Brucella infection is influenced largely by host factors, Brucella species/strain, and the ability of invading brucellae to survive and replicate within mononuclear phagocytic cells, preferentially macrophages (Mf). Consequently, the course of human infection may appear as an acute fatal or progress into chronic debilitating infection with periodical episodes that leads to bacteremia and death. The existence of brucellae inside Mf represents one of the strategies used by Brucella to evade the host immune response and is responsible for treatment failure in certain human populations treated with anti Brucella drugs. Moreover, the persistence of brucellae inside Mf complicates the diagnosis and may affect the host cell signaling pathways with consequent alterations in both innate and adaptive immune responses. Therefore, there is an urgent need to pursue the development of novel drugs and/or vaccine targets against human brucellosis using high throughput technologies in genomics, proteomics, and immunology. PMID- 26230117 TI - Prevalence of cagA and vacA among Helicobacter pylori-infected patients in Iran: a systematic review and meta-analysis. AB - The varieties of infections caused by Helicobacter pylori may be due to differences in bacterial genotypes and virulence factors as well as environmental and host-related factors. This study aimed to investigate the prevalence of cagA and vacA genes among H. pylori-infected patients in Iran and analyze their relevance to the disease status between two clinical groups via a meta-analysis method. Different databases including PubMed, ISI, Scopus, SID, Magiran, Science Direct, and Medlib were investigated, and 23 relevant articles from the period between 2001 and 2012 were finally analyzed. The relevant data obtained from these papers were analyzed by a random-effects model. Data were analyzed using R software and STATA. The prevalence of cagA and vacA genes among H. pylori infected patients was 70% (95% CI, 64-75) and 41% (95% CI, 24.3-57.7), respectively. The prevalence of duodenal ulcers, peptic ulcers, and gastritis among cagA+ individuals was 53% (95% CI, 20-86), 65% (95% CI, 34-97), and 71% (95% CI, 59-84), respectively. Odds ratio (OR) between cagA-positive compared with cagA-negative patients showed a 1.89 (95% CI, 1.38-2.57) risk of ulcers. In conclusion, the frequency of cagA gene among H. pylori strains is elevated in Iran and it seems to be more frequently associated with gastritis. Therefore, any information about cagA and vacA prevalence among different H. pylori-infected clinical groups in the country can help public health authorities to plan preventive policies to reduce the prevalence of diseases associated with H. pylori infection. PMID- 26230119 TI - In vitro susceptibility of a penicillin-resistant and tolerable isolate of Streptococcus pneumoniae to combination therapy. AB - INTRODUCTION: Preference for combination therapy to treat infection due to multidrug-resistant S. pneumoniae (MDRSP) has not been well elucidated in previous studies. METHODOLOGY: In the present study, 19 antibiotics in combinations were tested against an MDRSP isolate. In vitro susceptibility studies including minimum inhibitory concentration (MIC), minimal bactericidal concentrations (MBC) and disk agar diffusion (DAD), tolerance to resistant antibiotics, checkerboard assay, time-kill curve, hemolytic assay, and autolysis assay were performed on the test strain to study its in vitro susceptibility to combination therapy. RESULTS: From the checkerboard assay and time-kill curve, it was observed that a combination of levofloxacin (MIC, 16 ug/mL) and ceftriaxone (MIC, 2 ug/mL), at sub-MIC concentration was synergistic and most effective against the MDRSP isolate (penicillin MIC, > 64 ug/mL). Hemolytic activities also increased significantly with combination therapy compared to monotherapy (p < 0.05). Moreover, the hemolytic activity of levofloxacin in combination with ceftriaxone was better than ciprofloxacin plus ceftriaxone or cefepime. The autolysis rate was also found to increase rapidly within one hour of exposure to levofloxacin plus ceftriaxone, and this was found to be significantly different from the other combinations at the fifth and sixth hour post incubation (p < 0.05). CONCLUSIONS: This data suggests that this combination is bactericidal in vitro, and requires further studies in in vivo models for treatment against MDRSP infections. PMID- 26230120 TI - Cost-effective procedure for Streptococcus pyogenes immobilized DNA preparation and miniPFGE subtyping. AB - INTRODUCTION: Group A streptococci (GAS) is responsible of several human diseases ranging from mild infection to severe invasive toxin-mediated disease and post infectious sequelae. Accordingly, a GAS surveillance program based on molecular techniques is advisable for its epidemiological control. Pulsed-field gel electrophoresis (PFGE) is the gold standard for GAS molecular subtyping, but a major disadvantage is the length of the procedure, which takes 1-3 days of work, minimum. The aim of this study was to develop a rapid and cost-effective procedure for PFGE subtyping of GAS isolates. METHODOLOGY: Different incubation times of GAS, immobilized in agarose miniplugs, in solutions containing lysozyme and/or mutanolysine followed by solutions with urea instead of proteinase K, were assayed. DNA was restricted with SmaI and the fingerprints were obtained in clamped homogeneous electric field (CHEF) chambers and minichambers. The modified procedure was used to subtype 22 GAS isolates. RESULTS: Intact DNA molecules of GAS immobilized in agarose miniplugs were prepared incubating the cells, in situ, with a solution containing lysozyme for 4 hours, followed by the incubation in a non-enzymatic solution with urea for 2 hours. SmaIDNA macrorestriction fragments were well resolved in 5 hours and 14 minutes by electrophoresis in a CHEF minichamber at 10 V/cm. This procedure for GAS DNA preparation was useful for fingerprinting GAS strains in the format of CHEF Mapper (BioRad). CONCLUSIONS: The procedure took 13 hours for GAS strains subtyping. Both sample preparation and electrophoresis in CHEF minichamber represent an economic alternative for performing massive epidemiological studies of this human pathogen. PMID- 26230121 TI - Phylogenetic background of E. coli isolated from asymptomatic pregnant women from Kolkata, India. AB - INTRODUCTION: Asymptomatic bacteriuria (ABU) in pregnancy generates medical complications. E. coli is the common etiologic agent responsible for ABU associated infections. This study aimed to identify the phylogenetic background and drug resistance in asymptomatic E. coli from a pregnant population. METHODOLOGY: E. coli was confirmed biochemically from culture-positive urine samples collected from asymptomatic pregnant women. Phylogenetic typing was done by polymerase chain reaction (PCR). The isolates were subjected to antibiotic susceptibility testing and extended-spectrum beta-lactamase (ESBL) production. Statistical significance was determined using SPSS 17.0 software. RESULTS: Bacteriuria was observed in 113 (22.6%) of 500 asymptomatic pregnant females. E. coli was reported in 44 (38.9%) of 113 isolates. The mean age-wise distribution was 25.14 +/- 4.63. Although pathogenic phylogroup B2 was predominant (54.5%), incidence of non-pathogenic phylogroup B1 (27.3%) was found to be statistically significant (p <= 0.001), and B1 and B2 were correlated with respect to total ABU population. Antibiotic sensitivity against ampicillin (34.1%), ceftazidime (50%), cefotaxime (47.7%), ciprofloxacin (47.7%), amikacin (86.4%), nitrofurantion (79.5%), and co-trimoxazole (36.4%) was observed. Multidrug resistance (MDR) and ESBL production was reported in 26 (59.1%) of 44 and 18 (69.2%) of the 26 MDR isolates, respectively. A significant distribution of phylogroup B1 (p = 0.03) with drug resistance was also observed. CONCLUSIONS: This is the first study that reported significant incidence of non-pathogenic phylogroup B1 in asymptomatic E. coli with high incidence of MDR isolated from pregnant women in Kolkata, India. These varied resistance patterns present major therapeutic and infection control challenges during pregnancy. PMID- 26230122 TI - Inducible and constitutive clindamycin resistance in Staphylococcus aureus in a northeastern Indian tertiary care hospital. AB - INTRODUCTION: Staphylococcus aureus is one of the most common pyogenic bacteria. They are notorious for developing prompt resistance to newer antimicrobials. With increasing incidence of methicillin-resistant S. aureus (MRSA) isolates, the treatment options are also becoming limited. Clindamycin is an excellent drug for skin and soft tissue infections, but resistance mediated by the inducible phenotype (iMLS(B)) leads to in vivo therapeutic failure even though there may be in vitro susceptibility. The double disk approximation test (D-test) can reliably detect the presence of such isolates. This study was aimed to detect and report the prevalence of the iMLS(B) phenotype in NEIGRIHMS, a tertiary care center in Northeast India. METHODOLOGY: A total of 243 consecutive isolates were subjected to routine identification tests followed by antimicrobial sensitivity testing. Erythromycin-resistant isolates were tested for inducible resistance phenotype by the D-test. RESULTS: Among strains tested, 95 (39%) were erythromycin resistant. Twenty-six (10.7%) isolates were D-test positive (iMLS(B) phenotype), 41 (16.88%) were constitutively resistant (cMLS(B) phenotype), and 28 isolates (11.52%) were found to be negative by D-test. The incidence of both inducible and constitutive phenotypes was higher in MRSA isolates compared to methicillin-sensitive S. aureus (MSSA) isolates. CONCLUSIONS: This study revealed a moderate prevalence of the inducible clindamycin phenotype in the staphylococcal isolates tested. Clinical microbiology laboratories in areas of high MRSA prevalence should consider performing the D-test routinely. This will help prevent prescription of drug(s) whose therapeutic efficacy is doubtful. PMID- 26230123 TI - Prevalence of Clostridium difficile toxinotypes in infected patients at a tertiary care center in Lebanon. AB - INTRODUCTION: Due to the increase in the incidence of Clostridium difficile associated diseases at a tertiary care center in Lebanon, this study was undertaken to determine the prevalent C. difficile toxinotypes. METHODOLOGY: The immunocard method was used to test for toxins A and B in 88 collected stool samples, followed with API 20A to confirm for C. difficile. PCR amplification of the triose phosphate isomerase (tpi) gene, the toxin encoding genes tcdA, and tcdB, followed by toxinotyping, were performed on recovered isolates and stool specimens. RESULTS: Out of the 88 stool samples obtained, 30 (65.2%) were Immunocard positive, culture and or tpi positive for C. difficile. Of the 30 isolates, 4 were PCR negative for the tcdA and tcdB genes (A-B-), and 26 were PCR positive for the tcdA and / or tcdB genes with 4 being A+B+, 1 A+B-, and 21 A-B+. The results of toxinotyping showed that 2 isolates belonged to toxinotype 0, 4 to toxinotype XI, 2 to toxinotype XII, 1 to toxinotype XVI, 1(A+B-) and twenty (A B+) designated as toxinotype 0-like. C. difficile was detected in 65.2% of patients' stools with prevalence of toxinotype 0-like. CONCLUSION: Identification of toxinotypes of C. difficile is important to determine the virulence potential of strains and control their spread. PMID- 26230124 TI - Prevalence and patterns of infection in critically ill trauma patients admitted to the trauma ICU, South Africa. AB - INTRODUCTION: The aim of this study was to determine if any patterns of infection or bacterial resistance existed in critically ill polytrauma patients admitted to the intensive care unit (ICU) at the CM Johannesburg Academic Hospital (CMJAH). METHODS: This was a prospective, single-center study of patient laboratory records of 73 critically injured polytrauma patients admitted to an ICU. The data collected from each patient, beginning with admission and extending until discharge from the ICU, included age, gender, admission hemoglobin levels, injury severity score, length of ICU stay, microbiological cultures and sensitivity (MCS), and types and numbers of surgical procedures. RESULTS: Upon admission to the ICU, the injury severity score (ISS) was 40.86 (+/- 15.64). In total, 73.98% of the patients required the use of a ventilator during their ICU stay. The most prevalent organisms isolated from specimens were Pseudomonas aeruginosa (30.1%), Klebsiella species (25.7%), Acinetobacterbaumanni (16.4%), and Staphylococcus aureus (5.8%). Multi-drug resistance (MDR) was identified in 63% of patients, with Klebsiella (73.91%) and Pseudomonas (65.21%) occurring most frequently. Multivariate analysis showed MDR to be the only significant predictor associated with a higher risk for hospital mortality when age, gender, ventilation, duration of ICU stay, ISS score, and the number of surgeries undergone was taken into account. CONCLUSION: Critically ill polytrauma patients are at particularly high risk for Gram-negative sepsis. PMID- 26230125 TI - Molecular and phenotypic characteristics of methicillin-resistant Staphylococcus aureus isolated from hospitalized patients. AB - INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of infections acquired in both community and hospital settings. In this study, MRSA isolated from different sources of hospitalized patients was characterized by molecular and phenotypic methods. METHODOLOGY: A total of 123 S. aureus isolates were characterized according to their genetic relatedness by repetitive element sequence based-PCR (REP-PCR), in vitro antimicrobial susceptibility profile, SCCmec typing and presence of seven virulence factor encoding genes. RESULTS: REP-PCR fingerprinting showed low relatedness between the isolates, and the predominance of one specific lineage or clonal group was not observed. All isolates were susceptible to teicoplanin and linezolide. All isolates were resistant to cefoxitin and penicillin, and the majority were also resistant to one or more other antimicrobials. Fifty isolates (41.7%) were intermediately resistant to vancomycin. Most isolates harbored SCCmec type II (53.7%), followed by type I (22.8%), type IV (8.1%) and type III (1.6%). All isolates harbored at least two virulence factor-encoding genes, and the prevalence was as follows: coa, 100%; icaA, 100%; hla, 13.0%; hlb, 91.1%, hld, 91.1%; lukS-PV and lukF-PV, 2.4%; and tst, 34.1%. A positive association with the presence of hla and SCCmec type II, and tst and SCCmec type I was observed. CONCLUSION: This study showed the high virulence potential of multidrug-resistant MRSA circulating in a teaching hospital. A high prevalence of MRSA showing intermediate vancomycin resistance was also observed, indicating the urgent need to improve strategies for controlling the use of antimicrobials for appropriate management of S. aureus infections. PMID- 26230126 TI - Outcome of tuberculosis patients under directly observed short course treatment in western Ethiopia. AB - INTRODUCTION: Treatment outcome is an important indicator of tuberculosis control programs, as suggested by the World Health Organization. However, this has not been well documented in the study area. This work contributes to a better understanding this issue. METHODOLOGY: A five-year (2009-2013) retrospective cohort study was conducted between April and May 2014, in six randomly selected health institutions providing tuberculosis treatment in western Ethiopia. Bivariate and multivariate logistic regression analyses were used to assess the association between treatment outcomes and predictor variables. RESULTS: A total of 1,175 tuberculosis patients with a mean (standard deviation) age of 29.91 (13.99) were involved in the study. The majority of the study participants had smear-negative pulmonary tuberculosis (39.7%) and extrapulmonary tuberculosis (39.7%). Of all the study participants, 14.5% were cured, 56.3% completed treatment, 0.2% had treatment failure, 8.1% died during follow-up, 7.1% were reported as defaulters, and 13.8% were transferred out to another health institution. The overall treatment success rate was 70.8% and show progressive increases over the course of the study. The associated predictors were enrollment years, HIV co-infection, and sputum smear follow-up in the second, fifth, and seven months. CONCLUSIONS: The treatment success rate was unsatisfactory in spite of improvement seen over the study period. Thus, continued follow-up of patients, with frequent supportive supervision during the course of treatment, and provision of early detection and follow-up for HIV infection need to be strengthened to achieve an effective treatment outcome. PMID- 26230127 TI - Retrospective screening of acute undifferentiated fever serum samples with universal flavivirus primers. AB - INTRODUCTION: Fever is a common symptom of many tropical diseases and in many cases the etiologic agent remains unidentified as a consequence of either the etiologic agent not being part of routine diagnostic screening or as a consequence of false negatives on standard diagnostic tests. METHODOLOGY: This study screened a well characterized panel of 274 serum samples collected on day of admission from adult patients with acute undifferentiated fever admitted to a hospital in Nakhon Ratchasima, Thailand by RT-PCR using pan-flavivirus degenerate primers. RESULTS: Subsequent clinical diagnosis was achieved for 38 of the patients, and included 19 cases of dengue fever. RT-PCR screening identified seven positive samples (2.5%) which were revealed by sequence analysis to be dengue virus 1 (2 cases), dengue virus 2 (2 cases) and dengue virus 3 (3 cases). Only 5 out of 19 (26%) serum samples from patients subsequently diagnosed with dengue were positive, but 2 samples which clinically remained undiagnosed were shown to be positive for dengue virus. Sequence analysis suggested that the dengue virus 3 cases occurred as a result of importation of a strain of dengue from India or China. No other flaviviruses were identified. CONCLUSIONS: No evidence was found of other flaviviruses besides dengue circulating in this population. Despite improved diagnostic tests, cases of dengue are still evading correct diagnosis. PMID- 26230128 TI - Antiretroviral therapy, CD4, viral load, and disease stage in HIV patients in Saudi Arabia: a 2001-2013 cross-sectional study. AB - INTRODUCTION: The incidence of HIV/AIDS is increasing worldwide and in the Middle East. In this study, we analyzed the use of antiretroviral therapy (ART), the patterns of CD4 and viral load (VL), and stage of presentation. METHODOLOGY: Laboratory variables, ART use, and CD4 count were obtained and analyzed retrospectively. RESULTS: A total of 997 cases from eight HIV/AIDS care providers were included. Of the total cases, 274 (28.3%) had a CD4 count of < 200 cells/mm(3), and 413 (42.3%) had a viral load of > 5 log10. Of the total cases, 50% were on highly active antiretroviral therapy (HAART), and the majority of cases were asymptomatic (70%). Of those patients on ART, 247 (39.5%) took tenofovir/emtricitabine combined with either efavirenz (147; 14.7%) or lopinavir/ritonavir (100; 10%), and 158 (15.8%) were on lamivudine and zidovudine with either efavirenz (32; 3.2%) or lopinavir/ritonavir (126; 12.6%). Other combinations were used in 70 (7%) patients. The mean (+/- standard deviation) of baseline CD4 and viral load were 401 cells/mm(3) (322 cells/mm(3)) and 4.6 log1010 (1.3 log10), respectively. At diagnosis, 72% of patients were asymptomatic; 50% had AIDS and 20% had CD4 count < 350. CONCLUSIONS: ART use was in line with international guidelines, but the number of patients receiving ART was lower than expected. Large proportions of cases presented late with AIDS at diagnosis or had CD4 < 350. Further data is needed to evaluate the medical care of patients with HIV/AIDS in the Kingdom of Saudi Arabia. PMID- 26230129 TI - Seroprevalence of hepatitis B surface antigen and hepatitis B e antigen among childbearing-age women in Mianyang, China. AB - INTRODUCTION: Few studies have focused on hepatitis B virus (HBV) infection among childbearing-age women. This study explored hepatitis B surface antigen (HBsAg) seroprevalence and hepatitis B e antigen (HBeAg) seroprevalence and their associated factors among childbearing-age women. METHODOLOGY: A cross-sectional, population-based study was conducted between June 2013 and October 2013 in Mianyang; women 15-49 years of age were enrolled using a multistage cluster sampling design. Participants completed questionnaires about demographic characteristics and potential factors associated with HBV infection, and provided blood samples for screening HBsAg and HBeAg. The analysis methods included descriptive statistics, Chi-square test, and multivariate logistic regression. RESULTS: Among 62,007 childbearing-age women, 5.66% were HBsAg positive. The HBsAg seroprevalence rates were 7.28% in women 40-44 years of age, 7.0% in Fucheng women, 5.70% in Han women, 6.59% in married women, and 6.60% in agriculture workers. Multivariate models identified having HBsAg-positive family members, and having no self-reported immunization history to be positively associated with HBsAg positivity; being a healthcare worker was negatively associated with HBsAg positivity. Among 3,499 HBsAg-positive childbearing-age women, 9.97% were HBeAg positive. The HBeAg seroprevalence rates were 46.54% in women 15-19 years of age, 10.82% in Fucheng women, 38.51% in single women, and 42.86% in students. Multivariate models identified living in Fucheng and younger age to be positively associated with HBeAg positivity. CONCLUSIONS: These findings could provide scientific evidence for the Chinese government to plan efficient health care services and prevention initiatives, and to allocate health resources reasonably for this population. PMID- 26230130 TI - Bacterial pericarditis and antimicrobial resistance at the Tehran Heart Center, Iran. AB - INTRODUCTION: When bacterial pericarditis is suspected, urgent pericardial drainage combined with intravenous antibacterial therapy is mandatory to avert devastating, life-threatening complications. There have been scanty results on antimicrobial susceptibility of common causative microorganisms of bacterial pericarditis; most studies had small sample sizes and were performed decades ago. METHODOLOGY: This prospective study surveyed the causative bacteria in infectious pericardial effusions and their antimicrobial susceptibility among 320 consecutive cardiac patients who underwent pericardiocentesis at Tehran Heart Center between 2007 and 2012, using the European Society of Cardiology (ESC)'s criteria. RESULTS: Staphylococcus spp. (S. epidermidis, S. aureus, S. haemolyticus) were the main causative organisms isolated from cultures of pericardial effusion samples. Other causative organisms were Streptococcus spp., Enterococcus faecium, Pseudomonas aeruginosa, and Acinetobacter baumannii. In the cultures studied, 35% methicillin-resistant Staphylococcus epidermidis (MRSE) and 42.9% methicillin-resistant Staphylococcus aureus (MRSA) were detected. The most effective antimicrobial agents in S. epidermidis were gentamicin, ciprofloxacin, and cefoxitin. Clindamycin was relatively effective. S. aureus was highly susceptible to clindamycin and erythromycin. In cases of S. haemolyticus infection, clindamycin, erythromycin, cefoxitin, and ciprofloxacin were effective antibiotics. CONCLUSIONS: In order to diminish the nascence and extension of antimicrobial-resistant pathogens, logical and optimized antimicrobial usage and monitoring in hospitals are highly recommended. It is incumbent on healthcare systems to determine current local resistance patterns by which to guide empiric antimicrobial therapy for specific infections and microorganism types. PMID- 26230131 TI - Successful use of splenectomy in a patient with hepatitis C virus-related thrombocytopenia. AB - This case report describes a 44-year-old female with hepatitis C virus-related thrombocytopenia. The laboratory tests showed a platelet count of 3*109/l, positive HCV serology and high serum concentration of HCV-RNA of 6.74*106 copy/ml. She was refractory to standard therapies including corticosteroids, intravenous immunoglobulin (IVIG), thrombopoietin (TPO) and even interferon (IFN) regimens, due to the persistence of a low platelet count. At first, splenectomy was thought to be impossible, but then splenectomy was successfully performed and patient showed good tolerance and a constant normal platelet count after surgery. In conclusion, splenectomy is feasible in selected patients and may allow us to acquire a reasonable platelet count and completion of an anti-HCV protocol. Low platelet count itself should not be the contraindication of operation specifically for these patients. Further studies in larger numbers of patients and over a longer period of time are warranted. PMID- 26230132 TI - Eradication of Blastocystis hominis prevents the development of symptomatic Hashimoto's thyroiditis: a case report. AB - In this case report we describe a 49 year-old man who presented with chronic urticaria, angioedema and soft stool consistency. During diagnostic examinations Hashimoto's thyroiditis was found even though the patient never had clear symptoms of this disease. Blastocystis hominis was isolated through a stool microbiologic examination, implicating that this parasite can cause the development of Hashimoto's thyroiditis and chronic urticaria. After two-weeks treatment with metronidazole the Blastocystis hominis was eradicated, then urticaria and angioedema disappeared. During the four years of follow-up, the patient presented without any symptoms, whereas thyroid hormones were normalized and anti-thyroid antibodies declined. For the first time in the literature we show that eradication of Blastocystis hominis can prevent the development of both symptomatic Hashimoto's thyroiditis and chronic urticaria. PMID- 26230133 TI - Purple urine bag syndrome in an elderly patient from Colombia. AB - A 71-year-old woman in a nursing home, with indwelling urinary catheter, bedridden, presented with a purple urine collector bag. The purple urine bag syndrome is a rare condition associated with the metabolism of tryptophan by overgrowth of intestinal bacteria. The purple color is formed by a combination of indigo and indirubin produced as a result of phosphatase and sulfatase enzymatic activity of bacteria on indoxyl sulfate, under alkaline pH of the urine. We present the second case of this syndrome reported in Colombia detailing the management of this rare syndrome associated with urinary tract infection. Several conditions should be considered in the differential diagnose of diseases that cause discoloration of the urine. PMID- 26230134 TI - Response to the cost effectiveness analysis of pneumococcal conjugated vaccines in Peru. PMID- 26230135 TI - Sn(IV) Metalloporphyrin/Co(III) Complex: An All-Abundant-Element System for the Photocatalytic Production of H2 in Aqueous Solution. AB - A new, molecular system for the light-driven production of hydrogen in aqueous solution was developed by combining a water-soluble tin porphyrin ([Sn(IV)Cl2TPPC], A) acting as photosensitizer with a cobalt-based proton reduction catalyst ([Co(III)Cl(dmgH)2(py)], C). Under visible light illumination and with triethanolamine (TEOA) as electron source, the system evolves H2 for hours and is clearly catalytic in both dye and catalyst. A detailed analysis of the relevant redox potentials in combination with time-resolved spectroscopy resulted in the development of a Z-scheme type model for the flow of electrons in this system. Key intermediates of the proposed mechanism for the pathway leading to H2 are the porphyrin dye's highly oxidizing singlet excited state (1)A* (E ~ +1.3 V vs NHE), its strongly reducing isobacteriochlorin analogue (E ~ +0.95 V), and the Co(I) form of C (E ~ -0.8 V), acting as catalyst for H2 formation. Among other results, the suggested reaction sequence is supported by the detection of a shortened excited-state lifetime for singlet (1)A* (tau ~ 1.75 ns) in the presence of TEOA and the ultraviolet-visible detection of the Sn(IV) isobacteriochlorin intermediate at lambda = 610 nm. Thus, a molecular, conceptually biomimetic, and precious-metal-free reaction chain was found which photocatalytically generates H2 in a 100% aqueous system from an electron donor with a high oxidation potential (E(TEOA) ~ +1.1 V). On the other hand, at identical conditions, this photoreaction chain yields H2 markedly slower than a system using the photosensitizer [Re(I)(CO)3(bpy) (py)](+), probably due to the much longer excited-state lifetime (tau ~ 120 ns) of the rhenium dye and better electron-transfer rates caused by its simple single-electron photoreduction chemistry. PMID- 26230136 TI - Stop using the flotation technique and start weighing salbutamol pressurised metered-dose inhalers without dose counters. AB - Salbutamol pressurised metered-dose inhalers (pMDIs) are not equipped with dose counters outside the USA. The aim of this study was to describe a simple reproducible method for determining the number of doses remaining in a pMDI based on scale weight. With a laboratory scale, the mean weight of the canisters was 28.61 +/- 0.10 g after priming and 14.84 +/- 0.23 g after 200 puffs. Similar results were obtained with two common digital scales. We recommend weighing salbutamol canisters on a common digital scale, and replacing an old pMDI with a new one when the weight falls to <=15 g. PMID- 26230137 TI - Erratum: "Take Care in the Kitchen: Avoiding Cooking-Related Pollutants". PMID- 26230138 TI - Age Dependency of Myocardial Triglyceride Content: A 3T High-Field 1H-MR Spectroscopy Study. AB - PURPOSE: The role of myocardial triglyceride (mTG) content in the aging human heart is not entirely understood. The aim of this study was to measure concentrations of mTG content from healthy volunteers and to determine the association between age, mTG content and systolic heart function. Furthermore, the technical stability of the (1)H-magnetic resonance spectroscopy ((1)H-MRS) and the reliability of peak evaluation at 3 T were evaluated. MATERIALS AND METHODS: The total study population of 47 healthy volunteers was divided into 4 age classes, according to the age of the subjects (1(st) cohort 20 - 29 years (yrs.), n = 20; 2(nd) cohort 30 - 39 yrs., n = 10; 3(rd) cohort 40 - 49 yrs., n = 9; 4(th) cohort 50 - 60 yrs., n = 8). Cardiac MRI and double triggered (1)H-MRS of the myocardium were consecutively performed using a 3 T scanner. Each participant underwent spectroscopic measurements twice in the same investigation. RESULTS: mTG content increases with age. The correlation of age and mTG is minimal (r = 0.48; p < 0.001). The following age-averaged mTG content values expressed as % of mTG signal compared to the water signal were determined for each cohort: 1(st) cohort 0.25 % (+/- 0.17); 2(nd) cohort 0.48 % (+/- 0.30); 3(rd) cohort 0.48 % (+/- 0.18); 4(th) cohort 0.77 % (+/- 0.70). There was no significant correlation (r = 0.04; p = n.s.) between LV mass and mTG content in healthy volunteers. Within our cohorts, no effects of age or mTG content on systolic heart function were seen (r = - 0.01; p = n.s.). The intraclass correlation coefficient of spectroscopic measurements was high (r = 0.965; p < 0.001). CONCLUSION: Myocardial TG content increases with age. The normal age dependent concentration ranges of myocardial lipid metabolites reported in this study may be helpful for the correction of acquired (1)H-MRS data in patients when evaluating metabolic and cardiovascular diseases in future magnetic resonance spectroscopy studies. PMID- 26230139 TI - Internal Controlling of a Radiology Department. AB - Caused by legal reform initiatives there is a continuous need to increase effectiveness and efficiency in hospitals and surgeries, and thus to improve processes.Consequently the successful management of radiological departments and surgeries requires suitable structures and optimization processes to make optimization in the fields of medical quality, service quality and efficiency possible.In future in the DRG System it is necessary that the organisation of processes must focus on the whole clinical treatment of the patients (Clinical Pathways). Therefore the functions of controlling must be more established and adjusted. On the basis of select Controlling instruments like budgeting, performance indicators, process optimization, staff controlling and benchmarking the target-based and efficient control of radiological surgeries and departments is shown. PMID- 26230141 TI - Tautomerization of Some Methylacenes and the Role of Reverse Radical Disproportionation. AB - The thermokinetics for the tautomerization of a series of methylenedihydroacenes to the corresponding methylacenes (toluene to 6-methylpentacene) have been investigated by means of CBS-QB3 calculations. Only for 6-methylpentacene does the methylenedihydro form predominate at room temperature. The obtained equilibrium ratios are consistent with various theoretical methods, but the agreement with the scarce experimental data is only qualitative. The noncatalyzed thermal tautomerization of the methylenedihydroacene in an inert solvent may proceed by means of a reverse radical disproportionation reaction (RRD) as the rate-determining step. The benzylic BDE(C-H)s and the hydrogen atom affinities (HA) of the tautomers have been used to calculate the reaction enthalpy, DeltaRRDH. It appears that the Ea,RRD is substantially higher than DeltaRRDH. This implies that the opposite reaction (and the tautomer forming step), a radical-radical disproportionation (RD), is an activated process. This is an often ignored or overlooked kinetic feature. The consequence is that although the RRD reaction may be kinetically feasible at elevated temperatures, the products are not the tautomers but rather dimers stemming from radical-radical recombination reactions, with p-isotoluene as a clear exception. It is further shown that the RRD self-reaction of phenalene is too slow at 298 K, despite claims to the contrary. PMID- 26230140 TI - Imaging-Based Liver Function Tests--Past, Present and Future. AB - Preoperative assessment of liver function and prediction of postoperative functional reserve are important in patients scheduled for liver resection. While determination of absolute liver function currently mostly relies on laboratory tests and clinical scores, postoperative remnant liver function is estimated volumetrically using imaging data obtained with computed tomography (CT) or magnetic resonance imaging (MRI). Accurate estimation of hepatic function is also relevant for intensive care patients, oncologic patients, and patients with diffuse liver disease. The indocyanine green (ICG) test is still the only established test for estimating true global liver function. However, more recent tools such as the LiMAx test also allow global assessment of hepatic function. These tests are limited when liver function is inhomogeneously distributed, which is the case in such conditions as unilateral cholestasis or after portal vein embolization. Imaging-based liver function tests were first developed in nuclear medicine and, compared with laboratory tests, have the advantage of displaying the spatial distribution of liver function. Nuclear medicine scans are obtained using tracers such as 99mTc galactosyl and 99mTc mebrofenin. Liver function is typically assessed using planar scintigraphy. However, three-dimensional volumetry is possible with single-photon emission computed tomography (SPECT-CT). Another technique for image-based liver function estimation is Gd-EOB-enhanced MRI. While metabolization of Gd-EOB in the body is similar to that of ICG and mebrofenin, its distribution in the liver can be displayed by MRI with higher temporal and spatial resolution. Moreover, MRI-based determination of liver function can be integrated into routine preoperative imaging. This makes MRI an ideal candidate for preoperative determination of liver function, though the best pulse sequence and the parameter to be derived from the image information remain to be identified. Another question to be answered is how the results may be affected by renal function and the presence of hyperbilirubinemia. As more results from clinical evaluation including comparison with postoperative liver function data become available, image-based liver function tests, especially with use of Gd-EOB as the contrast medium, have the potential to add another dimension to preoperative imaging. KEY POINTS: Liver function consists of a multitude of subfunctions such as biotransformation, excretion and storage. Global liver function tests are score-based tests such as Child-Pugh or MELD as well as the ICG- and LiMAx-test. Imaging-based liver function tests add spatial information. Current clinical standard is the 99mTc-Mebrofenin-scintigraphy. MRI-based function tests with Gd-EOB-DTPA have the potential to integrate seamlessly into clinical workup, feature a higher temporal and spatial resolution and do not rely on ionizing radiation. PMID- 26230142 TI - Olfactometry Profiles and Quantitation of Volatile Sulfur Compounds of Swiss Tilsit Cheeses. AB - To establish the odor profiles of three differently fabricated commercial Swiss Tilsit cheeses, analyses were conducted using headspace solid-phase microextraction gas chromatography-mass spectrometry/pulsed flame photometric detection and gas chromatography-olfactometry to identify and quantitate volatile compounds. In addition, odor quality and the impact of target sulfur compounds on the overall odor of the cheeses were investigated. The odor profile was found to be mainly influenced by buttery-cheesy and sulfury odor notes in all cheeses. Buttery-cheesy odor notes were attributed to three main molecules: butanoic acid, 3-methylbutanoic acid, and butane-2,3-dione. Over a dozen volatile sulfur compounds were detected at parts per billion levels, but only a few influenced the odor profile of the cheeses: methanethiol, dimethyl disulfide, bis(methylthio)methane, dimethyl trisulfide, 3-(methylthio)propanal, and 2 methyltetrahydrothiophen-3-one (tentative). In conclusion, the conducted analyses allowed differentiation of the cheeses, and gas chromatography-olfactometry results confirmed that partially thermized milk cheese has a more intense and more multifaceted overall flavor. PMID- 26230143 TI - Synthesis of Molecular Wires Strapped by pi-Conjugated Side Chains: Integration of Dehydrobenzo[20]annulene Units. AB - In this study, pi-conjugated molecular wires strapped by cyclic pi-conjugated side chains were efficiently synthesized by the integration of dehydrobenzo[20]annulene units by intramolecular Glaser-type cyclization under high dilution conditions. PMID- 26230144 TI - Broad-Band N(?)N Pt(II) Bisacetylide Visible Light Harvesting Complex with Heteroleptic Bodipy Acetylide Ligands. AB - Pt(II) dbbpy bisacetylide (dbbpy = 4,4'-di(tert-butyl)-2,2'-bipyridine) complex (Pt-1) with two different Bodipy ligands was prepared with the goal to attain broad-band visible light absorbing, efficient funneling of the photoexcitation energy (via resonance energy transfer, RET) to the energy acceptor and high triplet formation quantum yields. Construction of the above-mentioned molecular structural motif is challenging because two different arylacetylide ligands are incorporated in the complex; normally two homoleptic acetylide ligands were used for this kind of N(?)N Pt(II) complexes. A reference complex with trans bis(tributylphosphine) Pt(II) bisacetylide protocol (Pt-4) was prepared for comparison of the photophysical properties. The two different Bodipy ligands in Pt-1 and Pt-4 constitute singlet/triplet energy donor/acceptor, as a result the harvested photoexcitation energy can be funneled to the triplet state confined on one of the two Bodipy ligands. The photophysical properties of the complexes were studied with steady state UV-vis absorption and luminescence spectroscopies, femto- and nanosecond transient absorption spectroscopies, cyclic voltammetry, as well as DFT/TDDFT calculations. Fluorescence/phosphorescence dual emission were observed for the complex. The ultrafast intramolecular singlet/triplet energy transfer in Pt-1 was confirmed by the transient absorption spectroscopy (kFRET = 2.6 * 10(11) s(-1), PhiFRET = 87.1%) followed by an intersystem crossing (kISC = 1.9 * 10(10) s(-1)), and the triplet state lifetime (tauT) is 54.1 MUs. The reference complex Pt-4 shows drastically different kinetics with kFRET = 6.9 * 10(10) s(-1), PhiFRET = 81.0%, kISC = 5.83 * 10(9) s(-1), and tauT = 147.9 MUs. Different singlet oxygen ((1)O2) quantum yields (PhiDelta = 75% and 70%) and triplet state quantum yields (PhiT = 91% and 69%, respectively) were observed for complexes Pt-1 and Pt-4. PMID- 26230145 TI - Heteroclitic Peptides Increase Proliferation and Reduce Evidence of Human Immunodeficiency Virus-Specific CD8+ T Cell Dysfunction. AB - Human immunodeficiency virus (HIV)-specific CD8(+) T cell dysfunction parallels disease progression; therefore, restoring potent HIV-specific CD8(+) T cell responses is a key therapeutic goal. Certain CD8(+) T cell peptide epitope variants, termed heteroclitic, enhance cytokine production by the HIV-specific CD8(+) T cells of some individuals. In this study, we investigated whether heteroclitic peptides that enhance cytokine production by HIV-specific CD8(+) T cells also reduce functional and phenotypic evidence of HIV-specific CD8(+) T cell exhaustion in those instances. Twenty-four variant peptides of human histocompatibility-linked leukocyte antigen (HLA)-A2-restricted reference HIV peptide epitopes designated as A2-7; Nef 83->91, A2-8; Nef 135->143, A2-Gag; Gag 77->85 and A2-9; Gag 433->440 were synthesized with conservative and semiconservative amino acid substitutions at positions 3, 5, and 7 or 3, 5, and 8 of Gag 433->440. Variants that enhanced interferon-gamma (IFN-gamma) and/or interleukin-2 (IL-2) production in enzyme-linked immunospot assays (29 cases overall) were subsequently tested by 7-day in vitro peptide stimulation for their effects on HIV-specific CD8(+) T cell proliferation and programmed death-1 (PD-1) expression. Heteroclitic variants enhanced HIV-specific CD8(+) T cell proliferation by >20% in 13/29 cases tested, reduced PD-1 expression on proliferating cells by 15-50% in 10 cases, and reduced PD-1 expression on proliferating cells by >50% in 3 cases. In five cases, the same heteroclitic peptide increased proliferation by >20% and reduced PD-1 expression by >15%. These data demonstrate that heteroclitic peptides can alter the magnitude and character of HIV-specific CD8(+) cell responses relative to reference peptides and may have a unique immunotherapeutic value in therapeutic vaccines. PMID- 26230146 TI - Autotetraploid Pacific oysters (Crassostrea gigas) obtained using normal diploid eggs: induction and impact on cytogenetic stability. AB - We describe two methods of producing viable and fertile autotetraploid Pacific oyster (Crassostrea gigas Thunberg) based on the use of normal-sized oocytes produced by normal diploid females. Our methods showed that the oocyte size is not a limiting factor for the success of the induction to autotetraploidy. These methods offer means of direct introgression of genetic progress from elite diploid lines to tetraploids used as broodstock, avoiding a triploid step with the risk of transferring undesirable traits from highly fecund triploids. High variability in the level of cytogenetic stability was found among the different tetraploid oysters tested, showing that induction method has an important impact on the long-term cytogenetic stability of the tetraploids. It appears that induction method based on the use of triploid females induces a greater cytogenetic instability among tetraploids so obtained, and this compared to tetraploids originating from the two methods described in our present study. As the aneuploidies and reversions observed in tetraploids can have serious consequences for the sustainability of tetraploid broodstock itself, as well as their triploid offspring, the two tetraploid induction methods described in the present work offer means to produce tetraploids with optimal cytogenetic, genetic, and zootechnical performances. PMID- 26230147 TI - Blood pressure monitoring during exercise: Comparison of pulse transit time and volume clamp methods. AB - During physical exercise, pulse transit time (PTT), expressed as the interval between ventricular electrical activity and peripheral pulse wave, may provide a surrogate estimate for blood pressure by the use of specific calibration procedures. The objective of this study was to determine systolic blood pressure (SBP) values derived from the PTT method and from an established method of non invasive continuous blood pressure measurement based on the volume clamp technique, and to compare their agreement with sphygmomanometry during exercise tests. In 18 subjects, electrocardiogram (ECG) and finger-photoplethysmography were continuously recorded during maximal cycle exercise tests. Intermittent and continuous blood pressure measurements were simultaneously taken using automated sphygmomanometry and a Portapres Model-2 device, respectively. PTT was calculated for each ECG R-wave and the corresponding steepest upstroke slope in the photoplethysmogram, and was transformed to a continuous blood pressure estimate using multipoint nonlinear regression calibration based on the individual subject's sphygmomanometer readings. Bland-Altman limits of agreement between PTT derived SBP estimates and sphygmomanometer values were -24.7 to 24.1 mmHg, and between Portapres and sphygmomanometer SBP values were -42.0 to 70.1 mmHg. For beat-to-beat SBP estimation during exercise, PTT measurement combined with multipoint nonlinear regression calibration based on intermittent sphygmomanometry may be an alternative to volume clamp devices. PMID- 26230148 TI - Extracorporeal life support in the treatment of colchicine poisoning. AB - CONTEXT: Ingestions of Colchicum autumnale may lead to severe poisoning. It begins with gastrointestinal symptoms and leukocytosis, followed by multi-organ failure with shock and a possible late recovery phase. Mortality is highly dependent on the ingested dose. We report a case of accidental C. autumnale poisoning with refractory cardiogenic shock and eventual survival after extracorporeal life support (ECLS). CASE DETAILS: A 68-year-old woman was admitted to the intensive care unit (ICU) on day 3 after ingestion of C. autumnale in a meal. She first suffered from nausea and vomiting leading to severe dehydration. She then developed multi-organ failure and refractory cardiogenic shock, with a mean arterial pressure nadir of 50 mmHg despite high doses of catecholamines and a left ventricular ejection fraction at 5-10%. Venous arterial ECLS was therefore started at an initial rate of 3.5 L/min and 3,800 rev/min. Her symptoms also included pancytopenia on day 4 with diffuse bleeding requiring iterative blood product transfusion. Platelet and leukocyte count nadirs were 13 * 10(9)/L (normal range: 150-400 * 10(9)/L) and 0.77 * 10(9)/L (normal range: 4.2-10.7 * 10(9)/L), respectively. ECLS allowed good cardiac contractility recovery within a few days, with complications including bleeding made controllable. Indeed, because of hemostasis disorders, the patient presented hemoptysis and hematuria. She was treated with tranexamic acid and transfused with blood products. She received 15 erythrocyte concentrates, 13 platelet concentrates, and 7 fresh frozen plasma. ECLS was removed by day 10, with subsequent weaning from mechanical ventilation as well as from hemodialysis in the following days. DISCUSSION: This patient survives after the use of ECLS in Colchicum poisoning, with controllable complications. Thus, ECLS might be indicated to overcome the potentially refractory cardiogenic shock phase. PMID- 26230149 TI - Prognostication of Mortality and Long term Functional Outcomes Following Traumatic Brain Injury: Can We Do Better? AB - Accurate prognostication of outcomes following traumatic brain injury (TBI) affects not only the aggressiveness of intervention and therapeutic decision making, but also the clinicians' ability to provide reliable expectations. To investigate the relative ability of clinicians to accurately predict a patient's outcomes when compared to point of care prognostic models, we surveyed clinical providers of 86 patients with moderate-severe TBI at admission, day 3, and day 7 post-injury for a patient's predicted functional outcome at six months and mortality. The predicted mortality and functional outcomes were compared to actual occurrence of 14 day mortality and functional outcomes at six months. A prognostic score was then calculated utilizing the Corticoid Randomization After Significant Head Injury (CRASH) and International Mission on Prognosis and Analysis of Clinical Trials (IMPACT) models and categorized as high, intermediate, and low likelihood of mortality or poor functional outcome and compared to clinical predictions. Overall, clinicians of varying backgrounds showed an accurate prediction of survival (87.2-97.4%) but struggled in prognosticating poor functional outcomes (24.3-36.6%). These values did not statistically improve over 7 days. Stratified CRASH (87.2%) and IMPACT (84.9%) accuracy rates were statistically better than clinical judgment alone in predicting functional outcomes (p<0.0001). Prognostic models calculated at admission showed to be potentially useful in conjunction with clinical judgment in accurately predicting both survival and six month functional outcomes. PMID- 26230151 TI - On the adaptive function of children's and adults' false memories. AB - Recent research has shown that memory illusions can successfully prime both children's and adults' performance on complex, insight-based problems (compound remote associates tasks or CRATs). The current research aimed to clarify the locus of these priming effects. Like before, Deese-Roediger-McDermott (DRM) lists were selected to prime subsequent CRATs such that the critical lures were also the solution words to a subset of the CRATs participants attempted to solve. Unique to the present research, recognition memory tests were used and participants were either primed during the list study phase, during the memory test phase, or both. Across two experiments, primed problems were solved more frequently and significantly faster than unprimed problems. Moreover, when participants were primed during the list study phase, subsequent solution times and rates were considerably superior to those produced by those participants who were simply primed at test. Together, these are the first results to show that false-memory priming during encoding facilitates problem-solving in both children and adults. PMID- 26230153 TI - Phytochemical constituents from the florets of tiger grass Thysanolaena latifolia from Nepal. AB - Phytochemical investigation on the florets of Thysanolaena latifolia leads to the isolation of a new compound 6"-O-acetylorientin-2"-O-alpha-L-rhamnopyranoside (1), named amrisoside and other 34 known compounds. The chemical structures of the compounds were determined from the interpretation of spectroscopic data including NMR, MS, and IR. This is the first report of phytochemical constituents from the monotypic genus Thysanolaena. PMID- 26230152 TI - A commensal symbiotic factor derived from Bacteroides fragilis promotes human CD39(+)Foxp3(+) T cells and Treg function. AB - Polysaccharide A (PSA) derived from the human commensal Bacteroides fragilis is a symbiosis factor that stimulates immunologic development within mammalian hosts. PSA rebalances skewed systemic T helper responses and promotes T regulatory cells (Tregs). However, PSA-mediated induction of Foxp3 in humans has not been reported. In mice, PSA-generated Foxp3(+) Tregs dampen Th17 activity thereby facilitating bacterial intestinal colonization while the increased presence and function of these regulatory cells may guard against pathological organ-specific inflammation in hosts. We herein demonstrate that PSA induces expression of Foxp3 along with CD39 among naive CD4 T cells in vitro while promoting IL-10 secretion. PSA-activated dendritic cells are essential for the mediation of this regulatory response. When cultured with isolated Foxp3(+) Tregs, PSA enriched Foxp3 expression, enhanced the frequency of CD39(+)HLA-DR(+) cells, and increased suppressive function as measured by decreased TNFalpha expression by LPS stimulated monocytes. Our findings are the first to demonstrate in vitro induction of human CD4(+)Foxp3(+) T cells and enhanced suppressive function of circulating Foxp3(+) Tregs by a human commensal bacterial symbiotic factor. Use of PSA for the treatment of human autoimmune diseases, in particular multiple sclerosis and inflammatory bowel disease, may represent a new paradigm in the approach to treating autoimmune disease. PMID- 26230154 TI - Small Cell Carcinoma of the Ovary, Hypercalcemic Type: Report of a Bilateral Case in a Teenager Associated with SMARCA4 Germline Mutation. AB - Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a highly aggressive neoplasm that typically occurs in young females. Paraneoplastic hypercalcemia is associated in two thirds of the cases. Recent studies demonstrated that this rare tumor harbors the same molecular features of malignant rhabdoid tumor secondary to SMARCA4/BRG1 mutations. We illustrate herein a typical bilateral case of SCCOHT with comprehensive molecular characterization in a 14-year-old girl. We also discuss the value of SMARCA4 immunostaining in the diagnostic approach of undifferentiated ovarian and pelvic malignancies. PMID- 26230155 TI - Preparation and drug controlled release of porous octyl-dextran microspheres. AB - In this work, porous octyl-dextran microspheres with excellent properties were prepared by two steps. Firstly, dextran microspheres were synthesized by reversed phase suspension polymerization. Secondly, octyl-dextran microspheres were prepared by the reaction between dextran microspheres and ethylhexyl glycidyl ether and freezing-drying method. Porous structure of microspheres was formed through the interaction between octyl groups and organic solvents. The structure, morphology, dry density, porosity and equilibrium water content of porous octyl dextran microspheres were systematically investigated. The octyl content affected the properties of microspheres. The results showed that the dry density of microspheres decreased from 2.35 to 1.21 g/ml, porosity increased from 80.68 to 95.05% with the octyl content increasing from 0.49 to 2.28 mmol/g. Meanwhile, the equilibrium water content presented a peak value (90.18%) when the octyl content was 2.25 mmol/g. Octyl-dextran microspheres showed high capacity. Naturally drug carriers play an important role in drug-delivery systems for their biodegradability, wide raw materials sources and nontoxicity. Doxorubicin (DOX) was used as a drug model to examine the drug-loading capacity of porous octyl dextran microspheres. The drug-loading efficiency increased with the increase in microspheres/drug ratio, while the encapsulation efficiency decreased. When microspheres/drug mass ratio was 4/1, the drug-loading efficiency and encapsulation efficiency were 10.20 and 51.00%, respectively. The release rate of DOX increased as drug content and porosity increased. In conclusion, porous octyl dextran microspheres were synthesized successfully and have the potential to serve as an effective delivery system in drug controlled release. PMID- 26230156 TI - Introducing RiskSOAP to communicate the distributed situation awareness of a system about safety issues: an application to a robotic system. AB - This paper introduces the RiskSOAP ('RiskSOAP' is the abbreviation for Risk SituatiOn Awareness Provision.) indicator to measure the capability of a complex socio-technical system to provide its agents with situation awareness (SA) about the presence of its threats and vulnerabilities and enables analysts to assess distributed SA. The RiskSOAP methodology adopts a comparative approach between two design versions of a system differing in the elements and characteristics that can enhance or cause the degradation of the awareness provision capability. The methodology uniquely combines three methods: (1) the STPA hazard analysis, (2) the EWaSAP early warning sign identification approach, and (3) a dissimilarity measure for calculating the distance between binary sets. In this paper, the RiskSOAP methodology was applied to a robotic system and the findings show that the indicator is an objective measure for the system's capability to provide its agents with SA about its threats and vulnerabilities. Practitioner Summary: This paper suggests a novel methodology for assessing distributed situation awareness (DSA) regarding safety issues. Given that systems consist of specifications and components possible to be mapped, the risk SA provision capability (RiskSOAP) methodology demonstrates the feasibility of measuring to what extent systems' elements contribute to the emergence of DSA. PMID- 26230157 TI - Serum- and Glucocorticoid-Inducible Kinase 1 Delay the Onset of Endothelial Senescence by Directly Interacting with Human Telomerase Reverse Transcriptase. AB - Endothelial senescence is characteristic of vascular aging. Serum- and glucocorticoid-inducible kinase (SGK)1 belongs to a family of serine/threonine kinases regulated by various external stimuli. SGK1 has been shown to be protective against reactive oxygen species (ROS) production and to be involved in processes regulating aging. However, data on the direct relationship between SGK1 and senescence are sparse. In the present study, we sought to investigate the role of SGK1 in cellular aging by using human umbilical vein endothelial cells (HUVECs) infected with different constructs. Senescence was measured at different cellular stages by senescence-associated beta-galactosidase (SA-beta-gal) activity, human telomerase reverse transcriptase (hTERT) activity, p21 protein levels, and ROS production. HUVECs over-expressing full-length SGK1 (wild-type SGK1 [SGK1WT]) showed a decrease in SA-beta-gal and p21 expression and a corresponding increase in hTERT activity in the early stages of aging. Moreover, SGK1WT presented lower levels of ROS production. A direct interaction between SGK1WT and hTERT was also shown by co-immunoprecipitation. The SGK1Delta60 isoform, lacking the amino-terminal 60 amino acids, did not show interaction with hTERT, suggesting a pivotal role of this protein site for the SGK1 anti-aging function. The results from this study may be of particular importance, because SGK1WT over-expression by activating telomerase and reducing ROS levels may delay the processes of endothelial senescence. PMID- 26230158 TI - Monitoring Protein Capsid Assembly with a Conjugated Polymer Strain Sensor. AB - Semiconducting polymers owe their optoelectronic properties to the delocalized electronic structure along their conjugated backbone. Their spectral features are therefore uniquely sensitive to the conformation of the polymer, where mechanical stretching of the chain leads to distinct vibronic shifts. Here we demonstrate how the optomechanical response of conjugated polyelectrolytes can be used to detect their encapsulation in a protein capsid. Coating of the sensor polymers by recombinant coat proteins induces their stretching due to steric hindrance between the proteins. The resulting mechanical planarizations lead to pronounced shifts in the vibronic spectra, from which the process of capsid formation can be directly quantified. These results show how the coupling between vibronic states and mechanical stresses inherent to conjugated polymers can be used to noninvasively measure strains at the nanoscale. PMID- 26230159 TI - Retrospective assessment of caries experience among US Naval Academy midshipmen. AB - OBJECTIVE: To assess the 4-year caries incidence among US Naval Academy midshipmen. METHODS: Dental records (n = 300) from a total population of 1,016 midshipmen from the 2011 graduating class at US Naval Academy, Annapolis, MD, were randomly selected for review. Patients were assigned a caries risk status based on the number of caries lesions recorded at initial examination (low = 0 lesions; moderate = 1-2 lesions; high = 3+ lesions). For each risk category, caries prevalence (DMFS, DMFT) and caries incidence were calculated based on findings recorded at the initial (E1), third year (E2), and fourth year (E3) examinations. The most significant predictors for caries incidence were determined for each risk category. RESULTS: Mean DMFS and DMFT were significantly different for each risk group at each examination (low < moderate < high; one-way ANOVA, P < 0.05). Within each caries risk category, mean DMFS and DMFT increased significantly from E1 to E3 (repeated measures ANOVA, all P < 0.05). Compared with low-risk patients, total caries incidence was over 2* greater for moderate risk and nearly 4* greater for high-risk patients (one-way ANOVA, P < 0.05). "Filled surfaces" was the most significant predictor for caries incidence among low-risk patients; among high-risk and all risk groups combined, the most significant predictors were "decayed surfaces" and "decayed surfaces plus incipient surfaces" (linear regression; all P < 0.047). CONCLUSIONS: Caries experience was consistently greater for moderate- and high-risk patients at all examinations. The magnitude of increase in caries experience was greater for moderate- and high-risk patients. Caries history and current disease status reliably predict future caries experience in this young adult population. PMID- 26230150 TI - Validation of the 'Test of the Adherence to Inhalers' (TAI) for Asthma and COPD Patients. AB - BACKGROUND: To validate the 'Test of Adherence to Inhalers' (TAI), a 12-item questionnaire designed to assess the adherence to inhalers in patients with COPD or asthma. METHODS: A total of 1009 patients with asthma or COPD participated in a cross-sectional multicenter study. Patients with electronic adherence >=80% were defined as adherents. Construct validity, internal validity, and criterion validity were evaluated. Self-reported adherence was compared with the Morisky Green questionnaire. RESULTS: Factor analysis study demonstrated two factors, factor 1 was coincident with TAI patient domain (items 1 to 10) and factor 2 with TAI health-care professional domain (items 11 and 12). The Cronbach's alpha was 0.860 and the test-retest reliability 0.883. TAI scores correlated with electronic adherence (rho=0.293, p=0.01). According to the best cut-off for 10 items (score 50, area under the ROC curve 0.7), 569 (62.5%) patients were classified as non-adherents. The non-adherence behavior pattern was: erratic 527 (57.9%), deliberate 375 (41.2%), and unwitting 242 (26.6%) patients. As compared to Morisky-Green test, TAI showed better psychometric properties. CONCLUSIONS: The TAI is a reliable and homogeneous questionnaire to identify easily non adherence and to classify from a clinical perspective the barriers related to the use of inhalers in asthma and COPD. PMID- 26230160 TI - Strategies for Success: Publishing Doctoral Work. PMID- 26230161 TI - Nursing Students' Qualitative Experiences in the Medical-Surgical Clinical Learning Environment: A Cross-Cultural Integrative Review. AB - BACKGROUND: The nature of the clinical learning environment has a huge impact on student learning. For instance, research has supported the idea that a positive learning environment increases student learning. Therefore, the ability to gain information from the student perspective about the learning environment is essential to nursing education. METHOD: This article reviews qualitative research on nursing students' experiences of the clinical learning environment. The significance of the issue, the purpose of the integrative review, the methods used in the literature search, and the results of the review are presented. RESULTS: Seventeen studies from 12 countries are identified for review, and six common themes are discussed. An exhaustive literature review revealed that among the 17 articles evaluated, six themes were common. CONCLUSION: The findings indicate the need to continue quality improvement to advance clinical education. PMID- 26230162 TI - Preceptorship and the Nurse Practitioner Student: Navigating the Liminal Space. AB - BACKGROUND: The purpose of this study was to explore the process occurring in preceptorship to prepare nurse practitioner students for their future role in professional practice. The researchers examined this process through the eyes of the preceptors, nurse practitioner students, and faculty. METHOD: A grounded theory method was used to explore the process involved in preceptorship to prepare nurse practitioner students in the clinical setting. RESULTS: The process of navigating the liminal space emerged from the data to explain what actually was occurring throughout the nurse practitioner student preceptorship. This process was reflected on three levels: (a) positioning in preceptorship, (b) repositioning on the threshold of nurse practitioner, and (c) embracing the new nurse practitioner role. CONCLUSION: As the data emerged, the researchers uncovered a multidimensional process that was occurring in preceptorship. This process was identified as navigating the liminal space. PMID- 26230163 TI - Resilience in Nursing Education: An Integrative Review. AB - BACKGROUND: Resilience is a phenomenon known to buffer the negative effects of stress. Resilience is important in the lives of nursing students and nurse educators. METHOD: An integrative literature review was conducted to explore the current state of knowledge of resilience in the context of nursing education. Implications from the review findings were deduced for nursing education practice and research. RESULTS: Three theoretical papers and 16 empirical reports were included in the review. Three themes emerged from the analysis: (a) Resilience Is Important in Nursing Education, (b) Resilience Is Conceptualized as Either a Trait or a Process, and (c) Resilience Is Related to Protective Factors. CONCLUSION: The findings provide data to support interventions to enhance the resilience of nursing students and nurse educators and offer a foundation for further research of resilience in nursing education. PMID- 26230164 TI - Ostomate-for-a-Day: A Novel Pedagogy for Teaching Ostomy Care to Baccalaureate Nursing Students. AB - BACKGROUND: The literature describing successful pedagogies for teaching ostomy care to baccalaureate nursing students is limited. This qualitative study investigated the potential benefits of participating in an immersive simulation that allowed baccalaureate nursing students to explore the physical and psychosocial impact of ostomy surgery. METHOD: Junior-level nursing students attended a 2-hour interactive session during which they learned about preoperative stoma site marking and practiced the maneuvers on a peer. Students then wore an ostomy appliance for the next 24 hours, completed tasks simulating ostomy self-care, and submitted a three- to four-page reflection on the experience. These data were coded using the iterative process of constant comparison described by Glaser. RESULTS: Six major themes were identified: Accommodation for Activities of Daily Living, Coping with Annoyances, Body Image and Feelings, Disclosure, Insights for Teaching, and Empathy. CONCLUSION: Each participant affirmed the value of the experience. Suggestions for future research studies are discussed. PMID- 26230165 TI - The Nature of Clinical Judgment Development in Reflective Journals. AB - BACKGROUND: Evaluating the development of clinical judgment after high-fidelity simulation (HFS) scenarios is essential for nurse educators to ensure that prelicensure nursing students are meeting course and curriculum outcomes. METHOD: This qualitative, interpretive description study reviewed the reflective journals of 30 prelicensure nursing students who participated in four progressive HFS scenarios during a medical-surgical nursing course to determine their levels of clinical judgment, using Lasater's Clinical Judgment Rubric (LCJR). RESULTS: Within journal one, 172 comments were identified as either beginning or developing in clinical judgment, whereas 52 comments were identified as such within journal four. In journal one, 65 comments were identified as accomplished or exemplary in clinical judgment, whereas 170 comments were identified as such within journal four. CONCLUSION: This study indicated that evaluating reflective journals using the LCJR is an effective method for ensuring that course and curriculum outcomes are met after prelicensure nursing students participate in HFS scenarios. PMID- 26230166 TI - Critical Thinking and the Use of Nontraditional Instructional Methodologies. AB - BACKGROUND: The purpose of this study was to examine the relationship between critical thinking and the use of concept mapping (CM) and problem-based learning (PBL) during care plan development. METHOD: A quasi-experimental study with a pretest-posttest design was conducted using a convenience sample (n = 49) of first-semester undergraduate baccalaureate nursing students. Critical thinking was measured using the Holistic Critical Thinking Scoring Rubric. Data analysis consisted of a repeated measures analysis of variance with post hoc mean comparison tests using the Bonferroni method. RESULTS: Findings indicated that mean critical thinking at phase 4 (CM and PBL) was significantly higher, compared with phase 1 (baseline), phase 2 (PBL), and phase 3 (CM [p < 0.001]). CONCLUSION: The results support the utilization of nontraditional instructional (CM and PBL) methodologies in undergraduate nursing curricula. PMID- 26230167 TI - Collaborative Clinical Placements: Interactions Among Students From Different Programs. AB - BACKGROUND: Shortages of clinical placements for health care students in Canada have led education and health care organizations to explore innovative ways to increase placement capacity. One way to increase capacity is to bring together students from various programs for their placements, which also allows students to learn about each other's roles and how to work collaboratively. This article describes shared placements for students from bachelor of nursing, practical nurse, and health care aide programs. METHOD: Qualitative interviews were used. RESULTS: Students benefited from this approach by learning about the roles of other providers and how to coordinate care with others. The challenges of the approach were competition among students for opportunities to practice clinical procedures and concerns about how to communicate with other students when sharing the care of patients. CONCLUSION: The objectives of increasing student placement capacity and expanding collaboration opportunities were partially achieved through this approach to clinical education. PMID- 26230168 TI - Emotional Intelligence and Health Risk Behaviors in Nursing Students. AB - BACKGROUND: To explore the association between emotional intelligence (EI) and risky health behaviors in nursing students at the University of Oviedo (Spain). METHOD: This cross-sectional study of 275 students used a validated questionnaire to measure EI level, nine risky behaviors (smoking, excessive alcohol consumption, illicit drug use, unhealthy diet, being overweight, sedentarism, risky sun exposure, occupational risk, and unsafe sex), and other factors that may influence EI. RESULTS: Students with the highest EI score had a lower probability of drinking too much alcohol (odds ratio [OR], 0.31; 95% confidence interval [CI] [0.19, 0.67]), eating too few fruits and vegetables (OR, 0.60; 95% CI [0.34, 0.99]), and having unsafe sex (OR, 0.10; 95% CI [0.01, 0.74]). A dose response effect was found for those three behaviors (p for trend <0.02). CONCLUSION: Poor EI is associated with excessive alcohol consumption, unhealthy diet, and unsafe sex. Training nursing students about EI could improve health behaviors, and thus the role of nurses as health promoters. PMID- 26230169 TI - Using Simulation to Promote Professional Development of Clinical Instructors. AB - BACKGROUND: Clinical instructors play an important role in the education of nursing students. Nursing faculty must provide orientation and support for clinical instructors to ensure quality clinical experiences for students. Simulation can be used as a teaching strategy to prepare clinical instructors for clinical teaching. The purpose of this article is to describe the use of simulation to prepare clinical instructors in the role of teaching and increase confidence to provide clinical education to students. METHOD: Clinical instructors attended an orientation program that included simulation. During the simulation, nursing student volunteers role-played situations that required instructors to intervene for patient safety. Following the simulation, clinical instructors completed an online survey to measure confidence in teaching students. RESULTS: Twenty-six clinical instructors participated in the simulation with student volunteers and completed the survey. CONCLUSION: Clinical instructors thought the simulation prepared them for clinical teaching, increased their confidence, and assisted them to provide student feedback. PMID- 26230170 TI - Student-Led Clinical Orientation. PMID- 26230171 TI - Developmental thermal plasticity among Drosophila melanogaster populations. AB - Many biotic and abiotic variables influence the dispersal and distribution of organisms. Temperature has a major role in determining these patterns because it changes daily, seasonally and spatially, and these fluctuations have a significant impact on an organism's behaviour and fitness. Most ecologically relevant phenotypes that are adaptive are also complex and thus they are influenced by many underlying loci that interact with the environment. In this study, we quantified the degree of thermal phenotypic plasticity within and among populations by measuring chill-coma recovery times of lines reared from egg to adult at two different environmental temperatures. We used sixty genotypes from six natural populations of Drosophila melanogaster sampled along a latitudinal gradient in South America. We found significant variation in thermal plasticity both within and among populations. All populations exhibit a cold acclimation response, with flies reared at lower temperatures having increased resistance to cold. We tested a series of environmental parameters against the variation in population mean thermal plasticity and discovered the mean thermal plasticity was significantly correlated with altitude of origin of the population. Pairing our data with previous experiments on viability fitness assays in the same populations in fixed and variable environments suggests an adaptive role of this thermal plasticity in variable laboratory environments. Altogether, these data demonstrate abundant variation in adaptive thermal plasticity within and among populations. PMID- 26230172 TI - Comparison of automatic versus manual procedures for the quantification of dopamine D2 receptor availability using I-123-IBZM-SPECT. AB - INTRODUCTION: I-123-IBZM-SPECT is often used to differentiate between idiopathic Parkinson's syndrome and atypical parkinsonian syndromes. The aim of this study was to compare three different procedures to quantify the receptor availability of striatal dopamine D2 receptors. (a) Manual quantification performed using individually adjusted volume of interests sets (mVoi). (b) Automatic quantification applying the commercially available Hermes BRASS software (BRASS). (c) Automatic quantification applying the open-source software IBZM Toolbox (TBX). MATERIALS AND METHODS: Using the three methods, we analyzed 100 scans. For the mVOI methods, three different investigators (two experienced, one inexperienced) carried out the analysis. We compared the different methods with each other and with the reference standard established by clinical follow-up. The diagnostic performance was assessed by calculating receiver-operating characteristic (ROC) curves. RESULTS: Correlation analyses resulted in the following: mVOI versus BRASS (r=0.694) (P<0.005), mVOI versus TBX (r=0.557) (P<0.005); BRASS versus TBX (r=0.466) (P<0.005). We found a fair agreement for mVOI versus BRASS; slight agreement for mVOI versus TBX; and fair agreement for BRASS versus TBX. Moreover, we found a substantial agreement between the experienced investigators, but not with the inexperienced investigator in the case of mVOI. The ROC analysis shows the largest area under the ROC curve (Az=0.7295) for mVOI, followed by BRASS (Az=0.709) and TBX (Az=0.627). CONCLUSION: In direct comparison, the manual quantification used by experienced observers shows the best results, although it does not differ significantly from the commercial Hermes BRASS software. Both are superior to TBX. PMID- 26230173 TI - Multiple Pregnancies. Foreword. PMID- 26230177 TI - Relative absence of studies in bipolar depression. PMID- 26230182 TI - Heart rate and oxygen demand of powered exoskeleton-assisted walking in persons with paraplegia. AB - Historically, persons with paralysis have limited options for overground ambulation. Recently, powered exoskeletons have become available, which are systems that translate the user's body movements to activate motors to move the lower limbs through a predetermined gait pattern. As part of an ongoing clinical study (NCT01454570), eight nonambulatory persons with paraplegia were trained to ambulate with a powered exoskeleton. Measurements of oxygen uptake (VO2) and heart rate (HR) were recorded for 6 min each during each maneuver while sitting, standing, and walking. The average value of VO2 during walking (11.2 +/- 1.7 mL/kg/min) was significantly higher than those for sitting and standing (3.5 +/- 0.4 and 4.3 +/- 0.9 mL/kg/min, respectively; p < 0.001). The HR response during walking was significantly greater than that of either sitting or standing (118 +/ 21vs 70 +/- 10 and 81 +/- 12 beats per minute, respectively: p < 0.001). Persons with paraplegia were able to ambulate efficiently using the powered exoskeleton for overground ambulation, providing potential for functional gain and improved fitness. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT01454570; "The ReWalk Exoskeletal Walking System for Persons with Paraplegia (VA_ReWalk)"; https://clinicaltrials.gov/ct2/show/NCT01454570. PMID- 26230184 TI - Erratum: "A Hard Nut to Crack: Reducing Chemical Migration in Food-Contact Materials". PMID- 26230183 TI - Substrate Temperature to Control Moduli and Water Uptake in Thin Films of Vapor Deposited N,N'-Di(1-naphthyl)-N,N'-diphenyl-(1,1'-biphenyl)-4,4'-diamine (NPD). AB - Ultrastable glasses are generated by vapor deposition on substrates heated near the glass transition temperature (Tg), but it is unclear if the remarkable properties of such glasses are present in ultrathin (<100 nm) films. Here, we demonstrate that the moduli of 50 nm thick N,N'-di(1-naphthyl)-N,N'-diphenyl (1,1'-biphenyl)-4,4'-diamine (NPD) film can be increased from 1.5 to 2.5 GPa by simply increasing the temperature of the substrate during deposition with a maximum in modulus found at T/Tg = 0.94. This maximum in modulus is the same modulus obtained for very thin (<15 nm) NPD films deposited at 295 K (T/Tg = 0.80). However, the modulus of films deposited at this lower temperature abruptly decreases to approximately 1.5 GPa for thicker films; the modulus from deposition at T/Tg = 0.94 is thickness independent. In addition to the thin film modulus, the substrate temperature significantly impacts the water uptake in NPD films. From QCM, the volume fraction of water at equilibrium with nearly saturated water vapor decreases from nearly 4% to less than 1% as the substrate temperature increases from T/Tg = 0.82 to T/Tg = 0.93. The substrate temperature provides a simple route to control mechanical properties and water uptake into vapor deposited NPD, and these concepts are likely extendable to other organic electronic materials; the increased moduli and decreased water uptake could enable improved performance and lifetime of small molecule glasses for a variety of organic electronic applications. PMID- 26230185 TI - Organic Anion Transporter 5 (Oat5) Urinary Excretion Is a Specific Biomarker of Kidney Injury: Evaluation of Urinary Excretion of Exosomal Oat5 after N Acetylcysteine Prevention of Cisplatin Induced Nephrotoxicity. AB - Cisplatin is a commonly used chemotherapeutic agent. Its main side-effect is nephrotoxicity. It was reported that the organic anion transporter 5 (Oat5) urinary excretion is elevated, implying renal perturbation, when no modifications of traditional markers of renal damage are still observed in cisplatin-induced acute kidney injury (AKI). It was also demonstrated that Oat5 is excreted in urine by the exosomal pathway. This study was designated to demonstrate the specific response of the urinary excretion of exosomal Oat5 to kidney injury independently of other cisplatin toxic effects, in order to strengthen Oat5 urinary levels as a specific biomarker of AKI. To accomplish that aim, we evaluated if urinary excretion of exosomal Oat5 returns to its basal levels when cisplatin renal damage is prevented by the coadministration of the renoprotective compound N-acetylcysteine. Four days after cisplatin administration, AKI was induced in cisplatin-treated male Wistar rats (Cis group), as it was corroborated by increased urea and creatinine plasma levels. Tubular damage was also observed. In cotreated animals (Cis + NAC group), plasma urea and creatinine concentrations tended to return to their basal values, and tubular damage was improved. Urinary excretion of exosomal Oat5 was notably increased in the Cis group, but when renal injury was ameliorated by N-acetylcysteine coadministration, that increase was undetected. So, in this work we observed that urinary excretion of exosomal Oat5 was only increased if renal insult is produced, demonstrating its specificity as a renal injury biomarker. PMID- 26230186 TI - Adenocarcinoma of the gastrointestinal tract in lung transplanted patients with cystic fibrosis: case series and review of the literature. AB - Cystic fibrosis (CF) is one of the most common genetic disorders. Mutations of the cystic fibrosis transmembrane regulator causes dysfunction of epithelial membranes within the gastrointestinal and respiratory system. Patients with CF are known to be at risk for gastrointestinal malignancies, and lung transplantation further increases this risk. We report a case series of three CF patients who developed adenocarcinoma of the gastrointestinal tract in the posttransplant setting. One of these case histories describes a gastric cancer, which is a novel and to date unreported observation. These data emphasise the importance of checking CF patients for the development of abdominal complications following lung transplantation. PMID- 26230188 TI - Quantitative analysis of 3-OHB[a]P and (+)-anti-BPDE as biomarkers of B[a]P exposure in rats. AB - The aim of this study was to develop an analytical method for the determination the levels of metabolites of benzo[a]pyrene (B[a]P), 3-hydroxybenzo(a)pyrene (3 OHB[a]P) and (+)-anti-benzo(a)pyrene diol-epoxide [(+)-anti-BPDE, combined with DNA to form adducts], in rat blood and tissues exposed to B[a]P exposure by high performance liquid chromatography with fluorescence detection (HPLC/FD), and to investigate the usefulness of 3-OHB[a]P and (+)-anti-BPDE as markers of intragastrical exposure to B[a]P in rats. The levels of 3-OH-B[a]P and B[a]P tetrol I-1 released after acid hydrolysis of (+)-anti-BPDE in the samples were measured by HPLC/FD. The calibration curves were linear (r(2) > 0.9904), and the lower limit of quantification ranged from 0.34 to 0.45 ng/mL for 3-OHB[a]P and from 0.43 to 0.58 ng/mL for (+)-anti-BPDE. The intra- and inter-day stability assay data suggested that the method is accurate and precise. The recoveries of 3 OHB[a]P and (+)-anti-BPDE were in the ranges of 73.6 +/- 5.0 to 116.5 +/- 6.3% and 73.3 +/- 8.5 to 141.2 +/- 13.8%, respectively. A positive correlation was found between the concentration of intragastrical B[a]P and the concentrations of 3-OH-B[a]P and (+)-anti-BPDE in the blood and in most of the tissues studied, except for the brain and kidney, which showed no correlation between B[a]P and 3 OHB[a]P and between B[a]P and (+)-anti-BPDE, respectively. A sensitive, reliable and rapid HPLC/FD was developed and validated for analysis of 3-OHB[a]P and (+) anti-BPDE in rat blood and tissues. There was a positive correlation between the concentration of 3-OHB[a]P or (+)-anti-BPDE in the blood and the concentration of 3-OHB[a]P or (+)-anti-BPDE in the most other tissues examined. The concentration of 3-OHB[a]P or (+)-anti-BPDE in the blood could be used as an indicator of the concentration of 3-OHB[a]P or (+)-anti-BPDE in the other tissues in response to B[a]P exposure. These results demonstrate that 3-OHB[a]P and (+)-anti-BPDE are potential biomarkers of B[a]P exposure, which would also be useful to assess the carcinogenic risks from B[a]P exposure. PMID- 26230187 TI - Uncommon BRAF mutations in the follicular variant of thyroid papillary carcinoma: New insights. AB - BACKGROUND: Mutational analysis is reshaping the practice of fine-needle aspiration cytology for the diagnosis of thyroid nodules. The v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) valine (V) to glutamic acid (E) substitution at codon 600 (BRAF(V600E)) is the most effective diagnostic/prognostic marker and is used mainly for papillary thyroid carcinomas (PTCs). Although BRAF(V600E) represents 95% of all BRAF mutations, uncommon BRAF mutations have been identified in thyroid carcinomas. For the current study, the authors evaluated morphologic (plump pink cells and sickle-shaped nuclei) anti BRAF(V600E) antibody (VE1) immunocytochemical and molecular findings of BRAF mutations in PTCs and in the follicular variant of PTC (FVPC). METHODS: Between January 2013 and June 2014, there were 150 cytologic samples with surgical follow up at the authors' institution. BRAF mutations, which were identified using liquid-based cytology, were classified into wild-type BRAF, BRAF(V600E), and uncommon BRAF mutations. All clinicopathologic correlations between BRAF and FVPCs were analyzed. RESULTS: Forty-four of 150 samples were identified as benign histologic lesions, and the authors focused on the 106 cytologic samples from patients who had malignant outcomes (60 PTCs and 46 FVPCs). The series included 16 follicular neoplasms, 36 samples diagnosed as suspicious of malignancy, and 54 samples diagnosed as positive for malignancy. The BRAF(V600E) mutation was detected in 17.4% of FVPCs and in 66.6% of PTCs, whereas uncommon BRAF mutations were detected only in FVPCs. Plump pink cells and VE1 expression were not identified in samples that had uncommon BRAF mutations. VE1 immunocytochemistry yielded positive results in all 36 samples that had the BRAF(V600E) mutation. CONCLUSIONS: Uncommon BRAF mutations were observed only in FVPCs and were linked to less aggressive behavior. Negative/weak VE1 expression was observed in both wild-type and uncommon BRAF mutations. The current investigation did not reveal any plump cells or morphologic BRAF findings in samples that had uncommon BRAF mutations. In the authors' experience, BRAF mutations detected by DNA methods were more accurate in identifying FVPCs. PMID- 26230189 TI - A divergent enantioselective strategy for the synthesis of griseusins. AB - The first enantioselective total synthesis of griseusin A, griseusin C, 4' deacetyl-griseusin A, and two non-native counterparts in 11-14 steps is reported. This strategy highlights a key hydroxy-directed C?H olefination of 1-methylene isochroman with an alpha,beta-unsaturated ketone followed by subsequent stereoselective epoxidation and regioselective cyclization to afford the signature tetrahydro-spiropyran ring. Colorectal cancer cell cytotoxicities of the final products highlight the impact of the griseusin tetrahydro-spiropyran ring on bioactivity. As the first divergent enantioselective synthesis, the strategy put forth sets the stage for further griseusin mechanism-of-action and SAR studies. PMID- 26230190 TI - Recognition of Artificial Nucleobases by E. coli Purine Nucleoside Phosphorylase versus its Ser90Ala Mutant in the Synthesis of Base-Modified Nucleosides. AB - A wide range of natural purine analogues was used as probe to assess the mechanism of recognition by the wild-type (WT) E. coli purine nucleoside phosphorylase (PNP) versus its Ser90Ala mutant. The results were analyzed from viewpoint of the role of the Ser90 residue and the structural features of the bases. It was found that the Ser90 residue of the PNP 1) plays an important role in the binding and activation of 8-aza-7-deazapurines in the synthesis of their nucleosides, 2) participates in the binding of alpha-D-pentofuranose-1-phosphates at the catalytic site of the PNP, and 3) catalyzes the dephosphorylation of intermediary formed 2-deoxy-alpha-D-ribofuranose-1-phosphate in the trans-2 deoxyribosylation reaction. 5-Aza-7-deazaguanine manifested excellent substrate activity for both enzymes, 8-amino-7-thiaguanine and 2-aminobenzothiazole showed no substrate activity for both enzymes. On the contrary, the 2-amino derivatives of benzimidazole and benzoxazole are substrates and are converted into the N1- and unusual N2-glycosides, respectively. 9-Deaza-5-iodoxanthine showed moderate inhibitory activity of the WT E. coli PNP, whereas 9-deazaxanthine and its 2' deoxyriboside are weak inhibitors. PMID- 26230191 TI - Clinical factors affecting the accuracy of a CT-based active infrared navigation system. AB - BACKGROUND: Computer-assisted navigation technology has been widely used during spine surgery; however, the desired accuracy cannot be easily obtained and sustained. Our goal was to determine whether and how clinical factors affect the accuracy of a CT-based active infrared navigation system. METHODS: Using the Sawbone model, we recorded the clinical accuracy of the navigation system, based on several clinical statuses. RESULTS: Clinical accuracy may change when the height or angle of the bed is changed. Within the visible area of the camera, the nearer the distance between the camera and the model, the better the clinical accuracy. The clinical accuracy of the CT-based active infrared navigation system may decrease due to exposure to shadowless lamps. CONCLUSIONS: The clinical accuracy of the CT-based active infrared navigation system may be influenced by the clinical status of shadowless lamps, different distances between the camera and model and different postures of the surgical bed. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26230192 TI - A Meta-Analysis Examining the Influence of Pro-Eating Disorder Websites on Body Image and Eating Pathology. AB - Previous research has indicated that exposure to pro-eating disorder websites might increase eating pathology; however, the magnitude of this effect is unknown. This study aimed to conduct a systematic review and meta-analysis to examine the effect of exposure to pro-eating disorder websites on body image and eating pathology. Studies examining the relationship between exposure to pro eating disorder websites and eating pathology-related outcomes were included. The systematic review identified nine studies. Findings revealed significant effect sizes of exposure to pro-eating disorder websites on body image dissatisfaction (five studies), d = .41, p = .003; dieting (six studies), d = .68, p < .001, and negative affect (three studies), d = 1.00, p < .001. No effect emerged for bulimic symptoms (four studies), d = .22, p = .73. Findings confirmed the effect of pro-eating disorder websites on body image and eating pathology, highlighting the need for enforceable regulation of these websites. PMID- 26230193 TI - Biochemical and Spectroscopic Studies of Epoxyqueuosine Reductase: A Novel Iron Sulfur Cluster- and Cobalamin-Containing Protein Involved in the Biosynthesis of Queuosine. AB - Queuosine is a hypermodified nucleoside present in the wobble position of tRNAs with a 5'-GUN-3' sequence in their anticodon (His, Asp, Asn, and Tyr). The 7 deazapurine core of the base is synthesized de novo in prokaryotes from guanosine 5'-triphosphate in a series of eight sequential enzymatic transformations, the final three occurring on tRNA. Epoxyqueuosine reductase (QueG) catalyzes the final step in the pathway, which entails the two-electron reduction of epoxyqueuosine to form queuosine. Biochemical analyses reveal that this enzyme requires cobalamin and two [4Fe-4S] clusters for catalysis. Spectroscopic studies show that the cobalamin appears to bind in a base-off conformation, whereby the dimethylbenzimidazole moiety of the cofactor is removed from the coordination sphere of the cobalt but not replaced by an imidazole side chain, which is a hallmark of many cobalamin-dependent enzymes. The bioinformatically identified residues are shown to have a role in modulating the primary coordination sphere of cobalamin. These studies provide the first demonstration of the cofactor requirements for QueG. PMID- 26230196 TI - Inflammation and hypoxia in the kidney: friends or foes? AB - Hypoxic injury is commonly associated with inflammatory-cell infiltration, and inflammation frequently leads to the activation of cellular hypoxia response pathways. The molecular mechanisms underlying this cross-talk during kidney injury are incompletely understood. Yamaguchi and colleagues identify CCAAT/enhancer-binding protein delta as a cytokine- and hypoxia-regulated transcription factor that fine-tunes hypoxia-inducible factor-1 signaling in renal epithelial cells and thus provide a novel molecular link between hypoxia and inflammation in kidney injury. PMID- 26230197 TI - Gluten and IgA nephropathy: you are what you eat? AB - Although extensively studied, the relationship between dietary antigens-in particular, gluten-and IgA nephropathy remains unclear. Using a double transgenic mouse model of IgA nephropathy that expresses both human IgA1 and human CD89, Papista et al. report that a gluten-free diet protects against the development of IgA deposition and glomerular injury, and that these events occur with the introduction of dietary gluten. PMID- 26230198 TI - Peritubular capillaritis in the renal allograft takes center stage. AB - Capillaritis in the renal allograft is important for diagnosis and prognosis. Although glomerulitis has been well studied, peritubular capillaritis has been defined only relatively recently. The finding that peritubular capillaritis severity score and extent may correlate independently with graft outcome mandates further prospective studies to confirm this finding, and to enhance recognition and quantitation of this important lesion. PMID- 26230199 TI - When there will never be a randomized controlled trial. AB - There are many unanswered questions about how to manage secondary hyperparathyroidism and associated alterations in mineral metabolism in patients with end-stage renal disease. We provide commentary on an observational study by Komaba et al. that presents interesting new insights into the long-standing controversy related to the impact of parathyroidectomy on survival of hemodialysis patients. PMID- 26230200 TI - Hepatitis C virus infection and kidney transplantation: newer options and a brighter future ahead? AB - Recent studies including the current article by Sawinski et al. demonstrate that hepatitis C virus (HCV) infection is associated with worse outcomes in kidney transplant recipients with and without HIV infection. We comment on the significance of these findings in the context of newer options for the treatment of HCV infection that have improved efficacy and fewer side effects when administered in both kidney transplant candidates and recipients. PMID- 26230201 TI - The Authors Reply. PMID- 26230202 TI - Changes in skeletal muscle fiber types induced by chronic kidney disease. PMID- 26230203 TI - Regarding long-term risk for kidney donors. PMID- 26230204 TI - The Author Replies. PMID- 26230205 TI - CKD in disadvantaged populations. PMID- 26230206 TI - Giant intragastric sodium polystyrene sulfonate bezoar. PMID- 26230207 TI - Giant multiple bladder diverticula in Williams-Beuren syndrome. PMID- 26230208 TI - Appendiceal tissue confirmation of Fabry's disease. PMID- 26230209 TI - The Case | Elevated lactate and osmolar gap after levothyroxine overdose. PMID- 26230210 TI - The Case | Diarrhea, weight loss, electrolyte abnormalities, and renal failure. PMID- 26230211 TI - Heparanase and heparanase 2 display differently deregulation in neuroendocrine tumors, depending on their differentiation grade. AB - Heparanase is a glucuronidase that appears upregulated in many human cancers and is involved in cellular invasion and tumor metastasis. Heparanase 2 is a homologue of heparanase that lacks enzymatic activity and displays anti metastatic features. The aim of this work was to analyze the expression of both molecules in neuroendocrine tumors. We investigated the transcription of heparanases in lung neuroendocrine tumors well- and poorly differentiated using RT-PCR, and the expresion of the proteins by means of immunohistochemistry. The tumors were selected according to different malignancy WHO 2013 grades and were arranged in tissue arrays. The prometastatic enzyme heparanase appeared overexpressed in well- but not in poorly differentiated tumors, irrespective of their location. Moreover, the anti-metastatic heparanase 2 increased its expression in well-differentiated tumors, but strongly decreased in poorly differentiated ones, again independently of anatomic origin. Given the involvement of both molecules in tumor progression, through both their catalytic and non-enzymatic properties, there would seem to be a relationship between the regulation of their expression and the features of the neuroendocrine tumor. PMID- 26230212 TI - New Umami Amides: Structure-Taste Relationship Studies of Cinnamic Acid Derived Amides and the Natural Occurrence of an Intense Umami Amide in Zanthoxylum piperitum. AB - A series of aromatic amides were synthesized from various acids and amines selected from naturally occurring structural frameworks. These synthetic amides were evaluated for umami taste in comparison with monosodium glutamate. The effect of the substitution pattern of both the acid and the amine parts on umami taste was investigated. The only intensely umami-tasting amides were those made from 3,4-dimethoxycinnamic acid. The amine part was more tolerant to structural changes. Amides bearing an alkyl- or alkoxy-substituted phenylethylamine residue displayed a clean umami taste as 20 ppm solutions in water. Ultraperformance liquid chromatography coupled with a high quadrupole-Orbitrap mass spectrometer (UPLC/MS) was subsequently used to show the natural occurrence of these amides. (E)-3-(3,4-Dimethoxyphenyl)-N-(4-methoxyphenethyl)acrylamide was shown to occur in the roots and stems of Zanthoxylum piperitum, a plant of the family Rutaceae growing in Korea, Japan, and China. PMID- 26230213 TI - Transition-Metal-Free Synthesis of 2-Substituted Methyl Benzo[b]furan-3 carboxylates. AB - A concise and highly efficient synthetic pathway was developed for 2-substituted methyl benzo[b]furan-3-carboxylates. This method provides convenient and cost effective access for 2-substituted methyl benzo[b]furan-3-carboxylates without the use of a transition metal catalyst for synthesis. Furthermore, in most cases, this method gives excellent yields and conventional flash column chromatography is not needed for purification. PMID- 26230214 TI - Theoretical Insight into the Ambiguous Endohedral Metallofullerene Er3C74: Covalent Interactions among Three Lanthanide Atoms. AB - All of C74-based endohedral metallofullerenes (EMFs) are found to be monometallofullerenes with the same D3h(14246)-C74 cage so far. An opening question is whether other C74 cages could survive during the production of some novel C74-EMFs. Theoretically, we studied the trimetallic endohedral fullerene Er3C74, the existence of which had been proven without any further characterizations. Two thermodynamically stable Er3C74 isomers were obtained, both of which could be expressed as Er3@C74, meaning that previously synthesized Er3C74 is indeed an endohedral trierbium fullerene. Besides the isomer with well known D3h(14246)-C74 cage which obeys isolated pentagon rule (IPR), another one possesses the C1(13771)-C74 cage with two adjacent pentagons. Notably, it is the first time an endohedral metallofullerene containing the C1(13771)-C74 cage has been reported. Frontier orbitals analysis, bonding analysis in terms of quantum theory of atoms-in-molecule (QTAIM) and Mayer bond order, together with two dimensional maps of electron localization function (ELF) and Laplacian of electron density of Er3@D3h(14246)-C74 and Er3@C1(13771)-C74 show obvious covalent interactions not only between metallic atoms and carbon cage but also among three erbium atoms. Finally, simulated IR spectra of Er3@D3h(14246)-C74 and Er3@C1(13771)-C74 were simulated, which should be useful to distinguish those two isomers. PMID- 26230216 TI - Mesenchymal stem cells in autism spectrum and neurodevelopmental disorders: pitfalls and potential promises. AB - OBJECTIVES: In this conceptual review, the authors discuss the promises and pitfalls in the use of mesenchymal stem cells as a potential experimental therapeutic for autism spectrum and other neurodevelopmental disorders. METHODS: The relevant literature in autism spectrum disorders and other neurodevelopmental disorders regarding immune dysregulation and neuroinflammation and relevant therapeutics with mesenchymal stem cell infusion is reviewed. The relevant literature pertaining to mesenchymal stem cells and their clinical applications is also reviewed. RESULTS: It is proposed that immune dysregulation and neuroinflammation play a role in the aetiology of autism spectrum disorders. Mesenchymal stem cells have been shown to have immune-modulating capabilities and are neuroprotective. There are three international studies that have utilized mesenchymal stem cell infusions as a treatment for children with autism spectrum disorders, all of which demonstrated improvement in autism rating scale scores, although each study has limitations which are described. CONCLUSIONS: Mesenchymal stem cell transplantation for the treatment of autism spectrum disorders is a novel approach that deserves further investigation, however substantial methodological and theoretical challenges and pitfalls remain before this can be considered a viable therapeutic option. PMID- 26230215 TI - Relationships of local lithium concentrations in drinking water to regional suicide rates in Italy. AB - OBJECTIVES: Higher natural concentrations of lithium in drinking water may be associated with lower local rates of suicide. METHODS: Lithium concentrations in drinking water were assayed by mass spectrometry at 145 sites in Italy, and compared with reported local suicide rates for men and women between 1980 and 2011. RESULTS: Lithium concentrations in drinking water averaged 5.28 [CI: 4.08 6.48] MUg/L (0.761 [0.588-0.934] MUEq/L) and ranged from 0.110 to 60.8 MUg/L (1.58 to 8.76 MUEq/L). Lithium concentrations and local suicide rates were not significantly inversely related, except in 1980-1989, particularly among women. CONCLUSIONS: A proposed association between trace lithium concentrations in drinking water and risk of suicide was only partially supported, and mechanisms for potential clinical effects of trace levels of lithium are unknown. PMID- 26230217 TI - A new sesquiterpenoid quinone with cytotoxicity from Abelmoschus sagittifolius. AB - A new sesquiterpenoid quinone, Acyl hibiscone B (1), together with five known compounds, (R)-lasiodiplodin (2), (R)-de-O-methyllasiodiplodin, (3) dibutyl phthalate (4), (R)-9-phenylnonan-2-ol (5) and hibiscone B (6), was obtained from the stem tuber of Abelmoschus sagittifolius. The structure of compound 1 was elucidated by analysing its (1)H and (13)C NMR, (1)H-(1)H COSY, HSQC, HMBC, NOESY and HR-ESI-MS values. Compound 1 showed significant cytotoxicity against Hela and HepG-2 human cancer cell lines. PMID- 26230218 TI - Repurposing the vaginal tampon for endometrial cancer detection. PMID- 26230219 TI - Acute Alcohol Intoxication in Patients with Mild Traumatic Brain Injury: Characteristics, Recovery, and Outcome. AB - A substantial number of patients (30% to 50%) sustains a mild traumatic brain injury (mTBI) while they are under the influence of alcohol. An acute alcohol intoxication (AAI) at the time of injury has been subject of research in severe TBI, but little is known about the relation between AAI and mTBI. This study aimed to describe the characteristics of this intoxicated subgroup and evaluate recovery and outcome in comparison to sober mTBI patients. We included 528 mTBI patients (Glasgow Coma Scale [GCS] score 13-15) admitted to two Level 1 trauma centers as part of a prospective follow-up study. We compared clinical characteristics, demographics, and injury mechanism between groups. Post concussive complaints, mood disorders, and post-traumatic stress-related complaints were assessed at 2 weeks post-injury, and outcome at 6 months with the Glasgow Outcome Scale Extended (GOSE). Thirty-three percent of the mTBI patients were intoxicated. Results showed that the intoxicated group was younger (36 vs. 40 years; p = 0.001) and were more frequently of male gender (78% vs. 60%; p < .001). The groups also differed in injury related characteristics, with intoxicated patients more frequently sustaining falls or violence-related injuries. The intoxicated group was assessed with a lower GCS score and had a higher hospital admission rate. However, at 2 weeks post-injury, intoxicated patients reported less complaints than the non-alcohol group and showed a better recovery at 6 months (average GOSE scores 7 vs. 7.3; p = 0.030). We conclude that AAI in mTBI represents a characteristically different group, which has implications for prevention measures, as well as the course of recovery. PMID- 26230224 TI - A comparison of methods to determine bilateral asymmetries in vertical leg stiffness. AB - Whilst the measurement and quantification of vertical leg stiffness (Kvert) asymmetry is of important practical relevance to athletic performance, literature investigating bilateral asymmetry in Kvert is limited. Moreover, how the type of task used to assess Kvert may affect the expression of asymmetry has not been properly determined. Twelve healthy males performed three types of performance tasks on a dual force plate system to determine Kvert asymmetries; the tasks were (a) bilateral hopping, (b) bilateral drop jumping and (c) unilateral drop jumping. Across all the three methods, Kvert was significantly different between compliant and stiff limbs (P < 0.001) with a significant interaction effect between limb and method (P = 0.005). Differences in Kvert between compliant and stiff limbs were -5.3% (P < 0.001), -21.8% (P = 0.007) and -15.1% (P < 0.001) for the bilateral hopping, bilateral drop jumping and unilateral drop jumping methods, respectively. All the three methods were able to detect significant differences between compliant and stiff limbs, and could be used as a diagnostic tool to assess Kvert asymmetry. Drop jumping tasks detected larger Kvert asymmetries than hopping, suggesting that asymmetries may be expressed to a greater extent in acyclic, maximal performance tasks. PMID- 26230225 TI - Preparation and phase transition behaviors of temperature-responsive 3-butoxy-2 hydroxypropyl hydroxyethyl celluloses. AB - 2-Hydroxy-3-butoxypropyl hydroxyethyl celluloses (HBPEC), which are thermoresponsive polymers, are prepared by grafting butyl glycidyl ether onto hydroxyethyl cellulose. The effects of several factors on the cloud point (Tc) of the HBPEC are also investigated. The Tc of HBPEC can be tuned to a ranging from 17.0 to 43.0 degrees C by changing the molar substitution of hydrophobic groups. Increasing the concentration of HBPEC leads to a faster phase transition as well as a corresponding linear decrease in the Tc. A series of salts with common anions or cations are used to investigate the effects of specific anions or cations on the Tc of HBPEC aqueous solutions. It is discovered that the Tc of HBPEC is largely influenced by the variation of cation identity and concentration. Plotting Tc as a function of cation activity shows that the Tc can be classified by charge density. PMID- 26230226 TI - Absent Aortic Valve in DiGeorge Syndrome. AB - A 20-week-old fetus with the 22q11.2 deletion characteristic of DiGeorge syndrome is described with vertebral segmentation abnormalities and complex cardiovascular anomalies including an absent aortic valve. This is only the second known case of absent aortic valve in association with DiGeorge syndrome. We discuss the association of absent aortic valve with other conotruncal defects and the utility of fetal echocardiography in the diagnosis of DiGeorge syndrome. PMID- 26230227 TI - Physical Inactivity as a Missing Link in Understanding the Progression of Chronic Obstructive Pulmonary Disease. PMID- 26230228 TI - Hyperinflation: A Potential Target for Treatment of Vascular Disease in Emphysema? PMID- 26230229 TI - Midkine: In the Middle of the Pathogenesis of Acute Respiratory Distress Syndrome associated Lung Fibrosis? PMID- 26230230 TI - Ozone and Respiratory Health. The Story Continues. PMID- 26230231 TI - First among Equals: Nerve Growth Factor in the Pathogenesis of Pulmonary Arterial Hypertension. PMID- 26230232 TI - The Need for More E-Cigarette Data: A Call to Action. PMID- 26230233 TI - Electronic Cigarette Use in Middle and High School Students Triples from 2013 to 2014. PMID- 26230234 TI - Missing the Diagnosis of Brain Death as a Self-Erasing Error. PMID- 26230236 TI - Utility of Endosonographic Mediastinal Lymph Node Staging in Lung Cancer, Withdrawal of Inhaled Steroids in Chronic Obstructive Pulmonary Disease, and Use of Mepolizumab in Severe Eosinophilic Asthma. PMID- 26230235 TI - Update in Lung Cancer 2014. AB - In the past 2 years, lung cancer research and clinical care have advanced significantly. Advancements in the field have improved outcomes and promise to lead to further reductions in deaths from lung cancer, the leading cause of cancer death worldwide. These advances include identification of new molecular targets for personalized targeted therapy, validation of molecular signatures of lung cancer risk in smokers, progress in lung tumor immunotherapy, and implementation of population-based lung cancer screening with chest computed tomography in the United States. In this review, we highlight recent research in these areas and challenges for the future. PMID- 26230237 TI - "Pomegranate" Spleen in Disseminated Tuberculosis. PMID- 26230238 TI - RNA-seq in Pulmonary Medicine: How Much Is Enough? PMID- 26230239 TI - Defects in Plasmacytoid Dendritic Cell Expression of Inducible Costimulator Ligand and IFN-alpha Are Associated in Asthma with Disease Persistence. PMID- 26230240 TI - Functionally Relevant Cut Point for Isometric Quadriceps Muscle Strength in Chronic Respiratory Disease. PMID- 26230241 TI - Sedation Options for Endobronchial Ultrasound-guided Transbronchial Needle Aspiration. PMID- 26230242 TI - Reply: Sedation Options for Endobronchial Ultrasound-guided Transbronchial Needle Aspiration. PMID- 26230243 TI - Mortality Reduction, Overdiagnosis, and the Benefit-to-Harm Ratio of Computed Tomography Screening. PMID- 26230244 TI - Reply: Mortality Reduction, Overdiagnosis, and the Benefit-to-Harm Ratio of Computed Tomography Screening. PMID- 26230245 TI - An Official American Thoracic Society Research Statement: Current Understanding and Future Research Needs in Tobacco Control and Treatment. AB - INTRODUCTION: Since the mid-20th century, the scientific community has substantially improved its understanding of the worldwide tobacco epidemic. Although significant progress has been made, the sheer enormity and scope of the global problem put it on track to take a billion lives this century. Curbing the epidemic will require maximizing the impact of proven tools as well as the development of new, breakthrough methods to help interrupt the spread of nicotine addiction and reduce the downstream morbidity. METHODS: Members of the Tobacco Action Committee of the American Thoracic Society queried bibliographic databases, including Medline, Embase, and the Cochrane Collaborative, to identify primary sources and reviews relevant to the epidemic. Exploded search terms were used to identify evidence, including tobacco, addiction, smoking, cigarettes, nicotine, and smoking cessation. Evidence was consolidated into three thematic areas: (1) determinants of risk, (2) maternal-fetal exposure, and (3) current tobacco users. Expert panel consensus regarding current gaps in understanding and recommendations for future research priorities was generated through iterative discussion. RESULTS: Although much has been accomplished, significant gaps in understanding remain. Implementation often lags well behind insight. This report identifies a number of investigative opportunities for significantly reducing the toll of tobacco use, including: (1) the need for novel, nonlinear models of population-based disease control; (2) refinement of "real-world" models of clinical intervention in trial design; and (3) understanding of mechanisms by which intrauterine smoke exposure may lead to persistent, tobacco-related chronic disease. DISCUSSION: In the coming era of tobacco research, pooled talent from multiple disciplines will be required to further illuminate the complex social, environmental and biological codeterminants of tobacco dependence. PMID- 26230246 TI - Chest Wall Vasculopathy in a Patient with Type 1 Neurofibromatosis. PMID- 26230247 TI - Determination of N-nitrosamines in processed meats by liquid extraction combined with gas chromatography-methanol chemical ionisation/mass spectrometry. AB - A simple, accessible and reproducible method was developed and validated as an alternative for the determination of nine volatile N-nitrosamines (NAs) in meat products, using a low volume of organic solvent and without requiring specific apparatus, offering the possibility of practical implementation in routine laboratories. The NAs were extracted with dichloromethane followed by a clean-up with phosphate buffer solution (pH 7.0). The extracts were analysed by gas chromatography-chemical ionisation/mass spectrometry (GC-CI/MS) in positive-ion mode using methanol as reagent. Limits of detection and quantification, recovery and reproducibility were determined for all NAs (N-nitrosodimethylamine, N nitrosomethylethylamine, N-nitrosodiethylamine, N-nitrosopyrrolidine, N nitrosodipropylamine, N-nitrosomorpholine, N-nitrosopiperidine, N nitrosodibutylamine and N-nitrosodiphenylamine). Satisfactory sensitivity and selectivity were obtained even without concentrating the extract by solvent evaporation, avoiding the loss of the nine NAs studied. Limits of detection ranged from 0.15 to 0.37 ug kg(-1), whereas limits of quantification ranged from 0.50 to 1.24 ug kg(-1). Recoveries calculated in cooked ham that had been spiked at 10 and 100 ug kg(-1) were found to be between 70% and 114% with an average relative standard deviation of 13.2%. The method was successfully used to analyse five samples of processed meat products on the day of purchase and 7 days later (after storage at 4 degrees C). The most abundant NAs found in the analysed products were N-nitrosodipropylamine and N-nitrosopiperidine, which ranged from 1.75 to 34.75 ug kg(-1) and from 1.50 to 4.26 ug kg(-1), respectively. In general, an increase in the level of NAs was observed after the storage period. The proposed method may therefore be a useful tool for food safety control once it allows assessing the profile and the dietary intake of NAs in food over time. PMID- 26230249 TI - Proactive interference and concurrent inhibitory processes do not differentially affect item and associative recognition: Implication for the age-related associative memory deficit. AB - Previous studies have suggested an associative deficit hypothesis [Naveh Benjamin, M. ( 2000 ). Adult age differences in memory performance: Tests of an associative deficit hypothesis. Journal of Experimental Psychology: Learning, Memory, and Cognition, 26, 1170-1187] to explain age-related episodic memory declines. The hypothesis attributes part of the deficient episodic memory performance in older adults to a difficulty in creating and retrieving cohesive episodes. In this article, we further evaluate this hypothesis by testing two alternative processes that potentially mediate associative memory deficits in older adults. Four experiments are presented that assess whether failure of inhibitory processes (proactive interference in Experiments 1 and 2), and concurrent inhibition (in Experiments 3 and 4) are mediating factors in age related associative deficits. The results suggest that creating conditions that require the operation of inhibitory processes, or that interfere with such processes, cannot simulate associative memory deficit in older adults. Instead, such results support the idea that associative memory deficits reflect a unique binding failure in older adults. This failure seems to be independent of other cognitive processes, including inhibitory and other resource-demanding processes. PMID- 26230248 TI - Prosthetic Antigen Receptors. AB - Chimeric antigen receptors (CARs) have shown great promise for the immunological treatment of cancer. Nevertheless, the need to genetically engineer a patient's T cells has presented significant production and safety challenges. To address these issues, we have demonstrated that chemically self-assembled nanorings (CSANs) displaying single chain antibodies can bind to both the CD3 epsilon subunit of the T-cell-receptor/CD3 complex and the CD22 antigen on malignant B cells such as B-leukemias or lymphomas. We demonstrate that the multivalent and bispecific format allows the antiCD3/antiCD22 CSANs to stably bind to T-cell surfaces for greater than 4 days, while being easily disassembled on the cell membrane by treatment with the nontoxic FDA approved drug, trimethoprim. In the presence of CD22+ Raji cells, T-cells modified with antiCD3/antiCD22 CSANs were shown to selectively up-regulate the production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) and to initiate cytotoxicity. Taken together, our results demonstrate that antiCD3/antiCD22 bispecific CSANs offer a potential alternative to CARs, as prosthetic antigen receptors. PMID- 26230250 TI - Incipient habitat race formation in an amphibian. AB - Theory defines conditions under which sympatric speciation may occur, and several possible examples of the process in action have been identified. In most cases, organisms specialize onto habitats that fall into discrete categories, such as host species used by herbivores and parasites. Ecological specialization within a continuous habitat gradient is theoretically possible, but becomes less likely with increasing gene flow among clinal habitat types. Here, I show that habitat race formation is underway in a frog, Rana temporaria, along a continuous and spatially mosaic habitat gradient. Tadpoles from 23 populations raised in an outdoor mesocosm experiment showed adaptive phenotypic variation correlated with the predator density in their pond of origin. A survey of microsatellite markers in 48 populations found that neutral genetic divergence was enhanced between ponds with very different densities of predators. This represents a new example of habitat specialization along a continuous habitat gradient with no spatial autocorrelation in habitat. PMID- 26230252 TI - Absent caudate lobe of liver: anatomical and clinical relevance. PMID- 26230251 TI - Using modern plant trait relationships between observed and theoretical maximum stomatal conductance and vein density to examine patterns of plant macroevolution. AB - Understanding the drivers of geological-scale patterns in plant macroevolution is limited by a hesitancy to use measurable traits of fossils to infer palaeoecophysiological function. Here, scaling relationships between morphological traits including maximum theoretical stomatal conductance (gmax ) and leaf vein density (Dv ) and physiological measurements including operational stomatal conductance (gop ), saturated (Asat ) and maximum (Amax ) assimilation rates were investigated for 18 extant taxa in order to improve understanding of angiosperm diversification in the Cretaceous. Our study demonstrated significant relationships between gop , gmax and Dv that together can be used to estimate gas exchange and the photosynthetic capacities of fossils. We showed that acquisition of high gmax in angiosperms conferred a competitive advantage over gymnosperms by increasing the dynamic range (plasticity) of their gas exchange and expanding their ecophysiological niche space. We suggest that species with a high gmax (> 1400 mmol m(-2) s(-1) ) would have been capable of maintaining a high Amax as the atmospheric CO2 declined through the Cretaceous, whereas gymnosperms with a low gmax would experience severe photosynthetic penalty. Expansion of the ecophysiological niche space in angiosperms, afforded by coordinated evolution of high gmax , Dv and increased plasticity in gop , adds further functional insights into the mechanisms driving angiosperm speciation. PMID- 26230253 TI - A Genetic Incompatibility Accelerates Adaptation in Yeast. AB - During mismatch repair (MMR) MSH proteins bind to mismatches that form as the result of DNA replication errors and recruit MLH factors such as Mlh1-Pms1 to initiate excision and repair steps. Previously, we identified a negative epistatic interaction involving naturally occurring polymorphisms in the MLH1 and PMS1 genes of baker's yeast. Here we hypothesize that a mutagenic state resulting from this negative epistatic interaction increases the likelihood of obtaining beneficial mutations that can promote adaptation to stress conditions. We tested this by stressing yeast strains bearing mutagenic (incompatible) and non mutagenic (compatible) mismatch repair genotypes. Our data show that incompatible populations adapted more rapidly and without an apparent fitness cost to high salt stress. The fitness advantage of incompatible populations was rapid but disappeared over time. The fitness gains in both compatible and incompatible strains were due primarily to mutations in PMR1 that appeared earlier in incompatible evolving populations. These data demonstrate a rapid and reversible role (by mating) for genetic incompatibilities in accelerating adaptation in eukaryotes. They also provide an approach to link experimental studies to observational population genomics. PMID- 26230254 TI - How to Sync to the Beat of a Persistent Fractal Metronome without Falling Off the Treadmill? AB - In rehabilitation, rhythmic acoustic cues are often used to improve gait. However, stride-time fluctuations become anti-persistent with such pacing, thereby deviating from the characteristic persistent long-range correlations in stride times of self-paced walking healthy adults. Recent studies therefore experimented with metronomes with persistence in interbeat intervals and successfully evoked persistent stride-time fluctuations. The objective of this study was to examine how participants couple their gait to a persistent metronome, evoking persistently longer or shorter stride times over multiple consecutive strides, without wandering off the treadmill. Twelve healthy participants walked on a treadmill in self-paced, isochronously paced and non isochronously paced conditions, the latter with anti-persistent, uncorrelated and persistent correlations in interbeat intervals. Stride-to-stride fluctuations of stride times, stride lengths and stride speeds were assessed with detrended fluctuation analysis, in conjunction with an examination of the coupling between stride times and stride lengths. Stride-speed fluctuations were anti-persistent for all conditions. Stride-time and stride-length fluctuations were persistent for self-paced walking and anti-persistent for isochronous pacing. Both stride times and stride lengths changed from anti-persistence to persistence over the four non-isochronous metronome conditions, accompanied by an increasingly stronger coupling between these gait parameters, with peak values for the persistent metronomes. These results revealed that participants were able to follow the beat of a persistent metronome without falling off the treadmill by strongly coupling stride-length fluctuations to the stride-time fluctuations elicited by persistent metronomes, so as to prevent large positional displacements along the treadmill. For self-paced walking, in contrast, this coupling was very weak. In combination, these results challenge the premise that persistent metronomes in gait rehabilitation would evoke stride-to-stride dynamics reminiscent of self-paced walking healthy adults. Future studies are recommended to include an analysis of the interrelation between stride times and stride lengths in addition to the correlational structure of either one in isolation. PMID- 26230255 TI - Distribution of Organic Carbon in the Sediments of Xinxue River and the Xinxue River Constructed Wetland, China. AB - Wetland ecosystems are represented as a significant reservoir of organic carbon and play an important role in mitigating the greenhouse effect. In order to compare the compositions and distribution of organic carbon in constructed and natural river wetlands, sediments from the Xinxue River Constructed Wetland and the Xinxue River, China, were sampled at two depths (0-15 cm and 15-25 cm) in both upstream and downstream locations. Three types of organic carbon were determined: light fraction organic carbon, heavy fraction organic carbon, and dissolved organic carbon. The results show that variations in light fraction organic carbon are significantly larger between upstream and downstream locations than they are between the two wetland types; however, the opposite trend is observed for the dissolved organic carbon. There are no significant differences in the distribution of heavy fraction organic carbon between the discrete variables (e.g., between the two depths, the two locations, or the two wetland types). However, there are significant cross-variable differences; for example, the distribution patterns of heavy fraction organic carbon between wetland types and depths, and between wetland types and locations. Correlation analysis reveals that light fraction organic carbon is positively associated with light fraction nitrogen in both wetlands, while heavy fraction organic carbon is associated with both heavy fraction nitrogen and the moisture content in the constructed wetland. The results of this study demonstrate that the constructed wetland, which has a relatively low background value of heavy fraction organic carbon, is gradually accumulating organic carbon of different types, with the level of accumulation dependent on the balance between carbon accumulation and carbon decomposition. In contrast, the river wetland has relatively stable levels of organic carbon. PMID- 26230256 TI - The Effect of Post-Reproductive Lifespan on the Fixation Probability of Beneficial Mutations. AB - Post-reproductive lifespan is a common trait among mammals and is usually considered to be neutral; i.e. with no influence on population dynamics. Here, we explore the role of post-reproductive lifespan in the fixation probability of beneficial genetic variation. We compare two separate, stationary populations living in a constant environment that are equivalent except for the average time their respective members spend in the post-reproductive stage of life. Using a recently derived approximation, we show that fixation of a beneficial mutation is more likely in the population with greater post-reproductive longevity. This finding is surprising, as the population with more prolonged post-reproductive lifespan has smaller effective size and the classic population-genetic model would suggest that decreasing effective size reduces fixation chances of beneficial mutations. Yet, as we explain, in the age-structured case, when effective size gets smaller because of longer post-reproductive lifespan but census size is kept equal, a beneficial mutation has a higher likelihood to get fixed because it finds itself at higher initial frequency. PMID- 26230257 TI - Correction: Processing of Feature Selectivity in Cortical Networks with Specific Connectivity. AB - [This corrects the article DOI: 10.1371/journal.pone.0127547.]. PMID- 26230259 TI - Correction: The Role of Phosphoinositide 3-Kinases in Neutrophil Migration in 3D Collagen Gels. AB - [This corrects the article DOI: 10.1371/journal.pone.0116250.]. PMID- 26230258 TI - Modelling the Contributions of Malaria, HIV, Malnutrition and Rainfall to the Decline in Paediatric Invasive Non-typhoidal Salmonella Disease in Malawi. AB - INTRODUCTION: Nontyphoidal Salmonellae (NTS) are responsible for a huge burden of bloodstream infection in Sub-Saharan African children. Recent reports of a decline in invasive NTS (iNTS) disease from Kenya and The Gambia have emphasised an association with malaria control. Following a similar decline in iNTS disease in Malawi, we have used 9 years of continuous longitudinal data to model the interrelationships between iNTS disease, malaria, HIV and malnutrition. METHODS: Trends in monthly numbers of childhood iNTS disease presenting at Queen's Hospital, Blantyre, Malawi from 2002 to 2010 were reviewed in the context of longitudinal monthly data describing malaria slide-positivity among paediatric febrile admissions, paediatric HIV prevalence, nutritional rehabilitation unit admissions and monthly rainfall over the same 9 years, using structural equation models (SEM). RESULTS: Analysis of 3,105 iNTS episodes identified from 49,093 blood cultures, showed an 11.8% annual decline in iNTS (p < 0.001). SEM analysis produced a stable model with good fit, revealing direct and statistically significant seasonal effects of malaria and malnutrition on the prevalence of iNTS disease. When these data were smoothed to eliminate seasonal cyclic changes, these associations remained strong and there were additional significant effects of HIV prevalence. CONCLUSIONS: These data suggest that the overall decline in iNTS disease observed in Malawi is attributable to multiple public health interventions leading to reductions in malaria, HIV and acute malnutrition. Understanding the impacts of public health programmes on iNTS disease is essential to plan and evaluate interventions. PMID- 26230260 TI - Phylogenetic Analysis of Hepatitis B Virus Genotypes Circulating in Different Risk Groups of Panama, Evidence of the Introduction of Genotype A2 in the Country. AB - The Hepatitis B Virus (HBV) can cause acute or chronic infection it is also associated with the development of liver cancer, thousands of new infections occur on a yearly basis, and many of these cases are located in certain areas of the Caribbean and Latin America. In these areas, the HBV prevalence is still high which makes this virus a serious public health concern to the entire region. Studies performed in Panama suggest a complex pattern in the distribution of HBV among the country's different risk groups. We use phylogenetic analysis in order to determine which HBV genotypes were circulating in these specific groups; for this we used a fragment of the PreS2/2 region of the HBV genome. Subsequently whole HBV genome sequences were used for Bayesian analysis of phylodynamics and phylogeography. Two main genotypes were found: genotype A (54.5%) and genotype F (45.5%). There was a difference in the distribution of genotypes according to risk groups: 72.9% of high risk groups were associated to genotype A, and 55.0% of samples of genotype F were associated to the low risk group (p<0.002). The Bayesian analysis of phylogeny-traits association revealed a statistically significant geographical association (p<0.0001) with both genotypes and different regions of the country. The Bayesian time of most recent common ancestor analysis (tMRCA) revealed a recent tMRCA for genotype A2 circulating in Panama (1997, 95% HPD: 1986-2005), when it is compared with Panamanian genotype F1c sequences (1930, 95% HPD: 1810 - 2005). These results suggest a possible change in the distribution of HBV genotypes in Panama and Latin America as a whole. They also serve to encourage the implementation of vaccination programs in high-risk groups, in order to prevent an increase in the number of new HBV cases in Latin America and worldwide. PMID- 26230261 TI - Ablation of CCAAT/Enhancer-Binding Protein Delta (C/EBPD): Increased Plaque Burden in a Murine Alzheimer's Disease Model. AB - Alzheimer's disease (AD) and prion diseases carry a significant inflammatory component. The astrocytic overexpression of CCAAT/enhancer-binding protein delta (C/EBPD) in prion- and AD-affected brain tissue prompted us to study the role of this transcription factor in murine model systems of these diseases. Ablation of C/EBPD had neither in the AD model (APP/PS1double transgenic mice) nor in the prion model (scrapie-infected C57BL/6 mice) an influence on overt clinical symptoms. Moreover, the absence of C/EBPD did not affect the extent of the disease-related gliosis. However, C/EBPD-deficient APP/PS1 double transgenic mice displayed significantly increased amyloid beta (Abeta) plaque burdens while amyloid precursor protein (APP) expression and expression of genes involved in beta amyloid transport and turnover remained unchanged. Gene expression analysis in mixed glia cultures demonstrated a strong dependency of complement component C3 on the presence of C/EBPD. Accordingly, C3 mRNA levels were significantly lower in brain tissue of C/EBPD-deficient mice. Vice versa, C3 expression in U 373 MG cells increased upon transfection with a C/EBPD expression vector. Taken together, our data indicate that a C/EBPD-deficiency leads to increased Abeta plaque burden in AD model mice. Furthermore, as shown in vivo and in vitro, C/EBPD is an important driver of the expression of acute phase response genes like C3 in the amyloid-affected CNS. PMID- 26230262 TI - A Comparison of Grizzly Bear Demographic Parameters Estimated from Non-Spatial and Spatial Open Population Capture-Recapture Models. AB - Capture-recapture studies are frequently used to monitor the status and trends of wildlife populations. Detection histories from individual animals are used to estimate probability of detection and abundance or density. The accuracy of abundance and density estimates depends on the ability to model factors affecting detection probability. Non-spatial capture-recapture models have recently evolved into spatial capture-recapture models that directly include the effect of distances between an animal's home range centre and trap locations on detection probability. Most studies comparing non-spatial and spatial capture-recapture biases focussed on single year models and no studies have compared the accuracy of demographic parameter estimates from open population models. We applied open population non-spatial and spatial capture-recapture models to three years of grizzly bear DNA-based data from Banff National Park and simulated data sets. The two models produced similar estimates of grizzly bear apparent survival, per capita recruitment, and population growth rates but the spatial capture-recapture models had better fit. Simulations showed that spatial capture-recapture models produced more accurate parameter estimates with better credible interval coverage than non-spatial capture-recapture models. Non-spatial capture-recapture models produced negatively biased estimates of apparent survival and positively biased estimates of per capita recruitment. The spatial capture-recapture grizzly bear population growth rates and 95% highest posterior density averaged across the three years were 0.925 (0.786-1.071) for females, 0.844 (0.703-0.975) for males, and 0.882 (0.779-0.981) for females and males combined. The non-spatial capture recapture population growth rates were 0.894 (0.758-1.024) for females, 0.825 (0.700-0.948) for males, and 0.863 (0.771-0.957) for both sexes. The combination of low densities, low reproductive rates, and predominantly negative population growth rates suggest that Banff National Park's population of grizzly bears requires continued conservation-oriented management actions. PMID- 26230263 TI - Combined Effects of Lanthanum (III) and Acid Rain on Antioxidant Enzyme System in Soybean Roots. AB - Rare earth element pollution (REEs) and acid rain (AR) pollution simultaneously occur in many regions, which resulted in a new environmental issue, the combined pollution of REEs and AR. The effects of the combined pollution on the antioxidant enzyme system of plant roots have not been reported. Here, the combined effects of lanthanum ion (La3+), one type of REE, and AR on the antioxidant enzyme system of soybean roots were investigated. In the combined treatment of La3+ (0.08 mM) and AR, the cell membrane permeability and the peroxidation of cell membrane lipid of soybean roots increased, and the superoxide dismutase, catalase, peroxidase and reduced ascorbic acid served as scavengers of reactive oxygen species. In other combined treatments of La3+ (0.40 mM, 1.20 mM) and AR, the membrane permeability, malonyldialdehyde content, superoxide dismutase activity, peroxidase activity and reduced ascorbic acid content increased, while the catalase activity decreased. The increased superoxide dismutase activity, peroxidase activity and reduced ascorbic acid content were inadequate to scavenge the excess hydrogen peroxide and superoxide, leading to the damage of the cell membrane, which was aggravated with the increase in the concentration of La3+ and the level of AR. The deleterious effects of the combined treatment of La3+ and AR were stronger than those of the single treatment of La3+ or AR. Moreover, the activity of antioxidant enzyme system in the combined treatment group was affected directly and indirectly by mineral element content in soybean plants. PMID- 26230264 TI - Eating Behaviour in the General Population: An Analysis of the Factor Structure of the German Version of the Three-Factor-Eating-Questionnaire (TFEQ) and Its Association with the Body Mass Index. AB - The Three-Factor-Eating-Questionnaire (TFEQ) is an established instrument to assess eating behaviour. Analysis of the TFEQ-factor structure was based on selected, convenient and clinical samples so far. Aims of this study were (I) to analyse the factor structure of the German version of the TFEQ and (II)--based on the refined factor structure--to examine the association between eating behaviour and the body mass index (BMI) in a general population sample of 3,144 middle-aged and older participants (40-79 years) of the ongoing population based cohort study of the Leipzig Research Center for Civilization Diseases (LIFE Health Study). The factor structure was examined in a split-half analysis with both explorative and confirmatory factor analysis. Associations between TFEQ-scores and BMI values were tested with multiple regression analyses controlled for age, gender, and education. We found a three factor solution for the TFEQ with an 'uncontrolled eating', a 'cognitive restraint' and an 'emotional eating' domain including 29 of the original 51 TFEQ-items. Scores of the 'uncontrolled eating domain' showed the strongest correlation with BMI values (partial r = 0.26). Subjects with scores above the median in both 'uncontrolled eating' and 'emotional eating' showed the highest BMI values (mean = 29.41 kg/m2), subjects with scores below the median in all three domains showed the lowest BMI values (mean = 25.68 kg/m2; F = 72.074, p<0.001). Our findings suggest that the TFEQ is suitable to identify subjects with specific patterns of eating behaviour that are associated with higher BMI values. Such information may help health care professionals to develop and implement more tailored interventions for overweight and obese individuals. PMID- 26230265 TI - The Epidemiology of Major Depressive Episode in the Iraqi General Population. AB - OBJECTIVE: To assess the prevalence, symptom severity, functional impairment, and treatment of major depressive episode (MDE) in the Iraqi general population. METHODS: The Iraq Mental Health Survey is a nationally representative face-to face survey of 4,332 non-institutionalized adults aged 18+ interviewed in 2006 2007 as part of the WHO World Mental Health Surveys. Prevalence and correlates of DSM-IV MDE were determined with the WHO Composite International Diagnostic Interview (CIDI). FINDINGS: Lifetime and 12-month prevalence of MDE were 7.4% and 4.0%, respectively. Close to half (46%) of the 12-month MDE cases were severe/very severe. MDE was more common among women and those previously married. Median age of onset was 25.2. Only one-seventh of 12-month MDE cases received treatment despite being associated with very substantial role impairment (on average 70 days out of role in the past year). CONCLUSIONS: MDE is a commonly occurring disorder in the Iraqi general population and is associated with considerable disability and low treatment. Efforts are needed to decrease the barriers to treatment and to educate general medical providers in Iraq about the recognition and treatment of depression. PMID- 26230266 TI - Associations of Individual-Related and Job-Related Risk Factors with Nonfatal Occupational Injury in the Coal Workers of Shanxi Province: A Cross-Sectional Study. AB - OBJECTIVES: To assess the relationships between the risk factors and the incidence of nonfatal occupational injury of coal mine workers of Shanxi Province. METHODS: A cross-sectional study was conducted from July 2013 to December 2013, and 4319 workers were recruited from more than 200,000 coal mine employees who are exposed to continuous potential risk of occupational injuries by using a two-stage stratified cluster sampling method. Trained interviewers having necessary medical knowledge conducted face-to-face interviews with the participants. Univariate and multivariable logistic regression models were used to estimate the odds ratio (OR) and the 95% confidence interval (CI). RESULTS: A total number of 3618 effective respondents were got from 4319 participants (83.77%) and the mean age of the participants was 41.5 years with the standard deviation of 8.65. Significant crude odds ratios were observed for all factors considered except for marital status, education, work duration, BMI, EPQ-RSC(P) scale and EPQ-RSC(L) scale. Results from multivariable logistic regression model showed significant adjusted odds ratios for risk factors including gender (female vs male 0.275, 0.094-0.800), age (>=55 vs <=25yr 0.169, 0.032-0.900), work type (light physical labor vs heavy physical labor 0.504, 0.328-0.774), workplace (underground auxiliary vs underground front-line 0.595, 0.385-0.919), length of shiftwork experience (0~5yr vs no shift 2.075, 1.287-3.344 and >=15yr vs no shift 2.076, 1.230-3.504) and EPQ-RSC(E) score (extraversion vs introversion 0.538, 0.334-0.867). CONCLUSIONS: Several risk factors of nonfatal occupational injury were identified including male, age, heavy physical labor, underground front line, length of shiftwork experience and introversion. The coal mining enterprises should pay attention to controlling the hazards associated with frontline physical work. Workers' behaviors, life styles and personality traits should also be considered, so that the enterprises could set achievable targets for workers and lessen the exposed period to the risky underground workstation. PMID- 26230268 TI - Effectiveness of long-acting paliperidone palmitate in borderline personality disorder. AB - The aim of the present study is to test the efficacy of palmitate paliperidone long-acting injection for patients with borderline personality disorder (BPD). A total of 16 patients with BPD were treated with intramuscular paliperidone palmitate (IMPP) over 12 weeks. Effectiveness measures included the CGI-BPD, HARS, MADRS, BIS-11, and STAXI-2. Functional improvement was assessed using the Global Assessment of Functioning scale. A list of adverse events was provided to clinicians and patients. Treatment with IMPP was associated with a significant average reduction of 1.6 (95% confidence interval: 1192-2008; P>0.01) in CGI-BPD scores and an average increase of psychosocial functioning as scored by the Global Assessment of Functioning scale of 13.3 (95% confidence interval: 8.35 18.31; P>0.01) was obtained. The treatment decreased impulsive-disruptive behaviors and improved general functioning. An acceptable tolerance was observed. The average weight gain was clinically irrelevant despite being statistically significant. No other relevant adverse side effects were reported, with the exception of galactorrhea, which required suspension of treatment in three patients. IMPP seems to be a well-tolerated alternative to other second generation antipsychotics in the treatment of BPD. More controlled studies replicating these results should be proposed in the future. PMID- 26230269 TI - Efficacy and tolerability of paliperidone ER in patients with unsatisfactorily controlled schizophrenia by other antipsychotics: a flexible-dose approach. AB - This study evaluates the effectiveness of paliperidone ER in patients with symptomatic but not highly acute schizophrenia in terms of efficacy, safety, and patients' perception of their social functioning and well-being. This is a multicenter, open-label prospective study with a flexible-dose approach; 133 patients were enrolled and followed for 13 weeks after switching to paliperidone ER. Outcome efficacy measures were as follows: the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity (CGI-S) scale, and the Personal and Social Performance (PSP) scale; in addition, the Subjective Well being under Neuroleptics (SWN-20) scale, the Drug Attitude Inventory (DAI-30), and the sleep evaluation scale were used. Symptom Rating Scale (ESRS), adverse events, and subjective side effects were recorded. 118/133(88.7%) patients completed the study. The mean PANSS score decreased (88.98 +/- 10.09 to 66.52 +/- 16.29; P < 0.001); 40.5% of the patients achieved improvement of at least 30%. PSP and CGI-S scores as well as DAI-30 and SWN-20 decreased (P < 0.001). ESRS (P < 0.001) decreased significantly from the baseline. Throughout the trial, no deaths occurred and only one serious adverse event was reported. Paliperidone ER has proved to be efficacious, safe, and well tolerated also with this approach more closely resembling actual clinical practice. Patient-relevant outcome parameters such as social functioning and quality of life improved, which is crucial for treatment adherence in clinical practice. PMID- 26230270 TI - Effects of 50 and 100 mg desvenlafaxine versus placebo on sexual function in patients with major depressive disorder: a meta-analysis. AB - The primary objective of this post-hoc analysis was to evaluate the effect of short-term treatment with desvenlafaxine versus placebo on sexual dysfunction (SD), assessed from Arizona Sexual Experiences Scale scores, in adult outpatients with major depressive disorder. Data from three randomized, double-blind, placebo controlled trials of 50 or 100 mg/day desvenlafaxine for major depressive disorder were pooled. SD status, determined from Arizona Sexual Experiences Scale scores, was assessed at baseline and week 8, last observation carried forward. Subgroup analyses addressed the effects of sex, baseline SD, and antidepressant response. At week 8, last observation carried forward (n=1562), SD rates were 54, 47, and 49% for 50 mg/day desvenlafaxine, 100 mg/day desvenlafaxine, and placebo, respectively [adjusted odds ratios (95% confidence interval) vs. placebo: 1.205 (0.928, 1.564) and 1.129 (0.795, 1.604), respectively]. The treatment by baseline SD interaction approached statistical significance (P=0.0663), mainly driven by poorer scores for desvenlafaxine versus placebo in the 100 mg group. Treatment by sex interactions were not statistically significant. Small but statistically significant treatment by sex interactions were observed for sex drive (P=0.0011) and ease of erection/lubrication (P=0.0151). Although there was no overall effect of desvenlafaxine on SD, a treatment by baseline SD interaction was suggested for 100 mg desvenlafaxine. PMID- 26230271 TI - Net Costs Due to Seasonal Influenza Vaccination--United States, 2005-2009. AB - BACKGROUND: Seasonal influenza causes considerable morbidity and mortality across all age groups, and influenza vaccination was recommended in 2010 for all persons aged 6 months and above. We estimated the averted costs due to influenza vaccination, taking into account the seasonal economic burden of the disease. METHODS: We used recently published values for averted outcomes due to influenza vaccination for influenza seasons 2005-06, 2006-07, 2007-08, and 2008-09, and age cohorts 6 months-4 years, 5-19 years, 20-64 years, and 65 years and above. Costs were calculated according to a payer and societal perspective (in 2009 US$), and took into account medical costs and productivity losses. RESULTS: When taking into account direct medical costs (payer perspective), influenza vaccination was cost saving only for the older age group (65>=) in seasons 2005-06 and 2007-08. Using the same perspective, influenza vaccination resulted in total costs of $US 1.7 billion (95%CI: $US 0.3-4.0 billion) in 2006-07 and $US 1.8 billion (95%CI: $US 0.1-4.1 billion) in 2008-09. When taking into account a societal perspective (and including the averted lost earnings due to premature death) averted deaths in the older age group influenced the results, resulting in cost savings for all ages combined in season 07-08. DISCUSSION: Influenza vaccination was cost saving in the older age group (65>=) when taking into account productivity losses and, in some seasons, when taking into account medical costs only. Averted costs vary significantly per season; however, in seasons where the averted burden of deaths is high in the older age group, averted productivity losses due to premature death tilt overall seasonal results towards savings. Indirect vaccination effects and the possibility of diminished case severity due to influenza vaccination were not considered, thus the averted burden due to influenza vaccine may be even greater than reported. PMID- 26230272 TI - Architecture and Chemical Coding of the Inner and Outer Submucous Plexus in the Colon of Piglets. AB - In the porcine colon, the submucous plexus is divided into an inner submucous plexus (ISP) on the epithelial side and an outer submucous plexus (OSP) on the circular muscle side. Although both plexuses are probably involved in the regulation of epithelial functions, they might differ in function and neurochemical coding according to their localization. Therefore, we examined expression and co-localization of different neurotransmitters and neuronal markers in both plexuses as well as in neuronal fibres. Immunohistochemical staining was performed on wholemount preparations of ISP and OSP and on cryostat sections. Antibodies against choline acetyltransferase (ChAT), substance P (SP), somatostatin (SOM), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), neuronal nitric oxide synthase (nNOS) and the pan-neuronal markers Hu C/D and neuron specific enolase (NSE) were used. The ISP contained 1,380 +/- 131 ganglia per cm2 and 122 +/- 12 neurons per ganglion. In contrast, the OSP showed a wider meshwork (215 +/- 33 ganglia per cm2) and smaller ganglia (57 +/- 3 neurons per ganglion). In the ISP, 42% of all neurons expressed ChAT. About 66% of ChAT positive neurons co-localized SP. A small number of ISP neurons expressed SOM. Chemical coding in the OSP was more complex. Besides the ChAT/+/-SP subpopulation (32% of all neurons), a nNOS-immunoreactive population (31%) was detected. Most nitrergic neurons were only immunoreactive for nNOS; 10% co-localized with VIP. A small subpopulation of OSP neurons was immunoreactive for ChAT/nNOS/+/-VIP. All types of neurotransmitters found in the ISP or OSP were also detected in neuronal fibres within the mucosa. We suppose that the cholinergic population in the ISP is involved in the control of epithelial functions. Regarding neurochemical coding, the OSP shares some similarities with the myenteric plexus. Because of its location and neurochemical characteristics, the OSP may be involved in controlling both the mucosa and circular muscle. PMID- 26230273 TI - Analyzing the Expression Profile of AREB/ABF and DREB/CBF Genes under Drought and Salinity Stresses in Grape (Vitis vinifera L.). AB - Expression patterns of four candidate AREB/ABF genes and four DREB/CBF genes were evaluated in leaf and root tissues of five grape varieties ('Qalati', 'Kaj Angoor', 'Sabz Angoor', 'Siahe Zarghan', 'Bidane Safid') with differential response to drought stress. Among the AREB/ABF genes, AREB1 and ABF2 showed up regulation in response to drought stress in leaf and root tissues of all varieties while AREB2 and ABF1 showed down-regulation in both leaf and root tissues of the sensitive variety 'Bidane Sefid' in response to drought and salt stress. Among the DREB/CBF genes, CBF4 was the most responsive to drought stress in both leaf and root tissues. CBF2 and CBF3 showed up-regulation in all varieties in response to drought stress in leaf except in 'Bidane Sefid'. Under salinity stress, AREB2 and ABF2 showed up-regulation in response to the increasing level of salinity in the leaf tissues but in the root tissues ABF2 was up-regulated in response to increasing NaCl concentration while AREB2 was down regulated. Therefore, it seems AREB2 has tissue-specific response to salinity stress. All CBF genes were up-regulated in response to salinity stress in the leaf and root tissues. Expression data suggested that CBF2 is more responsive to NaCl stress. Among all four promising and stress tolerant varieties 'Siah Zarghan' and 'Kaj Angoor' were more tolerant than 'Qalati' and 'Sabz Angoor' to drought and salinity. PMID- 26230274 TI - Optimal Threshold Determination for Interpreting Semantic Similarity and Particularity: Application to the Comparison of Gene Sets and Metabolic Pathways Using GO and ChEBI. AB - BACKGROUND: The analysis of gene annotations referencing back to Gene Ontology plays an important role in the interpretation of high-throughput experiments results. This analysis typically involves semantic similarity and particularity measures that quantify the importance of the Gene Ontology annotations. However, there is currently no sound method supporting the interpretation of the similarity and particularity values in order to determine whether two genes are similar or whether one gene has some significant particular function. Interpretation is frequently based either on an implicit threshold, or an arbitrary one (typically 0.5). Here we investigate a method for determining thresholds supporting the interpretation of the results of a semantic comparison. RESULTS: We propose a method for determining the optimal similarity threshold by minimizing the proportions of false-positive and false-negative similarity matches. We compared the distributions of the similarity values of pairs of similar genes and pairs of non-similar genes. These comparisons were performed separately for all three branches of the Gene Ontology. In all situations, we found overlap between the similar and the non-similar distributions, indicating that some similar genes had a similarity value lower than the similarity value of some non-similar genes. We then extend this method to the semantic particularity measure and to a similarity measure applied to the ChEBI ontology. Thresholds were evaluated over the whole HomoloGene database. For each group of homologous genes, we computed all the similarity and particularity values between pairs of genes. Finally, we focused on the PPAR multigene family to show that the similarity and particularity patterns obtained with our thresholds were better at discriminating orthologs and paralogs than those obtained using default thresholds. CONCLUSION: We developed a method for determining optimal semantic similarity and particularity thresholds. We applied this method on the GO and ChEBI ontologies. Qualitative analysis using the thresholds on the PPAR multigene family yielded biologically-relevant patterns. PMID- 26230276 TI - Assessment of diabetic teleretinal imaging program at the Portland Department of Veterans Affairs Medical Center. AB - We conducted a retrospective chart review of 200 diabetic patients who had teleretinal imaging performed between January 1, 2010, and January 1, 2011, at Portland Department of Veterans Affairs (VA) Medical Center outpatient clinics to assess the effectiveness of the diabetic teleretinal imaging program. Twenty patients (10%) had diabetic retinopathy. Ninety percent of the available teleretinal imaging studies were of adequate quality for interpretation. In accordance with local VA policy at that time, all teleretinal imaging patients should have been referred for a dilated retinal examination the following year. Image readers referred 97.5% of the patients to eye clinics for subsequent eye examinations, but the imagers scheduled appointments for only 80% of these patients. The redundancy rate, i.e., patients who had an eye examination within the past 6 mo, was 11%; the duplicate recall rate, i.e., patients who had a second teleretinal imaging performed within 1 yr of the eye examination, was 37%. Rates of timely diabetic eye examinations at clinics with teleretinal imaging programs, particularly when teleretinal imaging and eye clinics were colocated at the same community-based outpatient clinic, were higher than those without a teleretinal imaging program. We concluded that the Portland VA Medical Center's teleretinal imaging program was successful in increasing the screening rate for diabetic retinopathy. PMID- 26230275 TI - Reproducibility and Validity of a Food Frequency Questionnaire for Assessing Dietary Consumption via the Dietary Pattern Method in a Chinese Rural Population. AB - OBJECTIVE: This study was conducted to assess the reproducibility and validity of a food frequency questionnaire (FFQ) that was developed to assess the overall dietary consumption via dietary pattern method in a rural population in southwest China. METHODS: A total of 179 participants aged between 40 and 70 years old were included in this study. Participants administered FFQ at baseline (FFQ1) and one year later (FFQ2) to assess the reproducibility. Six 3-day 24-hour recalls (24HRs) were completed between the administrations of two FFQs to determine the validity. Dietary patterns from three separate dietary sources were derived by using principle component factor analysis. Comparisons between dietary pattern scores were made by using Pearson or intraclass correlation coefficient, cross classification analysis, weighted kappa (kappa) statistic and Bland-Altman analysis. The de-attenuated method was adopted to correct the monthly and seasonally variation and the partial correlation analysis was used correct the influence by total energy intake. RESULTS: Two major dietary factors, labeled as prudent pattern and processed food pattern, were identified. The prudent pattern was characterized by higher factor loadings of wheat, rice, fresh vegetables, bean products, nuts, red meat, white meat and fresh eggs; and the processed food pattern was characterized by higher factor loadings of pickled vegetables, preserved vegetables and salted meat. Between Two FFQs, intraclass correlation coefficients were 0.57 for prudent pattern and 0.55 for processed food pattern, partial Pearson correlation coefficients were 0.51 for the prudent pattern and 0.56 for the processed food pattern; weighted kappa statistic ranged from 0.45 (for the prudent pattern) to 0.56 (for the processed food pattern). Between FFQs and 24HRs, de-attenuated correlation coefficients ranged from 0.54 to 0.78 for the prudent pattern and from 0.55 to 0.61 for the processed food pattern; partial Pearson correlation coefficients ranged from 0.41 to 0.56 for the prudent pattern and from 0.42 to 0.44 for the processed food pattern; weighted kappa statistic ranged from 0.42 to 0.46 for prudent pattern and from 0.43 to 0.60 for processed food pattern. The Bland-Altman plots and limits of agreement indicated that the deviation/divergence was not obvious for both of the patterns between FFQ1 and FFQ2 and between FFQs and 24HRs. CONCLUSION: The study suggests that the FFQ is reasonably reproducible and valid to assess the overall dietary consumption via dietary pattern methods in the Chinese rural population. PMID- 26230277 TI - Delta Subsidence: An Imminent Threat to Coastal Populations. PMID- 26230278 TI - Mealtime Insulin Dosing by Carbohydrate Counting in Hospitalized Cardiology Patients: A Retrospective Cohort Study. AB - BACKGROUND: Carbohydrate counting may improve glycemic control in hospitalized cardiology patients by providing individualized insulin doses tailored to meal consumption. The purpose of this study was to compare glycemic outcomes with mealtime insulin dosed by carbohydrate counting versus fixed dosing in the inpatient setting. MATERIALS AND METHODS: This single-center retrospective cohort study included 225 adult medical cardiology patients who received mealtime, basal, and correction-scale insulin concurrently for at least 72 h and up to 7 days in the interval March 1, 2010-November 7, 2013. Mealtime insulin was dosed by carbohydrate counting or with fixed doses determined prior to meal intake. An inpatient diabetes consult service was responsible for insulin management. Exclusion criteria included receipt of an insulin infusion. The primary end point compared mean daily postprandial glucose values, whereas secondary end points included comparison of preprandial glucose values and mean daily rates of hypoglycemia. RESULTS: Mean postprandial glucose level on Day 7 was 204 and 183 mg/dL in the carbohydrate counting and fixed mealtime dose groups, respectively (unadjusted P=0.04, adjusted P=0.12). There were no statistical differences between groups on Days 2-6. Greater rates of preprandial hypoglycemia were observed in the carbohydrate counting cohort on Day 5 (8.6% vs. 1.5%, P=0.02), Day 6 (1.7% vs. 0%, P=0.01), and Day 7 (7.1% vs. 0%, P=0.008). No differences in postprandial hypoglycemia were seen. CONCLUSIONS: Mealtime insulin dosing by carbohydrate counting was associated with similar glycemic outcomes as fixed mealtime insulin dosing, except for a greater incidence of preprandial hypoglycemia. Additional comparative studies that include hospital outcomes are needed. PMID- 26230279 TI - Universal Scaling Law for the Collapse of Viscous Nanopores. AB - Below a threshold size, a small pore nucleated in a fluid sheet will contract to minimize the surface energy. Such behavior plays a key role in nature and technology, from nanopores in biological membranes to nanopores in sensors for rapid DNA and RNA sequencing. Here we show that nanopores nucleated in viscous fluid sheets collapse following a universal scaling law for the pore radius. High fidelity numerical simulations reveal that the scaling is largely independent of the initial conditions, including the size, shape, and thickness of the original nanopore. Results further show that the scaling law yields a constant speed of collapse as observed in recent experiments. Nanopores in fluid sheets of moderate viscosity also attain this constant terminal speed provided that they are sufficiently close to the singularity. PMID- 26230280 TI - Development of new antibiotics: taking off finally? AB - Since 2010, awareness of the global threat caused by antimicrobial resistance (AMR) has risen considerably and multiple policy and research initiatives have been implemented. Research and development (R&D) of much-needed new antibiotics active against multiresistant pathogens is a key component of all programmes aiming at fighting AMR, but it has been lagging behind owing to scientific, regulatory and economic challenges. Although a few new antibiotics might be available in Switzerland in the next 5 years, these new agents are not based on new mechanisms of action and are not necessarily active against resistant pathogens for which there is the highest unmet medical need, i.e. multiresistant Gram-negative bacteria. Of the three new antibiotics with pending authorisation in Switzerland for systemic treatment of severe infections, oritavancin and tedizolid target Gram-positive pathogens, while only ceftolozane+tazobactam partially covers multiresistant Gram-negative pathogens. Among six antibiotics currently in phase III of clinical development, delafloxacin and solithromycin will also be useful mostly for Gram-positive infections. Importantly, the four other compounds are active against multiresistant Gram-negative pathogens: ceftazidime+avibactam, meropenem+RPX7009, eravacycline and plazomicin. The three last compounds are also active against carbapenem-resistant Enterobacteriaceae (CRE). A few compounds active against such pathogens are currently in earlier clinical development, but their number may decrease, considering the risk of failure over the course of clinical development. At last, through public and political awareness of pathogens with high public health impact and unmet medical need, development of innovative economic incentives and updated regulatory guidance, R&D of new antibiotics is slowly taking off again. PMID- 26230281 TI - Determination of the chemical constituents of the different processed products of Anemarrhena asphodeloides Rhizomes by high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. AB - In this work, high-performance liquid chromatography (HPLC) coupled with a hybrid quadrupole time of-flight mass spectrometry (Q-TOF-MS/MS) was used to study chemical compositions of different processed products of Rhizoma Anemarrhenae (RA). A Grace Alltima(TM) C18 column (250 * 4.6 mm, 5 um) was used for separation. Mobile phase consisted of 0.1% formic acid and acetonitrile, using gradient elution. ESI-MS data was acquired in both positive and negative mode. The experiment was established on the basis of a series of reference substances (two xanthone and seven saponins) to qualitatively identify the chemical compounds of different processed products of RA by MS analysis. There was no difference in the type of chemical constituents between different processed products of RA. A total of 25 compounds were identified, including four xanthones, 21 steroidal saponins and eight pairs of isomers. PMID- 26230282 TI - A stable single-site palladium catalyst for hydrogenations. AB - We report the preparation and hydrogenation performance of a single-site palladium catalyst that was obtained by the anchoring of Pd atoms into the cavities of mesoporous polymeric graphitic carbon nitride. The characterization of the material confirmed the atomic dispersion of the palladium phase throughout the sample. The catalyst was applied for three-phase hydrogenations of alkynes and nitroarenes in a continuous-flow reactor, showing its high activity and product selectivity in comparison with benchmark catalysts based on nanoparticles. Density functional theory calculations provided fundamental insights into the material structure and attributed the high catalyst activity and selectivity to the facile hydrogen activation and hydrocarbon adsorption on atomically dispersed Pd sites. PMID- 26230283 TI - HPV DNA testing with cytology triage in cervical cancer screening: Influence of revealing HPV infection status. AB - BACKGROUND: Knowledge of cervical human papillomavirus (HPV) status might influence a cytotechnician's assessment of cellular abnormalities. The authors compared original cytotechnicians' Papanicolaou (Pap) readings for which HPV status was concealed with Pap rereads for which HPV status was revealed separately for 3 screening populations. METHODS: Previously collected cervical Pap smears and clinical data were obtained from the Canadian Cervical Cancer Screening Trial (study A), the Democratic Republic of Congo Community-Based Screening Study (study B), and the Brazilian Investigation into Nutrition and Cervical Cancer Prevention (study C). Smears were reread with knowledge of HPV status for all HPV-positive women as well as a sample of HPV-negative women. Diagnostic performance of Pap cytology was compared between original readings and rereads. RESULTS: A total of 1767 Pap tests were reread. Among 915 rereads for HPV-positive women, the contrast between "revealed" and "concealed" Pap readings demonstrated revisions from negative to positive results for 109 women (cutoff was atypical squamous cells of undetermined significance or worse) and 124 women (cutoff was low-grade squamous intraepithelial lesions [LSIL] or worse). For a disease threshold of cervical intraepithelial neoplasia of grade 2 or worse, specificity significantly declined at the atypical squamous cells of undetermined significance cutoff for studies A (86.6% to 75.3%) and C (42.5% to 15.5%), and at the LSIL cutoff for study C (61.9% to 37.6%). Sensitivity remained nearly unchanged between readings, except in study C, in which reread performance was superior (91.3% vs 71.9% for the LSIL cutoff). CONCLUSIONS: A reduction in the diagnostic accuracy of Pap cytology was observed when revealing patients' cervical HPV status, possibly due to a heightened awareness of potential abnormalities, which led to more false-positive results. PMID- 26230284 TI - Bioinorganic nanocomposite hydrogels formed by HRP-GOx-cascade-catalyzed polymerization and exfoliation of the layered composites. AB - The mild preparation of multifunctional nanocomposite hydrogels is of great importance for practical applications. We report that bioinorganic nanocomposite hydrogels, with calcium niobate nanosheets as cross-linkers, can be prepared by dual-enzyme-triggered polymerization and exfoliation of the layered composite. The layered HRP/calcium niobate composites (HRP=horseradish peroxidase) are formed by the assembly of the calcium niobate nanosheets with HRP. The dual enzyme-triggered polymerization can induce the subsequent exfoliation of the layered composite and final gelation through the interaction between polymer chains and inorganic nanosheets. The self-immobilized HRP-GOx enzymes (GOx=glucose oxidase) within the nanocomposite hydrogel retain most of enzymatic activity. Evidently, their thermal stability and reusability can be improved. Notably, our strategy could be easily extended to other inorganic layered materials for the fabrication of other functional nanocomposite hydrogels. PMID- 26230285 TI - Elevated growth differentiation factor 15 levels predict outcome in patients undergoing transcatheter aortic valve implantation. AB - AIMS: Transcatheter aortic valve implantation (TAVI) has emerged as a treatment of aortic stenosis in patients at high surgical risk. However, risk stratification in this elderly population is challenging, as patients at extreme risk might not benefit from TAVI. While several clinical criteria have been proposed for estimating the outcome, prediction of individual risk remains difficult. Therefore, our aim was to assess the prognostic value of the biomarker growth differentiation factor 15 (GDF15). METHODS AND RESULTS: Over a 2.9-year period, we prospectively enrolled 217 patients undergoing TAVI. Clinical parameters, risk scores, and biomarkers (NT-proBNP and GDF15) were measured at baseline. The primary endpoint was survival time; prognostic factors were analysed by Cox regression analysis. Mean age of study participants was 81.8 +/- 6.0 years. Median Logistic EuroSCORE was 20.1 (Q1-Q3 13.6-32.6). Thirty-day mortality was 6.9%; 30.4% of the patients died during follow-up [median 349 days (Q1-Q3 106-660)]. Median pre-procedural GDF15 values were 2256 pg/mL (1585-3082). High GDF15 levels were associated with numerous factors that could contribute to poor outcome. Analyses comparing the upper quartile with the lower three quartiles for biomarker levels revealed a hazard ratio (HR) of increased GDF15 for adverse outcome of 2.4 [95% confidence interval (CI) 1.5-3.9, P < 0.001]. Of note, in multiple analyses, elevated GDF15 levels were superior to NT-proBNP for predicting negative outcome (adjusted HR of GDF15 1.97, 95% CI 1.2-3.3; P = 0.009). CONCLUSION: Elevated GDF15 levels were superior to NT-proBNP for TAVI risk stratification and provided additional prognostic information. Thus, patient selection for TAVI may benefit from measurement of GDF15. PMID- 26230286 TI - Frequency of Paroxysmal Nocturnal Hemoglobinuria Clones by Multiparametric Flow Cytometry in Pediatric Aplastic Anemia Patients of Indian Ethnic Origin. AB - BACKGROUND: The literature on paroxysmal nocturnal hemoglobinuria (PNH) in aplastic anemia (AA) is largely focused on adults with few studies in children. Moreover, large studies are conspicuously absent from developing countries. Knowledge of the prevalence and utility of their detection is required before widespread use of PNH screening in pediatric AA in resource-limited settings. METHODS: We performed a retrospective audit over a period of 9 years to study the prevalence of PNH clones by flow cytometry (FCM) in children <=12 years of age presenting with AA, and analyzed their response to immunosuppressant therapy. RESULTS: Nine (12.9%) out of 70 patients had PNH clones comprising >1% of the target cell population, including five patients (7.14%) with PNH clone size >10%. The clone size in monocytes ranged from 3.7% to 95.2% (median 21.1%) and in neutrophils from 1.6% to 87.6% (median 19.5%). Fluorescent aerolysin (FLAER) based FCM screening significantly improved the detection of PNH clones compared to non-FLAER based screening techniques (18.4% vs. 6.25%). One child showed chronic intravascular hemolysis and another developed arterial stroke during the course of illness. None of our PNH-positive AA patients tested for chromosome breakage studies (n = 8) showed increased clastrogen-induced breakage. CONCLUSIONS: A lower frequency but moderate/large-sized PNH clones were seen in our pediatric AA population, compared to western data. FLAER-based FCM screening significantly improved the detection of PNH clones. We recommend routine FLAER based screening of PNH in pediatric AA patients. PMID- 26230289 TI - A Dominant Factor for Structural Classification of Protein Crystals. AB - With the increasing number of solved protein crystal structures, much information on protein shape and atom geometry has become available. It is of great interest to know the structural diversity for a single kind of protein. Our preliminary study suggested that multiple crystal structures of a single kind of protein can be classified into several groups from the viewpoint of structural similarity. In order to broadly examine this finding, cluster analysis was applied to the crystal structures of hemoglobin (Hb), myoglobin (Mb), human serum albumin (HSA), hen egg-white lysozyme (HEWL), and human immunodeficiency virus type 1 protease (HIV-1 PR), downloaded from the Protein Data Bank (PDB). As a result of classification by cluster analysis, 146 crystal structures of Hb were separated into five groups. The crystal structures of Mb (n = 284), HEWL (n = 336), HSA (n = 63), and HIV-1 PR (n = 488) were separated into six, five, three, and six groups, respectively. It was found that a major factor causing these structural separations is the space group of crystals and that crystallizing agents have an influence on the crystal structures. Amino acid mutation is a minor factor for the separation because no obvious point mutation making a specific cluster group was observed for the five kinds of proteins. In the classification of Hb and Mb, the species of protein source such as humans, rabbits, and mice is another significant factor. When the difference in amino sequence is large among species, the species of protein source is the primary factor causing cluster separation in the classification of crystal structures. PMID- 26230287 TI - Current Research and Opportunities to Address Environmental Asbestos Exposures. AB - Asbestos-related diseases continue to result in approximately 120,000 deaths every year in the United States and worldwide. Although extensive research has been conducted on health effects of occupational exposures to asbestos, many issues related to environmental asbestos exposures remain unresolved. For example, environmental asbestos exposures associated with a former mine in Libby, Montana, have resulted in high rates of nonoccupational asbestos-related disease. Additionally, other areas with naturally occurring asbestos deposits near communities in the United States and overseas are undergoing investigations to assess exposures and potential health risks. Some of the latest public health, epidemiological, and basic research findings were presented at a workshop on asbestos at the 2014 annual meeting of the Society of Toxicology in Phoenix, Arizona. The following focus areas were discussed: a) mechanisms resulting in fibrosis and/or tumor development; b) relative toxicity of different forms of asbestos and other hazardous elongated mineral particles (EMPs); c) proper dose metrics (e.g., mass, fiber number, or surface area of fibers) when interpreting asbestos toxicity; d) asbestos exposure to susceptible populations; and e) using toxicological findings for risk assessment and remediation efforts. The workshop also featured asbestos research supported by the National Institute of Environmental Health Sciences, the Agency for Toxic Substances and Disease Registry, and the U.S. Environmental Protection Agency. Better protection of individuals from asbestos-related health effects will require stimulation of new multidisciplinary research to further our understanding of what constitutes hazardous exposures and risk factors associated with toxicity of asbestos and other hazardous EMPs (e.g., nanomaterials). PMID- 26230290 TI - Suzuki-Miyaura Coupling Reactions of Conjunctive Reagents: 2-Borylated Allylic Sulfones. AB - In support of various efforts in our group, we developed methods for the convenient Suzuki-Miyaura coupling of borylated allylic sulfones with various electrophiles in both inter- and the less common intramolecular modes. The procedure facilitates the preparation of a wide variety of sulfones in a straightforward fashion, including six- through eight-membered rings. PMID- 26230291 TI - Progression of cervical dilatation in normal human labor is unpredictable. AB - INTRODUCTION: The aim of this study was to analyze how the progression of cervical dilatation in active labor can be predicted by digital assessment in low risk pregnant women, in spontaneous labor at term. MATERIAL AND METHODS: This prospective observational study was performed on 328 women with singleton term gestations experiencing midwife-led labor according to local protocols, progressing to full dilatation and spontaneous delivery without any medical intervention. Mixed nonlinear models were adopted to (i) model individual cervical data into centile curves and (ii) calculate the time needed to gain 1 cm in cervical dilatation (TNG1cm ) modeled as a function of current dilatation. We correlated the first and the last TNG1cm on parturients with at least four cervical data points. RESULTS: TNG1cm showed large variations, both before and after 6 cm. This variability of natural progression of cervical curves described by the 10th and 90th centiles exceeded the differences observed in published curves from cohorts homogeneous for parity, weight and ethnicity. There was no significant correlation between the first and the last TNG1cm . Neonatal base excess was not significantly different in women with TNG1cm <10th centile and >90th centile. CONCLUSIONS: The rate of cervical dilatation, traced by parsimonious nonlinear mixed models, is largely unpredictable in the case of spontaneous naturally progressing labor, even when possible larger individual variability is excluded by prudent clinical rules. Future research in labor and delivery should be focused on the diagnosis of the causes that lie behind apparently erratic cervical changes. PMID- 26230292 TI - The interplay of fibronectin functionalization and TGF-beta1 presence on fibroblast proliferation, differentiation and migration in 3D matrices. AB - Defined biomimetic three-dimensional (3D) matrices are needed to decipher the complex cellular signalling during wound healing at high resolution in vitro. Soluble factors like TGF-beta1 and adhesion promoting structural components of the extracellular matrix (ECM) are known to be key regulators of fibroblast behaviour. The ECM component fibronectin (FN) bears a complex function as adhesion promoter, fibrillar element and soluble factor binder. However, its implementation in biomimetic 3D matrices is frequently ill defined. To study the impact of FN on fibroblast cellular function under differentiating conditions (TGF-beta1 stimulation), we functionalized 3D collagen I matrices with FN using two strategies: co-assembly and adsorptive immobilization. In comparison to co assembly, adsorptive immobilization provided no alteration in collagen microstructure as well as mechanical properties. Moreover, this approach provided a controllable FN amount and a homogenous distribution of FN throughout collagen networks. A strong interplay of FN amount and TGF-beta1 stimulation on fibroblast function was found in terms of proliferation, migration and myofibroblast differentiation. High levels of FN alone reduced proliferation and showed no effect on differentiation of fibroblasts, but increased migration. In contrast, fibroblast stimulation with high amounts of FN together with TGF-beta1 increased proliferation. Independent of FN, the TGF-beta1 stimulation enhanced mRNA expression of matrix components like collagen type I alpha 1 chain (Coll I(a1), FN with extra domain A (EDA-FN) and reduced cell migration. The latter cell behaviour indicated a FN independent differentiation into a myofibroblast phenotype. Overall, our 3D biomimetic matrices allow dissecting the overlapping action of the ECM protein FN and the soluble factor TGF-beta1 on fibroblast proliferation, migration and differentiation in 3D microenvironments. Furthermore, this model enables the mimicking of important steps of the in vivo wound healing process in vitro. PMID- 26230293 TI - Injury control needs to move from research to implementation: the theme of Safety 2016 World Conference in Tampere, Finland. PMID- 26230294 TI - Why we permute blocks? PMID- 26230295 TI - Familial Longevity Is Associated With Higher TSH Secretion and Strong TSH-fT3 Relationship. AB - CONTEXT: Longevity is associated with changes in circulating levels of thyroid hormone (TH) and/or TSH in animals and humans, but underlying mechanisms remain elusive. OBJECTIVE: We explored in 38 offspring of nonagenarian participants from the Leiden Longevity Study, who are enriched for longevity and in their partners, ultradian and circadian rhythmicity of TSH, temporal relationship, and feedback and forward interplay between TSH and TH. METHODS: We collected blood samples every 10 minutes for 24 hours for TSH and TH profiles. We used a deconvolution analysis to estimate basal (nonpulsatile), pulsatile, and other secretion parameters to characterize ultradian rhythmicity and locally weighted polynomial regression of TSH to assess circadian rhythmicity. A cross-correlation analysis was used to investigate the temporal relationship between TSH and TH and cross approximate entropy to assess feedback and forward interplay between TSH and TH. RESULTS: Compared with partners, offspring displayed higher mean (95% confidence interval [CI]) basal TSH secretion (34.3 [95% CI 27.2-43.1] mU/L per 24 hours vs 18.5 [95% CI 14.4-23.7] mU/L per 24 hours, P = .001) but no differences in ultradian or circadian properties of TSH. The temporal relationship between TSH and free T3 at zero delay was higher in offspring (0.48 +/- 0.2) compared with partners (0.26 +/- 0.4) (P = .05), but the feedback and forward interplay between TSH and TH did not differ. CONCLUSIONS: Familial longevity is associated with increased basal TSH secretion and a strong temporal relationship between TSH and free T3 but not with differences in ultradian or circadian TSH rhythmicity or feedback and forward interplay between TSH and TH. PMID- 26230296 TI - The Impact of Chronic Liraglutide Therapy on Glucagon Secretion in Type 2 Diabetes: Insight From the LIBRA Trial. AB - CONTEXT: In patients with type 2 diabetes (T2DM), impaired suppression of postprandial glucagonemia is a metabolic defect that contributes to hyperglycemia. Treatment with a glucagon-like peptide-1 agonist can reduce hyperglucagonemia in the acute setting, but little is known about the durability of this effect with long-term treatment. OBJECTIVE: The purpose of this study was to evaluate the impact of chronic liraglutide therapy on glucagon regulation in early T2DM. Design/Setting/Participants/Intervention: In this double-blind, randomized, placebo-controlled trial, 51 patients with T2DM of 2.6 +/- 1.9 years' duration were randomized to either daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with serial assessment of the glucose, insulin, C-peptide, and glucagon responses to a 75-g oral glucose tolerance test every 12 weeks. MAIN OUTCOME MEASURES: The glucagon response was assessed with the incremental area under the glucagon curve (iAUCglucagon) from measurements at 0, 30, 60, 90, and 120 minutes on each oral glucose tolerance test. RESULTS: As expected, compared with placebo, liraglutide induced a robust enhancement of the postchallenge insulin and C-peptide response at each of the 12-, 24-, 36-, and 48 week time points, with a concomitant reduction in glycemic excursion. However, liraglutide also induced a paradoxical increase in postchallenge glucagonemia that first emerged at 12 weeks and persisted over the 48-week treatment period. Indeed, baseline-adjusted iAUCglucagon was significantly higher in the liraglutide group compared with placebo at 12 weeks (170.2 +/- 34.9 vs 65.4 +/- 36.4 pg/mL . 2 hours, P = .04), 36 weeks (162.2 +/- 27.9 vs 55.7 +/- 30.4 pg/mL . 2 hours, P = .01), and 48 weeks (155.5 +/- 26.5 vs 45.7 +/- 27.0 pg/mL . 2 hours, P = .006). CONCLUSION: In contrast to its acute glucagon-lowering effect, chronic treatment with liraglutide is associated with increased postchallenge hyperglucagonemia in patients with early T2DM. PMID- 26230297 TI - Clinicopathological significance of ALDH1A1 in lung, colorectal, and breast cancers: a meta-analysis. AB - AIM: Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) is a putative cancer stem cell marker. This meta-analysis evaluated ALDH1A1 expression's clinicopathological associations with lung cancer (LC), colorectal cancer (CRC) and breast cancer (BC). MATERIALS & METHODS: Publications were retrieved from various databases and assessed for relevance and quality. Relationships between ALDH1A1 expression and clinicopathological characteristics were evaluated using Review Manager 5.2 software. RESULTS: Thirty-eight studies were included (6057 patients). ALDH1A1 expression was significantly associated with the presence of LC; lymph node metastasis, clinical stage and differentiation in LC and BC; and molecular subtype in BC (p < 0.05). There were no significant association with BC tumor size and CRC. CONCLUSION: ALDH1A1 may be a stem cell marker in LC and BC. PMID- 26230299 TI - Cooling Strategies Outside the Central Nervous System. PMID- 26230300 TI - Explaining Fetal Death--What Are the Contributions of Fetal Autopsy and Placenta Examination? AB - The aim of our study was to categorize fetal deaths by different diagnostic groups and see to what extent an autopsy of a presumably normal fetus contributes to the final diagnosis and how many unexplained fetal deaths remain unexplained after examination of the placenta. We reviewed autopsy reports of 351 fetuses with a gestational age of 12 or more weeks at the Department of Pathology and Medical Genetics at St Olavs Hospital during the years 2001 through 2010. In our records, 38.5% (135 of 351) of the deaths were due to noninfectious placenta causes, 31.6% (111 of 351) were caused by infections, and 29.9% (105 of 351) of the fetal deaths remained unexplained after autopsy. We also found that an inconclusive report was more common early in pregnancy. The incidence of fetal loss due to circulatory disturbances in the placenta increased toward term. Infections were evenly distributed in intrauterine fetal deaths, although in spontaneous abortions, they were more frequent during the second trimester. For both explained and unexplained deaths, we observed a bimodal distribution, with peaks in the early second trimester and late third trimester toward term. PMID- 26230298 TI - Dysregulation of Mitochondrial Functions and Osteogenic Differentiation in Cisd2 Deficient Murine Induced Pluripotent Stem Cells. AB - Wolfram syndrome 2 (WFS2) is a premature aging syndrome caused by an irreversible mitochondria-mediated disorder. Cisd2, which regulates mitochondrial electron transport, has been recently identified as the causative gene of WFS2. The mouse Cisd2 knockout (KO) (Cisd2(-/-)) recapitulates most of the clinical manifestations of WFS2, including growth retardation, osteopenia, and lordokyphosis. However, the precise mechanisms underlying osteopenia in WFS2 and Cisd2 KO mice remain unknown. In this study, we collected embryonic fibroblasts from Cisd2-deficient embryos and reprogrammed them into induced pluripotent stem cells (iPSCs) via retroviral transduction with Oct4/Sox2/Klf4/c-Myc. Cisd2 deficient mouse iPSCs (miPSCs) exhibited structural abnormalities in their mitochondria and an impaired proliferative capability. The global gene expression profiles of Cisd2(+/+), Cisd2(+/-), and Cisd2(-/-) miPSCs revealed that Cisd2 functions as a regulator of both mitochondrial electron transport and Wnt/beta catenin signaling, which is critical for cell proliferation and osteogenic differentiation. Notably, Cisd2(-/-) miPSCs exhibited impaired Wnt/beta-catenin signaling, with the downregulation of downstream genes, such as Tcf1, Fosl1, and Jun and the osteogenic regulator Runx2. Several differentiation markers for tridermal lineages were globally impaired in Cisd2(-/-) miPSCs. Alizarin red S staining and flow cytometry analysis further revealed that Cisd2(-/-) miPSCs failed to undergo osteogenic differentiation. Taken together, our results, as determined using an miPSC-based platform, have demonstrated that Cisd2 regulates mitochondrial function, proliferation, intracellular Ca(2+) homeostasis, and Wnt pathway signaling. Cisd2 deficiency impairs the activation of Wnt/beta-catenin signaling and thereby contributes to the pathogeneses of osteopenia and lordokyphosis in WFS2 patients. PMID- 26230301 TI - Consistency of quality attributes for the glycosylated monoclonal antibody Humira(r) (adalimumab). AB - Humira(r) (adalimumab) is a recombinant human IgG1 monoclonal antibody (mAb) glycoprotein consisting of 1330 amino acids that is specific for human tumor necrosis factor (TNF). The biological activity and clinical profile of mAb therapeutics, including adalimumab, is influenced by their protein structure and glycosylation patterns, which can be affected by the expression system, cell culture conditions and purification process methodology. While clinical outcome cannot yet be attributed to many of the individual structural features that constitute a mAb, it is evident that detailed structural attribute analysis is necessary if structural contributions to function are to be comprehensively defined. Adalimumab product quality data generated from over a decade of manufacturing across multiple production sites and through a series of manufacturing scale changes are presented here. These data reveal a consistent and tightly controlled profile for the product. PMID- 26230303 TI - A new flavan from the Drynaria bonii H. Christ rhizomes. AB - In Vietnam, the medicinal plant Drynaria bonii H. Christ is used for the treatment of osteoporosis, bone fractures, and stimulate the growth of hair, treat tinnitus (Ho 2002; Loi 2004). In this article, experiments were designed to investigate the proliferation activity of ethanol, n-hexane, chloroform, ethyl acetate and methanol extracts from D. bonii rhizomes on MG-63 human osteoblast like cells. The results showed that methanol and hexane extracts had the ability to proliferate MG-63 cells at the concentration varying from 0.1 to 0.01 MUg/mL. In particular, at the concentration of 0.01 MUg/mL, hexane and methanol extracts illustrated the highest proliferation ratio with 9.31% and 6.16%, respectively. By column chromatography, a new compound named drynaether A (1) and five known compounds uracil (2), 4'-hydroxy-7-methoxyflavan (3), kaempferol (4), indole-3 carboxylic acid (5) and protocatechuic acid (6) were isolated and identified from the methanol extract. PMID- 26230304 TI - Unexpected Complete Heart Block and Anesthetic Implications. AB - A healthy, active duty military 25-year-old female with a history of congenital complete heart block presented for a routine septorhinoplasty. During the preoperative interview, she did not disclose her heart condition. A preordered electrocardiogram was not available. During induction of anesthesia, she became extremely bradycardic, approaching asystole, requiring resuscitation. This case highlights the potential anesthetic risks in individuals with a history of congenital heart rhythm disease. PMID- 26230305 TI - A Delayed Finding of a Tracheal Cartilaginous Sleeve in a Patient with Pfeiffer Syndrome Type 2 and a Complex Airway History. AB - Persistent airway obstruction symptoms in a 21/2-year-old boy with Pfeiffer syndrome were attributed to facial abnormalities, central and obstructive sleep apnea, and tracheomalacia from a vascular ring. These findings delayed the diagnosis of a tracheal cartilaginous sleeve. Life expectancy in tracheal cartilaginous sleeve is improved by tracheostomy. Tracheal cartilaginous sleeve should be considered and investigated through airway endoscopy in children with fibroblast growth factor receptor-related craniosynostosis syndromes. PMID- 26230306 TI - Smartphones in the Operating Room: Distraction or Diagnostic Aid? A Case of Newly Diagnosed Wolff-Parkinson White in a Pediatric Patient Having Bronchoscopy Under General Anesthesia. AB - A 4-year-old boy presented for elective bronchoscopy after years of pharmacologically unresponsive reactive airway disease that limited physical activity. After mask induction with nitrous oxide and sevoflurane, the patient was noted to be intermittently in a hemodynamically stable tachyarrhythmia. The anesthesia machine, though equipped with electrocardiogram (ECG) recording capabilities, malfunctioned during the case and was not able to print a rhythm strip. As a substitute, a smartphone picture and video were recorded. In the recovery room, initial 12-lead ECG showed sinus tachycardia. Shortly after, a presumptive diagnosis of Wolff-Parkinson White was given upon review of the smartphone recordings by the pediatric cardiologist on service. Twelve lead ECG was repeated which showed intermittent Wolff-Parkinson White. This case highlights 2 points. First, any prolonged or sustained pediatric dysrhythmia revealed during anesthesia warrants further investigation and should not be assumed secondary to an anesthetic drug. Second, ubiquitous smartphones are an excellent tool for capturing data that the monitor is unable to capture. PMID- 26230307 TI - Implications of National Anesthesia Workload on the Staffing of a Call Center: The Malignant Hyperthermia Consultant Hotline. AB - Recently, we analyzed data from the American Society of Anesthesiologist's (ASA) Anesthesia Quality Institute (AQI) to report the United States (U.S.) anesthesia workload by time of day and day of the week. The AQI data were reported using the Central Time zone. Times for the N = 613 calls to the Malignant Hyperthermia Association of the United States (MHAUS) Malignant Hyperthermia (MH) Hotline from August 1, 2012, through March 7, 2014, were adjusted similarly. The MH Hotline effectively provides at all times to each anesthesia group an additional board certified anesthesiologist who has expertise in managing, diagnosing, and/or preventing MH crises. We compared the timing of calls with the MH Hotline consultants relative to times of most anesthesia workload nationally. The interval 6:30 AM to 6:30 PM Central Time on regular workdays accounted for most (P < 0.0001) calls to the MH Hotline (62.5% +/- 2.0% [mean +/- standard error]). However, the interval accounted for significantly less than the 82.2% of anesthesia minutes and 84.5% of general anesthesia minutes during that interval nationally (both P < 0.0001). Thus, most calls to the MH Hotline occurred when anesthesia groups nationwide were the busiest. Weekends accounted for 15.3% +/- 1.5% of MH Hotline calls, significantly greater than the rates of 5.2% of anesthesia minutes and 4.3% of general anesthesia minutes during weekends nationally (both P < 0.0001). Thus, the MH Hotline was used proportionately more often when anesthesia providers have fewer colleagues present and available for consultation (all P < 0.0001). These findings may be expected of other (future) national support centers for anesthesia. PMID- 26230308 TI - Auditing Operating Room Recycling: A Management Case Report. AB - Much waste arises from operating rooms (ORs). We estimated the practical and financial feasibility of an OR recycling program, weighing all waste from 6 ORs in Melbourne, Australia. Over 1 week, 237 operations produced 1265 kg in total: general waste 570 kg (45%), infectious waste 410 kg (32%), and recyclables 285 kg (23%). The achieved recycling had no infectious contamination. The achieved recycling/potential recycling rate was 285 kg/517 kg (55%). The average waste disposal costs were similar for general waste and recycling. OR recycling rates of 20%-25% total waste were achievable without compromising infection control or financial constraints. PMID- 26230310 TI - Erratum. PMID- 26230309 TI - Restored Physiology in Protein-Deficient Yeast by a Small Molecule Channel. AB - Deficiencies of protein ion channels underlie many currently incurable human diseases. Robust networks of pumps and channels are usually responsible for the directional movement of specific ions in organisms ranging from microbes to humans. We thus questioned whether minimally selective small molecule mimics of missing protein channels might be capable of collaborating with the corresponding protein ion pumps to restore physiology. Here we report vigorous and sustainable restoration of yeast cell growth by replacing missing protein ion transporters with imperfect small molecule mimics. We further provide evidence that this tolerance for imperfect mimicry is attributable to collaboration between the channel-forming small molecule and protein ion pumps. These results illuminate a mechanistic framework for pursuing small molecule replacements for deficient protein ion channels that underlie a range of challenging human diseases. PMID- 26230311 TI - Speciation is not necessarily easier in species with sexually monomorphic mating signals. AB - Should we have different expectations regarding the likelihood and pace of speciation by sexual selection when considering species with sexually monomorphic mating signals? Two conditions that can facilitate rapid species divergence are Felsenstein's one-allele mechanism and a genetic architecture that includes a genetic association between signal and preference loci. In sexually monomorphic species, the former can manifest in the form of mate choice based on phenotype matching. The latter can be promoted by selection acting upon genetic loci for divergent signals and preferences expressed simultaneously in each individual, rather than acting separately on signal loci in males and preference loci in females. Both sexes in the Chrysoperla carnea group of green lacewings (Insecta, Neuroptera, Chrysopidae) produce sexually monomorphic species-specific mating signals. We hybridized the two species C. agilis and C. carnea to test for evidence of these speciation-facilitating conditions. Hybrid signals were more complex than the parents and we observed a dominant influence of C. carnea. We found a dominant influence of C. agilis on preferences in the form of hybrid discrimination against C. carnea. Preferences in hybrids followed patterns predicting preference loci that determine mate choice rather than a one-allele mechanism. The genetic association between signal and preference we detected in the segregating hybrid crosses indicates that speciation in these species with sexually monomorphic mating signals can have occurred rapidly. However, we need additional evidence to determine whether such genetic associations form more readily in sexually monomorphic species compared to dimorphic species and consequently facilitate speciation. PMID- 26230312 TI - Jewellery: alloy composition and release of nickel, cobalt and lead assessed with the EU synthetic sweat method. AB - BACKGROUND: Several studies have shown nickel and cobalt release from jewellery by using spot tests, but the metal composition of jewellery is largely unknown. OBJECTIVES: To evaluate the metal composition of a large worldwide sample of mainly inexpensive jewellery items, and investigate the release of nickel, cobalt and lead from a subsample by using EN 1811:1998-required methods. METHODS: A total of 956 metallic jewellery components were examined with X-ray fluorescence spectroscopy. A subsample of 96 jewellery items purchased in the United States were investigated for nickel, cobalt and lead release by the use of artificial sweat immersion and plasma optical emission spectroscopy. RESULTS: Eighteen elements were detected. The 10 most frequently occurring were, in order of frequency, copper, iron, zinc, nickel, silver, chromium, tin, manganese, lead, and cobalt. Release of nickel was noted from 79 of the 96 US samples (0.01-98 ug/cm(2) /week), release of cobalt from 35 samples (0.02-0.5 ug/cm(2) /week), and release of lead from 37 samples (0.03-2718 ug/cm(2) /week). CONCLUSIONS: We present here a comprehensive list of the most frequently encountered metals in jewellery and fashion accessories. Different allergenic and non-allergenic metals are utilized. We also report the frequent release of nickel, cobalt and lead from these objects, despite legislative restrictions. PMID- 26230313 TI - Salivary Concentration of Oxidative Stress Biomarkers in a Group of Patients with Peri-Implantitis: A Transversal Study. AB - PURPOSE: The purpose of this study was to know if peri-implantitis causes an increase in the total salivary concentration of oxidative stress markers. MATERIALS AND METHODS: Seventy patients, 28 men and 42 women, 60 of them with dental implants, 30 of which had peri-implantitis and 30 were healthy. The remaining 10 were the control group: healthy subjects without implants. The average number of implants per patient was 4.70 +/- 2.29 in the peri-implantitis group and 2 70 +/- 2.11 in the control group. Periodontal/peri-implant variables were assessed, including bleeding index, gingival index, clinical attachment level, probing depth, presence of pockets larger than 4 and 6 mm, pain to percussion, suppuration, gingival hyperplasia or granuloma, crestal bone loss (both mesially and distally), evaluated through periapical radiography. Saliva samples from the 70 subjects were collected for measurement of malondialdehyde high performance liquid chromatography (HPLC) and myeloperoxidase (enzyme-linked immunosorbent assay analysis) concentrations. RESULTS: Implants affected with peri-implantitis had an average follow-up of 26.40 +/- 7.97 months. 4.12% of implants with peri-implantitis had a painful response to percussion. 2.06% showed suppuration; 25.77% had granuloma. The mean crestal bone loss in implants wtih peri-implantitis was 3.78 +/- 1.17 mm. Total salivary malondialdehyde concentration in the peri-implantitis group (0.52 +/- 0.37 MUM/l) was slightly higher than that in the group with healthy implants (0.40 +/- 0.16 MUM/l) and also slightly higher than that in the group of healthy patients without implants (0.41 +/- 0.79 MUM/l), although the difference was not statistically significant, p value = .442. Myeloperoxidase concentration was slightly higher in the peri implantitis group (12.32 +/- 2.17 ng/ml) than in the group with healthy implants (11.54 +/- 2.80 ng/ml) and the group of healthy patients without implants (11.86 +/- 2.67 ng/ml), without statistically significant differences, p value = .584. CONCLUSIONS: The salivary concentration of oxidative stress markers in patients with peri-implantitis and without periodontitis is not higher than that found in healthy patients. PMID- 26230314 TI - Estimation of clinically relevant indicators for EVAR using patient-specific finite element simulation. PMID- 26230315 TI - The Shelterin TIN2 Subunit Mediates Recruitment of Telomerase to Telomeres. AB - Dyskeratosis Congenita (DC) is a heritable multi-system disorder caused by abnormally short telomeres. Clinically diagnosed by the mucocutaneous symptoms, DC patients are at high risk for bone marrow failure, pulmonary fibrosis, and multiple types of cancers. We have recapitulated the most common DC-causing mutation in the shelterin component TIN2 by introducing a TIN2-R282H mutation into cultured telomerase-positive human cells via a knock-in approach. The resulting heterozygous TIN2-R282H mutation does not perturb occupancy of other shelterin components on telomeres, result in activation of telomeric DNA damage signaling or exhibit other characteristics indicative of a telomere deprotection defect. Using a novel assay that monitors the frequency and extension rate of telomerase activity at individual telomeres, we show instead that telomerase elongates telomeres at a reduced frequency in TIN2-R282H heterozygous cells; this recruitment defect is further corroborated by examining the effect of this mutation on telomerase-telomere co-localization. These observations suggest a direct role for TIN2 in mediating telomere length through telomerase, separable from its role in telomere protection. PMID- 26230317 TI - Correction: Chronic Anatabine Treatment Reduces Alzheimer's Disease (AD)-Like Pathology and Improves Socio-Behavioral Deficits in a Transgenic Mouse Model of AD. AB - [This corrects the article DOI: 10.1371/journal.pone.0128224.]. PMID- 26230316 TI - Identification of Oxygen-Responsive Transcripts in the Silage Inoculant Lactobacillus buchneri CD034 by RNA Sequencing. AB - The Lactobacillus buchneri CD034 strain, known to improve the ensiling process of green fodder and the quality of the silage itself was transcriptionally analyzed by sequencing of transcriptomes isolated under anaerobic vs. aerobic conditions. L. buchneri CD034 was first cultivated under anaerobic conditions and then shifted to aerobic conditions by aeration with 21% oxygen. Cultivations already showed that oxygen was consumed by L. buchneri CD034 after aeration of the culture while growth of L. buchneri CD034 was still observed. RNA sequencing data revealed that irrespective of the oxygen status of the culture, the most abundantly transcribed genes are required for basic cell functions such as protein biosynthesis, energy metabolism and lactic acid fermentation. Under aerobic conditions, 283 genes were found to be transcriptionally up-regulated while 198 genes were found to be down-regulated (p-value < 0.01). Up-regulated genes i. a. play a role in oxygen consumption via oxidation of pyruvate or lactate (pox, lctO). Additionally, genes encoding proteins required for decomposition of reactive oxygen species (ROS) such as glutathione reductase or NADH peroxidase were also found to be up-regulated. Genes related to pH homeostasis and redox potential balance were found to be down-regulated under aerobic conditions. Overall, genes required for lactic acid fermentation were hardly affected by the growth conditions applied. Genes identified to be differentially transcribed depending on the aeration status of the culture are suggested to specify the favorable performance of the strain in silage formation. PMID- 26230318 TI - Understanding the Physical and Molecular Basis of Stability of Arabidopsis DNA Pol lambda under UV-B and High NaCl Stress. AB - Here, we have investigated the physical and molecular basis of stability of Arabidopsis DNA Pol lambda, the sole X family DNA polymerase member in plant genome, under UV-B and salinity stress in connection with the function of the N terminal BRCT (breast cancer-associated C terminus) domain and Ser-Pro rich region in the regulation of the overall structure of this protein. Tryptophan fluorescence studies, fluorescence quenching and Bis-ANS binding experiments using purified recombinant full length Pol lambda and its N-terminal deletion forms have revealed UV-B induced conformational change in BRCT domain deficient Pol lambda. On the other hand, the highly conserved C-terminal catalytic core PolX domain maintained its tertiary folds under similar condition. Circular dichroism (CD) and fourier transform infrared (FT-IR) spectral studies have indicated appreciable change in the secondary structural elements in UV-B exposed BRCT domain deficient Pol lambda. Increased thermodynamic stability of the C terminal catalytic core domain suggested destabilizing effect of the N-terminal Ser-Pro rich region on the protein structure. Urea-induced equilibrium unfolding studies have revealed increased stability of Pol lambda and its N-terminal deletion mutants at high NaCl concentration. In vivo aggregation studies using transient expression systems in Arabidopsis and tobacco indicated possible aggregation of Pol lambda lacking the BRCT domain. Immunoprecipitation assays revealed interaction of Pol lambda with the eukaryotic molecular chaperone HSP90, suggesting the possibility of regulation of Pol lambda stability by HSP90 in plant cell. Overall, our results have provided one of the first comprehensive information on the biophysical characteristics of Pol lambda and indicated the importance of both BRCT and Ser-Pro rich modules in regulating the stability of this protein under genotoxic stress in plants. PMID- 26230320 TI - Deceased Organ Donation Registration and Familial Consent among Chinese and South Asians in Ontario, Canada. AB - OBJECTIVE: For various reasons, people of Chinese (China, Hong Kong or Taiwan) and South Asian (Indian subcontinent) ancestry (the two largest ethnic minority groups in Ontario, Canada) may be less likely to register for deceased organ donation than the general public, and their families may be less likely to consent for deceased organ donation at the time of death. METHODS: We conducted two population-based studies: (1) a cross-sectional study of deceased organ donor registration as of May 2013, and (2) a cohort study of the steps in proceeding with deceased organ donation for patients who died in hospital from October 2008 to December 2012. RESULTS: A total of 49 938 of 559 714 Chinese individuals (8.9%) and 47 774 of 374 291 South Asians (12.8%) were registered for deceased organ donation, proportions lower than the general public (2 676 260 of 10 548 249 (25.4%). Among the 168 703 Ontarians who died in a hospital, the families of 33 of 81 Chinese (40.1%; 95% CI: 30.7%-51.6%) and 39 of 72 South Asian individuals (54.2%; 95% CI: 42.7-65.2%) consented for deceased organ donation, proportions lower than the general public (68.3%; 95% CI: 66.4%-70.0%). CONCLUSIONS: In Ontario, Canada Chinese and South Asian individuals are less likely to register and their families are less likely to consent to deceased organ donation compared to the remaining general public. There is an opportunity to build support for organ and tissue donation in these two large ethnic communities in Canada. PMID- 26230319 TI - Shame and Guilt-Proneness in Adolescents: Gene-Environment Interactions. AB - Rooted in people's preoccupation with how they are perceived and evaluated, shame and guilt are self-conscious emotions that play adaptive roles in social behavior, but can also contribute to psychopathology when dysregulated. Shame and guilt-proneness develop during childhood and adolescence, and are influenced by genetic and environmental factors that are little known to date. This study investigated the effects of early traumatic events and functional polymorphisms in the brain-derived neurotrophic factor (BDNF) gene and the serotonin transporter gene promoter (5-HTTLPR) on shame and guilt in adolescents. A sample of N = 271 healthy adolescents between 14 and 17 years of age filled in measures of early traumatic events and proneness to shame and guilt, and were genotyped for the BDNF Val66Met and 5-HTTLPR polymorphisms. Results of moderator analyses indicated that trauma intensity was positively associated with guilt-proneness only in carriers of the low-expressing Met allele of BDNF Val66Met. This is the first study that identifies a gene-environment interaction that significantly contributes to guilt proneness in adolescents, with potential implications for developmental psychopathology. PMID- 26230321 TI - The Influence of Parental Psychopathology on Offspring Suicidal Behavior across the Lifespan. AB - Suicide tends to occur in families, and parental psychopathology has been linked to offspring suicidal behaviors. This study explores the influence of parental mental disorders across the lifespan. Data are from the Sao Paulo Megacity Mental Health Survey, a cross-sectional household study with a representative sample of the adult population living in the Sao Paulo Metropolitan Area, Brazil (N=2,942). Survival models examined bivariate and multivariate associations between a range of parental disorders and offspring suicidality. After controlling for comorbidity, number of mental disorders and offspring psychopathology, we found that parental psychopathology influences suicidal behaviors throughout most part of the life cycle, from childhood until young adult years. Generalized anxiety disorder (GAD) and antisocial personality were associated with offspring suicidal ideation (OR 1.8 and 1.9, respectively), panic and GAD predicted suicidal attempts (OR 2.3 and 2.7, respectively), and panic was related to the transition from ideation to attempts (OR 2.7). Although noticed in many different stages of the lifespan, this influence is most evident during adolescence. In this period, depression and antisocial personality increased the odds of suicidal ideation (OR 5.1 and 3.2, respectively), and depression, panic disorder, GAD and substance abuse predicted suicidal attempts (OR varying from 1.7 to 3.8). In short, parental disorders characterized by impulsive-aggression and anxiety-agitation were the main predictors of offspring suicidality across the lifespan. This clinically relevant intergenerational transmission of suicide risk was independent of offspring mental disorders, and this underscores the need for a family approach to psychopathology. PMID- 26230323 TI - Posture and Texting: Effect on Balance in Young Adults. AB - Using a mobile phone while doing another activity is a common dual-task activity in our daily lives. This study examined the effect of texting on the postural stability of young adults. Twenty college students were asked to perform static and dynamic postural stability tasks. Traditional COP and multivariate multiscale entropy (MMSE) were used to assess the static postural stability and the Star Excursion Balance Test (SEBT) was used to assess the dynamic postural stability. Results showed that (1) texting impaired postural stability, (2) the complexity index did not change much although the task conditions changed, and (3) performing texting is perceived to be more difficult. PMID- 26230322 TI - Membrane-Active Sequences within gp41 Membrane Proximal External Region (MPER) Modulate MPER-Containing Peptidyl Fusion Inhibitor Activity and the Biosynthesis of HIV-1 Structural Proteins. AB - The membrane proximal external region (MPER) is a highly conserved membrane active region located at the juxtamembrane positions within class I viral fusion glycoproteins and essential for membrane fusion events during viral entry. The MPER in the human immunodeficiency virus type I (HIV-1) envelope protein (Env) interacts with the lipid bilayers through a cluster of tryptophan (Trp) residues and a C-terminal cholesterol-interacting motif. The inclusion of the MPER N terminal sequence contributes to the membrane reactivity and anti-viral efficacy of the first two anti-HIV peptidyl fusion inhibitors T20 and T1249. As a type I transmembrane protein, Env also interacts with the cellular membranes during its biosynthesis and trafficking. Here we investigated the roles of MPER membrane active sequences during both viral entry and assembly, specifically, their roles in the design of peptidyl fusion inhibitors and the biosynthesis of viral structural proteins. We found that elimination of the membrane-active elements in MPER peptides, namely, penta Trp->alanine (Ala) substitutions and the disruption of the C-terminal cholesterol-interacting motif through deletion inhibited the anti-viral effect against the pseudotyped HIV-1. Furthermore, as compared to C terminal dimerization, N-terminal dimerization of MPER peptides and N-terminal extension with five helix-forming residues enhanced their anti-viral efficacy substantially. The secondary structure study revealed that the penta-Trp->Ala substitutions also increased the helical content in the MPER sequence, which prompted us to study the biological relevance of such mutations in pre-fusion Env. We observed that Ala mutations of Trp664, Trp668 and Trp670 in MPER moderately lowered the intracellular and intraviral contents of Env while significantly elevating the content of another viral structural protein, p55/Gag and its derivative p24/capsid. The data suggest a role of the gp41 MPER in the membrane-reactive events during both viral entry and budding, and provide insights into the future development of anti-viral therapeutics. PMID- 26230324 TI - Key Factors Influencing Rapid Development of Potentially Dune-Stabilizing Moss Dominated Crusts. AB - Biological soil crusts (BSCs) are a widespread photosynthetic ground cover in arid and semiarid areas. They have many positive ecological functions, such as increasing soil stability, and reducing water and wind erosion. Using artificial technology to achieve the rapid development of BSCs is expected to become a low cost and highly beneficial ecological restoration measure. In the present study, typical moss-dominated crusts in a region characterized by mobile dunes (Mu Us Sandland, China) were collected, and a 40-day cultivation experiment was performed to investigate key factors, including watering frequency, light intensity and a nutrient addition, which affect the rapid development of moss crusts and their optimal combination. The results demonstrated that watering frequency and illumination had a significant positive effect (P=0.049, three factor ANOVA) and a highly significant, complicated effect (P=0.000, three-factor ANOVA), respectively, on the plant density of bryophytes, and a highly significant positive effect on the chlorophyll a and exopolysaccharide contents (P=0.000, P=0.000; P=0.000, P=0.000; one-way ANOVA). Knop nutrient solution did not have a significant positive but rather negative effect on the promotion of moss-dominated crust development (P=0.270, three-factor ANOVA). Moss-dominated crusts treated with the combination of moderate-intensity light (6,000 lx) + high watering frequency (1 watering/2 days) - Knop had the highest moss plant densities, while the treatment with high-intensity light (12,000 lx) + high watering frequency (1 watering/2 days) + Knop nutrient solution had higher chlorophyll a contents than that under other treatments. It is entirely feasible to achieve the rapid development of moss crusts under laboratory conditions by regulating key factors and creating the right environment. Future applications may seek to use cultured bryophytes to control erosion in vulnerable areas with urgent needs. PMID- 26230325 TI - Intestinal Commitment and Maturation of Human Pluripotent Stem Cells Is Independent of Exogenous FGF4 and R-spondin1. AB - Wnt/beta-catenin signaling plays a central role in guiding the differentiation of the posterior parts of the primitive gut tube into intestinal structures in vivo and some studies suggest that FGF4 is another crucial factor for intestinal development. The aim of this study was to define the effects of Wnt and FGF4 on intestinal commitment in vitro by establishing conditions for differentiation of human pluripotent stem cells (hPSC) into posterior endoderm (hindgut) and further to self-renewing intestinal-like organoids. The most prominent induction of the well-established intestinal marker gene CDX2 was achieved when hPSC-derived definitive endoderm cells were treated with Wnt agonist molecule CHIR99021 during differentiation to hindgut. FGF4 was found to be dispensable during intestinal commitment, but it had an early role in repressing development towards the hepatic lineage. When hindgut stage cells were further cultured in 3D, they formed self-renewing organoid structures containing all major intestinal cell types even without exogenous R-spondin1 (RSPO1), a crucial factor for the culture of epithelial organoids derived from adult intestine. This may be explained by the presence of a mesenchymal compartment in the hPSC-derived organoids. Addition of WNT3A increased the expression of the Paneth cell marker Lysozyme in hPSC derived organoid cultures, whereas FGF4 inhibited both the formation and maturation of intestinal-like organoids. Similar hindgut and organoid cultures were established from human induced pluripotent stem cells, implying that this approach can be used to create patient-specific intestinal tissue models for disease modeling in vitro. PMID- 26230327 TI - Prospective Study of Wound Infections in Mohs Micrographic Surgery Using a Single Set of Instruments. AB - BACKGROUND: Mohs micrographic surgery (MMS) has a low rate of surgical site infections (SSI). To date, there are variations in the measures surgeons take to prevent SSI, although these may be costly without benefit to patients. OBJECTIVE: The purpose of the study was to evaluate the rate of SSI in MMS performed with a clean technique using a single set of instruments for both tumor extirpation and reconstruction. MATERIALS AND METHODS: The author prospectively evaluated 338 patients undergoing MMS using a single set of instruments for SSI. RESULTS: There were 7 SSI among 332 patients, with an overall infection rate of 2.1% (7/332). Graft closures had an SSI rate of 3.1% (2/64) and flap closures had an SSI rate of 1.9% (5/268). CONCLUSION: Using a single set of sterile surgical instruments for both the tumor extirpation and repair stages of MMS leads to cost savings without harming patients and maintains SSI rates within an acceptable range. PMID- 26230328 TI - Commentary on Prospective Study of Wound Infections in Mohs Micrographic Surgery Using a Single Set of Instruments. PMID- 26230329 TI - What Is the Best Method for Removing Biopsy-Proven Atypical Nevi? A Comparison of Margin Clearance Rates Between Reshave and Full-Thickness Surgical Excisions. AB - BACKGROUND: It is a common practice to biopsy clinically atypical nevi, which may signify an individual's increased risk of developing melanoma. There is no consensus in the current literature, however, as to what the best method is to manage biopsy-proven atypical nevi. OBJECTIVE: The objective was to compare margin clearance rates between reshave excision and full-thickness surgical excision performed to manage biopsy-proven atypical nevi. MATERIALS AND METHODS: In this retrospective observational study, histopathology specimens from 201 patients whose atypical nevi were surgically removed were analyzed. RESULTS: For the majority (76%-79%) of the atypical nevi studied, all atypical melanocytes were removed by the initial shave biopsy. Of those atypical nevi with positive margins, shave re-excision was shown to have a lower clearance rate (76.2%) when compared with surgical excision (87.5%). CONCLUSION: This study shows that in most cases, no residual atypical melanocytes are left after the initial shave biopsy. However, of the lesions where margins are not clear, full-thickness surgical excision may have a higher rate of success at eventual clearance than reshave excision. PMID- 26230326 TI - The Effects of Xanthine Oxidoreductase Inhibitors on Oxidative Stress Markers following Global Brain Ischemia Reperfusion Injury in C57BL/6 Mice. AB - We demonstrated that 3-nitrotyrosine and 4-hydroxy-2-nonenal levels in mouse brain were elevated from 1 h until 8 h after global brain ischemia for 14 min induced with the 3-vessel occlusion model; this result indicates that ischemia reperfusion injury generated oxidative stress. Reactive oxygen species production was observed not only in the hippocampal region, but also in the cortical region. We further evaluated the neuroprotective effect of xanthine oxidoreductase inhibitors in the mouse 3-vessel occlusion model by analyzing changes in the expression of genes regulated by the transcription factor nuclear factor-kappa B (including pro-inflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), matrix metalloproteinase-9 and intercellular adhesion molecules-1). Administration of allopurinol resulted in a statistically significant decrease in IL-1beta and TNF-alpha mRNA expression, whereas febuxostat had no significant effect on expression of these genes; nevertheless, both inhibitors effectively reduced serum uric acid concentration. It is suggested that the neuroprotective effect of allopurinol is derived not from inhibition of reactive oxygen species production by xanthine oxidoreductase, but rather from a direct free-radical-scavenging effect. PMID- 26230330 TI - Clinical Experience With 11,460 mL of a 20-mg/mL, Smooth, Highly Cohesive, Viscous Hyaluronic Acid Filler. AB - BACKGROUND: A 3-dimensional approach to facial rejuvenation restores volume lost over time. Hyaluronic acid (HA) filling agents provide long-lasting correction with minimal side effects and a high level of patient satisfaction. The newest HA formulation is a 20-mg/mL smooth cohesive filler (Juvederm Voluma [HA-V]) that combines both low- and high-molecular-weight HA for more efficient cross-linking and greater lift capabilities. OBJECTIVE: To document the clinical experience with HA-V over the course of 68 months. MATERIALS AND METHODS: The authors conducted a retrospective chart review of patients who received HA-V for facial augmentation between February 1, 2009, and October 1, 2014. Clinical results were assessed 2 weeks after initial treatment, with touch-ups performed as necessary. Color photographs were taken before and after treatment, and adverse events were documented. RESULTS: Over 68 months, the authors treated 2,342 patients with 11,460 mL of HA-V. Aesthetic results lasted upwards of 12 months, and most side effects were transient and mild. Three patients developed signs of vascular compromise that was promptly treated and resolved within 2 months. Twenty-one patients (<0.5%) experienced late-onset, temporary, nontender nodules that were successfully managed with conservative measures. CONCLUSION: Easy to use and well tolerated, HA-V is ideally formulated for soft-tissue augmentation in the face, with clinical effects lasting 12 months or longer. PMID- 26230331 TI - An Open-Label, Multicenter, Evaluator-Blinded Study to Assess the Efficacy and Safety of a New Hyaluronic Acid-Based Gel Product for Lip Enhancement. AB - BACKGROUND: A stabilized hyaluronic acid (HA)-based lidocaine-containing gel of nonanimal origin has been developed for lip enhancement. OBJECTIVE: To evaluate the efficacy, safety, and injection procedure of the HA gel in subjects seeking lip enhancement. METHODS: Thirty subjects were treated in the upper and lower lips. Retreatment was offered at 3 months. Efficacy was assessed over 9 months using the Global Aesthetic Improvement Scale (GAIS), the Medicis Lip Fullness Scale, and a subject questionnaire. Safety was assessed by a 14-day subject diary and recording of adverse events (AEs) during the whole study. RESULTS: Over 9 months after treatment, 86% to 97% of subjects and independent evaluators assessed both lips as improved. At all study visits, 72% to 93% of the subjects were satisfied with their lips and >=96% reported that their lips had a natural look. Most AEs were mild-to-moderate local injection site reactions. CONCLUSION: Lip enhancement with this HA-based gel generated high subject satisfaction and natural-looking lips. The effect lasted for up to 9 months according to the GAIS ratings by subjects and independent evaluators. The product was well tolerated; most AEs were mild-to-moderate local injection site reactions. PMID- 26230332 TI - Brief Report: Significant Decreases in Both Total and Unbound Lopinavir and Amprenavir Exposures During Coadministration: ACTG Protocol A5143/A5147s Results. AB - This secondary analysis explored changes in protein-unbound concentrations of lopinavir and amprenavir when coadministered in HIV-infected subjects. Total and unbound pharmacokinetic parameters were calculated and compared between subjects receiving each agent alone and coadministration. When coadministered, unbound and total concentrations decrease. Coadministration significantly increased lopinavir unbound clearance, while significant changes in fraction unbound (fu) were not detected. For amprenavir, significant increases in fu and unbound clearance occurred with coadministration. This demonstrates the complex nature of drug-drug interactions between highly protein-bound, CYP-metabolized drugs, and the need to measure unbound concentrations in disease states such as hepatitis C, where such agents are coadministered. PMID- 26230333 TI - Effect of Twice-Daily Blue Light Treatment on Matrix-Rich Biofilm Development. AB - BACKGROUND: The use of blue light has been proposed as a direct means of affecting local bacterial infections, however the use of blue light without a photosensitizer to prevent the biofilm development has not yet been explored. The aim of this study was to determine how the twice-daily treatment with blue light affects the development and composition of a matrix-rich biofilm. METHODOLOGY/PRINCIPAL FINDINGS: Biofilms of Streptococcus mutans UA159 were formed on saliva-coated hydroxyapatite discs for 5 days. The biofilms were exposed twice-daily to non-coherent blue light (LumaCare; 420 nm) without a photosensitizer. The distance between the light and the sample was 1.0 cm; energy density of 72 J cm-2; and exposure time of 12 min 56 s. Positive and negative controls were twice-daily 0.12% chlorhexidine (CHX) and 0.89% NaCl, respectively. Biofilms were analyzed for bacterial viability, dry-weight, and extra (EPS insoluble and soluble) and intracellular (IPS) polysaccharides. Variable pressure scanning electron microscopy and confocal scanning laser microscopy were used to check biofilm morphology and bacterial viability, respectively. When biofilms were exposed to twice-daily blue light, EPS-insoluble was reduced significantly more than in either control group (CHX and 0.89% NaCl). Bacterial viability and dry weight were also reduced relative to the negative control (0.89% NaCl) when the biofilms were treated with twice-daily blue light. Different morphology was also visible when the biofilms were treated with blue light. CONCLUSIONS: Twice daily treatment with blue light without a photosensitizer is a promising mechanism for the inhibition of matrix-rich biofilm development. PMID- 26230334 TI - A Decision Support System Coupling Fuzzy Logic and Probabilistic Graphical Approaches for the Agri-Food Industry: Prediction of Grape Berry Maturity. AB - Agri-food is one of the most important sectors of the industry and a major contributor to the global warming potential in Europe. Sustainability issues pose a huge challenge for this sector. In this context, a big issue is to be able to predict the multiscale dynamics of those systems using computing science. A robust predictive mathematical tool is implemented for this sector and applied to the wine industry being easily able to be generalized to other applications. Grape berry maturation relies on complex and coupled physicochemical and biochemical reactions which are climate dependent. Moreover one experiment represents one year and the climate variability could not be covered exclusively by the experiments. Consequently, harvest mostly relies on expert predictions. A big challenge for the wine industry is nevertheless to be able to anticipate the reactions for sustainability purposes. We propose to implement a decision support system so called FGRAPEDBN able to (1) capitalize the heterogeneous fragmented knowledge available including data and expertise and (2) predict the sugar (resp. the acidity) concentrations with a relevant RMSE of 7 g/l (resp. 0.44 g/l and 0.11 g/kg). FGRAPEDBN is based on a coupling between a probabilistic graphical approach and a fuzzy expert system. PMID- 26230335 TI - Spatiotemporal Patterns of Tumor Occurrence in Children with Intraocular Retinoblastoma. AB - PURPOSE: To accurately map the retinal area covered by tumor in a prospectively enrolled cohort of children diagnosed with retinoblastoma. METHODS: Orbital MRI in 106 consecutive retinoblastoma patients (44 bilateral) was analyzed. For MRI visible tumors, the polar angle and angle of eccentricity of points defining tumor perimeter on the retina were determined by triangulation from images in three orthogonal planes. The centroid of the mapped area was calculated to approximate tumor origin, and the location and cumulative tumor burden were analyzed in relation to mutation type (germline vs. somatic), tumor area, and patient age at diagnosis. Location of small tumors undetected by MRI was approximated with fundoscopic images. RESULTS: Mapping was successful for 129 tumors in 91 eyes from 67 patients (39 bilateral, 43 germline mutation). Cumulative tumor burden was highest within the macula and posterior pole and was asymmetrically higher within the inferonasal periphery. Tumor incidence was lowest in the superotemporal periphery. Tumor location varied with age at diagnosis in a complex pattern. Tumor location was concentrated in the macula and superonasal periphery in patients <5.6 months, in the inferotemporal quadrant of the posterior pole in patients 5.6-8.8 months, in the inferonasal quadrant in patients 8.8-13.2 months, and in the nasal and superotemporal periphery in patients >13.2 months. The distribution of MRI-invisible tumors was consistent with the asymmetry of mapped tumors. CONCLUSIONS: MRI-based mapping revealed a previously unrecognized pattern of retinoblastoma localization that evolves with age at diagnosis. The structured spatiotemporal distribution of tumors may provide valuable clues about cellular or molecular events associated with tumorigenesis in the developing retina. PMID- 26230336 TI - Income Disparities and the Global Distribution of Intensively Farmed Chicken and Pigs. AB - The rapid transformation of the livestock sector in recent decades brought concerns on its impact on greenhouse gas emissions, disruptions to nitrogen and phosphorous cycles and on land use change, particularly deforestation for production of feed crops. Animal and human health are increasingly interlinked through emerging infectious diseases, zoonoses, and antimicrobial resistance. In many developing countries, the rapidity of change has also had social impacts with increased risk of marginalisation of smallholder farmers. However, both the impacts and benefits of livestock farming often differ between extensive (backyard farming mostly for home-consumption) and intensive, commercial production systems (larger herd or flock size, higher investments in inputs, a tendency towards market-orientation). A density of 10,000 chickens per km2 has different environmental, epidemiological and societal implications if these birds are raised by 1,000 individual households or in a single industrial unit. Here, we introduce a novel relationship that links the national proportion of extensively raised animals to the gross domestic product (GDP) per capita (in purchasing power parity). This relationship is modelled and used together with the global distribution of rural population to disaggregate existing 10 km resolution global maps of chicken and pig distributions into extensive and intensive systems. Our results highlight countries and regions where extensive and intensive chicken and pig production systems are most important. We discuss the sources of uncertainties, the modelling assumptions and ways in which this approach could be developed to forecast future trajectories of intensification. PMID- 26230337 TI - Negative Skeletal Effects of Locally Produced Adiponectin. AB - Epidemiological studies show that high circulating levels of adiponectin are associated with low bone mineral density. The effect of adiponectin on skeletal homeostasis, on osteoblasts in particular, remains controversial. We investigated this issue using mice with adipocyte-specific over-expression of adiponectin (AdTg). MicroCT and histomorphometric analysis revealed decreases (15%) in fractional bone volume in AdTg mice at the proximal tibia with no changes at the distal femur. Cortical bone thickness at mid-shafts of the tibia and at the tibiofibular junction was reduced (3-4%) in AdTg mice. Dynamic histomorphometry at the proximal tibia in AdTg mice revealed inhibition of bone formation. AdTg mice had increased numbers of adipocytes in close proximity to trabecular bone in the tibia, associated with increased adiponectin levels in tibial marrow. Treatment of BMSCs with adiponectin after initiation of osteoblastic differentiation resulted in reduced mineralized colony formation and reduced expression of mRNA of osteoblastic genes, osterix (70%), Runx2 (52%), alkaline phosphatase (72%), Col1 (74%), and osteocalcin (81%). Adiponectin treatment of differentiating osteoblasts increased expression of the osteoblast genes PPARgamma (32%) and C/ebpalpha (55%) and increased adipocyte colony formation. These data suggest a model in which locally produced adiponectin plays a negative role in regulating skeletal homeostasis through inhibition of bone formation and by promoting an adipogenic phenotype. PMID- 26230339 TI - Development and initial validation of the Seated Posture Scale. AB - Literature shows that some health outcomes (e.g., eating, breathing, and speaking) are directly related to posture. Evidence of outcomes mediated by wheelchair seated posture is limited to interface pressure, physical function, and wheelchair skills and safety. This study's purpose was to develop and validate a rapid, low-burden, paper-pencil assessment of wheelchair seated posture for research use and to test feasibility of its use with a sample of older adults. We used a prospective design and a convenience sample of older adults who were receiving rehabilitation services in a community living center. Forty-nine older wheelchair users participated. Main measures were the Seated Posture Scale (SPS), Modified Ashworth Scale, Barthel Index, Visual Descriptor Scale, scale-content validity index (S-CVI), Cronbach alpha, and test-retest reliability. Rating by six experts yielded the overall content validity score (S CVI) of 0.744. Total SPS score correlated positively with physical function (Barthel Index, r = 0.46, p < 0.001) and negatively with muscle tone (Modified Ashworth Scale, r = -0.44, p = 0.001), supporting SPS construct validity. Internal consistency was 0.66 (Cronbach alpha). Test-retest reliability yielded Pearson product-moment correlations of 0.89 to 0.99. We conclude that the SPS has sufficient preliminary validity and reliability to support its use as an evaluation of wheelchair seated posture in outcomes research. PMID- 26230338 TI - Preferential Interactions and the Effect of Protein PEGylation. AB - BACKGROUND: PEGylation is a strategy used by the pharmaceutical industry to prolong systemic circulation of protein drugs, whereas formulation excipients are used for stabilization of proteins during storage. Here we investigate the role of PEGylation in protein stabilization by formulation excipients that preferentially interact with the protein. METHODOLOGY/PRINCIPAL FINDINGS: The model protein hen egg white lysozyme was doubly PEGylated on two lysines with 5 kDa linear PEGs (mPEG-succinimidyl valerate, MW 5000) and studied in the absence and presence of preferentially excluded sucrose and preferentially bound guanine hydrochloride. Structural characterization by far- and near-UV circular dichroism spectroscopy was supplemented by investigation of protein thermal stability with the use of differential scanning calorimetry, far and near-UV circular dichroism and fluorescence spectroscopy. It was found that PEGylated lysozyme was stabilized by the preferentially excluded excipient and destabilized by the preferentially bound excipient in a similar manner as lysozyme. However, compared to lysozyme in all cases the melting transition was lower by up to a few degrees and the calorimetric melting enthalpy was decreased to half the value for PEGylated lysozyme. The ratio between calorimetric and van't Hoff enthalpy suggests that our PEGylated lysozyme is a dimer. CONCLUSION/SIGNIFICANCE: The PEGylated model protein displayed similar stability responses to the addition of preferentially active excipients. This suggests that formulation principles using preferentially interacting excipients are similar for PEGylated and non-PEGylated proteins. PMID- 26230341 TI - [Sarcopenia: toward its clinical utilisation]. AB - Sarcopenia is a term that was introduced to describe 'low muscle mass'. There is no consensus definition for sarcopenia; a variety of criteria are being used to establish the diagnosis of 'sarcopenia'. Depending on the criteria used, the prevalence of sarcopenia in elderly varies from 7% to over 50%. The presence of sarcopenia often remains unrecognized when the loss of muscle mass is replaced by fat and connective tissue; body weight thus remains stable or even increases. Sarcopenia can be detected by measuring muscle mass with dual-energy X-ray absorptiometry (DEXA) or bioimpedance analysis (BIA). Besides the generation of strength, muscle tissue is an important internal organ involved in protein storage, glucose regulation, hormonal homeostasis and cellular communication. Systemic, cellular, neuromechanical factors and lifestyle are linked to the pathophysiology of sarcopenia. Sarcopenia is associated with higher mortality, dependency in activities of daily living, toxicity of chemotherapy, and disturbed glucose regulation. PMID- 26230340 TI - Panaxadiol Saponin and Dexamethasone Improve Renal Function in Lipopolysaccharide Induced Mouse Model of Acute Kidney Injury. AB - BACKGROUND: Acute kidney injury (AKI) is a serious complication of systemic inflammatory response syndrome (SIRS), which has a high mortality rate. Previous studies showed that panaxadiol saponin (PDS) and Dexamethasone have similar anti inflammatory properties and protect cardiopulmonary function in lipopolysaccharide (LPS)-induced septic shock rats. In the present study, we investigated whether PDS or Dexamethasone has a similar role in improving kidney function in LPS-induced AKI mice. METHODS AND RESULTS: Mice subjected to LPS (10 mg/kg) treatment exhibited AKI demonstrated by markedly increased blood urea nitrogen and creatinine levels compared with controls (P<0.01). However, PDS and Dexamethasone induce similar reverse effects on renal function, such as reduced serum creatinine and blood urea nitrogen levels compared with the LPS group (P<0.05). PDS decreased the production and release of tumor necrosis factor (TNF) alpha and interleukin (IL)-6 by inhibiting the NF-kappaB signaling pathway, down regulating inducible nitric oxide synthase protein expression levels and inhibiting oxidative stress. In most anti-AKI mechanisms, PDS and dexamethasone were similar, but PDS are better at inhibition of TNF production, promote SOD activity and inhibition of IKB phosphorylation. In addition, nuclear glucocorticoid receptor expression was markedly enhanced in PDS and Dexamethasone treatment groups. Further research is required to determine whether PDS can combine with the glucocorticoid receptor to enter the nucleus. CONCLUSION: This study demonstrated that PDS and dexamethasone have similar reverse amelioration for renal functions, and have potential application prospects in the treatment of sepsis-induced AKI. PMID- 26230342 TI - [An infant with an asymmetric mouth when crying or laughing]. AB - BACKGROUND: If a child cries with an asymmetrical mouth it can be a sign of a nerve compression or a developmental defect in a facial muscle. In the latter case, a 22q11 deletion can be the cause, and multiple organs might be involved. CASE DESCRIPTION: A 2-month-old infant was referred to the paediatric outpatient clinic because he had an asymmetrical mouth when crying or laughing. There were no further symptoms. Genetic investigations and ultrasounds of the heart and kidneys were performed to exclude an underlying syndrome caused by a 22q11 deletion. These revealed no significant findings. It appeared to be a case of isolated 'asymmetric crying facies' as a result of hypoplasia of the depressor anguli oris muscle. CONCLUSION: An asymmetrical mouth in an infant can be a part of a genetic syndrome, in which there can be anomalies in multiple organ systems. For this reason, additional investigations are essential in cases of 'asymmetric crying facies'. PMID- 26230343 TI - [Auto-intoxication with an illegal slimming product]. AB - BACKGROUND: Dexaprine is an illegal slimming product with known serious adverse cardiac effects. Despite warnings from the Netherlands Food and Consumer Product Safety Authority, Dexaprine is still readily available online. CASE DESCRIPTION: A 29-year-old woman was brought into the emergency room after a suicide attempt with 29 Dexaprine tablets. The symptoms on admission were agitation, nausea and vomiting, hypotension, atrioventricular nodal reentrant tachycardia and hypothermia. Extensive drug screening revealed that Dexaprine contains caffeine, amphetamine and theophylline, explaining the symptoms. The patient was admitted to the intensive care unit for supportive therapy overnight before being discharged. CONCLUSIONS: In contrast to the advertised composition, Dexaprine contains several pharmacologically active substances including caffeine, amphetamine and theophylline. In intoxications caused by products of unknown composition, additional toxicological screening is invaluable to determine the extent and severity of intoxication. In this case, the patient's symptoms were due to theophylline intoxication. Ultimately, the theophylline levels did not indicate additional treatment such as haemodialysis. PMID- 26230344 TI - [A young woman with skin necrosis after sclerotherapy]. AB - A 23-year-old woman developed painful skin necrosis after injections with lauromacrogol 400 for varicose veins. This complication, called embolia cutis medicamentosa or Nicolau syndrome, is characterised by acute pain and necrosis of the skin, subcutaneous tissue and muscle. Surgical intervention by local excision seems to be the best therapy. PMID- 26230345 TI - [A woman with a chronic wound on her index finger]. AB - A 79-year-old woman consulted a plastic surgeon, because since 3 years she had a large wound at the base of her left index finger. Histology of a skin biopsy showed cutaneous squamous cell carcinoma. Because of the extension of the defect, amputation of the index finger with a split-skin-graft was performed. PMID- 26230346 TI - [A boy with a chronic swelling of the upper lip]. AB - A 14-year-old boy developed a chronic painless swelling of the upper lip. Histology of a skin biopsy showed non-necrotizing tuberculoid granulomas. The diagnosis cheilitis granulomatosa was made. PMID- 26230347 TI - [Broadening of opportunities for research with older persons: adaptation of the Medical Research Involving Human Subjects Act]. AB - Older persons represent a growing proportion of the population. However, few of them participate in medical research. Moreover, amendments have been proposed to the Medical Research Involving Human Subjects Act (WMO) concerning the participation of vulnerable subjects such as older persons. In light of these changes, the Dutch Ministry of Health, Welfare and Sport sought to develop a guideline to improve the quality of research involving older persons. This guideline will also be a tool for researchers to enhance the inclusion of older persons in their medical research. It focuses on six aspects to consider when setting up a research project: recruitment, informed consent, attrition, reluctance to participate, proportionality between the burden for participants and the benefits for the investigator, and societal relevance. PMID- 26230348 TI - [Dichotomy of psychiatric and somatic emergency care; fundamental flaw should be addressed]. AB - In the Netherlands, acute psychiatric care is characterised by mind-body dualism. For acute psychiatric patients, the first port of call is the general practitioner (GP); after-hour care is provided by the out-of-hours GP service. In contrast to patients with other medical illnesses, the out-of-hours GP service does not usually refer patients with acute psychiatric issues to the accident and emergency (A&E) department of the general hospital, but to the local ambulant psychiatric 'crisis' service. However, some of these patients still end up at the A&E department, as our three cases demonstrate. Integration of the out-of-hours GP service, A&E and acute psychiatric care, therefore, would enable elimination of the current partitioning of somatic and psychiatric medicine in acute emergency care. This solution would not only improve acute emergency care, but would also ensure a targeted and efficient implementation of services and might even lead to a decreased stigmatisation of psychiatric patients in general. PMID- 26230349 TI - [The European Working Time Directive and surgical residents' expertise: no effect on the number of operations]. AB - Residents' working hours in the Netherlands were first capped in the early 1990 s. In 2003, European legislation consolidated restrictions to a 48-hour week. No adverse effects were seen on the number of surgical operations performed either in the first or the second decade following these measures. Either the effect on surgical training is minimal, or the number of operations carried out during a residency is not a meaningful indicator of its quality. Personalized modular rotations in both university and teaching hospitals are needed for residents with sub-specializations. Training activities, in combination with more supervision, have to focus on a broader set of competencies beyond simply mastering surgical procedures. PMID- 26230350 TI - [The listening doctor; appropriate care in the last phase of life]. AB - In his report 'Everything that can be done should not necessarily be done. Appropriate care in the last phase of life', the chairman of the steering committee of the Royal Dutch Medical Association says: 'I wish that doctors would listen to their patients.' This wish sets the tone of the report, which signals overtreatment in patients' last years of life and advocates a more restrained approach by doctors in this phase. The message is, however, that for this to take place a complete U-turn in modern medical thinking and management is needed. PMID- 26230351 TI - Pollinator power: Nutrition security benefits of an ecosystem service. PMID- 26230352 TI - Differential influence of maternal and fetal pregnancy factors on the in-vitro induction of human regulatory T cells: a preliminary study. AB - PROBLEM: Given the important role of regulatory T cells (Treg) for successful pregnancy, the ability of soluble maternal and fetal pregnancy factors to induce human Treg was investigated. METHOD OF STUDY: Peripheral blood mononuclear cells (PBMCs) or isolated CD4+CD25- cells were cultured in the presence of pooled second or third trimester pregnancy sera, steroid hormones or supernatants from placental explants, and the numbers and function of induced CD4+CD25+FOXP3+ Treg were analysed. RESULTS: Third trimester pregnancy sera and supernatants of early placental explants, but not sex steroid hormones, induced an increase of Tregs from PBMCs. Early placental supernatant containing high levels of tumour necrosis factor-alpha, interferon-gamma, interleukins -1, -6 and -17, soluble human leucocyte antigen-G, and transforming growth factor-beta1, increased the proportion of Treg most effectively and was able to induce interleukin-10 secreting-Treg from CD4+CD25-cells. CONCLUSIONS: Compared with circulating maternal factors, placental- and fetal-derived factors appear to exert a more powerful effect on numerical changes of Treg, thereby supporting fetomaternal tolerance during human pregnancy. PMID- 26230353 TI - Pentafulvene for the synthesis of complex natural products: total syntheses of (+/-)-pallambins A and B. AB - The first total syntheses of pallambins A and B are enabled by the use of pentafulvene in an unprecedented Diels-Alder reaction. After elaboration of the adduct through chemoselective cyclopropanation, strategic C?H insertion affords the dense tetracyclic core of the natural products. 1,3-Dipolar cycloaddition and palladium(II)-catalyzed alkoxycarbonylation were leveraged for the construction of the hexacyclic scaffold en route to both natural products. PMID- 26230354 TI - Factors affecting the success of next-generation sequencing in cytology specimens. AB - BACKGROUND: The use of cytology specimens for next-generation sequencing (NGS) is particularly challenging because of the unconventional substrate of smears and the often limited sample volume. An analysis of factors affecting NGS testing in cytologic samples may help to increase the frequency of successful testing. METHODS: This study reviewed variables associated with all in-house cytology cases (n = 207) that were analyzed by NGS with the Ion Torrent platform during a 10-month interval. A statistical analysis was performed to measure the effects of the DNA input threshold, specimen preparation, slide type, tumor fraction, DNA yield, and cytopathologist bias. RESULTS: One hundred sixty-four of 207 cases (79%) were successfully sequenced by NGS; 43 (21%) failed because of either a low DNA yield or a template/library preparation failure. The median estimated tumor fraction and DNA concentration for the successfully sequenced cases were 70% and 2.5 ng/MUL, respectively, whereas they were 60% and 0.2 ng/MUL, respectively, for NGS failures. Cell block sections were tested in 91 cases, and smears were used in 116 cases. NGS success positively correlated with the DNA yield but not the tumor fraction. Cell block preparations showed a higher success rate than smears. Frosted-tip slides yielded significantly more DNA than fully frosted slides. Lowering the input DNA concentration below the manufacturer's recommended threshold of 10 ng (>0.85 ng/MUL) resulted in a marked increase in the NGS success rate from 58.6% to 89.8%. CONCLUSIONS: The failure of NGS with cytology samples is usually a result of suboptimal DNA due to multiple pre-analytical factors. Knowledge of these factors will allow better selection of cytology material for mutational analysis. PMID- 26230355 TI - Palladium-Catalyzed Synthesis of Phenanthridine/Benzoxazine-Fused Quinazolinones by Intramolecular C-H Bond Activation. AB - A highly efficient synthesis of phenanthridine/benzoxazine-fused quinazolinones by ligand-free palladium-catalyzed intramolecular C-H bond activation under mild conditions has been developed. The C-C coupling provides the corresponding N fused polycyclic heterocycles in good to excellent yields and with wide functional group tolerance. PMID- 26230357 TI - Screening for Anthracycline-Related Cardiac Dysfunction in Childhood Cancer Survivors: Can Less be More? PMID- 26230356 TI - Assessment and prevalence of pulmonary oedema in contemporary acute heart failure trials: a systematic review. AB - AIMS: Pulmonary oedema is a common and important finding in acute heart failure (AHF). We conducted a systematic review to describe the methods used to assess pulmonary oedema in recent randomized AHF trials and report its prevalence in these trials. METHODS AND RESULTS: Of 23 AHF trials published between 2002 and 2013, six were excluded because they were very small or not randomized, or missing full-length publications. Of the remaining 17 (n = 200-7141) trials, six enrolled patients with HF and reduced ejection fraction (HF-REF) and 11, patients with both HF-REF and HF with preserved ejection fraction (HF-PEF). Pulmonary oedema was an essential inclusion criterion, in most trials, based upon findings on physical examination ('rales'), radiographic criteria ('signs of congestion'), or both. The prevalence of pulmonary oedema in HF-REF trials ranged from 75% to 83% and in combined HF-REF and HF-PEF trials from 51% to 100%. Five trials did not report the prevalence or extent of pulmonary oedema assessed by either clinical examination or chest x-ray. Improvement of pulmonary congestion with treatment was inconsistently reported and commonly grouped with other signs of congestion into a score. One trial suggested that patients with rales over >2/3 of the lung fields on admission were at higher risk of adverse outcomes than those without. CONCLUSION: Although pulmonary oedema is a common finding in AHF, represents a therapeutic target, and may be of prognostic importance, recent trials used inconsistent criteria to define it, and did not consistently report its severity at baseline or its response to treatment. Consistent and ideally quantitative, methods for the assessment of pulmonary oedema in AHF trials are needed. PMID- 26230358 TI - Differential Expression of Adhesion-Related Proteins and MAPK Pathways Lead to Suitable Osteoblast Differentiation of Human Mesenchymal Stem Cells Subpopulations. AB - Cellular adhesion enables communication between cells and their environment. Adhesion can be achieved throughout focal adhesions and its components influence osteoblast differentiation of human mesenchymal stem cells (hMSCs). Because cell adhesion and osteoblast differentiation are closely related, this article aimed to analyze the expression profiles of adhesion-related proteins during osteoblastic differentiation of two hMSCs subpopulations (CD105(+) and CD105(-)) and propose a strategy for assembling bone grafts based on its adhesion ability. In vitro experiments of osteogenic differentiation in CD105(-) cells showed superior adhesion efficiency and 2-fold increase of alpha-actinin expression compared with CD105(+) cells at the maturation stage. Interestingly, levels of activated beta1-integrin increased in CD105(-) cells during the process. Additionally, the CD105(-) subpopulation showed 3-fold increase of phosphorylated FAK(Y397) compared to CD105(+) cells. Results also indicate that ERK1/2 was activated during CD105(-) bone differentiation and participation of mitogen activated protein kinase (MAPK)-p38 in CD105(+) differentiation through a focal adhesion kinase (FAK)-independent pathway. In vivo trial demonstrated that grafts containing CD105(-) showed osteocytes embedded in a mineralized matrix, promoted adequate graft integration, increased host vascular infiltration, and efficient intramembranous repairing. In contrast, grafts containing CD105(+) showed deficient endochondral ossification and fibrocartilaginous tissue. Based on the expression of alpha-actinin, FAKy,(397) and ERK1/2 activation, we define maturation stage as critical for bone graft assembling. By in vitro assays, CD105(-) subpopulation showed superior adhesion efficiency compared to CD105(+) cells. Considering in vitro and in vivo assays, this study suggests that integration of a scaffold with CD105(-) subpopulation at the maturation stage represents an attractive strategy for clinical use in orthopedic bioengineering. PMID- 26230359 TI - Comment on "Background Ionizing Radiation and the Risk of Childhood Cancer: A Census-Based Nationwide Cohort Study". PMID- 26230360 TI - Erratum: Structural and Dynamic Features of F-recruitment Site Driven Substrate Phosphorylation by ERK2. PMID- 26230361 TI - Correction to "Atomistic and Coarse Grain Topologies for the Cofactors Associated with the PhotoSystem II Core Complex". PMID- 26230362 TI - Evaluation of response to hormone therapy in patients with measurable adult granulosa cell tumors of the ovary. AB - INTRODUCTION: The aim of this study was to retrospectively determine the objective response rate to hormone therapy (HT) for patients with a measurable adult granulosa cell tumor (GCT) of the ovary in a consecutive series of patients. MATERIAL AND METHODS: All patients with an adult GCT who were treated with HT [steroidal progestins, selective estrogen receptor modulators, aromatase inhibitors and gonadotropin-releasing hormone agonists] within three referral hospitals were identified and their records were screened for HT administration. The main outcome measure was the objective response rate to HT. RESULTS: We identified 127 patients with an adult GCT, of whom 81 (64%) had a recurrence. Twenty-five of these patients (20%) were treated with hormones, of whom 22 had measurable disease at the start of their treatment, i.e. a tumor of more than 1 cm in diameter as seen on imaging, either as a recurrence or as residual disease. The pooled objective response rate, defined as the proportion of patients whose best overall response to hormone therapy was either complete response or partial response to HT, was 18% (4/22) (95% confidence interval 6-41%). In one patient (4.5%) a complete response and in three (14%) a partial response was described. Fourteen patients (64%) had stable disease and in four patients (18%) disease was progressive. CONCLUSIONS: Although several case reports described good responses to HT in patients with a GCT, we found a response in only four of 22 patients in this relatively large consecutive series of patients. PMID- 26230363 TI - Hexagonal Silicon Realized. AB - Silicon, arguably the most important technological semiconductor, is predicted to exhibit a range of new and interesting properties when grown in the hexagonal crystal structure. To obtain pure hexagonal silicon is a great challenge because it naturally crystallizes in the cubic structure. Here, we demonstrate the fabrication of pure and stable hexagonal silicon evidenced by structural characterization. In our approach, we transfer the hexagonal crystal structure from a template hexagonal gallium phosphide nanowire to an epitaxially grown silicon shell, such that hexagonal silicon is formed. The typical ABABAB... stacking of the hexagonal structure is shown by aberration-corrected imaging in transmission electron microscopy. In addition, X-ray diffraction measurements show the high crystalline purity of the material. We show that this material is stable up to 9 GPa pressure. With this development, we open the way for exploring its optical, electrical, superconducting, and mechanical properties. PMID- 26230364 TI - Interpreting equilibrium-conductivity and conductivity-relaxation measurements to establish thermodynamic and transport properties for multiple charged defect conducting ceramics. AB - A model-based interpretation of measured equilibrium conductivity and conductivity relaxation is developed to establish thermodynamic, transport, and kinetics parameters for multiple charged defect conducting (MCDC) ceramic materials. The present study focuses on 10% yttrium-doped barium zirconate (BZY10). In principle, using the Nernst-Einstein relationship, equilibrium conductivity measurements are sufficient to establish thermodynamic and transport properties. However, in practice it is difficult to establish unique sets of properties using equilibrium conductivity alone. Combining equilibrium and conductivity-relaxation measurements serves to significantly improve the quantitative fidelity of the derived material properties. The models are developed using a Nernst-Planck-Poisson (NPP) formulation, which enables the quantitative representation of conductivity relaxations caused by very large changes in oxygen partial pressure. PMID- 26230365 TI - Stereospecific Intramolecular Reductive Cross-Electrophile Coupling Reactions for Cyclopropane Synthesis. AB - The stereospecific reductive cross-electrophile coupling reaction of 2-aryl-4 chlorotetrahydropyrans to afford disubstituted cyclopropanes is reported. This ring contraction presents surprises with respect to the stereochemical outcome of reaction of the alkyl halide moiety. While cross-coupling and reductive cross electrophile coupling reactions of alkyl halides are typically stereoablative, using a chiral catalyst to set the stereocenter, this transformation proceeds with high stereochemical fidelity at the alkyl halide and ether bearing stereogenic centers. This approach provides straightforward access to highly substituted cyclopropanes in two steps from commercially available aldehydes. PMID- 26230366 TI - BDNF levels in adipose tissue and hypothalamus were reduced in mice with MSG induced obesity. AB - OBJECTIVES: To observe the expression of brain-derived neurotrophic factor (BDNF) in hypothalamic and adipose tissue in mice with monosodium glutamate (MSG) induced obesity. METHODS: The effects of hypothalamic lesions, specifically arcuate nucleus (ARC) lesions, induced by MSG injection were studied in male ICR mice at the neonatal stage. The following parameters were compared: body weight, body length, Lee's index, food intake, body temperature, fat weight, and levels of total cholesterol (CHOL), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and blood glucose (GLU). The BDNF expression levels in hypothalamic and adipose tissue were measured using western blotting. Results Compared with the control group, the model group body had significantly higher weight, Lee's index, food intake, fat weight, CHOL, TG, LDL, HDL, and GLU levels. BDNF expression levels in hypothalamic and adipose tissue were markedly down-regulated in the model group. DISCUSSION: BDNF may be closely associated with MSG-induced hypothalamic obesity. PMID- 26230367 TI - Functional Connectivity Between Superior Parietal Lobule and Primary Visual Cortex "at Rest" Predicts Visual Search Efficiency. AB - Spatiotemporal activity that emerges spontaneously "at rest" has been proposed to reflect individual a priori biases in cognitive processing. This research focused on testing neurocognitive models of visual attention by studying the functional connectivity (FC) of the superior parietal lobule (SPL), given its central role in establishing priority maps during visual search tasks. Twenty-three human participants completed a functional magnetic resonance imaging session that featured a resting-state scan, followed by a visual search task based on the alphanumeric category effect. As expected, the behavioral results showed longer reaction times and more errors for the within-category (i.e., searching a target letter among letters) than the between-category search (i.e., searching a target letter among numbers). The within-category condition was related to greater activation of the superior and inferior parietal lobules, occipital cortex, inferior frontal cortex, dorsal anterior cingulate cortex, and the superior colliculus than the between-category search. The resting-state FC analysis of the SPL revealed a broad network that included connections with the inferotemporal cortex, dorsolateral prefrontal cortex, and dorsal frontal areas like the supplementary motor area and frontal eye field. Noteworthy, the regression analysis revealed that the more efficient participants in the visual search showed stronger FC between the SPL and areas of primary visual cortex (V1) related to the search task. We shed some light on how the SPL establishes a priority map of the environment during visual attention tasks and how FC is a valuable tool for assessing individual differences while performing cognitive tasks. PMID- 26230368 TI - Evolution of Efficient Modular Polyketide Synthases by Homologous Recombination. AB - The structural scaffolds of many complex natural products are produced by multifunctional type I polyketide synthase (PKS) enzymes that operate as biosynthetic assembly lines. The modular nature of these mega-enzymes presents an opportunity to construct custom biocatalysts built in a lego-like fashion by inserting, deleting, or exchanging native or foreign domains to produce targeted variants of natural polyketides. However, previously engineered PKS enzymes are often impaired resulting in limited production compared to native systems. Here, we show a versatile method for generating and identifying functional chimeric PKS enzymes for synthesizing custom macrolactones and macrolides. PKS genes from the pikromycin and erythromycin pathways were hybridized in Saccharomyces cerevisiae to generate hybrid libraries. We used a 96-well plate format for plasmid purification, transformations, sequencing, protein expression, in vitro reactions and analysis of metabolite formation. Active chimeric enzymes were identified with new functionality. Streptomyces venezuelae strains that expressed these PKS chimeras were capable of producing engineered macrolactones. Furthermore, a macrolactone generated from selected PKS chimeras was fully functionalized into a novel macrolide analogue. This method permits the engineering of PKS pathways as modular building blocks for the production of new antibiotic-like molecules. PMID- 26230369 TI - National review of ambient air toxics observations. AB - Ambient air observations of hazardous air pollutant (HAPs), also known as air toxics, derived from routine monitoring networks operated by states, local agencies, and tribes (SLTs), are analyzed to characterize national concentrations and risk across the nation for a representative subset of the 187 designated HAPs. Observations from the National Air Toxics Trend Sites (NATTS) network of 27 stations located in most major urban areas of the contiguous United States have provided a consistent record of HAPs that have been identified as posing the greatest risk since 2003 and have also captured similar concentration patterns of nearly 300 sites operated by SLTs. Relatively high concentration volatile organic compounds (VOCs) such as benzene, formaldehyde, and toluene exhibit the highest annual average concentration levels, typically ranging from 1 to 5 ug/m(3). Halogenated (except for methylene chloride) and semivolatile organic compounds (SVOCs) and metals exhibit concentrations typically 2-3 orders of magnitude lower. Formaldehyde is the highest national risk driver based on estimated cancer risk and, nationally, has not exhibited significant changes in concentration, likely associated with the large pool of natural isoprene and formaldehyde emissions. Benzene, toluene, ethylbenzene, and 1,3-butadiene are ubiquitous VOC HAPs with large mobile source contributions that continue to exhibit declining concentrations over the last decade. Common chlorinated organic compounds such as ethylene dichloride and methylene chloride exhibit increasing concentrations. The variety of physical and chemical attributes and measurement technologies across 187 HAPs result in a broad range of method detection limits (MDLs) and cancer risk thresholds that challenge confidence in risk results for low concentration HAPs with MDLs near or greater than risk thresholds. From a national monitoring network perspective, the ability of the HAPs observational database to characterize the multiple pollutant and spatial scale patterns influencing exposure is severely limited and positioned to benefit by leveraging a variety of emerging measurement technologies. IMPLICATIONS: Ambient air toxics observation networks have limited ability to characterize the broad suite of hazardous air pollutants (HAPs) that affect exposures across multiple spatial scales. While our networks are best suited to capture major urban-scale signals of ubiquitous volatile organic compound HAPs, incorporation of sensing technologies that address regional and local-scale exposures should be pursued to address major gaps in spatial resolution. Caution should be exercised in interpreting HAPs observations based on data proximity to minimum detection limit and risk thresholds. PMID- 26230370 TI - Cytotoxic 19-oxygenated steroids from the South China Sea gorgonian, Pacifigorgia senta. AB - Bioassay guided chemical investigation of the gorgonian Pacifigorgia senta led to the discovery of a new 19-oxygenated steroid, cholesta-5,24-diene-3beta,7beta,19 triol (1), as well as three known steroids (2-4). The structure of 1 was determined by extensive spectroscopic analysis, including NMR and MS spectra. All of the compounds exhibited cytotoxicities against HepG2, Hep3B, MCF-7/ADR, PC-3 and HCT-116 cell lines, with the IC50 values ranging from 7.0 to 29.7 MUM. It is the first report on the chemical constituents of the coral species P. senta. PMID- 26230371 TI - Expression of Androgen Receptor in Estrogen Receptor-positive Breast Cancer. AB - OBJECTIVES: The aim of the study was to estimate the implications of androgen receptor (AR) expression in estrogen receptor (ER)-positive subset of invasive breast carcinoma patients. PATIENTS AND METHODS: We assessed the AR expression in a subset of 96 predominantly ER-positive invasive breast carcinomas and correlated this expression pattern with several clinical and pathologic parameters: histologic type and grade, tumor size, lymph node status, progesterone receptor (PgR) status, and human epidermal growth factor receptor type 2 (HER2) overexpression and evaluated the association of these parameters with 10-year survival using univariate and multivariate analyses. Data used for analysis were derived from medical records. Immunohistochemical analysis for AR, ER, PgR, and HER2 were carried out and semiquantitative evaluation of stainings was performed. RESULTS: AR expression was demonstrated in 43.7% of patients. AR was significantly related to well-differentiated tumors and positive PgR/HER2 status. No statistical difference was demonstrated in AR expression in relation to tumor size, lymph node status, menopausal status, and tumor histologic type. AR expression was not an independent prognostic factor related to 10-year survival in ER-positive cancers. In multivariate analyses, older age at diagnosis, larger tumor size, and positive lymph node status were significantly associated with poorer 10-year survival. CONCLUSIONS: AR expression is significantly associated with ER/PgR/HER2 status and positively related to well differentiated tumors. Although AR status in ER-positive cancers is not an independent prognostic factor, it might provide important additional information on prognosis and become a promising object for targeted therapy. PMID- 26230372 TI - Comparison of p63 and p40 (DeltaNp63) as Basal, Squamoid, and Myoepithelial Markers in Salivary Gland Tumors. AB - p40 is selective for DeltaNp63 isoforms and appears to be more specific for squamous differentiation than p63. Its performance as a basal/myoepithelial marker in salivary gland tumors has only rarely been addressed in the literature. We thus compared the performance of p63 and p40 (DeltaNp63) immunohistochemical stain as markers of basal, squamoid, and myoepithelial differentiation in 105 salivary gland tumors selected from our archives. The neoplasms were categorized according to their presumed phenotype as ductoacinar (n=45), biphasic (dual ductal and myoepithelial/basal differentiation, n=44), purely myoepithelial (n=5), and excretory duct phenotype (n=11). Only nuclear staining for p63 and p40 was considered positive. Distribution of staining was scored as: 0 (no staining), 1+ (1% to 25%), 2+ (26% to 50%), 3+ (51% to 75%), and 4+ (76% to 100%). Intensity was scored as weak, moderate, or strong. p63 and p40 highlighted the basal and myoepithelial cells in normal salivary gland tissue as well as basal/myoepithelial/squamoid elements in biphasic tumors, purely myoepithelial tumors, and excretory duct type tumors (4+ with strong staining for p63, and moderate staining for p40). All ductal tumors were negative for p40. However, 13/13 polymorphous low-grade adenocarcinoma/cribriform adenocarcinomas of salivary gland, 7/9 canalicular adenomas, and 3/5 mammary analog secretory carcinomas showed some degree of p63 staining. Thus, we confirm that p40 is a more specific basal/myoepithelial/squamoid marker than p63 in salivary gland tumors. A subset of ductal tumors show a discordant p63+/p40- immunoprofile that can be a pitfall if not recognized, but may also help distinguish these tumors from truly biphasic tumors and myoepithelial tumors. PMID- 26230373 TI - Calretinin-Immunoreactive Hypoinnervation in Down Syndrome (DS): Report of an Infant with Very Short-Segment Hirschsprung Disease and Comparison to Biopsy Findings in 20 Normal Infants and 11 Infants with DS and Chronic Constipation. AB - In Down syndrome (DS) constipation is common, and the incidence of Hirschsprung disease (HD) is 1-2%. Rectal suction biopsies (RSBs) in DS may show discordant features; calretinin immunoreactivity (CRir) often helps resolve discrepancies. We report a case of unequivocal very short-segment HD (vsHD) in an infant with DS who had aganglionosis with abnormal acetylcholine esterase (AChE) activity in 3 RSBs. The CRir patterns were scanty positive rather than the expected absent CRir innervation in the lamina propria (LP). The resection specimen was grossly typical for short-segment HD, with a 5.5-cm, narrow but normally ganglionated segment proximal to the verified very short distal anganglionic zone. Unequivocal calretinin hypoinnervation was limited to the distal 2 cm, substantiating the warning of Kapur that small numbers of CRir nerves in the LP do not exclude a diagnosis of vsHD. We evaluated RSBs from 11 DS and 20 randomly selected normal infants <6 months of age with chronic constipation. The normal infants had abundant mucosal calretinin innervation and AChE histochemistry. We observed variable CRir hypoinnervation in RSBs in DS infants (including 6/7 with "normal" original diagnosis and 1/4 with HD). Our findings caution against overdependence on "normal" calretinin immunohistochemistry and suggest that AChE may be more reliable than CRir in the context of DS. An unknown number of patients with DS may have enteric nervous system disorders functionally similar to HD, which are possibly related to abnormal or imbalanced autonomic innervation, of which distal calretinin hypoinnervation is one manifestation, despite the presence of ganglia. PMID- 26230375 TI - Motion capture for functional analysis of new biomaterials in a small animal model. PMID- 26230374 TI - Airway Inflammation after Bronchial Thermoplasty for Severe Asthma. AB - RATIONALE: Bronchial thermoplasty is an alternative treatment for patients with severe, uncontrolled asthma in which the airway smooth muscle is eliminated using radioablation. Although this emerging therapy shows promising outcomes, little is known about its effects on airway inflammation. OBJECTIVES: We examined the presence of bronchoalveolar lavage cytokines and expression of smooth muscle actin in patients with severe asthma before and in the weeks after bronchial thermoplasty. METHODS: Endobronchial biopsies and bronchoalveolar lavage samples from 11 patients with severe asthma were collected from the right lower lobe before and 3 and 6 weeks after initial bronchial thermoplasty. Samples were analyzed for cell proportions and cytokine concentrations in bronchoalveolar lavage and for the presence of alpha-SMA in endobronchial biopsies. MEASUREMENTS AND MAIN RESULTS: alpha-SMA expression was decreased in endobronchial biopsies of 7 of 11 subjects by Week 6. In bronchoalveolar lavage fluid, both transforming growth factor-beta1 and regulated upon activation, normal T-cell expressed and secreted (RANTES)/CCL5 were substantially decreased 3 and 6 weeks post bronchial thermoplasty in all patients. The cytokine tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in several cell types, was increased in concentration both 3 and 6 weeks post bronchial thermoplasty. CONCLUSIONS: Clinical improvement and reduction in alpha-SMA after bronchial thermoplasty in severe, uncontrolled asthma is associated with substantial changes in key mediators of inflammation. These data confirm the substantial elimination of airway smooth muscle post thermoplasty in the human asthmatic airway and represent the first characterization of significant changes in airway inflammation in the first weeks after thermoplasty. PMID- 26230376 TI - Occupational allergic contact dermatitis caused by epoxy chemicals: occupations, sensitizing products, and diagnosis. AB - BACKGROUND: Epoxy products are among the most common causes of occupational allergic contact dermatitis. Diglycidyl ether of bisphenol A resin (DGEBA-R) is the most important sensitizer in epoxy systems. OBJECTIVES: To describe patients with occupational allergic contact dermatitis caused by epoxy products. METHODS: Patients with allergic reactions to epoxy chemicals were chosen from test files (January 1991 to June 2014). Only patients with occupational contact allergy to some component of epoxy resin systems were included. We analysed patch test results, occupation, symptoms, and exposure data. RESULTS: We found a total of 209 cases with occupational contact allergy to epoxy chemicals. The largest occupational groups were painters (n = 41), floor layers (n = 19), electrical industry workers (n = 19), tile setters (n = 16), and aircraft industry workers (n = 15). A total of 82% of the patients reacted to DGEBA-R. Diagnosis of the DGEBA-R-negative patients required testing with m-xylylenediamine, N,N' tetraglycidyl-4,4'-methylenedianiline, 1,4-butanediol diglycidyl ether, 2,4,6 tris-(dimethylaminomethyl)phenol, diglycidyl ether of bisphenol F resin, N,N' diglycidyl-4-glycidyloxyaniline, isophoronediamine, 4,4'-diaminodiphenylmethane, diethylenetriamine, and cresyl glycidyl ether. The hands/upper extremities were most commonly affected (69%), but facial symptoms were also frequent (60%). CONCLUSIONS: Allergic contact dermatitis caused by to epoxy products cannot always be diagnosed by the use of commercial test substances. Workplace products need to be tested. PMID- 26230377 TI - Interprofessional experiences of recent healthcare graduates: A social psychology perspective on the barriers to effective communication, teamwork, and patient centred care. AB - Achieving safe, quality health care is highly dependent on effective communication between all members of the healthcare team. This study explored the attitudes and experiences of recent healthcare graduates regarding interprofessional teamwork and communication within a clinical setting. A total of 68 pharmacy, nursing, and medicine graduates participated in 12 semi structured focus group discussions in clinical workplaces across three Australian states. Discussion focussed on graduates' experiences of interprofessional education and its impact on their capacity for interprofessional teamwork and communication. The Social Identity and Realistic Conflict theories were used as a framework for qualitative data analysis. A consistent pattern of profession focussed, rather than patient- or team-focussed goals was revealed along with reports of negative stereotyping, hierarchical communication, and competition for time with the patient. Graduates acknowledged the importance of communication, teamwork, and patient-centred care and felt a better understanding of the roles of other health professionals would assist them to work together for patients' wellbeing. Identifying workplace identities and differential goals has uncovered possible motivations underlying health professionals' behaviour. These insights may help improve interprofessional collaboration by focusing attention on common team goals, increasing feelings of worth and being valued among different professionals, and decreasing the need for competition. PMID- 26230378 TI - Using learning theory, interprofessional facilitation competencies, and behavioral indicators to evaluate facilitator training. AB - Despite the increasing need for faculty and preceptors skilled in interprofessional facilitation (IPF), the relative novelty of the field poses a challenge to the development and evaluation of IPF programs. We use learning theory and IPF competencies with associated behavioral indicators to develop and evaluate six key messages in IPF training and experience. Our mixed methods approach included two phases: quantitative data collection with embedded qualitative data, followed by qualitative data collection in explanatory sequential fashion. This enabled triangulated analyses of both data types and of facilitation behaviors from facilitator and student perspectives. Results indicate the competency-based training was effective. Facilitators felt comfortable performing behaviors associated with IPF competencies; student observations of those behaviors supported facilitator self-reported performance. Overall, students perceived more facilitation opportunities than facilitators. Findings corroborate the importance of recruiting seasoned facilitators and establishing IPF guidelines that acknowledge variable team dynamics and help facilitators recognize teachable moments. PMID- 26230379 TI - Setting a research agenda for interprofessional education and collaborative practice in the context of United States health system reform. AB - Interprofessional education (IPE) and collaborative practice (CP) have been prolific areas of inquiry exploring research questions mostly concerned with local program and project assessment. The actual sphere of influence of this research has been limited. Often discussed separately, this article places IPE and CP in the same conceptual space. The interface of these form a nexus where new knowledge creation may be facilitated. Rigorous research on IPE in relation to CP that is relevant to and framed by health system reform in the U.S. is the ultimate research goal of the National Center for Interprofessional Practice and Education at the University of Minnesota. This paper describes the direction and scope for a focused and purposive IPECP research agenda linked to improvement in health outcomes, contextualized by health care reform in the U.S. that has provided a revitalizing energy for this area of inquiry. A research agenda articulates a focus, meaningful and robust questions, and a theory of change within which intervention outcomes are examined. Further, a research agenda identifies the practices the area of inquiry is interested in informing, and the types of study designs and analytic approaches amenable to carrying out the proposed work. PMID- 26230380 TI - Boundary work in inter-agency and interprofessional client transitions. AB - This article analyses the accomplishment of boundary work performed by professionals engaged in inter-agency collaboration. As a means of building authority within a particular field, boundary work is found to be a common feature of most professional practices. By analysing the talk of Finnish professionals who work in the field of supported housing in mental health, the article investigates the ways professionals--as collective representatives of their service--talk about doing boundary work when transferring their clients to another agency. The study drew on the principles of exploratory case study design and ethnomethodology. A key finding from the analysis of professionals' focus groups and team meetings indicated that boundary work is employed when disputes arise between supported housing and collaborating agencies. The article goes on to suggest that professionals accomplish boundary work by rhetorically presenting themselves as holders of "day-to-day evidence" of clients' mundane living skills and serious ill-health. The paper concludes by arguing that in inter-agency collaboration, boundary work building on day-to-day evidence is used to influence the decision on the most appropriate living arrangement for the client. Boundary work is also used for boosting the authority of professionals as representatives of a relatively new and fixed-term agency in the service system. PMID- 26230381 TI - Aberrant CYP2D6 metabolizer phenotypes do not show increased frequency in patients undergoing ECT after antidepressant therapy. AB - We investigated the accumulation of aberrant CYP2D6 genotypes and predicted metabolizer phenotypes (ultrarapid metabolizer, intermediate metabolizer and poor metabolizer) potentially affecting the antidepressant treatment response in depressive patients indicated for electroconvulsive therapy (ECT) compared with patients with a single episode of depression. Seventy-six Dutch White patients with unipolar or bipolar treatment-resistant depression who underwent ECT were genotyped using the Amplichip CYP450 Test for CYP2D6. Two hundred and eight patients with a single episode of unipolar or bipolar depression were used as controls. No difference was observed in the prevalence of CYP2D6 phenotypes (poor metabolizer, intermediate metabolizer, extensive metabolizer and ultrarapid metabolizer) between the ECT and the control patients (5.3, 38.7, 56.0 and 0.0% vs. 6.4, 51.0, 42.6 and 0.0%, respectively). The types of depression (odds ratio = 0.33, P = 0.018) and age (odds ratio = 1.55 for a 10-year increase, P < 0.001), but not CYP2D6 phenotype or activity score were associated with the response to antidepressant treatment. In conclusion, preemptive genotyping for CYP2D6 currently appears to have no clinical implications in treatment-resistant depressive patients indicated for ECT. PMID- 26230382 TI - Pharmacogenetic versus clinical dosing of warfarin in individuals of Chinese and African-American ancestry: assessment using data simulation. AB - BACKGROUND: Clinical trials of genotype-guided dosing of warfarin have yielded mixed results, which may in part reflect ethnic differences among study participants. However, no previous study has compared genotype-guided versus clinically guided or standard-of-care dosing in a Chinese population, whereas those involving African-Americans were underpowered to detect significant differences. We present a preclinical strategy that integrates pharmacogenetics (PG) and pharmacometrics to predict the outcome or guide the design of dosing strategies for drugs that show large interindividual variability. We use the example of warfarin and focus on two underrepresented groups in warfarin research. MATERIALS AND METHODS: We identified the parameters required to simulate a patient population and the outcome of dosing strategies. PG and pharmacogenetic plus loading (PG+L) algorithms that take into account a patient's VKORC1 and CYP2C9 genotype status were considered and compared against a clinical (CA) algorithm for a simulated Chinese population using a predictive Monte Carlo and pharmacokinetic-pharmacodynamic framework. We also examined a simulated population of African-American ancestry to assess the robustness of the model in relation to real-world clinical trial data. RESULTS AND CONCLUSION: The simulations replicated similar trends observed with clinical data in African Americans. They further predict that the PG+L regimen is superior to both the CA and the PG regimen in maximizing percentage time in therapeutic range in a Chinese cohort, whereas the CA regimen poses the highest risk of overanticoagulation during warfarin initiation. The findings supplement the literature with an unbiased comparison of warfarin dosing algorithms and highlights interethnic differences in anticoagulation control. PMID- 26230383 TI - Life-Cycle Energy Use and Greenhouse Gas Emissions of a Building-Scale Wastewater Treatment and Nonpotable Reuse System. AB - Treatment and water reuse in decentralized systems is envisioned to play a greater role in our future urban water infrastructure due to growing populations and uncertainty in quality and quantity of traditional water resources. In this study, we utilized life-cycle assessment (LCA) to analyze the energy consumption and greenhouse gas (GHG) emissions of an operating Living Machine (LM) wetland treatment system that recycles wastewater in an office building. The study also assessed the performance of the local utility's centralized wastewater treatment plant, which was found to be significantly more efficient than the LM (79% less energy, 98% less GHG emissions per volume treated). To create a functionally equivalent comparison, the study developed a hypothetical scenario in which the same LM design flow is recycled via centralized infrastructure. This comparison revealed that the current LM has energy consumption advantages (8% less), and a theoretically improved LM design could have GHG advantages (24% less) over the centralized reuse system. The methodology in this study can be applied to other case studies and scenarios to identify conditions under which decentralized water reuse can lower GHG emissions and energy use compared to centralized water reuse when selecting alternative approaches to meet growing water demands. PMID- 26230385 TI - Integrated pharmacokinetic, pharmacodynamic and immunogenicity profiling of an anti-CCL21 monoclonal antibody in cynomolgus monkeys. AB - QBP359 is an IgG1 human monoclonal antibody that binds with high affinity to human CCL21, a chemokine hypothesized to play a role in inflammatory disease conditions through activation of resident CCR7-expressing fibroblasts/myofibroblasts. The pharmacokinetics (PK) and pharmacodynamics (PD) of QBP359 in non-human primates were characterized through an integrated approach, combining PK, PD, immunogenicity, immunohistochemistry (IHC) and tissue profiling data from single- and multiple-dose experiments in cynomolgus monkeys. When compared with regular immunoglobulin typical kinetics, faster drug clearance was observed in serum following intravenous administration of 10 mg/kg and 50 mg/kg of QBP359. We have shown by means of PK/PD modeling that clearance of mAb ligand complex is the most likely explanation for the rapid clearance of QBP359 in cynomolgus monkey. IHC and liquid chromatography mass spectrometry data suggested a high turnover and synthesis rate of CCL21 in tissues. Although lymphoid tissue was expected to accumulate drug due to the high levels of CCL21 present, bioavailability following subcutaneous administration in monkeys was 52%. In human disease states, where CCL21 expression is believed to be expressed at 10-fold higher concentrations compared with cynomolgus monkeys, the PK/PD model of QBP359 and its binding to CCL21 suggested that very large doses requiring frequent administration of mAb would be required to maintain suppression of CCL21 in the clinical setting. This highlights the difficulty in targeting soluble proteins with high synthesis rates. PMID- 26230386 TI - Recurrent laryngeal nerve identification in thyroidectomy by intra-operative staining with methylene blue in forty-six patients. PMID- 26230387 TI - Within-population Y-linked genetic variation for lifespan in Drosophila melanogaster. AB - The view that the Y chromosome is of little importance for phenotypic evolution stems from early studies of Drosophila melanogaster. This species' Y chromosome contains only 13 protein-coding genes, is almost entirely heterochromatic and is not necessary for male viability. Population genetic theory further suggests that non-neutral variation can only be maintained at the Y chromosome under special circumstances. Yet, recent studies suggest that the D. melanogaster Y chromosome trans-regulates hundreds to thousands of X and autosomal genes. This finding suggests that the Y chromosome may play a far more active role in adaptive evolution than has previously been assumed. To evaluate the potential for the Y chromosome to contribute to phenotypic evolution from standing genetic variation, we test for Y-linked variation in lifespan within a population of D. melanogaster. Assessing variation for lifespan provides a powerful test because lifespan (i) shows sexual dimorphism, which the Y is primarily predicted to contribute to, (ii) is influenced by many genes, which provides the Y with many potential regulatory targets and (iii) is sensitive to heterochromatin remodelling, a mechanism through which the Y chromosome is believed to regulate gene expression. Our results show a small but significant effect of the Y chromosome and thus suggest that the Y chromosome has the potential to respond to selection from standing genetic variation. Despite its small effect size, Y linked variation may still be important, in particular when evolution of sexual dimorphism is genetically constrained elsewhere in the genome. PMID- 26230388 TI - JAK/STAT and Hox Dynamic Interactions in an Organogenetic Gene Cascade. AB - Organogenesis is controlled by gene networks activated by upstream selector genes. During development the gene network is activated stepwise, with a sequential deployment of successive transcription factors and signalling molecules that modify the interaction of the elements of the network as the organ forms. Very little is known about the steps leading from the early specification of the cells that form the organ primordium to the moment when a robust gene network is in place. Here we study in detail how a Hox protein induces during early embryogenesis a simple organogenetic cascade that matures into a complex gene network through the activation of feedback and feed forward interaction loops. To address how the network organization changes during development and how the target genes integrate the genetic information it provides, we analyze in Drosophila the induction of posterior spiracle organogenesis by the Hox gene Abdominal-B (Abd-B). Initially, Abd-B activates in the spiracle primordium a cascade of transcription factors and signalling molecules including the JAK/STAT signalling pathway. We find that at later stages STAT activity feeds back directly into Abd-B, initiating the transformation of the Hox cascade into a gene network. Focusing on crumbs, a spiracle downstream target gene of Abd-B, we analyze how a modular cis regulatory element integrates the dynamic network information set by Abd-B and the JAK/STAT signalling pathway during development. We describe how a Hox induced genetic cascade transforms into a robust gene network during organogenesis due to the repeated interaction of Abd-B and one of its targets, the JAK/STAT signalling cascade. Our results show that in this network STAT functions not just as a direct transcription factor, but also acts as a "counter-repressor", uncovering a novel mode for STAT directed transcriptional regulation. PMID- 26230389 TI - Patterns of Alcohol Consumption and Related Behaviors in Brazil: Evidence from the 2013 National Health Survey (PNS 2013). AB - This study uses data from a nationally representative household survey (the 2013 National Health Survey, n = 62,986) to describe patterns of alcohol consumption and related behaviors among Brazilian adults. Analyses include descriptive and multivariable Poisson regression for self-reports in the past 30 days of: drinking any alcohol, binge drinking, binge drinking 4 or more times, and driving after drinking (DD); as well as age of alcohol consumption initiation. Results show that current drinking prevalence was 26%, with an average age of initiation of 18.7 years. Binge drinking was reported by 51% of drinkers, 43% of whom reported binge drinking 4 or more times. Drinking and driving was reported by nearly one quarter of those who drive a car/motorcycle. Current drinking was more likely among males, ages 25-34, single, urban, and those with more education. Binge drinking was more likely among males, older age groups, and people who started drinking before 18. Drinking and driving was higher among males, those with more education, and rural residents. Those who binge-drink were nearly 70% more likely to report DD. All behaviors varied significantly among Brazilian states. Given their potential health consequences, the levels of injurious alcohol behaviors observed here warrant increased attention from Brazilian policymakers and civil society. PMID- 26230390 TI - Abnormally Low or High Ankle-Brachial Index Is Associated with Proliferative Diabetic Retinopathy in Type 2 Diabetic Mellitus Patients. AB - Although some studies have reported that low ankle-brachial index (ABI) is associated with diabetic retinopathy (DR) in diabetic patients, it remains controversial as to which stage of DR. The aim of this study is to assess whether peripheral artery disease (PAD), indicated by abnormally low or high ABI, is associated with different stages of DR in patients with type 2 diabetes mellitus (DM), and further evaluate the risk factors. A total of 2001 (858 men and 1143 women) patients with type 2 DM who underwent ABI measurement in an outpatient clinic were enrolled. PAD was defined as ABI < 0.9 or ? 1.3 in either leg. DR was classified as non-DR, nonproliferative DR and proliferative DR stages. The clinical data were analyzed and the risk factors for abnormal ABI were determined by multivariate logistic regression analysis. The prevalence of ABI < 0.9 or ? 1.3 was 3.0%. Multivariate forward logistic regression analysis identified proliferative DR (vs. non-DR) was associated with abnormal ABI (odds ratio, 1.718; 95% confidence interval, 1.152 to 2.562; p = 0.008), but nonproliferative DR was not. Furthermore, the presence of coronary artery disease, cerebrovascular disease, declining renal function and patients without diuretics use were associated with abnormal ABI in patients with proliferative DR. Our study in patients of type 2 DM demonstrated that PAD was associated with proliferative DR. We emphasize the recommendation of performing the ABI test in this population at risk. PMID- 26230391 TI - Understanding How Nanoparticle Attachment Enhances Phosphotriesterase Kinetic Efficiency. AB - As a specific example of the enhancement of enzymatic activity that can be induced by nanoparticles, we investigate the hydrolysis of the organophosphate paraoxon by phosphotriesterase (PTE) when the latter is displayed on semiconductor quantum dots (QDs). PTE conjugation to QDs underwent extensive characterization including structural simulations, electrophoretic mobility shift assays, and dynamic light scattering to confirm orientational and ratiometric control over enzyme display which appears to be necessary for enhancement. PTE hydrolytic activity was then examined when attached to ca. 4 and 9 nm diameter QDs in comparison to controls of freely diffusing enzyme alone. The results confirm that the activity of the QD conjugates significantly exceeded that of freely diffusing PTE in both initial rate (~4-fold) and enzymatic efficiency (~2 fold). To probe kinetic acceleration, various modified assays including those with increased temperature, presence of a competitive inhibitor, and increased viscosity were undertaken to measure the activation energy and dissociation rates. Cumulatively, the data indicate that the higher activity is due to an acceleration in enzyme-product dissociation that is presumably driven by the markedly different microenvironment of the PTE-QD bioconjugate's hydration layer. This report highlights how a specific change in an enzymatic mechanism can be both identified and directly linked to its enhanced activity when displayed on a nanoparticle. Moreover, the generality of the mechanism suggests that it could well be responsible for other examples of nanoparticle-enhanced catalysis. PMID- 26230392 TI - Numerical Methods for the Analysis of Power Transformer Tank Deformation and Rupture Due to Internal Arcing Faults. AB - Power transformer rupture and fire resulting from an arcing fault inside the tank usually leads to significant security risks and serious economic loss. In order to reveal the essence of tank deformation or explosion, this paper presents a 3-D numerical computational tool to simulate the structural dynamic behavior due to overpressure inside transformer tank. To illustrate the effectiveness of the proposed method, a 17.3 MJ and a 6.3 MJ arcing fault were simulated on a real full-scale 360MVA/220kV oil-immersed transformer model, respectively. By employing the finite element method, the transformer internal overpressure distribution, wave propagation and von-Mises stress were solved. The numerical results indicate that the increase of pressure and mechanical stress distribution are non-uniform and the stress tends to concentrate on connecting parts of the tank as the fault time evolves. Given this feature, it becomes possible to reduce the risk of transformer tank rupture through limiting the fault energy and enhancing the mechanical strength of the local stress concentrative areas. The theoretical model and numerical simulation method proposed in this paper can be used as a substitute for risky and costly field tests in fault overpressure analysis and tank mitigation design of transformers. PMID- 26230393 TI - Correction: Prevalence Study and Genetic Typing of Bovine Viral Diarrhea Virus (BVDV) in Four Bovine Species in China. PMID- 26230394 TI - Correction: Four-Year-Olds Use a Mixture of Spatial Reference Frames. PMID- 26230395 TI - Quantitative Evaluation of the Substantially Variable Morphology and Function of the Left Atrial Appendage and Its Relation with Adjacent Structures. AB - OBJECTIVE: To investigate quantitatively the morphology, anatomy and function of the left atrial appendage (LAA) and its relation with adjacent structures. MATERIALS AND METHODS: A total of 860 patients (533 men, 62.0%, age 55.9+/-10.4 year) who had cardiac multidetector computed tomography angiography from May to October 2012 were enrolled for analysis. RESULTS: Seven types and 6 subtypes of LAA morphology were found with Type 2 being the most prevalent. Type 5 was more significantly (P<0.05) present in women (8.0%) than in men (4.2%). LAA orifice was oval in 81.5%, triangular in 7.3%, semicircular in 4%, water drop-like in 3.2%, round in 2.4% and foot-like in 1.6%. The LAA orifice had a significantly greater (P<0.01) major axis in men (24.79+/-3.81) than in women (22.68+/-4.07). The LAA orifice long axis was significantly (P<0.05) positively correlated with the height, weight and surface area of the patient. The LAA morphology parameters displayed strong positive correlation with the left atrium volume, aortic cross area long axis or LSPV long axis but poor correlation with the height, weight, surface area and vertebral body height of the patients. Four types of LAA ridge were identified: AI, AII, B and C with the distribution of 17.6%, 69.9%, 5.9% and 6.6%, respectively. The LAA had a significantly (P<0.05) greater distance from its orifice to the mitral ring in women than in men. The LAA had two filling and two emptying processes with the greatest volume at 45% phase but the least volume at 5% phase. The LAA maximal, minimal and emptying volumes were all significantly (P<0.05) positively correlated with the body height, weight and surface area, whereas the LAA ejection fraction had an inverse correlation with the LAA minimal volume but no correlation with the maximal volume. CONCLUSION: The LAA has substantially variable morphologies and relation with the adjacent structures, which may be helpful in guiding the LAA trans-catheter occlusion or catheter ablation procedures. PMID- 26230396 TI - Comparison of Macitentan and Bosentan on Right Ventricular Remodeling in a Rat Model of Non-vasoreactive Pulmonary Hypertension. AB - AIMS: We compared the efficacy of macitentan, a novel dual endothelin A/endothelin B receptor antagonist, with that of another dual endothelin receptor antagonist, bosentan, in a rat model of non-vasoreactive pulmonary hypertension (PH) with particular emphasis on right ventricular (RV) remodeling. METHODS AND RESULTS: Unlike monocrotaline or hypoxic/sugen rats, bleomycin-treated rats presented a non-vasoreactive PH characterized by the absence of pulmonary dilatation to adenosine. We therefore chose the bleomycin rat model to compare the effects of the maximally effective doses of macitentan and bosentan on pulmonary vascular and RV remodeling. Macitentan (100 mg.kg(-1).d(-1)), but not bosentan (300 mg.kg(-1).d(-1)), significantly prevented pulmonary vascular remodeling, RV hypertrophy, and cardiomyocyte diameter increase. Cardiac protection by macitentan was associated with a significant attenuation of genes related to cell hypertrophy and extracellular matrix remodeling. Microautoradiography and high performance liquid chromatography analysis showed greater distribution of macitentan than bosentan in the RV and pulmonary tissue. CONCLUSIONS: Macitentan was more efficacious than bosentan in preventing the development of pulmonary and RV hypertrophies in a model of non-vasoreactive PH. Greater ability to distribute into the tissue could contribute to the greater structural improvement by macitentan compared with bosentan. PMID- 26230398 TI - Effects of Bioadvection by Arenicola marina on Microphytobenthos in Permeable Sediments. AB - We used hyperspectral imaging to study short-term effects of bioturbation by lugworms (Arenicola marina) on the surficial biomass of microphytobenthos (MPB) in permeable marine sediments. Within days to weeks after the addition of a lugworm to a homogenized and recomposed sediment, the average surficial MPB biomass and its spatial heterogeneity were, respectively, 150-250% and 280% higher than in sediments without lugworms. The surficial sediment area impacted by a single medium-sized lugworm (~4 g wet weight) over this time-scale was at least 340 cm2. While sediment reworking was the primary cause of the increased spatial heterogeneity, experiments with lugworm-mimics together with modeling showed that bioadvective porewater transport from depth to the sediment surface, as induced by the lugworm ventilating its burrow, was the main cause of the increased surficial MPB biomass. Although direct measurements of nutrient fluxes are lacking, our present data show that enhanced advective supply of nutrients from deeper sediment layers induced by faunal ventilation is an important mechanism that fuels high primary productivity at the surface of permeable sediments even though these systems are generally characterized by low standing stocks of nutrients and organic material. PMID- 26230397 TI - Down Syndrome Cognitive Phenotypes Modeled in Mice Trisomic for All HSA 21 Homologues. AB - Down syndrome (DS), trisomy for chromosome 21, is the most common genetic cause of intellectual disability. The genomic regions on human chromosome 21 (HSA21) are syntenically conserved with regions on mouse chromosomes 10, 16, and 17 (Mmu10, Mmu16, and Mmu17). Recently, we created a genetic model of DS which carries engineered duplications of all three mouse syntenic regions homologous to HSA21. This 'triple trisomic' or TTS model thus represents the most complete and accurate murine model currently available for experimental studies of genotype phenotype relationships in DS. Here we extended our initial studies of TTS mice. Locomotor activity, stereotypic and repetitive behavior, anxiety, working memory, long-term memory, and synaptic plasticity in the dentate gyrus were examined in the TTS and wild-type (WT) control mice. Changes in locomotor activity were most remarkable for a significant increase in ambulatory time and a reduction in average velocity of TTS mice. No changes were detected in repetitive and stereotypic behavior and in measures of anxiety. Working memory showed no changes when tested in Y-maze, but deficiency in a more challenging T-maze test was detected. Furthermore, long-term object recognition memory was significantly reduced in the TTS mice. These changes were accompanied by deficient long-term potentiation in the dentate gyrus, which was restored to the WT levels following blockade of GABAA receptors with picrotoxin (100 MUM). TTS mice thus demonstrated a number of phenotypes characteristic of DS and may serve as a new standard by which to evaluate and direct findings in other less complete models of DS. PMID- 26230400 TI - Design and Implementation of a Cloud Computing Adoption Decision Tool: Generating a Cloud Road. AB - Migrating to cloud computing is one of the current enterprise challenges. This technology provides a new paradigm based on "on-demand payment" for information and communication technologies. In this sense, the small and medium enterprise is supposed to be the most interested, since initial investments are avoided and the technology allows gradual implementation. However, even if the characteristics and capacities have been widely discussed, entry into the cloud is still lacking in terms of practical, real frameworks. This paper aims at filling this gap, presenting a real tool already implemented and tested, which can be used as a cloud computing adoption decision tool. This tool uses diagnosis based on specific questions to gather the required information and subsequently provide the user with valuable information to deploy the business within the cloud, specifically in the form of Software as a Service (SaaS) solutions. This information allows the decision makers to generate their particular Cloud Road. A pilot study has been carried out with enterprises at a local level with a two fold objective: to ascertain the degree of knowledge on cloud computing and to identify the most interesting business areas and their related tools for this technology. As expected, the results show high interest and low knowledge on this subject and the tool presented aims to readdress this mismatch, insofar as possible. PMID- 26230399 TI - Altering Knee Abduction Angular Impulse Using Wedged Insoles for Treatment of Patellofemoral Pain in Runners: A Six-Week Randomized Controlled Trial. AB - OBJECTIVE: Determine if a change in internal knee abduction angular impulse (KAAI) is related to pain reduction for runners with patellofemoral pain (PFP) by comparing lateral and medial wedge insole interventions, and increased KAAI and decreased KAAI groups. DESIGN: Randomized controlled clinical trial (ClinicalTrials.gov ID# NCT01332110). SETTING: Biomechanics laboratory and community. PATIENTS: Thirty-six runners with physician-diagnosed PFP enrolled in the trial, and 27 were analyzed. INTERVENTIONS: Runners with PFP were randomly assigned to either an experimental 3 mm lateral wedge or control 6 mm medial wedge group. Participants completed a biomechanical gait analysis to quantify KAAIs with their assigned insole, and then used their assigned insole for six weeks during their regular runs. Usual pain during running was measured at baseline and at six-week follow-up using a visual analog scale. Statistical tests were performed to identify differences between wedge types, differences between biomechanical response types (i.e. increase or decrease KAAI), as well as predictors of pain reduction. MAIN OUTCOME MEASURES: Percent change in KAAI relative to neutral, and % change in pain over six weeks. RESULTS: Clinically meaningful reductions in pain (>33%) were measured for both footwear groups; however, no significant differences between footwear groups were found (p = 0.697). When participants were regrouped based on KAAI change (i.e., increase or decrease), again, no significant differences in pain reduction were noted (p = 0.146). Interestingly, when evaluating absolute change in KAAI, a significant relationship between absolute % change in KAAI and % pain reduction was observed (R2 = 0.21; p = 0.030), after adjusting for baseline pain levels. CONCLUSION: The greater the absolute % change in KAAI during running, the greater the % reduction in pain over six weeks, regardless of wedge type, and whether KAAIs increased or decreased. Lateral and medial wedge insoles were similar in effectiveness for treatment of PFP. CLINICAL RELEVANCE: Altering KAAI should be a focus of future PFP research. Lateral wedges should be studied further as an alternative therapy to medial wedges for management of PFP. TRIAL REGISTRATION: ClinicalTrials.gov NCT01332110. PMID- 26230401 TI - Ambulatory assessment of shoulder abduction strength curve using a single wearable inertial sensor. AB - The aim of the present article was to assess the reliability of strength curves as determined from tridimensional linear accelerations and angular velocities measured by a single inertial measurement unit (IMU) fixed on the upper arm during a shoulder abduction movement performed holding a 1 kg dumbbell in the hand. Within-subject repeatability of the task was assessed on 45 subjects performing four trials consisting of one maximal shoulder abduction-adduction movement. Intraclass correlation coefficient (ICC) was computed on the average movement angular velocity (VEL) and range of movement (ROM) across the four trials. Within-subject repeatability of torque curves was assessed in terms of waveform similarities by computing the coefficient of multiple determination (CMD). Accuracy of the estimated ROM was assessed using an isokinetic dynamometer. High ICC values of ROM (0.955) and VEL (0.970) indicated a high within-subject repeatability of the task. A high waveform similarity of torque curves was also found between trials (CMD = 0.867). Accuracy with respect to isokinetic dynamometer in estimating ROM was always <1 degree (p = 0.37). This study showed the effectiveness of using a single wearable IMU for the assessment of strength curve during isoinertial movements in a way that complies with the needs of clinicians in an ambulatory setting. PMID- 26230402 TI - Twenty-Year Experience in the Diagnosis and Treatment of Infective Endocarditis. AB - AIMS: The aim of this study was to compare the etiology, clinical course, selected diagnostic methods and efficacy of the treatment used in patients with infective endocarditis (IE) in the nineteen eighties and nineties. MATERIAL AND METHODS: The study group comprised 300 patients with infective endocarditis hospitalized in the Institute of Cardiology in Warsaw in the following years: from 1982 to 1987 (150 patients: 75 successive patients with IE on the prosthetic valve and 75 successive patients with IE on the native valve), as well as from 1990 to 2003 (150 patients: 75 successive patients with IE on the prosthetic valve and 75 successive patients with IE on the native valve). RESULTS: In the nineties, immunological symptoms, embolism formation and progressive heart failure were diagnosed decidedly more frequently. Early prosthetic valve endocarditis (PVE) (up to 60 days after operation) occurred significantly more frequently in the eighties. The quantity of negative blood cultures in PVE has not decreased, it is still observed in over 20% of cases. For 20 years the etiology of PVE has remained the same, the dominant pathogen remains Staphylococcus. The frequency of PVE caused by Streptococci has markedly reduced. In both the decades analyzed the etiology of native valve endocarditis (NVE) was similar. In the eighties Streptococcus was predominant. In successive years the number of infections caused by Staphylococci was the same as that caused by Streptococci. CONCLUSIONS: The incidence of early PVE decreased in the nineties. More patients were treated surgically with lesser peri-operative mortality. A lower incidence of infective endocarditis on prosthetic valves caused by streptococci may signify better prophylaxis against infective endocarditis. Infective endocarditis with sterile blood cultures continues to occur frequently. PMID- 26230403 TI - How Good Is Good Enough? Cookstove Replacement Scenarios to Reach Indoor Air Goals. PMID- 26230404 TI - Cognitive Fatigue Destabilizes Economic Decision Making Preferences and Strategies. AB - OBJECTIVE: It is common for individuals to engage in taxing cognitive activity for prolonged periods of time, resulting in cognitive fatigue that has the potential to produce significant effects in behaviour and decision making. We sought to examine whether cognitive fatigue modulates economic decision making. METHODS: We employed a between-subject manipulation design, inducing fatigue through 60 to 90 minutes of taxing cognitive engagement against a control group that watched relaxing videos for a matched period of time. Both before and after the manipulation, participants engaged in two economic decision making tasks (one for gains and one for losses). The analyses focused on two areas of economic decision making--preferences and choice strategies. Uncertainty preferences (risk and ambiguity) were quantified as premium values, defined as the degree and direction in which participants alter the valuation of the gamble in comparison to the certain option. The strategies that each participant engaged in were quantified through a choice strategy metric, which contrasts the degree to which choice behaviour relies upon available satisficing or maximizing information. We separately examined these metrics for alterations within both the gains and losses domains, through the two choice tasks. RESULTS: The fatigue manipulation resulted in significantly greater levels of reported subjective fatigue, with correspondingly higher levels of reported effort during the cognitively taxing activity. Cognitive fatigue did not alter uncertainty preferences (risk or ambiguity) or informational strategies, in either the gains or losses domains. Rather, cognitive fatigue resulted in greater test-retest variability across most of our economic measures. These results indicate that cognitive fatigue destabilizes economic decision making, resulting in inconsistent preferences and informational strategies that may significantly reduce decision quality. PMID- 26230405 TI - microRNA-21 Regulates Cell Proliferation and Migration and Cross Talk with PTEN and p53 in Bladder Cancer. AB - This study aimed to determine the molecular mechanism by which the oncogenic micoRNA-21 (miR-21) functions in bladder cancer. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis showed that the expression of miR-21 considerably increased in primary cancer tissue compared with that in the paired adjacent noncancerous tissue and that in normal bladder mucosa. Knockdown of miR 21 by using antisense oligonucleotide significantly suppressed the proliferation and migration of bladder cancer cells (J82 and RT112). Mechanism studies showed that downregulation of miR-21 resulted in cell cycle arrest at the G1 phase and upregulation of the tumor suppressor PTEN (phosphatase and tensin homologue) and p53 phosphorylation at Ser46. The p53 phosphorylation at Ser15 and the whole level of p53 acetylation remained unchanged in response to miR-21 knockdown. MicroRNA-21 regulates proliferation and migration of bladder cancer cells and cross talk with PTEN and p53 in bladder cancer. PMID- 26230406 TI - Simulating Stochastic Reaction-Diffusion Systems on and within Moving Boundaries. AB - Chemical reactions inside cells are generally considered to happen within fixed size compartments. However, cells and their compartments are highly dynamic. Thus, such stringent geometrical assumptions may not reflect biophysical reality, and can highly bias conclusions from simulation studies. In this work, we present an intuitive algorithm for particle-based diffusion in and on moving boundaries, for both point particles and spherical particles. We first benchmark our proposed stochastic method against solutions of partial differential equations in appropriate scenarios, and further demonstrate that moving boundaries can give rise to super-diffusive motion as well as time-inhomogeneous reaction rates. Finally, we conduct a numerical experiment representing photobleaching of diffusing fluorescent proteins in dividing Saccharomyces cerevisiae cells to demonstrate that moving boundaries might cause important effects neglected in previously published studies of cell compartmentalization. PMID- 26230407 TI - Predictors of Dietary Supplement Use by U.S. Coast Guard Personnel. AB - BACKGROUND: Personnel in Armed Forces entities such as the US Coast Guard (USCG) engage in strenuous tasks requiring high levels of physiological and psychological fitness. Previous reports have found increased prevalence of dietary supplement (DS) use by military personnel to meet the demands of their occupation. OBJECTIVE: This study assessed DS prevalence and patterns of use in USCG personnel and compared these findings to reports from other Armed Forces personnel. DESIGN: Use of DS by USCG personnel (n = 1059) was assessed by survey at USCG installations. Data were weighted by age, sex, and rank to be representative of total USCG demographics. RESULTS: Seventy percent of USCG personnel reported using a DS at least 1 time/wk. Thirty-three percent used 1-2 DS <= 1 time/wk, 18% 3-4 DS >= 1 time/wk, and almost 19% >= 5 DS >= 1 time/wk. Average expenditure on DSs by UCSG personnel was $40/mo. More than 47% of USCG personnel used a multivitamin and mineral, 33% consumed protein supplements, 22% used individual vitamins and minerals, 23% reported taking combination products, and 9% consumed herbal supplements. Increased use of DS use was associated with high intensity operational occupations, participating in high volumes of aerobic exercise and strength training. Use of DS was not associated with age, education or body mass index. CONCLUSION: Occupation is an important determinate of DS use. Prevalence of DS use by USCG personnel is greater than reported for other Armed Forces personnel and reflects high levels of participation in aerobic and strength training activities. PMID- 26230409 TI - Pulseless electrical activity cardiac arrest: time to amend the mnemonic "4H&4T"? AB - BACKGROUND: Pulseless electrical activity (PEA) cardiac arrest is characterised by a residual organised electrical activity. PEA is frequently induced by reversible conditions. The mnemonic "4H&4T" was proposed as a reminder to assess for Hypoxia, Hypovolaemia, Hypo/Hyperkalaemia, Hypothermia, Thrombosis, cardiac Tamponade, Toxins, and Tension pneumothorax. Other potential aetiologies have been identified, but their respective probability and frequencies are unclear. The aim of this study was to analyse the aetiologies of PEA out-of-hospital cardiac arrests and to evaluate their relative frequencies. METHODS: This was a retrospective study based on data routinely and prospectively collected. All adult patients with PEA as the first recorded rhythm and admitted between 2002 and 2012 to the emergency department (ED) after return of spontaneous circulation or under resuscitation were included. RESULTS: A total of 1,866 out-of-hospital cardiac arrests were included. PEA was the first recorded rhythm in 232 adult patients (12.4%) and 144 of these were admitted to the ED. The mean age was 63.8 +/- 20.0 years, 58.3% were men. The survival rate at 48 hours was 29%. Hypoxia (23.6%), acute coronary syndrome (12.5%) and trauma (12.5%) were the most frequent causes. We were unable to identify a specific cause in 17.4%. Pulmonary embolism, hypovolaemia, intoxication and hypo/hyperkalaemia occurred in fewer than 10% of the cases. Nonischaemic cardiac disorders and intracranial haemorrhage occurred in 8.3% and 6.9%, respectively. CONCLUSIONS: Intracranial haemorrhage and nonischaemic cardiac disorders represent significant causes of PEA, with a prevalence equalling or exceeding the frequency of classical 4H&4T aetiologies. These conditions are potentially accessible to simple diagnostic procedures (computed tomography or echocardiography). PMID- 26230408 TI - Pseudomonas aeruginosa IscR-Regulated Ferredoxin NADP(+) Reductase Gene (fprB) Functions in Iron-Sulfur Cluster Biogenesis and Multiple Stress Response. AB - P. aeruginosa (PAO1) has two putative genes encoding ferredoxin NADP(+) reductases, denoted fprA and fprB. Here, the regulation of fprB expression and the protein's physiological roles in [4Fe-4S] cluster biogenesis and stress protection are characterized. The fprB mutant has defects in [4Fe-4S] cluster biogenesis, as shown by reduced activities of [4Fe-4S] cluster-containing enzymes. Inactivation of the gene resulted in increased sensitivity to oxidative, thiol, osmotic and metal stresses compared with the PAO1 wild type. The increased sensitivity could be partially or completely suppressed by high expression of genes from the isc operon, which are involved in [Fe-S] cluster biogenesis, indicating that stress sensitivity in the fprB mutant is partially caused by a reduction in levels of [4Fe-4S] clusters. The pattern and regulation of fprB expression are in agreement with the gene physiological roles; fprB expression was highly induced by redox cycling drugs and diamide and was moderately induced by peroxides, an iron chelator and salt stress. The stress-induced expression of fprB was abolished by a deletion of the iscR gene. An IscR DNA-binding site close to fprB promoter elements was identified and confirmed by specific binding of purified IscR. Analysis of the regulation of fprB expression supports the role of IscR in directly regulating fprB transcription as a transcription activator. The combination of IscR-regulated expression of fprB and the fprB roles in response to multiple stressors emphasizes the importance of [Fe-S] cluster homeostasis in both gene regulation and stress protection. PMID- 26230410 TI - The Ultrastructural Localization of Type II, IV, and VI Collagens at the Vitreoretinal Interface. AB - BACKGROUND: The vitreoretinal interface is the border of the cortical vitreous and the inner surface of the retina. The adhesion of the cortical vitreous to the ILM, namely vitreoretinal adhesion, involves a series of complex molecular adhesion mechanisms and has been considered as an important pathogenic factor in many vitreoretinal diseases. The presence of type VI collagen at the vitreoretinal interface and its possible interaction with collagens and glycoproteins indicates that type VI collagen may contribute to the vitreoretinal adhesion. PURPOSE: To clarify the ultrastructural location of type VI collagen and its relationship to type II and IV collagens at the vitreoretinal interface. METHODS: The ultrastructural localization of type II, IV and VI collagens in the adult human vitreoretinal interface of five donor eyes was evaluated by transmission electron microscopy using immunogold labeling. RESULTS: In the pre equatorial region, we observed densely packed vitreous lamellae with a partly intraretinal course containing type II and VI collagens, reticular structures containing type IV and VI collagens and a thin inner limiting membrane (ILM) containing type IV and VI collagens in a linear distribution pattern. From the anterior to the posterior retina, the linear pattern of type IV and VI collagen labeling gradually became more diffusely present throughout the entire thickness of the ILM. CONCLUSIONS: The presence of type VI collagen in vitreous lamellae penetrating the ILM into the superficial retina suggests that type VI collagen may be involved in the organization of vitreous fibers into lamellae and in the adhesion of the vitreous fibers to the retina. The close relation of type VI to type IV collagen in the ILM suggests that type VI collagen is an important collagen type in the ILM. The topographic variations of type IV and VI collagens in the different regions of the ILM suggest a regional heterogeneity of the ILM. The reticular labeling pattern of type IV and VI collagens observed in the anterior vitreous are highly similar to labeling patterns of blood vessel walls. In the anterior vitreous, they may represent remnants of the regressed embryonic hyaloid blood vessel system. Their presence is in support of the theory on interactive remodeling of the developing vitreous as opposed to the main stream theory of displacement and compression of the primary by the secondary vitreous. PMID- 26230411 TI - Inhibition of Prostaglandin Transporter (PGT) Promotes Perfusion and Vascularization and Accelerates Wound Healing in Non-Diabetic and Diabetic Rats. AB - Peripheral ischemia, resulting from diminished arterial flow and defective local vascularization, is one of the main causes of impaired wound healing in diabetes. Vasodilatory prostaglandins (PGs), including PGE2 and PGI2, regulate blood flow in peripheral tissues. PGs also stimulate angiogenesis by inducing vascular endothelial growth factor. However, PG levels are reduced in diabetes mainly due to enhanced degradation. We hypothesized that inhibition of the prostaglandin transporter (PGT) (SLCO2A1), which mediates the degradation of PGs, would increase blood flow and stimulate vascularization, thereby mitigating peripheral ischemia and accelerating wound healing in diabetes. Here we report that inhibiting PGT with intravenously injected PGT inhibitor, T26A, increased blood flow in ischemic hind limbs created in non-diabetic rats and streptozotocin induced diabetic rats. Systemic, or combined with topical, T26A accelerated closure of cutaneous wounds. Immunohistochemical examination revealed that inhibition of PGT enhanced vascularization (marked by larger numbers of vessels formed by CD34+ cells), and accelerated re-epithelialization of cutaneous wounds. In cultured primary human bone marrow CD34+ cells and human epidermal keratinocytes (HEKs) either inhibiting or silencing PGT increased migration in both cell lines. Thus PGT directly regulates mobilization of endothelial progenitor cells (EPCs) and HEKs, which could contribute to PGT-mediated vascularization and re-epithelialization. At the molecular level, systemic inhibition of PGT raised circulating PGE2. Taken together, our data demonstrate that PGT modulates arterial blood flow, mobilization of EPCs and HEKs, and vascularization and epithelialization in wound healing by regulating vasodilatory and pro-angiogenic PGs. PMID- 26230412 TI - Can Additional Homeopathic Treatment Save Costs? A Retrospective Cost-Analysis Based on 44500 Insured Persons. AB - OBJECTIVES: The aim of this study was to compare the health care costs for patients using additional homeopathic treatment (homeopathy group) with the costs for those receiving usual care (control group). METHODS: Cost data provided by a large German statutory health insurance company were retrospectively analysed from the societal perspective (primary outcome) and from the statutory health insurance perspective. Patients in both groups were matched using a propensity score matching procedure based on socio-demographic variables as well as costs, number of hospital stays and sick leave days in the previous 12 months. Total cumulative costs over 18 months were compared between the groups with an analysis of covariance (adjusted for baseline costs) across diagnoses and for six specific diagnoses (depression, migraine, allergic rhinitis, asthma, atopic dermatitis, and headache). RESULTS: Data from 44,550 patients (67.3% females) were available for analysis. From the societal perspective, total costs after 18 months were higher in the homeopathy group (adj. mean: EUR 7,207.72 [95% CI 7,001.14 7,414.29]) than in the control group (EUR 5,857.56 [5,650.98-6,064.13]; p<0.0001) with the largest differences between groups for productivity loss (homeopathy EUR 3,698.00 [3,586.48-3,809.53] vs. control EUR 3,092.84 [2,981.31-3,204.37]) and outpatient care costs (homeopathy EUR 1,088.25 [1,073.90-1,102.59] vs. control EUR 867.87 [853.52-882.21]). Group differences decreased over time. For all diagnoses, costs were higher in the homeopathy group than in the control group, although this difference was not always statistically significant. CONCLUSION: Compared with usual care, additional homeopathic treatment was associated with significantly higher costs. These analyses did not confirm previously observed cost savings resulting from the use of homeopathy in the health care system. PMID- 26230413 TI - Palladium-Catalyzed Decarbonylative Dehydration for the Synthesis of alpha-Vinyl Carbonyl Compounds and Total Synthesis of (-)-Aspewentins A, B, and C. AB - The direct alpha-vinylation of carbonyl compounds to form a quaternary stereocenter is a challenging transformation. It was discovered that delta oxocarboxylic acids can serve as masked vinyl compounds and be unveiled by palladium-catalyzed decarbonylative dehydration. The carboxylic acids are readily available through enantioselective acrylate addition or asymmetric allylic alkylation. A variety of alpha-vinyl quaternary carbonyl compounds are obtained in good yields, and an application in the first enantioselective total synthesis of (-)-aspewentins A, B, and C is demonstrated. PMID- 26230414 TI - Lanthanide Complexes with Multidentate Oxime Ligands as Single-Molecule Magnets and Atmospheric Carbon Dioxide Fixation Systems. AB - The synthesis, structure, and magnetic properties of five lanthanide complexes with multidentate oxime ligands are described. Complexes 1 and 2 (1: [La2 (pop)2 (acac)4 (CH3 OH)], 2: [Dy2 (pop)(acac)5 ]) are synthesized from the 2 hydroxyimino-N-[1-(2-pyridyl)ethylidene]propanohydrazone (Hpop) ligand, while 3, 4, and 5 (3: [Dy2 (naphthsaoH)2 (acac)4 H(OH)]?0.85 CH3 CN?1.58 H2 O; 4: [Tb2 (naphthsaoH)2 (acac)4 H(OH)]?0.52 CH3 CN?1.71 H2 O; 5: [La6 (CO3 )2 (naphthsao)5 (naphthsaoH)0.5 (acac)8 (CO3 )0.5 (CH3 OH)2.76 H5.5 (H2 O)1.24 ]?2.39 CH3 CN?0.12 H2 O) contain 1-(1-hydroxynaphthalen-2-yl)-ethanone oxime (naphthsaoH2 ). In 1-4, dinuclear [Ln2 ] complexes crystallize, whereas hexanuclear La(III) complex 5 is formed after fixation of atmospheric carbon dioxide. Dy(III) -based complexes 2 and 3 display single-molecule-magnet properties with energy barriers of 27 and 98 K, respectively. The presence of a broad and unsymmetrical relaxation mode observed in the ac susceptibility data for 3 suggest two different dynamics of the magnetization which might be a consequence of independent relaxation processes of the two different Dy(3+) ions. PMID- 26230415 TI - Response to "Comment on 'Background Ionizing Radiation and the Risk of Childhood Cancer: A Census-Based Nationwide Cohort Study'". PMID- 26230416 TI - From military to civil loadings: Preliminary numerical-based thorax injury criteria investigations. AB - Effects of the impact of a mechanical structure on the human body are of great interest in the understanding of body trauma. Experimental tests have led to first conclusions about the dangerousness of an impact observing impact forces or displacement time history with PMHS (Post Mortem human Subjects). They have allowed providing interesting data for the development and the validation of numerical biomechanical models. These models, widely used in the framework of automotive crashworthiness, have led to the development of numerical-based injury criteria and tolerance thresholds. The aim of this process is to improve the safety of mechanical structures in interaction with the body. In a military context, investigations both at experimental and numerical level are less successfully completed. For both military and civil frameworks, the literature list a number of numerical analysis trying to propose injury mechanisms, and tolerance thresholds based on biofidelic Finite Element (FE) models of different part of the human body. However the link between both frameworks is not obvious, since lots of parameters are different: great mass impacts at relatively low velocity for civil impacts (falls, automotive crashworthiness) and low mass at very high velocity for military loadings (ballistic, blast). In this study, different accident cases were investigated, and replicated with a previously developed and validated FE model of the human thorax named Hermaphrodite Universal Biomechanical YX model (HUBYX model). These previous validations included replications of standard experimental tests often used to validate models in the context of automotive industry, experimental ballistic tests in high speed dynamic impact and also numerical replication of blast loading test ensuring its biofidelity. In order to extend the use of this model in other frameworks, some real-world accidents were reconstructed, and consequences of these loadings on the FE model were explored. These various numerical replications of accident coming from different contexts raise the question about the ability of a FE model to correctly predict several kinds of trauma, from blast or ballistic impacts to falls, sports or automotive ones in a context of numerical injury mechanisms and tolerance limits investigations. PMID- 26230417 TI - Complications and outcomes of vasopressor usage in acute traumatic central cord syndrome. AB - OBJECT The optimal mean arterial pressure (MAP) for spinal cord perfusion after trauma remains unclear. Although there are published data on MAP goals after spinal cord injury (SCI), the specific blood pressure management for acute traumatic central cord syndrome (ATCCS) and the implications of these interventions have yet to be elucidated. Additionally, the complications of specific vasopressors have not been fully explored in this injury condition. METHODS The present study is a retrospective cohort analysis of 34 patients with ATCCS who received any vasopressor to maintain blood pressure above predetermined MAP goals at a single Level 1 trauma center. The collected variables were American Spinal Injury Association (ASIA) grades at admission and discharge, administered vasopressor and associated complications, other interventions and complications, and timing of surgery. The relationship between the 2 most common vasopressors-dopamine and phenylephrine-and complications within the cohort as a whole were explored, and again after stratification by age. RESULTS The mean age of the ATCCS patients was 62 years. Dopamine was the most commonly used primary vasopressor (91% of patients), followed by phenylephrine (65%). Vasopressors were administered to maintain MAP goals fora mean of 101 hours. Neurological status improved by a median of 1 ASIA grade in all patients, regardless of the choice of vasopressor. Sixty-four percent of surgical patients underwent decompression within 24 hours. There was no observed relationship between the timing of surgical intervention and the complication rate. Cardiogenic complications associated with vasopressor usage were notable in 68% of patients who received dopamine and 46% of patients who received phenylephrine. These differences were not statistically significant (OR with dopamine 2.50 [95% CI 0.82-7.78], p = 0.105). However, in the subgroup of patients > 55 years, dopamine produced statistically significant increases in the complication rates when compared with phenylephrine (83% vs 50% for dopamine and phenylephrine, respectively; OR with dopamine 5.0 [95% CI 0.99-25.34], p = 0.044). CONCLUSIONS Vasopressor usage in ATCCS patients is associated with complication rates that are similar to the reported literature for SCI. Dopamine was associated with a higher risk of complications in patients > 55 years. Given the increased incidence of ATCCS in older populations, determination of MAP goals and vasopressor administration should be carefully considered in these patients. While a randomized control trial on this topic may not be practical, a multiinstitutional prospective study for SCI that includes ATCCS patients as a subpopulation would be useful for examining MAP goals in this population. PMID- 26230418 TI - Qualitative analysis of spinal intramedullary lesions using PET/CT. AB - OBJECT Although the usefulness of PET for brain lesions has been established, few reports have examined the use of PET for spinal intramedullary lesions. This study investigated the diagnostic utility of PET/CT for spinal intramedullary lesions. METHODS l-[methyl-11C]-methionine (MET)- or [18F]-fluorodeoxyglucose (FDG)-PET/CT was performed in 26 patients with spinal intramedullary lesions. The region of interest (ROI) within the spinal cord parenchyma was placed manually in the axial plane. Maximum pixel counts in the ROIs were normalized to the maximum standardized uptake value (SUVmax) using subject body weight. For FDG-PET the SUVmax was corrected for lean body mass (SULmax) to exclude any influence of the patient's body shape. Each SUV was analyzed based on histopathological results after surgery. The diagnostic validity of the SUV was further compared with the tumor proliferation index using the MIB-1 monoclonal antibody (MIB-1 index). RESULTS A total of 16 patients underwent both FDG-PET and MET-PET, and the remaining 10 patients underwent either FDG-PET or MET-PET. Pathological diagnoses included high-grade malignancy such as glioblastoma multiforme, anaplastic astrocytoma, or anaplastic ependymoma in 5 patients; low-grade malignancy such as hemangioblastoma, diffuse astrocytoma, or ependymoma in 12 patients; and nonneoplastic lesion including cavernous malformation in 9 patients. Both FDG and MET accumulated significantly in high-grade malignancy, and the SULmax and SUVmax correlated with the tumor proliferation index. Therapeutic response after chemotherapy or radiation in high-grade malignancy was well monitored. However, a significant difference in SULmax and SUVmax for FDG-PET and MET-PET was not evident between low-grade malignancy and nonneoplastic lesions. CONCLUSIONS Spinal PET/CT using FDG or MET for spinal intramedullary lesions appears useful and practical, particularly for tumors with high-grade malignancy. Differentiation of tumors with low-grade malignancy from nonneoplastic lesions may still prove difficult. Further technological refinement, including the selection of radiotracer or analysis evaluation methods, is needed. PMID- 26230419 TI - Impact of obesity on complications, infection, and patient-reported outcomes in adult spinal deformity surgery. AB - OBJECT Adult spinal deformity (ASD) surgery is known for its high complication rate. This study examined the impact of obesity on complication rates, infection, and patient-reported outcomes in patients undergoing surgery for ASD. METHODS This study was a retrospective review of a multicenter prospective database of patients with ASD who were treated surgically. Patients with available 2-year follow-up data were included. Obesity was defined as having a body mass index (BMI) >= 30 kg/m2. Data collected included complications (total, minor, major, implant-related, radiographic, infection, revision surgery, and neurological injury), estimated blood loss (EBL), operating room (OR) time, length of stay (LOS), and patient-reported questionnaires (Oswestry Disability Index [ODI], Short Form-36 [SF-36], and Scoliosis Research Society [SRS]) at baseline and at 6 weeks, 1 year, and 2 years postoperatively. The impact of obesity was studied using multivariate modeling, accounting for confounders. RESULTS Of 241 patients who satisfied inclusion criteria, 175 patients were nonobese and 66 were obese. Regression models showed that obese patients had a higher overall incidence of major complications (IRR 1.54, p = 0.02) and wound infections (odds ratio 4.88, p = 0.02). Obesity did not increase the number of minor complications (p = 0.62), radiographic complications (p = 0.62), neurological complications (p = 0.861), or need for revision surgery (p = 0.846). Obesity was not significantly correlated with OR time (p = 0.23), LOS (p = 0.9), or EBL (p = 0.98). Both groups experienced significant improvement overtime, as measured on the ODI (p = 0.0001), SF-36 (p = 0.0001), and SRS (p = 0.0001) questionnaires. However, the overall magnitude of improvement was less for obese patients (ODI, p = 0.0035; SF 36, p = 0.0012; SRS, p = 0.022). Obese patients also had a lower rate of improvement over time (SRS, p = 0.0085; ODI, p = 0.0001; SF-36, p = 0.0001). CONCLUSIONS This study revealed that obese patients have an increased risk of complications following ASD correction. Despite these increased complications, obese patients do benefit from surgical intervention; however, their improvement in health-related quality of life (HRQL) is less than that of nonobese patients. PMID- 26230420 TI - Reconstructive surgery using dual U-shaped rod instrumentation after posterior en bloc sacral hemiresection for metastatic tumor: case report. AB - Despite various complications associated with sacrectomy to remove sacral tumors, total or en bloc sacrectomy has been suggested as the most appropriate surgical treatment in such cases. The authors present the case of a 62-year-old male patient with intractable back pain and voiding difficulty whom they treated with posterior en bloc sacral hemiresection followed by reconstruction using dual U shaped rods. They report that good spinopelvic stability was achieved without complications. The authors conclude that this technique is relatively simple compared with other sacral reconstructive techniques and can prevent complications, including herniation. PMID- 26230421 TI - Assessment of impact of standing long-cassette radiographs on surgical planning for lumbar pathology: an international survey of spine surgeons. AB - OBJECT The associations among global spinal alignment, patient-reported disability, and surgical outcomes have increasingly gained attention. The assessment of global spinal alignment requires standing long-cassette anteroposterior and lateral radiographs; however, spine surgeons routinely rely only on short-segment imaging when evaluating seemingly isolated lumbar pathology. This may prohibit adequate surgical planning and may predispose surgeons to not recognize associated pathology in the thoracic spine and sagittal spinopelvic malalignment. The authors used a case-based survey questionnaire to evaluate if including long-cassette radiographs led to changes to respondents' operative plans as compared with their chosen plan when cases contained standard imaging of the involved lumbar spine only. METHODS A case-based survey was distributed to AOSpine International members that consisted of 15 cases of lumbar spine pathology and lumbar imaging only. The same 15 cases were then shuffled and presented a second time with additional long-cassette radiographs. Each case required participants to select a single operative plan with 5 choices ranging from least to most extensive. The cases included 5 "control" cases with normal global spinal alignment and 10 "test" cases with significant sagittal and/or coronal malalignment. Mean scores were determined for each question with higher scores representing more invasive and/or extensive operative plans. RESULTS Of 712 spine surgeons who started the survey, 316 (44%) completed the entire series, including 68% of surgeons with spine fellowship training and representation from more than 40 countries. For test cases, but not for control cases, there were significantly higher average surgical invasiveness scores for cases presented with long-cassette radiographs (4.2) as compared with those cases with lumbar imaging only (3.4; p = 0.002). The addition of long-cassette radiographs resulted in 82.1% of respondents recommending instrumentation up to the thoracic spine, a 23.2% increase as compared with the same cases presented with lumbar imaging only (p = 0.008). CONCLUSIONS This study demonstrates the importance of maintaining a low threshold for performing standing long-cassette imaging when assessing seemingly isolated lumbar pathology. Such imaging is necessary for the assessment of spinopelvic and global spinal alignment, which can be important in operative planning. Deformity, particularly positive sagittal malalignment, may go undetected unless one maintains a high index of suspicion and obtains long cassette radiographs. It is recommended that spine surgeons recognize the prevalence and importance of such deformity when contemplating operative intervention. PMID- 26230423 TI - Ginkgo leaf sign: a highly predictive imaging feature of spinal meningioma. AB - OBJECT Spinal meningioma and schwannoma are the most common spinal intradural extramedullary tumors, and the differentiation of these 2 tumors by CT and MRI has been a matter of debate. The purpose of this article is to present a case series of spinal meningiomas showing unique imaging features: a combination of a fan-shaped spinal cord and a streak in the tumor. The authors termed the former imaging feature "ginkgo leaf sign" and evaluated its diagnostic value. METHODS The authors present 7 cases of spinal meningioma having the ginkgo leaf sign. Thirty spinal extramedullary tumors arising lateral or ventrolateral to the spinal cord were studied to evaluate the diagnostic value of the ginkgo leaf sign for spinal meningiomas. Among 30 cases, 12 tumors were spinal meningiomas and 18 tumors from the control group were all schwannomas. RESULTS Seven of the 12 spinal meningiomas were positive for the ginkgo leaf sign. The sign was not present in the control group tumors. The overall ability to use the ginkgo leaf sign to detect meningioma indicated a sensitivity of 58%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 78%. CONCLUSIONS The ginkgo leaf sign is highly specific to spinal meningiomas arising lateral or ventrolateral to the spinal cord. In the present series, the ginkgo leaf sign was perfectly predictive for spinal meningioma. PMID- 26230422 TI - Prognostic factors associated with pain palliation after spine stereotactic body radiation therapy. AB - OBJECT The number of patients with spinal tumors is rapidly increasing; spinal metastases develop in more than 30% of cancer patients during the course of their illness. Such lesions can significantly decrease quality of life, often necessitating treatment. Stereotactic radiosurgery has effectively achieved local control and symptomatic relief for these patients. The authors determined prognostic factors that predicted pain palliation and report overall institutional outcomes after spine stereotactic body radiation therapy (SBRT). METHODS Records of patients who had undergone treatment with SBRT for either primary spinal tumors or spinal metastases from June 2008 through June 2013 were retrospectively reviewed. Data were collected at the initial visit just before treatment and at 1-, 3-, 6-, and 12-month follow-up visits. Collected clinical data included Karnofsky Performance Scale scores, pain status, presence of neurological deficits, and prior radiation exposure at the level of interest. Radiation treatment plan parameters (dose, fractionation, and target coverage) were recorded. To determine the initial extent of epidural spinal cord compression (ESCC), the authors retrospectively reviewed MR images, assessed spinal instability according to the Bilsky scale, and evaluated lesion progression after treatment. RESULTS The study included 99 patients (mean age 60.4 years). The median survival time was 9.1 months (95% CI 6.9-17.2 months). Significant decreases in the proportion of patients reporting pain were observed at 3 months (p < 0.0001), 6 months (p = 0.0002), and 12 months (p = 0.0019) after treatment. Significant decreases in the number of patients reporting pain were also observed at the last follow-up visit (p = 0.00020) (median follow-up time 6.1 months, range 1.0-56.6 months). Univariate analyses revealed that significant predictors of persistent pain after intervention were initial ESCC grade, stratified by a Bilsky grade of 1c (p = 0.0058); initial American Spinal Injury Association grade of D (p = 0.011); initial Karnofsky Performance Scale score, stratified by a score of 80 (p = 0.002); the presence of multiple treated lesions (p = 0.044); and prior radiation at the site of interest (p < 0.0001). However, when multivariate analyses were performed on all variables with p values less than 0.05, the only predictor of pain at last follow-up visit was a prior history of radiation at the site of interest (p = 0.0038), although initial ESCC grade trended toward significance (p = 0.073). Using pain outcomes at 3 months, at this follow-up time point, pain could be predicted by receipt of radiation above a threshold biologically effective dose of 66.7 Gy. CONCLUSIONS Pain palliation occurs as early as 3 months after treatment; significant differences in pain reporting are also observed at 6 and 12 months. Pain palliation is limited for patients with spinal tumors with epidural extension that deforms the cord and for patients who have previously received radiation to the same site. Further investigation into the optimal dose and fractionation schedule are needed, but improved outcomes were observed in patients who received radiation at a biologically effective dose (with an a/b of 3.0) of 66.7 Gy or higher. PMID- 26230424 TI - Cervical disc arthroplasty with PRESTIGE LP disc versus anterior cervical discectomy and fusion: a prospective, multicenter investigational device exemption study. AB - OBJECT This study compared the safety and efficacy of treatment with the PRESTIGE LP cervical disc versus a historical control anterior cervical discectomy and fusion (ACDF). METHODS Prospectively collected PRESTIGE LP data from 20 investigational sites were compared with data from 265 historical control ACDF patients in the initial PRESTIGE Cervical Disc IDE study. The 280 investigational patients with single-level cervical disc disease with radiculopathy and/or myelopathy underwent arthroplasty with a low-profile artificial disc. Key safety/efficacy outcomes included Neck Disability Index (NDI), Neck and Arm Pain Numerical Rating Scale scores, 36-Item Short Form Health Survey (SF-36) score, work status, disc height, range of motion, adverse events (AEs), additional surgeries, and neurological status. Clinical and radiographic evaluations were completed preoperatively, intraoperatively, and at 1.5, 3, 6, 12, and 24 months postoperatively. Predefined Bayesian statistical methods with noninformative priors were used, along with the propensity score technique for controlling confounding factors. Analysis by independent statisticians confirmed initial statistical findings. RESULTS The investigational and control groups were mostly similar demographically. There was no significant difference in blood loss (51.0 ml [investigational] vs 57.1 ml [control]) or hospital stay (0.98 days [investigational] vs 0.95 days [control]). The investigational group had a significantly longer operative time (1.49 hours vs 1.38 hours); 95% Bayesian credible interval of the difference was 0.01-0.21 hours. Significant improvements versus preoperative in NDI, neck/arm pain, SF-36, and neurological status were achieved by 1.5 months in both groups and were sustained at 24 months. Patient follow-up at 24 months was 97.1% for the investigational group and 84.0% for the control group. The mean NDI score improvements versus preoperative exceeded 30 points in both groups at 12 and 24 months. SF-36 Mental Component Summary superiority was established (Bayesian probability 0.993). The mean SF-36 PCS scores improved by 14.3 points in the investigational group and by 11.9 points in the control group from baseline to 24 months postoperatively. Neurological success at 24 months was 93.5% in the investigational group and 83.5% in the control group (probability of superiority ~ 1.00). At 24 months, 12.1% of investigational and 15.5% of control patients had an AE classified as device or device/surgical procedure related; 14 (5.0%) investigational and 21 (7.9%) control patients had a second surgery at the index level. The median return-to work time for the investigational group was 40 days compared with 60 days for the control group (p = 0.020 after adjusting for preoperative work status and propensity score). Following implantation of the PRESTIGE LP device, the mean angular motion was maintained at 12 months (7.9 degrees ) and 24 months (7.5 degrees ). At 24 months, 90.0% of investigational and 87.7% of control patients were satisfied with the results of surgery. PRESTIGE LP superiority on overall success (without disc height success), a composite safety/efficacy end point, was strongly supported with 0.994 Bayesian probability. CONCLUSIONS This device maintains mean postoperative segmental motion while providing the potential for biomechanical stability. Investigational patients reported significantly improved clinical outcomes compared with baseline, at least noninferior to ACDF, up to 24 months after surgery. PMID- 26230425 TI - Self-Assembled Light-Harvesting System from Chromophores in Lipid Vesicles. AB - Lipid vesicles are used as the organizational structure of self-assembled light harvesting systems. Following analysis of 17 chromophores, six were selected for inclusion in vesicle-based antennas. The complementary absorption features of the chromophores span the near-ultraviolet, visible, and near-infrared region. Although the overall concentration of the pigments is low (~1 MUM for quantitative spectroscopic studies) in a cuvette, the lipid-vesicle system affords high concentration (>=10 mM) in the bilayer for efficient energy flow from donor to acceptor. Energy transfer was characterized in 13 representative binary mixtures using static techniques (fluorescence-excitation versus absorptance spectra, quenching of donor fluorescence, modeling emission spectra of a mixture versus components) and time-resolved spectroscopy (fluorescence, ultrafast absorption). Binary donor-acceptor systems that employ a boron-dipyrrin donor (S0 <-> S1 absorption/emission in the blue-green) and a chlorin or bacteriochlorin acceptor (S0 <-> S1 absorption/emission in the red or near infrared) have an average excitation-energy-transfer efficiency (PhiEET) of ~50%. Binary systems with a chlorin donor and a chlorin or bacteriochlorin acceptor have PhiEET ~ 85%. The differences in PhiEET generally track the donor fluorescence/acceptor-absorption spectral overlap within a dipole-dipole coupling (Forster) mechanism. Substantial deviation from single-exponential decay of the excited donor (due to the dispersion of donor-acceptor distances) is expected and observed. The time profiles and resulting PhiEET are modeled on the basis of (Forster) energy transfer between chromophores relatively densely packed in a two dimensional compartment. Initial studies of two ternary and one quaternary combination of chromophores show the enhanced spectral coverage and energy transfer efficacy expected on the basis of the binary systems. Collectively, this approach may provide one of the simplest designs for self-assembled light harvesting systems that afford broad solar collection and efficient energy transfer. PMID- 26230426 TI - Erratum: The up-scaling of ecosystem functions in a heterogeneous world. PMID- 26230427 TI - Light-Dependent Protochlorophyllide Oxidoreductase: Phylogeny, Regulation, and Catalytic Properties. AB - This Current Topic focuses on light-dependent protochlorophyllide oxidoreductase (POR, EC 1.3.1.33). POR catalyzes the penultimate reaction of chlorophyll biosynthesis, i.e., the light-triggered reduction of protochlorophyllide to chlorophyllide. In this reaction, the chlorin ring of the chlorophyll molecule is formed, which is crucial for photosynthesis. POR is one of very few enzymes that are driven by light; however, it is unique in the need for its substrate to absorb photons to induce the conformational changes in the enzyme, which are required for its catalytic activation. Moreover, the enzyme is also involved in the negative feedback of the chlorophyll biosynthesis pathway and controls chlorophyll content via its light-dependent activity. Even though it has been almost 70 years since the first isolation of active POR complexes, our knowledge of them has markedly advanced in recent years. In this review, we summarize the current state of knowledge of POR, including the phylogenetic roots of POR, the mechanisms of the regulation of POR genes expression, the regulation of POR activity, the import of POR into plastids, the role of POR in PLB formation, and the molecular mechanism of protochlorophyllide reduction by POR. To the best of our knowledge, no previous review has compiled such a broad set of recent findings about POR. PMID- 26230429 TI - Optical Epitaxial Growth of Gold Nanoparticle Arrays. AB - We use an optical analogue of epitaxial growth to assemble gold nanoparticles into 2D arrays. Particles are attracted to a growth template via optical forces and interact through optical binding. Competition between effects determines the final particle arrangements. We use a Monte Carlo model to design a template that favors growth of hexagonal particle arrays. We experimentally demonstrate growth of a highly stable array of 50 gold particles with 200 nm diameter, spaced by 1.1 MUm. PMID- 26230428 TI - Serum anti-Mullerian hormone assessment of ovarian reserve and polycystic ovary syndrome status over the reproductive lifespan. AB - BACKGROUND: To determine normal ranges for serum anti-Mullerian hormone (AMH) using the new automated Elecsys AMH assay platform, with a view to establishing values that signify premature loss of ovarian reserve, increased risk for an excessive response during IVF stimulation and a likely diagnosis of polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: Serum AMH was measured by the Elecsys automated electrochemiluminescence assay in 654 women undergoing gynaecological assessment. RESULTS: Serum AMH levels peaked before 25 years of age, with mean AMH levels halving by 36 and falling to a quarter of their peak by 40 years of age. Overall, AMH results of 95% of patients with PCOS exceeded the 50th percentile for their age, with 72.1% having an AMH result in the top quartile for age. ROC analysis suggested that a serum AMH >=36 pmol L(-1) is the best determinant of PCOS status (sensitivity 83.7% and specificity 82.3%). Serum AMH exhibited an excellent correlation with ultrasound-assessed antral follicle count (AFC) (r = 0.836, P < 0.0001), with a result of 20 pmol L(-1) corresponding to an AFC of 16 and, therefore, increased risk of ovarian hyperstimulation syndrome (OHSS) during IVF treatment. CONCLUSION: Serum AMH is a sensitive marker of age-related decline in ovarian reserve status. A serum AMH result >36 pmol L( 1) , or above the 75th percentile for age, is highly suggestive of a diagnosis of PCOS. A serum AMH result below the 10th percentile for age suggests accelerated loss of ovarian reserve, while an AMH result exceeding 20 pmol L(-1) suggests an increased risk of OHSS during IVF treatment. PMID- 26230430 TI - [Antibiotics utilization in the Intensive Care Unit of the Hospital Dr, Guillermo Rawson-San Juan, Argentina]. AB - INTRODUCTION: To achieve rational use of antibiotics (ATB), is necessary to know its use and prescription patterns over time, Objective: To describe and analyze the characteristics of the use of ATB in the Guillermo Rawson Hospital (GRH) adult intensive care unit (ICU). MATERIAL AND METHOD: Observational, descriptive, longitudinal and retrospective study (2008-2011). Pharmacy and Statistics records were consulted, ATC code was used, the group analyzed was J01, Oral or parenteral DDD were assigned, Data was processed with Excel 2007, Unit of measure: DDD/100 bed-days, for each ATB per year and an average of use. RESULTS AND DISCUSSION: Over 4 years, 48 different medicines were dispensed (33 drugs), The average consumption of ATB was 177,07 DDD/100 bed-days and distribution per year was: 183,10, 165,90, 180,94, 178,34, The DDD/100 bed-days average for treatment groups more used were: penicillin (57.10), other beta-lactam antibacterials (48.01), other antibacterials (21.07), trimethoprim and sulfonamides (19,54), quinolones (15,64), macrolides/azalides and lincosamides (6,53), aminoglycosides (5,65) and tetracyclines (3,53), There were changes in consumption without clear pattern of increase or decrease. CONCLUSIONS: ATB used in the ICU and its variation in use between 2008-2011 were described, The ATB most used were penicillins and other beta-lactams and 2008 was the year that more ATB was dispensed. Understanding these patterns of consumption will be useful to develop a founded antibiotic policy reached by consensus and beneficial to the patients. PMID- 26230431 TI - [Clinical characteristics of adult patients with herpetic meningoencephalitis: a nested case control study]. AB - INTRODUCTION: Herpes simplex virus (HSV) is the most common etiology of sporadic encephalitis and presents with an estimated mortality of 50-70%. OBJECTIVE: To describe baseline characteristics of patients with herpetic encephalitis admitted to a tertiary teaching hospital and their difference with patients with non herpetic encephalitis. MATERIALS AND METHODS: Nested case control study using a retrospective cohort of patients with suspected encephalitis admitted to the Hospital Italiano de Buenos Aires (2006-2013). Adult patients included had a lumbar puncture with a positive or negative polimerase reaction for HSV. A case of herpetic encephalitis was defined as a positive polimerase reaction in spinal fluid. For each case, 5 controls were randomly selected. RESULTS: There were no baseline differences present between cases and controls. The only covariate associated with herpetic encephalitis was an abnormal brain magnetic resonance imaging (MRI) (OR: 5.37, IC 95% 1.42-20.38, p < 0.01). The most frecuent alterations in the MRI were extratemporal lesions or temporal ones with or without haemorrhage. DISCUSSION: There are no apparent baseline clinical differences between patients with or without herpetic encephalitis. A positive finding in a brain MRI should be taken into account during clinical workup. PMID- 26230432 TI - [Effect of hydrogymnastics physical exercise on serum level of immunoglobulin A in elderly women]. AB - BACKGROUND: Decreases in function of the immune system with age contribute to the increase the risk of infectious diseases especially the upper respiratory tract. On the other hand, physical activity has been widely recommended for health. However, more studies are needed to support the benefit effect of exercise on immune system in elderly. AIM: To evaluate the effect of the hydrogymnastics on the serum level of immunoglobulin A (IgA) in elderly women. METHODS: Twenty-six participants were randomly assigned to an experimental (n: 16) or a control group (n: 10). IgA concentrations were determined by nephelometry (BN2 Analyzer, Dade Behring). The hydrogymnastics training protocol was performed 5 times a week during 12 weeks. The intensity of the aerobic exercise was 50-60% of the maximum heart rate monitored by telemetry (Polar-FT7). RESULTS: No significant differences (p: 0.797) resulted by ANOVA on serum IgA levels; the percentage of change in experimental group was Delta% = -6.7 mg/dL compared to the control group, Delta%= -7.4 mg/dL. CONCLUSION: After three months of hydrogymnastics the IgA level did not show significant change on elderly women; However, positive improvement in percentage of change Delta% was found. PMID- 26230434 TI - [Non symptomatic sexually transmitted infections: urine sample allows an adequate detection]. AB - Detection of non-symptomatic sexually transmitted infections (NSSTD) has taken great relevance, primarily due to global increase. This has led to implement various laboratory techniques with the aim of early detection of these silent infections to decrease the incidence. Techniques usually used for the detection and identification of NSSTD require invasive samples (blood, citobrush, etc.), so the urine could be a simpler option and noninvasive sample when the patient be subjected to test for some of these infections. PMID- 26230433 TI - [Risk of bacteremia associated with intravascular devices stratified by birth weight in born of a public hospital of high complexity: follow-up to seven years]. AB - INTRODUCTION: Bacteremia associated to vascular catheters is the most frequent nosocomial infection in Neonatal Intensive Care Units and increases cost and mortality. OBJECTIVE: To know the risk of bacteremia related to vascular devices in hospitalized newborns, stratified by birth weight. METHOD: A surveillance system was established considering birth weight and type of catheters in order to detect bacteremia and look for the risks associated to type of catheters and birth weight in the period 2005 to 2011, according to Chilean Ministry of Health's surveillance. RESULTS: We registered bacteremia associated to vascular devices in newborns considering birth weight between less than 1,000 g to more than 2,500 g from years 2005 and 2011. In the period, 4,704 patients were surveyed with 25,130 catheter days and 70 bacteremia were detected. The rates of bacteremia were 0.9 per 1,000 catheter days in peripheral catheters, 3.0 per 1000 catheter days in peripheral inserted central catheters and 9.6 per 1,000 catheter days in umbilical catheters (UC). On the other side the risk of bacteremia was 6.4% in newborns with birth weight less 1,000 g and 1.5% in newborns with birth weight over 2,500 g. Coagulase negative Staphylococcus was the most frequent isolate agents. CONCLUSIONS: The risk of developing bacteremia is associated with lower birth weight and the use of UC independent of weight. PMID- 26230436 TI - [HIV/AIDS patients in a Critical Care Unit: The experience of a general hospital in a developing country]. AB - INTRODUCTION AND AIMS: Despite general availability of HAART in Chile, admissions of HIV/AIDS patients to Intensive-Intermediate Care Units (IICU) are still happening, and a characterization of patient's profile, mortality and potentially avoidable admissions is necessary. METHODS: Observational retrospective study in one general hospital in Chile of HIV/AIDS patients admitted to IICU during 9 years. RESULTS: During 2005-2013, 32 patients were admitted to IICU, with 87,5% in AIDS stage, only 53,1% knew his/her condition, 43,8% were receiving HAART and 16.6% chemoprophylaxis for opportunistic infections, A CD4 count < 200/uL was registered in 75,9% of patients. Most admissions were driven by infectious conditions (84,4%) and 48,1% developed septic shock, IICU hospitalizations were motivated by respiratory failure, neurologic compromise, sepsis or a mixture of them (87,5%), By univariate analysis, admissions by respiratory failure were associated to no HAART, oral candidiasis or CD4 < 250/uL (p < 0.01). Eight patients died during their first hospitalization (25%) and other 5 in the following month after discharge. Death during hospitalization was significantly associated to vasoactive drug use >= 7 days (OR 16.5; IC95 2.1-128 p < 0.01). In multivariate analysis, APACHE score >= 18 was associated with death during hospitalization of after discharge (OR 3,3 IC95 1,1-10; p < 0,05), Four patients (12,5%) had potentially avoidable admissions. CONCLUSIONS: Despite HAART availability in Chile, hospitalizations of patients with HIV/AIDS are still happening, affecting those that either are unaware of his/her condition, are not receiving HAART and/or chemoprophylaxis. These admissions generate premature deaths and happen even after discharge in severely ill patients. PMID- 26230435 TI - [Wildlife veterinarians rabies vaccination in Chile: a survey]. AB - INTRODUCTION: Rabies is a lethal but preventable disease. Knowing the extent of immunization coverage among at risk populations, may help to guide immunization efforts, as well as increase the effectiveness of rabies control and prevention programs. AIM: To determine the proportion of wildlife veterinarians in Chile, as part of a group at risk of rabies transmission. METHODS: An electronic survey was sent to wildlife veterinarians in Chile. RESULTS: We found that veterinarians in Chile work mainly with carnivores and deer compared to other mammals (p < 0.001), rarely works with bats (p = 0.6572). Most of the participants had been bitten by domestic animals, while a lesser proportion (29%) by wild animals. Most of the participants never received rabies vaccination (53%), while within the group that had started a rabies vaccination scheme, a substantial proportion (39%) did not complete it. DISCUSSION AND CONCLUSION: Identify the vaccination status of risk groups is important for infectious disease control and prevention programs, as this information helps to identify priority groups during outbreaks or vaccine scarcity. Wildlife veterinarians in Chile are at risk of rabies transmission and should be included in rabies prevention programs, especially considering their vulnerability and lack of biosafety practices. Increasing education in rabies epidemiology and prevention is urgently needed in veterinary faculties in Chile. PMID- 26230438 TI - [Trichophyton mentagrophytes complex]. PMID- 26230437 TI - [Grupo Colaborativo de Resistencia Bacteriana, Chile: recommendations 2014 towards the control of bacteria resistance]. AB - Five issues were reviewed in depth at the 2014 annual meeting of Colaborative Group Against Bacterial Resistance and the antecedents and conclusions are detailed in this document. I.- News in CLSI 2014: the difficulties and implications on its implementation at the local level were reviewed and recommendations were set. II.- Criteria for determining the incidence of multi resistant microorganism in critical care units where indicators and monitoring methodology for better quantification of microorganisms were defined. III.- Quality requirements were established to be considered by the professionals involved in the selection of antimicrobials in the hospital. IV.- Transfer policies, screening and contact precautions for the control of transmission of multiresistant bacteria. V.- Recommendations for health facilities when a carbapenemase producing enterobacteriacea is detected, in a checklist format for rapid deployment in hospitals without endemia of these agents. These are suggestions that arise from the joint work of specialists from many hospitals that do not represent consensus or recommendation, but may help to control the resistance level of each health facility in the country. PMID- 26230439 TI - [Descriptive study of bone and joint infections in children in times of community acquired methicillin- resistant Staphylococcus aureus (CA-MRSA)]. AB - BACKGROUND: Bone and joint infections (BJI) are relatively common in children, and community -acquired methicillin resistant Staphylococcus aureus (CA-MRSA) is the leading cause in some countries. AIM: To evaluate epidemiological data, clinical and microbiological features and outcome of BJI. METHODS: A prospective descriptive study was conducted. RESULTS: 40 patients (p) completed the study. Bacterial cultures were positives in 30 p (75%): CA-MRSA was found in 19 p, methicillin-sensitive S. aureus in 6 p, and others in 5 p. Cultures were negatives in 10 p (25%). Median treatment duration was 28 days (r: 21-40 d); Analyzing patients with CA-MRSA positive cultures separately, initial CRP was higher (Md 76 vs 50 mg/L, p < 0.02), normalization occurred later (Md 14 days vs 7days, p < 0.03), and duration of treatment (Md 32 days vs 23, p < 0.004) as well as hospital stay (Md 9 days vs 7, p = 0.12) were longer. Sequelae were present in 3 p and 1 relapsed: All of them with CA-SAMR. CONCLUSION: CA-MRSA was the leading cause of BJI and was associated with higher CRP on admission, later normalization and longer treatment duration. Complications as drainage requirement, and sequelae were common in those p. PMID- 26230440 TI - [Measles outbreaks in developed countries: A lesson for Chile]. AB - The measles vaccine has been used for over 50 years and has proven to be safe, effective and inexpensive, Nevertheless, in 2013 145,700 measles deaths occurred, mostly in countries with low per capita income and weak health infrastructure. The occurrence of measles cases is not restricted to developing countries, but also affects developed countries (Europe and USA), where is associated with a reduction in vaccination coverage, explained by a loss of confidence of some parents in the vaccine. This perspective article addresses the loss of confidence in the vaccine, and the individual and collective consequences of the decision to not vaccinate a child. Various strategies to reverse this phenomenon are presented, most notably the continuing education of health professionals, parents and patients using scientific arguments, given in an understandable and interesting language. Finally, the current situation of Chile (a country with current certification of measles elimination) is presented, emphasizing the importance of maintaining this condition. PMID- 26230441 TI - [Rudolf Krauss, Giovanni Noe and a flash of infectious diseases in Chile, 1930]. AB - When there were giants on the earth, two of them, Rudolf Kraus and Giovanni Noe, met at the ancient Bacteriological Institute of Chile, and founded together a journal representing the principles of the institution. A nostalgic glance over the papers published therein for these so named giants lets us know a little about the study of infectious diseases in the thirties, when tuberculosis and malaria were two of the biggest problems for the world's public health... then and now. PMID- 26230442 TI - [Salmonella spp. gastroenteritis associated to pet turtles in three infants]. AB - Non-typhoidal salmonellosis is an important cause of acute diarrhea in children. Generally they are acquired by consumption of contaminated food, but contact with reptiles is an increasing cause of this zoonoses. We describe three pediatric cases of gastroenteritis by Salmonella (Montevideo, Newport and Pomona), related to having turtles as pets. In two cases, the bacteria were isolated from the patient's stools and the turtle's droppings. The same genetic subtype by PFGE was obtained in both isolates. All the children recovered. Information and public health measures should be undertaken to control this zoonoses which affects young children. PMID- 26230443 TI - [Cutaneous coccidioidomycoses: Six Mexican cases report]. AB - Coccidioidomycosis is a systemic airborne mycosis that may involve secondarily other organs through systemic dissemination. Fungi Coccidioides immitis and C. posadasii are the etiologic agents. The former is ubiquitous from the area of California in North America, and the latter is found elsewhere in the world. Primary cutaneous infection is rare. We present six Mexican male cases, residents of Tijuana B.C. Three of them with primary pulmonary infection and further cutaneous dissemination, and three cases of primary cutaneous coccicioidomycosis. In half the cases C. posadasii was isolated. The clinical suspicion is basic for reaching the diagnosis, and we must always keep in mind that the cutaneous manifestations are widely varied and that the lesions are more severe when systemic dissemination occurs. PMID- 26230444 TI - [Extrapulmonary pneumocystosis: a case report]. AB - We report a case of a middle-age male patient, with newly HIV infection in AIDS stage diagnosis, no comorbitidies, who was hospitalized for subacute malaise, fever, self-limited unproductive cough and no bloody chronic diarrea. The diagnosis of Pneumocystis jiroveci pneumonia was performed by imagenological suspicion and stains of cysts of this pathogen with bronchoalveolar lavage samples. Treatment was initiated with oral cotrimoxazole and starting HAART with good clinical outcome. Concomitantly, an etiologic study was conducted for chronic diarrhea and through histopathological examination of colonic mucosa, numerous extracellular cystic structures Pneumocystis characteristics were observed, performing the diagnosis of extrapulmonary pneumocystosis. Extrapulmonary pneumocystosis is a rare cause of P. jiroveci infection, requires a high index of suspicion and should be approached in HIV patients with severe AIDS which is common in co-infection of various infections and is peremptory to make an etiologic diagnosis and early treatment. PMID- 26230445 TI - [Community associated-methicillin-resistant Staphylococcus aureus (SAMR-AC): comunication of the first four pediatric cases in the Roberto del Rio Children's Hospital]. AB - Staphylococcus aureus is a known pathogen in pediatric patients that produces skin infections, cutaneous abscess, cellulitis and osteoarticular infections. Most of these infections are produced by a meticilin susceptible strain. The community associated methicillin resistant Staphylococcus aureus was published for the first time in 1993, ever since then is has been recognized as a cosmopolite pathogen. The first report in Latin America was published in 2003, and in Chile in 2008 from adult patients that have reported traveling to other countries. The following series describes four pediatric cases, all school-aged children, diagnosed since 2012 with clinical followups and molecular studies. Two cases presented as osteomyelitis of the lower extremity; and one presented as arm cellulitis. These three cases had Panton Valentine leukocidine (PV-L) negative strains from the clone complex 8. The last case presented a renal abscess, the strain was PV-L positive from the clone complex 30. This case series constitutes the first pediatric case report in Chile. PMID- 26230446 TI - [Granulicatella spp]. AB - Granulicatella spp. is a bacteria of the oral cavity, belonging to the nutritionally variant group streptococci, and has been identified in 5% of all bacterial endocarditis. It's an important etiologic species in endocarditis, particularly in the setting of negative blood cultures. Granulicatella is a non mobile, non- spore forming organism that is both catalase and oxidase negative. The treatment for Granulicatella, is the same for Enterococcus according to the American and European guidelines, however resistance to this treatment has been reported. PMID- 26230447 TI - [Adherence to HAART in HIV: The importance of sociocultural context involved]. PMID- 26230448 TI - [Information and Communication Technologies (ICTs): alternative or complement for surveillance, prevention and control of dengue in the Americas?]. PMID- 26230449 TI - [Bad response to ceftriaxone treatment in Chilean adults with acute bacterial meningitis caused by Streptococcus pneumoniae]. PMID- 26230450 TI - [Vancomycin in coagulase negative Staphylococcus bacteremia and survival in newborns]. PMID- 26230451 TI - Reaction of Cp*(Cl)M(Diene) (M = Ti, Hf) with Isonitriles. AB - We have investigated the reaction of isonitriles (RNC) with electronically unsaturated diene complexes of Ti and Hf. Cp*(Cl)Ti(2,3-dimethylbutadiene) (1) reacts with 2 equiv of RNC to give eta(1),eta(2)-diimine complexes 2 (R = (t)Bu) and 3 (R = 1-adamantyl). Cp*(Cl)Ti(N,N-di-(t)Bu-eta(1),eta(2)-diimine) (2), in the presence of pyridine, fragments to Cp*(Cl)Ti(N(t)Bu)(NC5H5) (10) and an alpha methylene cyclopent-3-enimine (11). The hafnium analogue of 1, Cp*(Cl)Hf(2,3 dimethylbutadiene) (14), has been reported to give a cyclic amidine complex when treated with 2 equiv of 2,6-dimethylphenyl isonitrile. By X-ray crystallography, however, we find that 14 and 2,6-dimethylphenyl isonitrile give instead a 2,5 diazahafnacyclopentane that features a sigma-interaction between the C-C bond of a cyclopropane ring and the Hf. PMID- 26230452 TI - Immobilization and volume reduction of heavy metals in municipal solid waste fly ash using nano-size calcium and iron-dispersed reagent. AB - This study was conducted to examine the synthesis and application of novel nano size calcium/iron-based composite material as an immobilizing and separation treatment of the heavy metals in fly ash from municipal solid waste incineration. After grinding with nano-Fe/Ca/CaO and with nano-Fe/Ca/CaO/[PO4], approximately 30 wt% and 25 wt% of magnetic fraction fly ash were separated. The highest amount of entrapped heavy metals was found in the lowest weight of the magnetically separated fly ash fraction (i.e., 91% in 25% of treated fly ash). Heavy metals in the magnetic or nonmagnetic fly ash fractions were about 98% and 100% immobilized, respectively. Additionally, scanning electron microscopy combined with energy-dispersive X-ray spectrometry (SEM-EDS) observations indicate that the main fraction of enclosed/bound materials on treated fly ash includes Ca/PO4 associated crystalline complexes. After nano-Fe/Ca/CaO/[PO4] treatment, the heavy metal concentrations in the fly ash leachate were much lower than the Japan standard regulatory limit for hazardous waste landfills. These results appear to be extremely promising. The addition of a nano-Fe/Ca/CaO/PO4mixture with simple grinding technique is potentially applicable for the remediation and volume reduction of fly ash contaminated by heavy metals. IMPLICATIONS: After grinding with nano-Fe/Ca/CaO and nano-Fe/Ca/CaO/[PO4], approximately 30 wt% and 25 wt% of magnetic fraction fly ash were separated. The highest amount of entrapped heavy metals was found in the lowest weight of the magnetically separated fly ash fraction (i.e., 91% in 25% of treated fly ash), whereas heavy metals either in the magnetic or nonmagnetic fly ash fractions were about 98% and 100% immobilized. These results appear to be very promising, and the addition of nano Fe/Ca/CaO/PO4mixture with simple grinding technique may be considered potentially applicable for the remediation and volume reduction of contaminated fly ash by heavy metals. PMID- 26230453 TI - Thinning of Choroidal Thickness in Patients with Rheumatoid Arthritis Unrelated to Disease Activity. AB - PURPOSE: To investigate subfoveal and perifoveal choroidal thickness (CT) in patients with rheumatoid arthritis (RA). METHODS: A study group of 117 patients with RA and a control group of 46 age-matched healthy individuals were enrolled in the study. Subfoveal and perifoveal CTs were measured using enhanced depth imaging optical coherence tomography (EDI-OCT). Perifoveal CT was measured 1,500 um nasally and 1,500 um temporally apart from the foveal center. Relationship between the disease activity score 28 (DAS-28) and subfoveal CT was also evaluated. RESULTS: The mean subfoveal CT values in the study and control groups were 226.90 +/- 43.61 MUm and 299.74 +/- 48.06 MUm, respectively, which made for a statistically significant difference (p < 0.001). Likewise, perifoveal CT values were significantly thinner in the study group when compared with control group. DAS-28 wasn't correlated with subfoveal CT in the study group. CONCLUSIONS: CT was significantly thinner in patients with RA when compared with healthy controls. PMID- 26230454 TI - A Decline in 2 Consecutive Postmortem Serum Tryptase Levels in an Anaphylactic Death. AB - The diagnosis of anaphylaxis in the postmortem setting remains a significant challenge for pathologists. The performance of postmortem serum tryptase is commonly used in the investigation of suspected anaphylactic deaths; however, not only have tryptase levels been found to be elevated in nonanaphylactic deaths, the effect of the postmortem interval on serum tryptase is not fully understood. There are no studies on serial measurement of tryptase in the postmortem setting. We report a death from anaphylaxis in which 2 separate serum tryptase measurements taken 24 hours apart from the same femoral vein showed a substantial decline from 130.0 ug/L at day 2 after death to 84.4 ug/L at day 3. We hypothesize that the decline may be due to degradation of the degranulated mast cell tryptase in anaphylactic deaths. Serial measurement of postmortem serum tryptase may assist in understanding the complex field of serum tryptase interpretation in the postmortem setting. We suggest that an early blood sample to be obtained as soon as possible after death in cases where anaphylaxis is suspected, because there appears to be a significant decline in tryptase levels with increasing postmortem interval. PMID- 26230455 TI - A Retrospective Study of Blade Wound Characteristics in Suicide and Homicide. AB - The distinction between self-inflicted blade wounds and blade wounds inflicted by another can be difficult in situations where there is little available history or context. We reviewed homicides and suicides in the past 10 years at the Vermont Office of the Chief Medical Examiner to define the characteristics of homicidal and suicidal blade wounds. All homicides and suicides involving blade wounds, not just those in which blade wounds were the cause of death, were included. Information regarding victim demographics, location and type of injuries, toxicology, and evidence of suicidality was gathered. Blade wounds were the cause of death in 85.7% of homicides but only in 36% of suicides. Hanging and gunshot wounds were the cause of death in 28% and 24% of suicides, respectively. Multiple stab wounds were found in 10% of homicides and in 0% of suicides, whereas multiple incised wounds were found in 60% of suicides and only 10% of homicides. However, several unusual instances of suicide were found, including suicides with clothing damage or bone or cartilage injury from blade wounds. No characteristics of blade wounds were definitive for homicide or suicide. History and circumstances of the scene are thus crucial in determining the manner of death. PMID- 26230456 TI - Longevity of attentional bias modification effects for food cues in overweight and obese individuals. AB - Accumulating evidence shows that overweight individuals exhibit an attentional bias for food and that this bias can be modified. This study investigated the longevity of such modification effects. Using a dot probe paradigm, a community sample of overweight and obese women (N = 104) was trained to direct attention towards ('attend') or away from ('avoid') food pictures. Participants completed five weekly training sessions. Attentional bias was measured before and after training, at 24 h and one-week follow-up. To increase generalisability, at each of the post-training and follow-up assessments, participants were shown a mix of old and new food pictures. They also completed another implicit bias measure, i.e. a word stem task. Attentional bias for food increased in the 'attend' group and decreased in the 'avoid' group. These retraining effects were maintained at 24 h and one-week follow-up, and extended to new food pictures. Participants in the 'avoid' group also produced relatively fewer food words on the word stem task than those in the 'attend' group. Results are consistent with predictions of cognitive-motivational models that attentional biases are malleable. They further suggest that attentional bias modification, which targets the implicit processes that underlie the heightened food responsivity in overweight individuals, could help combat pathological (over)eating. PMID- 26230457 TI - Unsung hero: Donald Darrow Matson's legacy in pediatric neurosurgery. AB - Donald Darrow Matson made seminal contributions to the field of pediatric neurosurgery. Born in 1913 in Fort Hamilton, New York, Matson was the youngest of four sons of an army colonel. He graduated from Cornell University and, years later, from Harvard Medical School. Matson selected Peter Bent Brigham Hospital for his neurosurgical training, which was interrupted during World War II. As a neurosurgeon, he worked close to the front lines under Brigadier General Elliot Cutler in Europe, earning a Bronze Star. Matson returned to Boston to become Franc Ingraham's fellow and partner. He was a masterful surgeon and, with Ingraham, published Neurosurgery of Infancy and Childhood in 1954, the first pediatric neurosurgery textbook in the world. Upon Ingraham's retirement, Matson became chairman of the department of neurosurgery at Boston Children's Hospital and Peter Bent Brigham. In 1968, he became the inaugural Franc D. Ingraham Professor of Neurological Surgery at Harvard Medical School. Among his neurosurgical accomplishments, Matson served as President of the Harvey Cushing Society, later known as the American Association of Neurological Surgeons. He was unable to preside at the 1969 meeting that marked the 100th anniversary of Cushing's birth, having contracted Creutzfeldt-Jakob disease. Matson died at the age of 55, surviving his mentor Ingraham by only 4 years. PMID- 26230458 TI - Outcome of children with severe traumatic brain injury who are treated with decompressive craniectomy. AB - OBJECT Decompressive craniectomy (DC) for the management of severe traumatic brain injury (TBI) is controversial. The authors sought to determine if DC improves the outcome of children with severe TBI. METHODS In a retrospective, case-control study, medical records of all patients admitted to the pediatric ICU between May 1998 and May 2008 with severe TBI and treated with DC were identified and matched to patients who were treated medically without DC. Medical records were reviewed for patients' demographic data and baseline characteristics. RESULTS During the study period, 17 patients with severe TBI treated with DC at a median of 2 hours (interquartile range [IQR] 1-14 hours) after admission were identified and matched to 17 contemporary controls. On admission, there were no differences between DC and control patients regarding age (10.2 +/- 5.9 years vs 12.4 +/- 5.4 years, respectively [mean +/- SD]), sex, weight, Glasgow Coma Scale score (median 5 [IQR 3-7] vs 4 [IQR 3-6], respectively; p = 0.14), or the highest intracranial pressure (median 42 [IQR 22-54] vs 30 [IQR 21-36], respectively; p = 0.77). However, CT findings were significant for a higher rate of herniation and cerebral edema among patients with DC versus controls (7/17 vs 2/17, respectively, had herniation [p = 0.05] and 14/17 vs 6/17, respectively, had cerebral edema [p = 0.006]). Overall there were no significant differences in survival between patients with DC and controls (71% [12/17] vs 82% [14/17], respectively; p = 0.34). However, among survivors, at 4 years (IQR 1-6 years) after the TBI, 42% (5/12) of the DC patients had mild disability or a Glasgow Outcome Scale score of 5 vs none (0/14) of the controls (p = 0.012). CONCLUSIONS In this retrospective, small case-control study, the authors have shown that early DC in pediatric patients with severe TBI improves outcome in survivors. Future prospective randomized controlled studies are needed to confirm these findings. PMID- 26230459 TI - Use of blood-sparing surgical techniques and transfusion algorithms: association with decreased blood administration in children undergoing primary open craniosynostosis repair. AB - OBJECT Craniofacial reconstruction surgery (CFR) is often associated with significant blood loss, coagulopathy, and perioperative blood transfusion. Due to transfusion risks, many different approaches have been used to decrease allogeneic blood transfusion for these patients during the perioperative period. Protocols have decreased blood administration during the perioperative period for many types of surgeries. The object of this study was to determine if a protocol involving blood-sparing surgical techniques and a transfusion algorithm decreased intraoperative blood transfusion and blood loss. METHODS A protocol using transfusion algorithms and implementation of blood-sparing surgical techniques for CFR was implemented at Vanderbilt University on January 1, 2013. Following Institutional Review Board approval, blood loss and transfusion data were gathered retrospectively on all children undergoing primary open CFR, using the protocol, for the calendar year 2013. This postprotocol cohort was compared with a preprotocol cohort, which consisted of all children undergoing primary open CFR during the previous calendar year, 2012. RESULTS There were 41 patients in the preprotocol and 39 in the postprotocol cohort. There was no statistical difference between the demographics of the 2 groups. When compared with the preprotocol cohort, intraoperative packed red blood cell transfusion volume decreased from 36.9 +/- 21.2 ml/kg to 19.2 +/- 10.9 ml/kg (p = 0.0001), whereas fresh-frozen plasma transfusion decreased from 26.8 +/- 25.4 ml/kg to 1.5 +/- 5.7 ml/kg (p < 0.0001) following implementation of the protocol. Furthermore, estimated blood loss decreased from 64.2 +/- 32.4 ml/kg to 52.3 +/- 33.3 ml/kg (p = 0.015). Use of fresh-frozen plasma in the postoperative period also decreased when compared with the period before implementation of the protocol. There was no significant difference in morbidity and mortality between the 2 groups. CONCLUSIONS The results of this study suggested that using a multidisciplinary protocol consisting of transfusion algorithms and implementation of blood-sparing surgical techniques during major CFR in pediatric patients is associated with reduced intraoperative administration of blood product, without shifting the transfusion burden to the postoperative period. PMID- 26230460 TI - Optimizing cerebrovascular surgical and endovascular procedures in children via personalized 3D printing. AB - OBJECT Despite the availability of multiplanar imaging, understanding relational 3D anatomy for complex cerebrovascular lesions can be difficult. A 3D printed model allows for instantaneous visualization of lesional anatomy from all perspectives, with the added ability to simulate operative approaches with tactile feedback. The authors report their experience with customized 3D printed models of pediatric cerebrovascular lesions as an educational and clinical tool for patients, trainees, and physicians. METHODS Via an "in-house" 3D print service, magnetic resonance imaging (MRI) and computerized tomography (CT) studies of pediatric patients with arteriovenous malformations (AVMs) were processed with specialized software, and regions of interest were selected by the surgical/endovascular team. Multiple models for each patient were then printed on a 3D printer, with each construct designed to illustrate different aspects of the specific lesion. Intraoperative validation of model fidelity was performed using perioperative imaging, surgical filming, and post hoc analysis of models with intraoperative photography. RESULTS Four cases involving pediatric patients (ages 0-16 years) were studied for initial proof of principle. Three of the patients had AVMs and one had a vein of Galen malformation (VOGM). The VOGM was embolized successfully and the AVMs were resected without complication. In the AVM cases, intraprocedural imaging and photography were performed and verified millimeter level fidelity of the models (n = 5, 98% concordance, range 94%-100% with average of < 2 mm variation in the largest AVM [6-cm diameter]). The use of 3D models was associated with a 30-minute reduction in operative time (12%) in 2 cases when they were compared with matched controls as a feasibility study. CONCLUSIONS Patient-specific 3D printed models of pediatric cerebrovascular conditions can be constructed with high fidelity. This proof-of-principle series demonstrates, for the first time, confirmation of model accuracy using intraprocedural assessment and potential benefit through shortened operative time. PMID- 26230461 TI - Editorial: Severe traumatic brain injury and decompressive craniectomy. PMID- 26230462 TI - Outcomes and factors associated with infant abusive head trauma in the US. AB - OBJECT Head trauma is the leading cause of death in abused children, particularly prior to the age of 2 years. An awareness of factors associated with this condition as well as with a higher risk of mortality is important to improve outcomes and prevent the occurrence of these events. The objective of this study was to evaluate outcomes and factors associated with poor outcomes in infants with diagnosed abusive head trauma (AHT). Patient characteristics, socioeconomic factors, and secondary conditions such as retinal bleeding, contusion, and fractures were considered. METHODS Data were obtained from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality. From the Kids' Inpatient Database (KID) sample, the authors identified infants no older than 23 months who had been diagnosed with AHT in 2000, 2003, 2006, and 2009. All statistical analyses were conducted in SAS 9.2. Descriptive statistics were provided, and multivariate logistic regression models were applied to evaluate factors associated with mortality and nonroutine discharge. RESULTS A total of 5195 infants were analyzed in this study. Most infants (85.5%) had ages ranging between 0 and 11 months and were male (61.6%). Overall mortality was 10.8%, with a rate of 9.8% in the 0- to 11-month-old cohort and 16.5% in the 12- to 23-month-olds (p = 0.0003). The overall nonroutine discharge rate of 25.6% increased significantly from 23.3% to 39.0% with increasing age (0-11 vs 12-23 months of age, p < 0.0001). Assuming a multivariate model that adjusted for multiple confounders, the authors found that older infants (12-23 vs 0-11 months, OR 1.81, 95% CI 1.18-2.77) with a secondary diagnosis of retinal bleeding (OR 2.85, 95% CI 2.02-4.00) or shaken baby syndrome (OR 2.09, 95% CI 1.48-2.94) had an increased risk of mortality; these factors were similarly associated with an increased odds of a nonroutine discharge. A higher income ($30,001-$35,000 vs $1 $24,999) was associated with a reduction in the odds of mortality (OR 0.46, 95% CI 0.29-0.72). In the subset of cases (1695 [32.6%]) that specified the perpetrator involved in infant injury, the authors found that the father, stepfather, or boyfriend was most frequently reported (67.4%). A trend for a higher AHT incidence was documented in the early ages (peak at 2 months) compared with older ages. CONCLUSIONS Despite the higher incidence of AHT among infants during the earlier months of life, higher mortality was documented in the 12- to 23-month-olds. Retinal bleeding and shaken baby syndrome were secondary diagnoses associated with higher mortality and nonroutine discharge. Males (67.4%) were overwhelmingly documented as the perpetrators involved in the injury of these infants. PMID- 26230463 TI - Shunt placement after cyst fenestration for middle cranial fossa arachnoid cysts in children. AB - OBJECT Some pediatric patients with middle cranial fossa arachnoid cysts present with symptoms of increased intracranial pressure (ICP) and require shunt placement after a cyst fenestration. However, factors concerning increased ICP after fenestration followed by shunt placement have not been elucidated. This study evaluated factors that are associated with shunt placement following cyst fenestration in pediatric patients with middle cranial fossa arachnoid cysts. METHODS Twenty-six pediatric patients with middle cranial fossa arachnoid cysts who were surgically treated at a single institution between 2004 and 2013 were retrospectively identified. The surgical indications for middle cranial fossa arachnoid cysts were as follows: 1) arachnoid cysts associated with symptoms such as headache and abnormally enlarging head circumference; 2) progressively expanding arachnoid cysts; and 3) large arachnoid cysts such as Galassi Type III. A cyst fenestration was performed as a first-line treatment, and shunt placement was required if symptoms associated with increased ICP were found following fenestration. The risk factors evaluated included age, sex, presenting symptoms, the presence of head enlargement, progressive cyst expansion, and subdural hematoma/hygroma. RESULTS Four patients (15.4%) required shunt placement after cyst fenestration. Younger age, abnormal head enlargement, and progressive cyst expansion before fenestration were significantly associated with the need for shunt placement following fenestration. Arachnoid cysts decreased in size in 22 patients (84.6%) after fenestration and/or shunt placement. The presence of symptoms was not associated with postoperative cyst size in this study. CONCLUSIONS In this study, younger age, abnormal head enlargement, and progressive cyst expansion were risk factors for shunt placement after cyst fenestration in pediatric patients with middle cranial fossa arachnoid cysts. It is important to consider that cyst fenestration may not be effective because of a latent derangement of CSF circulation in patients with these risk factors. PMID- 26230464 TI - Thermoregulatory vs. event sweating--comparison of clinical methodologies, physiology and results. AB - OBJECTIVES: Although the mechanisms of sweating due to thermoregulation vs. stress are distinct, the antiperspirant industry focuses primarily on perspiration due to heat as their method of efficacy testing. To better understand the overall protection afforded by a 'Clinical Strength' over-the counter antiperspirant product, we compare results from a standard hot-room study with results from two studies using the Trier Social Stress Test (TSST). METHODS: For each study, unscented antiperspirant was applied to one axilla, leaving the other untreated for internal control. The hot-room protocol involved a 40-min warm-up period with 2-20 min sweat collections at 100 +/- 2 degrees F (35% RH). The TSST requires naive subjects to give an impromptu speech and conduct mental arithmetic, with collections of sweat, heart rate and other biomarkers of stress before, during and after the event. RESULTS: During the TSST, heart rate and salivary cortisol data indicate significant emotional stress. Wetness results show that sweat was reduced by 69.4% in the hot-room study, compared with 83.7% and 89.3% reductions in the stress studies. CONCLUSION: We have found added value in investigating antiperspirancy from several causes of sweat production to give a more encompassing picture of the protection afforded by an antiperspirant product, specifically wetness protection from heat, activity and stress-induced sweat. PMID- 26230465 TI - Reduced CSF leak in complete calvarial reconstructions of microvascular decompression craniectomies using calcium phosphate cement. AB - OBJECT: Calcium phosphate cement provides a biomaterial that can be used for calvarial reconstruction in a retrosigmoid craniectomy for microvascular decompression (MVD). This study evaluates the outcomes of postoperative CSF leak and wound infection for patients undergoing a complete cranioplasty using calcium phosphate cement versus incomplete cranioplasty using polyethylene titanium mesh following a retrosigmoid craniectomy for MVD. METHODS: The authors evaluated 211 cases involving patients who underwent first-time retrosigmoid craniectomies performed by a single attending surgeon fortrigeminal neuralgia from October 2008 to June 2014. From this patient population, 111 patients underwent calvarial reconstruction after retrosigmoid craniectomy using polyethylene titanium mesh, and 100 patients had reconstructions using calcium phosphate cement. A Pearson's chi-square test was used to compare postoperative complications of CSF leak and wound infection in these 2 types of cranioplasties. RESULTS: The polyethylene titanium mesh group included 5 patients (4.5%) with postoperative CSF leak or pseudomeningocele and 3 patients (2.7%) with wound infections. In the calcium phosphate cement group, no patients had a CSF leak, and 2 patients (2%) had wound infections. This represented a statistically significant reduction of postoperative CSF leak in patients who underwent calcium phosphate reconstructions of their calvarial defect compared with those who underwent polyethylene titanium mesh reconstructions (p = 0.03). No significant difference was seen between the 2 groups in the number of patients with postoperative wound infections. CONCLUSIONS: Calcium phosphate cement provides a viable alternative biomaterial for calvarial reconstruction of retrosigmoid craniectomy defects in patients who have an MVD. The application of this material provides a biocompatible barrier that reduces the incidence of postoperative CSF leaks. PMID- 26230466 TI - Endoscopic endonasal clip ligation of cerebral aneurysms: an anatomical feasibility study and future directions. AB - OBJECTIVE: The expansion of endovascular procedures for obliteration of cerebral aneurysms highlights one of the drawbacks of clip ligation through the transcranial route, namely brain retraction or brain transgression. Sporadic case reports have emerged over the past 10 years describing endonasal endoscopic clip ligation of cerebral aneurysms. The authors present a detailed anatomical study to evaluate the feasibility of an endoscopic endonasal approach for application of aneurysm clips. METHODS: Nine human cadaveric head specimens were used to evaluate operative exposures for clip ligation of aneurysms in feasible anterior and posterior circulation locations. Measurements of trajectories were completed using a navigation system to calculate skull base craniectomy size, corridor space, and the surgeon's ability to gain proximal and distal control of parent vessels. RESULTS: In each of the 9 cadaveric heads, excellent exposure of the target vessels was achieved. The transplanum, transtuberculum, and transcavernous approaches were used to explore the feasibility of anterior circulation access. Application of aneurysm clips was readily possible to the ophthalmic artery, A1 and A2 segments of the anterior cerebral artery, anterior communicating artery complex, and the paraclinoid and paraclival internal carotid artery. The transclival approach was explored, and clips were successfully deployed along the proximal branches of the vertebrobasilar system and basilar trunk and bifurcation. The median sizes of skull base craniectomy necessary for exposure of the anterior communicating artery complex and basilar tip were 3.24 cm(2) and 4.62 cm(2), respectively. The mean angles of surgical corridors to the anterior communicating artery complex and basilar tip were 11.4 degrees and 14 degrees , respectively. Although clip placement was feasible on the basilar artery and its branches, the associated perforating arteries were difficult to visualize, posing unexpected difficulty for safe clip application, with the exception of ventrolateral-pointing aneurysms. CONCLUSIONS: The authors characterize the feasibility of endonasal endoscopic clip ligation of aneurysms involving the paraclinoid, anterior communicating, and basilar arteries and proximal control of the paraclival internal carotid artery. The endoscopic approach should be initially considered for nonruptured aneurysms involving the paraclinoid and anterior communicating arteries, as well as ventrolateral basilar trunk aneurysms. Clinical experience will be mandatory to determine the applicability of this approach in practice. PMID- 26230467 TI - Post-carotid endarterectomy changes in cerebral glucose metabolism on (18)F fluorodeoxyglucose positron emission tomography associated with postoperative improvement or impairment in cognitive function. AB - OBJECT: Cognitive function is often improved or impaired after carotid endarterectomy (CEA) for patients with cerebral hemodynamic impairment. Cerebral glucose metabolism measured using positron emission tomography (PET) with (18)F fluorodeoxyglucose (FDG) correlates with cognitive function in patients with neurodegenerative diseases. The present study aimed to determine whether postoperative changes in cerebral glucose metabolism are associated with cognitive changes after CEA. METHODS: In patients who were scheduled to undergo CEA for ipsilateral internal carotid artery (ICA) stenosis (>= 70% narrowing), cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) to acetazolamide were assessed preoperatively using brain perfusion single-photon emission computed tomography (SPECT). CBF measurement using SPECT was also performed immediately after CEA. For patients with reduced preoperative CVR to acetazolamide in the cerebral hemisphere ipsilateral to surgery, cerebral glucose metabolism was assessed using FDG-PET before surgery and 3 months after surgery and was analyzed using 3D stereotactic surface projection. Neuropsychological testing was also performed preoperatively and 3 months postoperatively. RESULTS: Twenty-two patients with reduced preoperative CVR to acetazolamide successfully underwent FDG-PET studies and neuropsychological testing before and after CEA. Seven, 9, and 6 patients were defined as showing improved, unchanged, and impaired postoperative cognition, respectively, based on the neuropsychological assessments. The cortical area with increased postoperative glucose metabolism was greater in patients with improved postoperative cognition than in those with unchanged (p < 0.001) or impaired (p < 0.001) postoperative cognition. The cortical area with decreased postoperative glucose metabolism was greater in patients with impaired postoperative cognition than in those with improved (p < 0.001) or unchanged (p < 0.001) postoperative cognition. All 7 patients with improved cognition exhibited postoperative hemispheric increases in glucose metabolism, while 5 of the 6 patients with impaired cognition exhibited postoperative hemispheric decreases in glucose metabolism. Brain perfusion SPECT revealed that the latter 6 patients experienced postoperative cerebral hyperperfusion, and 2 of the 6 patients exhibited cerebral hyperperfusion syndrome. The cortical area with decreased postoperative glucose metabolism in these 2 patients was greater than that in other patients. CONCLUSIONS: Postoperative changes in cerebral glucose metabolism, as measured using FDG-PET, are associated with cognitive improvement and impairment after CEA. PMID- 26230468 TI - Microendoscopy-guided percutaneous cordotomy for intractable pain: case series of 24 patients. AB - OBJECTIVE: The aim of this study was to show that microendoscopic guidance using a double-channel technique could be safely applied during percutaneous cordotomy and provides clear real-time visualization of the spinal cord and surrounding structures during the entire procedure. METHODS: Twenty-four adult patients with intractable cancer pain were treated by microendoscopic-guided percutaneous radiofrequency (RF) cordotomy using the double-channel technique under local anesthesia. A percutaneous lateral puncture was performed initially under fluoroscopy guidance to localize the target. When the subarachnoid space was reached by the guiding cannula, the endoscope was inserted for visualization of the spinal cord and surrounding structures. After target visualization, a second needle was inserted to guide the RF electrode. Cordotomy was performed by a standard RF method. RESULTS: The microendoscopic double-channel approach provided real-time visualization of the target in 91% of the cases. The other 9% of procedures were performed by the single-channel technique. Significant analgesia was achieved in over 90% of the cases. Two patients had transient ataxia that lasted for a few weeks until total recovery. CONCLUSIONS: The use of percutaneous microendoscopic cordotomy with the double-channel technique is useful for specific manipulations of the spinal cord. It provides real-time visualization of the RF probe, thereby adding a degree of safety to the procedure. PMID- 26230469 TI - Integrating risk management data in quality improvement initiatives within an academic neurosurgery department. AB - OBJECT While malpractice litigation has had many negative impacts on health care delivery systems, information extracted from lawsuits could potentially guide toward venues to improve care. The authors present a comprehensive review of lawsuits within a tertiary academic neurosurgical department and report institutional and departmental strategies to mitigate liability by integrating risk management data with quality improvement initiatives. METHODS The Comprehensive Risk Intelligence Tool database was interrogated to extract claims/suits abstracts concerning neurosurgical cases that were closed from January 2008 to December 2012. Variables included demographics of the claimant, type of procedure performed (if any), claim description, insured information, case outcome, clinical summary, contributing factors and subfactors, amount incurred for indemnity and expenses, and independent expert opinion in regard to whether the standard of care was met. RESULTS During the study period, the Department of Neurosurgery received the most lawsuits of all surgical specialties (30 of 172), leading to a total incurred payment of $4,949,867. Of these lawsuits, 21 involved spinal pathologies and 9 cranial pathologies. The largest group of suits was from patients with challenging medical conditions who underwent uneventful surgeries and postoperative courses but filed lawsuits when they did not see the benefits for which they were hoping; 85% of these claims were withdrawn by the plaintiffs. The most commonly cited contributing factors included clinical judgment (20 of 30), technical skill (19 of 30), and communication (6 of 30). CONCLUSIONS While all medical and surgical subspecialties must deal with the issue of malpractice and liability, neurosurgery is most affected both in terms of the number of suits filed as well as monetary amounts awarded. To use the suits as learning tools for the faculty and residents and minimize the associated costs, quality initiatives addressing the most frequent contributing factors should be instituted in care redesign strategies, enabling strategic alignment of quality improvement and risk management efforts. PMID- 26230470 TI - Early surgical removal of migrated coil/stent after failed embolization of intracranial aneurysm. AB - OBJECT: Distal coil or stent migration is a rare, but potentially morbid complication of intracranial aneurysm embolization. At present, there is no established standard of surgical evacuation of displaced material-in particular, there is no consensus on the optimum time for such intervention. The authors report their positive experiences with an ultra-early surgical evacuation of 2 migrated coils and a flow-diverter stent. METHODS: Uncontrolled coil or stent migration occurred in 3 (0.75%) of approximately 400 patients treated between 1999 and 2012 in the authors' institution. In all 3 cases, the materials moved from their intended position to the middle cerebral artery (MCA). Surgical evacuation was started immediately (within half an hour) after a futile attempt of removing them via intraarterial route, under the same anesthesia and with no active reversal of heparinization. RESULTS: No excessive bleeding was observed. Displaced coils were extracted through an incision of a branch of MCA-the anterior temporal artery, the stent was removed through a direct incision of MCA. Recombinant tissue plasminogen activator (rtPA) was injected to the stem of the internal carotid artery toward the end of the procedure, with no discernible adverse effects. Two patients were discharged with no deficit (Glasgow Outcome Scale [GOS] Score 5); the other patient was conscious with mild hemiparesis (GOS Score 4) at discharge. CONCLUSIONS: The experiences of these 3 cases suggest that immediate removal of a migrated stent/coil is feasible and may be effective. Indirect access to the MCA through its branch helps to shorten the time of temporary clipping of the artery to a minimum. Maintaining active heparinization and direct intraarterial injection of rtPA are helpful in promoting blood flow in the MCA. PMID- 26230471 TI - Preventive effect of continuous cisternal irrigation with magnesium sulfate solution on angiographic cerebral vasospasms associated with aneurysmal subarachnoid hemorrhages: a randomized controlled trial. AB - OBJECT Although cerebral vasospasm (CV) is one of the most important predictors for the outcome in patients with subarachnoid hemorrhage (SAH), no treatment has yet been established for this condition. This study investigated the efficacy of continuous direct infusion of magnesium sulfate (MgSO4) solution into the intrathecal cistern in patients with an aneurysmal SAH. METHODS An SAH caused by a ruptured aneurysm was identified on CT scans within 72 hours after SAH onset. All patients were treated by surgical clipping and randomized into 2 groups: a control group of patients undergoing a standard treatment and a magnesium (Mg) group of patients additionally undergoing continuous infusion of 5 mmol/L MgSO4 solution for 14 days. The Mg(2+) concentrations in serum and CSF were recorded daily. Neurological examinations were performed by intensive care clinicians. Delayed cerebral ischemia was monitored by CT or MRI. To assess the effect of the Mg treatment on CV, the CVs were graded on the basis of the relative degree of constriction visible on cerebral angiograms taken on Day 10 after the SAH, and transcranial Doppler ultrasonography was performed daily to measure blood flow velocity in the middle cerebral artery (MCA). Neurological outcomes and mortality rates were evaluated with the Glasgow Outcome Scale and modified Rankin Scale at 3 months after SAH onset. RESULTS Seventy-three patients admitted during the period of April 2008 to March 2013 were eligible and enrolled in this study. Three patients were excluded because of violation of protocol requirements. The 2 groups did not significantly differ in age, sex, World Federation of Neurosurgical Societies grade, or Fisher grade. In the Mg group, the Mg(2+) concentration in CSF gradually increased from Day 4 after initiation of the continuous MgSO4 intrathecal administration. No such increase was observed in the control group. No significant changes in the serum Mg(2+) levels were observed for 14 days, and no cardiovascular complications such as bradycardia or hypotension were observed in any of the patients. However, bradypnea was noted among patients in the Mg group. The Mg group had a significantly better CV grade than the control group (p < 0.05). Compared with the patients in the Mg group, those in the control group had a significantly elevated blood flow velocity in the MCA. Both groups were similar in the incidences of cerebral infarction, and the 2 groups also did not significantly differ in clinical outcomes. CONCLUSIONS Continuous cisternal irrigation with MgSO4 solution starting on Day 4 and continuing to Day 14 significantly inhibited CV in patients with aneurysmal SAH without severe cardiovascular complications. However, this improvement in CV neither reduced the incidence of delayed cerebral ischemia nor improved the functional outcomes in patients with SAH. PMID- 26230472 TI - Erratum: "Live cadavers" for training in the management of intraoperative aneurysmal rupture. PMID- 26230473 TI - Long-term results of endoscopic third ventriculostomy: an outcome analysis. AB - OBJECT: Endoscopic third ventriculostomy (ETV) is the procedure of choice in the treatment of obstructive hydrocephalus. The excellent clinical and radiological success rates are well known. Nevertheless, very few papers have addressed the very long term outcomes of the procedure in very large series. The authors present a large case series of 113 patients who underwent 126 ETVs, and they highlight the initial postoperative outcome after 3 months and long-term follow up with an average of 7 years. METHODS: All patients who underwent ETV at the Department of Neurosurgery, Mainz University Hospital, between 1993 and 1999 were evaluated. Obstructive hydrocephalus was the causative pathology in all cases. RESULTS: The initial clinical success rate was 82% and decreased slightly to 78% during long-term follow-up. Long-term success was analyzed using Kaplan-Meier curves. Overall, ETV failed in 31 patients. These patients underwent a second ETV or shunt treatment. A positive impact on long-term success was seen for age older than 6 months, and for obstruction due to cysts or benign aqueductal stenosis. The complication rate was 9% with 5 intraoperative and 5 postoperative events. CONCLUSIONS: The high clinical success rate in short-term and long-term follow-up confirms ETV's status as the gold standard for the treatment of obstructive hydrocephalus, especially for distinct pathologies. The patient's age and underlying pathology may influence the outcome. These factors should be considered carefully preoperatively by the surgeon. PMID- 26230474 TI - Aneurysm location and clipping versus coiling for development of secondary normal pressure hydrocephalus after aneurysmal subarachnoid hemorrhage: Japanese Stroke DataBank. AB - OBJECT: The present study aimed to investigate aneurysm locations and treatments for ruptured cerebral aneurysms associated with secondary normal-pressure hydrocephalus (sNPH) after subarachnoid hemorrhage (SAH) by using comprehensive data from the Japanese Stroke DataBank. METHODS: Among 101,165 patients with acute stroke registered between 2000 and 2013, 4693 patients (1482 men, 3211 women) were registered as having had an SAH caused by a ruptured saccular aneurysm. Of them, 1448 patients (438 men and 1010 women; mean age 61.9 +/- 13.4 years) who were confirmed to have or not have coexisting acute hydrocephalus and sNPH were included for statistical analyses. Locations of the ruptured aneurysms were subcategorized into 1 of the following 4 groups: middle cerebral artery (MCA; n = 354), anterior communicating artery and anterior cerebral artery (ACA; n = 496), internal carotid artery (ICA; n = 402), and posterior circulation (n = 130). Locations of 66 of the ruptured aneurysms were unknown/unrecorded. Treatments included craniotomy and clipping alone in 1073 patients, endovascular coil embolization alone in 285 patients, and a combination of coiling and clipping in 17 patients. The age-adjusted and multivariate odds ratios from logistic regression analyses were calculated after stratification using the Fisher CT scale to investigate the effects of the hematoma volume of SAH. RESULTS: Acute hydrocephalus was confirmed in 593 patients, and 521 patients developed sNPH. Patients with a ruptured ACA aneurysm had twice the risk for sNPH over those with a ruptured MCA aneurysm. Those with an ACA aneurysm with Fisher Grade 3 SAH had a 9-fold-higher risk for sNPH than those with an MCA aneurysm with Fisher Grade 1 or 2 SAH. Patients with a ruptured posterior circulation aneurysm did not have any significant risk for sNPH. Clipping of the ruptured aneurysm resulted in twice the risk for sNPH over coil embolization alone. CONCLUSIONS: Patients with low-grade SAH caused by a ruptured MCA aneurysm had a low risk for the development of sNPH. In contrast, patients with high-grade SAH caused by a ruptured ACA aneurysm had a higher risk for sNPH. Endovascular coiling might confer a lower risk of developing sNPH than microsurgical clipping. PMID- 26230475 TI - Downregulation of serum microRNA-205 as a potential diagnostic and prognostic biomarker for human glioma. AB - OBJECT Circulating microRNAs (miRNAs) are a new class of highly promising cancer biomarkers. Malignant glioma is one of the most devastating and lethal forms of intrinsic CNS tumor. Here, the authors evaluated serum miRNA 205 (miR-205) levels in patients with glioma. METHODS Sixty-four patients in whom glioma was diagnosed and 45 healthy controls were recruited between October 2011 and March 2012 and randomly assigned to the screening cohort or the validation cohort. Cohorts of patients with other brain tumors, including meningioma (n = 8), primary diffuse large B-cell lymphoma of the CNS (n = 6), and pituitary adenoma (n = 5), were investigated and compared. miR-205 extraction from serum was detected by real time quantitative reverse-transcription polymerase chain reaction. The Kaplan Meier method was applied to perform survival analysis, the risk factors were analyzed by using a Cox regression model, and the receiver operating characteristic working curve was used to analyze the value of miR-205 in the prognostic evaluation of the patients. RESULTS The authors first demonstrated that serum miR-205 expression was significantly lower in patients with glioma than in healthy controls (p < 0.001). It is important to note that serum miR-205 expression demonstrated a stepwise decrease with ascending pathological grades. The serum miR-205 biomarker had high sensitivity, specificity, and accuracy in patients with glioma. Serum levels of miR-205 were identified as an individual diagnostic marker and were significantly lower in the glioma cohort than in the other brain tumor cohorts. Serum miR-205 levels were significantly increased in postoperative samples over those in the preoperative samples and were reduced again during glioblastoma recurrences. Statistical analysis revealed a significant correlation between low serum miR-205 expression and both ascending pathological grades (p = 0.002) and low Karnofsky Performance Scale scores (p = 0.01). Patients with glioma at an advanced pathological grade (Grade III or IV) and a higher miR-205 serum level showed longer overall survival than those with a lower miR-205 serum concentration (p < 0.01). Furthermore, Cox regression analysis revealed that miR-205 serum levels were independently associated with overall survival. CONCLUSIONS These data indicate that serum miR-205 expression is a novel and valuable biomarker for the diagnosis of glioma and a prognostic factor for those with a tumor at an advanced pathological grade. PMID- 26230476 TI - Outcome and complications of endovascular embolization for vein of Galen malformations: a systematic review and meta-analysis. AB - OBJECT: There have been many multidisciplinary approaches to the treatment of vein of Galen malformations. Endovascular embolization is the first option for treatment. However, the effects of the treatment remain controversial. The aim of this study is to assess the efficacy and safety of endovascular embolization to treat patients with vein of Galen malformations. METHODS: This paper includes a retrospective analysis of a sample of 667 patients who underwent endovascular embolization to treat vein of Galen malformations. The data were obtained through a literature search of PubMed databases. The authors also evaluate the efficacy and safety of the treatment. Mortality within the follow-up period is analyzed. Pooled estimates of proportions with corresponding 95% CIs were calculated using raw (i.e., untransformed) proportions (PRAW). RESULTS: In the 34 studies evaluated, neonates accounted for 44% of the sample (95% CI 31%-57%; I(2) = 92.5%), infants accounted for 41% (95% CI 30%-51%; I(2) = 83.3%), and children and adults accounted for 12% (95% CI 7%-16%; I(2) = 52.9%). The meta-analysis revealed that complete occlusion was performed in 57% (95% CI 48%-65%; I(2) = 68.2%) of cases, with partial occlusion in 43% (95% CI 34%-51%; I(2) = 70.7%). The pooled proportion of patients showing a good outcome was 68% (95% CI 61%-76%; I(2) = 77.8%), while 31% showed a poor outcome (95% CI 24%-38%; I(2) = 75.6%). The proportional meta-analysis showed that postembolization mortality and complications were reported in 10% (95% CI 8%-12%; I(2) = 42.8%) and 37% (95% CI 29%-45%; I(2) = 79.1%), respectively. Complications included cerebral hemorrhage, cerebral ischemia, hydrocephalus, leg ischemia, and vessel perforation. CONCLUSIONS: The successful treatment of vein of Galen malformations remains a complex therapeutic challenge. The authors' analysis of clinical history and research literature suggests that vein of Galen malformations treated with endovascular embolization can result in an acceptable mortality rate, complications, and good clinical outcome. Future large-scale, multicenter, randomized trials are necessary to confirm these findings. PMID- 26230477 TI - "Rescue" of bilateral subthalamic stimulation by bilateral pallidal stimulation: case report. AB - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) orglobus pallidus pars interna (GPi) is well established as a treatment for advanced Parkinson's disease. In general, one of the 2 targets is chosen based on the clinical features of each patient. Stimulation of both targets could be viewed as redundant, given that the 2 targets are directly connected. However, it is possible that each target has different mechanisms, with clinical effects mediated by orthodromic or antidromic stimulation. The authors report the case of a patient with severe Parkinson's disease who had previously undergone bilateral subthalamic stimulation with excellent benefits. However, he presented with significant worsening associated with disease progression and pharmacological treatment, and then underwent bilateral GPi DBS. Follow-up assessment was conducted clinically as well as through blinded ratings of video recordings. Pallidal DBS may be a safe and useful strategy to manage dystonic features and behavioral complications of subthalamic stimulation and pharmacological management. While combined stimulation was quite successful in the reported patient, further studies with larger samples and longer follow-up periods will be necessary before recommending the addition of pallidal DBS as a routine strategy for patients previously implanted with STN DBS. PMID- 26230478 TI - Contemporary carotid imaging: from degree of stenosis to plaque vulnerability. AB - Carotid artery stenosis is a well-established risk factor of ischemic stroke, contributing to up to 10%-20% of strokes or transient ischemic attacks. Many clinical trials over the last 20 years have used measurements of carotid artery stenosis as a means to risk stratify patients. However, with improvements in vascular imaging techniques such as CT angiography and MR angiography, ultrasonography, and PET/CT, it is now possible to risk stratify patients, not just on the degree of carotid artery stenosis but also on how vulnerable the plaque is to rupture, resulting in ischemic stroke. These imaging techniques are ushering in an emerging paradigm shift that allows for risk stratifications based on the presence of imaging features such as intraplaque hemorrhage (IPH), plaque ulceration, plaque neovascularity, fibrous cap thickness, and presence of a lipid rich necrotic core (LRNC). It is important for the neurosurgeon to be aware of these new imaging techniques that allow for improved patient risk stratification and outcomes. For example, a patient with a low-grade stenosis but an ulcerated plaque may benefit more from a revascularization procedure than a patient with a stable 70% asymptomatic stenosis with a thick fibrous cap. This review summarizes the current state-of-the-art advances in carotid plaque imaging. Currently, MRI is the gold standard in carotid plaque imaging, with its high resolution and high sensitivity for identifying IPH, ulceration, LRNC, and inflammation. However, MRI is limited due to time constraints. CT also allows for high-resolution imaging and can accurately detect ulceration and calcification, but cannot reliably differentiate LRNC from IPH. PET/CT is an effective technique to identify active inflammation within the plaque, but it does not allow for assessment of anatomy, ulceration, IPH, or LRNC. Ultrasonography, with the aid of contrast enhancement, is a cost-effective technique to assess plaque morphology and characteristics, but it is limited in sensitivity and specificity for detecting LRNC, plaque hemorrhage, and ulceration compared with MRI. Also summarized is how these advanced imaging techniques are being used in clinical practice to risk stratify patients with low- and high-grade carotid artery stenosis. For example, identification of IPH on MRI in patients with low-grade carotid artery stenosis is a risk factor for failure of medical therapy, and studies have shown that such patients may fair better with carotid endarterectomy (CEA). MR plaque imaging has also been found to be useful in identifying revascularization candidates who would be better candidates for CEA than carotid artery stenting (CAS), as high intraplaque signal on time of flight imaging is associated with vulnerable plaque and increased rates of adverse events in patients undergoing CAS but not CEA. PMID- 26230479 TI - Hypertension of neurogenic origin: effect of microvascular decompression of the CN IX-X root entry/exit zone and ventrolateral medulla on blood pressure in a prospective series of 48 patients with hemifacial spasm associated with essential hypertension. AB - OBJECT: In spite of solid anatomical and physiological arguments and the promising results of Jannetta in the 1970s, treating essential hypertension by microvascular decompression (MVD) of the brainstem has not gained acceptance as a mainstream technique. The main reason has been a lack of established selection criteria. Because of this, the authors' attempts have been limited to patients referred for MVD for hemifacial spasm (HFS) who also had hypertension likely to be related to neurovascular compression (NVC). METHODS: Of 201 patients referred for HFS, 48 (23.8%) had associated hypertension. All had high-resolution MR images that demonstrated NVC. All underwent MVD of the root exit/entry zone (REZ) of the ninth and tenth cranial nerves (CN IX-X) and adjacent ventrolateral medulla in addition to the CN VII REZ. Effects on hypertension, graded using the WHO classification, were studied up to the latest follow-up, which was 2-16 years from the time of surgery, 7 years on average. Also, effects of MVD on blood pressure (BP) according to the side of vascular compression were evaluated. RESULTS: Preoperatively, hypertension was severe in all but 1 of the patients; in spite of medical treatment, 47 patients still had WHO Grade 1 or 2 hypertension, and 18 still had unstable BP. After MVD, at latest follow-up, BP had returned to normal (i.e., systolic pressure < 140 mm Hg) in 28 patients; 14 of these patients (29.10% of the whole series) were able to maintain normal BP without any antihypertensive treatment; the other 14 still required some medication to maintain their BP below 140 mm Hg (p < 0.0001). Also, at latest follow-up, BP remained unstable in only 8 of the 18 patients with instability prior to MVD (p < 0.02). Analysis according to side of compression showed that of the 30 patients with left-sided compression, 17 had their BP normalized (without medication in 11 cases), and of the 18 patients with right-sided compression, 11 had their BP normalized (without medication in 3 cases). The difference between sides was not significant. CONCLUSIONS: These results argue for considering MVD for the treatment of hypertension likely to be due to NVC at the CN IX-X REZ and adjacent ventrolateral medulla. Criteria for selecting patients with hypertension alone still need to be established and could include the following indications: apparently essential hypertension, likely to be neurogenic, in patients in whom high-resolution MRI shows clear-cut images of NVC at the CN IX-X REZ and adjacent ventrolateral medulla and in whom BP cannot be controlled by medical treatment. PMID- 26230480 TI - Effects of a prototype saddle (short panels) on the biomechanics of the equine back: preliminary results. PMID- 26230481 TI - Self-Esteem and the Acute Effect of Anxiety on Ambulatory Blood Pressure. AB - OBJECTIVES: Recent research suggests that self-esteem may be associated with improved parasympathetic nervous system functioning. This study tested whether high self-esteem is associated with decreased ambulatory systolic blood pressure (ASBP) reactivity to anxiety in healthy adults during the waking hours of a normal day. METHODS: Each of 858 participants completed a short version of the Rosenberg Self-Esteem Scale and then wore an ABP monitor that took two blood pressure readings per hour for 24 hours. Immediately after each blood pressure reading, participants completed an electronic diary report that included an anxiety rating on a 100-point visual analog scale. Using multilevel models, we assessed the association of momentary anxiety, high trait self-esteem, and their interaction on momentary ASBP, with adjustment for age, sex, race, ethnicity, and body mass index. Sensitivity analyses were conducted examining psychological factors associated with self-esteem: sense of mastery, optimism, social support, and depressive symptoms. RESULTS: On average, a 1-point increase in cube root transformed anxiety was associated with a 0.80-mm Hg (standard error = 0.09, p < .001) increase in ASBP, and the interaction of high self-esteem and momentary anxiety was significant, such that this effect was 0.48 (standard error = 0.20, p = .015) less in individuals with high self-esteem compared with all others. Results for self-esteem remained significant when adjusting for sex and psychological factors. CONCLUSIONS: Momentary increases in anxiety are associated with acute increases in ASBP, and high self-esteem buffers the effect of momentary anxiety on blood pressure. Thus, high self-esteem may confer cardiovascular benefit by reducing the acute effects of anxiety on systolic blood pressure. PMID- 26230482 TI - Changes in Depressive Symptoms and Mortality in Patients With Heart Failure: Effects of Cognitive-Affective and Somatic Symptoms. AB - OBJECTIVES: Depression is an independent predictor of adverse outcomes in patients with heart failure (HF). However, the effect of changes in cognitive affective and somatic symptoms on mortality of HF patients is not known. The purpose of this study was to examine whether changes in cognitive-affective and somatic depressive symptoms over time were associated with mortality in HF. METHODS: In this secondary analysis of data from the Rural Education to Improve Outcomes in Heart Failure clinical trial, we analyzed data from 457 HF patients (39% female, mean [standard deviation] age = 65.6 [12.8] years) who survived at least 1 year and repeated the Patient Health Questionnaire at 1 year. Cognitive affective and somatic depression scores were calculated, respectively, based on published Patient Health Questionnaire factor models. Using Cox proportional hazards regression analyses, we evaluated the effect of changes in cognitive affective and somatic symptoms from baseline to 1 year on cardiac and all-cause deaths. RESULTS: Controlling for baseline depression scores and other patient characteristics, the change in somatic symptoms was associated with increased risk of cardiac death during the subsequent 1-year period (hazard ratio = 1.24, 95% confidence interval = 1.07-1.44, p = .005), but the change in cognitive affective symptoms was not (hazard ratio = 0.94, 95% confidence interval = 0.81 1.08, p = .38). Similar results were found for all-cause mortality. CONCLUSIONS: Worsening somatic depressive symptoms, not cognitive-affective symptoms, are independently associated with increased mortality of HF patients. The findings suggest that routine and ongoing assessment of somatic depressive symptoms in HF patients may help clinicians identify patients at increased risk for adverse outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00415545. PMID- 26230483 TI - Illness Perceptions in Patients on Predialysis Care: Associations With Time Until Start of Dialysis and Decline of Kidney Function. AB - OBJECTIVES: Illness perceptions in patients with end-stage renal disease are associated with nonadherence and increased mortality. However, no data are available regarding the relationship between illness perceptions and accelerated disease progression in predialysis patients. METHODS: A total of 416 incident predialysis patients participating in a prospective cohort (PREPARE-2, Predialysis Patient Record-2) completed the Revised Illness Perception Questionnaire at the start of specialized predialysis care. The association between illness perceptions and time until start of dialysis was investigated using Cox regression models. Linear mixed modeling was used to test associations between illness perceptions and change of kidney function during predialysis care. Adjustments were made for sociodemographic, clinical, and biochemical factors. RESULTS: Five illness perceptions were associated with disease progression. Dialysis started earlier and kidney function declined faster (ml/min per 1.73 m/y) in patients who perceived their kidney disease as being cyclical in nature (adjusted hazard ratio [HRadj] = 1.32 [95% confidence interval {CI} = 1.11 1.56]; adjusted additional change = -0.64 [95% CI = -1.16 to -0.13]), having many negative consequences (HRadj = 1.47 [95% CI = 1.18-1.85]; adjusted additional change = -0.67 [-1.30 to -0.04]) and causing negative feelings (HRadj = 1.21 [95% CI = 1.03-1.42]; adjusted additional change = -0.65 [95% CI = -1.13 to -0.16]). In addition, kidney function declined faster in patients who perceived that their kidney disease cannot be personally controlled (adjusted additional change = 0.69 [95% CI = -1.31 to -0.09]) and who perceived that they did not fully understand their kidney disease (adjusted additional change = -0.53 [-1.05 to 0.01]). CONCLUSIONS: Stronger negative perceptions of illness at the start of predialysis care are a marker for accelerated disease progression. Detecting illness perceptions in predialysis patients may provide opportunities to intervene and slow down disease progression. PMID- 26230484 TI - Chronic Fatigue Syndrome and DNA Hypomethylation of the Glucocorticoid Receptor Gene Promoter 1F Region: Associations With HPA Axis Hypofunction and Childhood Trauma. AB - OBJECTIVES: Chronic fatigue syndrome (CFS) has been associated with hypothalamic pituitary-adrenal axis hypofunction and enhanced glucocorticoid receptor (GR) sensitivity. In addition, childhood trauma is considered a major risk factor for the syndrome. This study examines DNA methylation of the GR gene (NR3C1) in CFS and associations with childhood sexual and physical trauma. METHODS: Quantification of DNA methylation within the 1F promoter region of NR3C1 was performed in 76 female patients (46 with no/mild and 30 with moderate/severe childhood trauma) and 19 healthy controls by using Sequenom EpiTYPER. Further, we examined the association of NR3C1-1F promoter methylation with the outcomes of the low-dose (0.5 mg) dexamethasone/corticotropin-releasing factor test in a subset of the study population. Mann-Whitney U tests and Spearman correlations were used for statistical analyses. RESULTS: Overall NR3C1-1F DNA methylation was lower in patients with CFS than in controls. After cytosine guanine dinucleotide (CpG)-specific analysis, CpG_1.5 remained significant after Bonferroni correction (adjusted p = .0014). Within the CFS group, overall methylation (rho = 0.477, p = .016) and selective CpG units (CpG_1.5: rho = 0.538, p = .007; CpG_12.13: rho = 0.448, p = .025) were positively correlated with salivary cortisol after dexamethasone administration. There was no significant difference in NR3C1-1F methylation between traumatized and nontraumatized patients. CONCLUSIONS: We found evidence of NR3C1 promoter hypomethylation in female patients with CFS and the functional relevance of these differences was consistent with the hypothalamic-pituitary-adrenalaxis hypofunction hypothesis (GR hypersuppression). However, we found no evidence of an additional effect of childhood trauma on CFS via alterations in NR3C1 methylation. PMID- 26230485 TI - From Bioavailability Science to Regulation of Organic Chemicals. AB - The bioavailability of organic chemicals in soil and sediment is an important area of scientific investigation for environmental scientists, although this area of study remains only partially recognized by regulators and industries working in the environmental sector. Regulators have recently started to consider bioavailability within retrospective risk assessment frameworks for organic chemicals; by doing so, realistic decision-making with regard to polluted environments can be achieved, rather than relying on the traditional approach of using total-extractable concentrations. However, implementation remains difficult because scientific developments on bioavailability are not always translated into ready-to-use approaches for regulators. Similarly, bioavailability remains largely unexplored within prospective regulatory frameworks that address the approval and regulation of organic chemicals. This article discusses bioavailability concepts and methods, as well as possible pathways for the implementation of bioavailability into risk assessment and regulation; in addition, this article offers a simple, pragmatic and justifiable approach for use within retrospective and prospective risk assessment. PMID- 26230486 TI - WITHDRAWN: NSAIDS or paracetamol, alone or combined with opioids, for cancer pain. PMID- 26230487 TI - Ibuprofen for acute treatment of episodic tension-type headache in adults. AB - BACKGROUND: Tension-type headache (TTH) affects about one person in five worldwide. It is divided into infrequent episodic TTH (fewer than one headache per month), frequent episodic TTH (1 to 14 headaches per month), and chronic TTH (15 headaches a month or more). Ibuprofen is one of a number of analgesics suggested for acute treatment of headaches in frequent episodic TTH. OBJECTIVES: To assess the efficacy and safety of oral ibuprofen for treatment of acute episodic TTH in adults. SEARCH METHODS: We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, and our own in-house database to January 2015. We sought unpublished studies by asking personal contacts and searching on-line clinical trial registers and manufacturers' websites. SELECTION CRITERIA: We included randomised, placebo-controlled studies (parallel-group or cross-over) using oral ibuprofen for symptomatic relief of an acute episode of TTH. Studies had to be prospective and include at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, and extracted data. Numbers of participants achieving each outcome were used to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or number needed to treat for an additional harmful outcome (NNH) of oral ibuprofen compared to placebo for a range of outcomes, predominantly those recommended by the International Headache Society (IHS). MAIN RESULTS: We included 12 studies, all of which enrolled adult participants with frequent episodic TTH. Nine used the IHS diagnostic criteria, but two used the older classification of the Ad Hoc Committee, and one did not describe diagnostic criteria but excluded participants with migraines. While 3094 people with TTH participated in these studies, the numbers available for any form of analysis were lower than this; placebo was taken by 733, standard ibuprofen 200 mg by 127, standard ibuprofen 400 mg by 892, and fast-acting ibuprofen 400 mg by 230. Participants had moderate or severe pain at the start of treatment. Other participants were either in studies not reporting outcomes we could analyse, or were given one of several active comparators in single studies.For the IHS preferred outcome of being pain free at 2 hours the NNT for ibuprofen 400 mg (all formulations) compared with placebo was 14 (95% confidence interval (CI), 8.4 to 47) in four studies, with no significant difference from placebo at 1 hour (moderate quality evidence). The NNT was 5.9 (4.2 to 9.5) for the global evaluation of 'very good' or 'excellent' in three studies (moderate quality evidence). No study reported the number of participants experiencing no worse than mild pain at 1 or 2 hours. The use of rescue medication was lower with ibuprofen 400 mg than with placebo, with the number needed to treat to prevent one event (NNTp) of 8.9 (5.6 to 21) in two studies (low quality evidence).Adverse events were not different between ibuprofen 400 mg and placebo; RR 1.1 (0.64 to 1.7) (high-quality evidence). No serious adverse events were reported. AUTHORS' CONCLUSIONS: Ibuprofen 400 mg provides an important benefit in terms of being pain free at 2 hours for a small number of people with frequent episodic tension type headache who have an acute headache with moderate or severe initial pain. There is no information about the lesser benefit of no worse than mild pain at 2 hours. PMID- 26230488 TI - Recent insights into the transcriptional control of the Tcra/Tcrd locus by distant enhancers during the development of T-lymphocytes. AB - Tcra/Tcrd includes 2 genes with distinct developmental programs controlled by 2 distant enhancers, Ealpha and Edelta. These enhancers work as a developmental switch during thymocyte development and they are essential for generation of alphabeta and gammadelta T-lymphocytes. Tcra and Tcrd transit from an unrearranged configuration to a rearranged configuration during T-cell development. Ealpha and Edelta are responsible for transcription of their respective unrearranged genes in thymocytes but are dispensable for such functions in the context of the rearranged genes in mature T-cells. Interestingly, Ealpha activates transcription of the rearranged Tcrd in gammadelta T-lymphocytes but it is inactive in alphabeta T-lymphocytes. PMID- 26230490 TI - Prevalence of human parainfluenza virus in patients with acute respiratory tract infections in Beijing, 2011-2014. PMID- 26230489 TI - A Year of Infection in the Intensive Care Unit: Prospective Whole Genome Sequencing of Bacterial Clinical Isolates Reveals Cryptic Transmissions and Novel Microbiota. AB - Bacterial whole genome sequencing holds promise as a disruptive technology in clinical microbiology, but it has not yet been applied systematically or comprehensively within a clinical context. Here, over the course of one year, we performed prospective collection and whole genome sequencing of nearly all bacterial isolates obtained from a tertiary care hospital's intensive care units (ICUs). This unbiased collection of 1,229 bacterial genomes from 391 patients enables detailed exploration of several features of clinical pathogens. A sizable fraction of isolates identified as clinically relevant corresponded to previously undescribed species: 12% of isolates assigned a species-level classification by conventional methods actually qualified as distinct, novel genomospecies on the basis of genomic similarity. Pan-genome analysis of the most frequently encountered pathogens in the collection revealed substantial variation in pan genome size (1,420 to 20,432 genes) and the rate of gene discovery (1 to 152 genes per isolate sequenced). Surprisingly, although potential nosocomial transmission of actively surveilled pathogens was rare, 8.7% of isolates belonged to genomically related clonal lineages that were present among multiple patients, usually with overlapping hospital admissions, and were associated with clinically significant infection in 62% of patients from which they were recovered. Multi patient clonal lineages were particularly evident in the neonatal care unit, where seven separate Staphylococcus epidermidis clonal lineages were identified, including one lineage associated with bacteremia in 5/9 neonates. Our study highlights key differences in the information made available by conventional microbiological practices versus whole genome sequencing, and motivates the further integration of microbial genome sequencing into routine clinical care. PMID- 26230491 TI - Curcumin Attenuates Iron Accumulation and Oxidative Stress in the Liver and Spleen of Chronic Iron-Overloaded Rats. AB - OBJECTIVES: Iron overload is now recognized as a health problem in industrialized countries, as excessive iron is highly toxic for liver and spleen. The potential use of curcumin as an iron chelator has not been clearly identified experimentally in iron overload condition. Here, we evaluate the efficacy of curcumin to alleviate iron overload-induced hepatic and splenic abnormalities and to gain insight into the underlying mechanisms. DESIGN AND METHODS: Three groups of male adult rats were treated as follows: control rats, rats treated with iron in a drinking water for 2 months followed by either vehicle or curcumin treatment for 2 more months. Thereafter, we studied the effects of curcumin on iron overload-induced lipid peroxidation and anti-oxidant depletion. RESULTS: Treatment of iron-overloaded rats with curcumin resulted in marked decreases in iron accumulation within liver and spleen. Iron-overloaded rats had significant increases in malonyldialdehyde (MDA), a marker of lipid peroxidation and nitric oxide (NO) in liver and spleen when compared to control group. The effects of iron overload on lipid peroxidation and NO levels were significantly reduced by the intervention treatment with curcumin (P<0.05). Furthermore, the endogenous anti-oxidant activities/levels in liver and spleen were also significantly decreased in chronic iron overload and administration of curcumin restored the decrease in the hepatic and splenic antioxidant activities/levels. CONCLUSION: Our study suggests that curcumin may represent a new horizon in managing iron overload-induced toxicity as well as in pathological diseases characterized by hepatic iron accumulation such as thalassemia, sickle cell anemia, and myelodysplastic syndromes possibly via iron chelation, reduced oxidative stress derived lipid peroxidation and improving the body endogenous antioxidant defense mechanism. PMID- 26230492 TI - Coronary Endothelial Dysfunction in Women With Type 2 Diabetes Measured by Coronary Phase Contrast Flow Velocity Magnetic Resonance Imaging. AB - OBJECTIVE: The aim of this study was to determine if differences in coronary endothelial function are observed between asymptomatic women with type 2 diabetes mellitus (DM) and control subjects using coronary phase contrast flow velocity magnetic resonance imaging in response to cold pressor stress, an established endothelium-dependent vasodilatory stress. METHODS: Phase contrast flow velocity imaging of the right coronary artery was performed in 7 asymptomatic premenopausal women with DM and 8 healthy female participants in response to the cold pressor test at 3 T. RESULTS: There was no significant difference in percent increase in coronary flow velocity from rest to peak flow velocity between DM and control subjects (32% +/- 22% vs 46% +/- 17%; P = 0.11). However, percent increase in coronary flow velocity was lower in DM than in control subjects (-3% +/- 14% vs 31% +/- 30%; P = 0.01) during the second minute of cold pressor stress, when endothelial-mediated vasodilation should occur. CONCLUSIONS: Asymptomatic women with DM demonstrate reduced coronary flow velocity during the second minute of cold pressor stress, indicating coronary endothelial dysfunction. PMID- 26230493 TI - ER stress and development of type 1 diabetes. AB - Type 1 diabetes (T1D) results from an autoimmune-mediated destruction of pancreatic beta cells. The incidence of T1D is on the rise globally around 3% to 5% per year and rapidly increasing incidence in younger children is of the greatest concern. currently, there is no way to cure or prevent T1D; hence, a deeper understanding of the underlying molecular mechanisms of this disease is essential to the development of new effective therapies. The endoplasmic reticulum (ER) is an organelle with multiple functions that are essential for cellular homeostasis. Excessive demand on the ER, chronic inflammation, and environmental factors lead to ER stress and to re-establish cellular homeostasis, the adaptive unfolded protein response (UPR) is triggered. However, chronic ER stress leads to a switch from a prosurvival to a proapoptotic UPR, resulting in cell death. Accumulating data have implicated ER stress and defective UPR in the pathogenesis of inflammatory and autoimmune diseases, and ER stress has been implicated in beta-cell failure in type 2 diabetes. However, the role of ER stress and the UPR in beta-cell pathophysiology and in the initiation and propagation of the autoimmune responses in T1D remains undefined. This review will highlight the current understanding and recent in vivo data on the role of ER stress and adaptive responses in T1D pathogenesis and the potential therapeutic aspect of enhancing beta-cell ER function and restoring UPR defects as novel clinical strategies against this disease. PMID- 26230494 TI - The Cut-Off Level of Recombinant Human TSH-Stimulated Thyroglobulin in the Follow Up of Patients with Differentiated Thyroid Cancer. AB - BACKGROUND: The treatment of differentiated thyroid cancer (DTC) ends in full recovery in 80% of cases. However, in 20% of cases local recurrences or distant metastases are observed, for this reason DTC patients are under life-long follow up. The most sensitive marker for recurrence is stimulated thyroglobulin (Tg) which, together with neck ultrasound (US), enables correct diagnosis in nearly all cases of the active disease. For many years the only known stimulation was a 4-5 week withdrawal from the L-T4 therapy (THW). For the last couple of years stimulation with the use of recombinant human TSH (rhTSH) has been available. This method of stimulation may have a significant influence in obtaining the Tg level. However, it is important to determine the cut-off level for rhTSH stimulated Tg (rhTSH/Tg). MATERIALS AND METHODS: This is a retrospective analysis of consecutive patients from one facility who have qualified over a period of two years for repeated radioiodine therapy (RIA). In our facility the ablation effectiveness evaluation is always carried out with the use of rhTSH, with the repeated therapy following THW. Such a procedure enables two Tg measurements in the same patient after both types of stimulation within 4-5 weeks. The obtained values were compared, cut-off levels in THW conditions were used (2.0 ng/ml for patients in remission and 10.0 ng/ml for patients with an active disease). In order to determine the cut-off level for rhTSH/Tg, regression analysis and ROC curves were used. RESULTS: In 63 patients the Tg measurement of both methods of stimulation were obtained. It was observed that there was a high correlation between rhTSH/Tg and THW/Tg. However, the rhTSH/Tg level was significantly lower than THW/ Tg. The rhTSH/ Tg cut-off levels which corresponded to the 2.0 ng/ml and 10.0 ng/ml limits for THW/Tg were calculated and the values were 0.6 ng/ml and 2.3 ng/ml respectively. CONCLUSIONS: The method of stimulation has a significant impact on the obtained Tg concentrations. The assumed THW/Tg cut off levels must not be transferred to rhTSH/Tg. PMID- 26230495 TI - Masking Period Patterns and Forward Masking for Speech-Shaped Noise: Age-Related Effects. AB - OBJECTIVE: The purpose of this study was to assess age-related changes in temporal resolution in listeners with relatively normal audiograms. The hypothesis was that increased susceptibility to nonsimultaneous masking contributes to the hearing difficulties experienced by older listeners in complex fluctuating backgrounds. DESIGN: Participants included younger (n = 11), middle age (n = 12), and older (n = 11) listeners with relatively normal audiograms. The first phase of the study measured masking period patterns for speech-shaped noise maskers and signals. From these data, temporal window shapes were derived. The second phase measured forward-masking functions and assessed how well the temporal window fits accounted for these data. RESULTS: The masking period patterns demonstrated increased susceptibility to backward masking in the older listeners, compatible with a more symmetric temporal window in this group. The forward-masking functions exhibited an age-related decline in recovery to baseline thresholds, and there was also an increase in the variability of the temporal window fits to these data. CONCLUSIONS: This study demonstrated an age related increase in susceptibility to nonsimultaneous masking, supporting the hypothesis that exacerbated nonsimultaneous masking contributes to age-related difficulties understanding speech in fluctuating noise. Further support for this hypothesis comes from limited speech-in-noise data, suggesting an association between susceptibility to forward masking and speech understanding in modulated noise. PMID- 26230496 TI - Quantitative Analysis of Differential Proteome Expression in Bladder Cancer vs. Normal Bladder Cells Using SILAC Method. AB - The best way to increase patient survival rate is to identify patients who are likely to progress to muscle-invasive or metastatic disease upfront and treat them more aggressively. The human cell lines HCV29 (normal bladder epithelia), KK47 (low grade nonmuscle invasive bladder cancer, NMIBC), and YTS1 (metastatic bladder cancer) have been widely used in studies of molecular mechanisms and cell signaling during bladder cancer (BC) progression. However, little attention has been paid to global quantitative proteome analysis of these three cell lines. We labeled HCV29, KK47, and YTS1 cells by the SILAC method using three stable isotopes each of arginine and lysine. Labeled proteins were analyzed by 2D ultrahigh-resolution liquid chromatography LTQ Orbitrap mass spectrometry. Among 3721 unique identified and annotated proteins in KK47 and YTS1 cells, 36 were significantly upregulated and 74 were significantly downregulated with >95% confidence. Differential expression of these proteins was confirmed by western blotting, quantitative RT-PCR, and cell staining with specific antibodies. Gene ontology (GO) term and pathway analysis indicated that the differentially regulated proteins were involved in DNA replication and molecular transport, cell growth and proliferation, cellular movement, immune cell trafficking, and cell death and survival. These proteins and the advanced proteome techniques described here will be useful for further elucidation of molecular mechanisms in BC and other types of cancer. PMID- 26230497 TI - Microarray-Based Analysis of Methylation Status of CpGs in Placental DNA and Maternal Blood DNA--Potential New Epigenetic Biomarkers for Cell Free Fetal DNA Based Diagnosis. AB - Epigenetic markers for cell free fetal DNA in the maternal blood circulation are highly interesting in the field of non-invasive prenatal testing since such markers will offer a possibility to quantify the amount of fetal DNA derived from different chromosomes in a maternal blood sample. The aim of the present study was to define new fetal specific epigenetic markers present in placental DNA that can be utilized in non-invasive prenatal diagnosis. We have conducted a high resolution methylation specific beadchip microarray study assessing more than 450.000 CpG sites. We have analyzed the DNA methylation profiles of 10 maternal blood samples and compared them to 12 1st trimesters chorionic samples from normal placentas, identifying a number of CpG sites that are differentially methylated in maternal blood cells compared to chorionic tissue. To strengthen the utility of these differentially methylated CpG sites to be used with methyl sensitive restriction enzymes (MSRE) in PCR-based NIPD, we furthermore refined the list of selected sites, containing a restriction sites for one of 16 different methylation-sensitive restriction enzymes. We present a list of markers on chromosomes 13, 18 and 21 with a potential for aneuploidy testing as well as a list of markers for regions harboring sub-microscopic deletion- or duplication syndromes. PMID- 26230498 TI - Shifted T Helper Cell Polarization in a Murine Staphylococcus aureus Mastitis Model. AB - Mastitis, one of the most costly diseases in dairy ruminants, is an inflammation of the mammary gland caused by pathogenic infection. The mechanisms of adaptive immunity against pathogens in mastitis have not been fully elucidated. To investigate T helper cell-mediated adaptive immune responses, we established a mastitis model by challenge with an inoculum of 4 * 106 colony-forming units of Staphylococcus aureus in the mammary gland of lactating mice, followed by quantification of bacterial burden and histological analysis. The development of mastitis was accompanied by a significant increase in both Th17 and Th1 cells in the mammary gland. Moreover, the relative expression of genes encoding cytokines and transcription factors involved in the differentiation and function of these T helper cells, including Il17, Rorc, Tgfb, Il1b, Il23, Ifng, Tbx21, and Il12, was greatly elevated in the infected mammary gland. IL-17 is essential for neutrophil recruitment to infected mammary gland via CXC chemokines, whereas the excessive IL-17 production contributes to tissue damage in mastitis. In addition, a shift in T helper cell polarization toward Th2 and Treg cells was observed 5 days post infection, and the mRNA expression of the anti-inflammatory cytokine Il10 was markedly increased at day 7 post-infection. These results indicate that immune clearance of Staphylococcus aureus in mastitis is facilitated by the enrichment of Th17, Th1 and Th2 cells in the mammary gland mediated by pro-inflammatory cytokine production, which is tightly regulated by Treg cells and the anti inflammatory cytokine IL-10. PMID- 26230499 TI - The Relationship between Extensively Drug-Resistant Tuberculosis and Multidrug Resistant Gram-Negative Bacilli. AB - OBJECTIVE: The relationship between extensively drug-resistant tuberculosis (XDR TB) and multidrug-resistant Gram-negative bacilli (MDR-GNB) is unclear. Identification of the relationship between XDR-TB and MDR-GNB would have important implications for patient care. METHODS: We conducted a retrospective study reviewing the records of patients admitted with a confirmed pulmonary TB from 2011 to 2014. To identify the relationship between XDR-TB and MDR-GNB, univariable comparison and multivariable logistic regression were performed. RESULTS: Among 2962 pulmonary TB patients, 45(1.5%) patients had a diagnosis of XDR-TB. A total of 165 MDR-GNB strains were detected in 143 (4.8%) pulmonary TB patients. XDR-TB patients had a significantly higher occurrence of MDR-GNB than non-XDR-TB patients (24.4% vs. 4.5%; P<0.001). Age (OR 1.02, 95% CI 1.01-1.03), hypoalbuminemia (OR 1.48, 95% CI 1.18-1.85), chronic renal failure (OR 6.67, 95% CI 1.42-31.47), chronic hepatic insufficiency (OR 1.99, 95% CI 1.15-3.43), presence of XDR-TB (OR 6.56, 95% CI 1.61-26.69), and duration of TB diagnostic delay (OR 1.01, 95% CI 1.00-1.02) were the independent risk factors for MDR-GNB infection. CONCLUSIONS: Patients with XDR-TB have a significantly higher risk of being affected by MDR-GNB pathogen. The underlying mechanism association warrant further studies. PMID- 26230500 TI - Differences in myoelectric and body-powered upper-limb prostheses: Systematic literature review. AB - The choice of a myoelectric or body-powered upper-limb prosthesis can be determined using factors including control, function, feedback, cosmesis, and rejection. Although body-powered and myoelectric control strategies offer unique functions, many prosthesis users must choose one. A systematic review was conducted to determine differences between myoelectric and body-powered prostheses to inform evidence-based clinical practice regarding prescription of these devices and training of users. A search of 9 databases identified 462 unique publications. Ultimately, 31 of them were included and 11 empirical evidence statements were developed. Conflicting evidence has been found in terms of the relative functional performance of body-powered and myoelectric prostheses. Body-powered prostheses have been shown to have advantages in durability, training time, frequency of adjustment, maintenance, and feedback; however, they could still benefit from improvements of control. Myoelectric prostheses have been shown to improve cosmesis and phantom-limb pain and are more accepted for light=intensity work. Currently, evidence is insufficient to conclude that either system provides a significant general advantage. Prosthetic selection should be based on a patient's individual needs and include personal preferences, prosthetic experience, and functional needs. This work demonstrates that there is a lack of empirical evidence regarding functional differences in upper-limb prostheses. PMID- 26230501 TI - Long-Term Visual Outcomes of Secondary Intraocular Lens Implantation in Children with Congenital Cataracts. AB - AIM: The aim of this study was to evaluate the long-term visual outcomes and factors affecting visual results in children undergoing secondary intraocular lens (IOL) implantation following primary congenital cataract extraction. METHODS: Children with congenital cataracts who underwent secondary IOL implantation for aphakia at the Eye and ENT Hospital of Fudan University between January 1, 2001, and December 31, 2007, were retrospectively reviewed. One eye was randomly selected in children with bilateral cataracts. Laterality, type of cataract (total or partial opacity), sex, age at primary and secondary surgeries, visual axis opacity (VAO), compliance with amblyopia therapy, postoperative ocular complications, refractive error, ocular alignment, and best corrected visual acuity (BCVA) at last follow-up were recorded; potential factors that might have affected the visual results were evaluated. RESULTS: Seventy-six bilateral and 34 unilateral congenital cataract cases were analyzed; the mean ages of the children were 12.70+/-5.06 and 12.50+/-2.71 years at final follow-up, the mean follow-up periods from IOL implantation were 94.93+/-24.22 and 109.09+/ 18.89 months, and the mean BCVA (Log MAR) values were 0.51+/-0.37 and 1.05+/ 0.46, respectively. Final BCVA after secondary IOL implantation was significantly associated with laterality, type of cataract, age at primary cataract extraction, compliance with amblyopia therapy, and refractive correction after surgery. No significant associations were found between BCVA and sex, age at secondary IOL implantation, VAO, or other ocular complications. The most common ocular complications were VAO and elevated intraocular pressure after surgery. There were no other complications, with the exception of one eye with IOL dislocation. CONCLUSIONS: The results indicate that the important determinants of long-term visual outcomes in children with congenital cataracts undergoing secondary IOL implantation are laterality, cataract type, age at initial cataract extraction, compliance with amblyopia therapy, and refractive error. PMID- 26230502 TI - Membrane-Permeable Calpain Inhibitors Promote Rat Oral Mucosal Epithelial Cell Proliferation by Inhibiting IL-1alpha Signaling. AB - To standardise regenerative medicine using cultured cells, the use of serum-free, chemically defined media will be necessary. We have reported that IL-1alpha inhibits the growth of epithelial cells in culture and that recombinant IL-1 receptor antagonist (IL-1RA) significantly promotes epithelial cell growth in no feeder layer condition. In this study, we examined inhibitors of calpain, a cysteine proteinase that plays crucial roles in various cellular functions, including IL-1alpha maturation and secretion. The culturing of epithelial cells in serum-free media supplemented with a membrane-permeable calpain inhibitor significantly promoted growth while suppressing IL-1alpha maturation and secretion. By contrast, non-membrane-permeable calpain inhibitor treatment did not have these effects. Interestingly, immunoblotting analysis revealed that immature, untruncated, IL-1alpha expression was also downregulated by cell permeable calpain inhibitor treatment, and the difference in IL-1alpha gene expression increased from day 2 to day 6. Although IL-1RA has been reported to promote epithelial cell growth, we detected no synergistic promotion of epithelial cell growth using a calpain inhibitor and IL-1RA. These findings indicate that calpain inhibitors promote epithelial cell proliferation by inhibiting IL-1alpha maturation at an early phase of epithelial cell culture and by suppressing the positive feedback-mediated amplification of IL-1alpha signalling. PMID- 26230503 TI - Lung Beractant Increases Free Cytosolic Levels of Ca2+ in Human Lung Fibroblasts. AB - Beractant, a natural surfactant, induces an antifibrogenic phenotype and apoptosis in normal human lung fibroblasts (NHLF). As intracellular Ca2+ signalling has been related to programmed cell death, we aimed to assess the effect of beractant on intracellular Ca2+ concentration ([Ca2+]i) in NHLF in vitro. Cultured NHLF were loaded with Fura-2 AM (3 MUM) and Ca2+ signals were recorded by microfluorimetric techniques. Beractant causes a concentration dependent increase in [Ca2+]i with a EC50 of 0.82 MUg/ml. The application of beractant, at a concentration of 500 MUg/ml, which has been shown to exert an apoptotic effect in human fibroblasts, elicited different patterns of Ca2+ signals in NHLF: a) a single Ca2+ spike which could be followed by b) Ca2+ oscillations, c) a sustained Ca2+ plateau or d) a sustained plateau overlapped by Ca2+ oscillations. The amplitude and pattern of Ca2+ transients evoked by beractant were dependent on the resting [Ca2+]i. Pharmacological manipulation revealed that beractant activates a Ca2+ signal through Ca2+ release from intracellular stores mediated by phospholipase Cbeta (PLCbeta), Ca2+ release from inositol 1,4,5-trisphosphate receptors (IP3Rs) and Ca2+ influx via a store operated pathway. Moreover, beractant-induced Ca2+ release was abolished by preventing membrane depolarization upon removal of extracellular Na+ and Ca2+. Finally, the inhibition of store-operated channels prevented beractant-induced NHLF apoptosis and downregulation of alpha1(I) procollagen expression. Therefore, beractant utilizes SOCE to exert its pro-apoptotic and antifibrinogenic effect on NHLF. PMID- 26230504 TI - Long-Term Urban Market Dynamics Reveal Increased Bushmeat Carcass Volume despite Economic Growth and Proactive Environmental Legislation on Bioko Island, Equatorial Guinea. AB - Bushmeat hunting is extensive in west and central Africa as both a means for subsistence and for commercial gain. Commercial hunting represents one of the primary threats to wildlife in the region, and confounding factors have made it challenging to examine how external factors influence the commercial bushmeat trade. Bioko Island, Equatorial Guinea is a small island with large tracts of intact forest that support sizeable populations of commercially valuable vertebrates, especially endemic primates. The island also has a low human population and has experienced dramatic economic growth and rapid development since the mid-1990's. From October 1997 - September 2010, we monitored the largest bushmeat market on Bioko in Malabo, recording over 197,000 carcasses for sale. We used these data to analyze the dynamics of the market in relation to political events, environmental legislation, and rapid economic growth. Our findings suggest that bushmeat hunting and availability increased in parallel with the growth of Equatorial Guinea's GDP and disposable income of its citizens. During this 13-year study, the predominant mode of capture shifted from trapping to shotguns. Consequently, carcass volume and rates of taxa typically captured with shotguns increased significantly, most notably including intensified hunting of Bioko's unique and endangered monkey fauna. Attempts to limit bushmeat sales, including a 2007 ban on primate hunting and trade, were only transiently effective. The hunting ban was not enforced, and was quickly followed by a marked increase in bushmeat hunting compared to hunting rates prior to the ban. Our results emphasize the negative impact that rapid development and unenforced legislation have had on Bioko's wildlife, and demonstrate the need for strong governmental support if conservation strategies are to be successful at preventing extinctions of tropical wildlife. PMID- 26230506 TI - The Source, Spatial Distribution and Risk Assessment of Heavy Metals in Soil from the Pearl River Delta Based on the National Multi-Purpose Regional Geochemical Survey. AB - The data on the heavy metal content at different soil depths derived from a multi purpose regional geochemical survey in the Pearl River Delta (PRD) were analyzed using ArcGIS 10.0. By comparing their spatial distributions and areas, the sources of heavy metals (Cd, Hg, As and Pb) were quantitatively identified and explored. Netted measuring points at 25 *25 km were set over the entire PRD according to the geochemical maps. Based on the calculation data obtained from different soil depths, the concentrations of As and Cd in a large area of the PRD exceeded the National Second-class Standard. The spatial disparity of the geometric centers in the surface soil and deep soil showed that As in the surface soil mainly came from parent materials, while Cd had high consistency in different soil profiles because of deposition in the soil forming process. The migration of Cd also resulted in a considerable ecological risk to the Beijiang and Xijiang River watershed. The potential ecological risk index followed the order Cd >= Hg > Pb > As. According to the sources, the distribution trends and the characteristics of heavy metals in the soil from the perspective of the whole area, the Cd pollution should be repaired, especially in the upper reaches of the Xijiang and Beijiang watershed to prevent risk explosion while the pollution of Hg and Pb should be controlled in areas with intense human activity, and supervision during production should be strengthened to maintain the ecological balance of As. PMID- 26230505 TI - c-Myc and AMPK Control Cellular Energy Levels by Cooperatively Regulating Mitochondrial Structure and Function. AB - The c-Myc (Myc) oncoprotein and AMP-activated protein kinase (AMPK) regulate glycolysis and oxidative phosphorylation (Oxphos) although often for different purposes. Because Myc over-expression depletes ATP with the resultant activation of AMPK, we explored the potential co-dependency of and cross-talk between these proteins by comparing the consequences of acute Myc induction in ampk+/+ (WT) and ampk-/- (KO) murine embryo fibroblasts (MEFs). KO MEFs showed a higher basal rate of glycolysis than WT MEFs and an appropriate increase in response to activation of a Myc-estrogen receptor (MycER) fusion protein. However, KO MEFs had a diminished ability to increase Oxphos, mitochondrial mass and reactive oxygen species in response to MycER activation. Other differences between WT and KO MEFs, either in the basal state or following MycER induction, included abnormalities in electron transport chain function, levels of TCA cycle-related oxidoreductases and cytoplasmic and mitochondrial redox states. Transcriptional profiling of pathways pertinent to glycolysis, Oxphos and mitochondrial structure and function also uncovered significant differences between WT and KO MEFs and their response to MycER activation. Finally, an unbiased mass-spectrometry (MS) based survey capable of quantifying ~40% of all mitochondrial proteins, showed about 15% of them to be AMPK- and/or Myc-dependent in their steady state. Significant differences in the activities of the rate-limiting enzymes pyruvate kinase and pyruvate dehydrogenase, which dictate pyruvate and acetyl coenzyme A abundance, were also differentially responsive to Myc and AMPK and could account for some of the differences in basal metabolite levels that were also detected by MS. Thus, Myc and AMPK are highly co-dependent and appear to engage in significant cross-talk across numerous pathways which support metabolic and ATP generating functions. PMID- 26230507 TI - Unraveling Host-Vector-Arbovirus Interactions by Two-Gene High Resolution Melting Mosquito Bloodmeal Analysis in a Kenyan Wildlife-Livestock Interface. AB - The blood-feeding patterns of mosquitoes are directly linked to the spread of pathogens that they transmit. Efficient identification of arthropod vector bloodmeal hosts can identify the diversity of vertebrate species potentially involved in disease transmission cycles. While molecular bloodmeal analyses rely on sequencing of cytochrome b (cyt b) or cytochrome oxidase 1 gene PCR products, recently developed bloodmeal host identification based on high resolution melting (HRM) analyses of cyt b PCR products is more cost-effective. To resolve the diverse vertebrate hosts that mosquitoes may potentially feed on in sub-Saharan Africa, we utilized HRM profiles of both cyt b and 16S ribosomal RNA genes. Among 445 blood-fed Aedeomyia, Aedes, Anopheles, Culex, Mansonia, and Mimomyia mosquitoes from Kenya's Lake Victoria and Lake Baringo regions where many mosquito-transmitted pathogens are endemic, we identified 33 bloodmeal hosts including humans, eight domestic animal species, six peridomestic animal species and 18 wildlife species. This resolution of vertebrate host species was only possible by comparing profiles of both cyt b and 16S markers, as melting profiles of some pairs of species were similar for either marker but not both. We identified mixed bloodmeals in a Culex pipiens from Mbita that had fed on a goat and a human and in two Mansonia africana mosquitoes from Baringo that each had fed on a rodent (Arvicanthis niloticus) in addition to a human or baboon. We further detected Sindbis and Bunyamwera viruses in blood-fed mosquito homogenates by Vero cell culture and RT-PCR in Culex, Aedeomyia, Anopheles and Mansonia mosquitoes from Baringo that had fed on humans and livestock. The observed mosquito feeding on both arbovirus amplifying hosts (including sheep and goats) and possible arbovirus reservoirs (birds, porcupine, baboons, rodents) informs arbovirus disease epidemiology and vector control strategies. PMID- 26230508 TI - Host Jumps and Radiation, Not Co-Divergence Drives Diversification of Obligate Pathogens. A Case Study in Downy Mildews and Asteraceae. AB - Even though the microevolution of plant hosts and pathogens has been intensely studied, knowledge regarding macro-evolutionary patterns is limited. Having the highest species diversity and host-specificity among Oomycetes, downy mildews are a useful a model for investigating long-term host-pathogen coevolution. We show that phylogenies of Bremia and Asteraceae are significantly congruent. The accepted hypothesis is that pathogens have diverged contemporarily with their hosts. But maximum clade age estimation and sequence divergence comparison reveal that congruence is not due to long-term coevolution but rather due to host-shift driven speciation (pseudo-cospeciation). This pattern results from parasite radiation in related hosts, long after radiation and speciation of the hosts. As large host shifts free pathogens from hosts with effector triggered immunity subsequent radiation and diversification in related hosts with similar innate immunity may follow, resulting in a pattern mimicking true co-divergence, which is probably limited to the terminal nodes in many pathogen groups. PMID- 26230509 TI - Obesity Alters the Microbial Community Profile in Korean Adolescents. AB - Obesity is an increasing public health concern worldwide. According to the latest Organization for Economic Co-operation and Development (OECD) report (2014), the incidence of child obesity in Korea has exceeded the OECD average. To better understand and control this condition, the present study examined the composition of the gut microbial community in normal and obese adolescents. Fecal samples were collected from 67 obese (body mass index [BMI] >= 30 kg/m2, or >= 99th BMI percentile) and 67 normal (BMI < 25 kg/m2 or < 85th BMI percentile) Korean adolescents aged 13-16 years and subjected to 16S rRNA gene sequencing. Analysis of bacterial composition according to taxonomic rank (genus, family, and phylum) revealed marked differences in the Bacteroides and Prevotella populations in normal and obese samples (p < 0.005) at the genus and family levels; however, there was no difference in the Firmicutes-to-Bacteroidetes (F/B) ratio between normal and obese adolescents samples at the phylum level (F/B normal = 0.50 +/- 0.53; F/B obese = 0.56 +/- 0.86; p = 0.384). Statistical analysis revealed a significant association between the compositions of several bacterial taxa and child obesity. Among these, Bacteroides and Prevotella showed the most significant association with BMI (p < 0.0001 and 0.0001, respectively). We also found that the composition of Bacteroides was negatively associated with triglycerides (TG), total cholesterol, and high-sensitive C-reactive protein (hs crp) (p = 0.0049, 0.0023, and 0.0038, respectively) levels, whereas that of Prevotella was positively associated with TG and hs-crp levels (p = 0.0394 and 0.0150, respectively). We then applied the association rule mining algorithm to generate "rules" to identify the association between the populations of multiple bacterial taxa and obesity; these rules were able to discriminate obese from normal states. Therefore, the present study describes a systemic approach to identify the association between bacterial populations in the gut and childhood obesity. PMID- 26230510 TI - Surface-Based Display of Volume-Averaged Cerebellar Imaging Data. AB - The paper presents a flat representation of the human cerebellum, useful for visualizing functional imaging data after volume-based normalization and averaging across subjects. Instead of reconstructing individual cerebellar surfaces, the method uses a white- and grey-matter surface defined on volume averaged anatomical data. Functional data can be projected along the lines of corresponding vertices on the two surfaces. The flat representation is optimized to yield a roughly proportional relationship between the surface area of the 2D representation and the volume of the underlying cerebellar grey matter. The map allows users to visualize the activation state of the complete cerebellar grey matter in one concise view, equally revealing both the anterior-posterior (lobular) and medial-lateral organization. As examples, published data on resting state networks and task-related activity are presented on the flatmap. The software and maps are freely available and compatible with most major neuroimaging packages. PMID- 26230512 TI - Plumbing Pathogens: A Fixture in Hospitals and Homes. PMID- 26230511 TI - Genetic Analysis of Arrhythmogenic Diseases in the Era of NGS: The Complexity of Clinical Decision-Making in Brugada Syndrome. AB - BACKGROUND: The use of next-generation sequencing enables a rapid analysis of many genes associated with sudden cardiac death in diseases like Brugada Syndrome. Genetic variation is identified and associated with 30-35% of cases of Brugada Syndrome, with nearly 20-25% attributable to variants in SCN5A, meaning many cases remain undiagnosed genetically. To evaluate the role of genetic variants in arrhythmogenic diseases and the utility of next-generation sequencing, we applied this technology to resequence 28 main genes associated with arrhythmogenic disorders. MATERIALS AND METHODS: A cohort of 45 clinically diagnosed Brugada Syndrome patients classified as SCN5A-negative was analyzed using next generation sequencing. Twenty-eight genes were resequenced: AKAP9, ANK2, CACNA1C, CACNB2, CASQ2, CAV3, DSC2, DSG2, DSP, GPD1L, HCN4, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ5, KCNQ1, NOS1AP, PKP2, RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SNTA1, and TMEM43. A total of 85 clinically evaluated relatives were also genetically analyzed to ascertain familial segregation. RESULTS AND DISCUSSION: Twenty-two patients carried 30 rare genetic variants in 12 genes, only 4 of which were previously associated with Brugada Syndrome. Neither insertion/deletion nor copy number variation were detected. We identified genetic variants in novel candidate genes potentially associated to Brugada Syndrome. These include: 4 genetic variations in AKAP9 including a de novo genetic variation in 3 positive cases; 5 genetic variations in ANK2 detected in 4 cases; variations in KCNJ2 together with CASQ2 in 1 case; genetic variations in RYR2, including a de novo genetic variation and desmosomal proteins encoding genes including DSG2, DSP and JUP, detected in 3 of the cases. Larger gene panels or whole exome sequencing should be considered to identify novel genes associated to Brugada Syndrome. However, application of approaches such as whole exome sequencing would difficult the interpretation for clinical purposes due to the large amount of data generated. The identification of these genetic variants opens new perspectives on the implications of genetic background in the arrhythmogenic substrate for research purposes. CONCLUSIONS: As a paradigm for other arrhythmogenic diseases and for unexplained sudden death, our data show that clinical genetic diagnosis is justified in a family perspective for confirmation of genetic causality. In the era of personalized medicine using high throughput tools, clinical decision-making is increasingly complex. PMID- 26230513 TI - Modelling Hotspots for Invasive Alien Plants in India. AB - Identification of invasion hotspots that support multiple invasive alien species (IAS) is a pre-requisite for control and management of invasion. However, till recently it remained a methodological challenge to precisely determine such invasive hotspots. We identified the hotspots of alien species invasion in India through Ecological Niche Modelling (ENM) using species occurrence data from the Global Biodiversity Information Facility (GBIF). The predicted area of invasion for selected species were classified into 4 categories based on number of model agreements for a region i.e. high, medium, low and very low. About 49% of the total geographical area of India was predicted to be prone to invasion at moderate to high levels of climatic suitability. The intersection of anthropogenic biomes and ecoregions with the regions of 'high' climatic suitability was classified as hotspot of alien plant invasion. Nineteen of 47 ecoregions of India, harboured such hotspots. Most ecologically sensitive regions of India, including the 'biodiversity hotspots' and coastal regions coincide with invasion hotspots, indicating their vulnerability to alien plant invasion. Besides demonstrating the usefulness of ENM and open source data for IAS management, the present study provides a knowledge base for guiding the formulation of an effective policy and management strategy for controlling the invasive alien species. PMID- 26230514 TI - Cysteine-Specific Labeling of Proteins with a Nitroxide Biradical for Dynamic Nuclear Polarization NMR. AB - Dynamic nuclear polarization (DNP) enhances the signal in solid-state NMR of proteins by transferring polarization from electronic spins to the nuclear spins of interest. Typically, both the protein and an exogenous source of electronic spins, such as a biradical, are either codissolved or suspended and then frozen in a glycerol/water glassy matrix to achieve a homogeneous distribution. While the use of such a matrix protects the protein upon freezing, it also reduces the available sample volume (by ca. a factor of 4 in our experiments) and causes proportional NMR signal loss. Here we demonstrate an alternative approach that does not rely on dispersing the DNP agent in a glassy matrix. We synthesize a new biradical, ToSMTSL, which is based on the known DNP agent TOTAPOL, but also contains a thiol-specific methanethiosulfonate group to allow for incorporating this biradical into a protein in a site-directed manner. ToSMTSL was characterized by EPR and tested for DNP of a heptahelical transmembrane protein, Anabaena sensory rhodopsin (ASR), by covalent modification of solvent-exposed cysteine residues in two (15)N-labeled ASR mutants. DNP enhancements were measured at 400 MHz/263 GHz NMR/EPR frequencies for a series of samples prepared in deuterated and protonated buffers and with varied biradical/protein ratios. While the maximum DNP enhancement of 15 obtained in these samples is comparable to that observed for an ASR sample cosuspended with ~17 mM TOTAPOL in a glycerol d8/D2O/H2O matrix, the achievable sensitivity would be 4-fold greater due to the gain in the filling factor. We anticipate that the DNP enhancements could be further improved by optimizing the biradical structure. The use of covalently attached biradicals would broaden the applicability of DNP NMR to structural studies of proteins. PMID- 26230515 TI - Quantitative assessment of brain iron by R2* relaxometry in patients with cervical dystonia. AB - BACKGROUND: The pathophysiology of cervical dystonia is poorly understood. Increased brain iron deposition has been described in different movement disorders. Our aim was to investigate brain iron content in patients with cervical dystonia, using R2* relaxation rate, a validated MRI marker of brain iron level. METHODS: Twelve female patients with primary focal cervical dystonia (mean age: 45.4 +/- 8.0 years) and 12 age-matched healthy female subjects (mean age: 45.0 +/- 8.0 years) underwent 3T MRI to obtain regional R2* relaxation rates of the thalamus, caudate nucleus, putamen, and globus pallidus (GP). Regions of interest were delineated automatically on T1-weighted MRIs. RESULTS: R2* values in the putamen were positively correlated with age. Patients with cervical dystonia showed elevated R2* values in the GP. CONCLUSIONS: This pilot study provides the first quantitative support for increased brain iron deposition in cervical dystonia. Further studies are needed to explore the implications of this finding. PMID- 26230516 TI - Respiratory responses to stimulation of abdominal and upper-thorax intercostal muscles using multiple Permaloc electrodes. AB - Stimulation of abdominal and upper-thoracic muscles was studied with the long term goal of improved respiratory care for spinal cord injury (SCI) patients. A 12-channel stimulator and multiple surface and implanted Permaloc electrodes were evaluated in five anesthetized canines. Abdominal stimulation with 100 mA using four bilateral sets of surface electrodes placed on the midaxillary line at the 7th through 13th intercostal spaces and with a closed airway at a large lung volume produced an expiratory tracheal pressure of 109 +/- 29 cm H2O (n = 2, mean +/- standard error of the mean). Similar high pressures were induced with implanted electrodes at the same locations. Upper-thoracic stimulation with 40 mA and four sets of implanted electrodes ventral to the axilla induced inspiratory pressures of -12 +/- 2 cm H2O (n = 5). Combined extradiaphragmatic pacing with an open airway produced a tidal volume of 440 +/- 45 mL (n = 4). The robust respiratory volumes and pressures suggest applications in SCI respiratory care. PMID- 26230517 TI - Tetraphenylethene Derivatives with Different Numbers of Positively Charged Side Arms have Different Multimeric G-Quadruplex Recognition Specificity. AB - Some G-rich sequences in the human genome have the potential to fold into a multimeric G-quadruplex (G4) structure and the formation of telomeric multimeric G4 has been demonstrated. Searching for highly specific multimeric G4 ligands is important for structure probing and for study of the function of G-rich gene sequences, as well as for the design of novel anticancer drugs. We found different numbers of positively charged side-arm substituents confer tetraphenylethene (TPE) derivatives with different multimeric G4 recognition specificity. 1,2-Bis{4-[(trimethylammonium)butoxy]phenyl}-1,2-tetraphenylethene dibromide (DATPE), which contains two side arms and gives a fluorescence response to only multimeric G4, has a low level of cytotoxicity and little or no effect on multimeric G4 conformation or stability. These features make DATPE a promising fluorescent probe for detection of multimeric G4 specifically in biological samples or in vivo. 1,1,2,2-Tetrakis{4 [(trimethylammonium)butoxy]phenyl}tetraphenylethene tetrabromide (QATPE), which contains four side arms, has a lower level of specificity for multimeric G4 recognition compared to DATPE but its binding affinity to multimeric G4 is higher compared to other structural DNAs. Its high multimeric G4-binding affinity, excellent multimeric G4-stabilizing ability, and the promotion of parallel G4 formation make QATPE a good candidate for novel anticancer drugs targeting multimeric G4 specifically, especially telomeric multimeric G4. This work provides information that might aid the design of specific multimeric G4 probes and the development of novel anticancer drugs. PMID- 26230518 TI - Comparative Study of Regulatory Circuits in Two Sea Urchin Species Reveals Tight Control of Timing and High Conservation of Expression Dynamics. AB - Accurate temporal control of gene expression is essential for normal development and must be robust to natural genetic and environmental variation. Studying gene expression variation within and between related species can delineate the level of expression variability that development can tolerate. Here we exploit the comprehensive model of sea urchin gene regulatory networks and generate high density expression profiles of key regulatory genes of the Mediterranean sea urchin, Paracentrotus lividus (Pl). The high resolution of our studies reveals highly reproducible gene initiation times that have lower variation than those of maximal mRNA levels between different individuals of the same species. This observation supports a threshold behavior of gene activation that is less sensitive to input concentrations. We then compare Mediterranean sea urchin gene expression profiles to those of its Pacific Ocean relative, Strongylocentrotus purpuratus (Sp). These species shared a common ancestor about 40 million years ago and show highly similar embryonic morphologies. Our comparative analyses of five regulatory circuits operating in different embryonic territories reveal a high conservation of the temporal order of gene activation but also some cases of divergence. A linear ratio of 1.3-fold between gene initiation times in Pl and Sp is partially explained by scaling of the developmental rates with temperature. Scaling the developmental rates according to the estimated Sp-Pl ratio and normalizing the expression levels reveals a striking conservation of relative dynamics of gene expression between the species. Overall, our findings demonstrate the ability of biological developmental systems to tightly control the timing of gene activation and relative dynamics and overcome expression noise induced by genetic variation and growth conditions. PMID- 26230519 TI - Mitofusin 2 Deficiency Affects Energy Metabolism and Mitochondrial Biogenesis in MEF Cells. AB - Mitofusin 2 (Mfn2), mitochondrial outer membrane protein which is involved in rearrangement of these organelles, was first described in pathology of hypertension and diabetes, and more recently much attention is paid to its functions in Charcot-Marie-Tooth type 2A neuropathy (CMT2A). Here, cellular energy metabolism was investigated in mouse embryonic fibroblasts (MEF) differing in the presence of the Mfn2 gene; control (MEFwt) and with Mfn2 gene depleted MEFMfn2-/-. These two cell lines were compared in terms of various parameters characterizing mitochondrial bioenergetics. Here, we have shown that relative rate of proliferation of MEFMfn2-/- cells versus control fibroblasts depend on serum supplementation of the growth media. Moreover, MEFMfn2-/- cells exhibited significantly increased respiration rate in comparison to MEFwt, regardless of serum supplementation of the medium. This effect was correlated with increased level of mitochondrial markers (TOM20 and NAO) as well as mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) protein levels and unchanged total ATP content. Interestingly, mitochondrial DNA content in MEFMfn2-/- cells was not reduced. Fundamentally, these results are in contrast to a commonly accepted belief that mitofusin 2 deficiency inevitably results in debilitation of mitochondrial energy metabolism. However, we suggest a balance between negative metabolic consequences of mitofusin 2 deficiency and adaptive processes exemplified by increased level of PGC-1alpha and TFAM transcription factor which prevent an excessive depletion of mtDNA and severe impairment of cell metabolism. PMID- 26230521 TI - Risk Factors of Surgical Site Infection after Acetabular Fracture Surgery. AB - BACKGROUND: Surgical site infections (SSI) after acetabular fracture surgery are uncommon but devastating. It is still unknown which risk factors contribute to SSI. The primary objective of this study is to investigate the risk factors of SSI after acetabular fracture surgery. METHODS: A total of 338 patients who underwent the acetabular fracture surgical procedure were studied retrospectively. Post-operative SSI developed in 16 patients. From the medical record, age, gender, body mass index (BMI), Injury Severity Score (ISS), active smokers, diabetes mellitus, causes of fracture, associated injuries, classification of the acetabular fracture, time from injury to operation, operative approaches, use of the Intra-Aortic Balloon Occlusion (IABO), operative time, surgical blood loss, and days in the intensive care unit (ICU) were extracted. Univariate and multivariable analysis were performed to determine the association between risk factors and infection. RESULTS: There were 10 males and six females in the infected group. According to the univariate analysis, the patients in whom SSI developed were more obese (higher BMI), more severely injured in terms of ISS, and had longer ICU stays. The operative time was longer, and estimated blood loss was larger in the infected group. Associated injuries such as Morel-Lavallee lesion, abdominal trauma, and urinary tract trauma were common in the infected group. Combined approaches and IABO were more commonly applied in the infected group. Multivariate analysis indicated that the operative time, Morel-Lavallee lesion, and abdominal trauma are the independent risk factors for SSI. CONCLUSIONS: To reduce the incidence of SSI in patients with acetabular fractures, special attention should be paid to the obese patients, Morel-Lavallee lesion, and concomitant abdominal trauma. Keeping the operative time short also reduces the risk of SSI. It is important to perform surgical intervention immediately after the infection occurs. PMID- 26230520 TI - In Vivo Voltage-Sensitive Dye Study of Lateral Spreading of Cortical Activity in Mouse Primary Visual Cortex Induced by a Current Impulse. AB - In the mammalian primary visual cortex (V1), lateral spreading of excitatory potentials is believed to be involved in spatial integrative functions, but the underlying cortical mechanism is not well understood. Visually-evoked population level responses have been shown to propagate beyond the V1 initial activation site in mouse, similar to higher mammals. Visually-evoked responses are, however, affected by neuronal circuits prior to V1 (retina, LGN), making the separate analysis of V1 difficult. Intracortical stimulation eliminates these initial processing steps. We used in vivo RH1691 voltage-sensitive dye (VSD) imaging and intracortical microstimulation in adult C57BL/6 mice to elucidate the spatiotemporal properties of population-level signal spreading in V1 cortical circuits. The evoked response was qualitatively similar to that measured in single-cell electrophysiological experiments in rodents: a fast transient fluorescence peak followed by a fast and a slow decrease or hyperpolarization, similar to EPSP and fast and slow IPSPs in single cells. The early cortical response expanded at speeds commensurate with long horizontal projections (at 5% of the peak maximum, 0.08-0.15 m/s) however, the bulk of the VSD signal propagated slowly (at half-peak maximum, 0.05-0.08 m/s) suggesting an important role of regenerative multisynaptic transmission through short horizontal connections in V1 spatial integrative functions. We also found a tendency for a widespread and fast cortical response suppression in V1, which was eliminated by GABAA-antagonists gabazine and bicuculline methiodide. Our results help understand the neuronal circuitry involved in lateral spreading in V1. PMID- 26230522 TI - Streptococcus pneumoniae antibody titres in patients with primary antibody deficiency receiving intravenous immunoglobulin (IVIG) compared to subcutaneous immunoglobulin (SCIG). AB - Intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) are effective in the treatment of patients with primary antibody deficiency disorders (PAD). The purpose of this study was to evaluate Streptococcus pneumoniae (Spn) antibody titres to 14 serotypes in patients receiving IVIG compared to SCIG and to correlate Spn antibody levels to clinical outcome. The doses of immunoglobulin (Ig)G/kg/month were similar in both IVIG and SCIG groups. In 11 patients treated with IVIG, Spn antibody titres were >= 1.3 MUg/ml to 99.4 +/- 2.1% of the 14 serotypes at peak IVIG but decreased to 66.9 +/- 19.8% at trough IVIG. Loss of Spn titres >= 1.3 MUg/ml was most frequent for Spn serotypes 1, 4, 9V and 23. This correlated with lower Spn antibody titres to these serotypes at peak IVIG compared to the other serotypes. In 13 patients treated with SCIG, Spn antibody titres were protective to 58.2 +/- 23.3% of the serotypes 3-5 days after infusion, similar to trough IVIG. Similarly, the Spn serotypes with the least protective percentages were the same as the ones observed in trough IVIG. There were no annualized serious bacterial infections (aSBI) in either group. However, there were significantly decreased annualized other infections (aOI) in the SCIG group compared to the IVIG-treated group, 0.8 +/- 0.7 versus 2.2 +/- 1.2 infections/patient/year (P = 0.004). Breakthrough aOI did not correlate with protective or higher serum Spn antibody titres. PMID- 26230523 TI - Blame Conformity: Innocent Bystanders Can Be Blamed for a Crime as a Result of Misinformation from a Young, but Not Elderly, Adult Co-Witness. AB - This study examined whether or not exposing an eyewitness to a co-witness statement that incorrectly blames an innocent bystander for a crime can increase the likelihood of the eyewitness subsequently blaming the innocent bystander for the crime. It also examined whether or not the perceived age of the co-witness influences this effect. Participant eyewitnesses first watched a video of a crime featuring a perpetrator and an innocent bystander. They then read one of six bogus co-witness statements about the crime. All were presented as having been written by a female co-witness and they differed in terms of her age (young adult or elderly) and who she blamed for the crime (the perpetrator, the innocent bystander, or nobody). One week later the participants were asked who committed the crime. When the young adult co-witness had blamed the innocent bystander just over 40% of participants subsequently did the same. Few participants (less than 8%) in the other conditions subsequently blamed the innocent bystander. The elderly co-witness was also rated as less credible, less competent, and less accurate than the younger co-witness suggesting eyewitnesses were less likely to be influenced by her incorrect statement as they perceived her to be a less reliable source of information. The applied implications of these findings are discussed. PMID- 26230524 TI - Efficient Modeling of MS/MS Data for Metabolic Flux Analysis. AB - Metabolic flux analysis (MFA) is a widely used method for quantifying intracellular metabolic fluxes. It works by feeding cells with isotopic labeled nutrients, measuring metabolite isotopic labeling, and computationally interpreting the measured labeling data to estimate flux. Tandem mass spectrometry (MS/MS) has been shown to be useful for MFA, providing positional isotopic labeling data. Specifically, MS/MS enables the measurement of a metabolite tandem mass-isotopomer distribution, representing the abundance in which certain parent and product fragments of a metabolite have different number of labeled atoms. However, a major limitation in using MFA with MS/MS data is the lack of a computationally efficient method for simulating such isotopic labeling data. Here, we describe the tandemer approach for efficiently computing metabolite tandem mass-isotopomer distributions in a metabolic network, given an estimation of metabolic fluxes. This approach can be used by MFA to find optimal metabolic fluxes, whose induced metabolite labeling patterns match tandem mass isotopomer distributions measured by MS/MS. The tandemer approach is applied to simulate MS/MS data in a small-scale metabolic network model of mammalian methionine metabolism and in a large-scale metabolic network model of E. coli. It is shown to significantly improve the running time by between two to three orders of magnitude compared to the state-of-the-art, cumomers approach. We expect the tandemer approach to promote broader usage of MS/MS technology in metabolic flux analysis. PMID- 26230525 TI - DNA Persistence in a Sink Drain Environment. AB - Biofilms are organized structures composed mainly of cells and extracellular polymeric substances produced by the constituent microorganisms. Ubiquitous in nature, biofilms have an innate ability to capture and retain passing material and may therefore act as natural collectors of contaminants or signatures of upstream activities. To determine the persistence and detectability of DNA passing through a sink drain environment, Bacillus anthracis strain Ames35 was cultured (6.35 x 107 CFU/mL), sterilized, and disposed of by addition to a sink drain apparatus with an established biofilm. The sink drain apparatus was sampled before and for several days after the addition of the sterilized B. anthracis culture to detect the presence of B. anthracis DNA. Multiple PCR primer pairs were used to screen for chromosomal and plasmid DNA with primers targeting shorter sequences showing greater amplification efficiency and success. PCR amplification and detection of target sequences indicate persistence of chromosomal DNA and plasmid DNA in the biofilm for 5 or more and 14 or more days, respectively. PMID- 26230527 TI - Correction: Comparison between Different Intensity Normalization Methods in 123I Ioflupane Imaging for the Automatic Detection of Parkinsonism. PMID- 26230526 TI - Biogenesis, identification, and function of exonic circular RNAs. AB - Circular RNAs (circRNAs) arise during post-transcriptional processes, in which a single-stranded RNA molecule forms a circle through covalent binding. Previously, circRNA products were often regarded to be splicing intermediates, by-products, or products of aberrant splicing. But recently, rapid advances in high-throughput RNA sequencing (RNA-seq) for global investigation of nonco-linear (NCL) RNAs, which comprised sequence segments that are topologically inconsistent with the reference genome, leads to renewed interest in this type of NCL RNA (i.e., circRNA), especially exonic circRNAs (ecircRNAs). Although the biogenesis and function of ecircRNAs are mostly unknown, some ecircRNAs are abundant, highly expressed, or evolutionarily conserved. Some ecircRNAs have been shown to affect microRNA regulation, and probably play roles in regulating parental gene transcription, cell proliferation, and RNA-binding proteins, indicating their functional potential for development as diagnostic tools. To date, thousands of ecircRNAs have been identified in multiple tissues/cell types from diverse species, through analyses of RNA-seq data. However, the detection of ecircRNA candidates involves several major challenges, including discrimination between ecircRNAs and other types of NCL RNAs (e.g., trans-spliced RNAs and genetic rearrangements); removal of sequencing errors, alignment errors, and in vitro artifacts; and the reconciliation of heterogeneous results arising from the use of different bioinformatics methods or sequencing data generated under different treatments. Such challenges may severely hamper the understanding of ecircRNAs. Herein, we review the biogenesis, identification, properties, and function of ecircRNAs, and discuss some unanswered questions regarding ecircRNAs. We also evaluate the accuracy (in terms of sensitivity and precision) of some well-known circRNA-detecting methods. PMID- 26230528 TI - One-Pot Cannizzaro Cascade Synthesis of ortho-Fused Cycloocta-2,5-dien-1-ones from 2-Bromo(hetero)aryl Aldehydes. AB - An intramolecular Cannizzaro-type hydride transfer to an in situ prepared allene enables the synthesis of ortho-fused 4-substituted cycloocta-2,5-dien-1-ones with unprecedented technical ease for an eight-ring carboannulation. Various derivatives could be obtained from commercially available (hetero)aryl aldehydes, trimethylsilylacetylene, and simple propargyl chlorides in good yields. PMID- 26230530 TI - Erratum: A sensitised RNAi screen reveals a ch-TOG genetic interaction network required for spindle assembly. PMID- 26230529 TI - Systemic Fluorescence Imaging of Zebrafish Glycans with Bioorthogonal Chemistry. AB - Vertebrate glycans constitute a large, important, and dynamic set of post translational modifications that are notoriously difficult to manipulate and image. Although the chemical reporter strategy has been used in conjunction with bioorthogonal chemistry to image the external glycosylation state of live zebrafish and detect tumor-associated glycans in mice, the ability to image glycans systemically within a live organism has remained elusive. Here, we report a method that combines the metabolic incorporation of a cyclooctyne functionalized sialic acid derivative with a ligation reaction of a fluorogenic tetrazine, allowing for the imaging of sialylated glycoconjugates within live zebrafish embryos. PMID- 26230531 TI - Ischemic Stroke: From Next Generation Sequencing and GWAS to Community Genomics? AB - Stroke is a major cause of mortality and morbidity in both the developed and developing world. Next generation sequencing (NGS) and multi-omics integrative biology research offer new opportunities in the way we research and understand stroke. These biotechnologies also signal a shift from genetics to genomics of stroke, which is highlighted in this review. Stroke is a focal neurological deficit resulting from disruption of the cerebral blood supply. There are two main types of common stroke, ischemic stroke (IS), which comprises 80% of cases, and hemorrhagic stroke (HS) that accounts for about 20% of cases. IS is a complex multi-factorial disease with multiple environmental and genomic determinants. We discuss here IS from genomics and bioinformatics perspectives, including the highlights of the genome wide association studies (GWAS), NGS progress to date, and exome studies. While both 'common variant, common disease' and 'rare variant, common disease' approaches need to be assessed in tandem, future studies into IS omics should also consider pedigree and/or community based sampling to take account of the complex diversity of IS genetics. We conclude by presenting an example of such community genomics research from China in an extended pedigree sample, and the ways in which the intersection of genomics and global society can usefully inform our understanding of IS pathophysiology and potential preventive medicine interventions in the future. PMID- 26230532 TI - Computational Tools for Parsimony Phylogenetic Analysis of Omics Data. AB - High-throughput assays from genomics, proteomics, metabolomics, and next generation sequencing produce massive omics datasets that are challenging to analyze in biological or clinical contexts. Thus far, there is no publicly available program for converting quantitative omics data into input formats to be used in off-the-shelf robust phylogenetic programs. To the best of our knowledge, this is the first report on creation of two Windows-based programs, OmicsTract and SynpExtractor, to address this gap. We note, as a way of introduction and development of these programs, that one particularly useful bioinformatics inferential modeling is the phylogenetic cladogram. Cladograms are multidimensional tools that show the relatedness between subgroups of healthy and diseased individuals and the latter's shared aberrations; they also reveal some characteristics of a disease that would not otherwise be apparent by other analytical methods. The OmicsTract and SynpExtractor were written for the respective tasks of (1) accommodating advanced phylogenetic parsimony analysis (through standard programs of MIX [from PHYLIP] and TNT), and (2) extracting shared aberrations at the cladogram nodes. OmicsTract converts comma-delimited data tables through assigning each data point into a binary value ("0" for normal states and "1" for abnormal states) then outputs the converted data tables into the proper input file formats for MIX or with embedded commands for TNT. SynapExtractor uses outfiles from MIX and TNT to extract the shared aberrations of each node of the cladogram, matching them with identifying labels from the dataset and exporting them into a comma-delimited file. Labels may be gene identifiers in gene-expression datasets or m/z values in mass spectrometry datasets. By automating these steps, OmicsTract and SynpExtractor offer a veritable opportunity for rapid and standardized phylogenetic analyses of omics data; their model can also be extended to next generation sequencing (NGS) data. We make OmicsTract and SynpExtractor publicly and freely available for non commercial use in order to strengthen and build capacity for the phylogenetic paradigm of omics analysis. PMID- 26230533 TI - Proteomics Evidence for the Activity of the Putative Antibacterial Plant Alkaloid (-)-Roemerine: Mainstreaming Omics-Guided Drug Discovery. AB - Discovery of new antibacterials with novel mechanisms is important to counteract the ingenious resistance mechanisms of bacteria. In this connection, omics-guided drug discovery offers a rigorous method in the quest of new antibacterials. (-) Roemerine is a plant alkaloid that has been reported to possess putative antibacterial activity against Escherichia coli, Bacillus subtilis, and Salmonella typhimurium. The aim of the present study was to characterize the activity of (-)-roemerine in Escherichia coli TB1 using proteomics tools. With ( )-roemerine treatment, we found limited permeability through the outer membrane and repression of transport proteins involved in carbohydrate metabolism, resulting in poor carbon source availability. The shortfall of intracellular carbon sources in turn led to impaired cell growth. The reduction in the abundance of proteins related to translational machinery, amino acid biosynthesis, and metabolism was accompanied by a nutrient-limited state. The latter finding could suggest a metabolic shutdown in E. coli cells. High osmolarity was clearly not one of the reasons of bacterial death by (-) roemerine. These observations collectively attest to the promise of plant omics and profiling of putative drug candidates using proteomics tools. Omics-guided drug discovery deserves greater attention in mainstream pharmacology so as to better understand the plants' medicinal potentials. PMID- 26230535 TI - Repurposing a Prokaryotic Toxin-Antitoxin System for the Selective Killing of Oncogenically Stressed Human Cells. AB - Prokaryotes express intracellular toxins that pass unnoticed to carrying cells until coexpressed antitoxin partners are degraded in response to stress. Although not evolved to function in eukaryotes, one of these toxins, Kid, induces apoptosis in mammalian cells, an effect that is neutralized by its cognate antitoxin, Kis. Here we engineered this toxin-antitoxin pair to create a synthetic system that becomes active in human cells suffering a specific oncogenic stress. Inspired by the way Kid becomes active in bacterial cells, we produced a Kis variant that is selectively degraded in human cells expressing oncoprotein E6. The resulting toxin-antitoxin system functions autonomously in human cells, distinguishing those that suffer the oncogenic insult, which are killed by Kid, from those that do not, which remain protected by Kis. Our results provide a framework for developing personalized anticancer strategies avoiding off-target effects, a challenge that has been hardly tractable by other means thus far. PMID- 26230536 TI - Timing of Complications After Spinal Fusion Surgery. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To characterize the timing of complications after spinal fusion procedures. SUMMARY OF BACKGROUND DATA: Despite many publications on risk factors for complications after spine surgery, there are few publications on the timing at which such complications occur. METHODS: Patients undergoing anterior cervical decompression and fusion (ACDF) or posterior lumbar fusion (PLF; with or without interbody) procedures during 2011 2013 were identified in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. For each of 8 different complications, the median time from surgery until complication was determined, along with the interquartile range and middle 80%. RESULTS: A total of 12,067 patients undergoing ACDF and 11,807 patients undergoing PLF were identified. For ACDF, the median day of diagnosis (and interquartile range; middle 80%) for anemia requiring transfusion was 0 (0-1; 0-2), myocardial infarction 2 (1-5; 0 15), pneumonia 4 (2-9; 1-14), pulmonary embolism 5 (2-9; 1-10), deep vein thrombosis 10.5 (7-16.5; 5-21), sepsis 10.5 (4-18; 1-23), surgical site infection 13 (8-19; 5-25), and urinary tract infection 17 (8-22; 4-26). For PLF, the median day of diagnosis (and interquartile range; middle 80%) for anemia requiring transfusion was 0 (0-1; 0-2), myocardial infarction 2 (1-4; 1-8), pneumonia 4 (2 9; 1-17), pulmonary embolism 5 (3-11; 2-17), urinary tract infection 7 (4-14; 2 23), deep vein thrombosis 8 (5-16; 3-20), sepsis 9 (4-16; 2-22), and surgical site infection 17 (13-22; 9-27). CONCLUSION: These precisely described postoperative time periods enable heightened clinical awareness among spine surgeons. Spine surgeons should have the lowest threshold for testing for each complication during the time period of greatest risk. Authors, reviewers, and surgeons utilizing research on postoperative complications should carefully consider the impact that the duration of follow-up has on study results. LEVEL OF EVIDENCE: 3. PMID- 26230537 TI - Magnetic Expansion Control System Achieves Cost Savings Compared to Traditional Growth Rods: An Economic Analysis Model. AB - STUDY DESIGN: Medical economic model with multi-way sensitivity analysis. OBJECTIVE: To compare the direct costs of growing rod (GR) versus Magnetic Expansion Control System (MG) from a payer's perspective. We hypothesized that over time the MG will become more cost-effective. SUMMARY OF BACKGROUND DATA: Traditional GRs provide effective treatment, but require periodic lengthening surgery. MG allows rod lengthening in clinic, but the implant is expensive. The cumulative cost savings are not well understood. METHODS: Index surgery, implant cost, lengthening procedure, and revision surgery due to implant failure or infection were identified as major parameters contributing to the cumulative cost. The "base," "low," and "high" values for the cost and the incidence of each parameter were determined by literature reports, health care database search, or expert consultation. The cumulative cost was compared annually during 5 years of follow-up. Marginal cost was defined as the cost of (GR-MG) for each cumulative year. Final cumulative cost and extreme case scenario at year 5 were assessed by deterministic sensitivity analysis. RESULTS: MG resulted in higher cumulative cost at years 1 and 2, and became lower cost at years 3 through 5. The marginal cost at year 1 was a negative value of $16K, and trended toward positive values of $12K at year 3 and $40K by year 5. Sensitivity analysis revealed that in extreme case, MG could cost more, shown by a marginal cost of $26K by implementing the extreme values of the 3 parameters carrying highest variance: MG infection management, GR-revision surgery, and GR-lengthening procedure. CONCLUSION: MG achieved cost neutrality to GR at 3 years after index surgery. This is the first medical economic study in the United States comparing the cost of GR versus MG and demonstrates potential cost-effectiveness of MG from payer's perspective if in place for more than 3 years. LEVEL OF EVIDENCE: 2. PMID- 26230538 TI - The Relationship Between Osteoarthritis of the Lumbar Facet Joints and Lumbosacropelvic Morphology. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: To investigate the relation between lumbosacropelvic morphology and the presence and degree of facet joint degeneration. SUMMARY OF BACKGROUND DATA: Osteoarthritis of the facet joints is one of the most common degenerative changes in the spine. It is considered to be formed secondary to repetitive stress or trauma and spinal deformity with secondary overload. The cause(s) of facet joints osteoarthritis, however, have not been clearly identified. METHODS: Abdominal computed tomography (CT) images of 723 patients which were taken between the years 2010 and 2014 were evaluated retrospectively. Patients with prior lumbar spinal surgery, serious congenital anomalies on CT, incomplete or complete lumbosacral transition, severe scoliosis, were excluded from the study. To eliminate the age- and sex-related differences in spinopelvic morphology, a study group was formed of the remaining subjects by including patients from a specific age group (30-35 yr) and same sex (females). For each patient the presence and grade of facet joint degeneration was investigated. In addition, pelvic incidence (PI), sacral slope and the angles of L1-L5 lumbar lordosis, sacral table, L5 vertebra posterior, and sacral kyphosis were measured for each patient. RESULTS: Sacral slope, sacral kyphosis, and L1-L5 lumbar lordosis angle were significantly higher in patients with osteoarthritic compared with normal subjects (P = 0.015, P = 0.018, P = 0.016). L5 vertebra posterior and sacral table angle were found to be significantly lower in patients with osteoarthritic than in normal subjects (P = 0.019, P = 0.007). The degree of facet joint degeneration was noticed to increase parallel to the decrease in the sacral table angle and L5 vertebra posterior angle, and to the increase in the L1 L5 lumbar lordosis, PI, and sacral slope. CONCLUSION: A close relation exists between the presence and degree of degeneration in the facet joint and lumbosacral pelvic morphology. Prevalence and degree of the degeneration in facet joint increases as the angle of sacral slope, L1-L5 lumbar lordosis, and PI increases or the angle of sacral table and L5 vertebra posterior decreases. LEVEL OF EVIDENCE: 4. PMID- 26230539 TI - Antiapoptotic Effect of Highly Secreted GMCSF From Neuronal Cell-specific GMCSF Overexpressing Neural Stem Cells in Spinal Cord Injury Model. AB - STUDY DESIGN: Neuronal cell-specific gene expression system and neural stem cells (NSCs) were combined for treatment of spinal cord injury (SCI). OBJECTIVE: To verify the reproducibility of the neuronal cell-specific therapeutic gene overexpression system, we develop a neuronal cell-specific granulocyte-macrophage colony-stimulating factor expression system (NSE-GMCSF), and then examine the characteristics of GMCSF overexpression and protective effect on neural cells in vitro and vivo. SUMMARY OF BACKGROUND DATA: The stem cell transplantation is considered a promising therapy for SCI. However, stem cell monotherapy strategy is insufficient for complete recovery after SCI. Therefore, combined treatment method based on stem cells with other therapeutic system may be effective for improving the therapeutic efficacy. In this study, we established the gene and stem cell therapy platform based on NSCs and neuronal cell-specific gene expression system. METHODS: To examine the GMCSF expression pattern, we compared the amount of secreted GMCSF from the neuronal cell-specific GMCSF expressing NSCs with control GMCSF-expressing NSCs (respectively, NSE-GMCSF-NSCs vs. SV GMCSF-NSCs) by ELISA in vitro and in vivo, and then verified the neuronal protective effect of these cells in vitro and vivo. RESULTS: The results showed that NSE-GMCSF-NSCs secreted more GMCSF compared with SV-GMCSF-NSCs in normoxia, hypoxia and cytotoxic conditions. The cell viability of NSE-GMCSF-NSCs was increased depending on the amount of secreted GMCSF in cytotoxic condition. In addition, the amount of secreted GMCSF by NSE-GMCSF-NSCs transplanted into injured spinal cord was significantly higher than SV-GMCSF-NSCs. Higher amount of secreted GMCSF decreased the expression of proapoptotic protein, Bax. CONCLUSION: In this study, we demonstrated that the neuronal cell-specific gene expression system induced overexpression of GMCSF in NSCs. These combined NSCs & gene therapy treatment protocol would be an effective therapeutic system for SCI. LEVEL OF EVIDENCE: N/A. PMID- 26230540 TI - Postoperative Perfection: Ceiling Effects and Lack of Discrimination With Both SRS-22 and -24 Outcomes Instruments in Patients With Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: Review of a prospective database registry. OBJECTIVE: To compare the Scoliosis Research Society (SRS)-22 and SRS-24 outcomes instruments in terms of scores, rate of ceiling effects, and discriminant ability in patients with pre and postoperative adolescent idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: Despite improvements noted with the SRS-22, the SRS-24 is still occasionally used prospectively and for comparisons with previous studies reporting SRS-24 scores. Previous work has demonstrated that postoperative scores from the 2 versions are not interchangeable. METHODS: A multicenter prospective registry of patients who underwent surgical correction of adolescent idiopathic scoliosis was queried for preoperative and 2-year postoperative SRS-22 and SRS-24 scores. Scores were compared between versions and ceiling effects were identified. Groups of deformity severity were created to evaluate discriminant ability. RESULTS: 829 patients were identified. The SRS-22 scores for pain and general function were significantly greater than SRS-24 scores (P < 0.001), whereas the SRS-22 scores were significantly lower than the SRS-24 for self-image (P < 0.001). Preoperative ceiling effect was only noted in 1 domain each. Both versions were able to discriminate between large (80 degrees +) and small (<45 degrees ) preoperative curves in all domains and total scores (P < 0.05). Postoperatively, the SRS-22 scores for all shared domains and total score were significantly greater than SRS 24 scores (P < 0.001). Ceiling effects in 5 of 5 domain scores were noted postoperatively for SRS-22 and in 4 of 7 for SRS-24. With a smaller range of deformity postoperatively, only the SRS-22 self-image domain was able to discriminate between large (29 degrees +) and small (<=11 degrees ) residual curves (P < 0.05). CONCLUSION: Scores obtained by the SRS-22 and the SRS-24 are not translatable despite shared domains. Whereas both versions demonstrated preoperative discriminant ability, postoperative discrimination of residual deformity is lacking in both. Patient-reported outcomes of treatment are crucial in advancing treatment, and improvement in the ability to assess subjective outcomes is essential. LEVEL OF EVIDENCE: 3. PMID- 26230541 TI - Occupant and Crash Characteristics of Elderly Subjects With Thoracic and Lumbar Spine Injuries After Motor Vehicle Collisions. AB - STUDY DESIGN: Retrospective study of a prospectively gathered database. OBJECTIVE: To investigate the incidence and pattern of thoracic and lumbar (T and L) spine injuries among elderly subjects involved in motor vehicle collision (MVC). SUMMARY OF BACKGROUND DATA: Adults age 65 and older currently constitute more than 16% of all licensed drivers. Despite driving less than the young, older drivers are involved in a higher proportion of crashes. Notwithstanding the safety features in modern vehicles, 15.8% to 51% of all T and L spine injuries result from MVCs. METHODS: Crash Injury Research and Engineering Network database is a prospectively maintained, multicentered database that enrolls MVC occupants with moderate-to-severe injuries. It was queried for T and L spine injuries in subjects 65 and older. 142 Crash Injury Research and Engineering Network files for all elderly individuals were reviewed for demographic, injury, and crash data. Each occupant's T and L injury was categorized using a modified Denis classification. RESULTS: Of 661 elderly subjects, 142 (21.48%) sustained T and L spine injuries. Of the 102 major injuries, there were 63 compression, 20 burst and 12 extension fractures. Seatbelt use predisposed elderly subjects to compression and burst fractures, whereas seatbelt and airbag use predisposed to burst fractures. Deployment of airbags without seatbelt use appeared to predispose elderly subjects to neurological injury, higher Injury Severity Score, and higher mortality. Occupants using 3-point belts who had airbags deployed during the collision had the lowest rates of fatality and neurological injury. CONCLUSION: T and L spine injuries in the elderly are not uncommon despite restraint use. Whereas seatbelts used alone and in conjunction with airbag deployment reduced fatalities and neurological injuries in the elderly, deployment of airbags in occupants without seatbelts predisposed to more severe injury. PMID- 26230543 TI - An Isolated Posterior Spinal Aneurysm Resection in Which Intraoperative Electrophysiological Monitoring Was Successfully Used to Locate the Lesion and to Detect the Possibility of Ischemic Complications. AB - STUDY DESIGN: A case report. OBJECTIVE: To report the successful use of electrophysiological monitoring in the surgical resection of a ruptured spinal artery (SA) aneurysm to locate the lesion, and to predict ischemic complications. SUMMARY OF BACKGROUND DATA: Isolated aneurysm of the posterior SA is an extremely rare event without established treatment and diagnosis procedures. Reports describing the surgical intervention of aneurysm of the posterior SA using electrophysiological monitoring are scant. METHODS: We performed the surgical resection of a dissected posterior SA aneurysm in an older patient who presented with spinal subarachnoid hemorrhage using intraoperative electrophysiological monitoring. RESULTS: Intraoperatively, motor evoked potentials decreased over 50% when a distal site of the lesion was clipped, indicating that site was the posterior SA. This lead to further investigation of the vascular anatomy around the lesion, which revealed the descending part of the posterior SA buried deeply in a thick thrombus. Clipping and resection were successful, and ischemia of the posterior SA was avoided. The postoperative clinical course was good, and there was no recurrence or long-term squeal. CONCLUSION: Electrophysiological monitoring might be useful when intraoperative anatomical findings of the hemodynamic structure are inadequate. Moreover, in our case, intraoperative changes in motor evoked potentials indicated the risk to occlude one of posterior SAs, although it is said that posterior circulation of spinal cord has ischemic tolerance. PMID- 26230542 TI - Lumbar Radiculopathy Confounded: Total Knee Arthroplasty Diminishes the Patellar Tendon Reflex. AB - STUDY DESIGN: Patellar tendon reflexes were elicited among patients who had had a unilateral total knee replacement, those planned for unilateral total knee replacement, and a cohort of controlled patients. Patellar tendon reflex (PTR) response was measured with surface electromyography. OBJECTIVE: The aim of this study was to determine if total knee arthroplasty significantly alters the PTR. SUMMARY OF BACKGROUND DATA: As part of the clinical evaluation of the spine, extremity reflexes are provoked. Reflex variation between right and left extremities can be a pathological finding in disease of the spine. It has been noted that in patients who have undergone total knee arthroplasty (TKA), the PTR is diminished on the operative side compared with the contralateral nonoperative side. PTR is part of the clinical exam when evaluating a patient for lumbar radiculopathy. METHODS: The right and left patellar tendon reflex intensities were measured by quadriceps surface electromyography in 3 groups of patients. Group 1 consisted of 21 patients with unilateral TKA who were at least 6 months postoperative. Group 2 consisted of 18 patients with unilateral severe knee arthritis indicated for TKA. Group 3, serving as the control group, included 20 patients with no evidence of knee arthritis in either knee. The average reflex response for each group was recorded and comparisons were then made between each group. RESULTS: Patients who have undergone unilateral TKA have a PTR on average of 55.1% of their contralateral uninvolved side. This is statistically significant when compared with reflexes in patients who are planned for unilateral total knee arthroplasty, 96.03% (P = 0.001) and when compared with patients without evidence for knee arthritis, 102.2% (P < 0.001). CONCLUSION: The results of this case control study show that TKAs do significantly diminish PTRs when compared with a contralateral uninvolved knee in the same patient. LEVEL OF EVIDENCE: 3. PMID- 26230545 TI - Comment on "Background Ionizing Radiation and the Risk of Childhood Cancer: A Census-Based Nationwide Cohort Study". PMID- 26230544 TI - 'It's all there in black and white' - or is it? Consumer perspectives on the proposed Australian Medicine Information Box over-the-counter label format. AB - BACKGROUND: Over-the-counter (OTC) labels help support safe medication use by consumers. In 2012, the Australian Therapeutic Goods Administration (TGA) released a consultation paper proposing OTC label standardization to improve label quality via implementation of the Medicine Information Box (MIB) label. However, consumer opinions of the MIB and standardization of OTC labelling remain unexplored. OBJECTIVE: To explore consumer perspectives of OTC label standardization and the proposed MIB. DESIGN: Mock MIB labels were developed by the research team, guided by the TGA consultation paper, and used as interview stimulus material. PARTICIPANTS AND SETTING: Semi-structured interviews were conducted with 38 Australian and 39 UK adult participants. Participant perspectives on OTC label standardization, opinions on the MIB and perceived improvements were explored. All interviews were audio-recorded with permission, transcribed verbatim, and the content thematically analysed. RESULTS: Participants expressed a range of opinions towards OTC label standardization, from welcoming standardization to concern that important details may be overlooked. The MIB was generally positively received due to its perceived good information design and ease of navigation. Participants requested reordering of information-specifically, for the active ingredient to be moved to a less prominent position. Suggested improvements centred on content and design changes, for example colour, pictograms, bolding. CONCLUSIONS: Participants felt positively towards OTC label standardization and saw the MIB as a feasible standardized format to implement for OTC labels. Although they appreciated its good information design, they felt further improvements to its content and design are required to enhance its quality and usability. PMID- 26230547 TI - An ex vivo experimental study of strain and stiffness of different cadaveric mandible condyle sizes. PMID- 26230546 TI - Towards Personalized Cardiology: Multi-Scale Modeling of the Failing Heart. AB - BACKGROUND: Despite modern pharmacotherapy and advanced implantable cardiac devices, overall prognosis and quality of life of HF patients remain poor. This is in part due to insufficient patient stratification and lack of individualized therapy planning, resulting in less effective treatments and a significant number of non-responders. METHODS AND RESULTS: State-of-the-art clinical phenotyping was acquired, including magnetic resonance imaging (MRI) and biomarker assessment. An individualized, multi-scale model of heart function covering cardiac anatomy, electrophysiology, biomechanics and hemodynamics was estimated using a robust framework. The model was computed on n=46 HF patients, showing for the first time that advanced multi-scale models can be fitted consistently on large cohorts. Novel multi-scale parameters derived from the model of all cases were analyzed and compared against clinical parameters, cardiac imaging, lab tests and survival scores to evaluate the explicative power of the model and its potential for better patient stratification. Model validation was pursued by comparing clinical parameters that were not used in the fitting process against model parameters. CONCLUSION: This paper illustrates how advanced multi-scale models can complement cardiovascular imaging and how they could be applied in patient care. Based on obtained results, it becomes conceivable that, after thorough validation, such heart failure models could be applied for patient management and therapy planning in the future, as we illustrate in one patient of our cohort who received CRT-D implantation. PMID- 26230548 TI - How to Be a Male at Different Elevations: Ecology of Intra-Sexual Segregation in the Trawling Bat Myotis daubentonii. AB - Intra-sexual segregation is a form of social segregation widespread among vertebrates. In the bat Myotis daubentonii, males are disproportionately abundant at higher elevations, while females are restricted to lower altitude. Intra-male segregation is also known to occur yet its ecological and behavioural determinants are unclear. We studied male segregation along a river in Central Italy where we tested the following predictions: 1. Upstream ( > 1000 m a.s.l.) males will rely on scarcer prey; 2. To deal with this limitation and exploit a cooler roosting environment, they will employ more prolonged and deeper torpor than downstream (< 900 m a.s.l.) males; 3. Body condition will be better in downstream males as they forage in more productive areas; 4. To cope with less predictable foraging opportunities, upstream males will use more habitat types. Consistent with our predictions, we found that prey were less common at higher altitudes, where bats exhibited prolonged and deeper torpor. Body condition was better in downstream males than in upstream males but not in all summer months. This result reflected a decrease in downstream males' body condition over the season, perhaps due to the energy costs of reduced opportunities to use torpor and/or intraspecific competition. Downstream males mainly foraged over selected riparian vegetation whereas upstream males used a greater variety of habitats. One controversial issue is whether upstream males are excluded from lower elevations by resident bats. We tested this by translocating 10 upstream males to a downstream roost: eight returned to the high elevation site in 1-2 nights, two persisted at low altitude but did not roost with resident bats. These results are consistent with the idea of segregation due to competition. Living at high altitude allows for more effective heterothermy and may thus be not detrimental for survival, but by staying at lower altitude males increase proximity to females and potentially benefit from summer mating opportunities. PMID- 26230549 TI - Effect of Integrated Water-Nutrient Management Strategies on Soil Erosion Mediated Nutrient Loss and Crop Productivity in Cabo Verde Drylands. AB - Soil erosion, runoff and related nutrient losses are a big risk for soil fertility in Cabo Verde drylands. In 2012, field trials were conducted in two agro-ecological zones to evaluate the effects of selected techniques of soil water management combined with organic amendments (T1: compost/manure + soil surfactant; T2: compost/animal or green manure + pigeon-pea hedges + soil surfactant; T3: compost/animal or green manure + mulch + pigeon-pea hedges) on nitrogen (N) and phosphorus (P) losses in eroded soil and runoff and on crop yields. Three treatments and one control (traditional practice) were tested in field plots at three sites with a local maize variety and two types of beans. Runoff and eroded soil were collected after each erosive rain, quantified, and analysed for NO3-N and PO4-P concentrations. In all treatments runoff had higher concentrations of NO3-N (2.20-4.83 mg L-1) than of PO4-P (0.02-0.07 mg L-1), and the eroded soil had higher content of PO4-P (5.27-18.8 mg g-1) than of NO3-N (1.30-8.51 mg g-1). The control had significantly higher losses of both NO3-N (5.4, 4.4 and 19 kg ha-1) and PO4-P (0.2, 0.1 and 0.4 kg ha-1) than the other treatments. T3 reduced soil loss, runoff and nutrient losses to nearly a 100% while T1 and T2 reduced those losses from 43 to 88%. The losses of NO3-N and PO4 P were highly correlated with the amounts of runoff and eroded soil. Nutrient losses from the applied amendments were low (5.7% maximum), but the losses in the control could indicate long-term nutrient depletion in the soil (19 and 0.4 kg ha 1 of NO3-N and PO4-P, respectively). T1-T3 did not consistently increase crop yield or biomass in all three sites, but T1 increased both crop yield and biomass. We conclude that T3 (combining crop-residue mulch with organic amendment and runoff hedges) is the best treatment for steep slope areas but, the pigeon pea hedges need to be managed for higher maize yield. T1 (combining organic amendment with soil surfactant) could be a better choice for flatter areas with deeper soils. PMID- 26230550 TI - Impact of Study Design on Reported Incidences of Acute Mountain Sickness: A Systematic Review. AB - AIMS: Published incidences of acute mountain sickness (AMS) vary widely. Reasons for this variation, and predictive factors of AMS, are not well understood. We aimed to identify predictive factors that are associated with the occurrence of AMS, and to test the hypothesis that study design is an independent predictive factor of AMS incidence. We did a systematic search (Medline, bibliographies) for relevant articles in English or French, up to April 28, 2013. Studies of any design reporting on AMS incidence in humans without prophylaxis were selected. Data on incidence and potential predictive factors were extracted by two reviewers and crosschecked by four reviewers. Associations between predictive factors and AMS incidence were sought through bivariate and multivariate analyses for different study designs separately. Association between AMS incidence and study design was assessed using multiple linear regression. RESULTS: We extracted data from 53,603 subjects from 34 randomized controlled trials, 44 cohort studies, and 33 cross-sectional studies. In randomized trials, the median of AMS incidences without prophylaxis was 60% (range, 16%-100%); mode of ascent and population were significantly associated with AMS incidence. In cohort studies, the median of AMS incidences was 51% (0%-100%); geographical location was significantly associated with AMS incidence. In cross-sectional studies, the median of AMS incidences was 32% (0%-68%); mode of ascent and maximum altitude were significantly associated with AMS incidence. In a multivariate analysis, study design (p=0.012), mode of ascent (p=0.003), maximum altitude (p<0.001), population (p=0.002), and geographical location (p<0.001) were significantly associated with AMS incidence. Age, sex, speed of ascent, duration of exposure, or history of AMS were inconsistently reported and therefore not further analyzed. CONCLUSIONS: Reported incidences and identifiable predictive factors of AMS depend on study design. PMID- 26230551 TI - [Differences by age in clinical features of inflammatory bowel disease]. AB - BACKGROUND: Approximately, 15% of patients with Inflammatory Bowel Disease (IBD) are diagnosed at 60 years of age or more. AIM: To characterize and compare clinical variables between patients with IBD aged 60 years or more and their younger counterparts. MATERIAL AND METHODS: Retrospective study based on a registry of IBD patients diagnosed between the years 1976 and 2014. RESULTS: Four hundred and nine IBD patients were included. Among them, 294 had Ulcerative Colitis (UC), 104 had Crohn's Disease (CD) and eleven had an indeterminate IBD. Forty-six patients (11.2%) were older than 60 years and 16 (3.9%) had been diagnosed after this age. When comparing patients by age, those aged 60 years or more had a higher frequency of CD and indeterminate IBD (p < 0.01) and a lower ileocolic location in CD (p = 0.02). Both groups were similar in terms of hospitalization due to IBD flare, surgery, use of steroids, immunosuppressive or biological therapies and drug-related adverse events. When analyzing age at diagnosis of IBD, patients diagnosed at ages of 60 years or more had a lower frequency of UC (p < 0.01), a higher frequency of exclusive colonic involvement (p = 0.01), and lower use of mesalamine (p < 0.01). There were no differences in drug-related adverse events, hospitalizations due to IBD flares and surgery according to age at diagnosis. CONCLUSIONS: In this population, clinical features of IBD in older patients were similar to those in younger patients. PMID- 26230552 TI - [Serum lipid levels in a group of cocaine dependent subjects in recent abstinence]. AB - BACKGROUND: Chronic cocaine users develop multiple potentially lethal ischemic vascular complications associated with accelerated atherosclerosis. AIM: To assess biochemical and lipid profiles among cocaine dependent subjects in recent abstinence. MATERIAL AND METHODS: A blood sample to measure blood count, biochemical and lipid profiles was obtained from 78 patients aged 19 to 53 years (78% males) who complied with DSM-IV criteria for cocaine dependency. Laboratory results were compared with a group of normal subjects. RESULTS: All cases had positive urinary cocaine, with a mean consumption lapse of 7.6 years. The frequency of smoking was higher in cases. Dependent males had higher body mass index than controls. Compared to controls, dependent females had significantly higher triglyceride (TG) levels and lower HDL cholesterol. Therefore the relation total/HDL cholesterol was higher (p = 0.0365). Dependent males had higher TG levels than their normal counterparts. Dependent subjects consuming cocaine base paste had higher TG levels. Total proteins, albumin, urea and blood urea nitrogen were lower in dependent subjects. Among males, serum creatinine was lower and blood urea was positively correlated with the daily amount of cocaine use (p = 0.03). After a month of strict abstinence, lipid profile was repeated in 27 patients and remained unchanged. CONCLUSIONS: Chronic cocaine use was associated with higher TG in both genders and lower HDL cholesterol in women when compared with a group of healthy counterparts. PMID- 26230553 TI - [Alcohol consumption patterns and genotypes determining alcohol tolerance in Chilean university students]. AB - BACKGROUND: Alleles involved in inefficient (ADH1B2*2 and ALDH2*2) or efficient (SNP6, ADH4 gene) alcohol metabolism may influence the risk of alcoholism. Alcoholism susceptibility has been classified as protector and risk-dependence phenotypes, associated with inefficient and efficient alcohol genetic metabolizing variants, respectively. AIM: To investigate the possible association between genetic protective and risk-dependence variants and alcohol intake patterns. MATERIAL AND METHODS: Saliva DNA samples were obtained and the AUDIT (Alcohol Use Disorders Identification Test) questionnaire was applied to 210 university students aged between 18 and 25 years old. RESULTS: No statistically significant association between protective or risk-dependence genetic variants and alcohol pattern intake was detected. However, new categories of alcohol intake patterns-not included in the AUDIT questionnaire-were identified. CONCLUSIONS: No association between the protector and risk-dependence phenotypes and patterns of alcohol consumption was detected in this sample of students. PMID- 26230554 TI - [Influence of bullying on the quality of life perception of Chilean students]. AB - BACKGROUND: Bullying has a negative impact on the perception of adolescents of their quality of life. AIM: To analyze the association between being bullied and health related quality of life in Chilean adolescents. MATERIAL AND METHODS: The bullying module of the KIDSCREEN 52 survey and the KIDSCREEN 10 survey to assess health related quality of life were applied to 7737 students aged 10 to 18 years. Social and demographic data, information about disability and type of school were also gathered. RESULTS: Fifteen percent of surveyed students were bullied. A lower quality of life perception increased by a factor of 2.6 among bullied students. It also increased by a factor of 4.4 among students with a low self esteem, by a factor of 3.1 among those who perceived their health status as regular or bad and by a factor of 1.4 among women. CONCLUSIONS: Bullying is associated with a lower quality of life perception among Chilean students. PMID- 26230555 TI - [Predictive value of conventional immuno-histochemical biomarkers in breast cancer]. AB - BACKGROUND: Pathological complete response (pCR) after neoadjuvant chemotherapy (NCT) in breast cancer (BC) identifies patients with good prognosis. AIM: To assess if the clinico-pathological subtype, determined by classic immunohistochemical (IHC) markers, is able to predict pCR and prognosis in BC patients treated with NCT. MATERIAL AND METHODS: One hundred thirty three BC patients aged 24-80 years, were treated with NCT. Clinico-pathological subtype was defined based on classic IHC markers. pCR was defined as the absence of invasive neoplastic cells in the breast and lymph nodes, on final breast surgery. RESULTS: pCR was achieved in 8.2% of patients, 3.5 and 19.5% in luminal and hormonal receptor (HR) negative tumors respectively (p < 0.01). Median follow-up was 72.6 months (3.5-190). Patients who achieved pCR had higher overall survival (OS) (p = 0.04). A univariate analysis revealed that size of the tumor, ratio of metastatic to examined lymph nodes and absence of HR were significant predictors of pCR. These findings were not replicated in the multivariate analyses. CONCLUSIONS: Clinico-pathological subtypes were independent prognostic factors for pCR and OS in BC patients in our cohort. These findings support using classic and cheap biomarkers as a predictive tool for NCT in BC. PMID- 26230556 TI - [Psychometric properties of the diabetes mellitus 2 treatment adherence scale version III (EATDM-III) adapted for Chilean patients]. AB - BACKGROUND: The Diabetes Mellitus 2 treatment adherence scale version III (EATDM III) was devised in Costa Rica. Its seven factors are family support, community organization and support, physical exercise, medical control, hygiene and self care and assessment of physical condition. AIM: To assess the psychometric properties of the scale in Chilean patients. MATERIAL AND METHODS: The results of the EATDM-III scale, applied to 274 patients with Diabetes Mellitus 2 aged 59 +/- 11 years (59% women), were analyzed. Reliability, item, exploratory and confirmatory factorial analyses were carried out both in the initial and the proposed model. RESULTS: We propose a version of 30 items grouped in six dimensions, improving the fit indices obtained with the original scale. The review of item factor loadings shows that all are appropriate both in magnitude and statistical significance, with values between 0.46 and 0.93. Internal consistency measured by Cronbach's alpha, was 0.85 for the total scale. CONCLUSIONS: The adapted EATDM-III scale is reliable and can be used to assess treatment adherence in Chilean patients. PMID- 26230557 TI - [Effects of small-sided exercises on body composition and maximal oxygen uptake in adolescents]. AB - BACKGROUND: The regular practice of physical activity contributes to weight control and improves maximal oxygen uptake (VO2max), socialization and quality of life. AIM: To determine the effect of moderate-to-vigorous physical activity on body composition and VO2max in a group of overweight school-age males. MATERIAL AND METHODS: We studied fifty-five overweight males aged 15.6 +/- 0.7 years. Participants were divided in two groups (experimental and control groups). The intervention in the experimental group was the practice of small-sided games during 60 minutes, two days per week and during 11 weeks. At baseline and the end of the intervention, body composition was measured using bioimpedance and VO2max was calculated using the Course Navette test. RESULTS: A 7% reduction in the percentage of body fat and a 9% increase in VO2max were observed in the experimental group (p < 0.01). No changes were recorded in the control group. CONCLUSIONS: Eleven weeks of small-sided exercises performed twice per week increased VO2max and reduced fat mass in overweight adolescents. PMID- 26230559 TI - [Preoperative evaluation and predictors of mortality in lung cancer resection]. AB - Surgical resection of lung cancer, the only available curative option today, is strongly associated with mortality. The goal during the perioperative period is to identify and evaluate appropriate candidates for lung resection in a more careful way and reduce the immediate perioperative risk and posterior disability. This is a narrative review of perioperative risk assessment in lung cancer resection. Instruments designed to facilitate decision-making have been implemented in recent years but with contradictory results. Cardiovascular risk assessment should be the first step before a potential lung resection, considering that most of these patients are old, smokers and have atherosclerosis. Respiratory mechanics determined by postoperative forced expiratory volume in the first second (FEV1), the evaluation of the alveolar capillary membrane by diffusing capacity of carbon monoxide and cardiopulmonary function measuring the maximum O2 consumption, will give clues about the patient's respiratory and cardiac response to stress. With these assessments, the patient and its attending team can reach a treatment decision balancing the perioperative risk, the chances of survival and the pulmonary long-term disability. PMID- 26230558 TI - [Reactivity and evolution of 4022 patch tests in Chilean patients with contact dermatitis]. AB - BACKGROUND: Allergic Contact Dermatitis is a classic delayed hypersensitivity reaction. AIM: To study the reactivity and evolution in Chilean patients by gender, using the standard European patch test. MATERIALS AND METHODS: The results of the European standard patch test applied to 4,022 patients aged 1 to 93 years (64% female) with Allergic Contact Dermatitis, diagnosed between January 1995 and August 2011, were retrospectively analyzed. RESULTS: From a total of 4,022 patients, 2,439 (60.6%) had a positive reaction. Among reactive patients, 1,854 (76.04%) were female and 584 (23.96%) male. The most common positive allergens were nickel (35.3%), cobalt (15.1%), fragrance mix (14%), chromium (8.7%) and balsam of Peru (8.5%). In females, nickel was the most common reactive antigen (34.28%), and in males, fragrance mix (15.7%). During the period 2003 2011, an increased reactivity to nickel (26.6%) and a decreased reactivity to p phenylenediamine (29.6%) and fragrance (42.8%), was observed. CONCLUSIONS: Fragrance mix is the most common reactive allergen in males and the third for females. Nickel is the leading allergen in the female group and the second of importance for males, making it the most significant allergen for the Chilean population. We also observed that the reactivity of some allergens evolves and varies over time. PMID- 26230560 TI - [Transition to adulthood of adolescents with inflammatory bowel disease]. AB - Inflammatory bowel disease (IBD) is a prevalent chronic disorder, often diagnosed during childhood. Studies have suggested that the incidence of IBD in this group of patients is increasing. Children and adolescents with IBD frequently have more extensive and severe disease than adults. Transition is an important concept to ensure optimal health care management of adolescents and young adult patients with chronic physical and medical conditions. During this process there is a change in knowledge, attitudes and behavior towards the disease with a responsibility that gradually shifts from parents to the patient. The success of the transition process depends on the patient, pediatric and adult gastroenterologists. Thus, providers need to understand how to start, maintain and finish this process. When transition process is coordinated, staged and well planned, the adolescent and young adult will acquire the tools needed to successfully self-manage his or her own medical condition. Rather than a universal model of transition, each institution needs to adapt the most efficient model. The aim of this article is to review concepts pertinent to transition management for adolescents and young adults with IBD. PMID- 26230561 TI - [The Chilean Health Care System: the task ahead]. AB - The most important event in Chilean public health in the XXth Century was the creation of the National Health Service (NHS), in 1952. Systematic public policies for the promotion of health, disease prevention, medical care, and rehabilitation were implemented, while a number of more specific programs were introduced, such as those on infant malnutrition, complementary infant feeding, medical control of pregnant women and healthy infants, infant and adult vaccination, and essential sanitation services. In 1981, a parallel private health care system was introduced in the form of medical care financial institutions, which today cover 15% of the population, as contrasted with the public system, which covers about 80%. From 1952 to 2014, public health care policies made possible a remarkable improvement in Chile's health indexes: downward trends in infant mortality rate (from 117.8 to 7.2 x 1,000 live births), maternal mortality (from 276 to 18.5 x 100,000), undernourished children < 5 years old (from 63% to 0.5%); and upward trends in life expectancy at birth (from 50 to 79,8 years), professional hospital care of births (from 35% to 99.8%), access to drinking water (from 52% to 99%), and access to sanitary sewer (from 21% to 98.9%). This went hand in hand with an improvement in economic and social indexes: per capita income at purchasing power parity increased from US$ 3,827 to US$ 20,894 and poverty decreased from 60% to 14.4% of the population. Related indexes such as illiteracy, average schooling, and years of primary school education, were significantly improved as well. Nevertheless, compared with OECD countries, Chile has a relatively low public investment in health (45.7% of total national investment), a deficit in the number of physicians (1.7 x 1,000 inhabitants) and nurses (4.8 x 1,000), in the number of hospital beds (2.1 x 1,000), and in the availability of generic drugs in the market (30%). Chile and the USA are the two OECD countries with the lowest public investment in health. A generalized dissatisfaction with the current Chilean health care model and the need of the vast majority of the population for timely access to acceptable quality medical care are powerful arguments which point to the need for a universal public health care system. The significant increase in public expenditure on health care which such a system would demand requires a sustainable growth of the Chilean economy. PMID- 26230562 TI - [Painting realism and medicine: the two surgical clinics of Thomas Eakins]. AB - Realism is a painting style that began with Millet and Courbet in politically convulsed France in the middle of the nineteenth century. In the second half of that century, the pragmatic and democratic tradition of the United States fostered the careers of many realist painters, including that of Thomas Eakins. Eakins, trained in France, developed his career completely associated with Philadelphia at a time when this city was in the vanguard of American emerging industry, culture and medicine. Eakins "The clinic of Dr. Gross" and the "The clinic of Dr. Agnew" are icons of these developments and symbolize a perfect union of art and medicine. Both paintings permit the viewer to appreciate the artist's mastery, originality and Americanism while simultaneously tracking the progress of surgery as evidenced by the introduction of asepsis, anesthesia and nursing. Eakins mastery is revealed by its use of some European Old Masters approaches to portray medical professionals undertaking their daily duties in their work environments with critical and unadorned vision. This combination of vision and skills led Eakins to create a highly original yet analytical art. Unfortunately, his representations were far ahead of his time and resulted in under appreciation of his paintings and a censorious reaction to their content. His contemporaries rejection of Eakins work negatively affected his career as a painter, as a teacher and even his private life. This judgment was overturned in subsequent years and by the twentieth century Eakins was recognized as an American master without parallel. PMID- 26230563 TI - [Qualitative impact of a training program on depressive disorders for primary care physicians]. AB - BACKGROUND: There are suggestions that, despite training efforts for Primary Health Care physicians, difficulties in making accurate diagnoses and timely treatments persist. AIM: To evaluate the impact of a new training model in Depressive disorders integrated with Mindful Practice, on the diagnostic and therapeutic skills of primary care general physicians. MATERIAL AND METHODS: A voluntary sample of 56 general physicians was studied. The design of this study was experimental and randomized, with two groups attending theoretical sessions followed by differing workshops that were carried out in a parallel fashion. The Quantitative phase of this study considered measuring the impact of training in physician's skills. The Qualitative phase included nine semi-structured interviews and Qualitative Content Analysis. This paper reports the results of the interviews. RESULTS: As a consequence of training sessions, physicians learned that above the mental health problems, other issues such as self-efficacy and self-confidence are important for the management of depressive patients. CONCLUSIONS: This qualitative study shows that physicians are obtaining significant benefits from their training sessions. PMID- 26230564 TI - [Hyper-immunoglobulin E syndrome: report of one case]. AB - The Hyperimmunoglobulin E syndrome (HIES) is a rare sporadic or autosomal dominant immune and connective tissue disorder characterized by chronic eczema, cutaneous abscesses, pneumonias, invasive infections, high levels of Immunoglobulin E, primary teeth retention and bone abnormalities. We report a 24 year-old male with a history of cutaneous abscesses and esophageal candidiasis. He was admitted due to a left gluteal cellulitis. During the fifth day of hospitalization he presented a distal necrosis of the fourth finger of the right hand. Laboratory results showed high levels of IgE and positive cryoglobulins. The patient was discharged and was admitted again five days later with a new gluteal abscess. IgE levels were even higher. Applying Grimbacher scale, the diagnosis of Hyperimmunoglobulin E syndrome was reached. PMID- 26230565 TI - [Septic arthritis of the temporomandibular joint: report of one case]. AB - Septic arthritis of the temporomandibular joint (TMJ) is an uncommon condition, caused by hematic bacterial migration or direct migration of other head and neck infections. We report a 41 year old female who presented a right temporomandibular joint involvement, with bone destruction of the mandibular condyle and an infectious process spreading to the temporal space, following a necrotizing medial and external otitis with associated mastoiditis. A septic arthritis of the TMJ by continuity was diagnosed and treated with antimicrobials, TMJ arthrocentesis and occlusal stabilization, with a positive evolution. However, the patient remains in control due a secondary TMJ osteoarthritis caused by the septic arthritis. PMID- 26230566 TI - [Treatment of thrombotic thrombocytopenic purpura with rituximab. Report of eight cases]. AB - Thrombotic thrombocytopenic purpura, an immune/non-immune thrombotic microangiopathy (TTP/TMA) is associated with high morbidity and mortality, even with appropriate treatment. In patients refractory to standard treatment with plasmapheresis there is no certainty about the best therapeutic strategy. This report shows our experience in eight refractory patients who survived after treatment with rituximab. PMID- 26230567 TI - [Missing information in medical records: beyond the quality of registration]. PMID- 26230568 TI - [Flow sheet to evaluate Post Graduate Teaching Programs in Medicine]. PMID- 26230569 TI - [Latent variable theory in research in health topics]. PMID- 26230571 TI - Inducible Lentivirus-Mediated Expression of the Oct4 Gene Affects Multilineage Differentiation of Adult Human Bone Marrow-Derived Mesenchymal Stem Cells. AB - The octamer-binding transcription factor 4 (Oct4) gene plays an important role in maintaining the undifferentiated state of embryonic stem cells (ESCs) and reprogramming adult somatic cells into induced pluripotent stem cells (iPSCs). In the present study, we transduced human bone marrow-derived mesenchymal stem cells (hMSCs) using tetracycline-on (Tet-On) lentiviruses carrying human Oct4 to examine the effects of regulated expression of human Oct4 on the proliferation and differentiation of hMSCs. hMSCs were efficiently transduced by Tet-On lentiviruses to express regulated levels of human Oct4 with doxycycline (Dox), as examined by immunofluorescent staining, flow cytometry, and quantitative real time-PCR (qRT-PCR) assays. Ectopic expression of Oct4 in transduced hMSCs increased the ability of colony formation. Continued expression of Oct4 further enhanced adipogenic differentiation of hMSCs, and transient expression of Oct4 sufficiently enhanced osteogenic differentiation of hMSCs. qRT-PCR analysis showed that ectopic expression of Oct4 in transduced hMSCs temporally increased the expression of Sox2 and c-Myc. Interestingly, ectopic expression of Oct4 reduced neuronal differentiation of hMSCs when incubated under neuronal differentiation conditions. Our results suggest that ectopic expression of human Oct4 leads to temporal changes in multilineage differentiation of hMSCs and may inhibit neuronal differentiation of hMSCs. PMID- 26230572 TI - Universal versus genotype-guided use of direct oral anticoagulants in atrial fibrillation patients: a decision analysis. AB - AIM: This study aims to compare clinical and economic outcomes of CYP2C9 and VKORC1 genotype-guided (PG-DOAC) versus universal use of direct oral anticoagulant (DOAC) for stroke prevention in patients with atrial fibrillation (AF). METHODS: Outcomes of oral anticoagulation therapy were simulated using life long Markov modeling. In PG-DOAC, patients with genotype of high or low warfarin sensitivity were treated with DOAC, and patients with normal warfarin sensitivity genotype received warfarin. RESULTS: Expected quality-adjusted life-years (QALYs) and cost of DOAC were higher than PG-DOAC. Incremental cost per QALY (ICER) of DOAC versus PG-DOAC was 314,129 USD/QALY, exceeding willingness-to-pay threshold (50,000 USD/QALY). CONCLUSION: Using individual genotype to guide the use of DOAC versus warfarin appears to be the preferred strategy. PMID- 26230573 TI - Prostatic abscess caused by Mycobacterium tuberculosis and Escherichia coli in a patient with acquired immunodeficiency syndrome. PMID- 26230574 TI - Acute kidney injury, an Id reaction and HSP90. PMID- 26230575 TI - Palmomental reflex. PMID- 26230577 TI - Reactivity and Speciation of Anti-Diabetic Vanadium Complexes in Whole Blood and Its Components: The Important Role of Red Blood Cells. AB - Reactions with blood components are crucial for controlling the antidiabetic, anticancer, and other biological activities of V(V) and V(IV) complexes. Despite extensive studies of V(V) and V(IV) reactions with the major blood proteins (albumin and transferrin), reactions with whole blood and red blood cells (RBC) have been studied rarely. A detailed speciation study of Na3[V(V)O4] (A), K4[V(IV)2O2(citr)2].6H2O (B; citr = citrato(4-)); [V(IV)O(ma)2] (C; ma = maltolato(-)), and (NH4)[V(V)(O)2(dipic)] (D; dipic = pyridine-2,6 dicarboxylato(2-)) in whole rat blood, freshly isolated rat plasma, and commercial bovine serum using X-ray absorption near-edge structure (XANES) spectroscopy is reported. The latter two compounds are potential oral antidiabetic drugs, and the former two are likely to represent their typical decomposition products in gastrointestinal media. XANES spectral speciation was performed by principal component analysis and multiple linear regression techniques, and the distribution of V between RBC and plasma fractions was measured by electrothermal atomic absorption spectroscopy. Reactions of A, C, or D with whole blood (1.0 mM V, 1-6 h at 310 K) led to accumulation of ~50% of total V in the RBC fraction (~10% in the case of B), which indicated that RBC act as V carriers to peripheral organs. The spectra of V products in RBC were independent of the initial V complex, and were best fitted by a combination of V(IV)-carbohydrate (2-hydroxyacid moieties) and/or citrate (65-85%) and V(V) protein (15-35%) models. The presence of RBC created a more reducing environment in the plasma fraction of whole blood compared with those in isolated plasma or serum, as shown by the differences in distribution of V(IV) and V(V) species in the reaction products of A-D in these media. At physiologically relevant V concentrations (<50 MUM), this role of RBC may promote the formation of V(III) transferrin as a major V carrier in the blood plasma. The results reported herein have broad implications for the roles of RBC in the transport and speciation of metal pro-drugs that have broad applications across medicine. PMID- 26230576 TI - Symptoms of Insomnia and Sleep Duration and Their Association with Incident Strokes: Findings from the Population-Based MONICA/KORA Augsburg Cohort Study. AB - OBJECTIVE: To examine the relationship between symptoms of insomnia and sleep duration and incident total (non-fatal plus fatal) strokes, non-fatal strokes, and fatal strokes in a large cohort of men and women from the general population in Germany. METHODS: In four population-based MONICA (monitoring trends and determinants in cardiovascular disease)/KORA (Cooperative Health Research in the Region of Augsburg) surveys conducted between 1984 and 2001, 17,604 men and women (aged 25 to 74 years) were asked about issues like sleep, health behavior, and medical history. In subsequent surveys and mortality follow-ups, incident stroke cases (cerebral hemorrhage, ischemic stroke, transient ischemic attack, unknown stroke type) were gathered prospectively until 2009. Sex-specific hazard ratios (HR) and their 95% confidence intervals (CI) were estimated using sequential Cox proportional hazards regression models. RESULTS: During a mean follow-up of 14 years, 917 strokes (710 non-fatal strokes and 207 fatal strokes) were observed. Trouble falling asleep and difficulty staying asleep were not significantly related to any incident stroke outcome in either sex in the multivariable models. Among men, the HR for the association between short (<=5 hours) and long (>=10 hours) daily sleep duration and total strokes were 1.44 (95% CI: 1.01-2.06) and 1.63 (95% CI: 1.16-2.29), after adjustment for basic confounding variables. As for non-fatal strokes and fatal strokes, in the analyses adjusted for age, survey, education, physical activity, alcohol consumption, smoking habits, body mass index, hypertension, diabetes, and dyslipidemia, the increased risks persisted, albeit somewhat attenuated, but no longer remained significant. Among women, in the multivariable analyses the quantity of sleep was also not related to any stroke outcome. CONCLUSION: In the present study, symptoms of insomnia and exceptional sleep duration were not significantly predictive of incident total strokes, non-fatal strokes, and fatal strokes in either sex. PMID- 26230578 TI - Morphological differences in the mirror neuron system in Williams syndrome. AB - Williams syndrome (WS) is a genetic condition characterized by an overly gregarious personality, including high empathetic concern for others. Although seemingly disparate from the profile of autism spectrum disorder (ASD), both are associated with deficits in social communication/cognition. Notably, the mirror neuron system (MNS) has been implicated in social dysfunction for ASD; yet, the integrity of this network and its association with social functioning in WS remains unknown. Magnetic resonance imaging (MRI) methods were used to examine the structural integrity of the MNS of adults with WS versus typically developing (TD) individuals. The Social Responsiveness Scale (SRS), a tool typically used to screen for social features of ASD, was also employed to assess the relationships between social functioning with the MNS morphology in WS participants. WS individuals showed reduced cortical surface area of MNS substrates yet relatively preserved cortical thickness as compared to TD adults. Increased cortical thickness of the inferior parietal lobule (IPL) was associated with increased deficits in social communication, social awareness, social cognition, and autistic mannerisms. However, social motivation was not related to anatomical features of the MNS. Our findings indicate that social deficits typical to both ASD and WS may be attributed to an aberrant MNS, whereas the unusual social drive marked in WS is subserved by substrates distinct from this network. PMID- 26230579 TI - Analysis of Stress-Responsive Gene Expression in Cultivated and Weedy Rice Differing in Cold Stress Tolerance. AB - Rice (Oryza sativa L.) cultivars show impairment of growth in response to environmental stresses such as cold at the early seedling stage. Locally adapted weedy rice is able to survive under adverse environmental conditions, and can emerge in fields from greater soil depth. Cold-tolerant weedy rice can be a good genetic source for developing cold-tolerant, weed-competitive rice cultivars. An in-depth analysis is presented here of diverse indica and japonica rice genotypes, mostly weedy rice, for cold stress response to provide an understanding of different stress adaptive mechanisms towards improvement of the rice crop performance in the field. We have tested a collection of weedy rice genotypes to: 1) classify the subspecies (ssp.) grouping (japonica or indica) of 21 accessions; 2) evaluate their sensitivity to cold stress; and 3) analyze the expression of stress-responsive genes under cold stress and a combination of cold and depth stress. Seeds were germinated at 25 degrees C at 1.5- and 10-cm sowing depth for 10d. Seedlings were then exposed to cold stress at 10 degrees C for 6, 24 and 96h, and the expression of cold-, anoxia-, and submergence-inducible genes was analyzed. Control plants were seeded at 1.5cm depth and kept at 25 degrees C. The analysis revealed that cold stress signaling in indica genotypes is more complex than that of japonica as it operates via both the CBF-dependent and CBF independent pathways, implicated through induction of transcription factors including OsNAC2, OsMYB46 and OsF-BOX28. When plants were exposed to cold + sowing depth stress, a complex signaling network was induced that involved cross talk between stresses mediated by CBF-dependent and CBF-independent pathways to circumvent the detrimental effects of stresses. The experiments revealed the importance of the CBF regulon for tolerance to both stresses in japonica and indica ssp. The mechanisms for cold tolerance differed among weedy indica genotypes and also between weedy indica and cultivated japonica ssp. as indicated by the up/downregulation of various stress-responsive pathways identified from gene expression analysis. The cold-stress response is described in relation to the stress signaling pathways, showing complex adaptive mechanisms in different genotypes. PMID- 26230580 TI - Gout and Risk of Myocardial Infarction: A Systematic Review and Meta-Analysis of Cohort Studies. AB - INTRODUCTION: A high incidence of myocardial infarction among patients with gout has been suggested by several observational studies. We performed a meta-analysis to evaluate the association between gout and the risk of myocardial infarction. MATERIALS AND METHODS: The PubMed and Embase databases were searched from inception to October 2014 for cohort studies that evaluating the association between gout and the risk of myocardial infarction. Summary estimates were derived using a random-effects model and reported as relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: Five studies involving 8,656,413 participants with a total of 1000 MI events were included. Overall, gout was associated with an increased risk of myocardial infarction (RR 1.45; 95% CI, 1.19 1.75; p<0.001), and the association referred to non-fatal myocardial infarction (RR 1.29; 95% CI, 1.19-1.39; p <0.001) but not fatal myocardial infarction (RR 1.11; 95% CI, 0.96-1.28; p = 0.174). The increased risk was observed in both women (RR 1.62; 95% CI, 1.18-2.21; p = 0.003) and men (RR 1.45; 95% CI, 1.21 1.74; p <0.001). Stratified analysis revealed a gradual increase in myocardial infarction risk with a younger age of gout onset (age 20-44 years old (RR 2.82; 95% CI, 1.38-5.79; p = 0.05); 45-69 years old (RR 1.85; 95% CI, 1.22-2.82; p = 0.04); >=70 years old (RR 1.52; 95% CI, 1.22-1.88; p <0.001)). CONCLUSION: This meta-analysis suggests that patients with gout have an increased risk of myocardial infarction. PMID- 26230582 TI - The Adaptive Change of HLA-DRB1 Allele Frequencies Caused by Natural Selection in a Mongolian Population That Migrated to the South of China. AB - Pathogen-driven balancing selection determines the richness of human leukocyte antigen (HLA) alleles. Changes in the pathogen spectrum may cause corresponding changes in HLA loci. Approximately 700 years ago, a Mongolian population moved from the north of China to the Yunnan region in the south of China. The pathogen spectrum in the south of China differs from that in the north. In this study, changes in the HLA genes in the Yunnan Mongolian population, as well as the underlying mechanism, were investigated. A sequence-based typing method (SBT) was used to genotype HLA-DRB1 in 470 individuals from two Mongolian populations and another five ethnic groups. Meanwhile, 10 autosomal short tandem repeats (STRs) were genotyped to assess the influence of genetic background on HLA-DRB1 frequencies. The frequencies of certain alleles changed significantly in the Mongolian population that migrated to Yunnan. For example, DRB1*12:02:01 increased from 6.1% to 35.4%. STR analysis excluded the possibility of a recent bottleneck and indicated that 50% of the genetic consistency between northern and southern Mongolians; Tajima's D value for HLA-DRB1 exon2 and dN/dS analysis showed that the HLA-DRB1 genes in both Mongolian populations were under balancing selection. However, the sites under natural selection changed. We proposed that the dramatically change of HLA frequencies in southern Mongolian was caused by a combination of inter-population gene flow and natural selection. Certain diseases specific to the south of China, such as malaria, may be the driving force behind the enhanced DRB1*12:02:01 frequency. PMID- 26230581 TI - Feasibility Study: Comparison of Frontal Cortex Needle Core Versus Open Biopsy for Detection of Characteristic Proteinopathies of Neurodegenerative Diseases. AB - The clinical diagnosis and classification of neurodegenerative diseases based on clinical examination or available biomarkers are currently insufficiently accurate. Although histologic examination is considered the gold standard for diagnosis, brain biopsies have been avoided because of the high risk-benefit ratio. However, brain biopsies have previously been performed with a craniotomy and excision of approximately 1 cm of cerebral cortex tissue, and it is possible that needle core brain biopsies would have a lower morbidity and mortality risk. Here, we compared the ability of simulated needle core biopsy versus simulated open biopsy to detect the frontal cortex histopathology associated with common neurodegenerative diseases in the elderly using 144 autopsy-proven cases. Simulated needle core biopsy, as compared with simulated open biopsy, gave close to 90% sensitivity and specificity for identifying graded densities of beta amyloid and neuritic plaques, neurofibrillary tangles, phosphorylated alpha synuclein, and phosphorylated TDP-43 pathology. This study shows that the presence and densities of the most common molecular pathologies may be histopathologically assessed in simulated frontal cortex needle biopsies, with accuracy very close to that obtained by open cortical biopsy. An accurate estimation of the morbidity and mortality risk associated with cortical needle core biopsy will require specifically designed clinical trials in appropriate subjects. PMID- 26230583 TI - Differential Gene Expression in Colon Tissue Associated With Diet, Lifestyle, and Related Oxidative Stress. AB - Several diet and lifestyle factors may impact health by influencing oxidative stress levels. We hypothesize that level of cigarette smoking, alcohol, anti inflammatory drugs, and diet alter gene expression. We analyzed RNA-seq data from 144 colon cancer patients who had information on recent cigarette smoking, recent alcohol consumption, diet, and recent aspirin/non-steroidal anti-inflammatory use. Using a false discovery rate of 0.1, we evaluated gene differential expression between high and low levels of exposure using DESeq2. Ingenuity Pathway Analysis (IPA) was used to determine networks associated with de regulated genes in our data. We identified 46 deregulated genes associated with recent cigarette use; these genes enriched causal networks regulated by TEK and MAP2K3. Different differentially expressed genes were associated with type of alcohol intake; five genes were associated with total alcohol, six were associated with beer intake, six were associated with wine intake, and four were associated with liquor consumption. Recent use of aspirin and/or ibuprofen was associated with differential expression of TMC06, ST8SIA4, and STEAP3 while a summary oxidative balance score (OBS) was associated with SYCP3, HDX, and NRG4 (all up-regulated with greater oxidative balance). Of the dietary antioxidants and carotenoids evaluated only intake of beta carotene (1 gene), Lutein/Zeaxanthine (5 genes), and Vitamin E (4 genes) were associated with differential gene expression. There were similarities in biological function of de-regulated genes associated with various dietary and lifestyle factors. Our data support the hypothesis that diet and lifestyle factors associated with oxidative stress can alter gene expression. However genes altered were unique to type of alcohol and type of antioxidant. Because of potential differences in associations observed between platforms these findings need replication in other populations. PMID- 26230585 TI - Erratum. PMID- 26230584 TI - No association between body composition and cognition in ambulatory persons with multiple sclerosis: A brief report. AB - There is evidence that body fat is inversely associated with cognitive functioning in adults from the general population, and this has been associated with systemic inflammation. The association between body fat and cognition might further be augmented in the presence of an immune-mediated, inflammatory disease such as multiple sclerosis (MS). This cross-sectional study investigated the associations between objective measures of body composition and cognitive function in 60 persons with MS. Participants underwent a neurological examination for generating Expanded Disability Status Scale scores, followed by the Brief International Cognitive Assessment in Multiple Sclerosis neuropsychological battery for measurement of cognitive processing speed, verbal learning and memory, and visual learning and memory. Whole-body fat mass, percent body fat, lean body mass, and bone mineral density were measured using dual-energy X-ray absorptiometry. Whole-body fat mass and percent body fat were not associated with any cognitive outcome (all p > 0.41). However, lean body mass was associated with cognitive processing speed (p < 0.03), and bone mineral density was associated with cognitive processing speed and verbal learning and memory. Those associations were attenuated and nonsignificant after controlling for age and Expanded Disability Status Scale scores (p > 0.13). Body composition might not represent a target of interventions for improving cognitive processing speed or learning and memory in MS. PMID- 26230586 TI - Classification of Psammoma Bodies in the Revised College of American Pathologists Thyroid Cancer Protocol. PMID- 26230587 TI - In Reply. PMID- 26230588 TI - Changes of Ischemia- Modified Albumin During the Postoperative Period in Patients With Colorectal Surgery. PMID- 26230589 TI - Standardized Molecular Monitoring for Variant BCR-ABL1 Transcripts in Chronic Myeloid Leukemia. PMID- 26230590 TI - Brief Updates in Lung Pathology. PMID- 26230591 TI - Malignant Mesothelioma Diagnosis. AB - CONTEXT: Malignant mesothelioma is a relatively rare pleural tumor that may mimic benign mesothelial lesions and various other tumors including carcinomas and sarcomas. This makes the diagnosis challenging for the pathologist. OBJECTIVE: To provide a brief but useful update on the immunohistochemical, cytogenetic, and molecular markers that are currently available for the diagnosis of malignant mesothelioma. DATA SOURCES: Reference materials including peer-reviewed publications, text books, and consensus opinion reports among pathologists. CONCLUSIONS: It is important to correlate histologic findings on adequate biopsy samples with clinical and radiologic features. Useful diagnostic mesothelial markers include calretinin, WT-1, cytokeratin 5/6, and D2-40 (podoplanin). It is recommended that at least 2 mesothelial and 2 carcinoma markers with greater than 80% sensitivity and specificity be used for the diagnosis of mesothelioma when all clinical, radiologic, and histologic features are concordant. p16 deletion is reported in up to 70% of primary epithelioid and 90% to 100% of sarcomatoid pleural mesotheliomas. Presence of this homozygous gene deletion is so far the best indicator of mesothelioma. To date, this deletion has not been reported in any benign mesothelial lesion. The impact of various histologic patterns on the clinical and prognostic aspects of mesothelioma is addressed. The pleomorphic pattern, when present in more than 10% of tumor, translates into a highly aggressive behavior and is associated with poor survival. Recent studies have shown that the high-grade subgroup of deciduoid mesothelioma with pleomorphic histologic pattern also has a more aggressive clinical course. Nuclear grade (combination of nuclear atypia and mitotic count) may also prove to be an independent prognostic factor. PMID- 26230592 TI - The Demise of the Term Bronchioloalveolar Carcinoma. AB - CONTEXT: Bronchioloalveolar carcinoma is a term that has served lung pathology well for almost a century; however, more accurate terms have recently been suggested to better characterize the various lesions that have formerly all been considered bronchioloalveolar carcinoma. OBJECTIVES: To evaluate the origin and history of the term bronchioloalveolar carcinoma and to compare the term's traditional uses with current understanding and terminology of lung lesions formerly termed bronchioloalveolar carcinoma. DATA SOURCES: Review of the literature pertaining to bronchioloalveolar carcinoma. CONCLUSIONS: Bronchioloalveolar carcinoma has been an extremely useful term for many decades; however, it has now obtained respected obsolescence. Novel, more medically appropriate terms have been suggested for the group of lesions formerly termed bronchioloalveolar carcinoma, and these newer terms should now be routinely used. PMID- 26230593 TI - Interstitial Lung Diseases That Are Difficult to Classify: A Review of Bronchiolocentric Interstitial Lung Disease. AB - CONTEXT: Idiopathic bronchiolocentric interstitial pneumonia, airway-centered interstitial fibrosis, centrilobular fibrosis, and bronchiolitis interstitial pneumonia are increasingly recognized histopathologic variants of idiopathic interstitial pneumonia that are difficult to fit within existing classification schemes. OBJECTIVE: To review and analyze the appropriate literature that describes the spectrum of histopathologic changes in these conditions, in an effort to ascertain similarities as well as their differences. In addition, we examined associations with hypersensitivity, cigarette smoking, and survival data. DATA SOURCES: Relevant and peer-reviewed literature indexed in PubMed (National Library of Medicine) coupled with experience gained by review of personal cases with appropriate histopathology constitute the basis of this study. CONCLUSIONS: As anticipated, the common link among the above-cited conditions is their bronchiolocentricity, with a predominance of either fibrosis or inflammation. Clear-cut associations with hypersensitivity or cigarette smoking are not evident in this study. The airway-centered interstitial fibrosis variant of bronchiolocentric interstitial lung disease appears to have a poor outcome. PMID- 26230594 TI - Practices for Identifying and Rejecting Hemolyzed Specimens Are Highly Variable in Clinical Laboratories. AB - CONTEXT: Hemolysis is an important clinical laboratory quality attribute that influences result reliability. OBJECTIVE: To determine hemolysis identification and rejection practices occurring in clinical laboratories. DESIGN: We used the College of American Pathologists Survey program to distribute a Q-Probes-type questionnaire about hemolysis practices to Chemistry Survey participants. RESULTS: Of 3495 participants sent the questionnaire, 846 (24%) responded. In 71% of 772 laboratories, the hemolysis rate was less than 3.0%, whereas in 5%, it was 6.0% or greater. A visual scale, an instrument scale, and combination of visual and instrument scales were used to identify hemolysis in 48%, 11%, and 41% of laboratories, respectively. A picture of the hemolysis level was used as an aid to technologists' visual interpretation of hemolysis levels in 40% of laboratories. In 7.0% of laboratories, all hemolyzed specimens were rejected; in 4% of laboratories, no hemolyzed specimens were rejected; and in 88% of laboratories, some specimens were rejected depending on hemolysis levels. Participants used 69 different terms to describe hemolysis scales, with 21 terms used in more than 10 laboratories. Slight and moderate were the terms used most commonly. Of 16 different cutoffs used to reject hemolyzed specimens, moderate was the most common, occurring in 30% of laboratories. For whole blood electrolyte measurements performed in 86 laboratories, 57% did not evaluate the presence of hemolysis, but for those that did, the most common practice in 21 laboratories (24%) was centrifuging and visually determining the presence of hemolysis in all specimens. CONCLUSIONS: Hemolysis practices vary widely. Standard assessment and consistent reporting are the first steps in reducing interlaboratory variability among results. PMID- 26230595 TI - Comparison of 5 Immunohistochemical Markers of Hepatocellular Differentiation for the Diagnosis of Hepatocellular Carcinoma. AB - CONTEXT: Several immunohistochemical markers are available to establish the diagnosis of hepatocellular carcinoma. Judicious selection is essential to achieve a reliable diagnosis in limited tissue provided by liver biopsy. OBJECTIVE: To compare the efficacy of 5 hepatocellular markers for the diagnosis of hepatocellular carcinoma across various levels of differentiations. DESIGN: Immunohistochemistry for hepatocyte paraffin antigen 1 (Hep Par 1), polyclonal carcinoembryonic antigen (CEA), glypican-3, arginase-1, and bile salt export pump transporter was performed in 79 hepatocellular carcinomas, yielding 93 observations (13 well-differentiated [14%], 41 moderately differentiated [44%], and 39 poorly differentiated [42%] tumors). RESULTS: Arginase-1 and Hep Par 1 had the highest sensitivity for well-differentiated hepatocellular carcinoma, whereas arginase-1 and glypican-3 had the highest sensitivity for poorly differentiated hepatocellular carcinoma. When staining of more than 50% of the tumor was considered a positive result, arginase-1 remained the most sensitive marker for all differentiations, whereas sensitivity for Hep Par 1 in poorly differentiated hepatocellular carcinoma dropped to 30% and that of glypican-3 in well differentiated hepatocellular carcinoma was 15%. The addition of Hep Par 1 and/or polyclonal CEA to arginase-1 did not lead to an increase in sensitivity for any differentiation. The combined use of arginase-1 and glypican-3 yielded 100% sensitivity for poorly differentiated hepatocellular carcinoma. CONCLUSION: Arginase-1 was the most sensitive marker in all differentiations of hepatocellular carcinoma. Glypican-3 had high sensitivity for poorly differentiated cases and its combined use with arginase-1 enabled identification of nearly all cases of poorly differentiated hepatocellular carcinoma. Although bile salt export pump transporter has good overall sensitivity, it has a limited role in establishing hepatocellular differentiation when added to a panel of arginase-1 with either glypican-3 or Hep Par 1. PMID- 26230596 TI - Significance of MYD88 L265P Mutation Status in the Subclassification of Low-Grade B-Cell Lymphoma/Leukemia. AB - CONTEXT: Lymphoplasmacytic lymphoma (LPL), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) are well-defined clinicopathologic entities. However, distinguishing LPL from MZL and from atypical cases of CLL can sometimes be difficult because of overlapping features. Recent studies have identified a recurrent L265P mutation in the MYD88 gene in most cases of LPL. Although this represents a promising diagnostic marker for LPL, the mutation is also reported in rare cases of MZL and CLL (as well as other types of B-cell lymphoma). Detection rates for this mutation have varied depending on the analytic methodology. OBJECTIVE: To assess the diagnostic utility of MYD88 L265P mutation in diagnosing low-grade B-cell lymphomas. DESIGN: We developed a novel pyrosequencing assay for the MYD88 L265P mutation and assessed its diagnostic utility in 317 cases of low-grade B-cell lymphoma (45 LPL [14%], 53 MZL [17%], and 219 CLL [69%]). We incorporated formal clinical and pathologic review of selected cases to ensure the most accurate diagnosis and subclassification. RESULTS: The MYD88 L265P mutation was identified in 43 cases of LPL (96%), including 3 nonimmunoglobulin-M LPL cases. In contrast, the mutation was present in only 2 cases of MZL (4%), and 5 cases of CLL (2%). Thus, pyrosequencing for the MYD88 L265P mutation demonstrates a high clinical sensitivity and specificity to distinguish LPL from MZL and CLL. CONCLUSIONS: This study confirms the strong association of the MYD88 L265P mutation with LPL, as well as the existence of rare cases of small B-cell lymphoma that complicate this association. PMID- 26230597 TI - Development and Evaluation of a Logical Delta Check for Identifying Erroneous Blood Count Results in a Tertiary Care Hospital. AB - CONTEXT: Delta checks have been suggested to increase patient safety by identifying preanalytic and analytic errors, including wrong name mislabeling on the sample tube. OBJECTIVE: To implement an effective and practical complete blood cell count (CBC) delta check by optimizing specificity and sensitivity using weighted deltas of multiple parameters. DESIGN: The mean red blood cell volume (MCV) delta (>3.0 fL) check was retrospectively assessed. The composite CBC delta (CCD) test was formulated using serial same-patient CBC data and random interpatient CBCs. The logical delta check (LDC) ignores CCD failures due to platelet change only. The effect of LDC implementation was evaluated. RESULTS: The MCV delta check test recognized only 3 of 6 confessed mislabeled specimens in the initial review period, whereas all were identified using the CCD. The LDC flagged 2% (205 of 13 234) of eligible results, one-third as many as the MCV delta check. The CCD and LDC checks revealed 20 presumed or confirmed mislabeling events, only half of which were caught by the MCV delta check. Thirty-four percent of LDC failures not due to transfusion reflected problematic results, including presumed or confirmed wrongly labeled patient samples (36% of flags for real problems). Implementation of the LDC, requiring immediate verbal feedback to the caregivers, was associated with more retracted erroneous results in patients' medical records. CONCLUSIONS: The MCV delta check test was found not to have led to correction of errors in our laboratory due to impractically low specificity and sensitivity. The LDC is a useful tool for identifying preanalytic and analytic specimen problems, including wrong name mislabeling on the sample tube. PMID- 26230598 TI - Introducing 3-Dimensional Printing of a Human Anatomic Pathology Specimen: Potential Benefits for Undergraduate and Postgraduate Education and Anatomic Pathology Practice. AB - CONTEXT: Three-dimensional (3D) printing, a rapidly advancing technology, is widely applied in fields such as mechanical engineering and architecture. Three dimensional printing has been introduced recently into medical practice in areas such as reconstructive surgery, as well as in clinical research. Three dimensionally printed models of anatomic and autopsy pathology specimens can be used for demonstrating pathology entities to undergraduate medical, dental, and biomedical students, as well as for postgraduate training in examination of gross specimens for anatomic pathology residents and pathology assistants, aiding clinicopathological correlation at multidisciplinary team meetings, and guiding reconstructive surgical procedures. OBJECTIVE: To apply 3D printing in anatomic pathology for teaching, training, and clinical correlation purposes. DESIGN: Multicolored 3D printing of human anatomic pathology specimens was achieved using a ZCorp 510 3D printer (3D Systems, Rock Hill, South Carolina) following creation of a 3D model using Autodesk 123D Catch software (Autodesk, Inc, San Francisco, California). RESULTS: Three-dimensionally printed models of anatomic pathology specimens created included pancreatoduodenectomy (Whipple operation) and radical nephrectomy specimens. The models accurately depicted the topographic anatomy of selected specimens and illustrated the anatomic relation of excised lesions to adjacent normal tissues. CONCLUSIONS: Three-dimensional printing of human anatomic pathology specimens is achievable. Advances in 3D printing technology may further improve the quality of 3D printable anatomic pathology specimens. PMID- 26230599 TI - The So-called Short-Fiber Controversy: Literature Review and Critical Analysis. AB - CONTEXT: Numerous articles in the scientific literature indicate that pathogenic fibers with respect to asbestos-related diseases are those that exceed 5 MUm in length. Nonetheless, some authors have expressed concerns regarding pathogenicity of shorter fibers. OBJECTIVE: To review the scientific evidence regarding pathogenicity (or lack thereof) of fibers less than or equal to 5 MUm in length, with particular attention to publications indicating that such fibers might be hazardous. DATA SOURCES: The scientific literature was reviewed for experimental animal studies and human studies that address the role of fiber size in causation of disease. Sources included original studies, as well as review articles related to the topic. CONCLUSIONS: Experimental animal studies involving inhalation of fibers have demonstrated that fibers greater than 5 MUm in length are associated with both pulmonary fibrosis (ie, asbestosis) and malignancies (carcinoma of the lung and mesothelioma). There is no convincing evidence for a pathogenic effect for fibers that are 5 MUm or less in length. Fiber analyses of human lung tissue samples provide further support for pathogenicity of long fibers, particularly the more biopersistent amphibole fibers. Similar observations have been reported for nonasbestos mineral fibers. Concerns expressed by some authors (eg, the greater abundance of short fibers) do not alter these conclusions. Similarly, in vitro studies demonstrating biological activity of short fibers do not override inhalational studies of whole animals or the epidemiological findings in humans. PMID- 26230600 TI - Levamisole-Induced Vasculitis: A Characteristic Cutaneous Vasculitis Associated With Levamisole-Adulterated Cocaine. AB - Levamisole-induced vasculitis is a characteristic cutaneous vasculitis syndrome associated with the use of levamisole-adulterated cocaine. Patients will typically present with a painful, purpuric rash in a retiform or stellate pattern with or without central necrosis involving the extremities, trunk, nasal tip, digits, cheeks, and/or ears. A history of cocaine abuse can be elicited. Histologic features include microvascular thrombi and/or leukocytoclastic vasculitis involving small vessels of the superficial and deep dermis. Epidermal involvement is variably seen. Laboratory findings include leukopenia, neutropenia (including agranulocytosis), elevated erythrocyte sedimentation rate, normal coagulation studies, and positive autoantibodies including perinuclear and cytoplasmic antineutrophil cytoplasmic antibodies, antinuclear antibody, and lupus anticoagulant. Differential diagnosis includes other microscopic vasculitides, and clinical and laboratory correlation with histologic findings is essential. Lesions typically resolve with the cessation of cocaine use. Because of the treatment implications and rising incidence of this entity, rapid and accurate diagnosis is essential. PMID- 26230601 TI - Thyroid Paraganglioma. AB - Thyroid paragangliomas are rare tumors that arise from the inferior laryngeal paraganglia. Most patients are female and present with an asymptomatic thyroid nodule. Histologically, the tumor is composed of cells arranged in a well-defined nest (zellballen) pattern surrounded by a thin fibrovascular stroma. It is a diagnostic pitfall and is occasionally misdiagnosed as follicular neoplasm, medullary thyroid carcinoma, intrathyroid parathyroid proliferation, and especially secondary neuroendocrine tumors. Immunohistochemical stains (cytokeratin, parathyroid hormone, thyroid transcription factor 1, tyrosine hydroxylase, chromogranin A, synaptophysin, S100, calcitonin, carcinoembryonic antigen) are essential in establishing the diagnosis. Loss of succinate dehydrogenase complex, subunit B (SDHB), immunoexpression can be used to triage genetic testing because some mutations are associated with a higher risk for developing metastasis. Total thyroidectomy or lobectomy for solitary lesion is the preferred treatment. Elective lymph node dissection is usually not indicated. Postoperatively, patients should receive hormonal evaluation for functional disease and imaging for evaluation of multifocal or metastatic disease. PMID- 26230602 TI - Sclerosing Thymoma. AB - Sclerosing thymoma is an extremely rare entity described mostly in the recent past and, to our knowledge, described in only 14 cases, including one we recently diagnosed at our institution. The pathogenesis and biologic behavior of this relatively unknown entity is still largely uncertain. However, there are several consistent findings among the cases described so far. It is mostly asymptomatic or patients may present with shortness of breath or chest pain due to a large, well-circumscribed mass in the anterior mediastinum. It has a characteristic homogeneously white-tan, solid cut surface without any necrosis, hemorrhage, or cystic change. Microscopically, it is characterized by extensive sclerosis, hyalinization, and calcification. Only scant evidence of residual thymoma may be present to characterize this entity. Complete surgical resection has, so far, been curative. Knowledge of this rare entity in the general practice of surgical pathologists is important when considering the differential diagnosis of anterior mediastinal lesions. PMID- 26230603 TI - Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors. AB - ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity. PMID- 26230604 TI - Domino Hydrogenation-Reductive Amination of Phenols, a Simple Process To Access Substituted Cyclohexylamines. AB - Phenols can be efficiently reduced by sodium formate and Pd/C as the catalyst in water and in the presence of amines to give the corresponding cyclohexylamines. This reaction works at rt for 12 h or at 60 degrees C under microwave dielectric heating for 20 min. With the exception of aniline, primary, secondary amines, amino alcohols, and even amino acids can be used as nucleophiles. The reductive process is based on a sustainable hydrogen source and a catalyst that can be efficiently recovered and reused. The protocol was developed into a continuous flow production of cyclohexylamines in gram scale achieving very efficient preliminary results (TON 32.7 and TOF 5.45 h(-1)). PMID- 26230605 TI - The Effect of Aspirin on Bleeding and Transfusion in Contemporary Cardiac Surgery. AB - OBJECTIVE: Despite evidence that preoperative aspirin improves outcomes in cardiac surgery, recommendations for aspirin use are inconsistent due to aspirin's anti-platelet effect and concern for bleeding. The purpose of this study was to investigate preoperative aspirin use and its effect on bleeding and transfusion in cardiac surgery. METHODS: This retrospective study involved consecutive patients (n=1571) who underwent CABG, valve, or combined CABG and valve surgery at a single center between March 2007 and July 2012. Of all patients, 728 met the inclusion criteria and were divided into two groups: those using (n=603) or not using (n=125) aspirin within 5 days of surgery. Data were collected on chest tube drainage, re-operation for bleeding, and transfusion of red blood cells (RBCs), fresh frozen plasma (FFP), and platelets. RESULTS: No significant difference was observed between the two groups in chest tube drainage or re-operation for bleeding. An increase in patients transfused with RBCs was observed in the aspirin group (61.9 vs 51.2%, adjusted OR 1.77, p=0.027); however, among those transfused RBCs, no significant difference in mean units transfused or massive transfusion was observed. No significant difference was seen in transfusion requirement of FFP or platelets. CONCLUSIONS: In patients undergoing CABG, valve, or combined CABG/valve surgery, preoperative aspirin, within 5 days of surgery, was associated with an increased probability of receiving an RBC transfusion. Preoperative aspirin was not associated with an increase in chest tube drainage, re-operation for bleeding complications, or transfusion of FFP or platelets. PMID- 26230606 TI - Occurrence and Diversity of CRISPR-Cas Systems in the Genus Bifidobacterium. AB - CRISPR-Cas systems constitute adaptive immune systems for antiviral defense in bacteria. We investigated the occurrence and diversity of CRISPR-Cas systems in 48 Bifidobacterium genomes to gain insights into the diversity and co-evolution of CRISPR-Cas systems within the genus and investigate CRISPR spacer content. We identified the elements necessary for the successful targeting and inference of foreign DNA in select Type II CRISPR-Cas systems, including the tracrRNA and target PAM sequence. Bifidobacterium species have a very high frequency of CRISPR Cas occurrence (77%, 37 of 48). We found that many Bifidobacterium species have unusually large and diverse CRISPR-Cas systems that contain spacer sequences showing homology to foreign genetic elements like prophages. A large number of CRISPR spacers in bifidobacteria show perfect homology to prophage sequences harbored in the chromosomes of other species of Bifidobacterium, including some spacers that self-target the chromosome. A correlation was observed between strains that lacked CRISPR-Cas systems and the number of times prophages in that chromosome were targeted by other CRISPR spacers. The presence of prophage targeting CRISPR spacers and prophage content may shed light on evolutionary processes and strain divergence. Finally, elements of Type II CRISPR-Cas systems, including the tracrRNA and crRNAs, set the stage for the development of genome editing and genetic engineering tools. PMID- 26230608 TI - Quantitative Analysis of Adventitious Root Growth Phenotypes in Carnation Stem Cuttings. AB - Carnation is one of the most important species on the worldwide market of cut flowers. Commercial carnation cultivars are vegetatively propagated from terminal stem cuttings that undergo a rooting and acclimation process. For some of the new cultivars that are being developed by ornamental breeders, poor adventitious root (AR) formation limits its commercial scaling-up, due to a significant increase in the production costs. We have initiated a genetical-genomics approach to determine the molecular basis of the differences found between carnation cultivars during adventitious rooting. The detailed characterization of AR formation in several carnation cultivars differing in their rooting losses has been performed (i) during commercial production at a breeders' rooting station and (ii) on a defined media in a controlled environment. Our study reveals the phenotypic signatures that distinguishes the bad-rooting cultivars and provides the appropriate set-up for the molecular identification of the genes involved in AR development in this species. PMID- 26230607 TI - High Goblet Cell Count Is Inversely Associated with Ploidy Abnormalities and Risk of Adenocarcinoma in Barrett's Esophagus. AB - PURPOSE: Goblet cells may represent a potentially successful adaptive response to acid and bile by producing a thick mucous barrier that protects against cancer development in Barrett's esophagus (BE). The aim of this study was to determine the relationship between goblet cells (GC) and risk of progression to adenocarcinoma, and DNA content flow cytometric abnormalities, in BE patients. EXPERIMENTAL DESIGN: Baseline mucosal biopsies (N=2988) from 213 patients, 32 of whom developed cancer during the follow up period, enrolled in a prospective dynamic cohort of BE patients were scored in a blinded fashion, for the total number (#) of GC, mean # of GC/crypt (GC density), # of crypts with >= 1 GC, and the proportion of crypts with >=1 GC, in both dysplastic and non-dysplastic epithelium separately. The relationship between these four GC parameters and DNA content flow cytometric abnormalities and adenocarcinoma outcome was compared, after adjustment for age, gender, and BE segment length. RESULTS: High GC parameters were inversely associated with DNA content flow cytometric abnormalities, such as aneuploidy, ploidy >2.7N, and an elevated 4N fraction > 6%, and with risk of adenocarcinoma. However, a Kaplan-Meier analysis showed that the total # of GC and the total # crypts with >=1 GC were the only significant GC parameters (p<0.001 and 0.003, respectively). CONCLUSIONS: The results of this study show, for the first time, an inverse relationship between high GC counts and flow cytometric abnormalities and risk of adenocarcinoma in BE. Further studies are needed to determine if GC depleted foci within esophageal columnar mucosa are more prone to neoplastic progression or whether loss of GC occurs secondary to underlying genetic abnormalities. PMID- 26230609 TI - Self-rated health is prospectively associated with uptake of screening for the early detection of colorectal cancer, not vice versa. AB - Self-rated health (SRH) is a consistent predictor of mortality and other health outcomes. One of the mechanisms hypothesized to explain its validity as a predictor is that SRH affects the adoption of health behaviors. The present study examined the prospective association between SRH and performance of a recommended colorectal cancer (CRC) screening test. One thousand four hundred and seventy-six men and women aged 50-74 years, eligible for CRC screening, who had undergone the test a year before were interviewed 1-2 weeks (long interview, before testing) or 2 months (short interview, after testing) following the mailing of a test kit. Test performance was ascertained using an HMO's computerized data set. Respondents in the long interview group who rated their health as 'higher than others' performed the screening test 2 months following the invitation more than those who rated their health as similar to or lower than that of others (65.4, 61.6, and 49.1%, respectively, chi=8.02, P=0.018). At the same time, these respondents perceived the risk of CRC as significantly lower than that of those who rated their health as comparable with or lower than that of others. In a multivariate logistic regression of CRC screening behavior that included demographic and perceptual variables, age, intentions, and SRH were found to be significant predictors. Among respondents in the short interview, who tested before the interview, there was no significant association between SRH and behavior. SRH prospectively predicts uptake of CRC screening better than other perceptual variables, after accounting for demographic variables. PMID- 26230610 TI - Butyric acid fermentation from pretreated and hydrolysed wheat straw by an adapted Clostridium tyrobutyricum strain. AB - Butyric acid is a valuable building-block for the production of chemicals and materials and nowadays it is produced exclusively from petroleum. The aim of this study was to develop a suitable and robust strain of Clostridium tyrobutyricum that produces butyric acid at a high yield and selectivity from lignocellulosic biomasses. Pretreated (by wet explosion) and enzymatically hydrolysed wheat straw (PHWS), rich in C6 and C5 sugars (71.6 and 55.4 g l(-1) of glucose and xylose respectively), was used as substrate. After one year of serial selections, an adapted strain of C. tyrobutyricum was developed. The adapted strain was able to grow in 80% (v v(-1) ) PHWS without addition of yeast extract compared with an initial tolerance to less than 10% PHWS and was able to ferment both glucose and xylose. It is noticeable that the adapted C. tyrobutyricum strain was characterized by a high yield and selectivity to butyric acid. Specifically, the butyric acid yield at 60-80% PHWS lie between 0.37 and 0.46 g g(-1) of sugar, while the selectivity for butyric acid was as high as 0.9-1.0 g g(-1) of acid. Moreover, the strain exhibited a robust response in regards to growth and product profile at pH 6 and 7. PMID- 26230611 TI - Arsenic and Blood Pressure: A Long-Term Relationship. PMID- 26230613 TI - Are we close to the advent of closed loop deep brain stimulation in Parkinson's disease? PMID- 26230612 TI - Human umbilical cord blood-derived monocytes improve cognitive deficits and reduce amyloid-beta pathology in PSAPP mice. AB - Alzheimer's disease (AD) is the fourth major cause of mortality in the elderly in the US and the leading cause of dementia worldwide. While pharmacological targets have been discovered, there are no true disease-modifying therapies. We have recently discovered that multiple low-dose infusions of human umbilical cord blood cells (HUCBCs) ameliorate cognitive impairments and reduce Abeta-associated neuropathology in PSAPP transgenic mice. However, the mechanism for these effects of HUCBCs remains unclear. In the present study, we examined whether monocytes, as important components of HUCBCs, would have beneficial outcomes on the reduction of AD-like pathology and associated cognitive impairments in PSAPP transgenic AD model mice. PSAPP mice and their wild-type littermates were treated monthly with an infusion of peripheral human umbilical cord blood cell (HUCBC) derived monocytes over a period of 2 and 4 months, followed by behavioral evaluations, biochemical, and histological analyses. The principal findings of the present study confirmed that monocytes derived from HUCBCs (CB-M) play a central role in HUCBC-mediated cognition-enhancing and Abeta pathology ameliorating activities. Most importantly, we found that compared with CB-M, aged monocytes showed an ineffective phagocytosis of Abeta, while exogenous soluble amyloid precursor protein alpha (sAPPalpha) could reverse this deficiency. Pretreating monocytes with sAPPalpha upregulates Abeta internalization. Our further studies suggested that sAPPalpha could form a heterodimer with Abetas, with the APP672-688 (Abeta1-16) region being responsible for this effect. This in turn promoted binding of these heterodimers to monocyte scavenger receptors and thus promoted enhanced Abeta clearance. In summary, our findings suggest an interesting hypothesis that peripheral monocytes contribute to Abeta clearance through heterodimerization of sAPPalpha with Abeta. Further, declined or impaired sAPPalpha production, or reduced heterodimerization with Abeta, would cause a deficiency in Abeta clearance and thus accelerate the pathogenesis of AD. PMID- 26230614 TI - Timed loaded standing in female chronic fatigue syndrome compared with other populations. AB - Patients with chronic fatigue syndrome (CFS), like patients with osteoporosis, have similar difficulties in standing and sitting. The aim of the study was to compare combined trunk and arm endurance among women with CFS (n = 72), women with osteoporosis (n = 30), nondisabled women (n = 55), and women from non industrialized countries (n = 58) using the timed loaded standing (TLS) test. TLS measures how long a person can hold a 1 kg dumbbell in each hand in front of him or her with straight arms. TLS was higher in the industrialized nondisabled population than in the non-industrialized study population (p < 0.001) and in patients with osteoporosis (p = 0.002). TLS was lower in patients with CFS than in nondisabled controls (p < 0.001). After adjusting for age, body height, and weight, combined trunk and arm endurance was lower in CFS patients than in osteoporotic patients, even though the patients with osteoporosis were more than 25 yr older (p < 0.001) [corrected]. In CFS, TLS was lower than in the non industrialized group (p = 0.02). Since only women were studied, external validity of the results is limited to adult female patients with CFS. TLS revealed a specific biomechanical weakness in CFS patients that can be taken into account from the onset of a rehabilitation program. We propose that influencing the quality, rather than the quantity, of movement could be used in the rehabilitation. PMID- 26230615 TI - Callipeltosides A, B and C: Total Syntheses and Structural Confirmation. AB - Since their isolation almost 20 years ago, the callipeltosides have been of long standing interest to the synthetic community owing to their unique structural features and inherent biological activity. Herein we present our full research effort that has led to the synthesis of these molecules. Key aspects of our final strategy include 1) synthesis of the C1-C9 pyran core (5) using an AuCl3 catalysed cyclisation; 2) formation of C10-C22 vinyl iodide (55) by sequential bidirectional Stille reactions and 3) diastereoselective union of these advanced fragments by means of an alkenylzinc addition (d.r.=91:9 at C9). The common callipeltoside aglycon (4) was completed in a further five steps. Following this, all three sugar fragments were appended to provide the entire callipeltoside family. In addition to this, D-configured callipeltose B was synthesised and appended to the callipeltoside aglycon. The (1) H NMR spectrum of this molecule was found to be significantly different to the natural isolate, further supporting our assignment of callipeltoside B (2). PMID- 26230616 TI - In the Absence of a Mechanical Bowel Prep, Does the Addition of Pre-Operative Oral Antibiotics to Parental Antibiotics Decrease the Incidence of Surgical Site Infection after Elective Segmental Colectomy? AB - BACKGROUND: Pre-operative oral antibiotics administered the day prior to elective colectomy have been shown to decrease the incidence of surgical site infections (SSI) if a mechanical bowel prep (MBP) is used. Recently, the role for mechanical bowel prep has been challenged as being unnecessary and potentially harmful. We hypothesize that if MBP is omitted, oral antibiotics do not alter the incidence of SSI following colectomy. METHODS: We selected patients who underwent an elective segmental colectomy from the 2012 and 2013 National Surgical Quality Improvement Program colectomy procedure targeted database. Indications for surgery included colon cancer, diverticulitis, inflammatory bowel disease, or benign polyp. Patients who received mechanical bowel prep were excluded. The primary outcome measured was surgical site infection, defined as the presence of superficial, deep or, organ space infection within 30 d from surgery. RESULTS: A total of 6,399 patients underwent elective segmental colectomy without MBP. The incidence of SSI differed substantially between patients who received oral antibiotics, versus those who did not (9.7% vs. 13.7%, p=0.01). Multivariate analysis indicated that age, smoking status, operative time, perioperative transfusions, oral antibiotics, and surgical approach were associated with post operative SSI. When controlling for confounding factors, the use of pre-operative oral antibiotics decreased the incidence of surgical site infection (odds ratio=0.66, 95% confidence interval=0.48-0.90, p=0.01). CONCLUSION: Even in the absence of mechanical bowel prep, pre-operative oral antibiotics appear to reduce the incidence of surgical site infection following elective colectomy. PMID- 26230617 TI - Acetazolamide for electrical status epilepticus in slow-wave sleep. AB - Electrical status epilepticus in slow-wave sleep (ESES) is characterized by nearly continuous spike-wave discharges during non-rapid eye movement (REM) sleep. ESES is present in Landau-Kleffner syndrome (LKS) and continuous spike and wave in slow-wave sleep (CSWS). Sulthiame has demonstrated reduction in spike wave index (SWI) in ESES, but is not available in the United States. Acetazolamide (AZM) is readily available and has similar pharmacologic properties. Our aims were to assess the effect of AZM on SWI and clinical response in children with LKS and CSWS. Children with LKS or CSWS treated with AZM at our institution were identified retrospectively. Pre- and posttherapy electroencephalography (EEG) studies were evaluated for SWI. Parental and teacher report of clinical improvement was recorded. Six children met criteria for inclusion. Three children (50%) demonstrated complete resolution or SWI <5% after AZM. All children had improvement in clinical seizures and subjective improvement in communication skills and school performance. Five of six children had subjective improvement in hyperactivity and attention. AZM is a potentially effective therapy for children with LKS and CSWS. This study lends to the knowledge of potential therapies that can be used for these disorders, which can be challenging for families and providers. PMID- 26230618 TI - Predicting Redox Conditions in Groundwater at a Regional Scale. AB - Defining the oxic-suboxic interface is often critical for determining pathways for nitrate transport in groundwater and to streams at the local scale. Defining this interface on a regional scale is complicated by the spatial variability of reaction rates. The probability of oxic groundwater in the Chesapeake Bay watershed was predicted by relating dissolved O2 concentrations in groundwater samples to indicators of residence time and/or electron donor availability using logistic regression. Variables that describe surficial geology, position in the flow system, and soil drainage were important predictors of oxic water. The probability of encountering oxic groundwater at a 30 m depth and the depth to the bottom of the oxic layer were predicted for the Chesapeake Bay watershed. The influence of depth to the bottom of the oxic layer on stream nitrate concentrations and time lags (i.e., time period between land application of nitrogen and its effect on streams) are illustrated using model simulations for hypothetical basins. Regional maps of the probability of oxic groundwater should prove useful as indicators of groundwater susceptibility and stream susceptibility to contaminant sources derived from groundwater. PMID- 26230619 TI - Comparative Phylogenetic Studies on Schistosoma japonicum and Its Snail Intermediate Host Oncomelania hupensis: Origins, Dispersal and Coevolution. AB - BACKGROUND: Schistosoma japonicum causes major public health problems in China and the Philippines; this parasite, which is transmitted by freshwater snails of the species Oncomelania hupensis, causes the disease intestinal schistosomiasis in humans and cattle. Researchers working on Schistosoma in Africa have described the relationship between the parasites and their snail intermediate hosts as coevolved or even as an evolutionary arms race. In the present study this hypothesis of coevolution is evaluated for S. japonicum and O. hupensis. The origins and radiation of the snails and the parasite across China, and the taxonomic validity of the sub-species of O. hupensis, are also assessed. METHODOLOGY/PRINCIPAL FINDINGS: The findings provide no evidence for coevolution between S. japonicum and O. hupensis, and the phylogeographical analysis suggests a heterochronous radiation of the parasites and snails in response to different palaeogeographical and climatic triggers. The results are consistent with a hypothesis of East to West colonisation of China by Oncomelania with a re invasion of Japan by O. hupensis from China. The Taiwan population of S. japonicum appears to be recently established in comparison with mainland Chinese populations. CONCLUSIONS/SIGNIFICANCE: The snail and parasite populations of the western mountain region of China (Yunnan and Sichuan) appear to have been isolated from Southeast Asian populations since the Pleistocene; this has implications for road and rail links being constructed in the region, which will breach biogeographical barriers between China and Southeast Asia. The results also have implications for the spread of S. japonicum. In the absence of coevolution, the parasite may more readily colonise new snail populations to which it is not locally adapted, or even new intermediate host species; this can facilitate its dispersal into new areas. Additional work is required to assess further the risk of spread of S. japonicum. PMID- 26230620 TI - Educational level and chronic inflammation in the elderly--the role of obesity: results from the population-based CARLA study. AB - This study aimed to assess the mediating role of anthropometric parameters in the relation of education and inflammation in the elderly. Cross-sectional data from the population-based CARdio-vascular Disease, Living and Ageing in Halle study were used after excluding subjects with a plasma level of high-sensitive C reactive protein (hsCRP) above 10 mg L(-1) (916 men/760 women remaining). Education was categorized in accordance with International Standard Classification of Education. As inflammation parameters, the soluble tumour necrosis factor type 1 (sTNF-R1), hsCRP and interleukin 6 (IL-6) were taken into account. Anthropometric parameters were the body mass index (BMI), waist-to-hip ratio (WHR) and waist-to-height ratio (WHeR). We used covariate adjusted mixed models to assess associations. Effect measures were the natural indirect effect (NIE), controlled direct effect and total effect (TE). Education was associated with sTNF-R1, hsCRP and IL-6 in men, and sTNF-R1 and hsCRP in women. Anthropometric parameters correlated with all inflammation parameters after covariate adjustment. BMI and WHeR were strong mediators of educational differences in sTNF-R1 (percentage of NIE of TE: 28% in men; 33% in women) and hsCRP (percentage of NIE of TE: 35% in men; 52% in women), while WHR was the weakest mediator. General obesity mediates roughly one-third of the association of education with chronic inflammation in the elderly. PMID- 26230621 TI - A Risk Score with Additional Four Independent Factors to Predict the Incidence and Recovery from Metabolic Syndrome: Development and Validation in Large Japanese Cohorts. AB - BACKGROUND: Although many risk factors for Metabolic syndrome (MetS) have been reported, there is no clinical score that predicts its incidence. The purposes of this study were to create and validate a risk score for predicting both incidence and recovery from MetS in a large cohort. METHODS: Subjects without MetS at enrollment (n = 13,634) were randomly divided into 2 groups and followed to record incidence of MetS. We also examined recovery from it in rest 2,743 individuals with prevalent MetS. RESULTS: During median follow-up of 3.0 years, 878 subjects in the derivation and 757 in validation cohorts developed MetS. Multiple logistic regression analysis identified 12 independent variables from the derivation cohort and initial score for subsequent MetS was created, which showed good discrimination both in the derivation (c-statistics 0.82) and validation cohorts (0.83). The predictability of the initial score for recovery from MetS was tested in the 2,743 MetS population (906 subjects recovered from MetS), where nine variables (including age, sex, gamma-glutamyl transpeptidase, uric acid and five MetS diagnostic criteria constituents.) remained significant. Then, the final score was created using the nine variables. This score significantly predicted both the recovery from MetS (c-statistics 0.70, p<0.001, 78% sensitivity and 54% specificity) and incident MetS (c-statistics 0.80) with an incremental discriminative ability over the model derived from five factors used in the diagnosis of MetS (continuous net reclassification improvement: 0.35, p < 0.001 and integrated discrimination improvement: 0.01, p<0.001). CONCLUSIONS: We identified four additional independent risk factors associated with subsequent MetS, developed and validated a risk score to predict both incident and recovery from MetS. PMID- 26230622 TI - Do Nobel Laureates Create Prize-Winning Networks? An Analysis of Collaborative Research in Physiology or Medicine. AB - Nobel Laureates in Physiology or Medicine who received the Prize between 1969 and 2011 are compared to a matched group of scientists to examine productivity, impact, coauthorship and international collaboration patterns embedded within research networks. After matching for research domain, h-index, and year of first of publication, we compare bibliometric statistics and network measures. We find that the Laureates produce fewer papers but with higher average citations. The Laureates also produce more sole-authored papers both before and after winning the Prize. The Laureates have a lower number of coauthors across their entire careers than the matched group, but are equally collaborative on average. Further, we find no differences in international collaboration patterns. The Laureates coauthor network reveals significant differences from the non-Laureate network. Laureates are more likely to build bridges across a network when measuring by average degree, density, modularity, and communities. Both the Laureate and non-Laureate networks have "small world" properties, but the Laureates appear to exploit "structural holes" by reaching across the network in a brokerage style that may add social capital to the network. The dynamic may be making the network itself highly attractive and selective. These findings suggest new insights into the role "star scientists" in social networks and the production of scientific discoveries. PMID- 26230623 TI - Modular synthesis of multisubstituted furans through palladium-catalyzed three component condensation of alkynylbenziodoxoles, carboxylic acids, and imines. AB - Mild and regiocontrolled synthesis of a multisubstituted furan is achieved through Pd(OAc)2 -catalyzed room-temperature condensation of an alkynylbenziodoxole, a carboxylic acid, and an enolizable ketimine, which contribute to C1, CO, and C2 fragments, respectively, to the furan skeleton. The reaction tolerates a broad range of functional groups in each of the reaction components, and enables highly modular and flexible synthesis of variously substituted furans. The reaction is particularly effective for the rapid generation of tri- and tetraarylfurans and furan-containing oligoarylenes without relying on conventional cross-coupling chemistry. PMID- 26230624 TI - Protein Delivery System Containing a Nickel-Immobilized Polymer for Multimerization of Affinity-Purified His-Tagged Proteins Enhances Cytosolic Transfer. AB - Recombinant proteins with cytosolic or nuclear activities are emerging as tools for interfering with cellular functions. Because such tools rely on vehicles for crossing the plasma membrane we developed a protein delivery system consisting in the assembly of pyridylthiourea-grafted polyethylenimine (piPEI) with affinity purified His-tagged proteins pre-organized onto a nickel-immobilized polymeric guide. The guide was prepared by functionalization of an ornithine polymer with nitrilotriacetic acid groups and shown to bind several His-tagged proteins. Superstructures were visualized by electron and atomic force microscopy using 2 nm His-tagged gold nanoparticles as probes. The whole system efficiently carried the green fluorescent protein, single-chain antibodies or caspase 3, into the cytosol of living cells. Transduction of the protease caspase 3 induced apoptosis in two cancer cell lines, demonstrating that this new protein delivery method could be used to interfere with cellular functions. PMID- 26230625 TI - Corrigendum: An embryo of protocells: The capsule of graphene with selective ion channels. PMID- 26230627 TI - An Internal Reference Control Duplex Real-Time Polymerase Chain Reaction Assay for Detecting Bacterial Contamination in Blood Products. AB - Real-time polymerase chain reaction (RT-PCR) enables effective and sensitive screening for infectious risk in the field of blood safety. However, when using RT-PCR to detect bacterial contamination, several intractable points must be considered, one of which is the lack of appropriate quality control. In this study, we developed a simplified RT-PCR assay in which the same primer set and two distinct probes were used to detect both, an internal reference control and the target in a reaction. The copy number of the internal reference control represents the positive detection limit of the assay; therefore, when the threshold-cycle value of the target is less than or equal to that of the internal reference control, the result obtained for the target can be considered to be a true positive. When human gDNA was spiked with Escherichia coli gDNA and the detection limit for the internal reference control was set to five copies, the measured detection limit for E. coli gDNA was two copies. The internal reference control duplex RT-PCR assay showed high efficiency (0.91-1.02), high linearity (R2 > 0.99), and good reproducibility in intra- and inter-assay comparisons. Lastly, when human platelet-rich plasma samples were spiked with E. coli or other bacterial species, all species were detected efficiently, and the results of a two-sample pooled t test showed that the limit of detection for E. coli was 1 cfu/mL. Here, we present a synthetic internal reference control molecule and a new statistical method for improving the reliability of RT-PCR assays when screening for bacterial contamination in blood products. PMID- 26230626 TI - Impaired Verbal Learning Is Associated with Larger Caudate Volumes in Early Onset Schizophrenia Spectrum Disorders. AB - BACKGROUND: Both brain structural abnormalities and neurocognitive impairments are core features of schizophrenia. We have previously reported enlargements in subcortical brain structure volumes and impairment of neurocognitive functioning as measured by the MATRICS Cognitive Consensus Battery (MCCB) in early onset schizophrenia spectrum disorders (EOS). To our knowledge, no previous study has investigated whether neurocognitive performance and volumetric abnormalities in subcortical brain structures are related in EOS. METHODS: Twenty-four patients with EOS and 33 healthy controls (HC) were included in the study. Relationships between the caudate nucleus, the lateral and fourth ventricles volumes and neurocognitive performance were investigated with multivariate linear regression analyses. Intracranial volume, age, antipsychotic medication and IQ were included as independent predictor-variables. RESULTS: The caudate volume was negatively correlated with verbal learning performance uniquely in the EOS group (r=-.454, p=.034). There were comparable positive correlations between the lateral ventricular volume and the processing speed, attention and reasoning and problem solving domains for both the EOS patients and the healthy controls. Antipsychotic medication was related to ventricular enlargements, but did not affect the brain structure-function relationship. CONCLUSION: Enlargement of the caudate volume was related to poorer verbal learning performance in patients with EOS. Despite a 32% enlargement of the lateral ventricles in the EOS group, associations to processing speed, attention and reasoning and problem solving were similar for both the EOS and the HC groups. PMID- 26230628 TI - Cis-Acting Sequence Elements and Upstream Open Reading Frame in Mouse Utrophin-A 5'-UTR Repress Cap-Dependent Translation. AB - Utrophin, the autosomal homologue of dystrophin can functionally compensate for dystrophin deficiency. Utrophin upregulation could therefore be a therapeutic strategy in Duchenne Muscular Dystrophy (DMD) that arises from mutation in dystrophin gene. In contrast to its transcriptional regulation, mechanisms operating at post-transcriptional level of utrophin expression have not been well documented. Although utrophin-A 5'-UTR has been reported with internal ribosome entry site (IRES), its inhibitory effect on translation is also evident. In the present study we therefore aimed to compare relative contribution of cap independent and cap-dependent translation with mouse utrophin-A 5'-UTR through m7G-capped and A-capped mRNA transfection based reporter assay. Our results demonstrate that cap-independent translation with utrophin-A 5'-UTR is not as strong as viral IRES. However, cap-independent mode has significant contribution as cap-dependent translation is severely repressed with utrophin-A 5'-UTR. We further identified two sequence elements and one upstream open reading frame in utrophin-A 5'-UTR responsible for repression. The repressor elements in utrophin A 5'-UTR may be targeted for utrophin upregulation. PMID- 26230629 TI - Risk of radiation-induced secondary rectal and bladder cancer following radiotherapy of prostate cancer. AB - BACKGROUND: An elevated risk of radiation-induced secondary cancer (SC) has been observed in prostate cancer patients after radiotherapy (RT), rising to as high as one in 70 patients with more than 10 years follow-up. In this study we have estimated SC risks following RT with both previous and contemporary techniques, including proton therapy, using risk models based on different dose-response relationships. MATERIAL AND METHODS: RT plans treating the prostate and seminal vesicles with either conformal radiotherapy (CRT), volumetric modulated arc therapy (VMAT) or intensity-modulated proton therapy (IMPT) were created for 10 patients. The risks of radiation-induced cancer were estimated for the bladder and rectum using dose-response models reflecting varying degrees of cell sterilisation: a linear model, a linear-plateau model and a bell-shaped model also accounting for fractionated RT. RESULTS: The choice of risk models was found to rank the plans quite differently, with the CRT plans having the lowest SC risk using the bell-shaped model, while resulting in the highest risk applying the linear model. Considering all dose-response scenarios, median relative risks of VMAT versus IMPT were 1.1-1.7 for the bladder and 0.9-1.8 for the rectum. Risks of radiation-induced bladder and rectal cancers were lower from VMAT if exposed at 80 years versus IMPT if exposed at 50 years. CONCLUSIONS: The SC risk estimations for the bladder and rectum revealed no clear relative relationship between the contemporary techniques and CRT, with divergent results depending on choice of model. However, the SC risks for these organs when using IMPT were lower or comparable to VMAT. SC risks could be assessed when considering referral of prostate cancer patients to proton therapy, taking also general patient characteristics, such as age, into account. PMID- 26230630 TI - Transfer of Immunity from Mother to Offspring Is Mediated via Egg-Yolk Protein Vitellogenin. AB - Insect immune systems can recognize specific pathogens and prime offspring immunity. High specificity of immune priming can be achieved when insect females transfer immune elicitors into developing oocytes. The molecular mechanism behind this transfer has been a mystery. Here, we establish that the egg-yolk protein vitellogenin is the carrier of immune elicitors. Using the honey bee, Apis mellifera, model system, we demonstrate with microscopy and western blotting that vitellogenin binds to bacteria, both Paenibacillus larvae--the gram-positive bacterium causing American foulbrood disease--and to Escherichia coli that represents gram-negative bacteria. Next, we verify that vitellogenin binds to pathogen-associated molecular patterns; lipopolysaccharide, peptidoglycan and zymosan, using surface plasmon resonance. We document that vitellogenin is required for transport of cell-wall pieces of E. coli into eggs by imaging tissue sections. These experiments identify vitellogenin, which is distributed widely in oviparous species, as the carrier of immune-priming signals. This work reveals a molecular explanation for trans-generational immunity in insects and a previously undescribed role for vitellogenin. PMID- 26230632 TI - A Simplified Lateral Hinge Approach to the Proximal Interphalangeal Joint. AB - Proximal interphalangeal joint replacement is an effective treatment for painful arthritis affecting the joint. However, the complication rate is relatively high, with many of these complications related to soft-tissue imbalance or instability. Volar, dorsal, and lateral approaches have all been described with varying results. We describe a new simplified lateral hinge approach that splits the collateral ligament to provide adequate exposure of the joint. Following insertion of the prosthesis the collateral ligament is simply repaired, side-to side, which stabilizes the joint. As the central slip, opposite collateral ligament, flexor and extensor tendons have not been violated, early active mobilization without splinting is possible, and the risk of instability, swan neck, and boutonniere deformity are reduced. The indications, contraindications, surgical technique, and rehabilitation protocol are described. PMID- 26230631 TI - Gynecologic cancer outcomes in the elderly poor: A population-based study. AB - BACKGROUND: Adults aged >=65 years who are dually enrolled in Medicare and Medicaid are an at-risk group in health care. However, to the best of the authors' knowledge, the outcomes of women with gynecologic cancers in this population are unknown. METHODS: The current study was a population-based cohort study of North Carolina state cancer registry cases of uterine, ovarian, cervical, and vulvar/vaginal cancers (2003-2009), with linked enrollment in Medicare and state Medicaid. Outcomes of all-cause mortality and stage of disease at the time of diagnosis were analyzed as a function of enrollment status using multivariate analysis and survival curves. RESULTS: Of 4522 women aged >=65 years (3702 of whom were enrolled in Medicare [82%] and 820 of whom were dually enrolled [18%]), there were 2286 cases of uterine (51%), 1587 cases of ovarian (35%), 302 cases of cervical (7%), and 347 cases of vulvar/vaginal (8%) cancers. Dual enrollees had increased all-cause mortality overall (adjusted hazard ratio [aHR], 1.34; 95% confidence interval [95% CI], 1.19-1.49), and within each cancer site (uterine: aHR, 1.22 [95% CI, 1.02-1.47]; ovarian: aHR, 1.25 [95% CI, 1.05 1.49]; cervical: aHR, 1.34 [95% CI, 0.96-1.87]; and vulvar/vaginal: aHR, 1.93 [95% CI, 1.36-2.72]). Increased odds of advanced-stage disease at the time of diagnosis among dual enrollees was only present in patients with uterine cancer (adjusted odds ratio, 1.38; 95% CI, 1.06-1.79). Stratified survival curves demonstrated the strongest disparities among women with early-stage uterine and early-stage vulvar/vaginal cancers. CONCLUSIONS: Women aged >=65 years who were dually enrolled in Medicare and Medicaid were found to have an overall 34% increase in all-cause mortality after diagnosis with a gynecologic cancer compared with the non-dually enrolled Medicare population. Women with early-stage uterine and vulvar/vaginal cancers appeared to have the most disparate outcomes. Because these malignancies are generally curable, they have the most potential for benefit from targeted interventions. PMID- 26230634 TI - Response to "Comment on 'Background Ionizing Radiation and the Risk of Childhood Cancer: A Census-Based Nationwide Cohort Study'". PMID- 26230633 TI - Development and psychometric evaluation of a measure to evaluate the quality of integrated care: the Patient Assessment of Integrated Elderly Care. AB - BACKGROUND: Novel population-based integrated care services are being developed to adequately serve the growing number of elderly people. Suitable, reliable and valid measurement instruments are needed to evaluate the quality of care delivered. OBJECTIVE: To develop a measure to evaluate the quality of integrated care from the perspective of elderly people, the Patient Assessment of Integrated Elderly Care (PAIEC), and then to assess its psychometric properties. METHODS/DESIGN: After the Patient Assessment of Chronic Illness Care was adapted to the PAIEC, a cross-sectional postal-survey study was performed among 223 elderly people who received integrated elderly care and support. We assessed the factor structure, internal consistency, known groups and divergent validity using robust nonparametric tests. RESULTS: Mean age of participants was 83 years (standard deviation 4.7), and 69% was female. The original five-factor model was rejected; a good fit was found for a three-factor model, when excluding the item on patients' satisfaction with care. The PAIEC and its subscales showed good internal consistency (ordinal alphas > 0.90). Known-groups validity was supported regarding number of medications, prevalence of chronic conditions and home care received. No differences were found between groups based on sociodemographic aspects. Divergent validity was supported by low correlations (Spearman's rank correlation coefficients < 0.30) between PAIEC scales and measures of quality of life, complexity of care needs and frailty. CONCLUSION: The PAIEC seems to have considerable potential as a reliable and valid measurement instrument that evaluates quality of integrated care and support from the perspective of elderly people. PMID- 26230635 TI - The use of sugar and alcohol industry waste in the adsorption of potentially toxic metals. AB - One of the waste products of the industrial process of the sugar and alcohol agribusiness is filter cake (FC). This waste product has high levels of organic matter, mainly proteins and lipids, and is rich in calcium, nitrogen, potassium and phosphorous. In this work we characterized samples of FC from sugar and alcohol industries located in sugarcane-producing regions in Brazil and assessed the adsorption of potentially toxic metals (Cu(II), Cd(II), Pb(II), Ni(II) and Cr(III)) by this waste in mono- and multi-elemental systems, seeking to use FC as an adsorbent in contaminated environments. The characterization of FCs showed significant differences between the samples and the adsorption studies showed retention of over 90% of potentially toxic metals. In a competitive environment (multi-metallic solution), the FC was effective in adsorbing all metals except lead, but less effective compared to the mono-metallic solution. These results show the potential for use of this residue as an adsorbent in contaminated environments. PMID- 26230636 TI - Infant eye finite element model to investigate retinal hemorrhages after fall and shaking events. PMID- 26230637 TI - Optical properties of plasmon-resonant bare and silica-coated nanostars used for cell imaging. AB - We synthesized and characterized gold nanostars and their silica-coated derivatives with 7- to 50-nm shell thicknesses as contrast agents for optical imaging. The scattering and absorption coefficients of the nanoparticles (NPs) were estimated by means of collimated transmittance and diffuse reflectance/transmittance analyses. The contrasting properties of the nanostructures were studied in optical coherence tomography glass capillary imaging. The silica-coated nanostars with the thickest shell have higher scattering ability in comparison with bare nanostars. Viability assays confirmed weak in vitro toxicity of nanostructures at up to ~200-MUg/mL concentrations. We showed real-time visualization of nanostars in both agarose and cultured cells by analyzing the backscattering signal using a conventional laser confocal microscope. The signal intensity detected from the silica-coated NPs was almost 1.5 times higher in comparison with bare nanostars. To the best of our knowledge, this is the first time that conventional laser confocal microscopy was applied in combined scattering and transmitted light modes to detect the backscattered signal of gold nanostars, which is useful for direct monitoring of the uptake, translocation, and accumulation of NPs in living cells. PMID- 26230638 TI - Cognitive Reappraisal in Preschoolers: Neuropsychological Evidence of Emotion Regulation From an ERP Study. AB - Late positive potential (LPP) is associated with the magnitude and intensity of emotional reactivity. Studies have linked the adoption of cognitive reappraisal to the reduction of LPP amplitude in adults and school-age children but not in preschoolers. It may be due to preschoolers' difficulty in understanding and remembering given interpretations. We examined changes in LPP amplitudes following simplified interpretations of unpleasant pictures in 20 preschoolers (48-71 months). Results demonstrated that LPP amplitudes, following neutral interpretations, were lower as compared to negative interpretations, suggesting that preschoolers as young as four have developed the ability to use cognitive reappraisal strategies following instructions. PMID- 26230639 TI - Direct Facilitatory Role of Paragigantocellularis Neurons in Opiate Withdrawal Induced Hyperactivity of Rat Locus Coeruleus Neurons: An In Vitro Study. AB - Studies have shown that following opiate withdrawal, the spontaneous discharge rate of locus coeruleus (LC) neurons remarkably increases. Combination of intrinsic mechanisms with extrinsic excitatory modulations mediates the withdrawal-induced hyperactivity of LC neurons. The nucleus paragigantocellularis (PGi) provides the main excitatory inputs to LC and plays a pivotal role in opiate withdrawal. In the present study the direct facilitatory role of PGi on opiate withdrawal-induced hyperactivity of LC neurons was investigated using a newly developed brain slice, containing both LC and PGi. HRP retrograde neuronal tracing was used to verify the existence of both LC and PGi neurons in the developed slice. The spontaneous discharge rate (SDR), resting membrane potential (RMP) and spontaneous excitatory post-synaptic currents (sEPSCs) were recorded in LC neurons using whole cell patch clamp recording. Results showed that the net SDR and the net RMP of LC neurons in slices containing both LC and PGi neurons are significantly higher than slices lacking intact (uncut) PGi inputs. Also, the frequency of sEPSCs in those LC neurons receiving PGi inputs significantly increased compared to the slices containing no intact PGi inputs. Altogether, our results propose that increase in PGi-mediated excitatory transmission might facilitate the opiate withdrawal-induced hyperactivity of LC neurons. PMID- 26230640 TI - Boswellic acids synergize antitumor activity and protect against the cardiotoxicity of doxorubicin in mice bearing Ehrlich's carcinoma. AB - This study aimed to test whether boswellic acids add to the antitumor effects of doxorubicin against solid tumors of Ehrlich's ascites carcinoma (EAC) grown in mice, and to investigate the protective effects of boswellic acids against doxorubicin-induced cardiotoxicity. Sixty-four female Swiss albino mice bearing EAC solid tumors were distributed among 8 groups as follows: group 1, EAC control group; group 2, doxorubicin treatment group [mice were injected with doxorubicin (6 mg.(kg body mass)(-1).week(-1)) for 3 weeks]; groups 3-5, these mice were treated with boswellic acids (125, 250, or 500 mg.kg(-1).day(-1)), respectively; groups 6-8, these mice were treated with a combination of doxorubicin and boswellic acids (125, 250, or 500 mg.kg(-1).day(-1)), respectively, for 3 weeks. The results indicated that boswellic acids synergized the antitumor activity of doxorubicin. Doxorubicin-treated mice showed elevated serum activities of lactate dehydrogenase and creatine kinase isoenzyme MB as well as cardiac malondialdehyde. Further, decreases in cardiac levels of reduced glutathione, superoxide dismutase, and catalase activities were observed. These effects were accompanied by an increase in cardiac expression of caspase 3. Thus, treatment with boswellic acids attenuated doxorubicin-evoked disturbances in the above mentioned parameters, highlighting antioxidant and antiapoptotic activities. Therefore, boswellic acids could be potential candidates for ameliorating the cardiotoxicity of doxorubicin. PMID- 26230642 TI - Mitochondrial Genome Supports Sibling Species of Angiostrongylus costaricensis (Nematoda: Angiostrongylidae). AB - Angiostrongylus costaricensis is a zoonotic parasitic nematode that causes abdominal or intestinal angiostrongyliasis in humans. It is endemic to the Americas. Although the mitochondrial genome of the Brazil taxon has been published, there is no available mitochondrial genome data on the Costa Rica taxon. We report here the complete mitochondrial genome of the Costa Rica taxon and its genetic differentiation from the Brazil taxon. The whole mitochondrial genome was obtained from next-generation sequencing of genomic DNA. It had a total length of 13,652 bp, comprising 36 genes (12 protein-coding genes-PCGs, 2 rRNA and 22 tRNA genes) and a control region (A + T rich non-coding region). It is longer than that of the Brazil taxon (13,585 bp). The larger mitogenome size of the Costa Rica taxon is due to the size of the control region as the Brazil taxon has a shorter length (265 bp) than the Costa Rica taxon (318 bp). The size of 6 PCGs and the start codon for ATP6, CYTB and NAD5 genes are different between the Costa Rica and Brazil taxa. Additionally, the two taxa differ in the stop codon of 6 PCGs. Molecular phylogeny based on 12 PCGs was concordant with two rRNA, 22 tRNA and 36 mitochondrial genes. The two taxa have a genetic distance of p = 16.2% based on 12 PCGs, p = 15.3% based on 36 mitochondrial genes, p = 13.1% based on 2 rRNA genes and p = 10.7% based on 22 tRNA genes, indicating status of sibling species. The Costa Rica and Brazil taxa of A. costaricensis are proposed to be accorded specific status as members of a species complex. PMID- 26230641 TI - Genetic variants in SLC22A17 and SLC22A7 are associated with anthracycline induced cardiotoxicity in children. AB - AIM: To identify novel variants associated with anthracycline-induced cardiotoxicity and to assess these in a genotype-guided risk prediction model. PATIENTS & METHODS: Two cohorts treated for childhood cancer (n = 344 and 218, respectively) were genotyped for 4578 SNPs in drug ADME and toxicity genes. RESULTS: Significant associations were identified in SLC22A17 (rs4982753; p = 0.0078) and SLC22A7 (rs4149178; p = 0.0034), with replication in the second cohort (p = 0.0071 and 0.047, respectively). Additional evidence was found for SULT2B1 and several genes related to oxidative stress. Adding the SLC22 variants to the prediction model improved its discriminative ability (AUC 0.78 vs 0.75 [p = 0.029]). CONCLUSION: Two novel variants in SLC22A17 and SLC22A7 were significantly associated with anthracycline-induced cardiotoxicity and improved a genotype-guided risk prediction model, which could improve patient risk stratification. PMID- 26230644 TI - Hydrothermal Synthesis of Yttria-Stabilized Zirconia Nanocrystals with Controlled Yttria Content. AB - In this study, we demonstrate for the first time the hydrothermal synthesis of yttria-stabilized zirconia (YSZ) nanocrystals with controlled yttria content (x = 3-12 mol %; xYSZ) with negligible aggregation from aqueous solution. The nanocrystals were grown via the hydrothermal treatment of basic Zr(IV) and Y(III) carbonate complex aqueous solutions in the presence of a cationic ligand, N(CH3)4(+). The nanocrystals were characterized in detail by dynamic light scattering, zeta-potential measurement, X-ray diffraction, specific surface area measurement based on the Brunauer-Emmett-Teller theory, transmission electron microscopy, energy dispersive X-ray spectroscopy, and Raman spectroscopy. Shorter reaction times and higher Y2O3 content produce aqueous solutions with higher transparencies containing nanocrystals with sizes of 10 nm or less. Nanocrystals with the target composition were obtained by hydrothermal reaction for longer than 3 h, regardless of the Y2O3 content. The main phase is tetragonal for (3 6)YSZ and cubic with disordered oxygen vacancies for (8-12)YSZ. The characteristics of the nanocrystalline material synthesized are consistent with those of bulk YSZ crystals, indicating the growth of high-quality nanocrystals. PMID- 26230643 TI - Dumb and Lazy? A Comparison of Color Learning and Memory Retrieval in Drones and Workers of the Buff-Tailed Bumblebee, Bombus terrestris, by Means of PER Conditioning. AB - More than 100 years ago, Karl von Frisch showed that honeybee workers learn and discriminate colors. Since then, many studies confirmed the color learning capabilities of females from various hymenopteran species. Yet, little is known about visual learning and memory in males despite the fact that in most bee species males must take care of their own needs and must find rewarding flowers to obtain food. Here we used the proboscis extension response (PER) paradigm to study the color learning capacities of workers and drones of the bumblebee, Bombus terrestris. Light stimuli were paired with sucrose reward delivered to the insects' antennae and inducing a reflexive extension of the proboscis. We evaluated color learning (i.e. conditioned PER to color stimuli) in absolute and differential conditioning protocols and mid-term memory retention was measured two hours after conditioning. Different monochromatic light stimuli in combination with neutral density filters were used to ensure that the bumblebees could only use chromatic and not achromatic (e.g. brightness) information. Furthermore, we tested if bees were able to transfer the learned information from the PER conditioning to a novel discrimination task in a Y-maze. Both workers and drones were capable of learning and discriminating between monochromatic light stimuli and retrieved the learned stimulus after two hours. Drones performed as well as workers during conditioning and in the memory test, but failed in the transfer test in contrast to workers. Our data clearly show that bumblebees can learn to associate a color stimulus with a sugar reward in PER conditioning and that both workers and drones reach similar acquisition and mid-term retention performances. Additionally, we provide evidence that only workers transfer the learned information from a Pavlovian to an operant situation. PMID- 26230645 TI - Evidence for a C14 Frank-Kasper Phase in One-Size Gold Nanoparticle Superlattices. AB - The Frank-Kasper phases were already known in 1982 when quasi-crystals were discovered, but their complex architectures are now considered as making a link between simple close-packed periodic structures and some quasi-periodic ones. These tetrahedrally close packed structures are observed in many materials from elements to intermetallics as well as self-assembled soft materials like micellar systems, dendritric liquid crystals, star polymers, and more recently block copolymers or heated gold nanocrystal superlattices. We report here the existence of a Frank-Kasper phase with hexagonal symmetry (MgZn2 type, also labeled C14) in superlattices of monodisperse hydrophobically coated gold particles at room temperature obtained from suspensions in various solvents. The existence of such a structure in this system is analyzed in terms of geometrical parameters including gold core diameter, ligand length, and grafting density and an energetic approach based on van der Waals attraction. Hydrophobically coated gold nanoparticles is a new system that exhibits a Frank and Kasper phase built by one size objects. This result opens a route toward a nanoparticle superlattice with complex structures and thus original physical properties. PMID- 26230646 TI - The social buffering of the hypothalamic-pituitary-adrenocortical axis in humans: Developmental and experiential determinants. AB - Social buffering, a subset of social support, is the process through which the availability of a conspecific reduces the activity of stress-mediating neurobiological systems. While its role in coping and resilience is significant, we know little about its developmental history in humans. This brief review presents an integrative developmental account of the social buffering of hypothalamic-pituitary-adrenocortical (HPA) stress reactivity in humans, from infancy to adulthood. During infancy, parents are powerful stress-regulators for children, but child temperament also plays a role and interacts with parenting quality to predict the magnitude of stress responses to fear or pain stimuli. Recent work indicates that parental support remains a potent stress buffer into late childhood, but that it loses its effectiveness as a buffer of the HPA axis by adolescence. Puberty may be the switch that alters the potency of parental buffering. Beginning in middle childhood, friends may serve as stress buffers, particularly when other peers are the source of stress. By adulthood, romantic partners assume this protective role, though studies often reveal sex differences that are currently not well understood. Translational research across species will be critical for developing a mechanistic understanding of social buffering and the processes involved in developmental changes noted in this review. PMID- 26230647 TI - The Effect of Eating Disorder Memoirs in Individuals With Self-Identified Eating Pathologies. AB - As part of a larger, mixed-methods study, we posted an invitation to participate in a study on the effects of reading eating disorder memoirs on the website of an organization that provides support for people with eating disorders. Twenty-four women completed the questionnaire. Qualitative analysis of their responses indicated a recovery continuum, whereby the direction of memoir influence seemed to depend on an individual's recovery stage and motivation to recover. Individuals who reported that they were exposed to memoirs before, or during, their illness reported experiencing negative consequences including making unfavorable social comparisons, along with emulation and triggering of disordered behaviors, whereas those who reported being exposed when in recovery reported more positive outcomes including hope, validation, and social support. Findings have implications for the use of personal accounts as a means of facilitating patient recovery in eating disorder treatment settings. Future research should test the influence of memoirs using a larger eating disorder sample, and across different recovery stages. PMID- 26230648 TI - Comorbid Medical Conditions in Vascular Dementia: A Matched Case-Control Study. AB - The objective of the study was to compare the presence of comorbid medical conditions between patients with a vascular dementia (VaD) and a control group, from the Integrated Healthcare Information Services (IHCIS) database. VaD was defined by the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes 290.40, 290.4, 290.41, 290.42, and, 290.43. An individual matching method was used to select the controls, which were matched to cases on a 15:1 ratio by age, gender, type of health plan, and pharmacy benefits. Alzheimer's disease, any other dementia or cognitive deficits associated were considered exclusion criteria. Among the IHCIS patients 60 years of age or older and full year of eligibility during 2010, there were 898 VaD patients, from which 63.6% were women. Concurrent presence of cerebrovascular disease, atherosclerosis, heart failure, and atrial fibrillation were found at 12.6, 4.6, 2.8, and 1.7 times higher in VaD patients, respectively. Compared to controls, VaD patients had more septicemia, injuries, lung diseases including chronic obstructive pulmonary disease, and urinary diseases (all with df = 897,1; p < 0.0001). The present study confirms that these four medical comorbidities are frequent complications of VaD and physicians should be alert to the presence of them in patients with VaD. PMID- 26230649 TI - Barriers to and Reasons for Treatment Initiation Among Gambling Help-line Callers. AB - Identifying barriers to seeking treatment is essential for increasing problem gambler treatment initiation in the community, given that as few as 1 in 10 problem gamblers ever seek treatment. Further, many problem gamblers who take the initial step of contacting problem gambling help-lines do not subsequently go on to attend face-to-face treatment. There is limited research examining reasons for attending treatment among this population. This study addressed these gaps in the literature by examining barriers and attractions to treatment among callers to the State of Michigan Problem Gambling Help-line. In total, 143 callers (n = 86 women) completed the Barriers to Treatment for Problem Gambling (BTPG) questionnaire and responded to open-ended questions regarding barriers to and reasons for treatment initiation, as part of a telephone interview. Greater endorsement of barriers to treatment was associated with a lower likelihood of initiating treatment, especially perceived absence of problem and treatment unavailability. Correspondingly, problem gamblers who identified more reasons to attend treatment were more likely to attend, with positive treatment perceptions being the most influential. These findings can help get people into treatment by addressing barriers and fostering reasons for attending treatment, as well as reminding clinicians of the importance of identifying and addressing individual treatment barriers among patients with problem gambling. PMID- 26230650 TI - Effects of physical therapy delivery via home video telerehabilitation on functional and health-related quality of life outcomes. AB - This study examined functional outcomes, health-related quality of life (HRQoL), and satisfaction in a group of Veterans who received physical therapy via an in home video telerehabilitation program, the Rural Veterans TeleRehabilitation Initiative (RVTRI). A retrospective, pre-post study design was used. Measures obtained from 26 Veterans who received physical therapy in the RVTRI program between February 22, 2010, and April 1, 2011, were analyzed. Outcomes were the Functional Independence Measure (FIM); Quick Disabilities of the Arm, Shoulder, and Hand measure; Montreal Cognitive Assessment (MoCA); and the 2-minute walk test (2MWT). HRQoL was assessed using the Veterans RAND 12-Item Health Survey (VR 12), and program satisfaction was evaluated using a telehealth satisfaction scale. Average length of participation was 99.2 +/- 43.3 d and Veterans, on average, received 15.2 +/- 6.0 therapeutic sessions. Significant improvement was shown in the participants' FIM (p < 0.001, r = 0.63), MoCA (p = 0.01, r = 0.44), 2MWT (p = 0.006, r = 0.73), and VR-12 (p = 0.02, r = 0.42). All Veterans reported satisfaction with their telerehabilitation experiences. Those enrolled in the RVTRI program avoided an average of 2,774.7 +/- 3,197.4 travel miles, 46.3 +/- 53.3 hr of driving time, and $1,151.50 +/- $1,326.90 in travel reimbursement. RVTRI provided an effective real-time, home-based, physical therapy. PMID- 26230652 TI - Why Are Children Different in Their Daily Sedentariness? An Approach Based on the Mixed-Effects Location Scale Model. AB - This study aimed to investigate the between- and within-individual variability in sedentary time over seven days, using a mixed-effects location scale model. The sample comprised 686 Portuguese children (381 girls) aged 9-11 years, from 23 schools. Sedentary time was estimated by the Actigraph GT3X+ accelerometer, which was used 24 hours/day for 7 consecutive days; height, sitting height, and weight were measured, BMI was computed (WHO cut-points were used to classify subjects as normal weight or overweight/obese), and maturity offset was estimated. Information regarding the home environment was obtained by questionnaire. Results revealed that (i) children were more sedentary on Friday, but less so on Saturday and Sunday (compared to Monday), with significant variation between- and within subjects (between-subject variance=0.800, within-subject variance=1.793, intra subject correlation=0.308); (ii) there is a sex effect on sedentariness, with boys being less sedentary than girls (p<0.001), and the between-subject variance was 1.48 times larger for boys than girls; (iii) in terms of the within-subject variance, or erraticism, Tuesday, Wednesday and Friday have similar erraticism levels as Monday (Thursday has less, while Saturday and Sunday have more); in addition, girls (variance ratio=0.632, p<0.001), overweight/obese children (variance ratio=0.861, p=0.019), and those later mature (variance ratio=0.849, p=0.013) have less erraticism than their counterparts; (iv) the within-subject variance varied significantly across subjects (scale std dev=0.342+/-0.037, p<0.001); and (v) in the fixed part of the model, only biological maturation was positively related to sedentariness. This study demonstrated that there is significant between- and within-subject variability in sedentariness across a whole week. This implies that a focus on intra-individual variability, instead of only on mean values, would provide relevant information towards a more complete map of children's sedentary behaviour, which can be helpful when developing more efficient strategies to reduce sedentariness. PMID- 26230653 TI - Performance Characteristics of Urinary Tract Cytology: Observations From the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology. AB - CONTEXT: Urine cytology is used in the evaluation of hematuria or to follow patients with known urothelial neoplasia. OBJECTIVE: To investigate the performance characteristics of urinary cytology challenges in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology. DESIGN: Participant responses from 2000 to 2010 were evaluated for the reference diagnoses of high-grade urothelial carcinoma (HGUC), squamous cell carcinoma, adenocarcinoma, and benign diagnoses (including polyomavirus infection and ileal loop urine). Responses were compared for differences in sample preparation (conventional, liquid based, and cytospin) and participant type (laboratory, pathologist, cytotechnologist). RESULTS: There were 96 093 responses (46 637 pathologists [48.5%], 29 976 cytotechnologists [31.2%], and 19 480 laboratories [20.3%]); 69 814 of 74 821 responses (93.3%) for the general category positive for malignancy and 18 698 of 21 272 responses (87.9%) for positive for malignancy were concordant. Of the malignant reference diagnoses, 83.3% (59 985 of 71 581), 43.9% (732 of 1667), and 49.1% (370 of 756) were correctly identified as HGUC, adenocarcinoma, and squamous cell carcinoma, respectively. However, 802 of 1669 adenocarcinoma challenges (48.1%) and 275 of 755 squamous cell carcinoma challenges (36.4%) were misdiagnosed as HGUC. For the benign cases, the most common diagnostic pitfall was overinterpretation of ileal loop urines (330 of 5291; 6.2%) and Polyomavirus challenges (220 of 3535; 6.2%) as HGUC. For the general diagnosis of positive for malignancy, cytotechnologists performed slightly better that pathologists (94.5% [23 553 of 24 924] versus 92.3% [36 210 of 39 230]), whereas the reverse occurred for the negative category (85.6% [6423 of 7503] versus 88.8% [10 427 of 11 742]). CONCLUSIONS: Although the participants performed well in accurately classifying cases as benign and malignant, there were difficulties with the correct identification of adenocarcinoma and squamous cell carcinoma cases and with overinterpretation of ileal loop and Polyomavirus challenges as HGUC. PMID- 26230651 TI - Incremental Diagnostic Performance of Combined Parameters in the Detection of Severe Coronary Artery Disease Using Exercise Gated Myocardial Perfusion Imaging. AB - PURPOSE: Myocardial perfusion imaging (MPI) using gated single-photon emission tomography (gSPECT) may underestimate the severity of coronary artery disease (CAD). This study aimed to evaluate the significance of combined parameters derived from gSPECT, as well as treadmill stress test parameters, in the detection of severe CAD. METHODS: A total of 211 consecutive patients referred for exercise MPI between June 2011 and June 2013 (who received invasive coronary angiography within six months after MPI) were retrospectively reviewed. Exercise MPI was performed with Bruce protocol and 201Tl injected at peak exercise. Gated SPECT was performed using a cadmium-zinc-telluride camera and processed by QPS/QGS software. Perfusion defect abnormalities such as sum stress score (SSS); sum difference score, algorithm-derived total perfusion deficits, transient ischemic dilatation ratios of end-diastolic volumes and end-systolic volumes, post-stress changes in ejection fraction, and lung/heart ratio (LHR) were calculated. Treadmill parameters, including ST depression (STD) at the 1st and 3rd minutes of recovery stage (1'STD and 3'STD), maximal STD corrected by heart rate increment (ST/HR), heart rate decline in 1st and 3rd minutes of recovery stage, recovery heart rate ratio (HR ratio), systolic and mean blood pressure ratios (SBP ratio and MAP ratio) during recovery phase were recorded. Diagnostic performances of these parameters were analyzed with receiver operating characteristic (ROC) analysis and logistic regression for detection of left main (>= 50%) or 3-vessel disease (all >= 70% luminal stenosis) on invasive angiography. RESULTS: Among various MPI and treadmill parameters used for detection of severe CAD, SSS and ST/HR had the highest AUC (0.78, 0.73, p = NS) and best cut-off values (SSS > 6, ST/HR > 17.39 10-2mV/bpm), respectively. By univariate logistic regression, all parameters except 1'HRR, 3'HRR, SBP and MAP ratios increased the odds ratio of severe CAD. Only increased L/H ratio, 3'STD, and HR ratio remained significant after multivariate regression. The predicted values of combined MPI and treadmill parameters (LHR, 3'STD, and HR ratio) gave the best ROC (AUC: 0.91) than any individual parameter or parameter combination. CONCLUSIONS: Of all treadmill and gSPECT parameters, the combination of MPI and treadmill parameters can offer better diagnostic performance for severe CAD. PMID- 26230654 TI - Unexpected Regulatory Role of CCR9 in Regulatory T Cell Development. AB - T cells reactive to microbiota regulate the pathogenesis of inflammatory bowel disease (IBD). As T cell trafficking to intestines is regulated through interactions between highly specific chemokine-chemokine receptors, efforts have been made to develop intestine-specific immunosuppression based on blocking these key processes. CCR9, a gut-trophic chemokine receptor expressed by lymphocytes and dendritic cells, has been implicated in the regulation of IBD through mediating recruitment of T cells to inflamed sites. However, the role of CCR9 in inducing and sustaining inflammation in the context of IBD is poorly understood. In this study, we demonstrate that CCR9 deficiency in effector T cells and Tregs does not affect the development of colitis in a microbiota antigen-specific, T cell-mediated model. However, Treg cells express higher levels of CCR9 compared to those in effector T cells. Interestingly, CCR9 inhibits Treg cell development, in that CCR9-/- mice demonstrate a high level of Foxp3+ Tregs, and ligation of CCR9 by its ligand CCL25 inhibits Treg cell differentiation in vitro. Collectively, our data indicate that in addition to acting as a gut-homing molecule, CCR9 signaling shapes immune responses by inhibiting Treg cell development. PMID- 26230656 TI - Quantifying the Economic and Cultural Biases of Social Media through Trending Topics. AB - Online social media has recently irrupted as the last major venue for the propagation of news and cultural content, competing with traditional mass media and allowing citizens to access new sources of information. In this paper, we study collectively filtered news and popular content in Twitter, known as Trending Topics (TTs), to quantify the extent to which they show similar biases known for mass media. We use two datasets collected in 2013 and 2014, including more than 300.000 TTs from 62 countries. The existing patterns of leader-follower relationships among countries reveal systemic biases known for mass media: Countries concentrate their attention to small groups of other countries, generating a pattern of centralization in which TTs follow the gradient of wealth across countries. At the same time, we find subjective biases within language communities linked to the cultural similarity of countries, in which countries with closer cultures and shared languages tend to follow each other's TTs. Moreover, using a novel methodology based on the Google News service, we study the influence of mass media in TTs for four countries. We find that roughly half of the TTs in Twitter overlap with news reported by mass media, and that the rest of TTs are more likely to spread internationally within Twitter. Our results confirm that online social media have the power to independently spread content beyond mass media, but at the same time social media content follows economic incentives and is subject to cultural factors and language barriers. PMID- 26230655 TI - Quantifying Postural Control during Exergaming Using Multivariate Whole-Body Movement Data: A Self-Organizing Maps Approach. AB - BACKGROUND: Exergames are becoming an increasingly popular tool for training balance ability, thereby preventing falls in older adults. Automatic, real time, assessment of the user's balance control offers opportunities in terms of providing targeted feedback and dynamically adjusting the gameplay to the individual user, yet algorithms for quantification of balance control remain to be developed. The aim of the present study was to identify movement patterns, and variability therein, of young and older adults playing a custom-made weight shifting (ice-skating) exergame. METHODS: Twenty older adults and twenty young adults played a weight-shifting exergame under five conditions of varying complexity, while multi-segmental whole-body movement data were captured using Kinect. Movement coordination patterns expressed during gameplay were identified using Self Organizing Maps (SOM), an artificial neural network, and variability in these patterns was quantified by computing Total Trajectory Variability (TTvar). Additionally a k Nearest Neighbor (kNN) classifier was trained to discriminate between young and older adults based on the SOM features. RESULTS: Results showed that TTvar was significantly higher in older adults than in young adults, when playing the exergame under complex task conditions. The kNN classifier showed a classification accuracy of 65.8%. CONCLUSIONS: Older adults display more variable sway behavior than young adults, when playing the exergame under complex task conditions. The SOM features characterizing movement patterns expressed during exergaming allow for discriminating between young and older adults with limited accuracy. Our findings contribute to the development of algorithms for quantification of balance ability during home-based exergaming for balance training. PMID- 26230657 TI - Transition-Metal-Free Tandem Chlorocyclization of Amines with Carboxylic Acids: Access to Chloroimidazo[1,2-alpha]pyridines. AB - An efficient one-pot and transition-metal-free chlorocyclization cascade of 2 aminopyridines with aliphatic carboxylic acids is reported. This transformation provides a novel approach to 2-chloro- or 3-chloro-substituted imidazo[1, 2 alpha]pyridines with a broad range of substrate scopes. PMID- 26230658 TI - Igfbp2 Deletion in Ovariectomized Mice Enhances Energy Expenditure but Accelerates Bone Loss. AB - Previously, we reported sexually dimorphic bone mass and body composition phenotypes in Igfbp2(-/-) mice (-/-), where male mice exhibited decreased bone and increased fat mass, whereas female mice displayed increased bone but no changes in fat mass. To investigate the interaction between IGF-binding protein (IGFBP)-2 and estrogen, we subjected Igfbp2 -/- and +/+ female mice to ovariectomy (OVX) or sham surgery at 8 weeks of age. At 20 weeks of age, mice underwent metabolic cage analysis and insulin tolerance tests before killing. At harvest, femurs were collected for microcomputed tomography, serum for protein levels, brown adipose tissue (BAT) and inguinal white adipose tissue (IWAT) adipose depots for histology, gene expression, and mitochondrial respiration analysis of whole tissue. In +/+ mice, serum IGFBP-2 dropped 30% with OVX. In the absence of IGFBP-2, OVX had no effect on preformed BAT; however, there was significant "browning" of the IWAT depot coinciding with less weight gain, increased insulin sensitivity, lower intraabdominal fat, and increased bone loss due to higher resorption and lower formation. Likewise, after OVX, energy expenditure, physical activity and BAT mitochondrial respiration were decreased less in the OVX-/- compared with OVX+/+. Mitochondrial respiration of IWAT was reduced in OVX+/+ yet remained unchanged in OVX-/- mice. These changes were associated with significant increases in Fgf21 and Foxc2 expression, 2 proteins known for their insulin sensitizing and browning of WAT effects. We conclude that estrogen deficiency has a profound effect on body and bone composition in the absence of IGFBP-2 and may be related to changes in fibroblast growth factor 21. PMID- 26230659 TI - A comprehensive transcriptome of early development in yellowtail kingfish (Seriola lalandi). AB - Seriola lalandi is an ecologically and economically important species that is globally distributed in temperate and subtropical marine waters. The aim of this study was to identify large numbers of genic single nucleotide polymorphisms (SNPs) and differential gene expression (DGE) related to the early development of normal and deformed S. lalandi larvae using high-throughput RNA-seq data. A de novo assembly of reads generated 40,066 genes ranging from 300 bases to 64,799 bases with an N90 of 788 bases. Homology search and protein signature recognition assigned gene ontology (GO) terms to a total of 15,744 (39.34%) genes. A search against the Kyoto Encyclopedia of Genes and Genomes Pathway database (KEGG) retrieved 6808 KEGG orthology (KO) identifiers for 10,520 genes (26.25%), and mapping of KO identifiers generated 337 KEGG pathways. Comparisons of annotated genes revealed that 1262 genes were downregulated and 1047 genes were upregulated in the deformed larvae group compared to the normal group of larvae. Additionally, we identified 6989 high-quality SNPs from the assembled transcriptome. These putative SNPs contain 4415 transitions and 2574 transversions, which will be useful for further ecological studies of S. lalandi. This is the first study to use a global transcriptomic approach in S. lalandi, and the resources generated can be used further for investigation of gene expression of marine teleosts to investigate larval developmental biology. The results of the GO enrichment analysis highlight the crucial role of the extracellular matrix in normal skeleton development, which could be important for future studies of skeletal deformities in S. lalandi and other marine species. PMID- 26230660 TI - Circulating microRNAs as biomarkers of adult Crohn's disease. AB - OBJECTIVE: Previous studies have found a differential expression of microRNAs (miRNAs) in the blood of patients with Crohn's disease (CD) compared with healthy controls. The aim of this study was to identify circulating miRNAs expressed in CD and assess their performance as biomarkers in patients with clinically suspected or known CD. METHODS: The study consisted of two parts: (a) miRNA profiling: The miRNA expression pattern was examined in six patients with CD and six controls using OpenArray miRNA profiling, and the best miRNAs were selected according to their P-value. (b) Validation cohort: In a well-characterized cohort of 102 patients with suspected or known CD, miRNAs identified by miRNA profiling or selected from previously published studies (hsa-miR-16, hsa-miR-21, hsa-miR 106a, and hsa-miR-140-3p) were measured in plasma using reverse transcription PCR. RESULTS: miRNA profiling: hsa-miR-369-3p, hsa-miR-376a, hsa-miR-376, hsa-miR 411#, hsa-miR-411, and mmu-miR-379 were downregulated in CD patients compared with the controls; hsa-miR-200c, hsa-miR-181-2#, and hsa-miR-125a-5p were upregulated (P<0.05). Validation cohort: Only hsa-miR-16 was significantly downregulated in patients with CD compared with patients without CD (fold change 0.83, P=0.02). Receiver operating characteristic analyses showed an area under the curve of 0.65. miRNAs could not discriminate inflammatory from stricturing CD or small bowel CD from CD involving the colon. CONCLUSION: In a clinically relevant cohort of patients, miRNAs in plasma identified in the present and previous studies were inadequate biomarkers for the diagnosis of CD. PMID- 26230661 TI - Ionic Liquid Surfactant Mediated Structural Transitions and Self-Assembly of Bovine Serum Albumin in Aqueous Media: Effect of Functionalization of Ionic Liquid Surfactants. AB - The self-assembly of globular protein bovine serum albumin (BSA) has been investigated in aqueous solutions of ionic liquid surfactants (ILSs), 1-dodecyl-3 methyl imidazolium chloride, [C12mim][Cl], and its amide, [C12Amim][Cl], and ester, [C12Emim][Cl], functionalized counterparts. Dynamic light scattering (DLS) has provided insights into the alterations in hydrodynamic radii (D(h)) of BSA as a function of concentration of ILSs establishing the presence of different types of BSA-ILS complexes in different concentration regimes of ILSs. Isothermal titration calorimetry (ITC) has been exploited to quantify the ILSs interacting with BSA in dilute concentration regime of ILSs. The zeta-potential measurements shed light on changes in the charged state of BSA. The morphology of various self assembled structures of BSA in different concentration regimes of ILSs have been explored using confocal laser scanning microscopy (CLSM) and scanning electron microscopy. The structural variations in ILSs have been found to produce remarkable effect on the nature and morphology of self-assembled structures of BSA. The presence of nonfunctionalized [C12mim][Cl] IL at all investigated concentrations has led to the formation of unordered large self-assembled structures of BSA. On the other hand, in specific concentration regimes, ordered self-assembled structures such as long rods and right-handedly twisted helical amyloid fibers have been observed in the presence of functionalized [C12Amim][Cl] and [C12Emim][Cl] ILSs, respectively. The nature of the formed helical fibers as amyloid ones has been confirmed using FTIR spectroscopy. Steady-state fluorescence and circular dichroism (CD) spectroscopy have provided insights into folding and unfolding of BSA as fashioned by interactions with ILSs in different concentration regimes supporting the observations made from other studies. PMID- 26230663 TI - A Closer Look at Obesogens: Lipid Homeostasis Disruption in Daphnia. PMID- 26230662 TI - Functional Roles of Neural Preparatory Processes in a Cued Stroop Task Revealed by Linking Electrophysiology with Behavioral Performance. AB - It is well established that cuing facilitates behavioral performance and that different aspects of instructional cues evoke specific neural preparatory processes in cued task-switching paradigms. To deduce the functional role of these neural preparatory processes the majority of studies vary aspects of the experimental paradigm and describe how these variations alter markers of neural preparatory processes. Although these studies provide important insights, they also have notable limitations, particularly in terms of understanding the causal or functional relationship of neural markers to cognitive and behavioral processes. In this study, we sought to address these limitations and uncover the functional roles of neural processes by examining how variability in the amplitude of neural preparatory processes predicts behavioral performance to subsequent stimuli. To achieve this objective 16 young adults were recruited to perform a cued Stroop task while their brain activity was measured using high density electroencephalography. Four temporally overlapping but functionally and topographically distinct cue-triggered event related potentials (ERPs) were identified: 1) A left-frontotemporal negativity (250-700 ms) that was positively associated with word-reading performance; 2) a midline-frontal negativity (450 800 ms) that was positively associated with color-naming and incongruent performance; 3) a left-frontal negativity (450-800 ms) that was positively associated with switch trial performance; and 4) a centroparietal positivity (450 800 ms) that was positively associated with performance for almost all trial types. These results suggest that at least four dissociable cognitive processes are evoked by instructional cues in the present task, including: 1) domain specific task facilitation; 2) switch-specific task-set reconfiguration; 3) preparation for response conflict; and 4) proactive attentional control. Examining the relationship between ERPs and behavioral performance provides a functional link between neural markers and the cognitive processes they index. PMID- 26230664 TI - Hypothyroidism and Glaucoma in The United States. AB - PURPOSE: To investigate the association between hypothyroidism and glaucomatous disease. METHODS: This cross-sectional study included all subjects above the age of 40 years from two nationwide surveys: the 2008 National Health Interview Survey (NHIS) as well as the 2007 and 2008 National Health and Nutrition Examination Survey (NHANES). The presence or absence of glaucoma, thyroid disease and other demographic and health-related information including comorbidities was ascertained via interview. Blood samples were collected from NHANES subjects and analyzed for thyrotropin (TSH). RESULTS: A total of 13,599 and 3,839 NHIS and NHANES participants respectively were analyzed to assess for a possible relationship between self-reported glaucoma, and self-reported hypothyroidism as well as self-reported thyroid disease. The unadjusted odds ratio (OR) for NHIS showed a significant association between self-reported glaucoma and self-reported hypothyroidism (OR 1.46, 95% confidence interval [CI] 1.07-1.99). Multivariate logistic regression analysis adjusted for age, gender, race, comorbidities, and health-related behavior, however, showed no association between self-reported glaucoma and hypothyroidism or thyroid disease in both surveys (OR 1.60, 95%CI 0.87-2.95 for NHIS; OR 1.05, 95%CI 0.59-1.88 for NHANES). CONCLUSION: A previously reported association between hypothyroidism and glaucomatous disease was not confirmed in two large U.S. health survey populations. While such an association was noted in the univariate analysis for the NHIS survey, such a relationship was not found in the multivariate analysis after adjustment for potential confounding variables. PMID- 26230665 TI - Plasminogen Activator Inhibitor-2 Plays a Leading Prognostic Role among Protease Families in Non-Small Cell Lung Cancer. AB - BACKGROUND: In lung cancer, uPA, its receptor (uPAR), and the inhibitors PAI-1 and PAI-2 of the plasminogen activator family interact with MMP-2 and MMP-9 of the MMP family to promote cancer progression. However, it remains undetermined which of these markers plays the most important role and may be the most useful indicator to stratify the patients by risk. METHODS: We determined the individual prognostic value of these 6 markers by analyzing a derivation cohort with 98 non small cell lung cancer patients by immunohistochemical staining. The correlation between the IHC expression levels of these markers and disease prognosis was investigated, and an immunohistochemical panel for prognostic prediction was subsequently generated through prognostic model analysis. The value of the immunohistochemical panel was then verified by a validation cohort with 91 lung cancer patients. RESULTS: In derivation cohort, PAI-2 is the most powerful prognostic factor (HR = 2.30; P = 0.001), followed by MMP-9 (HR = 2.09; P = 0.019) according to multivariate analysis. When combining PAI-2 and MMP-9, the most unfavorable prognostic group (low PAI-2 and high MMP-9 IHC expression levels) showed a 6.40-fold increased risk of a poor prognosis compared to the most favorable prognostic group (high PAI-2 and low MMP-9 IHC expression levels). PAI-2 and MMP-9 IHC panel could more precisely identify high risk patients in both derivation and validation cohort. CONCLUSIONS: We revealed PAI-2 as the most powerful prognostic marker among PA and MMP protease family even after considering their close relationships with each other. By utilizing a combination of PAI-2 and MMP-9, more precise prognostic information than merely using pathological stage alone can be obtained for lung cancer patients. PMID- 26230666 TI - Influenza Sentinel Surveillance among Patients with Influenza-Like-Illness and Severe Acute Respiratory Illness within the Framework of the National Reference Laboratory, Niger, 2009-2013. AB - BACKGROUND: Little is known about the epidemiology of influenza in Africa, including Niger. We documented the epidemiology of seasonal and pandemic influenza among outpatients with influenza-like-illness (ILI) and inpatients with severe acute respiratory illness (SARI) presenting at selected sentinel sites in Niger from April 2009 through April 2013. METHODS: Patients meeting the ILI or the SARI case definitions and presenting at the outpatient or inpatient departments of selected sentinel sites were enrolled. Epidemiological data and nasopharyngeal swabs were collected. The respiratory samples were tested by real time reverse transcription polymerase chain reaction. RESULTS: From April 2009 to April 2013, laboratory results were obtained from 1176 ILI and 952 SARI cases, of which 146 (12%) and 54 (6%) tested positive for influenza virus, respectively. The influenza positivity rate was highest in the 5-14 year age-group (32/130; 24% among ILI patients and 6/61; 10% among SARI patients) followed by the 1-4 year age-group (69/438; 16% among ILI patients and 32/333; 9% among SARI patients). Of the 200 influenza positive cases 104 (52%) were A(H1N1)pdm09, 62 (31%) were A(H3N2) and 34 (17%) were B. Influenza viruses were detected predominantly from November to April with peak viral activity observed in February. CONCLUSIONS: The Niger sentinel surveillance system allowed to monitor the circulation of seasonal influenza as well as the introduction and spread of influenza A(H1N1)pdm09 in the country. Continuous influenza surveillance is needed to better understand the epidemiology of seasonal influenza and monitor the emergence of influenza strains with pandemic potential. PMID- 26230667 TI - Training with robot-applied resistance in people with motor-incomplete spinal cord injury: Pilot study. AB - People with motor-incomplete spinal cord injury (m-iSCI) can recover basic walking function but still have difficulty performing the skilled walking required for everyday environments. We hypothesized that a robotic-based gait rehabilitation strategy founded on principles of motor learning would be a feasible and potentially effective approach for improving skilled walking in people with m-iSCI. Fifteen individuals with chronic (>1 yr) m-iSCI were randomly allocated to body weight-supported treadmill training (BWSTT) with Lokomat applied resistance (Loko-R) or conventional Lokomat-assisted BWSTT (Control). Training sessions were 45 min, 3 times/week for 3 mo. Tolerance to training was assessed by ratings of perceived exertion and reports of pain/soreness. Overground skilled walking capacity (Spinal Cord Injury-Functional Ambulation Profile [SCI-FAP]), as well as walking speed and distance were measured at baseline, posttraining, and 1 and 6 mo follow-up. Our results indicate that Loko R training could be feasibly applied for people with m-iSCI, although participants in Loko-R tended to report higher levels of perceived exertion during training. Participants in the Loko-R group performed significantly better in the SCI-FAP than Control at posttraining and in follow-up assessments. This study provides evidence that Loko-R training is feasible in people with m-iSCI. Furthermore, there is preliminary evidence suggesting that Loko-R may help improve performance in skilled overground walking tasks. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT00610974. "Enhancing Walking in People With Incomplete Spinal Cord Injury: a Pilot Study"; https://clinicaltrials.gov/ct2/show/NCT00610974. PMID- 26230668 TI - The First Modular Route to Core-Chiral Bispidine Ligands and Their Application in Enantioselective Copper(II)-Catalyzed Henry Reactions. AB - The first modular and flexible synthesis of core-chiral bispidines was achieved by using an "inside-out" strategy. The key intermediate, a NBoc-activated bispidine lactam, was constructed in enantiomerically pure form from a chirally modified beta-amino acid and 2-(acetoxymethyl)acrylonitrile in just five steps and good 48% yield. A simple addition-reduction protocol permitted a highly endo selective introduction of substituents and, thus, a fast and variable access to 2 endo-substituted and 2-endo,N-fused bi- and tricyclic bispidines. The new diamines were evaluated as the chiral ligands in asymmetric Henry reactions. Excellent enantioselectivities of up to 99% ee and good diastereomeric ratios of up to 86:14 were reached with a copper(II) complex modified by a 2-endo,N-(3,3 dimethylpyrrolidine)-annelated bispidine. Its performance is superior to that of the well-known bispidines (-)-sparteine and the (+)-sparteine surrogate. PMID- 26230669 TI - Correlates of disability related to seizures in persons with epilepsy. AB - OBJECTIVE: Seizure-related disability is an important contributor to health related quality of life in persons with epilepsy. Yet, there is little information on patient-centered reports of seizure-related disability, as most studies focus on specific constructs of health-related disability, rather than epilepsy. We investigated how patients rate their own disability and how these ratings correlate with various clinical and sociodemographic characteristics. METHODS: In a prospective cohort of 250 adults with epilepsy consecutively enrolled in the Neurological Disease and Depression Study (NEEDs), we obtained a broad range of clinical and patient-reported measures, including patients' ratings of seizure-related disability and epilepsy severity using self-completed, single-item, 7-point response global assessment scales. Spearman's correlation, multiple linear regression, and mediation analyses were used to examine the association between seizure-related disability scores and clinical and demographic characteristics of persons with epilepsy. RESULTS: The mean age and duration of epilepsy was 39.8 and 16.7 years, respectively. About 29.5% of the patients reported their seizures as "not at all disabling," whereas 5.8% of the patients reported them as "extremely disabling." Age, seizure freedom at 1 year, anxiety, and epilepsy severity were identified as statistically significant predictors of disability scores. The indirect effects of age and seizure freedom, attributable to mediation through epilepsy severity, accounted for 25.0% and 30.3% of the total effects of these determinants on seizure-related disability, respectively. SIGNIFICANCE: Measuring seizure-related disability has heuristic value and it has important correlates and mediators that can be targeted for intervention in practice. Addressing modifiable factors associated with disability (e.g., seizure freedom and anxiety) could have a significant impact on decreasing the burden of disability in people with epilepsy. PMID- 26230670 TI - NMR Relaxometry for the Thermal Stability and Phase Transition Mechanism of Flower-like Micelles from Linear and Cyclic Amphiphilic Block Copolymers. AB - Linear and cyclic amphiphilic block copolymers consisting of poly(ethylene oxide) (PEO) as the hydrophilic segment and poly(methyl acrylate) or poly(ethyl acrylate) as the hydrophobic segments were synthesized and self-assembled to form flower-like micelles. The micelles from linear (methyl acrylate)12(ethylene oxide)73(methyl acrylate)12 (Mn = 1000-3200-1000, l-MOM) showed a cloud point (Tc) at 46 degrees C by the transmittance of the micellar solution, whereas that of cyclic (methyl acrylate)30(ethylene oxide)79 (Mn = 2600-3500, c-MO) increased to 72 degrees C, as previously reported. DLS showed comparable diameters (l-MOM, 14 nm; c-MO, 12 nm) and Tc values (l-MOM, 48 degrees C; c-MO, 75 degrees C). For the investigation of the difference in Tc and the phase transition mechanism based on the polymer topology, NMR relaxometry was performed to determine the spin-lattice (T1) and spin-spin (T2) relaxation times. A decrease in T2 of the PEO segment in both l-MOM and c-MO was observed above Tc, suggesting that slow large-scale motions, such as the detachment of a chain end from the core, bridging, and interpenetration of the micelles, were inhibited. T1 of the PEO segment in l-MOM continuously increased in the experimental temperature range, indicating that the segment is hydrated even above its Tc. On the other hand, that of c-MO reached a ceiling above its Tc, likely due to the prevention of the rotation of the PEO main chain bonds caused by dehydration. Similar results were obtained for linear (ethyl acrylate)8(ethylene oxide)79(ethyl acrylate)8 (Mn = 800-3500-800, l-EOE) and its cyclic (ethyl acrylate)15(ethylene oxide)78 (Mn = 1500-3400, c-EO). PMID- 26230671 TI - A randomized, double-blind phase I/IIa study of intranasal glutathione in Parkinson's disease. AB - BACKGROUND: Depletion of reduced glutathione is associated with PD and glutathione augmentation has been proposed as a disease-modifying strategy. The aim of this study was to determine the safety and tolerability of intranasal reduced glutathione in individuals with PD. METHODS: Thirty individuals with PD were randomized to either placebo (saline), 300 mg/day, or 600 mg/day of intranasal glutathione in three divided daily doses. Follow-up visits included side effect screening of PD symptoms and cognition, blood chemistry, sinus irritation, and hyposmia. Tolerability was measured by frequency and severity of reported adverse events, compliance, and withdrawals from the study. RESULTS: After 3 months, there were no substantial differences between groups in the number of adverse events reported or observed among all safety measures assessed. All groups met tolerability criteria. CONCLUSIONS: These data support the safety and tolerability of intranasal glutathione in this population. Pharmacokinetic and dose-finding studies are warranted. PMID- 26230673 TI - A Moonshot for Sustainability Assessment. PMID- 26230672 TI - Surgery for Conditions of Infectious Etiology in Resource-Limited Countries Affected by Crisis: The Medecins Sans Frontieres Operations Centre Brussels Experience. AB - BACKGROUND: Surgery for infection represents a substantial, although undefined, disease burden in low- and middle-income countries (LMICs). Medecins Sans Frontieres-Operations Centre Brussels (MSF-OCB) provides surgical care in LMICs and collects data useful for describing operative epidemiology of surgical need otherwise unmet by national health services. This study aimed to describe the experience of MSF-OCB operations for infections in LMICs. By doing so, the results might aid effective resource allocation and preparation of future humanitarian staff. METHODS: Procedures performed in operating rooms at facilities run by MSF-OCB from July 2008 through June 2014 were reviewed. Projects providing specialty care only were excluded. Procedures for infection were described and related to demographics and reason for humanitarian response. RESULTS: A total of 96,239 operations were performed at 27 MSF-OCB sites in 15 countries between 2008 and 2014. Of the 61,177 general operations, 7,762 (13%) were for infections. Operations for skin and soft tissue infections were the most common (64%), followed by intra-abdominal (26%), orthopedic (6%), and tropical infections (3%). The proportion of operations for skin and soft tissue infections was highest during natural disaster missions (p<0.001), intra-abdominal infections during hospital support missions (p<0.001) and orthopedic infections during conflict missions (p<0.001). CONCLUSION: Surgical infections are common causes for operation in LMICs, particularly during crisis. This study found that infections require greater than expected surgical input given frequent need for serial operations to overcome contextual challenges and those associated with limited resources in other areas (e.g., ward care). Furthermore, these results demonstrate that the pattern of operations for infections is related to nature of the crisis. Incorporating training into humanitarian preparation (e.g., surgical sepsis care, ultrasound-guided drainage procedures) and ensuring adequate resources for the care of surgical infections are necessary components for providing essential surgical care during crisis. PMID- 26230674 TI - Perspectives on Inhibiting beta-Amyloid Aggregation through Structure-Based Drug Design. AB - Targeting beta-amyloid (Abeta) remains the most desired strategy in Alzheimer's disease (AD) drug discovery research. Many peptides that specifically target Abeta aggregates are known, encompassing efforts from both industrial and academic research settings. However, in clinical terms, not much success has been gained with peptide research; in turn, small drug-like molecules are already globally recognized as showing promise as an alternate approach. Abeta aggregation inhibitors are the most important part of the multifunctional drug design regimen for treating AD. Unfortunately, rational drug design approaches with small molecules are still in the initial stages. Herein we highlight, update, and elaborate on the structural anatomy of Abeta and known Abeta aggregation inhibitors in hopes of helping to optimize their use in structure based drug design approaches toward inhibitors with greater specificity. Furthermore, we present the first review of efforts to target a previously uncharacterized region of acetylcholinesterase: the N-terminal 7-20 sub-region, which was experimentally elucidated to participate in Abeta aggregation and deposition. PMID- 26230675 TI - Fitness and Phenotypic Characterization of Miltefosine-Resistant Leishmania major. AB - Trypanosomatid parasites of the genus Leishmania are the causative agents of leishmaniasis, a neglected tropical disease with several clinical manifestations. Leishmania major is the causative agent of cutaneous leishmaniasis (CL), which is largely characterized by ulcerative lesions appearing on the skin. Current treatments of leishmaniasis include pentavalent antimonials and amphotericin B, however, the toxic side effects of these drugs and difficulty with distribution makes these options less than ideal. Miltefosine (MIL) is the first oral treatment available for leishmaniasis. Originally developed for cancer chemotherapy, the mechanism of action of MIL in Leishmania spp. is largely unknown. While treatment with MIL has proven effective, higher tolerance to the drug has been observed, and resistance is easily developed in an in vitro environment. Utilizing stepwise selection we generated MIL-resistant cultures of L. major and characterized the fitness of MIL-resistant L. major. Resistant parasites proliferate at a comparable rate to the wild-type (WT) and exhibit similar apoptotic responses. As expected, MIL-resistant parasites demonstrate decreased susceptibility to MIL, which reduces after the drug is withdrawn from culture. Our data demonstrate metacyclogenesis is elevated in MIL-resistant L. major, albeit these parasites display attenuated in vitro and in vivo virulence and standard survival rates in the natural sandfly vector, indicating that development of experimental resistance to miltefosine does not lead to an increased competitive fitness in L. major. PMID- 26230676 TI - Sodium salts of anionic chiral cobalt(III) complexes as catalysts of the enantioselective Povarov reaction. AB - The sodium salts of anionic chiral cobalt(III) complexes (CCC(-) Na(+) ) have been found to be efficient catalysts of the asymmetric Povarov reaction of easily accessible dienophiles, such as 2,3-dihydrofuran, ethyl vinyl ether, and an N protected 2,3-dihydropyrrole, with 2-azadienes. Ring-fused tetrahydroquinolines with up to three contiguous stereogenic centers were thus obtained in high yields, excellent diastereoselectivities (endo/exo up to >20:1), and high enantioselectivities (up to 95:5 e.r.). PMID- 26230677 TI - New Conclusions Regarding Comparison of Sevelamer and Calcium-Based Phosphate Binders in Coronary-Artery Calcification for Dialysis Patients: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Sevelamer hydrochloride is used widely, but its impact upon cardiovascular calcification, cardiovascular mortality, all-cause mortality and hospitalization is not known. OUTCOMES: Primary outcome was cardiovascular calcification (coronary artery calcification scores (CACS) and aortic calcification scores (ACS)). Secondary outcomes were serum characteristics, hospitalization, cardiovascular mortality and all-cause mortality. Risk ratio (RR), mean differences and standard mean difference with 95% confidence intervals (CIs) were pooled using random- or fixed-effects models. RESULTS: We identified 31 studies (on 23 randomized controlled trials with 4395 participants). An analysis pooling showed a significant decrease in serum levels of phosphate with calcium-based phosphate binders (CBPBs) by 0.17 mg/dL [mean difference (MD), 95% CI, 0.03, 0.31] than sevelamer. A significant difference in the change of CACS by -102.66 [MD: 95% CI, -159.51, -45.80] and ACS by -1008.73 [MD, 95% CI, -1664.75, 352.72] between sevelamer and CBPBs was observed. Prevalence of hypercalcemia (serum levels of calcium >10.2-10.5 mg/dL and >11.0 mg/dL) was significantly smaller for sevelamer (RR = 0.44, 95% CI, 0.33, 0.58; RR = 0.24, 95% CI, 0.14, 0.40). No significant difference was found in hospitalization, all-cause mortality or cardiovascular mortality. CONCLUSIONS: This meta-analysis suggests that sevelamer benefits dialysis patients in terms of CACS, ACS and hypercalcemia. PMID- 26230678 TI - Excess of Organic Carbon in Mountain Spruce Forest Soils after Bark Beetle Outbreak Altered Microbial N Transformations and Mitigated N-Saturation. AB - Mountain forests in National park Bohemian Forest (Czech Republic) were affected by bark beetle attack and windthrows in 2004-2008, followed by an extensive tree dieback. We evaluated changes in the biochemistry of the uppermost soil horizons with the emphasis on carbon (C) and nitrogen (N) cycling in a near-natural spruce (Picea abies) mountain forest after the forest dieback, and compared it with an undisturbed control plot of similar age, climate, elevation, deposition, N saturation level, and land use history. We hypothesised that the high litter input after forest dieback at the disturbed plot and its consequent decomposition might influence the availability of C for microorganisms, and consequently, N transformations in the soil. The concentrations of dissolved organic C (DOC) and N (DON) in soil water extracts rapidly increased at the disturbed plot for 3 yeas and then continually decreased. Net ammonification exhibited a similar trend as DOC and DON, indicating elevated mineralization. Despite the high ammonium concentrations found after the forest dieback (an increase from 0.5 mmol kg-1 to 2-3 mmol kg-1), net nitrification was stable and low during these 3 years. After the DOC depletion and decrease in microbial biomass 5 years after the forest dieback, net nitrification started to rise, and nitrate concentrations increased from 0.2-1 mmol kg-1 to 2-3 mmol kg-1. Our results emphasize the key role of the availability of organic C in microbial N transformations, which probably promoted microbial heterotrophic activity at the expense of slow-growing nitrifiers. PMID- 26230679 TI - Asynchronous Rate Chaos in Spiking Neuronal Circuits. AB - The brain exhibits temporally complex patterns of activity with features similar to those of chaotic systems. Theoretical studies over the last twenty years have described various computational advantages for such regimes in neuronal systems. Nevertheless, it still remains unclear whether chaos requires specific cellular properties or network architectures, or whether it is a generic property of neuronal circuits. We investigate the dynamics of networks of excitatory inhibitory (EI) spiking neurons with random sparse connectivity operating in the regime of balance of excitation and inhibition. Combining Dynamical Mean-Field Theory with numerical simulations, we show that chaotic, asynchronous firing rate fluctuations emerge generically for sufficiently strong synapses. Two different mechanisms can lead to these chaotic fluctuations. One mechanism relies on slow I I inhibition which gives rise to slow subthreshold voltage and rate fluctuations. The decorrelation time of these fluctuations is proportional to the time constant of the inhibition. The second mechanism relies on the recurrent E-I-E feedback loop. It requires slow excitation but the inhibition can be fast. In the corresponding dynamical regime all neurons exhibit rate fluctuations on the time scale of the excitation. Another feature of this regime is that the population averaged firing rate is substantially smaller in the excitatory population than in the inhibitory population. This is not necessarily the case in the I-I mechanism. Finally, we discuss the neurophysiological and computational significance of our results. PMID- 26230681 TI - Annette Trunschke. AB - "My favorite food is Japanese noodle soup, preferably with udon. My favorite song is Wild Horses by The Rolling Stones ..." This and more about Annette Trunschke can be found on page 11608. PMID- 26230682 TI - Correction: Antiarrhythmic Effects of Dantrolene in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia and Replication of the Responses Using iPSC Models. PMID- 26230680 TI - Neuregulin 1 Improves Glucose Tolerance in db/db Mice. AB - In vitro experiments using rodent skeletal muscle cells suggest that neuregulin 1 (NRG1) is involved in glucose metabolism regulation, although no study has evaluated the role of NRG1 in systemic glucose homeostasis. The purpose of this study was to investigate the effect of chronic and acute NRG1 treatment on glucose homeostasis in db/db mice. To this aim, glucose tolerance tests were performed in 8-week-old male db/db mice after treatment with NRG1 (50MUg.kg-1) or saline 3 times per week for 8 weeks. In other experiments, glucose tolerance and pyruvate tolerance tests were performed in db/db mice 15 minutes after a single NRG1 (50MUg.kg-1) or saline injection. Liver, adipose tissue, hypothalamus and skeletal muscle were also collected 30 minutes after acute NRG1 (50MUg.kg-1) or saline treatment, and the phosphorylation status of the ERBB receptors, AKT (on Ser473) and FOXO1 (on Ser256) was assessed by western blotting. Chronic treatment (8 weeks) with NRG1 improved glucose tolerance in db/db mice. Acute treatment also lowered glycemia and insulinemia during glucose or pyruvate tolerance tests. NRG1 acute injection induced activation of ERBB3 receptors and phosphorylation of AKT and FOXO1 only in liver. Altogether, this study shows that acute and chronic NRG1 treatments improve glucose tolerance in db/db mice. This effect could be mediated through inhibition of hepatic gluconeogenesis. PMID- 26230683 TI - Salix daphnoides: A Screening for Oligomeric and Polymeric Proanthocyanidins. AB - In the present study, a qualitative analysis of proanthocyanidins (PAs) from an aqueous-methanolic extract of Salix daphnoides VILL. bark is described. Procyanidin B1 (1), B2 (2), B3 (3), B4 (4), C1 (5), epicatechin-(4beta->8) epicatechin-(4beta->8)-catechin (6) and epicatechin-(4beta->8)-epicatechin-(4beta >8)-epicatechin-(4beta->8)-catechin (7) have been isolated by a combination of different chromatographic separations on Sephadex(r) LH-20-, MCI(r)-, Diol-and RP 18-phases. Mass spectrometry, 1D- and 2D-NMR, circular dichroism and polarimetry were used for their structure elucidation and verification by comparison with the literature. Additionally, two fractions of very polar flavan-3-ols were compared: "regular" polymeric PAs received at the very end of the Sephadex(r) LH-20 chromatography showing no mobility on silica TLC and "unusual" PAs with the same RF-value but already eluting together with flavonoids in the Sephadex(r) LH-20 system. These "unusual" PAs were subsequently enriched by centrifugal partition chromatography (CPC). 13C-NMR, polarimetry, thiolysis, acid hydrolysis and phloroglucinol degradation were used to characterize both fractions. Differences in the composition of different flavan-3-ol units and the middle chain length were observed. PMID- 26230684 TI - Mixed-Sequence Recognition of Double-Stranded DNA Using Enzymatically Stable Phosphorothioate Invader Probes. AB - Development of probes that allow for sequence-unrestricted recognition of double stranded DNA (dsDNA) continues to attract much attention due to the prospect for molecular tools that enable detection, regulation, and manipulation of genes. We have recently introduced so-called Invader probes as alternatives to more established approaches such as triplex-forming oligonucleotides, peptide nucleic acids and polyamides. These short DNA duplexes are activated for dsDNA recognition by installment of +1 interstrand zippers of intercalator functionalized nucleotides such as 2'-N-(pyren-1-yl)methyl-2'-N-methyl-2' aminouridine and 2'-O-(pyren-1-yl)methyluridine, which results in violation of the nearest neighbor exclusion principle and duplex destabilization. The individual probes strands have high affinity toward complementary DNA strands, which generates the driving force for recognition of mixed-sequence dsDNA regions. In the present article, we characterize Invader probes that are based on phosphorothioate backbones (PS-DNA Invaders). The change from the regular phosphodiester backbone furnishes Invader probes that are much more stable to nucleolytic degradation, while displaying acceptable dsDNA-recognition efficiency. PS-DNA Invader probes therefore present themselves as interesting probes for dsDNA-targeting applications in cellular environments and living organisms. PMID- 26230685 TI - Synthesis of Chiral 1,4,2-Oxazaphosphepines. AB - Synthesis and structural characterization of 1,4,2-oxazaphosphepines is described. The 1,4,2-oxazaphosphepines were obtained from reaction of chiral 1,3 benzoxazines with dichlorophenylphosphine or triethyl phosphite. The configuration of some of these compounds was stablished by X-ray analysis. PMID- 26230686 TI - Fenarimol, a Pyrimidine-Type Fungicide, Inhibits Brassinosteroid Biosynthesis. AB - The plant steroid hormone brassinosteroids (BRs) are important signal mediators that regulate broad aspects of plant growth and development. With the discovery of brassinoazole (Brz), the first specific inhibitor of BR biosynthesis, several triazole-type BR biosynthesis inhibitors have been developed. In this article, we report that fenarimol (FM), a pyrimidine-type fungicide, exhibits potent inhibitory activity against BR biosynthesis. FM induces dwarfism and the open cotyledon phenotype of Arabidopsis seedlings in the dark. The IC50 value for FM to inhibit stem elongation of Arabidopsis seedlings grown in the dark was approximately 1.8 +/- 0.2 MUM. FM-induced dwarfism of Arabidopsis seedlings could be restored by brassinolide (BL) but not by gibberellin (GA). Assessment of the target site of FM in BR biosynthesis by feeding BR biosynthesis intermediates indicated that FM interferes with the side chain hydroxylation of BR biosynthesis from campestanol to teasterone. Determination of the binding affinity of FM to purified recombinant CYP90D1 indicated that FM induced a typical type II binding spectrum with a Kd value of approximately 0.79 MUM. Quantitative real-time PCR analysis of the expression level of the BR responsive gene in Arabidopsis seedlings indicated that FM induces the BR deficiency in Arabidopsis. PMID- 26230687 TI - Combined Spectroscopic and Calorimetric Studies to Reveal Absorption Mechanisms and Conformational Changes of Protein on Nanoporous Biomaterials. AB - In this study the effect of surface modification of mesoporous silica nanoparticles (MSNs) on its adsorption capacities and protein stability after immobilization of beta-lactoglobulin B (BLG-B) was investigated. For this purpose, non-functionalized (KIT-6) and aminopropyl-functionalized cubic Ia3d mesoporous silica ([n-PrNH2-KIT-6]) nanoparticles were used as nanoporous supports. Aminopropyl-functionalized mesoporous nanoparticles exhibited more potential candidates for BLG-B adsorption and minimum BLG leaching than non functionalized nanoparticles. It was observed that the amount of adsorbed BLG is dependent on the initial BLG concentration for both KIT-6 and [n-PrNH2-KIT-6] mesoporous nanoparticles. Also larger amounts of BLG-B on KIT-6 was immobilized upon raising the temperature of the medium from 4 to 55 degrees C while such increase was undetectable in the case of immobilization of BLG-B on the [n-PrNH2 KIT-6]. At temperatures above 55 degrees C the amounts of adsorbed BLG on both studied nanomaterials decreased significantly. By Differential scanning calorimetry or DSC analysis the heterogeneity of the protein solution and increase in Tm may indicate that immobilization of BLG-B onto the modified KIT-6 results in higher thermal stability compared to unmodified one. The obtained results provide several crucial factors in determining the mechanism(s) of protein adsorption and stability on the nanostructured solid supports and the development of engineered nano-biomaterials for controlled drug-delivery systems and biomimetic interfaces for the immobilization of living cells. PMID- 26230688 TI - Distribution of ADAT-Dependent Codons in the Human Transcriptome. AB - Nucleotide modifications in the anticodons of transfer RNAs (tRNA) play a central role in translation efficiency, fidelity, and regulation of translation, but, for most of these modifications, the details of their function remain unknown. The heterodimeric adenosine deaminases acting on tRNAs (ADAT2-ADAT3, or ADAT) are enzymes present in eukaryotes that convert adenine (A) to inosine (I) in the first anticodon base (position 34) by hydrolytic deamination. To explore the influence of ADAT activity on mammalian translation, we have characterized the human transcriptome and proteome in terms of frequency and distribution of ADAT related codons. Eight different tRNAs can be modified by ADAT and, once modified, these tRNAs will recognize NNC, NNU and NNA codons, but not NNG codons. We find that transcripts coding for proteins highly enriched in these eight amino acids (ADAT-aa) are specifically enriched in NNC, NNU and NNA codons. We also show that the proteins most enriched in ADAT-aa are composed preferentially of threonine, alanine, proline, and serine (TAPS). We propose that the enrichment in ADAT codons in these proteins is due to the similarities in the codons that correspond to TAPS. PMID- 26230689 TI - DeepCNF-D: Predicting Protein Order/Disorder Regions by Weighted Deep Convolutional Neural Fields. AB - Intrinsically disordered proteins or protein regions are involved in key biological processes including regulation of transcription, signal transduction, and alternative splicing. Accurately predicting order/disorder regions ab initio from the protein sequence is a prerequisite step for further analysis of functions and mechanisms for these disordered regions. This work presents a learning method, weighted DeepCNF (Deep Convolutional Neural Fields), to improve the accuracy of order/disorder prediction by exploiting the long-range sequential information and the interdependency between adjacent order/disorder labels and by assigning different weights for each label during training and prediction to solve the label imbalance issue. Evaluated by the CASP9 and CASP10 targets, our method obtains 0.855 and 0.898 AUC values, which are higher than the state-of-the art single ab initio predictors. PMID- 26230690 TI - Infections and Systemic Lupus Erythematosus: Binding or Sparring Partners? AB - Extensive work on experimental animal models clearly demonstrates that infectious agents can break immunological tolerance to self-antigens and induce autoimmune disorders, mainly systemic lupus erythematosus (SLE). The establishment of a causative link between infections and autoimmunity has been largely studied in a host of clinical studies, proving the role of infectious agents in the induction, as well as in the progression or exacerbation of SLE. However, we are far from a plain understanding of microbial-host interactions in the pathogenesis of SLE. Much serological, molecular and geoepidemiological evidence supports the relationship of different environmental infectious triggers in the inception of SLE-related autoimmune phenomena with adjuvant effects. The promotion of autoimmune responses through bystander activation or epitope spreading via multiple inflammatory pathways has been confirmed in animal models. Different viruses have been implicated in SLE pathogenesis, particularly Epstein-Barr virus, but also parvovirus B19, cytomegalovirus and retroviruses. SLE patients usually have an impaired immune response towards Epstein-Barr virus and dysregulation of the viral latency period. Furthermore, the accumulation of endogenous retroviral products might trigger the production of interferon and anti-DNA antibodies. In addition, protozoan infections might even protect from autoimmune processes and rescind an ongoing B cell activation. Herein, we discuss which type of infections induce, exacerbate or inhibit autoimmune disorders and analyze the principal infection-induced immunological mechanisms influencing the development of SLE. PMID- 26230691 TI - Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Pathway Is Induced by Mechanical Load and Reduces the Activity of Hedgehog Signaling in Chondrogenic Micromass Cell Cultures. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurohormone exerting protective function during various stress conditions either in mature or developing tissues. Previously we proved the presence of PACAP signaling elements in chicken limb bud-derived chondrogenic cells in micromass cell cultures. Since no data can be found if PACAP signaling is playing any role during mechanical stress in any tissues, we aimed to investigate its contribution in mechanotransduction during chondrogenesis. Expressions of the mRNAs of PACAP and its major receptor, PAC1 increased, while that of other receptors, VPAC1, VPAC2 decreased upon mechanical stimulus. Mechanical load enhanced the expression of collagen type X, a marker of hypertrophic differentiation of chondrocytes and PACAP addition attenuated this elevation. Moreover, exogenous PACAP also prevented the mechanical load evoked activation of hedgehog signaling: protein levels of Sonic and Indian Hedgehogs and Gli1 transcription factor were lowered while expressions of Gli2 and Gli3 were elevated by PACAP application during mechanical load. Our results suggest that mechanical load activates PACAP signaling and exogenous PACAP acts against the hypertrophy inducing effect of mechanical load. PMID- 26230692 TI - Direct Reprogramming-The Future of Cardiac Regeneration? AB - Today, the only available curative therapy for end stage congestive heart failure (CHF) is heart transplantation. This therapeutic option is strongly limited by declining numbers of available donor hearts and by restricted long-term performance of the transplanted graft. The disastrous prognosis for CHF with its restricted therapeutic options has led scientists to develop different concepts of alternative regenerative treatment strategies including stem cell transplantation or stimulating cell proliferation of different cardiac cell types in situ. However, first clinical trials with overall inconsistent results were not encouraging, particularly in terms of functional outcome. Among other approaches, very promising ongoing pre-clinical research focuses on direct lineage conversion of scar fibroblasts into functional myocardium, termed "direct reprogramming" or "transdifferentiation." This review seeks to summarize strategies for direct cardiac reprogramming including the application of different sets of transcription factors, microRNAs, and small molecules for an efficient generation of cardiomyogenic cells for regenerative purposes. PMID- 26230694 TI - A Decentralized Wireless Solution to Monitor and Diagnose PV Solar Module Performance Based on Symmetrized-Shifted Gompertz Functions. AB - This paper proposes and assesses an integrated solution to monitor and diagnose photovoltaic (PV) solar modules based on a decentralized wireless sensor acquisition system. Both DC electrical variables and environmental data are collected at PV module level using low-cost and high-energy efficiency node sensors. Data is real-time processed locally and compared with expected PV module performances obtained by a PV module model based on symmetrized-shifted Gompertz functions (as previously developed and assessed by the authors). Sensor nodes send data to a centralized sink-computing module using a multi-hop wireless sensor network architecture. Such integration thus provides extensive analysis of PV installations, and avoids off-line tests or post-processing processes. In comparison with previous approaches, this solution is enhanced with a low-cost system and non-critical performance constraints, and it is suitable for extensive deployment in PV power plants. Moreover, it is easily implemented in existing PV installations, since no additional wiring is required. The system has been implemented and assessed in a Spanish PV power plant connected to the grid. Results and estimations of PV module performances are also included in the paper. PMID- 26230695 TI - V-Alert: Description and Validation of a Vulnerable Road User Alert System in the Framework of a Smart City. AB - V-Alert is a cooperative application to be deployed in the frame of Smart Cities with the aim of reducing the probability of accidents involving Vulnerable Road Users (VRU) and vehicles. The architecture of V-Alert combines short- and long range communication technologies in order to provide more time to the drivers and VRU to take the appropriate maneuver and avoid a possible collision. The information generated by mobile sensors (vehicles and cyclists) is sent over this heterogeneous communication architecture and processed in a central server, the Drivers Cloud, which is in charge of generating the messages that are shown on the drivers' and cyclists' Human Machine Interface (HMI). First of all, V-Alert has been tested in a simulated scenario to check the communications architecture in a complex scenario and, once it was validated, all the elements of V-Alert have been moved to a real scenario to check the application reliability. All the results are shown along the length of this paper. PMID- 26230696 TI - Temporal and Spatial Denoising of Depth Maps. AB - This work presents a procedure for refining depth maps acquired using RGB-D (depth) cameras. With numerous new structured-light RGB-D cameras, acquiring high resolution depth maps has become easy. However, there are problems such as undesired occlusion, inaccurate depth values, and temporal variation of pixel values when using these cameras. In this paper, a proposed method based on an exemplar-based inpainting method is proposed to remove artefacts in depth maps obtained using RGB-D cameras. Exemplar-based inpainting has been used to repair an object-removed image. The concept underlying this inpainting method is similar to that underlying the procedure for padding the occlusions in the depth data obtained using RGB-D cameras. Therefore, our proposed method enhances and modifies the inpainting method for application in and the refinement of RGB-D depth data image quality. For evaluating the experimental results of the proposed method, our proposed method was tested on the Tsukuba Stereo Dataset, which contains a 3D video with the ground truths of depth maps, occlusion maps, RGB images, the peak signal-to-noise ratio, and the computational time as the evaluation metrics. Moreover, a set of self-recorded RGB-D depth maps and their refined versions are presented to show the effectiveness of the proposed method. PMID- 26230697 TI - A Rapid Convergent Low Complexity Interference Alignment Algorithm for Wireless Sensor Networks. AB - Interference alignment (IA) is a novel technique that can effectively eliminate the interference and approach the sum capacity of wireless sensor networks (WSNs) when the signal-to-noise ratio (SNR) is high, by casting the desired signal and interference into different signal subspaces. The traditional alternating minimization interference leakage (AMIL) algorithm for IA shows good performance in high SNR regimes, however, the complexity of the AMIL algorithm increases dramatically as the number of users and antennas increases, posing limits to its applications in the practical systems. In this paper, a novel IA algorithm, called directional quartic optimal (DQO) algorithm, is proposed to minimize the interference leakage with rapid convergence and low complexity. The properties of the AMIL algorithm are investigated, and it is discovered that the difference between the two consecutive iteration results of the AMIL algorithm will approximately point to the convergence solution when the precoding and decoding matrices obtained from the intermediate iterations are sufficiently close to their convergence values. Based on this important property, the proposed DQO algorithm employs the line search procedure so that it can converge to the destination directly. In addition, the optimal step size can be determined analytically by optimizing a quartic function. Numerical results show that the proposed DQO algorithm can suppress the interference leakage more rapidly than the traditional AMIL algorithm, and can achieve the same level of sum rate as that of AMIL algorithm with far less iterations and execution time. PMID- 26230698 TI - Research on Parameter Estimation Methods for Alpha Stable Noise in a Laser Gyroscope's Random Error. AB - Alpha stable noise, determined by four parameters, has been found in the random error of a laser gyroscope. Accurate estimation of the four parameters is the key process for analyzing the properties of alpha stable noise. Three widely used estimation methods-quantile, empirical characteristic function (ECF) and logarithmic moment method-are analyzed in contrast with Monte Carlo simulation in this paper. The estimation accuracy and the application conditions of all methods, as well as the causes of poor estimation accuracy, are illustrated. Finally, the highest precision method, ECF, is applied to 27 groups of experimental data to estimate the parameters of alpha stable noise in a laser gyroscope's random error. The cumulative probability density curve of the experimental data fitted by an alpha stable distribution is better than that by a Gaussian distribution, which verifies the existence of alpha stable noise in a laser gyroscope's random error. PMID- 26230693 TI - Treatment Strategies that Enhance the Efficacy and Selectivity of Mitochondria Targeted Anticancer Agents. AB - Nearly a century has passed since Otto Warburg first observed high rates of aerobic glycolysis in a variety of tumor cell types and suggested that this phenomenon might be due to an impaired mitochondrial respiratory capacity in these cells. Subsequently, much has been written about the role of mitochondria in the initiation and/or progression of various forms of cancer, and the possibility of exploiting differences in mitochondrial structure and function between normal and malignant cells as targets for cancer chemotherapy. A number of mitochondria-targeted compounds have shown efficacy in selective cancer cell killing in pre-clinical and early clinical testing, including those that induce mitochondria permeability transition and apoptosis, metabolic inhibitors, and ROS regulators. To date, however, none has exhibited the standards for high selectivity and efficacy and low toxicity necessary to progress beyond phase III clinical trials and be used as a viable, single modality treatment option for human cancers. This review explores alternative treatment strategies that have been shown to enhance the efficacy and selectivity of mitochondria-targeted anticancer agents in vitro and in vivo, and may yet fulfill the clinical promise of exploiting the mitochondrion as a target for cancer chemotherapy. PMID- 26230700 TI - Multi-Stress Monitoring System with Fiber-Optic Mandrels and Fiber Bragg Grating Sensors in a Sagnac Loop. AB - Fiber Bragg grating sensors are placed in a fiber-optic Sagnac loop to combine the grating temperature sensors and the fiber-optic mandrel acoustic emission sensors in single optical circuit. A wavelength-scanning fiber-optic laser is used as a common light source for both sensors. A fiber-optic attenuator is placed at a specific position in the Sagnac loop in order to separate buried Bragg wavelengths from the Sagnac interferometer output. The Bragg wavelength shifts are measured with scanning band-pass filter demodulation and the mandrel output is analyzed by applying a fast Fourier transform to the interference signal. This hybrid-scheme could greatly reduce the size and the complexity of optical circuitry and signal processing unit, making it suitable for low cost multi-stress monitoring of large scale power systems. PMID- 26230699 TI - An Impedance Aptasensor with Microfluidic Chips for Specific Detection of H5N1 Avian Influenza Virus. AB - In this research a DNA aptamer, which was selected through SELEX (systematic evolution of ligands by exponential enrichment) to be specific against the H5N1 subtype of the avian influenza virus (AIV), was used as an alternative reagent to monoclonal antibodies in an impedance biosensor utilizing a microfluidics flow cell and an interdigitated microelectrode for the specific detection of H5N1 AIV. The gold surface of the interdigitated microelectrode embedded in a microfluidics flow cell was modified using streptavidin. The biotinylated aptamer against H5N1 was then immobilized on the electrode surface using biotin-streptavidin binding. The target virus was captured on the microelectrode surface, causing an increase in impedance magnitude. The aptasensor had a detection time of 30 min with a detection limit of 0.0128 hemagglutinin units (HAU). Scanning electron microscopy confirmed the binding of the target virus onto the electrode surface. The DNA aptamer was specific to H5N1 and had no cross-reaction to other subtypes of AIV (e.g., H1N1, H2N2, H7N2). The newly developed aptasensor offers a portable, rapid, low-cost alternative to current methods with the same sensitivity and specificity. PMID- 26230701 TI - Structured Light-Based 3D Reconstruction System for Plants. AB - Camera-based 3D reconstruction of physical objects is one of the most popular computer vision trends in recent years. Many systems have been built to model different real-world subjects, but there is lack of a completely robust system for plants. This paper presents a full 3D reconstruction system that incorporates both hardware structures (including the proposed structured light system to enhance textures on object surfaces) and software algorithms (including the proposed 3D point cloud registration and plant feature measurement). This paper demonstrates the ability to produce 3D models of whole plants created from multiple pairs of stereo images taken at different viewing angles, without the need to destructively cut away any parts of a plant. The ability to accurately predict phenotyping features, such as the number of leaves, plant height, leaf size and internode distances, is also demonstrated. Experimental results show that, for plants having a range of leaf sizes and a distance between leaves appropriate for the hardware design, the algorithms successfully predict phenotyping features in the target crops, with a recall of 0.97 and a precision of 0.89 for leaf detection and less than a 13-mm error for plant size, leaf size and internode distance. PMID- 26230702 TI - Bench to Bedside: Stability Studies of GMP Produced Trastuzumab-TCMC in Support of a Clinical Trial. AB - The first-in-human phase 1 clinical radioimmunotherapy (RIT) trial with 212Pb 1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane-trastuzumab (212Pb-TCMC-trastuzumab) was completed in October 2014 as a joint effort at the University of Alabama (UAB) and the University of California San Diego Moores Cancer Center. The preliminary reports indicate that after five dose-levels of intraperitoneally administered 212Pb-TCMC-trastuzumab, patients with carcinomatosis experienced minimal agent-related toxicity. This report presents the data accumulated to date on the stability of the clinical grade, produced according to current good manufacturing practices (cGMP), TCMC-trastuzumab conducted in support of that clinical trial. Of the eleven tests performed with the cGMP TCMC-trastuzumab all but one remained within specifications throughout the 5 year testing period. The protein concentration varied by 0.01 mg/mL at 48 months. Two other assays, ion-exchange high performance liquid chromatography (IEX-HPLC) and a competitive radioimmunoassay (RIA) indicated that the cGMP TCMC trastuzumab integrity may be changing, although the change thus far is within specifications. Subsequent stability testing will confirm if a trend has truly developed. The cGMP TCMC-trastuzumab was also evaluated for tolerance to higher temperatures and the potential of storage at -80 degrees C. The immunoconjugate proved stable when subjected to the lower temperatures and to multiple freeze thaw cycles. The size exclusion (SE) HPLC analysis of the 203Pb-TCMC-trastuzumab was the only indicator that cGMP TCMC-trastuzumab may be sensitive to storage at 37 degrees C for 3 months. PMID- 26230703 TI - The Bright Side of Gelatinous Blooms: Nutraceutical Value and Antioxidant Properties of Three Mediterranean Jellyfish (Scyphozoa). AB - Jellyfish are recorded with increasing frequency and magnitude in many coastal areas and several species display biological features comparable to the most popular Asiatic edible jellyfish. The biochemical and antioxidant properties of wild gelatinous biomasses, in terms of nutritional and nutraceutical values, are still largely unexplored. In this paper, three of the most abundant and commonly recorded jellyfish species (Aurelia sp.1, Cotylorhiza tuberculata and Rhizostoma pulmo) in the Mediterranean Sea were subject to investigation. A sequential enzymatic hydrolysis of jellyfish proteins was set up by pepsin and collagenase treatments of jellyfish samples after aqueous or hydroalcoholic protein extraction. The content and composition of proteins, amino acids, phenolics, and fatty acids of the three species were recorded and compared. Protein content (mainly represented by collagen) up to 40% of jellyfish dry weight were found in two of the three jellyfish species (C. tuberculata and R. pulmo), whereas the presence of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) was significantly higher in the zooxanthellate jellyfish C. tuberculata only. Remarkable antioxidant ability was also recorded from both proteinaceous and non proteinaceous extracts and the hydrolyzed protein fractions in all the three species. The abundance of collagen, peptides and other bioactive molecules make these Mediterranean gelatinous biomasses a largely untapped source of natural compounds of nutraceutical, cosmeceutical and pharmacological interest. PMID- 26230704 TI - Monacyclinones, New Angucyclinone Metabolites Isolated from Streptomyces sp. M7_15 Associated with the Puerto Rican Sponge Scopalina ruetzleri. AB - During an investigation of new actinomycete species from Caribbean sponges for novel bioactive natural products, frigocyclinone (1), dimethyldehydrorabelomycin (3) and six new angucyclinone derivatives were isolated from Streptomyces sp. strain M7_15 associated with the sponge Scopalina ruetzleri. Of these, monacyclinones A-B (4-5) contain the core ring structure of dehydrorabelomycin (2) with the aminodeoxysugar found in frigocyclinone (1). Monacyclinone C (6) is a hydroxylated variant of frigocyclinone (1) and monacyclinone D (7) is a Baeyer Villiger derivative of (6) which also exists as the open chain hydrolysis product monacyclinone E (8). Monacyclinone F (9) contains two unique epoxide rings attached to the angucyclinone moiety and an additional aminodeoxysugar attached through an angular oxygen bond. All structures were confirmed through spectral analyses. Activity against rhabdomycosarcoma cancer cells (SJCRH30) after 48 h of treatment was observed with frigocyclinone (1; EC50 = 5.2 uM), monacyclinone C (6; 160 uM), monacyclinone E (8; 270 uM), and monacyclinone F (9; 0.73 uM). The strongest bioactivity against rhabdomycosarcoma cancer cells and gram-positive bacteria was exhibited by compound 9, suggesting that the extra aminodeoxysugar subunit is important for biological activity. PMID- 26230705 TI - Cr(VI) Sorption/Desorption on Pine Sawdust and Oak Wood Ash. AB - The objective of this work was to study Cr(VI) sorption/desorption on two by products from the wood industry: pine sawdust and oak wood ash. The retention/release experiments were carried out using standard batch-type trials. In the sorption-phase experiments, pine sawdust showed 23% sorption when a concentration of 100 mg Cr(VI)?L-1 was added, whereas sorption on oak wood ash was 17%. In the desorption-phase, chromium release was clearly higher from pine sawdust than from oak wood ash (98% and 66%, respectively). Sorption curves were well fitted to the Freundlich and Lineal models. In view of the results, both materials can be considered of very limited value to remove Cr from polluted soil and water, which can be of relevance regarding its appropriate use as biosorbents and recycled by-products. PMID- 26230706 TI - Evaluation of Trichodysplasia Spinulosa-Associated Polyomavirus Capsid Protein as a New Carrier for Construction of Chimeric Virus-Like Particles Harboring Foreign Epitopes. AB - Recombinant virus-like particles (VLPs) represent a promising tool for protein engineering. Recently, trichodysplasia spinulosa-associated polyomavirus (TSPyV) viral protein 1 (VP1) was efficiently produced in yeast expression system and shown to self-assemble to VLPs. In the current study, TSPyV VP1 protein was exploited as a carrier for construction of chimeric VLPs harboring selected B and T cell-specific epitopes and evaluated in comparison to hamster polyomavirus VP1 protein. Chimeric VLPs with inserted either hepatitis B virus preS1 epitope DPAFR or a universal T cell-specific epitope AKFVAAWTLKAAA were produced in yeast Saccharomyces cerevisiae. Target epitopes were incorporated either at the HI or BC loop of the VP1 protein. The insertion sites were selected based on molecular models of TSPyV VP1 protein. The surface exposure of the insert positions was confirmed using a collection of monoclonal antibodies raised against the intact TSPyV VP1 protein. All generated chimeric proteins were capable to self-assemble to VLPs, which induced a strong immune response in mice. The chimeric VLPs also activated dendritic cells and T cells as demonstrated by analysis of cell surface markers and cytokine production profiles in spleen cell cultures. In conclusion, TSPyV VP1 protein represents a new potential carrier for construction of chimeric VLPs harboring target epitopes. PMID- 26230707 TI - The Fate of Fat: Pre-Exposure Fat Losses during Nasogastric Tube Feeding in Preterm Newborns. AB - Deficient nutritional support and subsequent postnatal growth failure are major covariates of short- and long-term outcome in preterm neonates. Despite its relevance, extrauterine growth restriction (EUGR) is still prevalent, occurring in an important portion of extremely preterm infants. Lipids provide infants with most of their energy needs, but also cover specific supplies critical to growth, development and health. The use of human milk in preterm neonates results in practices, such as milk storage, pasteurization and administration by an infusion system. All of these pre-exposure manipulations significantly affect the final extent of lipid deposition in the intestinal track available for absorption, but the impact of tube feeding is the most significant. Strategies to shift earlier to oral feeding are available, while adaptations of the infusion systems (inversion, variable flow) have only more recently been shown to be effective in "in vitro", but not yet in "in vivo" settings. Pre-exposure-related issues for drugs and nutritional compounds show similarities. Therefore, we suggest that the available practices for "in vitro" drug evaluations should also be considered in feeding strategies to further reduce pre-exposure losses as a strategy to improve the nutritional status and outcome of preterm neonates. PMID- 26230709 TI - Bee Venom Acupuncture Augments Anti-Inflammation in the Peripheral Organs of hSOD1G93A Transgenic Mice. AB - Amyotrophic lateral sclerosis (ALS) includes progressively degenerated motor neurons in the brainstem, motor cortex, and spinal cord. Recent reports demonstrate the dysfunction of multiple organs, including the lungs, spleen, and liver, in ALS animals and patients. Bee venom acupuncture (BVA) has been used for treating inflammatory diseases in Oriental Medicine. In a previous study, we demonstrated that BV prevented motor neuron death and increased anti-inflammation in the spinal cord of symptomatic hSOD1G93A transgenic mice. In this study, we examined whether BVA's effects depend on acupuncture point (ST36) in the organs, including the liver, spleen and kidney, of hSOD1G93A transgenic mice. We found that BV treatment at ST36 reduces inflammation in the liver, spleen, and kidney compared with saline-treatment at ST36 and BV injected intraperitoneally in symptomatic hSOD1G93A transgenic mice. Those findings suggest that BV treatment combined with acupuncture stimulation is more effective at reducing inflammation and increasing immune responses compared with only BV treatment, at least in an ALS animal model. PMID- 26230708 TI - Phylogeny of the Vitamin K 2,3-Epoxide Reductase (VKOR) Family and Evolutionary Relationship to the Disulfide Bond Formation Protein B (DsbB) Family. AB - In humans and other vertebrate animals, vitamin K 2,3-epoxide reductase (VKOR) family enzymes are the gatekeepers between nutritionally acquired K vitamins and the vitamin K cycle responsible for posttranslational modifications that confer biological activity upon vitamin K-dependent proteins with crucial roles in hemostasis, bone development and homeostasis, hormonal carbohydrate regulation and fertility. We report a phylogenetic analysis of the VKOR family that identifies five major clades. Combined phylogenetic and site-specific conservation analyses point to clade-specific similarities and differences in structure and function. We discovered a single-site determinant uniquely identifying VKOR homologs belonging to human pathogenic, obligate intracellular prokaryotes and protists. Building on previous work by Sevier et al. (Protein Science 14:1630), we analyzed structural data from both VKOR and prokaryotic disulfide bond formation protein B (DsbB) families and hypothesize an ancient evolutionary relationship between the two families where one family arose from the other through a gene duplication/deletion event. This has resulted in circular permutation of primary sequence threading through the four-helical bundle protein folds of both families. This is the first report of circular permutation relating distant a-helical membrane protein sequences and folds. In conclusion, we suggest a chronology for the evolution of the five extant VKOR clades. PMID- 26230710 TI - Murine Anorectic Response to Deoxynivalenol (Vomitoxin) Is Sex-Dependent. AB - Deoxynivalenol (DON, vomitoxin), a common trichothecene mycotoxin found in cereal foods, dysregulates immune function and maintenance of energy balance. The purpose of this study was to determine if sex differences are similarly evident in DON's anorectic responses in mice. A bioassay for feed refusal, previously developed by our lab, was used to compare acute i.p. exposures of 1 and 5 mg/kg bw DON in C57BL6 mice. Greater anorectic responses were seen in male than female mice. Male mice had higher organ and plasma concentrations of DON upon acute exposure than their female counterparts. A significant increase in IL-6 plasma levels was also observed in males while cholecystokinin response was higher in females. When effects of sex on food intake and body weight changes were compared after subchronic dietary exposure to 1, 2.5, and 10 ppm DON, males were found again to be more sensitive. Demonstration of male predilection to DON-induced changes in food intake and weight gain might an important consideration in future risk assessment of DON and other trichothecenes. PMID- 26230711 TI - Long Non-Coding RNAs: The Key Players in Glioma Pathogenesis. AB - Long non-coding RNAs (LncRNAs) represent a novel class of RNAs with no functional protein-coding ability, yet it has become increasingly clear that interactions between lncRNAs with other molecules are responsible for important gene regulatory functions in various contexts. Given their relatively high expressions in the brain, lncRNAs are now thought to play important roles in normal brain development as well as diverse disease processes including gliomagenesis. Intriguingly, certain lncRNAs are closely associated with the initiation, differentiation, progression, recurrence and stem-like characteristics in glioma, and may therefore be exploited for the purposes of sub-classification, diagnosis and prognosis. LncRNAs may also serve as potential therapeutic targets as well as a novel biomarkers in the treatment of glioma. In this article, the functional aspects of lncRNAs, particularly within the central nervous system (CNS), will be briefly discussed, followed by highlights of the important roles of lncRNAs in mediating critical steps during glioma development. In addition, the key lncRNA players and their possible mechanistic pathways associated with gliomagenesis will be addressed. PMID- 26230712 TI - Novel Insights into the Development and Function of Cilia Using the Advantages of the Paramecium Cell and Its Many Cilia. AB - Paramecium species, especially P. tetraurelia and caudatum, are model organisms for modern research into the form and function of cilia. In this review, we focus on the ciliary ion channels and other transmembrane proteins that control the beat frequency and wave form of the cilium by controlling the signaling within the cilium. We put these discussions in the context of the advantages that Paramecium brings to the understanding of ciliary motility: mutants for genetic dissections of swimming behavior, electrophysiology, structural analysis, abundant cilia for biochemistry and modern proteomics, genomics and molecular biology. We review the connection between behavior and physiology, which allows the cells to broadcast the function of their ciliary channels in real time. We build a case for the important insights and advantages that this model organism continues to bring to the study of cilia. PMID- 26230714 TI - Correction: The TAL Effector PthA4 Interacts with Nuclear Factors Involved in RNA Dependent Processes Including a HMG Protein That Selectively Binds Poly(U) RNA. PMID- 26230713 TI - Nonmechanical Roles of Dystrophin and Associated Proteins in Exercise, Neuromuscular Junctions, and Brains. AB - Dystrophin-glycoprotein complex (DGC) is an important structural unit in skeletal muscle that connects the cytoskeleton (f-actin) of a muscle fiber to the extracellular matrix (ECM). Several muscular dystrophies, such as Duchenne muscular dystrophy, Becker muscular dystrophy, congenital muscular dystrophies (dystroglycanopathies), and limb-girdle muscular dystrophies (sarcoglycanopathies), are caused by mutations in the different DGC components. Although many early studies indicated DGC plays a crucial mechanical role in maintaining the structural integrity of skeletal muscle, recent studies identified novel roles of DGC. Beyond a mechanical role, these DGC members play important signaling roles and act as a scaffold for various signaling pathways. For example, neuronal nitric oxide synthase (nNOS), which is localized at the muscle membrane by DGC members (dystrophin and syntrophins), plays an important role in the regulation of the blood flow during exercise. DGC also plays important roles at the neuromuscular junction (NMJ) and in the brain. In this review, we will focus on recently identified roles of DGC particularly in exercise and the brain. PMID- 26230716 TI - Vertically Aligned Ge Nanowires on Flexible Plastic Films Synthesized by (111) Oriented Ge Seeded Vapor-Liquid-Solid Growth. AB - Transfer-free fabrication of vertical Ge nanowires (NWs) on a plastic substrate is demonstrated using a vapor-liquid-solid (VLS) method. The crystal quality of Ge seed layers (50 nm thickness) prepared on plastic substrates strongly influenced the VLS growth morphology, i.e., the density, uniformity, and crystal quality of Ge NWs. The metal-induced layer exchange yielded a (111)-oriented Ge seed layer at 325 degrees C, which allowed for the VLS growth of vertically aligned Ge NWs. The Ge NW array had almost the same quality as that formed on a bulk Ge(111) substrate. Transmission electron microscopy demonstrated that the Ge NWs were defect-free single crystals. The present investigation paves the way for advanced electronic optical devices integrated on a low-cost flexible substrate. PMID- 26230715 TI - EhVps32 Is a Vacuole-Associated Protein Involved in Pinocytosis and Phagocytosis of Entamoeaba histolytica. AB - Here, we investigated the role of EhVps32 protein (a member of the endosomal sorting complex required for transport) in endocytosis of Entamoeba histolytica, a professional phagocyte. Confocal microscopy, TEM and cell fractionation revealed EhVps32 in cytoplasmic vesicles and also located adjacent to the plasma membrane. Between 5 to 30 min of phagocytosis, EhVps32 was detected on some erythrocytes-containing phagosomes of acidic nature, and at 60 min it returned to cytoplasmic vesicles and also appeared adjacent to the plasma membrane. TEM images revealed it in membranous structures in the vicinity of ingested erythrocytes. EhVps32, EhADH (an ALIX family member), Gal/GalNac lectin and actin co-localized in the phagocytic cup and in some erythrocytes-containing phagosomes, but EhVps32 was scarcely detected in late phagosomes. During dextran uptake, EhVps32, EhADH and Gal/GalNac lectin, but not actin, co-localized in pinosomes. EhVps32 recombinant protein formed oligomers composed by rings and filaments. Antibodies against EhVps32 monomers stained cytoplasmic vesicles but not erythrocytes-containing phagosomes, suggesting that in vivo oligomers are formed on phagosome membranes. The involvement of EhVps32 in phagocytosis was further study in pNeoEhvps32-HA-transfected trophozoites, which augmented almost twice their rate of erythrophagocytosis as well as the membranous concentric arrays built by filaments, spirals and tunnel-like structures. Some of these structures apparently connected phagosomes with the phagocytic cup. In concordance, the EhVps32-silenced G3 trophozoites ingested 80% less erythrocytes than the G3 strain. Our results suggest that EhVps32 participates in E. histolytica phagocytosis and pinocytosis. It forms oligomers on erythrocytes containing phagosomes, probably as a part of the scission machinery involved in membrane invagination and intraluminal vesicles formation. PMID- 26230717 TI - Signal Partitioning Algorithm for Highly Efficient Gaussian Mixture Modeling in Mass Spectrometry. AB - Mixture - modeling of mass spectra is an approach with many potential applications including peak detection and quantification, smoothing, de-noising, feature extraction and spectral signal compression. However, existing algorithms do not allow for automated analyses of whole spectra. Therefore, despite highlighting potential advantages of mixture modeling of mass spectra of peptide/protein mixtures and some preliminary results presented in several papers, the mixture modeling approach was so far not developed to the stage enabling systematic comparisons with existing software packages for proteomic mass spectra analyses. In this paper we present an efficient algorithm for Gaussian mixture modeling of proteomic mass spectra of different types (e.g., MALDI-ToF profiling, MALDI-IMS). The main idea is automated partitioning of protein mass spectral signal into fragments. The obtained fragments are separately decomposed into Gaussian mixture models. The parameters of the mixture models of fragments are then aggregated to form the mixture model of the whole spectrum. We compare the elaborated algorithm to existing algorithms for peak detection and we demonstrate improvements of peak detection efficiency obtained by using Gaussian mixture modeling. We also show applications of the elaborated algorithm to real proteomic datasets of low and high resolution. PMID- 26230719 TI - Correction: Epidemiology of Imported Leishmaniasis in Italy: Implications for a European Endemic Country. PMID- 26230718 TI - Neurohypophysial Hormones Regulate Amphibious Behaviour in the Mudskipper Goby. AB - The neurohypophysial hormones, arginine vasotocin and isotocin, regulate both hydromineral balance and social behaviors in fish. In the amphibious mudskipper, Periophthalmus modestus, we previously found arginine-vasotocin-specific regulation of aggressive behavior, including migration of the submissive subordinate into water. This migration also implies the need for adaptation to dehydration. Here, we examined the effects of arginine vasotocin and isotocin administration on the amphibious behavior of individual mudskippers in vivo. The mudskippers remained in the water for an increased period of time after 1-8 h of intracerebroventricular (ICV) injection with 500 pg/g arginine vasotocin or isotocin. The 'frequency of migration' was decreased after ICV injection of arginine vasotocin or isotocin, reflecting a tendency to remain in the water. ICV injections of isotocin receptor antagonist with arginine vasotocin or isotocin inhibited all of these hormonal effects. In animals kept out of water, mRNA expression of brain arginine vasotocin and isotocin precursors increased 3- and 1.5-fold, respectively. Given the relatively wide distribution of arginine vasotocin fibres throughout the mudskipper brain, induction of arginine vasotocin and isotocin under terrestrial conditions may be involved also in the preference for an aquatic habitat as ligands for brain isotocin receptors. PMID- 26230720 TI - Differential Impacts of Virus Diversity on Biomass Production of a Native and an Exotic Grass Host. AB - Pathogens are common and diverse in natural communities and have been implicated in the success of host invasions. Yet few studies have experimentally measured how pathogens impact native versus exotic hosts, particularly when individual hosts are simultaneously coinfected by diverse pathogens. To estimate effects of interactions among multiple pathogens within host individuals on both transmission of pathogens and fitness consequences for hosts, we conducted a greenhouse experiment using California grassland species: the native perennial grass Nassella (Stipa) pulchra, the exotic annual grass Bromus hordeaceus, and three virus species, Barley yellow dwarf virus-PAV, Barley yellow dwarf virus MAV, and Cereal yellow dwarf virus-RPV. In terms of virus transmission, the native host was less susceptible than the exotic host to MAV. Coinfection of PAV and MAV did not occur in any of the 157 co-inoculated native host plants. In the exotic host, PAV infection most strongly reduced root and shoot biomass, and coinfections that included PAV severely reduced biomass. Infection with single or multiple viruses did not affect biomass in the native host. However, in this species the most potentially pathogenic coinfections (PAV + MAV and PAV + MAV + RPV) did not occur. Together, these results suggest that interactions among multiple pathogens can have important consequences for host health, which may not be predictable from interactions between hosts and individual pathogens. This work addresses a key empirical gap in understanding the impact of multiple generalist pathogens on competing host species, with potential implications for population and community dynamics of native and exotic species. It also demonstrates how pathogens with relatively mild impacts independently can more substantially reduce host performance in coinfection. PMID- 26230721 TI - Promoter Hypermethylation and Decreased Expression of Syncytin-1 in Pancreatic Adenocarcinomas. AB - Syncytin-1 is a member of human endogenous retroviral W gene family (HERVW1). Known to be expressed in human placental trophoblast, syncytin-1 protein mediates the fusion of cytotrophoblasts for the formation of syncytiotrophoblasts, the terminally differentiated form of trophoblast lineage. In addition, in vitro studies indicate that syncytin-1 possessed nonfusogenic functions such as those for immune suppression, cell cycle regulation and anti-apoptotic activities. Overexpression of syncytin-1 has been observed in various malignant tissues including breast, endometrial and ovarian cancers. It was reported that syncytin 1 gene expression is associated with dynamic changes of DNA hypomethylation in the 5' LTR. In this study, applying the real-time PCR, Western blot analysis and immunohistochemistry methods, we demonstrate a constitutive expression of syncytin-1 in normal pancreas tissues as well as normal tissues adjacent to cancer lesions. Moreover, a reduced expression is found in the pancreatic adenocarcinoma tissues. The expression levels of syncytin-1 are not correlated with the stage, historical grade and gender, but inversely correlated with patients' age. Furthermore, COBRA and bisulfite sequencing results indicated that the lower expression of syncytin-1 is correlated with the hypermethylation of two CpG dinucleotides in the 5' LTR of syncytin-1 gene. The nonfusogenic function of syncytin-1 in normal pancreas as well as its role(s) in the pathogenesis and progression of pancreatic cancers remains to be investigated. Identification of the two CpG dinucleotides around transcription start site as key epigenetic elements has provided valuable information for further studies on the epigenetic regulation of syncytin-1 in pancreatic cancer cells. PMID- 26230722 TI - Limited surgical resection for graft salvage following recovery from complicated exfoliative rejection in pediatric intestinal recipients. AB - Complications of ER contribute significantly to morbidity and mortality following intestinal transplantation. The surgical management of three pediatric patients who experienced complications of late ER after composite LSB transplantation is described, highlighting the potential for allograft salvage after limited surgical resection. A retrospective case series was compiled. Data collected included time to ER from transplant, medical management of ER, complications, and surgical management of ER complications. All patients had undergone composite LSB transplantation between one and two yr of age. Time to ER after transplantation was 9.5-26.5 months. ER complications included ileal allograft stricture, intramural hematoma with perforation of jejunal allograft, and massive GI hemorrhage secondary to focal ulceration and pseudopolyp formation. With evidence of mucosal regeneration, all three patients underwent limited segmental allograft resection. Two patients continue to maintain satisfactory allograft function 39 44 months following operation. The third patient retained adequate allograft function until he developed PTLD, subsequently dying from disseminated Adenovirus infection 51 months after resection. Severe disruption of intestinal allograft integrity in ER can lend itself to medically refractory complications. Prompt recognition and surgical correction of complications can play a crucial role in allograft salvage and patient survival after ER. PMID- 26230723 TI - Effects of prenatal exposure to valproic acid on the development of juvenile typical social play in rats. AB - Autism is a severe neurodevelopmental disorder characterized by qualitative impairments in social behavior, communication, and aberrant repetitive behaviors. A major focus of animal models of autism has been to mimic the social deficits of the disorder. The present study assessed whether rats exposed prenatally to valproic acid (VPA) show deficits in social play as juveniles that are consistent with the social deficits observed in autism. Dams were exposed to an acute dose of VPA on gestational day 12.5. Later, the playful interactions and associated ultrasonic vocalizations of the juveniles were examined. It was predicted that VPA-treated rats should play less than the controls. Characteristic of neurobehavioral insult at this early age, the VPA-treated juveniles showed significant increases in the frequency of body shakes and sexual mounting, but played at the same frequency as the controls. However, when playing, they were less likely to use tactics that facilitated bodily contact and vocalized less. These data suggest that prenatal VPA exposure disrupts some aspects of being able to communicate effectively and engage partners in dynamic interactions - deficits that are consistent with those observed in autism. PMID- 26230725 TI - Commentary: ISEE Call for Action for Global Control of Lead Exposure to Eliminate Lead Poisoning. PMID- 26230726 TI - Evolutionary History of the Smyd Gene Family in Metazoans: A Framework to Identify the Orthologs of Human Smyd Genes in Drosophila and Other Animal Species. AB - The Smyd gene family code for proteins containing a conserved core consisting of a SET domain interrupted by a MYND zinc finger. Smyd proteins are important in epigenetic control of development and carcinogenesis, through posttranslational modifications in histones and other proteins. Previous reports indicated that the Smyd family is quite variable in metazoans, so a rigorous phylogenetic reconstruction of this complex gene family is of central importance to understand its evolutionary history and functional diversification or conservation. We have performed a phylogenetic analysis of Smyd protein sequences, and our results show that the extant metazoan Smyd genes can be classified in three main classes, Smyd3 (which includes chordate-specific Smyd1 and Smyd2 genes), Smyd4 and Smyd5. In addition, there is an arthropod-specific class, SmydA. While the evolutionary history of the Smyd3 and Smyd5 classes is relatively simple, the Smyd4 class has suffered several events of gene loss, gene duplication and lineage-specific expansions in the animal phyla included in our analysis. A more specific study of the four Smyd4 genes in Drosophila melanogaster shows that they are not redundant, since their patterns of expression are different and knock-down of individual genes can have dramatic phenotypes despite the presence of the other family members. PMID- 26230724 TI - New Frontiers in Druggability. AB - A powerful early approach to evaluating the druggability of proteins involved determining the hit rate in NMR-based screening of a library of small compounds. Here, we show that a computational analog of this method, based on mapping proteins using small molecules as probes, can reliably reproduce druggability results from NMR-based screening and can provide a more meaningful assessment in cases where the two approaches disagree. We apply the method to a large set of proteins. The results show that, because the method is based on the biophysics of binding rather than on empirical parametrization, meaningful information can be gained about classes of proteins and classes of compounds beyond those resembling validated targets and conventionally druglike ligands. In particular, the method identifies targets that, while not druggable by druglike compounds, may become druggable using compound classes such as macrocycles or other large molecules beyond the rule-of-five limit. PMID- 26230727 TI - The Mechanisms of Human Renal Epithelial Cell Modulation of Autologous Dendritic Cell Phenotype and Function. AB - Proximal tubule epithelial cells (PTEC) of the kidney line the proximal tubule downstream of the glomerulus and play a major role in the re-absorption of small molecular weight proteins that may pass through the glomerular filtration process. In the perturbed disease state PTEC also contribute to the inflammatory disease process via both positive and negative mechanisms via the production of inflammatory cytokines which chemo-attract leukocytes and the subsequent down modulation of these cells to prevent uncontrolled inflammatory responses. It is well established that dendritic cells are responsible for the initiation and direction of adaptive immune responses. Both resident and infiltrating dendritic cells are localised within the tubulointerstitium of the renal cortex, in close apposition to PTEC, in inflammatory disease states. We previously demonstrated that inflammatory PTEC are able to modulate autologous human dendritic cell phenotype and functional responses. Here we extend these findings to characterise the mechanisms of this PTEC immune-modulation using primary human PTEC and autologous monocyte-derived dendritic cells (MoDC) as the model system. We demonstrate that PTEC express three inhibitory molecules: (i) cell surface PD-L1 that induces MoDC expression of PD-L1; (ii) intracellular IDO that maintains the expression of MoDC CD14, drives the expression of CD80, PD-L1 and IL-10 by MoDC and inhibits T cell stimulatory capacity; and (iii) soluble HLA-G (sHLA-G) that inhibits HLA-DR and induces IL-10 expression by MoDC. Collectively the results demonstrate that primary human PTEC are able to modulate autologous DC phenotype and function via multiple complex pathways. Further dissection of these pathways is essential to target therapeutic strategies in the treatment of inflammatory kidney disorders. PMID- 26230728 TI - The Additive Value of Femoral Ultrasound for Subclinical Atherosclerosis Assessment in a Single Center Cohort of 962 Adults, Including High Risk Patients with Rheumatoid Arthritis, Human Immunodeficiency Virus Infection and Type 2 Diabetes Mellitus. AB - BACKGROUND: Presence of femoral atheromatic plaques, an emerging cardiovascular disease (CVD) biomarker additional to carotid plaques, is poorly investigated in conditions associating with accelerated atherosclerosis such as Rheumatoid Arthritis (RA), Human Immunodeficiency Virus (HIV) infection and Type 2 Diabetes Mellitus (T2DM). OBJECTIVE/METHODS: To assess the frequency of femoral/carotid subclinical atheromatosis phenotypes in RA, HIV and T2DM and search for each disease-specific probability of either femoral and/or carotid subclinical atheromatosis, we examined by ultrasound a single-center cohort of CVD-free individuals comprised of consecutive non-diabetic patients with RA (n=226) and HIV (n=133), T2DM patients (n=109) and non-diabetic individuals with suspected/known hypertension (n=494) who served as reference group. RESULTS: Subclinical atheromatosis--defined as local plaque presence in at least on arterial bed--was diagnosed in 50% of the overall population. Among them, femoral plaques only were found in 25% of either RA or HIV patients, as well as in 16% of T2DM patients and 35% of reference subjects. After adjusting for all classical CVD risk factors, RA and HIV patients had comparable probability to reference group of having femoral plaques, but higher probability (1.75; 1.17-2.63 (odds ratio; 95% confidence intervals), 2.04; 1.14-3.64, respectively) of having carotid plaques, whereas T2DM patients had higher probability to have femoral and carotid plaques, albeit, due to their pronounced dyslipidemic profile. CONCLUSION: RA and HIV accelerate predominantly carotid than femoral. A "two windows" carotid/femoral, rather than carotid alone ultrasound, screening improves substantially subclinical atheromatosis detection in patients at high CVD risk. PMID- 26230729 TI - Grey and White Matter Magnetisation Transfer Ratio Measurements in the Lumbosacral Enlargement: A Pilot In Vivo Study at 3T. AB - Magnetisation transfer (MT) imaging of the central nervous system has provided further insight into the pathophysiology of neurological disease. However, the use of this method to study the lower spinal cord has been technically challenging, despite the important role of this region, not only for motor control of the lower limbs, but also for the neural control of lower urinary tract, sexual and bowel functions. In this study, the feasibility of obtaining reliable grey matter (GM) and white matter (WM) magnetisation transfer ratio (MTR) measurements within the lumbosacral enlargement (LSE) was investigated in ten healthy volunteers using a clinical 3T MRI system. The mean cross-sectional area of the LSE (LSE-CSA) and the mean GM area (LSE-GM-CSA) were first obtained by means of image segmentation and tissue-specific (i.e. WM and GM) MTR measurements within the LSE were subsequently obtained. The reproducibility of the segmentation method and MTR measurements was assessed from repeated measurements and their % coefficient of variation (%COV). Mean (+/- SD) LSE-CSA across 10 healthy subjects was 59.3 (+/- 8.4) mm2 and LSE-GM-CSA was 17.0 (+/- 3.1) mm2. The mean intra- and inter-rater % COV for measuring the LSE-CSA were 0.8% and 2.3%, respectively and for the LSE-GM-CSA were 3.8% and 5.4%, respectively. Mean (+/- SD) WM-MTR was 43.2 (+/- 4.4) and GM-MTR was 40.9 (+/- 4.3). The mean scan-rescan % COV for measuring WM-MTR was 4.6% and for GM-MTR was 3.8%. Using a paired t-test, a statistically significant difference was identified between WM-MTR and GM-MTR in the LSE (p<0.0001). This pilot study has shown that it is possible to obtain reliable tissue-specific MTR measurements within the LSE using a clinical MR system at 3T. The MTR acquisition and analysis protocol presented in this study can be used in future investigations of intrinsic spinal cord diseases that affect the LSE. PMID- 26230730 TI - Differential Proteomic Analysis Using iTRAQ Reveals Alterations in Hull Development in Rice (Oryza sativa L.). AB - Rice hull, the outer cover of the rice grain, determines grain shape and size. Changes in the rice hull proteome in different growth stages may reflect the underlying mechanisms involved in grain development. To better understand these changes, isobaric tags for relative and absolute quantitative (iTRAQ) MS/MS was used to detect statistically significant changes in the rice hull proteome in the booting, flowering, and milk-ripe growth stages. Differentially expressed proteins were analyzed to predict their potential functions during development. Gene ontology (GO) terms and pathways were used to evaluate the biological mechanisms involved in rice hull at the three growth stages. In total, 5,268 proteins were detected and characterized, of which 563 were differentially expressed across the development stages. The results showed that the flowering and milk-ripe stage proteomes were more similar to each other (r=0.61) than either was to the booting stage proteome. A GO enrichment analysis of the differentially expressed proteins was used to predict their roles during rice hull development. The potential functions of 25 significantly differentially expressed proteins were used to evaluate their possible roles at various growth stages. Among these proteins, an unannotated protein (Q7X8A1) was found to be overexpressed especially in the flowering stage, while a putative uncharacterized protein (B8BF94) and an aldehyde dehydrogenase (Q9FPK6) were overexpressed only in the milk-ripe stage. Pathways regulated by differentially expressed proteins were also analyzed. Magnesium-protoporphyrin IX monomethyl ester [oxidative] cyclase (Q9SDJ2), and two magnesium-chelatase subunits, ChlD (Q6ATS0), and ChlI (Q53RM0), were associated with chlorophyll biosynthesis at different developmental stages. The expression of Q9SDJ2 in the flowering and milk-ripe stages was validated by qRT-PCR. The 25 candidate proteins may be pivotal markers for controlling rice hull development at various growth stages and chlorophyll biosynthesis pathway related proteins, especially magnesium-protoporphyrin IX monomethyl ester [oxidative] cyclase (Q9SDJ2), may provide new insights into the molecular mechanisms of rice hull development and chlorophyll associated regulation. PMID- 26230731 TI - Foraging Strategies of Laysan Albatross Inferred from Stable Isotopes: Implications for Association with Fisheries. AB - Fatal entanglement in fishing gear is the leading cause of population decline for albatross globally, a consequence of attraction to bait and fishery discards of commercial fishing operations. We investigated foraging strategies of Laysan albatross (Phoebastria immutabilis), as inferred from nitrogen and carbon isotope values of primary feathers, to determine breeding-related, seasonal, and historic factors that may affect the likelihood of association with Alaskan or Hawaiian longline fisheries. Feather samples were collected from live birds monitored for breeding status and breeding success on Midway Atoll in the northwestern Hawaiian Islands, birds salvaged as fisheries-bycatch, and birds added to museum collections before 1924. During the chick-rearing season (sampled April-May), means and variances of stable isotope values of birds with the highest, most consistent reproductive success were distinct from less productive conspecifics and completely different from birds caught in Hawaiian or Alaskan longline fisheries, suggesting birds with higher multi-annual reproductive success were less likely to associate with these fisheries. Contemporary birds with the highest reproductive success had mean values most similar to historic birds. Values of colony-bound, courting prebreeders were similar to active breeders but distinct from prebreeders caught in Alaskan longline fisheries. During the breeding season, delta15N values were highly variable for both contemporary and historic birds. Although some historic birds exhibited extremely low delta15N values unmatched by contemporary birds (< 11.20/00), others had values as high as the highest fishery-associated contemporary birds. During the non-breeding season (sampled July-September), isotopic variability coalesced into a more narrow set of values for both contemporary and historic birds. Our results suggest that foraging strategies of Laysan albatross are a complex function of season, breeding status, and multi-annual breeding success, factors that likely affect the probability of association with fisheries. PMID- 26230732 TI - The Origin of the Odd-Even Effect in the Tunneling Rates across EGaIn Junctions with Self-Assembled Monolayers (SAMs) of n-Alkanethiolates. AB - Odd-even effects in molecular junctions with self-assembled monolayers (SAMs) of n-alkanethiolates have been rarely observed. It is challenging to pinpoint the origin of odd-even effects and address the following question: are the odd-even effects an interface effect, caused by the intrinsic properties of the SAMs, or a combination of both? This paper describes the odd-even effects in SAM-based tunnel junctions of the form Ag(A-TS)-SC(n)//GaO(x)/EGaIn junctions with a large range of molecular lengths (n = 2 to 18) that are characterized by both AC and DC methods along with a detailed statistical analysis of the data. This combination of techniques allowed us to separate interface effects from the contributions of the SAMs and to show that the odd-even effect observed in the value of J obtained by DC-methods are caused by the intrinsic properties of the SAMs. Impedance spectroscopy (an AC technique) allowed us to analyze the SAM resistance (R(SAM)), SAM capacitance (C(SAM)), and contact resistance, within the junctions separately. We found clear odd-even effects in the values of both R(SAM) and C(SAM), but the odd-even effect in contact resistance is very weak (and not responsible for the observed odd-even effect in the current densities obtained by J(V) measurements). Therefore, the odd-even effects in Ag(A-TS) SC(n)//GaO(x)/EGaIn junctions are attributed to the properties of the SAMs and SAM-electrode interactions which both determine the shape of the tunneling barrier. PMID- 26230733 TI - Using large-scale genomics data to identify driver mutations in lung cancer: methods and challenges. AB - Lung cancer is the commonest cause of cancer death in the world and carries a poor prognosis for most patients. While precision targeting of mutated proteins has given some successes for never- and light-smoking patients, there are no proven targeted therapies for the majority of smokers with the disease. Despite sequencing hundreds of lung cancers, known driver mutations are lacking for a majority of tumors. Distinguishing driver mutations from inconsequential passenger mutations in a given lung tumor is extremely challenging due to the high mutational burden of smoking-related cancers. Here we discuss the methods employed to identify driver mutations from these large datasets. We examine different approaches based on bioinformatics, in silico structural modeling and biological dependency screens and discuss the limitations of these approaches. PMID- 26230735 TI - The influence of spatial barriers on the ingress/egress movement toward an aircraft seat for persons with reduced mobility: a preliminary study. PMID- 26230734 TI - Regulation of SREBPs by Sphingomyelin in Adipocytes via a Caveolin and Ras-ERK MAPK-CREB Signaling Pathway. AB - Sterol response element binding protein (SREBP) is a key transcription factor in insulin and glucose metabolism. We previously demonstrated that elevated levels of membrane sphingomyelin (SM) were related to peroxisome proliferator-activated receptor-gamma (PPARgamma), which is a known target gene of SREBP-1 in adipocytes. However, the role of SM in SREBP expression in adipocytes remains unknown. In human abdominal adipose tissue from obese women with various concentrations of fasting plasma insulin, SREBP-1 proteins decreased in parallel with increases in membrane SM levels. An inverse correlation was found between the membrane SM content and the levels of SREBP-1c/ERK/Ras/PPARgamma/CREB proteins. For the first time, we demonstrate the effects of SM and its signaling pathway in 3T3-F442A adipocytes. These cells were enriched or unenriched with SM in a range of concentrations similar to those observed in obese subjects by adding exogenous natural SMs (having different acyl chain lengths) or by inhibiting neutral sphingomyelinase. SM accumulated in caveolae of the plasma membrane within 24 h and then in the intracellular space. SM enrichment decreased SREBP-1 through the inhibition of extracellular signal-regulated protein kinase (ERK) but not JNK or p38 mitogen-activated protein kinase (MAPK). Ras/Raf 1/MEK1/2 and KSR proteins, which are upstream mediators of ERK, were down regulated, whereas SREBP-2/caveolin and cholesterol were up-regulated. In SM unmodulated adipocytes treated with DL-1-Phenyl-2-Palmitoylamino-3-morpholino-1 propanol (PPMP), where the ceramide level increased, the expression levels of SREBPs and ERK were modulated in an opposite direction relative to the SM enriched cells. SM inhibited the insulin-induced expression of SREBP-1. Rosiglitazone, which is an anti-diabetic agent and potent activator of PPARgamma, reversed the effects of SM on SREBP-1, PPARgamma and CREB. Taken together, these findings provide novel insights indicating that excess membrane SM might be critical for regulating SREBPs in adipocytes via a MAPK-dependent pathway. PMID- 26230736 TI - Photocatalytic degradation of methyl blue by silver ion-doped titania: Identification of degradation products by GC-MS and IC analysis. AB - An anionic triphenyl methane dye, methyl blue ((disodium;4-[4-[[4-(4 sulfonatoanilino)phenyl]-[4-(4-sulfonatophenyl)azaniumylidenecyclohexa-2,5-dien-1 ylidene]methyl]anilino]benzene sulfonate) was degraded photocatalytically with undoped micro-TiO2- and Ag(+)-doped micro TiO2 in a slurry-type batch reactor under UV irradiation and the efficiency was compared with that obtained using nano-TiO2- and Ag(+)-doped nano-TiO2. The influence of different parameters, i.e., photocatalyst loading, dye concentration, initial pH, temperature, depth of solution, interfering ions and electron acceptors on the dye degradation was investigated. The decolorization and mineralization efficiency was better for Ag(+)-doped micro-TiO2 than undoped micro-TiO2. Nano-TiO2 was more efficient than micro-TiO2, while Ag(+)-doped nano-TiO2 was the most efficient of all. Cost analysis showed degradation using micro-TiO2- and Ag(+)-doped micro-TiO2 are much cheaper than that using nano-TiO2 and Ag(+)-doped nano-TiO2. Therefore Ag(+) doped micro-TiO2 was used for the detailed study. The degradation products formed were identified using GC-MS analysis after photocatalytic degradation for 180 min with Ag(+) -doped micro TiO2. Ion chromatography analysis was carried out for anions to identify the end products of degradation. PMID- 26230737 TI - Performance of a pedometer to measure physical activity in a U.S. cohort with chronic obstructive pulmonary disease. AB - Objective assessment of physical activity (PA) in chronic obstructive pulmonary disease (COPD) is important. We examined the performance of the Omron HJ-720ITC pedometer. A sample of 176 persons with stable COPD wore the Omron and the StepWatch Activity Monitor (SAM) in the clinic and the community. A 4 s step filter in the Omron screens out erroneous intermittent steps; it captures continuous walking that lasts >4 s. The SAM captures all intermittent and continuous steps walked. Omron-steps were compared with manually counted steps in the clinic and with SAM-steps in the community. We calculated the intraclass correlation coefficient for the first 2 d, the first 3 d, etc., up to 14 d. The Omron registered >/= 90% of the manually counted steps from the in-clinic walk in 155 of 176 subjects (88%). In the community, 47 +/- 16% of SAM-steps were continuous ones that were captured by the Omron. For the Omron and the SAM, at least 7 d of monitoring should be used to capture decreases in PA on weekend days and obtain optimum reliability for all Global Initiative for Chronic Obstructive Lung Disease stages. The Omron accurately and reliably measures continuous walking in COPD. The Omron may be ideal for use in PA interventions that promote continuous walking as exercise. PMID- 26230739 TI - Contributions of physical function and satisfaction with social roles to emotional distress in chronic pain: a Collaborative Health Outcomes Information Registry (CHOIR) study. AB - Individuals with chronic pain show greater vulnerability to depression or anger than those without chronic pain, and also show greater interpersonal difficulties and physical disability. The present study examined data from 675 individuals with chronic pain during their initial visits to a tertiary care pain clinic using assessments from Stanford University's Collaborative Health Outcomes Information Registry (CHOIR). Using a path modeling analysis, the mediating roles of Patient-Reported Outcomes Measurement Information Systems (PROMIS) Physical Function and PROMIS Satisfaction with Social Roles and Activities were tested between pain intensity and PROMIS Depression and Anger. Pain intensity significantly predicted both depression and anger, and both physical function and satisfaction with social roles mediated these relationships when modeled in separate 1-mediator models. Notably, however, when modeled together, ratings of satisfaction with social roles mediated the relationship between physical function and both anger and depression. Our results suggest that the process by which chronic pain disrupts emotional well-being involves both physical function and disrupted social functioning. However, the more salient factor in determining pain-related emotional distress seems to be disruption of social relationships, than global physical impairment. These results highlight the particular importance of social factors to pain-related distress, and highlight social functioning as an important target for clinical intervention in chronic pain. PMID- 26230740 TI - Regular physical activity prevents chronic pain by altering resident muscle macrophage phenotype and increasing interleukin-10 in mice. AB - Regular physical activity in healthy individuals prevents development of chronic musculoskeletal pain; however, the mechanisms underlying this exercise-induced analgesia are not well understood. Interleukin-10 (IL-10), an antiinflammatory cytokine that can reduce nociceptor sensitization, increases during regular physical activity. Since macrophages play a major role in cytokine production and are present in muscle tissue, we propose that physical activity alters macrophage phenotype to increase IL-10 and prevent chronic pain. Physical activity was induced by allowing C57BL/6J mice free access to running wheels for 8 weeks and compared to sedentary mice with no running wheels. Using immunohistochemical staining of the gastrocnemius muscle to label regulatory (M2, secretes antiinflammatory cytokines) and classical (M1, secretes proinflammatory cytokines) macrophages, the percentage of M2-macrophages increased significantly in physically active mice (68.5% +/- 4.6% of total) compared with sedentary mice (45.8% +/- 7.1% of total). Repeated acid injections into the muscle enhanced mechanical sensitivity of the muscle and paw in sedentary animals, which does not occur in physically active mice; no sex differences occur in either sedentary or physically active mice. Blockade of IL-10 systemically or locally prevented the analgesia in physically active mice, ie, mice developed hyperalgesia. Conversely, sedentary mice pretreated systemically or locally with IL-10 had reduced hyperalgesia after repeated acid injections. Thus, these results suggest that regular physical activity increases the percentage of regulatory macrophages in muscle and that IL-10 is an essential mediator in the analgesia produced by regular physical activity. PMID- 26230741 TI - Analgesic and sedative effects of perioperative gabapentin in total knee arthroplasty: a randomized, double-blind, placebo-controlled dose-finding study. AB - Gabapentin has shown acute postoperative analgesic effects, but the optimal dose and procedure-specific benefits vs harm have not been clarified. In this randomized, double-blind, placebo-controlled dose-finding study, 300 opioid-naive patients scheduled for total knee arthroplasty were randomized (1:1:1) to either gabapentin 1300 mg/d (group A), gabapentin 900 mg/d (group B), or placebo (group C) daily from 2 hours preoperatively to postoperative day 6 in addition to a standardized multimodal analgesic regime. The primary outcome was pain upon ambulation 24 hours after surgery, and the secondary outcome was sedation 6 hours after surgery. Other outcomes were overall pain during well-defined mobilizations and at rest and sedation during the first 48 hours and from days 2-6, morphine use, anxiety, depression, sleep quality, and nausea, vomiting, dizziness, concentration difficulty, headache, visual disturbances, and adverse reactions. Pain upon ambulation (visual analog scale, mean [95% confidence interval]) 24 hours after surgery in group A vs B vs C was as follows: 41 [37-46] vs 41 [36-45] vs 42 [37-47], P = 0.93. Sedation (numeric rating scale, median [range]) 6 hours after surgery was as follows: 3.2 [0-10] vs 2.6 [0-9] vs 2.3 [0-9], the mean difference A vs C being 0.9 [0.2-1.7], P = 0.046. No between-group differences were observed in overall pain or morphine use the first 48 hours and from days 2 6. Sleep quality was better during the first 2 nights in group A and B vs C. Dizziness was more pronounced from days 2-6 in A vs C. More severe adverse reactions were observed in group A vs B and C. In conclusion, gabapentin may have a limited if any role in acute postoperative pain management of opioid-naive patients undergoing total knee arthroplasty and should not be recommended as a standard of care. PMID- 26230742 TI - From Galton to genome-wide association studies: evaluation of genetic and environmental factors predisposing to widespread pain. PMID- 26230743 TI - Pain after pediatric surgery. PMID- 26230744 TI - Kinetics of Thermal Conversion of Conjugated Polymers Investigated from Their Optical Absorption Spectra. AB - We report on a phenomenological, theoretical model to calculate the rate constants and activation energies for the thermal conversion reactions from poly(xylylidene tetrahydrothiophenium chloride) (PTHT) into poly(p phenylenevinylene) (PPV) using the optical absorption spectra of spin-coated films. The probabilities of electron transitions were calculated considering Franck-Condon states with a Gaussian distribution of conjugated segments and molecular excitons. The dependence on the conjugation degree (n) for the energy gap, transition dipole moment, and electron-phonon coupling were obtained semiempirically using published data for PPV. Fitting was performed for the C-C stretching of the aromatic ring 1550 cm(-1), for it is considered the most optically active. The isotherms for consumption and formation of PPV segments were fitted using a first-order and consecutive reactions, respectively. With this modeling we could identify the most probable reactions, where the formation of longer PPV segments n >= 3 occurs only via reactions from smaller conjugated segments (i.e., n = 1 and 2). The activation energies tend to decrease with longer conjugation lengths. Significantly, the modeling allows us to predict the conversion temperature and chemical composition yielding a predefined distribution of conjugated segments, which can be applied to any polymer undergoing thermal conversion, decomposition, or photo-oxidation. PMID- 26230745 TI - Programmed Physical Exertion in Recovery From Sports-Related Concussion: A Randomized Pilot Study. AB - Although no data exist, general practice recommends only rest following concussion. This randomized clinical trial found that programmed physical exertion during recovery produced no significant differences in recovery time between groups of participants. However, high levels of exertion were deleterious. This study provides initial evidence that moderate physical activity is a safe replacement behavior during recovery. PMID- 26230746 TI - Risk-taking on the road and in the mind: behavioural and neural patterns of decision making between risky and safe drivers. AB - Drivers' risk-taking is a key issue of road safety. This study explored individual differences in drivers' decision-making, linking external behaviours to internal neural activity, to reveal the cognitive mechanisms of risky driving. Twenty-four male drivers were split into two groups (risky vs. safe drivers) via the Drivier Behaviour Questionnaire-violation. The risky drivers demonstrated higher preference for the risky choices in the paradigms of Iowa Gambling Task and Balloon Analogue Risk Task. More importantly, the risky drivers showed lower amplitudes of feedback-related negativity (FRN) and loss-minus-gain FRN in both paradigms, which indicated their neural processing of error-detection. A significant difference of P300 amplitudes was also reported between groups, which indicated their neural processing of reward-evaluation and were modified by specific paradigm and feedback. These results suggested that the neural basis of risky driving was the decision patterns less revised by losses and more motivated by rewards. PRACTITIONER SUMMARY: Risk-taking on the road is largely determined by inherent cognitive mechanisms, which can be indicated by the behavioural and neural patterns of decision-making. In this regard, it is feasible to quantize drivers' riskiness in the cognitive stage before actual risky driving or accidents, and intervene accordingly. PMID- 26230747 TI - Individual identification from genetic marker data: developments and accuracy comparisons of methods. AB - Genetic marker-based identification of distinct individuals and recognition of duplicated individuals has important applications in many research areas in ecology, evolutionary biology, conservation biology and forensics. The widely applied genotype mismatch (MM) method, however, is inaccurate because it relies on a fixed and suboptimal threshold number (TM ) of mismatches, and often yields self-inconsistent pairwise inferences. In this study, I improved MM method by calculating an optimal TM to accommodate the number, mistyping rates, missing data and allele frequencies of the markers. I also developed a pairwise likelihood relationship (LR) method and a likelihood clustering (LC) method for individual identification, using poor-quality data that may have high and variable rates of allelic dropouts and false alleles at genotyped loci. The 3 methods together with the relatedness (RL) method were then compared in accuracy by analysing an empirical frog data set and many simulated data sets generated under different parameter combinations. The analysis results showed that LC is generally one or two orders more accurate for individual identification than the other methods. Its accuracy is especially superior when the sampled multilocus genotypes have poor quality (i.e. teemed with genotyping errors and missing data) and highly replicated, a situation typical of noninvasive sampling used in estimating population size. Importantly, LC is the only method that guarantees to produce self-consistent results by partitioning the entire set of multilocus genotypes into distinct clusters, each cluster containing one or more genotypes that all represent the same individual. The LC and LR methods were implemented in a computer program COLONY for free download from the Internet. PMID- 26230748 TI - A new scale for the assessment of pain in Parkinson's disease. PMID- 26230749 TI - Room-Temperature Decarboxylative Couplings of alpha-Oxocarboxylates with Aryl Halides by Merging Photoredox with Palladium Catalysis. AB - Enabled by merging iridium photoredox catalysis and palladium catalysis, alpha oxocarboxylate salts can be decarboxylatively coupled with aryl halides to generate aromatic ketones and amides at room temperature. DFT calculations suggest that this reaction proceeds through a Pd(0) -Pd(II) -Pd(III) pathway, in which the Pd(III) intermediate is responsible for reoxidizing Ir(II) to complete the Ir(III) -*Ir(III) -Ir(II) photoredox cycle. PMID- 26230750 TI - Development and Validation of a Novel Skills Training Model for Retrograde Intrarenal Surgery. AB - PURPOSE: The aim of this study is to validate a training model that combines the use of nonbiologic and biologic simulators as well as live porcine animal model in endoscopic retrograde intrarenal surgery (RIRS). MATERIALS AND METHODS: A total of 60 urologists took part in this study, and the activity lasted for 2 days. The training model was divided into three modules: Module-I, related to the acquisition of basic theoretical knowledge; Module-II, consisting of an internship with bench models; and Module III, in which animal models were used. First, trainees practiced with animals without using a lesion model (placement of an ureteral access sheath under fluoroscopic guidance and flexible ureterorenoscopy). Afterward, they practiced on a porcine animal model of bilateral renal lithiasis. Performance was measured using a validated global rating score and RIRS checklist score. Face and content validation as well as constructive validation provided by trainees in front of 15 experts were performed during the practice. RESULTS: Face and content validations were satisfactory. "Individual" constructive validity showed statistical significance between the first and the last time that trainees practiced on an animal model. Statistical significance was also found between trainees and expert scores. There were 73.4% of trainees who increased their skills by more than 40%. CONCLUSION: This RIRS training model allows for the acquisition of technical knowledge and skills as face, content, and constructive validation show. A structured use of nonbiologic, biologic, and animal model simulators allows the increase of RIRS skills. PMID- 26230751 TI - Varying Electronic Structures of Diosmium Complexes from Noninnocently Behaving Anthraquinone-Derived Bis-chelate Ligands. AB - The new compounds [(bpy)2Os(II)(MU-L1(2-))Os(II)(bpy)2](ClO4)2 ([1](ClO4)2) and [(pap)2Os(II)(MU-L1(2-))Os(II)(pap)2](ClO4)2 ([2](ClO4)2) (H2L1 = 1,4-dihydroxy 9,10-anthraquinone, bpy = 2,2(/)-bipyridine, and pap = 2-phenylazopyridine) and [(bpy)2Os(II)(MU-L2(*-))Os(II)(bpy)2](ClO4)3 ([3](ClO4)3) and [(pap)2Os(II)(MU L2(2-))Os(II)(pap)2](ClO4)2 ([4](ClO4)2) (H2L2 = 1,4-diamino-9,10-anthraquinone) have been analytically identified as the meso and rac diastereoisomers, respectively. The paramagnetic [3](ClO4)3 was also characterized by crystal structure determination. In CD3CN solution, [3](ClO4)3 displays rather narrow but widely split (13 > delta > -8 ppm) resonances in the (1)H NMR spectrum, yet no EPR signal was observed down to 120 K. Cyclic voltammetry and differential pulse voltammetry reveal several accessible redox states on oxidation and reduction, showing that the replacement of 1,4-oxido by imido donors causes cathodic shifts and that the substitution of bpy by the stronger pi-accepting pap ligands leads to a strong increase of redox potentials. Accordingly, system 3(n) with the lowest (2+/3+) potential was synthetically obtained in the mono-oxidized (3+) form. The (3+) intermediates display small comproportionation constants Kc of about 10(3) and long-wavelength near-infrared absorptions; an EPR signal with appreciable g splitting (1.84, 1.96, and 2.03) was only observed for 4(3+), which exhibits the smallest spin density on the osmium centers. An oxidation state formulation [Os(III)(MU-L(*3-))Os(III)](3+) with some [Os(II)(MU-L(2 ))Os(III)](3+) contribution was found to best describe the electronic structures. UV-vis-NIR absorption spectra were recorded for all accessible states by OTTLE spectroelectrochemistry and assigned on the basis of TD-DFT calculations. These results and additional EPR measurements suggest rather variegated oxidation state situations, e.g., the pap ligands competing with the bridge L for electrons, while the oxidation produces mixed spin systems with variable metal/ligand contributions. PMID- 26230752 TI - {MU-PbSe}: a heavy CO homologue as an unexpected ligand. AB - Reactions of [K(18-crown-6)]2 [Pb2 Se3 ] and [K([2.2.2]crypt)]2 [Pb2 Se3 ] with [Rh(PPh3 )3 Cl] in en (ethane-1,2-diamine) afforded ionic compounds with [Rh3 (PPh3 )6 (MU3 -Se)2 ](-) and [Rh3 (CN)2 (PPh3 )4 (MU3 -Se)2 (MU-PbSe)](3-) anions, respectively. The latter contains a PbSe ligand, a rather uncommon homologue of CO that acts as a MU-bridge between two Rh atoms. Quantum chemical calculations yield a significantly higher bond energy for PbSe than for CO, since the size of the ligand orbitals better matches the comparably rigid Rh-Se-Rh angles and the resulting Rh???Rh distance. To rationalize the bent coordination of the ligand, orbitals with significant ligand contributions and their dependence on the bonding angle were investigated in detail. PMID- 26230753 TI - Cerium Oxide Nanoclusters on Graphene/Ru(0001): Intercalation of Oxygen via Spillover. AB - Cerium oxide is an important catalytic material known for its ability to store and release oxygen, and as such, it has been used in a range of applications, both as an active catalyst and as a catalyst support. Using scanning tunneling microscopy and Auger electron spectroscopy, we investigated oxygen interactions with CeOx nanoclusters on a complete graphene monolayer-covered Ru(0001) surface at elevated temperatures (600-725 K). Under oxidizing conditions (PO2 = 1 * 10( 7) Torr), oxygen intercalation under the graphene layer is observed. Time dependent studies demonstrate that the intercalation proceeds via spillover of oxygen from CeOx nanoclusters through the graphene (Gr) layer onto the Ru(0001) substrate and extends until the Gr layer is completely intercalated. Atomically resolved images further show that oxygen forms a p(2 * 1) structure underneath the Gr monolayer. Temperature dependent studies yield an apparent kinetic barrier for the intercalation of 1.21 eV. This value correlates well with the theoretically determined value for the reduction of small CeO2 clusters reported previously. At higher temperatures, the intercalation is followed by a slower etching of the intercalated graphene (apparent barrier of 1.60 eV). Vacuum annealing of the intercalated Gr leads to the formation of carbon monoxide, causing etching of the graphene film, demonstrating that the spillover of oxygen is not reversible. In agreement with previous studies, no intercalation is observed on a complete graphene monolayer without CeOx clusters, even in the presence of a large number of point defects. These studies demonstrate that the easily reducible CeOx clusters act as intercalation gateways capable of efficiently delivering oxygen underneath the graphene layer. PMID- 26230754 TI - Amyloidosis: Modern Cross-sectional Imaging. AB - Amyloidosis is a rare diverse condition caused by the pathologic extracellular deposition of abnormal insoluble proteins throughout the body. It may exist as a primary disease or, more commonly, may be secondary to a wide variety of pathologic processes ranging from chronic infection or inflammation to malignancy. Hereditary forms also exist. On the basis of the structure of the protein deposits, more than two dozen subtypes of amyloidosis have been described. A single organ or multiple organ systems may be affected. The radiologic manifestations of amyloidosis are varied and often nonspecific, making amyloidosis a diagnostic challenge for the radiologist. In the chest, the lungs, mediastinum, pleura, and heart may be involved. Lung involvement may manifest as diffuse reticulonodular interstitial thickening, consolidations, or solitary or multiple parenchymal nodules that may calcify, cavitate, and slowly enlarge. Pleural involvement most commonly manifests as pleural effusions. Tracheobronchial involvement may exhibit concentric airway thickening, mural and intraluminal nodules, submucosal calcification, and airway obstruction. Mediastinal and hilar lymph nodes may enlarge and frequently calcify. At cardiac magnetic resonance (MR) imaging, the left ventricular wall is typically thickened, with associated diastolic dysfunction. Delayed contrast material enhanced cardiac MR imaging typically shows global transmural or subendocardial enhancement. The pathophysiology, classification, treatment, and prognosis of amyloidosis are reviewed, followed by case examples of the appearance of thoracic and cardiac amyloidosis on chest radiographs, computed tomographic (CT) images, and cardiac MR images. PMID- 26230755 TI - (90)Y Radioembolization: Multimodality Imaging Pattern Approach with Angiographic Correlation for Optimized Target Therapy Delivery. AB - Primary and metastatic liver cancers are responsible for considerable morbidity and mortality, and many patients are not curable at presentation. Therefore, new therapies such as radioembolization with yttrium 90 ((90)Y)-labeled microspheres are an alternative method to treat patients with unresectable primary or secondary liver tumors. Patient selection, treatment technique, and early recognition of potential complications are the keys for successful patient outcomes. The activity of administered (90)Y microspheres depends on multiple variables, including the tumor burden, the volume of the liver lobe to be treated, the type of (90)Y microspheres, and the hepatopulmonary shunt fraction. Preprocedural planning relies on the results of cross-sectional imaging to determine the extent of disease, tumoral and nontumoral liver volumes, patency of the portal vein, and the degree of extrahepatic disease. A multidisciplinary approach that combines expertise in cross-sectional imaging, nuclear medicine, and flow dynamics is critical to adequately target malignant tissue. Preprocedural multimodality imaging, particularly combined single photon emission computed tomography (SPECT) and computed tomography (CT) imaging (SPECT/CT), may be used to identify nontarget imaging patterns that, if recognized, can potentially be corrected with either branch vessel embolization or catheter repositioning. Postprocedural multimodality imaging is also useful to confirm the appropriate delivery of (90)Y microspheres, enabling early identification of potential complications and the adequacy of microsphere distribution, thereby optimizing planning for subsequent therapies. PMID- 26230756 TI - Invited Commentary: (90)Y Radioembolization. PMID- 26230757 TI - Analysis of the binding mode of laulimalide to microtubules: Establishing a laulimalide-tubulin pharmacophore. AB - Laulimalide (LA) is a microtubule-stabilizing agent, currently in preclinical studies. However, studying the binding of this species and successfully synthesizing potent analogues have been challenging. The LA binding site is located between tubulin protofilaments, and therefore LA is in contact with two adjacent [Formula: see text]-tubulin units. Here, an improved model of the binding mode of LA in microtubules is presented, using the newly available crystal structure pose and an extended tubulin heterodimer complex, as well as molecular dynamics simulations. With this model, a series of LA analogues developed by Mooberry and coworkers are also analyzed in order to establish important pharmacophores in LA binding and cytotoxicity. In the side chain, [Formula: see text]-[Formula: see text] interactions are important contributors to LA binding, as are water-mediated hydrogen bonds. An intramolecular hydrogen bond is correlated with high cytotoxicity, and is dependent on macrocycle conformation. Therefore, while the epoxide and olefin groups in the macrocycle do not engage in specific interactions with the protein, they are essential contributions to an active macrocycle conformation, and therefore potency. Calculations reveal that a balance in binding affinity is important for LA activity, where the more potent compounds have larger interactions with the adjacent tubulin unit than the less-active analogs. Several modifications are suggested for the rational design of LA analogues that should not disrupt the active macrocycle conformation. PMID- 26230758 TI - Missed Opportunities: Screening and Brief Intervention for Risky Alcohol Use in Women's Health Settings. AB - BACKGROUND: Although women's health settings could provide access to women for screening, brief intervention, and referral to treatment (SBIRT) for risky alcohol use, little is known about rates of alcohol use or associated risk for alcohol-exposed pregnancy (AEP) among women's health patients, receipt of SBIRT services in these settings, or patient attitudes towards SBIRT services. METHODS: This study reports the results of a self-administered survey to a convenience sample of women's health patients attending public clinics for family planning or sexually transmitted infection visits. RESULTS: Surveys were analyzed for 199 reproductive-aged women who had visited the clinic within the past year. The rate of risky drinking among the sample was (44%) and risk for AEP was (17%). Despite this, many patients did not receive SBIRT services, with more than half of risky drinking patients reporting that they were not advised about safe drinking limits (59%) and similar rates of patients at risk for AEP reporting that their medical provider did not discuss risk factors of AEP (53%). Patient attitudes towards receipt of SBIRT services were favorable; more than 90% of women agreed or strongly agreed that if their drinking was affecting their health, their women's health provider should advise them to cut down. CONCLUSIONS: Women's health clinics may be an ideal setting to implement SBIRT and future research should address treatment efficacy in these settings. PMID- 26230759 TI - Complement C5 Gene Confers Risk for Acute Anterior Uveitis. AB - PURPOSE: Polymorphisms in the genes encoding C3 and C5 are associated with several immune-mediated diseases. However, the association of C3 and C5 SNPs with acute anterior uveitis (AAU) has not yet been investigated and was the purpose of the study described. METHODS: Genotyping was performed for six SNPs in C3 and four SNPs in C5 in 395 AAU patients with ankylosing spondylitis (AS), 397 AAU patients without AS, and 597 healthy controls by PCR-restriction fragment length polymorphism (PCR-RFLP) or TaqMan SNP assay. The mRNA expression was detected by real-time PCR. Cytokine production and total C5 serum concentrations were measured by ELISA. RESULTS: The frequency of the GG genotype of rs2269067 in C5 was increased in AAU patients with or without AS compared to controls (Pc = 4.0 * 10(-5), odds ratio [OR] = 1.94 and Pc = 9.4 * 10(-5), OR = 1.89, respectively). The mRNA and serum concentrations of C5 were significantly increased in rs2269067 GG cases as compared to that in CG or CC cases (P = 0.012, P = 0.002; P = 0.021, P = 0.006, respectively). An increased production of interleukin-17 was observed in rs2269067 GG cases compared to CG or CC cases (P = 5.1 * 10(-4), P = 1.4 * 10( 4), respectively). CONCLUSIONS: The C5 rs2269067 GG genotype confers risk for AAU in a Chinese population and is associated with an elevated C5 serum concentration and an increased IL-17 production. PMID- 26230761 TI - Remembering David C. Beebe, PhD, 1944-2015. PMID- 26230760 TI - The Effect of PKCalpha on the Light Response of Rod Bipolar Cells in the Mouse Retina. AB - PURPOSE: Protein kinase C alpha (PKCalpha) is abundantly expressed in rod bipolar cells (RBCs) in the retina, yet the physiological function of PKCalpha in these cells is not well understood. To elucidate the role of PKCalpha in visual processing in the eye, we examined the effect of genetic deletion of PKCalpha on the ERG and on RBC light responses in the mouse. METHODS: Immunofluorescent labeling was performed on wild-type (WT), TRPM1 knockout, and PKCalpha knockout (PKC-KO) retina. Scotopic and photopic ERGs were recorded from WT and PKC-KO mice. Light responses of RBCs were measured using whole-cell recordings in retinal slices from WT and PKC-KO mice. RESULTS: Protein kinase C alpha expression in RBCs is correlated with the activity state of the cell. Rod bipolar cells dendrites are a major site of PKCalpha phosphorylation. Electroretinogram recordings indicated that loss of PKCalpha affects the scotopic b-wave, including a larger peak amplitude, longer implicit time, and broader width of the b-wave. There were no differences in the ERG a- or c-wave between PKCalpha KO and WT mice, indicating no measurable effect of PKCalpha in photoreceptors or the RPE. The photopic ERG was unaffected consistent with the lack of detectable PKCalpha in cone bipolar cells. Whole-cell recordings from RBCs in PKC-KO retinal slices revealed that, compared with WT, RBC light responses in the PKC-KO retina are delayed and of longer duration. CONCLUSIONS: Protein kinase C alpha plays an important modulatory role in RBCs, regulating both the peak amplitude and temporal properties of the RBC light response in the rod visual pathway. PMID- 26230762 TI - Suprachoroidal Drug Delivery: Unique New Observations. PMID- 26230764 TI - Circadian Intraocular Pressure Fluctuation and Disease Progression in Primary Angle Closure Glaucoma. AB - PURPOSE: To document the continuous circadian intraocular pressure (IOP) fluctuation using a contact lens sensor during normal daily activities, and to study the relationship between IOP fluctuation and disease progression in primary angle closure glaucoma (PACG) eyes. METHODS: Circadian IOP fluctuations were recorded by Sensimed Triggerfish sensors in 25 PACG eyes. The sensor output signals were smoothed using B-spline smoothing transform and described by functional data analysis. Glaucoma progression was documented with serial changes in mean deviation (MD) and visual field index (VFI) in Humphrey automated perimetry and retinal nerve fiber layer (RNFL) thickness. The signals were compared between the progressive and stable groups by permutation tests on functional t-statistic. RESULTS: Statistically significant differences were found from 2200 to 2300 and from 0700 to 0800 in gradients of the IOP fluctuation curve, as well as from 2300 to 2400 and 0800 to 0900 in curvatures of the IOP fluctuation curves, between the progressive MD and stable MD groups (P < 0.05). Significant gradient differences were also found from 1500 to 1600 and 0600 to 0800 between the progressive VFI and stable VFI groups, and from 2400 to 0100 and 0200 to 0300 between the progressive RNFL and stable RNFL groups (P < 0.05). CONCLUSIONS: Significant differences in circadian IOP fluctuation between progressive and stable PACG eyes were identified. Large IOP fluctuations may be associated with disease progression in PACG eyes. PMID- 26230765 TI - Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model. AB - PURPOSE: To measure depth-specific riboflavin concentrations in corneal stroma using two-photon fluorescence microscopy and compare commercially available transepithelial corneal collagen cross-linking (CXL) protocols. METHODS: Transepithelial CXL riboflavin preparations--MedioCross TE, Ribocross TE, Paracel plus VibeX Xtra, and iontophoresis with Ricrolin+--were applied to the corneal surface of fresh postmortem rabbit eyes in accordance with manufacturers' recommendations for clinical use. Riboflavin 0.1% (VibeX Rapid) was applied after corneal epithelial debridement as a positive control. After riboflavin application, eyes were snap frozen in liquid nitrogen. Corneal cross sections 35 MUm thick were cut on a cryostat, mounted on a slide, and imaged by two-photon fluorescence microscopy. Mean (SD) concentrations were calculated from five globes tested for each protocol. RESULTS: Peak riboflavin concentration of 0.09% (+/- 0.01) was observed within the most superficial stroma (stromal depth 0-10 MUm) in positive controls (epithelium-off). At the same depth, peak stromal riboflavin concentrations for MedioCross TE, Ricrolin+, Paracel/Xtra, and Ribocross TE were 0.054% (+/- 0.01), 0.031% (0.003), 0.021% (+/- 0.001), and 0.015% (+/- 0.004), respectively. At a depth of 300 MUm (within the demarcation zone commonly seen after corneal cross-linking), the stromal concentration in epithelium-off positive controls was 0.075% (+/- 0.006), while at the same depth MedioCross TE and Ricrolin+ achieved 0.018% (+/- 0.006) and 0.016% (0.002), respectively. None of the remaining transepithelial protocols achieved concentrations above 0.005% at this same 300-MUm depth. Overall, MedioCross TE was the best-performing transepithelial formulation. CONCLUSIONS: Corneal epithelium is a significant barrier to riboflavin absorption into the stroma. Existing commercial transepithelial CXL protocols achieve relatively low riboflavin concentrations in the anterior corneal stroma when compared to gold standard epithelium-off absorption. Reduced stromal riboflavin concentration may compromise the efficacy of riboflavin/ultraviolet corneal CXL. PMID- 26230763 TI - Myocyte Dedifferentiation Drives Extraocular Muscle Regeneration in Adult Zebrafish. AB - PURPOSE: The purpose of this study was to characterize the injury response of extraocular muscles (EOMs) in adult zebrafish. METHODS: Adult zebrafish underwent lateral rectus (LR) muscle myectomy surgery to remove 50% of the muscle, followed by molecular and cellular characterization of the tissue response to the injury. RESULTS: Following myectomy, the LR muscle regenerated an anatomically correct and functional muscle within 7 to 10 days post injury (DPI). Following injury, the residual muscle stump was replaced by a mesenchymal cell population that lost cell polarity and expressed mesenchymal markers. Next, a robust proliferative burst repopulated the area of the regenerating muscle. Regenerating cells expressed myod, identifying them as myoblasts. However, both immunofluorescence and electron microscopy failed to identify classic Pax7-positive satellite cells in control or injured EOMs. Instead, some proliferating nuclei were noted to express mef2c at the very earliest point in the proliferative burst, suggesting myonuclear reprogramming and dedifferentiation. Bromodeoxyuridine (BrdU) labeling of regenerating cells followed by a second myectomy without repeat labeling resulted in a twice-regenerated muscle broadly populated by BrdU-labeled nuclei with minimal apparent dilution of the BrdU signal. A double-pulse experiment using BrdU and 5-ethynyl-2'-deoxyuridine (EdU) identified double-labeled nuclei, confirming the shared progenitor lineage. Rapid regeneration occurred despite a cell cycle length of 19.1 hours, whereas 72% of the regenerating muscle nuclei entered the cell cycle by 48 hours post injury (HPI). Dextran lineage tracing revealed that residual myocytes were responsible for muscle regeneration. CONCLUSIONS: EOM regeneration in adult zebrafish occurs by dedifferentiation of residual myocytes involving a muscle-to-mesenchyme transition. A mechanistic understanding of myocyte reprogramming may facilitate novel approaches to the development of molecular tools for targeted therapeutic regeneration in skeletal muscle disorders and beyond. PMID- 26230766 TI - Spermidine Ameliorates Neurodegeneration in a Mouse Model of Normal Tension Glaucoma. AB - PURPOSE: To assess the therapeutic potential of spermidine in mice with excitatory amino acid carrier 1 (EAAC1) deletion (EAAC1 knockout [KO] mice), a mouse model of normal tension glaucoma. METHODS: Spermidine, at 30 mM in drinking water, was administered to EAAC1 KO mice from 5 to 12 weeks old. Optical coherence tomography, multifocal electroretinograms, and the measurement of intraocular pressure (IOP) were performed at 5, 8, and 12 weeks old. Histopathology analyses were carried out at 8 and 12 weeks old, and immunoblot and immunohistochemical analyses of 4-hydroxy-2-nonenal (4-HNE) in the retina were performed at 8 weeks old. RESULTS: Spermidine ameliorated retinal degeneration and improved visual function in EAAC1 KO mice at both 8 and 12 weeks old, without affecting IOP. A significant increase of 4-HNE was observed in vehicle-treated EAAC1 KO mice, but spermidine treatment reduced this increase, suggesting that spermidine alleviated the severity of the glaucoma-like phenotype by acting as an antioxidant. CONCLUSIONS: The results from this study suggest that oral spermidine administration could be a useful treatment for retinal degenerative disorders including glaucoma. PMID- 26230767 TI - Metabolome-Wide Association Study of Primary Open Angle Glaucoma. AB - PURPOSE: To determine if primary open-angle glaucoma (POAG) patients can be differentiated from controls based on metabolic characteristics. METHODS: We used ultra-high resolution mass spectrometry with C18 liquid chromatography for metabolomic analysis on frozen plasma samples from 72 POAG patients and 72 controls. Metabolome-wide Spearman correlation was performed to select differentially expressed metabolites (DEM) correlated with POAG. We corrected P values for multiple testing using Benjamini and Hochberg false discovery rate (FDR). Hierarchical cluster analysis (HCA) was used to depict the relationship between participants and DEM. Differentially expressed metabolites were matched to the METLIN metabolomics database; both DEM and metabolites significantly correlating with DEM were analyzed using MetaboAnalyst to identify metabolic pathways altered in POAG. RESULTS: Of the 2440 m/z (mass/charge) features recovered after filtering, 41 differed between POAG cases and controls at FDR = 0.05. Hierarchical cluster analysis revealed these DEM to associate into eight clusters; three of these clusters contained the majority of the DEM and included palmitoylcarnitine, hydroxyergocalciferol, and high-resolution METLIN matches to sphingolipids, other vitamin D-related metabolites, and terpenes. MetaboAnalyst also indicated likely alteration in steroid biosynthesis pathways. CONCLUSIONS: Global ultrahigh resolution metabolomics emphasized the importance of altered lipid metabolism in POAG. The results suggest specific metabolic processes, such as those involving palmitoylcarnitine, sphingolipids, vitamin D-related compounds, and steroid precursors, may contribute to POAG status and merit more detailed study with targeted methods. PMID- 26230768 TI - Flecks in Recessive Stargardt Disease: Short-Wavelength Autofluorescence, Near Infrared Autofluorescence, and Optical Coherence Tomography. AB - PURPOSE: We evaluated the incongruous observation whereby flecks in recessive Stargardt disease (STGD1) can exhibit increased short-wavelength autofluorescence (SW-AF) that originates from retinal pigment epithelium (RPE) lipofuscin, while near-infrared AF (NIR-AF), emitted primarily from RPE melanin, is usually reduced or absent at fleck positions. METHODS: Flecks in SW- and NIR-AF images and spectral-domain optical coherence tomography (SD-OCT) scans were studied in 19 STGD1 patients carrying disease-causing ABCA4 mutations. Fleck spatial distribution and progression were recorded in serial AF images. RESULTS: Flecks observed in SW-AF images typically colocalized with darkened foci in NIR-AF images; the NIR-AF profiles were larger. The decreased NIR-AF signal from flecks preceded apparent changes in SW-AF. Spatiotemporal changes in fleck distribution usually progressed centrifugally, but in one case centripetal expansion was observed. Flecks in SW-AF images corresponded to hyperreflective deposits that progressively traversed photoreceptor-attributable bands in SD-OCT images. Outer nuclear layer (ONL) thickness negatively correlated with expansion of flecks from outer to inner retina. CONCLUSIONS: In the healthy retina, RPE lipofuscin fluorophores form in photoreceptor cells but are transferred to RPE; thus the SW AF signal from photoreceptor cells is negligible. In STGD1, NIR-AF imaging reveals that flecks are predominantly hypofluorescent and larger and that NIR-AF darkening occurs prior to heightened SW-AF signal. These observations indicate that RPE cells associated with flecks in STGD1 are considerably changed or lost. Spectral-domain OCT findings are indicative of ongoing photoreceptor cell degeneration. The bright SW-AF signal of flecks likely originates from augmented lipofuscin formation in degenerating photoreceptor cells impaired by the failure of RPE. PMID- 26230769 TI - Levels of 8-OxodG Predict Hepatobiliary Pathology in Opisthorchis viverrini Endemic Settings in Thailand. AB - Opisthorchis viverrini is distinct among helminth infections as it drives a chronic inflammatory response in the intrahepatic bile duct that progresses from advanced periductal fibrosis (APF) to cholangiocarcinoma (CCA). Extensive research shows that oxidative stress (OS) plays a critical role in the transition from chronic O. viverrini infection to CCA. OS also results in the excision of a modified DNA lesion (8-oxodG) into urine, the levels of which can be detected by immunoassay. Herein, we measured concentrations of urine 8-oxodG by immunoassay from the following four groups in the Khon Kaen Cancer Cohort study: (1) O. viverrini negative individuals, (2) O. viverrini positive individuals with no APF as determined by abdominal ultrasound, (3) O. viverrini positive individuals with APF as determined by abdominal ultrasound, and (4) O. viverrini induced cases of CCA. A logistic regression model was used to evaluate the utility of creatinine adjusted urinary 8-oxodG among these groups, along with demographic, behavioral, and immunological risk factors. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive accuracy of urinary 8-oxodG for APF and CCA. Elevated concentrations of 8-oxodG in urine positively associated with APF and CCA in a strongly dose-dependent manner. Urinary 8-oxodG concentrations also accurately predicted whether an individual presented with APF or CCA compared to O. viverrini infected individuals without these pathologies. In conclusion, urinary 8-oxodG is a robust 'candidate' biomarker of the progression of APF and CCA from chronic opisthorchiasis, which is indicative of the critical role that OS plays in both of these advanced hepatobiliary pathologies. The findings also confirm our previous observations that severe liver pathology occurs early and asymptomatically in residents of O. viverrini endemic regions, where individuals are infected for years (often decades) with this food-borne pathogen. These findings also contribute to an expanding literature on 8-oxodG in an easily accessible bodily fluid (e.g., urine) as a biomarker in the multistage process of inflammation, fibrogenesis, and infection-induced cancer. PMID- 26230770 TI - Experimental Test of Entropic Noise-Disturbance Uncertainty Relations for Spin 1/2 Measurements. AB - Information-theoretic definitions for noise and disturbance in quantum measurements were given in [Phys. Rev. Lett. 112, 050401 (2014)] and a state independent noise-disturbance uncertainty relation was obtained. Here, we derive a tight noise-disturbance uncertainty relation for complementary qubit observables and carry out an experimental test. Successive projective measurements on the neutron's spin-1/2 system, together with a correction procedure which reduces the disturbance, are performed. Our experimental results saturate the tight noise-disturbance uncertainty relation for qubits when an optimal correction procedure is applied. PMID- 26230771 TI - Fate of Many-Body Localization Under Periodic Driving. AB - We study many-body localized quantum systems subject to periodic driving. We find that the presence of a mobility edge anywhere in the spectrum is enough to lead to delocalization for any driving strength and frequency. By contrast, for a fully localized many-body system, a delocalization transition occurs at a finite driving frequency. We present numerical studies on a system of interacting one dimensional bosons and the quantum random energy model, as well as simple physical pictures accounting for those results. PMID- 26230772 TI - Nonzero Classical Discord. AB - Quantum discord is the quantitative difference between two alternative expressions for bipartite mutual information, given respectively in terms of two distinct definitions for the conditional entropy. By constructing a stochastic model of shared states, classical discord can be similarly defined, quantifying the presence of some stochasticity in the measurement process. Therefore, discord can generally be understood as a quantification of the system's state disturbance due to local measurements, be it quantum or classical. We establish an operational meaning of classical discord in the context of state merging with noisy measurement and thereby show the quantum-classical separation in terms of a negative conditional entropy. PMID- 26230773 TI - Entanglement and Nonlocality are Inequivalent for Any Number of Parties. AB - Understanding the relation between nonlocality and entanglement is one of the fundamental problems in quantum physics. In the bipartite case, it is known that these two phenomena are inequivalent, as there exist entangled states of two parties that do not violate any Bell inequality. However, except for a single example of an entangled three-qubit state that has a local model, almost nothing is known about such a relation in multipartite systems. We provide a general construction of genuinely multipartite entangled states that do not display genuinely multipartite nonlocality, thus proving that entanglement and nonlocality are inequivalent for any number of parties. PMID- 26230774 TI - Qutrit Magic State Distillation Tight in Some Directions. AB - Magic state distillation is a crucial component in the leading approaches to implementing universal fault-tolerant quantum computation, with existing protocols for both qubit and higher dimensional systems. Early work focused on determining the region of distillable states for qubit protocols; yet comparatively little is known about which states can be distilled and with what distillable region for d>2. Here we focus on d=3 and present new four-qutrit distillation schemes that improve upon the known distillable region, and achieve distillation tight to the boundary of undistillable states for some classes of state. As a consequence of recent results, this implies that there is a family of quantum states that enable universality if and only if they exhibit contextuality with respect to stabilizer measurements. We also identify a new routine whose fixed point is a magic state with maximal sum negativity; i.e., it is maximally nonstablizer in a specific sense. PMID- 26230775 TI - Practical Relativistic Bit Commitment. AB - Bit commitment is a fundamental cryptographic primitive in which Alice wishes to commit a secret bit to Bob. Perfectly secure bit commitment between two mistrustful parties is impossible through an asynchronous exchange of quantum information. Perfect security is, however, possible when Alice and Bob each split into several agents exchanging classical information at times and locations suitably chosen to satisfy specific relativistic constraints. In this Letter we first revisit a previously proposed scheme [C. Crepeau et al., Lect. Notes Comput. Sci. 7073, 407 (2011)] that realizes bit commitment using only classical communication. We prove that the protocol is secure against quantum adversaries for a duration limited by the light-speed communication time between the locations of the agents. We then propose a novel multiround scheme based on finite-field arithmetic that extends the commitment time beyond this limit, and we prove its security against classical attacks. Finally, we present an implementation of these protocols using dedicated hardware and we demonstrate a 2 ms-long bit commitment over a distance of 131 km. By positioning the agents on antipodal points on the surface of Earth, the commitment time could possibly be extended to 212 ms. PMID- 26230776 TI - Postselection-Loophole-Free Bell Test Over an Installed Optical Fiber Network. AB - Device-independent quantum communication will require a loophole-free violation of Bell inequalities. In typical scenarios where line of sight between the communicating parties is not available, it is convenient to use energy-time entangled photons due to intrinsic robustness while propagating over optical fibers. Here we show an energy-time Clauser-Horne-Shimony-Holt Bell inequality violation with two parties separated by 3.7 km over the deployed optical fiber network belonging to the University of Concepcion in Chile. Remarkably, this is the first Bell violation with spatially separated parties that is free of the postselection loophole, which affected all previous in-field long-distance energy time experiments. Our work takes a further step towards a fiber-based loophole free Bell test, which is highly desired for secure quantum communication due to the widespread existing telecommunication infrastructure. PMID- 26230777 TI - Communication Tasks with Infinite Quantum-Classical Separation. AB - Quantum resources can be more powerful than classical resources-a quantum computer can solve certain problems exponentially faster than a classical computer, and computing a function of two parties' inputs can be done with exponentially less communication with quantum messages than with classical ones. Here we consider a task between two players, Alice and Bob where quantum resources are infinitely more powerful than their classical counterpart. Alice is given a string of length n, and Bob's task is to exclude certain combinations of bits that Alice might have. If Alice must send classical messages, then she must reveal nearly n bits of information to Bob, but if she is allowed to send quantum bits, the amount of information she must reveal goes to zero with increasing n. Next, we consider a version of the task where the parties may have access to entanglement. With this assistance, Alice only needs to send a constant number of bits, while without entanglement, the number of bits Alice must send grows linearly with n. The task is related to the Pusey-Barrett-Rudolph theorem which arises in the context of the foundations of quantum theory. PMID- 26230779 TI - Entropy Inequality Violations from Ultraspinning Black Holes. AB - We construct a new class of rotating anti-de Sitter (AdS) black hole solutions with noncompact event horizons of finite area in any dimension and study their thermodynamics. In four dimensions these black holes are solutions to gauged supergravity. We find that their entropy exceeds the maximum implied from the conjectured reverse isoperimetric inequality, which states that for a given thermodynamic volume, the black hole entropy is maximized for Schwarzschild-AdS space. We use this result to suggest more stringent conditions under which this conjecture may hold. PMID- 26230778 TI - Concentrating Tripartite Quantum Information. AB - We introduce the concentrated information of tripartite quantum states. For three parties Alice, Bob, and Charlie, it is defined as the maximal mutual information achievable between Alice and Charlie via local operations and classical communication performed by Charlie and Bob. We derive upper and lower bounds to the concentrated information, and obtain a closed expression for it on several classes of states including arbitrary pure tripartite states in the asymptotic setting. We show that distillable entanglement, entanglement of assistance, and quantum discord can all be expressed in terms of the concentrated information, thus revealing its role as a unifying informational primitive. We finally investigate quantum state merging of mixed states with and without additional entanglement. The gap between classical and quantum concentrated information is proven to be an operational figure of merit for mixed state merging in the absence of additional entanglement. Contrary to the pure state merging, our analysis shows that classical communication in both directions can provide an advantage for merging of mixed states. PMID- 26230780 TI - Approaching the Post-Newtonian Regime with Numerical Relativity: A Compact-Object Binary Simulation Spanning 350 Gravitational-Wave Cycles. AB - We present the first numerical-relativity simulation of a compact-object binary whose gravitational waveform is long enough to cover the entire frequency band of advanced gravitational-wave detectors, such as LIGO, Virgo, and KAGRA, for mass ratio 7 and total mass as low as 45.5M_{?}. We find that effective-one-body models, either uncalibrated or calibrated against substantially shorter numerical relativity waveforms at smaller mass ratios, reproduce our new waveform remarkably well, with a negligible loss in detection rate due to modeling error. In contrast, post-Newtonian inspiral waveforms and existing calibrated phenomenological inspiral-merger-ringdown waveforms display greater disagreement with our new simulation. The disagreement varies substantially depending on the specific post-Newtonian approximant used. PMID- 26230781 TI - (1+1)D Calculation Provides Evidence that Quantum Entanglement Survives a Firewall. AB - We analyze how preexisting entanglement between two Unruh-DeWitt particle detectors evolves when one of the detectors falls through a Rindler firewall in (1+1)-dimensional Minkowski space. The firewall effect is minor and does not wash out the detector-detector entanglement, in some regimes even preserving the entanglement better than Minkowski vacuum. The absence of cataclysmic events should continue to hold for young black hole firewalls. A firewall's prospective ability to resolve the information paradox must hence hinge on its detailed gravitational structure, presently poorly understood. PMID- 26230787 TI - Phase Reconstruction of Strong-Field Excited Systems by Transient-Absorption Spectroscopy. AB - The evolution of a V-type three-level system is studied, whose two resonances are coherently excited and coupled by two ultrashort laser pump and probe pulses, separated by a varying time delay. We relate the quantum dynamics of the excited multilevel system to the absorption spectrum of the transmitted probe pulse. In particular, by analyzing the quantum evolution of the system, we interpret how atomic phases are differently encoded in the time-delay-dependent spectral absorption profiles when the pump pulse either precedes or follows the probe pulse. This scheme is experimentally applied to atomic Rb, whose fine-structure split 5s (2)S{1/2}->5p(2)P{1/2} and 5s(2)S_{1/2}->5p(2)P{3/2} transitions are driven by the combined action of a pump pulse of variable intensity and a delayed probe pulse. The provided understanding of the relationship between quantum phases and absorption spectra represents an important step towards full time dependent phase reconstruction (quantum holography) of bound-state wave packets in strong-field light-matter interactions with atoms, molecules, and solids. PMID- 26230785 TI - Characterization of Molecular Breakup by Very Intense Femtosecond XUV Laser Pulses. AB - We study the breakup of H2+ exposed to superintense, femtosecond laser pulses with frequencies greater than that corresponding to the ionization potential. By solving the time-dependent Schrodinger equation in an extensive field parameter range, it is revealed that highly nonresonant dissociation channels can dominate over ionization. By considering field-dressed Born-Oppenheimer potential energy curves in the reference frame following a free electron in the field, we propose a simple physical model that characterizes this dissociation mechanism. The model is used to predict control of vibrational excitation, magnitude of the dissociation yields, and nuclear kinetic energy release spectra. Finally, the joint energy spectrum for the ionization process illustrates the energy sharing between the electron and the nuclei and the correlation between ionization and dissociation processes. PMID- 26230788 TI - Alkali-Metal Spin Maser. AB - Quantum measurement is a combination of a read-out and a perturbation of the quantum system. We explore the nonlinear spin dynamics generated by a linearly polarized probe beam in a continuous measurement of the collective spin state in a thermal alkali-metal atomic sample. We demonstrate that the probe-beam-driven perturbation leads, in the presence of indirect pumping, to complete polarization of the sample and macroscopic coherent spin oscillations. As a consequence of the former we report observation of spectral profiles free from collisional broadening. Nonlinear dynamics is studied through exploring its effect on radio frequency as well as spin noise spectra. PMID- 26230789 TI - Magneto-Optical Properties of Paramagnetic Superrotors. AB - We study the dynamics of paramagnetic molecular superrotors in an external magnetic field. An optical centrifuge is used to create dense ensembles of oxygen molecules in ultrahigh rotational states. In is shown, for the first time, that the gas of rotating molecules becomes optically birefringent in the presence of a magnetic field. The discovered effect of "magneto-rotational birefringence" indicates the preferential alignment of molecular axes along the field direction. We provide an intuitive qualitative model, in which the influence of the applied magnetic field on the molecular orientation is mediated by the spin-rotation coupling. This model is supported by the direct imaging of the distribution of molecular axes, the demonstration of the magnetic reversal of the rotational Raman signal, and by numerical calculations. PMID- 26230790 TI - Density-Functional Theory for Strongly Correlated Bosonic and Fermionic Ultracold Dipolar and Ionic Gases. AB - We introduce a density functional formalism to study the ground-state properties of strongly correlated dipolar and ionic ultracold bosonic and fermionic gases, based on the self-consistent combination of the weak and the strong coupling limits. Contrary to conventional density functional approaches, our formalism does not require a previous calculation of the interacting homogeneous gas, and it is thus very suitable to treat systems with tunable long-range interactions. Because of its asymptotic exactness in the regime of strong correlation, the formalism works for systems in which standard mean-field theories fail. PMID- 26230786 TI - Precision Test of Many-Body QED in the Be+ 2p Fine Structure Doublet Using Short Lived Isotopes. AB - Absolute transition frequencies of the 2s 2S{1/2}->2p2P{1/2,3/2} transitions in Be^{+} were measured for the isotopes ^{7,9-12}Be. The fine structure splitting of the 2p state and its isotope dependence are extracted and compared to results of ab initio calculations using explicitly correlated basis functions, including relativistic and quantum electrodynamics effects at the order of malpha(6) and malpha(7) ?ln alpha. Accuracy has been improved in both the theory and experiment by 2 orders of magnitude, and good agreement is observed. This represents one of the most accurate tests of quantum electrodynamics for many-electron systems, being insensitive to nuclear uncertainties. PMID- 26230791 TI - Quasiresonant van der Waals Interaction between Nonidentical Atoms. AB - We present a time-dependent quantum calculation of the van der Waals interaction between a pair of dissimilar atoms, one of which is initially excited while the other one is in its ground state. For small detuning, the interaction is predominantly mediated at all distances by the exchange of doubly resonant photons between the two atoms. We find that it presents both temporal and spatial oscillations. Spatially oscillating terms depend on the resonant frequencies of both atoms, while the frequency of the time oscillations is given by their detuning. We analyze the physical content of our findings and discuss to what extent previous conflicting stationary approaches provide compatible results. A proper account of causality is found essential in order to obtain the correct result. PMID- 26230792 TI - Absolute Differential Positronium-Formation Cross Sections. AB - The first absolute experimental determinations of the differential cross sections for the formation of ground-state positronium are presented for He, Ar, H2, and CO2 near 0 degrees . Results are compared with available theories. The ratio of the differential and integrated cross sections for the targets exposes the higher propensity for forward emission of positronium formed from He and H2. PMID- 26230793 TI - Hybrid Quantum Systems with Collectively Coupled Spin States: Suppression of Decoherence through Spectral Hole Burning. AB - Spin ensemble based hybrid quantum systems suffer from a significant degree of decoherence resulting from the inhomogeneous broadening of the spin transition frequencies in the ensemble. We demonstrate that this strongly restrictive drawback can be overcome simply by burning two narrow spectral holes in the spin spectral density at judiciously chosen frequencies. Using this procedure we find an increase of the coherence time by more than an order of magnitude as compared to the case without hole burning. Our findings pave the way for the practical use of these hybrid quantum systems for the processing of quantum information. PMID- 26230794 TI - Photoionization-Induced Emission of Tunable Few-Cycle Midinfrared Dispersive Waves in Gas-Filled Hollow-Core Photonic Crystal Fibers. AB - We propose a scheme for the emission of few-cycle dispersive waves in the midinfrared using hollow-core photonic crystal fibers filled with noble gas. The underlying mechanism is the formation of a plasma cloud by a self-compressed, subcycle pump pulse. The resulting free-electron population modifies the fiber dispersion, allowing phase-matched access to dispersive waves at otherwise inaccessible frequencies, well into the midinfrared. Remarkably, the pulses generated turn out to have durations of the order of two optical cycles. In addition, this ultrafast emission, which occurs even in the absence of a zero dispersion point between pump and midinfrared wavelengths, is tunable over a wide frequency range simply by adjusting the gas pressure. These theoretical results pave the way to a new generation of compact, fiber-based sources of few-cycle midinfrared radiation. PMID- 26230795 TI - Spin-Glass Model Governs Laser Multiple Filamentation. AB - We show that multiple filamentation patterns in high-power laser beams can be described by means of two statistical physics concepts, namely, self-similarity of the patterns over two nested scales and nearest-neighbor interactions of classical rotators. The resulting lattice spin model perfectly reproduces the evolution of intense laser pulses as simulated by the nonlinear Schrodinger equation, shedding new light on multiple filamentation. As a side benefit, this approach drastically reduces the computing time by 2 orders of magnitude as compared to the standard simulation methods of laser filamentation. PMID- 26230796 TI - Phase Diffusion in Unequally Noisy Coupled Oscillators. AB - We consider the dynamics of two directionally coupled unequally noisy oscillators, the first oscillator being noisier than the second oscillator. We derive analytically the phase diffusion coefficient of both oscillators in a heterogeneous setup (different frequencies, coupling coefficients, and intrinsic noise intensities) and show that the phase coherence of the second oscillator depends in a nonmonotonic fashion on the noise intensity of the first oscillator: as the first oscillator becomes less coherent, i.e., worse, the second one becomes more coherent, i.e., better. This surprising effect is related to the statistics of the first oscillator which provides a source of noise for the second oscillator, that is non-Gaussian, bounded, and possesses a finite bandwidth. We verify that the effect is robust by numerical simulations of two coupled FitzHugh-Nagumo models. PMID- 26230797 TI - Propagation Dynamics of Airy Water-Wave Pulses. AB - We observe the propagation dynamics of surface gravity water waves, having an Airy function envelope, in both the linear and the nonlinear regimes. In the linear regime, the shape of the envelope is preserved while propagating in an 18 m water tank, despite the inherent dispersion of the wave packet. The Airy wave function can propagate at a velocity that is slower (or faster if the Airy envelope is inverted) than the group velocity. Furthermore, the introduction of the Airy wave packet as surface water waves enables the observation of its position-dependent chirp and cubic-phase offset, predicted more than 35 years ago, for the first time. When increasing the envelope of the input Airy pulse, nonlinear effects become dominant, and are manifested by the generation of water wave solitons. PMID- 26230798 TI - Thin Films in Partial Wetting: Internal Selection of Contact-Line Dynamics. AB - When a liquid touches a solid surface, it spreads to minimize the system's energy. The classic thin-film model describes the spreading as an interplay between gravity, capillarity, and viscous forces, but it cannot see an end to this process as it does not account for the nonhydrodynamic liquid-solid interactions. While these interactions are important only close to the contact line, where the liquid, solid, and gas meet, they have macroscopic implications: in the partial-wetting regime, a liquid puddle ultimately stops spreading. We show that by incorporating these intermolecular interactions, the free energy of the system at equilibrium can be cast in a Cahn-Hilliard framework with a height dependent interfacial tension. Using this free energy, we derive a mesoscopic thin-film model that describes the statics and dynamics of liquid spreading in the partial-wetting regime. The height dependence of the interfacial tension introduces a localized apparent slip in the contact-line region and leads to compactly supported spreading states. In our model, the contact-line dynamics emerge naturally as part of the solution and are therefore nonlocally coupled to the bulk flow. Surprisingly, we find that even in the gravity-dominated regime, the dynamic contact angle follows the Cox-Voinov law. PMID- 26230782 TI - Measurement of CP Violation in B0->J/psiK{S}^{0} Decays. AB - Measurements are presented of the CP violation observables S and C in the decays of B(0) and Bover -]0 mesons to the J/psiK(S)(0) final state. The data sample corresponds to an integrated luminosity of 3.0 fb(-1) collected with the LHCb experiment in proton-proton collisions at center-of-mass energies of 7 and 8 TeV, and contains a total of 41 560 selected B^{0} and B[over -]^{0} decays. The analysis of the time evolution of these decays yields S=0.731+/-0.035(stat)+/ 0.020(syst) and C=-0.038+/-0.032(stat)+/-0.005(syst). In the standard model, S equals sin(2beta) to a good level of precision. The values are consistent with the current world averages and with the standard model expectations. PMID- 26230799 TI - Spatial Coherence and Stability in a Disordered Organic Polariton Condensate. AB - Although only a handful of organic materials have shown polariton condensation, their study is rapidly becoming more accessible. The spontaneous appearance of long-range spatial coherence is often recognized as a defining feature of such condensates. In this Letter, we study the emergence of spatial coherence in an organic microcavity and demonstrate a number of unique features stemming from the peculiarities of this material set. Despite its disordered nature, we find that correlations extend over the entire spot size, and we measure g(1)(r,r') values of nearly unity at short distances and of 50% for points separated by nearly 10 MUm . We show that for large spots, strong shot-to-shot fluctuations emerge as varying phase gradients and defects, including the spontaneous formation of vortices. These are consistent with the presence of modulation instabilities. Furthermore, we find that measurements with flat-top spots are significantly influenced by disorder and can, in some cases, lead to the formation of mutually incoherent localized condensates. PMID- 26230800 TI - Spatially Resolved Detection of a Spin-Entanglement Wave in a Bose-Hubbard Chain. AB - Entanglement is an essential property of quantum many-body systems. However, its local detection is challenging and was so far limited to spin degrees of freedom in ion chains. Here we measure entanglement between the spins of atoms located on two lattice sites in a one-dimensional Bose-Hubbard chain which features both local spin- and particle-number fluctuations. Starting with an initially localized spin impurity, we observe an outwards propagating entanglement wave and show quantitatively how entanglement in the spin sector rapidly decreases with increasing particle-number fluctuations in the chain. PMID- 26230802 TI - Plasmon Injection to Compensate and Control Losses in Negative Index Metamaterials. AB - Metamaterials have introduced a whole new world of unusual materials with functionalities that cannot be attained in naturally occurring material systems by mimicking and controlling the natural phenomena at subwavelength scales. However, the inherent absorption losses pose a fundamental challenge to the most fascinating applications of metamaterials. Based on a novel plasmon injection (PI or Pi) scheme, we propose a coherent optical amplification technique to compensate losses in metamaterials. Although the proof of concept device here operates under normal incidence only, our proposed scheme can be generalized to an arbitrary form of incident waves. The Pi scheme is fundamentally different from major optical amplification schemes. It does not require a gain medium, interaction with phonons, or any nonlinear medium. The Pi scheme allows for loss free metamaterials. It is ideally suited for mitigating losses in metamaterials operating in the visible spectrum and is scalable to other optical frequencies. These findings open the possibility of reviving the early dreams of making "magical" metamaterials from scratch. PMID- 26230801 TI - Quantitative Measurement of Density in a Shear Band of Metallic Glass Monitored Along its Propagation Direction. AB - Quantitative density measurements from electron scattering show that shear bands in deformed Al88Y7Fe5 metallic glass exhibit alternating high and low density regions, ranging from -9% to +6% relative to the undeformed matrix. Small deflections of the shear band from the main propagation direction coincide with switches in density from higher to lower than the matrix and vice versa, indicating that faster and slower motion (stick slip) occurs during the propagation. Nanobeam diffraction analyses provide clear evidence that the density changes are accompanied by structural changes, suggesting that shear alters the packing of tightly bound short- or medium-range atomic clusters. This bears a striking resemblance to the packing behavior in granular shear bands formed upon deformation of granular media. PMID- 26230803 TI - Nonequilibrium Casimir-like Forces in Liquid Mixtures. AB - In this Letter, we consider a liquid mixture confined between two thermally conducting walls subjected to a stationary temperature gradient. While in a one component liquid nonequilibrium fluctuation forces appear inside the liquid layer, nonequilibrium fluctuations in a mixture induce a Casimir-like force on the walls. The physical reason is that the temperature gradient induces large concentration fluctuations through the Soret effect. Unlike temperature fluctuations, nonequilibrium concentration fluctuations are also present near a perfectly thermally conducting wall. The magnitude of the fluctuation-induced Casimir force is proportional to the square of the Soret coefficient and is related to the concentration dependence of the heat and volume of mixing. PMID- 26230804 TI - Giant Osmotic Pressure in the Forced Wetting of Hydrophobic Nanopores. AB - The forced intrusion of water in hydrophobic nanoporous pulverulent material is of interest for quick storage of energy. With nanometric pores the energy storage capacity is controlled by interfacial phenomena. With subnanometric pores, we demonstrate that a breakdown occurs with the emergence of molecular exclusion as a leading contribution. This bulk exclusion effect leads to an osmotic contribution to the pressure that can reach levels never previously sustained. We illustrate, on various electrolytes and different microporous materials, that a simple osmotic pressure law accounts quantitatively for the enhancement of the intrusion and extrusion pressures governing the forced wetting and spontaneous drying of the nanopores. Using electrolyte solutions, energy storage and power capacities can be widely enhanced. PMID- 26230805 TI - Peeling by Nanomechanical Forces: A Route to Selective Creation of Surface Structures. AB - An emerging route to nanostructured hybrid organic-metal interfaces with tailored properties is their manipulation by nanomechanical forces as exerted by STM and AFM tips. Yet, despite impressive experimental progress, close to nothing is known about the underlying atomistic mechanisms of such nanomechanical techniques, thus hindering predictive, rational approaches. Here, we identify "surface peeling" as an important new mechanism for the modification of surfaces. Using density-functional calculations of thiolate self-assembled monolayers at gold and silver, we find that this phenomenon is very sensitive to the force vector, resulting in a high anisotropy in the systems' response that can be exploited for the selective creation of novel hybrid surfaces. PMID- 26230806 TI - THz-Pulse-Induced Selective Catalytic CO Oxidation on Ru. AB - We demonstrate the use of intense, quasi-half-cycle THz pulses, with an associated electric field component comparable to intramolecular electric fields, to direct the reaction coordinate of a chemical reaction by stimulating the nuclear motions of the reactants. Using a strong electric field from a THz pulse generated via coherent transition radiation from an ultrashort electron bunch, we present evidence that CO oxidation on Ru(0001) is selectively induced, while not promoting the thermally induced CO desorption process. The reaction is initiated by the motion of the O atoms on the surface driven by the electric field component of the THz pulse, rather than thermal heating of the surface. PMID- 26230807 TI - Quantitative Prediction of Molecular Adsorption: Structure and Binding of Benzene on Coinage Metals. AB - Interfaces between organic molecules and solid surfaces play a prominent role in heterogeneous catalysis, molecular sensors and switches, light-emitting diodes, and photovoltaics. The properties and the ensuing function of such hybrid interfaces often depend exponentially on molecular adsorption heights and binding strengths, calling for well-established benchmarks of these two quantities. Here we present systematic measurements that enable us to quantify the interaction of benzene with the Ag(111) coinage metal substrate with unprecedented accuracy (0.02 A in the vertical adsorption height and 0.05 eV in the binding strength) by means of normal-incidence x-ray standing waves and temperature-programed desorption techniques. Based on these accurate experimental benchmarks for a prototypical molecule-solid interface, we demonstrate that recently developed first-principles calculations that explicitly account for the nonlocality of electronic exchange and correlation effects are able to determine the structure and stability of benzene on the Ag(111) surface within experimental error bars. Remarkably, such precise experiments and calculations demonstrate that despite different electronic properties of copper, silver, and gold, the binding strength of benzene is equal on the (111) surface of these three coinage metals. Our results suggest the existence of universal binding energy trends for aromatic molecules on surfaces. PMID- 26230808 TI - Novel Electronic Behavior Driving NdNiO3 Metal-Insulator Transition. AB - We present evidence that the metal-insulator transition (MIT) in a tensile strained NdNiO3 (NNO) film is facilitated by a redistribution of electronic density and that it neither requires Ni charge disproportionation nor a symmetry change [U. Staub et al., Phys. Rev. Lett. 88, 126402 (2002); R. Jaramillo et al., Nat. Phys. 10, 304 (2014)]. Given that epitaxial tensile strain in thin NNO films induces preferential occupancy of the e(g) d(x(2)-y(2)) orbital we propose that the larger transfer integral of this orbital state with the O 2p orbital state mediates a redistribution of electronic density from the Ni atom. A decrease in the Ni d(x(2)-y(2)) orbital occupation is directly observed by resonant inelastic x-ray scattering below the MIT temperature. Furthermore, an increase in the Nd charge occupancy is measured by x-ray absorption at the Nd L(3) edge. Both spin orbit coupling and crystal field effects combine to break the degeneracy of the Nd 5d states, shifting the energy of the Nd e(g) d(x(2)-y(2)) orbit towards the Fermi level, allowing the A site to become an active acceptor during the MIT. This work identifies the relocation of electrons from the Ni 3d to the Nd 5d orbitals across the MIT. We propose that the insulating gap opens between the Ni 3d and O 2p states, resulting from Ni 3d electron localization. The transition seems to be neither a purely Mott-Hubbard transition nor a simple charge transfer. PMID- 26230809 TI - Strongly Constrained and Appropriately Normed Semilocal Density Functional. AB - The ground-state energy, electron density, and related properties of ordinary matter can be computed efficiently when the exchange-correlation energy as a functional of the density is approximated semilocally. We propose the first meta generalized-gradient approximation (meta-GGA) that is fully constrained, obeying all 17 known exact constraints that a meta-GGA can. It is also exact or nearly exact for a set of "appropriate norms," including rare-gas atoms and nonbonded interactions. This strongly constrained and appropriately normed meta-GGA achieves remarkable accuracy for systems where the exact exchange-correlation hole is localized near its electron, and especially for lattice constants and weak interactions. PMID- 26230810 TI - Non-Fermi-Liquid Behavior in Metallic Quasicrystals with Local Magnetic Moments. AB - Motivated by the intrinsic non-Fermi-liquid behavior observed in the heavy fermion quasicrystal Au51Al34Yb15, we study the low-temperature behavior of dilute magnetic impurities placed in metallic quasicrystals. We find that a large fraction of the magnetic moments are not quenched down to very low temperatures T, leading to a power-law distribution of Kondo temperatures P(T(K))~T(K)(alpha 1), with a nonuniversal exponent alpha, in a remarkable similarity to the Kondo disorder scenario found in disordered heavy-fermion metals. For alpha<1, the resulting singular P(T(K)) induces non-Fermi-liquid behavior with diverging thermodynamic responses as T->0. PMID- 26230811 TI - Competing d-Wave and p-Wave Spin-Singlet Superconductivities in the Two Dimensional Kondo Lattice. AB - The Kondo lattice model describes a quantum phase transition between the antiferromagnetic state and heavy-fermion states. Applying the dual-fermion approach, we explore possible superconductivities emerging due to the critical antiferromagnetic fluctuations. The d-wave pairing is found to be the leading instability only in the weak-coupling regime. As the coupling is increased, we observe a change of the pairing symmetry into a p-wave spin-singlet pairing. The competing superconductivities are ascribed to crossover between small and large Fermi surfaces, which occurs with the formation of heavy quasiparticles. PMID- 26230812 TI - Electronic Magnetization of a Quantum Point Contact Measured by Nuclear Magnetic Resonance. AB - We report an electronic magnetization measurement of a quantum point contact (QPC) based on nuclear magnetic resonance (NMR) spectroscopy. We find that NMR signals can be detected by measuring the QPC conductance under in-plane magnetic fields. This makes it possible to measure, from Knight shifts of the NMR spectra, the electronic magnetization of a QPC containing only a few electron spins. The magnetization changes smoothly with the QPC potential barrier height and peaks at the conductance plateau of 0.5*2e^{2}/h. The observed features are well captured by a model calculation assuming a smooth potential barrier, supporting a no bound state origin of the 0.7 structure. PMID- 26230813 TI - Dzyaloshinskii-Moriya Interaction and Hall Effects in the Skyrmion Phase of Mn(1 x) Fe(x)Ge. AB - We carry out density functional theory calculations which demonstrate that the electron dynamics in the Skyrmion phase of Fe-rich Mn_{1-x}Fe_{x}Ge alloys is governed by Berry phase physics. We observe that the magnitude of the Dzyaloshinskii-Moriya interaction directly related to the mixed space-momentum Berry phases, changes sign and magnitude with concentration x in direct correlation with the data of Shibata et al. [Nat. Nanotechnol. 8, 723 (2013)]. The computed anomalous and topological Hall effects in FeGe are also in good agreement with available experiments. We further develop a simple tight-binding model able to explain these findings. Finally, we show that the adiabatic Berry phase picture is violated in the Mn-rich limit of the alloys. PMID- 26230814 TI - Strongly Metallic Electron and Hole 2D Transport in an Ambipolar Si-Vacuum Field Effect Transistor. AB - We report experiment and theory on an ambipolar gate-controlled Si(111)-vacuum field effect transistor where we study electron and hole (low-temperature 2D) transport in the same device simply by changing the external gate voltage to tune the system from being a 2D electron system at positive gate voltage to a 2D hole system at negative gate voltage. The electron (hole) conductivity manifests strong (moderate) metallic temperature dependence with the conductivity decreasing by a factor of 8 (2) between 0.3 K and 4.2 K with the peak electron mobility (~18 m2/V s) being roughly 20 times larger than the peak hole mobility (in the same sample). Our theory explains the data well using random phase approximation screening of background Coulomb disorder, establishing that the observed metallicity is a direct consequence of the strong temperature dependence of the effective screened disorder. PMID- 26230815 TI - Universal Wave-Function Overlap and Universal Topological Data from Generic Gapped Ground States. AB - We propose a way-universal wave-function overlap-to extract universal topological data from generic ground states of gapped systems in any dimensions. Those extracted topological data might fully characterize the topological orders with a gapped or gapless boundary. For nonchiral topological orders in (2+1)D, these universal topological data consist of two matrices S and T, which generate a projective representation of SL(2,Z) on the degenerate ground state Hilbert space on a torus. For topological orders with a gapped boundary in higher dimensions, these data constitute a projective representation of the mapping class group MCG(M^{d}) of closed spatial manifold M^{d}. For a set of simple models and perturbations in two dimensions, we show that these quantities are protected to all orders in perturbation theory. These overlaps provide a much more powerful alternative to the topological entanglement entropy and allow for more efficient numerical implementations. PMID- 26230816 TI - Electric and Magnetic Tuning Between the Trivial and Topological Phases in InAs/GaSb Double Quantum Wells. AB - Among the theoretically predicted two-dimensional topological insulators, InAs/GaSb double quantum wells (DQWs) have a unique double-layered structure with electron and hole gases separated in two layers, which enables tuning of the band alignment via electric and magnetic fields. However, the rich trivial-topological phase diagram has yet to be experimentally explored. We present an in situ and continuous tuning between the trivial and topological insulating phases in InAs/GaSb DQWs through electrical dual gating. Furthermore, we show that an in plane magnetic field shifts the electron and hole bands relatively to each other in momentum space, functioning as a powerful tool to discriminate between the topologically distinct states. PMID- 26230817 TI - Molecular Adsorption Changes the Quantum Structure of Oxide-Supported Gold Nanoparticles: Chemisorption versus Physisorption. AB - STM conductance spectroscopy and mapping has been used to analyze the impact of molecular adsorption on the quantized electronic structure of individual metal nanoparticles. For this purpose, isophorone and CO2, as prototype molecules for physisorptive and chemisorptive binding, were dosed onto monolayer Au islands grown on MgO thin films. The molecules attach exclusively to the metal-oxide boundary, while the interior of the islands remains pristine. The Au quantum well states are perturbed due to the adsorption process and increase their mutual energy spacing in the CO2 case but move together in isophorone-covered islands. The shifts disclose the nature of the molecule-Au interaction, which relies on electron exchange for the CO2 ligands but on dispersive forces for the organic species. Our experiments reveal how molecular adsorption affects individual quantum systems, a topic of utmost relevance for heterogeneous catalysis. PMID- 26230818 TI - Electrically Tunable Magnetism in Magnetic Topological Insulators. AB - The external controllability of the magnetic properties in topological insulators would be important both for fundamental and practical interests. Here we predict the electric-field control of ferromagnetism in a thin film of insulating magnetic topological insulators. The decrease of band inversion by the application of electric fields results in a reduction of magnetic susceptibility, and hence in the modification of magnetism. Remarkably, the electric field could even induce the magnetic quantum phase transition from ferromagnetism to paramagnetism. We further propose a transistor device in which the dissipationless charge transport of chiral edge states is controlled by an electric field. In particular, the field-controlled ferromagnetism in a magnetic topological insulator can be used for voltage based writing of magnetic random access memories in magnetic tunnel junctions. The simultaneous electrical control of magnetic order and chiral edge transport in such devices may lead to electronic and spintronic applications for topological insulators. PMID- 26230819 TI - Dirac Line Nodes in Inversion-Symmetric Crystals. AB - We propose and characterize a new Z2 class of topological semimetals with a vanishing spin-orbit interaction. The proposed topological semimetals are characterized by the presence of bulk one-dimensional (1D) Dirac line nodes (DLNs) and two-dimensional (2D) nearly flat surface states, protected by inversion and time-reversal symmetries. We develop the Z2 invariants dictating the presence of DLNs based on parity eigenvalues at the parity-invariant points in reciprocal space. Moreover, using first-principles calculations, we predict DLNs to occur in Cu_{3}N near the Fermi energy by doping nonmagnetic transition metal atoms, such as Zn and Pd, with the 2D surface states emerging in the projected interior of the DLNs. This Letter includes a brief discussion of the effects of spin-orbit interactions and symmetry breaking as well as comments on experimental implications. PMID- 26230820 TI - Topological Node-Line Semimetal and Dirac Semimetal State in Antiperovskite Cu3PdN. AB - Based on first-principles calculation and effective model analysis, we propose that the cubic antiperovskite material Cu3PdN can host a three-dimensional (3D) topological node-line semimetal state when spin-orbit coupling (SOC) is ignored, which is protected by the coexistence of time-reversal and inversion symmetry. There are three node-line circles in total due to the cubic symmetry. Drumheadlike surface flat bands are also derived. When SOC is included, each node line evolves into a pair of stable 3D Dirac points as protected by C4 crystal symmetry. This is remarkably distinguished from the Dirac semimetals known so far, such as Na3Bi and Cd3As2, both having only one pair of Dirac points. Once C4 symmetry is broken, the Dirac points are gapped and the system becomes a strong topological insulator with (1;111) Z2 indices. PMID- 26230821 TI - Ising Incommensurate Spin Resonance of CeCoIn5: A Dynamical Precursor of the Q Phase. AB - It is shown through detailed inelastic neutron scattering experiments that the gapped collective magnetic excitation of the unconventional superconductor CeCoIn5, the spin resonance mode, is incommensurate and that the corresponding fluctuations are of an Ising nature. The incommensurate peak position of these fluctuations corresponds to the propagation vector of the adjacent field induced static magnetic ordered phase, the so-called Q phase. Furthermore, the direction of the magnetic moment fluctuations is also the direction of the ordered magnetic moments of the Q phase. Hence, the resonance mode and the Q phase share the same symmetry and this strongly supports a scenario where the static order is realized by a condensation of the magnetic excitation. PMID- 26230822 TI - ac Wien Effect in Spin Ice, Manifest in Nonlinear, Nonequilibrium Susceptibility. AB - The Wien effect is a model process for field-induced charge creation. Here it is derived for a nonelectrical system: the spin ice "magnetolyte"-a unique system showing perfect charge symmetry. An entropic reaction field, analogous to the Jaccard field in ice, opposes direct current, but a frequency window exists in which the Wien effect for magnetolyte and electrolyte are indistinguishable. The universal enhancement of monopole density speeds up the magnetization dynamics, which manifests in the nonlinear, nonequilibrium ac susceptibility. This is a rare instance where such effects may be calculated, providing new insights for electrolytes. Experimental predictions are made for Dy2Ti2O7 spin ice. PMID- 26230823 TI - Coulomb Liquid Phases of Bosonic Cluster Mott Insulators on a Pyrochlore Lattice. AB - Employing large-scale quantum Monte Carlo simulations, we reveal the full phase diagram of the extended Hubbard model of hard-core bosons on the pyrochlore lattice with partial fillings. When the intersite repulsion is dominant, the system is in a cluster Mott insulator phase with an integer number of bosons localized inside the tetrahedral units of the pyrochlore lattice. We show that the full phase diagram contains three cluster Mott insulator phases with 1/4, 1/2, and 3/4 boson fillings, respectively. We further demonstrate that all three cluster Mott insulators are Coulomb liquid phases and its low-energy property is described by the emergent compact U(1) quantum electrodynamics. In addition to measuring the specific heat and entropy of the cluster Mott insulators, we investigate the correlation function of the emergent electric field and verify it is consistent with the compact U(1) quantum electrodynamics description. Our result sheds light on the magnetic properties of various pyrochlore systems, as well as the charge physics of the cluster magnets. PMID- 26230824 TI - Thermal Transport and Nonequilibrium Temperature Drop Across a Magnetic Tunnel Junction. AB - In the field of spin caloritronics, spin-dependent transport phenomena are observed in a number of current experiments where a temperature gradient across a nanostructured interface is applied. The interpretation of these experiments is not clear as both phonons and electrons may contribute to thermal transport. Therefore, it still remains an open question how the temperature drop across a magnetic nanostructured interface arises microscopically. We answer this question for the case of a magnetic tunnel junction (MTJ) where the tunneling magneto Seebeck effect occurs. Our explanation may be extended to other types of nanostructured interfaces. We explicitly calculate phonon and electron thermal conductance across Fe/MgO/Fe MTJs in an ab initio approach using a Green function method. Furthermore, we are able to calculate the electron and phonon temperature profile across the Fe/MgO/Fe MTJ by estimating the electron-phonon interaction in the Fe leads. Our results show that there is an electron-phonon temperature imbalance at the Fe-MgO interfaces. As a consequence, a revision of the interpretation of current experimental measurements may be necessary. PMID- 26230825 TI - Large Flexoelectric Anisotropy in Paraelectric Barium Titanate. AB - The bending-induced polarization of barium titanate single crystals has been measured with an aim to elucidate the origin of the large difference between theoretically predicted and experimentally measured flexoelectricity in this material. The results indicate that part of the difference is due to polar regions (short-range order) that exist above T(C) and up to T*~200-225 degrees C. Above T*, however, the flexovoltage coefficient still shows an unexpectedly large anisotropy for a cubic material, with (001)-oriented crystals displaying 10 times more flexoelectricity than (111)-oriented crystals. Theoretical analysis shows that this anisotropy cannot be a bulk property, and we therefore interpret it as indirect evidence for the theoretically predicted but experimentally elusive contribution of surface piezoelectricity to macroscopic bending-induced polarization. PMID- 26230826 TI - Coupling Ferroelectricity with Spin-Valley Physics in Oxide-Based Heterostructures. AB - The coupling of spin and valley physics is nowadays regarded as a promising route toward next-generation spintronic and valleytronic devices. In the aim of engineering functional properties for valleytronic applications, we focus on the ferroelectric heterostructure BiAlO3/BiIrO3, where the complex interplay among a trigonal crystal field, layer degrees of freedom, and spin-orbit coupling mediates a strong spin-valley coupling. Furthermore, we show that ferroelectricity provides a nonvolatile handle to manipulate and switch the emerging valley-contrasting spin polarization. PMID- 26230827 TI - Detention Times of Microswimmers Close to Surfaces: Influence of Hydrodynamic Interactions and Noise. AB - After colliding with a surface, microswimmers reside there during the detention time. They accumulate and may form complex structures such as biofilms. We introduce a general framework to calculate the distribution of detention times using the method of first-passage times and study how rotational noise and hydrodynamic interactions influence the escape from a surface. We compare generic swimmer models to the simple active Brownian particle. While the respective detention times of source dipoles are smaller, the ones of pullers are larger by up to several orders of magnitude, and pushers show both trends. We apply our results to the more realistic squirmer model, for which we use lubrication theory, and validate them by simulations with multiparticle collision dynamics. PMID- 26230828 TI - Physical Limit to Concentration Sensing Amid Spurious Ligands. AB - To adapt their behavior in changing environments, cells sense concentrations by binding external ligands to their receptors. However, incorrect ligands may bind nonspecifically to receptors, and when their concentration is large, this binding activity may interfere with the sensing of the ligand of interest. Here, I derive analytically the physical limit to the accuracy of concentration sensing amid a large number of interfering ligands. A scaling transition is found when the mean bound time of correct ligands is twice that of incorrect ligands. I discuss how the physical bound can be approached by a cascade of receptor states generalizing kinetic proofreading schemes. PMID- 26230829 TI - Renewal Approach to the Analysis of the Asynchronous State for Coupled Noisy Oscillators. AB - We develop a framework in which the activity of nonlinear pulse-coupled oscillators is posed within the renewal theory. In this approach, the evolution of the interevent density allows for a self-consistent calculation that determines the asynchronous state and its stability. This framework can readily be extended to the analysis of systems with more state variables and provides a population density treatment to evolve them in their thermodynamical limits. To demonstrate this we study a nonlinear pulse-coupled system, where couplings are dynamic and activity dependent. We investigate its stability and numerically study the nonequilibrium behavior of the system after the bifurcation. We show that this system undergoes a supercritical Hopf bifurcation to collective synchronization. PMID- 26230830 TI - Nondecaying Hydrodynamic Interactions along Narrow Channels. AB - Particle-particle interactions are of paramount importance in every multibody system as they determine the collective behavior and coupling strength. Many well known interactions such as electrostatic, van der Waals, or screened Coulomb interactions, decay exponentially or with negative powers of the particle spacing r. Similarly, hydrodynamic interactions between particles undergoing Brownian motion decay as 1/r in bulk, and are assumed to decay in small channels. Such interactions are ubiquitous in biological and technological systems. Here we confine two particles undergoing Brownian motion in narrow, microfluidic channels and study their coupling through hydrodynamic interactions. Our experiments show that the hydrodynamic particle-particle interactions are distance independent in these channels. This finding is of fundamental importance for the interpretation of experiments where dense mixtures of particles or molecules diffuse through finite length, water-filled channels or pore networks. PMID- 26230831 TI - Identifying obstacles to return to duty in severely injured combat-related servicemembers with amputation. AB - The capacity of servicemembers with amputation to return to duty after combat related amputation and the associated disabilities remains largely unknown. The purpose of this study was to examine the disabling conditions and return to duty rates of servicemembers with amputation across all service branches following major limb amputations from September 2001 through July 2011. Pertinent medical information, military occupation status, return to duty designation, disabling conditions, and disability ratings for each servicemember were obtained from the Physical Evaluation Board Liaison Office (PEBLO). Across all service branches, 16 (2%) servicemembers were found fit for duty (Fit) and allowed to continue with their preinjury occupation. Another 103 (11%) were allowed to continue on Active Duty (COAD) in a less physically demanding role. More than half (554, 56%) were determined fully disabled (PEBLO rating > 75); the average disability rating was 73. COAD and Fit Army servicemembers had lower Injury Severity Scores than other servicemembers (17.4, p = 0.009 and 11.2, p < 0.001, respectively). Despite improvements in their care and rehabilitation, only 13% of all servicemembers with amputation are able to return to Active Duty and many have multiple disabling conditions that contribute to a very high level of disability. PMID- 26230832 TI - The Role of Angiotensin II and Cyclic AMP in Alveolar Active Sodium Transport. AB - Active alveolar fluid clearance is important in keeping airspaces free of edema. Angiotensin II plays a role in the pathogenesis of hypertension, heart failure and others. However, little is known about its contribution to alveolar fluid clearance. Angiotensin II effects are mediated by two specific receptors; AT1 and AT2. The localization of these two receptors in the lung, specifically in alveolar epithelial cells type II, was recently reported. We hypothesize that Angiotensin II may have a role in the regulation of alveolar fluid clearance. We investigated the effect of Angiotensin II on alveolar fluid clearance in rats using the isolated perfused lung model and isolated rat alveolar epithelial cells. The rate of alveolar fluid clearance in control rats was 8.6% +/- 0.1 clearance of the initial volume and decreased by 22.5%, 28.6%, 41.6%, 48.7% and 39% in rats treated with 10-10 M, 10-9 M, 10-8 M, 10-7 M or 10-6 M of Ang II respectively (P < 0.003). The inhibitory effect of Angiotensin II was restored in losartan, an AT1 specific antagonist, pretreated rats, indicating an AT1 mediated effect of Ang II on alveolar fluid clearance. The expression of Na,K-ATPase proteins and cAMP levels in alveolar epithelial cells were down-regulated following the administration of Angiotensin II; suggesting that cAMP may be involved in AngII-induced reduced Na,K-ATPase expression, though the contribution of additional factors could not be excluded. We herein suggest a novel mechanism of clinical relevance by which angiotensin adversely impairs the ability of the lungs to clear edema. PMID- 26230834 TI - Preparation of Vinylcyclopropanes by Sodium Mediated Reductive Isomerization of Methylenecyclopropanes. AB - We disclosed therein a new reaction of reductive isomerization of methylenecyclopropanes (MCPs) to vinylcyclopropanes (VCPs). On treatment with sodium metal in liquid ammonia, MCPs bearing a C-O bond at allylic position undergo both a reductive cleavage of the C-O bond and an isomerization of the C-C double bond giving rise to VCPs. The scope of the reductive isomerization was investigated and showed a broad applicability since various functional groups are tolerated. MCP substrates were straightforwardly prepared by a palladium-promoted [2 + 1] cycloaddition between norbornene derivatives with alkynes. PMID- 26230833 TI - Molecular In Vivo Imaging Using a Noninvasive Cardiac-Specific MLC-2v Promoter Driven Dual-Gene Recombinant Lentivirus Monitoring System. AB - BACKGROUND: Our study aimed to demonstrate the feasibility of using the sodium/iodide symporter (NIS) to monitor vascular endothelial growth factor (VEGF165) expression in vivo. METHODS: We constructed a recombinant lentivirus plasmid with the MLC-2v promoter driving the sodium/iodide symporter (NIS) reporter gene linked to the VEGF165 gene. Expression of NIS and VEGF gene were identified by Western blot. On days 2 and 54, 99mTc-MIBI imaging was used to evaluate changes in myocardial ischemia. Noninvasive 125I micro-SPECT/CT imaging was used to assess the expression of NIS reporter gene dynamically over the next 2 months. RESULTS: Western blot analysis showed that both NIS and VEGF165 were highly expressed in rat cardiomyoblast H9C2 cells transduced with Lenti-MLC-2v NIS--VEGF165. 125I micro-SPECT/CT reporter imaging showed higher uptake in mouse myocardium transduced with Lenti-MLC-2v-VEGF165-IRES-NIS. NIS expression peaked on day 1 after transduction followed by a progressive decline to negligible levels by day 21. On day 1, mean 125I activity value in group 1 was higher than that in group 2 (P<0.05). The mean 125I activity value in group 3 was statically lower than that in group 1 and 2 (P<0.01). On day 60, 125I uptakes in test and positive control groups became very low, and no significant differences in the mean 125I activity values were detected between group 1 and group 2 (P = 0.531 > 0.05). In group 1 (test group), 99mTc-MIBI SPECT/CT revealed improvements in perfusion and wall thickening in the apical anterior wall. Mean IOD values of NIS and CD34 were significantly higher in group 1 than group 3 (P<0.05). Our study proved mean I-125 uptake was significantly correlated with mean IOD value of NIS and CD34 (P<0.05). CONCLUSION: This study demonstrates the feasibility of using the NIS gene to monitor VEGF165 expression in a mouse myocardial ischemia model. PMID- 26230836 TI - Bioaccumulation of Stentorin, the Probable Causative Agent for Discolored ("Purple") Eggs and Ovaries in Blue Catfish (Ictalurus furcatus) from Eufaula Lake, Oklahoma, USA. AB - Observations of reddish to "purple" discolored eggs in the ovaries of adult female blue catfish (Ictalurus furcatus) from the northern arm of Eufaula Lake, a eutrophic multiuse impoundment in east-central Oklahoma, were first reported in 2006. Blue catfish eggs are normally cream to light yellow. Reports peaked in 2007-2008 and declined through 2009-2010; purple eggs have not been reported between 2010 and 2014. In the laboratory, all tissues and fluids of affected fish were strongly orange-red fluorescent under UV illumination, with the fluorescence most apparent in the lipid-rich ovaries and eggs. The causative agent was isolated chromatographically and confirmed by mass spectrometry as stentorin (1,3,4,6,8,10,11,13-octahydroxy-2,5-diisopropyl phenanthro[1,10,9,8,o,p,q,r,a]perylene-7,14-dione), the fluorescent, lipophilic pigment associated with the photoreceptor protein of the ciliated protozoan Stentor coeruleus (Heterotrichea; Stentoridae). Larval medaka (Orizias latipes) readily consumed S. coeruleus in the laboratory and were observed to fluoresce in the same manner as the affected blue catfish. Potential deleterious effects of stentorin bioaccumulation remain to be determined, as do the geographic extent and the identities of other fluorescent compounds isolated from catfish eggs and ovaries. PMID- 26230835 TI - Treatment with hESC-Derived Myocardial Precursors Improves Cardiac Function after a Myocardial Infarction. AB - BACKGROUND: We previously reported the generation of a reporter line of human embryonic stem cells (hESCs) with enhanced green fluorescent protein (eGFP) expression driven by the alpha-myosin heavy chain (alphaMHC) promoter. The GFP+/alphaMHC+ cells derived from this cell line behave as multipotent, human myocardial precursors (hMPs) in vitro. In this study, we evaluated the therapeutic effects of GFP+/alphaMHC+ cells isolated from the reporter line in a mouse model of myocardial infarction (MI). METHODS: MI was generated in immunodeficient mice. hMPs were injected into murine infarcted hearts under ultrasound guidance at 3 days post-MI. Human fetal skin fibroblasts (hFFs) were injected as control. Cardiac function was evaluated by echocardiography. Infarct size, angiogenesis, apoptosis, cell fate, and teratoma formation were analyzed by immunohistochemical staining. RESULTS: Compared with control, hMPs resulted in improvement of cardiac function post-MI with smaller infarct size, induced endogenous angiogenesis, and reduced apoptosis of host cardiomyocytes at the peri infarct zone at 28 days post-MI. CONCLUSION: Intramyocardial injection of hMPs improved cardiac function post-MI. The engraftment rate of these cells in the myocardium post-MI was low, suggesting that the majority of effect occurs via paracrine mechanisms. PMID- 26230838 TI - Correction: Sagittal Abdominal Diameter as a Surrogate Marker of Insulin Resistance in an Admixtured Population-Brazilian Metabolic Syndrome Study (BRAMS). PMID- 26230837 TI - Interdomain Contacts Control Native State Switching of RfaH on a Dual-Funneled Landscape. AB - RfaH is a virulence factor from Escherichia coli whose C-terminal domain (CTD) undergoes a dramatic alpha-to-beta conformational transformation. The CTD in its alpha-helical fold is stabilized by interactions with the N-terminal domain (NTD), masking an RNA polymerase binding site until a specific recruitment site is encountered. Domain dissociation is triggered upon binding to DNA, allowing the NTD to interact with RNA polymerase to facilitate transcription while the CTD refolds into the beta-barrel conformation that interacts with the ribosome to activate translation. However, structural details of this transformation process in the context of the full protein remain to be elucidated. Here, we explore the mechanism of the alpha-to-beta conformational transition of RfaH in the full length protein using a dual-basin structure-based model. Our simulations capture several features described experimentally, such as the requirement of disruption of interdomain contacts to trigger the alpha-to-beta transformation, confirms the roles of previously indicated residues E48 and R138, and suggests a new important role for F130, in the stability of the interdomain interaction. These native basins are connected through an intermediate state that builds up upon binding to the NTD and shares features from both folds, in agreement with previous in silico studies of the isolated CTD. We also examine the effect of RNA polymerase binding on the stabilization of the beta fold. Our study shows that native-biased models are appropriate for interrogating the detailed mechanisms of structural rearrangements during the dramatic transformation process of RfaH. PMID- 26230839 TI - Is the OJIP Test a Reliable Indicator of Winter Hardiness and Freezing Tolerance of Common Wheat and Triticale under Variable Winter Environments? AB - OJIP analysis, which explores changes in photosystem II (PSII) photochemical performance, has been used as a measure of plant susceptibility to stress. However, in the case of freezing tolerance and winter hardiness, which are highly environmentally variable, the use of this method can give ambiguous results depending on the species as well as the sampling year and time. To clarify this issue, we performed chlorophyll fluorescence measurements over three subsequent winters (2010/11, 2011/12 and 2012/13) on 220 accessions of common winter wheat and 139 accessions of winter triticale. After freezing, leaves were collected from cold-acclimated plants in the laboratory and field-grown plants. Observations of field survival in seven locations across Poland and measurements of freezing tolerance of the studied plants were also recorded. Our results confirm that the OJIP test is a reliable indicator of winter hardiness and freezing tolerance of common wheat and triticale under unstable winter environments. Regardless of species, the testing conditions giving the most reliable results were identical, and the reliability of the test could be easily checked by analysis of some relationships between OJIP-test parameters. We also found that triticale is more winter hardy and freezing tolerant than wheat. In addition, the two species were characterized by different patterns of photosynthetic apparatus acclimation to cold. PMID- 26230840 TI - Citrate-Coated Silver Nanoparticles Interactions with Effluent Organic Matter: Influence of Capping Agent and Solution Conditions. AB - Fate and transport studies of silver nanoparticles (AgNPs) discharged from urban wastewaters containing effluent organic matter (EfOM) into natural waters represent a key knowledge gap. In this study, EfOM interfacial interactions with AgNPs, and their aggregation kinetics were investigated by atomic force microscopy (AFM) and time-resolved dynamic light scattering (TR-DLS), respectively. Two well-characterized EfOM isolates, i.e., wastewater humic (WW humic) and wastewater colloids (WW colloids, a complex mixture of polysaccharides proteins-lipids), and a River humic isolate of different characteristics were selected. Citrate-coated AgNPs were selected as representative capped-AgNPs. Citrate-coated AgNPs showed a considerable stability in Na(+) solutions. However, Ca(2+) ions induced aggregation by cation bridging between carboxyl groups on citrate. Although the presence of River humic increased the stability of citrate coated AgNPs in Na(+) solutions due to electrosteric effects, they aggregated in WW humic-containing solutions, indicating the importance of humics characteristics during interactions. Ca(2+) ions increased citrate-coated AgNPs aggregation rates in both humic solutions, suggesting cation bridging between carboxyl groups on their structures as a dominant interacting mechanism. Aggregation of citrate-coated AgNPs in WW colloids solutions was significantly faster than those in both humic solutions. Control experiments in urea solution indicated hydrogen bonding as the main interacting mechanism. During AFM experiments, citrate-coated AgNPs showed higher adhesion to WW humic than to River humic, evidencing a consistency between TR-DLS and AFM results. Ca(2+) ions increased citrate-coated AgNPs adhesion to both humic isolates. Interestingly, strong WW colloids interactions with citrate caused AFM probe contamination (nanoparticles adsorption) even at low Na(+) concentrations, indicating the impact of hydrogen bonding on adhesion. These results suggest the importance of solution conditions and capping agents on the stability of AgNPs in solution. However, the characteristics of organics would play a crucial role in the fate and transport of these nano contaminants in urban wastewaters and natural water systems. PMID- 26230841 TI - Are Married Men Healthier than Single Women? A Gender Comparison of the Health Effects of Marriage and Marital Satisfaction in East Asia. AB - BACKGROUND: Although Asian societies are remarkably different from Western societies in terms of sociocultural characteristics, little is known about the gender differences in the health effects of marriage and marital satisfaction in Asian countries. METHODOLOGY/PRINCIPAL FINDINGS: Using a randomly sampled dataset from the 2006 East Asian Social Survey comprising 8528 individuals from China, Japan, Taiwan, and South Korea, this study performs analyses using a multivariate logistic regression model to predict the probability for a man or a woman to report poor health. Our results differ quite significantly from those of most studies focusing on Western countries. Considering marital satisfaction, there may be no health benefits from marriage for a specific gender in a given country, because the health loss associated with a dissatisfied marriage usually supersedes the health benefits from marriage. Moreover, women may reap greater health benefits from marriage than men. Additionally, those most likely to report poor health are found to be married and dissatisfied men or women, rather than never-married individuals. CONCLUSION/SIGNIFICANCE: The present study argues the need to design and carry out a gender- and country-specific social health policy approach to target individuals suffering from poor health, thereby reducing the gender differences in health status. PMID- 26230843 TI - Correction: Dissatisfaction with Veterinary Services Is Associated with Leopard (Panthera pardus) Predation on Domestic Animals. PMID- 26230842 TI - High-Level HOOK3 Expression Is an Independent Predictor of Poor Prognosis Associated with Genomic Instability in Prostate Cancer. AB - Hook microtubule-tethering protein 3 (HOOK3) is an adaptor protein for microtubule-dependent intracellular vesicle and protein trafficking. In order to assess the role of HOOK3 in prostate cancer we analyzed HOOK3 expression by immunohistochemistry on a TMA containing more than 12,400 prostate cancers. Results were compared to tumor phenotype and PSA recurrence as well as aberrations possibly defining relevant molecular subtypes such as ERG status and deletions of 3p13, 5q21, 6q15 and PTEN. HOOK3 immunostaining was negative in normal luminal cells of prostate epithelium, whereas 53.3% of 10,572 interpretable cancers showed HOOK3 expression, which was considered low in 36.4% and high in 16.9% of cases. High-level HOOK3 expression was linked to advanced tumor stage, high Gleason score, high proliferation index, positive lymph node stage, and PSA recurrence (p<0.0001 each). The prognostic role of HOOK3 expression was independent of established clinico-pathological parameters both in preoperative and postoperative settings. Comparisons with molecular features were performed to draw conclusions on the potential function of HOOK3 in the prostate. A strong association with all examined deletions is consistent with a role of HOOK3 for maintaining genomic integrity by contributing to proper centrosome assembly. Finding HOOK3 expression in 74% of ERG positive but in only 38% of ERG negative cancers (p<0.0001) further suggests functional interactions between these genes. In conclusion, the results of our study identify HOOK3 as a strong candidate prognostic marker with a possible role in maintaining genomic integrity in prostate cancer, which may have potential for inclusion into clinical routine assays. PMID- 26230844 TI - Hydrogen Bond Formation between the Carotenoid Canthaxanthin and the Silanol Group on MCM-41 Surface. AB - The formation of one or two hydrogen bonds (H-bonds) between canthaxanthin (CAN), a dye, and the silanol group(s) on the MCM-41 surface has been studied by density functional theory (DFT) calculations and calorimetric experiments. It was found that the formation of the H-bond(s) stabilized the CAN molecule more than its radical cation (CAN(*+)). The charge distribution, bond lengths, and the HOMO and LUMO energies of CAN are also affected. The formation of the H-bond(s) explains the lower photoinduced electron transfer efficiency of CAN imbedded in Cu-MCM-41 versus that for beta-carotene (CAR) imbedded in Cu-MCM-41 where complex formation with Cu(2+) dominates. These calculations show that to achieve high electron transfer efficiency for a dye-sensitized solar cell, H-bonding between the dye and the host should be avoided. PMID- 26230845 TI - Microenvironmental Modulation of Decorin and Lumican in Temozolomide-Resistant Glioblastoma and Neuroblastoma Cancer Stem-Like Cells. AB - The presence of cancer stem cells (CSCs) or tumor-initiating cells can lead to cancer recurrence in a permissive cell-microenvironment interplay, promoting invasion in glioblastoma (GBM) and neuroblastoma (NB). Extracellular matrix (ECM) small leucine-rich proteoglycans (SLRPs) play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM) components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs), SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN) and lumican (LUM) are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM) to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+) CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like) showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC like from the GBM and NB neurospheres were resistant to temozolomide (TMZ) at concentrations >750 MUM. Our results suggest that GBM and NB CSC-like promote the activation of huge quantities of SLRP in response to CSC enrichment, simultaneously acquiring TMZ resistance, cellular heterogeneity, and a quiescent phenotype, suggesting a novel pivotal role for SLRP in drug resistance and cell plasticity of CSC-like, allowing cell survival and ECM/niche modulation potential. PMID- 26230848 TI - Translation Elongation Factor Tuf of Acinetobacter baumannii Is a Plasminogen Binding Protein. AB - Acinetobacter baumannii is an important nosocomial pathogen, causing a variety of opportunistic infections of the skin, soft tissues and wounds, urinary tract infections, secondary meningitis, pneumonia and bacteremia. Over 63% of A. baumannii infections occurring in the United States are caused by multidrug resistant isolates, and pan-resistant isolates have begun to emerge that are resistant to all clinically relevant antibiotics. The complement system represents the first line of defense against invading pathogens. However, many A. baumannii isolates, especially those causing severe bacteremia are resistant to complement-mediated killing, though the underlying mechanisms remain poorly understood. Here we show for the first time that A. baumannii binds host-derived plasminogen and we identify the translation elongation factor Tuf as a moonlighting plasminogen-binding protein that is exposed on the outer surface of A. baumannii. Binding of plasminogen to Tuf is at least partly dependent on lysine residues and ionic interactions. Plasminogen, once bound to Tuf can be converted to active plasmin and proteolytically degrade fibrinogen as well as the key complement component C3b. Thus, Tuf acts as a multifunctional protein that may contribute to virulence of A. baumannii by aiding in dissemination and evasion of the complement system. PMID- 26230849 TI - Home Dampness Signs in Association with Asthma and Allergic Diseases in 4618 Preschool Children in Urumqi, China-The Influence of Ventilation/Cleaning Habits. AB - There is an increasing prevalence of childhood asthma and allergic diseases in mainland of China. Few studies investigated the indoor dampness, ventilation and cleaning habits and their interrelationship with childhood asthma and allergic diseases. A large-scale cross-sectional study was performed in preschool children in Urumqi, China. Questionnaire was used to collect information on children's health, home dampness and ventilation/cleaning (V/C) habits. Multiple logistic regressions were applied to analyze the associations between childhood asthma/allergic diseases and each sign of home dampness, dampness levels, each V/C habit and total V/C scores. The associations between dampness and health were further performed by strata analyses in two groups with low and high V/C scores. Totally 4618(81.7%) of 5650 children returned the questionnaire. Reports on home dampness were most common for water condensation on windows (20.8%) followed by damp beddings (18.0%). The most common ventilation measure was the use of exhaust fan in bathroom (59.3%), followed by daily home cleaning (48.3%), frequently putting beddings to sunshine (29.9%) and frequently opening windows in winter (8.4%). There were positive associations between the 6 signs of home dampness and children's health particularly the symptoms last 12 months. By comparing with the reference dampness level (dampness scored 0), both the low dampness (scored 1~2) level and the high dampness level (scored 3~6) showed significantly increasing associations with childhood symptoms. There were crude negative associations between V/C habits and childhood health but not significant adjusting for home dampness levels. The risks of home dampness on children's health were lower in the group with higher V/C score but the differences were not statistically significant. Home dampness is a potential risk factor for childhood asthma and allergic symptoms in preschool children in Urumqi, China. No significant effects were observed for ordinary home ventilation and cleaning habits in reducing the risks of home dampness on childhood asthma and allergic diseases in Urumqi, China. PMID- 26230851 TI - Telomere Length in Peripheral Blood Leukocytes Is Associated with Severity of Biliary Atresia. AB - OBJECTIVE: The purpose of this study was to investigate the association of telomere length in peripheral blood leukocytes with the severity of biliary atresia (BA). METHODS: One hundred and fourteen BA patients and 114 age-matched healthy controls were enrolled. Relative telomere length (RTL) was assessed using a quantitative real-time polymerase chain reaction. Multivariate regression analysis was used to estimate RTL as an independent risk factor of BA. Receiver operating characteristic curve analysis was used to calculate the accuracy of biomarkers in the prediction of liver cirrhosis. RESULTS: BA patients had significantly shorter telomeres than healthy controls (p < 0.0001). The RTL in BA patients with jaundice was considerably lower than that of patients without jaundice (p = 0.005). Moreover, RTL was markedly shorter in patients with cirrhosis (F4), as compared to patients with mild fibrosis (F2) and non-fibrosis (F0-F1, p < 0.0001). Logistic regression analysis indicated that short RTL was associated with a higher risk of liver cirrhosis in BA. Tertile analysis showed a dose-response effect for this association (p trend < 0.0001). Additionally, RTL in BA children revealed a negative correlation with age (r = -0.50, p < 0.001). We noted an association between reduction of RTL and liver stiffness scores, adjusted for age and gender (b = -0.01, p < 0.0001). Short RTL can be employed to distinguish cirrhosis patients from non-cirrhosis patients (AUC = 0.78). Further analysis showed a linear correlation between leukocyte RTL and liver RTL in BA patients (r = 0.83, p < 0.001). CONCLUSION: The findings of this study provide evidence that telomere shortening is associated with an elevated risk of liver cirrhosis in BA. PMID- 26230852 TI - Contrasting Propagation of Natural Calls of Two Anuran Species from the South American Temperate Forest. AB - The acoustic adaptation hypothesis predicts that sound communication signals have an optimal relationship with animals' native environments. However, species sharing a habitat produce signals stratified in the spectral domain and exhibit different temporal patterns resulting in acoustic niche partitioning. The diversity generated is likely to affect differently the characteristics of propagating signals. We recorded at various distances from the sound source calls of the frogs Eupsophus calcaratus and E. emiliopugini in the austral temperate forest where they communicate and breed syntopically. The calls of E. calcaratus have higher frequency components and lower amplitude relative to calls of E. emiliopugini, and the acoustic active space for the signals of E. calcaratus is restricted relative to E. emiliopugini. The signals of both species experience similar attenuation patterns, but calls of E. calcaratus are affected by spectral degradation to a larger extent, with linear decreases in spectral cross correlation and in the amplitude ratio between the first two harmonics. The calls of E. emiliopugini are affected by temporal degradation as a linear decrease in amplitude modulation depth of their pulsed structure. Further studies are needed to assess the relative importance of selective and phylogenetic factors on the divergent propagation patterns reported. PMID- 26230850 TI - Physical Activity Design Guidelines for School Architecture. AB - Increasing children's physical activity at school is a national focus in the U.S. to address childhood obesity. While research has demonstrated associations between aspects of school environments and students' physical activity, the literature currently lacks a synthesis of evidence to serve as a practical, spatially-organized resource for school designers and decision-makers, as well as to point to pertinent research opportunities. This paper describes the development of a new practical tool: Physical Activity Design Guidelines for School Architecture. Its aims are to provide architects and designers, as well as school planners, educators, and public health professionals, with strategies for making K-12 school environments conducive to healthy physical activity, and to engage scientists in transdisciplinary perspectives toward improved knowledge of the school environment's impact. We used a qualitative review process to develop evidence-based and theory-driven school design guidelines that promote increased physical activity among students. The design guidelines include specific strategies in 10 school design domains. Implementation of the guidelines is expected to enable students to adopt healthier physical activity behaviors. The tool bridges a translational gap between research and environmental design practice, and may contribute to setting new industry and education standards. PMID- 26230853 TI - Prognostic Relevance of Objective Response According to EASL Criteria and mRECIST Criteria in Hepatocellular Carcinoma Patients Treated with Loco-Regional Therapies: A Literature-Based Meta-Analysis. AB - BACKGROUND: The European Association for the Study of the Liver (EASL) criteria and the modified Response Evaluation Criteria in Solid Tumors (mRECIST) are currently adopted to evaluate radiological response in patients affected by HCC and treated with loco-regional procedures. Several studies explored the validity of these measurements in predicting survival but definitive data are still lacking. AIM: To conduct a systematic review of studies exploring mRECIST and EASL criteria usefulness in predictive radiological response in HCC undergoing loco-regional therapies and their validity in predicting survival. METHODS: A comprehensive search of the literature was performed in electronic databases EMBASE, MEDLINE, COCHRANE LIBRARY, ASCO conferences and EASL conferences up to June 10, 2014. Our overall search strategy included terms for HCC, mRECIST, and EASL. Loco-regional procedures included transarterial embolization (TAE), transarterial chemoembolization (TACE) and cryoablation. Inter-method agreement between EASL and mRECIST was assessed using the k coefficient. For each criteria, overall survival was described in responders vs. non-responders patients, considering all target lesions response. RESULTS: Among 18 initially found publications, 7 reports including 1357 patients were considered eligible. All studies were published as full-text articles. Proportion of responders according to mRECIST and EASL criteria was 62.4% and 61.3%, respectively. In the pooled population, 1286 agreements were observed between the two methods (kappa statistics 0.928, 95% confidence interval 0.912-0.944). HR for overall survival (responders versus non responders) according to mRECIST and EASL was 0.39 (95% confidence interval 0.26-0.61, p<0.0001) and 0.38 (95% confidence interval 0.24 0.61, p<0.0001), respectively. CONCLUSION: In this literature-based meta analysis, mRECIST and EASL criteria showed very good concordance in HCC patients undergoing loco-regional treatments. Objective response according to both criteria confirms a strong prognostic value in terms of overall survival. This prognostic value appears to be very similar between the two criteria. PMID- 26230855 TI - Agave Chewing and Dental Wear: Evidence from Quids. AB - Agave quid chewing is examined as a potential contributing behavior to hunter gatherer dental wear. It has previously been hypothesized that the contribution of Agave quid chewing to dental wear would be observed in communities wherever phytolith-rich desert succulents were part of subsistence. Previous analysis of coprolites from a prehistoric agricultural site, La Cueva de los Muertos Chiquitos in Durango, Mexico, showed that Agave was a consistent part of a diverse diet. Therefore, quids recovered at this site ought to be useful materials to test the hypothesis that dental wear was related to desert succulent consumption. The quids recovered from the site were found to be largely derived from chewing Agave. In this study, the quids were found to be especially rich in phytoliths, and analysis of dental casts made from impressions left in the quids revealed flat wear and dental attrition similar to that of Agave-reliant hunter gatherers. Based on evidence obtained from the analysis of quids, taken in combination with results from previous studies, it is determined that Agave quid chewing was a likely contributing factor to dental wear in this population. As such, our method provides an additional avenue of dental research in areas where quids are present. PMID- 26230854 TI - Bioinformatic Challenges in Clinical Diagnostic Application of Targeted Next Generation Sequencing: Experience from Pheochromocytoma. AB - BACKGROUND: Recent studies have demonstrated equal quality of targeted next generation sequencing (NGS) compared to Sanger Sequencing. Whereas these novel sequencing processes have a validated robust performance, choice of enrichment method and different available bioinformatic software as reliable analysis tool needs to be further investigated in a diagnostic setting. METHODS: DNA from 21 patients with genetic variants in SDHB, VHL, EPAS1, RET, (n=17) or clinical criteria of NF1 syndrome (n=4) were included. Targeted NGS was performed using Truseq custom amplicon enrichment sequenced on an Illumina MiSEQ instrument. Results were analysed in parallel using three different bioinformatics pipelines; (1) Commercially available MiSEQ Reporter, fully automatized and integrated software, (2) CLC Genomics Workbench, graphical interface based software, also commercially available, and ICP (3) an in-house scripted custom bioinformatic tool. RESULTS: A tenfold read coverage was achieved in between 95-98% of targeted bases. All workflows had alignment of reads to SDHA and NF1 pseudogenes. Compared to Sanger sequencing, variant calling revealed a sensitivity ranging from 83 to 100% and a specificity of 99.9-100%. Only MiSEQ reporter identified all pathogenic variants in both sequencing runs. CONCLUSIONS: We conclude that targeted next generation sequencing have equal quality compared to Sanger sequencing. Enrichment specificity and the bioinformatic performance need to be carefully assessed in a diagnostic setting. As acceptable accuracy was noted for a fully automated bioinformatic workflow, we suggest that processing of NGS data could be performed without expert bioinformatics skills utilizing already existing commercially available bioinformatics tools. PMID- 26230856 TI - Risk Factors of Ischemic Stroke and Subsequent Outcome in Patients Receiving Hemodialysis. AB - BACKGROUND AND PURPOSE: End-stage renal disease (ESRD) requiring hemodialysis carries up to a 10-fold greater risk of stroke than normal renal function. Knowledge on risk factors and management strategies derived from the general population may not be applicable to those with ESRD. We studied a large ESRD population to identify risk factors and outcomes for stroke. METHODS: All adult patients receiving hemodialysis for ESRD from January 1, 2007, to December 31, 2012, were extracted from the electronic patient record. Variables associated with stroke were identified by survival analysis; demographic, clinical, imaging, and dialysis-related variables were assessed, and case-fatality was determined. Follow-up was until December 31, 2013. RESULTS: A total of 1382 patients were identified (mean age, 60.5 years; 58.5% men). The prevalence of atrial fibrillation was 21.2%, and 59.4% were incident hemodialysis patients. One hundred and sixty patients (11.6%) experienced a stroke during 3471 patient-years of follow-up (95% ischemic). Stroke incidence was 41.5/1000 patient-years in prevalent and 50.1/1000 patient-years in incident hemodialysis patients. Factors associated with stroke on regression analysis were prior stroke, diabetes mellitus, and age at starting renal replacement therapy. Atrial fibrillation was not significantly associated with stroke, and warfarin did not affect stroke risk in warfarin-treated patients. Fatality was 18.8% at 7 days, 26.9% at 28 days, and 56.3% at 365 days after stroke. CONCLUSIONS: Incidence of stroke is high in patients with ESRD on hemodialysis with high case-fatality. Incident hemodialysis patients had the highest stroke incidence. Many, but not all, important risk factors commonly associated with stroke in the general population were not associated with stroke in patients receiving hemodialysis. PMID- 26230857 TI - Microbleed Status and 3-Month Outcome After Intravenous Thrombolysis in 717 Patients With Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Whether cerebral microbleeds (CMBs) detected on pretreatment magnetic resonance imaging increase the risks of symptomatic intracranial hemorrhage (sICH) and, most importantly, poor outcome in patients treated by intravenous thrombolysis for acute ischemic stroke is still debated. We assessed the effect of CMB presence and burden on 3-month modified Rankin Scale and sICH in a multicentric cohort. METHODS: We analyzed prospectively collected data of consecutive patients solely treated by intravenous thrombolysis for acute ischemic stroke, in 2 centers where magnetic resonance imaging is the first-line pretreatment imaging. Neuroradiologists blinded to clinical data rated CMBs on T2* sequence using a validated scale. Logistic regressions were used to assess relationships between CMBs and 3-month modified Rankin Scale or sICH. RESULTS: Among 717 patients, 150 (20.9%) had >=1 CMBs. CMB burden was associated with worse modified Rankin Scale in univariable shift analysis (odds ratio, 1.07; 95% confidence interval, 1.00-1.15 per 1-CMB increase; P=0.049), but significance was lost after adjustment for age, hypertension, and atrial fibrillation (odds ratio, 1.03; 95% confidence interval, 0.96-1.11 per 1-CMB increase; P=0.37). Results remained nonsignificant when taking into account CMB location or presumed underlying vasculopathy. The incidence of sICH ranged from 3.8% to 9.1%, depending on the definition. Neither CMB presence, burden, location, nor presumed underlying vasculopathy was independently associated with sICH. CONCLUSIONS: Poor outcome or sICH was not associated with CMB presence or burden on pre-intravenous thrombolysis magnetic resonance imaging after adjustment for confounding factors. An individual patient data meta-analysis is needed to determine whether a subgroup of patients with CMBs carries an independent risk of poor outcome that might outweigh the expected benefit of intravenous thrombolysis. PMID- 26230859 TI - Expression of EGFR Is Closely Related to Reduced 3-Year Survival Rate in Chinese Female NSCLC. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for approximately 80% of lung carcinoma cases, which becomes more and more important in the field of lung carcinoma as well as primary lung carcinoma in females. MATERIAL AND METHODS: We analyzed the medical history of 62 female NSCLC patients. Immunohistochemistry was used to observe and compare the expression of EGFR. The chi-square test was conducted to analyze associations between EGFR expression and the different variables. The cumulative survival rate was determined by the Kaplan-Meier product-limit method. The prognosis of female patients with NSCLC was examined by using a multivariate Cox proportional hazard regression model. RESULTS: The expression proportion of EGFR in Chinese female NSCLC patients was 70.97%, and it was remarkably higher in adenocarcinoma than in squamous cell carcinoma and bronchioloalveolar carcinoma. A positive correlation was observed between EGFR expression and tumor-node metastasis staging or lymph node metastasis. The Cox proportional risk model analysis showed a correlation between postoperative survival time of the patients and pathology of the tumor type and lymph node metastasis. CONCLUSIONS: Expression of EGFR was closely related to pathology of the tumor type, tumor-node metastasis staging, and lymph node metastasis, which could be used as a promising indicator of NSCLC in Chinese female patients. PMID- 26230858 TI - Comparative analysis between saliva and buccal swabs as source of DNA: lesson from HLA-B*57:01 testing. AB - AIM: Our work aimed to designate the optimal DNA source for pharmacogenetic assays, such as the screening for HLA-B*57:01 allele. MATERIALS & METHODS: A saliva and four buccal swab samples were taken from 104 patients. All the samples were stored at different time and temperature conditions and then genotyped for the HLA-B*57:01 allele by SSP-PCR and classical/capillary electrophoresis. RESULTS: The genotyping analysis reported different performance rates depending on the storage conditions of the samples. Given our results, the buccal swab demonstrated to be more resistant and stable in time with respect to the saliva. CONCLUSION: Our investigation designates the buccal swab as the optimal DNA source for pharmacogenetic assays in terms of resistance, low infectivity, low invasiveness and easy sampling, and safe transport in centralized medical centers providing specialized pharmacogenetic tests. PMID- 26230860 TI - Childhood Maltreatment Is Associated with Ulcerative Colitis but Not Crohn's Disease: Findings from a Population-based Study. AB - BACKGROUND: Previous research suggests a link between childhood adversities and inflammatory bowel disease (IBD); however, study limitations prevent generalization of findings. To address this, the current study uses a Canadian population-based sample to investigate the relationship between 3 childhood adversities and 2 types of IBD while controlling for a range of factors. METHODS: Secondary data analysis of a subsample of the nationally representative 2012 Canadian Community Health Survey-Mental Health consisted of those with no missing data on any of the variables of interest (n = 21,852). The survey response rate was 68.9%. This study used logistic regression to estimate odds ratios of 3 types of childhood adversities (physical abuse, sexual abuse, and witnessing parental domestic violence) separately for ulcerative colitis and Crohn's disease, each compared with those without IBD. The final model controls for sociodemographics, health behaviors, and mental health. The exposure was assessed by retrospective self-report, and the outcome was by self-report of a health professional diagnosis. RESULTS: In a fully adjusted model, those who are physically (odds ratio = 2.28; confidence interval, 1.39-3.75) or sexually abused (odds ratio = 2.64; confidence interval, 1.61-4.33) during childhood had significantly higher odds of ulcerative colitis than their non-maltreated peers. No relationship is found between witnessing parental domestic violence and ulcerative colitis. None of the early adversities are significantly related to Crohn's disease. CONCLUSIONS: Childhood physical and sexual abuse are related to ulcerative colitis, but not Crohn's disease. Future research that can address epigenetic and neuroendocrine factors should investigate pathways through which early adversities may translate into one type of IBD but not another. PMID- 26230861 TI - The Role of Ultrasound Elasticity Imaging in Predicting Ileal Fibrosis in Crohn's Disease Patients. AB - BACKGOUND: Bowel wall fibrosis is associated with a complicated disease behavior in patients with Crohn's disease (CD). The quantitative assessment of fibrosis severity in CD-affected bowel can help clinical decision making. Our aim was to evaluate the feasibility, reliability, and reproducibility of ultrasound elasticity imaging (UEI) toward the assessment of ileal fibrosis in CD patients. METHODS: Twenty-three consecutive patients with ileal or ileocolonic CD, elected for surgical resection of the terminal ileum, underwent bowel ultrasound and UEI. Twenty inflammatory CD patients without complications were enrolled as controls. Bowel wall stiffness was evaluated with UEI by means of color scale and quantitative strain ratio measurement. The severity of bowel wall fibrosis and inflammation were evaluated on histological sections by semiquantitative and quantitative image analysis and used as a reference standard. RESULTS: The UEI strain ratio measurement was significantly correlated with the severity of bowel fibrosis at both semiquantitative and quantitative histological image analysis: it was characterized by an excellent discriminatory ability for severe bowel fibrosis (area under the receiver operating characteristic curve: 0.917; 95% confidence interval, 0.788-1.000). UEI strain ratio measurements were characterized by an excellent interrater agreement. At multivariate analysis, bowel wall fibrosis proved the only independent determinant of the strain ratio. The ileal strain ratio of inflammatory CD patients was significantly lower than in operated CD patients with severe fibrosis. CONCLUSIONS: UEI can be used to assess ileal fibrosis in CD patients. PMID- 26230862 TI - The TGF-beta/Smad System in IBD Pathogenesis. AB - In Crohn's disease and ulcerative colitis, the tissue-damaging destructive immune response is sustained by defects of counterregulatory mechanisms, which normally attenuate inflammatory pathways and promote repair of mucosal injury. One such mechanism involves transforming growth factor-beta1 (TGF-beta1), a cytokine that is produced by multiple cell types and targets both immune and nonimmune cells. Both in vitro and in vivo studies strongly support the role of TGF-beta1 as a negative regulator of mucosal inflammation and indicate that defective production/activity of this cytokine can lead to the development of or exacerbate colitis. Interestingly, in the inflamed intestine of patients with inflammatory bowel disease, TGF-beta1 expression is upregulated but TGF-beta1-mediated immunosuppression is markedly impaired because of high Smad7, an intracellular inhibitor of TGF-beta1-associated signaling. Consistently, knockdown of Smad7 with a specific antisense oligonucleotide restores TGF-beta1 activity, thus leading to decreased production of inflammatory cytokines in both colitic mice and inflammatory bowel disease patients and attenuates clinical activity in Crohn's disease patients. In this article, we review data supporting the role of Smad7 in the pathogenesis of inflammatory bowel disease and discuss whether inhibition of Smad7 is therapeutically useful in Crohn's disease and how the benefit/risk of such an intervention should be monitored in the patients. PMID- 26230864 TI - Degradation Mechanisms and Reactions in Organic Light-Emitting Devices. PMID- 26230863 TI - Mesenchymal Stem Cell Therapy for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. AB - Recent advances in inflammatory bowel disease (IBD) therapeutics include novel medical, surgical, and endoscopic treatments. Among these, stem cell therapy is still in its infancy, although multiple studies suggest that the immunomodulatory effect of stem cell therapy may reduce inflammation and tissue injury in patients with IBD. This review discusses the novel avenue of stem cell therapy and its potential role in the management of ulcerative colitis and Crohn's disease. We conducted a comprehensive literature search to identify studies examining the role of stem cell therapy (without conditioning and immunomodulatory regimens) in IBD. Taken together, these studies suggest a promising role for stem cell therapy in IBD although the substantial challenges, such as cost and inadequate/incomplete characterization of effect, limit their current use in clinical practice. PMID- 26230865 TI - Recent progress in melasma pathogenesis. AB - Melasma is a common skin pigmentation condition. Given therapeutic difficulty as one of the biggest concerns, understanding of the etiology and pathogenesis of melasma becomes essential. UV irradiation, female sex hormones, and inflammatory processes are addressed as triggering factors with genetic predisposition. The mechanism of UV-induced melanogenesis has been extensively investigated as a model system to study melasma pathogenesis. Hitherto, treatment modalities for melasma are similar to other hyperpigmentation disorders. However, individual triggering factors induce a separate pigmentation disease, whose pathogenic mechanisms and clinical phenotypes are different from the ones encountered in melasma. Fortunately, there have been ongoing updates on melasma pathogenesis with regard to major triggering factors. Presence of certain factors working independently of UV exposure and role of dermal factors and microRNAs are being identified as novel discoveries about melasma pathogenesis. In this review, the melasma pathogenesis is reviewed in association with updated and new findings. PMID- 26230866 TI - Mechanical characterization of porcine ascending aorta. PMID- 26230868 TI - Surface Plasmon Resonance Enhanced Polymer Solar Cells by Thermally Evaporating Au into Buffer Layer. AB - Generally, the surface plasmon resonance (SPR) effect of metal nanoparticles is widely applied on polymer solar cells (PSCs) to improve device performance by doping method into solution. Herein, a diameter-controlled thermally evaporation method was used to realize Au nanoparticles (Au NPs) doping into WO3 anode buffer layer in inverted PSCs. The surface energy differences between Au and WO3 inevitably lead to Au growing up through the process from nucleation, isolated island, aggregation of metal islands to continuous films along with the process of evaporation. The atom force microscopy (AFM) images indicate that critical thickness of Au film formation is 8 nm, which is in accordance with current density-voltage (J-V) and incident photon-to-electron conversion efficiency (IPCE) measurement results of optimal device performance. The power conversion efficiency (PCE) with 8 nm Au is dramatically improved from 4.67 +/- 0.13% to 6.63 +/- 0.17% compared to the one without Au. Moreover, the optical absorption enhancement is demonstrated by steady state photoluminescence (PL), which agrees well with transmission spectrum. The optical and electrical improvement all suggest that thermal evaporation is the appropriate method to further enhance device performance. PMID- 26230867 TI - Pathologic Findings in NEMO Deficiency: A Surgical and Autopsy Survey. AB - Hypomorphic mutations in nuclear factor kappaB (NF-kappaB) essential modulator (NEMO), encoded by IKBKG, lead to a variable combined immunodeficiency, which puts patients at risk of early death from infectious complications. The spectrum of clinical manifestations includes inflammatory disorders, especially colitis. Because of the multiple complications of NEMO deficiency, a variety of biopsy, excisional, and autopsy materials from these patients may be subject to pathologic examination. Therefore, using samples from a cohort of patients with this disorder, we aimed to survey the pathologic spectrum of NEMO deficiency and search for correlations between specific genotypes and phenotypes. Clinical and laboratory data, mutation analysis, and pathology from 13 patients were examined, including 6 autopsies. No specific genotype-pathology correlation was identified. However, we confirmed an association between ectodermal dysplasia and inflammatory conditions. We found no characteristic pathology to identify patients with NEMO deficiency; therefore, history, physical examination, and specific infections must remain the clues to suggest the diagnosis. Variability among patients and by infection makes the pathologic recognition of NEMO deficiency challenging. PMID- 26230869 TI - External-Focus Feedback Benefits Free-Throw Learning in Children. AB - PURPOSE: Considerable research supports the motor-learning advantage associated with an external focus of attention; however, very few studies have attempted to generalize these findings to children especially with attentional focus feedback. Therefore, the purpose of this study was to determine the effect of attentional focus feedback on motor learning in children. METHOD: Boys (n = 14) and girls (n = 14) aged 9 to 11 years old were randomly assigned to 1 of 2 gender-stratified groups: (a) internal-focus feedback or (b) external-focus feedback. Following initial instructions and task demonstration, participants performed 100 modified free throws over 2 days while receiving feedback statements respective to their attentional focus condition. Approximately 24 hr later, participants performed a retention test consisting of 20 additional free throws. Participants were also asked to respond to a retrospective verbal report at the end of each day to serve as a manipulation check. RESULTS: Results of the analysis revealed a statistically significant learning advantage for participants receiving external focus feedback, and retrospective verbal reports provide support for the self invoking trigger and constrained action hypotheses. CONCLUSIONS: Future research should continue to incorporate retrospective verbal reports and explore potential causal links between internal attentional focus and self-evaluation. PMID- 26230871 TI - Preparation of Information-Containing Macromolecules by Ligation of Dyad-Encoded Oligomers. AB - A simplified strategy for preparing non-natural information-containing polymers is reported. The concept relies on the successive ligation of oligomers that contain minimal sequence motifs. It was applied here to the synthesis of digitally-encoded poly(triazole amide)s, in which propyl and 2-methyl propyl motifs are used to code 0 and 1, respectively. A library of four oligo(triazole amide)s containing the information dyads 00, 01, 10, and 11 was prepared. These oligomers contain two reactive functions, that is, an alkyne and a carboxylic acid. Thus, they can be linked to another with the help of a reactive spacer containing azide and amine functions. Using two successive chemoselective steps, that is, azide-alkyne Huisgen cycloaddition and carboxylic acid-amine coupling, monodisperse polymers can be obtained. In particular, the library of dyads permits the implementation of any desired sequence using a small number of steps. As a proof-of-concept, the synthesis of molecular bytes 00000000 and 00000110 is described. PMID- 26230870 TI - Genotypic Characterization of Methicillin-Resistant Staphylococcus aureus Recovered at Baseline from Phase 3 Pneumonia Clinical Trials for Ceftobiprole. AB - Baseline methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients with nosocomial and community-acquired pneumonia collected during Phase 3 trials for ceftobiprole were characterized. Eighty-four unique isolates from patients enrolled in Europe (50.0%), Asia-Western Pacific region (APAC; 20.2%), North America (19.0%), Latin America (8.3%), and South Africa (2.4%) were included. Antimicrobial susceptibility testing was performed by broth microdilution and isolates screened for Panton-Valentine leukocidin. SCCmec and agr types were determined. Strains were subjected to pulsed-field gel electrophoresis and spa typing. Clonal complexes (CCs) were assigned based on spa and/or multilocus sequence typing. Most isolates were CC5-MRSA-I/II/IV (44.0%; 37/84), followed by CC8-MRSA-IV (22.6%; 19/84) and CC239-MRSA-III (21.4%; 18/84). Other MRSA formed seven clonal clusters. Isolates from North America were associated with USA100, while those from South America belonged to the Cordobes/Chilean CC. A greater clonal diversity was observed in Europe; however, each country had CC5, CC8, or CC239 as prevalent lineages. Isolates from APAC were CC5-MRSA-II (47.1%; 8/17) or CC239-MRSA-III (47.1%; 8/17). Isolates carrying SCCmec I and III had ceftobiprole MIC50 values of 2 MUg/ml, while those isolates with SCCmec II and IV had MIC50 values of 1 MUg/ml. Ceftobiprole inhibited 96% and 100.0% of the isolates at <= 2 and <= 4 MUg/ml, respectively. These isolates represented common circulating MRSA clones. Ceftobiprole demonstrated in vitro activity with a slight variation of minimum inhibitory concentrations (MICs) according to SCCmec or clonal type. PMID- 26230872 TI - Estimated time of arrival and debiasing the time saving bias. AB - The time saving bias predicts that the time saved when increasing speed from a high speed is overestimated, and underestimated when increasing speed from a slow speed. In a questionnaire, time saving judgements were investigated when information of estimated time to arrival was provided. In an active driving task, an alternative meter indicating the inverted speed was used to debias judgements. The simulated task was to first drive a distance at a given speed, and then drive the same distance again at the speed the driver judged was required to gain exactly 3 min in travel time compared with the first drive. A control group performed the same task with a speedometer and saved less than the targeted 3 min when increasing speed from a high speed, and more than 3 min when increasing from a low speed. Participants in the alternative meter condition were closer to the target. The two studies corroborate a time saving bias and show that biased intuitive judgements can be debiased by displaying the inverted speed. Practitioner Summary: Previous studies have shown a cognitive bias in judgements of the time saved by increasing speed. This simulator study aims to improve driver judgements by introducing a speedometer indicating the inverted speed in active driving. The results show that the bias can be reduced by presenting the inverted speed and this finding can be used when designing in-car information systems. PMID- 26230874 TI - Synthesis and Characterization of Iron-Nitrogen-Doped Graphene/Core-Shell Catalysts: Efficient Oxidative Dehydrogenation of N-Heterocycles. AB - An important goal for nanocatalysis is the development of flexible and efficient methods for preparing active and stable core-shell catalysts. In this respect, we present the synthesis and characterization of iron oxides surrounded by nitrogen doped-graphene shells immobilized on carbon support (labeled FeOx@NGr-C). Active catalytic materials are obtained in a simple, scalable and two-step method via pyrolysis of iron acetate and phenanthroline and subsequent selective leaching. The optimized FeOx@NGr-C catalyst showed high activity in oxidative dehydrogenations of several N-heterocycles. The utility of this benign methodology is demonstrated by the synthesis of pharmaceutically relevant quinolines. In addition, mechanistic studies prove that the reaction progresses via superoxide radical anions (.O2(-)). PMID- 26230875 TI - Ligand efficiency metrics: why all the fuss? PMID- 26230876 TI - Repurposing of HDAC inhibitors toward anti-hepatitis C virus drug discovery: teaching an old dog new tricks. PMID- 26230877 TI - Pyrazin-2(1H)-ones as a novel class of selective A3 adenosine receptor antagonists. AB - BACKGROUND: A3AR antagonists are promising drug candidates as neuroprotective agents as well as for the treatment of inflammation or glaucoma. The most widely known A3AR antagonists are derived from polyheteroaromatic scaffolds, which usually show poor pharmacokinetic properties. Accordingly, the identification of structurally simple A3AR antagonists by the exploration of novel diversity spaces is a challenging goal. RESULTS: A convergent and efficient Ugi-based multicomponent approach enabled the discovery of pyrazin-2(1H)-ones as a novel class of A3AR antagonists. A combined experimental/computational strategy accelerated the establishment of the most salient features of the structure activity and structure-selectivity relationships in this series. CONCLUSION: The optimization process provided pyrazin-2(1H)-ones with improved affinity and a plausible hypothesis regarding their binding modes was proposed. PMID- 26230873 TI - Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases. AB - While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases. PMID- 26230878 TI - Hologram quantitative structure-activity relationship and comparative molecular interaction field analysis of aminothiazole and thiazolesulfonamide as reversible LSD1 inhibitors. AB - BACKGROUND: LSD-1 is an enzyme that removes methyl groups from lysine residues of histone proteins. LSD-1 inhibition decreases cellular proliferation and therefore represents a therapeutic target for cancer treatment. MAO and LSD-1 are both flavin adenine dinucleotide-dependent MAOs, and the MAO inhibitor, tranylcypromine, is currently undergoing clinical trials for cancer treatment because it acts as an irreversible LSD-1 inhibitor. MATERIALS & METHODS: The present study investigated new reversible LSD-1 inhibitors, in order to develop novel selective anticancer agents. We constructed 2 and 3D quantitative structure activity relationship models by using a series of 54 aminothiazole and thiazolesulfonamide derivatives. RESULTS: The models were validated internally and externally (q(2) , 0.691 and 0.701; r(2) , 0.894 and 0.937; r(2) test , 0.785 and 0.644, for 2 and 3D models, respectively). Fragment contribution maps, as well as steric and electrostatic contour maps were generated in order to obtain chemical information related to LSD-1 inhibition. CONCLUSION: The thiazolesulfonamide group was fundamental to the inhibition of LSD-1 by these compounds and that bulky and aromatic substituents at the thiazole ring were important for their steric and electrostatic interactions with the active site of LSD-1. PMID- 26230879 TI - The promise of zebrafish as a chemical screening tool in cancer therapy. AB - Cancer progression in zebrafish recapitulates many aspects of human cancer and as a result, zebrafish have been gaining popularity for their potential use in basic and translational cancer research. Human cancer can be modeled in zebrafish by induction using chemical mutagens, xenotransplantation or by genetic manipulation. Chemical screens based on zebrafish cancer models offer a rapid, powerful and inexpensive means of evaluating the potential of suppression or prevention on cancer. The identification of small molecules through such screens will serve as ideal entry points for novel chemical therapies for cancer treatment. This article outlines advances that have been made within the growing field of zebrafish cancer models and presents their advantages for chemical drug screening. PMID- 26230880 TI - Carbonic anhydrase IX inhibitors in cancer therapy: an update. AB - Carbonic anhydrases (CAs; EC 4.2.1.1) are well known zinc metalloproteins involved in the catalysis of a very simple but essential physiological reaction: carbon dioxide hydration to bicarbonate and proton. These enzymes are of clinical relevance in cancer therapy as among the 15 isoforms known in humans, two cell surface CA isoforms, namely CA IX (almost exclusively associated with tumors) and CA XII (overexpressed in some tumor types) are involved in tumorigenesis. Targeting the tumor associated isoforms IX is now considered as a pertinent approach for the development of new cancer therapeutics against hypoxic tumors. Different approaches and new family of pharmacological agents were described in the last 5 years for obtaining compounds that specifically target CA IX over the ubiquitous cytosolic off-target isoforms CA I and CA II. The aim of this review is to give a comprehensive update on the reported discoveries in the field of CA IX inhibitors with an emphasis on the new families of compounds which reach in vivo/preclinical studies for their potential in cancer therapy. PMID- 26230881 TI - Inosine 5'-monophosphate dehydrogenase inhibitors as antimicrobial agents: recent progress and future perspectives. AB - Inosine 5'-monophosphate dehydrogenase (IMPDH), a crucial enzyme required for de novo synthesis of guanine nucleotides, is an important target for cancer, bacterial, parasitic and viral infections and autoimmune disorders. Several classes of IMPDH inhibitors are known in the literature. The current review succinctly summarizes the progress made in the design and development of IMPDH inhibitors as antimicrobial agents in last five years or so. The focus is on the inhibitor and enzyme structural features responsible for imparting selectivity for the microbial over the host enzyme. Future perspectives clearly outline the inhibitor design opportunities available in this area to address the present challenges of drug resistance and re-emergence of newer and deadly strains of microbes, posing a serious threat to public. PMID- 26230882 TI - Type 2 17-beta hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis. AB - Low estradiol level in postmenopausal women is implicated in osteoporosis, which occurs because of the high bone resorption rate. Estrogen formation is controlled by 17-beta hydroxysteroid dehydrogenase 17-beta HSD enzymes, where 17-beta HSD type 1 contributes in the formation of estradiol, while type 2 catalyzes its catabolism. Inhibiting 17-beta HSD2 can help in increasing estradiol concentration. Several promising 17-beta HSD2 inhibitors that can act at low nanomolar range have been identified. However, there are some specific challenges associated with the application of these compounds. Our review provides an up-to date summary of the current status and recent progress in the production of 17 beta HSD2 inhibitors as well as the future challenges in their clinical application. PMID- 26230883 TI - Biological characteristics and agonists of GPR120 (FFAR4) receptor: the present status of research. AB - GPR120 receptor functions as a receptor for omega-3 fatty acid, involving regulating the secretion of gastrointestinal peptide hormone, adipogenesis, adipogenic differentiation and anti-inflammatory process and the like in the aspect of biological functions. In view that the dysfunction of GPR120 receptor is closely correlated with metabolic disorders, GPR120 may act as a novel potential therapeutic target for the treatment of obesity, insulin resistance, Type 2 diabetes and so on. Therefore, mounting scientists devote themselves to probing the molecular mechanism of the biological function of GPR120 receptor and their ligands for the treatment of impaired metabolic health. Herein, we summarize the mechanisms of signal transduction through GPR120 receptor, and discovery and development of GPR120 agonists thereof. PMID- 26230884 TI - Regional systems-of-care for primary percutaneous coronary intervention in ST elevation myocardial infarction. AB - ST-elevation myocardial infarction (STEMI) is a critical, time-dependent condition requiring immediate reperfusion of the coronary arteries to minimize mortality and morbidity. The preferred method of revascularization is a primary percutaneous coronary intervention (PCI) if this can be performed in a timely manner. This requires an effective and well-organized setup from symptom onset to revascularization. Such regional networks for the diagnosis and treatment of STEMI patients have been proven to be very effective in achieving the treatment goals stipulated by the international guidelines. Several trials have provided evidence that prehospital ECG recording and early diagnosis combined with direct referral to a primary PCI center reduces treatment delay considerably. In hospital awareness with early notification of the PCI operator and technicians and admission directly to the catheterization laboratory also reduces time to treatment. There is solid evidence that the reduction in treatment delay achieved by dedicated STEMI networks is associated with a lower mortality and morbidity. Regional STEMI networks are now implemented in many countries with highly varying geographical challenges and healthcare systems, allowing patients everywhere to receive optimal treatment with primary PCI. PMID- 26230885 TI - Optical coherence tomography assessment of efficacy of thrombus aspiration in patients undergoing a primary percutaneous coronary intervention for acute ST elevation myocardial infarction. AB - OBJECTIVE: We used optical coherence tomography (OCT) to assess the impact of thrombus aspiration before angioplasty on poststenting tissue protrusions in patients undergoing a primary percutaneous coronary intervention (PCI) for ST segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: A total of 188 patients with STEMI who underwent thrombus-aspiration PCI (n=113) or standard PCI (n=75) were examined in this study. OCT was performed immediately after primary PCI to assess lesion morphology in the stented segment. The minimum stent area was similar between the thrombus-aspiration PCI group and the standard PCI group [7.4 interquartile range (IQR): 5.8-9.4 vs. 7.4 IQR: 5.8-8.9 mm2, P=0.788]. The maximum tissue protrusion area [0.6 (IQR: 0.3-1.1) vs. 1.2 (IQR: 0.8-1.9) mm2, P<0.001], the mean tissue protrusion area [0.1 (IQR: 0.1-0.2) vs. 0.5 (IQR: 0.3-0.8) mm2, P<0.001], and tissue protrusion volume [2.3 (IQR: 1.3-4.3) vs. 8.3 (IQR: 5.4-14.6) mm2, P<0.001] were significantly smaller in the thrombus aspiration PCI group compared with the standard PCI group. Minimum lumen area was significantly greater in the thrombus-aspiration PCI group compared with the standard PCI group [6.9 (IQR: 5.4-8.8) vs. 6.3 (IQR: 4.6-7.8) mm2, P=0.033]. CONCLUSION: Thrombus aspiration before angioplasty in patients with STEMI was associated with significantly smaller tissue protrusion and larger lumen poststenting compared with standard PCI. Thrombus aspiration in primary PCI favorably influenced lesion morphologies in the stented segment. PMID- 26230886 TI - [When will it again really be summer...]. PMID- 26230888 TI - ["Dual Guidance"?- Parallel combination of ultrasound-guidance and nerve stimulation - Pro]. AB - Combination of ultrasound and nerve stimulation technique could be useful under several conditions. Nerve stimulation canvarify the position of the nerve in case of bad preconditions during ultrasound. The knowledge of the importance of low and critical threshold currents could help to identify the needle tip. Thus the combination of ultrasound and nerve stimulation could lead to reduced unintentional intraneural injections and may result in a higher safety standard in peripheral regional anesthesia. PMID- 26230889 TI - ["Dual Guidance"? - parallel combination of ultrasound-guidance and nerve stimulation - Contra]. AB - Sonography is a highly user-dependent technology. It presupposes a considerable degree of sonoanatomic and sonographic knowledge and requires good practical skills of the examiner. Sonography allows the identification of the puncture target, observes the needle feed and assesses the spread pattern of the local anesthetic in real time. Peripheral electrical nerve stimulation (PNS) cannot offer these advantages to the same degree, but may allow nerve localization under difficult sonographic conditions. The combination of the two locating techniques is complex in its practical implementation. Partially, the use of one location technique is made even more difficult by the combination with the second. PNS in parallel to sonography serves primarily as a warning technology in the case of an invisible cannula tip. It should not be construed as a compensation technique for the lack of sonographic skills or knowledge. However, PNS may be helpful in the sense of a bridging technology as long as the user is aware of its limitations. PMID- 26230890 TI - [Drowning - An update on prehospital and intrahospital treatment strategies]. AB - 500000 people die from unintentional drowning each year worldwide. Drowning accidents occur to humans of every age, while fatal drowning is the leading cause of death among boys 5 to 14 years of age. In Germany, however, most drowning victims are elderly people. Considering the multitude of accident settings, ranging from bathing accidents in lakes to shipwrecks at sea, professional first responders need to adapt to various scenarios. This article summarizes the pathophysiology of drowning, particular features of prehospital life support and current knowledge on the further therapy of victims of near fatal drowning accidents. PMID- 26230892 TI - [Epidural anesthesia -- epidural analgesia remains the gold standard]. PMID- 26230891 TI - [Quiz intensively -- make the diagnosis!]. PMID- 26230893 TI - [History and Technique of Epidural Anaesthesia]. AB - In 1901, the first Epidural anesthesia via a caudal approach was independently described by two FrenchmanJean-Anthanase Sicard and Fernand Cathelin.. The Spanish military surgeon, Fidel Pages Mirave, completed the lumbar approach successfully in 1921. The two possibilities for identification of the epidural space the "loss of resistance" technique and the technique of the "hanging drop" were developed by Achille Mario Dogliotti, an Italian, and Alberto Gutierrez, an Argentinean physician, at the same time. In 1956 John J. Bonica published the paramedian approach to the epidural space. As early as 1931 Eugene Aburel, a Romanian obstetrician, injected local anaesthetics via a silk catheter to perform lumbar obstetric Epidural analgesia. In 1949 the first successful continuous lumbar Epidural anaesthesia was reported by Manuel Martinez Curbelo, a Cuban. Epidural anaesthesia can be performed in sitting or lateral position in all segments of the spinal column via the median or paramedian approach. Different off-axis angles pose the challenge in learning the technique. PMID- 26230894 TI - [Epidural analgesia in combination with general anesthesia]. AB - Epidural anaesthesia is a widely used and accepted technique for perioperative analgesia in different kinds of surgery. Apart from analgetic effect and due to wide positve effects on patients outcome epidural analgesia is often used with general anaesthesia. It represents a reliable and reversible neural deafferentation technique that effectively contributes to a reduction of the surgical stress response with subsequent positive effects on cardiopulmonary, gastrointestinal, and immune function. Animal studies suggest that the use of epidural anaesthesia may be beneficial for cancer surgery because of less tumour recurrence. Further, a benefit is expected in patient's mortality. This article summarizes and critically discusses the current knowledge on the effects of epidural anaesthesia on pain management, cardiopulmonary as well as gastrointestinal functions and patient's outcome. PMID- 26230895 TI - [EnglischerTitel: Epidural anesthesia - complications and side effects]. AB - Thoracic epidural anesthesia remains the gold standard of intra- and postoperative analgesia for a multitude of surgical procedures as a reliable and relatively safe procedure with a low rate of complications as long as contraindications are respected. However, if complications do occur they often result in catastrophic sequelae for the patient. Apart from the well-known side effects and complications there are innumerous reports about procedural complications during placement and use of the catheter. Procedural complications often result in additionally required procedures and treatments, hence increasing morbidity of the affected patient. The aim of this review is to provide the reader with a current overview of the available literature with regards to classical and procedural complications. PMID- 26230896 TI - [The pregnant employee in anaesthesia and intensive care - An evidence-based approach to designing adequate workplaces]. AB - In the light of a rising percentage of women among employees in anaesthesia and intensive care designing adequate workplaces for pregnant employees plays an increasingly important role. Here it is necessary to align the varied interests of the pregnant employee, fellow employees and the employer, where the legal requirements of the Maternity Protection Act ("Mutterschutzgesetz") form the statutory framework. This review describes how adequate workplaces for pregnant employees in anaesthesia and intensive care can be established considering the scientific evidence on the subject. PMID- 26230900 TI - Breast Milk Protects Against Gastrointestinal Symptoms in Infants at High Risk for Autism During Early Development. AB - OBJECTIVES: Parents of children with autism spectrum disorders (ASDs) often report gastrointestinal (GI) dysfunction in their children. The objectives of the present study were to determine whether infants at high risk for developing ASD (ie, siblings of children diagnosed as having ASD) show greater prevalence of GI problems and whether this prevalence is associated with diet and age at weaning from breast milk. METHODS: Using questionnaires, diet history and GI problems were tracked prospectively and retrospectively in 57 high-risk infants and for comparison in 114 low-risk infants (infants from families without ASD history). RESULTS: In low-risk infants, prevalence of GI symptoms, in aggregate, did not vary with diet or age of weaning. By contrast, high-risk infants with GI symptoms were weaned earlier than those without symptoms (P < 0.04), and high-risk infants showed greater prevalence of GI symptoms, in aggregate, on a no breast milk diet than on an exclusive breast milk diet (P < 0.017). Constipation, in particular, was more prevalent in high-risk infants compared with low-risk infants (P = 0.01), especially on a no breast milk diet (P = 0.002). High-risk infants who completed weaning earlier than 6 months showed greater prevalence of constipation (P = 0.001) and abdominal distress (P = 0.004) than those fully weaned after 6 months. CONCLUSIONS: The greater prevalence of GI symptoms in high-risk infants suggests that GI dysfunction during early infant development may be a part of the ASD endophenotype. Late weaning and exclusive breast milk were associated with protection against GI symptoms in high-risk infants. PMID- 26230902 TI - Early Gut Colonization With Lactobacilli and Staphylococcus in Infants: The Hygiene Hypothesis Extended. AB - OBJECTIVES: The aim of the present study was to assess the mode of delivery and type-of-feeding impact on gut microbiota. We demonstrated higher fecal bifidobacteria in infants who were breast-fed (BF) or fed formula with prebiotics polydextrose (PDX) and galactooligosaccharides (GOS) versus formula without prebiotics. Here, we tested feces of that cohort for lactobacilli and Staphylococcus aureus, 2 types of bacteria present in breast milk. METHODS: In a double-blind, randomized study, 21- to 30-day-old term infants vaginally delivered and exclusively formula-fed received a cow's milk-based formula (control, n = 80) or the same formula with 4 g/L (1:1 ratio) of PDX/GOS (PDX/GOS, n = 77). A reference BF group (n = 71) was included. Stool samples were obtained at baseline and after 30 and 60 days of feeding to assess fecal bacteria by quantitative real-time polymerase chain reaction. RESULTS: Pairwise comparisons between baseline-adjusted means log10 colony-forming unit per gram feces of total lactobacilli counts (8.37 in control, 8.46 in PDX/GOS, and 8.42 in BF) showed a significant difference only between PDX/GOS and control at 30 and 60 days combined (P = 0.035), utilizing generalized estimating equations method. Baseline adjusted odds ratio (OR) of colonization with S aureus was lower in control (OR 0.47, 95% confidence interval 0.22-1.00, P = 0.049) and PDX/GOS (OR 0.44, 95% confidence interval 0.21-0.94, P = 0.03) groups versus the BF group. CONCLUSIONS: Bacteria found in breast milk, such as lactobacilli and S aureus can also be found in infant feces. S aureus, traditionally considered harmful, may aid in educating the coevolving immune system. Modifying formula by adding prebiotics may bring gut microbiota closer to that of BF infants in terms of beneficial microbes. PMID- 26230901 TI - Longitudinal Survey of Microbiota in Hospitalized Preterm Very-Low-Birth-Weight Infants. AB - OBJECTIVES: The aim of the present study was to examine the changes in bacteria in hospitalized preterm infants during the first month of life. METHODS: Rectal swabs were collected daily from 12 preterm infants. DNA was extracted from swabs from day of birth and weekly thereafter. Bacterial taxa were identified with next generation sequencing using universal bacterial primers targeted at the 16S ribosomal DNA on a 454 Roche titanium platform. Sequences were clustered into operational taxonomic units, and taxonomy was assigned against the Greengenes databank using Quantitative Insights Into Microbial Ecology version 1.4. Quantitative polymerase chain reaction was used to determine the abundance of Bifidobacterium spp. Functional assessment of the microbiome was performed with Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). RESULTS: Average birth weight and gestational age were 1055 g and 28 weeks, respectively. There were 6 to 35 different bacterial families identified in the day-of-birth samples, unrelated to the mode of delivery. Richness decreased through hospitalization (week 1, 16.9 +/- 7.7 vs weeks 3-5, 10.7 +/- 3.4, P < 0.001). The Shannon diversity index demonstrated the lowest diversity at birth, an increase at week 2, followed by a rapid decline at weeks 3 to 5, suggesting the development of a more uniform microbiota composition after 2 weeks of stay at a neonatal intensive care unit. Enterobacteriaceae, Staphylococcaceae, and Enterococcaceae constituted the majority of the bacterial families. Bifidobacterium spp were infrequently detected at extremely low levels. PICRUSt analysis revealed the enhancement of peroxisome, PPAR, and adipocytokine signaling; plant-pathogen interaction; and aminobenzoate degradation pathways in week 1 samples. CONCLUSIONS: Our results suggest that although preterm infants have individualized microbiota that are detectable at birth, the differences decrease during the neonatal intensive care unit hospitalization with increasing prominence of pathogenic microbiota. PMID- 26230903 TI - Zinc Therapy for Wilson Disease in Children in French Pediatric Centers. AB - BACKGROUND AND AIMS: Zinc therapy is considered a good option in Wilson disease (WD), as a first-line treatment in presymptomatic children and a maintenance therapy after the initial chelator therapy. The aim of the study was to determine the practical use of zinc treatment in French pediatric centers. METHODS: A national survey was conducted in the 6 French centers using zinc acetate to treat WD. Clinical and biological parameters, dosage, and outcome were recorded. RESULTS: A total of 26 children were reported to be treated with zinc acetate, alone or in association with chelators. Of the 9 children (35%) who received zinc alone as a first-line therapy, 2 were switched to D-penicillamine because of inefficacy and 7 remained on zinc alone, but serum transaminase levels normalized in only 4 of them. Five children (19%) were initially treated with zinc in association with D-penicillamine (n = 4) or Trientine (n = 1) with good efficacy. Among the 12 children (46%) who received zinc as a maintenance therapy after D penicillamine, no relapse of hepatic cytolysis occurred during a median follow-up of 5.2 years, but 2 of them were switched to Trientine because of zinc-related adverse effects. Epigastric pain was observed in 4 children, and a gastric perforation occurred in 1 child. CONCLUSIONS: The present study demonstrates poor efficacy of zinc as first-line therapy to control liver disease in half presymptomatic children and a high incidence of related gastrointestinal adverse effects in children with WD. PMID- 26230905 TI - Adherence to Oral Maintenance Treatment in Adolescents With Inflammatory Bowel Disease. AB - OBJECTIVES: The aim of this study was to systematically review the rates of nonadherence to oral maintenance treatment in adolescents with inflammatory bowel disease (IBD), and to describe perceived barriers to adherence and psychosocial factors involved. METHODS: The article considered studies published in MEDLINE, Embase, and PsycINFO up to March 2015. Studies that had collected data on adherence to thiopurines or aminosalicylates in a cohort of adolescents with IBD. Case reports and case series were excluded. RESULTS: A total of 25 studies were included. Lack of uniformity of outcome measures made pooling of data impossible. Rates of medication nonadherence ranged from 2% to 93%. The most frequently reported barriers were "just forgot," "wasn't home," and "interferes with activity." Family dysfunction, peer victimization, poor health-related quality of life, poor child-coping strategies, anxiety, and depressive symptoms were associated with medication nonadherence. CONCLUSIONS: Nonadherence to oral maintenance therapy in adolescents with IBD is a significant health care problem and can lead to unnecessary escalation in therapy. Difficulties in family and social interactions, and psychosocial dysfunction can jeopardize IBD treatment outcome and should receive attention early in the course of the disease. PMID- 26230904 TI - Acid Rather Than Nonacid Reflux Burden Is a Predictor of Tooth Erosion. AB - OBJECTIVES: The relation between tooth erosion (TE) and gastroesophageal reflux in children has not been clearly established, and there are no studies to determine the relation with refluxate height, nonacid reflux, and erosions. The aim of this study was to determine the relation between TE and acid and nonacid gastroesophageal refluxes measured using combined pH and multichannel intraluminal impedance (pH-MII). METHODS: We conducted a prospective cohort study of children presenting for pH-MII testing. Once informed consent was obtained, patients completed questionnaires about their reflux symptoms and diet, and then underwent pH-MII catheter placement and a dental examination. The Keels-Coffield erosion index was used to score the extent and severity of TE. Reflux parameters of patients with and without TE were compared using Student t test and correlations were performed using Spearman correlations. RESULTS: A total of 27 patients participated in the study, all of whom were on acid suppression at the time of pH-MII testing. Of the 27 patients, 10 (37%) had TE. There were significant positive correlations between acid reflux episodes (r = 0.44, P = 0.02), the percentage of time that acid reflux was present in the distal esophagus (r = 0.44, P = 0.02), and reflux index (r = 0.54, P = 0.004) with the number of TE in a given patient. The percentage of time that acid reflux was present in the proximal esophagus was positively correlated with the number of teeth erosions per patient with borderline significance (r = 0.38, P = 0.05). CONCLUSIONS: There was a positive correlation between acid reflux parameters and TE. Acid, rather than nonacid reflux, seems to have a significant role in the pathogenesis of TE. PMID- 26230906 TI - The native form of alpha-Synuclein: Monomer, tetramer, or a combination in equilibrium. PMID- 26230907 TI - Implementing the Select Agent Legislation: Perfect Record or Wrong Metric? PMID- 26230908 TI - Myocardial Late Gadolinium Enhancement: Accuracy of T1 Mapping-based Synthetic Inversion-Recovery Imaging. AB - PURPOSE: To compare the accuracy of detection and quantification of myocardial late gadolinium enhancement (LGE) with a synthetic inversion-recovery (IR) approach with that of conventional IR techniques. MATERIALS AND METHODS: This prospective study was approved by the institutional review board and compliant with HIPAA. All patients gave written informed consent. Between June and November 2014, 43 patients (25 men; mean age, 54 years +/- 16) suspected of having previous myocardial infarction underwent magnetic resonance (MR) imaging, including contrast material-enhanced LGE imaging and T1 mapping. Synthetic magnitude and phase-sensitive IR images were generated on the basis of T1 maps. Images were assessed by two readers. Differences in the per-patient and per segment LGE detection rates between the synthetic and conventional techniques were analyzed with the McNemar test, and the accuracy of LGE quantification was calculated with the paired t test and Bland-Altman statistics. Interreader agreement for the detection and quantification of LGE was analyzed with kappa and Bland-Altman statistics, respectively. RESULTS: Seventeen of the 43 patients (39%) had LGE patterns consistent with myocardial infarction. The sensitivity and specificity of synthetic magnitude and phase-sensitive IR techniques in the detection of LGE were 90% and 95%, respectively, with patient-based analysis and 94% and 99%, respectively, with segment-based analysis. The area of LGE measured with synthetic IR techniques showed excellent agreement with that of conventional techniques (4.35 cm(2) +/- 1.88 and 4.14 cm(2)+/- 1.62 for synthetic magnitude and phase-sensitive IR, respectively, compared with 4.25 cm(2) +/- 1.92 and 4.22 cm(2) +/- 1.86 for conventional magnitude and phase-sensitive IR, respectively; P > .05). Interreader agreement was excellent for the detection (kappa > 0.81) and quantification (bias range, -0.34 to 0.40; P > .05) of LGE. CONCLUSION: The accuracy of the T1 map-based synthetic IR approach in the detection and quantification of myocardial LGE in patients with previous myocardial infarction was similar to that of conventional IR techniques. The use of T1 mapping to derive synthetic LGE images may reduce imaging times and operator dependence in future T1 mapping protocols with full left ventricular coverage. PMID- 26230909 TI - Effect of a Quality Improvement Project to Use Exclusive Mother's Own Milk on Rate of Necrotizing Enterocolitis in Preterm Infants. AB - OBJECTIVE: Mother's own milk (MOM) remains the key strategy to prevent necrotizing enterocolitis (NEC) in preterm infants. We developed and implemented quality improvement (QI) initiatives to improve rate of using MOM in preterm infants of <32 weeks of gestation. The objective was to evaluate the impact of this QI project on NEC incidence in this population. STUDY DESIGN: In November 2009, we established a QI multidisciplinary team that reviewed literature and practices of other institutions to promote exclusive use of MOM in preterm infants of <32 weeks of gestation. The team developed practice changes that were implemented in February 2010. We tracked use of MOM and occurrence of NEC stage >= 2 from January 2009 until March 2012 when donor human milk was introduced. The subjects were divided into three groups: baseline (year 2009; n = 189), intervention phase (year 2010; n = 202), and sustain phase (January 2011-March 2012; n = 254). Clinical outcomes of the baseline and sustain phases were compared. RESULTS: Exclusive use of MOM improved significantly from 60.8% to 73.6% at time of first feed (p = 0.004) without any delay in feed introduction (median [interquartile range], 40 [26, 75.5] hours versus 43.5 [24, 69] hours; p = 0.96). There was a nonsignificant increase in exclusive use of MOM at time of full feed (from 79.5% to 85.2%; p = 0.11); however; use of any MOM increased significantly from 80.4% to 91.3% (p < 0.001) at discharge. Time to reach full feed and length of stay remained similar between the baseline and sustain periods. On regression analysis, risk of NEC decreased significantly in the sustain period (odds ratio = 0.32; 95% confidence interval, 0.11-0.93). CONCLUSIONS: QI initiatives were effective in increasing use of exclusive MOM at time of first feed and of any MOM at time of discharge and in reducing NEC incidence in our neonatal intensive care unit. PMID- 26230910 TI - Shock Tube Measurement of the High-Temperature Rate Constant for OH + CH3 -> Products. AB - The reaction between hydroxyl (OH) and methyl radicals (CH3) is critical to hydrocarbon oxidation. Motivated by the sparseness of its high-temperature rate constant data and the large uncertainties in the existing literature values, the current study has remeasured the overall rate constant of the OH + CH3 reaction and extended the measurement temperature range to 1214-1933 K, using simultaneous laser absorption diagnostics for OH and CH3 radicals behind incident and reflected shock waves. tert-Butyl hydroperoxide and azomethane were used as pyrolytic sources for the OH and CH3 radicals, respectively. The current study bridged the temperature ranges of existing experimental data, and good agreement is seen between the current measurement and some previous experimental and theoretical high-temperature studies. A recommendation for the rate constant expression of the title reaction, based on the weighted average of the high temperature data from selected studies, is given by k1 = 4.19 * 10(1)(T/K)(3.15) exp(5270 K/T) cm(3) mol(-1) s(-1) +/-30%, which is valid over 1000-2500 K. PMID- 26230911 TI - Programmed cell delivery from biodegradable microcapsules for tissue repair. AB - Injectable and resorbable hydrogels are an extremely attractive class of biomaterials. They make it possible to fill tissue defects accurately with an undoubtedly minimally invasive approach and to locally deliver cells that support repair or regeneration processes. However, their use as a cell carrier is often hindered by inadequate diffusion in bulk. A possible strategy for overcoming this transport limitation might be represented by injection of rapidly degradable cell loaded microcapsules, so that maximum material thickness is limited by sphere radius. Here, the possibility of achieving programmable release of viable cells from alginate-based microcapsules was explored in vitro, by evaluating variations in material stability resulting from changes in hydrogel composition and assessing cell viability after encapsulation and in vitro release from microcapsules. Degradation of pure alginate microspheres was varied from a few days to several weeks by varying sodium alginate and calcium chloride concentrations. The addition of poloxamer was also found to accelerate degradation significantly, with capsule breakdown almost complete by two weeks, while chitosan was confirmed to strengthen alginate cross-linking. The presence of viable cells inside microspheres was revealed after encapsulation, and released cells were observed for all the formulations tested after a time interval dependent on bead degradation speed. These findings suggest that it may be possible to fine tune capsule breakdown by means of simple changes in material formulation and regulate, and eventually optimize, cell release for tissue repair. PMID- 26230912 TI - Lattice-Modulated Phase Transition Coupled with Redox-Isomeric Interconversion of o-Semiquinone-Catecholato into Bis(o-semiquinonato) Cobalt Complexes. AB - Two redox-isomeric (valence tautomeric) complexes (2,2'-bpy)Co(3,6-DBSQ)2 (1) and (1,10-phen)Co(3,6-DBSQ)2 (2) (where 2,2'-bpy = 2,2'-dipyridine; 1,10-phen = 1,10 phenanthroline; 3,6-DBSQ = 3,6-di-tert-butyl-benzosemiquinone-1,2) reveal phase transitions that accompany redox-isomeric interconversions of semiquinone catecholato isomer into a bis-(semiquinonato) one. Phase transitions differ one from another by thermodynamic parameters (transition temperature and interval, enthalpy, and entropy). Complexes 1 and 2 have the same crystal system and space group, and they form solid solutions with any molar ratio. The number of solid solutions with the molar ratios of 2:1, 1:1, 1:2, 1:4, 1:8, and 1:16 of 1 per 2, respectively, were obtained. Product with 1:1 ratio was studied by precise calorimetry, by variable-temperature magnetic susceptibility, and by X-ray structural analysis. All solid solutions were investigated by means of differential scanning calorimetry. Each solid solution possesses phase transition whose parameters depend on its composition. Transition temperature and enthalpy gradually grow with increasing of molar fraction of 1. The diagram "enthalpy composition" is linear, whereas phase diagram "transition temperature composition" is the bent-up arc. PMID- 26230913 TI - Biomimetic Total Synthesis of (-)-Penibruguieramine A Using Memory of Chirality and Dynamic Kinetic Resolution. AB - The fully stereocontrolled total synthesis of (-)-penibruguieramine A, a naturally occurring marine pyrrolizidine alkaloid, is described in this study for the first time. The key synthetic sequence is the biomimetic aldol reaction of the proline pentaketide amide. The principles of "memory of chirality" (MOC) and "dynamic kinetic resolution" (DKR) are applied to this reaction for the asymmetric synthesis using proline as the only chiral source. A mechanistic rationale is discussed for the excellent stereochemical outcome in a protic solvent environment. PMID- 26230916 TI - Limited transfer of long-term motion perceptual learning with double training. AB - A significant recent development in visual perceptual learning research is the double training technique. With this technique, Xiao, Zhang, Wang, Klein, Levi, and Yu (2008) have found complete transfer in tasks that had previously been shown to be stimulus specific. The significance of this finding is that this technique has since been successful in all tasks tested, including motion direction discrimination. Here, we investigated whether or not this technique could generalize to longer-term learning, using the method of constant stimuli. Our task was learning to discriminate motion directions of random dots. The second leg of training was contrast discrimination along a new average direction of the same moving dots. We found that, although exposure of moving dots along a new direction facilitated motion direction discrimination, this partial transfer was far from complete. We conclude that, although perceptual learning is transferrable under certain conditions, stimulus specificity also remains an inherent characteristic of motion perceptual learning. PMID- 26230914 TI - Molecular cloning, epigenetic regulation, and functional characterization of Prkd1 gene promoter in dopaminergic cell culture models of Parkinson's disease. AB - We recently identified a compensatory survival role for protein kinase D1 (PKD1) in protecting dopaminergic neurons from oxidative insult. To investigate the molecular mechanism of Prkd1 gene expression, we cloned the 5'-flanking region (1620-bp) of the mouse Prkd1 gene. Deletion analyses revealed that the -250/+113 promoter region contains full promoter activity in MN9D dopaminergic neuronal cells. In silico analysis of the Prkd1 promoter uncovered binding sites for key redox transcription factors including Sp1 and NF-kappaB. Over-expression of Sp1, Sp3, and NF-kappaB-p65 proteins stimulated Prkd1 promoter activity. Binding of Sp3 and NF-kappaB-p65 to the Prkd1 promoter was confirmed using chromatin immunoprecipitation. Treatment with the Sp inhibitor mithramycin A significantly attenuated Prkd1 promoter activity and PKD1 mRNA and protein expression. Further mechanistic studies revealed that inhibition of histone deacetylation and DNA methylation up-regulated PKD1 mRNA expression. Importantly, negative modulation of PKD1 signaling by pharmacological inhibition or shRNA knockdown increased dopaminergic neuronal sensitivity to oxidative damage in a human mesencephalic neuronal cell model. Collectively, our findings demonstrate that Sp1, Sp3, and NF kappaB-p65 can transactivate the mouse Prkd1 promoter and that epigenetic mechanisms, such as DNA methylation and histone modification, are key regulatory events controlling the expression of pro-survival kinase PKD1 in dopaminergic neuronal cells. Previously, we demonstrated that protein kinase D1 (PKD1) plays a survival role during the early stage of oxidative stress in dopaminergic neuronal cells. PMID- 26230915 TI - Zinc finger X-chromosomal protein (ZFX) is a significant prognostic indicator and promotes cellular malignant potential in gallbladder cancer. AB - The Zinc finger X-chromosomal protein (ZFX), a novel member of the Krueppel C2H2 type zinc finger protein family, has been implicated in multiple human cancers. However, the clinical significance of ZFX expression in gallbladder cancer (GBC) remains largely unknown. In this study, we focused on the clinical significance, biological function and mechanism of ZFX in GBC, and found that ZFX protein overexpression was frequently detected in GBC tissues. The expression of ZFX was significantly correlated with histological grade, perineural invasion, and margin status and lead to a significantly poorer prognosis in GBC patients(P <0.001). Furthermore, knockdown of ZFX result in significant inhibition of proliferation, migration, invasion and cause cell cycle arrest in GBC-SD cells, while over expression of ZFX in NOZ shows the opposite results. Activation of PI3K/AKT pathway maybe the potential mechanism behind these effects. In conclusion, ZFX may serve as a oncogene and could be used as a potential prognostic marker and genetic treatment target for GBC patients. PMID- 26230917 TI - Behavioral training to improve collision detection. AB - Young drivers are a high-risk group for vehicle crashes due to inexperience in detecting an impending collision and are one group that may benefit from perceptual learning (PL) training. The present study assessed whether PL could be used to improve performance in collision detection. Ten college-aged subjects participated in the first experiment, which consisted of seven 1-hr sessions conducted on separate days. Thresholds at three observer/object speeds were measured prior to training using a two-alternative forced choice procedure during which they indicated whether an approaching object would result in a collision or noncollision event. Participants were then trained near threshold at one of these speeds for 5 days. After training, participants showed a significant reduction in the time needed to detect a collision at the trained speed. This improvement was also found to transfer to the higher observer speed condition. A second experiment was conducted to determine whether this improvement was due to training near threshold or whether this improvement was merely due to practice with the task. Training with stimuli well above threshold showed no significant improvement in performance, indicating that the improvement seen in the first experiment was not solely due to task practice. PMID- 26230918 TI - Specificity of motion discrimination learning even with double training and staircase. AB - Visual perceptual learning has been traditionally characterized by its specificity. Namely, learning transfers little to many untrained stimulus attributes. This result of specificity is the basis for the inference that perceptual learning takes place in low-level visual areas in the brain. Recently, however, Xiao and colleagues (2008) demonstrated a double training technique that enabled complete transfer of learning in all tasks that were tested. This technique has since been applied to motion direction discrimination learning. Learning along one average direction has been found to transfer completely to a new average direction, along which only dot number discrimination had been trained (J. Y. Zhang & Yang, 2014). In the current study, we first repeated the J. Y. Zhang and Yang (2014) experiment in exact procedure, stimuli, and task. We then continued the double training to examine transfer in longer-term perceptual learning. To our surprise, in both our exact replication attempt and in our longer-term learning study, we could not find complete transfer. In fact, the transfer to the dot number discrimination direction was no greater than to an untrained control direction. We suggest that individual differences and subtle differences in experimental setup between J. Y. Zhang and Yang (2014) and our studies are too strong and common to determine whether or not the new double training technique can bring about complete transfer in motion discrimination learning. PMID- 26230919 TI - Incidence, severity, and impact of hyperhidrosis in people with lower-limb amputation. AB - To assess the incidence and severity of self-reported hyperhidrosis in patients with amputation and understand its effects on prosthetic fit or function, a cross sectional survey of patients at two amputee clinics was performed. Responses from 121 subjects with lower-limb amputation were analyzed. Of these subjects, 66% reported sweating to a degree that it interfered with daily activities, as measured by the Hyperhidrosis Disease Severity Scale. There was a significant association between sweating and interference with prosthetic fit and function. Sweating was more severe in cases of transtibial amputations, patients under the age of 60, warm weather, and vigorous activity. There was no relationship between severity of sweating and time since amputation, etiology of amputation, duration of daily prosthetic use, or reported ability to perform functional tasks. Subjects reported trying multiple interventions, but the self-reported effectiveness of these treatments was low. Hyperhidrosis, a common problem associated with prosthetic usage, varies in severity and often interferes with daily activities. Sweating severity is associated with poor prosthetic fit and function. Risk factors include younger age and transtibial amputation status. Treatment strategies generally lack efficacy. The results of this study may provide guidance for future interventions and treatment options. PMID- 26230920 TI - Chemoselective Cleavage of p-Methoxybenzyl and 2-Naphthylmethyl Ethers Using a Catalytic Amount of HCl in Hexafluoro-2-propanol. AB - A new, fast, mild and chemoselective deprotection method to cleave p methoxybenzyl and 2-naphthylmethyl ethers using catalytic amounts of hydrochloric acid in a 1:1 mixture of hexafluoro-2-propanol (HFIP) and methylene chloride (DCM) is described. The scope of the methodology becomes apparent from 14 examples of orthogonally protected monosaccharides that are subjected to HCl/HFIP treatment. The applicability of the HCl/HFIP method is illustrated by the synthesis of a sulfated beta-mannuronic acid disaccharide. PMID- 26230921 TI - Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni. AB - BACKGROUND: As plans to expand mass drug treatment campaigns to fight schistosomiasis form, worries about reliance on praziquantel as the sole available treatment motivate the investigation for novel antischistosomal compounds. Drug repurposing might be an inexpensive and effective source of novel antischistosomal leads. METHODOLOGY: 1600 FDA approved compounds were first assayed against Schistosoma mansoni schistosomula at a concentration of 10 uM. Active compounds identified from this screen were advanced to the adult worm screen at 33.33 uM, followed by hit characterization. Leads with complementary pharmacokinetic and toxicity profiles were then selected for in vivo studies. PRINCIPAL FINDINGS: The in vitro screen identified 121 and 36 compounds active against the schistosomula and adult stage, respectively. Further, in vitro characterization and comparison with already available pharmacokinetic and toxicity data identified 11 in vivo candidates. Doramectin (10 mg/kg) and clofazimine (400 mg/kg) were found to be active in vivo with worm burden reductions of 60.1% and 82.7%, respectively. CONCLUSIONS/SIGNIFICANCE: The work presented here expands the knowledge of antischistosomal properties of already approved compounds and underscores variations observed between target-based and phenotypic approaches and among laboratories. The two in vivo-active drugs identified in this study, doramectin and clofazimine are widely available and present as novel drug classes as starting points for further investigation. PMID- 26230922 TI - Genetic Signatures of Demographic Changes in an Avian Top Predator during the Last Century: Bottlenecks and Expansions of the Eurasian Eagle Owl in the Iberian Peninsula. AB - The study of the demographic history of species can help to understand the negative impact of recent population declines in organisms of conservation concern. Here, we use neutral molecular markers to explore the genetic consequences of the recent population decline and posterior recovery of the Eurasian eagle owl (Bubo bubo) in the Iberian Peninsula. During the last century, the species was the object of extermination programs, suffering direct persecution by hunters until the 70's. Moreover, during the last decades the eagle owl was severely impacted by increased mortality due to electrocution and the decline of its main prey species, the European rabbit (Oryctolagus cuniculus). In recent times, the decrease of direct persecution and the implementation of some conservation schemes have allowed the species' demographic recovery. Yet, it remains unknown to which extent the past population decline and the later expansion have influenced the current species' pattern of genetic diversity. We used eight microsatellite markers to genotype 235 eagle owls from ten Spanish subpopulations and analyse the presence of genetic signatures attributable to the recent population fluctuations experienced by the species. We found moderate levels of differentiation among the studied subpopulations and Bayesian analyses revealed the existence of three genetic clusters that grouped subpopulations from central, south-western and south-eastern Spain. The observed genetic structure could have resulted from recent human-induced population fragmentation, a patchy distribution of prey populations and/or the philopatric behaviour and habitat selection of the species. We detected an old population bottleneck, which occurred approximately 10,000 years ago, and significant signatures of recent demographic expansions. However, we did not find genetic signatures for a recent bottleneck, which may indicate that population declines were not severe enough to leave detectable signals on the species genetic makeup or that such signals have been eroded by the rapid demographic recovery experienced by the species in recent years. PMID- 26230923 TI - Identification and Validation of Protein Biomarkers of Response to Neoadjuvant Platinum Chemotherapy in Muscle Invasive Urothelial Carcinoma. AB - BACKGROUND: The 5-year cancer specific survival (CSS) for patients with muscle invasive urothelial carcinoma of the bladder (MIBC) treated with cystectomy alone is approximately 50%. Platinum based neoadjuvant chemotherapy (NAC) plus cystectomy results in a marginal 5-10% increase in 5-year CSS in MIBC. Interestingly, responders to NAC (3) against Gram- (E. coli), Gram+ (S. aureus) and yeast (C. krusei); they are chemically stable in different media (distilled water, sea-like water, LB and DMEN media) as well as biocompatible. The cytotoxicity was evaluated by the Neutral Red Uptake using NIH-3T3 (mouse embryonic fibroblast cells) and the cell viability was >80%. These new glasses can be considered in several and important applications in the field of inorganic non-toxic biocide agents such as medical implants, surgical equipment, protective apparels in hospitals, water purifications systems, food packaging, food storages or textiles. PMID- 26230941 TI - Effects of Selenylation Modification on Antioxidative Activities of Schisandra chinensis Polysaccharide. AB - The selenylation modification of Schisandra chinensis polysaccharide (SCP) was conducted by the HNO3-Na2SeO3 method respectively under nine conditions according to L9(34) orthogonal design. Nine selenizing SCPs, sSCP1-sSCP9, were obtained, and their antioxidant activities were compared. In vitro test, the free radical scavenging rates of nine sSCPs were determined for DPPH., .OH and ABTS+. sSCP1 presented the most significant effect, and could inhibit the nonenzymatic protein glycation. In vivo test, 14-day-old chickens were injected respectively with sSCP1 and SCP, the serum contents of CAT, SOD and MDA were determined. The result showed that as compared with the SCP group, the SOD and CAT activities were significantly or numerically raised and MDA content was significantly or numerically lowered in the sSCP1 group. These results indicate that selenylation modification can significantly enhance the antioxidant and antiglycative activity of SCP in vitro or in vivo. sSCP1 possesses the best efficacy and its modification conditions can be as optimal modification conditions that were 200 mg of Na2SeO3 for 500 mg of SCP, reaction temperature of 50 degrees C and reaction time of 6 h. PMID- 26230943 TI - Human Serum Albumin Increases the Stability of Green Tea Catechins in Aqueous Physiological Conditions. AB - Epicatechin (EC), epigallocatechin (EGC), epicatechingallate (ECG) and epigallocatechingallate (EGCG) are antioxidants present in the green tea, a widely used beverage whose health benefits are largely recognized. Nevertheless, major physicochemical limitations, such as the high instability of catechins, pose important questions concerning their potential pharmacological use. Recent studies indicate that binding of catechins with plasmatic proteins may modulate their plasma concentration, tissue delivery and biological activity. After 5 minutes of incubation with HSA both ECG and EGCG were fully bound to HSA, while after 48h incubation only 41% of EC and 70% of EGC resulted linked. HSA had a strong stabilizing effect on all catechins, which could be found in solution between 29 and 85% even after 48h of incubation. In the absence of HSA, EGC and EGCG disappeared in less than 24h, while ECG and EC were found after 48h at 5 and 50%, respectively. The stabilizing effect of HSA toward EGCG, obtained in aqueous physiological conditions, resulted stronger in comparison to cysteine and HCl, previously reported to stabilize this polyphenol. Because of the multitude of contradictory data concerning in vivo and in vitro antioxidant-based experimentations, we believe our work may shed some light on this debated field of research. PMID- 26230944 TI - Olfaction improvement after nasal septal perforation repair with the "cross stealing" technique. AB - BACKGROUND: The surgical treatment of nasal septal perforation is known to improve nasal respiratory airflow and, thereby, should be beneficial to the patient's olfactory abilities. However, there are only limited data on the effect of nasal septal perforation repair (NSPR) on olfaction, and most studies reported contradictory results. OBJECTIVE: The aim of this prospective study was to investigate the change in the olfactory abilities of 42 patients with a primary concern of nasal septal perforation. METHODS: NSPR was performed with the "cross stealing" technique. The inferior-based mucoperichondrial flap in one side and the superior-based mucoperichondrial flap from the other side of the nasal septum were passed to the opposite sides through the perforation. Surgery was completed by placing an interpositional graft between the flaps before suturing. The interpositional grafts were residual cartilage. The olfactory performance of the patients before and at 1, 3, and 6 months after the closure of the nasal septal perforation was measured by using an olfaction test kit. RESULTS: The success rate with complete closure of nasal septal perforation with the "cross-stealing" technique was 92.8%. Analysis of the data indicated statistically significant improvement in olfactory function scored as odor threshold (T), odor discrimination (D), odor identification (I) and TDI at 1, 3, and 6 months after NSPR (p < 0.001 for all). The mean TDI score evaluated 6 months after NSPR was improved by 64%. Analyses of variance indicated statistically significant improvement in olfactory scores within time factors were calculated as preoperative versus 1, 3, and 6 months; 1 versus 3 and 6 months; and 3 versus 6 months (p < 0.001 for all). Analysis of the present data indicates a beneficial effect of NSPR on olfactory abilities of patients with perforation. CONCLUSION: Our data on the short- and long-term olfactory abilities of 42 patients with nasal septal perforation after NSPR when using an olfaction test kit indicated statistically significant improvement in olfactory function. PMID- 26230945 TI - Acupuncture plus Low-Frequency Electrical Stimulation (Acu-LFES) Attenuates Diabetic Myopathy by Enhancing Muscle Regeneration. AB - Mortality and morbidity are increased in patients with muscle atrophy resulting from catabolic diseases such as diabetes. At present there is no pharmacological treatment that successfully reverses muscle wasting from catabolic conditions. We hypothesized that acupuncture plus low frequency electric stimulation (Acu-LFES) would mimic the impact of exercise and prevent diabetes-induced muscle loss. Streptozotocin (STZ) was used to induce diabetes in mice. The mice were then treated with Acu-LFES for 15 minutes daily for 14 days. Acupuncture points were selected according to the WHO Standard Acupuncture Nomenclature guide. The needles were connected to an SDZ-II electronic acupuncture device delivering pulses at 20Hz and 1mA. Acu-LFES prevented soleus and EDL muscle weight loss and increased hind-limb muscle grip function in diabetic mice. Muscle regeneration capacity was significantly increased by Acu-LFES. The expression of Pax7, MyoD, myogenin and embryo myosin heavy chain (eMyHC) was significantly decreased in diabetic muscle vs. control muscle. The suppressed levels in diabetic muscle were reversed by Acu-LFES. The IGF-1 signaling pathway was also upregulated by Acu LFES. Phosphorylation of Akt, mTOR and p70S6K were downregulated by diabetes leading to a decline in muscle mass, however, Acu-LFES countered the diabetes induced decline. In addition, microRNA-1 and -206 were increased by Acu-LFES after 24 days of treatment. We conclude that Acu-LFES is effective in counteracting diabetes-induced skeletal muscle atrophy by increasing IGF-1 and its stimulation of muscle regeneration. PMID- 26230946 TI - A 3'-UTR Polymorphism in Soluble Epoxide Hydrolase Gene Is Associated with Acute Rejection in Renal Transplant Recipients. AB - BACKGROUND AND PURPOSE: Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites that play a protective role against damaging processes that may occur after re-oxygenation of the graft. We aimed to investigate whether the presence of functional polymorphisms in the gene encoding soluble epoxy hydrolase (EPHX2), which metabolizes EETs to less active compounds, may play a role in the outcome of renal transplantation. METHODS: In a group of 259 Caucasian renal transplant recipients and 183 deceased donors, we determined the presence of three common EPHX2 SNPs, namely rs41507953 (K55R), rs751141 (R287Q) and rs1042032 A/G. Associations with parameters of graft function and the incidence of acute rejection were retrospectively investigated throughout the first year after grafting by logistic regression adjusting for clinical and demographic variables. RESULTS: Carriers of the rs1042032 GG genotype displayed significantly lower estimated glomerular filtration rate (eGFR) (38.15 +/- 15.57 vs. 45.99 +/- 16.05; p = 0.04) and higher serum creatinine values (1.57 +/- 0.58 vs. 1.30 +/- 0.47 g/dL; p=0.02) one year after grafting, compared to patients carrying the wildtype A-allele. The same GG genotype was also associated to increased risk of acute rejection. Interestingly, this association was observed for the genotype of both recipients [OR =6.34 (1.35-29.90); p = 0.015] and donors [OR = 5.53 (1.10-27.80); p=0.042]. A statistical model including both genotypes along with other meaningful demographic and clinical variables resulted in an increased significance for the association with the recipients' genotype [OR=8.28 (1.21 74.27); p=0.031]. CONCLUSIONS: Our results suggest that genetic variability in the EETs-metabolizing gene, EPHX2, may have a significant impact on the outcome of deceased-donor renal transplantation. PMID- 26230947 TI - Moving forward in fall prevention: an intervention to improve balance among patients in a quasi-experimental study of hospitalized patients. AB - We investigated the effectiveness of three different rehabilitative programs: group exercise, individual core stability or balance training intervention with a stabilometric platform to improve balance ability in elderly hospitalized patients. We used a prospective quasi-experimental study design. Twenty-eight patients, 39.3% women [age (mean+/-SD) 72.4+/-6.5 years], known to have had at least a fall in the last 12 months, were consecutively assigned to one of the following three groups: group exercise intervention, individual core stability or balance training with a stabilometric platform (five sessions a week for 3 weeks in each group). Outcomes were collected at baseline and immediately following the intervention period. In each intervention group, patients showed improvement in balance and mobility, shown as an improvement in the three functional tests score (the Tinetti scale, the Berg Balance Scale, and the Time Up and Go test) (all, P<0.05), whereas, generally, the changes in the score of the test of the stabilometric platform (Postural Stability Test and Fall Risk Test) were not significant for all the interventions. No significant group-by-time interaction was detected for any of the intervention groups, which suggests that the groups improved in the same way. These findings indicate that participation in an exercise program can improve balance and functional mobility, which might contribute toward the reductions of the falls of elderly hospitalized patients and the subsequent fall-related costs. Functional scales might be more appropriate than an instrumental test (Postural Stability Test and Fall Risk Test of the Biodex Balance System) in detecting the functional improvement because of a rehabilitative intervention. PMID- 26230948 TI - Training of selective attention in work-active stroke patients. AB - The aim was to examine the effects of computer-based cognitive rehabilitation of attention in work-active patients after stroke. The study included 11 patients treated as inpatients at the University Rehabilitation Institute, Republic of Slovenia, who were included in intensive selective attention training four times a week for 3 months. Each patient was assessed at the initial and the final rehabilitation stage with the TAP system (Test of Attentional Performance), alertness, and divided attention tasks. The results indicate a moderate to strong increase in performance on the divided attention test and a mild effect on the alertness test. Early cognitive rehabilitation of the attentional system can contribute toward recovery of divided attention in work-active patients after stroke. PMID- 26230949 TI - A Comparison of South African National HIV Incidence Estimates: A Critical Appraisal of Different Methods. AB - BACKGROUND: The interpretation of HIV prevalence trends is increasingly difficult as antiretroviral treatment programs expand. Reliable HIV incidence estimates are critical to monitoring transmission trends and guiding an effective national response to the epidemic. METHODS AND FINDINGS: We used a range of methods to estimate HIV incidence in South Africa: (i) an incidence testing algorithm applying the Limiting-Antigen Avidity Assay (LAg-Avidity EIA) in combination with antiretroviral drug and HIV viral load testing; (ii) a modelling technique based on the synthetic cohort principle; and (iii) two dynamic mathematical models, the EPP/Spectrum model package and the Thembisa model. Overall, the different incidence estimation methods were in broad agreement on HIV incidence estimates among persons aged 15-49 years in 2012. The assay-based method produced slightly higher estimates of incidence, 1.72% (95% CI 1.38 - 2.06), compared with the mathematical models, 1.47% (95% CI 1.23 - 1.72) in Thembisa and 1.52% (95% CI 1.43 - 1.62) in EPP/Spectrum, and slightly lower estimates of incidence compared to the synthetic cohort, 1.9% (95% CI 0.8 - 3.1) over the period from 2008 to 2012. Among youth aged 15-24 years, a declining trend in HIV incidence was estimated by all three mathematical estimation methods. CONCLUSIONS: The multi method comparison showed similar levels and trends in HIV incidence and validated the estimates provided by the assay-based incidence testing algorithm. Our results confirm that South Africa is the country with the largest number of new HIV infections in the world, with about 1 000 new infections occurring each day among adults aged 15-49 years in 2012. PMID- 26230950 TI - FGF13 regulates proliferation and differentiation of skeletal muscle by down regulating Spry1. AB - OBJECTIVES: Generally, the secretory forms of FGF are known to regulate cell proliferation, differentiation and morphogenesis by binding to the extracellular domain of cell surface receptors. Intracellular FGFs (FGF11-14) are expressed principally in the nervous system. FGF13 is a microtubule-stabilizing protein that regulates neuronal polarization and migration. Previous studies have reported high expression of FGF13 in cultures of single muscle fibres. However, functions of FGF13 in muscle development have not been explored. MATERIALS AND METHODS: Real-time RT-PCR was performed to detect expression of FGF13 during C2C12 muscle cell proliferation and differentiation. To further understand the role of FGF13, its effects on proliferation and differentiation were examined by western blot analyses of cells transfected with FGF13 siRNA or FGF13 expression plasmids, or treated with chemical MEK inhibitors. Effects of FGF13 on related signalling pathways in C2C12 cell proliferation and differentiation were determined. RESULTS: FGF13 inhibited C2C12 cell proliferation by up-regulating p27 mRNA level and by down-regulating Cyclin E protein expression, during cell proliferation. Additionally, FGF13 down-regulated Spry1 protein expression, activating the ERK1/2 pathway by phosphorylation and leading to C2C12 cell differentiation inhibition. Consequently, FGF13 seemed to function as a repressor of myoblast differentiation via the ERK1/2 pathway. Although FGF13 inhibited Spry1 regardless of cell proliferation or differentiation, its pathway activation occurred only during the stage of myoblast differentiation. CONCLUSIONS: FGF13 inhibited C2C12 cell proliferation and differentiation by down-regulating Spry1. These findings indicate that FGF13 played a negative regulatory role in skeletal muscle development. PMID- 26230951 TI - Response to letter, 'immortal time bias in retrospective analysis'. PMID- 26230952 TI - IL-10 induces the development of immunosuppressive CD14(+)HLA-DR(low/-) monocytes in B-cell non-Hodgkin lymphoma. AB - The biological role of monocytes and macrophages in B-cell non-Hodgkin lymphoma (NHL) is not fully understood. We have previously reported that monocytes from patients with B-cell NHL have an immunosuppressive CD14(+)HLA-DR(low/-) phenotype that correlates with a poor prognosis. However, the underlying mechanism by which CD14(+)HLA-DR(low/-) monocytes develop in lymphoma is unknown. In the present study, we found that interleukin (IL)-10, which is increased in the serum of patients with B-cell NHL, induced the development of the CD4(+)HLA-DR(low/-) population. Using peripheral blood samples from patients with B-cell NHL, we found that absolute numbers of CD14(+) monocytic cells with an HLA-DR(low/-) phenotype were higher than healthy controls and correlated with a higher International Prognostic Index score. IL-10 serum levels were elevated in lymphoma patients compared with controls and were associated with increased peripheral monocyte counts. Treatment of monocytes with IL-10 in vitro significantly decreased HLA-DR expression and resulted in the expansion of CD14(+)HLA-DR(low/-) population. We found that lymphoma B cells produce IL-10 and supernatants from cultured lymphoma cells increased the CD14(+)HLA-DR(low/-) population. Furthermore, we found that IL-10-induced CD14(+)HLA-DR(low/-) monocytes inhibited the activation and proliferation of T cells. Taken together, these results suggest that elevated IL-10 serum levels contribute to increased numbers of immunosuppressive CD14(+)HLA-DR(low/-) monocytes in B-cell NHL. PMID- 26230953 TI - Clinical and prognostic significance of bone marrow abnormalities in the appendicular skeleton detected by low-dose whole-body multidetector computed tomography in patients with multiple myeloma. AB - Clinical significance of medullary abnormalities in the appendicular skeleton (AS) detected by low-dose whole-body multidetector computed tomography (MDCT) in patients with multiple myeloma (MM) was investigated. A total of 172 patients with monoclonal gammopathy of undetermined significance (MGUS) (n=17), smoldering MM (n=47) and symptomatic MM (n=108) underwent low-dose MDCT. CT values (CTv) of medullary density of AS?0 Hounsfield unit (HU) was considered as abnormal. Percentage of medullary abnormalities and the mean CTv of AS in patients with MGUS, smoldering MM and symptomatic MM were 18, 55 and 62% and -44.5 , -20.3 and 11.2 HU, respectively (P<0.001 and P<0.001). Disease progression of MM was independently associated with high CTv on multivariate analysis. In symptomatic MM, the presence of abnormal medullary lesions was associated with increased incidence of high-risk cytogenetic abnormalities (34.4% vs 7.7%; P=0.002) and extramedullary disease (10.4% vs 0%; P=0.032). It was also an independent poor prognostic predictor (hazard ratio 3.546, P=0.04). This study showed that CTv of AS by MDCT is correlated with disease progression of MM, and the presence of abnormal medullary lesions is a predictor for poor survival. PMID- 26230954 TI - PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation. AB - Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1(hi)TIM-3(+) cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1(hi)TIM 3(+) T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-alpha (TNF-alpha) and interferon gamma (IFN-gamma). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets. Importantly, increase of PD-1(hi)TIM-3(+) cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation. PMID- 26230956 TI - Anti-thymocyte globulin could improve the outcome of allogeneic hematopoietic stem cell transplantation in patients with highly aggressive T-cell tumors. AB - The early experiment result in our hospital showed that anti-thymocyte globulin (ATG) inhibited the proliferation of lymphoid tumor cells in the T-cell tumors. We used the ATG as the part of the conditioning regimen and to evaluate the long term anti-leukemia effect, the safety and complication in the patients with highly aggressive T-cell lymphomas. Twenty-three patients were enrolled into this study. At the time of transplant, six patients reached first or subsequent complete response, three patients had a partial remission and 14 patients had relapsed or primary refractory disease. The conditioning regimen consisted of ATG, total body irradiation, toposide and cyclophosphamide. The complete remission rate after transplant was 95.7%. At a median follow-up time of 25 months, 16 (69.6%) patients are alive and free from diseases, including nine patients in refractory and progressive disease. Seven patients died after transplant, five from relapse and two from treatment-related complications. The incidence of grades II-IV acute graft-vs-host disease (GvHD) was 39.1%. The maximum cumulative incidence of chronic GvHD was 30%. The most frequent and severe conditioning-related toxicities observed in 8 out of 23 patients were grades III/IV infections during cytopenia. Thus, ATG-based conditioning is a feasible and effective alternative for patients with highly aggressive T-cell tumors. PMID- 26230955 TI - TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow ups show the mutation is stable during disease evolution. AB - The TP53 mutation is frequently detected in acute myeloid leukemia (AML) patients with complex karyotype (CK), but the stability of this mutation during the clinical course remains unclear. In this study, TP53 mutations were identified in 7% of 500 patients with de novo AML and 58.8% of patients with CK. TP53 mutations were closely associated with older age, lower white blood cell (WBC) and platelet counts, FAB M6 subtype, unfavorable-risk cytogenetics and CK, but negatively associated with NPM1 mutation, FLT3/ITD and DNMT3A mutation. Multivariate analysis demonstrated that TP53 mutation was an independent poor prognostic factor for overall survival and disease-free survival among the total cohort and the subgroup of patients with CK. A scoring system incorporating TP53 mutation and nine other prognostic factors, including age, WBC counts, cytogenetics and gene mutations, into survival analysis proved to be very useful to stratify AML patients. Sequential study of 420 samples showed that TP53 mutations were stable during AML evolution, whereas the mutation was acquired only in 1 of the 126 TP53 wild-type patients when therapy-related AML originated from different clone emerged. In conclusion, TP53 mutations are associated with distinct clinic biological features and poor prognosis in de novo AML patients and are rather stable during disease progression. PMID- 26230957 TI - An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies. AB - Since its reclassification as a distinct disease entity, clinical research efforts have attempted to establish baseline characteristics and prognostic scoring systems for chronic myelomonocytic leukemia (CMML). Although existing data for baseline characteristics and CMML prognostication have been robustly developed and externally validated, these results have been limited by the small size of single-institution cohorts. We developed an international CMML data set that included 1832 cases across eight centers to establish the frequency of key clinical characteristics. Of note, we found that the majority of CMML patients were classified as World Health Organization CMML-1 and that a 7.5% bone marrow blast cut-point may discriminate prognosis with higher resolution in comparison with the existing 10%. We additionally interrogated existing CMML prognostic models and found that they are all valid and have comparable performance but are vulnerable to upstaging. Using random forest survival analysis for variable discovery, we demonstrated that the prognostic power of clinical variables alone is limited. Last, we confirmed the independent prognostic relevance of ASXL1 gene mutations and identified the novel adverse prognostic impact imparted by CBL mutations. Our data suggest that combinations of clinical and molecular information may be required to improve the accuracy of current CMML prognostication. PMID- 26230959 TI - The impact of depressive and bipolar symptoms on socioeconomic status, core symptoms, function and severity of fibromyalgia. AB - AIM: To evaluate the prevalence of depressive and bipolar symptoms in a cohort of consecutive fibromyalgia (FM) patients seen in a tertiary care center and to determine the relationship between depressive and manic symptoms with FM symptoms, socioeconomic status, severity and function. METHODS: Three hundred and five FM patients were enrolled; demographic, clinical and questionnaire data were collected. Depressive symptoms were measured by the Patient Health Questionnaire (PHQ-9), manic symptoms by the Mood Disorders Questionnaire (MDQ). RESULTS: The FM cohort had the following characteristics: age 43.53 (11.7) years; 86.5% white; 82.7% female; PHQ-9 >= 10, 59.7%, mean 11.9 (7.3); no depression 11.4%, mild 29.1%, moderate 27.5%, moderate severe 17.7%, severe 14%; anxiety 41.6%; 21.3% had either an MDQ score >= 7 and/or reported a past diagnosis of bipolar disorder (BD). Increasing levels of depression severity, as well as a positive screen for BD were significantly associated with increasing prevalence and severity of FM symptoms, longer duration of morning stiffness, and increased severity of FM. Increasing levels of depression were significantly associated with increase in prevalence of reported past sexual abuse, and a decline in socioeconomic status, including higher disability and unemployment rates. CONCLUSION: Patients with severe FM disease activity, high load of symptoms, prolonged morning stiffness, increased disability, lower socioeconomic status and those who take a lot of medications for FM should be evaluated for depressive and manic symptoms. PMID- 26230960 TI - Fracture characterization in cancellous bone specimens via surface difference evaluation of 3D registered pre- and post-compression micro-CT scans. PMID- 26230958 TI - Depression of Family Caregivers Is Associated with Disagreements on Life Sustaining Preferences for Treating Patients with Dementia. AB - BACKGROUND: Family caregivers may not agree with patients with dementia regarding attitudes toward end-of-life preferences, and the effects of this type of disagreement are not well understood. This study sought to identify such a disagreement and its predictors. METHODS: A cross-sectional sample of 84 family caregivers and patients with dementia was recruited from memory clinics. We used the Mini-Mental State Examination, Neuropsychiatric Inventory, Clinical Dementia Rating, and Katz index of independence in activities of daily living to assess patient symptoms, functions, and severity of dementia. Caregivers completed questionnaires on perceived patient end-of-life care preferences, caregiver end of-life care preferences for patients, Zarit Burden Interview (ZBI), Center for Epidemiological Studies-Depression Scale (CES-D), and knowledge of clinical complications of advanced dementia. RESULTS: The self-disclosure rates of patient preferences were 34.5% for tube feeding, 39.3% for cardiopulmonary resuscitation, and 45.2% for mechanical ventilation. For patients who had disclosed preferences, the disagreement rate between them and their caregivers was 48.3% for tube feeding, 48.5% for cardiopulmonary resuscitation, and 60.3% for mechanical ventilation. Caregiver depression (i.e., CES-D >=16) was associated with disagreements on cardiopulmonary resuscitation (adjusted odds ratio (aOR) = 6.6, 95% CI = 1.4-31.1, P = 0.01) and mechanical ventilation (aOR = 14, 95% CI = 2.2 87.2, P = 0.005) preferences. CONCLUSION: The preferences of end-of-life issues differed greatly between dementia patients and their caregivers. Depression in caregivers is associated with such discrepancy. PMID- 26230961 TI - Novel Association of Odontogenic Myxoma with Constitutional Chromosomal 1q21 Microduplication: Case Report and Review of the Literature. AB - Odontogenic myxoma (OM) is a rare, benign, and locally aggressive tumor. It tends to occur in the posterior maxilla and mandible and is often associated with root resorption and perforation of cortex. Histopathologically, there is a proliferation of spindle, bipolar, and stellate cells, with bland nuclei within a myxoid to infrequently fibromyxoid extracellular matrix. Long, thin residual bony trabeculae are often seen floating within the spindle cell proliferation because of the infiltrating nature of this tumor, and these trabeculae impart a "soap bubble" or "tennis-racket" radiologic appearance. No syndromic association of OM has been reported. Although similar histopathologic features are shared with cardiac myxoma and soft tissue myxoma, mutations in the GNAS gene have not been identified in OM to date, and only 2 of 17 OMs showed mutations in the PRKAR1A gene. In this report, we describe a case of OM in a patient with constitutional 1q21 microduplication, a locus that harbors genes encoding certain proteins in the cAMP-dependent protein kinase A (PKA) signaling pathway, including G-protein coupled receptors and 1 phosphodiesterase interacting protein. Review of the literature describes the key clinical features and molecular pathogenesis of 1q21 microduplication, as well as highlighting the role of PKA signaling pathway in the pathogenesis of myxomas in general. PMID- 26230962 TI - Highly Chemiluminescent Graphene Oxide Hybrids Bifunctionalized by N-(Aminobutyl) N-(Ethylisoluminol)/Horseradish Peroxidase and Sensitive Sensing of Hydrogen Peroxide. AB - N-aminobutyl-N-ethylisoluminol and horseradish peroxidase bifunctionalized graphene oxide hybrids (ABEI-GO@HRP) were prepared through a facile and green strategy for the first time. The hybrids exhibited excellent chemiluminescence (CL) activity over a wide range of pH from 6.1 to 13.0 when reacted with H2O2, whereas ABEI functionalized GO had no CL emission at neutral pH and showed more than 2 orders of magnitude lower CL intensity than ABEI-GO@HRP at pH 13.0. Such strong CL emission from ABEI-GO@HRP was probably due to that HRP and GO facilitated the formation of O2(*-), - CO4(*2-), HO(*), and pi-C?C(*) in the CL reaction, and GO as a reaction interface promoted the electron transfer of the radical-involved reaction. By virtue of ABEI-GO@HRP as a platform, an ultrasensitive, selective, and reagentless CL sensor was developed for H2O2 detection. The CL sensor exhibited a detection limit of 47 fM at physiological pH, which was more than 2 orders of magnitude lower than previously reported methods. This work reveals that bifunctionalization of GO by ABEI and HRP leads to excellent CL feature and enzyme selectivity, which can be used as an ideal platform for developing novel analytical methods. PMID- 26230963 TI - How Coaches' Motivations Mediate Between Basic Psychological Needs and Well Being/Ill-Being. AB - PURPOSE: The purpose of the present research was to test how behavioral regulations are mediated between basic psychological needs and psychological well being and ill-being in a sample of team-sport coaches. Based on self determination theory, we hypothesized a model where satisfaction and thwarting of the basic psychological needs predicted coaches' behavioral regulations, which in turn led them to experience well-being (i.e., subjective vitality, positive affect) or ill-being (i.e., perceived stress, negative affect). METHOD: Three hundred and two coaches participated in the study (Mage = 25.97 years; 82% male). For each instrument employed, the measurement model with the best psychometric properties was selected from a sequence of nested models sustained by previous research, including exploratory structural equation models and confirmatory factor analysis. These measurement models were included in 3 structural equation models to test for mediation: partial mediation, complete mediation, and absence of mediation. RESULTS: The results provided support for the partial mediation model. Coaches' motivation mediated the relationships from both relatedness need satisfaction and basic psychological needs thwarting for coaches' well-being. In contrast, relationships between basic psychological needs satisfaction and thwarting and ill-being were only predicted by direct effects. CONCLUSION: Our results highlight that 3 conditions seem necessary for coaches to experience psychological well-being in their teams: basic psychological needs satisfaction, especially relatedness; lack of basic psychological needs thwarting; and self determined motivation. PMID- 26230964 TI - Editorial: Selling Science in the 21st Century (Or, Trying to Teach an Old Dog New Tricks). PMID- 26230967 TI - Expanding the occupational health methodology: A concatenated artificial neural network approach to model the burnout process in Chinese nurses. AB - Artificial neural networks are sophisticated modelling and prediction tools capable of extracting complex, non-linear relationships between predictor (input) and predicted (output) variables. This study explores this capacity by modelling non-linearities in the hardiness-modulated burnout process with a neural network. Specifically, two multi-layer feed-forward artificial neural networks are concatenated in an attempt to model the composite non-linear burnout process. Sensitivity analysis, a Monte Carlo-based global simulation technique, is then utilised to examine the first-order effects of the predictor variables on the burnout sub-dimensions and consequences. Results show that (1) this concatenated artificial neural network approach is feasible to model the burnout process, (2) sensitivity analysis is a prolific method to study the relative importance of predictor variables and (3) the relationships among variables involved in the development of burnout and its consequences are to different degrees non-linear. PRACTITIONER SUMMARY: Many relationships among variables (e.g., stressors and strains) are not linear, yet researchers use linear methods such as Pearson correlation or linear regression to analyse these relationships. Artificial neural network analysis is an innovative method to analyse non-linear relationships and in combination with sensitivity analysis superior to linear methods. PMID- 26230968 TI - A guide on gene prioritization in studies of psychiatric disorders. AB - There has been an increasing interest in the identification of genetic variants causing individual differences in human behavior. Psychiatrists have contributed to the genetics field by defining the most important behavioral characteristics and by studying the association between genetic variants and behavioral differences within phenotypically well-characterized samples in which detailed assessments have been collected (e.g. neuroimaging). These samples are typically limited in size and are therefore not suitable for a genome-wide association analysis. Instead, gene association studies conducted in such samples typically focus on a few genes of interest, allowing smaller sample sizes. However, the selection of high-priority genes is not always straightforward and psychiatrists will usually have a limited background in genetics. We aim to fill this gap by (i) providing a basic introduction to genetics; (ii) showing how the selection of genes of interest can be optimized by the use of two web tools: Polysearch and Gene Prospector; (iii) illustrating how statistical power analyses can be performed and discussing the importance of sufficiently powered studies. This guide can help psychiatrists with limited experience in genetics in designing genetic studies that allow identification of specific behavioral, cognitive, or neural correlates of genetic risk variants, while avoiding common pitfalls. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26230969 TI - Morphology of Liquid-Liquid Phase Separated Aerosols. AB - The morphology of liquid-liquid phase separated aerosols has a strong impact on their rate of gas and water uptake, and the type and rate of heterogeneous reactions in the atmosphere. However, it is extremely challenging to experimentally distinguish different morphologies (core-shell or partial wetting) of aerosols and to quantify the extent of wetting between the two phases. The aim of this work is to quantitatively predict the morphology of liquid-liquid aerosols from fundamental physical properties of the aerosol phases. We determine the equilibrium structure of liquid-liquid phase separated aerosols through free energy minimization and predict that the contact angle between the two liquids in the aerosol depends on the composition but not the amount of each phase. We demonstrate that for aerosols of diameter larger than ~100 nm, the equilibrium contact angle can be accurately predicted from the surface tensions of each liquid with the vapor and between the two liquids through an expression that is identical to Young's equation. The internal structure of smaller, ultrafine aerosols depends also on the value of the line tension between the two liquids and the vapor. The thermodynamic model accurately predicts the experimental morphology, core-shell or partial wetting, of all aerosols for which surface tensions are provided in the literature, and provides contact angles that cannot be accurately determined with state of the art experimental methods. We find that the contact angle of model atmospheric aerosols is rarely higher than 30 degrees . We validate the thermodynamic predictions through molecular simulations of nonane-water droplets, and use the simulation data to compute line tension values that are in good agreement with theory and the analysis from experimental data in water-nonane droplets. Our finding of a simple analytical equation to compute the contact angle of liquid-liquid droplets should have broad application for the prediction of the morphology of two-phase atmospheric aerosols and its impact in their chemistry. PMID- 26230970 TI - Polyketides with alpha-Glucosidase Inhibitory Activity from a Mangrove Endophytic Fungus, Penicillium sp. HN29-3B1. AB - Five new compounds, pinazaphilones A and B (1, 2), two phenolic compounds (4, 5), and penicidone D (6), together with the known Sch 1385568 (3), (+/-)-penifupyrone (7), 3-O-methylfunicone (8), 5-methylbenzene-1,3-diol (9), and 2,4-dihydroxy-6 methylbenzoic acid (10) were obtained from the culture of the endophytic fungus Penicillium sp. HN29-3B1, which was isolated from a fresh branch of the mangrove plant Cerbera manghas collected from the South China Sea. Their structures were determined by analysis of 1D and 2D NMR and mass spectroscopic data. Structures of compounds 4 and 7 were further confirmed by a single-crystal X-ray diffraction experiment using Cu Kalpha radiation. The absolute configurations of compounds 1 3 were assigned by quantum chemical calculations of the electronic circular dichroic spectra. Compounds 2, 3, 5, and 7 inhibited alpha-glucosidase with IC50 values of 28.0, 16.6, 2.2, and 14.4 MUM, respectively, and are thus more potent than the positive control, acarbose. PMID- 26230783 TI - Search for a Heavy Neutral Particle Decaying to eMU, etau, or MUtau in pp Collisions at sqrt[s]=8 TeV with the ATLAS Detector. AB - This Letter presents a search for a heavy neutral particle decaying into an opposite-sign different-flavor dilepton pair, e^{+/-}MU^{?}, e^{+/-}tau^{?}, or MU^{+/-}tau^{?} using 20.3 fb^{-1} of pp collision data at sqrt[s]=8 TeV collected by the ATLAS detector at the LHC. The numbers of observed candidate events are compatible with the standard model expectations. Limits are set on the cross section of new phenomena in two scenarios: the production of nu[over ~]_{tau} in R-parity-violating supersymmetric models and the production of a lepton-flavor-violating Z^{'} vector boson. PMID- 26230972 TI - Evaluating Cryoablation of Metastatic Lung Tumors in Patients--Safety and Efficacy: The ECLIPSE Trial--Interim Analysis at 1 Year. AB - INTRODUCTION: To assess the feasibility, safety and local tumor control of cryoablation for treatment of pulmonary metastases. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act (HIPAA) compliant, IRB approved, multicenter, prospective, single arm study included 40 patients with 60 lung metastases treated during 48 cryoablation sessions, with currently a minimum of 12 months of follow-up. Patients were enrolled according to the following key inclusion criteria: 1 to 5 metastases from extrapulmonary cancers, with a maximal diameter of 3.5 cm. Local tumor control, disease-specific and overall survival rates were estimated using the Kaplan-Meier method. Complications and changes in physical function and quality of life were also evaluated using Karnofsky performance scale, Eastern Cooperative Oncology Group performance status classification, and Short Form-12 health survey. RESULTS: Patients were 62.6 +/- 13.3 years old (26-83). The most common primary cancers were colon (40%), kidney (23%), and sarcomas (8%). Mean size of metastases was 1.4 +/- 0.7 cm (0.3-3.4), and metastases were bilateral in 20% of patients. Cryoablation was performed under general anesthesia (67%) or conscious sedation (33%). Local tumor control rates were 56 of 58 (96.6%) and 49 of 52 (94.2%) at 6 and 12 months, respectively. Patient's quality of life was unchanged over the follow-up period. One-year overall survival rate was 97.5%. The rate of pneumothorax requiring chest tube insertion was 18.8%. There were three Common Terminology Criteria for Adverse Events grade 3 procedural complications during the immediate follow-up period (pneumothorax requiring pleurodesis, noncardiac chest pain, and thrombosis of an arteriovenous fistula), with no grade 4 or 5 complications. CONCLUSION: Cryoablation is a safe and effective treatment for pulmonary metastases with preserved quality of life following intervention. PMID- 26230971 TI - Assessing the Impact of an Interactive Mobile Game on Tobacco-Related Attitudes and Beliefs: The Truth Campaign's "Flavor Monsters". AB - Given that over 97 percent of American teens play videogames, it is not surprising that many "games for health" target youth. Although tobacco use is the leading cause of preventable death in the United States, few digital games focus on preventing this behavior. The aims of this study were twofold: (1) to determine if youth will play a game with tobacco-related information and themes and (2) to explain the relationship between the truth((r)) (Legacy, Washington, DC) campaign's "Flavor Monsters" gameplay and shifts in game-related tobacco knowledge, attitudes, and beliefs. First, two versions of the game, with different amounts of tobacco-related content, were developed to examine the influence of tobacco-related content on player engagement, length of play, awareness of the truth brand, and receptivity to the game. No statistically significant differences were found for engagement (P=0.81), length of play (P=0.10), or awareness of the truth brand (P=0.67). Using an online survey through a preexisting online panel of 13-24 year olds, a longitudinal (n=693) design was used whereby exposure to messages varied naturally over time. Because of the large number of anti-tobacco industry attitude questions, we created an Anti-Tobacco Industry (ATI) Index based on the results of a factor analysis. Although gameplay was not a predictor of lower levels of intention to smoke, level mastered was a significant positive predictor of ATI Index attitudes score at 3 months, controlling for baseline ATI Index score, age, gender, and ever cigarette use (P=0.002). Longitudinal findings indicate a cumulative and enduring effect, suggesting that anti-tobacco content can be successfully integrated within a mobile game to help increase anti-tobacco attitudes. PMID- 26230976 TI - Early Stage Triple-Negative Breast Cancer: Imaging and Clinical-Pathologic Factors Associated with Recurrence. AB - PURPOSE: To determine the imaging and clinical-pathologic factors associated with recurrence in patients with early stage triple-negative breast cancer. MATERIALS AND METHODS: This study was approved by the institutional review board, and the requirement to obtain informed consent was waived. The authors evaluated 398 patients with stage I or II triple-negative breast cancer (median age, 48 years; range, 21-81 years) who were treated between January 2003 and December 2008. Data collected included preoperative breast magnetic resonance (MR) images, mammographic density, patient age, symptoms, family history of breast cancer, histologic tumor characteristics, tumor grade, tumor size, lymphovascular invasion, lymph node involvement, surgery type, margin status, and adjuvant treatment received. Multivariate analysis was performed by using a Cox proportional hazards model, and recurrence-free survival was estimated with the adjusted Kaplan-Meier method. RESULTS: Of the 398 patients, 63 (15.8%) had recurrent disease after a median follow-up of 6.1 years. The absence of preoperative MR imaging (hazard ratio [HR] with multivariate analysis = 2.66; 95% confidence interval = 1.49, 4.75; P < .001), dense breast tissue (HR = 2.77; 95% confidence interval = 1.39, 5.51; P = .004), family history of breast cancer (HR = 2.32; 95% confidence interval = 1.10, 4.90; P = .028), and lymphovascular invasion (HR = 1.83; 95% confidence interval = 1.11, 3.03; P = .019) were found to be independently associated with recurrence. These same factors were also found to be associated with recurrence-free survival. CONCLUSION: The absence of preoperative MR imaging and the presence of dense breast tissue at mammography were associated with an increased risk of recurrence in patients with triple negative breast cancer. PMID- 26230977 TI - Effect of Bridgehead Steric Bulk on the Intramolecular C-H Heterolysis of [FeFe] Hydrogenase Active Site Models Containing a P2N2 Pendant Amine Ligand. AB - A series of pendant amine-containing [FeFe]-hydrogenase models, [X(CH2S MU)2{Fe(CO)3}{Fe(CO)(P2(Ph)N2(Bn))}] (1H, X = CH2; 2Me, C(CH3)2; 3Et, C(CH2CH3)2; and P2(Ph)N2(Bn) = 1,5-dibenzyl-3,7-diphenyl-1,5-diaza-3,7-diphosphacyclooctane) with different groups at the bridgehead carbon of the S-to-S linker were synthesized. The oxidations of these complexes as well as the reverse reduction reaction were studied by cyclic voltammetry and in situ IR spectroscopy. Regardless of the bridgehead steric bulk, all three complexes demonstrate intramolecular iron-mediated C(sp(3))-H bond heterolytic cleavage with the assistance of the pendant amine base within the chelating diphosphine ligand in the two-electron oxidation process. X-ray crystallographic analysis shows that the doubly oxidized products, [1'H](+), [2'Me](+), and [3'Et](+), all have a rigid FeSC three-membered ring at the open apical site of the rotated iron center. The most noticeable difference in structures of the oxidized complexes is that the single CO ligand of the rotated Fe(P2(Ph)N2(Bn))(CO) unit in [1'H](+) and [2'Me](+) is found below the Fe...Fe vector, while in [3'Et](+) an unusually rotated Fe(P2(Ph)N2(Bn))(CO) moiety positions one of the P donors within the bidentate ligand under the Fe...Fe vector. The starting Fe(I)Fe(I) complexes can be recovered from their corresponding doubly oxidized complexes by reduction in the presence of Bronsted acid. PMID- 26230979 TI - Reported death of psychophysics. PMID- 26230980 TI - Updating visual working memory in the change detection paradigm. AB - An updating version of a visual change detection paradigm was used to investigate the behavioral outcomes and event-related potential (ERP) correlates of visual working memory updating. In each trial, participants were either presented with a memory array followed by a test probe, or with two successive memory arrays. Participants were instructed to update their working memory with the information in the second array. The second array differed from the first one in all, some, or none of the items. When a subset of the items was updated, the probe could appear in the location of a repeated item or of an updated item. Two experiments are reported, using set-sizes of six and two items, respectively. Both experiments show a benefit for probing a repeated item compared to an updated item. This result is consistent with an item-specific updating process. Experiment 2 also revealed two distinct updating-related ERP components, observed in both contralateral and ipsilateral visual hemifields. Frontal electrodes were sensitive to the number of changed items in the array. This ERP component was interpreted as reflecting the modification of information in working memory. Lateral-posterior electrodes only showed a difference between a full repetition of the array and updating, regardless of the number of updated items. This component was interpreted as reflecting attention to task-relevant information rather than the updating process per se. The finding of item-specific updating supports discrete-item architecture models of working memory. PMID- 26230975 TI - Grading of Gliomas by Using Monoexponential, Biexponential, and Stretched Exponential Diffusion-weighted MR Imaging and Diffusion Kurtosis MR Imaging. AB - PURPOSE: To quantitatively compare the potential of various diffusion parameters obtained from monoexponential, biexponential, and stretched exponential diffusion weighted imaging models and diffusion kurtosis imaging in the grading of gliomas. MATERIALS AND METHODS: This study was approved by the local ethics committee, and written informed consent was obtained from all subjects. Both diffusion-weighted imaging and diffusion kurtosis imaging were performed in 69 patients with pathologically proven gliomas by using a 3-T magnetic resonance (MR) imaging unit. An isotropic apparent diffusion coefficient (ADC), true ADC, pseudo-ADC, and perfusion fraction were calculated from diffusion-weighted images by using a biexponential model. A water molecular diffusion heterogeneity index and distributed diffusion coefficient were calculated from diffusion-weighted images by using a stretched exponential model. Mean diffusivity, fractional anisotropy, and mean kurtosis were calculated from diffusion kurtosis images. All values were compared between high-grade and low-grade gliomas by using a Mann-Whitney U test. Receiver operating characteristic and Spearman rank correlation analysis were used for statistical evaluations. RESULTS: ADC, true ADC, perfusion fraction, water molecular diffusion heterogeneity index, distributed diffusion coefficient, and mean diffusivity values were significantly lower in high-grade gliomas than in low-grade gliomas (U = 109, 56, 129, 6, 206, and 229, respectively; P < .05). Pseudo-ADC and mean kurtosis values were significantly higher in high-grade gliomas than in low-grade gliomas (U = 98 and 8, respectively; P < .05). Both water molecular diffusion heterogeneity index (area under the receiver operating characteristic curve [AUC] = 0.993) and mean kurtosis (AUC = 0.991) had significantly greater AUC values than ADC (AUC = 0.866), mean diffusivity (AUC = 0.722), and fractional anisotropy (AUC = 0.500) in the differentiation of low grade and high-grade gliomas (P < .05). CONCLUSION: Water molecular diffusion heterogeneity index and mean kurtosis values may provide additional information and improve the grading of gliomas compared with conventional diffusion parameters. PMID- 26230973 TI - Premotor-motor excitability is altered in dopa-responsive dystonia. AB - BACKGROUND: Dopa-responsive dystonia is clinically dominated by a combination of dystonia and parkinsonism, both known to be associated with abnormal activity in premotor-motor circuits. METHODS: To probe premotor-motor excitability, we used a transcranial magnetic stimulation dual pulse conditioning paradigm in 15 genetically confirmed dopa-responsive dystonia patients and 20 controls under different medication states. We also determined silent periods, short-latency afferent inhibition, interhemispheric inhibition, and short-interval intracortical inhibition and facilitation. RESULTS: In contrast to healthy controls, no motor cortex inhibition was seen after premotor conditioning regardless of the dopaminergic state in patients. The duration of the ipsilateral silent period was increased in the OFF state, and short-latency afferent inhibition was reduced in the ON compared with the OFF state. CONCLUSION: Premotor-motor circuits appear hyporesponsive in dopa-responsive dystonia. PMID- 26230978 TI - Understanding spike-triggered covariance using Wiener theory for receptive field identification. AB - Receptive field identification is a vital problem in sensory neurophysiology and vision. Much research has been done in identifying the receptive fields of nonlinear neurons whose firing rate is determined by the nonlinear interactions of a small number of linear filters. Despite more advanced methods that have been proposed, spike-triggered covariance (STC) continues to be the most widely used method in such situations due to its simplicity and intuitiveness. Although the connection between STC and Wiener/Volterra kernels has often been mentioned in the literature, this relationship has never been explicitly derived. Here we derive this relationship and show that the STC matrix is actually a modified version of the second-order Wiener kernel, which incorporates the input autocorrelation and mixes first- and second-order dynamics. It is then shown how, with little modification of the STC method, the Wiener kernels may be obtained and, from them, the principal dynamic modes, a set of compact and efficient linear filters that essentially combine the spike-triggered average and STC matrix and generalize to systems with both continuous and point-process outputs. Finally, using Wiener theory, we show how these obtained filters may be corrected when they were estimated using correlated inputs. Our correction technique is shown to be superior to those commonly used in the literature for both correlated Gaussian images and natural images. PMID- 26230981 TI - Retinal topography maps in R: new tools for the analysis and visualization of spatial retinal data. AB - Retinal topography maps are a widely used tool in vision science, neuroscience, and visual ecology, providing an informative visualization of the spatial distribution of cell densities across the retinal hemisphere. Here, we introduce Retina, an R package for computational mapping, inspection of topographic model fits, and generation of average maps. Functions in Retina take cell count data obtained from retinal wholemounts using stereology software. Accurate visualizations and comparisons between different eyes have been difficult in the past, because of deformation and incisions of retinal wholemounts. We account for these issues by incorporation of the R package Retistruct, which results in a retrodeformation of the wholemount into a hemispherical shape, similar to the original eyecup. The maps are generated by thin plate splines, after the data were transformed into a two-dimensional space with an azimuthal equidistant plot projection. Retina users can compute retinal topography maps independent of stereology software choice and assess model fits with a variety of diagnostic plots. Functionality of Retina also includes species average maps, an essential feature for interspecific analyses. The Retina package will facilitate rigorous comparative studies in visual ecology by providing a robust quantitative approach to generate retinal topography maps. PMID- 26230974 TI - CAR T-Cell Therapy: The Role of Physical Barriers and Immunosuppression in Lymphoma. AB - Chimeric antigen receptor (CAR) T-cells have shown remarkable results in patients with B-cell leukemia and lymphoma. However, while CAR T-cells have shown complete responses in a majority of patients with acute lymphoblastic leukemia (ALL), lymphomas are more difficult to treat. Different CAR designs and conditioning protocols seem to affect the persistence of patient responses. However, factors that determine if patients receiving the same CARs will respond or not remain obscure. In Sweden, a phase I/IIa trial using third-generation CAR T-cells is ongoing in which we intend to compare tumor biology and immunology, in each patient, to treatment response. CAR T-cell therapy is a powerful tool to add to the treatment options for this patient group but we need to perform the necessary basic research on the multifactorial mechanisms of action to give patients the best possible option of survival. Such studies are also crucial to expand the success of CAR T-cells beyond CD19+ B-cell malignancy. This review will focus on possible barriers of treating lymphoma to define factors that need to be investigated to develop the next generation of CAR T-cell therapy. PMID- 26230982 TI - Computational modeling of depth ordering in occlusion through accretion or deletion of texture. AB - Understanding the depth ordering of surfaces in the natural world is one of the most fundamental operations of the primate visual system. Surfaces that undergo accretion or deletion (AD) of texture are always perceived to behind an adjacent surface. An updated ForMotionOcclusion model (Barnes & Mingolla, 2013) includes two streams for computing motion signals and boundary signals. The two streams generate depth percepts such that AD signals together with boundary signals generate a farther depth on the occluded side of the boundary. The model fits the classical data (Kaplan, 1969) as well as the observation that moving surfaces tend to appear closer in depth (Royden, Baker, & Allman, 1988), for both binary and grayscale stimuli. The recent "Moonwalk illusion" described by Kromrey, Bart, and Hegde (2011) upends the classical view that the surface undergoing AD always becomes the background. Here the surface that undergoes AD appears to be in front of the surrounding surface-a result of the random flickering noise in the surround. As an additional challenge, we developed an AD display with dynamic depth ordering. A new texture version of the Michotte rabbit hole phenomenon (Michotte, Thines, & Crabbe, 1964/1991) generates depth that changes in part of the display area. Because the ForMotionOcclusion model separates the computation of boundaries from the computation of AD signals, it is able to explain the counterintuitive Moonwalk stimulus. We show simulations that explain the workings of the model and how the model explains the Moonwalk and textured Michotte phenomena. PMID- 26230983 TI - Eye dominance in binocular viewing conditions. AB - Different degrees of eye dominance may need to be considered when comparing monocular and binocular performance or estimating binocular summation effects. The purpose of this study was to explore eye dominance under binocular viewing conditions and observe gradual differences in preference. Two binocular eye dominance tests were evaluated and compared to the hole-in-the-card sighting test. The first experiment was based on a binocular sighting test. The second originated from the variable-angle mirror test, utilizing physiological diplopia to determine which eye dominates the binocular percept. The participants were 32 healthy subject with normal sight. For both experiments there were plausible effects of different degrees of eye dominance affecting how the subjects positioned or perceived the scene. The outcomes were supported by a statistically significant correlation with an interocular difference in sensitivity to degraded visibility. A statistically significant correlation was found between the hole-in the-card test and the variable-angle mirror test (r = 0.527, p < 0.01). The experiments confirm the plausible occurrence of forms of eye dominance under binocular viewing conditions. The correlation with the hole-in-the-card test was weak to moderate, due to factors that appear to be related to testing and viewing conditions. Interocular differences in sensitivity to blur appear to be a useful factor in further grading of eye dominance. PMID- 26230984 TI - Can a Bayesian analysis account for systematic errors in judgments of 3D shape from texture? A reply to Saunders and Chen. AB - Saunders and Chen (2015) have recently proposed a Bayesian model of the perception of 3D shape from texture that they claim is superior to an alternative model based on scaling contrast that was originally proposed by Todd, Thaler, Dijkstra, Koenderink, and Kappers (2007). This commentary will review a variety of empirical findings that are relevant to this issue, and it will also evaluate how well these findings can be explained by different possible models that have been proposed in the literature. The results will demonstrate that the scaling contrast model can account for almost all of the factors that can influence apparent shape from texture with just two free parameters. The Bayesian model of Saunders and Chen has a greater number of free parameters than the scaling contrast model, yet it is not sufficiently developed to make quantitative predictions about any of these factors. Moreover, there are several other processes that would be necessary to actually implement their model that are not mentioned in their theoretical discussion. These include some mechanism for measuring veridical slant from texture, and a mechanism for computing global 3D shape from local estimates of optical slant. PMID- 26230985 TI - Overestimation of the number of elements in a three-dimensional stimulus. AB - Observers' numerosity judgments in binocular stereopsis were examined in four experiments, using random-dot stereograms (RDSs) that depicted a two-dimensional (2-D) stimulus side-by-side with a three-dimensional (3-D) stimulus. When the RDSs were correctly fused, a single surface and two (or three) transparent surfaces were observed for the 2-D and 3-D stimuli, respectively. Observers completed a numerosity discrimination task, where they judged which of the two stimuli had a greater number of dot elements. Results showed that (a) the 3-D stimulus was judged to contain more elements than the 2-D stimulus, even when both had the same number of elements, (b) the amount of overestimation increased as a function of the number of elements and the binocular disparity between the front and back surfaces of the 3-D stimulus, (c) the ratio of the physical number of elements in the front surface to that in the back surface of the 3-D stimulus had no effect on the magnitude of overestimation, and (d) when the number of elements for the two surfaces were judged separately, the ratio had more effect on the judged number of elements in the back surface than in the front surface. These results indicate that the extent of overestimation in the numerosity judgment of a set of elements in a stimulus depends on the number of depth layers in which the elements are embedded. PMID- 26230986 TI - Prior implicit knowledge shapes human threshold for orientation noise. AB - Although orientation coding in the human visual system has been researched with simple stimuli, little is known about how orientation information is represented while viewing complex images. We show that, similar to findings with simple Gabor textures, the visual system involuntarily discounts orientation noise in a wide range of natural images, and that this discounting produces a dipper function in the sensitivity to orientation noise, with best sensitivity at intermediate levels of pedestal noise. However, the level of this discounting depends on the complexity and familiarity of the input image, resulting in an image-class specific threshold that changes the shape and position of the dipper function according to image class. These findings do not fit a filter-based feed-forward view of orientation coding, but can be explained by a process that utilizes an experience-based perceptual prior of the expected local orientations and their noise. Thus, the visual system encodes orientation in a dynamic context by continuously combining sensory information with expectations derived from earlier experiences. PMID- 26230987 TI - No priming for global motion in crowding. AB - There is psychophysical evidence that low-level priming, e.g., from oriented gratings, as well as high-level semantic priming, survives crowding. We investigated priming for global translational motion in crowded and noncrowded conditions. The results indicated that reliable motion priming occurs in the noncrowded condition, but motion priming does not survive crowding. Crowding persisted despite variations in the direction of the flankers with respect to the prime's direction. Motion priming was still absent under crowding when 85% of the flankers moved in the same direction as the prime. Crowding also persisted despite variations in the speed of the flankers relative to the prime even when the flankers' speed was four times slower than the speed of the prime. However, a priming effect was evident when the prime's spatial location was precued and its distance to the flankers increased, suggesting a release from crowding. These results suggest that transient attention induced by precueing the spatial location of the prime may improve subjects' ability to discriminate its direction. Spatial cueing could act to decrease the integration field, thereby diminishing the influence of nearby distracters. In an additional experiment in which we used fewer flankers, we found a priming effect under conditions in which the interelement distance varied between flankers and prime. Overall, the results suggest that motion priming is strongly affected by crowding, but transient attention can partially retrieve such facilitation. PMID- 26230988 TI - Selective Deposition of Insulating Metal Oxide in Perovskite Solar Cells with Enhanced Device Performance. AB - We report a simple methodology for the selective deposition of an insulating layer on the nanoparticulate TiO2 (np-TiO2) mesoporous layer of perovskite solar cells. The deposited MgO insulating layer mainly covered the bottom part of the np-TiO2 layer with less coverage at the top. The so-called quasi-top-open structure is introduced to act as an efficient hole-blocking layer to prevent charge recombination at the physical contact of the transparent conducting oxide with the perovskite. This leads to an open-circuit voltage higher than that of the reference cell with a compact TiO2 hole-blocking layer. Moreover, such a quasi-top-open structure can facilitate the electron injection from perovskite into the np-TiO2 mesoporous layer and improve the spectral response at longer wavelength because of the less covered insulating layer at the top. This work provides an alternative way to fabricate perovskite solar cells without the need to use a conventional compact TiO2 layer. PMID- 26230989 TI - A Prospective Open-Label Study of Combined Treatment for Idiopathic Parkinson's Disease Using Acupuncture and Bee Venom Acupuncture as an Adjunctive Treatment. AB - OBJECTIVES: The purpose of this study was to examine the effectiveness and safety of combined treatment using acupuncture and bee venom acupuncture (BVA) as an adjunctive treatment for idiopathic Parkinson's disease (PD). METHODS: Eleven patients (7 men and 4 women) with idiopathic PD who had been receiving a stable dose of anti-parkinsonian medication for at least 4 weeks. Participants received conventional treatment for 12 weeks. Subsequently, they received additional treatment with acupuncture and BVA twice weekly for 12 weeks while still maintaining conventional treatment. All participants were assessed at baseline, 12 weeks, and 24 weeks by using the Unified Parkinson's Disease Rating Scale (UPDRS), the Parkinson's Disease Quality of Life Questionnaire (PDQL), the speed and number of steps required to walk 20 m, and the Beck Depression Inventory (BDI). Maximum excursion and directional control, measured by computerized dynamic posturography (Balance Master((r)) System, NeuroCom, San Carlos, CA), were used to assess postural stability. RESULTS: Patients who underwent 12 weeks of twice-weekly combined treatment with acupuncture and BVA showed significant improvements in gait speed, PDQL score, activities of daily living (UPDRS part II), motor symptoms (UPDRS part III), and combined UPDRS part II+III scores compared with assessments after conventional treatment. CONCLUSIONS: Combined treatment with acupuncture and BVA showed promising results as a safe adjunctive therapy for PD. PMID- 26230990 TI - The Rapid-Heat LAMPellet Method: A Potential Diagnostic Method for Human Urogenital Schistosomiasis. AB - BACKGROUND: Urogenital schistosomiasis due to Schistosoma haematobium is a serious underestimated public health problem affecting 112 million people - particularly in sub-Saharan Africa. Microscopic examination of urine samples to detect parasite eggs still remains as definitive diagnosis. This work was focussed on developing a novel loop-mediated isothermal amplification (LAMP) assay for detection of S. haematobium DNA in human urine samples as a high throughput, simple, accurate and affordable diagnostic tool to use in diagnosis of urogenital schistosomiasis. METHODOLOGY/PRINCIPAL FINDINGS: A LAMP assay targeting a species specific sequence of S. haematobium ribosomal intergenic spacer was designed. The effectiveness of our LAMP was assessed in a number of patients' urine samples with microscopy confirmed S. haematobium infection. For potentially large-scale application in field conditions, different DNA extraction methods, including a commercial kit, a modified NaOH extraction method and a rapid heating method were tested using small volumes of urine fractions (whole urine, supernatants and pellets). The heating of pellets from clinical samples was the most efficient method to obtain good-quality DNA detectable by LAMP. The detection limit of our LAMP was 1 fg/uL of S. haematobium DNA in urine samples. When testing all patients' urine samples included in our study, diagnostic parameters for sensitivity and specificity were calculated for LAMP assay, 100% sensitivity (95% CI: 81.32%-100%) and 86.67% specificity (95% CI: 75.40%-94.05%), and also for microscopy detection of eggs in urine samples, 69.23% sensitivity (95% CI: 48.21%-85.63%) and 100% specificity (95% CI: 93.08%-100%). CONCLUSIONS/SIGNIFICANCE: We have developed and evaluated, for the first time, a LAMP assay for detection of S. haematobium DNA in heated pellets from patients' urine samples using no complicated requirement procedure for DNA extraction. The procedure has been named the Rapid-Heat LAMPellet method and has the potential to be developed further as a field diagnostic tool for use in urogenital schistosomiasis-endemic areas. PMID- 26230991 TI - Quality of Diabetes Care: The Challenges of an Increasing Epidemic in Mexico. Results from Two National Health Surveys (2006 and 2012). AB - BACKGROUND: The quality of diabetes care remains suboptimal according to numerous studies assessing the achievement of quality indicators for diabetes care in various healthcare settings. We report about global and specific quality indicators for diabetes care and their association to glycemic control at the population level in two national health surveys in Mexico. METHODS: We conducted a cross-sectional analysis of the 2006 and 2012 National Health Surveys in Mexico. We examined quality of care for 2,965 and 4,483 adults (>= 20 years) with diagnosed type 2 diabetes using fourteen simple and two composite indicators derived from self-reported information. In a subsample for both surveys, glycated hemoglobin (HbA1c) was measured at the time of the interview. We obtained survey weight-adjusted estimators using multiple regression models (logistic and linear) with combined data files, including survey year as covariate to assess change. RESULTS: Global quality of care in 2012 was 40.8%, with a relative improvement of 11.7% between 2006 and 2012. Detections of cardiovascular disease risk factors (dyslipidemia and hypertension) were the indicators with the highest improvement, while non-pharmaceutical treatment and diabetic foot exams showed minor changes. We found a significant association between the quality of the process of diabetes care and glycemic control (OR 2.53, 95% CI 1.63-3.94). Age more than 65 years old, the type of health subsystem, gender (males), and high socio-economic status were also significantly associated to glycemic control. CONCLUSIONS: Quality diabetes care and glycemic control improved and are significantly associated. However, according to international standards, the current situation remains suboptimal. A more holistic approach is needed, with an emphasis on improving quality in outpatient care. PMID- 26230784 TI - Evidence of Wgammagamma Production in pp Collisions at sqrt[s]=8 TeV and Limits on Anomalous Quartic Gauge Couplings with the ATLAS Detector. AB - This Letter reports evidence of triple gauge boson production pp >W(lnu)gammagamma+X, which is accessible for the first time with the 8 TeV LHC data set. The fiducial cross section for this process is measured in a data sample corresponding to an integrated luminosity of 20.3 fb^{-1}, collected by the ATLAS detector in 2012. Events are selected using the W boson decay to enu or MUnu as well as requiring two isolated photons. The measured cross section is used to set limits on anomalous quartic gauge couplings in the high diphoton mass region. PMID- 26230992 TI - Modulation of Emotional Category Induced by Temporal Factors in Emotion Recognition. AB - Categorical perception (CP), the perceptual experience whereby continuous sensory phenomena are perceived as distinct and separate percepts, is one of the most characteristic features of information processing in human cognition. CP is considered as the result of the integration of the top-down processing including background knowledge and verbal labeling and the bottom-up processing such as physical characteristics of the sensory signal. However, the underlying mechanisms governing the integration remain unclear. To address this issue, we focused on the temporal characteristics of CP of facial expression. In the current study, we investigated the contributions of temporal factors in CP processes, using facial expression recognition tasks as an example of CP. Participants completed an identification task and a discrimination task, well established tasks for evaluating CP of facial expressions, with variable temporal parameters, that is, duration of stimulus presentation and delay time (interval between stimulus and response). The results demonstrated that the emotionally ambiguous stimuli are categorized more distinctively with the extension of delay length, not of stimulus duration. In contrast, the category boundary for facial expressions shifted toward "happy" with extention in stimulus duration, not in delay length. This dissociation between the impact of stimulus duration and delay suggests that there are two processes contributing to CP of facial emotion; one process may reflect the internal processing associated with the length of the delay period including verbal labeling of the stimuli, and the other process may reflect the temporal summation of stimulus inputs, associated with stimulus duration. These findings suggest that paying more attention to temporal factors in CP could be useful for further study of the mechanisms underlying CP. PMID- 26230993 TI - In Vivo Changes in Lamina Cribrosa Microarchitecture and Optic Nerve Head Structure in Early Experimental Glaucoma. AB - The lamina cribrosa likely plays an important role in retinal ganglion cell axon injury in glaucoma. We sought to (1) better understand optic nerve head (ONH) structure and anterior lamina cribrosa surface (ALCS) microarchitecture between fellow eyes of living, normal non-human primates and (2) characterize the time course of in vivo structural changes in the ONH, ALCS microarchitecture, and retinal nerve fiber layer thickness (RNFLT) in non-human primate eyes with early experimental glaucoma (EG). Spectral domain optical coherence tomography (SDOCT) images of the ONH were acquired cross-sectionally in six bilaterally normal rhesus monkeys, and before and approximately every two weeks after inducing unilateral EG in seven rhesus monkeys. ONH parameters and RNFLT were quantified from segmented SDOCT images. Mean ALCS pore area, elongation and nearest neighbor distance (NND) were quantified globally, in sectors and regionally from adaptive optics scanning laser ophthalmoscope images. In bilaterally normal monkeys, ONH parameters were similar between fellow eyes with few inter-eye differences in ALCS pore parameters. In EG monkeys, an increase in mean ALCS Depth (ALCSD) was the first structural change measured in 6 of 7 EG eyes. A decrease in mean minimum rim width (MRW) simultaneously accompanied this early change in 4 of 6 EG eyes and was the first structural change in the 7th EG eye. Mean ALCS pore parameters were among the first or second changes measured in 4 EG eyes. Mean ALCS pore area and NND increased in superotemporal and temporal sectors and in central and peripheral regions at the first time-point of change in ALCS pore geometry. RNFLT and/or mean ALCS radius of curvature were typically the last parameters to initially change. Survival analyses found mean ALCSD was the only parameter to significantly show an initial change prior to the first measured loss in RNFLT across EG eyes. PMID- 26230994 TI - Correction: Recollection-Based Retrieval Is Influenced by Contextual Variation at Encoding but Not at Retrieval. PMID- 26230997 TI - Assessing the Fate of an Aromatic Hydrocarbon Fluid in Agricultural Spray Applications Using the Three-Stage ADVOCATE Model Framework. AB - Components of emulsifiable concentrates (ECs) used in pesticide formulations may be emitted to air following application in agricultural use and contribute to ozone formation. A key consideration is the fraction of the ECs that is volatilized. This study is designed to provide a mechanistic model framework for estimating emissions of an aromatic hydrocarbon fluid used in ECs based on the results of spray chamber experiments that simulate fate as the fluids become subject to volatilization, sorption to soil, and biodegradation. The results indicate the need to treat the volatilization losses in three stages: (i) losses during spraying, (ii) losses up to 12 h after spraying in which the soil is coated with the ECs, and (iii) subsequent longer term losses in which the ECs become increasingly sorbed and subject to biodegradation. A mass balance model, the agrochemical derived volatile organic compound air transfer evaluation (ADVOCATE) tool, is developed, treating the ECs as seven hydrocarbon component groups, to estimate the volatilization and biodegradation losses using parameters fitted to empirical data. This enables losses to be estimated for each hydrocarbon component under field conditions, thereby providing a basis for improved estimation of ozone formation potential and for designing ECs that have lower emissions. PMID- 26230999 TI - An Economic Perspective on Personality Traits and Alcohol Misuse: Evidence from the Health and Retirement Study. AB - BACKGROUND: Recent economic work suggests a role for personality traits in determining socioeconomic outcomes. Much of this work has considered labor market outcomes, human capital accumulation, and, to some extent, health outcomes. No economic studies have explored the role of the Big Five taxonomy in alcohol use and misuse. Given defining characteristics of the Big Five, they are plausibly linked with these outcomes. Alcohol misuse is associated with large social costs through healthcare costs, traffic fatalities, violence, and reduced labor market productivity. Thus, understanding risk factors for such use is warranted. AIMS OF THE STUDY: To investigate the associations between the Big Five, and measures of alcohol use and alcohol misuse. METHODS: We obtain data on older adults 50 years and older from the Health and Retirement Study (HRS). Our outcomes include one measure of use (any use) and two measures of misuse (heavy drinking and binge drinking). Comparing across different measures of alcohol consumption can shed light on whether the Big Five are related to moderate alcohol use that need not impose social costs or alcohol misuse that may indeed impose such costs. A randomly selected sub-set of respondents completed a self-administered questionnaire developed for the Midlife Development Inventory in either the 2006 or 2008 round of the HRS. We use information collected in this instrument to generate our independent variables of primary interest: agreeableness, openness, extraversion, neuroticism, and conscientiousness traits. RESULTS: We find that the Big Five personality traits are linked with measures of both alcohol use and alcohol misuse. We observe substantial heterogeneity in the associations by personality traits. Specifically, agreeableness is associated with increased risk for alcohol use/misuse while extraversion and openness are negatively associated with risk for these patterns of alcohol consumption. We find no evidence that neuroticism or contentiousness predict alcohol use and misuse. We identify heterogeneity in the associations across demographic characteristics. DISCUSSION: We find associations between the Big Five and our measures of alcohol use and alcohol misuse. Our findings are subject to several data limitations, however. Although the Big Five personality taxonomy is well utilized, it has known limitations. Even in a survey as rich as the HRS, it is likely that we are unable to control for all important variables leading to omitted variable bias. Because we focus on a sample of older adults, the generalizability of our findings to other demographic groups is not clear. IMPLICATIONS FOR HEALTHCARE PROVISION AND USE: Agreeableness is significantly associated with alcohol use and misuse, which could lead to greater utilization of healthcare services and thus increased costs to the healthcare system. IMPLICATION FOR HEALTH POLICIES: Healthcare providers should consider aspects of personality when developing and communicating treatment options. Moreover, psychology and economic work documents that interventions can alter aspects of personality even among older adults. Further research on and implementation of effective interventions may be warranted. IMPLICATIONS FOR FURTHER RESEARCH: Future studies should examine the implications of personality for a broader range of outcomes. Survey administrators could consider including validated measures of personality in surveys to facilitate such research. PMID- 26230996 TI - Enhanced torque-based impedance control to assist brain targeting during open skull neurosurgery: a feasibility study. AB - BACKGROUND: Cooperatively-controlled robotic assistance could provide increased positional accuracy and stable and safe tissue targeting tasks during open-skull neurosurgical procedures, which are currently performed free-hand. METHODS: Two enhanced torque-based impedance control approaches, i.e. a variable damping criterion and a force-feedback enhancement control, were proposed in combination with an image-based navigation system. Control systems were evaluated on brain mimicking phantoms by 13 naive users and 8 neurosurgeons (4 novices and 4 experts). RESULTS: In addition to a 60% reduction of user effort, the combination of the proposed strategies showed comparable performances with respect to state of-the-art admittance controller, thus satisfying the clinical accuracy requirements (below 1 mm), reducing the hand tremor (by a factor of 10) and the tissue's indentation overshooting (by 80%). CONCLUSION: Although the perceived reliability of the system should be improved, the proposed control was suitable to assist targeting procedures, such as brain cortex stimulation, allowing for accurate, stable and safe contact with soft tissues. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26231000 TI - The Societal Costs of Schizophrenia in Switzerland. AB - BACKGROUND: Schizophrenia is a severe mental disorder that typically develops in early adulthood and becomes chronic in most cases. The disease is associated with elevated health care utilization, impaired functionality and the loss of life years and quality of life. The prevalence and costs of schizophrenia are not yet known for Switzerland. AIMS OF THE STUDY: This study aims to estimate the prevalence of schizophrenia in Switzerland and to assess its burden on patients, caregivers and society as a whole. METHODS: A hospital registry was combined with an outpatient physician survey and health insurance claims data to capture all patients living in the northern part of the canton of Zurich. Structured interviews with outpatient physicians were held to obtain information on outpatient care in private practices. Total costs included direct medical and nonmedical costs and lost production. All costs were calculated for the year 2012 from a societal perspective using a prevalence-based bottom-up approach. Intangible costs were expressed as quality-adjusted life years (QALY). Uncertainty and its sources were addressed in univariate and probabilistic sensitivity analyses. RESULTS: The point prevalence of schizophrenia in Switzerland was estimated at 0.39% of the population. The average costs of schizophrenia in 2012 were EUR 39,408 per patient. Lost production accounted for 64% (EUR 25,108) of the total cost of illness, direct medical costs for 24% (EUR 9,507) and care by relatives or in residential homes for the mentally ill for 12% (EUR 4,793). Inpatient hospital care amounted to EUR 6,242 per year or 66% of direct medical costs. DISCUSSION: The results show the high burden of schizophrenia on patients, caregivers and society. The prevalence estimate can be considered a lower bound because undiagnosed cases were not identified by our empirical strategy. The estimated costs are conservative because the costs of comorbidities were not considered. The strengths of this study are the full coverage of the sample region by a combination of different data sources and the careful evaluation of parameter uncertainty. The main limitation is the small sample size for the assessment of private practice outpatient care. IMPLICATIONS FOR HEALTH POLICIES AND FURTHER RESEARCH: The high costs of inpatient hospital care demonstrate the potential benefits of effectively preventing relapses associated with readmissions to inpatient care. Considering the high burden of lost production and the early onset of the disease, programs for reintegration into the labor market have high potential to reduce the costs of schizophrenia. Future research should address the evolution of costs over the disease course. This information would allow for assessing the cost-effectiveness of early detection and interventions that alter disease progression. PMID- 26230995 TI - MoSET1 (Histone H3K4 Methyltransferase in Magnaporthe oryzae) Regulates Global Gene Expression during Infection-Related Morphogenesis. AB - Here we report the genetic analyses of histone lysine methyltransferase (KMT) genes in the phytopathogenic fungus Magnaporthe oryzae. Eight putative M. oryzae KMT genes were targeted for gene disruption by homologous recombination. Phenotypic assays revealed that the eight KMTs were involved in various infection processes at varying degrees. Moset1 disruptants (Deltamoset1) impaired in histone H3 lysine 4 methylation (H3K4me) showed the most severe defects in infection-related morphogenesis, including conidiation and appressorium formation. Consequently, Deltamoset1 lost pathogenicity on wheat host plants, thus indicating that H3K4me is an important epigenetic mark for infection-related gene expression in M. oryzae. Interestingly, appressorium formation was greatly restored in the Deltamoset1 mutants by exogenous addition of cAMP or of the cutin monomer, 16-hydroxypalmitic acid. The Deltamoset1 mutants were still infectious on the super-susceptible barley cultivar Nigrate. These results suggested that MoSET1 plays roles in various aspects of infection, including signal perception and overcoming host-specific resistance. However, since Deltamoset1 was also impaired in vegetative growth, the impact of MoSET1 on gene regulation was not infection specific. ChIP-seq analysis of H3K4 di- and tri-methylation (H3K4me2/me3) and MoSET1 protein during infection-related morphogenesis, together with RNA-seq analysis of the Deltamoset1 mutant, led to the following conclusions: 1) Approximately 5% of M. oryzae genes showed significant changes in H3K4-me2 or -me3 abundance during infection-related morphogenesis. 2) In general, H3K4-me2 and -me3 abundance was positively associated with active transcription. 3) Lack of MoSET1 methyltransferase, however, resulted in up-regulation of a significant portion of the M. oryzae genes in the vegetative mycelia (1,491 genes), and during infection-related morphogenesis (1,385 genes), indicating that MoSET1 has a role in gene repression either directly or more likely indirectly. 4) Among the 4,077 differentially expressed genes (DEGs) between mycelia and germination tubes, 1,201 and 882 genes were up- and down-regulated, respectively, in a Moset1-dependent manner. 5) The Moset1-dependent DEGs were enriched in several gene categories such as signal transduction, transport, RNA processing, and translation. PMID- 26231001 TI - Estimating the Cost and Effect of Early Intervention on In-Patient Admission in First Episode Psychosis. AB - BACKGROUND: Early intervention in psychosis is an accepted policy internationally. When 'A Vision for Change', the national blueprint for mental health policy in Ireland, was published in 2007 there was one Irish pilot service for early intervention in psychosis. The National Clinical Mental Health Programme Plan (2011) identified early intervention in psychosis as one of three areas for roll out nationally. There is limited economic evaluation in the field of mental health in Ireland to guide service development. This is in part due to lack of robust patient level data. AIMS OF THE STUDY: The aim of the study was to investigate whether the introduction of an early intervention service in psychosis resulted in any change to the number and duration of admissions in people with first-episode psychosis. METHODS: We examined two prospective epidemiological cohorts of individuals presenting with first-episode psychosis to an urban community mental health service (population 172,000). The historical cohort comprised of individuals presenting from 1995 to 1998 and received treatment as usual (n=132). The early intervention cohort presented to the same catchment area between 2008 and 2011 (n=97) following the introduction of an early intervention service in 2005. RESULTS: We found significant reductions in the rates admitted for treatment across the two time periods. Reduction in the rate of admission was larger in this catchment than the reduction in the rate of admission in the country as a whole. There were significant reductions in the duration of untreated psychosis arising from the early intervention programme. Significant reductions in length of stay were accounted for by differences in baseline age and marital status. The average cost of admission declined from 15,821 to 9,398 in the early intervention cohort. DISCUSSION AND LIMITATIONS: The comparison pre and post early intervention service showed cost savings consistent with other studies internationally. Key issues are whether changes in the admission pattern were due to the implementation of early intervention or were explained by other factors. Examination of local and national factors showed that the dominant effect was from the implementation of early intervention. Limitations are that this is a comparison with a historical cohort and analysis is limited to in-patient costs only. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: While there are cost savings, these represent opportunity cost savings, as the majority of costs associated with in-patient care are fixed. Studies such as this provide evidence that it is feasible to consider disinvestment strategies such as home care in the community. IMPLICATIONS FOR HEALTH POLICIES: It is difficult to generalize interventions shown to work in one country to other countries, as health service structures differ and there are both local and national variations in service structure and delivery. It remains important to evaluate whether a policy is applicable within its local context. IMPLICATIONS FOR FURTHER RESEARCH: Further research in this area is required to evaluate contemporaneous services and to examine whether increased costs in the community incurred through implementation of early intervention negate the savings made through reduction of admissions. PMID- 26231002 TI - Cost-Effectiveness of Florbetapir-PET in Alzheimer's Disease: A Spanish Societal Perspective. AB - BACKGROUND: The rising prevalence of Alzheimer's disease (AD), and other diseases associated with dementia, imposes significant burden to various stakeholders who care for the elderly. Management of AD is complicated by multiple factors including disease-specific features which make it difficult to diagnose accurately during milder stages. Florbetapir F18 positron emission tomography (florbetapir-PET) is an approved imaging tool used to capture beta-amyloid neuritic plaque density in brains of cognitively impaired adults undergoing evaluation for AD and other causes of cognitive impairment. It has the potential to help improve healthcare outcomes as it may help clinicians identify patients with AD early so that treatments are initiated when most effective. AIMS OF THE STUDY: Evaluate the potential long-term clinical and economic outcomes of adopting florbetapir-PET--adjunctive to standard clinical evaluation (SCE)- versus SCE alone in the diagnostic assessment of cognitively impaired patients with suspected AD. METHODS: A decision analysis with a ten-year time horizon was developed in compliance with Good Research Practices and CHEERS guidelines. The target population was comprised of Spanish patients who were undergoing initial assessment for cognitive impairment (Mini-Mental State Examination [MMSE] score=20). Diagnostic accuracy, rate of cognitive decline, effect of drugs on cognition and dwelling status, economic burden (direct and indirect costs), and quality of life (QoL) were based on relevant clinical studies and published literature. Scenario analysis was applied to explore outcomes under different conditions, which included: (i) use of florbetapir-PET earlier in disease progression (MMSE score=22); and (ii) the addition of fluorodeoxyglucose (FDG) PET to SCE. RESULTS: Adjunctive florbetapir-PET increased quality-adjusted life years (QALYs) by 0.008 years and increased costs by 36 compared to SCE alone (incremental cost-effectiveness ratio [ICER], 4,769). Use of florbetapir-PET was dominant in alternate scenarios. Sensitivity analyses indicated rates of institutionalization (by MMSE) and MMSE score upon initiation of acetylcholinesterase inhibitor (AChEI) treatment most influenced the primary outcome (ICER) in the base case scenario. Over 82% of probabilistic simulations were cost-effective using the Spanish threshold (30,000/QALY). DISCUSSION: The addition of florbetapir-PET to SCE is expected to improve the accuracy of AD diagnoses for patients experiencing cognitive impairment; it is cost-effective due to decreased healthcare costs and caregiver burden. Prospective studies of the clinical utility of florbetapir-PET are necessary to evaluate the long-term implications of adopting florbetapir-PET on clinical outcomes and costs in real world settings. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: Florbetapir-PET is expected to improve decision-making regarding appropriate and sufficient care for cognitively impaired patients with suspected AD, while cost-effective. IMPLICATIONS FOR HEALTH POLICIES: Earlier and more accurate diagnosis of AD may help to improve patient's health status and reduce treatment costs by effectively allocating healthcare resources and maximizing the benefit of treatments and supportive services. IMPLICATIONS FOR FURTHER RESEARCH: Use of florbetapir-PET may help accurately identify patients with AD. The development of novel therapeutics for use with companion diagnostics may provide additional benefits by slowing or halting progressive cognitive decline with AD, increase QoL and prolong survival. PMID- 26230998 TI - Benefit of Treatment Individualization in Patients with Chronic Hepatitis C Receiving Peginterferon Alfa-2a and Ribavirin in a Large Noninterventional Cohort Study. AB - BACKGROUND AND AIMS: Individualization of treatment with peginterferon alfa and ribavirin in patients with chronic hepatitis C showed benefit in controlled trials and was implemented in treatment guidelines to increase response rates and to reduce side effects and costs. However, it is unknown whether individualization was adopted in routine daily practice and whether it translated into improved outcomes. METHODS: From a large noninterventional cohort study, clinical and virologic response data of 10,262 HCV patients who received peginterferon alfa-2a and ribavirin between 2003-2007 and 2008-2011 were analyzed. To account for treatment individualization, a matched-pair analysis (2,997 matched pairs) was performed. Variation in treatment duration and dosing of ribavirin were analyzed as indicators for individualization. RESULTS: Sustained virological response (SVR) rates were similar between 2003-2007 and 2008-2011 (62.0% vs. 63.7%). Patients with comorbidities were more abundant in the later period, (44.3% vs. 57.1%). The subsequent matched-pair analysis demonstrated higher SVR rates in the 2008-2011 period (64.3%) than in the 2003 2007 period (61.2%, p=0.008). More patients received abbreviated or extended treatment regimens in the later than the earlier period as an indicator of treatment individualization. To the same end, ribavirin doses were higher in the later period (12.6 versus 11.6 mg/kg/day). Factors independently associated with SVR included HCV genotype, low baseline viral load, younger age, route of infection, absence of concomitant diseases, lower APRI score, normal gamma-GT, higher ribavirin doses, no substitution for drug abuse, treatment duration, and treatment in the 2008-2011 period. CONCLUSIONS: Treatment individualization with peginterferon alfa and ribavirin was implemented in daily routine between 2003 2007 and 2008-2011, SVR rates improved in the same period. These findings may be most relevant in resource-limited settings. PMID- 26231004 TI - Correction: DebtRank: A Microscopic Foundation for Shock Propagation. PMID- 26231003 TI - Additive Effect on Survival of Anaesthetic Cardiac Protection and Remote Ischemic Preconditioning in Cardiac Surgery: A Bayesian Network Meta-Analysis of Randomized Trials. AB - INTRODUCTION: Cardioprotective properties of volatile agents and of remote ischemic preconditioning have survival effects in patients undergoing cardiac surgery. We performed a Bayesian network meta-analysis to confirm the beneficial effects of these strategies on survival in cardiac surgery, to evaluate which is the best strategy and if these strategies have additive or competitive effects. METHODS: Pertinent studies were independently searched in BioMedCentral, MEDLINE/PubMed, Embase, and the Cochrane Central Register (updated November 2013). A Bayesian network meta-analysis was performed. Four groups of patients were compared: total intravenous anesthesia (with or without remote ischemic preconditioning) and an anesthesia plan including volatile agents (with or without remote ischemic preconditioning). Mortality was the main investigated outcome. RESULTS: We identified 55 randomized trials published between 1991 and 2013 and including 6,921 patients undergoing cardiac surgery. The use of volatile agents (posterior mean of odds ratio = 0.50, 95% CrI 0.28-0.91) and the combination of volatile agents with remote preconditioning (posterior mean of odds ratio = 0.15, 95% CrI 0.04-0.55) were associated with a reduction in mortality when compared to total intravenous anesthesia. Posterior distribution of the probability of each treatment to be the best one, showed that the association of volatile anesthetic and remote ischemic preconditioning is the best treatment to improve short- and long-term survival after cardiac surgery, suggesting an additive effect of these two strategies. CONCLUSIONS: In patients undergoing cardiac surgery, the use of volatile anesthetics and the combination of volatile agents with remote preconditioning reduce mortality when compared to TIVA and have additive effects. It is necessary to confirm these results with large, multicenter, randomized, double-blinded trials comparing these different strategies in cardiac and non-cardiac surgery, to establish which volatile agent is more protective than the others and how to best apply remote ischemic preconditioning. PMID- 26231005 TI - Secretor Status Is Strongly Associated with Microbial Alterations Observed during Pregnancy. AB - During pregnancy there are significant changes in gut microbiota composition and activity. The impact of secretor status as determined by genotyping FUT2 (fucosyltransferase 2) gene was taken as one of the confounding factors associated with faecal microbiota changes during pregnancy. In this prospective study, we followed women during pregnancy (total = 123 of which secretors = 108, non-secretors = 15) and characterised their gut microbiota by quantitative polymerase chain reaction (qPCR), Fluorescence In situ Hybridisation (FISH), Denaturing Gradient Gel Electrophoresis (DGGE) and pyrosequencing. qPCR revealed that C. coccoides group counts decreased significantly in non-secretors in comparison to secretors (p = 0.02). Similar tendency was found by FISH analysis in Clostridium histolyticum and Lactobacillus-Enterococcus groups between the secretor and the non-secretor pregnant women. DGGE analysis showed significant decrease in richness of Clostridium sp. between secretor and non-secretor mothers during pregnancy. Pyrosequencing based analysis at phyla level showed that there is greater increase in Actinobacteria in secretors in comparison to non secretors, whereas Proteobacteria showed more increase in non-secretors. Change in relative abundance of Clostridiaceae family from first to third trimester were significantly associated with secretor status of pregnant women (p = 0.05). Polyphasic approach for microbiota analysis points out that the host secretor status (FUT2 genotype) affects the gut microbiota during pregnancy. This may lead to altered infant gut microbiota colonization. PMID- 26231006 TI - Childhood maltreatment and risk of suicide attempt: a nationally representative study. AB - BACKGROUND: Previous research suggests that various types of childhood maltreatment frequently co-occur and confer risk for attempting suicide. However, it is unknown whether the effect of childhood maltreatment on this risk occurs through diverse, specific mechanisms or through a generalized liability, independently of psychopathology. Although these competing explanations have different implications for intervention, they have never been evaluated empirically. METHOD: Structural equation modeling was used to examine the effect of different types of childhood maltreatment (ie, sexual abuse, physical and emotional abuse and neglect) on suicide attempt risk, and on age at first suicide attempt and repeated suicide attempts among attempters. Analyses controlled for demographic characteristics and DSM-IV Axis I and Axis II disorders. Data were drawn from a nationally representative survey of US adults, the 2004-2005 National Epidemiologic Survey on Alcohol and Related Conditions (N = 34,653). RESULTS: Childhood maltreatment was associated with an increased risk for attempting suicide and an earlier age at first suicide attempt among attempters, independently of psychopathology (P < .005). These associations operated mainly through the latent variable representing effects shared by the different types of childhood maltreatment, although sexual abuse had an additional, direct effect on the risk of suicide attempt. Childhood maltreatment types were not significantly associated with a history of multiple suicide attempts (all P values > .05). CONCLUSIONS: The association between childhood maltreatment and suicide attempt operates mainly through a single broad liability, suggesting that the mechanisms underlying this dimension should be considered as an important therapeutic target for suicide prevention. PMID- 26231007 TI - Focus on Women's Mental Health. Introduction. PMID- 26231008 TI - Psychotropic medication use during pregnancy: changes to the labeling system and the importance of exposure registries. AB - In this issue of JCP, Cohen et al present the methodology of the National Pregnancy Registry for Atypical Antipsychotics (NPRAA). In full disclosure, the investigators are my colleagues, and I have great interest in the topic of pregnancy registries, including this particular registry, as a perinatal psychiatrist and from a scientific perspective. Highlighting the importance of this paper is intuitive because we are at a defining moment in the application of data to inform the care of pregnant women. PMID- 26231009 TI - Asenapine once daily versus twice daily: impact on patient acceptance in a randomized, open-label, 14-day clinical trial. PMID- 26231010 TI - Neurodevelopment of children prenatally exposed to selective reuptake inhibitor antidepressants: Toronto sibling study. AB - BACKGROUND: The reproductive safety of selective reuptake inhibitor (SRI) antidepressants needs to be established to provide optimal control of maternal depression while protecting the fetus. OBJECTIVE: To define a child's neurodevelopment following prenatal exposure to SRIs and to account for genetic and environmental confounders in a sibling design using the Toronto Motherisk prospective database. METHOD: Intelligence and behavior of siblings prenatally exposed and unexposed to SRIs were assessed by using the Wechsler Preschool and Primary Scale of Intelligence-Third Edition, Child Behavior Checklist, and Conners Parent Rating Scale-Revised and subsequently compared. Mothers, diagnosed with depression using DSM-IV, were assessed for intelligence quotient (IQ) and for severity of depressive symptoms with the Center for Epidemiologic Studies Depression scale. Prenatal drug doses and durations of exposure, child's age, child's sex, birth order, severity of maternal depression symptoms, and Full Scale IQ, the primary outcome measure, of both the mother and the child were considered in the analyses. RESULTS: Forty-five sibling pairs (ages 3 years to 6 years 11 months, prenatally exposed and unexposed to SRIs) did not differ in their mean +/- SD Full Scale IQs (103 +/- 13 vs 106 +/- 12; P = .30; 95% CI, 7.06 to 2.21) or rates of problematic behaviors. Significant predictor of children's intelligence was maternal IQ (P = .043, beta = 0.306). Severity of maternal depression was a significant predictor of Child Behavior Checklist Internalizing (P = .019, beta = 0.366), Externalizing (P = .003, beta = 0.457), and Total scores (P = .001, beta = 0.494). Drug doses and durations of exposure during pregnancy did not predict any outcomes of interest in the exposed siblings. CONCLUSIONS: SRI antidepressants were not found to be neurotoxic. Maternal depression may risk the child's future psychopathology. The sibling design in behavioral teratology aids in separating the effects of maternal depression from those of SRIs, providing stronger evidence in clinical decision making. PMID- 26231012 TI - Understanding relative risk, odds ratio, and related terms: as simple as it can get. AB - Risk, and related measures of effect size (for categorical outcomes) such as relative risks and odds ratios, are frequently presented in research articles. Not all readers know how these statistics are derived and interpreted, nor are all readers aware of their strengths and limitations. This article examines several measures, including absolute risk, attributable risk, attributable risk percent, population attributable risk percent, relative risk, odds, odds ratio, and others. The concept and method of calculation are explained for each of these in simple terms and with the help of examples. The interpretation of each is presented in plain English rather than in technical language. Clinically useful notes are provided, wherever necessary. PMID- 26231011 TI - Long-chain polyunsaturated fatty acid status during pregnancy and maternal mental health in pregnancy and the postpartum period: results from the GUSTO study. AB - OBJECTIVE: Studies have demonstrated a relationship between lower omega-3 long chain polyunsaturated fatty acid (LC-PUFA) status and anxiety and depression. It is uncertain whether similar associations occur in pregnant women, when anxiety and depression could have long-term effects on the offspring. We examined the associations between plasma LC-PUFA status during pregnancy and perinatal mental health. METHOD: At 26-28 weeks' gestation, plasma LC-PUFAs were measured in mothers of the Growing Up in Singapore Toward healthy Outcomes (GUSTO) mother offspring cohort study, who were recruited between June 2009 and September 2010. Maternal symptoms of anxiety and depression were assessed with the State-Trait Anxiety Inventory (STAI) and Edinburgh Postnatal Depression Scale (EPDS) during the same period and at 3 months' postpartum. The STAI-state subscale was used as a continuous measure of current anxiety, while EPDS scores >= 15 during pregnancy or >= 13 postpartum were indicative of symptoms of probable depression. RESULTS: In adjusted regression analyses (n = 698), lower plasma total omega-3 PUFA concentrations (beta = -6.49 STAI-state subscale scores/unit increase of omega-3 fatty acid; 95% CI, -11.90 to -1.08) and higher plasma omega-6:omega-3 PUFA ratios (beta = 6.58 scores/unit increase of fatty acid ratio; 95% CI, 1.19 to 12.66), specifically higher arachidonic acid (AA):docosahexaenoic acid, AA:eicosapentaenoic acid, and AA:docosapentaenoic acid ratios, were associated with increased antenatal anxiety (P < .05 for all), but not postpartum anxiety. There was no association between plasma PUFAs and perinatal probable depression. CONCLUSIONS: No association was found with probable depression in pregnancy or postpartum. Lower plasma omega-3 fatty acids and higher omega-6:omega-3 fatty acid ratios were associated with higher antenatal anxiety, but not postpartum anxiety. Replication in other studies is needed to confirm the findings and determine the direction of causality. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01174875. PMID- 26231013 TI - Clinical use of the DSM categorical diagnostic system during the mental health intake session. AB - OBJECTIVE: The primary purpose of diagnostic systems is to improve the care of individuals suffering from mental disorders. Yet, few studies have explored the clinical use of the DSM. Here, we investigated clinicians' methods of obtaining and using diagnostic information during the mental health intake session. We examined the specific diagnostic information collected in usual care using unstructured interviews and the way this information was applied to make diagnostic decisions within naturalistic settings. We compared these decisions to diagnoses made using independent structured diagnostic interviews that served as the gold standard for psychiatric diagnosis. Finally, we examined ways to improve diagnostic efficiency by identifying the best probes for the diagnosis of major depressive disorder (MDD) in naturalistic settings. METHOD: A total of 122 intake sessions in 4 community mental health clinics in Israel were audiotaped. Data were collected from October 2012 to April 2013. Immediately following the intake, clinicians listed the service user's diagnoses according to the DSM-IV while the service user completed a structured diagnostic interview with an independent interviewer. Recorded intake sessions were coded by independent clinicians using an information checklist. RESULTS: Overall, clinicians tended to underuse the DSM, not collecting sufficient information to establish a correct diagnosis for most disorders. Accuracy of diagnostic decisions for MDD improved when only 2 screener items (depressed mood and diminished interest or pleasure) were assessed, compared to assessing 5 or more criteria as required by DSM-IV (diagnostic odds ratios = 9.44 and 3.85, respectively). CONCLUSION: The problem of missing diagnostic information may underlie the poor reliability of the clinical diagnostic decision process. Systematically evaluating clinicians' assessment process in regular care can help identify the best probes to use in clinical practice to increase diagnostic efficiency. PMID- 26231014 TI - Neuropsychiatric symptoms and expenditure on complementary and alternative medicine. AB - OBJECTIVE: Neuropsychiatric symptoms affect 37% of US adults. These symptoms are often refractory to standard therapies, and patients may consequently opt for complementary and alternative medicine therapies (CAM). We sought to determine the demand for CAM by those with neuropsychiatric symptoms compared to those without neuropsychiatric symptoms as measured by out-of-pocket expenditure. METHOD: We compared CAM expenditure between US adults with and without neuropsychiatric symptoms (n = 23,393) using the 2007 National Health Interview Survey. Symptoms included depression, anxiety, insomnia, attention deficits, headaches, excessive sleepiness, and memory loss. CAM was defined per guidelines from the National Institutes of Health as mind-body therapies, biological therapies, manipulation therapies, or alternative medical systems. Expenditure on CAM by those without neuropsychiatric symptoms was compared to those with neuropsychiatric symptoms. RESULTS: Of the adults surveyed, 37% had >= 1 neuropsychiatric symptom and spent $14.8 billion out-of-pocket on CAM. Those with >= 1 neuropsychiatric symptom were more likely than those without neuropsychiatric symptoms to spend on CAM (27.4% vs 20.3%, P < .001). Likelihood to spend on CAM increased with number of symptoms (27.2% with >= 3 symptoms, P < .001). After adjustment was made for confounders using logistic regression, those with >= 1 neuropsychiatric symptom remained more likely to spend on CAM (odds ratio [OR] = 1.34; 95% CI, 1.22-1.48), and the likelihood increased to 1.55 (95% CI, 1.34-1.79) for >= 3 symptoms. Anxiety (OR = 1.40 [95% CI, 1.22-1.60]) and excessive sleepiness (OR = 1.36 [95% CI, 1.21-1.54]) were the most closely associated with CAM expenditure. CONCLUSIONS: Those with >= 1 neuropsychiatric symptom had disproportionately higher demand for CAM than those without symptoms. Research regarding safety, efficacy, and cost-effectiveness of CAM is limited; therefore, future research should evaluate these issues given the tremendous demand for these treatments. PMID- 26231015 TI - Antidepressant use and risk of recurrent stroke: a population-based nested case control study. AB - OBJECTIVE: Antidepressants may carry an increased risk for incident stroke, but there is little safety evidence regarding poststroke antidepressant use. This study aimed to examine whether antidepressants are associated with an increased risk of stroke recurrence. METHOD: A population-based nested case-control study was conducted analyzing the Taiwan universal health care claims database from January 1, 2000, to December 31, 2008. We followed up 19,825 patients who survived a first admission for stroke at the age of >= 18 years, among which 3,536 hospitalized cases with stroke recurrence (ICD-9-CM codes 430.xx-437.xx) were identified and individually matched to 6,679 randomly-selected controls. Multivariate conditional logistic regression models were used to characterize the risk associated with antidepressant use. RESULTS: The study cohort had a mean age of 66 years and was followed up for a median of 2.9 person-years. Use of any tricyclic antidepressants (TCAs) was associated with a 1.41-fold (95% CI, 1.19 1.67) increased risk of stroke recurrence, whereas any use of selective serotonin reuptake inhibitors (SSRIs) or other antidepressants showed no association. Stopping TCAs for 1-30 days was associated with a 1.87-fold (95% CI, 1.22-2.86) increased risk of stroke recurrence, and the risk was attenuated for a longer discontinuation. The stroke risk associated with TCA use was not present in a dose-dependent or duration-dependent manner. CONCLUSIONS: Use of TCAs, but not SSRIs or other antidepressants, was associated with an increased risk of stroke recurrence. The risk is particularly elevated with abrupt cessation of TCA therapy. Health care professionals should be vigilant to that risk during TCA therapy in poststroke patients. PMID- 26231016 TI - Patients' preference for complementary and alternative medicine presents challenges for research. PMID- 26231017 TI - Does the adequacy of clinicians' diagnostic practice in routine clinical settings matter? PMID- 26231018 TI - Correction. Further Evidence for Robust Familiality of Pediatric Bipolar I Disorder: Results From a Very Large Controlled Family Study of Pediatric Bipolar I Disorder and a Meta-Analysis PMID- 26231019 TI - A case of psychosis associated with Pai You Guo slimming capsules containing sibutramine. PMID- 26231020 TI - Neuroanatomy and physiology of cognition. AB - Research into the neuroanatomy and physiology of cognition is a growing field with applications for the treatment of major depressive disorder. The most common cognitive impairments in people with depression are related to executive function, memory, attention, and processing speed along with negative bias. Based on data from improved imaging technology, many cognitive functions once assumed to be localized in specific areas of the brain are now thought to result from deficits in 3 key networks (the central executive network, the salience network, and the default mode network) and their interactions with each other and other brain areas. New discoveries in the connections and functions of brain networks and regions may provide novel treatment targets for cognitive symptoms in major depressive disorder. PMID- 26231021 TI - Impact of untreated major depressive disorder on cognition and daily function. AB - Cognitive symptoms are an emerging clinical focus in patients with major depressive disorder. Deficits in executive function, memory, attention, and processing speed, as well as negative cognitive bias, can contribute to low mood symptoms and reduced occupational and social functioning. Both patient reports and objective measures demonstrate that cognitive symptoms are common in patients with depression. Cognitive dysfunction may be present even before the first depressive episode and may remain after mood symptoms have remitted. Clinicians must assess cognitive symptoms in their patients with major depressive disorder, monitor symptoms throughout the course of the disorder and after remission, and understand how these symptoms affect daily function. PMID- 26231022 TI - Identifying the barriers to quality. AB - The Mental Health Quality Forum, a 2-meeting multidisciplinary panel, was held in March and June 2013 to identify problems and opportunities in the management of serious mental illness. In the first meeting, participants from a range of mental health care-related backgrounds identified components of quality care and the key issues that cause delivery of that care to be suboptimal. PMID- 26231023 TI - Guiding development of pilot projects to drive quality improvement. AB - The Mental Health Quality Forum, a 2-meeting multidisciplinary panel of 13 participants, was held in March and June 2013 to identify problems and opportunities in the management of serious mental illness. In the second meeting, participants reconvened to review issues identified at the first meeting, agree to principles that will guide solution development, and create a blueprint for pilots across 3 critical areas. They worked in 3 "ecosystem" groups to simulate the tension between real-world stakeholders in serious mental illness care. PMID- 26231024 TI - What adversely affects the unborn--psychotropic drugs or maternal morbidity? PMID- 26231025 TI - Childhood adversity and depression. PMID- 26231026 TI - A comprehensive approach to tobacco cessation for the homeless. PMID- 26231027 TI - Smoking cessation in homeless veterans. PMID- 26231028 TI - Desired and Undesired Effects of Energy Labels--An Eye-Tracking Study. AB - Saving energy is an important pillar for the mitigation of climate change. Electric devices (e.g., freezer and television) are an important player in the residential sector in the final demand for energy. Consumers' purchase decisions are therefore crucial to successfully reach the energy-efficiency goals. Putting energy labels on products is often considered an adequate way of empowering consumers to make informed purchase decisions. Consequently, this approach should contribute to reducing overall energy consumption. The effectiveness of its measurement depends on consumers' use and interpretation of the information provided. Despite advances in energy efficiency and a mandatory labeling policy, final energy consumption per capita is in many countries still increasing. This paper provides a systematic analysis of consumers' reactions to one of the most widely used eco-labels, the European Union (EU) energy label, by using eye tracking methodology as an objective measurement. The study's results partially support the EU's mandatory policy, showing that the energy label triggers attention toward energy information in general. However, the energy label's effect on consumers' actual product choices seems to be rather low. The study's results show that the currently used presentation format on the label is insufficient. The findings suggest that it does not facilitate the integration of energy-related information. Furthermore, the current format can attract consumers to focus more on energy-efficiency information, leading them to disregard information about actual energy consumption. As a result, the final energy consumption may increase because excellent ratings on energy efficiency (e.g., A++) do not automatically imply little consumption. Finally, implications for policymakers and suggestions for further research are discussed. PMID- 26231029 TI - The Importance of Landscape Elements for Bat Activity and Species Richness in Agricultural Areas. AB - Landscape heterogeneity is regarded as a key factor for maintaining biodiversity and ecosystem function in production landscapes. We investigated whether grassland sites at close vicinity to forested areas are more frequently used by bats. Considering that bats are important consumers of herbivorous insects, including agricultural pest, this is important for sustainable land management. Bat activity and species richness were assessed using repeated monitoring from May to September in 2010 with acoustic monitoring surveys on 50 grassland sites in the Biosphere Reserve Schorfheide-Chorin (North-East Germany). Using spatial analysis (GIS), we measured the closest distance of each grassland site to potentially connecting landscape elements (e.g., trees, linear vegetation, groves, running and standing water). In addition, we assessed the distance to and the percent land cover of forest remnants and urban areas in a 200 m buffer around the recording sites to address differences in the local landscape setting. Species richness and bat activity increased significantly with higher forest land cover in the 200 m buffer and at smaller distance to forested areas. Moreover, species richness increased in proximity to tree groves. Larger amount of forest land cover and smaller distance to forest also resulted in a higher activity of bats on grassland sites in the beginning of the year during May, June and July. Landscape elements near grassland sites also influenced species composition of bats and species richness of functional groups (open, edge and narrow space foragers). Our results highlight the importance of forested areas, and suggest that agricultural grasslands that are closer to forest remnants might be better buffered against outbreaks of agricultural pest insects due to higher species richness and higher bat activity. Furthermore, our data reveals that even for highly mobile species such as bats, a very dense network of connecting elements within the landscape is beneficial to promote activity in open areas and thus assure vital ecosystem function in agricultural landscapes. PMID- 26231030 TI - Effect of Agricultural Amendments on Cajanus cajan (Pigeon Pea) and Its Rhizospheric Microbial Communities--A Comparison between Chemical Fertilizers and Bioinoculants. AB - Inoculation of leguminous seeds with bioinoculants has been practiced in agriculture for decades to ameliorate grain yield by enhanced growth parameters and soil fertility. However, effective enhancement of plant growth parameters results not only from the direct effects these bioinoculants impose on them but also from their non-target effects. The ability of bioinoculants to reduce the application of chemicals for obtaining optimum yield of legume appears to be of great ecological and economic importance. In the present study, we compared the influence of seed inoculation of Cajanus cajan with a microbial consortium, comprising Bacillus megaterium, Pseudomonas fluorescens and Trichoderma harzianum, with that of application of chemical fertilizers on plant's growth parameters and its rhizospheric microbial communities. Real-time PCR assay was carried out to target the structure (16S rRNA) and function (nitrogen cycle) of rhizospheric microbiota, using both DNA and RNA as markers. The results showed that the microbial consortium was the most efficient in increasing grain yield (2.5-fold), even better than the recommended dose of chemical fertilizers (by 1.2 fold) and showed enhancement in nifH and amoA transcripts by 2.7- and 2.0-fold, respectively. No adverse effects of bioinoculants' application were observed over the rhizospheric microbial community, rendering the consortium to be safe for release in agricultural fields. PMID- 26231031 TI - Nanoelectroablation of Murine Tumors Triggers a CD8-Dependent Inhibition of Secondary Tumor Growth. AB - We have used both a rat orthotopic hepatocellular carcinoma model and a mouse allograft tumor model to study liver tumor ablation with nanosecond pulsed electric fields (nsPEF). We confirm that nsPEF treatment triggers apoptosis in rat liver tumor cells as indicated by the appearance of cleaved caspase 3 and 9 within two hours after treatment. Furthermore we provide evidence that nsPEF treatment leads to the translocation of calreticulin (CRT) to the cell surface which is considered a damage-associated molecular pattern indicative of immunogenic cell death. We provide direct evidence that nanoelectroablation triggers a CD8-dependent inhibition of secondary tumor growth by comparing the growth rate of secondary orthotopic liver tumors in nsPEF-treated rats with that in nsPEF-treated rats depleted of CD8+ cytotoxic T-cells. The growth of these secondary tumors was severely inhibited as compared to tumor growth in CD8 depleated rats, with their average size only 3% of the primary tumor size after the same one-week growth period. In contrast, when we depleted CD8+ T-cells the second tumor grew more robustly, reaching 54% of the size of the first tumor. In addition, we demonstrate with immunohistochemistry that CD8+ T-cells are highly enriched in the secondary tumors exhibiting slow growth. We also showed that vaccinating mice with nsPEF-treated isogenic tumor cells stimulates an immune response that inhibits the growth of secondary tumors in a CD8+-dependent manner. We conclude that nanoelectroablation triggers the production of CD8+ cytotoxic T cells resulting in the inhibition of secondary tumor growth. PMID- 26231032 TI - 5-HTTLPR Genotype Moderates the Effects of Past Ecstasy Use on Verbal Memory Performance in Adolescent and Emerging Adults: A Pilot Study. AB - OBJECTIVE: Ecstasy use is associated with memory deficits. Serotonin transporter gene (5-HTTLPR) polymorphisms have been linked with memory function in healthy samples. The present pilot study investigated the influence of 5-HTTLPR polymorphisms on memory performance in ecstasy users, marijuana-using controls, and non-drug-using controls, after a minimum of 7 days of abstinence. METHOD: Data were collected from 116 young adults (18-25 years-old), including 45 controls, 42 marijuana users, and 29 ecstasy users, and were balanced for 5 HTTLPR genotype. Participants were abstinent seven days prior to completing memory testing. Three MANCOVAs and one ANCOVA were run to examine whether drug group, 5-HTTLPR genotype, and their interactions predicted verbal and visual memory after controlling for gender, past year alcohol use, other drug use, and nicotine cotinine levels. RESULTS: MANCOVA and ANCOVA analysis revealed a significant interaction between drug group and genotype (p = .03) such that ecstasy users with the L/L genotype performed significantly worse on CVLT-2 total recall (p = .05), short (p = .008) and long delay free recall (p = .01), and recognition (p = .006), with the reverse pattern found in controls. Ecstasy did not significantly predict visual memory. 5-HTTLPR genotype significantly predicted memory for faces (p = .02); short allele carriers performed better than those with L/L genotype. CONCLUSIONS: 5-HTTLPR genotype moderated the effects of ecstasy on verbal memory, with L/L carriers performing worse compared to controls. Future research should continue to examine individual differences in ecstasy's impact on neurocognitive performance as well as relationships with neuronal structure. Additional screening and prevention efforts focused on adolescents and emerging adults are necessary to prevent ecstasy consumption. PMID- 26231033 TI - The Prevalence of Clinically Significant Ischemia in Patients Undergoing Percutaneous Coronary Intervention: A Report from the Multicenter Registry. AB - BACKGROUND: Myocardial perfusion scintigraphy (MPS) plays an important role in the evaluation and quantification of myocardial ischemia, and those with significant ischemia (SI) benefit most from revascularization procedures. This study aimed to identify the clinical factors and anatomical features associated with SI in patients with stable ischemic heart disease (SIHD). METHODS AND RESULTS: Data were analyzed from 4197 SIHD patients undergoing percutaneous coronary intervention (PCI). Ischemia was based on MPS findings prior to PCI, with SI defined as an ischemic region of more than 10% of the total left ventricular area. Logistic regression analysis was performed to identify any clinical factors associated with SI. MPS was used to evaluate 1070 (25.5%) patients pre-procedurally. Patients with a history of heart failure, stroke, or anginal symptoms with Canadian Cardiovascular Society class 2 or more were more likely to have SI (odds ratio [OR] 1.63, p = 0.025, OR: 1.85, p = 0.009, and OR: 1.49, p = 0.003, respectively). When angiographic variables were considered, a proximal left anterior descending artery (pLAD) lesion was the sole factor associated with SI (OR: 1.45, p = 0.012). Importantly, those with SI had more in hospital complications (p = 0.006), most notably post-PCI infarcts (p = 0.008). CONCLUSIONS: Patients' background data, such as stronger anginal symptoms or a pLAD lesion, were associated with SI. Patients with SI must be treated with PCI to improve their long-term prognosis; however, procedure-related complications happen more frequently in SI patients than in non-SI patients. Physicians must give their full attention when performing the PCI procedure in SI patients to minimize their complication rate. PMID- 26231034 TI - Circulating CCR7+ICOS+ Memory T Follicular Helper Cells in Patients with Multiple Sclerosis. AB - OBJECTIVE: This study is aimed at examining the potential roles of circulating memory T follicular helper (Tfh) cells in patients with multiple sclerosis (MS). METHODS: The numbers of different subsets of circulating memory Tfh cells in 25 patients with relapsed MS before and after treatment as well as 14 healthy controls (HC) were examined by flow cytometry. The levels of plasma IL-21 in all patients and cerebrospinal fluid (CSF) IL-21 in some MS patients and controls with non-inflammatory neuronal diseases (NND) were measured by ELISA. RESULTS: In comparison with that in the HC, the numbers of circulating CD3+CD4+CXCR5+CD45RA-, ICOS+, CCR7+ and CCR7+ICOS+ memory Tfh cells and the levels of plasma IL-21 significantly increased in MS patients, but significantly decreased in the patients with complete remission (CR). The levels of CSF IL-21 were significantly higher in the MS patients than that in the NND patients. The numbers of CCR7+ICOS+ memory Tfh cells were positively correlated with the EDSS scores, the levels of plasma and CSF IL-21, IgG, MBP-Ab or MOG-Ab. CONCLUSIONS: Our findings indicated that circulating memory Tfh cells, especially CCR7+ICOS+ memory Tfh cells, may be associated with the relapse of MS and may serve as a new therapeutic target. PMID- 26231035 TI - HCV NS5A Up-Regulates COX-2 Expression via IL-8-Mediated Activation of the ERK/JNK MAPK Pathway. AB - Chronic hepatitis C virus (HCV) infection leads to intrahepatic inflammation and liver cell injury, which are considered a risk factor for virus-associated hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. Inflammatory cytokines are critical components of the immune system and influence cellular signaling, and genetic imbalances. In this study, we found that cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) were significantly induced by HCV infection and HCV NS5A expression, and induction of COX-2 correlated with HCV-induced IL-8 production. We also found that the ERK and JNK signaling pathways were involved in the regulation of IL-8-mediated COX-2 induction in response to HCV infection. Using a promoter-linked reporter assay, we identified that the C/EBP regulatory element within the COX-2 promoter was the dominant factor responsible for the induction of COX-2 by HCV. Silencing C/EBP attenuated HCV-induced COX-2 expression. Our results revealed that HCV-induced inflammation promotes viral replication, providing new insights into the involvement of IL-8-mediated COX-2 induction in HCV replication. PMID- 26231036 TI - Enhanced Bacterial alpha(2,6)-Sialyltransferase Reaction through an Inhibition of Its Inherent Sialidase Activity by Dephosphorylation of Cytidine-5' Monophosphate. AB - Bacterial alpha(2,6)-sialyltransferases (STs) from Photobacterium damsela, Photobacterium sp. JT-ISH-224, and P. leiognathi JT-SHIZ-145 were recombinantly expressed in Escherichia coli and their ST activities were compared directly using a galactosylated bi-antennary N-glycan as an acceptor substrate. In all ST reactions, there was an increase of sialylated glycans at shorter reaction times and later a decrease in prolonged reactions, which is related with the inherent sialidase activities of bacterial STs. These sialidase activities are greatly increased by free cytidine monophosphate (CMP) generated from a donor substrate CMP-N-acetylneuraminic acid (CMP-Neu5Ac) during the ST reactions. The decrease of sialylated glycans in prolonged ST reaction was prevented through an inhibition of sialidase activity by simple treatment of alkaline phosphatase (AP), which dephosphorylates CMP to cytidine. Through supplemental additions of AP and CMP Neu5Ac to the reaction using the recombinant alpha(2,6)-ST from P. leiognathi JT SHIZ-145 (P145-ST), the content of bi-sialylated N-glycan increased up to ~98% without any decrease in prolonged reactions. This optimized P145-ST reaction was applied successfully for alpha(2,6)-sialylation of asialofetuin, and this resulted in a large increase in the populations of multi-sialylated N-glycans compared with the reaction without addition of AP and CMP-Neu5Ac. These results suggest that the optimized reaction using the recombinant P145-ST readily expressed from E. coli has a promise for economic glycan synthesis and glyco conjugate remodeling. PMID- 26231037 TI - Hepatocellular carcinoma associated microRNA expression signature: integrated bioinformatics analysis, experimental validation and clinical significance. AB - microRNA (miRNA) expression profiles varied greatly among current studies due to different technological platforms and small sample size. Systematic and integrative analysis of published datesets that compared the miRNA expression profiles between hepatocellular carcinoma (HCC) tissue and paired adjacent noncancerous liver tissue was performed to determine candidate HCC associated miRNAs. Moreover, we further validated the confirmed miRNAs in a clinical setting using qRT-PCR and Tumor Cancer Genome Atlas (TCGA) dataset. A miRNA integrated signature of 5 upregulated and 8 downregulated miRNAs was identified from 26 published datesets in HCC using robust rank aggregation method. qRT-PCR demonstrated that miR-93-5p, miR-224-5p, miR-221-3p and miR-21-5p was increased, whereas the expression of miR-214-3p, miR-199a-3p, miR-195-5p, miR-150-5p and miR 145-5p was decreased in the HCC tissues, which was also validated on TCGA dataset. A miRNA based score using LASSO regression model provided a high accuracy for identifying HCC tissue (AUC = 0.982): HCC risk score = 0.180E_miR 221 + 0.0262E_miR-21 - 0.007E_miR-223 - 0.185E_miR-130a. E_miR-n = Log 2 (expression of microRNA n). Furthermore, expression of 5 miRNAs (miR-222, miR 221, miR-21 miR-214 and miR-130a) correlated with pathological tumor grade. Cox regression analysis showed that miR-21 was related with 3-year survival (hazard ratio [HR]: 1.509, 95%CI: 1.079-2.112, P = 0.016) and 5-year survival (HR: 1.416, 95%CI: 1.057-1.897, P = 0.020). However, none of the deregulated miRNAs was related with microscopic vascular invasion. This study provides a basis for further clinical application of miRNAs in HCC. PMID- 26231040 TI - Registered report: Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. AB - The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered report describes the proposed replication plan of key experiments from 'Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha ketoglutarate-dependent dioxygenases' by Xu and colleagues, published in Cancer Cell in 2011 (Xu et al., 2011). The key experiments being replicated include Supplemental Figure 3I, which demonstrates that transfection with mutant forms of IDH1 increases levels of 2-hydroxyglutarate (2-HG), Figures 3A and 8A, which demonstrate changes in histone methylation after treatment with 2-HG, and Figures 3D and 7B, which show that mutant IDH1 can effect the same changes as treatment with excess 2-HG. The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife. PMID- 26231038 TI - CRNDE affects the malignant biological characteristics of human glioma stem cells by negatively regulating miR-186. AB - The long non-coding RNA Colorectal neoplasia differentially expressed (CRNDE) is a novel gene that activated early in colorectal neoplasia, but it is also up regulated in many other solid tumors. Herein, the function and underlying mechanism of CRNDE in regulating glioma stem cells (GSCs) were investigated. We found that CRNDE expression was up-regulated while miR-186 expression was down regulated in GSCs. Overexpression of CRNDE could promote the cellular proliferation, migration, invasion and inhibit the apoptosis in GSCs. Overexpression of miR-186 exerted functions of inhibiting the proliferation, migration and invasion of GSCs and promoting apoptosis. And CRNDE decreased the expression levels of XIAP and PAK7 by binding to miR-186 and negatively regulating it. In addition, miR-186 binded to XIAP and PAK7 3'UTR region, and decrease the expression of them, thus regulating the expression levels of downstream target proteins such as caspase 3, BAD, cyclin D1 and MARK2. The in vivo effect of CRNDE and miR-186 showed that the tumor formation rate was minimum in tumor-bearing nude mice with the knockdown of CRNDE and the overexpression of miR-186. In conclusion, CRNDE played an oncogenic role of GSCs through the negative regulation of miR-186. Both CRNDE and miR-186 could be regarded as potential targets in the glioma therapy. PMID- 26231039 TI - Contact-dependent carcinoma aggregate dispersion by M2a macrophages via ICAM-1 and beta2 integrin interactions. AB - Tumor-associated macrophages (TAMs) can constitute up to 50% of the tumor mass and have strong implications in tumor progression and metastasis. Macrophages are plastic and can polarize to various subtypes that differ in terms of surface receptor expression as well as cytokine and chemokine production and effector function. Conventionally, macrophages are grouped into two major subtypes: the classically activated M1 macrophages and the alternatively activated M2 macrophages. M1 macrophages are pro-inflammatory, promote T helper (Th) 1 responses, and show tumoricidal activity, whereas M2 macrophages contribute to tissue repair and promote Th2 responses. Herein, we present a microfluidic system integrating tumor cell aggregates and subtypes of human monocyte-derived macrophages in a three-dimensional hydrogel scaffold, in close co-culture with an endothelial monolayer to create an in vitro tumor microenvironment. This platform was utilized to study the role of individual subtypes of macrophages (M0, M1, M2a, M2b and M2c) in human lung adenocarcinoma (A549) aggregate dispersion, as a representation of epithelial-mesenchymal transition (EMT). A significant difference was observed when M2a macrophages were in direct contact with or separated from A549 aggregates, suggesting a possible mechanism for proximity induced, contact-dependent dissemination via ICAM-1 and integrin beta2 interactions. Indeed, M2a macrophages tended to infiltrate and release cells from carcinoma cell aggregates. These findings may help in the development of immunotherapies based on enhancing the tumor-suppressive properties of TAMs. PMID- 26231041 TI - Resection is responsible for loss of transcription around a double-strand break in Saccharomyces cerevisiae. AB - Emerging evidence indicate that the mammalian checkpoint kinase ATM induces transcriptional silencing in cis to DNA double-strand breaks (DSBs) through a poorly understood mechanism. Here we show that in Saccharomyces cerevisiae a single DSB causes transcriptional inhibition of proximal genes independently of Tel1/ATM and Mec1/ATR. Since the DSB ends undergo nucleolytic degradation (resection) of their 5'-ending strands, we investigated the contribution of resection in this DSB-induced transcriptional inhibition. We discovered that resection-defective mutants fail to stop transcription around a DSB, and the extent of this failure correlates with the severity of the resection defect. Furthermore, Rad9 and generation of gammaH2A reduce this DSB-induced transcriptional inhibition by counteracting DSB resection. Therefore, the conversion of the DSB ends from double-stranded to single-stranded DNA, which is necessary to initiate DSB repair by homologous recombination, is responsible for loss of transcription around a DSB in S. cerevisiae. PMID- 26231042 TI - Registered report: the microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. AB - The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altimetric scores (Errington et al., 2014). This Registered report describes the proposed replication plan of key experiments from 'The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44' by Liu and colleagues published in Nature Medicine in 2011 (Liu et al., 2011). Liu and colleagues first demonstrated that miR-34a levels were reduced in CD44+ prostate cancer cells (Figure 1B). They then showed that xenograft tumors from cells expressing exogenous miR-34a were smaller in size than control tumors (Supplemental Figure 5C). Tumors with exogenous miR-34a showed reduced levels of CD44 expression (Figure 4A), and mutation of two putative miR-34a binding sites in the CD33 3' UTR partially abrogated signal repression in a luciferase assay (Figure 4D). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife. PMID- 26231044 TI - Return to Pitching After Tommy John Surgery: Response. PMID- 26231043 TI - The presence of wild type p53 in hematological cancers improves the efficacy of combinational therapy targeting metabolism. AB - Manipulation of metabolic pathways in hematological cancers has therapeutic potential. Here, we determined the molecular mechanism of action of the metabolic modulator dichloroacetate (DCA) in leukemic cells. We found that DCA induces the AMP-activated protein kinase (AMPK)/p53 pathway with increased efficacy in tumors expressing wild type (wt p53). Clinically relevant, low concentrations of doxorubicin synergize in vitro and in vivo with DCA to further enhance p53 activation and to block tumor progression. Leukemia cell lines and primary leukemic cells containing mutant p53 are resistant to the above-described combination approach. However, DCA synergized with the Hsp90 inhibitor 17-AAG to specifically eliminate these cells. Our studies strongly indicate that depending on the p53 status, different combination therapies would provide better treatment with decreased side effects in hematological cancers. PMID- 26231046 TI - Dynamic contrast enhanced ultrasound for therapy monitoring. AB - Quantitative imaging is a crucial component of the assessment of therapies that target the vasculature of angiogenic or inflamed tissue. Dynamic contrast enhanced ultrasound (DCE-US) using microbubble contrast offers the advantages of being sensitive to perfusion, non-invasive, cost effective and well suited to repeated use at the bedside. Uniquely, it employs an agent that is truly intravascular. This papers reviews the principles and methodology of DCE-US, especially as applied to anti-angiogenic cancer therapies. Reproducibility is an important attribute of such a monitoring method: results are discussed. More recent technical advances in parametric and 3D DCE-US imaging are also summarised and illustrated. PMID- 26231045 TI - Diffusion-weighted MR imaging using FASE sequence for 3T MR system: Preliminary comparison of capability for N-stage assessment by means of diffusion-weighted MR imaging using EPI sequence, STIR FASE imaging and FDG PET/CT for non-small cell lung cancer patients. AB - PURPOSE: To prospectively compare the diagnostic capability of diffusion-weighted MR imaging obtained with fast advantage spin-echo sequence (FASE-DWI) and echo planar imaging sequence (EPI-DWI), short inversion time inversion recovery fast advanced spin-echo (STIR FASE) imaging and FDG PET/CT for N-stage assessment of non-small cell carcinoma (NSCLC) patients. MATERIALS AND METHODS: 95 consecutive operable NSCLC patients underwent STIR FASE imaging, FASE-DWI and EPI-DWI with a 3T system, integrated PET/CT, surgical treatment and pathological and follow-up examinations. Probability of lymph node metastasis was visually assessed using a 5-point visual scoring system. ROC analyses were used to compare diagnostic capability of all methods, while their diagnostic performance was also compared by means of McNemar's test on a per node basis. Finally, McNemar's test was also used for statistical comparison of accuracy of N-stage assessment. RESULTS: Areas under the curve (Azs) for STIR FASE imaging (Az=0.95) and FASE-DWI (Az=0.92) were significantly larger than those for EPI-DWI (Az=0.78; p<0.0001 for STIR FSE imaging and FASE-DWI) and PET/CT (Az=0.85; p=0.0001 for STIR FSE imaging, p=0.03 for FASE-DWI) on a per node basis analysis. Accuracy of N-stage assessment using STIR FASE imaging (84.2% [80/95]) and FASE-DWI (83.2% [79/95]) was significantly higher than that using EPI-DWI (76.8% [73/95]; p=0.02 for STIR FASE imaging, p=0.03 for FASE-DWI) and PET/CT (73.7% [70/95]; p=0.002 for STIR FSE imaging, p=0.004 for FASE-DWI). CONCLUSION: Qualitative N-stage assessments of NSCLC patients obtained with FASE-DWI as well as STIR FASE imaging are more sensitive and/or accurate than those obtained with EPI-DWI and FDG PET/CT. PMID- 26231047 TI - Obatoclax is a direct and potent antagonist of membrane-restricted Mcl-1 and is synthetic lethal with treatment that induces Bim. AB - BACKGROUND: Obatoclax is a clinical stage drug candidate that has been proposed to target and inhibit prosurvival members of the Bcl-2 family, and thereby contribute to cancer cell lethality. The insolubility of this compound, however, has precluded the use of many classical drug-target interaction assays for its study. Thus, a direct demonstration of the proposed mechanism of action, and preferences for individual Bcl-2 family members, remain to be established. METHODS: Employing modified proteins and lipids, we recapitulated the constitutive association and topology of mitochondrial outer membrane Mcl-1 and Bak in synthetic large unilamellar liposomes, and measured bakdependent bilayer permeability. Additionally, cellular and tumor models, dependent on Mcl-1 for survival, were employed. RESULTS: We show that regulation of bilayer permeabilization by the tBid - Mcl-1 - Bak axis closely resemblesthe tBid - Bcl XL - Bax model. Obatoclax rapidly and completely partitioned into liposomal lipid but also rapidly exchanged between liposome particles. In this system, obatoclax was found to be a direct and potent antagonist of liposome-bound Mcl-1 but not of liposome-bound Bcl-XL, and did not directly influence Bak. A 2.5 molar excess of obatoclax relative to Mcl-1 overcame Mcl-1-mediated inhibition of tBid-Bak activation. Similar results were found for induction of Bak oligomers by Bim. Obatoclax exhibited potent lethality in a cellmodel dependent on Mcl-1 for viability but not in cells dependent on Bcl-XL. Molecular modeling predicts that the 3-methoxy moiety of obatoclax penetrates into the P2 pocket of the BH3 binding site of Mcl-1. A desmethoxy derivative of obatoclax failed to inhibit Mcl 1 in proteoliposomes and did not kill cells whose survival depends on Mcl-1. Systemic treatment of mice bearing Tsc2(+) (/) (-) Em-myc lymphomas (whose cells depend on Mcl-1 for survival) with obatoclax conferred a survival advantage compared to vehicle alone (median 31 days vs 22 days, respectively; p=0.003). In an Akt-lymphoma mouse model, the anti-tumor effects of obatoclax synergized with doxorubicin. Finally, treatment of the multiple myeloma KMS11 cell model (dependent on Mcl-1 for survival) with dexamethasone induced Bim and Bim dependent lethality. As predicted for an Mcl-1 antagonist, obatoclax and dexamethasone were synergistic in this model. CONCLUSIONS: Taken together, these findings indicate that obatoclax is a potent antagonist of membranerestricted Mcl 1. Obatoclax represents an attractive chemical series to generate second generation Mcl-1 inhibitors. PMID- 26231048 TI - Republication of: Elevating the quality of disability and rehabilitation research: Mandatory use of the reporting guidelines. AB - Journal of NeuroEngineering and Rehabilitation advocates the complete and transparent reporting of research and methods, and is pleased to be part of an initiative to mandate the use of reporting guidelines. This Editorial is a republication of a previously published Editorial in Archives of Physical Medicine and Rehabilitation ( http://dx.doi.org/10.1016/j.apmr.2013.12.010 ), and is republished here under the terms of the Creative Commons Attribution NonCommercial-NoDerivs 3.0 License ( http://creativecommons.org/licenses/by-nc nd/3.0/ ). For citation purposes, please use the original publication details: Chan L, Heinemann AW, Roberts J. Elevating the Quality of Disability and Rehabilitation Research: Mandatory use of the Reporting Guidelines. Arch Phys Med Rehabil. 2014;95:415-7. PMID- 26231049 TI - Treatment of a case of emphysematous pyelonephritis that presented with acute abdomen and pneumoperitoneum: a case report. AB - BACKGROUND: Emphysematous pyelonephritis is a severe, life-threatening infection of the renal parenchyma and perinephric tissues. This condition is primarily encountered in patients with diabetes mellitus or ureteral obstruction, and is characterized by the production of intrarenal and perinephric gas. Emphysematous pyelonephritis is associated with a high degree of morbidity and a high mortality rate. CASE PRESENTATION: A 72-year-old woman with a history of diabetes mellitus, hypertension, and renal calculi was referred to our emergency department following 6 days of abdominal pain. She suddenly developed pain in the entire abdomen, and was transferred. Physical examination was a distended abdomen with hypoactive bowel sounds. The tenderness was diffuse, but was most prominent in the right upper abdominal quadrant; moreover, rebound tenderness was noted. Laboratory tests revealed a white blood cell count of 4,480/mm(3), platelet count of 17,000/mm(3), creatinine level of 1.64 mg/dl, and serum glucose level of 603 mg/dl. Abdominal computed tomography indicated the presence of free air in the intraperitoneal cavity and right perirenal space, hydronephrosis of the right kidney, and stones in the right distal ureter. After 1 hour, the vital signs changed and she appeared to become drowsy. Therefore, the patient was transferred to the operation room for laparotomy. On exploration of the abdomen, 1.5 L of pus colored fluid was removed. Although the abdominal viscera and pelvic organs were examined, hollow viscus perforation site could not be observed. Moreover, tissue necrosis and a perforation site were identified at the superior border of the right kidney. Thus, emphysematous pyelonephritis was diagnosed and she underwent right radical nephrectomy. After the surgery, the patient was admitted to the intensive care unit for postoperative management. Follow-up CT performed after 10 days showed fluid collection and hematoma at the nephrectomy site. Hence, percutaneous drainage was performed. Another follow-up computed tomography after 3 weeks indicated that the fluid collection at the nephrectomy site had nearly disappeared. CONCLUSIONS: We believe that cases with free intraperitoneal air should promptly undergo laparotomy to identify the cause of the pneumoperitoneum. Moreover, an immediate nephrectomy may be effective for the treatment of emphysematous pyelonephritis in cases with poor prognostic factors. PMID- 26231050 TI - Current status of Schistosoma mansoni and the factors associated with infection two years following mass drug administration programme among primary school children in Mwea irrigation scheme: A cross-sectional study. AB - BACKGROUND: Schistosomiasis is a major public health problem in Kenya as well as in many other tropical countries and is considered one of the most prevalent diseases in the rural population. Between 2004 and 2009, primary school children in Mwea irrigation scheme were treated for Schistosoma mansoni. In the four year control programme, there was occurrence of light re-infection with S. mansoni. Therefore, the aim of this study was to assess the current prevalence of S. mansoni, infection two years after the withdrawal of mass drug administration (MDA) programme. METHODS: We carried out a cross-sectional study on a population of 387 children attending 3 primary schools located in Mwea irrigation scheme. Children, aged 8-16 years were interviewed and screened for S. mansoni using duplicate Kato-Katz thick smears. Comparisons of prevalence by age group and gender were tested for significance on the basis of the Wald test. Best prediction factors for infection with S. mansoni were selected using forward - stepwise variable selection method. RESULTS: The overall prevalence of S. mansoni was 53.7 %, (95%CI: 49.0-59.0, p-value = 0.000). Male children had higher prevalence of infection, 66.1 % (95%CI: 59.8-73.2, p-value = 0.000) compared to females. The gender (sex) of a child was the only factor reported to be significantly associated with S. mansoni infection, (OR = 1.9, p-value = 0.015, 95%CI: 1.13-3.21). CONCLUSIONS: There was high prevalence of S. mansoni infections in the study area, two years after the withdrawal of MDA programme. We suggest that treatment should be continued in the school children at regular intervals, monitoring and surveillance intensified to ensure interruption of transmission areas. PMID- 26231051 TI - Modeling antecedents of electronic medical record system implementation success in low-resource setting hospitals. AB - BACKGROUND: With the increasing implementation of Electronic Medical Record Systems (EMR) in developing countries, there is a growing need to identify antecedents of EMR success to measure and predict the level of adoption before costly implementation. However, less evidence is available about EMR success in the context of low-resource setting implementations. Therefore, this study aims to fill this gap by examining the constructs and relationships of the widely used DeLone and MacLean (D&M) information system success model to determine whether it can be applied to measure EMR success in those settings. METHODS: A quantitative cross sectional study design using self-administered questionnaires was used to collect data from 384 health professionals working in five governmental hospitals in Ethiopia. The hospitals use a comprehensive EMR system since three years. Descriptive and structural equation modeling methods were applied to describe and validate the extent of relationship of constructs and mediating effects. RESULTS: The findings of the structural equation modeling shows that system quality has significant influence on EMR use (beta = 0.32, P < 0.05) and user satisfaction (beta = 0.53, P < 0.01); information quality has significant influence on EMR use (beta = 0.44, P < 0.05) and user satisfaction (beta = 0.48, P < 0.01) and service quality has strong significant influence on EMR use (beta = 0.36, P < 0.05) and user satisfaction (beta = 0.56, P < 0.01). User satisfaction has significant influence on EMR use (beta = 0.41, P < 0.05) but the effect of EMR use on user satisfaction was not significant. Both EMR use and user satisfaction have significant influence on perceived net-benefit (beta = 0.31, P < 0.01; beta = 0.60, P < 0.01), respectively. Additionally, computer literacy was found to be a mediating factor in the relationship between service quality and EMR use (P < 0.05) as well as user satisfaction (P < 0.01). Among all the constructs, user satisfaction showed the strongest effect on perceived net-benefit of health professionals. CONCLUSION: EMR implementers and managers in developing countries are in urgent need of implementation models to design proper implementation strategies. In this study, the constructs and relationships depicted in the updated D&M model were found to be applicable to assess the success of EMR in low resource settings. Additionally, computer literacy was found to be a mediating factor in EMR use and user satisfaction of health professionals. Hence, EMR implementers and managers in those settings should give priority in improving service quality of the hospitals like technical support and infrastructure; providing continuous basic computer trainings to health professionals; and give attention to the system and information quality of the systems they want to implement. PMID- 26231052 TI - Psychometric properties of the incontinence utility index among patients with idiopathic overactive bladder: data from two multicenter, double-blind, randomized, Phase 3, placebo-controlled clinical trials. AB - BACKGROUND: Overactive bladder is a prevalent and burdensome condition. Generic utility measures may fail to reflect its full impact on patients' health status. The Incontinence Utility Index (IUI) is a community-based preference index derived from the Incontinence Quality of Life Questionnaire (I-QOL) developed to value health states related to urinary symptoms in patients with neurogenic detrusor overactivity. This study assessed the measurement properties of the IUI in patients with idiopathic overactive bladder (OAB). METHODS: Data were used from two clinical trials which recruited patients with OAB whose symptoms were inadequately managed with >= 1 anticholinergic medication. Psychometric evaluation included: Differential Item Functioning (DIF) analysis, concordance between I-QOL and IUI (Intraclass correlation coefficient [ICC], criterion and convergent validity according to relevant patient reported outcomes and clinical variables (Spearman's correlation coefficient, rho), responsiveness, and agreement between utility measures (ICC and Bland-Altman method). RESULTS: A total of 1,105 idiopathic OAB patients were included. Mean age (range) was 60.4 years (18-90), 87.8% (n = 970) were female. DIF was identified in 3 items, none of which are contained in the IUI. ICC (CI95%) was 0.944 (0.936-0.950). Statistically significant differences (p < 0.001) were found in IUI scores for patients improving according to the Treatment Benefit Scale (TBS). Moderate to strong correlations (rho > |0.6|) were found in the expected direction with daily incontinence, urgency episodes and disease-specific domains of King's Health Questionnaire (KHQ). Low to moderate correlations (rho:<|0.6|) were found with Short Form version 2 (SF-12v2) summary components. A large effect size was found for patients reporting improvement (0.98-1.21) or great improvement (1.87-2.56) in the TBS, as well as in patients responding to treatment (1.19-2.40). Across utility measures, directional trends were consistent with OAB symptom profile, however, a lack of agreement in absolute values was observed. CONCLUSIONS: The IUI presents good psychometric properties for valuing the impact of UI-related problems in idiopathic OAB patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00910845 and NCT00910520. PMID- 26231053 TI - Evaluation of Physarum polycephalum plasmodial growth and lipid production using rice bran as a carbon source. AB - BACKGROUND: The myxomycete Physarum polycephalum appears to have remarkable potential as a lipid source for biodiesel production. The present study evaluated the use of rice bran as a carbon source and determined the medium components for optimum growth and lipid production for this organism. RESULTS: Optimization of medium components by response surface methodology showed that rice bran and yeast extract had significant influences on lipid and biomass production. The optimum medium consisted of 37.5 g/L rice bran, 0.79 g/L yeast extract and 12.5 g/L agar, and this yielded 7.5 g/L dry biomass and 0.9 g/L lipid after 5 days. The biomass and lipid production profiles revealed that these parameters increased over time and reached their maximum values (10.5 and 1.26 g/L, respectively) after 7 days. Physarum polycephalum growth decreased on the spent medium but using the latter increased total biomass and lipid concentrations to 14.3 and 1.72 g/L, respectively. CONCLUSIONS: An effective method for inoculum preparation was developed for biomass and lipid production by P. polycephalum on a low-cost medium using rice bran as the main carbon source. These results also demonstrated the feasibility of scaling up and reusing the medium for additional biomass and lipid production. PMID- 26231055 TI - Can patient centered outcomes research improve healthcare? PMID- 26231054 TI - ERG2 and ERG24 Are Required for Normal Vacuolar Physiology as Well as Candida albicans Pathogenicity in a Murine Model of Disseminated but Not Vaginal Candidiasis. AB - Several important classes of antifungal agents, including the azoles, act by blocking ergosterol biosynthesis. It was recently reported that the azoles cause massive disruption of the fungal vacuole in the prevalent human pathogen Candida albicans. This is significant because normal vacuolar function is required to support C. albicans pathogenicity. This study examined the impact of the morpholine antifungals, which inhibit later steps of ergosterol biosynthesis, on C. albicans vacuolar integrity. It was found that overexpression of either the ERG2 or ERG24 gene, encoding C-8 sterol isomerase or C-14 sterol reductase, respectively, suppressed C. albicans sensitivity to the morpholines. In addition, both erg2Delta/Delta and erg24Delta/Delta mutants were hypersensitive to the morpholines. These data are consistent with the antifungal activity of the morpholines depending upon the simultaneous inhibition of both Erg2p and Erg24p. The vacuoles within both erg2Delta/Delta and erg24Delta/Delta C. albicans strains exhibited an aberrant morphology and accumulated large quantities of the weak base quinacrine, indicating enhanced vacuolar acidification compared with that of control strains. Both erg mutants exhibited significant defects in polarized hyphal growth and were avirulent in a mouse model of disseminated candidiasis. Surprisingly, in a mouse model of vaginal candidiasis, both mutants colonized mice at high levels and induced a pathogenic response similar to that with the controls. Thus, while targeting Erg2p or Erg24p alone could provide a potentially efficacious therapy for disseminated candidiasis, it may not be an effective strategy to treat vaginal infections. The potential value of drugs targeting these enzymes as adjunctive therapies is discussed. PMID- 26231056 TI - Plentiful, Nutrient-Dense Food for the World: A Guide for Registered Dietitian Nutritionists. PMID- 26231057 TI - Regional Differences in Sugar-Sweetened Beverage Intake among US Adults. AB - BACKGROUND: Higher consumption of sugar-sweetened beverages (SSBs) is associated with obesity and type 2 diabetes, and the prevalence of obesity varies by geographic region. Although information on whether SSB intake differs geographically could be valuable for designing targeted interventions, this information is limited. OBJECTIVE: This cross-sectional study examined associations between living in specific census regions and frequency of SSB consumption among US adults using 2010 National Health Interview Survey data (n=25,431). METHODS: SSB consumption was defined as the consumption of four types of beverages (regular sugar-sweetened carbonated beverages, fruit drinks, sports/energy drinks, and sweetened coffee/tea drinks). The exposure variable was census region of residence (Northeast, Midwest, South, and West). We used multivariable logistic regression to estimate adjusted odds ratios (aORs) and 95% CIs for drinking SSBs after controlling for sociodemographic characteristics. RESULTS: Approximately 64% of adults consumed SSBs >=1 time/day. The odds of drinking SSBs >=1 time/day were significantly higher among adults living in the Northeast (aOR=1.13; 95% CI=1.01, 1.26) but lower among adults living in the Midwest (aOR=0.70; 95% CI=0.64, 0.78) or West (aOR=0.78; 95% CI=0.71, 0.87) compared with those living in the South. By type of SSB, the odds of drinking regular soda >=1 time/day was significantly lower among adults living in the Northeast (aOR=0.51; 95% CI=0.45, 0.57), Midwest (aOR=0.86; 95% CI=0.78, 0.96), or West (aOR=0.56; 95% CI=0.51, 0.62) than those living in the South. The odds of drinking sports/energy drinks >=1 time/day were significantly lower among adults living in the West (aOR=0.77; 95% CI=0.64, 0.93) than those living in the South. The odds of drinking a sweetened coffee/tea drink >=1 time/day were significantly higher among adults living in the Northeast (aOR=1.60; 95% CI=1.43, 1.78) but lower among adults living in the Midwest (aOR=0.70; 95% CI=0.62, 0.78) than those living in the South. CONCLUSIONS: Total frequency of SSB consumption and types of SSB consumption differed by geographic region. Interventions to reduce SSB intake could consider regional variations in SSB intake, particularly when more local data are not available. PMID- 26231058 TI - Linking Agriculture, Nutrition, and Health: The Role of the Registered Dietitian Nutritionist. PMID- 26231059 TI - Effects of omega-3 Polyunsaturated Fatty Acids on the Homeostasis of CD4+ T Cells and Lung Injury in Mice With Polymicrobial Sepsis. AB - BACKGROUND: Sepsis is a common cause of death in critically ill patients. An overwhelming inflammatory response and imbalance of helper T (Th) cells and regulatory T (Treg) cells are thought to be involved in the progression of sepsis. omega-3 Polyunsaturated fatty acids (PUFAs) were found to have anti inflammatory and immunomodulatory properties. This study investigated the effects of omega-3 PUFAs on the balance of Th subsets, Treg cells, and the inflammatory response in septic mice. METHODS: Mice were randomly assigned to soybean oil (SO) and fish oil (FO) groups. The 2 groups received an identical nutrient distribution except for the sources of the fat. The SO group was fed soybean oil, while part of the soybean oil was replaced by fish oil in the FO group. The FO group had an omega-6/omega-3 PUFA ratio of 2:1. After feeding the diets for 3 weeks, sepsis was induced by cecal ligation and puncture (CLP), and mice were sacrificed on days 0, 1, and 3. RESULTS: Compared with the SO group, the FO group had lower inflammatory mediator levels in the plasma and peritoneal lavage fluid after CLP. Also, the FO group had lower Th1, Th2, and Th17 percentages and a higher Th1/Th2 ratio in blood. In lung tissues, neutrophil infiltration was reduced, whereas peroxisome proliferator-activated receptor gamma expression was upregulated. CONCLUSIONS: A fish oil diet with an omega-6/omega-3 PUFA ratio of 2:1 may elicit more balanced Th polarization, alleviate inflammatory responses, and attenuate lung injury in CLP-induced sepsis. PMID- 26231060 TI - Primum Nocere: Medical Brain Drain and the Duty to Stay. AB - In this essay, we focus on the moral justification of a highly controversial measure to redress medical brain drain: the duty to stay. We argue that the moral justification for this duty lies primarily in the fact that medical students impose high risks on their fellow citizens while receiving their medical training, which in turn gives them a reciprocity-based reason to temporarily prioritize the medical needs of their fellow citizens. PMID- 26231061 TI - Letter to the editor: comparison of retinal detachment surgery outcome among patients undergoing pars plana vitrectomy with and without relaxing retinotomy. PMID- 26231062 TI - Impact of silver nanoparticles on benthic prokaryotes in heavy metal-contaminated estuarine sediments in a tropical environment. AB - Little knowledge is available about the potential impact of commercial silver nanoparticles (Ag-NPs) on estuarine microbial communities. The Hugli river estuary, India, is susceptible to heavy metals pollution through boat traffic, and there is the potential for Ag-NP exposure via effluent discharged from ongoing municipal and industrial activities located in close proximity. This study investigated the effects of commercial Ag-NPs on native microbial communities in estuarine sediments collected from five stations, using terminal restriction fragment length polymorphism (T-RFLP) technique. An increase in the number of bacteria in consortium in sediments was observed following exposure to Ag-NPs. In general microbial communities may be resistant in estuarine systems to the antimicrobial effects of commercial Ag-NPs, but key microorganisms, such as Pelobacter propionicus, disappeared following exposure to Ag-NPs. In conclusion, the T-RFLP analysis indicated that Ag-NPs have the potential to shape estuarine sediment bacterial community structure. PMID- 26231063 TI - Impact of industrial effluents on geochemical association of metals within intertidal sediments of a creek. AB - Metal speciation studies were carried out on three intertidal core sediments of the industrially impacted Dudh creek located along west coast of India. Metals indicated a drastic increase in the bioavailable fraction towards the surface of the cores, suggesting an increase in anthropogenic metal input in recent years as compared to the past. Also, when compared with Vaitarna estuary and Khonda creek of Thane district, the speciation of metals in Dudh creek sediments was observed to have been highly modified in recent years. High concentrations of metals associated with bioavailable fractions therefore suggested a risk of toxicity to sediment associated biota of Dudh creek. PMID- 26231064 TI - Screening for microplastic particles in plankton samples: How to integrate marine litter assessment into existing monitoring programs? AB - Microplastics (MPs) are a newly recognized type of environmental pollution in aquatic systems; however no monitoring of these contaminants is conducted, mostly due to the lack of routine quantification. In the net samples collected with a 90 MUm WP2 net, pelagic MP abundance was quantified by light microscopy and evaluated as a function of inshore-offshore gradient, depth, and season; the same samples were used for zooplankton analysis. The MP abundance was ~10(2) 10(4)particlesm(-3), with no significant inshore-offshore gradient during summer but increasing offshore in winter. MP abundance in deeper layers was positively affected by zooplankton abundance in the upper layers and significantly lower during winter compared to summer. These findings indicate heterogeneity of MP distribution due to biotic and abiotic factors and suggest that samples collected for other purposes can be used for quantification of MPs in the Baltic Sea, thus facilitating integration of MP assessment into existing monitoring schemes. PMID- 26231065 TI - Biodegradation of phthalate acid esters by different marine microalgal species. AB - Biodegradation of diethyl phthalate (DEP) and di-n-butyl phthalate (DBP) by three marine algae was investigated. When they were coexistent, DBP was degraded more quickly than DEP. The first-order biodegradation rate constants of DBP in the algal solutions were in the order of Cylindrotheca closterium (0.0169 h( 1))>Dunaliella salina (0.0035 h(-1)) and Chaetoceros muelleri (0.0034 h(-1)). When singly existed, DEP was degraded more quickly than in a mixture with DBP, indicating that DBP had inhibitory effect on the biodegradation of DEP. Moreover, the degradation trends of DEP and DBP in both extra- and intracellular crude extracts were similar to those in algal solutions. At the end, DEP was largely in water phase, whereas DBP remained in both water phase and algal phase. It can be concluded that biodegradation of DEP was mainly by algal extracellular enzymes, and both extra- and intracellular enzymes played key roles in the degradation of DBP. PMID- 26231066 TI - Sewage contamination in a tropical coastal area (Sao Sebastiao Channel, SP, Brazil). AB - Urban effluent discharges in Brazilian coastal areas are a chronic problem and often lead to changes in the quality of the marine environment. Sao-Sebastiao Channel (SSC) is an important aquatic ecosystem to be monitored for urban sewage contamination due to the intense urban activities in that region, as well as the relative high biodiversity of marine organisms. In the area are present three submarine sewage outfalls, a commercial harbour and also the biggest oil terminal in Brazil. Total organic carbon (TOC), total nitrogen (TN), total sulphur (TS), steroids and linear alkylbenzenes (LABs) were measured in sediment samples collected in three strategic locations of the SSC in order to monitor urban sewage contamination. Total LAB and total sterols levels ranged from below DL 51.3 ng g(-1) and below DL-10.40 MUg g(-1), respectively. Samples collected near sewage outfall in the central part of the SSC had higher concentrations of urban sewage-associated contaminants. PMID- 26231067 TI - Human-induced ecological changes in western part of Indian Sundarban megadelta: A threat to ecosystem stability. AB - The study first illustrates a comprehensive account of large-scale changes in water quality characteristics and plankton community structure due to occurrence of Annual Gangasagar Festival (AGF) at Sagar Island, western part of Indian Sundarban megadelta for 3-year duration (2012-2014; n=36). About 1 million pilgrims across India converge to take their holy bath at the confluence of Hooghly estuary and Bay of Bengal during January each year. This mass scale bathing results negative impact on water quality due to high turbidity (14.02 +/- 2.34 NTU) coupled with low chlorophyll a (1.02 +/- 0.21 mg m(-3)) and dissolved oxygen (3.94 +/- 1.1 mg l(-1)). A marked decrease in abundance (from 4140 to 2997 cells l(-1)) and diversity (H'=2.72-1.33) of phytoplankton and microzooplankton tintinnids (from 450 to 328 ind l(-1); H'=4.31-2.21) was recorded. The festival acts as multiple stressors modifying natural functions of the delta. Sound and sustainable management strategies are to be adopted to maintain the protection usage equilibrium. PMID- 26231068 TI - Metallothionein, oxidative stress and trace metals in gills and liver of demersal and pelagic fish species from Kuwaits' marine area. AB - Two fish species yellowfin seabream (Acanthopagrus latus) and tonguesole (Cynoglossus arel) were collected from two locations in Kuwait's territorial waters in non-reproductive periods and used as bio-indicator organism for the assessment of metals in the marine environment. Species variation in fish was observed; seabream contained high metal content and metallothionein in liver and gill tissues compared to tonguesole, especially from Kuwait Bay area. Oxidative injury was registered in the gills of both species, but in tonguesole liver was also involved. Consequently, antioxidant enzyme catalase was elevated in tonguesole enabling bottom dwelling fish to combat oxidative assault. The study provided information about the current status of metals in marine sediment and levels of metals accumulated in representative species along with oxidative damage in exposed tissues and the range of biomarker protein metallothionein and enzymes of antioxidant defence mechanism enhancing our understanding about the biological response to the existing marine environment in Kuwait. PMID- 26231069 TI - Marine litter in bottom trawls off the Portuguese coast. AB - Benthic marine litter along the Portuguese coast, was recorded in 14 trips on stern trawlers covering a distance of 2117 km and an area of 56.2 km(2), average depth range 90-349 m. 2034 items of marine litter were registered, 76% were plastics and 38.6% were originated from fishing related activities. Plastic was present in all the trawls and had the highest average density of all litter categories, 50 items km(-2). The highest density of marine litter (178.9 +/- 64.0 items km(-2)) was found in the proximity of the Tagus river mouth, probably related to the high population density in the Lisbon metropolitan area. This study highlights the need to raise fishermen awareness for the adoption of good environmental practices that will contribute to the reduction of marine litter. PMID- 26231070 TI - Automatic detection of protected health information from clinic narratives. AB - This paper presents a natural language processing (NLP) system that was designed to participate in the 2014 i2b2 de-identification challenge. The challenge task aims to identify and classify seven main Protected Health Information (PHI) categories and 25 associated sub-categories. A hybrid model was proposed which combines machine learning techniques with keyword-based and rule-based approaches to deal with the complexity inherent in PHI categories. Our proposed approaches exploit a rich set of linguistic features, both syntactic and word surface oriented, which are further enriched by task-specific features and regular expression template patterns to characterize the semantics of various PHI categories. Our system achieved promising accuracy on the challenge test data with an overall micro-averaged F-measure of 93.6%, which was the winner of this de-identification challenge. PMID- 26231071 TI - Determinants of tolerance to inhibitors in hardwood spent sulfite liquor in genome shuffled Pachysolen tannophilus strains. AB - Genome shuffling was used to obtain Pachysolen tannophilus mutants with improved tolerance to inhibitors in hardwood spent sulfite liquor (HW SSL). Genome shuffled strains (GHW301, GHW302 and GHW303) grew at higher concentrations of HW SSL (80 % v/v) compared to the HW SSL UV mutant (70 % v/v) and the wild-type (WT) strain (50 % v/v). In defined media containing acetic acid (0.70-0.90 % w/v), GHW301, GHW302 and GHW303 exhibited a shorter lag compared to the acetic acid UV mutant, while the WT did not grow. Genome shuffled strains produced more ethanol than the WT at higher concentrations of HW SSL and an aspen hydrolysate. To identify the genetic basis of inhibitor tolerance, whole genome sequencing was carried out on GHW301, GHW302 and GHW303 and compared to the WT strain. Sixty single nucleotide variations were identified that were common to all three genome shuffled strains. Of these, 40 were in gene sequences and 20 were within 5 bp-1 kb either up or downstream of protein encoding genes. Based on the mutated gene products, mutations were grouped into functional categories and affected a variety of cellular functions, demonstrating the complexity of inhibitor tolerance in yeast. Sequence analysis of UV mutants (UAA302 and UHW303) from which GHW301, GHW302 and GHW303 were derived, confirmed the success of our cross mating based genome shuffling strategy. Whole-genome sequencing analysis allowed identification of potential gene targets for tolerance to inhibitors in lignocellulosic hydrolysates. PMID- 26231072 TI - Cryopreservation of Bituminaria bituminosa varieties and hybrids. AB - Bituminaria bituminosa (L.) C.H. Stirton is a drought tolerant, perennial legume pasture species and a source of pharmaceutical compounds. Bituminaria breeding programs aim to develop and conserve hybrids with desirable traits such as high forage quality, tolerance to biotic or abiotic stresses, and high contents of furanocoumarins. In this work we present a cryopreservation study of different B. bituminosa accessions: two varieties and eight intervarietal hybrids resulting from crosses between the three botanical varieties: var. bituminosa, var. crassiuscula, and var. albomarginata. No previous work on cryopreservation of Bituminaria species has been reported. We applied the ultra-fast cooling method, using droplet vitrification on aluminum foil strips. First, we investigated the PVS2 toxicity and cryopreservation damage in two genotypes, comparing three PVS2 treatments and two culture media. An incubation of 30 min in PVS2 resulted in regeneration rates after cryopreservation higher than 80%. The MS medium was selected for optimal meristem outgrowth, in order to avoid the prominent callus formation that was observed in the presence of BAP. These conditions were subsequently used to cryopreserve eight other genotypes. The results were highly variable; 45 days after cryopreservation, survival ranged between 22% and 98% while regeneration ranged between 0% and 96%, depending on the accession. A significant and positive correlation was observed between survival and regeneration. At 90 days post culture plantlets could be recovered from cryopreserved explants of all genotypes. This study shows that the droplet vitrification method is promising for the cryopreservation of eight of the 10 genotypes assayed and the method can thus be applied to develop a cryobank of B. bituminosa. PMID- 26231073 TI - An efficient procedure for the expression and purification of HIV-1 protease from inclusion bodies. AB - Several studies have focused on HIV-1 protease for developing drugs for treating AIDS. Recombinant HIV-1 protease is used to screen new drugs from synthetic compounds or natural substances. However, large-scale expression and purification of this enzyme is difficult mainly because of its low expression and solubility. In this study, we constructed 9 recombinant plasmids containing a sequence encoding HIV-1 protease along with different fusion tags and examined the expression of the enzyme from these plasmids. Of the 9 plasmids, pET32a(+) plasmid containing the HIV-1 protease-encoding sequence along with sequences encoding an autocleavage site GTVSFNF at the N-terminus and TEV plus 6* His tag at the C-terminus showed the highest expression of the enzyme and was selected for further analysis. The recombinant protein was isolated from inclusion bodies by using 2 tandem Q- and Ni-Sepharose columns. SDS-PAGE of the obtained HIV-1 protease produced a single band of approximately 13 kDa. The enzyme was recovered efficiently (4 mg protein/L of cell culture) and had high specific activity of 1190 nmol min(-1) mg(-1) at an optimal pH of 4.7 and optimal temperature of 37 degrees C. This procedure for expressing and purifying HIV-1 protease is now being scaled up to produce the enzyme on a large scale for its application. PMID- 26231074 TI - A facile method for expression and purification of (15)N isotope-labeled human Alzheimer's beta-amyloid peptides from E. coli for NMR-based structural analysis. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting millions of people worldwide. AD is characterized by the presence of extracellular plaques composed of aggregated/oligomerized beta-amyloid peptides with Abeta42 peptide representing a major isoform in the senile plaques. Given the pathological significance of Abeta42 in the progression of AD, there is considerable interest in understanding the structural ensembles for soluble monomer and oligomeric forms of Abeta42. This report describes an efficient method to express and purify high quality (15)N isotope-labeled Abeta42 for structural studies by NMR. The protocol involves utilization of an auto induction system with (15)N isotope labeled medium, for high-level expression of Abeta42 as a fusion with IFABP. After the over-expression of the (15)N isotope-labeled IFABP Abeta42 fusion protein in the inclusion bodies, pure (15)N isotope-labeled Abeta42 peptide is obtained following a purification method that is streamlined and improved from the method originally developed for the isolation of unlabeled Abeta42 peptide (Garai et al., 2009). We obtain a final yield of ~ 6 mg/L culture for (15)N isotope-labeled Abeta42 peptide. Mass spectrometry and (1)H-(15)N HSQC spectra of monomeric Abeta42 peptide validate the uniform incorporation of the isotopic label. The method described here is equally applicable for the uniform isotope labeling with (15)N and (13)C in Abeta42 peptide as well as its other variants including any Abeta42 peptide mutants. PMID- 26231075 TI - Influence of Total Knee Arthroplasty on Gait Mechanics of the Replaced and Non Replaced Limb During Stair Negotiation. AB - This study compared biomechanics during stair ascent in replaced and non-replaced limbs of total knee arthroplasty (TKA) patients with control limbs of healthy participants. Thirteen TKA patients and fifteen controls performed stair ascent. Replaced and non-replaced knees of TKA patients were less flexed at contact compared to controls. The loading response peak knee extension moment was greater in control and non-replaced knees compared with replaced. The push-off peak knee abduction moment was elevated in replaced limbs compared to controls. Loading and push-off peak hip abduction moments were greater in replaced limbs compared to controls. The push-off peak hip abduction moment was greater in non-replaced limbs compared to controls. Future rehabilitation protocols should consider the replaced knee and also the non-replaced knee and surrounding joints. PMID- 26231076 TI - Minimum 10-Year Wear Analysis of Highly Cross-Linked Polyethylene in Cementless Total Hip Arthroplasty. AB - Fifty-four patients (64 hips) underwent cementless total hip arthroplasty between 2000 and 2003 with a 22-mm zirconia ceramic bearing on highly cross-linked polyethylene, and were evaluated with a mean 11.9-year postoperative follow-up (range, 10-14 years). Linear wear was measured on the anteroposterior radiograph of the hip. No evidence of osteolysis and loosening was found on the final radiograph in any of the cases, and the steady-state linear wear rate was 0.017+/ 0.018 mm/year. No significant correlation was found between the linear wear rate and age, body weight, cup inclination angle, or polyethylene thickness. Highly cross-linked polyethylene showed excellent wear resistance for >10 years when used in combination with 22-mm zirconia heads. PMID- 26231077 TI - Cost Analysis and Surgical Site Infection Rates in Total Knee Arthroplasty Comparing Traditional vs. Single-Use Instrumentation. AB - Surgical site infections (SSIs) are a significant complications in total knee arthroplasty (TKA). The purpose of this study was to evaluate if traditional vs. single-use instrumentation had an effect on SSI's. We compared SSI rates and costs of TKAs performed with single-use (449) and traditional (169) TKA instrumentation trays. Total OR Time was, on average, 30 min less when single-use instrumentation was used. SSIs decreased in the single-use group (n=1) compared to the traditional group (n=5) (P=0.006). Single-use instrumentation added $490 in initial costs; however it saved between $480 and $600. Single-use instrumentation may provide a benefit to the patient by potentially decreasing the risk of infection and reducing the overall hospital costs. PMID- 26231079 TI - Synthesis and biological evaluation of novel aromatic-heterocyclic biphenyls as potent anti-leukemia agents. AB - As a continuation to our previous research, twenty-eight aromatic-heterocyclic biphenyls were designed and synthesized as novel Bcr-Abl inhibitors. The title compounds were investigated for their antiproliferative activities against wild K562 cells and Imatinib-resistant K562 cells (K562R). The results indicated that most of them exhibited potent Bcr-Abl inhibition and moderate antiproliferative potency against K562 cells. Furthermore, three compounds 3, 7 and 21 displayed moderate antiproliferative activities against K562R cells. Molecular docking indicated that 3 bound more tightly with Bcr-Abl(T315I) compared to Bcr-Abl(WT). The higher affinity was consistent with its relatively promising K562R cell growth inhibition. These aromatic-heterocyclic biphenyls could be considered as novel lead compound for optimized as Bcr-Abl(T315I) inhibitors. They provide a good starting point for the further development of novel anti-leukemia agents capable of dealing with clinical acquired resistance against Imatinib. PMID- 26231078 TI - The expenditure of computer-related worktime using clinical decision support systems in chronic pain therapy. AB - BACKGROUND: Estimate the expenditure of computer-related worktime resulting from the use of clinical decision support systems (CDSS) to prevent adverse drug reactions (ADR) among patients undergoing chronic pain therapy and compare the employed check systems with respect to performance and practicability. METHODS: Data were collected retrospectively from 113 medical records of patients under chronic pain therapy during 2012/2013. Patient-specific medications were checked for potential drug-drug interactions (DDI) using two publicly available CDSS, Apotheken Umschau (AU) and Medscape (MS), and a commercially available CDSS AiDKlinik(r) (AID). The time needed to analyze patient pharmacotherapy for DDIs was taken with a stopwatch. Measurements included the time needed for running the analysis and printing the results. CDSS were compared with respect to the expenditure of time and usability. Only patient pharmacotherapies with at least two prescribed drugs and fitting the criteria of the corresponding CDSS were analyzed. Additionally, a qualitative evaluation of the used check systems was performed, employing a questionnaire asking five pain physicians to compare and rate the performance and practicability of the three CDSSs. RESULTS: The AU tool took a total of 3:55:45 h with an average of 0:02:32 h for 93 analyzed patient regimens and led to the discovery of 261 DDIs. Using the Medscape interaction checker required a total of 1:28:35 h for 38 patients with an average of 0:01:58 h and a yield of 178 interactions. The CDSS AID required a total of 3:12:27 h for 97 patients with an average time of analysis of 0:01:59 h and the discovery of 170 DDIs. According to the pain physicians the CDSS AID was chosen as the preferred tool. CONCLUSIONS: Applying a CDSS to examine a patients drug regimen for potential DDIs causes an average extra expenditure of work time of 2:09 min, which extends patient treatment time by 25 % on average. Nevertheless, the authors believe that the extra expenditure of time employing a CDSS is outweighed by their benefits, including reduced ADR risks and safer clinical drug management. PMID- 26231080 TI - Design, synthesis and biological evaluation of 1,3-diphenyl-1H-pyrazole derivatives containing benzimidazole skeleton as potential anticancer and apoptosis inducing agents. AB - A series of forty different pyrazole containing benzimidazole hybrids (6-45) have been designed, synthesized and evaluated for their potential anti-proliferative activity against three human tumor cell lines - lung (A549), breast (MCF-7), and cervical (HeLa). Some of the compounds, specifically 9, 17, and 28, showed potent growth inhibition against all the cell lines tested, with IC50 values in the range of 0.83-1.81 MUM. Breast cancer cells were used for further detailed studies to understand the mechanism of cell growth inhibition and apoptosis inducing effect of compounds. The morphology, cell migration and long term clonogenic survival of MCF-7 breast cancer cells were severely affected by treatment with these compounds. Flow-cytometry revealed the compounds arrested MCF-7 cells in the G1 phase of the cell cycle via down regulation of cyclin D2 and CDK2. Fluorescent staining and DNA fragmentation studies showed that cell proliferation was inhibited by induction of apoptosis. Moreover, the compounds led to collapse of mitochondrial membrane potential (DPsim) and increased levels of reactive oxygen species (ROS) were noted. The ease of synthesis and the remarkable biological activities make these compounds promising new frameworks for the development of cancer therapeutics. PMID- 26231081 TI - Lowering the pKa of a bisimidazoline lead with halogen atoms results in improved activity and selectivity against Trypanosoma brucei in vitro. AB - Diphenyl-based bis(2-iminoimidazolidines) are promising antiprotozoal agents that are curative in mouse models of stage 1 trypanosomiasis but devoid of activity in the late-stage disease, possibly due to poor brain penetration caused by their dicationic nature. We present here a strategy consisting in reducing the pKa of the basic 2-iminoimidazolidine groups though the introduction of chlorophenyl, fluorophenyl and pyridyl ring in the structure of the trypanocidal lead 4 (imidazolidin-2-ylideneamino)-N-(4-(imidazolidin-2-ylideneamino)phenyl)benzamide (1). The new compounds showed reduced pKa values (in the range 1-3 pKa units) for the imidazolidine group linked to the substituted phenyl ring. In vitro activities (EC50) against wild type and resistant strains of T. b. brucei (s427 and B48, respectively) were in the submicromolar range with four compounds being more active and selective than 1 (SI > 340). In particular, the two most potent compounds (3b and 5a) acted approximately 6-times faster than 1 to kill trypanosomes in vitro. No cross-resistance with the diamidine and melaminophenyl class of trypanocides was observed indicating that these compounds represent interesting leads for further in vivo studies. PMID- 26231082 TI - Synthesis and structure-activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain. AB - The discovery of new antiparasitic compounds against Trypanosoma cruzi, the etiological agent of Chagas disease, is necessary. Novel aryloxy/aryl thiosemicarbazone-based conformationally constrained analogs of thiosemicarbazones (1) and (2) were developed as potential inhibitors of the T. cruzi protease cruzain, using a rigidification strategy of the iminic bond of (1) and (2). A structure-activity relationship analysis was performed in substituents attached in both aryl and aryloxy rings. This study indicated that apolar substituents or halogen atom substitution at the aryl position improved cruzain inhibition and antiparasitic activity in comparison to unsubstituted thiosemicarbazone. Two of these compounds displayed potent inhibitory antiparasitic activity by inhibiting cruzain and consequently were able to reduce the parasite burden in infected cells and cause parasite cell death through necrosis. In conclusion, we demonstrated that conformational restriction is a valuable strategy in the development of antiparasitic thiosemicarbazones. PMID- 26231083 TI - Diverse contribution of bone marrow-derived late-outgrowth endothelial progenitor cells to vascular repair under pulmonary arterial hypertension and arterial neointimal formation. AB - AIMS: It is still controversial whether bone marrow (BM)-derived endothelial progenitor cells (EPCs) can contribute to vascular repair and prevent the progression of vascular diseases. We aimed to characterize BM-derived EPC subpopulations and to evaluate their therapeutic efficacies to repair injured vascular endothelium of systemic and pulmonary arteries. METHODS AND RESULTS: BM mononuclear cells of Fisher-344 rats were cultured under endothelial cell conditions. Early EPCs appeared on days 3-6. Late-outgrowth and very late outgrowth EPCs (LOCs and VLOCs) were defined as cells forming cobblestone colonies on days 9-14 and 17-21, respectively. Among EPC subpopulations, LOCs showed the highest angiogenic capability with enhanced proliferation potential and secretion of proangiogenic proteins. To investigate the therapeutic effects of these EPCs, Fisher-344 rats underwent wire-mediated endovascular injury in femoral artery (FA) and were concurrently injected intraperitoneally with 60mg/kg monocrotaline (MCT). Injured rats were then treated with six injections of one of three EPCs (1*10(6) per time). After 4weeks, transplanted LOCs, but not early EPCs or VLOCs, significantly attenuated neointimal lesion formation in injured FAs. Some of CD31(+) LOCs directly replaced the injured FA endothelium (replacement ratio: 11.7+/-7.0%). In contrast, any EPC treatment could neither replace MCT-injured endothelium of pulmonary arterioles nor prevent the progression of pulmonary arterial hypertension (PAH). LOCs modified protectively the expression profile of angiogenic and inflammatory genes in injured FAs, but not in MCT-injured lungs. CONCLUSION: BM-derived LOCs can contribute to vascular repair of injured systemic artery; however, even they cannot rescue injured pulmonary vasculature under MCT-induced PAH. PMID- 26231085 TI - Enrollment of underrepresented minorities in nursing majors: A cross sectional analysis of U.S. nursing schools. AB - PURPOSE: To investigate if underrepresented racial and ethnic minorities have distinct enrollment patterns when different diversity programmatic services are in place. DESIGN: Secondary analysis of linked data from an electronic survey conducted (2012-2013) and AACN baccalaureate enrollment data across 25 schools of nursing in 15 states. Logistic regression was used to determine the likelihood of minority student enrollment in nursing programs when 14 distinct programmatic support services were in operation. FINDINGS: Asian students were most likely to enroll in nursing programs with career services in place (O.R. 2.2, p=0.01). Black/African American student enrollment was associated with financial support (O.R., 1.52, p=<.001), mentoring (O.R.=2.49, p=<.001), community partnerships (O.R. 1.97, p=<.001), diversity workshops (O.R.=1.95, p=<.001) and clinical experiences (OR=2.25, p=<.001), academic (O.R.=2.58, p=<.001), and psychosocial (OR 1.74, p=<.001) services. Hispanic student enrollment was associated with academic support (O.R. 2.97, p=<.001), mentoring (O.R. 1.38, p=<.001), diversity workshops (O.R. 1.22, p=<.001), and community service (O.R. 1.66, p=<.001). Non Hispanic White students were more apt to be enrolled in nursing schools offering financial support (O.R., 1.27, p=<.001), internships/externships (O.R.=1.5, p=<.001), research opportunities (O.R. 2.01, p=<.001), clinical experiences (O.R.=1.71, p=<.001), diversity workshops (O.R. 1.2, p=<.001). CONCLUSIONS: Differences in enrollment patterns among minority students may be attributed to efficacy of individual structured support services. These differences suggest the importance of tailoring diversity support services to meet the unique needs of students from diverse backgrounds. PMID- 26231084 TI - Comparative effects of urocortins and stresscopin on cardiac myocyte contractility. AB - RATIONALE: There is a current need for the development of new therapies for patients with heart failure. OBJECTIVE: We test the effects of members of the corticotropin-releasing factor (CRF) family of peptides on myocyte contractility to validate them as potential heart failure therapeutics. METHODS AND RESULTS: Adult feline left ventricular myocytes (AFMs) were isolated and contractility was assessed in the presence and absence of CRF peptides Urocortin 2 (UCN2), Urocortin 3 (UCN3), Stresscopin (SCP), and the beta-adrenergic agonist isoproterenol (Iso). An increase in fractional shortening and peak Ca(2+) transient amplitude was seen in the presence of all CRF peptides. A decrease in Ca(2+) decay rate (Tau) was also observed at all concentrations tested. cAMP generation was measured by ELISA in isolated AFMs in response to the CRF peptides and Iso and significant production was seen at all concentrations and time points tested. CONCLUSIONS: The CRF family of peptides effectively increases cardiac contractility and should be evaluated as potential novel therapeutics for heart failure patients. PMID- 26231086 TI - Peripersonal space as the space of the bodily self. AB - Bodily self-consciousness (BSC) refers to experience of one's self as located within an owned body (self-identification) and as occupying a specific location in space (self-location). BSC can be altered through multisensory stimulation, as in the Full Body Illusion (FBI). If participants view a virtual body from a distance being stroked, while receiving synchronous tactile stroking on their physical body, they feel as if the virtual body were their own and they experience, subjectively, to drift toward the virtual body. Here we hypothesized that--while normally the experience of the body in space depends on the integration of multisensory body-related signals within a limited space surrounding the body (i.e. peripersonal space, PPS)--during the FBI the boundaries of PPS would shift toward the virtual body, that is, toward the position of experienced self-location. To test this hypothesis, we used synchronous visuo-tactile stroking to induce the FBI, as contrasted with a control condition of asynchronous stroking. Concurrently, we applied an audio tactile interaction paradigm to estimate the boundaries of PPS. PPS was measured in front of and behind the participants' body as the distance where tactile information interacted with auditory stimuli looming in space toward the participant's physical body. We found that during synchronous stroking, i.e. when participants experienced the FBI, PPS boundaries extended in the front-space, toward the avatar, and concurrently shrunk in the back-space, as compared to the asynchronous stroking control condition, when FBI was induced. These findings support the view that during the FBI, PPS boundaries translate toward the virtual body, such that the PPS representation shifts from being centered at the location of the physical body to being now centered at the subjectively experienced location of the self. PMID- 26231087 TI - Blood flow and endothelial cell phenotype regulation during sprouting angiogenesis. AB - The role of the endothelial cell environment and shear stress induced by blood flow in phenotype determination and lumen formation has been clearly illustrated in recent studies. In the present work, a model is developed to map environmental and flow induced signals in sprouting angiogenesis to endothelial cell phenotype and lumen formation. To follow the endothelial cell lumen formation, its signaling pathway is incorporated in the present work within the phenotype determination pathway that has been recently utilized to model endothelial cell migration, proliferation, and apoptosis. Moreover, a signaling cascade for shear stress activation of endothelial cells is proposed and used for phenotype determination with activation of blood flow. A Boolean network model is employed to build a hybrid map for the relation between the endothelial cell environmental signals and the endothelial cell fate in sprouting angiogenesis with and without blood flow. This map is very useful in the development of models for sprouting angiogenesis. Moreover, this study shows that inhibition of intracellular signaling molecules, solely or in pairs, blocks angiogenic-signaling pathways and can be used to inhibit angiogenesis. PMID- 26231088 TI - Effect of Longan polysaccharides on proliferation and phenotype maintenance in rabbit articular chondrocytes in vitro. AB - For autologous chondrocyte implantation (ACI) to restore cartilage defect, limited cell numbers and dedifferentiation of chondrocytes are the major difficulties. An alternative is the use of growth factors, but the high cost and potential tumorigenesis are the major obstacles. To ensure successful ACI therapy, it is of significance to find effective substituted pro-chondrogenic agent. Polysaccharides from plant extract have low toxicity and few undesirable side effects, which were reported to facilitate cartilage regeneration. In this study, we investigated the effect of Longan polysaccharides (LP) on rabbit articular chondrocytes through examination of the cell proliferation, morphology, viability, glycosaminoglycan synthesis and cartilage-specific gene expression. Results showed that close to the positive group which used the growth factor of TGF-beta, LP could effectively promote chondrocytes growth and enhance secretion and synthesis of cartilage extracellular matrix by up-regulating expression levels of aggrecan, collagen II and sox9 compared to the negative control. Expression of collagen I gene was effectively down-regulated, demonstrating the inhibition of chondrocytes dedifferentiation by LP. Hypertrophy that might lead to chondrocyte ossification was also undetectable in LP groups. Range of 4.69 18.76 ug/ml was recommended dose of LP, among which the most profound response was observed with 9.38 MUg/ml. All the evidences revealed that LP may replace the growth factors to be applied in ACI therapy. This study might provide a basis for development of a novel agent in the treatment of articular cartilage defect. PMID- 26231089 TI - Attitudes to outcomes measured in clinical trials of cardiovascular prevention. AB - BACKGROUND: Selecting outcome measures in cardiovascular prevention trials should be informed by their importance to selected populations. Major vascular event outcomes are usually prioritized in these trials with considerably less attention paid to cognitive and functional outcomes. AIM: To examine views on importance of outcome measures used in clinical trials. DESIGN: Cross-sectional survey. METHODS: Of 367 individuals approached, 280 (76%) participated: outpatients attending cardiovascular prevention clinics (n = 97), active retirement groups members (n = 75), medical students (n = 108). Participants were asked to rank, in order of importance, outcome measures, which may be included in cardiovascular prevention trials. Results were compared between two groups: <65s (n = 157) and >=65s (n = 104). RESULTS: When asked what outcomes were most important to measure in cardiovascular prevention trials, respondents reported: death (31.6%) stroke (28.5%), dementia (26.9%), myocardial infarction (MI) (7.9%) and requiring nursing home (NH) care (5.1%). When asked the most relevant outcomes regarding successful ageing respondents reported; maintaining independence (32.4%), avoiding major illness (24.3%), good family life (23.6%), living as long as possible (15.8%), avoiding NH care (3.1%) and contributing to society (0.8%) as most important. When asked what outcome concerned them most about the future, respondents reported: dementia (32.6%), dependence (30.4%), death (12.8%), stroke (12.5%), cancer (6.2%) requiring NH care (4.8%) and MI (0.7%). Maintaining independence was considered most important in younger and older cohorts. CONCLUSION: Cognitive and functional outcomes are important patient-relevant outcomes, sometimes more important than major vascular events. Incorporating these outcomes into trials may encourage patient participation and adherence to preventative regimens. PMID- 26231090 TI - Pretibial myxedema. PMID- 26231091 TI - Toward the processing speed theory of activities of daily living in healthy aging: normative data of the Functional Activities Questionnaire. AB - BACKGROUND: The aim of this study was to describe an instrumental activities of daily living (IADL) measure: Functional Activities Questionnaire (FAQ), which is often used in clinical settings as a self- or informant-based measure of IADL. However, the FAQ's relationship with age or education in healthy aging has not been investigated. METHODS: FAQ and a neuropsychological battery were administered to old and very old Czech adults (n = 540). Participants met strict inclusion criteria for the absence of any active or past neurodegenerative disorders. RESULTS: FAQ is significantly dependent on age and education, but not gender. Younger subjects and those with higher education have the lowest scores in the FAQ and show a higher degree of functional independence. FAQ moderately correlates with speed of processing, visual-perceptual and executive functions measures (Trail Making Tests, Stroop Test) and depressive symptoms, but not with episodic memory (WMS-III logical memory). We present normative percentile values for different age groups from 60 to 96 years of age. CONCLUSIONS: The present study shows conclusively that IADL measures, such as FAQ, should not be used without appropriate normative data, especially in very old adults. Thus, it has the ability to differentiate functional dependence due to age-related decline from neurodegenerative disease. PMID- 26231092 TI - Definitive chemotherapy and radiotherapy in patients with stage II non-small cell lung cancer: A population-based outcomes study. AB - OBJECTIVES: There is a paucity of data on non-surgical outcomes specific to stage II non-small cell lung cancer (NSCLC) patients receiving definitive chemotherapy and radiation therapy (CRT). This study reports population-based outcomes for this subgroup, and investigates a radiation dose-response for overall survival. MATERIALS AND METHODS: The National Oncology Data Alliance (NODA), a merging of multiple tumor registries maintained by Elekta((r)) medical systems, was queried for stage II patients and CRT. Only curative cases (RT doses >=59 Gy) were included. Both sequential and concurrent CRT were allowed. Univariate and Cox multivariate techniques were used to assess factors significant for overall survival. These factors included: gender, age, race, radiation dose, radiation total treatment time, stage, histology, tumor size, and chemotherapy sequence. RESULTS: A total of 568 patients were included in the analysis, with a median follow-up of 12.9 months for surviving patients. Patients were treated between 2004 and 2014. Median survival was 20.5 months (95% confidence interval (CI) 18 23 months), with 16% patients alive at 5 years. Only gender was found to be significantly associated with survival in the Cox model. Although median survival was higher in patients receiving greater than 60 Gy (21 months, 95% CI 18-24 moths) compared to 59-60 Gy (16.5 months 95% CI 10-23 months), this was not statistically significant (p=0.6). CONCLUSIONS: This is the first report on outcomes for stage II NSCLC patients receiving CRT as definitive therapy. Survival approximates stage III CRT patients from historical phase III trials. As an increasing aging population may parallel a rise in medically inoperable stage II patients, this study can provide useful information when reviewing treatment options. PMID- 26231093 TI - Elastographic features of triple negative breast cancers. AB - OBJECTIVES: To evaluate shear-wave elastographic (SWE) features of triple negative breast cancers (TNBC) and determine useful discriminators from other types of invasive breast cancers. METHODS: SWE features of 26 TNBC were reviewed and compared to 32 non-TNBC. Qualitative SWE features of lesion colour appearance, shape and homogeneity were analysed. Quantitative features were measured: mean (El mean), maximum (El max) and minimum (El min) elasticity value of the stiffest portion of the mass, mean elasticity of the surrounding tissue (El mean surr) and lesion to fat elasticity ratio (E ratio). RESULTS: TNBC are more often regularly shaped (57.7 % vs. 6.2 %), while non-TNBC are more commonly red (93.7 % vs 42.3 %) and heterogeneous (68.7 % vs 42.3 %). The stiffness of TNBC is significantly lower compared to non-TNBC. The two groups could be distinguished on the basis of El max (p = 0.001), El mean (p = 0.001), El min (p = 0.001) and E ratio (p = 0.0017). Lesion to fat elasticity ratio in TNBC group was statistically significantly lower than in the non-TNBC control group (p = 0.009). CONCLUSIONS: TNBC often demonstrate benign morphological features, are softer on SWE and have a lower lesion to fat stiffness ratio compared to the other, more common types of invasive breast cancers. KEY POINTS: * TNBC often demonstrate benign morphological features on SWE. * TNBC present on elastography mostly as red, regularly shaped, heterogeneous lesions. * TNBC are less stiff compared to other invasive breast cancers. * TNBC have lower lesion to fat stiffness ratio than other breast cancers. PMID- 26231094 TI - Extracellular vesicles in lung microenvironment and pathogenesis. AB - Increasing attention is being paid to the role of extracellular vesicles (EVs) in various lung diseases. EVs are released by a variety of cells, including respiratory cells and immune cells, and they encapsulate various molecules, such as proteins and microRNAs, as modulators of intercellular communication. Cancer cell-derived EVs play crucial roles in promoting tumor progression and modifying their microenvironment. By contrast, noncancerous cell-derived EVs demonstrate protective functions against injury, such as tissue recovery and repair, to maintain physiological homeostasis. Airway cells in contact with harmful substances may alter their EV composition and modify the balanced reciprocal interactions with surrounding mesenchymal cells. We summarize the novel findings of EV function in various lung diseases, primarily chronic obstructive pulmonary disease (COPD) and lung cancer. PMID- 26231096 TI - Race/ethnicity and socio-economic differences in breast cancer surgery outcomes. AB - BACKGROUND: The purpose of this study is to evaluate racial and socio-economic differences in breast cancer surgery treatment, post-surgical complications, hospital length of stay and mortality among hospitalized breast cancer patients. METHODS: We examined the association between race/ethnicity and socio-economic status with treatment and outcomes after surgery among 71,156 women hospitalized with a primary diagnosis of breast cancer using the Nationwide Inpatient Sample database from 2007 to 2011. Multivariable regression models were used to compute estimates, odds ratios and 95% confidence intervals adjusting for age, comorbidities, stage at diagnosis, insurance, and residential region. RESULTS: Black women were more likely to receive breast conserving surgery but less likely to receive mastectomies compared with white women. They also experienced significantly longer hospital stays (beta=0.31, 95% CI: 0.24, 0.39), post surgical complications (OR=1.21, 95% CI: 1.04-1.42) and in-hospital mortality (OR=1.26, 95% CI: 1.07-1.50) compared with Whites, after adjusting for other factors including the number of comorbidities and treatment type. CONCLUSION: Among patients hospitalized for breast cancer, there were racial differences observed in treatment and outcomes. Further studies are needed to fully characterize whether these differences are due to individual, provider level or hospital level factors, and to highlight areas for targeted approaches to eliminate these disparities. PMID- 26231097 TI - Impact of rheumatoid arthritis on career progression, productivity, and employability: The PRET Study. AB - OBJECTIVES: To evaluate the impact of rheumatoid arthritis (RA) on career, productivity, and employability. METHODS: A retrospective cross-sectional survey was conducted in 2012-2013 in France among patients with RA who were younger than 60 years of age and employed or unemployed. Patients were either recruited during a rheumatologist visit or among members of a nationwide patient-support organization (ANDAR). They completed a questionnaire on the functional impact of RA evaluated by the Health Assessment Questionnaire (HAQ) and on the impact of their disease on work ability. RESULTS: Of 488 surveyed patients, 364 (74.6%) were actively employed, 31 (6.4%) were job seekers, and 93 (19.1%) had left the workforce. In the employed group, mean age was 48.9 years; 82.1% of patients were women; mean RA duration was 11.6 years; and the HAQ score correlated strongly with various markers for decreased productivity including sick leaves, temporary or permanent work discontinuation, and having unwillingly downgraded from a full time to a part-time work schedule or changed to a different job. Among job seekers, 54% had lost their previous job because of their RA. CONCLUSION: RA is associated with various forms of work disability, which are directly related to the severity of disease-related functional impairments. PMID- 26231098 TI - Impact of juvenile idiopathic arthritis on quality of life during transition period at the era of biotherapies. AB - OBJECTIVE: Few studies have assessed Health-Related Quality of Life (HR-QoL) in adults following juvenile idiopathic arthritis, and none since the advent of biotherapies. The aim of our study is to assess the impact of juvenile idiopathic arthritis on quality of life in a large transitional cohort, evaluate which factors influence quality of life in juvenile idiopathic arthritis, and determine which questionnaire should be used in practice. METHODS: All consecutive juvenile idiopathic arthritis patients followed during adulthood in a transitional care program were included. Demographical, clinical and biological data were collected. The following quality of life questionnaires were administered: SF36 and EuroQoL. Age- and sex-matched controls (without rheumatic disease) were included. RESULTS: One hundred and sixty-one juvenile idiopathic arthritis (120 women and 41 men) and 76 (51/25) controls were included. Out of 161, sixty-five (40%) were considered to be in remission. Juvenile idiopathic arthritis had a large impact on the physical scales of quality of life. Pain seemed to be the most important factor affecting quality of life in cases of juvenile idiopathic arthritis. No significant difference was found between sub-types of juvenile idiopathic arthritis. CONCLUSION: In this large transitional cohort of patients at the era of biotherapies, juvenile idiopathic arthritis has a larger effect on physical than mental scale of quality of life measures. Pain was the main factor influencing quality of life. Sub-types of juvenile idiopathic arthritis do not seem to influence quality of life. PMID- 26231095 TI - Fast-folding proteins under stress. AB - Proteins are subject to a variety of stresses in biological organisms, including pressure and temperature, which are the easiest stresses to simulate by molecular dynamics. We discuss the effect of pressure and thermal stress on very-fast folding model proteins, whose in vitro folding can be fully simulated on computers and compared with experiments. We then discuss experiments that can be used to subject proteins to low- and high-temperature unfolding, as well as low- and high-pressure unfolding. Pressure and temperature are prototypical perturbations that illustrate how close many proteins are to instability, a property that cells can exploit to control protein function. We conclude by reviewing some recent in-cell experiments, and progress being made in simulating and measuring protein stability and function inside live cells. PMID- 26231105 TI - Fabrication of rectorite-contained nanoparticles for drug delivery with a green and one-step synthesis method. AB - The composite nanoparticles (NPs) consisted of quaternized chitosan (QC)/bovine serum albumin (BSA)/rectorite (REC) were prepared successfully just by adding BSA solution into QC-REC nanocomposites solution via electrostatic interactions. The average diameter of NPs increased with the accretion of REC, which was demonstrated with dynamic laser scattering (DLS) and transmission electron microscopy (TEM). The results of small angle X-ray diffraction (SAXRD) and selected area electron diffraction (SAED) demonstrated that the intercalated structure of REC was enlarged with the addition of REC. Besides, it can was proved that the interaction had occurred between QC and REC in NPs with fourier transform infrared (FT-IR) and X-ray photoelectron spectroscopy (XPS). In addition, doxorubicin (DOX) was used to investigate the entrapment efficiency and release pattern in NPs. It turned out to be that the addition of REC could increase the encapsulation efficiency (EE) and loading capacity (LC). The results also exhibited that the drug release in simulated gastric fluid reduced apparently with the addition of REC, which could ensure more DOX released in intestines. PMID- 26231106 TI - Formulation and process factors influencing product quality and in vitro performance of ophthalmic ointments. AB - Owing to its unique anatomical and physiological functions, ocular surface presents special challenges for both design and performance evaluation of the ophthalmic ointment drug products formulated with a variety of bases. The current investigation was carried out to understand and identify the appropriate in vitro methods suitable for quality and performance evaluation of ophthalmic ointment, and to study the effect of formulation and process variables on its critical quality attributes (CQA). The evaluated critical formulation variables include API initial size, drug percentage, and mineral oil percentage while the critical process parameters include mixing rate, temperature, time and cooling rate. The investigated quality and performance attributes include drug assay, content uniformity, API particle size in ointment, rheological characteristics, in vitro drug release and in vitro transcorneal drug permeation. Using design of experiments (DoE) as well as a novel principle component analysis approach, five of the quality and performance attributes (API particle size, storage modulus of ointment, high shear viscosity of ointment, in vitro drug release constant and in vitro transcorneal drug permeation rate constant) were found to be highly influenced by the formulation, in particular the strength of API, and to a lesser degree by processing variables. Correlating the ocular physiology with the physicochemical characteristics of acyclovir ophthalmic ointment suggested that in vitro quality metrics could be a valuable predictor of its in vivo performance. PMID- 26231107 TI - Antifungal activity against Candida albicans of starch Pickering emulsion with thymol or amphotericin B in suspension and calcium alginate films. AB - Conventional antifungal treatments against Candida albicans in the oral cavity often result in increased cytotoxicity. The goal of this study was to determine the potential of starch Pickering emulsion as a delivery vehicle for an antifungal natural phenolic compound such as thymol in simulated saliva fluid (SSF) compared to amphotericin B. An oil-in-water (o/w) emulsion was stabilized using starch particles. Physical stability of the emulsion and disruption induced by alpha-amylase activity in SSF was evaluated. Encapsulated thymol in o/w emulsion was compared to encapsulated amphotericin B for antifungal activity against C. albicans in suspension using emulsions or zone inhibition assay on agar plates using emulsions dispersed in alginate films. Results showed that the emulsions were stable for at least three weeks. Digestion of the emulsion by alpha-amylase led to coalescence of emulsion droplets. The antifungal activity of thymol and amphotericin B in emulsion formulation was enhanced upon incubation with alpha-amylase. Results from the zone inhibition assay demonstrated efficacy of the emulsions dispersed in alginate films. Interestingly, addition of alpha amylase to the alginate films resulted in a decreased inhibitory effect. Overall, this study showed that starch Pickering emulsions have a potential to deliver hydrophobic antifungal compounds to treat oral candidiasis. PMID- 26231108 TI - Direct Quantification and Comparison of Intratumoral Hypoxia following Transcatheter Arterial Embolization of VX2 Liver Tumors with Different Diameter Microspheres. AB - PURPOSE: To evaluate the effect of embolic diameter on achievement of hypoxia after embolization in an animal model of liver tumors. MATERIALS AND METHODS: Inoculation of VX2 tumors in the left liver lobe was performed successfully in 12 New Zealand white rabbits weighing 3.7 kg +/- 0.5 (mean +/- SD). Tumors were deemed eligible for oxygen measurements when the maximum transverse diameter measured 15 mm or more by ultrasound examination. Direct monitoring of oxygenation of implanted rabbit hepatic VX2 tumors was performed with a fiberoptic electrode during and after transarterial embolization of the proper hepatic artery to angiographic flow stasis with microspheres measuring 70-150 MUm, 100-300 MUm, or 300-500 MUm in diameter. RESULTS: Failure to achieve tumor hypoxia as defined despite angiographic flow stasis was observed in 10 of 11 animals. Embolization microsphere size effect failed to demonstrate a significant trend on hypoxia outcome among the diameters tested, and pair-wise comparisons of different embolic diameter treatment groups showed no difference in hypoxia outcome. All microsphere diameters tested resulted in similar absolute reduction (24.3 mm Hg +/- 18.3, 29.1 mm Hg +/- 1.8, and 19.9 mm Hg +/- 9.3, P = .66) and percentage decrease in oxygen (56.0 mm Hg +/- 23.9, 56.0 mm Hg +/- 6.4, and 35.8 mm Hg +/- 20.6, P = .65). Pair-wise comparisons for percent tumor area occupied by embolic agents showed a significantly reduced fraction for 300-500 MUm diameters compared with 70-150 MUm diameters (P < .05). CONCLUSIONS: In the rabbit VX2 liver tumor model, three tested microsphere diameters failed to cause tumor hypoxia as measured by a fiberoptic probe sensor according to the adopted hypoxia definitions. PMID- 26231109 TI - Retrieval of TRAPEASE and OPTEASE Inferior Vena Cava Filters with Extended Dwell Times. AB - PURPOSE: To demonstrate that OPTEASE and TRAPEASE filters can be removed after dwell times greater than 60 days. MATERIALS AND METHODS: A retrospective review was performed of patients who underwent an attempted removal of a TRAPEASE or OPTEASE filter with a greater than 60-day dwell time between 2009 and 2015 at a single institution. Eleven patients within that time span were identified, and 10 were included in the review. One patient was excluded from the study because the date of filter placement was unknown. RESULTS: All filters were successfully retrieved. The average dwell time for removed TRAPEASE filters was 1,273 days (range, 129-3,582 d), with a median of 492 days (n = 5). The average dwell time for OPTEASE filters was 977 days (range, 123-2,584 d), with a median of 661 days (n = 5). The average dwell time of all filters was 1,125 days (range, 123-3,582 d), with a median of 577 days (n = 10). All patients exhibited inferior vena cava (IVC) stenosis after filter retrieval. An IVC pseudoaneurysm was present following retrieval in one case and resolved. In one case, a fractured filter strut was left completely embedded in the caval wall. Two patients reported unilateral leg swelling on clinical follow-up, and the remainder reported no leg swelling or tightness. CONCLUSIONS: Initial experience suggests that TRAPEASE and OPTEASE filters can be removed after extended dwell times. PMID- 26231110 TI - Radiofrequency Ablation of Functioning Adrenal Adenomas: Preliminary Clinical and Laboratory Findings. AB - PURPOSE: To evaluate clinical and laboratory findings in patients undergoing radiofrequency (RF) ablation for functioning adrenal adenomas. MATERIALS AND METHODS: Eleven adult patients, nine with Conn syndrome and two with Cushing syndrome, underwent percutaneous computed tomography-guided RF ablation for benign adrenal neoplasms. Systolic, diastolic, and mean blood pressure and the number of classes of antihypertensive drugs used by each patient were analyzed before and 1, 4, and 12 weeks after the procedure. Serum hormone levels were analyzed within 30 days before and 12 weeks after the procedure. RESULTS: Of the nine patients with Conn syndrome, eight showed normal serum aldosterone levels after the procedure and one patient had a nodule located very close to the inferior vena cava, resulting in incomplete ablation. The two patients with Cushing syndrome had normal serum and salivary cortisol levels after the procedure. Mean aldosterone concentration at baseline was 63.3 ng/dL +/- 28.0 and decreased to 13.3 ng/dL +/- 13.5 at 12 weeks postoperatively (P = .008). Systolic, diastolic, and mean blood pressures decreased significantly in the first week after the procedure (P < .001) and remained stable during further follow-up. CONCLUSIONS: In patients with Conn syndrome or Cushing syndrome, percutaneous RF ablation of functioning adrenal adenomas may result in normalization of hormone secretion, improvement in blood pressure, and reduced need for antihypertensive drugs. PMID- 26231111 TI - Prevalence of sedentary behavior in children under 2years: A systematic review. AB - Sedentary behavior has negative health outcomes, evident even in young children. Identifying the prevalence of sedentary behavior in children <2years is important for determining the necessity for intervention strategies. The aim of this systematic review was to determine the prevalence of sedentary behavior in children <2years. Medline, PsycINFO, SPORTDiscus, and Education Research Complete electronic databases were searched, as were reference lists of included articles and the authors' own collections. Inclusion criteria were: published in a peer reviewed English language journal; mean age of children <2years; and a reported measure of the prevalence of sedentary behavior. Twenty-four studies met the inclusion criteria. Most studies used parent-reported screen time as the sedentary behavior measure; only one study reported time spent restrained (i.e., kept inactive) and no studies reported objectively assessed sedentary time. Estimates of young children's screen time ranged from 36.6 to 330.9min/day. The proportion of children meeting the zero screen time recommendation ranged from 2.3% to 83.0%. In conclusion, very little is known about sedentary behaviors other than screen time in this age group. Although highly variable, findings suggest that children are already engaging in high levels of screen time by age 2 and the majority exceed current recommendations. PMID- 26231112 TI - Consumption of ultra-processed foods and obesity in Brazilian adolescents and adults. AB - OBJECTIVES: The aim of this study was to evaluate the relationship between the consumption of ultra-processed foods and obesity indicators among Brazilian adults and adolescents. METHODS: We used cross-sectional data on 30,243 individuals aged >=10 years from the 2008-2009 Brazilian Dietary Survey. Food consumption data were collected through 24-h food records. We classified food items according to characteristics of food processing. Ultra-processed foods were defined as formulations made by the food industry mostly from substances extracted from foods or obtained with the further processing of constituents of foods or through chemical synthesis, with little if any whole food. Examples included candies, cookies, sugar-sweetened beverages, and ready-to-eat dishes. Regression models were fitted to evaluate the association of the consumption of ultra-processed foods (% of energy intake) with body-mass-index, excess weight, and obesity status, controlling for socio-demographic characteristics, smoking, and physical activity. RESULTS: Ultra-processed foods represented 30% of the total energy intake. Those in the highest quintile of consumption of ultra processed foods had significantly higher body-mass-index (0.94 kg/m(2); 95% CI: 0.42,1.47) and higher odds of being obese (OR=1.98; 95% CI: 1.26,3.12) and excess weight (OR=1.26; 95% CI: 0.95,1.69) compared with those in the lowest quintile of consumption. CONCLUSION: Our findings support the role of ultra-processed foods in the obesity epidemic in Brazil. PMID- 26231113 TI - Cellular Factor XIIIA Transglutaminase Localizes in Caveolae and Regulates Caveolin-1 Phosphorylation, Homo-oligomerization and c-Src Signaling in Osteoblasts. AB - Transglutaminases (TGs) are a family of widely distributed enzymes that catalyze protein crosslinking by forming a covalent isopeptide bond between the substrate proteins. We have shown that MC3T3-E1 osteoblasts express Factor XIII-A (FXIII A), and that the extracellular crosslinking activity of FXIII-A is involved in regulating matrix secretion and deposition. In this study, we have investigated the localization and potential role of intracellular FXIII-A. Conventional immunofluorescence microscopy and TIRF microscopy analyses showed that FXIII-A co localizes with caveolin-1 in specialized membrane structures, caveolae, in differentiating osteoblasts. The caveolae-disrupting agent methyl-beta cyclodextrin abolished FXIII-A staining and co-localization with caveolin-1 from the osteoblast plasma membrane. The presence of FXIII-A in caveolae was confirmed by preparing caveolae-enriched cellular fractions using sucrose density gradient ultracentrifugation followed by western blotting. Despite this association of FXIII-A with caveolae, there was no detectable transglutaminase activity in caveolae, as measured by monodansylcadaverine incorporation. TG inhibitor NC9- which can alter TG enzyme conformation--localized to caveolae and displaced FXIII A from these structures when added to the osteoblast cultures. The decreased FXIII-A levels in caveolae after NC9 treatment increased c-Src activation, which resulted in caveolin-1 phosphorylation, homo-oligomerization and Akt phosphorylation, suggesting cellular FXIII-A has a role in regulating c-Src signaling in osteoblasts. PMID- 26231114 TI - Protective Effects of Antioxidant Peptide SS-31 Against Multiple Organ Dysfunctions During Endotoxemia. AB - Oxidative stress causes mitochondrial impairment, the failure of energy production, and consequent organ dysfunctions. The aim of the present study was to investigate the potential therapeutic effects of mitochondrial antioxidant SS 31 on sepsis-induced organ dysfunctions and to explore the possible mechanism. Sepsis was induced by cecal ligation and puncture. Immediately and at 5 h after the operation, SS-31 (5 mg/kg) or vehicle was administered intraperitoneally. The levels of organ dysfunctions, malondialdehyde, superoxide dismutase, proinflammatory cytokines, pulmonary wet-to-dry weight ratio, myeloperoxidase activity, histological scores, nuclear factor kappa B p65, inducible nitric oxide synthase, reactive oxygen species, adenosine triphosphate, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells were assessed at the indicated time points. The 7-day survival rate was estimated by the Kaplan-Meier method. In the present study, SS-31 treatment significantly improved sepsis-induced organ dysfunctions as evidenced by decreased histological scores, increased arterial partial oxygen tension, and deceased serum alanine aminotransferase, urea nitrogen, and creatinine levels, which was accompanied by decreased levels of malondialdehyde, tumor necrosis factor-alpha, pulmonary myeloperoxidase activity, nuclear factor kappa B p65, inducible nitric oxide synthase, reactive oxygen species, and TUNEL-positive cells. In conclusion, our data suggested that the protective effects of SS-31 on sepsis-induced organ dysfunctions were associated with the inhibition of proinflammatory cytokines, oxidative stress, and apoptosis. PMID- 26231115 TI - Distinct Murine Mucosal Langerhans Cell Subsets Develop from Pre-dendritic Cells and Monocytes. AB - Langerhans cells (LCs) populate the mucosal epithelium, a major entry portal for pathogens, yet their ontogeny remains unclear. We found that, in contrast to skin LCs originating from self-renewing radioresistant embryonic precursors, oral mucosal LCs derive from circulating radiosensitive precursors. Mucosal LCs can be segregated into CD103(+)CD11b(lo) (CD103(+)) and CD11b(+)CD103(-) (CD11b(+)) subsets. We further demonstrated that similar to non-lymphoid dendritic cells (DCs), CD103(+) LCs originate from pre-DCs, whereas CD11b(+) LCs differentiate from both pre-DCs and monocytic precursors. Despite this ontogenetic discrepancy between skin and mucosal LCs, the transcriptomic signature and immunological function of oral LCs highly resemble those of skin LCs but not DCs. These findings, along with the epithelial position, morphology, and expression of the LC-associated phenotype strongly suggest that oral mucosal LCs are genuine LCs. Collectively, in a tissue-dependent manner, murine LCs differentiate from at least three distinct precursors (embryonic, pre-DC, and monocytic) in steady state. PMID- 26231117 TI - Transcription Factor Bcl11b Controls Identity and Function of Mature Type 2 Innate Lymphoid Cells. AB - Type 2 innate lymphoid cells (ILC2s) promote anti-helminth responses and contribute to allergies. Here, we report that Bcl11b, previously considered a T cell-specific transcription factor, acted directly upstream of the key ILC2 transcription factor Gfi1 to maintain its expression in mature ILC2s. Consequently, Bcl11b(-/-) ILC2s downregulated Gata3 and downstream genes, including Il1rl1 (encoding IL-33 receptor), and upregulated Rorc and type 3 ILC (ILC3) genes. Additionally, independent of Gfi1, Bcl11b directly repressed expression of the gene encoding the ILC3 transcription factor Ahr, further contributing to silencing of ILC3 genes in ILC2s. Thus, Bcl11b(-/-) ILC2s lost their functions and gained ILC3 functions, and although they expanded in response to the protease allergen papain, they produced ILC3 but not ILC2 cytokines and caused increased airway infiltration of neutrophils instead of eosinophils. Our results demonstrate that Bcl11b is more than just a T-cell-only transcription factor and establish that Bcl11b sustains mature ILC2 genetic and functional programs and lineage fidelity. PMID- 26231116 TI - Out-of-Sequence Signal 3 Paralyzes Primary CD4(+) T-Cell-Dependent Immunity. AB - Primary T cell activation involves the integration of three distinct signals delivered in sequence: (1) antigen recognition, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing "bystander" T cell activation, thereby increasing the potential for autoreactivity and need for control. We show that during strong stimulation, a profound suppression of primary CD4(+) T-cell-mediated immune responses ensued and was observed across preclinical models and patients undergoing high-dose interleukin-2 (IL-2) therapy. This suppression targeted naive CD4(+) but not CD8(+) T cells and was mediated through transient suppressor of cytokine signaling-3 (SOCS3) inhibition of the STAT5b transcription factor signaling pathway. These events resulted in complete paralysis of primary CD4(+) T cell activation, affecting memory generation and induction of autoimmunity as well as impaired viral clearance. These data highlight the critical regulation of naive CD4(+) T cells during inflammatory conditions. PMID- 26231118 TI - MyD88 Adaptor-Dependent Microbial Sensing by Regulatory T Cells Promotes Mucosal Tolerance and Enforces Commensalism. AB - Commensal microbiota promote mucosal tolerance in part by engaging regulatory T (Treg) cells via Toll-like receptors (TLRs). We report that Treg-cell-specific deletion of the TLR adaptor MyD88 resulted in deficiency of intestinal Treg cells, a reciprocal increase in T helper 17 (Th17) cells and heightened interleukin-17 (IL-17)-dependent inflammation in experimental colitis. It also precipitated dysbiosis with overgrowth of segmented filamentous bacteria (SFB) and increased microbial loads in deep tissues. The Th17 cell dysregulation and bacterial dysbiosis were linked to impaired anti-microbial intestinal IgA responses, related to defective MyD88 adaptor- and Stat3 transcription factor dependent T follicular regulatory and helper cell differentiation in the Peyer's patches. These findings establish an essential role for MyD88-dependent microbial sensing by Treg cells in enforcing mucosal tolerance and maintaining commensalism by promoting intestinal Treg cell formation and anti-commensal IgA responses. PMID- 26231121 TI - White matter structure in young adults with familial risk for psychosis - The Oulu Brain and Mind Study. AB - According to the disconnectivity model, disruptions in neural connectivity play an essential role in the pathology of schizophrenia. The aim of this study was to determine whether these abnormalities are present in young adults with familial risk (FR) for psychosis in the general population based sample. We used diffusion tensor imaging (DTI) and tract-based spatial statistics to compare whole-brain fractional anisotropy, mean diffusivity, and axial and radial diffusion in 47 (17 males) FR subjects to 51 controls (17 males). All the participants were aged between 20 and 25 years and were members of the Northern Finland Birth Cohort 1986 (Oulu Brain and Mind Study). Region of interest analyses were conducted for 12 tracts. Separately, we analysed whole-brain FA for the subgroup with FR for schizophrenia (n=13) compared with 13 gender-matched controls. Contrary to our expectations there were no differences in any of the DTI measures between FR and control groups. This suggests that white matter abnormalities may not be a genetic feature for risk of psychosis and preceding the onset of a psychotic disorder. Our findings do not support the theory of disconnectivity as a primary sign of psychosis in young adults with FR for the illness. PMID- 26231119 TI - A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3zetazeta. AB - The eight-subunit T cell receptor (TCR)-CD3 complex is the primary determinant for T cell fate decisions. Yet how it relays ligand-specific information across the cell membrane for conversion to chemical signals remains unresolved. We hypothesized that TCR engagement triggers a change in the spatial relationship between the associated CD3zetazeta subunits at the junction where they emerge from the membrane into the cytoplasm. Using three in situ proximity assays based on ID-PRIME, FRET, and EPOR activity, we determined that the cytosolic juxtamembrane regions of the CD3zetazeta subunits are spread apart upon assembly into the TCR-CD3 complex. TCR engagement then triggered their apposition. This mechanical switch resides upstream of the CD3zetazeta intracellular motifs that initiate chemical signaling, as well as the polybasic stretches that regulate signal potentiation. These findings provide a framework from which to examine triggering events for activating immune receptors and other complex molecular machines. PMID- 26231120 TI - Protein Tyrosine Phosphatase PTPRS Is an Inhibitory Receptor on Human and Murine Plasmacytoid Dendritic Cells. AB - Plasmacytoid dendritic cells (pDCs) are primary producers of type I interferon (IFN) in response to viruses. The IFN-producing capacity of pDCs is regulated by specific inhibitory receptors, yet none of the known receptors are conserved in evolution. We report that within the human immune system, receptor protein tyrosine phosphatase sigma (PTPRS) is expressed specifically on pDCs. Surface PTPRS was rapidly downregulated after pDC activation, and only PTPRS(-) pDCs produced IFN-alpha. Antibody-mediated PTPRS crosslinking inhibited pDC activation, whereas PTPRS knockdown enhanced IFN response in a pDC cell line. Similarly, murine Ptprs and the homologous receptor phosphatase Ptprf were specifically co-expressed in murine pDCs. Haplodeficiency or DC-specific deletion of Ptprs on Ptprf-deficient background were associated with enhanced IFN response of pDCs, leukocyte infiltration in the intestine and mild colitis. Thus, PTPRS represents an evolutionarily conserved pDC-specific inhibitory receptor, and is required to prevent spontaneous IFN production and immune-mediated intestinal inflammation. PMID- 26231122 TI - Reduced neural differentiation between self-referential cognitive and emotional processes in women with borderline personality disorder. AB - Borderline personality disorder (BPD) is associated with disturbed emotion regulation. Psychotherapeutic interventions using mindfulness elements have shown effectiveness in reducing clinical symptoms, yet little is known about their underlying neurobiology. In this functional magnetic resonance imaging (fMRI) study, 19 female BPD patients and 19 healthy controls were compared during mindful introspection, cognitive self-reflection and a neutral condition. The activation pattern in the right dorsomedial prefrontal cortex (DMPFC) in BPD patients was different from that in healthy subject when directing attention onto their emotions and bodily feelings in contrast to cognitively thinking about themselves. Mindful introspection compared with the neutral condition was associated with higher activations in bilateral motor/pre-motor regions, left inferior frontal gyrus (IFG), and left posterior cingulate cortex (PCC), while cognitive self-reflection activated the right motor and somatosensory cortex, extending into the right supramarginal gyrus (SMG) and superior temporal gyrus (STG) in BPD patients compared with the controls. Results indicate that self referential cognitive and emotional processes are not clearly differentiated in BPD patients at the neurobiological level. In particular, altered neural mechanism underlying self-referential thinking may be related to some aspects of the typical emotion dysregulation in BPD. Current data support the finding that mindful self-focused attention is effective in regulating amygdala activity in BPD as well as in healthy subjects. PMID- 26231123 TI - Biocatalysts for biomass deconstruction from environmental genomics. AB - Plant biomass offers a sustainable alternative to the energy and materials produced from fossil fuels. The industrial scale production or biorefining of fermentable sugars and aromatics from plant biomass is currently limited by the lack of cost effective and efficient biocatalysts. One potential solution to this problem is the discovery of biomass deconstructing biocatalysts from uncultivated microbial communities. Here we review recent progress in recovering such biological devices from environmental genomes and consider how this information can be used to build better biorefining ecosystems. PMID- 26231124 TI - Enhanced long-term ammonium removal and its ranked contribution of microbial genes associated with nitrogen cycling in a lab-scale multimedia biofilter. AB - The multimedia biofilter achieved high and stable removal efficiencies for chemical oxygen demand (COD, 62-98%) and NH4(+) (68-98%) without costly aeration. Results revealed that lower CL (less than 13.9gCOD/m(3)d) and ACL (less than 2.8gNH4(+)-N/m(3)d) or a C/N ratio exceeding five was required to reduce NO3(-)-N accumulation and NO/N2O emission. Integrated analyses indicated that the coupling of simultaneous nitrification, anammox and denitrification processes (SNAD) were the primary reason accounted for the enhanced NH4(+)-N treatment performance. NH4(+)-N removal pathways can be ranked as follows: nitrification (amoA, archaeal) (54.6%)>partial denitrification (nirS, nirK) and anammox (37.8%)>anammox and partial denitrification (narG, napA) (12.6%). Specifically, NH4(+)-N removal was significantly inhibited by NO2(-)-N accumulation in the system (-21.6% inhibition). Results from stepwise regression analysis suggested that the NH4(+) removal rate was collectively controlled by amoA, archaeal, anammox, nirS, nirK, narG and napA. PMID- 26231125 TI - Energy analysis for the production of biodiesel in a spiral reactor using supercritical tert-butyl methyl ether (MTBE). AB - In this study, energy analysis was conducted for the production of biodiesel in a spiral reactor using supercritical tert-butyl methyl ether (MTBE). This study aims to determine the net energy ratio (NER) and energy efficiency for the production of biodiesel using supercritical MTBE and to verify the effectiveness of the spiral reactor in terms of heat recovery efficiency. The analysis results revealed that the NER for this process was 0.92. Meanwhile, the energy efficiency was 0.98, indicating that the production of biodiesel in a spiral reactor using supercritical MTBE is an energy-efficient process. By comparing the energy supply required for biodiesel production between spiral and conventional reactors, the spiral reactor was more efficient than the conventional reactor. PMID- 26231126 TI - Alterations of the lipid content and fatty acid profile of Chlorella protothecoides under different light intensities. AB - Chlorella protothecoides is a valuable source of lipids that may be used for biodiesel production. The present work shows analysis of the potential of photoheterotrophic cultivation of C. protothecoides under various light intensities aiming to identify the conditions with maximal biomass and lipid content. An increase in light intensity was associated with an increased specific growth rate and a shortened doubling time. Also, the relative total lipid content increased from 24.8% to 37.5% with increase of light intensity. The composition of fatty acid methyl esters was affected by light intensity with the C16-18 fatty acids increased from 76.97% to 90.24% of total fatty acids. However, the content of linolenic acids decreased with the increase of the culture irradiance. These studies indicate that cultures irradiated with high light intensities achieve the minimal specifications for biodiesel quality on linolenic acids and thus are suitable for biodiesel production. PMID- 26231127 TI - Simulation of the ozone pretreatment of wheat straw. AB - Wheat straw is a potential feedstock in biorefinery for sugar production. However, the cellulose, which is the major source of sugar, is protected by lignin. Ozonolysis deconstructs the lignin and makes cellulose accessible to enzymatic digestion. In this study, the change in lignin concentration with different ozonolysis times (0, 1, 2, 3, 5, 7, 10, 15, 20, 30, 60min) was fit to two different kinetic models: one using the model developed by Garcia-Cubero et al. (2012) and another including an outer mass transfer barrier or "cuticle" region where ozone mass transport is reduced in proportion to the mass of unreacted insoluble lignin in the cuticle. The kinetic parameters of two mathematical models for predicting the soluble and insoluble lignin at different pretreatment time were determined. The results showed that parameters derived from the cuticle-based model provided a better fit to experimental results compared to a model without a cuticle layer. PMID- 26231128 TI - Mechanistic analysis of ultrasound assisted enzymatic desulfurization of liquid fuels using horseradish peroxidase. AB - This study has attempted to gain physical insight into ultrasound-assisted enzymatic desulfurization using system comprising horseradish peroxidase enzyme and dibenzothiophene (DBT). Desulfurization pathway (comprising DBT-sulfoxide and DBT-sulfone as intermediates and 4-methoxy benzoic acid as final product) has been established with GC-MS analysis. Intrinsic fluorescence and circular dichroism spectra of ultrasound-treated enzyme reveal conformational changes in secondary structure (reduction in alpha-helix and beta-conformations and increase in random coil content) leading to enhancement in activity. Concurrent analysis of desulfurization profiles, Arrhenius and thermodynamic parameters, and simulations of cavitation bubble dynamics reveal that strong micro-convection generated by sonication enhances enzyme activity and desulfurization kinetics. Parallel oxidation of DBT by radicals generated from transient cavitation gives further boost to desulfurization kinetics. However, random motion of enzyme molecules induced by shock waves reduces frequency factor and limits the ultrasonic enhancement of enzymatic desulfurization. PMID- 26231129 TI - Understanding low-lipid algae hydrothermal liquefaction characteristics and pathways through hydrothermal liquefaction of algal major components: crude polysaccharides, crude proteins and their binary mixtures. AB - Crude polysaccharides and proteins extracted from algae were chosen as model materials to investigate the hydrothermal liquefaction (HTL) characteristics and pathways of low-lipid algae. Liquefaction behavior of the two individuals and their binary mixtures with different mass ratios were evaluated under different temperatures. Formation pathways of bio-oil from crude polysaccharides/proteins were proposed. Results showed that polysaccharides had a small contribution to bio-oil (<5%) and approximately 60% distributed in aqueous phase, while proteins played a crucial role on bio-oil formation (maximum 16.29%). Bio-oil from polysaccharides mainly contained cyclic ketones and phenols and from proteins composed of pyrazines, pyrroles and amines. Interaction between polysaccharides and proteins forming polycyclic nitrogenous compounds had a negative effect on bio-oil yield at 220 and 260 degrees C. However, their further decomposition caused increase of bio-oil yield at 300 degrees C. Mixture liquefaction obtained the highest higher heating value (HHV) of bio-oil and energy recovery than polysaccharides/proteins liquefaction at 300 degrees C. PMID- 26231130 TI - Evaluation of the microbial cell structure damages in alkaline pretreatment of waste activated sludge. AB - This study investigated the damages of microbial cell structures, as well as the relationships between these damages and the release of cellular organic matter in the pretreatment of waste activated sludge (WAS) by using alkaline pretreatment as model. In the alkaline pretreatment of WAS, the most damage of bound extracellular polymeric substances (EPS), cell walls, cell membranes, and cell nuclei occurred at pH 11.5-12.0 (46.2%), pH 11.0-11.5 (27.3%), pH 9.0-10.0 (34.2%), and pH 11.5-12.0 (44.4%), respectively. The damage percentages of these cell structures in the pH stabilization stage were low because most of the damages occurred when the pH increased. The structural integrities of sludge microorganisms were all damaged in the pH increase stage. The damages of EPS, cell walls, and cell membranes were significantly correlated with the release of cellular organic matter, and these damages were necessary to release the cellular matter in WAS. PMID- 26231131 TI - Effect of Ca(OH)2 pretreatment on extruded rice straw anaerobic digestion. AB - It has been proven that extrusion can change the structure of rice straw and increase biogas production, but the effect of a single pretreatment is limited. Ca(OH)2 pretreatment was used to enhance the enzyme hydrolysis and biogas production of extruded rice straw. After Ca(OH)2 pretreatment, the glucose and xylose conversion rates in enzymatic hydrolysis increased from 36.0% and 22.4% to 66.8% and 50.2%, respectively. The highest biogas production observed in 8% and 10% Ca(OH)2 pretreated rice straw reached 564.7mL/g VS and 574.5mL/g VS, respectively, which are 34.3% and 36.7% higher than the non-Ca(OH)2-loaded sample. The Ca(OH)2 pretreatment can effectively remove the lignin and increase the fermentable sugar content. The structural changes in the extruded rice straw have also been analyzed by XRD, FTIR, and SEM. Considering all of the results, an 8% Ca(OH)2 loading rate is the best option for the pretreatment of extruded rice straw. PMID- 26231132 TI - Effect of electro-stimulation on activity of heterotrophic denitrifying bacteria and denitrification performance. AB - The effects of electro-stimulation on heterotrophic denitrifying bacterial activity and nitrate removal were investigated using a bench-scale bio electrochemical reactor in this study. Results showed that the maximum nitrate removal efficiency was 100% at the optimum current density of 200mA/m(2), at which low nitrite production and high ATP aggregate level were obtained. The activity of denitrifying bacteria was highest at the range densities of 200 250mA/m(2), although the terminative pH increased to 8.62 at 200mA/m(2) and 9.63 at 250mA/m(2). This demonstrates that suitable current densities could improve the activity of denitrifying bacteria. Therefore, this study provides a number of useful information to improve the bio-electrochemical reactor designs and promote the removal efficiency of pollutants. PMID- 26231133 TI - Cardiovascular Risk Factors in Central Retinal Artery Occlusion: Results of a Prospective and Standardized Medical Examination. AB - PURPOSE: To analyze the underlying risk factors in patients with nonarteritic central retinal artery occlusion (CRAO) in a well-defined and homogenous group of patients enrolled in the European Assessment Group for Lysis in the Eye (EAGLE) study. DESIGN: Analysis of the cardiovascular risk factors in a prospective, randomized clinical trial. PARTICIPANTS: Seventy-seven EAGLE patients with nonarteritic CRAO. METHODS: Analysis of vascular risk factors and underlying diseases detected by questionnaire and standardized physical examination within 1 month after occlusion. MAIN OUTCOME MEASURES: The standardized physical examination included carotid Doppler ultrasonography, echocardiography, electrocardiography, blood pressure monitoring, pulse rate, urine analysis, body mass index analysis, and laboratory tests. RESULTS: Seventy-seven of 84 patients had complete datasets for analysis. Fifty-two (67%) patients had cardiovascular risk factors in their medical history, and comprehensive phenotyping identified at least 1 new risk factor in 60 patients (78%; 95% confidence interval, 67% 87%). Thirty-one (40%) had carotid artery stenosis of at least 70%. Eleven patients experienced a stroke, 5 of those within 4 weeks after the CRAO occurred. Arterial hypertension was found in 56 (73%) patients and was newly diagnosed in 12 (16%) study participants. Cardiac diseases were also highly prevalent (22% coronary artery disease, 20% atrial fibrillation, and 17% valvular heart disease). CONCLUSIONS: Previously undiagnosed vascular risk factors were found in 78% of all CRAO patients. The most meaningful risk factor was ipsilateral carotid artery stenosis. A comprehensive and prompt diagnostic work-up is mandatory for all CRAO patients. PMID- 26231134 TI - Comparative analysis of two 16S rRNA gene-based PCR primer sets provides insight into the diversity distribution patterns of anammox bacteria in different environments. AB - Due to the high divergence among 16S rRNA genes of anammox bacteria, different diversity pattern of the community could be resulted from using different primer set. In this study, the efficiencies and specificities of two commonly used sets, Amx368F/Amx820R and Brod541F/Amx820R, were evaluated by exploring the diversity characteristics of anammox bacteria in sediments from marine, estuary, and freshwater wetland. Statistical analysis indicated that the base mispairing rate between bases on 16S rRNA gene sequences retrieved by Amx368F/Amx820R and their corresponding ones on primer Brod541F was quite high, suggesting the different efficiency and specificity of Amx368F/Amx820R and Brod541F/Amx820R. Further experimental results demonstrated that multiple genera of anammox bacteria, including Ca. Scalindua, Ca. Brocadia, and Ca. Kuenenia, were able to be detected by Amx368F/Amx820R, but only Ca. Scalindua could be retrieved by Brod541F/Amx820R. Moreover, the phylogenetic clusters of Ca. Scalindua by Amx368F/Amx820R were different completely from those by Brod541F/Amx820R, presenting a significant complementary effect. By joint application of these two primer sets, the diversity distribution patterns of anammox bacteria in different environments were analyzed. Almost all retrieved sequences from marine sediments belonged to Ca. Scalindua. Sequences from freshwater wetland were affiliated to Ca. Brocadia and two new clusters, while high diversity of anammox bacteria was found in estuary, including Ca. Scalindua, Ca. Brocadia, and Ca. Kuenenia, corresponding to the river-sea intersection environmental feature. In total, these two prime sets have different characteristic for anammox bacteria detecting from environmental samples, and their combined application could achieve better diversity display of anammox community. PMID- 26231135 TI - The influence of naphthaleneacetic acid (NAA) and coumarin on flavonoid production by fungus Phellinus sp.: modeling of production kinetic profiles. AB - For the purpose of improving the fungal production of flavonoids, the influence of naphthaleneacetic acid (NAA) and coumarin on flavonoid production by fungus Phellinus sp. P0988 was investigated by developing the corresponding kinetics of flavonoid production in a 7-L bioreactor. Phellinus sp. was confirmed to form flavonoids in pellets and broth when cultivated in basic medium, and the optimum concentration of NAA and coumarin in medium for flavonoid production were determined to be 0.03 and 0.02 g/L, respectively. The developed unstructured mathematical models were in good agreement with the experimental results with respect to flavonoid production kinetic profiles with NAA and coumarin supplementation at optimum levels and revealed significant accuracy in terms of statistical consistency and robustness. Analysis of these kinetic processes indicated that NAA and coumarin supplementations imposed a stronger positive influence on flavonoid production and substrate consumption compared to their effects on cell growth. The separate addition of NAA and coumarin resulted in enhancements in final product accumulation and productivity, achieving final flavonoid concentrations of 3.60 and 2.75 g/L, respectively, and glucose consumption showed a significant decrease compared to the non-supplemented control as well. Also, the separate presence of NAA and coumarin respectively decreased maintenance coefficients (M s) from 2.48 in the control to 1.39 and 0.22, representing decreases of 43.9 and 91.1 %, respectively. The current study is the first known application of mathematical kinetic models to explore the influence of medium components adding on flavonoid production by fungi. PMID- 26231136 TI - Biochemical properties of retinoid-converting enzymes and biotechnological production of retinoids. AB - Retinoids are a class of compounds that are forms of vitamin A and include retinal, retinol, retinoic acid, and retinyl ester. Retinal is involved in visual cycle, retinol has anti-infective, anticancer, antioxidant, and anti-wrinkle functions, and retinoic acid is used to treat acne and cancer. Retinol, retinoic acid, and retinyl ester are used in cosmetic and pharmaceutical industries. In this article, the biochemical properties and active sites and reaction mechanisms of retinoid-converting enzymes in animals and bacteria, including retinol dehydrogenase, alcohol dehydrogenase, aldo-keto reductase, and aldehyde dehydrogenase, are reviewed. The production of retinoids, using retinoid producing enzymes and metabolically engineered cells, is also described. Uncharacterized bacterial proteins are suggested as retinoid-converting enzymes, and the production of retinoids using metabolically engineered cells is proposed as a feasible method. PMID- 26231138 TI - Erratum to: Abstracts of the MASCC/ISOO 2015 Annual Meeting. PMID- 26231137 TI - Hydrocarbons, the advanced biofuels produced by different organisms, the evidence that alkanes in petroleum can be renewable. AB - It is generally regarded that the petroleum cannot be renewable. However, in recent years, it has been found that many marine cyanobacteria, some eubacteria, engineered Escherichia coli, some endophytic fungi, engineered yeasts, some marine yeasts, plants, and insects can synthesize hydrocarbons with different carbon lengths. If the organisms, especially some native microorganisms and engineered bacteria and yeasts, can synthesize and secret a large amount of hydrocarbons within a short period, alkanes in the petroleum can be renewable. It has been documented that there are eight pathways for hydrocarbon biosynthesis in different organisms. Unfortunately, most of native microorganisms, engineered E. coli and engineered yeasts, only synthesize a small amount of intracellular and extracellular hydrocarbons. Recently, Aureobasidium pullulans var. melanogenum isolated from a mangrove ecosystem has been found to be able to synthesize and secret over 21.5 g/l long-chain hydrocarbons with a yield of 0.275 g/g glucose and a productivity of 0.193 g/l/h within 5 days. The yeast may have highly potential applications in alkane production. PMID- 26231139 TI - Notochord to Nucleus Pulposus Transition. AB - A tissue that commonly deteriorates in older vertebrates is the intervertebral disc, which is located between the vertebrae. Age-related changes in the intervertebral discs are thought to cause most cases of back pain. Back pain affects more than half of people over the age of 65, and the treatment of back pain costs 50-100 billion dollars per year in the USA. The normal intervertebral disc is composed of three distinct regions: a thick outer ring of fibrous cartilage called the annulus fibrosus, a gel-like material that is surrounded by the annulus fibrosus called the nucleus pulposus, and superior and inferior cartilaginous end plates. The nucleus pulposus has been shown to be critical for disc health and function. Damage to this structure often leads to disc disease. Recent reports have demonstrated that the embryonic notochord, a rod-like structure present in the midline of vertebrate embryos, gives rise to all cell types found in adult nuclei pulposi. The mechanism responsible for the transformation of the notochord into nuclei pulposi is unknown. In this review, we discuss potential molecular and physical mechanisms that may be responsible for the notochord to nuclei pulposi transition. PMID- 26231140 TI - Effect of tannic acid, resveratrol and its derivatives, on oxidative damage and apoptosis in human neutrophils. AB - In this study we compared the antioxidant and DNA protective activity of tannic acid and stilbene derivatives, resveratrol, 3,5,4(')-trimethoxystilbene (TMS) and pterostilbene in human neutrophils stimulated to oxidative burst by 12-O tetradecanoyl-phorbol-13-acetate (TPA) in relation to apoptosis induction. All polyphenols within the concentration range 1-100 MUM reduced the intracellular ROS and H2O2 production in the TPA-stimulated cells. Tannic acid was the most effective polyphenol in protection against DNA damage induced by TPA. In the resting neutrophils resveratrol and to lesser extent other polyphenols increased DNA damage and increased the level of p53. Pretreatment of the TPA-stimulated cells with tannic acid or stilbenes led to the induction of apoptosis. The most significant effect was observed as a result of treatment with TMS and resveratrol. These compounds appeared the most effective inducers of p53 in the TPA-challenged neutrophils, what may suggest that pro-apoptotic activity of these stilbenes might be related to p53 activation. Overall, the results of our present study demonstrate that tannic acid and stilbenes modulate the ROS production, ultimately leading to cell apoptosis in human neutrophils stimulated to oxidative burst. In resting neutrophils they exhibit pro-oxidant activity, which is accompanied by p53 induction. PMID- 26231141 TI - A Role for Low Density Lipoprotein Receptor-Related Protein 1 in the Cellular Uptake of Tissue Plasminogen Activator in the Lungs. AB - PURPOSE: To gain knowledge of lung clearance mechanisms of inhaled tissue plasminogen activator (tPA). METHODS: Using an in vivo mouse model and ex vivo murine whole organ cell suspensions, we examined the capability of the lungs to utilize LRP1 receptor-mediated endocytosis (RME) for the uptake of exogenous tPA with and without an LRP1 inhibitor, receptor associated protein (RAP), and quantitatively compared it to the liver. We also used a novel imaging technique to assess the amount LRP1 in sections of mouse liver and lung. RESULTS: Following intratracheal administration, tPA concentrations in the bronchoalveolar lavage fluid (BALF) declined over time following two-compartment pharmacokinetics suggestive of a RME clearance mechanism. Ex vivo studies showed that lung and liver cells are similarly capable of tPA uptake via LRP1 RME which was reduced by ~50% by RAP. The comparable lung and liver uptake of tPA is likely due to equivalent amounts of LRP1 of which there was an abundance in the alveolar epithelium. CONCLUSIONS: Our findings indicate that LRP1 RME is a candidate clearance mechanism for inhaled tPA which has implications for the development of safe and effective dosing regimens of inhaled tPA for the treatment of plastic bronchitis and other fibrin-inflammatory airway diseases in which inhaled tPA may have utility. PMID- 26231145 TI - Genetic modification of the human germ line: The reasons why this project has no future. AB - Modification of the human germ line has remained a distant but valuable objective for most biologists since the emergence of genetics (and even before). To study the historical transformations of this project, I have selected three periods - the 1930s, at the pinnacle of eugenics, around 1974 when molecular biology triumphed, and today - and have adopted three criteria to estimate the feasibility of this project: the state of scientific knowledge, the existence of suitable tools, and societal demands. Although the long-awaited techniques to modify the germ line are now available, I will show that most of the expectations behind this project have disappeared, or are considered as being reachable by highly different strategies. PMID- 26231146 TI - A case for leveraging integrated regulation strategies to optimize health benefits from self-determined exercise behavior. PMID- 26231147 TI - Calcium phosphate cement enhances the torsional strength and stiffness of high tibial osteotomies. AB - PURPOSE: There has been a resurgence in the use of opening wedge high tibial osteotomy (owHTO). Calcium phosphate cement has been shown to improve strength in compression for augmentation of tibial plateau and owHTO fixation. However, knee kinematics includes a torsional load during ambulation, which is as yet unstudied in this model. The purpose of this paper is to investigate the effect of injectable calcium phosphate cement on the biomechanical stability of standard high tibial osteotomy defect with applied torsional load and ultimate stiffness of the supporting construct. METHODS: Testing was performed on 22 bone mineral density-matched and age-matched cadaver specimens. Intact specimens were treated with 10 degrees opening wedge osteotomies, identical surgical techniques as clinically used and fixation provided by iBalance(c) PEEK implant (Arthrex, Naples FL). Nine specimens were augmented with calcium phosphate injectable cement, Quickset (Arthrex Inc., Naples Fl). Constructs were for construct stiffness, torsional loads to failure, and mechanisms of failure. As a gold standard comparison group, four samples were tested with a titanium, fixed angle device alone: Contourlock plate (Arthrex Inc., Naples Fl). RESULTS: Peak torque to failure was significantly greater in samples augmented with calcium phosphate bone cement (23.0 +/- 9.6 Nm) compared with specimens fixed with PEEK implant alone (18.1 +/- 7.3). Construct stiffness in torsion was also significantly improved with bone cement application (349.0 +/- 126.8 Nm/ degrees ) compared with PEEK implant alone (202.2 +/- 153.4 Nm/ degrees ) and fixed angle implant system (142.9 +/- 74.7 Nm/ degrees ). CONCLUSION: Injectable calcium phosphate cement improves the initial maximal torsional strength and stiffness of high tibial osteotomy construct. PMID- 26231148 TI - The Bristow-Latarjet procedure, a historical note on a technique in comeback. AB - The Bristow-Latarjet procedure is a well-known surgical technique designed to treat shoulder instability. In this procedure, the coracoid process is transferred to the glenoid rim, to serve as augmentation of an associated bony defect. Because long-term results following a soft tissue procedure (Bankart repair) reveal that up to 21 and 33 % of the patients might experience recurrent instability and with the advent of the arthroscopic coracoid transfer, there is renewed interest in this procedure to treat shoulder instability. The aim of this study is to provide a historical overview, with emphasis on the original inventors Bristow and Latarjet, the complications and following modifications regarding the surgical approach, the coracoid transfer and the arthroscopic technique. Level of evidence V. PMID- 26231149 TI - Anterior cruciate ligament deficiency reduces walking economy in "copers" and "non-copers". AB - PURPOSE: Patients with ACL injury requiring surgical treatment (non-copers) demonstrate altered neuromuscular control and gait pattern compared with those returning to their pre-injury activities without surgery (copers). Pathological gait pattern may increase the energy cost of walking. We compared the energy cost of flat, uphill, and downhill walking between ACL-deficient and healthy individuals and between "copers" and "non-copers". METHODS: Nineteen young males with unilateral ACL injury were allocated into "copers" and "non-copers" according to their ability to return to pre-injury activity without ACL reconstruction. Lysholm and IKDC scales were recorded, and a control group (n = 10) matched for physical characteristics and activity levels was included. All participants performed 8-min walking tasks at 0, +10, and -10 % gradients. Energy cost was assessed by measurement of oxygen consumption (VO2). HR and ventilation (VE), respiratory exchange ratio (RER), and VE/VO2 were also measured. RESULTS: VO2 and HR were higher in ACL-deficient patients than in controls during walking at 0, +10, and -10 % gradients (p < 0.01-0.05). There were no differences between "copers" and "non-copers" in VO2 and HR for any gradient. No differences were observed in VE, RER, and VE/VO2 among the three groups. CONCLUSIONS: The walking economy of level, uphill, and downhill walking is reduced in ACL-deficient patients. Despite the improved functional and clinical outcome of "copers", their walking economy appears similar to that of "non-copers" but impaired compared with healthy individuals. The higher energy demand and effort during locomotion in "copers" and "non-copers" has clinical implications for designing safer rehabilitation programmes. The increased energy cost in "copers" may be another parameter to consider when deciding on the most appropriate therapeutic intervention (operative and non-operative), particularly for athletes. LEVEL OF EVIDENCE: II. PMID- 26231150 TI - A history of meniscal surgery: from ancient times to the twenty-first century. AB - The science and surgery of the meniscus have evolved significantly over time. Surgeons and scientists always enjoy looking forward to novel therapies. However, as part of the ongoing effort at optimizing interventions and outcomes, it may also be useful to reflect on important milestones from the past. The aim of the present manuscript was to explore the history of meniscal surgery across the ages, from ancient times to the twenty-first century. Herein, some of the investigations of the pioneers in orthopaedics are described, to underline how their work has influenced the management of the injured meniscus in modern times. Level of evidence V. PMID- 26231151 TI - The effectiveness of Pilates for partial anterior cruciate ligament injury. AB - PURPOSE: This study explored the effects of Pilates on the muscle strength, function, and instability of patients with partial anterior cruciate ligament (ACL) injuries in situations in which a non-surgical treatment option is preferred. METHODS: Fifty participants 20-45 years of age who were diagnosed with isolated ACL injuries were included in the study. The participants were randomly assigned to either the Pilates exercise group (n = 24) or the control group (n = 26). The subjects in the Pilates exercise group performed basic mat exercises that focused on the muscle strength and flexibility of the lower limbs and core muscles during each class session, which met three times per week for 12 weeks. The control group did not receive any treatment or home exercise programme. All patients were evaluated using the Lysholm Knee Scale, the Cincinnati Knee Rating System, and isokinetic quadriceps and hamstring strength. Patient satisfaction regarding improvement in knee stability was assessed using the Global Rating of Change scale. RESULTS: The Pilates group experienced significant improvement over the control group as measured by the difference in quadriceps strength at 12 weeks (p = 0.03). Both groups showed some clinical change over time, but the Pilates group improved for all outcome measurements at the 12-week follow-up, and the control group only improved for functional outcomes. Patient satisfaction with the level of knee stability based on the Global Rating of Change scale was higher in the Pilates group than in the control group. CONCLUSION: Although both groups exhibited improvements in knee strength and functional outcomes, the results suggest that Pilates is a superior management approach over a control treatment for increasing quadriceps strength in participants with partial ACL injury. Pilates may provide clinicians a novel option when choosing a treatment for a partial ACL injury. Further study is needed to determine whether certain subgroups of individuals might achieve an added benefit with this approach. LEVEL OF EVIDENCE: II. PMID- 26231152 TI - Evaluating healthcare resource utilization and outcomes for surgical hip dislocation and hip arthroscopy for femoroacetabular impingement. AB - PURPOSE: Surgical hip dislocation (SHD) and hip arthroscopy are surgical methods used to correct deformity associated with femoroacetabular impingement (FAI). Though both of these approaches appear to benefit patients, no studies exist comparing healthcare resource utilization of the two surgical approaches. This systematic review examines the literature and the records of two surgeons to evaluate the resource utilization associated with treating symptomatic FAI via these two methods. METHODS: EMBASE, MEDLINE and PubMed were searched for relevant articles. The articles were systematically screened, and data was abstracted in duplicate. To further supplement resource utilization data, a retrospective chart review of two surgeon's patient data (one using SHD and another using an arthroscopic approach) was completed. Experts in pharmacy, physiotherapy, radiology, anaesthesia, physiatry and the local hospital finance department were also consulted. RESULTS: There were 52 studies included with a total of 460 patients (535 hips) and 3886 patients (4147 hips) who underwent SHD and arthroscopic surgery for FAI, respectively. Regardless of approach, most patients treated for symptomatic FAI improved across various outcomes measures with low complication rates. Surgical time across all approaches was similar, averaging 118 +/- 2 min. On a per patient basis, hip arthroscopy ($10,976) uses approximately 41 % of the resources of SHD ($24,379). CONCLUSION: There were no significant differences in outcomes for FAI treated with SHD or arthroscopy. However, with regard to healthcare resource utilization based on the OHIP healthcare system, hip arthroscopy uses substantially less resources than SHD within the first post-operative year. LEVEL OF EVIDENCE: Systematic Review of Level IV Studies, Level IV. PMID- 26231153 TI - A matched-pair comparison of inlay and onlay trochlear designs for patellofemoral arthroplasty: no differences in clinical outcome but less progression of osteoarthritis with inlay designs. AB - PURPOSE: To compare clinical and radiographic results after isolated patellofemoral arthroplasty (PFA) using either a second-generation inlay or onlay trochlear design. The hypothesis was that an inlay design will produce better clinical results and less progression of tibiofemoral osteoarthritis (OA) compared to an onlay design. METHODS: Fifteen consecutive patients undergoing isolated PFA with an onlay design trochlear component (JourneyTM PFJ, Smith & Nephew) were matched with 15 patients after isolated PFA with an inlay design trochlear component (HemiCAP(r) Wave, Arthrosurface). Matching criteria were age, gender, body mass index, and follow-up period. An independent observer evaluated patients prospectively, whereas data were compared retrospectively. Clinical outcome was assessed using WOMAC, Lysholm score, and pain VAS. Kellgren-Lawrence grading was used to assess progression of tibiofemoral OA. RESULTS: Conversion to total knee arthroplasty was necessary in one patient within each group, leaving 14 patients per group for final evaluation. The mean follow-up was 26 months in the inlay group and 25 months in the onlay group (n.s.). Both groups displayed significant improvements of all clinical scores (p < 0.05). No significant differences were found between the two groups with regard to the clinical outcome and reoperation rate. No significant progression of tibiofemoral OA was observed in the inlay group, whereas 53 % of the onlay group showed progression of medial and/or lateral tibiofemoral OA (p = 0.009). CONCLUSION: Isolated PFA using either a second-generation inlay or onlay trochlear component significantly improves functional outcome scores and pain. The theoretical advantages of an inlay design did not result in better clinical outcome scores; however, progression of tibiofemoral OA was significantly less common in patients with an inlay trochlear component. This implant design may therefore improve long-term results and survival rates after isolated PFA. LEVEL OF EVIDENCE: III. PMID- 26231154 TI - The role of the scapula in preventing and treating shoulder instability. AB - The shoulder is a closed-chain mechanism that balances the mobility required by the ranges of motion in normal activities with the stability required to act as a stable ball and socket base for those activities. The scapula plays key roles in the closed-chain mechanism by being mobile enough to place the glenoid in optimal relation to the humerus to facilitate concavity/compression and by being a stable base for coordinated muscle activation to compress the humerus into the glenoid. Scapular dyskinesis alters these roles and is frequently present in many types of glenohumeral instability. It may create or exacerbate the abnormal glenohumeral kinematics in instability. Clinical evaluation methods can demonstrate scapular dyskinesis, and if dyskinesis is present, rehabilitation for the dyskinesis should be included in the non-operative, preoperative, or post-operative treatment. Rehabilitation for scapular dyskinesis can be performed by specific protocols and is more successful in muscle-predominant instabilities such as multidirectional instability and repetitive microtrauma instability. Level of evidence V. PMID- 26231156 TI - Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility. AB - Introducing a reactive carbonyl to a scaffold that does not otherwise have an electrophilic functionality to create a reversible covalent inhibitor is a potentially useful strategy for enhancing compound potency. However, aldehydes are metabolically unstable, which precludes the use of this strategy for compounds to be tested in animal models or in human clinical studies. To overcome this limitation, we designed ketone-based functionalities capable of forming reversible covalent adducts, while displaying high metabolic stability, and imparting improved water solubility to their pendant scaffold. We tested this strategy on the ferroptosis inducer and experimental therapeutic erastin, and observed substantial increases in compound potency. In particular, a new carbonyl erastin analog, termed IKE, displayed improved potency, solubility and metabolic stability, thus representing an ideal candidate for future in vivo cancer therapeutic applications. PMID- 26231155 TI - Re-exploring the N-phenylpicolinamide derivatives to develop mGlu4 ligands with improved affinity and in vitro microsomal stability. AB - In recent years, mGlu4 has received great attention and research effort because of the potential benefits of mGlu4 activation in treating numerous brain disorders, such as Parkinson's disease (PD). Many positive allosteric modulators of mGlu4 have been developed. To better understand the role of mGlu4 in healthy and disease conditions, we are interested in developing an mGlu4 selective radioligand for in vivo studies. Thus, we had synthesized and studied [(11)C]2 as a PET tracer for mGlu4, which demonstrated some promising features as a PET radioligand as well as the limitation need to be improved. In order to develop an mGlu4 ligand with enhanced affinity and improved metabolic stability, we have modified, synthesized and evaluated a series of new N-phenylpicolinamide derivatives. The SAR study has discovered a number of compounds with low nM affinity to mGlu4. The dideuteriumfluoromethoxy modified compound 24 is identified as a very promising mGlu4 ligand, which has demonstrated enhanced affinity, improved in vitro microsomal stability, good selectivity and good permeability. PMID- 26231157 TI - Coronaridine, an iboga type alkaloid from Tabernaemontana divaricata, inhibits the Wnt signaling pathway by decreasing beta-catenin mRNA expression. AB - Four alkaloids, voacangine (1), isovoacangine (2), coronaridine (3), and coronaridine hydroxyindolenine (4), were isolated from the MeOH extract of Tabernaemontana divaricata aerial parts by activity-guided fractionation for Wnt signal inhibitory activity. Compounds 1-4 exhibited TCF/beta-catenin inhibitory activities with IC50 values of 11.5, 6.0, 5.8, and 7.3 MUM, respectively. Of these, coronaridine (3) decreased beta-catenin levels in SW480 colon cancer cells, while this decrease in beta-catenin was not suppressed by a co-treatment with 3 and MG132, a proteasome inhibitor. These results suggested that the decrease observed in beta-catenin levels by coronaridine (3) did not depend on a proteasomal degradation process. On the other hand, the treatment of SW480 cells with coronaridine (3) caused a decrease in beta-catenin mRNA levels. Thus, coronaridine (3) may inhibit the Wnt signaling pathway by decreasing the mRNA expression of beta-catenin. PMID- 26231158 TI - Selective inhibition of PARP10 using a chemical genetics strategy. AB - The lack of inhibitors that are selective for individual poly-ADP-ribose polymerase (PARP) family members has limited our understanding of their roles in cells. Here, we describe a chemical genetics approach for generating selective inhibitors of an engineered variant of PARP10. We synthesized a series of C-7 substituted 3,4-dihydroisoquinolin-1(2H)-one (dq) analogues designed to selectively inhibit a mutant of PARP10 (LG-PARP10) that contains a unique pocket in its active site. A dq analogue containing a bromo at the C-7 position demonstrated a 10-fold selectivity for LG-PARP10 compared to its WT counterpart. This study provides a platform for the development of selective inhibitors of individual PARP family members that will be useful for decoding their cellular functions. PMID- 26231159 TI - Discovery of Tyk2 inhibitors via the virtual site-directed fragment-based drug design. AB - In this study, we synthesized compound 12 with potent Tyk2 inhibitory activity from FBDD study and carried out a cell-based assay for Tyk2/STAT3 signaling activation upon IFNalpha5 stimulation. Compound 12 completely suppressed the IFNalpha5-mediated Tyk2/STAT3 signaling pathway as well as the basal levels of pSTAT3. Stimulation with IFNalpha/beta leads to the tyrosine phosphorylation of the JAK1 and Tyk2 receptor-associated kinases with subsequent STATs activation, transmitting signals from the cell surface receptor to the nucleus. In conclusion, the potency of compound 12 to interrupt the signal transmission of Tyk2/STAT3 appeared to be equivalent or superior to that of the reference compound. PMID- 26231160 TI - Novel oxazolidinone calcitonin gene-related peptide (CGRP) receptor antagonists for the acute treatment of migraine. AB - In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 MUM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold). PMID- 26231162 TI - Structure-activity relationship study of syringolin A as a potential anticancer agent. AB - A detailed structure-activity relationship of syringolin A (1), which is a promising antitumor natural product, was described. We previously developed syringolin A analog 2 as a potent proteasome inhibitor by the structure-based drug design of syringolin A. In this Letter, we synthesized a range of analogs of 2, having a different length of the lipophilic chain and substituted aryl group, and their cytotoxicity against human cancer cells was evaluated. It turned out that these modifications greatly affected the cytotoxicity. Further optimization would lead to develop a novel proteasome inhibitor. PMID- 26231161 TI - Synthesis and antiviral evaluation of a novel series of homoserine-based inhibitors of the hepatitis C virus NS3/4A serine protease. AB - We disclose here the synthesis of a series of macrocyclic HCV protease inhibitors, where the homoserine linked together the quinoline P2' motif and the macrocyclic moiety. These compounds exhibit potent inhibitory activity against HCV NS3/4A protease and replicon cell based assay. Their enzymatic and antiviral activities are modulated by substitutions on the quinoline P2' at position 8 by methyl and halogens and by small heterocycles at position 2. The in vitro structure activity relationship (SAR) studies and in vivo pharmacokinetic (PK) evaluations of selected compounds are described herein. PMID- 26231164 TI - The Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) - 35 Years of Global Efforts to Ensure That International Trade in Wild Animals and Plants Is Legal and Sustainable. AB - CITES is a 35-year-old convention with a current total of 175 signatories, or parties. It regulates international trade in live specimens and products of more than 30,000 animal and plant species under three different trade regimes. CITES has clearly proved its importance for nature conservation, but its regulations often are difficult to implement and enforce, leading to unacceptably high levels of unsustainable and illegal trade in many wildlife species. There are ways, however, to improve the situation and to make compliance with CITES regulations both easier and more attractive. PMID- 26231163 TI - Discovery of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers. AB - Chemical evolution of mibefradil resulted in the identification of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers. A SAR study, in vitro and in vivo DMPK properties as well as the in vivo antihypertensive effect in rats are presented. PMID- 26231165 TI - Forensic Science in Support of Wildlife Conservation Efforts - Genetic Approaches (Global Trends). AB - Wildlife forensic science is a relatively recent development to meet the increasing need of the criminal justice system where there are investigations in alleged transgressions of either international or national legislation. This application of science draws on conservation genetics and forensic geneticists from mainstream forensic science. This review is a broad overview of the history of forensic wildlife science and some of the recent developments in forensic wildlife genetics with the application of DNA developments to nonhuman samples encountered in a forensic science investigation. The review will move from methods to look at the entire genome, when there is no previous knowledge of the species studied, through methods of species identification, using DNA to determine a possible geographic origin, through to assigning samples to a particular individual or a close genetic relative of this individual. The transfer of research methods into the criminal justice system for the investigation of wildlife crimes has been largely successful as is illustrated in the review. The review concludes with comments on the need for standardization and regulation in wildlife forensic science. PMID- 26231166 TI - Forensic Science in Support of Wildlife Conservation Efforts - Developments in Genetic Approaches in Taiwan. AB - To control illegal wildlife-product trade and protect endangered species of animals, unambiguous identification of the animal specimens is vitally important. Genetic approaches were adopted to identify animal species for conservation and to prevent their fraudulent misidentification in Taiwan, especially for samples of animal residues, powders, and processed products. PCR or nested PCR based on the nature of DNA was used for amplification of cyt b, COI, CHD, and D-loop DNA fragments. Sequences of these fragments were compared with those registered in DNA databases and phylogenetic analysis was performed. The established methods were applied in forensic cases for support of conservation efforts and they were proved to be robust. For conservation animal identification, various samples seized by law enforcement agents have been identified by our systems as rhinoceros horns, Indian sawback turtles, shahtoosh, ivories, dolphins, whales, etc. The systems were also successfully used in investigating the illegal trade of commercial turtle shells and the fraudulent misidentification of food contents on product labels in Taiwanese markets. This review summarizes the work conducted in our laboratory and describes the Taiwan experience. PMID- 26231167 TI - Forensic Science in Support of Wildlife Conservation Efforts - Morphological and Chemical Approaches (Global Trends). AB - Wildlife forensics is an emerging field and involves a number of players including the international community itself, national police agencies, nongovernmental organizations (NGOs), and forensic and scientific experts. Collectively, these players attempt to prevent or prosecute crimes that specifically target wildlife, and deal with what is becoming an increasingly burgeoning global problem. The number and type of methods that are used to answer questions related to wildlife crimes and to recover evidence for prosecutions are numerous. This paper outlines the key questions that concern crimes perpetrated against wildlife and provides a context for those methods that fall generally under the headings of morphological and chemical. A commentary is provided on the relative success of these methods and how they relate either directly or indirectly to evidence gathering and to one another. It is clear that a considerable forensic toolkit exists, and more could be achieved with further developments of newer methods. PMID- 26231168 TI - Forensic Science in Support of Wildlife Conservation Efforts - Developments in Morphological and Chemical Approaches in Taiwan. AB - Parts from animals that are now endangered species (such as bear bile, rhino horn, and tiger bone) have long been important ingredients of traditional Chinese medicine (TCM). Deeply believing in the potency of these ingredients and coupled with substantial gains in wealth of the population in Taiwan in the 1980s, ugly scenarios came to light. Taiwan quickly became the target of investigation pursued by international wildlife conservationists. To provide scientific bases for the government's investigation efforts, morphological, chemical/physical, and genetic methods were developed to characterize TCM products. This review focuses on Taiwanese scientists' efforts on the following topic matters: (a) morphological approach to identify CITES-listed species from the turtle shells traded in the TCM market; (b) chromatographic and spectrophotometric methods for the identification and differentiation of bile products of different animal origins; and (c) gas chromatography-mass spectrometry method for the analysis of deer musk components and alleged musk products. PMID- 26231169 TI - Milestones along the road of infection prevention in Egypt. AB - Sequela of infectious diseases include not only morbidity and mortality, but are also associated with chronic illnesses that has long constituted public health problems and huge economic burdens. This review gives a brief idea about important infectious diseases (ID) in Egypt, the main lines taken to combat them, the challenges still existing, and the possible barriers keeping IDs still forming threats to the community. Egypt has the highest prevalence rates of HCV infection worldwide. Significant evidence points towards that the HCV epidemic was initiated and propagated by the anti-schistosomal mass campaigns during the last century. Though the rates of HCV infection are declining, still the decline has not yet met the full expectations. Therefore, infection control programs are gaining more ground all over the country, especially with the growing problem of antimicrobial resistance complicating healthcare-associated infections (HAI) worldwide. Also, mass immnunization of childhood, mycobacterial tuberculosis infections, and avian influenza will be discussed. PMID- 26231170 TI - Loss of heterozygosity: what is it good for? AB - BACKGROUND: Loss of heterozygosity (LOH) is a common genetic event in cancer development, and is known to be involved in the somatic loss of wild-type alleles in many inherited cancer syndromes. The wider involvement of LOH in cancer is assumed to relate to unmasking a somatically mutated tumour suppressor gene through loss of the wild type allele. METHODS: We analysed 86 ovarian carcinomas for mutations in 980 genes selected on the basis of their location in common regions of LOH. RESULTS: We identified 36 significantly mutated genes, but these could only partly account for the quanta of LOH in the samples. Using our own and TCGA data we then evaluated five possible models to explain the selection for non random accumulation of LOH in ovarian cancer genomes: 1. Classic two-hit hypothesis: high frequency biallelic genetic inactivation of tumour suppressor genes. 2. Epigenetic two-hit hypothesis: biallelic inactivation through methylation and LOH. 3. Multiple alternate-gene biallelic inactivation: low frequency gene disruption. 4. Haplo-insufficiency: Single copy gene disruption. 5. Modified two-hit hypothesis: reduction to homozygosity of low penetrance germline predisposition alleles. We determined that while high-frequency biallelic gene inactivation under model 1 is rare, regions of LOH (particularly copy-number neutral LOH) are enriched for deleterious mutations and increased promoter methylation, while copy-number loss LOH regions are likely to contain under-expressed genes suggestive of haploinsufficiency. Reduction to homozygosity of cancer predisposition SNPs may also play a minor role. CONCLUSION: It is likely that selection for regions of LOH depends on its effect on multiple genes. Selection for copy number neutral LOH may better fit the classic two-hit model whereas selection for copy number loss may be attributed to its effect on multi gene haploinsufficiency. LOH mapping alone is unlikely to be successful in identifying novel tumour suppressor genes; a combined approach may be more effective. PMID- 26231171 TI - Seizures, Paraplegia, and Cough Unveiling Disseminated Tuberculosis. PMID- 26231172 TI - Analyzing allele specific RNA expression using mixture models. AB - BACKGROUND: Measuring allele-specific RNA expression provides valuable insights into cis-acting genetic and epigenetic regulation of gene expression. Widespread adoption of high-throughput sequencing technologies for studying RNA expression (RNA-Seq) permits measurement of allelic RNA expression imbalance (AEI) at heterozygous single nucleotide polymorphisms (SNPs) across the entire transcriptome, and this approach has become especially popular with the emergence of large databases, such as GTEx. However, the existing binomial-type methods used to model allelic expression from RNA-seq assume a strong negative correlation between reference and variant allele reads, which may not be reasonable biologically. RESULTS: Here we propose a new strategy for AEI analysis using RNA-seq data. Under the null hypothesis of no AEI, a group of SNPs (possibly across multiple genes) is considered comparable if their respective total sums of the allelic reads are of similar magnitude. Within each group of "comparable" SNPs, we identify SNPs with AEI signal by fitting a mixture of folded Skellam distributions to the absolute values of read differences. By applying this methodology to RNA-Seq data from human autopsy brain tissues, we identified numerous instances of moderate to strong imbalanced allelic RNA expression at heterozygous SNPs. Findings with SLC1A3 mRNA exhibiting known expression differences are discussed as examples. CONCLUSION: The folded Skellam mixture model searches for SNPs with significant difference between reference and variant allele reads (adjusted for different library sizes), using information from a group of "comparable" SNPs across multiple genes. This model is particularly suitable for performing AEI analysis on genes with few heterozygous SNPs available from RNA-seq, and it can fit over-dispersed read counts without specifying the direction of the correlation between reference and variant alleles. PMID- 26231173 TI - Durable recurrence-free survival after pneumonectomy for late lung metastasis from rectal cancer: case report with genetic and epigenetic analyses. AB - BACKGROUND: Treatment of pulmonary recurrence from colorectal cancer involving the main bronchus usually entails palliation using interventional bronchoscopy, because the prognosis is generally very poor. Surgical experience has clarified that in this setting pneumonectomy should only be performed in carefully selected patients showing favorable prognostic profiles (defined by low carcinoembryonic antigen serum levels pre-thoracotomy), solitary and completely resectable pulmonary metastasis, and long disease-free intervals. In the few long-term survivors after pneumonectomy for late-recurrent colorectal cancer, the disease has a relatively indolent metastatic course and genetic and epigenetic profiling may provide further insight regarding tumor evolution. CASE PRESENTATION: We describe a rare case of late hilar-endobronchial and lymph nodal recurrence of rectal cancer, sequential to hepatic metastasectomy, that we successfully treated with pneumonectomy and chemotherapy (leucovorin, 5-fluorouracil and oxaliplatin regimen); the patient achieved 7-year relapse-free survival after lung metastasectomy and 24-year overall survival after primary rectal cancer resection. To our knowledge, this is the longest survival reported after sequential liver resection and pneumonectomy for recurrent colorectal cancer. In our case the primary rectal cancer and its recurrences showed identical immunohistochemical patterns. The primary rectal cancer and the matched metastases (hepatic, pulmonary and lymph nodal) demonstrated no KRAS, NRAS, BRAF and PIK3CA mutations, a microsatellite stable phenotype, and no tumor protein p53 alterations or recurrent copy number alterations on chromosome 8. High genetic concordances between the paired primary tumor and metastases suggest that the key tumor biological traits remained relatively conserved in the three metastatic sites. Minor differences in gene specific hypermethylation were observed between the primary tumor and lung and nodal metastases. These differences suggest that epigenetic mechanisms may be causally involved in the microenvironmental regulation of cancer metastasis. CONCLUSION: The exceptionally long survival of the patient in our case study involving favorable clinical features was related to an excellent response to surgery and adjuvant chemotherapy; however, genetic or epigenetic factors that remain unidentified cannot be excluded as contributory factors. Our findings support the concept of a common clonal origin of the primary cancer and synchronous and late metastases, and suggest that aberrant DNA methylation may regulate tumor dormancy mechanisms. PMID- 26231174 TI - A retrospective review of telehealth services for children referred to a paediatric nephrologist. AB - BACKGROUND: Telemedicine has emerged as an alternative mode of health care delivery over the last decade. To date, there is very limited published information in the field of telehealth and paediatric nephrology. The aim of this study was to review our experience with paediatric telenephrology in Queensland, Australia. METHODS: A retrospective audit of paediatric nephrology telehealth consultations to determine the nature of the telehealth activity, reasons for referral to telehealth, and to compare costs and potential savings of the telehealth service. RESULTS: During a ten-year period (2004 - 2013), 318 paediatric telenephrology consultations occurred for 168 patients (95 male) with the median age of 8 years (range 3 weeks to 24 years). Congenital anomalies of the kidney and urinary tract (30 %), followed by nephrotic syndrome (16 %), kidney transplant (12 %), and urinary tract infection (9 %) were the most common diagnoses. The estimated cost savings associated with telehealth were $31,837 in 2013 (average saving of $505 per consultation). CONCLUSIONS: Our study suggests that paediatric telenephrology is a viable and economic method for patient assessment and follow up. The benefits include improved access to paediatric nephrology services for patients and their families, educational opportunity for the regional medical teams, and a substantial cost saving for the health care system. PMID- 26231175 TI - What is the failure rate in extending labour analgesia in patients with a body mass index >= 40 kg/m(2)compared with patients with a body mass index < 30 kg/m(2)? a retrospective pilot study. AB - BACKGROUND: Early utilisation of neuraxial anaesthesia has been recommended to reduce the need for general anaesthesia in obese parturients. The insertion and management of labour epidurals in obese women is not straight-forward. The aim of this pilot study was to compare the failure rate of extension of epidural analgesia for emergency caesarean section, in pregnant women with a body mass index (BMI) >= 40 kg/m(2), to those with a BMI < 30 kg/m(2). The results will be used to calculate the sample size of a planned prospective study. METHODS: In this retrospective, (1:1) case-control pilot study, obese subjects and control subjects were selected from the obstetric database, if they delivered between January 2007 and December 2011. All subjects used epidural analgesia during labour and subsequently required anaesthesia for Category 1 or 2 Caesarean Section. Data was extracted from the patient medical record. Failure to extend was analysed using liberal and restrictive definitions. Chi-square or Fisher's exact tests were used to detect differences between groups. Multiple logistic regression was used to examine variables predictive of extension failure. RESULTS: There were 63 subjects in each group. The mean BMI of the obese group was 45.4 (5.8) kg/m(2) and 23.9 (3.0) kg/m(2) in the control group. The odds ratio for failure to extend the existing epidural blockade (liberal definition) was 2.48 (95 % CI:1.02 - 6.03) for the obese group compared with the control group (adjusted for age, parity and gestation). Using the restrictive definition, the odds ratio for failure in the obese group was 6.78 (95 % CI:1.43 - 32.2). The combination of respiratory co-morbidity and gestational diabetes significantly predicted extension failure. Surgical time and epidural complications on labour ward were significantly greater in the obese group. CONCLUSIONS: In this small retrospective cohort, patients with a BMI >= 40 kg/m(2) were significantly more likely to fail epidural extension for caesarean section. The presence of respiratory co-morbidity and gestational diabetes were significant predictors of extension failure; their clinical relevance requires further evaluation. PMID- 26231176 TI - Thallium exists in opioid poisoned patients. AB - BACKGROUND: Thallium (Tl) is a toxic heavy metal that exists in nature. Tl poisoning (thallotoxicosis) may occur in opioid addicts. This study was designed to evaluate the frequency and level of urinary Tl in opioid abusers. In addition, clinical findings were evaluated. METHODS: A total of 150 subjects were examined. Cases with a history of at least 3 years of abuse were admitted in the Imam Reza Hospital as the case group; 50 non-opioid abusers from the target population were included as the control group. Twenty-four hour urinary qualitative and quantitative Tl analyses were performed on both groups. RESULTS: Out of the 150 subjects, 128 (85 %) were negative for qualitative urinary Tl, followed by 5 % (trace), 7 % (1+), 2 % (2+), and 1 % (3+). Mean (standard error (SE), Min-Max) quantitative urinary Tl level was 14 MUg/L (3.5 MUg/L, 0-346 MUg/L). Mean urinary Tl level in the case group was 21 MUg/L (5 MUg/L, 0-346 MUg/L) and that in the controls was 1 MUg/L (0.14 MUg/L, 0-26 MUg/L), which were significantly different (P = 0.001). The most frequent clinical findings were ataxia (86 %), sweating (81 %), and constipation (54 %). In all cases (n = 150), the mean (SE) value for cases with positive qualitative urinary Tl was 26.8 MUg/L (0.9 MUg/L) and that in the negative cases was 2.3 MUg/L (0.2 MUg/L), which were significantly different (P = 0.002). CONCLUSIONS: This study showed that long-term opioid abuse may lead to Tl exposure. In opioid abusers with the clinical manifestation of thallotoxicosis, urinary Tl should be determined. PMID- 26231177 TI - Responses and relationship dynamics of men and their spouses during active surveillance for prostate cancer: health literacy as an inquiry framework. AB - BACKGROUND: Early stage prostate cancer patients may be allocated to active surveillance, where the condition is observed over time with no intervention. Living with a cancer diagnosis may impose stress on both the men and their spouses. In this study we explore whether the scores of and verbal responses to a Health Literacy Questionnaire can be used to identify individuals in need of information and support and to reveal differences in perception and understanding in health related situations within couples. METHODS: We used the nine-domain Health Literacy Questionnaire (HLQ) as a framework to explore health literacy in eight couples where the men were on active surveillance for prostate cancer progression. Scores were calculated for each domain for both individuals. For each couple differences in scores were also calculated and related to the informants' self-reported experiences and reflections in relation to participating in an active surveillance program. Also an inductive analysis was performed to identify themes in the responses and these themes were compared to those of HLQ. RESULTS: The men tended to score higher than their spouses. There was no consistent relation between scores and the reported experiences and reflections. However, some interesting patterns emerged, e.g. in two of the three couples with the largest within couple differences in HLQ scores, responses revealed discrepancies in how the men and their spouses perceived their situation. Also, three themes emerged which related to six of the HLQ domains, i.e. involvement of spouses and other people around the men; support from and interaction with healthcare professionals; and use of the Internet for information retrieval. CONCLUSIONS: Using the HLQ as an interview framework provided insight into the differences within couples and provided new perspectives on their experiences, including their contact with health professionals and the patient-spouse interaction when dealing with prostate cancer. The HLQ used as a dialogue tool may be an adjunct to assist healthcare providers to understand the need for support and information of men with prostate cancer on active surveillance and the dynamics within couples. PMID- 26231178 TI - A qualitative study of the experiences of care and motivation for effective self management among diabetic and hypertensive patients attending public sector primary health care services in South Africa. AB - BACKGROUND: Diabetes and hypertension constitute a significant and growing burden of disease in South Africa. Presently, few patients are achieving adequate levels of control. In an effort to improve outcomes, the Department of Health is proposing a shift to a patient-centred model of chronic care, which empowers patients to play an active role in self-management by enhancing their knowledge, motivation and skills. The aim of this study was to explore patients' current experiences of chronic care, as well as their motivation and capacity for self management and lifestyle change. METHODS: The study involved 22 individual, qualitative interviews with a purposive sample of hypertensive and diabetic patients attending three public sector community health centres in Cape Town. Participants were a mix of Xhosa and Afrikaans speaking patients and were of low socio-economic status. RESULTS: The concepts of relatedness, competency and autonomy from Self Determination Theory proved valuable in exploring patients' perspectives on what a patient-centred model of care may mean and what they needed from their healthcare providers. Overall, the findings of this study indicate that patients experience multiple impediments to effective self management and behaviour change, including poor health literacy, a lack of self efficacy and perceived social support. With some exceptions, the majority of patients reported not having received adequate information; counselling or autonomy support from their healthcare providers. Their experiences suggests that the current approach to chronic care largely fails to meet patients' motivation needs, leaving many of them feeling anxious about their state of health and frustrated with the quality of their care. CONCLUSIONS: In accordance with other similar studies, most of the hypertensive and diabetic patients interviewed for this study were found to be ill equipped to play an active and empowered role in self-care. It was clear that patients desire greater assistance and support from their healthcare providers. In order to enable healthcare providers in South Africa to adopt a more patient-centred approach and to better assist and motivate patients to become effective partners in their care, training, resources and tools are needed. In addition, providers need to be supported by policy and organisational change. PMID- 26231179 TI - The psychometric performance of generic preference-based measures for patients with pressure ulcers. AB - BACKGROUND: Pressure ulcers are wounds that result from reduced mobility, and can have a significant impact on morbidity, mortality and quality of life. As pressure ulcers are a consequence of a wide range of conditions and interventions, it is unclear whether the best means of capturing the quality of life impacts is via generic or condition specific Patient Reported Outcome Measures (PROMs). The aim of this study was to investigate the psychometric performance of the generic EQ-5D and SF-6D amongst patients identified as having or being at risk of developing pressure ulceration. METHODS: A survey of patients who were using pressure relieving mattresses and other equipment was undertaken within inpatient and community settings using a handheld tablet and postal survey. Data on EQ-5D-3L, SF-12 (used to calculate SF-6D), an EQ-5D dignity bolt on question, demographic and wound specific questions were collected. Convergent validity was assessed using Spearman's correlations, and agreement using Bland Altman plots. Known group validity was assessed by examining whether the instruments discriminated between different pressure ulcer severity groups. Multivariate linear regression was used to examine the impact of a range of pressure ulcer related variables. RESULTS: The total number of participants was 307, including 273 from the acute setting (52% response rate) and 41 from the community (32%). SF-6D and EQ-5D were moderately correlated (0.61), suggesting that both instruments were capturing similar quality of life impacts. Both measures were able to significantly discriminate between groups based on the ulcer grade. Presence of a pressure ulcer and number of comorbidities were significant explanatory variables of EQ-5D and SF-6D score. CONCLUSIONS: The results suggest that generic PROMs can effectively capture the impact of pressure ulcers on quality of life, although there are significant challenges in collecting data from this group of patients related to poor clinical condition and mental capacity. The most effective method for obtaining survey data was through the hand held devices and interviewers. PMID- 26231180 TI - On est ensemble: social capital and maternal health care use in rural Cameroon. AB - BACKGROUND: Every day approximately 1500 women worldwide die due to pregnancy or childbirth related complications. Maternal health care use is critical in reducing maternal mortality worldwide. Cameroon has one of the highest maternal mortality rates worldwide, but there is little knowledge about maternal health care use in Cameroon, particularly in more remote areas. The purpose of this study was to examine the importance of social networks and social capital in maternal health care use in the Far-North province of Cameroon. METHODS: A sample of 110 Cameroonian women was recruited door-to-door in the urban town of Maroua and rural village of Moutourwa in the Far-North province in 2009. A maternal health questionnaire was administered to women between the ages of 18-45. The questionnaire assessed maternal health care history, social network, and social demographic characteristics. Social capital was measured in terms of the average educational level of women's networks. Bivariate and multivariable poisson regression analysis was used to assess the number of maternal health care visits as a function of social network characteristics, education, ethnicity, age, and urban and rural residence. RESULTS: Among the 110 participants, 13 percent reported not having visited a health care provider during the last pregnancy - 19 percent of the women sampled in Moutourwa and 6 percent in Maroua. Findings showed that women with higher social capital had a greater tendency to use maternal health care services (IRR: 1.13; 95 % CI: 1.02-1.26). Social network size and social participation were not significant in full models. Ethnic characteristics were also shown associated with MHCU in the Far-North province. CONCLUSION: Although the size of women's health-related networks were not shown significant, the resources to which women might have access through their social networks were associated with women's maternal health care use in remote areas of Cameroon. Although pregnancy may not be widely discussed in public, women's social networks may provide key social resources, e.g., information or financial capital, that facilitate MHCU. Leveraging women's social capital may provide a means to improve maternal health care use among women in low-income countries. ON EST ENSEMBLE: Social capital and participation in the use of maternal health care services in remote areas of Cameroon. PMID- 26231181 TI - Effects of an eight-week supervised, structured lifestyle modification programme on anthropometric, metabolic and cardiovascular risk factors in severely obese adults. AB - BACKGROUND: Lifestyle modification is fundamental to obesity treatment, but few studies have described the effects of structured lifestyle programmes specifically in bariatric patients. We sought to describe changes in anthropometric and metabolic characteristics in a cohort of bariatric patients after participation in a nurse-led, structured lifestyle programme. METHODS: We conducted a retrospective, observational cohort study of adults with a body mass index (BMI) >= 40 kgm(-2) (or >= 35 kgm(-2) with significant co-morbidity) who were attending a regional bariatric service and who completed a single centre, 8 week, nurse-led multidisciplinary lifestyle modification programme. Weight, height, waist circumference, blood pressure, HbA1c, fasting glucose and lipid profiles as well as functional capacity (Incremental Shuttle Walk Test) and questionnaire-based anxiety and depression scores before and after the programme were compared in per-protocol analyses. RESULTS: Of 183 bariatric patients enrolled, 150 (81.9%) completed the programme. Mean age of completers was 47.9 +/ 1.2 years. 34.7% were male. There were statistically significant reductions in weight (129.6 +/- 25.9 v 126.9 +/- 26.1 kg, p < 0.001), BMI (46.3 +/- 8.3 v 44.9 +/- 9.0 kgm(-2), p < 0.001), waist circumference (133.0 +/- 17.1 v 129.3 +/- 17.5 cm in women and 143.8 +/- 19.0 v 135.1 +/- 17.9 cm in men, both p < 0.001) as well as anxiety and depression scores, total- and LDL-cholesterol and triglyceride levels, with an increase in functional capacity (5.9 +/- 1.7 v 6.8 +/- 2.1 metabolic equivalents of thermogenesis (METS), p < 0.001) in completers at the end of the programme compared to the start. Blood pressure improved, with reductions in systolic and diastolic blood pressure from 135 +/- 16.2 to 131.6 +/ 17.1 (p = 0.009) and 84.7 +/- 10.2 to 81.4 +/- 10.9 mmHg (p < 0.001), respectively. The proportion of patients achieving target blood pressure increased from 50.3 to 59.3% (p = 0.04). The proportion of patients with diabetes achieving HbA1c <53 mmol/mol increased from 28.6 to 42.9%, p = 0.02. CONCLUSIONS: Bariatric patients completing an 8 week, nurse-led structured lifestyle programme had improved adiposity, fitness, lipid profiles, psychosocial health, blood pressure and glycaemia. Further assessment of this programme in a pragmatic randomised controlled trial seems warranted. PMID- 26231182 TI - Automation and Evaluation of the SOWH Test with SOWHAT. AB - The Swofford-Olsen-Waddell-Hillis (SOWH) test evaluates statistical support for incongruent phylogenetic topologies. It is commonly applied to determine if the maximum likelihood tree in a phylogenetic analysis is significantly different than an alternative hypothesis. The SOWH test compares the observed difference in log-likelihood between two topologies to a null distribution of differences in log-likelihood generated by parametric resampling. The test is a well-established phylogenetic method for topology testing, but it is sensitive to model misspecification, it is computationally burdensome to perform, and its implementation requires the investigator to make several decisions that each have the potential to affect the outcome of the test. We analyzed the effects of multiple factors using seven data sets to which the SOWH test was previously applied. These factors include a number of sample replicates, likelihood software, the introduction of gaps to simulated data, the use of distinct models of evolution for data simulation and likelihood inference, and a suggested test correction wherein an unresolved "zero-constrained" tree is used to simulate sequence data. To facilitate these analyses and future applications of the SOWH test, we wrote SOWHAT, a program that automates the SOWH test. We find that inadequate bootstrap sampling can change the outcome of the SOWH test. The results also show that using a zero-constrained tree for data simulation can result in a wider null distribution and higher p-values, but does not change the outcome of the SOWH test for most of the data sets tested here. These results will help others implement and evaluate the SOWH test and allow us to provide recommendations for future applications of the SOWH test. SOWHAT is available for download from https://github.com/josephryan/SOWHAT. PMID- 26231183 TI - An Efficient Independence Sampler for Updating Branches in Bayesian Markov chain Monte Carlo Sampling of Phylogenetic Trees. AB - Sampling tree space is the most challenging aspect of Bayesian phylogenetic inference. The sheer number of alternative topologies is problematic by itself. In addition, the complex dependency between branch lengths and topology increases the difficulty of moving efficiently among topologies. Current tree proposals are fast but sample new trees using primitive transformations or re-mappings of old branch lengths. This reduces acceptance rates and presumably slows down convergence and mixing. Here, we explore branch proposals that do not rely on old branch lengths but instead are based on approximations of the conditional posterior. Using a diverse set of empirical data sets, we show that most conditional branch posteriors can be accurately approximated via a [Formula: see text] distribution. We empirically determine the relationship between the logarithmic conditional posterior density, its derivatives, and the characteristics of the branch posterior. We use these relationships to derive an independence sampler for proposing branches with an acceptance ratio of ~90% on most data sets. This proposal samples branches between 2* and 3* more efficiently than traditional proposals with respect to the effective sample size per unit of runtime. We also compare the performance of standard topology proposals with hybrid proposals that use the new independence sampler to update those branches that are most affected by the topological change. Our results show that hybrid proposals can sometimes noticeably decrease the number of generations necessary for topological convergence. Inconsistent performance gains indicate that branch updates are not the limiting factor in improving topological convergence for the currently employed set of proposals. However, our independence sampler might be essential for the construction of novel tree proposals that apply more radical topology changes. PMID- 26231184 TI - Multistage sampling. PMID- 26231185 TI - Risk factors for endovenous heat-induced thrombosis after endovenous radiofrequency ablation performed in Thailand. AB - OBJECTIVE: We aimed to determine the incidence of and associated risk factors for endovenous heat-induced thrombosis (EHIT) after endovenous radiofrequency ablation (RFA). METHODS: We retrospectively reviewed the medical records of 82 patients with 97 great saphenous veins undergoing RFA from 2012 to 2014. RESULTS: The incidence of EHIT was 10.3%. Class 1, 2, and 3 EHIT was found in 50%, 30%, and 20% of legs, respectively. No class 4 EHIT, deep vein thrombosis, or pulmonary emboli occurred. Univariate analysis revealed that the associated risk factors for EHIT were a vein diameter of >10 mm, operative time of >40 min, and Caprini score of >6. Multivariate analysis revealed that the independent risk factors associated with EHIT were a vein diameter of >10 mm and operative time of >40 min. CONCLUSIONS: A vein diameter of >10 mm and operative time of >40 min might be predictive factors for EHIT following RFA. PMID- 26231186 TI - A novel approach to optimise glycaemic control in insulin users. AB - Insulin therapy has been available for almost a century. However, its success rate is still disappointing where the majority of users sustain harmfully elevated glycated haemoglobin (HbA1c) levels. The key element essential for effective and safe insulin therapy is frequent dosage titration to overcome constant variations in insulin requirements. In reality, dosage titration is done sporadically during clinic visits. A scalable solution to this problem is being reviewed. A diabetes nurses service improves glycaemic control without overburdening the health system. The service relies on a handheld device, which provides patients with an insulin dose recommendation for each injection while using the device to monitor glucose. Similar to the approach providers use during clinical encounters, the device analyses stored glucose trends and constantly titrates insulin dosage without care providers' supervision. In this report, we describe the logic behind the technology by providing examples from users. PMID- 26231187 TI - Iatrogenic magnesium toxicity following intravenous infusion of magnesium sulfate: risks and strategies for prevention. AB - A 65-year-old man being treated with radiotherapy and chemotherapy for recurrent colonic adenocarcinoma was admitted for management of hypokalaemia and hypomagnesaemia secondary to diarrhoea. He was treated with intravenous infusions of potassium chloride and magnesium sulfate. Following an infusion of magnesium sulfate, he experienced a sudden neurological deterioration. A CT of the head revealed no haemorrhage or evidence of acute ischaemic injury. Results of serum biochemistry later that day revealed an elevated magnesium level. Iatrogenic magnesium toxicity was suspected. Further discussions between the pharmacist and ward staff confirmed that a medication error had been made in the preparation of the infusion resulting in an overdose of intravenous magnesium. PMID- 26231188 TI - Clinicopathological significance of Melkersson-Rosenthal syndrome. AB - Melkersson-Rosenthal syndrome (MRS) classically shows a triad of orofacial swelling, fissured tongue and facial palsy, more commonly the oligosymptomatic form. The orofacial swelling is characterised by swollen reddish-brown non pruritic lips and facial oedema. In one-third to one half of patients, fissured tongue is seen, which also aids in diagnosis. The histological finding of MRS includes non-caseating, sarcoidal granulomas, but their absence does not exclude the diagnosis. All these findings together form a basis for a cautious search for confrontational reasons for the symptom complex of MRS. PMID- 26231189 TI - Epithelial-myoepithelial carcinoma of lacrimal gland from an ex pleomorphic adenoma. AB - A 47-year-old man with a history of recurrent pleomorphic adenoma of the right lacrimal gland presented with rapid onset of a swelling in the right orbit. Initial imaging with CT showed that the swelling was grossly involving the extraocular muscles. Hence we had a suspicion of malignant transformation, so a radical approach in the form of right orbital exenteration with anterior skull base resection and temporalis muscle reconstruction was taken. Postoperative histology revealed epithelial-myoepithelial carcinoma, with immunopositivity for epithelial and myoepithelial components. Adjuvant radiation of 60 Gy was given with three-dimensional CT-based planning. This case portrays the importance of adjuvant treatment in recurrent pleomorphic adenoma and chance of malignant transformation in rare histologies. PMID- 26231190 TI - Patient with lung adenocarcinoma manifesting as an unusual migratory pulmonary infiltration. PMID- 26231191 TI - Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan. AB - BACKGROUND AND OBJECTIVES: Recent animal experiments suggest that dysregulation of the EGF receptor pathway plays a role in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD). Research on EGF receptor ligands in humans with ADPKD is lacking. EGF receptor ligands were measured in patients with ADPKD at baseline and after treatment with a vasopressin V2 receptor antagonist (V2RA) because this information might provide a rationale for future V2RA combination therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Blood and urine concentrations of the EGF receptor ligands heparin-binding (HB)-EGF, EGF, and TGF-alpha were measured by ELISAs in 27 patients with ADPKD who participated in a single-center study investigating a V2RA in 2011-2013 and in 27 controls who were selected from a general population-based observational study. Cyst fluid concentrations were also measured. In patients with ADPKD, ligands were measured at baseline, after 3-week treatment with a V2RA, and 3 weeks after drug withdrawal. The measured GFR (mGFR) was determined by iothalamate infusion, and total kidney volume was measured by magnetic resonance imaging. RESULTS: Urinary HB-EGF excretion and plasma concentration were higher in patients with ADPKD than in controls (median, 1.4 [interquartile range, 1.2-1.9] versus 0.6 [0.4-0.8] ug/24 hours [P<0.001] and 157.9 [83.1-225.9] versus 77.2 [37.2-174.3] pg/ml [P=0.04]). In contrast, urinary EGF excretion and plasma EGF concentration were lower in patients with ADPKD, whereas TGF-alpha did not differ between patients and controls. Higher HB-EGF excretion was correlated with more severe disease, assessed as lower mGFR (r=-0.39; P=0.05), higher total kidney volume (r=0.39; P=0.05), and higher urinary excretion of albumin and heart-type fatty acid binding protein, whereas higher EGF excretion and TGF-alpha excretion were negatively correlated with disease severity. During V2RA treatment, HB-EGF excretion increased (from 1.4 [1.2-1.9] to 2.4 [2.1-3.1] ug/24 hours; P<0.001). CONCLUSION: In patients with ADPKD, higher urinary HB-EGF excretion is correlated with more severe disease. Whether this association is causal needs to be investigated in intervention studies. PMID- 26231192 TI - Hyponatremia and Cognitive Impairment in Patients Treated with Peritoneal Dialysis. AB - BACKGROUND AND OBJECTIVES: Hyponatremia has been identified as a relevant factor for cognitive impairment but has not been investigated in patients receiving peritoneal dialysis (PD). This study investigated the relationship between hyponatremia and cognitive functions in PD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 476 clinically stable patients from five PD units who were older than 18 years of age and had undergone PD for at least 3 months between March 2013 and March 2014 were enrolled in this multicenter cross sectional study. Global cognitive function was measured using the Modified Mini Mental State Examination (3MS); executive function, by trail making tests A (trails A) and B (trails B); and immediate memory, delayed memory, and language ability, by subtests of Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Hyponatremia was defined as serum sodium level <=135 mmol/L, which was calculated as the mean of measurements taken over the preceding 3 months. RESULTS: Fifty patients (10.5%) had hyponatremia; these patients tended to be older and less educated, to have less inflammation, and to have the higher prevalence of cognitive impairment. They also had lower scores on RBANS subtests. After adjustment for demographic and clinical confounders, hyponatremia was independently associated with lower 3MS score (coefficient, 5.28; 95% confidence interval [CI], -8.44 to -2.13) and longer completion time of trials A (coefficient, 22.68; 95% CI, 3.44 to 41.92) and B (coefficient, 45.56; 95% CI, 1.30 to 89.81). After additional adjustment for laboratory measures, hyponatremia was still associated with 3MS score and completion time of trails A. Hyponatremia was independently associated with CI (odds ratio, 2.17; 95% CI, 1.02 to 4.94) and executive dysfunction (odds ratio, 2.43; 95% CI, 1.01 to 5.87) using multivariate logistic regression analysis. Sensitivity analyses with multivariable models that included propensity score still supported the association between hyponatremia and cognitive impairment. CONCLUSIONS: Hyponatremia was associated with global and specific cognitive impairment in PD patients. PMID- 26231193 TI - Serotonin-Norepinephrine Reuptake Inhibitors and the Risk of AKI: A Cohort Study of Eight Administrative Databases and Meta-Analysis. AB - BACKGROUND AND OBJECTIVES: A safety signal regarding cases of AKI after exposure to serotonin-norepinephrine reuptake inhibitors (SNRIs) was identified by Health Canada. Therefore, this study assessed whether the use of SNRIs increases the risk of AKI compared with selective serotonin reuptake inhibitors (SSRIs) and examined the risk associated with each individual SNRI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Multiple retrospective population-based cohort studies were conducted within eight administrative databases from Canada, the United States, and the United Kingdom between January 1997 and March 2010. Within each cohort, a nested case-control analysis was performed to estimate incidence rate ratios (RRs) of AKI associated with SNRIs compared with SSRIs using conditional logistic regression, with adjustment for high-dimensional propensity scores. The overall effect across sites was estimated using meta-analytic methods. RESULTS: There were 38,974 cases of AKI matched to 384,034 controls. Current use of SNRIs was not associated with a higher risk of AKI compared with SSRIs (fixed-effect RR, 0.97; 95% confidence interval [95% CI], 0.94 to 1.01). Current use of venlafaxine and desvenlafaxine considered together was not associated with a higher risk of AKI (RR, 0.96; 95% CI, 0.92 to 1.00). For current use of duloxetine, there was significant heterogeneity among site specific estimates such that a random-effects meta-analysis was performed showing a 16% higher risk, although this risk was not statistically significant (RR, 1.16; 95% CI, 0.96 to 1.40). This result is compatible with residual confounding, because there was a substantial imbalance in the prevalence of diabetes between users of duloxetine and users of others SNRIs or SSRIs. After further adjustment by including diabetes as a covariate in the model along with propensity scores, the fixed-effect RR was 1.02 (95% CI, 0.95 to 1.10). CONCLUSIONS: There is no evidence that use of SNRIs is associated with a higher risk of hospitalization for AKI compared with SSRIs. PMID- 26231194 TI - Epidemiology and Clinical Correlates of AKI in Chinese Hospitalized Adults. AB - BACKGROUND AND OBJECTIVES: Comprehensive epidemiologic data on AKI are particularly lacking in Asian countries. This study sought to assess the epidemiology and clinical correlates of AKI among hospitalized adults in China. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a multicenter retrospective cohort study of 659,945 hospitalized adults from a wide range of clinical settings in nine regional central hospitals across China in 2013. AKI was defined and staged according to Kidney Disease Improving Global Outcomes criteria. The incidence of AKI in the cohort was estimated using a novel two-step approach with adjustment for the frequency of serum creatinine tests and other potential confounders. Risk factor profiles for hospital-acquired (HA) and community-acquired (CA) AKI were examined. The in-hospital outcomes of AKI, including mortality, renal recovery, length of stay, and daily cost, were assessed. RESULTS: The incidence of CA-AKI and HA-AKI was 2.5% and 9.1%, respectively, giving rise to an overall incidence of 11.6%. Although the risk profiles for CA-AKI and HA-AKI differed, preexisting CKD was a major risk factor for both, contributing to 20% of risk in CA-AKI and 12% of risk in HA-AKI. About 40% of AKI cases were possibly drug-related and 16% may have been induced by Chinese traditional medicines or remedies. The in-hospital mortality of AKI was 8.8%. The risk of in-hospital death was higher among patients with more severe AKI. Preexisting CKD and need for intensive care unit admission were associated with higher death risk in patients at any stage of AKI. Transiency of AKI did not modify the risk of in-hospital death. AKI was associated with longer length of stay and higher daily costs, even after adjustment for confounders. CONCLUSION: AKI is common in hospitalized adults in China and is associated with significantly higher in-hospital mortality and resource utilization. PMID- 26231196 TI - Reduction in Wound Complications After Total Ankle Arthroplasty Using a Compression Wrap Protocol. AB - BACKGROUND: The purpose of this study was to evaluate the clinical differences in wound complications after total ankle arthroplasty (TAA) between a cohort of patients that received a compression wrap protocol and a historical control group treated with cast immobilization. METHODS: Patient charts and postoperative wound pictures were reviewed for 42 patients who underwent a compression wrap protocol and 50 patients who underwent circumferential casting after primary TAA from 2008 to 2013. A blinded reviewer graded each wound using a novel postoperative wound classification system, and recorded whether the wound was completely healed by or after 3 months. A second blinded review was performed to determine intraobserver reliability. Mean patient age was 55 years (range, 24-80) and all patients had at least 6-month follow-up. RESULTS: There were significantly more total wound complications (P = .02) and mild wound complications (P = .02) in the casted group compared to the compression wrap group. There were no significant differences in the number of moderate and severe complications between each group. A significantly higher proportion of TAA incisions took longer than 3 months to heal in the casted group (P = .02). CONCLUSIONS: Based on our clinical experience with postoperative wound care after TAA, use of a compression wrap protocol was safe and effective at reducing wound-related complications, and well tolerated by patients. Further prospective, randomized clinical trials are warranted to evaluate the utility and cost-effectiveness of a compression wrap protocol after TAA. PMID- 26231195 TI - A New Grading System for the Management of Antenatal Hydronephrosis. AB - BACKGROUND AND OBJECTIVES: Standard clinical assessments do not predict surgical intervention in patients with a moderate degree of upper tract hydronephrosis. This study investigated whether combined measures of renal calyceal dilation and anteroposterior diameter (APD) of the renal pelvis at the first postnatal ultrasound better predict surgical intervention beyond standard assessments of the APD or Society of Fetal Urology (SFU) grading system. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A retrospective cohort of 348 children with antenatal hydronephrosis followed from 2003 to 2013 were studied. Using Cox regression, the risk for surgery by APD, SFU, and combined grading on the basis of the first postnatal ultrasound was calculated. The predictive capability of each grading system for surgery was determined by calculating the positive likelihood ratio (LR+). RESULTS: The combination of APD>=6-9 mm and diffuse caliectasis had a hazard ratio (HR) of 19.5 (95% confidence interval [95% CI], 3.94 to 96.9) versus 0.59 (95% CI, 0.05 to 6.53) for APD>=6-9 mm alone and a similar risk of 8.9 for SFU grade 3 (95% CI, 3.84 to 20.9). The combination of APD>=9-15 mm and diffuse caliectasis had an HR of 18.7 (95% CI, 4.36 to 80.4) versus 1.75 (95% CI, 0.29 to 10.5) for APD>=9-15 mm alone. The LR+ for surgery for diffuse caliectasis and APD>=6-9 mm was higher than for APD>=6-9 mm alone (HR=2.62; 95% CI, 0.87 to 7.94 versus HR=0.04; 95% CI, 0.01 to 0.32) and was higher for APD>=9-15 mm and diffuse caliectasis than APD>=9-15 mm alone (HR=2.0; 95% CI, 1.15 to 3.45 versus HR=0.14; 95% CI, 0.04 to 0.43). Both combined groups of moderate hydronephrosis (APD>=6-9 mm or >=9-15 mm with diffuse caliectasis) had only slightly higher LR+ than SFU grade 3 (HR=1.89; 95% CI, 1.17 to 3.05). CONCLUSIONS: These results suggest a grading system combining APD and diffuse caliectasis distinguishes those children with moderate degrees of upper tract hydronephrosis that are at higher risk of surgery. PMID- 26231197 TI - Effect of Arthroscopic Evaluation of Acute Ankle Fractures on PROMIS Intermediate Term Functional Outcomes. AB - BACKGROUND: Following open reduction internal fixation (ORIF) of unstable ankle fractures, some patients have persistent pain and poor outcomes. This may be secondary to intra-articular injuries that occur at the time of fracture, which occur in up to 88% of fractures. Ankle arthroscopy at the time of ORIF has been proposed to address these intra-articular injuries. This study compared patient reported functional outcomes in patients who underwent ankle ORIF with and without ankle arthroscopy. METHODS: An institutional database was used to retrospectively identify 93 patients who underwent ORIF for an unstable ankle fracture with an intact medial malleolus between 2002 and 2013. Forty-two patients had ankle arthroscopy at the time of ORIF and 51 did not. Functional outcomes between groups were compared using Patient Reported Outcomes Measurement Information System (PROMIS) physical function and pain interference computerized adaptive tests at a minimum follow-up of 1 year. Outcomes were also measured with the visual analog scale (VAS) pain score and the Olerud and Molander ankle fracture outcome scale. Average patient follow-up was 67 months (n = 51). RESULTS: PROMIS physical function and pain interference scores were not significantly different between groups (physical function, 57.8 vs. 54.5, P = .23; pain interference, 45.6 vs. 46.9, P = .56). Operative time was increased in the arthroscopy group (74 minutes vs. 59 minutes, P = .027). Overall, 60% (25/42) had chondral lesions of the talus, 7% (3/42) had chondral lesions of the tibial plafond, and 21% (9/42) had loose bodies requiring removal. There was no significant difference in complication rates between groups. CONCLUSION: At intermediate-term follow-up of patients with unstable ankle fractures and intact medial malleoli, functional outcomes were not significantly improved in patients who underwent ankle arthroscopy. However, there were no increased complications attributable to ankle arthroscopy, and average total operative time was increased by only 15 minutes. LEVEL OF EVIDENCE: Level III, retrospective cohort study. PMID- 26231198 TI - Total Ankle Arthroplasty Following Prior Infection About the Ankle. AB - BACKGROUND: We evaluated whether a history of prior infection about the native ankle joint, bone, or soft tissues was associated with a higher rate of infection following total ankle arthroplasty (TAA) when compared with that of primary TAA in the general population. METHODS: This is a retrospective review of our institution's TAA registry to identify all patients who reported a prior history of ankle joint sepsis or osteomyelitis and who were subsequently treated with TAA with at least 1-year follow-up. The primary outcome measure was re-infection rate. Secondary outcome measures were patient-reported outcome scores, implant survival, and complications. Twenty-two TAAs were performed in 22 patients, consisting of 9 men and 13 women, with a mean age of 58.4 years (range = 30-80 years). Patients were followed for a mean of 29.3 months (range = 11.4-83.8 months). The length of complete symptom-free interval between the index infection to time of TAA was 8.8 years (range = 0-44 years). These patients had a mean 2.7 (range = 0-13) procedures involving the ipsilateral ankle joint prior to TAA. RESULTS: No deep infection was observed in this series. Eleven patients were followed for more than 2 years, with postoperative visual analog scale scores decreasing from 53.1 (range = 12-90) to 20.6 (range = 0-89) of 100. Ten of the 11 ankles also had AOFAS ankle-hindfoot and SF-36 scores. Their AOFAS ankle-hindfoot score increased from 38.9 (range = 10-61) to 70.1 (range = 29-90), and SF-36 score improved from 40.6 (range = 3.3-76.4) to 67.6 (range = 36.4-85.4). CONCLUSION: Single-stage TAA can be a viable option to treat arthritic ankle pain for those patients with resolved bone or ankle joint infection, producing improved outcomes in pain and function. PMID- 26231199 TI - Increased Osseous (99m)Tc-DPD Uptake in End-Stage Ankle Osteoarthritis: Correlation Between SPECT-CT Imaging and Histologic Findings. AB - BACKGROUND: We analyzed the histopathologic findings in end-stage osteoarthritic ankle joint tissue that display increased uptake of bone-seeking radiotracer in single-photon emission computed tomography-computed tomography (SPECT-CT) imaging. METHODS: Six consecutive patients with end-stage osteoarthritis undergoing total ankle replacement received preoperative SPECT-CT imaging using (99m)Technetium dicarboxypropane diphosphonate ((99m)Tc-DPD). Using imaging data for stratification, osteochondral tissue sections were prepared from SPECT positive (+) and -negative (-) areas of tibial and talar resection specimens. Histomorphometric analyses of osteoblast numbers, collagen deposition, and cartilage degeneration were performed on hematoxylin and eosin, van Gieson's and Safranin-O stained tissue sections. Osteoclast activity was visualized using tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: Increased (99m)Tc DPD uptake was observed exclusively subjacent to the subchondral bone plate of tibial and talar joint compartments. SPECT(-) tissues displayed typical fatty marrow morphology containing mainly collagen-positive blood vessels and few marrow and bone-lining cells. SPECT(+) tissues were characterized by increased numbers of active bone-lining osteoblasts depositing collagen fibers. Collagen area fraction of subchondral bone marrow was significantly increased in SPECT(+) (0.52 +/- 0.21) compared with SPECT(-) (0.29 +/- 0.13) tissues (P = .30). Multinucleated TRAP(+) osteoclasts were absent from bone formation sites, but associated with vascular structures invading articular cartilage through the subchondral bone plate. Increased (99m)Tc-DPD uptake was specifically and strongly correlated with increased osteoblast numbers (P = .011), and with collagen area fraction (P = .030) but not with Mankin score (P = .202), or with osteoclast number (P = .576). CONCLUSION: Subchondral bone tissues in SPECT(+) areas of end-stage ankle osteoarthritis were histologically characterized by increased osteoblast-mediated bone formation in the absence of functional osteoclasts, and increased cellularity and collagen deposition in marrow tissues. CLINICAL SIGNIFICANCE: Our findings suggest a pathologic bone-remodeling process in end-stage ankle OA areas with increased (99m)Tc-DPD uptake. PMID- 26231200 TI - Safe Zone for Neural Structures in Medial Displacement Calcaneal Osteotomy: A Cadaveric and Radiographic Investigation. AB - BACKGROUND: We aimed to define reference lines on standard lateral ankle radiographs that could be used intraoperatively to minimize iatrogenic nerve injury risk in medial displacement calcaneal osteotomy. METHODS: Forty cadaveric specimens were used. In 20 specimens, the sural, medial plantar (MP), and lateral plantar (LP) nerves were sutured to radiopaque wire, and a lateral ankle radiograph was obtained. On the radiograph, a line was drawn from the posterior superior apex of the calcaneal tuberosity to the origin of the plantar fascia and labeled as the "landmark line." A parallel line was drawn 2 mm posterior to the most posterior nerve, and the area between these lines was defined as the safe zone. In 20 additional specimens, an osteotomy was performed 1 cm anterior to the landmark line using a percutaneous or open technique. Dissection was performed to assess for laceration of the sural, MP, LP, medial calcaneal (MC), or lateral calcaneal (LC) nerves. RESULTS: The safe zone was determined to be within the area 11.2 +/- 2.7 mm anterior to the landmark line. After open osteotomy, lacerations were found in 3 of 10 MC nerves and 3 of 10 LC nerves. After percutaneous osteotomy, lacerations were found in 2 of 10 MC nerves and 1 of 10 LC nerves. No lacerations of the sural, MP, or LP nerves were found with either osteotomy. CONCLUSIONS: The safe zone extended 11.2 +/- 2.7 mm anterior to the described landmark line. The MC and LC nerves were always at risk during medial displacement calcaneal osteotomy. CLINICAL RELEVANCE: Nerve injury to both major and minor sensory nerves is likely underrecognized as a source of morbidity after calcaneal osteotomy. The current study provides a ready intraoperative guideline for minimizing this risk. PMID- 26231201 TI - A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function. AB - The immunomodulatory drug (IMiD) thalidomide and its structural analogs lenalidomide and pomalidomide are highly effective in treating clinical indications. Thalidomide binds to cereblon (CRBN), a substrate receptor of the cullin-4 really interesting new gene (RING) E3 ligase complex. Here, we examine the effect of thalidomide and its analogs on CRBN ubiquitination and its functions in human cell lines. We find that the ubiquitin modification of CRBN includes K48-linked polyubiquitin chains and that thalidomide blocks the formation of CRBN-ubiquitin conjugates. Furthermore, we show that ubiquitinated CRBN is targeted for proteasomal degradation. Treatment of human myeloma cell lines such as MM1.S, OPM2, and U266 with thalidomide (100 MUM) and its structural analog lenalidomide (10 MUM) results in stabilization of CRBN and elevation of CRBN protein levels. This in turn leads to the reduced level of CRBN target proteins and enhances the sensitivity of human multiple myeloma cells to IMiDs. Our results reveal a novel mechanism by which thalidomide and its analogs modulate the CRBN function in cells. Through inhibition of CRBN ubiquitination, thalidomide and its analogs allow CRBN to accumulate, leading to the increased cullin-4 RING E3 ligase-mediated degradation of target proteins. PMID- 26231203 TI - Leo Kanner's Mention of 1938 in His Report on Autism Refers to His First Patient. AB - Leo Kanner begins his landmark 1943 case series on autistic children by stating the condition was first brought to his attention in 1938. Recent letters to JADD have described this reference as "mysterious" and speculated it refers to papers published that year by Despert or Asperger. In fact, as Kanner goes on to state, 1938 is when he examined the first child in his case series. An exchange of letters with Despert and later writing by Kanner also point to the originality of his observations. PMID- 26231202 TI - Hyperglycemia stimulates p62/PKCzeta interaction, which mediates NF-kappaB activation, increased Nox4 expression, and inflammatory cytokine activation in vascular smooth muscle. AB - Hyperglycemia leads to vascular smooth muscle cell (VSMC) dedifferentiation and enhances responses to IGF-I. Prior studies showed that hyperglycemia stimulated NADPH oxidase 4 (Nox4) synthesis, and IGF-I facilitated its recruitment to a signaling complex where it oxidized src, leading to AKT and MAPK activation. To determine the mechanism that led to these changes, we analyzed the roles of p62 (sequestrosome1) and PKCzeta. Hyperglycemia induced a 4.9 +/- 1.0-fold increase in p62/PKCzeta association, and disruption of PKCzeta/p62 using a peptide inhibitor or p62 knockdown reduced PKCzeta activation (78 +/- 6%). 3 Phosphoinoside-dependent protein kinase 1 was also recruited to the p62 complex and directly phosphorylated PKCzeta, leading to its activation (3.1 +/- 0.4 fold). Subsequently, activated PKCzeta phosphorylated p65 rel, which led to increased Nox4 synthesis. Studies in diabetic mice confirmed these findings (6.0 +/- 0.4-fold increase in p62/PKCzeta) and their disruption of attenuated Nox4 synthesis (76 +/- 9% reduction). PKCzeta/p62 activation stimulated inflammatory cytokine production and enhanced IGF-I-stimulated VSMC proliferation. These results define the molecular mechanism by which PKCzeta is activated in response to hyperglycemia and suggest that this could be a mechanism by which other stimuli such as cytokines or metabolic stress function to stimulate NF-kappaB activation, thereby altering VSMC sensitivity to IGF-I. PMID- 26231204 TI - Additional Evidence is Needed to Recommend Acquiring a Dog to Families of Children with Autism Spectrum Disorder: A Response to Wright and Colleagues. AB - Caregivers of children with autism spectrum disorder are vulnerable to overstated benefits of interventions, and such overstatements are common with interventions involving animals. This response to Wright, Hall, Hames, Hardmin, Mills, the Paws Team, and Mills' (2015) article, "Acquiring a Pet Dog Significantly Reduces Stress of Primary Careers for Children with Autism Spectrum Disorder: A Prospective Case Control Study," details why that study's conclusions are premature. Specific limitations of the study are detailed, including overstatements of the supportive literature, problems with the design, and mismatch between the findings and conclusions. The purpose is not to challenge the benefits of pet ownership, but to point out that those benefits have not yet been established. PMID- 26231205 TI - Vineland Adaptive Behavior Scales: II Profile of Young Children with Autism Spectrum Disorder. AB - Adaptive behaviour is a crucial area of assessment for individuals with Autism Spectrum Disorder (ASD). This study examined the adaptive behaviour profile of 77 young children with ASD using the Vineland-II, and analysed factors associated with adaptive functioning. Consistent with previous research with the original Vineland a distinct autism profile of Vineland-II age equivalent scores, but not standard scores, was found. Highest scores were in motor skills and lowest scores were in socialisation. The addition of the Autism Diagnostic Observation Schedule calibrated severity score did not contribute significant variance to Vineland-II scores beyond that accounted for by age and nonverbal ability. Limitations, future directions, and implications are discussed. PMID- 26231206 TI - Overactive Pattern Separation Memory Associated with Negative Emotionality in Adults Diagnosed with Autism Spectrum Disorder. AB - Bowler et al. (Journal of Autism and Developmental Disorders 44(9):2355-2362. doi:10.1007/s10803-014-2105-y, 2014) have suggested that a specific memory impairment in autism spectrum disorders (ASD) arises from hippocampal failure to consolidate multiple related pieces of information. Twenty-four adults diagnosed with ASD and matched healthy controls completed a pattern separation memory task that is known to critically depend on hippocampal involvement. They additionally completed questionnaires regarding anxiety, depression, and behavioral motivation. Specific deficits in pattern separation were significantly correlated with negative emotionality; the best predictor of memory deficit was from a measure of achievement motivation that has also been associated with hyperactivity and impulsivity. In the context of impaired emotion regulation in ASD, there is a need for integrated cognitive, affective, and neural systems approaches to build targeted interventions. PMID- 26231207 TI - The soybean R2R3 MYB transcription factor GmMYB100 negatively regulates plant flavonoid biosynthesis. AB - Soybean flavonoids, a group of important signaling molecules in plant-environment interaction, ubiquitously exist in soybean and are tightly regulated by many genes. Here we reported that GmMYB100, a gene encoding a R2R3 MYB transcription factor, is involved in soybean flavonoid biosynthesis. GmMYB100 is mainly expressed in flowers, leaves and immature embryo, and its level is decreased after pod ripening. Subcellular localization assay indicates that GmMYB100 is a nuclear protein. GmMYB100 has transactivation ability revealed by a yeast functional assay; whereas bioinformatic analysis suggests that GmMYB100 has a negative function in flavonoid biosynthesis. GmMYB100-overexpression represses the transcript levels of flavonoid-related genes in transgenic soybean hairy roots and Arabidopsis, and inhibits isoflavonoid (soybean) and flavonol (Arabidopsis) production in transgenic plants. Furthermore, the transcript levels of six flavonoid-related genes and flavonoid (isoflavonoid and flavone aglycones) accumulation are elevated in the GmMYB100-RNAi transgenic hairy roots. We also demonstrate that GmMYB100 protein depresses the promoter activities of soybean chalcone synthase and chalcone isomerase. These findings indicate that GmMYB100 is a negative regulator in soybean flavonoid biosynthesis pathway. PMID- 26231208 TI - Altered activation of protein kinase PKR and enhanced apoptosis in dystonia cells carrying a mutation in PKR activator protein PACT. AB - PACT is a stress-modulated activator of the interferon-induced double-stranded RNA-activated protein kinase (PKR). Stress-induced phosphorylation of PACT is essential for PACT's association with PKR leading to PKR activation. PKR activation leads to phosphorylation of translation initiation factor eIF2alpha inhibition of protein synthesis and apoptosis. A recessively inherited form of early-onset dystonia DYT16 has been recently identified to arise due to a homozygous missense mutation P222L in PACT. To examine if the mutant P222L protein alters the stress-response pathway, we examined the ability of mutant P222L to interact with and activate PKR. Our results indicate that the substitution mutant P222L activates PKR more robustly and for longer duration albeit with slower kinetics in response to the endoplasmic reticulum stress. In addition, the affinity of PACT-PACT and PACT-PKR interactions is enhanced in dystonia patient lymphoblasts, thereby leading to intensified PKR activation and enhanced cellular death. P222L mutation also changes the affinity of PACT-TRBP interaction after cellular stress, thereby offering a mechanism for the delayed PKR activation in response to stress. Our results demonstrate the impact of a dystonia-causing substitution mutation on stress-induced cellular apoptosis. PMID- 26231209 TI - C1q protein binds to the apoptotic nucleolus and causes C1 protease degradation of nucleolar proteins. AB - In infection, complement C1q recognizes pathogen-congregated antibodies and elicits complement activation. Among endogenous ligands, C1q binds to DNA and apoptotic cells, but whether C1q binds to nuclear DNA in apoptotic cells remains to be investigated. With UV irradiation-induced apoptosis, C1q initially bound to peripheral cellular regions in early apoptotic cells. By 6 h, binding concentrated in the nuclei to the nucleolus but not the chromatins. When nucleoli were isolated from non-apoptotic cells, C1q also bound to these structures. In vivo, C1q exists as the C1 complex (C1qC1r2C1s2), and C1q binding to ligands activates the C1r/C1s proteases. Incubation of nucleoli with C1 caused degradation of the nucleolar proteins nucleolin and nucleophosmin 1. This was inhibited by the C1 inhibitor. The nucleoli are abundant with autoantigens. C1q binding and C1r/C1s degradation of nucleolar antigens during cell apoptosis potentially reduces autoimmunity. These findings help us to understand why genetic C1q and C1r/C1s deficiencies cause systemic lupus erythematosus. PMID- 26231210 TI - Mechanistic Insights into Glucan Phosphatase Activity against Polyglucan Substrates. AB - Glucan phosphatases are central to the regulation of starch and glycogen metabolism. Plants contain two known glucan phosphatases, Starch EXcess4 (SEX4) and Like Sex Four2 (LSF2), which dephosphorylate starch. Starch is water insoluble and reversible phosphorylation solubilizes its outer surface allowing processive degradation. Vertebrates contain a single known glucan phosphatase, laforin, that dephosphorylates glycogen. In the absence of laforin, water-soluble glycogen becomes insoluble, leading to the neurodegenerative disorder Lafora Disease. Because of their essential role in starch and glycogen metabolism glucan phosphatases are of significant interest, yet a comparative analysis of their activities against diverse glucan substrates has not been established. We identify active site residues required for specific glucan dephosphorylation, defining a glucan phosphatase signature motif (CzetaAGPsiGR) in the active site loop. We further explore the basis for phosphate position-specific activity of these enzymes and determine that their diverse phosphate position-specific activity is governed by the phosphatase domain. In addition, we find key differences in glucan phosphatase activity toward soluble and insoluble polyglucan substrates, resulting from the participation of ancillary glucan binding domains. Together, these data provide fundamental insights into the specific activity of glucan phosphatases against diverse polyglucan substrates. PMID- 26231211 TI - Dual role of superoxide dismutase 2 induced in activated microglia: oxidative stress tolerance and convergence of inflammatory responses. AB - Microglia are activated quickly in response to external pathogens or cell debris and clear these substances via the inflammatory response. However, excessive activation of microglia can be harmful to host cells due to the increased production of reactive oxygen species and proinflammatory cytokines. Superoxide dismutase 2 (SOD2) is reportedly induced under various inflammatory conditions in the central nervous system. We herein demonstrated that activated microglia strongly express SOD2 and examined the role of SOD2, focusing on regulation of the microglial activity and the susceptibility of microglia to oxidative stress. When rat primary microglia were treated with LPS, poly(I:C), peptidoglycan, or CpG oligodeoxynucleotide, respectively, the mRNA and protein levels of SOD2 largely increased. However, an increased expression of SOD2 was not detected in the primary neurons or astrocytes, indicating that SOD2 is specifically induced in microglia under inflammatory conditions. The activated microglia showed high tolerance to oxidative stress, whereas SOD2 knockdown conferred vulnerability to oxidative stress. Interestingly, the production of proinflammatory cytokines was increased in the activated microglia treated with SOD2 siRNA compared with that observed in the control siRNA-treated cells. Pretreatment with NADPH oxidase inhibitors, diphenylene iodonium and apocynin, decreased in not only reactive oxygen species generation but also the proinflammatory cytokine expression. Notably, SOD2 knockdown largely potentiated the nuclear factor kappaB activity in the activated microglia. Taken together, increased SOD2 conferred tolerance to oxidative stress in the microglia and decreased proinflammatory cytokine production by attenuating the nuclear factor kappaB activity. Therefore, SOD2 might regulate neuroinflammation by controlling the microglial activities. PMID- 26231212 TI - Nuclear Calcium Buffering Capacity Shapes Neuronal Architecture. AB - Calcium-binding proteins (CaBPs) such as parvalbumin are part of the cellular calcium buffering system that determines intracellular calcium diffusion and influences the spatiotemporal dynamics of calcium signals. In neurons, CaBPs are primarily localized to the cytosol and function, for example, in nerve terminals in short-term synaptic plasticity. However, CaBPs are also expressed in the cell nucleus, suggesting that they modulate nuclear calcium signals, which are key regulators of neuronal gene expression. Here we show that the calcium buffering capacity of the cell nucleus in mouse hippocampal neurons regulates neuronal architecture by modulating the expression levels of VEGFD and the complement factor C1q-c, two nuclear calcium-regulated genes that control dendrite geometry and spine density, respectively. Increasing the levels of nuclear calcium buffers by means of expression of a nuclearly targeted form of parvalbumin fused to mCherry (PV.NLS-mC) led to a reduction in VEGFD expression and, as a result, to a decrease in total dendritic length and complexity. In contrast, mRNA levels of the synapse pruning factor C1q-c were increased in neurons expressing PV.NLS-mC, causing a reduction in the density and size of dendritic spines. Our results establish a close link between nuclear calcium buffering capacity and the transcription of genes that determine neuronal structure. They suggest that the development of cognitive deficits observed in neurological conditions associated with CaBP deregulation may reflect the loss of necessary structural features of dendrites and spines. PMID- 26231213 TI - DNA End Resection: Nucleases Team Up with the Right Partners to Initiate Homologous Recombination. AB - The repair of DNA double-strand breaks by homologous recombination commences by nucleolytic degradation of the 5'-terminated strand of the DNA break. This leads to the formation of 3'-tailed DNA, which serves as a substrate for the strand exchange protein Rad51. The nucleoprotein filament then invades homologous DNA to drive template-directed repair. In this review, I discuss mainly the mechanisms of DNA end resection in Saccharomyces cerevisiae, which includes short-range resection by Mre11-Rad50-Xrs2 and Sae2, as well as processive long-range resection by Sgs1-Dna2 or Exo1 pathways. Resection mechanisms are highly conserved between yeast and humans, and analogous machineries are found in prokaryotes as well. PMID- 26231214 TI - POTION: an end-to-end pipeline for positive Darwinian selection detection in genome-scale data through phylogenetic comparison of protein-coding genes. AB - BACKGROUND: Detection of genes evolving under positive Darwinian evolution in genome-scale data is nowadays a prevailing strategy in comparative genomics studies to identify genes potentially involved in adaptation processes. Despite the large number of studies aiming to detect and contextualize such gene sets, there is virtually no software available to perform this task in a general, automatic, large-scale and reliable manner. This certainly occurs due to the computational challenges involved in this task, such as the appropriate modeling of data under analysis, the computation time to perform several of the required steps when dealing with genome-scale data and the highly error-prone nature of the sequence and alignment data structures needed for genome-wide positive selection detection. RESULTS: We present POTION, an open source, modular and end to-end software for genome-scale detection of positive Darwinian selection in groups of homologous coding sequences. Our software represents a key step towards genome-scale, automated detection of positive selection, from predicted coding sequences and their homology relationships to high-quality groups of positively selected genes. POTION reduces false positives through several sophisticated sequence and group filters based on numeric, phylogenetic, quality and conservation criteria to remove spurious data and through multiple hypothesis corrections, and considerably reduces computation time thanks to a parallelized design. Our software achieved a high classification performance when used to evaluate a curated dataset of Trypanosoma brucei paralogs previously surveyed for positive selection. When used to analyze predicted groups of homologous genes of 19 strains of Mycobacterium tuberculosis as a case study we demonstrated the filters implemented in POTION to remove sources of errors that commonly inflate errors in positive selection detection. A thorough literature review found no other software similar to POTION in terms of customization, scale and automation. CONCLUSION: To the best of our knowledge, POTION is the first tool to allow users to construct and check hypotheses regarding the occurrence of site-based evidence of positive selection in non-curated, genome-scale data within a feasible time frame and with no human intervention after initial configuration. POTION is available at http://www.lmb.cnptia.embrapa.br/share/POTION/. PMID- 26231215 TI - Soil propagule banks of ectomycorrhizal fungi share many common species along an elevation gradient. AB - We conducted bioassay experiments to investigate the soil propagule banks of ectomycorrhizal (EM) fungi in old-growth forests along an elevation gradient and compared the elevation pattern with the composition of EM fungi on existing roots in the field. In total, 150 soil cores were collected from three forests on Mt. Ishizuchi, western Japan, and subjected to bioassays using Pinus densiflora and Betula maximowicziana. Using molecular analyses, we recorded 23 EM fungal species in the assayed propagule banks. Eight species (34.8 %) were shared across the three sites, which ranged from a warm-temperate evergreen mixed forest to a subalpine conifer forest. The elevation pattern of the assayed propagule banks differed dramatically from that of EM fungi on existing roots along the same gradient, where only a small proportion of EM fungal species (3.5 %) were shared across sites. The EM fungal species found in the assayed propagule banks included many pioneer fungal species and composition differed significantly from that on existing roots. Furthermore, only 4 of 23 species were shared between the two host species, indicating a strong effect of bioassay host identity in determining the propagule banks of EM fungi. These results imply that the assayed propagule bank is less affected by climate compared to EM fungal communities on existing roots. The dominance of disturbance-dependent fungal species in the assayed propagule banks may result in higher ecosystem resilience to disturbance even in old-growth temperate forests. PMID- 26231216 TI - Effects of myopia on different areas and layers of the macula: a Fourier-domain optical coherence tomography study of a Chinese cohort. AB - BACKGROUND: To explore the changes in thickness in different areas and layers of the macula under different refractive conditions. METHODS: Consecutive participants were enrolled in the study. Optical coherence tomography (OCT) images were obtained using a spectral-domain system. We studied the relationships of the full, inner and outer retinal thicknesses of the fovea, parafovea and perifovea relative to the spherical equivalent (SE) and axial length (AL). RESULTS: We included 107 eyes; the analysis revealed that the men had thicker foveas (man vs women: 236.70 +/- 18.97 MUm vs 247.25 +/- 16.70 MUm P = 0.002) and inner parafoveas (man vs women: 128.35 +/- 8.80 MUm vs 122.78 +/- 6.75 MUm P < 0.001) than the women had. Full foveal thickness was not correlated with AL or SE (all P > 0.05), whereas the full para- and perifoveal thicknesses had significant negative correlations with AL (r = 0.243 P = 0.006 and r = -0.446 P < 0.001, for para- and peri- respectively) and positive correlations with SE (r = 0.346 P < 0.001 and r = 0.464 P < 0.001, for para- and peri- respectively). Regarding the layers, the thickness of the inner layer of the fovea increased with the degree of myopia. The average inner and outer layer thicknesses of the para- and perifovea decreased with the degree of myopia (with the SE para, b = 0.307, peri b = 0.457; with the AL para, b = -0.266, peri b = -0.454),with the perifoveal thicknesses decreasing more rapidly. CONCLUSIONS: Macular thickness changes with the degree of myopia; however, the different areas and different layers change in different manners. PMID- 26231217 TI - Mutations in SIPA1L3 cause eye defects through disruption of cell polarity and cytoskeleton organization. AB - Correct morphogenesis and differentiation are critical in development and maintenance of the lens, which is a classic model system for epithelial development and disease. Through germline genomic analyses in patients with lens and eye abnormalities, we discovered functional mutations in the Signal Induced Proliferation Associated 1 Like 3 (SIPA1L3) gene, which encodes a previously uncharacterized member of the Signal Induced Proliferation Associated 1 (SIPA1 or SPA1) family, with a role in Rap1 signalling. Patient 1, with a de novo balanced translocation, 46,XY,t(2;19)(q37.3;q13.1), had lens and ocular anterior segment abnormalities. Breakpoint mapping revealed transection of SIPA1L3 at 19q13.1 and reduced SIPA1L3 expression in patient lymphoblasts. SIPA1L3 downregulation in 3D cell culture revealed morphogenetic and cell polarity abnormalities. Decreased expression of Sipa1l3 in zebrafish and mouse caused severe lens and eye abnormalities. Sipa1l3(-/-) mice showed disrupted epithelial cell organization and polarity and, notably, abnormal epithelial to mesenchymal transition in the lens. Patient 2 with cataracts was heterozygous for a missense variant in SIPA1L3, c.442G>T, p.Asp148Tyr. Examination of the p.Asp148Tyr mutation in an epithelial cell line showed abnormal clustering of actin stress fibres and decreased formation of adherens junctions. Our findings show that abnormalities of SIPA1L3 in human, zebrafish and mouse contribute to lens and eye defects, and we identify a critical role for SIPA1L3 in epithelial cell morphogenesis, polarity, adhesion and cytoskeletal organization. PMID- 26231218 TI - Silencing neuronal mutant androgen receptor in a mouse model of spinal and bulbar muscular atrophy. AB - Spinal and bulbar muscular atrophy (SBMA), an adult-onset neurodegenerative disease that affects males, results from a CAG triplet repeat/polyglutamine expansions in the androgen receptor (AR) gene. Patients develop progressive muscular weakness and atrophy, and no effective therapy is currently available. The tissue-specific pathogenesis, especially relative pathological contributions between degenerative motor neurons and muscles, remains inconclusive. Though peripheral pathology in skeletal muscle caused by toxic AR protein has been recently reported to play a pivotal role in the pathogenesis of SBMA using mouse models, the role of motor neuron degeneration in SBMA has not been rigorously investigated. Here, we exploited synthetic antisense oligonucleotides to inhibit the RNA levels of mutant AR in the central nervous system (CNS) and explore its therapeutic effects in our SBMA mouse model that harbors a mutant AR gene with 97 CAG expansions and characteristic SBMA-like neurogenic phenotypes. A single intracerebroventricular administration of the antisense oligonucleotides in the presymptomatic phase efficiently suppressed the mutant gene expression in the CNS, and delayed the onset and progression of motor dysfunction, improved body weight gain and survival with the amelioration of neuronal histopathology in motor units such as spinal motor neurons, neuromuscular junctions and skeletal muscle. These findings highlight the importance of the neurotoxicity of mutant AR protein in motor neurons as a therapeutic target. PMID- 26231219 TI - Altering 5-hydroxymethylcytosine modification impacts ischemic brain injury. AB - Epigenetic modifications such as cytosine methylation and histone modification are linked to the pathology of ischemic brain injury. Recent research has implicated 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5 methylcytosine (5mC) via oxidation by ten-eleven translocation (Tet) enzymes, in DNA methylation-related plasticity. Here we show that 5hmC abundance was increased after ischemic injury, and Tet2 was responsible for this increase; furthermore, inhibiting Tet2 expression abolished the increase of 5hmC caused by ischemic injury. The decrease in 5hmC modifications from inhibiting Tet2 activity was accompanied by increased infarct volume after ischemic injury. Genome-wide profiling of 5hmC revealed differentially hydroxymethylated regions (DhMRs) associated with ischemic injury, and DhMRs were enriched among the genes involved in cell junction, neuronal morphogenesis and neurodevelopment. In particular, we found that 5hmC modifications at the promoter region of brain-derived neurotrophic factor (BDNF) increased, which was accompanied by increased BDNF mRNA, whereas the inhibition of Tet2 reduced BDNF mRNA and protein expression. Finally, we show that the abundance of 5hmC in blood samples from patients with acute ischemic stroke was also significantly increased. Together, these data suggest that 5hmC modification could serve as both a potential biomarker and a therapeutic target for the treatment of ischemic stroke. PMID- 26231220 TI - A new model to study neurodegeneration in ataxia oculomotor apraxia type 2. AB - Ataxia oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive cerebellar ataxia. Recent evidence suggests that the protein defective in this syndrome, senataxin (SETX), functions in RNA processing to protect the integrity of the genome. To date, only patient-derived lymphoblastoid cells, fibroblasts and SETX knockdown cells were available to investigate AOA2. Recent disruption of the Setx gene in mice did not lead to neurobehavioral defects or neurodegeneration, making it difficult to study the etiology of AOA2. To develop a more relevant neuronal model to study neurodegeneration in AOA2, we derived neural progenitors from a patient with AOA2 and a control by induced pluripotent stem cell (iPSC) reprogramming of fibroblasts. AOA2 iPSC and neural progenitors exhibit increased levels of oxidative damage, DNA double-strand breaks, increased DNA damage induced cell death and R-loop accumulation. Genome-wide expression and weighted gene co-expression network analysis in these neural progenitors identified both previously reported and novel affected genes and cellular pathways associated with senataxin dysfunction and the pathophysiology of AOA2, providing further insight into the role of senataxin in regulating gene expression on a genome-wide scale. These data show that iPSCs can be generated from patients with the autosomal recessive ataxia, AOA2, differentiated into neurons, and that both cell types recapitulate the AOA2 cellular phenotype. This represents a novel and appropriate model system to investigate neurodegeneration in this syndrome. PMID- 26231221 TI - Genome-wide association study identifies SNPs in the MHC class II loci that are associated with self-reported history of whooping cough. AB - Whooping cough is currently seeing resurgence in countries despite high vaccine coverage. There is considerable variation in subject-specific response to infection and vaccine efficacy, but little is known about the role of human genetics. We carried out a case-control genome-wide association study of adult or parent-reported history of whooping cough in two cohorts from the UK: the ALSPAC cohort and the 1958 British Birth Cohort (815/758 cases and 6341/4308 controls, respectively). We also imputed HLA alleles using dense SNP data in the MHC region and carried out gene-based and gene-set tests of association and estimated the amount of additive genetic variation explained by common SNPs. We observed a novel association at SNPs in the MHC class II region in both cohorts [lead SNP rs9271768 after meta-analysis, odds ratio [95% confidence intervals (CIs)] 1.47 (1.35, 1.6), P-value 1.21E - 18]. Multiple strong associations were also observed at alleles at the HLA class II loci. The majority of these associations were explained by the lead SNP rs9271768. Gene-based and gene-set tests and estimates of explainable common genetic variation could not establish the presence of additional associations in our sample. Genetic variation at the MHC class II region plays a role in susceptibility to whooping cough. These findings provide additional perspective on mechanisms of whooping cough infection and vaccine efficacy. PMID- 26231224 TI - Generation of stable ARE- driven reporter system for monitoring oxidative stress. AB - BACKGROUND: NF-E2-related factor2 (Nrf2)-antioxidant response element (ARE) signaling pathway is the major defensive mechanism against oxidative stress and is up regulated by specific antioxidants and oxidants to comprise the chemoptotective response. Detection of ARE-activating compounds helps to develop new drugs and identify/quantify the tension range of the oxidants. Important reasons promoting this work are high throughput, rapid and inexpensive experiments relative to the in vitro studies for ARE-Nrf2 pathway monitoring of chemicals and environmental samples. METHODS: In this study hepatoma Huh7 reporter cell line was generated which contains a luciferase gene under the control of an ARE. This is the first example of ARE construct containing one copy of extended consensus response element. The cells were treated with hydroquinone (HQ) and p-benzoquinone (BQ) (oxidative stress inducers) and the antioxidant, curcumin. RESULTS: The luciferase activity was induced in a concentration dependent manner in a concentration range of 1-2 MUM for BQ and HQ. Curcumin was also validated as an ARE inducer in concentration above 10 MUM. In addition, this reporter cell line provides a rapid detection as early as 4 h to respond to the ARE inducers. CONCLUSION: It is a powerful tool for the sensitive and selective screening of chemicals, drugs and environmental samples for their antioxidant and oxidant activities. PMID- 26231223 TI - The mechanisms by which antidepressants may reduce coronary heart disease risk. AB - BACKGROUND: Depression is known to increase the risk for coronary heart disease (CHD) likely through various pathogenetic actions. Understanding the links between depression and CHD and the effects of mediating these links may prove beneficial in CHD prevention. METHODS: An integrated model of CHD was used to elucidate pathogenetic pathways of importance between depression and CHD. Using biomarker relative risk data the pathogenetic effects are representable as measurable effects based on changes in biomarkers. RESULTS: A 'connection graph' presents interactions by illustrating the relationship between depression and the biomarkers of CHD. The use of selective serotonin reuptake inhibitors (SSRIs) is postulated to have potential to decrease CHD risk. Comparing the 'connection graph' of SSRI's to that of depression elucidates the possible actions through which risk reduction may occur. CONCLUSIONS: The CHD effects of depression appear to be driven by increased inflammation and altered metabolism. These effects might be mediated with the use of SSRI's. PMID- 26231225 TI - Protocol for a randomised controlled trial of a web-based healthy relationship tool and safety decision aid for women experiencing domestic violence (I-DECIDE). AB - BACKGROUND: Domestic violence is a serious problem affecting the health and wellbeing of women globally. Interventions in health care settings have primarily focused on screening and referral, however, women often may not disclose abuse to health practitioners. The internet offers a confidential space in which women can assess the health of their relationships and make a plan for safety and wellbeing for themselves and their children. This randomised controlled trial is testing the effectiveness of a web-based healthy relationship tool and safety decision aid (I-DECIDE). Based broadly on the IRIS trial in the United States, it has been adapted for the Australian context where it is conducted entirely online and uses the Psychosocial Readiness Model as the basis for the intervention. METHODS/DESIGN: In this two arm, pragmatic randomised controlled trial, women who have experienced abuse or fear of a partner in the previous 6 months will be computer randomised to receive either the I-DECIDE website or a comparator website (basic relationship and safety advice). The intervention includes self directed reflection exercises on their relationship, danger level, priority setting, and results in an individualised, tailored action plan. Primary self reported outcomes are: self-efficacy (General Self-Efficacy Scale) immediately after completion, 6 and 12 months post-baseline; and depressive symptoms (Centre for Epidemiologic Studies Depression Scale, Revised, 6 and 12 months post baseline). Secondary outcomes include mean number of helpful actions for safety and wellbeing, mean level of fear of partner and cost-effectiveness. DISCUSSION: This fully-automated trial will evaluate a web-based self-information, self reflection and self-management tool for domestic violence. We hypothesise that the improvement in self-efficacy and mental health will be mediated by increased perceived support and awareness encouraging positive change. If shown to be effective, I-DECIDE could be easily incorporated into the community sector and health care settings, providing an alternative to formal services for women not ready or able to acknowledge abuse and access specialised services. TRIAL REGISTRATION: Trial registered on 15(th) December 2014 with the Australian New Zealand Clinical Trials Registry ACTRN12614001306606. PMID- 26231229 TI - SSIEM 2015 Annual Symposium : Lyon, Fance, August 2015. PMID- 26231226 TI - Osthole ameliorates hepatic fibrosis and inhibits hepatic stellate cell activation. AB - BACKGROUND: Hepatic fibrosis is a dynamic process which ultimately leads to cirrhosis in almost patients with chronic hepatic injury. However, progressive fibrosis is a reversible scarring response. Activation of hepatic stellate cells (HSCs) is the prevailing process during hepatic fibrosis. Osthole is an active component majorly contained in the fruit of Cnidium monnieri (L.) Cusson. This present study investigated the therapeutic effects of osthole on rat liver fibrosis and HSC activation. RESULTS: We established the thioacetamide (TAA) model of Sprague-Dawley (SD) rats to induce hepatic fibrosis. Rats were divided into three groups: control, TAA, and TAA + osthole (10 mg/kg). In vivo, osthole significantly reduced liver injury by diminishing levels of plasma AST and ALT, improving histological architecture, decreasing collagen and alpha-SMA accumulation, and improving hepatic fibrosis scores. Additionally, osthole reduced the expression of fibrosis-related genes significantly. Osthole also suppressed the production of fibrosis-related cytokines and chemokines. Moreover, nuclear translocation of p65 was significantly suppressed in osthole-treated liver. Osthole also ameliorated TAA-induced injury through reducing cellular oxidation. Osthole showed inhibitory effects in inflammation-related genes and chemokines production as well. In vitro, we assessed osthole effects in activated HSCs (HSC-T6 and LX-2). Osthole attenuated TGF-beta1-induced migration and invasion in HSCs. Furthermore, osthole decreased TNF-alpha-triggered NF-kappaB activities significantly. Besides, osthole alleviated TGF-beta1- or ET-1-induced HSCs contractility. CONCLUSIONS: Our study demonstrated that osthole improved TAA caused liver injury, fibrogenesis and inflammation in rats. In addition, osthole suppressed HSCs activation in vitro significantly. PMID- 26231227 TI - A multidisciplinary approach for peritoneal carcinomatosis and bilobar liver metastases from colorectal cancer: case report and review of the literature. AB - BACKGROUND: Peritoneal carcinomatosis develops in 15% of patients with primary colorectal cancer (CRC) and in 25% of those with recurrence. Liver metastases are also frequent and appear at some time in 35-55% of patients with CRC. When both conditions are present and treated palliatively, the expected median survival is 5-6 months. Recent publications suggest survival is improved when R0 resection of both peritoneal and liver diseases is achieved. CASE PRESENTATION: A 36-year-old woman with synchronous peritoneal and liver metastases of colorectal origin was treated with a stepwise approach consisting of initial cytoreductive surgery, minor liver resection, intraperitoneal intraoperative hyperthermic chemotherapy, adjuvant chemotherapy, right portal embolization, and finally, right hepatectomy achieving an R0 resection. The patient is alive and free of disease after 30 months of follow-up. DISCUSSION: Patients with peritoneal carcinomatosis and liver metastases from CRC must be carefully evaluated by multidisciplinary oncological teams in order to offer the possibility of surgery to obtain an R0 resection in selected patients (especially if the peritoneal cancer index is <19 and there is resectable or potentially resectable metastatic liver disease). PMID- 26231222 TI - Shared genetics underlying epidemiological association between endometriosis and ovarian cancer. AB - Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07 0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci. PMID- 26231230 TI - Betaine supplementation is less effective than methionine restriction in correcting phenotypes of CBS deficient mice. AB - Cystathionine beta synthase (CBS) deficiency is a recessive inborn error of metabolism characterized by elevated serum total homocysteine (tHcy). Betaine supplementation, which can lower tHcy by stimulating homocysteine remethylation to methionine, is often given to CBS deficient patients in combination with other treatments such as methionine restriction and supplemental B-vitamins. However, the effectiveness of betaine supplementation by itself in the treatment of CBS deficiency has not been well explored. Here, we have examined the effect of a betaine supplemented diet on the Tg-I278T Cbs (-/-) mouse model of CBS deficiency and compared its effectiveness to our previously published data using a methionine restricted diet. Tg-I278T Cbs (-/-) mice on betaine, from the time of weaning until for 240 days of age, had a 40 % decrease in mean tHcy level and a 137 % increase in serum methionine levels. Betaine-treated Tg-I278T Cbs (-/-) mice also exhibited increased levels of betaine-dependent homocysteine methyl transferase (BHMT), increased levels of the lipogenic enzyme stearoyl-coenzyme A desaturase (SCD-1), and increased lipid droplet accumulation in the liver. Betaine supplementation largely reversed the hair loss phenotype in Tg-I278T Cbs (-/-) animals, but was far less effective than methionine restriction in reversing the weight-loss, fat-loss, and osteoporosis phenotypes. Surprisingly, betaine supplementation had several negative effects in control Tg-I278T Cbs (+/ ) mice including decreased weight gain, lean mass, and bone mineral density. Our findings indicate that while betaine supplementation does have some beneficial effects, it is not as effective as methionine restriction for reversing the phenotypes associated with severe CBS deficiency in mice. PMID- 26231231 TI - Effect of intense pulsed light on the expression of aquaporin 3 in rat skin. AB - Intense pulsed light (IPL) technology has been popularly employed in clinical treatments for dermatological and cosmetic purposes in recent years; yet, the underlying mechanisms of its functions are not fully elucidated. On the other hand, aquaporin (AQP) 3, a member of a subgroup of the aquaporin family that transports both water and small solutes, such as glycerol, has been documented to play an important role in the skin homeostasis. We thus examined the possible involvement of AQP3 in the functional mechanisms of IPL irradiation. Rat dorsal skin areas were irradiated one to three times with IPL at doses of 15, 25, and 35 J/cm2. Skin specimens were collected 7 days after the final irradiation and analyzed for changes in histology, skin hydration, mRNA, and protein expressions of AQP3. IPL induced no significant variations in the mRNA expression levels. Twice or thrice irradiation at the dose of 25 or 35 J/cm2 significantly enhanced AQP3 protein expression. Immunofluorescence study revealed that AQP3 was mainly localized to keratinocyte membranes in the basal layer of epidermis, and the localization was unaltered by IPL. In addition, the pattern of IPL-induced changes in skin hydration was generally coincided with the expression profile of AQP3. These results suggest the possibility that one of the functional mechanisms of IPL might be related to the regulation of AQP3 protein expression. PMID- 26231232 TI - Unexplained association between cystitis glandularis and interstitial cystitis in females: a retrospective study. AB - INTRODUCTION AND HYPOTHESIS: An increasing number of female patients have received comorbid diagnoses of cystitis glandularis (CG) and interstitial cystitis (IC) at our institution. In addition, most of these patients suffer from coexisting obstructive lower urinary tract diseases (OLUTDs). In this study, we aimed to present evidence of the possible association between CG and IC and analyze the clinical features of this association. METHODS: We retrospectively reviewed the charts of 395 female patients diagnosed with CG and/or IC. The patients were divided into three groups: group A (CG only), group B (IC only), and group C (CG+IC). Chi-squared tests were applied to compare the prevalence rates of CG in patients with IC and in the general population, the prevalence rates of IC in patients with CG and in the general population, and the prevalence rates of OLUTD in the three patient groups. RESULTS: The prevalence rate of IC in patients with CG was significantly higher than that in the general population, while the prevalence rate of CG in patients with IC was also significantly higher than that in the general population. For groups A, B, and C, 93 (39.2 %), 30 (44.1 %), and 58 (64.4 %) cases respectively presented with OLUTDs, and the prevalence rate of OLUTDs varied significantly among the three groups. CONCLUSIONS: This retrospective study found a possible association between CG and IC, and coexisting OLUTDs influenced this association. PMID- 26231233 TI - MRI suggests increased tonicity of the levator ani in women with interstitial cystitis/bladder pain syndrome. AB - INTRODUCTION AND HYPOTHESIS: In interstitial cystitis/bladder pain syndrome (IC/BPS), pelvic floor dysfunction may contribute significantly to pelvic pain. To determine if pelvic floor hypertonicity manifests alterations on magnetic resonance imaging (MRI) in patients with IC/BPS, we retrospectively compared pelvic measurements between patients and controls. METHODS: Fifteen women with IC/BPS and 15 age-matched controls underwent pelvic MRI. Two blinded radiologists measured the pelvic musculature, including the H- and M lines, vaginal length, urethral length and cross-sectional area, levator width and length, and posterior puborectalis angle. MRI measures and clinical factors, such as age, parity, and duration of symptoms, were compared using a paired, two-tailed t test. RESULTS: There were no significant differences in age, parity, or symptom duration between groups. Patients with IC/BPS exhibited shorter levator muscles (right: 5.0 +/- 0.7 vs. 5.6 +/- 0.8, left: 5.0 +/- 0.8 vs. 5.7 +/- 0.8 cm, P < 0.002) and a wider posterior puborectalis angle (35.0 +/- 8.6 vs. 26.7 +/- 7.9 degrees , P < 0.01) compared with controls. The H line was shorter in patients with IC/BPS (7.8 +/- 0.8 vs. 8.6 +/- 0.9 cm, P < 0.02), while M line did not differ. Total urethral length was similar, but vaginal cuff and bladder neck distances to the H line were longer in patients with IC/BPS (5.7 +/- 0.6 vs. 5.1 +/- 0.9 cm, P < 0.02; 1.9 +/- 0.4 vs. 1.4 +/- 0.2 cm, P < 0.001, respectively). CONCLUSIONS: Patients with IC/BPS have pelvic floor hypertonicity on MRI, which manifests as shortened levator, increased posterior puborectalis angles, and decreased puborectal distances. We identified evidence of pelvic floor hypertonicity in patients with IC/BPS, which may contribute to or amplify pelvic pain. Future studies are necessary to determine the MRI utility in understanding pelvic floor hypertonicity in patients with IC/BPS. PMID- 26231235 TI - Biomarkers for the Identification of Alcohol Use/Abuse: A Critical Review. AB - Alcohol abuse represents a highly relevant medical, social, and economic problem all over the world. The diagnosis of conditions of alcohol use or abuse is complex, requiring different and integrated methodologies; among them the use of biomarkers is a very helpful and objective tool. This review article discusses the currently available biomarkers of alcohol abuse, showing their positive and negative characteristics in terms of detection window, diagnostic sensitivity, diagnostic specificity, and analytical feasibility. Particular attention is dedicated to the most used biomarkers, represented by liver enzymes (AST, ALT, and GGT), MCV, CDT, EtG and EtS, FAEE, and PEth. A critical analysis of the different biomarkers showed wide variability in terms of detection window, sensitivity, and specificity. On this basis, the choice of any indicator should depend on the aim and context for which the diagnosis of alcohol abuse is required (e.g., clinical, fitness for driver's license, fitness to work, child custody). Moreover, this study showed that the diagnosis of alcohol abuse cannot be based only on the use of biomarkers, but it must also consider the integration of anamnestic, clinical, instrumental, and laboratory data. PMID- 26231234 TI - Utilization of information from gene networks towards a better understanding of functional similarities between complex traits: a dairy cattle model. AB - Our study focused on quantifying functional similarities between complex traits recorded in dairy cattle: milk yield, fat yield, protein yield, somatic cell score and stature. Similarities were calculated based on gene sets forming gene networks and on gene ontology term sets underlying genes estimated as significant for the analysed traits. Gene networks were obtained by the Bisogenet and Gene Set Linkage Analysis (GSLA) software. The highest similarity was observed between milk yield and fat yield. A very low degree of similarity was attributed to protein yield and stature when using gene sets as a similarity criterion, as well as to protein yield and fat yield when using sets of gene ontology terms. Pearson correlation coefficients between gene effect estimates, representing additive polygenic similarities, were highest for protein yield and milk yield, and the lowest in case of protein yield and somatic cell score. Using the 50 K Illumina SNP chip from the national genomic selection data set only the most significant gene-trait associations can be retrieved, while enhancing it by the functional information contained in interaction data stored in public data bases and by metabolic pathways information facilitates a better characterization of the functional background of the traits and furthermore - trait comparison. The most interesting result of our study was that the functional similarity observed between protein yield and milk-/fat yields contradicted moderate genetic correlations estimated earlier for the same population based on a multivariate mixed model. The discrepancy indicates that an infinitesimal model assumed in that study reflects an averaged correlation due to polygenes, but fails to reveal the functional background underlying the traits, which is due to the cumulative composition of many genes involved in metabolic pathways, which appears to differ between protein-fat yield and protein-milk yield pairs. PMID- 26231236 TI - The Illegal Use of Synthetic Pharmaceuticals in Herbal Formulations: An Overview of Adulteration Practices and Analytical Investigations. AB - Alternative medicine has historically been very popular in developing countries. In this context, self-medication with herbal formulations has increased in both developing and developed nations in recent years. The adulteration of such formulations violates the laws of many countries because it can lead to unpredictable effects in the human body, either due to the isolated effects of an added pharmaceutical or to its interaction with other substances present in the formulation. The development of methodologies for the screening and quantification of adulterated samples should be of great interest for analytical, clinical, and forensic scientists. This review aims to provide a comprehensive approach to this topic and to discuss adulteration cases related to herbal formulations reported in the literature over the last few decades. Furthermore, a classification of the most commonly found synthetic adulterants that are linked to the active principle of herbal formulations was proposed according to their pharmacological action. The available analytical methodologies for the identification of adulteration practices are presented in a systematic and comprehensive way. PMID- 26231237 TI - Pharmacokinetics of Ethanol - Issues of Forensic Importance. AB - A reliable method for the quantitative analysis of ethanol in microvolumes (50 100 MUL) of blood became available in 1922, making it possible to investigate the absorption, distribution, metabolism, and excretion (ADME) of ethanol in healthy volunteers. The basic principles of ethanol pharmacokinetics were established in the 1930s, including the notion of zero-order elimination kinetics from blood and distribution of the absorbed dose into the total body water. The hepatic enzyme alcohol dehydrogenase (ADH) is primarily responsible for the oxidative metabolism of ethanol. This enzyme was purified and characterized in the early 1950s and shown to have a low Michaelis constant (km), being about ~0.1 g/L. Liver ADH is therefore saturated with substrate after the first couple of drinks and for all practical purposes the concentration-time (C-T) profiles of ethanol are a good approximation to zero-order kinetics. However, because of dose-dependent saturation kinetics, the entire postabsorptive declining part of the blood alcohol concentration (BAC) curve looks more like a hockey stick rather than a straight line. A faster rate of ethanol elimination from blood in habituated individuals (alcoholics) is explained by participation of a high km microsomal enzyme (CYP2E1), which is inducible after a period of chronic heavy drinking. Owing to the combined influences of genetic and environmental factors, one expects a roughly threefold difference in elimination rates of ethanol from blood (0.1-0.3 g/L/h) between individuals. The volume of distribution (Vd) of ethanol, which depends on a person's age, gender, and proportion of fat to lean body mass, shows a twofold variation between individuals (0.4-0.8 L/kg). This forensic science review traces the development of forensic pharmacokinetics of ethanol from a historical perspective, followed by a discussion of important issues related to the disposition and fate of ethanol in the body, including (a) quantitative evaluation of blood-alcohol curves and the factors influencing the peak concentration in blood (Cmax) and the time of its occurrence (tmax), (b) biological variations in the ADME of ethanol, including the apparent volume of distribution (Vd or rho), the disappearance rate from blood (beta or k0), and the disposal rate by the entire body in 1 h (B60), and (c) questions about ADME of ethanol often arising during the prosecuting of accused drunken drivers. PMID- 26231238 TI - Hormone Use in Food Animal Production: Assessing Potential Dietary Exposures and Breast Cancer Risk. AB - In recent years, increasing attention has been paid to the role of hormones in breast cancer etiology, following reports that heightened levels of endogenous hormones and exposure to exogenous hormones and other endocrine-disrupting chemicals through food and the environment are associated with increased breast cancer risk. Seven hormone drugs (testosterone propionate, trenbolone acetate, estradiol, zeranol, progesterone, melengestrol acetate, and bovine somatotropin) are approved by the U.S. Food and Drug Administration for use in food animals. There is concern that these drugs or their biologically active metabolites may accumulate in edible tissues, potentially increasing the risk of exposure for consumers. To date, the potential for human exposure to residues of these compounds in animal products, as well as the risks that may result from this exposure, is poorly understood. In this paper, we discuss the existing scientific evidence examining the toxicological significance of exposure to hormones used in food animal production in relation to breast cancer risk. Through a discussion of U.S. federal regulatory programs and the primary literature, we interpret the state of surveillance for residues of hormone drugs in animal products and discuss trends in meat consumption in relation to the potential for hormone exposure. Given the lack of chronic bioassays of oral toxicity of the seven hormone compounds in the public literature and the limitations of existing residue surveillance programs, it is not currently possible to provide a quantitative characterization of risks that result from the use of hormonal drugs in food animal production, complicating our understanding of the role of dietary hormone exposure in the population burden of breast cancer. PMID- 26231239 TI - Recent Developments in the Quantification and Regulation of Air Emissions from Animal Feeding Operations. AB - Animal feeding operations (AFOs) emit various air pollutants, including ammonia, hydrogen sulfide, particulate matter, volatile organic compounds, methane, and nitrous oxide. Several of these pollutants are regulated under federal clean air statutes, yet AFOs have largely escaped regulation under these laws because of challenges in accurately estimating the rate and quantity of emissions from various types of livestock operations. Recent Environmental Protection Agency (EPA) efforts to collect emissions data, develop an emissions model capable of estimating emissions at AFOs nationwide, and establish emissions estimating methodologies for certain key livestock air pollutants suffered from design flaws and omitted pollutants of concern. Moreover, this process seems to have stalled, delaying other regulatory reforms needed to increase transparency and increase regulation of these facilities. Until EPA establishes these methodologies, significant AFO pollution regulation under the Clean Air Act or emissions reporting statutes will be very difficult to achieve, and the public health and environmental impacts of these emissions will continue unabated. PMID- 26231240 TI - C6-Perfluorinated Compounds: The New Greaseproofing Agents in Food Packaging. AB - Due to their oleophobic and hydrophobic properties and stability, perfluorinated compounds (PFCs) are used in many applications, particularly as greaseproofing agents for food contact. However, PFCs 8-carbons in length or greater (C8-PFCs) have raised concerns regarding environmental biopersistence, bioaccumulation in humans, and potent toxicity that have resulted in their gradual phase-out for food contact use. Industry has replaced C8-PFCs with shorter-chained C6-based greaseproofing agents, which are intended to have the same favorable physicochemical properties without the problematic toxicological effects in humans and wildlife. Compared with the large body of data available for C8 compounds, however, the available database on toxicity and exposure to the C6 compounds is fairly limited. This article summarizes the information in this database, focusing on aspects of human exposure and potential health risks associated with two types of C6 PFCs found in food packaging: perfluorohexanoic acid (PFHxA) and 6-2 fluorotelomer alcohol (C6-FTOH). PMID- 26231241 TI - Human Infections with Staphylococcus aureus CC398. AB - Staphylococcus aureus isolates belonging to clonal cluster 398 (CC398) have emerged over the previous decade as a risk to livestock workers. Though most of the research to date has focused on colonization with these strains, a number of infections have also been documented, ranging from mild skin infections to more serious invasive infections and even death. Here, we review existing reports of human infections with CC398 and discuss their geographic distribution, general characteristics, and implications for future research. We identified 74 publications describing CC398 infections in humans in 19 different countries, suggesting this is an emerging worldwide issue. PMID- 26231242 TI - Drinking Water Arsenic Contamination, Skin Lesions, and Malignancies: A Systematic Review of the Global Evidence. AB - Skin lesions and cancer are known manifestations of chronic exposure to arsenic contaminated drinking water. Epidemiologic data primarily comes from regions with exposures 1-2 orders of magnitude above the current World Health Organization (WHO) guidelines of 10 MUg/L. Emerging evidence indicates that more common exposures may also be related to both noncancerous and cancerous changes to the skin. In this review, we focus on the body of epidemiologic literature that encompasses exposures within the WHO guidelines, excluding studies that lacked individual exposure estimates and case reports. For skin lesions and skin cancers, 15 and 10 studies were identified that met our criteria, respectively. For skin lesions, a consistent dose-response relationship with water arsenic has been observed, with increased risk evident at low- to moderate-dose exposure. Of the larger studies of specific histologic types of skin cancers, although with differing exposure definitions, there was evidence of dose-related relationships with both basal cell carcinomas and squamous cell carcinomas. The effect of arsenic exposure on skin lesion risk is likely modified by genetic variants that influence arsenic metabolism. Accumulating evidence suggests that arsenic may increase risk of skin lesions and skin cancers at levels not previously considered harmful, and that genetic factors may influence risk. PMID- 26231243 TI - Household Water Treatment and Safe Storage to Prevent Diarrheal Disease in Developing Countries. AB - Household water treatment and safe storage (HWTS), such as boiling, filtering, or chlorinating water at home, have been shown to be effective in improving the microbiological quality of drinking water. However, estimates of their protective effect against diarrhea, a major killer, have varied widely. While results may be exaggerated because of reporting bias, this heterogeneity is consistent with other environmental interventions that are implemented with varying levels of coverage and uptake in settings where the source of exposure represents one of many transmission pathways. Evidence suggests that the effectiveness of HWTS can be optimized by ensuring that the method is microbiologically effective; (2) making it accessible to an exposed population; and (3) securing their consistent and long-term use. PMID- 26231244 TI - Health Effects of Toxic Cyanobacteria in U.S. Drinking and Recreational Waters: Our Current Understanding and Proposed Direction. AB - Cyanobacterial-derived water quality impairment issues are a growing concern worldwide. In addition to their ecological impacts, these organisms are prolific producers of bioactive secondary metabolites, many of which are known human intoxicants. To date only a handful of these compounds have been thoroughly studied and their toxicological risks estimated. While there are currently no national guidelines in place to deal with this issue, it is increasingly likely that within the next several years guidelines will be implemented. The intent of this review is to survey all relevant literature pertaining to cyanobacterial harmful algal bloom secondary metabolites, to inform a discussion on how best to manage this global public health threat. PMID- 26231246 TI - ANIMA: A data-sharing initiative for neuroimaging meta-analyses. AB - Meta-analytic techniques allow cognitive neuroscientists to pool large amounts of data across many individual task-based functional neuroimaging experiments. These methods have been aided by the introduction of online databases such as Brainmap.org or Neurosynth.org, which collate peak activation coordinates obtained from thousands of published studies. Findings from meta-analytic studies typically include brain regions which are consistently activated across studies for specific contrasts, investigating cognitive or clinical hypotheses. These regions can be subsequently used as the basis for seed-based connectivity analysis, or formally compared to neuroimaging data in order to help interpret new findings. To facilitate such approaches, we have developed a new online repository of meta-analytic neuroimaging results, named the Archive of Neuroimaging Meta-analyses (ANIMA). The ANIMA platform consists of an intuitive online interface for querying, downloading, and contributing data from published meta-analytic studies. Additionally, to aid the process of organizing, visualizing, and working with these data, we present an open-source desktop application called Volume Viewer. Volume Viewer allows users to easily arrange imaging data into composite stacks, and save these sessions as individual files, which can also be uploaded to the ANIMA database. The application also allows users to perform basic functions, such as computing conjunctions between images, or extracting regions-of-interest or peak coordinates for further analysis. The introduction of this new resource will enhance the ability of researchers to both share their findings and incorporate existing meta-analytic results into their own research. PMID- 26231245 TI - Overview of Disinfection By-products and Associated Health Effects. AB - The presence of chemical compounds formed as disinfection by-products (DBPs) is widespread in developed countries, and virtually whole populations are exposed to these chemicals through ingestion, inhalation, or dermal absorption from drinking water and swimming pools. Epidemiological evidence has shown a consistent association between long-term exposure to trihalomethanes and the risk of bladder cancer, although the causal nature of the association is not conclusive. Evidence concerning other cancer sites is insufficient or mixed. Numerous studies have evaluated reproductive implications, including sperm quality, time to pregnancy, menstrual cycle, and pregnancy outcomes such as fetal loss, fetal growth, preterm delivery, and congenital malformation. The body of evidence suggests only minor effects from high exposure during pregnancy on fetal growth indices such as small for gestational age (SGA) at birth. Populations highly exposed to swimming pools such as pool workers and professional swimmers show a higher prevalence of respiratory symptoms and asthma, respectively, although the direction of the association, and thus causality, is not clear among professional swimmers. The risk of asthma, wheezing, eczema, and other respiratory outcomes among children attending swimming pools has been the object of extensive research. Early studies suggested a positive association, while subsequent larger studies found no correlations or showed a protective association. Future research should develop methods to evaluate the effects of the DBP mixture and the interaction with personal characteristics (e.g., genetics, lifestyle), clarify the association between swimming pools and respiratory health, evaluate the occurrence of DBPs in low- and middle-income countries, and evaluate outcomes suggested by animal studies that have not been considered in epidemiological investigations. PMID- 26231247 TI - Estimation of dynamic functional connectivity using Multiplication of Temporal Derivatives. AB - Functional connectivity provides an informative and powerful framework for exploring brain organization. Despite this, few statistical methods are available for the accurate estimation of dynamic changes in functional network architecture. To date, the majority of existing statistical techniques have assumed that connectivity structure is stationary, which is in direct contrast to emerging data that suggests that the strength of connectivity between regions is variable over time. Therefore, the development of statistical methods that enable exploration of dynamic changes in functional connectivity is currently of great importance to the neuroscience community. In this paper, we introduce the 'Multiplication of Temporal Derivatives' (MTD) and then demonstrate the utility of this metric to: (i) detect dynamic changes in connectivity using data from a novel state-switching simulation; (ii) accurately estimate graph structure in a previously-described 'ground-truth' simulated dataset; and (iii) identify task driven alterations in functional connectivity. We show that the MTD is more sensitive than existing sliding-window methods in detecting dynamic alterations in connectivity structure across a range of correlation strengths and window lengths in simulated data. In addition to the temporal precision offered by MTD, we demonstrate that the metric is also able to accurately estimate stationary network structure in both simulated and real task-based data, suggesting that the method may be used to identify dynamic changes in network structure as they evolve through time. PMID- 26231248 TI - Considerations of the chemical biology of microbial natural products provide an effective drug discovery strategy. AB - Conventional approaches to natural product drug discovery rely mainly on random searches for bioactive compounds using bioassays. These traditional approaches do not incorporate a chemical biology perspective. Searching for bioactive molecules using a chemical and biological rationale constitutes a powerful search paradigm. Here, the authors review recent examples of the discovery of bioactive natural products based on chemical and biological interactions between hosts and symbionts, and propose this method provides a more effective means of exploring natural chemical diversity and eventually of discovering new drugs. PMID- 26231249 TI - Accuracy of enhanced and unenhanced MRI in diagnosing scaphoid proximal pole avascular necrosis and predicting surgical outcome. AB - PURPOSE: Determine the sensitivity, specificity and accuracy of unenhanced and enhanced MRI in diagnosing scaphoid proximal pole (PP) avascular necrosis (AVN) and correlate whether MRI can help guide the selection of a vascularized or nonvascularized bone graft. METHODS: The study was approved by the IRB. Two MSK radiologists independently performed a retrospective review of unenhanced and enhanced MRIs from 18 patients (16 males, 2 females; median age, 17.5 years) with scaphoid nonunions and surgery performed within 65 days of the MRI. AVN was diagnosed on the unenhanced MRI when a diffusely decreased T1-W signal was present in the PP and on the enhanced MRI when PP enhancement was less than distal pole enhancement. Surgical absence of PP bleeding was diagnostic of PP AVN. Postoperative osseous union (OU) was assessed with computed tomography and/or radiographs. RESULTS: Sensitivity, specificity and accuracy for PP AVN were 71, 82 and 78% for unenhanced and 43, 82 and 67% for enhanced MRI. Patients with PP AVN on unenhanced MRI had 86% (6/7) OU; 100% (5/5) OU with vascularized bone grafts and 50% (1/2) OU with nonvascularized grafts. Patients with PP AVN on enhanced MRI had 80% (4/5) OU; 100% (3/3) OU with vascularized bone grafts and 50% (1/2) OU with nonvascularized grafts. Patients with viable PP on unenhanced and enhanced MRI had 91% (10/11) and 92% (12/13) OU, respectively, all but one with nonvascularized graft. CONCLUSIONS: When PP AVN is evident on MRI, OU is best achieved with vascularized grafts. If PP AVN is absent, OU is successful with nonvascularized grafts. PMID- 26231250 TI - Increased night duty loading of physicians caused elevated blood pressure and sympathetic tones in a dose-dependent manner. AB - PURPOSE: Night duty has been recognized as a significantly harmful stressor for physicians. However, the relationship between various levels of duty loading and stress response is unknown. This study examined whether duty load increases cardiovascular stress indicators in a dose-dependent manner. METHODS: An unallocated prospective observational study was conducted among physicians performing various levels of duties in a secondary referral medical center between 2011 and 2012. Heart rate variability (HRV), blood pressure (BP), and other stress markers of 12 attending physicians were compared during different duty loads: non-duty day (NDD), duty day with one duty area and three wards (1DD), and duty day with two duty areas and six wards (2DD). RESULTS: During the regular sleep time (i.e., 11 p.m. to 5 a.m.), the relative sympathetic modulations measured using the HRV were 59.0 +/- 9.3, 61.6 +/- 10.4, and 64.4 +/- 8.9 for NDD, 1DD, and 2DD, respectively (p = 0.0012); those for relative parasympathetic modulations were 37.4 +/- 9.4, 34.8 +/- 9.8, and 32.0 +/- 8.8 for NDD, 1DD, and 2DD, respectively (p = 0.0015). The percentages of abnormal systolic BPs were 9.7 +/- 13.2 %, 25.3 +/- 21.8 %, and 31.5 +/- 21.0 % for NDD, 1DD, and 2DD, respectively (p = 0.003), and the percentages of abnormal diastolic BP were 6.7 +/- 11.0 %, 18.3 +/- 11.1 %, and 27.1 +/- 30.9 % for NDD, 1DD, and 2DD, respectively (p = 0.002). Total sleep time was negatively associated with sympathetic/parasympathetic balance and the percentage of abnormal diastolic BP. Admitting new patients was positively associated with the percentages of abnormal systolic BP. CONCLUSIONS: This observational analysis suggests that the dose dependent stress responses of the cardiovascular system in physicians were caused by the duty load. PMID- 26231251 TI - Whole brain radiotherapy with hippocampal avoidance and simultaneous integrated boost for brain metastases: a dosimetric volumetric-modulated arc therapy study. AB - OBJECTIVE: To develop a feasible volumetric modulated arc therapy (VMAT) treatment in whole brain radiotherapy (WBRT) with a simultaneous integrated boost (SIB) and hippocampal (HP) sparing in 1-5 brain metastases (BMs). METHODS AND MATERIALS: Ten patients with 20 BMs received a WBRT prescription of 20 Gy, SIB dose on BMs of 40 Gy/5 fractions. PTVWBRT was generated from brain minus BMs-PTVs (PTVSIB) and planning organ at risk volume to HP. All plans were evaluated in: homogeneity index (HI), target coverage (TC), maximum dose to prescription dose ratio (MDPD), prescription isodose to target volume ratio (PITV) and paddick conformity index (CI). We also evaluate D100%, mean and maximum doses to HP. Planning objectives were for PTVWBRT, D2% = 25 Gy with acceptable deviation of 26.7 Gy and D98% >= 16.7 Gy; for PTVSIB D95% >= 38 Gy; for HP, D100% = 6 Gy with acceptable deviation of 6.7 Gy, Dmax = 10.7 Gy with acceptable deviation of 11.3 Gy, a mean dose of 8 Gy. RESULTS: Mean number of BMs was 2 (range 1-5). Mean values for BMs were volume of PTVSIB = 5.1 +/- 4.9 cc, dose to 95% of PTVSIB 39.3 +/- 0.9 Gy, HI 0.083 +/- 0.03, TC 0.96 +/- 0.24, CI 0.78 +/- 0.17. Mean MDPD was 1.06 +/- 0.02 and PITV 0.96 +/- 0.24. For WBRT, mean target volume was (13.46 +/- 2)*10(2) cc, mean dose to 90% of PTVWBRT 19.8 +/- 0.2 Gy, mean HI 0.42 +/- 0.12 and TC 0.78 +/- 0.11. Mean and maximum HP doses were 7.7 +/- 0.3 Gy and 10.5 +/- 0.5 Gy. Mean dose to 100% of HP volume (D100%) was 6.7 +/- 0.3 Gy. CONCLUSIONS: WBRT plus SIB with HP avoidance with VMAT was feasible. All dosimetric parameters were satisfied for PTVWBRT and PTVSIB. PMID- 26231252 TI - Clinical outcomes and toxicity after exclusive versus postoperative radiotherapy in supraglottic cancer: new solutions for old problems? The case of stage III and IV disease. AB - PURPOSE: To compare toxicity, survival and laryngeal preservation rate after radiotherapy alone (RR), radiotherapy after supraglottic horizontal laryngectomy (SHLR) and radiotherapy after total laryngectomy (TLR) for advanced supraglottic laryngeal cancer. MATERIALS AND METHODS: From 1984 to 2012, 532 patients (pts) were treated in our Department: 273 were potentially fit for conservative surgery (Group I) and 259 were not amenable to partial surgery (Group II). RESULTS: A younger age (p = 0.005), a better performance status (p < 0.001), the absence of comorbidities (p < 0.001) and the absence of nodal involvement (p = 0.006) favorably impacted on overall survival. More high-grade mucositis (p = 0.009), mild dysphagia (p < 0.001) and mild xerostomia (p < 0.001) were found in RR group; surgical patients had more edema of neck (p = 0.009) and skin toxicity (p = 0.008). Group I No differences in local, nodal and distant recurrences and in number of rescue laryngectomies were observed. The disease characteristics (T, N and stage) but not the treatment modality impacted on disease-free survival (DFS). Group II There was an higher number of local (p = 0.013) and nodal (p = 0.022) recurrences after RR. DFS (p = 0.01) was longer after TLR. No differences in DFS between TLR patients and RR patients who underwent radio-chemotherapy were found. CONCLUSION: In Group I, RR results in a local-regional control and organ preservation comparable to surgical treatments, with only slight increase of late mild xerostomia and dysphagia. In Group II RR was less effective than TLR, with a significantly worse DFS. The use of concurrent radical radio-chemotherapy seems to provide comparable loco-regional control to TLR. PMID- 26231253 TI - CT patterns of pleuro-pulmonary damage caused by inhalation of pumice as a model of pneumoconiosis from non-fibrous amorphous silicates. AB - PURPOSE: The aim of this article is to correlate the radiological features of pleuro-pulmonary damage caused by inhalation of pumice (an extrusive volcanic rock classified as a non-fibrous, amorphous, complex silicate) with exposure conditions. MATERIALS AND METHODS: 36 subjects employed in the pumice quarries were evaluated for annual follow-up in a preventive medical surveillance program including spirometry, chest CT lasting from 1999 to 2014. They were only male subjects, mean age 56.92 +/- 16.45 years. Subjects had worked in the quarries for an average of 25.03 +/- 9.39 years. Domestic or occupational exposure to asbestos or other mineral dusts other than pumice was excluded. Subjects were also classified as smokers, former smokers and nonsmokers. RESULTS: Among the 36 workers examined, we identified four CT patterns which resulted to be dependent on exposure duration and intensity, FVC, FEV1 and FEF25-75, but not on cigarette smoking. The most common symptoms reported by clinical examination were dyspnoea, cough and asthenia. In no case it was proven an evolution of CT findings during follow-up for 10 years. CONCLUSIONS: Liparitosis, caused by pumice inhalation, can be considered a representative example of pneumoconiosis derived by amorphous silica compounds, which are extremely widespread for industrial manufacturing as well as for applicative uses, such as nano-materials. Moreover, being pumice free of quartz contamination, it can represent a disease model for exposure to pure non-fibrous silicates. PMID- 26231254 TI - Unbiased metagenomic sequencing complements specific routine diagnostic methods and increases chances to detect rare viral strains. AB - Multiplex PCR assays for respiratory viruses are widely used in routine diagnostics, as they are highly sensitive, rapid, and cost effective. However, depending on the assay system, cross-reactivity between viruses that share a high sequence homology as well as detection of rare virus isolates with sequence variations can be problematic. Virus sequence-independent metagenomic high throughput sequencing allows for accurate detection of all virus species in a given sample, as we demonstrate here for human Enterovirus and Rhinovirus in a lung transplant patient. While early in infection a commercial PCR assay recorded Rhinovirus, high-throughput sequencing correctly identified human Enterovirus C104 as the source of infection, highlighting the potential of the technology and the benefit of applying open assay formats in complex diagnostic situations. PMID- 26231255 TI - Relaxed observer design of discrete-time T-S fuzzy systems via a novel slack variable approach. AB - The problem of further studies on observer design for discrete-time Takagi-Sugeno fuzzy systems is investigated in this paper. Different from the existing result, a new slack variable approach is presented by developing some useful matrix equalities which rely on both the current-time and the past-time normalized fuzzy weighting functions. As a result, the relaxation quality of recent fuzzy observer design is significantly enhanced. Moreover, the conditions for the existence of a fuzzy H(infinity) observer that minimizes an upper bound to H(infinity) norms are also proposed. Finally, two numerical examples are provided to show that the given results are less conservative than other results available in the literature. PMID- 26231256 TI - Natural course of total mismatch and predictors for tissue infarction. AB - OBJECTIVE: We longitudinally assessed patients presenting with total mismatch and hypothesized that hypoperfusion intensity ratio (HIR), severity of stroke, and occlusion of blood vessel are predictors of tissue fate. METHODS: Patients with suspected stroke or TIA admitted to our emergency department between September 2008 and October 2012 with suspected stroke or TIA were eligible to participate in the ongoing stroke imaging study 1000Plus. Patients received acute and follow up stroke MRI, basic demographics were collected, and stroke severity was rated according to the NIH Stroke Scale (NIHSS). Inclusion criteria for the substudy were total mismatch on admission examination and available follow-up. RESULTS: We identified 23 patients with total mismatch: median age 70 years (interquartile range 66-78), 10 female (43.5%). Infarction was found on follow-up diffusion weighted imaging (median lesion size 1.3 mL) in 9 patients (39.1%). Infarction was correlated with NIHSS at admission (p = 0.026) and HIR (p = 0.015) but not with vessel occlusion. Clinical outcome as measured by last recorded NIHSS score and modified Rankin Scale score at discharge was significantly worse in patients with infarction on follow-up. CONCLUSION: Final infarction is frequently seen in patients with total mismatch. Clinical presentation at admission and severity of hypoperfusion measured by HIR, but not occlusion of the supplying vessel, predict tissue fate. PMID- 26231257 TI - Effects of education on aging-related cortical thinning among cognitively normal individuals. AB - OBJECTIVES: We aimed to investigate the relationship between education and cortical thickness in cognitively normal individuals to determine whether education attenuated the association of advanced aging and cortical thinning. METHODS: A total of 1,959 participants, in whom education levels were available, were included in the final analysis. Cortical thickness was measured on high resolution MRIs using a surface-based method. Multiple linear regression analysis was performed for education level and cortical thickness, after controlling for possible confounders. RESULTS: High levels of education were correlated with increased mean cortical thickness throughout the entire cortex (p = 0.003). This association persisted after controlling for vascular risk factors. Statistical maps of cortical thickness showed that the high levels of education were correlated with increased cortical thickness in the bilateral premotor areas, anterior cingulate cortices, perisylvian areas, right superior parietal lobule, left lingual gyrus, and occipital pole. There were also interactive effects of age and education on the mean cortical thickness (p = 0.019). CONCLUSIONS: Our findings suggest the protective effect of education on cortical thinning in cognitively normal older individuals, regardless of vascular risk factors. This effect was found only in the older participants, suggesting that the protective effects of education on cortical thickness might be achieved by increased resistance to structural loss from aging rather than by simply providing a fixed advantage in the brain. PMID- 26231258 TI - CNS neutrophilic vasculitis in neuro-Sweet disease. PMID- 26231259 TI - N-terminal pro-brain natriuretic peptide and abnormal brain aging: The AGES Reykjavik Study. AB - OBJECTIVE: To investigate the independent association of serum N-terminal fragment of the prohormone natriuretic peptide (NT-proBNP) with structural and functional features of abnormal brain aging in older individuals. METHODS: In this cross-sectional study based on the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, we included 4,029 older community-dwelling individuals (born 1907 to 1935) with a measured serum level of NT-proBNP. Outcomes included parenchymal brain volumes estimated from brain MRI, cognitive function measured by tests of memory, processing speed, and executive functioning, and presence of depressive symptoms measured using the Geriatric Depression Scale. In a substudy, cardiac output of 857 participants was assessed using cardiac MRI. RESULTS: In multivariate analyses, adjusted for sociodemographic and cardiovascular factors, higher levels of NT-proBNP were independently associated with lower total (p < 0.001), gray matter (p < 0.001), and white matter (p = 0.001) brain volumes. Likewise, in multivariate analyses, higher levels of NT-proBNP were associated with worse scores in memory (p = 0.005), processing speed (p = 0.001), executive functioning (p < 0.001), and more depressive symptoms (p = 0.002). In the substudy, the associations of higher NT-proBNP with lower brain parenchymal volumes, impaired executive function and processing speed, and higher depressive symptoms were independent of the level of cardiac output. CONCLUSIONS: Higher serum levels of NT-proBNP, independent of cardiovascular risk factors and a measure of cardiac function, are linked with alterations in brain structure and function. Roles of natriuretic peptides in the process of brain aging need to be further elucidated. PMID- 26231260 TI - Pediatric cavernous sinus thrombosis: A case series and review of the literature. AB - OBJECTIVE: To describe clinical characteristics, imaging findings, morbidity, and mortality in a single-center cohort of 12 pediatric cavernous sinus thrombosis cases and to review all cases available in recent English literature. METHODS: Clinical data and radiographic studies on 12 cases from our institution were analyzed retrospectively. A literature search and review was conducted, with additional cases pooled with the new cohort for an aggregate analysis. RESULTS: Twelve cases of cavernous sinus thrombosis in children from the Children's Hospital of Philadelphia between January 1, 2000, and December 31, 2013, were reviewed. All patients survived to discharge; 3 of 12 (25%) experienced neurologic morbidity. Contrast-enhanced MRI and contrast-enhanced head CT were 100% sensitive for detecting cavernous sinus thrombosis, while noncontrast time of-flight magnetic resonance venography (TOF MRV) and noncontrast head CT were 0% sensitive. Literature review produced an additional 40 cases, and the aggregate mortality rate was 4 of 52 (8%) and morbidity rate was 10 of 40 (25%). Outcomes did not vary by treatment or with unilateral vs bilateral cavernous sinus involvement. There was a trend toward worse outcomes with fungal infections. CONCLUSION: Our case series demonstrates low morbidity and mortality with early, aggressive surgical, antimicrobial, and anticoagulation therapies. Although anticoagulation and surgery were not associated with significantly different outcomes, more study is needed. PMID- 26231261 TI - Ultrasound in neurolymphomatosis: The rise of the machines. PMID- 26231262 TI - Role of combined B-mode and Doppler sonography in evaluating neurolymphomatosis. AB - OBJECTIVE: To highlight the potential usefulness of nerve ultrasonography to identify lymphomatous peripheral nerve infiltration in patients with lymphoma. METHODS: We performed electrodiagnostic studies and nerve ultrasonography in 3 patients with lymphoma presenting with focal peripheral neuropathy. RESULTS: In all 3 patients, electrodiagnostic studies proved focal involvement of the peripheral nerves. Ultrasonography showed nerve thickening at sites of electrodiagnostic abnormality. All enlarged nerves showed increased blood flow within the area of nerve thickening. Abnormal sonographic studies prompted focused imaging and histologic studies, which confirmed the diagnosis of neurolymphomatosis. CONCLUSIONS: Nerve ultrasonography should be considered when evaluating focal neuropathic symptoms in patients with lymphoma. Demonstration of neural enlargement and increased blood flow in symptomatic and electrophysiologically abnormal nerves suggests a diagnosis of neurolymphomatosis, probably reflecting infiltration and neovascularization. Further sonographic studies on the detection and quantification of nerve abnormality in neurolymphomatosis will be of additional value. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with lymphoma and focal neuropathies, nerve ultrasound aids in identifying those with lymphomatous peripheral nerve infiltration on biopsy. PMID- 26231263 TI - Nocturia: Current Evaluation and Treatment for Urology. AB - Nocturia is a very common yet a highly underreported entity. Recently, there has been an increasing interest in nocturia because of its association with serious adverse health conditions such as diabetes, heart disease, elevated BMI, and mortality. Frequency volume charts are the cornerstone of initial assessment and are pivotal in determining the type of nocturia and associated causes. The diagnostic evaluation is aimed at clarifying the underlying cause: sleep disturbances, reduced bladder capacity (functional or extrinsic), and increased urine production (nocturnal or daily). Obstructive sleep apnea is an important cause of nocturnal polyuria and should always been considered. Management is focused on treating the underlying cause; a range of behavioral and pharmacologic options are available. PMID- 26231264 TI - Evaluation of Periodic Limb Movements in Sleep and Iron Status in Children With Autism. AB - OBJECTIVE: Recent data suggest that both disordered sleep and low serum iron occur more frequently in children with autism compared with children with typical development. Iron deficiency has been linked to specific sleep disorders. The goal of the current study was to evaluate periodic limb movements in sleep and iron status in a group of children with autism compared with typically developing children and children with nonautism developmental delay to determine if iron status correlated with polysomnographic measures of latency and continuity and periodic limb movements in sleep. METHODS: A total of 102 children (68 with autism, 18 typically developing, 16 with developmental delay) aged 2 to 7 years underwent a one-night modified polysomnography study and phlebotomy at the National Institutes of Health to measure serum markers of iron status (ferritin, iron, transferrin, percent transferrin saturation). RESULTS: No serum iron marker was associated with periodic limb movements of sleep or any other sleep parameter; this did not differ among the diagnostic groups. No significant differences among groups were observed on serum iron markers or most polysomnogram parameters: periodic limb movements in sleep, periodic limb movements index, wake after sleep onset, or sleep efficiency. Children in the autism group had significantly less total sleep time. Serum ferritin was uniformly low across groups. CONCLUSIONS: This study found no evidence that serum ferritin is associated with polysomnogram measures of latency or sleep continuity or that young children with autism are at increased risk for higher periodic limb movements index compared with typically developing and developmental delay peers. PMID- 26231265 TI - Structural Gray Matter Differences During Childhood Development in Autism Spectrum Disorder: A Multimetric Approach. AB - BACKGROUND: Autism spectrum disorder is a complex neurodevelopmental disorder characterized by impaired social interaction and communication, repetitive behaviors, and restricted interests. Gray matter differences linked to autism spectrum disorder have been studied using a variety of structural imaging methods, but yielded little consensus; the extent to which disparate results reflect differences in methodology or heterogeneity within autism spectrum disorder is not yet clear. Moreover, very few studies have examined gray matter changes as a function of age in autism spectrum disorder. METHOD: A detailed investigation of gray matter structural development was performed via voxel-based morphometry, cortical thickness, and cortical surface area analyses in 38 autism spectrum disorder versus 46 typically developing children. RESULTS: Relative to typically developing children, the autism spectrum disorder group showed gray matter increases most prominently in the frontal and temporal lobes (including regions such as medial frontal gyrus, Broca's area and posterior temporal cortex), as well as certain parietal and occipital subcortical regions. Gray matter decreases were found only near the temporoparietal junction. Subcortical gray matter increases were found in the putamen and caudate nucleus, while decreases were found in cerebellum. There were age-dependent GM differences in distributed regions including prefrontal cortex, primary sensorimotor cortex, and temporoparietal junction. CONCLUSION: The results underline the distributed nature of gray matter structural differences in autism spectrum disorder and provide a more comprehensive characterization of autism spectrum disorder-related cortical and subcortical gray matter structural differences during childhood and adolescent development. PMID- 26231266 TI - Mitochondrial Membrane Protein-Associated Neurodegeneration. PMID- 26231267 TI - Hemispherectomy for Hemimegalencephaly Due to Tuberous Sclerosis and a Review of the Literature. AB - BACKGROUND: Hemimegalencephaly with tuberous sclerosis complex is an uncommon association, usually associated with intractable seizures that begin in the neonatal period or early infancy. Typically, the seizures are managed with medications until the patient is older when surgical treatment is considered safe. PATIENT DESCRIPTION: We describe a 7-week-old infant with tuberous sclerosis (TSC1 mutation) and hemimegalencephaly who underwent a functional hemispherectomy for status epilepticus. No clinical seizures have occurred since surgery nearly 5 years ago and subsequent weaning of antiepileptic drugs 3 years ago. This is one of the youngest patients with tuberous sclerosis complex treated with a hemispherectomy and one of seven patients described in the literature. CONCLUSIONS: Our patient, along with previously reported cases, suggests that a hemispherectomy is a viable option in the very young. With evolution of this surgical process since its inception nearly 6 decades ago, it may now be performed safely in early infancy, engendering the possibility of seizure freedom in most and thus optimizing neurodevelopmental outcome. PMID- 26231268 TI - Efficacy of an ethanol-based hand sanitizer for disinfection of stethoscopes. PMID- 26231269 TI - A hospital-level cost-effectiveness analysis model for toxigenic Clostridium difficile detection algorithms. AB - BACKGROUND: Despite thorough analyses of the analytical performance of Clostridium difficile tests and test algorithms, the financial impact at hospital level has not been well described. Such a model should take institution-specific variables into account, such as incidence, request behaviour and infection control policies. AIM: To calculate the total hospital costs of different test algorithms, accounting for days on which infected patients with toxigenic strains were not isolated and therefore posed an infectious risk for new/secondary nosocomial infections. METHODS: A mathematical algorithm was developed to gather the above parameters using data from seven Flemish hospital laboratories (Bilulu Microbiology Study Group) (number of tests, local prevalence and hospital hygiene measures). Measures of sensitivity and specificity for the evaluated tests were taken from the literature. List prices and costs of assays were provided by the manufacturer or the institutions. The calculated cost included reagent costs, personnel costs and the financial burden following due and undue isolations and antibiotic therapies. Five different test algorithms were compared. FINDINGS AND CONCLUSION: A dynamic calculation model was constructed to evaluate the cost:benefit ratio of each algorithm for a set of institution- and time-dependent inputted variables (prevalence, cost fluctuations and test performances), making it possible to choose the most advantageous algorithm for its setting. A two-step test algorithm with concomitant glutamate dehydrogenase and toxin testing, followed by a rapid molecular assay was found to be the most cost-effective algorithm. This enabled resolution of almost all cases on the day of arrival, minimizing the number of unnecessary or missing isolations. PMID- 26231270 TI - Overview of the International Classification of Vestibular Disorders. AB - Classifications and definitions are essential to facilitate communication; promote accurate diagnostic criteria; develop, test, and use effective therapies; and specify knowledge gaps. This article describes the development of the International Classification of Vestibular Disorders (ICVD) initiative. It describes its history, scope, and goals. The Barany Society has played a central role in organizing the ICVD by establishing internal development processes and outreach to other scientific societies. The ICVD is organized in four layers. The current focus is on disorders with a high epidemiologic importance, such as Meniere disease, benign paroxysmal positional vertigo, vestibular migraine, and behavioral aspects of vestibular disorders. PMID- 26231271 TI - Bedside Assessment of Acute Dizziness and Vertigo. AB - Dizziness is a common symptom in emergency departments, general practice, and outpatient clinics. Faced with an acutely dizzy patient, the frontline physician must determine whether or not the symptoms are vestibular in origin and, if they are, which vestibular disorder they best fit. A focused history provides useful clues to the likely cause of dizziness, yet it is the clinical examination that yields the final answer. This article summarizes history and examination techniques that are useful in the assessment of acutely dizzy patients and discusses oculomotor signs that accompany common vestibular disorders. PMID- 26231272 TI - Misdiagnosing Dizzy Patients: Common Pitfalls in Clinical Practice. AB - This article highlights 5 pitfalls in the diagnosis of common vestibular disorders: (1) overreliance on dizziness symptom type to drive diagnostic inquiry; (2) underuse and misuse of timing and triggers to categorize patients; (3) underuse, misuse, and misconceptions linked to hallmark eye examination findings; (4) overweighting age, vascular risk factors, and neuroexamination to screen for stroke; and (5) overuse and overreliance on head computed tomography to rule out neurologic causes. This article discusses the evidence base describing each pitfall's frequency and likely causes, and potential alternative strategies that might be used to improve diagnostic accuracy or mitigate harms. PMID- 26231274 TI - Benign Paroxysmal Positional Vertigo in the Acute Care Setting. AB - Benign paroxysmal positional vertigo (BPPV) is a common cause of vertigo characterized by brief episodes provoked by head movements. The first attack of BPPV usually occurs in bed or upon getting up. Because it often begins abruptly, it can be alarming and lead to emergency department evaluation. The episodes of spinning often last 10 to 20 seconds, but may occasionally last as long as 1 minute. There are several forms of BPPV. In nearly all cases, highly effective treatment can be offered to patients. This article reviews the current state of our understanding of this condition and its management. PMID- 26231275 TI - Early Diagnosis and Management of Acute Vertigo from Vestibular Migraine and Meniere's Disease. AB - Vestibular migraine is the most common cause of acute episodic vestibular symptoms after benign paroxysmal positional vertigo. In contrast, Meniere's disease is an uncommon disorder. For both conditions, early and accurate diagnosis (or its exclusion) enables the correct management of patients with acute episodic vestibular symptoms. Long-term management of migraine requires changes in lifestyle to avoid triggers of migraine and/or prophylactic drugs if attacks become too frequent. The long-term management of Meniere's disease also involves lifestyle changes (low salt diet), medications (betahistine, steroids), and ablative therapy applied to the diseased ear (eg, intratympanic gentamicin). PMID- 26231273 TI - TiTrATE: A Novel, Evidence-Based Approach to Diagnosing Acute Dizziness and Vertigo. AB - Diagnosing dizziness can be challenging, and the consequences of missing dangerous causes, such as stroke, can be substantial. Most physicians use a diagnostic paradigm developed more than 40 years ago that focuses on the type of dizziness, but this approach is flawed. This article proposes a new paradigm based on symptom timing, triggers, and targeted bedside eye examinations (TiTrATE). Patients fall into 1 of 4 major syndrome categories, each with its own differential diagnosis and set of targeted examination techniques that help make a specific diagnosis. Following an evidence-based approach could help reduce the frequency of misdiagnosis of serious causes of dizziness. In the spirit of the flipped classroom, the editors of this Neurologic Clinics issue on emergency neuro-otology have assembled a collection of unknown cases to be accessed electronically in multimedia format. By design, cases are not linked with specific articles, to avoid untoward cueing effects for the learner. The cases are real and are meant to demonstrate and reinforce lessons provided in this and subsequent articles. In addition to pertinent elements of medical history, cases include videos of key examination findings. PMID- 26231276 TI - Transient Ischemic Attacks Presenting with Dizziness or Vertigo. AB - Dizziness with or without associated neurologic symptoms is the most common symptom of posterior circulation transient ischemic attack (TIA) and can be more frequent before posterior circulation strokes. This entity carries a high risk of recurrent events and should be considered as a potential cause of spontaneous episodic vestibular syndrome. Diagnostic evaluation should include intracranial and extracranial imaging of the vertebral arteries and basilar artery. Aggressive medical management with antiplatelet therapy, statin use, and risk factor modification is the mainstay of treatment. This article highlights the importance of diagnosing, evaluating, and treating posterior circulation TIAs manifesting as dizziness or vertigo. PMID- 26231277 TI - Medical and Psychiatric Causes of Episodic Vestibular Symptoms. AB - Dizziness and vertigo are among the most common presenting patient complaints in ambulatory settings. Specific vestibular causes are often not immediately identifiable. The first task of the clinician is to attempt to rule in specific vestibular disorders, such as benign paroxysmal positional vertigo through physical examination, diagnostic testing, and history taking. A large proportion of patients with dizziness and vertigo will not be easily classified or confirmed as having a specific vestibular cause. As with any undifferentiated patient, the focus in this setting is to attempt to exclude serious or threatening causes. PMID- 26231278 TI - Early Diagnosis and Treatment of Traumatic Vestibulopathy and Postconcussive Dizziness. AB - Mild traumatic brain injury (mTBI) is a common health condition in amateur and professional sports and in military operations but can occur in everyday life. Dizziness is the most common disorder seen after mTBI followed closely by headache. This article examines the diagnosis and treatment of vestibular disorders after mTBI. Data are included from the literature, and conclusions are drawn from the literature review and the experience of the authors. Much of what is known about this disorder comes from recent military experience, but the link to more common civilian injuries is detailed in this article. PMID- 26231279 TI - Acute Unilateral Vestibulopathy. AB - Normal vestibular end organs generate an equal resting-firing frequency of the axons, which is the same on both sides under static conditions. An acute unilateral vestibulopathy leads to a vestibular tone imbalance. Acute unilateral vestibulopathy is defined by the patient history and the clinical examination and, in unclear cases, laboratory examinations. Key signs and symptoms are an acute onset of spinning vertigo, postural imbalance and nausea as well as a horizontal rotatory nystagmus beating towards the non-affected side, a pathological head-impulse test and no evidence for central vestibular or ocular motor dysfunction. The so-called big five allow a differentiation between a peripheral and central lesion by the bedside examination. The differential diagnosis of peripheral labyrinthine and vestibular nerve disorders mimicking acute unilateral vestibulopathy includes central vestibular disorders, in particular "vestibular pseudoneuritis" and other peripheral vestibular disorders, such as beginning Meniere's disease. The management of acute unilateral vestibulopathy involves (1) symptomatic treatment with antivertiginous drugs, (2) causal treatment with corticosteroids, and (3) physical therapy. PMID- 26231280 TI - Acute Diagnosis and Management of Stroke Presenting Dizziness or Vertigo. AB - Stroke involving the brainstem and cerebellum frequently presents acute vestibular syndrome. Although vascular vertigo is known to usually accompany other neurologic symptoms and signs, isolated vertigo from small infarcts involving the cerebellum or brainstem has been increasingly recognized. Bedside neuro-otologic examination can reliably differentiate acute vestibular syndrome due to stroke from more benign inner ear disease. Sometimes acute isolated audiovestibular loss may herald impending infarction in the territory of the anterior inferior cerebellar artery. Accurate identification of isolated vascular vertigo is very important because misdiagnosis of acute stroke may result in significant morbidity and mortality. PMID- 26231281 TI - Medical and Nonstroke Neurologic Causes of Acute, Continuous Vestibular Symptoms. AB - Most patients with the acute vestibular syndrome (AVS) have vestibular neuritis or stroke or, in the setting of trauma, a posttraumatic vestibular cause. Some medical and nonstroke causes of the AVS must also be considered. Multiple sclerosis is the most common diagnosis in this group. Other less common causes include cerebellar masses, inflammation and infection, mal de debarquement, various toxins, Wernicke disease, celiac-related dizziness, and bilateral vestibulopathy. Finally, there may be unmasking of prior posterior circulation events by various physiologic alterations such as alterations of temperature, blood pressure, electrolytes, or various medications, especially sedating agents. PMID- 26231282 TI - Why Acute Dizziness and Vertigo? Articulating the Emergency Neuro-Otology Imperative. PMID- 26231283 TI - Updates to the Integrated Protein-Protein Interaction Benchmarks: Docking Benchmark Version 5 and Affinity Benchmark Version 2. AB - We present an updated and integrated version of our widely used protein-protein docking and binding affinity benchmarks. The benchmarks consist of non-redundant, high-quality structures of protein-protein complexes along with the unbound structures of their components. Fifty-five new complexes were added to the docking benchmark, 35 of which have experimentally measured binding affinities. These updated docking and affinity benchmarks now contain 230 and 179 entries, respectively. In particular, the number of antibody-antigen complexes has increased significantly, by 67% and 74% in the docking and affinity benchmarks, respectively. We tested previously developed docking and affinity prediction algorithms on the new cases. Considering only the top 10 docking predictions per benchmark case, a prediction accuracy of 38% is achieved on all 55 cases and up to 50% for the 32 rigid-body cases only. Predicted affinity scores are found to correlate with experimental binding energies up to r=0.52 overall and r=0.72 for the rigid complexes. PMID- 26231284 TI - IL-33 and IL-4 impair barrier functions of human vascular endothelium via different mechanisms. AB - The vascular endothelium forms a barrier that controls flow of solutes and proteins and the entry of leukocytes into tissue. Injured tissue releases IL-33, which then alarms the immune system and attracts Th2 cells, thus increasing local concentration of IL-4. The aim of the study was to assess the influence of IL-33 and IL-4 on barrier functions of the human endothelium, expression of tight and adherent junction proteins, apoptosis and adhesive molecule surface expression in human endothelium in order to describe the mechanism of this effect. IL-33 and IL 4 decreased endothelial integrity and increased permeability. When added together, both cytokines lowered the endothelial integrity twice as much as used alone. This effect was accompanied by the down-regulation of occludin and VE cadherin mRNA expression. Additionally, IL-4, but not IL-33, induced cell apoptosis. Both IL-33 and IL-4 showed the additive potency to down-regulate VE cadherin mRNA expression. IL-33, unlike IL-4, increased the surface expression of ICAM-1, but not PECAM-1 in endothelial cells. Our results indicate that IL-33 may reversibly destabilize the endothelial barrier, thus accelerating the supply with immunomodulators and assisting leukocytes to reach wounded tissue. However, extended and less-controlled down-regulation of endothelial barrier, which may be a consequence of IL-33-initiated, but in fact IL-4-induced apoptosis of endothelial cells, may be deleterious and may eventually lead to the aggravation of inflammatory processes and the prolongation of tissue dysfunction. PMID- 26231285 TI - Zonal NephRo Score: external validation for predicting complications after open partial nephrectomy. AB - PURPOSE: The aim of the study was to externally validate the Zonal NePhRO Score (ZNS) published in 2014 as latest and superior nephrometry score in terms of prediction of perioperative complications and outcome of open partial nephrectomies (OPNs). METHODS: We identified 200 consecutive patients who underwent OPN. Analysis of preoperative CT or MRI scans and retrospective analysis of the patients' clinical records were performed. Tumour complexity was stratified according to the ZNS into three categories: low (4-6), moderate (7-9) and high (10-12) complexity. Predictors for perioperative complications and surgical parameters were identified using univariate and multivariate logistic regression. RESULTS: Tumour complexity was graded in 19.8 % of the cases as low, in 50.3 % as moderate and in 29.9 % as high. In the multivariate analysis, ZNS was significantly associated with a higher complication rate (OR 1.25, 95 % CI 1.04-1.49, p = 0.014), longer ischaemia time (IT) (beta = 1.19, 95 % CI 0.33 2.05, p = 0.007), postoperative drop of estimated glomerular filtration rate (eGFR) (beta = -1.86, 95 % CI -3.71 to -0.01, p = 0.049) and opening of the collecting system (CS) (OR 1.72, 95 % CI 1.40-2.10, p < 0.001). In addition, age and body mass index were identified as independent predictors for complications (OR 1.03, 95 % CI 1.00-1.06, p = 0.043 and OR 1.08, 95 % CI 1.00-1.15, p = 0.031). CONCLUSION: The present study is the first external validation of the ZNS as a predictor of perioperative complications in patients undergoing OPN. A higher ZNS score was associated with a longer IT, a higher rate of opening the CS and drop of eGFR. PMID- 26231286 TI - Long-term efficacy of the trans-obturator and retropubic mid-urethral slings for stress urinary incontinence: update from a randomized clinical trial. AB - PURPOSE: To report the extended long-term results of the use of tension-free vaginal tape(TVT) and trans-obturator tape (TOT) for the treatment of female stress urinary incontinence (SUI). METHODS: A prospective, multicentre randomized clinical trial comparing the use of TVT and TOT was used to evaluate 87 patients. The inclusion criteria were stress or mixed UI associated with urethral hyper mobility (the stress component was clinically predominant), while the exclusion criteria were previous anti-incontinence surgery and/or pelvic organ prolapse. The objective cure criteria were a negative provocative stress test and a negative 1-h pad test, with no further treatment for SUI. The subjective cure criteria were a 3-day voiding diary, quality-of-life questionnaires (UDI6-IIQ7), and patient satisfaction on a scale from 0 to 10. RESULTS: Eighty-seven patients were evaluated (47 TOT and 40 TVT) at a median follow-up of 100 months. Subjective and objective cure rates were 59.6 and 70.2 % in the TOT group and 75 and 87.5 % in the TVT group. The mid-to-long-term trend was a decreasing continence rate in patients who underwent TOT, compared with a stable rate for TVT. The Kaplan-Meier survival curve showed that continence rate decreased for up to 25 months after surgery, with stabilization thereafter for the TVT group while continuing to drop in the TOT group, with no inter-group difference. CONCLUSION: The patients in both groups were highly satisfied at long-term follow-up. The overall continence rate worsened for both groups within 25 months. While the results tend to stabilize in the TVT group, a further decline in the TOT was observed. PMID- 26231287 TI - Evaluating results of outcome studies of biological drugs. PMID- 26231288 TI - Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. AB - BACKGROUND: Interleukin 13 is a central mediator of asthma. Tralokinumab is a human interleukin-13 neutralising monoclonal antibody. We aimed to assess the efficacy and safety of two dosing regimens of tralokinumab in patients with severe uncontrolled asthma. METHODS: We did a randomised, double-blind, placebo controlled, parallel-group, multicentre, phase 2b study at 98 sites in North America, South America, Europe, and Asia. Patients aged 18-75 years with severe asthma and two to six exacerbations in the previous year were randomly assigned (1:1), via an interactive voice-response or web-response system, to one of two dosing regimen groups (every 2 weeks, or every 2 weeks for 12 weeks then every 4 weeks) and further randomised (2:1), via computer-generated permuted-block randomisation (block size of six), to receive tralokinumab 300 mg or placebo for 1 year. All participants received high-dose fluticasone and salmeterol and continued other pre-study controller drugs. Treatment was administered by an unmasked study investigator not involved in the management of patients; all other study site personnel, patients, the study funder, and data analysts were masked to treatment allocation. The primary endpoint was the annual asthma exacerbation rate at week 52 in the intention-to-treat population. Key secondary endpoints included prebronchodilator forced expiratory volume in 1 s (FEV1), Asthma Control Questionnaire-6 (ACQ-6), and Asthma Quality of Life Questionnaire-Standardised Version (AQLQ[S]). This trial is registered with ClinicalTrials.gov, number NCT01402986. FINDINGS: Between Oct 4, 2011, and Feb 22, 2014, we randomly assigned 452 patients to receive placebo (n=151) or tralokinumab every 2 weeks (n=150) or every 4 weeks (n=151), of whom 383 (85%) completed the treatment period up to week 52. The annual asthma exacerbation rate at week 52 was similar between patients receiving tralokinumab every 2 weeks (0.91 per patient per year [95% CI 0.76-1.08]) and every 4 weeks (0.97 [0.81-1.14]), and those receiving placebo (0.90 [0.75-1.08]). At week 52, percentage changes in annual asthma exacerbation rate were not significant with tralokinumab every 2 weeks or every 4 weeks versus placebo (6% [95% CI -31 to 33; p=0.709] and -2% [-46 to 29; p=0.904], respectively), with positive changes showing a decrease in exacerbation rate and negative changes showing an increase. Prebronchodilator FEV1 was significantly increased compared with placebo for tralokinumab every 2 weeks (change from baseline 7.3% [95% CI 2.6-12.0]; p=0.003), but not every 4 weeks (1.8% [-2.9 to 6.6]; p=0.448); however, we did not identify significant changes in the other key secondary endpoints. In a post-hoc subgroup analysis of patients not on long-term oral corticosteroids and with baseline FEV1 reversibility of 12% or greater, we noted a non-significant improvement in asthma exacerbation rate (44% [95% CI -22 to 74]; p=0.147) and significant improvements in key secondary endpoints (FEV1 12.2% [1.7-22.7]; p=0.022; ACQ-6 -0.55 [-1.07 to -0.04]; p=0.036; and AQLQ[S] 0.70 [0.12-1.28]; p=0.019) in patients given tralokinumab every 2 weeks (n=33) compared with placebo (n=48). In patients in this subgroup who also had baseline serum dipeptidyl peptidase-4 (DPP-4) higher than the population baseline median, we noted additional improvements in prebronchodilator FEV1, ACQ 6, and AQLQ(S), and, in those with periostin concentrations higher than the median, we noted improvements in asthma exacerbation rate, prebronchodilator FEV1, and ACQ-6. The incidence of treatment-emergent adverse events was similar between the tralokinumab and placebo groups. Treatment-emergent serious adverse events regarded as related to the study drug were pneumonia (one [1%] patient in the placebo group), pneumococcal pneumonia (one [1%] in the tralokinumab every 2 weeks group), angioedema (one [1%] in the placebo group), and worsening asthma (one [1%] in the tralokinumab every 2 weeks group and two [1%] in the tralokinumab every 4 weeks group). INTERPRETATION: In this phase 2b study, both tralokinumab regimens had an acceptable safety and tolerability profile but did not significantly reduce asthma exacerbation rates in patients with severe uncontrolled asthma. Improvement in FEV1 with tralokinumab given every 2 weeks and results of post-hoc subgroup analyses suggested a possible treatment effect in a defined population of patients with severe uncontrolled asthma. This effect is being further investigated in ongoing phase 3 trials, along with the potential utility of DPP-4 and periostin as biomarkers of interleukin-13 pathway activation. FUNDING: MedImmune. PMID- 26231289 TI - Quality Improvement Targeting Adherence During the Transition from a Pediatric to Adult Liver Transplant Clinic. AB - The transition from pediatric to adult transplant care is a high risk period for non-adherence and poor health outcomes. This article describes a quality improvement initiative integrated into a pediatric liver transplant program that focused on improving outcomes following the transfer from pediatric to adult liver transplant care. Using improvement science methodology, we evaluated the impact of our center's transition readiness skills (TRS) program by conducting a chart review of 45 pediatric liver transplant recipients who transferred to adult transplant care. Medication adherence, clinic attendance, and health status variables were examined for the year pre-transfer and first year post-transfer. 19 recipients transferred without participating in the TRS program (control group) and 26 recipients participated in the program prior to transferring to the adult clinic (TRS group). The TRS group was significantly older at the time of transfer, more adherent with medications, and more likely to attend their first adult clinic visit compared to the control group. Among the TRS group, better adolescent and parent regimen knowledge were associated with greater adherence to post-transfer clinic appointments. Transition planning should focus on the gradual shift in responsibility for health management tasks, including clinic attendance, from parent to adolescent. There may be support for extending transition support for at least 1 year post-transfer to promote adherence. PMID- 26231290 TI - The view of severely burned patients and healthcare professionals on the blind spots in the aftercare process: a qualitative study. AB - BACKGROUND: In most Western countries burn centres have been developed to provide acute and critical care for patients with severe burn injuries. Nowadays, those patients have a realistic chance of survival. However severe burn injuries do have a devastating effect on all aspects of a person's life. Therefore a well organized and specialized aftercare system is needed to enable burn patients to live with a major bodily change. The aim of this study is to identify the problems and unmet care needs of patients with severe burn injuries throughout the aftercare process, both from patient and health care professional perspectives in Belgium. METHODS: By means of face-to-face interviews (n = 40) with individual patients, responsible physicians and patient organizations, current experiences with the aftercare process were explored. Additionally, allied healthcare professionals (n = 17) were interviewed in focus groups. RESULTS: Belgian burn patients indicate they would benefit from a more integrated aftercare process. Quality of care is often not structurally embedded, but depends on the good intentions of local health professionals. Most burn centres do not have a written discharge protocol including an individual patient-centred care plan, accessible to all caregivers involved. Patients reported discontinuity of care: nurses working at general wards or rehabilitation units are not specifically trained for burn injuries, which sometimes leads to mistakes or contradictory information transmission. Also professionals providing home care are often not trained for the care of burn injuries. Some have to be instructed by the patient, others go to the burn centre to learn the right skills. Finally, patients themselves underestimate the chronic character of burn injuries, especially at the beginning of the care process. CONCLUSIONS: The variability in aftercare processes and structures, as well as the failure to implement locally developed best-practices on a wider scale emphasize the need for a comprehensive network, which can initiate transversal activities such as the development of discharge protocols, common guidelines, and quality criteria. PMID- 26231291 TI - [Intercultural competence. Management of foreignness in intensive care medicine]. AB - BACKGROUND: Living in a multicultural society is characterized by different attitudes caused by a variety of religions and cultures. In intensive care medicine such a variety of cultural aspects with respect to pain, shame, bodiliness, dying and death is of importance in this scenario. AIM: To assess the importance of cultural and religious attitudes in the face of foreignness in intensive care medicine and nursing. Notification of misunderstandings and misinterpretations in communication and actions. MATERIAL AND METHODS: An analysis of the scientific literature was carried out and typical intercultural conflict burden situations regarding the management of brain death, organ donation and end of life decisions are depicted. RESULTS: Specific attitudes are found in various religions or cultures regarding the change of a therapeutic target, the value of the patient's living will and the organization of rituals for dying. Intercultural conflicts are mostly due to misunderstandings, assessment differences, discrimination and differences in values. CONCLUSION: Intercultural competence is crucial in intensive care medicine and includes knowledge of social and cultural influences of different attitudes on health and illness, the abstraction from own attitudes and the acceptance of other or foreign attitudes. PMID- 26231293 TI - Serious Pulmonary Toxicity Secondary to Novel Hepatitis C Antiviral Therapy in a Liver Transplant Recipient. AB - Historically, the treatment of hepatitis C virus infection has been difficult, but therapeutic options have improved markedly recently because of the development of novel antiviral therapies. These therapies have been well tolerated. We describe a patient who was receiving such therapy and had development of temporally related and histologically confirmed severe pulmonary toxicity. Pulmonary toxicity should be considered a potential serious complication of novel antiviral therapy for hepatitis C virus infection. PMID- 26231292 TI - Effect of Tumor Size on Cancer-Specific Survival in Small Hepatocellular Carcinoma. AB - OBJECTIVE: To further clarify the prognosis of small hepatocellular carcinoma (HCC) in different subgroups and to assess the connection between the tumor cutoff point and its impact on prognostic significance. PATIENTS AND METHODS: In this study, Surveillance, Epidemiology, and End Results Program-registered patients with small HCC and patients from the Liver Transplantation Center of Nanjing Medical University (LTCNJMU) were combined and analyzed. The optimal cutoff point of the tumor size was determined by using the "X-tile" program. The 60-month, cancer-specific survival data were obtained. Kaplan-Meier methods and multivariable Cox regression models were used to analyze long-term hepatocellular carcinoma-specific survival (HCSS) outcomes and risk factors. RESULTS: There were significant differences among these different tumor size subgroups with regard to 60-month HCSS rates (P<.001). The X-tile program indicated that the difference in survival was most significant (maximum of chi(2) log-rank values) (P<.001) for the tumor size 35 mm. A stratified analysis of the effect of tumor size on 60 month HCSS rate found that only localized and regional stages could be validated as independent predictors, but not advanced stages. CONCLUSION: These results confirmed that patients with small HCC are essentially a heterogeneous group. Tumor size is still an independent prognostic factor for resected small HCC, and patients with tumors of 0- to 35-mm diameter have a better 60-month HCSS rate than do those with larger tumors (36-50 mm). PMID- 26231294 TI - How to eliminate the formation of chlorogenic acids artefacts during plants analysis? Sea sand disruption method (SSDM) in the HPLC analysis of chlorogenic acids and their native derivatives in plants. AB - The analytical procedures for determining plant constituents involve the application of sample preparation methods to fully isolate and/or pre-concentrate the analyzed substances. High-temperature liquid extraction is still applied most frequently for this purpose. The present paper shows that high-temperature extraction cannot be applied for the analysis of chlorogenic acids (CQAs) and their derivatives in plants as it causes the CQAs transformation leading to erroneous quantitative estimations of these compounds. Experiments performed on different plants (black elder, hawthorn, nettle, yerba mate, St John's wort and green coffee) demonstrate that the most appropriate method for the estimation of CQAs/CQAs derivatives is sea sand disruption method (SSDM) because it does not induce any transformation and/or degradation processes in the analyzed substances. Owing to the SSDM method application we found that the investigated plants, besides four main CQAs, contain sixteen CQAs derivatives, among them three quinic acids. The application of SSDM in plant analysis not only allows to establish a true concentration of individual CQAs in the examined plants but also to determine which chlorogenic acids derivatives are native plant components and what is their concentration level. What is even more important, the application of SSDM in plant analysis allows to eliminate errors that may arise or might have arisen in the study of chlorogenic acids and their derivatives in plant metabolism. PMID- 26231295 TI - Upregulation of miRNA-17 and miRNA-19 is associated with unfavorable prognosis in patients with T-cell lymphoblastic lymphoma. AB - Lymphoblastic lymphoma is an aggressive subtype of non-Hodgkin lymphoma. Identification of prognostic factors for these patients, especially for patients with T-cell lymphoblastic lymphoma (T-LBL), remains a challenge. This is largely due to the relative rarity of the disease and lack of adequate samples for biological research. T-LBL is more common in Asia than in Western countries. In an attempt to explore novel prognostic markers for T-LBL, we conducted retrospective study of archived diagnostic specimens from 57 Chinese patients with well-defined diagnosis of T-LBL. Using quantitative real-time reverse transcription-PCR, we analyzed miR-17 and miR-19 expression levels in formalin fixed and paraffin-embedded lymph node specimens from these patients, together with reactive lymph node controls. We correlated molecular findings to patients' immunophenotype and clinical follow-up information. MYC protein expression was also evaluated in these patients. We found that miR-17 and miR-19 levels were concordant and upregulated in T-LBL in comparison with controls. Statistical analysis showed that higher expression of miR-17 and miR-19, and positive MYC protein results were associated with a shorter overall survival of T-LBL. In addition, miR-17 and miR-19 appeared to be independent prognostic factors for T LBL. We demonstrate here that upregulation of miR-17 and miR-19 correlates with poor clinical outcome of T-LBL, indicating that miR-17 and miR-19 may be considered as potential unfavorable prognostic markers for T-LBL. PMID- 26231296 TI - Immunopathologic effects of scorpion venom on hepato-renal tissues: Involvement of lipid derived inflammatory mediators. AB - Scorpion venoms are known to cause different inflammatory disorders through complex mechanisms in various tissues. In the study here, the involvement of phospholipase A2 (PLA2) and cyclo-oxygenase (COX)-derived metabolites in hepatic and renal inflammation responses were examined. Mice were envenomed with Androctonus australis hector scorpion venom in the absence or presence of inhibitors that can interfere with lipid inflammatory mediator synthesis, i.e., dexamethasone (PLA2 inhibitor), indomethacin (non-selective COX-1/COX-2 inhibitor), or celecoxib (selective COX-2 inhibitor). The inflammatory response was assessed by evaluating vascular permeability changes, inflammatory cell infiltration, oxidative/nitrosative stress marker levels, and by histologic and functional analyses of the liver and kidney. Results revealed that the venom alone induced an inflammatory response in this tissues marked by increased microvascular permeability and inflammatory cell infiltration, increases in levels of nitric oxide and lipid peroxidation, and decreases in antioxidant defense. Moreover, significant alterations in the histological architecture of these organs were associated with increased serum levels of some metabolic enzymes, as well as urea and uric acid. Pre-treatment of mice with dexamethasone led to significant decreases of the inflammatory disorders in the hepatic parenchyma; celecoxib pre-treatment seemed to be more effective against renal inflammation. Indomethacin pre-treatment only slightly reduced the inflammatory disorders in the tissues. These results suggest that the induced inflammation response in liver was mediated mainly by PLA2 activation, while the renal inflammatory process was mediated by prostaglandin formation by COX-2. These findings provide additional insight toward the understanding of activated pathways and related mechanisms involved in scorpion envenoming syndrome. PMID- 26231297 TI - Homozygosity for the common GAA gene splice site mutation c.-32-13T>G in Pompe disease is associated with the classical adult phenotypical spectrum. AB - Homozygosity for the common Caucasian splice site mutation c.-32-13T>G in intron 1 of the GAA gene is rather rare in Pompe patients. We report on the clinical, biochemical, morphological, muscle imaging, and genetic findings of six adult Pompe patients from five unrelated families with the c.-32-13T>G GAA gene mutation in homozygous state. All patients had decreased GAA activity and elevated creatine kinase levels. Five patients, aged between 43 and 61 years (median 53 years), initially presented with myalgia, hyperCKaemia, and/or exercise induced fatigue at an age of onset (12-55 years). All but one had proximal lower limb weakness combined with axial weakness and moderate respiratory insufficiency; the sixth patient presented with hyperCKaemia only. Muscle biopsies showed PAS-positive vacuolar myopathy with lysosomal changes and reduced GAA activity. Muscle MRI of lower limb muscles revealed a moderate adipose substitution of the gluteal muscles, biceps femoris and slight fatty infiltration of all thigh muscles. One MRI of the respiratory muscles revealed a diaphragmatic atrophy with unilateral diaphragm elevation. So, the common Caucasian, so called mild, splice site mutation c.-32-13T>G in intron 1 of the GAA gene in a homozygote status reflects the full adult Pompe disease phenotype severity spectrum. PMID- 26231298 TI - GNE myopathy in Roma patients homozygous for the p.I618T founder mutation. AB - GNE myopathy is an autosomal-recessive disorder caused by mutations in the GNE gene, encoding the key enzyme in the sialic acid biosynthetic pathway, UDP-N acetylglucosamine 2-epimerase/N-acetyl mannosamine kinase. We studied 50 Bulgarian Roma patients homozygous for p.I618T, an ancient founder mutation in the kinase domain of the GNE gene, dating before the Gypsy exodus from North West India. The clinical features in the Bulgarian GNE group can be described with disease onset mostly in the third decade, but in individual cases, onset was as early as 10 years of age. The majority of patients had foot drop as the first symptom, but three patients developed hand weakness first. Muscle weakness was early and severe for the tibialis anterior, and minimal or late for quadriceps femoris, and respiratory muscles were only subclinically affected even in the advanced stages of the disease. During a 15-year follow-up period, 32 patients became non-ambulant. The average period between disease onset and loss of ambulation was 10.34 +/- 4.31 years, ranging from 3 to 20 years. Our analysis of affected sib pairs suggested a possible role of genetic modifying factors, accounting for significant variation in disease severity. PMID- 26231299 TI - Fast and efficient detection of tuberculosis antigens using liposome encapsulated secretory proteins of Mycobacterium tuberculosis. AB - PURPOSE: A rapid and efficient diagnostic test was developed for the detection of Mycobacterium tuberculosis antigens in serum samples of active tuberculosis (TB) and extrapulmonary TB patients via a liposomal agglutination-based method. METHODS: A rapid card test has been developed to facilitate the recognition of high-affinity binding rabbit raised purified culture filtrate protein antibodies coupled on the surface of activated liposomal preparation. In the presence of TB antigens, the polyclonal antibodies bound to the liposomal particles demonstrate a visible agglutination reaction. RESULTS: The developed assay was simple, rapid, reliable, sensitive, and specific as a diagnostic test for the detection of antigens in serum samples of clinically confirmed cases of TB within 4-5 minutes' duration. The test was evaluated at different hospitals, medical colleges, and pathology centers, and involved 1483 participants. This investigation was conducted to detect the presence of these antigens during the period of active growth of the microorganism in serum samples for pulmonary TB and processed tissue biopsy for other extrapulmonary TB. Results obtained using this test were compared with acid-fast bacilli smear and culture results. CONCLUSION: Our study demonstrated that the newly developed liposome tuberculosis antigen card test detected antigens in our study population with approximately 97.48% sensitivity and 95.79% specificity. This is the first study to report the liposomal encapsulation of culture filtrate proteins from M. tuberculosis for diagnostic application. PMID- 26231300 TI - Two-year clinical trial of a universal adhesive in total-etch and self-etch mode in non-carious cervical lesions. AB - OBJECTIVES: To compare the clinical performance of ScotchbondTM Universal Adhesive used in self- and total-etch modes and two-bottle ScotchbondTM Multi purpose Adhesive in total-etch mode for Class 5 non-carious cervical lesions (NCCLs). METHODS: 37 adults were recruited with 3 or 6 NCCLs (>1.5mm deep). Teeth were isolated, and a short cervical bevel was prepared. Teeth were restored randomly with Scotchbond Universal total-etch, Scotchbond Universal self-etch or Scotchbond Multi-purpose followed with a composite resin. Restorations were evaluated at baseline, 6, 12 and 24 months for marginal adaptation, marginal discoloration, secondary caries, and sensitivity to cold using modified USPHS Criteria. Patients and evaluators were blinded. Logistic and linear regression models using a generalized estimating equation were applied to evaluate the effects of time and adhesive material on clinical assessment outcomes over the 24 month follow-up period. Kaplan-Meier method was used to compare the retention between adhesive materials. RESULTS: Clinical performance of all adhesive materials deteriorated over time for marginal adaptation, and discoloration (p<0.0001). Both Scotchbond Universal self-etch and Scotchbond Multi-purpose materials were more than three times as likely to contribute to less satisfying performance in marginal discoloration over time than Scotchbond Universal total etch. The retention rates up to 24 months were 87.6%, 94.9% and 100% for Scotchbond Multi-purpose and Scotchbond Universal self-etch and total-etch, respectively. CONCLUSIONS: Scotchbond Universal in self- and total- etch modes performed similar to or better than Scotchbond Multipurpose, respectively. CLINICAL SIGNIFICANCE: 24 month evaluation of a universal adhesive indicates acceptable clinical performance, particularly in a total-etch mode. PMID- 26231301 TI - Randomized controlled clinical trial of the 24-months survival of composite resin restorations after one-step incomplete and complete excavation on primary teeth. AB - OBJECTIVE: This randomized clinical trial aimed to compare the 24-months survival of composite restorations in primary molars after partial caries removal (PCR) and total caries removal (TCR). METHODS: Forty-eight children aged 3-8 years with at least one molar with a deep carious lesion were included (PCR; n=66; TCR; n=54). For PCR, excavation was stopped when dentine with a leathery consistency was achieved; in the TCR group, total absence of carious tissue was confirmed using a blunt-tipped probe. Pulpotomy was performed in cases of pulp exposure. Success was assessed by modified USPHS criteria with Alpha and Bravo scores recorded as success. RESULTS: Pulp exposure occurred in 1 and 15 of the teeth treated with PCR and TCR respectively (p<0.01). The restorations survival rate after 24 months was 66% (PCR) and 86% (TCR) (p=0.03). When teeth that received pulpotomy were analyzed separately, the survival rate was 92% (p=0.09). PCR performed in occlusoproximal restorations demonstrated the lowest success rate (p=0.002). PCR increases 2.90 times the probability of having a restorative failure compared to TCR (p=0.03), after adjusting for cavity type. When pulp exposure and restoration failure were considered as the outcome, there was no significant difference between the two groups (p=0.10) with success rates of 64% (PCR) and 61% (TCR). CONCLUSION: Collectively, deciduous teeth submitted to PCR prevented pulp exposure and, consequently, more invasive treatments; otherwise, PCR yielded lower longevity for composite restoration compared to TCR, suggesting that PCR restorations need to be followed over time, especially when multi surface restorations are involved. CLINICAL SIGNIFICANCE: Composite restorations on carious remaining tissue require monitoring over time, especially those performed in more than one surface. Even if the restorations present shortcomings over the time, the majority of them are subject to repair, allowing more conservative approaches for teeth with deep caries lesions. PMID- 26231302 TI - Seal, replacement or monitoring amalgam restorations with occlusal marginal defects? Results of a 10-year clinical trial. AB - The aim of this prospective and blind clinical trial was to assess the effectiveness of sealing localized marginal defects of amalgam restoration that were initially scheduled to be replaced. A cohort of twenty six patients with 60 amalgam restorations (n=44Class I and n=16Class II), that presented marginal defects deviating from ideal (Bravo) according to USPHS criteria, were assigned to either sealing or replacement groups: A: sealing n=20, Replacement n=20, and no treatment (n=20). Two blind examiners evaluated the restorations at baseline (K=0.74) and after ten years (K=0.84) according with USPHS criteria, in four parameters: marginal adaptation (MA), secondary caries (SC), marginal staining (MS) and teeth sensitivity (TS). Multiple comparison of restorations degradation/upgrade was analyzed by Friedman test and the comparisons within groups were performed by Wilcoxon test. After 10 years, 44 restorations were assessed (73.3%), Group A: n=14 and Group B: n=16; and Group C: n=14 sealing and replacement amalgam restorations presented similar level of quality in MA (p=0.76), SC (p=0.25) and TS (p=0.52), while in MS (p=0.007) presented better performance in replacement group after 10-years. Most of the occlusal amalgam restorations with marginal gaps showed similar long term outcomes than the restorations were sealed, replaced, or not treated over a 10-year period. Most of the restorations of the three groups were clinically acceptable, under the studied parameters. All restorations had the tendency to present downgrade/deterioration over time. PMID- 26231303 TI - Chiropractic Attitudes and Utilization of Evidence-Based Practice: The Use of the EBASE Questionnaire. AB - AIM: To examine the attitudes and utilization of evidence-based practice by chiropractors. METHODS: Utilizing a descriptive survey implemented as an online questionnaire, we examined chiropractors' perception, skills, and level of training, their engagement in, the barriers and facilitators to, and possible interventions to evidence-based practice. RESULTS: A total of 162 of 500 chiropractors completed the survey, providing a response rate of 32.4%. The majority of respondents were 30-39 years old, female, and worked in solo practice. A high proportion agreed/strongly agreed that evidence-based practice was necessary in the practice of chiropractic. Most respondents considered themselves to have above-average skills in locating professional literature, identifying answerable clinical questions, and identifying knowledge gaps in practice. However, many indicated receiving either no training or minimal education for conducting clinical research and systematic reviews and meta analyses Most respondents had read or reviewed one to five professional articles and/or clinical research reports pertinent to their practice in the preceding month. Identified minor to moderate barriers to evidence-based practice were lack of time and lack of clinical evidence. Activities "very useful" in participating in evidence-based practice were access to free online databases and the ability to download full-text journal articles. CONCLUSIONS: The responders of our survey embraced and considered themselves skillful in evidence-based practice. They utilized a number of resources to practice in such a manner and were not deterred by identified barriers. We support continued research in this field. PMID- 26231304 TI - Cochlear afferent innervation development. AB - Sound signal is detected by sensory hair cells located in the cochlear region of the inner ear, and transmitted to the central nervous system by the spiral ganglion neurons (SGNs). These bipolar neurons develop long peripheral processes to connect hair cells, forming ribbon synapses, specialised for the precision and speed required to process auditory information. The establishment of a complex innervation pattern relies on specific signals, intrinsic to SGNs or provided by neighbouring cells, which are tightly controlled in time and space. In this paper, we review recent advances about stepwise development of afferent auditory neuronal circuitries, from neuron specification within the early otic vesicle to definitive synaptic connections with target cells. We especially focus on the cellular and molecular developmental changes involved in fibre outgrowth and extension to the sensory epithelium, specific afferent targeting to hair cells, and synaptic pruning. PMID- 26231305 TI - Baseline Predictors of 12-Month Treatment Response to Ranibizumab in Patients With Wet Age-Related Macular Degeneration. AB - PURPOSE: To identify baseline characteristics predictive of visual acuity (VA) outcomes at month 12 (M12) and treatment frequency in the first 12 months of the phase III HARBOR study. DESIGN: Retrospective, exploratory analysis of multicenter randomized controlled trial data. METHODS: setting: Randomized, multicenter. STUDY POPULATION: Patients aged >=50 years with subfoveal wet age related macular degeneration (AMD) who had best-corrected VA (BCVA) values measured at baseline and M12. INTERVENTION: Intravitreal ranibizumab 0.5 mg administered monthly (n = 249) or as needed (PRN) after 3 monthly loading doses (n = 251). MAIN OUTCOME MEASURES: BCVA change from baseline at M12, percentage of patients who gained >=15 letters (3 lines) in BCVA from baseline at M12, and percentage of patients who achieved >=20/40 vision (Snellen) at M12 served as the basis for analyzing baseline predictors of observed VA outcomes in the monthly and PRN groups. Total number of ranibizumab PRN injections in the first 12 months was also evaluated. Only variables that were statistically significant (P < .05) remained in the final statistical models. RESULTS: Baseline predictors of BCVA change from baseline at M12 and/or percentage of 3-line gainers included lower BCVA, younger age, smaller total choroidal neovascularization (CNV) leakage area, smaller area of occult CNV, and presence of subretinal fluid (SRF). Baseline predictors of >=20/40 vision at M12 included higher BCVA, smaller total CNV leakage area, and presence of SRF. SRF thickness >118.25 MUm at baseline predicted requiring more ranibizumab injections in the first 12 months of treatment. CONCLUSIONS: Select baseline characteristics have predictive value for visual prognosis and treatment frequency in ranibizumab-treated patients with wet AMD. PMID- 26231306 TI - Longitudinal Change of Circumpapillary Retinal Nerve Fiber Layer Thickness in Children With Optic Pathway Gliomas. AB - PURPOSE: To evaluate longitudinal changes in circumpapillary retinal nerve fiber layer (RNFL) thickness, as measured by spectral-domain optical coherence tomography (SD OCT), in children with optic pathway gliomas. DESIGN: Longitudinal cohort study. METHODS: Global and quadrant-specific circumpapillary RNFL thickness measures were acquired using either a hand-held SD OCT during sedation or a table-top SD OCT in children old enough to cooperate. Vision loss was defined as either a 0.2 logMAR decline in visual acuity or progression of visual field. Percent change in circumpapillary RNFL thickness in eyes experiencing vision loss was compared to eyes with stable vision. RESULTS: Fifty-five eyes completed 250 study visits. Ten eyes (18%) from 7 patients experienced a new episode of vision loss during the study and 45 eyes (82%) from 39 patients demonstrated stable vision across study visits. Percent decline of RNFL thickness between the baseline visit and first event of vision loss event was greatest in the superior (-14%) and inferior (-10%) quadrants as well as global average ( 13%). Using a threshold of >=10% decline in RNFL, the positive and negative predictive value for vision loss when 2 or more anatomic sectors were affected was 100% and 94%, respectively. CONCLUSIONS: Children experiencing vision loss from their optic pathway gliomas frequently demonstrate a >=10% decline of RNFL thickness in 1 or more anatomic sectors. Global average and the inferior quadrant demonstrated the best positive and negative predictive values. Circumpapillary RNFL is a surrogate marker of vision and could be helpful in making treatment decisions for children with optic pathway gliomas. PMID- 26231308 TI - Network-based ranking methods for prediction of novel disease associated microRNAs. AB - BACKGROUND: Many studies have shown roles of microRNAs on human disease and a number of computational methods have been proposed to predict such associations by ranking candidate microRNAs according to their relevance to a disease. Among them, machine learning-based methods usually have a limitation in specifying non disease microRNAs as negative training samples. Meanwhile, network-based methods are becoming dominant since they well exploit a "disease module" principle in microRNA functional similarity networks. Of which, random walk with restart (RWR) algorithm-based method is currently state-of-the-art. The use of this algorithm was inspired from its success in predicting disease gene because the "disease module" principle also exists in protein interaction networks. Besides, many algorithms designed for webpage ranking have been successfully applied in ranking disease candidate genes because web networks share topological properties with protein interaction networks. However, these algorithms have not yet been utilized for disease microRNA prediction. METHODS: We constructed microRNA functional similarity networks based on shared targets of microRNAs, and then we integrated them with a microRNA functional synergistic network, which was recently identified. After analyzing topological properties of these networks, in addition to RWR, we assessed the performance of (i) PRINCE (PRIoritizatioN and Complex Elucidation), which was proposed for disease gene prediction; (ii) PageRank with Priors (PRP) and K-Step Markov (KSM), which were used for studying web networks; and (iii) a neighborhood-based algorithm. RESULTS: Analyses on topological properties showed that all microRNA functional similarity networks are small-worldness and scale-free. The performance of each algorithm was assessed based on average AUC values on 35 disease phenotypes and average rankings of newly discovered disease microRNAs. As a result, the performance on the integrated network was better than that on individual ones. In addition, the performance of PRINCE, PRP and KSM was comparable with that of RWR, whereas it was worst for the neighborhood-based algorithm. Moreover, all the algorithms were stable with the change of parameters. Final, using the integrated network, we predicted six novel miRNAs (i.e., hsa-miR-101, hsa-miR-181d, hsa-miR-192, hsa-miR 423-3p, hsa-miR-484 and hsa-miR-98) associated with breast cancer. CONCLUSIONS: Network-based ranking algorithms, which were successfully applied for either disease gene prediction or for studying social/web networks, can be also used effectively for disease microRNA prediction. PMID- 26231307 TI - Ocular Toxicity in Metastatic Melanoma Patients Treated With Mitogen-Activated Protein Kinase Kinase Inhibitors: A Case Series. AB - PURPOSE: To report the clinical features and management of mitogen-activated protein kinase kinase inhibitor-associated ocular side effects in 4 patients with advanced melanoma and a review of literature. DESIGN: Interventional case series. METHODS: Four patients with advanced cutaneous melanoma were treated with a mitogen-activated protein kinase kinase (MEK) inhibitor as single therapy or together with a v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor. All patients underwent ophthalmologic examinations at regular intervals or as needed, including visual acuity, intraocular pressure, external eye examination, and funduscopy. When pathologic findings were found, patients underwent visual field examination, optical coherence tomography (OCT), and/or fluorescein angiography. Ocular toxicity was assessed and handled according to the Common Terminology Criteria for Adverse Events. RESULTS: Ocular adverse events appeared early in the treatment. In 3 patients OCT revealed subfoveal neuroretinal elevation, often asymptomatic, also after discontinuation and re-starting of MEK inhibitor. Vascular injury appeared in 2 patients, in 1 case associated with a visual field defect reduced after discontinuation of the drug and use of systemic therapy. In 1 case an inflammatory reaction was observed in the anterior chamber. Visual symptoms were usually mild and short-lived. CONCLUSIONS: MEK inhibitor as a single agent or in combination with BRAF inhibitor induces transient retinopathy with time-dependent recurrence and usually mild visual symptoms. Vascular injuries can be observed and their management is essential in clinical practice. It is important to investigate all previous ocular disorders, systemic conditions, and pharmacologic interactions of MEK inhibitor that could facilitate the onset of associated ocular effects. PMID- 26231309 TI - Comparison of the effects of pretreatment with Veramix sponge (medroxyprogesterone acetate) or CIDR (natural progesterone) in combination with an injection of estradiol-17beta on ovarian activity, endocrine profiles, and embryo yields in cyclic ewes superovulated in the multiple-dose Folltropin-V (porcine FSH) regimen. AB - Follicular wave status at the beginning of exogenous FSH administration is an important contributor to variability in superovulatory responses in ruminants. Studies in ewes have shown a decrease in the number of ovulations when superovulation is initiated in the presence of ostensibly ovulatory-sized ovarian follicles. Hormonal ablation of large antral follicles with the progestin estradiol (E2-17beta) treatment significantly reduces this variability in superovulated anestrous ewes, but the effects of the treatment in cycling ewes have not yet been assessed. Sixteen Rideau Arcott * Polled Dorset ewes (November December) received either medroxyprogesterone acetate (MAP)-releasing intravaginal sponges (60 mg) or controlled internal drug release (CIDR) devices (containing 300 mg of natural progesterone) for 14 days (Days 0-14), with a single intramuscular injection of 350 MUg of E2-17beta on Day 6. The superovulatory treatment consisted of six injections of porcine FSH (Folltropin V) given twice daily, followed by a bolus GnRH injection (50 MUg intramuscular) on Day 15. There were no differences (P < 0.05) in the ovulatory responses and embryo yields between the two groups of ewes. In both subsets of animals, the next follicular wave emerged ~2.5 days after an E2-17beta injection (P > 0.05). A decline in maximum follicle size after an E2-17beta injection was more abrupt in CIDR- compared with MAP-treated animals, and the ewes pretreated with exogenous progesterone had significantly more 3-mm follicles at the start of the superovulatory treatment. The metabolic clearance rate of exogenous E2-17beta appeared to be greater in MAP-treated ewes, but circulating concentrations of porcine FSH failed to increase significantly after each Folltropin-V injection in CIDR-treated animals. The CIDR-treated ewes exceeded (P < 0.05) their MAP-treated counterparts in serum E2-17beta concentrations during superovulation. In spite of differences in antral follicle numbers and endocrine profiles between MAP- and CIDR-treated cyclic ewes receiving E2-17beta before ovarian superstimulation, there were no differences in superovulatory responses. PMID- 26231310 TI - Salvage ablative therapy in prostate cancer: international multidisciplinary consensus on trial design. AB - INTRODUCTION: Salvage ablative therapy (SAT) has been developed as a form of localized treatment for localized recurrence of prostate cancers following radiation therapy. To better address the utility of SAT, prospective clinical trials must address the aspects of accepted standards in the initial evaluation, treatment, follow-up, and outcomes in the oncology community. We undertook this study to achieve consensus on uniform standardized trial design for SAT trials. METHODS: A literature search was performed and an international multidisciplinary group of experts was identified. A questionnaire was constructed and sent out to 71 participants in 3 consecutive rounds according to the Delphi method. The project was concluded with a face-to-face meeting in which the results were reviewed and conclusions were formulated. RESULTS: Patients with recurrent disease after radiation therapy were considered candidates for a SAT trial using any ablation scenario performed with cryotherapy or high-intensity focused ultrasound. It is feasible to compare different sources of energy or to compare with historical data on salvage radical prostatectomy outcomes. The primary objective should be to assess the efficacy of the treatment for negative biopsy rate at 12 months. Secondary objectives should include safety parameters and quality-of-life assessment. Exclusion criteria should include evidence of local or distant metastases. The optimal biopsy strategy is image-guided targeted biopsies. Follow-up includes multiparametric magnetic resonance imaging, prostate specific antigen level, and quality of life for at least 5 years. CONCLUSIONS: A multidisciplinary board from international experts reached consensus on trial design for SAT in prostate cancer and provides a standard for designing a feasible SAT trial. PMID- 26231311 TI - Muscle-invasive bladder cancer is characterized by overexpression of thymidine kinase 1. AB - OBJECTIVE: Thymidine kinases have an important role in the synthesis of DNA and exhibit high activity in rapidly proliferating cells. Thymidine kinase 1 (TK1) activity has been shown to be increased in various cancer types and proposed as a prognostic parameter. Aim of the present study was to investigate TK1 in muscle invasive urothelial carcinoma (UC). METHODS: Corresponding UC and benign samples from paraffin embedded tissue of 111 patients treated with cystectomy for invasive UC from 1996 to 2006 were immunohistochemically (IHC) assessed for TK1. IHC expression patterns were evaluated in a semiquantitative fashion by 2 independent reviewers. Localization of staining was categorized into pure nuclear and additional cytoplasmic localization. Uni- and multivariate analyses were performed to assess differential expression in normal and UC tissue and to evaluate the diagnostic and predictive capability of TK1 by correlation to clinical data. To correlate TK1 expression with molecular subtypes of UC, analysis of TK1 RNA expression levels of the Cancer Genome Atlas UC cohort was performed. RESULTS: TK1 was significantly overexpressed in invasive UC, compared to benign urothelium (P<0.0001), and cytoplasmic expression was more often found in cancer tissue than in benign tissue (P = 0.0001). No correlations of TK1 protein expression patterns to standard histopathological determinants were detected. In univariate analysis, TK1 nuclear and cytoplasmic expression was associated with improved cancer-specific survival (P = 0.0119). However, only metastasis status and histologic grade were identified as independent predictors of cancer-specific survival in multivariate analysis. TK1 expression was merely found in the basal layers of benign urothelium. RNA overexpression of TK1 could be correlated to the biologically more aggressive basal UC subtype. CONCLUSIONS: TK1 expression is significantly different in invasive UC and benign urothelium, which underlines its potential as a diagnostic marker. Although TK1 is considered to be a marker of proliferation, and TK1 RNA overexpression is associated with an aggressive UC subtype, its capability as a predictive IHC biomarker for invasive UC remains limited. PMID- 26231312 TI - Right robotic adrenalectomy for a 8 cm pheochromocytoma (with video). PMID- 26231313 TI - Referral system for hard exudates in eye fundus. AB - Hard exudates are one of the most common anomalies/artifacts found in the eye fundus of patients suffering from diabetic retinopathy. These exudates are the major cause of loss of sight or blindness in people having diabetic retinopathy. Diagnosis of hard exudates requires considerable time and effort of an ophthalmologist. The ophthalmologists have become overloaded, so that there is a need for an automated diagnostic/referral system. In this paper a referral system for the hard exudates in the eye-fundus images has been presented. The proposed referral system works by combining different techniques like Scale Invariant Feature Transform (SIFT), K-means Clustering, Visual Dictionaries and Support Vector Machine (SVM). The system was also tested with Back Propagation Neural Network as a classifier. To test the performance of the system four fundus image databases were used. One publicly available image database was used to compare the performance of the system to the existing systems. To test the general performance of the system when the images are taken under different conditions and come from different sources, three other fundus image databases were mixed. The evaluation of the system was also performed on different sizes of the visual dictionaries. When using only one fundus image database the area under the curve (AUC) of maximum 0.9702 (97.02%) was achieved with accuracy of 95.02%. In case of mixed image databases an AUC of 0.9349 (93.49%) was recorded having accuracy of 87.23%. The results were compared to the existing systems and were found better/comparable. PMID- 26231314 TI - Bardet-Biedl syndrome: Is it only cilia dysfunction? AB - Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, pleiotropic disorder, characterized by both congenital and late onset defects. From the analysis of the mutational burden in patients to the functional characterization of the BBS proteins, this syndrome has become a model for both understanding oligogenic patterns of inheritance and the biology of a particular cellular organelle: the primary cilium. Here we briefly review the genetics of BBS to then focus on the function of the BBS proteins, not only in the context of the cilium but also highlighting potential extra-ciliary roles that could be relevant to the etiology of the disorder. Finally, we provide an overview of how the study of this rare syndrome has contributed to the understanding of cilia biology and how this knowledge has informed on the cellular basis of different clinical manifestations that characterize BBS and the ciliopathies. PMID- 26231315 TI - A scanning microscopy technique based on capacitive coupling with a field-effect transistor integrated with the tip. AB - We propose a method for measuring the capacitance of a thin layer using a Tip-on Gate of Field-Effect Transistor (ToGoFET) probe. A ToGoFET probe with a metal oxide-semiconductor field-effect transistor (MOSFET) with an ion-implant channel was embedded at the end of a cantilever and a Pt tip was fabricated using micro machining. The ToGoFET probe was used to detect an alternating electric field at the dielectric surface. A dielectric buried metal sample was prepared; a sinusoidal input signal was applied to the buried metal lines; and the ToGoFET probe detected the electric field at the tip via the dielectric. The AC signal detected by the ToGoFET probe was demodulated by a simple AC-to-DC converter. Experimentally, it was shown that an electric field could be measured at the surface of the dielectric layer above a buried metal line. This promising result shows that it is possible to measure the surface local capacitance. PMID- 26231316 TI - Fatal pneumonia and viremia due to human parainfluenza virus type 1 in a patient with adult T-cell leukemia-lymphoma treated with mogamulizumab. AB - We report a case of fatal pneumonia and viremia due to human parainfluenza virus type 1 (HPIV-1) in a 65-year-old male patient with adult T-cell leukemia-lymphoma (ATL) treated with mogamulizumab, a brand-new therapeutic agent for ATL. To our knowledge, this is the first report describing viremia due to HPIV-1. After administering mogamulizumab, lymphocyte count in the blood was drastically decreased and the patient suffered from complicated infections including gram negative bacterial sepsis, cytomegalovirus antigenemia and aspergillosis. Although these infections were successfully controlled by broad spectrum antimicrobial therapy, patchy ground-grass opacities in the both lungs were gradually worsened. He finally died due to acute respiratory failure. Since findings of the chest CT was consistent with typical patterns of viral pneumonia, we screened major respiratory viruses in the peripheral blood with multiplex PCR, and it turned out that RNA of HPIV-1 was positive. Although ATL cells were not detected in the autopsied lungs and a variety of other tissues, cytoplasmic inclusion bodies, which are commonly observed in RNA viral infection, were abundantly observed in the autopsied lung tissue. These findings suggest that mogamulizumab accomplished complete remission of ATL, while the chemotherapy induced prolonged lymphopenia caused fatal pneumonia and viremia due to HPIV-1. As it has been well recognized that community respiratory viruses including HPIV 1 often cause fatal pneumonia in patients with leukemia, but also there is no specific treatment for HPIV-1, we have to enforce standard precautions especially when we treat leukemic patients with intensively immunosuppressive agents such as mogamulizumab. PMID- 26231317 TI - Acute abdomen due to group A streptococcus bacteremia caused by an isolate with a mutation in the csrS gene. AB - Streptococcus pyogenes (group A streptococcus) is an aerobic gram-positive coccus that causes infections ranging from non-invasive pharyngitis to severely invasive necrotizing fasciitis. Mutations in csrS/csrR and rgg, negative regulator genes of group A streptococcus, are crucial factors in the pathogenesis of streptococcal toxic shock syndrome, which is a severe, invasive infection characterized by sudden onset of shock and multiorgan failure, resulting in a high mortality rate. Here we present a case of group A streptococcal bacteremia in a 28-year-old Japanese woman with no relevant previous medical history. The patient developed progressive abdominal symptoms that may have been due to spontaneous bacterial peritonitis, followed by a state of shock, which did not fulfill the proposed criteria for streptococcal toxic shock. The isolate was found to harbor a mutation in the negative regulator csrS gene, whereas the csrR and rgg genes were intact. It was noteworthy that this strain carrying a csrS mutation had caused group A streptococcal bacteremia characterized by acute abdomen as the presenting symptom in a young individual who had been previously healthy. This case indicates that group A streptococcus with csrS mutations has potential virulence factors that are associated with the onset of group A streptococcal bacteremia that does not meet the diagnostic criteria for streptococcal toxic shock syndrome. PMID- 26231319 TI - [The inconsistency of parental authority with minor parents]. PMID- 26231318 TI - Bicytopenia, especially thrombocytopenia in hemodialysis and non-hemodialysis patients treated with linezolid therapy. AB - One of the major adverse events associated with linezolid treatment is pancytopenia. However, there are few reports about the tolerability of linezolid among patients undergoing hemodialysis. This study retrospectively investigated the frequency of bicytopenia (thrombocytopenia and erythropenia) secondary to linezolid treatment in patients undergoing and not-undergoing hemodialysis. In total, 181 patients treated with linezolid from January 2010 to July 2012 at Aichi Medical University Hospital were divided into three groups; patients undergoing hemodialysis (HD group), those with creatinine clearance (CLCR) of <50 mL/min (CLCR < 50 group) and those with CLCR of >= 50 mL/min (CLCR >= 50 group). The incidence of thrombocytopenia, and changes in the platelet (PLT) counts during and after linezolid therapy were compared among three groups. Thrombocytopenia (<75% of the baseline level) occurred in 125 patients (69.1%). PLT reached its nadir 3-4 days after the end of linezolid therapy. In particular, the PLT nadir in HD group occurred earlier than that in non-HD groups (HD, 11.5 days [4-31 days]; CLCR < 50, 14 days [5-43 days]; CLCR >= 50, 15.5 days [4-49 days]; p = 0.11). HD group exhibited the greatest rate of reduction of PLT (HD, 24.0% [0.4-93.8%]; CLCR < 50, 23.8% [0.8-92.9%]; CLCR >= 50, 22.4% [0.92-92.9%]; p = 0.003). Finally, HD group exhibited the slowest recovery of PLT to its baseline level (HD, 10 days [5-29 days]; CLCR < 50, 9 days [2-16 days]; CLCR >= 50, 8 days [3-17 days]; p = 0.09). The incidence of erythropenia was not significantly different among three groups. These results indicate the need to monitor the PLT count during and after linezolid treatment in patients undergoing hemodialysis. PMID- 26231320 TI - [Hospital practices and breastfeeding cessation risk within 6 months of delivery]. AB - BACKGROUND: The impact of maternity ward practices on breastfeeding duration remains uncertain in France. OBJECTIVE: This study aimed to determine whether compliance with an increasing number of Baby-Friendly Hospital Initiative recommended practices was associated with a decreasing risk for breastfeeding cessation within 6 months of delivery. METHODS: We analyzed the original data from a prospective cohort study carried out in eight maternity centers in France in 2005-2006. A pediatrician or a midwife prospectively collected data on breastfeeding initiation within 1h of birth, rooming-in 24h a day, pacifier non use, and giving breast milk only for 908 mothers who were breastfeeding at discharge. RESULTS: Overall, 315 (34.7%), 309 (34.0%), 186 (20.5%), and 98 (10.8%) mothers experienced 4, 3, 2, or 0-1 maternity ward practices. The median breastfeeding duration was 18 weeks (25th-75th percentiles, 9 to >26), with 87.6% and 31.5% of mothers who were still breastfeeding by 4 and 26 weeks after delivery, respectively. After adjusting for study center and baseline characteristics, the hazard ratios of breastfeeding cessation associated with 3, 2, and 0-1 practices were 1.32 (95% confidence interval [CI], 1.06-1.64), 1.54 (95% CI, 1.20-1.98), and 1.59 (95% CI, 1.13-2.25) as compared with compliance with four practices (p for trend <0.001). CONCLUSION: Although the causal interpretation for this relationship remains speculative, these findings support interventions aimed to implement or reinforce Baby-Friendly Hospital Initiative recommended practices in order to establish prolonged breastfeeding and decrease the risk for early cessation after discharge to home. PMID- 26231321 TI - [Subcutaneous emphysema, pneumomediastinum, pneumopericardium, pneumorachis, and pneumoretroperitoneum revealing an unknown foreign body aspiration]. AB - Subcutaneous emphysema develops from the spread of air essentially from the mediastinum into the subcutaneous tissue causing progressive distension and infiltration. Diagnostic and therapeutic delay expose the patient to massive air effusion and risk of compression of cervical and mediastinal structures. The initial mechanism is a breach in the tracheobronchial tree with air diffusion into the interstitial space and along the perivascular spaces toward the mediastinum, and then spread and dissection in the subcutaneous tissue. A tracheobronchial foreign body is a very rare cause of emphysema and is often localized. An association with a combination of epidural emphysema, pneumopericardium, or pneumoretroperitoneum is exceptional. Here, we present a unique case associating massive subcutaneous emphysema, pneumomediastinum, pneumopericardium, pneumorrhachis, and pneumoretroperitoneum in a 3.5-year-old child complicating an unrecognized aspirated foreign body. The extraction of the foreign body resulted in gradual regression of the symptoms and the disappearance of these emphysematous locations. PMID- 26231322 TI - Sanjad-Sakati syndrome in a Tunisian child. AB - Sanjad-Sakati syndrome (SSS) (OMIM 241410) is a rare autosomal recessive disorder characterized by congenital hypoparathyroidism with growth and mental retardation associated with seizures and a characteristic physiognomy. SSS molecular pathology has been shown to be due to mutations in the TBCE gene on chromosome 1q42-q43. All affected patients of Arab origin are homozygous for a 12-bp (155 166del) deletion in exon 3 of this gene. We report on a Tunisian child with SSS who was homozygous for the 155-166del mutation. Our findings provide additional support of the common (155-166del) deletion founder effect in exon 3 of the TBCE gene in Arab patients. It is very likely that this mutation originated in the Middle East and was introduced in Tunisia by the Banu Hilal invaders. PMID- 26231323 TI - CML in pregnancy: A case report using leukapheresis and literature review. AB - Chronic myelogenous leukemia (CML) complicating pregnancy is uncommon. Literature search demonstrates only a few case reports and some case series but large studies are lacking due to its uncommon presentation. Management of these patients is particularly challenging due to limited available options as several chemotherapy drugs could potentially lead to adverse outcomes and fetal malformations. Leukapheresis has been used in these situations; however paucity of data exists regarding the outcome and complications associated with the procedure. Using leukapheresis alone for extended period to manage CML during pregnancy is also rare. Here we report a case of CML complicating pregnancy which was successfully managed utilizing leukapheresis, followed by a review of literature addressing this controversial issue. PMID- 26231324 TI - A Pilot Randomized Trial of Financial Incentives or Coaching to Lower Serum Phosphorus in Dialysis Patients. AB - OBJECTIVE: Among chronic hemodialysis patients, hyperphosphatemia is common and associated with mortality. Behavioral economics and complementary behavior-change theories may offer valuable approaches to achieving phosphorus (PO4) control. The aim was to determine feasibility of implementing financial incentives and structured coaching to improve PO4 in the hemodialysis setting. DESIGN AND METHODS: This pilot randomized controlled trial was conducted in 3 urban dialysis units for 10 weeks among 36 adults with elevated serum PO4 (median >5.5 mg/dL over 3 months). INTERVENTIONS: Twelve participants each were randomized to: (1) financial incentives for lowering PO4, (2) coaching about dietary and medication adherence, or (3) usual care. PO4 was measured during routine clinic operations. Each incentives arm participant received the equivalent of $1.50/day if the PO4 was <=5.5 mg/dL or >5.5 mg/dL but decreased >=0.5 mg/dL since the prior measurement. The coach was instructed to contact coaching arm participants at least 3 times per week. MAIN OUTCOME MEASURES: The outcome measures included: (1) enrollment rate, (2) dropout rate, and (3) change in PO4 from beginning to end of 10-week intervention period. RESULTS: Of 66 eligible patients, 36 (55%) enrolled. Median age was 53 years, 83% were black race, and 78% were male. Median baseline PO4 was 6.0 (interquartile range 5.6, 7.5). Using stratified generalized estimation equation analyses, the monthly decline in PO4 was -0.32 mg/dL (95% CI 0.60, -0.04) in the incentives arm, -0.40 mg/dL (-0.60, -0.20) in the coaching arm, and -0.24 mg/dL (-0.60, 0.08) in the usual care arm. No patients dropped out. All intervention arm participants expressed interest in receiving similar support in the future. CONCLUSIONS: This pilot trial demonstrated good feasibility in enrollment and implementation of novel behavioral health strategies to reduce PO4 in dialysis patients. PMID- 26231325 TI - New constitutive latex osmotin-like proteins lacking antifungal activity. AB - Proteins that share similar primary sequences to the protein originally described in salt-stressed tobacco cells have been named osmotins. So far, only two osmotin like proteins were purified and characterized of latex fluids. Osmotin from Carica papaya latex is an inducible protein lacking antifungal activity, whereas the Calotropis procera latex osmotin is a constitutive antifungal protein. To get additional insights into this subject, we investigated osmotins in latex fluids of five species. Two potential osmotin-like proteins in Cryptostegia grandiflora and Plumeria rubra latex were detected by immunological cross-reactivity with polyclonal antibodies produced against the C. procera latex osmotin (CpOsm) by ELISA, Dot Blot and Western Blot assays. Osmotin-like proteins were not detected in the latex of Thevetia peruviana, Himatanthus drasticus and healthy Carica papaya fruits. Later, the two new osmotin-like proteins were purified through immunoaffinity chromatography with anti-CpOsm immobilized antibodies. Worth noting the chromatographic efficiency allowed for the purification of the osmotin like protein belonging to H. drasticus latex, which was not detectable by immunoassays. The identification of the purified proteins was confirmed after MS/MS analyses of their tryptic digests. It is concluded that the constitutive osmotin-like proteins reported here share structural similarities to CpOsm. However, unlike CpOsm, they did not exhibit antifungal activity against Fusarium solani and Colletotrichum gloeosporioides. These results suggest that osmotins of different latex sources may be involved in distinct physiological or defensive events. PMID- 26231326 TI - Dual utility of a novel, copper enhanced laccase from Trichoderma aureoviridae. AB - Ever since the ability of laccase to oxidize non-phenolic lignin models was described, the oxidative degradation reactions catalyzed by laccase have been widely studied for paper pulp production or detoxification of aromatic pollutants. The viability of developing eco-friendly, laccase aided industrial processes has been explored. Here, we report the isolation and screening of fungi to explore their lignolytic ability on solid media using various substrates as indicators. The promising fungus was cultivated in submerged and solid state conditions. The crude enzyme obtained yielded elevated activity at 75 degrees C and pH 9.0. Addition of CuSO4 increased the activity by almost 25% proving that Cu(2+) catalytically enhances the action of laccases. Decolorization studies were carried out using industrial dye, Remazol Brilliant Blue R (CI 61200) on solid and liquid medium. Visual decolorization was observed within 2 days of inoculation on solid media whereas, liquid medium incorporated with varying concentrations of dye solution showed a final level of decolorization of up to 76%. Bamboo degradation studies revealed a decrease in lignin content by 51 and 43% within a month. To the best of our knowledge, this study for the first time reports that Trichoderma aureoviridae can produce lignolytic enzyme and degrade lignin. PMID- 26231327 TI - Importance of a stable topoisomerase IB clamping for an efficient DNA processing: Effect of the Lys(369)Glu mutation. AB - The role of lysine 369 of human topoisomerase IB in recognizing, clamping and processing its DNA substrate was experimentally investigated. Lys(369) is located in one of the two lips that interact to each other allowing the protein to embrace and firmly bind the DNA substrate. The lysine was mutated to a glutamate residue and the catalytic activity of the mutant enzyme was assayed. The mutant shows a distributive behavior, has a reduced binding to the substrate and a lower cleavage extent when compared to the wild type enzyme. The mutant displays reduced sensitivity to CPT both "in vitro" and in an "in vivo" yeast model, likely because of the low amount of cleaved DNA, however it displays cleavage and religation rates comparable to the wild type. These results demonstrate that the mutation causes a destabilization of the lips clamping around the DNA, impairing the protein-DNA interaction, emphasizing the importance of the ionic pair in tuning the stability of the protein-DNA complex. PMID- 26231328 TI - Fibrin matrices: The versatile therapeutic delivery systems. AB - Fibrin sealants, that have been employed for over a century by surgeons to stop post surgery bleeding, are finding novel applications in the controlled delivery of antibiotics and several other therapeutics. Fibrinogen can be easily purified from blood plasma and converted by thrombolysis to fibrin that undergoes spontaneous aggregation to form insoluble clot. During the gelling, fibrin can be formulated into films, clots, threads, microbeads, nanoconstructs and nanoparticles. Whole plasma clots in the form of beads and microparticles can also be prepared by activating endogenous thrombin, for possible drug delivery. Fibrin formulations offer remarkable scope for controlling the porosity as well as in vivo degradability and hence the release of the associated therapeutics. Binding/covalent-linking of therapeutics to the fibrin matrix, crosslinking of the matrix with bifunctional reagents and coentrapment of protease inhibitors have been successful in regulating both in vitro and in vivo release of the therapeutics. The release rates can also be remarkably lowered by preentrapment of therapeutics in insoluble particles like liposomes or by anchoring them to the matrix via molecules that bind them as well as fibrin. PMID- 26231329 TI - Evaluation of polyphenols as possible therapeutics for amyloidoses: Comparative analysis of Kaempferol and Catechin. AB - Several mammalian proteins fold abnormally under non physiological conditions, to form pathological deposits that are associated with many degenerative diseases. In vitro variation of solvent conditions and pH can lead to partial unfolding and subsequent fibril formation. In the present study, we examined the effects of low pH on goat brain cystatin (GBC) with a focus on amyloid fibril formation. The results demonstrate that GBC can form amyloid like fibrils at pH 3.0. Moreover this study is aimed at exploring the inhibitory activity of polyphenols, Kaempferol (KM) and Catechin (CA) against the fibrillation of GBC. Using fluorescence spectroscopic analysis with Thioflavin T, CD and electron microscopic studies, anti-fibrillation effects of polyphenols, KM and CA were analyzed. The study also revealed that KM and CA produced a concentration dependent anti-fibrillogenic effects with KM producing more pronounced effect compared to CA. The study proposed a mechanistic approach assuming structural constraints and specific aromatic interactions of polyphenols with beta sheets of GBC fibrils. PMID- 26231330 TI - Starch based biodegradable graft copolymer for the preparation of silver nanoparticles. AB - The synthesis and characterization of a novel biodegradable graft copolymer based on partially hydrolyzed polymethylacrylate (PMA) grafted amylopectin (AP) was reported which was developed for the synthesis of silver nanoparticles from silver nitrate solution by facile green technique. The prepared graft copolymer was biodegradable which was shown by fungal growth. Characterization of silver nanoparticles was carried out by UV-VIS spectroscopy (417nm), HR-TEM, SAED and FESEM analysis. The TEM findings revealed that the silver nanoparticles are crystalline and globular shaped with average particle size ranging from 11 to 15nm. The synthesized silver nanoparticles exhibit excellent antibacterial sensitivity towards both Gram negative and Gram positive bacteria namely Vibrio parahaemolyticus (ATCC-17802) and Bacillus cereus (ATCC-14579) respectively and were also shown a good catalytic activity towards 4-nitrophenol reduction. PMID- 26231331 TI - Effect of phosphorylation on antioxidant activities of pumpkin (Cucurbita pepo, Lady godiva) polysaccharide. AB - Phosphorylated derivatives of pumpkin polysaccharide with different degree of substitution were synthesized using POCl3 and pyridine. Antioxidant activities and cytoprotective effects of unmodified polysaccharide and phosphorylated derivatives were investigated employing various in vitro systems. Results showed that high ratio of POCl3/pyridine could increase the degree of substitution and no remarkable degradation occurred in the phosphorylation process. Characteristic absorption of phosphorylation appeared both in the IR and (31)P NMR spectrum. The df values between 2.27 and 2.55 indicated the relatively expanded conformation of the phosphorylated derivatives. All the phosphorylated polysaccharides exhibited higher antioxidant activities. H2O2-induced oxidative damages on rat thymic lymphocyte were also prevented by the derivatives. In general, phosphorylation could improve the antioxidant activities of pumpkin polysaccharide both in vitro and in a cell system. PMID- 26231332 TI - A cold-adapted, solvent and salt tolerant esterase from marine bacterium Psychrobacter pacificensis. AB - Lipolytic enzymes with unique physico-chemical characteristics are gaining more attention for their immense industrial importance. In this study, a novel lipolytic enzyme (Est11) was cloned from the genomic library of a marine bacterium Psychrobacter pacificensis. The enzyme was expressed in Escherichia coli and purified to homogeneity with molecular mass of 32.9kDa. The recombinant Est11 was able to hydrolyze short chain esters (C2-C8) and displayed an optimum activity against butyrate ester (C4). The optimal temperature and pH were 25 degrees C and 7.5, respectively. Est11 retained more than 70% of its original activity at 10 degrees C, suggesting that it was a cold-active esterase. The enzyme was highly active and stable at high concentration of NaCl (5M). Further, incubation with ethanol, isopropanol, propanediol, DMSO, acetonitrile, and glycerol rendered remarkable positive effects on Est11 activity. Typically, even at the concentration of 30% (v/v), ethanol, DMSO, and propanediol increased Est11 activity by 1.3, 2.0, and 2.4-folds, respectively. This new robust enzyme with remarkable properties like cold-adaptability, exceptional tolerance to salt and organic solvents provides us a promising candidate to meet the needs of some harsh industrial processes. PMID- 26231334 TI - Rates of Victimization of Violence Committed by Relatives With Psychiatric Disorders. AB - Persons with psychiatric disorders are at an increased risk of committing violence, with approximately half of all violence being perpetrated against family members. However, family violence perpetrated by persons with psychiatric disorders is a highly under-researched area, so much so that it is impossible to even approximately estimate the extent of the problem. This article presents the results of a national online survey of 573 adults with an adult relative with psychiatric disorders. Nearly half (47%) of all respondents reported being the victim of violence committed by their relative with psychiatric disorders since the onset of their relative's illness, and 22% reported being the victim of such violence in the past 6 months. Being the victim of minor versus serious violence was examined. The results of this study, in combination with sparse research previously conducted, suggest that 20% to 35% of persons with high levels of contact with a relative with psychiatric disorders have been the victim of violence committed by their relative with psychiatric disorders in the past 6 to 12 months, and that at least 40% have been the victim of said violence since the onset of their relative's illness. In the present study, no statistically significant differences were detected in rates of victimization based on the relationship type of the respondent to their relative with psychiatric disorders. It is imperative that further research be conducted that may inform the development of policies and interventions aiming to prevent family violence perpetrated by persons with psychiatric disorders. PMID- 26231333 TI - Vaccine potential of plasma bead-based dual antigen delivery system against experimental murine candidiasis. AB - The development of prophylactic anti-candidal vaccine comprising the Candida albicans cytosolic proteins (Cp) as antigen and plasma beads (PB) prepared from plasma as sustained delivery system, is described. The immune-prophylactic potential of various PBs-based dual antigen delivery systems, co-entrapping Cp pre-entrapped in PLGA microspheres were tested in the murine model. Induction of cell mediated immunity was measured by assaying DTH and NO production as well as in vitro proliferation of lymphocytes derived from the immunized animals. Expression of surface markers on APCs (CD80, CD86) and T-cells (CD4+, CD8+) was also evaluated. Humoral immune response was studied by measuring circulating anti Cp antibodies and their subclasses. When the prophylactic efficacy of the vaccines was tested in mice challenged with virulent C. albicans, the PB-based formulation (PB-PLGA-Cp vaccine) was found to be most effective in the generation of desirable immune response, in terms of suppression of fungal load and facilitating the survival of the immunized animals. PMID- 26231335 TI - Non-Violent Empowerment: Self-Help Group for Male Batterers on Recovery. AB - This research focused on a new and unique therapy group for male batterers who were violent toward their intimate partners. The group is based on a small self help group model, where a professional accompanies the group and serves as the facilitator of the process undergone by the group without interfering with the management of the group and its meetings. A total of seven group members were interviewed in a qualitative and phenomenological-interpretive research, which combined an outside observation by two authors with an inside observation by a professional who facilitated the group. The study focused on the method of empowerment of the group members, and it found three central themes: self efficacy, group efficacy, and social efficacy. The research findings are explained from the new perspective of positive criminology. PMID- 26231336 TI - Victimization and Polyvictimization of Spanish Youth Involved in Juvenile Justice. AB - Multiple victimization, or polyvictimization, is closely related to delinquency and crime, although few studies have studied these experiences in juvenile offenders. Therefore, the aim of this study is to present victimization rates in young offenders from a Southwestern European country. The sample consisted of 101 youth aged between 14 and 17 years, who were mainly recruited from detention centers (77.2%). From a lifetime perspective, the majority had suffered a criminal offense against the person (93.1%), exposure to community violence (95.0%), and peer victimization (86.1%). Prevalence rates for direct and indirect family violence were also high (63.4% and 43.6%). Electronic victimization reached a rate of 40.6% and sexual victimization of 15.8%. Past year experiences showed lower but similar patterns. Based on a community population criterion to define polyvictimization, 65.3% of the sample were considered lifetime polyvictims, while 41.6% were defined as past year polyvictims. Interventions to address multiple, concurrent forms of exposure to violence should be implemented in the justice system as polyvictimization has been revealed as a frequent reality in young offenders, which may result in antisocial behavior. PMID- 26231337 TI - Does physical activity moderate the relationship between depression symptomatology and low back pain? Cohort and co-twin control analyses nested in the longitudinal study of aging Danish twins (LSADT). AB - PURPOSE: To investigate whether depression symptomatology is associated with low back pain (LBP) in twins aged 70+ and whether this effect depends on a person's physical activity (PA) status. METHODS: This prospective cohort and nested case control study used a nationally representative sample of twins. Data on depression symptomatology (modified Cambridge Mental Disorders Examination) and self-reported PA were obtained from the Longitudinal Study of Aging Danish Twins using twins without LBP at baseline. Associations between depression symptomatology (highest quartile) at baseline and LBP two years later were investigated using logistic regression analyses adjusted for sex. To examine the moderating effect of PA, we tested its interaction with depression. Associations were analysed using the complete sample of 2446 twins and a matched case-control analysis of 97 twin pairs discordant for LBP at follow-up. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS: Using the whole sample, high depression scores were associated with an increased probability of LBP (OR 1.56, 95% CI 1.22-1.99, P <= 0.01). There was no statistically significant interaction of light PA and depression symptomatology (OR 0.78, 95% CI 0.46-1.35, P = 0.39) and strenuous PA and depression symptomatology (0.84, 95% CI 0.50-1.41, P = 0.51). The case-control analysis showed similar ORs, although statistically insignificant. CONCLUSIONS: High depression symptomatology predicted incident LBP. This effect is supposedly not attributable to genetic or shared environmental factors. Physical activity did not moderate the effect of depression symptomatology on LBP. PMID- 26231338 TI - Anterior column reconstruction with PMMA: an effective long-term alternative in spinal oncologic surgery. AB - A number of anterior reconstruction options are available in patients managed for symptomatic metastatic spinal column disease. Polymethylmethacrylate (PMMA) has been traditionally used as a reconstruction option in patients with limited life expectancy as an anterior fusion is not expected. In this article, we present the outcome of a 13-year follow-up of a long anterior reconstruction using PMMA of the upper thoracic spine in a myelopathic female secondary to a compressive breast metastasis affecting the upper 4 thoracic vertebrae. We discuss the use of PMMA in spinal oncological surgery and review the evidence pertinent to its use. PMID- 26231339 TI - Communication between family carers and health professionals about end-of-life care for older people in the acute hospital setting: a qualitative study. AB - BACKGROUND: This paper focuses on communication between hospital staff and family carers of patients dying on acute hospital wards, with an emphasis on the family carers' perspective. The age at which people in the UK die is increasing and many continue to die in the acute hospital setting. Concerns have been expressed about poor quality end of life care in hospitals, in particular regarding communication between staff and relatives. This research aimed to understand the factors and processes which affect the quality of care provided to frail older people who are dying in hospital and their family carers. METHODS: The study used mixed qualitative methods, involving non-participant observation, semi-structured interviews and a review of case notes. Four acute wards in an English University teaching hospital formed the setting: an admissions unit, two health care of older people wards and a specialist medical and mental health unit for older people. Thirty-two members of staff took part in interviews, five members of the palliative care team participated in a focus group and 13 bereaved family carers were interviewed. In all, 245 hours of observation were carried out including all days of the week and all hours of the day. Forty-two individual patient cases were constructed where the patient had died on the wards during the course of the study. Thirty three cases included direct observations of patient care. Interviews were completed with 12 bereaved family carers of ten patient cases. RESULTS: Carers' experience of the end of life care of their relative was enhanced when mutual understanding was achieved with healthcare professionals. However, some carers reported communication to be ineffective. They felt unsure about what was happening with their relative and were distressed by the experience of their relative's end of life care. CONCLUSIONS: Establishing a concordant relationship, based on negotiated understanding of shared perspectives, can help to improve communication between healthcare professionals and family carers of their patients. PMID- 26231340 TI - Comparing the adequacy of the MNA-SF, NRS-2002 and MUST nutritional tools in assessing malnutrition in hip fracture operated elderly patients. AB - BACKGROUND & AIMS: Malnutrition is common in hip fracture elderly patients. There is no gold standard for screening nutritional risk. We compared the adequacy of 3 screening tools, their association to nutritional measurements and their ability to predict outcome. METHODS: The Mini Nutrition Assessment Short Form (MNA-SF), the Malnutrition Universal Screening Tool (MUST) and the Nutrition Risk Screening 2002 (NRS-2002) were prospectively determined. Length of stay (LOS), complications, 6 months readmission and up-to 36 months mortality were recorded. RESULTS: 215 operated patients were included: 154 (71.6%) were women; mean age was 83.5 +/- 6.09 years (66-104). According to the MNA-SF, 95 patients were well nourished, 95 were at risk of malnutrition and 25 were malnourished. Based on the MUST, 171 patients were at a low risk of malnutrition, 31 at a medium risk, 13 at a high risk. According to the NRS-2002, 134 patients were at a low risk of malnutrition, 70 at a medium risk, 11 at a high risk. A significant relationship between the nutritional groups of the 3 scores (p < 0.001) was found. In all screening tools, body mass index, weight loss and food intake prior to admission were found to be related to the patients' nutritional status (p < 0.001). No differences in LOS and complications were found between the patients' nutritional status of each screening tool; only the MNA-SF predicted that well-nourished patients would have less readmissions during a 6 month follow-up (p = 0.024). During a 36 month follow-up, 79 patients died. According to the MNA-SF, mortality was lower in the well-nourished patients vs. the malnourished (p = 0.001) and at risk of malnutrition patients (p = 0.01). A less significant association was found between the NRS-2002 patients' nutritional status and mortality (p = 0.048). The MUST did not reveal this relationship. CONCLUSIONS: All screening tools were adequate in assessing malnutrition parameters in hip fracture operated elderly patients, however, only the MNA-SF could also predict readmissions and mortality. PMID- 26231341 TI - Echocardiographic evaluation of pre-diagnostic development in young relatives genetically predisposed to hypertrophic cardiomyopathy. AB - Identification of the first echocardiographic manifestations of hypertrophic cardiomyopathy may be important for clinical management and our understanding of the pathogenesis. We studied the development of pre-diagnostic echocardiographic changes in young relatives to HCM patients during long-term years follow-up. HCM relatives not fulfilling the diagnostic criteria for HCM and age of <18 years were included in this study. We performed echocardiographic evaluations at inclusion and after 12 +/- 1 years follow-up. Based on family screening of 11 sarcomere genes, CRYAB, alpha-GAL, and titin, we evaluated: (1) non-carriers (known family mutation ruled out-controls), (2) carriers (phenotype negative gene mutation carriers) and (3) phenotype negative relatives with unknown genetic status (relatives from families without identified mutations). At inclusion (age 11 +/- 5 years), there were no differences in echocardiographic chamber dimensions, systolic or diastolic function between the three groups. During follow-up (age 23 +/- 5 years), carriers (n = 8) developed lower left ventricular end-diastolic dimension (LVEDd) compared to non-carriers (n = 23) (41 +/- 4 vs. 46 +/- 4 mm; p = 0.04) and a higher ratio of early left ventricular filling velocity and early diastolic velocity of lateral mitral annulus (E/e' 6 +/- 1 vs. 5 +/- 1; p = 0.003). No significant differences in LVEDd or E/e' were found between relatives with unknown genetic status (n = 24) and non-carriers though Z scores for these parameters were >2 in a subset of relatives with unknown genetic status. Children carrying pathogenic sarcomere gene mutations develop reduced LVEDd and increased E/e' as first pre-diagnostic echocardiographic manifestations during follow-up into adulthood. PMID- 26231343 TI - The new frontier in systemic sclerosis: from epigenetics to new treatments. PMID- 26231342 TI - Exercise treadmill saline contrast echocardiography for the detection of patent foramen ovale in hypoxia. AB - Percutaneous patent foramen ovale (PFO) occluder placement improves dyspnea and oxygen requirement in hypoxic patients with PFO-mediated right-to-left shunt (RTLS). Although saline contrast echocardiography (SCE) in the resting state can identify PFO RTLS, SCE performed with exercise stress testing may provide incremental diagnostic yield compared to rest SCE. We evaluated the ability of exercise SCE to predict PFO presence and size using intracardiac echocardiography (ICE) as a gold standard in a hypoxic cohort. Thirty-three hypoxic patients with suspected PFO RTLS who underwent rest, Valsalva, and exercise stress SCE prior to ICE were evaluated retrospectively. PFO RTLS was defined by ICE findings including PFO anatomy, RTLS by saline contrast and color Doppler, and probe patency. SCE shunt severity was compared to the presence of ICE-defined PFO RTLS and PFO size. Exercise SCE for the detection of PFO RTLS performed with an area under the curve of 0.77, sensitivity of 73%, and specificity of 86%. Among 26 patients with PFO RTLS, exercise SCE identified four additional patients with PFO that had negative rest SCE and two patients with negative Valsalva SCE. Exercise SCE had a stronger correlation with PFO size than resting or Valsalva SCE. Exercise SCE detects PFO RTLS and predicts PFO size in a hypoxic cohort. In addition, exercise SCE can identify PFO RTLS that is otherwise undetected with rest or Valsalva SCE. Exercise SCE may be appropriate when a clinical suspicion for PFO RTLS persists despite negative rest and Valsalva SCE. PMID- 26231344 TI - High systemic levels of low-density lipoprotein cholesterol: fuel to the flames in inflammatory osteoarthritis? AB - There is increasing evidence that low-density lipoprotein (LDL) cholesterol plays a role in the pathology of OA. Specifically, oxidized LDL (oxLDL), which has been shown to play an essential role during development of atherosclerosis, could be involved in processes such as synovial inflammation, cartilage destruction and bone deformations. OxLDL can activate synovial cells such as macrophages, endothelial cells and synovial fibroblasts, resulting in release of growth factors, MMP and pro-inflammatory cytokines. In this review article, we discuss the role of LDL and oxLDL in OA joint pathology and share our viewpoint of possible mechanisms by which these proteins could influence the development and progression of OA. The proposed theory could provide insight into the aetiopathology of OA and give rise to new potential treatments. PMID- 26231345 TI - Characterization of systemic disease in primary Sjogren's syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal involvements. AB - OBJECTIVE: To reach a European consensus on the definition and characterization of the main organ-specific extraglandular manifestations in primary SS. METHODS: The EULAR-SS Task Force Group steering committee agreed to approach SS-related systemic involvement according to the EULAR SS Disease Activity Index (ESSDAI) classification and proposed the preparation of four separate manuscripts: articular, cutaneous, pulmonary and renal ESSDAI involvement; muscular, peripheral nervous system, CNS and haematological ESSDAI involvement; organs not included in the ESSDAI classification; and lymphoproliferative disease. Currently available evidence was obtained by a systematic literature review focused on SS related systemic features. RESULTS: The following information was summarized for articular, cutaneous, pulmonary and renal involvement: a clear, consensual definition of the clinical feature, a brief epidemiological description including an estimate of the prevalence reported in the main clinical series and a brief list of the key clinical and diagnostic features that could help physicians clearly identify these features. Unfortunately we found that the body of evidence relied predominantly on information retrieved from individual cases, and the scientific information provided was heterogeneous. The analysis of types of involvement was biased due to the unbalanced reporting of severe cases over non severe cases, although the main sources of bias were the heterogeneous definitions of organ involvement (or even the lack of definition in some studies) and the heterogeneous diagnostic approach used in studies to investigate involvment of each organ. CONCLUSION: The proposals included in this article are a first step to developing an optimal diagnostic approach to systemic involvement in primary SS and may pave the way for further development of evidence-based diagnostic and therapeutic guidelines. PMID- 26231346 TI - Interleukin-35 is upregulated in systemic sclerosis and its serum levels are associated with early disease. AB - OBJECTIVES: IL-35 is a member of the IL-12 family consisting of p35/IL-12a and EBI3/IL-27b subunits. IL-35 exerts immunomodulatory activities in experimental and human autoimmune inflammatory conditions. Our aim was to assess IL-35 expression in the skin and circulation of SSc patients and to characterize its potential association with SSc-related features. METHODS: Expression of IL-35 in skin and dermal fibroblasts was quantified by quantitative PCR, immunohistochemistry and immunofluorescence. Serum levels of IL-35 (by ELISA), CRP (by turbidimetry), ANA (by immunofluorescence) and autoantibodies of the ENA complex (by immunoblot) were measured in 40 SSc patients. Serum IL-35 was determined in 40 age- and sex-matched healthy controls. RESULTS: IL-35 expression was increased in SSc skin and dermal fibroblasts in a TGF-beta-dependent manner. IL-35 induced an activated phenotype in resting fibroblasts and enhanced the release of collagen. IL-35 serum levels were increased in patients with SSc compared with healthy controls [median 83.9 (interquartile range 45.1-146.1) vs 36.2 (interquartile range 17.2-49.4) pg/ml, P < 0.0001]. Serum IL-35 was negatively correlated with disease duration (r = -0.4339, P = 0.0052). In line with this finding, serum IL-35 was increased in patients with an early SSc pattern on capillaroscopy assessment compared with those with active and late SSc patterns. CONCLUSION: The present study demonstrates overexpression of IL-35 in SSc skin, dermal fibroblasts and serum. TGF-beta induces IL-35, which in turn activates resting fibroblasts and enhances the release of collagen, thereby contributing to aberrant TGF-beta signalling in SSc. Increased serum IL-35 is associated with early, inflammatory stages of SSc. PMID- 26231347 TI - David Oliver: Is the NHS at war? PMID- 26231348 TI - Capturing Polyradical Protein Cations after an Electron Capture Event: Evidence for their Stable Distonic Structures in the Gas Phase. AB - We report on the formation and "capture" of polyradical protein cations after an electron capture event. Performed in a unique electron-capture dissociation (ECD) instrument, these experiments can generate reduced forms of multiply protonated proteins by sequential charge reduction using electrons with ~1 eV. The true structures of these possible polyradicals is considered: Do the introduced unpaired electrons recombine quickly to form a new two-electron bond, or do these unpaired electrons exist as radical sites with appropriate chemical reactivity? Using an established chemical probe--radical quenching with molecular oxygen--we demonstrate that these charge-reduced protein cations are indeed polyradicals that form adducts with up to three molecules of oxygen (i.e., tri-radical protein cations) that are stable for at least 100 ms. PMID- 26231349 TI - Effects of Tanshinone IIA on osteogenic differentiation of mouse bone marrow mesenchymal stem cells. AB - Tanshinone IIA (TSA) is a lipophilic diterpene purified from the Chinese herb Danshen, which exhibits potent antioxidant and anti-inflammatory properties. Effect of TSA remains largely uninvestigated on the osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs), which are widely used in cell-based therapy of bone diseases. In the present study, both ALP activity at day 7 and calcium content at day 24 were upregulated during the osteogenesis of mouse BM MSCs treated with TSA (1 and 5 MUM), demonstrating that it promoted the osteogenesis at both early and late stages. We found that TSA promoted osteogenesis and inhibited osteoclastogenesis, evident by RT-PCR analysis of osteogenic marker gene expressions. However, osteogenesis was inhibited by TSA at 20 MUM. We further revealed that TSA (1 and 5 MUM) upregulated BMP and Wnt signaling. Co-treatment with Wnt inhibitor DKK-1 or BMP inhibitor noggin significantly decreased the TSA-promoted osteogenesis, indicating that upregulation of BMP and Wnt signaling plays a significant role and contributes to the TSA-promoted osteogenesis. Of clinical interest, our study suggests TSA as a promising therapeutic strategy during implantation of BM-MSCs for a more effective treatment of bone diseases. PMID- 26231350 TI - Adolescent exercise in association with mortality from all causes, cardiovascular disease, and cancer among middle-aged and older Chinese women. AB - BACKGROUND: Little is known regarding the role of early-life exercise, a potentially modifiable factor, in long-term adult morbidity and mortality. We utilized the Shanghai Women's Health Study (SWHS) to investigate adolescent exercise in association with cancer, cardiovascular disease (CVD), and all-cause mortality among middle-aged and older women. METHODS: The SWHS is a prospective cohort of 74,941 Chinese women ages 40 to 70 years recruited from 1996 to 2000. In-person interviews at enrollment assessed adolescent and adult exercise history, medical and reproductive history, and other lifestyle and socioeconomic (SES) factors. Mortality follow-up occurs via annual linkage to the Shanghai Vital Statistics Registry. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were derived from Cox regression models. RESULTS: Adjusting for birth year and other adolescent factors, adolescent exercise was associated with reduced risk of cancer, CVD, and total mortality [HRs (95% CI), 0.83 (0.72-0.95), 0.83 (0.70-0.98), and 0.78 (0.71-0.85), respectively for <=1.33 hours (h)/week, and 0.83 (0.74-0.93), 0.62 (0.53-0.72), and 0.71 (0.66-0.77), respectively for >1.33 h/week (reference = none)]. Results were attenuated after adjustment for adult SES and lifestyle factors. Participation in sports teams was inversely associated with cancer mortality [HR (95% CI), 0.86 (0.76-0.97)]. Joint adolescent and adult exercise was associated with reduced risk of all-cause, CVD, and cancer mortality [HRs (95% CIs), 0.80 (0.72-0.89), 0.83 (0.69-1.00), and 0.87 (0.74-1.01), respectively], adjusting for adult/adolescent factors, and adolescence exercise only was inversely associated with cancer mortality [HR (95% CI), 0.84 (0.71-0.98)]. CONCLUSIONS: Adolescent exercise participation, independent of adult exercise, was associated with reduced risk of cancer, CVD, and all-cause mortality. IMPACT: Results support promotion of exercise in adolescence to reduce mortality in later life. PMID- 26231352 TI - Is preoperative staging enough to guide lymph node dissection in clinically early gastric cancer? AB - BACKGROUND: Limited by the accuracy of preoperative staging, some cases of gastric cancer invading the muscularis propria (pT2) are underestimated as early gastric cancer (EGC) in the preoperative assessment. The aim of this present study was to determine prognostic factors and to propose indications for limited lymph node dissection in patients with clinically EGC (cEGC). METHODS: Patients of cEGC (n = 2072) who were postoperatively diagnosed as pT1 (cT1pT1, n = 1858) and pT2 (cT1pT2, n = 214) from 2005 to 2009 at Seoul National University Hospital were retrospectively analyzed. RESULTS: There was no difference in 5-year survival rate between the cT1pT1 and cT1pT2 group (95.5 % vs. 92.5 %, P = 0.059), and both groups had better overall survival than pT2 patients who were preoperatively diagnosed as locally advanced gastric cancer (cT2-4pT2), whose 5 year survival rate was 78.0 % (P < 0.001). Multivariate analysis indicated lymph node metastasis (LNM) was the independent prognostic factor for cEGC (P < 0.001). In cEGC patients, three preoperative factors, including N stage by multidetector row computed tomography (MDCT) (P < 0.001), preoperative histological type (P < 0.001), and tumor size (P < 0.001), were associated with LNM by multivariate analysis. Regarding the possibility of LNM, low-risk (4.4 %) and high-risk (17.3 %) groups were developed based on weighted scores of the aforementioned independent three variables. Among 52 patients in the low-risk group, the extension of LNM was limited to the perigastric area. CONCLUSIONS: Comprehensive evaluation based on MDCT, preoperative histological type, and tumor size is an effective method to predict LNM and guide tailored LN dissection for cEGC. PMID- 26231351 TI - Difficulties in deciding whether to ablate patients with putatively "low intermediate-risk" differentiated thyroid carcinoma: do guidelines mainly apply in the centres that produce them? Results of a retrospective, two-centre quality assurance study. AB - PURPOSE: We determined the reasons for radioiodine thyroid remnant ablation, and the procedure's necessity based on postsurgical remnant size, in patients with putatively "low-intermediate-risk" differentiated thyroid carcinoma (DTC). We identified key clinicopathological, treatment and remnant characteristics, and factors associated with remnant size in 336 patients with pT1/2, M0 DTC ablated during the period September 2010 to October 2013 at one Cypriot or one Greek referral centre. METHODS: Clinicopathological/treatment characteristics were compiled from charts. Experienced nuclear medicine physicians rated the numbers/intensities of uptake foci in the thyroid bed on postablation planar scintigrams using scales of 0-4 points and 0-3 points, respectively. The product of these scores was taken as the "remnant score" that ranged from 0 (no remnant) to 12 (multiple remnants, intense uptake). RESULTS: DTC was predominantly papillary. The median [25th-75th percentile] longest primary tumour diameter was 1.0 cm [0.7-1.5 cm]. Despite favourable histotypes and primary tumour classifications, patients often had preablation characteristics suggesting elevated or uncertain risk: 31.0% of patients (104 of 336) had primary tumour multifocality, 22.0% (74) had confirmed cervical lymph node metastases, 37.2% (125) had unknown nodal status, and 38.1% (128) had antithyroglobulin antibody seropositivity. The median [25th-75th percentile] remnant score was 4 [2-6]; 39.9% of patients (134 of 336) had scores >=6. For the entire cohort, T or N stages (r <= 0.174, P <= 0.05) correlated positively with the remnant score in a univariate Spearman analysis. The numbers of patients referred by the surgeon, cervical lymph nodes excised and metastatic nodes excised correlated negatively (r <= 0.243, P <= 0.038) with the remnant score, and the first two factors independently predicted the remnant score (P <= 0.037) in a multivariate analysis. CONCLUSION: Patients with putatively "low-intermediate-risk" DTC frequently had disease characteristics denoting high or uncertain risk, suggesting that "selective" radioiodine ablation in such patients may seldom be applicable outside international centres of excellence. Proxies for surgeon experience and surgical completeness correlated with remnant number/uptake intensity and may aid ablation-related decision-making. PMID- 26231353 TI - Liver-directed treatments for liver metastasis from gastric adenocarcinoma: comparison between liver resection and radiofrequency ablation. AB - BACKGROUND: Although various liver-directed treatment modalities, such as liver resection and radiofrequency ablation (RFA), have been applied to treat liver metastases from gastric cancer, optimal management of them remains controversial. In patients with liver metastasis from gastric cancer, we investigated the short- and long-term outcomes of liver resection and RFA and analyzed factors influencing survival. METHODS: A total of 98 gastric cancer patients with liver metastasis and no extrahepatic disease were treated by liver resection (n = 68) or RFA (n = 30). Short- and long-term outcomes were evaluated retrospectively for each of the liver-directed treatments. RESULTS: Severe complication rates did not differ between liver resection (18 %) and RFA (10 %) (p = 0.333). Only one treatment-related mortality occurred in the liver resection group. No statistically significant difference in survival was noted between the treatment groups. Median overall survival after liver resection was 24 months, with 3-year overall and progression-free survival rates of 40.6 % and 30.4 %, respectively. Median overall survival after RFA was 23 months, with 3-year overall and progression-free survival rates of 43.0 % and 37.4 %, respectively. Only the size of the metastases was shown to be an independent prognostic factor for gastric cancer patients with liver metastasis. CONCLUSIONS: In select patients with liver metastasis from gastric cancer, liver resection and RFA showed satisfactory and comparable short- and long-term results. Thus, systemic chemotherapy may not be the only therapeutic option for patients with liver metastasis, and possible liver-directed treatment options for such patients should be considered on an individual basis. PMID- 26231355 TI - Next-Generation STR Genotyping Kits for Forensic Applications. AB - Forensic DNA typing has been a constantly evolving field driven by innovations from academic laboratories as well as kit manufacturers. Central to these technological advances has been the transition from multilocus-probe restriction fragment length polymorphism (RFLP) methods to short tandem repeat (STR) PCR based assays. STRs are now the markers of choice for forensic DNA typing and a wide variety of commercial STR kits have been designed to meet the various needs of a forensic lab. This review provides an overview of the commercial STR kits made available since the year 2000 and explains the rationale for creating these kits. Substantial progress has been made in key areas such as sample throughput, speed, and sensitivity. For example, a significant advancement for databasing labs was the capability of direct amplification from a blood or buccal sample without need for DNA extraction or purification, enabling increased throughput. Other key improvements are greater tolerance for inhibitors (e.g., humic acid, hematin, and tannic acid) present in evidence samples, PCR cycling times decreased by 1-1.5 h, and greater sensitivity with improved buffer components and thermal cycling conditions. These improvements that have been made over the last 11 years have enhanced the ability of forensic laboratories to obtain a DNA profile from more challenging samples. However, with the proliferation of kits from different vendors the primer binding sequences of the loci vary, which could result in discordant events that would need to be resolved either via a database driven software solution or simply by evaluating discordant samples with multiple kits. PMID- 26231354 TI - Participation needs of older adults having disabilities and receiving home care: met needs mainly concern daily activities, while unmet needs mostly involve social activities. AB - BACKGROUND: Participation is a key determinant of successful aging and enables older adults to stay in their homes and be integrated into the community. Assessing participation needs involves identifying restrictions in the accomplishment of daily and social activities. Although meeting participation needs involves older adults, their caregivers and healthcare providers, little is known about their respective viewpoints. This study thus explored the participation needs of older adults having disabilities as perceived by the older adults themselves, their caregivers and healthcare providers. METHODS: A qualitative multiple case study consisted of conducting 33 semi-structured interviews in eleven triads, each composed of an older adult, his/her caregiver and a healthcare provider recruited in a Health and Social Services Centre (HSSC) in Quebec, Canada. Interview transcripts and reviews of clinical records were analyzed using content analysis and descriptive statistics based on thematic saliency analysis methods. RESULTS: Aged 66 to 88 years, five older adults had physical disabilities, five had mild cognitive impairment and one had psychological problems, leading to moderate to severe functional decline. Caregivers and healthcare providers were mainly women, respectively retired spouses and various professionals with four to 32 years of clinical experience. Participation needs reported by each triad included all domains of participation. Needs related to daily activities, such as personal care, nutrition, and housing, were generally met. Regarding social activities, few needs were met by various resources in the community and were generally limited to personal responsibilities, including making decisions and managing budgets, and some community life activities, such as going shopping. Unmet needs were mainly related to social activities, involving leisure, other community life activities and interpersonal relationships, and some daily activities, including fitness and mobility. CONCLUSIONS: This study highlights the complexity of older adults' participation needs, involving daily as well as social activities. Properly assessing and addressing these needs is thus necessary to improve older adults' health and well-being. Discrepancies in the various actors' perceptions of participation needs must be further explored. Additional research would help better understand how to optimize the contribution of community organizations and caregivers. PMID- 26231356 TI - Biology and Genetics of New Autosomal STR Loci Useful for Forensic DNA Analysis. AB - Short tandem repeats (STRs) are regions of tandemly repeated DNA segments found throughout the human genome that vary in length (through insertion, deletion, or mutation) with a core repeated DNA sequence. Forensic laboratories commonly use tetranucleotide repeats, containing a four base pair (4-bp) repeat structure such as GATA. In 1997, the Federal Bureau of Investigation (FBI) Laboratory selected 13 STR loci that form the backbone of the U.S. national DNA database. Building on the European expansion in 2009, the FBI announced plans in April 2011 to expand the U.S. core loci to as many as 20 STRs to enable more global DNA data sharing. Commercial STR kits enable consistency in marker use and allele nomenclature between laboratories and help improve quality control. The STRBase website, maintained by the U.S. National Institute of Standards and Technology (NIST), contains helpful information on STR markers used in human identity testing. PMID- 26231357 TI - Application of Autosomal SNPs and Indels in Forensic Analysis. AB - The potential applications of short binary markers to forensic analysis are reviewed. Short binary markers are the most common human genomic variation and include single nucleotide polymorphisms (SNPs) and insertion/deletion polymorphisms (Indels). This review outlines their use and performance in typing highly degraded DNA - the original rationale for developing SNPs for forensic analysis - as well as their ability to infer the ancestry or likely pigmentation characteristics of an individual not present on a national DNA database, thus potentially providing investigative leads. Throughout the review, reference is made to short Indels as a new and potentially powerful alternative to SNPs for enhancing short tandem repeat (STR) results by using a simple amplification to capillary electrophoresis (PCR-to-CE) technique that retains the direct relationship between input DNA and signal strength, offering much improved mixture-detection capabilities while retaining the favorable characteristics of short amplicon PCR. PMID- 26231358 TI - Additional Y-STRs in Forensics: Why, Which, and When. AB - Male-specific DNA profiling using nonrecombining Y-chromosomal genetic markers is becoming ubiquitous in forensic genetics, with many laboratories and jurisdictions taking advantage of the benefits that Y-chromosome short tandem repeat (Y-STR) profiling can bring. The current suite of 9-17 core Y-STRs, available as commercial kits, perform adequately for identifying male lineages in many populations, a feature highly suitable for excluding a male suspect from involvement in crimes such as sexual assaults where autosomal STR profiling is often troubled. However, there is a growing need to achieve higher resolution in paternal-lineage differentiation as adventitious matches between unrelated males are becoming increasingly common with the increasing size of Y-STR haplotype frequency databases. Furthermore, with the currently used Y-STRs, male relatives (both close and distant) usually cannot be separated, marking a strong limitation in forensic applications as conclusions cannot be drawn on the individual level as desired. Performing Y-chromosome analysis in familial testing, which outperforms autosomal STR profiling in certain deficiency cases, with the current Y-STR sets can be troubled by mutations that complicate relationship-probability estimations. To overcome these limitations, considerable research has been performed over recent years to identify and characterize additional Y-STRs. This review summarizes the forensic performance of current sets of Y-STRs, points out their limitations in the three main areas of forensic Y-STR applications (male lineage differentiation, male-relative differentiation, and paternity/familial testing), and discusses why and which additional Y-STRs are suitable to improve forensic Y-chromosome analysis in the future. PMID- 26231359 TI - Hidden Variation in Microsatellite Loci: Utility and Implications for Forensic DNA Analysis. AB - Short tandem repeat (STR) analysis has been the standard in forensic DNA examinations for almost 15 years. The purpose of this article is to provide some perspective on the biological nature of STR alleles themselves, examine underlying distributions of alleles in the STR loci that are routinely used, and to discuss features of these alleles that are not observable with the currently employed methods. Many of the internationally standardized STR loci contain variations of their interrupted repeat structures, either due to the compound or complex nature of the locus or due to nucleotide variations within the simple repeat motif, which inevitably leads them to become more stratified at the population level. Current STR typing procedures utilizing PCR amplification followed by fragment analysis via capillary or gel electrophoresis does not provide the resolution to discern these polymorphisms. Thus, current designation of alleles is operationally and not biologically defined. Although in the comparison of an evidentiary STR profile to that of a potential contributor, the biological nature of the allele may not be of consequence. When comparisons require assumptions of relatedness between individuals, the biological nature of shared alleles becomes an underlying focus. Herein we will discuss the nature of these additional allelic polymorphisms, what is known of their distribution among the STR loci utilized in forensic testing and within populations, and the advantages this level of allelic discrimination has in forensic and relationship testing. PMID- 26231360 TI - Identification of genes associated with shell color in the black-lipped pearl oyster, Pinctada margaritifera. AB - BACKGROUND: Color polymorphism in the nacre of pteriomorphian bivalves is of great interest for the pearl culture industry. The nacreous layer of the Polynesian black-lipped pearl oyster Pinctada margaritifera exhibits a large array of color variation among individuals including reflections of blue, green, yellow and pink in all possible gradients. Although the heritability of nacre color variation patterns has been demonstrated by experimental crossing, little is known about the genes involved in these patterns. In this study, we identify a set of genes differentially expressed among extreme color phenotypes of P. margaritifera using a suppressive and subtractive hybridization (SSH) method comparing black phenotypes with full and half albino individuals. RESULTS: Out of the 358 and 346 expressed sequence tags (ESTs) obtained by conducting two SSH libraries respectively, the expression patterns of 37 genes were tested with a real-time quantitative PCR (RT-qPCR) approach by pooling five individuals of each phenotype. The expression of 11 genes was subsequently estimated for each individual in order to detect inter-individual variation. Our results suggest that the color of the nacre is partially under the influence of genes involved in the biomineralization of the calcitic layer. A few genes involved in the formation of the aragonite tablets of the nacre layer and in the biosynthesis chain of melanin also showed differential expression patterns. Finally, high variability in gene expression levels were observed within the black phenotypes. CONCLUSIONS: Our results revealed that three main genetic processes were involved in color polymorphisms: the biomineralization of the nacreous and calcitic layers and the synthesis of pigments such as melanin, suggesting that color polymorphism takes place at different levels in the shell structure. The high variability of gene expression found within black phenotypes suggests that the present work should serve as a basis for future studies exploring more thoroughly the expression patterns of candidate genes within black phenotypes with different dominant iridescent colors. PMID- 26231361 TI - Epigenetic Signatures as Biomarkers of Exposure. AB - To advance our knowledge of the influence of environmental exposures on human health and disease, robust studies are needed. However, for many exposures, robust studies are not feasible due to limitations with current ascertainment methods and/or study designs. Epigenetics, the study of mitotically heritable, reversible information that regulates critical cell processes, has gained much attention because it offers a potential mechanism to explain how exposures can influence cell states. Therefore, most studies have focused on epigenetics as a mechanism for disease. However, emerging evidence also suggests that epigenetic marks may also serve as biomarkers of exposure. Here, we highlight findings showing that the epigenome is labile to the environment and that these exposure associated changes show long-term stability, are specific, are detectable in accessible tissues, can predict exposure status, and can be practically implemented, thus supporting the potential for epigenetic patterns to serve as robust measures of environmental exposure. PMID- 26231362 TI - Select Prenatal Environmental Exposures and Subsequent Alterations of Gene Specific and Repetitive Element DNA Methylation in Fetal Tissues. AB - Strong evidence implicates maternal environmental exposures in contributing to adverse outcomes during pregnancy and later in life through the developmental origins of health and disease hypothesis. Recent research suggests these effects are mediated through the improper regulation of DNA methylation in offspring tissues, specifically placental tissue, which plays a critical role in fetal development. This article reviews the relevant literature relating DNA methylation in multiple tissues at or near delivery to several prenatal environmental toxicants and stressors, including cigarette smoke, endocrine disruptors, heavy metals, as well as maternal diet. These human studies expand upon previously reported outcomes in animal model interventions and include effects on both imprinted and non-imprinted genes. We have also noted some of the strengths and limitations in the approaches used, and consider the appropriate interpretation of these findings in terms of their effect size and their relationship to differential gene expression and potential health outcomes. The studies suggest an important role of DNA methylation in mediating the effects of the intrauterine environment on children's health and a need for additional research to better clarify the role of this epigenetic mechanism as well as others. PMID- 26231363 TI - Arsenic Exposure and Epigenetic Alterations: Recent Findings Based on the Illumina 450K DNA Methylation Array. AB - Arsenic is a major public health concern worldwide. While it is an established carcinogen and associated with a number of other adverse health outcomes, the molecular mechanisms underlying arsenic toxicity are not completely clarified. There is mounting evidence from human studies suggesting that arsenic exposure is associated with epigenetic alterations, including DNA methylation. In this review, we summarize several recent human studies that have evaluated arsenic exposure using the Illumina HumanMethylation 450K BeadChip, which interrogates more than 485,000 methylation sites across the genome. Many of these studies have observed novel regions of the genome associated with arsenic exposure. However, few studies have evaluated the biological and functional relevance of these DNA methylation changes, which are still needed. We emphasize the need for future studies to replicate the identified DNA methylation signals as well as assess whether these markers are associated with risk of arsenic-related diseases. PMID- 26231364 TI - DNA Methylation in Whole Blood: Uses and Challenges. AB - Due to its convenience, the blood is commonly used in epigenomic studies, but its heterogeneous nature leads to interpretation difficulties, given the now widely recognized potential for confounding by cell composition effects. Many recent publications have reported significant associations between DNA methylation and a variety of health conditions or exposures. In this review, we summarize many of these recent publications, highlighting the findings in the context of potential cell composition effects, particularly findings that are indicative of immune response or inflammation. While there is substantial evidence for confounding by cell composition, there is nevertheless also evidence for differential DNA methylation suggestive of processes that are not cell mediated. We conclude that important biological insights still may be gained from studying DNA methylation in whole blood, either by investigating the cell composition effects themselves or processes that demonstrate associations even after adjusting for cell composition effects. PMID- 26231365 TI - The Role of the Epigenome in Translating Neighborhood Disadvantage Into Health Disparities. AB - The possible causal role of the environment in health disparities is not well understood, even though it has been a national priority for many years. Progress to investigate the relationship between genetics, environmental exposures, and health outcomes has been hampered by the lack of analytical tools to quantify the combined or cumulative effect of multiple chemical and non-chemical stressors on gene expression. The studies cited here provide a strong rationale for using epigenomic analysis to assess cumulative risk from multiple environmental exposures over the life course. The environment-specific "imprints" on the genome, coupled with transcriptomics and metabolomics, can be used to advance our understanding of the relationship between neighborhood disadvantage and health disparities. PMID- 26231366 TI - Health Effects of Noise Exposure in Children. AB - Environmental noise exposure, such as road traffic noise and aircraft noise, is associated with a range of health outcomes in children. Children demonstrate annoyance responses to noise, and noise is also related to lower well-being and stress responses, such as increased levels of adrenaline and noradrenaline. Noise does not cause more serious mental health problems, but there is growing evidence for an association with increased hyperactivity symptoms. Studies also suggest that noise might cause changes in cardiovascular functioning, and there is some limited evidence for an effect on low birth weight. There is robust evidence for an effect of school noise exposure on children's cognitive skills such as reading and memory, as well as on standardised academic test scores. Environmental noise does not usually reach levels that are likely to affect children's hearing; however, increasing use of personal electronic devices may leave some children exposed to harmful levels of noise. PMID- 26231367 TI - Effect of Gene-Mercury Interactions on Mercury Toxicokinetics and Neurotoxicity. AB - Individuals differ in susceptibility to mercury neurotoxicity, in part, due to underlying genetic differences. This review aims to evaluate the state-of-the-art of the effect of (1) genetics on mercury toxicokinetics and (2) gene-mercury interactions on neurodevelopment and neurotoxicity. We conducted a PubMed search in September 2014 and retrieved 14 studies on the influence of genetics on mercury toxicokinetics and ten on neurological effects of gene-mercury interactions. Genes frequently studied for their influence on mercury toxicokinetics were mainly related to the metabolism of glutathione, but the results were contradictory for most of the genes. The gene-mercury interactions on child neurodevelopment and adult neurotoxicity reported were too few to draw any definite conclusion. So far, candidate gene approaches have not identified any major gene/s modifying the kinetics or toxicity of mercury, suggesting that these might be polygenic traits. More research is highly warranted to clarify if there are vulnerable subgroups to mercury neurotoxicity in humans. PMID- 26231368 TI - The Pregnancy Exposome. AB - The exposome concept takes a holistic approach facilitated by new and emerging technologies to describe 'the totality of human environmental (i.e. non-genetic) exposures from conception onwards, complementing the genome'. It provides a framework to advance the environmental epidemiology field that has until now focused almost exclusively on single-exposure health effects. The exposome includes an external domain, measured by methods including geo-spatial modelling, questionnaire and biomonitoring of external exposures while the internal domain is commonly assessed through molecular omics platforms. The internal domain, in part, reflects the biological response to the external domain. New statistical frameworks are required to integrate and assess exposome-health effects. The pregnancy period is a key starting point to describe the dynamic exposome, due to its heightened sensitivity and potential lifetime impact. A handful of studies have started to move towards an exposome approach in assessing the effects of the multiple exposures during pregnancy on child development. New research projects are underway to test the exposome approach on a large scale. PMID- 26231369 TI - Contraceptive adoption in the extended postpartum period is low in Northwest Ethiopia. AB - BACKGROUND: The extended postpartum period is a one year period after delivery which is critical for women to prevent unintended pregnancy and to reduce the risk of maternal and child mortality by ensuring safe birth intervals. Studies indicate that birth intervals of three to five years reduce maternal mortality and provide health benefits to newborn babies, infants, and children. As a result, assessing postpartum contraceptive use and its determinants are an increasingly important component of global health. The objectives of the study were to determine postpartum contraceptive use and identify the variables which affect postpartum contraceptive use among women of Dabat district. METHODS: All women aged 15 to 49 years who delivered a child between January 1, 2012 and December 31, 2012 in the Debat district were interviewed by house-to- house survey. RESULTS: A total of 10.3 % of the mothers reported adopting contraception in the extended postpartum period. Women who delivered with the assistance of a skilled attendant [AOR = 1.88, 95 % CI (1.01-3.51)] and attended postnatal care services [AOR = 2.19, 95 % CI (1.06-4.52)] were more likely to use contraceptives. Secondary and above level of the husband's education was also a variable that significantly affected postpartum contraceptive use [AOR = 2.98, 95 % CI (1.49-5.97)]. CONCLUSIONS: Contraceptive use in the extended postpartum period was found to be low placing women at risk for a pregnancy in the extended postpartum period. Advice about contraceptives during postnatal clinic visits was limited. Improving utilization of institutional delivery by a skilled attendant and enhancing postnatal care services are important to increase contraceptive use in the extended postpartum period. PMID- 26231370 TI - Antibacterial potential of a small peptide from Bacillus sp. RPT-0001 and its capping for green synthesis of silver nanoparticles. AB - Infirmity and death from diseases caused by unsafe food are a continual hazard to communal health safety and socio-economic growth throughout the world. Chemical preservatives are associated with health hazards and toxicity issues. In the study reported here, 200 soil isolates from Western Himalayan region in India were screened for potential antibacterial activity against food-borne pathogens. This study led to the isolation of a bacterial strain belonging to the Genus Bacillus and was designated as RPT-0001. The associated antibacterial activity was sensitive to pronase E treatment. Bioassay-guided fractionation using reverse phase high performance liquid chromatography (RP-HPLC) led to isolation of the antibacterial peptide designated as RPT-0001. The molecular weight of RPT-0001 was determined by electro-spray ionization mass spectroscopy (ESI-MS) as 276.9 Da. RPT-0001 was inhibitory to both Gram-negative and Grampositive food-borne bacteria tested. The characteristics of RPT-0001 do not match with that of any other known antibacterial peptides produced by Bacillus sp. or related genera. Purified RPT-0001 was successfully used in synthesis of silver nanoparticles effective against food-borne pathogenic bacteria. The antibacterial peptide and silver nanoparticles synthesized utilizing it as a capping and reducing agent hold promising potential in food preservation, in packaging material and as a therapeutic agent in the treatment of foodborne infections. PMID- 26231371 TI - Transcriptional profiles of laccase genes in the brown rot fungus Postia placenta MAD-R-698. AB - One of the laccase isoforms in the brown rot fungus Postia placenta is thought to contribute to the production of hydroxyl radicals, which play an important role in lignocellulose degradation. However, the presence of at least two laccase isoforms in this fungus makes it difficult to understand the details of this mechanism. In this study, we systematically investigated the transcriptional patterns of two laccase genes, Pplcc1 and Pplcc2, by quantitative PCR (qPCR) to better understand the mechanism. The qPCR results showed that neither of the two genes was expressed constitutively throughout growth in liquid culture or during the degradation of a woody substrate. Transcription of Pplcc1 was upregulated under nitrogen depletion and in response to a high concentration of copper in liquid culture, and during the initial colonization of intact aspen wafer. However, it was subject to catabolite repression by a high concentration of glucose. Transcription of Pplcc2 was upregulated by stresses caused by ferulic acid, 2, 6-dimethylbenzoic acid, and ethanol, and under osmotic stress in liquid culture. However, the transcription of Pplcc2 was downregulated upon contact with the woody substrate in solid culture. These results indicate that Pplcc1 and Pplcc2 are differentially regulated in liquid and solid cultures. Pplcc1 seems to play the major role in producing hydroxyl radicals and Pplcc2 in the stress response during the degradation of a woody substrate. PMID- 26231372 TI - D101 is critical for the function of AttJ, a repressor of quorum quenching system in Agrobacterium tumefaciens. AB - The quorum quenching system of Agrobacterium tumefaciens is specifically activated upon entering the stationary phase. Evidence has shown that this system includes two key components: the IclR-type transcriptional factor AttJ (also named as BlcR) and the AHL-lactonase AttM (also named as BlcC). At exponential phase, AttJ binds to the promoter region of attM and thus suppresses the expression of attM. At stationary phase, however, the small molecule SSA directly binds to AttJ and relieves its inhibition of AttJ and thereby triggers the expression of attM. While the regulation of AttM has been extensively investigated, little is known about the regulation of AttJ. In this study, we demonstrated the D101 amino acid of AttJ is essential for the AttJ function. In vitro, the variant protein of AttJD101H appeared to be readily aggregated. In vivo, the D101H mutation in AttJ entirely abolished the inhibitory activity of AttJ and overexpressed attM in A. tumefaciens A6. In addition, D101H mutation led to an overexpression of attJ, indicating an auto-regulatory mechanism for the attJ regulation. Put together, these findings demonstrate that D101 is an important amino acid for the transcription activity of AttJ and the transcription of attJ is regulated by a negative feedback loop. These results expand previous biochemical characterization of AttJ and provide new mechanistic insights into the regulation of quorum quenching in A. tumefaciens. PMID- 26231373 TI - Pregnancy - associated human listeriosis: Virulence and genotypic analysis of Listeria monocytogenes from clinical samples. AB - Listeria monocytogenes, a life-threatening pathogen, poses severe risk during pregnancy, may cause abortion, fetal death or neonatal morbidity in terms of septicemia and meningitis. The present study aimed at characterizing L. monocytogenes isolated from pregnant women based on serotyping, antibiotic susceptibility, virulence genes, in vivo pathogenicity test and ERIC- and REP-PCR fingerprint analyses. The results revealed that out of 3700 human clinical samples, a total of 30 (0.81%) isolates [12 (0.80%) from placental bit (1500), 18 (0.81%) from vaginal swab (2200)] were positive for L. monocytogenes. All the isolates belonged to serogroup 4b, and were + ve for virulence genes tested i.e. inlA, inlC, inlJ, plcA, prfA, actA, hlyA, and iap. Based on the mice inoculation tests, 20 isolates showed 100% and 4 isolates 60% relative virulence while 6 isolates were non-pathogenic. Moreover, 2 and 10 isolates were resistant to ciprofloxacin and cefoxitin, respectively, while the rest susceptible to other antibiotics used in this study. ERIC- and REP-PCR collectively depicted that the isolates from placental bit and vaginal swab had distinct PCR fingerprints except a few isolates with identical patterns. This study demonstrates prevalence of pathogenic strains mostly resistant to cefoxitin and/or ciprofloxacin. The results indicate the importance of isolating and characterizing the pathogen from human clinical samples as the pre-requisite for accurate epidemiological investigations. PMID- 26231374 TI - The cAMP/protein kinase A signaling pathway in pathogenic basidiomycete fungi: Connections with iron homeostasis. AB - A number of pathogenic species of basidiomycete fungi are either life-threatening pathogens of humans or major economic pests for crop production. Sensing the host is a key aspect of pathogen proliferation during disease, and signal transduction pathways are critically important for detecting environmental conditions and facilitating adaptation. This review focuses on the contributions of the cAMP/protein kinase A (PKA) signaling pathway in Cryptococcus neoformans, a species that causes meningitis in humans, and Ustilago maydis, a model phytopathogen that causes a smut disease on maize. Environmental sensing by the cAMP/PKA pathway regulates the production of key virulence traits in C. neoformans including the polysaccharide capsule and melanin. For U. maydis, the pathway controls the dimorphic transition from budding growth to the filamentous cell type required for proliferation in plant tissue. We discuss recent advances in identifying new components of the cAMP/PKA pathway in these pathogens and highlight an emerging theme that pathway signaling influences iron acquisition. PMID- 26231375 TI - Regulation and function of the Salmonella MgtC virulence protein. AB - Salmonella enterica serovar Typhimurium produces many virulence proteins to cause diseases. The Salmonella MgtC protein is one of such virulence proteins specially required for intracellular proliferation inside macrophages and mouse virulence. In this review, we will cover how the mgtC gene is turned on or off and what the signals required for mgtC expression are. Later in this review, we will discuss a recent understanding of MgtC function in Salmonella pathogenesis by identifying its target proteins. PMID- 26231376 TI - A prospective, longitudinal, observational cohort study examining how glaucoma affects quality of life and visually-related function over 4 years: design and methodology. AB - BACKGROUND: The aim of this study is to summarize the design and methodology of a prospective, longitudinal, observational cohort study to investigate how glaucoma affects patients' quality of life and visually-related function over a 4-year period. METHODS/DESIGN: One hundred sixty-one (161) subjects were enrolled in this ongoing study. Patients between the ages of 21-85 years with a minimum 2 year diagnosis of primary open-angle glaucoma, chronic primary angle-closure glaucoma or pseudoexfoliation glaucoma were included. Each patient visited Wills Eye Hospital for a baseline visit. Follow-up is planned for a minimum of 4 years, with annual visits. Each visit includes (1) Clinical evaluation: a slit lamp examination, fundoscopy, intraocular pressure measurement, visual field examination, spectral domain optical coherence tomography, Pelli-Robson Contrast Sensitivity test and the Spaeth-Richman Contrast Sensitivity test; (2) a performance based measure: the Compressed Assessment of Ability Related to Vision; and (3) Subjective measures of vision-related quality of life (the National Eye Institute Visual Functioning Questionnaire 25 and the Modified Glaucoma Symptom Scale). DISCUSSION: The results of this ongoing, prospective, longitudinal study are expected to shed light on the relationships between clinical measures, performance-based measures and subjective measures of well being, in order to assess changes in the quality of life and the ability to function of patients with glaucoma over time. PMID- 26231377 TI - CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the Western world, given its association with obesity, type 2 diabetes, and dyslipidemia. Medications are widely used in NAFLD to manage comorbid conditions, and there is significant interest in developing new drug therapies to treat the disease. Despite this, little is known about the effects of NAFLD on drug metabolism. We examined the activity and expression of the major drug metabolizing enzyme subfamily, CYP3A, in subjects with NAFLD as well as in mouse and cellular models. CYP3A activity was determined in healthy volunteers and subjects with biopsy-proven NAFLD by oral midazolam phenotyping and measurement of plasma 4beta-hydroxycholesterol, an endogenous metabolic biomarker. CYP3A4 transcriptional activity, metabolic activity, and expression were also assessed in a mouse and cellular model of NAFLD. Subjects with nonalcoholic steatohepatitis (NASH) had 2.4-fold higher plasma midazolam levels compared with controls. Plasma 4beta-hydroxycholesterol was 51% and 37% lower than controls in subjects with simple steatosis and NASH, respectively. Fibrosis was associated with 57% lower plasma 4beta-hydroxycholesterol levels than controls. Furthermore, hepatic CYP3A4 mRNA expression in NASH was 69% lower than control livers. CYP3A4 gene luciferase activity in the livers of NAFLD mice was 38% lower than that of controls. Lipid-loaded Huh7 human hepatoma cells had a 38% reduction in CYP3A4 activity and 80% lower CYP3A4 mRNA expression compared with the control. CYP3A activity is reduced in human NAFLD in addition to mouse and in vitro cell models of the disease. PMID- 26231378 TI - Impact exercise and bone density in premenopausal women with below average bone density for age. AB - PURPOSE: To study the effects of two home-based impact exercise programs on areal bone mineral density (aBMD) in adult premenopausal women with below average aBMD for age (negative Z-scores; 40.8 years; n = 107). METHODS: Two unilateral impact exercise programs were employed, one targeting the total hip and lumbar spine (n = 42 pairs), the other the distal radius (n = 24 pairs) with some individuals performing both. Force plate data were used to establish exercise loading characteristics (peak loads, time to peak), dual-energy X-ray absorptiometry (DXA) provided bone data. Calcium intake, health and extraneous physical activity (PA) were determined by survey. Exercise for both hip and spine consisted of unilateral landings from adjustable steps (maximum height 63.5 cm) while impacts were delivered to the forearm by arresting falls against a wall. An exercise log was used to provide the exercise prescription, record each exercise bout and any injuries. Participants were randomly assigned to exercise or control groups and pair-matched (age, BMI, Z-score, aBMD). Compliance was calculated as the number of sessions completed divided by the total prescribed number (mean ~50 %). RESULTS: The programs delivered significant gains pre to post at each site compared with significant losses in controls (forearm: 3.9 vs -3.9 %; total hip: 2.0 vs -2.6 %; lumbar spine: 2.8 vs -2.9 % exercise and controls, respectively, all p < 0.001). No exerciser lost bone at the target site regardless of compliance which was strongly correlated with bone gains (R (2) = 0.53-0.68, all p < 0.001). CONCLUSIONS: Impact exercise provides an effective means of improving below average aBMD without supervision in this at risk population. PMID- 26231379 TI - Is the association between physical activity and healthcare utilization affected by self-rated health and socio-economic factors? AB - BACKGROUND: Physical activity and healthcare utilization has negative association. However, there appears to be limited knowledge of how this association is affected by self-rated health (SRH) and socio-economic status (SES). Therefore, the aim of this study was to examine the association between leisure-time physical activity (LTPA) and healthcare utilization, and investigate how SRH, gender, age and SES affected this association. METHODS: A cross sectional public health survey was conducted in Skane, Sweden 2012, based on a random sample with 55,000 participants (response rate 51 %; 28,028 individuals included in the study) aged 18-80 years. The data was linked to individual healthcare utilization data and socio-economic data. Logistic regression analyses were conducted to study the association between LTPA and healthcare utilization. Path analysis was used to investigate the possible mediation effect of SRH to the association between LTPA and healthcare utilization. RESULTS: Compared to sedentary leisure time the odds ratio for health care utilization decreased with increasing level of LPTA; physically active 0.89 (95 % CI: 0.81-0.96), for average exercise 0.74 (0.67-0.81) and for vigorous exercise 0.65 (0.60-0.72). The socio-economic variables attenuated this association to a small degree, but SRH had a strong impact. While the mediation analysis illustrated that the indirect effects were strong (and in the expected order so that higher levels of LTPA were more negatively associated with poor health) and highly significant, the direct effects suggested that higher levels of physical activity were more positively associated with healthcare utilization than lower levels. The indirect effects were substantially stronger than the direct effects. CONCLUSIONS: There was a significant negative association between decreased healthcare utilization and increased LPTA, and the association remained after adjustment for socio-economic variables. The mediation analysis (with SRH as the mediator between LTPA and healthcare utilization) showed that the indirect effects were strong and in the expected order, but the direct effects of LTPA on healthcare utilization was positive so that higher levels of LTPA had higher healthcare utilization. These results suggest that even though higher physical activity in total decreases the healthcare utilization, parts of the association that is not mediated through SRH actually increase healthcare utilization. PMID- 26231380 TI - STatistically Assigned Response Criteria in Solid Tumors (STARCIST). AB - BACKGROUND: Several reproducibility studies have established good test-retest reliability of FDG-PET in various oncology settings. However, these studies are based on relatively short inter-scan periods of 1-3 days while, in contrast, response assessments based on FDG-PET in early phase drug trials are typically made over an interval of 2-3 weeks during the first treatment cycle. With focus on longer, on-treatment scan intervals, we develop a data-driven approach to calculate baseline-specific cutoff values to determine patient-level changes in glucose uptake that are unlikely to be explained by random variability. Our method takes into account the statistical nature of natural fluctuations in SUV as well as potential bias effects. METHODS: To assess variability in SUV over clinically relevant scan intervals for clinical trials, we analyzed baseline and follow-up FDG-PET scans with a median scan interval of 21 days from 53 advanced stage cancer patients enrolled in a Phase 1 trial. The 53 patients received a sub pharmacologic drug dose and the trial data is treated as a 'test-retest' data set. A simulation-based tool is presented which takes as input baseline lesion SUVmax values, the variance of spurious changes in SUVmax between scans, the desired Type I error rate, and outputs lesion and patient based cut-off values. Bias corrections are included to account for variations in tracer uptake time. RESULTS: In the training data, changes in SUVmax follow an approximately zero mean Gaussian distribution with constant variance across levels of the baseline measurements. Because of constant variance, the coefficient of variation is a decreasing function of the magnitude of baseline SUVmax. This finding is consistent with published results, but our data shows greater variability. Application of our method to NSCLC patients treated with erlotinib produces results distinct from those based on the EORTC criteria. Based on data presented here as well as previous repeatability studies, the proposed method has greater statistical power to detect a significant %-decrease on SUVmax compared to published criteria relying on symmetric thresholds. CONCLUSIONS: Defining patient specific, baseline dependent cut-off values based on the (null) distribution of naturally occurring fluctuations in glucose uptake enable identification of statistically significant changes in SUVmax. For lower baseline values, the produced cutoff values are notably asymmetric with relatively large changes (e.g. >50 %) required for statistical significance. For use with prospectively defined endpoints, the developed method enables the use of one-armed trials to detect pharmacodynamic drug effects based on FDG-PET. The clinical importance of changes in SUVmax is likely to remain dependent on both tumor biology and the type of treatment. PMID- 26231381 TI - Phylogenetic relationships of Echinolaena and Ichnanthus within Panicoideae (Poaceae) reveal two new genera of tropical grasses. AB - Echinolaena and Ichnanthus are two tropical grass genera distributed mostly in the Americas, characterized by the presence of rachilla appendages in the shape of convex swellings, scars or wings at the base of the upper anthecium. However, recent studies have shown that rachilla appendages arose several times independently in several groups within Paniceae and Paspaleae (Panicoideae). Thus, this study aimed to assess the monophyly of Echinolaena and Ichnanthus and their relationship to other genera of Paniceae and Paspaleae, especially those including species with rachilla appendages. Parsimony and Bayesian analyses of the cpDNA regions ndhF, rpl16, trnH-(rps19)-psbA, trnL-trnF, trnS-(psbZ)-trnG, and the rDNA ITS region included 29 of the 39 known species of Echinolaena and Ichnanthus, 23 of which were sampled for the first time. The multiple loci analyses indicated that Echinolaena and Ichnanthus are polyphyletic in their current circumscriptions, with species in four distinct lineages within subtribe Paspalinae, each one characterized by a single type of rachilla appendage. Thus, Echinolaena and Ichnanthus are each circumscribed in a narrow sense, and the other two lineages excluded from them are proposed as the new genera Hildaea and Oedochloa, resulting in 15 new combinations and the restablishment of I. oplismenoides Munro ex Doll. PMID- 26231382 TI - Genetic diversity, paraphyly and incomplete lineage sorting of mtDNA, ITS2 and microsatellite flanking region in closely related Heliopora species (Octocorallia). AB - Examining genetic diversity and lineage sorting of different genes in closely related species provide useful information for phylogenetic analyses and ultimately for understanding the origins of biodiversity. In this study, we examined inter- and intraspecific genetic variation in internal transcribed spacer 2 (ITS2), partial mitochondrial gene (mtMutS), and nuclear microsatellite flanking region in two closely related octocoral species (Heliopora coerulea, HC A and HC-B). These species were recently identified in a population genetic study using microsatellite markers. The two species have different reproductive timing, which ecologically promotes lineage sorting. In this study, we examined whether species boundaries could be detected by the commonly used nuclear ITS2 and mtMutS, as well as by possibly neutral microsatellite flanking sequences. Haplotype network analysis of microsatellite flanking region revealed that a possible ancestral haplotype was still shared between the two species, indicating on-going lineage sorting. Haplotype network analysis of ITS2 and microsatellite flanking region revealed shared haplotypes between the two lineages. The two species shared fewer ITS2 sequences than microsatellite flanking region sequences. The almost fixed point mutation at the tip of helix 3 of ITS2 was not associated with the secondary structure or compensatory base changes (CBCs). The phylogenetic tree of ITS2 showed paraphyly and that of the microsatellite flanking region indicated that lineage sorting for the two species may be incomplete. Much higher intra- and inter-individual variation of ITS2 was observed in HC-B than that in HC-A, highlighting the importance of examining ITS2 from multiple individuals to estimate genetic diversity. The mitochondrial mtMutS gene sequences from 39 individuals, including both species collected from Japan and Taiwan, showed no variation because of slow rates of mitochondrial nucleotide substitution. This study suggests caution is warranted when reciprocal monophyly in a phylogenetic tree is used as the criterion for delimiting closely related octocoral species based on ITS2 or mtMtuS sequences. Detection of boundaries between closely related species requires multi-locus analysis, such as genetic admixture analysis using multiple individuals. PMID- 26231383 TI - The cost of prevention and treatment of pressure ulcers: A systematic review. AB - INTRODUCTION: Pressure ulcers impose a substantial financial burden. The need for high-quality health care while expenditures are constrained entails the interest to calculate the cost of preventing and treating pressure ulcers and their impact on patients, healthcare, and society. OBJECTIVES: The aim of this paper is to provide insight into the cost of pressure ulcer prevention and treatment in an adult population. METHODS: A systematic literature review was performed to conform the Cochrane Collaboration guidelines for systematic reviews. The search strategy contained index terms and key words related to pressure ulcers and cost. The search was performed in Medline, CINAHL, Web of Science, The Cochrane Library, Embase, and EconLit covering articles up to September 2013. Reference lists and conference abstracts were screened. Articles were eligible if they reported on direct medical cost of pressure ulcer prevention or treatment, and provided national cost estimates, cost per patient, or cost per patient per day. The Consensus on Health Economic Criteria checklist was used to assess methodological quality of the included studies. RESULTS: In total, 2542 records were retrieved. After assessing eligibility, 17 articles were included. Five articles reported on both the cost of prevention and treatment, three articles reported on cost of prevention, and nine articles reported on the cost of pressure ulcer treatment. All articles were published between 2001 and 2013. Cost of pressure ulcer prevention per patient per day varied between 2.65 ? to 87.57 ? across all settings. Cost of pressure ulcer treatment per patient per day ranged from 1.71 ? to 470.49 ? across different settings. The methodological heterogeneity among studies was considerable, and encompassed differences regarding type of health economic design, perspective, cost components, and health outcomes. CONCLUSIONS: Cost of pressure ulcer prevention and treatment differed considerable between studies. Although the cost to provide pressure ulcer prevention to patients at risk can importantly impact health care services' budgets, the costs to treat a severe pressure ulcer were found to be substantially higher. Methodological heterogeneity among studies identified the need to use available, and study design-specific methodological guidelines to conduct health economic studies, and the need for additional pressure ulcer specific recommendations. PMID- 26231396 TI - Building a better neonatal mouse model to understand infant respiratory syncytial virus disease. AB - BACKGROUND: Respiratory syncytial virus (RSV) is the number one cause of lower respiratory tract infection in infants; and severe RSV infection in infants is associated with asthma development. Today, there are still no vaccines or specific antiviral therapies against RSV. The mechanisms of RSV pathogenesis in infants remain elusive. This is partly due to the fact that the largely-used mouse model is semi-permissive for RSV. The present study sought to determine if a better neonatal mouse model of RSV infection could be obtained using a chimeric virus in which the F protein of A2 strain was replaced with the F protein from the line 19 clinical isolate (rA2-19F). METHODS: Five-day-old pups were infected with the standard laboratory strain A2 or rA2-19F and various immunological and pathophysiological parameters were measured at different time points post infection, including lung histology, bronchoalveolar lavage fluid (BALF) cellularity and cytokines, pulmonary T cell profile, and lung viral load. A cohort of infected neonates were allowed to mature to adulthood and reinfected. Pulmonary function, BALF cellularity and cytokines, and T cell profiles were measured at 6 days post reinfection. RESULTS: The rA2-19F strain in neonatal mice caused substantial lung pathology including interstitial inflammation and airway mucus production, while A2 caused minimal inflammation and mucus production. Pulmonary inflammation was characterized by enhanced Th2 and reduced Th1 and effector CD8(+) T cells compared to A2. As with primary infection, reinfection with rA2-19F induced similar but exaggerated Th2 and reduced Th1 and effector CD8(+) T cell responses. These immune responses were associated with increased airway hyperreactivity, mucus hyperproduction and eosinophilia that was greater than that observed with A2 reinfection. Pulmonary viral load during primary infection was higher with rA2-19F than A2. CONCLUSIONS: Therefore, rA2-19F caused enhanced lung pathology and Th2 and reduced effector CD8(+) T cell responses compared to A2 during initial infection in neonatal mice and these responses were exacerbated upon reinfection. The exact mechanism is unknown but appears to be associated with increased pulmonary viral load in rA2-19F vs. A2 infected neonatal lungs. The rA2-19F strain represents a better neonatal mouse model of RSV infection. PMID- 26231397 TI - Barriers related to non-adherence in a mammography breast-screening program during the implementation period in the interior of Sao Paulo State, Brazil. AB - Mammography is the best exam for early diagnosis of breast cancer. Developing countries frequently have a low income of mammography and absence of organized screening. The knowledge of vulnerable population and strategies to increase adherence are important to improve the implementation of an organized breast screening program. A mammography regional-screening program was implemented in a place around 54.238 women, aged 40-69 years old. It was proposed to perform biannual mammography free of cost for the women. We analyze the first 2 years of the implementation of the project. Mammography was realized in 17.964 women. 42.1% of the women hadn't done de mammography in their lives and these women were principally from low socio-economic status (OR=2.99), low education (OR=3.00). The best strategies to include these women were mobile unit (OR=1.43) and Family Health Program (OR=1.79). The incidence of early breast tumors before the project was 14.5%, a fact that changed to 43.2% in this phase. Multivariate analysis showed that the association of illiterate and the mobile unit achieve more women who had not performed mammography in their lives. The strategies to increase adherence to mammography must be multiple and a large organization is necessary to overpass the barriers related to system health and education. PMID- 26231398 TI - Spatial and non-spatial determinants of successful tuberculosis treatment outcomes: An implication of Geographical Information Systems in health policy making in a developing country. AB - This retrospective study aimed to address whether or to what extent spatial and non-spatial factors with a focus on a healthcare delivery system would influence successful tuberculosis (TB) treatment outcomes in Urmia, Iran. In this cross sectional study, data of 452 new TB cases were extracted from Urmia TB Management Center during a 5-year period. Using the Geographical Information System (GIS), health centers and study subjects' locations were geocoded on digital maps. To identify the statistically significant geographical clusters, Average Nearest Neighbor (ANN) index was used. Logistic regression analysis was employed to determine the association of spatial and non-spatial variables on the occurrence of adverse treatment outcomes. The spatial clusters of TB cases were concentrated in older, impoverished and outskirts areas. Although there was a tendency toward higher odds of adverse treatment outcomes among urban TB cases, this finding after adjusting for distance from a given TB healthcare center did not reach statistically significant. This article highlights effects of spatial and non spatial determinants on the TB adverse treatment outcomes, particularly in what way the policies of healthcare services are made. Accordingly, non-spatial determinants in terms of low socio-economic factors need more attention by public health policy makers, and then more focus should be placed on the health delivery system, in particular men's health. PMID- 26231399 TI - Estimating the potential impact fraction of hypertension as the main risk factor of stroke: Application of the distribution shift method. AB - Few published studies have assessed the impact of quantitative risk factors such as high blood pressure on stroke. The aim of this study was to quantify the potential impact fraction (PIF) of hypertension on stroke in Hamadan Province, western Iran. Avoidable burden of stroke associated with high blood pressure was calculated using distribution shift at different scenarios. Data on the prevalence of high blood pressure among residents of Hamadan province older than 19 years were extracted from non-communicable diseases risk factors surveillance system in 2009. Five mmHg hypothetical reduction in systolic blood pressure above 140 mmHg, leads to 3.5% (PIF=0.035) reduction in the total burden to stroke. This value may reach 7%, if systolic blood pressure decreases 10 mmHg. In addition, 5 mmHg hypothetical reduction in diastolic blood pressure above 82 mmHg, leads to 4.87% reduction in the total burden to stroke. PIF more than 10 mmHg modification on distribution of diastolic blood pressure was estimated as 9.38%. According to these findings, policy makers are advised to implement interventions on hypertension based on the distribution shift method rather than the proportion shift one. PMID- 26231400 TI - Smoking motivators are different among cigarette and waterpipe smokers: The results of ITUPP. AB - The present study explores different drivers of cigarette and water pipe smoking among middle and high school students in Isfahan province. A questionnaire-based cross-sectional study was conducted. Trained staff collected questionnaires and saliva samples for response accuracy evaluation. Prevalence by demographic, parental and educational factors was calculated. Logistic regression was applied to compare behavior drivers of those who purely smoked cigarettes or a waterpipe. Waterpipe smokers were considered as the reference category. This study reported ORs along 95% confidence intervals; 5408 questionnaires were returned. The sample age was 15.37+/-01.70 on average. The self-reported prevalence of cigarette and waterpipe experimentation was 11.60% (n=624) and 20.70% (n=1,109), respectively; and 5.08% (n=311), 11.06% (n=619) for smokers, and 13.30% (n=711) for the whole sample. Psychological factors were the most important driver for cigarette smoking; bad event happening with odds of 2.38 (95% CI: 1.29-4.39); angriness 2.58 times (95% CI: 1.51-4.43); and distress by 2.49 times (95% CI: 1.42-4.40). Habitual situations were strong predictors of cigarette smoking, but not a predictor of waterpipe smoking, such as smoking after a meal (OR=3.11, 95% CI: 1.67-5.77); and smoking after waking up (OR=2.56, 95% CI: 1.42-4.40). Comprehensive and multifaceted preventive programs must tailor identified factors and increase family's awareness. PMID- 26231401 TI - Symptom clusters on primary care medical service trips in five regions in Latin America. AB - Short-term primary care medical service trips organized by the North American non governmental organizations (NGOs) serve many communities in Latin America that are poorly served by the national health system. This descriptive study contributes to the understanding of the epidemiology of patients seen on such low resource trips. An analysis was conducted on epidemiologic data collected from anonymized electronic medical records on patients seen during 34 short-term medical service trips in five regions in Ecuador, Guatemala, and the Dominican Republic between April 2013 and April 2014. A total of 22,977 patients were assessed by North American clinicians (physicians, nurse practitioners, physician assistants) on primary care, low-resource medical service trips. The majority of patients were female (67.1%), and their average age was 36. The most common presenting symptoms in all regions were general pain, upper respiratory tract symptoms, skin disorders, eye irritation, dyspepsia, and nonspecific abdominal complaints; 71-78% of primary care complaints were easily aggregated into well defined symptom clusters. The results suggest that guideline development for clinicians involved in these types of medical service trips should focus on management of the high-yield symptom clusters described by these data. PMID- 26231402 TI - Prospective study of predictors of poor self-rated health in a 23-year cohort of earthquake survivors in Armenia. AB - Long-term prospective studies exploring general health outcomes among disaster survivors are rare. Self-rated health (SRH) - a proven correlate of morbidity and mortality prognosis - was used to investigate predictors of perceived health status among a 23-year cohort of survivors of 1988 Spitak earthquake in Armenia. A geographically-stratified subsample of 725 adults from a larger initial cohort was followed during the period of 1990-2012. A logistic regression model identified predictors of SRH. Adjusted relative risks for the long-term predictors of SRH were calculated. The rate of poor SRH among the survivors was 18.8%, fair 56.5%, and good/excellent 24.7%. In the fitted model, long-term risk factors of poor SRH included baseline body mass index, baseline multi-morbidity, number of experienced stressful life events, and perceived poor living standards during the post-earthquake decade, while participation in sports in the early 1990s was a protective factor. Short-term protective factors included socio economic status score, social support, employment and dignity, while current household size was a risk factor for poor SRH. No association was found between earthquake exposure severity and SRH after 23 years. However, the identified predictors included a number of modifiable lifestyle, material and psychological factors. Thus, interventions targeting these factors could have a long-lasting impact on disaster victims' health status. PMID- 26231403 TI - Volunteering to improve health worldwide. Current trends in Out of Programme Experience/Training in the UK 2014. PMID- 26231404 TI - Clinicopathological significance of KAI1 expression and epithelial-mesenchymal transition in non-small cell lung cancer. AB - BACKGROUND: KAI1 and epithelial-mesenchymal transition (EMT) is related to both angiogenesis and lymphangiogenesis and is an important target in new cancer treatment strategies. We aimed to investigate the KAI1 and marker of EMT expression and correlation with lymph node metastasis (LNM) and explore their prognostic impact in non-small cell lung cancer (NSCLC). METHODS: Tumor tissue specimens from 312 resected patients with stage I-IIIA NSCLC were obtained. Immunohistochemistry was used to assess the expression of the molecular markers KAI1, E-cadherin (E-cad), vimentin, CD34, and D2-40. RESULTS: There were 153 N0 and 159 N+ patients. Tumor cell expression of KAI1and the marker of EMT, lymphatic vessel density (LVD), and microvessel density (MVD) were related to LNM. In multivariate analyses, the ages of patients, high tumor cell KAI1 expression, EMT, and the scores of MVD were independent factor of prognosis. CONCLUSIONS: Tumor cell KAI1 expression, EMT, LVD, and MVD correlate with LNM. Thus, the detection of KAI1, expression of markers of EMT, and the scores of MVD may be used as a potential indicator of NSCLC prognosis. PMID- 26231405 TI - Biomechanical analysis of wrapping of the moderately dilated ascending aorta. AB - BACKGROUND: External wrapping is a surgical method performed to prevent the dilatation of the aorta and to decrease the risk of its dissection and rupture. However, it is also believed to cause degeneration of the aortic wall. A biomechanical analysis was thus performed to assess the stress of the aortic wall subjected to external wrapping. METHODS: A stress analysis using the finite elements method was carried out on three models: a non-dilated aorta, a moderately dilated aorta and a wrapped aorta. The models were subjected to a pulsatile flow (120/80 mmHg) and a systolic aortic annulus motion of 11 mm. RESULTS: The finite elements analysis showed that the stress exerted on the outer surface of the ascending aorta in the wrapping model (0.05-0.8 MPa) was similar to that observed in the normal aorta (0.03-0.7 MPa) and was lower than in the model of a moderately dilated aorta (0.06-1.4 MPa). The stress on the inner surface of the ascending aorta ranged from 0.2 MPa to 0.4 MPa in the model of the normal aorta, from 0.3 to 1.3 MPa in the model of the dilated aorta and from 0.05 MPa to 0.4 MPa in the wrapping model. CONCLUSIONS: The results of this study suggest that the aortic wall is subjected to similar stress following a wrapping procedure to the one present in the normal aorta. PMID- 26231406 TI - An Analysis of Medical Laboratory Technology Journals' Instructions for Authors. AB - Instructions for authors (IFA) need to be informative and regularly updated. We hypothesized that journals with a higher impact factor (IF) have more comprehensive IFA. The aim of the study was to examine whether IFA of journals indexed in the Journal Citation Reports 2013, "Medical Laboratory Technology" category, are written in accordance with the latest recommendations and whether the quality of instructions correlates with the journals' IF. 6 out of 31 journals indexed in "Medical Laboratory Technology" category were excluded (unsuitable or unavailable instructions). The remaining 25 journals were scored based on a set of 41 yes/no questions (score 1/0) and divided into four groups (editorial policy, research ethics, research integrity, manuscript preparation) by three authors independently (max score = 41). We tested the correlation between IF and total score and the difference between scores in separate question groups. The median total score was 26 (21-30) [portion of positive answers 0.63 (0.51-0.73)]. There was no statistically significant correlation between a journal's IF and the total score (rho = 0.291, P = 0.159). IFA included recommendations concerning research ethics and manuscript preparation more extensively than recommendations concerning editorial policy and research integrity (Ht = 15.91, P = 0.003). Some policies were poorly described (portion of positive answers), for example: procedure for author's appeal (0.04), editorial submissions (0.08), appointed body for research integrity issues (0.08). The IF of the "Medical Laboratory Technology" journals does not reflect a journals' compliance to uniform standards. There is a need for improving editorial policies and the policies on research integrity. PMID- 26231407 TI - Engineering Social Justice into Traffic Control for Self-Driving Vehicles? AB - The convergence of computing, sensing, and communication technology will soon permit large-scale deployment of self-driving vehicles. This will in turn permit a radical transformation of traffic control technology. This paper makes a case for the importance of addressing questions of social justice in this transformation, and sketches a preliminary framework for doing so. We explain how new forms of traffic control technology have potential implications for several dimensions of social justice, including safety, sustainability, privacy, efficiency, and equal access. Our central focus is on efficiency and equal access as desiderata for traffic control design. We explain the limitations of conventional traffic control in meeting these desiderata, and sketch a preliminary vision for a next-generation traffic control tailored to address better the demands of social justice. One component of this vision is cooperative, hierarchically distributed self-organization among vehicles. Another component of this vision is a priority system enabling selection of priority levels by the user for each vehicle trip in the network, based on the supporting structure of non-monetary credits. PMID- 26231408 TI - What Is the Prognosis of Nontraumatic Hypotension and Shock in the Out-of Hospital and Emergency Department Setting? PMID- 26231409 TI - Barriers and Facilitators to Detecting Child Abuse and Neglect in General Emergency Departments. AB - STUDY OBJECTIVE: Child abuse and neglect is common in the United States, and victims often present to emergency departments (EDs) for care. Most US children who seek care in EDs are treated in general EDs without specialized pediatric services. We aim to explore general ED providers' experiences with screening and reporting of child abuse and neglect to identify barriers and facilitators to detection of child abuse and neglect in the ED setting. METHODS: We conducted 29 semistructured interviews with medical providers at 3 general EDs, exploring experiences with child abuse and neglect. Consistent with grounded theory, researchers coded transcripts and then collectively refined codes and identified themes. Data collection and analysis continued until theoretical saturation was achieved. RESULTS: Barriers to recognizing child abuse and neglect included providers' desire to believe the caregiver, failure to recognize that a child's presentation could be due to child abuse and neglect, challenges innate to working in an ED such as lack of ongoing contact with a family and provider biases. Barriers to reporting child abuse and neglect included factors associated with the reporting process, lack of follow-up of reported cases, and negative consequences of reporting such as testifying in court. Reported facilitators included real-time case discussion with peers or supervisors and the belief that it was better for the patient to report in the setting of suspicion. Finally, providers requested case-based education and child abuse and neglect consultation for unclear cases. CONCLUSION: Our interviews identified several approaches to improving detection of child abuse and neglect by general ED providers. These included providing education through case review, improving follow-up by Child Protective Services agencies, and increasing real-time assistance with patient care decisions. PMID- 26231410 TI - Do Clinical Prediction Rules for Acute Pulmonary Embolism Have Sufficient Sensitivity to Identify Patients at Very Low Risk of Death? PMID- 26231411 TI - [Influence of tobacco smoking on quality of life in patients with lung cancer]. AB - Tobacco smoking is the leading cause of lung cancer. This cancer is the most specific indicator of the effects of tobacco on health. Regardless of the type of lung cancer and the stage of the disease, continued smoking has a negative impact on its development and its treatment. For this reason, smoking cessation is an essential step in the management of patients with lung cancer who smoke. It has been clearly demonstrated that quality of life is worse in smokers than in non smokers. The aim of this general review is to study the relationship between tobacco use and quality of life specifically in patients with lung cancer. Among the twelve studies selected, six of them clearly demonstrate a deleterious effect of continued smoking tobacco or a beneficial effect of smoking cessation on the quality of life in patients with lung cancer. These findings should lead clinicians to offer support to smokers with lung cancer in order to assist them to quit smoking. PMID- 26231412 TI - [Pulmonary manifestations of antisynthetase syndrome]. AB - Antisynthetase syndrome is an inflammatory myopathy frequently associated with pulmonary manifestations, especially interstitial lung diseases, and uncommonly pulmonary hypertension. In the context of a suggestive clinical and radiological picture, positive anti-RNA synthetase antibodies confirm the diagnosis. Anti-Jo1, anti-PL7, and anti-PL12 antibodies are the more commonly encountered. The presence of a number of extra-thoracic manifestations in association with pulmonary disease may suggest the diagnosis. These include: myalgia or muscular deficit, Raynaud's phenomenon, polyarthritis, fever, mechanics hands. Serum creatine kinase levels are usually increased. Electromyogram, muscular magnetic resonance imaging or muscle pathology are not mandatory to make the diagnosis. There is a high variability in symptoms and severity, between patients but also during the course of the disease in the same patient. The presence of an interstitial lung disease is a major prognostic factor and an indication for more intensive treatment, principally with systemic corticosteroids with or without immunosuppressive drugs. Improving respiratory physicians' knowledge of this disease, which is often revealed by its pulmonary manifestations, should help diagnosis, therapeutic management, and possibly prognosis. PMID- 26231413 TI - Models for the spread of white pine blister rust. AB - White pine blister rust (WPBR, Cronartium ribicola) is a fungal pathogen and a threat to whitebark pines (Pinus albicaulis). It has a complex life cycle that requires two hosts, a white pine and an alternate host, typically a currant or gooseberry (Ribes spp.). WPBR is transmitted between hosts by means of two types of airborne spores whose average dispersal distances differ by several orders of magnitude. In this paper, we introduce a discrete-time model based on the life cycle of WPBR. We then extend this model to include a continuous spatial domain, disease-induced mortality in the pines, and a latency period. After each extension, we find the pathogen's asymptotic speed of invasion analytically using exponential transforms and the method of steepest descent. Our results show that invasion speeds are strongly reduced by the latency period in the pine host. In addition, these speeds are highly dependent on the carrying capacity and infectiousness of each host type. If these parameters are sufficiently small, high mortality in pines may stop the spread of WPBR completely. PMID- 26231414 TI - An extended mathematical model for reproducing the phase response of Arabidopsis thaliana under various light conditions. AB - Experimental studies showed that light qualities such as color and strength influence the phase response properties of plant circadian systems. These effects, however, have yet to be properly addressed in theoretical models of plant circadian systems. To fill this gap, the present paper develops a mathematical model of a plant circadian clock that takes into account the intensity and wavelength of the input light. Based on experimental knowledge, we model three photoreceptors, Phytochrome A, Phytochrome B, and Cryptochrome 1, which respond to red and/or blue light, in Arabidopsis thaliana. The three photoreceptors are incorporated into a standard mathematical model of the plant system, in which activator and repressor genes form a single feedback loop. The model capability is examined by a phase response curve (PRC), which plots the phase shifts elicited by the light perturbation as a function of the perturbation phase. Numerical experiments demonstrate that the extended model reproduces the essential features of the PRCs measured experimentally under various light conditions. Particularly, unlike conventional models, the model generates the inherent shape of the PRC under dark pulse stimuli. The outcome of our modeling approach may motivate future theoretical and experimental studies of plant circadian rhythms. PMID- 26231415 TI - Emergence of structured communities through evolutionary dynamics. AB - Species-rich communities, in which many competing species coexist in a single trophic level, are quite frequent in nature, but pose a formidable theoretical challenge. In particular, it is known that complex competitive systems become unstable and unfeasible when the number of species is large. Recently, many studies have attributed the stability of natural communities to the structure of the interspecific interaction network, yet the nature of such structures and the underlying mechanisms responsible for them remain open questions. Here we introduce an evolutionary model, based on the generic Lotka-Volterra competitive framework, from which a stable, structured, diverse community emerges spontaneously. The modular structure of the competition matrix reflects the phylogeny of the community, in agreement with the hierarchial taxonomic classification. Closely related species tend to have stronger niche overlap and weaker fitness differences, as opposed to pairs of species from different modules. The competitive-relatedness hypothesis and the idea of emergent neutrality are discussed in the context of this evolutionary model. PMID- 26231416 TI - Protein cold adaptation: Role of physico-chemical parameters in adaptation of proteins to low temperatures. AB - During years 2007 and 2008, we published three papers (Jahandideh, 2007a, JTB, 246, 159-166; Jahandideh, 2007b, JTB, 248, 721-726; Jahandideh, 2008, JTB, 255, 113-118) investigating sequence and structural parameters in adaptation of proteins to low temperatures. Our studies revealed important features in cold adaptation of proteins. Here, we calculate values of a new set of physico chemical parameters and perform a comparative systematic analysis on a more comprehensive database of psychrophilic-mesophilic homologous protein pairs. Our obtained results confirm that psychrophilicity rules are not merely the inverse rules of thermostability; for instance, although contact order is reported as a key feature in thermostability, our results have shown no significant difference between contact orders of psychrophilic proteins compared to mesophilic proteins. We are optimistic that these findings would help future efforts to propose a strategy for designing cold-adapted proteins. PMID- 26231417 TI - Using the second law of thermodynamics for enrichment and isolation of microorganisms to produce fuel alcohols or hydrocarbons. AB - Fermentation of crops, waste biomass, or gases has been proposed as a means to produce desired chemicals and renewable fuels. The second law of thermodynamics has been shown to determine the net direction of metabolite flow in fermentation processes. In this article, we describe a process to isolate and direct the evolution of microorganisms that convert cellulosic biomass or gaseous CO2 and H2 to biofuels such as ethanol, 1-butanol, butane, or hexane (among others). Mathematical models of fermentation elucidated sets of conditions that thermodynamically favor synthesis of desired products. When these conditions were applied to mixed cultures from the rumen of a cow, bacteria that produced alcohols or alkanes were isolated. The examples demonstrate the first use of thermodynamic analysis to isolate bacteria and control fermentation processes for biofuel production among other uses. PMID- 26231418 TI - The dynamics of strangling among forest trees. AB - Strangler trees germinate and grow on other trees, eventually enveloping and potentially even girdling their hosts. This allows them to mitigate fitness costs otherwise incurred by germinating and competing with other trees on the forest floor, as well as minimize risks associated with host tree-fall. If stranglers can themselves host other strangler trees, they may not even seem to need non stranglers to persist. Yet despite their high fitness potential, strangler trees neither dominate the communities in which they occur nor is the strategy particularly common outside of figs (genus Ficus). Here we analyze how dynamic interactions between strangling and non-strangling trees can shape the adaptive landscape for strangling mutants and mutant trees that have lost the ability to strangle. We find a threshold which strangler germination rates must exceed for selection to favor the evolution of strangling, regardless of how effectively hemiepiphytic stranglers may subsequently replace their hosts. This condition describes the magnitude of the phenotypic displacement in the ability to germinate on other trees necessary for invasion by a mutant tree that could potentially strangle its host following establishment as an epiphyte. We show how the relative abilities of strangling and non-strangling trees to occupy empty sites can govern whether strangling is an evolutionarily stable strategy, and obtain the conditions for strangler coexistence with non-stranglers. We then elucidate when the evolution of strangling can disrupt stable coexistence between commensal epiphytic ancestors and their non-strangling host trees. This allows us to highlight parallels between the invasion fitness of strangler trees arising from commensalist ancestors, and cases where strangling can arise in concert with the evolution of hemiepiphytism among free-standing ancestors. Finally, we discuss how our results can inform the evolutionary ecology of antagonistic interactions more generally. PMID- 26231419 TI - Shortened telomere length is associated with paroxysmal atrial fibrillation among cardiovascular patients enrolled in the Intermountain Heart Collaborative Study. AB - BACKGROUND: Atrial fibrillation (AF) diminishes quality of life and accounts for approximately one-third of all strokes. Studies have associated mitochondrial dysfunction with both AF and telomere length (TL). OBJECTIVE: The purpose of this study was to test the hypothesis of a relationship between AF and TL. METHODS: Blood was collected from consenting participants in the Intermountain Heart Collaborative Study (n = 3576) and DNA extracted. TL was determined by multiplex quantitative polymerase chain reaction, normalized to a single copy gene, and reported as telomere/single gene ratio (t/s). Patient information was extracted from Intermountain Healthcare's electronic records database. Prevalent AF was determined by discharge ICD-9 code. AF subtype (paroxysmal [Px], persistent [Ps], long-standing persistent/permanent [Pm]) was determined by chart review. RESULTS: The t/s decreased with age (P <.00001). Subjects with a history of AF (n = 379 [10.6%] had shorter telomeres (mean t/s +/- SD = 0.87 +/- 0.29) compared to subjects without AF (mean t/s 0.95 +/- 0.32, P <.0001). The association remained after adjustment for age (P = .017) and cardiovascular risk factors (P = .016). AF subtype was determined for 277 subjects; 110 (39.7%) had Px AF, 65 (23.5%) Ps, and 102 (36.8%) Pm AF. Mean t/s did not differ between Ps, Pm, and subjects without AF (0.94 +/- 0.40, 0.94 +/- 0.27, and 0.95 +/- 0.32, respectively). However, the mean t/s for Px (0.81 +/- 0.22) was significantly shorter than for Ps (P = .026), Pm (P = .004), or subjects without AF (P <.0001). CONCLUSION: The present study supports an association between Px AF and TL. Short TL may be a previously unrecognized risk factor for AF with potential applications in diagnosis and therapy. PMID- 26231420 TI - Methicillin-resistant Staphylococcus aureus: Prevalence, incidence, risk factors, and effects on survival of patients in a specialist palliative care unit: A prospective observational study. AB - BACKGROUND: Little is known about the impact of methicillin-resistant Staphylococcus aureus in palliative care settings. To date, the clinical impact of methicillin-resistant Staphylococcus aureus in palliative care is unknown. AIM: To determine prevalence and incidence of methicillin-resistant Staphylococcus aureus colonisation in a specialist palliative care setting, to identify risk factors for methicillin-resistant Staphylococcus aureus colonisation, to determine the eradication success rate and to determine the impact of methicillin-resistant Staphylococcus aureus on survival. DESIGN: Prospective cohort study. SETTING/PARTICIPANTS: Data were collected for consecutive admissions to an inpatient palliative care service. Patients were screened for methicillin-resistant Staphylococcus aureus colonisation on admission and 1 week post admission. Methicillin-resistant Staphylococcus aureus eradication was attempted in methicillin-resistant Staphylococcus aureus positive patients. RESULTS: Data were collected from 609 admissions for 466 individual patients. Admission screening data were available in 95.5%. Prevalence of methicillin-resistant Staphylococcus aureus colonisation was 11.59% (54 patients). One week incidence of methicillin-resistant Staphylococcus aureus colonisation was 1.2%. Risk factors for methicillin-resistant Staphylococcus aureus colonisation were determined using Chi-Squared test and included high Waterlow score (p < 0.01), high palliative performance scale score (p < 0.01), methicillin-resistant Staphylococcus aureus status prior to admission (p < 0.01), admission from hospital (p < 0.05), presence of urinary catheter or percutaneous endoscopic gastrostomy tube (p < 0.05) and poor dietary intake (p < 0.05). Regression analysis did not identify independent risk factors. Methicillin resistant Staphylococcus aureus was eradicated in 8.1% of admissions, while 46 patients commenced on the protocol (62.2%) died before completing it. Methicillin resistant Staphylococcus aureus did not significantly impact survival but was significantly associated with having infection episodes and longer length of stay. CONCLUSION: This study identified risk factors for methicillin-resistant Staphylococcus aureus colonisation in palliative care patients. Methicillin resistant Staphylococcus aureus was eradicated in 8.1% of patients. Hence, restricting methicillin-resistant Staphylococcus aureus screening to high-risk palliative care patients may be prudent. PMID- 26231421 TI - Coverage and development of specialist palliative care services across the World Health Organization European Region (2005-2012): Results from a European Association for Palliative Care Task Force survey of 53 Countries. AB - BACKGROUND: The evolution of the provision of palliative care specialised services is important for planning and evaluation. AIM: To examine the development between 2005 and 2012 of three specialised palliative care services across the World Health Organization European Region - home care teams, hospital support teams and inpatient palliative care services. DESIGN AND SETTING: Data were extracted and analysed from two editions of the European Association for Palliative Care Atlas of Palliative Care in Europe. Significant development of each type of services was demonstrated by adjusted residual analysis, ratio of services per population and 2012 coverage (relationship between provision of available services and demand services estimated to meet the palliative care needs of a population). For the measurement of palliative care coverage, we used European Association for Palliative Care White Paper recommendations: one home care team per 100,000 inhabitants, one hospital support team per 200,000 inhabitants and one inpatient palliative care service per 200,000 inhabitants. To estimate evolution at the supranational level, mean comparison between years and European sub-regions is presented. RESULTS: Of 53 countries, 46 (87%) provided data. Europe has developed significant home care team, inpatient palliative care service and hospital support team in 2005-2012. The improvement was statistically significant for Western European countries, but not for Central and Eastern countries. Significant development in at least a type of services was in 21 of 46 (46%) countries. The estimations of 2012 coverage for inpatient palliative care service, home care team and hospital support team are 62%, 52% and 31% for Western European and 20%, 14% and 3% for Central and Eastern, respectively. CONCLUSION: Although there has been a positive development in overall palliative care coverage in Europe between 2005 and 2012, the services available in most countries are still insufficient to meet the palliative care needs of the population. PMID- 26231422 TI - Lycopene attenuates dichlorvos-induced oxidative damage and hepatotoxicity in rats. AB - Because of the widespread use of dichlorvos (DDVP) for domestic applications, evaluation of their toxic effects is of major concern to public health. Lycopene may lower oxidative stress by a mechanism that is not fully elucidated. The present study was undertaken to evaluate the protective efficacy of lycopene in terms of normalization of altered biochemical parameters following DDVP treatment in rats. Animals were divided into four groups. The first group was used as control, while groups 2, 3, and 4 were orally treated with lycopene (10 mg kg(-1) body weight (b.w.)), DDVP (1.6 mg kg(-1) b.w.), and DDVP plus lycopene, respectively. Results showed that oral administration of DDVP for 30 days increased the levels of lipid peroxidation markers such as malondialdehyde, 4 hydroxynonanal, and protein carbonyl content in liver. Also, a decrease in levels of vitamin C, vitamin E, and reduced glutathione was detected due to DDVP administration. These were accompanied by a decrease in the activities of antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase in the liver tissue. Moreover, DDVP increased the activities of serum transaminases, alkaline phosphatase, lactate dehydrogenase, and lipoxygenase, and the levels of bilirubin, total cholesterol, low-density lipoprotein cholesterol, triglyceride and DNA-protein crosslinks, and 8-hydroxy-2 deoxyguanosine, while decreased the level of high-density lipoprotein cholesterol. Our results provide new insights into the biochemical studies of relation between DDVP hepatotoxicity and lycopene treatment. Administration of lycopene to DDVP-treated rats reverted the status of hepatic markers to near normal levels. These data suggest that lycopene can protect against the liver damage induced by DDVP. PMID- 26231423 TI - Zearalenone-induced changes in biochemical parameters, oxidative stress and apoptosis in cardiac tissue: Protective role of crocin. AB - Zearalenone (ZEN) is a mycotoxin from Fusarium species commonly found in food commodities and is known to cause reproductive disorders. Several in vivo studies have shown that ZEN is haematotoxic and hepatotoxic and causes several alterations of immunological parameters. Meantime, the available information on the cardiotoxic effects of ZEN is very much limited. In the present study, we investigated the toxic effects of ZEN in heart tissues of Balb/c mice. We demonstrated that ZEN (40 mg kg(-1) body weight (b.w.)) increased creatine phosphokinase, lactate dehydrogenase, aspartate transaminase, alanine transaminase, total cholesterol and triglyceride levels and induced oxidative stress as monitored by measuring the malondialdehyde level, the generation of protein carbonyls, the catalase and superoxide dismutase activity and the expression of the heat shock proteins (Hsp 70). We also demonstrated that acute administration of ZEN triggers apoptosis in cardiac tissue. Furthermore, we aimed to evaluate the safety and efficacy of crocin (CRO), a natural carotenoid, to prevent ZEN-induced cardiotoxicity in mice. In fact, combined treatment of ZEN with different doses of CRO (50, 100, and 250 mg kg(-1) b.w.) showed a significant reduction of ZEN-induced toxicity for all tested markers in a dose dependent manner. It could be concluded that CRO was effective in the protection against ZEN-induced toxicity in cardiac tissue. PMID- 26231424 TI - Health worker roles in safe abortion care and post-abortion contraception. PMID- 26231426 TI - MICC: an R package for identifying chromatin interactions from ChIA-PET data. AB - ChIA-PET is rapidly emerging as an important experimental approach to detect chromatin long-range interactions at high resolution. Here, we present Model based Interaction Calling from ChIA-PET data (MICC), an easy-to-use R package to detect chromatin interactions from ChIA-PET sequencing data. By applying a Bayesian mixture model to systematically remove random ligation and random collision noise, MICC could identify chromatin interactions with a significantly higher sensitivity than existing methods at the same false discovery rate. AVAILABILITY AND IMPLEMENTATION: http://bioinfo.au.tsinghua.edu.cn/member/xwwang/MICCusage CONTACT: michael.zhang@utdallas.edu or xwwang@tsinghua.edu.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26231425 TI - Incidence of ischemic stroke and systemic embolism in patients with hypertrophic cardiomyopathy, nonvalvular atrial fibrillation, CHA2DS2-VASc score of <=1 and without anticoagulant therapy. AB - Data on the risk of ischemic stroke and systemic embolism (iSSE) events in patients with nonvalvular atrial fibrillation (NVAF), a CHA2DS2-VASc score of <=1, hypertrophic cardiomyopathy (HCM), and without anticoagulant therapy are still lacking. The aim of this study was to investigate the incidence of iSSE events in these patients. We consecutively screened medical records of patients with HCM and NVAF referred to Fuwai Hospital between January 1994 and March 2014. The primary end point was iSSE events, defined as a composite of ischemic stroke and systemic embolism. Follow-up was carried out to ascertain end point status. Medical records of 522 patients with NVAF and HCM were screened. A total of 108 patients (20.7 %) with a CHA2DS2-VASc score of <=1 and without anticoagulant therapy were enrolled and constituted our study population. After a median follow up of 2.4 years (range 0.6-14.1 years; 376.2 patient-years), ischemic stroke occurred in 2 patients, resulting in death of 1 patient in the first year and paralysis of the other patient in the fourth year. No other iSSE events occurred. The incidence of iSSE was 0.9 % [95 % confidence interval (CI) 0.0-5.0 %] in the first year, and 0.5 % per 100 patient-years (95 % CI 0.1-1.9 %). The risk of iSSE events seems low in patients with NVAF, a CHA2DS2-VASc score of <=1, HCM, and without anticoagulant therapy. Multicenter studies with sizeable study populations are needed to validate the risk of iSSE events in these patients. PMID- 26231427 TI - An efficient algorithm for the extraction of HGVS variant descriptions from sequences. AB - MOTIVATION: Unambiguous sequence variant descriptions are important in reporting the outcome of clinical diagnostic DNA tests. The standard nomenclature of the Human Genome Variation Society (HGVS) describes the observed variant sequence relative to a given reference sequence. We propose an efficient algorithm for the extraction of HGVS descriptions from two sequences with three main requirements in mind: minimizing the length of the resulting descriptions, minimizing the computation time and keeping the unambiguous descriptions biologically meaningful. RESULTS: Our algorithm is able to compute the HGVS descriptions of complete chromosomes or other large DNA strings in a reasonable amount of computation time and its resulting descriptions are relatively small. Additional applications include updating of gene variant database contents and reference sequence liftovers. AVAILABILITY: The algorithm is accessible as an experimental service in the Mutalyzer program suite (https://mutalyzer.nl). The C++ source code and Python interface are accessible at: https://github.com/mutalyzer/description-extractor. CONTACT: j.k.vis@lumc.nl. PMID- 26231428 TI - MEPSA: minimum energy pathway analysis for energy landscapes. AB - From conformational studies to atomistic descriptions of enzymatic reactions, potential and free energy landscapes can be used to describe biomolecular systems in detail. However, extracting the relevant data of complex 3D energy surfaces can sometimes be laborious. In this article, we present MEPSA (Minimum Energy Path Surface Analysis), a cross-platform user friendly tool for the analysis of energy landscapes from a transition state theory perspective. Some of its most relevant features are: identification of all the barriers and minima of the landscape at once, description of maxima edge profiles, detection of the lowest energy path connecting two minima and generation of transition state theory diagrams along these paths. In addition to a built-in plotting system, MEPSA can save most of the generated data into easily parseable text files, allowing more versatile uses of MEPSA's output such as the generation of molecular dynamics restraints from a calculated path. AVAILABILITY AND IMPLEMENTATION: MEPSA is freely available (under GPLv3 license) at: http://bioweb.cbm.uam.es/software/MEPSA/ CONTACT: pagomez@cbm.csic.es. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26231430 TI - stringgaussnet: from differentially expressed genes to semantic and Gaussian networks generation. AB - MOTIVATION: Knowledge-based and co-expression networks are two kinds of gene networks that can be currently implemented by sophisticated but distinct tools. We developed stringgaussnet, an R package that integrates both approaches, starting from a list of differentially expressed genes. CONTACT: henri jean.garchon@inserm.fr. AVAILABILITY AND IMPLEMENTATION: Freely available on the web at http://cran.r-project.org/web/packages/stringgaussnet. PMID- 26231429 TI - PBAP: a pipeline for file processing and quality control of pedigree data with dense genetic markers. AB - MOTIVATION: Huge genetic datasets with dense marker panels are now common. With the availability of sequence data and recognition of importance of rare variants, smaller studies based on pedigrees are again also common. Pedigree-based samples often start with a dense marker panel, a subset of which may be used for linkage analysis to reduce computational burden and to limit linkage disequilibrium between single-nucleotide polymorphisms (SNPs). Programs attempting to select markers for linkage panels exist but lack flexibility. RESULTS: We developed a pedigree-based analysis pipeline (PBAP) suite of programs geared towards SNPs and sequence data. PBAP performs quality control, marker selection and file preparation. PBAP sets up files for MORGAN, which can handle analyses for small and large pedigrees, typically human, and results can be used with other programs and for downstream analyses. We evaluate and illustrate its features with two real datasets. AVAILABILITY AND IMPLEMENTATION: PBAP scripts may be downloaded from http://faculty.washington.edu/wijsman/software.shtml. CONTACT: wijsman@uw.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26231431 TI - HHalign-Kbest: exploring sub-optimal alignments for remote homology comparative modeling. AB - MOTIVATION: The HHsearch algorithm, implementing a hidden Markov model (HMM)-HMM alignment method, has shown excellent alignment performance in the so-called twilight zone (target-template sequence identity with ~20%). However, an optimal alignment by HHsearch may contain small to large errors, leading to poor structure prediction if these errors are located in important structural elements. RESULTS: HHalign-Kbest server runs a full pipeline, from the generation of suboptimal HMM-HMM alignments to the evaluation of the best structural models. In the HHsearch framework, it implements a novel algorithm capable of generating k-best HMM-HMM suboptimal alignments rather than only the optimal one. For large proteins, a directed acyclic graph-based implementation reduces drastically the memory usage. Improved alignments were systematically generated among the top k suboptimal alignments. To recognize them, corresponding structural models were systematically generated and evaluated with Qmean score. The method was benchmarked over 420 targets from the SCOP30 database. In the range of HHsearch probability of 20-99%, average quality of the models (TM-score) raised by 4.1 16.3% and 8.0-21.0% considering the top 1 and top 10 best models, respectively. AVAILABILITY AND IMPLEMENTATION: http://bioserv.rpbs.univ-paris diderot.fr/services/HHalign-Kbest/ (source code and server). CONTACT: guerois@cea.fr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26231432 TI - AlignBucket: a tool to speed up 'all-against-all' protein sequence alignments optimizing length constraints. AB - MOTIVATION: The next-generation sequencing era requires reliable, fast and efficient approaches for the accurate annotation of the ever-increasing number of biological sequences and their variations. Transfer of annotation upon similarity search is a standard approach. The procedure of all-against-all protein comparison is a preliminary step of different available methods that annotate sequences based on information already present in databases. Given the actual volume of sequences, methods are necessary to pre-process data to reduce the time of sequence comparison. RESULTS: We present an algorithm that optimizes the partition of a large volume of sequences (the whole database) into sets where sequence length values (in residues) are constrained depending on a bounded minimal and expected alignment coverage. The idea is to optimally group protein sequences according to their length, and then computing the all-against-all sequence alignments among sequences that fall in a selected length range. We describe a mathematically optimal solution and we show that our method leads to a 5-fold speed-up in real world cases. AVAILABILITY AND IMPLEMENTATION: The software is available for downloading at http://www.biocomp.unibo.it/~giuseppe/partitioning.html. CONTACT: giuseppe.profiti2@unibo.it. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26231434 TI - [Surgery and justice--Critical illustration of arbitration cases]. PMID- 26231433 TI - Application of a Bayesian approach to physiological modelling of mavoglurant population pharmacokinetics. AB - Mavoglurant (MVG) is an antagonist at the metabotropic glutamate receptor-5 currently under clinical development at Novartis Pharma AG for the treatment of central nervous system diseases. The aim of this study was to develop and optimise a population whole-body physiologically-based pharmacokinetic (WBPBPK) model for MVG, to predict the impact of drug-drug interaction (DDI) and age on its pharmacokinetics. In a first step, the model was fitted to intravenous (IV) data from a clinical study in adults using a Bayesian approach. In a second step, the optimised model was used together with a mechanistic absorption model for exploratory Monte Carlo simulations. The ability of the model to predict MVG pharmacokinetics when orally co-administered with ketoconazole in adults or administered alone in 3-11 year-old children was evaluated using data from three other clinical studies. The population model provided a good description of both the median trend and variability in MVG plasma pharmacokinetics following IV administration in adults. The Bayesian approach offered a continuous flow of information from pre-clinical to clinical studies. Prediction of the DDI with ketoconazole was consistent with the results of a non-compartmental analysis of the clinical data (threefold increase in systemic exposure). Scaling of the WBPBPK model allowed reasonable extrapolation of MVG pharmacokinetics from adults to children. The model can be used to predict plasma and brain (target site) concentration-time profiles following oral administration of various immediate release formulations of MVG alone or when co-administered with other drugs, in adults as well as in children. PMID- 26231435 TI - [Complication management in implant dislocation]. AB - There are many reasons for an implant malposition. Besides knowlege about prevention of implant dislocation, accurate planning of the osteosynthesis, extensive knowlege of the anatomy of the region in question, using all necessary diagnostic tools, choosing the correct approach and the best implant for fracture fixation are also important factors. Nevertheless, implant complications can still be found and if an intraoperative or postoperative implant dislocation occurs a suitable management is necessary. This article describes the different osteosynthesis implants and possible malpositions and dislocations. Tips and tricks are described in order to facilitate the correct indications for the further procedure. PMID- 26231436 TI - Risk of major adverse cardiovascular events in patients with metabolic syndrome after revascularization: A meta-analysis of eighteen cohorts with 18,457 patients. AB - OBJECTIVE: To provide a comprehensive evaluation of the association between metabolic syndrome (MetS) and major adverse cardiovascular events (MACE) and to clarify the effect of revascularization methods among them in patients with coronary artery disease (CAD) undergoing successful revascularization. METHODS: PubMed and Embase databases were searched. Cohort studies evaluating the association between MetS and risk of MACE and providing the hazard ratio (HR) with 95% confidence interval (CI) or sufficient data to calculate HR and its 95%CI among patients after revascularization were included. The pooled estimates were performed by using a random-effects model despite heterogeneity. Subgroup and sensitivity analyses were also conducted adherence to guidelines. RESULTS: Eighteen trials with 18457 patients were included. Overall, MetS was associated with significant increased risks of MACE (HR 1.47, 95%CI 1.26-1.72, I(2)=46.4%, PH=0.016, P<0.001) and all-cause mortality (HR 1.58, 95%CI 1.29-1.92, I(2)=45.6%, PH=0.075, P<0.001) in CAD patients received revascularization. The results remained stable and robust in our subgroup analysis. However, no significant increased risk of MACE or all-cause mortality was found in patients undergoing coronary artery bypass graft (CABG) or drug-eluting stent (DES) in the sensitivity analysis. CONCLUSION: MetS was associated with increased risks of MACE and all-cause mortality in patients after revascularization, but not in patients receiving CABG or DES. Therefore, prevention and treatment of MetS are extremely necessary in patients undergoing revascularization. Moreover, CABG and DES should be recommended for CAD patients with MetS and future researches are still warranted. PMID- 26231437 TI - Objective comparison of subtotal vs. total abdominal hysterectomy regarding pelvic organ prolapse and urinary incontinence: a randomized controlled trial with 14-year follow-up. AB - OBJECTIVE: To compare subtotal and total abdominal hysterectomy regarding objective assessment of pelvic organ prolapse, urinary incontinence and voiding function 14 years after hysterectomy for benign diseases. STUDY DESIGN: Long-term follow-up of a randomized clinical trial of subtotal vs. total abdominal hysterectomy with objective outcomes. All randomized women still alive and living in Denmark (n=304) were invited to answer a questionnaire and come for clinical examination consisting of 20-min pad weighing test, urinary flow, measurement of residual urine, POP-Q measurement for pelvic organ prolapse, 3 day voiding diary and also filled out the pelvic floor distress inventory (PFDI-20) questionnaire. RESULTS: We included 100/304 (32.9%) women (subtotal hysterectomy: 53, total hysterectomy: 47) in the clinical examinations. The study questionnaire was answered by 197 (64.8%) (subtotal: 97, total: 100), the PFDI-20 questionnaire was answered by 140 (46.1%) (subtotal: 68, total: 72). We found no difference between subtotal and total abdominal hysterectomy in the PFDI-20 scores or regarding objectively assessed urinary incontinence or pelvic organ prolapse. In the subtotal hysterectomy group, 31 (59.6%) women had objective stage 2 pelvic organ prolapse compared with 33 (70.2%) in the total hysterectomy group (P=0.27); however, only 6/31 and 9/33 had symptoms (P=0.45). There were more anterior pelvic organ prolapses in the total hysterectomy group (N=10) than in the subtotal hysterectomy group (N=4) (P=0.048). We found a higher mean maximum flow rate (Qmax) in the subtotal hysterectomy group (34.78ml/s) than in the total hysterectomy group (27.08ml/s) (P=0.042) as well as a higher mean functional capacity in the subtotal hysterectomy group (526ml) than in the total hysterectomy group (443ml) (P=0.0147) according to the voiding diary. CONCLUSION: Subtotal and total abdominal hysterectomy are comparable regarding long-term objective pelvic organ prolapse and urinary incontinence. The subtotal hysterectomy group had a higher Qmax and voided volume. PMID- 26231438 TI - Cell-matrix interactions of Entamoeba histolytica and E. dispar. A comparative study by electron-, atomic force- and confocal microscopy. AB - Invasion of tissues by Entamoeba histolytica is a multistep process that initiates with the adhesion of the parasite to target tissues. The recognition of the non-invasive Entamoeba dispar as a distinct, but closely related protozoan species raised the question as to whether the lack of its pathogenic potential could be related to a weaker adhesion due to limited cytoskeleton restructuring capacity. We here compared the adhesion process of both amebas to fibronectin through scanning, transmission, atomic force, and confocal microscopy. In addition, electrophoretic and western blot assays of actin were also compared. Adhesion of E. histolytica to fibronectin involves a dramatic reorganization of the actin network that results in a tighter contact to and the subsequent focal degradation of the fibronectin matrix. In contrast, E. dispar showed no regions of focal adhesion, the cytoskeleton was poorly reorganized and there was little fibronectin degradation. In addition, atomic force microscopy using topographic, error signal and phase modes revealed clear-cut differences at the site of contact of both amebas with the substrate. In spite of the morphological and genetic similarities between E. histolytica and E. dispar the present results demonstrate striking differences in their respective cell-to-matrix adhesion processes, which may be of relevance for understanding the invasive character of E. histolytica. PMID- 26231439 TI - Intestinal absorption mechanisms of MTBH, a novel hesperetin derivative, in Caco 2 cells, and potential involvement of monocarboxylate transporter 1 and multidrug resistance protein 2. AB - Hesperetin, the aglycone of hesperidin, occurs naturally in citrus fruits. It exerts extensive pharmacological activities. However, hesperetin's poor solubility and low bioavailability limit its wide application. In order to overcome these limitations, recently a series of novel hesperitin derivatives containing Mannich base moieties were synthesized and the anti-inflammatory activity was evaluated, among which MTBH (8-methylene-tert-butylamine-3',5,7 trihydroxy-4'-methoxyflavanone) showed a significantly improved water solubility, and promising anti-inflammatory activity in vitro and in vivo compared with hesperitin. Thus, the aim of this study was to investigate the permeability and transport mechanisms of MTBH, using Caco-2 cell monolayer. MTBH was effectively absorbed by Caco-2 cells in a concentration-dependent manner in both directions at 7.5-480 MUM. Moreover, MTBH showed pH dependent and TEER values independent transport in both directions. Transport of MTBH was obviously decreased in the presence of sodium azide (an ATP inhibitor) or CCCP (a proton-ionophore). MTBH transport was markedly reduced by MCT inhibitors quercetin or phloretin, and the substrate analogs l-lactate or benzoic acid. We verified MCT1, MCT3, MCT4, MCT5, and MCT6 were expressed in Caco-2 cells by western blot. Silence MCT1 with siRNA resulted in significant inhibition of MTBH uptake. The verapamil, a P-gp inhibitor, and Ko143, a BCRP inhibitor, had no effect on the transport of MTBH. However, MK-571 or probenecid, MRP2 inhibitors, led to an apparently decrease in the efflux of MTBH. In summary, MTBH was absorbed by transcellular passive diffusion and a pH dependent mechanism mediated by MCT1. MRP2 but P-gp or BCRP may be involved in the transport of MTBH. PMID- 26231440 TI - [Clinical scale for the diagnosis of ventriculoperitoneal shunt malfunction in children in Emergency Department]. AB - INTRODUCTION: It is well known that some symptoms in children with ventriculoperitoneal shunt are associated with a higher risk of developing shunt malfunction. However none of those symptoms are sensitive or enough specific enough to diagnose the shunt malfunction. OBJECTIVE: To develop a diagnostic scale to identify children with an increased risk of shunt malfunction in the Emergency Department. MATERIAL AND METHODS: This is a prospective study including children aged one to eighteen years old admitted to the Emergency Department between April 2010 and March 2013 with symptoms of ventriculoperitoneal shunt malfunction. Logistic regression Analysis was used to determine whether or not the variables were considered independent risk factors for shunt malfunction. The results led to the development of a diagnostic scale. RESULTS: A scale was developed using 9 variables (erythema, swelling or discharge from the catheter trajectory, drowsiness, stiff neck, headache, afebrile, age>4 years, vomiting, recent neurological deficit, and time since last surgery <= 2 years) with a maximum score of 20 points. It was found that Scale scores >= 7 points were associated with an increased risk of shunt malfunction (OR 34.0, 95% CI 15.4 74.9; sensitivity 88.3%, specificity 81.1%, PPV 53.4%, NPV 96.7%). DISCUSSION: A diagnostic scale is designed for assessing the risk of shunt malfunction, selecting those patients with a higher risk. The use of this scale could help the management of these patients, reducing complementary tests, as well the usual radiation suffered by these children. PMID- 26231441 TI - Prevalence of cavum vergae in psychosis and mood spectrum disorders. AB - BACKGROUND: Midline brain abnormalities might increase susceptibility to both first-episode and chronic mental disorder. Evidence of cavum vergae (CV) abnormality in mental disorders is scarce. METHODS: The presence of CV was assessed by a researcher blind to clinical information in a cross-disorder sample of 639 patients with mood and psychotic disorders and in 223 healthy controls. Homogeneous magnetic resonance imaging methods of acquisition and assessment were applied. RESULTS: Seven out of 639 patients with mood or psychotic disorders were detected with CV which corresponds to a prevalence of 1.1%. There were no concurrent cases of CV in the healthy control group. Identified cases which are briefly described were diagnosed from bipolar I disorder (n=2), delusional disorder (n=1), brief psychotic disorder (n=1) and schizoaffective disorder (n=3). Patients with CV had descriptively lower current IQ, executive functioning and memory scores in relation to patients without CV but this was not statistically significant. LIMITATIONS: Effects of medication and lack of statistical power of the CV patient group. CONCLUSIONS: Midline brain abnormalities, such as CV, might represent an unspecific risk factor for the development of severe mental disorders. PMID- 26231442 TI - Patterns of DSM-5 posttraumatic stress disorder and depression symptoms in an epidemiological sample of Chinese earthquake survivors: A latent profile analysis. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) and depression are highly comorbid in association with serious clinical consequences. Nevertheless, to date, no study using latent class or latent profile analysis (LCA/LPA) has examined patterns of co-occurring PTSD and depression symptoms among natural disaster survivors, nor has the distinctiveness of DSM-5 PTSD and depression symptoms been clarified in the aftermath of trauma. This study was primarily aimed at filling these gaps. METHODS: LPA was used to examine self-reported PTSD and depression symptoms in an epidemiological sample of 1196 Chinese earthquake survivors. RESULTS: A 4-class solution characterized by low symptoms (53.9%), predominantly depression (18.2%), predominantly PTSD (18.9%) and combined PTSD depression (9.0%) patterns fit the data best. Demographic characteristics and earthquake-related exposures were specifically or consistently associated with the non-parallel profiles varying in physical health impairment. LIMITATIONS: A sample exposed to specific traumatic events was assessed by self-report measures. CONCLUSIONS: The distinctiveness of DSM-5 PTSD and depression symptoms following an earthquake suggests that PTSD and depression may be independent sequelae of psychological trauma rather than a manifestation of a single form of psychopathology. The current findings support the distinction between PTSD and depression constructs, and highlight the need for identifications of natural disaster survivors at high risk for PTSD and/or depression, and interventions individually tailored to one's symptom presentations. PMID- 26231443 TI - Depression symptoms during pregnancy: Evidence from Growing Up in New Zealand. AB - BACKGROUND: Depression during pregnancy has significant implications for pregnancy outcomes and maternal and child health. There is a need to identify which family, physical and mental health factors are associated with depression during pregnancy. METHODS: An ethnically and socioeconomically diverse sample of 5664 pregnant women living in New Zealand completed a face-to-face interview during the third trimester. Antenatal depression (AD) symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS). Maternal demographic, physical and mental health, and family and relationship characteristics were measured. The association between symptoms of AD and maternal characteristics was determined using multiple logistic regression. RESULTS: 11.9% of the participating women had EPDS scores (13+) that indicated probable AD. When considering sociodemographic predictors of AD symptoms, we found that women from non-European ethnicities, specifically Pacific Islander, Asian and other, were more likely to suffer from AD symptoms. Greater perceived stress during pregnancy and a diagnosis of anxiety both before and during pregnancy were also associated with greater odds of having AD according to the EPDS. LIMITATIONS: The women were in their third trimester of pregnancy at the interview. Therefore, we cannot discount the possibility of recall bias for questions relating to pre-pregnancy status or early-pregnancy behaviours. CONCLUSIONS: AD is prevalent amongst New Zealand women. Ethnicity, perceived stress and anxiety are particularly associated with a greater likelihood of depression during pregnancy. Further attention to supporting maternal mental health status in the antenatal period is required. PMID- 26231444 TI - Willingness to administer mouth-to-mouth ventilation in a first response program in rural Bangladesh. AB - BACKGROUND: Timely mouth-to-mouth ventilation is critical to resuscitate drowning victims. While drowning is frequent, there are no lay persons trained in cardio pulmonary resuscitation (CPR) in rural Bangladesh. As part of a feasibility study to create a first response system in a conservative Islamic village environment, a pilot was undertaken to examine willingness to provide mouth-to-mouth ventilation for drowning resuscitation. METHODS: A questionnaire was administered to 721 participants at the beginning of a village-based CPR training course. Trainees were asked regarding willingness to administer mouth-to-mouth ventilation on a variety of hypothetical victims. Responses were tabulated according to the age, sex and relationship of the trainee to the postulated victim. RESULTS: Willingness to deliver mouth-to-mouth ventilation was influenced by sex of a potential recipient and relationship to the trainee. Adolescent participants were significantly more willing to perform mouth-to-mouth ventilation on someone of the same sex. Willingness increased for both sexes when the postulated victim was an immediate family member. Willingness was lower with extended family members and lowest with strangers. Adult trainees were more likely to perform mouth-to-mouth ventilation than adolescent trainees in any scenario. CONCLUSION: Adults express more willingness to resuscitate a broader range of drowning victims than adolescents. However in rural Bangladesh, adolescents are more likely to be in close proximity to a drowning in progress. Further efforts are needed to increase willingness of adolescents to provide resuscitation to drowning victims. However, despite potential cultural limitations, trained responders appear to be willing to give mouth-to-mouth ventilation to various recipients. Final determination will require evidence on response outcomes which is being collected. PMID- 26231445 TI - Activation of presynaptic oxytocin receptors enhances glutamate release in the ventral hippocampus of prenatally restraint stressed rats. AB - Oxytocin receptors are known to modulate synaptic transmission and network activity in the hippocampus, but their precise function has been only partially elucidated. Here, we have found that activation of presynaptic oxytocin receptor with the potent agonist, carbetocin, enhanced depolarization-evoked glutamate release in the ventral hippocampus with no effect on GABA release. This evidence paved the way for examining the effect of carbetocin treatment in "prenatally restraint stressed" (PRS) rats, i.e., the offspring of dams exposed to repeated episodes of restraint stress during pregnancy. Adult PRS rats exhibit an anxious/depressive-like phenotype associated with an abnormal glucocorticoid feedback regulation of the hypothalamus-pituitary-adrenal (HPA) axis, and, remarkably, with a reduced depolarization-evoked glutamate release in the ventral hippocampus. Chronic systemic treatment with carbetocin (1mg/kg, i.p., once a day for 2-3 weeks) in PRS rats corrected the defect in glutamate release, anxiety- and depressive-like behavior, and abnormalities in social behavior, in the HPA response to stress, and in the expression of stress-related genes in the hippocampus and amygdala. Of note, carbetocin treatment had no effect on these behavioral and neuroendocrine parameters in prenatally unstressed (control) rats, with the exception of a reduced expression of the oxytocin receptor gene in the amygdala. These findings disclose a novel function of oxytocin receptors in the hippocampus, and encourage the use of oxytocin receptor agonists in the treatment of stress-related psychiatric disorders in adult life. PMID- 26231447 TI - Traditional management of diabetes in Pakistan: Ethnobotanical investigation from Traditional Health Practitioners. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The uses of anti-diabetic plants are well anchored in the traditional health care system of Pakistan. To the best of our knowledge, this is the first ethno-botanical study about the uses of plants for the treatment of diabetes. The aim of the study is to record indigenous knowledge on anti-diabetic plants from Traditional Health Practitioners (THPs) and diabetic patients. In addition, it is aimed to ascertain and validate the traditional uses of anti-diabetic plants by citing pharmacological activities and phytochemical constitutes from previously published literature. MATERIALS AND METHODS: The ethno-medicinal data was documented during 14 field surveys, each comprising of 10 days, from 3 regions of Pakistan (Islamabad, Khyber Pukhtoonkhwa and Deserts of Sindh). In total, 113 THPs and 44 diabetic patients were interviewed using open-ended and semi-structured questionnaires. Quantitative indices, including Relative Frequency of Citation percentage (RFC %) and Disease Consensus Index (DCI) were calculated. The documented data is authenticated by comparing with 28 published articles on ethno-botanical aspects and many pharmacological studies. RESULTS: In total, 120 plant species belonging to 50 families were reported. The ethno-botanical results indicated that Moraceae (11 species); herb (56 reports) is dominant life form; the leaves (56 reports) are the most used plant part and decoction (24%) is the preferred mode of preparation. The quantitative analysis shows that RFC% ranges from 14 to 42 and DCI varies from 0.15 to 0.74. By comparing to previous studies, 64 species are reported new in traditional treatment of DM; 40 species are new to pharmacological evidence and 3 species are new to phytochemical studies. CONCLUSIONS: This study recoded the significant indigenous knowledge about anti-diabetic plants among the THPs and diabetic patients in Pakistan. This type of ethno-botanical knowledge on traditional use of anti-diabetic plants is an important step in designing detailed pharmacological and clinical trials for Diabetes Miletus treatment. It is recommended that further pharmacological and phytochemical analysis should be conducted on those species which lack previous references in literature and have highest Frequency of Citation (FC), Disease Consensus Index (DCI) and Relative Frequency of Citation percentage (RFC%). PMID- 26231448 TI - Ethanol extract of Bupleurum falcatum and saikosaponins inhibit neuroinflammation via inhibition of NF-kappaB. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The root of Bupleurum falcatum L. (BF) has been used in traditional Korean and Chinese medicines for over 2000 years to treat infections, fever, and chronic liver diseases. Among the many active compounds in BF ethanol extract (BFE), saikosaponins exert pharmacological activities including anti-inflammatory effects. Activated microglial cells release a variety of pro-inflammatory substances, leading to neuronal cell death and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The aim of the present study was to investigate the mechanism of the anti neuroinflammatory effects of BFE using lipopolysaccharide (LPS)-stimulated microglial cells and LPS-intraperitoneal injected C57BL/6 mice. MATERIALS AND METHODS: Dried roots of BF were extracted with 70% ethanol (tenfold volume) on a stirring plate for 24h at room temperature to prepare BFE. Pure saikosaponins (SB3, SB4, and SD) were prepared by solvent extraction and column chromatography fractionation. BV2 murine microglial cells were treated with BFE or saikosaponins for 4h and stimulated with LPS. Generation of nitric oxide (NO), inflammatory cytokines, and reactive oxygen species (ROS) from activated microglial cells were monitored. The effects of BFE on NF-kappaB activation were determined using RT PCR, reporter assay, and immunostaining. The in vivo effects of BFE were also assessed by immunohistochemical staining of tissue sections from LPS-injected mouse brains. RESULTS: Treatment with BFE or saikosaponins dose-dependently attenuated LPS-induced production of NO, iNOS mRNA, and ROS by 30-50%. They reduced LPS-mediated increases in the mRNA levels of IL-6, IL-1beta, and TNF alpha by approximately 30-70% without affecting cell viability, and decreased LPS mediated NF-kappaB activity via reducing p65/RELA mRNA, transcriptional activity, and nuclear localization of NF-kappaB. BFE also reduced LPS-induced activation of microglia and astrocytes in the hippocampus and substantia nigra of LPS-injected mice. CONCLUSION: Our data suggest that BFE may be effective for reducing neuroinflammation-mediated neurodegeneration through suppressing NF-kappaB mediated inflammatory pathways. PMID- 26231446 TI - Regulation of Clostridium difficile spore germination by the CspA pseudoprotease domain. AB - Clostridium difficile is a spore-forming obligate anaerobe that is a leading cause of healthcare-associated infections. C. difficile infections begin when its metabolically dormant spores germinate in the gut of susceptible individuals. Binding of bile salt germinants to the Csp family pseudoprotease CspC triggers a proteolytic signaling cascade consisting of the Csp family protease CspB and the cortex hydrolase SleC. Conserved across many of the Clostridia, Csp proteases are subtilisin-like serine proteases that activate pro-SleC by cleaving off its inhibitory pro-peptide. Active SleC degrades the protective cortex layer, allowing spores to resume metabolism and growth. This signaling pathway, however, is differentially regulated in C. difficile, since CspC functions both as a germinant receptor and regulator of CspB activity. CspB is also produced as a fusion to a catalytically inactive CspA domain that subsequently undergoes interdomain processing during spore formation. In this study, we investigated the role of the CspA pseudoprotease domain in regulating C. difficile spore germination. Mutational analyses revealed that the CspA domain controls CspC germinant receptor levels in mature spores and is required for optimal spore germination, particularly when CspA is fused to the CspB protease. During spore formation, the YabG protease separates these domains, although YabG itself is dispensable for germination. Bioinformatic analyses of Csp family members suggest that the CspC-regulated signaling pathway characterized in C. difficile is conserved in related Peptostreptococcaceae family members but not in the Clostridiaceae or Lachnospiraceae. Our results indicate that pseudoproteases play critical roles in regulating C. difficile spore germination and highlight that diverse mechanisms control spore germination in the Clostridia. PMID- 26231449 TI - Systems pharmacology to decipher the combinational anti-migraine effects of Tianshu formula. AB - Migraine is the most common neurovascular disorder that imparts a considerable burden to health care system around the world. However, currently there are still no effective and widely applicable pharmacotherapies for migraine patients. Herbal formulae, characterized as multiple herbs, constituents and targets, have been acknowledged with clinical effects in treating migraine, which attract more and more researchers' attention although their exact molecular mechanisms are still unclear. In this work, a novel systems pharmacology-based method which integrates pharmacokinetic filtering, target fishing and network analysis was developed and exemplified by a probe, i.e. Tianshu formula, a widely clinically used anti-migraine herbal formula in China which comprises of Rhizoma chuanxiong and Gastrodia elata. The results exhibit that 20 active ingredients of Tianshu formula possess favorable pharmacokinetic profiles, which have interactions with 48 migraine-related targets to provide potential synergistic therapeutic effects. Additionally, from systematic analysis, we speculate that R. chuanxiong as the monarch herb mediates the major targets like PTGS2, ESR1, NOS2, HTR1B and NOS3 to regulate the vascular and nervous systems, as well as the inflammation and pain related pathways to benefit migraine patients. Meanwhile, as an adjuvant herb, G. elata may not only assist the monarch herb to improve the outcome of migraine patients, but also regulate multiple targets like ABAT, HTR1D, ALOX15 and KCND3 to modify migraine accompanying symptoms like vomiting, vertigo and gastrointestinal disorders. PMID- 26231450 TI - Abortifacient potential of methanolic extract of Anthocephalus cadamba stem bark in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants possessing abortifacient activity have been used traditionally for a long time in folk medicine. Anthocephalus cadamba, is one such herb that has been known to possess abortifacient potential in ethnobotanical literature, but has not been validated scientifically. MATERIALS AND METHODS: The methanolic extract of Anthocephalus cadamba stem bark (MEAC) was prepared and tested for abortifacient, estrogenic and uterotrophic activity. Pregnant Swiss albino mice were randomized into 5 groups (1-5). Group 1 (negative control) received 0.2% w/v agar, group 2-4 (received extract at the dose of 500, 1000 and 1500mg/kg b.w.) and group 5 received mifepristone at a dose of 5.86mg/kg b.w. respectively, by oral route from 10(th) to 18(th) day post-coitum daily, and various parameters recorded. The uterotrophic bioassay was performed in bilaterally ovariectomized mice dosed from 9(th) to 15(th) day of ovariectomy and change in uterotrophic parameters was observed. RESULTS: Preliminary phytochemical screening revealed presence of glycosides, alkaloids, steroids, saponins, triterpenoids, flavonoids and tannins. No signs of clinical toxicity were observed at any time during the period of treatment. The extract significantly reduced (P<0.05) the number of live fetus, weight and survival ratio of the fetus, number of corpora lutea, progesterone, estradiol and luteinizing hormone whereas the number of dead fetus, number of mice that aborted, percentage vaginal opening and post-implantation loss increased significantly (P<0.05). The estrogenicity experiments showed increase in uterine weight (P<0.05), ballooning of uterus, uterine glucose (P<0.05) and ALP (P<0.001) in extract treated group dose dependently. In addition, the extract also induced vaginal bleeding preceding parturition. CONCLUSION: This study has substantiated the abortifacient potential of the methanolic extract of Anthocephalus cadamba stem bark. The activity was more marked in 1000 and 1500mg/kg b.w. of the extract and was comparable to that of mifepristone. The mechanism of abortion could possibly be through changes in the uterine mileu, altered hormone levels, luteolysis and partly, estrogenicity. This study thus justifies the ethnobotanical claim of MEAC as an abortifacient. PMID- 26231451 TI - Ethnopharmacological evaluation of medicinal plants used against malaria by quilombola communities from Oriximina, Brazil. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Malaria is the most important parasitic disease in the world, including in the Amazon region, due to its high incidence. In addition, malaria is difficult to control because of the geographical characteristics of the endemic Amazon region. The quilombola communities of Oriximina, located in remote rainforest areas, have extensive experience with medicinal plants due to their close contact with and dependence on local biodiversity as a therapeutic resource. To search for active bioproducts against malaria, based on in vitro tests using blood culture-derived parasites and plants selected by an ethno-directed approach in traditional quilombola communities of Oriximina, in the Amazon region of Brazil. MATERIALS AND METHODS: Ethnobotanical data were collected from 35 informants in the quilombola communities of Oriximina, Brazil, by a free-listing method for the survey of species locally indicated to be effective against malaria and related symptoms. Data were analyzed by salience index (S) and major use agreement. The activity of extracts from 11 plants, selected based on their Salience values (four plants with S>1; seven plants with S<0.1), was measured in vitro in cultures of W2 clone Plasmodium falciparum parasites resistant to chloroquine. RESULTS: Thirty-five ethnospecies comprising 40 different plants belonging to 23 botanical families and 37 genera were listed as antimalarials by the ethno-directed approach. Among these, 11 species selected based on their S values were assayed against P. falciparum. The most active plant extracts, with an IC50 as low as 1.6MUg/mL, were obtained from Aspidosperma rigidum (Apocynaceae), Bertholletia excelsa (Lecythidaceae) and Simaba cedron (Simaroubaceae), all of which displayed an S value>1. CONCLUSION: A strong correlation between the consensus of the informants from quilombola communities living in a malaria endemic area and the salience index indicating antiplasmodial activity was observed, where the ethnospecies mostly cited to be effective against malaria produced the most active plant extracts in vitro. It was also evident from the data that these groups approached the treatment of malaria with an holistic view, making use of purgative, depurative, emetic and adaptogen plants. PMID- 26231452 TI - Comparative pharmacokinetics of the main compounds of Shanzhuyu extract after oral administration in normal and chronic kidney disease rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pharmacokinetic studies on traditional Chinese medicine are useful to evaluate and predict the drug efficacy and safety. The renal impairment may affect drug clearance and other pharmacokinetic processes which can increase toxicity and drug to drug interactions or cause ineffective therapy. Pharmacokinetic studies in pathological status rats might be meaningful for revealing the action mechanism and improving clinical medication of the herb medicine. MATERIALS AND METHODS: A highly sensitive and rapid ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method with multiple-reaction monitoring (MRM) mode was developed and validated for simultaneous quantitation of morroniside and loganin in normal and doxorubicin-induced chronic kidney disease (CKD) rat plasma after oral administration of Shanzhuyu (fruit of Cornus officinalis) extract. RESULTS: Both calibration curves gave satisfactory linearity (r>0.99) at linear range of 1.96-1962.5ngmL(-1) for morroniside, 1.53 1531.25ngmL(-1) for loganin. The precision and accuracy of the in vivo study were assessed by intra-day and inter-day assays. The percentages of relative standard deviation (RSD) were all within 9.58% and the accuracy (RE) was in the -6.02% to 8.11% range. The extraction recoveries of morroniside, loganin and internal standard (IS) were all >67.62% and the matrix effects ranged from 95.07% to 102.75%. CONCLUSIONS: The pharmacokinetic behavior of morroniside and loganin in normal and CKD rat plasma was determined in this paper. The significant different pharmacokinetic parameters might partly result from the changes of P-glycoprotein and metabolic enzymes in the pathological state. The pharmacokinetic research in the pathological state might provide more useful information to guide the clinical usage of the herb medicine. PMID- 26231453 TI - The Revised Quality Standards: "A Man's Reach Should Exceed His Grasp" or "A Bridge Too Far": Which is the Case? PMID- 26231454 TI - Vibrational relaxation as the driving force for wavelength conversion in the peridinin-chlorophyll a-protein. AB - We present a computationally derived energy transfer model for the peridinin chlorophyll a-protein (PCP), which invokes vibrational relaxation in the two lowest singlet excited states rather than internal conversion between them. The model allows an understanding of the photoinduced processes without assuming further electronic states or a dependence of the 2Ag state character on the vibrational sub-state. We report molecular dynamics simulations (CHARMM22 force field) and quantum mechanics/molecular mechanics (QM/MM) calculations on PCP. In the latter, the QM region containing a single peridinin (Per) chromophore or a Per-Chl a (chlorophyll a) pair is treated by density functional theory (DFT, CAM B3LYP) for geometries and by DFT-based multireference configuration interaction (DFT/MRCI) for excitation energies. The calculations show that Per has a bright, green light absorbing 2Ag state, in addition to the blue light absorbing 1Bu state found in other carotenoids. Both states undergo a strong energy lowering upon relaxation, leading to emission in the red, while absorbing in the blue or green. The orientation of their transition dipole moments indicates that both states are capable of excited-state energy transfer to Chl a, without preference for either 1Bu or 2Ag as donor state. We propose that the commonly postulated partial intramolecular charge transfer (ICT) character of a donating Per state can be assigned to the relaxed 1Bu state, which takes on ICT character. By assuming that both 1Bu and 2Ag are able to donate to the Chl a Q band, one can explain why different chlorophyll species in PCP exhibit different acceptor capabilities. PMID- 26231455 TI - Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. AB - BACKGROUND: The thrombopoietin receptor agonist eltrombopag has been shown to be safe, tolerable, and effective for adults with chronic immune thrombocytopenia. We aimed to investigate the safety and efficacy of eltrombopag for children with chronic immune thrombocytopenia. METHODS: PETIT2 was a two part, randomised, multicentre, placebo-controlled study done at 38 centres in 12 countries (Argentina, Czech Republic, Germany, Hong Kong, Israel, Italy, Russia, Spain, Taiwan, Thailand, UK, and USA). Paediatric patients aged 1-17 years who had chronic immune thrombocytopenia and platelet counts less than 30 * 10(9) per L were randomly assigned (2:1) to receive eltrombopag or placebo. We stratified patients by age into three cohorts (patients aged 12-17 years, 6-11 years, and 1 5 years) before randomly entering them into a 13 week, double-blind period. Randomisation was done by the GlaxoSmithKline Registration and Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who were allocated eltrombopag received tablets (except for those aged 1-5 years who received an oral suspension formulation) once per day for 13 weeks. Starting doses for patients aged 6-17 were based on bodyweight, and ethnic origin and ranged between 50 mg/day and 25 mg/day (starting dose for patients aged 1-5 years was 1.2 mg/kg/day or 0.8 mg/kg/day for east Asian patients). Patients who completed the double-blind period entered a 24 week open label treatment period in which all patients received eltrombopag at either the starting dose (if they were formerly on placebo) or their established dose. The primary outcome was the proportion of patients achieving platelet counts of at least 50 * 10(9) per L in the absence of rescue therapy for 6 or more weeks from weeks 5 to 12 of the double-blind period. The intention-to-treat population included in the efficacy assessment consisted of all patients who were randomly assigned to one of the treatment groups, and the safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01520909. FINDINGS: Beginning in March 15, 2012, 92 patients were enrolled, and the trial was completed on Jan 2, 2014. 63 patients were assigned to receive eltrombopag and 29 were assigned to receive placebo. In the double-blind period, three patients discontinued treatment because of adverse events: two patients in the eltrombopag group withdrew because of increased liver aminotransferases and one in the placebo group withdrew because of abdominal haemorrhage. 25 (40%) patients who received eltrombopag compared with one (3%) patient who received placebo achieved the primary outcome of platelet counts of at least 50 * 10(9) per L for 6 of the last 8 weeks of the double-blind period (odds ratio 18.0, 95% CI, 2.3-140.9; p=0.0004). Responses were similar in all cohorts (eltrombopag vs placebo: 39% vs 10% for patients aged 12-17 years, 42% vs 0% for patients aged 6-11 years, and 36% vs 0% for patients aged 1-5 years). Proportionately fewer patients who received eltrombopag (23 [37%] of 63 patients) had WHO grades 1-4 bleeding at the end of the double-blind period than did those who received placebo (16 [55%] of 29 patients); grades 2-4 bleeding were similar (three [5%] patients who received eltrombopag vs two [7%] patients who received placebo). During the 24-week open-label treatment period, 70 [80%] of 87 patients achieved platelet counts of 50 * 10(9) per L or more at least once. Adverse events that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (11 [17%] patients), rhinitis (10 [16%] patients), upper respiratory tract infection (7 [11%] patients), and cough (7 [11%] patients). Serious adverse events occurred in five (8%) patients who received eltrombopag and four (14%) who received placebo. Safety was consistent between the open-label and double-blind periods. No deaths, malignancies, or thromboses occurred during the trial. INTERPRETATION: Eltrombopag, which produced a sustained platelet response in 40% of patients with chronic immune thrombocytopenia, is a suitable therapeutic option for children with chronic symptomatic immune thrombocytopenia. We identified no new safety concerns and few patients discontinued treatment because of adverse events. FUNDING: GlaxoSmithKline. PMID- 26231456 TI - First clinical use of a bioprosthetic total artificial heart: report of two cases. AB - BACKGROUND: The development of artificial hearts in patients with end-stage heart disease have been confronted with the major issues of thromboembolism or haemorrhage. Since valvular bioprostheses are associated with a low incidence of these complications, we decided to use bioprosthetic materials in the construction of a novel artificial heart (C-TAH). We report here the device characteristics and its first clinical applications in two patients with end stage dilated cardiomyopathy. The aim of the study was to evaluate safety and feasibility of the CARMAT TAH for patients at imminent risk of death from biventricular heart failure and not eligible for transplant. METHODS: The C-TAH is an implantable electro-hydraulically actuated pulsatile biventricular pump. All components, batteries excepted, are embodied in a single device positioned in the pericardial sac after excision of the native ventricles. We selected patients admitted to hospital who were at imminent risk of death, having irreversible biventricular failure, and not eligible for heart transplantation, from three cardiac surgery centres in France. FINDINGS: The C-TAH was implanted in two male patients. Patient 1, aged 76 years, had the C-TAH implantation on Dec 18, 2013; patient 2, aged 68 years, had the implantation on Aug 5, 2014. The cardiopulmonary bypass times for C-TAH implantation were 170 min for patient 1 and 157 min for patient 2. Both patients were extubated within the first 12 postoperative hours and had a rapid recovery of their respiratory and circulatory functions as well as a normal mental status. Patient 1 presented with a tamponade on day 23 requiring re-intervention. Postoperative bleeding disorders prompted anticoagulant discontinuation. The C-TAH functioned well with a cardiac output of 4.8-5.8 L/min. On day 74, the patient died due to a device failure. Autopsy did not detect any relevant thrombus formation within the bioprosthesis nor the different organs, despite a 50-day anticoagulant-free period. Patient 2 experienced a transient period of renal failure and a pericardial effusion requiring drainage, but otherwise uneventful postoperative course. He was discharged from the hospital on day 150 after surgery with a wearable system without technical assistance. After 4 months at home, the patient suffered low cardiac output. A change of C-TAH was attempted but the patient died of multiorgan failure. INTERPRETATION: This preliminary experience could represent an important contribution to the development of total artificial hearts using bioprosthetic materials. FUNDING: CARMAT SA. PMID- 26231457 TI - The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. AB - BACKGROUND: Traditional genetic testing focusses on analysis of one or a few genes according to clinical features; this approach is changing as improved sequencing methods enable simultaneous analysis of several genes. Neonatal diabetes is the presenting feature of many discrete clinical phenotypes defined by different genetic causes. Genetic subtype defines treatment, with improved glycaemic control on sulfonylurea treatment for most patients with potassium channel mutations. We investigated the effect of early, comprehensive testing of all known genetic causes of neonatal diabetes. METHODS: In this large, international, cohort study, we studied patients with neonatal diabetes diagnosed with diabetes before 6 months of age who were referred from 79 countries. We identified mutations by comprehensive genetic testing including Sanger sequencing, 6q24 methylation analysis, and targeted next-generation sequencing of all known neonatal diabetes genes. FINDINGS: Between January, 2000, and August, 2013, genetic testing was done in 1020 patients (571 boys, 449 girls). Mutations in the potassium channel genes were the most common cause (n=390) of neonatal diabetes, but were identified less frequently in consanguineous families (12% in consanguineous families vs 46% in non-consanguineous families; p<0.0001). Median duration of diabetes at the time of genetic testing decreased from more than 4 years before 2005 to less than 3 months after 2012. Earlier referral for genetic testing affected the clinical phenotype. In patients with genetically diagnosed Wolcott-Rallison syndrome, 23 (88%) of 26 patients tested within 3 months from diagnosis had isolated diabetes, compared with three (17%) of 18 patients referred later (>4 years; p<0.0001), in whom skeletal and liver involvement was common. Similarly, for patients with genetically diagnosed transient neonatal diabetes, the diabetes had remitted in only ten (10%) of 101 patients tested early (<3 months) compared with 60 (100%) of the 60 later referrals (p<0.0001). INTERPRETATION: Patients are now referred for genetic testing closer to their presentation with neonatal diabetes. Comprehensive testing of all causes identified causal mutations in more than 80% of cases. The genetic result predicts the best diabetes treatment and development of related features. This model represents a new framework for clinical care with genetic diagnosis preceding development of clinical features and guiding clinical management. FUNDING: Wellcome Trust and Diabetes UK. PMID- 26231458 TI - Estimating the global prevalence of hepatitis B. PMID- 26231459 TI - Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. AB - BACKGROUND: The quantification of the burden of disease attributable to hepatitis B virus (HBV) infection and the adaptation of prevention and control measures requires knowledge on its prevalence in the general population. For most countries such data are not routinely available. We estimated the national, regional, and global prevalence of chronic HBV infection. METHODS: For this systematic review and pooled analysis, we searched for data on prevalence of chronic HBV infection published between Jan 1, 1965, and Oct 23, 2013, in the databases Medline, Embase, CAB Abstracts (Global health), Popline, and Web of Science. We included studies reporting the hepatitis B surface antigen (HBsAg) serological marker of chronic HBV infection in non-high-risk groups and extracted data into a customised database. For each country, we calculated HBsAg prevalence estimates and 95% CIs weighted by study size. We extrapolated prevalence estimates to population sizes in 2010 to obtain the number of individuals with chronic HBV infection. FINDINGS: Of the 17,029 records screened, 1800 report on the prevalence of HBsAg covering 161 countries were included. HBsAg seroprevalence was 3.61% (95% CI 3.61-3.61) worldwide with highest endemicity in countries of the African region (total 8.83%, 8.82-8.83) and Western Pacific region (total 5.26%, 5.26-5.26). Within WHO regions, prevalence ranged from 0.20% (0.19-0.21; Mexico) to 13.55% (9.00-19.89; Haiti) in the Americas, to 0.48% (0.12 1.90; the Seychelles) to 22.38% (20.10-24.83; South Sudan) in the African region. We estimated that in 2010, globally, about 248 million individuals were HBsAg positive. INTERPRETATION: This first global assessment of country-level population prevalence of chronic HBV infection found a wide variation between countries and highlights the need for continued prevention and control strategies and the collection of reliable epidemiologic data using standardised methodology. FUNDING: World Health Organization. PMID- 26231460 TI - A novel total artificial heart: search for haemocompatibility. PMID- 26231461 TI - Genetics and neonatal diabetes: towards precision medicine. PMID- 26231462 TI - Thrombopoietin-receptor agonists in children with immune thrombocytopenia. PMID- 26231463 TI - Legionnaires' disease. AB - Since first identified in early 1977, bacteria of the genus Legionella are recognised as a common cause of community-acquired pneumonia and a rare cause of hospital-acquired pneumonia. Legionella bacteria multisystem manifestations mainly affect susceptible patients as a result of age, underlying debilitating conditions, or immunosuppression. Water is the major natural reservoir for Legionella, and the pathogen is found in many different natural and artificial aquatic environments such as cooling towers or water systems in buildings, including hospitals. The term given to the severe pneumonia and systemic infection caused by Legionella bacteria is Legionnaires' disease. Over time, the prevalence of legionellosis or Legionnaires' disease has risen, which might indicate a greater awareness and reporting of the disease. Advances in microbiology have led to a better understanding of the ecological niches and pathogenesis of the condition. Legionnaires' disease is not always suspected because of its non-specific symptoms, and the diagnostic tests routinely available do not offer the desired sensitivity. However, effective antibiotics are available. Disease notification systems provide the basis for initiating investigations and limiting the scale and recurrence of outbreaks. This report reviews our current understanding of this disease. PMID- 26231464 TI - Uterus transplantation trial: Psychological evaluation of recipients and partners during the post-transplantation year. AB - OBJECTIVE: To explore the psychology and well-being of the nine patients undergoing uterus transplantation (UTx) as part of the first clinical trial, during the first 12 months of which seven patients experienced graft survival with occasional mild rejection episodes and two patients experienced graft failure, with hysterectomy. DESIGN: Prospective observational study. SETTING: University hospital. PATIENT(S): Nine female uterine recipients and their partners. INTERVENTION(S): Psychological evaluations by questionnaires focusing on quality of life, mood, relationship, and fertility quality of life were conducted at inclusion and at 3, 6, and 12 months after UTx. MAIN OUTCOME MEASURE(S): Scores of four different questionnaires regarding mood, quality of life, fertility quality of life, and relationship. RESULT(S): In all questionnaire domains, the recipients and their partners showed a similar pattern at baseline, and the UTx group, including both recipients and partners, scored similarly or better when compared with relevant norm groups. Among the recipients there was a reversible decline in score of physical activity and increased bodily pain at 3 months past surgery. CONCLUSION(S): The results show that participants of this first UTx trial were psychologically stable both at baseline and during the first year, despite rejection episodes and possible worries about viability of graft. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.govNCT01844362. PMID- 26231465 TI - Prediction of problematic complexes from PPI networks: sparse, embedded, and small complexes. AB - BACKGROUND: The prediction of protein complexes from high-throughput protein protein interaction (PPI) data remains an important challenge in bioinformatics. Three groups of complexes have been identified as problematic to discover. First, many complexes are sparsely connected in the PPI network, and do not form dense clusters that can be derived by clustering algorithms. Second, many complexes are embedded within highly-connected regions of the PPI network, which makes it difficult to accurately delimit their boundaries. Third, many complexes are small (composed of two or three distinct proteins), so that traditional topological markers such as density are ineffective. RESULTS: We have previously proposed three approaches to address these challenges. First, Supervised Weighting of Composite Networks (SWC) integrates diverse data sources with supervised weighting, and successfully fills in missing co-complex edges in sparse complexes to allow them to be predicted. Second, network decomposition (DECOMP) splits the PPI network into spatially- and temporally-coherent subnetworks, allowing complexes embedded within highly-connected regions to be more clearly demarcated. Finally, Size-Specific Supervised Weighting (SSS) integrates diverse data sources with supervised learning to weight edges in a size-specific manner-of being in a small complex versus a large complex-and improves the prediction of small complexes. Here we integrate these three approaches into a single system. We test the integrated approach on the prediction of yeast and human complexes, and show that it outperforms SWC, DECOMP, or SSS when run individually, achieving the highest precision and recall levels. CONCLUSION: Three groups of protein complexes remain challenging to predict from PPI data: sparse complexes, embedded complexes, and small complexes. Our previous approaches have addressed each of these challenges individually, through data integration, PPI-network decomposition, and supervised learning. Here we integrate these approaches into a single complex-discovery system, which improves the prediction of all three types of challenging complexes. With our approach, protein complexes can be more accurately and comprehensively predicted, allowing a clearer elucidation of the modular machinery of the cell. PMID- 26231466 TI - Economic realities and the health plight of Americans. PMID- 26231467 TI - Tiotropium for the treatment of adolescents with moderate to severe symptomatic asthma: a systematic review with meta-analysis. AB - BACKGROUND: The role of tiotropium for the treatment of adolescents with asthma has not yet been clearly defined. OBJECTIVE: To assess the efficacy and safety of inhaled tiotropium in adolescents with moderate to severe symptomatic asthma. METHODS: Randomized, placebo-controlled trials were included in this systematic review. Primary outcomes were peak and trough forced expiratory volume in 1 second (FEV1). RESULTS: Three studies (approximately 1,000 patients) were included. Tiotropium was associated with significant improvements in FEV1 peak (mean change from baseline) by 120 mL (P < .001) and trough by 100 mL (P < .001) compared with placebo. Tiotropium significantly reduced the percentage of patients who experienced an Asthma Control Questionnaire 7 worsening episode defined as a change from trial baseline of 0.5 points or more compared with placebo (2.1% vs 4.8%, number needed to treat = 38) and also was associated with a significantly decreased in the number of patients with at least one exacerbation compared with placebo (17.6 vs 23.8%, number needed to treat = 16). Finally, no significant differences were found in rescue medication use, withdrawals, withdrawals due to adverse events (AEs), AEs (27.3% vs 27.1%), and serious AEs (6.5% vs 7.1%). Tiotropium in doses of 2.5 MUg once daily or 5.0 MUg once daily resulted in equivalent effects. CONCLUSIONS: Tiotropium was well tolerated and efficacious as an addition to maintenance treatment with an inhaled corticosteroid or an inhaled corticosteroid plus a long-acting beta-agonist in adolescents with moderate to severe asthma. Available data do not suggest an advantage of the 5-MUg once-daily dose (used in adults) compared with the 2.5-MUg once-daily dose of tiotropium. PMID- 26231468 TI - Advanced virtual monoenergetic images: improving the contrast of dual-energy CT pulmonary angiography. AB - AIM: To investigate the value of advanced virtual monoenergetic image reconstruction (mono-plus) from dual-energy computed tomography (CT) for improving the contrast of CT pulmonary angiography (CTPA). MATERIALS AND METHODS: Forty consecutive patients (25 women, mean 62.5 years, range 28-87 years) underwent 192-section dual-source CTPA with dual-energy CT (90/150 SnkVp) after the administration of 60 ml contrast media (300 mg iodine/ml). Conventional virtual monochromatic images at 60 keV and 17 mono-plus image datasets from 40 190 keV (in 10 keV steps) were reconstructed. Subjective image quality (artefacts, subjective noise) was rated. Attenuation was measured in the pulmonary trunk and in the right lower lobe pulmonary artery; noise was measured in the periscapular musculature. The signal-to-noise (SNR) and contrast-to-noise ratios (CNR) were calculated for each patient and dataset. Comparisons between monochromatic images and mono-plus images were performed by repeated measures analysis of variance (ANOVA) with post-hoc Bonferroni correction. RESULTS: Interreader agreement was good to excellent for subjective image quality (ICC: 0.616-0.889). As compared to conventional 60 keV images, artefacts occurred less (p=0.001) and subjective noise was rated lower (p<0.001) in mono-plus 40 keV images. Noise was lower (p<0.001), and the SNR and CNR in the pulmonary trunk and right lower lobe pulmonary artery were higher (both, p<0.001) in mono-plus 40 keV images compared to conventional monoenergetic 60 keV images. Transient interruption of contrast (TIC) was found in 14/40 (35%) of patients, with subjective contrast being similar 8/40 (20%) or higher 32/40 (80%) in mono-plus 40 keV as compared to conventional monoenergetic 60 keV images. CONCLUSIONS: Compared to conventional virtual monoenergetic imaging, mono-plus images at 40 keV improve the contrast of dual-energy CTPA. PMID- 26231469 TI - Pro-angiogenic cellular and genomic expression patterns within glioblastoma influences dynamic susceptibility weighted perfusion MRI. AB - AIM: To investigate whether quantitative dynamic susceptibility-weighted contrast enhanced (DSC) perfusion magnetic resonance imaging (MRI) metrics are influenced by cellular and genomic expression patterns of glioblastoma angiogenesis. MATERIALS AND METHODS: Twenty-five stereotactic neurosurgical tissue samples were prospectively obtained from enhancing and non-enhancing tumour regions from 10 patients with treatment-naive glioblastoma. Using monoclonal antibodies, histopathological features of angiogenesis were examined: total microvascular density, vascular morphology, and hypoxia. Angiogenic expression patterns of tissue samples were investigated using RNA microarrays. DSC perfusion MRI metrics were measured from the tissue sampling sites. MRI and histopathological variables were compared using Pearson's correlations. Microarray analysis was performed using false discovery rate (FDR) statistics. RESULTS: Thirteen enhancing and 12 non-enhancing MR image-guided tissue specimens were prospectively obtained. Enhancing tumour regions demonstrated a significant difference in DSC perfusion and histopathological metrics of angiogenesis when compared to non-enhancing regions. Four angiogenic pathways (vascular endothelial growth factor [VEGF], hypoxia inducible factor [HIF], platelet-derived growth factor [PDGF], fibroblast growth factor [FGF]; 25 individual genes) were significantly up-regulated within enhancing regions when compared to non-enhancing regions (adjusted p<0.05, FDR <0.05). A statistically significant correlation was observed between VEGF-A expression, microvascular density, microvascular morphology, and DSC perfusion MRI metrics (p<0.05). CONCLUSION: Pro-angiogenic genomic and cellular expression patterns of treatment-naive primary glioblastoma significantly influences morphological and physiological DSC perfusion metrics suggesting that expression levels of therapeutically relevant genetic signatures can be quantified using MRI. PMID- 26231470 TI - PI-RADS version 2: what you need to know. AB - Prostate cancer is the second most prevalent cancer in men worldwide and its incidence is expected to double by 2030. Multi-parametric magnetic resonance imaging (MRI) incorporating anatomical and functional imaging has now been validated as a means of detecting and characterising prostate tumours and can aid in risk stratification and treatment selection. The European Society of Urogenital Radiology (ESUR) in 2012 established the Prostate Imaging-Reporting and Data System (PI-RADS) guidelines aimed at standardising the acquisition, interpretation and reporting of prostate MRI. Subsequent experience and technical developments have highlighted some limitations, and a joint steering committee formed by the American College of Radiology, ESUR, and the AdMeTech Foundation have recently announced an updated version of the proposals. We summarise the main proposals of PI-RADS version 2, explore the evidence behind the recommendations, and highlight key differences for the benefit of those already familiar with the original. PMID- 26231471 TI - SCA1 patients may present as hereditary spastic paraplegia and must be included in spastic-ataxias group. AB - INTRODUCTION: The combination of cerebellar ataxia and spasticity is common. However, autosomal dominant genetic diseases presenting with spastic-ataxia are a smaller group. Pyramidal signs have been frequently observed in several SCA subtypes, particularly in spinocerebellar ataxia type 1. METHODS: We prospectively evaluated the pyramidal signs and spasticity in SCA1 patients, and correlated the data with genetic and clinical features. RESULTS: In this study, we observed that spasticity may be an early and presenting feature of SCA1, since 3 patients had pyramidal signs and spasticity as the first neurological sign. SCA1 patients with spasticity were significantly younger. CONCLUSION: SCA1 may rarely present with pure spastic paraplegia, resembling hereditary spastic paraplegia, before the appearance of cerebellar signs. This observation may confuse the neurologist when a genetic testing is requested for an autosomal dominant spastic paraplegia, directing research to hereditary spastic paraplegia group. PMID- 26231472 TI - Elevated salivary protein in Parkinson's disease and salivary DJ-1 as a potential marker of disease severity. AB - INTRODUCTION: There is an urgent need to identify robust biomarkers for Parkinson's disease (PD). Previous studies have shown changes in composition and secretion of saliva in patients with PD, including an increase in salivary DJ-1 concentration. Autonomic dysfunction is a known feature of PD and could contribute to abnormal salivary gland function. METHODS: In this pilot cross sectional study, characterisation of the saliva of 16 patients with PD and 22 age matched controls was performed. Salivary DJ-1 concentration was measured with quantitative immunoblotting; total protein concentration with a BCA assay and spectrophotometry; amylase with an amylase activity assay; albumin with an ELISA and mucin concentration with periodic-acid Schiff staining of SDS-gels. RESULTS: Patient saliva showed an increase in both total protein concentration (8.4 vs 5.0 mg/ml, p = 0.0002) and DJ-1 concentration (0.84 vs 0.42 MUg/ml, p = 0.001), but there was no difference in salivary DJ-1 after adjusting for total protein concentration. In patients, adjusted DJ-1 levels correlated with disease severity measured with the MDS-Unified Parkinson's Disease Rating Scale (p = 0.019). Patient saliva had elevated concentrations of amylase (127 vs 64 units/ml, p = 0.0005) and albumin (110 vs 47MUg/ml, p = 0.0003) but not mucins. CONCLUSIONS: This study suggests that the saliva of patients with PD is different in composition to that of healthy age-matched controls, supporting the notion that saliva may be a good candidate for biomarker discovery in PD. The specific differences suggest that major salivary glands and gingival crevicular fluid may both be sources of additional DJ-1 and protein in patient saliva. PMID- 26231473 TI - Practice Change after Evaluation of an Offline Correction Protocol for Image guided Radiotherapy in Head and Neck Cancer. PMID- 26231474 TI - The National Institutes of Health Stroke Scale Lacks Validity in Chronic Hemiparetic Stroke. AB - BACKGROUND: The National Institutes of Health Stroke Scale (NIHSS) is purported to be associated with long-term outcomes. This study determined the concurrent validity of the NIHSS with the Stroke Impact Scale (SIS), a previously validated measure of health status in chronic stroke survivors. METHODS: The NIHSS and the SIS were administered to 147 subjects before participation in a multicenter, randomized, controlled trial. A Spearman's rho was used to determine correlations between NIHSS total score and (1) SIS physical dimension scores, (2) SIS overall perception of recovery scores, and (3) the SIS activities and independent activities of daily living (ADL/IADL) scores. SIS score variation and medians between subjects who scored a zero versus a nonzero on the NIHSS was also assessed. RESULTS: There was no association between total NIHSS scores and SIS physical dimension scores, SIS overall perception of recovery scores, and SIS ADL/IADL scores (P = -.036, P = .782; P = -.039, P = .640; P = -.054, P = .520; respectively). Lastly, significant variation and similar median scores on the SIS were found between those scoring a zero on the NIHSS versus those who did not score a zero. CONCLUSIONS: The NIHSS has no association with health status in chronic stroke and lacks association with measures of impairment and functional limitation. From these findings, we conclude that the NIHSS has poor validity to discern long-term poststroke outcomes and is not associated with health status. Because of possible limitation in the NIHSS's ability to accurately determine outcomes in this population, we recommend restriction of its use to the acute stage of recovery. PMID- 26231475 TI - Safety and Hemodynamic Profile of Propofol and Dexmedetomidine Anesthesia during Intra-arterial Acute Stroke Therapy. AB - BACKGROUND: There is limited data on the safety, hemodynamic profile, and outcome of patients undergoing intra-arterial therapy (IAT) for acute ischemic stroke (AIS) under sedation with dexmedetomidine (DEX) versus propofol (PROP). METHODS: Retrospective study of patients with anterior circulation AIS, who underwent IAT without intubation, and received either DEX or PROP between January 2008 and December 2012, was performed. Demographics, stroke treatments, time metrics, anesthesia, intraprocedural hemodynamics, vasopressor use, infarct volumes, recanalization status, and intracerebral hemorrhage were collected. RESULTS: Seventy-two patients met inclusion criteria, of which 35 received DEX and 37 PROP. There was no difference in baseline demographics, stroke treatments, successful recanalization, hemorrhages, infarct volume growth, good clinical outcome (mRS <= 2 [19% versus 22%, P = .742]), or in-hospital mortality (18% versus 8%, P = .225) between DEX and PROP. The DEX group had lower intraprocedural minimum systolic blood pressure (103 +/- 27 versus 114 +/- 18 mm Hg, P = .032) and minimum mean arterial pressure (MAP; 67 +/- 17 versus 77 +/- 10 mm Hg, P = .006). More patients in the DEX group experienced episodes of hypotension (MAP < 60 mm Hg; 24% versus 3%; P = .010) and had higher vasopressor requirement (phenylephrine: 1825 +/- 2390 versus 491 +/- 884 mcg, P = .007) compared to PROP. CONCLUSIONS: There was no difference in good clinical outcome or in-hospital mortality in patients undergoing IAT for AIS using DEX versus PROP sedation. However, hemodynamic instability and vasopressor requirement were significantly higher in the DEX group. DEX should be cautiously utilized in IAT. PMID- 26231476 TI - The CHADS2 Components Are Associated with Stroke-Related In-hospital Mortality in Patients with Atrial Fibrillation. AB - BACKGROUND: The CHADS2 score predicts stroke risk in patients with atrial fibrillation. Although strokes caused by atrial fibrillation carry the highest mortality when compared with other etiologies, it is not known whether the CHADS2 score predicts stroke-related mortality in patients with atrial fibrillation. We hypothesized that higher CHADS2 scores would be associated with higher stroke related in-hospital mortality. METHODS: Data were obtained from administrative claims data from all emergency department encounters and hospitalizations at California's nonfederal acute care hospitals between 2008 and 2011. Patients with atrial fibrillation and an admission for acute stroke were identified using appropriate International Classification of Diseases, Ninth Revision (ICD-9), Clinical Modification codes. Age and ICD-9 codes for hypertension, diabetes, congestive heart failure, and prior stroke were used to calculate the CHADS2 score of patients with atrial fibrillation. The primary outcome was in-hospital stroke mortality and the primary predictor was CHADS2 score. A multivariate logistic regression model adjusted for sex and race was used to determine the odds ratio (OR) and 95% confidence interval (CI) for the association between CHADS2 and mortality. RESULTS: Between January 1, 2008, and December 31, 2011, 25,599 patients with atrial fibrillation were hospitalized with a stroke. The odds of in-hospital mortality was significantly higher with a CHADS2 score of 2 more versus less than 2 (OR, 1.15; 95% CI, 1.08-1.23); however, there was no dose response association between the CHADS2 score and in-hospital mortality. Among the individual CHADS2 score items, factors associated with increased in-hospital mortality were congestive heart failure (OR, 1.61; 95% CI, 1.53-1.70), age 75 years or older (OR, 1.27; 95% CI, 1.19-1.35), and diabetes (OR, 1.24; 95% CI, 1.14-1.35). CONCLUSIONS: Unlike prior studies, our studies show that the prestroke CHADS2 score is of limited use in predicting in-hospital mortality in ischemic stroke hospitalizations in patients with atrial fibrillation. PMID- 26231477 TI - Development of an in vitro model system to study the interactions between Mycobacterium marinum and teleost neutrophils. AB - The lack of a reliable mammalian neutrophil in vitro culture system has restricted our ability to examine their precise roles in mycobacterial infections. Previously, we developed the procedures for the isolation and culture of primary kidney-derived neutrophil-like cells from goldfish that are functionally and morphologically similar to mammalian neutrophils. The cultured primary goldfish neutrophils exhibited prolonged viability and functional effector responses. In this study, we demonstrate that when exposed to live or heat-killed Mycobacterium marinum, goldfish neutrophils increased their mRNA levels for several pro-inflammatory cytokines (il-1beta1, il-1beta2, tnfalpha-1, tnfalpha-2) and the cytokine receptors (ifngr1-1, tnfr1, tnfr2). These neutrophils also exhibited chemotaxis toward live mycobacteria, internalized the bacilli, and produced reactive oxygen intermediates (ROI) in response to pathogen exposure. The survival of intracellular mycobacteria was significantly reduced in activated neutrophils, indicating a robust killing response by these teleost granulocytes. We suggest that this goldfish primary neutrophil in vitro model system will provide important information regarding neutrophil-mediated host defense mechanisms against mycobacteria in teleosts as well as in higher vertebrates. PMID- 26231478 TI - Old and new challenges in Chagas disease. AB - Chagas disease, caused by the parasite Trypanosoma cruzi, is a neglected disease, which can lead to cardiomyopathy, arrhythmias, megaviscera, and more rarely, polyneuropathy in up to 30-40% of patients around 20 to 30 years after acute infection. Although it is endemic in the Americas, global population movements mean that it can be located wherever migrants from endemic areas settle. The disease was first described 100 years ago and still challenges clinicians worldwide, since diagnostic, therapeutic, and prognostic methods remain insufficient. Furthermore, factors such as HIV co-infection, immunosuppressive drugs, transplantation, and neoplastic disease can alter the natural course of the infection. We present the case of a Bolivian woman with chronic T cruzi infection diagnosed at our clinic in Madrid, Spain, who subsequently developed non-Hodgkin lymphoma. Our report illustrates the challenges of an increasingly common infection seen in non-endemic countries, and highlights both daily management dilemmas and associated difficulties that arise. PMID- 26231479 TI - Ebola: missed opportunities for Europe-Africa research. PMID- 26231480 TI - Transanal drainage tube placement to prevent anastomotic leakage following colorectal cancer surgery with double stapling reconstruction. AB - PURPOSE: Anastomotic leakage (AL) is a critical complication of colorectal cancer surgery. The transanal drainage tube (TDT) is designed to prevent AL caused by decompression and stasis at the anastomosis. We conducted this study to investigate the feasibility of using the TDT to prevent AL following double stapling technique reconstruction (DST). METHODS: The subjects of this study were 179 patients who underwent curative resection and DST reconstruction for sigmoid colon and rectal cancer in our institution between 2008 and 2013. We analyzed the effectiveness of the TDT for preventing AL. RESULTS: A TDT was placed in 78 patients (43.6 %, TDT group) and not placed in the remaining 101 patients (56.4 %, NTDT group). AL developed in 2 (2.6 %) patients from the TDT group and in 14 (13.9 %) patients from the NTDT group (p = 0.009). Univariate analysis revealed that AL was significantly correlated with tumor distance from the anal verge (AV), the number of staples, and TDT placement. Multivariate analysis revealed a significantly positive correlation between AL and AV [OR 0.877 (0.783-0.982) p = 0.023] and a significantly negative correlation between AL and TDT placement [OR 0.07 (0.013-0.374) p = 0.002]. CONCLUSIONS: Anastomotic decompression with TDT placement may prevent AL after colorectal cancer surgery with DST reconstruction. PMID- 26231481 TI - Kirschner Wire Exposure in Hand and Wrist Trauma. PMID- 26231482 TI - Physician Empathy as a Driver of Hand Surgery Patient Satisfaction. AB - PURPOSE: To examine the relationship between patient-rated physician empathy and patient satisfaction after a single new hand surgery office visit. METHODS: Directly after the office visit, 112 consecutive new patients rated their overall satisfaction with the provider and completed the Consultation and Relational Empathy Measure, the Newest Vital Sign health literacy test, a sociodemographic survey, and 3 Patient-Reported Outcomes Measurement Information System-based questionnaires: Pain Interference, Upper-Extremity Function, and Depression. We also measured the waiting time in the office to see the physician, the duration of the visit, and the time from booking until appointment. Multivariable logistic and linear regression models were used to identify factors independently associated with patient satisfaction. RESULTS: Patient-rated physician empathy correlated strongly with the degree of overall satisfaction with the provider. After controlling for confounding effects, greater empathy was independently associated with patient satisfaction, and it alone accounted for 65% of the variation in satisfaction scores. Older patient age was also associated with satisfaction. There were no differences between satisfied and dissatisfied patients with regard to waiting time in the office, duration of the appointment, time from booking until appointment, and health literacy. CONCLUSIONS: Physician empathy was the strongest driver of patient satisfaction in the hand surgery office setting. As patient satisfaction plays a growing role in reimbursement, targeted educational programs to enhance empathic communication skills in hand surgeons merit consideration. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 26231483 TI - Intraoperative Physical Examination for Diagnosis of Interosseous Ligament Rupture-Cadaveric Study. AB - PURPOSE: To study the intraobserver and interobserver reliability of the diagnosis of interosseous ligament (IOL) rupture in a cadaver model. METHODS: On 12 fresh frozen cadavers, radial heads were cut using an identical incision and osteotomy. After randomization, the soft tissues of the limbs were divided into 4 groups: both IOL and triangular fibrocartilage (TFCC) intact; IOL disruption but TFCC intact; both IOL and TFCC divided; and IOL intact but TFCC divided. All incisions had identical suturing. After standard instruction and demonstration of radius pull-push and radius lateral pull tests, 10 physician evaluators with different levels of experience examined the cadaver limbs in a standardized way (elbow at 90 degrees with the forearm held in both supination and pronation) and were asked to classify them into one of the 4 groups. Next, the same examiners were asked to re-examine the limbs after randomly changing the order of examination. RESULTS: The interobserver reliability of agreement for the diagnosis of IOL injury (groups 2 and 3) was fair in both rounds of examination and the intraobserver reliability was moderate. The intra- and interobserver reliabilities of agreement for the 4 groups of injuries among the examiners were fair in both rounds of examination. The sensitivity, specificity, accuracy, positive, and negative predictive values were all around 70%. The likelihood of a positive test corresponding with the presence of IOL rupture (positive likelihood ratio) was 2.2. The likelihood of a negative test correctly diagnosing an intact IOL was 0.40. CONCLUSIONS: In cadavers, intraoperative tests had fair reliability and 70% accuracy for the diagnosis of IOL rupture using the push-pull and lateral pull maneuvers. The level of experience did not have any effect on the correct diagnosis of intact versus disrupted IOL. CLINICAL RELEVANCE: Although not common, some failure of surgeries for traumatic elbow fracture-dislocations is because of failure in timely diagnosis of IOL disruption. PMID- 26231484 TI - Nuclear Factor-kappaB Activation as a Pathological Mechanism of Lipid Metabolism and Atherosclerosis. AB - Atherosclerosis is a chronic inflammatory disease of the arterial wall with lipid laden lesions, involving a complex interaction between multiple different cell types and cytokine networks. Inflammatory responses mark all stages of atherogenesis: from lipid accumulation in the intima to plaque formation and eventual rupture. One of the most important regulators of inflammation is the transcription factor nuclear factor-kappaB (NF-kappaB), which is activated through the canonical and noncanonical pathways in response to various stimuli. NF-kappaB has long been regarded as a proatherogenic factor, because it is implicated in multiple pathological processes during atherogenesis, including foam cell formation, vascular inflammation, proliferation of vascular smooth muscle cells, arterial calcification, and plaque progression. In contrast, inhibition of NF-kappaB signaling has been shown to protect against atherosclerosis. This chapter aims to discuss recent progress on the roles of NF kappaB in lipid metabolism and atherosclerosis and also to highlight its potential therapeutic benefits. PMID- 26231485 TI - Plasma/Serum Plasmalogens: Methods of Analysis and Clinical Significance. AB - Age-related diseases, such as atherosclerosis and dementia, are associated with oxidative stress and chronic inflammation. Peroxisome dysfunction may be related to aging and age-related pathologies, possibly through the derangement of redox homeostasis. The biosyntheses of plasmalogens (Pls), a subclass of glycerophospholipids, are primarily regulated by peroxisomes. Thus, plasma Pls may reflect the systemic functional activity of peroxisomes and serve as potential biomarkers for diseases related to oxidative stress and aging. Recently, we have established three promising analytical methods for plasma/serum Pls using high-performance liquid chromatography with radioactive iodine, liquid chromatography-tandem mass spectrometry, and enzymatic assay. These methods were validated and used to obtain detailed molecular information regarding these molecules. In cross-sectional studies on asymptomatic, coronary artery disease, and elderly dementia individuals, we found that serum choline Pls, particularly those containing oleic and linoleic acid in the sn-2 position of the glycerol backbone, may serve as reliable antiatherogenic biomarkers. Furthermore, we also found that serum ethanolamine Pls were effective in discriminating cognitive impairment. These results support our hypothesis and further studies are clearly needed to elucidate Pls pathophysiologic significance. PMID- 26231486 TI - Monitoring Trastuzumab Resistance and Cardiotoxicity: A Tale of Personalized Medicine. AB - While approval of trastuzumab, a recombinant monoclonal antibody directed against HER2, along with a diagnostic kit to detect breast cancers which are positive for HER2 overexpression, has advanced a new era of stratified and personalized medicine, it also created several challenges to our scientific and clinical practice. These problems include trastuzumab resistance and trastuzumab-induced cardiotoxicity. In this review, we will summarize data from the literature regarding mechanisms of trastuzumab resistance and trastuzumab-induced cardiotoxicity and present some promising model systems that may advance our understanding of these mechanisms. Our discussion will include development of circulating tumor cells and circulating tumor DNA for monitoring tumor burden, of patient-derived xenograft models for preclinical testing of novel therapies, and of novel therapeutic strategies for trastuzumab-resistance and possible integration of these strategies in the design of co-clinical studies for testing in relevant patient subpopulations. PMID- 26231487 TI - Biomarkers in HCV Infection. AB - Liver-related biomarkers have been developed and validated mainly in patients with chronic hepatitis C for the prediction of liver fibrosis or cirrhosis, which is a final pathway of chronic liver injury. They are noninvasive, traceable, and easy-to-use. Biomarkers provide implications related to screening, diagnosis, treatment, and prognosis of chronic hepatitis. For the improvement of performance and coverage, biomarker panels, imaging biomarkers, and even genetic biomarkers have been developed. With the advancement of genomics and proteomics, earlier and more precise prediction is expected in the near future. In this review, multiple biomarker panels for the estimation of the degree of fibrosis in chronic hepatitis C, biomarkers for the screening and diagnosis of hepatitis C, biomarkers for the treatment of hepatitis C, biomarkers for the prediction of complications related to the chronic hepatitis C, and future perspectives will be summarized. PMID- 26231488 TI - Assessment of DNA Integrity, Applications for Cancer Research. AB - Many methods have been developed for DNA integrity assessment including electrophoresis-based procedures, quantitative PCR, and, more recently, microfluidics-based procedures. DNA integrity evaluation can be employed for characterizing biological samples quality before extensive genomic analysis and also finds applications in reproductive medicine, prenatal diagnostics, or cancer research. In this chapter, we will focus on the assessment of DNA integrity in cancer research. In particular, we will present the application of the determination of DNA integrity for tracking of circulating tumor DNA. Finally, we will conclude by illustrating the potential innovative application of DNA integrity as a biomarker in clinical research, especially for prognostic purposes, patient follow-up, or early diagnosis. PMID- 26231489 TI - Current Progress in Sports Genomics. AB - Understanding the genetic architecture of athletic performance is an important step in the development of methods for talent identification in sport. Research concerned with molecular predictors has highlighted a number of potentially important DNA polymorphisms contributing to predisposition to success in certain types of sport. This review summarizes the evidence and mechanistic insights on the associations between DNA polymorphisms and athletic performance. A literature search (period: 1997-2014) revealed that at least 120 genetic markers are linked to elite athlete status (77 endurance-related genetic markers and 43 power/strength-related genetic markers). Notably, 11 (9%) of these genetic markers (endurance markers: ACE I, ACTN3 577X, PPARA rs4253778 G, PPARGC1A Gly482; power/strength markers: ACE D, ACTN3 Arg577, AMPD1 Gln12, HIF1A 582Ser, MTHFR rs1801131 C, NOS3 rs2070744 T, PPARG 12Ala) have shown positive associations with athlete status in three or more studies, and six markers (CREM rs1531550 A, DMD rs939787 T, GALNT13 rs10196189 G, NFIA-AS1 rs1572312 C, RBFOX1 rs7191721 G, TSHR rs7144481 C) were identified after performing genome-wide association studies (GWAS) of African-American, Jamaican, Japanese, and Russian athletes. On the other hand, the significance of 29 (24%) markers was not replicated in at least one study. Future research including multicenter GWAS, whole-genome sequencing, epigenetic, transcriptomic, proteomic, and metabolomic profiling and performing meta-analyses in large cohorts of athletes is needed before these findings can be extended to practice in sport. PMID- 26231490 TI - Preface. PMID- 26231491 TI - Effects of treatment with Astragalus Membranaceus on function of rat leydig cells. AB - BACKGROUND: Astragalus membranaceus (AM) is a Chinese traditional herb which has been reported to have broad positive effects on many diseases, including hepatitis, heart disease, diabetes and skin disease. AM can promote cell proliferation, increase the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx), and inhibit apoptosis by regulating the transcription of proto-oncogenes controlling cell death. While AM is included in some commercially available "testosterone boosting supplements", studies directly testing ability of AM to modulate testosterone production are lacking. In the present study, we examined the effects of AM on Leydig cell function in vitro. METHODS: Rat Leydig cells were purified and treated with AM at different concentrations (0 MUg/mL, 10 MUg/mL, 20 MUg/mL, 50 MUg/mL, 100 MUg/mL and 150 MUg/mL) and cell counting-8 (CCK-8) assay, Enzyme-linked immunosorbent assay, quantitative real time PCR and analysis of activities of SOD and GPx were done respectively. RESULTS: Treatment with 100 MUg/mL (P<0.05) and 150 MUg/mL AM (P<0.01) significantly increased Leydig cell numbers. Treatment with AM (20 MUg/mL, 50 MUg/mL and 100 MUg/mL) significantly increased testosterone production (P<0.01). In addition, increased Leydig cell SOD and GPx activities were observed in response to 20 MUg/mL and 50 MUg/mL AM treatment (P<0.01). Furthermore, expression of Bax mRNA was significantly decreased (P<0.01), and the ratio of Bcl 2/Bax mRNA was significantly increased in response to 20 MUg/mL AM in the culture medium (P<0.05). CONCLUSIONS: Results supported a beneficial effect of AM on multiple aspects of rat Leydig cell function in vitro including testosterone production. PMID- 26231492 TI - Osteogenic potential of in vitro osteo-induced adipose-derived mesenchymal stem cells combined with platelet-rich plasma in an ectopic model. AB - PURPOSE: The osteogenic potential of in vitro osteo-induced adipose-derived mesenchymal stem cells (ADSCs) combined with platelet-rich plasma (PRP) and implanted on bone mineral matrix (BMM) carrier was examined in a subcutaneous model in Balb/c mice. METHODS: In vitro osteogenic differentiation of ADSCs was monitored by relative bone-related gene expression and osteocalcin expression at the third, seventh and 15th day. Test implants consisting of in vitro osteo induced ADSCs, PRP and BMM (OPC implants) and control implants consisting of PRP and BMM (PC implants) were examined. The relative expression of the bone-related genes encoding osterix, osteocalcin, collagen type I alpha1 and alkaline phosphatase was examined in implants extracted at one, two, four and eight weeks. Histochemical, immunohistochemical and histomorphometric analyses of implants extracted at two and eight weeks were performed. RESULTS: The highest relative expression of bone-related genes and osteocalcin expression was found at the 15th day of in vitro osteogenic induction of the ADSCs. Permanent and continuous increased expression of bone-related genes was noticed in OPC implants at eight weeks. Expression peaks of bone-related genes in PC implants were at two and four weeks, but they significantly decreased at eight weeks. The signs of resorption, formation of callus-like tissue positive for osteocalcin and increased presence of bone cells were found in OPC implants compared with PC implants. A higher percentage of infiltrated tissue and vascularisation was found in OPC than in PC implants. CONCLUSIONS: The combination of in vitro osteo-induced ADSCs and PRP on BMM carrier represents a promising approach for bone regeneration. PMID- 26231493 TI - The application of a three-column internal fixation system with anatomical locking plates on comminuted fractures of the tibial plateau. AB - AIM: The purpose of this study was to describe the operative procedures and clinical outcomes of a new three-column internal fixation system with anatomical locking plates on the tibial plateau to treat complex three-column fractures of the tibial plateau. METHODS: From June 2011 to May 2015, 14 patients with complex three-column fractures of the tibial plateau were treated with reduction and internal fixation through an anterolateral approach combined with a posteromedial approach. The patients were randomly divided into two groups: a control group which included seven cases using common locking plates, and an experimental group which included seven cases with a new three-column internal fixation system with anatomical locking plates. RESULTS: The mean operation time of the control group was 280.7 +/- 53.7 minutes, which was 215.0 +/- 49.1 minutes in the experimental group. The mean intra-operative blood loss of the control group was 692.8 +/- 183.5 ml, which was 471.4 +/- 138.0 ml in the experimental group. The difference was statistically significant between the two groups above. The differences were not statistically significant between the following mean numbers of the two groups: Rasmussen score immediately after operation; active extension-flexion degrees of knee joint at three and 12 months post-operatively; tibial plateau varus angle (TPA) and posterior slope angle (PA) immediately after operation, at three and at 12 months post-operatively; HSS (The Hospital for Special Surgery) knee-rating score at 12 months post-operatively. All fractures healed. CONCLUSION: A three-column internal fixation system with anatomical locking plates on tibial plateau is an effective and safe tool to treat complex three column fractures of the tibial plateau and it is more convenient than the common plate. PMID- 26231494 TI - A 21% conversion rate to total knee arthroplasty of a first-generation patellofemoral prosthesis at a mean follow-up of 9.7 years. AB - PURPOSE: To evaluate the mid- to long-term results of the Richards' type II patellofemoral arthroplasty (PFA) in terms of functional scores, number and type of complications, patient satisfaction and survival. METHODS: We retrospectively studied patients that received a Richards' type II PFA at our institution between 1998 and 2007. Patients with a functioning PFA at the time of this study were evaluated. Outcomes included survival rates with endpoint loss of prosthesis, number and type of complications, Knee Society Scores (KSS) and Visual Analogue Scale (VAS) for pain. In addition, patients were asked how surgery influenced their original symptoms. RESULTS: Twenty-four patients (33 prostheses) were included. Follow-up ranged from 2.2 to 18.8 years with a mean of 9.7 years. Survival at 10 years was 73% (95% CI, 57-93%). Median KSS score was 163 (range, 110-200). Median VAS Pain was 30 (range, 0-80) and VAS Satisfaction median was 90 (range, 50-100). Thirteen (62%) PFAs were rated excellent, six (28%) as good and two (10%) as fair. Twelve (36%) of the cases required further surgery within 4 years after implantation. Seven of these (21%) were converted to TKA after a mean time of 5.5 years, five out of seven were converted because of ongoing tibiofemoral osteoarthritis (TFOA). CONCLUSIONS: We found a rate of 21% (7/33) conversion of the Richards' II PFA to TKA after a mean of 5.5 years; 71% (5/7) of cases were because of TFOA. We strongly advise not to use PFA if there is any sign of joint disease in other compartments than patellofemoral. PMID- 26231495 TI - Outcomes of reverse shoulder arthroplasty using a mini 25-mm glenoid baseplate. AB - PURPOSE: As worldwide use of reverse shoulder arthroplasty (RSA) increases, a range of implant sizes may be required to match regional and ethnic variation in patients' height and bone size. The purpose of this study was to report the outcomes of RSA using a mini 25-mm-diameter glenoid baseplate in smaller patients with rotator cuff arthropathy. METHODS: Between 2009 and 2012, 28 patients underwent RSA for cuff-tear arthropathy using a 25-mm circular glenoid baseplate (Aequlais Reversed, Tornier, Bloomington, MN, USA). Twenty-four patients were able to return for comprehensive follow-up. The mean height of the entire cohort was 158 +/- 10 cm (5 ft. 2 in.). The indication to use a smaller baseplate was a combination of preoperative templating using computed tomography (CT) and intraoperative measurements of glenoid width. RESULTS: At a mean of 36 +/- 8 months' follow-up, there were no revisions or glenoid-sided failures. The mean American Shoulder and Elbow Surgeons (ASES) score was 70 +/- 10, the Simple Shoulder Test (SST) was 10 +/- 2, the Constant was 60 +/- 10 and the Disabilities of the Arm, Shoulder and Hand (DASH) was 18 +/- 15. Mean active forward elevation was 140 +/- 15 degrees , active external rotation was 21 +/- 15 degrees and active internal rotation was to the sacroiliac joint. Mean shoulder strength in flexion was 5.2 +/- 1.7 kg, in external rotation was 2.9 +/- 1.4 kg and in internal rotation was 4.3 +/- 1.2 kg. Radiographs demonstrated no evidence of glenoid loosening. There was, however, a 62 % rate of scapular notching. CONCLUSIONS: Short-term outcomes of mini 25-mm baseplate RSA in proportionally smaller patients are good and demonstrate implant safety and effectiveness. Scapular notching rates are worrisome, and additional follow-up is necessary to determine if notching is progressive and becomes symptomatic. PMID- 26231496 TI - Brain DNA damage and behavioral changes after repeated intermittent acute ethanol withdrawal by young rats. AB - RATIONALE: Alcohol addiction causes severe problems, and its deprivation may potentiate symptoms such as anxiety. Furthermore, ethanol is a neurotoxic agent that induces degeneration and the consequences underlying alcohol-mediated brain damage remain unclear. OBJECTIVES: This study assessed the behavioral changes during acute ethanol withdrawal periods and determined the levels of DNA damage and reactive oxygen species (ROS) in multiple brain areas. METHODS: Male Wistar rats were subjected to an oral ethanol self-administration procedure with a forced diet where they were offered 8% (v/v) ethanol solution for 21 days followed by five repeated 24-h cycles alternating between ethanol withdrawal and re-exposure. Control animals received an isocaloric control diet without ethanol. Behavioral changes were analyzed on ethanol withdrawal days in the open-field (OF) and elevated plus-maze (EPM) tests within the first 6 h of ethanol deprivation. The pre-frontal cortex, hypothalamus, striatum, hippocampus, and cerebellum were dissected for alkaline and neutral comet assays and for dichlorofluorescein ROS testing. RESULTS: The repeated intermittent ethanol access enhanced solution intake and alcohol-seeking behavior. Decreased exploratory activity was observed in the OF test, and the animals stretched less in the EPM test. DNA single-strand breaks and ROS production were significantly higher in all structures evaluated in the ethanol-treated rats compared with controls. CONCLUSIONS: The animal model of repeated intermittent ethanol access induced behavioral changes in rats, and this ethanol exposure model induced an increase in DNA single-strand breaks and ROS production in all brain areas. Our results suggest that these brain damages may influence future behaviors. PMID- 26231497 TI - The cardiac safety of aripiprazole treatment in patients at high risk for torsade: a systematic review with a meta-analytic approach. AB - RATIONALE: Certain antipsychotics increase the risk of heart rate-corrected QT (QTc) prolongation and consequently Torsades de Pointes (TdP) and sudden cardiac death (SCD). Drug-induced Brugada syndrome (BrS) is also associated with SCD. Most SCDs occur in patients with additional cardiac risk factors. OBJECTIVES: Aripiprazole's cardiac safety has not been assessed in patients at high risk for torsade, where QTc prolongation risk is highly increased. METHODS: MEDLINE, Embase, and The Cochrane Library were searched for preclinical, clinical, and epidemiological studies. Eligible studies were reviewed and cardiac safety data were extracted. Continuous and dichotomous QTc data were used in the meta analysis. RESULTS: Preclinical studies suggested that aripiprazole has limited affinity for the delayed rectifier potassium current. TdP was reported in two case reports and SCD was reported in one case report and one case series. No clinical studies assessing aripiprazole's cardiac safety in patients at high risk for torsade were found. No thorough QT (TQT) study with aripiprazole was found. The meta-analysis revealed that the mean DeltaQTc interval was decreased with aripiprazole and QTc prolongation risk was lower compared with placebo and active controls. Epidemiological studies linked aripiprazole to weak/moderate torsadogenicity. No studies were found associating aripiprazole with BrS suggesting low affinity for the fast sodium current. CONCLUSIONS: Aripiprazole is a low-risk antipsychotic regarding cardiac safety in healthy patients. However, baseline and steady state electrocardiogram is recommended in patients at high risk for torsade due to marked QTc prolongation, absence of a TQT study, and lack of data in this group. PMID- 26231499 TI - The Challenges of Limiting Exposure to THS in Vulnerable Populations. AB - Research on active smoking and secondhand smoke exposure has led to policy changes to protect individuals from the adverse health impacts of tobacco smoke. Despite the extensive literature on tobacco, only recently has there been recognition that long-lived tobacco smoke components (known as "thirdhand smoke" or THS) in indoor environments where smoking has taken place may have adverse health consequences. This paper describes THS and addresses the challenges of limiting exposure to THS in vulnerable populations (e.g., nonsmokers and young children). We conducted a limited survey of key stakeholders in the Los Angeles area to better understand approaches to address THS in the real estate and automobile industries. Most respondents indicated concerns about past smoking for property value and reported using various techniques to eliminate THS. We consider examples of other pollutants as case studies, including radon, asbestos, and lead, to help frame policy directions for THS. Based on the information collected from stakeholders and the case studies, we offer policy approaches to managing THS. PMID- 26231498 TI - Psilocybin-induced spiritual experiences and insightfulness are associated with synchronization of neuronal oscillations. AB - RATIONALE: During the last years, considerable progress has been made toward understanding the neuronal basis of consciousness by using sophisticated behavioral tasks, brain-imaging techniques, and various psychoactive drugs. Nevertheless, the neuronal mechanisms underlying some of the most intriguing states of consciousness, including spiritual experiences, remain unknown. OBJECTIVES: To elucidate state of consciousness-related neuronal mechanisms, human subjects were given psilocybin, a naturally occurring serotonergic agonist and hallucinogen that has been used for centuries to induce spiritual experiences in religious and medical rituals. METHODS: In this double-blind, placebo controlled study, 50 healthy human volunteers received a moderate dose of psilocybin, while high-density electroencephalogram (EEG) recordings were taken during eyes-open and eyes-closed resting states. The current source density and the lagged phase synchronization of neuronal oscillations across distributed brain regions were computed and correlated with psilocybin-induced altered states of consciousness. RESULTS: Psilocybin decreased the current source density of neuronal oscillations at 1.5-20 Hz within a neural network comprising the anterior and posterior cingulate cortices and the parahippocampal regions. Most intriguingly, the intensity levels of psilocybin-induced spiritual experience and insightfulness correlated with the lagged phase synchronization of delta oscillations (1.5-4 Hz) between the retrosplenial cortex, the parahippocampus, and the lateral orbitofrontal area. CONCLUSIONS: These results provide systematic evidence for the direct association of a specific spatiotemporal neuronal mechanism with spiritual experiences and enhanced insight into life and existence. The identified mechanism may constitute a pathway for modulating mental health, as spiritual experiences can promote sustained well-being and psychological resilience. PMID- 26231500 TI - Using the Pillars of Infection Prevention to Build an Effective Program for Reducing the Transmission of Emerging and Reemerging Infections. AB - Preventing transmission of emerging infectious diseases remains a challenge for infection prevention and occupational safety programs. The recent Ebola and measles outbreaks highlight the need for pre-epidemic planning, early identification, and appropriate isolation of infected individuals and health care personnel protection. To optimally allocate limited infection control resources, careful consideration of major modes of transmission, the relative infectiousness of the agent, and severity of the pathogen-specific disease are considered. A framework to strategically approach pathogens proposed for health care settings includes generic principles (1) elimination of potential exposure, (2) implementation of administrative controls, (3) facilitation of engineering and environmental controls, and (4) protection of the health care worker and patient using hand hygiene and personal protective equipment. Additional considerations are pre-epidemic vaccination and incremental costs and benefits of infection prevention interventions. Here, major strategies for preventing health-care associated transmissions are reviewed, including reducing exposure; vaccination; administrative, engineering, and environmental controls; and personal protective equipment. Examples from recent outbreaks are used to highlight key infection prevention aspects and controversies. PMID- 26231501 TI - A New Era of Low-Dose Radiation Epidemiology. AB - The last decade has introduced a new era of epidemiologic studies of low-dose radiation facilitated by electronic record linkage and pooling of cohorts that allow for more direct and powerful assessments of cancer and other stochastic effects at doses below 100 mGy. Such studies have provided additional evidence regarding the risks of cancer, particularly leukemia, associated with lower-dose radiation exposures from medical, environmental, and occupational radiation sources, and have questioned the previous findings with regard to possible thresholds for cardiovascular disease and cataracts. Integrated analysis of next generation genomic and epigenetic sequencing of germline and somatic tissues could soon propel our understanding further regarding disease risk thresholds, radiosensitivity of population subgroups and individuals, and the mechanisms of radiation carcinogenesis. These advances in low-dose radiation epidemiology are critical to our understanding of chronic disease risks from the burgeoning use of newer and emerging medical imaging technologies, and the continued potential threat of nuclear power plant accidents or other radiological emergencies. PMID- 26231502 TI - Green Buildings and Health. AB - Green building design is becoming broadly adopted, with one green building standard reporting over 3.5 billion square feet certified to date. By definition, green buildings focus on minimizing impacts to the environment through reductions in energy usage, water usage, and minimizing environmental disturbances from the building site. Also by definition, but perhaps less widely recognized, green buildings aim to improve human health through design of healthy indoor environments. The benefits related to reduced energy and water consumption are well-documented, but the potential human health benefits of green buildings are only recently being investigated. The objective of our review was to examine the state of evidence on green building design as it specifically relates to indoor environmental quality and human health. Overall, the initial scientific evidence indicates better indoor environmental quality in green buildings versus non-green buildings, with direct benefits to human health for occupants of those buildings. A limitation of much of the research to date is the reliance on indirect, lagging and subjective measures of health. To address this, we propose a framework for identifying direct, objective and leading "Health Performance Indicators" for use in future studies of buildings and health. PMID- 26231503 TI - Industrial Food Animal Production and Community Health. AB - Industrial food animal production (IFAP) is a source of environmental microbial and chemical hazards. A growing body of literature suggests that populations living near these operations and manure-applied crop fields are at elevated risk for several health outcomes. We reviewed the literature published since 2000 and identified four health outcomes consistently and positively associated with living near IFAP: respiratory outcomes, methicillin-resistant Staphylococcus aureus (MRSA), Q fever, and stress/mood. We found moderate evidence of an association of IFAP with quality of life and limited evidence of an association with cognitive impairment, Clostridium difficile, Enterococcus, birth outcomes, and hypertension. Distance-based exposure metrics were used by 17/33 studies reviewed. Future work should investigate exposure through drinking water and must improve exposure assessment with direct environmental sampling, modeling, and high-resolution DNA typing methods. Investigators should not limit study to high profile pathogens like MRSA but include a broader range of pathogens, as well as other disease outcomes. PMID- 26231504 TI - Use of Systematic Review and Meta-Analysis in Environmental Health Epidemiology: a Systematic Review and Comparison with Guidelines. AB - Systematic review (SR) and meta-analysis (MA) have potential to contribute substantially to environmental health (EH) risk assessment and policy-making, provided study questions are clear and methods sound. We undertook a systematic review of the published epidemiological literature for studies using both SR and MA examining associations between chronic low-dose chemical exposures and adverse health outcomes in general populations and compared actual methods and reporting with a checklist based on available published guidelines. We identified 48 EH SRMAs meeting these criteria. Associations were mainly positive and statistically significant, often involving large populations. A majority of studies followed most general SRMA guidance, although we identified weaknesses in problem formulation, study search, selection and data extraction, and integrating policy implications. Fewer studies followed EH-specific SRMA recommendations, particularly regarding exposure heterogeneity and other risks of bias. Development and adoption of EH-specific SRMA guidelines would contribute to strengthening these tools for public health decision-making. PMID- 26231505 TI - Perinatal and Childhood Exposure to Cadmium, Manganese, and Metal Mixtures and Effects on Cognition and Behavior: A Review of Recent Literature. AB - Lead (Pb) and mercury (Hg) neurotoxicity is well established. In recent years, a growing body of evidence suggests that environmental exposure to other metals including arsenic (As), cadmium (Cd), and manganese (Mn) and their mixtures also poses public health threats. In this paper, we summarize the recent literature examining the relationship of prenatal and childhood environmental metal exposures with cognitive and behavioral outcomes in children. We conducted a literature search to identify epidemiologic studies that examined the relationship of Cd, Mn, and metal mixtures with children's neurodevelopmental/cognitive and behavioral outcomes. We restricted the search to peer-reviewed studies published in English between January 2009 and March 2015. We identified a total of 31 articles of which 16, 17, and 16 studies examined the effects of Cd, Mn, or metal mixtures, respectively. Based on our review, there is suggestive evidence that prenatal/childhood Cd exposure may be associated with poorer cognition, but additional research is clearly needed. We found little evidence of behavioral effects of early life Cd exposure, and no studies found a significant relationship with attention deficit hyperactivity disorder. Studies of early life Mn exposure consistently reported negative impacts on both cognition and behavior. There is also growing evidence that co-exposure to multiple metals can result in increased neurotoxicity compared to single-metal exposure, in particular during early life. Few studies have evaluated behavioral effects related to metal co-exposure. PMID- 26231507 TI - Mercury Exposure and Heart Rate Variability: a Systematic Review. AB - BACKGROUND: Mercury affects the nervous system and has been implicated in altering heart rhythm and function. We sought to better define its role in modulating heart rate variability, a well-known marker of cardiac autonomic function. DESIGN: This is a systematic review study. METHODS: We searched PubMed, Embase, TOXLINE, and DART databases without language restriction. We report findings as a qualitative systematic review because heterogeneity in study design and assessment of exposures and outcomes across studies, as well as other methodological limitations of the literature, precluded a quantitative meta analysis. RESULTS: We identified 12 studies of mercury exposure and heart rate variability in human populations (ten studies involving primarily environmental methylmercury exposure and two studies involving occupational exposure to inorganic mercury) conducted in Japan, the Faroe Islands, Canada, Korea, French Polynesia, Finland, and Egypt. The association of prenatal mercury exposure with lower high-frequency band scores (thought to reflect parasympathetic activity) in several studies, in particular the inverse association of cord blood mercury levels with the coefficient of variation of the R-R intervals and with low frequency and high-frequency bands at 14 years of age in the Faroe Islands birth cohort study, suggests that early mercury exposure could have a long-lasting effect on cardiac parasympathetic activity. Studies with later environmental exposures to mercury in children or in adults were heterogeneous and did not show consistent associations. CONCLUSIONS: The evidence was too limited to draw firm causal inferences. Additional research is needed to elucidate the effects of mercury on cardiac autonomic function, particularly as early-life exposures might have lasting impacts on cardiac parasympathetic function. PMID- 26231506 TI - Oral Chromium Exposure and Toxicity. AB - Hexavalent chromium [Cr(VI)] is a known carcinogen when inhaled. However, inhalational exposure to Cr(VI) affects only a small portion of the population, mainly by occupational exposures. In contrast, oral exposure to Cr(VI) is widespread and affects many people throughout the globe. In 2008, the National Toxicology Program (NTP) released a 2-year study demonstrating that ingested Cr(VI) was carcinogenic in rats and mice. The effects of Cr(VI) oral exposure are mitigated by reduction in the gut; however, a portion evades the reductive detoxification and reaches target tissues. Once Cr(VI) enters the cell, it ultimately gets reduced to Cr(III), which mediates its toxicity via induction of oxidative stress during the reduction while Cr intermediates react with protein and DNA. Cr(III) can form adducts with DNA that may lead to mutations. This review will discuss the potential adverse effects of oral exposure to Cr(VI) by presenting up-to-date human and animal studies, examining the underlying mechanisms that mediate Cr(VI) toxicity, as well as highlighting opportunities for future research. PMID- 26231508 TI - Manganese Toxicity Upon Overexposure: a Decade in Review. AB - Exposure to manganese (Mn) causes clinical signs and symptoms resembling, but not identical to, Parkinson's disease. Since our last review on this subject in 2004, the past decade has been a thriving period in the history of Mn research. This report provides a comprehensive review on new knowledge gained in the Mn research field. Emerging data suggest that beyond traditionally recognized occupational manganism, Mn exposures and the ensuing toxicities occur in a variety of environmental settings, nutritional sources, contaminated foods, infant formulas, and water, soil, and air with natural or man-made contaminations. Upon fast absorption into the body via oral and inhalation exposures, Mn has a relatively short half-life in blood, yet fairly long half-lives in tissues. Recent data suggest Mn accumulates substantially in bone, with a half-life of about 8-9 years expected in human bones. Mn toxicity has been associated with dopaminergic dysfunction by recent neurochemical analyses and synchrotron X-ray fluorescent imaging studies. Evidence from humans indicates that individual factors such as age, gender, ethnicity, genetics, and pre-existing medical conditions can have profound impacts on Mn toxicities. In addition to body fluid-based biomarkers, new approaches in searching biomarkers of Mn exposure include Mn levels in toenails, non-invasive measurement of Mn in bone, and functional alteration assessments. Comments and recommendations are also provided with regard to the diagnosis of Mn intoxication and clinical intervention. Finally, several hot and promising research areas in the next decade are discussed. PMID- 26231509 TI - MDI Biological Laboratory Arsenic Summit: Approaches to Limiting Human Exposure to Arsenic. AB - This report is the outcome of the meeting "Environmental and Human Health Consequences of Arsenic" held at the MDI Biological Laboratory in Salisbury Cove, Maine, August 13-15, 2014. Human exposure to arsenic represents a significant health problem worldwide that requires immediate attention according to the World Health Organization (WHO). One billion people are exposed to arsenic in food, and more than 200 million people ingest arsenic via drinking water at concentrations greater than international standards. Although the US Environmental Protection Agency (EPA) has set a limit of 10 MUg/L in public water supplies and the WHO has recommended an upper limit of 10 MUg/L, recent studies indicate that these limits are not protective enough. In addition, there are currently few standards for arsenic in food. Those who participated in the Summit support citizens, scientists, policymakers, industry, and educators at the local, state, national, and international levels to (1) establish science-based evidence for setting standards at the local, state, national, and global levels for arsenic in water and food; (2) work with government agencies to set regulations for arsenic in water and food, to establish and strengthen non-regulatory programs, and to strengthen collaboration among government agencies, NGOs, academia, the private sector, industry, and others; (3) develop novel and cost-effective technologies for identification and reduction of exposure to arsenic in water; (4) develop novel and cost-effective approaches to reduce arsenic exposure in juice, rice, and other relevant foods; and (5) develop an Arsenic Education Plan to guide the development of science curricula as well as community outreach and education programs that serve to inform students and consumers about arsenic exposure and engage them in well water testing and development of remediation strategies. PMID- 26231511 TI - UK academic general practice and primary care. PMID- 26231512 TI - Looking back at the past and projecting ahead to the future. PMID- 26231510 TI - The behavioral urgency of objects approaching your avatar. AB - The behavioral-urgency hypothesis (Franconeri & Simons, Psychological Science, 19, 686-692, 2003) states that dynamic visual properties capture human visual attention if they signal the need for immediate action. The seminal example is the potential collision of a looming object with one's body. However, humans are also capable of identifying with entities outside one's own body. Here we report evidence that behavioral urgency transfers to an avatar in a simple 2-D computer game. By controlling the avatar, the participant responded to shape changes of the target in a visual search task. Simultaneously, and completely irrelevant to the task, one of the objects on screen could move. Responses were overall fastest when the target happened to be the moving object and was on a collision course with the avatar, as compared to when the moving target just passed by the avatar or moved away from it. The effects on search efficiency were less consistent, except that search was more efficient overall whenever a target moved. Moreover, response speeding was frequently accompanied by an increase in errors, consistent with recent evidence that the urgency of looming is at least to a large extent expressed in response processes rather than in perceptual selection of the looming object. Thus, a general version of the behavioral-urgency hypothesis also holds for external entities with which the observer can identify. PMID- 26231513 TI - Antibiosis functions during interactions of Trichoderma afroharzianum and Trichoderma gamsii with plant pathogenic Rhizoctonia and Pythium. AB - Trichoderma afroharzianum is one of the best characterized Trichoderma species, and strains have been utilized as plant disease suppressive inoculants. In contrast, Trichoderma gamsii has only recently been described, and there is limited knowledge of its disease suppressive efficacies. Comparative studies of changes in gene expression during interactions of these species with their target plant pathogens will provide fundamental information on pathogen antibiosis functions. In the present study, we used complementary DNA amplified fragment length polymorphism (cDNA-AFLP) analysis to investigate changes in transcript profiling of T. afroharzianum strain LTR-2 and T. gamsii strain Tk7a during in vitro interactions with plant pathogenic Rhizoctonia solani and Pythium irregulare. Considerable differences were resolved in the overall expression profiles of strains LTR-2 and Tk7a when challenged with either plant pathogen. In strain LTR-2, previously reported mycoparasitism-related genes such as chitinase, polyketide synthase, and non-ribosomal peptide synthetase were found to be differentially expressed. This was not so for strain Tk7a, with the only previously reported antibiosis-associated genes being small secreted cysteine rich proteins. Although only one differentially expressed gene was common to both strains LTR-2 and Tk7a, numerous genes reportedly associated with pathogen antibiosis processes were differentially expressed in both strains, including degradative enzymes and membrane transport proteins. A number of novel potential antibiosis-related transcripts were found from strains LTR-2 and Tk7a and remain to be identified. The expression kinetics of 20 Trichoderma (10 from strain LTR 2, 10 from strain Tk7a) transcript-derived fragments (TDFs) were quantified by quantitative reverse transcription PCR (RT-qPCR) at pre- and post-mycelia contact stages of Trichoderma-prey interactions, thereby confirming differential gene expression. Collectively, this research is providing information to elucidate the antibiosis mechanisms and disease suppressive activities of T. afroharzianum and T. gamsii against soilborne fungal and oomycete plant pathogens. PMID- 26231515 TI - Individual differences in resting-state functional connectivity with the executive network: support for a cerebellar role in anxiety vulnerability. AB - This study characterized cerebellar connectivity with executive intrinsic functional connectivity networks. Using seed regions at the right and left dorsolateral prefrontal cortices (dlPFC) and right orbital frontoinsula, we measured resting-state brain connectivity in healthy college-aged participants. Based on the previous research demonstrating a relationship between the cerebellum and self-report measures of behavioral inhibition, we assessed individual differences in connectivity between groups. Overall, intrinsic activity in cerebellar lobule VIII was significantly correlated with the executive network and cerebellar Crus I with the salience network. Between-group comparisons indicated stronger cerebellar connectivity with the executive network in behaviorally inhibited individuals. Intrinsic activity in Crus I, a region previously implicated in non-motor cerebellar functions, significantly correlated with intrinsic activity in the right dlPFC seed region. These findings support a growing number of studies demonstrating cerebellar influence on higher cognitive processes, extending this relationship to individual differences in anxiety vulnerability. PMID- 26231514 TI - Longitudinal Changes in Cerebellar and Thalamic Spontaneous Neuronal Activity After Wide-Awake Surgery of Brain Tumors: a Resting-State fMRI Study. AB - Hypometabolism has been observed in the contralesional cerebellar hemisphere after various supratentorial cortical lesions. It is unknown whether the consequences of the dee- and deafferentation subsequent to wide-awake surgery for brain diffuse low-grade glioma can be assessed within remote and unresected subcortical structures such as the cerebellum or thalamus. To answer this question, we have conducted several regional analyses. More specifically, we have performed amplitude of low-frequency fluctuations (neuronal activity magnitude) and regional homogeneity (local temporal correlations) analyses on resting state functional magnetic resonance imaging (rs-fMRI) data and at different time points, before and after surgery. Our main results demonstrated that it is possible to evaluate subtle subcortical changes using these tools dedicated to the analysis of rs-fMRI data. The observed variations of spontaneous neuronal activity were particularly significant within the cerebellum which showed altered regional homogeneity and neuronal activity intensity in very different, specialized and non-overlapping subregions, in accordance to its neuro-anatomo functional topography. These variations were moreover observed in the immediate postoperative period and recovered after 3 months. PMID- 26231516 TI - Strategies to overcome barriers to implementing osteoporosis and fracture prevention guidelines in long-term care: a qualitative analysis of action plans suggested by front line staff in Ontario, Canada. AB - BACKGROUND: Osteoporosis is a major global health problem, especially among long term care (LTC) facilities. Despite the availability of effective clinical guidelines to prevent osteoporosis and bone fractures, few LTC homes actually adhere to these practical recommendations. The purpose of this study was to identify barriers to the implementation of evidence-based practices for osteoporosis and fracture prevention in LTC facilities and elicit practical strategies to address these barriers. METHODS: We performed a qualitative analysis of action plans formulated by Professional Advisory Committee (PAC) teams at 12 LTC homes in the intervention arm of the Vitamin D and Osteoporosis Study (ViDOS) in Ontario, Canada. PAC teams were comprised of medical directors, administrators, directors of care, pharmacists, dietitians, and other staff. Thematic content analysis was performed to identify the key themes emerging from the action plans. RESULTS: LTC teams identified several barriers, including lack of educational information and resources prior to the ViDOS intervention, difficulty obtaining required patient information for fracture risk assessment, and inconsistent prescribing of vitamin D and calcium at the time of admission. The most frequently suggested recommendations was to establish and adhere to standard admission orders regarding vitamin D, calcium, and osteoporosis therapies, improve the use of electronic medical records for osteoporosis and fracture risk assessment, and require bone health as a topic at quarterly reviews and multidisciplinary conferences. CONCLUSIONS: This qualitative study identified several important barriers and practical recommendations for improving the implementation of osteoporosis and fracture prevention guidelines in LTC settings. PMID- 26231517 TI - Altered Levels of Fatty Acids and Inflammatory and Metabolic Mediators in Epicardial Adipose Tissue in Patients With Systolic Heart Failure. AB - BACKGROUND: Adipose tissue has endocrine properties, secreting a wide range of mediators into the circulation, including factors involved in cardiovascular disease. However, little is known about the potential role of adipose tissue in heart failure (HF), and the aim of this study was to investigate epicardial (EAT) and subcutaneous (SAT) adipose tissue in HF patients. METHODS AND RESULTS: Thirty patients with systolic HF and 30 patients with normal systolic function undergoing thoracic surgery were included in the study. Plasma was sampled and examined with the use of enzyme-linked immunosorbent assays, whereas SAT and EAT biopsies were collected and examined by means of reverse-transcription polymerase chain reaction and gas chromatography. Significantly higher expressions of mRNA encoding interleukin-6, adrenomedullin, peroxisome proliferator-activated receptor alpha, and fatty acid (FA)-binding protein 3, as well as higher levels of monounsaturated FA and palmitoleic acid, were seen in the EAT of HF patients, whereas the levels of docosahexaenoic acid were lower. Palmitoleic acid levels in EAT were correlated with 2 parameters of cardiac remodeling: increasing left ventricular end-diastolic diameter and N-terminal pro-B-type natriuretic peptide. CONCLUSIONS: Our results demonstrate adipose tissue depot-specific alterations of synthesis of FA and inflammatory and metabolic mediators in systolic HF patients. EAT may be a source of increased circulatory and myocardial levels of these mediators through endocrine actions. PMID- 26231518 TI - MAC: identifying and correcting annotation for multi-nucleotide variations. AB - BACKGROUND: Next-Generation Sequencing (NGS) technologies have rapidly advanced our understanding of human variation in cancer. To accurately translate the raw sequencing data into practical knowledge, annotation tools, algorithms and pipelines must be developed that keep pace with the rapidly evolving technology. Currently, a challenge exists in accurately annotating multi-nucleotide variants (MNVs). These tandem substitutions, when affecting multiple nucleotides within a single protein codon of a gene, result in a translated amino acid involving all nucleotides in that codon. Most existing variant callers report a MNV as individual single-nucleotide variants (SNVs), often resulting in multiple triplet codon sequences and incorrect amino acid predictions. To correct potentially misannotated MNVs among reported SNVs, a primary challenge resides in haplotype phasing which is to determine whether the neighboring SNVs are co-located on the same chromosome. RESULTS: Here we describe MAC (Multi-Nucleotide Variant Annotation Corrector), an integrative pipeline developed to correct potentially mis-annotated MNVs. MAC was designed as an application that only requires a SNV file and the matching BAM file as data inputs. Using an example data set containing 3024 SNVs and the corresponding whole-genome sequencing BAM files, we show that MAC identified eight potentially mis-annotated SNVs, and accurately updated the amino acid predictions for seven of the variant calls. CONCLUSIONS: MAC can identify and correct amino acid predictions that result from MNVs affecting multiple nucleotides within a single protein codon, which cannot be handled by most existing SNV-based variant pipelines. The MAC software is freely available and represents a useful tool for the accurate translation of genomic sequence to protein function. PMID- 26231519 TI - A study to prolong breastfeeding duration: design and rationale of the Parent Infant Feeding Initiative (PIFI) randomised controlled trial. AB - BACKGROUND: Very few Australian infants are exclusively breastfed to 6 months as recommended by the World Health Organization. There is strong empirical evidence that fathers have a major impact on their partner's decision to breastfeed and continuation of breastfeeding. Fathers want to participate in the breastfeeding decision making process and to know how they can support their partner to achieve their breastfeeding goals. The aim of the Parent Infant Feeding Initiative (PIFI) is to evaluate the effect on duration of any and exclusive breastfeeding of three breastfeeding promotion interventions of differing intensity and duration, targeted at couples but channelled through the male partner. The study will also undertake a cost-effectiveness evaluation of the interventions. METHODS/DESIGN: The PIFI study is a factorial randomised controlled trial. Participants will be mothers and their male partners attending antenatal classes at selected public and private hospitals with maternity departments in Perth, Western Australia. Fathers will be randomly allocated to either the usual care control group (CG), one of two medium intensity (MI1 and MI2) interventions, or a high intensity (HI) intervention. MI1 will include a specialised antenatal breastfeeding education session for fathers with supporting print materials. MI2 will involve the delivery of an antenatal and postnatal social support intervention delivered via a smartphone application and HI will include both the specialised antenatal class and the social support intervention. Outcome data will be collected from couples at baseline and at six and 26 weeks postnatally. A total of 1600 couples will be recruited. This takes into account a 25% attrition rate, and will detect at least a 10% difference in the proportion of mothers breastfeeding between any two of the groups at 26 weeks at 80% power and 5% level of significance, using a Log rank survival test. Multivariable survival and logistic regression analyses will be used to assess the effect of the treatment groups on the outcomes after adjusting for covariates. DISCUSSION: The PIFI study will be the first Australian study to provide Level II evidence of the impact on breastfeeding duration of a comprehensive, multi-level, male-partner-focused breastfeeding intervention. Unique features of the intervention include its large sample size, delivery of two of the interventions by mobile device technology, a rigorous assessment of intervention fidelity and a cost-effectiveness evaluation. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614000605695. Registered 6 June 2014. PMID- 26231520 TI - Ligand Field Strength Mediates Electron Delocalization in Octahedral [((H)L)2Fe6(L')m](n+) Clusters. AB - To assess the impact of terminal ligand binding on a variety of cluster properties (redox delocalization, ground-state stabilization, and breadth of redox state accessibility), we prepared three electron-transfer series based on the hexanuclear iron cluster [((H)L)2Fe6(L')m](n+) in which the terminal ligand field strength was modulated from weak to strong (L' = DMF, MeCN, CN). The extent of intracore M-M interactions is gauged by M-M distances, spin ground state persistence, and preference for mixed-valence states as determined by electrochemical comproportionation constants. Coordination of DMF to the [((H)L)2Fe6] core leads to weaker Fe-Fe interactions, as manifested by the observation of ground states populated only at lower temperatures (<100 K) and by the greater evidence of valence trapping within the mixed-valence states. Comproportionation constants determined electrochemically (Kc = 10(4)-10(8)) indicate that the redox series exhibits electronic delocalization (class II-III), yet no intervalence charge transfer (IVCT) bands are observable in the near-IR spectra. Ligation of the stronger sigma donor acetonitrile results in stabilization of spin ground states to higher temperatures (~300 K) and a high degree of valence delocalization (Kc = 10(2)-10(8)) with observable IVCT bands. Finally, the anionic cyanide-bound series reveals the highest degree of valence delocalization with the most intense IVCT bands (Kc = 10(12)-10(20)) and spin ground state population beyond room temperature. Across the series, at a given formal oxidation level, the capping ligand on the hexairon cluster dictates the overall properties of the aggregate, modulating the redox delocalization and the persistence of the intracore coupling of the metal sites. PMID- 26231522 TI - Capsule Commentary on Shih et al., Functional Status Outperforms Comorbidities in Predicting Acute Care Readmissions in Medically Complex Patients. PMID- 26231521 TI - Hypoglutamatergic state is associated with reduced cerebral glucose metabolism in anti-NMDA receptor encephalitis: a case report. AB - BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was first described in 2005 in association with ovarian teratoma. The diagnostic workup of this common autoimmune encephalitis includes cerebrospinal fluid analysis, electroencephalography, magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography (FDG-PET). In addition to standard diagnostics, we performed metabolic investigations using proton magnet resonance spectroscopy ((1)H-MRS). CASE PRESENTATION: We describe the case of a non-limbic anti-NMDAR encephalitis with a long course of disease (21 months). Laboratory diagnostics showed antibodies against NMDAR; an MRI revealed unspecific findings. (1)H-MRS indicated a hypoglutamatergic state in the left prefrontal cortex associated with a left hemispherical hypometabolism on FDG-PET. Despite the long course of disease, immunosuppressive therapy with methylprednisolone and azathioprine led to almost complete remission of clinical symptoms. Clinical improvement developed in parallel with remarkable normalization of cerebral glucose metabolism on FDG PET. CONCLUSION: This case of long-lasting extra-limbic anti-NMDAR encephalitis is of high clinical relevance. First, it illustrates that a very good outcome is possible even if adequate therapy is started only 21 months after the onset of severe symptoms. Second, it provides valuable insights into the pathophysiology of such anti-NMDAR encephalitis; these insights prove that anti-NMDAR encephalitis is linked not only to hyperglutamatergic signals but also to hypoglutamatergic states. These findings, contradictory at first glance, can be integrated within the model of excitatory/inhibitory imbalance and local area network inhibition. PMID- 26231523 TI - Liquid chromatography-high resolution mass spectrometry with immunoaffinity clean up for the determination of the oxidative stress biomarker 8-iso-prostaglandin F2alpha in wastewater. AB - A reliable oxidative stress biomarker, 8-iso-prostaglandin F2alpha (8-iso PGF2alpha), was for the first time quantitatively analysed in wastewater using an analytical method consisting of liquid chromatography-high resolution mass spectrometry coupled to immunoaffinity clean-up (IAC-LC-HRMS). Factors influencing the method's robustness were investigated, including analyte stability in sewage and enzymatic deconjugation with beta-glucuronidase. The IAC LC-HRMS method was linear over the range of 0.1-100ng/mL with correlation coefficient (R(2)) of 0.999. The quantification limits were sufficiently low to detect 8-iso-PGF2alpha in sewage (method quantification limit of 0.3ng/L) and precision, expressed as relative standard deviation was less than 7% and the accuracy expressed as relative recovery was in the 103-113% range. As a result, the application of the method to 24-h composite wastewater samples from Oslo showed 8-iso-PGF2alpha concentrations of 18.9-23.3ng/L for 8 days in March 2015. This study demonstrates a standard method to analyse 8-iso-PGF2alpha in sewage that will contribute to the further investigation of the potential use of 8-iso PGF2alpha as a sewage biomarker for assessing the status of community health. PMID- 26231525 TI - Activity of antimicrobial drugs against bacterial pathogens under mild hypothermic conditions. AB - BACKROUND: Infections are a common problem in cardiac arrest survivors. Antimicrobial drugs are often administered in routine care during treatment of patients with mild therapeutic hypothermia (MTH). Because there is to date no evidence for the pharmacodynamics of antimicrobial drugs under MTH conditions, we investigated the in vitro activity of common antimicrobials against clinically relevant bacterial pathogens. MATERIAL AND METHODS: Activities of antimicrobial drugs against clinically relevant bacterial pathogens were assessed in vitro by disk diffusion and broth microdilution assays at normothermic (37 degrees C) and hypothermic (32 degrees C) conditions. RESULTS: Seventy-three bacterial isolates were tested in disk diffusion and 15 in broth microdilution assays. Mean differences in zone diameters and minimal inhibitory concentration ratios were 0.6 mm (95% confidence interval, 0.3-0.9 mm) and 0.98 (95% confidence interval, 0.95-1.02), respectively, meeting predefined criteria for equivalence of in vitro antimicrobial activity. CONCLUSIONS: The presented data provide reassuring evidence that the intrinsic activity of antimicrobials seems to be unaltered in MTH. However, further studies evaluating the pharmacokinetics including target site concentrations of the respective drugs and in vivo pharmacodynamics are necessary to complement our understanding of the appropriate use of antimicrobials in MTH. PMID- 26231524 TI - Factors associated with recent HIV testing among high-risk men who have sex with men: a cross-sectional study in Cambodia. AB - BACKGROUND: Despite remarkable success in the fight against HIV, HIV prevalence in many countries remains high among key populations including men who have sex with men (MSM), and HIV testing rates is relatively low among this hard-to-reach population. This cross-sectional study explores factors associated with recent HIV testing among MSM in Cambodia. METHODS: This study was conducted in 2014 and included 384 MSM randomly selected from two provinces of Battembang and Siem Reap, using a two-stage cluster sampling method. A structured questionnaire was used for face-to-face interviews to collect data on socio-demographic characteristics, HIV testing history, sexual behaviors, HIV testing attitudes, and HIV knowledge. Multivariate logistic regression analysis was performed to identify factors independently associated with recent HIV testing. RESULTS: Mean age of the participants was 23.4 (SD = 5.2). Of total, 83.6 % had been tested for HIV at least once in their lifetime, and 65.1 % had been tested for HIV in the past six months. After controlling for other covariates, MSM who had been tested for HIV in the past six months were significantly more likely to regard themselves as female (AOR = 2.29, 95 % CI = 1.06-5.37), have received some form of HIV education in the past six months (AOR = 3.97, 95 % CI = 1.91-8.26), perceive that they were at higher HIV risk compared to the general population (AOR = 2.48, 95 % CI = 1.14-4.86), have been diagnosed with an STI in the past six months (AOR = 3.19, 95 % CI = 1.02-9.24), report using a condom at last sexual intercourse with a man or woman (AOR = 2.24, 95 % CI = 1.06-3.13), and report using a condom at last sexual intercourse with a boyfriend (AOR = 2.17, 95 % CI = 1.04-5.31). CONCLUSIONS: This study highlights the common practices of risky sexual behaviors and relatively low rate of recent HIV testing among MSM in Cambodia. HIV education and social marketing should be expanded and tailored for MSM, specifically addressing the risk of unprotected anal intercourse and the importance of regular HIV testing for early enrolment in the care and treatment cascade. PMID- 26231526 TI - Acute Generalized Exanthematous Pustulosis: An Uncommon Cause of Fever and Rash. AB - Fever and rash are common presenting complaints to the Emergency Department. This report documents an uncommon diagnosis involving this presentation. The patient presented with signs and symptoms consistent with severe sepsis. Once the diagnosis of Acute Generalized Exanthematous Pustulosis was recognized, the outcome was favorable. PMID- 26231527 TI - Ultrasound-guided infraclavicular brachial plexus block for emergency management of a posterior elbow dislocation. PMID- 26231539 TI - Functional and genomic diversity of methylotrophic Rhodocyclaceae: description of Methyloversatilis discipulorum sp. nov. AB - Three strains of methylotrophic Rhodocyclaceae (FAM1(T), RZ18-153 and RZ94) isolated from Lake Washington sediment samples were characterized. Based on phylogenetic analysis of 16S rRNA gene sequences the strains should be assigned to the genus Methyloversatilis. Similarly to other members of the family, the strains show broad metabolic capabilities and are able to utilize a number of organic acids, alcohols and aromatic compounds in addition to methanol and methylamine. The main fatty acids were 16:1omega7c (49-59%) and 16:0 (32-29%). Genomes of all isolates were sequenced, assembled and annotated in collaboration with the DOE Joint Genome Institute (JGI). Genome comparison revealed that the strains FAM1T, RZ18-153 and RZ94 are closely related to each other and almost equally distant from two previously described species of the genus Methyloversatilis, Methyloversatilis universalis and Methyloversatilis thermotolerans. Like other methylotrophic species of the genus Methyloversatilis, all three strains possess one-subunit PQQ-dependent ethanol/methanol dehydrogenase (Mdh-2), the N-methylglutamate pathway and the serine cycle (isocitrate lyase/malate synthase, Icl/ms(+) variant). Like M. universalis, strains FAM1(T), RZ18-153 and RZ94 have a quinohemoprotein amine dehydrogenase, a tungsten-containing formaldehyde ferredoxin oxidoreductase, phenol hydroxylase, and the complete Calvin cycle. Similarly to M. thermotolerans, the three strains possess two-subunit methanol dehydrogenase (MxaFI), monoamine oxidase (MAO) and nitrogenase. Based on the phenotypic and genomic data, the strains FAM1(T), RZ18 153 and RZ94 represent a novel species of the genus Methyloversatilis, for which the name Methyloversatilis discipulorum sp. nov. is proposed. The type strain is FAM1(T) ( = JCM 30542(T) = VKM = B-2888(T)). PMID- 26231540 TI - Algoriphagus trabzonensis sp. nov., isolated from freshwater, and emended description of Algoriphagus alkaliphilus. AB - A Gram-staining-negative, non-motile, catalase- and oxidase-positive strain, designated MS7(T), was isolated from freshwater of a river near Trabzon, Turkey. Its taxonomy was investigated using a polyphasic approach. The strain grew optimally at 28 degrees C and pH 7.5 and in the presence of 2.0% NaCl. 16S rRNA gene sequence analysis revealed that the strain belonged to the genus Algoriphagus; strain MS7(T) showed highest sequence similarity to the type strains of Algoriphagus alkaliphilus (97.3%), Algoriphagus terrigena (96.8%), Algoriphagus jejuensis (96.2%), Algoriphagus boritolerans (96.1%) and Algoriphagus aquatilis (95.8%). The major fatty acids of strain MS7(T) were iso C15 : 0 (30.14%) and summed future 9 (10-methyl C16 : 0 and/or iso-C17 : 1omega9c 18.75%). Polar lipid analysis revealed phosphatidylethanolamine, a variety of unidentified lipids, an unidentified aminophospholipid, an unidentified phospholipid and an unidentified aminolipid. The major isoprenoid quinone was MK 7.The DNA G+C content of MS7(T) was 41.6 mol%, a value consistent with that of members of the genus Algoriphagus. The level of DNA-DNA relatedness between strain MS7(T) and A. alkaliphilus LMG 22694(T) was 41%, which is clearly below the 70% threshold accepted for species delineation. Thus, our results support the placement of strain MS7(T) within a separate and previously unrecognized species. On the basis of these data, the strain is considered to represent a novel species of the genus Algoriphagus, for which the name Algoriphagus trabzonensis sp. nov. is proposed. The type strain is MS7(T) ( = NCCB 100372(T) = LMG 26290(T)). An emended description of A. alkaliphilus is also provided. PMID- 26231541 TI - Marmoricola aquaticus sp. nov., an actinomycete isolated from a marine sponge. AB - A novel marine actinomycete, designated B374(T), was isolated from a marine sponge, Glodia corticostylifera, which was collected from Sao Paulo, Brasil. The taxonomic position of B374(T) was established by using data derived from a polyphasic approach. The organism showed a combination of chemotaxonomic and morphological characteristics consistent with its classification in the genus Marmoricola and it formed a distinct phyletic line in the clade of the genus Marmoricola, based on 16S rRNA gene sequences. Strain B374(T) was most closely related to Marmoricola aequoreus SST-45(T) (98.5% 16S rRNA gene sequence similarity), but was distinguished from this strain and from the other type strains of species of the genus Marmoricola on the basis of a combination of phenotypic properties. The data obtained, therefore, indicates that isolate B374(T) ( = CBMAI 1089(T) = DSM 28169(T)) should be classified as a novel species of the genus Marmoricola, for which the name Marmoricola aquaticus sp. nov. is proposed. PMID- 26231542 TI - Gelidibacter sediminis sp. nov., isolated from a sediment sample of the Yellow Sea. AB - The Gram-stain-negative, yellow-pigmented, rod-shaped bacterial strain, designated S11-41(T), was isolated from a sediment sample of the Yellow Sea in China. The strain was able to grow well over a wide temperature range (1-35 degrees C). Phylogenetic analysis based on 16S rRNA gene sequences showed that strain S11-41(T) was related to the members of the genus Gelidibacter, sharing highest sequence similarities with the type strains of Geldibacter salicanalis (98.2%), Geldibacter algens (97.4%) and Geldibacter mesophilus (96.9%). The genomic DNA G+C content of strain S11-41(T) was 39.2 mol%. The predominant cellular fatty acids were iso-C15 : 0 (13.2%), iso-C17 : 0 3-OH (12.8%) and iso C15 : 1 G (12.2%). Phosphatidylethanolamine was identified as the major polar lipid. Combined data from phenotypic, phylogenetic and DNA-DNA relatedness studies demonstrated that strain S11-41(T) is a representative of a novel species of the genus Gelidibacter, for which we propose the name Gelidibacter sediminis sp. nov. (type strain S11-41(T)= DSM 28135(T) = LMG 28076(T)). PMID- 26231543 TI - A commentary on the interpretation of the International Code of Nomenclature of Bacteria. PMID- 26231544 TI - Rac1 and Cdc42 Play Important Roles in Arsenic Neurotoxicity in Primary Cultured Rat Cerebellar Astrocytes. AB - This study aimed to explore whether Rac1 and Cdc42, representative members of Ras homologue guanosine triphosphatases (Rho GTPases), are involved in neurotoxicity induced by arsenic exposure in rat nervous system. Expressions of Rac1 and Cdc42 in rat cerebellum and cerebrum exposed to different doses of NaAsO2 (Wistar rats drank 0, 2, 10, and 50 mg/L NaAsO2 water for 3 months) were examined. Both Rac1 and Cdc42 expressions increased significantly in a dose-dependent manner in cerebellum (P < 0.01) by Western blot and immunohistochemistry assay, but in cerebrum, Rac1 and Cdc42 expressions only in 2 mg/L exposure groups were significantly higher than those in control groups (P < 0.01). Five to 50 MUM NaAsO2 decreased cell viability in a dose-dependent manner in primary cultured rat astrocytes, whereas 1 MUM NaAsO2 increased the cell viability in these cells. Rac1 inhibitor, NSC23766, decreased NaAsO2-induced apoptosis and increased the cell viability in primary cultured rat cerebellar astrocytes exposed to 30 MUM NaAsO2. Cdc42 inhibitor, ZCL278, increased cell viability in the cells exposed to 30 MUM NaAsO2. Taken together, our current studies in vivo and in vitro indicate that activations of Rac1 and Cdc42 play a very important role in arsenic neurotoxicity in rat cerebellum, providing a new insight into arsenic neurotoxicity. PMID- 26231546 TI - Response to letter to the editor regarding: "Surgical site infections after hip arthroplasty in Norway, 2005-2011: Influence of duration and intensity of postdischarge surveillance". PMID- 26231545 TI - Epigenetic regulation of serotype expression antagonizes transcriptome dynamics in Paramecium tetraurelia. AB - Phenotypic variation of a single genotype is achieved by alterations in gene expression patterns. Regulation of such alterations depends on their time scale, where short-time adaptations differ from permanently established gene expression patterns maintained by epigenetic mechanisms. In the ciliate Paramecium, serotypes were described for an epigenetically controlled gene expression pattern of an individual multigene family. Paradoxically, individual serotypes can be triggered in Paramecium by alternating environments but are then stabilized by epigenetic mechanisms, thus raising the question to which extend their expression follows environmental stimuli. To characterize environmental adaptation in the context of epigenetically controlled serotype expression, we used RNA-seq to characterize transcriptomes of serotype pure cultures. The resulting vegetative transcriptome resource is first analysed for genes involved in the adaptive response to the altered environment. Secondly, we identified groups of genes that do not follow the adaptive response but show co-regulation with the epigenetically controlled serotype system, suggesting that their gene expression pattern becomes manifested by similar mechanisms. In our experimental set-up, serotype expression and the entire group of co-regulated genes were stable among environmental changes and only heat-shock genes altered expression of these gene groups. The data suggest that the maintenance of these gene expression patterns in a lineage represents epigenetically controlled robustness counteracting short time adaptation processes. PMID- 26231547 TI - Evaluation and quantitative microbial risk assessment of a unique antimicrobial agent for hospital surface treatment. AB - BACKGROUND: It is generally agreed that contaminated hospital surfaces play a role in the transmission of hospital-acquired infections (HAIs). The ability of an antimicrobial agent, engineered at Emory University, to reduce bacterial bioburden on hospital surfaces was examined. A quantitative microbial risk assessment was also conducted to quantify the potential reduction of human health risks associated with application of this antimicrobial product. METHODS: A 1 arm, prospective observational study was conducted. High-frequency contact surfaces within 18 hospital patient rooms were sampled in between patient use. Negative binomial regression with repeated measures was used to examine log CFU/100 cm(2) reductions in total, gram-negative, and Staphylococcus aureus microorganisms. Standard risk assessment methods were used. RESULTS: Multivariate regression demonstrated significant reductions in gram-negative (P < .0001) and S aureus (P = .009) bacteria with increasing patient turnover. No reduction was observed in total bacteria (P = .93). Infection risks were reduced by 4 and 3 logs for gram-positive and gram-negative bacteria, respectively. These risk reductions, along with HAI survey studies, suggest that application of this antimicrobial product could prevent as many as 5%-10% of HAIs. CONCLUSIONS: This study was the first evaluation of a distinctive antimicrobial agent for hospital surface treatment. The findings provide support for the utility of an antimicrobial product in potentially reducing HAI transmission from contaminated environment surfaces. PMID- 26231548 TI - Job embeddedness factors as a predictor of turnover intention among infection control nurses in Korea. AB - BACKGROUND: Job embeddedness indicates the degree to which an employee of an organization intends to remain in his or her position at that organization. This study examined how job embeddedness affects infection control nurses' turnover intention along with general characteristics, job satisfaction, and perceived job alternatives. METHODS: We collected data from a total of 133 infection control nurses using self-reporting questionnaire methods. All questions were answered on a 5-point Likert scale. RESULTS: The average turnover intention was 3.01 +/- 0.72 (100-point conversion, 60.2%), and average job satisfaction was 3.48 +/- 0.79 (100-point conversion, 69.6%). The average perceived availability of job alternatives was 3.02 +/- 0.78 (100-point conversion, 60.4%), and average job embeddedness was 3.33 +/- 0.57 (100-point conversion, 66.6%). Predictors of turnover intention were monthly income, perceived availability of job alternatives, and job embeddedness. Job embeddedness among predictors has high explanatory power as a predictor of infection control nurses' turnover intention. CONCLUSION: Through this study we identified predictors of turnover intention and found that job embeddedness among predictors has high explanatory power as a predictor of infection control nurses' turnover intention. Strategies to enhance infection control nurses' job embeddedness are needed. PMID- 26231549 TI - Surgical site infections, occurrence, and risk factors, before and after an alcohol-based handrub intervention in a general surgical department in a rural hospital in Ujjain, India. AB - BACKGROUND: This study set out to determine occurrence of and risk factors for surgical site infections (SSIs) before and after implementation of an alcohol based handrub (ABHR) intervention in general surgery wards in a rural, tertiary care hospital in India. METHODS: Patients who underwent surgery between October 2010 and August 2011 (preintervention period) or September 2011 and August 2013 (intervention period) in the department of surgery were included. ABHR was introduced in September 2011. SSI was defined as per the Centers for Disease Control and Prevention guidelines. Comparison of SSI rate between the 2 periods was performed using analysis of variance. Risk factors were determined using multiple logistic regression models. RESULTS: Incidence of SSI was 5% (36/720) and 6.5% (103/1,581) respectively, showing nonsignificant difference (P = .5735). The risk factor common for SSI in both periods was the duration of surgery (OR = 2.6 vs OR = 1.96, pre- and intervention periods, respectively). Risk factors in the intervention period were being a woman (OR = 2.18), renal disease (OR = 3.61), diabetes (OR = 4.43), smoking (OR = 2.14), preoperative hospitalization (<3 vs >15 days; OR = 3.22), and previous hospitalization (OR = 3.5). Compared with other studies, the amount of ABHR used in our study was low. CONCLUSION: The amount of ABHR used might not be sufficient to interrupt the chain of contamination of microorganisms; therefore, continuation of the intervention and surveillance is recommended. PMID- 26231550 TI - Assessing the level of knowledge, attitudes, and beliefs about Ebola virus disease among college students. PMID- 26231551 TI - Resistance to synthetic blood penetration of National Institute for Occupational Safety and Health-approved N95 filtering facepiece respirators and surgical N95 respirators. AB - BACKGROUND: Surgical N95 filtering facepiece respirators (FFRs), certified by the National Institute for Occupational Safety and Health (NIOSH) as a respirator and cleared by the Food and Drug Administration (FDA) as a surgical mask, are often used to protect from the inhalation of infectious aerosols and from splashes/sprays of body fluids in health care facilities. A shortage of respirators can be expected during a pandemic. The availability of surgical N95 FFRs can potentially be increased by incorporating FDA clearance requirements in the NIOSH respirator approval process. METHODS: Fluid resistance of NIOSH approved N95 FFRs, and FDA-cleared surgical N95 FFRs and surgical masks was tested using the ASTM F1862 method at 450 and 635 cm/sec velocities and compared with the results from a third-party independent laboratory. Blood penetration through different layers of filter media of masks were also analyzed visually. RESULTS: Four N95 FFR models showed no test failures at both velocities. The penetration results obtained in the NIOSH laboratory were comparable to those from the third-party independent laboratory. The number of respirator samples failing the test increased with increasing test velocity. CONCLUSIONS: The results indicate that several NIOSH-approved N95 FFR models would likely pass FDA clearance requirements for resistance to synthetic blood penetration. PMID- 26231552 TI - Relationship between sharps disposal containers and Clostridium difficile infections in acute care hospitals. AB - BACKGROUND: Sharps disposal containers are ubiquitous in health care facilities; however, there is paucity of data on their potential role in pathogen transmission. This study assessed the relationship between use of single-use versus reusable sharps containers and rates of Clostridium difficile infections in a national sample of hospitals. METHODS: A 2013 survey of 1,990 hospitals collected data on the use of sharps containers. Responses were linked to the 2012 Medicare Provider Analysis and Review dataset. Bivariate and multivariable negative binomial regression were conducted to examine differences in C difficile rates between hospitals using single-use versus reusable containers. RESULTS: There were 604 hospitals who completed the survey; of these, 539 provided data on use of sharps containers in 2012 (27% response rate). Hospitals had, on average, 289 beds (SD +/- 203) and were predominantly non-for-profit (67%) and nonteaching (63%). Most used reusable sharps containers (72%). In bivariate regression, hospitals using single-use containers had significantly lower rates of C difficile versus hospitals using reusable containers (incidence rate ratio [IRR] = 0.846, P = .001). This relationship persisted in multivariable regression (IRR = 0.870, P = .003) after controlling for other hospital characteristics. CONCLUSION: This is the first study to show a link between use of single-use sharps containers and lower C difficile rates. Future research should investigate the potential for environmental contamination of reusable containers and the role they may play in pathogen transmission. PMID- 26231553 TI - Support for the usefulness of passive postdischarge surveillance in surgical site infection. PMID- 26231554 TI - Effects of Patient Centered Interventions on Persistent Urinary Incontinence after Prostate Cancer Treatment: A Randomized, Controlled Trial. AB - PURPOSE: We examined whether an intervention combining pelvic floor muscle exercise and symptom self-management would improve urinary continence and quality of life in patients with prostate cancer. MATERIALS AND METHODS: In a randomized, controlled, longitudinal clinical trial 279 patients with prostate cancer with persistent urinary incontinence were randomized to 1 of 3 groups, including biofeedback pelvic floor muscle exercise plus a support group, the biofeedback exercise plus telephone contact and usual care without intervention. The biofeedback plus support and plus telephone groups received 1 session of biofeedback assisted exercise and 6 biweekly sessions of problem solving therapy. This delivered symptom management skills through a peer support group or telephone contacts for 3 months. All subjects were assessed in blinded fashion at baseline, and 3 and 6 months for urinary leakage frequency, leakage amount and disease specific quality of life. RESULTS: A total of 244 subjects completed the study. The biofeedback plus support and biofeedback plus telephone groups had a lower frequency of daily urinary leakage than the group with usual care without intervention at 3 months (p=0.019 and p<=0.001, respectively) but not at 6 months. The biofeedback plus support group but not the biofeedback plus telephone group had 13.3 gm lower leakage at 6 months than the usual care group (p=0.003). Overall the biofeedback plus support and plus telephone groups reported less symptom severity (p<=0.001) and fewer incontinence problems (p<=0.01) than the usual care group at 6 months. CONCLUSIONS: Study findings show that pelvic floor muscle exercise practice plus symptom self-management in a peer support setting can significantly improve urinary continence and quality of life in patients with prostate cancer. PMID- 26231555 TI - Characterization of Nuclease Activity in Human Seminal Plasma and its Relationship to Semen Parameters, Sperm DNA Fragmentation and Male Infertility. AB - PURPOSE: Some studies have shown that complementary biomarkers are needed in semen analysis to provide a more accurate diagnosis for couples with infertility problems. To our knowledge no study has been done to determine the relationships among nuclease activity in seminal plasma, semen parameters, sperm DNA fragmentation and male infertility. MATERIALS AND METHODS: A total of 94 semen samples were collected according to WHO 2010 semen analysis parameters. Samples were analyzed using the single radial enzyme diffusion method for nuclease activity in seminal plasma, and alkaline and neutral Comet assay for sperm DNA fragmentation. Samples were obtained from 11 fertile donors with proven fertility, 17 patients with normozoospermia in an infertile couple, and 16 patients with asthenozoospermia, 19 with teratozoospermia, 21 with asthenoteratozoospermia and 10 with azoospermia. RESULTS: Nuclease activity analyzed in seminal plasma was higher in patients than in controls. It correlated with sperm motility and morphology, and sperm DNA fragmentation measured by the alkaline Comet assay. No correlation with sperm DNA fragmentation was measured by the neutral Comet assay. ROC curves to determine male infertility revealed 0.658 sensitivity, 0.727 specificity and 0.705 cm(2) AUC for the single radial enzyme diffusion method, 0.918, 1 and 0.994 cm(2) for the alkaline Comet assay, and 0.917, 0.250 and 0.373 cm(2), respectively, for the neutral Comet assay. CONCLUSIONS: Nuclease activity in seminal plasma corrected by sperm count is a good variable to predict male infertility. Results indicate that it could be a useful complementary parameter for male infertility diagnosis. PMID- 26231556 TI - Closeout of the HALT-PKD trials. AB - BACKGROUND: The HALT Polycystic Kidney Disease Trials Network consisted of two randomized, double blind, placebo-controlled trials among patients with autosomal dominant polycystic kidney disease. The trials involved 5-8years of participant follow-up with interventions in blood pressure and antihypertensive therapy. We provide a framework for designing and implementing closeout near the end of a trial while ensuring patient safety and maintaining scientific rigor and study morale. METHODS: We discuss issues and resolutions for determining the last visit, tapering medications, and unblinding of participants to study allocation and results. We also discuss closure of clinical sites and Data Coordinating Center responsibilities to ensure timely release of study results and meeting the requirements of regulatory and funding authorities. RESULTS: Just over 90% of full participants had a 6-month study visit prior to their last visit preparing them for trial closeout. Nearly all patients wanted notification of study results (99%) and treatment allocation (99%). All participants were safely tapered off study and open label blood pressure medications. Within 6months, the trials were closed, primary papers published, and 805 letters distributed to participants with results and allocation. DCC obligations for data repository and clinicaltrials.gov reporting were completed within 12months of the last study visit. CONCLUSIONS: Closeout of our trials involved years of planning and significant human and financial resources. We provide questions for investigators to consider when planning closeout of their trials with focus on (1) patient safety, (2) dissemination of study results and (3) compliance with regulatory and funding responsibilities. PMID- 26231558 TI - Statistical analysis of electromagnetic radiation measurements in the vicinity of GSM/UMTS base station installed on buildings in Serbia. AB - As a result of dense deployment of public mobile base stations, additional electromagnetic (EM) radiation occurs in the modern human environment. At the same time, public concern about the exposure to EM radiation emitted by such sources has increased. In order to determine the level of radio frequency radiation generated by base stations, extensive EM field strength measurements were carried out for 664 base station locations, from which 276 locations refer to the case of base stations with antenna system installed on buildings. Having in mind the large percentage (42 %) of locations with installations on buildings, as well as the inevitable presence of people in their vicinity, a detailed analysis of this location category was performed. Measurement results showed that the maximum recorded value of total electric field strength has exceeded International Commission on Non-Ionizing Radiation Protection general public exposure reference levels at 2.5 % of locations and Serbian national reference levels at 15.6 % of locations. It should be emphasised that the values exceeding the reference levels were observed only outdoor, while in indoor total electric field strength in no case exceeded the defined reference levels. PMID- 26231557 TI - Increased ectodomain shedding of cell adhesion molecule 1 as a cause of type II alveolar epithelial cell apoptosis in patients with idiopathic interstitial pneumonia. AB - BACKGROUND: Lung alveolar epithelial cell (AEC) apoptosis has attracted attention as an early pathogenic event in the development of idiopathic interstitial pneumonia (IIP); however, the causative mechanism remains unclear. Cell adhesion molecule 1 (CADM1) is an AEC adhesion molecule in the immunoglobulin superfamily. It generates a membrane-associated C-terminal fragment, alphaCTF, through protease-mediated ectodomain shedding, termed alpha-shedding. Increased CADM1 alpha-shedding contributes to AEC apoptosis in emphysematous lungs. METHODS: Formalin-fixed, paraffin-embedded lung lobes (n = 39) from 36 autopsied patients with IIP were classified as acute IIP (n = 10), fibrosing-type nonspecific IIP (f NSIP, n = 10), cryptogenic organizing IIP (n = 9), and usual IIP (n = 10). CADM1 expression in the lung sections was examined by western blotting and compared with control lungs (n = 10). The rate of CADM1 alpha-shedding was calculated as the relative amount of alphaCTF to full-length CADM1, and the full-length CADM1 level was estimated per epithelial cell by normalization to cytokeratin 7, a lung epithelial marker. Apoptotic AECs were detected by immunohistochemistry for single-stranded DNA (ssDNA). NCI-H441 and A549 human lung epithelial cells were transfected with small interfering RNA (siRNA) to silence CADM1 expression and analyzed by terminal nucleotide nick end labeling assays. RESULTS: The rate of CADM1 alpha-shedding was higher in all IIP subtypes than in the control (P <= 0.019), and the full-length CADM1 level was lower in f-NSIP (P = 0.007). The alpha-shedding rate and full-length CADM1 level were correlated with each other (P = 0.015) and with the proportion of ssDNA-positive AECs (P <= 0.024). NCI-H441 cells transfected with siRNA exhibited a 61 % lower rate of expression of full length CADM1 and a 17-fold increased proportion of apoptotic cells. Similar results were obtained with A549 cells. CONCLUSIONS: CADM1 alpha-shedding appeared to be increased in all four IIP subtypes and consequently contributed to AEC apoptosis by decreasing the full-length CADM1 level. This mechanism particularly impacted f-NSIP. The molecular mechanism causing AEC apoptosis may be similar between IIP and emphysema. PMID- 26231559 TI - Radiation exposure of the investigator's hand during fusion imaging of the thyroid with 99mTcO4-free-hand SPECT and ultrasound. AB - The objective of this study was to assess the radiation exposure of the investigators' hand during free-hand single photon emission tomography/ultrasound ((99m)TcO4-fhSPECT/US) of the thyroid. Conventional dosimetry by rings with thermoluminescent detectors (TLDs) was performed in 32 patients (Group A), followed by TLD-chipstrate dosimetry in further 20 patients (Group B). In both the groups, the ambient dose rate was measured by dose rate meter (DRM). The applied activity was in the range of 60-80 MBq (99m)TcO4. In Group A, the exposure per investigation was 7.53 uSv (calculated average) by ring dosimetry and 9.02+/-5.64 uSv by DRM; in Group B, 10.93 and 9.51 +/- 1.76 uSv, respectively. Based on estimated 1224 yearly thyroid investigations per nuclear medicine specialist in Germany, the estimated cumulative yearly exposure of the hand was 11.32 mSv. The hand exposure during a thyroid (99m)TcO4-fhSPECT/US of 20 min duration proved modest and comparable with different methods. Yearly examinations in excess of 1000 per investigator are not expected to add a relevant cumulative risk. PMID- 26231560 TI - CXCR2 expression and postoperative complications affect long-term survival in patients with esophageal cancer. AB - BACKGROUND: Esophagectomy is one of the most invasive surgical treatments for digestive tract cancer, and the blood levels of inflammatory cytokines such as interleukin-1, interleukin-6, and interleukin-8 are increased for several hours after surgery or in patients experiencing postoperative complications. CXCR2, an interleukin-8 receptor, is reportedly expressed in several carcinomas, and interleukin-8 signaling promotes cancer cell proliferation. The impact of postoperative complications following esophagectomy on long-term survival is controversial. In this study, we demonstrate the significance of CXCR2 expression and validate the effects of CXCR2 expression and postoperative complications on long-term prognosis of esophageal squamous cell carcinoma using resected specimens. METHODS: Eighty-two specimens were sectioned from archived, paraffin embedded tumor tissues obtained from patients with esophageal squamous cell carcinoma who underwent esophagectomy and extended lymphadenectomy for complete resection of cancer in our institute between 1997 and 2002. Immunohistochemistry was performed using a polyclonal antibody to CXCR2, and the correlation of stainability with clinicopathological factors and long-term survival was examined. RESULTS: CXCR2 was expressed in 33 of 82 (40.2 %) specimens. In the CXCR2-positive group, the recurrence-free survival and overall survival rates of patients who developed postoperative complications were both significantly lower than those for patients who did not develop any complications. In contrast, in the CXCR2-negative group, there was no significant difference in long-term prognosis between patients with and without complications. CXCR2 positivity combined with postoperative complications was an independent risk factor for subsequent tumor recurrence, showing the highest hazard ratio. CONCLUSIONS: Our results suggest that the patients with CXCR2-positive esophageal cancer who develop postoperative complications have a poor prognosis and should be carefully followed. TRIAL REGISTRATION: This study was approved by Keio University School of Medicine Ethics Committee with a trial registration number of 2011-241. PMID- 26231561 TI - Redesigning a General Education Science Course to Promote Critical Thinking. AB - Recent studies question the effectiveness of a traditional university curriculum in helping students improve their critical thinking and scientific literacy. We developed an introductory, general education (gen ed) science course to overcome both deficiencies. The course, titled Foundations of Science, differs from most gen ed science offerings in that it is interdisciplinary; emphasizes the nature of science along with, rather than primarily, the findings of science; incorporates case studies, such as the vaccine-autism controversy; teaches the basics of argumentation and logical fallacies; contrasts science with pseudoscience; and addresses psychological factors that might otherwise lead students to reject scientific ideas they find uncomfortable. Using a pretest versus posttest design, we show that students who completed the experimental course significantly improved their critical-thinking skills and were more willing to engage scientific theories the general public finds controversial (e.g., evolution), while students who completed a traditional gen ed science course did not. Our results demonstrate that a gen ed science course emphasizing the process and application of science rather than just scientific facts can lead to improved critical thinking and scientific literacy. PMID- 26231562 TI - Preparing Biology Graduate Teaching Assistants for Their Roles as Instructors: An Assessment of Institutional Approaches. AB - The inconsistency of professional development (PD) in teaching for graduate teaching assistants (GTAs) is a widespread problem in higher education. Although GTAs serve an important role in retention of undergraduate science majors and in promotion of scientific literacy in nonmajors, they often lack preparation and ongoing support for teaching. Given the recent national focus on instructional quality in introductory courses, our goal was to use an online survey to identify current practices of teaching PD for biology GTAs and compare these results with the last national survey on this topic. In responses from 71 participant institutions, 96% reported some mandatory teaching preparation for biology GTAs; however, 52% of these programs required 10 or fewer hours per year. Respondents wanted to change their programs to include more pedagogical information and teaching observations with feedback to their GTAs. Programmatic self-ratings of satisfaction with GTA PD were positively correlated with the number of topics discussed during PD. Although more schools are requiring GTA PD for teaching compared with the last national survey, the lack of program breadth at many schools warrants a national conversation with regard to recent calls for improving undergraduate instruction. PMID- 26231563 TI - Perception of children's faces with unilateral coronal synostosis--an eye tracking investigation. AB - PURPOSE: Premature unilateral coronal craniosynostosis results in distinctive cranial and facial abnormalities of varying severity, including orbital dystopia and an abnormal head shape. As the face is affected, these children may encounter stigmatization. To avoid this scenario, many parents elect for their child to undergo surgical correction. Laypeople's perception of children with either untreated or treated unilateral coronal craniosynostosis (UCS) has not yet been objectively evaluated. METHODS: This study introduces eye tracking as an objective instrument in order to evaluate the perception of 14 children with coronal synostosis, both pre- and postoperatively. Age-matched healthy children served as a control group. Using standardized photos, the involuntary eye movements and the fixations of 30 unaffected laypeople were evaluated. RESULTS: In the untreated children, whose faces were characterized by striking orbital dystopia, the eyes drew more attention than those of the healthy children. The results of our study demonstrate that the operative correction of unilateral coronal synostosis results in the normalization of the asymmetry of the fronto orbital region, whereas the C-shaped deformity of the midface, which is not addressed via surgery, subsequently attracts more attention. CONCLUSION: Eye tracking objectively evaluates both the perception of craniofacial abnormalities and the extent of the approximation of normality after surgical correction. We introduce eye tracking as an objective measurement tool for craniofacial abnormalities for the first time. PMID- 26231564 TI - Successful delayed non-operative management of C2 neurosynchondrosis fractures in a pediatric patient: a case report and review of management strategies and considerations for treatment. AB - Upper cervical synchondrosis fractures are the most common types of cervical fractures in the pediatric population less than 7 years of age (Blauth et al (Eur Spine J 5:63-70, 1996); Connolly et al (Pediatr Radiol 25(Suppl1):S129-133, 1995); Mandabach et al (Pediatr Neurosurg 19(5):225-232, 1993); Schippers et al (Acta Neurochir 138:524-530, 1990)) The vast majority occur through the dentocentral or basilar synchondrosis. We present the second reported case in recent literature of a unilateral neurosynchondrosis fracture. The patient, a 4 year-old male, was initially managed conservatively with a rigid cervical collar for a period of 3 months. Despite multiple counseling sessions with family, the patient remained poorly compliant with cervical immobilization. After 3 months, imaging demonstrated partial fusion with persistent anterolisthesis of C2 on C3. The decision was made to place the child in external halo fixation as an attempt to achieve fusion prior to committing to internal surgical fixation and the associated sequelae. Immobilization with a hard cervical collar is often first line treatment. In the case of failed fusion, debate exists regarding surgical fixation in children. Occipito-atlanto-axial fusion leads to permanent loss of a significant degree of flexion, extension, and rotatory movement. The pediatric population has a strong propensity to fuse; however, compliance is often a barrier to conservative treatment due to age-related behavioral practices. We demonstrate that even with initial failed fusion and progression of deformity while in a cervical collar, conservative management with external halo fixation can potentially obviate the need for internal fixation. PMID- 26231565 TI - Split cerebral aqueduct: a neuroendoscopic illustration. AB - PURPOSE: Forking of the cerebral aqueduct is a developmental malformation that is infrequently encountered by neurosurgeons as a rare cause of hydrocephalus, sometimes with a delayed onset. The etiology of an apparently forked aqueduct might be different. However, neuroendoscopy can often be the optimal treatment. The purpose of this study was to review the literature by analyzing the anatomical, functional, diagnostic, and therapeutic features of this unusual condition and adding our personal cases. METHODS: We present a case of forking of the cerebral aqueduct that was detected in vivo and treated with a flexible scope. A thorough review of the pertinent literature is also discussed. In the past years, diagnosis of forked aqueduct was possible only postmortem. RESULTS: A forked aqueduct is occasionally encountered in patients when a delayed hydrocephalic decompensation occurs. CONCLUSIONS: Flexible neuroendoscopy enables for a direct, in vivo diagnosis and immediate treatment through a third ventriculostomy. PMID- 26231566 TI - Subcortical heterotopia appearing as huge midline mass in the newborn brain. AB - INTRODUCTION: We report the case of a 2-year-old boy who showed a huge midline mass in the brain at prenatal assessment. CASE REPORT: After birth, magnetic resonance imaging (MRI) revealed a conglomerate mass with an infolded microgyrus at the midline, which was suspected as a midline brain-in-brain malformation. MRI also showed incomplete cleavage of his frontal cortex and thalamus, consistent with lobar holoprosencephaly. The patient underwent an incisional biopsy of the mass on the second day of life. The mass consisted of normal central nervous tissue with gray and white matter, representing a heterotopic brain. The malformation was considered to be a subcortical heterotopia. With maturity, focal signal changes and decreased cerebral perfusion became clear on brain imaging, suggesting secondary glial degeneration. Coincident with these MRI abnormalities, the child developed psychomotor retardation and severe epilepsy focused on the side of the intracranial mass. PMID- 26231567 TI - Expansion and compression distraction osteogenesis based on volumetric and neurodevelopmental analysis in sagittal craniosynostosis. AB - PURPOSE: Distraction osteogenesis (DO) is a less daunting procedure than extensive cranial vault remodeling and has been used to correct sagittal craniosynostosis. The purposes of this study are to describe DO in combination with expansion and compression procedures and to report analytic results based on the cranial index (CI), volumetric measurement, and neurodevelopmental tests. METHODS: Between June 2002 and May 2013, 32 patients with non-syndromic sagittal synostosis who had undergone antero-posterior compression with bitemporal expansion were recruited. Circumferential baseline, mid-sagittal, and bicoronal craniotomies were performed in addition to four-quadrant bone flap procedures via distraction with dural attachment. CI, intracranial volume (ICV), head circumference (HC), and neurodevelopmental outcomes using the Bayley Scales of Infant Development-II (BSID-II) scoring system were analyzed. RESULTS: Dolichocephalic CI (68.85 +/- 3.61) was altered to mesocephalic CI (78.28 +/- 3.74) postoperatively. Preoperative ICV and HC determinations were within the normal range for the majority of participants (normal ICV 87.5%, n = 28; normal HC 75%, n = 24). ICV and HC did not show significant changes with postoperative measurements and were maintained within normal ranges. Regarding neurodevelopment, both the mental and psychomotor developmental indices (MDI, PDI) demonstrated significant improvement (MDI, 88.69 +/- 17.38 to 96.23 +/- 21.05; PDI, 91.38 +/- 16.31 to 100 +/- 11.51; p < 0.05). CONCLUSIONS: Symmetric sagittal synostosis can be treated comprehensively through DO in combination with expansion and compression procedures. ICV and HC measurements were useful for designing surgical and postoperative distraction strategies. Achievement of mesocephalic CI and neurodevelopmental improvement validated morphological and functional effectiveness. PMID- 26231568 TI - Encephalocraniocutaneous lipomatosis, a rare neurocutaneous disorder: report of additional three cases. AB - PURPOSE: Encephalocraniocutaneous lipomatosis (ECCL) is a rare congenital neurocutaneous disorder. It was described by Haberland in 1970 and is also called Haberland syndrome. It is characterized by unilateral skin lesions such as lipomas, connective tissue nevi, and alopecia with ipsilateral ophthalmological and cerebral malformations with or without psychomotor and mental retardation and early-onset seizure. METHODS: We present three pediatric cases (two boys, one girl) with ECCL. All the patients' sociodemographic, clinical, and neuroradiological data was collected. RESULTS: We describe two male (5 and 1.3 years old) and one female (15 years old) cases. All patients have unilateral left sided alopecia with ipsilateral ocular lesion and the cerebral lesion. All patients were born at term; their past history and family histories were unremarkable. Their electroencephalograms showed hemispheric asymmetry. All of the cases had right-sided mild to moderate hemiparesis. In addition, our second case is having optic glioma and this case is the fifth case with glioma associated with ECCL. CONCLUSIONS: We describe three additional cases with ECCL which is an extremely rare neurocutaneous syndrome. Also, case 2 has optic glioma and according to the literature this is the fifth case of low-grade gliomas with ECCL. We suggest that patients who have ocular lesion and ipsilateral skin lesion must be examined for ECCL, and the patients must be followed up with cerebral MRI once a year for low-grade gliomas. PMID- 26231569 TI - Cavernous angioma after chemotherapy for desmoplastic/nodular medulloblastoma associated with anhidrotic ectodermal dysplasia. AB - PURPOSE: While cavernous angioma (CVA) after cranial irradiation has been documented, its development after high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) has not. We present a patient with desmoplastic/nodular medulloblastoma (DNMB) associated with anhidrotic ectodermal dysplasia (AED) who developed CVA 2 years after high-dose chemotherapy and PBSCT. METHODS: A 1-year-old boy with ingravescent vomiting was admitted to our institute. He presented with a large head, a depressed nasal bridge, low-set ears, thick lips with peg-shaped teeth, hypohidrosis, sparse hair, thin atrophic skin, scaly dermatitis with frontal bossing, and a bulging anterior fontanel. Neuroradiological examination revealed multiple cerebellar masses with heterogeneous enhancement and speckled calcifications and severe obstructive hydrocephalus. The histological diagnosis of surgical specimens was DNMB, and he underwent postoperative multiple-drug chemotherapy with autologous PBSCT. The outcome was favorable and he did not undergo radiotherapy. RESULTS: After 2 years, intracranial hemorrhage was detected at his regular radiological check-up and he again underwent surgery. The histological diagnosis was CVA. CONCLUSIONS: To our knowledge, this is the first report of AED-associated DNMB and CVA. PMID- 26231570 TI - Comparison of clinical and radiological manifestations and surgical outcomes of pediatric Chiari I malformations in different age groups. AB - PURPOSE: The aim of this study was to elucidate the differences in clinical and radiological manifestations and treatment outcomes of pediatric Chiari I malformation patients according to age. METHODS: We retrospectively reviewed the patients who received surgery in our institution for symptomatic Chiari I malformations between January 1991 and December 2012. Fifty-four patients were identified, and their medical records were reviewed for clinical presentation, radiological findings, surgical treatment, and outcomes including complications. We divided the patients into 3 groups: Group I (n = 4) younger than 3 years old; Group II (n = 9) between 3 and 5 years old; and Group III (n = 41) older than 5 years old. Surveyed data were compared among the groups. The mean follow-up period was 82.8 months. RESULTS: All of Group I patients presented with stem compression signs. Ventriculomegaly was common (3/4, 75%), but no syrinx or scoliosis was observed. In Group II, scoliosis was the most common presentation (5/9, 56%), and these patients rarely complained any other symptoms. Pain, such as headache (18/41, 44%), was the predominant presentation in Group III. The incidences of syrinx and scoliosis were similar in Groups II and III. There were no differences in the treatment outcomes among the groups. The spinal curve did not improve in 4 of 5 Group II patients despite their early FMD surgeries. The incidence of complications related to cerebrospinal fluid leakage was higher in the young age group. CONCLUSIONS: The clinical and radiological manifestations of pediatric Chiari I malformation appeared to be different according to age. PMID- 26231571 TI - Purification and Initial Functions of Sex-Specific Storage Protein 2 in Bombyx mori. AB - In this study, we identified a heat-resistant protein from the chrysalis stage of the silkworm which we named sex-specific storage protein 2 (SSP2). This protein was stable even at 80 degrees C, and has an amino acid sequence that is 90.65 % homologous to SP2. We utilized the heat-resistant characteristics of SSP2 to purify the protein and maintain its biological activity. In addition, using flow cytometry and the MTT assay, we found that SSP2 had anti-apoptotic effects on BmN cells, and that SSP2 could also inhibit cell apoptosis induced by chemical factors. These results suggest that SSP2 has a cell-protective function, and provides a basis for future work on the function of storage proteins in silkworm. PMID- 26231572 TI - [Pemphigus. Model disease for targeted therapy]. AB - BACKGROUND: Pemphigus is a severe bullous autoimmune dermatosis that represents a clinical challenge despite high-dose immunosuppressive therapy due to the therapy related comorbidities and the lack of long-term control of disease activity. OBJECTIVES: Which targeted therapies are currently used in pemphigus and which innovative therapeutic strategies are in clinical development? MATERIALS AND METHODS: A review of the literature in PubMed was performed under consideration of the current guideline for the treatment of pemphigus as well as of our own results. Discussion of basic findings and results of targeted therapies in autoantibody-mediated autoimmune disorders were taken into account. RESULTS: Immunapheresis and high-dose intravenous immunoglobulins with the aim of reducing circulating autoantibodies have been successfully used in the treatment of pemphigus. Depletion of autoreactive B-lymphocytes provides the rationale for the use of the monoclonal anti-CD20 antibody rituximab which demonstrated long-term clinical remission of pemphigus in clinical trials. Current developments include the investigation of humanised B-cell depleting antibodies in other B-cell driven autoimmune disorders as well as the identification of new cellular and molecular target structures that are essential in the humoral autoimmune cascade and exert important immune regulatory functions, respectively. CONCLUSIONS: The well characterised basic pathogenesis of pemphigus results in targeted therapies. Currently, therapies aiming at rapid reduction of circulating autoantibodies and the depletion of autoreactive B-cells are in clinical use. More cellular and molecular target structures are being investigated in other autoantibody-driven autoimmune disorders and they provide promising candidates for innovative pathogenesis-related therapeutic strategies in pemphigus in the future. PMID- 26231573 TI - Non-communicable disease risk factor patterns among mining industry workers in Papua, Indonesia: longitudinal findings from the Cardiovascular Outcomes in a Papuan Population and Estimation of Risk (COPPER) Study. AB - OBJECTIVES: Non-communicable diseases (NCDs) constitute an increasing slice of the global burden of disease, with the South-East Asia region projected to see the highest increase in NCD-related deaths over the next decade. Mining industry employees may be exposed to various factors potentially elevating their NCD risk. This study aimed to assess the distribution and 5-year longitudinal trends of key metabolic NCD risk factors in a cohort of copper-gold mining company workers in Papua, Indonesia. METHODS: Metabolic indicators of NCD risk were assessed among employees (15 580 at baseline, 6496 prospectively) of a large copper-gold mining operation in Papua, Indonesia, using routinely collected 5-year medical surveillance data. The study cohort comprised individuals aged 18-68 years employed for >=1 year during 2008-2013. Assessed risk factors were based on repeat measures of cholesterol, blood glucose, blood pressure and body weight, using WHO criteria. RESULTS: Metabolic risk indicator rates were markedly high and increased significantly from baseline through 5-year follow-up (p<0.001). Adjusting for gender and age, longer duration of employment (>=10 years) predicted raised cholesterol (adjusted OR (AOR)=1.13, p=0.003), raised blood pressure (AOR=1.16, p=0.009) and overweight/obesity (AOR=1.14, p=0.001) at baseline; and persistent raised cholesterol (AOR=1.26, p=0.003), and both incident (AOR=1.33, p=0.014) and persistent raised blood glucose (AOR=1.62, p=0.044) at 3-year follow-up. CONCLUSIONS: Individuals employed for longer periods in a mining operations setting in Papua, Indonesia, may face elevated NCD risk through various routes. Workplace health promotion interventions and policies targeting modifiable lifestyle patterns and environmental exposures present an important opportunity to reduce such susceptibilities and mitigate associated health risks. PMID- 26231574 TI - Motor behaviors in the sheep evoked by electrical stimulation of the subthalamic nucleus. AB - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is used to treat movement disorders, including advanced Parkinson's disease (PD). The pathogenesis of PD and the therapeutic mechanisms of DBS are not well understood. Large animal models are essential for investigating the mechanisms of PD and DBS. The purpose of this study was to develop a novel sheep model of STN DBS and quantify the stimulation-evoked motor behaviors. To do so, a large sample of animals was chronically-implanted with commercial DBS systems. Neuroimaging and histology revealed that the DBS leads were implanted accurately relative to the neurosurgical plan and also precisely relative to the STN. It was also possible to repeatedly conduct controlled evaluations of stimulation-evoked motor behavior in the awake-state. The evoked motor responses depended on the neuroanatomical location of the electrode contact selected for stimulation, as contacts proximal to the STN evoked movements at significantly lower voltages. Tissue stimulation modeling demonstrated that selecting any of the contacts stimulated the STN, whereas selecting the relatively distal contacts often also stimulated thalamus but only the distal-most contact stimulated internal capsule. The types of evoked motor behaviors were specific to the stimulation frequency, as low but not high frequencies consistently evoked movements resembling human tremor or dyskinesia. Electromyography confirmed that the muscle activity underlying the tremor-like movements in the sheep was consistent with human tremor. Overall, this work establishes that the sheep is a viable a large-animal platform for controlled testing of STN DBS with objective motor outcomes. Moreover, the results support the hypothesis that exaggerated low-frequency activity within individual nodes of the motor network can drive symptoms of human movement disorders, including tremor and dyskinesia. PMID- 26231575 TI - Involvement of chondroitin 6-sulfation in temporal lobe epilepsy. AB - Chondroitin sulfate proteoglycans (CSPGs) are predominant components of the extracellular matrix in the central nervous system (CNS). Previously, we found an increase in the 4-sulfation/6-sulfation (4S/6S) ratio of CSPGs is required for perineuronal net (PNN) formation and results in functional maturation of parvalbumin-expressing interneurons (PV cells) and termination of the critical period in the visual cortex. Here, we report that chondroitin 6-sulfation and chondroitin 6-sulfation-enriched PNNs increased in the mouse cerebral cortex and hippocampus after kainic acid (KA) treatment; simultaneously, chondroitin 4 sulfation-enriched PNNs and the 4S/6S ratio decreased. Furthermore, chondroitin 6 O-sulfotransferase-1 (C6ST-1) transgenic (TG) mice, which overexpress chondroitin 6-sulfated chains and have a decreased 4S/6S ratio, were more susceptible to KA induced seizures than wild-type mice. These results suggested that chondroitin 6 sulfation is relevant to epilepsy most probably because of dysregulated PNN formation and PV cell maturation. PMID- 26231576 TI - Comparison of laparoscopic versus open surgery in a three-stage operation for obstructive left-sided colorectal cancer. AB - BACKGROUND: Treatment for obstructive left-sided colorectal cancer (OLCC) typically consists of a three-staged procedure. During the first stage, the obstruction is managed with diversion colostomy. Traditionally in the second stage, we perform open resection for the primary tumor. In this study, we evaluated the feasibility of laparoscopic resection of OLCC with diversion colostomy in terms of operative results and short-term outcomes. METHODS: A total of 20 patients underwent laparoscopic resection for OLCC (study group), 48 patients underwent open resection for OLCC (control group 1), and 53 patients underwent laparoscopic resection for non-OLCC (control group 2). Afterwards, results from the procedures were obtained and clinical data were analyzed. RESULTS: The operative time was significantly longer in the study group than in the control group 1 (153 minutes vs. 126 minutes, p = 0.041), and the length of hospitalization was shorter in the study group than in the control group 1 (5.3 days vs. 7.6 days, p = 0.032). Regarding the operative results and short-term outcomes, there were no significant differences between the study group and control group 2. Colostomy retraction was a specific morbidity which occurred in two patients of the study group. CONCLUSION: Laparoscopic resection of OLCC with diversion colostomy is feasible. Abdominal cavity adhesion is only limited. We strongly recommend that laparoscopic resection should be performed at least 2 weeks after diversion colostomy, and the plastic rod should be left in place during the pneumoperitoneum to reduce the risk of colostomy retraction. PMID- 26231577 TI - Effect of minodronate on the speed of sound of the calcaneus in postmenopausal women with an increased risk of fractures: A clinical practice-based observational study. AB - BACKGROUND: We previously reported that alendronate and risedronate reduce the urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX) by 44.9% and 34.7%, respectively, at 3 months after the start of treatment, and increase the speed of sound (SOS) of the calcaneus by 0.6% and 0.65%, respectively, at 12 months after the start of treatment in postmenopausal women with osteoporosis. The aim of the present clinical practice-based observational study was to examine the effect of treatment with minodronate for 12 months on the SOS of the calcaneus and on bone turnover markers in postmenopausal women with an increased risk of fractures. METHODS: Forty-two postmenopausal women with osteoporosis or osteopenia with a clinical risk factor for fractures who had been treated with minodronate for > 12 months were enrolled in the study. The SOS and bone turnover markers were monitored during treatment with minodronate for 12 months. RESULTS: Compared to their baseline values, the urinary levels of NTX at 3 months and the serum levels of alkaline phosphatase at 12 months were significantly decreased at 47.5% and 25.8%, respectively. At 12 months, the SOS increased modestly, but significantly, by 0.47%, compared to the baseline value. CONCLUSION: The present study confirmed that minodronate suppressed bone turnover and modestly increased the SOS of the calcaneus in postmenopausal women with an increased risk of fractures. PMID- 26231578 TI - Languages and dialects: bacterial communication beyond homoserine lactones. AB - Gram-negative bacteria use N-acyl homoserine lactones (acyl-HSLs) for communication, predominantly mediated by LuxR-type receptors. Recent studies uncovered aryl-HSLs, alpha-pyrones and dialkylresorcinols as further chemical languages of Gram-negative bacteria. These findings extend the number of bacterial signaling molecules and suggest that cell-cell communication goes far beyond acyl-HSL signaling in nature. PMID- 26231579 TI - Use of log-transformed absorbance spectra for online monitoring of the reactivity of natural organic matter. AB - This study examined the significance of water quality monitoring parameters obtained via logarithmic transformation of the absorbance spectra of raw and treated drinking water. The data were generated using samples of the influent, settled and filtered water acquired weekly over a six months period at two full scale treatment plants. Examination of the weekly plant samples combined with the data of laboratory fractionation and chlorination experiments showed that the slopes of the log-transformed spectra are correlated with typically reported water quality parameters (e.g., its specific absorbance at 254 nm, SUVA254); yet the determination of spectral slopes is considerably simpler and potentially information-rich. The spectral slopes determined for the range of wavelength 280 350 nm were shown to be correlated with the yields of trihalomethanes (THMs) and haloacetic acids (HAAs). These results support the notion that multi-wavelength monitoring of the absorbance spectra of drinking water and their interpretation via logarithmic transformation constitutes a promising practically implementable approach for online water quality monitoring. PMID- 26231580 TI - Impact of virus surface characteristics on removal mechanisms within membrane bioreactors. AB - In this study we investigated the removal of viruses with similar size and shape but with different external surface capsid proteins by a bench-scale membrane bioreactor (MBR). The goal was to determine which virus removal mechanisms (retention by clean backwashed membrane, retention by cake layer, attachment to biomass, and inactivation) were most impacted by differences in the virus surface properties. Seven bench-scale MBR experiments were performed using mixed liquor wastewater sludge that was seeded with three lab-cultured bacteriophages with icosahedral capsids of ~30 nm diameter (MS2, phiX174, and fr). The operating conditions were designed to simulate those at a reference, full-scale MBR facility. The virus removal mechanism most affected by virus type was attachment to biomass (removals of 0.2 log for MS2, 1.2 log for phiX174, and 3 log for fr). These differences in removal could not be explained by electrostatic interactions, as the three viruses had similar net negative charge when suspended in MBR permeate. Removals by the clean backwashed membrane (less than 1 log) and cake layer (~0.6 log) were similar for the three viruses. A comparison between the clean membrane removals seen at the bench-scale using a virgin membrane (~1 log), and the full-scale using 10-year old membranes (~2-3 logs) suggests that irreversible fouling, accumulated on the membrane over years of operation that cannot be removed by cleaning, also contributes towards virus removal. This study enhances the current mechanistic understanding of virus removal in MBRs and will contribute to more reliable treatment for water reuse applications. PMID- 26231581 TI - Impacts of ozonation on the competition between organic micro-pollutants and effluent organic matter in powdered activated carbon adsorption. AB - This study investigates if ozonation of wastewater treatment plant (WWTP) effluent can reduce the negative impacts of effluent organic matter (EfOM) on the adsorption of organic micro-pollutants (OMP) onto powdered activated carbon (PAC). Pre-treatment of the water included membrane filtration for the removal of suspended/colloidal organics, ozonation with various specific ozone consumptions, and subsequent OMP spiking to comparable initial concentrations in all of the ozonated waters. This approach allowed for comparative PAC adsorption tests. Adsorption analyses show that the adsorbability of EfOM decreases with increasing specific ozone consumptions. This is also reflected by liquid chromatography with online carbon and UV254 detection (LC-OCD) which shows the ozone-induced disintegration of large EfOM into smaller fragments. Also, small organic neutrals are decreased while the small organic acids peak continuously increases with rising specific ozone consumptions. UV254 demonstrates that the aromaticity of all LC-OCD fractions continuously declines together with increasing specific O3 consumptions. This explains the varying EfOM adsorbabilities that occur due to ozonation. The ozone-induced decrease of EfOM adsorbability directly translates into reduced adsorption competition against the adsorption of OMP. With higher specific ozone consumptions, OMP removal and OMP loadings increase. The reduced adsorption competition is reflected in the outputs from equivalent background compound (EBC) modeling. In each of the ozonated waters, correlations between the OMP removals and the UV254 removal were found. PMID- 26231582 TI - Dose-response relations between second-hand smoke exposure and depressive symptoms among middle-aged women. AB - A growing body of evidence indicates a strong association between smoking and depression. However, little is known about the possible effects of second-hand smoke (SHS) exposure on depression. This study aimed to examine the potential dose-response relation between SHS exposure and depressive symptoms among non smoking middle-aged women. A cross-sectional survey was conducted using a stratified three-stage sampling method. Depressive symptoms were measured by the Center for Epidemiologic Studies Depression Scale with a cut-off point of 16. Self-reported SHS exposure was defined as non-smokers' inhalation of the smoke exhaled from smokers on at least one day a week. The multivariable logistic regression analysis was completed with adjustment for potential confounders. Among 1280 middle-aged women, 19.4% were classified as having depressive symptoms. There was a 104% increased odds of depressive symptoms corresponding to SHS exposure in general (OR=2.04, 95% CI 1.48-2.79) using no exposure as reference. There were significant positive relations between SHS exposure in general and depressive symptoms in a dose-response manner. These significant trends were observed consistently whether SHS exposure occurred in homes or workplaces. Our findings suggest that long-term and regular SHS exposure is associated with a significant, dose-dependent increase in risk of depressive symptoms. PMID- 26231583 TI - Cognitive emotion regulation in patients with schizophrenia: Evidence for effective reappraisal and distraction. AB - Negative emotions trigger psychotic symptoms, according to a growing body of evidence. Thus, there is a need for effective emotion regulation in schizophrenia. Reappraisal is an effective, cognitive emotion regulation strategy in healthy individuals. However, it is an open research question whether individuals with schizophrenia have difficulties in successfully applying reappraisal. This study experimentally tests the efficacy of reappraisal compared to distraction in patients with schizophrenia and non-clinical controls. An experimental design with group as between-subject factor (non-clinical controls versus patients with schizophrenia) and emotion regulation during anxiety induction as within-subject factor (reappraisal, distraction, no regulation). Seventeen patients with schizophrenia and 27 healthy participants were instructed to respond to anxiety-inducing stimuli by either using reappraisal, distraction or by just watching. Both reappraisal and distraction were effective in down regulating anxiety, compared to no regulation. The main effect of group and the interaction of emotion regulation condition and group were not significant indicating that the efficacy of both cognitive emotion regulation strategies was independent of group. Patients with schizophrenia are able to apply reappraisal successfully under experimental conditions. Conclusions are limited by the small sample size of this pilot study. Clinical implications for cognitive behavioral therapy for psychosis are discussed. PMID- 26231584 TI - Effects of adverse childhood experiences on the association between intranasal oxytocin and social stress reactivity among individuals with cocaine dependence. AB - BACKGROUND: Drug dependence and adverse childhood experiences (ACE) are commonly reflected by dysregulation of the hypothalamic-pituitary-adrenal axis (HPA). Accumulating research indicates that the neuropeptide oxytocin may regulate HPA function, resulting in reductions in neuroendocrine reactivity to social stress among individuals with drug dependence. However, emerging literature suggests that individual differences may differentially impact intranasal oxytocin's effects on human social behaviors. METHODS: This study employed a double-blind, placebo-controlled design to examine the extent to which ACE influenced the effects of intranasal oxytocin (40IU) on neuroendocrine reactivity to a laboratory social stress paradigm in a sample of 31 cocaine-dependent individuals. RESULTS: ACE scores modified the relationship between intranasal oxytocin and cortisol reactivity. While ACE modified the relationship between intranasal oxytocin and DHEA response in a similar direction to what was seen in cortisol, it did not reach statistical significance. CONCLUSIONS: Findings are congruent with the emerging hypothesis that intranasal oxytocin may differentially attenuate social stress reactivity among individuals with specific vulnerabilities. Future research examining the nuances of intranasal oxytocin's therapeutic potential is necessary. PMID- 26231585 TI - Sex chromosome complement determines sex differences in aromatase expression and regulation in the stria terminalis and anterior amygdala of the developing mouse brain. AB - Aromatase, which converts testosterone in estradiol, is involved in the generation of brain sex dimorphisms. Here we used the "four core genotypes" mouse model, in which the effect of gonadal sex and sex chromosome complement is dissociated, to determine if sex chromosomes influence the expression of brain aromatase. The brain of 16 days old XY mouse embryos showed higher aromatase expression in the stria terminalis and the anterior amygdaloid area than the brain of XX embryos, independent of gonadal sex. Furthermore, estradiol or dihydrotestosterone increased aromatase expression in cultures of anterior amygdala neurons derived from XX embryos, but not in those derived from XY embryos. This effect was also independent of gonadal sex. The expression of other steroidogenic molecules, estrogen receptor-alpha and androgen receptor was not influenced by sex chromosomes. In conclusion, sex chromosomes determine sex dimorphisms in aromatase expression and regulation in the developing mouse brain. PMID- 26231588 TI - Comparative study of the mechanism of action of the antimicrobial peptide gomesin and its linear analogue: The role of the beta-hairpin structure. AB - Gomesin (Gm) is an antimicrobial peptide first isolated from the hemolymph of a Brazilian spider. Its powerful antimicrobial activity is, however, accompanied by hemolysis. As an alternative to this issue, a linear analogue (named GmL) lacking the disulfide bonds was designed. Here, CD spectroscopy, a fluorescence-based leakage assay, isothermal titration calorimetry (ITC) and light scattering are used to study the interaction of both Gm and GmL with large unilamellar vesicles (LUVs) composed of POPC (palmitoyl oleoyl phosphatidylcholine) with 25 and 50 mol% POPG (palmitoyl oleoyl phosphatidylglycerol). The activities of Gm and GmL in respect to their binding affinity/enthalpy, ability to permeabilize membranes and to induce vesicle aggregation are correlated with peptide secondary structure. Whereas Gm displays a quite stable beta-hairpin motif irrespective of the environment, GmL assumes a random conformation in aqueous solution and in the presence of 25 mol% POPG but adopts a beta-like structure in the presence of 50 mol% POPG. Gm exhibited high lytic activity against both surface charge densities. Instead, the activity of GmL was found to be negligible in the presence of 25 mol% POPG LUVs, but comparable to that of the native peptide against 50 mol% POPG as a consequence of peptide structuring. We conclude that the activity of Gm and its linear analogue is intimately related to the formation of a beta-turn motif, in which the hydrophobic residues form a hydrophobic face able to insert into the membrane and disrupt it. PMID- 26231587 TI - Dynamic single cell measurements of kinase activity by synthetic kinase activity relocation sensors. AB - BACKGROUND: Mitogen activated protein kinases (MAPK) play an essential role in integrating extra-cellular signals and intra-cellular cues to allow cells to grow, adapt to stresses, or undergo apoptosis. Budding yeast serves as a powerful system to understand the fundamental regulatory mechanisms that allow these pathways to combine multiple signals and deliver an appropriate response. To fully comprehend the variability and dynamics of these signaling cascades, dynamic and quantitative single cell measurements are required. Microscopy is an ideal technique to obtain these data; however, novel assays have to be developed to measure the activity of these cascades. RESULTS: We have generated fluorescent biosensors that allow the real-time measurement of kinase activity at the single cell level. Here, synthetic MAPK substrates were engineered to undergo nuclear-to cytoplasmic relocation upon phosphorylation of a nuclear localization sequence. Combination of fluorescence microscopy and automated image analysis allows the quantification of the dynamics of kinase activity in hundreds of single cells. A large heterogeneity in the dynamics of MAPK activity between individual cells was measured. The variability in the mating pathway can be accounted for by differences in cell cycle stage, while, in the cell wall integrity pathway, the response to cell wall stress is independent of cell cycle stage. CONCLUSIONS: These synthetic kinase activity relocation sensors allow the quantification of kinase activity in live single cells. The modularity of the architecture of these reporters will allow their application in many other signaling cascades. These measurements will allow to uncover new dynamic behaviour that previously could not be observed in population level measurements. PMID- 26231589 TI - Preferred reporting items for studies mapping onto preference-based outcome measures: the MAPS statement. AB - BACKGROUND AND AIM: 'Mapping' onto generic preference-based outcome measures is increasingly being used as a means of generating health utilities for use within health economic evaluations. Despite publication of technical guides for the conduct of mapping research, guidance for the reporting of mapping studies is currently lacking. The MApping onto Preference-based measures reporting Standards (MAPS) statement is a new checklist, which aims to promote complete and transparent reporting of mapping studies. METHODS: In the absence of previously published reporting checklists or reporting guidance documents, a de novo list of reporting items was created by a working group comprised of six health economists and one Delphi methodologist. A two-round, modified Delphi survey with representatives from academia, consultancy, health technology assessment agencies and the biomedical journal editorial community was used to identify a list of essential reporting items from this larger list. RESULTS: From the initial de novo list of 29 candidate items, a set of 23 essential reporting items was developed. The items are presented numerically and categorised within six sections, namely (1) title and abstract; (2) introduction; (3) methods; (4) results; (5) discussion; and (6) other. The MAPS statement is best applied in conjunction with the accompanying MAPS explanation and elaboration document. CONCLUSIONS: It is anticipated that the MAPS statement will improve the clarity, transparency and completeness of reporting of mapping studies. To facilitate dissemination and uptake, the MAPS statement is being co-published by seven health economics and quality of life journals, and broader endorsement is encouraged. The MAPS working group plans to assess the need for an update of the reporting checklist in 5 years' time. PMID- 26231590 TI - Screening commercial drivers for obstructive sleep apnea: translation and validation of Serbian version of Berlin Questionnaire. AB - PURPOSE: Obstructive sleep apnea (OSA) can lead to severe health consequences. Drivers of motor vehicles with untreated or undiagnosed OSA have a greater risk of traffic accidents. Use of self-reported questionnaires is the first step in OSA diagnosis. The main aim of this study was to perform the translation and validation of Berlin Questionnaire in a sample of commercial drivers. METHODS: After formal translation, validation was performed on a sample of commercial drivers and included evaluation of internal consistency, test-retest reliability, construct and criterion validity. Full-night attended polysomnography or cardiorespiratory polygraphy was used for OSA diagnosis. RESULTS: One hundred male participants, 24-62 years old, were included. Berlin Questionnaire classified 35 % subjects as potential OSA patients. Polysomnography confirmed OSA in 58 % of the subjects. Berlin Questionnaire showed good internal consistency (Cronbach's alpha 0.82-first category, 0.73-0.95-second category). Test-retest reliability (Cohen's kappa 0.78) was adequate. Berlin score was significantly correlated with OSA category and apnea-hypopnea index (AHI). Sensitivity of Berlin Questionnaire was from 50.9 (AHI >= 5) to 75 % (AHI >= 30), while specificity ranged from 86 to 70.5 %. CONCLUSIONS: Berlin Questionnaire (Serbian version) showed good measurement properties, creating basis for further research of its usefulness as OSA screening tool in populations of interest. PMID- 26231591 TI - Finding a Fit or Developing It: Implicit Theories About Achieving Passion for Work. AB - "Passion for work" has become a widespread phrase in popular discourse. Two contradictory lay perspectives have emerged on how passion for work is attained, which we distill into the fit and develop implicit theories. Fit theorists believe that passion for work is achieved through finding the right fit with a line of work; develop theorists believe that passion is cultivated over time. Four studies examined the expectations, priorities, and outcomes that characterize these implicit theories. Our results show that these beliefs elicit different motivational patterns, but both can facilitate vocational well-being and success. This research extends implicit theory scholarship to the work domain and provides a framework that can fruitfully inform career advising, life coaching, mentorship, and employment policies. PMID- 26231592 TI - Effects of Power on Mental Rotation and Emotion Recognition in Women. AB - Based on construal-level theory (CLT) and its view of power as an instance of social distance, we predicted that high, relative to low power would enhance women's mental-rotation performance and impede their emotion-recognition performance. The predicted effects of power emerged both when it was manipulated via a recall priming task (Study 1) and environmental cues (Studies 2 and 3). Studies 3 and 4 found evidence for mediation by construal level of the effect of power on emotion recognition but not on mental rotation. We discuss potential mediating mechanisms for these effects based on both the social distance/construal level and the approach/inhibition views of power. We also discuss implications for optimizing performance on mental rotation and emotion recognition in everyday life. PMID- 26231586 TI - Opportunities and challenges in three-dimensional brown adipogenesis of stem cells. AB - The formation of brown adipose tissue (BAT) via brown adipogenesis has become a notable process due to its ability to expend energy as heat with implications in the treatment of metabolic disorders and obesity. With the advent of complexity within white adipose tissue (WAT) along with inducible brown adipocytes (also known as brite and beige), there has been a surge in deciphering adipocyte biology as well as in vivo adipogenic microenvironments. A therapeutic outcome would benefit from understanding early events in brown adipogenesis, which can be accomplished by studying cellular differentiation. Pluripotent stem cells are an efficient model for differentiation and have been directed towards both white adipogenic and brown adipogenic lineages. The stem cell microenvironment greatly contributes to terminal cell fate and as such, has been mimicked extensively by various polymers including those that can form 3D hydrogel constructs capable of biochemical and/or mechanical modifications and modulations. Using bioengineering approaches towards the creation of 3D cell culture arrangements is more beneficial than traditional 2D culture in that it better recapitulates the native tissue biochemically and biomechanically. In addition, such an approach could potentially protect the tissue formed from necrosis and allow for more efficient implantation. In this review, we highlight the promise of brown adipocytes with a focus on brown adipogenic differentiation of stem cells using bioengineering approaches, along with potential challenges and opportunities that arise when considering the energy expenditure of BAT for prospective therapeutics. PMID- 26231593 TI - Seasonal changes on microbial metabolism and biomass in the euphotic layer of Sicilian Channel. AB - As a part of a wider project on fisheries ecology, several biological and environmental parameters were monitored during two oceanographic cruises (BANSIC 2012 and NOVESAR 2013) in the Sicily Channel, which connects the Western and Eastern Mediterranean basins. The prokaryotic abundances and biomass as well as hydrolysis rates on organic matter were investigated in the euphotic layer of a retention area for fish larval stages including anchovy (Engraulis encrasicolus, Linnaeus, 1758) with the aim to investigate the different biogeochemical signatures in two seasonal conditions. The environmental parameters, particulate organic carbon and nitrogen together with heterotrophic production were also measured. Results showed significant increases for most of the studied parameters with increasing temperature during summer. This had effects on the Carbon cycle and recycling of nutrients; in fact total prokaryotic abundance and biomass, as well as carbon hydrolyzed by two enzymes (Leucine aminopeptidase and beta glucosidase), increased significantly during summer. Conversely Alkaline phosphatase activity, Chlorophyll concentration and Oxygen increased during winter. The same environmental parameters affected also the presence of fish eggs. Moreover high percentages of free enzymes (i.e., enzymes not associated with cells) were measured, accounting for percentages variable from 12 to 95 % of the total enzymatic activity, with values generally higher in summer than in winter. In this oligotrophic environment, the prokaryotic biomass was supported by the C hydrolyzed by enzymatic activities. The ratio between the hydrolyzed C and prokaryotic biomass was higher in winter than in summer, indicating that alkaline phosphatase activity contribute to an efficient incorporation of C into biomass in winter. PMID- 26231594 TI - Prospective assessment of deep inspiration breath-hold using 3-dimensional surface tracking for irradiation of left-sided breast cancer. AB - PURPOSE: Deep inspiration breath hold (DIBH) is used to decrease cardiac irradiation during radiation therapy (RT) for breast cancer. The patients most likely to benefit and the impact on treatment time remain largely unknown. We sought to identify predictors for the use of DIBH and to quantify differences in dosimetry and treatment time using a prospective registry. METHODS AND MATERIALS: A total of 150 patients with left breast cancer were enrolled. All patients were simulated with both free breathing (FB) and DIBH. RT was delivered by either modality. Alternate scans were planned with use of deformable registration to include identical RT volumes. DIBH patients were monitored by a real-time surface tracking system, AlignRT (Vision RT, Ltd, London, United Kingdom). Baseline characteristics and treatment times were compared by Fisher exact test and Wilcoxon rank sum test. Dosimetric endpoints were analyzed by Wilcoxon signed rank test, and linear regression identified predictors for change in mean heart dose (?MHD). RESULTS: We treated 38 patients with FB and 110 with DIBH. FB patients were older, more likely to have heart and lung disease, and less likely to receive chemotherapy or immediate reconstruction (all P < .05). Treatment times were not significantly different, but DIBH patients had greater variability in times (P = .0002). Of 146 evaluable patients, DIBH resulted in >20 cGy improvement in MHD in 107 patients but a >20 cGy increase in MHD in 14. Both MHD and lung V20 were significantly lower in DIBH than in paired FB plans. On multivariate analysis, younger age (4.18 cGy per year; P < .0001), higher body mass index (6.06 cGy/kg/m(2); P = .0018), and greater change in lung volumes (130 cGy/L; P = .003) were associated with greater ?MHD. CONCLUSIONS: DIBH improves cardiac dosimetry without significantly impacting treatment time in most patients. Greater inspiratory lung volumes augment this benefit. Because the improvement with DIBH was not uniform, patients should be scanned with both FB and DIBH. PMID- 26231595 TI - Metrics of success: Measuring impact of a departmental near-miss incident learning system. AB - PURPOSE: There is a growing interest in the application of incident learning systems (ILS) to radiation oncology. The purpose of the present study is to define statistical metrics that may serve as benchmarks for successful operation of an incident learning system. METHODS AND MATERIALS: A departmental safety and quality ILS was developed to monitor errors, near-miss events, and process improvement suggestions. Event reports were reviewed by a multiprofessional quality improvement committee. Events were scored by a near-miss risk index (NMRI) and categorized by event point of origination and discovery. Reporting trends were analyzed over a 2-year period, including total number and rates of events reported, users reporting, NMRI, and event origination and discovery. RESULTS: A total of 1897 reports were evaluated (1.0 reports/patient, 0.9 reports/unique treatment course). Participation in the ILS increased as demonstrated by total events (2.1 additional reports/month) and unique users (0.5 new users/month). Sixteen percent of reports had an NMRI of 0 (none), 42% had an NMRI of 1 (mild), 25% had an NMRI of 2 (moderate), 12% had an NMRI of 3 (severe), and 5% had an NMRI of 4 (critical). Event NMRI showed a significant decrease in the first 6 months (1.68-1.42, P < .001). Trends in origination and discovery of reports were broadly distributed between radiation therapy process steps and staff groups. The highest risk events originated in imaging for treatment planning (NMRI = 2.0 +/- 1.1; P < .0001) and were detected in on-treatment quality management (NMRI = 1.7 +/- 1.1; P = .003). CONCLUSIONS: Over the initial 2-year period of ILS operation, rates of reporting increased, staff participation increased, and NMRI of reported events declined. These data mirror previously reported findings of improvement in safety culture endpoints. These metrics may be useful for other institutions seeking to create or evaluate their own ILS. PMID- 26231596 TI - Anatomic optimization of lung tumor stereotactic ablative radiation therapy. AB - PURPOSE: The purpose of this study was to demonstrate that anatomic optimization through selection of the degree of breath hold that yields the largest separation between the target and nearby organ at risk could result in dosimetrically superior treatment plans. METHODS AND MATERIALS: Thirty patients with 41 plans were included in this planned secondary analysis of a prospective trial. Fifteen plans were created for treatment with use of natural end exhale (NEE), and 26 plans used deep inspiration breath hold (DIBH). To evaluate whether the original plan was dosimetrically optimal, we replanned treatment using the opposite respiratory state with the same beam configuration as the original plan. A treatment plan was deemed superior if it met protocol constraints when the other did not. If both plans met or violated the constraints, the plans were deemed equivalent. RESULTS: Of the 26 plans originally planned with DIBH and replanned with NEE, 3 plans were dosimetrically superior with NEE, 1 plan was dosimetrically superior with DIBH, and 22 plans were dosimetrically equivalent. Of the 15 plans originally planned with NEE, 4 plans were dosimetrically superior with NEE, 2 plans were dosimetrically superior with DIBH, and 9 plans were dosimetrically equivalent. CONCLUSIONS: For 10 of 41 plans, planning with 1 respiratory state was superior. To obtain uniformly optimal plans, individual anatomic optimization would be needed. PMID- 26231597 TI - Patterns of practice for safety-critical processes in radiation oncology in the United States from the AAPM safety profile assessment survey. AB - PURPOSE: The purpose of this study is to report an overview of the patterns of practice for safety-critical processes in radiation oncology clinics in the United States. METHODS AND MATERIALS: The Safety Profile Assessment (spa.aapm.org), developed by the American Association of Physicists in Medicine, was released in July 2013. It consists of 92 indicator questions designed to assess the safety and quality of radiation oncology operations. By December 2014, 114 surveys had been completed by clinics within the United States. This database was analyzed to identify those indicators of safety and quality performance with which there was the highest degree of compliance and those indicators with which there was the least. Additionally, we assessed the extent to which key clinical activities were supported by formal policies. Voluntary post assessment surveys were completed by 86 respondents (75%). RESULTS: The mean number of patients treated per day on external beam radiation therapy devices was 64 (range, 8-600) in the clinics that responded to the survey. The average overall score for the 92 SPA indicator questions was 1.45 (range, 1.00-2.78) on a 5-point scale, with 1 being the most positive. Those indicators that were associated with the highest levels of compliance are dominated by activities that are either strongly recommended, regulated, or associated with revenue generation. Surprisingly, several of those indicators for which there was the least compliance relate to activities that are known to have contributed to serious radiation therapy misadministrations in the past. Formal policies, which are widely regarded as a backbone of a safe clinical system, were reported as lacking for some safety critical procedures. CONCLUSIONS: Although overall this analysis demonstrated reasonable performance across participating departments, several important areas for improvement were identified. The results may guide the allocation of resources both at the level of individual departments and at the professional society level. PMID- 26231598 TI - Reply: To PMID 25616752. PMID- 26231599 TI - A Hidden Cause of Dysphagia. Primary Esophageal Lymphoma. PMID- 26231600 TI - Abdominal Discomfort Due to an Unusual Abnormality. A Stool Bezoar in a Colonic Duplication. PMID- 26231601 TI - Drooling, Irritability, and Refusal to Eat in a 22-Month-Old Child. Button Battery Ingestion. PMID- 26231602 TI - A Painful Perianal Lesion. Cytomegalovirus-Associated Perianal Ulcers. PMID- 26231603 TI - Acute Anemia in a Patient With Hepatocellular Carcinoma. HCC Rupture With Intraperitoneal Hemorrhage. PMID- 26231604 TI - Probe-Based Confocal Laser Endomicroscopy for Indeterminate Bile Duct Strictures: The Inaccuracies of Accuracy When Appraising the Value of a Diagnostic Test. PMID- 26231605 TI - Hepatocellular Carcinoma Surveillance: Does Alpha-Fetoprotein Have a Role? PMID- 26231607 TI - AGA Guidelines for the Management of Pancreatic Cysts. PMID- 26231608 TI - The Role of Kisspeptin in the Onset of Puberty and in the Ovulatory Mechanism: A Mini-review. AB - The onset of puberty has been a fascinating topic for reproductive endocrinologists for decades; however, its underlying physiological mechanisms have remained elusive until recently. The discovery and understanding of the effects exerted by the peptide hormone kisspeptin have shed light on this research area. This review is aimed to discuss the functions of kisspeptin, with special focus on its role in the onset of puberty and in the ovulatory mechanism. The points under discussion are (1) the characteristics of kisspeptin and its receptor, (2) the relevance of this hormone and its interaction with leptin in the onset of puberty, (3) the role of kisspeptin in the ovulatory mechanism based on its differential expression at hypothalamic nuclei, which is modulated by sex steroid hormones, and (4) the clinical relevance of kisspeptin and its antagonists in new therapeutic strategies for the treatment of various reproductive pathologies. All of this explains the revolution that kisspeptin has caused among researchers working in the field of gynecological endocrinology and reproductive biology. PMID- 26231609 TI - Menstrual Patterns and Treatment of Heavy Menstrual Bleeding in Adolescents with Bleeding Disorders. AB - STUDY OBJECTIVE: To characterize menstrual bleeding patterns and treatment of heavy menstrual bleeding in adolescents with bleeding disorders. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective review of female patients aged nine to 21 years with known bleeding disorders who attended a pediatric gynecology, hematology, and comprehensive hematology/gynecology clinic at a children's hospital in a metropolitan area. MAIN OUTCOME MEASURES: Prevalence of heavy menstrual bleeding at menarche, prolonged menses, and irregular menses among girls with bleeding disorders and patterns of initial and subsequent treatment for heavy menstrual bleeding in girls with bleeding disorders. RESULTS: Of 115 participants aged nine to 21 years with known bleeding disorders, 102 were included in the final analysis. Of the 69 postmenarcheal girls, almost half (32/69, 46.4%) noted heavy menstrual bleeding at menarche. Girls with von Willebrand disease were more likely to have menses lasting longer than seven days. Only 28% of girls had discussed a treatment plan for heavy menstrual bleeding before menarche. Hormonal therapy was most commonly used as initial treatment of heavy menstrual bleeding. Half (53%) of the girls failed initial treatment. Combination (hormonal and non-hormonal therapy) was more frequently used for subsequent treatment. CONCLUSIONS: Adolescents with bleeding disorders are at risk of heavy bleeding at and after menarche. Consultation with a pediatric gynecologist and/or hematologist prior to menarche may be helpful to outline abnormal patterns of menstrual bleeding and to discuss options of treatment in the event of heavy menstrual bleeding. PMID- 26231611 TI - Comparison of psoas major muscle thickness measured by sonography during active straight leg raising in subjects with and without uncontrolled lumbopelvic rotation. AB - BACKGROUND: The psoas major (PM) is important for stabilizing lumbopelvic region during active straight leg raising (ASLR). Uncontrolled lumbopelvic rotation (ULPR) frequently occurs during ASLR in subjects with poor lumbo-pelvic stability and may contribute to asymmetric symptoms including pain in lumbopelvic region. OBJECTS: This study compared the thickness of contralateral PM (cPM) using ultrasound imaging during ASLR in subjects with and without ULPR. METHOD: Healthy male subjects (18 without ULPR, 19 with ULPR) were recruited. The thickness of the cPM during rest and ASLR without loading and with a 1-kg load was measured by ultrasound imaging. The relative muscle thickness was calculated as the thickness during ASLR/thickness at rest. Two-way mixed-model analysis of variance was used to identify significant differences in the relative thickness of the cPM between groups and within a loading status. The level of statistical significance was set at alpha = 0.05. RESULTS: The resting thickness of the cPM in subjects without ULPR did not differ from that of subjects with ULPR. The relative thickness of the cPM in subjects without ULPR was significantly greater during ASLR than that in subjects with ULPR both without loading and with a load (p < 0.01). No significant change in thickness of the cPM was evident in those with ULPR. CONCLUSION: The thickness of the cPM was significantly greater during ASLR in subjects without ULPR than with ULPR. This result indicates that persons with ULPR have less activation of the cPM to stabilize the lumbar spine during ASLR. PMID- 26231610 TI - Does oral sodium bicarbonate therapy improve function and quality of life in older patients with chronic kidney disease and low-grade acidosis (the BiCARB trial)? Study protocol for a randomized controlled trial. AB - BACKGROUND: Metabolic acidosis is more common with advancing chronic kidney disease, and has been associated with impaired physical function, impaired bone health, accelerated decline in kidney function and increased vascular risk. Although oral sodium bicarbonate is widely used to correct metabolic acidosis, there exist potential risks of therapy including worsening hypertension and fluid overload. Little trial evidence exists to decide whether oral bicarbonate therapy is of net benefit in advanced chronic kidney disease, particularly in older people who are most commonly affected, and in whom physical function, quality of life and vascular health are at least as important outcomes as decline in renal function. METHODS/DESIGN: BiCARB is a multi-centre, double-blind, placebo controlled, randomised trial evaluating the clinical and cost-effectiveness of oral sodium bicarbonate in the management of older people with chronic kidney disease and severely reduced glomerular filtration rate (GFR) who have a mild degree of metabolic acidosis. The trial will recruit 380 patients from renal, Medicine for the Elderly, and primary care services across centres in the United Kingdom. Male and female patients aged 60 years and older with an estimated glomerular filtration rate of <30 mL/min/1.73 m(2), not on dialysis, and with serum bicarbonate concentrations <22 mmol/L will be eligible for participation. The primary clinical outcome for the trial is the between-group difference in the Short Physical Performance Battery score at 12 months. Secondary outcomes include muscle strength, quality of life measured using the EQ-5D score and KDQoL tools, cost effectiveness, renal function, presence of albuminuria and blood pressure. Markers of bone turnover (25-hydroxyvitamin D, 1,25-hydroxyvitamin D, tartrate resistant acid phosphatase-5b and bone-specific alkaline phosphatase) and vascular health (B-type natriuretic peptide) will be measured. Participants will receive a total of 24 months of either bicarbonate or placebo. The results will provide the first robust test of the overall clinical and cost-effectiveness of this commonly used therapy in older patients with severely reduced kidney function. TRIAL REGISTRATION: www.isrctn.com; ISRCTN09486651, registered 17 February 2012. PMID- 26231612 TI - Clinic expert information extraction based on domain model and block importance model. AB - To extract expert clinic information from the Deep Web, there are two challenges to face. The first one is to make a judgment on forms. A novel method based on a domain model, which is a tree structure constructed by the attributes of query interfaces is proposed. With this model, query interfaces can be classified to a domain and filled in with domain keywords. Another challenge is to extract information from response Web pages indexed by query interfaces. To filter the noisy information on a Web page, a block importance model is proposed, both content and spatial features are taken into account in this model. The experimental results indicate that the domain model yields a precision 4.89% higher than that of the rule-based method, whereas the block importance model yields an F1 measure 10.5% higher than that of the XPath method. PMID- 26231613 TI - Morphogenesis of respiratory syncytial virus in human primary nasal ciliated epithelial cells occurs at surface membrane microdomains that are distinct from cilia. AB - The distribution of cilia and the respiratory syncytial virus (RSV) nucleocapsid (N) protein, fusion (F) protein, attachment (G) protein, and M2-1 protein in human ciliated nasal epithelial cells was examined at between 1 and 5 days post infection (dpi). All virus structural proteins were localized at cell surface projections that were distinct from cilia. The F protein was also trafficked into the cilia, and while its presence increased as the infection proceeded, the N protein was not detected in the cilia at any time of infection. The presence of the F protein in the cilia correlated with cellular changes in the cilia and reduced cilia function. At 5dpi extensive cilia loss and further reduced cilia function was noted. These data suggested that although RSV morphogenesis occurs at non-cilia locations on ciliated nasal epithelial cells, RSV infection induces changes in the cilia body that leads to extensive cilia loss. PMID- 26231614 TI - Perceived ethnic and language-based discrimination and Latina immigrant women's health. AB - Perceiving ethnic discrimination can have aversive consequences for health. However, little is known about whether perceiving language-based (how one speaks a second language) discrimination poses the same risks. This study examined whether perceptions of language-based and ethnic discrimination are associated with mental and physical health. Among 132 Mexican and Dominican immigrant women, perceiving ethnic and language-based discrimination each predicted psychological distress and poorer physical health. When examined together, only ethnic discrimination remained a significant predictor. These results emphasize the importance of understanding how perceived ethnic and language-based discrimination play an integral role in the health of Latina immigrant women. PMID- 26231615 TI - "Champion" behavior in a community obesity reduction program: Feedback from peers. AB - Current interventions to reduce obesity have limited success. This study aimed to determine the characteristics of successful champions (non health professional/community leaders) and to assess how these relate to acceptability ratings of an obesity reduction intervention-the Waist Disposal Challenge. A total of 200 peer participants completed questionnaires. Positive ratings of champions' performance were significantly correlated with perceptions of the success and suitability of the Waist Disposal Challenge. The qualitative feedback concurred that the program prompted weight loss and was a positive social experience which resulted in actual behavioral changes. Selecting suitable champions is likely to influence the success of such community health programs. PMID- 26231616 TI - A longitudinal test of the Comprehensive Indoor Tanning Expectations Scale: The importance of affective beliefs in predicting indoor tanning behavior. AB - In order to better understand drivers of dangerous indoor tanning behaviors, researchers developed the Comprehensive Indoor Tanning Expectations scale. To examine the longitudinal effectiveness of Comprehensive Indoor Tanning Expectations, we surveyed young women in the Southeastern United States at two time points ( N = 553). The scale demonstrated strong test-retest reliability. Participants who believed indoor tanning would improve their mood and afford social approval were significantly more likely to tan 6 months later, while participants who believed indoor tanning leads to psychological/physical discomfort were significantly less likely to tan 6 months later. Knowing the psychological bases for indoor tanning can inform intervention and message design. PMID- 26231617 TI - Association of branched-chain amino acids with coronary artery disease: A matched pair case-control study. AB - BACKGROUND AND AIM: Several recent studies have found an independent relationship between levels of plasma branched-chain amino acids (BCAAs) and risk factors for coronary artery disease (CAD); however, few studies have investigated the associations of BCAAs with CAD and the risk of cardiovascular events. Therefore, the aim of this study was to investigate the relationship between BCAAs and CAD. METHODS AND RESULTS: We studied 143 patients with CAD diagnosed by coronary angiography at Beijing Hospital (Beijing, China) during 2008-2011. Apparently healthy control individuals (n = 286) and the patients with CAD were matched (2:1 ratio) by age and gender. The healthy control individuals were selected at random from a set of subjects who attended an annual physical examination at the same hospital in 2011. Conditional logistic regression models were used to evaluate the associations between measured variables and CAD. After multivariate adjustment for traditional CAD risk factors, each one-standard-deviation increase in BCAA concentration was associated with an approximately twofold increase in the risk of CAD (odds ratio = 1.63, 95% confidence interval (CI): 1.21-2.20, P = 0.001). As compared with subjects in the lowest quartile of BCAA levels, the odds ratios (95% CIs) for CAD risk in subjects belonging to quartiles 2, 3, and 4 were 1.65 (0.75-3.61), 2.04 (0.92-4.53), and 3.86 (1.71-8.69), respectively (P trend = 0.01). CONCLUSION: Our results demonstrate that BCAAs are significantly related to CAD development. This relationship is independent of diabetes, hypertension, dyslipidemia, and body mass index. PMID- 26231618 TI - Prevalence of diabetes across different immigrant groups in North-eastern Italy. AB - BACKGROUND AND AIMS: Type 2 diabetes, one of the most important non-communicable diseases, represents a major health problem worldwide. Immigrants may contribute relevantly to the increase in diabetes. The aim of the study was to investigate variability in diabetes prevalence across different immigrant groups in the Veneto Region (northeastern Italy). METHODS AND RESULTS: Diabetic subjects on January 2013 were identified by record linkage of hospital discharge records, drug prescriptions, and exemptions from medical charges for diabetes. Immigrant groups were identified based on citizenship. Age-standardized prevalence rates were obtained for residents aged 20-59 years by the direct method, taking the whole regional population as reference. Prevalence rate ratios (RR) with 95% Confidence Intervals (CI) were computed with respect to Italian citizens. Among residents aged 20-59 years, 45280 Italian and 7782 foreign subjects affected by diabetes were identified. Prevalence rates were highest among immigrants from South-East Asia, RR 4.9 (CI 4.7-5.1) among males, and 7.6 (7.2-8.1) among females, followed by residents from both North and Sub-Saharan Africa. Citizens from Eastern Europe (the largest immigrant group) showed rates similar to Italians. Most South-Asian patients aged 20-39 years were not insulin-treated, suggesting a very high risk of early onset type 2 diabetes in this ethnic group. CONCLUSION: Large variations in diabetes prevalence by ethnicity should prompt tailored strategies for primary prevention, diabetes screening, and disease control. An increased demand for prevention and health care in selected population groups should guide appropriate resource allocation. PMID- 26231619 TI - Neonatal fatty acid status and neurodevelopmental outcome at 9 years. AB - BACKGROUND: Long-chain polyunsaturated fatty acids (LCPUFA) are important for prenatal brain development. Previous studies of others assessed outcome until 7 years. The associations between neonatal LCPUFA status and long-term developmental outcome are debated. AIM: To investigate the relationship between fatty acid status at birth and neurodevelopment at 9 years. Age 9 is a unique age after a significant neurodevelopmental transition. STUDY DESIGN: Correlation study. Multivariable analyses were carried out to adjust for potential confounders. SUBJECTS: 317 children who participated in a trial on effects of postnatal LCPUFA supplementation were eligible. 235 children (74%) were reassessed at age 9. OUTCOME MEASURES: At birth, docosahexaenoic acid (DHA) and arachidonic acid (AA) were determined in the wall of the umbilical vein. We primarily studied the correlation between DHA and AA with the complex form of minor neurological dysfunction (cMND). Secondary correlations that were studied were DHA and AA levels with cognitive development in terms of full IQ, and with behavioural development in terms of a total problem score. RESULTS: Boys with cMND showed lower DHA values in the umbilical vein than children with better neurological condition (p=0.033). A similar association was absent in girls. Neonatal AA values were not associated with neurological outcome. Neither neonatal DHA nor AA values were associated with cognition and behaviour at 9. CONCLUSIONS: Higher umbilical DHA levels in boys are associated with better neurological development at 9 years. AA status at birth was not associated with neurodevelopment at 9 years. PMID- 26231620 TI - A new informed tensor factorization approach to EEG-fMRI fusion. AB - BACKGROUND: In this paper exploitation of correlation between post-movement beta rebound in EEG and blood oxygenation level dependent (BOLD) in fMRI is addressed. Brain studies do not reveal any clear relationship between synchronous neuronal activity and BOLD signal. Simultaneous recording of EEG and fMRI provides a great opportunity to recognize different areas of the brain involved in EEG events. NEW METHOD: In order to incorporate information derived from EEG signals into fMRI analysis a specific constraint is introduced in this paper. Here, PARAFAC as a variant of tensor factorization, exploits the data changes in more than two modes in order to reveal the information about the fMRI BOLD and its time course simultaneously. In addition, various constraints can be applied during the alternating process for estimation of its parameters. RESULTS: The achieved results from extensive set of experiments confirm effectiveness of the proposed method to detect the brain regions responsible for beta rebound. Moreover, fMRI only and EEG-fMRI analysis using PARAFAC2 illustrate correct expected activities in the brain area. COMPARISON WITH EXISTING METHODS: The advantages of the proposed method are revealed when comparing the results with those of obtained using general linear model (GLM) which is a well-known model-based approach. CONCLUSIONS: The proposed method is a semi-blind decomposition technique which employs PARAFAC2 without relying on a predefined time course. The achieved results indicate that this approach can pave the path for multi-task analysis in BCI applications. PMID- 26231621 TI - A novel method for device-related electroencephalography artifact suppression to explore cochlear implant-related cortical changes in single-sided deafness. AB - BACKGROUND: Quantitative electroencephalography (qEEG) is effective when used to analyze ongoing cortical oscillations in cochlear implant (CI) users. However, localization of cortical activity in such users via qEEG is confounded by the presence of artifacts produced by the device itself. Typically, independent component analysis (ICA) is used to remove CI artifacts in auditory evoked EEG signals collected upon brief stimulation and it is effective for auditory evoked potentials (AEPs). However, AEPs do not reflect the daily environments of patients, and thus, continuous EEG data that are closer to such environments are desirable. In this case, device-related artifacts in EEG data are difficult to remove selectively via ICA due to over-completion of EEG data removal in the absence of preprocessing. NEW METHODS: EEGs were recorded for a long time under conditions of continuous auditory stimulation. To obviate the over-completion problem, we limited the frequency of CI artifacts to a significant characteristic peak and apply ICA artifact removal. RESULTS: Topographic brain mapping results analyzed via band-limited (BL)-ICA exhibited a better energy distribution, matched to the CI location, than data obtained using conventional ICA. Also, source localization data verified that BL-ICA effectively removed CI artifacts. COMPARISON WITH EXISTING METHOD: The proposed method selectively removes CI artifacts from continuous EEG recordings, while ICA removal method shows residual peak and removes important brain activity signals. CONCLUSION: CI artifacts in EEG data obtained during continuous passive listening can be effectively removed with the aid of BL-ICA, opening up new EEG research possibilities in subjects with CIs. PMID- 26231622 TI - Phase-clustering bias in phase-amplitude cross-frequency coupling and its removal. AB - BACKGROUND: Cross-frequency coupling methods allow for the identification of non linear interactions across frequency bands, which are thought to reflect a fundamental principle of how electrophysiological brain activity is temporally orchestrated. In this paper we uncover a heretofore unknown source of bias in a commonly used method that quantifies cross-frequency coupling (phase-amplitude coupling, or PAC). NEW METHOD: We demonstrate that non-uniform phase angle distributions--a phenomenon that can readily occur in real data--can under some circumstances produce statistical errors and uninterpretable results when using PAC. We propose a novel debiasing procedure that, through a simple linear subtraction, effectively ameliorates this phase clustering bias. RESULTS: Simulations showed that debiased PAC (dPAC) accurately detected the presence of coupling. This was true even in the presence of moderate noise levels, which inflated the phase clustering bias. Finally, dPAC was applied to intracranial sleep recordings from a macaque monkey, and to hippocampal LFP data from a freely moving rat, revealing robust cross-frequency coupling in both data sets. COMPARISON WITH EXISTING METHODS: Compared to dPAC, regular PAC showed inflated or deflated estimations and statistically negative coupling values, depending on the strength of the bias and the angle of coupling. Noise increased these unwanted effects. Two other frequently used phase-amplitude coupling methods (the Modulation Index and Phase Locking Value) were also affected by the bias, though allowed for statistical inferences that were similar to dPAC. CONCLUSION: We conclude that dPAC provides a simple modification of PAC, and thereby offers a cleaner and possibly more sensitive alternative method, to more accurately assess phase-amplitude coupling. PMID- 26231623 TI - Constraint-induced movement therapy translated into practice. PMID- 26231624 TI - Home-based constraint-induced movement therapy for patients with upper limb dysfunction after stroke (HOMECIMT): a cluster-randomised, controlled trial. AB - BACKGROUND: Constraint-induced movement therapy (CIMT) is recommended for patients with upper limb dysfunction after stroke, yet evidence to support the implementation of CIMT in ambulatory care is insufficient. We assessed the efficacy of home CIMT, a modified form of CIMT that trains arm use in daily activities within the home environment. METHODS: In this parallel, cluster randomised controlled trial, we selected 71 therapy practices in northern Germany that treat adult patients with upper limb dysfunction after stroke. Practices were stratified by region and randomly allocated by an external biometrician (1:1, block size of four) using a computer-generated sequence. 37 practices were randomly assigned to provide 4 weeks of home CIMT and 34 practices to provide 4 weeks of standard therapy. Eligible patients had mild to moderate impairment of arm function at least 6 months after stroke and a friend or family member willing to participate as a non-professional coach. Patients of both groups received 5 h of professional therapist contact in 4 weeks. In the home CIMT group, therapists used the contact time to instruct and supervise patients and coaches in home CIMT. Patients in the standard therapy group received conventional physical or occupational therapy, but additional home training was not obligatory. All assessments were done by masked outcome assessors at baseline, after 4 weeks of intervention, and at 6 month follow-up. The primary outcomes were quality of movement, assessed by the Motor Activity Log (MAL-QOM, assessor-assisted self reported), and performance time, assessed by the Wolf Motor Function Test (WMFT PT, assessor-reported). Primary outcomes were tested hierarchically after 4 weeks of intervention and analysed by intention to treat, using mixed linear models. This trial is registered with ClinicalTrials.gov, NCT01343602. FINDINGS: Between July 11, 2011, and June 4, 2013, 85 of 156 enrolled patients were assigned home CIMT and 71 patients were assigned standard therapy. 82 (96%) patients in the home CIMT group and 71 (100%) patients in the standard therapy group completed treatment and were assessed at 4 weeks. Patients in both groups improved in quality of movement (MAL-QOM; change from baseline 0.56, 95% CI 0.41-0.71, p<0.0001 for home CIMT vs 0.31, 0.15-0.46, p=0.0003 for standard therapy). Patients in the home CIMT group improved more than patients in the standard therapy group (between-group difference 0.26, 95% CI 0.05-0.46; p=0.0156). Both groups also improved in motor function performance time (WMFT-PT; change from baseline -25.60%, 95% CI -36.75 to -12.49, p=0.0006 for home CIMT vs -27.52%, 38.94 to -13.94, p=0.0004 for standard therapy), but the extent of improvement did not differ between groups (2.65%, -17.94 to 28.40; p=0.8152). Nine adverse events (of which six were serious) were reported in the home CIMT group and ten (of which seven were serious) in the standard therapy group; however, none was deemed related to the study intervention. INTERPRETATION: Home-based CIMT can enhance the perceived use of the stroke-affected arm in daily activities more effectively than conventional therapy, but was not superior with respect to motor function. Further research is needed to confirm whether home CIMT leads to clinically significant improvements and if so to identify patients that are most likely to benefit. FUNDING: German Federal Ministry of Education and Research. PMID- 26231625 TI - Structure and signaling at hydroid polyp-stolon junctions, revisited. AB - The gastrovascular system of colonial hydroids is central to homeostasis, yet its functional biology remains poorly understood. A probe (2',7' dichlorodihydrofluorescein diacetate) for reactive oxygen species (ROS) identified fluorescent objects at polyp-stolon junctions that emit high levels of ROS. A nuclear probe (Hoechst 33342) does not co-localize with these objects, while a mitochondrial probe (rhodamine 123) does. We interpret these objects as mitochondrion-rich cells. Confocal microscopy showed that this fluorescence is situated in large columnar cells. Treatment with an uncoupler (2,4-dinitrophenol) diminished the ROS levels of these cells relative to background fluorescence, as did removing the stolons connecting to a polyp-stolon junction. These observations support the hypothesis that the ROS emanate from mitochondrion-rich cells, which function by pulling open a valve at the base of the polyp. The open valve allows gastrovascular fluid from the polyp to enter the stolons and vice versa. The uncoupler shifts the mitochondrial redox state in the direction of oxidation, lowering ROS levels. By removing the stolons, the valve is not pulled open, metabolic demand is lowered, and the mitochondrion-rich cells slowly regress. Transmission electron microscopy identified mitochondrion-rich cells adjacent to a thick layer of mesoglea at polyp-stolon junctions. The myonemes of these myoepithelial cells extend from the thickened mesoglea to the rigid perisarc on the outside of the colony. The perisarc thus anchors the myoepithelial cells and allows them to pull against the mesoglea and open the lumen of the polyp-stolon junction, while relaxation of these cells closes the lumen. PMID- 26231626 TI - Local motion detectors are required for the computation of expansion flow-fields. AB - Avoidance of predators or impending collisions is important for survival. Approaching objects can be mimicked by expanding flow-fields. Tethered flying fruit flies, when confronted with an expansion flow-field, reliably turn away from the pole of expansion when presented laterally, or perform a landing response when presented frontally. Here, we show that the response to an expansion flow-field is independent of the overall luminance change and edge acceleration. As we demonstrate by blocking local motion-sensing neurons T4 and T5, the response depends crucially on the neural computation of appropriately aligned local motion vectors, using the same hardware that also controls the optomotor response to rotational flow-fields. PMID- 26231627 TI - Fluorescent proteins function as a prey attractant: experimental evidence from the hydromedusa Olindias formosus and other marine organisms. AB - Although proteins in the green fluorescent protein family (GFPs) have been discovered in a wide array of taxa, their ecological functions in these organisms remain unclear. Many hypothesized roles are related to modifying bioluminescence spectra or modulating the light regime for algal symbionts, but these do not explain the presence of GFPs in animals that are non-luminous and non-symbiotic. Other hypothesized functions are unrelated to the visual signals themselves, including stress responses and antioxidant roles, but these cannot explain the localization of fluorescence in particular structures on the animals. Here we tested the hypothesis that fluorescence might serve to attract prey. In laboratory experiments, the predator was the hydromedusa Olindias formosus (previously known as O. formosa), which has fluorescent and pigmented patches on the tips of its tentacles. The prey, juvenile rockfishes in the genus Sebastes, were significantly more attracted (P<1*10(-5)) to the medusa's tentacles under lighting conditions where fluorescence was excited and tentacle tips were visible above the background. The fish did not respond significantly when treatments did not include fluorescent structures or took place under yellow or white lights, which did not generate fluorescence visible above the ambient light. Furthermore, underwater observations of the behavior of fishes when presented with a brightly illuminated point showed a strong attraction to this visual stimulus. In situ observations also provided evidence for fluorescent lures as supernormal stimuli in several other marine animals, including the siphonophore Rhizophysa eysenhardti. Our results support the idea that fluorescent structures can serve as prey attractants, thus providing a potential function for GFPs and other fluorescent proteins in a diverse range of organisms. PMID- 26231628 TI - International differences in the management of intracranial aneurysms: implications for the education of the next generation of neurosurgeons. AB - BACKGROUND: The publication of the International Subarachnoid Aneurysm Trial rapidly changed the management of patients with subarachnoid hemorrhage. The present and perceived future trends of aneurysm management have significant implications for patients and how we educate future cerebrovascular specialists. OBJECTIVE: To determine present perceived competencies of final-year neurosurgical residents who have just finished their residencies and to relate those to what practitioners from a variety of continents expect of these persons. The goal is to provide a basis for further discussion regarding the design of further educational programs in neurosurgery. METHODS: A 55-item questionnaire with 33 questions related to competencies and expectations of competency from final-year residents who have just finished residency was completed by 229 neurosurgeons and neuro-radiologists (81 % response rate) of mixed seniority from 45 countries. We used bivariate and descriptive analyses to determine future trends and geographic differences in cerebral aneurysm management as well as the educational implications on the future. RESULTS: More North Americans than those from the rest of the world are of the opinion that graduating residents are presently competent to perform basic cerebrovascular procedures like evacuation of a hematoma and clipping a simple 7-mm middle cerebral artery aneurysm. Extremely few graduating neurosurgical residents anywhere are presently capable of performing endovascular techniques for even the most basic of aneurysms. Most of those surveyed also believe that endovascular and open surgical management of aneurysms should be a part of residency training for all residents (70.4 and 88.7 %, respectively). CONCLUSIONS: Our findings have implications for the design of neurosurgical curricula for residents as well as for certification examinations and procedures. Specialty and educational organizations and those responsible for the education of future clinicians who will care for patients with cerebrovascular problems should adjust educational objectives and implement curricula and learning experiences that will ensure that cerebrovascular specialists are capable of providing the best care possible to the patient with an aneurysm, whether that be open surgery or endovascular management. These findings mean that organizations around the world will need to make these adjustments to the education of future specialists. PMID- 26231629 TI - Stereotactic Gamma Knife surgery safety and efficacy in the management of symptomatic benign confined cavernous sinus meningioma. AB - BACKGROUND: Considering the proximity to cranial nerves from II to VI and the internal carotid artery microsurgery for cavernous sinus meningioma (CSM) has its limits of complete resection, with high potential tumor recurrences, cranial nerve and vascular morbidity. Gamma Knife surgery (GKS) is an advanced modality as primary treatment for patients harboring symptomatic benign confined CSM as well as adjuvant therapy to postoperative residual tumor giving a high rate of tumor control, stabilizing or even improving clinical condition with low morbidity. MATERIALS AND METHODS: The aim of this study is to evaluate the safety and efficacy of GKS used in the management of 62 patients with symptomatic benign confined CSM < 3 cm in maximum diameters treated at the International Medical Centre (IMC), Cairo, Egypt, from 2005 to end of 2012, with mean follow-up period of 36 months (range, 24-96 months) by reviewing their clinical and radiological data. For 51 patients GKS was performed as a primary treatment. The diagnosis was based on typical clinical and imaging findings and in 11 patients GKS was used as adjuvant to post-operative tumor residual with histological confirmation. RESULTS: There were 43 females and 19 males. The median age at the time of treatment was 48 years. The mean tumor volume was 5.7 cc, the mean tumor marginal radiation dose was 14.4 Gy, the mean isodose line was 38 %, and the mean tumor coverage was 94.4 %. The optic pathway received < 8 Gy and the brain stem < 10 Gy. At most recent follow-up, 57 patients (92 %) had stable or improved cranial nerve deficits. Post-GKS cranial nerve complications were detected in five patients (8 %). Tumor volume was controlled in 60 patients (96 %) at most recent follow-up MRI; 12 patients had a reduction in tumor size and 42 had stable tumor size, while tumor size progression was detected in two patients. The tumor progression-free survival at 3 and 5 years in 40 patients who completed at least 5 years of follow-up was 95 %. CONCLUSIONS: Gamma Knife surgery is a safe and effective option for the treatment of cavernous sinus meningioma not only as an adjuvant to surgery but also as an alternative to surgical removal in tumors confined mainly to the cavernous sinus. PMID- 26231630 TI - The Influence of Patient Characteristics on the Perceived Value of Inpatient Educational Experiences by Medical Trainees. AB - BACKGROUND AND OBJECTIVE: Medical education relies heavily on workplace learning where trainees are educated through their clinical experience. Few studies have explored trainees' perceptions of the educational value of these patient care experiences. The aim of this study was to identify pediatric patient characteristics that medical trainees perceive as educationally valuable. METHODS: Over 2 months, trainees on pediatric inpatient wards ranked the perceived educational value of patients under their care on a 4-point bipolar Likert scale. Three patient characteristics were examined: complex-chronic and noncomplex-chronic preexisting conditions, difficult social circumstances, and rare diseases. Patient-level predictors of cases perceived as educationally valuable (defined as scores>=3) were examined by using univariate and multivariate analyses. RESULTS: A total of 325 patients were rated by 51 trainees (clinical medical students [45%], first-year residents [29%], third-year residents/fellows [26%]). Rare diseases had a higher educational value score (adjusted odds ratio 1.76, 95% confidence interval 1.08-2.88, P=.02). Complex chronic and noncomplex-chronic preexisting conditions and difficult social circumstances did not affect the perceived educational value. CONCLUSIONS: Trainees attribute the most educational value to caring for patients with rare diseases. Although trainees' perceptions of learning do not necessarily reflect actual learning, they may influence personal interest and limit learning from an educational experience. Knowledge of trainee perceptions of educational experience therefore can direct medical educators' approaches to inpatient education. PMID- 26231631 TI - Hospitalization for Community-Acquired Pneumonia in Children: Effect of an Asthma Codiagnosis. AB - BACKGROUND AND OBJECTIVE: Community-acquired pneumonia (CAP) is a common and expensive cause of hospitalization among US children, many of whom receive a codiagnosis of acute asthma. The objective of this study was to describe demographic characteristics, cost, length of stay (LOS), and adherence to clinical guidelines among these groups and to compare health care utilization and guideline adherence between them. METHODS: This was a multicenter retrospective cohort study using data from the Pediatric Health Information System. Children aged 2 to 18 who were hospitalized with uncomplicated CAP from July 1, 2007, to June 30, 2012 were included. Demographics, LOS, total standardized cost, and clinical guideline adherence were compared between patients with CAP only and CAP plus acute asthma. RESULTS: Among the 25,124 admissions, 57% were diagnosed with CAP only; 43% had a codiagnosis of acute asthma. The geometric mean for standardized cost was $4830; for LOS, it was 2.01 days. Eighty-four percent of patients had chest radiographs; CAP+acute asthma patients were less likely to have a blood culture performed (36% vs 62%, respectively) and more likely not to have a complete blood count performed (49% vs 27%, respectively). Greater guideline adherence was associated with higher cost at the patient-level but lower average cost per hospitalization at the hospital level. CAP+acute asthma patients had higher relative costs (11.8%) and LOS (5.6%) within hospitals and had more cost variation across hospitals, compared with patients with CAP only. CONCLUSIONS: A codiagnosis of acute asthma is common for children with CAP. This could be from misdiagnosis or co-occurrence. Diagnostic and/or management variability appears to be greater in patients with CAP+asthma, which may increase resource utilization and LOS for these patients. PMID- 26231632 TI - Clinical and Geographic Characterization of 30-Day Readmissions in Pediatric Sickle Cell Crisis Patients. AB - BACKGROUND AND OBJECTIVES: Sickle cell disease (SCD) is a blood disorder affecting many US children that is often associated with hospital readmission. Although previous studies have reported on the clinical factors that influence readmission risk, potential geographic factors have not been fully investigated. The goal of this study was to investigate the importance of geographic risk factors and to confirm previously derived clinical risk factors that influence readmissions for SCD pain crises. METHODS: Retrospective analyses were performed on pediatric inpatients with sickle cell crises at a single center. Readmission rates and risk factors were assessed. Geospatial analysis was conducted on point variables that represented health service access, and multivariable logistic regression models were constructed. RESULTS: The study identified 373 patients experiencing sickle cell crises, with 125 (33.5%) having at least one 30-day readmission. Age (mean difference: 2.2 years; P<0.001), length of stay (median difference: 1 day; P<.001), admission pain score>7 of 10 (odds ratio [OR]: 2.21; P<0.01), discharge pain score>4 of 10 (OR: 2.098; P<.01), living within 5 miles of the center's main hospital (OR: 0.573; P=.04), and >3 hospital utilizations in the previous 12 months (OR: 5.103; P<.001) were identified as potential indicators of 30-day readmission risk. Logistic regression models for 30-day readmissions yielded similar results. CONCLUSIONS: Increased age, high admission and discharge pain scores, decreased length of stay, and increased hospital utilizations were found to be associated with an increased risk of readmission for sickle cell crisis. Patient's residence was also found to be a significant risk indicator, supporting the utility of geospatial analysis in assessing readmission risk. PMID- 26231633 TI - Association of Respiratory Picornaviruses With High Acuity and Severe Illness in a Pediatric Health Care System. AB - OBJECTIVES: We aimed to determine the illness severity associated with respiratory picornaviruses (rhinovirus/enterovirus). METHODS: Electronic medical records of pediatric emergency department (PED) visits were reviewed. The percent positive of respiratory pathogens, tested by using viral polymerase chain reaction panel, was determined for the July 2012 to June 2013 period. Logistic regression was used to determine the association of picornaviruses, respiratory syncytial virus (RSV), and influenza with ICU admission during the 2012-2013 academic year. Medical records of visits leading to ICU admission with picornaviruses were reviewed. RESULTS: During 2012-2013, picornaviruses were more commonly identified (22.6%) among admitted patients than influenza (6.4%) or RSV (15.1%). Picornaviruses and RSV were associated with ICU admission (picornaviruses: adjusted odds ratio [aOR], 1.99 [95% confidence interval (CI): 1.68-2.36]; RSV: aOR, 1.49 [95% CI: 1.20-1.85]) while influenza was not (aOR, 0.93 [95% CI: 0.66-1.29]). Of visits resulting in ICU admission, 79% were from patients with previous high-risk medical conditions, of which asthma or a history of wheezing was the most common (43%). CONCLUSIONS: Picornaviruses can be associated with severe disease in children, especially those with underlying medical conditions. During times of high picornavirus activity, hospitals should target infection control measures to limit the spread of picornaviruses and protect the vulnerable patients. Future research into targeted therapies for picornaviruses and vaccines is needed. PMID- 26231634 TI - Medication Discrepancies at Pediatric Hospital Discharge. AB - BACKGROUND: The pediatric hospital discharge process presents significant challenges, and medication discrepancies remain an unsolved problem. The purpose of this study was to determine the discrepancy rates at the time of discharge when multiple sources of medication documentation exist, and to characterize the medication discrepancies into error type, medication category, and discharge summary authorship. METHODS: A prospective study was performed on pediatric patients admitted to a general inpatient floor for >24 hours. After discharge, medication lists were obtained from the patients' parent/guardian, discharge summary, and Patient Summary List, a medication list that is part of the electronic medical record. These 3 medication lists were then compared with the pharmacy record to identify discrepancies, defined as any difference in medication name, dose, route, or frequency. Medication discrepancies were analyzed in terms of error type (dosage or addition/omission), category of medication, and final signers of the discharge summary. RESULTS: Sixty-nine patient charts were analyzed, and 8% of medications contained a documentation discrepancy between sources. Overall, 26% (18 of 69) of the charts contained >=1 discrepant medication; the Patient Summary List had the highest rate of discrepancy at 29%. Allergy (27%) and seizure medications (25%) were the categories with the highest rates of discrepancy. Addition/omission errors were much more common than dosage errors. CONCLUSIONS: Medication discrepancies exist in inpatient documentation at the time of pediatric hospital discharge when multiple sources of documentation exist. PMID- 26231635 TI - Do beta-Blockers Decrease the Hypermetabolic State in Critically Ill Children With Severe Burns? AB - BACKGROUND AND OBJECTIVES: Severe burns result in a hypermetabolic state that is associated with increased morbidity and mortality. We reviewed the literature to determine if there is strong evidence that short-term beta-blockers reduce the hypermetabolic state or mortality and length of stay (LOS) compared with no therapy in patients with severe burns. METHODS: A literature search of PubMed, Embase, the Cochrane Database of Systematic Reviews, and BestBETs was conducted on the use of adrenergic beta-antagonists in burn patients. RESULTS: Six randomized controlled trials met the inclusion criteria. Five pediatric trials found that beta-blockers reduced the hypermetabolic state (as defined by reduction of cardiac work, rate pressure product, resting energy expenditure, central deposition of fat, and bone mineral loss) and were associated with an improvement in lean muscle mass in patients with severe burns. However, there was no change in LOS or mortality in these children. One adult study in burn patients found shorter LOS in patients treated with beta-blockers but no difference in mortality rate. beta-blockers were relatively well tolerated, with no differences in adverse effects reported. CONCLUSIONS: beta-blockers seem to reduce the hypermetabolic state in pediatric patients with burns, but there is insufficient evidence to suggest they have an impact on mortality rates or LOS. PMID- 26231636 TI - A Case of Fever of Unknown Origin. PMID- 26231637 TI - An Ounce of Anticipatory Guidance Is Worth a Pound of Testing. PMID- 26231638 TI - Stresses in Pediatric Hospital Medicine. PMID- 26231639 TI - Biosynthesis and Secretion of Indole-3-Acetic Acid and Its Morphological Effects on Tricholoma vaccinum-Spruce Ectomycorrhiza. AB - Fungus-derived indole-3-acetic acid (IAA), which is involved in development of ectomycorrhiza, affects both partners, i.e., the tree and the fungus. The biosynthesis pathway, excretion from fungal hyphae, the induction of branching in fungal cultures, and enhanced Hartig net formation in mycorrhiza were shown. Gene expression studies, incorporation of labeled compounds into IAA, heterologous expression of a transporter, and bioinformatics were applied to study the effect of IAA on fungal morphogenesis and on ectomycorrhiza. Tricholoma vaccinum produces IAA from tryptophan via indole-3-pyruvate, with the last step of this biosynthetic pathway being catalyzed by an aldehyde dehydrogenase. The gene ald1 was found to be highly expressed in ectomycorrhiza and induced by indole-3 acetaldehyde. The export of IAA from fungal cells is supported by the multidrug and toxic extrusion (MATE) transporter Mte1 found in T. vaccinum. The addition of IAA and its precursors induced elongated cells and hyphal ramification of mycorrhizal fungi; in contrast, in saprobic fungi such as Schizophyllum commune, IAA did not induce morphogenetic changes. Mycorrhiza responded by increasing its Hartig net formation. The IAA of fungal origin acts as a diffusible signal, influencing root colonization and increasing Hartig net formation in ectomycorrhiza. PMID- 26231640 TI - Active-Site Engineering of omega-Transaminase for Production of Unnatural Amino Acids Carrying a Side Chain Bulkier than an Ethyl Substituent. AB - omega-Transaminase (omega-TA) is a promising enzyme for use in the production of unnatural amino acids from keto acids using cheap amino donors such as isopropylamine. The small substrate-binding pocket of most omega-TAs permits entry of substituents no larger than an ethyl group, which presents a significant challenge to the preparation of structurally diverse unnatural amino acids. Here we report on the engineering of an (S)-selective omega-TA from Ochrobactrum anthropi (OATA) to reduce the steric constraint and thereby allow the small pocket to readily accept bulky substituents. On the basis of a docking model in which L-alanine was used as a ligand, nine active-site residues were selected for alanine scanning mutagenesis. Among the resulting variants, an L57A variant showed dramatic activity improvements in activity for alpha-keto acids and alpha amino acids carrying substituents whose bulk is up to that of an n-butyl substituent (e.g., 48- and 56-fold increases in activity for 2-oxopentanoic acid and L-norvaline, respectively). An L57G mutation also relieved the steric constraint but did so much less than the L57A mutation did. In contrast, an L57V substitution failed to induce the improvements in activity for bulky substrates. Molecular modeling suggested that the alanine substitution of L57, located in a large pocket, induces an altered binding orientation of an alpha-carboxyl group and thereby provides more room to the small pocket. The synthetic utility of the L57A variant was demonstrated by carrying out the production of optically pure L- and D-norvaline (i.e., enantiomeric excess [ee]>99%) by asymmetric amination of 2 oxopantanoic acid and kinetic resolution of racemic norvaline, respectively. PMID- 26231641 TI - Nitrogen Cycling Potential of a Grassland Litter Microbial Community. AB - Because microorganisms have different abilities to utilize nitrogen (N) through various assimilatory and dissimilatory pathways, microbial composition and diversity likely influence N cycling in an ecosystem. Terrestrial plant litter decomposition is often limited by N availability; however, little is known about the microorganisms involved in litter N cycling. In this study, we used metagenomics to characterize the potential N utilization of microbial communities in grassland plant litter. The frequencies of sequences associated with eight N cycling pathways differed by several orders of magnitude. Within a pathway, the distributions of these sequences among bacterial orders differed greatly. Many orders within the Actinobacteria and Proteobacteria appeared to be N cycling generalists, carrying genes from most (five or six) of the pathways. In contrast, orders from the Bacteroidetes were more specialized and carried genes for fewer (two or three) pathways. We also investigated how the abundance and composition of microbial N cycling genes differed over time and in response to two global change manipulations (drought and N addition). For many pathways, the abundance and composition of N cycling taxa differed over time, apparently reflecting precipitation patterns. In contrast to temporal variability, simulated global change had minor effects on N cycling potential. Overall, this study provides a blueprint for the genetic potential of N cycle processes in plant litter and a baseline for comparisons to other ecosystems. PMID- 26231642 TI - Three Novel Lantibiotics, Ticins A1, A3, and A4, Have Extremely Stable Properties and Are Promising Food Biopreservatives. AB - Lantibiotics are antimicrobial peptides with potential applications as the next generation of antimicrobials in the food industry and/or the pharmaceutical industry. Nisin has successfully been used as a food preservative for over 40 years, but its major drawback is its limited stability under neutral and alkaline pH conditions. To identify alternatives with better biochemical properties, we screened more than 100 strains of the Bacillus cereus group. Three novel lantibiotics, ticins A1 (4,062.98 Da), A3 (4,048.96 Da), and A4 (4,063.02 Da), which were highly thermostable (121 degrees C for 30 min) and extremely pH tolerant (pH 2.0 to 9.0), were identified in Bacillus thuringiensis BMB3201. They all showed potent antimicrobial activities against all tested Gram-positive bacteria and greater activities than those of nisin A against Bacillus cereus and Listeria monocytogenes, two important foodborne pathogens. These three novel lantibiotics, with their extremely stable properties and potent antimicrobial activities, have the potential for use as biopreservatives. PMID- 26231643 TI - Identification and Characterization of a Novel Staphylococcal Emetic Toxin. AB - Staphylococcal enterotoxins (SEs) produced by Staphylococcus aureus have superantigenic and emetic activities, which cause toxic shock syndrome and staphylococcal food poisoning, respectively. Our previous study demonstrated that the sequence of SET has a low level of similarity to the sequences of other SEs and exhibits atypical bioactivities. Hence, we further explored whether there is an additional SET-related gene in S. aureus strains. One SET-like gene was found in the genome of S. aureus isolates that originated from a case of food poisoning, a human nasal swab, and a case of bovine mastitis. The deduced amino acid sequence of the SET-like gene showed 32% identity with the amino acid sequence of SET. The SET-like gene product was designated SElY. In the food poisoning and nasal swab isolates, mRNA encoding SElY was highly expressed in the early log phase of cultivation, whereas a high level of expression of this mRNA was found in the bovine mastitis isolate at the early stationary phase. To estimate whether SElY has both superantigenic and emetic activities, recombinant SElY was prepared. Cell proliferation and cytokine production were examined to assess the superantigenic activity of SElY. SElY exhibited superantigenic activity in human peripheral blood mononuclear cells but not in mouse splenocytes. In addition, SElY exhibited emetic activity in house musk shrews after intraperitoneal and oral administration. However, the stability of SElY against heating and pepsin and trypsin digestion was different from that of SET and SEA. From these results, we identified SElY to be a novel staphylococcal emetic toxin. PMID- 26231644 TI - Botrytis pseudocinerea Is a Significant Pathogen of Several Crop Plants but Susceptible to Displacement by Fungicide-Resistant B. cinerea Strains. AB - Botrytis cinerea is one of the most important pathogens worldwide, causing gray mold on a large variety of crops. Botrytis pseudocinerea has been found previously to occur together with B. cinerea in low abundance in vineyards and strawberry fields. Here, we report B. pseudocinerea to be common and sometimes dominant over B. cinerea on several fruit and vegetable crops in Germany. On apples with calyx end rot and on oilseed rape, it was the major gray mold species. Abundance of B. pseudocinerea was often negatively correlated with fungicide treatments. On cultivated strawberries, it was frequently found in spring but was largely displaced by B. cinerea following fungicide applications. Whereas B. cinerea strains with multiple-fungicide resistance were common in these fields, B. pseudocinerea almost never developed resistance to any fungicide even though resistance mutations occurred at similar frequencies in both species under laboratory conditions. The absence of resistance to quinone outside inhibitors in B. pseudocinerea was correlated with an intron in cytB preventing the major G143A resistance mutation. Our work indicates that B. pseudocinerea has a wide host range similar to that of B. cinerea and that it can become an important gray mold pathogen on cultivated plants. PMID- 26231645 TI - Hansenula polymorpha Hac1p Is Critical to Protein N-Glycosylation Activity Modulation, as Revealed by Functional and Transcriptomic Analyses. AB - Aggregation of misfolded protein in the endoplasmic reticulum (ER) induces a cellular protective response to ER stress, the unfolded protein response (UPR), which is mediated by a basic leucine zipper (bZIP) transcription factor, Hac1p/Xbp1. In this study, we identified and studied the molecular functions of a HAC1 homolog from the thermotolerant yeast Hansenula polymorpha (HpHAC1). We found that the HpHAC1 mRNA contains a nonconventional intron of 177 bp whose interaction with the 5' untranslated region is responsible for the translational inhibition of the HpHAC1 mRNA. The H. polymorpha hac1-null (Hphac1Delta) mutant strain grew slowly, even under normal growth conditions, and was less thermotolerant than the wild-type (WT) strain. The mutant strain was also more sensitive to cell wall-perturbing agents and to the UPR-inducing agents dithiothreitol (DTT) and tunicamycin (TM). Using comparative transcriptome analysis of the WT and Hphac1Delta strains treated with DTT and TM, we identified HpHAC1-dependent core UPR targets, which included genes involved in protein secretion and processing, particularly those required for N-linked protein glycosylation. Notably, different glycosylation and processing patterns of the vacuolar glycoprotein carboxypeptidase Y were observed in the WT and Hphac1Delta strains. Moreover, overexpression of active HpHac1p significantly increased the N linked glycosylation efficiency and TM resistance. Collectively, our results suggest that the function of HpHac1p is important not only for UPR induction but also for efficient glycosylation in H. polymorpha. PMID- 26231646 TI - Meat Processing Plant Microbiome and Contamination Patterns of Cold-Tolerant Bacteria Causing Food Safety and Spoilage Risks in the Manufacture of Vacuum Packaged Cooked Sausages. AB - Refrigerated food processing facilities are specific man-made niches likely to harbor cold-tolerant bacteria. To characterize this type of microbiota and study the link between processing plant and product microbiomes, we followed and compared microbiota associated with the raw materials and processing stages of a vacuum-packaged, cooked sausage product affected by a prolonged quality fluctuation with occasional spoilage manifestations during shelf life. A total of 195 samples were subjected to culturing and amplicon sequence analyses. Abundant mesophilic psychrotrophs were detected within the microbiomes throughout the different compartments of the production plant environment. However, each of the main genera of food safety and quality interest, e.g., Leuconostoc, Brochothrix, and Yersinia, had their own characteristic patterns of contamination. Bacteria from the genus Leuconostoc, commonly causing spoilage of cold-stored, modified atmosphere-packaged foods, were detected in high abundance (up to >98%) in the sausages studied. The same operational taxonomic units (OTUs) were, however, detected in lower abundances in raw meat and emulsion (average relative abundance of 2%+/-5%), as well as on the processing plant surfaces (<4%). A completely different abundance profile was found for OTUs phylogenetically close to the species Yersinia pseudotuberculosis. These OTUs were detected in high abundance (up to 28%) on the processing plant surfaces but to a lesser extent (<1%) in raw meat, sausage emulsion, and sausages. The fact that Yersinia-like OTUs were found on the surfaces of a high-hygiene packaging compartment raises food safety concerns related to their resilient existence on surfaces. PMID- 26231647 TI - Highly Virulent Non-O157 Enterohemorrhagic Escherichia coli (EHEC) Serotypes Reflect Similar Phylogenetic Lineages, Providing New Insights into the Evolution of EHEC. AB - Enterohemorrhagic Escherichia coli (EHEC) is the causative agent of bloody diarrhea and extraintestinal sequelae in humans, most importantly hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Besides the bacteriophage-encoded Shiga toxin gene (stx), EHEC harbors the locus of enterocyte effacement (LEE), which confers the ability to cause attaching and effacing lesions. Currently, the vast majority of EHEC infections are caused by strains belonging to five O serogroups (the "big five"), which, in addition to O157, the most important, comprise O26, O103, O111, and O145. We hypothesize that these four non-O157 EHEC serotypes differ in their phylogenies. To test this hypothesis, we used multilocus sequence typing (MLST) to analyze a large collection of 250 isolates of these four O serogroups, which were isolated from diseased as well as healthy humans and cattle between 1952 and 2009. The majority of the EHEC isolates of O serogroups O26 and O111 clustered into one sequence type complex, STC29. Isolates of O103 clustered mainly in STC20, and most isolates of O145 were found within STC32. In addition to these EHEC strains, STC29 also included stx-negative E. coli strains, termed atypical enteropathogenic E. coli (aEPEC), yet another intestinal pathogenic E. coli group. The finding that aEPEC and EHEC isolates of non-O157 O serogroups share the same phylogeny suggests an ongoing microevolutionary scenario in which the phage-encoded Shiga toxin gene stx is transferred between aEPEC and EHEC. As a consequence, aEPEC strains of STC29 can be regarded as post- or pre-EHEC isolates. Therefore, STC29 incorporates phylogenetic information useful for unraveling the evolution of EHEC. PMID- 26231648 TI - Comparison of Sewage and Animal Fecal Microbiomes by Using Oligotyping Reveals Potential Human Fecal Indicators in Multiple Taxonomic Groups. AB - Most DNA-based microbial source tracking (MST) approaches target host-associated organisms within the order Bacteroidales, but the gut microbiota of humans and other animals contain organisms from an array of other taxonomic groups that might provide indicators of fecal pollution sources. To discern between human and nonhuman fecal sources, we compared the V6 regions of the 16S rRNA genes detected in fecal samples from six animal hosts to those found in sewage (as a proxy for humans). We focused on 10 abundant genera and used oligotyping, which can detect subtle differences between rRNA gene sequences from ecologically distinct organisms. Our analysis showed clear patterns of differential oligotype distributions between sewage and animal samples. Over 100 oligotypes of human origin occurred preferentially in sewage samples, and 99 human oligotypes were sewage specific. Sequences represented by the sewage-specific oligotypes can be used individually for development of PCR-based assays or together with the oligotypes preferentially associated with sewage to implement a signature-based approach. Analysis of sewage from Spain and Brazil showed that the sewage specific oligotypes identified in U.S. sewage have the potential to be used as global alternative indicators of human fecal pollution. Environmental samples with evidence of prior human fecal contamination had consistent ratios of sewage signature oligotypes that corresponded to the trends observed for sewage. Our methodology represents a promising approach to identifying new bacterial taxa for MST applications and further highlights the potential of the family Lachnospiraceae to provide human-specific markers. In addition to source tracking applications, the patterns of the fine-scale population structure within fecal taxa suggest a fundamental relationship between bacteria and their hosts. PMID- 26231649 TI - Burkholderia Diffusible Signal Factor Signals to Francisella novicida To Disperse Biofilm and Increase Siderophore Production. AB - In many bacteria, the ability to modulate biofilm production relies on specific signaling molecules that are either self-produced or made by neighboring microbes within the ecological niche. We analyzed the potential interspecies signaling effect of the Burkholderia diffusible signal factor (BDSF) on Francisella novicida, a model organism for Francisella tularensis, and demonstrated that BDSF both inhibits the formation and causes the dispersion of Francisella biofilm. Specificity was demonstrated for the cis versus the trans form of BDSF. Using transcriptome sequencing, quantitative reverse transcription-PCR, and activity assays, we found that BDSF altered the expression of many F. novicida genes, including genes involved in biofilm formation, such as chitinases. Using a chitinase inhibitor, the antibiofilm activity of BDSF was also shown to be chitinase dependent. In addition, BDSF caused an increase in RelA expression and increased levels of (p)ppGpp, leading to decreased biofilm production. These results support our observation that exposure of F. novicida to BDSF causes biofilm dispersal. Furthermore, BDSF upregulated the genes involved in iron acquisition (figABCD), increasing siderophore production. Thus, this study provides evidence for a potential role and mechanism of diffusible signal factor (DSF) signaling in the genus Francisella and suggests the possibility of interspecies signaling between Francisella and other bacteria. Overall, this study suggests that in response to the interspecies DSF signal, F. novicida can alter its gene expression and regulate its biofilm formation. PMID- 26231650 TI - Toolbox Approaches Using Molecular Markers and 16S rRNA Gene Amplicon Data Sets for Identification of Fecal Pollution in Surface Water. AB - In this study, host-associated molecular markers and bacterial 16S rRNA gene community analysis using high-throughput sequencing were used to identify the sources of fecal pollution in environmental waters in Brisbane, Australia. A total of 92 fecal and composite wastewater samples were collected from different host groups (cat, cattle, dog, horse, human, and kangaroo), and 18 water samples were collected from six sites (BR1 to BR6) along the Brisbane River in Queensland, Australia. Bacterial communities in the fecal, wastewater, and river water samples were sequenced. Water samples were also tested for the presence of bird-associated (GFD), cattle-associated (CowM3), horse-associated, and human associated (HF183) molecular markers, to provide multiple lines of evidence regarding the possible presence of fecal pollution associated with specific hosts. Among the 18 water samples tested, 83%, 33%, 17%, and 17% were real-time PCR positive for the GFD, HF183, CowM3, and horse markers, respectively. Among the potential sources of fecal pollution in water samples from the river, DNA sequencing tended to show relatively small contributions from wastewater treatment plants (up to 13% of sequence reads). Contributions from other animal sources were rarely detected and were very small (<3% of sequence reads). Source contributions determined via sequence analysis versus detection of molecular markers showed variable agreement. A lack of relationships among fecal indicator bacteria, host-associated molecular markers, and 16S rRNA gene community analysis data was also observed. Nonetheless, we show that bacterial community and host associated molecular marker analyses can be combined to identify potential sources of fecal pollution in an urban river. This study is a proof of concept, and based on the results, we recommend using bacterial community analysis (where possible) along with PCR detection or quantification of host-associated molecular markers to provide information on the sources of fecal pollution in waterways. PMID- 26231651 TI - Geographical and Temporal Structures of Legionella pneumophila Sequence Types in Comunitat Valenciana (Spain), 1998 to 2013. AB - Legionella pneumophila is an accidental human pathogen associated with aerosol formation in water-related sources. High recombination rates make Legionella populations genetically diverse, and nearly 2,000 different sequence types (STs) have been described to date for this environmental pathogen. The spatial distribution of STs is extremely heterogeneous, with some variants being present worldwide and others being detected at only a local scale. Similarly, some STs have been associated with disease outbreaks, such as ST578 or ST23. Spain is among the European countries with the highest incidences of reported legionellosis cases, and specifically, Comunitat Valenciana (CV) is the second most affected area in the country. In this work, we aimed at studying the overall diversity of Legionella pneumophila populations found in the period from 1998 to 2013 in 79 localities encompassing 23 regions within CV. To do so, we performed sequence-based typing (SBT) on 1,088 L. pneumophila strains detected in the area from both environmental and clinical sources. A comparison with the genetic structuring detected in a global data set that included 20 European and 7 non European countries was performed. Our results reveal a level of diversity in CV that can be considered representative of the diversity found in other countries worldwide. PMID- 26231652 TI - High Specificity of a Quantitative PCR Assay Targeting a Saxitoxin Gene for Monitoring Toxic Algae Associated with Paralytic Shellfish Toxins in the Yellow Sea. AB - The identification of core genes involved in the biosynthesis of saxitoxin (STX) offers a great opportunity to detect toxic algae associated with paralytic shellfish toxins (PST). In the Yellow Sea (YS) in China, both toxic and nontoxic Alexandrium species are present, which makes it a difficult issue to specifically monitor PST-producing toxic algae. In this study, a quantitative PCR (qPCR) assay targeting sxtA4, a domain in the sxt gene cluster that encodes a unique enzyme involved in STX biosynthesis, was applied to analyze samples collected from the YS in spring of 2012. The abundance of two toxic species within the Alexandrium tamarense species complex, i.e., A. fundyense and A. pacificum, was also determined with TaqMan-based qPCR assays, and PSTs in net-concentrated phytoplankton samples were analyzed with high-performance liquid chromatography coupled with a fluorescence detector. It was found that the distribution of the sxtA4 gene in the YS was consistent with the toxic algae and PSTs, and the quantitation results of sxtA4 correlated well with the abundance of the two toxic species (r=0.857). These results suggested that the two toxic species were major PST producers during the sampling season and that sxtA-based qPCR is a promising method to detect toxic algae associated with PSTs in the YS. The correlation between PST levels and sxtA-based qPCR results, however, was less significant (r=0.552), implying that sxtA-based qPCR is not accurate enough to reflect the toxicity of PST-producing toxic algae. The combination of an sxtA-based qPCR assay and chemical means might be a promising method for monitoring toxic algal blooms. PMID- 26231653 TI - Exploring Vertical Transmission of Bifidobacteria from Mother to Child. AB - Passage through the birth canal and consequent exposure to the mother's microbiota is considered to represent the initiating event for microbial colonization of the gastrointestinal tract of the newborn. However, a precise evaluation of such suspected vertical microbiota transmission has yet to be performed. Here, we evaluated the microbiomes of four sample sets, each consisting of a mother's fecal and milk samples and the corresponding infant's fecal sample, by means of amplicon-based profiling supported by shotgun metagenomics data for two key samples. Notably, targeted genome reconstruction from microbiome data revealed vertical transmission of a Bifidobacterium breve strain and a Bifidobacterium longum subsp. longum strain from mother to infant, a notion confirmed by strain isolation and genome sequencing. Furthermore, PCR analyses targeting unique genes from these two strains highlighted their persistence in the infant gut at 6 months. Thus, this study demonstrates the existence of specific bifidobacterial strains that are common to mother and child and thus indicative of vertical transmission and that are maintained in the infant for at least relatively short time spans. PMID- 26231654 TI - Quantitative Analysis of Lysobacter Predation. AB - Bacteria of the genus Lysobacter are considered to be facultative predators that use a feeding strategy similar to that of myxobacteria. Experimental data supporting this assumption, however, are scarce. Therefore, the predatory activities of three Lysobacter species were tested in the prey spot plate assay and in the lawn predation assay, which are commonly used to analyze myxobacterial predation. Surprisingly, only one of the tested Lysobacter species showed predatory behavior in the two assays. This result suggested that not all Lysobacter strains are predatory or, alternatively, that the assays were not appropriate for determining the predatory potential of this bacterial group. To differentiate between the two scenarios, predation was tested in a CFU-based bioassay. For this purpose, defined numbers of Lysobacter cells were mixed together with potential prey bacteria featuring phenotypic markers, such as distinctive pigmentation or antibiotic resistance. After 24 h, cocultivated cells were streaked out on agar plates and sizes of bacterial populations were individually determined by counting the respective colonies. Using the CFU-based predation assay, we observed that Lysobacter spp. strongly antagonized other bacteria under nutrient-deficient conditions. Simultaneously, the Lysobacter population was increasing, which together with the killing of the cocultured bacteria indicated predation. Variation of the predator/prey ratio revealed that all three Lysobacter species tested needed to outnumber their prey for efficient predation, suggesting that they exclusively practiced group predation. In summary, the CFU-based predation assay not only enabled the quantification of prey killing and consumption by Lysobacter spp. but also provided insights into their mode of predation. PMID- 26231655 TI - Permeable Reactive Barriers Designed To Mitigate Eutrophication Alter Bacterial Community Composition and Aquifer Redox Conditions. AB - Permeable reactive barriers (PRBs) consist of a labile carbon source that is positioned to intercept nitrate-laden groundwater to prevent eutrophication. Decomposition of carbon in the PRB drives groundwater anoxic, fostering microbial denitrification. Such PRBs are an ideal habitat to examine microbial community structure under high-nitrate, carbon-replete conditions in coastal aquifers. We examined a PRB installed at the Waquoit Bay National Estuarine Research Reserve in Falmouth, MA. Groundwater within and below the PRB was depleted in oxygen compared to groundwater at sites upgradient and at adjacent reference sites. Nitrate concentrations declined from a high of 25 MUM upgradient and adjacent to the barrier to <0.1 MUM within the PRB. We analyzed the total and active bacterial communities filtered from groundwater flowing through the PRB using amplicons of 16S rRNA and of the 16S rRNA genes. Analysis of the 16S rRNA genes collected from the PRB showed that the total bacterial community had high relative abundances of bacteria thought to have alternative metabolisms, such as fermentation, including candidate phyla OD1, OP3, TM7, and GN02. In contrast, the active bacteria had lower abundances of many of these bacteria, suggesting that the bacterial taxa that differentiate the PRB groundwater community were not actively growing. Among the environmental variables analyzed, dissolved oxygen concentration explained the largest proportion of total community structure. There was, however, no significant correlation between measured environmental parameters and the active microbial community, suggesting that controls on the active portion may differ from the community as a whole. PMID- 26231657 TI - Employment of ex-prisoners with mental health problems, a realistic evaluation protocol. AB - BACKGROUND: Offenders with a mental illness are routinely excluded from vocational services due to their mental health. Employment has shown to be very important in improving mental health, reducing recidivism, and connecting people to society. This study examines the effectiveness of an established intervention which is relatively untested in this population, Individual Placement and Support (IPS), to help offenders with mental health problems into competitive employment. The overall research question is whether IPS is effective in gaining and sustaining competitive employment for offenders with a Severe Mental Illness (SMI). The context is an English criminal justice setting across different populations. The study will also measure non-vocational outcomes such as recidivism, mental health and social stability. METHODS/DESIGN: A Realistic Evaluation (RE) design will address the questions "What works, for whom, and in what circumstances?" This study includes pre and post comparisons for a cohort of approximately 20 people taking part in IPS, and a similar number of controls, over a one year period. The RE also consists of interviews with practitioners and offenders in order to understand how IPS works and develops within the criminal justice system (CJS). By applying this framework the research can go from discovering whether IPS works, to how and why (or why not) IPS works. This is achieved by examining where the intervention is occurring (Context (C)), the mechanisms (M) that create particular behaviours, and how the outcomes (O) from the intervention all come together (CMOs). Employment outcomes will also be examined for all participants. DISCUSSION: By applying RE the research will permit inferences to be drawn about how and why (or why not) IPS works, by examining context, mechanisms and outcomes. IPS has never been implemented within the CJS in the United Kingdom. As a result, this evaluative research will not only provide a novel insight into the core research areas, but also how the intervention can be improved for others in the future. PMID- 26231656 TI - SDF-1alpha concentration dependent modulation of RhoA and Rac1 modifies breast cancer and stromal cells interaction. AB - BACKGROUND: The interaction of SDF-1alpha with its receptor CXCR4 plays a role in the occurrence of distant metastasis in many solid tumors. This interaction increases migration from primary sites as well as homing at distant sites. METHODS: Here we investigated how SDF-1alpha could modulate both migration and adhesion of cancer cells through the modulation of RhoGTPases. RESULTS: We show that different concentrations of SDF-1alpha modulate the balance of adhesion and migration in cancer cells. Increased migration was obtained at 50 and 100 ng/ml of SDF-1alpha; however migration was reduced at 200 ng/ml. The adhesion between breast cancer cells and BMHC was significantly increased by SDF-1alpha treatment at 200 ng/ml and reduced using a blocking monoclonal antibody against CXCR4. We showed that at low SDF-1alpha concentration, RhoA was activated and overexpressed, while at high concentration Rac1 was promoting SDF-1alpha mediating-cell adhesion. CONCLUSION: We conclude that SDF-1alpha concentration modulates migration and adhesion of breast cancer cells, by controlling expression and activation of RhoGTPases. PMID- 26231658 TI - Induction of reactive oxygen species-mediated apoptosis by purified Schisandrae semen essential oil in human leukemia U937 cells through activation of the caspase cascades and nuclear relocation of mitochondrial apoptogenic factors. AB - The aim of this study was to evaluate the beneficial effects of Schisandrae semen essential oil (SSeo) on apoptosis events and the mechanisms associated with these effects in human leukemia U937 cells. The treatment of U937 cells with SSeo significantly inhibited survival and induced apoptosis. Schisandrae semen essential oil treatment increased the levels of death receptors and Fas, and activated caspases accompanied by proteolytic degradation of poly(ADP-ribose) polymerase, which was associated with the downregulation of members of the inhibitor of apoptosis protein family protein expression; however, a pan-caspase inhibitor reversed SSeo-induced apoptosis. Treating the cells with SSeo also caused truncation of Bid, translocation of proapoptotic Bax to the mitochondria, and loss of mitochondrial membrane permeabilization, thereby inducing the release of cytochrome c into the cytosol. Subsequently, SSeo upregulated the translocation of mitochondrial apoptogenic factors, such as endonuclease G and apoptosis-inducing factor, into the nucleus during the apoptotic process. Notably, SSeo immediately increased the generation of intracellular reactive oxygen species (ROS); however, pretreatment with N-acetylcysteine, a common ROS quencher, almost completely blocked SSeo-induced apoptosis. Taken together, these findings indicate that SSeo caused ROS- and caspase-dependent cell death involving mitochondrial dysfunction and nuclear translocation of mitochondrial proapoptosis proteins. Based on our data, the consumption of Schisandrae semen or its essential oil is a good natural therapeutic agent for anticancer activity and regression. PMID- 26231659 TI - Fish oil-supplemented parenteral nutrition could alleviate acute lung injury, modulate immunity, and reduce inflammation in rats with abdominal sepsis. AB - The objectives were to confirm that intravenous fish oil (FO) emulsions could alleviate acute lung injury, modulate immunity, and reduce inflammation in rats with abdominal sepsis and to explore the mechanisms of these effects. Thirty-six adult male Sprague-Dawley rats were divided into 4 groups randomly. Two days after central venous catheterization, rats were subjected to cecal ligation and puncture to produce abdominal sepsis. Rats were assigned to receive normal saline or total parenteral nutrition (TPN) containing standard soybean oil emulsions or FO-supplemented TPN at the onset of sepsis for 5 days. A sham operation and control treatment were performed in control group rats. Acute lung injury scores, peripheral blood lymphocyte subsets, plasma cytokines, and Foxp3 expression in the spleen were determined. Compared with the normal saline and TPN without FO, FO-supplemented TPN beneficially altered the distributions of the T-lymphocyte subsets and downregulated the acute lung injury scores, plasma cytokines, and expression of Foxp3 due to sepsis. Fish oil-supplemented TPN can decrease acute lung injury scores, alleviate histopathology, reduce the bacterial load in the peritoneal lavage fluid, modulate the lymphocyte subpopulation in the peripheral blood, downregulate Foxp3 expression in the spleen, and reduce plasma cytokines, which means that FO-supplemented TPN can alleviate acute lung injury, modulate immunity, and reduce inflammation in rats with abdominal sepsis. PMID- 26231660 TI - Identification and functional analysis of early gene expression induced by circadian light-resetting in Drosophila. AB - BACKGROUND: The environmental light-dark cycle is the dominant cue that maintains 24-h biological rhythms in multicellular organisms. In Drosophila, light entrainment is mediated by the photosensitive protein CRYPTOCHROME, but the role and extent of transcription regulation in light resetting of the dipteran clock is yet unknown. Given the broad transcriptional changes in response to light previously identified in mammals, we have sought to analyse light-induced global transcriptional changes in the fly's head by using Affymetrix microarrays. Flies were subjected to a 30-min light pulse during the early night (3 h after lights off), a stimulus which causes a substantial phase delay of the circadian rhythm. We then analysed changes in gene expression 1 h after the light stimulus. RESULTS: We identified 200 genes whose transcripts were significantly altered in response to the light pulse at a false discovery rate cut-off of 10%. Analysis of these genes and their biological functions suggests the involvement of at least six biological processes in light-induced delay phase shifts of rhythmic activities. These processes include signalling, ion channel transport, receptor activity, synaptic organisation, signal transduction, and chromatin remodelling. Using RNAi, the expression of 22 genes was downregulated in the clock neurons, leading to significant effects on circadian output. For example, while continuous light normally causes arrhythmicity in wild-type flies, the knockdown of Kr-h1, Nipped-A, Thor, nrv1, Nf1, CG11155 (ionotropic glutamate receptor), and Fmr1 resulted in flies that were rhythmic, suggesting a disruption in the light input pathway to the clock. CONCLUSIONS: Our analysis provides a first insight into the early responsive genes that are activated by light and their contribution to light resetting of the Drosophila clock. The analysis suggests multiple domains and pathways that might be associated with light entrainment, including a mechanism that was represented by a light-activated set of chromatin remodelling genes. PMID- 26231661 TI - Genetic diversity and molecular epidemiology of multidrug-resistant Mycobacterium tuberculosis in Minas Gerais State, Brazil. AB - BACKGROUND: We aimed to characterize the genetic diversity of drug-resistant Mycobacterium tuberculosis (MTb) clinical isolates and investigate the molecular epidemiology of multidrug-resistant (MDR) tuberculosis from Minas Gerais State, Brazil. METHODS: One hundred and four MTb clinical isolates were assessed by IS6110-RFLP, 24-locus mycobacterial interspersed repetitive units variable-number tandem repeats (MIRU-VNTR), TB-SPRINT (simultaneous spoligotyping and rifampicin isoniazid drug-resistance mutation analysis) and 3R-SNP-typing (analysis of single-nucleotide polymorphisms in the genes involved in replication, recombination and repair functions). RESULTS: Fifty-seven different IS6110-RFLP patterns were found, among which 50 had unique patterns and 17 were grouped into seven clusters. The discriminatory index (Hunter and Gaston, HGDI) for RFLP was 0.9937. Ninety-nine different MIRU-VNTR patterns were found, 95 of which had unique patterns and nine isolates were grouped into four clusters. The major allelic diversity index in the MIRU-VNTR loci ranged from 0.6568 to 0.7789. The global HGDI for MIRU-VNTR was 0.9991. Thirty-two different spoligotyping profiles were found: 16 unique patterns (n = 16) and 16 clustered profiles (n = 88). The HGDI for spoligotyping was 0.9009. The spoligotyped clinical isolates were phylogenetically classified into Latin-American Mediterranean (66.34 %), T (14.42 %), Haarlem (5.76 %), X (1.92 %), S (1.92 %) and U (unknown profile; 8.65 %). Among the U isolates, 77.8 % were classified further by 3R-SNP-typing as 44.5 % Haarlem and 33.3 % LAM, while the 22.2 % remaining were not classified. Among the 104 clinical isolates, 86 were identified by TB-SPRINT as MDR, 12 were resistant to rifampicin only, one was resistant to isoniazid only, three were susceptible to both drugs, and two were not successfully amplified by PCR. A total of 42, 28 and eight isolates had mutations in rpoB positions 531, 526 and 516, respectively. Correlating the cluster analysis with the patient data did not suggest recent transmission of MDR-TB. CONCLUSIONS: Although our results do not suggest strong transmission of MDR-TB in Minas Gerais (using a classical 100 % MDR-TB identical isolates cluster definition), use of a smoother cluster definition (>85 % similarity) does not allow us to fully eliminate this possibility; hence, around 20-30 % of the isolates we analyzed might be MDR-TB transmission cases. PMID- 26231662 TI - Life Balance - a mindfulness-based mental health promotion program: conceptualization, implementation, compliance and user satisfaction in a field setting. AB - BACKGROUND: Mental health disorders account for a large percentage of the total burden of illness and constitute a major economic challenge in industrialized countries. Several prevention programs targeted at high-risk or sub-clinical populations have been shown to decrease risk, to increase quality of life, and to be cost-efficient. However, there is a paucity of primary preventive programs aimed at the general adult population. "Life Balance" is a program that employs strategies borrowed from well-established psychotherapeutic approaches, and has been made available to the public in one federal German state by a large health care insurance company. The data presented here are the preliminary findings of an ongoing field trial examining the outcomes of the Life Balance program with regard to emotional distress, life satisfaction, resilience, and public health costs, using a matched control group design. METHODS: Life Balance courses are held at local health-care centers, in groups of 12 to 15 which are led by laypeople who have been trained on the course materials. Participants receive instruction on mindfulness and metacognitive awareness, and are assigned exercises to practice at home. Over an 8-month period in 2013-2014, all individuals who signed up for the program were invited at the time of enrollment to take part in a study involving the provision of psychometric data and of feedback on the course. A control group of subjects was invited to complete the questionnaires on psychometric data but did not receive any intervention. RESULTS: Of 4,898 adults who attended Life Balance courses over the specified period, 1,813 (37.0 %) provided evaluable study data. The average age of study participants was 49.5 years, and 83 % were female. At baseline, participants' self-reported symptoms of depression and anxiety, life satisfaction, and resilience were significantly higher than those seen in the general German population. Overall, evaluations of the course were positive, and 83 % of participants attended at least at 6 of the 7 sessions. Some sociodemographic correlations were noted: men carried out the assigned exercises less often than did women, and younger participants practiced mindfulness less frequently than did older ones. However, satisfaction and compliance with the program were similar across all sociodemographic categories. CONCLUSIONS: While the Life Balance program is publicized as a primary prevention course that is not directed at a patient population, the data indicate that it was utilized by people with a significant mental health burden, and that the concept can be generalized to a broad population. As data from the control group are not yet available, conclusions about effectiveness cannot yet be drawn. TRIAL REGISTRATION: German Clinical Trials Registration ID: DRKS00006216. PMID- 26231663 TI - Simulated driving performance under alcohol: Effects on driver-risk versus driver skill. AB - BACKGROUND: Those who place their vehicles closer to others on the roadway are said to have high risk acceptance, and this contributes to motor vehicle crashes. However, the effect of alcohol on this risky driving behavior is understudied. Behavioral mechanisms that contribute to risky driving are also not well understood. Further, whether increased risk-taking behavior in a driver co-occurs with pronounced impairment in the driver's skill is unknown. METHODS: The study examined the effect of alcohol on driver risk and skill and whether riskier drivers were also those who showed high skill impairment. The relationship between driving behavior and inhibitory control was also tested. Participants completed two driving simulations. In the first drive test, risky driving was encouraged and in the second test, skill-based performance was emphasized. The cued go/no-go task provided a measure inhibitory control. Tests were completed under a 0.65g/kg alcohol and 0.0g/kg (placebo) dose of alcohol. RESULTS: Alcohol impaired a measure of driving skill and increased driver risk taking. It was also found that riskier drivers were not necessarily those who showed the greatest impairments in skill. Poorer inhibitory control was associated with greater driver risk in the sober state. CONCLUSIONS: Alcohol-induced risk-taking behaviors can be dissociable from impairing effects on driver skill and poor inhibitory control is selectively related to risky driving. As such, a distinction between driver risk and driver skill needs to be made in the investigation of problems concerning DUI-related accidents and fatalities in future research. PMID- 26231665 TI - The Dual Layer Casper Micromesh Stent: Taking Advantage of Flow-Diverting Capabilities for the Treatment of Extracranial Aneurysms and Pseudoaneurysms. PMID- 26231666 TI - Erratum to: Cone Beam Computed Tomography (CBCT) in the Field of Interventional Oncology of the Liver. PMID- 26231667 TI - Metabolic and bariatric surgery offers benefits to women beyond weight loss. PMID- 26231669 TI - Human breast cancer bone metastasis in vitro and in vivo: a novel 3D model system for studies of tumour cell-bone cell interactions. AB - Bone is established as the preferred site of breast cancer metastasis. However, the precise mechanisms responsible for this preference remain unidentified. In order to improve outcome for patients with advanced breast cancer and skeletal involvement, we need to better understand how this process is initiated and regulated. As bone metastasis cannot be easily studied in patients, researchers have to date mainly relied on in vivo xenograft models. A major limitation of these is that they do not contain a human bone microenvironment, increasingly considered to be an important component of metastases. In order to address this shortcoming, we have developed a novel humanised bone model, where 1 * 10(5) luciferase-expressing MDA-MB-231 or T47D human breast tumour cells are seeded on viable human subchaodral bone discs in vitro. These discs contain functional osteoclasts 2-weeks after in vitro culture and positive staining for calcine 1 week after culture demonstrating active bone resorption/formation. In vitro inoculation of MDA-MB-231 or T47D cells colonised human bone cores and remained viable for <4 weeks, however, use of matrigel to enhance adhesion or a moving platform to increase diffusion of nutrients provided no additional advantage. Following colonisation by the tumour cells, bone discs pre-seeded with MDA-MB-231 cells were implanted subcutaneously into NOD SCID mice, and tumour growth monitored using in vivo imaging for up to 6 weeks. Tumour growth progressed in human bone discs in 80 % of the animals mimicking the later stages of human bone metastasis. Immunohistochemical and PCR analysis revealed that growing MDA-MB-231 cells in human bone resulted in these cells acquiring a molecular phenotype previously associated with breast cancer bone metastases. MDA-MB-231 cells grown in human bone discs showed increased expression of IL-1B, HRAS and MMP9 and decreased expression of S100A4, whereas, DKK2 and FN1 were unaltered compared with the same cells grown in mammary fat pads of mice not implanted with human bone discs. PMID- 26231668 TI - Expression array analysis of the hepatocyte growth factor invasive program. AB - Signaling by human hepatocyte growth factor (hHGF) via its cell surface receptor (MET) drives mitogenesis, motogenesis and morphogenesis in a wide spectrum of target cell types and embryologic, developmental and homeostatic contexts. Oncogenic pathway activation also contributes to tumorigenesis and cancer progression, including tumor angiogenesis and metastasis, in several prevalent malignancies. The HGF gene encodes full-length hHGF and two truncated isoforms known as NK1 and NK2. NK1 induces all three HGF activities at modestly reduced potency, whereas NK2 stimulates only motogenesis and enhances HGF-driven tumor metastasis in transgenic mice. Prior studies have shown that mouse HGF (mHGF) also binds with high affinity to human MET. Here we show that, like NK2, mHGF stimulates cell motility, invasion and spontaneous metastasis of PC3M human prostate adenocarcinoma cells in mice through human MET. To identify target genes and signaling pathways associated with motogenic and metastatic HGF signaling, i.e., the HGF invasive program, gene expression profiling was performed using PC3M cells treated with hHGF, NK2 or mHGF. Results obtained using Ingenuity Pathway Analysis software showed significant overlap with networks and pathways involved in cell movement and metastasis. Interrogating The Cancer Genome Atlas project also identified a subset of 23 gene expression changes in PC3M with a strong tendency for co-occurrence in prostate cancer patients that were associated with significantly decreased disease-free survival. PMID- 26231677 TI - Simultaneous determination of ten compounds in rat plasma by UPLC-MS/MS: Application in the pharmacokinetic study of Ma-Zi-Ren-Wan. AB - Ma-Zi-Ren-Wan (MZRW) is a classic Chinese formula which has been used to treat human constipation in China for over 2000 years. In order to make good and rational use of this formula in the future, this paper presents the first attempt to track the pharmacokinetic features of MZRW in rat using rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Ten chemical components of MZRW, namely, rhein, emodin, aloe emodin, hesperidin, naringin, amygdalin, albiflorin, paeoniflorin, magnolol and honokiol, were simultaneously determined in rat plasma after a single oral administration (10g/kg body weight) of MZRW to rats. Geniposide and liquiritin were used as internal standards. The separation was performed on a Waters ACQUITY BEH C18 column (100mm*2.1mm, 1.7MUm). The detection was conducted by multiple-reaction monitoring (MRM) in negative ionization mode. Two highest abundant MRM transitions without interference were optimized for each analyte. This method was well validated in terms of linearity, precision, accuracy, recovery, matrix effect and stability. All calibration curves had good linearity (r(2)>0.995) over the concentration range from 3.9 to 125.0ng/mL for emodin, 3.9-500.0ng/mL for amygdalin, 2.0-4000.0ng/mL for naringin and hesperidin, 3.9-2000.0ng/mL for magnolol, 7.8-2000.0ng/mL for rhein and 3.9-4000.0ng/mL for albiflorin, paeoniflorin, aloe emodin and honokiol. The intra-day and inter-day precision (relative standard deviation) was within 15%, the accuracy (relative error) ranged from -13.6% to 15.1%, and the lower limit of quantification in plasma ranged between 2.0ng/mL and 7.8ng/mL. Extraction recovery, matrix effect and stability were satisfactory. The validated method was successfully applied to a pharmacokinetic study of these ten compounds after oral administration of MZRW to rats. The pharmacokinetic parameters of each compound can facilitate clinical studies in the future. PMID- 26231678 TI - Metabolism of nitazoxanide in rats, pigs, and chickens: Application of liquid chromatography coupled to hybrid linear ion trap/Orbitrap mass spectrometer. AB - Nitazoxanide (NTZ) is a nitrothiazole benzamide compound with a broad activity spectrum against parasites, Gram-positive and Gram-negative anaerobic bacteria, and viruses. In this study, hybrid linear ion trap/Orbitrap mass spectrometer providing a high mass resolution and accuracy was used to investigate the metabolism of NTZ in rats, pigs, and chickens. The results revealed that acetylation and glucuronidation were the main metabolic pathways in rats and pigs, whereas acetylation and sulfation were the major metabolic pathways in chickens, which indicated interspecies variations in drug metabolism and elimination. With the accurate mass data and the characteristic MS(n) product ions, we identified six metabolites in which tizoxanide and hydroxylated tizoxanide were phase I metabolites and tizoxanide glucuronide, tizoxanide glucose, tizoxanide sulfate and hydroxyl tizoxanide sulfate were phase II metabolites. Hydroxylated tizoxanide and tizoxanide glucose were identified for the first time. All the comprehensive data were provided to make out the metabolism of NTZ in rats, pigs and chickens more clearly. PMID- 26231679 TI - Retroperitoneal hemorrhage caused by inferior epigastric artery injury. PMID- 26231680 TI - Systematic Review by Multivariate Meta-analyses on the Possible Role of Tumor Necrosis Factor-alpha Gene Polymorphisms in Association with Ischemic Stroke. AB - A number of studies have investigated the association between tumor necrosis factor (TNF)-alpha gene polymorphisms and ischemic stroke susceptibility. However, results of different individual studies are often inconsistent. To provide a more robust evaluation of the association between polymorphisms of the TNF-alpha gene and ischemic stroke risk, we performed a systematic review with multivariate meta-analyses. PubMed, Embase, CNKI, and WanFang databases were searched up to December 20, 2014. Two reviewers independently extracted information and assessed quality of included studies after all the eligible studies were identified. Afterward, multivariate meta-analyses were performed using Stata 13. The estimation of polymorphisms and disease risk was presented by odds ratios (ORs) and corresponding 95 % confidence intervals (CIs). Forty-nine eligible case-control studies from 25 articles that explored the association between 10 TNF-alpha polymorphisms and ischemic stroke were indentified from aforementioned databases. The results of multivariate meta-analysis showed a significant association between -238G/A polymorphism (4760 patients and 4389 controls) and ischemic stroke risk in heterozygotes compared with wild genotype (AG vs. GG: OR 1.44, 95 % CI 1.11-1.87; AA vs. GG: OR 1.98, 95 % CI 0.73-5.40). No significant association of -308G/A, -857C/T, and -1031T/C polymorphisms was observed. The results of stratification analyses of -238G/A polymorphism showed that the AG genotype only increased the risk of ischemic stroke in Asians compared to GG genotype. No additional significant association was observed in this study. In conclusion, the present systematic review and meta-analysis support a prominent role of the TNF-alpha -238G/A polymorphism in the risk of ischemic stroke in Asian adults only, but do not support the role of -308G/A, 857C/T, -1031T/C, -244G/A, -367G/A, -646G/A, -806C/T, -863C/A, and +448G/A in the risk of ischemic stroke. The current evidence warrants further studies with high quality and large sample size to confirm. PMID- 26231681 TI - Two microtubule-plus-end binding proteins LIS1-1 and LIS1-2, homologues of human LIS1 in Neurospora crassa. AB - LIS1 is a microtubule (Mt) plus-end binding protein that interacts with the dynein/dynactin complex. In humans, LIS1 is required for proper nuclear and organelle migration during cell growth. Although gene duplication is absent from Neurospora crassa, we found two paralogues of human LIS1. We named them LIS1-1 and LIS1-2 and studied their dynamics and function by fluorescent tagging. At the protein level, LIS1-1 and LIS1-2 were very similar. Although, the characteristic coiled-coil motif was not present in LIS1-2. LIS1-1-GFP and LIS1-2-GFP showed the same cellular distribution and dynamics, but LIS1-2-GFP was less abundant. Both LIS1 proteins were found in the subapical region as single fluorescent particles traveling toward the cell apex, they accumulated in the apical dome forming prominent short filament-like structures, some of which traversed the Spitzenkorper (Spk). The fluorescent structures moved exclusively in anterograde fashion along straight paths suggesting they traveled on Mts. There was no effect in the filament behavior of LIS1-1-GFP in the Deltalis1-2 mutant but the dynamics of LIS1-2-GFP was affected in the Deltalis1-1 mutant. Microtubular integrity and the dynein-dynactin complex were necessary for the formation of filament-like structures of LIS1-1-GFP in the subapical and apical regions; however, conventional kinesin (KIN-1) was not. Deletion mutants showed that the lack of lis1-1 decreased cell growth by ~75%; however, the lack of lis1-2 had no effect on growth. A Deltalis1-1;Deltalis1-2 double mutant showed slower growth than either single mutant. Conidia production was reduced but branching rate increased in Deltalis1-1 and the Deltalis1-1;Deltalis1-2 double mutants. The absence of LIS1-1 had a strong effect on Mt organization and dynamics and indirectly affected nuclear and mitochondrial distribution. The absence of LIS1-1 filaments in dynein mutants (ropy mutants) or in benomyl treated hyphae indicates the strong association between this protein and the regulation of the dynein-dynactin complex and Mt organization. LIS1-1 and LIS1-2 had a high amino acid homology, nevertheless, the absence of the coiled-coil motif in LIS1-2 suggests that its function or regulation may be distinct from that of LIS1-1. PMID- 26231682 TI - Deletion of the MED13 and CDK8 subunits of the Mediator improves the phenotype of a long-lived respiratory deficient mutant of Podospora anserina. AB - In Podospora anserina, the loss of function of the cytochrome segment of the mitochondrial respiratory chain is viable. This is due to the presence in this organism, as in most filamentous fungi, of an alternative respiratory oxidase (AOX) that provides a bypass to the cytochrome pathway. However mutants lacking a functional cytochrome pathway present multiple phenotypes including poorly colored thin mycelium and slow growth. In a large genetic screen based on the improvement of these phenotypes, we isolated a large number of independent suppressor mutations. Most of them led to the constitutive overexpression of the aox gene. In this study, we characterize a new suppressor mutation that does not affect the production of AOX. It is a loss-of-function mutation in the gene encoding the MED13 subunit of the kinase module of the Mediator complex. Inactivation of the cdk8 gene encoding another subunit of the same module also results in partial suppression of a cytochrome-deficient mutant. Analysis of strains lacking the MED13 or CDK8 subunits points to the importance of these subunits as regulators involved in diverse physiological processes such as growth, longevity and sexual development. Interestingly, transcriptional analyses indicate that in P. anserina, loss of the respiratory cytochrome pathway results in the up-regulation of glycolysis-related genes revealing a new type of retrograde regulation. The loss of MED13 augments the up-regulation of some of these genes. PMID- 26231683 TI - Late detection of cleft palate. AB - Cleft palate only (CPO) is a common congenital malformation, and most patients are diagnosed within the first weeks after birth. Late diagnosis of the cleft palate (CP) could initially result in feeding and growth impairment, and subsequently speech and hearing problems later in life. The purpose of this study is to retrospectively investigate (1) at which age CPO is diagnosed and (2) how the presence of syndromes and other factors relate to the age at diagnosis. The mean age of all children at our centre with CPO included between 1997 and 2014 at diagnosis (n = 271) was 1 year and 4 months. In all, 24.8% (n = 67) was older than 12 months when diagnosed, and 37.3% (n = 101) of all children had been diagnosed >30 days. These findings remain valid when a cut-off point of 14 days is used (44.3% late). Moreover, the grade of the cleft was a determining factor for successful diagnosis; submucous clefts were detected much later on average (89.3% > 30 days; p = .000). Similar results were found using Kaplan-Meier survival analyses. CONCLUSION: CPO is often diagnosed late. Patients diagnosed <=30 days after birth more often presented with an associated disorder. Early diagnoses became more frequent as the severity of the cleft increased (grades 1 4). Professionals should perform more thorough intra-oral investigations, including manual palpations and visual inspections of the palate; they should be made more aware of the frequent accompanying symptoms. WHAT IS KNOWN: The presence of cleft palate only (CPO) is known to negatively affect feeding, hearing, speech and (social) development. Submucous clefts are often underdiagnosed due to their difficulty to detect. As far as we know the literature shows that symptomatic submucous CPs are often diagnosed at an average age of 4.9 years. WHAT IS NEW: 37.3% respectively of all children with CPO were diagnosed relatively late (>30 days after birth), 24.8% was older than 12 months when diagnosed. Mean age of all children with CPO was 1 year and 4 months. We conclude that midwives and pediatricians should perform more through intra-oral investigations of all new-borns, including both a manual palpation, als well a visual inspection of the palate. PMID- 26231685 TI - Electrical, structural, and optical properties of sulfurized Sn-doped In2O 3 nanowires. AB - Sn-doped In2O3 nanowires have been grown on Si via the vapor-liquid-solid mechanism at 800 degrees C and then exposed to H2S between 300 to 600 degrees C. We observe the existence of cubic bixbyite In2O3 and hexagonal SnS2 after processing the Sn:In2O3 nanowires to H2S at 300 degrees C but also cubic bixbyite In2O3, which remains dominant, and the emergence of rhombohedral In2(SO4)3 at 400 degrees C. The resultant nanowires maintain their metallic-like conductivity, and exhibit photoluminescence at 3.4 eV corresponding to band edge emission from In2O3. In contrast, Sn:In2O3 nanowires grown on glass at 500 degrees C can be treated under H2S only below 200 degrees C which is important for the fabrication of Cu2S/Sn:In2O3 core-shell p-n junctions on low-cost transparent substrates such as glass suitable for quantum dot-sensitized solar cells. PMID- 26231684 TI - CeasIng Cpap At standarD criteriA (CICADA): predicting a successful outcome. AB - This is a retrospective analysis of a multicentre randomised controlled trial (RCT) where we concluded that CeasIng Cpap At standerD criteriA (CICADA) in premature babies (PBs) <30 weeks gestational age (GA) was the significantly better method of ceasing CPAP. To identify factors that may influence the number of attempts to cease CPAP, we reviewed the records of 50 PBs from the RCT who used the CICADA method. PBs were grouped according to number of attempts to cease CPAP (fast group <=2 attempts and slow group >2 attempts to cease CPAP). There were 26 (fast group) and 24 (slow group) PBs included in the analysis. Results showed significant differences in mean GA (27.8 +/- 0.3 vs 26.9 +/- 0.3 [weeks +/ SE], p = 0.03) and birth weight ([Bwt]; 1080 +/- 48.8 vs 899 +/- 45.8 [grams +/- SE], p = 0.01) between groups. Significantly fewer PBs in the fast group had a patent ductus arteriosus (PDA) compared to the slow group (5/26 (19.2%) vs 13/24 (54.2 %), p = 0.02). Bwt was a significant negative predictor of CPAP duration (r = -0.497, p = 0.03) and CPAP ceasing attempts (r = -0.290, p = 0.04). CONCLUSION: PBs with a higher GA and Bwt without a PDA ceased CPAP earlier using the CICADA method. Bwt was better than GA for predicting CPAP duration and attempts to cease CPAP. WHAT IS KNOWN: Our previous studies showed that CeasIng Cpap At standarD criteriA (CICADA) significantly reduces CPAP time, oxygen requirements and caffeine use. Some PBs however using the CICADA method required >2 attempts to cease CPAP ('slow CICADA' group). WHAT IS NEW: PBs in the 'fast CICADA' group (<3 attempts to cease CPAP) (a) have longer gestational age and higher birth weight, (b) shorter mechanical ventilation and (c) lower incidence of patent ductus arteriosus. Attempts to cease CPAP decreased by 0.5 times per 1 week increase in GA and 0.3 times per 100-g increase in birth weight for PBs <30 weeks gestation. PMID- 26231686 TI - Analytical characterization of IgG Fc subclass variants through high-resolution separation combined with multiple LC-MS identification. AB - With the rapid growth of recombinant monoclonal antibodies and intravenous immunoglobulin (IVIg) medicines, the understanding of human immunoglobulin G (IgG) subclasses becomes more necessary. It is essential to develop effective techniques and methodologies which have the capability for deep characterization. We have created an approach by applying LC and liquid chromatography-mass spectrometry (LC-MS) methods to thoroughly characterize Fc/2 sequence variants for human IgG subclasses in complex samples. Identification and relative quantitation of sequence variants have been provided. Unique glycan information of each IgG subclass can also be obtained by this method. The approach was based on high-resolution HPLC separation followed by intact LC-MS. Peptide mapping was performed following sample fractionation to identify sequence variants. IVIg, a purified IgG mixture from pooled human plasma of thousands of blood donors, was selected as an example for method development. The amino acid sequence variants in IgG Fc/2 constant region were fully investigated for all subclasses by these methods. A total of 19 sequence variants were identified, and their relative abundances were quantitated, which included six variants in IgG1, eight in IgG2, three in IgG3, and two in IgG4. Unique glycan data was also provided for each Fc subclass, which is particularly important for IgG3; glycans from this subclass have only previously been reported together with IgG2 or IgG4. The method described in this paper has been proved to be an effective approach for deep characterization of IgG Fc/2 for complex samples. The findings of IVIg from these studies are also valuable for better understanding of human IgGs. PMID- 26231687 TI - Identification of vancomycin interaction with Enterococcus faecalis within 30 min of interaction time using Raman spectroscopy. AB - Vancomycin is an important glycopeptide antibiotic which is used to treat serious infections caused by Gram-positive bacteria. However, during the last years, a tremendous rise in vancomycin resistances, especially among Enterococci, was reported, making fast diagnostic methods inevitable. In this contribution, we apply Raman spectroscopy to systematically characterize vancomycin-enterococci interactions over a time span of 90 min using a sensitive Enterococcus faecalis strain and two different vancomycin concentrations above the minimal inhibitory concentration (MIC). Successful action of the drug on the pathogen could be observed already after 30 min of interaction time. Characteristic spectral changes are visualized with the help of multivariate statistical analysis (linear discriminant analysis and partial least squares regressions). Those changes were employed to train a statistical model to predict vancomycin treatment based on the Raman spectra. The robustness of the model was tested using data recorded by an independent operator. Classification accuracies of >90 % were obtained for vancomycin concentrations in the lower range of a typical trough serum concentration recommended for most patients during appropriate vancomycin therapy. Characterization of drug-pathogen interactions by means of label-free spectroscopic methods, such as Raman spectroscopy, can provide the knowledge base for innovative and fast susceptibility tests which could speed up microbiological analysis as well as finding applications in novel antibiotic screenings assays. Graphical Abstract E. faecalis is incubated with vancomycin and characterized by means of Raman spectroscopy after different time points. Characteristic spectral changes reveal efficient vancomycin-enterococci-interaction. PMID- 26231688 TI - Real-time Raman spectroscopy for automatic in vivo skin cancer detection: an independent validation. AB - In a recent study, we have demonstrated that real-time Raman spectroscopy could be used for skin cancer diagnosis. As a translational study, the objective of this study is to validate previous findings through a completely independent clinical test. In total, 645 confirmed cases were included in the analysis, including a cohort of 518 cases from a previous study, and an independent cohort of 127 new cases. Multi-variant statistical data analyses including principal component with general discriminant analysis (PC-GDA) and partial least squares (PLS) were used separately for lesion classification, which generated similar results. When the previous cohort (n = 518) was used as training and the new cohort (n = 127) was used as testing, the area under the receiver operating characteristic curve (ROC AUC) was found to be 0.889 (95 % CI 0.834-0.944; PLS); when the two cohorts were combined, the ROC AUC was 0.894 (95 % CI 0.870-0.918; PLS) with the narrowest confidence intervals. Both analyses were comparable to the previous findings, where the ROC AUC was 0.896 (95 % CI 0.846-0.946; PLS). The independent study validates that real-time Raman spectroscopy could be used for automatic in vivo skin cancer diagnosis with good accuracy. PMID- 26231689 TI - Glucaminium ionic liquid-functionalized stationary phase for the separation of nucleosides in hydrophilic interaction chromatography. AB - A glucaminium-based ionic liquid stationary phase was prepared via facile epoxy amine reaction and subsequent quaternization. Successful immobilization of glucaminium-based ionic liquid onto silica surface was validated by elemental analysis and infrared spectroscopy. The new stationary phase was evaluated for the separation of nucleosides in hydrophilic interaction liquid chromatography (HILIC). Effects of various factors, such as acetonitrile concentration, salt concentration, pH value, as well as column temperature, on the chromatographic behavior toward nucleosides were studied in detail. The results indicated that this new stationary phase can be used for separation of water-soluble polar substances in HILIC mode. The retention of solutes on the stationary phase was influenced by a mixed-mode retention mechanism with a combination of adsorptive and partitioning interactions. PMID- 26231690 TI - Dielectrophoretic characterization of antibiotic-treated Mycobacterium tuberculosis complex cells. AB - Multi-drug resistant tuberculosis (MDR-TB) has become a serious concern for proper treatment of patients. As a phenotypic method, dielectrophoresis can be useful but is yet to be attempted to evaluate Mycobacterium tuberculosis complex cells. This paper investigates the dielectrophoretic behavior of Mycobacterium bovis (Bacillus Calmette-Guerin, BCG) cells that are treated with heat or antibiotics rifampin (RIF) or isoniazid (INH). The experimental parameters are designed on the basis of our sensitivity analysis. The medium conductivity (sigma(m)) and the frequency (f) for a crossover frequency (f(xo1)) test are decided to detect the change of sigma(m)-f(xo1) in conjunction with the drug mechanism. Statistical modeling is conducted to estimate the distributions of viable and nonviable cells from the discrete measurement of f (xo1). Finally, the parameters of the electrophysiology of BCG cells, C(envelope) and sigma(cyto), are extracted through a sampling algorithm. This is the first evaluation of the dielectrophoresis (DEP) approach as a means to assess the effects of antimicrobial drugs on M. tuberculosis complex cells. PMID- 26231691 TI - Sengers syndrome: a unique cause of severe hypertrophic cardiomyopathy. PMID- 26231692 TI - J wave pattern in unexplained syncope. AB - J wave pattern (JWP), characterized by J-point elevation in the anterolateral or inferior leads of the 12-lead electrocardiogram, has been associated with increased risk for idiopathic ventricular fibrillation and mortality. However, its prevalence in syncope of different etiologies is unknown and was evaluated in this study. The study sample comprised 170 consecutive patients with vasovagal syncope or syncope that remained unexplained after complete work-up. JWP in inferior leads and with a horizontal/descending ST-segment is more frequently found in subjects with unexplained syncope than in subjects with vasovagal syncope. This finding may be linked with worse prognosis of unexplained syncope. PMID- 26231693 TI - Ischemia-induced Brugada phenocopy. AB - A 65-year-old man with history of schizoaffective disorder was admitted with a suspicion for syncope. ECG changes consistent with type-1 Brugada pattern were noted on admission. A personal history of angina was reported but a family history of sudden cardiac death or ICD implantation was denied. A fixed perfusion defect and hypokinesis of the distal infero-lateral wall were reported on a pharmacological stress test prompting a coronary angiography. A stent was deployed across a 95% stenosis of the dominant mid right coronary artery with satisfactory results. Resolution of the Brugada type pattern was noted on ECGs repeated after the stenting. PMID- 26231694 TI - Expectation and cooperation in prisoner's dilemmas: The moderating role of game riskiness. AB - This paper investigated the effect of risk orientation, game riskiness, and expectation of cooperation on cooperation in one-shot prisoner's dilemmas (PD). Participants in pairs played PD games that varied on game riskiness such that for half of the games cooperation was more risky than defection (more risky games) while for another half cooperation was less risky (less risky games). They estimated how likely it was that the other player was going to cooperate (expectation of cooperation) before they made their cooperation/defection decision on each game. Supporting the Goal/Expectation Hypothesis, we replicated the effect that expectation of cooperation enhanced cooperation. We also found that risk-seeking individuals cooperated more in more risky games whereas risk averse individuals cooperated more in less risky games. More importantly, we found that game riskiness moderated the effect of expectation of cooperation on cooperation. The positive effect of expectation of cooperation on cooperation was stronger for more risky games than for less risky games. Our results illustrated how the relation between expectation and cooperation as stipulated by the Goal/Expectation Hypothesis was moderated by riskiness of the situations. PMID- 26231695 TI - Can fish oil supplementation and physical training improve oxidative metabolism in aged rat hearts? AB - AIMS: It is well known that in the aging process a variety of physiological functions such as cardiac physiology and energy metabolism decline. Imbalance in production and elimination of reactive oxygen species (ROS) may induce oxidative stress. Research shows that oxidative stress is an important factor in the aging process. Studies suggest that omega-3 polyunsaturated fatty acids (PUFAs) and moderate physical exercise modulate the ROS system. Therefore, the present study aimed to investigate whether omega-3 present in fish oil supplementation coupled with moderate physical training could improve antioxidant and metabolic enzymes in the hearts of adult and aged rats and, if these effects could be associated to glycemia, plasma lipid profile or murinometric parameters. MAIN METHODS: Adult (weighing 315.1+/-9.3g) and aged rats (weighing 444.5+/-11.8g) exercised and receive fish oil supplementation for 4weeks. Then they were used to evaluate murinometric parameters, fasting glucose and lipid profile. After this, their hearts were collected to measure the levels of malondialdehyde (MDA), antioxidant enzyme activity (superoxide dismutase-SOD, catalase-CAT, glutathione peroxidase GPx) and oxidative metabolism marker (citrate synthase-CS activity). KEY FINDINGS: Fish oil supplementation increases HDL concentration and activity of CAT and CS. Moreover, physical training coupled with fish oil supplementation induces additional effects on SOD, GPx and CS activity mainly in aged rats. SIGNIFICANCE: Our data suggest that combined treatment in aged rat hearts improves the antioxidant capacities and metabolic enzyme that can prevent the deleterious effects of aging. PMID- 26231696 TI - Sensorial, structural and functional response of rats subjected to hind limb immobilization. AB - AIMS: This study analyzed the sensorial, structural and functional response of rats subjected to paw immobilization. MAIN METHODS: Animal pelvis, hip, knee and ankle were immobilized using waterproof tape during two weeks for assessment of sensorial response to thermal (hot plate test) and mechanical stimuli (Von Frey test), motor system structure (histology and radiography) and muscle function (soleus contractility). KEY FINDINGS: Disuse animals became more responsive to thermal stimuli (49%), although less responsive to mechanical challenge (58%). Disuse animals showed local injuries such as reduction in muscle fiber diameter (16.7% in gastrocnemius, 5.7% in soleus), contractile activity (55% of the control maximal tonic contraction) and tibia cortical thickness (9.3%), besides increased nitrite:protein ratio, suggestive of protein degradation. Disuse also evoked systemic adaptations that include increase in serum lactate dehydrogenase (36.1%) and alkaline phosphatase (400%), but reduction in calcium (8.4%) and total serum protein (5.5%), especially albumin (34.2%). SIGNIFICANCE: Two weeks of functional paw disuse leads to local and systemic harmful adaptive changes in sensorial and structural systems. This study brings new insights into nervous and motor system mechanism associated with therapeutic limb immobilization in muscle and skeletal pathological conditions. PMID- 26231697 TI - Effectiveness of Motivational Incentives for Adolescent Marijuana Users in a School-Based Intervention. AB - PURPOSE: This study examined whether adolescents receiving Motivational Interviewing (MI) intervention have different outcomes compared to those receiving Motivational Incentives (Motivational Interviewing combined with Contingency Management; MI+CM). METHOD: A total of 136 adolescents (from a parent study of 220 adolescents) with problematic substance use were recruited from 8 high schools in Washington State, where they completed either 8-weeks of MI or MI+CM. Frequency of marijuana use was assessed at baseline, at the end-of treatment, and at 16-week follow-up. RESULTS: A balanced and matched sample was created using propensity scores, then analyzed using Hierarchical Linear Modeling (HLM). Multilevel regression analyses revealed that adolescents who received MI+CM exhibited a greater reduction in use across time (p<.05). Reductions at the end-of-treatment were greater for the MI+CM condition (Cohen's d=-.82) compared to MI alone (Cohen's d=-.33), but did not differ at 16-week follow-up. Adolescents receiving MI+CM showed significantly fewer negative consequences of marijuana use at the end-of-treatment (t1, 124=2.26, p<.05), higher use of coping strategies (t1, 124=3.01, p<.01), and increased likelihood to attend additional treatment for substance use (chi2 1, 124=4.12 p<.05), though hypothesized improvements in motivation and school attendance were not found. Use of coping strategies at the end-of-treatment had a significant indirect effect on the relationship between the intervention condition and marijuana use at the end-of treatment (F3, 121=10.20, R2=.20, p<.01). CONCLUSION: These results suggest that the inclusion of contingencies into adolescent marijuana treatment decreases the end-of-treatment frequency of marijuana use and related consequences while increasing the use of coping strategies and the pursuit of additional treatment. PMID- 26231698 TI - Smartphone and Mobile Application Utilization Prior to and Following Treatment Among Individuals Enrolled in Residential Substance Use Treatment. AB - BACKGROUND: Following completion of substance use treatment, it is crucial for patients to continue to utilize skills learned in treatment for optimal treatment outcomes. Mobile applications (apps) on smartphones offer a unique platform to promote utilization of evidence-based skills following completion of substance use treatment. Despite the promise of mobile apps and smartphones for treatment delivery, it remains unknown whether patients in substance use treatment in the United States have access to smartphones and utilize mobile apps on smartphones. The present study sought to determine smartphone utilization among individuals enrolled in one residential substance use treatment center in the U.S. catering specifically to low-income adults. METHODS: Participants included 251 individuals at a residential substance use treatment center in Washington DC admitted to the center between March, 2014 and January, 2015. During the intake process, participants completed interviewer-administered demographics and psychiatric questionnaires as well as a self-report of technology utilization. RESULTS: Results indicated that the majority of patients in this residential substance use treatment center owned mobile phones prior to treatment entry (86.9%) and expected to own mobile phones after leaving treatment (92.6%). Moreover, the majority of these phones were (68.5%) or will be smartphones (72.4%) on which patients reported utilizing mobile applications (prior to treatment: 61.3%; post treatment: 64.3%) and accessing the Internet (prior to treatment: 61.3%; post treatment: 65.9%). CONCLUSIONS: Mobile phone and smartphone ownership among this sample were comparable to ownership among U.S. adults broadly. Findings suggest that smartphones and mobile apps may hold clinical utility for fostering continued use of treatment skills following substance use treatment completion. PMID- 26231699 TI - Genetic evidence for contribution of human dispersal to the genetic diversity of EBA-175 in Plasmodium falciparum. AB - BACKGROUND: The 175-kDa erythrocyte binding antigen (EBA-175) of Plasmodium falciparum plays a crucial role in merozoite invasion into human erythrocytes. EBA-175 is believed to have been under diversifying selection; however, there have been no studies investigating the effect of dispersal of humans out of Africa on the genetic variation of EBA-175 in P. falciparum. METHODS: The PCR direct sequencing was performed for a part of the eba-175 gene (regions II and III) using DNA samples obtained from Thai patients infected with P. falciparum. The divergence times for the P. falciparum eba-175 alleles were estimated assuming that P. falciparum/Plasmodium reichenowi divergence occurred 6 million years ago (MYA). To examine the possibility of diversifying selection, nonsynonymous and synonymous substitution rates for Plasmodium species were also estimated. RESULTS: A total of 32 eba-175 alleles were identified from 131 Thai P. falciparum isolates. Their estimated divergence time was 0.13-0.14 MYA, before the exodus of humans from Africa. A phylogenetic tree for a large sequence dataset of P. falciparum eba-175 alleles from across the world showed the presence of a basal Asian-specific cluster for all P. falciparum sequences. A markedly more nonsynonymous substitutions than synonymous substitutions in region II in P. falciparum was also detected, but not within Plasmodium species parasitizing African apes, suggesting that diversifying selection has acted specifically on P. falciparum eba-175. CONCLUSIONS: Plasmodium falciparum eba-175 genetic diversity appeared to increase following the exodus of Asian ancestors from Africa. Diversifying selection may have played an important role in the diversification of eba-175 allelic lineages. The present results suggest that the dispersals of humans out of Africa influenced significantly the molecular evolution of P. falciparum EBA-175. PMID- 26231703 TI - Immunoprecipitation of Cdk-Cyclin Complexes for Determination of Kinase Activity. AB - Cyclin-dependent kinases (Cdks) belong to a family of key regulators of cell division cycle and transcription. The activity of some of them is deregulated in tumor cells and to find specific inhibitors is an important goal to be achieved. We report here the current methods to determine their in vitro activity in order to facilitate the identification of specific inhibitors. Mainly, the activity can be determined by using immunoprecipitates from cell samples with antibodies against specific Cdks as a source of the enzymes. PMID- 26231704 TI - Expression and Purification of Recombinant Cyclins and CDKs for Activity Evaluation. AB - Cyclin-dependent kinases (Cdks) belong to a family of key regulators of cell division cycle and transcription. Their activity is mainly regulated by association with regulatory subunits named cyclins but their activities are also regulated by phosphorylation, acetylation, and the association with specific inhibitory proteins (CKIs). The activity of different Cdks is deregulated in many different type of tumors, and thus, Cdks are considered targets for antitumoral therapy. For large screenings of inhibitors the use of purified recombinant Cdks and cyclins is recommended. We report here the current methods to determine their in vitro activity for large screenings of inhibitors. PMID- 26231705 TI - Expression and Purification of Recombinant CDKs: CDK7, CDK8, and CDK9. AB - Cyclin-dependent kinases have established roles in the regulation of cell cycle, in gene expression and in cell differentiation. Many of these kinases have been considered as drug targets and numerous efforts have been made to develop specific and potent inhibitors against them. The first step in all of these attempts and in many other biochemical analyses is the production of highly purified and reliable kinase, most frequently in a recombinant form. In this chapter we describe our experience in the cloning, expression, and purification of CDKs using CDK7/CycH, CDK8/CycC, and CDK9/CycT1 as an example. PMID- 26231702 TI - Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis. AB - BACKGROUND: The beneficial outcome associated with the use of proton pump inhibitors (PPIs) in idiopathic pulmonary fibrosis (IPF) has been reported in retrospective studies. To date, no prospective study has been conducted to confirm these outcomes. In addition, the potential mechanism by which PPIs improve measures of lung function and/or transplant-free survival in IPF has not been elucidated. METHODS: Here, we used biochemical, cell biological and preclinical studies to evaluate regulation of markers associated with inflammation and fibrosis. In our in vitro studies, we exposed primary lung fibroblasts, epithelial and endothelial cells to ionizing radiation or bleomycin; stimuli typically used to induce inflammation and fibrosis. In addition, we cultured lung fibroblasts from IPF patients and studied the effect of esomeprazole on collagen release. Our preclinical study tested efficacy of esomeprazole in a rat model of bleomycin-induced lung injury. Furthermore, we performed retrospective analysis of interstitial lung disease (ILD) databases to examine the effect of PPIs on transplant-free survival. RESULTS: The cell culture studies revealed that esomeprazole controls inflammation by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha (TNF alpha) and interleukins (IL-1beta and IL-6). The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 (HO1) and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor beta (TGFbeta), fibronectin and matrix metalloproteinases (MMPs). Furthermore, esomeprazole showed robust effect in mitigating the inflammatory and fibrotic responses in a murine model of acute lung injury. Finally, retrospective analysis of two ILD databases was performed to assess the effect of PPIs on transplant-free survival in IPF patients. Intriguingly, this data demonstrated that IPF patients on PPIs had prolonged survival over controls (median survival of 3.4 vs 2 years). CONCLUSIONS: Overall, these data indicate the possibility that PPIs may have protective function in IPF by directly modulating the disease process and suggest that they may have other clinical utility in the treatment of extra-intestinal diseases characterized by inflammatory and/or fibrotic phases. PMID- 26231706 TI - Preparation of CDK/Cyclin Inhibitor Complexes for Structural Determination. AB - The abundance of biochemical and structural knowledge on the Cyclin-Dependent Kinases (CDKs) has provided a comprehensive but not exhaustive insight into the molecular determinants that govern their function mechanisms. The implementation of structural and functional CDK models towards developing novel anticancer strategies that will specifically target individual or multiple CDKs remains a critical need.More than 250 CDKs crystal structures are available to-date, including truncated or whole, modified or not, active or inactive forms, co crystallized with the cyclins and/or their respective putative inhibitors, though, to our knowledge, there is no NMR solved structure available to date. We hitherto attempt to provide a useful guide from protein production to crystallization for CDK/Inhibitors complexes based on an overview of the already elucidated CDK structures, constructs and the preferable expression vectors in each case, in order to yield the respective crystals. PMID- 26231707 TI - Fragment-Based De Novo Design of Cyclin-Dependent Kinase 2 Inhibitors. AB - Cyclin-dependent kinases (CDKs) are core components of the cell cycle machinery that govern the transition between phases during cell cycle progression. Abnormalities in CDKs activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. One of the main bottlenecks hampering the development of drugs for kinase is the difficulty to attain selectivity. A huge variety of small molecules have been reported as CDK inhibitors, as potential anticancer agents, but none of these has been approved for commercial use. Computer-based molecular design supports drug discovery by suggesting novel new chemotypes and compound modifications for lead candidate optimization. One of the methods known as de novo ligand design technique has emerged as a complementary approach to high throughput screening. Several automated de novo software programs have been written, which automatically design novel structures to perfectly fit in known binding site. The de novo design supports drug discovery assignments by generating novel pharmaceutically active agents with desired properties in a cost as well as time efficient approach. This chapter describes procedure and an overview of computer-based molecular de novo design methods on a conceptual level with successful examples of CDKs inhibitors. PMID- 26231709 TI - Identification of Cyclin A Binders with a Fluorescent Peptide Sensor. AB - A peptide sensor that integrates the 4-dimethylaminophthalimide (4-DMAP) fluorophore in a short cyclin A binding sequence displays a large fluorescence emission increase upon interacting with the cyclin A Binding Groove (CBG). Competitive displacement assays of this probe allow the straightforward identification of peptides that interact with the CBG, which could potentially block the recognition of CDK/cyclin A kinase substrates. PMID- 26231708 TI - Protein-Protein Interaction for the De Novo Design of Cyclin-Dependent Kinase Peptide Inhibitors. AB - The homology of the inhibitor binding site regions on the surface of cyclin dependent kinases (CDKs) makes actual CDK inhibitors unable to bind specifically to their molecular targets. Most of them are ATP competitive inhibitors with low specificity that also affect the phosphorylation mechanisms of other nontarget kinases giving rise to harmful side effects. So, the search of specific and potent inhibitors able to bind to the desired CDK target is still a pending issue. Structure based drug design minimized the erroneous binding and increased the affinity of the inhibitor interaction. In the case of CDKs their activation and regulation mechanisms mainly depend on protein-protein interactions (PPIs). The design of drugs targeting these PPIs makes feasible and promising towards the discovery of new and specific CDK inhibitors. Development of peptide inhibitors for a target protein is an emerging approach in computer aided drug designing. This chapter describes in detail methodology for use of the VitAL-Viterbi algorithm for de novo peptide design of CDK2 inhibitors. PMID- 26231710 TI - Cell Synchronization Techniques to Study the Action of CDK Inhibitors. AB - Cell synchronization techniques have been used for the studies of mechanisms involved in cell cycle regulation. Synchronization involves the enrichment of subpopulations of cells in specific stages of the cell cycle. These subpopulations are then used to study regulatory mechanisms of the cell cycle such as DNA synthesis, gene expression, protein synthesis, protein phosphorylation, protein degradation, and development of new drugs (e.g., CDK inhibitors). Here, we describe several protocols for synchronization of cells from different phases of the cell cycle. We also describe protocols for determining cell viability and mitotic index and for validating the synchrony of the cells by flow cytometry. PMID- 26231711 TI - Analysis of CDK Inhibitor Action on Mitochondria-Mediated Apoptosis. AB - The role of cyclin-dependent kinase inhibitors (CDKIs) is to negatively regulate cyclin-dependent kinases as a mechanism of control of cell proliferation. As such, CDKIs are being used to induce apoptosis in cancer cells to prevent their excessive reproduction. This chapter describes procedures to study apoptosis induction upon treatment with any CDKI through the evaluation of morphological and functional mitochondrial alterations, in particular, how to measure the mitochondrial membrane potential (DeltaPsim) using TMRE dye, determine the content of intracellular ATP, observe mitochondrial network morphology using HeLa cells stably expressing fluorescent reporter DsRed targeting mitochondrial matrix, observe ultrastructure of the organelle using transmission electron microscopy, and, finally, assure that mitochondrial outer membrane permeabilization takes place by assessing the subcellular localization of cyt C in HeLa cells stably expressing fluorescent cyt C-GFP. PMID- 26231712 TI - Evaluating the Effects of CDK Inhibitors in Ischemia-Reperfusion Injury Models. AB - CDK inhibitors have been used to induce protection in various experimental models. Kidney ischemia-reperfusion (I/R) is a form of acute kidney injury resulting in a cascade of cellular events prompting rapid cellular damage and suppression of kidney function. I/R injury, an inevitable impairment during renal transplant surgery, remains one of the major causes of acute kidney injury and represents the most prominent factor leading to delayed graft function after transplantation. Understanding the molecular events responsible for tubule damage and recovery would help to develop new strategies for organ preservation. This chapter describes procedures to study the effect of CDK inhibitors in the cellular I/R model developed from an epithelial cell line deriving from pig kidney proximal tubule cells (LLC-PK1). We briefly describe methods for determining the protective effect of CDK inhibitors such as activation of caspase 3/7, western blot analysis, gene silencing, and immunoprecipitation. PMID- 26231713 TI - Assessing Cell Cycle Independent Function of the CDK Inhibitor p21(CDKN1A) in DNA Repair. AB - The cyclin-dependent kinase (CDK) inhibitor p21(CDKN1A) is a small protein that is able to regulate many important cell functions, often independently of its activity of CDK inhibitor. In addition to cell cycle, this protein regulates cell transcription, apoptosis, cell motility, and DNA repair. In particular, p21 may participate in different DNA repair processes, like the nucleotide excision repair (NER), base excision repair (BER), and double-strand breaks (DSB) repair, because of its ability to interact with DNA repair proteins, such as proliferating cell nuclear antigen (PCNA), a master regulator of many DNA transactions. Although this role has been debated for a long time, the influence of p21 in DNA repair has been now established. However, it remain to be clarified how this role is coupled to proteasomal degradation that has been shown to occur after DNA damage. This chapter describes procedures to study p21 protein recruitment to localized DNA damage sites in the cell nucleus. In particular, we describe a technique based on local irrradiation with UV light through a polycarbonate filter with micropores; an in situ lysis procedure to detect chromatin-bound proteins by immunofluorescence; a cell fractionation procedure to study chromatin association of p21 by Western blot analysis, and p21 protein protein interactions by an immunoprecipitation assay. PMID- 26231714 TI - Drug Delivery Strategies of Chemical CDK Inhibitors. AB - The pharmacological use of new therapeutics is often limited by a safe and effective drug-delivery system. In this sense, new chemical CDK inhibitors are not an exception. Nanotechnology may be able to solve some of the main problems limiting cancer treatments such as more specific delivery of therapeutics and reduction of toxic secondary effects. It provides new delivery systems able to specifically target cancer cells and release the active molecules in a controlled fashion. Specifically, silica mesoporous supports (SMPS) have emerged as an alternative for more classical drug delivery systems based on polymers. In this chapter, we describe the synthesis of a SMPS containing the CDK inhibitor roscovitine as cargo molecule and the protocols for confirmation of the proper cargo release of the nanoparticles in cell culture employing cell viability, cellular internalization, and cell death induction studies. PMID- 26231715 TI - Animal Models for Studying the In Vivo Functions of Cell Cycle CDKs. AB - Multiple Cdks (Cdk4, Cdk6, and Cdk2) and a mitotic Cdk (Cdk1) are involved in cell cycle progression in mammals. Cyclins, Cdk inhibitors, and phosphorylations (both activating and inhibitory) at different cellular levels tightly modulate the activities of these kinases. Based on the results of biochemical studies, it was long believed that different Cdks functioned at specific stages during cell cycle progression. However, deletion of all three interphase Cdks in mice affected cell cycle entry and progression only in certain specialized cells such as hematopoietic cells, beta cells of the pancreas, pituitary lactotrophs, and cardiomyocytes. These genetic experiments challenged the prevailing biochemical model and established that Cdks function in a cell-specific, but not a stage specific, manner during cell cycle entry and the progression of mitosis. Recent in vivo studies have further established that Cdk1 is the only Cdk that is both essential and sufficient for driving the resumption of meiosis during mouse oocyte maturation. These genetic studies suggest a minimal-essential cell cycle model in which Cdk1 is the central regulator of cell cycle progression. Cdk1 can compensate for the loss of the interphase Cdks by forming active complexes with A , B-, E-, and D-type Cyclins in a stepwise manner. Thus, Cdk1 plays an essential role in both mitosis and meiosis in mammals, whereas interphase Cdks are dispensable. PMID- 26231716 TI - Evaluating Chemical CDK Inhibitors as Cell Death Inducers. AB - The cell cycle of eukaryotic cells is regulated by a family of protein kinases called cyclin-dependent kinases (Cdks). We have reported the identification and biological characterization of a highly potent, small-molecule pan-Cdk inhibitor, which inhibited Cdk1, 2, 4, 5, 6, and 9 with equal potency in the nM range. This compound inhibited multiple events in the cell cycle and induced cell death in human cancer cell lines as well as in peripheral blood or purified resting lymphocytes ex vivo. We describe the materials and methods to determine antitumor efficacy in vivo xenograft models. Pharmacodynamic marker assays that have been performed using tumors and normal tissues are explained. Moreover, we briefly describe methods for determining the effects of chemical Cdk inhibitors on peripheral blood cells or lymphocytes ex vivo. PMID- 26231717 TI - Models for the Study of the Cross Talk Between Inflammation and Cell Cycle. AB - Cyclin-dependent kinases (CDKs) have been traditionally associated with the cell cycle. However, it is now known that CDK7 and CDK9 regulate transcriptional activity via phosphorylation of RNA polymerase II and subsequent synthesis of, for example, inflammatory mediators and factors that influence the apoptotic process; including apoptosis of granulocytes such as neutrophils and eosinophils. Successful resolution of inflammation and restoration of normal tissue homeostasis requires apoptosis of these inflammatory cells and subsequent clearance of apoptotic bodies by phagocytes such as macrophages. It is believed that CDK7 and CDK9 influence resolution of inflammation since they are involved in the transcription of anti-apoptotic proteins such as Mcl-1 which is especially important in granulocyte survival.This chapter describes various in vitro and in vivo models used to investigate CDKs and their inhibitors in granulocytes and particularly the role of CDKs in the apoptosis pathway. This can be performed in vitro by isolation and use of primary granulocytes and in vivo using animal models of inflammatory disease in rodents and zebrafish. Some of the methods described here to assess the role of CDKs in inflammation and apoptosis include flow cytometry and western blotting, together with imaging and quantification of apoptosis in fixed tissue, as well as in vivo models of inflammation. PMID- 26231718 TI - Metabolomic Applications to the Characterization of the Mode-of-Action of CDK Inhibitors. AB - Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and some of them are also involved in the control of cellular transcription. Dysregulation of these critical cellular processes, due to the aberrant expression of some of these proteins, is common in many neoplastic malignancies. Consequently, the development of chemical compounds capable of inhibiting the biological activity of CDKs represents an attractive strategy in the anticancer area. CDK inhibition can trigger apoptosis and could be particularly useful in hematological malignancies, which are more sensitive to inhibition of cell cycle and apoptosis induction. Over the last few years, a number of pharmacological inhibitors of CDKs (CDKIs) belonging to different chemical families have been developed, and some of them have been tested in clinical trials. Given the complexity of the role of CDKs in cell functioning, it would be desirable to develop new tools that could facilitate a better understanding of the new insights into CDK functions and the mode-of-actions of CDKIs. In this context, this chapter describes an experimental approach to evaluate the metabolic consequences of CDKIs at the cellular level based on metabolomics by NMR. More specifically, a description of a strategy to characterize the biochemical effects of CDKIs acting on mammalian cells is provided, including protocols for the extraction of hydrophilic and lipophilic metabolites, the acquisition of 1D and 2D metabolomic Nuclear Magnetic Resonance (NMR) experiments, the identification and quantification of metabolites, and the annotation of the results in the context of biochemical pathways. PMID- 26231719 TI - A Swedish National Prospective and Co-relative Study of School Achievement at Age 16, and Risk for Schizophrenia, Other Nonaffective Psychosis, and Bipolar Illness. AB - While cognitive ability is inversely associated with risk for schizophrenia (SZ), the association is less clear with other nonaffective psychoses (ONAP) and bipolar illness (BPI). Using national Swedish hospital registry data, we examined the prospective relationship between school achievement (SA) and development of SZ, ONAP, and BPI in 1800643 adolescents born 1972-1990. We used Cox proportional hazard and co-relative control models to predict onset of SZ, ONAP, and BPI from standardized SA scores at age 16. The hazard ratio (HRs; and 95% CIs) for first onset of SZ as a function of SA was 0.66 (0.64-0.68) for both sexes. For ONAP, the HRs equaled 0.66 (0.64-0.68) for males and 0.72 (0.70-0.75) for females. For BPI, parallel HRs were 0.81 (0.78-0.84) and 0.71 (0.70-0.73). The association between SA and risk was stronger in the lower vs the higher ranges of SA. In most analyses, moderate increases in risk were observed at the highest levels of SA, with the strongest evidence for females and risk of ONAP. Co-relative control analyses indicated that common genetic or familial-environmental effects only marginally confounded these associations. Consistent with prior studies, these results have 3 major implications for neurodevelopmental models: (1) adolescent cognitive deficits that increase risk are not the result of prodromal changes,( 2) individual specific environmental exposures are largely responsible for the association between low SA and psychosis risk, and (3) neurodevelopmental disturbances (as indicated by low SA) are not unique to SZ but also occur in ONAP and to a lesser degree BPI. PMID- 26231720 TI - Genetic diversity of human rhinoviruses in Cambodia during a three-year period reveals novel genetic types. AB - Acute respiratory viral infections are a major cause of morbidity during early childhood in developing countries. Human rhinoviruses are the most frequent cause of upper respiratory tract infections in humans, which can range in severity from asymptomatic to clinically severe disease. In this study we collected 4170 nasopharyngeal swabs from patients hospitalised with influenza-like illness in two Cambodian provincial hospitals between 2007 and 2010. Samples were screened for 18 respiratory viruses using 5 multiplex PCRs. A total of 11.2% of samples tested positive for human rhinoviruses (HRV). VP4/2 and VP1 regions were amplified and sequenced to study the distribution of rhinoviruses genotypes and species in Cambodia during this three-year period. Five novel genotypes, 2 species A, 2 species B and 1 species C were identified based on VP1 sequences. Co infections with other viruses were demonstrated. PMID- 26231721 TI - Time scale evolution of avipoxviruses. AB - Avipoxviruses are divided into three clades: canarypox-like viruses, fowlpox-like viruses, and psittacinepox-like viruses. Several molecular clock and demographic models available in the BEAST package were compared on three avipoxvirus genes (P4b, cnpv186 and DNA polymerase genes), which enabled to determine that avipoxviruses evolved at a rate of 2-8*10(-5)substitution/site/year, in the range of poxviruses previously reported evolution rates. In addition, the date of mean time of divergence of avipoxviruses from a common ancestor was extrapolated to be about 10,000-30,000years ago, at the same period as modern poxvirus species. Our findings will facilitate epidemiological investigations on avipoxviruses' spread, origin and circulation. PMID- 26231722 TI - [Not Available]. PMID- 26231723 TI - Vocal Attack Time of Different Pitch Levels and Vowels in Mandarin. AB - The purpose of this study was to investigate how vocal attack time (VAT) varies when young adults articulate the three vertex vowels in Mandarin Chinese at five linguistically unconstrained pitch levels. Sound pressure and electroglottographic signals were recorded simultaneously from 53 male and 53 female subjects saying sustained /A/, /i/, and /u/ at five equally spaced pitch heights, each being higher than the preceding one. Then analyses of means, variance, and correlation were performed to explore the relationships of VAT/pitch levels and VAT/vowels. Findings were As mean STs (semitone) increase linearly from levels 1 to 5, mean VATs decrease nonlinearly in a big group of subjects but increase nonlinearly in a small group of them. Based on the body cover model of F0 control, data here lead to the guess that different people incline to use different strategies in increasing pitch height. When males, females, and males plus females are considered as a whole, average STs and VATs tend to be positively correlated among the three vertex vowels. PMID- 26231724 TI - Lateral internal sphincterotomy for surgically recurrent chronic anal fissure. AB - BACKGROUND: Lateral internal sphincterotomy cures chronic anal fissure by preventing internal sphincter hypertonia. However, cutting sphincter predisposes to sphincter dysfunction, manifests as incontinence of gas, liquid, or stool. Surgeons, therefore, can be too cautious in its use, making ineffective superficial incisions or avoiding the operation altogether. This study is designed to confirm the role of redo lateral internal sphincterotomy in the treatment of surgically recurrent chronic anal fissure. METHODS: Patients undergoing repeat lateral internal sphincterotomy for surgically recurrent chronic anal fissure were accessed from a prospectively maintained database. Chronicity was defined by symptoms persisting more than 3 weeks. Contralateral sphincterotomy was performed with electrocautery through a stab incision over the intersphincteric plane. The length of sphincter division was the same as the length of the fissure. Phone questionnaire was administered and fecal continence was assessed by modified Cleveland Clinic Incontinence Score. Patients were asked to rank their overall satisfaction with the operation, and pre- and postoperative quality of life. RESULTS: There were 57 patients, 24 women and 33 men; mean age was 47.9 +/- 14.8 years. Mean follow-up was 12.5 +/- 4.2 years (range 6.2 to 25.2 years). Presenting symptoms included pain (100%), bleeding (80%), pruritus ani (39%), constipation (26%), and diarrhea. Fifty patients (90%) presented with 1 fissure, and 40 were posterior. Most procedures were performed on an outpatient basis. Fissure healing rate was 98%, and 2 patients (4%) developed minor incontinence postoperatively (one of gas, the other, gas and seepage). Overall satisfaction was 9.7 +/- .9 out of 10 with a significant improvement in the quality of life from 5.7 +/- 2.4 out of 10 to 9.3 +/- 1.4 out of 10 (P < .001). CONCLUSION: Judicious repeat lateral sphincterotomy cures recurrent chronic fissures with minimal risk of incontinence. PMID- 26231725 TI - [Spiradenocarcinoma of the forehead : A rare skin tumor in the head and neck region]. AB - Spiradenocarcinomas are rare malignant tumors that originate from the sweat glands of the skin and demonstrate aggressive growth. We report the case of an 86 year-old female patient presenting with a growth on the forehead which had been apparent for 2 years. After surgical removal of the tumor, histological workup culminated in the diagnosis of a spiradenocarcinoma. Surgical margins were free of tumor on pathological examination. Metastasis was excluded by positron emission tomography-computed tomography (PET-CT). Due to the advanced age of the patient and the absence of metastatic disease, no adjuvant therapy was performed. Six months postoperatively there is no evidence of relapse. PMID- 26231726 TI - Different surface sensing of the cell body and nucleus in healthy primary cells and in a cancerous cell line on nanogrooves. AB - Cancer cells are known to have alterations compared to healthy cells, but can these differences extend to the way cells interact with their environment? Here, the authors focused on the alignment on an array of grooves of nanometer depth using two cell types: healthy osteoprogenitor primary cells (HOP) and a cancerous osteosarcoma (SaOs-2) cell line. Another concern was how this alignment affects the cell's interior, namely, the nucleus. Based on the results, it is proposed that these two cell types respond to different size regimes: SaOs-2 cells are more sensitive to shallow grooves while HOP cells are strongly aligned with deep grooves. As a measure of the impact of cell alignment on the nucleus the orientation and elongation of the nucleus were determined. Compared to HOP cells, the cell nucleus of SaOs-2 cells is more aligned and elongated in response to grooves, suggesting a softer nucleus and/or increased force transmission. These results support the hypothesis that cancer cells have reduced nucleus rigidity compared to healthy ones and further indicate differences in sensing, which may be important during metastasis. PMID- 26231727 TI - Factors Affecting Disability-Related Depression in Patients with Lost Limbs: A Mediational Model. AB - The objective of the present study was to determine the mediating role of self efficacy between religiosity, social support, and depression in patients with lost limbs. We sampled 67 male and 33 female disabled patients who had lost limbs in accidents or amputations from four public hospitals in Lahore, Pakistan, and used Religiosity Index (Farooq and Imam, in The effect of religiosity on locus of control. Department of Psychology, Govt College University, Lahore, 1997), General Self-efficacy Scales (Tabassum et al., in Urdu adaptation of the general self-efficacy scale. Retrieved from http://userpage.fu-berlin.de/~health/urdu.htm , 2003), Berlin Social Support Scale (Schwarzer and Schulz, in Berlin Social Support Scales. Retrieved online from http://userpage.fuberlin.de/~gesund/skalen/Language_Selection/Turkish/BerlinSocia SupportScales/berlin_social_support_scales.htm , 2000), and Siddiqui-Shah Depression Scale (Siddiqui and Shah, in Pychol Dev Soc 9(2):245-262, 1997), and used a correlation matrix and mediational analyses along with other inferential statistics to develop a model that suggested self-efficacy mediated between religiosity, social support, and depression with negative correlations that partially mediated this relationship. The findings suggest that low level of religiosity, social support, and self-efficacy may play a role in the onset and continuation of depression or its symptoms. We found no significant differences in gender, education, and cause of disability in patients with lost limbs. Results have implications for clinical psychologists, counselors, and health psychologists to develop a treatment plan for such patients with depression focusing on the factors implicated above. PMID- 26231728 TI - The Physical Activity-Related Barriers and Facilitators Perceived by Men Living in Rural Communities. AB - Men, especially those living in rural areas, experience chronic disease at higher rates than the general population. Physical activity is a well-established protective factor against many chronic diseases; however, only a small fraction of men are meeting national guidelines for physical activity. The purpose of this study was to examine the perceived physical activity-related barriers and facilitators experienced by men living in rural areas in Canada. Participants completed a paper-and-pencil or online survey and asked to select personally relevant physical activity-related barriers and facilitators from a list of 9 and 10 choices, respectively. A total of 149 men completed the survey (50.3% between the ages of 18 and 55 years; 43.0% older than 55 years). Participants were predominantly from rural areas and smaller communities. Overall, the response options "I'm too tired," "I don't have enough time," and "I think I get enough exercise as work" were the three most frequently cited barriers to regular physical activity. The response options "Personal motivation to be healthy," "I enjoy it," and "Support from family and/or friends" were the three most often cited facilitators to physical activity. Results are similar to those shown in other populations. Results can be used to inform the development of policies and programs that aim to increase the physical activity levels of men living in rural areas and small communities. PMID- 26231729 TI - Muscle Dysmorphia and the Perception of Men's Peer Muscularity Preferences. AB - Research suggests that peer muscularity norms preferences are related to men's body image, but little information is known about how perceptions of specific peer group norms preferences are related to men's body image disturbances and specific health behaviors. This study investigated how men perceived the muscularity preferences of male, female, close, and distant peers and whether the perceptions of specific peer preferences were related to muscle dysmorphia and steroid use. Data on muscle dysmorphia and the perceptions of peer muscularity norms were collected from 117 male college students. Results indicated that men perceived distant and male peers as having the most exaggerated preferences for muscularity and that those perceptions were not an accurate reflection of their distant male peers' reported preferences. Results also indicated that perceptions of close female peer muscularity preferences were predictive of symptoms of muscle dysmorphia, but this relationship did not exist for other peer groups, suggesting that the perceptions of close female peer preferences may play a role in the development of muscle dysmorphia. No relationship was found between perceptions of peer muscularity preferences and steroid use. PMID- 26231730 TI - Self-Rated Health and Health Care Access Associated With African American Men's Health Self-Efficacy. AB - Health self-efficacy, a measure of one's self-assurance in taking care of their own health, is known to contribute to a range of health outcomes that has been under examined among African American men. The purpose of this investigation was to identify and contextualize predictors of general health self-efficacy in this population. A cross-sectional sample of surveys from 558 African American was examined. These men were older than 18 years, could read and write English, and attended a hospital-based community health fair targeting minority men in 2011. The outcome of interest was health self-efficacy, which was assessed by asking, "Overall, how confident are you in your ability to take good care of your health?" Responses ranged from 1 ( not confident at all) to 5 ( completely confident). Covariates included age, self-rated health, health insurance status, having a regular physician, and being a smoker. The mean age of participants was 54.4 years, and 61.3% of participants indicated confidence in their ability to take good care of their health. Older age and being a smoker were inversely associated with the outcome. Good self-rated health, having health insurance, and having a regular doctor were positively associated with reports of health self efficacy. Findings suggest that multiple points of connection to the health care system increase the likelihood of health self-efficacy for this sample and interventions to support older African American men who may evaluate their own health status as poor and who may face barriers to health care access are implicated. PMID- 26231731 TI - Are Men's Reproductive Health Problems and Sexual Behavior Predictors of Welfare? AB - The study examined men's reproductive health problems and sexual behavior and their implications for men's welfare in Nigeria. It used the Nigeria Demographic and Health Survey data set of 2013. The analysis used only male recode files, representing 17,359 males. The dependent variable is the computed wealth index, which was selected as proxy for welfare condition. Analysis involved univariate and multivariate levels. The findings indicated that 49.3% of the respondents currently have more than one sexual partner. The total lifetime sexual partner index identifies 70.2% of the men interviewed have had at least two sexual partners in their lifetime. It revealed that men who experience reproductive health challenges, such as sexually transmitted infections and genital ulcer, are 44% and 93%, respectively, less likely to enjoy good welfare condition. It also indicated that men in urban area are 7.256 times more likely to enjoy good welfare condition compared with their rural counterparts. There is a negative association between total lifetime sexual partnerships and exposure to good welfare. The study concludes that social workers, marriage counselors, other health personnel, and policy makers need to focus on the practice of multiple sexual partnership and reproductive health diseases as major determinants of men's welfare. The authors suggest that the index of welfare should include reproductive health issues and indicators of sexual behavior. Also, there is need for the establishment of specialized reproductive health care services and centers that are accessible to all men for effective servicing of reproductive health needs of men in the country. PMID- 26231732 TI - Routine abdominal X-rays in the emergency department: a thing of the past? AB - The large number of abdominal X-ray examinations done in the emergency department is striking considering the scant diagnostic yield of this imaging test in urgent disease. Most of these examinations have normal or nonspecific findings, bringing into question the appropriateness of these examinations. Abdominal X-ray examinations are usually considered a routine procedure or even a "defensive" screening tool, whose real usefulness is unknown. For more than 30 years, the scientific literature has been recommending a reduction in both the number of examinations and the number of projections obtained in each examination to reduce the dose of radiation, unnecessary inconvenience for patients, and costs. Radiologists and clinicians need to know the important limitations of abdominal X rays in the diagnostic management of acute abdomen and restrict the use of this technique accordingly. This requires the correct clinical selection of patients that can benefit from this examination, which would allow better use of alternative techniques with better diagnostic yield, such as ultrasonography or computed tomography. PMID- 26231733 TI - Cell death decision by p53 via control of the mitochondrial membrane. AB - The tumor suppressor p53 is mutated in more than half of human cancers. Recent evidence has revealed that p53 not only regulates apoptosis but also regulates necrotic/necroptotic cell death via the mitochondria. The regulation of apoptosis by p53 is tightly connected to the mitochondrial outer membrane permeabilization and the induction of and interaction with Bcl-2 family members. Interestingly, p53-mediated regulation of necrosis/necroptosis is correlated with mitochondrial permeabilization pore opening via interactions with CypD and Drp1. This review discusses the p53-regulating molecules that induce apoptosis or necrosis/necroptosis via the mitochondria. PMID- 26231734 TI - The insulin-like growth factor (IGF) axis as an anticancer target in prostate cancer. AB - Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer death in males. In recent years, several new targeting agents have been introduced for the treatment of advanced stages of the disease. However, development of resistance limits the efficacy of new drugs and there is a further need to develop additional novel treatment approaches. One of the most investigated targets in cancer research is the insulin-like growth factor (IGF) axis, whose receptors are overexpressed in several cancer entities including PCa. In preclinical studies in PCa, targeting of the IGF axis receptors showed promising anti-tumor effects. Currently available data on clinical studies do not meet the expectations for this new treatment approach. In this review we provide a summary of preclinical and clinical studies on the IGF axis in PCa including treatment with monoclonal antibodies and tyrosine kinase inhibitors. Moreover, we summarize preliminary results from ongoing studies and discuss limitations and side effects of the substances used. We also address the role of the IGF axis in the biomarkers setting including IGF-binding proteins and genetic variants. PMID- 26231736 TI - Multidimensional Perfectionism and Burnout: A Meta-Analysis. AB - A meta-analysis of research examining the relationships between multidimensional perfectionism and burnout is provided. In doing so, relationships before and after controlling for the relationship between dimensions of perfectionism were examined along with whether relationships were moderated by domain (work, sport, or education). A literature search yielded 43 studies (N = 9,838) and 663 effect sizes. Meta-analysis using random-effects models revealed that perfectionistic strivings had small negative or non-significant relationships with overall burnout and symptoms of burnout. By contrast, perfectionistic concerns displayed medium-to-large and medium positive relationships with overall burnout and symptoms of burnout. After controlling for the relationship between dimensions of perfectionism, "pure" perfectionistic strivings displayed notably larger negative relationships. In terms of moderation, in some cases, perfectionistic strivings were less adaptive and perfectionistic concerns more maladaptive in the work domain. Future research should examine explanatory mechanisms, adopt longitudinal designs, and develop interventions to reduce perfectionistic concerns fueled burnout. PMID- 26231735 TI - Infiltrating neutrophils promote renal cell carcinoma (RCC) proliferation via modulating androgen receptor (AR) -> c-Myc signals. AB - Early studies found critical roles for neutrophils in renal cell carcinoma (RCC) progression. However, detailed mechanisms of how infiltrating neutrophils in the kidney tumor microenvironment impact RCC progression remain unclear. Here we found more neutrophils were infiltrated in human RCC lesions than those found in surrounding normal kidney tissues. Similarly, in vitro studies also revealed that RCC cells recruited more neutrophil HL-60N cells than normal kidney epithelial cells. Furthermore, in vitro and in vivo experiments also showed that the infiltrated neutrophils could promote RCC cell growth. Mechanism studies showed that co-culture of RCC cells with neutrophil HL-60N cells could selectively upregulate the androgen receptor (AR) signals, which might then alter the c-Myc signals. Interruption approaches using AR-siRNA to knock down AR in RCC cells blocked neutrophil-enhanced RCC cell proliferation. In vivo data using an orthotopically xenografted RCC mouse model also confirmed that infiltrated neutrophils could promote RCC proliferation via modulating the expressions of related cytokines. Together, these results conclude that infiltrated neutrophils may function through modulating the AR -> c-Myc signals to promote RCC cell proliferation. Targeting this newly identified infiltrating neutrophil -> AR -> c Myc signal pathway in the kidney tumor microenvironment may provide a new potential therapy to better suppress RCC progression. PMID- 26231737 TI - The electrostatic behavior of the bacterial cell wall using a smoothing function to describe the charge-regulated volume charge density profile. AB - The Donnan potential can be observed in many biological systems due to the presence of polyelectrolytes as proteins and nucleic acids. The aim of this work was to present a useful tool to describe the fixed and charge-regulated volume charge density profile through the use of a smoothing function and to obtain the electrostatic potential profile as well as the Donnan potential of this system by solving Poisson-Boltzmann (PB) equation. When we use the smoothing function, the Donnan potential arises automatically from the solution of only one Poisson Boltzmann equation and it is not necessary to impose this potential for treating charged system in the presence of a membrane. The electrostatic behavior across the Bacillus brevis wall considering the dependence on the ionization of the cell wall functional groups as a function of the solution pH was analyzed. An important issue was to show that potentiometric titration data could be used together with the Poisson-Boltzmann equation to predict the electrostatic behavior (e.g., zeta potential) of the bacterial cell surface. PMID- 26231738 TI - Fabrication of a BMP-2-immobilized porous microsphere modified by heparin for bone tissue engineering. AB - The purpose of this study was to fabricate BMP-2-immobilized porous poly(lactide co-glycolide) (PLGA) microspheres (PMS) modified with heparin for bone regeneration. A fluidic device was used to fabricate PMS and the fabricated PMS was modified with heparin-dopamine (Hep-DOPA). Bone morphogenic protein-2 (BMP-2) was immobilized on the heparinized PMS (Hep-PMS) via electrostatic interactions. Both PMS and modified PMS were characterized using scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). MG-63 cell activity on PMS and modified PMS were assessed via alkaline phosphatase (ALP) activity, calcium deposition, and osteocalcin and osteopontin mRNA expression. Immobilized Hep-DOPA and BMP-2 on PMS were demonstrated by XPS analysis. BMP-2-immobilized Hep-PMS provided significantly higher ALP activity, calcium deposition, and osteocalcin and osteopontin mRNA expression compared to PMS alone. These results suggest that BMP-2-immobilized Hep-PMS effectively improves MG-63 cell activity. In conclusion, BMP-2-immobilized Hep-PMS can be used to effectively regenerate bone defects. PMID- 26231739 TI - Metabolically programmed iron chelators. AB - Extensive structure activity relationship (SAR) studies focused on the desferrithiocin [DFT, (S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-methyl-4 thiazolecarboxylic acid] pharmacophore have led to three different DFT analogs being evaluated clinically for the treatment of iron overload diseases, for example, thalassemia. The SAR work revealed that the lipophilicity of a ligand, as determined by its partition between octanol and water, logP(app), could have a profound effect on the drug's iron clearing efficiency (ICE), organ distribution, and toxicity profile. While within a given structural family the more lipophilic a chelator the better the ICE, unfortunately, the more lipophilic ligands are often more toxic. Thus, a balance between lipophilicity, ICE, and toxicity must be achieved. In the current study, we introduce the concept of 'metabolically programmed' iron chelators, that is, highly lipophilic, orally absorbable, effective deferration agents which, once absorbed, are quickly converted to their nontoxic, hydrophilic counterparts. PMID- 26231740 TI - Initial experience from a multidisciplinary pediatric salivary gland disorder clinic. AB - OBJECTIVE: This study is the first in the literature to characterize and detail the clinical and surgical experience of one of the few multidisciplinary salivary gland disorder clinics in North America. METHODS: This is a retrospective chart review of a descriptive nature, including patient information from February 2013 to August 2014. The Salivary Gland Disorder Clinic (SGDC) is located at Nationwide Children's Hospital, a public academic hospital. All patients seen at the SGDC were included in this study, 54 in total. Patients were seen for any salivary gland disorder presentation, ranging from sialorrhea to glandular masses. RESULTS: A total of 70.4% of patients presented to the SGDC with a chief complaint of sialorrhea. Nearly 28% had previously experienced documented aspiration, and drooling severity and frequency was 4.06 and 3.3 on the Thomas Stonell and Greenberg Drooling Rating Scales. 50% of patients presented with neurologic comorbidities and 25.9% with aerodigestive tract anatomic defects. Over 35% of patients had previously attempted medical treatment and 31.5% had no prior treatment attempts. 87% of all patients were offered further treatment options, including interventional, surgical, medical, and conservative measures. CONCLUSIONS: Pediatric salivary gland disorders, especially sialorrhea, can profoundly impact overall health and quality of life. Appropriate management of this symptom requires expert training and knowledge of the upper aerodigestive tract anatomy and appropriate treatment modalities. Our study demonstrates that there is community need for a centralized salivary gland disorder clinic given the complex comorbidities and social challenges that face this population. Many patients present with great risk for aspiration-related complications and the vast majority are offered new treatment options. PMID- 26231741 TI - Cochlear functions in children with familial Mediterranean fever: any role of the severity of the disease? AB - OBJECTIVES: The aim of the study was to compare the cochlear functions of children diagnosed with familial Mediterranean fever (FMF) with healthy controls and to determine their cochlear functions according to their disease severity. METHODS: Seventy-three children with FMF and 30 healthy controls were included in the study. All the patients and controls were evaluated by audiologic evaluation, including high-frequency pure-tone audiometry and distortion product otoacoustic emission tests (DPOAE). The disease severity was evaluated by scoring systems adapted from those used by Pras et al. and with severity scoring systems from the Sheba Medical Center. RESULTS: High-frequency pure-tone audiometry and DPOAE levels were normal in both patients and controls. Significant differences in the hearing levels of FMF patients were not found, according to both adapted severity scoring systems. CONCLUSIONS: Cochlear functions in children with FMF had been evaluated by previous studies, but in our study we evaluated hearing functions according to both controls and disease severity. As a unique study comparing cochlear functions according to severity scores, no significant differences were shown between the groups and controls. PMID- 26231742 TI - A comparison of two myringoplasty techniques in Nepalese children: a prospective randomized trial. AB - BACKGROUND: In children, the success of myringoplastywith temporalis fascia is lower compared to adults and cartilage as an alternative graft material has shown higher success rate. OBJECTIVE: To compare results of myringoplasty using tragal cartilage palisades with the use of temporalis fascia in children with large tympanic membrane perforations. MATERIALS AND METHODS: This is a prospective and randomized study conducted in children of age 6-14 years with large tympanic membrane perforation of more than two quadrants. Status of graft at or around 6 weeks after surgery was used as morphological outcome measure. Pre- and postoperative audiograms were compared to evaluate audiological outcome in two groups. RESULTS: Forty seven out of 55 patients completed follow-up. The graft uptake rate in the cartilage palisades and temporalis fascia myringoplasty group was 91.3% (21/23) and 83.33% (20/24), respectively; the difference was not statistically significant (P=0.666). The mean preoperative air-bone gaps (ABG) in cartilage palisades and temporalis fascia group were 36.2+/-8.9dB and 33.8+/ 7.5dB, the difference was not statistically significant (P=0.412). Similarly, the postoperative ABG in cartilage palisades and temporalis fascia group were 25.1+/ 12.2dB and 17.2+/-9.2dB, respectively, the difference was statistically significant (P=0.040). The gap closure was 11.0dB in palisades group and 16.8dB in fascia group, but it was not significant (P=0.133). CONCLUSION: In our study of pediatric myringoplasty, the morphological and functional outcomes in both cartilage palisades and temporalis fascia groups were comparable. PMID- 26231743 TI - Reduction in oxidative stress biomarkers after adenotonsillectomy. AB - OBJECTIVES: A number of otolaryngic conditions such as chronic tonsillitis, adenoid hypertrophy, and obstructive sleep apnea are associated with oxidative stress and elevated levels of serum oxidants. The objective of this study is to measure changes in urine biomarkers of oxidative stress in children after adenotonsillectomy. METHODS: Twenty-two children with sleep disordered breathing (SDB) with tonsil and adenoid hypertrophy were enrolled prior to adenotonsillectomy. Controls consisted of 20 healthy children. Urine samples were collected from all patients. Levels of three urinary biomarkers for oxidative status, 8-hydroxy-2-deoxyguanosine (8-OxodG), F(2)-isoprostane, and malondialdehyde (MDA) were measured using high performance liquid chromatography. For the study group, urine samples were repeated 3 weeks after surgery. RESULTS: In the study group, preoperative urinary levels of 8-OxodG were higher than in controls (p=0.015). Levels decreased after surgery compared to preoperative levels (p=0.002), and reached control levels (p=0.167) at 3 weeks. Levels of urinary F(2)-isoprostane were similar in both groups (p=0.252), but decreased significantly after surgery (p=0.020). CONCLUSIONS: Children with SDB have elevated levels of urinary 8-OxodG, a marker of oxidative stress. Adenotonsillectomy results in decreased 8-OxodG and F(2)-isoprostane. These findings suggest that urine analysis may represent a valuable tool for the measurement of oxidative stress. PMID- 26231744 TI - An evidence-based guide for intraoperative cochlear implant backup use. AB - OBJECTIVES: Intraoperative assessment of electrode function and position is essential for cochlear implant outcomes. Electrophysiological measures and radiographic imaging modalities have been used for this purpose. This study was conducted to determine the relative utility of X-ray, impedance measurements and ECAP for cochlear implant function. METHODS: A retrospective review was conducted for 132 children (age range from 5 to 13 years old) who underwent cochlear implantation. 3 months after switch on, aided free field (FF) and Ling Six Sounds were compared between patients who had intraoperative ECAP and those who had not intraoperative ECAP (but with normally located electrode array as confirmed by plain X-ray). RESULTS: Only 4 cases (3%) had abnormal impedance measurements that became normal after reinsertion of the same electrode array. 3 cases (2.3%) showed malposition of the electrode array on plain radiograph. They underwent immediate revision. 11 cases (8.3%) had absent intraoperative ECAP response for all electrodes, and 4 cases (3%) had absent intraoperative ECAP response for basal electrodes. These devices were not explanted at the time of surgery. 3 months after switch on, FF and the ling 6 sounds were tested for all patients. No statistical significant differences were found between cases with normal intraoperative ECAP and those who gave no response in ECAP. CONCLUSION: From the study we can conclude that plain X-ray is the guideline for backup use. Results of plain X-ray impacted surgical decision making and led to the use of the backup device. In patients with correct electrode placement in normally developed cochlea as detected by X-ray, it is not recommended to use the backup even if there is no intraoperative ECAP. Also, it is recommended to follow how those children performed after 1 or 2 years to see if making the decision of using or not a backup device based in electrophysiology measures vs X-ray made a difference. PMID- 26231745 TI - Rhabdomyosarcoma of the head and neck in children: review and update. AB - OBJECTIVE: To review the clinical presentation, histology, staging, treatment modalities, and survival for pediatric head and neck rhabdomyosarcoma (non orbital). STUDY DESIGN: Retrospective chart review at a tertiary pediatric hospital of children treated over 18 years (1996-2014) for primary head and neck non-orbital rhabdomyosarcoma. METHODS: Medical charts were examined for clinical presentation, staging, histology, genetic abnormalities, treatment modalities, recurrence and complications from treatment. RESULTS: Our cohort was 17 children (7 male, 10 female) with rhabdomyosarcoma with a median age of 6.3 years (range <1-19). The majority of tumors were of parameningeal location (13/17) with embryonal histology (11/17). Twenty-nine percent (5/17) demonstrated advanced metastatic disease at initial referral. Fifty-three percent (9/17) had skull base erosion and/or cranial nerve deficits. PET CT scan was performed in 4 patients. The overall survival was 75% for the duration of the study. Primary surgical excision was performed in all 4 patients with nonparameningeal tumors as compared to only 1 patient with a parameningeal tumor. All received chemotherapy and radiotherapy, as none had completely resectable disease. CONCLUSION: Pediatric non-orbital primary rhabdomyosarcoma of the head and neck usually has a rapid onset and presents with advanced disease. Our analysis found that the majority of patients in our series had a cranial neuropathy at presentation, which highlights how advanced the disease is in these patients at presentation. The first mode of surgical intervention should be directed toward biopsy in junction with a metastatic work-up. Primary excision with negative microscopic margins for nonparameningeal rhabdomyosarcoma is ideal to spare radiotherapy but was not achievable in our cohort. The benefits of second-look biopsy after chemotherapy and radiation are still unproven; however, we believe that it was beneficial in two patients in our review for further resection thus decreasing subsequent radiation. Fluorodeoxy-d-glucose positron emission tomography (PET) to evaluate disease post treatment may further define the role for second look surgery. PMID- 26231746 TI - Cdx ParaHox genes acquired distinct developmental roles after gene duplication in vertebrate evolution. AB - BACKGROUND: The functional consequences of whole genome duplications in vertebrate evolution are not fully understood. It remains unclear, for instance, why paralogues were retained in some gene families but extensively lost in others. Cdx homeobox genes encode conserved transcription factors controlling posterior development across diverse bilaterians. These genes are part of the ParaHox gene cluster. Multiple Cdx copies were retained after genome duplication, raising questions about how functional divergence, overlap, and redundancy respectively contributed to their retention and evolutionary fate. RESULTS: We examined the degree of regulatory and functional overlap between the three vertebrate Cdx genes using single and triple morpholino knock-down in Xenopus tropicalis followed by RNA-seq. We found that one paralogue, Cdx4, has a much stronger effect on gene expression than the others, including a strong regulatory effect on FGF and Wnt genes. Functional annotation revealed distinct and overlapping roles and subtly different temporal windows of action for each gene. The data also reveal a colinear-like effect of Cdx genes on Hox genes, with repression of Hox paralogy groups 1 and 2, and activation increasing from Hox group 5 to 11. We also highlight cases in which duplicated genes regulate distinct paralogous targets revealing pathway elaboration after whole genome duplication. CONCLUSIONS: Despite shared core pathways, Cdx paralogues have acquired distinct regulatory roles during development. This implies that the degree of functional overlap between paralogues is relatively low and that gene expression pattern alone should be used with caution when investigating the functional evolution of duplicated genes. We therefore suggest that developmental programmes were extensively rewired after whole genome duplication in the early evolution of vertebrates. PMID- 26231747 TI - Fine-needle aspiration biopsy of uveal melanoma: outcomes and complications. AB - PURPOSE: To report outcomes and complications of fine-needle aspiration biopsy (FNAB) of uveal melanoma performed for diagnostic and prognostic purposes. METHODS: Prospective interventional case series of 150 consecutive patients with a clinical diagnosis of uveal melanoma. The FNAB approach (transcorneal (TCO), transscleral (TSC) and transvitreal (TVT) was primarily determined by the location of the tumour. The FNAB was performed using a 25-gauge needle using a previously published technique. Prognostication was done using fluorescent in situ hybridisation detection of monosomy of chromosome 3. RESULTS: FNAB was obtained via TCO (8), TSC (71) and TVT (64) approach and impression smear in seven cases. Diagnostic yield was 92%. False-negative results were observed in 8%. Diagnostic yield was significantly correlated to biopsy approach (TCO 100%, TSC 96%, TSV 86%; p=0.029) and tumour size (basal diameter >5.0 mm; height >2.5 mm). Persistent haemorrhage (subretinal haemorrhage or vitreous) requiring surgical intervention (1%) and rhegmatogenous retinal detachment (1%) were rare. Endophthalmitis, hypotony, tumour recurrence, episcleral seeding were not observed over the average follow-up of 37 months. Prognostication could be performed in 85% of cases. Overall, only 47% of eligible patients enrolled into the adjuvant therapy trial. CONCLUSIONS: FNAB for uveal melanoma with 25-gauge needle is a safe procedure that can yield diagnostic and prognostic information in vast majority of cases (92% and 85%, respectively). Even so, only about half of the eligible cases eventually enrolled into the adjuvant therapy trial. Possibility of negative FNAB yield should be considered when counselling patients with small tumours. Alternative means of diagnostic biopsy and methods of prognostication need to be assessed for small tumours. PMID- 26231748 TI - Trends of fluoroquinolone-resistant Escherichia coli amongst urinary isolates in children: a 10 year surveillance study. AB - We evaluated 3122 children with E. coli urinary isolates over a 10 year period in order to assess the emergence of fluoroquinolone resistance. Susceptibilities remained stable; however, hospitalized children had a statistically higher risk of developing fluoroquinolone-resistant isolates when compared with outpatients. Stewardship monitoring of fluoroquinolone use amongst hospitalized children is warranted. PMID- 26231749 TI - Career intentions of final year medical students in Uganda after graduating: the burden of brain drain. AB - BACKGROUND: Uganda has severe shortage of human resources for health despite the heavy disease burden. The country has one of the highest fertility, and population growth rates in the world and is in dire need of trained health workers. The current doctor: patient ratio of 1:15000 is inadequate and this is further constrained by trained health workers leaving the country while others abandon the health sector. The aim of the study was to determine the career intentions of the final year medical students to leave the county and health field after graduating and the associated factors. METHODS: We conducted a cross sectional study among 251 final year medical students from Makerere, Mbarara, Gulu and Kampala International Universities. We enrolled all the eligible final year medical students. The study was conducted using face-to-face questionnaires in each university. We determined the demographics, reasons for leaving the country and health sector and the intended destinations of medical students who planned to leave the country. Data was entered in Epidata then exported and analyzed in stata 12. RESULTS: Of the 251 students enrolled in the study, 28(11.2 %) wanted to leave the health sector, with Mbarara University of Science and Technology (MUST) having the highest percentage, 16.7 % and Kampala International University (KIU) the least, 7.7 %. Of the 28 who intended to leave the health sector, 82.1 % wanted to join the business sector, 10.7 % agriculture, and 7.1 % politics. Reasons given for the intent to leave were; lack of equipment and supplies in hospitals, over whelming patient numbers, very risky working environment, low payment to doctors, and political reasons. Overall, 112 (44.6 %) of the participants wanted to leave the country with 30.3 % intending to migrate to United States of America (USA), 11.9 % to United Kingdom (UK), 11.0 % to South Africa among others. Some of the reasons given were; doctors are paid a high salary abroad, safe working environment, and desire to continue academics. Age was associated with intention to leave the country (OR = 1.64; 95 % CI: 1.00 - 4.82). CONCLUSIONS: In a country in dire need of health workers, the study showed high proportion of trainee health workers planning to abandon their professions or emigrate from Uganda after training. PMID- 26231750 TI - Patients' perspectives of the feasibility, acceptability and impact of a group based psychoeducation programme for bipolar disorder: a qualitative analysis. AB - BACKGROUND: Although there is some quantitative evidence to suggest the benefits of group psychoeducation for people with bipolar disorder, patients' perspectives and experiences of group psychoeducation require in-depth exploration to enable us to better understand the feasibility, acceptability and impact of these interventions, the potential facilitators and barriers to engagement, and how to improve these interventions in the future. METHODS: In-depth, semi-structured interviews were conducted with 13 participants of a psychoeducation programme for bipolar disorder in Wales, following their involvement in the programme. The data were recorded and transcribed verbatim and analysed using thematic analysis. RESULTS: Findings demonstrate that group psychoeducation may impact on participants' perceived social support, knowledge and acceptance of bipolar disorder, personal insights, attitude towards medication and access to services. Key recommendations for improvement included: allowing more time for group discussions, offering group sessions to family members and avoiding use of hospital or university venues for the groups. CONCLUSIONS: This is the first qualitative study of patients' perspectives of a UK-based group psychoeducation programme for people with bipolar disorder, and findings present an in-depth account of how group psychoeducation may be experienced by patients. The recommendations for improving the content and delivery of group psychoeducation for bipolar disorder may enhance engagement and widen access to such programmes. Future research into psychoeducation for bipolar disorder should explore how to target and engage people of diverse ethnic backgrounds and those in lower socioeconomic groups who are less likely to access healthcare services. PMID- 26231751 TI - Sex-specific genetic effects in physical activity: results from a quantitative genetic analysis. AB - BACKGROUND: The objective of this study is to present a model to estimate sex specific genetic effects on physical activity (PA) levels and sedentary behaviour (SB) using three generation families. METHODS: The sample consisted of 100 families covering three generations from Portugal. PA and SB were assessed via the International Physical Activity Questionnaire short form (IPAQ-SF). Sex specific effects were assessed by genotype-by-sex interaction (GSI) models and sex-specific heritabilities. GSI effects and heterogeneity were tested in the residual environmental variance. SPSS 17 and SOLAR v. 4.1 were used in all computations. RESULTS: The genetic component for PA and SB domains varied from low to moderate (11% to 46%), when analyzing both genders combined. We found GSI effects for vigorous PA (p = 0.02) and time spent watching television (WT) (p < 0.001) that showed significantly higher additive genetic variance estimates in males. The heterogeneity in the residual environmental variance was significant for moderate PA (p = 0.02), vigorous PA (p = 0.006) and total PA (p = 0.001). Sex specific heritability estimates were significantly higher in males only for WT, with a male-to-female difference in heritability of 42.5 (95% confidence interval: 6.4, 70.4). CONCLUSIONS: Low to moderate genetic effects on PA and SB traits were found. Results from the GSI model show that there are sex-specific effects in two phenotypes, VPA and WT with a stronger genetic influence in males. PMID- 26231753 TI - Evaluating the effectiveness of care integration strategies in different healthcare systems in Latin America: the EQUITY-LA II quasi-experimental study protocol. AB - INTRODUCTION: Although fragmentation in the provision of healthcare is considered an important obstacle to effective care, there is scant evidence on best practices in care coordination in Latin America. The aim is to evaluate the effectiveness of a participatory shared care strategy in improving coordination across care levels and related care quality, in health services networks in six different healthcare systems of Latin America. METHODS AND ANALYSIS: A controlled before and after quasi-experimental study taking a participatory action research approach. In each country, two comparable healthcare networks were selected- intervention and control. The study contains four phases: (1) A baseline study to establish network performance in care coordination and continuity across care levels, using (A) qualitative methods: semi-structured interviews and focus groups with a criterion sample of health managers, professionals and users; and (B) quantitative methods: two questionnaire surveys with samples of 174 primary and secondary care physicians and 392 users with chronic conditions per network. Sample size was calculated to detect a proportion difference of 15% and 10%, before and after intervention (alpha=0.05; beta=0.2 in a two-sided test); (2) a bottom-up participatory design and implementation of shared care strategies involving micro-level care coordination interventions to improve the adequacy of patient referral and information transfer. Strategies are selected through a participatory process by the local steering committee (local policymakers, health care network professionals, managers, users and researchers), supported by appropriate training; (3) Evaluation of the effectiveness of interventions by measuring changes in levels of care coordination and continuity 18 months after implementation, applying the same design as in the baseline study; (4) Cross country comparative analysis. ETHICS AND DISSEMINATION: This study complies with international and national legal stipulations on ethics. Conditions of the study procedure were approved by each country's ethical committee. A variety of dissemination activities are implemented addressing the main stakeholders. Registration No.257 Clinical Research Register of the Santa Fe Health Department, Argentina. PMID- 26231752 TI - Having older siblings is associated with gut microbiota development during early childhood. AB - BACKGROUND: Evidence suggests that early life infections, presence of older siblings and furred pets in the household affect the risk of developing allergic diseases through altered microbial exposure. Recently, low gut microbial diversity during infancy has also been linked with later development of allergies. We investigated whether presence of older siblings, furred pets and early life infections affected gut microbial communities at 9 and 18 months of age and whether these differences were associated with the cumulative prevalence of atopic symptoms of eczema and asthmatic bronchitis at 3 years of age. Bacterial compositions and diversity indices were determined in fecal samples collected from 114 infants in the SKOT I cohort at age 9 and 18 months by 16S rRNA gene sequencing. These were compared to the presence of older siblings, furred pets and early life infections and the cumulative prevalence of diagnosed asthmatic bronchitis and self-reported eczema at 3 years of age. RESULTS: The number of older siblings correlated positively with bacterial diversity (p = 0.030), diversity of the phyla Firmicutes (p = 0.013) and Bacteroidetes (p = 0.004) and bacterial richness (p = 0.006) at 18 months. Further, having older siblings was associated with increased relative abundance of several bacterial taxa at both 9 and 18 months of age. Compared to the effect of having siblings, presence of household furred pets and early life infections had less pronounced effects on the gut microbiota. Gut microbiota characteristics were not significantly associated with cumulative occurrence of eczema and asthmatic bronchitis during the first 3 years of life. CONCLUSIONS: Presence of older siblings is associated with increased gut microbial diversity and richness during early childhood, which could contribute to the substantiation of the hygiene hypothesis. However, no associations were found between gut microbiota and atopic symptoms of eczema and asthmatic bronchitis during early childhood and thus further studies are required to elucidate whether sibling-associated gut microbial changes influence development of allergies later in childhood. PMID- 26231754 TI - Factors associated with induced abortion among female entertainment workers: a cross-sectional study in Cambodia. AB - OBJECTIVE: To explore risk factors associated with induced abortion among sexually active female entertainment workers (FEWs) in Cambodia. DESIGN: Cross sectional study. SETTING: Phnom Penh and Siem Reap, Cambodia. PARTICIPANTS: This study included 556 FEWs aged 18-47 years randomly selected from entertainment establishments in the two cities in 2014 using a two-stage cluster sampling method. Data were collected through face-to-face interviews using a structured questionnaire. PRIMARY OUTCOME MEASURE: History of induced abortion during the time working as a FEW. RESULTS: Of the total sample, 45.6% reported currently using a contraceptive method with condom (42.4%) being the most common method, followed by pills (25.6%). One-fourth (25%) of the respondents reported having been pregnant at least once, and 21.4% reported having at least one induced abortion during the time working as a FEW. After controlling for other covariates in a multivariate logistic regression model, FEWs with a history of induced abortion remained significantly more likely to be currently working in a karaoke bar (AOR=1.75, 95% CI 1.10 to 2.78), to have worked longer as a FEW (AOR=1.42, 95% CI 1.06 to 1.43), to have had a greater number of sexual partners in the past 12 months (AOR=1.86, 95% CI 1.02 to 1.54), to be currently using a contraceptive method (AOR=1.52, 95% CI 1.01 to 2.29), to be able to find condoms when they needed them (AOR=2.03, 95% CI 1.09 to 3.82), and to report inconsistent condom use with non-commercial partners in the past 3 months (AOR=1.62, 95% CI 1.06 to 3.44). CONCLUSIONS: This study highlights the high rates of unwanted pregnancies that ended in induced abortions among FEWs in Cambodia. Access of FEWs to quality sexual and reproductive healthcare services is deemed a high priority. Integrated interventions to improve sexual and reproductive health among these vulnerable women should be tailored to reach the most-at-risk groups. PMID- 26231755 TI - The effectiveness of providing peer benchmarked feedback to hip replacement surgeons based on patient-reported outcome measures--results from the PROFILE (Patient-Reported Outcomes: Feedback Interpretation and Learning Experiment) trial: a cluster randomised controlled study. AB - OBJECTIVE: To test whether providing surgeons with peer benchmarked feedback about patient-reported outcomes is effective in improving patient outcomes. DESIGN: Cluster randomised controlled trial. SETTING: Secondary care--Ireland. PARTICIPANTS: Surgeons were recruited through the Irish Institute of Trauma and Orthopaedic Surgery, and patients were recruited in hospitals prior to surgery. We randomly allocated 21 surgeons and 550 patients. INTERVENTION: Surgeons in the intervention group received peer benchmarked patient-reported outcome measures (PROMs) feedback and education. MAIN OUTCOME VARIABLE: Postoperative Oxford Hip Score (OHS). RESULTS: Primary outcome data were available for 11 intervention surgeons with responsibility for 230 patients and 10 control surgeons with responsibility for 228 patients. The mean postoperative OHS for the intervention group was 40.8 (95% CI 39.8 to 41.7) and for the control group was 41.9 (95% CI 41.1 to 42.7). The adjusted effect estimate was -1.1 (95% CI -2.4 to 0.2, p=0.09). Secondary outcomes were the Hip Osteoarthritis Outcome Score (HOOS), EQ 5D and the proportion of patients reporting a problem after surgery. The mean postoperative HOOS for the intervention group was 36.2 and for the control group was 37.1. The adjusted effect estimate was -1.1 (95% CI -2.4 to 0.3, p=0.1). The mean postoperative EQ-5D for the intervention group was 0.85 and for the control group was 0.87. The adjusted effect estimate was -0.02 (95% CI -0.05 to 0.008, p=0.2). 27% of intervention patients and 24% of control patients reported at least one complication after surgery (adjusted OR=1.2, 95% CI 0.6 to 2.3, p=0.6). CONCLUSIONS: Outcomes for patients operated on by surgeons who had received peer benchmarked PROMs data were not statistically different from the outcomes of patients operated on by surgeons who did not receive feedback. PROMs information alone seems to be insufficient to identify opportunities for quality improvement. TRIAL REGISTRATION NUMBER: ISRCTN 69032522. PMID- 26231756 TI - Management of persistent postconcussion symptoms in youth: a randomised control trial protocol. AB - INTRODUCTION: Current management of concussion consists of early education, rest until symptom free, with gradual return to school and physical activity protocols. Although this management strategy is effective for most youth who sustain a concussion, it is not an appropriate strategy for youth with persistent postconcussion symptoms. Prolonged rest and periods of restricted activity may place youth at risk for secondary issues and contribute to the chronicity of postconcussion symptoms. The purpose of this study is to evaluate the efficacy of an active rehabilitation protocol for youth who are slow to recover from concussion. It is hypothesised that an active rehabilitation intervention can reduce persistent postconcussion symptoms, improve function and facilitate return to activity. This article describes the research protocol. METHODS AND ANALYSIS: This is a randomised clinical trial with blinded outcome measurement. Participants will be recruited and randomly assigned to 1 of 2 treatment groups, an active rehabilitation intervention or a standard care education group. Both groups will receive standard care education. However, the active rehabilitation group will participate in an additional low-intensity exercise programme consisting of aerobic, coordination and visualisation exercises. Both the active rehabilitation and the standard care education interventions will be 6 weeks in duration. The primary outcome measure is postconcussion symptoms. Secondary outcome measures include functional recovery (cognitive, motor, psychosocial and emotional functioning) and return to activity. Outcome measures will be administered preintervention and postintervention. The primary outcome measure will also be repeated 2 weeks into the intervention period. ETHICS AND DISSEMINATION: This study has been approved by the Holland Bloorview Kids Rehabilitation Hospital research ethics board (REB # 13-459). The findings from this study will be shared with the general public, sport associations, relevant brain injury organisations and healthcare professionals. TRIAL REGISTRATION NUMBER: NCT02257749. PMID- 26231757 TI - Eating As Treatment (EAT) study protocol: a stepped-wedge, randomised controlled trial of a health behaviour change intervention provided by dietitians to improve nutrition in patients with head and neck cancer undergoing radiotherapy. AB - INTRODUCTION: Maintaining adequate nutrition for Head and Neck Cancer (HNC) patients is challenging due to both the malignancy and the rigours of radiation treatment. As yet, health behaviour interventions designed to maintain or improve nutrition in patients with HNC have not been evaluated. The proposed trial builds on promising pilot data, and evaluates the effectiveness of a dietitian-delivered health behaviour intervention to reduce malnutrition in patients with HNC undergoing radiotherapy: Eating As Treatment (EAT). METHODS AND ANALYSIS: A stepped-wedge cluster randomised design will be used. All recruitment hospitals begin in the control condition providing treatment as usual. In a randomly generated order, oncology staff at each hospital will receive 2 days of training in EAT before switching to the intervention condition. Training will be supplemented by ongoing supervision, coaching and a 2-month booster training provided by the research team. EAT is based on established behaviour change counselling methods, including motivational interviewing, cognitive-behavioural therapy, and incorporates clinical practice change theory. It is designed to improve motivation to eat despite a range of barriers (pain, mucositis, nausea, reduced or no saliva, taste changes and appetite loss), and to provide patients with practical behaviour change strategies. EAT will be delivered by dietitians during their usual consultations. 400 patients with HNC (nasopharynx, hypopharynx, oropharynx, oral cavity or larynx), aged 18+, undergoing radiotherapy (>60 Gy) with curative intent, will be recruited from radiotherapy departments at 5 Australian sites. Assessments will be conducted at 4 time points (first and final week of radiotherapy, 4 and 12 weeks postradiotherapy). The primary outcome will be a nutritional status assessment. ETHICS AND DISSEMINATION: Ethics approval from all relevant bodies has been granted. Study findings will be disseminated widely through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12613000320752. PMID- 26231758 TI - Household antimicrobial self-medication: a systematic review and meta-analysis of the burden, risk factors and outcomes in developing countries. AB - BACKGROUND: Antimicrobial self-medication is common in most low and middle income countries (LMICs). However there has been no systematic review on non prescription antimicrobial use in these settings. This review thus intended to establish the burden, risk factors and effects of antimicrobial self-medication in Low and Middle Income Countries. METHODS: In 2012, we registered a systematic review protocol in PROSPERO (CRD42012002508). We searched PubMed, Medline, Scopus, and Embase databases using the following terms; "self-medication", "non prescription", 'self-treatment', "antimicrobial", "antimalarial", "antibiotic", "antibacterial" "2002-2012" and combining them using Boolean operators. We performed independent and duplicate screening and abstraction of study administrative data, prevalence, determinants, type of antimicrobial agent, source, disease conditions, inappropriate use, drug adverse events and clinical outcomes of antibiotic self-medication where possible. We performed a Random Effects Meta-analysis. RESULTS: A total of thirty four (34) studies involving 31,340 participants were included in the review. The overall prevalence of antimicrobial self-medication was 38.8 % (95 % CI: 29.5-48.1). Most studies assessed non-prescription use of antibacterial (17/34: 50 %) and antimalarial (5/34: 14.7 %) agents. The common disease symptoms managed were, respiratory (50 %), fever (47 %) and gastrointestinal (45 %). The major sources of antimicrobials included, pharmacies (65.5 %), leftover drugs (50 %) and drug shops (37.5 %). Twelve (12) studies reported inappropriate drug use; not completing dose (6/12) and sharing of medicines (4/12). The main determinants of antimicrobial self medication include, level of education, age, gender, past successful use, severity of illness and income. Reported negative outcomes of antimicrobial self medication included, allergies (2/34: 5.9 %), lack of cure (4/34: 11.8 %) and causing death (2/34: 5.9 %). The commonly reported positive outcome was recovery from illness (4/34: 11.8 %). CONCLUSION: The prevalence of antimicrobial self medication is high and varies in different communities as well as by social determinants of health and is frequently associated with inappropriate drug use. PMID- 26231759 TI - Cellular and molecular regulation of the activation of mammalian primordial follicles: somatic cells initiate follicle activation in adulthood. AB - BACKGROUND: The first small follicles to appear in the mammalian ovaries are primordial follicles. The initial pool of primordial follicles serves as the source of developing follicles and oocytes for the entire reproductive lifespan of the animal. Although the selective activation of primordial follicles is critical for female fertility, its underlying mechanisms have remained poorly understood. METHODS: A search of PubMed was conducted to identify peer-reviewed literature pertinent to the study of mammalian primordial follicle activation, especially recent reports of the role of primordial follicle granulosa cells (pfGCs) in regulating this process. RESULTS: In recent years, molecular mechanisms that regulate the activation of primordial follicles have been elucidated, mostly through the use of genetically modified mouse models. Several molecules and pathways operating in both the somatic pfGCs and oocytes, such as the phosphatidylinositol 3 kinase (PI3K) and the mechanistic target of rapamycin complex 1 (mTORC1) pathways, have been shown to be important for primordial follicle activation. More importantly, recent studies have provided an updated view of how exactly signaling pathways in pfGCs and in oocytes, such as the KIT ligand (KL) and KIT, coordinate in adult ovaries so that the activation of primordial follicles is achieved. CONCLUSIONS: In this review, we have provided an updated picture of how mammalian primordial follicles are activated. The functional roles of pfGCs in governing the activation of primordial follicles in adulthood are highlighted. The in-depth understanding of the cellular and molecular mechanisms of primordial follicle activation will hopefully lead to more treatments of female infertility, and the current progress indicates that the use of existing primordial follicles as a source for obtaining fertilizable oocytes as a new treatment for female infertility is just around the corner. PMID- 26231760 TI - Body maps in the infant brain. AB - Researchers have examined representations of the body in the adult brain but relatively little attention has been paid to ontogenetic aspects of neural body maps in human infants. Novel applications of methods for recording brain activity in infants are delineating cortical body maps in the first months of life. Body maps may facilitate infants' registration of similarities between self and other an ability that is foundational to developing social cognition. Alterations in interpersonal aspects of body representations might also contribute to social deficits in certain neurodevelopmental disorders. PMID- 26231761 TI - Reconstructing and deconstructing the self: cognitive mechanisms in meditation practice. AB - Scientific research highlights the central role of specific psychological processes, in particular those related to the self, in various forms of human suffering and flourishing. This view is shared by Buddhism and other contemplative and humanistic traditions, which have developed meditation practices to regulate these processes. Building on a previous paper in this journal, we propose a novel classification system that categorizes specific styles of meditation into attentional, constructive, and deconstructive families based on their primary cognitive mechanisms. We suggest that meta-awareness, perspective taking and cognitive reappraisal, and self-inquiry may be important mechanisms in specific families of meditation and that alterations in these processes may be used to target states of experiential fusion, maladaptive self schema, and cognitive reification. PMID- 26231763 TI - Transcription factor Nrf1 is negatively regulated by its O-GlcNAcylation status. AB - O-Linked N-acetylglucosamine transferase (OGT) was identified as an Nrf1 interacting protein. Herein, we show that Nrf1 enables interaction with OGT and their co-immunoprecipitates are O-GlcNAcylated by the enzyme. The putative O GlcNAcylation negatively regulates Nrf1/TCF11 to reduce both its protein stability and transactivation activity of target gene expression. The turnover of Nrf1 is enhanced upon overexpression of OGT, which promotes ubiquitination of the CNC-bZIP protein. Furthermore, the serine/theorine-rich sequence of PEST2 degron within Nrf1 is identified to be involved in the protein O-GlcNAcylation by OGT. Overall, Nrf1 is negatively regulated by its O-GlcNAcylation status that depends on the glucose concentrations. PMID- 26231764 TI - CLIP-170 tethers kinetochores to microtubule plus ends against poleward force by dynein for stable kinetochore-microtubule attachment. AB - The cytoplasmic linker protein (CLIP)-170 localizes to kinetochores and is suggested to function in stable attachment of kinetochores to microtubule ends. Here we show that defects in kinetochore-microtubule attachment and chromosome alignment in CLIP-170-depleted cells were rescued by co-depletion of p150glued, a dynactin subunit required for kinetochore localization of CLIP-170. CLIP-170 recruited p150glued to microtubule ends. Kinetochore localization at microtubule ends was perturbed by CLIP-170 depletion, which was rescued by co-depleting p150glued. Our results imply that CLIP-170 tethers kinetochores to microtubule ends against the dynein-mediated poleward force to slide kinetochores along microtubules, facilitating the stable kinetochore attachment to microtubules. PMID- 26231762 TI - Prognostic significance of multiple kallikreins in high-grade astrocytoma. AB - BACKGROUND: Kallikreins have clinical value as prognostic markers in a subset of malignancies examined to date, including kallikrein 3 (prostate specific antigen) in prostate cancer. We previously demonstrated that kallikrein 6 is expressed at higher levels in grade IV compared to grade III astrocytoma and is associated with reduced survival of GBM patients. METHODS: In this study we determined KLK1, KLK6, KLK7, KLK8, KLK9 and KLK10 protein expression in two independent tissue microarrays containing 60 grade IV and 8 grade III astrocytoma samples. Scores for staining intensity, percent of tumor stained and immunoreactivity scores (IR, product of intensity and percent) were determined and analyzed for correlation with patient survival. RESULTS: Grade IV glioma was associated with higher levels of kallikrein-immunostaining compared to grade III specimens. Univariable Cox proportional hazards regression analysis demonstrated that elevated KLK6- or KLK7 IR was associated with poor patient prognosis. In addition, an increased percent of tumor immunoreactive for KLK6 or KLK9 was associated with decreased survival in grade IV patients. Kaplan-Meier survival analysis indicated that patients with KLK6-IR < 10, KLK6 percent tumor core stained < 3, or KLK7-IR < 9 had a significantly improved survival. Multivariable analysis indicated that the significance of these parameters was maintained even after adjusting for gender and performance score. CONCLUSIONS: These data suggest that elevations in glioblastoma KLK6, KLK7 and KLK9 protein have utility as prognostic markers of patient survival. PMID- 26231765 TI - Order and disorder in intermediate filament proteins. AB - Intermediate filaments (IFs), important components of the cytoskeleton, provide a versatile, tunable network of self-assembled proteins. IF proteins contain three distinct domains: an alpha-helical structured rod domain, flanked by intrinsically disordered head and tail domains. Recent studies demonstrated the functional importance of the disordered domains, which differ in length and amino acid sequence among the 70 different human IF genes. Here, we investigate the biophysical properties of the disordered domains, and review recent findings on the interactions between them. Our analysis highlights key components governing IF functional roles in the cytoskeleton, where the intrinsically disordered domains dictate protein-protein interactions, supramolecular assembly, and macro scale order. PMID- 26231766 TI - Platelet-endothelial cell interaction in brain microvessels of angiotensin II type-2 receptor knockout mice following transient bilateral common carotid artery occlusion. AB - The purpose of this study was to investigate the behavior of platelets (rolling and adhesion) in cerebral microvessels of angiotensin II type-2 receptor-knockout (AT2RKO) mice after transient bilateral carotid artery occlusion using intravital fluorescence microscopy. Twenty AT2RKO mice, consisting of 11 mice in the sham group and 9 mice in the ischemia reperfusion group (reperfusion after 15 min of bilateral, total carotid artery occlusion) were used in this study. The hole traversed the bone and dura mater, but arachnoid, pia mater, and cerebral parenchyma were preserved. Platelets were harvested from donor mice and stained using carboxyfluorescein diacetate succinimidyl ester. The number of platelets showing rolling and adhesion to pial vessels in AT2 deficient mice at 3 and 6 h after cerebral ischemia reperfusion was significantly higher than that in the sham group (P < 0.05). In addition, AT2 receptor has an inhibitory role in platelet rolling and adhesion after cerebral ischemia reperfusion. PMID- 26231767 TI - Inhibition of the OAS/RNase L pathway by viruses. AB - The OAS/RNase L system was one of the first characterized interferon effector pathways. It relies on the synthesis, by oligoadenylate synthetases (OAS), of short oligonucleotides that act as second messengers to activate the latent cellular RNase L. Viruses have developed diverse strategies to escape its antiviral effects. This underscores the importance of the OAS/RNase L pathway in antiviral defenses. Viral proteins such as the NS1 protein of Influenza virus A act upstream of the pathway while other viral proteins such as Theiler's virus L* protein act downstream. The diversity of escape strategies used by viruses likely stems from their relative susceptibility to OAS/RNase L and other antiviral pathways, which may depend on their host and cellular tropism. PMID- 26231768 TI - Home environment and indoor air pollution exposure in an African birth cohort study. AB - BACKGROUND: Household indoor air pollution (IAP) is a global health problem and a risk factor for childhood respiratory disease; the leading cause of mortality in African children. This study aimed to describe the home environment and measure IAP in the Drakenstein Child Health Study (DCHS), an African birth cohort. METHODS: An antenatal home visit to assess the home environment and measure IAP (particulate matter, sulphur dioxide, nitrogen dioxide, carbon monoxide and volatile organic compounds (VOCs)) was done on pregnant women enrolled to the DCHS, in a low-socioeconomic, peri-urban South African community. Urine cotinine measured maternal tobacco smoking and exposure. Dwellings were categorised according to 6 household dimensions. Univariate and multivariate analysis explored associations between home environment, seasons and IAP levels measured. RESULTS: 633 home visits were completed, with IAP measured in 90% of homes. Almost a third of participants were of the lowest socio-economic status and the majority of homes (65%) lacked 2 or more of the dwelling category dimensions. Most households had electricity (92%), however, fossil fuels were still used for cooking (19%) and heating (15%) in homes. Antenatal maternal smoking prevalence was 31%; 44% had passive smoke exposure. Of IAP measured, benzene (VOC) was significantly above ambient standards with median 5.6 MUg/m3 (IQR 2.6-17.1). There were significant associations between the use of fossil fuels for cooking and increased benzene [OR 3.4 (95% CI 2.1-5.4)], carbon monoxide [OR 2.9 (95% CI 1.7-5.0)] and nitrogen dioxide [OR 18.6 (95% CI 3.9-88.9)] levels. A significant seasonal association was found with higher IAP levels in winter. CONCLUSION: In this low-socioeconomic African community, multiple environmental factors and pollutants, with the potential to affect child health, were identified. Measurement of IAP in a resource-limited setting is feasible. Recognising and quantifying these risk factors is important in effecting public health policy changes. PMID- 26231769 TI - Calculating salt loads to Great Salt Lake and the associated uncertainties for water year 2013; updating a 48 year old standard. AB - Effective management of surface waters requires a robust understanding of spatiotemporal constituent loadings from upstream sources and the uncertainty associated with these estimates. We compared the total dissolved solids loading into the Great Salt Lake (GSL) for water year 2013 with estimates of previously sampled periods in the early 1960s. We also provide updated results on GSL loading, quantitatively bounded by sampling uncertainties, which are useful for current and future management efforts. Our statistical loading results were more accurate than those from simple regression models. Our results indicate that TDS loading to the GSL in water year 2013 was 14.6 million metric tons with uncertainty ranging from 2.8 to 46.3 million metric tons, which varies greatly from previous regression estimates for water year 1964 of 2.7 million metric tons. Results also indicate that locations with increased sampling frequency are correlated with decreasing confidence intervals. Because time is incorporated into the LOADEST models, discrepancies are largely expected to be a function of temporally lagged salt storage delivery to the GSL associated with terrestrial and in-stream processes. By incorporating temporally variable estimates and statistically derived uncertainty of these estimates, we have provided quantifiable variability in the annual estimates of dissolved solids loading into the GSL. Further, our results support the need for increased monitoring of dissolved solids loading into saline lakes like the GSL by demonstrating the uncertainty associated with different levels of sampling frequency. PMID- 26231770 TI - Aquatic toxicology studies with macrophytes and algae should balance experimental pragmatism with environmental realism. PMID- 26231771 TI - Life in a landfill slum, children's health, and the Millennium Development Goals. AB - People living in slums can be considered left behind with regard to national successes in achieving Millennium Development Goals (MDGs). The objective of this study was to evaluate the living and working conditions of waste pickers and their children in a landfill slum located in the largest city in eastern Indonesia. A total of 113 people from the landfill slum and 1184 people from the general population participated in face-to-face interviews. Municipal solid waste (MSW) was analyzed for metals, metalloids and fecal indicator bacteria. Ambient air quality including particulate matter was measured in the landfill. Households in the landfill slum were 5.73 (p=0.04) times more likely to be below the international poverty line (MDG 1: Poverty) and 15.6 times (p<0.01) more likely to have no one in the household possessing a primary education (MDG 2: Universal Education), and 107 times (p<0.01) more likely not to have improved sanitation facilities (MDG 7: Environmental Sustainability) when compared to the general population. Diarrhea is one of the leading causes of death in children under five in Indonesia. Young children living in the landfill slum were 2.87 times (p=0.02) more likely to develop diarrhea than their general population counterparts. Other survey results and environmental measurements suggest that landfill slum children have additional adverse health effects (e.g. infections and poisoning). Poverty underlies several MDG issues that directly or indirectly affect child health. Therefore, eradicating extreme poverty will continue to be the most critical challenge for the MDGs beyond 2015. PMID- 26231772 TI - Biodiversity conservation: The key is reducing meat consumption. AB - The consumption of animal-sourced food products by humans is one of the most powerful negative forces affecting the conservation of terrestrial ecosystems and biological diversity. Livestock production is the single largest driver of habitat loss, and both livestock and feedstock production are increasing in developing tropical countries where the majority of biological diversity resides. Bushmeat consumption in Africa and southeastern Asia, as well as the high growth rate of per capita livestock consumption in China are of special concern. The projected land base required by 2050 to support livestock production in several megadiverse countries exceeds 30-50% of their current agricultural areas. Livestock production is also a leading cause of climate change, soil loss, water and nutrient pollution, and decreases of apex predators and wild herbivores, compounding pressures on ecosystems and biodiversity. It is possible to greatly reduce the impacts of animal product consumption by humans on natural ecosystems and biodiversity while meeting nutritional needs of people, including the projected 2-3 billion people to be added to human population. We suggest that impacts can be remediated through several solutions: (1) reducing demand for animal-based food products and increasing proportions of plant-based foods in diets, the latter ideally to a global average of 90% of food consumed; (2) replacing ecologically-inefficient ruminants (e.g. cattle, goats, sheep) and bushmeat with monogastrics (e.g. poultry, pigs), integrated aquaculture, and other more-efficient protein sources; and (3) reintegrating livestock production away from single-product, intensive, fossil-fuel based systems into diverse, coupled systems designed more closely around the structure and functions of ecosystems that conserve energy and nutrients. Such efforts would also impart positive impacts on human health through reduction of diseases of nutritional extravagance. PMID- 26231773 TI - Environmental impacts of innovative dairy farming systems aiming at improved internal nutrient cycling: A multi-scale assessment. AB - Several dairy farms in the Netherlands aim at reducing environmental impacts by improving the internal nutrient cycle (INC) on their farm by optimizing the use of available on-farm resources. This study evaluates the environmental performance of selected INC farms in the Northern Friesian Woodlands in comparison to regular benchmark farms using a Life Cycle Assessment. Regular farms were selected on the basis of comparability in terms of milk production per farm and per hectare, soil type and drainage conditions. In addition, the environmental impacts of INC farming at landscape level were evaluated with the integrated modelling system INITIATOR, using spatially explicit input data on animal numbers, land use, agricultural management, meteorology and soil, assuming that all farms practised the principle of INC farming. Impact categories used at both farm and landscape levels were global warming potential, acidification potential and eutrophication potential. Additional farm level indicators were land occupation and non-renewable energy use, and furthermore all farm level indicators were also expressed per kg fat and protein corrected milk. Results showed that both on-farm and off-farm non-renewable energy use was significantly lower at INC farms as compared with regular farms. Although nearly all other environmental impacts were numerically lower, both on-farm and off-farm, differences were not statistically significant. Nitrogen losses to air and water decreased by on average 5 to 10% when INC farming would be implemented for the whole region. The impact of INC farming on the global warming potential and eutrophication potential was, however, almost negligible (<2%) at regional level. This was due to a negligible impact on the methane emissions and on the surplus and thereby on the soil accumulation and losses of phosphorus to water at INC farms, illustrating the focus of these farms on closing the nitrogen cycle. PMID- 26231774 TI - Preliminary report on a new surgical technique for the management of bothersome scrotomegaly in selected adolescent males. AB - Idiopathic scrotomegaly in adolescent boys can be a bothersome and distressing complaint. The challenge lies in accepting its potential impact on the patient's body image, offering a simple solution with minimal morbidity. Herein, we present a novel approach to reduction scrotoplasty, which adds to the limited published strategies available, and provides surgeons with a safe and effective procedure to correct this condition. Our report also calls attention to a potentially under recognized medical problem in adolescents and young adults. PMID- 26231775 TI - Penile prosthesis implantation in a patient with congenital aphallia treated using the De Castro technique 10 years previously. Is it feasible? AB - OBJECTIVE: Aphallia is a rare congenital abnormality with an incidence of 1 in 30 million births. In this video, we demonstrate implantation of a penile prosthesis in a neophallus performed 10 years previously in a patient aged 21. METHODS: Through a midline perineal incision aiming to reach the inferior surface of the pubic arch, we created a 16-cm tunnel for prosthesis insertion into the neophallus. We dressed the prosthesis with a polypropylene mesh to give stability to the component and avoid its extrusion. We anchored the lateral mesh to the inferior aspect of the pubic arch with 2.0 vicryl sutures in both sides. RESULTS: The patient had an excellent initial outcome, without any complaints of pain or other inflammatory findings. CONCLUSION: We acknowledge limited clinical experience with this technique. Further psychological evaluation will confirm if patients can have pleasant sexual experiences. PMID- 26231777 TI - Neophalloplasty to congenital aphallia using two transverse skin-flaps: an alternative approach. AB - OBJECTIVE: Penile agenesis is a rare congenital abnormality with an incidence of 1 in 30 million births. We want to demonstrate in this video a new technique of neophalloplasty based on two transverse skin flaps from lower abdominal wall. METHODS: The patient was placed into a prone position; the urethral meatus was found inside the rectum, 2 cm from the anal border. An Anterior Sagittal Transrectal Approach (ASTRA) approach was performed; the urethra was isolated and repositioned as a perineal urethrostomy. We created the neophallus based on two flaps, each measuring 7 * 3 cm. After incision, flaps were rotated 90 degrees and sutured to each other creating the neophallus. We also created a Mitrofanoff channel to secure bladder emptying in cases of urethrostomy stricture. RESULTS: The patient had an uneventful immediate postoperative evolution, but later showed some degree of penile retraction. He voids preferably through the urethrostomy and his mother uses the Mitrofanoff once a day. The current follow-up is 18 months. CONCLUSION: We acknowledge limited clinical experience with this technique. However, the same principle has been used to create catheterizable urinary channels, with favorable results and longer follow-up. The use of transverse skin flaps might be an interesting alternative for neophalloplasty in aphallia. PMID- 26231778 TI - A computational study on surface-enhanced Raman spectroscopy of para-substituted Benzenethiol derivatives adsorbed on gold nanoclusters. AB - We presented a computational study on para-substituted Benzenethiol (x-BT, x=H, F, Cl, Br, OH, SH, SeH, NH2, CH3) derivatives interacting with gold cluster for chemical effects related to surface-enhanced Raman spectroscopy (SERS). Density functional theory (DFT) calculations were performed on a series of bridge-type and vertex type x-BT/Au13 complexes for geometric, electronic and excitation properties to determine the key factor in spectral enhancement. Results indicated that off-resonance enhancement factors of bridge-type and vertex-type complexes exhibited different dependency on substitutions, which was greatly influenced by molecule-cluster transitions instead of properties such as interaction energy and charge transfer due to same origination for off-resonance and resonance chemical enhancement. PMID- 26231776 TI - Impact and frequency of extra-genitourinary manifestations of prune belly syndrome. AB - INTRODUCTION: Prune belly syndrome (PBS) extra-genitourinary (extra-GU) manifestations are serious comorbidities beyond the genitourinary (GU) anomalies of this disease. We hypothesized an underestimation of the reported frequency and understated impact on quality of life (QOL) of extra-GU comorbidities in PBS survivors beyond the newborn period. To assess this, the frequencies of extra-GU manifestations of PBS in a contemporary cohort of living patients were compared to compiled frequencies from published literature. Second, the impact of extra-GU PBS manifestations on patient/family QOL was assessed via a non-validated open ended survey. MATERIAL AND METHODS: From 2010 to 2013, PBS survivors were prospectively recruited locally or at three PBS Network National Conventions. The family/subject was asked to complete a detailed PBS questionnaire, non-validated QOL survey, and provide medical records for review. Clinical data were extracted from medical records for local patients. The frequencies of extra-GU manifestations were compared between the contemporary, living cohort and a published literature cohort derived from PubMed. RESULTS AND DISCUSSION: Seven of 706 published studies met criteria for frequencies tabulation of extra-GU PBS manifestations. This largest reported living PBS patient cohort (n = 65) was 99% male with mean age 10 years (1 month-45 years). The living PBS cohort had a statistically significantly higher incidence of gastrointestinal (63%), orthopedic (65%), and cardiopulmonary (49%) diagnoses compared to the compiled published cohort (n = 204). Eleven PBS males and 32 family members completed the QOL survey. Of these, 47% listed at least one non-GU problem (i.e. lung disease, skeletal problems, constipation) as negatively affecting their QOL; 42% listed at least one GU problem (i.e. self-catheterization, recurrent UTIs) as negatively affecting their QOL; 56% reported musculoskeletal surgery and 21% reported gastrointestinal surgery/medication as positively impacting their QOL. CONCLUSIONS: In this large contemporary series, surviving individuals with PBS had a significantly higher incidence of orthopedic, gastrointestinal, and cardiopulmonary diagnoses than previously reported in PBS publications. From the patient/family QOL perspective, non-GU PBS manifestations negatively impact their QOL and treatment of these non-GU conditions improves their lives. As urologic surgeons for these medically complex patients, it is extremely important to be aware of and prepare for the high incidence of non-GU PBS comorbidities directly impacting the medical and surgical treatment and QOL of PBS patients and their families. PMID- 26231779 TI - Rational design, synthesis of reaction-based dual-channel cyanide sensor in aqueous solution. AB - A new dual-channel sensor for the detection of cyanide was developed based on the conjugated of naphthalene and malononitrile. Upon the addition of CN(-), the sensor displayed very large blue-shift in both fluorescence (80nm) and absorption (120nm) spectra. The sensor of cyanide was performed via the nucleophilic attack of cyanide anion to vinylic groups of the sensor with a 1:1 binding stoichiometry and the color changed of the sensor is mainly due to the intramolecular charge transfer process improvement. The intramolecular charge transfer progress was blocked with color changed and fluorescence blue-shift. The mechanism of sensor reaction with CN(-) ion was studied using (1)H NMR and mass spectrometry. PMID- 26231780 TI - Spectroscopic study of the highly homogeneous polyaniline film formation on gold support. AB - The oxidation of aniline with ammonium peroxydisulfate in the aqueous solution of acetic acid has two subsequent phases: the oxidation of the neutral aniline molecules at low acidity, which was followed by the oxidation of the anilinium cations after the acidity became higher. The final polyaniline film deposited on immersed surfaces is usually contaminated with semi-crystalline oligomers which precipitated during induction period from the reaction medium. To obtain a homogeneous film, which is important in the fabrication of many molecular electronic devices, we have studied the course of aniline oxidation in a view of new experimental evidence. In the unique series of experiments, the silicon or gold supports have been immersed in the reaction mixture at crucial stages of oxidation reaction, and the deposits at the end of the reaction were analyzed. The growth of a highly homogenous film on the gold-coated glass substrate immersed in the reaction mixture at the end of the polymerization period has been observed. The molecular structure of the products was monitored with UV-visible, infrared, and Raman spectroscopies. The possible mechanism of the film formation and the molecular mechanism of the surface interaction of chemisorbed aniline oligomers with gold support are proposed. PMID- 26231781 TI - Vitamin D deficiency is associated with increased risk of Alzheimer's disease and dementia: evidence from meta-analysis. AB - BACKGROUND: In recent years, the associations between vitamin D status and Alzheimer's disease (AD) and dementia have gained increasing interests. The present meta-analysis was designed to estimate the association between vitamin D deficiency and risk of developing AD and dementia. METHODS: A literature search conducted until February 2015 identified 10 study populations, which were included in the meta-analysis. Pooled risk ratios (RRs) and 95% confidence interval (CI) were calculated with a random-effect model using Stata software package. RESULTS: Results of our meta-analysis showed that subjects with deficient vitamin D status (25(OH)D level < 50 nmol/L) were at increased risk of developing AD by 21% compared with those possessing 25(OH)D level > 50 nmol/L. Similar analysis also found a significantly increased dementia risk in vitamin D deficient subjects. There is no evidence for significant heterogeneity among the included studies. CONCLUSION: Available data indicates that lower vitamin D status may be associated with increased risk of developing AD and dementia. More studies are needed to further confirm the associations and to evaluate the beneficial effects of vitamin D supplementation in preventing AD and dementia. PMID- 26231782 TI - A 3-bp Deletion VK600-1E in the BRAF Gene Detected in a Young Woman with Papillary Thyroid Carcinoma. AB - Papillary thyroid cancer (PTC) derived from follicular cells is a frequent thyroid tumor. The incidence of this type of malignancy is still growing worldwide. Several major genetic causes are recognized to cause PTC-mutations in the BRAF and RAS genes or rearrangements with the RET proto-oncogene. The most common genetic change found in PTC is a V600E mutation in the BRAF gene presented in 36-69 % of all PTC cases. For routine purposes, several methods were developed to selectively detect only this mutation. However, these methods miss other mutations in the BRAF gene located elsewhere. We focused on the analysis of the exon 15 of the BRAF gene by next-generation sequencing. Here we report a three nucleotide deletion VK600-1E in one patient and present this finding in the context of 13 previously described PTC cases with this deletion. Our patient is the second youngest one among the reported cases. Clinical features of PTC patients with VK600-1E are summarized. For the future, it is important to evaluate genotype-phenotype characteristics of patients with rare BRAF mutations and to follow up them for years. PMID- 26231783 TI - Diabetes and Screening for Coronary Heart Disease: Where Should We Focus our Efforts? PMID- 26231785 TI - AFM13: a first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy. AB - Monoclonal antibodies against CD20 molecule have been leading the revolution of lymphoma treatment. In addition to monoclonal antibodies against CD20 and CD30, novel agents of immunotherapeutics in clinical development are being developed and are rapidly migrating to clinical application. One area of active development is NK cell activators, such as AFM13. This review will highlight the latest development of AFM13 as the first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy. PMID- 26231784 TI - A review of 3D first-pass, whole-heart, myocardial perfusion cardiovascular magnetic resonance. AB - A comprehensive review is undertaken of the methods available for 3D whole-heart first-pass perfusion (FPP) and their application to date, with particular focus on possible acceleration techniques. Following a summary of the parameters typically desired of 3D FPP methods, the review explains the mechanisms of key acceleration techniques and their potential use in FPP for attaining 3D acquisitions. The mechanisms include rapid sequences, non-Cartesian k-space trajectories, reduced k-space acquisitions, parallel imaging reconstructions and compressed sensing. An attempt is made to explain, rather than simply state, the varying methods with the hope that it will give an appreciation of the different components making up a 3D FPP protocol. Basic estimates demonstrating the required total acceleration factors in typical 3D FPP cases are included, providing context for the extent that each acceleration method can contribute to the required imaging speed, as well as potential limitations in present 3D FPP literature. Although many 3D FPP methods are too early in development for the type of clinical trials required to show any clear benefit over current 2D FPP methods, the review includes the small but growing quantity of clinical research work already using 3D FPP, alongside the more technical work. Broader challenges concerning FPP such as quantitative analysis are not covered, but challenges with particular impact on 3D FPP methods, particularly with regards to motion effects, are discussed along with anticipated future work in the field. PMID- 26231787 TI - A flow-FISH assay for the quantitative analysis of parvovirus B19 infected cells. AB - Human parvovirus B19 (B19V) replication is a process highly dependent on the cellular environment, therefore methodologies allowing for analysis at single cell level could represent effective tools to understand cell-to cell differences in the replication process and to investigate cell-virus interactions. Fluorescence in situ hybridization (FISH) can be combined with flow cytometry (flow-FISH) to enable the detection of target nucleic acid sequences in thousands of individual cells in a short amount of time. In the present study, a flow-FISH assay based on the use of a digoxigenin-labeled genomic probe has been developed to discriminate B19V infected cells following in vitro infection of UT7/EpoS1 cell line and EPCs (erythroid progenitor cells) generated from peripheral blood mononuclear cells. In B19V infected UT7/EpoS1 and EPCs, viral nucleic acids were detected by the flow-FISH assay starting from 24 hpi up to 48 hpi. The method, used together with quantitative PCR techniques, can be very useful to describe the kinetics of B19V infection within a heterogeneous cell population. PMID- 26231786 TI - Multiplexed one-step RT-PCR VP7 and VP4 genotyping assays for rotaviruses using updated primers. AB - The current two-step VP7 and VP4 genotyping RT-PCR assays for rotaviruses have been linked consistently to genotyping failure in an estimated 30% of RVA positive samples worldwide. We have developed a VP7 and VP4 multiplexed one-step genotyping assays using updated primers generated from contemporary VP7 and VP4 sequences. To determine assay specificity and sensitivity, 17 reference virus strains, 6 non-target gastroenteritis viruses and 725 clinical samples carrying the most common VP7 (G1, G2, G3, G4, G9, and G12) and VP4 (P[4], P[6], P[8], P[9] and P[10]) genotypes were tested in this study. All reference RVA strain targets yielded amplicons of the expected sizes and non-target genotypes and gastroenteritis viruses were not detected by either assay. Out of the 725 clinical samples tested, the VP7 and VP4 assays were able to assigned specific genotypes to 711 (98.1%) and 714 (98.5%), respectively. The remaining unassigned samples were re-tested for RVA antigen using EIA and qRT-PCR assays and all were found to be negative. The overall specificity, sensitivity and limit of detection of the VP7 assay were in the ranges of 99.0-100%, 94.0-100% and 8.6*10(1) to 8.6*10(2) copies of RNA/reaction, respectively. For the VP4 assay, the overall specificity, sensitivity and limit of detection assay were in the ranges of 100%, 94.0-100% and <=1 to 8.6*10(2) copies of RNA/reaction, respectively. Here we report two highly robust, accurate, efficient, affordable and documentable gel based genotyping systems which are capable of genotyping 97.8% of the six common VP7 and 98.3% of the five common VP4 genotypes of RVA strains which are responsible for approximately 88.2% of all RVA infections worldwide. PMID- 26231788 TI - Development of a fluorescent in situ hybridization (FISH) technique for visualizing CGMMV in plant tissues. AB - Cucumber green mottle mosaic virus (CGMMV), which belongs to the genus Tobamovirus, is a major pathogen of cucurbit crops grown indoors and in open fields. Currently, immunology (e.g., ELISA) and molecular amplification techniques (e.g., RT-PCR) are employed extensively for virus detection in plant tissues and commercial seed lots diagnostics. In this study, a fluorescent in situ hybridization (FISH) technique, using oligonucleotides whose 5'-terminals were labeled with red cyanine 3 (Cy3) or green fluorescein isothiocyanate (FITC), was developed for the visualization of the pathogen in situ. This simple and reliable method allows detection and localization of CGMMV in the vegetative and reproductive tissues of cucumber and melon. When this technique was applied in male flowers, anther tissues were found to be infected; whereas the pollen grains were found to be virus-free. These results have meaningful epidemiological implications for the management of CGMMV, particularly with regard to virus transfer via seed and the role of insects as CGMMV vectors. PMID- 26231789 TI - Microcirculation in Acute and Chronic Kidney Diseases. AB - The renal microvasculature is emerging as a key player in acute and chronic kidney diseases. Renal microvascular disease involves alterations in endothelial barrier permeability, exaggerated inflammation, impairment of endothelium dependent vasorelaxation involving the nitric oxide system, increased oxidative stress, and loss of angiogenic factors. Moreover, evidence suggests that there is a microvascular component to the pathogenesis of renal scarring. New technology is being developed to explore renal microcirculation in vivo in experimental models and humans. This technology will provide a better understanding of the pathogenesis of kidney diseases and will help guide specific therapeutic strategies aimed at restoring the renal microcirculation. This article reviews the cellular and molecular mechanisms of renal microvascular dysfunction in acute and chronic kidney diseases and the potential diagnostic and therapeutic implications of these findings. Recent developments in the monitoring of renal microcirculation are described with respect to their advantages and limitations, and future directions are outlined. PMID- 26231790 TI - Enantioseparation of Timolol on a Novel beta-Cyclodextrin Derivative Chiral Stationary Phase in HPLC. AB - A novel chiral stationary phase was prepared by bonding a novel beta-cyclodextrin derivative on silica gel, and it was used for the separation of timolol in high efficiency liquid phase. In the reverse mode, the factors such as the proportion of chiral additives, flow rate, column temperature, repeatability and stability were investigated. The optimum chromatographic conditions are as follows: column temperature was 25 degrees C, flow rate was 0.6 mL min(-1) and mobile phase was methanol-25 mM KH2PO4 (80/20, v/v). The chiral column has good reproducibility (Rs = 4.49, 4.51 and 4.40, respectively) and a certain degree of stability (Rs = 4.49, 3.01 and 0.72, respectively). This chiral stationary phase presented good chiral recognition performance toward timolol with good resolution (Rs = 4.49). PMID- 26231797 TI - miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer. AB - Microarray data analyses were performed to search for metastasis-associated oncogenes in prostate cancer (PCa). RNF31 mRNA expressions in tumor tissues and benign prostate tissues were evaluated. The RNF31 protein expression levels were also analyzed by western blot and immunohistochemistry. Luciferase reporter assays were used to identify miRNAs that can regulate RNF31. The effect of RNF31 on PCa progression was studied in vitro and in vivo. We found that RNF31 was significantly increased in PCa and its expression level was highly correlated with seminal vesicle invasion, clinical stage, prostate specific antigen (PSA) level, Gleason score, and BCR. Silence of RNF31 suppressed PCa cell proliferation and metastasis in vitro and in vivo. miR-503 can directly regulate RNF31. Enforced expression of miR-503 inhibited the expression of RNF31 significantly and the restoration of RNF31 expression reversed the inhibitory effects of miR 503 on PCa cell proliferation and metastasis. These findings collectively indicated an oncogene role of RNF31 in PCa progression which can be regulated by miR-503, suggesting that RNF31 could serve as a potential prognostic biomarker and therapeutic target for PCa. PMID- 26231798 TI - The regulation of glucose on milk fat synthesis is mediated by the ubiquitin proteasome system in bovine mammary epithelial cells. AB - Glucose as one of the nutrition factors plays a vital role in the regulation of milk fat synthesis. Ubiquitin-proteasome system (UPS) is a vital proteolytic pathway in all eukaryotic cells through timely marking, recognizing and degrading the poly-ubiquitinated protein substrates. Previous studies indicated that UPS plays a considerable role in controlling the triglyceride (TG) synthesis. Therefore, the aim of this study is to confirm the link between high-glucose and UPS and its regulation mechanism on milk fat synthesis in BMEC (bovine mammary epithelial cells). We incubated BMEC with normal (17.5 mm/L) and high-glucose (25 mm/L) with and without proteasome inhibitor epoxomicin and found that, compared with the control (normal glucose and without proteasome inhibitor), both high glucose concentration and proteasome inhibitor epoxomicin could increase the accumulation of TG and poly-ubiquitinated proteins, and reduce significantly three proteasome activities (chymotrypsin-like, caspase-like, and trypsin-like). In addition, high-glucose concentration combined with proteasome inhibitor further enhanced the increase of the poly-ubiquitinated protein level and the decrease of proteasome activities. Our results suggest that the regulation of high-glucose on milk fat synthesis is mediated by UPS in BMEC, and high-glucose exposure could lead to a hypersensitization of BMEC to UPS inhibition which in turn results in increased milk fat synthesis. PMID- 26231799 TI - miR-4295 promotes cell proliferation and invasion in anaplastic thyroid carcinoma via CDKN1A. AB - MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. However, the role of microRNAs in anaplastic thyroid carcinoma (ATC), has remained elusive. Here, we identified that miR-4295 promotes ATC cell proliferation by negatively regulates its target gene CDKN1A. In ATC cell lines, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-4295, while miR-4295 inhibitor significantly inhibited the cell proliferation. Transwell assay showed that miR-4295 mimics significantly promoted the migration and invasion of ATC cells, whereas miR-4295 inhibitors significantly reduced cell migration and invasion. luciferase assays confirmed that miR-4295 directly bound to the 3'untranslated region of CDKN1A, and western blotting showed that miR-4295 suppressed the expression of CDKN1A at the protein levels. This study indicated that miR-4295 negatively regulates CDKN1A and promotes proliferation and invasion of ATC cell lines. Thus, miR-4295 may represent a potential therapeutic target for ATC intervention. PMID- 26231800 TI - Impaired adult hippocampal neurogenesis and its partial reversal by chronic treatment of fluoxetine in a mouse model of Angelman syndrome. AB - Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe cognitive and motor deficits, caused by the loss of function of maternally inherited Ube3a. Ube3a-maternal deficient mice (AS model mice) recapitulate many essential features of AS, but how the deficiency of Ube3a lead to such behavioural abnormalities is poorly understood. Here we have demonstrated significant impairment of adult hippocampal neurogenesis in AS mice brain. Although, the number of BrdU and Ki67-positive cell in the hippocampal DG region was nearly equal at early postnatal days among wild type and AS mice, they were significantly reduced in adult AS mice compared to wild type controls. Reduced number of doublecortin-positive immature neurons in this region of AS mice further indicated impaired neurogenesis. Unaltered BrdU and Ki67-positive cells number in the sub ventricular zone of adult AS mice brain along with the absence of imprinted expression of Ube3a in the neural progenitor cell suggesting that Ube3a may not be directly linked with altered neurogenesis. Finally, we show that the impaired hippocampal neurogenesis in these mice can be partially rescued by the chronic treatment of antidepressant fluoxetine. These results suggest that the chronic stress may lead to reduced hippocampal neurogenesis in AS mice and that impaired neurogenesis could contribute to cognitive disturbances observed in these mice. PMID- 26231801 TI - Gene expression profiling of hormonal regulation related to the residual feed intake of Holstein cattle. AB - An accumulation of over a decade of research in cattle has shown that genetic selection for decreased residual feed intake (RFI), defined as the difference between an animal's actual feed intake and its expected feed intake, is a viable option for improving feed efficiency and reducing the feed requirements of herds, thereby improving the profitability of cattle producers. Hormonal regulation is one of the most important factors in feed intake. To determine the relationship between hormones and feed efficiency, we performed gene expression profiling of jugular vein serum on hormonal regulation of Chinese Holstein cattle with low and high RFI coefficients. 857 differential expression genes (from 24683 genes) were found. Among these, 415 genes were up-regulated and 442 genes were down-regulated in the low RFI group. The gene ontology (GO) search revealed 6 significant terms and 64 genes associated with hormonal regulation, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) selected the adipocytokine signaling pathway, insulin signaling pathway. In conclusion, the study indicated that the molecular expression of genes associated with hormonal regulation differs in dairy cows, depending on their RFI coefficients, and that these differences may be related to the molecular regulation of the leptin-NPY and insulin signaling pathways. PMID- 26231802 TI - MYD88 mutation analysis of a rare composite chronic lymphocyte leukemia and lymphoplasmacytic lymphoma by flow cytometry cell sorting. PMID- 26231804 TI - Early palliative care and integration of palliative care models in modern oncology practices. PMID- 26231803 TI - Can increased visceral adiposity without body weight changes accelerate carotid atherosclerosis in South Korean participants with type 2 diabetes? AB - AIMS: Type 2 diabetes mellitus (T2DM) and visceral obesity are associated with each other and with cardiovascular diseases. We determined whether increased visceral adiposity without weight gain was associated with sex-specific accelerated carotid atherosclerosis in South Koreans with T2DM. METHODS: From 2003 to 2012, we recruited 280 participants with T2DM for the Seoul Metabolic Syndrome cohort who had body weight, visceral fat thickness (VFT), and carotid intima-media thickness (CIMT) measured at intervals of 2years. According to VFT change, sex-specific quartiles of clinical characteristics and changes of CIMT were determined. Logistic regression models predicted the odds of the progression of CIMTs in each quartile. RESULTS: During 2years of observation, VFTs fell by 5.2+/-13.5mm in men (P<0.001) and 3.4+/-10.5mm in women (P<0.001). Progression of CIMT was only significant for women's maximal CIMT (0.031+/-0.145mm, P=0.012), while significant improvements in HbA1c were found (0.9%; P<0.001 in both sexes). There were no significant differences in clinical characteristics, or in progression of CIMT in men or women according to 2-year quartiles of VFT change. CONCLUSIONS: Our results do not suggest that increased visceral adiposity without body weight changes impacts the CIMT progression in South Korean men or women with T2DM. PMID- 26231805 TI - Early palliative care: philosophy vs. reality. PMID- 26231806 TI - Models of integration of oncology and palliative care. AB - OBJECTIVE: Palliative care aims to improve cancer patients' quality of life through expert symptom management, psychosocial and spiritual care, patient clinician communication, facilitation of complex decision making, and end-of-life care planning. Over the past few years, there has been increasing interest and evidence to support integration of oncology and palliative care. However, it remains unclear how best to promote integration. The goal of this review is to examine contemporary conceptual models and clinical approaches to integrate oncology and palliative care. METHODS: Narrative review. RESULTS: Conceptual models are useful to help stakeholders understand the rationale for integration, to compare the risks and benefits among different practices, and to define a vision towards integration. We will review four major conceptual models of integration, including (I) the time-based model which emphasizes on integration based on chronological criterion; (II) the provider-based (palli-centric) model which discusses primary, secondary and tertiary palliative care; (III) the issue based (onco-centric) model which illustrates the advantages and disadvantages of the solo practice, congress and integrated care approaches; and (IV) the system based (patient-centric) model which emphasizes automatic referral based on clinical events. Clinical models provide actual data on the feasibility, efficacy and effectiveness of integration in specific settings. The evidence and challenges related to selected clinical models in integrating oncology and palliative care, such as outpatient palliative care clinics and embedded clinics will be discussed. CONCLUSIONS: There are multiple conceptual models and clinical models to promote integration. Further research is needed to inform best practices for integration at different healthcare settings. PMID- 26231807 TI - A review of the trials which examine early integration of outpatient and home palliative care for patients with serious illnesses. AB - BACKGROUND: Palliative care has emerged as care that specifically aims to address gaps inherent in disease-centered approaches in order to enhance care quality in serious illness, both for patients and families and for health care systems. Late palliative care for patients with serious illness mitigates benefits to patients, families, and health care systems. Efforts have been made by investigators to define the impact of earlier palliative care interventions on patient, family and health care systems outcomes. We conducted a systematic review of randomized trials of outpatient and home palliative care, two locations where earlier palliative care do occur, to examine the evidence for palliative care benefits. METHODS: Various terms were used; the search was performed in PubMed. From this search randomized trials were selected from 62 references derive from this search which appeared to be primary studies. Hand searches were done on references. Fifteen randomized control trials of outpatient palliative care and 13 randomized control trials of palliative home care were collected and collated into tables. Seven systematic reviews obtained and outcomes summarized in a table. RESULTS: Advantages to palliative care include improvement in certain symptoms such as depression, improved patient quality of life, reduced aggressive care at the end of life, increased advanced directives, reduced hospital length of stay and hospitalizations, improved caregiver burden and better maintenance of caregiver quality of life and reduction in the medical cost of care as well as patient and family satisfaction. There are randomized trials which demonstrate that symptoms and quality of life are not improved, and resource utilization and costs are not different from "usual" care. Seven systematic reviews of randomized trials came to similar conclusions. DISCUSSION: Notable methodological issues account for differences in results. Definitions of "early" palliative care vastly differed. There were no descriptions of what was meant by "usual" care in the control arm. Study designs and procedures were frequently flawed. Populations were heterogeneous in many studies and imbalances between randomly-allocated occurred frequently. Direct patient care versus consultation only, played a role. The assumption that the same model of care was equally effective across different diseases was unsubstantiated. Attrition was on average 40% and blinding of individuals who assessed outcomes frequently not mentioned. Power calculations were infrequent. Intention to treat analysis was often not done. Current studies fell short of the goal of measuring all relevant factors to assessing costs benefits, having largely ignored the cost to the patient and family and instead focused narrowly on patient medical costs. CONCLUSIONS: Multiple studies have demonstrated several benefits to early outpatient palliative care for patients with newly diagnosed metastatic cancer. However, better designed and executed studies are needed to determine the best time to intervene and the best model of care. PMID- 26231808 TI - Early integration of palliative care into oncology: evidence, challenges and barriers. AB - Palliative care has proven to be an important component during the care of seriously ill oncology patients. In the past decade, early integration of both specialties demonstrated benefits in improving patient symptoms and pain, facilitating advance directive planning and reducing medical cost. Newer evidence also suggests it can prolong life. Several different integration models have been studied and all appear to work. Yet, palliative care is underused, and there are still many challenges and barriers preventing us from delivering the best care to our patients. In this review, we will summarize the available data from multiple randomized clinical trials, encountered challenges, and potential strategies to overcome them. PMID- 26231809 TI - Clinical oncology and palliative medicine as a combined specialty--a unique model in Hong Kong. AB - The importance of early integration of palliative care (PC) into oncology treatment is increasingly being recognized. However, there is no consensus on what is the optimal way of integration. This article describes a unique model in Hong Kong where clinical oncology and palliative medicine (PM) is integrated through the development of PM as a subspecialty under clinical oncology. PMID- 26231810 TI - Early palliative care and its translation into oncology practice in Canada: barriers and challenges. AB - This article reviews the progress Canada has made integrating palliative care into oncologic practice. Key clinical practice guidelines (CPGs) have influenced and have been translated into Canadian oncology policy and operations. Comprehensive accreditation standards exist to guide oncology practice in institutional and ambulatory care settings. Common barriers and challenges are discussed: education and attitudes, compassion fatigue, terminology, paucity of research, aggressive cancer care, and organization and operational considerations. As a result, eight made-in-Canada innovations emerged and are described. Lessons learned and recommendations describe a plan for action. PMID- 26231811 TI - Nursing perspectives on palliative care 2015. AB - Nurses have an integral role in promoting and providing early palliative care. The provision of palliative care is aligned to the basic tenants of nursing in providing holistic care to individuals and family members. In many parts of the world nurses are the primary health care provider in a community and a primary link between patients and other members of the heath care team. Unfortunately, access to accredited palliative care education remains a challenge for nurses. PMID- 26231812 TI - Resource allocation issues concerning early palliative care. AB - BACKGROUND: The concept of early palliative care (ePC) has received enormous recognition in the field of cancer care. Increasing evidence supports this approach, but outside the research arena, the implementation of sustainable clinical concepts rely on solutions for practical problems such as funding issues. Therefore, the article presented here discusses economic considerations associated with different concepts of ePC. MAIN POINTS: The specialist approach: the most frequently cited ePC trials assessing examine the concurrent provision of specialist palliative care in addition to routine care. Most of this specialist palliative care has been provided by multiprofessional teams in an outpatient setting of tertiary care centers. A number of the research groups have also provided data about the resource utilizations of this approach. From this, a rough estimate of the cost of early specialist palliative care can be derived. Yet, in many parts of North-America, Europe and other regions, funding modes for such outpatient specialist palliative care is non-existent. Recent studies have pointed out that ePC for inpatients is associated with cost-savings. These cost savings are even more pronounced the earlyer specialist palliative care is integrated in the care for the patients. Strengthening of general palliative care: most institutions recommend that palliative care as an approach should be strengthened as a part of standard care. To accomplish this, different measures such as teaching of general palliative care competencies of oncology teams, routine symptom assessment or the mandatory implementation of advanced care planning in care trajectories are being promoted. Due to the heterogeneity of these approaches, cost calculations are difficult, but can be weight against cost saving estimated associated with for example less utilization of futile diagnostic and therapeutic procedures. CONCLUSIONS: Researchers, health care providers and policy makers need to distinguish the different concepts behind ePC before providing cost estimates. Detailed information is provided in this article. From our view, it is evident that neither of the two approaches (general vs. specialist) can be a one-or-the-other choice. Successful ePC will most likely rely on a joint effort of all medical disciplines and profession in close cooperation and early integration of specialist PC services. For such an approach, additional resources may be necessary, but from the public health perspective, cost-savings can also be assumed. PMID- 26231813 TI - Incorporation of life expectancy estimates in the treatment of palliative care patients receiving radiotherapy: treatment approaches in light of incomplete prognostic models. AB - Physician estimates of patients' survival times have historically been inaccurate. In particular, physicians have often been overly optimistic in their predictions. Our review begins by documenting some of the literature addressing these concerns and proceeds to a discussion of prognostic models that have been created to aid physicians in providing more accurate estimates. We then discuss new findings showing survival to be influenced by particular treatment factors. Given such findings, currently existing prognostic models are now incomplete. However, with the abundance of evidence-based treatment options in a wide variety of patient populations, we propose that radiation oncologists need no longer rely so heavily on the precise prognostic capacity of survival models. Patients of different age demographics and survival prognoses benefit from palliative radiation treatment. More specifically, our report documents studies which show that for uncomplicated bone metastases, a single 8 Gy fraction of radiation is an equally effective tool for palliation regardless of whether a patient will have a short or long duration of survival. In addition we discuss evidence-based treatment options for patients with complicated bone metastases, lung and brain metastases. Further research is required to incorporate treatment factors in future survival prediction models. PMID- 26231814 TI - Response of indigenously developed bacterial consortia in progressive degradation of polyvinyl chloride. AB - Thermoplastic-based materials are recalcitrant in nature, which extensive use affect environmental health. Here, we attempt to compare the response of indigenously produced bacterial consortium-I and consortium-II in degrading polyvinyl chloride (PVC). These consortia were developed by using different combination of bacterial strains of Pseudomonas otitidis, Bacillus cereus, and Acanthopleurobacter pedis from waste disposal sites of Northern India after their identification via 16S rDNA sequencing. The progressive degradation of PVC by consortia was examined via scanning electron microscopy, atomic force microscopy, UV-vis, FT-IR spectra, gel permeation chromatography, and differential scanning calorimetry analysis at different incubations and time intervals. The consortium II was superior over consortium-I in degrading the PVC. Further, the carbon source utilization analysis revealed that the extensive use of consortia has not any effect on functional diversity of native soil microbes. PMID- 26231815 TI - Medical Management of Patients Undergoing Dentoalveolar Surgery. AB - The oral and maxillofacial surgeon (OMS) should have an understanding of common medical comorbidities. This understanding allows for risk stratification and thus prevention of potential problems. Remaining knowledgeable regarding diseases, diagnosis, treatment strategies, and pharmacology ultimately improves patient care. This article provides an update on some of the most common medical diseases for the patient undergoing dentoalveolar surgery. PMID- 26231816 TI - Soft Tissue Grafting Around Teeth and Implants. AB - The presence of healthy attached tissue at the tooth and implant soft tissue interface correlates with long-term success and stability in function and esthetics. There are several soft tissue grafting procedures that increase the volume of keratinized tissue and provide coverage on both teeth and implants. Many of these techniques can be used in conjunction with implant placement, or after placement as a means of salvage. This article describes the techniques for augmentation of keratinized tissue as well as root and implant coverage. These tools should be in the armamentarium of oral and maxillofacial surgeons providing implant services. PMID- 26231817 TI - Surgical Treatment of Impacted Canines: What the Orthodontist Would Like the Surgeon to Know. AB - When an impacted permanent maxillary canine has been diagnosed, the general practitioner or pediatric dentist thinks in terms of surgery and orthodontics, usually in that order. If there is an existing malocclusion that requires orthodontic treatment, a full orthodontic appraisal is needed for planning the overall mechanotherapy. The orthodontist will undertake a clinical examination. When all the information is collated, a treatment plan will be formulated to resolve the overall malocclusion, which may lead to a decision to extract permanent teeth. The orthodontist is ultimately responsible to the patient for the success of the treatment plan. PMID- 26231818 TI - Preprosthetic Surgery. AB - Preprosthetic oral and maxillofacial surgery has changed dramatically over the last 3 decades. Surgical preparation for dentures has been displaced by site development for implants. Nonetheless, there is still a role to play for several preprosthetic procedures. In this article, historical context is provided, enduring concepts are reviewed, and procedures that remain relevant are described and discussed. PMID- 26231819 TI - Randomized controlled equivalence trial comparing videoconference and in person delivery of cognitive processing therapy for PTSD. AB - INTRODUCTION: In an effort to improve access to and utilization of health care, the Veterans Health Administration (VHA) continues to investigate the effectiveness of video-teleconferencing (VTC) technologies for service delivery. While previous research focused on the efficacy of VTC treatment for post traumatic stress disorder (PTSD) in Vietnam era veterans, few studies have evaluated the efficacy of this modality and treatment for the Iraq/Afghanistan era veterans. The aim of this randomized clinical trial was to evaluate equivalence between in person and VTC psychotherapy for PTSD in this newer cohort. METHODS: Veterans of the Iraq/Afghanistan conflict from two VHA hospitals in the United States were recruited and randomized to receive cognitive processing therapy (CPT) for PTSD either in person (IP) or over VTC. Clinician administered and self-report measures were collected before, during, and after treatment. RESULTS: A trend was observed which suggested that CPT over VTC may be equivalent to the treatment delivered in person, as suggested by previous studies. Regardless of treatment, veterans who received the intervention in both conditions reported significant decreases on post-treatment measures. DISCUSSION: This study highlighted research and clinical challenges in providing services to the newest veteran generation in general as well as unique challenges with VTC. One complicating factor to the statistical power of this study was a treatment dropout rate twice the original estimate. Factors that could have influenced this high dropout rate are explored. PMID- 26231820 TI - gamma-H2AX is a sensitive marker of DNA damage induced by metabolically activated 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. AB - 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a nicotine-derived nitrosamine, is a potent pulmonary carcinogen present in tobacco smoke. DNA adducts induced by metabolically activated NNK cause carcinogenesis; however, the DNA adducts are difficult to detect in cultured cells because of low intrinsic metabolic enzyme activity. In this study, we indirectly detected NNK-induced DNA adducts via the phosphorylation of histone H2AX (gamma-H2AX) in A549 human lung adenocarcinoma epithelial cells. NNK treatment dose-dependently induced gamma H2AX. This gamma-H2AX induction was suppressed by ataxia telangiectasia mutated inhibitors, suggesting that DNA double-strand breaks (DSBs) are formed during replication and repair of DNA adducts; however, DSBs could not be directly detected by biased sinusoidal field gel electrophoresis (BSFGE). CYP2A13 overexpressing cells showed prolonged gamma-H2AX induction compared with control cells, and DSBs could be detected by BSFGE in CYP2A13-overexpressing cells as a clear migration of double-stranded DNA. These findings suggest that gamma-H2AX is a sensitive marker of DNA adducts and provides a possible system for genotoxicity screening of chemicals such as NNK, which need metabolic activation to induce DNA damage. PMID- 26231821 TI - Sodium nitrite-induced oxidative stress causes membrane damage, protein oxidation, lipid peroxidation and alters major metabolic pathways in human erythrocytes. AB - Nitrite salts are present as contaminants in drinking water and in the food and feed chain. In this work, the effect of sodium nitrite (NaNO2) on human erythrocytes was studied under in vitro conditions. Incubation of erythrocytes with 0.1-10.0 mM NaNO2 at 37 degrees C for 30 min resulted in dose dependent decrease in the levels of reduced glutathione, total sulfhydryl and amino groups. It was accompanied by increase in hemoglobin oxidation and aggregation, lipid peroxidation, protein oxidation and hydrogen peroxide levels suggesting the induction of oxidative stress. Activities of all major erythrocyte antioxidant defense enzymes were decreased in NaNO2-treated erythrocytes. The activities of enzymes of glycolytic and pentose phosphate pathways were also compromised. However, there was a significant increase in acid phosphatase and also AMP deaminase, a marker of erythrocyte oxidative stress. Thus, the major metabolic pathways of cell were altered. Erythrocyte membrane damage was suggested by lowered activities of membrane bound enzymes and confirmed by electron microscopic images. These results show that NaNO2-induced oxidative stress causes hemoglobin denaturation and aggregation, weakens the cellular antioxidant defense mechanism, damages the cell membrane and also perturbs normal energy metabolism in erythrocytes. This nitrite-induced damage can reduce erythrocyte life span in the blood. PMID- 26231822 TI - Detection and measurement of the agonistic activities of PCBs and mono hydroxylated PCBs to the constitutive androstane receptor using a recombinant yeast assay. AB - Polychlorinated biphenyls (PCBs) are thought to exert their toxicities mainly by binding to the aryl hydrocarbon receptor and by stimulating transcription of various genes, notably metabolizing enzymes including the cytochrome P450 (CYP) 1 family. However, PCBs and their metabolites could have potential to activate other nuclear receptors and subsequent events. We focused on the constitutive androstane receptor (CAR) inducing CYP2B and measured the agonistic activity of PCBs and mono-hydroxylated PCBs (OH-PCBs) to the CAR using yeast cells transduced with the human CAR and its response pathway. Twenty-nine of 34 tested PCBs and 72 of 91 OH-PCBs exhibited CAR agonistic effects. Of 41 OH-PCBs that had the same chlorination patterns as the tested PCBs, 9 had activities more than twice those of their non-hydroxylated analogs. In particular, 2',4',6'-trichlorobiphenyl-4-ol and 2,2',4',6'-tetrachlorobiphenyl-4-ol were 332- and 22-fold more potent than their analogs and were 15 times and 2.8 times, respectively, as active as a reference substance, 4-tert-octylphenol. The activities of 17 of the OH-PCBs were reduced to less than half those of their non-hydroxylated analogs. Four OH-PCBs derived from 3 active PCBs were inactive. However, a consistent relationship between hydroxyl substituent position and activity could not be discerned. Comprehensive evaluation of the toxic potential of PCBs and their hydroxylated metabolites and their concentrations in the environment are required. PMID- 26231824 TI - Using Ligasure or Harmonic Ace in Laparoscopic Sleeve Gastrectomies? A Prospective Randomised Study. PMID- 26231823 TI - Longitudinal Changes in Serum Levels of Angiopoietin-Like Protein 6 and Selenoprotein P After Gastric Bypass Surgery. AB - BACKGROUND: Bariatric surgery has beneficial effects on weight loss and metabolic profiles. Recent evidence suggests that liver-derived hepatokines play a role in the pathophysiology of metabolic diseases. However, few studies have reported longitudinal changes in hepatokines after gastric bypass surgery. We investigated changes in the serum levels of angiopoietin-like protein 6 (Angptl6) and selenoprotein P after gastric bypass surgery. METHODS: We followed 10 patients who were treated with gastric bypass for weight loss. We measured metabolic parameters and the serum levels of Angptl6 and selenoprotein P before, 1 month after, and 9 months after surgery. We investigated the changes in those hepatokines after surgery and the associations between changes in Angptl6 and selenoprotein P, respectively, and metabolic parameters. RESULTS: Body mass index decreased linearly. Levels of hemoglobin A1c (HbA1c), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (GGT), total cholesterol, triglyceride, LDL cholesterol, and Angptl6 were significantly lower 1 and 9 months after surgery. Fasting plasma glucose was normal throughout the study. Fasting insulin decreased 1 month after surgery but increased 9 months post-surgery. Levels of selenoprotein P increased linearly. Significant correlations were detected between the levels of Angptl6 and LDL cholesterol and fasting insulin. Changes in Angptl6 levels were significantly correlated with changes in total cholesterol and LDL cholesterol. Selenoprotein P levels were inversely correlated with GGT, and changes in selenoprotein P were inversely correlated with changes in homeostasis model assessment for insulin resistance (HOMA-IR). CONCLUSIONS: Our results suggest that gastric bypass may alter the serum levels of hepatokines independent of weight loss, and these changes are related to certain hepatic metabolic changes. PMID- 26231825 TI - Endoscopic Management of Massive Hemorrhage 12 h Post Laparoscopic Roux-en-Y Gastric Bypass. AB - BACKGROUND: Acute (<24 h) staple line bleeding is not common but a known complication after bariatric surgery at a rate of 1-3%. In most cases, acute postoperative bleeding is mild and can be managed conservatively. Nonetheless, there are times when massive hemorrhage is encountered. Endoscopic treatment of these patients within 24 h of Roux-en-Y (RYGB) is controversial, due to fear of staple line dehiscence and/or perforation. Therefore, most surgeons prefer to undergo diagnostic laparoscopy for exploration and treatment. However, it has been reported that laparoscopic management of acute bleeding can be technically challenging with a high rate of morbidity as well as conversion to laparotomy. We herein present a multimedia video (6 min) demonstrating the management of acute massive hemorrhage after RYGB. METHODS: A 46-year-old female with hemodynamic instability after massive hematemesis and melena underwent endoscopy. An overtube was utilized to allow removal of large blood clots which obstructed endoscopic visualization. Two bleeding points were noted, and these were successfully treated with adrenaline and endoscopic clips. RESULTS: The patient rapidly improved during her hospital stay and commenced oral intake on day 1. A surveillance endoscopy was performed on day 5, and no stigmata of recent bleeding was noted. She was discharged home and is progressing well. CONCLUSIONS: We suggest endoscopy is an appropriate first step for the investigation and management of acute intraluminal bleeding post bariatric surgery. PMID- 26231826 TI - Development of a Measure of Barriers to Laparoscopic Adjustable Gastric Banding (LAGB) Aftercare Attendance. AB - BACKGROUND: Regular aftercare attendance following laparoscopic adjustable gastric banding (LAGB) is associated with greater weight loss and fewer post surgical complications. Despite high reported rates of attrition from LAGB aftercare, the reasons for non-attendance have not been thoroughly explored. The aim of the current study was to describe the scale development, explore the factor structure and evaluate the psychometric properties of the Gastric Banding Aftercare Attendance Questionnaire (GBAAQ)-a tool that measures barriers to aftercare attendance in LAGB patients. METHODS: One hundred and eighty-three participants completed the GBAAQ; 107 regular attendees and 76 non-attendees. RESULTS: A factor analysis identified four factors (Treatment Approach, Time Constraints, Stress and Pressures, Uncomfortable Participating) that demonstrated good known-groups validity and internal consistency. CONCLUSIONS: Although further validation is needed, the results of the present study provide preliminary support for the validity of the GBAAQ. Knowledge about the barriers to LAGB aftercare attendance can be used to identify those most at risk of non attendance and can inform strategies aimed at reducing non-attendance. PMID- 26231827 TI - Erratum to: Impact of Extent of Antral Resection on Surgical Outcomes of Sleeve Gastrectomy for Morbid Obesity (A Prospective Randomized Study). PMID- 26231828 TI - Secondhand Smoke Exposure and Illness Severity among Children Hospitalized with Pneumonia. AB - OBJECTIVE: To assess the relationship between secondhand smoke (SHS) exposure and disease severity among children hospitalized with community-acquired pneumonia (CAP). STUDY DESIGN: Children hospitalized with clinical and radiographic CAP were enrolled between January 1, 2010, and June 30, 2012 at 3 hospitals in Tennessee and Utah as part of the Centers for Disease Control and Prevention's Etiology of Pneumonia in the Community study. Household SHS exposure was defined based on the number of smokers in the child's home. Outcomes included hospital length of stay, intensive care unit admission, and mechanical ventilation. Proportional hazards and logistic regression models were used to assess associations between SHS exposure and outcomes. All models were adjusted for age, sex, race/ethnicity, household education level, government insurance, comorbidities, enrollment site, year, and season. RESULTS: Of the 2219 children included in the study, SHS exposure was reported in 785 (35.4%), including 325 (14.8%) with >=2 smokers in the home. Compared with nonexposed children, the children exposed to >=2 smokers had longer length of stay (median, 70.4 hours vs 64.4 hours; adjusted hazard ratio, 0.85; 95% CI, 0.75-0.97) and were more likely to receive intensive care (25.2% vs 20.9%; aOR, 1.44; 95% CI, 1.05-1.96), but not mechanical ventilation. Outcomes in children exposed to only 1 household smoker were similar to those in nonexposed children. CONCLUSION: Children hospitalized with CAP from households with >=2 smokers had a longer length of stay and were more likely to require intensive care compared with children from households with no smokers, suggesting that they experienced greater pneumonia severity. PMID- 26231829 TI - Brain Abscess Due to Staphylococcus lugdunenis: A CoNSiderable Pathogen. PMID- 26231831 TI - Molecular structure and function of P2X receptors. AB - ATP-gated P2X receptors are trimeric ion channels selective to cations. Recent progress in the molecular biophysics of these channels enables a better understanding of their function. In particular, data obtained from biochemical, electrophysiogical and molecular engineering in the light of recent X-ray structures now allow delineation of the principles of ligand binding, channel opening and allosteric modulation. However, although a picture emerges as to how ATP triggers channel opening, there are a number of intriguing questions that remain to be answered, in particular how the pore itself opens in response to ATP and how the intracellular domain, for which structural information is limited, moves during activation. In this review, we provide a summary of functional studies in the context of the post-structure era, aiming to clarify our understanding of the way in which P2X receptors function in response to ATP binding, as well as the mechanism by which allosteric modulators are able to regulate receptor function. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID- 26231832 TI - [Adult onset Still's disease with small vessel vasculitis]. AB - This article presents a particularly severe case of adult onset Still's disease aggravated by small vessel vasculitis. A satisfactory therapy was concluded 1.5 years after onset of the disease. The small vessel vasculitis was difficult to treat: methotrexate (MTX), cyclophosphamide and rituximab were not sufficiently effective. Tocilizumab in combination with intravenous immunoglobulin (IVIG) induced remission and maintenance therapy was carried out with tocilizumab. PMID- 26231833 TI - Analyses of basal media and serum for in vitro expansion of suspension peripheral blood mononucleated stem cell. AB - Transplantation of stem cells requires a huge amount of cells, deeming the expansion of the cells in vitro necessary. The aim of this study is to define the optimal combination of basal medium and serum for the expansion of suspension peripheral blood mononucleated stem cells (PBMNSCs) without resulting in loss in the differentiation potential. Mononucleated cells were isolated from both mice and human peripheral blood samples through gradient centrifugation and expanded in alpha-MEM, RPMI, MEM or DMEM supplemented with either NBCS or FBS. The suspension cells were then differentiated to osteoblast. Our data suggested that alpha-MEM supplemented with 10 % (v/v) NBCS gives the highest fold increase after 14 days of culture for both mice and human PBMNSCs, which were ~1.51 and ~2.01 times, respectively. The suspension PBMNSCs in the respective medium were also able to maintain osteoblast differentiation potential as supported by the significant increase in ALP specific activity. The cells are also viable during the differentiated states when using this media. All these data strongly suggested that alpha-MEM supplemented with 10 % NBCS is the best media for the expansion of both mouse and human suspension PBMNSCs. PMID- 26231834 TI - Equipment characterization to mitigate risks during transfers of cell culture manufacturing processes. AB - The production of monoclonal antibodies by mammalian cell culture in bioreactors up to 25,000 L is state of the art technology in the biotech industry. During the lifecycle of a product, several scale up activities and technology transfers are typically executed to enable the supply chain strategy of a global pharmaceutical company. Given the sensitivity of mammalian cells to physicochemical culture conditions, process and equipment knowledge are critical to avoid impacts on timelines, product quantity and quality. Especially, the fluid dynamics of large scale bioreactors versus small scale models need to be described, and similarity demonstrated, in light of the Quality by Design approach promoted by the FDA. This approach comprises an associated design space which is established during process characterization and validation in bench scale bioreactors. Therefore the establishment of predictive models and simulation tools for major operating conditions of stirred vessels (mixing, mass transfer, and shear force.), based on fundamental engineering principles, have experienced a renaissance in the recent years. This work illustrates the systematic characterization of a large variety of bioreactor designs deployed in a global manufacturing network ranging from small bench scale equipment to large scale production equipment (25,000 L). Several traditional methods to determine power input, mixing, mass transfer and shear force have been used to create a data base and identify differences for various impeller types and configurations in operating ranges typically applied in cell culture processes at manufacturing scale. In addition, extrapolation of different empirical models, e.g. Cooke et al. (Paper presented at the proceedings of the 2nd international conference of bioreactor fluid dynamics, Cranfield, UK, 1988), have been assessed for their validity in these operational ranges. Results for selected designs are shown and serve as examples of structured characterization to enable fast and agile process transfers, scale up and troubleshooting. PMID- 26231830 TI - Prioritizing the development of mouse models for childhood brain disorders. AB - Mutations in hundreds of genes contribute to cognitive and behavioral dysfunction associated with developmental brain disorders (DBDs). Due to the sheer number of risk factors available for study combined with the cost of developing new animal models, it remains an open question how genes should be prioritized for in-depth neurobiological investigations. Recent reviews have argued that priority should be given to frequently mutated genes commonly found in sporadic DBD patients. Intrigued by this idea, we explored to what extent "high priority" risk factors have been studied in animals in an effort to assess their potential for generating valuable preclinical models capable of advancing the neurobiological understanding of DBDs. We found that in-depth whole animal studies are lacking for many high priority genes, with relatively few neurobiological studies performed in construct valid animal models aimed at understanding the pathological substrates associated with disease phenotypes. However, some high priority risk factors have been extensively studied in animal models and they have generated novel insights into DBD patho-neurobiology while also advancing early pre-clinical therapeutic treatment strategies. We suggest that prioritizing model development toward genes frequently mutated in non-specific DBD populations will accelerate the understanding of DBD patho-neurobiology and drive novel therapeutic strategies. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'. PMID- 26231835 TI - Extracellular synthesis of silver nanoparticles using Bacillus megaterium against malarial and dengue vector (Diptera: Culicidae). AB - Biosynthesis of silver nanoparticles has provoked nowadays and alternative to physical and chemical approaches. In the present study, silver nanoparticles (AgNPs) were synthesized extracellular method using Bacillus megaterium. The AgNPs formations were confirmed initially through color change, and the aliquots were characterized through UV-visible spectrophotometer, followed by scanning electron microscopy (SEM), energy-dispersive X-ray (EDX) spectroscopy, and Fourier transform infrared (FTIR) spectra. The surface plasmon resonance band was shown at 430 nm in UV-vis spectrophotometer. The bioreduction was categorized through identifying the compounds responsible for the AgNP synthesis, and the functional group present in B. megaterium cell-free culture was scrutinized using FTIR. The topography and morphology of the particles were determined using SEM. In addition, this biosynthesized AgNPs were found to show higher insecticidal efficacy against vector mosquitoes. The LC50 and LC90 were found to be 0.567, 2.260; 0.90, 4.44; 1.349, 8.269; and 1.640, 9.152 and 0.240, 0.955; 0.331, 1.593; 0.494, 2.811; and 0.700, 4.435 with respect to the first, second, third, and fourth instar larvae of Culex quinquefasciatus and Aedes aegypti. All the calculated chi (2) values are highly significant compared with the tabulated value. Therefore, B. megaterium-synthesized silver nanoparticles would be used as a potent larvicidal agent against Cx. quinquefasciatus and Ae. aegypti. PMID- 26231836 TI - A new gonad-infecting species of Philometra, P. barnesi sp. n. (Nematoda: Philometridae), from the marine fish Pomadasys argenteus (Haemulidae) off the northern coast of Australia. AB - A new nematode species, Philometra barnesi sp. n. (Philometridae), is described from the ovary of the marine teleost Pomadasys argenteus (Fosskal) (Haemulidae) off the northern coast of Australia (near Darwin). The new species is characterized by short subequal spicules (84 and 87 MUm long), a gubernaculum without a dorsal protuberance at its distal tip, the structure of male anterior and posterior body ends, the body lengths of males (1.67 mm) and gravid females (320-597 mm) and the structure of the oesophagus and caudal end of gravid females. Philometra barnesi is the sixth nominal gonad-infecting species of this genus recorded from marine fishes in Australian waters and the third species of philometrids described from fishes of the family Haemulidae. PMID- 26231837 TI - The siRNA-mediated silencing of Trichinella spiralis nudix hydrolase results in reduction of larval infectivity. AB - Previous studies showed that Trichinella spiralis Nudix hydrolase (TsNd) bound to intestinal epithelial cells (IECs), and vaccination of mice with rTsNd or TsNd DNA produced a partial protective immunity against T. spiralis infection. In this study, three TsNd specific small interfering RNA (siRNA) were designed to silence the expression of TsNd in T. spiralis larvae. SiRNAs were delivered to the larvae by electroporation. Silencing effect of TsNd transcription and expression was determined by real-time PCR and Western blotting, respectively. The infectivity of the larvae treated with siRNA was investigated by the in vitro larval invasion of IECs and experimental infection in mice. The results showed that siRNAs were efficiently delivered into T. spiralis larvae through electroporation. Real-time PCR and Western blotting showed that transcription and expression level of TsNd gene was inhibited 73.3 and 76.7 %, respectively, after being electroporated with 2 MUM of siRNA-275 for 1 day. Silencing TsNd expression inhibited significantly the larval invasion of IECs (P < 0.01) and was in a dose-dependent manner (r = 0.97941). The mice with infected larvae treated with TsNd siRNA displayed a 63.6 % reduction in intestinal adult worms and 68.8 % reduction in muscle larval burden compared with mice infected with control siRNA-treated larvae. Our results showed that silencing TsNd expression in T. spiralis significantly reduced the larval infectivity and survival in host. PMID- 26231838 TI - Herd-level prevalence and associated risk factors for Toxoplasma gondii, Neospora caninum, Chlamydia abortus and bovine viral diarrhoea virus in commercial dairy and beef cattle in eastern, northern and northeastern China. AB - Although the seroprevalence of Toxoplasma gondii, Neospora caninum, Chlamydia abortus and bovine viral diarrhea virus infection in cattle have been reported in some areas in China, most of them were conducted with small number of cattle samples and very limited districts and neglected the assessment of herd management factors associated with herd-level prevalence of these pathogen infections. Thus, from September 2013 to December 2014, a large-scale seroprevalence study was conducted to determine the animal-level and herd-level seroprevalence and identify herd-level risk factors associated with these pathogen infections in 4487 cattle from 134 herds in five provinces (Heilongjiang, Jilin, Liaoning, Shandong, Hebei) and Inner Mongolia Autonomous Region of China. At animal level, the true prevalence of antibodies against T. gondii, N. caninum, C. abortus and bovine viral diarrhoea virus (BVDV) was 10.48, 17.14, 11.92 and 50.10%, respectively. At herd level, the true prevalence of antibodies against T. gondii, N. caninum, C. abortus and BVDV was 27.16, 29.10, 37.31 and 40.30%, respectively. Multivariate analysis of these characteristics showed that source of water and presence of felids were significantly associated with T. gondii infection in the studied cattle herds. Source of water was significantly associated with N. caninum infection in the studied cattle herds. While herd size and management system were significantly associated with BVDV infection in the studied cattle herds, this is the first report of herd-level prevalence and associated risk factors of T. gondii, N. caninum, C. abortus and BVDV infection in cattle in China. PMID- 26231839 TI - Molecular reproductive characteristics of the reef coral Pocillopora damicornis. AB - Coral reefs are an indispensible worldwide resource, accounting for billions of dollars in cultural, economic, and ecological services. An understanding of coral reproduction is essential to determining the effects of environmental stressors on coral reef ecosystems and their persistence into the future. Here, we describe the presence of and changes in steroidal hormones along with associated steroidogenic and steroid removal enzymes during the reproductive cycle of the brooding, pan-Pacific, hermaphroditic coral, Pocillopora damicornis. Detectable levels of 17beta-estradiol, estrone, progesterone and testosterone were consistently detected over two consecutive lunar reproductive cycles in coral tissue. Intra-colony variation in steroid hormone levels ranged between 1.5- and 2.2-fold and were not statistically different. Activities of the steroidogenic enzymes 3beta-hydroxysteroid dehydrogenase and cytochrome P450 (CYP) 17 dehydrogenase were detectable and did not fluctuate over the reproductive cycle. Aromatase-like activity was detected during the lunar reproductive cycle with no significant fluctuations. Activities of regeneration enzymes did not fluctuate over the lunar cycle; however, activity of the clearance enzyme UDP-glucuronosyl transferases increased significantly (ANOVA, post hoc p<0.01) during the two weeks before and after peak larval release (planulation), suggesting that the activity of this enzyme family may be linked to the reproductive state of the coral. Sulfotransferase enzymes could not be detected. Our findings provide the first data defining normal physiological and lunar/reproductive variability in steroidal enzymes in a coral species with respect to their potential role in coral reproduction. PMID- 26231840 TI - Magnetic resonance imaging signs of high intraventricular pressure--comparison of findings in dogs with clinically relevant internal hydrocephalus and asymptomatic dogs with ventriculomegaly. AB - BACKGROUND: Magnetic resonance imaging (MRI) findings of canine brains with enlarged ventricles in asymptomatic dogs were compared to those in dogs with clinically relevant internal hydrocephalus, in order to determine the imaging findings indicative of a relevant increase in intraventricular pressure. Discrimination between clinically relevant hydrocephalus and ventriculomegaly based on MRI findings has not been established yet and is anything but trivial because of the wide variation in ventricular size in different dog breeds and individuals. The MRI scans of the brains of 67 dogs of various breeds, skull conformation and weight were reviewed retrospectively. Based on clinical and imaging findings, the dogs were divided into three groups: a normal group (n = 20), a group with clinically silent ventriculomegaly (n = 25) and a group with severe clinically relevant internal hydrocephalus (n = 22). In addition to the ventricle/brain-index, a number of potential subjective signs of increased intraventricular pressure were recorded and compared between the groups. RESULTS: The ventricle/brain-index was significantly higher in dogs with relevant hydrocephalus (p < 0.001) and a threshold value of 0.6 was specified as a discriminator between internal hydrocephalus and ventriculomegaly. Other MR imaging findings associated with clinically relevant hydrocephalus were an elevation of the corpus callosum (p < 0.01), dorsoventral flattening of the interthalamic adhesion (p < 0.0001), periventricular edema (p < 0.0001), dilation of the olfactory recesses (p < 0.0001), thinning of the cortical sulci (p < 0.0001) and/or the subarachnoid space (p < 0.0027) and disruption of the internal capsule adjacent to the caudate nucleus (p < 0.0001). CONCLUSION: A combination of the abovementioned criteria may support a diagnosis of hydrocephalus that requires treatment. PMID- 26231841 TI - Association of genetic loci for migraine susceptibility in the she people of China. AB - BACKGROUND: The purpose of this study was to investigate the association of the genotype and allele frequencies of the polymorphisms rs4379368, rs10504861, rs10915437, rs12134493 and rs13208321 in She people of China with migraine headache susceptibility. The five alleles were previously identified as being associated with migraine in a Western population, but it was not known if this association would hold in a She population. rs4379368 is in the succinic HMG coenzyme A transferase (C7orf10) gene; rs10504861 is near the matrix metallopeptidase 16 (MMP16) gene; rs10915437 is near the adherens junctions associated protein 1 (AJAP1) gene; rs12134493 is upstream of the tetraspanin 2 (TSPAN2) gene; and rs13208321 is within the four and a half LIM domains protein 5 (FHL5) gene. METHODS: This was a case-controlled study conducted in She people of Fujian province in China. Polymerase chain reaction-restriction fragment length polymorphism and direct sequencing were performed. Univariate and multivariate analyses were used to assess the association of the different genotypes of each SNP with migraine. RESULTS: The rs4379368 T allele was not in Hardy-Weinberg equilibrium and was more common than the C allele in subjects with migraine (58.7 %; P = 0.049), possibly suggesting a selection bias for T allele in this population. In support of this, the CT and TT genotypes were more frequent in the migraine compared with the control groups (54.0 % and 31.7 % vs. 48.0 % and 28.7 %, respectively; P = 0.019). These genotypes were also more common in females with migraines than females without migraines (53.8 % and 30.9 % vs. 46.7 % and 27.6 %; P = 0.026). Univariate and multivariate analyses found the CC genotype of rs4379368 and AA or AG genotype of rs13208321 were associated with a reduced risk of migraine (P values <=0.039). CONCLUSIONS: Our findings suggest that rs4379368 and rs13208321 are potential genetic markers for migraine in this She population. The findings of this study and others indicate important differences between ethnic populations in regard to genetic markers of migraine susceptibility. PMID- 26231842 TI - Left Ventricular Dilatation Increases the Risk of Ventricular Arrhythmias in Patients With Reduced Systolic Function. AB - BACKGROUND: Reduced left ventricular (LV) ejection fraction increases the risk of ventricular arrhythmias; however, LV ejection fraction has a low sensitivity to predict ventricular arrhythmias. LV dilatation and mass may be useful to further risk-stratify for ventricular arrhythmias. METHODS AND RESULTS: Patients from the Genetic Risk of Assessment of Defibrillator Events (GRADE) study (N=930), a study of heart failure subjects with defibrillators, were assessed for appropriate implantable cardioverter-defibrillator shock and death, heart transplant, or ventricular assist device placement by LV diameter and mass. LV mass was divided into normal, mild, moderate, and severe classifications. Severe LV end-diastolic diameter had worse shock-free survival than normal and mild LV end-diastolic diameter (P=0.0002 and 0.0063, respectively; 2-year shock free, severe 74%, moderate 80%, mild 91%, normal 88%; 4-year shock free, severe 62%, moderate 69%, mild 72%, normal 81%) and freedom from death, transplant, or ventricular assist device compared with normal and moderate LV end-diastolic diameter (P<0.0001 and 0.0441, respectively; 2-year survival: severe 78%, moderate 85%, mild 82%, normal 89%; 4-year survival: severe 55%, moderate 64%, mild 63%, normal 74%). Severe LV mass had worse shock-free survival than normal and mild LV mass (P=0.0370 and 0.0280, respectively; 2-year shock free: severe 80%, moderate 81%, mild 91%, normal 87%; 4-year shock free: severe 68%, moderate 73%, mild 76%, normal 76%) but no association with death, transplant, or ventricular assist device (P=0.1319). In a multivariable Cox proportional hazards analysis adjusted for LV ejection fraction, LV end-diastolic diameter was associated with appropriate implantable cardioverter-defibrillator shocks (hazard ratio 1.22, P=0.020). LV end-diastolic diameter was associated with time to death, transplant, or ventricular assist device (hazard ratio 1.29, P=0.0009). CONCLUSIONS: LV dilatation may complement ejection fraction to predict ventricular arrhythmias. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02045043. PMID- 26231843 TI - Venous Stenosis After Transvenous Lead Placement: A Study of Outcomes and Risk Factors in 212 Consecutive Patients. AB - BACKGROUND: Venous stenosis is a common complication of transvenous lead implantation, but the risk factors for venous stenosis have not been well defined to date. This study was designed to evaluate the incidence of and risk factors for venous stenosis in a large consecutive cohort. METHODS AND RESULTS: A total of 212 consecutive patients (136 male, 76 female; mean age 69 years) with existing pacing or implantable cardioverter-defibrillator systems presented for generator replacement, lead revision, or device upgrade with a mean time since implantation of 6.2 years. Venograms were performed and percentage of stenosis was determined. Variables studied included age, sex, number of leads, lead diameter, implant duration, insulation material, side of implant, and anticoagulant use. Overall, 56 of 212 patients had total occlusion of the subclavian or innominate vein (26%). There was a significant association between the number of leads implanted and percentage of venous stenosis (P=0.012). Lead diameter, as an independent variable, was not a risk factor; however, greater sum of the lead diameters implanted was a predictor of subsequent venous stenosis (P=0.009). Multiple lead implant procedures may be associated with venous stenosis (P=0.057). No other variables approached statistical significance. CONCLUSIONS: A significant association exists between venous stenosis and the number of implanted leads and also the sum of the lead diameters. When combined with multiple implant procedures, the incidence of venous stenosis is increased. PMID- 26231844 TI - Increased Heme Levels in the Heart Lead to Exacerbated Ischemic Injury. AB - BACKGROUND: Heme is an essential iron-containing molecule for cardiovascular physiology, but in excess it may increase oxidative stress. Failing human hearts have increased heme levels, with upregulation of the rate-limiting enzyme in heme synthesis, delta-aminolevulinic acid synthase 2 (ALAS2), which is normally not expressed in cardiomyocytes. We hypothesized that increased heme accumulation (through cardiac overexpression of ALAS2) leads to increased oxidative stress and cell death in the heart. METHODS AND RESULTS: We first showed that ALAS2 and heme levels are increased in the hearts of mice subjected to coronary ligation. To determine the causative role of increased heme in the development of heart failure, we generated transgenic mice with cardiac-specific overexpression of ALAS2. While ALAS2 transgenic mice have normal cardiac function at baseline, their hearts display increased heme content, higher oxidative stress, exacerbated cell death, and worsened cardiac function after coronary ligation compared to nontransgenic littermates. We confirmed in cultured cardiomyoblasts that the increased oxidative stress and cell death observed with ALAS2 overexpression is mediated by increased heme accumulation. Furthermore, knockdown of ALAS2 in cultured cardiomyoblasts exposed to hypoxia reversed the increases in heme content and cell death. Administration of the mitochondrial antioxidant MitoTempo to ALAS2-overexpressing cardiomyoblasts normalized the elevated oxidative stress and cell death levels to baseline, indicating that the effects of increased ALAS2 and heme are through elevated mitochondrial oxidative stress. The clinical relevance of these findings was supported by the finding of increased ALAS2 induction and heme accumulation in failing human hearts from patients with ischemic cardiomyopathy compared to nonischemic cardiomyopathy. CONCLUSIONS: Heme accumulation is detrimental to cardiac function under ischemic conditions, and reducing heme in the heart may be a novel approach for protection against the development of heart failure. PMID- 26231845 TI - Publication Speed, Reporting Metrics, and Citation Impact of Cardiovascular Trials Supported by the National Heart, Lung, and Blood Institute. AB - BACKGROUND: We previously demonstrated that cardiovascular (CV) trials funded by the National Heart, Lung, and Blood Institute (NHLBI) were more likely to be published in a timely manner and receive high raw citation counts if they focused on clinical endpoints. We did not examine the metrics of trial reports, and our citation measures were limited by failure to account for topic-related citation behaviors. METHODS AND RESULTS: Of 244 CV trials completed between 2000 and 2011, we identified 184 whose main results were published by August 20, 2014. One investigator who was blinded to rapidity of publication and citation data read each publication and characterized it according to modified Delphi criteria. There were 46 trials (25%) that had Delphi scores of 8 or 9 (of a possible 9); these trials published faster (median time from trial completion to publication, 12.6 [interquartile range {IQR}, 6.7 to 23.3] vs. 21.8 [IQR, 12.1 to 34.9] months; P<0.01). They also had better normalized citation impact (median citation percentile for topic and date of publication, with 0 best and 100 worst, 1.92 [IQR, 0.64 to 7.83] vs. 8.41 [IQR, 1.80 to 24.75]; P=0.002). By random forest regression, we found that the 3 most important predictors of normalized citation percentile values were total costs, intention-to-treat analyses (as a modified Delphi quality measure), and focus on clinical (not surrogate) endpoints. CONCLUSIONS: NHLBI CV trials were more likely to publish results quickly and yield higher topic-normalized citation impact if they reported results according to well-defined metrics, along with focus on clinical endpoints. PMID- 26231846 TI - The first record of a soft-shelled turtle (Testudines: Pan-Trionychidae) from southern Balkans (Pliocene, Gefira, N. Greece) and new information from bone histology. AB - Soft-shelled turtles (Pan-Trionychidae) are not included in the present-day chelonian fauna of Greece and have been unknown in the Greek fossil record up to now. Here, we report the first fossil occurrence of a soft-shelled turtle from Greece, originating from the Pliocene Gefira Member (Angelochori Formation), in the lower Axios valley. The corresponding specimens were discovered with several mammalian remains, most of them attributable to the mastodon of Auvergne, Anancus arvernensis. The chelonian material includes five carapacial fragments that belong to the same individual and can be attributed to Pan-Trionychidae based on the typical sculpturing on the dorsal side of the carapace. Most of these bony plates were histologically sampled and thereby provide evidence for the "plywood" structure, another characteristic of pan-trionychids. They represent the first extended sampling of trionychid plates that belong to the same individual, allowing the documentation of the variation of the relevant trionychid morphologies in the carapace. These findings expand the paleobiogeographic range of this taxon to the southern Balkans and Greece and allow a better estimation of the chelonian paleo-fauna of the area. They are also important for the temporal distribution of this clade in the Paleoarctic, as they join specimens from Italy as being the last trionychids in Europe. PMID- 26231847 TI - Engineering of Nitrosomonas europaea to express Vitreoscilla hemoglobin enhances oxygen uptake and conversion of ammonia to nitrite. AB - Nitrosomonas europaea was transformed with a recombinant plasmid bearing the gene (vgb) encoding the hemoglobin (VHb) from the bacterium Vitreoscilla under control of the N. europaea amoC P1 promoter. Vgb was maintained stably and appeared to be expressed in the transformants at VHb levels of about 0.75 nmol/g wet weight. Expression of VHb in the N. europaea transformants was correlated with an approximately 2 fold increase in oxygen uptake rate by whole cells at oxygen concentrations in the range of 75-100% saturation, but no change in oxygen uptake rate at oxygen concentrations below 25% saturation. VHb expression was also correlated with an increase of as much as about 30% in conversion of ammonia to nitrite by growing cells. The results suggest that engineering of key aerobic wastewater bacteria to express bacterial hemoglobins may be a useful strategy to produce species with enhanced respiratory abilities. PMID- 26231848 TI - Erratum to: Efficacy of fluralaner flavored chews (Bravecto) administered to dogs against the adult cat flea, Ctenocephalides felis felis and egg production. PMID- 26231849 TI - Pediatric caregiver involvement in the assessment of physicians. AB - BACKGROUND: Given the growth and benefits of consumerist and family-centred approaches to pediatric health care, there is a need to involve pediatric caregivers in the assessment of their children's physicians. DISCUSSION: We present interconnected questions that are important to address in order to facilitate pediatric caregiver involvement in the assessment of their children's physicians. Pediatric caregivers can be valuable assessors of physicians' non technical skills. It is important to conduct additional research on caregiver involvement in assessment activities and create a reflective discourse on this topic. To ensure that pediatric caregivers' assessments of physicians are formally recognized and advantageous, it is important to understand: (a) what pediatric caregivers can assess; (b) what assessment tools exist for pediatric caregivers; PMID- 26231852 TI - Welcome from Tanya Parish, new Editor-in-Chief. PMID- 26231851 TI - Detection of Anaplasma phagocytophilum in Ixodes ricinus ticks from Norway using a realtime PCR assay targeting the Anaplasma citrate synthase gene gltA. AB - BACKGROUND: A TaqMan real-time PCR assay targeting the Anaplasma citrate synthase gene, gltA, was developed and used for detection of Anaplasma phagocytophilum in 765 Ixodes ricinus ticks collected from dogs and cats in northern Norway (n = 669) and Telemark county in southern Norway (n = 96). RESULTS: Among the ticks from northern Norway the prevalence of A. phagocytophilum was 3.0 %, while the prevalence in southern Norway was 2.1 % (p = 0.63). The gltA PCR assay showed a high analytical sensitivity (30 genomic units) and efficiency (98.5 %), and its utility in clinical diagnostics should be evaluated in future studies. CONCLUSION: This is the first report of A. phagocytophilum occurrence in ticks collected north of the Arctic Circle in Norway. The prevalence is comparable to that found in Telemark county in southern Norway. PMID- 26231853 TI - Farewell. PMID- 26231854 TI - The serine/threonine kinase PknB of Mycobacterium tuberculosis phosphorylates PBPA, a penicillin-binding protein required for cell division. AB - The authors would like to retract the article as the published versions of Figs. 3b, 6a, b, d, 7a, b(lower panel) were modified prior to publication. The authors would like to apologise to thereaders, reviewers and editors of Microbiology for this error. PMID- 26231850 TI - The More and Less Study: a randomized controlled trial testing different approaches to treat obesity in preschoolers. AB - BACKGROUND: While obesity has been shown to be difficult to treat in school aged children and in adolescence, promising results have been detected for children who started treatment in early childhood. Yet knowledge on the effectiveness of structured early childhood obesity treatment programs is limited, preventing the widespread implementation of such programs. The main objective of this study is to evaluate the effectiveness of early treatment of childhood obesity with respect to treatment focus (parenting practices or lifestyle), length and intensity. The study will also examine the influence of gender, age, parental weight status, parenting practices, child behavior as well as parents' socioeconomic status and child and parental psychosocial health on children's weight status. METHODS/DESIGN: This is a parallel open label randomized controlled trial assessing two different behavioral treatment approaches offered in three conditions to families with children aged 4-6 years in Stockholm County, Sweden. Children (n = 180) identified as obese will be referred from primary child health care, school health care, and from outpatient pediatric clinics, and randomized to: 1) a standard treatment with focus on lifestyle, provided within the current healthcare system (n = 90); 2) a 10-session, 1.5 h/week group treatment with focus on parenting (n = 45); or 3) the same group treatment as 2) with additional follow-up sessions (n = 45). The primary study outcome is change in children's body mass index standard deviation score (BMI SDS) one year post baseline. Secondary outcomes include changes in children's waist circumference, metabolic health, lifestyle patterns (Food Frequency Questionnaire), obesity related child behaviors (Child Eating Behavior Questionnaire and Lifestyle Behavior Checklist, Problem Scale), parents' general and feeding parenting practices (Communicating with Children and Child Feeding Questionnaire) and lifestyle-specific self-efficacy (Lifestyle Behavior Checklist, Confidence Scale), family functioning (Family Assessment Device), child and parental psychosocial health (Child Behavior Checklist and Beck's Depression Inventory II). DISCUSSION: This study will facilitate a close examination of key components of treatment for obesity during early childhood and mechanisms of change. Results from this study will lead to better healthcare options for obesity treatment during early childhood and ultimately to the prevention of obesity later in life. TRIAL REGISTRATION: ClinicalTrials.gov NCT01792531 Registered February 14, 2013. PMID- 26231855 TI - Alcohol Use, Partner Violence, and Depression: A Cluster Randomized Controlled Trial Among Urban South African Mothers Over 3 Years. AB - INTRODUCTION: Pregnant South African women with histories of drinking alcohol, abuse by violent partners, depression, and living with HIV are likely to have their post-birth trajectories over 36 months significantly influenced by these risks. DESIGN: All pregnant women in 24 Cape Town neighborhoods were recruited into a cluster RCT by neighborhood to either: (1) a standard care condition (n=12 neighborhoods, n=594 mothers); or (2) a home-visiting intervention condition (n=12 neighborhoods, n=644 mothers). SETTING/PARTICIPANTS: Pregnant women residing in urban, low-income neighborhoods in Cape Town, South Africa. INTERVENTION: Home visiting included prenatal and postnatal visits by community health workers (Mentor Mothers) focusing on general maternal and child health, HIV/tuberculosis, alcohol use, and nutrition. MAIN OUTCOME MEASURES: Mothers were assessed in pregnancy and at 18 and 36 months post birth: 80.6% of mothers completed all assessments between 2009 and 2014 and were included in these analyses performed in 2014. Longitudinal structural equation modeling examined alcohol use, partner violence, and depression at the baseline and 18-month interviews as predictors of maternal outcomes at 36 months post birth. RESULTS: Relative to standard care, intervention mothers were significantly less likely to report depressive symptoms and more positive quality of life at 36 months. Alcohol use was significantly related to use over time, but was also related to depression and HIV status at each assessment and partner violence at 36 months. CONCLUSIONS: Alcohol, partner violence, and depression are significantly related over time. A home-visiting intervention improved the emotional health of low income mothers even when depression was not initially targeted. PMID- 26231857 TI - A genome-wide association study of mitochondrial DNA in Chinese men identifies two risk single nucleotide substitutions for idiopathic oligoasthenospermia. AB - Mitochondrial DNA (mtDNA) is believed to be both the source and target of reactive oxygen species (ROS), and mtDNA genetic alterations have been reported to be associated with molecular defects in the oxidative phosphorylation (OXPHOS) system. In order to investigate the potentially susceptible mtDNA genetic variants to oligoasthenospermia, we conducted a two-stage study in 921 idiopathic infertile men with oligoasthenospermia and 766 healthy controls using comprehensive molecular analysis. In the screen stage, we used next generation sequencing (NGS) in 233 cases and 233 controls to screen oligoasthenospermia susceptible mitochondrial genetic variants. In total, seven variants (C5601T, T12338C, A12361G, G13928C, A15235G, C16179T and G16291A) were screened to be potentially associated with idiopathic oligoasthenospermia. In the validation stage, we replicated these variants in 688 cases and 533 healthy controls using SNPscan. Our results demonstrated that the genetic alteration of C16179T was associated with idiopathic male infertility (odds ratio (OR) 3.10, 95% CI 1.41 6.79) (p=3.10*10(-3)). To elucidate the exact role of the genetic variants in spermatogenesis, two main sperm parameters (sperm count and motility) were taken into account. We found that C16179T was associated with both low sperm count and motility, with ORs of 4.18 (95% CI 1.86-9.40) (p=1.90*10(-4)) and 3.17 (95% CI 1.40-7.16) (p=3.50*10(-3)), respectively. Additionally, A12361G was found to be associated with low sperm count, with an OR of 3.30 (95% CI 1.36-8.04) (p=5.50*10(-3)). These results indicated that C16179T influenced both the process of spermatogenesis and sperm motility, while A12361G may just only participate in the process of spermatogenesis. Further investigation in larger populations and functional characterizations are needed to validate our findings. PMID- 26231856 TI - Efficacy of a Behavioral Intervention for Pediatric Type 1 Diabetes Across Income. AB - INTRODUCTION: Youth with Type 1 diabetes and lower family income typically have poorer glycemic control. This post hoc analysis examines whether a family oriented behavioral intervention for this population is differentially effective across income levels. METHODS: Families of youth aged 9-15 years with Type 1 diabetes (N=390; 49.2% female; age, 12.4 [1.7] years; hemoglobin A1c [HbA1c], 8.4 [1.2]; pump, 33.8%) at four U.S. pediatric endocrinology clinics participated in a 2-year RCT (data collected 2006-2011) of a clinic-integrated behavioral intervention designed to improve diabetes management by facilitating problem solving skills, communication skills, and responsibility sharing. HbA1c was analyzed centrally. Family income was categorized as <$50,000 (low); $50,000 to <$100,000 (middle); and >=$100,000 (high). Treatment effect was defined as the change in HbA1c from baseline to 2-year follow-up. A linear model tested the interaction of treatment effect with family income, controlling for race, insulin regimen, and site (analyzed in 2014). RESULTS: Baseline HbA1c was significantly poorer (p=0.004) in the low-income group. There was a significant overall effect of treatment group on change in HbA1c from baseline to follow-up (p=0.04). The interaction term for treatment by income group was not significant (p=0.44). Within each income category, a smaller deterioration in glycemic control was observed for the treatment group relative to controls. CONCLUSIONS: This clinic integrated behavioral intervention was similarly effective in improving glycemic control among youth with Type 1 diabetes across income levels. This family oriented problem-solving approach offers flexibility in addressing families' needs and may optimize impact on health outcomes across income groups. PMID- 26231858 TI - Radiologic Evaluation of Small Lepidic Adenocarcinomas to Guide Decision Making in Surgical Resection. AB - BACKGROUND: The International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of pulmonary adenocarcinomas identifies indolent lesions associated with low recurrence, superior survival, and the potential for sublobar resection. The distinction, however, is determined on the pathologic evaluation, limiting preoperative surgical planning. We sought to determine whether preoperative computed tomography (CT) characteristics could guide decisions about the extent of the pulmonary resection. METHODS: We reviewed the preoperative CT scans for 136 patients identified to have adenocarcinomas with lepidic features on the final pathologic evaluation. The solid component on CT was substituted for the invasive component, and patients were radiologically classified as adenocarcinoma in situ, 3 cm or less with no solid component; minimally invasive adenocarcinoma, 3 cm or less with a solid component of 5 mm or less; or invasive adenocarcinoma, exceeding 3 cm or solid component exceeding 5 mm, or both. Analysis of variance, t test, chi(2) test, and Kaplan-Meier methods were used for analysis. RESULTS: The radiologic classification identified 35 adenocarcinomas in situ (26%) and 12 minimally invasive (9%) and 89 invasive adenocarcinoma (65%) lesions. At a 32 month median follow-up, patient outcomes associated with the radiologic classification were similar to the pathologic-based classification: the radiologic classification identified 14 of 16 patients with recurrent disease and all 6 who died of lung cancer. In addition, patients with radiologic adenocarcinoma in situ and minimally invasive adenocarcinoma who underwent sublobar resections had no recurrence and 100% disease-free and overall survival at 5 years. CONCLUSIONS: The radiologic classification of patients with lepidic adenocarcinomas is associated with similar oncologic and survival outcomes compared with the pathologic classification and may guide decision making in the approach to surgical resection. PMID- 26231859 TI - [Airway management of a patient with a knife in the neck]. PMID- 26231861 TI - Polyelectrolyte-coated nanocapsules containing undecylenic acid: Synthesis, biocompatibility and neuroprotective properties. AB - The main objectives of the present study were to investigate the biocompatibility of polyelectrolyte-coated nanocapsules and to evaluate the neuroprotective action of the nanoencapsulated water-insoluble neuroprotective drug-undecylenic acid (UDA), in vitro. Core-shell nanocapsules were synthesized using nanoemulsification and the layer-by-layer (LbL) technique (by saturation method). The average size of synthesized nanocapsules was around 80 nm and the concentration was 2.5 * 10(10) particles/ml. Their zeta potential values ranged from less than -30 mV for the ones with external polyanion layers through -4 mV for the PEG-ylated layers to more than 30 mV for the polycation layers. Biocompatibility of synthesized nanocarriers was evaluated in the SH-SY5Y human neuroblastoma cell line using cell viability/toxicity assays (MTT reduction, LDH release). The results obtained showed that synthesized nanocapsules coated with PLL and PGA (also PEG-ylated) were non-toxic to SH-SY5Y cells, therefore, they were used as nanocarriers for UDA. Moreover, studies with ROD/FITC-labeled polyelectrolytes demonstrated approximately 20% cellular uptake of synthetized nanocapsules. Further studies showed that nanoencapsulated form of UDA was biocompatible and protected SH-SY5Y cells against the staurosporine-induced damage in lower concentrations than those of the same drug added directly to the culture medium. These data suggest that designed nanocapsules might serve as novel, promising delivery systems for neuroprotective agents. PMID- 26231860 TI - Oncologic outcomes in men with metastasis to the prostatic anterior fat pad lymph nodes: a multi-institution international study. AB - BACKGROUND: The presence of lymph nodes (LN) within the prostatic anterior fat pad (PAFP) has been reported in several recent reports. These PAFP LNs rarely harbor metastatic disease, and the characteristics of patients with PAFP LN metastasis are not well-described in the literature. Our previous study suggested that metastatic disease to the PAFP LN was associated with less severe oncologic outcomes than those that involve the pelvic lymph node (PLN). Therefore, the objective of this study is to assess the oncologic outcome of prostate cancer (PCa) patients with PAFP LN metastasis in a larger patient population. METHODS: Data were analyzed on 8800 patients from eleven international centers in three countries. Eighty-eight patients were found to have metastatic disease to the PAFP LNs (PAFP+) and 206 men had isolated metastasis to the pelvic LNs (PLN+). Clinicopathologic features were compared using ANOVA and Chi square tests. The Kaplan-Meier method was used to calculate the time to biochemical recurrence (BCR). RESULTS: Of the eighty-eight patients with PAFP LN metastasis, sixty-three (71.6%) were up-staged based on the pathologic analysis of PAFP and eight (9.1%) had a low-risk disease. Patients with LNs present in the PAFP had a higher incidence of biopsy Gleason score (GS) 8-10, pathologic N1 disease, and positive surgical margin in prostatectomy specimens than those with no LNs detected in the PAFP. Men who were PAFP+ with or without PLN involvement had more aggressive pathologic features than those with PLN disease only. However, there was no significant difference in BCR-free survival regardless of adjuvant therapy. In 300 patients who underwent PAFP LN mapping, 65 LNs were detected. It was also found that 44 out of 65 (67.7%) nodes were located in the middle portion of the PAFP. CONCLUSIONS: There was no significant difference in the rate of BCR between the PAFP LN+ and PLN+ groups. The PAFP likely represents a landing zone that is different from the PLNs for PCa metastasis. Therefore, the removal and pathologic analysis of PAFP should be adopted as a standard procedure in all patients undergoing radical prostatectomy. PMID- 26231862 TI - Solid lipid nanoparticles for delivery of Calendula officinalis extract. AB - Solid lipid nanoparticles (SLN) composed of long-chain fatty acids (palmitic acid, stearic acid or arachidic acid), Epikuron 200 (purified phosphatidylcholine), and bile salts (cholate, taurocholate or taurodeoxycholate) have been prepared by dilution of a microemulsion. A total of five different systems were prepared, and characterized by photon correlation spectroscopy, transmission electron microscopy, differential scanning calorimetry, and infrared spectroscopy. The SLN formulation showing optimal properties (lowest size and polydispersity index and highest zeta potential) was obtained with stearic acid and taurodeoxycholate as cosurfactant. This formulation was loaded with Calendula officinalis extract, a natural compound used on ophthalmic formulations given its anti-inflammatory, emollient, and wound repairing activity. Calendula-loaded SLN preparations were characterized in order to determine loading capacity and entrapment efficiency. In vitro cytotoxicity and wound healing efficacy of Calendula-loaded SLN compared to that of a free plant extract were evaluated on a conjunctival epithelium cell line WKD. Our results suggest that this SLN formulation is a safe and solvent-free Calendula extract delivery system which could provide a controlled therapeutic alternative for reducing disease-related symptoms and improving epithelium repair in ocular surface. PMID- 26231864 TI - A higher Charlson comorbidity index is related to more aggressive characteristics in de novo vesical tumours. AB - OBJECTIVE: To analyze the relationship between the age--adjusted Charlson Comorbidity Index (aCCI) and pathological outcomes of transurethral resection of de novo bladder tumours (BT). MATERIAL AND METHODS: Data from 208 patients who underwent a transurethral resection (TUR) of a de novo BT between 2007 and 2008 were collected. We recorded the following variables: age, sex, tobacco consumption, comorbidities assessed according to the ICCa (score and mortality rate), disease stage, tumour grade and risk of recurrence and progression. The relationship between the preoperative variables and the final pathological characteristics was analyzed. The multivariate study was conducted with the significant variables (P<.05) from the univariate analysis. RESULTS: The mean age of the patients was 69.5 +/- 12 years, and 77% were men. The mean ICCa was 6.4 +/ 2.5. The final pathology results showed a Tx, T0, Ta, T1 and T >= 2 in 5.3, 6.7, 31.7, 26.9, and 28.8% of the cases, respectively. 33.3% of the tumours were low grade and 66.7% were high-grade. 14.3% of the tumours were associated with carcinoma in situ. Among those non musculo-invasive bladder tumour (non-MIBT), 34.7% had a low risk of recurrence and progression, 18.1% had an intermediate risk and 47.2% had a high risk. The patients with a ICCa >= 5 had an increased number of MIBT (RR: 2.29; 1.1-4.8; P=.032), high-grade tumours (RR: 3.1; CI: 1.6 6; P=.001) and tumours with a high risk of recurrence and progression (RR: 2.9; CI: 1.4-5.9; P<.001). CONCLUSION: The ICCa is related to the pathological characteristics of de novo BT. Patients with greater comorbidity can present more aggressive tumours. The ICCa could therefore be useful in clinical practice for identifying patients with worse prognosis. PMID- 26231865 TI - Defra seeks views on testing the language skills of EU migrant vets. PMID- 26231866 TI - FAO appeals for $20 million to help tackle avian influenza in West Africa. PMID- 26231867 TI - Video explains the benefits of the PDP. PMID- 26231868 TI - Combined report on antimicrobial resistance in people and animals. PMID- 26231869 TI - Recognition for contributions to feline infectious disease research. PMID- 26231870 TI - Bursting at the seams: managing the companion animal population. AB - Overproduction of companion animals in the UK was one of the topics considered at this year's Animal Welfare Foundation discussion forum. Other subjects discussed included antimicrobial resistance and the ethical dilemmas surrounding advanced treatment options for pets. Laura Honey reports. PMID- 26231871 TI - FVE must continue to be active, says outgoing president. AB - Karin de Lange reports from the recent general assembly of the Federation of Veterinarians of Europe, where issues on the agenda included proposed European regulations on animal health and veterinary medicines. PMID- 26231872 TI - Veterinary medicines: product update. AB - The following information has been produced for Veterinary Record by the Veterinary Medicines Directorate (VMD) to provide an update for veterinary surgeons on recent changes to marketing authorisations for veterinary medicines in the UK and on other relevant issues. PMID- 26231873 TI - Keeping cats safe. PMID- 26231874 TI - Toxocara vitulorum identified in a suckled calf in Scotland. AB - * Toxocara vitulorum infection in calves * Bovine viral diarrhoea virus infection in bovine fetuses * Jaundice and hydronephrosis associated with border disease in lambs * Virulent Escherichia coli isolated from cases of oedema disease in weaned pigs * Outbreaks of erysipelas in pigs and turkeys * These are among matters discussed in the disease surveillance report for April from SAC Consulting: Veterinary Services (SAC C VS). PMID- 26231875 TI - Novice to expert? Teaching and development of moral reasoning skills. PMID- 26231876 TI - Randomised Badger Culling Trial: interpreting the results. AB - Simon More and Guy McGrath raise issues relating to the Randomised Badger Culling Trial, that they feel warrant further discussion and study. PMID- 26231877 TI - Sheep worrying. PMID- 26231878 TI - Veterinary All Trials Initiative. PMID- 26231879 TI - Study on the effects of imepitoin on the behaviour of dogs with epilepsy. PMID- 26231881 TI - Making a difference. AB - Hayley Walters worked in mixed practice for 10 years but then realised she wanted to make more of a difference to animals' lives. She joined Animals Asia, and began a new career in animal welfare. This year, she won the 'Vet Nurse of the Year' category in the Ceva Animal Welfare Awards. PMID- 26231882 TI - Challenges of hemodialysis in Vietnam: experience from the first standardized district dialysis unit in Ho Chi Minh City. AB - BACKGROUND: Hemodialysis is an increasingly common treatment in Vietnam as the diagnosis of end stage renal disease continues to rise. To provide appropriate hemodialysis treatment for end-stage renal disease patients, we conducted a 1 year cross-sectional study to measure the prevalence of bloodborne infection and factors associated with non-compliant behaviors in hemodialysis patients. METHODS: One hundred forty-two patients were tested for hepatitis B virus (HBV) surface antigen and hepatitis C virus (HCV) core antigen. They provided demographic, medical and dialysis information. Non-compliant behaviors were obtained from their medical records. RESULTS: Overall, 99 % of patients reused their dialyzers and 46 % had arteriovenous fistula on admission. Both HBV and HCV equally accounted for 8 % of patients and concurrent infection accounted for 1 %. Non-compliance rates of dietary and medication were 39 and 27 % respectively. 42 % of patients missed hemodialysis session, 8 % were verbally or physically abusive and 9 % were non-cooperative. Of the 54 % catheterized patients, 7 % improperly cared for their dialysis access. Dietary non-adherence was associated with male patients (p = 0.03) and medication non-adherence was associated with younger age (p = 0.05). Duration between diagnosis of chronic kidney disease and initiation of hemodialysis was associated with improper care of dialysis access (p = 0.04). Time on hemodialysis was associated with missed hemodialysis session (p = 0.007) and verbal or physical abuse (p = 0.01). CONCLUSION: Health services need to provide safe practice for dialyzer reuse given the endemicity of hepatitis. We believe a national survey similar to ours about seroprevalence and infection control challenges would prepare Vietnam for providing safer satellite treatment units. Safe hemodialysis services should also comprise patient preparedness, education and counseling. PMID- 26231883 TI - The stock alloplastic temporomandibular joint implant can influence the behavior of the opposite native joint: A numerical study. AB - PURPOSE: The objective of the study was to investigate the effect of total stock temporomandibular implants on load mechanisms in both condyles in a specific patient. The patient presented with a disc with wear, and the introduction of a total temporomandibular prosthesis was simulated to compare the articular behavior. MATERIAL AND METHODS: Based on specific patient computed tomographic images, two finite element models were created: one model with two intact temporomandibular joints (one joint with pathology), and other model with one implanted joint. The simulations considered the five most important muscles acting in the mandible, and it was possible to evaluate the biomechanical changes in the structures (skull, mandible, and articular disc). RESULTS: The results revealed more load transfer in the opposite condyle than in the damaged one; the insertion of a total temporomandibular implant changed the load transfer to the opposite condyle. There was decreased stress in the disc by about 50% and increased strain distribution. In the mandibular condyle with implant, the screw fixation is critical, with minimum strain around -9430 MUepsilon for first screw position. In the cranium, the implant changed the bone strains with a minimum principal strain observed around -2500 MUepsilon in six screw positions. CONCLUSION: This study indicates that replacing the damaged joint by an implant in an ideal position will improve joint position and consequently redistribute the loads. The study findings provide strong evidence that placing an implant on one side of the mandible will affect the load distribution on that structure and particularly on the opposite side. The temporomandibular joint changes condyle movement; with an implanted condyle, the movement is almost blocked. PMID- 26231885 TI - Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. AB - BACKGROUND: The age at which heart failure develops varies widely between countries and drug tolerance and outcomes also vary by age. We have examined the efficacy and safety of LCZ696 according to age in the Prospective comparison of angiotensin receptor neprilysin inhibitor with angiotensin converting enzyme inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF). METHODS: In PARADIGM-HF, 8399 patients aged 18-96 years and in New York Heart Association functional class II-IV with an LVEF <=40% were randomized to either enalapril or LCZ696. We examined the pre-specified efficacy and safety outcomes according to age category (years): <55 (n = 1624), 55-64 (n = 2655), 65-74 (n = 2557), and >=75 (n = 1563). FINDINGS: The rate (per 100 patient years) of the primary outcome of cardiovascular (CV) death or heart failure hospitalization (HFH) increased from 13.4 to 14.8 across the age categories. The LCZ696:enalapril hazard ratio (HR) was <1.0 in all categories (P for interaction between age category and treatment = 0.94) with an overall HR of 0.80 (0.73, 0.87), P < 0.001. The findings for HFH were similar for CV and all-cause mortality and the age category by treatment interactions were not significant. The pre-specified safety outcomes of hypotension, renal impairment and hyperkalaemia increased in both treatment groups with age, although the differences between treatment (more hypotension but less renal impairment and hyperkalaemia with LCZ696) were consistent across age categories. INTERPRETATION: LCZ696 was more beneficial than enalapril across the spectrum of age in PARADIGM HF with a favourable benefit-risk profile in all age groups. PMID- 26231884 TI - Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo embolic pulmonary hypertension: a prospective, randomized, controlled trial. AB - AIMS: The impact of exercise training on the right heart and pulmonary circulation has not yet been invasively assessed in patients with pulmonary hypertension (PH) and right heart failure. This prospective randomized controlled study investigates the effects of exercise training on peak VO2/kg, haemodynamics, and further clinically relevant parameters in PH patients. METHODS AND RESULTS: Eighty-seven patients with pulmonary arterial hypertension and inoperable chronic thrombo-embolic PH (54% female, 56 +/- 15 years, 84% World Health Organization functional class III/IV, 53% combination therapy) on stable disease-targeted medication were randomly assigned to a control and training group. Medication remained unchanged during the study period. Non-invasive assessments and right heart catheterization at rest and during exercise were performed at baseline and after 15 weeks. Primary endpoint was the change in peak VO2/kg. Secondary endpoints included changes in haemodynamics. For missing data, multiple imputation and responder analyses were performed. The study results showed a significant improvement of peak VO2/kg in the training group (difference from baseline to 15 weeks: training +3.1 +/- 2.7 mL/min/kg equals +24.3% vs. control -0.2 +/- 2.3 mL/min/kg equals +0.9%, P < 0.001). Cardiac index (CI) at rest and during exercise, mean pulmonary arterial pressure, pulmonary vascular resistance, 6 min walking distance, quality of life, and exercise capacity significantly improved by exercise training. CONCLUSION: Low-dose exercise training at 4-7 days/week significantly improved peak VO2/kg, haemodynamics, and further clinically relevant parameters. The improvements of CI at rest and during exercise indicate that exercise training may improve the right ventricular function. Further, large multicentre trials are necessary to confirm these results. PMID- 26231886 TI - Identification of two novel critical mutations in PCNT gene resulting in microcephalic osteodysplastic primordial dwarfism type II associated with multiple intracranial aneurysms. AB - Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a highly detrimental human autosomal inherited recessive disorder. The hallmark characteristics of this disease are intrauterine and postnatal growth restrictions, with some patients also having cerebrovascular problems such as cerebral aneurysms. The genomic basis behind most clinical features of MOPD II remains largely unclear. The aim of this work was to identify the genetic defects in a Chinese family with MOPD II associated with multiple intracranial aneurysms. The patient had typical MOPD II syndrome, with subarachnoid hemorrhage and multiple intracranial aneurysms. We identified three novel mutations in the PCNT gene, including one single base alteration (9842A>C in exon 45) and two deletions (Del-C in exon 30 and Del-16 in exon 41). The deletions were co-segregated with the affected individual in the family and were not present in the control population. Computer modeling demonstrated that the deletions may cause drastic changes on the secondary and tertiary structures, affecting the hydrophilicity and hydrophobicity of the mutant proteins. In conclusion, we identified two novel mutations in the PCNT gene associated with MOPD II and intracranial aneurysms, and the mutations were expected to alter the stability and functioning of the protein by computer modeling. PMID- 26231887 TI - Extracellular vesicle-mediated phenotype switching in malignant and non-malignant colon cells. AB - BACKGROUND: Extracellular vesicles (EVs) are secreted from many cells, carrying cargoes including proteins and nucleic acids. Research has shown that EVs play a role in a variety of biological processes including immunity, bone formation and recently they have been implicated in promotion of a metastatic phenotype. METHODS: EVs were isolated from HCT116 colon cancer cells, 1459 non-malignant colon fibroblast cells, and tumor and normal colon tissue from a patient sample. Co-cultures were performed with 1459 cells and malignant vesicles, as well as HCT116 cells and non-malignant vesicles. Malignant phenotype was measured using soft agar colony formation assay. Co-cultures were also analyzed for protein levels using mass spectrometry. The importance of 14-3-3 zeta/delta in transfer of malignant phenotype was explored using siRNA. Additionally, luciferase reporter assay was used to measure the transcriptional activity of NF-kappaB. RESULTS: This study demonstrates the ability of EVs derived from malignant colon cancer cell line and malignant patient tissue to induce the malignant phenotype in non-malignant colon cells. Similarly, EVs derived from non-malignant colon cell lines and normal patient tissue reversed the malignant phenotype of HCT116 cells. Cells expressing an EV-induced malignant phenotype showed increased transcriptional activity of NF-kappaB which was inhibited by the NF--kappaB inhibitor, BAY117082. We also demonstrate that knock down of 14-3-3 zeta/delta reduced anchorage-independent growth of HCT116 cells and 1459 cells co-cultured with HCT derived EVs. CONCLUSIONS: Evidence of EV-mediated induction of malignant phenotype, and reversal of malignant phenotype, provides rational basis for further study of the role of EVs in tumorigenesis. Identification of 14-3-3 zeta/delta as up-regulated in malignancy suggests its potential as a putative drug target for the treatment of colorectal cancer. PMID- 26231888 TI - Radiation reduction and faster acquisition times with SPECT gated blood pool scans using a high-efficiency cardiac SPECT camera. AB - BACKGROUND: Planar gated blood pool scans are an established method for the evaluation of left ventricular ejection fraction (LVEF) but the camera technology used for these studies has not significantly changed in decades. The purpose of this study was to determine the diagnostic accuracy of new high-efficiency SPECT gated blood pool scans compared to traditional scans and determine if they can be performed with lower radiation doses or faster acquisition times. METHODS: Patients undergoing a planar gated blood pool scan on a Na-I SPECT camera who consented to participate were subsequently imaged for 5 minutes in "List Mode" using a high-efficiency SPECT camera. LVEF was calculated for both the planar study and at 1, 2, 3, 4, and 5 minutes of acquisition on the high-efficiency camera. Counts acquired in the field of view, counts in the cardiac blood pool and LVEF were compared. RESULTS: A total of 46 patients were analyzed (48% male, mean age 55 years, and BMI 27.6 kg/m(2)) who received an average Tc-99m dose of 20.3 mCi (5.3 mSv), 17 (37%) with abnormal LVEF's. The Na-I camera averaged 24,514 counts/min/mCi in the field of view and 8662 counts/min/mCi in the cardiac blood pool while the high-efficiency camera averaged 65,219 counts/min/mCi and 41,427 counts/min/mCi, respectively. Compared to the planar calculation of LVEF, 1-minute SPECT LVEF was on average 8.6 +/- 10.7 higher, 2 minutes 3.5 +/- 7.6 higher, 3 minutes 2.9 +/- 8.5 higher, 4 minutes 2.5 +/- 7.0 higher, and 5 minutes 1.1 +/- 6.2 higher. Good correlation was seen between the SPECT LVEF's and the planar LVEF's across all acquisition times with correlation coefficients of 0.74 0.93. CONCLUSIONS: High-efficiency SPECT technology can reduce radiation exposure to patients during gated blood pool imaging or decrease acquisition time while maintaining diagnostic accuracy. Based on the improved count sensitivity with high-efficiency SPECT, a 50% reduction in injected activity may be achievable while maintaining short imaging times of 5 minutes, with further reduction possible at longer imaging times. PMID- 26231889 TI - Lipidomic data analysis: tutorial, practical guidelines and applications. AB - Lipids are a broad group of biomolecules involved in diverse critical biological roles such as cellular membrane structure, energy storage or cell signaling and homeostasis. Lipidomics is the -omics science that pursues the comprehensive characterization of lipids present in a biological sample. Different analytical strategies such as nuclear magnetic resonance or mass spectrometry with or without previous chromatographic separation are currently used to analyze the lipid composition of a sample. However, current analytical techniques provide a vast amount of data which complicates the interpretation of results without the use of advanced data analysis tools. The choice of the appropriate chemometric method is essential to extract valuable information from the crude data as well as to interpret the lipidomic results in the biological context studied. The present work summarizes the diverse methods of analysis than can be used to study lipidomic data, from statistical inference tests to more sophisticated multivariate analysis methods. In addition to the theoretical description of the methods, application of various methods to a particular lipidomic data set as well as literature examples are presented. PMID- 26231890 TI - Review of validation and reporting of non-targeted fingerprinting approaches for food authentication. AB - Food fingerprinting approaches are expected to become a very potent tool in authentication processes aiming at a comprehensive characterization of complex food matrices. By non-targeted spectrometric or spectroscopic chemical analysis with a subsequent (multivariate) statistical evaluation of acquired data, food matrices can be investigated in terms of their geographical origin, species variety or possible adulterations. Although many successful research projects have already demonstrated the feasibility of non-targeted fingerprinting approaches, their uptake and implementation into routine analysis and food surveillance is still limited. In many proof-of-principle studies, the prediction ability of only one data set was explored, measured within a limited period of time using one instrument within one laboratory. Thorough validation strategies that guarantee reliability of the respective data basis and that allow conclusion on the applicability of the respective approaches for its fit-for-purpose have not yet been proposed. Within this review, critical steps of the fingerprinting workflow were explored to develop a generic scheme for multivariate model validation. As a result, a proposed scheme for "good practice" shall guide users through validation and reporting of non-targeted fingerprinting results. Furthermore, food fingerprinting studies were selected by a systematic search approach and reviewed with regard to (a) transparency of data processing and (b) validity of study results. Subsequently, the studies were inspected for measures of statistical model validation, analytical method validation and quality assurance measures. In this context, issues and recommendations were found that might be considered as an actual starting point for developing validation standards of non-targeted metabolomics approaches for food authentication in the future. Hence, this review intends to contribute to the harmonization and standardization of food fingerprinting, both required as a prior condition for the authentication of food in routine analysis and official control. PMID- 26231891 TI - Introduction of organic/hydro-organic matrices in inductively coupled plasma optical emission spectrometry and mass spectrometry: a tutorial review. Part I. Theoretical considerations. AB - Due to their outstanding analytical performances, inductively coupled plasma optical emission spectrometry (ICP-OES) and mass spectrometry (ICP-MS) are widely used for multi-elemental measurements and also for isotopic characterization in the case of ICP-MS. While most studies are carried out in aqueous matrices, applications involving organic/hydro-organic matrices become increasingly widespread. This kind of matrices is introduced in ICP based instruments when classical "matrix removal" approaches such as acid digestion or extraction procedures cannot be implemented. Due to the physico-chemical properties of organic/hydro-organic matrices and their associated effects on instrumentation and analytical performances, their introduction into ICP sources is particularly challenging and has become a full topic. In this framework, numerous theoretical and phenomenological studies of these effects have been performed in the past, mainly by ICP-OES, while recent literature is more focused on applications and associated instrumental developments. This tutorial review, divided in two parts, explores the rich literature related to the introduction of organic/hydro-organic matrices in ICP-OES and ICP-MS. The present Part I, provides theoretical considerations in connection with the physico-chemical properties of organic/hydro-organic matrices, in order to better understand the induced phenomena. This focal point is divided in four chapters highlighting: (i) the impact of organic/hydro-organic matrices from aerosol generation to atomization/excitation/ionization processes; (ii) the production of carbon molecular constituents and their spatial distribution in the plasma with respect to analytes repartition; (iii) the subsequent modifications of plasma fundamental properties; and (iv) the resulting spectroscopic and non spectroscopic interferences. This first part of this tutorial review is addressed either to beginners or to more experienced scientists who are interested in the analysis of organic/hydro-organic matrices by ICP sources and would like to consider the theoretical background of effects induced by such matrices. The second part of this tutorial review will be dedicated to more practical consideration on instrumentation, such as adapted introductions devices, as well as instrumental and operating parameters optimization. The analytical strategies for elemental quantification in such matrices will also be addressed. PMID- 26231892 TI - Introduction of organic/hydro-organic matrices in inductively coupled plasma optical emission spectrometry and mass spectrometry: a tutorial review. Part II. Practical considerations. AB - Inductively coupled plasma optical emission spectrometry (ICP-OES) and mass spectrometry (ICP-MS) are increasingly used to carry out analyses in organic/hydro-organic matrices. The introduction of such matrices into ICP sources is particularly challenging and can be the cause of numerous drawbacks. This tutorial review, divided in two parts, explores the rich literature related to the introduction of organic/hydro-organic matrices in ICP sources. Part I provided theoretical considerations associated with the physico-chemical properties of such matrices, in an attempt to understand the induced phenomena. Part II of this tutorial review is dedicated to more practical considerations on instrumentation, instrumental and operating parameters, as well as analytical strategies for elemental quantification in such matrices. Two important issues are addressed in this part: the first concerns the instrumentation and optimization of instrumental and operating parameters, pointing out (i) the description, benefits and drawbacks of different kinds of nebulization and desolvation devices and the impact of more specific instrumental parameters such as the injector characteristics and the material used for the cone; and, (ii) the optimization of operating parameters, for both ICP-OES and ICP-MS. Even if it is at the margin of this tutorial review, Electrothermal Vaporization and Laser Ablation will also be shortly described. The second issue is devoted to the analytical strategies for elemental quantification in such matrices, with particular insight into the isotope dilution technique, particularly used in speciation analysis by ICP-coupled separation techniques. PMID- 26231893 TI - Innovative approach for the electrochemical detection of non-electroactive organophosphorus pesticides using oxime as electroactive probe. AB - An innovative approach for sensitive and simple electrochemical detection of non electroactive organophosphorus pesticides (OPs) was described in this report. The novel strategy emphasized the fabrication of an oxime-based sensor via attaching pralidoxime (PAM) on graphene quantum dots (GQDs) modified glassy carbon electrode. The introduction of GQDs significantly increased the effective electrode area, and then enlarged the immobilization quantity of PAM. Thus, the oxidation current of PAM was obviously increased. Relying on the nucleophilic substitution reaction between oxime and OPs, fenthion was detected using PAM as the electroactive probe. Under optimum conditions, the difference of oxidation current of PAM was proportional to fenthion concentration over the range from 1.0*10(-11)M to 5.0*10(-7)M with a detection limit of 6.8*10(-12)M (S/N=3). Moreover, the favorable detection performance in water and soil samples heralded the promising applications in on-site OPs detection. PMID- 26231894 TI - Nano polypyrrole-coated magnetic solid phase extraction followed by dispersive liquid phase microextraction for trace determination of megestrol acetate and levonorgestrel. AB - The aim of the present work is combination of the advantages of magnetic solid phase extraction (MSPE) and dispersive liquid phase microextraction (DLLME) followed by filtration-based phase separation. A new pretreatment method was developed for trace determination of megestrol acetate and levonorgestrel by liquid chromatography/ultraviolet detection in biological and wastewater samples. After magnetic solid phase extraction, the eluent of MSPE was used as the disperser solvent for DLLME. Emulsion resulted from DLLME procedure was passed through the in-line filter for phase separation. Finally the retained analytes in the filter was washed with mobile phase of liquid chromatography and transferred to the column for separation. This approach offers the preconcentration factors of 3680 and 3750 for megestrol acetate and levonorgestrel, respectively. This guarantees determination of the organic compounds at trace levels. The important parameters influencing the extraction efficiency were studied and optimized. Under the optimal extraction conditions, a linear range of 0.05-50ngmL(-1) (R(2)>0.998) and limit of detection of 0.03ngmL(-1) were obtained for megestrol acetate and levonorgestrel. Under optimal conditions, the method was successfully applied for determination of target analytes in urine and wastewater samples and satisfactory results were obtained (RSDs<6.8%). PMID- 26231895 TI - Selective extraction and release using (EDTA-Ni)-layered double hydroxide coupled with catalytic oxidation of 3,3',5,5'-tetramethylbenzidine for sensitive detection of copper ion. AB - Copper is an important heavy metal in various biological processes. Many methods have been developed for detecting of copper ions (Cu(2+)) in aqueous samples. However, an easy, cheap, selective and sensitive method is still desired. In this study, a selective extraction-release-catalysis approach has been developed for sensitive detection of copper ion. Ethylenediaminetetraacetic acid (EDTA) chelated with nickel ion (Ni(2+)) were intercalated in a layered double hydroxide via a co-precipitation reaction. The product was subsequently applied as sorbent in dispersive solid-phase extraction for the enrichment of Cu(2+) at pH 6. Since Cu(2+) has a stronger complex formation constant with EDTA, Ni(2+) exchanged with Cu(2+) selectively. The resulting sorbent containing Cu(2+) was transferred to catalyze the 3,3',5,5'-tetramethylbenzidine oxidation reaction, since Cu(2+) could be released by the sorbent effectively and has high catalytic ability for the reaction. Blue light emitted from the oxidation product was measured by ultraviolet-visible spectrophotometry for the determination of Cu(2+). The extraction temperature, extraction time, and catalysis time were optimized. The results showed that this method provided a low limit of detection of 10nM, a wide linear range (0.05-100MUM) and good linearity (r(2)=0.9977). The optimized conditions were applied to environmental water samples. Using Cu(2+) as an example, this work provided a new and interesting approach for the convenient and efficient detection of metal cations in aqueous samples. PMID- 26231896 TI - In-tube magnetic solid phase microextraction of some fluoroquinolones based on the use of sodium dodecyl sulfate coated Fe3O4 nanoparticles packed tube. AB - In-tube magnetic solid phase microextraction (in-tube MSPME) of fluoroquinolones from water and urine samples based on the use of sodium dodecyl sulfate (SDS) coated Fe3O4 nanoparticles packed tube has been reported. After the preparation of Fe3O4 nanoparticles (NPs) by a batch synthesis, these NPs were introduced into a stainless steel tube by a syringe and then a strong magnet was placed around the tube, so that the Fe3O4 NPs were remained in the tube and the tube was used in the in-tube SPME-HPLC/UV for the analysis of fluoroquinolones in water and urine samples. Plackett-Burman design was employed for screening the variables significantly affecting the extraction efficiency. Then, the significant factors were more investigated by Box-Behnken design. Calibration curves were linear (R(2)>0.990) in the range of 0.1-1000MUgL(-1) for ciprofloxacin (CIP) and 0.5 500MUgL(-1) for enrofloxacin (ENR) and ofloxacin (OFL), respectively. LODs for all studied fluoroquinolones ranged from 0.01 to 0.05MUgL(-1). The main advantages of this method were rapid and easy automation and analysis, short extraction time, high sensitivity, possibility of fully sorbent collection after analysis, wide linear range and no need to organic solvents in extraction. PMID- 26231897 TI - Development of counter current salting-out homogenous liquid-liquid extraction for isolation and preconcentration of some pesticides from aqueous samples. AB - In this paper, a new version of salting-out homogenous liquid-liquid extraction based on counter current mode combined with dispersive liquid-liquid microextraction has been developed for the extraction and preconcentration of some pesticides from aqueous samples and their determination by gas chromatography-flame ionization detection. In order to perform the method, aqueous solution of the analytes containing acetonitrile and 1,2-dibromoethane is transferred into a narrow bore tube which is filled partially with NaCl. During passing the solution through the tube, fine droplets of the organic phase are produced at the interface of solution and salt which go up through the tube and form a separated layer on the aqueous phase. The collected organic phase is removed and injected into de-ionized water for more enrichment of the analytes. Under the optimum extraction conditions, the method shows broad linear ranges for the target analytes. Enrichment factors and limits of detection for the selected pesticides are obtained in the ranges of 3480-3800 and 0.1-5MUgL(-1), respectively. Relative standard deviations are in the range of 2-7% (n=6, C=50 or 100MUgL(-1), each analyte). Finally, some aqueous samples were successfully analyzed using the developed method. PMID- 26231898 TI - Toehold-mediated DNA displacement-based surface-enhanced Raman scattering DNA sensor utilizing an Au-Ag bimetallic nanodendrite substrate. AB - A simple and sensitive surface enhanced Raman scattering (SERS)-based DNA sensor that utilizes the toehold-mediated DNA displacement reaction as a target capturing scheme has been demonstrated. For a SERS substrate, Au-Ag bimetallic nanodendrites were electrochemically synthesized and used as a sensor platform. The incorporation of both Ag and Au was employed to simultaneously secure high sensitivity and stability of the substrate. An optimal composition of Ag and Au that satisfied these needs was determined. A double-strand composed of 'a probe DNA (pDNA)' complementary to 'a target DNA (tDNA)' and 'an indicator DNA tagged with a Raman reporter (iDNA)' was conjugated on the substrate. The conjugation made the reporter molecule close to the surface and induced generation of the Raman signal. The tDNA released the pre-hybridized iDNA from the pDNA via toehold mediated displacement, and the displacement of the iDNA resulted in the decrease of Raman intensity. The variation of percent intensity change was sensitive and linear in the concentration range from 200fM to 20nM, and the achieved limit of detection (LOD) was 96.3fM, superior to those reported in previous studies that adopted different signal taggings based on such as fluorescence and electrochemistry. PMID- 26231899 TI - Evaluation of the oxidase like activity of nanoceria and its application in colorimetric assays. AB - Nanomaterial-based enzyme mimics have attracted considerable interest in chemical analysis as alternative catalysts to natural enzymes. However, the conditions in which such particles can replace biological catalysts and their selectivity and reactivity profiles are not well defined. This work explored the oxidase like properties of nanoceria particles in the development of colorimetric assays for the detection of dopamine and catechol. Selectivity of the system with respect to several phenolic compounds, the effect of interferences and real sample analysis are discussed. The conditions of use such as buffer composition, selectivity, pH, reaction time and particle type are defined. Detection limits of 1.5 and 0.2MUM were obtained with nanoceria for dopamine and catechol. The same assay could be used as a general sensing platform for the detection of other phenolics. However, the sensitivity of the method varies significantly with the particle type, buffer composition, pH and with the structure of the phenolic compound. The results demonstrate that nanoceria particles can be used for the development of cost effective and sensitive methods for the detection of these compounds. However, the selection of the particle system and experimental conditions is critical for achieving high sensitivity. Recommendations are provided on the selection of the particle system and reaction conditions to maximize the oxidase like activity of nanoceria. PMID- 26231900 TI - Influence of the settling of the resin beads on diffusion gradients in thin films measurements. AB - Binding resin beads used in DGT (diffusion gradients in thin films) tend to settle to one side of the resin during casting. This phenomenon might be relevant for metal accumulation when partially labile complexes dominate the metal speciation, especially after recognizing the important role played by complex dissociation in the resin domain. The influence of the inhomogeneity of the binding agent distribution on metal accumulation is here assessed by numerical simulation of DGT devices with binding beads in only one half of the resin disc, as a reasonable model of the standard resin discs. Results indicate that a decrease in mass accumulation of less than 13% can arise in these inhomogeneous devices (as compared with an ideal disc with homogeneous dispersion of the resin beads) when complexes with stability constant K<10(2)m(3)mol(-1) (K<10(5)Lmol( 1)) dominate the metal speciation. The loss increases as K increases, but the percentage of mass loss always remains lower than the volume fraction of resin disc without beads. For very labile or inert complexes, the impact of the inhomogeneous distribution of binding resin beads is negligible. As kinetic dissociation constants of complexes can be estimated from the distribution of the metal accumulation in a DGT device with a stack of two resin discs, the influence of the inhomogeneity on the recovered kinetic constant is also assessed. For the cases studied, the recovered kinetic dissociation constant, kd,recovered, retains the correct order of magnitude, being related to the true kd by kd~f( 1)kd,recovered, quite independently of K and kd values, being f the fraction of volume of the resin disc where resin beads are dispersed. PMID- 26231901 TI - Ratiometric fluorescence transduction by hybridization after isothermal amplification for determination of zeptomole quantities of oligonucleotide biomarkers with a paper-based platform and camera-based detection. AB - Paper is a promising platform for the development of decentralized diagnostic assays owing to the low cost and ease of use of paper-based analytical devices (PADs). It can be challenging to detect on PADs very low concentrations of nucleic acid biomarkers of lengths as used in clinical assays. Herein we report the use of thermophilic helicase-dependent amplification (tHDA) in combination with a paper-based platform for fluorescence detection of probe-target hybridization. Paper substrates were patterned using wax printing. The cellulosic fibers were chemically derivatized with imidazole groups for the assembly of the transduction interface that consisted of immobilized quantum dot (QD)-probe oligonucleotide conjugates. Green-emitting QDs (gQDs) served as donors with Cy3 as the acceptor dye in a fluorescence resonance energy transfer (FRET)-based transduction method. After probe-target hybridization, a further hybridization event with a reporter sequence brought the Cy3 acceptor dye in close proximity to the surface of immobilized gQDs, triggering a FRET sensitized emission that served as an analytical signal. Ratiometric detection was evaluated using both an epifluorescence microscope and a low-cost iPad camera as detectors. Addition of the tHDA method for target amplification to produce sequences of ~100 base length allowed for the detection of zmol quantities of nucleic acid targets using the two detection platforms. The ratiometric QD-FRET transduction method not only offered improved assay precision, but also lowered the limit of detection of the assay when compared with the non-ratiometric QD-FRET transduction method. The selectivity of the hybridization assays was demonstrated by the detection of single nucleotide polymorphism. PMID- 26231902 TI - A repeatable assembling and disassembling electrochemical aptamer cytosensor for ultrasensitive and highly selective detection of human liver cancer cells. AB - In this work, a repeatable assembling and disassembling electrochemical aptamer cytosensor was proposed for the sensitive detection of human liver hepatocellular carcinoma cells (HepG2) based on a dual recognition and signal amplification strategy. A high-affinity thiolated TLS11a aptamer, covalently attached to a gold electrode through Au-thiol interactions, was adopted to recognize and capture the target HepG2 cells. Meanwhile, the G-quadruplex/hemin/aptamer and horseradish peroxidase (HRP) modified gold nanoparticles (G-quadruplex/hemin/aptamer-AuNPs HRP) nanoprobe was designed. It could be used for electrochemical cytosensing with specific recognition and enzymatic signal amplification of HRP and G quadruplex/hemin HRP-mimicking DNAzyme. With the nanoprobes as recognizing probes, the HepG2 cancer cells were captured to fabricate an aptamer-cell nanoprobes sandwich-like superstructure on a gold electrode surface. The proposed electrochemical cytosensor delivered a wide detection range from 1*10(2) to 1*10(7) cells mL(-1) and high sensitivity with a low detection limit of 30 cells mL(-1). Furthermore, after the electrochemical detection, the activation potential of -0.9 to -1.7V was performed to break Au-thiol bond and regenerate a bare gold electrode surface, while maintaining the good characteristic of being used repeatedly. The changes of gold electrode behavior after assembling and desorption processes were investigated by electrochemical impedance spectroscopy and cyclic voltammetry techniques. These results indicate that the cytosensor has great potential in disease diagnostic of cancers and opens new insight into the reusable gold electrode with repeatable assembling and disassembling in the electrochemical sensing. PMID- 26231904 TI - Determination of organophosphate flame retardants and plasticizers in lipid-rich matrices using dispersive solid-phase extraction as a sample cleanup step and ultra-high performance liquid chromatography with atmospheric pressure chemical ionization mass spectrometry. AB - A fast, robust and highly sensitive analysis method for determination of trace levels of organophosphate ester (OPE) flame retardants and plasticizers in lipid rich samples was presently developed, and based on ultra-high performance liquid chromatography-tandem mass spectrometry coupled to a positive atmospheric pressure chemical ionization source (UHPLC-MS/MS-APCI(+)). The target OPEs in the sample were extracted from the biota samples, such as egg and liver, by ultrasonic extraction, and cleaned up further by dispersive solid phase extraction (d-ESP). As a result, background contamination was largely reduced. Different dispersive ESP sorbents were tested and primary secondary amine (PSA) bonded silica sorbents showed the best recoveries for these target OPEs. The recoveries obtained were in the range 54-113% (RSD<17%), with method limits of quantification (MLOQs) ranging between 0.06 and 0.29ng/g in egg, and 0.05 and 0.50ng/g w.w. in liver sample. The matrix effects (MEs) associated with using APCI(+) and ESI(+) sources were investigated. APCI(+) showed much less ion suppression than ESI(+) for the determination of these OPEs. For egg and liver samples, the APCI(+) ME values ranged from 40% to 94%, while ESI(+) ME values ranged from 0% to 36%. Although APCI(+) was used for the determination of OPEs, the ionization mechanism might mainly be a thermospray ionization process. This UHPLC-MS/MS-APCI(+) method showed good response linearity for calibration (R2>0.99). The proposed method was applied to real environmental bird egg and fish samples, where several OPE were quantifiable and different OPE patterns was observed between samples. PMID- 26231903 TI - Diastereo- and enantioseparation of a N(alpha)-Boc amino acid with a zwitterionic quinine-based stationary phase: focus on the stereorecognition mechanism. AB - A chiral chromatography method enabling the simultaneous diastereo- and enantioseparation of N(alpha)-Boc-N(4)-(hydroorotyl)-4-aminophenylalanine [Boc Aph(Hor)-OH, 1] was optimized with a quinine-based zwitterionic stationary phase. The polar-ionic eluent system consisting of ACN:MeOH:water-49.7:49.7:0.6 (v/v/v) with formic acid (4.0mM) and diethylamine (2.5mM), allowed the successful separation of the four acid stereoisomers: alphad,d-/d,l-1=1.08; alphad,l-/l,d 1=1.08; alphal,d-/l,l-1=1.40. According to the in-house developed synthetic procedure and the recorded electronic circular dichroism spectra, the following stereoisomeric elution order was readily established in the optimal chromatographic conditions: d,d-199.9% less than 10 MUm diameter) generated by a wear simulator for 24 h. T cell phenotype was assessed by immunostaining and secretion of 8 different pro- and anti-inflammatory cytokines was measured using multiplex technology. Clear differences were seen between individuals in the induction of Th17 and Th1 responses, with some donors showing pro-inflammatory responses (increased IL17 or IFNgamma) and others showing anti-inflammatory responses (decreased IL17 or IFNgamma). The only differences seen for gender and age related to increased IL-10 expression from T cells in females (p = 0.008) and a trend towards decreased IL-6 expression systemically for older donors (p = 0.058). We conclude that individuals show differential responses to CoCrMo wear debris and that these responses could give early indications of the suitability of the patient for a metal-on-metal prosthesis. PMID- 26231915 TI - In vitro myogenesis induced by human recombinant elastin-like proteins. AB - Mammalian adult skeletal muscle has a limited ability to regenerate after injury, usage or trauma. A promising strategy for successful regenerative technology is the engineering of bio interfaces that mimic the characteristics of the extracellular matrix. Human elastin-like polypeptides (HELPs) have been synthesized as biomimetic materials that maintain some peculiar properties of the native protein. We developed a novel Human Elastin Like Polypeptide obtained by fusing the elastin-like backbone to a domain present in the alpha2 chain of type IV collagen, containing two RGD motives. We employed this peptide as adhesion substrate for C2C12 myoblasts and compared its effects to those induced by two other polypeptides of the HELP series. Myoblast adhered to all HELPs coatings, where they assumed morphology and cytoarchitecture that depended on the polypeptide structure. Adhesion to HELPs stimulated at a different extent cell proliferation and differentiation, the expression of Myosin Heavy Chain and the fusion of aligned fibers into multinucleated myotubes. Adhesion substrates significantly altered myotubes stiffness, measured by Atomic Force Microscopy, and differently affected the cells Ca(2+) handling capacity and the maturation of excitation-contraction coupling machinery, evaluated by Ca(2+) imaging. Overall, our findings indicate that the properties of HELP biopolymers can be exploited for dissecting the molecular connections underlying myogenic differentiation and for designing novel substrates for skeletal muscle regeneration. PMID- 26231916 TI - Macroporous thin membranes for cell transplant in regenerative medicine. AB - The aim of this paper is to present a method to produce macroporous thin membranes made of poly (ethyl acrylate-co-hydroxyethyl acrylate) copolymer network with varying cross-linking density for cell transplantation and prosthesis fabrication. The manufacture process is based on template techniques and anisotropic pore collapse. Pore collapse was produced by swelling the membrane in acetone and subsequently drying and changing the solvent by water to produce 100 microns thick porous membranes. These very thin membranes are porous enough to hold cells to be transplanted to the organism or to be colonized by ingrowth from neighboring tissues in the organism, and they present sufficient tearing stress to be sutured with surgical thread. The obtained pore morphology was observed by Scanning Electron Microscope, and confocal laser microscopy. Mechanical properties were characterized by stress-strain experiments in tension and tearing strength measurements. Morphology and mechanical properties were related to the different initial thickness of the scaffold and the cross-linking density of the polymer network. Seeding efficiency and proliferation of mesenchymal stem cells inside the pore structure were determined at 2 h, 1, 7, 14 and 21 days from seeding. PMID- 26231917 TI - 3D printing of layered brain-like structures using peptide modified gellan gum substrates. AB - The brain is an enormously complex organ structured into various regions of layered tissue. Researchers have attempted to study the brain by modeling the architecture using two dimensional (2D) in vitro cell culturing methods. While those platforms attempt to mimic the in vivo environment, they do not truly resemble the three dimensional (3D) microstructure of neuronal tissues. Development of an accurate in vitro model of the brain remains a significant obstacle to our understanding of the functioning of the brain at the tissue or organ level. To address these obstacles, we demonstrate a new method to bioprint 3D brain-like structures consisting of discrete layers of primary neural cells encapsulated in hydrogels. Brain-like structures were constructed using a bio-ink consisting of a novel peptide-modified biopolymer, gellan gum-RGD (RGD-GG), combined with primary cortical neurons. The ink was optimized for a modified reactive printing process and developed for use in traditional cell culturing facilities without the need for extensive bioprinting equipment. Furthermore the peptide modification of the gellan gum hydrogel was found to have a profound positive effect on primary cell proliferation and network formation. The neural cell viability combined with the support of neural network formation demonstrated the cell supportive nature of the matrix. The facile ability to form discrete cell-containing layers validates the application of this novel printing technique to form complex, layered and viable 3D cell structures. These brain-like structures offer the opportunity to reproduce more accurate 3D in vitro microstructures with applications ranging from cell behavior studies to improving our understanding of brain injuries and neurodegenerative diseases. PMID- 26231919 TI - Reply to: Diagnosing appendicitis with serum bilirubin level: Is there any problem? PMID- 26231918 TI - 2-fluoro-RNA oligonucleotide CD40 targeted aptamers for the control of B lymphoma and bone-marrow aplasia. AB - Recent studies have underscored the importance of immunomodulatory antibodies in the treatment of solid and hematological tumors. ODN-Aptamers are rising as a novel class of drugs that can rival therapeutic antibodies. The success of some of the current cancer immunotherapy approaches in oncological patients depends on the intrinsic antigenicity of each tumor as has recently been disclosed, and it is hampered in those patients that are treated with myeloablative chemotherapy or radiotherapy, which induce profound immunosuppression. CD40 agonist and antagonist molecules offer a new therapeutic alternative which has the potential to generate anticancer effects by different mechanisms. HS-SELEX was performed to identify high-affinity aptamers against CD40, and three therapeutic CD40 constructs were engineered as: CD40 agonist aptamer, CD40 antagonist aptamer and CD40 agonistic aptamer-shRNA chimera. It is shown that CD40 agonist aptamers can be used to promote bone-marrow aplasia recovery. CD40 antagonist aptamers are revealed to have a direct antitumor effect on CD40-expressing B-cell lymphoma in vitro and in vivo. Further, in order to identify a therapeutic reagent that will generate the optimal conditions for cancer immunotherapy (antigen-presenting cell activation, tumor antigenicity enhancement and bone-marrow aplasia recovery), CD40 agonist aptamer-shRNA chimera was generated to target the inhibition of the Nonsense mRNA Mediated Decay (NMD) to tumor cells. PMID- 26231920 TI - Comparative study of sentinel lymph node biopsy in clinically N0 oral tongue squamous cell carcinoma: Long-term oncologic outcomes between validation and application phases. AB - OBJECTIVE: This study tested the long-term outcomes of sentinel lymph node biopsy (SLNB) for oral tongue squamous cell carcinoma (SCC) during the transition from validation to application phase. MATERIALS AND METHODS: Sensitivity, negative predictive value (NPV), neck control rate, disease-specific survival (DSS), disease-free survival (DFS), and overall survival (OS) were compared in cN0 oral tongue SCC patients from different phases. RESULTS: A total of 133 SLNs from 61 patients (21 in the validation phase, 40 in the application phase) were harvested. Fourteen SLNs of 12 patients (6 in each phase) were positive for metastasis (occult metastasis rate, 19.6%). Regional recurrences developed from 5 negative SLNs (one in the validation phase, 4 in the application phase), of whom 3 patients were successfully salvaged. Sensitivity and NPV of the validation phase were both 100%, with 60.0% and 88.2% in the application phase. False omission rates were 6.6% (1/15) in the validation group, and 11.7% (4/34) in the application group, respectively. The neck control rate was 95.2% in the validation phase and 97.5% in the application phase (p=0.52). No differences were evident in DSS, DFS, and OS between the two phases (DSS: 92.5% vs 95.2%, p=0.69; DFS: 85.0% vs 90.4%, p=0.40; OS: 90% vs 85.5%, p=0.62). Subgroup analyses between negative- and positive-SLNs within each phase revealed no significant differences in all endpoints. CONCLUSION: Given higher false negative cases in the application phase, stringent strategy of follow-up and salvage treatment is mandatory to maintain acceptable outcomes. PMID- 26231921 TI - Cold tolerance of the montane Sierra leaf beetle, Chrysomela aeneicollis. AB - Small ectothermic animals living at high altitude in temperate latitudes are vulnerable to lethal cold throughout the year. Here we investigated the cold tolerance of the leaf beetle Chrysomela aeneicollis living at high elevation in California's Sierra Nevada mountains. These insects spend over half their life cycle overwintering, and may therefore be vulnerable to winter cold, and prior studies have demonstrated that survival is reduced by exposure to summertime cold. We identify overwintering microhabitat of this insect, describe cold tolerance strategies in all life stages, and use microclimate data to determine the importance of snow cover and microhabitat buffering for overwinter survival. Cold tolerance varies among life history stages and is typically correlated with microhabitat temperature: cold hardiness is lowest in chill-susceptible larvae, and highest in freeze-tolerant adults. Hemolymph osmolality is higher in quiescent (overwintering) than summer adults, primarily, but not exclusively, due to elevated hemolymph glycerol. In nature, adult beetles overwinter primarily in leaf litter and suffer high mortality if early, unseasonable cold prevents them from entering this refuge. These data suggest that cold tolerance is tightly linked to life stage. Thus, population persistence of montane insects may become problematic as climate becomes more unpredictable and climate change uncouples the phenology of cold tolerance and development from the timing of extreme cold events. PMID- 26231922 TI - Preovulatory follicle diameter, growth rate and time of ovulation during induced oestrus using a CIDR(r) in trypanotolerant female Bos taurus N'Dama cattle. AB - The aim of this study was to assess the dose (300 to 600 IU) effects of equine chorionic gonadotropin (eCG) on the preovulatory follicle diameter, growth rate and time of ovulation characterized by echography. The eCG was injected at the end (D0) of the 7-day treatment with a controlled internal device release (CIDR(r)) and a PGF2alpha being injected 2 days before the removal of the CIDR(r) (d-2). The 120 N'Dama female were distributed into five experimental groups. The control group (n = 26) was treated with physiological saline at the removal of the CIDR(r), while the animals in the four treated groups received, respectively, 300 IU (n = 25), 400 IU (n = 24), 500 IU (n = 22) and 600 IU (n = 23) of eCG. The diameter of the preovulatory follicle was significantly higher (P < 0.05) in the animals treated with 300 IU (10.1 +/- 1.4 mm) than in untreated animals (9.3 +/- 1.2 mm). Follicle growth rate was significantly (P < 0.05) higher in treated animals (1.0 +/- 0.4 mm/day) than in the control group (0.9 +/- 0.4 mm/day). The average interval between the time of eCG injection and ovulation was similar in the non-treated (83.7 +/- 14.4 h) and treated animals (79.7 +/- 11.9). Treated animals showed a significant increase in the percentage of ovulation (94.7 % compared to 73.1 %) (P < 0.01). Use of eCG contributed towards synchronising the time of ovulation between 72 to 96 h, which would facilitate the use of systematic insemination. PMID- 26231924 TI - The Leishmania donovani peroxin 14 binding domain accommodates a high degeneracy in the pentapeptide motifs present on peroxin 5. AB - BACKGROUND: The glycosome is a unique organelle found in Kinetoplastids known to compartmentalize vital metabolic pathways including glycolysis, beta-fatty acid oxidation and purine salvage. Organelle biogenesis depends on a network of proteins for trafficking and translocation of nascent protein into the glycosome. The interaction of the proteins LdPEX14 and LdPEX5 at the glycosome membrane is crucial for targeting proteins into this organelle. METHODS: Deletion mutagenesis, pull-down, and bacterial two hybrid assay were used to map the LdPEX5 domain bound by LdPEX14. ELISA assays, ITC, intrinsic fluorescence and size exclusion chromatography to monitor binding and structural changes associated with the LdPEX5-LdPEX14 interaction. RESULTS AND CONCLUSIONS: The LdPEX14 binding site was mapped to residues 280-300 on LdPEX5, a region containing the pentapeptide motif W(293)AQEY(297). Deletion of this region abolished the LdPEX5-LdPEX14 interaction. Intrinsic fluorescence spectroscopy suggests that the stabilization of the LdPEX5-LdPEX14 complex is dependent on W293 docking into a hydrophobic pocket within the binding domain of ldpex14. Studies using a panel of synthetic peptides suggest a critical role for Y297 and to a lesser extent E296 in stabilizing the LdPEX5-LdPEX14 association. GENERAL SIGNIFICANCE: We show that the LdPEX14 binding site is more promiscuous and in contrast to other eukaryotic systems will accommodate a more degenerate pentapeptide motif with the sequences WXXXW or FXXXF, findings which may be exploited for potential drug design. PMID- 26231923 TI - Functional characterization of zebrafish cytochrome P450 1 family proteins expressed in yeast. AB - BACKGROUND: Zebrafish express five cytochrome P450 1 genes: CYP1A, CYP1B1, CYP1C1, CYP1C2, inducible by aryl hydrocarbon receptor agonists, and CYP1D1, a constitutively expressed CYP1A-like gene. We examined substrate selectivity of CYP1s expressed in yeast. METHODS: CYP1s were expressed in W(R) yeast, engineered to over-express P450 reductase, via pYES/DEST52 and via pYeDP60. Microsomal fractions from transformed yeast were examined for activity with fluorogenic substrates, benzo[a]pyrene and testosterone. Modeling and docking approaches were used to further evaluate sites of oxidation on benzo[a]pyrene and testosterone. RESULTS: CYP1s expressed in yeast dealkylated ethoxy-, methoxy-, pentoxy- and benzoxy-resorufin (EROD, MROD, PROD, BROD). CYP1A and CYP1C2 had the highest rates of EROD activity, while PROD and BROD activities were low for all five CYP1s. The relative rates of resorufin dealkylation by CYP1C1, CYP1C2 and CYP1D1 expressed via pYeDP60 were highly similar to relative rates obtained with pYES/DEST52-expressed enzymes. CYP1C1 and CYP1C2 dealkylated substituted coumarins and ethoxy-fluorescein-ethylester, while CYP1D1 did not. The CYP1Cs and CYP1D1 co-expressed with epoxide hydrolase oxidized BaP with different rates and product profiles, and all three produced BaP-7,8,9,10-tetrol. The CYP1Cs but not CYP1D1 metabolized testosterone to 6beta-OH-testosterone. However, CYP1D1 formed an unidentified testosterone metabolite better than the CYP1Cs. Testosterone and BaP docked to CYP homology models with poses consistent with differing product profiles. CONCLUSIONS: Yeast-expressed zebrafish CYP1s will be useful in determining further functionality with endogenous and xenobiotic compounds. GENERAL SIGNIFICANCE: Determining the roles of zebrafish CYP1s in physiology and toxicology depends on knowing the substrate selectivity of these enzymes. PMID- 26231925 TI - Comparison in dietary patterns derived for the Canadian Newfoundland and Labrador population through two time-separated studies. AB - BACKGROUND: While a dietary pattern is often believed to be stable in a population, there is limited research assessing its stability over time. The objective of this study is to explore and compare major dietary patterns derived for the Canadian subpopulation residing in Newfoundland and Labrador (NL), through two time-separated studies using an identical method. METHODS: In this study, we derived and compared the major dietary patterns derived from two independent studies in the NL adult population. The first study was based on the healthy controls from a large population-based case-control study (CCS) in 2005. The second was from a food-frequency questionnaire validation project (FFQVP) conducted in 2012. In both studies, participants were recruited in the same manner and dietary information was collected by an identical self-administered food-frequency questionnaire (FFQ). Exploratory common factor analysis was conducted to identify major dietary patterns. A comparison was conducted between the two study populations. RESULTS: Four major dietary patterns were identified: Meat, Vegetables/fruits, Fish, and Grains explaining 22%, 20%, 12% and 9% variance respectively, with a total variance of 63%. Three major dietary patterns were derived for the controls of the CCS: Meat, Plant-based diet, and Fish explaining 24%, 20%, and 10% variance respectively, with a total variance of 54%. As the Plant-based diet pattern derived for the CCS was a combination of the Vegetables/fruits and Grains patterns derived for the FFQVP, no considerable difference in dietary patterns was found between the two studies. CONCLUSION: A comparison between two time-separated studies suggests that dietary patterns of the NL adult population have remained reasonably stable over almost a decade. PMID- 26231926 TI - Assessment of CCL2 and CXCL8 chemokines in serum, bronchoalveolar lavage fluid and lung tissue samples from dogs affected with canine idiopathic pulmonary fibrosis. AB - Canine idiopathic pulmonary fibrosis (CIPF) is a progressive disease of the lung parenchyma that is more prevalent in dogs of the West Highland white terrier (WHWT) breed. Since the chemokines (C-C motif) ligand 2 (CCL2) and (C-X-C motif) ligand 8 (CXCL8) have been implicated in pulmonary fibrosis in humans, the aim of the present study was to investigate whether these same chemokines are involved in the pathogenesis of CIPF. CCL2 and CXCL8 concentrations were measured by ELISA in serum and bronchoalveolar lavage fluid (BALF) from healthy dogs and WHWTs affected with CIPF. Expression of the genes encoding CCL2 and CXCL8 and their respective receptors, namely (C-C motif) receptor 2 (CCR2) and (C-X-C motif) receptor 2 (CXCR2), was compared in unaffected lung tissue and biopsies from dogs affected with CIPF by quantitative PCR and localisation of CCL2 and CXCL8 proteins were determined by immunohistochemistry. Significantly greater CCL2 and CXCL8 concentrations were found in the BALF from WHWTs affected with CIPF, compared with healthy dogs. Significantly greater serum concentrations of CCL2, but not CXCL8, were found in CIPF-affected dogs compared with healthy WHWTs. No differences in relative gene expression for CCL2, CXCL8, CCR2 or CXCR2 were observed when comparing lung biopsies from control dogs and those affected with CIPF. In affected lung tissues, immunolabelling for CCL2 and CXCL8 was observed in bronchial airway epithelial cells in dogs affected with CIPF. The study findings suggest that both CCL2 and CXCL8 are involved in the pathogenesis of CIPF. Further studies are required to determine whether these chemokines might have a clinical use as biomarkers of fibrosis or as targets for therapeutic intervention. PMID- 26231927 TI - Cardiac T2-mapping using a fast gradient echo spin echo sequence - first in vitro and in vivo experience. AB - BACKGROUND: The aim of this study was the evaluation of a fast Gradient Spin Echo Technique (GraSE) for cardiac T2-mapping, combining a robust estimation of T2 relaxation times with short acquisition times. The sequence was compared against two previously introduced T2-mapping techniques in a phantom and in vivo. METHODS: Phantom experiments were performed at 1.5 T using a commercially available cylindrical gel phantom. Three different T2-mapping techniques were compared: a Multi Echo Spin Echo (MESE; serving as a reference), a T2-prepared balanced Steady State Free Precession (T2prep) and a Gradient Spin Echo sequence. For the subsequent in vivo study, 12 healthy volunteers were examined on a clinical 1.5 T scanner. The three T2-mapping sequences were performed at three short-axis slices. Global myocardial T2 relaxation times were calculated and statistical analysis was performed. For assessment of pixel-by-pixel homogeneity, the number of segments showing an inhomogeneous T2 value distribution, as defined by a pixel SD exceeding 20 % of the corresponding observed T2 time, was counted. RESULTS: Phantom experiments showed a greater difference of measured T2 values between T2prep and MESE than between GraSE and MESE, especially for species with low T1 values. Both, GraSE and T2prep resulted in an overestimation of T2 times compared to MESE. In vivo, significant differences between mean T2 times were observed. In general, T2prep resulted in lowest (52.4 +/- 2.8 ms) and GraSE in highest T2 estimates (59.3 +/- 4.0 ms). Analysis of pixel-by-pixel homogeneity revealed the least number of segments with inhomogeneous T2 distribution for GraSE-derived T2 maps. CONCLUSIONS: The GraSE sequence is a fast and robust sequence, combining advantages of both MESE and T2prep techniques, which promises to enable improved clinical applicability of T2-mapping in the future. Our study revealed significant differences of derived mean T2 values when applying different sequence designs. Therefore, a systematic comparison of different cardiac T2-mapping sequences and the establishment of dedicated reference values should be the goal of future studies. PMID- 26231928 TI - Airflow limitation in COPD is associated with increased left ventricular wall stress in coincident heart failure. AB - BACKGROUND: COPD and heart failure occur with a considerable coincidence. Beside well-known mechanisms of increased right heart load in COPD, dedicated changes of the left ventricle (LV) are ill-defined and the question remains, whether specific interactions exist beyond common shared risk factors. METHODS: LV wall stress was calculated based on cardiac magnetic resonance imaging in 28 patients with COPD (GOLD I to III) and coexistent heart failure (LVEF 42 +/- 19%) due to non-ischaemic and ischaemic cardiomyopathy. RESULTS: LV enddiastolic (p = 0.048) and endsystolic wall stress (p = 0.034) increased from GOLD stage I to III. Reduced FEV1 was correlated with increased enddiastolic (p = 0.0210) and endsystolic LV volume (p = 0.0413) and with increased enddiastolic (p = 0.0161) and endsystolic LV wall stress (p = 0.0315), respectively. Increased wall stress was associated with a decreased FEV1/FVC ratio. CONCLUSIONS: The severity of airflow limitation in COPD was correlated with increased LV wall stress. It is suggested that respiration in pulmonary obstruction is associated with an increased negative intrathoracic pressure when compared with normal lung function, which is transmitted to the heart and increases the transmural pressure gradient and thereby distending forces on the heart. Increased ventricular wall stress is known to be associated with a broad variety of unfavourable consequences, which should be taken into account to contribute to a worse prognosis in COPD. PMID- 26231930 TI - Principles of Cancer Staging for Clinical Obstetrics and Gynecology. AB - Cancer represents a complex group of diseases characterized by uncontrolled growth and the ability to metastasize. Cancer may affect any part of the body, and within the female reproductive systems, there exist a variety of cancers each associated with different presenting symptoms, clinical course, etiology, and natural history of disease. The essential features of each cancer include the presenting site of disease (topography), the histopathologic (morphology), molecular and genetic tumor profile, and the anatomic disease extent (stage). Without knowing these features, it is impossible to discuss investigation, treatment, and prognosis in cancer. PMID- 26231929 TI - Innovation in catheter design for intra-arterial liver cancer treatments results in favorable particle-fluid dynamics. AB - BACKGROUND: Liver tumors are increasingly treated with radioembolization. Here, we present first evidence of catheter design effect on particle-fluid dynamics and downstream branch targeting during microsphere administrations. MATERIALS AND METHODS: A total of 7 experiments were performed in a bench-top model of the hepatic arterial vasculature with recreated hemodynamics. Fluorescent microspheres and clinically used holmium microspheres were administered with a standard microcatheter (SMC) and an anti-reflux catheter (ARC) positioned at the same level along the longitudinal vessel axis. Catheter-related particle flow dynamics were analyzed by reviewing video recordings of UV-light illuminated fluorescent microsphere administrations. Downstream branch distribution was analyzed by quantification of collected microspheres in separate filters for two first-order branches. Mean deviation from a perfectly homogenous distribution (DHD) was used to compare the distribution homogeneity between catheter types. RESULTS: The SMC administrations demonstrated a random off-centered catheter position (in 71 % of experiments), and a laminar particle flow pattern with an inhomogeneous downstream branch distribution, dependent on catheter position and injection force. The ARC administrations demonstrated a fixed centro-luminal catheter position, and a turbulent particle flow pattern with a more consistent and homogenous downstream branch distribution. Quantitative analyses confirmed a significantly more homogeneous distribution with the ARC; the mean DHD was 40.85 % (IQR 22.76 %) for the SMC and 15.54 % (IQR 6.46 %) for the ARC (p = 0.047). CONCLUSION: Catheter type has a significant impact on microsphere administrations in an in-vitro hepatic arterial model. A within-patient randomized controlled trial has been initiated to investigate clinical catheter-related effects during radioembolization treatment. PMID- 26231931 TI - Synergy of two human endogenous retroviruses in multiple myeloma. AB - Multiple myeloma (MM) is a severe, incurable neoplasm of the plasma cells. In this study we have used genetic epidemiology to associate the risk of MM with endogenous retroviral loci in humans. We used SNP analysis on a Sequenom platform and statistical analysis in SPSS. Markers near two endogenous retroviral loci, HERV-Fc1 on chromosome X and HERV-K on chromosome 1, were associated with MM. Moreover, there was strong gene-gene interaction in relation to risk of MM. We take this as indirect confirmation of the association. PMID- 26231932 TI - [High recurrence and good functional results after arthroscopic resection of pigmented villonodular synovitis]. AB - INTRODUCTION: Pigmented villonodular synovitis (PVS) is a synovial proliferation disorder of uncertain aetiology, with some controversy as regards its proper treatment. The purpose of the study was to evaluate the functional outcome and recurrence rate in a series of patients diagnosed with both the diffuse and the localised type of PVS and treated by arthroscopic resection. MATERIAL AND METHODS: Twenty-four patients diagnosed with PVS were retrospectively assessed. There were 11 cases with the diffuse type, and 13 cases with the localised type of PVS. They were followed-up for a median of 60 months (range, 34-204). They underwent arthroscopic synovectomy, and were functionally evaluated with IKDC, WOMET, and Kujala scores. RESULTS: There was recurrence in 8 out of 13 (61.5%) cases with the diffuse type of PVS. Two of these patients were treated with radiation. One patient underwent surgical resection with an open procedure due to extra-articular involvement. The remaining 5 patients underwent a second arthroscopic resection, and no recurrence was subsequently observed. Cases with localised PVS did not recur after a single arthroscopic resection. IKDC, WOMET and Kujala scores improved by 30.6, 37.4 and 34.03 points, respectively. DISCUSSION: Pigmented villonodular synovitis treated by arthroscopic resection showed good functional results at mid-term follow-up. A single arthroscopic resection was sufficient to treat the localised PVS, whereas the diffuse type of PVS required a second arthroscopic resection in most cases, due to its high rate of recurrence. PMID- 26231933 TI - In situ Fourier transform infrared analysis of live cells' response to doxorubicin. AB - The study of the response of cancer cells to chemotherapy drugs is of high importance due to the specificity of some drugs to certain types of cancer and the resistance of some specific cancer types to chemotherapy drugs. Our aim was to develop and apply the label-free and non-destructive Fourier transform infrared (FTIR) method to determine the sensitivity of three different cancer cell-lines to a common anti-cancer drug doxorubicin at different concentrations and to demonstrate that information about the mechanism of resistance to the chemotherapy drug can be extracted from spectral data. HeLa, PC3, and Caco-2 cells were seeded and grown on an attenuated total reflection (ATR) crystal, doxorubicin was applied at the clinically significant concentration of 0.1-20 MUM, and spectra of the cells were collected hourly over 20 h. Analysis of the amide bands was correlated with cell viability, which had been cross validated with MTT assays, allowing to determine that the three cell lines had significantly different resistance to doxorubicin. The difference spectra and principal component analysis (PCA) highlighted the subtle chemical changes in the living cells under treatment. Spectral regions assigned to nucleic acids (mainly 1085 cm(-1)) and carbohydrates (mainly 1024 cm(-1)) showed changes that could be related to the mode of action of the drug and the mechanism of resistance of the cell lines to doxorubicin. This is a cost-effective method that does not require bioassay reagents but allows label-free, non-destructive and in situ analysis of chemical changes in live cells, using standard FTIR equipment adapted to ATR measurements. PMID- 26231934 TI - Application of phenol red as a marker ligand for bilirubin binding site at subdomain IIA on human serum albumin. AB - The drug-bilirubin interaction for all drugs administered especially to infants with hyperbilirubinemia should be evaluated for their ability to displace bilirubin and vice versa. In order to examine whether phenol red (PhRed) can be used as a marker for bilirubin binding site located in subdomain IIA the interaction between PhRed and human serum albumin (HSA) in buffer solution or in normal and pathological sera solutions with different HSA:bilirubin molar ratio was investigated using absorption/absorption difference spectroscopy and molecular docking method. Six sulfonamides representing the binding site in the subdomain IIA and known to influence the binding of bilirubin were used for the PhRed displacement studies. The absorption spectra for PhRed completely bound to HSA showed significant differences in the spectral characteristic relative to the spectral profile of free PhRed. The intensity of the peak originating from the bivalent anionic form of dye was strongly reduced and the maximum peak position was red-shifted by 12 nm. The binding constant (K) of the bivalent anionic form of PhRed, calculated from absorbance data, was 1.61 . 10(4) L mol(-1). The variations of the absorption and absorption difference spectra of PhRed in the presence of HSA-bilirubin complex were indicative of the inhibition of PhRed binding process by bilirubin. Binding of PhRed carried out in the presence of sulfonamides showed that drugs and PhRed have a common site which also involves bilirubin. In agreement with the results of the spectroscopic analysis and molecular docking it was concluded that PhRed may be applied as a marker in the study of the binding of drugs to high-affinity bilirubin binding site. PMID- 26231935 TI - Three N-Glycosylation Sites of Human Acetylcholinesterase Shares Similar Glycan Composition. AB - Acetylcholinesterase (AChE; EC 3.1.1.7) is a glycoprotein possessing three conserved N-linked glycosylation sites in mammalian species, locating at 296, 381, and 495 residues of the human sequence. Several lines of evidence demonstrated that N-glycosylation of AChE affected the enzymatic activity, as well as its biosynthesis. In order to determine the role of three N-glycosylation sites in AChE activity and glycan composition, the site-directed mutagenesis of N glycosylation sites in wild-type human AChE(T) sequence was employed to generate the single-site mutants (i.e., AChE(T) (N296Q), AChET (N381Q), and AChE(T) (N495Q)) and all site mutant (i.e., AChE(T) (3N->3Q)). The mutation did not affect AChE protein expression in the transfected cells. The mutants, AChE(T) (3N >3Q) and AChE(T) (N381Q), showed very minimal enzymatic activity, while the other mutants showed reduced activity. By binding to lectins, Con A, and SNA, the glycosylation profile was revealed in those mutated AChE. The binding affinity with lectins showed no significant difference between various N-glycosylation mutants, which suggested that similar glycan composition should be resulted from different N-glycosylation sites. Although the three glycosylation sites within AChE sequence have different extent in affecting the enzymatic activity, their glycan compositions are very similar. PMID- 26231936 TI - Elevated Expression of the Delta-Subunit of Epithelial Sodium Channel in Temporal Lobe Epilepsy Patients and Rat Model. AB - Epilepsy is one of the most common, chronic, neurological diseases. The pathology of epilepsy is based on abnormal synchronization of neuronal discharges. Epithelial sodium channels, which are constitutively active, non-voltage-gated, highly selective sodium channels belonging to the epithelial sodium channel/degenerin (ENaC/deg) family, contribute to resting membrane potential modulation and subsequent neuronal excitability by providing a sodium influx pathway. Different from the other three subunits, delta ENaC expression is prominent in the human brain cortex and restricted to neurons. The aim of this study was to investigate the expression pattern of delta ENaC in patients with temporal lobe epilepsy (TLE) and in a pilocarpine-induced rat model of epilepsy. Adopting immunohistochemistry, immunofluorescence, and western blot analysis, we found that delta ENaC was restricted to neurons in the temporal neocortices of TLE patients and the cortices and hippocampus of pilocarpine-induced epilepsy rats, which were similar to the corresponding controls. However, delta ENaC expression was significantly elevated in TLE patients and the pilocarpine-induced epileptic rats. The physiological role, the unchanged localization, and the elevated expression of delta ENaC suggested it could play an important role in epilepsy. PMID- 26231937 TI - XPR1: a Gene Linked to Primary Familial Brain Calcification Might Help Explain a Spectrum of Neuropsychiatric Disorders. AB - Primary familial brain calcifications (PFBC) compose a rare neurologic condition characterized by a bilateral pattern of hydroxyapatite deposits in basal ganglia, dentate nuclei, and thalamus. PFBC is identified through neuroimaging screenings such as computerized tomography. Patients with PFBC might present a wide variety of neurological symptoms such as mental and motor impairments, often misdiagnosed as Parkinson's disease, schizophrenia, Alzheimer's disease, and migraine. Four genes were confirmed as causative of PFBC: SLC20A2, PDGFB, PDGFRB, and XPR1. Curiously, other studies made occasional links between XPR1 variations or expression changes, in a few neuropsychiatric models. This letter is an assembly on XPR1 variants and expression change pattern data that were published in recent scientific reports, even before the current connection between that gene and brain calcification. PMID- 26231938 TI - Association between popliteal artery wall thickness and knee cartilage volume loss in community-based middle-aged women without clinical knee disease. AB - OBJECTIVE: Increasing evidence suggests a role of vascular pathology in the pathogenesis of osteoarthritis. This study examined the association between popliteal artery wall thickness, a surrogate marker of cardiovascular disease, and knee cartilage volume loss in an asymptomatic cohort of women. STUDY DESIGN: Prospective cohort study of 170 women with no significant knee pain, injury, or history of clinical knee disease. Participants underwent knee magnetic resonance imaging at baseline and 2 years later. Popliteal artery wall thickness was assessed using validated methods. MAIN OUTCOME MEASURES: Tibial cartilage volume assessed using validated methods. RESULTS: 142 women (83.5%) completed 2-year follow-up. After adjusting for age, body mass index and tibial bone area, greater popliteal artery wall thickness was associated with increased rate of medial tibial cartilage volume loss. With increasing tertiles of popliteal artery wall thickness, the mean (standard error) of annual medial tibial cartilage volume loss was 1.62 (0.45)%, 2.18 (0.43)%, and 2.98 (0.48)%, respectively, p for trend=0.04. No significant association was observed in lateral tibial cartilage. CONCLUSION: In community-based women greater popliteal artery wall thickness is associated with increased rate of tibial cartilage volume loss over 2 years. These findings suggest an adverse effect of vascular pathology on articular knee cartilage, supporting the hypothesis that there might be a vascular contribution to the development of knee osteoarthritis. Although needing to be confirmed in other studies, these results suggest that targeting vascular pathology may provide a potential target for the prevention and early treatment of knee osteoarthritis in women. PMID- 26231939 TI - Evidence for the acquisition of dual-task coordination skills in older adults. AB - Practicing two simultaneously presented tasks in dual-task situations results in improved dual-task performance, in both younger and older adults. Recent findings with younger adults demonstrated that this improvement is attributable in part to improved task coordination skills acquired through practice. However, it is unclear whether practice also improves older adults' skills at dual-task coordination. To clarify this, the present study examined the acquisition of task coordination skills, reflecting one specific mechanism of practice-dependent improvement in dual-task performance for this particular age group. This examination was based on two assumptions, namely, that (1) these skills are acquired during practice of the tasks presented simultaneously (dual-task situations), but not during the separate practice of the two tasks (single-task situations), and (2), rather than being dependent on the specific properties of practiced tasks, these skills are transferable to new dual-task situations. In the context of dual-task situations with well-structured reaction-time tasks, the results indeed revealed improved dual-task performance following dual-task practice, as compared to single-task practice, in both the practiced dual-task and new dual-task (transfer) situations. These findings are consistent with the notion that, similar to younger adults, acquired task coordination skills represent one practice-related mechanism that contributes to improved dual-task performance in the age group of older adults. PMID- 26231941 TI - Methadone's effect on nAChRs--a link between methadone use and smoking? AB - Methadone is a long-acting opioid agonist that is frequently prescribed as a treatment for opioid addiction. Almost all methadone maintenance patients are smokers, and there is a correlation between smoking habit and use of methadone. Methadone administration increases tobacco smoking, and heavy smokers use higher doses of methadone. Nevertheless, methadone maintenance patients are willing to quit smoking although their quit rates are low. Studies on nicotine-methadone interactions provide an example of the bedside-to-bench approach, i.e., observations in clinical settings have been studied experimentally in vivo and in vitro. In vivo studies have revealed the interplay between nicotine and the endogenous opioid system. At the receptor level, methadone has been shown to be an agonist of human alpha7 nAChRs and a non-competitive antagonist of human alpha4beta2 and alpha3* nAChRs. These drugs do not have significant interactions at the level of drug metabolism, and thus the interaction is most likely pharmacodynamic. The net effect of the interaction may depend on individual characteristics because pharmacogenetic factors influence the disposition of both methadone and nicotine. PMID- 26231940 TI - Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders. AB - The challenges associated with developing more effective treatments for neurologic and psychiatric illness such as Alzheimer's disease and schizophrenia are considerable. Both the symptoms and the pathophysiology of these conditions are complex and poorly understood and the clinical presentations across different patients can be very heterogeneous. Moreover, it has become apparent that the reductionist approach to drug discovery for these illnesses that has dominated the field for decades (i.e., the development of highly selective compounds or other treatment modalities focused on a very specific pathophysiologic target) has not been widely successful. Accordingly, a variety of new strategies have emerged including the development of "multitarget-directed ligands" (MTDLs), the development and/or identification of compounds that exhibit "multifunctional" activity (e.g., pro-cognitive plus neuroprotective, pro-cognitive plus antipsychotic activity), "repurposing" strategies for existing compounds that have other clinical indications, and novel "adjunctive" treatment strategies that might enhance the efficacy of the currently available treatments. Interestingly, a variety of ligands at nicotinic acetylcholine receptors (nAChRs) appear to have the potential to fulfill one or more of these desirable properties (i.e., multifunctional, repurposing, or adjunctive treatment potential). The purpose of this review (while not all-inclusive) is to provide an overview of a variety of nAChR ligands that demonstrate potential in these categories, particularly, "multifunctional" properties. Due to their densities in the mammalian brain and the amount of literature available, the review will focus on ligands of the high affinity alpha4beta2 nAChR and the low affinity alpha7 nAChR. PMID- 26231943 TI - Allosteric modulation of nicotinic acetylcholine receptors. AB - Nicotinic acetylcholine receptors (nAChRs) are receptors for the neurotransmitter acetylcholine and are members of the 'Cys-loop' family of pentameric ligand-gated ion channels (LGICs). Acetylcholine binds in the receptor extracellular domain at the interface between two subunits and research has identified a large number of nAChR-selective ligands, including agonists and competitive antagonists, that bind at the same site as acetylcholine (commonly referred to as the orthosteric binding site). In addition, more recent research has identified ligands that are able to modulate nAChR function by binding to sites that are distinct from the binding site for acetylcholine, including sites located in the transmembrane domain. These include positive allosteric modulators (PAMs), negative allosteric modulators (NAMs), silent allosteric modulators (SAMs) and compounds that are able to activate nAChRs via an allosteric binding site (allosteric agonists). Our aim in this article is to review important aspects of the pharmacological diversity of nAChR allosteric modulators and to describe recent evidence aimed at identifying binding sites for allosteric modulators on nAChRs. PMID- 26231948 TI - Differentiation between borderline and benign ovarian tumors: combined analysis of MRI with tumor markers for large cystic masses (>=5 cm). AB - BACKGROUND: There is overlap in imaging features between borderline and benign ovarian tumors. PURPOSE: To analyze diagnostic performance of magnetic resonance imaging (MRI) combined with tumor markers for differentiating borderline from benign ovarian tumor. MATERIAL AND METHODS: Ninety-nine patient with MRI and surgically confirmed ovarian tumors 5 cm or larger (borderline, n = 37; benign, n = 62) were included. On MRI, tumor size, septal number (0; 1-4; 5 or more), and presence of solid portion such as papillary projection or septal thickening 0.5 cm or larger were investigated. Serum tumor markers (carbohydrate antigen 125 [CA 125] and CA 19-9) were recorded. Multivariate analysis was conducted for assessing whether combined MRI with tumor markers could differentiate borderline from benign tumor. The diagnostic performance was also analyzed. RESULTS: Incidence of solid portion was 67.6% (25/37) in borderline and 3.2% (2/62) in benign tumors (P < 0.05). In all patients, without combined analysis of MRI with tumor markers, multivariate analysis revealed solid portion (P < 0.001) and CA 125 (P = 0.039) were significant for predicting borderline tumors. When combined analysis of MRI with CA 125 ((i) the presence of solid portion or (ii) CA 125 > 44.1 U/mL with septal number >=5 for borderline tumor) is incorporated to multivariate analysis, it was only significant (P = 0.001). The sensitivity, specificity, PPV, NPV, and accuracy of combined analysis of MRI with CA 125 were 89.1%, 91.9%, 86.8%, 93.4, and 90.9%, respectively. CONCLUSION: Combined analysis of MRI with CA 125 may allow better differentiation between borderline and benign ovarian tumor compared with MRI alone. PMID- 26231949 TI - Clinical presentation and CT/MRI findings of alveolar soft part sarcoma: a retrospective single-center analysis of 14 cases. AB - BACKGROUND: Alveolar soft part sarcoma (ASPS) is a relatively rare malignant tumor and early diagnosis and appropriate treatment for ASPS are essential for a good prognosis. PURPOSE: To retrospectively review the clinical presentation and computed tomography (CT) and magnetic resonance imaging (MRI) findings of ASPS so as to improve the accuracy of imaging diagnosis. MATERIAL AND METHODS: Fourteen patients with pathologically proven ASPS were enrolled. Their clinical and imaging findings were retrospectively reviewed. RESULTS: The median age of the patients was 29 years (range, 13-37 years). Most tumors were located in the soft tissues of the trunk and lower limbs. The median maximal diameter of the masses was 91 mm. Thirteen masses presented with ovoid or irregular shapes. Eleven masses had less clear boundaries. Compared with the adjacent muscles, the masses were isodense or hypodense on CT, hypo-, iso-, or hyperintense on T1-weighted images, and heterogeneous hyperintense on T2-weighted images. Intense enhancement was seen after contrast agent administration, with prominent intra- or peri tumoral feeders on CT or flow voids on MRI. By the end of the last follow-up, 13 patients had distant metastasis and three patients had local recurrence. CONCLUSION: ASPS should be included in the differential diagnosis when a bulky, heterogeneous soft tissue mass in the trunk and the lower limbs with intense enhancement after contrast administration and prominent intra- or peri-tumoral feeders on CT or flow voids on MRI is seen, particularly in young patients. PMID- 26231950 TI - Magnetic resonance imaging evaluation of residual tumors in breast cancer after neoadjuvant chemotherapy: surgical implications. AB - BACKGROUND: Magnetic resonance imaging (MRI) can be used to guide breast cancer surgery with breast conservation for large tumors with a substantially reduced size after neoadjuvant chemotherapy (NAC). PURPOSE: To evaluate the value of dynamic contrast-enhanced MRI (DCE-MRI) for measuring residual tumor size and enhancement patterns following preoperative NAC. MATERIAL AND METHODS: Eighty nine patients with breast cancer underwent breast DCE-MRI; 38 patients (39 lesions) were treated with NAC and examined for residual disease following therapy. Two patients were excluded because surgery had been performed >2 weeks after the final MR examination. Thus, we correlated the DCE-MRI results of 36 patients (37 lesions) with postoperative histopathological findings. Residual disease was confirmed by more enhancement compared to normal glandular tissue at the initial tumor site. Residual tumor size on DCE-MRI was compared with postoperative pathology findings. Tumor enhancement patterns on DCE-MRI were analyzed and correlated with pathological classification. RESULTS: MRI revealed 34 cases of residual tumors, with two false positives and one false negative. Pathological and MR measurements were correlated (r = 0.793). The correlation of mass enhancement size (r = 0.87, n = 14) with pathology and DCE-MRI was higher than for non-mass-like enhancement (NME) (r = 0.735, n = 23). The distribution of pathologic classification was significantly different between different MRI enhancement patterns (P = 0.006). Mass enhancement had higher cellularity than NME. CONCLUSION: MRI is useful for evaluating residual carcinoma following NAC. Mass enhancement with higher cellularity after NAC can be evaluated more accurately, which is suitable for evaluating lumpectomy. However, other approaches are required for NME, which has lower cellularity. PMID- 26231951 TI - Therapeutic angiographic procedures: differences in dose area product between analog image intensifier and digital flat panel detector. AB - BACKGROUND: Radiation exposure remains an unceasing concern in angiographic procedures. Modern angiography machines such as analog image intensifiers (AII) or the new flat panel detectors (FPD) aim at a further dose reduction. PURPOSE: To present dose area products (DAP) in a broad spectrum of therapeutic angiographic procedures, comparing an AII to an FPD angiography system. MATERIAL AND METHODS: A total of 999 peripheral therapeutic angiography procedures performed with an FPD (n = 562) and an AII system (n = 437) were evaluated. DAP, fluoroscopy time, and patients' body mass index (BMI) were recorded. Interventions were classified into five main groups: percutaneous transluminal angioplasty (PTA); PTA and stent placement; intra-arterial thrombolysis; embolization procedures; and specialized interventions. RESULTS: DAP values in therapeutic angiographic procedures were significantly higher when performed with the FPD compared to the AII system. The increase of the FPD versus AII system was 100.1% for PTA, 39.9% for PTA and stent placement, 187% for intra-arterial thrombolysis, 31.3% for embolization procedures, and 361% for specialized interventions. These differences persisted after standardizing DAP values to the geometric mean fluoroscopy duration of each procedure. Fluoroscopy times were shorter in all interventions performed at the FPD as compared to the AII system. DAPs increased with higher BMI, but the DAP increase of both systems with elevated BMI was variable, depending on the individual intervention. CONCLUSION: In therapeutic angiographic procedures, the FPD system required higher DAPs despite shorter fluoroscopy times as compared to an AII system. Better ergonomics and speediness of the FPD system may be advantageous in the emergency setting. PMID- 26231942 TI - Nicotine modulation of fear memories and anxiety: Implications for learning and anxiety disorders. AB - Anxiety disorders are a group of crippling mental diseases affecting millions of Americans with a 30% lifetime prevalence and costs associated with healthcare of $42.3 billion. While anxiety disorders show high levels of co-morbidity with smoking (45.3% vs. 22.5% in healthy individuals), they are also more common among the smoking population (22% vs. 11.1% in the non-smoking population). Moreover, there is clear evidence that smoking modulates symptom severity in patients with anxiety disorders. In order to better understand this relationship, several animal paradigms are used to model several key symptoms of anxiety disorders; these include fear conditioning and measures of anxiety. Studies clearly demonstrate that nicotine mediates acquisition and extinction of fear as well as anxiety through the modulation of specific subtypes of nicotinic acetylcholine receptors (nAChRs) in brain regions involved in emotion processing such as the hippocampus. However, the direction of nicotine's effects on these behaviors is determined by several factors that include the length of administration, hippocampus-dependency of the fear learning task, and source of anxiety (novelty driven vs. social anxiety). Overall, the studies reviewed here suggest that nicotine alters behaviors related to fear and anxiety and that nicotine contributes to the development, maintenance, and reoccurrence of anxiety disorders. PMID- 26231952 TI - High frequency of H3F3A (K27M) mutations characterizes pediatric and adult high grade gliomas of the spinal cord. PMID- 26231953 TI - TDP-43 proteinopathies: pathological identification of brain regions differentiating clinical phenotypes. AB - The pathological sequestration of TAR DNA-binding protein 43 (TDP-43, encoded by TARDBP) into cytoplasmic pathological inclusions characterizes the distinct clinical syndromes of amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia, while also co-occurring in a proportion of patients with Alzheimer's disease, suggesting that the regional concentration of TDP-43 pathology has most relevance to specific clinical phenotypes. This has been reflected in the three different pathological staging schemes for TDP-43 pathology in these different clinical syndromes, with none of these staging schemes including a preclinical phase similar to that which has proven beneficial in other neurodegenerative diseases. To apply each of these three staging schemes for TDP-43 pathology, the clinical phenotype must be known undermining the potential predictive value of the pathological examination. The present study set out to test whether a more unified approach could accurately predict clinical phenotypes based solely on the regional presence and severity of TDP-43 pathology. The selection of brain regions of interest was based on key regions routinely sampled for neuropathological assessment under current consensus criteria that have also been used in the three TDP-43 staging schemes. The severity of TDP-43 pathology in these regions of interest was assessed in four clinicopathological phenotypes: amyotrophic lateral sclerosis (n = 27, 47-78 years, 15 males), behavioural variant frontotemporal dementia (n = 15, 49-82 years, seven males), Alzheimer's disease (n = 26, 51-90 years, 11 males) and cognitively normal elderly individuals (n = 17, 80-103 years, nine males). Our results demonstrate that the presence of TDP-43 in the hypoglossal nucleus discriminates patients with amyotrophic lateral sclerosis with an accuracy of 98%. The severity of TDP-43 deposited in the anterior cingulate cortex identifies patients with behavioural variant frontotemporal dementia with an accuracy of 99%. This identification of regional pathology associated with distinct clinical phenotypes suggests key regions on which probabilistic pathological criteria, similar to those currently available for Alzheimer's disease and dementia with Lewy bodies, can be developed for TDP-43 proteinopathies. We propose and validate a simplified probabilistic statement that involves grading the presence of TDP-43 in the hypoglossal nucleus and the severity of TDP-43 in the anterior cingulate for the pathological identification of TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia. PMID- 26231954 TI - Outcomes for newly diagnosed patients with acute myeloid leukemia dosed on actual or adjusted body weight. AB - PURPOSE: Data from solid tumor malignancies suggest that actual body weight (ABW) dosing improves overall outcomes. There is the potential to compromise efficacy when chemotherapy dosages are reduced, but the impact of dose adjustment on clinical response and toxicity in hematologic malignancies is unknown. The purpose of this study was to evaluate the outcomes of utilizing a percent of ABW for acute myeloid leukemia (AML) induction chemotherapy dosing. METHODS: This retrospective, single-center study included 146 patients who received 7 + 3 induction (cytarabine and anthracycline) for treatment of AML. Study design evaluated the relationship between percentage of ABW dosing and complete response (CR) rates in patients newly diagnosed with AML. RESULTS: Percentage of ABW dosing did not influence CR rates in patients undergoing induction chemotherapy for AML (p = 0.83); nor did it influence rate of death at 30 days or relapse at 6 months (p = 0.94). When comparing patients dosed at 90-100 % of ABW compared to <90 % ABW, CR rates were not significantly different in patients classified as poor risk (p = 0.907). All favorable risk category patients obtained CR. CONCLUSIONS: Preemptive dose reductions for obesity did not influence CR rates for patients with AML undergoing induction chemotherapy and did not influence the composite endpoint of death at 30 days or disease relapse at 6 months. PMID- 26231956 TI - Guideline Development Process in a Public Workers' Compensation System. AB - Washington state's public workers' compensation system has had a formal process for developing and implementing evidence-based clinical practice guidelines since 2007. Collaborating with the Industrial Insurance Medical Advisory Committee and clinicians from the medical community, the Office of the Medical Director has provided leadership and staff support necessary to develop guidelines that have improved outcomes and reduced the number of potentially harmful procedures. Guidelines are selected according to a prioritization schema and follow a development process consistent with that of the national Institute of Medicine. Evaluation criteria are also applied. Guidelines continue to be developed to provide clinical recommendations for optimizing care and reducing risk of harm. PMID- 26231957 TI - Introduction to Evidence-Based Decision Making in a Public Workers' Compensation Agency. AB - Peer-reviewed medical literature plays a decisive role in policy development at the Washington State Department of Labor and Industries (L&I). L&I relies on multiple evidence-based mechanisms to make coverage decisions and translate medical science into public policy, including statute, rule writing, executive policy, real-time evidence assessment, pilot testing, and collaboration with researchers. Elements of L&I's policy process structure and evidence-based culture are also observed in original literature discussing the needs and barriers of incorporating evidence into public policy. PMID- 26231955 TI - Albumin-bound nanoparticle (nab) paclitaxel exhibits enhanced paclitaxel tissue distribution and tumor penetration. AB - PURPOSE: nab-paclitaxel demonstrates improved clinical efficacy compared with conventional Cremophor EL (CrEL)-paclitaxel in multiple tumor types. This study explored the distinctions in drug distribution between nab-paclitaxel and CrEL paclitaxel and the underlying mechanisms. METHODS: Uptake and transcytosis of paclitaxel were analyzed by vascular permeability assay across human endothelial cell monolayers. The tissue penetration of paclitaxel within tumors was evaluated by local injections into tumor xenografts and quantitative image analysis. The distribution profile of paclitaxel in solid-tumor patients was assessed using pharmacokinetic modeling and simulation. RESULTS: Live imaging demonstrated that albumin and paclitaxel were present in punctae in endothelial cells and could be observed in very close proximity, suggesting cotransport. Uptake and transport of albumin, nab-paclitaxel and paclitaxel were inhibited by clinically relevant CrEL concentrations. Further, nab-paclitaxel causes greater mitotic arrest in wider area within xenografted tumors than CrEL- or dimethyl sulfoxide-paclitaxel following local microinjection, demonstrating enhanced paclitaxel penetration and uptake by albumin within tumors. Modeling of paclitaxel distribution in patients with solid tumors indicated that nab-paclitaxel is more dependent upon transporter-mediated pathways for drug distribution into tissues than CrEL paclitaxel. The percent dose delivered to tissue via transporter-mediated pathways is predicted to be constant with nab-paclitaxel but decrease with increasing CrEL-paclitaxel dose. CONCLUSIONS: Compared with CrEL-paclitaxel, nab paclitaxel demonstrated more efficient transport across endothelial cells, greater penetration and cytotoxic induction in xenograft tumors, and enhanced extravascular distribution in patients that are attributed to carrier-mediated transport. These observations are consistent with the distinct clinical efficacy and toxicity profile of nab-paclitaxel. PMID- 26231958 TI - Application and Outcomes of Treatment Guidelines in a Utilization Review Program. AB - The value of treatment guidelines in improving outcomes for patients and controlling costs is significantly enhanced in Washington by incorporating guidelines into a structured UR program. This article describes: (1) how the Washington Department of Labor and Industries (L&I) UR program uses guidelines; and (2) the impact of the UR program on costs and outcomes. The impact of guideline implementation in the Washington program is considerable. In 2014, the L&I program produced net savings of $7,519,823, and the return on investment was approximately $2.00. The impact on clinical outcomes includes an overarching effect from use of best practices. PMID- 26231959 TI - Guideline for Prescribing Opioids to Treat Pain in Injured Workers. AB - Recently, there has been a dramatic increase in the use of opioids to treat chronic noncancer pain. Opioids are also being prescribed in stronger potencies and larger doses for musculoskeletal injuries. In some cases, the use of opioids for work-related injuries may actually increase the likelihood of disability. Chronic opioid use is associated with increased risk for overdose morbidity and mortality and other nonfatal adverse outcomes. The risk of dependence and addiction is much more common than previously thought. This guideline provides recommendations for prudent opioid prescribing and addresses issues critical to the care and rehabilitation of injured workers. PMID- 26231960 TI - Shoulder Conditions: Diagnosis and Treatment Guideline. AB - The following guideline covers a wide array of shoulder conditions seen in the workers' compensation, as well as the nonworkers' compensation, population. The guideline is intended to help establish work relatedness and aid in making the diagnosis of shoulder injuries and degenerative conditions. It also provides a nonoperative and operative guideline for the treatment of several shoulder conditions, not limited to rotator cuff tears, subacromial impingement syndrome, acromioclavicular arthritis and dislocations, as well as glenohumeral arthritis. PMID- 26231961 TI - Diagnosis and Treatment of Cervical Radiculopathy and Myelopathy. AB - This article is a guideline covering a wide array of cervical conditions seen in the workers' compensation, as well as the nonworkers' compensation, population. The guideline is intended to provide a diagnostic and treatment algorithm to commonly seen cervical conditions such as single-level and multilevel radiculopathies and myelopathies. PMID- 26231962 TI - Diagnosis and Treatment of Work-Related Ulnar Neuropathy at the Elbow. AB - Ulnar neuropathy at the elbow (UNE) is the second most common entrapment neuropathy after carpal tunnel syndrome and occurs most commonly at the elbow due to mechanical forces that produce traction or ischemia to the nerve. The primary symptom associated with UNE is diminished sensation or dysesthesias in the fourth or fifth digits, often coupled with pain in the proximal medial aspect of the elbow. Treatment may be conservative or surgical, but optimal management remains controversial. Surgery should include exploration of the ulnar nerve throughout its course around the elbow and release of all compressive structures. PMID- 26231963 TI - Work-Related Carpal Tunnel Syndrome: Diagnosis and Treatment Guideline. AB - Carpal tunnel syndrome is the most common entrapment neuropathy, and its risk of occurrence in the presence of repetitive, forceful angular hand movements, or vibration, is common. It is critical to make the diagnosis based on appropriate clinical history and findings and with corroborating electrodiagnostic studies. Conservative management should be undertaken with the goal of maintaining employment; surgical decompression can be highly effective, particularly if undertaken early on. PMID- 26231964 TI - Diagnosis and Treatment of Work-Related Proximal Median and Radial Nerve Entrapment. AB - Proximal median (PMNE) and radial (RNE) nerve entrapment syndromes are uncommon. This article provides an evidenced-based treatment guideline for PMNE and RNE based on the available literature. Arriving at an accurate diagnosis must involve an electrodiagnostic (EDx) workup. EDx, including nerve conduction velocity studies and needle electromyography, should corroborate the clinical diagnosis and must be done before consideration of any surgical treatment. Conservative care includes rest, modified activities, splinting at wrist and elbow, physical therapy, antiinflammatory drug therapy, and corticosteroid injections. Conservative care should be required for at least 6 weeks before any operative interventions are considered. PMID- 26231965 TI - Work-Related Neurogenic Thoracic Outlet Syndrome: Diagnosis and Treatment. AB - Outcomes of surgery for neurogenic thoracic outlet syndrome (NTOS) in workers' compensation are poor in a majority of patients, partly due to nonspecificity of diagnosis. Most cases have no objective evidence of the presence of brachial plexus dysfunction. Up to 20% of patients experience a new adverse event. Objective neurologic signs and electrodiagnostic evidence of brachial plexus dysfunction must be present before proceeding with invasive procedures. This guideline includes objective criteria that must be met before thoracic outlet syndrome surgery can be approved in Washington State. Evidence does not support the use of scalene blocks, botulinum toxin therapy, or vascular studies to diagnose NTOS. PMID- 26231966 TI - Work-Related Complex Regional Pain Syndrome: Diagnosis and Treatment. AB - Complex regional pain syndrome can be a debilitating disorder, which, in its earliest stages, can be prevented by aggressive rehabilitation based on reactivation. It is critical to follow international criteria on making the diagnosis; overdiagnosis can lead to inappropriate interventions and further disability. When present, early recognition with reactivation is the cornerstone of treatment. This article presents a phased approach to treatment that suggests movements of nonresponders quickly to more integrated levels of care. Some commonly used invasive interventions, such as sympathectomy and spinal cord stimulation, have not been proved effective; these unproven and potentially harmful therapies should be avoided. PMID- 26231967 TI - Physical Medicine and Rehabilitation Clinics of North America. Evidence-Based Treatment Guidelines for Treating Injured Workers. Foreword. PMID- 26231968 TI - Evidence-Based Guidelines in Workers' Compensation. PMID- 26231969 TI - Evidence-based Guidelines in Workers' Compensation. PMID- 26231970 TI - Sweet's or not: a cutaneous presentation of a severe disease. PMID- 26231971 TI - Clematichinenoside protects blood brain barrier against ischemic stroke superimposed on systemic inflammatory challenges through up-regulating A20. AB - Suppression of excessive inflammation can ameliorate blood brain barrier (BBB) injury, which shows therapeutic potential for clinical treatment of brain injury induced by stroke superimposed on systemic inflammatory diseases. In this study, we investigated whether and how clematichinenoside (AR), an anti-inflammatory triterpene saponin, protects brain injury from stroke superimposed on systemic inflammation. Lipopolysaccharide (LPS) was intraperitoneally injected immediately after middle cerebral artery occlusion (MCAO) in rats. Rat microvessel endothelial cells (rBMECs) were exposed to hypoxia/reoxygenation (H/R) coexisting with LPS. The results revealed that AR suppressed the excessive inflammation, restored BBB dysfunction, alleviated brain edema, decreased neutrophil infiltration, lessened neurological dysfunction, and decreased infarct rate. Further study demonstrated that the expression of nucleus nuclear factor kappa B (NF-kappaB), inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-alpha (TNF-alpha) and interlukin-1beta (IL-1beta) were suppressed by AR via zinc finger protein A20. Besides, AR increased in vitro BBB integrity through A20. In conclusion, AR alleviated cerebral inflammatory injury through A20-NF-kappaB signal pathway, offering an alternative medication for stroke associated with systemic inflammatory diseases. PMID- 26231972 TI - Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress. AB - Chronic stress is one of the most relevant triggering factors for major depression. Microglial cells are highly sensitive to stress and, more generally, to environmental challenges. However, the role of these brain immune cells in mediating the effects of stress is still unclear. Fractalkine signaling - which comprises the chemokine CX3CL1, mainly expressed by neurons, and its receptor CX3CR1, almost exclusively present on microglia in the healthy brain - has been reported to critically regulate microglial activity. Here, we investigated whether interfering with microglial function by deleting the Cx3cr1 gene affects the brain's response to chronic stress. To this purpose, we housed Cx3cr1 knockout and wild-type adult mice in either control or stressful environments for 2weeks, and investigated the consequences on microglial phenotype and interactions with synapses, synaptic transmission, behavioral response and corticosterone levels. Our results show that hampering neuron-microglia communication via the CX3CR1-CX3CL1 pathway prevents the effects of chronic unpredictable stress on microglial function, short- and long-term neuronal plasticity and depressive-like behavior. Overall, the present findings suggest that microglia-regulated mechanisms may underlie the differential susceptibility to stress and consequently the vulnerability to diseases triggered by the experience of stressful events, such as major depression. PMID- 26231973 TI - PREPP: postpartum depression prevention through the mother-infant dyad. AB - Most interventions to prevent postpartum depression (PPD) focus on the mother rather than the mother-infant dyad. As strong relationships between infant sleep and cry behavior and maternal postpartum mood have been demonstrated by previous research, interventions targeted at the dyad may reduce symptoms of PPD. The goal of the current study was to examine the effectiveness of Practical Resources for Effective Postpartum Parenting (PREPP). PREPP is a new PPD prevention protocol that aims to treat women at risk for PPD by promoting maternally mediated behavioral changes in their infants, while also including mother-focused skills. Results of this randomized control trial (RCT) (n = 54) indicate that this novel, brief intervention was well tolerated and effective in reducing maternal symptoms of anxiety and depression, particularly at 6 weeks postpartum. Additionally, this study found that infants of mothers enrolled in PREPP had fewer bouts of fussing and crying at 6 weeks postpartum than those infants whose mothers were in the Enhanced TAU group. These preliminary results indicate that PREPP has the potential to reduce the incidence of PPD in women at risk and to directly impact the developing mother-child relationship, the mother's view of her child, and child outcomes. PMID- 26231974 TI - Imaging surveillance and survival for surgically resected non-small-cell lung cancer. AB - INTRODUCTION: The importance of imaging surveillance after treatment for lung cancer is not well characterized. We examined the association between initial guideline recommended imaging surveillance and survival among early-stage resected non-small-cell lung cancer (NSCLC) patients. METHODS: A retrospective study was conducted using Surveillance, Epidemiology, and End Results-Medicare data (1995-2010). Surgically resected patients, with stage I and II NSCLC, were categorized by imaging received during the initial surveillance period (4-8 mo) after surgery. Primary outcome was overall survival. Secondary treatment interventions were examined as intermediary outcomes. RESULTS: Most (88%) patients had at least one outpatient clinic visit, and 24% received an initial computerized tomography (CT) during the first surveillance period. Five-year survival by initial surveillance imaging was 61% for CT, 58% for chest radiography, and 60% for no imaging. After adjustment, initial CT was not associated with improved overall survival (hazard ratio [HR], 1.04; 95% confidence interval [CI] 0.96-1.14). On subgroup analysis, restricted to patients with demonstrated initial postoperative follow-up, CT was associated with a lower overall risk of death for stage I patients (HR, 0.85; 95% CI, 0.74-0.98), but not for stage II (HR, 1.01; 95% CI, 0.71-1.42). There was no significant difference in rates of secondary interventions predicted by type of initial imaging surveillance. CONCLUSIONS: Initial surveillance CT is not associated with improved overall or lung cancer-specific survival among early-stage NSCLC patients undergoing surgical resection. Stage I patients with early follow-up may represent a subpopulation that benefits from initial surveillance although this may be influenced by healthy patient selection bias. PMID- 26231975 TI - Reactive angioendotheliomatosis as a presenting cutaneous manifestation of Hughes syndrome. AB - BACKGROUND: Antiphospholipid antibody syndrome is an autoimmune disorder associated with pregnancy complications, venous and/or arterial thrombosis and the presence of antiphospholipid antibodies. This syndrome is known to present with various cutaneous features, but association with reactive angioendotheliomatosis has been described rarely in the literature. RESULTS: A woman in her thirties with a past history of three consecutive abortions developed purpuric, ulcerative plaque over the plantar aspect of the foot. Her biopsy showed marked expansion of dermal vasculature due to intravascular cellular proliferation suggestive of reactive angioendotheliomatosis. The intravascular cells stained positive for CD31. Her blood investigations showed positive lupus anticoagulant, antiphospholipid antibodies and anticardiolipin antibodies, leading to a diagnosis of antiphospholipid syndrome also known as Hughes syndrome. CONCLUSION: We suggest that a hypercoagulable state caused the formation of intravascular thrombi leading to reactive angioendotheliomatosis. We report a case of Hughes syndrome with reactive angioendotheliomatosis as the first clinical cutaneous manifestation and treated satisfactorily with anticoagulants and immunomodulators. PMID- 26231976 TI - Taxonomic diversity and structure of the molluscan fauna in Oualidia lagoon (Moroccan Atlantic coast). AB - The spatial distribution of the molluscan fauna of Oualidia lagoon (Moroccan Atlantic coast) was studied during winter 2013. Samples were collected from 43 stations over the whole of the lagoon. Twenty-eight taxa (19 species of gastropods, 7 species of bivalves, 1 species of polyplacophora, and 1 species of cephalopod) were listed, 21 of which are newly reported for Oualidia lagoon. Four taxa, Hydrobia sp. (78.29%), followed by Abra alba (13.99 ), Nassarius pfeifferi (5.07%), and Cerastoderma edule (1.32%), were accounted for 98% of the total abundance. A classification analysis used to characterize the lagoon on the basis of molluscs showed the existence of three main clusters from downstream to upstream: a Nassarius pfeifferi community, a Hydrobia sp.-Abra alba community and a Hydrobia sp.-Cerastoderma edule community. PMID- 26231977 TI - Cempedak durian as a potential biosorbent for the removal of Brilliant Green dye from aqueous solution: equilibrium, thermodynamics and kinetics studies. AB - Cempedak durian peel (CDP) was used to remove Brilliant Green (BG) dye from aqueous solution. The adsorption of BG onto CDP was studied as functions of contact time, pH, temperature, ionic strength and initial concentration. In order to understand the adsorption process and its mechanisms, adsorption isotherm and kinetics models were used. The experiments were done under optimized 2-h contact time and ambient pH. Adsorption study showed that the Langmuir model best fitted with experimental data, and the maximum adsorption capacity was determined as 0.203 mmol g(-1) (97.995 mg g(-1)). Adsorption kinetics followed the pseudo 2nd order model, and intraparticle diffusion is involved but not as the rate-limiting step while Boyd model suggests that film diffusion might be in control of the adsorption process. Fourier transform infrared (FTIR) analysis showed that OH, C=O, C=C and NH functional groups might be involved in the adsorption of BG onto CDP. Thermodynamic study suggested that the adsorption of BG onto CDP is endothermic with DeltaH (o) value of 12 kJ mol(-1) and adsorption is feasible. Regeneration of CDP's ability to remove BG was also studied using three different washing solutions. NaOH (0.1 M) was not only sufficient to be used to regenerate CDP's ability to remove BG but also improved its adsorption capability. PMID- 26231978 TI - Visual expertise for horses in a case of congenital prosopagnosia. AB - A major question in the domain of face perception is whether faces comprise a distinct visual category that is processed by specialized mechanisms, or whether face processing merely represents an extreme case of visual expertise. Here, we examined O.H, a 22 years old woman with congenital prosopagnosia (CP), who despite her severe deficits in face processing, acquired superior recognition skills for horses. To compare the nature of face and horse processing, we utilised the inversion manipulation, known to disproportionally affect faces compared to other objects, with both faces and horses. O.H's performance was compared to data obtained from two control groups that were either horse experts, or non-experts. As expected, both control groups exhibited the face inversion effect, while O.H did not show the effect, but importantly, none of the participants showed an inversion effect for horses. Finally, gaze behaviour toward upright and inverted faces and horses was indicative of visual skill but in a distinct fashion for each category. Particularly, both control groups showed different gaze patterns for upright compared to inverted faces, while O.H presented a similar gaze pattern for the two orientations that differed from that of the two control groups. In contrast, O.H and the horse experts exhibited a similar gaze pattern for upright and inverted horses, while non-experts showed different gaze patterns for different orientations. Taken together, these results suggest that visual expertise can be acquired independently from the mechanisms mediating face recognition. PMID- 26231979 TI - Multisensory integration and cross-modal learning in synaesthesia: A unifying model. AB - Recent research into synaesthesia has highlighted the role of learning, yet synaesthesia is clearly a genetic condition. Here we ask how can the idea that synaesthesia reflects innate, genetic differences be reconciled with models that suggest it is driven by learning. A number of lines of evidence suggest that synaesthesia relies on, or at least interacts with, processes of multisensory integration that are common across all people. These include multisensory activations that arise in early regions of the brain as well as feedback from longer-term cross-modal associations generated in memory. These cognitive processes may interact independently to influence the phenomenology of the synaesthetic experience, as well as the individual differences within particular types of synaesthesia. The theoretical framework presented here is consistent with both an innate difference as the fundamental driver of the condition of synaesthesia, and with experiential and semantic influences on the eventual phenotype that emerges. In particular, it proposes that the internally generated synaesthetic percepts are treated similarly to other sensory information as the brain is learning the multisensory attributes of objects and developing cross modal associations that merge in the concept of the object. PMID- 26231980 TI - High prevalence of Pneumocystis jirovecii pneumonia among Mozambican children <5 years of age admitted to hospital with clinical severe pneumonia. AB - We aimed to describe Pneumocystis jirovecii pneumonia (PCP) prevalence and features in children from sub-Saharan Africa and to investigate PCP-associated risk factors. During 2006-2007 we used molecular methods to test children younger than 5 years old admitted with severe pneumonia to a hospital in southern Mozambique for Pneumocystis infection. We recruited 834 children. PCP prevalence was 6.8% and HIV prevalence was 25.7%. The in-hospital and delayed mortality were significantly higher among children with PCP (20.8% vs. 10.2%, p 0.021, and 11.5% vs. 3.6%, p 0.044, respectively). Clinical features were mostly overlapping between the two groups. Independent risk factors for PCP were age less than a year (odds ratio (OR) 6.34, 95% confidence interval (CI) 1.86-21.65), HIV infection (OR 2.99, 95% CI 1.16-7.70), grunting (OR 2.64, 95% CI 1.04-6.73) and digital clubbing (OR 10.75, 95% CI 1.21-95.56). PCP is a common and life threatening cause of severe pneumonia in Mozambican children. Mother-to-child HIV transmission prevention should be strengthened. Better diagnostic tools are needed. PMID- 26231981 TI - Active transposable elements recover species boundaries and geographic structure in Madagascan coffee species. AB - The completion of the genome assembly for the economically important coffee plant Coffea canephora (Rubiaceae) has allowed the use of bioinformatic tools to identify and characterize a diverse array of transposable elements (TEs), which can be used in evolutionary studies of the genus. An overview of the copy number and location within the C. canephora genome of four TEs is presented. These are tested for their use as molecular markers to unravel the evolutionary history of the Millotii Complex, a group of six wild coffee (Coffea) species native to Madagascar. Two TEs from the Gypsy superfamily successfully recovered some species boundaries and geographic structure among samples, whereas a TE from the Copia superfamily did not. Notably, species occurring in evergreen moist forests of eastern and southeastern Madagascar were divergent with respect to species in other habitats and regions. Our results suggest that the peak of transpositional activity of the Gypsy and Copia TEs occurred, respectively, before and after the speciation events of the tested Madagascan species. We conclude that the utilization of active TEs has considerable potential to unravel the evolutionary history and delimitation of closely related Coffea species. However, the selection of TE needs to be experimentally tested, since each element has its own evolutionary history. Different TEs with similar copy number in a given species can render different dendrograms; thus copy number is not a good selection criterion to attain phylogenetic resolution. PMID- 26231982 TI - Association between the methylenetetrahydrofolate reductase c.677C>T polymorphism and bone mineral density: an updated meta-analysis. AB - Many studies have reported an association between the methylenetetrahydrofolate reductase (MTHFR) c.677C>T polymorphism and reduced bone mineral density (BMD), but results have been inconsistent. We, therefore, performed a meta-analysis to further explore this association. Twenty-one studies, comprising 33,045 subjects, analyzed the association of MTHFR c.677C>T with femoral neck BMD. Significant association with reduced BMD was observed in Caucasians (recessive model: WMD = 0.004 g/cm(2), 95 % CI -0.008 to -0.006), post-menopausal women (recessive model: WMD = -0.005 g/cm(2), 95 % CI -0.007 to -0.003), men (dominant model: WMD = 0.004 g/cm(2), 95 % CI -0.005 to -0.004; recessive model: WMD = -0.004 g/cm(2), 95 % CI -0.005 to -0.004; TT vs. CC: WMD = -0.006 g/cm(2), 95 % CI -0.006 to 0.006; CT vs. CC: WMD = -0.003 g/cm(2), 95 % CI -0.003 to -0.003), and cohort studies (recessive model: WMD = -0.003 g/cm(2), 95 % CI -0.006 to -0.001). Twenty two studies, which included 32,271 subjects, analyzed the MTHFR c.677C>T association with lumbar spine BMD. Significant association with reduced BMD was observed in Caucasians, women, post-menopausal women, men, and cohort studies. Seven studies, comprising 6806 subjects, analyzed the MTHFR c.677C>T association with total hip BMD, but no significant association was observed in any population. Nine studies involving 5591 subjects analyzed the association with total body BMD. Significant association with reduced BMD was observed in overall and women subgroup analyses. In summary, this meta-analysis indicates that the MTHFR c.677C>T polymorphism is associated with reduced BMD in lumbar spine and femoral neck in Caucasians, post-menopausal women, and men, and with total body BMD in women. In addition, our results suggest that new studies examining the association between MTHFR c.677C>T polymorphism and BMD of lumbar spine and femoral neck in Asians is warranted, because I (2) > 75.0 % was observed. PMID- 26231983 TI - Using the deductible for patient channeling: did preferred providers gain patient volume? AB - In market-based health care systems, channeling patients to designated preferred providers can increase payer's bargaining clout, other things being equal. In the unique setting of the new Dutch health care system with regulated competition, this paper evaluates the impact of a 1-year natural experiment with patient channeling on providers' market shares. In 2009 a large regional Dutch health insurer designated preferred providers for two different procedures (cataract surgery and varicose veins treatment) and gave its enrollees a positive financial incentive for choosing them. That is, patients were exempted from paying their deductible when they went to a preferred provider. Using claims data over the period 2007-2009, we apply a difference-in-difference approach to study the impact of this channeling strategy on the allocation of patients across individual providers. Our estimation results show that, in the year of the experiment, preferred providers of varicose veins treatment on average experienced a significant increase in patient volume relative to non-preferred providers. However, for cataract surgery no significant effect is found. Possible explanations for the observed difference between both procedures may be the insurer's selection of preferred providers and the design of the channeling incentive resulting in different expected financial benefits for both patient groups. PMID- 26231984 TI - Reply to comment on Cost of poor adherence to anti-hypertensive therapy in five European country. PMID- 26231986 TI - Respective influence of veterinarians and local institutional stakeholders on the event-driven surveillance system for bovine brucellosis in France. AB - BACKGROUND: The event-driven surveillance system for bovine brucellosis implemented in France aims to ensure the early detection of cases of bovine brucellosis, a disease of which the country has been declared free since 2005. It consists of mandatory notification of bovine abortions by farmers and veterinarians. However, as underlined by a previous qualitative study, several factors influence the decision-making process of actors in the field. This process is particularly influenced by the level of cooperation between institutional stakeholders in their departement (a French departement being an administrative and territorial unit), veterinarians and farmers. In this context, the objectives of this study were 1) to quantify the respective influence of veterinarians and all local institutional stakeholders on the proportion of notifying farmers and identify which actors have most influence on farmers' decisions; 2) to analyse whether the influence of veterinarians is correlated with that of local institutional stakeholders. RESULTS: In addition to factors relating to the farm itself (production type and herd size), the proportion of notifying farmers was influenced by the number of veterinarians per practice and the veterinary practice's membership of a technical association. This proportion was also influenced by unknown factors relating to the veterinary practice and, to a lesser extent, the departement in which the farm was located. There was no correlation between variability in the proportion of notifying farmers among veterinary practices per departement and the effect of the departement itself. CONCLUSION: To our knowledge, this is the first study to quantify the influence of veterinarians and local institutional stakeholders on the notification process for a mandatory disease. In addition to carrying out regulatory interventions, veterinarians play a major role in encouraging farmers to participate in the surveillance systems. The results of this study, combined with a previous qualitative study, shed light on the need to consolidate the involvement of veterinarians and local stakeholders in the organisation of surveillance by national institutional bodies. PMID- 26231985 TI - Forecasting the accuracy of genomic prediction with different selection targets in the training and prediction set as well as truncation selection. AB - KEY MESSAGE: Deterministic formulas accurately forecast the decline in predictive ability of genomic prediction with changing testers, target environments or traits and truncation selection. Genomic prediction of testcross performance (TP) was found to be a promising selection tool in hybrid breeding as long as the same tester and environments are used in the training and prediction set. In practice, however, selection targets often change in terms of testers, target environments or traits leading to a reduced predictive ability. Hence, it would be desirable to estimate for given training data the expected decline in the predictive ability of genomic prediction under such settings by deterministic formulas that require only quantitative genetic parameters available from the breeding program. Here, we derived formulas for forecasting the predictive ability under different selection targets in the training and prediction set and applied these to predict the TP of lines based on line per se or testcross evaluations. On the basis of two experiments with maize, we validated our approach in four scenarios characterized by different selection targets. Forecasted and empirically observed predictive abilities obtained by cross-validation generally agreed well, with deviations between -0.06 and 0.01 only. Applying the prediction model to a different tester and/or year reduced the predictive ability by not more than 18%. Accounting additionally for truncation selection in our formulas indicated a substantial reduction in predictive ability in the prediction set, amounting, e.g., to 53% for a selected fraction alpha = 10%. In conclusion, our deterministic formulas enable forecasting the predictive abilities of new selection targets with sufficient precision and could be used to calculate parameters required for optimizing the allocation of resources in multi-stage genomic selection. PMID- 26231987 TI - Preferred Reporting Items for Studies Mapping onto Preference-Based Outcome Measures: The MAPS Statement. AB - BACKGROUND: 'Mapping' onto generic preference-based outcome measures is increasingly being used as a means of generating health utilities for use within health economic evaluations. Despite publication of technical guides for the conduct of mapping research, guidance for the reporting of mapping studies is currently lacking. The MAPS (MApping onto Preference-based measures reporting Standards) statement is a new checklist, which aims to promote complete and transparent reporting of mapping studies. METHODS: In the absence of previously published reporting checklists or reporting guidance documents, a de novo list of reporting items was created by a working group comprising six health economists and one Delphi methodologist. A two-round, modified Delphi survey, with representatives from academia, consultancy, health technology assessment agencies and the biomedical journal editorial community, was used to identify a list of essential reporting items from this larger list. RESULTS: From the initial de novo list of 29 candidate items, a set of 23 essential reporting items was developed. The items are presented numerically and categorized within six sections: (1) title and abstract; (2) introduction; (3) methods; (4) results; (5) discussion; and (6) other. The MAPS statement is best applied in conjunction with the accompanying MAPS Explanation and Elaboration paper. CONCLUSION: It is anticipated that the MAPS statement will improve the clarity, transparency and completeness of the reporting of mapping studies. To facilitate dissemination and uptake, the MAPS statement is being co-published by seven health economics and quality-of-life journals, and broader endorsement is encouraged. The MAPS working group plans to assess the need for an update of the reporting checklist in 5 years' time. PMID- 26231988 TI - [To err is human? Interests of chaotic models to study adult psychiatric disorders and developmental disorders]. AB - BACKGROUND: Many clinical and biological parameters have nonlinear chaotic fluctuations. These variations result in unexpected pseudo-random transitions. In these models, few risk factors can lead to unexpected phenomena if oscillations and self-reinforcement patterns occur. Complex rhythms could ease the ability of a physiological system to adapt and react quickly to a constantly changing environment. OBJECTIVES: It has been proposed that several psychiatric disorders and developmental disorders are characterized by a loss of complex rhythm in favor of a more organized pattern. We examine evidence to support these assumptions in literatures. METHODS: We performed a literature review of the main computerized databases (Medline, PubMed) and manual searches of the literature concerning non dynamic rhythms in time series analysis, in adults with psychiatric disorder and children with developmental disorder. These results were interpreted through a developmental approach that highlights the role of the learning process in the emergence of abilities. RESULTS: Analysis of clinical scores and electroencephalographic data have found that subjects with bipolar disorder or schizophrenia, tested over a time series, have lower chaotic rhythms compared with healthy subjects. Growing children share several properties of a complex system: the interdependence of developmental axes (motor, emotional, language, social skills), multiple hierarchical levels (i.e. genetic, biological, environmental, and cultural), the two-way transactions between the child and his environment, and the sensitivity to initial conditions. This could explain the difficulty to predict the emergence of abilities or the long-term prognosis of impairment in children. This limitation is not only due to errors in the explanatory model or the lack of explanatory variable. It is also caused by instability, which is a core characteristic of a chaotic system. CONCLUSION: The study of chaotic rhythms in time-series clinical and nonclinical data (e.g. EEG, functional neuroimaging) could improve the prediction of an acute event, such as relapse of mood disorder. Moreover, the complex rhythms in children may play a major part in synchronicity during interactions with a caregiver, held as essential for later development of self-regulation skills, such as emotional stability. PMID- 26231989 TI - Decision-tree-model identification of nitrate pollution activities in groundwater: A combination of a dual isotope approach and chemical ions. AB - To develop management practices for agricultural crops to protect against NO3(-) contamination in groundwater, dominant pollution activities require reliable classification. In this study, we (1) classified potential NO3(-) pollution activities via an unsupervised learning algorithm based on delta(15)N- and delta(18)O-NO3(-) and physico-chemical properties of groundwater at 55 sampling locations; and (2) determined which water quality parameters could be used to identify the sources of NO3(-) contamination via a decision tree model. When a combination of delta(15)N-, delta(18)O-NO3(-) and physico-chemical properties of groundwater was used as an input for the k-means clustering algorithm, it allowed for a reliable clustering of the 55 sampling locations into 4 corresponding agricultural activities: well irrigated agriculture (28 sampling locations), sewage irrigated agriculture (16 sampling locations), a combination of sewage irrigated agriculture, farm and industry (5 sampling locations) and a combination of well irrigated agriculture and farm (6 sampling locations). A decision tree model with 97.5% classification success was developed based on SO4(2-) and Cl(-) variables. The NO3(-) and the delta(15)N- and delta(18)O-NO3(-) variables demonstrated limitation in developing a decision tree model as multiple N sources and fractionation processes both resulted in difficulties of discriminating NO3( ) concentrations and isotopic values. Although only the SO4(2-) and Cl(-) were selected as important discriminating variables, concentration data alone could not identify the specific NO3(-) sources responsible for groundwater contamination. This is a result of comprehensive analysis. To further reduce NO3( ) contamination, an integrated approach should be set-up by combining N and O isotopes of NO3(-) with land-uses and physico-chemical properties, especially in areas with complex agricultural activities. PMID- 26231991 TI - Utilization and Costs of Postoperative Physical Therapy After Rotator Cuff Repair: A Comparison of Privately Insured and Medicare Patients. AB - PURPOSE: To evaluate the utilization and charges related to physical therapy (PT) after rotator cuff repair in privately insured and Medicare patients and between arthroscopic and open/mini-open repair techniques. METHODS: The PearlDiver insurance database was queried for patients receiving postoperative PT using Current Procedural Terminology codes. Data were available from 2007 to 2011 for United Healthcare and from 2005 to 2011 for Medicare patients. Patients undergoing arthroscopic (CPT 29827) or open/mini-open approaches (CPT 23410, 23412, 23420) were identified in both populations. Utilization was determined by both the percentage of patients with at least one postoperative PT-related code and the average number of encounters per patient. Per-patient average charge was determined by dividing total charges within the billing period by the patient total. RESULTS: A total of 365,891 patients undergoing rotator cuff repair were identified. There was an increase in the number of arthroscopic repairs (+29.1%, P = .027, United Healthcare; +78.9%, P < .001, Medicare) and a decrease in the number of open/mini-open repairs (-18.2%, P = .038, United Healthcare; -18.2%, P < .001, Medicare) across the study period. At 6 months postoperatively, PT utilization was greater in the United Healthcare groups (82.9% arthroscopic, 81.0% open/mini-open) than in the Medicare groups (41.8% arthroscopic, 43.2% open/mini-open). Utilization-weighted per-patient average charge was comparable among all 4 groups, with slightly higher charges in the United Healthcare groups ($3,376 arthroscopic, $3,251 open/mini-open) compared with the Medicare groups ($2,940 arthroscopic, $2,807 open/mini-open). The United Healthcare groups had a greater number of utilization-weighted billed encounters (36.1 for open/mini open, 9.5 for arthroscopic) than their Medicare counterparts (12.8 open/mini open, 16.7 arthroscopic). CONCLUSIONS: Utilization of PT after rotator cuff repair is substantially higher in privately insured than in Medicare patients. Utilization rates appear to be comparable between surgical approaches. Per patient costs were comparable irrespective of surgical approach and insurance modality. LEVEL OF EVIDENCE: Level IV, economic. PMID- 26231990 TI - Evidence for a role of the reticulospinal system in recovery of skilled reaching after cortical stroke: initial results from a model of ischemic cortical injury. AB - The purposes of this pilot study were to create a model of focal cortical ischemia in Macaca fascicularis and to explore contributions of the reticulospinal system in recovery of reaching. Endothelin-1 was used to create a focal lesion in the shoulder/elbow representation of left primary motor cortex (M1) of two adult female macaques. Repetitive microstimulation was used to map upper limb motor outputs from right and left cortical motor areas and from the pontomedullary reticular formation (PMRF). In subject 1 with a small lesion and spontaneous recovery, reaching was mildly impaired. Changes were evident in the shoulder/elbow representations of both the lesioned and contralesional M1, and there appeared to be fewer than expected upper limb responses from the left (ipsilesional) PMRF. In subject 2 with a substantial lesion, reaching was severely impaired immediately after the lesion. After 12 weeks of intensive rehabilitative training, reach performance recovered to near-baseline levels, but movement times remained about 50% slower. Surprisingly, the shoulder/elbow representation in the lesioned M1 remained completely absent after recovery, and there was a little change in the contralesional M1. There was a definite difference in motor output patterns for left versus right PMRF for this subject, with an increase in right arm responses from right PMRF and a paucity of left arm responses from left PMRF. The results are consistent with increased reliance on PMRF motor outputs for recovery of voluntary upper limb motor control after significant cortical ischemic injury. PMID- 26231992 TI - Recent advances in genome editing and creation of genetically modified pigs. AB - The field of xenotransplantation is benefiting greatly from recent advances in genetic engineering. The efficiency and pace with which new model animals are being created has dramatically sped progress towards clinical relevance. Endonuclease-driven genome editing now allows for the efficient generation of targeted genetic alterations. Herein we review the available methods of genetic engineering that have been successfully employed to create genetically modified pigs. PMID- 26231993 TI - Safety and feasibility of laparoscopic sigmoid colon and rectal cancer surgery in patients with previous vertical abdominal laparotomy. AB - INTRODUCTION: Current study aims to analyze the impact of previous vertical laparotomy on safety and feasibility of laparoscopic sigmoid colon and rectal cancer operations. METHODS: All consecutive patients who underwent a laparoscopic resection for sigmoid colon or rectal cancer were included. These aspects were abstracted and compared within no laparotomy and previous vertical laparotomy groups: demographics, perioperative aspects, pathological features and survival. RESULTS: There were 252 patients in no laparotomy group, and 25 cases with previous vertical incisions including lower (n = 12, 48%), upper (n = 7, 28%), and lower&upper (n = 2, 8%) midline and paramedian (n = 4, 16%) laparotomies. Veress insufflation and open technique were used in 19 (76%) and 6 (24%) cases, respectively, during the insertion of the first trocar in previous laparotomy group. Patients in previous laparotomy group were significantly older (59.2 +/- 13.4 vs. 66.2 +/- 10.1, p = 0.01), but gender, ASA scores, tumor and technique related factors were similar within the groups, including operation time (200 [70 600] vs. 200 [130-390] min, p = 0.353), blood loss (250 [100-1500] vs. 250 [0 2200] ml, p = 0.46), additional trocar insertion (10 [4%] vs. 3 [12%], p = 0.101), conversion (20 [7.9%] vs. 4 [16%], p = 0.25), postoperative complication (59 [23.4%] vs. 4 [16%], p = 0.06) and 30-day mortality (7 [2.8%] vs. 1 [4%], p = 0.536) rates. Oncological outcomes regarding pathological features and 5-year survival rates (65% vs. 73.2%, p = 0.678) were not different. CONCLUSION: The presence of a previous laparotomy does not worsen the outcomes in patients undergoing laparoscopic removal of sigmoid or rectal cancer, thus laparoscopy may be considered to be safe and feasible in these cases. PMID- 26231994 TI - Early implementation of Enhanced Recovery After Surgery (ERAS(r)) protocol - Compliance improves outcomes: A prospective cohort study. AB - Enhanced Recovery After Surgery protocol in colorectal surgery allows shortening length of hospital stay and reducing complication rate. Despite the clear guidelines and conclusive evidence their full implementation and putting them into daily practice meets certain difficulties, especially in the early stage. The aim of the study was to analyse the course of implementation of the ERAS protocol into daily practice on the basis of adherence to the protocol. Group included 92 patients (43F/49M) with colorectal cancer submitted to laparoscopic resection during the years 2013-2014. Perioperative care in all of them based on ERAS protocol consisting of 16 items. Its principles and discharge criteria were based on the guidelines of the ERAS Society guidelines. The entire analysed group of patients was divided into 3 subgroups (30 patients) depending on the time from ERAS protocol implementation. We analysed the compliance with the protocol and its influence on length of hospital stay, postoperative complications and readmission rate in different subgroups. The average compliance with the protocol differed significantly between groups and was 65% in group 1, 83.9% in group 2 and 89.6% in group 3. The compliance with subsequent protocol elements was different. The length of stay and complication rate was statistically different in analysed subgroups. The whole group demonstrated an inverse correlation between compliance and length of stay. This analysis leads to the conclusion that the introduction of the ERAS protocol is a gradual process, and its compliance at the level of 80% or more requires at least 30 patients and the period of about 6 months. The initial derogation from the assumed proceedings is inevitable and should not discourage further action. Particular emphasis in the initial stage should be put on continuous training of personnel of all specialties and continuous evaluation of the results. PMID- 26231995 TI - Current status of corneal xenotransplantation. AB - Corneal allo-transplantation is a well-established technique to treat corneal blindness. However, the limited availability of human donors demands the exploration of alternative treatments such as corneal xenotransplantation (e.g., pigs as donors) and bioengineered corneas. Since the first attempt of corneal xenotransplantation using a donor pig cornea in 1844, great advances have been made in the development of genetically-engineered pigs, effective immunosuppressive protocols and the establishment of guidelines for the conduction of clinical trials. We highlight immunological and physio-anatomical barriers of corneal xenotransplantation, recent progress of corneal xenotransplantation in non-human-primates studies, and regulatory guidelines to conduct clinical trials for corneal xenotransplantation. PMID- 26231996 TI - Laparoscopic appendectomy: Which factors are predictors of conversion? A high volume prospective cohort study. AB - Appendicitis represents one of the most frequent condition requiring surgery. In Italy almost 0.2% of the population will be affected by acute appendicitis every year. Laparoscopic appendectomy (LA) has gained acceptance over the past years and despite several meta-analyses, randomized studies and retrospective studies have been conducted, the indications and results are still conflicting especially in cases of complicated appendicitis. The aim of our study is to evaluate which factors are related to conversion to open appendectomy (OA) during laparoscopic appendectomy (LA). MATHERIALS AND METHODS: From September 2011 to May 2013, appendectomy for acute appendicitis was performed on 434 patients in our Surgical Unit at S. Orsola-Malpighi Hospital, Bologna, Italy. Of these, 369 patients (85%) underwent LA. The clinical, demographic, surgical and pathological data of these patients were included in a prospective database. To note, only laparoscopic appendectomies were considered to be included in the analysis. The following factors were analyzed in order to identify which were associated with the conversion: age, sex, body mass index (BMI), previous abdominal surgery, comorbidities, clinical and laboratory parameters including Alvarado score, PCR, intraoperative findings such as anatomy and degree of inflammation. During our study period, laparoscopic appendectomies were performed by different surgeons both residents and attending surgeons. The decision to convert the intervention in an open procedure was taken by the individual surgeon. Regarding the postoperative period, were considered the time of hospitalization and related costs, time of oral intake of liquid and solid, time of passage of stool, readmissions and reoperations. RESULTS: At univariate analysis, the factors significantly related to the conversion were the presence of comorbidities (p < 0.001) and, among these, the presence of arterial hypertension (p = 0.006) or other cardiovascular diseases (p = 0.031) and the history of previous abdominal surgery (p = 0.023). Patients with higher mean age (33.9 +/- 15.4 vs. 46.0 +/- 19.3, p = 0.001) and higher body mass index (BMI) (23.5 +/- 4.3 vs 25.8 +/- 4.9 kg/m(2), p = 0.006) had a higher risk of conversion. Multivariate analysis finally showed that factors significantly related to the conversion were the presence of comorbidities (p = 0.029), the presence of an appendiceal perforation (p = 0.003), a retrocecal appendix (p = 0.004), the presence of appendicular abscess (p = 0.023) and the presence of diffuse peritonitis (p = 0.008). CONCLUSION: The majority of patients with acute appendicitis can be successfully managed with laparoscopy. We found that the only preoperative independent factor related to conversion during laparoscopic appendectomy is the presence of comorbidities. Nevertheless surgeons should take into account that presence of peri-appendicular abscess and diffuse peritonitis are both independently related not only to higher rate of conversion but also to higher risk of postoperative complication. PMID- 26231997 TI - Rwandan family medicine residents expanding their training into South Africa: the use of South-South medical electives in enhancing learning experiences. AB - BACKGROUND: International medical electives are well-accepted in medical education, with the flow of students generally being North-South. In this article we explore the learning outcomes of Rwandan family medicine residents who completed their final year elective in South Africa. We compare the learning outcomes of this South-South elective to those of North-South electives from the literature. METHODS: In-depth interviews were conducted with Rwandan postgraduate family medicine residents who completed a 4-week elective in South Africa during their final year of training. The interviews were thematically analysed in an inductive way. RESULTS: The residents reported important learning outcomes in four overarching domains namely: medical, organisational, educational, and personal. CONCLUSIONS: The learning outcomes of the residents in this South-South elective had substantial similarities to findings in literature on learning outcomes of students from the North undertaking electives in the Southern hemisphere. Electives are a useful learning tool, both for Northern students, and students from universities in the South. A reciprocity-framework is needed to increase mutual benefits for Southern universities when students from the North come for electives. We suggest further research on the possibility of supporting South-South electives by Northern colleagues. PMID- 26231998 TI - Low intensity-pulsed ultrasound induced apoptosis of human hepatocellular carcinoma cells in vitro. AB - The present study was conducted to determine whether low intensity-pulsed ultrasound (LIPUS) could induce apoptosis of human hepatocellular carcinoma cells, SMMC-7721, and to define the mechanism of ultrasound-induced apoptosis, in vitro. MTT assay was used to measure cell proliferation. Apoptosis was investigated by multiple methods such as flow cytometry, DNA fragmentation, Ca(2+) mobilizations, pro- and anti-apoptotic protein expression, and light as well as ultramicroscopic morphology. The results provide evidence that LIPUS induced a dose-dependent effect on cell viability and apoptosis of SMMC-7721 cells. Specifically, exposure of cells to >0.5 W/cm(2) intensity significantly increased cell apoptosis, caused shifts in cell cycle phase, and induced structural changes. Ultrasound significantly increased intracellular Ca(2+) concentrations and modulated expression of caspase-3, Bcl-2 and Bax. The findings suggest that this novel technology can be used to induce SMMC-7721 apoptosis via the Ca(2+)/mitochondrial pathway and could potentially be of clinical use for the treatment of hepatocellular carcinoma (SMMC-7721 cell line) and other cancers. PMID- 26231999 TI - Analytical modeling, finite-difference simulation and experimental validation of air-coupled ultrasound beam refraction and damping through timber laminates, with application to non-destructive testing. AB - Reliable non-destructive testing (NDT) ultrasound systems for timber composite structures require quantitative understanding of the propagation of ultrasound beams in wood. A finite-difference time-domain (FDTD) model is described, which incorporates local anisotropy variations of stiffness, damping and density in timber elements. The propagation of pulsed air-coupled ultrasound (ACU) beams in normal and slanted incidence configurations is reproduced by direct definition of material properties (gas, solid) at each model pixel. First, the model was quantitatively validated against analytical derivations. Time-varying wavefronts in unbounded timber with curved growth rings were accurately reproduced, as well as the acoustic properties (velocity, attenuation, beam skewing) of ACU beams transmitted through timber lamellas. An experimental sound field imaging (SFI) setup was implemented at NDT frequencies (120 kHz), which for specific beam incidence positions allows spatially resolved ACU field characterization at the receiver side. The good agreement of experimental and modeled beam shifts across timber laminates allowed extrapolation of the inner propagation paths. The modeling base is an orthotropic stiffness dataset for the desired wood species. In cross-grain planes, beam skewing leads to position-dependent wave paths. They are well-described in terms of the growth ring curvature, which is obtained by visual observation of the laminate. Extraordinary refraction phenomena were observed, which lead to well-collimated quasi-shear wave coupling at grazing beam incidence angles. The anisotropic damping in cross-grain planes is satisfactorily explained in terms of the known anisotropic stiffness dataset and a constant loss tangent. The incorporation of high-resolution density maps (X-ray computed tomography) provided insight into ultrasound scattering effects in the layered growth ring structure. Finally, the combined potential of the FDTD model and the SFI setup for material property and defect inversion in anisotropic materials was demonstrated. A portable SFI demonstrator was implemented with a multi-sensor MEMs receiver array that captures and compensates for variable wave propagation paths in glued laminated timber, and improves the imaging of lamination defects. PMID- 26232000 TI - Efficacy and safety in clinical practice of a rilpivirine, tenofovir and emtricitabine single-tablet regimen in virologically suppressed HIV-positive patients on stable antiretroviral therapy. AB - INTRODUCTION: Switching to a rilpivirine, tenofovir and emtricitabine (RTE) single-tablet regimen (STR) has been evaluated in a limited number of virologically suppressed patients. The aim of this study was to describe clinical outcomes in HIV-positive patients switched from a suppressive antiretroviral regimen to RTE STR in routine clinical practice. METHODS: In this retrospective study of antiretroviral-treated patients with <50 copies of HIV RNA/mL switched to RTE STR, virological failure (VF) was defined as two consecutive measurements of >=50 copies/mL or a single measurement of >=50 copies/mL followed by any change in treatment. Treatment failure (TF) was defined as VF or discontinuation of the STR for any reason. Univariate mixed-linear models were used to identify differences in laboratory parameters over time. RESULTS AND DISCUSSION: The analysis involved 307 patients (83% males) with a median age of 45.8 years (interquartile range (IQR 39.3-50.9), who were followed up for a median of 7.4 months (IQR 4.6-10.9). VF occurred in three patients (1%) switched from a protease inhibitor (PI)-based regimen, after a median of 2.6 months (IQR 1.6 3.0), and TF in 34 patients (11%) after a median of three months (IQR 1.4-5.8), 24 of whom (71%) were receiving a PI-based regimen at baseline. Overall, there was a slight but statistically significant improvement in the mean monthly change from baseline in CD4+ cell counts (p=0.027), the CD4+/CD8+ ratio (p=0.0001), and Hb (p=0.024), alanine amino transferase (ALT) (p=0.009), total bilirubin (p<0.0001), indirect bilirubin (p<0.0001), total cholesterol (p<0.0001) and triglyceride (p<0.0001) levels. There was also a slight but statistically significant increase in serum creatinine (p=0.0004), aspartate amino transferase (AST) (p=0.001) and liver fibrosis index (FIB-4) (p=0.002), and a decrease in eGFRcreat (p<0.0001) and high-density lipoprotein (HDL) cholesterol (p<0.0001) values. The study limitations include its retrospective design, the relatively short follow-up, and the absence of data concerning the severity of clinical adverse events; however, it does provide new information concerning the laboratory changes that occur in patients switching from PI-based or PI-sparing regimens to RTE STR. CONCLUSIONS: The study findings confirm the efficacy and safety in clinical practice of switching to RTE STR in virologically suppressed patients receiving other antiretrovirals. PMID- 26232003 TI - Highly sensitive electrochemical immunosensor for the detection of alpha fetoprotein based on PdNi nanoparticles and N-doped graphene nanoribbons. AB - An ultrasensitive sandwich-type electrochemical immunosensor was designed for the quantitative detection of alpha fetoprotein (AFP). The beta-cyclodextrins functionalized graphene sheets (CD-GS) were used as the sensing matrix for immobilizing adamantine-1-carboxylic acid functionalized primary anti-AFP (ADA Ab1) and enhanced the electron transfer. PdNi alloy nanoparticles decorated N doped graphene nanoribbons (PdNi/N-GNRs) were used as labels of secondary anti AFP (Ab2), and PdNi alloy nanoparticles (PdNi NPs) exhibited high catalytic performance towards the reduction of H2O2. Meanwhile, with good dispersion, large specific surface area and good catalytic performance, N-doped graphene nanoribbons (N-GNRs) significantly amplified the electrochemical signal. Under the optimal conditions, the electrochemical immunosensor exhibited a wide linear range of 0.0001-16 ng/mL with a low detection limit of 0.03 pg/mL. Additionally, the proposed immunosensor showed high specificity, good reproducibility and long term stability, which have promising application in bioassay analysis. PMID- 26232001 TI - Intracerebral hemorrhage outcomes following selective blockade or stimulation of the PGE2 EP1 receptor. AB - BACKGROUND: Inflammation following intracerebral hemorrhage (ICH) significantly contributes to secondary brain damage and poor outcomes. Prostaglandin E2 (PGE2) is known to modulate neuroinflammatory responses and is upregulated in response to brain injury as a result of changes in inducible cyclooxygenase 2 (COX-2) and the membrane-bound type of PGE synthase. Inhibition of COX-2 activity has been reported to attenuate ICH-induced brain injury; however, the clinical utility of such drugs is limited due to the potential for severe side effects. Therefore, it is now important to search for downstream targets capable of preferentially modulating PGE2 signaling, and the four E prostanoid receptors, EP1-4, which are the main targets of PGE2, remain a viable therapeutic option. We have previously shown that EP1 receptor deletion aggravates ICH-induced brain injury and impairs functional recovery, thus the current study aimed to elaborate on these results by including a pharmacologic approach targeting the EP1 receptor. RESULTS: Chronic post-treatment with the selective EP1 receptor antagonist, SC-51089, increased lesion volume by 30.1 +/- 14.5% (p < 0.05) and treatment with the EP1 agonist, 17-pt-PGE2, improved neuromuscular functional recovery on grip strength (p < 0.01) and hanging wire (p < 0.05) behavioral testing. To begin identifying the mechanisms involved in EP1-mediated neuroprotection after ICH, histology was performed to assess ferric iron content, neuroinflammation, leukocyte transendothelial migratory potential, and peripheral neutrophil and immunoglobulin infiltration. Following ICH, mice treated with the antagonist displayed increased ferric iron (p < 0.05) and cortical microgliosis (p < 0.05), whereas treatment with the agonist decreased cortical (p < 0.01) and striatal (p < 0.001) astrogliosis, leukocyte transendothelial migratory potential (p < 0.01), neutrophil infiltration (p < 0.05), and blood brain barrier breakdown (p < 0.05). CONCLUSIONS: In agreement with our previous results, selective antagonism of the EP1 receptor aggravated ICH-induced brain injury. Furthermore, EP1 receptor agonism improved anatomical outcomes and functional recovery. Thus, the present data continues to reinforce a putative role for EP1 as a new and more selective therapeutic target for the treatment of ICH that could reduce the side effects associated with COX-2 inhibition while still exploiting the beneficial effects. PMID- 26232004 TI - Molecularly imprinted electrochemical sensing interface based on in-situ polymerization of amino-functionalized ionic liquid for specific recognition of bovine serum albumin. AB - A molecularly imprinted polymer film was in situ polymerized on a carboxyl functionalized multi-walled carbon nanotubes modified glassy carbon electrode surface under room temperature. This technique provides a promising imprinting approach for protein in an aqueous solution using 3-(3-aminopropyl)-1 vinylimidazolium tetrafluoroborate ionic liquid as functional monomer, N, N' methylenebisacrylamide as crossing linker, ammonium persulfate and N,N,N',N' tetramethylethylenediamine as initiator, and bovine serum albumin (BSA) as template. The molecularly imprinted polymerized ionic liquid film shows enhanced accessibility, high specificity and sensitivity towards BSA. Electrochemical sensing performance of the imprinted sensor was thoroughly investigated using K3Fe[CN]6/K4Fe[CN]6 as electroactive probes. Under optimal conditions, the current difference before and after specific recognition of BSA was found linearly related to its concentration in the range from 1.50*10(-9) to 1.50*10( 6) mol L(-1). The detection limit was calculated to be 3.91*10(-10) mol L(-1) (S/N=3). The practical application of the imprinted sensor was demonstrated by determining BSA in liquid milk samples. PMID- 26232005 TI - Effects of three-layered nanodisk size on cell detection sensitivity of plasmon resonance biosensors. AB - The double resonance plasmonic biosensors based on Au nanodisks (NDs) with a thin SiO2 spacer between the top and bottom Au layers were employed to detect MCF-7 breast cancer cells. The hybridized modes between the localized surface plasmon resonance of Au NDs and the gap coupling resonance of NDs with the Au film underneath have been observed. These multiple metallic layer NDs exhibit higher sensitivity than the common single metallic layer NDs. The extinction spectra showed double resonance bands that could be tailored by varying the ND size. Three sizes of multiple layer NDs ranging from 60 to 200 nm diameter (dia.) were generated and their refractive sensitivity to the surrounding media were analyzed for cell detection. Nanodisks with 120 dia. showed the highest refractive sensitivity up to 230 nm/refractive index unit. These sensors could be used to detect a broad range of MCF-7 cells from a low cell concentration down of 1.0*10(3)cells/ml up to a high cell concentration of 1.7*10(7) cells/ml. PMID- 26232009 TI - [Metastatic intestinal obstruction secondary to a primary lung tumour]. PMID- 26232010 TI - Clinical Relevance of Poststent Fractional Flow Reserve After Drug-Eluting Stent Implantation. AB - BACKGROUND: The prognostic value of poststent fractional flow reserve (FFR) has not been clearly defined in patients with drug-eluting stent (DES) implantation. This study sought to evaluate the association between FFR and clinical outcomes after DES implantation with intravascular ultrasound (IVUS) assistance. METHODS: A total of 115 lesions (107 patients) with FFR measurement after IVUS-assisted DES implantation were enrolled. Poststent angiographic and IVUS parameters were compared with FFR values. Clinical outcomes were assessed by target vessel failure (TVF), defined as a composite of target vessel revascularization, death, or non-fatal myocardial infarction attributed to the target vessel. RESULTS: Mean poststent FFR was 0.92 +/- 0.04. Minimal stent area by IVUS had a positive correlation with poststent FFR (r = 0.36; P<.01). Poststent FFR >=0.89 was a physiologic cut-off value for 1-year TVF-free survival. The best cut-off value of minimal stent area to define poststent FFR >=0.89 was >5.4 mm2 (sensitivity, 63.2%; specificity, 90.0%). At 3-year follow-up, lesions with poststent FFR >=0.89 had a better TVF-free survival rate than those with poststent FFR <0.89 (89.3% vs 61.1%, P =.03). CONCLUSION: Poststent FFR can be a useful predictor for long-term clinical outcomes after DES implantation and relevant to IVUS minimal stent area. PMID- 26232011 TI - What Was, What Is, and What Will Be! PMID- 26232012 TI - The Correlation Between Cigarette Smoking and Other Risk Factors With Coronary Stenosis Composition. PMID- 26232013 TI - Variations in Clinical Presentation, Risk Factors, Treatment, and Prognosis of Spontaneous Coronary Artery Dissection. AB - Spontaneous coronary artery dissection (SCAD) has been considered a rare cause of acute coronary syndrome (ACS) in younger patients without known cardiovascular risk factors. However, recent studies have reported a higher incidence of SCAD in patients presenting with ACS with use of advanced invasive imaging modalities. In light of increasing awareness, the diagnosis of SCAD has increased significantly. We conducted a single-center retrospective analysis of cases with reported SCAD during a 10-year period between 2003 and 2013. Ten cases of SCAD were identified after review of coronary angiograms and clinical records. Basic demographic details, comorbidities, initial presentation, length of dissection, specific vessels involved in dissection, initial management, subsequent outcome, and incidence of recurrence were documented. All patients were female, with mean age of 42 years. One-third of cases occurred in the peripartum period. All patients presented with acute coronary syndromes. The left anterior descending artery was the predominant vessel involved in 80% of the patients on initial presentation. Out of 10 patients, 6 were managed conservatively, 2 had emergent coronary artery bypass graft, and 2 had percutaneous coronary intervention with placement of stents. Three of the 6 patients undergoing medical management after the initial presentation had recurrence within the same hospitalization. PMID- 26232014 TI - Spontaneous Coronary Artery Dissection: Time for Development of a Large National Registry. PMID- 26232015 TI - The Efficacy and Safety of Antegrade Inoue-Balloon Aortic Valvuloplasty to Treat Calcific Critical Aortic Stenosis. AB - BACKGROUND: Critical aortic stenosis (AS) with severe calcific degeneration often resists conventional retrograde percutaneous balloon aortic valvuloplasty (PBAV). To enhance therapeutic efficacy, a novel PBAV technique has been developed by utilizing a single Inoue balloon via an antegrade approach, performing multiple inflations with step-up increases (M-PBAV) of balloon diameter to the size of the surgical valve ring. PATIENTS AND METHODS: A total of 405 non-surgical patients with critical AS were treated by M-PBAV and the acute therapeutic response and long-term clinical course were evaluated; some patients underwent the procedure on two or three occasions. RESULTS: In a total of 456 procedures, mean transaortic valve pressure gradient improved from an initial 63.6 +/- 17.3 mm Hg to 22.7 +/- 8.9 mm Hg post PBAV (P<.01). Mean aortic valve area increased from an initial 0.55 +/- 0.15 cm2 to 0.98 +/- 0.20 cm2 immediately after M-PBAV (P<.01). Clinical symptoms (New York Heart Association [NYHA] class) improved over time. Prior to M-PBAV, baseline NYHA class I-II was 9.1%, and NYHA class III-IV was 90.9%. At 12 months post M-PBAV, mortality was 17.1%, with repeat M-PBAV plus surgical AVR at 12.7%, 10.5% NYHA class III-IV, and 59.6% NYHA class I-II. At 24 months post M-PBAV, mortality was 25.8%, with repeat PBAV plus surgical AVR at 19.0%, 8.8% NYHA class III-IV, and 46.2% NYHA class I-II. Adverse events related to the procedure included critical AR (0.5%), cardiac tamponade (1.8%), intraprocedure hemodynamic compromise requiring percutaneous cardiopulmonary support (0.5%), and reversible cerebral ischemia (1.3%). No myocardial infarct or vascular complications occurred. CONCLUSION: M-PBAV enhanced the therapeutic efficacy and procedural safety of valvuloplasty to treat severely calcified critical AS, and diversified its clinical roles. PMID- 26232017 TI - Clinical Outcomes After Percutaneous Coronary Intervention in Acute Myocardial Infarction Due to Unprotected Left Main Coronary Artery Disease. AB - OBJECTIVE: Patients with acute myocardial infarction (AMI) with unprotected left main coronary artery (ULMCA) as culprit lesion are a high-risk subgroup with a substantial mortality. Percutaneous coronary intervention (PCI) has become an option for these patients, but the data are limited. We therefore analyzed the clinical characteristics and the short-term and long-term outcomes of this subgroup of patients. METHODS: This is a retrospective, single-center, observational study with 30 AMI patients admitted between July 2005 and March 2013 and treated with emergency PCI to an ULMCA culprit lesion. RESULTS: Twenty four males and 6 females with an average age of 63 +/- 17 years were enrolled. Nineteen patients (63.3%) presented with ST-segment elevation MI, while 11 patients presented with non-ST segment elevation MI. Cardiac shock was present in 8 patients, total occlusion of left main coronary artery was identified by coronary angiography in 13 patients, and coexisting right coronary artery disease was present in 10 patients. Angiographic procedural success was achieved in 93% of patients, with intraaortic balloon pump used in 9 patients. Overall in hospital mortality was 20%, all secondary to refractory cardiogenic shock and multiorgan failure. During a follow-up period of 1099 +/- 819 days, no deaths or MIs were detected. Probability of freedom from death at 3 years was 79.7 +/- 7.4%. CONCLUSION: We demonstrate that in patients with LMCA disease in the setting of AMI, PCI is a feasible treatment option with an in-hospital survival of 80%. The long-term clinical outcome of patients surviving to hospital discharge is excellent. PMID- 26232016 TI - Impact of Advanced Age on Procedural and Acute Angiographic Outcomes in Patients Treated for Peripheral Artery Disease With Orbital Atherectomy: A CONFIRM Registries Subanalysis. AB - PURPOSE: Data on the outcomes of elderly patients with peripheral arterial disease (PAD) who undergo orbital atherectomy are limited. This analysis compares the procedural and acute angiographic outcomes of PAD patients treated with orbital atherectomy stratified by age (>= 75 years of age [elderly] vs <75 years of age [younger]). METHODS: The CONFIRM registry series with non-missing age was analyzed and included 2995 real-world PAD patients (4557 lesions) with 1753 younger patients (2637 lesions) and 1242 elderly patients (1920 lesions) treated with orbital atherectomy. The composite rate of adverse events including dissection, perforation, slow flow, vessel closure, spasm, embolism, and thrombus formation was compared between groups. RESULTS: Elderly patients had a higher proportion of females (47.5% vs 35.3%; P<.001), more patients with critical limb ischemia (49.9% vs 39.3%; P<.001), longer lesion length (75.0 +/- 74.1 mm vs 69.9 +/- 68.9 mm; P=.01), and more lesions treated below the knee (38.9% vs 34.4%; P=.01). Younger and elderly patients had similar rates of composite adverse events (22.0% vs 21.3%; P=.81), dissection (11.4% vs 10.5%; P=.72), vessel closure (1.7% vs 1.1%; P=.13), spasm (6.3% vs 6.4%; P=.96), and embolism (2.5% vs 1.6%; P=.31). Elderly patients had a lower rate of thrombus formation (0.9% vs 1.6%; P=.03), but a higher perforation rate (1.2% vs 0.4%; P=.01). CONCLUSIONS: Orbital atherectomy resulted in similar composite rates of adverse events despite the elderly having unfavorable baseline Rutherford classification and lesion characteristics. The higher rate of perforation may be explained by longer and more below-the-knee lesions. PMID- 26232018 TI - Identification of Risk Factors for Arrhythmia Post Transcatheter Closure of Perimembranous Ventricular Septal Defect. AB - OBJECTIVE: Arrhythmias are frequently observed after transcatheter closure of perimembranous ventricular septal defect (pmVSD), especially in the early postprocedure period. Independent risk factors associated with postclosure arrhythmias are still elusive. The current study aimed to identify such risk factors via regression analysis with a long-term follow-up. METHODS: A group of 553 patients from June 2003 to December 2010 who received symmetric Amplatzer type pmVSD occluders for pmVSD in our center were followed for 2-8 years. The complications during the follow-up period were classified as early (within 1 year), continuous (persisted >1 year), or late (recurrent or onset after 1 year). We first evaluated the potential risk factors (age, procedure time, size of the defect, size of the occluder, diameter of the defect, distance of lesion to aortic rim, distance of lesion to tricuspid rim, presence of aneurysm, orifice size on aneurysm, arrhythmia before procedure, procedure time) by comparing complicated and uncomplicated cases using univariate analysis, then logistic analysis for independent risk factors. RESULTS: We identified 90 cases of early, 59 cases of continuous, and 13 cases of late complications. The size of the occluder was identified as an independent risk factor for early, continuous, and late arrhythmias. Preexisting arrhythmias were found to be risk factors for early and late arrhythmias, while the distance between the defect and the tricuspid rim was identified as a risk factor for continuous arrhythmias. CONCLUSION: The size of the occluder, preexisting arrhythmias, and the distance between the defect and the tricuspid rim were found to be risk factors for arrhythmias after transcatheter closure of pmVSD. Selection of properly sized occluders might be crucial to reduce postclosure complications. PMID- 26232019 TI - Bioresorbable Vascular Scaffolds for Heavily Calcified Lesions: How to Tackle the Rugged Passage? AB - We present a case of a heavily calcified left anterior descending artery lesion successfully treated with bioresorbable vascular scaffold (BVS). Despite a 360 degrees heavy calcification at the site of the culprit lesion and prior implantation of a proximal metal stent, meticulous lesion preparation with scoring balloon and use of a deep-seated child catheter facilitated the successful deployment of two BVSs. This case report demonstrates how optimal lesion preparation, adequate dedicated device support, and careful assessment with the use of intracoronary imaging device can facilitate implantation of BVS in complex lesions. PMID- 26232020 TI - "Candy Cane" Guide Catheter Extension for Stent Delivery. AB - Stent delivery to a native coronary artery lesion located proximal to the anastomosis of a bypass graft can be challenging due to severe tortuosity. Guide catheter extensions, such as the GuideLiner, can facilitate equipment delivery. In the presented case, a 180 degrees anastomotic bend in the saphenous vein graft resulted in several failed attempts at stent delivery. A 6 Fr guide catheter extension was then advanced through the extreme angulation at the SVG anastomosis using a distal-anchor technique and assuming a "candy cane" configuration, enabling stent delivery. PMID- 26232021 TI - Late Malapposition After Bare-Metal Stent, But Not Bioresorbable Scaffold: Insights on Intraindividual Heterogeneity in Plaque and Device Response. AB - We present a case of late acquired bare-metal stent malapposition and uncovered struts, visible at angiography and confirmed by optical frequency domain imaging. In the same patient, an everolimus-eluting biovascular scaffold in another vessel was well apposed and all struts were covered. This case highlights the potential heterogeneity in the evolution of atherosclerotic plaques and response to different devices in the same patient. PMID- 26232023 TI - Saphenous Vein Graft Intervention: The "EPD Gap" and How it Can be Approached With a Simple Technique. PMID- 26232022 TI - Clopidogrel and Genotyping. PMID- 26232024 TI - Performance of 5-aminolevulinic-acid-based photodynamic diagnosis for radical prostatectomy. AB - BACKGROUND: The aim of this study was to investigate whether we could detect positive surgical margins during open and laparoscopic radical prostatectomy by 5 aminolevulinic acid (ALA) photodynamic diagnosis (PDD) and mapping of red fluorescence in human prostate cancer cells. METHODS: All 52 patients were diagnosed with prostate cancer by biopsy. They had a positive core in the apex or highly suspicious positive margins. Open and laparoscopic radical prostatectomy was performed in 18 and 34 cases, respectively. One gram of ALA solution was given intraoperatively, orally through a stomach tube. An endoscopic PDD system, including a D-Light C, CCU Tricam SLII/3CCD CH Tricam-P PDD, and HOPKINS II Straight Forward Telescope 0 degrees , was used. The D-Light C light source was equipped with a band-pass filter. The CCU Tricam SLII/3CCD CHTricam-P PDD video camera system was equipped with a long-pass filter. The laparoscopy optic component was equipped with a yellow long-pass filter. RESULTS: One of the 52 patients had a red-fluorescent-positive margin of the excised whole prostate and the positive surgical margin was histologically confirmed. In the section of excised prostate, we obtained 141 biopsied samples. The sensitivity and specificity were 75.0% and 87.3%, respectively. CONCLUSIONS: Intraoperative ALA PDD is feasible. However, heat degeneration and length of positive surgical margin have crucial influences on red fluorescence. In future, a randomized clinical trial should be carried out. PMID- 26232025 TI - Photochemistry of free and bound Zn-chlorophyll analogues to synthetic peptides depend on the quinone and pH. AB - A synthetic peptide was used as a scaffold to bind Zn-Chlorophyll (ZnChl) analogues through histidine ligation to study their photochemistry in the presence of different type of quinones. The Chl analogues were chlorin e6 (Ce6), chlorin e6 trimethyl ester, pyropheophorbide a, and pheophorbide a while the quinones were PPBQ, DMBQ, NPHQ, DBTQ, DCBQ and PBQ. The binding of each ZnChl analogue to the peptide was verified by native gel electrophoresis. First the photo-stability of the ZnChl analogues were tested under continuous light. The ZnCe6 and ZnCe6TM analogues showed the least stability judged by the loss of optical signal intensity at their Qy band. The photoactivity of each ZnChl analogue was measured in the presence of each of the six quinones using time resolved EPR spectroscopy. DMBQ was found to be the most efficient electron acceptor when all four ZnChl analogues were compared. The light-induced electron transfer between the ZnChl analogues complexed with the peptide and DMBQ were also measured using time-resolved EPR spectroscopy. The ZnCe6-peptide complex exhibited the highest photoactivity. The electron transfer in the complex was faster and the photoactivity yield was higher than those values obtained for free ZnCe6 and DMBQ. The fast phase of kinetics can be attributed to intra-protein electron transfer in the complex since it was not observed in the presence of DMBQ-glutathione adduct. Unlike free ZnCe6, the ZnCe6-peptide complex was robust and demonstrated very similar photoactivity efficiency in pH values 10, 8.0 and 5.0. The electron transfer kinetics were pH dependent and appeared to be modulated by the peptide charge and possibly fold. The charge recombination rate was slowed by an order of magnitude when the pH value was changed from 10.0 to 5.0. The implications of constructing the photoactive peptide complexes in terms of artificial photosynthesis are discussed. PMID- 26232026 TI - Synthesis of enyne and aryl vinyl sulfoxides: functionalization via Pummerer rearrangement. AB - An efficient methodology for the synthesis of aryl-substituted vinyl sulfoxides through direct substitution of aryl-substituted alkynyl grignard reagents on menthyl-p-toluenesulfinate followed by Suzuki-Miyaura cross-coupling reaction has been developed. It has also been described that the reaction of alkyl-substituted and cycloalkyl-substituted alkynyl grignard reagents with menthyl-p toluenesulfinate led to two products, i.e., alkynyl sulfoxide derivatives, as a result of substitution, and enyne sulfoxide derivatives, which resulted from substitution followed by Michael type addition. It was possible to selectively synthesize the enyne sulfoxide derivatives by changing the concentration of the grignard reagent. These alkenyl sulfoxides were transformed into the corresponding [Formula: see text]-thio aldehydes in high yields via additive Pummerer rearrangement. PMID- 26232027 TI - Synthesis and anticancer activity of novel fused pyrimidine hybrids of myrrhanone C, a bicyclic triterpene of Commiphora mukul gum resin. AB - Myrrhanone C [8(R)-3-oxo-8-hydroxypolypoda-13E,17E,21-triene], a bicyclic triterpene isolated from the gum resin of Commiphora mukul, has been chemically transformed to synthesize a series of ten novel pyrimidine hybrids in good to excellent yields. The synthesized compounds (2-22) were evaluated for their anticancer potential against a panel of six cancer cell lines, namely A-549 (lung), Hela (cervical), MCF-7 (breast), ACHN (renal), Colo-205 (colon) and B-16 (mouse melanoma) by employing the MTT assay. In general, the synthesized compounds showed significant anticancer activity against all the cancer cell lines tested. Interestingly, the pyrimidine hybrids 18 and 19 showed good activity against the A-549, MCF-7, B-16, Colo-205 and ACHN cancer cell lines with [Formula: see text] values between 7.7-37.8 [Formula: see text]M. Most significantly, compounds 19 (IC[Formula: see text]: 7.7 [Formula: see text]M) and 18 (IC[Formula: see text]: 9.5 [Formula: see text]M) showed about five- and six fold enhanced activities, respectively, compared to the parent myrrhanone C (1) against A-549 cell line. Flow cytometric analysis revealed that compounds 18 and 19 induced apoptosis in A-549 cells and arrested the cell growth in the G0/G1 phase. PMID- 26232028 TI - Combined isocyanide-based multi-component Ullmann-type reaction: an efficient access to novel nitrogen-containing pentacyclic compounds. AB - 2-Chloro-3-formyl quinoline has been applied as an aldehyde moiety in the Groebke Blackburn-Bienayme multi-component reaction with isocyanides, 2-aminoazines, and 2-aminoazole to afford the desired adducts which are amenable for further cyclization on the basis of Ullmann-type coupling. The copper iodide-mediated intramolecular C-N bond formation in the second step gave an easy access to a series of imidazo[4[Formula: see text],5[Formula: see text]:4,5]pyrrolo[2,3 b]quinoline derivatives in moderate to good yields. PMID- 26232030 TI - Real-time ultrasound-guided epidural catheter insertion in obese parturients. PMID- 26232029 TI - Discovery of new Mycobacterium tuberculosis proteasome inhibitors using a knowledge-based computational screening approach. AB - Mycobacterium tuberculosis bacteria cause deadly infections in patients [Corrected]. The rise of multidrug resistance associated with tuberculosis further makes the situation worse in treating the disease. M. tuberculosis proteasome is necessary for the pathogenesis of the bacterium validated as an anti-tubercular target, thus making it an attractive enzyme for designing Mtb inhibitors. In this study, a computational screening approach was applied to identify new proteasome inhibitor candidates from a library of 50,000 compounds. This chemical library was procured from the ChemBridge (20,000 compounds) and the ChemDiv (30,000 compounds) databases. After a detailed analysis of the computational screening results, 50 in silico hits were retrieved and tested in vitro finding 15 compounds with IC50 values ranging from 35.32 to 64.15 MUM on lysate. A structural analysis of these hits revealed that 14 of these compounds probably have non-covalent mode of binding to the target and have not reported for anti-tubercular or anti-proteasome activity. The binding interactions of all the 14 protein-inhibitor complexes were analyzed using molecular docking studies. Further, molecular dynamics simulations of the protein in complex with the two most promising hits were carried out so as to identify the key interactions and validate the structural stability. PMID- 26232031 TI - Primary myelofibrosis associated glomerulopathy: significant improvement after therapy with ruxolitinib. AB - BACKGROUND: Primary myelofibrosis (PMF) is a type of myeloproliferative neoplasm (MPN) characterized by the predominant proliferation of megakaryocytes and granulocytes in the bone marrow, leading to the deposition of fibrous tissue, and by a propensity toward extramedullary hematopoiesis. Renal involvement in PMF is rare, but kidney tissue samples from these patients reveal MPN-related glomerulopathy, a recently discovered condition, in the late stages of the disease. CASE PRESENTATION: We present the first case described in the medical literature of a patient with early renal glomerular involvement in PMF/MPN. A 60 year-old man with stage 4 chronic kidney disease and a recent diagnosis of PMF (within 4 weeks of presentation at our renal division) presented with generalized body swelling, acute kidney injury, and massive nephrotic-range proteinuria. Kidney biopsy was performed to determine the etiology of the patient's renal dysfunction and revealed early renal glomerular involvement that was histologically characteristic of MPN-related glomerulopathy. Early diagnosis and prompt medical management returned the patient's kidney functionality to the levels seen on initial presentation at our hospital. CONCLUSION: Large studies with long follow-up durations are necessary to identify and categorize the risk factors for the development of MPN-related glomerulopathy, to standardize therapeutic regimens, and to determine whether aggressive management of the myelofibrosis slows the progression of kidney disease. PMID- 26232032 TI - Physiological mechanisms, behavioral and psychological factors influencing the transfer of milk from mothers to their young. AB - This article is part of a Special Issue "Parental Care".Producing milk to support the growth of their young is a central element of maternal care in mammals. In spite of the facts that ecological constraints influence nursing frequency, length of time until weaning and the composition of milk, there is considerable similarity in the anatomy and physiology of milk production and delivery across mammalian species. Here we provide an overview of cross species variation in nursing patterns and milk composition as well as the mechanisms underlying mammary gland development, milk production and letdown. Not all women breastfeed their infants, thus in later sections we review studies of factors that facilitate or impede the initiation and duration of breastfeeding. The results of these investigations suggest that the decisions to initiate and maintain breastfeeding are influenced by an array of personal, social and biological factors. Finally, studies comparing the development of breastfed and formula fed infants as well as those investigating associations between breastfeeding, maternal health and mother/infant interaction are reviewed. Leading health agencies including the World Health Organization and CDC advocate breastfeeding for at least the first 6months postpartum. To achieve these rates will require not only institutional support but also a focus on individual mother/infant dyads and their experience. PMID- 26232033 TI - Thermodynamics-based design of microbial cell factories for anaerobic product formation. AB - The field of metabolic engineering has delivered new microbial cell factories and processes for the production of different compounds including biofuels, (di)carboxylic acids, alcohols, and amino acids. Most of these processes are aerobic, with few exceptions (e.g., alcoholic fermentation), and attention is focused on assembling a high-flux product pathway with a production limit usually set by the oxygen transfer rate. By contrast, anaerobic product synthesis offers significant benefits compared to aerobic systems: higher yields, less heat generation, reduced biomass production, and lower mechanical energy input, which can significantly reduce production costs. Using simple thermodynamic calculations, we demonstrate that many products can theoretically be produced under anaerobic conditions using several conventional and non-conventional substrates. PMID- 26232034 TI - Hypertension Prevalence, Awareness, Treatment, and Control Following China's Healthcare Reform. AB - BACKGROUND: In 2009, China started an impressive national healthcare system reform. One of the key components is to promote equity in access to essential healthcare services including chronic disease management. We assessed the changes in hypertension management and its equity before and after China's healthcare reform in 2009. METHODS: We used data from the 2008 and 2012 waves of the China Health and Retirement Longitudinal Study (CHARLS). The surveys were conducted in Zhejiang and Gansu provinces, containing 1,961 and 1,836 respondents aged 45 and older in 2008 and 2012 respectively. We measured the prevalence of hypertension, and proportions of respondents with hypertension aware of their conditions, receiving treatment and under effective control, separately for 2008 and 2012. We also reported these measures in provinces and rural/urban areas. RESULTS: From 2008 to 2012, the age standardized prevalence of hypertension was steady at 46.2%, but hypertension management improved substantially. Among those with hypertension, the proportion of patients aware of their conditions increased from 57.8% to 69.9%, the proportion of patients receiving treatment increased from 38.1% to 56.1%, and the proportion of patients with hypertension under effective control increased from 21.7% to 36.4%. The highest improvement was found in rural areas of the underdeveloped province, which indicated that the inequity across regions declined over time. CONCLUSIONS: Among Chinese population aged 45 and older in Zhejiang and Gansu provinces, hypertension management improved following healthcare reform. The rate of improvement was faster in rural and underdeveloped areas, possibly related to additional governmental subsidies to these areas. PMID- 26232035 TI - Association of Endothelial and Mild Renal Dysfunction With the Severity of Left Ventricular Hypertrophy in Hypertensive Patients. AB - BACKGROUND: The association between impaired renal function and increase left ventricular mass was shown to be related to increase in arterial stiffness, which indicates that vascular homeostasis and remodeling may impact the left ventricular hypertrophy (LVH) in patients with renal dysfunction. METHODS: We measured the peripheral arterial reactive hyperemia index (RHI) and estimated glomerular filtration rate (eGFR) in 317 hypertensive patients comprising 115 normal RHI (RHI > 1.67) and normal eGFR (eGFR >= 90ml/min per 1.73 m(2)), 136 low RHI (RHI <= 1.67), 27 low eGFR (60 <= eGFR < 90ml/min per 1.73 m(2)) and 39 low RHI combined with low eGFR. RESULTS: Multivariate logistic regression analysis identified lg RHI (odds ratio (OR): 0.001, 95% confidence interval (CI): 10(-6) to 0.426, P = 0.024) and lg eGFR (OR: 0.009, 95% CI: 10(-4) to 0.414, P = 0.016) as independent factors correlated with LVH respectively in hypertensive patients. Compared with normal RHI and eGFR patients, the extent of LVH in patients with either low RHI (OR: 1.224 95% CI: 0.451 to 3.327, P = 0.691) or low eGFR (OR: 0.593 95% CI: 0.070 to 5.037, P = 0.632) did not significantly increase, while it increased significantly in patients with low RHI combined with low eGFR (OR: 4.629 95% CI: 1.592 to 13.458, P = 0.005). CONCLUSIONS: The concurrence of endothelial and mild renal dysfunction was significantly associated with the severity of LVH in hypertensive patients. PMID- 26232036 TI - Repeatability of Central and Peripheral Pulse Wave Velocity Measures: The Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: Arterial stiffness measures are emerging tools for risk assessment and stratification for hypertension and cardiovascular disease (CVD). Carotid femoral pulse wave velocity (cfPWV) is an established measure of central arterial stiffness. Other measures of PWV include femoral-ankle (faPWV), a measure of peripheral stiffness, and brachial-ankle PWV (baPWV), a composite measure of central and peripheral stiffness. Repeatability of central, peripheral, and composite PWV measures has not been adequately examined or compared. METHODS: Participants (n = 79; mean age 75.7 years; USA) from a repeatability study nested within the Atherosclerosis Risk in Communities (ARIC) Study visit 5 (2011-2013) underwent 2 standardized visits, 4-8 weeks apart. Trained technicians obtained 2 PWV measurements at each visit using the VP-1000 Plus system. We calculated the intraclass correlation coefficient (ICC), SE of measurement, and minimal detectable change (MDC95; 95% confidence interval) and difference (MDD). RESULTS: The ICCs and 95% confidence intervals (95% CIs) were 0.70 (0.59, 0.81) for cfPWV, 0.84 (0.78, 0.90) for baPWV, and 0.69 (0.59, 0.79) for faPWV. The MDC95 between repeat measures within an individual was 411.0 cm/s for cfPWV, 370.6 cm/s for baPWV, and 301.4 cm/s for faPWV. The MDD for 2 independent samples of 100 per group was 139.3 cm/s for cfPWV, 172.3 cm/s for baPWV, and 100.4 cm/s for faPWV. CONCLUSIONS: Repeatability was acceptable for all PWV measures in a multicenter, population-based study of older adults and supports its use in epidemiologic studies. Quantifying PWV measurement variation is critical for applications to risk assessment and stratification and eventual translation to clinical practice. PMID- 26232037 TI - A network meta-analysis of therapeutic outcomes after new image technology assisted transurethral resection for non-muscle invasive bladder cancer: 5 aminolaevulinic acid fluorescence vs hexylaminolevulinate fluorescence vs narrow band imaging. AB - BACKGROUND: This study included a network meta-analysis of evidence from randomized controlled trials (RCTs) to assess the therapeutic outcome of transurethral resection (TUR) in patients with non-muscle-invasive bladder cancer assisted by photodynamic diagnosis (PDD) employing 5-aminolaevulinic acid (5-ALA) or hexylaminolevulinate (HAL) or by narrow band imaging (NBI). METHODS: Relevant RCTs were identified from electronic databases. The proceedings of relevant congresses were also searched. Fifteen articles based on RCTs were included in the analysis, and the comparisons were made by qualitative and quantitative syntheses using pairwise and network meta-analyses. RESULTS: Seven of 15 RCTs were at moderate risk of bias for all quality criteria and two studies were classified as having a high risk of bias. The recurrence rate of cancers resected with 5-ALA-based PDD was lower than of those resected using HAL-based PDD (odds ratio (OR) = 0.48, 95 % confidence interval (CI) [0.26-0.95]) but was not significantly different than those resected with NBI (OR = 0.53, 95 % CI [0.26 1.09]). The recurrence rate of cancers resected using HAL-based PDD versus NBI did not significantly differ (OR = 1.11, 95 % CI [0.55-2.1]). All cancers resected using 5-ALA-based PDD, HAL-based PDD, or NBI recurred at a lower rate than those resected using white light cystoscopy (WLC). No difference in progression rate was observed between cancers resected by all methods investigated. CONCLUSIONS: The recurrence rate of some bladder cancers can be decreased by the implementation of either PDD- and NBI-assisted TUR; in real settings, clinicians should consider replacing WLC as the standard imaging technology to guide TUR. PMID- 26232038 TI - Exposure of sea bream (Sparus aurata) to toxic concentrations of benzo[a]pyrene: possible human health effect. AB - Polycyclic aromatic hydrocarbons (PAHs) can accumulate in the food chain, due to their lipophilic properties. Fish can accumulate contaminants including PAHs and frequent consumption of such contaminated fish can pose risk to human health. The aim of this study was to clarify if acute exposure of sea bream (Sparus aurata, a fish species of great economic importance in the Atlantic and Mediterranean areas) to a PAH, benzo[a]pyrene (B[a]P), at a dose that can induce CYP1A and pathological changes in fish gills, liver and muscle, can induce accumulation in muscle. We investigated the cytotoxic effects (as changes in cell viability, DNA laddering and glutathione content) of in vitro exposure of human peripheral blood mononuclear cells (PBMCs) to organic extracts obtained from muscle of sea breams previously exposed via water to B[a]P (2mg/l, for 12, 24 and 72 h). At this level of exposure, B[a]P caused morphological changes, inflammatory response and CYP1A induction not only in sea bream gills and liver but also in muscle; furthermore, in fish muscle we observed a substantial B[a]P accumulation, which may be associated with the increased CYP1A activity in liver and especially in muscle. However, when PBMCs were exposed to organic extracts obtained from sea bream muscle contaminated with B[a]P, a toxic, although modest effect was revealed, consisting in a significant decrease in cell glutathione levels without alterations in cell viability and DNA laddering. This suggests that consumption of sea breams from B[a]P contaminated waters might represent a risk for human health. PMID- 26232039 TI - Changes in metabolites, antioxidant system, and gene expression in Microcystis aeruginosa under sodium chloride stress. AB - Microcystis (M.) aeruginosa, one of the most common bloom-forming cyanobacteria, occurs worldwide. The Qingcaosha (QCS) Reservoir is undergoing eutrophication and faces the problem of saltwater intrusion. The aim of this study was to investigate the effects of sudden salinity changes on physiological parameters and related gene transcription in M. aeruginosa under controlled laboratory conditions. The results showed that sodium chloride (50, 200 and 500 mg L(-1) NaCl) inhibited the algal growth and decreased pigment concentrations (chlorophyll a, carotenoid and phycocyanin). Sodium chloride increased both the intracellular and extracellular microcystin contents and elevated the mcyD transcript level in M. aeruginosa. It also increased the malondialdehyde (MDA) content and caused cytomembrane damage. This damage caused the release of intracellular toxins into the culture medium. In addition, NaCl decreased the maximum electron transport rate, increased the levels of reactive oxygen species (ROS) and changed the cellular redox status. Consequently, NaCl inhibited the expression of cpcB, psbA and rbcL. Furthermore, NaCl increased the activities of superoxide dismutases (SOD), catalase (CAT), glutathione reductase (GR), and total glutathione peroxidase (GPx). The transcript levels of sod and reduced glutathione (gsh) were also increased after exposure to NaCl. Our results indicate that a sudden increase in salinity increases the production and excretion of microcystin, changes the cellular redox status, enhances the activities of antioxidant enzymes, inhibits photosynthesis, and affects transcript levels of related genes in M. aeruginosa. PMID- 26232040 TI - Bioaccumulation and effects of lanthanum on growth and mitotic index in soybean plants. AB - Rare earth elements such as lanthanum (La) have been used as agricultural inputs in some countries in order to enhance yield and improve crop quality. However, little is known about the effect of La on the growth and structure of soybean, which is an important food and feed crop worldwide. In this study, bioaccumulation of La and its effects on the growth and mitotic index of soybean was evaluated. Soybean plants were exposed to increasing concentrations of La (0, 5, 10, 20, 40, 80, and 160 uM) in nutrient solution for 28 days. Plant response to La was evaluated in terms of plant growth, nutritional characteristics, photosynthetic rate, chlorophyll content, mitotic index, modifications in the ultrastructure of roots and leaves, and La mapping in root and shoot tissues. The results showed that the roots of soybean plants can accumulate sixty-fold more La than shoots. La deposition occurred mainly in cell walls and in crystals dispersed in the root cortex and in the mesophyll. When La was applied, it resulted in increased contents of some essential nutrients (i.e., Ca, P, K, and Mn), while Cu and Fe levels decreased. Moreover, low La concentrations stimulated the photosynthetic rate and total chlorophyll content and lead to a higher incidence of binucleate cells, resulting in a slight increase in roots and shoot biomass. At higher La levels, soybean growth was reduced. This was caused by ultrastructural modifications in the cell wall, thylakoids and chloroplasts, and the appearance of c-metaphases. PMID- 26232041 TI - Is UV radiation changing the toxicity of compounds to zebrafish embryos? AB - At ecosystems level, environmental parameters such as temperature, pH, dissolved oxygen concentration and intensity of UV radiation (UVR) have an important role on the efficiency of organisms' physiological and behavioral performances and consequently on the capacity of response to contaminants. Insignificant alterations of these parameters may compromise this response. In addition, these parameters can additionally alter chemical compounds by inducing their degradation, producing thereafter other metabolites. Understanding the combined effects of chemicals and environmental parameters is absolutely necessary for an adequate prediction of risk in aquatic environments. According to this scenario, this work aims at studying the combined toxicity of UVR and three xenobiotics: the biocide triclosan (TCS), the metal chromium (as potassium dichromate, PD) and the fungicide prochloraz (PCZ). To achieve this goal zebrafish (Danio rerio) embryos (3h post fertilization (hpf)) were exposed to several concentrations of each chemical combined with different UV intensities; mortality and eggs were recorded every 24h for the all test duration (96 h). Results showed different response patterns depending on the toxicant, stress levels and duration of exposure. The combination of UVR and TCS indicated a dose ratio deviation where synergism was observed when UVR was the dominant stressor (day 2). The combination of UVR and PD presented a dose level dependency at day 3 indicating antagonism at low stress levels, changing with time where at day 4, a dose ratio deviation showed statistically that synergism occurred at higher PD concentrations. Finally, UVR combined with PCZ indicated a dose ratio at day 3 and dose level deviation at day 4 of exposure, suggesting a synergistic response when PCZ is the dominant stressor in the combination. The obtained results in this study highlighted the importance of taking into account the possible interaction of stressors and time of exposure to better predict environmental risk. PMID- 26232042 TI - Heavy metals in navel orange orchards of Xinfeng County and their transfer from soils to navel oranges. AB - This study investigated heavy metal concentrations in soils and navel oranges of Xinfeng County, a well-known navel orange producing area of China. The results showed that the average concentrations of lead (Pb), cadmium (Cd), chromium (Cr), arsenic (As) and mercury (Hg) in orchard soils all increased compared to the regional background values, especially for Cd, which increased by 422%. When compared to the Chinese Environmental Quality Standard for soil (GB15618-1995), Pb, Cr and Hg concentrations in all orchard soil samples were below the limit standards, but Cd concentrations in 24 soil samples (21%) and As concentrations in 8 soil samples (7%) exceeded the limit standards. However, concentrations of all heavy metals in navel orange pulps were within the National Food Safety Standard of China (GB 2762-2012). Dietary risk assessment also showed that the exposure to these five heavy metals by consumption of navel oranges could hardly pose adverse health effects on adults and children. Since the range and degree of soil Cd pollution was widest and the most severe of all, Cd was taken as an example to reveal the transfer characteristics of heavy metals in soil-navel orange system. Cd concentrations in different organs of navel orange trees decreased in the following order: root>leaf>peel>pulp. That navel oranges planted in the Cd contaminated soils were within the national food safety standard was mainly due to the low transfer factor for Cd from soil to pulp (TFpulp). Further studies showed that TFpulp was significantly negatively correlated with soil pH, organic carbon (OC) and cation exchange capacity (CEC). Based on these soil properties, a prediction equation for TFpulp was established, which indicated that the risk for Cd concentration of navel orange pulp exceeding the national food limit is generally low, when soil Cd concentration is below 7.30 mg/kg. If appropriate actions are taken to increase soil pH, OC and CEC, Cd concentrations in navel orange pulps could be further reduced. PMID- 26232043 TI - Prediction in epidemiology and medicine. PMID- 26232044 TI - Overwintering of the parasitic dinoflagellate Hematodinium perezi in dredged blue crabs (Callinectes sapidus) from Wachapreague Creek, Virginia. AB - Parasitic dinoflagellates in the genus Hematodinium cause disease and mortality in several commercially important marine decapod crustaceans. One species, Hematodinium perezi, occurs in blue crabs, Callinectes sapidus, along the eastern seaboard and Gulf coast of the USA. The parasite infects blue crabs, other decapods, and amphipods in the high salinity waters of coastal bays. Epizootics of the parasite often reach prevalence levels of 75-80% during outbreaks with diseased crabs dying from the infection. Prevalence of the parasite is bimodal, with a minor peak in late spring or summer, and a major peak in fall, and declining rapidly to nearly zero in late November and December. The rapid decline in infections in the late fall brings up the question of whether the parasite overwinters in crabs or whether it uses an unidentified resting stage, such as a cyst. We report observations on the prevalence of the parasite from winter dredge surveys undertaken in 2011 and 2012. Crabs were examined via hemolymph smears, histology, and PCR diagnosis for the presence of H. perezi and other pathogens. Active infections were observed from January through March in 2011 and 2012, indicating the parasite can overwinter in blue crabs. However, several crabs that were positive by PCR had presumptive effete infections that were difficult to diagnose in histological slides and hemolymph smears. These infections did not appear to be active and may have been in subsidence. Dredged crabs with light and moderate active infections were held at 15 degrees C to determine if the parasite was capable of rapid progression. In 8 cases, infections exhibited logarithmic growth progressing rapidly over 8-12days. We present evidence that overwintering of H. perezi occurs in the blue crab hosts, that infections are capable of responding rapidly to increases in temperatures, and that overwintering provides a reservoir of infected animals for transmission to occur in the spring. PMID- 26232045 TI - Erratum to: On the Unidentifiability of the Fixed-Effects 3PL Model. AB - Condition 2 of Theorem 2 was incorrect in the published version. The correct condition 2 appears in this erratum. Theorem 2. Suppose that I >= 3 for the fixed effects 3PL model. If omega1 = (alpha1, beta1, c1) is fixed at(1, 0, 0), then1. The person parameters are identified by the observations.2. The item parameters (alpha2:J , beta2:J , c2:J ) are not identified by the observations. PMID- 26232046 TI - ETB receptor-mediated MMP-9 activation induces vasogenic edema via ZO-1 protein degradation following status epilepticus. AB - The blood-brain barrier (BBB) is formed by the endothelial cells with specialized tight junctions (TJs) lining the blood vessels and astroglial endfeet surrounding the blood vessels. Although BBB disruption during brain insults leads to vasogenic edema as one of the primary steps in the epileptogenic process, little is known about the molecular and physiological events concerning vasogenic edema formation. In the present study, status epilepticus (SE) changed the expressions and subcellular localizations of TJ proteins (claudin-5, occludin and zonula occludens-1 (ZO-1)) in endothelial cells of the rat piriform cortex. Among TJ proteins, the alteration in ZO-1 expression was relevant to endothelin B (ETB) receptor-mediated endothelial nitric oxide synthase (eNOS) activation, which increased matrix metalloproteinase-9 (MMP-9) activity. Indeed, BQ788 (an ETB receptor antagonist) effectively attenuated SE-induced vasogenic edema by inhibiting eNOS-mediated MMP-9 activation and ZO-1 protein degradation in endothelial cells, although astroglial endfeet were detached from endothelial cells. Therefore, we suggest that SE-induced ETB receptor/eNOS-mediated MMP-9 activation may lead to impairments of endothelial cell function via TJ protein degradation, which are involved in vasogenic edema formation independent of perivascular astroglial functions. PMID- 26232047 TI - MiR-207/352 regulate lysosomal-associated membrane proteins and enzymes following ischemic stroke. AB - The role of microRNAs (miRNAs) in lysosome-mediated neuronal death and survival following ischemic stroke remains unknown. Herein, using miRNA and mRNA gene expression profiling microarrays, we identified the differentially expressed 24 miRNAs and 494 genes in the cortical peri-infarct area, respectively. Integrating the miRNA targets and mRNA expression profiles, we found 47 genes of miRNA targets, including lysosomal-associated membrane protein 2 (LAMP2), Hexb, Bcl2, etc. MiR-207 and miR-352 were mainly downregulated after ischemic stroke, followed by a slight return to baseline during post-middle cerebral artery occlusion (MCAO) 1d to 7d. Furthermore, the luciferase reporter assay demonstrated that LAMP2 and Hexb were the direct targets of miR-207 and miR-352, respectively. After lateral ventricle injection with miR-207 agonist mimics, the neurological deficit scores and infarct volumes were attenuated, and the structure of mitochondria ridges was improved. In addition, miR-207 mimics could reduce the number of cellular lysosome and autophagosome, whereas increase the number of autophagic vacuoles, indicating miR-207 might affect the latter part of lysosomal-autophagy pathway and mitochondria-induced apoptosis. These results suggested that miR-207 and miR-352 were involved in lysosomal pathway for mediating ischemic injury and spontaneous recovery. MiR-207 mimics as potential target drugs could protect against autophagic cell death after ischemic stroke. PMID- 26232048 TI - Palliative Surgery for Pseudomyxoma Peritonei. AB - INTRODUCTION: Pseudomyxoma peritonei is a rare disease causing peritoneal carcinomatosis. In patients with extensive carcinomatosis, curative treatment is unachievable. Palliative debulking therapy is the only treatment in relieving symptoms. We report our results from palliative debulking surgery at a national pseudomyxoma peritonei center in Denmark. METHODS: From January 2007 to October 2012, we performed 27 palliative operations for pseudomyxoma peritonei with debulking at our institution. All patients were evaluated and found eligible for palliative treatment only. Patients were prospectively registered, while perioperative data were collected retrospectively from patient records. RESULTS: The majority of patients (n = 25) received an omentectomy (93%) as the primary procedure. In total, 17 (63%) received additional surgery. Median operative time was 88 min (range: 33-160 min). Median stay at the recovery ward was 6 h (2-288 h). Median hospital stay was 8 days (4-105 days). In all, 23 (85%) patients had no in-hospital complications, whereas 4 patients experienced complications (15%). Two of the complications were mild (Clavien-Dindo grade II), and two experienced severe complications (grade III and IV). Thirty-day mortality was 0%. Median survival was 3.0 years (0.2-6.2 years). CONCLUSION: Palliative debulking is a safe procedure with an acceptable morbidity and mortality offering immediate disease control. PMID- 26232049 TI - Intravenous immunoglobulin replacement induces an in vivo reduction of inflammatory monocytes and retains the monocyte ability to respond to bacterial stimulation in patients with common variable immunodeficiencies. AB - Intravenous IgG administration induces significant modifications in the innate and adaptive compartment of the immune system including the monocyte/macrophage system. We analyzed the in vivo effect of IgG administered at replacement dosages on the frequency of monocytes subsets, on the modulation of CD11b and sialic acid binding immunoglobulin-like lectin receptor (Siglec 9) expression and on monocytes production of reactive oxygen species. We showed that patients with Common Variable Immune Deficiency have an increased frequency pro-inflammatory intermediate CD14(++)CD16(+) monocytes and an increased expression of CD11b and Siglec 9 on monocytes. IgG administered at replacement dosages exerted an in vivo anti-inflammatory effect as shown by a reduction of circulating monocytes, of intermediate pro-inflammatory monocytes, of CD11b and Siglec 9 expression and of ex vivo monocytes oxidative burst. Nevertheless, intravenous IgG administration did not affect the monocyte functional ability to respond to a bacterial stimulation in terms of CD11b and Siglec 9 expression and reactive oxygen species production. PMID- 26232050 TI - Clinical and neuroimaging findings in children with posterior reversible encephalopathy syndrome. AB - OBJECTIVE: To clarify the clinical and radiological spectrum of posterior reversible encephalopathy syndrome (PRES) in children, and to identify the prognostic factors. METHODS: The records of 40 children with PRES were reviewed. Acute clinical symptoms, MRI including apparent diffusion coefficient (ADC) maps in the acute and follow-up periods and neurological sequelae, including epilepsy, were noted. RESULTS: Age at onset ranged from 2 to 16 years. Underlying disorders were hematological or neoplastic disorders (n = 20), renal diseases (n = 14) and others (n = 6). In the acute period, 31 patients had seizures, 25 had altered consciousness, 11 had visual disturbances and 10 had headache. Of 29 patients who had ADC maps in the acute period, 13 had reduced diffusivity as shown by ADC within PRES lesions. Of 26 patients with follow-up MRI, 13 had focal gliosis or cortical atrophy. No patients had motor impairment, and four patients had focal epilepsy. No clinical variables were associated with focal gliosis or cortical atrophy on follow-up MRI, but lesional ADC reduction in the acute period was prognostic for focal gliosis or cortical atrophy on follow-up MRI (p = 0.005). CONCLUSIONS: To the best of our knowledge, this is the largest cohort study to date involving PRES in children. Acute symptoms in pediatric patients are similar to those reported in adults, but altered consciousness was more frequent in children. Lesional ADC reduction in the acute period was common and was a good predictor of later, irreversible MRI lesions. PMID- 26232051 TI - Evolution of maple syrup urine disease in patients diagnosed by newborn screening versus late diagnosis. AB - Maple syrup urine disease (MSUD) is a rare metabolic disorder for which the newborn screening (NBS) is possible but it has not been yet implemented for most Spanish regions. In the present study, we assess the clinical features and outcome of 14 MSUD Spanish patients with similar treatment protocol diagnosed either by NBS or by clinical symptoms. Eight patients were detected by NBS, four classic and four moderate MSUD. The average age at detection was 4.6 days, the mean plasmatic concentration of leucine at diagnosis was 1807 MUM; the average number of days with leucine >1000 MUM was 0.7 (0-4) and the mean number of total hospitalizations was 1.6 (0-5). Mean follow-up time was 70 months. They had good evolution: all remain asymptomatic, but 2 patients have attention deficit and hyperactivity disorder. Six patients with late diagnosis of classic MSUD were followed during 41 months. All presented with acute encephalopathy during the first month of life, mean leucine levels of 2355 MUM, mean number of days with leucine >1000 MUM of 6.6 (1-13) and mean number of total hospitalizations of 5.3 (4-7). Only two patients have a psychomotor development index in the lower limit (80 and 83). For all patients a good genotype-phenotype correlation was found and four novel mutations were identified: p.A311H, p.T84S, p.T397L, pL398P. Our study support that NBS improves prognosis of MSUD patients. But early diagnosis and an aggressive treatment together with a close monitoring of leucine levels improve neurological evolution in MSUD patients, even for those not detected by NBS. PMID- 26232052 TI - Myoclonus in childhood-onset neurogenetic disorders: The importance of early identification and treatment. AB - BACKGROUND: In clinical practice, myoclonus in childhood-onset neurogenetic disorders frequently remains unrecognized, because it is often overshadowed by other neurological features. Since treatment can lead to significant functional improvement, accurate phenotyping is essential. To demonstrate the importance of early identification and treatment, we report on four patients with various childhood-onset neurogenetic disorders suffering from myoclonus. METHODS: We evaluated four patients with established childhood-onset neurogenetic disorders and involuntary jerky movements, who visited our young-onset movement disorder outpatient clinic. RESULTS: We present the clinical data of four patients (aged 8 21 years) with childhood-onset neurogenetic disorders, including ataxia telangiectasia, Coffin-Lowry syndrome and epileptic encephalopathy due to SCN1A mutations. All four suffered from jerky movements that hampered normal daily activities and that had gone unrecognized for several years. The presence of multifocal myoclonus was confirmed by polymyography. In all patients, treatment resulted in marked improvement of both myoclonus and overall functioning. CONCLUSION: These cases highlight the relevance of actively searching for myoclonus in childhood-onset neurogenetic disorders, even when a molecular diagnosis has already been established. To further improve the awareness and recognition of myoclonus in children, we provide a list of childhood-onset neurogenetic disorders with myoclonus as important associated feature. PMID- 26232053 TI - Novel parameters of global and regional mitral annulus geometry in man: comparison between normals and organic mitral regurgitation, before and after mitral valve repair. AB - AIMS: The mitral annulus (MA) saddle shape is complex but vital for a normal functioning mitral apparatus. Although conventional parameters of MA geometry such as area and height are helpful, they fall short of describing its complex regional geometry. METHODS AND RESULTS: In this prospective study, novel parameters of MA curvature and torsion were derived from three-dimensional (3D) transoesophageal echocardiography. These quantitative indices were computed in 15 patients with normal valves (age 53 +/- 8 years) and in 15 patients with organic significant mitral regurgitation (MR, age 66 +/- 11 years), before and after mitral valve repair (MVR). The MA was traced and modelled in mid- and end systole. Curvature and torsion were computed at 500 points across the MA to derive regional and global indices. Overall, patients with organic MR presented the smallest global curvature and torsion; this decrease in curvature and torsion reflects a loss of tonicity of the MA tissue. These changes were largely corrected with MVR surgery, to higher values, compared with normals. The regional analysis revealed similar trends. The maximal MA curvature was found to be at the MA 'anterior horn', whereas the MA 'posterior horn' had the lowest curvature values. CONCLUSION: Novel MA parameters of curvature and torsion can be computed from 3D echocardiography and provide quantitative characteristics of dynamic regional MA geometry. In patients with organic MR, the reduced regional and global curvatures improve following surgical MVR. These quantitative parameters may help further refine the quantitative description of MA geometry in various mitral valve pathologies and after MVR. PMID- 26232054 TI - Unroofed coronary sinus atrial septal defect: a multi-modality imaging approach. PMID- 26232055 TI - Human rights and access to hepatitis C treatment for people who inject drugs. AB - BACKGROUND: People who inject drugs (PWID) achieve adherence to and outcomes from hepatitis C virus (HCV) treatment comparable to other patients. Nonetheless, this population has been excluded from treatment by regulation or practice. Approval of safer and more effective oral HCV medicines should offer greater treatment options for PWID, although high medicine prices have led to continued treatment rationing and exclusion in developed countries. In middle-income countries (MICS), treatment is largely unavailable and unaffordable for most PWID. METHODS: Human rights analysis, with its emphasis on the universal and interconnected nature of the economic, social and political spheres, offers a useful framework for HCV treatment reform. Using peer-reviewed and grey literature, as well as community case reports, we discuss barriers to treatment, correlate these barriers to rights violations, and highlight examples of community advocacy to increase treatment for PWID. RESULTS: Structural drivers of lack of treatment access for PWID include stigma in health settings; drug use status as a criterion for treatment exclusion; requirements for fees or registration by name as a drug user prior to treatment initiation; and incarceration/detention in prisons and rehabilitation centers where treatment is unavailable. High medicine prices force further exclusion of PWID, with cost containment masked as concern about treatment adherence. These barriers correlate to multiple rights violations, including of the rights to privacy; non-discrimination; health; freedom of information; fair trial; and freedom from cruel, inhuman and degrading treatment. CONCLUSIONS: Needed reforms include decriminalization of drug use, possession of drugs and drug injecting equipment; removal of exclusionary or discriminatory treatment protocols; approaches to strengthen links between health providers and increase participation of PWID in treatment design and implementation; and measures to increase transparency in government/pharmaceutical company negotiations and reduce treatment price. PMID- 26232056 TI - Epidemiology of juvenile idiopathic arthritis in Oman. AB - BACKGROUND: There is a worldwide variation in the prevalence and subtype distribution of juvenile idiopathic arthritis (JIA) which may be affected by ethnicity and genetic factors. The purpose of this study is to determine the prevalence, subtype distribution and characteristic features of JIA among Omani children and to compare our results with other ethnic populations worldwide. METHODS: A population-based, multicenter study among pediatric rheumatology clinics in the Sultanate over a 10 year period between 2004-2013. The diagnosis of JIA and identification of JIA subtypes was based on the ILAR 2004 revised criteria. The hospital charts of these patients were retrospectively reviewed and information was collected. All patients were screened for uveitis by an ophthalmologist using slit lamp examination during regular follow up visits. RESULTS: The study included a total of 107 cases of JIA in Oman over the study period. Among the 107 patients, 71 % (n = 77) were girls with a female:male ratio of 2.5:1. The mean age of disease onset was 6.85 +/- 3.86 years (range 1-13years) while the mean disease duration of 4.8 +/- 2.9 years (range 1-11 years). The incidence of JIA was estimated at 2/100,000 with a prevalence of JIA of 20/100,000. The prevalence of JIA in girls was 28/100,000 while the prevalence in boys was 12/100,000. According to disease distribution, the most frequent subtype was polyarticular JIA rheumatoid factor negative (39.2 %) followed by oligoarthritis (31.8 %), systemic (17.8 %), polyarticular JIA rheumatoid factor positive (7.5 %). The unique feature of the Omani cohort is the lack of occurrence of uveitis. CONCLUSIONS: This is the first epidemiological JIA study conducted in Oman that highlights unique geographical disease phenotype. Compared to Western counties, there were higher frequency of polyarticular disease and lack of occurrence of uveitis. Further studies are needed to evaluate the implications of genetic, ethnic and environmental differences of disease expression. PMID- 26232058 TI - Children's involvement in care order decision-making: A cross-country analysis. AB - This international comparative paper examines how child protection workers in four countries, England, Finland, Norway, USA (CA), involve children in decision making regarding involuntary child removal. The analysis is based on 772 workers' responses to a vignette describing preparations for care order proceedings. We examine children's involvement along three dimensions including information given to the child, information gathered from the child, and opportunities for their perspectives and interests to be considered. Results show that child protection workers weigh children's involvement differently based upon age. Staff in the four countries were more likely to talk with an older child, to provide information, to gather information, and to include in relevant decision making if the child were 11 compared to five in our vignette. Although the Nordic countries and England provide policy guidance regarding children's role in child protection decision making, we did not see consistently higher indicators of children's involvement from the respondents in these countries. Using child protection system frames to analyze the findings did not produce consistent differences between the family service systems and child protection systems included in this study. Findings highlight the wide range in practices concerning children's involvement in decision making, and the wide space for professional discretion in implementing practice with children at the local level. PMID- 26232057 TI - MicroRNAs in ovarian function and disorders. AB - MicroRNAs (miRNAs) are endogenous, small, noncoding single-stranded RNA molecules approximately 22 nucleotides in length. miRNAs are involved in the post transcriptional regulation of various important cellular physiological and pathological processes, including cell proliferation, differentiation, apoptosis, and hormone biosynthesis and secretion. Ovarian follicles are the key functional units of female reproduction, and the development of these follicles is a complex and precise process accompanied by oocyte maturation as well as surrounding granulosa cell proliferation and differentiation. Numerous miRNAs expressed in the ovary regulate ovarian follicle growth, atresia, ovulation and steroidogenesis and play an important role in ovarian disorders. This review considers recent advances in the identification of miRNAs involved in the regulation of ovarian function as well as the possible influence of miRNAs on ovarian-derived disorders, such as ovarian cancer, polycystic ovarian syndrome and premature ovarian failure. An improved understanding of the regulation of ovarian function by miRNAs may shed light on new strategies for ovarian biology and ovarian disorders. PMID- 26232059 TI - Trastuzumab Rechallenge After Lapatinib- and Trastuzumab-Resistant Disease Progression in HER2-Positive Breast Cancer. AB - BACKGROUND: Multiple anti-HER2 therapies have improved the outcome for patients with HER2-positive breast cancer. However, optimal management has yet to be established for lapatinib (LAP)- and trastuzumab (Tmab)-resistant disease progression. Data from our institution were reviewed to contribute to the search for best practices. PATIENTS AND METHODS: Between June 2009 and March 2013, 74 HER2-positive advanced breast cancer (ABC) patients were treated with LAP with capecitabine (LAPCAP). Patients re-treated with Tmab-based chemotherapies were identified, with a focus on baseline characteristics, chemotherapies, and efficacy. The study focused on the clinical outcomes of 50 patients re-treated with Tmab after LAPCAP-resistant disease progression (LAPCAP-PD), with an assessment of tumor response and clinical benefit (CB). Progression-free survival (PFS) was used as a predictive surrogate marker for the efficacy of Tmab rechallenge. RESULTS: All patients were pretreated with Tmab- and LAP-based chemotherapies. At a median follow-up of 7.9 months, PFS was 4.6 months, and overall survival was 33.7 months after LAPCAP-PD. Rechallenges with Tmab-based chemotherapies included gemcitabine (GEM) in 23 patients, vinorelbine in 14, taxanes in 5, endocrine treatments in 2, and others. The CB rate was 32%, including complete response for 1, partial response for 3, and > 6 months of stable disease for 12. Although the median PFS was longer for patients treated with microtubule inhibitors (MTIs) than with GEM, various chemotherapies had different efficacy regardless of whether or not previous LAPCAP had CBs. CONCLUSION: Tmab rechallenge combined with not only MTIs but also an antimetabolite agent is effective against some LAPCAP-PD HER2-positive ABC. PMID- 26232060 TI - An Evaluation of a Multicomponent Mental Competency and Stress Management Training for Entrants in Surgery Medicine. AB - OBJECTIVE: Stress occurs in surgeons with a significantly higher prevalence than in the general population. At the same time, learning of coping techniques and improving personal skills how to handle the daily workload are not integral parts of the medical education or during adjustment to the job as a surgeon. In this pilot study, we developed a training course to teach different stress management and coping techniques and analyzed individual conditions of the surgeons before and after the course. METHODS: In total, 68 junior surgeons in their first year at work participated in the training and were randomized in an intervention (n = 35) or a control group (n = 33). At the beginning and the end of the training, the intervention and the comparison group answered a standardized, validated questionnaire on job satisfaction, perceived stress, and personal skills (such as self-efficacy). RESULTS: The surgeons showed a significant decline in perceived stress. Furthermore, they showed an improvement in self-reported resilience and self-efficacy. Job satisfaction increased at the same time. The comparison cohort of surgeons showed comparable scores for the specified outcome variables at the beginning but showed no progressive changes during time. CONCLUSIONS: The study findings indicate that the training for junior surgeons in their first year at work is suitable to implement as a group training program. Moreover, the training provides statistically significant improvement in perceptions of distress and strengthens individual protective factors and job satisfaction. PMID- 26232061 TI - Smart Phones: Friend or Foe? PMID- 26232062 TI - A Multifaceted Intervention to Increase Surgery Resident Engagement in Reporting Adverse Events. AB - BACKGROUND: Although most residents have been involved in an adverse or near-miss event, they are not likely to report these incidents. To improve the culture of patient safety and to increase adverse event reporting among General Surgery residents, a multifaceted intervention focused on education, feedback, and event resolution was developed and implemented. METHODS: Adverse events involving surgery patients at Boston Medical Center were monitored for 2 months before and for 10 months after implementation of the intervention in May 2014. RESULTS: There was a significant increase in the number of adverse events reported by residents, from 0 to 30 per 2-month period (chi(2) = 8.56, p = 0.003). The classification types of reports filed by residents differed significantly from those of incidents submitted by other reporters (p < 0.0001). CONCLUSION: An intervention focused on addressing barriers to reporting adverse events can significantly increase the volume of incidents reported by surgery residents. Involving residents in patient safety efforts may enhance an institution's ability to identify adverse events and to improve the overall culture of care. PMID- 26232063 TI - Reinstatement of contextual anxiety in humans: Effects of state anxiety. AB - After successful extinction of conditioned fear, the presentation of an unsignaled unconditioned stimulus (US) leads to return of fear, thus, the previously extinguished conditioned stimulus (CS) triggers fear responses again. Human studies on such reinstatement processes are still inconclusive. Some revealed a general increase of fear reactions, both to the fear (CS+) and the safety stimulus (CS-), whereas other studies discovered a differential return of fear with enhanced fear responses to the CS+ only. Moreover, we know little about reinstatement of contextual anxiety, a state of general anxious apprehension and chronic worry. Therefore, the present study investigated reinstatement of contextual anxiety with an ecological valid virtual reality (VR) design. Additionally, we examined whether the current state anxiety might modulate the reinstatement of contextual anxiety. To this end, two groups underwent context conditioning on Day 1, i.e., one context (CXT+) became paired with unpredictable USs, but not the other context (CXT-), and an extinction training on Day 2. On Day 3 a reinstatement test was conducted, i.e., one group (reinstatement group, n=21) received one unsignaled US before testing, whereas the control group (n=21) did not. Only the reinstatement group showed a differential return of contextual anxiety as measured by fear-potentiated startle and anxiety ratings. Interestingly, the reinstatement of fear-potentiated startle was additionally influenced by state anxiety. Conclusively, an anxious state before an unsignaled aversive event might favor a return of contextual anxiety. PMID- 26232064 TI - Autologous Bone Marrow Mononuclear Cell Transplantation Delays Progression of Carotid Atherosclerosis in Rabbits. AB - Bone marrow mononuclear cells (BMMNCs) can counteract oxidative stress and inhibit the inflammatory response in focal ischemic stroke models. However, the effect of BMMNC transplantation on carotid atherosclerosis needs to be determined. The carotid atherosclerotic plaque model was established in New Zealand White rabbits by balloon injury and 8 weeks of high-fat diet. Rabbits were randomized to receive an intravenous injection of autologous bromodeoxyuridine (BrdU)-labeled BMMNCs or an equal volume of phosphate-buffered saline. Plaques were evaluated for expression of proinflammatory and anti inflammatory cytokines, anti-oxidant proteins, and markers of cell death. BMMNCs migrated into atherosclerotic plaque on the first day after cell transplantation. BMMNC-treated rabbits had smaller plaques and more collagen deposition than did the vehicle-treated controls on day 28 (p < 0.05). BMMNC treatment significantly increased endothelial nitric oxide synthase and the anti-oxidant enzymes glutathione peroxidase and superoxide dismutase in plaques compared to vehicle treatment on day 7. BMMNC-treated rabbits also had lower levels of cleaved caspase-3 expression; lower levels of proinflammatory cytokines interleukin 1beta, tumor necrosis factor alpha, and matrix metalloproteinase 9; and higher levels of insulin-like growth factor-1 and its receptor (p < 0.05). Autologous BMMNC transplantation can suppress the process of atherosclerotic plaque formation and is associated with enhanced anti-oxidative effect, reduced levels of inflammatory cytokines and cleaved caspase-3, and increased expression of insulin-like growth factor-1 and its receptor. BMMNC transplantation represents a novel approach for the treatment of carotid atherosclerosis. PMID- 26232065 TI - An Epigenetic Mechanism of High Gdnf Transcription in Glioma Cells Revealed by Specific Sequence Methylation. AB - Glioma cells express high levels of GDNF. When investigating its transcriptional regulation mechanism, we observed increased or decreased methylation of different cis-acting elements in the gdnf promoter II. However, it is difficult to determine the contributions of methylation changes of each cis-acting element to the abnormally high transcription of gdnf gene. To elucidate the contributions of methylation changes of specific cis-acting elements to the regulation of gdnf transcription, we combined gene site-directed mutation, molecular cloning, and dual luciferase assay to develop the "specific sequence methylation followed by plasmid recircularization" method to alter methylation levels of specific cis acting elements in the gdnf promoter in living cells and assess gene transcriptional activity. This method successfully introduced artificial changes in the methylation of different cis-acting elements in the gdnf promoter II. Moreover, compared with unmethylated gdnf promoter II, both silencer II hypermethylation plus enhancer II unmethylation and hypermethylation of the entire promoter II (containing enhancer II and silencer II) significantly enhanced gdnf transcriptional activity (P < 0.05), and no significant difference was noted between these two hypermethylation patterns (P > 0.05). Enhancer II hypermethylation plus silencer II unmethylation did not significantly affect gene transcription (P > 0.05). Furthermore, we found significantly increased DNA methylation in the silencer II of the gdnf gene in high-grade astroglioma cells with abnormally high gdnf gene expression (P < 0.01). The absence of silencer II significantly increased gdnf promoter II activity in U251 cells (P < 0.01). In conclusion, our specific sequence methylation followed by plasmid recircularization method successfully altered the methylation levels of a specific cis-acting element in a gene promoter in living cells. This method allows in-depth investigation of the impact of methylation changes of different cis-acting elements in the same promoter on gene transcriptional activity. Our findings provide preliminary evidence that silencer II hypermethylation in the gdnf promoter II may underlie high gene transcription in high-grade glioma cells. PMID- 26232066 TI - Impact of Common Variations in PLD3 on Neuroimaging Phenotypes in Non-demented Elders. AB - Rare variants of phospholipase D3 (PLD3) have been identified as Alzheimer's disease (AD) susceptibility loci, whereas little is known about the potential role of common variants in the progression of AD. To examine the impact of genetic variations in PLD3 on neuroimaging phenotypes in a large non-demented population. A total of 261 normal cognition (NC) and 456 mild cognitive impairment (MCI) individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database are included in our analysis. Multiple linear regression models were applied to examine the association between four single-nucleotide polymorphisms (SNPs; rs7249146, rs4490097, rs12151243, and rs10407447) with the florbetapir retention on florbetapir 18F amyloid positron emission tomography (AV45-PET), the cerebral metabolic rate for glucose (CMRgl) on 18F fluorodeoxyglucose PET (FDG-PET), and regional volume on magnetic resonance imaging (MRI) at baseline and in the cohort study. We did not detect any significant associations of PLD3 SNPs with florbetapir retention on AV45-PET. In the analysis of FDG-PET, rs10407447 was associated with the CMRgl in the left angular gyrus and bilateral posterior cingulate cortex in the MCI group. Regarding the MRI analysis, rs10407447 was also associated with bilateral inferior lateral ventricle and lateral ventricle volume in MCI group. The main findings of our study provide evidence that support the possible role of PLD3 common variants in influencing AD-related neuroimaging phenotypes. Nevertheless, further work is necessary to explain the functional mechanisms of differences and confirm the causal variants. PMID- 26232067 TI - Gelatin Nanostructured Lipid Carriers Incorporating Nerve Growth Factor Inhibit Endoplasmic Reticulum Stress-Induced Apoptosis and Improve Recovery in Spinal Cord Injury. AB - Clinical translation of growth factor therapies faces multiple challenges; the most significant one is the short half-life of the naked protein. Gelatin nanostructured lipid carriers (GNLs) had previously been used to encapsulate the basic fibroblast growth factor to enhance the functional recovery in hemiparkinsonian rats. In this research, we comparatively study the enhanced therapy between nerve growth factor (NGF) loaded GNLs (NGF-GNLs) and NGF only in spinal cord injury (SCI). The effects of NGF-GNLs and NGF only were tested by the Basso-Beattie-Bresnahan (BBB) locomotion scale, inclined plane test, and footprint analysis. Western blot analysis and immunofluorescent staining were further performed to identify the expression of ER stress-related proteins, neuron-specific marker neuronal nuclei (NeuN), and growth-associated protein 43 (GAP43). Correlated downstream signals Akt/GSK-3beta and ERK1/2 were also analyzed with or without inhibitors. Results showed that NGF-GNLs, compared to NGF only, enhanced the neuroprotection effect in SCI rats. The ER stress-induced apoptosis response proteins CHOP, GRP78 and caspase-12 inhibited by NGF-GNL treatment were more obvious. Meanwhile, NGF-GNLs in the recovery of SCI are related to the inhibition of ER stress-induced cell death via the activation of downstream signals PI3K/Akt/GSK-3beta and ERK1/2. PMID- 26232069 TI - [Radiological trap and oncological precautions in a patient who has undergone a permanent withdrawal of PIP breast implants]. AB - We report the case of a 57-year-old patient who presented radiological images similar to ruptured breast implants one year after the supposed withdrawal of the latter. This woman had benefited for the first time from cosmetic PIP breast implants in 2000. Early in 2014, she requested the removal of the implants without renewal because she was feeling pain and functional discomfort. A few months after the operation, she consulted for breast swelling in the upper pole of the breast. Radiological assessment showed liquid formations compatible with the presence of implants. At our request, the rereading of the MRI by the radiologist definitively concluded on a bilateral seroma within the persistent fibrous capsule. In the absence of symptoms, clinical monitoring had been decided. But at the recrudescence of anaplastic large cell lymphoma cases associated with breast implants, a cytological sampling was intended. In case of cytological abnormality or recurrence of the seroma, a surgical procedure should be performed. In conclusion, the removal of a breast implant without capsulectomy may result in the formation of a seroma whose images resemble those of an implant. It is always worthwhile to provide precise clinical data to the radiologist in order to help him to make informed interpretations. Every serous effusion in a breast lodge having contained a silicone implant must evoke the diagnosis of anaplastic large cell lymphoma. PMID- 26232068 TI - DSePA Antagonizes High Glucose-Induced Neurotoxicity: Evidences for DNA Damage Mediated p53 Phosphorylation and MAPKs and AKT Pathways. AB - Hyperglycemia as the major hallmark of diabetic neuropathy severely limited its therapeutic efficiency. Evidences have revealed that selenium (Se) as an essential trace element could effectively reduce the risk of neurological diseases. In the present study, 3,3'-diselenodipropionic acid (DSePA), a derivative of selenocystine, was employed to investigate its protective effect against high glucose-induced neurotoxicity in PC12 cells and evaluate the underlying mechanism. The results suggested that high glucose showed significant cytotoxicity through launching mitochondria-mediated apoptosis in PC12 cells, accompanied by poly (ADP-ribose) polymerase (PARP) cleavage, caspase activation, and mitochondrial dysfunction. Moreover, high glucose also triggered DNA damage and dysregulation of MAPKs and AKT pathways through reactive oxygen species (ROS) overproduction. p53 RNA interference partially suppressed high glucose-induced cytotoxicity and apoptosis, indicating the role of p53 in high glucose-induced signal. However, DSePA pretreatment effectively attenuated high glucose-induced cytotoxicity, inhibited the mitochondrial dysfunction through regulation of Bcl-2 family, and ultimately reversed high glucose-induced apoptotic cell death in PC12 cells. Attenuation of caspase activation, PARP cleavage, DNA damage, and ROS accumulation all confirmed its protective effects. Moreover, DSePA markedly alleviated the dysregulation of AKT and MAPKs pathways induced by high glucose. Our findings revealed that the strategy of using DSePA to antagonize high glucose induced neurotoxicity may be a highly effective strategy in combating high glucose-mediated neurological diseases. PMID- 26232071 TI - Protection effect of piperine and piperlonguminine from Piper longum L. alkaloids against rotenone-induced neuronal injury. AB - Currently available treatment approaches for Parkinson's disease (PD) are limited in terms of variety and efficacy. Piper longum L. (PLL; Piperaceae) is used in traditional medicine in Asia and the Pacific Islands, with demonstrated anti inflammatory and antioxidant activities in preclinical studies, and alkaloid extracts of PLL have shown protective effects in PD models. The present study investigated the mechanistic basis for the observed protective effects of PLL. Rats treated with PLL-derived alkaloids showed improvement in rotenone-induced motor deficits, while reactive oxygen species (ROS) production was decreased, mitochondrial membrane potential was stabilized, and the opening of the mitochondrial permeability transition pore (mPTP)-which is involved in ROS production-was inhibited. In addition, rotenone-induced apoptosis was abrogated in the presence of these alkaloids, while a pretreatment stimulated autophagy, likely mitigating neuronal injury by the removal of damaged mitochondria. These findings provide novel insight into the neuroprotective function of PLL as well as evidence in favor of its use in PD treatment. This article is part of a Special Issue entitled SI: Neuroprotection. PMID- 26232072 TI - SomethiNG 2 talk about-Transcriptional regulation in embryonic and adult oligodendrocyte precursors. AB - Glial cells that express the chondroitin sulfate proteoglycan NG2 represent an inherently heterogeneous population. These so-called NG2-glia are present during development and in the adult CNS, where they are referred to as embryonic oligodendrocyte precursors and adult NG2-glia, respectively. They give rise to myelinating oligodendrocytes at all times of life. Over the years much has been learnt about the transcriptional network in embryonic oligodendrocyte precursors, and several transcription factors from the HLH, HMG-domain, zinc finger and homeodomain protein families have been identified as main constituents. Much less is known about the corresponding network in adult NG2-glia. Here we summarize and discuss current knowledge on functions of each of these transcription factor families in NG2-glia, and where possible compare transcriptional regulation in embryonic oligodendrocyte precursors and adult NG2-glia. This article is part of a Special Issue entitled SI:NG2-glia (Invited only). PMID- 26232070 TI - The reactions and role of NG2 glia in spinal cord injury. AB - Oligodendrocyte precursor cells (OPCs) react rapidly to brain and spinal cord injuries. This reaction is characterized by the retraction of cell processes, cell body swelling and increased expression of the NG2 chondroitin sulfate proteoglycan. Reactive OPCs rapidly divide and accumulate surrounding the injury site where they become major cellular components of the glial scar. The glial reaction to injury is an attempt to restore normal homeostasis and re-establish the glia limitans but the exact role of reactive OPCs in these processes is not well understood. Traumatic injury results in extensive oligodendrocyte cell death and the proliferating OPCs generate the large number of precursor cells necessary for remyelination. Reactive OPCs, however, also are a source of axon-growth inhibitory proteoglycans and may interact with invading inflammatory cells in complex ways. Here, I discuss these and other properties of OPCs after spinal cord injury. Understanding the regulation of these disparate properties may lead to new therapeutic approaches to devastating injuries of the spinal cord. This article is part of a Special Issue entitled SI:NG2-glia(Invited only). PMID- 26232073 TI - Social factors modulate restraint stress induced hyperthermia in mice. AB - Stress-induced hyperthermia (SIH) was examined in three different social conditions in mice by thermographic measurement of the body surface temperature. Placing animals in cylindrical holders induced restraint stress. I examined the effect of the social factors in SIH using the thermograph (body surface temperature). Mice restrained in the holders alone showed SIH. Mice restrained in the holders at the same time as other similarly restrained cage mates (social equality condition) showed less hyperthermia. Interestingly, restrained mice with free moving cage mates (social inequality condition) showed the highest hyperthermia. These results are consistent with a previous experiment measuring the memory-enhancing effects of stress and the stress-induced elevation of corticosterone, and suggest that social inequality enhances stress. PMID- 26232076 TI - Response to Stubbs's Letter to the Editor. PMID- 26232078 TI - [41st National Congress of the Spanish Society of Intensive Care and Coronary Unit Nurses, San Sebastian 2015]. PMID- 26232077 TI - Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains. AB - Schizophrenia is an incurable and debilitating mental disorder that may affect up to 1% of the world population. Morphological, electrophysiological, and neurophysiological studies suggest that the corpus callosum (CC), which is the largest portion of white matter in the human brain and responsible for inter hemispheric communication, is altered in schizophrenia patients. Here, we employed mass spectrometry-based proteomics to investigate the molecular underpinnings of schizophrenia. Brain tissue samples were collected postmortem from nine schizophrenia patients and seven controls at the University of Heidelberg, Germany. Because the CC has a signaling role, we collected cytoplasmic (soluble) proteins and submitted them to nano-liquid chromatography mass spectrometry (nano LC-MS/MS). Proteomes were quantified by label-free spectral counting. We identified 5678 unique peptides that corresponded to 1636 proteins belonging to 1512 protein families. Of those proteins, 65 differed significantly in expression: 28 were upregulated and 37 downregulated. Our data increased significantly the knowledge derived from an earlier proteomic study of the CC. Among the differentially expressed proteins are those associated with cell growth and maintenance, such as neurofilaments and tubulins; cell communication and signaling, such as 14-3-3 proteins; and oligodendrocyte function, such as myelin basic protein and myelin-oligodendrocyte glycoprotein. Additionally, 30 of the differentially expressed proteins were found previously in other proteomic studies in postmortem brains; this overlap in findings validates the present study and indicates that these proteins may be markers consistently associated with schizophrenia. Our findings increase the understanding of schizophrenia pathophysiology and may serve as a foundation for further treatment strategies. PMID- 26232080 TI - Polyelectrolyte complexes of hTERT siRNA and polyethyleneimine: Effect of degree of PEG grafting on biological and cellular activity. AB - Gene silencing by siRNA (short interfering RNA)-targeted human telomerase reverse transcriptase (hTERT) is considered a successful strategy for cancer gene therapy. Polyelectrolyte complexes (PEC) of siRNA and cationic polymers such as polyethyleneimine (PEI) have been widely used for cellular transfection; however, they demonstrate some disadvantages such as cytotoxicity and extracellular matrix restrictions. PEG grafting technology was used in an attempt to improve the biocompatibility of PECs. Considering that this technology may compromise the cellular uptake of PECs, we aimed to study the effect of degree of PEI PEGylation on the carrier cytotoxicity, cellular association, and transfection efficiency of hTERT siRNA in the lung cancer cell line A549. Activated NHS ester of methoxy PEG COOH 5 KDa was grafted to hyperbranched PEI 25 KDa in the molar ratios of 0.2 and 1. The copolymers were characterized by (1)H-NMR spectroscopy. PECs of PEI or PEG g-PEI with siRNA, alone or co-incubated with heparin sulfate, were studied by the ethidium bromide exclusion assay. Cytotoxicity of the polymers (PEG-g-PEI vs PEI), alone and upon formation of PEC nanoparticles with hTERT siRNA, was determined by a validated MTT assay, in comparison to a scrambled control sequence, in A549 human lung carcinoma cells. The cellular uptake of the PECs of FITC-labeled siRNA was investigated by flow cytometry at different N/P ratios, and the silencing effect of the transfected siRNA was compared to that of the control sequence for different PECs by real time RT-PCR. The cytotoxicity of PEI decreased significantly by PEG grafting, even at a low degree of PEGylation. Moreover, the nonspecific cytotoxicity of PECs decreased by PEG grafting. PECs of PEG-g-PEI showed more biologic stability on incubation with heparin sulfate. Average particle size and zeta potential of PEC nanoparticles were diminished for those of PEG-g-PEI. The cellular association was more pronounced at an N/P ratio of 2.5 for PECs of PEI and PEG-g-PEI alike. The level of silencing of hTERT mRNA by PEC of PEG-g-PEI was sequence-dependent, and determined non-inferior when compared to the native PEI. Conclusively, the biocompatibility of PEI was improved by a low degree of PEGylation, with no adverse effect on the cellular uptake and the transfection activity. PEC nanoparticles of hTERT siRNA and PEG-g PEI could act as a promising weapon against A549 cells, which has to be considered for an in vivo evaluation. PMID- 26232079 TI - Using the power of genetic suppressors to probe the essential functions of RNase E. AB - This review describes how, using the power of genetic suppressor analysis, mRNA turnover in bacteria was shown to be an essential function of RNase E. RNase E is an essential multifunctional enzyme in bacteria, involved in the processing of stable RNAs to their mature forms (rRNAs and tRNAs) and in the turnover of most mRNAs. Genetic suppressor analysis was successfully used to address whether mRNA turnover is one of the essential functions of RNase E. Conditional lethal mutations in rne were shown to be suppressible by three different classes of extragenic suppressors, including a class that caused overexpression of RelE. The only known function of RelE is the cleavage of mRNA in the ribosomal A-site. Suppression of the conditional lethal defect in rne by RelE overexpression provides strong genetic evidence that mRNA turnover is one of the essential functions of RNase E. Several hypotheses that could explain why mRNA turnover is essential are discussed. Suppressor analysis is an old-fashioned but very powerful approach that can be usefully applied to address a wide variety of important questions in biology and genetics. In this work suppressor analysis has revealed that mRNA turnover is an essential function of RNase E, a conclusion that raises a host of interesting questions for future research. PMID- 26232081 TI - Pseudomonas deceptionensis DC5-mediated synthesis of extracellular silver nanoparticles. AB - The biological synthesis of metal nanoparticles is of great interest in the field of nanotechnology. The present work highlights the extracellular biological synthesis of silver nanoparticles using Pseudomonas deceptionensis DC5. The particles were synthesized in the culture supernatant within 48 h of incubation. Extracellular synthesis of silver nanoparticles in the culture supernatant was confirmed by ultraviolet-visible spectroscopy, which showed the absorption peak at 428 nm, and also under field emission transmission electron microscopy which displayed the spherical shape. In addition, the particles were characterized by X ray diffraction spectroscopy, which corresponds to the crystalline nature of nanoparticles, and energy-dispersive X-ray analysis which exhibited the intense peak at 3 keV, resembling the silver nanoparticles. Further, the synthesized nanoparticles were examined by elemental mapping which displayed the dominance of the silver element in the synthesized product, and dynamic light scattering which showed the distribution of silver nanoparticles with respect to intensity, volume, and number of particles. Moreover, the silver nanoparticles have been found to be quite active in antimicrobial activity and biofilm inhibition activity against pathogenic microorganisms. Thus, the present work emphasized the prospect of using the P. deceptionensis DC5 to achieve the extracellular synthesis of silver nanoparticles in a facile and environmental manner. PMID- 26232082 TI - Directed differentiation of airway epithelial cells of human bone marrow mesenchymal stem cells. AB - The ability to generate lung and airway epithelial cells from human bone marrow mesenchymal stem cells (hBMSCs) would have applications in regenerative medicine, modeling of lung disease, drug screening, and studies of human lung development. In this research, hBMSCs were cultured in specialized airway epithelial cell growth media for differentiation of airway epithelial cells, including keratinocyte growth factor transferrin, bovine pituitary extract, epinephrine, triiodothyronine and retinoic acid. The surfactant protein C, a specific marker of type II pneumocytes, and its corresponding protein were demonstrated by immunofluorescence and western blotting after differentiation of airway epithelial cells, respectively. These cells were then transferred into an induced acute lung injury model. The results showed that the hBMSCs could induce differentiation in airway epithelial cells under the special conditions of the medium, the result for surfactant protein C was positive in differentiated airway epithelial cells using immunofluorescence and western blotting, and these cells were successfully colonized in the injured lung airway. In conclusion, our research shows that a population of airway epithelial cells can be specifically generated from hBMSCs and that induced cells may be allowed to participate in tissue repair. PMID- 26232083 TI - Competing risk bias was common in Kaplan-Meier risk estimates published in prominent medical journals. AB - OBJECTIVE: Risk estimates from Kaplan-Meier curves are well known to medical researchers, reviewers, and editors. In this study, we determined the proportion of Kaplan-Meier analyses published in prominent medical journals that are potentially biased because of competing events ("competing risk bias"). STUDY DESIGN AND SETTING: We randomly selected 100 studies that had at least one Kaplan Meier analysis and were recently published in prominent medical journals. Susceptibility to competing risk bias was determined by examining the outcome and potential competing events. In susceptible studies, bias was quantified using a previously validated prediction model when the number of outcomes and competing events were given. RESULTS: Forty-six studies (46%) contained Kaplan-Meier analyses susceptible to competing risk bias. Sixteen studies (34.8%) susceptible to competing risk cited the number of outcomes and competing events; in six of these studies (6/16, 37.5%), the outcome risk from the Kaplan-Meier estimate (relative to the true risk) was biased upward by 10% or more. CONCLUSION: Almost half of Kaplan-Meier analyses published in medical journals are susceptible to competing risk bias and may overestimate event risk. This bias was found to be quantitatively important in a third of such studies. PMID- 26232084 TI - Changes of ubiquitin C-terminal hydrolase-L1 levels in serum and urine of patients with white matter lesions. AB - OBJECTIVES: Ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) has been established as a potential biomarker of neuronal damage. There is not much information about the effects of white matter lesions (WMLs) on serum and urine UCH-L1 levels in white matter disease patients. This study was aimed to assess whether serum or urine UCH-L1 levels are a reliable marker of brain damage in patients with WMLs. DESIGN AND METHODS: Serum and urine levels of UCH-L1 were assessed in 125 patients with dizziness, hypertension, type 2 diabetes mellitus, or dyslipidemia. Of these 125 patient cases, 41 showed periventricular WMLs (P-WMLs), 46 showed subcortical WMLs (S-WMLs), and 38 displayed no well-defined WMLs (controls). RESULTS: Serum UCH-L1 levels were significantly different between the WML group and controls (p<0.05). Further subgroup analysis proved that serum UCH-L1 levels in participants with S-WMLs were significantly increased when compared with controls (p<0.001), but there was no significant differences between controls and patients with P-WMLs (p>0.05). However, urine levels of UCH-L1 were similar between these three groups (p>0.05). In addition, multivariate analysis showed that increased serum UCH-L1 levels were independently associated with the severity of WMLs using Fazekas scale (beta=0.432, p<0.001). CONCLUSIONS: These findings suggest that serum UCH-L1 levels may serve as a novel biomarker for neuronal damage from WMLs, especially S-WMLs. PMID- 26232085 TI - Temporal aspects of visual perception in demyelinative diseases. AB - The study aims to test whether impaired conduction velocities following optic neuritis (ON) serve as a limiting factor on various temporal, as compared to static, aspects of vision. Critical Flicker fusion frequency (CFFF), two motion perception tasks (object and number-from-motion extraction tasks), high and low contrast acuities, and visual evoked potentials (VEPs) were assessed in 23 ON patients. Strong correlations were found between the various dynamic visual function scores. Furthermore, regression models revealed that each of the dynamic visual functions significantly predicted VEP latencies. These findings were specific to patients' affected eyes and were not evident for static visual functions. Fellow eyes' VEP latencies were best predicted by the VEP latencies of the affected eyes. The similar impact of VEP latencies on various dynamic visual functions suggests conduction velocity to be the common limiting factor for temporal-related visual perceptual abilities. The specificity of these findings to the patients' affected eyes and to dynamic visual functions highlights the precision of dynamic visual functions for identifying demyelinative attack. Prolonged VEP latencies in the fellow eyes seem to stem from different patho physiological processes. The hypothesis that inter-eye synchronization in conduction latencies is important to accomplish visual processing (binocular vision) is further discussed. PMID- 26232086 TI - Changes in digestive enzyme activities during larval development of Chinese loach Paramisgurnus dabryanus (Dabry de Thiersant, 1872). AB - The digestive physiology of Chinese loach (Paramisgurnus dabryanus) was studied by assessing the specific and total activities of different pancreatic (trypsin, chymotrypsin, amylase and lipase), gastric (pepsin) and intestinal (alkaline phosphatase and leucine-aminopeptidase) enzymes from hatching to 40 days after hatching (DAH). Larvae were reared at 24.4 +/- 0.4 degrees C and fed with rotifers from mouth opening (4 DAH) to 15 DAH, from 10 to 35 DAH with Cladocera and from 30 to 40 DAH with compound diet. Enzyme activities for trypsin, chymotrypsin, amylase and lipase were detected before the onset of exogenous feeding, indicating that these enzymes were genetically pre-programmed. Most of the pancreatic enzyme specific activities increased until 20 DAH and decreased thereafter. The pepsin activity of Chinese loach was firstly detected at 30 DAH, indicating the appearance of functional gastric gland. Alkaline phosphatase specific activity was detected from hatching onward, showed marked increase and reached the second peak at 20 DAH, while a gradual increase in specific leucine aminopeptidase activity was observed until the end of the experiment. Accordingly, the larvae of Chinese loach possess a functional digestive system before the onset of exogenous feeding and the digestive capacity gradually increases as development progresses. The abrupt increase in intestinal enzyme activities between 10 and 20 DAH demonstrates onset of juvenile-like digestive mode in Chinese loach larvae. The increase in pepsin activity after 30 DAH indicates the shift from alkaline to acidic digestion in Chinese loach larvae, which may be considered as the onset of weaning. PMID- 26232087 TI - Superoxide Dismutase 1 In Vivo Ameliorates Maternal Diabetes Mellitus-Induced Apoptosis and Heart Defects Through Restoration of Impaired Wnt Signaling. AB - BACKGROUND: Oxidative stress is manifested in embryos exposed to maternal diabetes mellitus, yet specific mechanisms for diabetes mellitus-induced heart defects are not defined. Gene deletion of intermediates of Wingless-related integration (Wnt) signaling causes heart defects similar to those observed in embryos from diabetic pregnancies. We tested the hypothesis that diabetes mellitus-induced oxidative stress impairs Wnt signaling, thereby causing heart defects, and that these defects can be rescued by transgenic overexpression of the reactive oxygen species scavenger superoxide dismutase 1 (SOD1). METHODS AND RESULTS: Wild-type (WT) and SOD1-overexpressing embryos from nondiabetic WT control dams and nondiabetic/diabetic WT female mice mated with SOD1 transgenic male mice were analyzed. No heart defects were observed in WT and SOD1 embryos under nondiabetic conditions. WT embryos of diabetic dams had a 26% incidence of cardiac outlet defects that were suppressed by SOD1 overexpression. Insulin treatment reduced blood glucose levels and heart defects. Diabetes mellitus increased superoxide production, canonical Wnt antagonist expression, caspase activation, and apoptosis and suppressed cell proliferation. Diabetes mellitus suppressed Wnt signaling intermediates and Wnt target gene expression in the embryonic heart, each of which were reversed by SOD1 overexpression. Hydrogen peroxide and peroxynitrite mimicked the inhibitory effect of high glucose on Wnt signaling, which was abolished by the SOD1 mimetic, tempol. CONCLUSIONS: The oxidative stress of diabetes mellitus impairs Wnt signaling and causes cardiac outlet defects that are rescued by SOD1 overexpression. This suggests that targeting of components of the Wnt5a signaling pathway may be a viable strategy for suppression of congenital heart defects in fetuses of diabetic pregnancies. PMID- 26232088 TI - Voluntary exercise and increased food intake after mild chronic stress improve social avoidance behavior in mice. AB - It is well-established that exercise can influence psychological conditions, cognitive function, and energy metabolism in peripheral tissues including the skeletal muscle. However, it is not clear whether exercise can influence social interaction with others and alleviate defeat stress. This study investigated the effect of voluntary wheel running on impaired social interaction induced by chronic social defeat stress (SDS) using the resident-intruder social defeat model. Mice were divided into three groups: control, stress alone, and stress+exercise. SDS was performed by exposing C57BL/6 mice to retired ICR mice for 2.5 min. The C57BL/6 mice were continuously defeated by these resident (aggressor) mice and, following 5 days of SDS, experienced 2 days of rest with no SDS. Mice in the stress+exercise group were allowed to voluntarily run on a wheel for 2h after every SDS exposure. Two weeks later, compared to the control group, the stress group showed a higher ratio of time spent in the corner zone of a social interaction paradigm even though SDS did not elicit depressive- and anxiety-like behaviors. We also observed that voluntary exercise, which did not affect muscle weight and gene expression, decreased social avoidance behavior of stressed mice without clear changes in brain monoamine levels. Interestingly, food intake in the stress+exercise group was the greatest among the three groups. To test the effect of the exercise-induced increase in food intake on social behavior, we set up a pair-fed group where food intake was restricted. We then compared these mice to mice in the stress alone group. We found that the ratio of time spent in the corner zone of the social interaction test was not different between ad libitum- and pair-fed groups, although pair-fed mice spent more time in the corner zone when an aggressor mouse was present than when it was absent. In addition, pair-feeding did not show exercise-induced reductions of adrenal gland weight and enhanced the loss of body fat. Our findings indicate that voluntary exercise reduces social avoidance behavior induced by SDS. Further, we determined that SDS and exercise-induced increases in food intake partially influence energy metabolism and social avoidance behavior. PMID- 26232089 TI - Strongly bonded family members in common marmosets show synchronized fluctuations in oxytocin. AB - Oxytocin is a key regulator of social bonding and is positively linked to affiliation and prosocial behavior in several mammal species. In chimpanzees, this link is dyad-specific as affiliative interactions only elicit high oxytocin release if they involve strongly bonded individuals. These studies involved isolated dyads and sampling events. Little is known about the role of oxytocin in affiliation and social bonding, and about potential long-term patterns of bonding related and dyad-specific oxytocin effects within highly affiliative and cooperative social groups. Our aim was to investigate whether bonding-related oxytocin signatures linked to dyadic affiliation are present in family groups of cooperatively breeding marmoset monkeys (Callithrix jacchus) that show high levels of cohesion and cooperation. In 30 dyads from four family groups and one pair, we measured urinary baseline oxytocin over six weeks and analyzed the link to bond strength (mean dyadic affiliation). Strongly bonded dyads showed synchronized longitudinal fluctuations of oxytocin, indicating that dyad-specific oxytocin effects can also be traced in the group context and in an interdependent species. We discuss these results in light of the potential function of differentiated relationships between marmoset dyads other than the breeding pair, and the role of oxytocin as a mediator for social bonding. PMID- 26232090 TI - A case of severe babesiosis treated successfully with exchange transfusion. AB - Babesiosis is a zoonotic disease that may be asymptomatic or result in severe clinical conditions, with severe hemolysis, hepatic, and renal failure, in humans. Clinical symptoms depend on the species and immune status of the host. The disease is especially severe in those of advanced age, those with an immune deficiency, and the splenectomized. A severe case of babesiosis that developed in a splenectomy patient is presented here; the patient was admitted from a rural region with severe anemia and a deterioration in her general condition, with an initial diagnosis of malaria. In such situations, an exchange transfusion (ET), in addition to antimicrobial treatment, could be lifesaving. PMID- 26232091 TI - Contrasting environments shape thermal physiology across the spatial range of the sandhopper Talorchestia capensis. AB - Integrating thermal physiology and species range extent can contribute to a better understanding of the likely effects of climate change on natural populations. Generally, broadly distributed species show variation in thermal physiology between populations. Within their distributional ranges, populations at the edges are assumed to experience more challenging environments than central populations (fundamental niche breadth hypothesis). We have investigated differences in thermal tolerance and thermal sensitivity under increasing/decreasing temperatures among geographically separated populations of the sandhopper Talorchestia capensis along the South African coasts. We tested whether the thermal tolerance and thermal sensitivity of T. capensis differ between central and marginal populations using a non-parametric constraint space analysis. We linked thermal sensitivity to environmental history by using historical climatic data to evaluate whether individual responses to temperature could be related to natural long-term fluctuations in air temperatures. Our results demonstrate that there were significant differences in the thermal response of T. capensis populations to both increasing/decreasing temperatures. Thermal sensitivity (for increasing temperatures only) was negatively related to temperature variability and positively related to temperature predictability. Two different models fitted the geographical distribution of thermal sensitivity and thermal tolerance. Our results confirm that widespread species show differences in physiology among populations by providing evidence of contrasting thermal responses in individuals subject to different environmental conditions at the limits of the species' spatial range. When considering the complex interactions between individual physiology and species ranges, it is not sufficient to consider mean environmental temperatures, or even temperature variability; the predictability of that variability may be critical. PMID- 26232092 TI - Predator evasion in zooplankton is suppressed by polyunsaturated fatty acid limitation. AB - Herbivorous zooplankton avoid size-selective predation by vertical migration to a deep, cold water refuge. Adaptation to low temperatures in planktonic poikilotherms depends on essential dietary lipids; the availability of these lipids often limits growth and reproduction of zooplankton. We hypothesized that limitation by essential lipids may affect habitat preferences and predator avoidance behavior in planktonic poikilotherms. We used a liposome supplementation technique to enrich the green alga Scenedesmus obliquus and the cyanobacterium Synecchococcus elongatus with the essential lipids, cholesterol and eicosapentaenoic acid (EPA), and an indoor system with a stratified water column (plankton organ) to test whether the absence of these selected dietary lipids constrains predator avoidance (habitat preferences) in four species of the key-stone pelagic freshwater grazer Daphnia. We found that the capability of avoiding fish predation through habitat shift to the deeper and colder environment was suppressed in Daphnia unless the diet was supplemented with EPA; however, the availability of cholesterol did not affect habitat preferences of the tested taxa. Thus, their ability to access a predator-free refuge and the outcome of predator-prey interactions depends upon food quality (i.e. the availability of an essential fatty acid). Our results suggest that biochemical food quality limitation, a bottom-up factor, may affect the top-down control of herbivorous zooplankton. PMID- 26232094 TI - Quality care in anaesthesia: roles of regulation and accreditation. PMID- 26232093 TI - Blood flow mechanics and oxygen transport and delivery in the retinal microcirculation: multiscale mathematical modeling and numerical simulation. AB - The scientific community continues to accrue evidence that blood flow alterations and ischemic conditions in the retina play an important role in the pathogenesis of ocular diseases. Many factors influence retinal hemodynamics and tissue oxygenation, including blood pressure, blood rheology, oxygen arterial permeability and tissue metabolic demand. Since the influence of these factors on the retinal circulation is difficult to isolate in vivo, we propose here a novel mathematical and computational model describing the coupling between blood flow mechanics and oxygen ([Formula: see text]) transport in the retina. Albeit in a simplified manner, the model accounts for the three-dimensional anatomical structure of the retina, consisting in a layered tissue nourished by an arteriolar/venular network laying on the surface proximal to the vitreous. Capillary plexi, originating from terminal arterioles and converging into smaller venules, are embedded in two distinct tissue layers. Arteriolar and venular networks are represented by fractal trees, whereas capillary plexi are represented using a simplified lumped description. In the model, [Formula: see text] is transported along the vasculature and delivered to the tissue at a rate that depends on the metabolic demand of the various tissue layers. First, the model is validated against available experimental results to identify baseline conditions. Then, a sensitivity analysis is performed to quantify the influence of blood pressure, blood rheology, oxygen arterial permeability and tissue oxygen demand on the [Formula: see text] distribution within the blood vessels and in the tissue. This analysis shows that: (1) systemic arterial blood pressure has a strong influence on the [Formula: see text] profiles in both blood and tissue; (2) plasma viscosity and metabolic consumption rates have a strong influence on the [Formula: see text] tension at the level of the retinal ganglion cells; and (3) arterial [Formula: see text] permeability has a strong influence on the [Formula: see text] saturation in the retinal arterioles. PMID- 26232095 TI - Overexpression of heterogeneous nuclear ribonucleoprotein F stimulates renal Ace 2 gene expression and prevents TGF-beta1-induced kidney injury in a mouse model of diabetes. AB - AIMS/HYPOTHESIS: We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-beta1 signalling, TGF-beta1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita mouse model of type 1 diabetes. METHODS: Adult male Akita transgenic (Tg) mice overexpressing specifically hnRNP F in their renal proximal tubular cells (RPTCs) were studied. Non-Akita littermates and Akita mice served as controls. Immortalised rat RPTCs stably transfected with plasmid containing either rat Hnrnpf cDNA or rat Ace-2 gene promoter were also studied. RESULTS: Overexpression of hnRNP F attenuated systemic hypertension, glomerular filtration rate, albumin/creatinine ratio, urinary angiotensinogen (AGT) and angiotensin (Ang) II levels, renal fibrosis and profibrotic gene (Agt, Tgf-beta1, TGF-beta receptor II [Tgf-betarII]) expression, stimulated anti-profibrotic gene (Ace-2 and Ang 1-7 receptor [MasR]) expression, and normalised urinary Ang 1-7 level in Akita Hnrnpf-Tg mice as compared with Akita mice. In vitro, hnRNP F overexpression stimulated Ace-2 gene promoter activity, mRNA and protein expression, and attenuated Agt, Tgf-beta1 and Tgf-betarII gene expression. Furthermore, hnRNP F overexpression prevented TGF-beta1 signalling and TGF-beta1 inhibition of Ace-2 gene expression. CONCLUSIONS/INTERPRETATION: These data demonstrate that hnRNP F stimulates Ace-2 gene transcription, prevents TGF-beta1 inhibition of Ace-2 gene transcription and induction of kidney injury in diabetes. HnRNP F may be a potential target for treating hypertension and renal fibrosis in diabetes. PMID- 26232096 TI - The diabetes gene Zfp69 modulates hepatic insulin sensitivity in mice. AB - AIMS/HYPOTHESIS: Zfp69 was previously identified by positional cloning as a candidate gene for obesity-associated diabetes. C57BL/6J and New Zealand obese (NZO) mice carry a loss-of-function mutation due to the integration of a retrotransposon. On the NZO background, the Zfp69 locus caused severe hyperglycaemia and loss of beta cells. To provide direct evidence for a causal role of Zfp69, we investigated the effects of its overexpression on both a lean [B6-Tg(Zfp69)] and an obese [NZO/B6-Tg(Zfp69)] background. METHODS: Zfp69 transgenic mice were generated by integrating the cDNA into the ROSA locus of the C57BL/6 genome and characterised. RESULTS: B6-Tg(Zfp69) mice were normoglycaemic, developed hyperinsulinaemia, and exhibited increased expression of G6pc and Pck1 and slightly reduced phospho-Akt levels in the liver. During OGTTs, glucose clearance was normal but insulin levels were significantly higher in the B6 Tg(Zfp69) than in control mice. The liver fat content and plasma triacylglycerol levels were significantly increased in B6-Tg(Zfp69) and NZO/B6-Tg(Zfp69) mice on a high-fat diet compared with controls. Liver transcriptome analysis of B6 Tg(Zfp69) mice revealed a downregulation of genes involved in glucose and lipid metabolism. Specifically, expression of Nampt, Lpin2, Map2k6, Gys2, Bnip3, Fitm2, Slc2a2, Ppargc1alpha and Insr was significantly decreased in the liver of B6 Tg(Zfp69) mice compared with wild-type animals. However, overexpression of Zfp69 did not induce overt diabetes with hyperglycaemia and beta cell loss. CONCLUSIONS/INTERPRETATION: Zfp69 mediates hyperlipidaemia, liver fat accumulation and mild insulin resistance. However, it does not induce type 2 diabetes, suggesting that the diabetogenic effect of the Zfp69 locus requires synergy with other as yet unidentified genes. PMID- 26232098 TI - Pancreatic triacylglycerol distribution in type 2 diabetes. PMID- 26232097 TI - Retinal microvascular calibre and risk of diabetes mellitus: a systematic review and participant-level meta-analysis. AB - AIMS/HYPOTHESIS: The calibre of the retinal vessels has been linked to diabetes mellitus but studies have not shown consistent results. We conducted a participant-level meta-analysis to evaluate the association between retinal arteriolar and venular calibre and diabetes. METHODS: We performed a systematic review on MEDLINE and EMBASE for articles published up to December 2014. We identified five population-based prospective cohort studies that provided individual-level data on 18,771 diabetes-free participants. We used discrete time proportional hazards models to estimate pooled HRs of diabetes associated with 1 SD (20 MUm) change in retinal vascular calibre. RESULTS: We identified 2,581 incident cases of diabetes over a median follow-up period of 10 years (interquartile interval of 3.4-15.8 years). After adjustment for demographic, lifestyle and clinical factors, retinal venular calibre was significantly associated with incident diabetes (pooled HR 1.09 [95% CI 1.02, 1.15] per SD increase in venular calibre). This association persisted in analyses excluding individuals with <5 years of follow-up (1.07 [1.0, 1.12]) or those with impaired fasting glucose at baseline (1.10 [1.03, 1.17]); in subgroup analyses, the association was stronger in men than in women but was consistent across subgroups of race/ethnicity, smoking status, hypertension and BMI categories. Retinal arteriolar calibre was not associated with diabetes (0.95 [0.86, 1.06] per SD decrease in arteriolar calibre). CONCLUSIONS/INTERPRETATION: Wider retinal venules but not narrower retinal arterioles were associated with a modestly increased risk for diabetes. Knowledge of pathological mechanisms underlying wider retinal venule may provide further insights concerning microvascular alterations in diabetes. PMID- 26232099 TI - Ethnic differences in hepatic and systemic insulin sensitivity and their associated determinants in obese black and white South African women. AB - AIMS/HYPOTHESIS: There is evidence to suggest that ectopic fat deposition in liver and skeletal muscle may differ between black and white women resulting in organ-specific differences in insulin sensitivity. Accordingly, the aim of the study was to examine ethnic differences in hepatic and peripheral insulin sensitivity, and the association with hepatic and skeletal muscle lipid content, and skeletal muscle gene expression. METHODS: In a cross-sectional study including 30 obese premenopausal black and white women, body composition (dual energy x-ray absorptiometry), liver fat and skeletal muscle (soleus and tibialis anterior) fat accumulation (proton-magnetic resonance spectroscopy), skeletal muscle gene expression, insulin sensitivity (two-step isotope labelled, hyperinsulinaemic-euglycaemic clamp with 10 mU m(-2) min(-1) and 40 mU m(-2) min( 1) insulin infusions), and serum adipokines were measured. RESULTS: We found that, although whole-body insulin sensitivity was not different, obese white women presented with lower hepatic insulin sensitivity than black women (% suppression of endogenous glucose production [% supp EGP], median [interquartile range (IQR)]: 17 [5-51] vs 56 [29-100] %, p = 0.002). While liver fat tended to be lower (p = 0.065) and skeletal muscle fat deposition tended to be higher (p = 0.074) in black compared with white women, associations with insulin sensitivity were only observed in black women (% supp EGP vs liver fat: r = -0.57, p < 0.05 and % supp EGP vs soleus fat: r = -0.56, p < 0.05). CONCLUSIONS/INTERPRETATION: These findings may suggest that black women are more sensitive to the effects of ectopic lipid deposition than white women. PMID- 26232100 TI - The Chalder Fatigue Questionnaire is a valid and reliable measure of perceived fatigue severity in multiple sclerosis. AB - BACKGROUND: Fatigue is one of the most distressing symptoms of multiple sclerosis (MS). Measuring MS fatigue poses a number of challenges. Many measures confound definitions of severity and impact of fatigue and/or lack psychometric validation in MS. OBJECTIVE: To evaluate the psychometric properties of an 11-item fatigue severity measure, the Chalder Fatigue Questionnaire (CFQ) in MS including validity of the factor structure, internal reliability, discriminant validity and sensitivity to change. METHODS: Data were pooled from four previous studies investigating MS fatigue using the CFQ (n=444). Data analysis included confirmatory factor analysis to determine the factor structure and model fit, correlations to assess discriminant validity and effects sizes to determine sensitivity to change. RESULTS: A bi-factor model with one general fatigue factor, incorporating two smaller group factors (mental and physical fatigue) had good model fit and appeared the most appropriate factor structure underlying the CFQ scale. The CFQ had high internal consistency, showed small to moderate correlations with impact of fatigue and mood, and was sensitive to change across low and high intensity behavioural interventions. CONCLUSIONS: The CFQ measuring a composite of physical and mental fatigue severity (i.e. a total score) is a psychometrically sound measure of fatigue severity in MS. PMID- 26232101 TI - Impact of Inappropriate Drug Use on Hospitalizations, Mortality, and Costs in Older Persons and Persons with Dementia: Findings from the SNAC Study. AB - BACKGROUND: Inappropriate drug use (IDU) is an important risk factor for adverse outcomes in older persons. We aimed to investigate IDU and the risk of hospitalizations and mortality in older persons and in persons with dementia and to estimate the costs of IDU-related hospitalizations. METHODS: We analyzed 4108 individuals aged >=60 years from the Swedish National Study on Aging and Care (SNAC) data from Kungsholmen and Nordanstig (2001-2004). IDU was assessed by indicators developed by the Swedish National Board of Health and Welfare. Hospitalizations and mortality data were collected from Swedish registers. Regression models were used to investigate associations between IDU, hospitalizations, and mortality in the whole population and in the subpopulation of persons with dementia (n = 319), after adjustment for sociodemographics, physical functioning, and co-morbidity. Costs for hospitalizations were derived from the Nord-Diagnose Related Group cost database. RESULTS: IDU was associated with a higher risk of hospitalization [adjusted odds ratio (OR) = 1.46; 95% confidence interval (CI) 1.18-1.81] and mortality [adjusted hazard ratio (HR) = 1.15; 95% CI 1.01-1.31] within 1 year in the whole study population and with hospitalization (adjusted OR = 1.88; 95% CI 1.03-3.43) in the subpopulation of persons with dementia, after adjustment for confounding factors. There was also a tendency for higher costs for hospitalizations with IDU than without IDU, although this was not statistically significant. CONCLUSIONS: Our findings suggest that IDU is associated with an increased risk of hospitalization in older persons and in persons with dementia. IDU is also associated with mortality among older persons. These findings highlight the need for cautious prescribing of long acting benzodiazepines, anticholinergic drugs, concurrent use of three or more psychotropic drugs and drug combinations that may lead to serious drug-drug interactions to older patients. Further studies are needed to investigate the association between IDU and costs for hospitalizations. PMID- 26232103 TI - Negative Impact of Aromatase Inhibitors on Proximal Femoral Bone Mass and Geometry in Postmenopausal Women with Breast Cancer. AB - Aromatase inhibitors (AIs), the standard therapy for estrogen receptor- or progesterone receptor-positive breast cancer in postmenopausal women, lead to increased hip fractures in breast cancer patients. To investigate the mechanism of increased incidence of hip fractures in breast cancer patients treated with AIs, we evaluated bone mineral density (BMD) in the cortical and trabecular compartments and assessed femoral geometry using quantitative computed tomography (QCT) in breast cancer patients. In total, 249 early breast cancer patients who underwent QCT in their fifties (mean age 54.3 years) were retrospectively analyzed. Proximal femoral BMD and geometrical parameters were compared. In all regions of the proximal femur, cortical areal BMDs were lower in the AI group than in the non-AI group (p < 0.05). Cortical thickness of the femoral neck, trochanter, and total hip was significantly lower in the AI group compared with the non-AI group (p < 0.05). Analysis of the narrowest section of the femoral neck showed significantly thinner cortical bone and smaller cortical area in the AI group than in the non-AI group (p < 0.05), especially in the superoposterior quadrant. Bone strength parameters in the femoral neck, such as the section modulus and cross-sectional moment of inertia, were significantly lower in the AI group than in the non-AI group (p < 0.05). In conclusion, AI treatment in breast cancer patients is associated with deterioration of femoral cortical BMD and geometry, which could contribute in site-specific weakened bone strength and increased incidence of hip fractures. PMID- 26232102 TI - Correlates of gambling on high-school grounds. AB - OBJECTIVE: This study examined adolescent gambling on school grounds (GS+) and how such behavior was associated with gambling-related attitudes. Further, we examined whether GS+ moderated associations between at-risk problem-gambling (ARPG) and gambling behaviors related to gambling partners. METHOD: Participants were 1988 high-school students who completed survey materials. Demographic, perceptions, attitudes, and gambling variables were stratified by problem gambling severity (ARPG versus recreational gambling) and GS+ status. Chi-square and adjusted logistic regression models were used to examine relationships among study variables. RESULTS: Nearly 40% (39.58%) of students reported past-year GS+, with 12.91% of GS+ students, relative to 2.63% of those who did not report gambling on school grounds (GS-), meeting DSM-IV criteria for pathological gambling (p<0.0001). In comparison to GS- students, GS+ students were more likely to report poorer academic achievement and more permissive attitudes towards gambling behaviors. Weaker links in GS+ students, in comparison with GS-, students, were observed between problem-gambling severity and gambling with family members (interaction odds ratio (IOR)=0.60; 95% CI=0.39-0.92) and gambling with friends (IOR=0.21; 95% CI=0.11-0.39). CONCLUSIONS: GS+ is common and associated with pathological gambling and more permissive attitudes towards gambling. The finding that GS+ (relative to GS-) youth show differences in how problem-gambling is related to gambling partners (friends and family) warrants further investigation regarding whether and how peer and familial interactions might be improved to diminish youth problem-gambling severity. The high frequency of GS+ and its relationship with ARPG highlights a need for school administrators and personnel to consider interventions that target school-based gambling. PMID- 26232104 TI - Laser-evoked potential habituation and central sensitization symptoms in childhood migraine. AB - OBJECTIVES: Few studies have addressed central sensitization symptoms and pain processing in childhood migraine. Our aims were to examine pain sensitivity and responses, including habituation, evoked by CO2 laser stimuli (laser-evoked potentials (LEPs)) in a cohort of children with migraine compared to non-migraine controls and to determine the correlation between LEP features and signs of central sensitization. METHODS: Thirty-five patients 8-15 years of age with migraines without aura were evaluated during the inter-critical phase and were compared to 17 controls. LEPs were analyzed, and their main features were correlated with clinical symptoms including allodynia and pericranial tenderness. RESULTS: The laser-evoked pain threshold was lower and the N2P2 vertex complex amplitude was higher in children with migraines. Furthermore, habituation of vertex waves of LEPs clearly showed a tendency toward progressive amplitude enhancement in the migraine group. Acute allodynia and inter-critical pericranial tenderness correlated with trigeminal LEP features, particularly with the abnormal habituation pattern. DISCUSSION: Abnormalities of pain processing and symptoms of central sensitization appear to be characteristics of children with migraine. Reduced habituation and progressive amplification of cortical responses to laser stimuli indicate an overactive nociceptive system at the onset of migraine, and this hyperactivity may subtend allodynia and pericranial tenderness. Future prospective trials may aid in the early identification of clinical phenotypes that display a tendency to develop into the chronic form of migraine, warranting a timely therapeutic approach. PMID- 26232105 TI - Pilot study of sphenopalatine injection of onabotulinumtoxinA for the treatment of intractable chronic cluster headache. AB - OBJECTIVE: The main object of this pilot study was to investigate the safety of administering onabotulinumtoxinA (BTA) towards the sphenopalatine ganglion (SPG) in intractable chronic cluster headache. Efficacy data were also collected to provide indication on whether future placebo-controlled studies should be performed. METHOD: In a prospective, open-label, uncontrolled study, we performed a single injection of 25 IU (n = 5) or 50 IU BTA (n = 5) towards the SPG in 10 patients with intractable chronic cluster headache with a follow-up of 24 weeks. The primary outcome was adverse events (AEs) and the main efficacy outcome was attack frequency in weeks 3 and 4 post-treatment. RESULTS: A total of 11 AEs were registered. There was one severe adverse event (SAE): posterior epistaxis. The number of cluster headache attacks (main efficacy outcome) was statistically significantly reduced in the intention-to-treat analysis from 18 +/- 12 per week in baseline to 11 +/- 14 (p = 0.038) in weeks 3 and 4, and five out of 10 patients had at least 50% reduction of attack frequency compared to baseline. The cluster attack frequency was significantly reduced for five out of six months post-treatment. CONCLUSION: Randomised, placebo-controlled studies are warranted to establish the potential of this possible novel treatment of cluster headache. PMID- 26232107 TI - [3rd French day of idiopathic pulmonary fibrosis. September 19, 2014]. PMID- 26232106 TI - Development of an indirect ELISA, blocking ELISA, fluorescent microsphere immunoassay and fluorescent focus neutralization assay for serologic evaluation of exposure to North American strains of Porcine Epidemic Diarrhea Virus. AB - BACKGROUND: Recent, severe outbreaks of porcine epidemic diarrhea virus (PEDV) in Asia and North America highlight the need for well-validated diagnostic tests for the identification of PEDV infected animals and evaluation of their immune status to this virus. PEDV was first detected in the U.S. in May 2013 and spread rapidly across the country. Some serological assays for PEDV have been previously described, but few were readily available in the U.S. Several U.S. laboratories quickly developed indirect fluorescent antibody (IFA) assays for the detection of antibodies to PEDV in swine serum, indicating prior exposure. However, the IFA has several disadvantages, including low throughput and relatively subjective interpretation. Different serologic test formats have advantages and disadvantages, depending on the questions being asked, so a full repertoire of tests is useful. Therefore, the objective of this study was to develop and validate multiple improved serological assays for PEDV, including an indirect ELISA (iELISA); a highly specific monoclonal antibody-based blocking ELISA (bELISA); fluorescent microsphere immunoassays (FMIA) that can be multiplexed to monitor exposure to multiple antigens and pathogens simultaneously; and a fluorescent focus neutralization assay (FFN) to measure functional virus neutralizing antibodies. RESULTS: A recombinant North American nucleoprotein (NP) based iELISA was developed and validated along with a bELISA using newly developed PEDV-NP specific biotinylated monoclonal antibodies (mAbs) and an FMIA using magnetic beads coupled with expressed NA PEDV-NP. Receiver operating characteristic (ROC) analysis was performed using swine serum samples (iELISA n = 1486, bELISA n = 1186, FMIA n = 1420). The ROC analysis for the FMIA showed estimated sensitivity and specificity of 98.2 and 99.2 %, respectively. The iELISA and bELISA showed a sensitivity and specificity of 97.9 and 97.6 %; and 98.2 and 98.9 %, respectively. Inter-rater (kappa) agreement was calculated to be 0.941 between iELISA and IFA, 0.945 between bELISA and IFA and 0.932 between FMIA and IFA. Similar comparative kappa values were observed between the iELISA, bELISA and FMIA, which demonstrated a significant level of testing agreement among the three assays. No cross-reactivity with the closely related coronaviruses, transmissible gastroenteritis virus (TGEV) or porcine respiratory coronavirus (PRCV) was noted with these assays. All three assays detected seroconversion of naive animals within 6-9 days post exposure. The FFN assay allows relative quantitation of functional neutralizing antibodies in serum, milk or colostrum samples. CONCLUSION: Well-validated iELISA, bELISA and FMIA assays for the detection of PEDV antibodies were developed and showed good correlation with IFA and each other. Each assay format has advantages that dictate how they will be used in the field. Newly developed mAbs to the PEDV-NP were used in the bELISA and for expediting FFN testing in the detection and quantitation of neutralizing antibodies. In addition, these PEDV mAbs are useful for immunohistochemistry, fluorescent antibody staining and other antigen-based tests. Measurement of neutralizing antibody responses using the FFN assay may provide a valuable tool for assessment of vaccine candidates or protective immunity. PMID- 26232108 TI - Definition of a serum marker panel for glioblastoma discrimination and identification of Interleukin 1beta in the microglial secretome as a novel mediator of endothelial cell survival induced by C-reactive protein. AB - Glioblastoma (GBM) is the most common malignant adult primary brain tumor. We profiled 724 cancer-associated proteins in sera of healthy individuals (n=27) and GBM (n=28) using antibody microarray. While 69 proteins exhibited differential abundance in GBM sera, a three-marker panel (LYAM1, BHE40 and CRP) could discriminate GBM sera from that of healthy donors with an accuracy of 89.7% and p<0.0001. The high abundance of C-reactive protein (CRP) in GBM sera was confirmed in 264 independent samples. High levels of CRP protein was seen in GBM but without a change in transcript levels suggesting a non-tumoral origin. Glioma secreted Interleukin 6 (IL6) was found to induce hepatocytes to secrete CRP, involving JAK-STAT pathway. The culture supernatant from CRP-treated microglial cells induced endothelial cell survival under nutrient-deprivation condition involving CRP-FcgammaRIII signaling cascade. Transcript profiling of CRP-treated microglial cells identified Interleukin 1beta (IL1beta) present in the microglial secretome as the key mediator of CRP-induced endothelial cell survival. IL1beta neutralization by antibody-binding or siRNA-mediated silencing in microglial cells reduced the ability of the supernatant from CRP-treated microglial cells to induce endothelial cell survival. Thus our study identifies a serum based three marker panel for GBM diagnosis and provides leads for developing targeted therapies. Biological significance A complex antibody microarray based serum marker profiling identified a three-marker panel - LYAM1, BHE40 and CRP as an accurate discriminator of glioblastoma sera from that of healthy individuals. CRP protein is seen in high levels without a concomitant increase of CRP transcripts in glioblastoma. Glioma-secreted IL6 induced hepatocytes to produce CRP in a JAK STAT signaling dependent manner. CRP induced microglial cells to release IL1beta which in turn promoted endothelial cell survival. This study, besides defining a serum panel for glioblastoma discrimination, identified IL1beta as a potential candidate for developing targeted therapy. PMID- 26232109 TI - Multi-omics profiling reveals that eating difficulties developed consecutively to artificial nutrition in the neonatal period are associated to specific saliva composition. AB - Prolonged enteral or parenteral nutrition in neonatal periods sometimes results in eating difficulties persisting for years, with reduced food intake through the oral route and thereby reduced stimulation of the oral cavity. Aiming at describing the consequences on oral physiology, saliva of 21 children with eating difficulties (ED) was compared to that of 23 healthy controls, using various omics and targeted methods. Overall, despite heterogeneity within the groups (age, medication etc.), the three spectral methods (MALDI-TOF, SELDI-TOF, (1)H NMR) allowed discriminating ED and controls, confirming that oral stimulation by food intake plays a role in shaping the composition of saliva. Saliva of ED patients exhibited a lower antioxidant status and lower levels of the salivary protease inhibitors cystatins. Other discriminant features (IgA1, dimethylamine) may relate to modified oral and/or intestinal microbial ecology. Finally, salivary profiles of ED patients were partly comparable to those of subjects with exacerbated gustatory sensitivities, in particular with reduced abundance of cystatin SN and higher abundance of zinc-alpha-2-glycoprotein. Whether this translates taste hypersensitivity and contributes to the eating difficulties deserves further attention. PMID- 26232110 TI - An extensive library of surrogate peptides for all human proteins. AB - Selecting the most appropriate surrogate peptides to represent a target protein is a major component of experimental design in Multiple Reaction Monitoring (MRM). Our software PeptidePicker with its v-score remains distinctive in its approach of integrating information about the proteins, their tryptic peptides, and the suitability of these peptides for MRM that is available online in UniProtKB, NCBI's dbSNP, ExPASy, PeptideAtlas, PRIDE, and GPMDB. The scoring algorithm reflects our "best knowledge" for selecting candidate peptides for MRM, based on the uniqueness of the peptide in the targeted proteome, its physiochemical properties, and whether it has previously been observed. Here we present an updated approach where we have already compiled a list of all possible surrogate peptides of the human proteome. Using our stringent selection criteria, the list includes 165k suitable MRM peptides covering 17k proteins of the human reviewed proteins in UniProtKB. Compared to average of 2-4min per protein for retrieving and integrating the information, the precompiled list includes all peptides available instantly. This allows a more cohesive and faster design of a multiplexed MRM experiment and provides insights into evidence for a protein's existence. We will keep this list up-to-date as proteomics data repositories continue to grow. This article is part of a Special Issue entitled: Computational Proteomics. PMID- 26232111 TI - mIMT-visHTS: A novel method for multiplexing isobaric mass tagged datasets with an accompanying visualization high throughput screening tool for protein profiling. AB - Isobaric mass tagging (IMT) methods enable the analysis of thousands of proteins simultaneously. We used tandem mass tagging reagents (TMTTM) to monitor the relative changes in the proteome of the mouse macrophage cell line RAW264.7 at the same six time points after no stimulation (baseline phenotype), stimulation with interferon gamma (pro-inflammatory phenotype) or stimulation with interleukin-4 (anti-inflammatory phenotype). The combined TMT datasets yielded nearly 12,000 protein profiles for comparison. To facilitate this large analysis, we developed a novel method that combines or multiplexes the separate IMT (mIMT) datasets into a single super dataset for subsequent model-based clustering and co regulation analysis. Specially designed visual High Throughput Screening (visHTS) software screened co-regulated proteins. visHTS generates an interactive and visually intuitive color-coded bullseye plot that enables users to browse the cluster outputs and identify co-regulated proteins. PMID- 26232112 TI - Do amount of variant differentiation and mitotic rate in bladder cancer change with neoadjuvant chemotherapy? AB - Neoadjuvant chemotherapy (NAC) is currently recommended to all candidate patients with muscularis propria-invasive bladder cancer. However, NAC is effective in only a subset of patients, and predictors of response are lacking. Our study aimed to characterize tumoral changes with NAC usage and to identify features at bladder biopsy/transurethral resection (Bx/TUR) that may predict response. A retrospective search was performed to identify patients with bladder cancer that were pT2 at Bx/TUR upon whom a radical cystectomy (RC) was performed from 2007 to 2010. A blinded slide review of the Bx/TUR and RC was conducted. Presence, type, percent of tumor variant morphology, and tumoral mitotic rate were assessed. Ninety RC patients with slides available were identified (46 NAC, 44 non-NAC). In NAC-treated patients, there was a significantly higher percentage of nonurothelial variant differentiation in the RC compared with Bx/TUR, whereas there was no difference in the non-NAC subgroup. Percent variant differentiation at Bx/TUR was not a predictor of response. There was a significant decrease in mitotic rate between Bx/TUR and RC in NAC patients, whereas there was no difference in the non-NAC subgroup, although mitotic rate was not a predictor of response. In conclusion, percent variant differentiation and mitotic rate changed significantly from Bx/TUR to RC with NAC usage, although neither predicted response. Pathologists should be aware that variant differentiation is common in bladder cancer, with increased presence after NAC, in order to improve recognition and documentation of these findings. PMID- 26232113 TI - Ovarian high-grade serous carcinoma with a noninvasive growth pattern simulating a serous borderline tumor. AB - Ovarian serous borderline tumors (SBTs) being a precursor of low-grade serous carcinomas are morphologically characterized by noninvasive growth and low-grade cytology. On the other hand, many pathologists regard cytologically high-grade, noninvasive (HG-noninv) ovarian serous tumors resembling SBTs in low magnification as conventional high-grade serous carcinomas (HGSCs) by personal experiences. Nonetheless, there are no established molecular characteristic of such tumors. In this study, therefore, we attempted to provide the molecular evidence. We selected 37 ovarian serous tumors that exhibited a cytologically HG noninv growth pattern, including 36 tumors that coexisted with conventional invasive HGSC components (HG-inv) and a single tumor exclusively composed of pure HG-noninv. Histologically, all HG-noninv showed many mitotic figures, and serous tubal intraepithelial carcinomas were identified in 3 tumors with HG-noninv. Immunohistochemically, most HG-noninv showed aberrant p53 expression, frequent IMP3 positivity, p16 overexpression, a high MIB-1 labeling index, and infrequent PAX2. By molecular analysis, the pure HG-noninv and 13 HGSCs with HG-noninv showed TP53 mutations, but KRAS/BRAF mutations were not detected in any of them. In 1 tumor, we detected an identical TP53 mutation in both HG-noninv and HG-inv components by using laser capture microdissection. These immunohistochemical and molecular features of HG-noninv were similar to those of conventional invasive HGSCs but different from those of SBTs. In conclusion, our results showed that a cytologically HG-noninv growth pattern simulating an SBT is a morphological spectrum of HGSC, but not a true SBT. PMID- 26232114 TI - Insightful Practice: a robust measure of medical students' professional response to feedback on their performance. AB - BACKGROUND: Healthcare professionals need to show accountability, responsibility and appropriate response to audit feedback. Assessment of Insightful Practice (engagement, insight and appropriate action for improvement) has been shown to offer a robust system, in general practice, to identify concerns in doctors' response to independent feedback. This study researched the system's utility in medical undergraduates. METHODS: SETTING AND PARTICIPANTS: 28 fourth year medical students reflected on their performance feedback. Reflection was supported by a staff coach. Students' portfolios were divided into two groups (n = 14). Group 1 students were assessed by three staff assessors (calibrated using group training) and Group 2 students' portfolios were assessed by three staff assessors (un-calibrated by one-to-one training). Assessments were by blinded web based exercise and assessors were senior Medical School staff. DESIGN: Case series with mixed qualitative and quantitative methods. A feedback dataset was specified as (1) student-specific End-of-Block Clinical Feedback, (2) other available Medical School assessment data and, (3) an assessment of students' identification of prescribing errors. Analysis and statistical tests: Generalisability G-theory and associated Decision D- studies were used to assess the reliability of the system and a subsequent recommendation on students' suitability to progress training. One-to-one interviews explored participants' experiences. MAIN OUTCOME MEASURES: The primary outcome measure was inter-rater reliability of assessment of students' Insightful Practice. Secondary outcome measures were the reaction of participants and their self-reported behavioural change. RESULTS: The method offered a feasible and highly reliable global assessment for calibrated assessors, G (inter-rater reliability) > 0.8 (two assessors), but not un-calibrated assessors G < 0.31. Calibrated assessment proved an acceptable basis to enhance feedback and identify concern in professionalism. Students reported increased awareness in teamwork and in the importance of heeding advice. Coaches reported improvement in their feedback skills and commitment to improving the quality of student feedback. CONCLUSIONS: Insightful practice offers a reliable and feasible method to evaluate medical undergraduates' professional response to their training feedback. The piloted system offers a method to assist the early identification of students at risk and monitor, where required, the remediation of students to get their level(s) of professional response to feedback back 'on track'. PMID- 26232115 TI - Tackling student neurophobia in neurosciences block with team-based learning. AB - INTRODUCTION: Traditionally, neurosciences is perceived as a difficult course in undergraduate medical education with literature suggesting use of the term "Neurophobia" (fear of neurology among medical students). Instructional strategies employed for the teaching of neurosciences in undergraduate curricula traditionally include a combination of lectures, demonstrations, practical classes, problem-based learning and clinico-pathological conferences. Recently, team-based learning (TBL), a student-centered instructional strategy, has increasingly been regarded by many undergraduate medical courses as an effective method to assist student learning. METHODS: In this study, 156 students of year three neuroscience block were divided into seven male and seven female groups, comprising 11-12 students in each group. TBL was introduced during the 6 weeks of this block, and a total of eight TBL sessions were conducted during this duration. We evaluated the effect of TBL on student learning and correlated it with the student's performance in summative assessment. Moreover, the students' perceptions regarding the process of TBL was assessed by online survey. RESULTS: We found that students who attended TBL sessions performed better in the summative examinations as compared to those who did not. Furthermore, students performed better in team activities compared to individual testing, with male students performing better with a more favorable impact on their grades in the summative examination. There was an increase in the number of students achieving higher grades (grade B and above) in this block when compared to the previous block (51.7% vs. 25%). Moreover, the number of students at risk for lower grades (Grade B- and below) decreased in this block when compared to the previous block (30.6% vs. 55%). Students generally elicited a favorable response regarding the TBL process, as well as expressed satisfaction with the content covered and felt that such activities led to improvement in communication and interpersonal skills. CONCLUSION: We conclude that implementing TBL strategy increased students' responsibility for their own learning and helped the students in bridging the gap in their cognitive knowledge to tackle 'neurophobia' in a difficult neurosciences block evidenced by their improved performance in the summative assessment. PMID- 26232116 TI - The short and long telomere syndromes: paired paradigms for molecular medicine. AB - Recent advances have defined a role for abnormally short telomeres in a broad spectrum of genetic disorders. They include rare conditions such as dyskeratosis congenita as well pulmonary fibrosis and emphysema. Now, there is new evidence that some familial cancers, such as melanoma, are caused by mutations that lengthen telomeres. Here, we examine the significance of these short and long telomere length extremes for understanding the molecular basis of age-related disease and cancer. PMID- 26232119 TI - Cheek reconstruction following facial malignant melanoma surgery with the platysma myocutaneous flap. AB - The aim of this study was to evaluate the results of large cheek skin defect reconstruction using a superiorly based platysma myocutaneous flap accompanied by facial artery and vein preservation, following cutaneous head and neck melanoma surgery. This study offers new insight into a procedure that is a viable, but infrequently used reconstruction option. The authors report the cases of 13 consecutive patients with cheek skin defects following melanoma surgery who underwent reconstruction with a superiorly based platysma myocutaneous flap. The procedures were performed at a tertiary clinical centre and a national melanoma surgery referral centre between 2001 and 2008. According to the disease stage, eight patients underwent sentinel lymph node biopsy and five underwent comprehensive neck dissections. All of the patients were monitored for any complications related to the donor and recipient sites. Minor venous congestion of the flap was noted in two patients, with minor marginal skin necrosis in one patient. None of the patients had donor site complications. The superiorly based platysma flap proved to be a safe and reliable option for large cheek defect reconstruction, especially considering that it is a single-stage reconstruction procedure ensuring excellent colour-matching and low donor site morbidity. PMID- 26232118 TI - Genome wide comprehensive analysis and web resource development on cell wall degrading enzymes from phyto-parasitic nematodes. AB - BACKGROUND: The plant cell wall serves as a primary barrier against pathogen invasion. The success of a plant pathogen largely depends on its ability to overcome this barrier. During the infection process, plant parasitic nematodes secrete cell wall degrading enzymes (CWDEs) apart from piercing with their stylet, a sharp and hard mouthpart used for successful infection. CWDEs typically consist of cellulases, hemicellulases, and pectinases, which help the nematode to infect and establish the feeding structure or form a cyst. The study of nematode cell wall degrading enzymes not only enhance our understanding of the interaction between nematodes and their host, but also provides information on a novel source of enzymes for their potential use in biomass based biofuel/bioproduct industries. Although there is comprehensive information available on genome wide analysis of CWDEs for bacteria, fungi, termites and plants, but no comprehensive information available for plant pathogenic nematodes. Herein we have performed a genome wide analysis of CWDEs from the genome sequenced phyto pathogenic nematode species and developed a comprehensive publicly available database. RESULTS: In the present study, we have performed a genome wide analysis for the presence of CWDEs from five plant parasitic nematode species with fully sequenced genomes covering three genera viz. Bursaphelenchus, Glorodera and Meloidogyne. Using the Hidden Markov Models (HMM) conserved domain profiles of the respective gene families, we have identified 530 genes encoding CWDEs that are distributed among 24 gene families of glycoside hydrolases (412) and polysaccharide lyases (118). Furthermore, expression profiles of these genes were analyzed across the life cycle of a potato cyst nematode. Most genes were found to have moderate to high expression from early to late infectious stages, while some clusters were invasion stage specific, indicating the role of these enzymes in the nematode's infection and establishment process. Additionally, we have also developed a Nematode's Plant Cell Wall Degrading Enzyme (NCWDE) database as a platform to provide a comprehensive outcome of the present study. CONCLUSIONS: Our study provides collective information about different families of CWDEs from five different sequenced plant pathogenic nematode species. The outcomes of this study will help in developing better strategies to curtail the nematode infection, as well as help in identification of novel cell wall degrading enzymes for biofuel/bioproduct industries. PMID- 26232120 TI - Use of autogenous bone and beta-tricalcium phosphate in maxillary sinus lifting: a prospective, randomized, volumetric computed tomography study. AB - The correction of bone defects can be performed using autogenous or alloplastic materials, such as beta-tricalcium phosphate (beta-TCP). This study compared the changes in bone volume (CBV) after maxillary sinus lifting using autogenous bone (n = 12), autogenous bone associated with beta-TCP 1:1 (ChronOS; DePuy Synthes, Paoli, CA, USA) (n = 9), and beta-TCP alone (n = 11) as grafting material, by means of cone beam computed tomography (CBCT). CBV was evaluated by comparing CBCT scans obtained in the immediate postoperative period (5-7 days) and at 6 months postoperative in each group using OsiriX software (OsiriX Foundation, Geneva, Switzerland). The results showed an average resorption of 45.7 +/- 18.6% for the autogenous bone group, 43.8 +/- 18.4% for the autogenous bone+beta-TCP group, and 38.3 +/- 16.6% for the beta-TCP group. All bone substitute materials tested in this study presented satisfactory results for maxillary sinus lifting procedures regarding the maintenance of graft volume during the healing phase before the insertion of implants, as assessed by means of CBCT. PMID- 26232121 TI - [Influenza vaccination. Effectiveness of current vaccines and future challenges]. AB - Seasonal influenza is an annual challenge for health-care systems, due to factors such as co-circulation of 2 influenza A subtypes jointly with 2 influenza B lineages; the antigenic drift of these virus, which eludes natural immunity, as well as immunity conferred by vaccination; together with influenza impact in terms of morbidity and mortality. Influenza vaccines have been available for more than 70 years and they have progressed in formulation, production and delivery route. Recommendations on vaccination are focused on those with a higher probability of severe disease, and have a progressively wider coverage, and classically based on inactivated vaccines, but with an increasing importance of attenuated live vaccines. More inactivated vaccines are becoming available, from adyuvanted and virosomal vaccines to intradermal delivery, cell-culture or quadrivalent. Overall vaccine effectiveness is about 65%, but varies depending on characteristics of vaccines, virus, population and the outcomes to be prevented, and ranges from less than 10% to almost 90%. Future challenges are formulations that confer more extensive and lasting protection, as well as increased vaccination coverage, especially in groups such as pregnant women and health-care professionals, as well as being extended to paediatrics. PMID- 26232122 TI - Kinesiology Taping does not Modify Electromyographic Activity or Muscle Flexibility of Quadriceps Femoris Muscle: A Randomized, Placebo-Controlled Pilot Study in Healthy Volleyball Players. AB - BACKGROUND: Kinesiology taping (KT) is a popular method of supporting professional athletes during sports activities, traumatic injury prevention, and physiotherapeutic procedures after a wide range of musculoskeletal injuries. The effectiveness of KT in muscle strength and motor units recruitment is still uncertain. The objective of this study was to assess the effect of KT on surface electromyographic (sEMG) activity and muscle flexibility of the rectus femoris (RF), vastus lateralis (VL), and vastus medialis (VM) muscles in healthy volleyball players. MATERIAL AND METHODS: Twenty-two healthy volleyball players (8 men and 14 women) were included in the study and randomly assigned to 2 comparative groups: "kinesiology taping" (KT; n=12; age: 22.30 +/- 1.88 years; BMI: 22.19 +/- 4.00 kg/m(2)) in which KT application over the RF muscle was used, and "placebo taping" (PT; n=10; age: 21.50 +/- 2.07 years; BMI: 22.74 +/- 2.67 kg/m(2)) in which adhesive nonelastic tape over the same muscle was used. All subjects were analyzed for resting sEMG activity of the VL and VM muscles, resting and functional sEMG activity of RF muscle, and muscle flexibility of RF muscle. RESULTS: No significant differences in muscle flexibility of the RF muscle and sEMG activity of the RF, VL, and VM muscles were registered before and after interventions in both groups, and between the KT and PT groups (p>0.05). CONCLUSIONS: The results show that application of the KT to the RF muscle is not useful to improve sEMG activity. PMID- 26232123 TI - A systematic review including meta-analysis of work environment and depressive symptoms. AB - BACKGROUND: Depressive symptoms are potential outcomes of poorly functioning work environments. Such symptoms are frequent and cause considerable suffering for the employees as well as financial loss for the employers. Accordingly good prospective studies of psychosocial working conditions and depressive symptoms are valuable. Scientific reviews of such studies have pointed at methodological difficulties but still established a few job risk factors. Those reviews were published some years ago. There is need for an updated systematic review using the GRADE system. In addition, gender related questions have been insufficiently reviewed. METHOD: Inclusion criteria for the studies published 1990 to June 2013: 1. European and English speaking countries. 2. Quantified results describing the relationship between exposure (psychosocial or physical/chemical) and outcome (standardized questionnaire assessment of depressive symptoms or interview-based clinical depression). 3. Prospective or comparable case-control design with at least 100 participants. 4. Assessments of exposure (working conditions) and outcome at baseline and outcome (depressive symptoms) once again after follow-up 1-5 years later. 5. Adjustment for age and adjustment or stratification for gender. Studies filling inclusion criteria were subjected to assessment of 1.) relevance and 2.) quality using predefined criteria. Systematic review of the evidence was made using the GRADE system. When applicable, meta-analysis of the magnitude of associations was made. Consistency of findings was examined for a number of possible confounders and publication bias was discussed. RESULTS: Fifty nine articles of high or medium high scientific quality were included. Moderately strong evidence (grade three out of four) was found for job strain (high psychological demands and low decision latitude), low decision latitude and bullying having significant impact on development of depressive symptoms. Limited evidence (grade two) was shown for psychological demands, effort reward imbalance, low support, unfavorable social climate, lack of work justice, conflicts, limited skill discretion, job insecurity and long working hours. There was no differential gender effect of adverse job conditions on depressive symptoms CONCLUSION: There is substantial empirical evidence that employees, both men and women, who report lack of decision latitude, job strain and bullying, will experience increasing depressive symptoms over time. These conditions are amenable to organizational interventions. PMID- 26232124 TI - Comparison of early recovery and cognitive function after desflurane and sevoflurane anaesthesia in elderly patients: A meta-analysis of randomized controlled trials. AB - OBJECTIVES: A meta-analysis to compare postoperative cognitive function and the time to specific recovery events in elderly patients (aged >65 years) anaesthetized with sevoflurane or desflurane. METHODS: A systematic search of the PubMed((r)), Embase((r)), Cochrane Library and Chinese Biomedical databases was performed using the keywords 'sevoflurane' and 'desflurane'. Data and characteristics of appropriate randomized controlled trials (RCTs) were extracted. RESULTS: The meta-analysis included five trials (n = 300). The time taken to follow commands (mean difference [MD] -3.27; 95% confidence intervals [CI] -4.95, -1.59), extubation (MD -1.59; 95%CI -2.62, -0.55), orientation (MD 4.31; 95%CI -4.99, -3.62), and recovery room discharge (MD -9.38; 95%CI -13.43, 5.42) were significantly shorter in the desflurane group than in the sevoflurane group. There was no significant between-drug difference in the incidence of postoperative cognitive dysfunction or the time taken to open the eyes. CONCLUSIONS: Desflurane is associated with a faster recovery from general anaesthesia than sevoflurane in elderly patients. PMID- 26232125 TI - Paracoccidioides brasiliensis Infection in Small Wild Mammals. AB - Paracoccidioidomycosis (PCM) is a systemic mycosis prevalent in Brazil and other Latin American countries. The etiological agents of PCM are the thermo-dimorphic fungi Paracoccidioides brasiliensis and P. lutzii. Taking into account that the natural habitat of Paracoccidioides spp. is still undefined, domestic and wild animals could be useful as indicators of Paracoccidioides spp. presence in endemic areas. The objective of this study was to evaluate the infection of small wild mammals by P. brasiliensis in an endemic area for human PCM. Samples from 38 wild mammals from different species such as Akodon sp., Thaptomys nigrita, Euryoryzomys russatus, Oligoryzomys nigripes, Monodelphis sp., Sooretamys angouya, Abrawayaomys angouya, Abrawayaomys ruschii and Akodontinae sp. were evaluated by ELISA, immunodiffusion, histopathology, nested PCR and culture. The overall positivity to gp43 observed in the ELISA was 23.7%. Samples from heart and liver of one O. nigripes were PCR positive, and the animal was also seropositive to gp43 in ELISA. This study showed that wild animals living in endemic areas for PCM are infected with P. brasiliensis and can be valuable epidemiological markers of the fungus presence in the environment. This is the first evidence of PCM infection in Akodon sp., E. russatus, T. nigrita and O. nigripes. PMID- 26232126 TI - Perinatal probiotic supplementation in the prevention of allergy related disease: 6 year follow up of a randomised controlled trial. AB - BACKGROUND: Perinatal probiotics supplementation has been shown to be effective in the primary prevention of atopic dermatitis (AD) in early childhood, although the long term effects of probiotics on AD and other allergic diseases is less certain. We have previously reported a significant reduction in the cumulative incidence of AD at 2 years after maternal probiotic supplementation. In this study we present the effects of perinatal probiotics given to women from a general population on allergy related diseases in their offspring at 6 years. METHODS: Four hundred and fifteen pregnant women were randomised to receive probiotic or placebo milk in a double-blinded trial from 36 week gestation until 3 months postpartum. Probiotic milk contained Lactobacillus rhamnosos GG, L. acidophilus La-5 and Bifidobacterium animalis subsp. lactis Bb-12. At 6 years, children were re-assessed for AD, atopic sensitisation, asthma and allergic rhinoconjunctivitis (ARC). RESULTS: At 6 years, 81 and 82 children were assessed for AD in the probiotic and placebo groups, respectively. In a multiple imputation analysis, there was as trend towards a lower cumulative incidence of AD in the probiotic group compared to the placebo group (OR 0.64, 95 % CI 0.39 1.07, p = 0.086; NNT = 10). This finding was statistically significantly in the complete case analysis (OR 0.48, 95 % CI 0.25-0.92, p = 0.027, NNT = 6). The prevalence of asthma and atopic sensitisation, and the cumulative incidence of ARC were not significantly affected by the probiotic regime at 6 years of age. CONCLUSIONS: Maternal probiotic ingestion alone may be sufficient for long term reduction in the cumulative incidence of AD, but not other allergy related diseases. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00159523. PMID- 26232127 TI - An improved method for HLA-B and -C supratyping. AB - A growing body of evidence links the analysis of the KIR genotype and the presence of their HLA-B and -C ligands to a wide repertoire of human diseases. We noticed that, using a panel of 184 Caucasoid donors, a limited number of HLA alleles were incorrectly supratyped by previously described pyrosequence-based assays. Here we describe a simple implementation of the reported methods that corrects all the discrepancies found with HLA-B and -C molecular typing and allows establishing a quick and high-throughput method for the determination of HLA-Bw4 I(80), Bw4T(80), Bw6 and HLA-C1 or -C2 supratype. PMID- 26232128 TI - Proton versus conventional radiotherapy for pediatric salivary gland tumors: Acute toxicity and dosimetric characteristics. AB - PURPOSE: We evaluated acute toxicity profiles and dosimetric data for children with salivary gland tumors treated with adjuvant photon/electron-based radiation therapy (X/E RT) or proton therapy (PRT). METHODS AND MATERIALS: We identified 24 patients who had received adjuvant radiotherapy for salivary gland tumors. Data were extracted from the medical records and the treatment planning systems. Toxicity was scored according to the Common Terminology Criteria for Adverse Effects 4.0. RESULTS: Eleven patients received X/E RT and 13 PRT, with a median prescribed dose of 60 Gy in each group. In the X/E RT group, 54% of patients developed acute grade II/III dermatitis, 27% grade II/III dysphagia, and 91% grade II/III mucositis, and the median weight loss was 5.3% with one patient requiring feeding tube placement. In the PRT group, 53% had acute grade II/III dermatitis, 0% grade II/III dysphagia, and 46% grade II/III mucositis, with a median weight gain of 1.2%. Additionally, PRT was associated with lower mean doses to several normal surrounding midline and contralateral structures. CONCLUSION: In this retrospective study of pediatric salivary tumors, PRT was associated with a favorable acute toxicity and dosimetric profile. Continued follow-up is needed to identify long-term toxicity and survival data. PMID- 26232129 TI - Comparison of two different rectal spacers in prostate cancer external beam radiotherapy in terms of rectal sparing and volume consistency. AB - BACKGROUND AND PURPOSE: In external beam radiation (EBRT) of the prostate, the rectum is the dose-limiting organ at risk, and sparing of the anterior rectal wall is a prerequisite for safe delivery of doses beyond 70 Gy. Spatial sparing of the rectum can be achieved by introducing a spacer material into the retroprostatic space, thus separating the anterior rectal wall from the PTV. MATERIALS AND METHODS: Two spacer technologies, Spacer OAR, a polyethylene glycol gel and ProSpace, a saline inflated balloon, were compared in terms of spacer volume, stability, and dose reduction to the anterior rectum wall in 78 patients. RESULTS: Both spacer systems significantly reduced the rectum surface encompassed by the 95% isodose (gel: -35%, p<0.01; balloon -63.4%, p<0.001) compared to a control group. The balloon spacer was superior in reducing rectum dose (-27.7%, p=0.034), but exhibited an average volume loss of >50% during the full course of treatment of 37-40 fractions, while the volume of gel spacers remained fairly constant. CONCLUSIONS: In choosing between the two spacer technologies, the advantageous dose reduction of the balloon needs to be weighed up against the better volume consistency of the gel spacer with respect to the duration of hypofractionated vs normofractionated regimens. PMID- 26232130 TI - Salvage surgery and radiotherapy including intraoperative electron radiotherapy in isolated locally recurrent tumors: Predictors of outcome. AB - PURPOSE: To evaluate the influence of equivalent dose (EQD2) in clinical outcomes of patients with isolated locally recurrent tumors (ILRT), treated with salvage surgery and intra-operative electron beam radiation therapy (IOERT). METHODS AND MATERIALS: We retrospectively reviewed 128 patients with non-metastatic ILRT of different tissues (soft tissue sarcomas, head and neck, uterine, and colorectal). Patients had received salvage surgery (R0/R1/R2) and IOERT. Previously not irradiated patients had received additional external beam radiation therapy (EBRT). RESULTS: IOERT was delivered at a median dose of 15 Gy (range, 5-25 Gy). Seventy-five patients (60.9%) received additional EBRT of 46 Gy. Median EQD2 of salvage program was 62 Gy and median EQD2 of exclusive IORT was 31.2 Gy. Median follow-up was 19.2 months (range: 1.3-220). Thirty-one patients (24.2%) developed severe (grade 3-5) complications. New locoregional recurrence was documented in 86 (67.2%) of the 123 cases. Five-year rates were 31% for locoregional control, 57% for distant metastasis-free and 31% for overall survival. On multivariate analysis, R0-1 vs. R2 resection (HR 2.2, 95 CI: 1.2-4.1) was statistically significant for locoregional recurrence and EQD2 ?62 Gy for survival (HR 2.2, 95 CI: 1.1-4.1). CONCLUSIONS: Surgical radicality (gross macroscopic resection) and radiation dose (EQD2 ?62 Gy in radiation salvage program) are the dominant prognostic factors beside ILRT histology. Modest rates of long-term disease control are expected when both factors are fulfilled. PMID- 26232131 TI - Towards science-based sediment quality standards-Effects of field-collected sediments in rainbow trout (Oncorhynchus mykiss). AB - Sediments can act as long-term sinks for environmental pollutants. Within the past decades, dioxin-like compounds (DLCs) such as polychlorinated dibenzo-p dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) have attracted significant attention in the scientific community. To investigate the time- and concentration dependent uptake of DLCs and PAHs in rainbow trout (Oncorhynchus mykiss) and their associated toxicological effects, we conducted exposure experiments using suspensions of three field-collected sediments from the rivers Rhine and Elbe, which were chosen to represent different contamination levels. Five serial dilutions of contaminated sediments were tested; these originated from the Prossen and Zollelbe sampling sites (both in the river Elbe, Germany) and from Ehrenbreitstein (Rhine, Germany), with lower levels of contamination. Fish were exposed to suspensions of these dilutions under semi-static conditions for 90 days. Analysis of muscle tissue by high resolution gas chromatography and mass spectrometry and of bile liquid by high-performance liquid chromatography showed that particle-bound PCDD/Fs, PCBs and PAHs were readily bioavailable from re suspended sediments. Uptake of these contaminants and the associated toxicological effects in fish were largely proportional to their sediment concentrations. The changes in the investigated biomarkers closely reflected the different sediment contamination levels: cytochrome P450 1A mRNA expression and 7 ethoxyresorufin-O-deethylase activity in fish livers responded immediately and with high sensitivity, while increased frequencies of micronuclei and other nuclear aberrations, as well as histopathological and gross pathological lesions, were strong indicators of the potential long-term effects of re-suspension events. Our study clearly demonstrates that sediment re-suspension can lead to accumulation of PCDD/Fs and PCBs in fish, resulting in potentially adverse toxicological effects. For a sound risk assessment within the implementation of the European Water Framework Directive and related legislation, we propose a strong emphasis on sediment-bound contaminants in the context of integrated river basin management plans. PMID- 26232132 TI - Wide-pulse-high-frequency neuromuscular electrical stimulation in cerebral palsy. AB - OBJECTIVE: The present study assesses whether wide-pulse-high-frequency (WPHF) neuromuscular electrical stimulation (NMES) could result in extra-force production in cerebral palsy (CP) patients as previously observed in healthy individuals. METHODS: Ten CP and 10 age- and sex-matched control participants underwent plantar flexors NMES. Two to three 10-s WPHF (frequency: 100 Hz, pulse duration: 1 ms) and conventional (CONV, frequency 25 Hz, pulse duration: 50 MUs) trains as well as two to three burst-like stimulation trains (2s at 25 Hz, 2s at 100 Hz, 2s at 25 Hz; pulse duration: 1 ms) were evoked. Resting soleus and gastrocnemii maximal H-reflex amplitude (Hmax) was normalized by maximal M-wave amplitude (Mmax) to quantify alpha-motoneuron modulation. RESULTS: Similar Hmax/Mmax ratio was found in CP and control participants. Extra-force generation was observed both in CP (+18 +/- 74%) and control individuals (+94 +/- 124%) during WPHF (p<0.05). Similar extra-forces were found during burst-like stimulations in both groups (+108 +/- 110% in CP and +65 +/- 85% in controls, p>0.05). CONCLUSION: Although the mechanisms underlying extra-force production may differ between WPHF and burst-like NMES, similar increases were observed in patients with CP and healthy controls. SIGNIFICANCE: Development of extra-forces in response to WPHF NMES evoked at low stimulation intensity might open new possibilities in neuromuscular rehabilitation. PMID- 26232133 TI - Urinary adiponectin and albuminuria in non-diabetic hypertensive patients: an analysis of the ESPECIAL trial. AB - BACKGROUND: Although adiponectin levels have been reported to be correlated with albuminuria, this issue remains unresolved in non-diabetic hypertensive subjects, particularly when urinary adiponectin is considered. METHODS: Urinary adiponectin levels were examined using an enzyme-linked immunosorbent assay in 229 participants. who used olmesartan as a hypertensive agent. Their albuminuria levels were measured for 16 weeks after randomization and initiation of conventional or intensive diet education. Linear or logistic regression models were applied, as appropriate, to explore the relationship with albuminuria itself or its response after the intervention. RESULTS: Urinary adiponectin levels were positively related to baseline albuminuria level (r = 0.529). After adjusting for several covariates, the adiponectin level was associated with the albuminuria level (beta = 0.446). Among the 159 subjects with baseline macroalbuminuria, the risk of consistent macroalbuminuria (> 300 mg/day) at 16 weeks was higher in the 3(rd) tertile of adiponectin than in the 1(st) tertile (odds ratio = 6.9), despite diet education. In contrast, among all subjects, the frequency of the normoalbuminuria achievement (< 30 mg/day) at 16 weeks was higher in the 1(st) tertile than in the 3(rd) tertile (odds ratio = 13.0). CONCLUSIONS: Urinary adiponectin may be a useful biomarker for albuminuria or its response after treatment in non-diabetic hypertensive patients. PMID- 26232134 TI - In vitro growth-inhibitory effect of ethanol GRAS plant and supercritical CO2 hop extracts on planktonic cultures of oral pathogenic microorganisms. AB - Conventional chemical antiseptics used for treatment of oral infections often produce side-effects, which restrict their long-term use. Plants are considered as perspective sources of novel natural antiseptics. However, little is still known about their inhibitory properties against oral pathogens. The objective of this study was to test in vitro antimicrobial activities of generally recognized as safe (GRAS) species against planktonic cultures of cariogenic, periodontal and candidal microorganisms and identify active compounds of the most active extracts. Growth-inhibitory effects of ethanol extracts from 109 GRAS plant species, six Humulus lupulus cultivars and two hop supercritical CO2 extracts were evaluated using broth microdilution method. The chemical analysis was done through high-performance liquid chromatography. Best results were obtained for supercritical CO2 and ethanol extracts of H. lupulus with minimum inhibitory concentrations (MIC) >=8 MUg/mL and >=16 MUg/mL, respectively. The chemical analysis of supercritical CO2H. lupulus extracts revealed that alpha- and beta acids were their main constituents. Capsicum annuum and Capsicum frutescens showed antibacterial effect against Streptococcus sobrinus and Streptococcus salivarius (MIC=64-128 MUg/mL). These strains were further inhibited by Zanthoxylum clava-herculis (MIC=64-128 MUg/mL) and Myristica fragrans (both MIC>=128 MUg/mL). The latter also exhibited antimicrobial activity against Fusobacterium nucleatum (MIC=64 MUg/mL). Punica granatum possessed inhibitory effects against Candida albicans (MIC=128 MUg/mL) and F. nucleatum (MIC=64 MUg/mL). The results indicate that supercritical CO2H. lupulus extracts together with ethanol extracts of C. annuum, C. frutescens, M. fragrans, P. granatum and Z. clava-herculis are promising materials for further investigation on new antiseptic agents of oral care products. PMID- 26232137 TI - Impact of fruit juice and beverage portion size on snack intake in preschoolers. AB - It has been recommended that beverages other than 100% fruit juice, such as water, be served at meals and snacks for preschool-aged children to reduce excessive energy intake. Using a 2 * 2 * 2 design (between-subjects factor of order and within-subjects factors of beverage type and size), 26 children (3.9 +/ 0.6 years of age, 50% female, 73% white, and 88.5% non-Hispanic or Latino) completed four, 20-min snack sessions consisting of 200 g of applesauce, 60 g of graham crackers, and either 6 oz. (approximately 180 g) or 12 oz. (approximately 360 g) of 100% berry fruit juice or water, to examine the influence of 100% fruit juice and the portion size of the provided fruit juice, on beverage, food, and overall snack intake. Mixed-factor analyses of covariance revealed a significant (p < 0.05) beverage type and size interaction for amount of beverage consumed, with the 12 oz. juice condition consuming the greatest amount of beverage (226.6 +/- 116.4 g), and for energy consumed from food, with the 12 oz. water condition consuming more than the 12 oz. juice condition (117.7 +/- 69.1 kcal vs. 88.5 +/- 64.1 kcal). A main effect of beverage type was found on overall snack energy intake, with more overall energy consumed when juice was provided (175.4 +/- 50.0 kcal vs. 104.8 +/- 62.8 kcal, p < 0.001). Providing preschool-aged children with a larger size of beverage at a snack increased beverage and/or food intake, and serving 100% juice led to greater overall snack energy intake. Future research should examine the role of 100% fruit juice, and beverage portion size, in contributing to excessive daily energy intake in preschool-aged children. PMID- 26232136 TI - Visual illusions and inattention: Their association with adiposity among adolescent girls. AB - The Delboeuf concentric circle illusion is frequently invoked as an explanation for the hypothesized association between dinner plate size and overeating. We examined its association with adiposity among 162 girls, aged 14-18 years. We also examined the association of adiposity with neural and behavioral responses during a separate visual discrimination task. The analysis showed that girls with a body mass index percentile >= 85, or with greater triceps skinfold thickness, exhibited less sensitivity to the Delboeuf illusion than girls with normal adiposity. The excess adiposity group also exhibited significantly smaller electroencephalographic responses and more errors during the separate visual discrimination task. In combination, the findings from the two tasks suggest that girls with an elevated body mass are less sensitive to visual cues in their environment. The implications of these findings for weight loss education should be considered. PMID- 26232135 TI - Mechanisms of the anorexia of aging-a review. AB - Many, even healthy, older people fail to adequately regulate food intake and experience loss of weight. Aging-associated changes in the regulation of appetite and the lack of hunger have been termed as the anorexia of aging. The etiology of the anorexia of aging is multi-factorial and includes a combination of physiological changes associated with aging (decline in smell and taste, reduced central and peripheral drive to eat, delayed gastric emptying), pathological conditions (depression, dementia, somatic diseases, medications and iatrogenic interventions, oral-health status), and social factors (poverty, loneliness). However, exact mechanisms of the anorexia of aging remain to be elucidated. Many neurobiological mechanisms may be secondary to age-related changes in body composition and not associated with anorexia per se. Therefore, further studies on pathophysiological mechanisms of the anorexia of aging should employ accurate measurement of body fat and lean mass. The anorexia of aging is associated with protein-energy malnutrition, sarcopenia, frailty, functional deterioration, morbidity, and mortality. Since this symptom can lead to dramatic consequences, early identification and effective interventions are needed. One of the most important goals in the geriatric care is to optimize nutritional status of the elderly. PMID- 26232138 TI - Food behavior change in late-life widowhood: A two-stage process. AB - Widowhood is a common life event for married older women. Prior research has found disruptions in eating behaviors to be common among widows. Little is known about the process underlying these disruptions. The aim of this study was to generate a theoretical understanding of the changing food behaviors of older women during the transition of widowhood. Qualitative methods based on constructivist grounded theory guided by a critical realist worldview were used. Individual active interviews were conducted with 15 community-living women, aged 71-86 years, living alone, and widowed six months to 15 years at the time of the interview. Participants described a variety of educational backgrounds and levels of health, were mainly white and of Canadian or European descent, and reported sufficient income to meet their needs. The loss of regular shared meals initiated a two-stage process whereby women first fall into new patterns and then re establish the personal food system, thus enabling women to redirect their food system from one that satisfied the couple to one that satisfied their personal food needs. Influences on the trajectory of the change process included the couple's food system, experience with nutritional care, food-related values, and food-related resources. Implications for research and practice are discussed. PMID- 26232139 TI - Picky/fussy eating in children: Review of definitions, assessment, prevalence and dietary intakes. AB - Picky eating (also known as fussy, faddy or choosy eating) is usually classified as part of a spectrum of feeding difficulties. It is characterised by an unwillingness to eat familiar foods or to try new foods, as well as strong food preferences. The consequences may include poor dietary variety during early childhood. This, in turn, can lead to concern about the nutrient composition of the diet and thus possible adverse health-related outcomes. There is no single widely accepted definition of picky eating, and therefore there is little consensus on an appropriate assessment measure and a wide range of estimates of prevalence. In this review we first examine common definitions of picky eating used in research studies, and identify the methods that have been used to assess picky eating. These methods include the use of subscales in validated questionnaires, such as the Children's Eating Behaviour Questionnaire and the Child Feeding Questionnaire as well as study-specific question(s). Second, we review data on the prevalence of picky eating in published studies. For comparison we present prevalence data from the UK Avon Longitudinal Study of Parents and Children (ALSPAC) in children at four time points (24, 38, 54 and 65 months of age) using a study-specific question. Finally, published data on the effects of picky eating on dietary intakes (both variety and nutrient composition) are reviewed, and the need for more health-related data and longitudinal data is discussed. PMID- 26232140 TI - Food addiction symptomology, impulsivity, mood, and body mass index in people with type two diabetes. AB - This research explored how food addiction (FA) and impulsivity (non-planning, motor, and attentional) relate to body mass index (BMI) in a sample of people with type 2 diabetes (t2d). Participants with t2d (N = 334, Mage = 41.0, SDage = 9.5, 66% female, MBMI = 37.6 kg/m(2), SDBMI = 8.0 kg/m(2)) completed an online survey including the Depression Anxiety Stress Scale (DASS-21), the Barratt Impulsiveness Scale (BIS-II), and the Yale Food Addiction Scale (YFAS). Results demonstrated that over 70% of the sample with t2d met the YFAS criteria for FA. Results also demonstrated that participants classified as FA had significantly higher BMI, t (332) = 12.11, p < .001. The food addict classification group also had a significantly higher percentage of obese participants, chi(2) (2) = 87.1, p < .001, phi = .511. Utilising a cross-sectional design to predict BMI, significant forward stepwise multiple regression demonstrated that FA (beta = .386) and impulsivity (non-planning) (beta = .286) were significant predictors. In combination FA and impulsivity (non-planning) significantly explained 38% of BMI variance; however depression, anxiety, and stress did not significantly improve the model. These results suggest FA and impulsivity (non-planning) are more salient cross-sectional predictors of BMI, in people with t2d, than indices of depression, anxiety, stress and impulsivity (motor and attentional). These results, implicating FA in the development of obesity, have important ramifications for potential future treatment methods of t2d where FA symptomology could be routinely screened, and if present, treated via addiction models rather than purely attempting to treat the potential consequences of FA. PMID- 26232142 TI - Evaluation of 3D-human skin equivalents for assessment of human dermal absorption of some brominated flame retardants. AB - Ethical and technical difficulties inherent to studies in human tissues are impeding assessment of the dermal bioavailability of brominated flame retardants (BFRs). This is further complicated by increasing restrictions on the use of animals in toxicity testing, and the uncertainties associated with extrapolating data from animal studies to humans due to inter-species variations. To overcome these difficulties, we evaluate 3D-human skin equivalents (3D-HSE) as a novel in vitro alternative to human and animal testing for assessment of dermal absorption of BFRs. The percutaneous penetration of hexabromocyclododecanes (HBCD) and tetrabromobisphenol-A (TBBP-A) through two commercially available 3D-HSE models was studied and compared to data obtained for human ex vivo skin according to a standard protocol. No statistically significant differences were observed between the results obtained using 3D-HSE and human ex vivo skin at two exposure levels. The absorbed dose was low (less than 7%) and was significantly correlated with log Kow of the tested BFR. Permeability coefficient values showed increasing dermal resistance to the penetration of gamma-HBCD>beta-HBCD>alpha-HBCD>TBBPA. The estimated long lag times (>30 min) suggests that frequent hand washing may reduce human exposure to HBCDs and TBBPA via dermal contact. PMID- 26232141 TI - Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer. AB - BACKGROUND: Tamoxifen, the most frequently used drug for treating estrogen receptor-positive breast cancer, must be converted into active metabolites to exert its therapeutic efficacy, mainly through CYP2D6 enzymes. The objective of this study was to investigate the impact of CYP2D6 polymorphisms on (Z)-endoxifen directed tamoxifen metabolism and to assess the usefulness of CYP2D6 genotyping for identifying patients who are likely to have insufficient (Z)-endoxifen concentrations to benefit from standard therapy. METHODS: Blood samples from 279 Polish women with breast cancer receiving tamoxifen 20 mg daily were analyzed for CYP2D6 genotype and drug metabolite concentration. Steady-state plasma levels of tamoxifen and its 14 metabolites were measured by using the ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. RESULTS: In nearly 60 % of patients, including over 30 % of patients with fully functional CYP2D6, (Z)-endoxifen concentration was below the predefined threshold of therapeutic efficacy. The most frequently observed CYP2D6 genotype was EM/PM (34.8 %), among which 83.5 % of patients had a combination of wild-type and *4 alleles. Plasma concentration of five metabolites was significantly correlated with CYP2D6 genotype. For the first time, we identified an association between decreased (E/Z)-4-OH-N-desmethyl-tamoxifen-beta-D-glucuronide levels (r (2) = 0.23; p < 10(-16)) and increased CYP2D6 functional impairment. The strongest correlation was observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 null allele, compared with EM/EM patients. The CYP2D6 genotype accounted for plasma level variability of (Z)-endoxifen by 27 % (p < 10(-16)) and for the variability of metabolic ratio indicating (Z)-endoxifen-directed metabolism of tamoxifen by 51 % (p < 10(-43)). CONCLUSIONS: The majority of breast cancer patients in Poland may not achieve a therapeutic level of (Z)-endoxifen upon receiving a standard dose of tamoxifen. This finding emphasizes the limited value of CYP2D6 genotyping in routine clinical practice for identifying patients who might not benefit from the therapy. In its place, direct monitoring of plasma steady-state (Z)-endoxifen concentration should be performed to personalize and optimize the treatment. PMID- 26232143 TI - Perfluoroalkyl acid (PFAA) levels and profiles in breast milk, maternal and cord serum of French women and their newborns. AB - One major concern regarding perfluoroalkyl acids (PFAAs) is their potential role in onset of health troubles consecutive to early exposure during the perinatal period. In the present work, the internal exposure levels of 18 targeted PFAAs were determined in ca. 100 mother-newborn pairs recruited in France between 2010 and 2013. In serum, the cumulated concentrations of the 7 most frequently detected compounds were 5.70ng/mL and 2.83ng/mL (median values) in maternal and cord serum, respectively. Perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexylesulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) contributed to around 90% of the total PFAAs contamination, with concentration levels and contamination profiles in accordance with other published work in Europe. Levels measured in breast milk were far lower (20 to 150 fold) than those determined in serum. Associations between the different monitored substances as well as between levels determined in the different investigated biological matrices mostly do not appear statistically significant. The estimated materno-foetal transfer would be thus substance-dependant, mainly driven by the physico-chemical properties of the different PFAAs (nature of polar group and length of alkylated side chain). We conclude that trans-placental passage and breastfeeding are both significant routes of human exposure to PFAAs. PMID- 26232144 TI - [Results of a health education intervention in the continuity of breastfeeding]. AB - AIM: evaluate the efficacy of a nursing intervention based on active observation and resolution of the problems of breastfeeding in the period 24-48h post-partum as regards stopping breastfeeding in mothers who gave birth in Hospital General Universitario, Ciudad Real. METHODS: A clinical trial was conducted on 100 healthy women who had given birth to a healthy baby in the maternity unit of the Hospital General Universitario Ciudad Real. RESULTS: The results showed that 39.8% of women have problems, and 72% need help to initiate the breastfeeding. Approximately 79.9% continue with breastfeeding after hospital discharge as a result of our intervention. Breastfeeding was stopped by 31.1% of the control group, and by 10.9% in the experimental group (nursing intervention), with significant differences being observed in both groups, with RR 1.29 and 95% CI; 1.04-1.61. Hypogalactia (low milk production) was the most frequent reason for stopping, with no differences in both groups. At 3 months, 16.9% had stopped breastfeeding in the control group, and 9% in the experimental group. At 6 months, 19.3% of the control group did not continue with breastfeeding versus 15.9% in the experimental group. CONCLUSION: Action, and not only intervention, protocols in the period 48h pospartum when there were problems with breastfeeding were effective for initiation breastfeeding at hospital discharge. PMID- 26232145 TI - Evanescent wave fluorescence biosensors: Advances of the last decade. AB - Biosensor development has been a highly dynamic field of research and has progressed rapidly over the past two decades. The advances have accompanied the breakthroughs in molecular biology, nanomaterial sciences, and most importantly computers and electronics. The subfield of evanescent wave fluorescence biosensors has also matured dramatically during this time. Fundamentally, this review builds on our earlier 2005 review. While a brief mention of seminal early work will be included, this current review will focus on new technological developments as well as technology commercialized in just the last decade. Evanescent wave biosensors have found a wide array applications ranging from clinical diagnostics to biodefense to food testing; advances in those applications and more are described herein. PMID- 26232146 TI - An up-date on health-related quality of life in myasthenia gravis -results from population based cohorts. AB - Current available therapies control Myasthenia gravis (MG) reasonably well, but Health Related Quality of life (HRQOL) remains lower than expected. The aim was provide insights in how HRQOL in MG stands across borders and time, compare the scores to general population controls and other chronic disorders and assess the impact of potential predictors for quality of life such as a) clinical characteristics b) antibodies c) thymoma and d) treatment in a population-based cohort. METHODS: We designed a population-based cross-sectional study including 858 patients, 373 from Norway and 485 from the Netherlands. The Short Form Health Survey 36 (SF-36) and a cross-cultural validated questionnaire were used. Data were in addition compared to the general population, other chronic diseases and previous studies. RESULTS: Mean physical composite score was 59.4 and mental composite score 69.0 with no differences between the countries. The mean HRQOL score was lower in patients with bulbar and generalized symptoms (p < 0.001) compared to sex and age adjusted healthy controls, but not in patients with ocular symptoms or patients in remission. Multivariate analysis revealed that female gender, generalized symptoms and use of secondary immunosuppressive drugs at the time of testing were risk factors for reduced HRQOL. CONCLUSIONS: Remission and absence of generalized symptoms were favorable factors for HRQOL in MG patients. Historically, the HRQOL levels have not changed since 2001 and no new clinical predictors could be detected in this exhaustive population-based study. Further studies should explore the impact of non clinical factors like ethnic variations, socio-economic and hormonal factors on HRQOL. PMID- 26232147 TI - Selective advantage of HLA matching in successful uncomplicated oocyte donation pregnancies. AB - Oocyte donation (OD) enables women with various causes of reproductive failure to conceive, but is accompanied by a high risk of certain pregnancy disorders. Possibly, the allogeneic nature of the fetus in OD pregnancies plays a role in the development of these disorders. In this study, we investigated whether there is a selection for some degree of HLA matching in successful and uncomplicated OD pregnancies. Mothers and children from OD pregnancies that used unrelated donors (n=75) were typed for HLA-A, -B, -C, -DR, and -DQ and the observed number of HLA matches of the child was compared with the expected number of HLA matches. Moreover, we studied the possibility of a preferential selection for maternal KIR and fetal C combinations. We observed a significantly higher level of HLA matching between mother and child than expected by chance. In particular, the incidence of children with 5 or more HLA matches, which is the situation in autologous pregnancy, was higher than expected. A higher level of matching was shown, especially for HLA class I, while no significant differences were observed for the individual HLA loci. With respect to maternal KIR and fetal HLA-C no selection for a favorable combination was found. Larger observational studies including uncomplicated, preeclamptic, and aborted pregnancies are essential to determine to what extent HLA matching affects the outcome of OD pregnancies. PMID- 26232148 TI - The effect of body mass index on post-vaccination maternal and neonatal pertussis antibody levels. AB - The objective was to determine if there is an association between maternal body mass index (BMI) and maternal and neonatal pertussis antibody concentrations following vaccination. This is a nested cohort study of 123 women who received the Tdap vaccine during pregnancy. Women were stratified by BMI into three groups -normal, overweight, and obese, based on first trimester or pre-pregnancy BMI. Maternal and umbilical cord serum samples were tested for post-vaccination pertussis IgG antibody. The mean maternal pertussis antibody concentration was 167.5 U/mL for normal BMI (n=29), 169.8 U/mL for overweight BMI (n=54), and 175.5 U/mL for the obese BMI groups (n=40). The mean fetal pertussis antibody concentrations were 182.3 U/mL, 191.4 U/mL, and 197.7 U/mL for these groups respectively. Seroprotection was achieved in 89.7% of neonates (26/29) in the normal BMI group, 87.0% (47/54) in the overweight BMI group, and 97.5% (39/40) in the obese BMI group. None of these differences reached statistical significance. Maternal BMI does not affect the maternal or neonatal pertussis antibody response to the Tdap vaccine in women who receive the vaccine in pregnancy. Maternal BMI is unlikely to affect the neonatal protective effects of a standard dose of Tdap vaccine in pregnancy. PReCIS: Maternal and umbilical cord antibody response to the pertussis vaccine is not affected by maternal body mass index. PMID- 26232149 TI - Increased circulating interleukin-17 levels in preeclampsia. AB - Increasing evidence suggests that an exaggerated maternal systemic inflammatory response and an angiogenic imbalance might play a central role in the pathogenesis of preeclampsia. We determined circulating levels of interleukin-17 (IL-17) along with those of angiogenic factors in healthy nonpregnant and pregnant women and preeclamptic patients, and examined whether serum IL-17 levels of preeclamptic patients were related to their clinical features and angiogenic factor concentrations. Fifty-nine preeclamptic patients, 60 healthy pregnant women and 56 healthy nonpregnant women were involved in this case-control study. Serum levels of IL-17A were measured using a high-sensitivity ELISA. Serum total soluble fms-like tyrosine kinase-1 (sFlt-1) and biologically active placental growth factor (PlGF) levels were determined by electrochemiluminescence immunoassay. For statistical analyses, nonparametric methods were applied. Serum IL-17 levels were significantly higher in preeclamptic patients than in healthy nonpregnant and pregnant women. We did not find any relationship between serum IL 17 concentrations of preeclamptic patients and their clinical features and serum sFlt-1 and PlGF levels or sFlt-1/PlGF ratios. However, elevated serum IL-17 level and sFlt-1/PlGF ratio were found to have an additive effect on the risk of preeclampsia, as shown by the substantially higher odds ratios of a combination of the two than of either alone. In conclusion, serum IL-17 levels are increased in preeclampsia, which may contribute to the development of the excessive systemic inflammatory response characteristic of the maternal syndrome of the disease. In addition, elevated serum IL-17 level and sFlt-1/PlGF ratio had an additive (joint) effect on the risk of preeclampsia. PMID- 26232150 TI - Predictive biomarkers of preterm delivery in women with ongoing IVF pregnancies. AB - In vitro fertilization (IVF) pregnancies potentially have a higher rate of preterm delivery (PTD) than do spontaneously conceived gestations, and differences persist following adjustment for multiple gestation, maternal age, and parity. The reasons for this increased susceptibility to PTD remain incompletely elucidated. To identify potential biomarkers predictive of PTD in IVF subjects, we performed a retrospective analysis of multiple markers in sera obtained during early gestation that have been suggested to be associated with peri-implantation events. Sera from 35 women with a preterm birth and 68 women with a term delivery, obtained between 9 and 11 days after embryo transfer, were tested blindly for concentrations of interleukin (IL)-1beta, IL-6, IL-13, IL-17, human epididymal protein 4 (HE4), secretory leukocyte protease inhibitor (SLPI), insulin-like growth factor (IGF)-I, IGF-II, IGF binding protein (BP)-1, and interferon-gamma. Concentrations of HE4 (p=0.001) and IL-13 (p=0.029) were reduced, and levels of IGF-II (p=0.023) and SLPI (p=0.043) were increased, in women who subsequently delivered preterm. By receiver operator curve analysis, the combination of HE4 and IL-13 levels best predicted the outcome preterm birth. The association between deficiencies in circulating HE4 and IL-13 levels during early pregnancy and subsequent PTD suggest that factors contributing to sub optimal embryo implantation influence length of gestation in women undergoing IVF. PMID- 26232151 TI - Better to burn out than it is to rust: coordinating cellular redox states during aging and stress. PMID- 26232152 TI - Analysis of hospitalizations due to intussusception in Sicily in the pre rotavirus vaccination era (2003-2012). AB - BACKGROUND: Intussusception is the most common cause of bowel obstruction in infants with an incidence ranging from 9-328 cases per 100,000 infants aged 0-11 months. Causes underlining this clinical manifestation are still unknown. Possible relationship with a withdrawn tetravalent rotavirus vaccine was not confirmed by post-licensure studies and actually no increased risk of intussusception was found between infants vaccinated with both the recently licensed rotavirus vaccines. Aim of this study is to analyze the intussusception hospitalizations in Sicily from 2003 to 2012 before the introduction of rotavirus universal vaccination and its possible relation with rotavirus gastroenteritis trend. METHODS: Were collected data from hospital discharge records occurred from 1(st) January 2003 to 31(st) December 2012 in Sicily. Intussusception cases were defined as all hospitalizations with an ICD-9-CM code of 560.0 on any discharge diagnoses. As a proxy for the severity of cases were considered ICD-9-CM procedure codes accounting for surgical or radiologic reduction. RESULTS: A total of 340 intussusception cases were hospitalized in Sicily from 2003 to 2012 in children aged 0-59 months. 46.8 % occurred in the age class 0-11 months. Hospitalization rate for intussusception was 11.4 cases per 100,000 per year (32.6 cases per 100,000 among 0-11 months children; 7.3 cases per 100,000 among 12-59 months children), with a M:F sex ratio of 1.8. During hospitalization only 25 % of intussusceptions had a spontaneous resolution, 56.5 % of cases required a surgical intervention. From 2003 to 2012 intussusception cases were equally distributed during the year without any seasonality, while gastroenteritis hospitalizations due to rotavirus infection have a typically late winter and spring distribution. CONCLUSIONS: In Sicily from 2003 to 2012 hospitalizations due to intestinal invagination were higher among children aged 0-11 months with observed rates similar to other European countries. Regional baseline data analysis of intussusception among 0-59 children is recognized as an evidence based public health strategy by international health authorities. Indeed, this strategy is necessary to compare any post-licensure age or sex-related change in intussusception trend after universal rotavirus vaccination introduction. PMID- 26232153 TI - Striatal and extrastriatal dopamine release in the common marmoset brain measured by positron emission tomography and [(18)F]fallypride. AB - Previous studies have demonstrated that patients with schizophrenia show greater sensitivity to psychostimulants than healthy subjects. Sensitization to psychostimulants and resultant alteration of dopaminergic neurotransmission in rodents has been suggested as a useful model of schizophrenia. This study sought to examine the use of methylphenidate as a psychostimulant to induce dopamine release and that of [(18)F]fallypride as a radioligand to quantify the release in a primate model of schizophrenia. Four common marmosets were scanned by positron emission tomography twice, before and after methylphenidate challenge, to evaluate dopamine release. Four other marmosets were sensitized by repeated methamphetamine (MAP) administration. Then, they were scanned twice, before and after methylphenidate challenge, to evaluate whether MAP-sensitization induced greater sensitivity to methylphenidate. We revealed a main effect of the methylphenidate challenge but not the MAP pretreatment on the striatal binding potential. These results suggest that methylphenidate-induced striatal dopamine release in the common marmoset could be evaluated by [(18)F]fallypride. PMID- 26232155 TI - Unexpected death caused by rupture of a dilated aorta in an adult male with aortic coarctation. AB - Aortic coarctation (AC) is a congenital aortic narrowing. We describe for the first time the findings obtained by unenhanced post mortem computed tomography (PMCT) in a case where the death was caused by cardiac tamponade from a ruptured aneurysmal dilatation of the ascending aorta and the aortic arch without dissection combined with aortic coarctation. The patient, a 46-year-old man, was found dead at home. PMCT showed haemopericardium and dilatation of the ascending aorta and the aortic arch. This appearance led to the mistaken interpretation that the images represented a dissecting aneurysm. The autopsy showed instead a thin-walled and floppy dilatation of the ascending aorta and aortic arch with a coarctation just proximal to the ligamentum arteriosum. A longitudinal tear was found in the posterior aortic wall just above the valves. Blood in the surrounding soft tissue intersected with a large haematoma (1000ml) in the pericardial sac. Cardiac hypertrophy (556g) was observed in the patient, though no other cardiovascular abnormalities were found. Histological analysis showed cystic medial necrosis of the ascending aortic wall. A ruptured aneurysmal dilatation of the ascending aorta and the aortic arch without aortic dissection associated with AC is an uncommon cause of haemopericardium that has only been described a few times before. The case is discussed in relation to other reported cases and in the context of the present understanding of this condition. PMID- 26232154 TI - Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. AB - BACKGROUND: Microglia are dependent upon colony-stimulating factor 1 receptor (CSF1R) signaling for their survival in the adult brain, with administration of the dual CSF1R/c-kit inhibitor PLX3397 leading to the near-complete elimination of all microglia brainwide. Here, we determined the dose-dependent effects of a specific CSF1R inhibitor (PLX5622) on microglia in both wild-type and the 3xTg-AD mouse model of Alzheimer's disease. METHODS: Wild-type mice were treated with PLX5622 for up to 21 days, and the effects on microglial numbers were assessed. 3xTg-AD mice were treated with PLX5622 for 6 or 12 weeks and effects on microglial numbers and pathology subsequently assessed. RESULTS: High doses of CSF1R inhibitor eliminate most microglia from the brain, but a 75% lower-dose results in sustained elimination of ~30 of microglia in both wild-type and 3xTg AD mice. No behavioral or cognitive deficits were found in mice either depleted of microglia or treated with lower CSF1R inhibitor concentrations. Aged 3xTg-AD mice treated for 6 or 12 weeks with lower levels of PLX5622 resulted in improved learning and memory. Abeta levels and plaque loads were not altered, but microglia in treated mice no longer associated with plaques, revealing a role for the CSF1R in the microglial reaction to plaques, as well as in mediating cognitive deficits. CONCLUSIONS: We find that inhibition of CSF1R alone is sufficient to eliminate microglia and that sustained microglial elimination is concentration-dependent. Inhibition of the CSF1R at lower levels in 3xTg-AD mice prevents microglial association with plaques and improves cognition. PMID- 26232156 TI - A clinical approach to solving discrepancies in therapeutic drug monitoring results for patients on sirolimus or tacrolimus: Towards personalized medicine, immunosuppression and pharmacogenomics. AB - BACKGROUND: Unexpected clinical laboratory concentrations often need to be investigated before they are acted upon in a clinical setting. Therapeutic drug monitoring (TDM) frequently involves drugs with narrow therapeutic windows and can be harmful to the patient if changes are made based on erroneous serum drug concentrations. Too little of the drug will result in ineffective therapy and too much of the drug can cause life threatening toxicities. There are many factors that can result in unexpected serum drug concentrations including differences in analytical methods being used, diet, timing of blood draw, genotype and compliance. All these factors should all be considered before deciding if changes should be made in a patient's therapeutic course. CASE REPORT: We determined the cause of 2 patient's unexpected TDM concentrations for sirolimus and tacrolimus. Using this approach in 2 patient cases, we describe how co-treatment and uncommon genotypes result in unexpected drug concentrations. CONCLUSIONS: Both cases involved unexpected drug values. In the first case, the cause was revealed to be a drug that was added to the patient's treatment regimen (posaconazole) that inhibits CYP3A4 which is responsible for sirolimus metabolism. In the second case, the patient was revealed to have an uncommon genotype for CYP3A5, causing higher metabolism and lower serum tacrolimus concentrations than the general population. PMID- 26232157 TI - Rapid, single-phase extraction of glucosylsphingosine from plasma: A universal screening and monitoring tool. AB - BACKGROUND: Glucosylsphingosine (GluSph) has emerged as a biomarker for the inherited metabolic disorder, Gaucher disease (GD). We developed a simple laboratory test to measure plasma GluSph and show that elevated GluSph is diagnostic for GD as well as informing on disease burden for monitoring patients on treatment. METHODS: GluSph was measured from a single-phase total lipid extraction of 0.01 mL of plasma by liquid chromatography-electrospray ionisation tandem mass spectrometry and concentrations extrapolated from a seven point standard curve (0.04 to 20 pmoL). A total of 1464 samples were tested and longitudinal assessment of an additional 20 GD patients. RESULTS: All patients with GD had elevated GluSph compared to unaffected controls and 16 other metabolic disorders. GluSph was also slightly elevated in three patients with Krabbe disease but not at concentrations to confuse a GD diagnosis. GluSph correlated with chitotriosidase in the majority of GD patients on treatment who were informative for this marker. CONCLUSIONS: GluSph can be easily measured from 0.01 mL of plasma and is useful as a diagnostic marker for GD with the current platform suited to high-throughput screening. It outperforms other GD biomarkers for biochemical monitoring of patients receiving enzyme replacement therapy for all individuals. PMID- 26232158 TI - Defining thresholds of specific IgE levels to grass pollen and birch pollen allergens improves clinical interpretation. AB - BACKGROUND: Cut-off values and predictive values are used for the clinical interpretation of specific IgE antibody results. However, cut-off levels are not well defined, and predictive values are dependent on the prevalence of disease. The objective of this study was to document clinically relevant diagnostic accuracy of specific IgE for inhalant allergens (grass pollen and birch pollen) based on test result interval-specific likelihood ratios. Likelihood ratios are independent of the prevalence and allow to provide diagnostic accuracy information for test result intervals. METHODS: In a prospective study we included consecutive adult patients presenting at an allergy clinic with complaints of rhinitis or rhinoconjunctivitis. The standard for diagnosis was a suggestive clinical history of grass or birch pollen allergy and a positive skin test. Specific IgE was determined with the ImmunoCAP Fluorescence Enzyme Immuno Assay. RESULTS: We established specific IgE test result interval related likelihood ratios for clinical allergy to inhalant allergens (grass pollen, rPhl p 1,5, birch pollen, rBet v 1). The likelihood ratios for allergy increased with increasing specific IgE antibody levels. The likelihood ratio was <0.03 for specific IgE <0.1 kU/L, between 0.1 and 1.4 for specific IgE between 0.1 kU/L and 0.35 kU/L, between 1.4 and 4.2 for specific IgE between 0.35 kU/L and 3.5 kU/L, >6.3 for specific IgE>0.7, and very high (infinity) for specific IgE >3.5 kU/L. CONCLUSION: Test result interval specific likelihood ratios provide a useful tool for the interpretation of specific IgE test results for inhalant allergens. PMID- 26232159 TI - Soluble CD14 subtype (sCD14-ST) presepsin in premature and full term critically ill newborns with sepsis and SIRS. AB - Neonatal sepsis still remains a major cause of morbidity and mortality in neonatal intensive care unit (NICU). Recently, soluble CD14 subtype (sDC14-ST) also named presepsin, was proposed as an effective biomarker for diagnosing, monitoring, and assessing the risk of neonatal sepsis and septic shock. The aim of this study was to investigate the diagnostic accuracy of sCD14-ST presepsin in diagnosing neonatal bacterial sepsis and in discriminating non-bacterial systemic inflammatory response syndrome (SIRS) from bacterial sepsis. This study involved 65 critically ill full-term and preterm newborns admitted to the neonatal intensive care unit (NICU), divided into three groups: 25 newborns with bacterial neonatal sepsis (group A); 15 newborns with a diagnosis of non-bacterial SIRS and with no localizing source of bacterial infection (group B); and 25 babies with no clinical or bacteriological signs of systemic or local infection receiving routine NICU care, most of them treated with phototherapy for neonatal jaundice (group C). A total of 102 whole blood samples were collected, 40 in group A, 30 in group B and 32 in group C. In 10 babies included in group A, sCD14-ST presepsin was also measured in an additional second blood sample collected 3 days after the start of antibiotic treatment. sCD14-ST presepsin was measured by a commercially available chemiluminescent enzyme immunoassay (CLEIA) optimized on an automated immunoassay analyzer. Statistical analysis was performed by means of MedCalc(r) statistical package; receiver operating characteristic (ROC) analysis was computed, and the area under the ROC curve (AUC) was used to evaluate the ability of sCD14-ST to discriminate neonatal bacterial sepsis from non-bacterial SIRS. Blood sCD14-ST presepsin levels were found significantly higher in bacterial sepsis when compared with controls (p<0.0001); similarly, they were higher in non-bacterial SIRS when compared with controls (p<0.0001). However, no statistically significant difference was found between bacterial sepsis and non bacterial SIRS (p=0.730). In our population, CRP and sCD14-ST did not correlate with each other. ROC analysis revealed that sCD14-ST presepsin has an area under the curve (AUC) of 0.995 (95% C.I.: 0.941-1.00) greater than that of CRP (0.827; 95% C.I.: 0.72-0.906). Similarly, in the group of babies with non-infectious SIRS, sCD14-ST AUC was greater than CRP AUC (0.979; 95% C.I.: 0.906-0.999 versus 0.771; 95% C.I.: 0.647-0.868). In controls, preliminary reference intervals for sCD14-ST ranged 223.4-599.7 ng/L, being significantly different from those previously published elsewhere. In conclusion, sCD14-ST presepsin could be introduced in clinical practice as a diagnostic tool for improving the management of neonatal sepsis and non-bacterial SIRS. PMID- 26232160 TI - Therapeutic concentrations of hydroxocobalamin interferes with several spectrophotometric assays on the Beckman Coulter DxC and AU680 chemistry analyzers. AB - BACKGROUND: High doses of hydroxocobalamin (OHCob) are used to treat cyanide poisoning and cardiac complications. Since OHCob absorbs at multiple wavelengths often used in colorimetric assays, spurious laboratory results are likely to occur. The objective of this study was to examine interference caused by OHCob in colorimetric assays measured using the Beckman Coulter DxC and AU680. METHODS: OHCob was dissolved in water and spiked into pooled "healthy" and "unhealthy" patient samples at two different concentrations (0.15 and 1.5 mg/mL). Spiked and unspiked samples were analyzed on both instruments and bias was calculated. A total of 23 analytes were tested on the DxC and 27 analytes were tested on the AU680. For analytes showing a bias >= 10%, OHCob was titrated from 0.2-1.5mg/mL. RESULTS: The following analytes were affected on the DxC and AU680: alanine aminotransferase, amylase, total bilirubin, cholesterol, creatine kinase, creatinine, magnesium, uric acid. Direct bilirubin, iron, phosphate, total protein and triglycerides were only affected on the DxC. Biases observed were positive or negative and fixed or proportional. CONCLUSIONS: Between the DxC and AU680, several analytes were affected at therapeutic OHCob concentrations. Hence, it is important for laboratories to know how their instruments are affected, and for clinicians to alert the lab when these samples are expected. PMID- 26232163 TI - Increased cholesterol efflux capacity in metabolic syndrome: Relation with qualitative alterations in HDL and LCAT. AB - BACKGROUND: Metabolic syndrome (MetS) is associated with changes in HDL levels, composition and sub-fraction profile. Whether these alterations affect HDL anti atherogenic function, specifically measured as its capacity to perform cholesterol efflux, is not yet clearly known. OBJECTIVE: To evaluate the relation between serum cholesterol efflux capacity and the changes in HDL composition and sub-fraction profile in MetS. METHODS: In 35 non-treated MetS patients and 15 healthy controls, HDL mediated cholesterol efflux was measured as the ability of apoB-depleted serum to accept cholesterol from cholesterol-loaded BHK cells expressing either ABCA1 or ABCG1. Additionally we determined: lipid profile, HDL sub-fractions (NMR) and LCAT mass (ELISA). Isolated HDL (delta:1.063-1.210 g/mL) was chemically characterized. Pre-beta1-HDL was determined by 2D-electrophoresis in a sub-group of MetS and controls (n = 6 each). RESULTS: Surprisingly, MetS patients presented higher ABCA1 mediated cholesterol efflux (10.4 +/- 1.8 vs. 8.7 +/- 0.3%; p = 0.0001), without differences in ABCG1 efflux. In MetS, HDL showed reduction in particle size and number (p < 0.02) and lower large/small HDL ratio (p = 0.05), as well as triglyceride enrichment (p = 0.0001). Pre-beta1-HDL was increased in MetS (p = 0.048) and correlated with ABCA1-cholesterol efflux (r = 0.64; p = 0.042). LCAT mass showed a tendency to reduction in MetS (p = 0.08), and inversely correlated with ABCA1-cholesterol efflux (r = -0.51; p = 0.001), independently of obesity and insulin-resistance (beta = -0.40, p = 0.034). CONCLUSION: This is the first description of ABCA1 mediated cholesterol efflux in MetS. Regardless the reduced HDL-cholesterol, in vitro cholesterol efflux capacity by ABCA1 was enhanced, linked to increased pre-beta1-HDL and slightly reduced in LCAT mass that would probably reflect a delay in reverse cholesterol transport occurring in MetS. PMID- 26232164 TI - Relationship of the triglyceride to high-density lipoprotein cholesterol (TG/HDL C) ratio to the remainder of the lipid profile: The Very Large Database of Lipids 4 (VLDL-4) study. AB - BACKGROUND: High levels of the triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio are associated with obesity, metabolic syndrome, and insulin resistance. OBJECTIVES: We evaluated variability in the remaining lipid profile, especially remnant lipoprotein particle cholesterol (RLP-C) and its components (very low-density lipoprotein cholesterol subfraction 3 and intermediate-density lipoprotein cholesterol), with variability in the TG/HDL-C ratio in a very large study cohort representative of the general U.S. METHODS: We examined data from 1,350,908 US individuals who were clinically referred for lipoprotein cholesterol ultracentrifugation (Atherotech, Birmingham, AL) from 2009 to 2011. Demographic information other than age and sex was not available. Changes to the remaining lipid profile across percentiles of the TG/HDL-C ratio were quantified, as well as by three TG/HDL-C cut-off points previously proposed in the literature: 2.5 (male) and 2 (female), 3.75 (male) and 3 (female), and 3.5 (male and female). RESULTS: The mean age of our study population was 58.7 years, and 48% were men. The median TG/HDL-C ratio was 2.2. Across increasing TG/HDL-C ratios, we found steadily increasing levels of RLP-C, non-HDL-C and LDL density. Among the lipid parameters studied, RLP-C and LDL density had the highest relative increase when comparing individuals with elevated TG/HDL-C levels to those with lower TG/HDL-C levels using established cut-off points. Approximately 47% of TG/HDL-C ratio variance was attributable to RLP-C. CONCLUSIONS: In the present analysis, a higher TG/HDL-C ratio was associated with an increasingly atherogenic lipid phenotype, characterized by higher RLP-C along with higher non HDL-C and LDL density. PMID- 26232165 TI - Valvular interstitial cells suppress calcification of valvular endothelial cells. AB - BACKGROUND: Calcific aortic valve disease (CAVD) is the most common heart valve disease in the Western world. We previously proposed that valvular endothelial cells (VECs) replenish injured adult valve leaflets via endothelial-to mesenchymal transformation (EndMT); however, whether EndMT contributes to valvular calcification is unknown. We hypothesized that aortic VECs undergo osteogenic differentiation via an EndMT process that can be inhibited by valvular interstitial cells (VICs). APPROACH AND RESULTS: VEC clones underwent TGF-beta1 mediated EndMT, shown by significantly increased mRNA expression of the EndMT markers alpha-SMA (5.3 +/- 1.2), MMP-2 (13.5 +/- 0.6) and Slug (12 +/- 2.1) (p < 0.05), (compared to unstimulated controls). To study the effects of VIC on VEC EndMT, clonal populations of VICs were derived from the same valve leaflets, placed in co-culture with VECs, and grown in control/TGF-beta1 supplemented media. In the presence of VICs, EndMT was inhibited, shown by decreased mRNA expression of alpha-SMA (0.1 +/- 0.5), MMP-2 (0.1 +/- 0.1), and Slug (0.2 +/- 0.2) (p < 0.05). When cultured in osteogenic media, VECs demonstrated osteogenic changes confirmed by increase in mRNA expression of osteocalcin (8.6 +/- 1.3), osteopontin (3.7 +/- 0.3), and Runx2 (5.5 +/- 1.5). The VIC presence inhibited VEC osteogenesis, demonstrated by decreased expression of osteocalcin (0.4 +/- 0.1) and osteopontin (0.2 +/- 0.1) (p < 0.05). Time course analysis suggested that EndMT precedes osteogenesis, shown by an initial increase of alpha-SMA and MMP-2 (day 7), followed by an increase of osteopontin and osteocalcin (day 14). CONCLUSIONS: The data indicate that EndMT may precede VEC osteogenesis. This study shows that VICs inhibit VEC EndMT and osteogenesis, indicating the importance of VEC-VIC interactions in valve homeostasis. PMID- 26232167 TI - Modelling atherosclerosis by proteomics: Molecular changes in the ascending aortas of cholesterol-fed rabbits. AB - The cholesterol-fed rabbit is commonly used as a model to study the vascular effects of hypercholesterolemia and resulting atherosclerotic lesions. Here we undertook a proteomic case-control investigation of ascending aortas from male New Zealand White rabbits after 10 weeks on a high-cholesterol (2% w/w) diet (HCD, n = 5) or control diet (n = 5), in order to determine the changes in response to the HCD. Histology confirmed intimal thickening in the HCD group consistent with atherosclerosis, and LC-MS/MS analysis of individually-obtained ascending aortic extracts labelled with isobaric (iTRAQ) tags enabled the identification and quantitation of 453 unique proteins above the 1% false discovery rate threshold. Of 67 proteins showing significant differences in relative abundance (p < 0.05), 62 were elevated and five decreased in ascending aortas from HCD-fed rabbits compared to controls. Six proteins were selected for validation using Multiple Reaction Monitoring, which confirmed the iTRAQ results. Many of the observed protein changes are consistent with known molecular perturbations in the ascending aorta that occur in response to hypercholesterolemia, e.g. elevation of tissue levels of apolipoproteins, extracellular matrix adhesion proteins, glycolytic enzymes, heat shock proteins and proteins involved in immune defense. We also made a number of novel observations, including a 15-fold elevation of glycoprotein (trans-membrane) nmb like (Gpnmb) in response to HCD. Gpnmb has previously been linked to angiogenesis but not to atherosclerosis. This and additional novel observations merit further investigation as these perturbations may play important and as yet undiscovered roles in the pathogenesis of atherosclerosis in rabbits as well as humans. PMID- 26232166 TI - Utility of a genetic risk score to predict recurrent cardiovascular events 1 year after an acute coronary syndrome: A pooled analysis of the RISCA, PRAXY, and TRIUMPH cohorts. AB - BACKGROUND: Limited evidence exists regarding the utility of genetic risk scores (GRS) in predicting recurrent cardiovascular events after acute coronary syndrome (ACS). We sought to determine whether a GRS would predict early recurrent cardiovascular events within 1 year of ACS. METHODS & RESULTS: Participants admitted with acute coronary syndromes from the RISCA, PRAXY, and TRIUMPH cohorts, were genotyped for 30 single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD) or myocardial infarction (MI) in prior genome wide association studies. A 30 SNP CAD/MI GRS was constructed. The primary endpoint was defined as all-cause mortality, recurrent ACS or cardiac re hospitalization within 1 year of ACS admission. Results across all cohorts for the 30 SNP CAD/MI GRS were pooled using a random-effects model. There were 1040 patients from the RISCA cohort, 691 patients from the PRAXY cohort, and 1772 patients from the TRIUMPH cohort included in the analysis and 389 occurrences of the primary endpoint of recurrent events at 1-year post-ACS. In unadjusted and fully adjusted analyses, a 30 SNP GRS was not significantly associated with recurrent events (HR per allele 0.97 (95%CI 0.91-1.03) for RISCA, HR 0.99 (95%CI 0.93-1.05) for PRAXY, 0.98 (95%CI 0.94-1.02) for TRIUMPH, and 0.98 (95%CI 0.95 1.01) for the pooled analysis). Addition of this GRS to the GRACE risk model did not significantly improve risk prediction. CONCLUSION: The 30 MI SNP GRS was not associated with recurrent events 1-year post ACS in pooled analyses across cohorts and did not improve risk discrimination or reclassification indices. Our results suggest that the genetic etiology of early events post-ACS may differ from later events. PMID- 26232168 TI - Landmark position paper on paediatric familial hypercholesterolaemia from the EAS Consensus Panel. PMID- 26232169 TI - Effects of amount and type of dietary fats on postprandial lipemia and thrombogenic markers in individuals with metabolic syndrome. AB - OBJECTIVE: Postprandial lipemia has been reported to affect endothelial function by thrombogenic and inflammatory pathways. We set out to investigate the impact of a) specific amount (50 g vs 20 g fat), and b) type of fatty acids (saturated, monounsaturated or n-6 polyunsaturated fatty acids; SFA, MUFA, PUFA) on postprandial lipemia, thrombogenic and inflammatory factors in metabolic syndrome subjects. DESIGN: 30 subjects (15 men, 15 women) participated in a double-blind, randomized crossover design study with both the subjects and investigators blinded to treatments. Blood samples were collected at fasting and 30 min, hourly interval for a total of 6 h. RESULTS: As expected, lower triacylglycerol response was observed for low fat/high carbohydrate meal; whereas no difference was detected between the types of fatty acids. The incremental area under the curve (iAUC) for low fat/high carbohydrate meal was 70%, 81% and 61% lower than the SFA, MUFA and PUFA meals, respectively. The iAUC 0-6 h for triacylglycerol was 42% lower in women compared with the men (P = 0.024), with the similar trend observed for non-esterified fatty acids. There were significant meal * time interaction (P = 0.000) for plasma plasminogen activator inhibitor-1 and thromboxane B2 (P = 0.022) from baseline. No differences were observed between meals for plasma D-dimer, interleukin-6, interleukin-1beta, tumor necrosis factor alpha and high sensitivity C-reactive protein. CONCLUSION: These data indicate that in metabolic syndrome subjects, only the amount of dietary fatty acids affects postprandial lipemia but both amount and type of dietary fats alter thrombogenic factors. TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov (NCT01571947). PMID- 26232170 TI - Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL. AB - This phase 2 study evaluated whether substituting bortezomib for vincristine in frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy could improve efficacy in non-germinal center B-cell like diffuse large B-cell lymphoma (non-GCB DLBCL), centrally confirmed by immunohistochemistry (Hans method). In total, 164 patients were randomized 1:1 to receive six 21-day cycles of rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), and doxorubicin 50 mg/m(2), all IV day 1, prednisone 100 mg/m(2) orally days 1-5, plus either bortezomib 1.3 mg/m(2) IV days 1, 4, 8, 11 (rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib [VR-CAP]; n = 84) or vincristine 1.4 mg/m(2) (maximum 2 mg) IV day 1 (R-CHOP; n = 80). There were no significant differences between VR-CAP and R-CHOP in complete response rate (64.5%, 66.2%; odds ratio [OR], 0.91; P = .80), overall response rate (93.4%, 98.6%; OR, 0.21; P = .11), progression-free survival (hazard ratio [HR], 1.12; P = .76), or overall survival (HR, 0.89; P = .75). Rates of grade >=3 adverse events (AEs; 88%, 89%), serious AEs (38%, 34%), discontinuations due to AEs (7%, 3%), and deaths due to AEs (2%, 5%) were similar with VR-CAP and R-CHOP. Grade >=3 peripheral neuropathy rates were 6% and 3%, respectively. VR-CAP did not improve efficacy vs R-CHOP in non-GCB DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT01040871. PMID- 26232171 TI - Platelets induce apoptosis via membrane-bound FasL. AB - After tissue injury, both wound sealing and apoptosis contribute to restoration of tissue integrity and functionality. Although the role of platelets (PLTs) for wound closure and induction of regenerative processes is well established, the knowledge about their contribution to apoptosis is incomplete. Here, we show that PLTs present the death receptor Fas ligand (FasL) on their surface after activation. Activated PLTs as well as the isolated membrane fraction of activated PLTs but not of resting PLTs induced apoptosis in a dose-dependent manner in primary murine neuronal cells, human neuroblastoma cells, and mouse embryonic fibroblasts. Membrane protein from PLTs lacking membrane-bound FasL (FasL(?m/?m)) failed to induce apoptosis. Bax/Bak-mediated mitochondrial apoptosis signaling in target cells was not required for PLT-induced cell death, but increased the apoptotic response to PLT-induced Fas signaling. In vivo, PLT depletion significantly reduced apoptosis in a stroke model and an inflammation-independent model of N-methyl-d-aspartic acid-induced retinal apoptosis. Furthermore, experiments using PLT-specific PF4Cre(+) FasL(fl/fl) mice demonstrated a role of PLT-derived FasL for tissue apoptosis. Because apoptosis secondary to injury prevents inflammation, our findings describe a novel mechanism on how PLTs contribute to tissue homeostasis. PMID- 26232172 TI - A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children. AB - Magnesium, a vasodilator, anti-inflammatory, and pain reliever, could alter the pathophysiology of sickle cell pain crises. We hypothesized that intravenous magnesium would shorten length of stay, decrease opioid use, and improve health related quality of life (HRQL) for pediatric patients hospitalized with sickle cell pain crises. The Magnesium for Children in Crisis (MAGiC) study was a randomized, double-blind, placebo-controlled trial of intravenous magnesium vs normal saline placebo conducted at 8 sites within the Pediatric Emergency Care Applied Research Network (PECARN). Children 4 to 21 years old with hemoglobin SS or Sbeta(0) thalassemia requiring hospitalization for pain were eligible. Children received 40 mg/kg of magnesium or placebo every 8 hours for up to 6 doses plus standard therapy. The primary outcome was length of stay in hours from the time of first study drug infusion, compared using a Van Elteren test. Secondary outcomes included opioid use and HRQL. Of 208 children enrolled, 204 received the study drug (101 magnesium, 103 placebo). Between-group demographics and prerandomization treatment were similar. The median interquartile range (IQR) length of stay was 56.0 (27.0-109.0) hours for magnesium vs 47.0 (24.0-99.0) hours for placebo (P = .24). Magnesium patients received 1.46 mg/kg morphine equivalents vs 1.28 mg/kg for placebo (P = .12). Changes in HRQL before discharge and 1 week after discharge were similar (P > .05 for all comparisons). The addition of intravenous magnesium did not shorten length of stay, reduce opioid use, or improve quality of life in children hospitalized for sickle cell pain crisis. This trial was registered at www.clinicaltrials.gov as #NCT01197417. PMID- 26232173 TI - Transcriptome analysis highlights the conserved difference between embryonic and postnatal-derived alveolar macrophages. AB - Alveolar macrophages (AMs) reside on the luminal surfaces of the airways and alveoli where they maintain host defense and promote alveolar homeostasis by ingesting inhaled particulates and regulating inflammatory responses. Recent studies have demonstrated that AMs populate the lungs during embryogenesis and self-renew throughout life with minimal replacement by circulating monocytes, except under extreme conditions of depletion or radiation injury. Here we demonstrate that on a global scale, environment appears to dictate AM development and function. Indeed, transcriptome analysis of embryonic host-derived and postnatal donor-derived AMs coexisting within the same mouse demonstrated >98% correlation and overall functional analyses were similar. However, we also identified several genes whose expression was dictated by origin rather than environment. The most differentially expressed gene not altered by environment was Marco, a gene recently demonstrated to have enhancer activity in embryonic derived but not postnatal-derived tissue macrophages. Overall, we show that under homeostatic conditions, the environment largely dictates the programming and function of AMs, whereas the expression of a small number of genes remains linked to the origin of the cell. PMID- 26232174 TI - Functions of the MRE11 complex in the development and maintenance of oocytes. AB - The MRE11 complex (MRE11, RAD50, and NBS1) is a central component of the DNA damage response, governing both double-strand break repair and DNA damage response signaling. To determine the functions of the MRE11 complex in the development and maintenance of oocytes, we analyzed ovarian phenotypes of mice harboring the hypomorphic Mre11 (ATLD1) allele. Mre11 (ATLD1/ATLD1) females exhibited premature oocyte elimination attributable to defects in homologous chromosome pairing and double-strand break repair during meiotic prophase. Other aspects of meiotic progression, including attachment of telomeres to the nuclear envelope and recruitment of RAD21L, a component of the meiotic cohesin complex to the synaptonemal complex, were normal. Unlike Dmc1 (-/-) and Trp13 (Gt/Gt) mice which exhibit comparable defects in double-strand break repair and oocyte depletion by 5 days post-partum, we found that oocyte attrition occurred by 12 weeks in Mre11 (ATLD1/ATLD1) . Disruption of the oocyte checkpoint pathway governed by Chk2 gene further enhanced the survival of Mre11 (ATLD1/ATLD1) follicles. Together our data suggest that the MRE11 complex influences the elimination of oocytes with unrepaired meiotic double-strand breaks post-natally, in addition to its previously described role in double-strand break repair and homologous synapsis during female meiosis. PMID- 26232175 TI - Operative Treatment of Haglund Syndrome With Central Achilles Tendon-Splitting Approach. AB - Haglund syndrome is characterized by chronic posterior heel pain associated with a posterosuperior calcaneal prominence. We assessed the clinical and radiologic outcomes after operative treatment of Haglund syndrome using the central tendon splitting approach. Fifteen feet in 15 patients were investigated retrospectively after surgery. Of the 15 patients, 14 were males (93.3%) and 1 was female (6.7%). Their mean age was 33.1 +/- 8.2 (range 20 to 50) years. The mean follow-up duration was 3.5 +/- 1.5 years (range 24 to 90 months). The American Orthopaedic Foot and Ankle Society ankle-hindfoot Scale and Victorian Institute of Sport Assessment-Achilles scores were investigated to assess the clinical outcomes. Patient satisfaction was assessed at the latest follow-up visit. The lateral talo first metatarsal angle, calcaneal pitch angle, Fowler-Philip angle, and parallel pitch line were measured to assess the foot shape and radiographic outcomes. Clinically, the mean American Orthopaedic Foot and Ankle Society ankle-hindfoot scale score increased from 62.1 +/- 7.5 preoperatively to 92.5 +/- 3.5 at the latest follow-up visit. The mean Victorian Institute of Sport Assessment-Achilles score increased from 53.2 +/- 7.4 to 89.6 +/- 3.4. All patients were satisfied with the operative results. Radiographically, all patients had cavus feet with an increased lateral talo-first metatarsal angle (mean +5.9 degrees +/- 5.0 degrees ) and calcaneal pitch angle (mean 26.0 degrees +/- 3.8 degrees ). The mean Fowler-Philip angle decreased from 58.9 degrees +/- 15.0 degrees to 32.5 degrees +/- 7.2 degrees postoperatively, and the positive parallel pitch line had changed to a negative value in all cases. Operative treatment with the central tendon-splitting approach appears to be safe and satisfactory for intractable Haglund syndrome. PMID- 26232176 TI - Custom-Made Total Talonavicular Replacement in a Professional Rock Climber. AB - Professional athletes are often eager to resume sporting activities at preinjury levels. When facing the challenge of restoring joint function after a complex articular fracture, innovative solutions must be explored. We describe the results of what we believe to be the first custom-made talonavicular prosthesis implanted in a professional rock climber who had developed post-traumatic ankle and talonavicular arthritis as sequelae of a complex talar and navicular fracture. Using computed tomography scan reconstruction of the contralateral healthy ankle and direct metal laser sintering, a custom-made talonavicular prosthesis was obtained and implanted using an anteromedial approach. The patient was clinically and radiographically evaluated every 6 months after surgery for 30 months. A 3-dimensional videofluoroscopic analysis was performed to assess the range of motion about the prosthesis. At the last follow-up visit, the functional scores were excellent (Tegner activity scale score of 9 of 10), and he had completely resumed his sporting activity. The American Orthopaedic Foot and Ankle Society score had increased from 36 to 81 points, and no signs of radiolucency were observed on the radiographs. The 3-dimensional videofluoroscopic analysis showed 15 degrees of dorsiflexion and 4 degrees of plantar flexion at the ankle. A customized solution is an option when the patient's expectations are not likely to be met by standard treatment, such as arthrodesis. A custom-made talonavicular prosthesis can be an effective solution for complex ankle injury sequelae in patients demanding high functionality. PMID- 26232177 TI - Evaluation of duplicate publications: an article retraction by the Journal of Pain. PMID- 26232178 TI - Concerted public health strategies should address the barriers to transformative pain research. PMID- 26232179 TI - The associations between PD-1, CTLA-4 gene polymorphisms and susceptibility to ankylosing spondylitis: a meta-analysis and systemic review. AB - Previous surveys had evaluated the effects of the PD-1, CTLA-4 gene polymorphisms on susceptibility to ankylosing spondylitis (AS), but the results remained controversial. To briefly examine these consequences, a comprehensive meta analysis was conducted to estimate the relationships between PD-1 rs11568821, rs2227982, rs2227981, CTLA-4 +49 A/G and -318 C/T polymorphisms and AS risk. The available articles dated to December 2014 were searched in the PUBMED, MEDLINE and EMBASE databases. The data of the genotypes and/or alleles for the PD-1 rs11568821, rs2227982, rs2227981, CTLA-4 +49 A/G and -318 C/T polymorphisms in the AS and control subjects were extracted, and statistical analysis was conducted by STATA 11.2 software. Summary odds ratios (ORs) with their 95 % confidence intervals (95 % CIs) were calculated to determine the strength of associations with fixed-effects or random-effects models. A total of eight published studies were finally involved in this meta-analysis. Meta-analysis of PD-1 rs2227982 polymorphism under the T allele versus C allele (OR 1.744, 95 % CI 1.477-2.059, P < 0.0001), TT+TC versus CC (OR 2.292, 95 % CI 1.654-3.175, P < 0.0001), TT versus CC (OR 1.883, 95 % CI 1.299-2.729, P = 0.001) revealed a significant association with AS. Our meta-analysis demonstrated that the rs2227982 polymorphism in the PD-1 gene might contribute to AS susceptibility. However, further studies with large sample sizes and among different ethnicity populations should be required to confirm this association. PMID- 26232183 TI - Bonding, aromaticity, and planar tetracoordinated carbon in Si2CH 2 and Ge 2CH 2. AB - Natural bond orbital (NBO) analyses and dissected nucleus-independent chemical shifts (NICS pi z z ) were computed to evaluate the bonding (bond type, electron occupation, hybridization) and aromatic character of the three lowest-lying Si2CH2 (1-Si, 2-Si, 3-Si) and Ge2CH2 (1-Ge, 2-Ge, 3-Ge) isomers. While their carbon C3H2 analogs favor classical alkene, allene, and alkyne type bonding, these Si and Ge derivatives are more polarizable and can favor "highly electron delocalized"? and "non-classical"? structures. The lowest energy Si 2CH2 and Ge 2CH2 isomers, 1-Si and 1-Ge, exhibit two sets of 3-center 2-electron (3c-2e) bonding; a pi-3c-2e bond involving the heavy atoms (C-Si-Si and C-Ge-Ge), and a sigma-3c-2e bond (Si-H-Si, Ge-H-Ge). Both 3-Si and 3-Ge exhibit pi and sigma-3c 2e bonding involving a planar tetracoordinated carbon (ptC) center. Despite their highly electron delocalized nature, all of the Si2CH2 and Ge2CH2 isomers considered display only modest two pi electron aromatic character (NICS(0) pi z z =--6.2 to -8.9 ppm, computed at the heavy atom ring center) compared to the cyclic-C 3H2 (-13.3 ppm). Graphical Abstract The three lowest Si2CH2 and Ge2CH2 isomers. PMID- 26232184 TI - Rational design of multifunctional star-shaped molecules with a 1,3,5-triazine core and different arms for application in organic light-emitting diodes and organic solar cells. AB - A series of star-shaped 1,3,5-triazine derivatives for intended application in organic light-emitting diodes (OLEDs) and organic solar cells (OSCs) were investigated theoretically to explore their optical, electronic, and charge transport properties. Analysis of their frontier molecular orbitals (FMOs) indicated that vertical electronic transitions associated with absorption and emission by these derivatives can be characterized as intramolecular charge transfer (ICT) processes. The calculated results show that the optical, electronic, and charge-transport properties of the derivatives are influenced by the end groups and pi-bridges present. Our results suggest that the molecules under investigation could serve as donor materials in OSCs and/or luminescent materials in OLEDs. In addition, all of the molecules are expected to be promising candidates for hole- and electron-transport materials. Based on our results, we were able to propose a rational method of designing multifunctional materials for application in OLEDs and OSCs. Graphical abstract A series of multifunctional star-shaped small molecules were investigated as charge-transport and luminescent materials for OLEDs as well as charge-transport and donor materials for OSCs. PMID- 26232180 TI - NR2B-dependent cyclophilin D translocation suppresses the recovery of synaptic transmission after oxygen-glucose deprivation. AB - N-methyl d-aspartate receptor (NMDA) subunit 2B (NR2B)-containing NMDA receptors and mitochondrial protein cyclophilin D (CypD) are well characterized in mediating neuronal death after ischemia, respectively. However, whether and how NR2B and CypD work together in mediating synaptic injury after ischemia remains elusive. Using an ex vivo ischemia model of oxygen-glucose deprivation (OGD) in hippocampal slices, we identified a NR2B-dependent mechanism for CypD translocation onto the mitochondrial inner membrane. CypD depletion (CypD null mice) prevented OGD-induced impairment in synaptic transmission recovery. Overexpression of neuronal CypD mice (CypD+) exacerbated OGD-induced loss of synaptic transmission. Inhibition of CypD-dependent mitochondrial permeability transition pore (mPTP) opening by cyclosporine A (CSA) attenuated ischemia induced synaptic perturbation in CypD+ and non-transgenic (non-Tg) mice. The treatment of antioxidant EUK134 to suppress mitochondrial oxidative stress rescued CypD-mediated synaptic dysfunction following OGD in CypD+ slices. Furthermore, OGD provoked the interaction of CypD with P53, which was enhanced in slices overexpressing CypD but was diminished in CypD-null slices. Inhibition of p53 using a specific inhibitor of p53 (pifithrin-MU) attenuated the CypD/p53 interaction following OGD, along with a restored synaptic transmission in both non-Tg and CypD+ hippocampal slices. Our results indicate that OGD-induced CypD translocation potentiates CypD/P53 interaction in a NR2B dependent manner, promoting oxidative stress and loss of synaptic transmission. We also evaluate a new ex vivo chronic OGD-induced ischemia model for studying the effect of oxidative stress on synaptic damage. PMID- 26232185 TI - Probing the selective separation of potassium ion from sodium ion with cyclopentadienyl anion as receptor: a computational study. AB - A systematic computational study has been carried out using post-Hartree-Fock and density functional theory methods on half sandwich (M-Cp), sandwich (Cp-M-Cp), inversed sandwich (M-Cp-M), and multi-decker chain complexes of alkali metal ions (Na(+), and K(+)). The binding affinity of cyclopentadienyl anion (Cp) with K(+) and Na(+) ions has been studied in half sandwich, sandwich, inversed sandwich, and multi-decker chain complexes. These complexes have been examined in the aqueous phase. The calculated results show that Cp anion can preferentially bind with Na(+) ion over K(+) ion in aqueous phase. The results obtained from DFT calculations have been compared with the crystal structures of Cp-Na and Cp-K complexes. The Bader's atoms in molecule (AIM) analysis were performed to characterize the non-covalent cation-pi interactions in the Cp-M complexes. The calculated electron density at cage critical point indicates the strength of the Cp-M complexes. Energy decomposition analysis (EDA) has also been performed to investigate the origins of these interactions. The electrostatic interaction contributes significantly to the total interaction energy in Cp-M complexes. The relative stability difference of cyclopentadienyl anion (Cp) with K(+) and Na(+) ions in aqueous phase can be exploited for the separations from mixture such as sea bittern. The lower stability of K-Cp complex can induce to precipitate the K(+) ions more easily than the corresponding Na(+) ions. Graphical Abstract Potassium ion from sodium ion with cyclopentadienyl anion as receptor. PMID- 26232186 TI - Introduction--Special Section: Harvard Fatigue Laboratory. PMID- 26232187 TI - Comparing probabilistic and descriptive analyses of time-dose-toxicity relationship for determining no-observed-adverse-effect level in drug development. AB - The no-observed-adverse-effect level (NOAEL) of a drug defined from animal studies is important for inferring a maximal safe dose in human. However, several issues are associated with its concept, determination and application. It is confined to the actual doses used in the study; becomes lower with increasing sample size or dose levels; and reflects the risk level seen in the experiment rather than what may be relevant for human. We explored a pharmacometric approach in an attempt to address these issues. We first used simulation to examine the behaviour of the NOAEL values as determined by current common practice; and then fitted the probability of toxicity as a function of treatment duration and dose to data collected from all applicable toxicology studies of a test compound. Our investigation was in the context of an irreversible toxicity that is detected at the end of the study. Simulations illustrated NOAEL's dependency on experimental factors such as dose and sample size, as well as the underlying uncertainty. Modelling the probability as a continuous function of treatment duration and dose simultaneously to data from multiple studies allowed the estimation of the dose, along with its confidence interval, for a maximal risk level that might be deemed as acceptable for human. The model-based data integration also reconciled between study inconsistency and explicitly provided maximised estimation confidence. Such alternative NOAEL determination method should be explored for its more efficient data use, more quantifiable insight to toxic doses, and the potential for more relevant animal-to-human translation. PMID- 26232188 TI - The presence of Estrogen Receptor beta modulates the response of breast cancer cells to therapeutic agents. AB - Breast cancer is a leading cause of death for women. The estrogen receptors (ERs) ratio is important in the maintenance of mitochondrial redox status, and higher levels of ERbeta increases mitochondrial functionality, decreasing ROS production. Our aim was to determine the interaction between the ERalpha/ERbeta ratio and the response to cytotoxic treatments such as cisplatin (CDDP), paclitaxel (PTX) and tamoxifen (TAM). Cell viability, apoptosis, autophagy, ROS production, mitochondrial membrane potential, mitochondrial mass and mitochondrial functionality were analyzed in MCF-7 (high ERalpha/ERbeta ratio) and T47D (low ERalpha/ERbeta ratio) breast cancer cell lines. Cell viability decreased more in MCF-7 when treated with CDDP and PTX. Apoptosis was less activated after cytotoxic treatments in T47D than in MCF-7 cells. Nevertheless, autophagy was increased more in CDDP-treated MCF-7, but less in TAM-treated cells than in T47D. CDDP treatment produced a raise in mitochondrial mass in MCF-7, as well as the citochrome c oxidase (COX) and ATP synthase protein levels, however significantly reduced COX activity. In CDDP-treated cells, the overexpression of ERbeta in MCF-7 caused a reduction in apoptosis, autophagy and ROS production, leading to higher cell survival; and the silencing of ERbeta in T47D cells promoted the opposite effects. In TAM-treated cells, ERbeta-overexpression led to less cell viability by an increment in autophagy; and the partial knockdown of ERbeta in T47D triggered an increase in ROS production and apoptosis, leading to cell death. In conclusion, ERbeta expression plays an important role in the response of cancer cells to cytotoxic agents, especially for cisplatin treatment. PMID- 26232189 TI - [Health care professionals' attitudes and beliefs towards older back pain patients. Analysis of the assessment methods and research gaps]. AB - In recent years, the influence of doctors' and therapists' attitudes and beliefs for the treatment of chronic low back pain patients has been increasingly investigated. Attitudes and beliefs of health care providers have been identified as important contributors for an activity based, guideline-oriented therapeutic approach and different questionnaires were developed to evaluate this interaction. Recent reviews discuss the quality of those questionnaires as well as the impact of attitudes towards therapeutic choices and activity recommendations by health care professionals. This article summarizes these results and illuminates transferability of existing questionnaires to older patients with back pain. A literature review shows that most studies were conducted with physiotherapists and general practitioners. At present the most thoroughly investigated tool for its psychometric validity is the Pain Attitudes and Beliefs Scale (PABS). The PABS could be a suitable instrument for examinations regarding therapist attitudes towards older pain patients by using more age-neutral wording. Concluding from the literature, an additional methodological assessment tool could be the utilization of case vignettes. However, those case vignettes, which had been used in studies in England, should be translated and culturally adapted before its application in Germany. Overall, it must be assumed that attitudes and beliefs of clinicians are also important in the care of older patients in pain. With regards to activity recommendations, ageism and the special situation of older people should also be taken into account including possible risk of falling, multimorbidity, polypharmacy, and cognitive impairment. These topics should all be considered in adapted or newly developed questionnaires for the evaluation of attitudes and beliefs of health care providers regarding back pain in older persons. PMID- 26232190 TI - Unraveling the sub-processes of selective attention: insights from dynamic modeling and continuous behavior. AB - Selective attention biases information processing toward stimuli that are relevant for achieving our goals. However, the nature of this bias is under debate: Does it solely rely on the amplification of goal-relevant information or is there a need for additional inhibitory processes that selectively suppress currently distracting information? Here, we explored the processes underlying selective attention with a dynamic, modeling-based approach that focuses on the continuous evolution of behavior over time. We present two dynamic neural field models incorporating the diverging theoretical assumptions. Simulations with both models showed that they make similar predictions with regard to response times but differ markedly with regard to their continuous behavior. Human data observed via mouse tracking as a continuous measure of performance revealed evidence for the model solely based on amplification but no indication of persisting selective distracter inhibition. PMID- 26232191 TI - Selection-for-action emerges in neural networks trained to learn spatial associations between stimuli and actions. AB - The objects present in our environment evoke multiple conflicting actions at every moment. Thus, a mechanism that resolves this conflict is needed in order to avoid the production of chaotic ineffective behaviours. A plausible candidate for such role is the selective attention, capable of inhibiting the neural representations of the objects irrelevant in the ongoing context and as a consequence the actions they afford. In this paper, we investigated whether a selective attention mechanism emerges spontaneously during the learning of context-dependent behaviour, whereas most neurocomputational models of selective attention and action selection imply the presence of architectural constraints. To this aim, we trained a deep neural network to learn context-dependent visual action associations. Our main result was the spontaneous emergence of an inhibitory mechanism aimed to solve conflicts between multiple afforded actions by directly suppressing the irrelevant visual stimuli eliciting the incorrect actions for the current context. This suggests that such an inhibitory mechanism emerged as a result of the incorporation of context-independent probabilistic regularities occurring between stimuli and afforded actions. PMID- 26232192 TI - Spatial orienting around the fovea: exogenous and endogenous cueing effects. AB - The effect of covert attention in perifoveal and peripheral locations has been studied extensively. However, it is less clear whether attention operates similarly in the foveal area itself. The present study aims to investigate whether the attentional orienting elicited by an exogenous or endogenous cue can operate within the foveal area and whether attentional orienting operates similarly between foveal and perifoveal regions. By manipulating exogenous orienting in Experiment 1 and endogenous orienting in Experiment 2, we observed both forms of cueing in the foveal area. Specifically, we observed a larger exogenous cue-induced inhibitory effect (i.e., inhibition of return effect) and a similar endogenous cue-elicited facilitatory effect for the perifoveal relative to the foveal targets. We conclude that exogenous and endogenous orienting subject to two independent attentional systems with distinct modulation patterns in the foveal area. PMID- 26232193 TI - Dual filtering in operational and joint spaces for reaching and grasping. AB - To study human movement generation, as well as to develop efficient control algorithms for humanoid or dexterous manipulation robots, overcoming the limits and drawbacks of inverse-kinematics-based methods is needed. Adequate methods must deal with high dimensionality, uncertainty, and must perform in real time (constraints shared by robots and humans). This paper introduces a Bayesian filtering method, hierarchically applied in the operational and joint spaces to break down the complexity of the problem. The method is validated in simulation on a robotic arm in a cluttered environment, with up to 51 degrees of freedom. PMID- 26232194 TI - The influence of anxiety and personality factors on comfort and reachability space: a correlational study. AB - Although the effects of several personality factors on interpersonal space (i.e. social space within personal comfort area) are well documented, it is not clear whether they also extend to peripersonal space (i.e. reaching space). Indeed, no study has directly compared these spaces in relation to personality and anxiety factors even though such a comparison would help to clarify to what extent they share similar mechanisms and characteristics. The aim of the present paper was to investigate whether personality dimensions and anxiety levels are associated with reaching and comfort distances. Seventy university students (35 females) were administered the Big Five Questionnaire and the State-Trait Anxiety Inventory; afterwards, they had to provide reachability- and comfort-distance judgments towards human confederates while standing still (passive) or walking towards them (active). The correlation analyses showed that both spaces were positively related to anxiety and negatively correlated with the Dynamism in the active condition. Moreover, in the passive condition higher Emotional Stability was related to shorter comfort distance, while higher cognitive Openness was associated with shorter reachability distance. The implications of these results are discussed. PMID- 26232195 TI - Remember down, look down, read up: Does a word modulate eye trajectory away from remembered location? AB - Previous studies show that eye movement trajectory curves away from a remembered visual location if a saccade needs to be made in the same direction as the location. Data suggest that part of the process of maintaining the location in working memory is the mental simulation of that location, so that the oculomotor system treats the remembered location as a real one. Other research suggests that word meaning may also behave like a 'real object' in space. The current study aimed to combine the two streams of research examining the effect of word meaning on the memory of a dot location. The results of two experiments showed that word meaning for 'up' (but not 'down') modulated both eye movement trajectory and location recognition time. Thus, mental simulation of task-irrelevant space related word meaning affected both earlier stages of memory processes (maintenance of the location in the working memory) and later ones (location recognition). PMID- 26232196 TI - Insights into emergency physicians' minds in the seconds before and into a patient encounter. AB - Clinical reasoning is a core competency in medical practice. No study has explored clinical reasoning occurring before a clinical encounter, when physicians obtain preliminary information about the patient, and during the first seconds of the observation phase. This paper aims to understand what happens in emergency physicians' minds when they acquire initial information about a patient, and when they first meet a patient. The authors carried out in-depth interviews based on the video recordings of emergency situations filmed in an "own-point-of-view-perspective". 15 expert emergency physicians were interviewed between 2011 and 2012. Researchers analysed data using an interpretive approach based on thematic analysis and constant comparison. Almost all participants used a few critical pieces of information to generate hypotheses even before they actually met the patient. Pre-encounter hypotheses played a key role in the ensuing encounter by directing initial data gathering. Initial data, collected within the first few seconds of the encounter, included the patient's position on the stretcher, the way they had been prepared, their facial expression, their breathing, and their skin colour. Physicians also rapidly appraised the seriousness of the patient's overall condition, which determined their initial goals, i.e. initiating emergency treatment or pursuing the diagnostic investigation. The study brings new insights on what happens at the very beginning of the encounter between emergency physicians and patients. The results obtained from an innovative methodological approach open avenues for the development of clinical reasoning in learners. PMID- 26232197 TI - Estimation and Validation of Propanil Residues in Rice and Soil Samples by Gas Liquid Chromatography with Electron Capture Detector. AB - The purpose of this analysis was to develop an efficient analysis for the estimation of residues of propanil in rice grain, husk, straw and soil samples. A liquid-liquid partitioning method was used for the extraction of propanil residues from the rice grains and its contents. For this, representative 10 g samples of blended rice grain, husk, straw and soil were soaked in acetone for 24 h, and the contents then partitioned two times into 100 and 50 mL dichloromethane and one time with 100 mL hexane. The combined organic layers were collected and were concentrated to 10 mL acetone using a rotary vacuum evaporator at 40 degrees C. The extract was then subjected to cleanup by dispersive solid phase extraction. The final extract was injected onto a GLC column, where the propanil residues were determined by electron capture detector. The percentage recoveries were ranged from 84.9 % to 98.3 % when samples were spiked at the levels of 0.05, 0.25 and 0.50 mg/kg. The limits of quantification and detection were 0.05 and 0.017 mg/kg, respectively. PMID- 26232198 TI - Olfactory Sampling Recovery Following Sublethal Copper Exposure in the Rusty Crayfish, Orconectes rusticus. AB - Increasing levels of anthropogenic chemicals within an aquatic ecosystem may inhibit animals from extracting information from chemical signals. We investigated whether antennular flicking, a behavioral mechanism involved in chemically-mediated behaviors of the rusty crayfish, Orconectes rusticus, was altered following a sublethal copper exposure (450 ug/L). Crayfish exposed to copper exhibited lower flicking rates than control crayfish and were significantly less successful in their ability to orient to a food odor. Copper was then eliminated from the housing tanks, providing a recovery period. Groups of crayfish were assayed for antennular flicking rates and orientation success three times over the course of the 21 day recovery period. Crayfish demonstrated significant increases in rates of successful localization of odors and antennular flicking during this portion of the experiment. These results indicate that the mechanism by which copper impairs chemoreception in the rusty crayfish is reversible if elevated levels of copper concentrations are eliminated from aquatic ecosystems contaminated by runoff from agricultural or aquacultural chemicals. PMID- 26232199 TI - Valuing QALYs in Relation to Equity Considerations Using a Discrete Choice Experiment. AB - BACKGROUND: To judge whether an intervention offers value for money, the incremental costs per gained quality-adjusted life-year (QALY) need to be compared with some relevant threshold, which ideally reflects the monetary value of health gains. Literature suggests that this value may depend on the equity context in which health gains are produced, but the value of a QALY in relation to equity considerations has remained largely unexplored. OBJECTIVE: The objective of this study was to estimate the social marginal willingness to pay (MWTP) for QALY gains in different equity subgroups, using a discrete choice experiment (DCE). Both severity of illness (operationalized as proportional shortfall) and fair innings (operationalized as age) were considered as grounds for differentiating the value of health gains. METHODS: We obtained a sample of 1205 respondents, representative of the adult population of the Netherlands. The data was analysed using panel mixed multinomial logit (MMNL) and latent class models. RESULTS: The panel MMNL models showed counterintuitive results, with more severe health states reducing the probability of receiving treatment. The latent class models revealed distinct preference patterns in the data. MWTP per QALY was sensitive to severity of disease among a substantial proportion of the public, but not to the age of care recipients. CONCLUSION: These findings emphasize the importance of accounting for preference heterogeneity among the public on value laden issues such as prioritizing health care, both in research and decision making. This study emphasises the need to further explore the monetary value of a QALY in relation to equity considerations. PMID- 26232200 TI - The MAPS Reporting Statement for Studies Mapping onto Generic Preference-Based Outcome Measures: Explanation and Elaboration. AB - BACKGROUND: The process of "mapping" is increasingly being used to predict health utilities, for application within health economic evaluations, using data on other indicators or measures of health. Guidance for the reporting of mapping studies is currently lacking. OBJECTIVE: The overall objective of this research was to develop a checklist of essential items, which authors should consider when reporting mapping studies. The MAPS (MApping onto Preference-based measures reporting Standards) statement is a checklist, which aims to promote complete and transparent reporting by researchers. This paper provides a detailed explanation and elaboration of the items contained within the MAPS statement. METHODS: In the absence of previously published reporting checklists or reporting guidance documents, a de novo list of reporting items and accompanying explanations was created. A two-round, modified Delphi survey, with representatives from academia, consultancy, health technology assessment agencies and the biomedical journal editorial community, was used to identify a list of essential reporting items from this larger list. RESULTS: From the initial de novo list of 29 candidate items, a set of 23 essential reporting items was developed. The items are presented numerically and categorised within six sections, namely, (i) title and abstract, (ii) introduction, (iii) methods, (iv) results, (v) discussion and (vi) other. For each item, we summarise the recommendation, illustrate it using an exemplar of good reporting practice identified from the published literature, and provide a detailed explanation to accompany the recommendation. CONCLUSIONS: It is anticipated that the MAPS statement will promote clarity, transparency and completeness of reporting of mapping studies. It is targeted at researchers developing mapping algorithms, peer reviewers and editors involved in the manuscript review process for mapping studies, and the funders of the research. The MAPS working group plans to assess the need for an update of the reporting checklist in 5 years' time. PMID- 26232201 TI - Preferred Reporting Items for Studies Mapping onto Preference-Based Outcome Measures: The MAPS Statement. AB - 'Mapping' onto generic preference-based outcome measures is increasingly being used as a means of generating health utilities for use within health economic evaluations. Despite the publication of technical guides for the conduct of mapping research, guidance for the reporting of mapping studies is currently lacking. The MAPS (MApping onto Preference-based measures reporting Standards) statement is a new checklist, which aims to promote complete and transparent reporting of mapping studies. The primary audiences for the MAPS statement are researchers reporting mapping studies, the funders of the research, and peer reviewers and editors involved in assessing mapping studies for publication. A de novo list of 29 candidate reporting items and accompanying explanations was created by a working group comprising six health economists and one Delphi methodologist. Following a two-round modified Delphi survey with representatives from academia, consultancy, health technology assessment agencies and the biomedical journal editorial community, a final set of 23 items deemed essential for transparent reporting, and accompanying explanations, was developed. The items are contained in a user-friendly 23-item checklist. They are presented numerically and categorised within six sections, namely: (1) title and abstract; (2) introduction; (3) methods; (4) results; (5) discussion; and (6) other. The MAPS statement is best applied in conjunction with the accompanying MAPS explanation and elaboration document. It is anticipated that the MAPS statement will improve the clarity, transparency and completeness of reporting of mapping studies. To facilitate dissemination and uptake, the MAPS statement is being co published by seven health economics and quality-of-life journals, and broader endorsement is encouraged. The MAPS working group plans to assess the need for an update of the reporting checklist in 5 years' time. PMID- 26232202 TI - Hyperactivity in boys with attention-deficit/hyperactivity disorder (ADHD): The role of executive and non-executive functions. AB - Motor activity of boys (age 8-12 years) with (n=19) and without (n=18) ADHD was objectively measured with actigraphy across experimental conditions that varied with regard to demands on executive functions. Activity exhibited during two n back (1-back, 2-back) working memory tasks was compared to activity during a choice-reaction time (CRT) task that placed relatively fewer demands on executive processes and during a simple reaction time (SRT) task that required mostly automatic processing with minimal executive demands. Results indicated that children in the ADHD group exhibited greater activity compared to children in the non-ADHD group. Further, both groups exhibited the greatest activity during conditions with high working memory demands, followed by the reaction time and control task conditions, respectively. The findings indicate that large-magnitude increases in motor activity are predominantly associated with increased demands on working memory, though demands on non-executive processes are sufficient to elicit small to moderate increases in motor activity as well. PMID- 26232203 TI - Bayley-III scales at 12 months of corrected age in preterm infants: Patterns of developmental performance and correlations to environmental and biological influences. AB - BACKGROUND AND AIMS: Premature infants are at high risk for neurodevelopmental impairment (NDI) even in the absence of known brain complications of prematurity. Evaluation of the effectiveness of therapeutic interventions in association to neurodevelopmental outcome is required to improve or prevent the neurodevelopmental consequences of prematurity. The Bayley-III is currently the most commonly applied measurement tool for assessing early development both in clinical practice and research settings. OBJECTIVE: To evaluate the relationship between known risk factors and early performance on the Bayley Scales of Infant Development-Third Edition at 12 months adjusted age in premature infants. METHODS: Prospective study in a cohort of premature infants with gestational age <=32 weeks, who underwent comprehensive developmental assessment using the five domains of Bayley Scales, cognitive, language, motor, social emotional and adaptive behavior at 12 months corrected age. Developmental scores were evaluated in relation to environmental influences, therapeutic interventions or practices and complications of prematurity. RESULTS: Composite and Subscale scores for the cognitive, language and motor scales were below the 50th percentile, with no significant differences among them. Scores for the social-emotional and adaptive behavior, which are derived from the parent-report questionnaires, were near the average and significantly higher than the scores derived by the examiners. Multiple regression analyses showed that blood transfusions, apart from severely abnormal head ultrasound, gender, being small for gestational age and duration of invasive mechanical ventilation and oxygen administration were consistently related to neurodevelopmental outcome. CONCLUSIONS: Bayley-III assessments are important for getting early information about development following premature birth. Parents may overestimate children's performance. Neurodevelopmental outcome is related to several environmental, biological or medical conditions associated with prematurity. Adoption of therapeutic strategies targeting known neonatal risk factors could positively affect neurodevelopmental outcome. PMID- 26232204 TI - Paradoxical perfusion metrics of high-grade gliomas with an oligodendroglioma component: quantitative analysis of dynamic susceptibility contrast perfusion MR imaging. AB - INTRODUCTION: The aim of this study is to investigate perfusion characteristics of glioblastoma with an oligodendroglioma component (GBMO) compared with conventional glioblastoma (GBM) using dynamic susceptibility contrast (DSC) perfusion magnetic resonance (MR) imaging and microvessel density (MVD). METHODS: The study was approved by the institutional review board. Newly diagnosed high grade glioma patients were enrolled (n = 72; 20 GBMs, 14 GBMOs, 19 anaplastic astrocytomas (AAs), 13 anaplastic oligodendrogliomas (AOs), and six anaplastic oligoastrocytomas (AOAs)). All participants underwent preoperative MR imaging including DSC perfusion MR imaging. Normalized cerebral blood volume (nCBV) values were analyzed using a histogram approach. Histogram parameters were subsequently compared across each tumor subtype and grade. MVD was quantified by immunohistochemistry staining and correlated with perfusion parameters. Progression-free survival (PFS) was assessed according to the tumor subtype. RESULTS: GBMO displayed significantly reduced nCBV values compared with GBM, whereas grade III tumors with oligodendroglial components (AO and AOA) exhibited significantly increased nCBV values compared with AA (p < 0.001). MVD analyses revealed the same pattern as nCBV results. In addition, a positive correlation between MVD and nCBV values was noted (r = 0.633, p < 0.001). Patients with oligodendroglial tumors exhibited significantly increased PFS compared with patients with pure astrocytomas in each grade. CONCLUSION: In contrast to grade III tumors, the presence of oligodendroglial components in grade IV tumors resulted in paradoxically reduced perfusion metrics and MVD. In addition, patients with GBMO exhibited a better clinical outcome compared with patients with GBM. PMID- 26232206 TI - A realist synthesis of the evidence on outreach programmes for health improvement of Traveller Communities. AB - BACKGROUND: Improving the health of Traveller Communities is an international public health concern but there is little evidence on effective interventions. This study aimed to explain how, for whom and in what circumstances outreach works in Traveller Communities. METHODS: A realist synthesis was undertaken. Systematic literature searches were conducted between August and November 2011. Grey literature was sought and key stakeholders were involved throughout the review process. Iterative steps of data extraction, analysis and synthesis, followed by additional searches were undertaken. RESULTS: An explanatory framework details how, why and in what circumstances participation, behaviour change or social capital development happened. The trust status of outreach workers is an important context of outreach interventions, in conjunction with their ability to negotiate the intervention focus. The higher the outreach worker's trust status, the lower the imperative that they negotiate the intervention focus. A 'menu' of reasoning mechanisms is presented, leading to key engagement outcomes. CONCLUSIONS: Adopting a realist analysis, this study offers a framework with explanatory purchase as to the potential of outreach to improve health in marginalized groups. PMID- 26232205 TI - Lp-PLA2 Antagonizes Left Ventricular Healing After Myocardial Infarction by Impairing the Appearance of Reparative Macrophages. AB - BACKGROUND: Healing after myocardial infarction (MI) involves the biphasic accumulation of inflammatory Ly-6C(high) and reparative Ly-6C(low) monocytes/macrophages. Excessive inflammation disrupts the balance between the 2 phases, impairs infarct healing, and contributes to left ventricle remodeling and heart failure. Lipoprotein-associated phospholipase A2 (Lp-PLA2), a member of the phospholipase A2 family of enzymes, produced predominantly by leukocytes, participates in host defenses and disease. Elevated Lp-PLA2 levels associate with increased risk of cardiovascular events across diverse patient populations, but the mechanisms by which the enzyme elicits its effects remain unclear. This study tested the role of Lp-PLA2 in healing after MI. METHODS AND RESULTS: In response to MI, Lp-PLA2 levels markedly increased in the circulation. To test the functional importance of Lp-PLA2, we generated chimeric mice whose bone marrow derived leukocytes were Lp-PLA2-deficient (bmLp-PLA2 (-/-)). Compared with wild type controls, bmLp-PLA2 (-/-) mice subjected to MI had lower serum levels of inflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6, and decreased number of circulating inflammatory myeloid cells. Accordingly, bmLp-PLA2 (-/-) mice developed smaller and less inflamed infarcts with reduced numbers of infiltrating neutrophils and inflammatory Ly-6C(high) monocytes. During the later, reparative phase, infarcts of bmLp-PLA2 (-/-) mice contained Ly-6C(low) macrophages with a skewed M2-prone gene expression signature, increased collagen deposition, fewer inflammatory cells, and improved indices of angiogenesis. Consequently, the hearts of bmLp-PLA2 (-/-) mice healed more efficiently, as determined by improved left ventricle remodeling and ejection fraction. CONCLUSIONS: Lp-PLA2 augments the inflammatory response after MI and antagonizes healing by disrupting the balance between inflammation and repair, providing a rationale for focused study of ventricular function and heart failure after targeting this enzyme acutely in MI. PMID- 26232207 TI - Influence of premature birth on the health conditions, receipt of special education and sport participation of children aged 6-17 years in the USA. AB - BACKGROUND: To investigate the influence of premature birth on conditions among children aged 6-17 years. METHODS: The National Survey of Children's Health in the USA added a question on premature birth for the first time in the 2011-12 wave. The influence of being born premature on different conditions while controlling for sociodemographic factors was assessed using logistic regression. A total of 6882 out of 62 078 (11.1%) of children aged 6-17 years were born premature. RESULTS: Compared with children who were not born premature, those who were born premature were more likely to have cerebral palsy [odds ratio (OR) = 9.6, confidence interval (CI): 7.4-12.4], vision problems (OR = 2.3, CI: 2.0 2.6), hearing problems (OR = 1.7, CI: 1.6-2.0) and a special healthcare need (OR = 1.7, CI: 1.6-1.8). Children who were born premature had an increased likelihood of not being on a sports team or not taking sports lessons after school or on weekends during the past 12 months than those who were not born premature (OR = 1.2, CI: 1.1-1.3). CONCLUSIONS: Prematurity may be associated with negative outcomes as infants transition into childhood and adolescence. Interventions within the life-course perspective are needed to alleviate the long-term consequences of prematurity. PMID- 26232208 TI - [Foreign body of dental origin: How to retrieve the dentist's drill?]. AB - INTRODUCTION: Inhalation of foreign bodies is an unusual complication of dental care. When it occurs immediately during the intervention, it is generally a dental tool, such as the little screwdrivers used for dental implant procedures. CASE REPORT: A 59-year-old man was referred to our hospital for asymptomatic inhalation of a small drill during dental surgery. Because the drill had a barbed tip, prompt removal was indicated. The foreign body was localized in a sub segmental division of the left lower lobe (B10b) and could be removed via a flexible bronchoscope under a short general anesthetic without intubation. There was no significant injury of the bronchial mucosa. CONCLUSION: Inhalation of foreign bodies during dental interventions is unusual and sometimes asymptomatic but their removal is always indicated. In some cases, the removal can be performed with a flexible bronchoscope. PMID- 26232209 TI - [Posterior mediastinal mass]. PMID- 26232210 TI - Surgical Management of Giant Intracranial Arteriovenous Malformations: A Single Center Experience over 32 years. AB - OBJECTIVE: Treatment of giant intracranial arteriovenous malformations (gAVMs) is a formidable challenge for neurosurgeons and carries significant morbidity and mortality rates for patients compared with smaller AVMs. In this study, we reviewed the treatments, angiographic results, and clinical outcomes in 64 patients with gAVMs who were treated at Henry Ford Hospital between 1980 and 2012. METHODS: The arteriovenous malformation (AVM) database at our institution was queried for patients with gAVMs (>= 6 cm) and data regarding patient demographics, presentation, AVM angioarchitecture, and treatments were collected. Functional outcomes as well as complications were analyzed. RESULTS: Of the 64 patients, 33 (51.6%) were female and 31 (48.4%) were male, with an average age of 45.7 years (SD +/- 15.5). The most common symptoms on presentation were headaches (50%), seizures (50%), and hemorrhage (41%). The mean AVM size was 6.65 cm (range, 6-9 cm). Only 6 AVMs (9.4%) were located in the posterior fossa. The most common Spetzler-Martin grade was V, seen in 64% of patients. Of the 64 patients, 42 (66%) underwent surgical excision, 10 (15.5%) declined any treatment, 8 (12.5%) were deemed inoperable and followed conservatively, 2 (3%) had stand alone embolization, 1 (1.5%) had embolization before stereotactic radiosurgery, and 1 (1.5%) received stereotactic radiosurgery only. Complete obliteration was achieved in 90% of the surgical patients. Mortality rate was 19% in the surgical cohort compared with 22% in the observation cohort (P = 0.770). CONCLUSIONS: Treatment of gAVMs carries significant morbidity and mortality; however, good outcomes are attainable with a multimodal treatment approach in carefully selected patients. PMID- 26232211 TI - Venous-Preserving Sylvian Dissection. AB - OBJECTIVE: The Sylvian fissure has been dissected through the frontal side of the superficial Sylvian veins with sacrifice of the tributaries of the frontal superficial Sylvian vein, which may lead to venous infarction. In addition, disturbed venous drainage makes the brain susceptible to brain retraction. Therefore, preservation of the vein is essential in modern neurosurgery to decrease morbidity. METHODS: We describe the technical nuances of Sylvian dissection with an emphasis on preserving the veins. RESULTS: The arachnoid between the frontal and temporal superficial Sylvian veins is divided as to enter the fissure. After the deep part in the Sylvian fissure is reached, the inside of the fissure is dissected along the "microvascular Sylvian fissure," the temporal side of the frontal vessels or the frontal side of the temporal vessels. The Sylvian fissure is dissected in a deep-to-superficial and posterior-to-anterior fashion ("paperknife technique") up to the skull base. The frontal superficial Sylvian vein usually tethers the brain to the dura, restricting the surgical corridor when approaching deep lesions. Peeling off the arachnoid that wraps this vein ("denude technique") allows the vein to stretch. CONCLUSIONS: Keeping the proper dissection plane ("microvascular Sylvian fissure") is crucial to preserve the veins. The "paperknife technique" makes the division of the frontal and temporal lobe easier. The "denude technique" provides a wider space between the frontal lobe and the skull base. These techniques make it possible to obtain a sufficiently wide surgical corridor to the basal cistern without sacrificing the veins and their tributaries. PMID- 26232212 TI - Air pollution and cardiovascular and respiratory emergency visits in Central Arkansas: A time-series analysis. AB - BACKGROUND: Heart disease and stroke mortality and morbidity rates in Arkansas are among the highest in the U.S. While the effect of air pollution on cardiovascular health was identified in traffic-dominated metropolitan areas, there is a lack of studies for populations with variable exposure profiles, demographic and disease characteristics. OBJECTIVE: Determine the short-term effects of air pollution on cardiovascular and respiratory morbidity in the stroke and heart failure belt. METHODS: We investigated the associations of fine particles and ozone with respiratory and cardiovascular emergency room visits during the 2002-2012 period for adults in Central Arkansas using Poisson generalized models adjusted for temporal, seasonal and meteorological effects. We evaluated sensitivity of the associations to mutual pollutant adjustment and effect modification patterns by sex, age, race and season. RESULTS: We found effects on cardiovascular and respiratory emergencies for PM2.5 (1.52% [95% (confidence interval) CI: -1.10%, 4.20%]; 1.45% [95%CI: -2.64%, 5.72%] per 10 MUg/m3) and O3 (0.93% [95%CI: -0.87%, 2.76%]; 0.76 [95%CI: -1.92%, 3.52%] per 10 ppbv) during the cold period (October-March). The effects were stronger among whites, except for the respiratory effects of O3 that were higher among Blacks/African-Americans. Effect modification patterns by age and sex differed by association. Both pollutants were associated with increases in emergency room visits for hypertension, heart failure and asthma. Effects on cardiovascular and respiratory emergencies were observed during the cold period when particulate matter was dominated by secondary nitrate and wood burning. CONCLUSION: Outdoor particulate pollution during winter had an effect on cardiovascular morbidity in central Arkansas, the region with high stroke and heart disease incidence rates. PMID- 26232213 TI - Uterine inversion after an unskilled delivery - still a concern for maternal mortality: A case report and discussion of the related medico-legal issues. AB - Uterine inversion is a life-threatening medical emergency, which can result in fatal shock and sudden unexpected death during and after delivery. Most cases of uterine inversion occur due to mismanagement of the third stage of labour. We report a case of sudden death occurring post full-term vaginal delivery conducted by a traditional birth attendant (TBA) popularly known as dai. Autopsy revealed signs of haemorrhage and shock due to an inverted uterus. This emergency medical condition, though frequently fatal, can be treated if prompt action is taken by a trained and skilled obstetrician, preventing morbidity and mortality. We discuss the incidence, aetiology, symptomatology, complications and the management of uterine inversion. We also review the capability and eligibility of TBAs in handling such obstetrical emergencies, along with their culpability, if any, in such cases of negligence as per the applicable statutes. PMID- 26232214 TI - Leptin Does Not Mediate Hypertension Associated With Human Obesity. AB - Hypertension and obesity are known to be linked, with recent studies in mice proposing that leptin may be mediating this effect. This regulation, however, may not extend to humans, where a yet-to-be-identified factor is likely the underlying cause of hypertension. PMID- 26232215 TI - Daughter's Tolerance of Mom Matters in Mate Choice. AB - Mendelian genetics presumes inheritance of fitness through DNA. Kinder et al. find that maternal microchimerism induces stable immune tolerance to non inherited maternal antigens in offspring. Female offspring that share these antigens with their mate experience reduced fetal wasting, establishing a role for vertical transmission of non-genetic information in reproductive fitness. PMID- 26232216 TI - Barley: From Brittle to Stable Harvest. AB - Selection and domestication of plants with genes that prevent grains from shattering in cereals was essential for human civilization's transition to agriculture-based societies. In this issue, Pourkheirandish et al. show that domestication of barley required evolution of a molecular system distinct from other grains, such as rice and maize, and reveal that present-day cultivars derive from two ancient domestication centers. PMID- 26232217 TI - You Down With ETC? Yeah, You Know D! AB - Although the mitochondrial electron transport chain (ETC) is best known for its role in ATP synthesis, two studies, Sullivan et al. and Birsoy et al., conclude that its only essential function in proliferating cells is making aspartate (D). PMID- 26232218 TI - Electron Microscopy at Scale. AB - The essential details of cellular interactions at synaptic level in the brain are still largely unknown. In this issue, Kasthuri et al. report new experimental and computational technologies for large-scale electron microscopy data collection and analysis, and through saturated reconstruction uncover synaptic connectional specificity that cannot be predicted by simple axonal-dendritic proximity. PMID- 26232219 TI - Stem Cells Show Parental Control. AB - Stem cells interact with their niche to maintain an undifferentiated state. The study by Pardo-Saganta et al. shows that airway basal stem cells maintain secretory daughter cells in airway epithelia through forward regulation, suggesting that stem cells may serve as a niche for their progeny. PMID- 26232220 TI - A Call for Systematic Research on Solute Carriers. AB - Solute carrier (SLC) membrane transport proteins control essential physiological functions, including nutrient uptake, ion transport, and waste removal. SLCs interact with several important drugs, and a quarter of the more than 400 SLC genes are associated with human diseases. Yet, compared to other gene families of similar stature, SLCs are relatively understudied. The time is right for a systematic attack on SLC structure, specificity, and function, taking into account kinship and expression, as well as the dependencies that arise from the common metabolic space. PMID- 26232221 TI - Molecular Insight into Dengue Virus Pathogenesis and Its Implications for Disease Control. AB - Dengue virus (DENV) is a mosquito-transmitted RNA virus that infects an estimated 390 million humans each year. Here, we review recent advances in our understanding of the biology of DENV and describe knowledge gaps that have impacted the development of effective vaccines and therapeutics. PMID- 26232222 TI - Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease. AB - As a Mendelian neurodegenerative disorder, the genetic risk of Huntington's disease (HD) is conferred entirely by an HTT CAG repeat expansion whose length is the primary determinant of the rate of pathogenesis leading to disease onset. To investigate the pathogenic process that precedes disease, we used genome-wide association (GWA) analysis to identify loci harboring genetic variations that alter the age at neurological onset of HD. A chromosome 15 locus displays two independent effects that accelerate or delay onset by 6.1 years and 1.4 years, respectively, whereas a chromosome 8 locus hastens onset by 1.6 years. Association at MLH1 and pathway analysis of the full GWA results support a role for DNA handling and repair mechanisms in altering the course of HD. Our findings demonstrate that HD disease modification in humans occurs in nature and offer a genetic route to identifying in-human validated therapeutic targets in this and other Mendelian disorders. PMID- 26232223 TI - Evolution of the Grain Dispersal System in Barley. AB - About 12,000 years ago in the Near East, humans began the transition from hunter gathering to agriculture-based societies. Barley was a founder crop in this process, and the most important steps in its domestication were mutations in two adjacent, dominant, and complementary genes, through which grains were retained on the inflorescence at maturity, enabling effective harvesting. Independent recessive mutations in each of these genes caused cell wall thickening in a highly specific grain "disarticulation zone," converting the brittle floral axis (the rachis) of the wild-type into a tough, non-brittle form that promoted grain retention. By tracing the evolutionary history of allelic variation in both genes, we conclude that spatially and temporally independent selections of germplasm with a non-brittle rachis were made during the domestication of barley by farmers in the southern and northern regions of the Levant, actions that made a major contribution to the emergence of early agrarian societies. PMID- 26232224 TI - An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. AB - The mitochondrial electron transport chain (ETC) enables many metabolic processes, but why its inhibition suppresses cell proliferation is unclear. It is also not well understood why pyruvate supplementation allows cells lacking ETC function to proliferate. We used a CRISPR-based genetic screen to identify genes whose loss sensitizes human cells to phenformin, a complex I inhibitor. The screen yielded GOT1, the cytosolic aspartate aminotransferase, loss of which kills cells upon ETC inhibition. GOT1 normally consumes aspartate to transfer electrons into mitochondria, but, upon ETC inhibition, it reverses to generate aspartate in the cytosol, which partially compensates for the loss of mitochondrial aspartate synthesis. Pyruvate stimulates aspartate synthesis in a GOT1-dependent fashion, which is required for pyruvate to rescue proliferation of cells with ETC dysfunction. Aspartate supplementation or overexpression of an aspartate transporter allows cells without ETC activity to proliferate. Thus, enabling aspartate synthesis is an essential role of the ETC in cell proliferation. PMID- 26232225 TI - Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. AB - Mitochondrial respiration is important for cell proliferation; however, the specific metabolic requirements fulfilled by respiration to support proliferation have not been defined. Here, we show that a major role of respiration in proliferating cells is to provide electron acceptors for aspartate synthesis. This finding is consistent with the observation that cells lacking a functional respiratory chain are auxotrophic for pyruvate, which serves as an exogenous electron acceptor. Further, the pyruvate requirement can be fulfilled with an alternative electron acceptor, alpha-ketobutyrate, which provides cells neither carbon nor ATP. Alpha-ketobutyrate restores proliferation when respiration is inhibited, suggesting that an alternative electron acceptor can substitute for respiration to support proliferation. We find that electron acceptors are limiting for producing aspartate, and supplying aspartate enables proliferation of respiration deficient cells in the absence of exogenous electron acceptors. Together, these data argue a major function of respiration in proliferating cells is to support aspartate synthesis. PMID- 26232226 TI - Deterministic Restriction on Pluripotent State Dissolution by Cell-Cycle Pathways. AB - During differentiation, human embryonic stem cells (hESCs) shut down the regulatory network conferring pluripotency in a process we designated pluripotent state dissolution (PSD). In a high-throughput RNAi screen using an inclusive set of differentiation conditions, we identify centrally important and context dependent processes regulating PSD in hESCs, including histone acetylation, chromatin remodeling, RNA splicing, and signaling pathways. Strikingly, we detected a strong and specific enrichment of cell-cycle genes involved in DNA replication and G2 phase progression. Genetic and chemical perturbation studies demonstrate that the S and G2 phases attenuate PSD because they possess an intrinsic propensity toward the pluripotent state that is independent of G1 phase. Our data therefore functionally establish that pluripotency control is hardwired to the cell-cycle machinery, where S and G2 phase-specific pathways deterministically restrict PSD, whereas the absence of such pathways in G1 phase potentially permits the initiation of differentiation. PMID- 26232227 TI - The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an AT Motif Driven Axis. AB - We identified a dominant missense mutation in the SCN transcription factor Zfhx3, termed short circuit (Zfhx3(Sci)), which accelerates circadian locomotor rhythms in mice. ZFHX3 regulates transcription via direct interaction with predicted AT motifs in target genes. The mutant protein has a decreased ability to activate consensus AT motifs in vitro. Using RNA sequencing, we found minimal effects on core clock genes in Zfhx3(Sci/+) SCN, whereas the expression of neuropeptides critical for SCN intercellular signaling was significantly disturbed. Moreover, mutant ZFHX3 had a decreased ability to activate AT motifs in the promoters of these neuropeptide genes. Lentiviral transduction of SCN slices showed that the ZFHX3-mediated activation of AT motifs is circadian, with decreased amplitude and robustness of these oscillations in Zfhx3(Sci/+) SCN slices. In conclusion, by cloning Zfhx3(Sci), we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms. PMID- 26232228 TI - Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping. AB - Dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) integrate complex inputs to encode multiple signals that influence motivated behaviors via diverse projections. Here, we combine axon-initiated viral transduction with rabies-mediated trans-synaptic tracing and Cre-based cell-type-specific targeting to systematically map input-output relationships of VTA-DA neurons. We found that VTA-DA (and VTA-GABA) neurons receive excitatory, inhibitory, and modulatory input from diverse sources. VTA-DA neurons projecting to different forebrain regions exhibit specific biases in their input selection. VTA-DA neurons projecting to lateral and medial nucleus accumbens innervate largely non overlapping striatal targets, with the latter also sending extensive extra striatal axon collaterals. Using electrophysiology and behavior, we validated new circuits identified in our tracing studies, including a previously unappreciated top-down reinforcing circuit from anterior cortex to lateral nucleus accumbens via VTA-DA neurons. This study highlights the utility of our viral-genetic tracing strategies to elucidate the complex neural substrates that underlie motivated behaviors. PMID- 26232229 TI - Intact-Brain Analyses Reveal Distinct Information Carried by SNc Dopamine Subcircuits. AB - Recent progress in understanding the diversity of midbrain dopamine neurons has highlighted the importance--and the challenges--of defining mammalian neuronal cell types. Although neurons may be best categorized using inclusive criteria spanning biophysical properties, wiring of inputs, wiring of outputs, and activity during behavior, linking all of these measurements to cell types within the intact brains of living mammals has been difficult. Here, using an array of intact-brain circuit interrogation tools, including CLARITY, COLM, optogenetics, viral tracing, and fiber photometry, we explore the diversity of dopamine neurons within the substantia nigra pars compacta (SNc). We identify two parallel nigrostriatal dopamine neuron subpopulations differing in biophysical properties, input wiring, output wiring to dorsomedial striatum (DMS) versus dorsolateral striatum (DLS), and natural activity patterns during free behavior. Our results reveal independently operating nigrostriatal information streams, with implications for understanding the logic of dopaminergic feedback circuits and the diversity of mammalian neuronal cell types. PMID- 26232230 TI - Saturated Reconstruction of a Volume of Neocortex. AB - We describe automated technologies to probe the structure of neural tissue at nanometer resolution and use them to generate a saturated reconstruction of a sub volume of mouse neocortex in which all cellular objects (axons, dendrites, and glia) and many sub-cellular components (synapses, synaptic vesicles, spines, spine apparati, postsynaptic densities, and mitochondria) are rendered and itemized in a database. We explore these data to study physical properties of brain tissue. For example, by tracing the trajectories of all excitatory axons and noting their juxtapositions, both synaptic and non-synaptic, with every dendritic spine we refute the idea that physical proximity is sufficient to predict synaptic connectivity (the so-called Peters' rule). This online minable database provides general access to the intrinsic complexity of the neocortex and enables further data-driven inquiries. PMID- 26232231 TI - SnapShot: Spliceosome Dynamics III. AB - The complex compositional and conformational dynamics of spliceosomes required for regulated splicing are prone to malfunction when mutations affect splicing factors or cis-acting regulatory sequences. Indeed, many such mutations have been linked to heritable diseases or malignancies in humans. Small molecule modulators and antisense oligonucleotides or analogs harbor great potential for therapies and several substances that can modulate splicing events have entered clinical trials. PMID- 26232232 TI - The role of sirtuins in cardiac disease. AB - Modification of histones is one of the important mechanisms of epigenetics, in which genetic control is determined by factors other than an individual's DNA sequence. Sirtuin family proteins, which are class III histone deacetylases, were originally identified as gene silencers that affect the mating type of yeast, leading to the name "silent mating-type information regulation 2" (SIR2). They are characterized by their requirement of nicotinamide adenine dinucleotide for their enzyme activity, unlike other classes of histone deacetylases. Sirtuins have been traditionally linked to longevity and the beneficial effects of calorie restriction and DNA damage repair. Recently, sirtuins have been shown to be involved in a wide range of physiological and pathological processes, including aging, energy responses to low calorie availability, and stress resistance, as well as apoptosis and inflammation. Sirtuins can also regulate mitochondrial biogenesis and circadian clocks. Seven sirtuin family proteins (Sirt1-7) have been identified as mammalian SIR2 orthologs, localized in different subcellular compartments, namely, the cytoplasm (Sirt1, 2), the mitochondria (Sirt3, 4, 5), and the nucleus (Sirt1, 2, 6, 7). Sirt1 is evolutionarily close to yeast SIR2 and has been the most intensively investigated in the cardiovascular system. Endogenous Sirt1 plays a pivotal role in mediating the cell death/survival process and has been implicated in the pathogenesis of cardiovascular disease. Downregulation of Sirt2 is protective against ischemic-reperfusion injury. Increased Sirt3 expression has been shown to correlate with longevity in humans. In addition, Sirt3 protects cardiomyocytes from aging and oxidative stress and suppresses cardiac hypertrophy. Sirt6 has also recently been demonstrated to attenuate cardiac hypertrophy, and Sirt7 is known to regulate apoptosis and stress responses in the heart. On the other hand, the roles of Sirt4 and Sirt5 in the heart remain largely uncharacterized. PMID- 26232234 TI - Chronic antihypertensive treatment improves pulse pressure but not large artery mechanics in a mouse model of congenital vascular stiffness. AB - Increased arterial stiffness is a common characteristic of humans with Williams Beuren syndrome and mouse models of elastin insufficiency. Arterial stiffness is associated with multiple negative cardiovascular outcomes, including myocardial infarction, stroke, and sudden death. Therefore, identifying therapeutic interventions that improve arterial stiffness in response to changes in elastin levels is of vital importance. The goal of this study was to determine the effect of chronic pharmacologic therapy with different classes of antihypertensive medications on arterial stiffness in elastin insufficiency. Elastin-insufficient mice 4-6 wk of age and wild-type littermates were subcutaneously implanted with osmotic micropumps delivering a continuous dose of one of the following: vehicle, losartan, nicardipine, or propranolol for 8 wk. At the end of treatment period, arterial blood pressure and large artery compliance and remodeling were assessed. Our results show that losartan and nicardipine treatment lowered blood pressure and pulse pressure in elastin-insufficient mice. Elastin and collagen content of abdominal aortas as well as ascending aorta and carotid artery biomechanics were not affected by any of the drug treatments in either genotype. By reducing pulse pressure and shifting the working pressure range of an artery to a more compliant region of the pressure-diameter curve, antihypertensive medications may mitigate the consequences of arterial stiffness, an effect that is drug class independent. These data emphasize the importance of early recognition and long-term management of hypertension in Williams-Beuren syndrome and elastin insufficiency. PMID- 26232233 TI - Translational approaches to understanding metabolic dysfunction and cardiovascular consequences of obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is known to be independently associated with several cardiovascular diseases including hypertension, myocardial infarction, and stroke. To determine how OSA can increase cardiovascular risk, animal models have been developed to explore the underlying mechanisms and the cellular and end organ targets of the predominant pathophysiological disturbance in OSA intermittent hypoxia. Despite several limitations in translating data from animal models to the clinical arena, significant progress has been made in our understanding of how OSA confers increased cardiovascular risk. It is clear now that the hypoxic stress associated with OSA can elicit a broad spectrum of pathological systemic events including sympathetic activation, systemic inflammation, impaired glucose and lipid metabolism, and endothelial dysfunction, among others. This review provides an update of the basic, clinical, and translational advances in our understanding of the metabolic dysfunction and cardiovascular consequences of OSA and highlights the most recent findings and perspectives in the field. PMID- 26232235 TI - Differential effects of octanoate and heptanoate on myocardial metabolism during extracorporeal membrane oxygenation in an infant swine model. AB - Nutritional energy support during extracorporeal membrane oxygenation (ECMO) should promote successful myocardial adaptation and eventual weaning from the ECMO circuit. Fatty acids (FAs) are a major myocardial energy source, and medium chain FAs (MCFAs) are easily taken up by cell and mitochondria without membrane transporters. Odd-numbered MCFAs supply carbons to the citric acid cycle (CAC) via anaplerotic propionyl-CoA as well as acetyl-CoA, the predominant beta oxidation product for even-numbered MCFA. Theoretically, this anaplerotic pathway enhances carbon entry into the CAC, and provides superior energy state and preservation of protein synthesis. We tested this hypothesis in an immature swine model undergoing ECMO. Fifteen male Yorkshire pigs (26-45 days old) with 8-h ECMO received either normal saline, heptanoate (odd-numbered MCFA), or octanoate (even numbered MCFA) at 2.3 MUmol.kg body wt(-1).min(-1) as MCFAs systemically during ECMO (n = 5/group). The 13-carbon ((13)C)-labeled substrates ([2-(13)C]lactate, [5,6,7-(13)C3]heptanoate, and [U-(13)C6]leucine) were systemically infused as metabolic markers for the final 60 min before left ventricular tissue extraction. Extracted tissues were analyzed for the (13)C-labeled and absolute concentrations of metabolites by nuclear magnetic resonance and gas chromatography-mass spectrometry. Octanoate produced markedly higher myocardial citrate concentration, and led to a higher [ATP]-to-[ADP] ratio compared with other groups. Unexpectedly, octanoate and heptanoate increased the flux of propionyl CoA relative to acetyl-CoA into the CAC compared with control. MCFAs promoted increases in leucine oxidation, but were not associated with a difference in protein synthesis rate. In conclusion, octanoate provides energetic advantages to the heart over heptanoate. PMID- 26232237 TI - Diagnostic biases in translational bioinformatics. AB - BACKGROUND: With the surge of translational medicine and computational omics research, complex disease diagnosis is more and more relying on massive omics data-driven molecular signature detection. However, how to detect and prevent possible diagnostic biases in translational bioinformatics remains an unsolved problem despite its importance in the coming era of personalized medicine. METHODS: In this study, we comprehensively investigate the diagnostic bias problem by analyzing benchmark gene array, protein array, RNA-Seq and miRNA-Seq data under the framework of support vector machines for different model selection methods. We further categorize the diagnostic biases into different types by conducting rigorous kernel matrix analysis and provide effective machine learning methods to conquer the diagnostic biases. RESULTS: In this study, we comprehensively investigate the diagnostic bias problem by analyzing benchmark gene array, protein array, RNA-Seq and miRNA-Seq data under the framework of support vector machines. We have found that the diagnostic biases happen for data with different distributions and SVM with different kernels. Moreover, we identify total three types of diagnostic biases: overfitting bias, label skewness bias, and underfitting bias in SVM diagnostics, and present corresponding reasons through rigorous analysis. Compared with the overfitting and underfitting biases, the label skewness bias is more challenging to detect and conquer because it can be easily confused as a normal diagnostic case from its deceptive accuracy. To tackle this problem, we propose a derivative component analysis based support vector machines to conquer the label skewness bias by achieving the rivaling clinical diagnostic results. CONCLUSIONS: Our studies demonstrate that the diagnostic biases are mainly caused by the three major factors, i.e. kernel selection, signal amplification mechanism in high-throughput profiling, and training data label distribution. Moreover, the proposed DCA-SVM diagnosis provides a generic solution for the label skewness bias overcome due to the powerful feature extraction capability from derivative component analysis. Our work identifies and solves an important but less addressed problem in translational research. It also has a positive impact on machine learning for adding new results to kernel-based learning for omics data. PMID- 26232236 TI - Fibroblast growth factors in cardiovascular disease: The emerging role of FGF21. AB - Early detection of risk factors for enhanced primary prevention and novel therapies for treating the chronic consequences of cardiovascular disease are of the utmost importance for reducing morbidity. Recently, fibroblast growth factors (FGFs) have been intensively studied as potential new molecules in the prevention and treatment of cardiovascular disease mainly attributable to metabolic effects and angiogenic actions. Members of the endocrine FGF family have been shown to increase metabolic rate, decrease adiposity, and restore glucose homeostasis, suggesting a multiple metabolic role. Serum levels of FGFs have been associated with established cardiovascular risk factors as well as with the severity and extent of coronary artery disease and could be useful for prediction of cardiovascular death. Furthermore, preclinical investigations and clinical trials have tested FGF administration for therapeutic angiogenesis in ischemic vascular disease, demonstrating a potential role in improving angina and limb function. FGF21 has lately emerged as a potent metabolic regulator with multiple effects that ultimately improve the lipoprotein profile. Early studies show that FGF21 is associated with the presence of atherosclerosis and may play a protective role against plaque formation by improving endothelial function. The present review highlights recent investigations suggesting that FGFs, in particular FGF21, may be useful as markers of cardiovascular risk and may also serve as protective/therapeutic agents in cardiovascular disease. PMID- 26232238 TI - Impact of multi-morbidity on quality of healthcare and its implications for health policy, research and clinical practice. A scoping review. AB - The simultaneous presence of multiple conditions in one patient (multi-morbidity) is a key challenge facing healthcare systems globally. It potentially threatens the coordination, continuity and safety of care. In this paper, we report the results of a scoping review examining the impact of multi-morbidity on the quality of healthcare. We used its results as a basis for a discussion of the challenges that research in this area is currently facing. In addition, we discuss its implications for health policy and clinical practice. The review identified 37 studies focussing on multi-morbidity but using conceptually different approaches. Studies focusing on 'comorbidity' (i.e. the 'index disease' approach) suggested that quality may be enhanced in the presence of synergistic conditions, and impaired by antagonistic or neutral conditions. Studies on 'multi morbidity' (i.e. multiplicity of problems) and 'morbidity burden' (i.e. the total severity of conditions) suggested that increasing number of conditions and severity may be associated with better quality of healthcare when measured by process or intermediate outcome indicators, but with worse quality when patient centred measures are used. However, issues related to the conceptualization and measurement of multi-morbidity (inconsistent across studies) and of healthcare quality (restricted to evaluations for each separate condition without incorporating considerations about multi-morbidity itself and its implications for management) compromised the generalizability of these observations. Until these issues are addressed and robust evidence becomes available, clinicians should apply minimally invasive and patient-centred medicine when delivering care for clinically complex patients. Health systems should focus on enhancing primary care centred coordination and continuity of care. PMID- 26232239 TI - Mirror neuron deficit in schizophrenia: Evidence from repetition suppression. AB - BACKGROUND: Schizophrenia is associated with impaired cognition, especially cognition in social contexts. The mirror neuron system (MNS) serves as an important neuronal basis for social cognitive skills; however, previous investigations on the integrity of MNS function in schizophrenia remain approximate. METHODS: We employed a repetition suppression paradigm that allows for measuring neuronal responses to gesture observation and gesture execution. Cross-modal repetition suppression, i.e., adaptation between observe/execute and execute/observe conditions, was defined as the decisive experimental condition characterizing the unique sensori-motor properties of mirror neurons. Event related potentials (ERPs) were assessed in 15 schizophrenia patients and 15 matched controls. RESULTS: We isolated an ERP signature of specific adaptation effects to identical hand gestures. Of critical importance, this ERP signature indicated intact intra-modal adaptive pattern, i.e., observe/observe and execute/execute, of comparable magnitude between groups, but deficient cross modal adaptation, i.e., observe/execute and execute/observe, in schizophrenia patients. CONCLUSION: Our data provide robust evidence that pure perception and execution of hand gestures are relatively intact in schizophrenia. In contrast, visuo-motor transformation processes mediated by the MNS seem to be specifically disturbed in schizophrenia. These results unambiguously demonstrate MNS deficits in schizophrenia and extend our understanding of the neuronal bases of social dysfunction in this disorder. PMID- 26232240 TI - Structural correlates of formal thought disorder in schizophrenia: An ultra-high field multivariate morphometry study. AB - BACKGROUND: Persistent formal thought disorder (FTD) is one of the most characteristic features of schizophrenia. Several neuroimaging studies report spatially distinct neuroanatomical changes in association with FTD. Given that most studies so far have employed a univariate localisation approach that obscures the study of covarying interregional relationships, the present study focussed on the multivariate systemic pattern of anatomical changes that contribute to FTD. METHODS: Speech samples from nineteen medicated clinically stable schizophrenia patients and 20 healthy controls were evaluated for subtle formal thought disorder. Ultra high-field (7T) anatomical Magnetic Resonance Imaging scans were obtained from all subjects. Multivariate morphometric patterns were identified using an independent component approach (source based morphometry). Using multiple regression analysis, the morphometric patterns predicting positive and negative FTD scores were identified. RESULTS: Morphometric variations in grey matter predicted a substantial portion of inter individual variance in negative but not positive FTD. A pattern of concomitant striato-insular/precuneus reduction along with frontocingular grey matter increase had a significant association with negative FTD. CONCLUSIONS: These results suggest that concomitant increase and decrease in grey matter occur in association with persistent negative thought disorder in clinically stable individuals with schizophrenia. PMID- 26232241 TI - Qualify: a randomized head-to-head study of aripiprazole once-monthly and paliperidone palmitate in the treatment of schizophrenia. AB - OBJECTIVE: To directly compare aripiprazole once-monthly 400mg (AOM 400) and paliperidone palmitate once-monthly (PP) on the Heinrichs-Carpenter Quality-of Life Scale (QLS), a validated health-related quality of life and functioning measure in schizophrenia. METHOD: This 28-week, randomized, non-inferiority, open label, rater-blinded, head-to-head study (QUALIFY) of AOM 400 and PP in adult patients (18-60 years) comprised oral conversion, initiation of AOM 400 or PP treatment, and continuation with intramuscular injections every 4weeks. The primary endpoint assessed non-inferiority and superiority on QLS total score analyzed using a mixed model for repeated measurements. RESULTS: Of 295 randomized patients, 100/148 (67.6%) of AOM 400 and 83/147 (56.5%) of PP patients completed 28weeks of treatment. A statistically significant least squares mean difference in change from baseline to week 28 on QLS total score (4.67 [95%CI: 0.32;9.02], p=0.036) confirmed non-inferiority and established superiority of AOM 400 vs PP. There were also significant improvements in Clinical Global Impression - Severity scale and the Investigator's Assessment Questionnaire for AOM 400 vs PP, and pre-defined sub-group analyses revealed a consistent pattern of significance favoring AOM 400 in patients <=35years. Common treatment-emergent adverse events in the treatment continuation phase were more frequent with PP vs AOM 400, and adverse events were the most frequent reason for discontinuation (27/137 [19.7%] for PP and 16/144 [11.1%] for AOM 400). All-cause discontinuation was numerically lower with AOM 400. CONCLUSION: Superior improvements on clinician-rated health-related quality of life and a favorable tolerability profile suggest greater overall effectiveness for aripiprazole once-monthly vs paliperidone palmitate. ClinicalTrials.gov identifier:NCT01795547. PMID- 26232242 TI - Mindfulness in schizophrenia: Associations with self-reported motivation, emotion regulation, dysfunctional attitudes, and negative symptoms. AB - Mindfulness-based interventions are gaining empirical support as alternative or adjunctive treatments for a variety of mental health conditions, including anxiety, depression, and substance use disorders. Emerging evidence now suggests that mindfulness-based treatments may also improve clinical features of schizophrenia, including negative symptoms. However, no research has examined the construct of mindfulness and its correlates in schizophrenia. In this study, we examined self-reported mindfulness in patients (n=35) and controls (n=25) using the Five-Facet Mindfulness Questionnaire. We examined correlations among mindfulness, negative symptoms, and psychological constructs associated with negative symptoms and adaptive functioning, including motivation, emotion regulation, and dysfunctional attitudes. As hypothesized, patients endorsed lower levels of mindfulness than controls. In patients, mindfulness was unrelated to negative symptoms, but it was associated with more adaptive emotion regulation (greater reappraisal) and beliefs (lower dysfunctional attitudes). Some facets of mindfulness were also associated with self-reported motivation (behavioral activation and inhibition). These patterns of correlations were similar in patients and controls. Findings from this initial study suggest that schizophrenia patients may benefit from mindfulness-based interventions because they (a) have lower self-reported mindfulness than controls and (b) demonstrate strong relationships between mindfulness and psychological constructs related to adaptive functioning. PMID- 26232243 TI - Environmental factors and the age at onset in first episode psychosis. AB - OBJECTIVE: Factors that influence the age at onset in psychotic disorders could provide valuable insights into precipitating or causative factors of the disorder. Despite being established risk factors, it is not yet known whether migration status, place of birth, social class at birth and season of birth influence the age at onset of psychotic disorders. This study aimed to determine whether these environmental factors, in addition to cannabis abuse and obstetric complications, influence the age at onset. Additionally, we investigated whether environmental factors could have a cumulative effect on the age at onset. METHOD: Data was obtained from two first episode of psychosis (FEP) cohort studies. Diagnosis was established using the Structured Clinical Interview for DSM IV diagnoses. RESULTS: The age at onset was determined for 555 individuals with a FEP and the median age at onset was 27.3years. Individuals with a history of cannabis abuse had an earlier age at onset by nearly six years. There was a trend for a history of obstetric complications to be associated with a younger age at onset by 2.7years and this was significant in the subgroup with a family history of psychosis. Social class at birth, migration status, place of birth and season of birth were not associated with the age at onset. Exposure to a higher number of environmental factors was associated with an earlier age at onset. CONCLUSIONS: Cannabis and obstetric complications are associated with an earlier age at onset and there appears to be a cumulative effect of exposure to multiple environmental factors. PMID- 26232244 TI - A Review Study on Punica granatum L. AB - Punica granatum L (pomegranate) is a deciduous shrub, native to Iran. Nowadays, besides its use as a fruit, its medicinal properties have attracted the interest of researchers of many countries. Pomegranate fruit has medicinal properties such as anti-inflammatory and antibacterial activities. The pomegranate seed oil has inhibitory effect on skin and breast cancers. The pomegranate seed oil has phytoestrogenic compounds and the fruit is rich in phenolic compounds with strong antioxidant activity. Ellagic acid is one of the main components of pomegranate with phenolic structure and antioxidant activity. This review article presents the recently published findings on different aspects of this plant focusing on its medicinal properties. PMID- 26232245 TI - Translation and psychometric properties of the Chinese version of the Leeds Attitudes to Concordance II scale. AB - BACKGROUND: Concordance is characterised as a negotiation-like health communication approach based on an equal and collaborative partnership between patients and health professionals. The Leeds Attitudes to Concordance II (LATCon II) scale was developed to measure the attitudes towards concordance. The purpose of this study was to translate the LATCon II into Chinese and psychometrically test the Chinese version of LATCon II (C-LATCon II). METHODS: The study involved three phases: i) translation and cross-cultural adaptation; ii) pilot study; and iii) a cross-sectional survey (n = 366). Systematic random sampling was used to recruit hypertensive patients from nine communities covering around 78,000 residents in China. Tests of psychometric properties included content validity, construct validity, criteria-related validity (correlation between the C-LATCon II and the Therapeutic Adherence Scale for Hypertensive Patients (TASHP)), internal reliability, and test-retest reliability (n = 30). RESULTS: The study found that the C-LATCon II had a satisfactory content validity (item-level Content Validity Index (CVI) = 0.83-1, scale-level CVI/universal agreement = 0.89, and scale-level CVI/averaging calculation = 0.98), construct validity (four components extracted explained 56.66 % of the total variance), internal reliability (Cronbach's alpha of overall scale and four components was 0.78 and 0.66-0.84, respectively), and test-retest reliability (Pearson's correlation coefficient = 0.82, p < 0.001; interclass correlation coefficient = 0.82, p < 0.001; linear weighted kappa statistic for each item = 0.40-0.65, p < 0.05). Criteria-related validity showed a weak association (Pearson's correlation coefficient = 0.11, p < 0.05) between patients' attitudes towards concordance during health communication and their health behaviours for hypertension management. CONCLUSIONS: The C-LATCon II is a validated and reliable instrument which can be used to evaluate the attitudes to concordance in Chinese populations. Four components (health professionals' attitudes, partnership between two parties, therapeutic decision making, and patients' involvement) describe the attitudes towards concordance during health communication. PMID- 26232246 TI - Context-Sensitive Spelling Correction of Consumer-Generated Content on Health Care. AB - BACKGROUND: Consumer-generated content, such as postings on social media websites, can serve as an ideal source of information for studying health care from a consumer's perspective. However, consumer-generated content on health care topics often contains spelling errors, which, if not corrected, will be obstacles for downstream computer-based text analysis. OBJECTIVE: In this study, we proposed a framework with a spelling correction system designed for consumer generated content and a novel ontology-based evaluation system which was used to efficiently assess the correction quality. Additionally, we emphasized the importance of context sensitivity in the correction process, and demonstrated why correction methods designed for electronic medical records (EMRs) failed to perform well with consumer-generated content. METHODS: First, we developed our spelling correction system based on Google Spell Checker. The system processed postings acquired from MedHelp, a biomedical bulletin board system (BBS), and saved misspelled words (eg, sertaline) and corresponding corrected words (eg, sertraline) into two separate sets. Second, to reduce the number of words needing manual examination in the evaluation process, we respectively matched the words in the two sets with terms in two biomedical ontologies: RxNorm and Systematized Nomenclature of Medicine -- Clinical Terms (SNOMED CT). The ratio of words which could be matched and appropriately corrected was used to evaluate the correction system's overall performance. Third, we categorized the misspelled words according to the types of spelling errors. Finally, we calculated the ratio of abbreviations in the postings, which remarkably differed between EMRs and consumer-generated content and could largely influence the overall performance of spelling checkers. RESULTS: An uncorrected word and the corresponding corrected word was called a spelling pair, and the two words in the spelling pair were its members. In our study, there were 271 spelling pairs detected, among which 58 (21.4%) pairs had one or two members matched in the selected ontologies. The ratio of appropriate correction in the 271 overall spelling errors was 85.2% (231/271). The ratio of that in the 58 spelling pairs was 86% (50/58), close to the overall ratio. We also found that linguistic errors took up 31.4% (85/271) of all errors detected, and only 0.98% (210/21,358) of words in the postings were abbreviations, which was much lower than the ratio in the EMRs (33.6%). CONCLUSIONS: We conclude that our system can accurately correct spelling errors in consumer-generated content. Context sensitivity is indispensable in the correction process. Additionally, it can be confirmed that consumer-generated content differs from EMRs in that consumers seldom use abbreviations. Also, the evaluation method, taking advantage of biomedical ontology, can effectively estimate the accuracy of the correction system and reduce manual examination time. PMID- 26232247 TI - Cytidine-5-diphosphocholine reduces microvascular permeability during experimental endotoxemia. AB - BACKGROUND: Microvascular permeability and leukocyte adhesion are pivotal mechanisms in sepsis pathophysiology contributing to the development of shock and mortality. No effective pharmacological therapy is currently available to restore microvascular barrier function in sepsis. Cholinergic mediators have been demonstrated to exert anti-inflammatory effects during inflammation. Cytidine-5 diphosphocholine (CDP-choline) is an extensively studied cholinergic drug due to its brain protective characteristics in cerebrovascular diseases. This study evaluated the effect of CDP-choline on microvascular permeability and leukocyte adhesion during endotoxemia. METHODS: Macromolecular leakage, leukocyte adhesion, and venular wall shear rate were examined in mesenteric postcapillary venules of rats by using intravital microscopy (IVM). Lipopolysaccharide (LPS) (4 mg/kg/h) or equivalent volumes of saline were continuously infused following baseline IVM at 0 min. IVM was repeated after 60 and 120 min in endotoxemic and nonendotoxemic animals. CDP-choline (100 mg/kg) was applied as an i.v. bolus. Animals received either saline alone, CDP-choline alone, CDP-choline 10 min before or 30 min after LPS administration, or LPS alone. Due to nonparametric data distribution, Wilcoxon test and Dunn's multiple comparisons test were used for data analysis. Data were considered statistically significant at p < 0.05. RESULTS: Treatment with LPS alone significantly increased microvascular permeability and leukocyte adhesion and decreased venular wall shear rate. CDP-choline significantly reduced microvascular permeability in animals treated with LPS. Leukocyte adhesion and venular wall shear rate were not affected by CDP-choline during endotoxemia. CONCLUSION: CDP-choline has a protective effect on microvascular barrier function during endotoxemia. Considering the excellent pharmacologic safety profile of CDP choline, its use could be an approach for the treatment of capillary leakage in sepsis. PMID- 26232248 TI - Reprint of "pFind-Alioth: A novel unrestricted database search algorithm to improve the interpretation of high-resolution MS/MS data". AB - Database search is the dominant approach in high-throughput proteomic analysis. However, the interpretation rate of MS/MS spectra is very low in such a restricted mode, which is mainly due to unexpected modifications and irregular digestion types. In this study, we developed a new algorithm called Alioth, to be integrated into the search engine of pFind, for fast and accurate unrestricted database search on high-resolution MS/MS data. An ion index is constructed for both peptide precursors and fragment ions, by which arbitrary digestions and a single site of any modifications and mutations can be searched efficiently. A new re-ranking algorithm is used to distinguish the correct peptide-spectrum matches from random ones. The algorithm is tested on several HCD datasets and the interpretation rate of MS/MS spectra using Alioth is as high as 60%-80%. Peptides from semi- and non-specific digestions, as well as those with unexpected modifications or mutations, can be effectively identified using Alioth and confidently validated using other search engines. The average processing speed of Alioth is 5-10 times faster than some other unrestricted search engines and is comparable to or even faster than the restricted search algorithms tested.This article is part of a Special Issue entitled: Computational Proteomics. PMID- 26232250 TI - A novel ultrasound based approach for lesion segmentation and its applications in gynecological laparoscopic surgery. AB - Laparoscopic ultrasound (LUS) has been widely utilized as a surgical aide in general, urological, and gynecological applications. Our study summarizes the clinical applications of laparoscopic ultrasonography in laparoscopic gynecologic surgery. Retrospective analyses were performed on 42 women subjects using laparoscopic surgery during laparoscopic extirpation and excision of gynecological tumors in our hospital from August 2011 to August 2013. Specifically, the Esaote 7.5 * 10 MHz laparoscopic transducer was used to detect small residual lesions, as well as to assess, locate and guide in removing the lesions during laparoscopic operations. The findings of LUS were compared with those of preoperative trans-vaginal ultrasound, postoperative, and pathohistological examinations. In addition, a novel method for lesion segmentation was proposed in order to facilitate the laparoscopic gynecologic surgery. In our experiment, laparoscopic operation was performed using a higher frequency and more close to pelvic organs via laparoscopic access. LUS facilitates the ability of gynaecologists to find small residual lesions under laparoscopic visualization and their accurate diagnosis. LUS also helps to locate residual lesions precisely and provides guidance for the removal of residual tumor and eliminate its recurrence effectively. Our experiment provides a safer and more valuable assistance for clinical applications in laparoscopic gynecological surgery that are superior to trans-abdominal ultrasound and trans vaginal ultrasound. PMID- 26232249 TI - Mitochondrial and Oxidative Stress Aspects in Hippocampus of Rats Submitted to Dietary n-3 Polyunsaturated Fatty Acid Deficiency After Exposure to Early Stress. AB - Chronic dietary long-chain polyunsaturated fatty acids (PUFAs) deficiency may lead to changes in cortex and hippocampus neuronal membrane phospholipids, and may be linked to impaired central nervous system function. Particularly docosahexaenoic acid deficiency appears to be involved in neuropsychiatric disorders. On the other hand, adverse events early in life may also profoundly affect brain development, leading to long-lasting effects on neurophysiology, neurobiology and behavior. This research assessed if neonatal stress and a dietary n-3 PUFAs deficiency could interact to produce hippocampal alterations related to mitochondrial functions in adult rats. There were no effects of diet, neonatal intervention or interactions on superoxide dismutase or catalase enzymatic activities, mitochondrial membrane potential and respiratory chain complexes. Rats fed n-3 PUFAs deficient diet displayed higher levels of glutathione peroxidase and catalase activity, higher free radicals production and higher thiol content compared to rats fed n-3 PUFAs adequate diet. There were interactions among diets and neonatal stress, since glutathione peroxidase, free radicals production and thiol content were increased in groups that were subjected to neonatal interventions fed n-3 PUFAs deficient diet. Additionally, reduced mitochondrial potential was observed in handled animals. Total thiol revealed a neonatal stress effect, since animals subjected to neonatal interventions displayed lower thiol content. In conclusion, we observed that a chronic treatment with deficient n-3 PUFAs diet, from the puberty period on, increased free radicals production and imbalanced antioxidant enzymes activities, and these increases were higher in animals subjected to neonatal interventions. PMID- 26232251 TI - Monte Carlo and experimental internal radionuclide dosimetry in RANDO head phantom. AB - Monte Carlo techniques are widely employed in internal dosimetry to obtain better estimates of absorbed dose distributions from irradiation sources in medicine. Accurate 3D absorbed dosimetry would be useful for risk assessment of inducing deterministic and stochastic biological effects for both therapeutic and diagnostic radiopharmaceuticals in nuclear medicine. The goal of this study was to experimentally evaluate the use of Geant4 application for tomographic emission (GATE) Monte Carlo package for 3D internal dosimetry using the head portion of the RANDO phantom. GATE package (version 6.1) was used to create a voxel model of a human head phantom from computed tomography (CT) images. Matrix dimensions consisted of 319 * 216 * 30 voxels (0.7871 * 0.7871 * 5 mm(3)). Measurements were made using thermoluminescent dosimeters (TLD-100). One rod-shaped source with 94 MBq activity of (99m)Tc was positioned in the brain tissue of the posterior part of the human head phantom in slice number 2. The results of the simulation were compared with measured mean absorbed dose per cumulative activity (S value). Absorbed dose was also calculated for each slice of the digital model of the head phantom and dose volume histograms (DVHs) were computed to analyze the absolute and relative doses in each slice from the simulation data. The S-values calculated by GATE and TLD methods showed a significant correlation (correlation coefficient, r(2) >= 0.99, p < 0.05) with each other. The maximum relative percentage differences were <=14% for most cases. DVHs demonstrated dose decrease along the direction of movement toward the lower slices of the head phantom. Based on the results obtained from GATE Monte Carlopackage it can be deduced that a complete dosimetry simulation study, from imaging to absorbed dose map calculation, is possible to execute in a single framework. PMID- 26232252 TI - Microcatheter entrapment retrieval from Onyx embolization in brain arteriovenous malformations: A technical note. AB - OBJECTIVE: Many techniques have been use for retrieval of an entrapped microcatheter during Onyx (eV3 Neurovascular) embolization of brain arteriovenous malformations (BAVMs). We report our technique that we term "pull-push-pull" that can be utilized as first management in retrieving the microcatheter. METHOD: We analyzed a total of 37 patients that underwent BAVM embolization with either Onyx 18 or 34 at our institution. Standard embolization techniques were utilized with the use of Marathon (eV3 Neurovascular) microcatheter. When difficulty in retrieving the microcatheter arose, we used the "pull-push-pull" technique. The technique comprises the eV3 protocol of retraction. In addition, the microcatheter is stretched causing the Onyx cast to stretch in its inner core, creating a more thorough cohesive property amongst the Onyx mixture. Then the microcatheter is pushed back and to its point of embolization origin. Afterwards, retraction of the microcatheter is enabled as it can be easily dislodged from the cast. Multiple attempts can be repeated as needed. RESULT AND DISCUSSION: We had three patients that had difficulty with removal of microcatheter (8.1%). Utilization of the "pull-push-pull" technique was used on two of those patients. No neurological complication was observed with our technique. We believe the cohesive property of Onyx solution helps in the retrieval of the catheter by our method and technique. CONCLUSION: We believe the "pull-push-pull" can be utilized and be an additional technique before attempting other catheter retrieval techniques in Onyx BAVM embolization. PMID- 26232253 TI - Assessment of dose and DNA damages in individuals exposed to low dose and low dose rate ionizing radiations during computed tomography imaging. AB - PURPOSE: Computed tomography (CT) is a frequently used imaging modality that contributes to a tenfold increase in radiation exposure to the public when compared to other medical imaging modalities. The use of radiation for therapeutic need is always rationalized on the basis of risk versus benefit thereby increasing concerns on the dose received by patients undergoing CT imaging. Therefore, it was of interest to us to investigate the effects of low dose and low dose-rate X-irradiation in patients who underwent CT imaging by recording the doses received by the eye, forehead and thyroid, and to study the levels of damages in the lymphocytes in vivo. MATERIALS AND METHODS: Lithium manganese borate doped with terbium (LMB:Tb) thermo luminescence dosimeters (TLD) were used to record the doses in the patient's (n = 27) eye, forehead, and thyroid and compared with the dose length product (DLP) values. The in vivo DNA damages measured were compared before and after CT imaging using chromosomal aberration (CA) and micronucleus (MN) assays. RESULTS: The overall measured organ dose ranged between 2 +/- 0.29 and 520 +/- 41.63 mGy for the eye, 0.84 +/- 0.29 and 210 +/- 20.50 mGy for the forehead, and 1.79 +/- 0.43 and 185 +/- 0.70 mGy for the thyroid. The in vivo damages measured from the blood lymphocytes of the subjects showed an extremely significant (p < 0.0001) increase in CA frequency and significant (p < 0.001) increase in MN frequency after exposure, compared to before exposure. CONCLUSION: The results suggest that CT imaging delivers a considerable amount of radiation dose to the eye, forehead, and thyroid, and the observed increase in the CA and MN frequencies show low dose radiation effects calling for protective regulatory measures to increase patient's safety. This study is the first attempt to indicate the trend of doses received by the patient's eye, forehead and thyroid and measured directly in contrast to earlier values obtained by extrapolation from phantoms, and to assess the in vivo low dose effects in an Indian patient population undergoing CT procedures. PMID- 26232254 TI - Relationships between p53 status, apoptosis and induction of micronuclei in different human and mouse cell lines in vitro: Implications for improving existing assays. AB - Accumulated evidence has shown that in vitro mammalian cell genotoxicity assays produce high frequencies of "misleading" positive results, i.e. predicted hazard is not confirmed in in vivo and/or carcinogenicity studies [1], raising the question of relevance to human risk assessment. A recent study of micronucleus (MN) induction [2] showed that commonly used p53-deficient rodent cell lines (CHL, CHO and V79) gave a higher frequency of "misleading" positive results with 9 non-DNA reactive, Ames-negative and in vivo negative chemicals [3] than human p53-competent cells (blood lymphocytes, TK6 and HepG2 cell lines). This raised the question of whether these differences were due to p53 status or species origin. This present study compared human versus mouse and p53-competent versus p53-mutated function. The same 9 chemicals were tested for induction of MN in mouse lymphoma L5178Y (mutated p53), human TK6 (functional p53) and WIL2-NS (TK6 related, with mutated p53) cells. Six chemicals provided clear positive increases in MN frequency in at least one cell type. L5178Y cells yielded clear positive responses with more chemicals than either TK6 or WIL2-NS, indicating origin rather than p53 functionality was most relevant. Apoptosis induction (measured via caspase-3/7) was also investigated with clear differences in the timing and extent of apoptosis induction between mouse and human cells noted. With curcumin in TK6 cells, induction of caspase-3/7 activity coincided with MN induction, whereas for L5178Y cells, MN induction occurred in the absence of increased caspase activity. By contrast, with MMS in TK6 cells, MN induction preceded increased caspase-3/7 activity. These data suggest that MN induction by "misleading positive" genotoxins in p53-competent human cell lines may result from apoptosis, whereas in p53-defective rodent cells such as L5178Y, MN induction may be independent of apoptosis. PMID- 26232255 TI - A new genotoxicity assay based on p53 target gene induction. AB - The p53 tumor suppressor protein has emerged as a universal sensor of genotoxic stress that regulates the transcription of numerous genes required for appropriate cellular response to DNA damage. Therefore, transcriptional induction of p53 target genes can be considered as a global and early indicator of genotoxic stress. By performing expression microarrays and RNA-Seq analysis on wild-type and mutant TP53 human lymphocytes respectively derived from controls and Li-Fraumeni patients and exposed to different classes of genotoxic agents, we first determined a common p53-dependent transcriptional signature of DNA damage. We then derived a simple and fast assay based on the exposure of wild-type TP53 lymphocytes to physical or chemical agents and on the quantitative measurement of selected p53 target gene transcriptional induction. The specificity of the p53 genotoxicity assay can easily be demonstrated by performing the same experiment in control lymphocytes with heterozygous TP53 mutations, which compromise responses to DNA damage. This assay allowed us to show that most of the drugs commonly used in cancer treatment, except the microtubule poisons, are highly genotoxic. The p53 genotoxicity assay should facilitate the measurement of the genotoxic effects of chemical and physical agents and the identification of drugs that are not genotoxic and do not expose patients to the risk of secondary malignancies, especially those with a constitutional defect in response to DNA damage, such as patients with Li-Fraumeni syndrome. PMID- 26232256 TI - Male-mediated F1 effects in mice exposed to bisphenol A, either alone or in combination with X-irradiation. AB - We investigated the possible transmission of heritable changes via the sperm, following preconceptional exposure of mice to bisphenol A (BPA), either alone or in combination with X-irradiation. Males were exposed for 8 weeks to BPA, X-rays or both agents, and mated to unexposed females. Pre- and postnatal development of the offspring of exposed males was examined. Both BPA alone and the combined exposure slightly affected postnatal development. Combined exposure induced two fold higher postnatal mortality than BPA the alone, whereas BPA exposure caused reduced body weight and diminished sperm quality in F1 generation. PMID- 26232257 TI - Evaluation of cII mutations in lung of male Big Blue mice exposed by inhalation to vanadium pentoxide for up to 8 weeks. AB - Chronic inhalation of vanadium pentoxide (V2O5) increases the incidence of alveolar/bronchiolar tumors in male and female B6C3F1 mice at 1, 2, or 4 mg/m(3). The genotoxicity of V2O5 has been extensively investigated in the literature with mixed results. In general, tests for gene mutations have been negative. Both positive and negative results were reported for clastogenicity in vitro with some reports suggesting aneugenic potential. In vivo, V2O5 was negative in the mouse micronucleus test (erythrocyte) and comet assay (lung). Previously, K-ras mutations have been detected in the lung tumors in mice exposed to V2O5. Recently, a short-term inhalation study in B6C3F1 mice reported slight induction of 8-oxodGuo DNA lesions in lungs. Because 8-oxodGuo DNA lesions can lead to gene mutations if not repaired or if misrepaired, we have used groups of transgenic Big Blue (BB) mice (B6C3F1) to test whether V2O5 has mutagenic potential in vivo in the tumor target tissue under the conditions of the bioassay. Groups of six male BB mice were exposed to particulate aerosols containing 0, 0.1, or 1 mg/m(3) (tumorigenic concentration) V2O5 for 4 or 8 weeks (6h/day, 5 days/week) and cII mutant frequencies (MFs) were evaluated in the right lungs. A significant increase in lung weight was noted in mice exposed to 1 mg/m(3) V2O5 (P <= 0.05) compared to sham control, confirming exposure to an inflammatory level of the test material. The mean MFs (* 10(-6)) of mice in the 4-week exposure groups were 30 (sham control), 39 (0.1 mg/m(3)), and 24 (1 mg/m(3)) while the corresponding values in the 8-week exposure groups were 29, 48, and 17, respectively. None of these cII MFs measured at any time point was significantly higher than the corresponding control MFs (P >= 0.1). Overall, these results suggest that mutagenicity is not likely to be an initial key event in the lung tumorigenicity of V2O5. PMID- 26232258 TI - Quantification of Kras mutant fraction in the lung DNA of mice exposed to aerosolized particulate vanadium pentoxide by inhalation. AB - This study investigated whether Kras mutation is an early event in the development of lung tumors induced by inhalation of particulate vanadium pentoxide (VP) aerosols. A National Toxicology Program tumor bioassay of inhaled particulate VP aerosols established that VP-induced alveolar/bronchiolar carcinomas of the B6C3F1 mouse lung carried Kras mutations at a higher frequency than observed in spontaneous mouse lung tumors. Therefore, this study sought to: (1) characterize any Kras mutational response with respect to VP exposure concentration, and (2) investigate the possibility that amplification of preexisting Kras mutation is an early event in VP-induced mouse lung tumorigenesis. Male Big Blue B6C3F1 mice (6 mice/group) were exposed to aerosolized particulate VP by inhalation, 6h/day, 5 days/week for 4 or 8 weeks, using VP exposure concentrations of 0, 0.1, and 1 mg/m(3). The levels of two different Kras codon 12 mutations [GGT -> GAT (G12D) and GGT -> GTT (G12V)] were measured in lung DNAs by Allele-specific Competitive Blocker PCR (ACB-PCR). For both exposure concentrations (0.1 and 1.0mg/m(3)) and both time points (4 and 8 weeks), the mutant fractions observed in VP-exposed mice were not significantly different from the concurrent controls. Given that 8 weeks of inhalation of a tumorigenic concentration of particulate aerosols of VP did not result in a significant change in levels of lung Kras mutation, the data do not support either a direct genotoxic effect of VP on Kras or early amplification of preexisting mutation as being involved in the genesis of VP-induced mouse lung tumors under the exposure conditions used. Rather, the data suggest that accumulation of Kras mutation occurs later with chronic VP exposure and is likely not an early event in VP-induced mouse lung carcinogenesis. PMID- 26232259 TI - Duodenal crypt health following exposure to Cr(VI): Micronucleus scoring, gamma H2AX immunostaining, and synchrotron X-ray fluorescence microscopy. AB - Lifetime exposure to high concentrations of hexavalent chromium [Cr(VI)] in drinking water results in intestinal damage and an increase in duodenal tumors in B6C3F1 mice. To assess whether these tumors could be the result of a direct mutagenic or genotoxic mode of action, we conducted a GLP-compliant 7-day drinking water study to assess crypt health along the entire length of the duodenum. Mice were exposed to water (vehicle control), 1.4, 21, or 180 ppm Cr(VI) via drinking water for 7 consecutive days. Crypt enterocytes in Swiss roll sections were scored as normal, mitotic, apoptotic, karyorrhectic, or as having micronuclei. A single oral gavage of 50mg/kg cyclophosphamide served as a positive control for micronucleus induction. Exposure to 21 and 180 ppm Cr(VI) significantly increased the number of crypt enterocytes. Micronuclei and gamma H2AX immunostaining were not elevated in the crypts of Cr(VI)-treated mice. In contrast, treatment with cyclophosphamide significantly increased numbers of crypt micronuclei and qualitatively increased gamma-H2AX immunostaining. Synchrotron-based X-ray fluorescence (XRF) microscopy revealed the presence of strong Cr fluorescence in duodenal villi, but negligible Cr fluorescence in the crypt compartment. Together, these data indicate that Cr(VI) does not adversely effect the crypt compartment where intestinal stem cells reside, and provide additional evidence that the mode of action for Cr(VI)-induced intestinal cancer in B6C3F1 mice involves chronic villous wounding resulting in compensatory crypt enterocyte hyperplasia. PMID- 26232260 TI - Eating disorders and diabetes mellitus. PMID- 26232261 TI - FGF signaling repertoire of the indirect developing hemichordate Ptychodera flava. AB - Fibroblast growth factors (FGFs) are a group of ligands that play multiple roles during development by transducing signals through FGF receptors (FGFRs) to downstream factors. At least 22 FGF ligands and 4 receptors have been identified in vertebrates, while six to eight FGF ligands and a single FGFR are present in invertebrate chordates, such as tunicates and amphioxus. The chordate FGFs can be categorized into at least seven subfamilies, and the members of which expanded during the evolution of early vertebrates. In contrast, only one FGF and two FGFRs have been found in sea urchins. Thus, it is unclear whether the FGF subfamilies duplicated in the lineage leading to the chordates, or sea urchins lost several fgf genes. Analyses of the FGF signaling repertoire in hemichordates, which together with echinoderms form the closest group to the chordates, may provide insights into the evolution of FGF signaling in deuterostomes. In this study, we identified five FGFs and three FGFRs from Ptychodera flava, an indirect-developing hemichordate acorn worm. Phylogenetic analyses revealed that hemichordates possess a conserved FGF8/17/18 in addition to several putative hemichordate-specific FGFs. Analyses of sequence similarity and protein domain organizations suggested that the sea urchin and hemichordate FGFRs arose from independent lineage-specific duplications. Furthermore, the acorn worm fgf and fgfr genes were demonstrated to be expressed during P. flava embryogenesis. These results set the foundations for further functional studies of FGF signaling in hemichordates and provided insights into the evolutionary history of the FGF repertoire. PMID- 26232262 TI - Potential role for drug-induced sleep endoscopy (DISE) in paediatric OSA. PMID- 26232263 TI - Antipredator strategy of female goitered gazelles (Gazella subgutturosa Guld., 1780) with hiding fawn. AB - In ungulates, predation is often a major cause of infant mortality and likely plays an important role in shaping maternal care strategies that favor progeny survival. The anti-predator strategies of ungulates can be broadly categorized into two groups, hiding infants and following infants. We studied the maternal behavioral strategies of goitered gazelle, which is a typical representative of a hiding species. We found that shortly after birth, goitered gazelle mothers (1) stayed at the greatest distances from their hiding fawns; (2) spent the shortest amount of time together with their fawns, and then only for suckling (during the active phase) which was also the longest inter-suckling intervals (during the hiding phase); (3) kept twins separated in different hiding places and suckled them individually one after the other; (4) changed fawns' hiding places after every active period, travelling with them during the whole suckling bout; (5) oriented their body and muzzle most often toward their hiding young during the fawn's hiding phase; and (6) demonstrated the highest level of vigilance during their approaches to their hiding fawns. The anti-predator strategy of goitered gazelle females was similar to that observed in some North American (Antilocapra americana, Odocoileus hemionus and Odocoileus virginianus) and Eurasian (Dama dama and Capreolus capreolus) ungulate species that also demonstrate hiding behavior. Females of these species live on different continents with disparate environments and different predatory threats, but share anti-predator strategies, which are likely the result of convergent evolution in Bovids and Cervids. PMID- 26232264 TI - A structural comparison of female-male and female-female mounting in Japanese macaques (Macaca fuscata). AB - In certain populations, female Japanese macaques (Macaca fuscata) mount both males and females. Vasey (2007) proposed that female-female sexual mounting in Japanese macaques may be a neutral evolutionary by-product of a purported adaptation, namely, female-male mounting. In this study, we aim to further examine the proposed link between female-male and female-female mounting in Japanese macaques by comparing the structural characteristics that define both forms of mounting. We do so using Eshkol-Wachman Movement Notation (EWMN), a globographic reference system that can be used to describe the position of body segments. No significant differences were observed in the female mounters' positioning of eight different body segments (i.e., lower torso, mid-torso, upper torso, upper arm, lower arm, upper leg, lower leg, and foot) during female-male and female-female mounting. This finding lends support to the conclusion that female-female and female-male mounting are structurally, and thus, evolutionarily, related. PMID- 26232265 TI - Alterations in Spinal Cord Metabolism during Treatment of Neuropathic Pain. AB - Therapeutic options for neuropathic pain have improved over the last 20 years yet still only provide partial relief with numerous side effects. Recently, metabolomics revealed that the concentration of the endogenous metabolite N,N dimethylsphingosine (DMS) is increased in the spinal cord in a model of neuropathic pain. Additionally, it was shown that introduction of DMS to the central nervous system (CNS) resulted in mechanical allodynia. Here, we have examined two compounds; pregabalin (Lyrica(r)), a drug used to treat neuropathic pain, and N-oleoylethanolamine (NOE), an endogenous endocannabinoid-like compound that is known to affect multiple lipid pathways. We found that the concentration of DMS in the spinal cord was not significantly altered upon pregabalin treatment of rats suffering from neuropathic pain. We further explored whether modulating lipid metabolism may impact neuropathic pain by testing NOE as a potential novel therapeutic. PMID- 26232266 TI - Evidence for normal letter-sound integration, but altered language pathways in a case of recovered Landau-Kleffner Syndrome. AB - Landau-Kleffner Syndrome (LKS) is a rare form of acquired aphasia in children, characterized by epileptic discharges, which occur mostly during sleep. After normal speech and language development, aphasia develops between the ages of 3-7 years in a period ranging from days to months. The epileptic discharges usually disappear after reaching adulthood, but language outcomes are usually poor if no treatment focused on restoration of (non-) verbal communication is given. Patients often appear deaf-mute, but sign language, as part of the treatment, may lead to recovery of communication. The neural mechanisms underlying poor language outcomes in LKS are not yet understood. In this detailed functional MRI study of a recovered LKS patient - that is, a patient no longer suffering from epileptic discharges, audiovisual multi-sensory processing was investigated, since LKS patients are often proficient in reading, but not in speech perception. In the recovered LKS patient a large difference in the neural activation to auditory stimuli was found in the left versus the right auditory cortex, which cannot be attributed to hearing loss. Compared to healthy proficient readers investigated earlier with the same fMRI experiment, the patient demonstrated normal letter sound integration in the superior temporal gyrus as demonstrated by the multi sensory interaction index, indicating intact STG function. Diffusion Tensor Imaging (DTI) based fiber tracking in the LKS patient showed fibers originating from Heschl's gyrus that seem to be left-right inverted with respect to HG fiber pattern described in the literature for healthy controls. In the patient, in both hemispheres we found arcuate fibers projecting from (homologues of) Broca's to Wernicke's areas, and a lack of fibers from arcuate left inferior parietal and sylvian areas reported in healthy subjects. We observed short arcuate segments in the right hemisphere. Although speculative, our results suggest intact temporal lobe processing but an altered temporal to frontal connectivity. The altered connectivity might explain observed short-term verbal memory problems, disturbed (speech) sound-motor interaction and online feedback of speech and might be one of the neuronal factors underlying LKS. PMID- 26232267 TI - Effective connectivity in the neural network underlying coarse-to-fine categorization of visual scenes. A dynamic causal modeling study. AB - According to current models of visual perception scenes are processed in terms of spatial frequencies following a predominantly coarse-to-fine processing sequence. Low spatial frequencies (LSF) reach high-order areas rapidly in order to activate plausible interpretations of the visual input. This triggers top-down facilitation that guides subsequent processing of high spatial frequencies (HSF) in lower-level areas such as the inferotemporal and occipital cortices. However, dynamic interactions underlying top-down influences on the occipital cortex have never been systematically investigated. The present fMRI study aimed to further explore the neural bases and effective connectivity underlying coarse-to-fine processing of scenes, particularly the role of the occipital cortex. We used sequences of six filtered scenes as stimuli depicting coarse-to-fine or fine-to coarse processing of scenes. Participants performed a categorization task on these stimuli (indoor vs. outdoor). Firstly, we showed that coarse-to-fine (compared to fine-to-coarse) sequences elicited stronger activation in the inferior frontal gyrus (in the orbitofrontal cortex), the inferotemporal cortex (in the fusiform and parahippocampal gyri), and the occipital cortex (in the cuneus). Dynamic causal modeling (DCM) was then used to infer effective connectivity between these regions. DCM results revealed that coarse-to-fine processing resulted in increased connectivity from the occipital cortex to the inferior frontal gyrus and from the inferior frontal gyrus to the inferotemporal cortex. Critically, we also observed an increase in connectivity strength from the inferior frontal gyrus to the occipital cortex, suggesting that top-down influences from frontal areas may guide processing of incoming signals. The present results support current models of visual perception and refine them by emphasizing the role of the occipital cortex as a cortical site for feedback projections in the neural network underlying coarse-to-fine processing of scenes. PMID- 26232268 TI - Preferred reporting items for studies mapping onto preference-based outcome measures: The MAPS statement. AB - 'Mapping' onto generic preference-based outcome measures is increasingly being used as a means of generating health utilities for use within health economic evaluations. Despite publication of technical guides for the conduct of mapping research, guidance for the reporting of mapping studies is currently lacking. The MAPS (MApping onto Preference-based measures reporting Standards) statement is a new checklist, which aims to promote complete and transparent reporting of mapping studies. The primary audiences for the MAPS statement are researchers reporting mapping studies, the funders of the research, and peer reviewers and editors involved in assessing mapping studies for publication.A de novo list of 29 candidate reporting items and accompanying explanations was created by a working group comprised of six health economists and one Delphi methodologist. Following a two-round, modified Delphi survey with representatives from academia, consultancy, health technology assessment agencies and the biomedical journal editorial community, a final set of 23 items deemed essential for transparent reporting, and accompanying explanations, was developed. The items are contained in a user friendly 23 item checklist. They are presented numerically and categorised within six sections, namely: (i) title and abstract; (ii) introduction; (iii) methods; (iv) results; (v) discussion; and (vi) other. The MAPS statement is best applied in conjunction with the accompanying MAPS explanation and elaboration document.It is anticipated that the MAPS statement will improve the clarity, transparency and completeness of reporting of mapping studies. To facilitate dissemination and uptake, the MAPS statement is being co published by eight health economics and quality of life journals, and broader endorsement is encouraged. The MAPS working group plans to assess the need for an update of the reporting checklist in five years' time.This statement was published jointly in Applied Health Economics and Health Policy, Health and Quality of Life Outcomes, International Journal of Technology Assessment in Health Care, Journal of Medical Economics, Medical Decision Making, PharmacoEconomics, and Quality of Life Research. PMID- 26232269 TI - Clinical usefulness of the ablative margin assessed by magnetic resonance imaging with Gd-EOB-DTPA for radiofrequency ablation of hepatocellular carcinoma. AB - BACKGROUND & AIMS: The aim of this study was to investigate the feasibility of ablative margin (AM) grading by magnetic resonance imaging (MRI) with Gd-EOB-DTPA administered prior to radiofrequency ablation (RFA), and to identify factors for achieving a sufficient AM and predictors for local tumor progression. METHODS: A total of 124 hepatocellular carcinomas (HCCs) were treated by RFA after Gd-EOB DTPA administration. MRI and enhanced CT were performed within seven hours and one month after RFA. The AM assessment was categorized using three grades: AM (+), low-intensity area with continuous high-intensity rim; AM zero, low intensity area with discontinuous high-intensity rim; and AM (-), low-intensity area extends beyond the high-intensity rim. Patients were followed and local tumor progression was observed. RESULTS: AM (+), AM zero, AM (-), and indeterminate were found in 34, 33, 26, and 31 nodules, respectively. The overall agreement rate between MRI and enhanced CT for the diagnosis of AM was 56.8%. The kappa coefficient was 0.326 (p<0.001), indicating moderate agreement. Multivariate logistic regression analysis showed that a significant factor for the achievement of AM (+) on MRI was no contiguous vessels. The cumulative local tumor progression rates (0% at 1, 2, and 3 years) in 33 AM (+) nodules were significantly lower than those (3.6%, 11.5%, and 18.3% at 1, 2, and 3 years respectively) in 32 AM zero nodules. A multivariate Cox proportional hazards model identified tumor size as an independent predictor for local tumor progression. CONCLUSION: Gd-EOB-DTPA-MRI enabled an early assessment of RFA effectiveness in the majority ofHCC nodules. Local tumor progression was not detected in AM (+) nodules during the follow-up. PMID- 26232270 TI - Carboplatin therapeutic monitoring in preterm and full-term neonates. AB - INTRODUCTION: Administration of the most appropriate dose of chemotherapy to neonates is particularly challenging and frequently not standardised based on any scientific rationale. We report the clinical utility of carboplatin therapeutic drug monitoring in preterm and full-term neonates within the first month of life. METHODS: Carboplatin therapeutic monitoring was performed to achieve target drug exposures area under the plasma concentration-time curve (AUC values) in nine preterm and full-term neonates diagnosed with retinoblastoma or neuroblastoma treated over an 8 year period. Carboplatin was administered over 3 days with therapeutic drug monitoring utilised to target cumulative AUC values of 5.2-7.8 mg/ml min. RESULTS: AUC values achieved were within 15% of target values for the individual courses of treatment in all but one patient (12/13 courses of treatment), with dose modifications of up to 215% required to achieve target AUC values, based on initial mg/kg dosing schedules. Carboplatin clearance determined across three consecutive chemotherapy courses in two patients increased from 3.4 to 7.1 ml/min and from 7.2 to 16.5 ml/min, representing increases of 210-230% over several weeks of treatment. Complete remission was observed in 8/9 patients, with no renal toxicity reported and only one patient experiencing ototoxicity. CONCLUSION: The study highlights the benefits of utilising therapeutic drug monitoring to achieve target carboplatin AUC values in preterm and full-term neonates treated within the first few weeks of life, particularly in view of marked increases in drug clearance observed over consecutive chemotherapy courses. In the absence of therapeutic drug monitoring, body-weight based dosing is recommended, with dosing guidance provided for both approaches to inform future treatment. PMID- 26232271 TI - Selection of haplotype variables from a high-density marker map for genomic prediction. AB - BACKGROUND: Using haplotype blocks as predictors rather than individual single nucleotide polymorphisms (SNPs) may improve genomic predictions, since haplotypes are in stronger linkage disequilibrium with the quantitative trait loci than are individual SNPs. It has also been hypothesized that an appropriate selection of a subset of haplotype blocks can result in similar or better predictive ability than when using the whole set of haplotype blocks. This study investigated genomic prediction using a set of haplotype blocks that contained the SNPs with large effects estimated from an individual SNP prediction model. We analyzed protein yield, fertility and mastitis of Nordic Holstein cattle, and used high density markers (about 770k SNPs). To reach an optimum number of haplotype variables for genomic prediction, predictions were performed using subsets of haplotype blocks that contained a range of 1000 to 50 000 main SNPs. RESULTS: The use of haplotype blocks improved the prediction reliabilities, even when selection focused on only a group of haplotype blocks. In this case, the use of haplotype blocks that contained the 20 000 to 50 000 SNPs with the highest effect was sufficient to outperform the model that used all individual SNPs as predictors (up to 1.3 % improvement in prediction reliability for mastitis, compared to individual SNP approach), and the achieved reliabilities were similar to those using all haplotype blocks available in the genome data (from 0.6 % lower to 0.8 % higher reliability). CONCLUSIONS: Haplotype blocks used as predictors can improve the reliability of genomic prediction compared to the individual SNP model. Furthermore, the use of a subset of haplotype blocks that contains the main SNP effects from genomic data could be a feasible approach to genomic prediction in dairy cattle, given an increase in density of genotype data available. The predictive ability of the models that use a subset of haplotype blocks was similar to that obtained using either all haplotype blocks or all individual SNPs, with the benefit of having a much lower computational demand. PMID- 26232273 TI - Patients with multiple GP consultations before cancer diagnosis are less satisfied with care. PMID- 26232272 TI - Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis. AB - BNip3 is a hypoxia-inducible protein that targets mitochondria for autophagosomal degradation. We report a novel tumor suppressor role for BNip3 in a clinically relevant mouse model of mammary tumorigenesis. BNip3 delays primary mammary tumor growth and progression by preventing the accumulation of dysfunctional mitochondria and resultant excess ROS production. In the absence of BNip3, mammary tumor cells are unable to reduce mitochondrial mass effectively and elevated mitochondrial ROS increases the expression of Hif-1alpha and Hif target genes, including those involved in glycolysis and angiogenesis-two processes that are also markedly increased in BNip3-null tumors. Glycolysis inhibition attenuates the growth of BNip3-null tumor cells, revealing an increased dependence on autophagy for survival. We also demonstrate that BNIP3 deletion can be used as a prognostic marker of tumor progression to metastasis in human triple negative breast cancer (TNBC). These studies show that mitochondrial dysfunction caused by defects in mitophagy-can promote the Warburg effect and tumor progression, and suggest better approaches to stratifying TNBC for treatment. PMID- 26232274 TI - A novel set of DIP-STR markers for improved analysis of challenging DNA mixtures. AB - Currently available molecular biology tools allow forensic scientists to characterize DNA evidence found at crime scenes for a large variety of samples, including those of limited quantity and quality, and achieve high levels of individualization. Yet, standard forensic markers provide limited or no results when applied to mixed DNA samples where the contributors are present in very different proportions (unbalanced DNA mixtures). This becomes an issue mostly for the analysis of trace samples collected on the victim or from touched objects. To this end, we recently proposed an innovative type of genetic marker, named DIP STR that relies on pairing deletion/insertion polymorphisms (DIP) with standard short tandem repeats (STR). This novel compound marker allows detection of the minor DNA contributor in a DNA mixture of any gender and cellular origin with unprecedented resolution (beyond a DNA ratio of 1:1000). To provide a novel analytical tool useful in practice to common forensic laboratories, this article describes the first set of 10 DIP-STR markers selected according to forensic technical standards. The novel DIP-STR regions are short (between 146 and 271 bp), include only highly polymorphic tri-, tetra- and pentanucleotide tandem repeats and are located on different chromosomes or chromosomal arms to provide statistically independent results. This novel set of DIP-STR can target the amplification of 0.03-0.1 ng of DNA when mixed with a 1000-fold excess of major DNA. DIP-STR relative allele frequencies are estimated based on a survey of 103 Swiss individuals. Finally, this study provides an estimate of the occurrence of informative alleles and a calculation of the corresponding random match probability of the detected minor DIP-STR genotype assessed across 10,506 pairwise conceptual mixtures. PMID- 26232275 TI - Persistence of DNA from laundered semen stains: Implications for child sex trafficking cases. AB - In sexual assault cases, particularly those involving internal child sex trafficking (ICST), victims often hide their semen-stained clothing. This can result in a lag time of several months before the items are laundered and subsequently seized during a criminal investigation. Although it has been demonstrated previously that DNA can be recovered from clothing washed immediately after semen deposition, laundered items of clothing are not routinely examined in ICST cases, due to the assumption that the time delay and washing would result in no detectable DNA. The aim of this study was to examine whether viable DNA profiles could be recovered from laundered semen stains where there has been a significant lag time between semen deposition from one or more individuals and one or more washes of the stained clothing. Items of UK school uniform (T-shirts, trousers, tights) were stained with fresh semen (either from a single donor or a 1:1 mixture from two donors) and stored in a wardrobe for eight months. Stained and unstained items (socks) were then washed at 30 degrees C or 60 degrees C and with non-biological or biological detergent. DNA samples extracted from the semen-stained sites and from the unstained socks were quantified and profiled. High quantities of DNA, (6-18 MUg) matching the DNA profiles of the semen donors, were recovered from all semen-stained clothing that had been laundered once, irrespective of wash conditions. This quantity,and profile quality,did not decline significantly with multiple washes. The two donor semen samples yielded ~ 10-fold more DNA from the T-shirts than from the trousers. This disparity resulted in the T-shirts yielding a ~ 1:1 mixture of DNA from the two donors, whereas the trousers yielded a major DNA profile matching only that of the second donor. The quantities of DNA recovered from the unstained socks were an order of magnitude lower, with most of the DNA being attributable to the donor of the semen on the stained clothing within the same wash, demonstrating the transfer of semen-derived DNA among items of clothing in the washing machine. This study demonstrates that complete DNA profiles can be obtained from laundered semen stains on school uniform-type clothing, with an eight-month lag time between semen deposition and laundering, despite multiple washes and stains from two semen donors. These data emphasise the need to recover and examine the clothing of victims for semen and DNA evidence, even if the clothing has been stored for several months or washed multiple times since the sexual offence took place. PMID- 26232276 TI - Procedural success of CTO recanalization: Comparison of the J-CTO score determined by coronary CT angiography to invasive angiography. AB - OBJECTIVES: The J-CTO score is based on invasive angiography, combines several parameters of chronic total coronary occlusions (CTO), and is well established to predict the likelihood of success of percutaneous recanalization. The purpose of this study was to evaluate and validate a J-CTOCT score derived from coronary computed tomography angiography (coronary CTA). METHODS: Between April 2011 and December 2014, 159 consecutive patients were retrospectively included. All had at least one CTO in invasive angiography, had coronary CTA performed at an interval of no more than one week from invasive angiography, and had an attempt at percutaneous coronary intervention (PCI) following coronary CTA In parallel to the angiographic J-CTO score, the J-CTOCT score was determined by awarding one point each for a blunt vessel stump, bending > 45 degrees , occlusion length >= 20 mm, presence of calcium covering > 50% of any vessel cross-section within the occlusion, or a previously failed attempt at PCI. a. Both scores were compared regarding their ability to predict successful recanalization. RESULTS: A total of 171 CTO lesions were analyzed. Intraobserver (k = 0.814, p < 0.001) and interobserver agreement (k = 0.771, p < 0.001) for calculation of the J-CTOCT score were close. The mean occlusion length measured by coronary CTA was significantly shorter than in invasive angiography (27.6 +/- 14.8 mm vs. 37.2 +/- 18.8 mm, p < 0.001). The J-CTOCT score (mean: 1.9 +/- 1.4) correlated closely to the angiographic J-CTO score (mean: 1.8 +/- 1.3, r = 0.856, p < 0.001), and in 122/171 lesions (71%), the scores were identical. Both J-CTOCT score (area under curve: 0.882, p < 0.001) and angiographic J-CTO score (area under curve: 0.868, p < 0.001) yielded similarly high predictive value for successful guidewire crossing within 30 min (p = 0.496). CONCLUSIONS: While the length of coronary occlusions in coronary CTA is significantly shorter than in invasive angiography, a J-CTOCT score determined by coronary CTA closely correlates to the angiographic J-CTO score. . PMID- 26232279 TI - Something Blossoms in Between: Silence-Phenomena as a Bordering Notions in Psychology. AB - Mysterious yet unavoidable, silence-phenomena appear to us in inherent ambiguity. In its plurality of meanings, phenomena related to silence are often perceived as overwhelming because they transcend the communicative capacity of language making it a challenge for cultural psychology to understand its involvement in our processes of making sense of experience and existence. Human growth and development involve processes where presence, void and content, voice, sound and noise, motion, transition and stillness, have dialectic interactions. In this article I discuss silence-phenomena as a bordering notion in terms of its discursive quality, the silent quality of speech, and the awareness of the ineffable. In addition, I highlight the possible implications of such notion in the understanding of affect from the perspective of Semiotic Cultural Psychology. I also emphasize the importance of considering psychological borders as multi dimensional, taking the phenomenological experience of temporality as an illustration, which is also related to high emotional involvement of attention. PMID- 26232280 TI - [Hyperuricemia in systemic lupus erythematosus: is it associated with the neuropsychiatric manifestations of the disease?] AB - OBJECTIVES: To assess the association between hyperuricemia and different neuropsychiatric manifestations and stroke risk factors in systematic lupus erythematosus (SLE) patients. METHODS: This study was conducted on 204 SLE patients who were admitted to a tertiary referral center. A standardized questionnaire was completed for all the participants and the medical records were reviewed regarding the occurrence of arterial or venous thrombotic events, stroke, seizure, depression, headache, psychosis, and peripheral neuropathy. In addition blood samples were drawn to obtain serum uric acid, triglyceride (TG), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and total cholesterol levels. RESULTS: Hyperuricemia (serum uric acid >= 6mg/dl for women and >= 7mg/dl for men) was detected in 16.1% of SLE patients and was significantly associated with the occurrence of stroke (OR, 2.38; 95%CI, 1.2-7.24), and peripheral neuropathy (OR, 3.49; 95% CI, 1.52-12.23), independent of hypertension and hyperlipidemia. Hyperuricemia was also significantly associated with hypertension (OR, 7.76; 95% CI, 2.72-15.76), hyperlipidemia (OR, 5.05; 95% CI, 1.59-11.32), and history of arterial thrombosis (OR, 4.95; 95% CI, 1.98-15.34), independent of age and body mass index. CONCLUSIONS: Hyperuricemia in SLE patients is independently associated with the occurrence of stroke and peripheral neuropathy. It is also independently associated with hypertension, hyperlipidemia, and history of arterial thrombosis, which are the major stroke and myocardial infarction risk factors in SLE patients. PMID- 26232277 TI - Recanalization therapies in acute ischemic stroke patients: impact of prior treatment with novel oral anticoagulants on bleeding complications and outcome. AB - BACKGROUND: We explored the safety of intravenous thrombolysis (IVT) or intra arterial treatment (IAT) in patients with ischemic stroke on non-vitamin K antagonist oral anticoagulants (NOACs, last intake <48 hours) in comparison with patients (1) taking vitamin K antagonists (VKAs) or (2) without previous anticoagulation (no-OAC). METHODS AND RESULTS: This is a multicenter cohort pilot study. Primary outcome measures were (1) occurrence of intracranial hemorrhage (ICH) in 3 categories: any ICH (ICHany), symptomatic ICH according to the criteria of the European Cooperative Acute Stroke Study II (ECASS-II) (sICHECASS II) and the National Institute of Neurological Disorders and Stroke (NINDS) thrombolysis trial (sICHNINDS); and (2) death (at 3 months). Cohorts were compared by using propensity score matching. Our NOAC cohort comprised 78 patients treated with IVT/IAT and the comparison groups of 441 VKA patients and 8938 no-OAC patients. The median time from last NOAC intake to IVT/IAT was 13 hours (interquartile range, 8-22 hours). In VKA patients, median pre-IVT/IAT international normalized ratio was 1.3 (interquartile range, 1.1-1.6). ICHany was observed in 18.4% NOAC patients versus 26.8% in VKA patients and 17.4% in no-OAC patients. sICHECASS-II and sICHNINDS occurred in 2.6%/3.9% NOAC patients, in comparison with 6.5%/9.3% of VKA patients and 5.0%/7.2% of no-OAC patients, respectively. At 3 months, 23.0% of NOAC patients in comparison with 26.9% of VKA patients and 13.9% of no-OAC patients had died. Propensity score matching revealed no statistically significant differences. CONCLUSIONS: IVT/IAT in selected patients with ischemic stroke under NOAC treatment has a safety profile similar to both IVT/IAT in patients on subtherapeutic VKA treatment or in those without previous anticoagulation. However, further prospective studies are needed, including the impact of specific coagulation tests. PMID- 26232281 TI - Plaque vulnerability at non-culprit lesions in obese patients with coronary artery disease: Frequency-domain optical coherence tomography analysis. AB - BACKGROUND: Obesity is associated with adverse atherosclerotic cardiovascular events. While various metabolic abnormalities associated with obesity promote plaque formation, the morphological phenotype of atherosclerotic plaque has not been well characterized in the setting of obesity. Frequency-domain optical coherence tomography (FD-OCT) enables in vivo visualization of plaque microstructures associated with vulnerability. We characterized plaque microstructures in obese patients. METHODS: FD-OCT imaging was performed in 308 patients with coronary artery disease undergoing percutaneous coronary intervention. Patients were stratified according to the presence or absence of obesity (body mass index > 30 kg/m(2)). Plaques in obese (n = 129) and non-obese (n = 179) patients were compared with regard to clinical characteristics and FD OCT-derived features of plaque vulnerability. RESULTS: Obese patients were more likely to be younger (p = 0.01), female (p = 0.01) and have a history of hypertension (p = 0.01). Higher levels of triglyceride (p < 0.0001) and glucose (p = 0.02), whereas a lower level of high-density lipoprotein cholesterol (HDL-C) (p = 0.02) was observed in obese patients. FD-OCT imaging demonstrated thinner fibrous caps (85.3 +/- 31.1 vs 110.1 +/- 32.4 um, p = 0.01) and a higher prevalence of thin-cap fibroatheroma (28.8 vs 14.3%, p = 0.01) in obese patients, which remained significant after controlling for differences in clinical characteristics. Achieving a low-density lipoprotein cholesterol (LDL-C) level < 1.8 mmol/l was associated with thicker fibrous caps in obese patients, but only to the level observed in non-obese patients with suboptimal lipid control. CONCLUSIONS: Obese patients harbor more vulnerable plaques in association with atherogenic risk factors. The limited benefit of lipid control suggests the need to adopt novel anti-atherosclerotic strategies in higher-risk patients. PMID- 26232282 TI - Removal of mercury from aqueous solution using mesoporous silica nanoparticles modified with polyamide receptor. AB - Based on the principle of supramolecular recognition and fluorescent chemical sensors, a novel kind of material for the separation of toxic heavy metal ions was designed and synthesized. Mesoporous silica nanoparticles MCM-41 with high surface areas and large ordered pores were used as the supporting matrix. Poly amide derivative, was grafted to the mesoporous silica nanoparticles for extracting and separating trace Hg(2+) from aqueous solution, with a short adsorption time (t=3min) and a wide range of pH application (pH 3-11). The separation material could also extract trace mercury from Traditional Chinese Medicine, and has no influence on their effective components. PMID- 26232283 TI - Novel reduced graphene oxide wrapped Bi2.38Mo0.81O6 microspheres for highly efficient visible light photocatalysis. AB - Novel reduced graphene oxide (RGO) wrapped Bi2.38Mo0.81O6 (Bi2.38Mo0.81O6@RGO) composites were successfully synthesized via a facile method. The morphology, structure and photocatalytic performance of the composites in the degradation of Rhodamine B (RhB) and phenol were characterized by scanning electron microscopy, X-ray diffraction, nitrogen adsorption-desorption, UV-vis absorption spectroscopy and electrochemical impedance spectra, respectively. The results show that the Bi2.38Mo0.81O6@RGO composites exhibit enhanced photocatalytic performance in the degradation of RhB and phenol with maximum degradation rates of 99% (80min) and 88% (240min) under visible light irradiation, respectively. The improved photocatalytic performance is mainly ascribed to the enhanced light absorption and the reduced electron-hole pair recombination with the presence of RGO in the composites. PMID- 26232284 TI - How colloid-colloid interactions and hydrodynamic effects influence the percolation threshold: A simulation study in alumina suspensions. AB - The percolation behavior of alumina suspensions is studied by computer simulations. The percolation threshold phic is calculated, determining the key factors that affect its magnitude: the strength of colloid-colloid attraction and the presence of hydrodynamic interactions (HIs). To isolate the effects of HIs, we compare the results of Brownian Dynamics, which do not include hydrodynamics, with those of Stochastic Rotation Dynamics-Molecular Dynamics, which include hydrodynamics. Our results show that phic decreases with the increase of the attraction between the colloids. The inclusion of HIs always leads to more elongated structures during the aggregation process, producing a sizable decrease of phic when the colloid-colloid attraction is not too strong. On the other hand, the effects of HIs on phic tend to become negligible with increasing attraction strength. Our phic values are in good agreement with those estimated by the yield stress model by Flatt and Bowen. PMID- 26232285 TI - The utility of presentation and 4-hour high sensitivity troponin I to rule-out acute myocardial infarction in the emergency department. AB - OBJECTIVES: International guidance recommends that early serial sampling of high sensitivity troponin be used to accurately identify acute myocardial infarction (AMI) in chest pain patients. The background evidence for this approach is limited. We evaluated whether on presentation and 4-hour high-sensitivity troponin I (hs-cTnI) could be used to accurately rule-out AMI. DESIGN AND METHODS: hs-cTnI was measured on presentation and at 4-hours in adult patients attending an emergency department with possible acute coronary syndrome. We determined the sensitivity for AMI for at least one hs-cTnI above the 99th percentile for a healthy population or alone or in combination with new ischemic ECG changes. Both overall and sex-specific 99th percentiles were assessed. Patients with negative tests were designated low-risk. RESULTS: 63 (17.1%) of 368 patients had AMI. The median (interquartile range) time from symptom onset to first blood sampling was 4.8h (2.8-8.6). The sensitivity of the presentation and 4h hs-cTnI using the overall 99th percentile was 92.1% (95% CI 82.4% to 97.4%) and negative predictive value 95.4% (92.3% to 97.4%) with 78.3% low-risk. Applying the sex-specific 99th percentile did not change the sensitivity. The addition of ECG did not change the sensitivity. CONCLUSION: Hs-cTnI >99th percentile thresholds measured on presentation and at 4-hours was not a safe strategy to rule-out AMI in this clinical setting irrespective of whether sex specific 99th percentiles were used, or whether hs-cTnI was combined with ECG results. PMID- 26232286 TI - KDIGO 2012 Clinical Practice Guideline CKD classification rules out creatinine clearance 24 hour urine collection? AB - OBJECTIVES: The recent guideline for the evaluation and management of Chronic Kidney Disease recommends assessing GFR employing equations based on serum creatinine; despite this, creatinine clearance 24-hour urine collection is used routinely in many settings. In this study we compared the classification assessed from CrCl (creatinine clearance 24h urine collection) and e-GFR calculated with CKD-EPI or MDRD formulas. DESIGN AND METHODS: In this retrospective study we analyze consecutive laboratory data: creatinine clearance 24h urine collection, serum creatinine and demographic data such as sex and age from 15,777 patients >18 years of age collected from 2011 to 2013 in our laboratory at Careggi Hospital. The results were then compared to the estimated GFR calculated with the equations according to the recent treatment guidelines. Consecutive and retrospective laboratory data (creatinine clearance 24h urine collection, serum creatinine and, demographic data such as sex and age) from 15,777 patients >18 years of age seen at Careggi Hospital were collected. RESULTS: Comparison between e-GFR calculated with CKD-EPI or MDRD formulas and GFR according CrCl determinations and bias [95% CI] were 11.34 [-47,4/70.1] and 11.4 [-50.2/73] respectively. The concordance for 18/65 years aged group when compared with e-GFR classification between MDRD vs CKDEPI, MDRD vs CrCl and CKD-EPI vs CrCl were 0.78, 0.34, and 0.41 respectively, while in the 65/110years aged group the concordance Kappas were 0.84, 0.38, and 0.36 respectively. CONCLUSIONS: The use of CrCl provides a different classification than the estimation of GFR using a prediction equation. The CrCl is unreliable when it is necessary to identify CKD subjects with decrease of GFR of 5ml/min/1.73m(2)/year. PMID- 26232287 TI - Multicentric evaluation of eight glucose and four ketone blood meters. AB - OBJECTIVES: High precision meters for blood glycemia are mandatory for monitoring glucose status in patients, avoiding both hypo- and hyper-glycemia. Health care providers routinely used in both out- and in-patients point-of-care measurements of glucose and ketone. These measurements, frequently used for medical decisions, are known to be less accurate than those performed in laboratories. Our aim was to evaluate, within the frame of an Assistance Publique-Hopitaux de Paris (AP-HP) multicentric study, the performances of eight glucose and four ketone meters, either connected or non-connected to a laboratory software. DESIGN AND METHODS: Glucose meter accuracy, precision, correlation with plasma glucose determined in central laboratories and hematocrit interferences were determined according to the ISO 15197:2003 norm. The same norm was applied for the determination of accuracy, precision and recovery of ketone meters for B-hydroxybutyrate measurements. RESULTS AND CONCLUSION: Among those meters, seven were considered as acceptable for glucose measurement and two for ketone measurement. Since all meters do not fit clinically relevant criteria, meters' performances have to be evaluated before use in clinical practice. PMID- 26232288 TI - Plasma concentrations of novel cardiac biomarkers before and after hemodialysis session. AB - OBJECTIVES: Biomarkers are useful for establishing disease severity or prognosis in patients with chronic kidney disease. The aim of our study was to determine the plasma concentrations of novel cardiovascular biomarkers in patients on chronic hemodialysis in the context of published upper reference limits (URL) of these biomarkers; and to compare the plasma concentrations of those same analytes before and after hemodialysis session. DESIGN AND METHODS: Plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-A-type natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C terminal pro-endothelin-1 (CT-proET-1), C-terminal pro-arginine vasopressin (CT proAVP, also known as Copeptin) and soluble ST2 (sST2) were measured in 28 patients before and after dialysis session. Of the 28 patients with conventional hemodialysis, 24 had low-flux hemofiltration and 4 had high-flux hemodiafiltration. RESULTS: Median plasma concentrations of the biomarkers obtained before hemodialysis were as follows: NT-proBNP, 11,307ng/L (URL, 500ng/L); MR-proANP, 778pmol/L (URL, 250pmol/L); MR-proADM, 2.57nmol/L (URL, 0.52nmol/L); median CT-proET-1, 252pmol/L (URL, 75pmol/L); median CT-proAVP, 142pmol/L (URL, 19pmol/L); and median sST2, 27ng/mL (URL, 50ng/mL). Median relative analyte changes after low-flux vs. high-flux dialysis compared to predialysis values were +19% vs. -43% for NT-proBNP; +7% vs. -45% for MR-proANP; 2% vs. -63% for MR-proADM; -19% vs. -61% for CT-proET-1; +13% vs. -64% for CT proAVP; and +2% vs. +3% for sST2. CONCLUSIONS: Plasma concentrations of the investigated biomarkers were markedly increased in chronic hemodialysis patients (with the exception of sST2). After hemodialysis session, analyte concentrations (with the exception of sST2) decreased significantly using a high-flux membrane but not if using a low-flux membrane. PMID- 26232289 TI - Erratum to: Potential relationship between single nucleotide polymorphisms used in forensic genetics and diseases or other traits in European population. PMID- 26232291 TI - Standing for two hours a day may benefit heart health, study finds. PMID- 26232290 TI - Dental age estimation in living individuals using 3.0 T MRI of lower third molars. AB - In order to increase the validity of age estimation in adolescents and young adults when there is no legitimation for X-ray examinations, it seems desirable to be able to assess the mineralization of third molars using X-ray-free imaging procedures. In the present study, the mineralization stages of lower third molars were determined prospectively in 269 male and 248 female individuals aged 12 to 24 years using 3.0 T MRI. The classification system of Demirjian et al. was used to determine the stages. This study presents the minima and maxima, means and standard deviations, median values, and lower and upper quartiles separately for both sexes, for the mineralization stages B-H. Statistically significant sex differences were observed for the mineralization stages C, E, F, and G, and a faster developmental rate was observed for males. It was concluded that magnetic resonance imaging is an X-ray-free alternative to orthopantomography when assessing mineralization of third molars. PMID- 26232292 TI - Fabry's disease: an example of cardiorenal syndrome type 5. AB - Cardiorenal syndrome type 5 (CRS-5) includes conditions where there is a simultaneous involvement of the heart and kidney from a systemic disorder. This is a bilateral organ cross talk. Fabry's disease (FD) is a devastating progressive inborn error of metabolism with lysosomal glycosphingolipid deposition in variety of cell types, capillary endothelial cells, renal, cardiac and nerve cells. Basic effect is absent or deficient activity of lysosomal exoglycohydrolase a-galactosidase A. Renal involvement consists of proteinuria, isosthenuria, altered tubular function, presenting in second or third decade leading to azotemia and end-stage renal disease in third to fifth decade mainly due to irreversible changes to glomerular, tubular and vascular structures, especially highlighted by podocytes foot process effacement. Cardiac involvement consists of left ventricular hypertrophy, right ventricular hypertrophy, arrhythmias (sinus node and conduction system impairment), diastolic dysfunction, myocardial ischemia, infarction, transmural replacement fibrosis, congestive heart failure and cardiac death. Management of FD is based on enzymatic replacement therapy and control of renal (with anti-proteinuric agents such as angiotensin-converting enzyme inhibitors-and/or angiotensin II receptor blockers), brain (coated aspirin, clopidogrel and statin to prevent strokes) and heart complications (calcium channel blockers for ischemic cardiomyopathy, warfarin and amiodarone or cardioverter device for arrhythmias). PMID- 26232293 TI - Effective Coordination and Management of Emerging Infectious Diseases in Wildlife Populations. AB - A transdisciplinary, One Health approach is proposed for the coordination of wildlife health diagnostics, research, and policy development. In some countries, considerable effort has been made to establish specific activities including surveillance and integration of wildlife health within diagnostic and research laboratories. We suggest that some of these activities can be improved and many countries still require national structures to deal with wildlife disease investigation and management. We also suggest that scientists in this field should actively engage with national and international organizations and conferences to influence the development of policy, diagnostics, research, and management of emerging wildlife diseases. PMID- 26232296 TI - ERRATUM. PMID- 26232295 TI - Mental Health Help Seeking Among Traumatized Individuals: A Systematic Review of Studies Assessing the Role of Substance Use and Abuse. AB - OBJECTIVE: Prior research has suggested that competing neurobehavioral decision making processes might affect health outcomes among traumatized populations. Regulatory imbalances to impulsive and executive decision systems are affected by high levels of stress, including stress resulting from traumatic events. Such regulatory imbalances have been associated with addictive behaviors. However, it is not well known whether addictive behavior increases or decreases the likelihood of utilization of behavioral health services among traumatized populations. The aim of this study is to systematically review mental health utilization studies targeting traumatized populations to determine the direction of association between substance use and behavioral health utilization. METHOD: Databases of literature were searched in a systematic manner, and 37 relevant studies were recovered and analyzed. FINDINGS: Of the 37 relevant studies that included addictive behaviors as a predictor of utilization, 16 showed a positive significant relationship and 6 showed a negative significant relationship. Studies showing a negative significant relationship used younger samples with more recent trauma exposure. CONCLUSION: Studies have shown that for the most part, substance abuse increases the likelihood of utilization, except among younger populations with more recent trauma. Longitudinal studies that access how utilization evolves over time among traumatized populations and interacts with posttraumatic stress disorder (PTSD) and substance abuse severity are necessary to better understand how decision-making processes of traumatized individuals may increase the likelihood of chronic PTSD. PMID- 26232297 TI - First cases of pyridoxine-dependent epilepsy in Bulgaria: novel mutation in the ALDH7A1 gene. AB - Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder characterized by intractable seizures in neonates and infants. The seizures cannot be controlled with antiepileptic medications but respond both clinically and electrographically to large daily supplements of pyridoxine (vitamin B6). PDE is caused by mutations in the ALDH7A1 gene. Molecular genetic analysis of the ALDH7A1 gene was performed in seven patients, referred with clinical diagnosis of PDE. Mutations were detected in a dizygotic twin pair and a non-related boy with classical form of PDE. Direct sequencing of the ALDH7A1 gene revealed one novel (c.297delG, p.Trp99*) and two already reported (c.328C>T, p.Arg110*; c.584A>G, p.Asn195Ser) mutations. Here, we report the first genetically proven cases of PDE in Bulgaria. PMID- 26232299 TI - The H2S-generating enzymes cystathionine beta-synthase and cystathionine gamma lyase play a role in vascular development during normal lung alveolarization. AB - The gasotransmitter hydrogen sulfide (H2S) is emerging as a mediator of lung physiology and disease. Recent studies revealed that H2S administration limited perturbations to lung structure in experimental animal models of bronchopulmonary dysplasia (BPD), partially restoring alveolarization, limiting pulmonary hypertension, limiting inflammation, and promoting epithelial repair. No studies have addressed roles for endogenous H2S in lung development. H2S is endogenously generated by cystathionine beta-synthase (Cbs) and cystathionine gamma-lyase (Cth). We demonstrate here that the expression of Cbs and Cth in mouse lungs is dynamically regulated during lung alveolarization and that alveolarization is blunted in Cbs(-/-) and Cth(-/-) mouse pups, where a 50% reduction in the total number of alveoli was observed, without any impact on septal thickness. Laser capture microdissection and immunofluorescence staining indicated that Cbs and Cth were expressed in the airway epithelium and lung vessels. Loss of Cbs and Cth led to a 100-500% increase in the muscularization of small- and medium-sized lung vessels, which was accompanied by increased vessel wall thickness, and an apparent decrease in lung vascular supply. Ablation of Cbs expression using small interfering RNA or pharmacological inhibition of Cth using propargylglycine in lung endothelial cells limited angiogenic capacity, causing a 30-40% decrease in tube length and a 50% decrease in number of tubes formed. In contrast, exogenous administration of H2S with GYY4137 promoted endothelial tube formation. These data confirm a key role for the H2S-generating enzymes Cbs and Cth in pulmonary vascular development and homeostasis and in lung alveolarization. PMID- 26232298 TI - Animal Models of Speech and Vocal Communication Deficits Associated With Psychiatric Disorders. AB - Disruptions in speech, language, and vocal communication are hallmarks of several neuropsychiatric disorders, most notably autism spectrum disorders. Historically, the use of animal models to dissect molecular pathways and connect them to behavioral endophenotypes in cognitive disorders has proven to be an effective approach for developing and testing disease-relevant therapeutics. The unique aspects of human language compared with vocal behaviors in other animals make such an approach potentially more challenging. However, the study of vocal learning in species with analogous brain circuits to humans may provide entry points for understanding this human-specific phenotype and diseases. We review animal models of vocal learning and vocal communication and specifically link phenotypes of psychiatric disorders to relevant model systems. Evolutionary constraints in the organization of neural circuits and synaptic plasticity result in similarities in the brain mechanisms for vocal learning and vocal communication. Comparative approaches and careful consideration of the behavioral limitations among different animal models can provide critical avenues for dissecting the molecular pathways underlying cognitive disorders that disrupt speech, language, and vocal communication. PMID- 26232301 TI - Smart imaging of acute lung injury: exploration of myeloperoxidase activity using in vivo endoscopic confocal fluorescence microscopy. AB - The pathophysiology of acute lung injury (ALI) is well characterized, but its real-time assessment at bedside remains a challenge. When patients do not improve after 1 wk despite supportive therapies, physicians have to consider open lung biopsy (OLB) to identify the process(es) at play. Sustained inflammation and inadequate repair are often observed in this context. OLB is neither easy to perform in a critical setting nor exempt from complications. Herein, we explore intravital endoscopic confocal fluorescence microscopy (ECFM) of the lung in vivo combined with the use of fluorescent smart probe(s) activated by myeloperoxidase (MPO). MPO is a granular enzyme expressed by polymorphonuclear neutrophils (PMNs) and alveolar macrophages (AMs), catalyzing the synthesis of hypoclorous acid, a by-product of hydrogen peroxide. Activation of these probes was first validated in vitro in relevant cells (i.e., AMs and PMNs) and on MPO-non-expressing cells (as negative controls) and then tested in vivo using three rat models of ALI and real-time intravital imaging with ECFM. Semiquantitative image analyses revealed that in vivo probe-related cellular/background fluorescence was associated with corresponding enhanced lung enzymatic activity and was partly prevented by specific MPO inhibition. Additional ex vivo phenotyping was performed, confirming that fluorescent cells were neutrophil elastase(+) (PMNs) or CD68(+) (AMs). This work is a first step toward "virtual biopsy" of ALI without OLB. PMID- 26232300 TI - Experimental progressive emphysema in BALB/cJ mice as a model for chronic alveolar destruction in humans. AB - Emphysema, one of the major components of chronic obstructive pulmonary disease (COPD), is characterized by the progressive and irreversible loss of alveolar lung tissue. Even though >80% of COPD cases are associated with cigarette smoking, only a relatively small proportion of smokers develop emphysema, suggesting a potential role for genetic factors in determining individual susceptibility to emphysema. Although strain-dependent effects have been shown in animal models of emphysema, the molecular basis underlying this intrinsic susceptibility is not fully understood. In this present study, we investigated emphysema development using the elastase-induced experimental emphysema model in two commonly used mouse strains, C57BL/6J and BALB/cJ. The results demonstrate that mice with different genetic backgrounds show disparate susceptibility to the development of emphysema. BALB/cJ mice were found to be much more sensitive than C57BL/6J to elastase injury in both a dose-dependent and time-dependent manner, as measured by significantly higher mortality, greater body weight loss, greater decline in lung function, and a greater loss of alveolar tissue. The more susceptible BALB/cJ strain also showed the persistence of inflammatory cells in the lung, especially macrophages and lymphocytes. A comparative gene expression analysis following elastase-induced injury showed BALB/cJ mice had elevated levels of il17A mRNA and a number of classically (M1) and alternatively (M2) activated macrophage genes, whereas the C57BL/6J mice demonstrated augmented levels of interferon-gamma. These findings suggest a possible role for these cellular and molecular mediators in modulating the severity of emphysema and highlight the possibility that they might contribute to the heterogeneity observed in clinical emphysema outcomes. PMID- 26232302 TI - Prediction of Postoperative Complications Using Multidimensional Frailty Score in Older Female Cancer Patients with American Society of Anesthesiologists Physical Status Class 1 or 2. AB - BACKGROUND: Even low-risk, elderly patients are at increased risk for postoperative morbidity compared with their younger counterparts. We sought to evaluate the role of a scoring model in predicting adverse surgical outcomes in low-risk, older, female cancer patients. STUDY DESIGN: From October 2011 to May 2014, two hundred and eighty-one low-risk female patients (aged 65 years and older, American Society of Anesthesiologists class 1 or 2) undergoing curative cancer surgery were included. The Multidimensional Frailty Score (MFS) was calculated by comprehensive geriatric assessment. The primary end point was postoperative complication (eg, pneumonia, urinary tract infection, delirium, acute pulmonary thromboembolism, and unplanned ICU admission). Secondary outcomes were length of hospital stay and institutionalization. RESULTS: Twenty patients experienced postoperative complications and 15 patients were discharged to nursing facilities. The fully adjusted odds ratio (OR) per 1-point increase in MFS was 1.412 (95% CI, 1.012-1.969; p = 0.042) for postoperative complications, 1.377 (95% CI, 0.935-2.026; p = 0.105) for institutionalization, and 1.411 (95% CI, 1.110-1.793; p = 0.005) for prolonged hospital stay. The high-risk group (MFS >=7) showed an increased risk for postoperative complications (OR = 8.513; 95% CI, 2.210-32.785; p = 0.002), institutionalization (OR = 1.291; 95% CI, 0.324 5.152; p = 0.717), and prolonged hospital stay (OR = 2.336; 95% CI, 1.090-5.006; p = 0.029) compared with the low-risk group (MFS <7), after adjusting confounders. CONCLUSIONS: Multidimensional Frailty Score based on a preoperative comprehensive geriatric assessment is useful for predicting postoperative complications and prolonged hospital stay, even in low-risk elderly women who are undergoing cancer surgery. PMID- 26232303 TI - Impact of Neoadjuvant Chemotherapy on Hypertrophy of the Future Liver Remnant after Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy. AB - BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been demonstrated as a feasible procedure in extended liver resections as a means of successfully increasing the volume of the future liver remnant (FLR). Neoadjuvant chemotherapy (CTx) is toxic to the organ and may impair hepatic regeneration. This study was performed to assess the procedure's effect on hypertrophy of the FLR, including the short-term survival. STUDY DESIGN: We analyzed 19 consecutive ALPPS patients, of whom 58% (n = 11) received neoadjuvant CTx because of colorectal liver metastasis (CRM). Patients presented with multifocal CRM (n = 11, 58%); cholangiocarcinoma (n = 7, 37%), of which 5 were in the Klatskin position; and gallbladder carcinoma (n = 1, 5%). Hepatectomy was performed within 6 to 13 days after hepatic partition. Volumetry was performed before both liver partitioning and hepatectomy. A survival analysis was performed. RESULTS: Liver partition and portal vein ligation induced sufficient hypertrophy of the FLR, with an increased volume of 74% +/- 35%. Patients underwent hepatectomy after a median of 8 days; in all cases R0 resection was achieved. Neoadjuvant CTx was shown to significantly impair hypertrophy. The volume of the FLR in non-CTx patients increased by 98% +/- 35%; an increase of 59% +/- 22% was observed in patients who underwent CTx (p = 0.027). Chemotherapy did not have an impact on either morbidity or in-hospital mortality, which were 68% and 16%, respectively. One-year overall survival was 53%, with a 1-year survival of 67% in CRM patients and 38% in non-CRM patients (p > 0.05). CONCLUSIONS: Data presented here demonstrate for the first time that neoadjuvant CTx significantly impairs hypertrophy of the FLR after ALPPS. PMID- 26232304 TI - Trauma Surge Index: Advancing the Measurement of Trauma Surges and Their Influence on Mortality. AB - BACKGROUND: Increases in trauma patient volume and acuity, such as during mass casualty events, can overwhelm hospitals, potentially worsening patient outcomes. Due to methodological limitations, the effect of trauma surges on clinical outcomes remains unclear, so hospitals have not prepared for such events in an evidence-based manner. The objective of this study was to develop a new measure of hospital capacity strain corresponding to trauma admissions and to examine the relationship between trauma surges and inpatient mortality. STUDY DESIGN: Using trauma registry data from hospitals across the United States and Canada (2010 to 2011), we developed the Trauma Surge Index (TSI), a measure of capacity strain that controls for variation in hospital admission volume and patient acuity. Using the TSI and an established definition of mass casualty events, we quantified hospital surges and entered each measure as an exposure variable in separate risk-adjusted mortality models. RESULTS: Using the TSI method, we observed that patients admitted during high-surge periods display significantly increased mortality compared with patients admitted during low-surge periods (odds ratio [OR] = 2.05; 95% CI, 1.36-3.10), and patients with firearms injuries were particularly at risk (OR = 7.29; 95% CI, 2.13-24.91). Using mass casualty event criteria, we found no difference between the mortality of patients admitted during trauma surges and nonsurge periods (OR = 0.94; 95% CI, 0.88-1.01). CONCLUSIONS: We demonstrate the TSI, which is a novel method that identified periods of high-capacity strain in hospitals associated with increased trauma patient mortality. Our newly developed TSI method can be implemented by hospitals and trauma systems to examine periods of high-capacity strain retrospectively, identify specific resources that might have been needed, and better direct future investments in an evidence-based manner. PMID- 26232305 TI - Development of an ELISA-Based HDAC Activity Assay for Characterization of Isoform Selective Inhibitors. AB - Histone deacetylase (HDAC) proteins are promising targets for cancer treatment, with several HDAC inhibitors used clinically as anticancer drugs. Most HDAC inhibitors nonspecifically interact with all or many of the 11 HDAC isoforms. Isoform-selective HDAC inhibitors would be useful tools to dissect the individual functions of HDAC proteins in cancer formation, in addition to potentially displaying effective anticancer properties. We report here a robust HDAC activity assay for screening selective HDAC inhibitors, which is inspired by the traditional enzyme-linked immunosorbent assay (ELISA). The key feature of the ELISA-based HDAC activity assay is use of mammalian cell-derived HDAC isoforms instead of recombinant proteins. Importantly, the assay was validated with several known HDAC inhibitors. The ELISA-based HDAC activity assay will facilitate the characterization of isoform-selective HDAC inhibitors against mammalian cell-derived HDAC proteins, which will enhance HDAC-centered cancer research and provide a foundation for anticancer drug development. PMID- 26232307 TI - Intradermal Melanoma Associated With an Intradermal Melanocytic Nevus. PMID- 26232306 TI - Phenotyping and follow up of forty-seven Iranian patients with common variable immunodeficiency. AB - BACKGROUND: Common variable immune deficiency (CVID) is a heterogeneous syndrome with a wide variety of signs and symptoms. This study describes the phenotyping and survival of the CVID patients in the allergy and clinical immunology department of Rasol-E-Akram Hospital of Iran University of Medical Sciences in Tehran. METHOD: We retrospectively reviewed hospital files of CVID patients in our department until January 2014. All patients were diagnosed with standard diagnostic criteria of CVID, treated and visited monthly, during the follow-up period. We divided the patients into four phenotypes; infection only, cytopenia, polyclonal lymphocytic infiltration and unexplained enteropathy. The immunologic, demographic and clinical findings in different phenotypes were analysed. RESULTS: The study included 47 CVID patients with mean age at onset of symptoms and diagnosis of 11.2 and 20.2 years, respectively. Phenotyping of our patients was: only infection (62%), cytopenia (26%) and PLI (19%) and 94% of cases had only one phenotype. We did not find a significant relation between the clinical phenotypes and immunologic or demographic data. Rate of parental consanguinity in our cases was 47%. Parental consanguinity was related to lower age at onset, lower age at diagnosis and higher baseline IgG levels. Patients with malignancy and autoimmunity had significantly higher age at onset. Our patients were followed-up for 6.9 years and the mortality rate during this time was 6%. CONCLUSIONS: Parental consanguinity and age at onset of CVID symptoms may have important roles in CVID manifestations. PMID- 26232308 TI - Mixed Connective Tissue Disease in a Patient With Castleman Disease and Hodgkin Lymphoma: Excellent Clinical Response to Rituximab. PMID- 26232309 TI - Hand-Foot Skin Reaction to Regorafenib. PMID- 26232310 TI - Geographic Variation in Characteristics of Postpartum Women Using Female Sterilization. AB - BACKGROUND: Southern states have higher rates of female sterilization compared with other areas of the United States, and the reasons for this are not well understood. We examined whether low-income and racial/ethnic minority women, who were previous targets of coercive practices, disproportionately report using sterilization in the South. METHODS: We used data from 12 states participating in the Pregnancy Risk Assessment Monitoring System that collected information on women's contraceptive method use between 2006 and 2009. We categorized states according to geographic region: South, Midwest/West, and Northeast. Within each region, we computed the percentage of women using sterilization according to their demographic and obstetric characteristics and estimated multivariable adjusted prevalence ratios to evaluate whether the same characteristics were associated with sterilization use. FINDINGS: The percentage of postpartum women using sterilization ranged from 5.0% to 9.9% in the Northeast, 8.9% to 10.6% in the Midwest/West, and 11.6% to 22.4% in the South. Women in nearly all subgroups in Southern states were more likely to use sterilization than women in the Northeast. After multivariable adjustment, there were no differences in the prevalence of sterilization for Blacks compared with Whites in the Northeast (0.76; 95% CI, 0.55-1.06), Midwest/West (0.91; 95% CI, 0.80-1.04), and South (0.96; 95% CI, 0.85-1.07). Women with Medicaid-paid deliveries (vs. private insurance) had a higher prevalence of sterilization in all regions (p < .05). CONCLUSIONS: These findings do not indicate that low-income and racial/ethnic minority women in the South use sterilization at disproportionately higher rates compared with other regions, and suggest that other differences, such as social norms and family planning policies, may contribute to this geographic variation. PMID- 26232312 TI - [Not Available]. PMID- 26232311 TI - 2-Litre polyethylene glycol-citrate-simethicone plus bisacodyl versus 4-litre polyethylene glycol as preparation for colonoscopy in chronic constipation. AB - BACKGROUND: Chronic constipation is a risk factor of inadequate bowel preparation for colonoscopy; however, no large clinical trials have been performed in this subgroup of patients. AIMS: To compare bowel cleansing efficacy, tolerability and acceptability of 2-L polyethylene-glycol-citrate-simethicone (PEG-CS) plus 2-day bisacodyl (reinforced regimen) vs. 4-L PEG in patients with chronic constipation undergoing colonoscopy. METHODS: Randomized, observer-blind, parallel group study. Adult outpatients undergoing colonoscopy were randomly allocated to 2-L PEG-CS/bisacodyl or 4-L PEG, taken as split regimens before colonoscopy. Quality of bowel preparation was assessed by the Ottawa Bowel Cleansing Scale (OBCS). The amount of foam/bubble interfering with colonic visualization was also measured. RESULTS: 400 patients were enrolled. There was no significant difference in successful cleansing (OBCS score <=6): 80.2% in the 2-L PEG-CS/bisacodyl vs. 81.4% in the 4-L PEG group. Significantly more patients taking 2L PEG CS/bisacodyl showed no or minimal foam/bubbles in all colonic segments (80% vs. 63%; p<0.001). 2-L PEG-CS/bisacodyl was significantly more acceptable for ease of administration (p<0.001), willingness to repeat (p<0.001) and showed better compliance (p=0.002). CONCLUSION: Split 2-L PEG-CS plus bisacodyl was not superior to split 4-L PEG for colonoscopy bowel cleansing in patients with chronic constipation; however, it performed better than the standard regimen in terms of colonic mucosa visualization, patient acceptance and compliance. PMID- 26232313 TI - Lessons Learned From Using Focus Groups to Refine Digital Interventions. AB - There is growing interest in applying novel eHealth approaches for the prevention and management of various health conditions, with the ultimate goal of increasing positive patient outcomes and improving the effectiveness and efficiency of health services delivery. Coupled with the use of innovative approaches is the possibility for adverse outcomes, highlighting the need to strategically refine digital practices prior to implementation with patients. One appropriate method for modification purposes includes focus groups. Although it is a well established method in qualitative research, there is a lack of guidance regarding the use of focus groups for digital intervention refinement. To address this gap, the purpose of our paper is to highlight several lessons our research team has learned in using focus groups to help refine digital interventions prior to use with patients. PMID- 26232314 TI - [Are extensive fields useful for radiotherapy of esophageal cancer?]. AB - PURPOSE: Study of the pattern of relapse for locally advanced oesophageal cancer and analysis of the local recurrences according to irradiated volume. PATIENTS AND METHODS: We performed a monocentric retrospective study of patients treated in the integrated centre of oncology (Angers, France). Two treatment strategies were used: concurrent chemoradiation alone or followed by surgery. Recurrences were classified as: locoregional, either isolated or associated with distant metastasis, and metastatic only. Locoregional relapses were subclassified as in field, out-field, or mixed. RESULTS: Between March 2004 and October 2011, 168 patients were treated: 130 by chemoradiation, and 38 by chemoradiation followed by surgery. The median supero-inferior margins added to the gross tumour volume in order to create the planning tumour volume was 5cm (range: 0.5-21). Sixty-two percent of patients (n=104) relapsed: 82 locoregional relapses (49%), including 45 isolated relapses (27%) and 37 associated with distant metastasis relapses (22%), and 22 metastatic relapses (13%). From the 82 locoregional relapses, only four isolated relapses were exclusively out-field. CONCLUSION: With 5cm supero inferior margins added to gross tumour volume, less than 3% of patients had an isolated out-field recurrence. However, half of the patients suffered in-field local recurrence and one third had metastases. These findings advocate for a limited prophylactic nodal irradiation. Trials are ongoing to assess dose escalation or surgery in order to increase local control. PMID- 26232315 TI - Ex vivo lung perfusion: Theme and variation. PMID- 26232316 TI - Primary cardiac tumors: Rare but important. PMID- 26232317 TI - Biodiesel production by direct transesterification of microalgal biomass with co solvent. AB - In this study, a direct transesterification process using 75% ethanol and co solvent was studied to reduce the energy consumption of lipid extraction process and improve the conversion yield of the microalgae biodiesel. The addition of a certain amount of co-solvent (n-hexane is most preferable) was required for the direct transesterification of microalgae biomass. With the optimal reaction condition of n-hexane to 75% ethanol volume ratio 1:2, mixed solvent dosage 6.0mL, reaction temperature 90 degrees C, reaction time 2.0h and catalyst volume 0.6mL, the direct transesterification process of microalgal biomass resulted in a high conversion yield up to 90.02+/-0.55wt.%. PMID- 26232318 TI - A collaborative approach to enabling stratified cancer medicine in the UK. AB - Embedding stratified cancer medicine into the patient pathway will require adaptation of the diagnostic pathway to incorporate predictive molecular analysis, presenting challenges of accessing tumour samples of sufficient quality and quantity for analysis and ensuring the timeliness, accuracy, and clinical validity of results. In 2010, Cancer Research UK (CRUK), in partnership with AstraZeneca and Pfizer, set up the Stratified Medicine Programme (SMP1) to work collaboratively with a small number of hospital and genetics laboratories to demonstrate the feasibility of testing large volumes of samples, while working towards more standardised and efficient processes. By June 2013, 9010 patient samples had been sent for genetic testing and here we present an overview of our experience and the wealth of insights that have been generated into the complexities of attempting this transformation of National Health Service (NHS) care. PMID- 26232319 TI - Addressing unmet needs in inflammatory bowel disease. PMID- 26232320 TI - [Primary cardiac lymphoma, a extremely rare presentation]. PMID- 26232321 TI - Running: Improving Form to Reduce Injuries. AB - Running is often perceived as a good option for "getting into shape," with little thought given to the form, or mechanics, of running. However, as many as 79% of all runners will sustain a running-related injury during any given year. If you are a runner-casual or serious-you should be aware that poor running mechanics may contribute to these injuries. A study published in the August 2015 issue of JOSPT reviewed the existing research to determine whether running mechanics could be improved, which could be important in treating running-related injuries and helping injured runners return to pain-free running. PMID- 26232322 TI - Fracture of the Scaphoid During a Bench-Press Exercise. AB - The patient was a 21-year-old male cadet at a military academy who was evaluated by a physical therapist in a direct-access capacity for a chief complaint of left wrist pain that began 1 day after injuring his wrist while performing a bench press exercise. Due to concern for a scaphoid fracture and because radiographic imaging was not immediately available, a physical therapist credentialed to utilize fluoroscopy evaluated the left wrist. Radiographs were subsequently ordered, which confirmed a mid-waist, nondisplaced scaphoid fracture. PMID- 26232324 TI - PAQR3 plays a suppressive role in laryngeal squamous cell carcinoma. AB - Laryngeal squamous cell carcinoma (LSCC) is a common type of head and neck malignancy worldwide. The molecular mechanism of LSCC remains not well understood. PAQR3 (progestin and AdipoQ receptors) is a member of the progestin and adipoQ receptor (PAQR) family. Many studies have showed that PAQR3 acts as a new tumor suppressor. However, its expression and functions in LSCC are still unknown. In our study, the expression of PAQR3 was downregulated in human LSCC tissues compared to that in adjacent tissues. Moreover, overexpression of PAQR3 suppressed LSCC cell proliferation and invasion. In addition, PAQR3 inhibited cell proliferation and invasion by regulating ERK phosphorylation. In conclusion, our data demonstrated that PAQR3 acted a tumor suppressive role in LSCC, providing a novel diagnostic and therapeutic option for LSCC in the future. PMID- 26232323 TI - Contribution of resident and recruited macrophages to the photodynamic intervention of colorectal tumor microenvironment. AB - The study of cellular interactions in the tumor microenvironment has become one of the main areas of research in the fight against cancer. Tumor-associated macrophages (TAMs) influence tumor progression and therapy response due to its functional plasticity. Regarding cancer treatment, photodynamic therapy (PDT) is a minimally invasive and clinically approved procedure that involves the administration of a photosensitizer (PS), a nontoxic photosensitizing drug which is selectively retained in neoplastic tissue. Here, we investigated the role of resident and nonresident macrophages in the context of a PDT-treated colorectal tumor by developing a combination of 2-D and three-dimensional (3-D) experimental platform, recreating tumor-stroma interactions in vitro. Enhancement of cytotoxicity of PDT was achieved in the presence of nonresident macrophages which had a strong anti-tumor phenotype mediated by the production of nitric oxide, IL 6, and tumor necrosis factor alpha (TNF-alpha). On the contrary, tumor resident macrophages induced a pro-tumor phenotype promoting tumor cell migration and endothelial stimulation. Due to their plasticity, tumor-resident or tumor recruited macrophages can differentially influence the response of tumors to PDT, so their multifactorial roles should be considered in the overall design of anti tumor therapeutic. PMID- 26232325 TI - CXCL12-CXCR4/CXCR7 axis contributes to cell motilities of oral squamous cell carcinoma. AB - The chemokine CXCL12 and its receptors CXCR4 and CXCR7 might play important roles in the occurrence and development of oral squamous cell carcinoma (OSCC). While CXCR4 expression is associated to initiation and progression of OSCC, the role of CXCR7, the recently founded second CXCL12 receptor, has not yet been elucidated in OSCC. In this study, CXCR4 and CXCR7 expressions were evaluated using western blot and quantitative RT-PCR in OSCC cells. AMD3100 (CXCR4 antagonist) was used to inhibit the activation of CXCR4. In contrast to CXCR4, effective CXCR7 small interfering RNA (siRNA) segments were used to silence CXCR7 in OSCC cells. The biological effects of CXCL12-CXCR4/CXCR7 axis on OSCC cell lines were studied by CCK-8 and transwell assay. As determined by RT-PCR and Western blot, CXCR7 expression was significantly downregulated after siRNA transfection in OSCC cells, and thus significantly promoted OSCC cell migration and invasion in vitro. The relative roles of the two CXCL12 receptors were further assessed by CXCR7 knockdown or deactivate CXCR4 receptor alone, or in combination, in the OSCC cells. In vitro functional analyses indicated that, in response to their common ligand (CXCL12), both receptors induced inhibition of proliferation and migration in OSCC cells in a dose-dependent manner. Exogenous CXCL12 could promote cell migration and invasion. In conclusion, our results indicated that CXCL12 which combined its receptor CXCR4 and CXCR7 together could promote cell motilities of OSCC. PMID- 26232326 TI - PTEN gene polymorphisms and susceptibility to oral squamous cell carcinoma in a Chinese Han population. AB - The tumor suppressor gene phosphatase and tensin homologue (PTEN) plays a significant role in regulating cell growth, proliferation, and apoptosis. However, there are no data regarding the role of PTEN polymorphisms in the development of oral squamous cell carcinoma (OSCC). A hospital-based case-control study was conducted to investigate the potential association between PTEN polymorphisms and the risk of OSCC in a Chinese Han population. The study population comprised 201 patients with OSCC and 199 healthy controls. Seventeen single-nucleotide polymorphisms (SNPs) of PTEN were investigated and genotyped using Sequenom Mass ARRAY and iPLEX-MALDI-TOF technology. The observed genotype frequencies of these polymorphisms were in agreement with Hardy-Weinberg equilibrium in the control group (P > 0.05 for all). The heterozygous CT genotype was not associated with significantly increased risk for OSCC (OR = 0.89, 95 % CI = (0.55-1.42), P = 0.83), the TT genotype was not associated with increased risk for OSCC (OR = 1.01, 95 % CI = (0.58-1.74), P = 0.74) compared to the PTEN SNP rs1234224 homozygous CC genotype. Meanwhile, CT/TT variants were not associated with increased risk for OSCC compared with the CC genotype (OR = 0.93, 95 % CI = 0.60-1.44, P = 0.73). The T allele was not associated with significantly increased risk compared to the C allele (OR = 0.99, 95 % CI = 0.72-1.58, P = 0.69). Similar associations with the risk of OSCC were observed for the other genotypes of PTEN gene polymorphisms. There were no significant differences in the distribution of the genotype and allele frequencies of polymorphisms of the PTEN gene between the OSCC patients and controls in a Chinese Han population. Further studies are needed to clarify the specific roles of PTEN polymorphisms in the etiology of OSCC. PMID- 26232327 TI - Carbonic anhydrase 1 is a promising biomarker for early detection of non-small cell lung cancer. AB - This study aimed to identify candidate biomarkers associated with stage I non small cell lung cancer (NSCLC). Sera from three groups, a lung cancer group (n = 11), benign control group (n = 12), and normal control group (n = 10), were collected and pooled. Protein expression profiles were analyzed by a combination of two-dimensional electrophoresis (2DE) and matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS). These methods were used to separate, screen, and identify proteins that were differentially expressed between stage I NSCLC and controls. Differentially expressed proteins were validated by both Western blot and ELISA in an expanded sample size (22, 18, and 18 in three groups, respectively). MALDI-MS identified 12 differentially expressed proteins in the lung cancer group compared to the two control groups. Expression of carbonic anhydrase 1 (CA1) was validated by Western blot. CA1 was significantly elevated in the lung cancer group compared to controls. ELISA results confirmed that CA1 in the lung cancer group (3.18 +/- 1.27 ng/mL, n = 22) was highly expressed in stage I NSCLC patients compared to those in the benign control group (2.21 +/- 0.71 ng/mL, n = 18) and the normal control group (2.04 +/- 0.63 ng/mL, n = 18) (P = 0.001). In conclusion, we provide evidence that CA1 is highly expressed in the sera of stage I NSCLC patients. Additionally, CA1 might serve as a novel biomarker for early detection of NSCLC. PMID- 26232328 TI - Insights into the effector functions of human IgG3 in the context of an antibody targeting transferrin receptor 1. AB - The transferrin receptor 1 (TfR1) is involved in cellular iron uptake and regulation of cell proliferation. The increased expression of TfR1 observed in malignant cells, compared to normal cells, together with its extracellular accessibility, make this receptor an attractive target for antibody-mediated cancer therapy. We have developed a mouse/human chimeric IgG3 specific for human TfR1 (ch128.1), which shows anti-tumor activity against certain malignant B cells in vitro through TfR1 degradation and iron deprivation, and in vivo through a mechanism yet to be defined. To further explore potential mechanisms of action of ch128.1, we examined its ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC). We now report that ch128.1 is capable of mediating ADCC and CDC against malignant B cells, which is consistent with its ability to bind FcgammaRI, FcgammaRIIIa, and the complement component C1q. To delineate the residues involved in these effector functions, we developed a panel of three constructs with mutations in the lower hinge region and CH2 domain: 1) L234A/L235A, 2) P331S, and 3) L234A/L235A/P331S. The triple mutant consistently displayed a significant reduction in ADCC, while the L234A/L235A mutant exhibited less reduction in ADCC, and the P331S mutant did not show reduced ADCC. However, all three mutants exhibited impaired binding to FcgammaRI and FcgammaRIIIa. These results suggest that all three residues contribute to ADCC, although to different degrees. The P331S mutant showed drastically decreased C1q binding and abolished CDC, confirming the critical role of this residue in complement activation, while the other residues play a less important role in CDC. Our study provides insights into the effector functions of human IgG3 in the context of an antibody targeting TfR1. PMID- 26232329 TI - Ultrasound-guided mini-percutaneous nephrolithotomy in patients aged less than 3 years: the largest reported single-center experience in China. AB - To investigate the efficacy and safety of mini-percutaneous nephrolithotomy (mini PCNL) under total ultrasonography in patients aged <3 years. METHODS: We reviewed 56 patients (67 renal units) aged <3 years between August 2006 and December 2012 in our units, including 31 renal units with a single stone, 6 with staghorn stones, 10 with upper ureteral stones, and 20 with multiple stones. The mean age of the patients was 24 (range 6-36) months and the mean maximum stone diameter was 18.9 (range 10-32) mm. The puncture site selection and tract dilation were guided by Doppler ultrasonography solely. All procedures were performed using 12 16 Fr tracts. Stones were fragmented using pneumatic lithotripsy and a holmium laser with an 8/9.8 Fr rigid ureteroscope. Forty-five patients with unilateral stones underwent a single procedure, and 11 patients with bilateral stones underwent two procedures. The mean time to establish access was 2.9 (range 2.1-5) min, the mean operative time was 36.8 (range 20-88) min, the mean decrease in hemoglobin concentration was 8.7 (2-15) g/L, and the stone-free rate at hospital discharge was 92.5%. The mean postoperative hospital stay was 7.1 (range 3-13) days. Post-procedure complications included fever (>38.5 degrees C) in four patients, and reactive pleural effusion in one patient. Blood loss requiring transfusion, sepsis, adjacent organ injury, and kidney loss were not observed. Ultrasound-guided mini-PCNL is feasible and safe in patients aged <3 years, without major complications or radiation exposure. PMID- 26232330 TI - Sweet promises: Candy advertising to children and implications for industry self regulation. AB - Candy advertising illustrates limitations of the Children's Food and Beverage Advertising Initiative (CFBAI) self-regulatory program to improve food marketing to children. Participating companies pledge to not advertise candy in child directed media. Yet independent analyses show that children viewed 65% more candy ads on U.S. television in 2011 than in 2007, before CFBAI implementation. The present research corroborates these findings, characterizes the increase, and examines how CFBAI-participating and non-participating companies use child targeted techniques and media placement to advertise candy on U.S. television. Content analysis identified child-targeted messages and techniques in 2011 television candy ads, and Nielsen data (2008-2011) quantified candy advertising viewed on children's and other types of television programming. Differences between brands according to CFBAI status and use of child-targeted techniques in ads are evaluated. Data were obtained and analyzed in 2013. CFBAI-company non approved brands represented 65% of candy ads viewed by children in 2011, up from 45% in 2008, and 77% of these ads contained child-targeted techniques. Although CFBAI companies only placed ads for approved brands on children's networks, 31% of ads viewed by children for CFBAI non-approved brands appeared on networks with higher-than-average youth audiences. CFBAI non-participating companies placed child-targeted candy ads primarily on children's networks. Despite CFBAI pledges, companies continue to advertise candy during programming with large youth audiences utilizing techniques that appeal to children. Both increased CFBAI participation and a more effective definition of "child-directed advertising" are required to reduce children's exposure to targeted advertising for foods that can harm their health. PMID- 26232332 TI - Effects of Peptone Supplementation in Different Culture Media on Growth, Metabolic Pathway and Productivity of CHO DG44 Cells; a New Insight into Amino Acid Profiles. AB - BACKGROUND: The optimization of bioprocess conditions towards improved growth profile and productivity yield is considered of great importance in biopharmaceutical manufacturing. Peptones as efficient sources of nutrients have been studied for their effect on media development; however, their role on metabolic pathway is not well understood. METHODS: In the present study, the effect of different concentration of peptones on a recombinant Chinese hamster ovary (CHO) cell line grown in three serum-free suspension cultures was determined. Six peptones of different origins and available amino acid profiles were investigated regarding their impact on cell growth, productivity, and metabolic pathways changes. RESULTS: In optimized feeding strategies, increases of 136% and 159% in volumetric productivity (for a low-nutrient culture media) and 55% (for a high-nutrient culture media) were achieved. Furthermore, particular sources of peptones with specific amino acid profile developed preferential results for each different culture medium. Two peptones, SoyA2SC and SoyE-110, were the only hydrolysates that showed production improvement in all three media. Casein Peptone plus Tryptone N1 and SoyA3SC showed different improved results based on their implemented concentration for each individual basal medium. CONCLUSION: The amino acid profile of peptones may provide clues to identify the most effective feeding strategies for recombinant CHO cells. PMID- 26232333 TI - Deep sequencing-generated modules demonstrate coherent expression patterns for various cardiac diseases. AB - As sequencing technology rapidly develops, gene annotations have also become increasingly sophisticated with incorporation of information regarding the temporal-spatial context of alternative splicing patterns, developmental stages, and tissue specificity. The present study aimed to identify the heart-enriched genes based on next-generation sequencing data and to investigate the gene modules demonstrating coherent expression patterns for various cardiac disease related perturbations. Seven gene modules, including 382 heart-enriched genes, were identified. At least two modules containing differentially expressed genes were experimentally confirmed to be highly sensitive to various cardiac diseases. Transcription factors regulating the gene modules were then analyzed based on knowledgebase information; the expression of eight transcription factors changed significantly during pressure-overload cardiac hypertrophy, suggesting possible regulation of the modules by the identified transcription factors. Collectively, our results contribute to the classification of heart-enriched genes and their modules and would aid in identification of the transcription factors involved in cardiac pathogenesis in the future. PMID- 26232334 TI - Induction of human ADAMTS-2 gene expression by IL-1alpha is mediated by a multiple crosstalk of MEK/JNK and PI3K pathways in osteoblast like cells. AB - Up-regulation of ADAMTS genes with proinflammatory cytokines is important for some pathological conditions such as osteoarthritis (OA) that is a disease based on ECM degradation in cartilage. IL-1alpha is a proinflammatory cytokine and important both to normal and pathophysiologic conditions in cartilage and bone. Effects of some proinflammatory cytokines such as TNF-alpha and IL-1beta on the some members of ADAMTS family have been investigated in some chondrocyte tissues or cell lines. However the effect of the IL-1alpha on the expression of ADAMTS-2 and ADAMTS-3 gene expression in osteoblast like cell lines, remains unclear. Therefore, the aim of this study is to investigate the effect of IL-1alpha on ADAMTS-2 and ADAMTS-3 gene expression in osteoblast like cells, Saos-2 and MG-63. The present study, for the first time, demonstrated that IL-1alpha increases ADAMTS-2 and ADAMTS-3 gene expressions in both Saos-2 and MG-63 cells. Having correlation to mRNA induction, the upregulation of ADAMTS-2,-3 protein levels by IL-1alpha stimulation is also observed. The inhibition studies showed that this upregulation occurred at the level of transcription, and there was no effect of IL-1alpha on ADAMTS-2 mRNA half-life in Saos-2 cells. Transactivation potential of IL-1alpha on ADAMTS-2 promoter was investigated by transient transfection assay. Specifically, IL-1alpha strongly increased -658/+112 and -530/+112 ADAMTS 2 promoter constructs. Further, we analyzed signaling pathways involved in ADAMTS 2 induction. Pathway inhibition studies revealed that this upregulation depends on the activation of MEK, JNK and PI3K pathways. These findings suggested that IL 1alpha is a strong positive regulator of ADAMTS-2 and ADAMTS-3 expression. These findings would provide novel insight into the pathophysiology of OA. PMID- 26232336 TI - Genome-wide identification, classification and analysis of HD-ZIP gene family in citrus, and its potential roles in somatic embryogenesis regulation. AB - The homeodomain-leucine zipper (HD-Zip) transcription factors, which belong to a class of Homeobox proteins, has been reported to be involved in different biological processes of plants, including growth and development, photomorphogenesis, flowering, fruit ripening and adaptation responses to environmental stresses. In this study, 27 HD-Zip genes (CsHBs) were identified in Citrus. Based on the phylogenetic analysis and characteristics of individual gene or protein, the HD-Zip gene family in Citrus can be classified into 4 subfamilies, i.e. HD-Zip I, HD-Zip II, HD-Zip III, and HD-Zip IV containing 16, 2, 4, and 5 members respectively. The digital expression patterns of 27 HD-Zip genes were analyzed in the callus, flower, leaf and fruit of Citrus sinensis. The qRT-PCR and RT-PCR analyses of six selected HD-Zip genes were performed in six citrus cultivars with different embryogenic competence and in the embryo induction stages, which revealed that these genes were differentially expressed and might be involved in citrus somatic embryogenesis (SE). The results exhibited that the expression of CsHB1 was up-regulated in somatic embryo induction process, and its expression was higher in citrus cultivars with high embryogenic capacity than in cultivars recalcitrant to form somatic embryos. Moreover, a microsatellite site of three nucleotide repeats was found in CsHB1 gene among eighteen citrus genotypes, indicating the possible association of CsHB1 gene to the capacity of callus induction. PMID- 26232337 TI - Characterization of patient-derived tumor xenograft models of endometrial cancer for preclinical evaluation of targeted therapies. AB - OBJECTIVE: Endometrial carcinoma (EC) is the sixth most common cancer in women and therapies are limited for advanced and recurrent disease. Patient-derived tumor xenograft (PDTX) models are becoming popular tools in translational research because of their histological and genetic similarity to the original tumors and the ability to predict therapeutic response to treatments. Here, we established and characterized a panel of 24 EC PDTX models which includes the major histological and genetic subtypes observed in patients. METHODS: Fresh tumor tissues collected from primary, metastatic and recurrent type I and type II EC patients were engrafted in immunocompromised mice. Histology, vimentin, and cytokeratin expression were evaluated, together with Microsatellite instability (MSI), mutation profiling by Whole Exome Sequencing and copy number profiling by Whole Genome Low Coverage Sequencing. The efficacy of both PI3K and MEK inhibitors was evaluated in a model of endometrioid carcinoma harboring PTEN, PIK3CA and KRAS mutations. RESULTS: We observed good similarity between primary tumors and the corresponding xenografts, at histological and genetic level. Among the engrafted endometrioid models, we found a significant enrichment of MSI and POLE mutated tumors, compared to non-engrafted samples. Combination treatment with NVP-BEZ235 and AZD6244 showed the possibility to stabilize the tumor growth in one model originated from a patient who already received several lines of chemotherapy. CONCLUSION: The established EC PDTX models, resembling the original human tumors, promise to be useful for preclinical evaluation of novel combination and targeted therapies in specific EC subgroups. PMID- 26232335 TI - Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs. AB - In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca(2+) or Mg(2+) under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure. PMID- 26232338 TI - Expression and clinical role of chemoresponse-associated genes in ovarian serous carcinoma. AB - OBJECTIVE: To validate our earlier observation that 11 chemoresistance-associated mRNAs are molecular markers of poor overall survival in ovarian serous carcinoma. METHODS: Ovarian serous carcinomas (n=112) and solid metastases (n=63; total=175) were analyzed for mRNA expression of APC, BAG3, EGFR, S100A10, ITGAE, MAPK3, TAP1, BNIP3, MMP9, FASLG and GPX3 using quantitative real-time PCR. mRNA expression was studied for association with clinicopathologic parameters and survival. Tumor heterogeneity was assessed in 20 cases with >1 specimen per patient. APC, BAG3, S100A10 and ERK1 protein expression by immunohistochemistry was analyzed in 58 specimens (38 primary carcinomas, 20 metastases). RESULTS: BAG3 (p=0.013), TAP1 (p=0.014), BNIP3 (p<0.001) and MMP9 (p=0.036) were overexpressed in primary tumors, whereas S100A10 (p=0.027) and FASLG (p=0.006) were overexpressed in metastases. Analysis of patient-matched primary carcinomas and metastases showed overexpression of APC (p=0.022), MAPK3 (p=0.002) and BNIP3 (p=0.004) in the former. In primary carcinomas, higher APC (p=0.003) and MAPK3 (p=0.005) levels were related to less favorable chemoresponse. Higher S100A10 (p=0.029) and MAPK3 (p=0.041) levels were related to primary chemoresistance. Higher BAG3 (p=0.026) and APC (p=0.046) levels in primary carcinomas were significantly related to poor overall survival in univariate, though not in multivariate survival analysis. S100A10 protein expression was related to poor chemoresponse (p=0.002) and shorter overall (p=0.005) and progression-free (p<0.001) survival, the latter finding retained in multivariate analysis (p=0.035). CONCLUSIONS: Our data provide evidence of heterogeneity in ovarian serous carcinoma and identify APC, MAPK3, BAG3 and S100A10 as potential biomarkers of poor chemotherapy response and/or poor outcome in this cancer. PMID- 26232339 TI - Symposium on advances in endometrial cancer epidemiology and biology. PMID- 26232341 TI - What do we know about carbon monoxide poisoning and cardiac compromise? AB - Carbon monoxide (CO) poisoning is one of the most common types of poisoning and the leading cause of death by poisoning worldwide. Cardiac injury caused by CO poisoning has been little described despite being a predictor of poor prognosis. We present the case of a healthy 24-year-old woman, admitted to our emergency room due to an episode of lipothymia without loss of consciousness. She reported holocranial headache for the previous two weeks associated with nausea and vomiting. Laboratory tests revealed blood gas analysis: pH 7.392, pCO2 32 mmHg, pO2 101 mmHg, lactate 3.5 mmol/l, HCO3 20.8 mmol/l; COHb 29.2%; serial troponin I 1.21 -> 5.25 -> 6.13 -> 3.65 MUg/l; myoglobin 1378 -> 964 -> 352 MUg/l; and NT proBNP 1330 pg/l. The electrocardiogram showed sinus rhythm, heart rate 110 bpm, and ST-segment depression of 2 mm in V4 and 1 mm in V5. Transthoracic echocardiography revealed a left ventricle with normal wall motion and preserved ejection fraction. Given the clinical and epidemiological context, myocardial and central nervous system ischemia due to prolonged CO exposure was assumed and normobaric oxygen therapy was immediately started. In view of evidence of injury to two major organ systems the indication for hyperbaric oxygen therapy was discussed with a specialist colleague, who suggested maintaining conservative treatment with oxygen therapy and in-hospital monitoring for 72 h. The patient was discharged on the third day and was still asymptomatic at 400 days of follow up. Besides symptoms and signs of central nervous system dysfunction, myocardial damage should also always be considered in the context of CO poisoning. Hyperbaric therapy is still controversial and the lack of objective data highlights the need for new randomized studies. PMID- 26232340 TI - Real world effectiveness of warfarin among ischemic stroke patients with atrial fibrillation: observational analysis from Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study. AB - OBJECTIVE: To examine the association between warfarin treatment and longitudinal outcomes after ischemic stroke in patients with atrial fibrillation in community practice. DESIGN: Observational study. SETTING: Hospitals (n = 1487) participating in the Get With The Guidelines (GWTG)-Stroke program in the United States, from 2009 to 2011. PARTICIPANTS: 12,552 warfarin naive atrial fibrillation patients admitted to hospital for ischemic stroke and treated with warfarin compared with no oral anticoagulant at discharge, linked to Medicare claims for longitudinal outcomes. MAIN OUTCOME MEASURES: Major adverse cardiovascular events (MACE) and home time, a patient centered outcomes measure defined as the total number of days free from institutional care after discharge. A propensity score inverse probability weighting method was used to account for all differences in observed characteristics between treatment groups. RESULTS: Among 12,552 survivors of stroke, 11,039 (88%) were treated with warfarin at discharge. Warfarin treated patients were slightly younger and less likely to have a history of previous stroke or coronary artery disease but had similar severity of stroke as measured by the National Institutes of Health Stroke Scale. Relative to those not treated, patients treated with warfarin had more days at home (as opposed to institutional care) during the two years after discharge (adjusted home time difference 47.6 days, 99% confidence interval 26.9 to 68.2). Patients discharged on warfarin treatment also had a reduced risk of MACE (adjusted hazard ratio 0.87, 99% confidence interval 0.78 to 0.98), all cause mortality (0.72, 0.63 to 0.84), and recurrent ischemic stroke (0.63, 0.48 to 0.83). These differences were consistent among clinically relevant subgroups by age, sex, stroke severity, and history of previous coronary artery disease and stroke. CONCLUSIONS: Among ischemic stroke patients with atrial fibrillation, warfarin treatment was associated with improved long term clinical outcomes and more days at home. Clinical trial registration Clinical trials NCT02146274. PMID- 26232342 TI - Immunogenicity and protective efficacy of the norovirus P particle-M2e chimeric vaccine in chickens. AB - The ectodomain of the influenza matrix protein 2 (M2e) is highly conserved across strains and has been shown to be a promising candidate for universal influenza vaccine in the mouse model. In this study, we tested immune response and protective efficacy of a chimeric norovirus P particle containing the avian M2e protein against challenges with three avian influenza (AI) viruses (H5N2, H6N2, H7N2) in chickens. Two-week-old specific pathogen free chickens were vaccinated 3 times with an M2e-P particle (M2e-PP) vaccine via the subcutaneous (SQ) route with oil adjuvant, and transmucosal routes (intranasal, IN; eye drop, ED; microspray, MS) without adjuvant. M2e-PP vaccination via the SQ route induced significant IgG antibody responses which were increased by each booster vaccination. In groups vaccinated via IN, ED or MS, neither IgG nor IgA responses were detected from sera or nasal washes of immunized birds. The M2e-PP vaccination via the SQ route significantly reduced the virus shedding in the trachea and the cloaca for all three challenge viruses. Despite the absence of detectable IgG and IgA responses in birds vaccinated with the M2e-PP via intranasal routes, a similar level of reduction in virus shedding was observed in the IN group compared to the SQ group. Our results supports that the universal vaccine approach using M2e-based vaccine can provide cross-protection against challenge viruses among different HA subtypes although the efficacy of the vaccine should be enhanced further to be practical. Better understanding of the protective immune mechanism will be critical for the development of an M2e-based vaccine in chickens. PMID- 26232343 TI - Dutch influenza vaccination rate drops for fifth consecutive year. AB - AIM: To determine the prevalence and trend of the influenza vaccination-rate of the overall target population in the period 2008-2013, with a specific focus on groups at risk such as patients with cardiovascular diseases, lung diseases, diabetes and aged 60 years and older. METHODS: In an observational longitudinal study electronic medical records data from the Dutch representative network of general practices, LINH, were analyzed. For each influenza vaccination season, 2008-2013, the number of vaccinated and unvaccinated patients at risk are compared by chi-square tests (chi(2)) for linear trends, linear-by-linear association. The level of significance was set at p<0.001 based on the large number of available records. RESULTS: The influenza vaccination rate of the overall at risk group decreased significantly from 71.5% in the 2008 season, to 59.6% in the 2013 vaccination season. The difference of 11.9% was gradual over the years, with a mean decrease of 2.4% per year. The decrease was seen in all specified groups at risk, but was mainly among patients aged 60-65 years (mean yearly decrease of 3.3%). CONCLUSION: For the fifth subsequent year, we notice a lowering trend of the influenza vaccination rate in the population at risk. Reports in the mass media on questioning the effectiveness of the vaccination program may have been an influence; as well as the relatively light outbreaks of influenza in the past years, which may have affected the sense of urgency. The gradual decrease in vaccination rates over recent years requires further research and a public health debate is needed on the usefulness and necessity of the vaccination program. PMID- 26232345 TI - The effect of various types of patients' reminders on the uptake of pneumococcal vaccine in adults: A randomized controlled trial. AB - BACKGROUND: Invasive pneumococcal disease is one of the most important vaccine preventable diseases threatening the adult community due to missed opportunities for vaccination. This study compares the effect of three different types of patient reminder system on adulthood Streptococcus pneumoniae immunization in a primary care setting. METHODS: The study targeted patients aged 40 and older eligible for pneumococcal vaccine, but did not receive it yet (89.5% of 3072 patients) based on their electronic medical records in a family medicine center in Beirut. The sample population was randomized using an automated computer randomization system into six equal groups, receiving short phone calls, short text messaging system (sms-text) or e-mails each with or without patient education. Each group received three identical reminders spaced by a period of four weeks. Documentation of vaccine administration was then added to the longitudinal electronic patient record. The primary outcome was the vaccine administration rate in the clinics. RESULTS: Of the eligible patients due for the pneumococcal 23-polyvalent vaccine, 1380 who had mobile phone numbers and e-mails were randomized into six equal intervention groups. The various reminders increased vaccination rate to 14.9%: 16.5% of the short phone calls group, 7.2% of the sms-text group and 5.7% of the e-mail group took the vaccine. The vaccination rate was independent of the age, associated education message and the predisposing condition. CONCLUSION: Use of electronic text reminders via e-mails and mobile phones seems to be a feasible and sustainable model to increase pneumococcal vaccination rates in a primary care center. PMID- 26232344 TI - Advax delta inulin adjuvant overcomes immune immaturity in neonatal mice thereby allowing single-dose influenza vaccine protection. AB - Neonates are at high risk for influenza morbidity and mortality due to immune immaturity and lack of priming by prior influenza virus exposure. Inactivated influenza vaccines are ineffective in infants under six months and to provide protection in older children generally require two doses given a month apart. This leaves few options for rapid protection of infants, e.g. during an influenza pandemic. We investigated whether AdvaxTM, a novel polysaccharide adjuvant based on delta inulin microparticles could help overcome neonatal immune hypo responsiveness. We first tested whether it was possible to use Advax to obtain single-dose vaccine protection of neonatal pups against lethal influenza infection. Inactivated influenza A/H1N1 vaccine (iH1N1) combined with AdvaxTM adjuvant administered as a single subcutaneous immunization to 7-day-old mouse pups significantly enhanced serum influenza-specific IgM, IgG1, IgG2a and IgG2b levels and was associated with a 3-4 fold increase in the frequency of splenic influenza-specific IgM and IgG antibody secreting cells. Pups immunized with Advax had significantly higher splenocyte influenza-stimulated IFN-gamma, IL-2, IL-4, and IL-10 production by CBA and a 3-10 fold higher frequency of IFN-gamma, IL-2, IL-4 or IL-17 secreting T cells by ELISPOT. Immunization with iH1N1+Advax induced robust protection of pups against virus challenge 3 weeks later, whereas pups immunized with iH1N1 antigen alone had no protection. Protection by Advax adjuvanted iH1N1 was dependent on memory B cells rather than memory T cells, with no protection in neonatal MUMT mice that are B-cell deficient. Hence, Advax adjuvant overcame neonatal immune hypo-responsiveness and enabled single-dose protection of pups against otherwise lethal influenza infection, thereby supporting ongoing development of AdvaxTM as a neonatal vaccine adjuvant. PMID- 26232346 TI - Development of an AIDS vaccine using Sendai virus vectors. AB - Development of an effective AIDS vaccine is crucial for the control of global human immunodeficiency virus type 1 (HIV-1) prevalence. We have developed a novel AIDS vaccine using a Sendai virus (SeV) vector and investigated its efficacy in a macaque AIDS model of simian immunodeficiency virus (SIV) infection. Its immunogenicity and protective efficacy have been shown, indicating that the SeV vector is a promising delivery tool for AIDS vaccines. Here, we describe the potential of SeV vector as a vaccine antigen delivery tool to induce effective immune responses against HIV-1 infection. PMID- 26232347 TI - Vaccination for 2009 pandemic H1N1 influenza A did not induce conserved epitope specific memory CD8 T cell responses in HIV+ northern Thai children. AB - The influenza virus causes severe illness in susceptible populations, including children and people living with human immunodeficiency virus (HIV). Here, we investigated cell-mediated immune responses (CMI) against influenza CD8 T cell conserved epitopes in HIV-infected (HIV+) northern Thai children following the 2009 pandemic H1N1 influenza A vaccination. Sixty HIV+ children were vaccinated with two doses of the 2009 pandemic influenza vaccine and their CD8T cell responses were assessed. We found no significant differences in the increase of cytokines-producing and CD107a-expressing CD8+ T cells or CD8+ memory T cells in response to pooled conserved epitopes stimulation in vitro between children with different serologic responses to the vaccine at all time points of the study. Our results suggest that the 2009 pandemic H1N1 vaccine did not induce the conserved epitope-specific immune responses in HIV+ children. Vaccine design and vaccination strategy against influenza in these populations warrant further studies. PMID- 26232348 TI - Randomized evaluation of live attenuated vs. inactivated influenza vaccines in schools (RELATIVES) cluster randomized trial: Pilot results from a household surveillance study to assess direct and indirect protection from influenza vaccination. AB - BACKGROUND: Children are key drivers of influenza transmission. Vaccinating school age children decreases influenza in the community. OBJECTIVE: To pilot test the methods for a future trial to compare the direct and indirect benefits of inactivated influenza vaccine (IIV) vs. live attenuated influenza vaccine (LAIV) in preventing influenza infection. METHODS: During the 2013-14 influenza vaccination campaign, we piloted an open-label cluster randomized trial involving 10 elementary schools in Peterborough, Ontario, Canada. We randomized schools on a 1:1 basis to have students receive IIV or LAIV. We invited a subset of vaccinated students and their households to participate in a surveillance sub study, which involved completing daily symptom diaries during influenza season and collecting mid-turbinate swabs from symptomatic individuals to detect influenza infection. The main outcome measure was confirmed influenza infection using a real-time reverse transcriptase polymerase chain reaction (PCR) assay. RESULTS: One hundred and nineteen households (166 students and 293 household members) participated. During 15 weeks of surveillance, we detected 22 episodes of PCR-confirmed influenza (21 influenza A/H1N1 and 1 influenza B). The incidence of influenza per 1000 person-days was 1.24 (95% CI, 0.40-2.89) for IIV-vaccinated students, compared to 0.13 (95% CI, 0.003-0.72) for LAIV-vaccinated students; the incidence rate ratio was 0.10 (95% CI, 0.002-0.94). Similarly, the incidence of influenza per 1000 person-days was 1.33 (95% CI, 0.64-2.44) for IIV household members, compared to 0.47 (95% CI, 0.17-1.03) for LAIV household members; the incidence rate ratio was 0.36 (95% CI, 0.11-1.08). The overall incidence rate ratio (combining students and household members) was 0.27 (95% CI, 0.09-0.69). CONCLUSIONS: Household surveillance involving participant monitoring and reporting of symptoms and self-collection of mid-turbinate swabs is feasible. A larger study is required to validate the suggestion that vaccinating children with LAIV might confer more protection against influenza for both children and their household contacts, compared to IIV. TRIAL REGISTRATION: ClinicalTrials.gov NCT01995851. PMID- 26232350 TI - Reliability of thromboelastometry for detecting the safe coagulation threshold in patients taking acenocoumarol after elective heart valve replacement. AB - BACKGROUND: Reversal of anticoagulation can be needed in patients undergoing heart valve surgery. ROTEM(r) has been correlated with international normalized ratio (INR) in patients on warfarin but not with patients on acenocoumarol. This study investigates the reliability of ROTEM(r) for detecting INR values below the 1.5 threshold in patients on acenocoumarol therapy. MATERIAL AND METHODS: Patients on oral anticoagulation with acenocoumarol after elective heart valve replacement were prospectively included in the study. INR and the ROTEM(r) were measured simultaneously. ROTEM(r) parameters included coagulation time, clot formation time, alpha angle, and maximal clot firmness after tissue factor activation (EXTEM). Concordance between INR and ROTEM(r) was analyzed by Lin's concordance coefficient (LCC) and the correlation with Spearman's rho. RESULTS: Fifty-four consecutive patients (40 female; median age 67years) were included. Clotting time (CT) was the parameter that best correlated with INR (r=0.81, p<0,001), and LCC was substantial (0.67). CT was able to predict INR values above or below 1.5: area under curve=0.998. CT>=84seconds, corresponding to a cut-off for likelihood ratio (LR+)=5, had a sensitivity and specificity of 100% and 80%, respectively, to detect an INR below 1.5. For the same INR threshold, CT>=84seconds had a predictive positive value of 92.9% and a predictive negative value of 100%. CONCLUSION: Our preliminary results suggest that CT>=84seconds in the EXTEM ROTEM(r) test is a feasible method for predicting an insufficient reversion of oral anticoagulant therapy in patients taking acenocoumarol after elective heart valve surgery. PMID- 26232349 TI - A high efficient protocol for soybean root transformation by Agrobacterium rhizogenes and most stable reference genes for RT-qPCR analysis. AB - KEY MESSAGE: A 55% transformation efficiency was obtained by our optimized protocol; and we showed that GmELF1 - beta and GmELF1 - alpha are the most stable reference genes for expression analyses under this specific condition. Gene functional analyses are essential to the validation of results obtained from in silico and/or gene-prospecting studies. Genetic transformation methods that yield tissues of transient expression quickly have been of considerable interest to researchers. Agrobacterium rhizogenes-mediated transformation methods, which are employed to generate plants with transformed roots, have proven useful for the study of stress caused by root phytopathogens via gene overexpression and/or silencing. While some protocols have been adapted to soybean plants, transformation efficiencies remain limited; thus, few viable plants are available for performing bioassays. Furthermore, mRNA analyses that employ reverse transcription quantitative polymerase chain reactions (RT-qPCR) require the use of reference genes with stable expression levels across different organs, development steps and treatments. In the present study, an A. rhizogenes-mediated soybean root transformation approach was optimized. The method delivers significantly higher transformation efficiency levels and rates of transformed plant recovery, thus enhancing studies of soybean abiotic conditions or interactions between phytopathogens, such as nematodes. A 55% transformation efficiency was obtained following the addition of an acclimation step that involves hydroponics and different selection processes. The present study also validated the reference genes GmELF1-beta and GmELF1-alpha as the most stable to be used in RT-qPCR analysis in composite plants, mainly under nematode infection. PMID- 26232351 TI - Extracellular histone H3 levels are inversely correlated with antithrombin levels and platelet counts and are associated with mortality in sepsis patients. AB - OBJECTIVE: Sepsis is a leading cause of death worldwide. Extracellular histones are cytotoxic compounds mediating death in murine sepsis and circulating nucleosome levels predict mortality in human inflammation and sepsis. Whether or not circulating extracellular histone H3 correlates with other plasma parameters and/or ICU scoring systems has not been completely established, nor if levels of circulating extracellular histones can be used as predictive markers for clinical outcome in sepsis. METHODS: We measured plasma histone H3 (H3) levels in the plasma of 43 sepsis patients who were admitted to the Intensive Care Unit and determined their correlation with disease severity, organ failure, mortality and coagulation- and tissue homeostasis parameters including LDH levels, thrombin potential (ETP), prothrombin levels, antithrombin levels and platelet counts. RESULTS: Median H3 levels of sepsis patients at the ICU were significantly increased in non-survivors as compared to survivors with levels found being 3.15MUg/ml versus 0.57MUg/ml respectively, P=0.04. H3 levels are positively correlated with lactate dehydrogenase (LDH) activity (Spearman's rho=0.49, P<0.001), and negatively correlated with antithrombin levels (rho=-0.34, P=0.027) and platelet counts (rho=-0.33, P=0.031). CONCLUSIONS: We conclude that circulating H3 levels correlate with mortality in sepsis patients and inversely correlate with antithrombin levels and platelet counts. PMID- 26232352 TI - Explanatory models of psychosis amongst British South Asians. AB - PURPOSE: A strong interest in the understanding, exploring, and extracting explanatory models of psychosis has recently arisen. Explanatory models (EMs) offer justifications and propose explanations when coping with and treating illnesses. Therefore, they may be important predictors of clinical outcome. Explanatory models of psychosis have been explored in many non-Western countries. However, very little research has examined EMs of psychosis in the UK. We therefore, aimed to elicit and describe explanatory models of psychosis amongst British South Asians, using both quantitative and qualitative methods. METHOD: EMs of psychosis were examined using the Short Explanatory Model Interview (SEMI) in a cross-sectional sample of 45 patients. RESULTS: Most patients (55.5%) attributed their illness to supernatural causes. Few patients cited a biological (4.4%) cause. Majority of patients held dual EMs of psychosis (77.7%), combining prescribed medication and seeing a traditional healer as a treatment method. Duration of Untreated Psychosis (DUP) was not significantly associated with EMs of psychosis. CONCLUSION: The results suggest that patients hold multi explanatory models in order to make sense of their illness and these stem from deep rooted traditional beliefs. This highlights the importance of educational intervention, culturally adapted psychological interventions and possibly working together with traditional healers in the UK to provide a positive support system. Further work is required in order to fully understand the relationship between EMs of psychosis and DUP. PMID- 26232353 TI - Thiosemicarbazone modification of 3-acetyl coumarin inhibits Abeta peptide aggregation and protect against Abeta-induced cytotoxicity. AB - Aggregation of amyloid beta peptide (Abeta) is an important event in the progression of Alzheimer's disease. Therefore, among the available therapeutic approaches to fight with disease, inhibition of Abeta aggregation is widely studied and one of the promising approach for the development of treatments for Alzheimer's disease. Thiosemicarbazone compounds are known for their variety of biological activities. However, the potential of thiosemicarbazone compounds towards inhibition of Abeta peptide aggregation and the subsequent toxicity is little explored. Herein, we report synthesis and x-ray crystal structure of novel compound 3-acetyl coumarin thiosemicarbazone and its efficacy toward inhibition of Abeta(1-42) peptide aggregation. Our results indicate that 3-acetyl coumarin thiosemicarbazone inhibits Abeta(1-42) peptide aggregation up to 80% compared to the parent 3-acetyl coumarin which inhibits 52%. Further, 3-acetyl coumarin thiosemicarbazone provides neuroprotection against Abeta-induced cytotoxicity in SH-SY5Y cell line. These findings indicate that thiosemicarbazone modification renders 3-acetyl coumarin neuroprotective properties. PMID- 26232354 TI - Feeling the burn: When it looks like it hurts, and belongs to me, it really does hurt more. AB - We examined changes in pain sensitivity in the rubber hand illusion (RHI). Experiment 1 investigated changes in pain tolerance immediately after a "healthy" and "wounded" RHI when immersing the hand in a cold pressor ice bath. There was 19% increased pain tolerance and increased perception detection threshold after the healthy RHI, but 11% reduction after the wounded RHI. Experiment 2 examined pain experience during the wounded RHI with capsaicin-induced hyperalgesia. Pain intensity and unpleasantness was higher on the illusion arm during the synchronous RHI, compared with asynchronous trials. There was no change in pain experience on the control arm, and both arms had similar pain sensitivity after the experiment. Our results highlight the impact of embodying a substitute limb on pain, with increased tolerance and reduced tactile sensitivity when the fake limb is healthy and apparently pain-free, but increased pain sensitivity when the self-attributed limb appears to be wounded. PMID- 26232355 TI - Association of complementary and alternative medicine use with symptoms and physical functional performance among adults with arthritis. AB - BACKGROUND: Research shows high prevalence of complementary and alternative medicine (CAM) use in individuals with arthritis. Little is known about CAM use and objectively measured physical functional performance. OBJECTIVE: The main objective was to determine if CAM use was associated with self-reported symptoms and physical functional performance in adults with arthritis. The secondary objectives were to describe the perceived helpfulness and correlates of CAM use. METHODS: We analyzed cross-sectional data from a self-administered questionnaire and objectively measured physical functional performance prior to randomization to a self-paced exercise program or control condition (n = 401). We used the Fisher's exact test, analysis of variance, and general linear models to examine the association of CAM use with socio-demographic characteristics, symptoms and functional performance. Logistic regression computed the odds of perceiving CAM as helpful by level of use. RESULTS: Most respondents had used CAM (76%). Dietary supplements were the most-used (53.1%). Female gender and college education predicted greater number of modalities used. Compared to non-users, use of any CAM was associated with greater fatigue and lower grip strength; relaxation techniques with lower walk distance and gait speed; dietary change with greater pain and stiffness and lower walk distance; and yoga with lower pain and stiffness, greater walk distance, chair stands, seated reach and gait, but lower grip strength. Perceived help was positively associated with the number of modalities used. CONCLUSIONS: Associations between CAM and symptoms or functional performance were mixed. Only yoga showed positive associations; however, yoga practitioners were more physically active overall than non-practitioners. PMID- 26232356 TI - Acute limb ischemia: contemporary approach. AB - Acute limb ischemia is a critical condition with high mortality and morbidity even after surgical or endovascular intervention. Early recognition is important, but a delayed presentation is not uncommon. Viability of the limb is assessed by motor and sensory function and with interrogating Doppler flow signals in pedal arteries and popliteal veins as categorized by Rutherford. Category IIa indicates mild-to-moderate threat to limb salvage over a time frame without revascularization. Limb ischemia is critical without prompt revascularization in category IIb. Because the risk of reperfusion injury is high in this group of patients, perioperative management is important. In category III, reperfusion is not indicated except for embolism within several hours of onset. Intimal injury should be avoided by careful tactile control of a balloon with a smaller size catheter and under radiographic monitoring. Adjunctive treatment with catheter directed thrombolysis or bypass surgery is sometimes necessary. Endovascular treatment is a promising option for thrombotic occlusion of an atherosclerotic artery. Ischemia-reperfusion injury is a serious problem. Controlled reperfusion with low-pressure perfusion at a reduced temperature and use of a leukocyte filter should be considered. The initial reperfusate is hyperosmolar, hypocalcemic, slightly alkaline, and contains free radical scavengers such as allopurinol. Immediate hemodialysis is necessary for acute renal injury caused by myoglobinemia. Compartment syndrome should be managed with assessment of intra compartment pressure and fasciotomy. PMID- 26232357 TI - Overview of multimodal therapy for adenocarcinoma of the esophagogastric junction. AB - The incidence of adenocarcinoma of the esophagogastric junction (AEG) has been rising. There is no standard treatment strategy for locally advanced AEG. The standard surgical treatment of Siewert type I AEG is Ivor-Lewis esophagectomy with mediastinal lymph node dissection. The optimal extent of mediastinal lymph node dissection for Siewert type II or III AEG with esophageal invasion of >3 cm remains unclear. Adjuvant chemotherapy should be added to the treatment of AEG. Many trials have demonstrated the beneficial effect of adjuvant chemotherapy. However, the combinations of chemotherapeutic agents and timing of administration of the drugs remains undefined. Adjuvant chemoradiotherapy has been investigated especially in Western countries. The INT-0116 revealed that adjuvant chemoradiotherapy with surgery is effective for AEG, and the CROSS trial showed that neoadjuvant chemoradiotherapy with surgery is effective for AEG. However, notice should be given to the relatively higher rate of distant metastasis after curative resection of AEG. Several molecular targeted agents have been investigated for the treatment of unresectable advanced AEG. Trastuzumab exhibited a beneficial effect for unresectable advanced AEG with overexpression of HER2. Whether the same effect is true in the adjuvant setting is being investigated. Systemic chemotherapy and surgical resection with adequate lymph node dissection may be more effective than localized treatment of chemoradiotherapy and surgical resection with limited lymph node dissection for locally advanced AEG. Molecular targeted agents may be beneficial for the treatment of locally advanced AEG. PMID- 26232358 TI - Simultaneous repair of pectus excavatum and pulmonary valve implantation years after complete repair of tetralogy of Fallot. AB - Although pectus excavatum is a common congenital abnormality of the chest wall, its coexistence with congenital heart defects is rarely encountered. In this report, we present a young adult who was re-operated for pulmonary valve regurgitation and pectus excavatum years after complete repair of tetralogy of Fallot. The surgical challenge and pitfalls are discussed along with a brief review of the literature. PMID- 26232359 TI - Gastrojejunal tube placement through an established gastrostomy via an endoscopic transgastric approach in a pediatric population. AB - BACKGROUND AND AIMS: Gastrojejunal feeding tubes (GJTs) are typically converted from gastrostomy feeding tubes by interventional radiology in many pediatric centers to provide both postpyloric feeding and gastric decompression. Endoscopic transgastric GJT placement via an established gastric stoma can be performed without sedation and with minimal fluoroscopy but is relatively new in pediatrics with limited description. This study analyzed the success rate, adverse events, and technical issues associated with endoscopic GJT placement via a transgastric approach in pediatric patients at a large children's hospital. METHODS: We retrospectively reviewed endoscopic GJT placements in pediatric patients performed over a 16-month period at the Children's Hospital of New York Presbyterian, Columbia University Medical Center. Indication for GJT placement, patient demographic characteristics and medical history, use of sedation, fluoroscopy time, and procedural and postprocedural adverse events were assessed. RESULTS: A total of 47 GJT placements were performed, all successful, in a patient cohort with a mean age of 8 years. The mean fluoroscopy time was 10 seconds, and sedation was used in 30% of placements. In 8 patients who had undergone GJT placement by endoscopy and interventional radiology, the fluoroscopy time was significantly reduced by using the endoscopic method (10 seconds vs 299 seconds, P = .001). CONCLUSIONS: Endoscopic transgastric GJT placement via an established gastrostomy with fluoroscopic confirmation can be safely performed by pediatric gastroenterologists without sedation and with minimal radiation exposure. PMID- 26232360 TI - International consensus guidelines for endoscopic papillary large-balloon dilation. PMID- 26232361 TI - EUS-guided ethanol ablation of symptomatic pancreatic insulinomas. PMID- 26232362 TI - ASGE Bariatric Endoscopy Task Force systematic review and meta-analysis assessing the ASGE PIVI thresholds for adopting endoscopic bariatric therapies. AB - The increasing global burden of obesity and its associated comorbidities has created an urgent need for additional treatment options to fight this pandemic. Endoscopic bariatric therapies (EBTs) provide an effective and minimally invasive treatment approach to obesity that would increase treatment options beyond surgery, medications, and lifestyle measures. This systematic review and meta analysis were performed by the American Society for Gastrointestinal Endoscopy (ASGE) Bariatric Endoscopy Task Force comprising experts in the subject area and the ASGE Technology Committee Chair to specifically assess whether acceptable performance thresholds outlined by an ASGE Preservation and Incorporation of Valuable endoscopic Innovations (PIVI) document for clinical adoption of available EBTs have been met. After conducting a comprehensive search of several English-language databases, we performed direct meta-analyses by using random effects models to assess whether the Orbera intragastric balloon (IGB) (Apollo Endosurgery, Austin, Tex) and the EndoBarrier duodenal-jejunal bypass sleeve (DJBS) (GI Dynamics, Lexington, Mass) have met the PIVI thresholds. The meta analyses results indicate that the Orbera IGB meets the PIVI thresholds for both primary and nonprimary bridge obesity therapy. Based on a meta-analysis of 17 studies including 1683 patients, the percentage of excess weight loss (%EWL) with the Orbera IGB at 12 months was 25.44% (95% confidence interval [CI], 21.47% 29.41%) (random model) with a mean difference in %EWL over controls of 26.9% (95% CI, 15.66%-38.24%; P <= .01) in 3 randomized, controlled trials. Furthermore, the pooled percentage of total body weight loss (% TBWL) after Orbera IGB implantation was 12.3% (95% CI, 7.9%-16.73%), 13.16% (95% CI, 12.37%-13.95%), and 11.27% (95% CI, 8.17%-14.36%) at 3, 6, and 12 months after implantation, respectively, thus exceeding the PIVI threshold of 5% TBWL for nonprimary (bridge) obesity therapy. With the data available, the DJBS liner does appear to meet the %EWL PIVI threshold at 12 months, resulting in 35% EWL (95% CI, 24%-46%) but does not meet the 15% EWL over control required by the PIVI. We await review of the pivotal trial data on the efficacy and safety of this device. Data are insufficient to evaluate PIVI thresholds for any other EBT at this time. Both evaluated EBTs had <=5% incidence of serious adverse events as set by the PIVI document to indicate acceptable safety profiles. Our task force consequently recognizes the Orbera IGB for meeting the PIVI criteria for the management of obesity. As additional data from the other EBTs become available, we will update our recommendations accordingly. PMID- 26232363 TI - Field-stepped direct detection electron paramagnetic resonance. AB - The widest scan that had been demonstrated previously for rapid scan EPR was a 155G sinusoidal scan. As the scan width increases, the voltage requirement across the resonating capacitor and scan coils increases dramatically and the background signal induced by the rapidly changing field increases. An alternate approach is needed to achieve wider scans. A field-stepped direct detection EPR method that is based on rapid-scan technology is now reported, and scan widths up to 6200G have been demonstrated. A linear scan frequency of 5.12kHz was generated with the scan driver described previously. The field was stepped at intervals of 0.01 to 1G, depending on the linewidths in the spectra. At each field data for triangular scans with widths up to 11.5G were acquired. Data from the triangular scans were combined by matching DC offsets for overlapping regions of successive scans. This approach has the following advantages relative to CW, several of which are similar to the advantages of rapid scan. (i) In CW if the modulation amplitude is too large, the signal is broadened. In direct detection field modulation is not used. (ii) In CW the small modulation amplitude detects only a small fraction of the signal amplitude. In direct detection each scan detects a larger fraction of the signal, which improves the signal-to-noise ratio. (iii) If the scan rate is fast enough to cause rapid scan oscillations, the slow scan spectrum can be recovered by deconvolution after the combination of segments. (iv) The data are acquired with quadrature detection, which permits phase correction in the post processing. (v) In the direct detection method the signal typically is oversampled in the field direction. The number of points to be averaged, thereby improving the signal-to-noise ratio, is determined in post processing based on the desired field resolution. A degased lithium phthalocyanine sample was used to demonstrate that the linear deconvolution procedure can be employed with field stepped direct detection EPR signals. Field-stepped direct detection EPR spectra were obtained for Cu(2+) doped in Ni(diethyldithiocarbamate)2, Cu(2+) doped in Zn tetratolylporphyrin, perdeuterated tempone in sucrose octaacetate, vanadyl ion doped in a parasubstituted Zn tetratolylporphyrin, Mn(2+) impurity in CaO, and an oriented crystal of Mn(2+) doped in Mg(acetylacetonate)2(H2O)2. PMID- 26232364 TI - First and second order derivatives for optimizing parallel RF excitation waveforms. AB - For piecewise constant magnetic fields, the Bloch equations (without relaxation terms) can be solved explicitly. This way the magnetization created by an excitation pulse can be written as a concatenation of rotations applied to the initial magnetization. For fixed gradient trajectories, the problem of finding parallel RF waveforms, which minimize the difference between achieved and desired magnetization on a number of voxels, can thus be represented as a finite dimensional minimization problem. We use quaternion calculus to formulate this optimization problem in the magnitude least squares variant and specify first and second order derivatives of the objective function. We obtain a small tip angle approximation as first order Taylor development from the first order derivatives and also develop algorithms for first and second order derivatives for this small tip angle approximation. All algorithms are accompanied by precise floating point operation counts to assess and compare the computational efforts. We have implemented these algorithms as callback functions of an interior-point solver. We have applied this numerical optimization method to example problems from the literature and report key observations. PMID- 26232365 TI - Single voxel localization for dynamic hyperpolarized (13)C MR spectroscopy. AB - The PRESS technique has been widely used to achieve voxel localization for in vivo(1)H MRS acquisitions. However, for dynamic hyperpolarized (13)C MRS experiments, the transition bands of the refocusing pulses may saturate the pre polarized substrate spins flowing into the voxel. This limitation may be overcome by designing refocusing pulses that do not perturb the resonance of the hyperpolarized substrate, but selectively refocuses the spins of the metabolic products. In this study, a PRESS pulse sequence incorporating spectral-spatial refocusing pulses that have a stop band ('notch') at the substrate resonance is tested in vivo using hyperpolarized [1-(13)C]pyruvate. Higher metabolite SNR was observed in experiments using the spectral-spatial refocusing pulses as compared to conventional refocusing pulses. PMID- 26232366 TI - Comparison of various NMR methods for the indirect detection of nitrogen-14 nuclei via protons in solids. AB - We present an experimental comparison of several through-space Hetero-nuclear Multiple-Quantum Correlation experiments, which allow the indirect observation of homo-nuclear single- (SQ) or double-quantum (DQ) (14)N coherences via spy (1)H nuclei. These (1)H-{(14)N} D-HMQC sequences differ not only by the order of (14)N coherences evolving during the indirect evolution, t1, but also by the radio frequency (rf) scheme used to excite and reconvert these coherences under Magic Angle Spinning (MAS). Here, the SQ coherences are created by the application of center-band frequency-selective pulses, i.e. long and low-power rectangular pulses at the (14)N Larmor frequency, nu0((14)N), whereas the DQ coherences are excited and reconverted using rf irradiation either at nu0((14)N) or at the (14)N overtone frequency, 2nu0((14)N). The overtone excitation is achieved either by constant frequency rectangular pulses or by frequency-swept pulses, specifically Wide-band, Uniform-Rate, and Smooth-Truncation (WURST) pulse shapes. The present article compares the performances of four different (1)H-{(14)N} D-HMQC sequences, including those with (14)N rectangular pulses at nu0((14)N) for the indirect detection of homo-nuclear (i) (14)N SQ or (ii) DQ coherences, as well as their overtone variants using (iii) rectangular or (iv) WURST pulses. The compared properties include: (i) the sensitivity, (ii) the spectral resolution in the (14)N dimension, (iii) the rf requirements (power and pulse length), as well as the robustness to (iv) rf offset and (v) MAS frequency instabilities. Such experimental comparisons are carried out for gamma-glycine and l-histidine.HCl monohydrate, which contain (14)N sites subject to moderate quadrupole interactions. We demonstrate that the optimum choice of the (1)H-{(14)N} D-HMQC method depends on the experimental goal. When the sensitivity and/or the robustness to offset are the major concerns, the D-HMQC sequence allowing the indirect detection of (14)N SQ coherences should be employed. Conversely, when the highest resolution and/or adjusted indirect spectral width are needed, overtone experiments are the method of choice. The overtone scheme using WURST pulses results in broader excitation bandwidths than that using rectangular pulses, at the expense of reduced sensitivity. Numerically exact simulations also show that the sensitivity of the overtone (1)H-{(14)N} D-HMQC experiment increases for larger quadrupole interactions. PMID- 26232367 TI - Tree-ring-based drought reconstruction in the Iberian Range (east of Spain) since 1694. AB - Droughts are a recurrent phenomenon in the Mediterranean basin with negative consequences for society, economic activities, and natural systems. Nevertheless, the study of drought recurrence and severity in Spain has been limited so far due to the relatively short instrumental period. In this work, we present a reconstruction of the standardized precipitation index (SPI) for the Iberian Range. Growth variations and climatic signals within the network are assessed developing a correlation matrix and the data combined to a single chronology integrating 336 samples from 169 trees of five different pine species distributed throughout the province of Teruel. The new chronology, calibrated against regional instrumental climatic data, shows a high and stable correlation with the July SPI integrating moisture conditions over 12 months forming the basis for a 318-year drought reconstruction. The climate signal contained in this reconstruction is highly significant (p < 0.05) and spatially robust over the interior areas of Spain located above 1000 meters above sea level (masl). According to our SPI reconstruction, seven substantially dry and five wet periods are identified since the late seventeenth century considering >=+/-1.76 standard deviations. Besides these, 36 drought and 28 pluvial years were identified. Some of these years, such as 1725, 1741, 1803, and 1879, are also revealed in other drought reconstructions in Romania and Turkey, suggesting that coherent larger scale synoptic patterns drove these extreme deviations. Since regional drought deviations are also retained in historical documents, the tree-ring-based reconstruction presented here will allow us to cross-validate drought frequency and magnitude in a highly vulnerable region. PMID- 26232368 TI - Dry period cooling ameliorates physiological variables and blood acid base balance, improving milk production in murrah buffaloes. AB - This study aimed to evaluate the impact of evaporative cooling during late gestation on physiological responses, blood gas and acid base balance and subsequent milk production of Murrah buffaloes. To investigate this study sixteen healthy pregnant dry Murrah buffaloes (second to fourth parity) at sixty days prepartum were selected in the months of May to June and divided into two groups of eight animals each. One group of buffaloes (Cooled/CL) was managed under fan and mist cooling system during dry period. Group second buffaloes (Noncooled/NCL) remained as control without provision of cooling during dry period. The physiological responses viz. Rectal temperature (RT), Respiratory rate (RR) and Pulse rate were significantly (P < 0.05) lower in group 2, with the provision of cooling. Skin surface temperature at thorax was significantly lower in cooled group relative to noncooled group. Blood pH and pO2 were significantly (P < 0.05) higher in heat stressed group as compared to the cooled group. pCO2, TCO2, HCO3, SBC, base excess in extracellular fluid (BEecf), base excess in blood (BEb), PCV and Hb were significantly (P < 0.05) higher in cooled group as compared to noncooled group. DMI was significantly (P < 0.05) higher in cooled relative to noncooled animals. Milk yield, FCM, fat yield, lactose yield and total solid yield was significantly higher (P < 0.05) in cooled group of Murrah buffaloes. PMID- 26232369 TI - Metabolic Imaging as a Biomarker of Early Radiation Response in Tumors. AB - (13)C-pyruvate hyperpolarized magnetic resonance imaging (HP-MRI) is emerging as a viable quantitative biomarker for solid tumor response and normal tissue toxicity after radiotherapy. This technology effectively predicts response related to metabolic agents or alterations in the tumor microenvironment, but challenges remain to be addressed to ensure successful translational implementation. See related article by Saito et al., p. 5073. PMID- 26232370 TI - Can the Lung Cancer Pie Be Divided into Angiogenic Slices? AB - There are no validated markers for predicting benefit from angiogenesis inhibitors or classifying tumors with distinct angiogenic phenotypes. In patients with non-small cell lung cancer treated with bevacizumab and erlotinib, Franzini and colleagues find that angiogenesis- and hypoxia-associated gene expression signatures predict tumor response and/or clinical outcome, and may define distinct angiogenic patterns. PMID- 26232371 TI - Parsimonious Description of Glucose Variability in Type 2 Diabetes by Sparse Principal Component Analysis. AB - BACKGROUND: Abnormal glucose variability (GV) is a risk factor for diabetes complications, and tens of indices for its quantification from continuous glucose monitoring (CGM) time series have been proposed. However, the information carried by these indices is redundant, and a parsimonious description of GV can be obtained through sparse principal component analysis (SPCA). We have recently shown that a set of 10 metrics selected by SPCA is able to describe more than 60% of the variance of 25 GV indicators in type 1 diabetes (T1D). Here, we want to extend the application of SPCA to type 2 diabetes (T2D). METHODS: A data set of CGM time series collected in 13 T2D subjects was considered. The 25 GV indices considered for T1D were evaluated. SPCA was used to select a subset of indices able to describe the majority of the original variance. RESULTS: A subset of 10 indicators was selected and allowed to describe 83% of the variance of the original pool of 25 indices. Four metrics sufficient to describe 67% of the original variance turned out to be shared by the parsimonious sets of indices in T1D and T2D. CONCLUSIONS: Starting from a pool of 25 indices assessed from CGM time series in T2D subjects, reduced subsets of metrics virtually providing the same information content can be determined by SPCA. The fact that these indices also appear in the parsimonious description of GV in T1D may indicate that they could be particularly informative of GV in diabetes, regardless of the specific type of disease. PMID- 26232372 TI - Decreased eGFR as a Risk Factor for Heart Failure in 13 781 Individuals With Type 1 Diabetes. AB - BACKGROUND: Impaired renal function is a well-known risk factor of cardiovascular disease, but its relation to heart failure in individuals with type 1 diabetes has been sparsely studied. The aim of our study was to quantify the risk increase for development of heart failure with decreasing kidney function in individuals with type 1 diabetes. METHODS: Three equations were used to calculate eGFR (estimated glomerular filtration rate) for individuals with T1D and no known heart failure in the Swedish National Diabetes Registry. Proportional hazards regression models were constructed to evaluate the association between eGFR and hospitalization for heart failure (HF). RESULTS: Among 13 781 individuals (mean age 41.1 [SD 13.3] years at baseline), 330 (2.4%) were hospitalized for HF over median follow-up of 7.0 years. Renal function was normal (eGFR > 90 mL/min/1.73 m(2)) in 67% of individuals according to the Cockcroft-Gault formula, compared to 51% and 41% according to the Chronic Kidney Disease Epidemiology (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) formulas. For eGFR 45-60 ml/min/1.73 m(2), hazard ratios (HRs) for hospitalization (reference >90 mL/min/1.73 m(2)) were 3.18 (95% CI 2.17, 4.65), 2.12 (1.16, 3.08), and 2.44 (1.69, 3.55) using the Cockcroft-Gault, MDRD, and CKD-EPI formulas. With eGFR <30 ml/min/1.73 m(2) there was a HR of 3.78 (2.15, 5.91), 3.44 (2.14, 5.51), and 3.51 (2.21, 5.51) compared to normal kidney function (>90 mL/min/1.73 m(2)). CONCLUSIONS: In individuals with T1D, risk of hospitalization for heart failure was over 2 times greater at eGFR 45-60 ml/min/1.73 m(2) and more than 3 times greater at eGFR <30 ml/min/1.73 m(2) when compared to normal eGFR. PMID- 26232373 TI - Optimizing tamoxifen-inducible Cre/loxp system to reduce tamoxifen effect on bone turnover in long bones of young mice. AB - For tamoxifen-dependent Cre recombinase, also known as CreER recombinase, tamoxifen (TAM) is used to activate the Cre to generate time- and tissue-specific mouse mutants. TAM is a potent CreER system inducer; however, TAM is also an active selective estrogen receptor modulator (SERM) that can influence bone homeostasis. The purpose of this study was to optimize the TAM dose for Cre recombinase activation while minimizing the effects of TAM on bone turnover in young growing mice. METHODS: To evaluate the effects of TAM on bone turnover and bone mass, 1-month-old wild-type male and female mice were intraperitoneally injected with TAM at 0, 1, 10 or 100mg/kg/day for four consecutive days, or 100, 300 mg/kg/day for one day. The distal femurs were analyzed one month after the last TAM injection by microCT, mechanical test, and surface-based bone histomorphometry. Similar doses of TAM were used in Col1 (2.3 kb)-CreERT2; mT/mG reporter male mice to evaluate the dose-dependent efficacy of Cre-ER activation in bone tissue. RESULTS: A TAM dose of 100 mg/kg * 4 days significantly increased trabecular bone volume/total volume (BV/TV) of the distal femur, femur length, bone strength, and serum bone turnover markers compared to the 0mg control group. In contrast, TAM doses <= 10 mg/kg did not significantly change any of these parameters compared to the 0mg group, although a higher bone strength was observed in the 10mg group. Surface-based histomorphometry revealed that the 100mg/kg dose of TAM dose significantly increased trabecular bone formation and decreased periosteal bone formation at 1-week post-TAM treatment. Using the reporter mouse model Col1-CreERT2; mT/mG, we found that 10mg/kg TAM induced Col1 CreERT2 activity in bone at a comparable level to the 100mg/kg dose. CONCLUSIONS: TAM treatment at 100mg/kg/day * 4 days significantly affects bone homeostasis, resulting in an anabolic bone effect on trabecular bone in 1-month-old male mice. However, a lower dose of TAM at 10 mg/kg/day * 4 days can yield similar Col1 CreERT2 induction efficacy with minimum effects on bone turnover in young male mice. PMID- 26232375 TI - Administration of romosozumab improves vertebral trabecular and cortical bone as assessed with quantitative computed tomography and finite element analysis. AB - Romosozumab inhibits sclerostin, thereby increasing bone formation and decreasing bone resorption. This dual effect of romosozumab leads to rapid and substantial increases in areal bone mineral density (aBMD) as measured by dual-energy X-ray absorptiometry (DXA). In a phase 1b, randomized, double-blind, placebo-controlled study, romosozumab or placebo was administered to 32 women and 16 men with low aBMD for 3 months, with a further 3-month follow-up: women received six doses of 1 or 2mg/kg every 2 weeks (Q2W) or three doses of 2 or 3mg/kg every 4 weeks (Q4W); men received 1mg/kg Q2W or 3mg/kg Q4W. Quantitative computed tomography (QCT) scans at lumbar (L1-2) vertebrae and high-resolution QCT (HR-QCT) scans at thoracic vertebra (T12) were analyzed in a subset of subjects at baseline, month 3, and month 6. The QCT subset included 24 romosozumab and 9 placebo subjects and the HR-QCT subset included 11 romosozumab and 3 placebo subjects. The analyses pooled the romosozumab doses. Linear finite element modeling of bone stiffness was performed. Compared with placebo, the romosozumab group showed improvements at month 3 for trabecular BMD by QCT and HR-QCT, HR-QCT trabecular bone volume fraction (BV/TV) and separation, density-weighted cortical thickness, and QCT stiffness (all p<0.05). At month 6, improvements from baseline were observed in QCT trabecular BMD and stiffness, and in HR-QCT BMD, trabecular BV/TV and separation, density-weighted cortical thickness, and stiffness in the romosozumab group (all p<0.05 compared with placebo). The mean (SE) increase in HR-QCT stiffness with romosozumab from baseline was 26.9% +/- 6.8% and 35.0% +/-6.8% at months 3 and 6, respectively; subjects administered placebo had changes of -2.7% +/- 13.4% and -6.4% +/- 13.4%, respectively. In conclusion, romosozumab administered for 3 months resulted in rapid and large improvements in trabecular and cortical bone mass and structure as well as whole bone stiffness, which continued 3 months after the last romosozumab dose. PMID- 26232376 TI - Mechanisms of liver fibrosis resolution. PMID- 26232374 TI - Phospho1 deficiency transiently modifies bone architecture yet produces consistent modification in osteocyte differentiation and vascular porosity with ageing. AB - PHOSPHO1 is one of principal proteins involved in initiating bone matrix mineralisation. Recent studies have found that Phospho1 KO mice (Phospho1-R74X) display multiple skeletal abnormalities with spontaneous fractures, bowed long bones, osteomalacia and scoliosis. These analyses have however been limited to young mice and it remains unclear whether the role of PHOSPHO1 is conserved in the mature murine skeleton where bone turnover is limited. In this study, we have used ex-vivo computerised tomography to examine the effect of Phospho1 deletion on tibial bone architecture in mice at a range of ages (5, 7, 16 and 34 weeks of age) to establish whether its role is conserved during skeletal growth and maturation. Matrix mineralisation has also been reported to influence terminal osteoblast differentiation into osteocytes and we have also explored whether hypomineralised bones in Phospho1 KO mice exhibit modified osteocyte lacunar and vascular porosity. Our data reveal that Phospho1 deficiency generates age-related defects in trabecular architecture and compromised cortical microarchitecture with greater porosity accompanied by marked alterations in osteocyte shape, significant increases in osteocytic lacuna and vessel number. Our in vitro studies examining the behaviour of osteoblast derived from Phospho1 KO and wild type mice reveal reduced levels of matrix mineralisation and modified osteocytogenic programming in cells deficient in PHOSPHO1. Together our data suggest that deficiency in PHOSPHO1 exerts modifications in bone architecture that are transient and depend upon age, yet produces consistent modification in lacunar and vascular porosity. It is possible that the inhibitory role of PHOSPHO1 on osteocyte differentiation leads to these age-related changes in bone architecture. It is also intriguing to note that this apparent acceleration in osteocyte differentiation evident in the hypomineralised bones of Phospho1 KO mice suggests an uncoupling of the interplay between osteocytogenesis and biomineralisation. Further studies are required to dissect the molecular processes underlying the regulatory influences exerted by PHOSPHO1 on the skeleton with ageing. PMID- 26232378 TI - Prolonged Somnolence in Alcoholic Patients with Epilepsy: A Case Report. PMID- 26232377 TI - Desire for female sterilization among women wishing to limit births in rural Rakai, Uganda. AB - OBJECTIVE: Uganda has an unmet need for family planning of 34% and a total fertility rate of 6.2. We assessed the desire for female sterilization among sexually active women who wanted to stop childbearing in rural Rakai district, Uganda. STUDY DESIGN: 7192 sexually active women enrolled in a community cohort between 2002 and 2008 were asked about fertility intentions. Those stating that they did not want another child (limiters) were asked whether they would be willing to accept female sterilization, if available. Trends in desire for sterilization were determined by chi-square test for trend, and Modified Poisson regression was used to estimate prevalence rate ratios and 95% confidence intervals of the associations between desire for sterilization and socio demographic characteristics and HIV status. RESULTS: From 2002 to 2008, the proportion of limiters dropped (from 47.2% to 43.7%; p<.01). Use of pills and injectables among limiters significantly increased, 38.9% to 50.3% (p<.0001), while use of intrauterine devices and implants declined from 3.3% to 1.7% (p<0.001). The desire for sterilization significantly increased from 54.2% to 63.1% (p<0.0001), and this was consistently higher among the HIV-positive (63.6 70.9%, p<0.01) than HIV-negative women (53.3-61.2%, p<0.0001). Factors significantly associated with the desire for sterilization included higher number of living children (>=3), being HIV-infected and having received HIV counseling and testing. CONCLUSION: There is latent and growing desire for sterilization in this population. Our findings suggest a need to increase permanent contraception services for women who want to limit childbearing in this setting. IMPLICATIONS: A large unmet need for permanent female contraception services exists in Uganda. Efforts to increase the method mix by increasing permanent contraception services could reduce fertility rates and undesired births. PMID- 26232388 TI - Clinical and Patient-reported Outcomes of a Zirconia Oral Implant: Three-year Results of a Prospective Cohort Investigation. AB - The objective of this study was to determine the clinical, radiographic, and patient-reported outcomes of a 1-piece alumina-toughened zirconia implant restored with single crowns (SCs) or 3-unit fixed dental prostheses (FDPs) after 3 y of observation. Forty patients received 53 implants, placed in a 1-stage operation with immediate temporization. Finally, 50 implants were restored with 24 SCs and 13 FDPs. To evaluate peri-implant bone loss, standardized radiographs were taken at implant insertion, at final restoration delivery, and after 1 and 3 y. Additionally, several soft tissue parameters and patient-reported outcome measures were evaluated. Linear mixed models with random intercept for each patient and patients as clusters were used to compare subgroups. Three patients did not receive a SC due to early implant loss, and 1 patient died. As a result, 36 patients with 49 implants were followed-up for 3 y, giving a cumulative survival rate of 94.2%. The average marginal bone loss amounted to 0.79 mm (SCs, 0.47 mm; FDPs, 1.07 mm; P < 0.001). After the delivery of the final prosthetic restoration, further bone loss was not statistically significant (0.09 mm; P = 0.700). Probing depth, clinical attachment level, and modified bleeding index increased significantly at the implant sites, whereas gingival recession decreased significantly. Compared with the pretreatment questionnaires, the patient-reported outcome measures showed a permanently improved perception of function, aesthetics, sense, speech and self-esteem. The survival rate of the investigated ceramic implant system seems to be comparable to reported survival rates of titanium implants when immediately restored. The recorded parameters suggest its potential for clinical utilization. PMID- 26232387 TI - Store-operated Ca2+ Entry Modulates the Expression of Enamel Genes. AB - Dental enamel formation is an intricate process tightly regulated by ameloblast cells. The correct spatiotemporal patterning of enamel matrix protein (EMP) expression is fundamental to orchestrate the formation of enamel crystals, which depend on a robust supply of Ca2+. In the extracellular milieu, Ca2+ -EMP interactions occur at different levels. Despite its recognized role in enamel development, the molecular machinery involved in Ca2+ homeostasis in ameloblasts remains poorly understood. A common mechanism for Ca2+ influx is store-operated Ca2+ entry (SOCE). We evaluated the possibility that Ca2+ influx in enamel cells might be mediated by SOCE and the Ca2+ release-activated Ca2+ (CRAC) channel, the prototypical SOCE channel. Using ameloblast-like LS8 cells, we demonstrate that these cells express Ca2+ -handling molecules and mediate Ca2+ influx through SOCE. As a rise in the cytosolic Ca2+ concentration is a versatile signal that can modulate gene expression, we assessed whether SOCE in enamel cells had any effect on the expression of EMPs. Our results demonstrate that stimulating LS8 cells or murine primary enamel organ cells with thapsigargin to activate SOCE leads to increased expression of Amelx, Ambn, Enam, Mmp20. This effect is reversed when cells are treated with a CRAC channel inhibitor. These data indicate that Ca2+ influx in LS8 cells and enamel organ cells is mediated by CRAC channels and that Ca2+ signals enhance the expression of EMPs. Ca2+ plays an important role not only in mineralizing dental enamel but also in regulating the expression of EMPs. PMID- 26232389 TI - Aneurysms of the foot arteries. AB - Aneurysms of the foot arteries are uncommon but can lead to devastating complications such as acute foot ischemia or arterial rupture if left untreated. In this case series, we present four cases of aneurysms of the foot: one true dorsalis pedis artery aneurysm and three cases of post-traumatic plantar artery pseudoaneurysms with arteriovenous fistulas. All four patients were successfully managed with surgical excision of the aneurysm with or without arteriovenous fistulas ligation. Our case series is followed by discussion on the etiology, clinical presentation and management strategy of patients with aneurysms of the foot arteries. PMID- 26232390 TI - Mortality outcomes of ruptured abdominal aortic aneurysms and rural presentation. AB - OBJECTIVES: Centralisation of vascular surgery services has coincided with a move towards endovascular repair of ruptured abdominal aortic aneurysms with the goal to improve patient outcomes. The aim of this study was to assess the effect of rural presentation and transfer times on survival from ruptured abdominal aortic aneurysm. DESIGN: A retrospective review. MATERIALS: All patients presenting with ruptured abdominal aortic aneurysm to public hospitals in Tasmania between July 2006 and April 2013. METHODS: Demographic data, Glasgow aneurysm score, Hardman index, transfer times, operative technique and 30-day mortality were collected from medical records. RESULTS: Over the study period 127 patients presented to public hospitals in Tasmania with ruptured abdominal aortic aneurysm. A total of 27 presented to north west hospitals where no vascular surgery service is provided (NWRH), 23 to a northern hospital where an intermittent vascular surgery service is provided (LGH) and 77 to the state tertiary vascular surgery service (RHH). Of these, 4 (14.8%) died at NWRH, 6 (26.1%) died at LGH and 43 (55.8%) died at RHH without operation. Of the 35 patients transferred from NWRH and LGH to RHH, 5 died without operation. Median time from presentation to theatre at RHH if transferred from NWRH was 6.25 hours, from the LGH 4.75 hours, compared to 2.75 hours when presenting directly to RHH. Open repair was performed in 41 patients and endovascular repair in 23 patients. Overall 30-day mortality in those treated at RHH was 26.6% (39.0% for open repair, 4.3% for endovascular repair). Mortality for intended operative patients initially presenting to non RHH hospitals was 33.3% vs. 32.3% for those initially presenting to RHH. p Value 0.93. CONCLUSION: There was no clinical or statistical disadvantage to rural presentation and transfer for patients presenting with ruptured abdominal aortic aneurysm in Tasmania. Endovascular repair has a role despite long transfer times. PMID- 26232391 TI - The shear stess profile of the pivotal fenestrated endograft at the level of the renal branches: A computational study for complex aortic aneurysms. AB - PURPOSE: This study investigated the impact of the variant angulations on the values and distribution of wall shear stress on the renal branches and the mating vessels of a pivotal fenestrated design. METHODS: An idealized endograft model of two renal branches was computationally reconstructed with variable angulations of the left renal branch. These ranged from the 1:30' to 3:30' o'clock position, corresponding from 45 degrees to 105 degrees with increments of 15 degrees . A fluid-structure-interaction analysis was performed to estimate the wall shear stress. RESULTS: The proximal part of the renal branch preserved quite constant wall shear stress. The transition zone between its distal end and the renal artery showed the highest values compared to the proximal and middle segments, ranging from 8.9 to 12.4 Pa. The lowest stress values presented at 90 degrees whereas the highest at 45 degrees . The post-mating arterial segment showed constantly low stress values regardless of the pivotal branch angle (6.3 to 6.6 Pa). The 45 degrees configuration showed a distribution of the highest stress posteriorly whereas the 105 degrees -angulation anteriorly. CONCLUSIONS: The variant horizontal branch orientation influences the wall shear stress distribution across its length and affects its values only at its transition with the mating vessel. These findings and their potential association with adverse effects deserve further clinical validation. PMID- 26232392 TI - Inflammation in Alzheimer's Disease and Molecular Genetics: Recent Update. AB - Alzheimer's disease (AD) is a complex age-related neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease. After three decades of genetic study in AD, dozens of loci harboring genetic variants influencing inflammatory pathways in AD patients has been identified through genome-wide association studies (GWAS). The most well-known GWAS risk factor that is responsible for immune response and inflammation in AD development should be APOE epsilon4 allele. However, a growing number of other GWAS risk AD candidate genes in inflammation have recently been discovered. In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2. PMID- 26232393 TI - Long term outcomes of transplantation using kidneys from expanded criteria donors: prospective, population based cohort study. AB - OBJECTIVES: To assess the long term outcomes of transplantation using expanded criteria donors (ECD; donors aged >= 60 years or aged 50-59 years with vascular comorbidities) and assess the main determinants of its prognosis. DESIGN: Prospective, population based cohort study. SETTING: Four French referral centres. PARTICIPANTS: Consecutive patients who underwent kidney transplantation between January 2004 and January 2011, and were followed up to May 2014. A validation cohort included patients from another four referral centres in France who underwent kidney transplantation between January 2002 and December 2011. MAIN OUTCOME MEASURES: Long term kidney allograft survival, based on systematic assessment of donor, recipient, and transplant clinical characteristics; preimplantation biopsy; and circulating levels of donor specific anti-HLA (human leucocyte antigen) antibody (DSA) at baseline. RESULTS: The study included 6891 patients (2763 in the principal cohort, 4128 in the validation cohort). Of 2763 transplantations performed, 916 (33.2%) used ECD kidneys. Overall, patients receiving ECD transplants had lower allograft survival after seven years than patients receiving transplants from standard criteria donors (SCD; 80% v 88%, P<0.001). Patients receiving ECD transplants who presented with circulating DSA at the time of transplantation had worse allograft survival after seven years than patients receiving ECD kidneys without circulating DSA at transplantation (44% v 85%, P < 0.001). After adjusting for donor, recipient, and transplant characteristics, as well as preimplantation biopsy findings and baseline immunological parameters, the main independent determinants of long term allograft loss were identified as allocation of ECDs (hazard ratio 1.84 (95% confidence interval 1.5 to 2.3); P < 0.001), presence of circulating DSA on the day of transplantation (3.00 (2.3 to 3.9); P < 0.001), and longer cold ischaemia time (> 12 h; 1.53 (1.1 to 2.1); P = 0.011). Recipients of ECD kidneys with circulating DSA showed a 5.6-fold increased risk of graft loss compared with all other transplant therapies (P < 0.001). ECD allograft survival at seven years significantly improved with screening and transplantation in the absence of circulating DSA (P < 0.001) and with shorter (<12 h) cold ischaemia time (P=0.030), respectively. This strategy achieved ECD graft survival comparable to that of patients receiving an SCD transplant overall, translating to a 544.6 allograft life years saved during the nine years of study inclusion time. CONCLUSIONS: Circulating DSA and cold ischaemia time are the main independent determinants of outcome from ECD transplantation. Allocation policies to avoid DSA and reduction of cold ischaemia time to increase efficacy could promote wider implement of ECD transplantation in the context of organ shortage and improve its prognosis. PMID- 26232395 TI - Hierarchical regression for analyses of multiple outcomes. AB - In cohort mortality studies, there often is interest in associations between an exposure of primary interest and mortality due to a range of different causes. A standard approach to such analyses involves fitting a separate regression model for each type of outcome. However, the statistical precision of some estimated associations may be poor because of sparse data. In this paper, we describe a hierarchical regression model for estimation of parameters describing outcome specific relative rate functions and associated credible intervals. The proposed model uses background stratification to provide flexible control for the outcome specific associations of potential confounders, and it employs a hierarchical "shrinkage" approach to stabilize estimates of an exposure's associations with mortality due to different causes of death. The approach is illustrated in analyses of cancer mortality in 2 cohorts: a cohort of dioxin-exposed US chemical workers and a cohort of radiation-exposed Japanese atomic bomb survivors. Compared with standard regression estimates of associations, hierarchical regression yielded estimates with improved precision that tended to have less extreme values. The hierarchical regression approach also allowed the fitting of models with effect-measure modification. The proposed hierarchical approach can yield estimates of association that are more precise than conventional estimates when one wishes to estimate associations with multiple outcomes. PMID- 26232394 TI - Modulatory influences of estradiol and other anorexigenic hormones on metabotropic, Gi/o-coupled receptor function in the hypothalamic control of energy homeostasis. AB - The appetite suppressant actions of estradiol are due to its ability to attenuate orexigenic signals and potentiate anorexigenic signals. The work from my laboratory has shown that male guinea pigs are more sensitive to the hyperphagic and hypothermic effects of cannabinoids than their female counterparts. Cannabinoid sensitivity is further dampened by the activational effects of estradiol. This occurs via the hypothalamic feeding circuitry, where estradiol rapidly attenuates the cannabinoid CB1 receptor-mediated presynaptic inhibition of glutamatergic input onto anorexigenic proopiomelanocortin (POMC) neurons in the arcuate nucleus. This disruption is blocked by the estrogen receptor antagonist ICI 182,780, and associated with increased expression of phosphatidylinositol-3-kinase (PI3K). Moreover, the ability of estradiol to reduce both the cannabinoid-induced hyperphagia and glutamate release onto POMC neurons is abrogated by the PI3K inhibitor PI 828. The peptide orphanin FQ/nociceptin (OFQ/N) activates opioid receptor-like (ORL)1 receptors to hyperpolarize and inhibit POMC neurons via the activation of postsynaptic G protein-gated, inwardly-rectifying (GIRK) channels. We have demonstrated that the fasting-induced hyperphagia observed in ORL1-null mice is blunted compared to wild type controls. In addition, the ORL1 receptor-mediated activation of GIRK channels in POMC neurons from ovariectomized female rats is markedly impaired by estradiol. The estrogenic attenuation of presynaptic CB1 and postsynaptic ORL1 receptor function may be part of a more generalized mechanism through which anorexigenic hormones suppress orexigenic signaling. Indeed, we have found that leptin robustly suppresses the OFQ/N-induced activation of GIRK channels in POMC neurons. Furthermore, its ability to augment excitatory input onto POMC neurons is blocked by PI 828. Thus, estradiol and other hormones like leptin reduce energy intake at least partly by activating PI3K to disrupt the pleiotropic functions of Gi/o-coupled receptors that inhibit anorexigenic POMC neurons. PMID- 26232397 TI - Ebola vaccine trial results are "extremely promising," says WHO. PMID- 26232398 TI - Early Experience With a Novel Hybrid Vascular Graft for Hemodialysis Access Creation in Patients With Disadvantaged Anatomy. AB - PURPOSE: To describe the use of the Hybrid vascular graft in disadvantaged anatomy for hemodialysis access creation and compare outcomes to standard-wall polytetrafluoroethylene (PTFE) grafts. METHODS: In a retrospective analysis, 25 patients (mean age 65+/-14 years; 13 men) who received the Hybrid graft were compared with 35 contemporaneous patients (mean age 63+/-12 years; 20 men) who received a standard PTFE graft for hemodialysis access over a 2-year period. Criteria for Hybrid graft placement were (1) exhausted or inadequate peripheral veins for arteriovenous fistula (AVF) creation and concomitant small target veins that precluded conventional PTFE graft placement, (2) previous graft anastomosis or a stent in the venous target at the level of the axilla, or (3) failed brachial-basilic or brachial-brachial upper arm transposition AVF with a small target vein at the axilla. Efficacy, anatomic and clinical considerations, and technique were reviewed; patency rates, complications, and reinterventions were examined. RESULTS: Technical success was achieved in all cases, and all grafts were usable for hemodialysis. Seven of 25 Hybrid patients required stent-graft extensions and 3 patients required angioplasty to improve venous outflow at the time of Hybrid graft insertion. Three of 35 standard PTFE graft patients required angioplasty to improve venous outflow at the time of graft insertion. There was no perioperative mortality or procedure-related morbidity in either group. Median follow-up was 21 months. The patient survival estimate was 66% at 2 years. Estimated primary patency (24% vs 18%, p>0.05), assisted primary patency (34% vs 28%; p>0.05), and secondary patency rates (40% vs 38%, p>=0.05) at 24 months were equivalent for Hybrid vs PTFE grafts, respectively. Venous hypertension was not a complication following Hybrid graft implantation but was seen in 2 patients with the standard PTFE graft. CONCLUSION: The Hybrid graft offers a safe, technically effective alternative for patients with disadvantaged anatomy requiring hemodialysis access and has comparable outcomes to standard PTFE grafts. Further clinical experience and long-term data are required for determining the proper utility of this device in chronic dialysis-dependent patients. PMID- 26232396 TI - KLF/SP Transcription Factor Family Evolution: Expansion, Diversification, and Innovation in Eukaryotes. AB - The Kruppel-like factor and specificity protein (KLF/SP) genes play key roles in critical biological processes including stem cell maintenance, cell proliferation, embryonic development, tissue differentiation, and metabolism and their dysregulation has been implicated in a number of human diseases and cancers. Although many KLF/SP genes have been characterized in a handful of bilaterian lineages, little is known about the KLF/SP gene family in nonbilaterians and virtually nothing is known outside the metazoans. Here, we analyze and discuss the origins and evolutionary history of the KLF/SP transcription factor family and associated transactivation/repression domains. We have identified and characterized the complete KLF/SP gene complement from the genomes of 48 species spanning the Eukarya. We have also examined the phylogenetic distribution of transactivation/repression domains associated with this gene family. We report that the origin of the KLF/SP gene family predates the divergence of the Metazoa. Furthermore, the expansion of the KLF/SP gene family is paralleled by diversification of transactivation domains via both acquisitions of pre-existing ancient domains as well as by the appearance of novel domains exclusive to this gene family and is strongly associated with the expansion of cell type complexity. PMID- 26232399 TI - Meta-analysis of the Effect of Stent Design on 30-Day Outcome After Carotid Artery Stenting. AB - PURPOSE: To review the contemporary literature and analyze whether stent cell design plays a role in 30-day outcomes after carotid artery stenting (CAS). METHODS: A systematic review of the literature was undertaken that identified 9 studies comparing the effect of different cell design on 30-day outcome in patients undergoing CAS. Random-effects models were applied to calculate pooled outcome data for mortality and cerebrovascular morbidity. Results are reported as the odds ratio (OR) and 95% confidence interval (CI). RESULTS: The 9 studies included 8018 patients who underwent 8028 CAS procedures (4018 open-cell stents, 4010 closed-cell stents). Six studies were retrospective in design, one was a registry, and only two studies prospectively compared the effect of different cell designs. Nearly half of the patients (3452, 43.1%) were symptomatic, with no significant difference between the closed- and open-cell stent groups (p=0.93). During the first month after the procedure, there were no significant differences in mortality (OR 0.69, 95% CI 0.39 to 1.24, p=0.21), transient ischemic attacks (OR 0.95, 95% CI 0.69 to 1.30, p=0.74), or strokes (OR 1.17, 95% CI 0.83 to 1.66, p=0.37). CONCLUSION: This meta-analysis showed that 30-day cerebrovascular complications after CAS were not significantly different for the open-cell group in comparison to the closed-cell group. Future prospective clinical trials comparing different free cell areas and other stent design properties are still needed to further investigate whether stent design plays a significant role in the results of carotid stenting. PMID- 26232400 TI - Insights into the mechanism of type I dehydroquinate dehydratases from structures of reaction intermediates. PMID- 26232401 TI - Dopamine transporter activity is modulated by alpha-synuclein. AB - This article was withdrawn by the authors before final publication on June 30, 2015. PMID- 26232402 TI - Demonstration of GTG as an endogenous initiation codon for a human mRNA transcript revealed by molecular cloning of the serpin endopin 2B. AB - This article was withdrawn by the authors before final publication on August 25, 2004. PMID- 26232403 TI - Quantification of mutation-derived bias for alternate mating functionalities of the Saccharomyces cerevisiae Ste2p pheromone receptor. AB - Although well documented for mammalian G-protein-coupled receptors, alternate functionalities and associated alternate signalling remain to be unequivocally established for the Saccharomyces cerevisiae pheromone Ste2p receptor. Here, evidence supporting alternate functionalities for Ste2p is re-evaluated, extended and quantified. In particular, strong mating and constitutive signalling mutations, focusing on residues S254, P258 and S259 in TM6 of Ste2p, are stacked and investigated in terms of their effects on classical G-protein-mediated signal transduction associated with cell cycle arrest, and alternatively, their impact on downstream mating projection and zygote formation events. In relative dose response experiments, accounting for systemic and observational bias, mutational derived functional differences were observed, validating the S254L-derived bias for downstream mating responses and highlighting complex relationships between TM6-mutation derived constitutive signalling and ligand-induced functionalities. Mechanistically, localization studies suggest that alterations to receptor trafficking may contribute to mutational bias, in addition to expected receptor conformational stabilization effects. Overall, these results extend previous observations and quantify the contributions of Ste2p variants to mediating cell cycle arrest versus downstream mating functionalities. PMID- 26232404 TI - Cloning and characterization of the first polysaccharide lyase family 6 oligoalginate lyase from marine Shewanella sp. Kz7. AB - Alginate, the most abundant carbohydrate in brown macroalgae, is widely used in the food and pharmaceutical industries. Recently, alginate has attracted increasing attention, as it may serve as an alternative biomass for the production of biofuel. The degradation of alginate into monomeric units is the prerequisite for bioethanol production. All known oligoalginate lyases belong to the polysaccharide lyase (PL) family 7, 14, 15 and 17, and most of them preferred to degrade the polyM blocks to yield 4-deoxy-l-erythro-5-hexoseulose uronic acid as the primary product. In this study, we cloned an oligoalginate lyase gene, oalS6, from Shewanella sp. Kz7 and expressed it in Escherichia coli. The PL family 6 oligoalginate lyase (OalS6) has no significant sequence similarity with other known oligoalginate lyases. OalS6 contains a chondroitinase-like domain and was assigned to the PL family 6. This lyase is an exo-type oligoalginate lyase and prefer to depolymerize polyG block into 2, 4, 5, 6-tetrahydroxytetrahydro-2H pyran-2-carboxylic acid. All of these results indicate that OalS6 is a novel oligoalginate lyase that is structurally and functionally different from other known oligoalginate lyases. This finding provides new insights into the development of biofuel processing biotechnologies from seaweed. PMID- 26232405 TI - Autonomic Nervous System Dysfunction in Patients With Parkinson Disease Having Depression. AB - BACKGROUND AND AIM: Both depression and cardiovascular autonomic dysfunctions, such as orthostatic hypotension, supine hypertension, and the absence of normal nocturnal blood pressure (BP) fall ("nondipping"), occur relatively commonly in Parkinson disease (PD); however, the relationship between depression and cardiovascular autonomic abnormalities has not been established. In this study, we sought to determine whether the cardiovascular autonomic abnormalities found in PD are associated with depression. METHODS: Among 129 nondemented, levodopa naive patients with mild PD, 44 had depression. Orthostatic vital signs and ambulatory 24-hour BP monitoring were recorded, and geriatric depressive scales were obtained in all patients. Associations between orthostatic hypotension, supine hypertension, nocturnal hypertension, nondipping, and depression were analyzed. The ratio of the standard deviation of 24-hour heart rate to that of systolic BP (SBP) was utilized as an index of baroreflex-cardiovagal function. RESULTS: Depression was associated with orthostatic hypotension, and patients with depression had higher SBP change during orthostasis and attenuated cardiovagal dysfunction as observed during ambulatory BP monitoring. Across individuals, values for orthostatic changes in BP were correlated with values for geriatric depressive scale. CONCLUSION: Depression is associated with neurocirculatory abnormalities-especially orthostatic hypotension-in early PD. Although the association does not imply causation, this result suggests that depression in PD might be associated with functional impairment of the autonomic nervous system and its pathologic substrate. PMID- 26232406 TI - Visual Priming and Visual Hallucinations in Parkinson's Disease. Evidence for Normal Top-Down Processes. AB - BACKGROUND: Visual hallucinations (VH) are common in Parkinson's disease (PD) and are associated with increased morbidity and mortality. Current explanations for VH in PD suggest combined impairments in top-down attentional and bottom-up perceptual processes, which allow the passive "release" of stored images. Alternative models in other disorders have suggested that top-down factors may actively encourage hallucinations. In order to explore the interaction between top-down and bottom-up visual processing in PDVH, we developed novel experimental priming tasks in which top-down verbal cues were used to prime the bottom-up recognition of partial or ambiguous pictures. METHOD: Two groups of PD participants with (PD + VH, n = 16), and without VH (PD - VH, n = 20) were compared to a group of healthy older adults (NC, n = 20) on 3 novel measures of visual priming. RESULTS: All tasks showed significant priming effects. The PD + VH group was more impaired at accurately identifying silhouette and fragmented images compared to the PD - VH group. There were no differences in priming between the 2 PD groups. CONCLUSIONS: The study showed that VH in PD are not associated with relatively greater top-down activation, and that the interaction between top-down and bottom-up processes is intact. PMID- 26232407 TI - Emotional Decoding Abilities Do Not Influence Neuropsychiatric Disturbances in Patients With Frontotemporal Dementia. AB - The ability to accurately recognize emotional information belongs to very important interpersonal communication skills in humans. Disturbance of emotional processing is present in behavioral variant of frontotemporal dementia (bvFTD), and the severity of pathological behavior may be linked to misunderstanding of other people's emotions. In our study, we examined hypothesis that patients with worse ability to decode emotions have more behavioral and psychopathological disturbances--the most challenging manifestations of dementia--than those who decode emotions better. We were not able to prove this hypothesis. The ability to decode emotions in patients with bvFTD did not influenced their behavior. PMID- 26232408 TI - Regulatory Rewiring in a Cross Causes Extensive Genetic Heterogeneity. AB - Genetic heterogeneity occurs when individuals express similar phenotypes as a result of different underlying mechanisms. Although such heterogeneity is known to be a potential source of unexplained heritability in genetic mapping studies, its prevalence and molecular basis are not fully understood. Here we show that substantial genetic heterogeneity underlies a model phenotype--the ability to grow invasively--in a cross of two Saccharomyces cerevisiae strains. The heterogeneous basis of this trait across genotypes and environments makes it difficult to detect causal loci with standard genetic mapping techniques. However, using selective genotyping in the original cross, as well as in targeted backcrosses, we detected four loci that contribute to differences in the ability to grow invasively. Identification of causal genes at these loci suggests that they act by changing the underlying regulatory architecture of invasion. We verified this point by deleting many of the known transcriptional activators of invasion, as well as the gene encoding the cell surface protein Flo11 from five relevant segregants and showing that these individuals differ in the genes they require for invasion. Our work illustrates the extensive genetic heterogeneity that can underlie a trait and suggests that regulatory rewiring is a basic mechanism that gives rise to this heterogeneity. PMID- 26232409 TI - Modeling the Manipulation of Natural Populations by the Mutagenic Chain Reaction. AB - The use of recombinant genetic technologies for population manipulation has mostly remained an abstract idea due to the lack of a suitable means to drive novel gene constructs to high frequency in populations. Recently Gantz and Bier showed that the use of CRISPR/Cas9 technology could provide an artificial drive mechanism, the so-called mutagenic chain reaction (MCR), which could lead to rapid fixation of even a deleterious introduced allele. We establish the near equivalence of this system to other gene drive models and review the results of simple models showing that, when there is a fitness cost to the MCR allele, an internal equilibrium may exist that is usually unstable. In this case, introductions must be at a frequency above this critical point for the successful invasion of the MCR allele. We obtain estimates of fixation and invasion probabilities for the appropriate scenarios. Finally, we discuss how polymorphism in natural populations may introduce sources of natural resistance to MCR invasion. These modeling results have important implications for application of MCR in natural populations. PMID- 26232410 TI - Efficient Genome Editing in Caenorhabditis elegans with a Toolkit of Dual-Marker Selection Cassettes. AB - Use of the CRISPR/Cas9 RNA-guided endonuclease complex has recently enabled the generation of double-strand breaks virtually anywhere in the C. elegans genome. Here, we present an improved strategy that makes all steps in the genome editing process more efficient. We have created a toolkit of template-mediated repair cassettes that contain an antibiotic resistance gene to select for worms carrying the repair template and a fluorescent visual marker that facilitates identification of bona fide recombinant animals. Homozygous animals can be identified as early as 4-5 days post-injection, and minimal genotyping by PCR is required. We demonstrate that our toolkit of dual-marker vectors can generate targeted disruptions, deletions, and endogenous tagging with fluorescent proteins and epitopes. This strategy should be useful for a wide variety of additional applications and will provide researchers with increased flexibility when designing genome editing experiments. PMID- 26232411 TI - Cooperative target mRNA destabilization and translation inhibition by miR-58 microRNA family in C. elegans. AB - In animals, microRNAs frequently form families with related sequences. The functional relevance of miRNA families and the relative contribution of family members to target repression have remained, however, largely unexplored. Here, we used the Caenorhabditis elegans miR-58 miRNA family, composed primarily of the four highly abundant members miR-58.1, miR-80, miR-81, and miR-82, as a model to investigate the redundancy of miRNA family members and their impact on target expression in an in vivo setting. We found that miR-58 family members repress largely overlapping sets of targets in a predominantly additive fashion. Progressive deletions of miR-58 family members lead to cumulative up-regulation of target protein and RNA levels. Phenotypic defects could only be observed in the family quadruple mutant, which also showed the strongest change in target protein levels. Interestingly, although the seed sequences of miR-80 and miR-58.1 differ in a single nucleotide, predicted canonical miR-80 targets were efficiently up-regulated in the mir-58.1 single mutant, indicating functional redundancy of distinct members of this miRNA family. At the aggregate level, target binding leads mainly to mRNA degradation, although we also observed some degree of translational inhibition, particularly in the single miR-58 family mutants. These results provide a framework for understanding how miRNA family members interact to regulate target mRNAs. PMID- 26232412 TI - Comparison against 186 canid whole-genome sequences reveals survival strategies of an ancient clonally transmissible canine tumor. AB - Canine transmissible venereal tumor (CTVT) is a parasitic cancer clone that has propagated for thousands of years via sexual transfer of malignant cells. Little is understood about the mechanisms that converted an ancient tumor into the world's oldest known continuously propagating somatic cell lineage. We created the largest existing catalog of canine genome-wide variation and compared it against two CTVT genome sequences, thereby separating alleles derived from the founder's genome from somatic mutations that must drive clonal transmissibility. We show that CTVT has undergone continuous adaptation to its transmissible allograft niche, with overlapping mutations at every step of immunosurveillance, particularly self-antigen presentation and apoptosis. We also identified chronologically early somatic mutations in oncogenesis- and immune-related genes that may represent key initiators of clonal transmissibility. Thus, we provide the first insights into the specific genomic aberrations that underlie CTVT's dogged perseverance in canids around the world. PMID- 26232414 TI - A visual horizon affects steering responses during flight in fruit flies. AB - To navigate well through three-dimensional environments, animals must in some way gauge the distances to objects and features around them. Humans use a variety of visual cues to do this, but insects, with their small size and rigid eyes, are constrained to a more limited range of possible depth cues. For example, insects attend to relative image motion when they move, but cannot change the optical power of their eyes to estimate distance. On clear days, the horizon is one of the most salient visual features in nature, offering clues about orientation, altitude and, for humans, distance to objects. We set out to determine whether flying fruit flies treat moving features as farther off when they are near the horizon. Tethered flies respond strongly to moving images they perceive as close. We measured the strength of steering responses while independently varying the elevation of moving stimuli and the elevation of a virtual horizon. We found responses to vertical bars are increased by negative elevations of their bases relative to the horizon, closely correlated with the inverse of apparent distance. In other words, a bar that dips far below the horizon elicits a strong response, consistent with using the horizon as a depth cue. Wide-field motion also had an enhanced effect below the horizon, but this was only prevalent when flies were additionally motivated with hunger. These responses may help flies tune behaviors to nearby objects and features when they are too far off for motion parallax. PMID- 26232413 TI - Timing matters: tuning the mechanics of a muscle-tendon unit by adjusting stimulation phase during cyclic contractions. AB - A growing body of research on the mechanics and energetics of terrestrial locomotion has demonstrated that elastic elements acting in series with contracting muscle are critical components of sustained, stable and efficient gait. Far fewer studies have examined how the nervous system modulates muscle tendon interaction dynamics to optimize 'tuning' or meet varying locomotor demands. To explore the fundamental neuromechanical rules that govern the interactions between series elastic elements (SEEs) and contractile elements (CEs) within a compliant muscle-tendon unit (MTU), we used a novel work loop approach that included implanted sonomicrometry crystals along muscle fascicles. This enabled us to decouple CE and SEE length trajectories when cyclic strain patterns were applied to an isolated plantaris MTU from the bullfrog (Lithobates catesbeianus). Using this approach, we demonstrate that the onset timing of muscle stimulation (i.e. stimulation phase) that involves a symmetrical MTU stretch-shorten cycle during active force production results in net zero mechanical power output, and maximal decoupling of CE and MTU length trajectories. We found it difficult to 'tune' the muscle-tendon system for strut like isometric force production by adjusting stimulation phase only, as the zero power output condition involved significant positive and negative mechanical work by the CE. A simple neural mechanism - adjusting muscle stimulation phase - could shift an MTU from performing net zero to net positive (energy producing) or net negative (energy absorbing) mechanical work under conditions of changing locomotor demand. Finally, we show that modifications to the classical work loop paradigm better represent in vivo muscle-tendon function during locomotion. PMID- 26232415 TI - Focal enhancement of the skeleton to exercise correlates with responsivity of bone marrow mesenchymal stem cells rather than peak external forces. AB - Force magnitudes have been suggested to drive the structural response of bone to exercise. As importantly, the degree to which any given bone can adapt to functional challenges may be enabled, or constrained, by regional variation in the capacity of marrow progenitors to differentiate into bone-forming cells. Here, we investigate the relationship between bone adaptation and mesenchymal stem cell (MSC) responsivity in growing mice subject to exercise. First, using a force plate, we show that peak external forces generated by forelimbs during quadrupedal locomotion are significantly higher than hindlimb forces. Second, by subjecting mice to treadmill running and then measuring bone structure with MUCT, we show that skeletal effects of exercise are site-specific but not defined by load magnitudes. Specifically, in the forelimb, where external forces generated by running were highest, exercise failed to augment diaphyseal structure in either the humerus or radius, nor did it affect humeral trabecular structure. In contrast, in the ulna, femur and tibia, exercise led to significant enhancements of diaphyseal bone areas and moments of area. Trabecular structure was also enhanced by running in the femur and tibia. Finally, using flow cytometry, we show that marrow-derived MSCs in the femur are more responsive to exercise induced loads than humeral cells, such that running significantly lowered MSC populations only in the femur. Together, these data suggest that the ability of the progenitor population to differentiate toward osteoblastogenesis may correlate better with bone structural adaptation than peak external forces caused by exercise. PMID- 26232416 TI - Body temperature changes during simulated bacterial infection in a songbird: fever at night and hypothermia during the day. AB - Although fever (a closely regulated increase in body temperature in response to infection) typically is beneficial, it is energetically costly and may induce detrimentally high body temperatures. This can increase the susceptibility to energetic bottlenecks and risks of overheating in some organisms. Accordingly, it could be particularly interesting to study fever in small birds, which have comparatively high metabolic rates and high, variable body temperatures. We therefore investigated two aspects of fever and other sickness behaviours (circadian variation, dose dependence) in a small songbird, the zebra finch. We injected lipopolysaccharide (LPS) at the beginning of either the day or the night, and subsequently monitored body temperature, body mass change and food intake for the duration of the response. We found pronounced circadian variation in the body temperature response to LPS injection, manifested by (dose-dependent) hypothermia during the day but fever at night. This resulted in body temperature during the peak response being relatively similar during the day and night. Day to-night differences might be explained in the context of circadian variation in body temperature: songbirds have a high daytime body temperature that is augmented by substantial heat production peaks during activity. This might require a trade-off between the benefit of fever and the risk of overheating. In contrast, at night, when body temperature is typically lower and less variable, fever can be used to mitigate infection. We suggest that the change in body temperature during infection in small songbirds is context dependent and regulated to promote survival according to individual demands at the time of infection. PMID- 26232417 TI - Pushing the limits of glucose kinetics: how rainbow trout cope with a carbohydrate overload. AB - Rainbow trout are generally considered to be poor glucoregulators. To evaluate this, exogenous glucose was administered to chronically hyperglycemic fish at twice the endogenous rate of hepatic production, and their ability to modulate glucose fluxes was tested. Our goals were to determine: (1) whether hyperglycemic fish maintain higher glucose fluxes than normal; (2) whether they can lower hepatic production (Ra glucose) or stimulate disposal (Rd glucose) to cope with a carbohydrate overload; and (3) an estimate of the relative importance of glucose as an oxidative fuel. Results show that hyperglycemic trout sustain elevated baseline Ra and Rd glucose of 10.6 +/- 0.1 umol kg(-1) min(-1) (or 30% above normal). If 50% of Rd glucose was oxidized as in mammals, glucose could account for 36 to 100% of metabolic rate when exogenous glucose is supplied. In response to exogenous glucose, rainbow trout can completely suppress hepatic glucose production and increase disposal 2.6-fold, even with chronically elevated baseline fluxes. Such large changes in fluxes limit the increase in blood glucose to 2.5-fold and are probably mediated by the effects of insulin on glucose transporters 2 and 4 and on key enzymes of carbohydrate metabolism. Without this strong and rapid modulation of glucose kinetics, glycemia would rise four times faster to reach dangerous levels, exceeding 100 mmol l(-1). Such responses are typical of mammals, but rather unexpected for an ectotherm. The impressive plasticity of glucose kinetics demonstrated here suggests that trout have a much better glucoregulatory capacity than is usually portrayed in the literature. PMID- 26232418 TI - Differences in scaling and morphology between lumbricid earthworm ecotypes. AB - Many soft-bodied invertebrates use a flexible, fluid-filled hydrostatic skeleton for burrowing. The aim of our study was to compare the scaling and morphology between surface-dwelling and burrowing earthworm ecotypes to explore the specializations of non-rigid musculoskeletal systems for burrowing locomotion. We compared the scaling of adult lumbricid earthworms across species and ecotypes to determine whether linear dimensions were significantly associated with ecotype. We also compared the ontogenetic scaling of a burrowing species, Lumbricus terrestris, and a surface-dwelling species, Eisenia fetida, using glycol methacrylate histology. We show that burrowing species are longer, thinner and have higher length-to-diameter ratios than non-burrowers, and that L. terrestris is thinner for any given body mass compared with E. fetida. We also found differences in the size of the musculature between the two species that may correlate with surface crawling or burrowing. Our results suggest that adaptations to burrowing for soft-bodied animals include a disproportionately thin body and strong longitudinal muscles. PMID- 26232419 TI - European birth cohorts offer insights on environmental factors affecting human development and health. PMID- 26232420 TI - Cohort Profile Update: The British Regional Heart Study 1978-2014: 35 years follow-up of cardiovascular disease and ageing. PMID- 26232421 TI - N-linked (N-) Glycoproteomics of Urinary Exosomes. PMID- 26232422 TI - Antibody Profiling of Bipolar Disorder Using Escherichia coli Proteome Microarrays. PMID- 26232423 TI - North-South Colonization Associated with Local Adaptation of the Wild Tomato Species Solanum chilense. AB - After colonization population sizes may vary across the species range depending on environmental conditions and following colonizations. An interesting question is whether local adaptation occurs more frequently in large ancestral populations or in small derived populations. A higher number of new mutations and a lower effect of genetic drift should favor selection in large populations, whereas small derived populations may require an initial local adaptation event to facilitate the colonization of new habitats. Wild tomatoes are native to a broad range of different habitats characterized by variable abiotic conditions in South America, and represent an ideal system to study this interplay between demography and natural selection. Population genetic analyses and statistical inference of past demography were conducted on pooled-sequencing data from 30 genes (8,080 single nucleotide polymorphisms) from an extensive sampling of 23 Solanum chilense populations over Chile and Peru. We reveal first a north-south colonization associated with relaxed purifying selection in the south as shown by a decrease of genetic variation and an increasing proportion of nonsynonymous polymorphism from north to south, and population substructure with at least four genetic groups. Second, we uncover a dual picture of adaptation consisting of 1) a decreasing proportion of adaptive amino acid substitutions from north to south suggesting that adaptation is favored in large populations, whereas 2) signatures of local adaptation predominantly occur in the smaller populations from the marginal ranges in the south. PMID- 26232424 TI - USP44+ Cancer Stem Cell Subclones Contribute to Breast Cancer Aggressiveness by Promoting Vasculogenic Mimicry. AB - Vasculogenic mimicry (VM), a newly defined pattern of tumor blood supply, describes the functional plasticity of aggressive cancer cells that form vascular networks. In our previous study, breast cancer stem cells (CSC) were shown to potentially participate in VM formation. In this study, breast CSCs presented centrosome amplification (CA) phenotype and ubiquitin-specific protease 44 (USP44) upregulation. USP44 expression contributed to the establishment of bipolar spindles in breast CSCs with supernumerary centrosomes by localizing at pole-associated centrosomes. The bipolar spindle patterns of breast CSCs with CA, including planar-like and apico-basal-like, functioned differently during the VM process of CSCs. Moreover, the ability of transendothelial migration in VM forming cells was increased. In vivo experiment results showed that CSC xenografts presented linearly patterned programmed cell necrosis, which provided a spatial foundation for VM formation as well as angiogenesis. Breast CSCs further showed increased levels of IL6 and IL8. However, USP44 silencing induced spindle multipolarity, abated VM, reduced transendothelial migration, and consequently decreased IL6 and IL8 levels in breast CSCs. Finally, USP44(+) CSC subclones (ALDH1(+)/USP44(+)/IL6(+)/IL8(+)) were identified in breast cancer specimens through consecutive sections scanning. The subclones were related not only to CA, but also to VM. Statistical analysis suggested that USP44(+) CSC subclones could be used as an independent prognostic biomarker of poor clinical outcomes in patients with breast cancer. Collectively, the identification of USP44(+) CSC subclones may contribute to the prediction of VM formation and aggressive behavior. This study provides novel insights into the therapy for advanced breast cancer. PMID- 26232425 TI - Pregnane X Receptor Represses HNF4alpha Gene to Induce Insulin-Like Growth Factor Binding Protein IGFBP1 that Alters Morphology of and Migrates HepG2 Cells. AB - Upon treatment with the pregnane X receptor (PXR) activator rifampicin (RIF), human hepatocellular carcinoma HepG2-derived ShP51 cells that stably express PXR showed epithelial-mesenchymal transition (EMT)-like morphological changes and migration. Our recent DNA microarrays have identified hepatocyte nuclear factor (HNF) 4alpha and insulin-like growth factor-binding protein (IGFBP) 1 mRNAs to be downregulated and upregulated, respectively, in RIF-treated ShP51 cells, and these regulations were confirmed by the subsequent real-time polymerase chain reaction and Western blot analyses. Using this cell system, we demonstrated here that the PXR-HNF4alpha-IGFBP1 pathway is an essential signal for PXR-induced morphological changes and migration. First, we characterized the molecular mechanism underlying the PXR-mediated repression of the HNF4alpha gene. Chromatin conformation capture and chromatin immunoprecipitation (ChIP) assays revealed that PXR activation by RIF disrupted enhancer-promoter communication and prompted deacetylation of histone H3 in the HNF4alpha P1 promoter. Cell-based reporter and ChIP assays showed that PXR targeted the distal enhancer of the HNF4alpha P1 promoter and stimulated dissociation of HNF3beta from the distal enhancer. Subsequently, small interfering RNA knockdown of HNF4alpha connected PXR-mediated gene regulation with the PXR-induced cellular responses, showing that the knockdown resulted in the upregulation of IGFBP1 and EMT-like morphological changes without RIF treatment. Moreover, recombinant IGFBP1 augmented migration, whereas an anti-IGFBP1 antibody attenuated both PXR-induced morphological changes and migration in ShP51 cells. PXR indirectly activated the IGFBP1 gene by repressing the HNF4alpha gene, thus enabling upregulation of IGFBP1 to change the morphology of ShP51 cells and cause migration. These results provide new insights into PXR-mediated cellular responses toward xenobiotics including therapeutics. PMID- 26232426 TI - Regulatory Dendritic Cells Restrain NK Cell IFN-gamma Production through Mechanisms Involving NKp46, IL-10, and MHC Class I-Specific Inhibitory Receptors. AB - Cross-talk between mature dendritic cells (mDC) and NK cells through the cell surface receptors NKp30 and DNAM-1 leads to their reciprocal activation. However, the impact of regulatory dendritic cells (regDC) on NK cell function remains unknown. As regDC constrain the immune response in different physiological and pathological conditions, the aim of this work was to investigate the functional outcome of the interaction between regDC and NK cells and the associated underlying mechanisms. RegDC generated from monocyte-derived DC treated either with LPS and dexamethasone, vitamin D3, or vitamin D3 and dexamethasone instructed NK cells to secrete lower amounts of IFN-gamma than NK cells exposed to mDC. Although regDC triggered upregulation of the activation markers CD69 and CD25 on NK cells, they did not induce upregulation of CD56 as mDC, and silenced IFN-gamma secretion through mechanisms involving insufficient secretion of IL-18, but not IL-12 or IL-15 and/or induction of NK cell apoptosis. Blocking experiments demonstrated that regDC curb IFN-gamma secretion by NK cells through a dominant suppressive mechanism involving IL-10, NK cell inhibitory receptors, and, unexpectedly, engagement of the activating receptor NKp46. Our findings unveil a previously unrecognized cross-talk through which regDC shape NK cell function toward an alternative activated phenotype unable to secrete IFN-gamma, highlighting the plasticity of NK cells in response to tolerogenic stimuli. In addition, our findings contribute to identify a novel inhibitory role for NKp46 in the control of NK cell function, and have broad implications in the resolution of inflammatory responses and evasion of antitumor responses. PMID- 26232428 TI - Caspase-1 but Not Caspase-11 Is Required for NLRC4-Mediated Pyroptosis and Restriction of Infection by Flagellated Legionella Species in Mouse Macrophages and In Vivo. AB - Gram-negative bacteria from the Legionella genus are intracellular pathogens that cause a severe form of pneumonia called Legionnaires' disease. The bacteria replicate intracellularly in macrophages, and the restriction of bacterial replication by these cells is critical for host resistance. The activation of the NAIP5/NLRC4 inflammasome, which is readily triggered in response to bacterial flagellin, is essential for the restriction of bacterial replication in murine macrophages. Once activated, this inflammasome induces pore formation and pyroptosis and facilitates the restriction of bacterial replication in macrophages. Because investigations related to the NLRC4-mediated restriction of Legionella replication were performed using mice double deficient for caspase-1 and caspase-11, we assessed the participation of caspase-1 and caspase-11 in the functions of the NLRC4 inflammasome and the restriction of Legionella replication in macrophages and in vivo. By using several species of Legionella and mice singly deficient for caspase-1 or caspase-11, we demonstrated that caspase-1 but not caspase-11 was required for pore formation, pyroptosis, and restriction of Legionella replication in macrophages and in vivo. By generating F1 mice in a mixed 129 * C57BL/6 background deficient (129 * Casp-11(-/-) ) or sufficient (129 * C57BL/6) for caspase-11 expression, we found that caspase-11 was dispensable for the restriction of Legionella pneumophila replication in macrophages and in vivo. Thus, although caspase-11 participates in flagellin-independent noncanonical activation of the NLRP3 inflammasome, it is dispensable for the activities of the NLRC4 inflammasome. In contrast, functional caspase-1 is necessary and sufficient to trigger flagellin/NLRC4-mediated restriction of Legionella spp. infection in macrophages and in vivo. PMID- 26232427 TI - The Src-Family Kinases Hck and Fgr Regulate Early Lipopolysaccharide-Induced Myeloid Cell Recruitment into the Lung and Their Ability To Secrete Chemokines. AB - Myeloid leukocyte recruitment into the lung in response to environmental cues represents a key factor for the induction of lung damage. We report that Hck- and Fgr-deficient mice show a profound impairment in early recruitment of neutrophils and monocytes in response to bacterial LPS. The reduction in interstitial and airway neutrophil recruitment was not due to a cell-intrinsic migratory defect, because Hck- and Fgr-deficient neutrophils were attracted to the airways by the chemokine CXCL2 as wild type cells. However, early accumulation of chemokines and TNF-alpha in the airways was reduced in hck(-/-)fgr(-/-) mice. Considering that chemokine and TNF-alpha release into the airways was neutrophil independent, as suggested by a comparison between control and neutrophil-depleted mice, we examined LPS-induced chemokine secretion by neutrophils and macrophages in wild type and mutant cells. Notably, mutant neutrophils displayed a marked deficit in their capability to release the chemokines CXCL1, CXCL2, CCL3, and CCL4 and TNF alpha in response to LPS. However, intracellular accumulation of these chemokines and TNF-alpha, as well as secretion of a wide array of cytokines, including IL 1alpha, IL-1beta, IL-6, and IL-10, by hck(-/-)fgr(-/-) neutrophils was normal. Intriguingly, secretion of CXCL1, CXCL2, CCL2, CCL3, CCL4, RANTES, and TNF-alpha, but not IL-1alpha, IL-1beta, IL-6, IL-10, and GM-CSF, was also markedly reduced in bone marrow-derived macrophages. Consistently, the Src kinase inhibitors PP2 and dasatinib reduced chemokine secretion by neutrophils and bone marrow-derived macrophages. These findings identify Src kinases as a critical regulator of chemokine secretion in myeloid leukocytes during lung inflammation. PMID- 26232429 TI - Proteolytic Cleavage of AMPKalpha and Intracellular MMP9 Expression Are Both Required for TLR4-Mediated mTORC1 Activation and HIF-1alpha Expression in Leukocytes. AB - LPS-induced TLR4 activation alters cellular bioenergetics and triggers proteolytic cleavage of AMPKalpha and HIF-1alpha expression in leukocytes. In human leukocytes, and more specifically neutrophils, AMPKalpha cleavage yields 55 and 35-kDa protein fragments. In this study, we address the mechanism by which AMPKalpha is cleaved and its relevance to human health. Our data indicate that AMPKalpha cleavage is linked to MMP9 expression and that both are required for mammalian target of rapamycin complex-1 and S6K1 activation and HIF-1alpha expression in LPS-stimulated human and mice leukocytes. Three key observations support this conclusion. First, no changes in AMPKalpha and TLR4 signaling intermediates (mammalian target of rapamycin complex-1/S6 kinase 1/HIF-1alpha) were detected in LPS-stimulated MMP9-deficient mice leukocytes. Second, rMMP9 cleaved human AMPKalpha ex vivo, producing degradation products similar in size to those detected following LPS stimulation. Third, MMP9 inhibitors prevented AMPKalpha degradation and HIF-1alpha expression in LPS-activated human leukocytes, whereas AMPK activators blocked MMP9 and HIF-1alpha expression. Significantly, AMPKalpha degradation, MMP9, and TLR4 signaling intermediates were all detected in leukocytes from patients with type 2 diabetes mellitus and patients following cardiopulmonary bypass surgery. Plasma from these two patient cohorts induced AMPKalpha cleavage and TLR4 signaling intermediates in healthy donor leukocytes and either a TLR4 inhibitor or polymyxin prevented these outcomes. Detection of AMPKalpha degradation, MMP9 expression, and TLR4 signaling intermediates described in this study in leukocytes, the most readily available human cells for clinical investigation, may provide a powerful tool for further exploring the role of TLR4 signaling in human diseases and lead to identification of new, context-specific therapeutic modalities for precision medicine. PMID- 26232431 TI - Cholesterol Modification of p40-Specific Small Interfering RNA Enables Therapeutic Targeting of Dendritic Cells. AB - Small interfering RNA (siRNA)-based therapies allow targeted correction of molecular defects in distinct cell populations. Although efficient in multiple cell populations, dendritic cells (DCs) seem to resist siRNA delivery. Using fluorescence labeling and radiolabeling, we show that cholesterol modification enables siRNA uptake by DCs in vitro and in vivo. Delivery of cholesterol modified p40 siRNA selectively abolished p40 transcription and suppressed TLR triggered p40 production by DCs. During immunization with peptide in CFA, cholesterol-modified p40 siRNA generated p40-deficient, IL-10-producing DCs that prevented IL-17/Th17 and IFN-gamma/Th1 responses. Only cholesterol-modified p40 siRNA established protective immunity against experimental autoimmune encephalomyelitis and suppressed IFN-gamma and IL-17 expression by CNS infiltrating mononuclear cells without inducing regulatory T cells. Because cholesterol-modified siRNA can thus modify selected DC functions in vivo, it is intriguing for targeted immune therapy of allergic, autoimmune, or neoplastic diseases. PMID- 26232430 TI - Cardif (MAVS) Regulates the Maturation of NK Cells. AB - Cardif, also known as IPS-1, VISA, and MAVS, is an intracellular adaptor protein that functions downstream of the retinoic acid-inducible gene I family of pattern recognition receptors. Cardif is required for the production of type I IFNs and other inflammatory cytokines after retinoic acid-inducible gene I-like receptors recognize intracellular antigenic RNA. Studies have recently shown that Cardif may have other roles in the immune system in addition to its role in viral immunity. In this study, we find that the absence of Cardif alters normal NK cell development and maturation. Cardif(-/-) mice have a 35% loss of mature CD27( )CD11b(+) NK cells in the periphery. In addition, Cardif(-/-) NK cells have altered surface marker expression, lower cytotoxicity, decreased intracellular STAT1 levels, increased apoptosis, and decreased proliferation compared with wild type NK cells. Mixed chimeric mice revealed that the defective maturation and increased apoptotic rate of peripheral Cardif(-/-) NK cells is cell intrinsic. However, Cardif(-/-) mice showed enhanced control of mouse CMV (a DNA beta herpesvirus) by NK cells, commensurate with increased activation and IFN-gamma production by these immature NK cell subsets. These results indicate that the skewed differentiation and altered STAT expression of Cardif(-/-) NK cells can result in their hyperresponsiveness in some settings and support recent findings that Cardif-dependent signaling can regulate aspects of immune cell development and/or function distinct from its well-characterized role in mediating cell intrinsic defense to RNA viruses. PMID- 26232432 TI - Role of SHIP1 in Invariant NKT Cell Development and Functions. AB - SHIP1 is a 5'-inositol phosphatase known to negatively regulate the signaling product of the PI3K pathway, phosphatidylinositol (3-5)-trisphosphate. SHIP1 is recruited to a large number of inhibitory receptors expressed on invariant NK (iNKT) cells. We hypothesized that SHIP1 deletion would have major effects on iNKT cell development by altering the thresholds for positive and negative selection. Germline SHIP1 deletion has been shown to affect T cells as well as other immune cell populations. However, the role of SHIP1 on T cell function has been controversial, and its participation on iNKT cell development and function has not been examined. We evaluated the consequences of SHIP1 deletion on iNKT cells using germline-deficient mice, chimeric mice, and conditionally deficient mice. We found that T cell and iNKT cell development are impaired in germline deficient animals. However, this phenotype can be rescued by extrinsic expression of SHIP1. In contrast, SHIP1 is required cell autonomously for optimal iNKT cell cytokine secretion. This suggests that SHIP1 calibrates the threshold of iNKT cell reactivity. These data further our understanding of how iNKT cell activation is regulated and provide insights into the biology of this unique cell lineage. PMID- 26232434 TI - Parafibromin Is a Component of IFN-gamma-Triggered Signaling Pathways That Facilitates JAK1/2-Mediated Tyrosine Phosphorylation of STAT1. AB - IFN-gamma (also known as type II IFN) is a cytokine that is critically involved in antiviral and immunomodulatory effects. IFN-gamma activates JAK1 and JAK2, which lead to the phosphorylation and activation of the transcription factor STAT1. Whether and how additional molecules are involved in the process are not fully clear. In this study, we identified parafibromin as an important component of the IFN-gamma-triggered signaling pathways. Overexpression of parafibromin promoted IFN-gamma-triggered phosphorylation of STAT1 at Tyr(701), subsequent expression of downstream genes, and cellular antiviral response, whereas knockdown of parafibromin had opposite effects. Parafibromin interacted with JAK1/2, promoted the interactions of JAK1-JAK2 and JAK1/2-STAT1, and promoted tyrosine phosphorylation of STAT1 by JAKs after IFN-gamma stimulation. Our results reveal a previously uncharacterized role of parafibromin in mediating IFN gamma-triggered signaling and cellular effects. PMID- 26232435 TI - Id3 Controls Cell Death of 2B4+ Virus-Specific CD8+ T Cells in Chronic Viral Infection. AB - Sustained Ag persistence in chronic infection results in a deregulated CD8(+) T cell response that is characterized by T cell exhaustion and cell death of Ag specific CD8(+) T cells. Yet, the underlying transcriptional mechanisms regulating CD8(+) T cell exhaustion and cell death are poorly defined. Using the experimental mouse model of lymphocytic choriomeningitis virus infection, we demonstrate that the transcriptional regulator Id3 controls cell death of virus specific CD8(+) T cells in chronic infection. By comparing acute and chronic infection, we showed that Id3 (-) virus-specific CD8(+) T cells were less abundant, whereas the absolute numbers of Id3 (+) virus-specific CD8(+) T cells were equal in chronic and acute infection. Phenotypically, Id3 (-) and Id3 (+) cells most prominently differed with regard to expression of the surface receptor 2B4; although Id3 (-) cells were 2B4(+), almost all Id3 (+) cells lacked expression of 2B4. Lineage-tracing experiments showed that cells initially expressing Id3 differentiated into Id3 (-)2B4(+) cells; in turn, these cells were terminally differentiated and highly susceptible to cell death under conditions of persisting Ag. Enforced Id3 expression specifically increased the persistence of 2B4(+) virus-specific CD8(+) T cells by decreasing susceptibility to Fas/Fas ligand-mediated cell death. Thus, our findings reveal that the transcriptional regulator Id3 promotes the survival of virus-specific CD8(+) T cells in chronic infection and suggest that targeting Id3 might be beneficial for preventing cell death of CD8(+) T cells in chronic infection or for promoting cell death of uncontrolled, hyperactive CD8(+) T cells to prevent immunopathology. PMID- 26232433 TI - B Lymphocyte-Specific Loss of Ric-8A Results in a Galpha Protein Deficit and Severe Humoral Immunodeficiency. AB - Resistance to inhibitors of cholinesterase 8A (Ric-8A) is a highly evolutionarily conserved cytosolic protein initially identified in Caenorhabditis elegans, where it was assigned a regulatory role in asymmetric cell divisions. It functions as a guanine nucleotide exchange factor for Galphai, Galphaq, and Galpha12/13 and as a molecular chaperone required for the initial association of nascent Galpha subunits with cellular membranes in embryonic stem cell lines. To test its role in hematopoiesis and B lymphocytes specifically, we generated ric8 (fl/fl) vav1 cre and ric8 (fl/fl) mb1-cre mice. The major hematopoietic cell lineages developed in the ric8 (fl/fl) vav1-cre mice, notwithstanding severe reduction in Galphai2/3, Galphaq, and Galpha13 proteins. B lymphocyte-specific loss of Ric-8A did not compromise bone marrow B lymphopoiesis, but splenic marginal zone B cell development failed, and B cells underpopulated lymphoid organs. The ric8 (fl/fl) mb1-cre B cells exhibited poor responses to chemokines, abnormal trafficking, improper in situ positioning, and loss of polarity components during B cell differentiation. The ric8 (fl/fl) mb1-cre mice had a severely disrupted lymphoid architecture and poor primary and secondary Ab responses. In B lymphocytes, Ric 8A is essential for normal Galpha protein levels and is required for B cell differentiation, trafficking, and Ab responses. PMID- 26232436 TI - Exclusive Transduction of Human CD4+ T Cells upon Systemic Delivery of CD4 Targeted Lentiviral Vectors. AB - Playing a central role in both innate and adaptive immunity, CD4(+) T cells are a key target for genetic modifications in basic research and immunotherapy. In this article, we describe novel lentiviral vectors (CD4-LV) that have been rendered selective for human or simian CD4(+) cells by surface engineering. When applied to PBMCs, CD4-LV transduced CD4(+) but not CD4(-) cells. Notably, also unstimulated T cells were stably genetically modified. Upon systemic or intrasplenic administration into mice reconstituted with human PBMCs or hematopoietic stem cells, reporter gene expression was predominantly detected in lymphoid organs. Evaluation of GFP expression in organ-derived cells and blood by flow cytometry demonstrated exclusive gene transfer into CD4(+) human lymphocytes. In bone marrow and spleen, memory T cells were preferentially hit. Toward therapeutic applications, we also show that CD4-LV can be used for HIV gene therapy, as well as for tumor therapy, by delivering chimeric Ag receptors. The potential for in vivo delivery of the FOXP3 gene was also demonstrated, making CD4-LV a powerful tool for inducible regulatory T cell generation. In summary, our work demonstrates the exclusive gene transfer into a T cell subset upon systemic vector administration opening an avenue toward novel strategies in immunotherapy. PMID- 26232437 TI - Onyx extrusion through the scalp after embolization of dural arteriovenous fistula. AB - A man in his sixties referred with symptoms of episodic left lip numbness and left arm weakness was diagnosed with a Borden type 3 dural arteriovenous fistula (DAVF) on DSA. Successful Onyx embolization of the DAVF was performed via the distal left occipital artery using an ev3 Apollo detachable tip microcatheter. He underwent surgical obliteration for the residual DAVF 3 days later. Three months later during a routine postoperative clinic visit, the patient produced a plastic bag containing multiple small pieces of Onyx cast and the detached tip of the Apollo microcatheter that had extruded out from his scalp through small spontaneous holes about 5 weeks after the embolization procedure. This spontaneous extrusion of Onyx can be alarming to the patient not expecting it; however, prior knowledge and discussion can lessen the anxiety of both the treating physician and the patient dealing with such a situation. PMID- 26232438 TI - Rapid Declines in Age Group-Specific Rotavirus Infection and Acute Gastroenteritis Among Vaccinated and Unvaccinated Individuals Within 1 Year of Rotavirus Vaccine Introduction in England and Wales. AB - BACKGROUND: The oral infant rotavirus vaccine, Rotarix, was introduced in England and Wales in July 2013. We estimated the impact on laboratory-confirmed rotavirus infections and hospitalizations for all-cause acute gastroenteritis (AGE) during the first year after introduction. METHODS: We extracted data on laboratory confirmed rotavirus infections (July 2000 through June 2015) and all-cause AGE associated hospitalizations (July 2007 through June 2014) for all age groups using national databases (LabBase2 and HES). We determined the ratio of the rate during the 2013-2014 rotavirus season to the rate during the prevaccination era. RESULTS: In infants, there was a 77% decline (rate ratio [RR], 0.23; 95% confidence interval [CI], .16-.32) in laboratory-confirmed rotavirus infections and a 26% decline (RR, 0.74; 95% CI, .65-.84) in all-cause AGE-associated hospitalizations in 2013-2014, compared with the prevaccination era. Large reductions were also observed in older children, adults, and older adults. We estimated that 10 884 laboratory-confirmed infections and 50 427 all-cause AGE associated hospital admissions were averted in 2013-2014. Similar reductions have been observed for laboratory-confirmed rotavirus infections during the 2014-2015 season. CONCLUSIONS: The rapid declines in rotavirus infection and AGE in vaccinated and unvaccinated age groups within 1 year of introducing an infant rotavirus vaccination program are far greater than expected and than previously reported by other countries. PMID- 26232439 TI - Ebola Virus Diagnostics: The US Centers for Disease Control and Prevention Laboratory in Sierra Leone, August 2014 to March 2015. AB - In August 2014, the Viral Special Pathogens Branch of the US Centers for Disease Control and Prevention established a field laboratory in Sierra Leone in response to the ongoing Ebola virus outbreak. Through March 2015, this laboratory tested >12 000 specimens from throughout Sierra Leone. We describe the organization and procedures of the laboratory located in Bo, Sierra Leone. PMID- 26232441 TI - "The Glamour of Arabic Numbers": Pliny Earle's Challenge to Nineteenth-Century Psychiatry. AB - A well-established interpretation associates the nineteenth-century psychiatrist Pliny Earle's deflation of high cure rates for insanity with the onset of a persistent malaise in patient treatment and public health policy during the Gilded Age. This essay comes not to praise Earle but to correct and clarify interpretations, however well intentioned, that are incomplete and inaccurate. Several points are made: the overwhelming influence of antebellum enthusiasm on astonishing therapeutic claims; the interrogation of high "recovery" rates begun decades before Earle's ultimate provocation; and, however disruptive, the heuristically essential contribution of Earle's challenge to furthering a meaningful model of mental disorder. In spite of the impression created by existing historiography, Earle, a principled Quaker, remained committed to "moral treatment." PMID- 26232443 TI - Normalizing clinical terms using learned edit distance patterns. AB - BACKGROUND: Variations of clinical terms are very commonly encountered in clinical texts. Normalization methods that use similarity measures or hand-coded approximation rules for matching clinical terms to standard terminologies have limited accuracy and coverage. MATERIALS AND METHODS: In this paper, a novel method is presented that automatically learns patterns of variations of clinical terms from known variations from a resource such as the Unified Medical Language System (UMLS). The patterns are first learned by computing edit distances between the known variations, which are then appropriately generalized for normalizing previously unseen terms. The method was applied and evaluated on the disease and disorder mention normalization task using the dataset of SemEval 2014 and compared with the normalization ability of the MetaMap system and a method based on cosine similarity. RESULTS: Excluding the mentions that already exactly match in UMLS and the training dataset, the proposed method obtained 64.7% accuracy on the rest of the test dataset. The accuracy was calculated as the number of mentions that correctly matched the gold-standard concept unique identifiers (CUIs) or correctly matched to be without a CUI. In comparison, MetaMap's accuracy was 41.9% and cosine similarity's accuracy was 44.6%. When only the output CUIs were evaluated, the proposed method obtained 54.4% best F-measure (at 92.1% precision and 38.6% recall) while MetaMap obtained 19.4% best F-measure (at 38.0% precision and 13.0% recall) and cosine similarity obtained 38.1% best F measure (at 70.3% precision and 26.1% recall). CONCLUSIONS: The novel method was found to perform much better than the MetaMap system and the cosine similarity based method in normalizing disease mentions in clinical text that did not exactly match in UMLS. The method is also general and can be used for normalizing clinical terms of other semantic types as well. PMID- 26232440 TI - Development of Prototype Filovirus Recombinant Antigen Immunoassays. AB - BACKGROUND: Throughout the 2014-2015 Ebola outbreak in West Africa, major gaps were exposed in the availability of validated rapid diagnostic platforms, protective vaccines, and effective therapeutic agents. These gaps potentiated the development of prototype rapid lateral flow immunodiagnostic (LFI) assays that are true point-of-contact platforms, for the detection of active Ebola infections in small blood samples. METHODS: Recombinant Ebola and Marburg virus matrix VP40 and glycoprotein (GP) antigens were used to derive a panel of monoclonal and polyclonal antibodies. Antibodies were tested using a multivariate approach to identify antibody-antigen combinations suitable for enzyme-linked immunosorbent assay (ELISA) and LFI assay development. RESULTS: Polyclonal antibodies generated in goats were superior reagents for capture and detection of recombinant VP40 in test sample matrices. These antibodies were optimized for use in antigen-capture ELISA and LFI assay platforms. Prototype immunoglobulin M (IgM)/immunoglobulin G (IgG) ELISAs were similarly developed that specifically detect Ebola virus specific antibodies in the serum of experimentally infected nonhuman primates and in blood samples obtained from patients with Ebola from Sierra Leone. CONCLUSIONS: The prototype recombinant Ebola LFI assays developed in these studies have sensitivities that are useful for clinical diagnosis of acute ebolavirus infections. The antigen-capture and IgM/IgG ELISAs provide additional confirmatory assay platforms for detecting VP40 and other ebolavirus-specific immunoglobulins. PMID- 26232445 TI - Improvement Without Value. PMID- 26232442 TI - A method for systematic discovery of adverse drug events from clinical notes. AB - OBJECTIVE: Adverse drug events (ADEs) are undesired harmful effects resulting from use of a medication, and occur in 30% of hospitalized patients. The authors have developed a data-mining method for systematic, automated detection of ADEs from electronic medical records. MATERIALS AND METHODS: This method uses the text from 9.5 million clinical notes, along with prior knowledge of drug usages and known ADEs, as inputs. These inputs are further processed into statistics used by a discriminative classifier which outputs the probability that a given drug disorder pair represents a valid ADE association. Putative ADEs identified by the classifier are further filtered for positive support in 2 independent, complementary data sources. The authors evaluate this method by assessing support for the predictions in other curated data sources, including a manually curated, time-indexed reference standard of label change events. RESULTS: This method uses a classifier that achieves an area under the curve of 0.94 on a held out test set. The classifier is used on 2,362,950 possible drug-disorder pairs comprised of 1602 unique drugs and 1475 unique disorders for which we had data, resulting in 240 high-confidence, well-supported drug-AE associations. Eighty-seven of them (36%) are supported in at least one of the resources that have information that was not available to the classifier. CONCLUSION: This method demonstrates the feasibility of systematic post-marketing surveillance for ADEs using electronic medical records, a key component of the learning healthcare system. PMID- 26232446 TI - Author's Response. PMID- 26232447 TI - Positive voided urine cytology predicts worse pathological findings of nephroureterectomy specimens in patients with upper tract urothelial carcinoma: does selective ureteral cytology have an additional efficacy? AB - OBJECTIVE: After radical nephroureterectomy, substantial numbers of patients with upper tract urothelial carcinoma are ineligible for adjuvant chemotherapy owing to diminished renal function. Accurate pre-operative prediction of worse pathological findings in radical nephroureterectomy specimens can guide appropriate patient selection for neoadjuvant chemotherapy. Herein, we evaluated pre-operative voided urine cytology and the additional efficacy of selective ureteral cytology for predicting pathological features in upper tract urothelial carcinoma patients. METHODS: This retrospective cohort study comprised 722 patients with upper tract urothelial carcinoma who underwent radical nephroureterectomy. Patients with concomitant bladder cancer and those who received neoadjuvant therapy were excluded. Finally, 437 patients with urinary cytology data were enrolled in the study. We assessed the positive voided urine and selective ureteral cytology for predicting higher pathological T stage (>= pT3), higher tumor grade (3) and positive lymphovascular invasion. RESULTS: Previous bladder cancer, tumor location, clinical T stage and voided urine cytology (P = 0.029) were independently associated with >= pT3, whereas selective ureteral cytology was not. Gender, clinical N category and voided urine cytology (P = 0.017) were independently associated with tumor Grade 3, whereas selective ureteral cytology was not. Hydronephrosis, clinical T stage, clinical N category and voided urine cytology (P = 0.0021) were independently associated with lymphovascular invasion, whereas selective ureteral cytology was not. CONCLUSIONS: Pre-operative positive voided urine cytology was an independent predictor for worse pathological findings in radical nephroureterectomy specimens, while selective ureteral cytology had no additional efficacy. However, further studies with larger numbers of patients and complete data sets are needed to select patients for more aggressive treatments including neoadjuvant chemotherapy. PMID- 26232448 TI - Health-related quality of life in long-term survivors with Grade II gliomas: the contribution of disease recurrence and Karnofsky Performance Status. AB - OBJECTIVE: Although the number of long-term survivors of glioma has increased, there has been little research on the health-related quality of life of long-term survivors of Grade II glioma following treatment with surgery, radiotherapy and chemotherapy. In this study, we aimed to document the health-related quality of life of people diagnosed with Grade II glioma who had survived >10 years with no evidence of disease at the time of the health-related quality of life survey. METHODS: To investigate the health-related quality of life of Grade II glioma survivors without evidence of disease, we surveyed 50 patients 0-20 years after their initial treatments. Each patient completed a multi-part health-related quality of life questionnaire. Based on these surveys, we examined the relationships between health-related quality of life scores and time since initial treatment, Karnofsky Performance Scale scores at the time of the survey, and history of recurrence, radiotherapy and chemotherapy. RESULTS: Excepting bladder control, long-term survivors maintained their quality of life as determined by comparing patients surveyed < 5 and >= 10 years after their initial treatment (P < 0.05). Neither radiotherapy nor chemotherapy at the initial treatment was observed to affect health-related quality of life. However, a history of recurrence was significantly associated with deteriorations in many health-related quality of life functional and symptom scores. The Karnofsky Performance Scale scores of patients with a history of recurrence were significantly lower than those without it (P = 0.02). This deterioration was observed in both univariate and multivariate analyses. CONCLUSIONS: Our results indicate that declines in health-related quality of life among long-term survivors of Grade II glioma mainly result from impaired Karnofsky Performance Scale, which is a consequence of disease recurrence. PMID- 26232449 TI - Phase II study of amrubicin at a dose of 45 mg/m2 in patients with previously treated small-cell lung cancer. AB - OBJECTIVE: Most of the previous studies of amrubicin in patients with previously treated small-cell lung cancer were conducted at a dose of 40 mg/m(2). The aim of this study was to assess the efficacy and safety of amrubicin at a dose of 45 mg/m(2) in patients with relapsed or refractory small-cell lung cancer. METHODS: Previously treated small-cell lung cancer patients were eligible. Amrubicin at a dose of 45 mg/m(2) was administered on Days 1-3 every 3 weeks. The primary endpoint was the response rate. RESULTS: From June 2003 to January 2005, 35 patients were enrolled, of whom 34 received this study treatment. Four cycles or more could be administered in 21 patients (62%). Dose reduction was required in 15 (52%) of the 29 patients who had received two cycles or more. Three complete responses and 15 partial responses were observed among the 34 treated patients, yielding a response rate of 53% (95% confidence interval, 35-71%). Median progression-free survival of the patients was 4.4 months (95% confidence interval, 2.4-5.1 months). Median survival time was 8.2 months (95% confidence interval, 6.6-10.0 months) and 1-year survival rate was 24% (95% confidence interval, 9-39%). Grade 3/4 leukopenia, neutropenia and thrombocytopenia were observed in 76, 97 and 38% of the patients, respectively. Febrile neutropenia occurred in 12 patients (35%), and one patient died from pneumonia. CONCLUSIONS: While amrubicin at a dose of 45 mg/m(2) showed high response rate for both sensitive and refractory relapse, the incidence of febrile neutropenia was also high. The utility of amrubicin at 45 mg/m(2) might accordingly be limited. PMID- 26232450 TI - Quantification of Drugs in Brain Samples. AB - Due to the lack of certified reference material, a reliable quantification in complex postmortem matrices can only be performed either by the addition of isotope-labelled standards or by the standard addition method. Although standard addition is a basic quantification procedure, its practical implementation is challenging, and a highly reproducible extraction method is essential. Therefore, an automated solid-phase extraction screening procedure was validated in respect to the specific requirements in postmortem analyses, using pig brain fortified with nine compounds to represent a realistic postmortem setting. The validation parameters linearity, repeatability, reproducibility and recovery were selected to test the method's 'fitness for purpose'. All obtained results were satisfying, although the method was not optimized for the selected compounds. Therefore, this validated method could be used for further standard addition experiments to evaluate the importance of the initial estimated concentration for the calculation of concentrations to set up the calibration curve. We could show that the best results were obtained when the estimated concentration was close to the real concentration. In case of a deviation, an underestimation is more favorable than an overestimation. PMID- 26232451 TI - Quantification of Salivary Arecoline, Arecaidine and N-Methylnipecotic Acid Levels in Volunteers by Liquid Chromatography-Tandem Mass Spectrometry. AB - Relatively little is known about the metabolism of areca nut in human saliva. We here describe the simultaneous quantification of areca nut metabolites: arecoline, arecaidine and N-methylnipecotic acid in saliva samples after chewing one 5 g areca nut by using liquid chromatography-tandem mass spectrometry (LC-MS MS). Time courses of salivary areca nut metabolites in five adult male areca nut chewer volunteers were investigated. The limits of quantification were all 1.25 ng/mL for arecoline, arecaidine and N-methylnipecotic acid. Intra- and interday imprecisions were <4.2 and 13.6%, respectively. The within-day accuracy ranged from 82.2 to 116.7%, and the between-day accuracy ranged from 78.3 to 115.6%. Through areca nut chewing time course study, we found that salivary arecoline, arecaidine and N-methylnipecotic acid concentrations varied greatly over time between experiment individuals. Our findings suggest that arecoline might be metabolized slightly to arecaidine at 30 min after areca nut chewing and arecoline might be metabolized slightly to N-methylnipecotic acid at 25 min after areca nut chewing in the mouth. We first provide simultaneous quantification of human salivary arecoline, arecaidine and N-methylnipecotic acid levels using LC MS-MS. This method may facilitate future research design in the pathogenic effects of areca nut exposure. PMID- 26232452 TI - IFNAR signaling directly modulates T lymphocyte activity, resulting in milder experimental autoimmune encephalomyelitis development. AB - Although interferon-beta is used as first-line therapy for multiple sclerosis, the cell type-specific activity of type I interferons in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis, remains obscure. In this study, we have elucidated the in vivo immunomodulatory role of type I interferon signaling in T cells during experimental autoimmune encephalomyelitis by use of a novel transgenic mouse, carrying a cd2-ifnar1 transgene on a interferon-alpha/beta receptor 1 null genetic background, thus allowing expression of the interferon-alpha/beta receptor 1 and hence, a functional type I interferon receptor exclusively on T cells. These transgenic mice exhibited milder experimental autoimmune encephalomyelitis with reduced T cell infiltration, demyelination, and axonal damage in the central nervous system. It is noteworthy that interferon-beta administration in transgenic mice generated a more pronounced, protective effect against experimental autoimmune encephalomyelitis compared with untreated littermates. In vivo studies demonstrated that before experimental autoimmune encephalomyelitis onset, endogenous type I interferon receptor signaling in T cells led to impaired T helper 17 responses, with a reduced fraction of CCR6(+) CD4(+) T cells in the periphery. At the acute phase, an increased proportion of interleukin-10- and interferon-gamma-producing CD4(+) T cells was detected in the periphery of the transgenic mice, accompanied by up-regulation of the interferon-gamma-induced gene Irgm1 in peripheral T cells. Together, these results reveal a hitherto unknown T cell-associated protective role of type I interferon in experimental autoimmune encephalomyelitis that may provide valuable clues for designing novel therapeutic strategies for multiple sclerosis. PMID- 26232454 TI - Senescent profile of angiogenic T cells from systemic lupus erythematosus patients. AB - The chronic inflammatory environment associated with systemic lupus erythematosus can lead to an accelerated immunosenescence responsible for the endothelial damage and increased cardiovascular risk observed in these patients. The present study analyzed two populations with opposite effects on vascular endothelium, angiogenic T cells and the senescent CD4(+)CD28(null) subset, in 84 systemic lupus erythematosus patients and 46 healthy controls. Also, 48 rheumatoid arthritis patients and 72 individuals with traditional cardiovascular risk factors participated as disease controls. Phenotypic characterization of CD28(+) and CD28(null) cells was performed by analyzing markers of senescence (CCR7, CD27, CD57) and cytotoxicity (CD56, perforin, granzyme B, IFN-gamma). IL-1beta, IL-6, IL-8, IL-10, IL-12, IL-17A, IFN-alpha, IFN-gamma, TNF-alpha, B lymphocyte stimulator, and GM-CSF serum levels were analyzed in systemic lupus erythematosus patients and healthy controls. CD4(+)CD28(null) cells were notably increased in the systemic lupus erythematosus patients and disease controls compared with healthy controls. In contrast, angiogenic T cells were only reduced in the disease controls (those with rheumatoid arthritis or traditional cardiovascular risk factors). Nevertheless, an anomalous presence of CD28(null)-angiogenic T cells, with cytotoxic and senescent characteristics, was noted in systemic lupus erythematosus patients in association with anti-dsDNA titer, anti-SSA/Ro antibodies and circulating TNF-alpha, IL-8, IFN-alpha, and B lymphocyte stimulator amounts. This subset was also detected in those with traditional cardiovascular risk factors but not in the rheumatoid arthritis patients. In contrast, CD28(+)-angiogenic T cells were reduced in the systemic lupus erythematosus patients with cardiovascular disorders. In conclusion, CD28 expression must be used to redefine the angiogenic T cell population, because in pathologic conditions, a senescent CD28(null)-angiogenic T cell subset with inflammatory, rather than protective, effects could be present. PMID- 26232453 TI - Interleukin-10 production by myeloid-derived suppressor cells contributes to bacterial persistence during Staphylococcus aureus orthopedic biofilm infection. AB - Staphylococcus aureus is known to establish biofilms on medical devices. We recently demonstrated that Ly6G(high)Ly6C(+) myeloid-derived suppressor cells are critical for allowing S. aureus biofilms to subvert immune-mediated clearance; however, the mechanisms whereby myeloid-derived suppressor cells promote biofilm persistence remain unknown. Interleukin-10 expression was significantly increased in a mouse model of S. aureus orthopedic implant biofilm infection with kinetics that mirrored myeloid-derived suppressor cell recruitment. Because myeloid derived suppressor cells produce interleukin-10, we explored whether it was involved in orchestrating the nonproductive immune response that facilitates biofilm formation. Analysis of interleukin-10-green fluorescent protein reporter mice revealed that Ly6G(high)Ly6C(+) myeloid-derived suppressor cells were the main source of interleukin-10 during the first 2 wk of biofilm infection, whereas monocytes had negligible interleukin-10 expression until day 14. Myeloid-derived suppressor cell influx into implant-associated tissues was significantly reduced in interleukin-10 knockout mice at day 14 postinfection, concomitant with increased monocyte and macrophage infiltrates that displayed enhanced proinflammatory gene expression. Reduced myeloid-derived suppressor cell recruitment facilitated bacterial clearance, as revealed by significant decreases in S. aureus burdens in the knee joint, surrounding soft tissue, and femur of interleukin-10 knockout mice. Adoptive transfer of interleukin-10 wild-type myeloid-derived suppressor cells into S. aureus-infected interleukin-10 knockout mice restored the local biofilm-permissive environment, as evidenced by increased bacterial burdens and inhibition of monocyte proinflammatory activity. These effects were both interleukin-10-dependent and interleukin-10-independent because myeloid-derived suppressor cell-derived interleukin-10 was required for promoting biofilm growth and anti-inflammatory gene expression in monocytes but was not involved in monocyte recruitment to biofilm-infected tissues. These results demonstrate that interleukin-10 production by myeloid-derived suppressor cells contributes to the persistence of S. aureus orthopedic biofilm infections. PMID- 26232456 TI - Good, or Just Better? PMID- 26232455 TI - Immune deficiency vs. immune excess in inflammatory bowel diseases-STAT3 as a rheo-STAT of intestinal homeostasis. AB - Genome-wide association studies have provided many genetic alterations, conferring susceptibility to multifactorial polygenic diseases, such as inflammatory bowel diseases. Yet, how specific genetic alterations functionally affect intestinal inflammation often remains elusive. It is noteworthy that a large overlap of genes involved in immune deficiencies with those conferring inflammatory bowel disease risk has been noted. This has provided new arguments for the debate on whether inflammatory bowel disease arises from either an excess or a deficiency in the immune system. In this review, we highlight the functional effect of an inflammatory bowel disease-risk allele, which cannot be deduced from genome-wide association studies data alone. As exemplified by the transcription factor signal transducer and activator of transcription 3 (STAT3), we show that a single gene can have a plethora of effects in various cell types of the gut. These effects may individually contribute to the restoration of intestinal homeostasis on the one hand or pave the way for excessive immunopathology on the other, as an inflammatory "rheo-STAT". PMID- 26232457 TI - The Biomechanical Function of the Anterolateral Ligament of the Knee: Letter to the Editor. PMID- 26232458 TI - The Biomechanical Function of the Anterolateral Ligament of the Knee: Response. PMID- 26232459 TI - External Rotation and Abduction Bracing in the Management of First-Time Anterior Shoulder Dislocation: Letter to the Editor. PMID- 26232460 TI - External Rotation and Abduction Bracing in the Management of First-Time Anterior Shoulder Dislocation: Response. PMID- 26232461 TI - Corrigendum. Early versus delayed passive range of motion exercise for arthroscopic rotator cuff repair: a meta-analysis of randomized controlled trials. PMID- 26232462 TI - Corrigendum. Intraoperative fluoroscopic imaging to treat cam deformities: correlation with 3-dimensional computed tomography. PMID- 26232463 TI - Caring for Refugee Children. PMID- 26232464 TI - Worm Infections in Children. AB - * On the basis of research evidence, worm infections are important global child health conditions causing chronic disability that lasts from childhood into adulthood (Table 1). (2)(3) Evidence Quality: B * On the basis of research evidence, the major worm infections found in developing countries include ascariasis, trichuriasis, hookworm infection, and schistosomiasis; toxocariasis, enterobiasis, and cysticercosis are also found in poor regions of North America and Europe. (4)(9)(13) Evidence Quality: B * On the basis of expert consensus, children and adolescents are often vulnerable to acquiring large numbers of worms, ie, high-intensity infections (Fig 1)(21)(22)(23) Evidence Quality: D * On the basis of expert consensus and research evidence, moderate and heavy worm burdens cause increased morbidity because of growth and intellectual stunting in children and adolescents. Many of these effects may result from helminth-induced malnutrition. (21)(22)(23) Evidence Quality: C * On the basis of expert consensus and research evidence, worm infections are also commonly associated with eosinophilia. (48) (49) Evidence Quality: B * On the basis of research evidence as well as consensus, helminthes can cause inflammation in the lung (asthma), gastrointestinal tract (enteritis and colitis), liver (hepatitis and fibrosis), and urogenital tract. (7)(21)(22)(23)(27)(28)(40)(41)(43) Evidence Quality: B * On the basis of research evidence, microscopy techniques for diagnosis of worm infections in children often exhibit suboptimal sensitivities and specificities, necessitating new or improved diagnostic modalities such as polymerase chain reaction. (54)(55) Evidence Quality: A * On the basis of research evidence and expert consensus, mass drug administration ("preventive chemotherapy") has becomea standard practice for ministries of health in low- and middle-income countries to control intestinal helminth infections and schistosomiasis. (67)(68) Evidence Quality: B. PMID- 26232465 TI - Autism, Language Disorder, and Social (Pragmatic) Communication Disorder: DSM-V and Differential Diagnoses. AB - * Based on strong research evidence (1), the prevalence of autism spectrum disorders (ASDs) has increased over the past decade, with a 2010 prevalence of 1:68 (1.5%) in children age 8 years. * Based on some research evidence as well as consensus (3), the most recent revision of the American Psychiatric Association's Diagnostic and Statistical Manual (DSM-V) identifies two core dimensions for the diagnosis of ASD: social (social communication and social interaction) and nonsocial (restricted, repetitive patterns of behaviors, interests, or activities). * Based on some research evidence as well as consensus (3) (31) (32) (33) (34), DSM-V identifies social pragmatic communication disorder (SPCD) as a dissociable dimension of language and communication ability that affects how individuals use language for social exchanges. SPCD is often found in children with language impairments and children with attention-deficit/hyperactivity disorder and other genetic/neurologic conditions. * Based on strong research evidence (2) (26) (27) (28), childhood language disorders affect 7.4% of kindergarteners, and 50% to 80% of these children experience persistent language, academic, and social-emotional difficulties into their adult years, despite having normal nonverbal cognitive abilities. * Based primarily on consensus due to lack of relevant clinical studies, differential diagnosis of autism and language disorders may require a multidisciplinary evaluation that takes into account a child's overall development, including cognitive, communication, and social abilities. Monitoring the response to appropriate interventions and trajectory of development over time may improve the accuracy of diagnosis, especially in very young children. PMID- 26232466 TI - Surveys and Response Rates. AB - Surveys continue to be an important research methodology. However, when assessing survey studies, clinicians should review the response rate and consider potential selection bias. Methods of survey administration (electronic, postal, or other means) may differ in cost, missing data, and response rates. In addition, reviewing the questionnaire construction, including the understandability of the questions and response formats, is important in assessing the validity of findings. PMID- 26232467 TI - Case 1: Wheezing Unresponsive to Bronchodilators in a 4-month-old Boy. PMID- 26232468 TI - CME Quiz Correction. PMID- 26232469 TI - Case 2: Back Pain and Difficulty Ambulating in a 4-year-old Girl. PMID- 26232470 TI - Case 3: Abdominal Pain and Chronic Constipation in a 14-year-old Girl. PMID- 26232471 TI - Esophagitis: Allergic and Eosinophilic. PMID- 26232472 TI - Visual Diagnosis: 8-year-old Male with a Skin Mass and Inguinal Lymphadenopathy. Clear Cell Sarcoma. PMID- 26232473 TI - A tale of two global emergencies: tuberculosis control efforts can learn from the Ebola outbreak. PMID- 26232474 TI - Navigating the uncharted waters of combination therapy in pulmonary arterial hypertension: COMPASS or dead-reckoning. PMID- 26232475 TI - Pulmonary arterial hypertension or left heart disease with pulmonary hypertension? Toward noninvasive clarity, but time for a new paradigm. PMID- 26232476 TI - Inflammation in chronic thromboembolic pulmonary hypertension: accomplice or bystander in altered angiogenesis? PMID- 26232477 TI - The role of eHealth and mHealth in tuberculosis and tobacco control: a WHO/ERS consultation. PMID- 26232479 TI - Delineating the hierarchy of lung progenitor cells and their response to influenza. PMID- 26232478 TI - Telomeres revisited: RTEL1 variants in pulmonary fibrosis. PMID- 26232480 TI - ERJ Open Research: FAQs. PMID- 26232481 TI - Acute exacerbation of idiopathic pulmonary fibrosis: shifting the paradigm. AB - The goal of this review is to summarise the clinical features, management, and prognosis of acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF). AE IPF has previously been defined based on clinical and radiological features that include the subacute onset of dyspnoea, bilateral ground glass changes on chest high-resolution computed tomography, and the absence of an identifiable aetiology. The annual incidence of AE-IPF is typically reported at 5-15%, but is less common in mild disease. Features of diffuse alveolar damage are present when a biopsy is performed. Idiopathic pulmonary fibrosis (IPF) patients with acute respiratory worsening are often initially treated with high dose corticosteroids and antimicrobials; however, there are no clear data to support these therapies, and the short-term mortality of AE-IPF is ~50%. Recent studies have shown that the features and prognosis of AE-IPF are similar to other causes of acute respiratory worsening, including infection, aspiration, air pollution and mechanical injury to the alveolar epithelium. Based on this emerging evidence, we propose a novel approach to the classification of acute respiratory worsening events in patients with IPF that focuses on clinical and radiological findings consistent with an underlying pathobiology of diffuse alveolar damage. PMID- 26232482 TI - Defining low-dose corticosteroid: the pendulum still oscillates. PMID- 26232483 TI - Defining low-dose corticosteroid: the pendulum still oscillates. PMID- 26232484 TI - Computed tomography in the diagnosis of bronchiectasis. PMID- 26232485 TI - "Contact investigation for tuberculosis: a systematic review and meta-analysis." Gregory J. Fox, Simone E. Barry, Warwick J. Britton and Guy B. Marks. Eur Respir J 2013; 41: 140-156. PMID- 26232487 TI - A Repressor Protein Complex Regulates Leaf Growth in Arabidopsis. AB - Cell number is an important determinant of final organ size. In the leaf, a large proportion of cells are derived from the stomatal lineage. Meristemoids, which are stem cell-like precursor cells, undergo asymmetric divisions, generating several pavement cells adjacent to the two guard cells. However, the mechanism controlling the asymmetric divisions of these stem cells prior to differentiation is not well understood. Here, we characterized PEAPOD (PPD) proteins, the only transcriptional regulators known to negatively regulate meristemoid division. PPD proteins interact with KIX8 and KIX9, which act as adaptor proteins for the corepressor TOPLESS. D3-type cyclin encoding genes were identified among direct targets of PPD2, being negatively regulated by PPDs and KIX8/9. Accordingly, kix8 kix9 mutants phenocopied PPD loss-of-function producing larger leaves resulting from increased meristemoid amplifying divisions. The identified conserved complex might be specific for leaf growth in the second dimension, since it is not present in Poaceae (grasses), which also lack the developmental program it controls. PMID- 26232488 TI - Bioinformatics Reveal Five Lineages of Oleosins and the Mechanism of Lineage Evolution Related to Structure/Function from Green Algae to Seed Plants. AB - Plant cells contain subcellular lipid droplets with a triacylglycerol matrix enclosed by a layer of phospholipids and the small structural protein oleosin. Oleosins possess a conserved central hydrophobic hairpin of approximately 72 residues penetrating into the lipid droplet matrix and amphipathic amino- and carboxyl (C)-terminal peptides lying on the phospholipid surface. Bioinformatics of 1,000 oleosins of green algae and all plants emphasizing biological implications reveal five oleosin lineages: primitive (in green algae, mosses, and ferns), universal (U; all land plants), and three in specific organs or phylogenetic groups, termed seed low-molecular-weight (SL; seed plants), seed high-molecular-weight (SH; angiosperms), and tapetum (T; Brassicaceae) oleosins. Transition from one lineage to the next is depicted from lineage intermediates at junctions of phylogeny and organ distributions. Within a species, each lineage, except the T oleosin lineage, has one to four genes per haploid genome, only approximately two of which are active. Primitive oleosins already possess all the general characteristics of oleosins. U oleosins have C-terminal sequences as highly conserved as the hairpin sequences; thus, U oleosins including their C terminal peptide exert indispensable, unknown functions. SL and SH oleosin transcripts in seeds are in an approximately 1:1 ratio, which suggests the occurrence of SL-SH oleosin dimers/multimers. T oleosins in Brassicaceae are encoded by rapidly evolved multitandem genes for alkane storage and transfer. Overall, oleosins have evolved to retain conserved hairpin structures but diversified for unique structures and functions in specific cells and plant families. Also, our studies reveal oleosin in avocado (Persea americana) mesocarp and no acyltransferase/lipase motifs in most oleosins. PMID- 26232489 TI - Ethylene and Hormonal Cross Talk in Vegetative Growth and Development. AB - Ethylene is a gaseous plant hormone that most likely became a functional hormone during the evolution of charophyte green algae, prior to land colonization. From this ancient origin, ethylene evolved into an important growth regulator that is essential for myriad plant developmental processes. In vegetative growth, ethylene appears to have a dual role, stimulating and inhibiting growth, depending on the species, tissue, and cell type, developmental stage, hormonal status, and environmental conditions. Moreover, ethylene signaling and response are part of an intricate network in cross talk with internal and external cues. Besides being a crucial factor in the growth control of roots and shoots, ethylene can promote flowering, fruit ripening and abscission, as well as leaf and petal senescence and abscission and, hence, plays a role in virtually every phase of plant life. Last but not least, together with jasmonates, salicylate, and abscisic acid, ethylene is important in steering stress responses. PMID- 26232490 TI - Bypassing Iron Storage in Endodermal Vacuoles Rescues the Iron Mobilization Defect in the natural resistance associated-macrophage protein3natural resistance associated-macrophage protein4 Double Mutant. AB - To improve seed iron (Fe) content and bioavailability, it is crucial to decipher the mechanisms that control Fe storage during seed development. In Arabidopsis (Arabidopsis thaliana) seeds, most Fe is concentrated in insoluble precipitates, with phytate in the vacuoles of cells surrounding the vasculature of the embryo. NATURAL RESISTANCE ASSOCIATED-MACROPHAGE PROTEIN3 (AtNRAMP3) and AtNRAMP4 function redundantly in Fe retrieval from vacuoles during germination. When germinated under Fe-deficient conditions, development of the nramp3nramp4 double mutant is arrested as a consequence of impaired Fe mobilization. To identify novel genes involved in seed Fe homeostasis, we screened an ethyl methanesulfonate-mutagenized population of nramp3nramp4 seedlings for mutations suppressing their phenotypes on low Fe. Here, we report that, among the suppressors, two independent mutations in the VACUOLAR IRON TRANSPORTER1 (AtVIT1) gene caused the suppressor phenotype. The AtVIT1 transporter is involved in Fe influx into vacuoles of endodermal and bundle sheath cells. This result establishes a functional link between Fe loading in vacuoles by AtVIT1 and its remobilization by AtNRAMP3 and AtNRAMP4. Moreover, analysis of subcellular Fe localization indicates that simultaneous disruption of AtVIT1, AtNRAMP3, and AtNRAMP4 limits Fe accumulation in vacuolar globoids. PMID- 26232491 TI - Clinical outcomes of elderly patients receiving neoadjuvant chemoradiation for locally advanced rectal cancer. AB - BACKGROUND: Studies of clinical outcomes of elderly patients treated with neoadjuvant chemoradiation (nCRT) for locally advanced rectal cancer (LARC) are limited. Our aim was to assess the impact of age on clinical outcomes in a large multi-institutional database. PATIENTS AND METHODS: Data for patients diagnosed with LARC who received nCRT and curative-intent surgery between 2005 and 2012 were collected from five major Canadian cancer centers. Age was analyzed as a continuous and dichotomous variable (< 70 versus >= 70 years) and correlated with disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Cox regression models were used to adjust for important prognostic factors. RESULTS: Of 1172 patients included, 295 (25%) were >= 70 years, and they were less likely to receive adjuvant chemotherapy (ACT; 60% versus 79%, P < 0.0001), oxaliplatin-based ACT (12% versus 31%, P < 0.0001), less likely to complete nCT (76% versus 86%, P < 0.001), and more likely to be anemic at initiation of nCRT (42% versus 30%, P = 0.0004). In multivariate analyses, age >= 70 years was associated with similar DFS [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.68-1.26, P = 0.63], similar CSS (HR 0.81, 95% CI 0.46-1.41, P = 0.45), and similar OS (HR 1.28, 95% CI 0.88-1.86, P = 0.20), compared with the younger age group. As a continuous variable, increasing age was not predictive of DFS (HR 1.00, 95% CI 0.99-1.02, P = 0.49) or CSS (HR 1.002, 95% CI 0.98-1.02, P = 0.88); however, it correlated with an inferior OS (HR 1.02, 95% CI 1.00-1.03, P = 0.04). CONCLUSIONS: Elderly patients (>= 70 years) who receive nCRT followed by surgery appear to have similar outcomes compared with younger patients. Decisions regarding eligibility for nCRT and surgery should not be based on age alone. PMID- 26232492 TI - Why has active immunotherapy not worked in lung cancer? AB - Vaccines that rely on active specific stimulation of the host immune system have the potential to trigger durable antitumor responses with minimal toxicity. However, in nonsmall-cell lung cancer (NSCLC), several large phase III trials of vaccines reported within the last year have yielded disappointing results. Compared with placebo, belagenpumatucel-L (an allogenic tumor cell vaccine), tecemotide (a peptide vaccine targeting MUC-1) and melanoma-associated antigen-A3 (a protein-based vaccine) did not improve outcomes in NSCLC. The lack of clinically significant outcomes, despite their ability to prime and expand tumor antigen-specific T cells could at least partly be attributed to the inability of vaccine-induced T-cell responses to overcome the tumoral mechanisms of immune escape which limit the clonal expansion of T cells following vaccination. A number of such mechanisms have been recognized including reduced antigen presentation, antigenic loss, cytokines, immunosuppressive cells and immune checkpoints. Strategies aimed at modulating the immune checkpoints have shown promise and are on the verge of revolutionizing the therapeutic landscape of metastatic NSCLC. Overcoming immune tolerance and improving the activation of antitumor T cells via combinatorial approaches may represent a new and more promising therapeutic application for active immunotherapies in NSCLC. PMID- 26232493 TI - Unliganded EphA3 dimerization promoted by the SAM domain. AB - The erythropoietin-producing hepatocellular carcinoma A3 (EphA3) receptor tyrosine kinase (RTK) regulates morphogenesis during development and is overexpressed and mutated in a variety of cancers. EphA3 activation is believed to follow a 'seeding mechanism' model, in which ligand binding to the monomeric receptor acts as a trigger for signal-productive receptor clustering. We study EphA3 lateral interactions on the surface of live cells and we demonstrate that EphA3 forms dimers in the absence of ligand binding. We further show that these dimers are stabilized by interactions involving the EphA3 sterile alpha-motif (SAM) domain. The discovery of unliganded EphA3 dimers challenges the current understanding of the chain of EphA3 activation events and suggests that EphA3 may follow the 'pre-formed dimer' model of activation known to be relevant for other receptor tyrosine kinases. The present work also establishes a new role for the SAM domain in promoting Eph receptor lateral interactions and signalling on the cell surface. PMID- 26232494 TI - Environmental factors and their association with emergency department hand hygiene compliance: an observational study. AB - OBJECTIVES: Hand hygiene is effective in preventing healthcare-associated infections. Environmental conditions in the emergency department (ED), including crowding and the use of non-traditional patient care areas (ie, hallways), may pose barriers to hand hygiene compliance. We examined the relationship between these environmental conditions and proper hand hygiene. METHODS: This was a single-site, observational study. From October 2013 to January 2014, trained observers recorded hand hygiene compliance among staff in the ED according to the World Health Organization 'My 5 Moments for Hand Hygiene'. Multivariable logistic regression was used to analyse the relationship between environmental conditions and hand hygiene compliance, while controlling for important covariates (eg, hand hygiene indication, glove use, shift, etc). RESULTS: A total of 1673 hand hygiene opportunities were observed. In multivariable analyses, hand hygiene compliance was significantly lower when the ED was at its highest level of crowding than when the ED was not crowded and lower among hallway care areas than semiprivate care areas (OR=0.39, 95% CI 0.28 to 0.55; OR=0.73, 95% CI 0.55 to 0.97). CONCLUSIONS: Unique environmental conditions pose barriers to hand hygiene compliance in the ED setting and should be considered by ED hand hygiene improvement efforts. Further study is needed to evaluate the impact of these environmental conditions on actual rates of infection transmission. PMID- 26232496 TI - The significance of the squeeze test to identify arthritis was underestimated or not? PMID- 26232499 TI - Editorial: Neutrophil elastase and the lung: is it degradation, repair, emphysema, or fibrosis? What tilts it left or right? PMID- 26232495 TI - Incidence and predictors of cutaneous manifestations during the early course of systemic sclerosis: a 10-year longitudinal study from the EUSTAR database. AB - OBJECTIVES: To longitudinally map the onset and identify risk factors for skin sclerosis and digital ulcers (DUs) in patients with systemic sclerosis (SSc) from an early time point after the onset of Raynaud's phenomenon (RP) in the European Scleroderma Trials and Research (EUSTAR) cohort. METHODS: 695 patients with SSc with a baseline visit within 1 year after RP onset were followed in the prospective multinational EUSTAR database. During the 10-year observation period, cumulative probabilities of cutaneous lesions were assessed with the Kaplan-Meier method. Cox proportional hazards regression analysis was used to evaluate risk factors. RESULTS: The median modified Rodnan skin score (mRSS) peaked 1 year after RP onset, and was 15 points. The 1-year probability to develop an mRSS >=2 in at least one area of the arms and legs was 69% and 25%, respectively. Twenty five per cent of patients developed diffuse cutaneous involvement in the first year after RP onset. This probability increased to 36% during the subsequent 2 years. Only 6% of patients developed diffuse cutaneous SSc thereafter. The probability to develop DUs increased to a maximum of 70% at the end of the 10 year observation. The main factors associated with diffuse cutaneous SSc were the presence of anti-RNA polymerase III autoantibodies, followed by antitopoisomerase autoantibodies and male sex. The main factor associated with incident DUs was the presence of antitopoisomerase autoantibodies. CONCLUSION: Early after RP onset, cutaneous manifestations exhibit rapid kinetics in SSc. This should be accounted for in clinical trials aiming to prevent skin worsening. PMID- 26232500 TI - Specialized pro-resolving mediators: do they circulate in plasma? PMID- 26232501 TI - E3 ligase CHIP and Hsc70 regulate Kv1.5 protein expression and function in mammalian cells. AB - Kv1.5 confers ultra-rapid delayed-rectifier potassium channel current (IKur) which contributes to repolarization of the atrial action potential. Kv1.5 proteins, degraded via the ubiquitin-proteasome pathway, decreased in some atrial fibrillation patients. Carboxyl-terminus heat shock cognate 70-interacting protein (CHIP), an E3 ubiquitin ligase, is known to ubiquitinate short-lived proteins. Here, we investigated the roles of CHIP in Kv1.5 degradation to provide insights into the mechanisms of Kv1.5 decreases and treatments targeting Kv1.5 for atrial fibrillation. Coexpression of CHIP with Kv1.5 in HEK293 cells increased Kv1.5 protein ubiquitination and decreased the protein level. Immunofluorescence revealed decreases of Kv1.5 proteins in the endoplasmic reticulum and on the cell membrane. A siRNA against CHIP suppressed Kv1.5 protein ubiquitination and increased its protein level. CHIP mutants, lacking either the N-terminal tetratricopeptide region domain or the C-terminal U-box domain, failed to exert these effects on Kv1.5 proteins. Immunoprecipitation showed that CHIP formed complexes with Kv1.5 proteins and heat shock cognate protein 70 (Hsc70). Effects of Hsc70 on Kv1.5 were similar to CHIP by altering interaction of CHIP with Kv1.5 protein. Coexpression of CHIP and Hsc70 with Kv1.5 additionally enhanced Kv1.5 ubiquitination. Kv1.5 currents were decreased by overexpression of CHIP or Hsc70 but were increased by knockdown of CHIP or Hsc70 in HEK 293 cells stably expressing Kv1.5. These effects of CHIP and Hsc70 were also observed on endogenous Kv1.5 in HL-1 mouse cardiomyocytes, decreasing IKur and prolonging action potential duration. These results indicate that CHIP decreases the Kv1.5 protein level and functional channel by facilitating its degradation in concert with chaperone Hsc70. PMID- 26232502 TI - Strategies of NF-kappaB signaling modulation by ectromelia virus in BALB/3T3 murine fibroblasts. AB - Nuclear factor kappaB (NF-kappaB) is a pleiotropic transcription factor that regulates the expression of immune response genes. NF-kappaB signaling can be disrupted by pathogens that prevent host immune response. In this work, we examined the influence of ectromelia (mousepox) virus (ECTV) on NF-kappaB signaling in murine BALB/3T3 fibroblasts. Activation of NF-kappaB via tumor necrosis factor (TNF) receptor 1 (TNFR1) in these cells induces proinflammatory cytokine secretion. We show that ECTV does not recruit NF-kappaB to viral factories or induce NF-kappaB nuclear translocation in BALB/3T3 cells. Additionally, ECTV counteracts TNF-alpha-induced p65 NF-kappaB nuclear translocation during the course of infection. Inhibition of TNF-alpha-induced p65 nuclear translocation was also observed in neighboring cells that underwent fusion with ECTV-infected cells. ECTV inhibits the key step of NF-kappaB activation, i.e. Ser32 phosphorylation and degradation of inhibitor kappaBalpha (IkappaBalpha) induced by TNF-alpha. We also observed that ECTV prevents TNF alpha-induced Ser536 of p65 phosphorylation in BALB/3T3 cells. Studying TNFR1 signaling provides information about regulation of inflammatory response and cell survival. Unraveling poxviral immunomodulatory strategies may be helpful in drug target identification as well as in vaccine development. PMID- 26232503 TI - Antigen I/II encoded by integrative and conjugative elements of Streptococcus agalactiae and role in biofilm formation. AB - Streptococcus agalactiae (i.e. Group B streptococcus, GBS) is a major human and animal pathogen. Genes encoding putative surface proteins and in particular an antigen I/II have been identified on Integrative and Conjugative Elements (ICEs) found in GBS. Antigens I/II are multimodal adhesins promoting colonization of the oral cavity by streptococci such as Streptococcus gordonii and Streptococcus mutans. The prevalence and diversity of antigens I/II in GBS were studied by a bioinformatic analysis. It revealed that antigens I/II, which are acquired by horizontal transfer via ICEs, exhibit diversity and are widespread in GBS, in particular in the serotype Ia/ST23 invasive strains. This study aimed at characterizing the impact on GBS biology of proteins encoded by a previously characterized ICE of S. agalactiae (ICE_515_tRNA(Lys)). The production and surface exposition of the antigen I/II encoded by this ICE was examined using RT PCR and immunoblotting experiments. Surface proteins of ICE_515_tRNA(Lys) were found to contribute to GBS biofilm formation and to fibrinogen binding. Contribution of antigen I/II encoded by SAL_2056 to biofilm formation was also demonstrated. These results highlight the potential for ICEs to spread microbial adhesins between species. PMID- 26232504 TI - Traveling with children: beyond car seat safety. AB - OBJECTIVE: To spread knowledge and instigate the health professional to give advice on childcare during travels and on child transport safety. SOURCES OF DATA: Literature review through the LILACS and MEDLINE((r)) databases, using the terms: travel, safety, protective equipment, child, preventive medicine, retrieving articles published in the last 21 years. SUMMARY OF THE FINDINGS: The authors analyzed 93 articles, of which 66 met the inclusion criteria after summaries were read. For drafting this article, the following sub-themes were proposed: getting ready to travel with children; knowing some of the transfer risks (air, land and water transportation) and exploring the destination with children (sun exposure, accommodations, altitude, food, traveler's diarrhea, insect bites) and return from the trip with children. CONCLUSIONS: Over the years, there has been an increase in the number of children who travel around the world. However, this population is still subject to health problems while traveling and may be even more susceptible than the adult age group. These problems arise from a variety of factors, including exposure to infectious organisms, the use of certain types of transportation, and participation in some activities, such as hiking at high altitudes, among others. However, when traveling with children, these risk factors can be overlooked; a trip that is considered safe for an adult might not be a good choice for this age group. The pediatric consultation should be a good opportunity to optimize preventive guidelines at the pre-trip planning. PMID- 26232505 TI - Effect of 4'galactooligosaccharide on constipation symptoms. AB - OBJECTIVE: Fructooligosacharides and galactooligosacharides soften fecal bolus and increase frequency of depositions when added to infant formula. This study aimed to determine the effects of galactooligosaccharide in pediatric patients with chronic constipation. METHODS: From 2010 to 2012, 20 constipated patients (4 16 years of age) attended to at a primary healthcare unit were enrolled in a double-blinded, placebo-controlled crossover trial. Eleven children ingested galactooligosaccharide (1.7 g) for 30 days, followed by a 15-day washout period, and a 30-day period of placebo (maltodextrin). Nine patients ingested maltodextrin for 30 days, followed by 15-day washout period, and galactooligosaccharide (1.7 g) for 30 days. Constipation symptoms were considered as primary outcomes: bowel movements/week, straining during defecation, and stool consistency. Outcome symptoms were ranked according to a numerical scale elaborated for this study. Data were recorded at baseline, and on days 15 and 30 of each 30-day crossover period. Repeated-measures analysis of variance (ANOVA) was used to analyze symptoms along time. RESULTS: At baseline, there was no significant difference in symptoms severity between groups (p=0.45). Galactooligosaccharide ingestion was related to increase of the bowel movement frequency, p<0.0001; relief of defecation straining, p<0.0001; and decrease in stool consistency, p=0.0014, compared to placebo ingestion. Patients reported no side effects from galactooligosaccharide. CONCLUSION: Galactooligosaccharide was effective at improving clinical symptoms in this group of constipated children. PMID- 26232506 TI - The impact of maternal obesity during pregnancy on offspring immunity. AB - In the United States, approximately 64% of women of childbearing age are either overweight or obese. Maternal obesity during pregnancy is associated with a greater risk for adverse maternal-fetal outcomes. Adverse health outcomes for the offspring can persist into adulthood, increasing the incidence of several chronic conditions including cardiovascular disease, diabetes, and asthma. Since these diseases have a significant inflammatory component, these observations are indicative of perturbation of the normal development and maturation of the immune system of the offspring in utero. This hypothesis is strongly supported by data from several rodent studies. Although the mechanisms of these perturbations are not fully understood, it is thought that increased placental inflammation due to obesity may directly affect neonatal development through alterations in nutrient transport. In this review we examine the impact of maternal obesity on the neonatal immune system, and potential mechanisms for the changes observed. PMID- 26232507 TI - Magnesium sulfate prevents maternal inflammation-induced impairment of learning ability and memory in rat offspring. AB - OBJECTIVE: Maternal chorioamnionitis is associated with newborn neurologic injury. Recent evidence suggests that maternal administration of magnesium sulphate (MG) may protect fetuses from white matter injury. Previously we demonstrated evidence by magnetic resonance imaging that MG may prevent maternal inflammation-induced gray matter injury of offspring. Thus, we sought to determine the potential of maternal inflammation to induce fetal neurological/behavioral deficits and assess whether maternal MG attenuates these effects. STUDY DESIGN: Pregnant rats at day 18 received injections of intraperitoneal lipopolysaccharide (LPS) or saline. Dams were treated with subcutaneous saline/MG (270 mg/kg followed by 27 mg/kg every 20 minutes) for 2 hours before and following LPS/saline injections. Pups were delivered spontaneously. At 1 and 3 months of age, 11-12 offspring of each group (saline, LPS, MG, LPS-MG) underwent a 2-way shuttle box avoidance testing. The shuttle box is divided in half and the animal moves between compartments to avoid an electric shock in response to an auditory stimulus. RESULTS: Control offspring demonstrated significantly improved learning and memory abilities from age 1 to 3 months. At 1 month, LPS-treated dams' offspring were similar to controls with no improvement in learning abilities at 3 months. MG treatment of LPS dams significantly improved offspring learning at 3 months, to equal or better than that of controls. CONCLUSION: LPS-stimulated inflammation during pregnancy impairs offspring learning ability and memory, which is ameliorated by maternal MG treatment. These results suggest that maternal MG therapy may prevent white and gray matter injuries associated with maternal infection/inflammation. PMID- 26232509 TI - Fetal programming and systemic sclerosis. AB - OBJECTIVE: This study investigated whether birthweight is linked to an increased risk of the development of systemic sclerosis. STUDY DESIGN: This was a multicenter case-control study with perinatal data that were obtained from 332 cases with systemic sclerosis and 243 control subjects. Birthweight was treated as a dichotomous variable (<2500 g vs >=2500 g); low birthweight was defined as a weight <2500 g; small for gestational age was defined as birthweight <10th percentile for gestational age adjusted for sex. The relationship between systemic sclerosis and both low birthweight and small for gestational age was expressed with the crude (univariate analysis) and adjusted (multivariate analysis) odds ratio (OR). RESULTS: Significantly increased ORs were observed in the univariate analysis for low birthweight (OR, 2.59; 95% confidence interval [CI], 1.39-5.05) and small for gestational age (OR, 2.60; 95% CI, 1.34-5.32) subjects. Similarly increased risks were confirmed for both conditions in the multivariate analysis (OR, 3.93; 95% CI, 1.92-8.07; and OR, 2.58; 95% CI, 1.28 5.19), respectively. CONCLUSION: Low birthweight and small for gestational age at birth are risk factors for the adult onset of systemic sclerosis. PMID- 26232510 TI - The potential utility of some legal highs in CNS disorders. AB - Over the last decade there has been an explosion of new drugs of abuse, so called legal highs or novel psychoactive substances (NPS). Many of these abused drugs have unknown pharmacology, but their biological effects can be anticipated from their molecular structure and possibly also from online user reports. When considered with the findings that some prescription medications are increasingly abused and that some abused drugs have been tested clinically one could argue that there has been a blurring of the line between drugs of abuse and clinically used drugs. In this review we examine these legal highs/NPS and consider whether, based on their known or predicted pharmacology, some might have the potential to be clinically useful in CNS disorders. PMID- 26232511 TI - Microelectronics, bioinformatics and neurocomputation for massive neuronal recordings in brain circuits with large scale multielectrode array probes. AB - Deciphering neural network function in health and disease requires recording from many active neurons simultaneously. Developing approaches to increase their numbers is a major neurotechnological challenge. Parallel to recent advances in optical Ca(2+) imaging, an emerging approach consists in adopting complementary metal-oxide-semiconductor (CMOS) technology to realize MultiElectrode Array (MEA) devices. By implementing signal conditioning and multiplexing circuits, these devices allow nowadays to record from several thousands of single neurons at sub millisecond temporal resolution. At the same time, these recordings generate very large data streams which become challenging to analyze. Here, at first we shortly review the major approaches developed for data management and analysis for conventional, low-resolution MEAs. We highlight how conventional computational tools cannot be easily up-scaled to very large electrode array recordings, and custom bioinformatics tools are an emerging need in this field. We then introduce a novel approach adapted for the acquisition, compression and analysis of extracellular signals acquired simultaneously from 4096 electrodes with CMOS MEAs. Finally, as a case study, we describe how this novel large scale recording platform was used to record and analyze extracellular spikes from the ganglion cell layer in the wholemount retina at pan-retinal scale following patterned light stimulation. PMID- 26232512 TI - Hypoxia inducible factor 1alpha down regulates cell surface expression of alpha1,2-fucosylated glycans in human pancreatic adenocarcinoma cells. AB - The alpha1,2-fucosyltransferase activity in pancreatic tumors is much lower compared to normal pancreatic tissue. Here we show that hypoxia inducible factor (HIF) 1alpha is constitutively expressed in the pancreatic cancer cell lines Pa Tu-8988S and Pa-Tu-8988T and suppresses the expression of the alpha1,2 fucosyltransferase genes FUT1 and FUT2. Down regulation of HIF-1alpha expression resulted in elevated FUT1 and FUT2 transcript levels and an increased expression of alpha1,2-fucosylated glycan structures on the surface of these cells. In conclusion, our data are the first to identify HIF-1alpha as a suppressor of FUT1/2 expression, thereby regulating alpha1,2-fucosylation of cell-surface glycans. PMID- 26232508 TI - Evidence of perturbations of the cytokine network in preterm labor. AB - OBJECTIVE: Intraamniotic inflammation/infection is the only mechanism of disease with persuasive evidence of causality for spontaneous preterm labor/delivery. Previous studies about the behavior of cytokines in preterm labor have been largely based on the analysis of the behavior of each protein independently. Emerging evidence indicates that the study of biologic networks can provide insight into the pathobiology of disease and improve biomarker discovery. The goal of this study was to characterize the inflammatory-related protein network in the amniotic fluid of patients with preterm labor. STUDY DESIGN: A retrospective cohort study was conducted that included women with singleton pregnancies who had spontaneous preterm labor and intact membranes (n = 135). These patients were classified according to the results of amniotic fluid culture, broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry, and amniotic fluid concentration of interleukin (IL)-6 into the following groups: (1) those without intraamniotic inflammation (n = 85), (2) those with microbial-associated intraamniotic inflammation (n = 15), and (3) those with intraamniotic inflammation without detectable bacteria (n = 35). Amniotic fluid concentrations of 33 inflammatory-related proteins were determined with the use of a multiplex bead array assay. RESULTS: Patients with preterm labor and intact membranes who had microbial-associated intraamniotic inflammation had a higher amniotic fluid inflammatory-related protein concentration correlation than those without intraamniotic inflammation (113 perturbed correlations). IL-1beta, IL-6, macrophage inflammatory protein (MIP) 1alpha, and IL-1alpha were the most connected nodes (highest degree) in this differential correlation network (degrees of 20, 16, 12, and 12, respectively). Patients with sterile intraamniotic inflammation had correlation patterns of inflammatory-related proteins, both increased and decreased, when compared to those without intraamniotic inflammation (50 perturbed correlations). IL-1alpha, MIP-1alpha, and IL-1beta were the most connected nodes in this differential correlation network (degrees of 12, 10, and 7, respectively). There were more coordinated inflammatory-related protein concentrations in the amniotic fluid of women with microbial-associated intraamniotic inflammation than in those with sterile intraamniotic inflammation (60 perturbed correlations), with IL-4 and IL 33 having the largest number of perturbed correlations (degrees of 15 and 13, respectively). CONCLUSIONS: We report for the first time an analysis of the inflammatory-related protein network in spontaneous preterm labor. Patients with preterm labor and microbial-associated intraamniotic inflammation had more coordinated amniotic fluid inflammatory-related proteins than either those with sterile intraamniotic inflammation or those without intraamniotic inflammation. The correlations were also stronger in patients with sterile intraamniotic inflammation than in those without intraamniotic inflammation. The findings herein could be of value in the development of biomarkers of preterm labor. PMID- 26232513 TI - Drospirenone-only oral contraceptive: results from a multicenter noncomparative trial of efficacy, safety and tolerability. AB - OBJECTIVES: This study was performed to assess the contraceptive efficacy of the drospirenone (DRSP)-only pill and to provide information regarding its safety and cycle-control profile. STUDY DESIGN: This prospective, multicenter, noncomparative study was conducted at 41 European sites in healthy women at risk of pregnancy, aged 18 to 45 years. The study medication was DRSP 4.0mg daily for 24 days followed by a placebo for 4 days (DRSP 4 mg 24/4, Exeltis, Spain) for thirteen 28-day treatment cycles. The primary efficacy endpoint was the overall Pearl Index (PI). Bleeding patterns, changes in vital signs and changes in laboratory values were also analyzed. RESULTS: A total of 713 participants with 7638 DRSP treatment cycles were analyzed. The overall PI was 0.51 (95% confidence interval, 0.1053-1.4922). The proportion of participants with any bleeding decreased from 72.7% in Cycle 1 to 40% in Cycle 6 and 32.1% in Cycle 13. Unscheduled bleeding decreased from 49.1% in Cycle 1 to 27.8% in Cycle 6 and to 22.8% in Cycle 13. Prolonged bleeding was reported by 6.5% during Cycles 2 to 4 decreasing to 4.2% during Cycles 11 to 13. There were no reports of deep vein thrombosis, pulmonary embolism or hyperkalemia. No relevant changes were observed for laboratory parameters, body weight, body mass index, blood pressure or heart rate. Study drug acceptability was considered as "excellent/good" by over 82% of subjects. CONCLUSION: This new DRSP-only oral contraceptive provides clinical contraceptive efficacy similar to that of the currently marketed Combination estrogen plus progestin Oral Contraceptive, with a good safety profile, and favorable cycle control. IMPLICATIONS: A novel 4-mg DRSP-only pill taken daily for 24 days followed by a placebo for 4 days demonstrated contraceptive efficacy similar to that of currently marketed Combination estrogen plus progestin Oral Contraceptive, with a good safety profile, and favorable cycle control. PMID- 26232514 TI - Chest compression fraction: A time dependent variable of survival in shockable out-of-hospital cardiac arrest. AB - INTRODUCTION: The role of chest compression fraction (CCF) in resuscitation of shockable out-of-hospital cardiac arrest (OHCA) is uncertain. We evaluated the relationship between CCF and clinical outcomes in a secondary analysis of the Resuscitation Outcomes Consortium PRIMED trial. METHODS: We included patients presenting in a shockable rhythm who suffered OHCA prior to EMS arrival. Multivariable logistic regression was used to determine the relationship between CCF and survival to hospital discharge, return of spontaneous circulation (ROSC), and neurologically intact survival. We also performed a secondary analysis restricted to patients without ROSC in the first 10 min of EMS resuscitation. RESULTS: Among the 2011 patients, median (IQR) age was 65 (54, 75) years, 78.2% were male, and mean (SD) CCF was 0.71 (0.14). Compared to the reference group (CCF<0.60), the odds ratio (OR) for survival was 0.49 (95% CI: 0.36, 0.68) for CCF 0.60-0.79 and 0.30 (95% CI: 0.20, 0.44) for CCF>=0.80. Results were similar for outcomes of ROSC and neurologically intact survival. Conversely, when restricted to the cohort who did not achieve ROSC during the first 10 min (n=1633), compared to the reference group (CCF<0.60), the OR for survival was 0.79 (95% CI: 0.53, 1.18) for CCF 0.60-0.79 and OR 0.88 (95% CI: 0.56, 1.36) for CCF>=0.80. CONCLUSIONS: In this study of OHCA patients presenting in a shockable rhythm, CCF was paradoxically associated with lower odds of survival. CCF is a complex measure and taken by itself may not be a consistent predictor of good clinical outcomes. PMID- 26232515 TI - Outcome and risk factors in children after traumatic cardiac arrest and successful resuscitation. AB - INTRODUCTION: Prospective collected data of the TraumaRegister DGU((r)) were analyzed to derive survival rates and predictors for non-survival in the children who had suffered traumatic cardiorespiratory arrest. Different time points of resuscitation efforts (only preclinical, in the emergency room (ER) or preclinical+ER) were analyzed in terms of mortality and neurological outcome. METHODS: The database of the TraumaRegister DGU((r)) comprising 122,742 patients from 1993 to 2013 was analyzed. The main focus of this survey was on the paediatric group defined by an age <= 14 years who could be compared to adults. Different statistical analysis (univariate and multivariate analysis, logistic regression) were performed with mortality as the target variable. Differences between the paedatric group and adults were analysed by Fisher's exact test. RESULTS: Data after preclinical and/or ER resuscitation from 152 children and 1690 adults were analyzed. A good or moderate outcome (GOS 5+4) was found in 19.4% of the children's group compared to 12.4% of the adults (p=0.02). Analysis of the GOS 5+4 subgroups after preclinical resuscitation only revealed that these outcomes were achieved by 19.4% of the paediatric group and 13.2% of the adults (p=0.24), after ER-only resuscitation by 37.0% of the children and 19.6% of the adults (p=0.046), and after preclinical and ER resuscitation by only 10.9% of the children compared to 2.5% of the adults (p=0.006). Taking only survivors into account, 84.8% of the children and 62% of the adults had a GOS 4+5. The highest risk for mortality in the logistic regression model was associated with preclinical intubation, followed by GCS 3, blood transfusion and severe head injury with AIS >=3 and ISS. CONCLUSIONS: CPR in children after severe trauma seems to yield a better outcome than in adults, and appears to be more justified than the current guidelines would imply. Resuscitation in the ER is associated with better neurological outcomes compared with resuscitation in a preclinical context or in both the preclinical phase and the ER. Our children's outcomes seem to be better than those in most of the earlier studies, and the data presented might support algorithms in the future especially for paediatric resuscitation. PMID- 26232516 TI - Prognostic values of gray matter to white matter ratios on early brain computed tomography in adult comatose patients after out-of-hospital cardiac arrest of cardiac etiology. AB - AIM OF THE STUDY: Previous studies found that the gray matter to white matter ratio (GWR) on brain computed tomography (CT) could be used to predict poor outcomes in cardiac arrest survivors. However, these studies have included cardiac arrests of both cardiac and non-cardiac etiologies. We sought to evaluate if the GWR on brain CT can help to predict poor outcomes after out-of-hospital cardiac arrest (OHCA) of cardiac etiology. METHODS: Using a multicenter retrospective registry of adult cardiac arrest survivors treated with therapeutic hypothermia, we identified survivors of OHCA of cardiac etiology who underwent brain CT within 24h after successful resuscitation. Gray and white matter attenuations were measured, and the GWRs were calculated as in previous studies. The prognostic values of the GWRs were analyzed, and a logistic regression analysis was performed to determine the contribution of the GWR in predicting poor outcomes (Cerebral Performance Category 3-5). RESULTS: of 283 included patients, 140 had good outcomes and 143 had poor outcomes. Although the GWRs could predict poor outcomes with statistical significance, the sensitivities were remarkably low (3.5% to 5.6%) at cutoff values with 100% specificity. No significant difference in predictive performance was found between the primary predictive model, containing independent poor outcome predictors, and the primary predictive model combined with the GWR. CONCLUSION: In a cohort of comatose adults after OHCA of cardiac etiology, the GWR demonstrated poor predictive performance and was not helpful in predicting poor outcomes. PMID- 26232517 TI - Postoperative hormone replacement therapy for epithelial ovarian cancer patients: a systematic review and meta-analysis. AB - BACKGROUND: Hormone replacement therapy (HRT) has been proven highly effective for menopausal symptoms caused by radical surgery. However, the impact of postoperative HRT on the clinical outcomes of patients previously treated for epithelial ovarian cancer (EOC) remains unclear. OBJECTIVE: To determine whether postoperative HRT use has any positive or negative impacts on prognosis and recurrence among EOC survivors. METHODS: Studies that provided an assessment of postoperative HRT use and prognosis or recurrence in EOC patients were included for analysis. Two reviewers independently evaluated the eligibility of identified studies and abstracted the data. A fixed effects model was used to pool study specific estimates of hazard ratios (HRs) or relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: Two randomized controlled trials (RCTs) and four cohort studies included 419 EOC survivors who used HRT and 1029 non-users. The aggregated HR of overall survival (OS) suggested that HRT use after surgery for EOC had a favorable impact on OS (HR=0.69, 95% CI: 0.61-0.79), but when these studies were categorized into cohort study and RCT subgroups, not all of them demonstrated positive results (HR=0.63, 95% CI: 0.49-0.81 and HR=1.03, 95% CI: 0.58-1.83, respectively). The meta-analysis of EOC recurrence of three available studies demonstrated that postoperative HRT use was not associated with an increased risk of recurrence in EOC survivors (RR=0.83, 95% CI: 0.64-1.07). This pattern also emerged in the subgroup analysis for the stage and type of HRT. CONCLUSIONS: In EOC patients, postoperative HRT does not have a negative effect on overall survival and tumor recurrence. However, well-designed and large-scale RCTs are needed to verify this relationship in the future. PMID- 26232518 TI - Bariatric surgery as a means to decrease mortality in women with type I endometrial cancer - An intriguing option in a population at risk for dying of complications of metabolic syndrome. AB - OBJECTIVE: To estimate the cost-effectiveness and utility of a strategy of offering weight loss surgery (WLS) to women with low risk stage I endometrial cancer (EC) and BMI>=40kg/m(2). METHODS: A modified Markov state transition model was designed to compare routine care to WLS for women with low risk stage I endometrioid EC, age<70, with a mean BMI 40. A time horizon of 15years was used to simulate the overall survival (OS) of 96,232 women treated from 1988-2010 from SEER*Stat data. To simulate the effects of WLS on OS, a hazard ratio (0.76, 95% CI 0.59-0.99) representing the OS improvement achieved from this intervention (derived from a prospective trial) was modeled. We assumed that 90% of women undergoing bariatric procedures would experience a reduction in BMI. We assumed that 5% of women not undergoing WLS would achieve weight loss to a BMI of 35. Costs of treatment for obesity-related chronic diseases and quality of life (QOL) related utilities were modeled from published reports. RESULTS: The mean cost effectiveness for each strategy was: $69,295 and 8.10 quality-adjusted life years (QALYs) for routine care versus $100,675 and 9.30 QALYs for WLS. WLS had an incremental cost-effectiveness ratio (ICER) of $26,080/QALY compared to routine care. At a willingness to pay threshold of $50,000/QALY, WLS was the strategy of choice in 100% of simulations. CONCLUSIONS: WLS is a potentially cost-effective intervention in women with low risk, early stage EC, at least in part due to improved quality of life with weight reduction. PMID- 26232519 TI - Sexual satisfaction and quality of life in survivors of localized cervical and ovarian cancers following fertility-sparing surgery. AB - OBJECTIVE: To determine if sexual satisfaction and sexual quality of life (QOL) are different in survivors of localized cervical and ovarian cancers who undergo fertility-sparing surgery (FSS) as compared with standard surgery. METHODS: 470 survivors of localized cervical and ovarian cancers diagnosed between the ages of 18-40 were recruited from the California Cancer Registry to complete a cross sectional survey. Validated questionnaires were used to assess sexual satisfaction and sexual QOL. RESULTS: 228 women with localized cervical cancer and 125 with localized ovarian cancer completed the survey. In the cervical cancer group, 92 underwent FSS. Compared with the 84 women who did not undergo FSS (had a hysterectomy, but retained at least one ovary), there was no significant difference in sexual satisfaction or sexual QOL mean scores in women who maintained their uterus (cold-knife cone or trachelectomy), after controlling for age and menopausal status. 82 women with ovarian cancer underwent FSS. Compared with the 39 women that had a bilateral salpingo-oophorectomy, we found no significant differences in sexual satisfaction or sexual QOL in women who maintained at least one ovary (USO or cystectomy), after controlling for age and menopausal status. CONCLUSIONS: While FSS may allow for post-treatment fertility, it may not confer a significant benefit with regard to sexual satisfaction or sexual QOL. Thus, the decision to perform FSS should not be dictated based on preservation of sexual functioning. PMID- 26232520 TI - Cytosolic Ca(2+) Signals Enhance the Vacuolar Ion Conductivity of Bulging Arabidopsis Root Hair Cells. AB - Plant cell expansion depends on the uptake of solutes across the plasma membrane and their storage within the vacuole. In contrast to the well-studied plasma membrane, little is known about the regulation of ion transport at the vacuolar membrane. We therefore established an experimental approach to study vacuolar ion transport in intact Arabidopsis root cells, with multi-barreled microelectrodes. The subcellular position of electrodes was detected by imaging current-injected fluorescent dyes. Comparison of measurements with electrodes in the cytosol and vacuole revealed an average vacuolar membrane potential of -31 mV. Voltage clamp recordings of single vacuoles resolved the activity of voltage-independent and slowly deactivating channels. In bulging root hairs that express the Ca(2+) sensor R-GECO1, rapid elevation of the cytosolic Ca(2+) concentration was observed, after impalement with microelectrodes, or injection of the Ca(2+) chelator BAPTA. Elevation of the cytosolic Ca(2+) level stimulated the activity of voltage-independent channels in the vacuolar membrane. Likewise, the vacuolar ion conductance was enhanced during a sudden increase of the cytosolic Ca(2+) level in cells injected with fluorescent Ca(2+) indicator FURA-2. These data thus show that cytosolic Ca(2+) signals can rapidly activate vacuolar ion channels, which may prevent rupture of the vacuolar membrane, when facing mechanical forces. PMID- 26232521 TI - Orexinergic bouton density is lower in the cerebral cortex of cetaceans compared to artiodactyls. AB - The species of the cetacean and artiodactyl suborders, which constitute the order Cetartiodactyla, exhibit very different sleep phenomenology, with artiodactyls showing typical bihemispheric slow wave and REM sleep, while cetaceans show unihemispheric slow wave sleep and appear to lack REM sleep. The aim of this study was to determine whether cetaceans and artiodactyls have differently organized orexinergic arousal systems by examining the density of orexinergic innervation to the cerebral cortex, as this projection will be involved in various aspects of cortical arousal. This study provides a comparison of orexinergic bouton density in the cerebral cortex of twelve Cetartiodactyla species (ten artiodactyls and two cetaceans) by means of immunohistochemical staining and stereological analysis. It was found that the morphology of the axonal projections of the orexinergic system to the cerebral cortex was similar across all species, as the presence, size and proportion of large and small orexinergic boutons were similar. Despite this, orexinergic bouton density was lower in the cerebral cortex of the cetaceans studied compared to the artiodactyls studied, even when corrected for brain mass, neuron density, glial density and glial:neuron ratio. Results from correlational and principal component analyses indicate that glial density is a major determinant of the observed differences between artiodactyl and cetacean cortical orexinergic bouton density. PMID- 26232522 TI - Transcriptional profiling of rat white adipose tissue response to 2,3,7,8 tetrachlorodibenzo-rho-dioxin. AB - Polychlorinated dibenzodioxins are environmental contaminants commonly produced as a by-product of industrial processes. The most potent of these, 2,3,7,8 tetrachlorodibenzo-rho-dioxin (TCDD), is highly lipophilic, leading to bioaccumulation. White adipose tissue (WAT) is a major site for energy storage, and is one of the organs in which TCDD accumulates. In laboratory animals, exposure to TCDD causes numerous metabolic abnormalities, including a wasting syndrome. We therefore investigated the molecular effects of TCDD exposure on WAT by profiling the transcriptomic response of WAT to 100MUg/kg of TCDD at 1 or 4days in TCDD-sensitive Long-Evans (Turku/AB; L-E) rats. A comparative analysis was conducted simultaneously in identically treated TCDD-resistant Han/Wistar (Kuopio; H/W) rats one day after exposure to the same dose. We sought to identify transcriptomic changes coinciding with the onset of toxicity, while gaining additional insight into later responses. More transcriptional responses to TCDD were observed at 4days than at 1day post-exposure, suggesting WAT shows mostly secondary responses. Two classic AHR-regulated genes, Cyp1a1 and Nqo1, were significantly induced by TCDD in both strains, while several genes involved in the immune response, including Ms4a7 and F13a1 were altered in L-E rats alone. We compared genes affected by TCDD in rat WAT and human adipose cells, and observed little overlap. Interestingly, very few genes involved in lipid metabolism exhibited altered expression levels despite the pronounced lipid mobilization from peripheral fat pads by TCDD in L-E rats. Of these genes, the lipolysis associated Lpin1 was induced slightly over 2-fold in L-E rat WAT on day 4. PMID- 26232523 TI - High-throughput cardiac safety evaluation and multi-parameter arrhythmia profiling of cardiomyocytes using microelectrode arrays. AB - Microelectrode arrays (MEAs) recording extracellular field potentials of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) provide a rich data set for functional assessment of drug response. The aim of this work is the development of a method for a systematic analysis of arrhythmia using MEAs, with emphasis on the development of six parameters accounting for different types of cardiomyocyte signal irregularities. We describe a software approach to carry out such analysis automatically including generation of a heat map that enables quick visualization of arrhythmic liability of compounds. We also implemented signal processing techniques for reliable extraction of the repolarization peak for field potential duration (FPD) measurement even from recordings with low signal to noise ratios. We measured hiPS-CM's on a 48 well MEA system with 5minute recordings at multiple time points (0.5, 1, 2 and 4h) after drug exposure. We evaluated concentration responses for seven compounds with a combination of hERG, QT and clinical proarrhythmia properties: Verapamil, Ranolazine, Flecainide, Amiodarone, Ouabain, Cisapride, and Terfenadine. The predictive utility of MEA parameters as surrogates of these clinical effects were examined. The beat rate and FPD results exhibited good correlations with previous MEA studies in stem cell derived cardiomyocytes and clinical data. The six-parameter arrhythmia assessment exhibited excellent predictive agreement with the known arrhythmogenic potential of the tested compounds, and holds promise as a new method to predict arrhythmic liability. PMID- 26232524 TI - Volume ratios between the thermophilic and the mesophilic digesters of a temperature-phased anaerobic digestion system affect their performance and microbial communities. AB - An experimental temperature-phased anaerobic digestion (TPAD) system, with the thermophilic digester operated at neutral pH and with a balanced acidogenesis and methanogenesis (referred to as NT-TPAD), was evaluated with respect to the microbial communities and population dynamics of methanogens when digesting dairy cattle manure at 15-day overall system hydraulic retention time (HRT). When fed a manure slurry of 10% total solid (TS), similar system performance, 36-38% volatile solid (VS) removal and 0.21-0.22 L methane g(-1) VS fed, was achieved between a 5-day and 7.5-day HRT for the thermophilic digester. However, the thermophilic digester achieved a greater volumetric biogas yield when operated at a 5-day RT than at a 7.5-day HRT (6.3 vs. 4.7 L/L/d), while the mesophilic digester had a stable volumetric biogas yield (about 1.0 L/L/d). Each of the digesters harbored distinct yet dynamic microbial populations, and some of the methanogens were significantly correlated with methane productions. Methanosarcina and Methanosaeta were the most important methanogenic genera in the thermophilic and the mesophilic digesters, respectively. The microbiological findings may help understand the metabolism that underpins the anaerobic processes within each of the two digesters of TPAD systems when fed dairy manure. PMID- 26232526 TI - Development of three triplex real-time reverse transcription PCR assays for the qualitative molecular typing of the nine serotypes of African horse sickness virus. AB - Blood samples collected as part of routine diagnostic investigations from South African horses with clinical signs suggestive of African horse sickness (AHS) were subjected to analysis with an AHS virus (AHSV) group specific reverse transcription quantitative polymerase chain reaction (AHSV RT-qPCR) assay and virus isolation (VI) with subsequent serotyping by plaque inhibition (PI) assays using AHSV serotype-specific antisera. Blood samples that tested positive by AHSV RT-qPCR were then selected for analysis using AHSV type specific RT-qPCR (AHSV TS RT-qPCR) assays. The TS RT-qPCR assays were evaluated using both historic stocks of the South African reference strains of each of the 9 AHSV serotypes, as well as recently derived stocks of these same viruses. Of the 503 horse blood samples tested, 156 were positive by both AHSV RT-qPCR and VI assays, whereas 135 samples that were VI negative were positive by AHSV RT-qPCR assay. The virus isolates made from the various blood samples included all 9 AHSV serotypes, and there was 100% agreement between the results of conventional serotyping of individual virus isolates by PI assay and AHSV TS RT-qPCR typing results. Results of the current study confirm that the AHSV TS RT-qPCR assays for the identification of individual AHSV serotypes are applicable and practicable and therefore are potentially highly useful and appropriate for virus typing in AHS outbreak situations in endemic or sporadic incursion areas, which can be crucial in determining appropriate and timely vaccination and control strategies. PMID- 26232527 TI - Abnormal fast fluctuations of electrocochleography and otoacoustic emissions in Meniere's disease. AB - The responses of cochlear hair cells to sound stimuli depend on the resting position of their stereocilia bundles, which is sensitive to the chemical and mechanical environment. Cochlear hydrops, a hallmark of Meniere's disease (MD), which is likely to come with disruption of this environment, results in hearing symptoms and electrophysiological signs, such as excessive changes in the cochlear summating potential (SP) and in the postural shifts of distortion product otoacoustic emissions (DPOAEs). Here, SP from the basal part of the cochlea and DPOAEs from the apical part of the cochlea were recorded concomitantly in 73 patients with a definite MD, near an attack (n = 40) or between attacks with no clinical symptoms (n = 33), to compare their sensitivities to posture and evaluate their stability. The phase of the 2f1-f2 DPOAEs was monitored during body tilt, with stimuli f1 = 1 kHz and f2 = 1.2 kHz at 72 dB SPL. Extratympanic electrocochleography was performed in response to 95 dBnHL clicks. The normal limits of the DPOAE phase shift with body tilt, [-18 degrees , +38 degrees ], and of the SP to action-potential (AP) ratio, <0.40, were exceeded in 75% and 60% of patients, respectively, near an attack. In these patients, but not in the asymptomatic ones, both tests reveal fluctuating cochlear responses from one data sample to the next. They emphasize how hydrops hinders normal hair-cell operation and may generate fast fluctuations in inner ear functioning. If these fluctuations also occur on shorter time scales, it might explain the imperfect diagnostic sensitivity of SP and DPOAE tests, as averaging procedures would tend to level out transient fluctuations characteristic of hydrops. PMID- 26232529 TI - Speech quality evaluation of a sparse coding shrinkage noise reduction algorithm with normal hearing and hearing impaired listeners. AB - Although there are numerous papers describing single-channel noise reduction strategies to improve speech perception in a noisy environment, few studies have comprehensively evaluated the effects of noise reduction algorithms on speech quality for hearing impaired (HI). A model-based sparse coding shrinkage (SCS) algorithm has been developed, and has shown previously (Sang et al., 2014) that it is as competitive as a state-of-the-art Wiener filter approach in speech intelligibility. Here, the analysis is extended to include subjective quality ratings and a method called Interpolated Paired Comparison Rating (IPCR) is adopted to quantitatively link the benefit of speech intelligibility and speech quality. The subjective quality tests are performed through IPCR to efficiently quantify noise reduction effects on speech quality. Objective measures including frequency-weighted segmental signal-to-noise ratio (fwsegSNR), perceptual evaluation of speech quality (PESQ) and hearing aid speech quality index (HASQI) are adopted to predict the noise reduction effects. Results show little difference in speech quality between the SCS and the Wiener filter algorithm but a difference in quality rating between the HI and NH listeners. HI listeners generally gave better quality ratings of noise reduction algorithms than NH listeners. However, SCS reduced the noise more efficiently at the cost of higher distortions that were detected by NH but not by the HI. SCS is a promising candidate for noise reduction algorithms for HI. In general, care needs to be taken when adopting algorithms that were originally developed for NH participants into hearing aid applications. An algorithm that is evaluated negatively with NH might still bring benefits for HI participants. PMID- 26232528 TI - Mice with conditional deletion of Cx26 exhibit no vestibular phenotype despite secondary loss of Cx30 in the vestibular end organs. AB - Connexins are components of gap junctions which facilitate transfer of small molecules between cells. One member of the connexin family, Connexin 26 (Cx26), is prevalent in gap junctions in sensory epithelia of the inner ear. Mutations of GJB2, the gene encoding Cx26, cause significant hearing loss in humans. The vestibular system, however, does not usually show significant functional deficits in humans with this mutation. Mouse models for loss of Cx26 function demonstrate hearing loss and cochlear pathology but the extent of vestibular dysfunction and organ pathology are less well characterized. To understand the vestibular effects of Cx26 mutations, we evaluated vestibular function and histology of the vestibular sensory epithelia in a conditional knockout (CKO) mouse with Cx26 loss of function. Transgenic C57BL/6 mice, in which cre-Sox10 drives excision of the Cx26 gene from non-sensory cells flanking the sensory epithelium of the inner ear (Gjb2-CKO), were compared to age-matched wild types. Animals were sacrificed at ages between 4 and 40 weeks and their cochlear and vestibular sensory organs harvested for histological examination. Cx26 immunoreactivity was prominent in the peripheral vestibular system and the cochlea of wild type mice, but absent in the Gjb2-CKO specimens. The hair cell population in the cochleae of the Gjb2-CKO mice was severely depleted but in the vestibular organs it was intact, despite absence of Cx26 expression. The vestibular organs appeared normal at the latest time point examined, 40 weeks. To determine whether compensation by another connexin explains survival of the normal vestibular sensory epithelium, we evaluated the presence of Cx30 in the Gjb2-CKO mouse. We found that Cx30 labeling was normal in the cochlea, but it was decreased or absent in the vestibular system. The vestibular phenotype of the mutants was not different from wild-types as determined by time on the rotarod, head stability tests and physiological responses to vestibular stimulation. Thus presence of Cx30 in the cochlea does not compensate for Cx26 loss, and the absence of both connexins from vestibular sensory epithelia is no more injurious than the absence of one of them. Further studies to uncover the physiological foundation for this difference between the cochlea and the vestibular organs may help in designing treatments for GJB2 mutations. PMID- 26232531 TI - 13C NMR based profiling unveils different alpha-ketoglutarate pools involved into glutamate and lysine synthesis in the milk yeast Kluyveromyces lactis. AB - BACKGROUND: The construction of efficient cell factories for the production of metabolites requires the rational improvement/engineering of the metabolism of microorganisms. The subject of this paper is directed towards the quantitative understanding of the respiratory/fermentative Kluyveromyces lactis yeast metabolism and its rag8 casein kinase mutant, taken as a model for all rag gene mutations. METHODS: (13)C NMR spectroscopy and [1,2-(13)C2]glucose were used as metabolic stable-isotope tracer to define the metabolic profiling of a K. lactis yeast and its derivative mutants. RESULTS: Rag8 showed a decrease of all (13)C glutamate fractional enrichments, except for [4-(13)C]glutamate that was higher than wild type ones. A decrease of TCA cycle flux in rag8 mutants and a contribution of a [4-(13)C]ketoglutarate pool not originating from mitochondria were suggested. (13)C lysine enrichments confirmed the presence of two compartmentalized alpha-ketoglutarate (alpha-KG) pools participating to glutamate and lysine synthesis. Moreover, an increased transaldolase, as compared to transketolase activity, was observed in the rag8 mutant by (13)C NMR isotopomer analysis of alanine. CONCLUSIONS: (13)C NMR-based isotopomer analysis showed the existence of different alpha-KG metabolic pools for glutamate and lysine biosynthesis. In the rag8 mutant, (13)C labeled pentose phosphate intermediates participated in the synthesis of this compartmentalized alpha-KG pool. GENERAL SIGNIFICANCE: A compartmentalization of the alpha-KG pools involved in lysine biosynthesis has been revealed for the first time in K. lactis. Given its great impact in metabolic engineering field, its existence should be validated/compared with other yeasts and/or fungal species. PMID- 26232530 TI - Age-related shifts in distortion product otoacoustic emissions peak-ratios and amplitude modulation spectra. AB - Amplitude modulation (AM) is an important temporal cue for precise speech and complex sound recognition. However, functional decline of the auditory periphery as well as degradation of central auditory processing due to aging can reduce the salience and resolution of temporal cues. Age-related deficits in central temporal processing have previously been observed at more rapid AM frequencies and various AM depths. These centrally observed changes result from cochlear changes compounded with changes along the ascending auditory pathway. In fact, a decrease in ability to detect temporally modulated sounds accurately could originate from changes in cochlear filtering properties and in cochlear mechanics due to aging. Nonetheless, few studies have examined cochlear mechanisms in AM detection. To assess integrity of the mechanical properties of the auditory periphery, distortion product otoacoustic emissions (DPOAEs) are a tool commonly used in clinics and in research. In this study, we measured DPOAEs to reveal age related changes in peak f2/f1 ratio and degradation in AM detection by basilar membrane vibration. Two tones (f1 and f2, f2 > f1) at various f2/f1 ratios and simultaneous presentation of one AM and one pure tone were used as stimuli to evoke DPOAEs. In addition of observing reduced DPOAE amplitudes and steeper slopes in the input-output DPOAE functions, higher peak f2/f1 ratios and broader f2/f1 tuning were also observed in aged animals. Aged animals generally had lower distortion product (DP) and first sideband (SB 1) responses evoked by an f1 pure tone and an f2 AM tone, regardless of whether the AM frequency was 45 Hz or 128 Hz. SB 1 thresholds, which corresponds to the smallest stimulus AM depth that can induce cochlear vibrations at the DP generator locus, were higher in aged animals as well. The results suggest that age-related changes in peak f2/f1 ratio and AM detection by basilar membrane vibration are consistent with a reduction in endocochlear potential and reduced prestin activity but with preserved hair cell bundle function. SB 1 responses evoked by f2 AM/f1 pure tone with various AM depths could serve as an estimate for cochlear AM detection. The sidebands of DP could also serve as additional physiological cues for detection of AM in the presence of other tone(s), even at typical conversational levels in speech. PMID- 26232525 TI - Electrical and mechanical stimulation of cardiac cells and tissue constructs. AB - The field of cardiac tissue engineering has made significant strides over the last few decades, highlighted by the development of human cell derived constructs that have shown increasing functional maturity over time, particularly using bioreactor systems to stimulate the constructs. However, the functionality of these tissues is still unable to match that of native cardiac tissue and many of the stem-cell derived cardiomyocytes display an immature, fetal like phenotype. In this review, we seek to elucidate the biological underpinnings of both mechanical and electrical signaling, as identified via studies related to cardiac development and those related to an evaluation of cardiac disease progression. Next, we review the different types of bioreactors developed to individually deliver electrical and mechanical stimulation to cardiomyocytes in vitro in both two and three-dimensional tissue platforms. Reactors and culture conditions that promote functional cardiomyogenesis in vitro are also highlighted. We then cover the more recent work in the development of bioreactors that combine electrical and mechanical stimulation in order to mimic the complex signaling environment present in vivo. We conclude by offering our impressions on the important next steps for physiologically relevant mechanical and electrical stimulation of cardiac cells and engineered tissue in vitro. PMID- 26232532 TI - ZDHHC17 promotes axon outgrowth by regulating TrkA-tubulin complex formation. AB - Correct axonal growth during nervous system development is critical for synaptic transduction and nervous system function. Proper axon outgrowth relies on a suitable growing environment and the expression of a series of endogenous neuronal factors. However, the mechanisms of these neuronal proteins involved in neuronal development remain unknown. ZDHHC17 is a member of the DHHC (Asp-His-His Cys)-containing family, a family of highly homologous proteins. Here, we show that loss of function of ZDHHC17 in zebrafish leads to motor dysfunction in 3-day post-fertilization (dpf) larvae. We performed immunolabeling analysis to reveal that mobility dysfunction was due to a significant defect in the axonal outgrowth of spinal motor neurons (SMNs) without affecting neuron generation. In addition, we found a similar phenotype in zdhhc17 siRNA-treated neural stem cells (NSCs) and PC12 cells. Inhibition of zdhhc17 limited neurite outgrowth and branching in both NSCs and PC12. Furthermore, we discovered that the level of phosphorylation of extracellular-regulated kinase (ERK) 1/2, a major downstream effector of tyrosine kinase (TrkA), was largely upregulated in ZDHHC17 overexpressing PC12 cells by a mechanism independent on its palmitoyltransferase (PAT) activity. Specifically, ZDHHC17 is necessary for proper TrkA-tubulin module formation in PC12 cells. These results strongly indicate that ZDHHC17 is essential for correct axon outgrowth in vivo and in vitro. Our findings identify ZDHHC17 as an important upstream factor of ERK1/2 to regulate the interaction between TrkA and tubulin during neuronal development. PMID- 26232533 TI - Detection of the NS3 Q80K polymorphism by Sanger and deep sequencing in hepatitis C virus genotype 1a strains in the UK. AB - The Q80K polymorphism in the hepatitis C virus (HCV) NS3 enzyme reduces susceptibility to simeprevir and other novel protease inhibitors. The aims of this study were to determine the prevalence of Q80K in treatment-naive HCV-1a carriers in the North West region (NW) and South East region (SE) of England, investigate the occurrence of Q80K as a minority variant, and characterize viral phylogeny. Plasma samples from subjects who were naive to anti-HCV therapy were subjected to conventional (Sanger) and deep (Illumina-Miseq, 1% interpretative cut-off) sequencing of NS3. Q80K occurred in 44 of 238 subjects (18.5%, 95% CI 13.6-23.4%), including 19 of 70 (27.1%) in the NW and 25 of 168 (14.9%) in the SE (p 0.0425), with no difference in HCV RNA load or human immunodeficiency virus (HIV) status. Q80K frequencies in reads of samples subjected to Illumina sequencing were >40% in all cases. Among subjects with Q80K, five of 44 (11.4%) showed one additional major resistance-associated mutation in NS3, detected at frequencies of >10% (V36L and V55A) or <10% (V36M). Phylogenetic analyses identified the two recognized HCV-1a lineages with (clade I) and without (clade II) Q80K. Overall, 148 of 238 (62.2%) sequences occurred within regional or inter regional clusters, each comprising 3-20 sequences. There was no unique clustering of English sequences relative to strains from continental Europe and North America. In conclusion, Q80K was found at a high prevalence among treatment-naive HCV-1a carriers in England, and was reliably detected by conventional sequencing, with no increased detection by deep sequencing. English sequences were highly interspersed with sequences from elsewhere in Europe (clade II) and North America (clade I), and their phylogeny was consistent with multiple introductions from different areas. PMID- 26232535 TI - Low sensitivity of fecal toxin A/B enzyme immunoassay for diagnosis of Clostridium difficile infection in immunocompromised patients. AB - The optimal approach in laboratory diagnosis of Clostridium difficile infection (CDI) is still not well defined. Toxigenic culture (TC) or alternatively fecal toxin assay by cell cytotoxicity neutralization assay are considered to be the reference standard, but these methods are time-consuming and labor intensive. In many medical centers, diagnosis of CDI is therefore still based on fecal toxin A/B enzyme immunoassay (EIA) directly from stool alone, balancing cost and speed against limited diagnostic sensitivity. The aim of the study was to assess in which patient population the additional workload of TC is justified. All consecutive stool specimens submitted for diagnosis of suspected CDI between 2004 and 2011 at a tertiary-care center were examined by toxin EIA and TC. Clinical data of patients with established diagnosis of CDI were collected in a standardized case-report form. From 12,481 stool specimens submitted to the microbiologic laboratory, 480 (3.8%) fulfilled CDI criteria; 274 (57.1%) were diagnosed by toxin EIA; and an additional 206 (42.9%) were diagnosed by TC when toxin EIA was negative. Independent predictors for negative toxin EIA but positive TC were high-dose corticosteroids (odds ratio (OR) 2.97, 95% confidence interval (CI) 1.50-5.90, p 0.002), leukocytopenia <1000/MUL (OR 2.52, 95% CI 1.22 5.23, p 0.013) and nonsevere CDI (OR 2.21, 95% CI 1.39-3.50, p 0.001). There was no difference in outcomes such as in-hospital mortality and recurrence between both groups. In conclusion, negative toxin EIA does not rule out CDI in immunocompromised patients in the setting of relevant clinical symptoms. Methods with improved sensitivity such as TC or PCR should be used, particularly in this patient population. PMID- 26232534 TI - The course of spinal tuberculosis (Pott disease): results of the multinational, multicentre Backbone-2 study. AB - We aimed to describe clinical, laboratory, diagnostic and therapeutic features of spinal tuberculosis (ST), also known as Pott disease. A total of 314 patients with ST from 35 centres in Turkey, Egypt, Albania and Greece were included. Median duration from initial symptoms to the time of diagnosis was 78 days. The most common complications presented before diagnosis were abscesses (69%), neurologic deficits (40%), spinal instability (21%) and spinal deformity (16%). Lumbar (56%), thoracic (49%) and thoracolumbar (13%) vertebrae were the most commonly involved sites of infection. Although 51% of the patients had multiple levels of vertebral involvement, 8% had noncontiguous involvement of multiple vertebral bodies. The causative agent was identified in 41% of cases. Histopathologic examination was performed in 200 patients (64%), and 74% were consistent with tuberculosis. Medical treatment alone was implemented in 103 patients (33%), while 211 patients (67%) underwent diagnostic and/or therapeutic surgical intervention. Ten percent of the patients required more than one surgical intervention. Mortality occurred in 7 patients (2%), and 77 (25%) developed sequelae. The distribution of the posttreatment sequelae were as follows: 11% kyphosis, 6% Gibbus deformity, 5% scoliosis, 5% paraparesis, 5% paraplegia and 4% loss of sensation. Older age, presence of neurologic deficit and spinal deformity were predictors of unfavourable outcome. ST results in significant morbidity as a result of its insidious course and delayed diagnosis because of diagnostic and therapeutic challenges. ST should be considered in the differential diagnosis of patients with vertebral osteomyelitis, especially in tuberculosis-endemic regions. Early establishment of definitive aetiologic diagnosis and appropriate treatment are of paramount importance to prevent development of sequelae. PMID- 26232536 TI - The high burden of hospitalizations for primary EBV infection: a 6-year prospective survey in a French hospital. AB - Primary Epstein-Barr virus infection (PEI) is acquired increasingly later in life in developed countries, involving a growing number of adults. No studies have examined the effect of age on PEI. We conducted a prospective, single-centre, noninterventional survey to assess the clinical and economic effects of PEI care according to age. We included all serology-confirmed cases observed in all departments of a large regional hospital. Clinical and biologic data, therapeutics and costs of care were examined. Over a 6-year period, we included 292 subjects (148 children and 144 adults) with a median age of 15.4 years (range 9 months to 79 years). Adults were hospitalized more often (83% vs. 60%) and for longer periods of time (median 4 days vs. 2 days) than children (p <= 0.0001 for both). Two adults required a secondary transfer into the intensive care unit, although no children did. Typically, adults showed higher levels of activated lymphocytes and liver abnormalities. They also required the use of systemic corticosteroids more often (45% vs. 23%, p < 0.0001) and for longer periods of time (median 7 days vs. 3 days, p 0.02) than children. Overall, the costs were significantly higher for adults than for children (median, ?1940 vs. ?1130, p < 0.0001), mainly because of the frequency and duration of hospitalizations. Age increases the immune response and clinical severity of PEI, resulting in substantial additional costs for the community. Better recognition of the disease in adults could shorten the average length of hospital stay. PMID- 26232538 TI - Learning from bottom-up dissemination: Importing an evidence-based trauma intervention for infants and young children to Israel. AB - This article describes a pilot study of a "bottom up" dissemination process of a new evidence based intervention for treating early childhood trauma. Clinicians applied to learn Child-Parent Psychotherapy (CPP), imported to Israel from the U.S. A focus group of six graduates of a CPP training program responded to questions concerning their experiences learning and using CPP. All 39 CPP graduates from two cohorts also completed a cross sectional survey related to their use of CPP. Within the focus group, the openness of the workplace and the intervention's characteristics were considered major factors impacting CPP use; the training program was perceived to promote CPP implementation, and lack of supervision and secondary traumatic stress were the major inhibiting factors. Using CPP-informed therapy, as opposed to CPP with fidelity, was perceived to be one of the main outcomes of the training. Survey results showed that 53% of graduates were using CPP in over three cases, and almost all intended to use CPP within the next year. Ninety-five percent were using CPP principles in their therapeutic work. The implications of importing a new evidence based intervention to a foreign country that utilizes a different dissemination system within a different professional culture are discussed. PMID- 26232537 TI - Influenza vaccination during the first 6 months after solid organ transplantation is efficacious and safe. AB - Preventing influenza infection early after transplantation is essential, given the disease's high mortality. A multicentre prospective cohort study in adult solid organ transplant recipients (SOTR) receiving the influenza vaccine during four consecutive influenza seasons (2009-2013) was performed to assess the immunogenicity and safety of influenza vaccination in SOTR before and 6 months after transplantation. A total of 798 SOTR, 130 of them vaccinated within 6 months of transplantation and 668 of them vaccinated more than 6 months since transplantation. Seroprotection was similar in both groups: 73.1% vs. 76.5% for A/(H1N1)pdm (p 0.49), 67.5% vs. 74.1% for A/H3N2 (p 0.17) and 84.2% vs. 85.2% for influenza B (p 0.80), respectively. Geometric mean titres after vaccination did not differ among groups: 117.32 (95% confidence interval (CI) 81.52, 168.83) vs. 87.43 (95% CI 72.87, 104.91) for A/(H1N1)pdm, 120.45 (95% CI 82.17, 176.57) vs. 97.86 (95% CI 81.34, 117.44) for A/H3N2 and 143.32 (95% CI 103.46, 198.53) vs. 145.54 (95% CI 122.35, 174.24) for influenza B, respectively. After adjusting for confounding factors, time since transplantation was not associated with response to vaccination. No cases of rejection or severe adverse events were detected in patients vaccinated within the first 6 months after transplantation. In conclusion, influenza vaccination within the first 6 months after transplantation is as safe and immunogenic as vaccination thereafter. Thus, administration of the influenza vaccine can be recommended as soon as 1 month after transplantation. PMID- 26232541 TI - Seroprevalence of anti-HBs antibodies at young adulthood, before and after a booster vaccine dose, among medical personnel vaccinated in infancy. AB - BACKGROUND: Questions remain regarding the long-term protection provided by childhood HBV vaccination. The goals of this study were to assess HBV seroprevalence among medical personnel purportedly vaccinated in infancy; to investigate the immune response after a booster dose given in young adulthood; and to identify predictors of non-responders. METHODS: Between 2011 and 2013 we studied Israeli male military recruits purportedly vaccinated in infancy. All subjects were born after January 1st 1992 and were undergoing medic training. We collected personal data and blood samples at baseline, and administered a dose of HBV vaccine. Subjects were retested one month later and received a second dose. A third blood draw was conducted one month after the second dose. Data collected at baseline were used as predictor variables of seropositivity (anti-HBs>=10mIU/ml). RESULTS: 617 subjects were available for baseline analysis and 539 for paired observations at one month. Baseline seropositivity was 33.7%. Subjects who received post-infancy vaccine doses had a seropositivity rate double that of those denying additional doses (RR 2.22, 95% CI 1.55-3.18). One month after the first booster dose, the overall cumulative population seropositivity reached 87.7%. One month after the second vaccine dose, population seropositivity was 97.9%. Heavy smokers were 5 times less likely to demonstrate detectable antibodies after a single booster dose (OR 0.196, 95% CI 0.060-0.641, P=0.007). CONCLUSIONS: This population-based study is important for informing public health vaccination policy. Our results strongly indicate that among cohorts vaccinated in infancy, two doses in adulthood will provide maximal protective antibody levels, while one dose will provide sufficient population protection. PMID- 26232540 TI - Long-term impact of pneumococcal polysaccharide vaccination on nasopharyngeal carriage in children previously vaccinated with various pneumococcal conjugate vaccine regimes. AB - Previously, the Fiji Pneumococcal Project (FiPP) evaluated reduced dose immunization schedules that incorporated pneumococcal protein conjugate and/or polysaccharide vaccine (PCV7 and 23vPPV, respectively). Immune hyporesponsiveness was observed in children vaccinated with 23vPPV at 12 months of age compared with children who did not receive 23vPPV. Here we assess the long-term impact of 23vPPV vaccination on nasopharyngeal carriage rates and densities of Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and Moraxella catarrhalis. Nasopharyngeal swabs (n=194) were obtained from healthy children who participated in FiPP (now aged 5-7 years). S. pneumoniae were isolated and identified by standard culture-based methods, and serotyped using latex agglutination and the Quellung reaction. Carriage rates and densities of S. pneumoniae, H. influenzae, S. aureus and M. catarrhalis were determined using real-time quantitative PCR. There were no differences in the rate or density of S. pneumoniae, H. influenzae or M. catarrhalis carriage by PCV7 dose or 23vPPV vaccination in the vaccinated participants overall. However, differences were observed between the two main ethnic groups: Fijian children of Indian descent (Indo-Fijian) were less likely to carry S. pneumoniae, H. influenzae and M. catarrhalis, and there was evidence of a higher carriage rate of S. aureus compared with indigenous Fijian (iTaukei) children. Polysaccharide vaccination appeared to have effects that varied between ethnic groups, with 23vPPV vaccination associated with a higher carriage rate of S. aureus in iTaukei children, while there was a lower carriage rate of S. pneumoniae associated with 23vPPV vaccination in Indo-Fijian children. Overall, polysaccharide vaccination had no long-term impact on pneumococcal carriage, but may have impacted on S. aureus carriage and have varying effects in ethnic groups, suggesting current WHO vaccine schedule recommendations against the use of 23vPPV in children under two years of age are appropriate. PMID- 26232539 TI - New approaches to understanding the immune response to vaccination and infection. AB - The immune system is a network of specialized cell types and tissues that communicates via cytokines and direct contact, to orchestrate specific types of defensive responses. Until recently, we could only study immune responses in a piecemeal, highly focused fashion, on major components like antibodies to the pathogen. But recent advances in technology and in our understanding of the many components of the system, innate and adaptive, have made possible a broader approach, where both the multiple responding cells and cytokines in the blood are measured. This systems immunology approach to a vaccine response or an infection gives us a more holistic picture of the different parts of the immune system that are mobilized and should allow us a much better understanding of the pathways and mechanisms of such responses, as well as to predict vaccine efficacy in different populations well in advance of efficacy studies. Here we summarize the different technologies and methods and discuss how they can inform us about the differences between diseases and vaccines, and how they can greatly accelerate vaccine development. PMID- 26232542 TI - Immune responses to a recombinant, four-component, meningococcal serogroup B vaccine (4CMenB) in adolescents: a phase III, randomized, multicentre, lot-to-lot consistency study. AB - BACKGROUND: For decades, a broadly effective vaccine against serogroup B Neisseria meningitidis (MenB) has remained elusive. Recently, a four-component recombinant vaccine (4CMenB) has been developed and is now approved in Europe, Canada, Australia and some Latin American countries. This phase III, randomized study evaluated the lot consistency, early immune responses and the safety profile of 4CMenB in 11 to 17-year-old adolescents in Australia and Canada (NCT01423084). METHODS: In total, 344 adolescents received two doses of one of 2 lots of 4CMenB, 1-month apart. Immunogenicity was assessed before, 2-weeks and 1 month following the second vaccination. Serum bactericidal activity using human complement (hSBA) was measured against three reference strains 44/76-SL, 5/99 and NZ98/254, selected to express one of the vaccine antigens; Neisseria adhesin A (NadA), factor H binding protein (fHbp) and porin A (PorA) containing outer membrane vesicle (OMV), respectively. Responses to the Neisseria heparin binding antigen (NHBA) were assessed with enzyme linked immunosorbent assay (ELISA). Local and systemic reactions were recorded for 7 days following each vaccination; unsolicited adverse events were monitored throughout the study. RESULTS: Immunological equivalence of the two lots of 4CMenB was established at 1-month. At baseline, <=7% of participants had hSBA titers >=5 to all three reference strains. Two weeks following the second dose of 4CMenB, all participants had hSBA titers >=5 against fHbp and NadA compared with 84-96% against the PorA reference strains. At 1-month, corresponding proportions were 99%, 100% and 70-79%, respectively. Both lots were generally well tolerated and had similar adverse event profiles. CONCLUSIONS: Two doses of 4CMenB had an acceptable safety profile and induced a robust immune response in adolescents. Peak antibody responses were observed at 14 days following vaccination. While a substantial non-uniform antigen-dependent early decline in antibody titers was seen thereafter, a significant percentage of participants continued to maintain protective hSBA titers at 1-month. PMID- 26232543 TI - Japanese Encephalitis Vaccines: WHO position paper, February 2015- Recommendations. AB - This article presents the World Health Organization's (WHO) recommendations on the use of Japanese Encephalitis (JE) vaccines excerpted from the WHO position paper on Japanese Encephalitis vaccines recently published in the Weekly Epidemiological Record [1]. This updated position paper on JE vaccines replaces the 2006 position paper on this subject [2]; it focuses on new information concerning the availability, safety, immunogenicity and effectiveness of JE vaccines and the duration of protection they confer. Recent data on global prevalence and burden of disease caused by JE and cost-effectiveness considerations regarding JE vaccination are also summarized. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. This paper reflects the recommendations of WHO's Strategic Advisory Group of Experts (SAGE) on immunization. These recommendations were discussed by SAGE at its October 2014 meeting. Evidence presented at the meeting can be accessed at http://www.who.int/immunization/sage/previous/en/index.html. PMID- 26232544 TI - No evidence in US of HPV16/18 cancer precursor reduction. PMID- 26232545 TI - Estimating the cost of cholera-vaccine delivery from the societal point of view: A case of introduction of cholera vaccine in Bangladesh. AB - Cholera is a major global public health problem that causes both epidemic and endemic disease. The World Health Organization recommends oral cholera vaccines as a public health tool in addition to traditional prevention practices and treatments in both epidemic and endemic settings. In many developing countries like Bangladesh, the major issue concerns the affordability of this vaccine. In February 2011, a feasibility study entitled, "Introduction of Cholera Vaccine in Bangladesh (ICVB)", was conducted for a vaccination campaign using inactivated whole-cell cholera vaccine (Shanchol) in a high risk area of Mirpur, Dhaka. Empirical data obtained from this trial was used to determine the vaccination cost for a fully immunized person from the societal perspective. A total of 123,661 people were fully vaccinated receiving two doses of the vaccine, while 18,178 people received one dose of the same vaccine. The total cost for vaccine delivery was US$ 492,238 giving a total vaccination cost per fully-vaccinated individual of US$ 3.98. The purchase cost of the vaccine accounted for 58% of the overall cost of vaccination. Attempts to reduce the per-dose cost of the vaccine are likely to have a large impact on the cost of similar vaccination campaigns in the future. PMID- 26232546 TI - Hepatitis E vaccine: WHO position paper, May 2015--Recommendations. AB - This article presents the World Health Organization's (WHO) recommendations on the use of hepatitis E vaccine excerpted from the WHO position paper on hepatitis E vaccines - May 2015 recently published in the Weekly Epidemiological Record [1]. The current document is the first WHO position paper on hepatitis E vaccination and focuses primarily on the available evidence concerning the only hepatitis E vaccine that is currently licensed. The position paper gives consideration to the epidemiological features of the disease and assesses the use of the vaccine for public health benefits. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. This paper reflects the recommendations of WHO's Strategic Advisory Group of Experts (SAGE) on immunization. These recommendations were discussed by SAGE at its October 2014 meeting. Evidence presented at the meeting can be accessed at http://www.who.int/immunization/sage/previous/en/index.html. PMID- 26232547 TI - What is the responsibility of national government with respect to vaccination? Response of Marcel F. Verweij and Hans Houweling to Ronald de Groot. PMID- 26232548 TI - Mitochondrial introgression and complex biogeographic history of the genus Picea. AB - Biogeographic history of plants is much more complex in the Northern Hemisphere than in the Southern Hemisphere due to that both the Bering and the North Atlantic land bridges contributed to floristic exchanges in the Cenozoic, which led to hybridization between congeneric species from different continents. It would be interesting to know how intercontinental gene flow and introgression have affected plant phylogenetic reconstruction and biogeographic inference. In this study, we reinvestigated the phylogenetic and biogeographic history of Picea, a main component of the Northern Hemisphere forest with many species that originated from recent radiation, using two chloroplast (cp), one mitochondrial (mt) and three single-copy nuclear gene markers. The generated gene trees are topologically highly discordant and the geographically closely related species generally show a close affinity of mtDNA rather than cp- or nuclear DNA, suggesting that inter- and intra-continental gene flow and mtDNA introgression might have occurred commonly. However, all gene trees resolved Picea breweriana as the basal-most lineage, which, together with fossil evidence, supports the North American origin hypothesis for the genus. Both dispersal and vicariance have played important roles in the evolution of Picea, and the Bering Land Bridge could have mediated the "North America to Eurasia" dispersal at least two times during the Miocene and Pliocene. Our study again demonstrates the importance of applying data from three genomes for a clear understanding of evolutionary histories in the pine family. Any markers from a single genome alone will not reveal a clear picture of the phylogenetic relationships among closely related congeneric species. In particular, mtDNA markers should be cautiously used, considering that introgression of the maternally inherited mtDNA with a lower rate of gene flow (by seeds) could have occurred much more frequently than that of the paternally inherited cpDNA with a higher rate of gene flow (by pollen) in Pinaceae. PMID- 26232550 TI - Calendering as a direct shaping tool for the continuous production of fixed-dose combination products via co-extrusion. AB - In this study calendering is used as a downstream technique to shape monolithic co-extruded fixed-dose combination products in a continuous way. Co-extrudates with a metoprolol tartrate-loaded sustained-release core and a hydrochlorothiazide-loaded immediate-release coat were produced and immediately shaped into a monolithic drug delivery system via calendering, using chilled rolls with tablet-shaped cavities. In vitro metoprolol tartrate release from the ethylcellulose core of the calendered tablets was prolonged in comparison with the sustained release of a multiparticulate dosage form, prepared manually by cutting co-extrudates into mini-matrices. Analysis of the dosage forms using X ray micro-computed tomography only detected small differences between the pore structure of the core of the calendered tablet and the mini-matrices. Diffusion path length was shown to be the main mechanism behind the release kinetics. Terahertz pulsed imaging visualized that adhesion between the core and coat of the calendered tablet was not complete and a gradient in coat thickness (varying from 200 to 600MUm) was observed. Modulated differential scanning calorimetry and X-ray diffraction indicated that the solid-state properties of both drugs were not affected by the calendering procedure. PMID- 26232549 TI - A potential role of X-linked inhibitor of apoptosis protein in mitochondrial membrane permeabilization and its implication in cancer therapy. AB - X-chromosome-linked inhibitor of apoptosis protein (XIAP) has an important regulatory role in programmed cell death by inhibiting the caspase cascade. Activation of XIAP-dependent signaling culminates into regulation of multiple cellular processes including apoptosis, innate immunity, epithelial-to mesenchymal transition, cell migration, invasion, metastasis and differentiation. Although XIAP localizes to the cytosolic compartment, XIAP-mediated cellular signaling encompasses mitochondrial and post-mitochondrial levels. Recent findings demonstrate that XIAP also localizes to mitochondria and regulates mitochondria functions. XIAP acts upstream of mitochondrial cytochrome c release and modulates caspase-dependent apoptosis. The new function of XIAP has potential to enhance mitochondrial membrane permeabilization and other cellular functions controlling cytochrome c release. These findings could exploit the overexpression of XIAP in human tumors for therapeutic benefits. PMID- 26232551 TI - Phonological short-term memory in logopenic variant primary progressive aphasia and mild Alzheimer's disease. AB - It has been argued that individuals with logopenic variant primary progressive aphasia (lvPPA) have an impairment of the phonological loop, which is a component of the short-term memory (STM) system. In contrast, this type of impairment is not thought to be present in mild typical Alzheimer's disease (AD). Thus, one would predict that people with lvPPA would score significantly lower than a matched AD group on tasks that require phonological STM. In the current study, an lvPPA group was compared with a mild AD group that was matched on age, education, and general cognitive functioning. For a subset of the tasks that involved pseudowords, the AD and lvPPA groups were compared to a healthy control group that was matched on age and education. The lvPPA group was more impaired than the AD group on all of the tasks that required phonological STM, including the pseudoword tasks, but there were no significant differences between these groups on tasks that required visuospatial STM. Compared to the healthy controls, the lvPPA group performed significantly worse on the repetition and reading of pseudowords, while the AD group did not differ significantly from the controls on these tasks. These findings are consistent with the hypothesis that phonological STM is impaired in lvPPA. PMID- 26232552 TI - On the importance of cognitive profiling: A graphical modelling analysis of domain-specific and domain-general deficits after stroke. AB - Cognitive problems following stroke are typically analysed using either short but relatively uninformative general tests or through detailed but time consuming tests of domain specific deficits (e.g., in language, memory, praxis). Here we present an analysis of neuropsychological deficits detected using a screen designed to fall between other screens by being 'broad' (testing multiple cognitive abilities) but 'shallow' (sampling the abilities briefly, to be time efficient) - the BCoS. Assessment using the Birmingham Cognitive Screen (BCoS) enables the relations between 'domain specific' and 'domain general' cognitive deficits to be evaluated as the test generates an overall cognitive profile for individual patients. We analysed data from 287 patients tested at a sub-acute stage of stroke (<3 months). Graphical modelling techniques were used to investigate the associative structure and conditional independence between deficits within and across the domains sampled by BCoS (attention and executive functions, language, memory, praxis and number processing). The patterns of deficit within each domain conformed to existing cognitive models. However, these within-domain patterns underwent substantial change when the whole dataset was modelled, indicating that domain-specific deficits can only be understood in relation to linked changes in domain-general processes. The data point to the importance of using over-arching cognitive screens, measuring domain-general as well as domain-specific processes, in order to account for neuropsychological deficits after stroke. The paper also highlights the utility of using graphical modelling to understand the relations between cognitive components in complex datasets. PMID- 26232553 TI - Biotransformation of oleanolic and maslinic methyl esters by Rhizomucor miehei CECT 2749. AB - The pentacyclic triterpenoids methyl oleanolate, methyl maslinate, methyl 3beta hydroxyolean-9(11),12-dien-28-oate, and methyl 2alpha,3beta-dihydroxy 12beta,13beta-epoxyolean-28-oate were biotransformed by Rhizomucor miehei CECT 2749. Microbial transformation of methyl oleanolate produced only a 7beta,30 dihydroxylated metabolite with a conjugated 9(11),12-diene system in the C ring. Biotransformation of the substrate with this 9(11),12-diene system gave the same 7beta,30-dihydroxylated compound together with a 7beta,15alpha,30-trihydroxyl derivative. The action of this fungus (R. miehei) on methyl maslinate was more varied, isolating metabolites with a 30-hydroxyl group, a 9(11),12-diene system, an 11-oxo group, or an 12-oxo group. Microbial transformation of the substrate with a 12beta,13beta-epoxy function resulted in the isolation of two metabolites with 12-oxo and 28,13beta-olide groups, hydroxylated or not at C-7beta, together with a 30-hydroxy-12-oxo derivative. The structures of these derivatives were deduced by extensive and rigorous spectroscopic studies. PMID- 26232554 TI - Molecular and biochemical characterization of mannitol-1-phosphate dehydrogenase from the model brown alga Ectocarpus sp. AB - The sugar alcohol mannitol is important in the food, pharmaceutical, medical and chemical industries. It is one of the most commonly occurring polyols in nature, with the exception of Archaea and animals. It has a range of physiological roles, including as carbon storage, compatible solute, and osmolyte. Mannitol is present in large amounts in brown algae, where its synthesis involved two steps: a mannitol-1-phosphate dehydrogenase (M1PDH) catalyzes a reversible reaction between fructose-6-phosphate (F6P) and mannitol-1-phosphate (M1P) (EC 1.1.1.17), and a mannitol-1-phosphatase hydrolyzes M1P to mannitol (EC 3.1.3.22). Analysis of the model brown alga Ectocarpus sp. genome provided three candidate genes for M1PDH activities. We report here the sequence analysis of Ectocarpus M1PDHs (EsM1PDHs), and the biochemical characterization of the recombinant catalytic domain of EsM1PDH1 (EsM1PDH1cat). Ectocarpus M1PDHs are representatives of a new type of modular M1PDHs among the polyol-specific long-chain dehydrogenases/reductases (PSLDRs). The N-terminal domain of EsM1PDH1 was not necessary for enzymatic activity. Determination of kinetic parameters indicated that EsM1PDH1cat displayed higher catalytic efficiency for F6P reduction compared to M1P oxidation. Both activities were influenced by NaCl concentration and inhibited by the thioreactive compound pHMB. These observations were completed by measurement of endogenous M1PDH activity and of EsM1PDH gene expression during one diurnal cycle. No significant changes in enzyme activity were monitored between day and night, although transcription of two out of three genes was altered, suggesting different levels of regulation for this key metabolic pathway in brown algal physiology. PMID- 26232555 TI - Antrocarines A-F, antiplasmodial ergostane steroids from the stem bark of Antrocaryon klaineanum. AB - During a study on the chemistry and biological activity of Antrocaryon klaineanum Pierre, six new sterols including 4,24(28)-ergostadiene-6alpha,7alpha-diol (1), 6alpha-methoxy-4,24(28)-ergostadiene-7alpha,20S-diol (2), 6alpha-methoxy-4,24(28) ergostadien-7alpha-ol (3), 20S-hydroxy-24(28)-ergosten-3-one (4), 7alpha-hydroxy 4,24(28)-ergostadien-3-one (5), and 24(28)-ergostene-3beta,6alpha-diol (6) were characterized by physical and spectroscopic means. The known steroids 7 and 8 were also isolated. The crude extract and the isolated compounds were evaluated for their ability to inhibit the 3D7 strain of Plasmodium falciparum. Compounds 2, 3, and 8 showed potent activity while that of the crude extract was moderate. PMID- 26232556 TI - Erythropoietin protects neuroblastoma cells against etoposide and vincristine by activating ERK and AKT pathways but has no effect in kidney cells. AB - AIMS: Chemotherapy induces anaemia in neuroblastoma patients. Cancer-associated anaemia may be treated with recombinant erythropoietin. However, the potential effects of erythropoietin on neuroblastoma and kidney cells have not been extensively evaluated. The present study was designed to investigate the effect of erythropoietin on the proliferation, and protection against vincristine- and etoposide-induced cell death in neuroblastoma (MSN), and embryonic kidney (HEK 293) cells. MAIN METHODS: The expression of erythropoietin and its receptor in MSN and HEK 293 was analysed by RT-PCR, immunocytochemistry, and Western blotting. The effect of erythropoietin on cell viability and proliferation was evaluated by the MTT assay, and by the Click-iT EdU Alexa Fluor 647 kit, respectively. For the cyto-protective assays, cells were incubated with erythropoietin before etoposide and vincristine treatment. Activation of signalling pathways was studied by Western blotting. KEY FINDINGS: MSN and HEK 293 cells expressed the erythropoietin receptor, but not erythropoietin. Erythropoietin induced proliferation and protection against vincristine and etoposide in MSN cells. HEK 293 cells were not affected by erythropoietin. Erythropoietin showed an anti-apoptotic effect which was dependent on the activation of ERK1/2 and AKT. HEK 293 cells presented constitutively phosphorylated AKT, and showed no activation of ERK1/2 upon erythropoietin stimulation. SIGNIFICANCE: These results indicate that erythropoietin induces proliferation of MSN cells, and that it can ameliorate vincristine- and etoposide induced apoptosis of these cells. Erythropoietin-mediated neuroprotection was regulated by the combined effect of the ERK1/2 and AKT signalling pathways. Our findings provide further insights into the potential effect of erythropoietin on neuroblastoma cells. PMID- 26232557 TI - Regional brain disorders of serotonin neurotransmission are associated with functional dyspepsia. AB - AIMS: To elucidate the role of cerebral serotonin neurotransmission in visceral perception in functional dyspepsia (FD), we observationally examined the regional expression level of the serotonin transporter (SERT) and its correlation with clinical symptoms. MAIN METHODS: FD patients (Rome III criteria; N=9, age range: 36-76years) and healthy controls (N=8, age range: 25-61years) participated in this study. Positron emission tomography scanning with [(11)C]N,N-dimethyl-2-(2 amino-4-cyanophenylthio) benzylamine ([(11)C]DASB), which binds specifically to SERT, was used to quantify the binding potential (BPND) of [(11)C]DASB in the midbrain, thalamus, caudate, putamen, amygdala, and hippocampus with reference to co-registered magnetic resonance images. Clinical symptoms were assessed using the Gastrointestinal Symptoms Rating Scale (GSRS). Self-Rating Depression Scale (SDS), and State-Trait Anxiety Inventory (STAI). KEY FINDINGS: BPND of the midbrain (P=0.041) and thalamus (P=0.031) was higher in FD patients than in controls. The BPND values in the midbrain correlated with total GSRS (r=0.663, P=0.004) and abdominal pain (r=0.419, P=0.047) scores. Its values in the thalamus correlated with total GSRS (r=0.423, P=0.044), abdominal pain (r=0.502, P=0.022), and indigestion (r=0.476, P=0.028) scores. Its value in the hippocampus correlated with abdominal pain and state-STAI scores (r=0.528, P=0.017; r=0.428, P=0.043). SIGNIFICANCE: Up-regulation of the SERT level in the midbrain and thalamus may underlie the pathogenesis of FD such as abdominal and psychological symptoms via a brain-gut interaction. PMID- 26232558 TI - Incorporation of charged residues in the CYP2J2 F-G loop disrupts CYP2J2-lipid bilayer interactions. AB - CYP2J2 epoxygenase is an extrahepatic, membrane bound cytochrome P450 (CYP) that is primarily found in the heart and mediates endogenous fatty acid metabolism. CYP2J2 interacts with membranes through an N-terminal anchor and various non contiguous hydrophobic residues. The molecular details of the motifs that mediate membrane interactions are complex and not fully understood. To gain better insights of these complex protein-lipid interactions, we employed molecular dynamics (MD) simulations using a highly mobile membrane mimetic (HMMM) model that enabled multiple independent spontaneous membrane binding events to be captured. Simulations revealed that CYP2J2 engages with the membrane at the F-G loop through hydrophobic residues Trp-235, Ille-236, and Phe-239. To explore the role of these residues, three F-G loop mutants were modeled from the truncated CYP2J2 construct (Delta34) which included Delta34-I236D, Delta34-F239H and Delta34-I236D/F239H. Using the HMMM coordinates of CYP2J2, the simulations were extended to a full POPC membrane which showed a significant decrease in the depth of insertion for each of the F-G loop mutants. The CYP2J2 F-G loop mutants were expressed in E. coli and were shown to be localized to the cytosolic fraction at a greater percentage relative to construct Delta34. Notably, the functional data demonstrated that the double mutant, Delta34-I236D/F239H, maintained native-like enzymatic activity. The membrane insertion characteristics were examined by monitoring CYP2J2 Trp-quenching fluorescence spectroscopy upon binding nanodiscs containing pyrene phospholipids. Relative to the Delta34 construct, the F-G loop mutants exhibited lower Trp quenching and membrane insertion. Taken together, the results suggest that the mutants exhibit a different membrane topology in agreement with the MD simulations and provide important evidence towards the involvement of key residues in the F-G loop of CYP2J2. PMID- 26232559 TI - Membrane accessibility of glutathione. AB - Regulation of the ion pumping activity of the Na+,K+-ATPase is crucial to the survival of animal cells. Recent evidence has suggested that the activity of the enzyme could be controlled by glutathionylation of cysteine residue 45 of the beta-subunit. Crystal structures so far available indicate that this cysteine is in a transmembrane domain of the protein. Here we have analysed via fluorescence and NMR spectroscopy as well as molecular dynamics simulations whether glutathione is able to penetrate into the interior of a lipid membrane. No evidence for any penetration of glutathione into the membrane was found. Therefore, the most likely mechanism whereby the cysteine residue could become glutathionylated is via a loosening of the alpha-beta subunit association, creating a hydrophilic passageway between them to allow access of glutathione to the cysteine residue. By such a mechanism, glutathionylation of the protein would be expected to anchor the modified cysteine residue in a hydrophilic environment, inhibiting further motion of the beta-subunit during the enzyme's catalytic cycle and suppressing enzymatic activity, as has been experimentally observed. The results obtained, therefore, suggest a possible structural mechanism of how the Na+,K+-ATPase could be regulated by glutathione. PMID- 26232560 TI - Are current standards of reporting quality for clinical trials sufficient in addressing important sources of bias? AB - Determining the quality of a randomized clinical trial (RCT) is necessary for decision-makers to determine the believability and applicability of the trial findings. Issues that are likely to affect the utility of RCT evidence include issues of bias, random error and applicability. In this article we focus primarily on issues of bias and examine the evidence for whether reporting methodological items, including allocation concealment, sequence generation, and blinding of participants can be relied upon as evidence of bias. We present the findings of a systematic review of meta-epidemiological studies and a simulation study demonstrating that commonly examined sources of bias likely play little role in treatment exaggeration. We discuss other issues that may additionally influence trial outcomes including sample size, publication bias, and expertise of trialists. We conclude by discussing strategies to moderate the effect of known biases in assessing overall estimates of treatment effects. PMID- 26232561 TI - Determination and validation of psammaplin A and its derivatives in rat plasma by liquid chromatography-tandem mass spectrometry and its application in pharmacokinetic study. AB - A liquid chromatography-tandem mass (LC-MS/MS) method was developed for the determination of psammaplin A (PsA) and its newly synthesized derivatives (PsA 107, PsA 109, and PsA 123) in rat plasma using bupropion as an internal standard (IS). The plasma samples were deproteinized with acetonitrile. Chromatographic separation was performed on hydro-RP column (75*2.0mm, 80A, 4MUm) with isocratic elution using 5mM ammonium formate buffer/acetonitrile (30:70, v/v) at a flow rate of 0.4mL/min and the total run time was 5min. Mass spectrometric detection was performed with positive electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. The ion transitions monitored were m/z 663.2->331.0, 687.2 >343.1, 587.3->293.1, 563.3->281.0, and 240.0->184.0 for PsA, PsA 107, PsA 109, PsA 123, and IS, respectively. All analytes showed good linearity over the concentration range of 5.00-5000ng/mL (r(2)>=0.994). The lower limit of quantification was 5ng/mL for PsA and its three PsA derivatives. Within- and between-run precisions (relative standard deviation, RSD) were less than 9.66% and accuracy (relative error, RE) ranged from -9.34% to 7.25%. Established method was successfully applied to the investigation of pharmacokinetic properties of PsA and its derivatives in rats after intravenous administration at a dose of 2mg/kg. PMID- 26232562 TI - Radiolabeling optimization and characterization of (68)Ga labeled DOTA-polyamido amine dendrimer conjugate - Animal biodistribution and PET imaging results. AB - The present study describes the optimization of (68)Ga radiolabeling with PAMAM dendrimer-DOTA conjugate. A conjugate (PAMAM-DOTA) concentration of 11.69uM, provided best radiolabeling efficiency of more than 93.0% at pH 4.0, incubation time of 30.0min and reaction temperature ranging between 90 and 100 degrees C. The decay corrected radiochemical yield was found to be 79.4+/-0.01%. The radiolabeled preparation ([(68)Ga]-DOTA-PAMAM-D) remained stable (radiolabeling efficiency of 96.0%) at room temperature and in serum for up to 4-h. The plasma protein binding was observed to be 21.0%. After intravenous administration, 50.0% of the tracer cleared from the blood circulation by 30-min and less than 1.0% of the injected activity remained in blood by 1.0h. The animal biodistribution studies demonstrated that the tracer excretes through the kidneys and about 0.33% of the %ID/g accumulated in the tumor at 1h post injection. The animal organ's biodistribution data was supported by animal PET imaging showing good 'non specific' tracer uptake in tumor and excretion is primarily through kidneys. Additionally, DOTA-PAMAM-D conjugation with alphaVbeta3 receptors targeting peptides and drug loading on the dendrimers may improve the specificity of the (68)Ga labeled product for imaging and treating angiogenesis respectively. PMID- 26232563 TI - Photosynthesis of Scenedesmus obliquus in outdoor open thin-layer cascade system in high and low CO2 in Belgium. AB - Two outdoor open thin-layer cascade systems operated as batch cultures with the alga Scenedesmus obliquus were used to compare the productivity and photosynthetic acclimations in control and CO2 supplemented cultures in relation with the outdoor light irradiance. We found that the culture productivity was limited by CO2 availability. In the CO2 supplemented culture, we obtained a productivity of up to 24gdwm(-2)day(-1) and found a photosynthetic efficiency (value based on the PAR solar radiation energy) of up to 5%. In the CO2 limited culture, we obtained a productivity of up to 10gdwm(-2)day(-1) while the photosynthetic efficiency was up to 3.3% and decreased to 2.1% when the integrated daily PAR increased. Fluorescence and oxygen evolution measurements showed that ETR and oxygen evolution light saturation curves, as well as light dependent O2 uptake were similar in algal samples from both cultures when the CO2 limitation was removed. In contrast, we found that CO2 limitation conducted to a decreased PSII photochemical efficiency and an increased light-induced heat dissipation in the control culture compared to the CO2 supplemented culture. These features are in line with a lower light use efficiency and may therefore contribute to the lower productivity observed in absence of CO2 supplementation in outdoor mass cultures of S. obliquus. PMID- 26232564 TI - Antioxidant and enzymatic responses to oxidative stress induced by pre-harvest water supply reduction and ripening on mango (Mangifera indica L. cv. 'Cogshall') in relation to carotenoid content. AB - The effects of a reduction in water supply during fruit development and postharvest fruit ripening on the oxidative status and the antioxidant defense system were studied in the mango fruit (Mangifera indica L.) cv. Cogshall. Changes in non-enzymatic (ascorbate) and enzymatic (SOD, CAT, APX, MDHAR, DHAR and GR) antioxidants, as well as oxidative parameters (H2O2 and MDA) and major carotenoids, were measured in unripe and ripe fruits from well-irrigated and non irrigated trees. Under non-limiting water supply conditions, ripening induced oxidation as a result of the production of ROS and decreased ascorbate content. Antioxidant enzymatic systems were activated to protect fruit tissues and to regenerate the ascorbate pool. The carotenoid pool, mainly represented by beta carotene and esterified violaxanthine isomers, accumulated naturally during mango ripening. The suppression of irrigation decreased fruit size and induced accumulation of ABA and of its storage form, ABA-GE, in fruit pulp from the earliest harvest. It also increased oxidation, which was observable by the high levels of ascorbate measured at the early stages at harvest, and by the delay in the time it took to reach the pseudo constant carotene-to-xanthophyll ratio in ripe fruits. Nevertheless, differences between the irrigation treatments on the antioxidant system in ripe fruits were not significant, mainly because of the drastic changes in this system during ripening. PMID- 26232565 TI - Proteomic LC-MS analysis of Arabidopsis cytosolic ribosomes: Identification of ribosomal protein paralogs and re-annotation of the ribosomal protein genes. AB - Arabidopsis thaliana cytosolic ribosomes are large complexes containing eighty one distinct ribosomal proteins (r-proteins), four ribosomal RNAs (rRNA) and a plethora of associated (non-ribosomal) proteins. In plants, r-proteins of cytosolic ribosomes are each encoded by two to seven different expressed and similar genes, forming an r-protein family. Distinctions in the r-protein coding sequences of gene family members are a source of variation between ribosomes. We performed proteomic investigation of actively translating cytosolic ribosomes purified using both immunopurification and a classic sucrose cushion centrifugation-based protocol from plants of different developmental stages. Both 1D and 2D LC-MS(E) with data-independent acquisition as well as conventional data dependent MS/MS procedures were applied. This approach provided detailed identification of 165 r-protein paralogs with high coverage based on proteotypic peptides. The detected r-proteins were the products of the majority (68%) of the 242 cytosolic r-protein genes encoded by the genome. A total of 70 distinct r proteins were identified. Based on these results and information from DNA microarray and ribosome footprint profiling studies a re-annotation of Arabidopsis r-proteins and genes is proposed. This compendium of the cytosolic r protein proteome will serve as a template for future investigations on the dynamic structure and function of plant ribosomes. BIOLOGICAL SIGNIFICANCE: Translation is one of the most energy demanding processes in a living cell and is therefore carefully regulated. Translational activity is tightly linked to growth control and growth regulating mechanism. Recently established translational profiling technologies, including the profiling of mRNAs associated with polysomes and the mapping of ribosome footprints on mRNAs, have revealed that the expression of gene expression is often fine-tuned by differential translation of gene transcripts. The eukaryotic ribosome, the hub of these important processes, consists of close to eighty different proteins (depending on species) and four large RNAs assembled into two highly conserved subunits. In plants and to lesser extent in yeast, the r-proteins are encoded by more than one actively transcribed gene. As r-protein gene paralogs frequently do not encode identical proteins and are regulated by growth conditions and development, in vivo ribosomes are heterogeneous in their protein content. The regulatory and physiological importance of this heterogeneity is unknown. Here, an improved annotation of the more than two hundred r-protein genes of Arabidopsis is presented that combines proteomic and advanced mRNA expression data. This proteomic investigation and re annotation of Arabidopsis ribosomes establish a base for future investigations of translational control in plants. PMID- 26232566 TI - Genetic material present in hospital wastewaters: Evaluation of the efficiency of DNA denaturation by ozonolysis and ozonolysis/sonolysis treatments. AB - Hospital wastewater treatments must ensure that all genetic material is destroyed, since nuclear and extra-nuclear DNA can show antimicrobial resistance and contain recombinant genes, which promote vertical and/or horizontal gene transfer, amplifying the current problem of the emergence of antibiotic-resistant microorganisms. In this study, we investigated whether ozonolysis or ozonolysis/sonolysis in combination can denature genetic material, i.e., destroy the integrity of DNA molecules, present in hospital wastewaters. To achieve this goal, hospital wastewaters were treated by ozonolysis or ozonolysis/sonolysis in combination (at 70 and 100 W L(-1)) and both raw and treated wastewaters were analyzed in terms of disinfection and DNA denaturation efficiency quantified by viable cell counts and by agarose gel electrophoresis. In the ozonolysis treatment, the agarose gel electrophoresis technique showed that the ozone treated samples contained DNA molecules, while combined ozonolysis/sonolysis destroyed the DNA in a power density-dependent manner (64% at 70 W L(-1) and 81% at 100 W L(-1)). Care must be taken by environmental managers to distinguish disinfection processes from DNA denaturation processes, since these two terms are not synonymous. PMID- 26232567 TI - Effect of K2FeO4/US treatment on textile dyeing sludge disintegration and dewaterability. AB - The effect of potassium ferrate/ultrasonic (K2FeO4/US) treatment on the physicochemical features of textile dyeing sludge was studied. The soluble chemical oxygen demand (SCOD), deoxyribonucleic acid (DNA), sludge volume index (SVI), sludge viscosity, capillary suction time (CST) and particle size were measured to understand the observed changes in the sludge physicochemical features. The results showed that the combined K2FeO4/US treatment presented great advantages for disrupting the sludge floc structure over K2FeO4 or ultrasonic treatments alone. The optimal parameters of sludge disintegration were found to be a K2FeO4 treatment time of 60 min, a K2FeO4 dosage of 0.5936 g/g SS, an ultrasonic time of 15 min and an ultrasonic intensity of 0.72 W/mL. The initial median diameter of the sludge particles was 15.24 MUm, and this value decreased by 35.89%. The CST was initially 59.6 s and increased by 231%, whereas the SVI was 97.78 mL/g and decreased by 25.89%. Scanning electron microscope (SEM) images indicated that the sludge surface was irregular and loose with a large amount of channels or voids during K2FeO4/US treatment. K2FeO4/US treatment synergistically enhanced the sludge solubilization and reached 668.67 mg/L SCOD, which is 31.81% greater than the additive value obtained with K2FeO4 treatment alone (215.95 mg/L) or with ultrasonic treatment alone (240 mg/L). PMID- 26232568 TI - Sampling effects on the identification of roadkill hotspots: Implications for survey design. AB - Although locating wildlife roadkill hotspots is essential to mitigate road impacts, the influence of study design on hotspot identification remains uncertain. We evaluated how sampling frequency affects the accuracy of hotspot identification, using a dataset of vertebrate roadkills (n = 4427) recorded over a year of daily surveys along 37 km of roads. "True" hotspots were identified using this baseline dataset, as the 500-m segments where the number of road killed vertebrates exceeded the upper 95% confidence limit of the mean, assuming a Poisson distribution of road-kills per segment. "Estimated" hotspots were identified likewise, using datasets representing progressively lower sampling frequencies, which were produced by extracting data from the baseline dataset at appropriate time intervals (1-30 days). Overall, 24.3% of segments were "true" hotspots, concentrating 40.4% of roadkills. For different groups, "true" hotspots accounted from 6.8% (bats) to 29.7% (small birds) of road segments, concentrating from <40% (frogs and toads, snakes) to >60% (lizards, lagomorphs, carnivores) of roadkills. Spatial congruence between "true" and "estimated" hotspots declined rapidly with increasing time interval between surveys, due primarily to increasing false negatives (i.e., missing "true" hotspots). There were also false positives (i.e., wrong "estimated" hotspots), particularly at low sampling frequencies. Spatial accuracy decay with increasing time interval between surveys was higher for smaller-bodied (amphibians, reptiles, small birds, small mammals) than for larger-bodied species (birds of prey, hedgehogs, lagomorphs, carnivores). Results suggest that widely used surveys at weekly or longer intervals may produce poor estimates of roadkill hotspots, particularly for small bodied species. Surveying daily or at two-day intervals may be required to achieve high accuracy in hotspot identification for multiple species. PMID- 26232569 TI - Pretreatment effects on the sorption of Cr(VI) onto surfactant-modified zeolite: Mechanism analysis. AB - Adsorption of Cr(VI) onto different pretreated zeolites modified with cetylpyridinium chloride (CPC) is investigated using batch studies, Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) measurements and scanning electron microscopy (SEM). The results indicate that acidification after alkalization is the most effective pretreatment method, and only alkalization would significantly reduce the sorption capability. This behavior is due to the precipitates, such as CaCO3 and MgCO3, generated after alkalization on zeolite surface interfere the formation of the CPC bilayer, which provides active sites for sorbing Cr(VI). The schematic of the adsorption mechanism is presented. The results indicate that developing a better understanding of the influence of different pretreatments is quite helpful and suggest that the content of Ca/Mg/Fe could be a good indication of the effectiveness of preprocessing. PMID- 26232570 TI - The effect of self-management training on health-related quality of life in patients with epilepsy. AB - PURPOSE: Epilepsy is the most common chronic neurological disease after headache. Health-related quality of life in patients with epilepsy is disturbed by psychosocial factors, seizures, and treatment side effects. This study was conducted to determine the effect of a self-management training program on quality of life in patients with epilepsy. METHODS: In this controlled clinical trial, 60 patients with epilepsy going to Zanjan Neurology Clinic were examined. The samples were selected using convenience sampling and divided randomly into the case group (30 people) and control group (30 people) using the table of random numbers. Four training sessions on the nature of epilepsy and self managementwere run for the case group. All the patients completed an inventory for quality of life twice: before and one month after the intervention. The data were analyzed using the chi-square test, independent t-test, and paired t-test. RESULTS: There was no statistically significant difference between the two groups before the intervention in terms of personal specifications and scores and dimensions of the quality of life. One month after the intervention, a statistically significant difference was observed between the two groups in terms of the scores and dimensions of quality of life that indicated improved quality of life in the case group (P<0.001). CONCLUSION: The self-management training program improved the quality of life in patients with epilepsy. The present findings highlight that psychosocial variables can have incremental significance over biomedical variables in the health-related quality of life of patients with epilepsy. PMID- 26232571 TI - Different protocols of treadmill exercise induce distinct neuroplastic effects in rat brain motor areas. AB - A variety of exercise protocols have been used to promote experimental neuroplasticity. However, the plastic brain responses generated by several aspects of training (types, frequency, regimens, duration) remain undetermined. The aim of this study was to compare the plastic changes in the glutamatergic system and synaptic proteins in motor cortex, striatum and cerebellum promoted by two different treadmill exercise regimens. The present study analyzed by immunohistochemistry and Western blotting the expression of the subunits of AMPA receptors (GluA1 and GluA2/3) and synaptic proteins (synapsin I and synaptophysin) in adult male Wistar rat brains. The animals were divided into animals subjected to two different frequencies of aerobic exercise groups and sedentary animals. The exercise groups were: intermittent treadmill exercise (ITE) - animals that exercised 3 times a week (every other day) during four weeks, and continuous treadmill exercise (CTE) - animals that exercised every day during four weeks. Our results reveal that different protocols of treadmill exercise were able to promote distinct synaptic reorganization processes among the exercised groups. In general, the intermittent exercise regimen induced a higher expression of presynaptic proteins, whereas the continuous exercise regimen increased postsynaptic GluA1 and GluA2/3 receptors. PMID- 26232574 TI - Scientific investigation of the Imperial Gates belonging to the wooden church from Sacel, Turda County, Romania. AB - Cultural heritage objects have a major contribution to the historical patrimony of every country. In Romania, wooden churches are famous, they are mostly dated in between the XVth and XXth century, but unfortunately many of them have been destroyed, by natural or anthropic means. Therefore, the necessity of conservation and restoration has appeared, to the ones that still exist, as legacy for the future generations. In the present article, an Imperial Gate from a wooden church in Cluj County, Romania, has been investigated, using scientific techniques (FTIR and XRF). A 3D reconstruction has been performed, using similar colors with the original artwork, as resulted from the scientific investigation of the painting materials. A limited number of constituent materials have been used for this artwork, and the wood species used was lime, due to the ease of carving. PMID- 26232572 TI - Metabolism and epigenetics in the nervous system: Creating cellular fitness and resistance to neuronal death in neurological conditions via modulation of oxygen , iron-, and 2-oxoglutarate-dependent dioxygenases. AB - Modern definitions of epigenetics incorporate models for transient but biologically important changes in gene expression that are unrelated to DNA code but responsive to environmental changes such as injury-induced stress. In this scheme, changes in oxygen levels (hypoxia) and/or metabolic co-factors (iron deficiency or diminished 2-oxoglutarate levels) are transduced into broad genetic programs that return the cell and the organism to a homeostatic set point. Over the past two decades, exciting studies have identified a superfamily of iron-, oxygen-, and 2-oxoglutarate-dependent dioxygenases that sit in the nucleus as modulators of transcription factor stability, co-activator function, histone demethylases, and DNA demethylases. These studies have provided a concrete molecular scheme for how changes in metabolism observed in a host of neurological conditions, including stroke, traumatic brain injury, and Alzheimer's disease, could be transduced into adaptive gene expression to protect the nervous system. We will discuss these enzymes in this short review, focusing primarily on the ten eleven translocation (TET) DNA demethylases, the jumonji (JmJc) histone demethylases, and the oxygen-sensing prolyl hydroxylase domain enzymes (HIF PHDs). This article is part of a Special Issue entitled SI: Neuroprotection. PMID- 26232573 TI - Synthesis, photoluminescence and biological properties of terbium(III) complexes with hydroxyketone and nitrogen containing heterocyclic ligands. AB - The ternary terbium(III) complexes [Tb(HDAP)3?biq], [Tb(HDAP)3?dmph] and [Tb(HDAP)3?bathophen] were prepared by using methoxy substituted hydroxyketone ligand HDAP (2-hydroxy-4,6-dimethoxyacetophenone) and an ancillary ligand 2,2 biquinoline or 5,6-dimethyl-1,10-phenanthroline or bathophenanthroline respectively. The ligand and synthesized complexes were characterised based on elemental analysis, FT-IR and (1)H NMR. Thermal behaviour of the synthesized complexes illustrates the general decomposition patterns of the complexes by thermogravimetric analysis. Photophysical properties such as excitation spectra, emission spectra and luminescence decay curves of the complexes were investigated in detail. The main green emitting peak at 548nm can be attributed to (5)D4 >(7)F5 of Tb(3+) ion. Thus, these complexes might be used to make a bright green light-emitting diode for display purpose. In addition the in vitro antibacterial activities of HDAP and its Tb(III) complexes against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and antifungal activities against Candida albicans and Aspergillus niger are reported. The Tb(3+) complexes were found to be more potent antimicrobial agent as compared to the ligand. Among all these complexes, [Tb(HDAP)3?bathophen] exhibited excellent antimicrobial activity which proves its potential usefulness as an antimicrobial agent. Furthermore, in vitro antioxidant activity tests were carried out by using DPPH method which indicates that the complexes have considerable antioxidant activity when compared with the standard ascorbic acid. PMID- 26232575 TI - Synthesis, spectroscopic and computational characterization of the tautomerism of pyrazoline derivatives from chalcones. AB - In the present study a series of novel pyrazolines derivatives has been synthesized, and their structures assigned on the basis of FT-Raman, (1)H and (13)C NMR spectral data and computational DFT calculations. A joint computational study using B3LYP/6-311G(2d,2p) density functional theory and FT-Raman investigation on the tautomerism of 3-(4-substituted-phenyl)-4,5-dihydro-5-(4 substituted-phenyl)pyrazole-1-carbothioamide and 3-(4-substituted-phenyl)-4,5 dihydro-5-(4-substituted-phenyl)pyrazole-1-carboxamide are presented. The structures were characterized as a minimum in the potential energy surface using DFT. The calculated Raman and NMR spectra were of such remarkable agreement to the experimental results that the equilibrium between tautomeric forms has been discussed in detail. Our study suggests the existence of tautomers, the carboxamide/carbothioamide group may tautomerize, in the solid state or in solution. Thermodynamic data calculated suggests that the R(CS)NH2 and R(CO)NH2 species are more stable than the R(CNH)SH and R(CNH)OH species. Additionally, results found for the (1)H NMR shifting, pointed out to which structure is present. PMID- 26232576 TI - 5-Hydroxymethylfurfural modified rhodamine B dual-function derivative: Highly sensitive and selective optical detection of pH and Cu(2+). AB - A dual-function optical chemosensor (RBF) was designed and easily synthesized by condensation reaction of 5-Hydroxymethylfurfural and rhodamine B hydrazide. RBF exhibited highly sensitive, highly selective and quick response to acidic pH. The fluorescence intensity of RBF exhibited a more than 41-fold increase within the pH range from 7.50 to 3.73 with a pKa value of 5.02, which could be successfully applied to monitor intracellular pH in living PC12 cells and HeLa cells. Additionally, the spectroscopy of UV-Vis and EDTA-adding experiments indicated that RBF was a highly selective and reversible colorimetric chemosensor for Cu(2+) in Tris-HCl (10mM, pH=7.2) aqueous buffer solution as well as other metal ions had no obvious interference. Moreover, RBF has been successfully applied to detect Cu(2+) in real water samples. PMID- 26232577 TI - Controlling dynamic SERS hot spots on a monolayer film of Fe3O4@Au nanoparticles by a magnetic field. AB - A large surface-enhanced Raman scattering (SERS) effect is critically dependent on the gap distance of adjacent nanostructures, i.e., "hot spots". However, the fabrication of dynamically controllable hot spots still remains a remarkable challenge. In the present study, we employed an external magnetic field to dynamically control the interparticle spacing of a two-dimensional monolayer film of Fe3O4@Au nanoparticles at a hexane/water interface. SERS measurements were performed to monitor the expansion and shrinkage of the nanoparticles gaps, which produced an obvious effect on SERS activities. The balance between the electrostatic repulsive force, surface tension, and magnetic attractive force allowed observation of the magnetic-field-responsive SERS effect. Upon introduction of an external magnetic field, a very weak SERS signal appeared initially, indicating weak enhancement due to a monolayer film with large interparticle spacing. The SERS intensity reached maximum after 5s and thereafter remained almost unchanged. The results indicated that the observed variations in SERS intensities were fully reversible after removal of the external magnetic field. The reduction of interparticle spacing in response to a magnetic field resulted in about one order of magnitude of SERS enhancement. The combined use of the monolayer film and external magnetic field could be developed as a strategy to construct hot spots both for practical application of SERS and theoretical simulation of enhancement mechanisms. PMID- 26232578 TI - The fluorescent interactions between amphiphilic chitosan derivatives and water soluble quantum dots. AB - The LCC-CdTe quantum dots (QDs) hybrid was fabricated by mixing the N-lauryl-N, O carboxymethyl chitosan (LCC) micelle with water-soluble CdTe QDs in an aqueous solution via hydrophobic forces and the electronic attraction. The structures of LCC and LCC-CdTe QDs hybrid were determined by differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy and transmission electron microscopy (TEM). The results showed that the lauryl and carboxymethyl were successfully grafted to chitosan oligosaccharide (CSO), and a number of CdTe QDs were encapsulated by LCC micelle to form a core/shell structure. The tested results of the fluorescent characteristics of LCC, CdTe QDs and LCC-CdTe QDs hybrid showed that there were some obvious fluorescent interactions between LCC and CdTe QDs. Meanwhile, with the change in LCC space structure, the fluorescent interactions between LCC and QDs showed different fluorescent characteristics. The QDs fluorescent (FL) intensity increased first and then decreased to almost quenching, while LCC FL intensity decreased continually. PMID- 26232579 TI - Two Schiff-base fluorescent sensors for selective sensing of aluminum (III): Experimental and computational studies. AB - Two Schiff-base fluorescent sensors have been synthesized, which both can act as fluorescent probes for Al(3+), upon addition of Al(3+), they exhibit a large fluorescence enhancement which might be attributed to the formation of 1:1 ligand Al complexes which inhibit photoinduced electron transfer (PET) progress, and that the proposed binding modes of the sensors and Al(3+) are identified by theoretical calculations. PMID- 26232580 TI - New formamidine ligands and their mixed ligand palladium(II) oxalate complexes: Synthesis, characterization, DFT calculations and in vitro cytotoxicity. AB - A series of new ternary palladium(II) complexes of the type [Pd(L1-4)ox].xH2O where L=formamidine ligands and ox=oxalate, were synthesized and characterized by elemental analyses, magnetic susceptibility, UV-Vis, infrared (IR) and mass spectroscopy and thermal analysis. The spectroscopic data indicated that the formamidine ligands act as bidentate N2 donors and the oxalate as O2 ligand. The complexes (1-4) are diamagnetic and the optimization of their structures indicated that the geometry is distorted square planer with O-Pd-O and N-Pd-N bond angles ranged 82.70-83.87 degrees and 88.21-95.02 degrees ; respectively which is acceptable for the heteroleptic complexes. The dipole moment of the complexes (13.97-18.77Debye) indicating that the complexes are more polarized than the ligands (1.93-4.96Debye). The complexes are thermally stable as shown from their relatively higher overall activation energies (441-688kJmol(-1)). The ligands and the complexes are proved to have good cytotoxicity with IC50 (MUM) in the range of (0.011-0.168) against MCF-7, (0.012-0.150) against HCT-116, (0.042 0.094) against PC-3 and (0.006-0.222) against HepG-2 cell lines, which open the field for further application as antitumor compounds. PMID- 26232581 TI - Arsenate substitution in lead hydroxyl apatites: A Raman spectroscopic study. AB - A total of seven compounds of the hydroxylpyromorphite Pb10(PO4)6(OH)2 - hydroxylmimetite Pb10(AsO4)6(OH)2 (HPY-HMI) solid solution series were synthesized at 80 degrees C from aqueous solutions and characterized using Raman spectroscopy. The positions of the bands in all spectra of the series depend on the content of arsenates and phosphates shifting to lower wavenumbers with substitution of (AsO4)(3-) for (PO4)(3-). This shift results from the decreasing bond strength of X-O (where X=P, As) and higher atomic mass of As than P. The position and intensity of major (PO4)(3-) and (AsO4)(3-) bands in Raman spectra exhibit linear correlation with As content, while the ratio of the intensities of these peaks shows exponential correlation. This results due to different polarizability of (PO4)(3-) and (AsO4)(3-) molecules. A small carbonate band develops with increasing As content indicating that hydroxyl lead apatites adopt the (CO3)(2-) ions, particularly at the arsenate end of the series. PMID- 26232582 TI - New insights into the acute actions from a high dosage of fluoxetine on neuronal and cardiac function: Drosophila, crayfish and rodent models. AB - The commonly used mood altering drug fluoxetine (Prozac) in humans has a low occurrence in reports of harmful effects from overdose; however, individuals with altered metabolism of the drug and accidental overdose have led to critical conditions and even death. We addressed direct actions of high concentrations on synaptic transmission at neuromuscular junctions (NMJs), neural properties, and cardiac function unrelated to fluoxetine's action as a selective 5-HT reuptake inhibitor. There appears to be action in blocking action potentials in crayfish axons, enhanced occurrences of spontaneous synaptic vesicle fusion events in the presynaptic terminals at NMJs of both Drosophila and crayfish. In rodent neurons, cytoplasmic Ca(2+) rises by fluoxetine and is thapsigargin dependent. The Drosophila larval heart showed a dose dependent effect in cardiac arrest. Acute paralytic behavior in crayfish occurred at a systemic concentration of 2mM. A high percentage of death as well as slowed development occurred in Drosophila larvae consuming food containing 100MUM fluoxetine. The release of Ca(2+) from the endoplasmic reticulum in neurons and the cardiac tissue as well as blockage of voltage-gated Na(+) channels in neurons could explain the effects on the whole animal as well as the isolated tissues. The use of various animal models in demonstrating the potential mechanisms for the toxic effects with high doses of fluoxetine maybe beneficial for acute treatments in humans. Future studies in determining how fluoxetine is internalized in cells and if there are subtle effects of these mentioned mechanisms presented with chronic therapeutic doses are of general interest. PMID- 26232583 TI - Comparative study of the effect of BPA and its selected analogues on hemoglobin oxidation, morphological alterations and hemolytic changes in human erythrocytes. AB - Bisphenol A (BPA) has been shown to provoke many deleterious impacts on human health, and thus it is now successively substituted by BPA analogues, whose effects have been poorly investigated. Up to now, only one study has been realized to assess the effect of BPA on human erythrocytes, which showed its significant hemolytic and oxidative potential. Moreover, no study has been conducted to evaluate the effect of BPA analogues on red blood cells. The purpose of the present study was to compare the impact of BPA and its selected analogues such as bisphenol F (BPF), bisphenol S (BPS) and bisphenol AF (BPAF) on hemolytic and morphological changes and hemoglobin oxidation (methemoglobin formation) of human erythrocytes. The erythrocytes were incubated with different bisphenols concentrations ranging from 0.5 to 500MUg/ml for 1, 4 and 24h. The compounds examined caused hemolysis in human erythrocytes with BPAF exhibiting the strongest effect. All bisphenols examined caused methemoglobin formation with BPA inducing the strongest oxidative potential. Flow cytometry analysis showed that all bisphenols (excluding BPS) induced significant changes in erythrocytes size. Changes in red blood cells shape were conducted using phase contrast microscopy. It was noticed that BPA and BPAF induced echinocytosis, BPF caused stomatocytosis, while BPS did not provoke significant changes in shape of red blood cells. Generally, the results showed that BPS, which is the main substituent of bisphenol A in polymers and thermal paper production, exhibited significantly lower disturbance of erythrocyte functions than BPA. PMID- 26232584 TI - Segmental and age differences in the elastin network, collagen, and smooth muscle phenotype in the tunica media of the porcine aorta. AB - The porcine aorta is often used in studies on morphology, pathology, transplantation surgery, vascular and endovascular surgery, and biomechanics of the large arteries. Using quantitative histology and stereology, we estimated the area fraction of elastin, collagen, alpha-smooth muscle actin, vimentin, and desmin within the tunica media in 123 tissue samples collected from five segments (thoracic ascending aorta; aortic arch; thoracic descending aorta; suprarenal abdominal aorta; and infrarenal abdominal aorta) of porcine aortae from growing domestic pigs (n=25), ranging in age from 0 to 230 days. The descending thoracic aorta had the greatest elastin fraction, which decreased proximally toward the aortic arch as well as distally toward the abdominal aorta. Abdominal aortic segments had the highest fraction of actin, desmin, and vimentin positivity and all of these vascular smooth muscle markers were lower in the thoracic aortic segments. No quantitative differences were found when comparing the suprarenal abdominal segments with the infrarenal abdominal segments. The area fraction of actin within the media was comparable in all age groups and it was proportional to the postnatal growth. Thicker aortic segments had more elastin and collagen with fewer contractile cells. The collagen fraction decreased from ascending aorta and aortic arch toward the descending aorta. By revealing the variability of the quantitative composition of the porcine aorta, the results are suitable for planning experiments with the porcine aorta as a model, i.e. power test analyses and estimating the number of samples necessary to achieving a desirable level of precision. The complete primary morphometric data, in the form of continuous variables, are made publicly available for biomechanical modeling of site-dependent distensibility and compliance of the porcine aorta. PMID- 26232585 TI - The planning and execution of natural sequential actions in the preschool years. AB - Preschool children's abilities to learn from observation has been the focus of considerable theoretical and empirical work. A wealth of developmental research suggests that young children reliably over-imitate modeled actions. Across two experiments, we asked whether a single misleading demonstration significantly impacts preschoolers' planning and execution of a familiar event sequence. In Experiment 1, we found that, despite sufficient task knowledge, 3- and 5-year olds readily incorporated irrelevant modeled actions into their own performances. In Experiment 2, we found that when the underlying event structure was spatially cued, over-imitation was no longer apparent in preschooler's re-enactment of the sequence. These findings serve as evidence for a tight coupling between perceptual and conceptual processing systems in early action planning. Taken together, findings from both experiments suggest that over-imitation behaviour in these tasks results from a failure to evaluate the observed links between procedural components of the sequence in respect to the overarching goal of the task. These results further contrast with the existing developmental literature by suggesting that, in the context of familiar actions, over-imitation significantly decreases during the preschool period. Findings are discussed in the context of preschoolers' abilities to plan and execute sequential actions. PMID- 26232586 TI - Interference of viral effector proteins with chromatin, transcription, and the epigenome. AB - Pathogens exploit cellular functions to create an environment conducive to their persistence and propagation. Viruses and bacteria express effector-proteins or virulence factors, known to interfere at the molecular level with regulatory 'checkpoints' of numerous physiological events in the cell. A newly prominent area of research is the identification of pathogenic effector proteins that function on the host chromatin, their subversion/interference with chromatin regulatory processes, the short/long/heritable effects on the infected cell and the ultimate consequence of their expression at the organismal level. PMID- 26232587 TI - Simultaneous determination of thirteen flavonoids from Xiaobuxin-Tang extract using high-performance liquid chromatography coupled with electrospray ionization mass spectrometry. AB - A simple and reliable high performance liquid chromatography coupled with electrospray ionization mass spectrometry (HPLC-ESI-MS) analysis method was established to simultaneously determine thirteen flavonoids of Xiaobuxing-Tang in intestine perfusate, namely onpordin, 3'-O-methylorobol, glycitein, patuletin, genistein, luteolin, quercetin, nepitrin, quercimeritrin, daidzin, patulitrin, quercetagitrin and 3-glucosylisorhamnetin. Detection was performed on a quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source operating in negative ionization mode. Negative ion ESI was used to form deprotonated molecules at m/z 315 for onpordin, m/z 299 for 3'-O-methylorobol, m/z 283 for glycitein, m/z 331 for patuletin, m/z 269 for genistein, m/z 285 for luteolin, m/z 301 for quercetin, m/z 477 for nepitrin, m/z 463 for quercimeritrin, m/z 461 for daidzin, m/z 493 for patulitrin, m/z 479 for quercetagitrin, m/z 477 for 3-glucosylisorhamnetin and m/z 609.2 for rutin. The linearity, sensitivity, selectivity, repeatability, accuracy, precision, recovery and matrix effect of the assay were evaluated. The proposed method was successfully applied to simultaneous determination of these thirteen flavonoids, and using this method, the intestinal absorption profiles of thirteen flavonoids were preliminarily predicted. PMID- 26232588 TI - Cystamine/cysteamine rescues the dopaminergic system and shows neurorestorative properties in an animal model of Parkinson's disease. AB - The neuroprotective properties of cystamine identified in pre-clinical studies have fast-tracked this compound to clinical trials in Huntington's disease, showing tolerability and benefits on motor symptoms. We tested whether cystamine could have such properties in a Parkinson's disease murine model and now provide evidence that it can not only prevent the neurodegenerative process but also can reverse motor impairments created by a 6-hydroxydopamine lesion 3 weeks post surgery. Importantly, we report that cystamine has neurorestorative properties 5 weeks post-lesion as seen on the number of nigral dopaminergic neurons which is comparable with treatments of cysteamine, the reduced form of cystamine used in the clinic, as well as rasagiline, increasingly prescribed in early parkinsonism. All three compounds induced neurite arborization of the remaining dopaminergic cells which was further confirmed in ex vivo dopaminergic explants derived from Pitx3-GFP mice. The disease-modifying effects displayed by cystamine/cysteamine would encourage clinical testing. PMID- 26232589 TI - The tumor suppressor PTEN regulates motor responses to striatal dopamine in normal and Parkinsonian animals. AB - Phosphatase and Tensin homolog deleted on chromosome 10 (PTEN) is a dual lipid protein phosphatase known primarily as a growth preventing tumor suppressor. PTEN is also expressed in neurons, and pathways modulated by PTEN can influence neuronal function. Here we report a novel function of PTEN as a regulator of striatal dopamine signaling in a model of Parkinson's disease (PD). Blocking PTEN expression with an adeno-associated virus (AAV) vector expressing a small hairpin RNA (shRNA) resulted in reduced responses of cultured striatal neurons to dopamine, which appeared to be largely due to reduction in D2 receptor activation. Co-expression of shRNA-resistant wild-type and mutant forms of PTEN indicated that the lipid-phosphatase activity was essential for this effect. In both normal and Parkinsonian rats, inhibition of striatal PTEN in vivo resulted in motor dysfunction and impaired responses to dopamine, particularly D2 receptor agonists. Expression of PTEN mutants confirmed the lipid-phosphatase activity as critical, while co-expression of a dominant-negative form of Akt overcame the PTEN shRNA effect. These results identify PTEN as a key mediator of striatal responses to dopamine, and suggest that drugs designed to potentiate PTEN expression or activity, such as cancer chemotherapeutics, may also be useful for improving striatal responses to dopamine in conditions of dopamine depletion such as PD. This also suggests that strategies which increase Akt or decrease PTEN expression or function, such as growth factors to prevent neuronal death, may have a paradoxical effect on neurological functioning by inhibiting striatal responses to dopamine. PMID- 26232590 TI - Anti-cancerous efficacy and pharmacokinetics of 6-mercaptopurine loaded chitosan nanoparticles. AB - 6-Mercaptopurine is a cytotoxic and immunosuppressant drug. The use of this drug is limited due to its poor bioavailability and short plasma half-life. In order to nullify these drawbacks, 6-mercaptopurine-chitosan nanoparticles (6-MP-CNPs) were prepared and evaluated to study the influence of preparation conditions on the physicochemical properties by using DLS, SEM, XRD and FTIR. The in vitro drug release profile at pH 4.8 and 7.4 revealed sustained release patterns for a period of 2 days. The nanoformulations showed enhanced in vitro anti-cancer activities (MTT assay, apoptosis assay, cell cycle arrest and ROS indices) on HT 1080 and MCF-7 cells. In vivo pharmacokinetics profiles of 6-MP-CNPs showed improved bioavailability. Thus, the results of the present study revealed that, the prepared 6-MP-CNPs have a significant role in increasing anti-cancer efficacy, bioavailability and in vivo pharmacokinetics profiles. PMID- 26232591 TI - Processes in the development of mathematics in kindergarten children from Title 1 schools. AB - This study examined how well nonverbal IQ (or fluid intelligence), vocabulary, phonological awareness (PA), rapid autonomized naming (RAN), and phonological short-term memory (STM) predicted mathematics outcomes. The 208 participating kindergartners were administered tests of fluid intelligence, vocabulary, PA, RAN, STM, and numeracy in the fall of kindergarten, whereas tests of numeracy and applied problems were administered in the spring of kindergarten. Fall numeracy scores accounted for substantial variation in spring outcomes (R(2) values = .49 and .32 for numeracy and applied problems, respectively), which underscores the importance of preschool math instruction and screening for mathematics learning difficulties on entry into kindergarten. Fluid intelligence and PA significantly predicted unique variation in spring numeracy scores (DeltaR(2) = .05) after controlling for autoregressive effects and classroom nesting. Fluid intelligence, PA, and STM significantly predicted unique variation in spring applied problems scores (DeltaR(2) = .14) after controlling for autoregressive effects and classroom nesting. Although the contributions of fluid intelligence, PA, and STM toward math outcomes were reliable and arguably important, they were small. PMID- 26232592 TI - Developmental improvements in reaching correction efficiency are associated with an increased ability to represent action mentally. AB - We investigated the purported association between developmental changes in the efficiency of online reaching corrections and improved action representation. Younger children (6-7 years), older children (8-12 years), adolescents (13-17 years), and young adults (18-24 years) completed a double-step reaching paradigm and a motor imagery task. Results showed similar nonlinear performance improvements across both tasks, typified by substantial changes in efficiency after 6 or 7 years followed by incremental improvements. Regression showed that imagery ability significantly predicted reaching efficiency and that this association stayed constant across age. Findings provide the first empirical evidence that more efficient online control through development is predicted, partly, by improved action representation. PMID- 26232593 TI - Associations of group level popularity with observed behavior and influence in a dyadic context. AB - This study examined the association between popularity in the peer group and adolescents' behavior in a dyadic context. After collecting peer nominations for popularity, 218 early adolescents (M(age) = 11.0 years) in 109 randomly composed same-sex dyads participated in a discussion task where they planned a party for their classroom. From digital recordings of the sessions, each participant's influence, involvement, skillful leadership, coercive resource control, submissiveness, positivity, and negativity were observed. Analyses with the actor partner interdependence model (APIM) demonstrated that for girls high group level popularity was associated with a socially sensitive interaction style and influence in the dyadic context. For both boys and girls, the interaction partner's group level popularity negatively predicted their use of coercive resource control strategies and negative behavior in the dyad. For girls, in addition, the interaction partner's group level popularity also positively predicted their submissiveness and negatively predicted their task influence. These results indicate that, in particular for girls, adolescents' group level popularity plays an important role in the behavior of both peers in a cooperative dyadic context. PMID- 26232594 TI - Adolescent predictors of satisfaction with social support six years later: An Australian longitudinal study. AB - The importance of socially supportive relationships in assisting people to cope with stress and adverse events is well recognised, but the trajectories whereby individuals develop the capacity to attract those supports have been infrequently studied. Taking advantage of a substantial longitudinal data set, we aimed to explore the precursors during mid-adolescence, of satisfaction with social supports in young adulthood. Both personality factors (extraversion, neuroticism) and adolescent experiences of high-quality interpersonal relationships with parents and peers were hypothesised to predict subsequent satisfactory supports; we wished to compare the influence of these factors. Participants in a study of the school to work transition (N = 558) provided psychosocial information at 16 17 years of age and then again six years later at 23, using paper and online questionnaires and standardised measures. Personality and family climate variables both predicted adult social support, with family cohesiveness and neuroticism having the largest roles. The possible implications for mental health promotion are discussed. PMID- 26232595 TI - Laying Futility to Rest. AB - In this essay I examine the formal structure of the concept of futility, enabling identification of the appropriate roles played by patient, professional, and society. I argue that the concept of futility does not justify unilateral decisions to forego life-sustaining medical treatment over patient or legitimate surrogate objection, even when futility is determined by a process or subject to ethics committee review. Furthermore, I argue for a limited positive ethical obligation on the part of health care professionals to assist patients in achieving certain restricted goals, including the preservation of life, even in circumstances in which most would agree that that life is of no benefit to the patient. Finally, I address the objection that professional integrity overrides this limited obligation and find the objection unconvincing. In short, my aim in this essay is to see the concept of futility finally buried, once and for all. PMID- 26232597 TI - Laparoscopic removal of gastric band after laparoscopic gastric bypass and following placement of adjustable gastric band. AB - Banded gastric bypass is a bariatric surgical intervention that has been regularly performed in many centers. According to some series, banded gastric bypass is safe and feasible. We describe the case of a 42-year-old woman undergoing laparoscopic gastric bypass in 2008. Subsequently, she underwent surgery in order to place adjustable gastric banding on previous bypass because of gastric pouch dilatation. Five months later, patient showed anorexia and signs of malnutrition. For this reason, she underwent laparoscopic removal of gastric banding. In our opinion, placing a device to restrict an already dilated gastric pouch must be avoided. PMID- 26232596 TI - Inflammatory group 2 innate lymphoid cells. AB - Group 2 innate lymphoid cells (ILC2 cells) are able to produce type 2 cytokines and to mediate type 2 immune protection and tissue homeostasis. ILC2 cells have often been considered to be a single set of cells that respond to IL-33 and/or IL 25. Recent evidence now indicates that ILC2 cells can be grouped into two distinct subsets: homeostatic or natural ILC2s (nILC2 cells); and inflammatory ILC2 cells (iILC2 cells). nILC2 cells reside in barrier tissues and primarily respond to IL-33. They play critical roles not only in immune protection but also in tissue repair and beige fat biogenesis. iILC2 cells are not present in peripheral tissues in the steady state but can be elicited at many sites by helminth infection or IL-25 treatment. IL-25-elicited ilLC2 cells act as transient ILC progenitors with multipotency. They can be mobilized by distinct types of infections to develop into nILC2-like or ILC3-like cells, functioning in corresponding immune responses. The demonstration of the existence of iILC2 cells adds to our understanding of the complexity of ILC2 biology and makes necessary an analysis of the relationship between nILC2 cells and iILC2 cells. PMID- 26232598 TI - Infected urinoma secondary to a ruptured renal calyx from a partial staghorn stone. AB - A urinoma is a collection of urine outside the urinary tract as a result of disruption of the collecting system. Obstructive causes of urine extravasation secondary to stones are not unseen but display a delayed diagnosis due to the gradual onset of symptoms, which can mimic pyelonephritis. We present the case of a 70-year-old female patient who was admitted to hospital with symptoms of right loin pain and sepsis. We describe her case from the initial clinical diagnosis of pyelonephritis to the final diagnosis of an infected urinoma after a calyceal rupture from an obstructive partial staghorn calculus. This case highlights the importance of early computerized tomography imaging in patients with renal stones and suspected pyelonephritis as ultrasound scans can sometimes be misleading. Misdiagnosis of infected urinomas delays definitive treatment and leads to increased morbidity. PMID- 26232599 TI - Acute and chronic acalculous cholecystitis associated with aortic dissection. AB - Acalculous cholecystitis is a rare but life-threatening disease, but its pathogenesis is not fully revealed yet. We experienced two acalculous cholecystitis cases associated with aortic dissection. In Case 1, acalculous cholecystitis occurred just after the exacerbation of the aortic dissection. Laparotomy showed necrotized cholecystitis with fresh thrombi formation. Case 2 developed acalculous cholecystitis on the 65th hospital day of aortic dissection. Laparotomy revealed the perforation of the gallbladder. Histological study revealed fibrosis and hemosiderosis in the subserosal layer. The histological findings of these two patients are quite different: Case 1 is acute ischemic and Case 2 is chronic ischemic. While a few cases of acute ischemic cholecystitis have been reported previously, chronic acalculous cholecystitis (CAC) has not been documented. History of aortic dissection could be a risk factor of acute and CAC due to relatively decreased splanchnic blood flow. PMID- 26232600 TI - Reply: To PMID 25805375. PMID- 26232602 TI - Featuring the special issue editor: Professor Alexandros G. Georgakilas. PMID- 26232601 TI - Prevention of Cystoid Macular Edema After Cataract Surgery in Nondiabetic and Diabetic Patients: A Systematic Review and Meta-Analysis. AB - PURPOSE: To evaluate the optimum medical strategy to prevent cystoid macular edema (CME) after cataract surgery. DESIGN: Systematic review and meta-analysis. METHODS: setting: Cochrane, MEDLINE, and EMBASE databases were searched to identify eligible randomized controlled trials (RCTs). STUDY POPULATION: RCTs comparing medical strategies to prevent CME after uncomplicated cataract surgery in nondiabetic and diabetic patients. OBSERVATION PROCEDURES: Data were extracted by 2 authors independently. Quality of individual RCTs was assessed using the Cochrane Collaboration's tool for assessing risk of bias and Delphi criteria. MAIN OUTCOME MEASURES: Odds of developing CME within 3 months postoperatively and foveal thickness, macular volume and corrected distance visual acuity change within 3 months postoperatively, as compared to baseline. RESULTS: Seventeen trials reported incidence rates. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) significantly reduced the odds of developing CME as compared to topical corticosteroids in nondiabetic (odds ratio [OR] 0.11; 95% confidence interval [95% CI] 0.03-0.37) and mixed populations (OR 0.05; 95% CI 0.02-0.11). A combination of topical corticosteroids and NSAIDs significantly reduced the odds of developing CME as compared to topical corticosteroids in nondiabetic (OR 0.21; 95% CI 0.10-0.44) and diabetic patients (OR 0.17; 95% CI 0.05-0.50). Intravitreal corticosteroid or anti-vascular endothelial growth factor injections did not show any additional benefit in diabetic subjects. CONCLUSIONS: Topical NSAIDs significantly reduced the odds of developing CME, as compared to topical corticosteroids, in nondiabetic and mixed populations. A combination of topical NSAIDs and corticosteroids reduced the odds of developing CME in nondiabetic and diabetic patients, as compared to topical corticosteroids. PMID- 26232603 TI - Highly Collapsed Conformation of the Initial Folding Intermediates of beta Lactoglobulin with Non-Native alpha-Helix. AB - In the folding of beta-lactoglobulin (betaLG), a predominantly beta-sheet protein, a transient intermediate possessing an excess amount of non-native alpha helix is formed within a few milliseconds. To characterize the early folding dynamics of betaLG in terms of secondary structure content and compactness, we performed submillisecond-resolved circular dichroism (CD) and small-angle X-ray scattering (SAXS) measurements. Time-resolved CD after rapid dilution of urea showed non-native alpha-helix formation within 200MUs. Time-resolved SAXS showed that the radius of gyration (R(g)) of the intermediate at 300 MUs was 23.3+/-0.7 A, indicating a considerable collapse from the unfolded state having R(g) of 35.1+/-7.1 A. Further compaction to R(g) of 21.2+/-0.3 A occurred with a time constant of 28+/-11 ms. Pair distribution functions showed that the intermediate at 300 MUs comprises a single collapsed domain with a small fluctuating domain, which becomes more compact after the second collapse. Kinetic measurements in the presence of 2,2,2-trifluoroethanol showed that the intermediate at several milliseconds possessed an increased amount of alpha-helix but similar R(g) of 23.0+/-0.8 A, suggesting similarity of the shape of the intermediate in different solvents. Consequently, the initial collapse occurs globally to a compact state with a small fluctuating domain irrespective of the non-native alpha-helical contents. The second collapse of the fluctuating domain occurs in accordance with the reported stabilization of the non-native helix around strand A. The non native helix around strand A might facilitate the formation of long-range contacts required for the folding of betaLG. PMID- 26232604 TI - Regulator of Calcineurin (RCAN-1) Regulates Thermotaxis Behavior in Caenorhabditis elegans. AB - Regulator of calcineurin (RCAN) is a calcineurin-interacting protein that inhibits calcineurin phosphatase when overexpressed, often upregulated under neuropathological conditions with impaired learning and memory processes, such as Down syndrome or Alzheimer's disease. Thermotactic behavior in the nematode Caenorhabditis elegans is a form of memory in which calcineurin signaling plays a pivotal role in the thermosensation of AFD neurons. In this study, we found that rcan-1 deletion mutants exhibited cryophilic behavior dependent on tax-6, which was rescued by expressing rcan-1 in AFD neurons. Interaction between RCAN-1 and TAX-6 requires the conserved PxIxIT motif of RCAN-1, without which thermotactic behavior could not be fully rescued. In addition, the loss of crh-1/CREB suppressed the thermotaxis phenotypes of rcan-1 and tax-6 mutants, indicating that crh-1 is crucial in thermotaxis memory in these mutants. Taken together, our results suggest that rcan-1 is an inhibitory regulator of tax-6 and that it acts in the formation of thermosensory behavioral memory in C. elegans. PMID- 26232606 TI - Collaborative research in light of the prevailing criteria for promotion and tenure in academia. PMID- 26232605 TI - Molecular biomarkers for prediction of response to treatment and survival in triple negative breast cancer patients from Egypt. AB - BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive phenotype of breast cancer with reduced survival and poor prognosis. Increased VEGF-A, IGF-I, IGF-IR and TGF-beta1 expressions were detected in breast cancer. However, little is known about their prognostic and predictive roles in TNBC. AIM: We assessed the possible prognostic and predictive values of VEGF-A, IGF-I/IGF-IR and TGF beta1 in TNBC cases by measuring their protein and mRNA expression in TNBC and non-TNBC cases. METHODS: VEGF-A, IGF-I, IGF-IR and TGF-beta1 RNA and their corresponding proteins were assessed in 43 TNBCs, 53 non-TNBCs and 30 normal breast tissues (NBT) by real time PCR (qPCR) and immunohistochemistry (IHC); respectively. Results were related to clinico-pathological factors, response to treatment and survival rates. RESULTS: Increased mRNA expression of VEGF-A, IGF I, and IGF-IR was significantly higher in TNBC (65.1%, 65.1%, and 72.1%) than non TNBC (28.1%, 33.96% and 28.3%) and NBT (0.00%) (P<0.001). Similarly, TNBC patients were significantly associated with high expression of VEGF-A, IGF-I, and IGF-IR proteins (67.44%, 62.79% and 83.72%) than non-TNBC (20.75%, 35.86% and 20.75%) and NBT (0.00%) (P<0.001). Protein and RNA expression levels of all studied markers showed high concordance in all investigated patients (correlation coefficient exceeding 0.5 and 0.4, respectively). In the TNBC group, metastasis and poor response to treatment were significantly associated with VEGF-A (P<0.001, P=0.007, respectively), IGF-I (P<0.001, P<0.001, respectively), IGF-IR (P=0.001, P=0.015, respectively) and TGF-beta1 (P<0.001, P=0.007, respectively) protein levels. Multivariate logistic regression showed that IGF-I was the only independent prognostic factor for reduced OS (P=0.034) and DFS (P=0.026) in the TNBC patients. CONCLUSIONS: VEGF-A, IGF-I and IGF-IR play an important role in the development and progression of TNBC compared to non-TNBC. Therefore, they could be used as prognostic and predictive biomarkers as well as candidates for targeted therapy. However, only IGF-I can predict survival in those patients. PMID- 26232607 TI - Impact of partial DAZ1/2 deletion and partial DAZ3/4 deletion on male infertility. AB - This study aims to investigate the effect of the partial DAZ1/2 deletion and partial DAZ3/4 deletion on male infertility through a comprehensive literature search. All case-control studies related to partial DAZ1/2 and DAZ3/4 deletions and male infertility risk were included in our study. Odd ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association and its precision, respectively. Eleven partial DAZ1/2 deletion and nine partial DAZ3/4 deletion studies were included. Partial DAZ1/2 deletion was significantly associated with male infertility risk in the overall analysis (ORs=2.58, 95%CI: 1.60-4.18, I(2)=62.1%). Moreover, in the subgroup analysis stratified by ethnicity, partial DAZ1/2 deletion was significantly associated with male infertility risk in the East Asian populations under the random effect model (ORs=2.96, 95%CI: 1.87-4.71, I(2)=51.3%). Meanwhile, the analysis suggested that partial DAZ3/4 deletion was not associated with male infertility risk in East Asian ethnicity (ORs=1.02, 95%CI: 0.54-1.92, I(2)=71.3%), but not in Non-East Asian under the random effect model (ORs=3.56, 95%CI: 1.13-11.23, I(2)=0.0%,). More interestingly, partial DAZ1/2 deletion was associated with azoospermia (ORs=2.63, 95%CI: 1.19-5.81, I(2)=64.7%) and oligozoospermia (ORs=2.53, 95%CI: 1.40-4.57, I(2)=51.8%), but partial DAZ3/4 deletion was not associated with azoospermia (ORs=0.71, 95%CI: 0.23-2.22, I(2)=71.7%,) and oligozoospermia (ORs=1.21, 95%CI: 0.65-2.24, I(2)=55.5%). In our meta-analysis, partial DAZ1/2 deletion is a risk factor for male infertility and different ethnicities have different influences, whereas partial DAZ3/4 deletion has no effect on fertility but partial DAZ3/4 deletion might have an impact on Non-East Asian male. PMID- 26232608 TI - Identification of gene variants related to the nitric oxide pathway in patients with acute coronary syndrome. AB - Dysfunction of vascular endothelium is known to have an essential role in the atherosclerotic process by releasing mediators including nitric oxide (NO). Nitric oxide maintains endothelial balance by controlling cellular processes of vascular smooth muscle cells. Evidence suggests that variations in the NO pathway could include atherosclerotic events. The objective of this study was to determine the possible effects of genes on the nitric oxide pathway in the development of acute coronary syndrome (ACS). The blood samples of 100 patients with ACS and 100 controls were collected at Istanbul University, Department of Cardiology. DNA samples were genotyped by using Illumina Cyto-SNP-12 BeadChip. The additive model and Correlation/Trend Test were selected for association analysis. Afterwards, a Q-Q graphic was drawn to compare expected and obtained values. A Manhattan plot was produced to display p-values that were generated by log10(P) function for each SNP. The p-values under 1*10(-4) were selected as statistically significant SNPs while p-values under 5*10(-2) were considered as suspicious biomarker candidates. Nitric oxide pathway analysis was then used to find the single nucleotide polymorphisms (SNPs) related to ACS. As a result, death-associated protein kinase 3 (DAPK) (rs10426955) was found to be most statistically significant SNP. The most suspicious biomarker candidates associated with the nitric oxide pathway analysis were vascular endothelial growth factor A (VEGFA), methionine sulfoxide reductase A (MSRA), nitric oxide synthase 1 (NOS1), and GTP cyclohydrolase I (GCH-1). Further studies with large sample groups are necessary to clarify the exact role of nitric oxide in the development of disease. PMID- 26232609 TI - High-accuracy haplotype imputation using unphased genotype data as the references. AB - Enormously growing genomic datasets present a new challenge on missing data imputation, a notoriously resource-demanding task. Haplotype imputation requires ethnicity-matched references. However, to date, haplotype references are not available for the majority of populations in the world. We explored to use existing unphased genotype datasets as references; if it succeeds, it will cover almost all of the populations in the world. The results showed that our HiFi software successfully yields 99.43% accuracy with unphased genotype references. Our method provides a cost-effective solution to breakthrough the bottleneck of limited reference availability for haplotype imputation in the big data era. PMID- 26232610 TI - Pre-heating of high-viscosity bulk-fill resin composites: effects on shrinkage force and monomer conversion. AB - OBJECTIVES: To investigate the influence of pre-heating of high-viscosity bulk fill composite materials on their degree of conversion and shrinkage force formation. METHODS: Four bulk-fill composite materials (Tetric EvoCeram Bulk Fill TECBF, x-tra fil-XF, QuixFil-QF, SonicFill-SF) and one conventional nano-hybrid resin composite (Tetric EvoCeram-TEC) were used. The test materials were either kept at room temperature or pre-heated to 68 degrees C by means of a commercial heating device, before being photoactivated with a LED curing unit for 20s at 1170mW/cm(2). Shrinkage forces (n=5) of 1.5-mm-thick specimens were recorded in real-time for 15min inside a temperature-controlled chamber at 25 degrees C (simulating intraoral temperature after rubber dam application) with a custom made stress analyzer. Degree of conversion (n=5) was determined at the bottom of equally thick (1.5mm) specimens using Fourier transform infrared spectroscopy. Data were analyzed with Student's t-test, ANOVA and Tukey's HSD post-hoc test (alpha=0.05). RESULTS: Composite pre-heating significantly increased the degree of conversion of TECBF, but had no effect on monomer conversion of the other materials investigated. For each of the test materials, pre-heated composite generated significantly lower shrinkage forces than room-temperature composite. At both temperature levels, TECBF created the significantly highest shrinkage forces, and QF caused significantly higher shrinkage forces than both XF and TEC. CONCLUSIONS: Both the composite material and the pre-cure temperature affect shrinkage force formation. Pre-heating of bulk-fill and conventional restorative composites prior to photoactivation decreases polymerization-induced shrinkage forces without compromising the degree of conversion. CLINICAL SIGNIFICANCE: Composite pre-heating significantly reduces shrinkage force formation of high viscosity bulk-fill and conventional resin composites, while maintaining or increasing the degree of monomer conversion, dependent upon the specific composite material used. PMID- 26232611 TI - A unified account of tilt illusions, association fields, and contour detection based on elastica. AB - As expressed in the Gestalt law of good continuation, human perception tends to associate stimuli that form smooth continuations. Contextual modulation in primary visual cortex, in the form of association fields, is believed to play an important role in this process. Yet a unified and principled account of the good continuation law on the neural level is lacking. In this study we introduce a population model of primary visual cortex. Its contextual interactions depend on the elastica curvature energy of the smoothest contour connecting oriented bars. As expected, this model leads to association fields consistent with data. However, in addition the model displays tilt-illusions for stimulus configurations with grating and single bars that closely match psychophysics. Furthermore, the model explains not only pop-out of contours amid a variety of backgrounds, but also pop-out of single targets amid a uniform background. We thus propose that elastica is a unifying principle of the visual cortical network. PMID- 26232612 TI - Motion parallax thresholds for unambiguous depth perception. AB - The perception of unambiguous depth from motion parallax arises from the neural integration of retinal image motion and extra-retinal eye movement signals. It is only recently that these parameters have been articulated in the form of the motion/pursuit ratio. In the current study, we explored the lower limits of the parameter space in which observers could accurately perform near/far relative depth-sign discriminations for a translating random-dot stimulus. Stationary observers pursued a translating random dot stimulus containing relative image motion. Their task was to indicate the location of the peak in an approximate square-wave stimulus. We measured thresholds for depth from motion parallax, quantified as motion/pursuit ratios, as well as lower motion thresholds and pursuit accuracy. Depth thresholds were relatively stable at pursuit velocities 5 20 deg/s, and increased at lower and higher velocities. The pattern of results indicates that minimum motion/pursuit ratios are limited by motion and pursuit signals, both independently and in combination with each other. At low and high pursuit velocities, depth thresholds were limited by inaccurate pursuit signals. At moderate pursuit velocities, depth thresholds were limited by motion signals. PMID- 26232613 TI - Sex, estradiol, and spatial memory in a food-caching corvid. AB - Estrogens significantly impact spatial memory function in mammalian species. Songbirds express the estrogen synthetic enzyme aromatase at relatively high levels in the hippocampus and there is evidence from zebra finches that estrogens facilitate performance on spatial learning and/or memory tasks. It is unknown, however, whether estrogens influence hippocampal function in songbirds that naturally exhibit memory-intensive behaviors, such as cache recovery observed in many corvid species. To address this question, we examined the impact of estradiol on spatial memory in non-breeding Western scrub-jays, a species that routinely participates in food caching and retrieval in nature and in captivity. We also asked if there were sex differences in performance or responses to estradiol. Utilizing a combination of an aromatase inhibitor, fadrozole, with estradiol implants, we found that while overall cache recovery rates were unaffected by estradiol, several other indices of spatial memory, including searching efficiency and efficiency to retrieve the first item, were impaired in the presence of estradiol. In addition, males and females differed in some performance measures, although these differences appeared to be a consequence of the nature of the task as neither sex consistently out-performed the other. Overall, our data suggest that a sustained estradiol elevation in a food-caching bird impairs some, but not all, aspects of spatial memory on an innate behavioral task, at times in a sex-specific manner. PMID- 26232614 TI - Two aromatase inhibitors inhibit the ability of a third to promote mating in male rats. AB - Aromatase, the enzyme that aromatizes androstenedione (A) to estrone and testosterone (T) to estradiol (E), affects androgen control of male sex behavior in many vertebrates. In male monkeys, rats and quail, E mimics the ability of T to promote mating, and aromatase inhibitors block mating induced by T but not E. Aromatase inhibitors include androgens with different A-rings than T and A, e.g., 1,4,6-androstatriene-3,17-dione (ATD), azoles, e.g., fadrozole, and androgens alpha-halogenated at carbon 6, e.g., 6alpha-bromoA, 6alpha-fluoroA and 6alpha fluoroT. 6alpha-FluoroT is the only 6alpha-halogenated androgen studied in regard to mating. It promotes mating in male rats and quail and was studied, before it was known to inhibit aromatase, because it cannot be aromatized yet has the same A-ring as T. 6alpha-FluoroT might promote mating by binding estrogen receptors (ER) directly, i.e., unassisted, or by metabolism to an androgen that binds ER. Since neither process would require aromatase, this study tested both hypotheses by determining how mating induced in castrated male rats by 6alpha-fluoroT is affected by ATD and fadrozole. Both aromatase inhibitors inhibited the effects of 6alpha-fluoroT on mating. Thus, 6alpha-fluoroT does not promote mating by direct ER binding or metabolism to another androgen. Since aromatase underlies a process in which 6alpha-fluoroT, unlike most nonaromatizable androgens, mimics T effects on male sex behavior, the process must involve a feature that 6alpha-fluoroT shares with T but not other nonaromatizable androgens. A-ring structure is a candidate. A hypothesis is also offered for how aromatase may participate without aromatizing the androgen. PMID- 26232616 TI - Ceramide generation during curcumin-induced apoptosis is controlled by crosstalk among Bcl-2, Bcl-xL, caspases and glutathione. AB - Curcumin exhibits anti-cancer properties manifested by activation of pro apoptotic signaling. We have demonstrated earlier that apoptosis of HL-60 human leukemia cells induced by curcumin is controlled by ceramide generated by neutral sphingomyelinase (nSMase) which contributes to sphingomyelin synthase (SMS) inhibition favoring accumulation of ceramide in cells. Here we report that the activity of nSMase, ceramide accumulation and death of HL-60 cells are inhibited by overexpression of Bcl-xL or Bcl-2 proteins, while down-regulation of nSMase interferes with degradation of Bcl-2 but not Bcl-xL. Activation of nSMase in curcumin-treated cells requires the activity of apoptosis initiator caspase-8 and executioner caspase-3, whereas nSMase depletion prevents activation of caspase-3, but not caspase-8. These data place nSMase activation downstream of caspase-8 and Bcl-xL and indicate a mutual regulation between nSMase and caspase-3 activity on one hand, and Bcl-2 level on the other hand in curcumin-treated cells. The activation of nSMase and ceramide accumulation also depended on the depletion of glutathione. The depletion of glutathione required the activity of caspase-8 and caspase-3 as well as the down-regulation of Bcl-2 and Bcl-xL. Together, the data indicate a crosstalk among Bcl-2, Bc-xL, caspases and glutathione during curcumin induced apoptosis and point to the superior role of caspase-8 activity, Bcl-xL down-regulation and glutathione depletion in the pro-apoptotic cascade leading to nSMase activation and generation of ceramide. PMID- 26232615 TI - Arginine vasopressin receptor signaling and functional outcomes in heart failure. PMID- 26232617 TI - Involvement of miR-34c in high glucose-insulted mesenchymal stem cells leads to inefficient therapeutic effect on myocardial infarction. AB - High glucose-insulted bone marrow-derived mesenchymal stem cells (BMCs) showed impaired angiogenesis along with downregulation of stem cell factor (SCF). This study was designed to determine the involvement of microRNAs (miR), which are actively involved in the physiological function of stem cells. We observed that miR-34c was significantly induced by high glucose treatment and blunted tube formation of BMCs. Stem cell factor (SCF) was confirmed as a target of miR-34c by 3'-UTR promoter analysis and Western blot. SCF knockdown by siRNA induced Kruppel like factor 4 (KLF4) and resulted in the blockade of angiogenesis of BMCs. Sequentially, KLF4 overexpression completely blocked tube formation through inducing PAI-1 (plasminogen activator inhibitor-1). To study the action of miR 34c in terms of the therapeutic potential of BMCs, myocardial infarction (MI) was induced by ligation of the coronary artery in nude mice, BMCs transfected with miR-control or miR-34c were injected into the infarcted myocardium 7 days later, and histological studies were performed 2 weeks later. Cardiac fibrosis was 18.24+/-4.7% in the miR-34c-BMC group and 10.01+/-0.2% in the miR-control-BMC group (p<0.05). Cardiac function and vessel density were decreased in the miR-34c BMC group compared with the miR-con-BMC group. Particularly, miR-34c-BMCs failed to incorporate into vessels. Our results show that the angiogenic activity of BMCs is finely regulated by the miR-34c-SCF-KLF4 axis, which is a potent translational target for optimizing the therapeutic activity of autologous BMCs for cardiac repair. PMID- 26232618 TI - Histidine-domain-containing protein tyrosine phosphatase regulates platelet derived growth factor receptor intracellular sorting and degradation. AB - Histidine domain-containing protein tyrosine phosphatase (HD-PTP) is a putative phosphatase that has been shown to affect the signaling and downregulation of certain receptor tyrosine kinases. To investigate if HD-PTP affects platelet derived growth factor receptor beta (PDGFRbeta) signaling, we employed the overexpression of HA-tagged HD-PTP, as well as siRNA-mediated and lentivirus shRNA-mediated silencing of HD-PTP in NIH3T3 cells. We found that HD-PTP was recruited to the PDGFRbeta in a ligand-dependent manner. Depletion of HD-PTP resulted in an inability of PDGF-BB to promote tyrosine phosphorylation of the ubiquitin ligases c-Cbl and Cbl-b, with a concomitant missorting and reduction of the degradation of activated PDGFRbeta. In contrast, ligand-induced internalization of PDGFRbeta was unaffected by HD-PTP silencing. Furthermore, the levels of STAM and Hrs of the ESCRT0 machinery were decreased, and immunofluorescence staining showed that in HD-PTP-depleted cells, PDGFRbeta accumulated in large aberrant intracellular structures. After the reduction of HD PTP expression, an NIH3T3-derived cell line that has autocrine PDGF-BB signaling (sis-3T3) showed increased ability of anchorage-independent growth. However, exogenously added PDGF-BB promoted efficient additional colony formation in control cells, but was not able to do so in HD-PTP-depleted cells. Furthermore, cells depleted of HD-PTP migrated faster than control cells. In summary, HD-PTP affects the intracellular sorting of activated PDGFRbeta and the migration, proliferation and tumorigenicity of cells stimulated by PDGF. PMID- 26232619 TI - Chronic cannabis use and ERP correlates of visual selective attention during the performance of a flanker go/nogo task. AB - The aim of the study was to investigate the relationship between chronic cannabis use and visual selective attention by examining event-related potentials (ERPs) during the performance of a flanker go/nogo task. Male participants were 15 chronic cannabis users (minimum two years use, at least once per week) and 15 drug naive controls. Cannabis users showed longer reaction times compared to controls with equivalent accuracy. Cannabis users also showed a reduction in the N2 'nogo effect' at frontal sites, particularly for incongruent stimuli, and particularly in the right hemisphere. This suggests differences between chronic cannabis users and controls in terms of inhibitory processing within the executive control network, and may implicate the right inferior frontal cortex. There was also preliminary evidence for differences in early selective attention, with controls but not cannabis users showing modulation of N1 amplitude by flanker congruency. Further investigation is required to examine the potential reversibility of these residual effects after long-term abstinence and to examine the role of early selective attention mechanisms in more detail. PMID- 26232620 TI - Neonatal abstinence syndrome: Historical perspective, current focus, future directions. AB - BACKGROUND: Neonatal abstinence syndrome (NAS) occurs following prenatal opioid exposure. It is characterized by signs and symptoms indicating central nervous system hyperirritability and autonomic nervous system, gastrointestinal tract, and respiratory system dysfunction. OBJECTIVE: This article: (1) briefly reviews NAS history, including initial identification, assessment, and treatment efforts; (2) summarizes the current status of and current issues surrounding recent NAS assessment and treatment, and (3) details future directions in NAS conceptualization, measurement, and treatment. RESULTS: Mortality rate estimates in neonates treated for NAS exceeded 33%, and surpassed 90% for un-treated infants during the late-1800s until the mid-1900s. The focus of both assessment and treatment over the past 50years is predominantly due to two forces. First, methadone pharmacotherapy for "heroin addiction" led to women in methadone maintenance programs who were, or became pregnant. The second was defining NAS and developing a measure of neonatal withdrawal, the Neonatal Abstinence Scoring System (NASS). Various NAS treatment protocols were based on the NASS as well as other NAS measures. CONCLUSIONS: Future research must focus on psychometrically sound screening and assessment measures of neonatal opioid withdrawal for premature, term and older infants, measuring and treating possible withdrawal from non-opioids, particularly benzodiazepines, integrated non-pharmacological treatment of NAS, weight-based versus symptom-based treatment of NAS, and second line treatment for NAS. PMID- 26232621 TI - Interlaboratory studies on in vitro test methods for estimating in vivo resorption of calcium phosphate ceramics. AB - A potential standard method for measuring the relative dissolution rate to estimate the resorbability of calcium-phosphate-based ceramics is proposed. Tricalcium phosphate (TCP), magnesium-substituted TCP (MgTCP) and zinc substituted TCP (ZnTCP) were dissolved in a buffer solution free of calcium and phosphate ions at pH 4.0, 5.5 or 7.3 at nine research centers. Relative values of the initial dissolution rate (relative dissolution rates) were in good agreement among the centers. The relative dissolution rate coincided with the relative volume of resorption pits of ZnTCP in vitro. The relative dissolution rate coincided with the relative resorbed volume in vivo in the case of comparison between microporous MgTCPs with different Mg contents and similar porosity. However, the relative dissolution rate was in poor agreement with the relative resorbed volume in vivo in the case of comparison between microporous TCP and MgTCP due to the superimposition of the Mg-mediated decrease in TCP solubility on the Mg-mediated increase in the amount of resorption. An unambiguous conclusion could not be made as to whether the relative dissolution rate is predictive of the relative resorbed volume in vivo in the case of comparison between TCPs with different porosity. The relative dissolution rate may be useful for predicting the relative amount of resorption for calcium-phosphate-based ceramics having different solubility under the condition that the differences in the materials compared have little impact on the resorption process such as the number and activity of resorbing cells. STATEMENT OF SIGNIFICANCE: The evaluation and subsequent optimization of the resorbability of calcium phosphate are crucial in the use of resorbable calcium phosphates. Although the resorbability of calcium phosphates has usually been evaluated in vivo, establishment of a standard in vitro method that can predict in vivo resorption is beneficial for accelerating development and commercialization of new resorbable calcium phosphate materials as well as reducing use of animals. However, there are only a few studies to propose such an in vitro method within which direct comparison was carried out between in vitro and in vivo resorption. We propose here an in vitro method based on measuring dissolution rate. The efficacy and limitations of the method were evaluated by international round-robin tests as well as comparison with in vivo resorption studies for future standardization. This study was carried out as one of Versailles Projects on Advanced Materials and Standards (VAMAS). PMID- 26232622 TI - Cholesterol - A putative endogenous contributor towards Parkinson's disease. AB - Elevated levels of cholesterol and its metabolites (oxysterols) have been reported to be associated not only with several metabolic syndromes, but also become a prognostic risk factor of neurodegenerative diseases particularly Alzheimer's disease. The incidence and the prospect of Alzheimer's disease with respect to elevated levels of cholesterol have been studied extensively and reviewed earlier. Recently, several interesting findings have shown the occurrence of equivalent Parkinsonian pathologies in cellular neuronal models, mediated by oxysterols or excess exposure to cholesterol. In this regard, oxysterols are particular in causing alpha-synuclein aggregation and destruction of dopamine containing neurons in in vitro models, which is linked to their direct influence on oxidative stress provoking potency. Inspite of the significant in vitro reports, which suggest the relativeness of cholesterol or oxysterol towards Parkinsonism, several prospective clinical reports provided a negative or no correlation. However, few prospective clinical studies showed a positive correlation between plasma cholesterol and incidence of Parkinson's disease (PD). Also, few significant studies have convincingly demonstrated that high fat diet exacerbates parkinsonian pathologies, including loss of dopaminergic neurons and oxidative stress parameters in animal models of PD. The present review brings together all the neuropathological proceedings mediated by excess cholesterol or its metabolites in brain in the light of their contribution towards the onset of PD. Also we have reviewed the possibilities of cholesterol lowering efficacy of statin therapy, in reducing the occurrence of PD. PMID- 26232623 TI - Edaravone leads to proteome changes indicative of neuronal cell protection in response to oxidative stress. AB - Neuronal cell death, in neurodegenerative disorders, is mediated through a spectrum of biological processes. Excessive amounts of free radicals, such as reactive oxygen species (ROS), has detrimental effects on neurons leading to cell damage via peroxidation of unsaturated fatty acids in the cell membrane. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) has been used for neurological recovery in several countries, including Japan and China, and it has been suggested that Edaravone may have cytoprotective effects in neurodegeneration. Edaravone protects nerve cells in the brain by reducing ROS and inhibiting apoptosis. To gain further insight into the cytoprotective effects of Edaravone against oxidative stress condition we have performed comparative two-dimensional gel electrophoresis (2DE)-based proteomic analyses on SH-SY5Y neuroblastoma cells exposed to oxidative stress and in combination with Edaravone. We showed that Edaravone can reverse the cytotoxic effects of H2O2 through its specific mechanism. We observed that oxidative stress changes metabolic pathways and cytoskeletal integrity. Edaravone seems to reverse the H2O2-mediated effects at both the cellular and protein level via induction of Peroxiredoxin-2. PMID- 26232624 TI - Fast endocytic recycling determines TRPC1-STIM1 clustering in ER-PM junctions and plasma membrane function of the channel. AB - Stromal interaction molecule 1 (STIM1) senses depletion of ER-Ca2+ store and clusters in ER-PM junctions where it associates with and gates Ca2+ influx channels, Orai1 and TRPC1. Clustering of TRPC1 with STIM1 and Orai1 in these junctions is critical since Orai1-mediated Ca2+ entry triggers surface expression of TRPC1 while STIM1 gates the channel. Thus, plasma membrane function of TRPC1 depends on the delivery of the channel to the sites where STIM1 puncta are formed. This study examines intracellular trafficking mechanism(s) that determine plasma membrane expression and function of TRPC1 in cells where Orai1 and TRPC1 are endogenously expressed and contribute to Ca2+ entry. We report that TRPC1 is internalized by Arf6-dependent pathway, sorted to Rab5-containing early endosomes, and trafficked to ER-PM junctions by Rab4-dependent fast recycling. Overexpression of Arf6, or Rab5, but not the respective dominant negative mutants, induced retention of TRPC1 in early endosomes and suppressed TRPC1 function. Notably, cells expressing Arf6 or Rab5 displayed an inwardly rectifying ICRAC current that is mediated by Orai1 instead of TRPC1-associated ISOC, demonstrating that Orai1 function was not altered. Importantly, expression of Rab4, but not STIM1, with Rab5 rescued surface expression and function of TRPC1, restoring generation of ISOC. Together, these data demonstrate that trafficking via fast recycling endosomes determines TRPC1-STIM1 clustering within ER-PM junctions following ER-Ca2+ store depletion which is critical for the surface expression and function of the channel. Ca2+ influx mediated by TRPC1 modifies Ca2+-dependent physiological response of cells. PMID- 26232626 TI - Cancer serum biomarkers based on aberrant post-translational modifications of glycoproteins: Clinical value and discovery strategies. AB - Due to the increase in life expectancy in the last decades, as well as changes in lifestyle, cancer has become one of the most common diseases both in developed and developing countries. Early detection remains the most promising approach to improve long-term survival of cancer patients and this may be achieved by efficient screening of biomarkers in biological fluids. Great efforts have been made to identify specific alterations during oncogenesis. Changes at the cellular glycosylation profiles are among such alterations. The "glycosylation machinery" of cells is affected by malignant transformation due to the altered expression of glycogens, leading to changes in glycan biosynthesis and diversity. Alterations in the post-translational modifications of proteins that occur in cancer result in the expression of antigenically distinct glycoproteins. Therefore, these aberrant and cancer-specific glycoproteins and the autoantibodies that are produced in response to their presence constitute targets for cancer biomarkers' search. Different strategies have been implemented for the discovery of cancer glycobiomarkers and are herein reviewed, along with their potentialities and limitations. Practical issues related with serum analysis are also addressed, as well as the challenges that this area faces in the near future. PMID- 26232627 TI - Methanol extracts of Xanthium sibiricum roots inhibit inflammatory responses via the inhibition of nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) in murine macrophages. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Xanthium sibiricum has been used as a traditional Chinese medicine for the treatment of appendicitis, bronchitis, arthritis, and other inflammatory ailments. However, its pharmacological activity related to an anti-inflammatory effect remain unknown. This present study aims to investigate the anti-inflammatory effect of methanol extracts of X. sibiricum roots (MXS), and to further determine its underlying mechanism of action in order to assess the medicinal value of X. sibiricum roots. MATERIALS AND METHODS: To assess the anti-inflammatory activity of MXS in lipopolysaccharides (LPS)-stimulated RAW 264.7 macrophages, the production of nitric oxide (NO) was measured using the Griess reagent system. The levels of pro-inflammatory cytokines and mediators were quantified using an Enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR). Subsequently, immunoblotting analyses were employed to detect inflammatory mediators as well as to elucidate the underlying regulatory mechanisms suppressed by MXS. RESULTS: MXS inhibited LPS-stimulated NO production and inducible nitric oxide synthase (iNOS) expression in RAW 264.7 macrophages within the non-cytotoxic concentration range (50-400 MUg/ml). In addition, mRNA and protein levels of pro-inflammatory cytokines such as interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF) alpha were significantly suppressed by MXS at the concentration of 400 MUg/ml. Furthermore, MXS (200 MUg/ml) clearly reduced the phosphorylation levels of the inhibitor of kappa Balpha (IkappaBalpha) and signal transducer and activator of transcription 3 (STAT3), without affecting changes in the phosphorylation levels of mitogen-activated protein kinases (MAPKs). When five major components (betulin, betulinic acid, beta-sitosterol, stigmasterol, and scopoletin) of MXS were separately investigated, stigmasterol and beta-sitosterol seemed to play major inhibitory roles in the LPS-induced production of inflammatory mediators such as NO, IL-6, and TNF-alpha. CONCLUSION: Our results demonstrate that MXS has an anti-inflammatory property in LPS-stimulated RAW 264.7 macrophages, and its anti-inflammatory activity is exerted by the regulation of nuclear factor-kappaB (NF-kappaB) and STAT3 signaling pathways. PMID- 26232625 TI - SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans. AB - The mammalian Nrf/CNC proteins (Nrf1, Nrf2, Nrf3, p45 NF-E2) perform a wide range of cellular protective and maintenance functions. The most thoroughly described of these proteins, Nrf2, is best known as a regulator of antioxidant and xenobiotic defense, but more recently has been implicated in additional functions that include proteostasis and metabolic regulation. In the nematode Caenorhabditis elegans, which offers many advantages for genetic analyses, the Nrf/CNC proteins are represented by their ortholog SKN-1. Although SKN-1 has diverged in aspects of how it binds DNA, it exhibits remarkable functional conservation with Nrf/CNC proteins in other species and regulates many of the same target gene families. C. elegans may therefore have considerable predictive value as a discovery model for understanding how mammalian Nrf/CNC proteins function and are regulated in vivo. Work in C. elegans indicates that SKN-1 regulation is surprisingly complex and is influenced by numerous growth, nutrient, and metabolic signals. SKN-1 is also involved in a wide range of homeostatic functions that extend well beyond the canonical Nrf2 function in responses to acute stress. Importantly, SKN-1 plays a central role in diverse genetic and pharmacologic interventions that promote C. elegans longevity, suggesting that mechanisms regulated by SKN-1 may be of conserved importance in aging. These C. elegans studies predict that mammalian Nrf/CNC protein functions and regulation may be similarly complex and that the proteins and processes that they regulate are likely to have a major influence on mammalian life- and healthspan. PMID- 26232628 TI - Medicinal plants used by Burundian traditional healers for the treatment of microbial diseases. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Infectious diseases represent a serious and worldwide public health problem. They lead to high mortality, especially in non developed countries. In Burundi, the most frequent infectious diseases are skin and respiratory (mainly in children) infections, diarrhea, added to malaria, HIV/AIDS and tuberculosis. Local population used mostly traditional herbal medicines, sometimes animal and mineral substances, to fight against these plagues. OBJECTIVES: To survey in different markets and herbal shops in Bujumbura city, medicinal plants sold to treat microbial infections, with particular emphasis on the different practices of traditional healers (THs) regarding plant parts used, methods of preparation and administration, dosage and treatment duration. MATERIALS AND METHODS: The ethnobotanical survey was conducted by interviewing, using a pre-set questionnaire, sixty representative healers, belonging to different associations of THs approved and recognised by the Ministry of Health. Each interviewed herbalist also participated in the collection of samples and the determination of the common names of plants. The plausibility of recorded uses has been verified through an extensive literature search. RESULTS: Our informants enabled us to collect 155 different plant species, distributed in 51 families and 139 genera. The most represented families were Asteraceae (20 genera and 25 species), Fabaceae (14 genera and 16 species), Lamiaceae (12 genera and 15 species), Rubiaceae (9 genera and 9 species), Solanaceae (6 genera and 6 species) and Euphorbiaceae (5 genera and 6 families). These plants have been cited to treat 25 different alleged symptoms of microbial diseases through 271 multi-herbal recipes (MUHRs) and 60 mono-herbal recipes (MOHRs). Platostoma rotundifolium (Briq.) A. J. Paton (Lamiaceae), the most cited species, has been reported in the composition of 41 MUHRs, followed by Virectaria major (Schum.) Verdc (Rubiaceae, 39 recipes), Kalanchoe crenata (Andrews) Haw. (Crassulaceae, 37 recipes), Stomatanthes africanus (Oliv. & Hiern) R. M. King & H. Rob. (35 recipes), and Helichrysum congolanum Schltr. & O. Hoffm. (Asteraceae, 33 recipes). Regarding MOHRs, Pentas longiflora Oliv. (Rubiaceae) is the most important species with 19 recipes, followed by Kalanchoe crenata (Andrews) Haw. (Crassulaceae, 10 recipes), Gymnosporia senegalensis (Lam.) Loes. (Celastraceae, 9 recipes), Tetradenia riparia (Hochst.) Codd (Lamiaceae, 8 recipes) and Cardiospermum halicacabum L. (Sapindaceae, 6 recipes). Concerning the preparation and administration of recipes, our informants state to be able to adjust the doses based on the patient's age (child or adult) and/or his/her physiology (e.g. pregnancy). CONCLUSION: This study indicates that medicinal plants are still widely used for the treatment of microbial diseases in Bujumbura city. However, there is much to do in this area, especially in the assessment and monitoring of the quality, effectiveness and safety of the different recipes preconised by Burundian traditional healers. PMID- 26232629 TI - Proteomics approach to analyze protein profiling related with ADME/Tox in rat treated with Scutellariae radix and Coptidis rhizoma as well as their compatibility. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Scutellariae radix (Scutellaria baicalensis Georgi) and Coptidis rhizoma (Coptis chinensis Franch), known as traditional Chinese medicine (TCM), have been widely used with the effects of suppressing fever, dispelling dampness, purging fire and removing toxicosis. Owing to their unimaginable complexity, it is difficult to understand their pharmacokinetic properties in detail. The aim of this study was to develop an optimal proteomics approach to analyze the protein profiling related with ADME/Tox in rat liver treated with S. radix and C. rhizoma as well as their compatibility. MATERIALS AND METHODS: Male rats were respectively administered the extracts of S. radix, C. rhizoma and their mixture for 7 days, and their liver tissue samples were prepared for the comparative proteomic analysis. The significantly differentially expressed proteins between the experimental groups and the control group were found and identified by 2-DE and MALDI-TOF-MS analyses. To validate the proteomic analysis results, glutathion peroxidase, catalase and betaine homocysteine methyl transferase were selected and confirmed by western blotting. RESULTS: Seventy eight significantly differentially expressed proteins between the experimental groups and the control group were found and identified. By querying the relational databases, the identified differentially expressed proteins were summarized and classified into three groups, phase I drug metabolic enzymes, phase II drug metabolic enzymes and the rest proteins which mainly involve in energy metabolism, signal transduction and cytoskeleton. These proteins involved in ADME/Tox may be the targets for metabolic studies or markers for toxicity. CONCLUSIONS: Our findings indicated S. radix and C. rhizoma as well as their compatibility can assuredly influence the expression of the proteins in rat liver. After administration, the majority of these expressions presented a downward trend, which may be closely related to the pharmacological properties of the medicine. The method in this study may open up a new road for the complementary tests for ADME/Tox properties of S. radix and C. rhizoma as well as their compatibility. PMID- 26232630 TI - Disseminated Talaromyces marneffei and Mycobacterium intracellulare coinfection in an HIV-infected patient. AB - A 25-year-old man with human immunodeficiency virus (HIV) infection presented with fever that had lasted 1 month. The CD4+ T lymphocyte count was 7 cells/MUL and computed tomography showed several small lung nodules, splenomegaly, and multiple lymphadenopathy. Talaromyces marneffei was isolated in the initial blood cultures. As the fever persisted despite clearance of fungemia and 10 days of liposomal amphotericin B treatment, cervical lymph node fine-needle aspiration was performed. Mycobacterium intracellulare was isolated from sputum and neck node aspiration cultures. The patient was successfully treated with liposomal amphotericin B, clarithromycin, and ethambutol in addition to antiretroviral therapy. This case suggests that we should consider coinfection of opportunistic pathogens in febrile immunosuppressed patients if the patient does not respond properly to the initial treatment. PMID- 26232631 TI - Comparison of transcriptomic responses to pancreas disease (PD) and heart and skeletal muscle inflammation (HSMI) in heart of Atlantic salmon (Salmo salar L). AB - Pancreas disease (PD) and heart and skeletal muscle inflammation (HSMI) are viral diseases associated with SAV (salmonid alphavirus) and PRV (piscine reovirus), which induce systemic infections and pathologies in cardiac and skeletal muscle tissue of farmed Atlantic salmon (Salmo salar L), resulting in severe morbidity and mortality. While general features of the clinical symptoms and pathogenesis of salmonid viral diseases are relatively well studied, much less is known about molecular mechanisms associated with immunity and disease-specific changes. In this study, transcriptomic analyses of heart tissue from PD and HSMI challenged Atlantic salmon were done, focusing on the mature phases of both diseases at respectively 28-35 and 42-77 days post infection. A large number of immune genes was activated in both trials with prevalence of genes associated with early innate antiviral responses, their expression levels being slightly higher in PD challenged fish. Activation of the IFN axis was in parallel with inflammatory changes that involved diverse humoral and cellular factors. Adaptive immune response genes were more pronounced in fish with HSMI, as suggested by increased expression of a large number of genes associated with differentiation and maturation of B lymphocytes and cytotoxic T cells. A similar down-regulation of non-immune genes such as myofiber and mitochondrial proteins between diseases was most likely reflecting myocardial pathology. A suite of genes important for cardiac function including B-type natriuretic peptide and four neuropeptides displayed differential expression between PD and HSMI. Comparison of results revealed common and distinct features and added to the understanding of both diseases at their mature phases with typical clinical pictures. A number of genes that showed disease-specific changes can be of interest for diagnostics. PMID- 26232632 TI - Sources and human exposure implications of concentrations of organophosphate flame retardants in dust from UK cars, classrooms, living rooms, and offices. AB - Concentrations of a number of organophosphate flame retardants (PFRs) were measured in floor dust collected from UK living rooms (n = 32), cars (n = 21), school and child daycare centre classrooms (n = 28), and offices (n = 61). While concentrations were overall broadly within the range of those reported previously for North America, Japan, and other European countries, median concentrations of TCIPP in all UK microenvironments exceeded those reported elsewhere in the world. Moreover, concentrations of TCIPP and TDCIPP in 2 UK car dust samples were--at 370 MUg g(-1) and 740 MUg g(-1) respectively--amongst the highest reported globally in indoor dust to date. Consistent with this, concentrations of TDCIPP in dust from UK cars exceed significantly those detected in the other microenvironments studied. Concentrations of EHDPP were shown for the first time to be significantly higher in classroom dust than in samples from other microenvironments. When compared to concentrations of PBDEs determined previously in the classroom dust samples; concentrations of all target PFRs exceeded substantially those of those PBDEs that are the principal constituents of the Penta- and Octa-BDE formulations. Moreover, while mass-based concentrations of BDE-209 exceeded those of most of our target PFRs, they still fell below those of TCIPP and EHDPP. In line with a previous observation in Sweden that indoor air contamination with TNBP was significantly lower in newer buildings; concentrations of TNBP in classroom dust were significantly higher in older compared to more recently-constructed schools. Consistent with the reported extensive use of TCIPP and TDCIPP in polyurethane foam, the highest concentrations of both TCIPP and TDCIPP in the classrooms studied, were observed in rooms containing the highest numbers of foam chairs (n = 31 and 18 respectively). Exposure to PFRs of both adults and young children via ingestion of indoor dust was estimated. While even our high-end exposure estimate for young children was ~100 times lower than one previously reported health-based limit (HBLV) value for TCIPP; the margin of safety was only 5-fold when compared to another HBLV for this contaminant. PMID- 26232633 TI - Life-cycle and genetic characterization of Astiotrema odhneri Bhalerao, 1936 sensu Cho & Seo 1977 from the Primorsky Region (Russian Far East). AB - Adult Astiotrema odhneri Bhalerao, 1936 sensu Cho & Seo 1977 were found in the intestine of a freshwater turtle, Pelodiscus sinensis (Wiegmann), from the Komissarovka River Basin, Primorsky Region, Russia. It was established that the first intermediate host of this parasite is a snail, Anisus centrifugops, and that the second intermediate hosts include the snails, Helicorbis sujfunensis and A. centrifugops, tadpoles of the frog Rana dybowskii, and the fish Perccottus glenii. The development of A. odhneri includes the formation of sporocyst and xiphidiocercariae, which is typical for species belonging to Plagiorchioidea. Phylogenetic analysis based on 28S rRNA gene sequences showed that A. odhneri, together with Astiotrema monticellii, form a monophyletic clade that was closer to Opisthorchioidea than to any other taxon represented in the tree. However, phylogenetic analysis without outgroup taxon indicated a high degree of differentiation of Astiotrema from both Plagiorchioidea and Opisthorchioidea. PMID- 26232634 TI - Host cytoplasmic processing bodies assembled by Trypanosoma cruzi during infection exert anti-parasitic activity. AB - Processing bodies (PBs) are cytoplasmic granules containing mRNAs and proteins involved in translation and degradation of mRNAs. PBs are constitutively present in cells and are induced to accumulate when external stressors including microbial infection are applied to cells, followed by a rapid translational arrest. We have examined the impact of Trypanosoma cruzi (T. cruzi, Tc) infection on host cytoplasmic PB assembly. Within 24h post-infection, we found the average number of PB foci per cell increased by more than 2-fold. Protein levels of PB components were unaltered during infection. These results indicated that Tc infection caused accumulation of PBs by changing the localization pattern of PB protein components. To elucidate the role of the accumulated PBs on Tc infection, we knocked down PBs using a siRNA specific for PB components EDC4 and Lsm14A, which are involved in mRNA decapping and translational repression, respectively. We observed that the inhibition of PB accumulation significantly enhanced the infectivity and growth of intracellular amastigotes. Depletion of PBs did not affect nitric oxide (NO) production during Tc infection, indicating that the growth promotion was not caused by modulation of NO-mediated killing of Tc. Our results suggest that the accumulated PBs partially contribute to anti-parasitic responses by manipulating the host's mRNA metabolism. PMID- 26232635 TI - Synthesis, metabolism, and biological activity of 2-[3-(tetrazolyl)propyl] 1alpha,25-dihydroxy-19-norvitamin D3. AB - Recently, we found that 2alpha-[2-(tetrazol-2-yl)ethyl]-1alpha,25 dihydroxyvitamin D3 showed higher osteocalcin promoter transactivation activity in human osteosarcoma (HOS) cells and a greater therapeutic effect in ovariectomized (OVX) rats in vivo than those of active vitamin D3, 1alpha,25(OH)2D3. We were interested in introducing a heterocyclic ring to the C2 position of the seco-steroidal structure via an alkyl linker, and four novel C2 (3-tetrazolylpropyl) substituted 1alpha,25-dihydroxy-19-norvitamin D3 analogs, 2alpha-[3-(tetrazol-1-yl)propyl]-, 2beta-[3-(tetrazol-1-yl)propyl]-, 2alpha-[3 (tetrazol-2-yl)propyl]-, and 2beta-[3-(tetrazol-2-yl)propyl]-19-nor 1alpha,25(OH)2D3 were synthesized. Among them, 2alpha-[3-(tetrazol-1-yl)propyl] 19-nor-1alpha,25(OH)2D3 showed weak binding affinity for human vitamin D receptor (hVDR) (2.6% of 1alpha,25(OH)2D3 and ca. 15% of 19-nor-1alpha,25(OH)2D3) and weak VDR transactivation activity in HOS cells (EC50 7.3nM, when 1alpha,25(OH)2D30.23nM). Although the other three compounds could not act as VDR binders by evaluation of the competition assays, 2alpha-[3-(tetrazol-2-yl)propyl] 19-nor-1alpha,25(OH)2D3 showed weak transactivation activity (EC50 12.5nM). Metabolic stability of the 2alpha-substituted compounds 2alpha-[3-(tetrazol-1 yl)propyl]- and 2alpha-[3-(tetrazol-2-yl)propyl]-19-nor-1alpha,25(OH)2D3 was higher than that of the 2beta-substituted counterparts 2beta-[3-(tetrazol-1 yl)propyl]- and 2beta-[3-(tetrazol-2-yl)propyl]-19-nor-1alpha,25(OH)2D3 against human CYP24A1. Introduction of a tetrazole ring to the C2-position of the 19 norvitamin D3 skeleton with the propyl linker led to weak VDR agonistic activity with stability against CYP24A1 metabolism. PMID- 26232636 TI - Perspectives in steroid research. PMID- 26232638 TI - Body Mass Index Does Not Predict Mortality After Left Ventricular Assist Device Implantation. PMID- 26232637 TI - Forkhead box O transcription factors in chondrocytes regulate endochondral bone formation. AB - The differentiation of embryonic mesenchymal cells into chondrocytes and the subsequent formation of a cartilaginous scaffold that enables the formation of long bones are hallmarks of endochondral ossification. During this process, chondrocytes undergo a remarkable sequence of events involving proliferation, differentiation, hypertrophy and eventually apoptosis. Forkhead Box O (FoxO) transcription factors (TFs) are well-known regulators of such cellular processes. Although FoxO3a was previously shown to be regulated by 1,25-dihydroxyvitamin D3 in osteoblasts, a possible role for this family of TFs in chondrocytes during endochondral ossification remains largely unstudied. By crossing Collagen2-Cre mice with FoxO1lox/lox;FoxO3alox/lox;FoxO4lox/lox mice, we generated mice in which the three main FoxO isoforms were deleted in growth plate chondrocytes (chondrocyte triple knock-out; CTKO). Intriguingly, CTKO neonates showed a distinct elongation of the hypertrophic zone of the growth plate. CTKO mice had increased overall body and tail length at eight weeks of age and suffered from severe skeletal deformities at older ages. CTKO chondrocytes displayed decreased expression of genes involved in redox homeostasis. These observations illustrate the importance of FoxO signaling in chondrocytes during endochondral ossification. PMID- 26232639 TI - Positive allosteric modulators of alpha 7 nicotinic acetylcholine receptors reverse ketamine-induced schizophrenia-like deficits in rats. AB - Alpha 7 nicotinic acetylcholine receptors (alpha7-nAChRs) have generated great interest as targets of new pharmacological treatments for cognitive dysfunction in schizophrenia. One promising recent approach is based on the use of positive allosteric modulators (PAMs) of alpha7-nAChRs, which demonstrate several advantages over direct agonists. Nevertheless, the efficacy of these newly introduced alpha7-nAChR agents has not been extensively characterised in animal models of schizophrenia. The aim of the present study was to evaluate the efficacy of type I and II PAMs, N-(5-chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3 isoxazolyl)urea (PNU-120596) and N-(4-chlorophenyl)-[[(4 chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide (CCMI), respectively, and galantamine, an acetylcholinesterase inhibitor (AChE) that also allosterically modulates nAChRs, against ketamine-induced cognitive deficits and social withdrawal in rats. The orthosteric alpha7-nAChR agonist octahydro-2 methyl-5-(6-phenyl-3-pyridazinyl)-pyrrolo[3,4-c]pyrrole (A-582941) was used as a positive control. Additionally, the antipsychotic activities of the tested compounds were assessed using the conditioned avoidance response (CAR) test. PNU 120596, CCMI, galantamine and A-582941 reversed ketamine-induced cognitive inflexibility, as assessed in the attentional set-shifting task (ASST). The tested compounds were also effective against ketamine-induced impairment in the novel object recognition task (NORT). PNU-120596, CCMI, and A-582941 ameliorated ketamine-induced social interaction deficits, whereas galantamine was ineffective. Moreover, all tested compounds selectively suppressed the CAR. The positive allosteric modulation of alpha7-nAChRs demonstrates preclinical efficacy not only against schizophrenia-like cognition impairments but also positive and negative symptoms. Therefore, the use of alpha7-nAChR PAMs as a potential treatment strategy in schizophrenia is supported. PMID- 26232640 TI - The emerging pharmacology and function of GPR35 in the nervous system. AB - G protein-coupled receptor 35 (GPR35) is an orphan G protein-coupled receptor (GPCR) that can be activated by kynurenic acid at high micromolar concentrations. A previously unappreciated mechanism of action of GPR35 has emerged as a Galphai/o-coupled inhibitor of synaptic transmission, a finding that has significant implications for the accepted role of kynurenic acid as a broad spectrum antagonist of the NMDA, AMPA/kainite and alpha7 nicotinic receptors. In conjunction with previous findings that link agonism of GPR35 with significant reduction in nociceptive pain, GPR35 has emerged as a potential effector of regulation of mechanical sensitivity and analgesia of the Ret tyrosine kinase, and as a receptor involved in the transmission of anti-inflammatory effects of aspirin- potentially through affecting leucocyte rolling, adhesion and extravasation. Single nucleotide polymorphisms of GPR35 have linked this receptor to coronary artery calcification, inflammatory bowel disease and primary sclerosing cholangitis, while chromosomal aberrations of the 2q37.3 locus and altered copy number of GPR35 have been linked with autism, Albight's hereditary osteodystrophy-like syndrome, and congenital malformations, respectively. Herein, we present an update on both the pharmacology and potential function of GPR35, particularly pertaining to the nervous system. This review forms part of a special edition focussing on the role of lipid-sensing GPCRs in the nervous system. This article is part of the Special Issue entitled 'Lipid Sensing G Protein-Coupled Receptors in the CNS'. PMID- 26232641 TI - Hemorrhagic shock-induced cerebral bioenergetic imbalance is corrected by pharmacologic treatment with EF24 in a rat model. AB - Maintenance of cerebral viability and function is an important goal of critical care in victims of injury due to ischemia and hypovolemia. As part of the multiple organ dysfunction syndrome, the brain function after trauma is influenced by the systemic inflammatory response. We investigated the effect of EF24, an anti-inflammatory bis-chalcone, on cerebral bioenergetics in a rat model of 45% hemorrhagic shock. The rats were treated with EF24 (0.4 mg/kg) or EF24 with an artificial oxygen carrier liposome-encapsulated hemoglobin (LEH). The volume of LEH administered was equal to the shed blood. The brain was collected after 6 h of shock for biochemical assays. EF24 treatment showed significant recovery of ATP, phosphocreatine, and NAD/NADH ratio. It also increased citrate synthase activity and cytochrome c oxidase subunit IV expression which were reduced in shock brain. Furthermore, it reduced the shock-induced accumulation of pyruvate and pyruvate dehydrogenase kinase-1 expression, suggesting that EF24 treatment improves cerebral energetics by restoring perturbed pyruvate metabolism in the mitochondria. These effects of EF24 were associated with reduced poly(ADP ribose) polymerase cleavage and a significant improvement in the levels of nerve growth factor and brain-derived neurotrophic factor in shock brain. Co administration of LEH with EF24 was only marginally more effective as compared to the treatment with EF24 alone. These results show that EF24 treatment sets up a pro-survival phenotype in shock by resurrecting cerebral bioenergetics. Since EF24 was effective in the absence of accompanying fluid resuscitation, it has potential utility as a pre-hospital pharmacotherapy in shock due to accidental blood loss. PMID- 26232642 TI - In adult female hamsters hypothyroidism stimulates D1 receptor-mediated breathing without altering D1 receptor expression. AB - Hypothyroidism affects cardiopulmonary regulation and function of dopaminergic receptors. Here we evaluated effects of 5 months of hypothyroidism on dopamine D1 receptor modulation of breathing in female hamsters using a D1 receptor antagonist SCH 23390. Euthyroid hamsters (EH) served as controls. Results indicated that hypothyroid female hamsters (HH) exhibited decreased body weights and minute ventilation (VE) following hypoxia due to decreased frequency of breathing (F). Moreover, SCH 23390 administration in HH increased VE by increasing tidal volume during exposure to air, hypoxia and following hypoxia. Relative to vehicle, SCH 23390 treatment decreased body temperature and hypoxic VE responsiveness in both groups. In EH, SCH 23390 decreased F in air, hypoxia and post hypoxia, and VE during hypoxia trended to decrease (P=0.053). Finally, expression of D1 receptor protein was not different between the two groups in any region evaluated. Thus, hypothyroidism in older female hamsters affected D1 receptor modulation of ventilation differently relative to euthyroid animals, but not expression of D1 receptors. PMID- 26232644 TI - Receptor protein kinase FERONIA controls leaf starch accumulation by interacting with glyceraldehyde-3-phosphate dehydrogenase. AB - Cell expansion is coordinated by several cues, but available energy is the major factor determining growth. Receptor protein kinase FERONIA (FER) is a master regulator of cell expansion, but the details of its control mechanisms are not clear. Here we show that FER interacts with cytosolic enzyme glyceraldehyde-3 phosphate dehydrogenase (GAPDH, GAPC1 and GAPC2), that catalyzes a key reaction in glycolysis, which contributes to energy production. When there is an FER deficiency, there are corresponding decreases in the enzyme activity of GAPDH and increased amounts of starch. More importantly, gapc1/2 mutants mimic fer4 mutants. These data indicate that FER regulated starch content is an evolutionarily conserved function in plants that connects the cell expansion and energy metabolism pathways. PMID- 26232643 TI - Expression of adenosine receptors in monocytes from patients with bronchial asthma. AB - Adenosine is generated from adenosine triphosphate, which is released by stressed and damaged cells. Adenosine levels are significantly increased in patients with bronchial asthma (BA) and mediate mast cell degranulation and bronchoconstriction. Over the last decade, increasing evidence has shown that adenosine can modulate the innate immune response during monocytes differentiation towards mature myeloid cells. These adenosine-differentiated myeloid cells, characterized by co-expression of monocytes/macrophages and dendritic cell markers such as CD14 and CD209, produce high levels of pro inflammatory cytokines, thus contributing to the pathogenesis of BA and chronic obstructive pulmonary disease. We found that expression of ADORA2A and ADORA2B are increased in monocytes obtained from patients with BA, and are associated with the generation of CD14(pos)CD209(pos) pro-inflammatory cells. A positive correlation between expression of ADORA2B and IL-6 was identified in human monocytes and may explain the increased expression of IL-6 mRNA in asthmatics. Taken together, our results suggest that monocyte-specific expression of A2 adenosine receptors plays an important role in pro-inflammatory activation of human monocytes, thus contributing to the progression of asthma. PMID- 26232645 TI - Bilirubin treatment suppresses pulmonary inflammation in a rat model of smoke induced emphysema. AB - BACKGROUND: Cigarette smoking is a significant risk factor for emphysema, which is characterized by airway inflammation and oxidative damage. OBJECTIVES: To assess the capacity of bilirubin to protect against smoke-induced emphysema. METHODS: Smoking status and bilirubin levels were recorded in 58 patients with chronic obstructive pulmonary diseases (COPD) and 71 non-COPD participants. The impact of smoking on serum bilirubin levels and exogenous bilirubin (20 mg/kg/day) on pulmonary injury was assessed in a rat model of smoking-induced emphysema. At sacrifice lung histology, airway leukocyte accumulation and cytokine and chemokine levels in serum, bronchoalveolar lavage fluid (BALF) and lung were analyzed. Oxidative lipid damage and anti-oxidative components was assessed by measuring malondialdehyde, superoxide dismutase (SOD) activity and glutathione. RESULTS: Total serum bilirubin levels were lower in smokers with or without COPD than non-smoking patients without COPD (P < 0.05). Indirect serum bilirubin levels were lower in COPD patients than patients without COPD (P < 0.05). In rats, cigarette smoke reduced serum total and indirect bilirubin levels. Administration of bilirubin reduced mean linear intercept and mean alveoli area, increased mean alveoli number, reduced macrophage, neutrophil and TNF-alpha content of BALF, and increased BALF and serum IL-10 level, but lowered local and systemic CCL2, CXCL2, CXCL8 and IL-17 levels. Bilirubin suppressed the smoke-induced systemic and regional oxidative lipid damage associated with increased SOD activity. CONCLUSION: Bilirubin attenuated smoking-induced pulmonary injury by suppressing inflammatory cell recruitment and pro inflammatory cytokine secretion, increasing anti-inflammatory cytokine levels, and anti-oxidant SOD activity in a rat model of smoke-induced emphysema. PMID- 26232646 TI - Effects of fluoride on microtubule ultrastructure and expression of Tubalpha1a and Tubbeta2a in mouse hippocampus. AB - Axonal and dendrictic degenerations were observed in non-skeleton fluorosis as the neurological manifestations. Microtubules, composed of the assembled tubulin dimers, are the essential cytoskeleton of axon and dendron. However, the effect of fluoride (F) on microtubules status and tubulin dimer expression in central nerves system remains largely unknown. In this study, the ultrastructure of microtubules and expression of Tubalpha1a and Tubbeta2a were detected in hippocampus of mice orally administrated with 25, 50, or 100mgL(-1) NaF for 60d. Results showed that in F treatment groups, microtubules were broken into discrete fragments and bended, which were no longer stretched and went along the axon well. In addition, the expression of Tubalpha1a and Tubbeta2a on both gene and protein levels were significantly reduced in high F group. The visual results of immunocytochemistry also confirmed the decreased protein expressions of Tubalpha1a and Tubbeta2a. These findings suggested that microtubule lesions could be an important cause for neurodegeneration observed in fluorosis, and F may threaten the microtubule stability by affecting the expression of tubulin dimers. PMID- 26232647 TI - Molecular cloning, expression profiles and characterization of a glutathione reductase in Hevea brasiliensis. AB - Glutathione reductase (GR; EC 1.8.1.7) is an important oxidoreductase that can protect organisms against various oxidative stresses. In this study, a new GR gene, named as HbGR2, was isolated from Hevea brasiliensis. The HbGR2 cDNA contained a 1674-bp open reading frame encoding 557 amino acids and the deduced HbGR2 protein showed high identities to the chloroplastic GRs from other plant species. HbGR2 was localized in the chloroplasts of tobacco mesophyll protoplasts. The cis-acting regulatory elements related to stress or hormone responses were predicted in the promoter region of HbGR2. The results from real time RT-PCR analyses showed that HbGR2 was expressed throughout different tissues and developmental stages of leaves. Besides being related to tapping panel dryness (TPD), HbGR2 was regulated by several treatments including ethephon (ET), methyl jasmonate (MeJA), drought, low temperature, high salt, wounding and hydrogen peroxide (H2O2). The Escherichia coli (E. coli) cells overexpressing HbGR2 markedly increased their tolerance and survival at high concentrations of H2O2, suggesting that HbGR2 might play an important role in oxidative stress response in Hevea brasiliensis. PMID- 26232648 TI - Expression and characterization of a new isoform of the 9 kDa allergenic lipid transfer protein from tomato (variety San Marzano). AB - Lipid transfer proteins (LTPs) are food allergens found first in fruits of the Rosaceae family and later identified in other food plants. Their high structural stability causes them to behave as allergens in cooked and processed foods. Allergenic LTPs have been identified in tomato fruits as well, but studies of their thermal stability and structural characteristics are limited. In this article we report the identification of the coding region for a novel 9 kDa LTP isoform in the tomato variety San Marzano, together with the expression of the recombinant mature protein. The purified recombinant protein was further characterized for its thermal stability and was found to bind 1-palmitoil-2 lysophosphatidylcholine (Lyso-C16) after thermal treatments up to 105 degrees C. Analysis of a modeling derived structure of the protein allowed the identification of possible epitope regions on the molecular surface. PMID- 26232649 TI - Depressive symptoms, anxiety and well-being among metabolic health obese subtypes. AB - BACKGROUND: The metabolically healthy obese (MHO) phenotype is characterized by favorable lipid and inflammatory profiles, preserved insulin sensitivity and normal blood pressure. Limited data regards whether metabolically healthy obesity also confers beneficial effects on mental health and well-being exists. METHODS: We investigated depressive symptoms, anxiety and well-being among metabolically healthy and unhealthy obese and non-obese adults from a cross-sectional sample of 2047 middle-aged Irish men and women. Subjects were classified as obese (BMI >=30kg/m(2)) and non-obese (BMI <30kg/m(2)). Metabolic health status was defined using three metabolic health definitions based on a range of cardiometabolic abnormalities including metabolic syndrome criteria, insulin resistance and inflammation. Depressive symptoms, anxiety and well-being were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D), the Hospital Anxiety and Depression Scale (HADS) and the World Health Organization (WHO)-5 Well Being Index. RESULTS: Relative to the metabolically healthy non-obese individuals the risk of anxiety and depressive symptoms was greater among the metabolically unhealthy obese subjects (odds ratios (ORs) 1.63-1.66 and ORs 1.82-1.83 for anxiety and depressive symptoms, respectively depending on metabolic health definition). Increased risk of these conditions was not observed among the MHO subjects. CONCLUSIONS: Our data suggest that a favorable metabolic profile is positively associated with mental health among obese middle-aged adults, although findings were dependent on metabolic health definition. Improved understanding of the relationship between obesity associated metabolic health subtypes, anxiety and depressive symptoms may inform future targeted screening and interventions for those at greatest risk of adverse mental and cardiometabolic health outcomes. PMID- 26232650 TI - Activation of the kynurenine pathway is associated with striatal volume in major depressive disorder. AB - Inflammation, which may be present in a subgroup of individuals with major depressive disorder (MDD), activates the kynurenine metabolic pathway to produce kynurenine metabolites kynurenic acid (KynA) and quinolinic acid (QA). We have previously reported an association between the ratio of KynA to QA and hippocampal volume in MDD. In animals, inflammation leads to deficits in incentive motivation. Given the central role of the nucleus accumbens (NAcc) and other regions of the striatum in motivated behavior, reward processing, and anhedonia, we hypothesized that abnormalities in the concentrations of kynurenine pathway metabolites would be associated with striatal volumes. As previously reported, after controlling for relevant confounds, the KynA/QA ratio was reduced in the serum of unmedicated patients with MDD (n=53) versus healthy controls (HC, n=47) and there was a non-significant trend in the correlation between KynA/QA and severity of anhedonia (r=-0.27, p<0.1). There was no significant difference between the MDD and HC groups in any of the individual kynurenine metabolites or volume of the striatum defined as the sum of the volumes of the NAcc, caudate, and putamen. After regressing out the effects of sex, analysis batch, and supratentorial volume, the kynurenine concentration and the ratio of kynurenine to tryptophan were inversely associated with striatal volumes in the MDD sample (p<0.05, uncorrected). Further, striatal volume was correlated with the items, "concentration difficulties", "lassitude", and "pessimism" from the Montgomery Asberg Depression Rating Scale. Our results raise the possibility that activation of the kynurenine pathway is a marker of an inflammatory process that leads to reductions in striatal volume. However, unlike the hippocampus, the association does not appear to be mediated by the relative balance between KynA and QA. PMID- 26232651 TI - Hospital sector choice and support for public hospital care in New Zealand: Results from a labeled discrete choice survey. AB - This study uses a discrete choice experiment (DCE) to measure patients' preferences for public and private hospital care in New Zealand. A labeled DCE was administered to 583 members of the general public, with the choice between a public and private hospital for a non-urgent surgery. The results suggest that cost of surgery, waiting times for surgery, option to select a surgeon, convenience, and conditions of the hospital ward are important considerations for patients. The most important determinant of hospital choice was whether it was a public or private hospital, with respondents far more likely to choose a public hospital than a private hospital. The results have implications for government policy toward using private hospitals to clear waiting lists in public hospitals, with these results suggesting the public might not be indifferent to policies that treat private hospitals as substitutes for public hospitals. PMID- 26232652 TI - Appointment of the Editor in Chief, 2016-2020. PMID- 26232653 TI - In Tribute: David L. Sackett. PMID- 26232654 TI - The N-terminus of classical swine fever virus (CSFV) nonstructural protein 2 modulates viral genome RNA replication. AB - Pestivirus nonstructural protein 2 (NS2) is a multifunctional, hydrophobic protein with an important but poorly understood role in viral RNA replication and infectious virus production. In the present study, based on sequence analysis, we mutated several representative conserved residues within the N-terminus of NS2 of classical swine fever virus (CSFV) and investigated how these mutations affected viral RNA replication and infectious virus production. Our results demonstrated that the mutation of two aspartic acids, NS2/D60A or NS2/D60K and NS2/D78K, in the N-terminus of NS2 abolished infectious virus production and that the substitution of arginine for alanine at position 100 (NS2/R100A) resulted in significantly decreased viral titer. The serial passage of cells containing viral genomic RNA molecules generated the revertants NS2/A60D, NS2/K60D and NS2/K78D, leading to the recovery of infectious virus. In the context of the NS2/R100A mutant, the NS2/I90L mutation compensated for infectious virus production. The regulatory roles of the indicated amino acid residues were identified to occur at the viral RNA replication level. These results revealed a novel function for the NS2 N-terminus of CSFV in modulating viral RNA replication. PMID- 26232655 TI - Little known chewing lice (Phthiraptera) infesting crab plover Dromas ardeola Paykull, 1805 (Charadriiformes: Dromadidae) from the Red Sea. AB - Scanty information is available for many species of chewing lice of marine birds. Through this work we investigated one of most characteristic marine bird for chewing lice. Seven individuals of crab plovers Dromas ardeola Paykull, 1805 were trapped using standard mist nets on Humr Island in Farasan Archipelago, Saudi Arabia. Two species of chewing lice were found to infest these birds: Actornithophilus ardeolae Timmermann, 1954 of suborder Amblycera and Quadraceps brunneus (Nitzsch in Giebel, 1866) of suborder Ischnocera. Diagnostic characters, data of specimens examined, high definition photos and host distribution map are provided through this paper. PMID- 26232656 TI - Human-armadillo interaction in Ceara, Brazil: Potential for transmission of Mycobacterium leprae. AB - Several factors suggest that armadillos present an important risk for human leprosy infection. This study uses semi-structured interviews to better illustrate how human interaction with armadillos may increase the risk of leprosy transmission. The participants were all residents of the state of Ceara, in northeastern Brazil, all acknowledged contact with armadillos either through hunting, through cooking, or through consumption of its meat. This study raises important issues about contact between human beings and armadillos. The interviews provide evidence of numerous situations in which leprosy transmission via the armadillo is possible. At a minimum, people who hunt armadillos need to be made aware of the risk of infection. PMID- 26232657 TI - Natural infection of bats with Leishmania in Ethiopia. AB - The leishmaniases, a group of diseases with a worldwide-distribution, are caused by different species of Leishmania parasites. Both cutaneous and visceral leishmaniasis remain important public health problems in Ethiopia. Epidemiological cycles of these protozoans involve various sand fly (Diptera: Psychodidae) vectors and mammalian hosts, including humans. In recent years, Leishmania infections in bats have been reported in the New World countries endemic to leishmaniasis. The aim of this study was to survey natural Leishmania infection in bats collected from various regions of Ethiopia. Total DNA was isolated from spleens of 163 bats belonging to 23 species and 18 genera. Leishmania infection was detected by real-time (RT) PCR targeting a kinetoplast (k) DNA and internal transcribed spacer one (ITS1) gene of the parasite. Detection was confirmed by sequencing of the PCR products. Leishmania kDNA was detected in eight (4.9%) bats; four of them had been captured in the Aba-Roba and Awash-Methara regions that are endemic for leishmaniasis, while the other four specimens originated from non-endemic localities of Metu, Bedele and Masha. Leishmania isolates from two bats were confirmed by ITS1 PCR to be Leishmania tropica and Leishmania major, isolated from two individual bats, Cardioderma cor and Nycteris hispida, respectively. These results represent the first confirmed observation of natural infection of bats with the Old World Leishmania. Hence, bats should be considered putative hosts of Leishmania spp. affecting humans with a significant role in the transmission. PMID- 26232658 TI - Reappraisal of Microsurgical Revascularization for Anterior Circulation Ischemia in Patients with Progressive Stroke. AB - BACKGROUND: Intravenous thrombolysis using tissue plasminogen activator and endovascular treatment for acute ischemic stroke is becoming an established standard therapy. However, there is no consensus in the treatment of patients who are suffering from progressive neurologic symptoms in the later stages. The purpose of this study was to evaluate the safety and efficacy of microsurgical revascularization in such patients with progressive stroke. METHODS: We retrospectively reviewed the clinical and radiological records of 14 consecutive patients with progressive stroke who underwent emergency open surgery for anterior circulation occlusion within 7 days after onset. Surgical candidates were carefully selected on the basis of symptom severity, diffusion-weighted imaging, and perfusion study. Superficial temporal artery to middle cerebral artery bypass was applied for atherosclerotic occlusion, and microsurgical embolectomy was applied for embolic occlusion. RESULTS: Superficial temporal artery to middle cerebral artery bypass was performed in 12 patients, microsurgical embolectomy in 1, and the combination of these modalities in 1. As a result, complete revascularization was achieved in all patients. The National Institutes of Health Stroke Scale scores significantly improved after surgery (at third postoperative day, P < 0.05; at 14th postoperative day, P < 0.01). A favorable outcome (modified Rankin Scale 0-2) was achieved in 12 of the 14 (85.7%) patients. Minor intracerebral hemorrhage occurred in 1 patient and hyperperfusion syndrome occurred in 1 patients; however, the patients subsequently recovered without additional treatment. CONCLUSIONS: Microsurgical revascularization is a feasible treatment option for patients with progressive stroke due to anterior circulation major vessel occlusion. PMID- 26232659 TI - Prenatal exposure to persistent organochlorine pollutants is associated with high insulin levels in 5-year-old girls. AB - BACKGROUND: Several persistent organochlorine pollutants (POPs) possess endocrine disrupting abilities, thereby potentially leading to an increased risk of obesity and metabolic diseases, especially if the exposure occurs during prenatal life. We have previously found associations between prenatal POP exposures and increased BMI, waist circumference and change in BMI from 5 to 7 years of age, though only among girls with overweight mothers. OBJECTIVES: In the same birth cohort, we investigated whether prenatal POP exposure was associated with serum concentrations of insulin and leptin among 5-year-old children, thus possibly mediating the association with overweight and obesity at 7 years of age. METHODS: The analyses were based on a prospective Faroese Birth Cohort (n=656), recruited between 1997 and 2000. Major POPs, polychlorinated biphenyls (PCBs), p,p' dichlorodiphenyldichloroethylene (DDE) and hexachlorobenzene (HCB), were measured in maternal pregnancy serum and breast milk. Children were followed-up at the age of 5 years where a non-fasting blood sample was drawn; 520 children (273 boys and 247 girls) had adequate serum amounts available for biomarker analyses by Luminex(r) technology. Insulin and leptin concentrations were transformed from continuous to binary variables, using the 75th percentile as a cut-off point. Multiple logistic regression was used to investigate associations between prenatal POP exposures and non-fasting serum concentrations of insulin and leptin at age 5 while taking into account confounders. RESULTS: Girls with highest prenatal POP exposure were more likely to have high non-fasting insulin levels (PCBs 4th quartile: OR=3.71; 95% CI: 1.36, 10.01. DDE 4th quartile: OR=2.75; 95% CI: 1.09, 6.90. HCB 4th quartile: OR=1.98; 95% CI: 1.06, 3.69) compared to girls in the lowest quartile. No significant associations were observed with leptin, or among boys. A mediating effect of insulin or leptin on later obesity was not observed. CONCLUSION: These findings suggest, that for girls, prenatal exposure to POPs may play a role for later development of metabolic diseases by affecting the level of insulin. PMID- 26232661 TI - Lateral organization, bilayer asymmetry, and inter-leaflet coupling of biological membranes. AB - Understanding of cell membrane organization has evolved significantly from the classic fluid mosaic model. It is now recognized that biological membranes are highly organized structures, with differences in lipid compositions between inner and outer leaflets and in lateral structures within the bilayer plane, known as lipid rafts. These organizing principles are important for protein localization and function as well as cellular signaling. However, the mechanisms and biophysical basis of lipid raft formation, structure, dynamics and function are not clearly understood. One key question, which we focus on in this review, is how lateral organization and leaflet compositional asymmetry are coupled. Detailed information elucidating this question has been sparse because of the small size and transient nature of rafts and the experimental challenges in constructing asymmetric bilayers. Resolving this mystery will require advances in both experimentation and modeling. We discuss here the preparation of model systems along with experimental and computational approaches that have been applied in efforts to address this key question in membrane biology. We seek to place recent and future advances in experimental and computational techniques in context, providing insight into in-plane and transverse organization of biological membranes. PMID- 26232660 TI - Dual targeting DNA gyrase B (GyrB) and topoisomerse IV (ParE) inhibitors: A review. AB - GyrB and ParE are type IIA topoisomerases and found in most bacteria. Its function is vital for DNA replication, repair and decatenation. The highly conserved ATP-binding subunits of DNA GyrB and ParE are structurally related and have been recognized as prime candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, no natural product or small molecule inhibitors targeting ATPase catalytic domain of both GyrB and ParE enzymes have succeeded in the clinic. Moreover, no inhibitors of these enzymes with broad-spectrum antibacterial activity against Gram-negative pathogens have been reported. Availability of high resolution crystal structures of GyrB and ParE made it possible for the design of many different classes of inhibitors with dual mechanism of action. Among them benzimidazoles, benzothiazoles, thiazolopyridines, imidiazopyridazoles, pyridines, indazoles, pyrazoles, imidazopyridines, triazolopyridines, pyrrolopyrimidines, pyrimidoindoles as well as related structures are disclosed in literatures. Unfortunately most of these inhibitors are found to be active against Gram positive pathogens. In the present review we discuss about studies on novel dual targeting ATPase inhibitors. PMID- 26232662 TI - Caged ceramide 1-phosphate (C1P) analogs: Novel tools for studying C1P biology. AB - Ceramide 1-phosphate (C1P) is a bioactive sphingolipid metabolite that is produced in cells by the action of ceramide kinase (CerK) acting upon ceramide, and is also found in the circulation. C1P was first demonstrated to be mitogenic and antiapoptotic in different cell types, and was later shown to induce cell migration. Understanding the precise mechanisms by which C1P exerts its biological effects has been possible using specific photosensitive caged C1P analogues synthesized by Robert Bittman's group. These compounds are cell permeable, bypass cell plasma membrane receptors, and can be released into the cytosol upon light irradiation, thereby allowing precise determination of the intracellular mechanisms of actions of C1P. Two derivatives of N-palmitoyl ceramide 1-phosphate have been used in most studies. In one C1P derivative the cage was 7-(N,N-diethylamino)coumarin (DECM-C1P) while in the other it was a 4 bromo-5-hydroxy-2-nitrobenzhydryl moiety (BHNB-C1P). The uncaging process released C1P in the cytosol, and this was accompanied by stimulation of cell proliferation, inhibition of apoptosis, and production of low levels of reactive oxygen species. However, intracellular accumulation of C1P did not affect chemotaxis. The caged C1P analogues allowed distinction between the extracellular events evoked by C1P, as for example through interaction with a putative cell surface receptor, from its intracellular effects. PMID- 26232663 TI - Bilayer membrane interactions with nanofabricated scaffolds. AB - Membrane function is facilitated by lateral organization within the lipid bilayer, including phase-separation of lipids into more ordered domains (lipid rafts) and anchoring of the membrane to a cytoskeleton. These features have proven difficult to reproduce in model membrane systems such as black lipid membranes, unilamellar vesicles and supported bilayers. However, advances in micro/nanofabrication have resulted in more realistic synthetic models of membrane-cytoskeleton interactions that can help uncover the design rules responsible for biological membrane formation and organization. This review will focus on describing micro-/nanostructured scaffolds that can emulate the connections of a cellular membrane to an underlying "cytoskeleton". Examples include molecular-based scaffolds anchored to a solid substrate through surface chemistry, solid-state supports modified by material deposition, lithography and etching, the creation of micro/nanoporous arrays, integration with microfluidics, and droplet-based bilayers at interfaces.Model systems such as these are increasing our understanding of structure and organization in cell membranes, and how they result in the emergence of functionality at the nanoscale. PMID- 26232664 TI - PIP2Clustering: From model membranes to cells. AB - Phosphoinositides, derived from phosphorylation of phosphatidylinositol at one or more positions on the inositol ring, are minor but significant lipids in eukaryotic cell membranes. Phosphatidylinositol (4,5)-bisphosphate (PIP2) is the most abundant phosphoinositide and is concentrated in the plasma membrane. PIP2 functions in cell motility, adhesion, exocytosis, and endocytosis, among other processes. Model membrane studies have shown that PIP2 can form electrostatic based clusters with Ca++ and with basic peptides. Recent studies in cells have shown that PIP2 can co-cluster with polybasic peptides present in cellular proteins as well, with important functional consequences. PMID- 26232665 TI - The interactions of peripheral membrane proteins with biological membranes. AB - The interactions of peripheral proteins with membrane surfaces are critical to many biological processes, including signaling, recognition, membrane trafficking, cell division and cell structure. On a molecular level, peripheral membrane proteins can modulate lipid composition, membrane dynamics and protein protein interactions. Biochemical and biophysical studies have shown that these interactions are in fact highly complex, dominated by several different types of interactions, and have an interdependent effect on both the protein and membrane. Here we examine three major mechanisms underlying the interactions between peripheral membrane proteins and membranes: electrostatic interactions, hydrophobic interactions, and fatty acid modification of proteins. While experimental approaches continue to provide critical insights into specific interaction mechanisms, emerging bioinformatics resources and tools contribute to a systems-level picture of protein-lipid interactions. Through these recent advances, we begin to understand the pivotal role of protein-lipid interactions underlying complex biological functions at membrane interfaces. PMID- 26232666 TI - Interaction of fluorescent phospholipids with cyclodextrins. AB - Fluorescent analogs of phospholipids are often employed to investigate the structure and dynamics of lipids in membranes. Some of those studies have used cyclodextrins e.g., to modulate the lipid phase. However, the role of the fluorescence moiety of analogs for the interaction between cyclodextrins and fluorescent lipids has not been investigated so far in detail. Therefore, in the present study the interaction of various fluorescent phospholipid analogs with methylated alpha-, beta- and gamma- cyclodextrins was investigated. The analogs differed in their structure, in the length of the fatty acyl chain, in the position of the fluorescence group, and in the attached fluorescence moiety (7 nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) or dipyrrometheneboron difluoride (BODIPY)). In aqueous buffer, cyclodextrins bind fluorescent lipids disturbing the organization of the analogs. When incorporated into lipid vesicles, analogs are selectively extracted from the membrane upon addition of cyclodextrins. The results show that the interaction of cyclodextrins with fluorescent phospholipids depends on the cyclodextrin species, the fluorescence moiety and the phospholipid structure. The presented data should be of interest for studies using fluorescent phospholipids and cyclodextrins, since the interaction between the fluorescence group and the cyclodextrin may interfere with the process(es) under study. PMID- 26232667 TI - Unique choline-containing phosphoglycolipids in Mycoplasma fermentans. PMID- 26232668 TI - Knowledge discovery and sequence-based prediction of pandemic influenza using an integrated classification and association rule mining (CBA) algorithm. AB - Pandemic influenza is a major concern worldwide. Availability of advanced technologies and the nucleotide sequences of a large number of pandemic and non pandemic influenza viruses in 2009 provide a great opportunity to investigate the underlying rules of pandemic induction through data mining tools. Here, for the first time, an integrated classification and association rule mining algorithm (CBA) was used to discover the rules underpinning alteration of non-pandemic sequences to pandemic ones. We hypothesized that the extracted rules can lead to the development of an efficient expert system for prediction of influenza pandemics. To this end, we used a large dataset containing 5373 HA (hemagglutinin) segments of the 2009 H1N1 pandemic and non-pandemic influenza sequences. The analysis was carried out for both nucleotide and protein sequences. We found a number of new rules which potentially present the undiscovered antigenic sites at influenza structure. At the nucleotide level, alteration of thymine (T) at position 260 was the key discriminating feature in distinguishing non-pandemic from pandemic sequences. At the protein level, rules including I233K, M334L were the differentiating features. CBA efficiently classifies pandemic and non-pandemic sequences with high accuracy at both the nucleotide and protein level. Finding hotspots in influenza sequences is a significant finding as they represent the regions with low antibody reactivity. We argue that the virus breaks host immunity response by mutation at these spots. Based on the discovered rules, we developed the software, "Prediction of Pandemic Influenza" for discrimination of pandemic from non-pandemic sequences. This study opens a new vista in discovery of association rules between mutation points during evolution of pandemic influenza. PMID- 26232669 TI - New antibiotics against gram-positives: present and future indications. AB - Gram-positive cocci are the most frequent aetiology of community and nosocomially bacterial acquired infections. The prevalence of multidrug-resistant gram positive bacteria is increasing and is associated with high morbidity and mortality. New antibiotics will be available in the European market during the next months. This revision is focused on lipoglycopeptides, new cephalosporins active against methicillin-resistant Staphylococcus aureus (MRSA) and the new oxazolidinone, tedizolid. The purpose of this review is to describe their in vitro activity, pharmacokinetic and pharmacodynamic characteristics, and experience from clinical trials. PMID- 26232670 TI - Biocomposite scaffolds for bone regeneration: Role of chitosan and hydroxyapatite within poly-3-hydroxybutyrate-co-3-hydroxyvalerate on mechanical properties and in vitro evaluation. AB - Bio-engineered scaffolds for bone tissue regeneration is an exploding area of research mainly because they can satisfy the essential demands and current challenges in bone replacement therapies, by imitating the extracellular matrix (ECM) of the native bone. We fabricated bio-composite nanofibrous scaffolds with a blend of poly-3-hydroxybutyrate-co-3-hydroxyvalerate (PHBV), chitosan (CTS) and hydroxyapatite (HA) during this study. Morphological evaluation confirmed the fiber diameters of PHBV, PHBV/CTS (90:10), PHBV/CTS/HA4 (85.5:9.5:5) and PHBV/CTS/HA8 (81:9:10) as 405 +/- 74 nm, 334 +/- 82 nm, 316 +/- 103 nm and 256 +/ 110 nm, respectively. The PHBV/CTS/HA4 and PHBV/CTS/HA8 scaffolds were capable of enduring the long term culture of human fetal osteoblasts (hFOB) with ultimate tensile strength of 3.55 +/- 0.22 MPa and 4.19 +/- 0.19 MPa, respectively. The proliferation of osteoblasts on PHBV/CTS/HA8 scaffold was found 34.10% higher than that on PHBV scaffold on day 20. Cell maturation identified by alkaline phosphatase activity on day 20 was significantly higher on PHBV/CTS/HA8 scaffold than that on PHBV scaffold. The cells on PHBV/CTS/HA8 scaffold also acquired higher mineral deposition (25.79%) than the mineral deposition on PHBV scaffold by day 20, confirmed by EDX analysis. Based on the results, we concluded that the electrospun PHBV/CTS/HA8 scaffolds hold great potential to promote the regeneration of bone tissue due to the synergistic effect of chitosan and HA, whereby chitosan provided cell recognition sites while HA acted as a chelating agent for organizing the apatite-like mineralization. PMID- 26232671 TI - Similarity-balanced discriminant neighbor embedding and its application to cancer classification based on gene expression data. AB - The family of discriminant neighborhood embedding (DNE) methods is typical graph based methods for dimension reduction, and has been successfully applied to face recognition. This paper proposes a new variant of DNE, called similarity-balanced discriminant neighborhood embedding (SBDNE) and applies it to cancer classification using gene expression data. By introducing a novel similarity function, SBDNE deals with two data points in the same class and the different classes with different ways. The homogeneous and heterogeneous neighbors are selected according to the new similarity function instead of the Euclidean distance. SBDNE constructs two adjacent graphs, or between-class adjacent graph and within-class adjacent graph, using the new similarity function. According to these two adjacent graphs, we can generate the local between-class scatter and the local within-class scatter, respectively. Thus, SBDNE can maximize the between-class scatter and simultaneously minimize the within-class scatter to find the optimal projection matrix. Experimental results on six microarray datasets show that SBDNE is a promising method for cancer classification. PMID- 26232672 TI - Stabilizing 3D in vivo intravital microscopy images with an iteratively refined soft-tissue model for immunology experiments. AB - We describe a set of new algorithms and a software tool, StabiTissue, for stabilizing in vivo intravital microscopy images that suffer from soft-tissue background movement. Because these images lack predetermined anchors and are dominated by noise, we use a pixel weighted image alignment together with a correction for nonlinear tissue deformations. We call this correction a poor man's diffeomorphic map since it ascertains the nonlinear regions of the image without resorting to a full integral equation method. To determine the quality of the image stabilization, we developed an ensemble sampling method that quantifies the coincidence between image pairs from randomly distributed image regions. We obtain global stabilization alignment through an iterative constrained simulated annealing optimization procedure. To show the accuracy of our algorithm with existing software, we measured the misalignment error rate in datasets taken from two different organs and compared the results to a similar and popular open source solution. Present open-source stabilization software tools perform poorly because they do not treat the specific needs of the IV-2pM datasets with soft tissue deformation, speckle noise, full 5D inter- and intra-stack motion error correction, and undefined anchors. In contrast, the results of our tests demonstrate that our method is more immune to noise and provides better performance for datasets' possessing nonlinear tissue deformations. As a practical application of our software, we show how our stabilization improves cell tracking, where the presence of background movement would degrade track information. We also provide a qualitative comparison of our software with other open-source libraries/applications. Our software is freely available at the open source repository http://sourceforge.net/projects/stabitissue/. PMID- 26232673 TI - Regulatory B cells in CVID patients fail to suppress multifunctional IFN-gamma+ TNF-alpha+ CD4+ T cells differentiation. AB - Common variable immunodeficiency (CVID) refers to primary hypogammaglobulinemia with unknown pathogenesis. Although there is evidence for intrinsic B cell defects in some CVID patient groups, various abnormalities in cytokine production by T cells in CVID patients are frequently observed. Here, we demonstrate a relationship in the production of pro-inflammatory Th1 cytokines and regulatory B cells producing IL-10 between CVID patients and healthy controls. We describe CD19(+)CD24(hi)CD38(hi)IL-10(+) regulatory B cells generated after T cell stimulation of human peripheral blood lymphocytes ex vivo are able to suppress IFN-gamma(+)TNF-alpha(+) producing CD4(+) T cells. This process is impaired in CVID patients, who present with both low numbers of CD19(+)CD24(hi)CD38(hi)IL 10(+) B cells and increased numbers of IFN-gamma(+)TNF-alpha(+)CD4(+) T cells. Disruption of the regulatory B cell response to T cell stimulation explains the excessive T cell activation regarded as an immunoregulatory abnormality that is a frequent finding in CVID patients. PMID- 26232674 TI - Determinants of disinfectant pretreatment efficacy for nitrosamine control in chloraminated drinking water. AB - Utilities using chloramines need strategies to mitigate nitrosamine formation to meet potential future nitrosamine regulations. The ability to reduce NDMA formation under typical post-chloramination conditions of pretreatment with ultraviolet light from a low pressure mercury lamp (LPUV), free chlorine (HOCl), ozone (O3), and UV light from a medium pressure mercury lamp (MPUV) were compared at exposures relevant to drinking water treatment. The order of efficacy after application to waters impacted by upstream wastewater discharges was O3 > HOCl ~ MPUV > LPUV. NDMA precursor abatement generally did not correlate well between oxidants, and waters exhibited different behaviors with respect to pH and temperature, suggesting a variety of source-dependent NDMA precursors. For wastewater-impacted waters, the observed pH dependence for precursor abatement suggested the important role of secondary or tertiary amine precursors. Although hydroxyl radicals did not appear to be important for NDMA precursor abatement during O3 or MPUV pretreatment, the efficacy of MPUV correlated strongly with dissolved organic carbon concentration (p = 0.01), suggesting alternative indirect photochemical pathways. The temperature dependences during pre- and post disinfection indicated that NDMA formation is likely to increase during warm seasons for O3 pretreatment, decrease for HOCl pretreatment, and remain unchanged for MPUV treatment, although seasonal changes in source water quality may counteract the temperature effects. For two waters impacted by relatively high polyDADMAC coagulant doses, pretreatment with HOCl, O3, and MPUV increased NDMA formation during post-chloramination. For O3 pretreatment, hydroxyl radicals likely led to precursor formation from the polymer in the latter tests. MPUV treatment of polymer-impacted water increased subsequent NDMA formation through an indirect photochemical process. Many factors may mitigate the importance of this increased NDMA formation, including the low polyDADMAC doses typically applied, and simultaneous degradation of watershed-associated precursors. PMID- 26232675 TI - SPRi-based adenovirus detection using a surrogate antibody method. AB - Adenovirus infection, which is a waterborne viral disease, is one of the most prevelant causes of human morbidity in the world. Thus, methods for rapid detection of this infectious virus in the environment are urgently needed for public health protection. In this study, we developed a rapid, real-time, sensitive, and label-free SPRi-based biosensor for rapid, sensitive and highly selective detection of adenoviruses. The sensing protocol consists of mixing the sample containing adenovirus with a predetermined concentration of adenovirus antibody. The mixture was filtered to remove the free antibodies from the sample. A secondary antibody, which was specific to the adenovirus antibody, was immobilized onto the SPRi chip surface covalently and the filtrate was flowed over the sensor surface. When the free adenovirus antibodies bound to the surface immobilized secondary antibodies, we observed this binding via changes in reflectivity. In this approach, a higher amount of adenoviruses resulted in fewer free adenovirus antibodies and thus smaller reflectivity changes. A dose-response curve was generated, and the linear detection range was determined to be from 10 PFU/mL to 5000 PFU/mL with an R(2) value greater than 0.9. The results also showed that the developed biosensing system had a high specificity towards adenovirus (less than 20% signal change when tested in a sample matrix containing rotavirus and lentivirus). PMID- 26232676 TI - Enhanced sandwich immunoassay using antibody-functionalized magnetic iron-oxide nanoparticles for extraction and detection of soluble transferrin receptor on a photonic crystal biosensor. AB - Iron deficiency anemia (IDA) has detrimental effects on individuals and societies worldwide. A standard sandwich assay (SA) for the detection of soluble transferrin receptor (sTfR), a biomarker of IDA, on a photonic crystal (PC) biosensor was established, but it was susceptible to non-specific signals from complex matrixes. In this study, iron-oxide nanoparticles (fAb-IONs) were used as magnetic immuno-probes to bind sTfR and minimize non-specific signals, while enhancing detection on the PC biosensor. This inverse sandwich assay (IA) method completely bound sTfR with low variability (<4% RSD) in buffer and allowed for its accurate and precise detection in sera (LiquichekTM control sera) on the PC biosensor using two certified ELISAs as reference methods. A linear dose-response curve was elicited at the fAb-IONs concentration in which the theoretical binding ratio (sTfR:fAb-IONs) was calculated to be <1 on the IA. The LoDs for sTfR in the SA and IA were similar (P>0.05) at 14 and 21 MUg/mL, respectively. The inherent imprecision of the IA and reference ELISAs was sigma(delta)=0.45 ug/mL and the mean biases for LiquichekTM 1, 2 and 3 were 0.18, 0.19 and -0.04 ug/mL, respectively. Whereas the inherent imprecision of the SA and reference ELISAs was sigma(delta)=0.52 ug/mL and the biases for LiquichekTM 1, 2 and 3 were 0.66, 0.14 and -0.67 ug/mL, respectively. Thus, unlike the SA, the IA method measures sTfR with the same bias as the reference ELISAs. Combined magnetic separation and detection of nutrition biomarkers on PC biosensors represents a facile method for their accurate and reliable quantification in complex matrixes. PMID- 26232677 TI - Branched zinc oxide nanorods arrays modified paper electrode for electrochemical immunosensing by combining biocatalytic precipitation reaction and competitive immunoassay mode. AB - Branched zinc oxide nanorods (BZR) arrays, an array with high charge carries collection efficiency and specific surface area, are grown on the reduced graphene oxide-paper working electrode for the first time to construct a paper based electrochemical (EC) immunosensor. Typically, the BZR are fabricated via a simple hydrothermal process, which can provide abundant sites for antibodies loading. By combining the large surface area of porous zinc oxide (PZS) and good biocompatibility of gold nanoparticles (AuNPs), PZS-AuNPs (PZS@Au) nanocomposites are designed to label horseradish peroxide (HRP) and antigens. After a competitive reaction between antigens and PZS@Au nanocomposites labeled antigens, the signal labels are introduced into the immunosensor, in which, HRP participate in biocatalytic precipitation process. The produced precipitate reduces the electrode surface area and hinders the electron transfer. With the increase of concentration of antigens, the signal labels introduced into the sensor decrease, thus, a signal-on immunoassay for alpha-fetoprotein detection is constructed. The proposed paper-based EC immunosensor combines enzymatic biocatalytic precipitation reaction and competitive immunoassay mode for the first time, and possesses a wide linear range from 0.2 pg mL(-1) to 500 ng mL(-1) with a detection limit of 0.08 pg mL(-1). In addition, the proposed method is simple, sensitive and specific and can be a promising platform for other protein detection. PMID- 26232678 TI - Highly sensitive electrochemical biosensor for bisphenol A detection based on a diazonium-functionalized boron-doped diamond electrode modified with a multi walled carbon nanotube-tyrosinase hybrid film. AB - A highly sensitive electrochemical biosensor for the detection of Bisphenol A (BPA) in water has been developed by immobilizing tyrosinase onto a diazonium functionalized boron doped diamond electrode (BDD) modified with multi-walled carbon nanotubes (MWCNTs). The fabricated biosensor exhibits excellent electroactivity towards o-quinone, a product of this enzymatic reaction of BPA oxidation catalyzed by tyrosinase. The developed BPA biosensor displays a large linear range from 0.01 nM to 100 nM, with a detection limit (LOD) of 10 pM. The feasibility of the proposed biosensor has been demonstrated on BPA spiked water river samples. Therefore, it could be a promising and reliable analytical tool for on-site monitoring of BPA in waste water. PMID- 26232679 TI - Absolute quantification of lung cancer related microRNA by droplet digital PCR. AB - Digital polymerase chain reaction (digital PCR) enables the absolute quantification of nucleic acids through the counting of single molecules, thus eliminating the need for standard curves or endogenous controls. In this study, we developed a droplet digital PCR (ddPCR) system based on an oil saturated PDMS (OSP) microfluidic chip platform for quantification of lung cancer related microRNA (miRNA). The OSP chip was made with PDMS and was oil saturated to constrain oil swallow and maintain the stability of droplets. Two inlets were designed for oil and sample injection with a syringe pump at the outlet. Highly uniform monodisperse water-in-oil emulsion droplets to be used for subsequent detection and analysis were generated at the cross section of the channel. We compared miRNA quantification by the ddPCR system and quantitative real-time PCR (qPCR) to demonstrate that the ddPCR system was superior to qPCR both in its detection limit and smaller fold changes measurement. This droplet PCR system provides new possibilities for highly sensitive and efficient detection of cancer related genes. PMID- 26232680 TI - PIKfyve mediates the motility of late endosomes and lysosomes in neuronal dendrites. AB - The endosome/lysosome system in the nervous system is critically important for a variety of neuronal functions such as neurite outgrowth, retrograde transport, and synaptic plasticity. In neurons, the endosome/lysosome system is crucial for the activity-dependent internalization of membrane proteins and contributes to the regulation of lipid level on the plasma membrane. Although homeostasis of membrane dynamics plays important roles in the properties of central nervous systems, it has not been elucidated how endosome/lysosome system is regulated. Here, we report that phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) mediates the motility of late endosomes and lysosomes in neuronal dendrites. Endosomes and lysosomes are highly motile in resting neurons, however knockdown of PIKfyve led to a significant reduction in late endosomes and lysosomes motility. We also found that vesicle acidification is crucial for their motility and PIKfyve is associated with this process indirectly. These data suggest that PIKfyve mediates vesicle motility through the regulation of vesicle integrity in neurons. PMID- 26232681 TI - Blast induced neurotrauma causes overpressure dependent changes to the DNA methylation equilibrium. AB - Traumatic brain injury (TBI) has a high prevalence in our society and often leads to morbidity and mortality. TBI also occurs frequently in a military setting where exposure to blast waves is common. Abnormal gene expression involved with oxidative stress, inflammation and neuronal apoptosis has been well documented following blast induced neurotrauma (BINT). Altered epigenetic transcriptional regulation through DNA methylation has been implicated in the pathology of the injury. Imbalance between DNA methylation and DNA demethylation may lead to altered methylation patterns and subsequent changes in gene transcription. DNA methyltransferase enzymes (DNMT1, DNMT3a, and DNMT3b) are responsible for the addition of methyl groups to DNA, DNA methylation. Whereas the combined function of ten-eleven translocation enzymes (TET1, TET2, and TET3) and thymine-DNA glycosylase (TDG) result in the removal of methyl groups from DNA, DNA demethylation. We used an established rodent model of BINT to assess changes in DNA methylation and demethylation enzymes following injury. Three different blast overpressures were investigated (10, 17 and 23psi). Gene expression was investigated in the prefrontal cortex and hippocampus two weeks following injury. We observed DNMT, TET and TDG expression changes between pressure groups and brain regions. The hippocampus was more vulnerable to enzyme expression changes than the prefrontal cortex, which correlated with aberrant DNA methylation. A significant negative correlation was found between global DNA methylation and the magnitude of blast overpressure exposure. Through transcriptional regulation, altered DNA methylation patterns may offer insight into the characteristic outcomes associated with the injury pathology including inflammation, oxidative stress and apoptosis. As such, these enzymes may be important targets to future therapeutic intervention strategies. PMID- 26232682 TI - Genetic variability in tryptophan hydroxylase 2 gene in alcohol dependence and alcohol-related psychopathological symptoms. AB - Heritability plays an important role in the development and expression of alcohol dependence. The present genetic association study explored the role of TPH2 polymorphisms and their haplotypes to investigate its role in alcohol dependence and comorbid psychopathological symptoms. The sample included 101 subjects currently diagnosed as alcohol abusers, 100 abstinent alcohol-dependent subjects and 97 healthy controls. Subjects were genotyped for TPH2 rs4570625, rs1843809, rs7305115, rs4290270. TPH2 genotypes were not associated with alcohol dependence, but GGAA haplotype was less common (p=0.038) and GTAA and GGGT were more common (p=0.011 and p=0.021, respectively), in currently dependent patients compared to controls. Exploratory analysis of genotypes in currently dependent patients showed that rs1843809 was associated with depressive and aggressive traits (p=0.045 and p=0.001, respectively), rs4290270 with depressive and anxiety traits (p=0.040 and p=0.025, respectively) and rs4570625 with aggressive traits (p=0.011). In abstinent subjects rs1843809 genotype was associated with traits of social anxiety (p=0.003). Only association between rs1843809 and the BDHI score (p=0.001) and associations between GTAA haplotype and Zung Anxiety Scale and BDHI score (p=0.001 and p<0.001, respectively), in currently dependent patients remained significant after applying the Bonferroni's correction. Our findings support a potential role of TPH2 in alcohol dependence. TPH2 genetic variability may be also associated with anxiety and aggression traits in alcohol dependent subjects. PMID- 26232683 TI - Monosynaptic excitatory transmission from the hippocampal CA1 region to the subiculum. AB - The subiculum is a major output region of the hippocampus, receiving inputs from the CA1 region. We obtained paired patch-clamp recordings from synaptically coupled pairs of CA1 pyramidal cells (CA1PCs) and subicular principal cells (SubPCs), using rat hippocampal organotypic slice cultures. A single action potential in a presynaptic CA1PC evoked a unitary excitatory postsynaptic current in a SubPC (EPSCCA1->Sub). The failure rate of the monosynaptic transmission was remarkably low (0.08). Paired-pulse depression in SubPCs was apparent when an interval of presynaptic action potentials was shorter than 50ms. When trains of action potentials were induced in a CA1PC, EPSCCA1->Sub was significantly depressed with increasing spike frequency (20-100Hz). Thus the unitary monosynaptic transmission from a CA1PC to a SubPC is reliable, and depressed in response to frequent inputs, suggesting that the subiculum may function as a low pass filter to provide the downstream brain regions with appropriate information. PMID- 26232685 TI - Editorial Comment. PMID- 26232684 TI - Effectiveness of a Wheelchair Skills Training Program for Powered Wheelchair Users: A Randomized Controlled Trial. AB - OBJECTIVES: To test the hypothesis that powered wheelchair users who receive the Wheelchair Skills Training Program (WSTP) improve their wheelchair skills in comparison with a control group that receives standard care, and secondarily to assess goal achievement, satisfaction with training, retention, injury rate, confidence with wheelchair use, and participation. DESIGN: Randomized controlled trial. SETTING: Rehabilitation centers and communities. PARTICIPANTS: Powered wheelchair users (N=116). INTERVENTION: Five 30-minute WSTP training sessions. MAIN OUTCOME MEASURES: Assessments were done at baseline (t1), posttraining (t2), and 3 months posttraining (t3) using the Wheelchair Skills Test Questionnaire (WST-Q version 4.1), Goal Attainment Score (GAS), Satisfaction Questionnaire, injury rate, Wheelchair Use Confidence Scale for Power Wheelchair Users (WheelCon), and Life Space Assessment (LSA). RESULTS: There was no significant t2 t1 difference between the groups for WST-Q capacity scores (P=.600), but the difference for WST-Q performance scores was significant (P=.016) with a relative (t2/t1 * 100%) improvement of the median score for the intervention group of 10.8%. The mean GAS +/- SD for the intervention group after training was 92.8%+/ 11.4%, and satisfaction with training was high. The WST-Q gain was not retained at t3. There was no clinically significant difference between the groups in injury rate and no statistically significant differences in WheelCon or LSA scores at t3. CONCLUSIONS: Powered wheelchair users who receive formal wheelchair skills training demonstrate modest, transient posttraining improvements in their WST-Q performance scores, have substantial improvements on individualized goals, and are positive about training. PMID- 26232686 TI - Tuning cell adhesion by direct nanostructuring silicon into cell repulsive/adhesive patterns. AB - Developing platforms that allow tuning cell functionality through incorporating physical, chemical, or mechanical cues onto the material surfaces is one of the key challenges in research in the field of biomaterials. In this respect, various approaches have been proposed and numerous structures have been developed on a variety of materials. Most of these approaches, however, demand a multistep process or post-chemical treatment. Therefore, a simple approach would be desirable to develop bio-functionalized platforms for effectively modulating cell adhesion and consequently programming cell functionality without requiring any chemical or biological surface treatment. This study introduces a versatile yet simple laser approach to structure silicon (Si) chips into cytophobic/cytophilic patterns in order to modulate cell adhesion and proliferation. These patterns are fabricated on platforms through direct laser processing of Si substrates, which renders a desired computer-generated configuration into patterns. We investigate the morphology, chemistry, and wettability of the platform surfaces. Subsequently, we study the functionality of the fabricated platforms on modulating cervical cancer cells (HeLa) behaviour. The results from in vitro studies suggest that the nanostructures efficiently repel HeLa cells and drive them to migrate onto untreated sites. The study of the morphology of the cells reveals that cells evade the cytophobic area by bending and changing direction. Additionally, cell patterning, cell directionality, cell channelling, and cell trapping are achieved by developing different platforms with specific patterns. The flexibility and controllability of this approach to effectively structure Si substrates to cell-repulsive and cell-adhesive patterns offer perceptible outlook for developing bio-functionalized platforms for a variety of biomedical devices. Moreover, this approach could pave the way for developing anti-cancer platforms that selectively repel cancer cells while favoring the adhesion of normal cells. PMID- 26232688 TI - Heme oxygenase-1 ameliorates kidney ischemia-reperfusion injury in mice through extracellular signal-regulated kinase 1/2-enhanced tubular epithelium proliferation. AB - Heme oxygenase (HO)-1 confers transient resistance against oxidative damage, including renal ischemia-reperfusion injury (IRI). We investigated the potential protective effect of HO-1 induction in a mouse model of renal IRI induced by bilateral clamping of the kidney arteries. The mice were randomly assigned to five groups to receive an intraperitoneal injection of PBS, hemin (an HO-1 inducer, 100MUmol/kg), hemin+ZnPP (an HO-1 inhibitor, 5mg/kg), hemin+PD98059 (a MEK-ERK inhibitor, 10mg/kg) or a sham operation. All of the groups except for the sham-operated group underwent 25min of ischemia and 24 to 72h of reperfusion. Renal function and tubular damage were assessed in the mice that received hemin or the vehicle treatment prior to IRI. The renal injury score and HO-1 protein levels were evaluated via H&E and immunohistochemistry staining. Hemin preconditioned mice exhibited preserved renal cell function (BUN: 40+/-2mg/dl, creatinine: 0.53+/-0.06mg/dl), and the tubular injury score at 72h (1.65+/-0.12) indicated that tubular damage was prevented. Induction of HO-1 induced the phosphorylation of extracellular signal-regulated kinases (ERK) 1/2. However, these effects were abolished with ZnPP treatment. Kidney function (BUN: 176+/ 49mg/dl, creatinine: 1.54+/-0.39mg/dl) increased, and the tubular injury score (3.73+/-0.09) indicated that tubular damage also increased with ZnPP treatment. HO-1-induced tubular epithelial proliferation was attenuated by PD98059. Our findings suggest that HO-1 preconditioning promotes ERK1/2 phosphorylation and enhances tubular recovery, which subsequently prevents further renal injury. PMID- 26232687 TI - The deletion of the estrogen receptor alpha gene reduces susceptibility to estrogen-induced cholesterol cholelithiasis in female mice. AB - Compelling evidence has demonstrated that estrogen is a critical risk factor for gallstone formation and enhances cholesterol cholelithogenesis through the hepatic estrogen receptor alpha (ERalpha), but not ERbeta. To study the lithogenic mechanisms of estrogen through ERalpha, we investigated whether the deletion of Eralpha protects against gallstone formation in ovariectomized (OVX) female mice fed a lithogenic diet and treated with 17beta-estradiol (E2) at 0 or 6MUg/day for 56days. Our results showed that the prevalence of gallstones was reduced from 100% in OVX ERalpha (+/+) mice to 30% in OVX ERalpha (-/-) mice in response to high doses of E2 and the lithogenic diet for 56days. Hepatic cholesterol secretion was significantly diminished in OVX ERalpha (-/-) mice compared to OVX ERalpha (+/+) mice even fed the lithogenic diet and treated with E2 for 56days. These alterations decreased bile lithogenicity by reducing cholesterol saturation index of gallbladder bile. Immunohistochemical studies revealed that ERalpha was expressed mainly in the gallbladder smooth muscle cells. High levels of E2 impaired gallbladder emptying function mostly through the ERalpha and cholecystokinin-1 receptor pathway, leading to gallbladder stasis in OVX ERalpha (+/+) mice. By contrast, gallbladder emptying function was greatly improved in OVX ERalpha (-/-) mice. This markedly retarded cholesterol crystallization and the growth and agglomeration of solid cholesterol crystals into microlithiasis and stones. In conclusion, the deletion of Eralpha reduces susceptibility to the formation of E2-induced gallstones by diminishing hepatic cholesterol secretion, desaturating gallbladder bile, and improving gallbladder contraction function in female mice. PMID- 26232689 TI - Subsequent Neoplasms in Adult Survivors of Childhood Genitourinary Tumors. AB - Treatment for childhood genitourinary tumors such as Wilms tumor, rhabdomyosarcoma, and germ cell tumors has progressed to the point that cure can be expected in many cases. However, survivorship is often coupled with a variety of late effects, of which subsequent neoplasms may be the most concerning if not the most life threatening. Here, we review current literature to assess and report issues relating to subsequent neoplasms in patients with a history of childhood genitourinary tumors, including causative factors, overall risks, the most prevalent subsequent neoplasms, and current recommendations for surveillance and screening. PMID- 26232690 TI - Risk of Recurrence for Clinical Stage I and II Patients With Teratoma Only at Primary Retroperitoneal Lymph Node Dissection. AB - OBJECTIVE: To evaluate the oncologic outcomes of patients with retroperitoneal teratoma only at primary retroperitoneal lymph node dissection (RPLND) who did not receive adjuvant chemotherapy. MATERIALS AND METHODS: Between 1979 and 2010, 23 patients with clinical stage (CS) I and II disease underwent primary RPLND at our institution with teratoma only in the retroperitoneum. No patient received adjuvant chemotherapy and the minimum follow-up was 2 years. RESULTS: At the initial diagnosis, 13 patients (56.5%) had CS I disease and 10 patients (43.5%) had CS II disease. Pathologic staging demonstrated IIA in 13 patients (56.5%), IIB in 8 patients (34.8%), and IIC in 2 patients (8.7%). The 5-year disease-free survival (DFS) was 100% with a median follow-up of 5.8 years (range, 2.1-25.4). DFS was not significantly different comparing pathologic stage IIA vs IIB/IIC disease (P = .73). Two patients (14%) developed late relapses. One patient had a pelvic recurrence 11 years after primary RPLND. Final pathology from the pelvic resection demonstrated embryonal carcinoma. He remains disease free after his second surgery. The second patient had a contralateral retroperitoneal recurrence with yolk-sac tumor and teratoma 11 years after primary RPLND. He was treated with chemotherapy followed by postchemotherapy RPLND. CONCLUSION: The relapse rate for patients with teratoma only at primary RPLND is low irrespective of PS. Adjuvant chemotherapy is therefore not recommended in the management of these patients. PMID- 26232691 TI - Urinary Lignans Are Associated With Decreased Incontinence in Postmenopausal Women. AB - OBJECTIVE: To examine the association between urinary phytoestrogens and self reported urinary incontinence in postmenopausal women in the United States using a large, cross-sectional, population-based cohort survey. METHODS: Data were analyzed for 1789 postmenopausal women aged 50 years or older who participated in one of the 2001-2010 cycles of National Health and Nutrition Examination Survey and underwent measurement of 4 isoflavone (soy derived) and 2 lignan (flax derived) phytoestrogens in their urine. Incontinence was defined as self-reported stress, urge, other, or mixed incontinence. Urine phytoestrogen concentrations were examined in weighted, multivariate logistic regression models for association with each of the lower urinary tract symptoms. All models were adjusted for age, body mass index, diabetes, race, smoking, and parity. RESULTS: Increasing urine concentrations of the lignan phytoestrogen enterodiol was associated with decreased likelihood of urge (odds ratio [OR], 0.92; 95% confidence interval [CI], 0.85-0.99), mixed (OR, 0.90; 95% CI, 0.82-0.98), and other (OR, 0.90; 95% CI, 0.81-0.99) incontinence, whereas increasing urine concentrations of the lignan phytoestrogen enterolactone was associated with decreased likelihood of urge (OR, 0.92; 95% CI, 0.86-0.99) and mixed (OR, 0.91; 95% CI, 0.84-0.99) incontinence. No association was observed between any isoflavone phytoestrogens and types of incontinence. CONCLUSION: This study demonstrates that lignan phytoestrogens may have a protective effect against incontinence in postmenopausal women. Prospective clinical and laboratory studies are warranted to investigate the mechanism of this relationship. PMID- 26232692 TI - Diclofenac Suppository as a Preemptive Analgesia in Ultrasound-guided Biopsy of Prostate: Randomized Controlled Trial. AB - OBJECTIVE: To compare preprocedure Diclofenac suppository and Xylocaine gel with Xylocaine gel only in patients undergoing transrectal ultrasound (TRUS)-guided biopsy of prostate for pain. MATERIALS AND METHODS: It is a randomized controlled trial conducted on patients undergoing TRUS-guided biopsy for clinical or biochemical suspicion of prostate cancer following a written informed consent and Ethics Review Committee approval. Patients were randomized into 2 groups. Group A included those patients who received Diclofenac suppository 2 hours before in combination with 10 mL of 2% Xylocaine gel 5 minutes before biopsy. Group B received Xylocaine gel only. A visual analog scale was used to measure the pain scores at the time of TRUS probe insertion, just after taking biopsy cores and 2 hours after biopsy. RESULTS: A total of 100 patients were recruited in the study with 50 patients each in group A and B. Mean age of group A was 69.1 +/- 10 years and 67.3 +/- 8.1 years for group B. The mean pain score for group A and B at the time of probe insertion was 0.08 +/- 0.27 and 0.34 +/- 0.63 (P = .032), immediately after taking biopsy cores was 1.46 +/- 1.15 and 4.68 +/- 0.77 (P = .000), and 2 hours after biopsy was 0.14 +/- 0.45 vs 2.40 +/- 0.81 (P = .000), respectively. CONCLUSION: The mean pain score at the time of TRUS probe insertion, immediately after taking biopsy cores, and 2 hours after biopsy is statistically significantly higher in group B. PMID- 26232694 TI - Mathematical model of radiation effects on thrombopoiesis in rhesus macaques and humans. AB - A mathematical model that describes the effects of acute radiation exposure on thrombopoiesis in primates and humans is presented. Thrombopoiesis is a complex multistage dynamic process with potential differences between species. Due to known differences in cellular radiosensitivities, nadir times, and cytopenia durations, direct extrapolation from rhesus to human platelet dynamics is unrealistic. Developing mathematical models of thrombopoiesis for both humans and primates allows for the comparison of the system's response across species. Thus, data obtained in primate experiments can be extrapolated to predictions in humans. Parameter values for rhesus macaques and humans were obtained either from direct experimental measurements or through optimization procedures using dynamic data on platelet counts following radiation exposure. Model simulations accurately predict trends observed in platelet dynamics: at low radiation doses platelet counts decline after a time lag, and nadir depth is dose dependent. The models were validated using data that was not used during the parameterization process. In particular, additional experimental data was used for rhesus, and accident and platelet donor data was used for humans. The model aims to simulate the average response in rhesus and humans following irradiation. Variation in platelet dynamics due to individual variability can be modeled using Monte Carlo simulations in which parameter values are sampled from distributions. This model provides insight into the time course of the physiological effects of radiation exposure, information which could be valuable for disaster planning and survivability analysis and help in drug development of radiation medical countermeasures. PMID- 26232693 TI - NIEHS/FDA CLARITY-BPA research program update. AB - Bisphenol A (BPA) is a chemical used in the production of numerous consumer products resulting in potential daily human exposure to this chemical. The FDA previously evaluated the body of BPA toxicology data and determined that BPA is safe at current exposure levels. Although consistent with the assessment of some other regulatory agencies around the world, this determination of BPA safety continues to be debated in scientific and popular publications, resulting in conflicting messages to the public. Thus, the National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), and U.S. Food and Drug Administration (FDA) developed a consortium-based research program to link more effectively a variety of hypothesis-based research investigations and guideline-compliant safety testing with BPA. This collaboration is known as the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY BPA). This paper provides a detailed description of the conduct of the study and a midterm update on progress of the CLARITY-BPA research program. PMID- 26232695 TI - Editorial. Tibor Ganti (1933-2009): Towards the Principles of Life and Systems Chemistry. PMID- 26232696 TI - Evaluation of varicella zoster virus-specific cell-mediated immunity by using an interferon-gamma enzyme-linked immunosorbent assay. AB - BACKGROUND: Administration of the varicella vaccine induces both varicella-zoster virus (VZV)-specific humoral and cell-mediated immunity (CMI). OBJECTIVE: To assess VZV-CMI, we developed an interferon gamma enzyme-linked immunosorbent assay (IFN-gamma ELISA) that measures the quantity of total IFN-gamma in culture supernatants of human peripheral blood mononuclear cells. STUDY DESIGN: We evaluated this method by comparing the pre- and post-vaccination immune response in peripheral blood mononuclear cells of 30 healthy children who were administered an initial varicella vaccination at Konan Kosei hospital. RESULTS: IFN-gamma ELISA showed well-validated results; CMI was not detectable pre immunization but became detectable post-immunization. Seroconversion was detected in 92.6% of subjects by the immune adherence hemagglutination test; however, half of the subjects did not display an increase in CMI levels. We also compared the incidence of breakthrough varicella and herpes zoster development between CMI post-positive and post-negative vaccinees at 1-2years after the last VZV vaccination. Eight subjects had a history of varicella or herpes zoster exposure post-VZV vaccination. Two of them with post-negative CMI contracted breakthrough varicella 15-16months after the last vaccination, even though they had sufficient VZV-specific antibody levels to be considered seropositive and seroprotected. Conversely, the others with post-positive CMI did not contract breakthrough varicella, despite experiencing extensive VZV exposure through casual contact with playmates and family. CONCLUSIONS: The CMI data generated by this IFN-gamma ELISA may accurately reflect real-world immune status, and CMI may be closely related to immunoprotection against breakthrough varicella development. PMID- 26232697 TI - Neuroectoderm-specific deletion of cathepsin D in mice models human inherited neuronal ceroid lipofuscinosis type 10. AB - Cathepsin D (Ctsd) is a ubiquitously expressed aspartic protease functioning primarily in the acidic endosomal/lysosomal cell compartment. At an age of 26 +/- 1 days, mice with constitutive Ctsd deficiency (Ctsd(-/-)) die from a neurodegenerative lysosomal storage disease equivalent to the congenital neuronal ceroid lipofuscinosis (NCL) type 10 in humans. In addition to neurodegeneration, Ctsd(-/-) mice exhibit a loss of CD4(+)/CD8(+)-double-positive thymocytes and an atrophy of the intestinal mucosa. To date, it is not understood if and how these phenotypes are triggering each other. In addition, the cell type causing initiation of NCL in Ctsd(-/-) mice has not been identified yet. To investigate the tissue- and cell type-specific functions of Ctsd, we generated a novel conditional Ctsd allele by flanking the second exon with loxP sites. We compared a ubiquitous Ctsd deletion with a deletion of the protease by a Nestin-promoter controlled Cre-recombinase expression in cells of neuroectodermal origin, e.g. in neurons and astroglia, but not in microglia. First, we confirmed absence of Ctsd in the respective cell- and tissue types. The neuroectoderm specific knock-out mice survived about 5.5 days longer than the mice with ubiquitous Ctsd deletion, which was in line with the progress in brain histopathology. Atrophies of thymus and small intestine were delayed to similar extend. The conditional Ctsd knock out mouse model established in this study not only demonstrates that this type of NCL is initiated by cells of neuroectodermal origin, but will also help to further study tissue-specific functions of Ctsd in vivo. PMID- 26232698 TI - Disease dynamics in patients with acute myeloid leukemia: new biomarkers. AB - Acute myeloid leukemia (AML) is characterized by rapid growth of leukemic blast cells. Extracellular vesicles (EVs), shedding from various cells, express antigens, reflecting their cellular origin. The current study was designed to explore the role of circulating EVs as potential biomarkers of AML activity and predictors of thrombogenicity in patients with this malignancy. Blood samples were collected from healthy controls and patients with newly diagnosed AML at three time points: diagnosis, nadir, and remission. EV concentration, cell origin, and expression of coagulation proteins were characterized using fluorescence-activated cell sorting. EV cytokine contents were evaluated by protein array. Procoagulant activity was assessed using Factor Xa chromogenic assay. Forty-two AML patients were enrolled in the study. Total EV numbers were higher in patients in first remission compared with controls, whereas blast EV counts were higher in patients at diagnosis compared with controls and patients in remission. Blast EV levels were significantly lower in patients who achieved remission and were alive at 3-year follow up compared with their succumbed counterparts. At all three time points, percentage of endothelial EVs was higher in patients compared with controls. EV procoagulant activity was elevated at diagnosis and in remission, and, unlike controls' EVs, patients' EVs increased endothelial cell thrombogenicity. EVs of AML patients express membrane proteins of blast cells and might serve as biomarkers of leukemia dynamics and presence of minimal residual disease. Increased levels of endothelial EVs and their procoagulant activity may indicate a vascular injury associated with a hypercoagulable state in AML. PMID- 26232699 TI - Transcranial direct current stimulation (tDCS) in the treatment of depression: Systematic review and meta-analysis of efficacy and tolerability. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a potential alternative treatment option for major depressive episodes (MDE). OBJECTIVES: We address the efficacy and safety of tDCS in MDE. METHODS: The outcome measures were Hedges' g for continuous depression ratings, and categorical response and remission rates. RESULTS: A random effects model indicated that tDCS was superior to sham tDCS (k=11, N=393, g=0.30, 95% CI=[0.04, 0.57], p=0.027). Adjunctive antidepressant medication and cognitive control training negatively impacted on the treatment effect. The pooled log odds ratios (LOR) for response and remission were positive, but statistically non-significant (response: k=9, LOR=0.36, 95% CI[-0.16, 0.88], p=0.176, remission: k=9, LOR=0.25, 95% CI [-0.42, 0.91], p=0.468). We estimated that for a study to detect the pooled continuous effect (g=0.30) at 80% power (alpha=0.05), a total N of at least 346 would be required (with the total N required to detect the upper and lower bound being 49 and 12,693, respectively). CONCLUSIONS: tDCS may be efficacious for treatment of MDE. The data do not support the use of tDCS in treatment-resistant depression, or as an add-on augmentation treatment. Larger studies over longer treatment periods are needed. PMID- 26232700 TI - Magnetic nanoparticles: In vivo cancer diagnosis and therapy. AB - Recently, significant research efforts have been devoted to the finding of efficient approaches in order to reduce the side effects of traditional cancer therapy and diagnosis. In this context, magnetic nanoparticles have attracted much attention because of their unique physical properties, magnetic susceptibility, biocompatibility, stability and many more relevant characteristics. Particularly, magnetic nanoparticles for in vivo biomedical applications need to fulfill special criteria with respect to size, size distribution, surface charge, biodegradability or bio-eliminability and optionally bear well selected ligands for specific targeting. In this context, many routes have been developed to synthesize these materials, and tune their functionalities through intriguing techniques including functionalization, coating and encapsulation strategies. In this review article, the use of magnetic nanoparticles for cancer therapy and diagnosis is evaluated addressing potential applications in MRI, drug delivery, hyperthermia, theranostics and several other domains. In view of potential biomedical applications of magnetic nanoparticles, the review focuses on the most recent progress made with respect to synthetic routes to produce magnetic nanoparticles and their salient accomplishments for in vivo cancer diagnosis and therapy. PMID- 26232701 TI - Examining drug hydrophobicity in continuous wet granulation within a twin screw extruder. AB - The influence of active pharmaceutical ingredient (API) hydrophobicity on continuous wet granulation was studied in twin screw granulation utilizing foamed binder delivery. The APIs examined were caffeine, acetaminophen, ibuprofen and griseofulvin and the drug load was maintained constant at 15 wt%. In order to understand the impact of these APIs on the granulation process, API and binder distribution, particle size, porosity, and fracture strength were analyzed on samples collected along the screw length. It was found that the API and binder distributions were uniform along the screws regardless of the hydrophobicity of the formulation, in contrast to literature results with liquid injection. The absence of de-mixing of the hydrophobic ingredient was hypothesized to be a result of the high spread-to-soak ratio of a foamed binder that 'cages' those particles within the mass of local hydrophilic solids. PMID- 26232702 TI - Self-assembled nanoparticles from hyaluronic acid-paclitaxel prodrugs for direct cytosolic delivery and enhanced antitumor activity. AB - A prodrug-based nanosystem obtained by formulating prodrug and nanotechnology into a system is one of the most promising strategies to enhance drug delivery for disease treatment. Herein, we report a new nanosystem based on HA-PTX conjugates (HA-PTX Ns), which penetrated across cell membranes into cytosol, thus enhancing paclitaxel (PTX) delivery. HA-PTX Ns were successfully obtained based on HA-PTX, and their average particle size was approximately 200 nm. Importantly, unlike other prodrug-based nanosystems, HA-PTX Ns obtained cellular entry without entrapment within the lysosomal-endosomal system by using pathways including clathrin-mediated endocytosis, microtubule-associated internalization, macropinocytosis and cholesterol-dependence. Due to significant accumulation in tumors, HA-PTX Ns had more than a 4-fold decrease in tumor volume on day 14 in contrast with PTX alone. In conclusion, HA-PTX Ns could enter cells, bypass the lysosomal-endosomal system and improve PTX delivery. PMID- 26232703 TI - Body shape dissatisfaction is a 'normative discontent' in a young-adult Nigerian population: A study of prevalence and effects on health-related quality of life. AB - This study investigates the prevalence of weight misperception, weight preference, and body shape dissatisfaction (BSD) among young-adult Nigerians and assesses the impact of these factors on population quality-of-life (QOL). Relevant anthropometric data were collected according to internationally accepted protocols. Weight perception, weight preference, and BSD were measured using Stunkard silhouettes, while QOL was determined by subjective self-reporting. The results show that 26.7% of the population (18.8% for males and 34.5% for females) misperceived their weight. Among overweight participants, 56.6% (males) and 38.3% (females) thought they were thinner, while 11.5% (males) and 43.3% (females) thought they were heavier. Thin and obese males misperceived their weights more than their female counterparts. BSD was found in 62% of the population (52% for males and 71% for females) and was highest among obese participants (91.9%) and lowest among normal-weight participants (58.2%), irrespective of sex. In participants with BSD, QOL was worse in thin and normal-weight respondents who preferred to be heavier and in overweight respondents who preferred to be thinner. The high prevalence of weight misperception may lead to inappropriate weight loss habits, while BSD, a normative discontent in this population, negatively impacts subject QOL. PMID- 26232704 TI - Evaluation of medication adherence in Lebanese hypertensive patients. AB - Controlling hypertension is essential in cardiovascular diseases. Poor medication adherence is associated with poor disease outcomes, waste of healthcare resources, and contributes to reduced blood pressure control. This study evaluates treatment adherence to antihypertensive therapy in Lebanese hypertensive patients by estimating the proportion of adherent hypertensive patients using a validated tool and investigates what factors predict this behavior. A questionnaire-based cross-sectional study was conducted on a random sample of 210 hypertensive outpatients selected from clinics located in tertiary care hospitals and from private cardiology clinics located in Beirut. Adherence level was measured using a validated 8-item Modified Morisky Medication Adherence Scale (MMMAS). Among 210 patients, 50.5% showed high adherence, 27.1% medium adherence, and 22.4% low adherence to medication. Mean MMMAS score was 6.59+/ 2.0. In bivariate analyses, having controlled blood pressure (p=0.003) and taking a combination drug (p=0.023) were predictors of high adherence. Forgetfulness (p<0.01), complicated drug regimen (p=0.001), and side effects (p=0.006) were predictors of low adherence after multiple liner regression. Logistic regression results showed that calcium channel blockers (p=0.030) were associated with increased adherence levels. In conclusion, developing multidisciplinary intervention programs to address the factors identified, in addition to educational strategies targeting healthcare providers, are necessary to enhance patient adherence. PMID- 26232705 TI - Carcinogenicity testing of eliglustat in mice and rats. AB - Eliglustat is a novel glucosylceramide synthase inhibitor for long-term oral treatment of type 1 Gaucher disease (GD1), an inherited metabolic disorder. The carcinogenic potential of this drug has been evaluated in lifetime carcinogenicity bioassays in mice and rats. Administration of eliglustat to Swiss CD-1 mice at 0, 10, 25 or 75 mg/kg/day for 104 weeks by dietary admixture did not influence survival or bodyweight evolution, or produce any clinical indication of poor condition. At histopathology, no increases in tumor incidence for any tumor type were attributed to treatment with eliglustat. Systemic exposure to eliglustat was confirmed by a reduction in circulating levels of glucosylceramide. Administration of eliglustat to Sprague-Dawley rats by oral gavage for 105 weeks at 0, 10, 25 or 75 mg/kg/day (males) or 103 weeks at 0, 5, 15 or 50 mg/kg/day (females) did not affect survival rates, but resulted in reduced bodyweight evolution in male rats (-18% at high dose), indicating that the MTD had been achieved. At histopathology, no increases in tumor incidence were attributed to treatment with eliglustat. Systemic exposure was confirmed by toxicokinetic analyses. In conclusion, eliglustat was not carcinogenic to mice or rats in standard lifetime bioassays. PMID- 26232706 TI - Assessment of pyrogenic response of lipoteichoic acid by the monocyte activation test and the rabbit pyrogen test. AB - Lipoteichoic acid (LTA) is a non-endotoxin pyrogen of a great importance in the pathogenesis of sepsis. The Rabbit Pyrogen Test (RPT) is able to detect all types of pyrogens but involves the use of animals. The Bacterial Endotoxin Test (BET) cannot fully replace the RPT because it only detects endotoxins. The Monocyte Activation Test (MAT) is sensitive to all types of pyrogens and it is based on the same biological mechanism that is responsible for the fever reaction in humans. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) has recommended its use for other pyrogens than endotoxin because its equivalence to RPT can be demonstrated. The aim of this study was to evaluate the pyrogenic responses of the RPT and MAT that was induced by LTA. Different LTA concentrations were assayed by the MAT in parallel to the RPT. The results showed that the MAT was more sensitive than the RPT, demonstrating that the MAT detected LTA. This result may contribute to the acceptance of this test by the Brazilian regulatory agencies as a replacement for the animals used in the RPT. PMID- 26232707 TI - Impact analysis of ICH S9 on non-clinical development of anticancer drugs. AB - Cancer presents a major healthcare challenge worldwide, with several millions new cases a year, and represents a therapeutic area with a high need for new drugs. To respond to this, the parties of the International Conference for Harmonization agreed in 2007 to develop a guideline on nonclinical requirements for oncology therapeutics' development (ICH S9), which came into effect in early 2010. This guideline includes recommendations to facilitate and accelerate the development and marketing of cancer therapeutic agents for serious and life threatening malignancies and aims to address this need through a refinement and a reduction in the use of experimental animals, following the 3Rs principles. To assess the impact of ICH S9 on drug development and reduction of animal use, we performed an analysis of Marketing Authorization Applications at the European Medicines Agency relevant to the period in which the development of the guideline was approaching the final steps and its early implementation period. From the analysis performed, a consistent trend towards a decrease in the average number of non-clinical studies performed (-40.7%) and number of animals used per development program ( 58.1%) for new chemical entities has been detected, highlighting increasing compliance by companies to the recommendations of ICH S9. PMID- 26232708 TI - Sensitive and rapid RT-qPCR quantification of pathogenic Candida species in human blood. AB - For accurate diagnosis and appropriate treatment of candidiasis, we developed a highly sensitive quantitative RT-PCR (RT-qPCR) system for five Candida species that have been reported to be the major causes of bloodstream fungal infection (Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, and Candida krusei), together with a system for all pathogenic Candida species. Cells of each fungal species spiked into human peripheral blood (PB) were specifically detected at a lower detection limit of 10(0) cell/1 mL PB by this system using the newly developed specific primer sets targeting 18S or 26S rRNA of the five Candida species, together with the existing group primer set. The total count of the five Candida spp. as the sum of those obtained by using the five species primer sets was equivalent to the count obtained by using the group primer set, indicating that the group set covered the major five Candida spp. in human blood with the same degree of accuracy as the species primer sets. The RT qPCR counts of the Candida species were in good agreement with CFU counts obtained by their culture on CHROMagarTM, with a lower detection limit of 10(0)cell/mL of PB. Candida rRNA molecules were stably stored for at least 7 days at 4 degrees C by keeping the blood specimens in an RNA stabilizing reagent. These results strongly suggest that this sensitive system is useful for accurate and rapid diagnosis of Candida bloodstream infections. PMID- 26232709 TI - A method to determine photosynthetic activity from oxygen microsensor data in biofilms subjected to evaporation. AB - Phototrophic biofilms are widely distributed in nature and their ecological importance is well recognized. More recently, there has been a growing interest in using artificial phototrophic biofilms in innovative photobioreactors for production of microalgal biomass in biotechnological applications. To study physiological processes within these biofilms, microsensors have been applied in several studies. Here, the 'light-dark shift method' relies on measurement of photosynthetic activity in terms of light-induced oxygen production. However, when applied to non-submerged biofilms that can be found in numerous locations in nature, as well as in some types of photobioreactors, limitations of this approach are obvious due to rapid removal of gaseous species at the biofilm surface. Here, we introduce a mathematical correction to recover the distribution of the actual photosynthetic activity along the depth gradient in the biofilm, based on a numerical solution of the inversed diffusion equation of oxygen. This method considers changes in mass transport during the measurement period as can found on biofilms possessing a thin flow/mass transfer boundary layer (e. g., non submerged biofilms). Using both simulated and real microsensor data, the proposed method was shown to be much more accurate than the classical method, which leads to underestimations of rates near the biofilm surface. All test profiles could be recovered with a high fit. According to our simulated microsensor measurements, a depth resolution of <=20 MUm is recommended near the surface. We conclude that our method strongly improves the quality of data acquired from light-dark measurements of photosynthetic activity in biofilms. PMID- 26232710 TI - Development of single chain variable fragment (scFv) antibodies against Xylella fastidiosa subsp. pauca by phage display. AB - Xylella fastidiosa is a member of the gamma proteobacteria. It is fastidious, insect-vectored and xylem-limited and causes a variety of diseases, some severe, on a wide range of economically important perennial crops, including grape and citrus. Antibody based detection assays are commercially available for X. fastidiosa, and are effective at the species, but not at the subspecies level. We have made a library of scFv antibody fragments directed against X. fastidiosa subsp. pauca strain 9a5c (citrus) by using phage display technology. Antibody gene repertoires were PCR-amplified using 23 primers for the heavy chain variable region (V(H)) and 21 primers for the light chain variable region (V(L)). The V(H) and V(L) were joined by overlap extension PCR, and then the genes of the scFv library were ligated into the phage vector pKM19. The library contained 1.2*10(7) independent clones with full-length scFv inserts. In each of 3cycles of affinity selection with 9a5c, about 1.0*10(12) phage were used for panning with 4.1*10(6), 7.1*10(6), 2.1*10(7) phage recovered after the first, second and third cycles, respectively. Sixty-six percent of clones from the final library bound X. fastidiosa 9a5c in an ELISA. Some of these scFv antibodies recognized strain 9a5c and did not recognize X. fastidiosa strains that cause Pierce's disease of grapevine. PMID- 26232711 TI - The "postcode lottery" for the surgical correction of gynaecomastia in NHS England. AB - INTRODUCTION: Action On Plastic Surgery (AOPS) criteria for funding of gynaecomastia surgery are: the patient should be post-pubertal, have a BMI <= 25 kg/m(2), endocrine and drug causes and breast cancer should be excluded and the patient should demonstrate psychological distress. We evaluated how NHS funding for gynaecomastia surgery varies between Clinical Commissioning Groups (CCGs) in England and whether there is a "postcode lottery". METHODS: The gynaecomastia surgery policies for 211 CCGs in NHS England were reviewed against the AOPS criteria and grouped according to their funding policies: group 1 (if criteria met, funding approved); group 2, (if criteria met, prior approval required); group 3 (no criteria, individual funding request only) and group 4 (no funding). RESULTS: Policies were available for all CCGs. Fifty-nine (28.0%) CCGs were in group 1, 87 (41.2%) in group 2, 44 (20.9%) in group 3 and 21 (10.0%) in group 4. Of those in groups 1 and 2, five (3.4%) CCGs used all six AOPS criteria. Approximately 70% CCGs with criteria (in groups 1 and 2) stipulated that the patient should be post-pubertal, have a BMI <= 25 kg/m(2) and endocrine and drug causes should be excluded. Breast cancer should be excluded in 51.4% and the patient should show psychological distress in 13.7% CCGs. Of those in groups 1 and 2, 118 (80.8%) CCGs specified additional criteria. CONCLUSIONS: CCGs do not use the AOPS criteria uniformly and restrict surgery according to their own criteria. Overall, there is a "postcode lottery" for gynaecomastia surgery within NHS England. PMID- 26232712 TI - Reconstruction using massive allografts after resection of extremity osteosarcomas the study design: A retrospective cohort study. AB - PURPOSE: Allografts have been shown useful in the reconstruction of bone defects after tumor resection. This study aimed to investigate the feasibility of using massive allografts to reconstruct bone defects after resection of extremity osteosarcomas. METHODS: The clinical data of 15 patients treated with massive allograft reconstruction after resection of extremity osteosarcomas from January 2005 to January 2008 were retrospectively reviewed. Neoadjuvant and postoperative chemotherapy was used in all patients. The postoperative functions of the salvaged limbs were evaluated using the scoring system proposed by the Musculoskeletal Tumor Society (MSTS). RESULTS: All patients were followed up for a mean of 61 months (range, 14-99 months). No nonunion occurred during follow-up. The mean time to union was 9 months (range, 3-21 months). No immune rejection, allograft infection, allograft fracture, and limb length disparity occurred. However, 2 patients had broken implants. The mean MSTS score at the last follow up was 26 points. Four patients died and 2 patients had tumor recurrence. The 5 year disease free survival rate was 73.3%. CONCLUSION: Massive allograft reconstruction is safe and effective for bone defects caused by resection of extremity osteosarcomas. PMID- 26232713 TI - High-gamma band fronto-temporal coherence as a measure of functional connectivity in speech motor control. AB - The neural basis of human speech is unclear. Intracranial electrophysiological recordings have revealed that high-gamma band oscillations (70-150Hz) are observed in the frontal lobe during speech production and in the temporal lobe during speech perception. Here, we tested the hypothesis that the frontal and temporal brain regions had high-gamma coherence during speech. We recorded electrocorticography (ECoG) from the frontal and temporal cortices of five humans who underwent surgery for medically intractable epilepsy, and studied coherence between the frontal and temporal cortex during vocalization and playback of vocalization. We report two novel results. First, we observed high-gamma band as well as theta (4-8Hz) coherence between frontal and temporal lobes. Second, both high-gamma and theta coherence were stronger when subjects were actively vocalizing as compared to playback of the same vocalizations. These findings provide evidence that coupling between sensory-motor networks measured by high gamma coherence plays a key role in feedback-based monitoring and control of vocal output for human vocalization. PMID- 26232715 TI - Noise-induced damage to ribbon synapses without permanent threshold shifts in neonatal mice. AB - Recently, ribbon synapses to the hair cells (HCs) in the cochlea have become a novel site of interest in the investigation of noise-induced cochlear lesions in adult rodents (Kujawa and Liberman, 2009; Lin et al., 2011; Liu et al., 2012; Shi et al., 2013). Permanent noise-induced damage to this type of synapse can result in subsequent degeneration of spiral ganglion neurons (SGNs) in the absence of permanent changes to hearing sensitivity. To verify whether noise exposure during an early developmental period produces a similar impact on ribbon synapses, the present study examined the damaging effects of noise exposure in neonatal Kunming mice. The animals received exposure to broadband noise at 105-decibel (dB) sound pressure level (SPL) for 2h on either postnatal day 10 (P10d) or postnatal day 14 (P14d), and then hearing function (based on the auditory brainstem response (ABR)) and cochlear morphology were evaluated during either postnatal weeks 3-4 (P4w) or postnatal weeks 7-8 (P8w). There were no significant differences in the hearing threshold between noise-exposed and control animals, which suggests that noise did not cause permanent loss of hearing sensitivity. However, noise exposure did produce a significant loss of ribbon synapses, particularly in P14d mice, which continued to increase from P4w to P8w. Additionally, a corresponding reduction in the amplitude of compound action potential (CAP) was observed in the noise-exposed groups at P4w and P8w, and the CAP latency was elongated, indicating a change in synaptic function. PMID- 26232716 TI - GABA transporters control GABAergic neurotransmission in the mouse subplate. AB - The subplate is a transient layer between the cortical plate and intermediate zone in the developing cortex. Thalamo-cortical axons form temporary synapses on subplate neurons (SPns) before invading the cortical plate. Neuronal activity within the subplate is of critical importance for the development of neocortical circuits and architecture. Although both glutamatergic and GABAergic inputs on SPns were reported, short-term plasticity of GABAergic transmission has not been investigated yet. GABAergic postsynaptic currents (GPSCs) were recorded from SPns in coronal neocortical slices prepared from postnatal day 3-4 mice using whole cell patch-clamp technique. Evoked GPSCs (eGPSCs) elicited by electrical paired pulse stimulation demonstrated paired-pulse depression at all interstimulus intervals tested. Baclofen, a specific GABAB receptor (GABABR) agonist, reduced eGPSC amplitudes and increased paired-pulse ratio (PPR), suggesting presynaptic location of functional GABABRs. Baclofen-induced effects were alleviated by (2S) 3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2 hydroxypropyl](phenylmethyl)phosphinic acid (CGP55845), a selective GABABR blocker. Moreover, CGP55845 increased eGPSC amplitudes and decreased PPR even under control conditions, indicating that GABABRs are tonically activated by ambient GABA. Because extracellular GABA concentration is mainly regulated by GABA transporters (GATs), we asked whether GATs release GABA. 1,2,5,6-tetrahydro 1-[2-[[(diphenylmethylene)amino]oxy]ethyl]-3-pyridinecarboxylic acid (NNC-711) (10MUM), a selective GAT-1 blocker, increased eGPSC decay time, decreased eGPSC amplitudes and PPR. The two last effects but not the first one were blocked by CGP55845, indicating that GAT-1 blockade causes an elevation of extracellular GABA concentration and in turn activation of extrasynaptic GABAARs and presynaptic GABABRs. 1-[2-[tris(4-methoxyphenyl)methoxy]ethyl]-(S)-3 piperidinecarboxylic acid (SNAP-5114), a specific GAT-2/3 blocker, failed to affect eGPSC kinetics. However, in contrast to NNC-711 SNAP-5114 increased eGPSC amplitudes and decreased PPR. In the presence of SNAP-5114 CGP55845 did not influence GABAergic transmission, indicating that GABABRs are not activated any longer. We conclude that in the subplate GAT-2/3 operates in reverse mode. GABA released via GAT-2/3 activates presynaptic GABABRs on GABAergic synapses and tonically inhibits GABAergic inputs on SPns. PMID- 26232714 TI - The gestational foundation of sex differences in development and vulnerability. AB - Despite long-standing interest in the role of sex on human development, the functional consequences of fetal sex on early development are not well understood. Here we explore the gestational origins of sex as a moderator of development. In accordance with the focus of this special issue, we examine evidence for a sex differential in vulnerability to prenatal and perinatal risks. Exposures evaluated include those present in the external environment (e.g., lead, pesticides), those introduced by maternal behaviors (e.g., alcohol, opioid use), and those resulting from an adverse intrauterine environment (e.g., preterm birth). We also provide current knowledge on the degree to which sex differences in fetal neurobehavioral development (i.e., cardiac and motor patterns) are present prior to birth. Also considered are contemporaneous and persistent sex of fetus effects on the pregnant woman. Converging evidence confirms that infant and early childhood developmental outcomes of male fetuses exposed to prenatal and perinatal adversities are more highly impaired than those of female fetuses. In certain circumstances, male fetuses are both more frequently exposed to early adversities and more affected by them when exposed than are female fetuses. The mechanisms through which biological sex imparts vulnerability or protection on the developing nervous system are largely unknown. We consider models that implicate variation in maturation, placental functioning, and the neuroendocrine milieu as potential contributors. Many studies use sex as a control variable, some analyze and report main effects for sex, but those that report interaction terms for sex are scarce. As a result, the true scope of sex differences in vulnerability is unknown. PMID- 26232717 TI - Bringing plant-based veterinary vaccines to market: Managing regulatory and commercial hurdles. AB - The production of recombinant vaccines in plants may help to reduce the burden of veterinary diseases, which cause major economic losses and in some cases can affect human health. While there is abundant research in this area, a knowledge gap exists between the ability to create and evaluate plant-based products in the laboratory, and the ability to take these products on a path to commercialization. The current report, arising from a workshop sponsored by an Organisation for Economic Co-operation and Development (OECD) Co-operative Research Programme, addresses this gap by providing guidance in planning for the commercialization of plant-made vaccines for animal use. It includes relevant information on developing business plans, assessing market opportunities, manufacturing scale-up, financing, protecting and using intellectual property, and regulatory approval with a focus on Canadian regulations. PMID- 26232718 TI - Chronic exposure to broadband noise at moderate sound pressure levels spatially shifts tone-evoked responses in the rat auditory midbrain. AB - Noise-induced hearing disorders are a significant public health concern. One cause of such disorders is exposure to high sound pressure levels (SPLs) above 85 dBA for eight hours/day. High SPL exposures occur in occupational and recreational settings and affect a substantial proportion of the population. However, an even larger proportion is exposed to more moderate SPLs for longer durations. Therefore, there is significant need to better understand the impact of chronic, moderate SPL exposures on auditory processing, especially in the absence of hearing loss. In this study, we applied functional magnetic resonance imaging (fMRI) with tonal acoustic stimulation on an established broadband rat exposure model (65 dB SPL, 30 kHz low-pass, 60 days). The auditory midbrain response of exposed subjects to 7 kHz stimulation (within exposure bandwidth) shifts dorsolaterally to regions that typically respond to lower stimulation frequencies. This shift is quantified by a region of interest analysis that shows that fMRI signals are higher in the dorsolateral midbrain of exposed subjects and in the ventromedial midbrain of control subjects (p<0.05). Also, the center of the responsive region in exposed subjects shifts dorsally relative to that of controls (p<0.05). A similar statistically significant shift (p<0.01) is observed using 40 kHz stimulation (above exposure bandwidth). The results suggest that high frequency midbrain regions above the exposure bandwidth spatially expand due to exposure. This expansion shifts lower frequency regions dorsolaterally. Similar observations have previously been made in the rat auditory cortex. Therefore, moderate SPL exposures affect auditory processing at multiple levels, from the auditory cortex to the midbrain. PMID- 26232719 TI - Antimicrobial efficacy of photodynamic therapy, Nd:YAG laser and QMiX solution against Enterococcus faecalis biofilm. AB - BACKGROUND: Lasers have been recommended in final root canal disinfection protocol, however, there is no clear evidence about their efficacy against bacteria in biofilms. The aim of the study was to evaluate and compare the disinfection effect of antimicrobial photodynamic therapy (aPDT), Nd:YAG laser and QMiX solution against Enterococcus faecalis biofilm. METHODS: The study sample consisted of 65 dentine slices, which were inoculated with E. faecalis and incubated anaerobically for three weeks. The dentine discs were randomly allocated to one of the following experimental groups: aPDT (100 mW, 10 mg/ml phenothiazinium chloride, 1 min), Nd:YAG laser (2 W, 15 Hz, 4*5 s), QMiX solution (1 min). Positive controls did not receive any treatment and negative controls were treated with 5.25% NaOCl. To harvest surviving adherent cells, each dentine sample was transffered to a test tube containing of TSB, serial ten-fold dilutions were made and aliquot of 1 ml was plated onto blood agar plates and incubated for 48 h. Colony forming units grown were counted and transformed into actual counts based on the dilution factor. The remaining viable cells after each protocol were analysed by FISH. RESULTS: The aPDT and the QMiX solution were equally effective, with the reduction rate of E. faecalis CFUs of 98.8% and 99.3% respectively (p=1.107). The Nd:YAG laser caused 96% reduction of E. faecalis (P<0.001). CONCLUSION: The aPDT and the QMiX solution showed similar antibacterial efficacy against old E. faecalis biofilm, followed by Nd:YAG irradiation. PMID- 26232720 TI - Over-the-counter cough medicines: New approaches. AB - The global market for over-the-counter (OTC) medicines in the category cough/cold is enormous amounting to 5.77 billion euro in 2014 (source IMS). Despite this enormous healthcare investment, mainly by direct consumer purchase, evidence for efficacy is poor by modern standards. Because of a lack of new drug development existing OTC medicines are supported by trials of inadequate design. This has led to the claim that cough medicines are inefficacious. Recent developments in measuring cough support some existing agents but investment in modern studies to provide comprehensive proof of efficacy has not happened. The switch from prescription medicine to OTC which has occurred in other markets will not occur in antitussives since novel therapies have yet to be developed. One area, that of herbal derived medicines, has seen innovation because it is less hampered by regulatory constraints. PMID- 26232721 TI - ETHICS, EMBRYOS, AND EVIDENCE: A LOOK BACK AT WARNOCK. AB - The Report of the Committee of Inquiry into Human Fertilisation and Embryology, the Warnock Report, forms the basis of the UK legislation on embryo research, and its influence continues to be felt, even though over 30 years have passed since its publication. The Warnock Committee was the first of its kind to consider how advancements in human fertilisation and embryology should be regulated. This article examines the evidence submitted to the Warnock Committee, upon which its members ultimately reached their conclusions. With ongoing debate as to the status of the human embryo, it is important to recognise that the legislative position is one that was reached after extensive consultation and consideration of submitted evidence by the Warnock Committee. This article considers the differing ethical viewpoints that were expressed by organisations both prior and post-publication of the Warnock Report, and how the Committee used that evidence to reach their conclusions, and ultimately calls for a new Warnock-style committee. PMID- 26232722 TI - Family practice and the quality of primary care: a study of Chinese patients in Guangdong Province. AB - BACKGROUND: In 2009, China launched its new round of health care reform. One of its priorities was to strengthen primary care and establish a family practice system. OBJECTIVE: This study examined the relationship between use of family practice physician for primary care and the quality of primary care. METHODS: Eight health care organizations were sampled from three cities in Guangdong Province, China. One thousand six hundred and forty five patients of age 18 and older who visited one of the study sites as their usual source of primary care were systematically selected and surveyed using Johns Hopkins China-validated Primary Care Assessment Tool (PCAT). Analyses were performed to compare the quality of primary care experienced between patients who contracted for family practice services and those who did not. RESULTS: Total PCAT score as well as scores in first contact-access, continuity, comprehensiveness and coordination domains were higher among patients who contracted with family practice services, compared to those who did not. In addition, patients who sought care through family practice services reported greater satisfaction with their care experience. CONCLUSION: This study provided evidence that family practice has the potential to provide higher-quality primary care, which may encourage patients to seek family practice physicians for their primary care needs, and help family practitioners better perform gatekeeping functions. PMID- 26232723 TI - From mouth to anus: Functional and structural relevance of enteric neurons in the Drosophila melanogaster gut. AB - The intestinal tract is the main organ involved in host nutritional homeostasis. Intestinal function in both vertebrates and invertebrates is partly controlled by enteric neurons that innervate the gut. Though anatomical and functional aspects of enteric neurons are relatively less characterized in Drosophila than in large insects, analyses of the role of the enteric neurons in flies have remarkably progressed in the last few years. In this review, we first provide a summary of the structure and function of the Drosophila intestine. We then discuss recent studies of the structure and function of enteric neurons in Drosophila melanogaster. PMID- 26232724 TI - Intracellular transduction of TAT-Hsp27 fusion protein enhancing cell survival and regeneration capacity of cardiac stem cells in acute myocardial infarction. AB - Myocardial infarction (MI) results in the substantial loss of functional cardiomyocytes, which frequently leads to intractable heart disorders. Cardiac stem cells (CSCs) that retain the capacity to replace all cardiac cells might be a promising strategy for providing a source of new functional cardiomyocytes; however, the poor survival and engraftment of transplanted CSCs in the hostile environment of MI critically mitigate their therapeutic benefits. To capitalize their therapeutic potential, an ex vivo strategy in which CSCs were introduced to the recombinant heat shock protein 27 (Hsp27) through a TAT protein transduction domain for increasing the viability and engraftment in the infarcted myocardium was designed. A recombinant TAT fused Hsp27 (TAT-Hsp27) was able to enter CSCs in a dose-dependent manner. CSCs transduced with TAT-Hsp27 expressed not only endogenous Hsp27 but externally introduced Hsp27, resulting in substantial increase of their anti-oxidative and anti-apoptotic properties via suppressing reactive oxygen species production, the MAPKs signaling pathway, and caspase activation. TAT-Hsp27 enabled CSCs to be protected from apoptotic- and hypoxic induced cell death during in vitro cardiomyogenic differentiation. In vivo studies demonstrated that CSCs transduced TAT-Hsp27 significantly increased the survival and engraftment in the acutely infarcted myocardium, which is closely related to caspase activity suppression. Finally, CSCs transduced TAT-Hsp27 improved cardiac function and attenuated cardiac remodeling in comparison with non-transduced CSCs. Overall, our approach, which is based on the ex vivo intracellular transduction of TAT-Hsp27 into CSCs before myocardial delivery, might be effective in treating MI. PMID- 26232725 TI - Clinical impact of migraine for the management of glaucoma patients. AB - Migraine is a common and debilitating primary headache disorder that affects 10 15% of the general population, particularly people of working age. Migraine is relevant to providers of clinical eye-care because migraine attacks are associated with a range of visual sensory symptoms, and because of growing evidence that the results of standard tests of visual function necessary for the diagnosis and monitoring of glaucoma (visual fields, electrophysiology, ocular imaging) can be abnormal due to migraine. These abnormalities are measureable in between migraine events (the interictal period), despite patients being asymptomatic and otherwise healthy. This picture is further complicated by epidemiological data that suggests an increased prevalence of migraine in patients with glaucoma, particularly in patients with normal tension glaucoma. We discuss how migraine, as a co-morbidity, can confound the results and interpretation of clinical tests that form part of contemporary glaucoma evaluation, and provide practical evidence-based recommendations for the clinical testing and management of patients with migraine who attend eye-care settings. PMID- 26232726 TI - Feasibility and efficacy of laparoscopic restaging surgery for women with unexpected ovarian malignancy. AB - OBJECTIVE: To evaluate the feasibility, surgical outcomes and complications of laparoscopic restaging surgery for women with unexpected ovarian malignancy. STUDY DESIGN: We conducted a retrospective chart review of 14 women with unexpected ovarian malignancy who underwent laparoscopic restaging surgery including peritoneal washing cytology, laparoscopic pelvic and paraaortic lymphadenectomy up to the left renal vein level, omentectomy, and multiple peritoneal biopsies, and hysterectomy except three fertility saving surgery. RESULTS: The median age and median body mass index women were 49 years (range, 22 63) and 24.2m/kg(2) (range, 18.9-25.3), respectively. The median operating time was 230min (range, 155-370). The median numbers of harvested pelvic and paraaortic lymph nodes were 26 (range, 6-41) and 18 (range, 2-40), respectively. The median return of bowel activity was 28h (range, 21-79). Four of the women were upstaged from the initial presumed stage. There were two intraoperative complications, laceration of the inferior vena cava and cisterna chyli rupture. There was one postoperative complication, port-site metastasis. There was no conversion to laparotomic surgery. The median follow-up period was 33 months. Thirteen of the patients have no evidence of recurrences, however one patient died after 22 months after the surgery. CONCLUSION: Laparoscopic restaging surgery, performed by a specialized laparoscopic oncologist with sufficient laparoscopic experience and a well-trained operating team, is both feasible and effective in the management of unexpected ovarian malignancies. PMID- 26232727 TI - Ethnic disparities in maternal obesity and weight gain during pregnancy. The Generation R Study. AB - OBJECTIVE: To examine ethnic disparities in maternal prepregnancy obesity and gestational weight gain, and to examine to which extent these differences can be explained by socio-demographic, lifestyle and pregnancy related characteristics. METHODS: In a multi-ethnic population-based prospective cohort study among 6444 pregnant women in Rotterdam, the Netherlands, maternal anthropometrics were repeatedly measured throughout pregnancy. Ethnicity, socio-demographic, lifestyle and pregnancy related characteristics were assessed by physical examinations and questionnaires. RESULTS: The prevalence of prepregnancy overweight and obesity was 23.1% among Dutch-origin women. Statistically higher prevalences were observed among Dutch Antillean-origin (40.8%), Moroccan-origin (49.9%), Surinamese-Creole-origin (38.6%) and Turkish-origin (41.1%) women (all p-values <0.05). Only Dutch Antillean-origin, Moroccan-origin, Surinamese-Creole-origin and Turkish-origin women had higher risks of maternal prepregnancy overweight and obesity as compared to Dutch-origin women (p-values <0.05). Socio-demographic and lifestyle related characteristics explained up to 45% of the ethnic differences in body mass index. Compared to Dutch-origin women, total gestational weight gain was lower in all ethnic minority groups, except for Cape Verdean-origin and Surinamese-Creole-origin women (p-values <0.05). Lifestyle and pregnancy related characteristics explained up to 33% and 40% of these associations, respectively. The largest ethnic differences in gestational weight gain were observed in late pregnancy. CONCLUSION: We observed moderate ethnic differences in maternal prepregnancy overweight, obesity and gestational weight gain. Socio-demographic, lifestyle and pregnancy related characteristics partly explained these differences. Whether these differences also lead to ethnic differences in maternal and childhood outcomes should be further studied. PMID- 26232728 TI - Kupffer cell inactivation by carbon monoxide bound to red blood cells preserves hepatic cytochrome P450 via anti-oxidant and anti-inflammatory effects exerted through the HMGB1/TLR-4 pathway during resuscitation from hemorrhagic shock. AB - Red blood cell (RBC) transfusions for controlling hemorrhaging induce systemic ischemia reperfusion, resulting in a decrease in hepatic cytochrome P450 (CYP) levels. Carbon monoxide (CO), when bound to red blood cells (CO-RBC) has the potential to protect the hepatic CYP protein to produce a resuscitative effect in a hemorrhagic shock rat model. The aim of this study was to investigate the mechanism by which CO-RBC resuscitation from a massive hemorrhage protects against a decrease in hepatic CYP. In the early phase (~1h) after a hemorrhage and RBC resuscitation, hepatic CYP protein levels were significantly decreased with increasing hepatic free heme levels, but were maintained by a pre-treatment of gadolinium chloride (GdCl3), a Kupffer cell inhibitor, and Trolox, an anti oxidant agent, as well as CO-RBC resuscitation. Under these conditions, the production of reactive oxygen species (ROS) derived from activated Kupffer cells was increased, but this increase was suppressed by CO-RBC resuscitation. At a late phase (6~24h), CYP mRNA levels decreased after hemorrhage and RBC resuscitation, but not in the case of CO-RBC resuscitation. The increases in plasma IL-6 and TNF-alpha levels were decreased by CO-RBC resuscitation via the suppression of the toll-like receptor-4 (TLR-4) and the expression of the high mobility group box-1 (HMGB-1). Hepatic CYP protection after a hemorrhage and CO RBC resuscitation can be attributed to the inactivation of Kupffer cells, resulting in the suppression of ROS production in the early phase and the suppression of inflammatory cytokine production via the TLR-4/HMGB-1signal pathway in the late phase. PMID- 26232730 TI - Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection. AB - Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the central nervous system, being expressed in neurons and non-neuronal cells, where they participate in a variety of physiological responses like memory, learning, locomotion, attention, among others. We will focus on the alpha7 nAChR subtype, which has been implicated in neuroprotection, synaptic plasticity and neuronal survival, and is considered as a potential therapeutic target for several neurological diseases. Oxidative stress and neuroinflammation are currently considered as two of the most important pathological mechanisms common in neurodegenerative diseases such as Alzheimer, Parkinson or Huntington diseases. In this review, we will first analysed the distribution and expression of nAChR in mammalian brain. Then, we focused on the function of the alpha7 nAChR subtype in neuronal and non-neuronal cells and its role in immune responses (cholinergic anti-inflammatory pathway). Finally, we will revise the anti-inflammatory pathway promoted via alpha7 nAChR activation that is related to recruitment and activation of Jak2/STAT3 pathway, which on the one hand inhibits NF-kappaB nuclear translocation, and on the other hand, activates the master regulator of oxidative stress Nrf2/HO-1. This review provides a profound insight into the role of the alpha7 nAChR subtype in microglia and point out to microglial alpha7/HO-1 pathway as an anti-inflammatory therapeutic target. PMID- 26232731 TI - Floc properties of polyaluminum ferric chloride in water treatment: The effect of Al/Fe molar ratio and basicity. AB - Producing flocs with desired properties is significant for contaminants removal in water treatment works. In this study, an inorganic composite coagulant, polyaluminum ferric chloride (PAFC), was prepared and used in surface water treatment, and the influence of Al/Fe molar ratio and basicity (B) on floc properties was investigated. The contribution of metal species analysis showed a competition relationship between Al and Fe in the pre-hydrolysis, while the monomeric contents decreased with the increase of B value. The investigation of floc properties was conducted on a laser scattering instrument, in terms of floc size, strength, recovery capacity and fractal dimension (Df). The largest floc size and the highest growth rate was achieved when Al/Fe=7:1 and B=1.5. Floc formed at the Al/Fe ratios of 5:1 and 7:1 were considered to be more compact. Meanwhile, the Df value increased when B value was increased. At Al/Fe=7:1 and B=1.5, strongest flocs were obtained. During the breakage period, the Df value increased. As lower shear was replaced, the floc size decreased continuously, with a further increase of Df value. However, after breakage at higher shear, all of the PAFC flocs showed capacity for regrowth and loose structures were formed. PMID- 26232729 TI - Development of [(18)F]ASEM, a specific radiotracer for quantification of the alpha7-nAChR with positron-emission tomography. AB - The alpha-7 subtype of the nicotinic acetylcholine receptor (alpha7-nAChR) is fundamental to physiology; it mediates various brain functions and represents an important target for drug discovery. Exploration of the brain nicotinic acetylcholine receptors (nAChRs) using positron-emission tomography (PET) will make it possible to better understand the important role of this receptor and to study its involvement in schizophrenia, bipolar disorder, Alzheimer's and Parkinson's diseases, drug dependence, inflammation and many other disorders and simplify the development of nicotinic drugs for treatment of these disorders. Until recently, PET imaging of alpha7-nAChRs has been impeded by the absence of good radiotracers. This review describes various endeavors to develop alpha7 nAChR PET tracers by several research groups including the author's group. Most initial PET tracers for imaging alpha7-nAChRs did not exhibit suitable imaging properties due to their low specific binding. Newly discovered [(18)F]ASEM is the first highly specific alpha7-nAChR radioligand and in 2014 it was translated to human PET imaging. PMID- 26232732 TI - Construction of adhesion maps for contacts between a sphere and a half-space: Considering size effects of the sphere. AB - Previous adhesion maps, such as the JG (Johnson-Greenwood) and YCG (Yao Ciavarella-Gao) maps, are used to guide the selection of Bradley, DMT, M-D, JKR and Hertz models. However, when the size of the contact sphere decreases to the small scale, the applicability of JG and YCG maps is limited because the assumptions regarding the contact region profile, interaction between contact bodies and sphere shape in the classical models constituting these two maps are no longer valid. To avoid this limitation, in this paper, a new numerical model considering size effects of the sphere is established first and then introduced into the new adhesion maps together with the YGG (Yao-Guduru-Gao) model and Hertz model. Regimes of these models in the new map under a certain sphere radius are demarcated by the criteria related to the relative force differences and the ratio of contact radius to sphere radius. In addition, the approaches at pull off, jump-in and jump-out for different Tabor parameters and sphere radii are provided in the new maps. Finally, to make the new maps more feasible, the numerical results of approaches, force and contact radius involved in the maps are formularized by using the piecewise fitting. PMID- 26232734 TI - Candida albicans and Streptococcus pyogenes balanitis: diabetes or STI? PMID- 26232733 TI - Developmentally determined reduction in CD31 during gestation is associated with CD8+ T cell effector differentiation in preterm infants. AB - Homeostatic T cell proliferation is more robust during human fetal development. In order to understand the relative effect of normal fetal homeostasis and perinatal exposures on CD8+ T cell behavior in PT infants, we characterized umbilical cord blood CD8+ T cells from infants born between 23-42weeks gestation. Subjects were recruited as part of the NHLBI-sponsored Prematurity and Respiratory Outcomes Program. Cord blood from PT infants had fewer naive CD8+ T cells and lower regulatory CD31 expression on both naive and effector, independent of prenatal exposures. CD8+ T cell in vitro effector function was greater at younger gestational ages, an effect that was exaggerated in infants with prior inflammatory exposures. These results suggest that CD8+ T cells earlier in gestation have loss of regulatory co-receptor CD31 and greater effector differentiation, which may place PT neonates at unique risk for CD8+ T cell-mediated inflammation and impaired T cell memory formation. PMID- 26232735 TI - Management of cytomegalovirus retinitis in HIV infection in the era of highly active antiretroviral therapy. PMID- 26232736 TI - Response to article - T Farmer et al. Are text reminders useful to reduce DNA rates in routine GUM clinics? (Int J STD AIDS 2014; 25: 289-293). PMID- 26232737 TI - BASHH/EAGA position statement on the HIV window period. PMID- 26232738 TI - International scale implementation of the CNOSSOS-EU road traffic noise prediction model for epidemiological studies. AB - The EU-FP7-funded BioSHaRE project is using individual-level data pooled from several national cohort studies in Europe to investigate the relationship of road traffic noise and health. The detailed input data (land cover and traffic characteristics) required for noise exposure modelling are not always available over whole countries while data that are comparable in spatial resolution between different countries is needed for harmonised exposure assessment. Here, we assess the feasibility using the CNOSSOS-EU road traffic noise prediction model with coarser input data in terms of model performance. Starting with a model using the highest resolution datasets, we progressively introduced lower resolution data over five further model runs and compared noise level estimates to measurements. We conclude that a low resolution noise model should provide adequate performance for exposure ranking (Spearman's rank = 0.75; p < 0.001), but with relatively large errors in predicted noise levels (RMSE = 4.46 dB(A)). PMID- 26232739 TI - Antibiotic resistance marker genes as environmental pollutants in GMO-pristine agricultural soils in Austria. AB - Antibiotic resistance genes may be considered as environmental pollutants if anthropogenic emission and manipulations increase their prevalence above usually occurring background levels. The prevalence of aph(3')-IIa/nptII and aph(3') IIIa/nptIII - frequent marker genes in plant biotechnology conferring resistance to certain aminoglycosides - was determined in Austrian soils from 100 maize and potato fields not yet exposed to but eligible for GMO crop cultivation. Total soil DNA extracts were analysed by nptII/nptIII-specific TaqMan real time PCR. Of all fields 6% were positive for nptII (median: 150 copies/g soil; range: 31-856) and 85% for nptIII (1190 copies/g soil; 13-61600). The copy-number deduced prevalence of nptIII carriers was 14-fold higher compared to nptII. Of the cultivable kanamycin-resistant soil bacteria 1.8% (95% confidence interval: 0 3.3%) were positive for nptIII, none for nptII (0-0.8%). The nptII-load of the studied soils was low rendering nptII a typical candidate as environmental pollutant upon anthropogenic release into these ecosystems. PMID- 26232740 TI - Four limb amputations due to peripheral gangrene from inotrope use - Case report and review of the literature. AB - INTRODUCTION: We present a rare case of 4 limb amputations due to peripheral gangrene which resulted from the use of inotropes for septic shock. PRESENTATION OF CASE: A 72-year-old woman with no past medical history presented with fever and pain in bilateral big toes. She was diagnosed with Streptococcal pneumoniae septicaemia and was started on broad spectrum antibiotics, dopamine and noradrenaline in the medical intensive care unit. She developed peripheral gangrene of all 4 extremities due to microvascular spasm from inotrope use and 4 limb amputations were performed electively in a single stage. DISCUSSION: The gangrene was contributed by the presence of disseminated intravascular coagulation and septic shock. There was no evidence of an autoimmune disorder or vasculitis on laboratory investigations and tissue histology. CONCLUSION: Microvascular spasm is a rare complication of inotrope use which may lead to extensive peripheral gangrene. Anecdotal reports of reversal agents have been discussed. Four limb amputations are a reasonable option especially if done in an elective setting after the gangrene has demarcated itself. Rehabilitation with prosthesis after 4 limb amputations can result in good functional outcome. PMID- 26232741 TI - Rhinolith mimicking a toothache. AB - INTRODUCTION: A rhinolith is a calcified mass formed as a result of solidification of mucous foreign objects and gradual accretion of mineral salts. Toothache is not known to be the typical presenting symptom, and to our knowledge, has yet to be reported. CASE REPORT: A 42-year old female referred by her general dental practitioner with a four month history of constant pain of the unrestored upper right central incisor tooth. Incidentally, she also gave a one year history of right-sided sinonasal congestion and intermittent blood stained rhinorrhea. DISCUSSION: Rhinoliths are uncommon and rarely encountered in clinical practice. This is due to the fact that they remain asymptomatic, and undetected for many years. They may present as incidental radio-opaque lesions in the nasal maxillary antrum on routine dental panoramic radiographs. CONCLUSION: Rhinolith should be part of the differential diagnosis of atypical anterior maxillary dental pain in the absence of obvious clinical dental pathology. PMID- 26232742 TI - A rare cause of claudication treated with IVC reconstruction: A case report. AB - INTRODUCTION: Inferior vena cava (IVC) agenesis is one of rare entities of IVC anomalies which presents in young patients with unprovoked deep venous thrombosis (DVT) or unexplained bilateral lower venous insufficiency. We are presenting a case of IVC agenesis which was treated with IVC reconstruction. CASE: We describe a case of 28 years old male with painful bilateral lower extremity varicose veins and a history of right lower extremity DVT and was on anticoagulation with warfarin. He was found to have extensive bilateral greater saphenous veins (GSVs) and right femoral vein reflux with patent bilateral deep veins. He was treated with bilateral GSV ablation and microphlebectomies. Six weeks later he presented with acute bilateral iliofemoral DVTs treated with tissue plasminogen activator thrombolysis tPA via bilateral popliteal vein access which helped relieve his leg swelling but he continued to have debilitating venous claudication. A computed tomography (CT scan) demonstrated resolution of DVT but revealed IVC agenesis. He underwent IVC reconstruction with prosthetic graft which helped complete resolution of his chronically debilitating bilateral lower extremity claudication. CONCLUSION: In young patients with severe manifestations of lower extremity venous hypertension i.e. edema, varicosity and DVT, central venous anomaly should be considered. Severely symptomatic cases of IVC agenesis can be treated with IVC reconstruction. PMID- 26232743 TI - Unitization supports lasting performance and generalization on a relational memory task: Evidence from a previously undocumented developmental amnesic case. AB - Recently, the amnesic case D.A. was shown to circumvent his relational memory impairments, as observed in the transverse patterning (TP) task, using a self generated unitization strategy, and such performance benefits were maintained over extended delays (Ryan et al., 2013). "Unitization" encourages fusing of distinct items, through an action, into a single unit from which the relations among the items may then be derived. Here, we provide the first documentation of the developmental amnesic case, N.C., who presents with relatively circumscribed lesions to the extended hippocampal system, and with impaired episodic memory. Despite impairments on standard versions of TP, N.C. benefited from unitization, showed evidence of transfer to novel stimuli, and maintained his performance over extended delays. These findings suggest that self-generation is not a requirement for the successful implementation of unitization, and further provides the first evidence of rapid transfer and long-lasting success of a learning strategy in a human amnesic case. PMID- 26232744 TI - Infant VEPs reveal neural correlates of implicit naming: Lateralized differences between lexicalized versus name-unknown pictures. AB - Recent behavioural studies with toddlers have demonstrated that simply viewing a picture in silence triggers a cascade of linguistic processing which activates a representation of the picture's name (Mani and Plunkett, 2010, 2011). Electrophysiological studies have also shown that viewing a picture modulates the auditory evoked potentials (AEPs) triggered by later speech, from early in the second year of life (Duta et al., 2012; Friedrich and Friederici, 2005; Mani et al., 2011) further supporting the notion that picture viewing gives rise to a representation of the picture's name against which later speech can be matched. However, little is known about how and when the implicit name arises during picture viewing, or about the electrophysiological activity which supports this linguistic process. We report differences in the visual evoked potentials (VEPs) of fourteen-month-old infants who saw photographs of animals and objects, some of which were name-known (lexicalized), while waiting for an auditory label to be presented. During silent picture viewing, lateralized neural activity was selectively triggered by lexicalized items, as compared to nameless items. Lexicalized items generated a short-lasting negative-going deflection over frontal, left centro-temporal, and left occipital regions shortly after the picture appeared (126-225 ms). A positive deflection was also observed over the right hemisphere (particularly centro-temporal regions) in a later, longer lasting window (421-720 ms). The lateralization of these differences in the VEP suggests the possible involvement of linguistic processes during picture viewing, and may reflect activity involved in the implicit activation of the picture's name. PMID- 26232745 TI - Effects and outcomes of third-party reproduction: parents. AB - Third-party reproduction has introduced a host of changing family constellations. Research has shown that children conceived through third-party reproduction are doing well psychologically and developmentally, but what about their parents? How have they coped with the transition to third-party reproduction? Has the experience impacted their marital stability or the quality of their parenting? This review will address parents of children conceived through oocyte donation, parents of children conceived through gestational surrogacy, and gay male parents of children conceived through oocyte donation and gestational surrogacy. PMID- 26232746 TI - Effects of fertility drugs on cancers other than breast and gynecologic malignancies. AB - OBJECTIVE: To examine the relationship of ovulation-stimulating drugs to risk of cancers other than breast and gynecologic malignancies. DESIGN: Retrospective cohort study, with additional follow-up since initial report. SETTING: Reproductive endocrinology practices. PATIENT(S): Among a cohort of 12,193 women evaluated for infertility between 1965 and 1988, a total of 9,892 women (81.1% of the eligible population) were followed through 2010, via passive and active (questionnaire) approaches. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Hazard ratios (HRs) and 95% confidence intervals (CIs) for various fertility treatment parameters for select cancers. RESULT(S): During 30.0 median years of follow-up (285,332 person-years), 91 colorectal cancers, 84 lung cancers, 55 thyroid cancers, and 70 melanomas were diagnosed among study subjects. Clomiphene citrate (CC), used by 38.1% of patients, was not associated with colorectal or lung cancer risks, but was related significantly to melanoma (HR = 1.95; 95% CI: 1.18-3.22), and non-significantly to thyroid cancer risks (HR = 1.57; 95% CI: 0.89-2.75). The highest melanoma risks were seen among those with the lowest drug exposure levels, but thyroid cancer risk was greatest among the heavily exposed patients (HR = 1.96; 95% CI: 0.92-4.17 for those receiving >2,250 mg). Clomiphene citrate-associated risks for thyroid cancer were somewhat higher among nulligravid, compared with gravid, women, but did not differ according to distinct causes of infertility. Gonadotropins, used by only 9.7% of subjects, were not related to risk of any of the assessed cancers. CONCLUSION(S): Our results provide support for continued monitoring of both melanoma and thyroid cancer risk among patients receiving fertility drugs. PMID- 26232747 TI - Quinoxaline based bio-active mixed ligand transition metal complexes: Synthesis, characterization, electrochemical, antimicrobial, DNA binding, cleavage, antioxidant and molecular docking studies. AB - Co(II), Ni(II), Cu(II) and Zn(II) mixed ligand complexes have been synthesized from N(2), N(3)-bis(4-nitrophenyl)quinoxaline-2,3-diamine and 1,10 phenanthroline. The compounds were characterized by elemental analyses, molar conductance, magnetic susceptibility, IR, UV-Vis., (1)H NMR, mass and ESR spectra. Octahedral geometry has been assigned for Co(II), Ni(II) and Zn(II) complexes and distorted octahedral geometry for Cu(II) complex. Electrochemical behavior of the synthesized complexes was studied using cyclic voltammetry. Grain size and surface morphologies of the complexes were determined by powder XRD and SEM analyses. The mixed ligand metal complexes were screened for antimicrobial activity against bacterial species Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus; fungal species Aspergillus niger, and Candida albicans by disc diffusion method. The DNA binding and DNA cleavage activities of the compounds were determined using electronic absorption titration and agarose gel electrophoresis respectively. The superoxide radical scavenging and free radical scavenging activities of the Cu(II) complex was also evaluated. Molecular docking studies of the synthesized mixed ligand metal complexes were carried out against B-DNA dodecamer and the protein Plasmodium falciparum dihydrofolate reductase (pf DHFR). PMID- 26232748 TI - Purple non-sulfur photosynthetic bacteria monitor environmental stresses. AB - Heavy metal ion pollution and oxygen deficiency are major environmental risks for microorganisms in aqueous habitat. The potential of purple non-sulfur photosynthetic bacteria for biomonitoring and bioremediation was assessed by investigating the photosynthetic capacity in heavy metal contaminated environments. Cultures of bacterial strains Rhodobacter sphaeroides, Rhodospirillum rubrum and Rubrivivax gelatinosus were treated with heavy metal ions in micromolar (Hg(2+)), submillimolar (Cr(6+)) and millimolar (Pb(2+)) concentration ranges. Functional assays (flash-induced absorption changes and bacteriochlorophyll fluorescence induction) and electron micrographs were taken to specify the harmful effects of pollution and to correlate to morphological changes of the membrane. The bacterial strains and functional tests showed differentiated responses to environmental stresses, revealing that diverse mechanisms of tolerance and/or resistance are involved. The microorganisms were vulnerable to the prompt effect of Pb(2+), showed weak tolerance to Hg(2+) and proved to be tolerant to Cr(6+). The reaction center controlled electron transfer in Rvx. gelatinosus demonstrated the highest degree of resistance against heavy metal exposure. PMID- 26232749 TI - Filled hydrogel particles as a delivery system for n-3 long chain PUFA in low-fat frankfurters: Consequences for product characteristics with special reference to lipid oxidation. AB - This article examines the suitability of filled hydrogel particles for use as a delivery system for n-3 long chain PUFAs in low-fat frankfurters. Their effects on product characteristics over chilled storage were compared with those of frankfurters containing all-pork fat (control) or a comparable amount of fish oil (n-3 LCPUFA) incorporated in liquid form or in an oil-in-water emulsion. In modified samples n-3 fatty acids ranged between 801.34 to 996.37 mg/100g as opposed to 66 mg/100g in all-pork fat product. As compared with the control, hardness and chewiness values were similar (P>0.05) in filled hydrogel frankfurter. The presence of fish oil favoured lipid oxidation to varying degrees depending on delivery system, in descending order: direct oil addition>oil-in water emulsion>hydrogels. Sensory evaluation demonstrated the advantages, from a sensory point of view, of hydrogel filled particles as n-3 delivery systems in frankfurters. PMID- 26232750 TI - Threat to democracy: Physical and mental health impact of democracy movement in Hong Kong. AB - BACKGROUND: This study examined the prevalence and critical predictors of anxiety and depressive symptoms and self-rated health, following the Umbrella Movement in Hong Kong. METHODS: Random digit dialing recruited a population-representative sample of 1208 Chinese Hong Kong citizens (mean age=46.89 years; 63% female) in the first two weeks of February 2015. Respondents gave their informed consent and reported personal, social, and economic resource loss since the Umbrella Movement (Conservation of Resources-Evaluation), current anxiety symptoms (State-Trait Anxiety Inventory) and depressive symptoms (Patient Health Questionnaire-9), and self-rated health (1=very good, 4=very bad). RESULTS: A total of 47.35% (95% CI=44.55, 50.17) respondents reported moderate/severe anxiety symptoms and 14.4% (95% CI=12.54, 16.50) reported moderate/severe depressive symptoms; 9.11% (95% CI=7.61, 10.86) reported "poor" or "very poor" health. Multivariable regressions revealed that personal and social resource loss was associated with higher anxiety and depressive symptoms and greater odds of "very poor" health (adjusted odds ratios/incidence rate ratios=5-102%), independent of lower education level and income and being unmarried. LIMITATIONS: This study was cross-sectional in nature and thus could not determine causality from the associations between resource loss and outcome variables. Second, the telephone survey relied on self reports; response bias and social desirability could influence respondents' answers and discount data validity. Third, potential confounders such as preexisting mental and physical health issues and concurrent predictors like exposure to the Umbrella Movement were not assessed. CONCLUSIONS: This is one of the first studies following any recent political movement (e.g., The Arab Spring) to quantify distress and the associated correlates of distress among affected citizens. Perceived psychosocial resource losses were critical predictors of poor outcomes. PMID- 26232751 TI - Interaction of the 5-HTTLPR and childhood trauma influences memory bias in healthy individuals. AB - The tendency to recall more negative and less positive information has been frequently related to the genetic susceptibility to depression. This memory bias may be associated with depression candidate genes especially in individuals who experienced stressful childhood events. The serotonin transporter gene, SLC6A4/5 HTT, regulates the reuptake of serotonin. The 5-HTTLPR polymorphism in the gene's promoter region has a short (S) and a long (L) allele, of which L contains a further SNP (rs25531), resulting in a triallelic polymorphism: La, Lg, and S. Both S and Lg result in increased serotonin signaling (to simplify, we refer to both alleles as 'S'), which in turn appears associated with depression vulnerability, specifically in individuals with stressful events. In non depressed individuals (N=1083), we examined the interaction between the 5-HTTLPR genotype (LaLa, SLa, and SS) and stressful childhood events in association with explicit verbal memory bias (positive, negative). Two types of stressful childhood events were studied, namely childhood adverse events (e.g. parental loss) and interpersonal traumatic childhood events (e.g. abuse). Less positive memory bias was found for individuals with the SS genotype who had experienced interpersonal childhood traumatic events. No general association of genotype with memory bias was found, nor was there a significant interaction between genotype and childhood adverse events. Our results suggest that the depression susceptibility genotype of the 5-HTTLPR is associated with depressive information processing styles when occurring in combination with traumatic childhood events. Tailoring treatment to specific risk profiles based on genetic susceptibility and childhood stress could be promising. PMID- 26232752 TI - Hiccups: An Unappreciated Cause of the Mallory-Weiss Syndrome. PMID- 26232753 TI - Extracellular microRNAs in bronchoalveolar lavage samples from patients with lung diseases as predictors for lung cancer. AB - OBJECTIVE: The detection of tumor-associated microRNA expression in bronchial lavage (BL) samples of lung cancer patients could improve the non-invasive tumor diagnostic. METHODS: The profile of extracellular microRNAs in bronchial lavage was evaluated using three pools for lung cancer group (malignant) and three pools for non-cancerous group (benign) of 10 patients each. To confirm the results for the selected microRNAs in a qRT-PCR the BL of 30 different lung cancer and non cancerous patients was used. We examined total-RNA from cell-free supernatant of BL samples. For normalization we added exogenous cel-miR 39. RESULTS: Using microRNA arrays we found a panel of eight microRNAs (hsa-miR 19b-1, 1285, 1289, 1303, 217, 29a-5p, 548-3p, 650) that were differentially expressed between the lung cancer and the non-cancerous group. Further investigation by qPCR revealed five microRNAs (U6 snRNA, hsa-miR 1285, 1303, 29a-5p, 650) that were significantly up-regulated in patients with lung cancer. CONCLUSIONS: In bronchial lavage samples the five microRNAs identified in this study have a diagnostic potential for use as noninvasive biomarkers in lung cancer. PMID- 26232754 TI - Wildfire patterns and landscape changes in Mediterranean oak woodlands. AB - Fire is infrequent in the oak woodlands of southern Portugal (montado) but large and severe fires affected these agro-forestry systems in 2003-2005. We hypothesised transition from forest to shrubland as a fire-driven process and investigated the links between fire incidence and montado change to other land cover types, particularly those related with the presence of pioneer communities (generically designed in this context as "transitions to early-successional communities"). We present a landscape-scale framework for assessing the probability of transition from montado to pioneer communities, considering three sets of explanatory variables: montado patterns in 1990 and prior changes from montado to early-successional communities (occurred between 1960 and 1990), fire patterns, and spatial factors. These three sets of factors captured 78.2% of the observed variability in the transitions from montado to pioneer vegetation. The contributions of fire patterns and spatial factors were high, respectively 60.6% and 43.4%, the influence of montado patterns and former changes in montado being lower (34.4%). The highest amount of explained variation in the occurrence of transitions from montado to early-successional communities was related to the pure effect of fire patterns (19.9%). Low spatial connectedness in montado landscape can increase vulnerability to changes, namely to pioneer vegetation, but the observed changes were mostly explained by fire characteristics and spatial factors. Among all metrics used to characterize fire patterns and extent, effective mesh size provided the best modelling results. Transitions from montado to pioneer communities are more likely in the presence of high values of the effective mesh size of total burned area. This cross-boundary metric is an indicator of the influence of large fires in the distribution of the identified transitions and, therefore, we conclude that the occurrence of large fires in montado increases its probability of transition to shrubland. PMID- 26232755 TI - Biochar-macrofauna interplay: Searching for new bioindicators. AB - Biochar incorporation in agricultural soils has been proposed as a climate change mitigation strategy and has proved to substantially increase crop productivity via physical, chemical and biological mechanisms. The changes induced in soil properties are known to have a direct impact on soil ecosystem with consequences for soil biota community that, in turn, can influence biochar aging in soil. Despite several studies investigated in the interplay between biochar and soil microbiology, there is a clear lack of information on groups that live in the most superficial ground layers: soil meso and macro fauna. These groups are of great importance if we consider that biochar application should ideally be located in the soil's surface layer (0-30 cm). Our study is the first attempt to investigate the interactions between biochar soil amendments and aboveground soil macro-meso fauna in a field crop. This was made setting-up a randomized-block experiment on a processing tomato crop in northern Italy, using three different biochar types and periodically monitoring soil parameters and fauna abundances along the crop growing cycle in summer 2013. Results show that the impact of biochar application on soil fauna as a whole is small when compared to that of agricultural management, suggesting that this amendment does not have short-term ecological interferences. Nevertheless, ants exhibited variations in abundances and distribution connected to properties of amended soils such as temperature, pH and humidity, proving that they can be effectively used as a target group in the study of interactions between biochar and soil biota. PMID- 26232756 TI - Statistical evaluation of the impact of shale gas activities on ozone pollution in North Texas. AB - Over the past decade, substantial growth in shale gas exploration and production across the US has changed the country's energy outlook. Beyond its economic benefits, the negative impacts of shale gas development on air and water are less well known. In this study the relationship between shale gas activities and ground-level ozone pollution was statistically evaluated. The Dallas-Fort Worth (DFW) area in north-central Texas was selected as the study region. The Barnett Shale, which is one the most productive and fastest growing shale gas fields in the US, is located in the western half of DFW. Hourly meteorological and ozone data were acquired for fourteen years from monitoring stations established and operated by the Texas Commission on Environmental Quality (TCEQ). The area was divided into two regions, the shale gas region (SGR) and the non-shale gas (NSGR) region, according to the number of gas wells in close proximity to each monitoring site. The study period was also divided into 2000-2006 and 2007-2013 because the western half of DFW has experienced significant growth in shale gas activities since 2007. An evaluation of the raw ozone data showed that, while the overall trend in the ozone concentration was down over the entire region, the monitoring sites in the NSGR showed an additional reduction of 4% in the annual number of ozone exceedance days than those in the SGR. Directional analysis of ozone showed that the winds blowing from areas with high shale gas activities contributed to higher ozone downwind. KZ-filtering method and linear regression techniques were used to remove the effects of meteorological variations on ozone and to construct long-term and short-term meteorologically adjusted (M.A.) ozone time series. The mean value of all M.A. ozone components was 8% higher in the sites located within the SGR than in the NSGR. These findings may be useful for understanding the overall impact of shale gas activities on the local and regional ozone pollution. PMID- 26232757 TI - Modeling groundwater nitrate concentrations in private wells in Iowa. AB - Contamination of drinking water by nitrate is a growing problem in many agricultural areas of the country. Ingested nitrate can lead to the endogenous formation of N-nitroso compounds, potent carcinogens. We developed a predictive model for nitrate concentrations in private wells in Iowa. Using 34,084 measurements of nitrate in private wells, we trained and tested random forest models to predict log nitrate levels by systematically assessing the predictive performance of 179 variables in 36 thematic groups (well depth, distance to sinkholes, location, land use, soil characteristics, nitrogen inputs, meteorology, and other factors). The final model contained 66 variables in 17 groups. Some of the most important variables were well depth, slope length within 1 km of the well, year of sample, and distance to nearest animal feeding operation. The correlation between observed and estimated nitrate concentrations was excellent in the training set (r-square=0.77) and was acceptable in the testing set (r-square=0.38). The random forest model had substantially better predictive performance than a traditional linear regression model or a regression tree. Our model will be used to investigate the association between nitrate levels in drinking water and cancer risk in the Iowa participants of the Agricultural Health Study cohort. PMID- 26232758 TI - Mercury and selenium status of bottlenose dolphins (Tursiops truncatus): A study in stranded animals on the Canary Islands. AB - The mercury (Hg) level in the marine environment has tripled in recent decades, becoming a great concern because of its high toxic potential. This study reports Hg and selenium (Se) status, and the first Se/Hg molar ratio assessment in bottlenose dolphins (Tursiops truncatus) inhabiting the waters of the Canary Islands. Total Hg and Se concentrations were determined in the blubber and liver collected from 30 specimens stranded along the coasts of the archipelago from 1997 to 2013. The median values for total Hg in the blubber and liver were 80.83 and 223.77 MUg g(-1) dry weight (dw), and the median levels for Se in both tissues were 7.29 and 68.63 MUg g(-1) dw, respectively. Hg concentrations in the liver were lower than 100 MUg g(-1) wet weight (ww), comparable to those obtained in bottlenose dolphins from the North Sea, the Western Atlantic Ocean and several locations in the Pacific Ocean. The Mediterranean Sea and South of Australia are the most contaminated areas for both elements in this cetacean species. In addition, it must be stressed that the levels of Hg and Se in the liver showed an increasing trend with the age of the animals. As expected, a strong positive correlation between Hg and Se was observed (rs=0.960). Surprisingly, both younger and older specimens had a Se/Hg molar ratio different from 1, suggesting that these individuals may be at greater toxicological risk for high concentrations of both elements or a deficiency of Se without a protective action against Hg toxicity. PMID- 26232759 TI - Assessment of groundwater-surface water interaction using long-term hydrochemical data and isotope hydrology: Headwaters of the Condamine River, Southeast Queensland, Australia. AB - A spatial analysis of hydrochemical data of groundwater and surface water was undertaken to identify groundwater-surface water connectivity in the headwaters of the Condamine River catchment, Southeast Queensland, Australia. An assessment of long-term hydrochemical and water level data supplemented by stable- and radioisotope measurements following a prolonged dry period dominated by baseflow, helped in determining patterns of interaction in different tributaries of the upper Condamine catchment. A conceptual hydrological model representing the major hydrochemical processes and their implications for stream-aquifer connectivity was developed and tested using multiple lines of evidence. The results of a multivariate statistical analysis highlight that there are two main regions with distinct hydrochemical facies (salinity, alkalinity, and predominant ions) in surface water. Geomorphology, geology, anthropogenic and climate influence were identified as the most relevant controlling factors of the spatial variability in water quality. Stable isotope data confirmed a clear evaporation trend in almost all surface water samples during baseflow conditions. Two water types can be identified and separated by the degree of evaporation and the proximity of one group to the local meteoric water line. The results confirm the discharge of groundwater from aquifers recharged by rainfall and located upstream of the surface water sampling sites. Overall, 222Rn data show a trend of increased activity in surface water towards the upstream portions of these tributaries, validating the use of this tracer to estimate groundwater input to the local creeks. The proportion of groundwater contribution to stream flow calculated by 222Rn and chloride mass balance is in agreement, and ranges between 20-70% in tributaries in the northern areas, and between 8-50% in the upper reaches of the main river channel. This study shows the efficacy of an integrated approach combining long-term hydrochemical data interpreted via multivariate statistics, hydraulic water level data and stable and radiogenic isotope hydrology for the determination of groundwater-surface interactions in headwater catchments. PMID- 26232760 TI - Characterization of a Novel Neutralizing Monoclonal Antibody Against Ebola Virus GP. AB - Ebola virus is the etiological agent of a severe hemorrhagic fever with a high mortality rate. As the only protein exposed on the surface of viral particles, the spike glycoprotein GP is the unique target for neutralizing monoclonal antibodies. In this study, we demonstrate the strong neutralization capacity of the monoclonal antibody #3327 and characterize its activity. GP residues that are required for recognition and neutralization were found to be located both in the internal fusion loop and in the receptor-binding domain. Analysis of Ebola virus entry in the presence of #3327 allows us to hypothesize that this antibody binds to the virus particle before internalization and endosomal processing of GP and likely prevents the final viral fusion step. Importantly, #3327 is able to block entry of virions bearing GP that contain the Q508 escape mutation common to a number of virus-neutralizing antibodies, and therefore provides future perspectives for treatment strategies against Ebola virus infection. PMID- 26232762 TI - The Imperative for a New Approach to Toxicity Analysis in Oncology Clinical Trials. AB - A consistent system for reporting adverse events (AEs) is paramount in cancer clinical trials and is crucial to ensure the safety and tolerability of chemotherapy. The shift towards individualized medicine in oncology over the last decade has brought with it an impressive array of novel, targeted therapies and increasingly complex clinical trials to investigate them. Many of the newer drugs are oral agents that are taken continuously over protracted periods of time. They stand sharply in contrast to conventional cytotoxic intravenous chemotherapy given over a prefixed number of cycles. With its narrow emphasis on high-grade events, the consensus method for reporting of AEs in current cancer trials has not evolved to reflect the longitudinal toxicity profiles of the newer agents. Current methods do not incorporate patient-reported outcomes, which are of rising importance when therapy lasts for months or even years in a patient's life. Additionally, tables focusing on worst-grade events do not depict evolution of toxicity over time and therefore cannot offer patients and clinicians information about the onset or duration of a given AE. Most importantly, current methods do not capture lower-grade but longer-lasting toxicity that may have important ramifications on patients' quality of life. The failure to include any time related information in our current methods of toxicity reporting provides an incomplete and even inaccurate depiction of AEs. To remain in step with the advancing science of cancer and the vast array of new therapies with extended treatment durations, our consensus method of AE analysis in oncology clinical trials must modernize to include the dimension of time. PMID- 26232761 TI - A Prospective Evaluation of Endogenous Sex Hormone Levels and Colorectal Cancer Risk in Postmenopausal Women. AB - BACKGROUND: Postmenopausal hormone therapy use has been associated with lower colorectal cancer risk in observational studies. However, the role of endogenous sex hormones in colorectal cancer development in postmenopausal women is uncertain. METHODS: The relation of colorectal cancer risk with circulating levels of estradiol, estrone, free (bioactive) estradiol, progesterone and sex hormone-binding globulin (SHBG) was determined in a nested case-control study of 1203 postmenopausal women (401 case patients and 802 age and race/ethnicity matched control patients) enrolled in the Women's Health Initiative Clinical Trial (WHI-CT) who were not assigned to the estrogen-alone or combined estrogen plus progestin intervention groups. We used multivariable-adjusted conditional logistic regression models that included established colorectal cancer risk factors. All statistical tests were two-sided. RESULTS: Comparing extreme quartiles, estrone (odds ratio [OR]q4-q1 = 0.44, 95% confidence interval [CI] = 0.28 to 0.68, P trend = .001), free estradiol (ORq4-q1 = 0.43, 95% CI = 0.27 to 0.69, P trend <= .0001), and total estradiol (ORq4-q1 = 0.58, 95% CI = 0.38 to 0.90, P trend = .08) were inversely associated with colorectal cancer risk. SHBG levels were positively associated with colorectal cancer development (OR[q4-q1] = 2.30, 95% CI = 1.51 to 3.51, P trend <= .0001); this association strengthened after further adjustment for estradiol and estrone (ORq4-q1 = 2.50, 95% CI = 1.59 to 3.92, P trend < .0001). Progesterone was not associated with colorectal cancer risk. CONCLUSION: Endogenous estrogen levels were inversely, and SHBG levels positively, associated with colorectal cancer risk, even after control for several colorectal cancer risk factors. These results suggest that endogenous estrogens may confer protection against colorectal tumorigenesis among postmenopausal women. PMID- 26232763 TI - Structure and genetics of the O-antigen of Escherichia coli O169 related to the O antigen of Shigella boydii type 6. AB - The O-polysaccharide (O-antigen) of Escherichia coli O169 was studied by sugar analysis along with 1D and 2D (1)H and (13)C NMR spectroscopy. The following structure of the branched hexasaccharide repeating unit was established: [Formula: see text] The O-polysaccharide of E. coli O169 differs from that of Shigella boydii type 6 only in the presence of a side-chain glucose residue. A comparison of the O-antigen biosynthesis gene clusters between the galF to gnd genes in the genomes of the two bacteria revealed their close relationship. The glycosyltransferase gene responsible for the formation of the beta-D-Glcp-(1 -> 6)-alpha-D-Galp linkage in the O-antigen was identified in the gene cluster. PMID- 26232764 TI - Multimodality imaging in cardiac sarcoidosis: predicting treatment response. PMID- 26232765 TI - Electrical storm in patients with implantable cardioverter-defibrillator in the era of catheter ablation: Implications for better rhythm control. AB - BACKGROUND: The modern era of cardiology has changed the population of implantable cardioverter-defibrillator (ICD) recipients. Identifying predictors of electrical storm (ES) in contemporary ICD patients could improve risk stratification, therapeutic strategies, and mortality. OBJECTIVE: The purpose of this study was to address these points in a real-world setting. METHODS: In 330 consecutive patients (65 +/- 11 years, 81% male, left ventricular ejection fraction 29% +/- 9%) with ICD implanted because of ischemic (n, 204) or nonischemic dilated cardiomyopathy (n, 126), we analyzed the prevalence, predictors, and outcome of ES (>=3 separate VT/VF episodes within 24 hours) therapy. RESULTS: During a median of 21 months (range 17-36 months), 23 patients (7%) had ES. Secondary prevention (61% vs 24%, P <.01), single-chamber devices (57% vs 38%, P = .02), and prior appropriate (96% vs 24%, P < .001) and inappropriate (30% vs 9%, P = .004) therapies were more prevalent in these patients. In ES patients, first appropriate therapy occurred more often in the first year after implantation than in the rest of the cohort (85% vs 45%, P = .008), and mortality was significantly higher (22% vs 2%, P < .001). Multivariate Cox regression analysis showed that secondary prevention (hazard ratio [HR] 2.83, 95% confidence interval [CI] 1.21-6.61, P = .016) and prior appropriate (HR 88.99, 95% CI 11.73-675, P < .001) and inappropriate (HR 2.83, 95% CI 1.14-7.0, P = .04) therapies were independent predictors of ES. CONCLUSION: ES is not uncommon in ICD recipients. A secondary prevention indication and the occurrence of both appropriate and inappropriate ICD therapies increase the risk for ES. Prompt initiation of aggressive treatment, especially catheter ablation, should be considered for these patients. PMID- 26232766 TI - Vectorcardiographic QRS area identifies delayed left ventricular lateral wall activation determined by electroanatomic mapping in candidates for cardiac resynchronization therapy. AB - BACKGROUND: Delayed left ventricular (LV) lateral wall (LVLW) activation is considered the electrical substrate underlying LV dysfunction amenable to cardiac resynchronization therapy (CRT). OBJECTIVE: The purpose of this study was to assess LVLW activation in CRT candidates using coronary venous electroanatomic mapping (EAM) and to investigate whether the QRS area (QRSAREA) on the vectorcardiogram (VCG) can identify delayed LVLW activation. METHODS: Fifty-one consecutive CRT candidates (29 left bundle branch block [LBBB], 15 intraventricular conduction delay [IVCD], 7 right bundle branch block [RBBB]) underwent intraprocedural coronary venous EAM using EnSite NavX. VCGs were constructed from preprocedural digital 12-lead ECGs using the Kors method. QRSAREA was assessed and compared to QRS duration and 5 different LBBB definitions. RESULTS: Delayed LVLW activation (activation time >75% of QRS duration) occurred in 38 of 51 patients (29/29 LBBB, 8/15 IVCD, 1/7 RBBB). QRSAREA was larger in patients with than in patients without delayed LVLW activation (108 +/- 42 uVs vs 51 +/- 27 uVs, P < .001), and identified delayed LVLW activation better than QRS duration (area under the curve 0.89 [95% confidence interval 0.79-0.99] vs 0.49 [95% confidence interval 0.33-0.65]). QRSAREA >69 uVs diagnosed delayed LVLW activation with a higher sum of sensitivity (87%) and specificity (92%) than any of the LBBB definitions. Of the different LBBB definitions, the European Society of Cardiology textbook definition performed best with sensitivity of 76% and specificity of 100%. CONCLUSION: Coronary venous EAM can be used during CRT implantation to determine the presence of delayed LVLW activation. QRSAREA is a noninvasive alternative for intracardiac measurements of electrical activation, which identifies delayed LVLW activation better than QRS duration and LBBB morphology. PMID- 26232767 TI - Genome-wide identification of galactinol synthase (GolS) genes in Solanum lycopersicum and Brachypodium distachyon. AB - GolS genes stand as potential candidate genes for molecular breeding and/or engineering programs in order for improving abiotic stress tolerance in plant species. In this study, a total of six galactinol synthase (GolS) genes/proteins were retrieved for Solanum lycopersicum and Brachypodium distachyon. GolS protein sequences were identified to include glyco_transf_8 (PF01501) domain structure, and to have a close molecular weight (36.40-39.59kDa) and amino acid length (318 347 aa) with a slightly acidic pI (5.35-6.40). The sub-cellular location was mainly predicted as cytoplasmic. S. lycopersicum genes located on chr 1 and 2, and included one segmental duplication while genes of B. distachyon were only on chr 1 with one tandem duplication. GolS sequences were found to have well conserved motif structures. Cis-acting analysis was performed for three abiotic stress responsive elements, including ABA responsive element (ABRE), dehydration and cold responsive elements (DRE/CRT) and low-temperature responsive element (LTRE). ABRE elements were found in all GolS genes, except for SlGolS4; DRE/CRT was not detected in any GolS genes and LTRE element found in SlGolS1 and BdGolS1 genes. AU analysis in UTR and ORF regions indicated that SlGolS and BdGolS mRNAs may have a short half-life. SlGolS3 and SlGolS4 genes may generate more stable transcripts since they included AATTAAA motif for polyadenylation signal POLASIG2. Seconder structures of SlGolS proteins were well conserved than that of BdGolS. Some structural divergences were detected in 3D structures and predicted binding sites exhibited various patterns in GolS proteins. PMID- 26232768 TI - Uranium decay daughters from isolated mines: Accumulation and sources. AB - This study combines in situ gamma spectrometry performed at different scales, in order to accurately locate the contamination pools, to identify the concerned radionuclides and to determine the distribution of the contaminants from soil to bearing phase scale. The potential mobility of several radionuclides is also evaluated using sequential extraction. Using this procedure, an accumulation area located downstream of a former French uranium mine and concentrating a significant fraction of radioactivity is highlighted. We report disequilibria in the U-decay chains, which are likely related to the processes implemented on the mining area. Coupling of mineralogical analyzes with sequential extraction allow us to highlight the presence of barium sulfate, which may be the carrier of the Ra-226 activities found in the residual phase (Ba(Ra)SO4). In contrast, uranium is essentially in the reducible fraction and potentially trapped in clay-iron coatings located on the surface of minerals. PMID- 26232769 TI - Proton-detected 3D (14)N/(14)N/(1)H isotropic shift correlation experiment mediated through (1)H-(1)H RFDR mixing on a natural abundant sample under ultrafast MAS. AB - In this contribution, we have demonstrated a proton detection-based approach on a natural abundant powdered l-Histidine HCl-H2O sample at ultrafast magic angle spinning (MAS) to accomplish (14)N/(14)N correlation from a 3D (14)N/(14)N/(1)H isotropic shift correlation experiment mediated through (1)H finite-pulse radio frequency-driven recoupling (fp-RFDR). Herein the heteronuclear magnetization transfer between (14)N and (1)H has been achieved by HMQC experiment, whereas (14)N/(14)N correlation is attained through enhanced (1)H-(1)H spin diffusion process due to (1)H-(1)H dipolar recoupling during the RFDR mixing. While the use of ultrafast MAS (90kHz) provides sensitivity enhancement through increased (1)H transverse relaxation time (T2), the use of micro-coil probe which can withstand strong (14)N radio frequency (RF) fields further improves the sensitivity per unit sample volume. PMID- 26232770 TI - Theoretical aspects of Magic Angle Spinning - Dynamic Nuclear Polarization. AB - Magic Angle Spinning (MAS) combined with Dynamic Nuclear Polarization (DNP) has been proven in recent years to be a very powerful method for increasing solid state NMR signals. Since the advent of biradicals such as TOTAPOL to increase the nuclear polarization new classes of radicals, with larger molecular weight and/or different spin properties have been developed. These have led to unprecedented signal gain, with varying results for different experimental parameters, in particular the microwave irradiation strength, the static field, and the spinning frequency. Recently it has been demonstrated that sample spinning imposes DNP enhancement processes that differ from the active DNP mechanism in static samples as upon sample spinning the DNP enhancements are the results of energy level anticrossings occurring periodically during each rotor cycle. In this work we present experimental results with regards to the MAS frequency dependence of the DNP enhancement profiles of four nitroxide-based radicals at two different sets of temperature, 110 and 160K. In fact, different magnitudes of reduction in enhancement are observed with increasing spinning frequency. Our simulation code for calculating MAS-DNP powder enhancements of small model spin systems has been improved to extend our studies of the influence of the interaction and relaxation parameters on powder enhancements. To achieve a better understanding we simulated the spin dynamics of a single three-spin system {ea-eb-n} during its steady state rotor periods and used the Landau-Zener formula to characterize the influence of the different anti-crossings on the polarizations of the system and their necessary action for reaching steady state conditions together with spin relaxation processes. Based on these model calculations we demonstrate that the maximum steady state nuclear polarization cannot become larger than the maximum polarization difference between the two electrons during the steady state rotor cycle. This study also shows the complexity of the MAS-DNP process and therefore the necessity to rely on numerical simulations for understanding parametric dependencies of the enhancements. Finally an extension of the spin system up to five spins allowed us to probe the first steps of the transfer of polarization from the nuclei coupled to the electrons to further away nuclei, demonstrating a decrease in the spin-diffusion barrier under MAS conditions. PMID- 26232771 TI - Techno-economic evaluation of conditioning with sodium sulfite for bioethanol production from softwood. AB - Conditioning with reducing agents allows alleviation of inhibition of biocatalytic processes by toxic by-products generated during biomass pretreatment, without necessitating the introduction of a separate process step. In this work, conditioning of steam-pretreated spruce with sodium sulfite made it possible to lower the yeast and enzyme dosages in simultaneous saccharification and fermentation (SSF) to 1g/L and 5FPU/g WIS, respectively. Techno-economic evaluation indicates that the cost of sodium sulfite can be offset by benefits resulting from a reduction of either the yeast load by 0.68g/L or the enzyme load by 1FPU/g WIS. As those thresholds were surpassed, inclusion of conditioning can be justified. Another potential benefit results from shortening the SSF time, which would allow reducing the bioreactor volume and result in capital savings. Sodium sulfite conditioning emerges as an opportunity to lower the financial uncertainty and compensate the overall investment risk for commercializing a softwood-to-ethanol process. PMID- 26232772 TI - Isoconversional kinetic study of the thermal decomposition of sugarcane straw for thermal conversion processes. AB - The aim of this work was investigate the kinetics of the thermal decomposition reaction of sugarcane straw. The thermal decomposition experiments were conducted at four heating rates (1.25, 2.5, 5 and 10 degrees C/min) in a thermogravimetric analyzer using nitrogen as inert atmosphere. The kinetic analysis was carried out applying the isoconversional method of Friedman, and the activation energies obtained varied from 154.1kJ/mol to 177.8kJ/mol. The reaction model was determined through master plots, corresponding to a two-dimensional diffusion. The pre-exponential factor of 1.82*10(9)s(-1) was determined by linearization of the conversion rate equation as a function of the inverse of absolute temperature, concerning to activation energy of 149.7kJ/mol, which are in the order of magnitude for biomass thermal decomposition reported in literature. Finally, the theoretical and experimental conversion data showed a very good agreement, indicating that these results could be used for future process modeling involving sugarcane straw. PMID- 26232773 TI - Comparison of flocculation methods for harvesting Dunaliella. AB - Low cell concentrations of Dunaliella salina in production scale cultivations require high energy input for biomass harvesting. Flocculation is a potential preconcentration method to lower the dewatering costs for the beta-carotene production. In the present study, optimal flocculant dosages were determined for several metal salts, NaOH, Ca(OH)2 and Al-electrolysis. Beside harvesting efficiency etaH and concentration factor CF, also the recyclability of the separated medium as well as the influence of the cell physiology on the harvesting performance were analyzed for selected flocculants. To assess the possible recycle of non-sedimented cells for the inoculation of new cultivations, cell vitality and the photosynthetic activity of D. salina were analyzed after the flocculation. As a result, the flocculation with NaOH led to a clear inhibition of both, the algal growth on recycled medium and the algal photosynthetic activity. The addition of FeCl3 seems most promising to flocculate D. salina. PMID- 26232775 TI - Left ventricular vs. biventricular mechanical support: Decision making and strategies for avoidance of right heart failure after left ventricular assist device implantation. AB - Left ventricular assist devices (LVADs) are safer and provide better survival and better quality of life than biventricular assist devices (BVADs) but end-stage heart failure often involves both ventricles, even if its initial cause was left sided heart disease. Right ventricular failure (RVF) is also a severe complication in about 25% of patients receiving an LVAD, with high perioperative morbidity (renal, hepatic or multi-organ failure) and mortality. Patients who receive an RV assist device (RVAD) only days after LVAD insertion fare much worse than those who receive an RVAD simultaneously with LVAD implantation. Temporary RVAD support in LVAD recipients with high risk for postoperative RVF can avoid permanent BVAD support. Thus, patients who definitely need a BVAD should already be identified preoperatively or at least intra-operatively. However, although the initial biochemical, hemodynamic and echocardiographic patient profiles at admission may suggest the need for a BVAD, many risk factors may be favorably modified by various strategies that may result in avoidance of RVF after LVAD implantation. This article summarizes the knowledge of risk factors for irreversible RVF after LVAD implantation and strategies to optimize RV function (preoperatively, intra-operatively and post-operatively) aimed to reduce the number of BVAD implantations. Special attention is focused on assessment of RV size, geometry and function in relation to loading conditions with the goal of predicting preoperatively the RV changes which might be induced by RV afterload reduction with the LVAD. The review also provides a theoretical and practical basis for clinicians intending to be engaged in this field. PMID- 26232776 TI - Development and Validation of a Farmers' Market Audit Tool in Rural and Urban Communities. AB - The number of farmers' markets in the United States is growing. Although there are tools to analyze food availability at grocery stores, corner stores, and convenience stores, little research exists about the availability of food types at farmers' markets. This research developed an audit tool to measure the food environment at farmers' markets in rural and urban food environments and examined its psychometric properties, including face validity, interrater reliability, and discriminant validity. The Farmers' Market Audit Tool was reviewed by content experts, revised, and then tested in six farmers' markets by researchers across three states in 2013, including Kentucky, North Carolina, and Montana. Seven food categories were developed, including vegetables, fruits, meats, cheeses, eggs, grains, and samples. Interrater reliability was high within farmers' market across states. As expected, discriminant validity indicated a systematic disagreement within and between states due to seasonality and ability to grow different types of food across different farmers' markets. The total scores assessing the healthfulness of each farmers' market was 38 (range = 28-50). Using the Farmers' Market Audit Tool at farmers' markets is a reliable and valid method to capture the availability of food offerings. PMID- 26232774 TI - Microenvironment abnormalities and lymphomagenesis: Immunological aspects. AB - Innate and adaptive immune cells within the microenvironment identify and eliminate cells displaying signs of malignant potential. Immunosurveillance effector Natural Killer (NK) cells and Cytotoxic T Lymphocytes (CTL) identify malignant cells through germline receptors such as NKG2D and in the case of CTLs, presentation of antigen through the T cell receptor. Manipulation of immunosurveillance through altered tumor-identifying ligand expression or secretion, resistance to cytotoxicity, or compromised cytotoxic cell activity through immune tolerance mechanisms all contribute to failure of these systems to prevent cancer development. This review examines the diverse mechanisms by which alterations in the immune microenvironment can promote lymphomagenesis. PMID- 26232777 TI - Building Capacity in a Rural North Carolina Community to Address Prostate Health Using a Lay Health Advisor Model. AB - Background Prostate cancer is a critical concern for African Americans in North Carolina (NC), and innovative strategies are needed to help rural African American men maximize their prostate health. Engaging the community in research affords opportunities to build capacity for teaching and raising awareness. Approach and Strategies A community steering committee of academicians, community partners, religious leaders, and other stakeholders modified a curriculum on prostate health and screening to include interactive knowledge- and skill building activities. This curriculum was then used to train 15 African American lay health advisors, dubbed Prostate Cancer Ambassadors, in a rural NC community. Over the 2-day training, Ambassadors achieved statistically significant improvements in knowledge of prostate health and maintained confidence in teaching. The Ambassadors, in turn, used their personal networks to share their knowledge with over 1,000 individuals in their community. Finally, the Ambassadors became researchers, implementing a prostate health survey in local churches. Discussion and Conclusions It is feasible to use community engagement models for raising awareness of prostate health in NC African American communities. Mobilizing community coalitions to develop curricula ensures that the curricula meet the communities' needs, and training lay health advisors to deliver curricula helps secure community buy-in for the information. PMID- 26232778 TI - The Influence of Setting on Care Coordination for Childhood Asthma. AB - Asthma affects 7.1 million children in the United States, disproportionately burdening African American and Latino children. Barriers to asthma control include insufficient patient education and fragmented care. Care coordination represents a compelling approach to improve quality of care and address disparities in asthma. The sites of The Merck Childhood Asthma Network Care Coordination Programs implemented different models of care coordination to suit specific settings-school district, clinic or health care system, and community and organizational structures. A variety of qualitative data sources were analyzed to determine the role setting played in the manifestation of care coordination at each site. There were inherent strengths and challenges of implementing care coordination in each of the settings, and each site used unique strategies to deliver their programs. The relationship between the lead implementing unit and entities that provided (1) access to the priority population and (2) clinical services to program participants played a critical role in the structure of the programs. The level of support and infrastructure provided by these entities to the lead implementing unit influenced how participants were identified and how asthma care coordinators were integrated into the clinical care team. PMID- 26232779 TI - Differential Effect of Initiating Moderate Red Wine Consumption on 24-h Blood Pressure by Alcohol Dehydrogenase Genotypes: Randomized Trial in Type 2 Diabetes. AB - AIMS: Observational studies report inconsistent associations between moderate alcohol intake and blood pressure (BP). In a sub-study of a larger randomized controlled trial, we assessed the effect of initiating moderate red wine consumption on 24-h BP recordings and the effect of a common genetic variant of alcohol dehydrogenases (ADH) among patients with type 2 diabetes. METHODS: Fifty four type 2 diabetes, alcohol abstainers were randomized to consume 150 ml/dinner dry red wine or mineral water. Both groups were guided to adhere to a Mediterranean diet, without caloric restriction. We measured 24-h ambulatory BP monitoring (ABPM) at baseline and after 6 months. RESULTS: Participants (age = 57 years; 85% men; mean 24-h BP = 129/77 mm Hg) had 92% 6-month retention. After 6 months of intervention, the average 24-h BP did not differ between the wine and water groups. A transient decrease in BP was observed in the red wine group at midnight (3-4 hours after wine intake: systolic BP: red wine = -10.6mm Hg vs. mineral water = +2.3 mm Hg; P = 0.031) and the following morning at 7-9 am (red wine: -6.2mm Hg vs. mineral water: +5.6mm Hg; P = 0.014). In a second post hoc sub-analysis among the red wine consumers, individuals who were homozygous for the gene encoding ADH1B*2 variant (Arg48His; rs1229984, TT, fast ethanol metabolizers), exhibited a reduction in mean 24-h systolic BP (-8.0mm Hg vs. +3.7 mm Hg; P = 0.002) and pulse pressure (-3.8 mm Hg vs. +1.2 mm Hg; P = 0.032) compared to heterozygotes and those homozygous for the ADH1B*1 variant (CC, slow metabolizers). CONCLUSIONS: Initiating moderate red wine consumption at dinner among type 2 diabetes patients does not have a discernable effect on mean 24-h BP. Yet, a modest temporal BP reduction could be documented, and a more pronounced BP-lowering effect is suggested among fast ethanol metabolizers. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT00784433. PMID- 26232781 TI - Arteriovenous fistula as a nephroprotective intervention in advanced CKD: scientific discovery and explanation, and the evaluation of interventions. PMID- 26232780 TI - Relationship Between Carotid Atherosclerosis and Pulse Pressure with Renal Hemodynamics in Hypertensive Patients. AB - BACKGROUND: Structural atherosclerotic damage, arterial stiffness, pulse pressure (PP), and renal hemodynamics may interact and influence each other. Renal resistance index (RRI) appears as a good indicator of systemic vascular changes. The aim of our study was to assess the independent relationships of carotid intima-media thickness (cIMT), aortic pulse wave velocity (aPWV), and peripheral PP with RRI in hypertensives with various degrees of renal function. METHODS: We enrolled 463 hypertensive patients (30-70 years) with normal renal function (group 0; n = 280) and with chronic kidney disease (groups I-V; n = 183). All subjects underwent ultrasonographic examination of intrarenal and carotid vasculature, as well as a 24-h ambulatory blood pressure monitoring. RESULTS: A statistically significant difference in RRI, cIMT, aPWV, and clinic PP was observed in the different 6 groups (all P < 0.001), even after adjustment for age. RRI correlated with cIMT (r = 0.460, P < 0.001), aPWV (r = 0.386, P < 0.001), clinic PP (r = 0.279, P < 0.001), and 24-h PP (r = 0.229, P < 0.001) in the entire study population. These correlations were similar in subjects with and without renal dysfunction. In the overall study population, the association between RRI, cIMT, and clinic PP remained statistically significant even after adjustment for various confounding factors, whereas the relationship between RRI and aPWV was lost in multivariate analysis. CONCLUSIONS: cIMT and clinic PP rather than directly aPWV are associated with intrarenal hemodynamics. Our results confirm that in hypertensives RRI not only detects derangement of intrarenal circulation but may also be considered as a sensor of systemic vascular changes, independently of level of renal function. PMID- 26232782 TI - A case of early onset rectal cancer of Lynch syndrome with a novel deleterious PMS2 mutation. AB - Heterozygous deleterious mutation of the PMS2 gene is a cause of Lynch syndrome, an autosomal dominant cancer disease. However, the frequency of PMS2 mutation is rare compared with that of the other causative genes; MSH2, MLH1 and MSH6. PMS2 mutation has so far only been reported once from a Japanese facility. Detection of PMS2 mutation is relatively complicated due to the existence of 15 highly homologous pseudogenes, and its gene conversion event with the pseudogene PMS2CL. Therefore, for PMS2 mutation analysis, it is crucial to clearly distinguish PMS2 from its pseudogenes. We report here a novel deleterious 11 bp deletion mutation of exon 11 of PMS2 distinguished from PMS2CL in a 34-year-old Japanese female with rectal cancer. PMS2 mutated at c.1492del11 results in a truncated 500 amino acid protein rather than the wild-type protein of 862 amino acids. This is supported by the fact that, although there is usually concordance between MLH1 and PMS2 expression, cells were immunohistochemically positive for MLH1, whereas PMS2 could not be immunohistochemically stained using an anti-C-terminal PMS2 antibody, or effective PMS2 mRNA degradation with NMD caused by the frameshift mutation. PMID- 26232783 TI - Determinants of water circulation in a woody bamboo species: afternoon use and night-time recharge of culm water storage. AB - To understand water-use strategies of woody bamboo species, sap flux density (Fd) in the culms of a woody bamboo (Bambusa vulgaris Schrader ex Wendland) was monitored using the thermal dissipation method. The daytime and night-time Fd were analyzed in the dry and rainy seasons. Additionally, diurnal changes in root pressure, culm circumference, and stomatal conductance (gs) were investigated to characterize the mechanisms used to maintain diurnal water balance of woody bamboos. Both in the dry and rainy seasons, daytime Fd responded to vapor pressure deficit (VPD) in an exponential fashion, with a fast initial increase in Fd when VPD increased from 0 to 1 kPa. The Fd and gs started to increase very fast as light intensity and VPD increased in the morning, but they decreased sharply once the maximum value was achieved. The Fd response of this woody bamboo to VPD was much faster than that of representative trees and palms growing in the same study site, suggesting its fast sap flow and stomatal responses to changes in ambient environmental factors. The Fd in the lower and higher culm positions started to increase at the same time in the morning, but the Fd in the higher culm position was higher than that of the lower culm in the afternoon. Consistently, distinct decreases in its culm circumference in the afternoon were detected. Therefore, unlike trees, water storage of bamboo culms was not used for its transpiration in the morning but in the afternoon. Nocturnal sap flow of this woody bamboo was also detected and related to root pressure. We conclude that this bamboo has fast sap flow/stomatal responses to irradiance and evaporative demands, and it uses substantial water storage for transpiration in the afternoon, while root pressure appears to be a mechanism resulting in culm water storage recharge during the night. PMID- 26232784 TI - Fertilization with urea, ammonium and nitrate produce different effects on growth, hydraulic traits and drought tolerance in Pinus taeda seedlings. AB - Urea fertilization decreases Pinus taeda L. growth in clay soils of subtropical areas. The negative effect of urea is related to changes in some hydraulic traits, similar to those observed in plants growing under drought. The aims of this work were (i) to determine whether different sources of nitrogen applied as fertilizers produce similar changes in growth and hydraulic traits to those observed by urea fertilization and (ii) to analyze the impact of those changes in plant drought tolerance. Plants fertilized with urea, nitrate [Formula: see text] or ammonium [Formula: see text] were grown well watered or with reduced water supply. Urea and [Formula: see text] fertilization reduced plant growth and increased root hydraulic conductance scaled by root dry weight (DW). [Formula: see text] fertilization did not reduce plant growth and increased shoot hydraulic conductance and stem hydraulic conductivity. We conclude that [Formula: see text] is the ion involved in the changes linked to the negative effect of urea fertilization on P. taeda growth. [Formula: see text] fertilization does not change drought susceptibility and it produces changes in shoot hydraulic traits, therefore plants avoid the depressive effect of fertilization. Urea and [Formula: see text] fertilizers induce changes in DW and root hydraulic conductance and consequently plants are less affected by drought. PMID- 26232785 TI - Stand density, tree social status and water stress influence allocation in height and diameter growth of Quercus petraea (Liebl.). AB - Even-aged forest stands are competitive communities where competition for light gives advantages to tall individuals, thereby inducing a race for height. These same individuals must however balance this competitive advantage with height related mechanical and hydraulic risks. These phenomena may induce variations in height-diameter growth relationships, with primary dependences on stand density and tree social status as proxies for competition pressure and access to light, and on availability of local environmental resources, including water. We aimed to investigate the effects of stand density, tree social status and water stress on the individual height-circumference growth allocation (Deltah-Deltac), in even aged stands of Quercus petraea Liebl. (sessile oak). Within-stand Deltac was used as surrogate for tree social status. We used an original long-term experimental plot network, set up in the species production area in France, and designed to explore stand dynamics on a maximum density gradient. Growth allocation was modelled statistically by relating the shape of the Deltah-Deltac relationship to stand density, stand age and water deficit. The shape of the Deltah-Deltac relationship shifted from linear with a moderate slope in open-grown stands to concave saturating with an initial steep slope in closed stands. Maximum height growth was found to follow a typical mono-modal response to stand age. In open grown stands, increasing summer soil water deficit was found to decrease height growth relative to radial growth, suggesting hydraulic constraints on height growth. A similar pattern was found in closed stands, the magnitude of the effect however lowering from suppressed to dominant trees. We highlight the high phenotypic plasticity of growth in sessile oak trees that further adapt their allocation scheme to their environment. Stand density and tree social status were major drivers of growth allocation variations, while water stress had a detrimental effect on height in the Deltah-Deltac allocation. PMID- 26232786 TI - Higher photosynthetic capacity from higher latitude: foliar characteristics and gas exchange of southern, central and northern populations of Populus angustifolia. AB - Narrowleaf cottonwood (Populus angustifolia James) is an obligate riparian poplar that is a foundation species in river valleys along the Rocky Mountains, spanning 16 degrees of latitude from southern Arizona, USA to southern Alberta, Canada. Its current distribution is fragmented, and genetic variation shows regional population structure consistent with the effects of geographic barriers and past climate. It is thus very well-suited for investigating ecophysiological adaptation associated with latitude. In other section Tacamahaca poplar species, genotypes from higher latitudes show evidence of short-season adaptation with foliar traits that contribute to higher photosynthetic capacity. We tested for similar adaptation in three populations of narrowleaf cottonwoods: from Arizona (south), Alberta (north) and Utah, near the centre of the latitudinal distribution. We propagated 20 genotypes from each population in a common garden in Alberta, and measured foliar and physiological traits after 3 years. Leaves of genotypes from the northern population had higher leaf mass per area (LMA), increased nitrogen (N) content and higher carotenoid and chlorophyll content, and these were associated with higher light-saturated net photosynthesis (Asat). In leaves of all populations the majority of stomata were abaxial, with the proportion of abaxial stomata highest in the southern population. Stomatal conductance (gs) and transpiration rates were higher in the northern population but water-use efficiency (Asat/gs) and leaf carbon isotope composition (delta(13)C) did not differ across the populations. These results (i) establish links between Asat and gs, N, chlorophyll and LMA among populations within this species, (ii) are consistent with the discrimination of populations from prior investigation of genetic variation and (iii) support the concept of latitudinal adaptation, whereby deciduous trees from higher latitudes display higher photosynthetic capacity, possibly compensating for a shorter and cooler growth season and reduced insolation. PMID- 26232788 TI - Low-Level Stress Induces Production of Neuroprotective Factors in Wild-Type but Not BDNF+/- Mice: Interleukin-10 and Kynurenic Acid. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) deficiency confers vulnerability to stress, but the mechanisms are unclear. BDNF(+/-) mice exhibit behavioral, physiological, and neurochemical changes following low-level stress that are hallmarks of major depression. After immune challenge, neuroinflammation induced changes in tryptophan metabolism along the kynurenine pathway mediate depressive-like behaviors. METHODS: We hypothesized that BDNF(+/-) mice would be more susceptible to stress-induced neuroinflammation and kynurenine metabolism, so BDNF(+/-) or wild-type littermate mice were subject to repeated unpredictable mild stress. Proinflammatory cytokine expression and kynurenine metabolites were measured. RESULTS: Unpredictable mild stress did not induce neuroinflammation. However, only wild-type mice produced the neuroprotective factors interleukin-10 and kynurenic acid in response to repeated unpredictable mild stress. In BDNF(+/ ) mice, kynurenine was metabolized preferentially to the neurotoxic intermediate 3-hydroxykynurenine following repeated unpredictable mild stress. CONCLUSIONS: Our data suggest that BDNF may modulate kynurenine pathway metabolism during stress and provide a novel molecular mechanism of vulnerability and resilience to the development of stress-precipitated psychiatric disorders. PMID- 26232787 TI - Prefrontal microRNA-221 Mediates Environmental Enrichment-Induced Increase of Locomotor Sensitivity to Nicotine. AB - BACKGROUND: Environmental enrichment alters susceptibility in developing drug addiction. We have demonstrated that rats raised in an enriched condition are more sensitive than rats raised in an impoverished condition to nicotine-induced locomotor activity, and this is associated with alterations of phosphorylated extracellular signal-regulated kinase 1/2 within the prefrontal cortex. This study determined the impact of microRNA-221 in the prefrontal cortex on phosphorylated extracellular signal-regulated kinase 1/2 and the enriched environment-dependent behavioral changes in response to nicotine. METHODS: A microRNA array was conducted to profile microRNA expression in the prefrontal cortex of enriched condition and impoverished condition rats in response to repeated nicotine (0.35 mg/kg, s.c.) administration. microRNA-221 in the prefrontal cortex, nucleus accumbens, and striatum was further verified by quantitative real-time PCR. Lentiviral-mediated overexpression of microRNA-221 in PC12 cells and the medial prefrontal cortex was performed to determine the effects of microRNA-221 on nicotine-mediated phosphorylated extracellular signal regulated kinase 1/2, phosphorylated cAMP-response element-binding protein, and locomotor activity. RESULTS: microRNA-221 was profoundly upregulated in the prefrontal cortex but not in nucleus accumbens and striatum of enriched condition rats relative to impoverished condition rats following repeated administration of nicotine. Overexpression of lentiviral-microRNA-221 attenuated nicotine-induced increase in phosphorylated extracellular signal-regulated kinase 1/2 in PC12 cells. Lentiviral-microRNA-221 overexpression in the medial prefrontal cortex further increased locomotor activity in impoverished condition but not in enriched condition rats in response to repeated nicotine administration. Accordingly, lentiviral-microRNA-221 attenuated nicotine-induced increases in phosphorylated extracellular signal-regulated kinase 1/2 and phosphorylated cAMP response element-binding protein in the medial prefrontal cortex of impoverished condition but not enriched condition rats. CONCLUSION: These findings suggest that environmental enrichment, via upregulation of prefrontal microRNA-221 expression, suppresses the nicotine-induced activation of extracellular signal regulated kinase and cAMP-response element-binding protein, which provides a potential mechanism underlying enhanced locomotor sensitivity to nicotine. PMID- 26232789 TI - Impaired 2-AG Signaling in Hippocampal Glutamatergic Neurons: Aggravation of Anxiety-Like Behavior and Unaltered Seizure Susceptibility. AB - BACKGROUND: Postsynaptically generated 2-arachidonoylglycerol activates the presynaptic cannabinoid type-1 receptor, which is involved in synaptic plasticity at both glutamatergic and GABAergic synapses. However, the differential function of 2-arachidonoylglycerol signaling at glutamatergic vs GABAergic synapses in the context of animal behavior has not been investigated yet. METHODS: Here, we analyzed the role of 2-arachidonoylglycerol signaling selectively in hippocampal glutamatergic neurons. Monoacylglycerol lipase, the primary degrading enzyme of 2 arachidonoylglycerol, is expressed at presynaptic sites of excitatory and inhibitory neurons. By adeno-associated virus-mediated overexpression of monoacylglycerol lipase in glutamatergic neurons of the mouse hippocampus, we selectively interfered with 2-arachidonoylglycerol signaling at glutamatergic synapses of these neurons. RESULTS: Genetic modification of monoacylglycerol lipase resulted in a 50% decrease in 2-arachidonoylglycerol tissue levels without affecting the content of the second major endocannabinoid anandamide. A typical electrophysiological read-out for 2-arachidonoylglycerol signaling is the depolarization-induced suppression of excitation and of inhibition. Elevated monoacylglycerol lipase levels at glutamatergic terminals selectively impaired depolarization-induced suppression of excitation, while depolarization-induced suppression of inhibition was not significantly changed. At the behavioral level, mice with impaired hippocampal glutamatergic 2-arachidonoylglycerol signaling exhibited increased anxiety-like behavior but showed no alterations in aversive memory formation and seizure susceptibility. CONCLUSION: Our data indicate that 2 arachidonoylglycerol signaling selectively in hippocampal glutamatergic neurons is essential for the animal's adaptation to aversive situations. PMID- 26232795 TI - Food handlers as a link in the chain of transmission of Giardia duodenalis and other protozoa in public schools in southern Brazil. AB - BACKGROUND: Food handlers (FHs) may facilitate transmission and dissemination of pathogens. The importance of FHs as a link in the epidemiological chain of transmission of Giardia duodenalis and other intestinal protozoa was assessed. METHODS: Fecal and subungual material from 27 FHs were analyzed using parasitological methods. G. duodenalis was identified by direct immunofluorescence and genotyped by PCR-RFLP for the bg and gdh genes, and gdh was sequenced. RESULTS: At least one protozoan was detected in 30% (8/27) of the FHs and G. duodenalis (19%; 5/27) was the most common species. The AII and BIV genotypes were found in 20% (1/5) and 60% (3/5) of FHs infected with G. duodenalis, respectively. CONCLUSIONS: FHs can be involved in the chain of transmission of G. duodenalis and other protozoa. GENBANK ACCESSION NUMBERS: KJ741310 - KJ741313. PMID- 26232790 TI - Quetiapine Ameliorates Schizophrenia-Like Behaviors and Protects Myelin Integrity in Cuprizone Intoxicated Mice: The Involvement of Notch Signaling Pathway. AB - BACKGROUND: White matter disturbances and myelin impairment are key features of schizophrenia. The antipsychotic drug quetiapine can promote the maturation of oligodendrocytes, but the molecular mechanisms remain largely unknown. METHODS: The schizophrenia-like behaviors, degrees of demyelination, and levels of Notch signaling molecules in forebrains of adult male C57BL/6 mice were examined after fed with cuprizone (0.2% wt/wt) in the presence or absence of 10mg/kg/d quetiapine for 6 weeks. These parameters were also observed after the transcranial injection of Notch signaling inhibitor MW167 (1mM) daily during the last week of the treatment period. RESULTS: Quetiapine ameliorated the schizophrenia-like behaviors and decreased expression of myelin basic protein and inhibition of Notch signaling molecules, such as Notch1, Hes1, and Hes5, in the forebrain that induced by cuprizone. These beneficial effects of quetiapine were abolished by MW167. CONCLUSIONS: The antipsychotic and myelin protective effects of quetiapine are mediated by Notch signaling in a mouse model of cuprizone induced demyelination associated with schizophrenia-like behaviors. The Notch pathway might therefore be a novel target for the development of antipsychotic drugs. PMID- 26232797 TI - Corrections. AB - In the April article by Cooper, "Biventricular Pacemakers in Patients With Heart Failure" (Critical Care Nurse. 2015; 35[2]:20-28), there was an error referring to right and left atrial chambers on page 25. The last full sentence in the first column on this page should read: "When biventricular pacemakers were first implanted, it was not always evident that both right and left ventricular chambers were being paced as there was no programmed delay between right and left ventricular pacing." PMID- 26232798 TI - Stop the Noise: A Quality Improvement Project to Decrease Electrocardiographic Nuisance Alarms. AB - BACKGROUND: As many as 99% of alarm signals may not need any intervention and can result in patients' deaths. Alarm management is now a Joint Commission National Patient Safety Goal. OBJECTIVES: To reduce the number of nuisance electrocardiographic alarm signals in adult patients on the medical cardiovascular care unit. METHODS: A quality improvement process was used that included eliminating duplicative alarms, customizing alarms, changing electrocardiography electrodes daily, standardizing skin preparation, and using disposable electrocardiography leads. RESULTS: In the cardiovascular care unit, the mean number of electrocardiographic alarm signals per day decreased from 28.5 (baseline) to 3.29, an 88.5% reduction. CONCLUSION: Use of a bundled approach to managing alarm signals decreased the mean number of alarm signals in a cardiovascular care unit. PMID- 26232799 TI - New Guidelines for Assessment of Malnutrition in Adults: Obese Critically Ill Patients. AB - Recently released recommendations for detection and documentation of malnutrition in adults in clinical practice define 3 types of malnutrition: starvation related, acute disease or injury related, and chronic disease related. The first 2 are more easily recognized, but the third may be more often unnoticed, particularly in obese patients. Critical care patients tend to be at high risk for malnutrition and thus require a thorough nutritional assessment. Compared with patients of earlier times, intensive care unit patients today tend to be older, have more complex medical and comorbid conditions, and often are obese. Missed or delayed detection of malnutrition in these patients may contribute to increases in hospital morbidity and longer hospital stays. Critical care nurses are in a prime position to screen patients at risk for malnutrition and to work with members of the interprofessional team in implementing nutritional intervention plans. PMID- 26232800 TI - Compassion Satisfaction and Compassion Fatigue Among Critical Care Nurses. AB - BACKGROUND: Although critical care nurses gain satisfaction from providing compassionate care to patients and patients' families, the nurses are also at risk for fatigue. The balance between satisfaction and fatigue is considered professional quality of life. OBJECTIVES: To establish the prevalence of compassion satisfaction and compassion fatigue in adult, pediatric, and neonatal critical care nurses and to describe potential contributing demographic, unit, and organizational characteristics. METHODS: In a cross-sectional design, nurses were surveyed by using a demographic questionnaire and the Professional Quality of Life Scale to measure levels of compassion fatigue and compassion satisfaction. RESULTS: Nurses (n = 221) reported significant differences in compassion satisfaction and compassion fatigue on the basis of sex, age, educational level, unit, acuity, change in nursing management, and major systems change. CONCLUSIONS: Understanding the elements of professional quality of life can have a positive effect on work environment. The relationship between professional quality of life and the standards for a healthy work environment requires further investigation. Once this relationship is fully understood, interventions to improve this balance can be developed and tested. PMID- 26232801 TI - Understanding Clinical Alarm Safety. AB - Patient safety organizations and health care accreditation agencies recognize the significance of clinical alarm hazards. The Association for the Advancement of Medical Instrumentation, a nonprofit organization focused on development and use of safe and effective medical equipment, identifies alarm management as a major issue for health care organizations. ECRI Institute, a nonprofit organization that researches approaches for improving patient safety and quality of care, identifies alarm hazards as the most significant of the "Top Ten Health Technology Hazards" for 2014. A new Joint Commission National Patient Safety Goal focusing on clinical alarm safety contains new requirements for accredited hospitals to be fully implemented by 2016. Through a fictional unfolding case study, this article reviews selected contributing factors to clinical alarm hazards present in inpatient, high-acuity settings. Understanding these factors improves contributions by nurses to clinical alarm safety practice. PMID- 26232802 TI - Prolonged Mechanical Ventilation: Challenges to Nurses and Outcome in Extremely Preterm Babies. AB - Worldwide, about 15 million infants are born prematurely each year. Technological advances, including invasive mechanical ventilation, play a major role in the survival of extremely preterm babies. Those who survive may have prolonged morbid conditions that result in long-term sequelae. Nurses face several challenges during the hospitalization of these infants. Vigilant care, monitoring, and careful handling of the infants can prevent infections and long-term complications. Newer, less invasive technologies are promising for improved outcomes in extremely preterm infants. PMID- 26232803 TI - Change Is the Only Constant in Critical Care. PMID- 26232804 TI - Prone Position for Acute Respiratory Distress Syndrome. PMID- 26232805 TI - Debridement for Surgical Wounds. PMID- 26232806 TI - Preventing Radial Artery Occlusion by Using Reverse Barbeau Assessment: Bringing Evidence-Based Practice to the Bedside. PMID- 26232808 TI - I Am a Critical Care Nurse. AB - Alisha Burnett, RN, is a staff nurse in the surgical trauma intensive care unit at Tampa General Hospital, Tampa, Florida. PMID- 26232809 TI - Early Mobilization: Changing the Mindset. AB - BACKGROUND: Staff in the surgical intensive care unit (SICU) had several concerns about mobilizing patients receiving mechanical ventilation. OBJECTIVE: To assess and improve the mindset of SICU staff toward early mobilization of patients receiving mechanical ventilation before, 6 months after, and 1 year after implementation of early mobilization. METHODS: The Plan-Do-Study-Act model was used to guide the planning, implementation, evaluation, and interventions to change the mindset and practice of SICU staff in mobilizing patients receiving mechanical ventilation. Interventions to overcome barriers to early mobilization included interdisciplinary collaboration, multimodal education, and operational changes. The mindset of the SICU staff toward early mobilization of patients receiving mechanical ventilation was assessed by using a survey questionnaire distributed 2 weeks before, 6 months after, and 1 year after implementation of early mobilization. RESULTS: The median score on 6 of 7 survey questions changed significantly from before, to 6 months after, to 1 year after implementation, indicating a change in the mindset of SICU staff toward early mobilization of patients receiving mechanical ventilation. The SICU staff agreed that most patients receiving mechanical ventilation are able to get out of bed safely with coordination among personnel and that early mobilization of intubated patients decreases length of stay and decreases occurrence of ventilator-associated pneumonia, deep vein thrombosis, and skin breakdown. CONCLUSIONS: SICU interdisciplinary team collaboration, multimodal education, and operational support contribute to removing staff bias against mobilizing patients receiving mechanical ventilation. PMID- 26232810 TI - Development of a Tele-ICU Postorientation Support Program for Bedside Nurses. AB - The end of the formal unit orientation program is a stressful time of adjustment for nurses hired into critical care without previous critical care experience. Although most units offer reassurance that experienced colleagues will provide the needed guidance, consistent support may not be available for many reasons. Development of a structured postorientation program designed to provide support and ongoing feedback to bedside nurses who have completed orientation is one strategy to assist nurses through this period of adjustment. The experience and expertise of the tele-intensive care unit nurse are excellent resources that can be called on to provide the needed support. PMID- 26232811 TI - No Difference in Perceived Intensity of Linoleic Acid in the Oral Cavity between Obese and Nonobese Individuals. AB - Findings from studies examining interactions between fat taste and dietary fat intake or body weight are mixed. A convenience sample of 735 visitors to the Denver Museum of Nature & Science >=8 years old rated the taste intensity of edible taste strips impregnated with varying concentrations (%v/v) of linoleic acid (LA) (blank = 0.0, low = 0.06, medium = 0.15, high = 0.38). Percent body fat (BF%) was measured using bioelectrical impedance. Fat taste intensity was rated as significantly different across all concentrations (P < 0.001) except between the blank and low concentrations (P = 0.1). Ratings increased monotonically across concentrations. Children (<18 years; N = 180) rated all concentrations as more intense than adults (P < 0.001 for all). Women and girls rated the highest concentration as more intense than men and boys (P < 0.02 for all). BF% was not correlated with fat taste intensity ratings. Self-reported dietary intake indicated that obese individuals' intensity ratings for medium and high concentrations of LA were inversely related to recent mono- and poly-unsaturated fat exposure (r = -0.19 to -0.27; P < 0.03 for all). No such associations were observed in the nonobese group. Findings suggest that factors other than simple adiposity status influence fat taste intensity ratings, and that participants in fat taste studies should receive standardized meals prior to testing. PMID- 26232813 TI - Decomposition of motor unit tetanic contractions of rat soleus muscle: Differences between males and females. AB - Mathematical decomposition of tetanic contractions of slow motor units (MUs) of the rat heterogeneous medial gastrocnemius muscle revealed immense variability of twitch-shape responses to successive pulses, contrary to results obtained for fast MUs. The aim of this study in rat soleus muscle, almost exclusively composed of slow MUs, was to reveal whether such variability of twitch-shape decomposed components was a common property of slow MUs in the two studied muscles, and whether ranges of the force amplitude or time parameters of these decomposed twitches showed sex differences. Unfused tetanic contractions evoked by stimulation at variable interpulse intervals were analyzed for 10 MUs of males and 10 MUs of females. Significantly higher variability between parameters of the decomposed responses was observed for male soleus MUs, as the mean ratio of forces of the strongest decomposed twitch and the first (the weakest) decomposed twitch amounted to 3.8 for males and 2.8 for females. The ratios of the contraction times of the longest decomposed to the first twitch were much more similar between male and female MUs, 2.6 and 2.9, respectively. Consequently, the mean ratio of the force-time area for the strongest decomposed to the first twitch was much bigger in male than female MUs (7.35 vs. 5.07, respectively). Our observations indicate that high variability of responses to successive stimuli is a general property of slow MUs in different rat muscles, but the mechanisms of summation of individual twitches into tetanic contractions of MUs are not identical for male and female rats. PMID- 26232812 TI - Peak strain magnitudes and rates in the tibia exceed greatly those in the skull: An in vivo study in a human subject. AB - Bone mass and architecture are the result of a genetically determined baseline structure, modified by the effect of internal hormonal/biochemical regulators and the effect of mechanical loading. Bone strain is thought to drive a feedback mechanism to regulate bone formation and resorption to maintain an optimal, but not excessive mass and organisation of material at each skeletal location. Because every site in the skeleton has different functions, we have measured bone strains induced by physiological and more unusual activities, at two different sites, the tibia and cranium of a young human male in vivo. During the most vigorous activities, tibial strains were shown to exceed 0.2%, when ground reaction exceeded 5 times body weight. However in the skull the highest strains recorded were during heading a heavy medicine/exercise ball where parietal strains were up to 0.0192%. Interestingly parietal strains during more physiological activities were much lower, often below 0.01%. Strains during biting were not dependent upon bite force, but could be induced by facial contortions of similar appearance without contact between the teeth. Rates of strain change in the two sites were also very different, where peak tibial strain rate exceeded rate in the parietal bone by more than 5 fold. These findings suggest that the skull and tibia are subject to quite different regulatory influences, as strains that would be normal in the human skull would be likely to lead to profound bone loss by disuse in the long bones. PMID- 26232814 TI - Unified viscoelasticity: Applying discrete element models to soft tissues with two characteristic times. AB - Discrete element models have often been the primary tool in investigating and characterising the viscoelastic behaviour of soft tissues. However, studies have employed varied configurations of these models, based on the choice of the number of elements and the utilised formation, for different subject tissues. This approach has yielded a diverse array of viscoelastic models in the literature, each seemingly resulting in different descriptions of viscoelastic constitutive behaviour and/or stress-relaxation and creep functions. Moreover, most studies do not apply a single discrete element model to characterise both stress-relaxation and creep behaviours of tissues. The underlying assumption for this disparity is the implicit perception that the viscoelasticity of soft tissues cannot be described by a universal behaviour or law, resulting in the lack of a unified approach in the literature based on discrete element representations. This paper derives the constitutive equation for different viscoelastic models applicable to soft tissues with two characteristic times. It demonstrates that all possible configurations exhibit a unified and universal behaviour, captured by a single constitutive relationship between stress, strain and time as: sigma+Asigma+Bsigma=Pepsilon+Qepsilon. The ensuing stress-relaxation G(t) and creep J(t) functions are also unified and universal, derived as [Formula: see text] and J(t)=c2+(epsilon0-c2)e(-PQt)+sigma0Pt, respectively. Application of these relationships to experimental data is illustrated for various tissues including the aortic valve, ligament and cerebral artery. The unified model presented in this paper may be applied to all tissues with two characteristic times, obviating the need for employing varied configurations of discrete element models in preliminary investigation of the viscoelastic behaviour of soft tissues. PMID- 26232815 TI - Oxygen therapy for corneal edema after cataract surgery. AB - PURPOSE: To evaluate the effects of oxygen therapy on corneal edema after cataract surgery. SETTING: Imam Khomeini Hospital, Ahvaz, Iran. DESIGN: Randomized controlled trial. METHODS: Patients with severe corneal edema were randomized into 3 groups. Group 1 (control) received conventional therapy including topical sodium chloride, timolol, and betamethasone. Group 2 received the same therapy in addition to systemic normobaric oxygen at a flow rate of 10 L/min for 1 hour twice daily for 3 weeks. Group 3 received conventional therapy and transcorneal oxygen at a flow rate of 5 L/min for 1 hour twice daily for 3 weeks. Preoperative pachymetry and specular microscopy were performed. Pachymetry was performed 1, 3, 5, 7, 10, and 14 days postoperatively. At 1, 3 and 12 months, pachymetry and specular microscopy were performed. RESULTS: The study enrolled 45 patients. Preoperatively, there was no significant difference between the groups. Pachymetry was more than 1000 MUm 1 day postoperatively in all patients. The preoperative pachymetry was restored in 14 days in Group 3 only. After 1 year, the endothelial cell count (ECC) was 1603 cells/mm(2), 1693 cells/mm(2), and 1911 cells/mm(2) with a loss of 37%, 32%, and 25% in Group 1, Group 2, and Group 3, respectively (P = .034, Groups 1 and 3). Group 3 had a higher ECC than the control group at 3 months (P = .037) and 1 year (P = .025). One patient in Group 1 and 1 patient in Group 2 developed bullous keratopathy. CONCLUSION: Transcorneal oxygen decreased corneal edema more rapidly than conventional and systemic oxygen therapies and preserved more endothelial cells than conventional therapy. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26232816 TI - Refractive and topographic effects of single-segment intrastromal corneal ring segments in eyes with moderate to severe keratoconus and inferior cones. AB - PURPOSE: To evaluate the efficacy and safety of a single intrastromal corneal ring segment (ICRS) (450 MUm Intacs SK) in moderate to severe keratoconic eyes with an inferiorly located cone and a noninvolved center. SETTING: Ophthalmology Department, American University of Beirut Medical Center, Beirut, Lebanon. DESIGN: Retrospective case series. METHODS: The uncorrected (UDVA) and corrected (CDVA) distance visual acuities, central and inferior maximum topographic keratometry (K) values, manifest cylinder, and spherical equivalent (SE) were recorded preoperatively and 1 week and 1, 3, and 6 months postoperatively. RESULTS: Thirty eyes were studied. The mean age was 29.6 years +/- 8.0 (SD). The mean preoperative UDVA and CDVA were 20/86 and 20/42, respectively. The mean center K was 49.14 +/- 4.39 diopters (D); the mean maximum K, 56.78 +/- 6.02 D; and the mean center K - maximum K, -7.45 +/- 5.61 D. The mean SE and cylinder were -2.24 +/- 2.32 D and -4.33 +/- 1.43 D, respectively, with sphere ranging from +2.00 to -18.00 D. At 6 months, the UDVA improved to 20/32. The mean SE was 1.02 +/- 2.04 D (P = .0330); the mean cylinder, -1.67 +/- 1.00 D (P < .00); and the mean center K - maximum K, -4.92 +/- 4.36 D (P < .05). The CDVA improved more than 2 lines; no eye lost any lines. Topographic indices improved in all eyes. CONCLUSIONS: Single ICRS implantation in eyes with moderate to severe keratoconus and inferiorly located cones was safe and effective. The development of a nomogram relying more on topographic data is suggested. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26232817 TI - The image we cast. PMID- 26232818 TI - Graduate Orthodontic Residents Program: Exactly what is GORP? PMID- 26232819 TI - Solving the faculty shortage might require more than money. PMID- 26232820 TI - Orthodontic quackery. PMID- 26232821 TI - Use of Hounsfield units in cone-beam computed tomography. PMID- 26232822 TI - Authors' response. PMID- 26232823 TI - Limitation of a cross-sectional study. PMID- 26232824 TI - Authors' response. PMID- 26232825 TI - P. Raymond Begg. PMID- 26232827 TI - How much is too much? PMID- 26232828 TI - Coenraad F. A. Moorrees: Journey to the top of Mons Scolaris (Mount Scholar). AB - Coenraad F. A. Moorrees was a pioneer in orthodontic education and research. He was the first academic leader to merge clinical and research requirements in a 3 year residency. Beyond his lifelong association with the Harvard School of Dental Medicine and the Forsyth Dental Center (now the Forsyth Institute), his scholarly impact has reached worldwide through his multifaceted publications, but perhaps more potently through his postdoctoral fellows, 52% of whom achieved professorial ranks at academic institutions, and 15% became heads of orthodontic departments. His scholarly productivity cut across various components of facial growth and development, including the critical consideration of the soft tissue profile in evaluating the total face and the assessment of constitutional and psychobiologic panels in diagnosis and treatment of the individual patient. His investigations on dental development yielded cornerstone knowledge that was readily transferred to clinical applications. His contributions in various organizations included extended service for the prestigious National Institute for Dental Research, which oversees the most important research output in the United States. Numerous national and international recognitions were bestowed on him. He combined in his person the attributes of "renaissance educator" and "citizen of the world," reflecting a unique combination of science and humanity. PMID- 26232829 TI - American Association of Orthodontists Foundation Craniofacial Growth Legacy Collection: Overview of a powerful tool for orthodontic research and teaching. AB - This article reports on the current status of the American Association of Orthodontists Foundation (AAOF) Craniofacial Growth Legacy Collection--an AAOF supported multi-institutional project that uses the Internet and cloud computing to collect and share craniofacial images and data for orthodontic research and education. The project gives investigators and clinicians all over the world online access to longitudinal information on craniofacial development in untreated children with malocclusions of various types. It also is a unique source of control samples for testing the validity of consensually accepted beliefs about the effects of orthodontic treatment or of failure to treat. PMID- 26232830 TI - A century of influence: Part 2. The greatest generation. AB - The story of orthodontics during the first 100 years of Journal publication can be told through the people who lived it. As part of the American Journal of Orthodontics and Dentofacial Orthopedics' Centennial celebration, we present 100 people who most influenced the specialty during the last 100 years. Part 2 picks up with "the greatest generation" and describes those born in the first 2 decades of the 20th century. Whether born in Europe or the United States, their lives and educations were disrupted by world war. Many served during the years of conflict, and a few paid an even heavier price. After World War II, they returned home or immigrated to the United States and resumed their life's work in orthodontics. PMID- 26232831 TI - Effect of social media in improving knowledge among patients having fixed appliance orthodontic treatment: A single-center randomized controlled trial. AB - INTRODUCTION: Research has shown that orthodontic patients are more likely to retain information presented in an audiovisual format. However, there has been little research on the effectiveness of audiovisual information provided through different routes such as the Internet. This parallel-group randomized controlled trial assessed whether provision of audiovisual information on the YouTube (Google, San Bruno, Calif) Web site to orthodontic patients undergoing fixed appliance treatment results in improved patient knowledge when compared with conventional methods of information provision. The effects of sex and ethnicity were also investigated. METHODS: Participants were recruited from the Department of Orthodontics of the Eastman Dental Hospital, University College London Hospitals NHS Foundation Trust, United Kingdom. The patients were 13 years of age and over, with no history of orthodontic treatment, and patient and parental (where appropriate) consent were obtained. The participants were randomized into control (n = 34) and intervention (n = 33) groups using a random number table; there was stratification based on age group, with permuted blocks of 10 patients. Both groups were given routine verbal and written patient information related to fixed appliances, and the participants in the intervention group were sent 3 e mails over 6 weeks requesting that they view a 6-minute YouTube video containing similar information but in audiovisual format. Patient knowledge was measured using identical questionnaires answered on the day of recruitment (baseline) and again 6 to 8 weeks later. The researchers were unaware of group allocations when enrolling patients and scoring questionnaires. RESULTS: Sixty participants (89.55%) completed the study. Those who completed the trial in the intervention group (n = 30) demonstrated significantly greater improvements in knowledge than did those in the control group (n = 30), scoring, on average, almost 1 point more (95% CI for the difference, 0.305-1.602; P = 0.005) on the final questionnaire. Ethnicity had a statistically significant effect on improvement in knowledge, but sex did not. No harm to any patient was noted during the trial. CONCLUSIONS: Presenting audiovisual information through the YouTube Web site to orthodontic patients resulted in a significant improvement in patient knowledge. Supplementation of verbal and written patient information with audiovisual information via the Internet is therefore worthy of consideration. REGISTRATION: National Research and Ethics Service (REC number 12/LO/0863), United Kingdom. PROTOCOL: The protocol was not published before trial commencement. FUNDING: No funding or conflict of interest to be declared. PMID- 26232832 TI - Long-term bonded retention after closure of maxillary midline diastema. AB - INTRODUCTION: The objectives of this study were to evaluate fixed bonded palatal surface retainers between the maxillary central incisors that were placed to maintain midline diastema closure and record their longevity, proclivity for damage, and periodontal health of the central incisors in patients 5 or more years after treatment. METHODS: Twenty-nine subjects were contacted and interviewed by phone concerning the status of their bonded retainer and midline diastema. Eleven subjects with intact retainers came for a periodontal health evaluation of the maxillary central incisors. The measures used were the plaque index, the periodontal screening and recording score, and the gingival index. A split-mouth design was used. Statistical analyses of retainer duration, damage probability, and gingival health were performed. RESULTS: Of the 29 subjects, 52% of the initial retainers were in place for an average of 23 years. For the total of 34 bonded retainers, the mean longevity was 17 years. The risk of breakage for any particular year the retainer was in place was 2%. The mean differences in scores between the maxillary central incisors and the control teeth were -0.06 for the plaque index, -0.14 for the periodontal screening and recording score, and -0.11 for the gingival index. Statistical tests on the differences indicated no evidence that the long-term presence of the bonded palatal surface retainer adversely affected the periodontal health of the maxillary central incisors. CONCLUSIONS: The study's sample demonstrated that a bonded retainer for maintaining closure of a maxillary midline diastema can last an average of 17 years or more, with a yearly 2% chance of breakage and with no expected adverse effects on the periodontal health of the maxillary central incisors. PMID- 26232833 TI - Comparison of 5 types of interocclusal recording materials on the accuracy of articulation of digital models. AB - INTRODUCTION: One method of articulating digital models is to use a digitized interocclusal record. However, the accuracy of different interocclusal record materials to articulate digital models has yet to be evaluated. METHODS: A plastic typodont was modified with reference points for interarch measurements and articulated in maximum intercuspal position on a semiadjustable hinge articulator. Twenty-five interocclusal records of each of the 5 experimental materials (Regisil Rigid, Dentsply, York, Pa; Futar Scan, Kettenbach, Huntington Beach, Calif; Byte Right, Motion View Software, Chattanooga, Tenn; Aluwax, Aluwax Dental Products, Allendale, Mich; and Beauty Pink wax, Miltex, York, Pa) were made on the mounted typodont and digitized using an Ortho Insight 3D laser surface scanner (Motion View Software). Motion View Software was used to articulate the digital models by matching points from the models to the digitized interocclusal records. The distances between corresponding interarch markers were measured and compared with the measurements taken on the physical typodont (gold standard). RESULTS: Polyvinyl siloxane materials were significantly more likely to lead to successful articulation than were the other interocclusal record materials. Statistical analysis showed a significant effect of the bite registration material on the probability of success of the articulation (P <0.005). CONCLUSIONS: Polyvinyl siloxane is a more accurate interocclusal recording material when articulating digital models according to the process described in this study. Using a bite registration to articulate digital models should be considered the first step in the articulation process, with a likely residual need to manipulate the models manually. PMID- 26232834 TI - Cone-beam computed tomography transverse analyses. Part 2: Measures of performance. AB - INTRODUCTION: The aim of this study was to compare the predictability of the cone beam transverse (CBT), jugale (J-point), and transpalatal width measurement (TWM) analyses in identifying clinical crossbite. METHODS: From a pool of patients with cone-beam computed tomography scans who came for orthodontic treatment, a sample of 133 patients was identified, with 54 in posterior crossbite (28 boys, 26 girls) and 79 not in crossbite (77 boys, 110 girls). No patient had dental compensation in this sample. After correcting for lateral mandibular shift, 33 of the 54 posterior crossbite patients had a bilateral crossbite, and 21 had a unilateral crossbite with no shift. The CBT, J-point, and TWM analyses were done for each patient from a coronal cross-section through the middle of both the maxillary and mandibular first molar crowns. The landmarks and measurements used were described in detail in a previous study. Posteroanterior cephalograms were constructed to simulate the geometry of the conventional cephalometric radiographs. All 3 analyses were performed on the same data set to predict whether crossbite was present. We used 2 assessments of diagnostic predictability: sensitivity and specificity, and positive and negative predictive values. While the 2 methods answer different questions, the prevalence of crossbite in a population will affect the positive and negative predictive values, but the sensitivity and specificity will not change. RESULTS: Of the 133 patients studied, 54 had a clinical crossbite, and 79 had no crossbite. The J point analysis accurately predicted that 38 patients would have a crossbite, and 45 would not. This resulted in a positive predictive value of 52.78%, a negative predictive value of 73.77%, sensitivity of 70.4%, and specificity of 57%. The TWM analysis accurately predicted that 53 patients would have a crossbite, but it falsely predicted that an additional 68 patients would have crossbite. This resulted in a positive predictive value of 43.8%, a negative predictive value of 91.67%, sensitivity of 98.1%, and specificity of 13.9%. The CBT analysis correctly predicted a crossbite in 47 patients and accurately predicted no crossbite in 73 patients. This resulted in a positive predictive value of 88.68%, a negative predictive value of 91.25%, sensitivity of 87.0%, and specificity of 92.4%. CONCLUSIONS: This study showed that although the TWM analysis had slightly better negative predictive and sensitivity values, the CBT analysis was overall better at both predictive value and sensitivity/specificity because of the limitations in J-point landmarks and the extent of the TWM analysis. Furthermore, the CBT analysis can distinguish between skeletal and dental discrepancies. Further work will test the analysis on additional samples with differing prevalences of crossbite. PMID- 26232835 TI - Agreement among orthodontists experienced with cone-beam computed tomography on the need for follow-up and the clinical impact of craniofacial findings from multiplanar and 3-dimensional reconstructed views. AB - INTRODUCTION: In this study, we aimed to assess interrater and intrarater agreement among orthodontic clinicians in their assessments of reported incidental findings in regard to both the need for additional follow-up and the impact on future orthodontic treatment in large-field maxillofacial cone-beam computed tomography (CBCT) imaging. METHODS: The study sample consisted of 18 nonrandomly selected large-field maxillofacial CBCT volumes containing a reported total of 88 radiographic findings. All scans were associated with formal radiologic reports. However, the suggestions of further follow-up were removed from the radiologic reports so as to not bias the 3 evaluating orthodontists in their subsequent decision making. The evaluators had on average 7.6 years of CBCT usage and self-interpretation experience. Reliability was determined by quantifying the level of agreement between the evaluators' assessments for both research questions for all 88 findings using a binary response (yes/no) as the outcome measure. The Cohen kappa statistic was calculated to quantify intrarater and interrater agreement globally for both statements. RESULTS: Although interrater agreement was considerable, potential decisions with clinical impact were not consistent. This needs to be considered when interpreting maxillofacial incidental findings. Evaluators demonstrated higher levels of agreement for dentoalveolar findings compared with all other extragnathic regions when assessing clinical significance. CONCLUSIONS: Among the evaluators who were considered experienced in CBCT, "fair-to-good" interrater agreement and "excellent" intrarater agreement were demonstrated in terms of the need for further follow-up and their potential impact on future orthodontic treatment. PMID- 26232836 TI - Ultraviolet photofunctionalization increases removal torque values and horizontal stability of orthodontic miniscrews. AB - INTRODUCTION: The objective of this study was to examine the effects of ultraviolet-mediated photofunctionalization of miniscrews and the in-vivo potential of bone-miniscrew integration. METHODS: Self-drilling orthodontic miniscrews made from a titanium alloy were placed in rat femurs. Photofunctionalization was performed by treating the miniscrews with ultraviolet light for 12 minutes with a photo device immediately before implantation. Maximum insertion torque (week 0), removal torque (weeks 0 and 3), and resistance to lateral tipping force (week 3) were examined. RESULTS: The removal torque at 3 weeks of healing was higher for the photofunctionalized screws than for the untreated screws. The regenerated bone tissue was more intact and contiguous around the photofunctionalized miniscrews than around the untreated ones. The miniscrew-bone complex seemed to produce interface failure, not cohesive fracture, in both groups. The displacement of untreated screws under a lateral tipping force was greater than that of photofunctionalized miniscrews. CONCLUSIONS: These results suggest that photofunctionalization increases the bioactivity of titanium-alloy miniscrews and improves the anchoring capability of orthodontic miniscrews, even without modification of the surface topography. PMID- 26232837 TI - Physical and adhesive properties of dental enamel after radiotherapy and bonding of metal and ceramic brackets. AB - INTRODUCTION: The increasing success rates for cancer patients treated with radiotherapy and the frequent occurrence of tooth loss during treatment have led to an increased demand for orthodontic treatment after radiotherapy. The aim of this study was to evaluate tooth enamel of irradiated teeth after the bonding and debonding of metal and ceramic brackets. METHODS: Ten permanent molars were cut into enamel fragments measuring 1 mm(2) and divided into an irradiated group (total dose of 60 Gy) and a nonirradiated group. The fragments were subjected to microshear testing to evaluate whether radiotherapy altered the strength of the enamel. Furthermore, 90 prepared premolars were divided into 6 groups and subgroups (n = 15): group 1, nonirradiated and nonaged; group 2, nonirradiated and aged (thermal cycled); group 3, irradiated and aged; each group was divided into 2 subgroups: metallic and ceramic brackets. After thermal cycling and radiotherapy, the brackets were bonded onto the specimens with Transbond XT (3M Unitek, Monrovia, Calif). After 24 hours, the specimens were subjected to the shear tests. Images of the enamel surfaces were classified using the adhesive remnant index. The composite resin-enamel interface was also evaluated. RESULTS: Enamel fragments subjected to radiation had lower strength than did the nonirradiated samples (P <0.05). The groups and subgroups submitted to radiation and bonded ceramic brackets had the lowest strength values. Groups 1 and 2 with metallic brackets had less adhesive on the surface, whereas groups 1 and 2 with ceramic brackets and group 3 with both metallic and ceramic brackets had more adhesive on the surfaces. On the images of the composite resin-enamel interface, resin tags were more extensive on irradiated tooth enamel. CONCLUSIONS: Radiation decreased tooth enamel strength, and the specimens treated with radiotherapy had higher frequencies of adhesive failure between the bracket and the composite resin as well as more extensive tags. PMID- 26232838 TI - Cytokine measurements in gingival crevicular fluid and periodontal ligament: Are they correlated? AB - INTRODUCTION: Mechanical stress can induce molecular changes in gingival crevicular fluid (GCF) and the periodontal ligament (PDL). It is still not clear whether changes in the PDL and GCF are linked. In this study, we aimed to analyze the expression of cytokines in GCF and PDL after mechanical stress. METHODS: Twenty-three healthy patients were included. The experimental group consisted of premolars subjected to a force of 0.980 N for 1, 3, 7, 14, 21, or 28 days. The contralateral teeth were the controls. GCF and PDL samples were collected at the same time points for analysis of cytokines using the cytometric bead array. RESULTS: Interleukin (IL)-6 (IL-6) production was significantly elevated in the PDL on day 1 after force application. Significantly strong positive correlations between GCF and PDL in experimental group were seen on days 3 (interferon-gamma), 7 (IL-10), 14 (IL-17A), and 28 (IL-17A, tumor necrosis factor-alpha), and significantly strong negative correlation were seen on days 14 (interferon-gamma) and 21 (IL-2, IL-10). CONCLUSIONS: Different patterns of IL-6 expression were seen in the PDL and GCF after mechanical stress. Despite occasional correlations between GCF and PDL, the molecular contributions of the PDL to the GCF changes could not be clearly defined by our model. PMID- 26232839 TI - Interleukin-17 is involved in orthodontically induced inflammatory root resorption in dental pulp cells. AB - INTRODUCTION: The objectives of this study were (1) to investigate the expressions of interleukin (IL)-17, RANKL (the receptor activator of NF-kappaB ligand), and osteoprotegerin (OPG) in root resorption areas during experimental tooth movement in rats, and (2) to determine the effect of IL-17 on the expressions of RANKL and OPG mRNA from human dental pulp cells. METHODS: Twelve male 6-week-old Wistar rats were subjected to an orthodontic force of 50 g to induce a mesially tipping movement of the maxillary first molars for 7 days. The expression levels of tartrate resistant acid phosphatase (TRAP), interleukin (IL) 17, IL-17 receptor (IL-17R), receptor activator of nuclear factor-kappa B ligand (RANKL), and OPG proteins were determined in dental pulp by immunohistochemical analysis. Furthermore, the effects of IL-17 on the expressions of RANKL and OPG mRNA were investigated using human dental pulp cells in vitro. RESULTS: In the experimental tooth movements in vivo, resorption lacunae with multinucleated cells were observed in the 50-g group. The immunoreactivities for IL-17, IL-17R, and RANKL were detected in dental pulp tissues subjected to the orthodontic force on day 7. Moreover, IL-17 increased the mRNA expression of RANKL from human dental pulp cells in vitro. CONCLUSIONS: The results of this study suggest that IL-17 and RANKL may be involved in the process of orthodontically induced inflammatory root resorption in dental pulp cells. PMID- 26232840 TI - Correction of severe bimaxillary protrusion with first premolar extractions and total arch distalization with palatal anchorage plates. AB - Correction of a severe protrusive soft tissue profile without orthognathic surgery can be challenging. This case report describes the treatment of a young woman with a severe bimaxillary protrusion. Orthodontic treatment included extraction of her 4 first premolars and total arch distalization of both arches using a palatal plate appliance. The total treatment time was 24 months. Her occlusion and facial appearance were significantly improved. PMID- 26232841 TI - Treatment of lateral open bite with vertical dentoalveolar distraction osteogenesis. AB - The aim of this article is to describe the surgical, orthodontic, and periodontal treatment of an adult patient with a lateral open bite, anterior crowding, and gingival recession on the mandibular right lateral incisor. The lateral open bite, which resisted conventional mechanics, was successfully corrected by the combination of dento-osseous osteotomies and vertical alveolar distraction using orthodontic multibracket appliances in conjunction with nickel-titanium archwires and intermaxillary elastics. After the orthodontic treatment, the denuded root surface of the mandibular right lateral incisor was closed using a coronally advanced flap technique with platelet-rich fibrin. The results at the 2-year posttreatment follow-up were satisfactory from both the occlusal and the periodontal standpoints. PMID- 26232842 TI - Orthodontic treatment of a mandibular incisor fenestration resulting from a broken retainer. AB - This article describes the orthodontic relapse with mandibular incisor fenestration in a 36-year-old man who had undergone orthodontic treatment 21 years previously. The patient reported that his mandibular 3 * 3 bonded retainer had been partially debonded and broken 4 years earlier. The mandibular left lateral incisor remained bonded to the retainer and received the entire load of the incisors; consequently, there was extreme labial movement of the root, resulting in dental avulsion. As part of the treatment, the root was repositioned lingually using a titanium-molybdenum segmented archwire for 8 months, followed by endodontic treatment, an apicoectomy, and 4 months of alignment and leveling of both arches. The treatment outcomes were excellent, and the tooth remained stable, with good integrity of the mesial, distal, and lingual alveolar bones and periodontal ligament. The 1-year follow-up showed good stability of the results. PMID- 26232843 TI - Development of a novel spike-like auxiliary skeletal anchorage device to enhance miniscrew stability. AB - INTRODUCTION: Miniscrews are frequently used for skeletal anchorage during edgewise treatment, and their clinical use has been verified. However, their disadvantage is an approximately 15% failure rate, which is primarily attributed to the low mechanical stability between the miniscrew and cortical bone and to the miniscrew's close proximity to the dental root. To solve these problems, we developed a novel spike-like auxiliary skeletal anchorage device for use with a miniscrew to increase its stability. METHODS: The retention force was compared between miniscrews with and without the auxiliary skeletal anchorage device at each displacement of the miniscrew. The combined unit was also implanted into the bones of 2 rabbits in vivo, and implantation was visually assessed at 4 weeks postoperatively while the compression force was applied. RESULTS: The retention force of the combined unit was significantly and approximately 3 to 5 times stronger on average than that of the miniscrew alone at each displacement. The spiked portion of the auxiliary anchorage device embedded into the cortical bone of the hind limb at approximately a 0.3-mm depth at 4 weeks postimplantation in both rabbits. CONCLUSIONS: The auxiliary skeletal anchorage device may increase miniscrew stability, allow a shortened miniscrew, and enable 3-dimensional absolute anchorage. Further evaluation of its clinical application is necessary. PMID- 26232844 TI - Litigation and Legislation. Risk management strategies in orthodontics. Part 1: Clinical considerations. PMID- 26232845 TI - Comparison of 2 means (independent z test or independent t test). PMID- 26232846 TI - Investigations into the initial composition of latent fingermark lipids by gas chromatography-mass spectrometry. AB - A more comprehensive understanding of the variability of latent fingermark composition is essential to improving current fingermark detection capabilities in an informed manner. Gas chromatography-mass spectrometry was used to examine the composition of the lipid fraction of latent fingermarks collected from a population of over 100 donors. Variations in the appearances of chromatograms from different donors were apparent in the relative peak sizes of compounds including free fatty acids, squalene, cholesterol and wax esters. Principal component analysis was used as an exploratory tool to explore patterns in this variation, but no correlation to donor traits could be discerned. This study also highlights the practical and inherent difficulties in collecting reproducible samples. PMID- 26232847 TI - Regioisomeric and enantiomeric analyses of 24 designer cathinones and phenethylamines using ultra high performance liquid chromatography and capillary electrophoresis with added cyclodextrins. AB - DESIGNER: phenethylamines (PEAs) and cathinones have been encountered worldwide. Complete characterization of these substances can be challenging due to their chirality and variably substituted phenyl rings. In this study, 24 PEAs and cathinones were analyzed by ultra high performance liquid chromatography with photo diode array detection (UHPLC-PDA) on a variety of stationary phases, and by capillary electrophoresis on a dynamically coated capillary with PDA detection (CE-PDA). In the UHPLC-PDA study, a BEH Phenyl column resolved 18 of the 24 regioisomers in 8min, with good discrimination of the PEAs. In contrast, capillary zone electrophoresis (CZE) on a dynamically coated capillary partially or baseline resolved only 10 of the 24 regioisomers, but with improved discrimination of mono-substituted cathinones. A second series of CE-PDA experiments using 80mM (2-hydroxypropyl)-beta-cyclodextrin (HP-beta-CD) in the run buffer resolved all 24 regioisomers and all but two sets of enantiomers within 18min. Five illicit samples were successfully analyzed using the described methods. PMID- 26232848 TI - A new model for the estimation of time of death from vitreous potassium levels corrected for age and temperature. AB - Analysis of potassium concentration in the vitreous fluid of the eye is frequently used by forensic pathologists to estimate the postmortem interval (PMI), particularly when other methods commonly used in the early phase of an investigation can no longer be applied. The postmortem rise in vitreous potassium has been recognized for several decades and is readily explained by a diffusion of potassium from surrounding cells into the vitreous fluid. However, there is no consensus regarding the mathematical equation that best describes this increase. The existing models assume a linear increase, but different slopes and starting points have been proposed. In this study, vitreous potassium levels, and a number of factors that may influence these levels, were examined in 462 cases with known postmortem intervals that ranged from 2h to 17 days. We found that the postmortem rise in potassium followed a non-linear curve and that decedent age and ambient temperature influenced the variability by 16% and 5%, respectively. A long duration of agony and a high alcohol level at the time of death contributed less than 1% variability, and evaluation of additional possible factors revealed no detectable impact on the rise of vitreous potassium. Two equations were subsequently generated, one that represents the best fit of the potassium concentrations alone, and a second that represents potassium concentrations with correction for decedent age and/or ambient temperature. The former was associated with narrow confidence intervals in the early postmortem phase, but the intervals gradually increased with longer PMIs. For the latter equation, the confidence intervals were reduced at all PMIs. Therefore, the model that best describes the observed postmortem rise in vitreous potassium levels includes potassium concentration, decedent age, and ambient temperature. Furthermore, the precision of these equations, particularly for long PMIs, is expected to gradually improve by adjusting the constants as more reference data are added over time. A web application that facilitates this calculation process and allows for such future modifications has been developed. PMID- 26232849 TI - [Anti-angiogenic treatments in metastatic colorectal cancer: Does a continuous angiogenic blockade make sense?]. AB - Ten years after the approval of bevacizumab in colorectal cancer patients, results from ML18147 and CORRECT studies have recently demonstrated the possibility to target angiogenesis in patients previously exposed to anti-VEGF. An increasing number of anti-angiogenic treatments are now available, however, no biomarker has yet succeeded in rationalizing our therapeutic strategies. Nevertheless, several lessons have been learned from preclinical and pivotal clinical studies. The first clinical trials demonstrated a survival benefit, adding VEGFA targeting monoclonal antibodies to chemotherapy in metastatic colorectal cancer patients (AVF2107, ECOG 3200). Many phase III clinical trials confirmed the interest of this strategy, in combination with chemotherapies containing irinotecan, oxaliplatin, or with 5-fluorouracil in monotherapy. To date, such results have not been reproduced with tyrosine kinase inhibitors targeting the angiogenesis pathways, with an increasing rate of chemotherapy related toxicities. Clinical trials performed in the adjuvant setting (AVANT, NSABPC08) failed to demonstrate any efficacy of the anti-VEGFA treatments on the micrometastatic disease, encouraging its prescription in the unresectable cases. On the other hand, a continuous inhibition of angiogenesis during the course of the metastatic disease was shown to be feasible and to extend colon cancer patient's survival in two recent randomized trials. For these patients, the continuation of bevacizumab beyond progression in first line improves overall survival. Lastly, results achieved by the CORRECT and CONCUR studies demonstrated that anti-angiogenics might be effective in colorectal cancers resistant to chemotherapy. This review presents the main results of preclinical and clinical studies sustaining the prescription of anti-angiogenics in metastatic colorectal cancers. The future challenge is to promote the development of biomarkers to enable the stratification of the different therapeutic strategies. PMID- 26232850 TI - Intraductal US-directed management of bile duct stones without radiocontrast cholangiography. AB - BACKGROUND/AIMS: Intraductal US (IDUS) is an examination of the bile duct by using a thin-caliber ultrasonic probe, yielding real-time, high-quality cross sectional images. We prospectively evaluated the feasibility and safety of IDUS directed stone removal without radiocontrast cholangiography (RC) in naive patients with common bile duct (CBD) stones. METHODS: A total of 38 naive patients with suspected CBD stones (<20 mm) were enrolled in this study. If IDUS showed CBD stones, we performed endoscopic sphincterotomy and removed the identified CBD stones without RC. The primary outcome was success rate of CBD stone removal without RC. The secondary outcomes were conversion rate to conventional ERCP with RC, fluoroscopy time, clinical responses, and adverse events. RESULTS: IDUS was successfully performed in all enrolled patients (38/38, 100%). No echogenic material was observed in 3 patients (1 Mirizzi syndrome, 2 spontaneous passages of CBD stones). After endoscopic sphincterotomy, IDUS directed stone removal was successfully performed without RC in 26 patients (74.3%) in the first session. In the 9 patients, after deployment of plastic stents, IDUS-directed stone removal was successfully completed without RC in a second session. There was no conversion to conventional ERCP with RC. Median fluoroscopy time was 10 seconds. There were no immediate and delayed adverse events related to the IDUS-directed stone removal. However, asymptomatic hyperamylasemia developed in 3 patients (7.9%), who recovered without adverse events. CONCLUSIONS: IDUS-directed stone removal without RC is feasible and safe for patients with CBD stones. We anticipate a potentially important role of IDUS in the field of various therapeutic interventions. PMID- 26232851 TI - Phytotoxicity of ionic, micro- and nano-sized iron in three plant species. AB - Potential environmental impacts of engineered nanoparticles (ENPs) can be understood taking into consideration phytotoxicity. We reported on the effects of ionic (FeCl3), micro- and nano-sized zerovalent iron (nZVI) about the development of three macrophytes: Lepidium sativum, Sinapis alba and Sorghum saccharatum. Four toxicity indicators (seed germination, seedling elongation, germination index and biomass) were assessed following exposure to each iron concentration interval: 1.29-1570mg/L (FeCl3), 1.71-10.78mg/L (micro-sized iron) and 4.81 33,560mg/L (nano-iron). Exposure effects were also observed by optical and transmission electron microscopy. Results showed that no significant phytotoxicity effects could be detected for both micro- and nano-sized zerovalent irons, including field nanoremediation concentrations. Biostimulation effects such as an increased seedling length and biomass production were detected at the highest exposure concentrations. Ionic iron showed slight toxicity effects only at 1570mg/L and, therefore, no median effect concentrations were determined. By microscopy, ENPs were not found in palisade cells or xylem. Apparently, aggregates of nZVI were found inside S. alba and S. saccharatum, although false positives during sample preparation cannot be excluded. Macroscopically, black spots and coatings were detected on roots of all species especially at the most concentrated treatments. PMID- 26232852 TI - Single-Fraction Versus 5-Fraction Radiation Therapy for Metastatic Epidural Spinal Cord Compression in Patients With Limited Survival Prognoses: Results of a Matched-Pair Analysis. AB - PURPOSE: This study compared single-fraction to multi-fraction short-course radiation therapy (RT) for symptomatic metastatic epidural spinal cord compression (MESCC) in patients with limited survival prognosis. METHODS AND MATERIALS: A total of 121 patients who received 8 Gy * 1 fraction were matched (1:1) to 121 patients treated with 4 Gy * 5 fractions for 10 factors including age, sex, performance status, primary tumor type, number of involved vertebrae, other bone metastases, visceral metastases, interval between tumor diagnosis and MESCC, pre-RT ambulatory status, and time developing motor deficits prior to RT. Endpoints included in-field repeated RT (reRT) for MESCC, overall survival (OS), and impact of RT on motor function. Univariate analyses were performed with the Kaplan-Meier method and log-rank test for in-field reRT for MESCC and OS and with the ordered-logit model for effect of RT on motor function. RESULTS: Doses of 8 Gy * 1 fraction and 4 Gy * 5 fractions were not significantly different with respect to the need for in-field reRT for MESCC (P=.11) at 6 months (18% vs 9%, respectively) and 12 months (30% vs 22%, respectively). The RT regimen also had no significant impact on OS (P=.65) and post-RT motor function (P=.21). OS rates at 6 and 12 months were 24% and 9%, respectively, after 8 Gy * 1 fraction versus 25% and 13%, respectively, after 4 Gy * 5 fractions. Improvement of motor function was observed in 17% of patients after 8 Gy * 1 fraction and 23% after 4 Gy * 5 fractions, respectively. CONCLUSIONS: There were no significant differences with respect to need for in-field reRT for MESCC, OS, and motor function by dose fractionation regimen. Thus, 8 Gy * 1 fraction may be a reasonable option for patients with survival prognosis of a few months. PMID- 26232853 TI - Experimental Studies of Boronophenylalanine ((10)BPA) Biodistribution for the Individual Application of Boron Neutron Capture Therapy (BNCT) for Malignant Melanoma Treatment. AB - PURPOSE: Patients with the same histopathologic diagnosis of cutaneous melanoma treated with identical protocols of boron neutron capture therapy (BNCT) have shown different clinical outcomes. The objective of the present studies was to evaluate the biodistribution of boronophenilalanina ((10)BPA) for the potential application of BNCT for the treatment of melanoma on an individual basis. METHODS AND MATERIALS: The boronophenilalanine (BPA) uptake was evaluated in 3 human melanoma cell lines: MEL-J, A375, and M8. NIH nude mice were implanted with 4 10(6) MEL-J cells, and biodistribution studies of BPA (350 mg/kg intraperitoneally) were performed. Static infrared imaging using a specially modified infrared camera adapted to measure the body infrared radiance of small animals was used. Proliferation marker, Ki-67, and endothelial marker, CD31, were analyzed in tumor samples. RESULTS: The in vitro studies demonstrated different patterns of BPA uptake for each analyzed cell line (P<.001 for MEL-J and A375 vs M8 cells). The in vivo studies showed a maximum average boron concentration of 25.9 +/- 2.6 MUg/g in tumor, with individual values ranging between 11.7 and 52.0 MUg/g of (10)B 2 hours after the injection of BPA. Tumor temperature always decreased as the tumors increased in size, with values ranging between 37 degrees C and 23 degrees C. A significant correlation between tumor temperature and tumor-to-blood boron concentration ratio was found (R(2) = 0.7, rational function fit). The immunohistochemical studies revealed, in tumors with extensive areas of viability, a high number of positive cells for Ki-67, blood vessels of large diameter evidenced by the marker CD31, and a direct logistic correlation between proliferative status and boron concentration difference between tumor and blood (R(2) = 0.81, logistic function fit). CONCLUSION: We propose that these methods could be suitable for designing new screening protocols applied before melanoma BNCT treatment for each individual patient and lesion. PMID- 26232854 TI - Are State-Sponsored New Radiation Therapy Facilities Economically Viable in Low- and Middle-Income Countries? AB - PURPOSE: The economic viability of establishing a state-funded radiation therapy (RT) infrastructure in low- and middle-income countries (LMICs) in accordance with the World Bank definition has been assessed through computation of a return on investment (ROI). METHODS AND MATERIALS: Of the 139 LMICs, 100 were evaluated according to their RT facilities, gross national income (GNI) per capita, and employment/population ratio. The assumption was an investment of US$5 million for a basic RT center able to treat 1000 patients annually. The national breakeven points and percentage of ROI (%ROI) were calculated according to the GNI per capita and patient survival rates of 10% to 50% at 2 years. It was assumed that 50% of these patients would be of working age and that, if employed and able to work after treatment, they would contribute to the country's GNI for at least 2 years. The cumulative GNI after attaining the breakeven point until the end of the 15-year lifespan of the teletherapy unit was calculated to estimate the %ROI. The recurring and overhead costs were assumed to vary from 5.5% to 15% of the capital investment. RESULTS: The %ROI was dependent on the GNI per capita, employment/population ratio and 2-year patient survival (all P<.001). Accordingly, none of the low-income countries would attain an ROI. If 50% of the patients survived for 2 years, the %ROI in the lower-middle and upper-middle income countries could range from 0% to 159.9% and 11.2% to 844.7%, respectively. Patient user fees to offset recurring and overhead costs could vary from "nil" to US$750, depending on state subsidies. CONCLUSIONS: Countries with a greater GNI per capita, higher employment/population ratio, and better survival could achieve a faster breakeven point, resulting in a higher %ROI. Additional factors such as user fees have also been considered. These can be tailored to the patient's ability to pay to cover the recurring costs. Certain pragmatic steps that could be undertaken to address these issues are discussed in the present study. PMID- 26232855 TI - A Phase 1/2 Study of Definitive Chemoradiation Therapy Using Docetaxel, Nedaplatin, and 5-Fluorouracil (DNF-R) for Esophageal Cancer. AB - PURPOSE: Patient survival in esophageal cancer (EC) remains poor. The purpose of this study was to investigate a regimen of definitive chemoradiation therapy (CRT) that exerts good local control of EC. We performed a phase 1/2 study to assess the safety and efficacy of CRT with docetaxel, nedaplatin, and 5 fluorouracil (DNF-R). METHODS AND MATERIALS: Eligible patients presented with stage IB to IV EC. Patients received 2 cycles of docetaxel (20, 30, or 40 mg/m(2)) and nedaplatin (50 mg/m(2)) on days 1 and 8 and a continuous infusion of 5-fluorouracil (400 mg/m(2)/day) on days 1 to 5 and 8 to 12, every 5 weeks, with concurrent radiation therapy (59.4 Gy/33 fractions). The recommended dose (RD) was determined using a 3 + 3 design. RESULTS: In the phase 1 study, the dose limiting toxicities were neutropenia and thrombocytopenia. The RD of docetaxel was determined to be 20 mg/m(2). In the phase 2 study, grade 3 to 4 acute toxicities included neutropenia (42.8%), febrile neutropenia (7.14%), thrombocytopenia (17.9%), and esophagitis (21.4%). Grade 3 to 4 late radiation toxicity included esophagostenosis (10.7%). The complete response rate was 82.1% (95% confidence interval: 67.9-96.3%). Both the median progression-free survival and overall survival were 41.2 months. CONCLUSIONS: DNF-R showed good tolerability and strong antitumor activity, suggesting that it is a potentially effective therapeutic regimen for EC. PMID- 26232856 TI - Medical Malpractice Claims in Radiation Oncology: A Population-Based Study 1985 2012. AB - PURPOSE: The purpose of this study was to determine trends in radiation oncology malpractice claims and expenses during the last 28 years and to compare radiation oncology malpractice claims to those of other specialties. METHODS AND MATERIALS: We performed a retrospective analysis of closed malpractice claims filed from 1985 to 2012, collected by a nationwide medical liability insurance trade association. We analyzed characteristics and trends among closed claims, indemnity payments (payments to plaintiff), and litigation expenses. We also compared radiation oncology malpractice claims to those of 21 other medical specialties. Time series dollar amounts were adjusted for inflation (2012 was the index year). RESULTS: There were 1517 closed claims involving radiation oncology, of which 342 (22.5%) were paid. Average and median indemnity payments were $276,792 and $122,500, respectively, ranking fifth and eighth, respectively, among the 22 specialty groups. Linear regression modeling of time trends showed decreasing total numbers of claims (beta = -1.96 annually, P=.003), increasing average litigation expenses paid (beta = +$1472 annually, P <= .001), and no significant changes in average indemnity payments (beta = -$681, P=.89). CONCLUSIONS: Medical professional liability claims filed against radiation oncologists are not common and have declined in recent years. However, indemnity payments in radiation oncology are large relative to those of many other specialties. In recent years, the average indemnity payment has been stable, whereas litigation expenses have increased. PMID- 26232857 TI - Adjuvant Radiation Therapy Treatment Time Impacts Overall Survival in Gastric Cancer. AB - PURPOSE: Prolonged radiation therapy treatment time (RTT) is associated with worse survival in several tumor types. This study investigated whether delays during adjuvant radiation therapy impact overall survival (OS) in gastric cancer. METHODS AND MATERIALS: The National Cancer Data Base was queried for patients with resected gastric cancer who received adjuvant radiation therapy with National Comprehensive Cancer Network--recommended doses (45 or 50.4 Gy) between 1998 and 2006. RTT was classified as standard (45 Gy: 33-36 days, 50.4 Gy: 38-41 days) or prolonged (45 Gy: >36 days, 50.4 Gy: >41 days). Cox proportional hazards models evaluated the association between the following factors and OS: RTT, interval from surgery to radiation therapy initiation, interval from surgery to radiation therapy completion, radiation therapy dose, demographic/pathologic and operative factors, and other elements of adjuvant multimodality therapy. RESULTS: Of 1591 patients, RTT was delayed in 732 (46%). Factors associated with prolonged RTT were non-private health insurance (OR 1.3, P=.005) and treatment at non academic facilities (OR 1.2, P=.045). Median OS and 5-year actuarial survival were significantly worse in patients with prolonged RTT compared with standard RTT (36 vs 51 months, P=.001; 39 vs 47%, P=.005); OS worsened with each cumulative week of delay (P<.0004). On multivariable analysis, prolonged RTT was associated with inferior OS (hazard ratio 1.2, P=.002); the intervals from surgery to radiation therapy initiation or completion were not. Prolonged RTT was particularly detrimental in patients with node positivity, inadequate nodal staging (<15 nodes examined), and those undergoing a cycle of chemotherapy before chemoradiation therapy. CONCLUSIONS: Delays during adjuvant radiation therapy appear to negatively impact survival in gastric cancer. Efforts to minimize cumulative interruptions to <7 days should be considered. PMID- 26232858 TI - Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery. AB - PURPOSE: To characterize local tumor control and toxicity risk in very long-term survivors (>5 years) after high-dose spinal image guided, intensity modulated radiation therapy delivered as single-dose stereotactic radiosurgery (SRS). Previously published spinal SRS outcome analyses have included a heterogeneous population of cancer patients, mostly with short survival. This is the first study reporting the long-term tumor control and toxicity profiles after high-dose single-fraction spinal SRS. METHODS AND MATERIALS: The study population included all patients treated from June 2004 to July 2009 with single-fraction spinal SRS (dose 24 Gy) who had survived at least 5 years after treatment. The endpoints examined included disease progression, surgical or radiation retreatment, in field fracture development, and radiation-associated toxicity, scored using the Radiation Therapy Oncology Group radiation morbidity scoring criteria and the Common Terminology Criteria for Adverse Events, version 4.0. Local control and fracture development were assessed using Kaplan-Meier analysis. RESULTS: Of 278 patients, 31 (11.1%), with 36 segments treated for spinal tumors, survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 6.1 years (maximum 102 months). The histopathologic findings for the 5-year survivors included radiation-resistant metastases in 58%, radiation-sensitive metastases in 22%, and primary bone tumors in 19%. In this selected cohort, 3 treatment failures occurred at a median of 48.6 months, including 2 recurrences in the radiation field and 1 patient with demonstrated progression at the treatment margins. Ten lesions (27.8%) were associated with acute grade 1 cutaneous or gastrointestinal toxicity. Delayed toxicity >= 3 months after treatment included 8 cases (22.2%) of mild neuropathy, 2 (5.6%) of gastrointestinal discomfort, 8 (22.2%) of dermatitides, and 3 (8.3%) of myalgias/myositis. Thirteen treated levels (36.1%) in 12 patients demonstrated progressive vertebral body collapse or endplate fractures at a median of 25.7 months (range 11.6-76.0), of which 5 (14%) became symptomatic and subsequently required percutaneous cement augmentation or surgery. CONCLUSIONS: In the longest term series to date, high-dose single-fraction spinal SRS retained an excellent safety profile among long-term survivors (>5 years). PMID- 26232860 TI - Cell-penetrating peptide-mediated subunit vaccine generates a potent immune response and protection against Streptococcus iniae in Japanese flounder (Paralichthys olivaceus). AB - The efficiency of antigen capture, processing, and presentation by antigen presenting cells is the key to induce an effective immune response. Cell penetrating peptides (CPPs) are short peptides that facilitate cellular uptake of various molecular cargoes and have an attractive potential for vaccine delivery. In this study, the Drosophila Antennapedia homeoprotein (Antp) and the human immunodeficiency virus-1 transactivator of transcription (TAT) peptides were fused to the N- or C-terminus of Sia10, a protective antigen of Streptococcus iniae, resulting in four recombinant fusion proteins, i.e., rAntp-Sia10, rSia10 Antp, rTAT-Sia10, and rSia10-TAT. All fusion proteins were expressed and purified, and their ability to penetrate into cells was examined. The results showed that rTAT-Sia10 had the strongest ability to translocate through the cellular membrane into cells. Immunofluorescence microscopy and Western blot assay confirmed that rTAT-Sia10 could penetrate into the head kidney lymphocytes and gill cells of Japanese flounder (Paralichthys olivaceus). Immunological analysis showed that rTAT-Sia10 significantly enhanced macrophage activation and peripheral blood leukocyte proliferation, and induced production of specific serum antibodies at 2-8 weeks post-vaccination. Transcriptional analysis showed that vaccination with rTAT-Sia10 up-regulated the expression of the genes encoding IL-1beta, IL-8, NKEF, Mx, IgD, IgM, TNFalpha, MHC I alpha, MHC IIalpha, and CD8alpha. Fish vaccinated with rTAT-Sia10 exhibited significantly higher levels of survival rates (98% at 1 month and 92% at 2 months) compared to fish vaccinated with rSia10 (57% at 1 month and 53% at 2 months). Taken together, these results indicate that TAT-derived peptide has a great potential in the application of bacterial vaccines. PMID- 26232859 TI - A review of breast cancer awareness among women in India: Cancer literate or awareness deficit? AB - BACKGROUND: Breast cancer is the most common female cancer worldwide including India, where advanced stages at diagnosis, and rising incidence and mortality rates, make it essential to understand cancer literacy in women. We conducted a literature review to evaluate the awareness levels of risk factors for breast cancer among Indian women and health professionals. METHODS: A structured literature search using combined keywords was undertaken on bibliographic databases including MEDLINE, Cochrane Database of Systematic Reviews, Cumulative Index to Nursing and Allied Health (CINAHL) and SCOPUS. Searches were restricted to research published in English language peer-reviewed journals through December, 2014 in India. RESULTS: A total of 7066 women aged 15-70 years showed varied levels of awareness on risk factors such as family history (13-58%), reproductive history (1-88%) and obesity (11-51%). Literacy levels on risk factors did not improve over the 8-year period (2005-2013). On average, nurses reported higher, though still varied, awareness levels for risk factors such as family history (40.8-98%), reproductive history (21-90%) and obesity (34-6%). Awareness levels were not consistently higher for the stronger determinants of risk. CONCLUSION: Our review revealed low cancer literacy of breast cancer risk factors among Indian women, irrespective of their socio-economic and educational background. There is an urgent need for nation- and state-wide awareness programmes, engaging multiple stakeholders of society and the health system, to help improve cancer literacy in India. PMID- 26232861 TI - Quantitative analysis of intraneuronal transport in human iPS neurons. AB - Induced pluripotent stem (iPS) cells are promising tools to investigate disease mechanism and develop new drugs. Intraneuronal transport, which is fundamental for neuronal survival and function, is vulnerable to various pharmacological and chemical agents and is disrupted in some neurodegenerative disorders. We applied a quantification method for axonal transport by counting CM-DiI-labeled particles traveling along the neurite, which allowed us to monitor and quantitate, for the first time, intraneuronal transport in human neurons differentiated from iPS cells (iCell neurons). We evaluated the acute effects of several anti-neoplastic agents that have been previously shown to affect intraneuronal transport. Vincristine, paclitaxel and oxaliplatin decreased the number of moving particle along neurites. Cisplatin, however, produced no effect on intraneuronal transport, which is in contrast to our previous report indicating that it inhibits transport in chick dorsal root ganglion neurons. Our system may be a useful method for assessing intraneuronal transport and neurotoxicity in human iPS neurons. PMID- 26232862 TI - In vitro anti-osteoclastogenic activity of p38 inhibitor doramapimod via inhibiting migration of pre-osteoclasts and NFATc1 activity. AB - The mitogen activated protein kinase p38 plays a role in the receptor activator of NF-KB ligand (RANKL)-induced osteoclast differentiation. In this study, we investigated the effect of p38 inhibitor doramapimod on the osteoclast differentiation. Doramapimod significantly inhibited the osteoclastogenesis of bone marrow macrophages (BMMs) via attenuating the activation of p38 induced by M CSF and RANKL. Importantly, doramapimod blocked the migration and fusion in pre osteoclasts via the down-regulating NFATc1. The inhibitory effect of doramapimod on the migration/fusion of pre-osteoclasts via inhibiting NFATc1 activity were confirmed by measuring NFATc1 luciferase activity and evaluating the mRNA expression of NFATc1-responsive genes related to the osteoclastic migration/fusion. These results suggested anti-osteoclastogenic activity of doramapimod via inhibiting migration/fusion of pre-osteoclasts and NFATc1 activity. PMID- 26232863 TI - A novel biomarker ARMc8 promotes the malignant progression of ovarian cancer. AB - Ovarian cancer is the most lethal gynecologic malignancy worldwide, and the survival rates have remained low in spite of medical advancements. More research is dedicated to the identification of novel biomarkers for this deadly disease. The association between ARMc8 and ovarian cancer remained unraveled. In this study, immunohistochemical staining was used to examine ARMc8 expression in 247 cases of ovarian cancer, 19 cases of borderline ovarian tumors, 41 cases of benign ovarian tumors, and 9 cases of normal ovarian tissues. It was shown that ARMc8 was predominantly located in the cytoplasm of tumor cells, and its expression was up-regulated in the ovarian cancer (61.9%) and the borderline ovarian tumor tissues (57.9%), in comparison with the benign ovarian tumors (12.2%; P < .05) and the normal ovarian tissues (11.1%; P < .05). In ovarian cancer, ARMc8 expression was closely related to International Federation of Gynecology and Obstetrics stages (P = .002), histology grade (P < .001), lymph node metastasis (P = .008), and poor prognosis (P < .001). Univariate and multivariate Cox analyses revealed that ARMc8 expression was an independent prognostic factor for ovarian cancer (P = .039 and P = .005). In addition, ARMc8 could promote the invasion and migration of ovarian cancer cells. Overexpressing ARMc8 enhanced the invasion and metastasis capacity of ARMc8-low Cavo-3 cells (P < .001), whereas interfering ARMc8 significantly reduced cell invasion and metastasis in ARMc8-high SK-OV-3 cells (P < .001). Furthermore, ARMc8 could up regulate matrix metalloproteinase-7 and snail and down-regulate alpha-catenin, p120ctn, and E-cadherin. Collectively, ARMc8 may enhance the invasion and metastasis of ovarian cancer cells and likely to become a potential therapeutic target for ovarian cancer. PMID- 26232864 TI - Immunoprofile-based subgrouping of urothelial bladder carcinomas for survival prediction. AB - One of the major challenges in bladder cancer management is in distinguishing aggressive from indolent tumors with similar clinicopathological factors, especially in cases of high-grade T1 stage tumors. To define a set of prognostic factors that can be easily assessed in clinical practice with a high cost effectiveness, the expressions of 11 proteins were examined immunohistochemically in 403 cases of transurethral resection of bladder tumors, then correlated to clinical outcomes. Based on the protein immunoprofiles, urothelial carcinomas were divided into 4 intrinsic molecular subgroups with different clinical outcomes: subgroups 1 and 4 with the poorest survival, subgroup 2 with the best survival, and subgroup 3 with the intermediate survival outcome. The protein expression patterns of the 4 subgroups were mutually exclusive: overexpression of p53, EZH2, E2F1, and IMP3 and high Ki-67 proliferation index in subgroup 1; overexpression of cytoplasmic survivin in subgroup 4; overexpression of membranous TSP1 and cytoplasmic p27 in subgroup 2; and no representative protein overexpression in subgroup 3. Using these protein immunoprofiles, 3 risk groups were generated, which predicted disease-specific survival not only in total bladder carcinoma cases with 0.737 of predictive accuracy but also in high-grade stage T1 tumors with 0.658 of predictive accuracy. These results showed that urothelial carcinomas were composed of 4 clinically relevant molecular subgroups based on protein expression and that overall survival of those patients could be predicted using a set of a small number of protein expressions not only in total cases but also in high-grade stage T1 tumors. PMID- 26232865 TI - Diagnostic value of fine needle aspiration BRAF(V600E) mutation analysis in papillary thyroid cancer: a systematic review and meta-analysis. AB - Fine needle aspiration (FNA) with cytologic analysis is an initial step in diagnosing thyroid nodules that are suspicious for cancer. We systematically reviewed the test accuracy of B-type Raf kinase (BRAF(V600E)) gene mutation analysis plus conventional FNA in the diagnosis of papillary thyroid cancer. We identified studies reporting BRAF(V600E) mutation analysis after FNA for evaluation of thyroid nodules through searching MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, scanning reference lists of relevant studies, and contacting experts. Two independent reviewers screened literature results, abstracted data, and appraised study quality. When appropriate, bivariate and univariate random-effects meta-analyses of sensitivity and specificity were considered for all outcomes. Forty-seven studies met our inclusion criteria after screening 1560 citations and 169 full-text articles. The included studies enrolled approximately 16170 patients with 9924 FNA samples evaluated for BRAF(V600E) mutation. Univariate pooled sensitivity was 69% (95% confidence interval, 61%-76%) for papillary thyroid cancer. For thyroid nodules that were diagnosed cytologically as suspicious for papillary thyroid cancer, univariate pooled sensitivity using FNA and BRAF(V600E) results was 52% (95% confidence interval, 39%-64%). Despite its high specificity, our meta-analysis shows that BRAF(V600E) mutation analysis has a low sensitivity in diagnosing papillary thyroid cancer in thyroid nodules. The feasibility of this test as a single molecular tool is not well established, which indicates the need for well designed prospective clinical studies. PMID- 26232866 TI - How important is young children's actual and perceived movement skill competence to their physical activity? AB - OBJECTIVES: To determine the associations between young children's actual and perceived object control and locomotor skills and physical activity and whether associations differ by sex. DESIGN: Cross sectional study. METHODS: A total of 136 children consented. Children had actual skill (Test of Gross Motor Development-2), perceived skill (Pictorial Scale of Perceived Movement Skill Competence for Young Children), and moderate- to vigorous-intensity physical activity (MVPA) (accelerometers) assessed. Independent t-tests assessed sex differences. A regression (with MVPA as the outcome) was performed with all predictor variables (i.e. Actual Object Control, Actual Locomotor, Perceived Object Control, and Perceived Locomotor). Model 2 also adjusted for age, sex, accelerometer wear time and whether the child was from an English speaking background. Interaction terms between the respective actual or perceived skill factor and sex were added to assess sex differences. RESULTS: Analyses were conducted on 109 children (59 boys, 50 girls; mean age=6.5 years, SD=1.0). Boys had higher actual and perceived object control skill and were more active by an average of 19min per day. There were no sex differences in locomotor skills. There were no associations between skill factors and MVPA, except for girls, where locomotor skill was a significant predictor of MVPA (B=3.66, p=0.016). CONCLUSIONS: Actual rather than perceived skill competence was more important to MVPA in this sample. Locomotor skill competence may be more important than object control skill competence for girls as they may engage in types of physical activity that do not require object control mastery. PMID- 26232867 TI - Auditory verbal hallucinations increase the risk for suicide attempts in adolescents with suicidal ideation. AB - OBJECTIVE: It is important to prevent patients with suicidal ideation from actually attempting suicide. A school based cohort study suggested that auditory verbal hallucinations (AVHs) might play an important role in driving young people with mental health problems to attempt suicide. However, no clinical study to date has specifically investigated the association between AVHs and suicide attempts among young patients with suicidal ideation. METHOD: We conducted a cross-sectional study of first-visit psychiatric referrals aged 10-15years at two general child and adolescent mental health hospitals in Japan. We administered self-reported questionnaires to measure suicidal ideation and suicide attempts, AVHs, and depression in the two weeks prior to the date of first-visit. RESULTS: Among 188 patients with suicidal ideation, the presence of AVHs was associated with increased odds of suicide attempts (OR 3.4, 95% CI 1.7-6.9; p<0.05); however, depression was not associated with a significant change of odds (OR 0.7, 95% CI 0.4-1.3; p=0.29). CONCLUSIONS: AVHs may increase the risk of suicide attempts made by adolescents with suicidal ideation. Clinicians should consider AVHs when adolescent patients present with suicidal ideation. PMID- 26232868 TI - Testosterone and reward prediction-errors in healthy men and men with schizophrenia. AB - Sex hormones impact reward processing, which is dysfunctional in schizophrenia; however, the degree to which testosterone levels relate to reward-related brain activity in healthy men and the extent to which this relationship may be altered in men with schizophrenia has not been determined. We used functional magnetic resonance imaging (fMRI) to measure neural responses in the striatum during reward prediction-errors and hormone assays to measure testosterone and prolactin in serum. To determine if testosterone can have a direct effect on dopamine neurons, we also localized and measured androgen receptors in human midbrain with immunohistochemistry and quantitative PCR. We found correlations between testosterone and prediction-error related activity in the ventral striatum of healthy men, but not in men with schizophrenia, such that testosterone increased the size of positive and negative prediction-error related activity in a valence specific manner. We also identified midbrain dopamine neurons that were androgen receptor immunoreactive, and found that androgen receptor (AR) mRNA was positively correlated with tyrosine hydroxylase (TH) mRNA in human male substantia nigra. The results suggest that sex steroid receptors can potentially influence midbrain dopamine biosynthesis, and higher levels of serum testosterone are linked to better discrimination of motivationally-relevant signals in the ventral striatum, putatively by modulation of the dopamine biosynthesis pathway via AR ligand binding. However, the normal relationship between serum testosterone and ventral striatum activity during reward learning appears to be disrupted in schizophrenia. PMID- 26232869 TI - Neural activity changes in unaffected children of patients with schizophrenia: A resting-state fMRI study. AB - Previous neuroimaging studies have suggested that individuals at risk for schizophrenia exhibit structural and functional brain abnormalities. However, few studies focus on resting state baseline activity in individuals with genetic high risk for schizophrenia (HR). We examined cerebral spontaneous neural activity in HR by measuring the amplitude of low frequency fluctuations (ALFF) in the blood oxygen level-dependent (BOLD) functional magnetic resonance signal during resting state. Using a 3T MRI scanner, 28 non-psychotic young adult participants with at least one parent with schizophrenia and 44 matched unrelated healthy comparison subjects (HC) were scanned during the resting-state. The ALFF of the BOLD signal for each participant was calculated, and these values were then compared between groups using voxel-based analysis of the ALFF maps. The HR group showed significantly increased ALFF compared to the HC group in the striatum, including the left caudate nucleus extending to the putamen and the right caudate nucleus. There was also increased ALFF in HR relative to controls in the left medial temporal region including hippocampus, parahippocampal gyrus and the fusiform gyrus, as well as regions including the left lateral thalamus, bilateral ventral and dorsal anterior cingulate cortex, bilateral calcarine sulcus and precuneus. There was significantly decreased ALFF in the HR group relative to controls in the left inferior parietal lobule/postcentral gyrus. Our findings suggest that altered intrinsic neuronal activity in cortico-striato-thalamic networks may represent genetic vulnerability for the development of schizophrenia. PMID- 26232870 TI - Shortened leukocyte telomere length in patients with schizophrenia is related to disease status. PMID- 26232871 TI - Differences in central serotoninergic transmission among patients with recent onset, sub-chronic, and chronic schizophrenia as assessed by the loudness dependence of auditory evoked potentials. AB - Previous research has shown that abnormalities in serotonin systems are associated with schizophrenia. The loudness dependence of auditory evoked potentials (LDAEP) has been used as a metric of central serotonin activity. The present study aimed to evaluate LDAEP in patients with schizophrenia of differing chronicity. Sixty-four patients with schizophrenia and 50 healthy controls were enrolled in this study. LDAEP and psychometric ratings, such as the positive and negative syndrome scale (PANSS), were measured. The cohort was stratified into three subgroups according to the duration of illness: recent onset (<2years, n=21), sub-chronic (2-9years, n=28), and chronic (>=10years, n=15) groups. The LDAEP differed significantly among the three groups. A post-hoc analysis (Bonferroni) demonstrated that the LDAEP differed significantly between the recent onset and chronic groups (p=0.029), and between the healthy control and chronic groups (p=0.008). Age, sex, dosage of antipsychotics, and smoking did not significantly affect the group differences. In the correlation analysis, there was a significant correlation of LDAEP values with illness duration (r=-0.259, p=0.045). The present study verifies that the LDAEP is related to the duration of illness in patients with schizophrenia. This suggests that central serotonin neurotransmission is changeable, and it may depend on the chronicity of schizophrenia pathology. PMID- 26232872 TI - All in the Family Presence. PMID- 26232873 TI - Exploring the Management of Death: Emergency Nurses' Perceptions of Challenges and Facilitators in the Provision of End-of-Life Care in the Emergency Department. AB - INTRODUCTION: The importance of end-of-life (EOL) care for dying patients and their families is well described; however, little research has been performed in emergency settings. The purpose of this study was to explore emergency nurses' perceptions of challenges and facilitators in the care of patients at the EOL. METHODS: A mixed-methods design using survey data (N = 1,879) and focus group data (N = 17). Data were collected on questions regarding care of the EOL patient in the emergency department, specifically nurses' perceptions of the care of these patients; educational content needs; barriers to safe and effective care; and the availability of resources. RESULTS: High scores on the quantitative survey showed a high mean level of consistently positive attitudes and beliefs toward caring for dying patients and their families and loved ones (131.26 +/- 10.88). Analysis of the focus group transcripts uncovered 9 themes, reflecting concerns around comfort and challenges with EOL care, appropriate training for nurses, and the availability of resources to provide this type of care in the emergency setting. Also noted was dissonance between the nature of emergency care and the nature of EOL care. DISCUSSION: Emergency nurses are comfortable providing EOL care in the emergency setting but note that challenges to providing good care include lack of space, time, and staff. Other challenges involve the mismatch between the goals of emergency care and those of EOL care, as well as the emotional burden of caring for the dying, especially when the appropriate resources are lacking. PMID- 26232874 TI - Vomiting at Triage: Is it "Just the Flu"? PMID- 26232875 TI - Getting the Word Out: Dissemination of Research Results. PMID- 26232876 TI - Resiliency in Emergency Nurses. AB - The aim of this study is to explore the resiliency characteristics of certified emergency nurses. Emergency departments are highly acute patient care environments that are often unpredictable and stressful workplaces. Resiliency theory identifies individual characteristics that allow people to overcome stress. This study describes the resiliency characteristics and experiences of certified emergency nurses. METHODS: In this qualitative directed content analysis study, the resiliency characteristics of emergency nurses were explored. Sixteen certified emergency nurses were interviewed. RESULTS: Seven resiliency characteristics were described: presence d'esprit, decisive action, tenacity, interpersonal connectedness, honesty, self-control, and optimism. An additional finding of resetting was also relayed. DISCUSSION: Resiliency may be adapted and fostered in emergency nurses to guide future workplace stress reduction and adaptation techniques. Promoting resiliency programs for emergency nurses is a promising future intervention. PMID- 26232877 TI - Zebrafish germ cells: motility and guided migration. AB - In the course of embryonic development, the process of cell migration is critical for establishment of the embryonic body plan, for morphogenesis and for organ function. Investigating the molecular mechanisms underlying cell migration is thus crucial for understanding developmental processes and clinical conditions resulting from abnormal cell migration such as cancer metastasis. The long-range migration of primordial germ cells toward the region at which the gonad develops occurs in embryos of various species and thus constitutes a useful in vivo model for single-cell migration. Recent studies employing zebrafish embryos have greatly contributed to the understanding of the mechanisms facilitating the migration of these cells en route to their target. PMID- 26232878 TI - Biodegradable, phosphate-containing, dual-gelling macromers for cellular delivery in bone tissue engineering. AB - Injectable, biodegradable, dual-gelling macromer solutions were used to encapsulate mesenchymal stem cells (MSCs) within stable hydrogels when elevated to physiologic temperature. Pendant phosphate groups were incorporated in the N isopropyl acrylamide-based macromers to improve biointegration and facilitate hydrogel degradation. The MSCs were shown to survive the encapsulation process, and live cells were detected within the hydrogels for up to 28 days in vitro. Cell-laden hydrogels were shown to undergo significant mineralization in osteogenic medium. Cell-laden and acellular hydrogels were implanted into a critical-size rat cranial defect for 4 and 12 weeks. Both cell-laden and acellular hydrogels were shown to degrade in vivo and help to facilitate bone growth into the defect. Improved bone bridging of the defect was seen with the incorporation of cells, as well as with higher phosphate content of the macromer. Furthermore, direct bone-to-hydrogel contact was observed in the majority of implants, which is not commonly seen in this model. The ability of these macromers to deliver stem cells while forming in situ and subsequently degrade while facilitating bone ingrowth into the defect makes this class of macromers a promising material for craniofacial bone tissue engineering. PMID- 26232880 TI - Synergy between IL-6 and soluble IL-6 receptor enhances bone morphogenetic protein-2/absorbable collagen sponge-induced bone regeneration via regulation of BMPRIA distribution and degradation. AB - Bone morphogenetic protein-2/absorbable collagen sponge (BMP-2/ACS) implants have been approved for clinical use to induce bone regeneration. We previously showed that exaggerated inflammation characterized by elevated level of inflammatory cytokines including TNF-alpha, IL-1beta, and IL-6 has been shown to inhibit BMP 2/ACS-induced bone regeneration. Furthermore, unlike the negative effects of TNF alpha and IL-1beta, IL-6 seemed not to affect BMP-2-induced osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs). We hypothesized that there may be a regulatory loop between IL-6 and BMP-2 singling to affect BMP 2/ACS-induced bone regeneration. Here, we established a BMP-2/ACS-induced ectopic bone formation model in rats and fund that IL-6 injection significantly increased BMP-2/ACS-induced bone mass. Consistent with this animal model, an in vitro study demonstrated that synergy between IL-6 and soluble IL-6 receptor (IL-6/sIL-6R) promotes BMP-2-induced osteoblastic differentiation of human BMSCs through amplification of BMP/Smad signaling. Strikingly, IL-6 injection did not activate osteoclast-mediated bone resorption in the ectopic bone formation model, and IL 6/sIL-6R treatment did not affect receptor activator of NF-kappaB ligand (RANKL) induced osteoclastic differentiation of human peripheral blood mononuclear cells (PBMCs) in vitro. Furthermore, IL-6/sIL-6R treatment did not affect expression of BMP receptors, but enhanced the cell surface translocation of BMP receptor IA (BMPRIA) and inhibited the degradation of BMPRIA. Collectively, these findings indicate that synergy between IL-6 and sIL-6R promotes the cell surface translocation of BMPRIA and maintains the stability of BMPRIA expression, leading to enhanced BMP-2/ACS-induced bone regeneration. PMID- 26232879 TI - The use of covalently immobilized stem cell factor to selectively affect hematopoietic stem cell activity within a gelatin hydrogel. AB - Hematopoietic stem cells (HSCs) are a rare stem cell population found primarily in the bone marrow and responsible for the production of the body's full complement of blood and immune cells. Used clinically to treat a range of hematopoietic disorders, there is a significant need to identify approaches to selectively expand their numbers ex vivo. Here we describe a methacrylamide functionalized gelatin (GelMA) hydrogel for in vitro culture of primary murine HSCs. Stem cell factor (SCF) is a critical biomolecular component of native HSC niches in vivo and is used in large dosages in cell culture media for HSC expansion in vitro. We report a photochemistry based approach to covalently immobilize SCF within GelMA hydrogels via acrylate-functionalized polyethylene glycol (PEG) tethers. PEG-functionalized SCF retains the native bioactivity of SCF but can be stably incorporated and retained within the GelMA hydrogel over 7 days. Freshly-isolated murine HSCs cultured in GelMA hydrogels containing covalently-immobilized SCF showed reduced proliferation and improved selectivity for maintaining primitive HSCs. Comparatively, soluble SCF within the GelMA hydrogel network induced increased proliferation of differentiating hematopoietic cells. We used a microfluidic templating approach to create GelMA hydrogels containing gradients of immobilized SCF that locally direct HSC response. Together, we report a biomaterial platform to examine the effect of the local presentation of soluble vs. matrix-immobilized biomolecular signals on HSC expansion and lineage specification. This approach may be a critical component of a biomaterial-based artificial bone marrow to provide the correct sequence of niche signals to grow HSCs in the laboratory. PMID- 26232881 TI - Persistent luminescence nanoprobe for biosensing and lifetime imaging of cell apoptosis via time-resolved fluorescence resonance energy transfer. AB - Time-resolved fluorescence technique can reduce the short-lived background luminescence and auto-fluorescence interference from cells and tissues by exerting the delay time between pulsed excitation light and signal acquisition. Here, we prepared persistent luminescence nanoparticles (PLNPs) to design a universal time-resolved fluorescence resonance energy transfer (TR-FRET) platform for biosensing, lifetime imaging of cell apoptosis and in situ lifetime quantification of intracellular caspase-3. Three kinds of PLNPs-based nanoprobes are assembled by covalently binding dye-labeled peptides or DNA to carboxyl functionalized PLNPs for the efficient detection of caspase-3, microRNA and protein. The peptides-functionalized nanoprobe is also employed for fluorescence lifetime imaging to monitor cell apoptosis, which shows a dependence of cellular fluorescence lifetime on caspase-3 activity and thus leads to an in situ quantification method. This work provides a proof-of-concept for PLNPs-based TR FRET analysis and demonstrates its potential in exploring dynamical information of life process. PMID- 26232882 TI - Structural and functional insights into sclerostin-glycosaminoglycan interactions in bone. AB - In order to improve bone defect regeneration, the development of new adaptive biomaterials and their functional and biological validation is warranted. Glycosaminoglycans (GAGs) are important extracellular matrix (ECM) components in bone and may display osteogenic properties that are potentially useful for biomaterial coatings. Using hyaluronan (HA), chondroitin sulfate (CS) and chemically modified highly sulfated HA and CS derivatives (sHA3 and sCS3; degree of sulfation ~3), we evaluated how GAG sulfation modulates Wnt signaling, a major regulator of osteoblast, osteoclast and osteocyte biology. GAGs were tested for their capability to bind to sclerostin, an inhibitor of Wnt signaling, using surface plasmon resonance and molecular modeling to characterize their interactions. GAGs bound sclerostin in a concentration- and sulfate-dependent manner at a common binding region. These findings were confirmed in an LRP5/sclerostin interaction study and an in vitro model of Wnt activation. Here, pre-incubation of sclerostin with different GAGs led to a sulfate- and dose dependent loss of its bioactivity. Using GAG-biotin derivatives in a competitive ELISA approach sclerostin was shown to be the preferred binding partner over Wnt3a. In conclusion, highly sulfated GAGs might control bone homeostasis via interference with sclerostin/LRP5/6 complex formation. Whether these properties can be utilized to improve bone regeneration needs to be validated in vivo. PMID- 26232883 TI - Nanostructured platinum grass enables superior impedance reduction for neural microelectrodes. AB - Micro-sized electrodes are essential for highly sensitive communication at the neural interface with superior spatial resolution. However, such small electrodes inevitably suffer from high electrical impedance and thus high levels of thermal noise deteriorating the signal to noise ratio. In order to overcome this problem, a nanostructured Pt-coating was introduced as add-on functionalization for impedance reduction of small electrodes. In comparison to platinum black deposition, all used chemicals in the deposition process are free from cytotoxic components. The grass-like nanostructure was found to reduce the impedance by almost two orders of magnitude compared to untreated samples which was lower than what could be achieved with conventional electrode coatings like IrOx or PEDOT. The realization of the Pt-grass coating is performed via a simple electrochemical process which can be applied to virtually any possible electrode type and accordingly shows potential as a universal impedance reduction strategy. Elution tests revealed non-toxicity of the Pt-grass and the coating was found to exhibit strong adhesion to the metallized substrate. PMID- 26232884 TI - Spontaneous ventilation of the frontal sinus after fractures involving the frontal recess. AB - PURPOSE: Frontal sinus fractures (FSF) have potentially catastrophic consequences due to frontal recess (FR) obstruction and proximity to the brain and orbit. Lack of follow-up and ability to predict which type of fractures predispose to complications has biased surgeons toward definitive interventions such as sinus obliteration and cranialization. These procedures carry inherent risk and may be unnecessary in a subset of patients. This study seeks to better characterize spontaneous ventilation in subjects with FSFs, including those involving the FR. MATERIALS AND METHODS: Review of a prospectively maintained trauma database between 2009 and 2013 at a level 1 trauma center. Patients with frontal sinus fractures with follow-up imaging (>6 weeks) available were included. The medical records and imaging were reviewed for evidence of spontaneous ventilation of the frontal sinus. RESULTS: Nineteen patients sustained frontal sinus fractures in the study period with mean imaging interval of 67.4 weeks (range, 6-188.4 weeks). Injury mechanisms included fall (32%), assault (31%), motor vehicle accident (17%), pedestrian-versus-automobile (12%), and gunshot wound (8%). 8/19 patients (42%) sustained FSFs involving the FR and 7/8 (87.5%) spontaneously ventilated by time of interval imaging. The one patient with persistent radiographic sinus opacification was associated with a naso orbital ethmoid and medial orbital blowout fracture. 6/19 patients (32%) sustained FSF sparing the FR, and all spontaneously ventilated by the time of interval imaging. 5/19 patients (26%) underwent surgical intervention. CONCLUSIONS: An expectant, sinus-preserving approach to acute FSFs involving the FR is safe and effective. Etiology of re ventilation failure may be due to tissue obstruction, rather than the frontal recess fracture itself. PMID- 26232885 TI - Surgical Resection of Bilateral Coalition of the Third and Fourth Metatarsals: A Case Report. AB - An intermetatarsal coalition is an uncommon pathologic entity, previously reported in published studies as being primarily unilateral, most commonly between the first and second metatarsals and less so between the third and fourth metatarsals. We report an unusual case of a bilateral coalition of the third and fourth metatarsals in a 43-year-old male who presented with nonspecific dorsolateral foot pain. Conservative therapy initially failed, and resolution of pain was noted bilaterally after coalition resection. PMID- 26232886 TI - Use of 3D reconstruction of emergency and postoperative craniocerebral CT images to explore craniocerebral trauma mechanism. AB - We report a craniocerebral trauma case in which a man sustained severe skull fractures and cerebral contusions and it demanded elucidating the injury mechanism of being formed by strike or tumble. However, the initial features of skull fractures were mostly lost when the forensic pathologists involved in the case 5 months later because of injury healing and craniocerebral surgery. Therefore, we aimed to reconstruct the original skull fracture features by utilizing the digital reconstruction technologies in terms of CT (computed tomography) scanning, 3D (3-dimentional) reconstruction, and virtual surgical tools. The original fracture skull was assembled by using Mimics 13.0 based on the CT slices of postoperative head and the removed craniotomy skull flaps, which revealed fracture features of focal and overall skull deformation. Based on the assembly skull model and the contrecoup cerebral contusions, we conclude that the man suffered a tumble after being drunk and the serious craniocerebral trauma occurred. The case demonstrated that the digital reconstruction technologies can serve as effective approaches for forensic investigation in case of survived craniocerebral trauma patients without direct evidences interpreting the original trauma patterns, which could potentially be helpful in exploring the injury mechanisms. PMID- 26232887 TI - Plasma Brain Natriuretic Peptide is a Marker of Prognostic Functional Outcome in Non-Cardioembolic Infarction. AB - BACKGROUND: High plasma levels of brain natriuretic peptide (BNP) may also be observed in patients with non-cardioembolic infarction (CEI). We aimed to evaluate the relation between plasma BNP level, clinical parameters, and functional outcome in patients with and without CEI. METHOD: This study analyzed consecutive Japanese patients with acute ischemic stroke. Correlations between plasma BNP level and conventional risk factors for ischemic stroke were examined. Values of P less than .05 were considered statistically significant. RESULTS: This study analyzed 718 acute ischemic stroke patients (445 men and 273 women; mean age, 73.9 years). Mean plasma level of BNP was significantly higher for CEI (366.6 pg/ml) than for non-CEI (105.6 pg/ml; P < .01). Poor outcome (modified Rankin Scale score >=3) at hospitalization and discharge were associated with significantly higher plasma BNP level than good outcome (modified Rankin Scale score <=2) for both CEI and non-CEI. On multiple regression analysis, log-BNP was significantly associated with female sex, smoking, triglyceride, and creatinine clearance in CEI. In non-CEI, log-BNP was significantly associated with systolic/diastolic blood pressure, triglyceride, high-density lipoprotein cholesterol, and creatinine clearance. CONCLUSION: Irrespective of the presence of CEI, plasma BNP offers a marker of prognostic functional outcome. We clarified the characteristics and differences associated with plasma BNP in CEI and non CEI, and our results suggest that plasma BNP can provide a useful marker of brain damage and neurohumoral dynamics in acute ischemic stroke. PMID- 26232888 TI - Dietary Patterns and Risk of Stroke in Adults: A Systematic Review and Meta analysis of Prospective Cohort Studies. AB - BACKGROUND: The effect of whole diet on the development of stroke has recently achieved much interest by various prospective studies, but with inconclusive results. Herein, we carried this meta-analysis to identify the potential associations between different dietary patterns and the risk of stroke by pooling available data from existing studies. METHODS: PubMed and EBSCO were searched for pertinent articles that identify dietary patterns published from January 1991 to November 2014, with the following keywords: dietary pattern, dietary patterns, food pattern, eating pattern, alcohol drinking, alcohol consumption, and stroke. RESULTS: A total of 21 studies met the inclusion criteria and were included in this meta-analysis. A decreased risk of stroke was shown for the highest compared with the lowest categories of healthy dietary pattern (odds ratio [OR] = .77; 95% confidence interval [CI] = .63-.93; P < .00001) and light-moderate drinking pattern (OR = .80; 95% CI = .72-.90; P = .0002). There was evidence of the increase in the risk of stroke in the highest compared with heavy alcohol drinking pattern (OR = 1.25; 95% CI = 1.17-1.33; P < .00001), whereas no significant association with Western-style dietary pattern was observed (OR = 1.05; 95% CI = .82-1.35; P = .70). CONCLUSIONS: The results of this meta-analysis indicated that some dietary patterns may be associated with the risk of stroke. PMID- 26232889 TI - Efficacy of Botulinum Toxin A Treatment for Pes Varus during Gait. AB - BACKGROUND: The efficacy of botulinum toxin A (BoNTA) injection on spasticity is usually measured using Modified Ashworth Scale (MAS), but this only evaluates muscle tone at rest and has poor reliability. There are no reports that quantitatively evaluate pes varus during walking after botulinum treatment. The purpose of this study was to evaluate the efficacy of BoNTA injection on pes varus during gait using 3-dimensional motion analysis. METHODS: Twenty-four hemiplegic patients with spastic pes varus deformity during gait received BoNTA injection into lower limb muscles. MAS score, comfortable overground gait velocity, and pes varus angle during treadmill walking were evaluated before, 2, 6, and 12 weeks after the injection. Five healthy subjects were also recruited to develop the pes varus/valgus angle as a normal reference. RESULTS: The median MAS scores were significantly lower at 2 and 6 weeks after the injection. The maximum pes varus angle during the swing phase was significantly lower at 2, 6, and 12 weeks after the injection. It was significantly lower at 6 weeks after the injection during stance phase. The comfortable overground gait velocity was also improved after the injection. However, 2 patients experienced pain during gait and their pes varus angle increased during the follow-up period. CONCLUSIONS: BoNTA injection improved pes varus angle during gait. Evaluating motion in addition to spasticity at rest is recommended because improvements in limb function do not always parallel improvements in spasticity at rest. PMID- 26232890 TI - Effect of Plasma Fibrinogen, High-Sensitive C-Reactive Protein, and Cigarette Smoking on Carotid Atherosclerosis: The Suita Study. AB - BACKGROUND: Few studies have reported on the association between inflammatory markers and atherosclerosis by smoking status. We investigated the effect of plasma levels of fibrinogen and high-sensitive C-reactive protein (hsCRP) on subclinical atherosclerosis stratified by smoking in a general urban population. METHODS: From participants of the Suita study without a history of cardiovascular diseases, a total of 2502 subjects (805 men, median age 64 years) who underwent carotid ultrasonography were enrolled. Subjects were divided into current smokers (n = 566) and never-smokers. Ex-smokers were not included in the study. Each group was subdivided according to the median levels of markers (plasma fibrinogen [2.99 g/L] and hsCRP [.51 mg/L]) and the smoking amounts. We compare the adjusted maximum and mean intima-media thickness (IMT). RESULTS: In men and women, maximum IMT and mean IMT of the high fibrinogen and high hsCRP (Fib(H)CRP(H)) with smoking were thicker than those of the low fibrinogen and low hsCRP (Fib(L)CRP(L)) without smoking, the Fib(L)CRP(L) with smoking, and the Fib(H)CRP(H) without smoking after adjusting for covariates. The Fib(L)CRP(L) with smoking had thicker IMTs than the Fib(L)CRP(L) without smoking. There was a dose-dependent smoking effect on IMT in men. These trends were similar in age 60, 65, and 70. CONCLUSIONS: Plasma fibrinogen and hsCRP levels were related to multivariate-adjusted IMT, and smoking was associated with IMT in men. The combination of plasma fibrinogen and hsCRP levels could be a potential marker on subclinical carotid atherosclerosis in urban people. PMID- 26232891 TI - International Normalized Ratio Variability: A Measure of Anticoagulation Quality or a Powerful Mortality Predictor. AB - BACKGROUND: As atrial fibrillation (AF) carries twice the mortality hazard when compared with a similar population without diagnosed AF, the importance of risk stratifying is obvious. Several variables are related to outcome: age, comorbidities, and use of several medications, particularly oral anticoagulants. The CHA2DS2VASc score is an extremely useful tool to predict thromboembolic events and also mortality. The international normalized ratio (INR) variability is a treatment efficacy variable also associated with morbidity in patients receiving warfarin. The objective of the study is to compare the prognostic value of the CHA2DS2VASc versus the INR variability or its combination to predict mortality. METHODS: In this observational study, we analyzed 589 patients from our Atrial Fibrillation Cohort, all on warfarin for more than 1 year and had more than 5 INRs performed in the last 2 years. The CHA2DS2VASc, HAS-BLED, and SAMe TT2R2 scores were calculated as well as the INR variability using the time-in therapeutic-range (TTR), the percentage of INRs (%INRs) within range, and the standard deviation of the INRs (SDINRs). Kaplan-Meier survival curves were plotted via different cutoff points. RESULTS: The mean TTR was 53 +/- 23%; 34.6% of the patients had a TTR above 64%. The mean %INRs in range was 50.2 +/- 20.2; 17.3% of the population had %INRs in range above 70%. The mean SDINRs was .84 +/- .54, and 38.4% had SDINRs below .79. Of 598, 139 (22%) discontinued warfarin treatment. Death was responsible for almost 50% of treatment discontinuation. Of 598, 68 patients died during the study period (11.5 %); the most frequent causes of death were heart failure (30%), bleeding (17%), and ischemic stroke (15%). Patient survival had a correlation with TTR, %INRs in range, SDINRs, left ventricular ejection fraction, CHA2DS2VASc, and the combination of CHA2DS2VASc + SDINRs (cutoff >1 and >.79, respectively). CONCLUSIONS: INR variability is an extremely useful tool to assess anticoagulation quality. Calculation of both CHA2DS2VASc and INR variability appears to be extremely useful to predict mortality in patients with AF receiving warfarin. The SDINRs emerges as a strong mortality predictor compared to the other INR variability indexes. PMID- 26232892 TI - Role of Diastolic Function in Preserved Exercise Capacity in Patients with Reduced Ejection Fractions. AB - BACKGROUND: Some patients with markedly reduced ejection fractions (EFs) (<35%) have preserved exercise performance greater than predicted for age and gender. Because diastolic function may be a determinant of exercise performance, this study was conducted to test the hypothesis that patients with preserved exercise tolerance despite EFs < 35% may have relatively normal diastolic function. METHODS: Sixty-five subjects with EFs < 35% who underwent exercise Doppler echocardiography and had no inducible ischemia were retrospectively examined. Forty-five subjects with normal EFs (>60%) and preserved exercise capacity were analyzed as a control group. RESULTS: Sixteen of 65 patients with EFs < 35% had greater than predicted normal exercise capacity for their age and gender, and the remaining 49 patients had reduced exercise capacity. Patients with reduced EFs and preserved exercise capacity had E/e' ratios (mean, 10 +/- 4) similar to those of control subjects (mean, 10 +/- 3) and lower than those with reduced exercise tolerance (mean, 16 +/- 8) (P < .01). In addition, they had better diastolic filling patterns and smaller left atrial sizes than patients with EFs < 35% and reduced exercise capacity. Multivariate logistic regression analyses indicated that E/e' ratio was an independent predictor of preserved exercise capacity in patients with reduced EFs. CONCLUSIONS: Relatively intact diastolic function contributes to preserved exercise capacity in patients with reduced EFs (<35%). PMID- 26232893 TI - IL-17A and IL-17F polymorphisms in rheumatoid arthritis and Sjogren's syndrome. AB - OBJECTIVE: The aim of this study was to evaluate the influence of Th17 polymorphisms on the susceptibility or severity of rheumatoid arthritis (RA) and Sjogren's syndrome (SS). MATERIALS AND METHODS: The study sample comprised 206 individuals of both genders divided into three groups: exclusive rheumatoid arthritis (RA-100 patients), rheumatoid arthritis and Sjogren's syndrome (RA/SS 31 patients), and healthy controls (C-75 individuals). All the individuals were submitted to clinical evaluation, unstimulated sialometry, and Schirmer test; some patients with RA were also submitted to minor salivary gland biopsy for definition of SS diagnosis. Saliva samples were collected for isolation of DNA and genotyping of Th17 genes; IL-17A (-197G/A) and IL-17F (7488T/C). RESULTS: IL 17A (-197G/A) and IL-17F (7488T/C) SNPs were not associated with susceptibility to RA or secondary SS (sSS, p > 0.05 for both SNPs). In addition, they did not influence RA activity or clinical markers of SS. CONCLUSION: IL-17A (-197G/A) and IL-17F (7488T/C) polymorphisms are not associated with the susceptibility nor to the severity of RA and sSS in the studied population. CLINICAL RELEVANCE: A better understanding of the pathogenesis of SS is demanded to an adequate treatment as well as to the development of new management strategies. PMID- 26232894 TI - Is there an association between obstructive sleep apnea syndrome and periodontal inflammation? AB - OBJECTIVES: The aim of this study is to assess salivary, serum biomarkers, and subgingival bacteria as putative candidates in the potential association between obstructive sleep apnea syndrome (OSAS) and periodontal disease. MATERIALS AND METHODS: Fifty-two patients were grouped according to the severity of OSAS: 13 participants served as controls, 17 patients had mild-to-moderate OSAS, and 22 severe OSAS. Serum, saliva, and subgingival plaque samples were collected, and clinical periodontal parameters were recorded. Salivary, serum concentrations of interleukin-6 (IL-6), tumour necrosis factor (TNF-alpha), osteoprotegerin, soluble Receptor activator of nuclear factor kappa B ligand (sRANKL), and apelin were analysed by enzyme-linked immunosorbent assay. Bacterial counts were determined by real-time QPCR on plaque microbial DNA preparations. RESULTS: There was a significant change in the composition of microbes in plaque particularly in severe OSAS samples (p < 0.01). Statistical analyses indicated significantly higher salivary IL-6 levels in both OSAS groups compared to controls (p < 0.05). Salivary apelin levels were significantly higher in the severe OSAS group compared to the control group. Serum levels of these biomarkers and salivary osteoprotegerin, sRANKL levels were similar in the study groups. The incidence and duration of apnea positively correlated with clinical periodontal parameters (p < 0.05). CONCLUSION: OSAS appeared to alter the tested bacteria in plaque, correlate with increasing periodontal disease severity, have additive effect on salivary IL-6. CLINICAL RELEVANCE: OSAS is likely to associate with periodontal disease. PMID- 26232895 TI - Non-infectious makers of Kawasaki syndrome: tangible or elusive triggers? PMID- 26232896 TI - Phytochemical analysis and effects of Pteris vittata extract on visual processes. AB - The present study was designed to explore the possible effects of Pteris vittata on visual sensitivity, ERG waves, and other components of the visual system. Electrophysiological techniques including electroretinography (ERG) were used in the present study. The phytochemical composition of the extract was investigated using liquid chromatography-mass spectrometry (LC-MS) techniques. The results indicated that the extract significantly augmented dark- and light-adapted ERG b wave amplitude. Furthermore, these findings showed that P. vittata extract does not have Gamma-aminobutyric acid receptor antagonistic activity but may function as a retinal neural antagonist in bullfrog retina. P. vittata extract improved the visual sensitivity by 0.8 log unit of light intensity, and reduced the regeneration time for rhodopsin. The six main peaks obtained through LC-MS were identified as flavonoids. Based on these results, it was concluded that P. vittata extract or its constituents may be used to treat eye diseases. PMID- 26232897 TI - Reducing Income Inequalities in Food Consumption: Explorations With an Agent Based Model. AB - INTRODUCTION: Individual and environmental factors dynamically interact in shaping income inequalities in healthy food consumption. The agent-based model, Health Behaviors Simulation (HEBSIM), was developed to describe income inequalities in healthy food consumption. It simulates interactions between households and their environment. HEBSIM was used to explore the impact of interventions aimed at reducing food consumption inequalities. METHODS: HEBSIM includes households and food outlets. Households are characterized by location, composition, income, and preference for food. Decisions about where to shop for food (fruit/vegetable stores, supermarkets, or discount supermarkets) and whether to visit fast food outlets are based on distance, price, and food preference. Food outlets can close and new food outlets can enter the system. Three interventions to reduce healthy food consumption inequalities were tested: (1) eliminating residential segregation; (2) lowering the prices of healthy food; and (3) providing health education. HEBSIM was quantified using data from Statistics Netherlands, Statistics Eindhoven, and the GLOBE study (2011). RESULTS: The model mimicked food consumption in Eindhoven. High-income households visited healthy food shops more often than low-income households. Eliminating residential segregation had the largest impact in reducing income inequalities in food consumption, but resulted partly from a worsening in healthy food consumption in high-income households. Lowering prices and health education could also substantially reduce inequalities. Most interventions took 5-10 years to reach their (almost) full effects. CONCLUSIONS: HEBSIM is a promising tool for studying dynamic interactions between households and their environment and for assessing the impact of interventions on income inequalities in food consumption. PMID- 26232898 TI - Team-Based Care: A Step in the Right Direction for Hypertension Control. PMID- 26232899 TI - Leisure-Time Physical Activity, Falls, and Fall Injuries in Middle-Aged Adults. AB - INTRODUCTION: Although exercise and strength training have been shown to be protective against falls in older adults (aged 65 years and older), evidence for the role of leisure-time physical activity (LTPA) in the prevention of falls and resulting injuries in middle-aged adults (aged 45-64 years) is lacking. In the present study, we investigate the association between self-reported engagement in LTPA and the frequency of falls and fall-related injuries among middle-aged and older adults, while controlling for key sociodemographic and health characteristics. METHODS: Nationally representative data from the 2010 U.S. Behavioral Risk Factor Surveillance Survey were analyzed in April 2014 to examine the number of adults aged >=45 years who self-reported their fall experience in the previous 3 months and any injuries that resulted from those falls. We then evaluated the association between LTPA and self-reported falls and injuries across three age strata (45-54, 55-64, and >=65 years). The two main self reported outcome measures were (1) frequency of falls in the 3 months prior to the survey interview date and (2) the number of injuries resulting from these falls. Prevalence ratios (PRs) and 95% CIs were calculated using Poisson regression models with robust SEs. RESULTS: Of 340,680 survey participants aged >=45 years, 70.7% reported engaging in LTPA, and 17% reported one or more falls. Among those reporting a fall within 3 months, 25.6% experienced one injurious fall (fall resulting in an injury) and 8.4% reported two or more injurious falls. Controlling for sociodemographic and health characteristics, among adults aged 45 54 years, those who engaged in LTPA were significantly less likely to report one fall (PR=0.90, 95% CI=0.81, 0.99); two or more falls (PR=0.84, 95% CI=0.77, 0.93); one injurious fall (PR=0.88, 95% CI=0.78, 0.99); and two or more injurious falls (PR=0.69, 95% CI=0.58, 0.83) than those who did not exercise. A similar protective effect of LTPA on reporting falls and injuries was noted for adults aged 55-64 and >=65 years. CONCLUSIONS: Similar to older adults, middle-aged adults who engage in LTPA report fewer falls and fall-related injuries. Upon further confirmation of the relationship between LTPA and falls among middle-aged adults, fall prevention interventions could be developed for this population. PMID- 26232900 TI - Growth Charts for Muscular Strength Capacity With Quantile Regression. AB - INTRODUCTION: Muscle strength preservation may play an important role in protecting against cardiometabolic diseases, functional decline, musculoskeletal deterioration, and early all-cause mortality. However, sex-specific strength growth charts and curves using data from a U.S.-representative sample and clinically feasible measurement remain to be established. METHODS: A sample of 7,119 individuals, aged 6-80 years, was included from the 2011-2012 National Health and Nutrition Examination Survey. Analyses were performed in 2015. Grip strength was assessed using a hydraulic handheld dynamometer; peak force values were normalized per body mass. Parametric quantile regression was used to determine unique normalized and absolute strength percentiles for men and women. Responses were fitted with a parametric model, involving six powers of age. RESULTS: Growth charts and curves were created using output from the quantile regression from reference values of normalized and absolute grip strength corresponding to the fifth, tenth, 25th, 50th, 75th, 90th, and 95th percentiles across all ages. For men, there was a small drop in normalized strength at age 6 years followed by quick growth until about age 25 years. Among women, normalized strength grew gradually until about age 15 years. For both men and women, normalized strength declined throughout middle age and later adulthood; however, these rates were greater among men. More-pronounced patterns of growth and decline were observed for absolute strength in men and women. CONCLUSIONS: The established strength quantiles can easily be incorporated into a clinical setting for screening individuals that would benefit from lifestyle interventions to improve muscular fitness and reduce health risks. PMID- 26232901 TI - Grip Strength as a Marker of Hypertension and Diabetes in Healthy Weight Adults. AB - INTRODUCTION: Muscle strength may play a role in cardiometabolic disease. We examined the relationship between hand grip strength and diabetes and hypertension in a sample of healthy weight adults. METHODS: In 2015, we analyzed the National Health and Nutrition Examination Survey 2011-2012 for adults aged >=20 years with healthy BMIs (between 18.5 and <25) and no history of cardiovascular disease (unweighted n=1,467; weighted n=61,587,139). Hand grip strength was assessed with a dynamometer. Diabetes was based on hemoglobin A1c level and reported diabetes diagnosis. Hypertension was based on measured blood pressure and reported hypertension diagnosis. RESULTS: Individuals with undiagnosed diabetes compared with individuals without diabetes had lower grip strength (51.9 vs 69.8, p=0.0001), as did individuals with diagnosed diabetes compared with individuals without diabetes (61.7 vs 69.8, p=0.008). Mean grip strength was lower among individuals with undiagnosed hypertension compared with individuals without hypertension (63.5 vs 71.5, p=0.008) as well as among individuals with diagnosed hypertension compared with those without hypertension (60.8 vs 71.5, p<0.0001). In adjusted analyses controlling for age, sex, race, smoking status, and first-degree relative with disease, mean grip strength was lower for undiagnosed diabetes (beta=-10.02, p<0.0001) and diagnosed diabetes (beta=-8.21, p=0.03) compared with individuals without diabetes. In adjusted analyses, grip strength was lower among individuals with undiagnosed hypertension (beta=-6.6, p=0.004) and diagnosed hypertension (beta=-4.27, p=0.04) compared with individuals without hypertension. CONCLUSIONS: Among healthy weight adults, combined grip strength is lower in individuals with diagnosed and undiagnosed diabetes and hypertension. PMID- 26232902 TI - Patterns of Walkability, Transit, and Recreation Environment for Physical Activity. AB - INTRODUCTION: Diverse combinations of built environment (BE) features for physical activity (PA) are understudied. This study explored whether patterns of GIS-derived BE features explained objective and self-reported PA, sedentary behavior, and BMI. METHODS: Neighborhood Quality of Life Study participants (N=2,199, aged 20-65 years, 48.2% female, 26% ethnic minority) were sampled in 2001-2005 from Seattle / King County WA and Baltimore MD / Washington DC regions. Their addresses were geocoded to compute net residential density, land use mix, retail floor area ratio, intersection density, public transit, and public park and private recreation facility densities using a 1-km network buffer. Latent profile analyses (LPAs) were estimated from these variables. Multilevel regression models compared profiles on accelerometer-measured moderate to vigorous PA (MVPA) and self-reported PA, adjusting for covariates and clustering. Analyses were conducted in 2013-2014. RESULTS: Seattle region LPAs yielded four profiles, including low walkability/transit/recreation (L-L-L); mean walkability/transit/recreation (M-M-M); moderately high walkability/transit/recreation (MH-MH-MH); and high walkability/transit/recreation (H-HH). All measures were higher in the HHH than the LLL profile (difference of 17.1 minutes/day for MVPA, 146.5 minutes/week for walking for transportation, 58.2 minutes/week for leisure-time PA, and 2.2 BMI points; all p<0.05). Baltimore region LPAs yielded four profiles, including L-L L; M-M-M; high land use mix, transit, and recreation (HLU-HT-HRA); and high intersection density, high retail floor area ratio (HID-HRFAR). HLU-HT-HRA and L L-L differed by 12.3 MVPA minutes/day; HID-HRFAR and L-L-L differed by 157.4 minutes/week for walking for transportation (all p<0.05). CONCLUSIONS: Patterns of environmental features explain greater differences in adults' PA than the four component walkability index. PMID- 26232904 TI - Encouraging Influenza Vaccination Among Text4baby Pregnant Women and Mothers. AB - INTRODUCTION: Pregnant women, postpartum women, and infants are at high risk for complications from influenza. From October to November 2012, Text4baby, a free national text service for pregnant women and mothers of infants aged <1 year, implemented a module of interactive messages encouraging maternal influenza vaccination. A program evaluation examined whether a text-based reminder or tailored education improved self-reported influenza vaccination or intent to be vaccinated later in the influenza season among Text4baby participants. METHODS: Nearly one third (28,609/89,792) of enrollees responded to a text asking about their vaccination plans. Those planning to receive vaccination were randomly assigned to receive an encouragement message or an encouragement message plus the opportunity to schedule a reminder (n=3,021 at follow-up). Those not planning to be vaccinated were randomly assigned to receive general education or education tailored to their reason for non-vaccination (n=3,820 at follow-up). The effect of the enhanced messages was assessed using multinomial logistic regression in 2013-2014. RESULTS: A reminder increased the odds of vaccination at follow-up among mothers (AOR=2.0, 95% CI=1.4, 2.9) and of continued intent to be vaccinated later in the season (pregnant, AOR=2.1, 95% CI=1.4, 3.1; mother, AOR=1.7, 95% CI=1.1, 2.5). Among mothers not planning to be vaccinated because of cost, those who received a tailored message about low-cost vaccination had higher odds of vaccination at follow-up (AOR=1.9, 95% CI=1.1, 3.5). Other tailored messages were not effective. CONCLUSIONS: Text reminders and tailored education may encourage influenza vaccination among this vulnerable population; both have now been incorporated into Text4baby. PMID- 26232903 TI - Telephone Intervention to Improve Diabetes Control: A Randomized Trial in the New York City A1c Registry. AB - INTRODUCTION: Scalable self-management interventions are necessary to address suboptimal diabetes control, especially among minority populations. The study tested the effectiveness of a telephone behavioral intervention in improving glycemic control among adults with diabetes in the New York City A1c Registry. DESIGN: RCT comparing a telephone intervention to print-only intervention in the context of the A1c Registry program. SETTING/PARTICIPANTS: Nine hundred forty-one adults with diabetes and hemoglobin A1c (A1c) >7% from a low-income, predominantly Latino population in the South Bronx were recruited from the A1c Registry. INTERVENTION: All study participants were mailed print diabetes self management materials at baseline and modest lifestyle incentives quarterly. Only the telephone participants received four calls from health educators evenly spaced over 1 year if baseline A1c was >7%-9%, or eight calls if baseline A1c was >9%. Medication adherence was the main behavioral focus and, secondarily, nutrition and exercise. MAIN OUTCOME MEASURES: Primary outcome was difference between two study arms in change in A1c from baseline to 1 year. Secondary outcomes included diabetes self-care activities, including self-reported medication adherence. Data were collected in 2008-2012 and analyzed in 2012-2014. RESULTS: Participants were predominantly Latino (67.7%) or non-Latino black (28%), with 69.7% foreign-born and 55.1% Spanish-speaking. Among 694 (74%) participants with follow-up A1c, mean A1c decreased by 0.9 (SD=0.1) among the telephone group compared with 0.5 (SD=0.1) among the print-only group, a difference of 0.4 (95% CI=0.09, 0.74, p=0.01). The intervention had significant effect when baseline A1c was >9%. Both groups experienced similar improvements in self-care activities, medication adherence, and intensification. CONCLUSIONS: A telephone intervention delivered by health educators can be a clinically effective tool to improve diabetes control in diverse populations, specifically for those with worse metabolic control identified using a registry. This public health approach could be adopted by health systems supported by electronic record capabilities. CLINICALTRIALS. GOV REGISTRATION: NCT00797888. PMID- 26232905 TI - Cardiovascular Disease Risk Factors Among Male Veterans, U.S., 2009-2012. AB - INTRODUCTION: Cardiovascular disease remains an important cause of death in the U.S. where veterans of the U.S. Armed Forces represent a significant segment of the population. Limited national estimates of cardiovascular disease risk factors using physical measurements and reported veteran status in the U.S. civilian population have been reported. The purpose of this study was to compare the prevalence of cardiovascular disease risk factors among veteran and non-veteran men in the U.S. civilian population. METHODS: Using data from the 2009-2012 National Health and Nutrition Examination Surveys, 1,107 veteran and 3,972 non veteran men were identified for this study (analyzed in 2014-2015). Differences in hypertension, dsylipidemia, diabetes, obesity, and smoking between veterans and non-veterans were compared using chi-square and t-tests. Predicted prevalence from multivariable logistic regression models adjusted for age, race/Hispanic origin, and poverty level were used to assess whether previous military service was associated with having a cardiovascular disease risk factor. RESULTS: Veteran men were older than non-veteran men (59.9 years vs 43.4 years) and were more likely to be non-Hispanic white (79.9% vs 65.7%). Adjusted predicted prevalence estimates show that veterans were more likely than non-veterans to be obese (42.6% vs 33.7%, p<0.01). After adjustment for obesity, there was no difference in hypertension, dyslipidemia, diagnosed diabetes, or smoking between veteran and non-veteran men. CONCLUSIONS: This study identified a segment of the U.S. civilian population-veteran men-who have a higher prevalence for obesity, a risk factor associated with increased risk for other cardiovascular disease risk factors. PMID- 26232906 TI - Military Sexual Trauma Among Recent Veterans: Correlates of Sexual Assault and Sexual Harassment. AB - INTRODUCTION: Military sexual trauma (MST) includes sexual harassment or sexual assault that occurs during military service and is of increasing public health concern. The population prevalence of MST among female and male veterans who served during Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) has not been estimated to our knowledge. The purpose of this study is to assess the population prevalence and identify military correlates of MST, sexual harassment, and sexual assault among OEF/OIF veterans. METHODS: MST was assessed in the 2009 2011 National Health Study for a New Generation of U.S. Veterans, a survey of 60,000 veterans who served during the OEF/OIF eras (response rate, 34%, n=20,563). Weighted prevalence estimates and AORs of MST, sexual harassment, and sexual assault among women and men were calculated. Gender-stratified logistic regression models controlled for military and demographic characteristics. Data analyses were conducted in 2013-2014. RESULTS: Approximately 41% of women and 4% of men reported experiencing MST. Deployed men had lower risk for MST compared with non-deployed men, though no difference was found among women. However, veterans reporting combat exposure during deployment had increased risk for MST compared with those without, while controlling for OEF/OIF deployment. Among women, Marines and Navy veterans had increased risk for MST compared with Air Force veterans. MST was significantly higher among veterans who reported using Veterans Affairs healthcare services. CONCLUSIONS: These prevalence estimates underscore the importance of public awareness and continued investigation of the public health impact of MST. PMID- 26232907 TI - Screening for Depression in African-American Churches. AB - INTRODUCTION: Substantial racial/ethnic disparities exist in the identification and management of major depression. Faith-Based Health Promotion interventions reduce disparities in health screenings for numerous medical conditions. However, the feasibility of systematically screening for depression in faith-based settings has not been investigated. The purpose of this study was to assess the feasibility of using a validated instrument to screen for depression in African American churches. METHODS: Participants were recruited between October and November 2012 at three predominantly African-American churches in New York City. A participatory research approach was used to determine screening days. The Patient Health Questionnaire-9 (PHQ-9) was administered to 122 participants. Positive depression screen was defined as a PHQ-9 score >=10. Descriptive statistics were used to report sample characteristics, prevalence of participants who screened positive, and history of help seeking. Logistic regression analyses were conducted to determine the association of positive depression screen and sociodemographic characteristics. Initial analyses were conducted in 2013, with additional analyses in 2014. RESULTS: The prevalence estimate for positive depression screen was 19.7%. More men (22.5%) screened positive than women (17.7%). Total household income was inversely related to positive depression screen. A similar percentage of respondents had previously sought help from primary care providers as from clergy. CONCLUSIONS: It was feasible to screen for depression with the PHQ-9 in African-American churches. The prevalence of positive depression screen was high, especially among black men. Churches may be an important setting in which to identify depressive symptoms in this underserved population. PMID- 26232908 TI - Assessment of metacognitive monitoring and control in baboons (Papio papio). AB - Metacognition refers to the ability of an organism to evaluate its states of knowledge (metacognitive monitoring) and engage in appropriate information seeking behaviors when a lack of knowledge is detected (metacognitive control). This study assessed metacognitive monitoring and control in three Guinea baboons (Papio papio). Monkeys were required to report on a touchscreen the location of two target stimuli that had previously appeared briefly on a grid. They could either respond directly or use a "Repeat" key providing an opportunity to repeat the target stimuli. In Experiment 1, the baboons used the Repeat key more frequently in difficult trials and transferred this use of the key to novel conditions. Two baboons showed higher accuracy when they declined using the key compared to Baseline trials in which the key was not available, suggesting accurate metacognitive monitoring judgments. The same two baboons were consistently faster at reporting the targets' locations after a repetition of the stimulus. In Experiment 2, the baboons had to choose between two Repeat keys, one for each target. Two baboons showed a preference for repeating the presentation of the less visible target, suggesting that they identified what information they lack. Overall, results support the hypothesis of metacognitive monitoring in baboons, and also provide limited evidence for metacognitive control. We propose that tests requiring subjects to choose between several metacognitive responses in computerized tasks provide a suitable new approach for studying targeted information-seeking behaviors in animals. PMID- 26232909 TI - Altered microRNA expression profile in synovial fluid from patients with knee osteoarthritis with treatment of hyaluronic acid. AB - OBJECTIVE: The aim of this study was to investigate the microRNA (miRNA) expression pattern in synovial fluid from patients with knee osteoarthritis (OA) after treatment with intra-articular injection of hyaluronan (HA). METHODS: Twelve OA patients were enrolled in accordance with the Kellgren-Lawrence classification of knee OA. All patients received intra-articular injection of HA once a week for 5 weeks and were evaluated with the Western Ontario and McMaster Universities (WOMAC) index at baseline. TaqMan miRNA assay profiling was performed on synovial fluid RNAs extracted from OA patients pre-injection and after 5 weeks of treatment with HA. Validation was performed using independent samples, including ten healthy controls and ten matched OA patients. RESULTS: Forty-three miRNAs (21 overexpressed miRNAs and 22 underexpressed miRNAs) were differentially expressed in OA patients before and after treatment with HA (P < 0.05, false discovery rate corrected). Further bioinformatics prediction by mirPath indicated that the differential miRNA signatures in synovial fluid extracted from the OA patients demonstrated primarily upregulation of the PI3K Akt signaling pathway, mitogen-activated protein kinase signaling pathway, regulation of autophagy, mRNA surveillance pathway, and B cell receptor signaling pathway. In addition, TaqMan real-time reverse transcription polymerase chain reaction was performed for validation on miR-146a, miR-155, let-7a, miR-181a, miR 454, and let-7b, which were significantly changed in abundance, using an independent cohort of ten healthy controls and ten OA patients as compared with those with intra-articular injection of HA. CONCLUSION: Our results demonstrated that dysregulation in miRNAs in synovial fluid from OA patients and their affected biologic cellular processes might play important role in OA pathogenesis and HA-mediated therapeutics. PMID- 26232910 TI - Insulin degludec results in lower rates of nocturnal hypoglycaemia and fasting plasma glucose vs. insulin glargine: A meta-analysis of seven clinical trials. AB - BACKGROUND AND AIMS: Basal insulin analogues have a reduced risk of hypoglycaemia compared with NPH insulin, but hypoglycaemia still remains a major impediment to achieving recommended fasting plasma glucose (FPG) targets in patients with diabetes. Insulin degludec (IDeg) is a new basal insulin that forms soluble multihexamers after subcutaneous injection resulting in an ultra-long duration of action and stable glucose-lowering effect. The aim of this analysis was to compare the effect of IDeg on FPG and nocturnal confirmed hypoglycaemia as compared to insulin glargine (IGlar). METHODS AND RESULTS: Data were included from seven phase 3a, randomised, open-label, treat-to-target clinical trials in which once-daily IDeg was compared with once-daily IGlar. Two trials included a total of 957 patients with type 1 diabetes (T1D) and five trials included a total of 3360 patients with type 2 diabetes (T2D); all trials were 26 or 52 weeks in duration. Confirmed hypoglycaemia was defined as plasma glucose <3.1 mmol/L or severe episodes requiring assistance, and nocturnal hypoglycaemia occurred between 00:01 and 05:59. In all trials, the mean end-of-trial FPG was lower for IDeg than IGlar, reaching statistical significance in three trials. Similarly, IDeg was associated with a lower rate of nocturnal confirmed hypoglycaemia vs. IGlar, which was statistically significant in three trials, regardless of type of diabetes or background therapy. CONCLUSION: This analysis shows that the lower rate of nocturnal confirmed hypoglycaemia seen with IDeg relative to IGlar is accompanied by a reduced mean FPG, in particular in patients with T2D. PMID- 26232911 TI - Effect of different fat-enriched meats on non-cholesterol sterols and oxysterols as markers of cholesterol metabolism: Results of a randomized and cross-over clinical trial. AB - BACKGROUND AND AIM: Different kinds of fatty acids can affect the synthesis, absorption, and elimination of cholesterol. This study was carried out to assess the associations of cholesterol metabolism with the intake of two meats with different fatty acid composition in healthy volunteers. METHODS AND RESULTS: The study group was composed of 20 subjects (12 males and eight females; age, 34.4 +/ 11.6 years; body mass index (BMI), 23.5 +/- 2.3 kg/m(2); low-density lipoprotein (LDL) cholesterol, 2.97 +/- 0.55 mmol/l; high-density lipoprotein (HDL) cholesterol, 1.61 +/- 0.31 mmol/l; triglycerides (TG), 1.06 +/- 0.41 mmol/l) who completed a 30-day randomized and cross-over study to compare the cholesterol metabolism effect of 250 g of low-fat lamb versus 250 g of high-fat lamb per day in their usual diet. Cholesterol absorption, synthesis, and elimination were estimated from the serum non-cholesterol sterol and oxysterol concentrations analyzed by a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). No changes in weight, plasma lipids, or physical activity were observed across the study. Cholesterol intestinal absorption was decreased with both diets. Cholesterol synthesis and elimination decreased during the low-fat lamb dietary intervention (rho = 0.048 and rho = 0.005, respectively). CONCLUSION: Acute changes in the diet fat content modify the synthesis, absorption, and biliary elimination of cholesterol. These changes were observed even in the absence of total and LDL cholesterol changes in plasma. REGISTRATION NUMBER FOR CLINICAL TRIALS: ClinicalTrials.gov PRS, NCT02259153. PMID- 26232912 TI - Bioinformatic analyses revealed underlying biological functions correlated with oxaliplatin responsiveness. AB - Colorectal cancer is one of the most common cancers worldwide. Surgery is usually the primary treatment for colon cancers that have not spread to distant sites. However, chemotherapy may be considered after surgery to eliminate remaining cancer cells or in case the cancer has a high risk of recurrence. Oxaliplatin is often used in combination regimens such as FOLFOX, CapeOX, and FOLFOXIRI because of the cost-effectiveness of adjuvant treatment for patients and also the good tolerability profile. However, some patients show resistance to oxaliplatin which causes poor treatment outcomes. Most colon cancer studies focused on treatments and patient survival. Some studies focused on genetic associations of specific genes. However, pathway and network analyses of oxaliplatin resistance in colon cancer cells using gene expression patterns are still lacking. We performed a microarray analysis and found that endothelin-1 (EDN1), dishevelled segment polarity protein (DV1), toll-like receptor 5(TLR5), mitogen-activated protein kinase 3 (MAP2K3), phosphatidylinositol-4,5-bisphosphate 3-kinase, and catalytic subunit beta (PIK3CB) were closely related to responsiveness to oxaliplatin treatment. Furthermore, we found that the signal transduction, melanogenesis, and toll-like receptor signaling pathways might be involved in oxaliplatin-resistant colon cancer. These genes and pathways might be potential targets for improving oxaliplatin treatment in colon cancer patients. PMID- 26232914 TI - MiR-153 regulates metastases of gastric cancer through Snail. AB - MicroRNAs (miRNAs) play critical roles in tumorigenesis and cancer metastases of gastric carcinoma (GC). Recently, miR-153 was reported as a tumor suppressor miRNA silenced in GC, whereas the underlying mechanisms are much lacking. Here, we reported that miR-153 levels were significantly decreased and Snail levels were significantly increased in GC specimens, compared to paired adjacent non tumor gastric tissue. Moreover, the levels of miR-153 and Snail were inversely correlated. Bioinformatics analyses and luciferase reporter assay showed that miR 153 targeted the 3'-untranslated region (3'-UTR) of Snail messenger RNA (mRNA) to inhibit its translation. Overexpression of miR-153 inhibited Snail-mediated cell invasiveness, while depletion of miR-153 increased Snail-mediated cell invasiveness in both Transwell cell migration assay and scratch wound healing assay. Thus, our data suggest that miR-153 suppression in GC promotes Snail mediated cancer metastases. Re-establishment of miR-153 levels in GC may suppress cancer invasion. PMID- 26232915 TI - [Not Available]. PMID- 26232917 TI - Editorial. PMID- 26232913 TI - Endothelial progenitor cells support tumour growth and metastatisation: implications for the resistance to anti-angiogenic therapy. AB - Endothelial progenitor cells (EPCs) have recently been shown to promote the angiogenic switch in solid neoplasms, thereby promoting tumour growth and metastatisation. The genetic suppression of EPC mobilization from bone marrow prevents tumour development and colonization of remote organs. Therefore, it has been assumed that anti-angiogenic treatments, which target vascular endothelial growth factor (VEGF) signalling in both normal endothelial cells and EPCs, could interfere with EPC activation in cancer patients. Our recent data, however, show that VEGF fails to stimulate tumour endothelial colony-forming cells (ECFCs), i.e. the only EPC subtype truly belonging to the endothelial lineage. The present article will survey current evidence about EPC involvement in the angiogenic switch: we will focus on the controversy about EPC definition and on the debate around their actual incorporation into tumour neovessels. We will then discuss how ECFC insensitivity to VEGF stimulation in cancer patients could underpin their well-known resistance to anti-VEGF therapies. PMID- 26232916 TI - Intraindividual comparison of preoperative (99m)Tc-MDP SPECT/CT and intraoperative and histopathological findings in patients with bisphosphonate- or denosumab-related osteonecrosis of the jaw. AB - PURPOSE: Bisphosphonate- or denosumab-related osteonecrosis of the jaw (BRONJ/DRONJ) requires reliable preoperative assessment of the extent of disease for surgical planning. The aim of this study was to compare the extent of BRONJ/DRONJ as detected by Tc-99m-methylene diphosphonate (MDP) bone scintigraphy with intraoperative and histopathological findings, and to assess the additional value of hybrid single photon emission computed tomography/computed tomography (SPECT/CT) for evaluation of disease. MATERIAL AND METHODS: Twenty-one patients with BRONJ/DRONJ underwent three-phase bone scintigraphy including SPECT/CT. The diagnostic certainty using conventional SPECT or fused SPECT/CT imaging was compared. Location and extent of disease on scintigraphic imaging and pre- and intra-operative clinical assessment were compared. Intraoperative and histopathological findings served as reference standard. RESULTS: A total of 29 sites of BRONJ/DRONJ were histopathologically confirmed in 21 patients. Bone scintigraphy demonstrated increased perfusion in 57.1% of patients, increased blood pool in 76.2%, and increased tracer accumulation at the metabolic phase in all patients. The intensity of tracer accumulation at the metabolic phase correlated significantly with clinical stage of disease (rs = 0.47, p = 0.03). Clinical examination (p < 0.0001), but not SPECT (p = 0.19), underestimated the extent of disease as determined by surgical evaluation. SPECT/CT offered a significantly higher diagnostic certainty (p < 0.0001). CONCLUSION: In patients with BRONJ/DRONJ, the true extent of osseous lesions as determined by surgery is significantly underestimated by clinical examination. Tc-99m-MDP bone scintigraphy can reliably predict the extent of disease. Hybrid SPECT/CT may significantly increase the diagnostic certainty of anatomical localization. PMID- 26232918 TI - Effects of nitrogen deposition on carbon cycle in terrestrial ecosystems of China: A meta-analysis. AB - Nitrogen (N) deposition in China has increased greatly, but the general impact of elevated N deposition on carbon (C) dynamics in Chinese terrestrial ecosystems is not well documented. In this study we used a meta-analysis method to compile 88 studies on the effects of N deposition C cycling on Chinese terrestrial ecosystems. Our results showed that N addition did not change soil C pools but increased above-ground plant C pool. A large decrease in below-ground plant C pool was observed. Our result also showed that the impacts of N addition on ecosystem C dynamics depend on ecosystem type and rate of N addition. Overall, our findings suggest that 1) decreased below-ground plant C pool may limit long term soil C sequestration; and 2) it is better to treat N-rich and N-limited ecosystems differently in modeling effects of N deposition on ecosystem C cycle. PMID- 26232919 TI - A high-density genetic map for P genome of Agropyron Gaertn. based on specific locus amplified fragment sequencing (SLAF-seq). AB - MAIN CONCLUSION: This genetic map for Agropyron Gaertn. contained 1023 markers on seven linkage groups, with a total of 907.8 cM and an average distance of 1.5 cM between adjacent loci. Many wheat- Agropyron cristatum derivative lines exhibit superior agronomic traits, and part of them are valuable for future wheat breeding. To date, no high-density genetic map for Agropyron Gaertn. has been published. Specific-locus amplified fragment sequencing (SLAF-seq), a recently developed strategy for large scale de novo discovery and genotyping of single nucleotide polymorphisms (SNPs), was employed in this study to develop sufficient markers for a segregating Agropyron F1 population derived from an interspecific cross between two cross-pollinated diploid collections A. cristatum (L.) Beauv. 'Z1842' and A. mongolicum Keng 'Z2098'. In total, we obtained raw data consisting of 128,932,358 pair-end reads of ~80 bp long after sequencing. Then 69,325 high quality SLAFs were detected, of which 26,248 SLAFs were polymorphic and 1752 of the polymorphic markers were used for the genetic map construction. The final map contained 1023 markers on the seven linkage groups (LGs), which spanned a total of 907.8 cM with an average number of 146 markers and 89 loci per LG and an average distance of 1.5 cM between adjacent loci. To our knowledge, this map is the densest genetic linkage map for Agropyron so far. Through BLAT alignment of Agropyron SLAF marker sequences with the draft genome assemblies of wheat and barley, the Agropyron LGs were assigned as LG1-7 according to their corresponding homoeologous chromosomal groups of wheat. Results of this study will not only provide a platform for gene/QTL fine mapping, but also serve as a reference to assist the assembling of the P genome sequence in future. PMID- 26232920 TI - Narciclasine, a potential allelochemical, affects subcellular trafficking of auxin transporter proteins and actin cytoskeleton dynamics in Arabidopsis roots. AB - MAIN CONCLUSION: The present study documented the action of a potential allelochemical, narciclasine, on auxin transport in Arabidopsis by mainly affecting subcellular trafficking of PIN and AUX1 proteins and through interfering actin cytoskeletal organization. Narciclasine (NCS), an Amaryllidaceae alkaloid isolated from Narcissus tazetta bulbs, has potential allelopathic activity and affects auxin transport. However, little is known about the cellular mechanism of this inhibitory effect of NCS on auxin transport. The present study characterizes the effects of NCS at the cellular level using transgenic Arabidopsis plants harboring the promoters of PIN, in combination with PIN-GFP proteins or AUX1-YFP fusions. NCS treatment caused significant reduction in the abundance of PIN and AUX1 proteins at the plasma membrane (PM). Analysis of the subcellular distribution of PIN and AUX1 proteins in roots revealed that NCS induced the intracellular accumulation of auxin transporters, including PIN2, PIN3, PIN4, PIN7 and AUX1. However, other PM proteins, such as PIP2, BRI1, and low temperature inducible protein 6b (LTI6b), were insensitive to NCS treatment. NCS-induced PIN2 compartments were further defined using endocytic tracer FM 4-64 labeled early endosomes and suggested that this compound affects the endocytosis trafficking of PIN proteins. Furthermore, pharmacological analysis indicated that the brefeldin A (BFA)-insensitive pathway is employed in the cellular effects of NCS on PIN2 trafficking. Although NCS did not alter actin dynamics in vitro, it resulted in the depolymerization of the actin cytoskeleton in vivo. This disruption of actin filaments by NCS subsequently influences the actin-based vesicle motility. Hence, the elucidation of the specific role of NCS is useful for further understanding the mechanisms of allelopathy at the phytohormone levels. PMID- 26232921 TI - Quantitative proteomics analysis reveals that S-nitrosoglutathione reductase (GSNOR) and nitric oxide signaling enhance poplar defense against chilling stress. AB - MAIN CONCLUSION: NO acts as the essential signal to enhance poplar tolerance to chilling stress via antioxidant enzyme activities and protein S -nitrosylation modification, NO signal is also strictly controlled by S -nitrosoglutathione reductase and nitrate reductase to avoid the over-accumulation of reactive nitrogen species. Poplar (Populus trichocarpa) are fast growing woody plants with both ecological and economic value; however, the mechanisms by which poplar adapts to environmental stress are poorly understood. In this study, we used isobaric tags for relative and absolute quantification proteomic approach to characterize the response of poplar exposed to cold stress. We identified 114 proteins that were differentially expressed in plants exposed to cold stress. In particular, some of the proteins are involved in reactive oxygen species (ROS) and reactive nitrogen species (RNS) metabolism. Further physiological analysis showed that nitric oxide (NO) signaling activated a series of downstream defense responses. We further demonstrated that NO activated antioxidant enzyme activities and S-nitrosoglutathione reductase (GSNOR) activities, which would reduce ROS and RNS toxicity and thereby enhance poplar tolerance to cold stress. Suppressing NO accumulation or GSNOR activity aggravated cold damage to poplar leaves. Moreover, our results showed that RNS can suppress the activities of GSNOR and NO nitrate reductase (NR) by S-nitrosylation to fine-tune the NO signal and modulate ROS levels by modulating the S-nitrosylation of ascorbate peroxidase protein. Hence, our data demonstrate that NO signaling activates multiple pathways that enhance poplar tolerances to cold stress, and that NO signaling is strictly controlled through protein post-translational modification by S nitrosylation. PMID- 26232922 TI - First trimester prediction of preeclampsia. AB - Preeclampsia (PE) is a serious pregnancy-related condition that causes severe maternal and fetal morbidity and mortality. Within the recent years, there has been an increasing focus in predicting PE at the end of the first trimester of pregnancy. In this review, literature published between 2011 and 2015 was evaluated. In a total of six biomarker algorithms, for first and early second trimester, the prediction of preeclampsia is discussed. In addition, one randomized clinical trial was included. Several algorithms were based on placental biomarkers such as pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PLGF), and soluble FMS-like tyrosine kinase 1 (s-FLT-1). The algorithms containing these biomarkers showed a high prediction rate (PR) for early onset PE, ranging from 44 to 92 % at 5 % false positive rate (FPR). New biomarkers suggest an alternative model based on free HbF and the heme scavenger alpha-1-microglobulin (A1M) with a prediction rate of 69 % at an FPR of 5 %. Interestingly, this model performs well without uterine artery Doppler pulsatility index (UtAD-PI), which is an advantage particularly if the screening method were to be implemented in developing countries. The randomized clinical trial showed a clear reduction in early onset PE as well as reducing preterm PE if identified high-risk pregnancies were treated with low-dose aspirin. In conclusion, PE prediction is now possible through several prediction algorithms and prophylaxis is beneficial in high-risk cases. PMID- 26232923 TI - Endophthalmitis After Intravitreal Injections: Incidence, Presentation, Management, and Visual Outcome. PMID- 26232924 TI - Clear cell odontogenic carcinoma: report of 7 new cases and systematic review of the current knowledge. AB - OBJECTIVE: The goal of this study is to describe 7 cases of clear cell odontogenic carcinoma among a Brazilian population and compare these data with a systematic review of the English-language literature. STUDY DESIGN: Descriptive statististics were used to compare the clinicopathologic data gathered retrospectively with those compiled from a review. Tumor sections were immunostained for Ki-67, p16, p53, and cytokeratins (CKs) 7, 8, 14, 18, and 19. Log-rank tests were performed for survival analysis. RESULTS: Most cases occurred in the posterior mandible (5/7, 71.4%), and recurrence was diagnosed in all treated patients. Metastatic disease occurred in 2 patients (28.6%). Tumors were focally positive for CKs 7, 8, 14, and 18 and diffusely positive for CK19, p53, and p16. The mean number of Ki-67-positive cells was 35.2 cells/high-power field. Our systematic review provided evidence that tumor size (P = .046), histologic pattern (P = .034), regional metastasis (P = .001), distant metastasis (P = .001), and local recurrence (P = .05) were of significant prognostic value. CONCLUSIONS: This study has contributed to improved characterization of clear cell odontogenic carcinoma, which is an aggressive odontogenic malignant neoplasm diagnosed mainly in the posterior mandible of middle-aged women and typically at an advanced stage. Radical surgical procedures remain the gold standard treatment. PMID- 26232925 TI - Towards Substantive Standardization: Ethical Rules as Ethical Presumptions. AB - This paper argues that substantive ethical rules serve a critical ethical function, even in those cases where we should deviate from those rules. Assuming that the rules are valid provides decision-makers with the context essential to reaching a well-justified decision. Recognizing this helps to reconcile two attractive but incompatible positions regarding the evaluation of healthcare ethics consultants. The first position is that ethical rules can validly be used to evaluate the quality of consultants' advice, ensuring conformity to standards promoted by a significant portion of medical ethicists. The second position-the message of ethical particularism-is that we should not evaluate consultants according to strict rules, since good ethical advice may deviate from even the most carefully wrought moral rules. Steering a path between these extremes, I argue that we should evaluate the quality of consultations by examining whether consultants have communicated the relevant ethical rules to participants as ethical presumptions. In communicating presumptions, a consultant provides an indispensable ingredient to ethical decision-making, while leaving open the possibility that the ethical course of action involves violating the very ethical rules that one should presume. PMID- 26232926 TI - AFNMR: automated fragmentation quantum mechanical calculation of NMR chemical shifts for biomolecules. AB - We evaluate the performance of the automated fragmentation quantum mechanics/molecular mechanics approach (AF-QM/MM) on the calculation of protein and nucleic acid NMR chemical shifts. The AF-QM/MM approach models solvent effects implicitly through a set of surface charges computed using the Poisson Boltzmann equation, and it can also be combined with an explicit solvent model through the placement of water molecules in the first solvation shell around the solute; the latter substantially improves the accuracy of chemical shift prediction of protons involved in hydrogen bonding with solvent. We also compare the performance of AF-QM/MM on proteins and nucleic acids with two leading empirical chemical shift prediction programs SHIFTS and SHIFTX2. Although the empirical programs outperform AF-QM/MM in predicting chemical shifts, the differences are in some cases small, and the latter can be applied to chemical shifts on biomolecules which are outside the training set employed by the empirical programs, such as structures containing ligands, metal centers, and non standard residues. The AF-QM/MM described here is implemented in version 5 of the SHIFTS software, and is fully automated, so that only a structure in PDB format is required as input. PMID- 26232927 TI - Effects of serum uric acid levels on the arginase pathway in women with metabolic syndrome. AB - BACKGROUND: Elevated serum uric acid levels and increased arginase activity are risk factors for cardiovascular diseases (CVD). The aim of the present study was to investigate effects of serum uric acid levels on the arginase pathway in women with metabolic syndrome (MetS). METHODS: Serum arginase activity, and nitrite and uric acid levels were measured in 48 women with MetS and in 20 healthy controls. The correlation of these parameters with components of MetS was also evaluated. RESULTS: Our data show statistically higher arginase activity and uric acid levels but lower nitrite levels in women with MetS compared to controls. Serum uric acid levels were negatively correlated with HDL cholesterol, nitrite levels and positively with Body Mass Index, waist to hip ratio, triglyceride and total cholesterol levels, systolic blood pressure, Homeostasis Model Assessment-Insulin Resistance-Index, serum arginase activity, and LDL-cholesterol levels in women with MetS. CONCLUSION: Results of the present study suggest that serum uric acid levels may contribute to the pathogenesis of MetS through a process mediated by arginase pathway, and serum arginase activity and nitrite and uric acid levels can be used as indicators of CVD in women with MetS. PMID- 26232928 TI - Effect of thyroglobulin gene polymorphisms on growth, carcass composition and meat quality traits in Chinese beef cattle. AB - The thyroglobulin (TG) gene has been studied as an important gene related to fat deposition, since not only does TG gene locate in a quantitative trait locus with an effect on fat deposition, but also it encodes the precursor of thyroid hormones which have crucial biological functions in energy metabolism. In the present study, we identified four novel SNPs at the 5' flanking region of the bovine TG gene. Association analysis indicated that the G275A, G277C, G280A and C281G SNPs were significantly associated with average daily gain (ADG, P < 0.01 for G275A and G277C, P < 0.05 for G280A and C281G). Five haplotypes for the 4 SNPs were constructed and their effects on growth, carcass composition and meat quality traits were evaluated. The results showed no significant effect of haplotype on ADG. Meanwhile, no significant association was found between 4 SNPs and other growth, carcass composition and meat quality traits including intramuscular fat. Bioinformatics analysis showed that 4 SNPs may results in potential transcription factor binding site changes. Results of this study suggest that TG gene-specific SNPs may be a useful marker for growth traits in marker assisted selection programs in beef cattle. PMID- 26232929 TI - [18F]fluorodeoxyglucose uptake as a predictor of large joint destruction in patients with rheumatoid arthritis. AB - The present retrospective study investigated the relationship between [(18)F]fluorodeoxyglucose-positron emission tomography (FDG-PET) findings and subsequent progression of joint destruction on plain X-ray. Nineteen rheumatoid arthritis (RA) patients (59 joints) who underwent FDG-PET and whose joints could be evaluated on plain X-ray 5 years later were included in this retrospective investigation. The relationship between the standardized uptake value (SUV) on FDG-PET and Larsen grade progression on plain X-ray was investigated for each joint. Factors related to progression of joint destruction were also investigated. Joints with advanced joint destruction (Larsen grades IV and V) on X-ray imaging at the time of FDG-PET were excluded. On initial plain X-ray images taken at the time of FDG-PET, a significant correlation was observed between the initial SUV of each joint and the progression of joint destruction 5 years later (R = 0.47, P < 0.01). Significant correlations between the SUV and progression of joint destruction were observed in both load-bearing (R = 0.52, P < 0.01) and non load-bearing joints (R = 0.52, P < 0.01). On logistic regression analysis, higher SUV and lower prednisolone dose were associated with greater risk of progressive joint destruction (P < 0.05). On receiver operating characteristics curve analysis, the optimum threshold for identifying preceding joint destruction was an SUVmean of 1.33. In RA joints, FDG uptake was seen mostly by inflammatory cells; therefore, FDG uptake reflected joint inflammation. Additionally, the activity seen on FDG-PET might be associated with future radiographic changes in RA patients. PMID- 26232930 TI - Evaluation of different keV-settings in dual-energy CT angiography of the aorta using advanced image-based virtual monoenergetic imaging. AB - To compare quantitative image quality in dual-energy CT angiography (DE-CTA) studies of the aorta using different virtual monoenergetic imaging (MEI) and advanced image-based virtual monoenergetic (MEI+) settings at varying kiloelectron volt (keV) levels. Fifty consecutive patients with clinically indicated CT of the whole aorta to evaluate suspected aortic disease underwent DE CTA on a third-generation dual-source CT scanner. Quantitative image quality indices were assessed. Contrast material, saline flush and flow rate were kept equal for optimum comparability. DE-CTA MEI and MEI+ series ranging from 40 to 100 keV (10-keV intervals) were reconstructed. Signal intensity, noise, signal-to noise ratio and contrast-to-noise ratio (CNR) of multiple aortic segments were evaluated. Comparisons between the different MEI and MEI+ datasets were performed. Three-hundred aortic segments total were evaluated. In the MEI+ series the 40, 50 and 100 keV MEI+ showed superior noise and CNR levels (+84, +58, +103 % on average; all p < 0.05) compared to MEI. However, signal intensity between MEI+ and MEI at nearly all aortic segments showed no significant difference (p > 0.1). MEI+ shows lower image noise compared to MEI, resulting in superior quantitative image quality, in particular at low keV levels (40 or 50 keV). PMID- 26232931 TI - Development and evaluation of methods for starch dissolution using asymmetrical flow field-flow fractionation. Part II: Dissolution of amylose. AB - In this paper, we investigate whether dissolution in water under autoclaving conditions (140 degrees C, 20 min) or in dimethyl sulfoxide, DMSO (100 degrees C, 1 h), is preferable for characterization of amylose. Two types of amylose, potato and maize, were dissolved either in water using an autoclave or in DMSO. On the aqueous solutions obtained, the extent of molecular dissolution of the sample (referred to as the dissolution yield) was determined by enzymatic analysis as well as the molecular properties, such as molar mass and root-mean square radius, obtained with asymmetrical flow field-flow fractionation coupled to multi-angle light scattering and differential refractive index detection (AF4 MALS-dRI). The results showed that both dissolution methods are efficient at dissolving amylose. However, AF4-MALS-dRI analysis revealed substantial differences. Amylose aqueous solutions obtained by dissolution in DMSO were relatively stable over time, but the dissolution method in autoclave caused some degradation of the molecules, and their solutions display a high tendency to retrograde. PMID- 26232932 TI - A guiding light: spectroscopy on digital microfluidic devices using in-plane optical fibre waveguides. AB - We present a novel method for in-plane digital microfluidic spectroscopy. In this technique, a custom manifold (.stl file available online as ESM) aligns optical fibres with a digital microfluidic device, allowing optical measurements to be made in the plane of the device. Because of the greater width vs thickness of a droplet on-device, the in-plane alignment of this technique allows it to outperform the sensitivity of vertical absorbance measurements on digital microfluidic (DMF) devices by ~14*. The new system also has greater calibration sensitivity for thymol blue measurements than the popular NanoDrop system by ~2.5*. The improvements in absorbance sensitivity result from increased path length, as well as from additional effects likely caused by liquid lensing, in which the presence of a water droplet between optical fibres increases fibre-to fibre transmission of light by ~2* through refraction and internal reflection. For interrogation of dilute samples, stretching of droplets using digital microfluidic electrodes and adjustment of fibre-to-fibre gap width allows absorbance path length to be changed on-demand. We anticipate this new digital microfluidic optical fibre absorbance and fluorescence measurement system will be useful for a wide variety of analytical applications involving microvolume samples with digital microfluidics. PMID- 26232933 TI - Rickettsial infection in ticks from wild birds from Cerrado and the Pantanal region of Mato Grosso, midwestern Brazil. AB - The involvement of different species of ticks and wild animals, such as birds, play an important role in the epidemiology of tick-borne diseases. Birds may serve as reservoirs for some tick-borne diseases, and may carry and spread hematophagous ectoparasites mechanically. This study aimed to show the diversity of ticks on birds and molecular detection of rickettsial infection in ticks from Pantanal and Cerrado, two similar Brazilian biomes characterized by hydrological seasons. During two years, August 2012 to May 2014, ticks were collected from birds and from the environment in total of 14 visits for collecting samples, distributed in all hydrological seasons. A total of 674 birds were captured representing 113 species from 26 families. In total, 71 birds were parasitized (10.5%), and 155 ticks of the following 7 tick species (in decreasing order of prevalence) were identified: Amblyomma longirostre Koch, Amblyomma nodosum Neumann, Amblyomma cajennense Fabricius sensu lato (s.l.), Amblyomma calcaratum Neumann, Ornithodoros mimon Kohls, Clifford & Jones, Amblyomma ovale Koch, and Amblyomma triste Koch. Among free-living ticks collected in the environment, A. cajennense s.l. was the most common. This is the first occurrence of O. mimon on birds, and of A. triste on Passeriformes in Brazil. Molecular analyses revealed that 6 A. longirostre ticks were infected by 'Candidatus Rickettsia amblyommii', whereas 1 A. nodosum was infected by a Rickettsia parkeri-like agent, previously reported as Rickettsia sp. strain NOD. Spotted fever group (SFG) agents were, for the first time, reported in ticks from birds captured in Pantanal biome, and the potential involvement of these agents as human pathogens should be considered in further studies. PMID- 26232934 TI - Nlrp1 inflammasome is downregulated in trauma patients. AB - After a major trauma, IL-1beta-producing capacity of monocytes is reduced. Generation of IL-1beta is important for appropriate immune response after trauma and requires not only synthesis and transcription of inflammasome components but also their activation. Altered IL-1beta-processing due to deregulated NLRP inflammasomes assembly is associated with several inflammatory diseases. However, the precise role of NLRP1 inflammasome in monocytes after trauma is unknown. Here, we investigated if NLRP1 inflammasome components are responsible for depressed monocyte function after trauma. We found in ex vivo in vitro assays that LPS-stimulation of CD14(+)-isolated monocytes from healthy volunteers (HV) results in remarkably higher capacity of the IL-1beta-release compared to trauma patients (TP). During the 10-day time course, this monocyte depression was highest immediately after admission. Inflammasome activation correlating with this inflammatory response was demonstrated by enhanced protein production of cleaved IL-1beta and caspase-1. Furthermore, we found that the gene expression of IL-1beta, caspase-1, and ASC was comparable in TP and HV after LPS-stimulation during the 10-day course, while NLRP1 was markedly reduced in TP. We demonstrated that transfected monocytes from TP, which expressed the lacking components, were recovered in their LPS-induced IL-1beta-release and that lacking of NLRP1 is responsible for the suppressed monocyte activity after trauma. The restoration of NLRP1 inflammasome suggests new mechanistic target for the recovery of dysbalanced immune reaction after trauma. KEY MESSAGE: Suppression in monocyte function occurs early after a major trauma or surgery. Reduced gene expression abrogates NLRP1 inflammasome assembly after trauma. Limited availability of inflammasome components may cause reduced host defense. Restoring NLRP1 in immune suppressed monocytes recovers NLPR1 activity after trauma. Recovered inflammasome activity may improve the immune response to PAMPs/DAMPs. PMID- 26232935 TI - Critical role of IL-6 in dendritic cell-induced allergic inflammation of asthma. AB - Interleukin (IL)-6 plays important roles in autoimmunity and inflammation and is essential for T helper (Th) 2 and Th17 differentiation. However, whether it is involved in the development and function of dendritic cells (DCs) during allergen induced airway inflammation and airway hyper-reactivity (AHR) remains undefined. In this study, Dermatophagoides pteronyssinus (Der p)-induced airway inflammation and AHR were studied in IL-6 knockout (KO) mice. Der p-loaded bone marrow-derived DCs (BMDCs) from IL-6 KO mice were used to assaying their ability to induce airway inflammation in naive wild-type mice. Our results showed that IL-6 KO mice showed reduced AHR, significant decreases in inflammatory cell recruitment and Th2 and Th17 cytokine production in the airways, and lowered Der p-specific immunoglobulin G1 after Der p exposure. Further exploration of BMDCs from IL-6 KO mice revealed decreased activity of phagocytosis and reduced expression of MHC class II and CD86 after Der p stimulation. Adoptive transfer of Der p-loaded BMDCs from IL-6 KO mice also showed a functional defect in their inability to induce Th2 and Th17 immune responses and trigger airway inflammation and AHR in recipient mice. Finally, in allergic asthmatics, DCs that differentiated from monocytes treated with anti-IL-6 receptor antibody (tocilizumab) had poor capacity for eliciting Th2 polarization as compared to DCs generated from monocytes without antibody treatment. In conclusion, IL-6 signaling in DCs is essential for their uptake of allergens, maturation, and initiation of Th2/Th17 mediated airway inflammation and AHR in asthma, thus providing a new potential target for treating allergic asthma. KEY MESSAGES: IL-6 signaling is important for DCs to take up allergens and to initiate Th2/Th17-mediated airway inflammation. DCs from allergic asthmatics treated with anti-IL-6 receptor antibody had poor capacity for eliciting Th2 polarization. Anti-IL-6 treatment may provide a new potential target for treating allergic asthma. PMID- 26232936 TI - The cytoskeletal protein LASP-1 differentially regulates migratory activities of choriocarcinoma cells. AB - PURPOSE: During healthy pregnancy, a distinct but limited invasion of trophoblast cells into the uterus occurs. In contrast, excessive trophoblast invasion is associated with placental choriocarcinoma (CC). Overexpression of the cytoskeletal protein LASP-1 was shown to contribute to cancer aggressiveness. Here, the yet unknown role of LASP-1 in CC cells is analysed. METHODS: Expression of LASP-1 in human primary carcinoma was assessed by immunohistochemistry and confirmed in CC-derived cell lines by immunocytochemistry, RT-PCR and Western blot. After down-regulation of LASP-1 expression with specific si-RNA in CC derived cell lines, migratory and proliferative activities were analysed by matrigel migration assay and WST-8 test. RESULTS: LASP-1 expression was detected in human primary choriocarcinoma and in JEG-3, JAR and BeWo cells. Knock down of LASP-1 resulted in a decreased expression of LASP-1 protein in JEG-3 and JAR cells accompanied by a diminished migration and a decreased proliferative activity of these two cell lines. Knockdown of LASP-1 in BeWo cells failed. In consequence, migratory function and proliferation was unaffected. CONCLUSION: This is the first study describing LASP-1 expression in CC cells. Detecting an affection of migratory processes after LASP-1 silencing, we propose that LASP-1 could impact on metastasis of CC cells. PMID- 26232937 TI - Clinical presentation, treatment and outcome of vaginal intraepithelial neoplasia. AB - PURPOSE: To characterize the clinical presentation and outcome of patients with vaginal intraepithelial neoplasia (VAIN). METHODS: Medical records of 65 women with VAIN treated between 2005 and 2012 at the colposcopy clinic of a German university hospital were retrospectively evaluated for VAIN grade, HPV status, VAIN localization, treatment method and relapse rate. Follow-up data were available for 53 patients (82 %). RESULTS: Mean age was 61 years (range 32-89 years). Most lesions (55 %) were found in the upper vaginal third; 42 % were multifocal. Multifocal VAIN was more frequently HPV positive than single lesions (p = 0.059). Of all women with known HPV status, 83 % were high-risk (HR) HPV positive and 32 % had a simultaneous CIN earlier or at the same time as the VAIN, mostly CIN 3 (66 %). Two-thirds had a hysterectomy in the past, often because of high-grade CIN. Most cases of VAIN were treated with CO2 laser vaporization. A relapse of the disease could be confirmed for 57 %. HR-HPV positive VAIN was significantly more likely to relapse than HR-HPV negative VAIN (p = 0.005). There were three cases of vaginal cancer with surrounding VAIN 3 or vaginal cancer diagnosed after primary treatment of VAIN 3 and one case of vaginal cancer during follow-up 22 months after the first laser vaporization. All of these cases were HR-HPV positive. CONCLUSIONS: VAIN has a high relapse rate and a high progression rate to invasive cancer especially if HR-HPV positive. Therefore, adequate follow up examinations are mandatory. PMID- 26232938 TI - Might a beta blocker finally provide some relief from postoperative atrial fibrillation? PMID- 26232939 TI - Discussion. PMID- 26232940 TI - The thoracic duct: Predictably unpredictable? PMID- 26232941 TI - The kissing stents technique for a patient with chronic type B aortic dissection. PMID- 26232942 TI - Transcoronary infusion of cardiac progenitor cells in hypoplastic left heart syndrome: Three-year follow-up of the Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single-Ventricle Physiology (TICAP) trial. AB - OBJECTIVES: Our aim was to assess midterm safety and clinical outcomes of intracoronary infusion of cardiosphere-derived cells (CDCs) after staged palliation in patients with hypoplastic left heart syndrome (HLHS). METHODS: In this prospective, controlled study, 14 consecutive patients with HLHS who were undergoing 2- or 3-stage surgical palliations were assigned to receive intracoronary CDC infusion 1 month after cardiac surgery (n = 7), followed by 7 patients allocated to a control group with standard care alone. The primary end point was to assess procedural feasibility and safety; the secondary end point was to evaluate cardiac function and heart failure status through 36-month follow up. RESULTS: No complications, including tumor formation, were reported within 36 months after CDC infusion. Echocardiography showed significantly greater improvement in right ventricular ejection fraction (RVEF) in infants receiving CDCs than in controls at 36 months (+8.0% +/- 4.7% vs +2.2% +/- 4.3%; P = .03). These cardiac function improvements resulted in reduced brain natriuretic peptide levels (P = .04), lower incidence of unplanned catheter interventions (P = .04), and higher weight-for-age z score (P = .02) at 36 months relative to controls. As independent predictors of treatment responsiveness, absolute changes in RVEF at 36 months were negatively correlated with age, weight-for-age z score, and RVEF at CDC infusion. CONCLUSIONS: Intracoronary CDC infusion after staged procedure in patients with HLHS is safe and improves RVEF, which persists during 36-month follow-up. This therapeutic strategy may enhance somatic growth and reduce incidence of heart failure. PMID- 26232944 TI - Precipitation reconstruction for the northwestern Chinese Altay since 1760 indicates the drought signals of the northern part of inner Asia. AB - Based on the significant positive correlations between the regional tree-ring width chronology and local climate data, the total precipitation of the previous July to the current June was reconstructed since AD 1760 for the northwestern Chinese Altay. The reconstruction model accounts for 40.7 % of the actual precipitation variance during the calibration period from 1959 to 2013. Wet conditions prevailed during the periods 1764-1777, 1784-1791, 1795-1805, 1829 1835, 1838-1846, 1850-1862, 1867-1872, 1907-1916, 1926-1931, 1935-1943, 1956 1961, 1968-1973, 1984-1997, and 2002-2006. Dry episodes occurred during 1760 1763, 1778-1783, 1792-1794, 1806-1828, 1836-1837, 1847-1849, 1863-1866, 1873 1906, 1917-1925, 1932-1934, 1944-1955, 1962-1967, 1974-1983, 1998-2001, and 2007 2012. The spectral analysis of the precipitation reconstruction shows the existence of some cycles (15.3, 4.5, 3.1, 2.7, and 2.1 years). The significant correlations with the gridded precipitation dataset revealed that the precipitation reconstruction represents the precipitation variation for a large area of the northern part of inner Asia. A comparison with the precipitation reconstruction from the southern Chinese Altay shows the high level of confidence for the precipitation reconstruction for the northwestern Chinese Altay. Precipitation variation of the northwestern Chinese Altay is positively correlated with sea surface temperatures in tropical oceans, suggesting a possible linkage of the precipitation variation of the northwestern Chinese Altay to the El Nino-Southern Oscillation (ENSO) and the North Atlantic Oscillation (NAO). The synoptic climatology analysis reveals that there is the relationship between anomalous atmospheric circulation and extreme climate events in the northwestern Chinese Altay. PMID- 26232943 TI - Transgenic mice overexpressing glia maturation factor-beta, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation. AB - Glia Maturation Factor-beta (GMF), a brain specific protein, is induced by proteinuria in renal tubules. Ectopic GMF overexpression causes apoptosisin vitro via cellular vulnerability to oxidative stress. In order to examine the roles of GMF in non-brain tissue, we constructed transgenic mice overexpressing GMF (GMF TG). The GMF-TG mice exhibited appearance phenotypes associated with premature aging. The GMF-TG mice also demonstrated short lifespans and reduced hair regrowth, suggesting an accelerated aging process. The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies. Importantly, we identified the abnormal lamin A (prelamin A), accompanied by a down-regulation of a lamin A processing enzyme (Zmpste24) in the kidney of the GMF-TG mice. The GMF-TG mice showed accelerated aging in the kidney, compared with wild-type mice, showing increased TGF-beta1, CTGF gene and serum creatinine. The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks. In conclusion, we propose that GMF-TG mice might be a novel mouse model of accelerated aging, due to the abnormal lamin A. PMID- 26232945 TI - Identification of couple-stress moduli of vertebral trabecular bone based on the 3D internal architectures. AB - The purpose of this paper is to develop a homogeneous, orthotropic couple-stress continuum model as a substitute of the 3D periodic heterogeneous cellular solid model of vertebral trabecular bone. Vertebral trabecular bone is modeled as a porous material with an idealized periodic structure made of 3D open cubic cells, which is effectively orthotropic. The chosen architecture is based on studies of samples taken from the central part of vertebral bodies. The effective properties are obtained based on the response of the representative volume element under prescribed boundary conditions. Mixed boundary conditions comprising both traction and displacement boundary conditions are applied on the structure boundaries. In this contribution, the effective mechanical constants of the effective couple-stress continuum are deduced by an equivalent strain energy method. The characteristic lengths for bending and torsion are identified from the resulting homogenized orthotropic moduli. We conduct this study computationally using a finite element approach. Vertebral trabecular bone is modeled either as a cellular solid or as a two-phase material consisting of bone tissue (stiff phase) forming a trabecular network, and a surrounding soft tissue referring to the bone marrow present in the pores. Both the bone tissue forming the network and the pores are assumed to be homogeneous linear elastic, and isotropic media. The scale effects on the predicted couple stress moduli of these networks are investigated by varying the size of the bone specimens over which the boundary conditions are applied. The analysis using mixed boundary conditions gives results that are independent of unit cell size when computing the first couple stress tensor, while it is dependent on the cell size as to the second couple stress tensor moduli. This study provides overall guidance on how the size of the trabecular specimen influence couple stresses elastic moduli of cellular materials, with focus on bones. The developed approach is quite general and applicable to any heterogeneous cellular and composite materials. PMID- 26232946 TI - Gender Comparison of Scholarly Production in the Musculoskeletal Tumor Society Using the Hirsch Index. AB - OBJECTIVE: Despite an increase in the proportion of female medical school graduates, the number of women in orthopedic surgery remains low. To examine the presence of gender disparities in scholarly production, the authors used the Hirsch index (h-index) to assess members of the Musculoskeletal Tumor Society (MSTS), a well-defined subspecialty of orthopedic surgery. DESIGN: Using the MSTS Membership Directory, the authors assessed those practicing at an academic institution in the United States. Members' sex and rank was obtained from their department's website, and their h-index and years since initial publication was collected from the Scopus database. SETTING: Research was performed at New Jersey Medical School, an institution, using online databases. PARTICIPANTS: A total of 247 members of the MSTS were eligible, of whom 125 practiced at a US academic medical center and were included in the study. RESULTS: The MSTS is composed of 247 members, 28 (11%) of whom are women. Within US academic medical centers, there are 125 members, including 17 (14%) women. Mean h-indices increased with rising academic rank from 5.42 for assistant professors to 19.28 for professors. Publication ranges showed an increase from 11.03 years for assistant professors to 29.52 years for professors. The h-index and publication years of chairpersons were nearly equal to those of professors. Using the h-index, it was found that men outproduce women-13.4:7.9. Men outnumber women at every rank, increasingly so at higher ranks. The authors found that there was a significant difference in productivity between ranks (p < 0.01) and between sexes (p = 0.035), but not between sexes at the assistant professor, associate professor, or professor levels (p = 0.147, 0.581, and 0.263, respectively). CONCLUSIONS: The h-index shows differing production among the sexes and ranks in the MSTS. No significant difference exists between the sexes when members are organized by academic title. PMID- 26232947 TI - Medical Students in Breast Clinics-How Welcome are They and How Can We Improve Their Learning Opportunities? PMID- 26232948 TI - It's Not Just Nomenclature, It's a Patient With Heart Failure. PMID- 26232949 TI - Can child-pedestrians' hazard perception skills be enhanced? AB - OBJECTIVE: Traffic collisions yield a substantial rate of morbidity and injury among child-pedestrians. We explored the formation of an innovative hazard perception training intervention - Child-pedestrians Anticipate and Act Hazard Perception Training (CA(2)HPT). Training was based upon enhancing participants' ability to anticipate potential hazards by exposing them to an array of traffic scenes viewed from different angles. METHOD: Twenty-four 7-9-year-olds have participated. Trainees underwent a 40-min intervention of observing typical residential traffic scenarios in a simulated dome projection environment while engaging in a hazard detection task. Trainees were encouraged to note differences between the scenarios presented to them from separate angles (a pedestrian's point-of-view and a higher perspective angle). Next, trainees and control group members were required to perform crossing decision tasks. RESULTS: Trainees were found to be more aware of potential hazards related to restricted field of view relative to control. CONCLUSIONS: Child pedestrians are responsive to training and actively detecting materialized hazards may enrich child-pedestrians' ability to cross roads. PMID- 26232952 TI - Transitions between dynamical behaviors of oscillator networks induced by diversity of nodes and edges. AB - We study the impact of dynamical and structural heterogeneity on the collective dynamics of large small-world networks of pulse-coupled integrate-and-fire oscillators endowed with refractory periods and time delay. Depending on the choice of homogeneous control parameters (here, refractoriness and coupling strength), these networks exhibit a large spectrum of dynamical behaviors, including asynchronous, partially synchronous, and fully synchronous states. Networks exhibit transitions between these dynamical behaviors upon introducing heterogeneity. We show that the probability for a network to exhibit a certain dynamical behavior (network susceptibility) is affected differently by dynamical and structural heterogeneity and depends on the respective homogeneous dynamics. PMID- 26232953 TI - Chaos control of the brushless direct current motor using adaptive dynamic surface control based on neural network with the minimum weights. AB - This paper investigates chaos control for the brushless DC motor (BLDCM) system by adaptive dynamic surface approach based on neural network with the minimum weights. The BLDCM system contains parameter perturbation, chaotic behavior, and uncertainty. With the help of radial basis function (RBF) neural network to approximate the unknown nonlinear functions, the adaptive law is established to overcome uncertainty of the control gain. By introducing the RBF neural network and adaptive technology into the dynamic surface control design, a robust chaos control scheme is developed. It is proved that the proposed control approach can guarantee that all signals in the closed-loop system are globally uniformly bounded, and the tracking error converges to a small neighborhood of the origin. Simulation results are provided to show that the proposed approach works well in suppressing chaos and parameter perturbation. PMID- 26232950 TI - Kineococcus gypseus sp. nov., isolated from saline sediment. AB - A novel Gram-stain-positive, aerobic, motile, non-spore-forming coccus-shaped actinomycete, designated strain YIM 121300T, was isolated from alkaline sediment in Yuanjiang, Yunnan province, south-west China. Phylogenetic analyses based on the 16S rRNA gene sequence showed that strain YIM 121300T was affiliated to the genus Kineococcus, and was closely related to Kineococcus aurantiacus IFO 15268T (97.3 % similarity). 16S rRNA gene sequence similarity to other species of the genus Kineococcus was < 97 %. The cell wall contained meso-diaminopimelic acid as the diagnostic diamino acid. The whole-cell sugars contained arabinose, galactose, glucose, mannose and ribose. The predominant menaquinone was MK-9(H2). Mycolic acids were not detected. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside and an unknown phospholipid. The predominant fatty acids were anteiso-C15 : 0 and anteiso-C15 : 1 A. The G+C content of the genomic DNA was 75.1 mol%. DNA-DNA relatedness (55 +/- 4 % to K. aurantiacus IFO 15268T) and differential phenotypic data demonstrated that strain YIM 121300T was distinguished from all related species of the genus Kineococcus. On the basis of data from the present polyphasic study, the organism should be assigned to a novel species of the genus Kineococcus, for which the name Kineococcus gypseus sp. nov. is proposed. The type strain is YIM 121300T ( = CCTCC AA 2013232T = DSM 27627T). PMID- 26232954 TI - On the fractional Eulerian numbers and equivalence of maps with long term power law memory (integral Volterra equations of the second kind) to Grunvald-Letnikov fractional difference (differential) equations. AB - In this paper, we consider a simple general form of a deterministic system with power-law memory whose state can be described by one variable and evolution by a generating function. A new value of the system's variable is a total (a convolution) of the generating functions of all previous values of the variable with weights, which are powers of the time passed. In discrete cases, these systems can be described by difference equations in which a fractional difference on the left hand side is equal to a total (also a convolution) of the generating functions of all previous values of the system's variable with the fractional Eulerian number weights on the right hand side. In the continuous limit, the considered systems can be described by the Grunvald-Letnikov fractional differential equations, which are equivalent to the Volterra integral equations of the second kind. New properties of the fractional Eulerian numbers and possible applications of the results are discussed. PMID- 26232955 TI - Is a two-dimensional generalization of the Higuchi algorithm really necessary? AB - Fractal dimensions of data series, particularly time series can be estimated very well by using Higuchi's algorithm. Without phase space constructions, the fractal dimension of a one-dimensional data stream is calculated. Higuchi's method is well accepted and widely applied, because it is very reliable and easy to implement. A generalization of the genuine 1D algorithm to two dimensions would be desirable in order to investigate digital images. In this study, we propose several 2D generalization algorithms and evaluate differences between them. Additionally, a comparison to previously published pseudo 2D generalizations, and to the Fourier and the Blanket method are presented. The algorithms were tested on artificially generated grey value and red-green-blue colour images. It turned out that the proposed 2D generalized Higuchi algorithms are very robust, but differences in between the generalizations as well as differences to the pseudo 2D algorithms are astonishingly small. PMID- 26232956 TI - Series-nonuniform rational B-spline signal feedback: From chaos to any embedded periodic orbit or target point. AB - The self-controlling feedback control method requires an external periodic oscillator with special design, which is technically challenging. This paper proposes a chaos control method based on time series non-uniform rational B splines (SNURBS for short) signal feedback. It first builds the chaos phase diagram or chaotic attractor with the sampled chaotic time series and any target orbit can then be explicitly chosen according to the actual demand. Second, we use the discrete timing sequence selected from the specific target orbit to build the corresponding external SNURBS chaos periodic signal, whose difference from the system current output is used as the feedback control signal. Finally, by properly adjusting the feedback weight, we can quickly lead the system to an expected status. We demonstrate both the effectiveness and efficiency of our method by applying it to two classic chaotic systems, i.e., the Van der Pol oscillator and the Lorenz chaotic system. Further, our experimental results show that compared with delayed feedback control, our method takes less time to obtain the target point or periodic orbit (from the starting point) and that its parameters can be fine-tuned more easily. PMID- 26232957 TI - Nonlinear energy channeling in the two-dimensional, locally resonant, unit-cell model. I. High energy pulsations and routes to energy localization. AB - Present paper is the first one in the series devoted to the analytical investigation of energy channeling phenomena emerging in the locally resonant unit-cell model comprising an outer mass incorporating internal rotator and subject to the 2D, nonlinear local potential. In the current study, we mainly focus on the analysis of the mechanisms of formation and bifurcations of the special type of non-stationary regimes, characterized by the massive, bidirectional energy transport between the axial and the lateral vibrations of the outer element controlled by the internal, rotational device as well as the regimes of the unidirectional energy localization. The devised analytical procedure is based on a singular multi-scale analysis constructed for the special asymptotic limit corresponding to the high energy excitations. The basic question of possible coexistence of various stationary and non-stationary system regimes as well as their local and global bifurcations is addressed via the reduction of the global flow on the slow invariant manifold in the vicinity of the fundamental resonance. Numerical simulations fully confirm the analytical predictions concerning the structure of the response regimes and their bifurcations. PMID- 26232958 TI - Nonlinear energy channeling in the two-dimensional, locally resonant, unit-cell model. II. Low energy excitations and unidirectional energy transport. AB - This paper completes a series of two publications devoted to the analytical investigation of energy channeling phenomena, emerging in a locally resonant unit cell model. The system under consideration comprises an outer mass with internal rotator and subject to the 2D nonlinear local potential. In the present study, we focus on the analysis of the regimes of two-dimensional, nonlinear energy transport forming in the special asymptotic limit of low energy excitations. Unlike the previously considered case, this limit can also be characterized by the absence of resonant interactions between the internal rotator and the motion of an outer element. In the considered limit, we report the emergence of all new, highly nonlinear, transient regimes of unidirectional energy channeling. This phenomenon is manifested by partial and complete targeted energy flow from axial to lateral vibrations, controlled by an internal device. Here, we also show that regimes corresponding to the bidirectional energy channeling as well as the spontaneous energy locking reported in the first paper of the series-persist in the low energy limit as well. In this study, we use a regular multi-scale asymptotic procedure and completely unveil the intrinsic mechanisms governing bi- and unidirectional energy channeling. Numerical simulations are found to be in a fairly good agreement with the predictions of analytic model. PMID- 26232959 TI - Chaotic attractors with separated scrolls. AB - This paper proposes a new behavior of chaotic attractors with separated scrolls while combining Julia's process with Chua's attractor and Lorenz's attractor. The main motivation of this work is the ability to generate a set of separated scrolls with different behaviors, which in turn allows us to choose one or many scrolls combined with modulation (amplitude and frequency) for secure communication or synchronization. This set seems a new class of hyperchaos because each element of this set looks like a simple chaotic attractor with one positive Lyapunov exponent, so the cardinal of this set is greater than one. This new approach could be used to generate more general higher-dimensional hyperchaotic attractor for more potential application. Numerical simulations are given to show the effectiveness of the proposed theoretical results. PMID- 26232960 TI - Entropy constraints on convergence in the infinite-N Kuramoto model. AB - We clarify the degree to which the entropy functional puts constraints on the possibility of convergence of states in the infinite-N Kuramoto model. It is shown that convergence to the uniform incoherent state is impossible in the L2 norm but it is left as an open question whether the same can be said about convergence in the L1 norm. We conclude with a discussion on the entropy of the marginal density function where similar constraints do not apply. PMID- 26232961 TI - A financial market model with endogenous fundamental values through imitative behavior. AB - In this paper, we propose a financial market model with heterogeneous speculators, i.e., optimistic and pessimistic fundamentalists that, respectively, overestimate and underestimate the true fundamental value due to ambiguity in the stock market, which prevents them from relying on the true fundamental value in their speculations. Indeed, we assume that agents use in its place fundamental values determined by an imitative process. Namely, in forming their beliefs, speculators consider the relative profits realized by optimists and pessimists and update their fundamental values proportionally to those relative profits. Moreover, differently from the majority of the literature on the topic, the stock price is determined by a nonlinear mechanism that prevents divergence issues. For our model, we study, via analytical and numerical tools, the stability of the unique steady state, its bifurcations, as well as the emergence of complex behaviors. We also investigate multistability phenomena, characterized by the presence of coexisting attractors. PMID- 26232962 TI - Fibonacci stairs and the Afraimovich-Pesin dimension for a stroboscopic section of a nonautonomous van der Pol oscillator. AB - Statistics of Poincare recurrences is studied in the stroboscopic section of trajectories of a nonautonomous van der Pol oscillator in the framework of the global approach. It is shown that when the oscillator frequency and the frequency of the external force are irrationally related, the set obtained stroboscopically is equivalent to the circle map. For small values of the external amplitude, the Fibonacci stairs is constructed for the golden and silver ratios and its universal properties are confirmed. It is established that the Afraimovich-Pesin dimension for the map in the stroboscopic section is alphac = 1 for Diophantine irrational rotation numbers. PMID- 26232963 TI - Periodic orbit analysis of a system with continuous symmetry--A tutorial. AB - Dynamical systems with translational or rotational symmetry arise frequently in studies of spatially extended physical systems, such as Navier-Stokes flows on periodic domains. In these cases, it is natural to express the state of the fluid in terms of a Fourier series truncated to a finite number of modes. Here, we study a 4-dimensional model with chaotic dynamics and SO(2) symmetry similar to those that appear in fluid dynamics problems. A crucial step in the analysis of such a system is symmetry reduction. We use the model to illustrate different symmetry-reduction techniques. The system's relative equilibria are conveniently determined by rewriting the dynamics in terms of a symmetry-invariant polynomial basis. However, for the analysis of its chaotic dynamics, the "method of slices," which is applicable to very high-dimensional problems, is preferable. We show that a Poincare section taken on the "slice" can be used to further reduce this flow to what is for all practical purposes a unimodal map. This enables us to systematically determine all relative periodic orbits and their symbolic dynamics up to any desired period. We then present cycle averaging formulas adequate for systems with continuous symmetry and use them to compute dynamical averages using relative periodic orbits. The convergence of such computations is discussed. PMID- 26232964 TI - A simple non-chaotic map generating subdiffusive, diffusive, and superdiffusive dynamics. AB - Analytically tractable dynamical systems exhibiting a whole range of normal and anomalous deterministic diffusion are rare. Here, we introduce a simple non chaotic model in terms of an interval exchange transformation suitably lifted onto the whole real line which preserves distances except at a countable set of points. This property, which leads to vanishing Lyapunov exponents, is designed to mimic diffusion in non-chaotic polygonal billiards that give rise to normal and anomalous diffusion in a fully deterministic setting. As these billiards are typically too complicated to be analyzed from first principles, simplified models are needed to identify the minimal ingredients generating the different transport regimes. For our model, which we call the slicer map, we calculate all its moments in position analytically under variation of a single control parameter. We show that the slicer map exhibits a transition from subdiffusion over normal diffusion to superdiffusion under parameter variation. Our results may help to understand the delicate parameter dependence of the type of diffusion generated by polygonal billiards. We argue that in different parameter regions the transport properties of our simple model match to different classes of known stochastic processes. This may shed light on difficulties to match diffusion in polygonal billiards to a single anomalous stochastic process. PMID- 26232965 TI - Regular and chaotic dynamics of a piecewise smooth bouncer. AB - The dynamical properties of a particle in a gravitational field colliding with a rigid wall moving with piecewise constant velocity are studied. The linear nature of the wall's motion permits further analytical investigation than is possible for the system's sinusoidal counterpart. We consider three distinct approaches to modeling collisions: (i) elastic, (ii) inelastic with constant restitution coefficient, and (iii) inelastic with a velocity-dependent restitution function. We confirm the existence of distinct unbounded orbits (Fermi acceleration) in the elastic model, and investigate regular and chaotic behavior in the inelastic cases. We also examine in the constant restitution model trajectories wherein the particle experiences an infinite number of collisions in a finite time, i.e., the phenomenon of inelastic collapse. We address these so-called "sticking solutions" and their relation to both the overall dynamics and the phenomenon of self reanimating chaos. Additionally, we investigate the long-term behavior of the system as a function of both initial conditions and parameter values. We find the non-smooth nature of the system produces novel bifurcation phenomena not seen in the sinusoidal model, including border-collision bifurcations. The analytical and numerical investigations reveal that although our piecewise linear bouncer is a simplified version of the sinusoidal model, the former not only captures essential features of the latter but also exhibits behavior unique to the discontinuous dynamics. PMID- 26232966 TI - The relationship between node degree and dissipation rate in networks of diffusively coupled oscillators and its significance for pancreatic beta cells. AB - Self-sustained oscillatory dynamics is a motion along a stable limit cycle in the phase space, and it arises in a wide variety of mechanical, electrical, and biological systems. Typically, oscillations are due to a balance between energy dissipation and generation. Their stability depends on the properties of the attractor, in particular, its dissipative characteristics, which in turn determine the flexibility of a given dynamical system. In a network of oscillators, the coupling additionally contributes to the dissipation, and hence affects the robustness of the oscillatory solution. Here, we therefore investigate how a heterogeneous network structure affects the dissipation rate of individual oscillators. First, we show that in a network of diffusively coupled oscillators, the dissipation is a linearly decreasing function of the node degree, and we demonstrate this numerically by calculating the average divergence of coupled Hopf oscillators. Subsequently, we use recordings of intracellular calcium dynamics in pancreatic beta cells in mouse acute tissue slices and the corresponding functional connectivity networks for an experimental verification of the presented theory. We use methods of nonlinear time series analysis to reconstruct the phase space and calculate the sum of Lyapunov exponents. Our analysis reveals a clear tendency of cells with a higher degree, that is, more interconnected cells, having more negative values of divergence, thus confirming our theoretical predictions. We discuss these findings in the context of energetic aspects of signaling in beta cells and potential risks for pathological changes in the tissue. PMID- 26232967 TI - Alternating current-driven graphene superlattices: Kinks, dissipative solitons, dynamic chaotization. AB - The possibility of the solitary electromagnetic wave formation in graphene superlattice subjected to the electromagnetic radiation is discussed. The chaotic behavior of the electron subsystem in graphene superlattice is studied by Melnikov method. Dynamic chaos of electrons is shown to appear for certain intervals of frequencies of incident electromagnetic radiation. The frequency dependence of the radiation critical amplitude which determines the bound of chaos appearance is investigated. The values of radiation frequency at which the critical amplitude increases indefinitely were found. PMID- 26232968 TI - Modeling a bus through a sequence of traffic lights. AB - We propose a model of a bus traveling through a sequence of traffic lights, which is required to stop between the traffic signals to pick up passengers. A two dimensional model, of velocity and traveled time at each traffic light, is constructed, which shows non-trivial and chaotic behaviors for realistic city traffic parameters. We restrict the parameter values where these non-trivial and chaotic behaviors occur, by following analytically and numerically the fixed points and period 2 orbits. We define conditions where chaos may arise by determining regions in parameter space where the maximum Lyapunov exponent is positive. Chaos seems to occur as long as the ratio of the braking and accelerating capacities are greater than about ~3. PMID- 26232969 TI - Exact calculations of first-passage properties on the pseudofractal scale-free web. AB - In this paper, we consider discrete time random walks on the pseudofractal scale free web (PSFW) and we study analytically the related first passage properties. First, we classify the nodes of the PSFW into different levels and propose a method to derive the generation function of the first passage probability from an arbitrary starting node to the absorbing domain, which is located at one or more nodes of low-level (i.e., nodes with large degree). Then, we calculate exactly the first passage probability, the survival probability, the mean, and the variance of first passage time by using the generating functions as a tool. Finally, for some illustrative examples corresponding to given choices of starting node and absorbing domain, we derive exact and explicit results for such first passage properties. The method we propose can as well address the cases where the absorbing domain is located at one or more nodes of high-level on the PSFW, and it can also be used to calculate the first passage properties on other networks with self-similar structure, such as (u, v) flowers and recursive scale free trees. PMID- 26232970 TI - Driven synchronization in random networks of oscillators. AB - Synchronization is a universal phenomenon found in many non-equilibrium systems. Much recent interest in this area has overlapped with the study of complex networks, where a major focus is determining how a system's connectivity patterns affect the types of behavior that it can produce. Thus far, modeling efforts have focused on the tendency of networks of oscillators to mutually synchronize themselves, with less emphasis on the effects of external driving. In this work, we discuss the interplay between mutual and driven synchronization in networks of phase oscillators of the Kuramoto type, and explore how the structure and emergence of such states depend on the underlying network topology for simple random networks with a given degree distribution. We find a variety of interesting dynamical behaviors, including bifurcations and bistability patterns that are qualitatively different for heterogeneous and homogeneous networks, and which are separated by a Takens-Bogdanov-Cusp singularity in the parameter region where the coupling strength between oscillators is weak. Our analysis is connected to the underlying dynamics of oscillator clusters for important states and transitions. PMID- 26232971 TI - Evolutionary game dynamics of controlled and automatic decision-making. AB - We integrate dual-process theories of human cognition with evolutionary game theory to study the evolution of automatic and controlled decision-making processes. We introduce a model in which agents who make decisions using either automatic or controlled processing compete with each other for survival. Agents using automatic processing act quickly and so are more likely to acquire resources, but agents using controlled processing are better planners and so make more effective use of the resources they have. Using the replicator equation, we characterize the conditions under which automatic or controlled agents dominate, when coexistence is possible and when bistability occurs. We then extend the replicator equation to consider feedback between the state of the population and the environment. Under conditions in which having a greater proportion of controlled agents either enriches the environment or enhances the competitive advantage of automatic agents, we find that limit cycles can occur, leading to persistent oscillations in the population dynamics. Critically, however, these limit cycles only emerge when feedback occurs on a sufficiently long time scale. Our results shed light on the connection between evolution and human cognition and suggest necessary conditions for the rise and fall of rationality. PMID- 26232972 TI - On the stochastic behaviors of locally confined particle systems. AB - We investigate a class of Hamiltonian particle systems and their stochastic behaviors. Using both rigorous proof and numerical simulations, we show that the geometric configuration can qualitatively change key statistical characteristics of the particle system, which are expected to be retained by stochastic modifications. In particular, whether a particle system has an exponential mixing rate or a polynomial mixing rate depends on whether the geometric setting allows a slow particle being reached by adjacent fast particles. PMID- 26232973 TI - Introduction to the Focus Issue: Physics of Scaling and Self-similarity in Hydrologic Dynamics, Hydrodynamics, and Climate. PMID- 26232974 TI - A physical scaling model for aggregation and disaggregation of field-scale surface soil moisture dynamics. AB - Scaling relationships are needed as measurements and desired predictions are often not available at concurrent spatial support volumes or temporal discretizations. Surface soil moisture values of interest to hydrologic studies are estimated using ground based measurement techniques or utilizing remote sensing platforms. Remote sensing based techniques estimate field-scale surface soil moisture values, but are unable to provide the local-scale soil moisture information that is obtained from local measurements. Further, obtaining field scale surface moisture values using ground-based measurements is exhaustive and time consuming. To bridge this scale mismatch, we develop analytical expressions for surface soil moisture based on sharp-front approximation of the Richards equation and assumed log-normal distribution of the spatial surface saturated hydraulic conductivity field. Analytical expressions for field-scale evolution of surface soil moisture to rainfall events are utilized to obtain aggregated and disaggregated response of surface soil moisture evolution with knowledge of the saturated hydraulic conductivity. The utility of the analytical model is demonstrated through numerical experiments involving 3-D simulations of soil moisture and Monte-Carlo simulations for 1-D renderings-with soil moisture dynamics being represented by the Richards equation in each instance. Results show that the analytical expressions developed here show promise for a principled way of scaling surface soil moisture. PMID- 26232975 TI - Symmetry breaking and uniqueness for the incompressible Navier-Stokes equations. AB - The present article establishes connections between the structure of the deterministic Navier-Stokes equations and the structure of (similarity) equations that govern self-similar solutions as expected values of certain naturally associated stochastic cascades. A principle result is that explosion criteria for the stochastic cascades involved in the probabilistic representations of solutions to the respective equations coincide. While the uniqueness problem itself remains unresolved, these connections provide interesting problems and possible methods for investigating symmetry breaking and the uniqueness problem for Navier-Stokes equations. In particular, new branching Markov chains, including a dilogarithmic branching random walk on the multiplicative group (0, infinity), naturally arise as a result of this investigation. PMID- 26232976 TI - Scaling of geochemical reaction rates via advective solute transport. AB - Transport in porous media is quite complex, and still yields occasional surprises. In geological porous media, the rate at which chemical reactions (e.g., weathering and dissolution) occur is found to diminish by orders of magnitude with increasing time or distance. The temporal rates of laboratory experiments and field observations differ, and extrapolating from laboratory experiments (in months) to field rates (in millions of years) can lead to order of-magnitude errors. The reactions are transport-limited, but characterizing them using standard solute transport expressions can yield results in agreement with experiment only if spurious assumptions and parameters are introduced. We previously developed a theory of non-reactive solute transport based on applying critical path analysis to the cluster statistics of percolation. The fractal structure of the clusters can be used to generate solute distributions in both time and space. Solute velocities calculated from the temporal evolution of that distribution have the same time dependence as reaction-rate scaling in a wide range of field studies and laboratory experiments, covering some 10 decades in time. The present theory thus both explains a wide range of experiments, and also predicts changes in the scaling behavior in individual systems with increasing time and/or length scales. No other theory captures these variations in scaling by invoking a single physical mechanism. Because the successfully predicted chemical reactions include known results for silicate weathering rates, our theory provides a framework for understanding changes in the global carbon cycle, including its effects on extinctions, climate change, soil production, and denudation rates. It further provides a basis for understanding the fundamental time scales of hydrology and shallow geochemistry, as well as the basis of industrial agriculture. PMID- 26232977 TI - Scaling and self-similarity in two-dimensional hydrodynamics. AB - The conditions under which depth-averaged two-dimensional (2D) hydrodynamic equations system as an initial-boundary value problem (IBVP) becomes self-similar are investigated by utilizing one-parameter Lie group of point scaling transformations. Self-similarity conditions due to the 2D k-epsilon turbulence model are also investigated. The self-similarity conditions for the depth averaged 2D hydrodynamics are found for the flow variables including the time, the longitudinal length, the transverse length, the water depth, the flow velocities in x- and y-directions, the bed shear stresses in x- and y-directions, the bed shear velocity, the Manning's roughness coefficient, the kinematic viscosity of the fluid, the eddy viscosity, the turbulent kinetic energy, the turbulent dissipation, and the production and the source terms in the k-epsilon model. By the numerical simulations, it is shown that the IBVP of depth-averaged 2D hydrodynamic flow process in a prototype domain can be self-similar with that of a scaled domain. In fact, by changing the scaling parameter and the scaling exponents of the length dimensions, one can obtain several different scaled domains. The proposed scaling relations obtained by the Lie group scaling approach may provide additional spatial, temporal, and economical flexibility in setting up physical hydraulic models in which two-dimensional flow components are important. PMID- 26232978 TI - On identifying relationships between the flood scaling exponent and basin attributes. AB - Floods are known to exhibit self-similarity and follow scaling laws that form the basis of regional flood frequency analysis. However, the relationship between basin attributes and the scaling behavior of floods is still not fully understood. Identifying these relationships is essential for drawing connections between hydrological processes in a basin and the flood response of the basin. The existing studies mostly rely on simulation models to draw these connections. This paper proposes a new methodology that draws connections between basin attributes and the flood scaling exponents by using observed data. In the proposed methodology, region-of-influence approach is used to delineate homogeneous regions for each gaging station. Ordinary least squares regression is then applied to estimate flood scaling exponents for each homogeneous region, and finally stepwise regression is used to identify basin attributes that affect flood scaling exponents. The effectiveness of the proposed methodology is tested by applying it to data from river basins in the United States. The results suggest that flood scaling exponent is small for regions having (i) large abstractions from precipitation in the form of large soil moisture storages and high evapotranspiration losses, and (ii) large fractions of overland flow compared to base flow, i.e., regions having fast-responding basins. Analysis of simple scaling and multiscaling of floods showed evidence of simple scaling for regions in which the snowfall dominates the total precipitation. PMID- 26232979 TI - Scaling and scale invariance of conservation laws in Reynolds transport theorem framework. AB - Scale invariance is the case where the solution of a physical process at a specified time-space scale can be linearly related to the solution of the processes at another time-space scale. Recent studies investigated the scale invariance conditions of hydrodynamic processes by applying the one-parameter Lie scaling transformations to the governing equations of the processes. Scale invariance of a physical process is usually achieved under certain conditions on the scaling ratios of the variables and parameters involved in the process. The foundational axioms of hydrodynamics are the conservation laws, namely, conservation of mass, conservation of linear momentum, and conservation of energy from continuum mechanics. They are formulated using the Reynolds transport theorem. Conventionally, Reynolds transport theorem formulates the conservation equations in integral form. Yet, differential form of the conservation equations can also be derived for an infinitesimal control volume. In the formulation of the governing equation of a process, one or more than one of the conservation laws and, some times, a constitutive relation are combined together. Differential forms of the conservation equations are used in the governing partial differential equation of the processes. Therefore, differential conservation equations constitute the fundamentals of the governing equations of the hydrodynamic processes. Applying the one-parameter Lie scaling transformation to the conservation laws in the Reynolds transport theorem framework instead of applying to the governing partial differential equations may lead to more fundamental conclusions on the scaling and scale invariance of the hydrodynamic processes. This study will investigate the scaling behavior and scale invariance conditions of the hydrodynamic processes by applying the one-parameter Lie scaling transformation to the conservation laws in the Reynolds transport theorem framework. PMID- 26232980 TI - Scaling of extreme rainfall areas at a planetary scale. AB - Event magnitude and area scaling relationships for rainfall over different regions of the world have been presented in the literature for relatively short durations and over relatively small areas. In this paper, we present the first ever results on a global analysis of the scaling characteristics of extreme rainfall areas for durations ranging from 1 to 30 days. Broken power law models are fit in each case. The past work has been focused largely on the time and space scales associated with local and regional convection. The work presented here suggests that power law scaling may also apply to planetary scale phenomenon, such as frontal and monsoonal systems, and their interaction with local moisture recycling. Such features may have persistence over large areas corresponding to extreme rain and regional flood events. As a result, they lead to considerable hazard exposure. A caveat is that methods used for empirical power law identification have difficulties with edge effects due to finite domains. This leads to problems with robust model identification and interpretability of the underlying relationships. We use recent algorithms that aim to address some of these issues in a principled way. Theoretical research that could explain why such results may emerge across the world, as analyzed for the first time in this paper, is needed. PMID- 26232981 TI - Classical and generalized Horton laws for peak flows in rainfall-runoff events. AB - The discovery of the Horton laws for hydrologic variables has greatly lagged behind geomorphology, which began with Robert Horton in 1945. We define the classical and the generalized Horton laws for peak flows in rainfall-runoff events, which link self-similarity in network geomorphology with river basin hydrology. Both the Horton laws are tested in the Iowa River basin in eastern Iowa that drains an area of approximately 32 400 km(2) before it joins the Mississippi River. The US Geological Survey continuously monitors the basin through 34 stream gauging stations. We select 51 rainfall-runoff events for carrying out the tests. Our findings support the existence of the classical and the generalized Horton laws for peak flows, which may be considered as a new hydrologic discovery. Three different methods are illustrated for estimating the Horton peak-flow ratio due to small sample size issues in peak flow data. We illustrate an application of the Horton laws for diagnosing parameterizations in a physical rainfall-runoff model. The ideas and developments presented here offer exciting new directions for hydrologic research and education. PMID- 26232982 TI - Statistical scaling, Shannon entropy, and Generalized space-time q-entropy of rainfall fields in tropical South America. AB - We study diverse scaling and information theory characteristics of Mesoscale Convective Systems (MCSs) as seen by the Tropical Rainfall Measuring Mission (TRMM) over continental and oceanic regions of tropical South America, and 2-D radar rainfall fields from Amazonia. The bi-dimensional Fourier spectra of MCSs exhibit inverse power laws with respect to the spatial scale, whose scaling exponents, beta, capture the type of spatial correlation of rainfall among the study regions, including those over the Andes of Colombia as well as over oceanic and Amazonian regions. The moment-scaling analysis evidences that the structure function deviates from simple scaling at order q > 1.0, thus signaling the multi scaling nature of rainfall fields within MCSs in tropical South America, with departures from simple scaling associated with the physical characteristics of MCSs over the different study regions. Entropy is estimated for a large set of radar rainfall fields during the distinctive atmospheric regimes (Easterly and Westerly events) in this part of Amazonia. Results evidence that there are significant differences in the dynamics of rainfall among regimes. No clear-cut relationship is found between entropy and the first two statistical moments, but power fits in space and time, S(gamma) ~ gamma(-eta) for skewness and, S(kappa) ~ kappa(-epsilon) for kurtosis. The exponents eta and epsilon are statistically different between Easterly and Westerly events, although the significance of fits is less when L-moments are used to estimate skewness and kurtosis. Interesting differences are identified between the time and space generalized q-entropy functions of Amazonian rainfall fields. In both cases, the functions are a continuous set of power laws (analogous to the structure function in turbulence), S(T, q) ~ T(beta), and, S(lambda, q) ~ lambda(beta), covering a broad range of temporal and spatial scales. Both time and space generalized q-entropy functions exhibit linear growth in the range -1.0 < q < -0.5, and saturation of the exponent beta for q >= 1.0. In the case of the spatial analysis, the exponent saturates at ~1.0, whereas at =0.5 for the temporal case. Results are similar for time series extracted from the S-POL radar and time series of rainfall in tropical Andes. Additionally, differences in values of for q >= 1.0 between Easterly and Westerly events are not statistically significant. PMID- 26232983 TI - The joint space-time statistics of macroweather precipitation, space-time statistical factorization and macroweather models. AB - Over the range of time scales from about 10 days to 30-100 years, in addition to the familiar weather and climate regimes, there is an intermediate "macroweather" regime characterized by negative temporal fluctuation exponents: implying that fluctuations tend to cancel each other out so that averages tend to converge. We show theoretically and numerically that macroweather precipitation can be modeled by a stochastic weather-climate model (the Climate Extended Fractionally Integrated Flux, model, CEFIF) first proposed for macroweather temperatures and we show numerically that a four parameter space-time CEFIF model can approximately reproduce eight or so empirical space-time exponents. In spite of this success, CEFIF is theoretically and numerically difficult to manage. We therefore propose a simplified stochastic model in which the temporal behavior is modeled as a fractional Gaussian noise but the spatial behaviour as a multifractal (climate) cascade: a spatial extension of the recently introduced ScaLIng Macroweather Model, SLIMM. Both the CEFIF and this spatial SLIMM model have a property often implicitly assumed by climatologists that climate statistics can be "homogenized" by normalizing them with the standard deviation of the anomalies. Physically, it means that the spatial macroweather variability corresponds to different climate zones that multiplicatively modulate the local, temporal statistics. This simplified macroweather model provides a framework for macroweather forecasting that exploits the system's long range memory and spatial correlations; for it, the forecasting problem has been solved. We test this factorization property and the model with the help of three centennial, global scale precipitation products that we analyze jointly in space and in time. PMID- 26232984 TI - Publisher's Note: "On identifying relationships between the flood scaling exponent and basin attributes" [Chaos 25, 075405 (2015)]. PMID- 26232986 TI - Specific miRNA and its target in neutrophils after traumatic injury. AB - Traumatic injury is a leading cause of mortality and morbidity. MicroRNAs (miRNAs) regulate the cellular responses when traumatic injury occurs. Previously, we reported that miR-3945, miR-125a-5p, miR-363-3p, and miR-150-5p were significantly altered in neutrophils of patients who suffered traumatic injury. In the present study, by comparing neutrophils of patients suffering from major trauma with neutrophils of patients with a inflammatory disease, we found that the variation trend of miR-150-5p was relatively different in the process of these two diseases. Gene Ontology and pathway analysis of miR-150-5p revealed that it may activate the mitogen-activated protein kinase and Toll-like receptor signaling pathways and cell adhesion molecules when the traumatic injury occurs. In addition, protein kinase C alpha (PRKCA) was also identified as a direct target of miR-150-5p by establishing a miRNA-mRNA network, and this target was validated via dual-luciferase reporter and western blot analysis. Our results suggested that the expression of miR-150-5p was down-regulated in neutrophils after a major traumatic injury. miR-150-5p and its identified target PRKCA play important roles in the development of traumatic process. PMID- 26232985 TI - No-React(r) Injectable BioPulmonicTM valves re-evaluated: discouraging follow-up results. AB - OBJECTIVES: The No-React(r) Injectable BioPulmonicTM valve (BioIntegral) was introduced for minimally invasive off-pump replacement of the pulmonary valve almost 10 years ago. We present our mid- to long-term follow-up results. METHODS: We conducted a retrospective analysis of all 7 patients treated at our institution at the median age of 9 (range 1-24) years. The children underwent cardiac catheterization when worsening strain on the right heart was suspected after examining their medical history and/or observing significant changes on echocardiography. RESULTS: After a median follow-up period lasting 5.2 (range 0.7 6.7) years, all patients presented the indication for recatheterization, particularly because the maximum instantaneous velocity measured by Doppler had revealed systolic gradients of a median 63 (dP 18-74) mmHg across the right ventricular outflow. Catheterization confirmed severe stenosis in 2, and moderate stenosis together with moderate insufficiency in 4 patients. We observed two principal failure mechanisms: technical problems resulting from poor alignment to the right ventricular outflow tract and structural problems leading to neointimal proliferation even in cases with appropriate prosthesis positioning. At median of 5.7 (0.7-7) years after implantation, 6 of the 7 patients underwent valve rereplacement. Redo surgery was necessary in 3, and percutaneous valve-in-valve implantation in the remaining 3 patients. Histological analysis of two explanted valves confirmed significant neointima proliferation and thickened valve cusps leading to stenosis of the graft. CONCLUSIONS: These mid-term results after implantation of the No-React(r) Injectable BioPulmonicTM valve are disappointing. Graft failure was mainly due to neointimal formation and valve malposition. PMID- 26232987 TI - Predicting Subjective Affective Salience from Cortical Responses to Invisible Object Stimuli. AB - The affective value of a stimulus substantially influences its potency to gain access to awareness. Here, we sought to elucidate the neural mechanisms underlying such affective salience in a combined behavioral and fMRI experiment. Healthy individuals with varying degrees of spider phobia were presented with pictures of spiders and flowers suppressed from view by continuous flash suppression. Applying multivoxel pattern analysis, we found that the average time that spider stimuli took relative to flowers to gain access to awareness in each participant could be decoded from fMRI signals evoked by suppressed spider versus flower stimuli in occipitotemporal and orbitofrontal cortex. Our results indicate neural signals during unconscious processing of complex visual information in orbitofrontal and ventral visual areas predict access to awareness of this information, suggesting a crucial role for these higher-level cortical regions in mediating affective salience. PMID- 26232988 TI - The Suppression of Beta Oscillations in the Primate Supplementary Motor Complex Reflects a Volatile State During the Updating of Action Sequences. AB - The medial motor areas play crucial but flexible roles in the temporal organizations of multiple movements. The beta oscillation of local field potentials is the predominant oscillatory activity in the motor areas, but the manner in which increases and decreases in beta power contribute to updating of multiple action plans is not yet fully understood. In the present study, beta and high-gamma activities in the supplementary motor area (SMA) and pre-SMA of monkeys were analyzed during performance of a bimanual motor sequence task that required updating and maintenance of the memory of action sequences. Beta power was attenuated during early delay periods of updating trials but was increased during maintenance trials, while there was a reciprocal increase in high-gamma power during updating trials. Moreover, transient attenuation of beta power during maintenance trials resulted in the erroneous selection of an action sequence. Therefore, it was concluded that the suppression of beta power during the early delay period reflects volatility of neural representation of the action sequence. This neural representation would be properly updated to the appropriate instructed action sequence via increases in high-gamma power in updating trials whereas it would be erroneously updated without the appropriate updating signal in maintenance trials. PMID- 26232990 TI - Linking extracellular electric potential in the brain to neural activity - a review of source localization and component identification methods. AB - Due to technological advances in electrophysiology, there is renewed interest in the analysis of local field potentials recorded at many sites simultaneously. In this paper the main problems related to the analysis of LFP are presented, and recent developments in the data analysis methods are reviewed. The focus of the paper is on reconstruction of current source den sity from extracellular recordings and on decomposition of neural activity into meaningful components. PMID- 26232989 TI - Association between Genetic Polymorphisms in DEFB1 and Susceptibility to Digestive Diseases. AB - BACKGROUND: Aberrant expression of defensins is implicated in the pathogenesis of digestive diseases. However, the contribution of specific defensins and the influence of their genetic polymorphisms on the progression of digestive diseases remain controversial. In the present meta-analysis, we investigated the association between DEFB1 SNPs and the susceptibility to digestive diseases. MATERIAL AND METHODS: Case-control studies that reported the correlation between DEFB1 SNPs and the susceptibility to digestive diseases were identified through electronic databases searches, and high-quality studies that satisfied our inclusion criteria were selected for this meta-analysis. Statistical analyses were performed utilizing STATA software version 12.0. RESULTS: The present meta analysis revealed that patients with digestive diseases exhibited higher frequencies of the DEFB1 genetic variants rs11362G>A, rs1800972C>G, and rs1799946G>A compared to healthy controls under the allele model. Subgroup analysis based on country showed that the rs1800972C>G variant under allele model and rs1799946G>A are associated with the susceptibility to digestive diseases in Hungarian and Italian populations, respectively. Subgroup analysis based on disease type showed that: (1) rs11362G>A variant was strongly associated with severe acute pancreatitis (SAP) and chronic gastritis, (2) frequency of rs1800972C>G variant was higher in SAP subgroup, and (3) frequency of rs1799946G>A variant was positively associated with the susceptibility to Crohn's disease (CD) under the allele model and with SAP. CONCLUSIONS : Our meta-analysis provides evidence that DEFB1 genetic polymorphisms rs11362G>A, rs1800972C>G and rs1799946G>A are important contributing factors to the development of digestive diseases. PMID- 26232991 TI - Molecular pathogenesis, experimental therapy and genetic counseling in hereditary sensory neuropathies. AB - Hereditary sensory and autonomic neuropathies (HSANs) represent a group of heritable peripheral nerve disorders usually taking a severe clinical course. HSAN-affected patients manifest with deep, poorly-healing ulcerations of the feet and hands. To date no definitive cure for HSANs has been developed and the molecular pathology of these disorders is complex. The aim of this review is therefore to present recent findings in terms of HSAN molecular pathogenesis. So far, mutations in 12 genes coding for different proteins have been reported in association with HSAN and the molecular pathogenesis has been elucidated in HSAN1a, HSAN4 and HSAN5. The genes involved in molecular pathogenesis of HSAN code for a wide spectrum of proteins from enzymes to specific nerve growth factors. As far as HSAN1a is concerned, the enhanced understanding has given rise to achievements in experimental therapy particularly in respect to disease models. Despite a rapid progress in studies on the molecular background of HSAN, numerous loci and genes remain still to be discovered. PMID- 26232993 TI - Zolpidem withdrawal induced uncoupling of GABA(A) receptors in vitro associated with altered GABA(A) receptor subunit mRNA expression. AB - Hypnotic zolpidem produces its effects via the benzodiazepine binding site in alpha1-containing GABAA receptors. The aim of the study was to assess the influence of duration of zolpidem treatment and its withdrawal, as well as the role of alpha1-containing GABAA receptors in the development of physical dependence and tolerance. Namely, recombinant receptors can be used to characterize mechanisms involved in different processes in the brain and to delineate the contribution of specific receptor subtypes. To address the influence of chronic zolpidem treatment we exposed HEK293 cells stably expressing alpha1beta2gamma2S recombinant GABAA receptors for seven consecutive days, while withdrawal periods lasted for 24, 48, 72 and 96 hours. Using radioligand binding studies we determined that chronic zolpidem treatment did not induce changes in either GABAA receptor number or in the expression of subunit mRNAs. We observed the enhancement of binding sites and upregulated expression of subunit mRNAs only following 96-hour withdrawal. Moreover, zolpidem treatment and its withdrawal (All time points) induced functional uncoupling between GABA and benzodiazepine binding sites in the GABAA receptor complex. Accordingly, it might be assumed that zolpidem withdrawal-induced uncoupling of GABAA receptors is associated with altered GABAA receptor subunit mRNA expression. The results presented here provide an insight into molecular and cellular mechanisms probably underlying adaptive changes of GABAA receptor function in response to chronic usage and withdrawal of zolpidem and perhaps the observed molecular changes could be linked to the tolerance and dependence produced upon prolonged treatment with other GABAergic drugs. PMID- 26232992 TI - Effect of MRI tags: SPIO nanoparticles and 19F nanoemulsion on various populations of mouse mesenchymal stem cells. AB - Transplantation of mesenchymal stem cells (MSCs) has emerged as a promising strategy for the treatment of myriad human disorders, including several neurological diseases. Superparamagnetic iron oxide nanoparticles (SPION) and fluorine nanoemulsion (19F) are characterized by low toxicity and good sensitivity, and, as such, are among the most frequently used cell-labeling agents. However, to date, their impact across the various populations of MSCs has not been comprehensively investigated. Thus, the impact of MRI tags (independent variable) has been set as a primary endpoint. The various populations of mouse MSCs in which the effect of tag was investigated consisted of (1) tissue of cell origin: bone marrow vs. Adipose tissue; (2) age of donor: young vs. old; (3) cell culture conditions: hypoxic vs. normal vs. normal + ascorbic acid (AA); (4) exposure to acidosis: yes vs. no. The impact of those populations has been also analyzed and considered as secondary endpoints. The experimental readouts (dependent variables) included: (1) cell viability; (2) cell size; (3) cell doubling time; (4) colony formation; (5) efficiency of labeling; and (6) cell migration. We did not identify any impact of cell labeling for these investigated populations in any of the readouts. In addition, we found that the harsh microenvironment of injured tissue modeled by a culture of cells in a highly acidic environment has a profound effect on all readouts, and both age of donor and cell origin tissue also have a substantial influence on most of the readouts, while oxygen tension in the cell culture conditions has a smaller impact on MSCs. A detailed characterization of the factors that influence the quality of MSCs is vital to the proper pursuit of preclinical and clinical studies. PMID- 26232994 TI - The influence of BDNF on human umbilical cord blood stem/progenitor cells: implications for stem cell-based therapy of neurodegenerative disorders. AB - Umbilical cord blood (UCB)-derived stem/progenitor cells (SPCs) have demonstrated the potential to improve neurologic function in different experimental models. SPCs can survive after transplantation in the neural microenvironment and indu ce neuroprotection, endogenous neurogenesis by secreting a broad repertoire of trophic and immunomodulatory cytokines. In this study, the influence of brain derived neurotrophic factor (BDNF) pre-treatment was comprehensively evaluated in a UCB-derived lineage-negative (Lin-) SPC population. UCB-derived Lin- cells were evaluated with respect to the expression of (i) neuronal markers using immunofluorescence staining and (ii) specific (TrkB) receptors for BDNF using flow cytometry. Next, after BDNF pre-treatment, Lin- cells were extensively assessed with respect to apoptosis using Western blotting and proliferation via BrdU incorporation. Furthermore, NT-3 expression levels in Lin- cells using RQ PCR and antioxidative enzyme activities were assessed. We demonstrated neuronal markers as well as TrkB expression in Lin- cells and the activation of the TrkB receptor by BDNF. BDNF pre-treatment diminished apoptosis in Lin- cells and influenced the proliferation of these cells. We observed significant changes in antioxidants as well as in the increased expression of NT-3 in Lin- cells following BDNF exposure. Complex global miRNA and mRNA profiling analyses using microarray technology and GSEA revealed the differential regulation of genes involved in the proliferation, gene expression, biosynthetic processes, translation, and protein targeting. Our results support the hypothesis that pre treatment of stem/progenitor cells could be beneficial and may be used as an auxiliary strategy for improving the properties of SPCs. PMID- 26232995 TI - Long-term ascorbic acid administration causes anticonvulsant activity during moderate and long-duration swimming exercise in experimental epilepsy. AB - The benefits of regular exercise on brain health are undeniable. Long-term exercise increases the production of reactive oxygen species in brain. Therefore, athletes often consume antioxidant supplements to remedy exercise-related damage and fatigue during exercise. The aim of this study is to evaluate the role of ascorbic acid in the effects of different intensities of swimming exercise on the brain susceptibility to experimental epilepsy in rats. Ascorbic acid was administered intraperitoneally (ip) during three different swimming exercise programme for 90 days (15 min, 30 min, 90 min/day). The anticonvulsant activity regarding the frequency of epileptiform activity appeared in the 80 min after 500 units intracortical penicillin injection in 30 min and 90 min/day exercise groups. The administration of ascorbic acid (100 mg/kg, ip) did not alter the anticonvulsant properties seen in the in short-duration (15 min/day) swimming exercise group. The amplitude of epileptiform activity also became significant in the 110 and 120 min after penicillin injection in the moderate (30 min/day) and long duration (60 min/day) groups, respectively. The results of the present study provide electrophysiologic evidence that long-term administration of ascorbic acid causes anticonvulsant activities in the moderate and long-duration swimming exercise. Antioxidant supplementation such as ascorbic acid might be suggested for moderate and long-duration swimming exercise in epilepsy. PMID- 26232996 TI - Effects of intracortical microinjection of vitamin B12 on penicillin-induced epileptiform activity in rats. AB - There are increasing studies indicating neuroprotective effects for vitamin B12. In the present study, the effect of intracortical microinjection of vitamin B12 was investigated on penicillin-induced epileptiform activity. We also examined the effects of intracortical microinjection of diazepam (a GABA-benzodiazepine receptor agonist) and flumazenil (a GABAbenzodiazepine receptor antagonist) to clarify the possible mechanism of vitamin B12. In urethane-anesthetized rats, epileptiform activity was induced by intracortical microinjection of penicillin (300 IU, 1.5 microL), and the number and amplitude of spike waves were analyzed using electroencephalographic (EEG) recordings. Intracortical microinjections of vitamin B12 at doses of 100 and 200 ng/site, diazepam at a dose of 200 ng/site and their ineffective doses (50 ng/site of vitamin B12 with 50 ng/site of diazepam) co-microinjection treatment significantly (P less than 0.05) reduced both the number and amplitude of spike waves. In addition, combined microinjection of effective doses of vitamin B12 (100 ng/site) and diazepam (200 ng/site) produced more antiepileptiform effect in comparison with their alone used doses. The antiepileptic effects induced by microinjection of vitamin B12 and diazepam at a same dose of 200 ng/site were prevented by the same site microinjection of 50 ng/site of flumazenil. The results showed antiepileptiform activities for vitamin B12 and diazepam AT the cerebral cortex level. A central GABA-benzodiazepine receptor complex-mediated mechanism might be involved in the antiepileptiform activity of vitamin B12. PMID- 26232997 TI - Protective effect of crocin on acrolein-induced tau phosphorylation in the rat brain. AB - Acrolein, as a by-product of lipid peroxidation, is implicated in brain aging and in the pathogenesis of oxidative stressmediated neurodegenerative disorders such as Alzheimer's disease (AD). Widespread human exposure to the toxic environmental pollutant that is acrolein renders it necessary to evaluate the effects of exogenous acrolein on the brain. This study investigated the toxic effects of oral administration of 3 mg/kg/day acrolein on the rat cerebral cortex. Moreover, the neuroprotective effects of crocin, the main constituent of saffron, against acrolein toxicity were evaluated. We showed that acrolein decreased concentration of glutathione (GSH) and increased levels of malondialdehyde (MDA), Amyloid-beta (Abeta) and phospho-tau in the brain. Simultaneously, acrolein activated Mitogen Activated Protein Kinases (MAPKs) signalling pathways. Co-administration of crocin significantly attenuated MDA, Abeta and p-tau levels by modulating MAPKs signalling pathways. Our data demonstrated that environmental exposure to acrolein triggers some molecular events which contribute to brain aging and neurodisorders. Additionally, crocin as an antioxidant is a promising candidate for treatment of neurodegenerative disorders, such as brain aging and AD. PMID- 26232998 TI - Comparative immunohistochemical study of the effects of pilocarpine on the mossy cells, mossy fibres and inhibitory neurones in murine dentate gyrus. AB - Treatment with pilocarpine (PILO) induces variable degrees of loss of mossy cells (MCs) and mossy fibre (MF) sprouting in rodents, the relationships of which have not been examined in individual animals. Our aim was to test whether the loss of MCs and MF sprouting are coupled processes in PILO-treated rodents. Animals which exhibited intense PILO-induced convulsions for at least 30 min were used in this study. After a 2-month survival period, the incidence of epileptic seizures was checked individually by neuropeptide-Y (NPY) immunohistochemistry, and the numbers of MCs were counted by means of immunohistochemistry, for calretinin (CR) in mice and calcitonin gene-related peptide (CGRP) in rats. MF sprouting was checked by using Timm's silver-sulphide method for zinc. In our comparative studies, NPY immunohistochemistry resulted in more positive animals than on zinc staining. The CR immunoreactivity remained unchanged even in those mice that displayed MF sprouting and greatly increased NPY immunoreactivity. CR immunoreactivity was also verified after transection of the fornix to exclude the extrahippocampal source of this peptide. However, the CGRP immunoreactivity was severely reduced in those rats that exhibited simultaneous increases in zinc content and NPY immunoreactivity in the supragranular layer and stratum lucidum. Our findings suggest that the MCs survive PILO treatment in mice, but not in rats. There is direct evidence of a close relationship between the loss of MCs and MF sprouting in rats, but not in mice. Thus, similar PILO seizures may result from different changes in the neuronal circuits of rodents. PMID- 26232999 TI - A quantitative analysis of illusion magnitude changes induced by rotation of contextual distractor. AB - In the present study, the predictions of the computational model of centroid extraction were verified in psychophysical examination of the length illusion induced by stimuli comprising the conventional or asymmetric Muller-Lyer wings as the contextual distractors. In experiments, the illusion magnitude changes evoked by rotation of distractors with different spatial parameters were quantitatively determined. It was demonstrated that the model calculations adequately account for the illusion magnitude variations shown by all the subjects for all modifications of stimuli. A good correspondence between the experimental and theoretical data supports the suggestion that local positional biases caused by the neural processes of automatic centroid extraction can be one of the main reasons of emergence of illusions of the Muller-Lyer type. PMID- 26233000 TI - Perceptual evaluation of voice source models. AB - Models of the voice source differ in their fits to natural voices, but it is unclear which differences in fit are perceptually salient. This study examined the relationship between the fit of five voice source models to 40 natural voices, and the degree of perceptual match among stimuli synthesized with each of the modeled sources. Listeners completed a visual sort-and-rate task to compare versions of each voice created with the different source models, and the results were analyzed using multidimensional scaling. Neither fits to pulse shapes nor fits to landmark points on the pulses predicted observed differences in quality. Further, the source models fit the opening phase of the glottal pulses better than they fit the closing phase, but at the same time similarity in quality was better predicted by the timing and amplitude of the negative peak of the flow derivative (part of the closing phase) than by the timing and/or amplitude of peak glottal opening. Results indicate that simply knowing how (or how well) a particular source model fits or does not fit a target source pulse in the time domain provides little insight into what aspects of the voice source are important to listeners. PMID- 26233001 TI - Structural sensing of interior sound for active control of noise in structural acoustic cavities. AB - This paper proposes a method for structural sensing of acoustic potential energy for active control of noise in a structural-acoustic cavity. The sensing strategy aims at global control and works with a fewer number of sensors. It is based on the established concept of radiation modes and hence does not add too many states to the order of the system. Acoustic potential energy is sensed using a combination of a Kalman filter and a frequency weighting filter with the structural response measurements as the inputs. The use of Kalman filter also makes the system robust against measurement noise. The formulation of the strategy is presented using finite element models of the system including that of sensors and actuators so that it can be easily applied to practical systems. The sensing strategy is numerically evaluated in the framework of Linear Quadratic Gaussian based feedback control of interior noise in a rectangular box cavity with a flexible plate with single and multiple pairs of piezoelectric sensor actuator patches when broadband disturbances act on the plate. The performance is compared with an "acoustic filter" that models the complete transfer function from the structure to the acoustic domain. The sensing performance is also compared with a direct estimation strategy. PMID- 26233002 TI - Erratum: Accounting for binaural detection as a function of masker interaural correlation: Effects of center frequency and bandwidth [J. Acoust. Soc. Am. 136, 3211-3220 (2014)]. PMID- 26233003 TI - Viscous torque on spherical micro particles in two orthogonal acoustic standing wave fields. AB - This paper reports the experimental results of the acoustic rotation of spherical micro particles because of two orthogonal standing waves. When the standing waves are excited at equal frequency but with a phase shift between two external voltage signals there is an acoustic streaming around the particles. This streaming is due to a time averaging of the acoustic wave field and produces a nonzero viscous torque on the particles, driving them to rotate. The work investigates the micro-particle rotation due to the viscous torque and predict the particle's steady state rotational velocity. The previous theoretical discussions [Nyborg, J. Acoust. Soc. Am. 85, 329-339 (1958); Lee and Wang, J. Acoust. Soc. Am. 85, 1081-1088 (1989)] of the viscous torque on a non-rotating sphere are expanded to allow free rotations. The analytical calculations provide a deeper understanding of the viscous torque and explain the experimental observations of rotating particles. A macroscopic experimental device is designed to provide the necessary boundary conditions for the viscous torque to rotate spherical particles. The experiments not only show good agreement with the analysis, but also demonstrate that the viscous torque due to acoustic streaming may dominate for the case of near-spherical particle dynamics. PMID- 26233005 TI - A proposed mechanism for rapid adaptation to spectrally distorted speech. AB - The mechanisms underlying perceptual adaptation to severely spectrally-distorted speech were studied by training participants to comprehend spectrally-rotated speech, which is obtained by inverting the speech spectrum. Spectral-rotation produces severe distortion confined to the spectral domain while preserving temporal trajectories. During five 1-hour training sessions, pairs of participants attempted to extract spoken messages from the spectrally-rotated speech of their training partner. Data on training-induced changes in comprehension of spectrally-rotated sentences and identification/discrimination of spectrally-rotated phonemes were used to evaluate the plausibility of three different classes of underlying perceptual mechanisms: (1) phonemic remapping (the formation of new phonemic categories that specifically incorporate spectrally-rotated acoustic information); (2) experience-dependent generation of a perceptual "inverse-transform" that compensates for spectral-rotation; and (3) changes in cue weighting (the identification of sets of acoustic cues least affected by spectral-rotation, followed by a rapid shift in perceptual emphasis to favour those cues, combined with the recruitment of the same type of "perceptual filling-in" mechanisms used to disambiguate speech-in-noise). Results exclusively support the third mechanism, which is the only one predicting that learning would specifically target temporally-dynamic cues that were transmitting phonetic information most stably in spite of spectral-distortion. No support was found for phonemic remapping or for inverse-transform generation. PMID- 26233004 TI - Segregating two simultaneous sounds in elevation using temporal envelope: Human psychophysics and a physiological model. AB - The ability to segregate simultaneous sound sources based on their spatial locations is an important aspect of auditory scene analysis. While the role of sound azimuth in segregation is well studied, the contribution of sound elevation remains unknown. Although previous studies in humans suggest that elevation cues alone are not sufficient to segregate simultaneous broadband sources, the current study demonstrates they can suffice. Listeners segregating a temporally modulated noise target from a simultaneous unmodulated noise distracter differing in elevation fall into two statistically distinct groups: one that identifies target direction accurately across a wide range of modulation frequencies (MF) and one that cannot identify target direction accurately and, on average, reports the opposite direction of the target for low MF. A non-spiking model of inferior colliculus neurons that process single-source elevation cues suggests that the performance of both listener groups at the population level can be accounted for by the balance of excitatory and inhibitory inputs in the model. These results establish the potential for broadband elevation cues to contribute to the computations underlying sound source segregation and suggest a potential mechanism underlying this contribution. PMID- 26233006 TI - Influence of sound-conditioning on noise-induced susceptibility of distortion product otoacoustic emissions. AB - Cochlear damage caused by loud sounds can be attenuated by "sound-conditioning" methods. The amount of adaptation for distortion product otoacoustic emissions (DPOAEs) measured in alert rabbits previously predicted an ear's susceptibility to a subsequent noise exposure. The present study investigated if sound conditioning influenced the robustness of such DPOAE adaptation, and if such conditioning elicited more protection by increasing the amount of DPOAE adaptation. Toward this end, rabbits were divided into two study groups: (1) experimental animals exposed to a sound-conditioning protocol, and (2) unconditioned control animals. After base-line measures, all rabbits were exposed to an overstimulation paradigm consisting of an octave band noise, and then re assessed 3 weeks post-exposure to determine permanent changes in DPOAEs. A major result was that prior sound-conditioning protected reductions in DPOAE levels by an average of 10-15 dB. However, DPOAE adaptation decreased with sound conditioning, so that such conditioning was no longer related to noise-induced reductions in DPOAEs. Together, these findings suggest that sound-conditioning affected neural pathways other than those that likely mediate DPOAE adaptation (e.g., medial olivocochlear efferent and/or middle-ear muscle reflexes). PMID- 26233007 TI - Vowel identification by cochlear implant users: Contributions of duration cues and dynamic spectral cues. AB - A recent study from our laboratory assessed vowel identification in cochlear implant (CI) users, using full /dVd/ syllables and partial (center- and edges only) syllables with duration cues neutralized [Donaldson, Rogers, Cardenas, Russell, and Hanna (2013). J. Acoust. Soc. Am. 134, 3021-3028]. CI users' poorer performance for partial syllables as compared to full syllables, and for edges only syllables as compared to center-only syllables, led to the hypotheses (1) that CI users may rely strongly on vowel duration cues; and (2) that CI users have more limited access to dynamic spectral cues than steady-state spectral cues. The present study tested those hypotheses. Ten CI users and ten young normal hearing (YNH) listeners heard full /dVd/ syllables and modified (center- and edges-only) syllables in which vowel duration cues were either preserved or eliminated. The presence of duration cues significantly improved vowel identification scores in four CI users, suggesting a strong reliance on duration cues. Duration effects were absent for the other CI users and the YNH listeners. On average, CI users and YNH listeners demonstrated similar performance for center-only stimuli and edges-only stimuli having the same total duration of vowel information. However, three CI users demonstrated significantly poorer performance for the edges-only stimuli, indicating apparent deficits of dynamic spectral processing. PMID- 26233008 TI - Evaluation and analysis of whispered speech for cochlear implant users: Gender identification and intelligibility. AB - This study investigates the degree to which whispered speech impacts speech perception and gender identification in cochlear implant (CI) users. Listening experiments with six CI subjects under neutral and whispered speech conditions using sentences from the UT-Vocal Effort II corpus (recordings from male and female speakers) were conducted. Results indicated a significant effect of whispering on gender identification and speech intelligibility scores. In addition, no significant effect of talker gender on the speech/gender identification scores was observed. Results also suggested that exposure to longer speech stimuli, and consequently more temporal cues, would not improve gender identification performance in CI subjects. PMID- 26233010 TI - Analysis of an impulse response measured at the basilar membrane of the chinchilla. AB - In a recent paper [J. Acoust. Soc. Am. 133, 2224-2239 (2013)], Shera and Cooper report on the impulse response of the basilar membrane (BM) of a chinchilla, a waveform which shows repetitive bursts. They explain the bursts in terms of repeated coherent reflection at BM discontinuities and partial reflection at the stapes ("coherent reflection filtering"). Here the same waveform is examined in detail, highlighting features which indicate that the coherent reflection model, with calls for the same repetitive process to act on each successive burst, does not fully account for the shape of the measured impulse response. PMID- 26233011 TI - Auditory attention strategy depends on target linguistic properties and spatial configuration. AB - Whether crossing a busy intersection or attending a large dinner party, listeners sometimes need to attend to multiple spatially distributed sound sources or streams concurrently. How they achieve this is not clear-some studies suggest that listeners cannot truly simultaneously attend to separate streams, but instead combine attention switching with short-term memory to achieve something resembling divided attention. This paper presents two oddball detection experiments designed to investigate whether directing attention to phonetic versus semantic properties of the attended speech impacts listeners' ability to divide their auditory attention across spatial locations. Each experiment uses four spatially distinct streams of monosyllabic words, variation in cue type (providing phonetic or semantic information), and requiring attention to one or two locations. A rapid button-press response paradigm is employed to minimize the role of short-term memory in performing the task. Results show that differences in the spatial configuration of attended and unattended streams interact with linguistic properties of the speech streams to impact performance. Additionally, listeners may leverage phonetic information to make oddball detection judgments even when oddballs are semantically defined. Both of these effects appear to be mediated by the overall complexity of the acoustic scene. PMID- 26233012 TI - Evaluation of a spectral subtraction strategy to suppress reverberant energy in cochlear implant devices. AB - The smearing effects of room reverberation can significantly impair the ability of cochlear implant (CI) listeners to understand speech. To ameliorate the effects of reverberation, current dereverberation algorithms focus on recovering the direct sound from the reverberated signal by inverse filtering the reverberation process. This contribution describes and evaluates a spectral subtraction (SS) strategy capable of suppressing late reflections. Late reflections are the most detrimental to speech intelligibility by CI listeners as reverberation increases. By tackling only the late part of reflections, it is shown that users of CI devices can benefit from the proposed strategy even in highly reverberant rooms. The proposed strategy is also compared against an ideal reverberant (binary) masking approach. Speech intelligibility results indicate that the proposed SS solution is able to suppress additive reverberant energy to a degree comparable to that achieved by an ideal binary mask. The added advantage is that the SS strategy proposed in this work can allow for a potentially real time implementation in clinical CI processors. PMID- 26233014 TI - Measurements of ultrasonic diffusivity and transport speed from coda waves in a resonant multiple scattering medium. AB - Frequency-resolved experimental measurements of ultrasonic diffusivity in the MHz range are presented. The samples under study are two-dimensional random arrangements of parallel steel rods immersed in water and exhibit high-order multiple scattering. Their physical characteristics, particularly the density and pair-correlation functions of the scatterers, are well controlled. These synthetic samples are used as phantoms for actual inhomogeneous materials. The resonant nature of the scatterers has a strong effect on diffusivity, which is shown to vary significantly with frequency. This may affect the result of broadband measurements of apparent diffusivity, which can be expected to depend on time and sample thickness, whereas diffusivity is intrinsically an intensive parameter. Moreover, the transport speed is shown to vary drastically with frequency, sometimes by more than 50%, due to a very narrow resonance that slows down transport. Interestingly, this sharp resonance could only be revealed by experiments performed with coda waves, and not with ballistic or coherent waves whose frequency resolution is intrinsically limited from an experimental point of view. PMID- 26233013 TI - Temporal weighting of binaural information at low frequencies: Discrimination of dynamic interaural time and level differences. AB - The importance of sound onsets in binaural hearing has been addressed in many studies, particularly at high frequencies, where the onset of the envelope may carry much of the useful binaural information. Some studies suggest that sound onsets might play a similar role in the processing of binaural cues [e.g., fine structure interaural time differences (ITD)] at low frequencies. This study measured listeners' sensitivity to ITD and interaural level differences (ILD) present in early (i.e., onset) and late parts of 80-ms pure tones of 250-, 500-, and 1000-Hz frequency. Following previous studies, tones carried static interaural cues or dynamic cues that peaked at sound onset and diminished to zero at sound offset or vice versa. Although better thresholds were observed in static than dynamic conditions overall, ITD discrimination was especially impaired, regardless of frequency, when cues were not available at sound onset. Results for ILD followed a similar pattern at 1000 Hz; at lower frequencies, ILD thresholds did not differ significantly between dynamic-cue conditions. The results support the "onset" hypothesis of Houtgast and Plomp [(1968). J. Acoust. Soc. Am. 44, 807 812] for ITD discrimination, but not necessarily ILD discrimination, in low frequency pure tones. PMID- 26233015 TI - Laryngeal flow due to longitudinal sweeping motion of the vocal folds and its contribution to auto-oscillation. AB - Analysis of published depth-kymography data [George, de Mul, Qiu, Rakhorst, and Schutte (2008). Phys. Med. Biol. 53, 2667-2675] shows that, for the subject studied, the flow due to the longitudinal sweeping motion of the vocal folds contributes several percent of a typical acoustic flow at the larynx. This sweeping flow is a maximum when the glottis is closed. This observation suggests that assumption of zero laryngeal flow during the closed phase as a criterion when determining parameters in inverse filtering should be used with caution. Further, these data suggest that the swinging motion contributes work to overcome mechanical losses and thus to assist auto-oscillation. PMID- 26233016 TI - Modeling distance-dependent individual head-related transfer functions in the horizontal plane using frontal projection headphones. AB - The veracity of virtual audio is degraded by the use of non-individualized head related transfer functions (HRTFs) due to the introduction of front-back, elevation confusions, and timbral coloration. Hence, an accurate reproduction of spatial sound demands the use of individualized HRTFs. Measuring distance dependent individualized HRTFs can be extremely tedious, since it requires precise measurements at several distances in the proximal region (<1 m) for each individual. This paper proposes a technique to model distance-dependent individualized HRTFs in the horizontal plane using "frontal projection headphones playback" that does not require individualized measurements. The frontal projection headphones [Sunder, Tan, and Gan (2013). J. Audio Eng. Soc. 61, 989 1000] project the sound directly onto the pinnae from the front, and thus inherently create listener's idiosyncratic pinna cues at the eardrum. Perceptual experiments were conducted to investigate cues (auditory parallax and interaural level differences) that aid distance perception in anechoic conditions. Interaural level differences were identified as the prominent cue for distance perception and a spherical head model was used to model these distance-dependent features. Detailed psychophysical experiments revealed that the modeled distance dependent individualized HRTFs exhibited localization performance close to the measured distance-dependent individualized HRTFs for all subjects. PMID- 26233017 TI - Improving the efficiency of deconvolution algorithms for sound source localization. AB - The localization of sound sources with delay-and-sum (DAS) beamforming is limited by a poor spatial resolution-particularly at low frequencies. Various methods based on deconvolution are examined to improve the resolution of the beamforming map, which can be modeled by a convolution of the unknown acoustic source distribution and the beamformer's response to a point source, i.e., point-spread function. A significant limitation of deconvolution is, however, an additional computational effort compared to beamforming. In this paper, computationally efficient deconvolution algorithms are examined with computer simulations and experimental data. Specifically, the deconvolution problem is solved with a fast gradient projection method called Fast Iterative Shrikage-Thresholding Algorithm (FISTA), and compared with a Fourier-based non-negative least squares algorithm. The results indicate that FISTA tends to provide an improved spatial resolution and is up to 30% faster and more robust to noise. In the spirit of reproducible research, the source code is available online. PMID- 26233018 TI - Experimental analysis of the relationship between reverberant acoustic intensity and energy density inside long rooms. AB - In this paper, the validity of the Fick's law of diffusion in room acoustics is experimentally investigated inside long rooms. The room-acoustics diffusion model relies on Fick's law stating a proportionality relationship between sound intensity and energy density gradient inside a room through a constant diffusion coefficient. This relationship is investigated in the stationary state for the particular case of long rooms with different amounts of boundary scattering. Measurements were performed inside a 1:16 scale model, using a p-u sound intensity probe (calibrated with digital filters) to collect concurrent data in terms of sound pressure and axial velocity components. Then for each receiver position, sound intensity and energy density gradient were derived. The results show that inside long rooms the diffusion coefficient is not a constant but increases with the distance from the source with a slope depending on the scattering coefficient of the walls. Numerical simulations of the enclosures were performed too by using a sound particle-tracing code; a substantial agreement with the experimental findings is observed. The results imply that for such long enclosures, the diffusion model should consider a space-varying diffusion coefficient to be more consistent with real phenomena. PMID- 26233019 TI - Nonlinear response to a click in a time-domain model of the mammalian ear. AB - In this paper, a state-space implementation of a previously developed frequency domain model of the cochlea is coupled to a lumped parameter model of the middle ear. After validation of the time-domain model by comparison of its steady-state response to results obtained with a frequency-domain formulation, the nonlinear response of the cochlea to clicks is investigated. As observed experimentally, a compressive nonlinearity progressively develops within the first few cycles of the response of the basilar membrane (BM). Furthermore, a time-frequency analysis shows that the instantaneous frequency of the BM response to a click progressively approaches the characteristic frequency. This phenomenon, called glide, is predicted at all stimulus intensities, as in experiments. In typical experiments with sensitive animals, the click response is characterized by a long ringing and the response envelope includes several lobes. In order to achieve similar results, inhomogeneities are introduced in the cochlear model. Simulations demonstrate the strong link between characteristics of the frequency response, such as dispersion and frequency-dependent nonlinearity, and characteristics of the time-domain response, such as the glide and a time dependent nonlinearity. The progressive buildup of cochlear nonlinearity in response to a click is shown to be a consequence of the glide and of frequency dependent nonlinearity. PMID- 26233021 TI - How the thermocline affects the value of the waveguide invariant in a shallow water waveguide. AB - On the basis of the principle of stationary phase, Chuprov [Ocean Acoustics: Current State (Nauka, Moscow, 1982)] proposed a scalar parameter-the waveguide invariant beta, to interpret the dispersive properties of underwater acoustic waveguide. It has been found that beta may be useful in many applications in underwater acoustics. A reasonable prediction of the value of beta is often necessary in such applications. It was known that beta has some "canonical" values for waveguides with simple sound speed profiles (SSP). When a thermocline exists, beta for refractive modes (with a turning point) is no longer constant and can even change its sign. In this paper, by dividing the SSP into the non refractive part and the refractive part, a clear explanation of how the value of beta is affected by the thermocline is presented. The results show that beta can be positive and increase continually from around 1 to +infinity; or negative from -infinity to about -3. An analytic criterion of the sign of beta is developed. This method can also be used to analyze the value of beta for any other kind of SSP. PMID- 26233020 TI - Numerical calculation of listener-specific head-related transfer functions and sound localization: Microphone model and mesh discretization. AB - Head-related transfer functions (HRTFs) can be numerically calculated by applying the boundary element method on the geometry of a listener's head and pinnae. The calculation results are defined by geometrical, numerical, and acoustical parameters like the microphone used in acoustic measurements. The scope of this study was to estimate requirements on the size and position of the microphone model and on the discretization of the boundary geometry as triangular polygon mesh for accurate sound localization. The evaluation involved the analysis of localization errors predicted by a sagittal-plane localization model, the comparison of equivalent head radii estimated by a time-of-arrival model, and the analysis of actual localization errors obtained in a sound-localization experiment. While the average edge length (AEL) of the mesh had a negligible effect on localization performance in the lateral dimension, the localization performance in sagittal planes, however, degraded for larger AELs with the geometrical error as dominant factor. A microphone position at an arbitrary position at the entrance of the ear canal, a microphone size of 1 mm radius, and a mesh with 1 mm AEL yielded a localization performance similar to or better than observed with acoustically measured HRTFs. PMID- 26233022 TI - Locating and characterizing a crack in concrete with diffuse ultrasound: A four point bending test. AB - This paper describes an original imaging technique, named Locadiff, that benefits from the diffuse effect of ultrasound waves in concrete to detect and locate mechanical changes associated with the opening of pre-existing cracks, and/or to the development of diffuse damage at the tip of the crack. After giving a brief overview of the theoretical model to describe the decorrelation of diffuse waveforms induced by a local change, the article introduces the inversion procedure that produces the three dimensional maps of density of changes. These maps are interpreted in terms of mechanical changes, fracture opening, and damage development. In addition, each fracture is characterized by its effective scattering cross section. PMID- 26233023 TI - Experimental and numerical study of the excitability of zero group velocity Lamb waves by laser-ultrasound. AB - The excitability of zero group velocity (ZGV) Lamb waves using a pulsed laser source is investigated experimentally and through numerical simulation. Experimentally, a laser based ultrasonic technique is used to find the optical spot size on the sample surface that allows an optimal coupling of the optical energy into the ZGV mode. Numerical simulations, using the time domain finite differences technique, are carried out to model the thermoelastic generation process by laser irradiation and the propagation of the generated acoustic waves. The experimental results are in good agreement with the numerical predictions. The experimentally and numerically obtained responses of the plate are investigated by a short-time Fourier transform. The responses show that the source diameter does not affect the fundamental behavior of the temporal decay of the ZGV mode. PMID- 26233024 TI - Killer whale call frequency is similar across the oceans, but varies across sympatric ecotypes. AB - Killer whale populations may differ in genetics, morphology, ecology, and behavior. In the North Pacific, two sympatric populations ("resident" and "transient") specialize on different prey (fish and marine mammals) and retain reproductive isolation. In the eastern North Atlantic, whales from the same populations have been observed feeding on both fish and marine mammals. Fish eating North Pacific "residents" are more genetically related to eastern North Atlantic killer whales than to sympatric mammal-eating "transients." In this paper, a comparison of frequency variables in killer whale calls recorded from four North Pacific resident, two North Pacific transient, and two eastern North Atlantic populations is reported to assess which factors drive the large-scale changes in call structure. Both low-frequency and high-frequency components of North Pacific transient killer whale calls have significantly lower frequencies than those of the North Pacific resident and North Atlantic populations. The difference in frequencies could be related to ecological specialization or to the phylogenetic history of these populations. North Pacific transient killer whales may have genetically inherited predisposition toward lower frequencies that may shape their learned repertoires. PMID- 26233025 TI - A computational method to predict and study underwater noise due to pile driving. AB - A hybrid modeling approach that uses the parabolic equation (PE) with an empirical source model is presented to study and predict the underwater noise due to pile driving in shallow, inhomogeneous environments over long propagation ranges. The empirical source model uses a phased point source array to simulate the time-dependent pile source. The pile source is coupled with a broadband application of a PE wave propagation model that includes range dependent geoacoustic properties and bathymetry. Simulation results are shown to be in good agreement with several acoustic observations of pile driving in the Columbia River between Portland, OR and Vancouver, WA. The model is further applied to predict sound levels in the Columbia River and study the effects of variable bathymetry and sediment configurations on underwater sound levels. PMID- 26233026 TI - Effects of subsampling of passive acoustic recordings on acoustic metrics. AB - Passive acoustic monitoring is an important tool in marine mammal studies. However, logistics and finances frequently constrain the number and servicing schedules of acoustic recorders, requiring a trade-off between deployment periods and sampling continuity, i.e., the implementation of a subsampling scheme. Optimizing such schemes to each project's specific research questions is desirable. This study investigates the impact of subsampling on the accuracy of two common metrics, acoustic presence and call rate, for different vocalization patterns (regimes) of baleen whales: (1) variable vocal activity, (2) vocalizations organized in song bouts, and (3) vocal activity with diel patterns. To this end, above metrics are compared for continuous and subsampled data subject to different sampling strategies, covering duty cycles between 50% and 2%. The results show that a reduction of the duty cycle impacts negatively on the accuracy of both acoustic presence and call rate estimates. For a given duty cycle, frequent short listening periods improve accuracy of daily acoustic presence estimates over few long listening periods. Overall, subsampling effects are most pronounced for low and/or temporally clustered vocal activity. These findings illustrate the importance of informed decisions when applying subsampling strategies to passive acoustic recordings or analyses for a given target species. PMID- 26233029 TI - Perceptual space, pleasantness and periodicity of multi-tone sounds. AB - Technical sounds often contain several tonal components, forming a multi-tone sound. The present study investigates the perception of multi-tone sounds consisting of two harmonic complexes with different fundamental frequencies and combination tones with frequencies that are equal to the sum of multiple integers of the two fundamentals. The experimental parameter is the ratio between the two fundamental frequencies rho. A total of 15 synthetic multi-tone sounds are rated by 37 participants. In the first experiment, the perceptual space is assessed based on 16 adjective scales using categorical scaling. The resulting perceptual space has the four dimensions (i) pleasant, (ii) power, (iii) temporal structure, and (iv) spectral content of the sounds. In the second experiment, the pleasantness is measured with a paired comparison test. The data consistently show that sounds based on ratios of small integers (e.g., rho=4:3) are significantly less pleasant than sounds with ratios based on large integers which were constructed by a slight detuning from a ratio of small integers. The repetition rate derived from an autocorrelation analysis of the stimuli turns out to be a good predictor of the (un-)pleasantness sensation. PMID- 26233027 TI - Amplitude modulation reduces loudness adaptation to high-frequency tones. AB - Long-term loudness perception of a sound has been presumed to depend on the spatial distribution of activated auditory nerve fibers as well as their temporal firing pattern. The relative contributions of those two factors were investigated by measuring loudness adaptation to sinusoidally amplitude-modulated 12-kHz tones. The tones had a total duration of 180 s and were either unmodulated or 100%-modulated at one of three frequencies (4, 20, or 100 Hz), and additionally varied in modulation depth from 0% to 100% at the 4-Hz frequency only. Every 30 s, normal-hearing subjects estimated the loudness of one of the stimuli played at 15 dB above threshold in random order. Without any amplitude modulation, the loudness of the unmodulated tone after 180 s was only 20% of the loudness at the onset of the stimulus. Amplitude modulation systematically reduced the amount of loudness adaptation, with the 100%-modulated stimuli, regardless of modulation frequency, maintaining on average 55%-80% of the loudness at onset after 180 s. Because the present low-frequency amplitude modulation produced minimal changes in long-term spectral cues affecting the spatial distribution of excitation produced by a 12-kHz pure tone, the present result indicates that neural synchronization is critical to maintaining loudness perception over time. PMID- 26233030 TI - Experimental analysis and prediction of antisymmetric wave motion in a tapered anisotropic waveguide. AB - This paper presents experimental results for wave propagation in an anisotropic multilayered structure with linearly varying cross section. Knowing the dispersion and wave propagation properties in such a structure is of great importance for non-destructive material testing and structural health monitoring applications for accurate damage detection and localization. In the proposed study, the wavefield is generated by a circular piezoelectric wafer active sensor and measured by a scanning laser-Doppler-vibrometer. The measurements are compared with a theoretical group delay estimation and a signal prediction for the antisymmetric wave motion along the non-uniform propagation path. The required dispersion curves are derived from the well-known global matrix method for segments of constant thickness. A multidimensional frequency-wavenumber analysis of linescan data and the full wavefield provides further insight of the adiabatic wave motion because the wavenumber changes along the tapered geometry of the waveguide. In addition, it is demonstrated that a terahertz time-domain system can be used in glass-fiber reinforced plastic structures as a tool to estimate the thickness profile of thin structures by means of time-of-flight measurements. This information is particularly important for guided wave-based diagnostics of structures with unknown thickness. PMID- 26233031 TI - Perception of acoustic cues to Tokyo Japanese pitch-accent contrasts in native Japanese and naive English listeners. AB - This study examines how native language shapes the perception of a prosodic contrast. In Tokyo Japanese, a high-low pitch accent is a lexical property of a word, and the F0 fall after the peak associated with the accented syllable is the fundamental cue to accent perception. In English, pitch accents do not create lexically contrastive F0 patterns. A hypothesis that English listeners naive to Japanese use the F0 fall cue less than Japanese listeners was tested in two experiments. The alignment of F0 peak, the presence and magnitude of F0 fall were manipulated in a trisyllabic nonword to resynthesize Japanese 1st-syllable accented, 2nd-syllable accented, and unaccented patterns. In an AX-discrimination experiment, both listener groups showed sensitivity to the presence of F0 fall at every peak location. In a categorization experiment, the English group did not use the F0 fall cue in decisions about whether the 1st or the 2nd syllable sounded more prominent. The Japanese group relied on the F0 fall information, some listeners much heavily than others. These findings suggest that one's native language constrains how much attention the prosodic dimension of F0 change receives and that individual listeners may have qualitatively different perceptual strategies. PMID- 26233033 TI - Calculated wind noise for an infrasonic wind noise enclosure. AB - A simple calculation of the wind noise measured at the center of a large porous wind fence enclosure is developed. The calculation provides a good model of the measured wind noise, with a good agreement within +/-5 dB, and is derived by combining the wind noise contributions from (a) the turbulence-turbulence and turbulence-shear interactions inside the enclosure, (b) the turbulence interactions on the surface of the enclosure, and (c) the turbulence-shear interactions outside of the enclosure. Each wind noise contribution is calculated from the appropriate measured turbulence spectra, velocity profiles, correlation lengths, and the mean velocity at the center, surface, and outside of the enclosure. The model is verified by comparisons of the measured wind noise to the calculated estimates of the differing noise contributions and their sum. PMID- 26233032 TI - Spatial release from masking in children with bilateral cochlear implants and with normal hearing: Effect of target-interferer similarity. AB - In complex auditory environments, it is often difficult to separate a target talker from interfering speech. For normal hearing (NH) adult listeners, similarity between the target and interfering speech leads to increased difficulty in separating them; that is, informational masking occurs due to confusability of the target and interferers. This study investigated performance of children with bilateral cochlear implants (BiCIs) when target and interferers were either same-sex (male) talkers, or different-sex talkers (male target, female interferer). Comparisons between children with BiCIs and NH, when matched for age, were also conducted. Speech intelligibility was measured for target and interferers spatially co-located, or spatially separated with the interferers positioned symmetrically (+90 degrees and -90 degrees ) or asymmetrically (both at +90 degrees , right). Spatial release from masking (SRM) was computed as the difference between co-located and separated conditions. Within group BiCI comparisons revealed that in the co-located condition speech intelligibility was worse with the same-sex vs different-sex stimuli. There was also a trend for more SRM with the same-sex vs different-sex stimuli. When comparing BiCI to NH listeners, SRM was larger for the NH groups, suggesting that NH children are better able to make use of spatial cues to improve speech understanding in noise. PMID- 26233034 TI - Acoustic cue weighting in the singleton vs geminate contrast in Lebanese Arabic: The case of fricative consonants. AB - This paper is the first reported investigation of the role of non-temporal acoustic cues in the singleton-geminate contrast in Lebanese Arabic, alongside the more frequently reported temporal cues. The aim is to explore the extent to which singleton and geminate consonants show qualitative differences in a language where phonological length is prominent and where moraic structure governs segment timing and syllable weight. Twenty speakers (ten male, ten female) were recorded producing trochaic disyllables with medial singleton and geminate fricatives preceded by phonologically short and long vowels. The following acoustic measures were applied on the medial fricative and surrounding vowels: absolute duration; intensity; fundamental frequency; spectral peak and shape, dynamic amplitude, and voicing patterns of medial fricatives; and vowel quality and voice quality correlates of surrounding vowels. Discriminant analysis and receiver operating characteristics (ROC) curves were used to assess each acoustic cue's contribution to the singleton-geminate contrast. Classification rates of 89% and ROC curves with an area under the curve rate of 96% confirmed the major role played by temporal cues, with non-temporal cues contributing to the contrast but to a much lesser extent. These results confirm that the underlying contrast for gemination in Arabic is temporal, but highlight [+tense] (fortis) as a secondary feature. PMID- 26233035 TI - Corrections to Morse and Ingard's variational-based treatment of weakly-nonlinear acoustics in lossless gases. AB - Errors in Morse and Ingard's treatment of the topic of weakly-nonlinear acoustics in Sec. 6.2 of their book [Theoretical Acoustics (1968)] are noted and corrected. PMID- 26233037 TI - Spectrum pattern resolution after noise exposure in a beluga whale, Delphinapterus leucas: Evoked potential study. AB - Temporary threshold shift (TTS) and the discrimination of spectrum patterns after fatiguing noise exposure (170 dB re 1 MUPa, 10 min duration) was investigated in a beluga whale, Delphinapterus leucas, using the evoked potential technique. Thresholds were measured using rhythmic (1000/s) pip trains of varying levels and recording the rhythmic evoked responses. Discrimination of spectrum patterns was investigated using rippled-spectrum test stimuli of various levels and ripple densities, recording the rhythmic evoked responses to ripple phase reversals. Before noise exposure, the greatest responses to rippled-spectrum probes were evoked by stimuli with a low ripple density with a decrease in the response magnitude occurring with an increasing ripple density. After noise exposure, both a TTS and a reduction of the responses to rippled-spectrum probes appeared and recovered in parallel. The reduction of the responses to rippled-spectrum probes was maximal for high-magnitude responses at low ripple densities and was negligible for low-magnitude responses at high ripple densities. It is hypothesized that the impacts of fatiguing sounds are not limited by increased thresholds and decreased sensitivity results in reduced ability to discriminate fine spectral content with the greatest impact on the discrimination of spectrum content that may carry the most obvious information about stimulus properties. PMID- 26233036 TI - Lexical influences on competing speech perception in younger, middle-aged, and older adults. AB - The influence of lexical characteristics of words in to-be-attended and to-be ignored speech streams was examined in a competing speech task. Older, middle aged, and younger adults heard pairs of low-cloze probability sentences in which the frequency or neighborhood density of words was manipulated in either the target speech stream or the masking speech stream. All participants also completed a battery of cognitive measures. As expected, for all groups, target words that occur frequently or that are from sparse lexical neighborhoods were easier to recognize than words that are infrequent or from dense neighborhoods. Compared to other groups, these neighborhood density effects were largest for older adults; the frequency effect was largest for middle-aged adults. Lexical characteristics of words in the to-be-ignored speech stream also affected recognition of to-be-attended words, but only when overall performance was relatively good (that is, when younger participants listened to the speech streams at a more advantageous signal-to-noise ratio). For these listeners, to-be ignored masker words from sparse neighborhoods interfered with recognition of target speech more than masker words from dense neighborhoods. Amount of hearing loss and cognitive abilities relating to attentional control modulated overall performance as well as the strength of lexical influences. PMID- 26233039 TI - Sound production in the tiger-tail seahorse Hippocampus comes: Insights into the sound producing mechanisms. AB - Acoustic signals of the tiger-tail seahorse (Hippocampus comes) during feeding were studied using wavelet transform analysis. The seahorse "click" appears to be a compounded sound, comprising three acoustic components that likely come from two sound producing mechanisms. The click sound begins with a low-frequency precursor signal, followed by a sudden high-frequency spike that decays quickly, and a final, low-frequency sinusoidal component. The first two components can, respectively, be traced to the sliding movement and forceful knock between the supraorbital bone and coronet bone of the cranium, while the third one (purr) although appearing to be initiated here is produced elsewhere. The seahorse also produces a growling sound when under duress. Growling is accompanied by the highest recorded vibration at the cheek indicating another sound producing mechanism here. The purr has the same low frequency as the growl; both are likely produced by the same structural mechanism. However, growl and purr are triggered and produced under different conditions, suggesting that such "vocalization" may have significance in communication between seahorses. PMID- 26233038 TI - Consonant identification in noise using Hilbert-transform temporal fine-structure speech and recovered-envelope speech for listeners with normal and impaired hearing. AB - Consonant-identification ability was examined in normal-hearing (NH) and hearing impaired (HI) listeners in the presence of steady-state and 10-Hz square-wave interrupted speech-shaped noise. The Hilbert transform was used to process speech stimuli (16 consonants in a-C-a syllables) to present envelope cues, temporal fine-structure (TFS) cues, or envelope cues recovered from TFS speech. The performance of the HI listeners was inferior to that of the NH listeners both in terms of lower levels of performance in the baseline condition and in the need for higher signal-to-noise ratio to yield a given level of performance. For NH listeners, scores were higher in interrupted noise than in steady-state noise for all speech types (indicating substantial masking release). For HI listeners, masking release was typically observed for TFS and recovered-envelope speech but not for unprocessed and envelope speech. For both groups of listeners, TFS and recovered-envelope speech yielded similar levels of performance and consonant confusion patterns. The masking release observed for TFS and recovered-envelope speech may be related to level effects associated with the manner in which the TFS processing interacts with the interrupted noise signal, rather than to the contributions of TFS cues per se. PMID- 26233040 TI - Formant compensation for auditory feedback with English vowels. AB - Past studies have shown that speakers spontaneously adjust their speech acoustics in response to their auditory feedback perturbed in real time. In the case of formant perturbation, the majority of studies have examined speaker's compensatory production using the English vowel /E/ as in the word "head." Consistent behavioral observations have been reported, and there is lively discussion as to how the production system integrates auditory versus somatosensory feedback to control vowel production. However, different vowels have different oral sensation and proprioceptive information due to differences in the degree of lingual contact or jaw openness. This may in turn influence the ways in which speakers compensate for auditory feedback. The aim of the current study was to examine speakers' compensatory behavior with six English monophthongs. Specifically, the current study tested to see if "closed vowels" would show less compensatory production than "open vowels" because closed vowels' strong lingual sensation may richly specify production via somatosensory feedback. Results showed that, indeed, speakers exhibited less compensatory production with the closed vowels. Thus sensorimotor control of vowels is not fixed across all vowels; instead it exerts different influences across different vowels. PMID- 26233041 TI - Application of the Fourier pseudospectral time-domain method in orthogonal curvilinear coordinates for near-rigid moderately curved surfaces. AB - The Fourier pseudospectral time-domain method is an efficient wave-based method to model sound propagation in inhomogeneous media. One of the limitations of the method for atmospheric sound propagation purposes is its restriction to a Cartesian grid, confining it to staircase-like geometries. A transform from the physical coordinate system to the curvilinear coordinate system has been applied to solve more arbitrary geometries. For applicability of this method near the boundaries, the acoustic velocity variables are solved for their curvilinear components. The performance of the curvilinear Fourier pseudospectral method is investigated in free field and for outdoor sound propagation over an impedance strip for various types of shapes. Accuracy is shown to be related to the maximum grid stretching ratio and deformation of the boundary shape and computational efficiency is reduced relative to the smallest grid cell in the physical domain. The applicability of the curvilinear Fourier pseudospectral time-domain method is demonstrated by investigating the effect of sound propagation over a hill in a nocturnal boundary layer. With the proposed method, accurate and efficient results for sound propagation over smoothly varying ground surfaces with high impedances can be obtained. PMID- 26233042 TI - The effects of acoustic variability on absolute pitch categorization: Evidence of contextual tuning. AB - Absolute pitch (AP) is defined as the ability to label a musical note without the aid of a reference note. Despite the large amounts of acoustic variability encountered in music, AP listeners generally experience perceptual constancy for different exemplars within note categories (e.g., recognizing that a C played on a tuba belongs to the same category as a C played on a piccolo). The present studies investigate whether AP possessors are sensitive to context variability along acoustic dimensions that are not inherently linked to the typical definition of a note category. In a speeded target recognition task, AP participants heard a sequence of notes and pressed a button whenever they heard a designated target note. Within a trial the sequence of notes was either blocked according to note-irrelevant variation or contained a mix of different instruments (Experiment 1), amplitude levels (Experiment 2), or octaves (Experiment 3). Compared to the blocked trials, participants were significantly slower to respond in the mixed-instrument and mixed-octave trials, but not the mixed-amplitude trials. Importantly, this performance difference could not be solely attributed to initial performance differences between instruments, amplitudes, or octaves. These results suggest that AP note identification is contextually sensitive. PMID- 26233043 TI - Broadband implementation of coprime linear microphone arrays for direction of arrival estimation. AB - Coprime arrays represent a form of sparse sensing which can achieve narrow beams using relatively few elements, exceeding the spatial Nyquist sampling limit. The purpose of this paper is to expand on and experimentally validate coprime array theory in an acoustic implementation. Two nested sparse uniform linear subarrays with coprime number of elements ( M and N) each produce grating lobes that overlap with one another completely in just one direction. When the subarray outputs are combined it is possible to retain the shared beam while mostly canceling the other superfluous grating lobes. In this way a small number of microphones ( N+M-1) creates a narrow beam at higher frequencies, comparable to a densely populated uniform linear array of MN microphones. In this work beampatterns are simulated for a range of single frequencies, as well as bands of frequencies. Narrowband experimental beampatterns are shown to correspond with simulated results even at frequencies other than the arrays design frequency. Narrowband side lobe locations are shown to correspond to the theoretical values. Side lobes in the directional pattern are mitigated by increasing bandwidth of analyzed signals. Direction of arrival estimation is also implemented for two simultaneous noise sources in a free field condition. PMID- 26233044 TI - Predicting the timing of dynamic events through sound: Bouncing balls. AB - Dynamic information in acoustical signals produced by bouncing objects is often used by listeners to predict the objects' future behavior (e.g., hitting a ball). This study examined factors that affect the accuracy of motor responses to sounds of real-world dynamic events. In experiment 1, listeners heard 2-5 bounces from a tennis ball, ping-pong, basketball, or wiffle ball, and would tap to indicate the time of the next bounce in a series. Across ball types and number of bounces, listeners were extremely accurate in predicting the correct bounce time (CT) with a mean prediction error of only 2.58% of the CT. Prediction based on a physical model of bouncing events indicated that listeners relied primarily on temporal cues when estimating the timing of the next bounce, and to a lesser extent on the loudness and spectral cues. In experiment 2, the timing of each bounce pattern was altered to correspond to the bounce timing pattern of another ball, producing stimuli with contradictory acoustic cues. Nevertheless, listeners remained highly accurate in their estimates of bounce timing. This suggests that listeners can adopt their estimates of bouncing-object timing based on acoustic cues that provide most veridical information about dynamic aspects of object behavior. PMID- 26233046 TI - The effects of different test methods on the just noticeable difference of clarity index for music. AB - The just noticeable differences (JNDs) of room acoustics metrics are necessary for research and design of performing arts venues. The goal of this work was to evaluate the effects of different testing methods on the measured JND of clarity index for music (C80). An initial study was conducted to verify the findings of other published works that the C80 JND is approximately 1 dB, as currently listed in ISO 3382:2009 (International Organization for Standardization, Switzerland, 2009), however, the results suggested a higher value. In the second study, the effects of using two variations of the method of constant stimuli were examined, where one variation required the subjects to evaluate the pair of signals by listening to each of them in their entirety, while the second approach allowed the participants to switch back and forth in real-time. More consistent results were obtained with the latter variation and the results indicated a C80 JND greater than 1 dB. In the final study, an extensive training period using the first variation was required, based on the second study, and the data were collected using the second variation. The analysis revealed that for the conditions used in this study (concert hall and chamber music hall) that the C80 JND is approximately 3 dB. PMID- 26233048 TI - A single-station method for the detection, classification and location of fin whale calls using ocean-bottom seismic stations. AB - Passive seismic monitoring in the oceans uses long-term deployments of Ocean Bottom Seismometers (OBSs). An OBS usually records the three components of ground motion and pressure, typically at 100 Hz. This makes the OBS an ideal tool to investigate fin and blue whales that vocalize at frequencies below 45 Hz. Previous applications of OBS data to locate whale calls have relied on single channel analyses that disregard the information that is conveyed by the horizontal seismic channels. Recently, Harris, Matias, Thomas, Harwood, and Geissler [J. Acoust. Soc. Am. 134, 3522-3535 (2013)] presented a method that used all four channels recorded by one OBS to derive the range and azimuth of fin whale calls. In this work, the detection, classification, and ranging of calls using this four-channel method were further investigated, focusing on methods to increase the accuracy of range estimates to direct path arrivals. Corrections to account for the influences of the sound speed in the water layer and the velocity structure in the top strata of the seabed were considered. The single station method discussed here is best implemented when OBSs have been deployed in deep water on top of seabed strata with low P-wave velocity. These conditions maximize the ability to detect and estimate ranges to fin whale calls. PMID- 26233047 TI - Comparing auditory filter bandwidths, spectral ripple modulation detection, spectral ripple discrimination, and speech recognition: Normal and impaired hearing. AB - Some listeners with hearing loss show poor speech recognition scores in spite of using amplification that optimizes audibility. Beyond audibility, studies have suggested that suprathreshold abilities such as spectral and temporal processing may explain differences in amplified speech recognition scores. A variety of different methods has been used to measure spectral processing. However, the relationship between spectral processing and speech recognition is still inconclusive. This study evaluated the relationship between spectral processing and speech recognition in listeners with normal hearing and with hearing loss. Narrowband spectral resolution was assessed using auditory filter bandwidths estimated from simultaneous notched-noise masking. Broadband spectral processing was measured using the spectral ripple discrimination (SRD) task and the spectral ripple depth detection (SMD) task. Three different measures were used to assess unamplified and amplified speech recognition in quiet and noise. Stepwise multiple linear regression revealed that SMD at 2.0 cycles per octave (cpo) significantly predicted speech scores for amplified and unamplified speech in quiet and noise. Commonality analyses revealed that SMD at 2.0 cpo combined with SRD and equivalent rectangular bandwidth measures to explain most of the variance captured by the regression model. Results suggest that SMD and SRD may be promising clinical tools for diagnostic evaluation and predicting amplification outcomes. PMID- 26233049 TI - Acoustic intensity near a high-powered military jet aircraft. AB - The spatial variation in vector acoustic intensity has been calculated between 100 and 3000 Hz near a high-performance military aircraft. With one engine of a tethered F-22A Raptor operating at military power, a tetrahedral intensity probe was moved to 27 locations in the geometric near and mid-fields to obtain the frequency-dependent intensity vector field. The angles of the maximum intensity region rotate from aft to sideline with increasing frequency, becoming less directional above 800 Hz. Between 100 and 400 Hz, which are principal radiation frequencies, the ray-traced dominant source region rapidly contracts and moves upstream, approaching nearly constant behavior by 1000 Hz. PMID- 26233050 TI - Vocal classification of vocalizations of a pair of Asian small-clawed otters to determine stress. AB - Asian Small-Clawed Otters (Aonyx cinerea) are a small, protected but threatened species living in freshwater. They are gregarious and live in monogamous pairs for their lifetimes, communicating via scent and acoustic vocalizations. This study utilized a hidden Markov model (HMM) to classify stress versus non-stress calls from a sibling pair under professional care. Vocalizations were expertly annotated by keepers into seven contextual categories. Four of these-aggression, separation anxiety, pain, and prefeeding-were identified as stressful contexts, and three of them-feeding, training, and play-were identified as non-stressful contexts. The vocalizations were segmented, manually categorized into broad vocal type call types, and analyzed to determine signal to noise ratios. From this information, vocalizations from the most common contextual categories were used to implement HMM-based automatic classification experiments, which included individual identification, stress vs non-stress, and individual context classification. Results indicate that both individual identity and stress vs non stress were distinguishable, with accuracies above 90%, but that individual contexts within the stress category were not easily separable. PMID- 26233051 TI - An assessment of individualized technical ear training for audio production. AB - An individualized technical ear training method is compared to a non individualized method. The efficacy of the individualized method is assessed using a standardized test conducted before and after the training period. Participants who received individualized training improved better than the control group on the test. Results indicate the importance of individualized training for acquisition of spectrum-identification and spectrum-matching skills. Individualized training, therefore, should be implemented by default into technical ear training programs used in audio production industry and education. PMID- 26233052 TI - Bayesian identification of acoustic impedance in treated ducts. AB - The noise reduction of a liner placed in the nacelle of a turbofan engine is still difficult to predict due to the lack of knowledge of its acoustic impedance that depends on grazing flow profile, mode order, and sound pressure level. An eduction method, based on a Bayesian approach, is presented here to adjust an impedance model of the liner from sound pressures measured in a rectangular treated duct under multimodal propagation and flow. The cost function is regularized with prior information provided by Guess's [J. Sound Vib. 40, 119-137 (1975)] impedance of a perforated plate. The multi-parameter optimization is achieved with an Evolutionary-Markov-Chain-Monte-Carlo algorithm. PMID- 26233053 TI - Untrained listeners experience difficulty detecting interaural correlation changes in narrowband noises. AB - Interaural correlation change detection was measured in untrained normal-hearing listeners. Narrowband (10-Hz) noises were varied by center frequency (CF; 500 or 4000 Hz) and diotic level roving (absent or present). For the 500-Hz CF, 96% of listeners could achieve threshold (79.4% correct at the easiest testing level) if roving was absent, but only 36% of listeners could if level roving was present. No one could achieve threshold at the 4000-Hz CF, unlike trained listeners in the literature. The results raise questions about how individual differences affect learning and generalization of monaural and binaural cues related to interaural correlation detection. PMID- 26233054 TI - Real-time estimation of aerodynamic features for ambulatory voice biofeedback. AB - The development of ambulatory voice monitoring devices has the potential to improve the diagnosis and treatment of voice disorders. In this proof-of-concept study, real-time biofeedback is incorporated into a smartphone-based platform that records and processes neck surface acceleration. The focus is on utilizing aerodynamic measures of vocal function as a basis for biofeedback. This is done using regressed Z-scores to compare recorded values to normative estimates based on sound pressure level and fundamental frequency. Initial results from the analysis of different voice qualities suggest that accelerometer-based estimates of aerodynamic parameters can be used for real-time ambulatory biofeedback. PMID- 26233055 TI - Estimation of minimum oral tract constriction area in sibilant fricatives from aerodynamic data. AB - Speech screening of sibilant fricative phonemes is an important tool for oral health care. Nevertheless, screening as a function of quantitative geometrical markers is mostly limited to teeth features whereas the minimum area of the narrowed air passage upstream from the tooth is known to be a key production feature. The minimum area is estimated from non-invasive aerodynamic measurements using a laminar flow model. The influence of viscid flow losses on the area estimation is shown to be negligible. Current data suggest that speech screening is most effective for phoneme /s/, which supports common practice in oral health care. PMID- 26233056 TI - Stimulus-independent semantic bias misdirects word recognition in older adults. AB - Older adults' normally adaptive use of semantic context to aid in word recognition can have a negative consequence of causing misrecognitions, especially when the word actually spoken sounds similar to a word that more closely fits the context. Word-pairs were presented to young and older adults, with the second word of the pair masked by multi-talker babble varying in signal to-noise ratio. Results confirmed older adults' greater tendency to misidentify words based on their semantic context compared to the young adults, and to do so with a higher level of confidence. This age difference was unaffected by differences in the relative level of acoustic masking. PMID- 26233057 TI - The acoustic nonlinearity parameter in Fluorinert up to 381 K and 13.8 MPa. AB - This work reports on the determination of the acoustic nonlinearity parameter, B/A, from measured sound speed data, in Fluorinert FC-43 at temperatures up to 381 K and pressures up to 13.8 MPa using the thermodynamic method. Sound speed was measured using Swept Frequency Acoustic Interferometry at 11 pressures between ambient and 13.8 MPa along 6 isotherms between ambient and 381 K. Second order least-squares polynomial fits of measured sound speeds were used to determine temperature and pressure dependence. A room temperature B/A = 11.7 was determined and this parameter was found to increase by a factor of 2.5 over the temperature/pressure range investigated. PMID- 26233058 TI - The phonological function of vowels is maintained at fundamental frequencies up to 880 Hz. AB - In a between-subject perception task, listeners either identified full words or vowels isolated from these words at F0s between 220 and 880 Hz. They received two written words as response options (minimal pair with the stimulus vowel in contrastive position). Listeners' sensitivity (A') was extremely high in both conditions at all F0s, showing that the phonological function of vowels can also be maintained at high F0s. This indicates that vowel sounds may carry strong acoustic cues departing from common formant frequencies at high F0s and that listeners do not rely on consonantal context phenomena for their identification performance. PMID- 26233059 TI - Effects of indoor rattle sounds on annoyance caused by sonic booms. AB - To expand national air transportation capabilities, NASA's Commercial Supersonic Technology Project is working to make supersonic flight practical for commercial passengers. As an aid in designing and certifying quiet supersonic aircraft, a noise metric is sought that will correspond to indoor annoyance caused by sonic booms, including the effects of indoor rattle sounds. This study examines how well several common aircraft noise metrics predict indoor annoyance based on the indoor and outdoor sound fields. The results suggest notional community annoyance models that include the effects of indoor rattle sounds. PMID- 26233060 TI - Time reversal transfer: Exploring the robustness of time reversed acoustics in media with geometry perturbations. AB - In this letter, fundamentals of transferring a time reversal experiment between similar objects are discussed. The time reversal experiment consists of two steps: forward propagation, when a source excites the medium and a complex wave field is created, and back propagation, resulting in time reversal focusing. Here the procedure of performing the first step on one specimen and the second step on another is investigated. The theory of time reversal transfer is explained on an example of object shape variations. However, conclusions of the theoretical analysis are applicable universally. The feasibility of the proposed procedure is validated in experiments modeling conditions in practice. PMID- 26233061 TI - Passive acoustic source localization using sources of opportunity. AB - The feasibility of using data derived replicas from ships of opportunity for implementing matched field processing is demonstrated. The Automatic Identification System (AIS) is used to provide the library coordinates for the replica library and a correlation based processing procedure is used to overcome the impediment that the replica library is constructed from sources with different spectra and will further be used to locate another source with its own unique spectral structure. The method is illustrated with simulation and then verified using acoustic data from a 2009 experiment for which AIS information was retrieved from the United States Coast Guard Navigation Center Nationwide AIS database. PMID- 26233063 TI - Envelope analysis with a genetic algorithm-based adaptive filter bank for bearing fault detection. AB - This paper proposes a fault detection methodology for bearings using envelope analysis with a genetic algorithm (GA)-based adaptive filter bank. Although a bandpass filter cooperates with envelope analysis for early identification of bearing defects, no general consensus has been reached as to which passband is optimal. This study explores the impact of various passbands specified by the GA in terms of a residual frequency components-to-defect frequency components ratio, which evaluates the degree of defectiveness in bearings and finally outputs an optimal passband for reliable bearing fault detection. PMID- 26233062 TI - Effects of vocal fold epithelium removal on vibration in an excised human larynx model. AB - This study investigated the impact of selective epithelial injury on phonation in an excised human larynx apparatus. With intact epithelium, the vocal folds exhibited a symmetrical vibration pattern with complete glottal closure during vibration. The epithelium was then enzymatically removed from one, then both vocal folds, which led to left-right asymmetric vibration and a decreased closed quotient. Although the mechanisms underlying these vibratory changes are unclear, these results demonstrate that some component of an intact surface layer may play an important role in achieving normal symmetric vibration and glottal closure. PMID- 26233064 TI - Acoustical analysis of Canadian French word-final vowels in varying phonetic contexts. AB - This study analyzed Canadian French (CF) vowels /i y o e E o u a/ in word-final position. Of particular interest was the stability of /e-E/; although some dialects of French have merged /e-E/ to /e/ in word-final context, this contrast is maintained in CF. The present study investigated the stability of this contrast in various preceding phonetic contexts and in lexical vs morphological contrasts. Results showed that the contrast was maintained by all four speakers, although to varying degrees. PMID- 26233065 TI - Dispersion suppression of guided elastic waves by anisotropic metamaterial. AB - This investigation presents a method to engineer a metamaterial exhibiting the desired anisotropic wave behavior with the specific applications toward the dispersion suppression of elastic guided waves. In the proposed approach, effective anisotropic properties required for dispersion suppression were first determined. Then the slowness curves for the metamaterial were used to find the specific unit cell configuration through inverse design. When the metamateral layers were attached to the homogeneous waveguide, the target guided mode was shown to exhibit little dispersion. Detailed engineering procedures were given, and the direct numerical simulations were performed to confirm the effectiveness of the proposed approach. PMID- 26233066 TI - Adults, but not children, benefit from a pretrial signal cue in a random frequency, two-tone masker. AB - This study examined the benefit of a pretrial cue, a preview of the signal, on children's (5-10 years) and adults' detection of a 1000-Hz pure-tone signal in a broadband noise or a random-frequency, two-tone masker. No cuing effect was observed with the noise masker, regardless of listener age. In contrast, all but one adult benefited from the cue with the two-tone masker (average = 9.4 dB). Most children showed no cuing effect (average = 0.1 dB) with the two-tone masker. These results suggest that, unlike adults, the provision of a pretrial cue does not promote frequency-selective listening during detection for 5- to 10-year olds. PMID- 26233067 TI - Ultrasonic wave properties of human bone marrow in the femur and tibia. AB - Ultrasonic wave properties of human bone marrow obtained in the femur and tibia were measured using an ultrasound pulse technique. The measured frequency range was 4-10 MHz, and the temperature range was 30 degrees C-40 degrees C. The sound velocity was 1410 m/s, and the attenuation coefficient was 4.4 dB/cm at 36 degrees C (10 MHz). These values decreased with temperature. Site dependence and individual differences in elderly human bone marrow were negligible. The slopes of the attenuation coefficient were estimated by a power law. The values of the exponent n were 2.0 (30 degrees C-38 degrees C) and 2.3 (40 degrees C). PMID- 26233068 TI - Poisson's ratio from polarization of acoustic zero-group velocity Lamb mode. AB - Poisson's ratio of an isotropic and free elastic plate is estimated from the polarization of the first symmetric acoustic zero-group velocity Lamb mode. This polarization is interpreted as the ratio of the absolute amplitudes of the surface normal and surface in-plane components of the acoustic mode. Results from the evaluation of simulated datasets indicate that the presented relation, which links the polarization and Poisson's ratio, can be extended to incorporate plates with material damping. Furthermore, the proposed application of the polarization is demonstrated in a practical field case, where an increased accuracy of estimated nominal thickness is obtained. PMID- 26233069 TI - Linguistically-based informational masking in preschool children. AB - Previous work has shown that young children exhibit more difficulty understanding speech in the presence of speech-like distractors than do adults, and are more susceptible to at least some form of informational masking (IM). Yet little is known about how/when the "susceptibility" to linguistically-based IM develops. The authors tested adults, school-age children (aged 8 yrs), and preschool-age children (aged 4 yrs) on sentence recognition in the presence of normal speech, "jumbled" speech, and reversed speech distractors. As has been found previously with adults [e.g., Summers and Molis (2004). J. Speech, Lang. Hear. Res. 47, 245 256], children in both age groups showed a release of masking when the distractor was uninterpretable (reversed speech). This suggests that children already demonstrate linguistically-based IM by the age of 4 yrs. PMID- 26233070 TI - Just-noticeable difference of tone pitch contour change for Mandarin congenital amusics. AB - Congenital amusia is a neuro-developmental disorder that may affect the processing of both music pitch and lexical tone. In the present study, the just noticeable differences (JNDs) of tone pitch contour change were examined for three groups of Mandarin-native listeners: amusics with (tone agnosics) and without lexical tone difficulties (pure amusics), and matched controls. Tone agnosics showed significantly larger JNDs than normal controls, while pure amusics performed comparably with the controls. These results suggest that only those amusics with behavioral lexical tone deficits might be psychophysically impaired in pitch contour discrimination. PMID- 26233071 TI - Infectious diseases in Poland in 2013. AB - This article aims at evaluating the epidemiological situation of infectious and parasitic diseases in Poland in 2013. MATERIAL AND METHODS: This article was mainly based on the statistical data derived from annual bulletins "Infectious diseases and poisonings in Poland in 2013" and "Vaccinations in Poland in 2013" (NIPH-NIH, CSI, Warsaw 2014) and data specified in particular articles of the epidemiological chronicle of the current issue of the Epidemiological Review. Data on fatal cases due to infectious and parasitic diseases registered in Poland in 2013 and previous years were obtained from the Demographic Surveys and Labour Market Department of the Central Statistical Office. RESULTS: As with the previous years, upper respiratory tract infections classified as "influenza and influenza-like illness" were the most prevalent with a total number cases amounting to 3,164,405 (8,218.7/100,000). Compared to 1,460,037 (3,789.0/100,000) cases registered in 2012 and the median of 2007-2011, it was an increase of incidence by 116.9% and 469.5%, respectively. In 2013, a decreasing tendency of incidence of bacterial intestinal infections was sustained. Out of bacterial infections, those caused by coccobacilli of Salmonella spp. were still predominant. In 2013, a total of 7 578 (19.7/100,000) such cases were reported. Compared to 2012 and the median of 2007-2011, it was a decrease of incidence by 10.0% and 21.9%, respectively. A total of 42 699 (110.9/100,000) viral intestinal infections were reported. In this group, the most common were infections caused by rotaviruses--23,529 (61.1/100,000). Having referred to 2012, incidence decreased by ca 0.6%, while in comparison with the median of 2007-2011, it was an increase by 5.5%. Compared to 2012, an incidence of diarrhoea of unspecified origin in children under 2 years old increased by 28.4%. In 2013, a total of 2,183 pertussis cases (5.7/100,000) were registered, which compared to the previous year indicated a decrease of incidence by 53%. In 2013, a decrease of mumps incidence by 12.3% was noted. Compared to the previous year, there was more than 5-fold increase of rubella incidence. In 2012, the number of rubella cases was 6,263 (16.3/100,000), while in 2013--38,548 (100.1/100,000). Considerable increase in the number of rubella cases resulted from compensatory epidemic which affected mainly boys who were not inoculated with MMR vaccine. In 2013, there were 2 cases of congenital rubella. A total of 84 cases (0.22/100,000) of measles were reported. In 2013, the number of invasive disease cases caused by H. influenzae was 25 (0.06/100,000). Compared to 2012 and the median of 2007-2011, incidence decreased by 30.5% and 19.3%, respectively. The number of infections of Streptococcus pneumoniae etiology in 2013 amounted to 540. Compared to 2012 and the median of 2007-2011, there was an increase by 22.5% and 95.3%, respectively. Having considered the data of 2012, the number of sepsis cases caused by this pathogen increased by 32.9%. Compared to 2012, tuberculosis incidence in 2013 in total (all tuberculosis manifestations) decreased from 19.6/100,000 to 18.8, while respiratory tuberculosis from 18.2 to 17.8/100,000. In 2013, a total of 1,097 HIV infections (2.85/100,000) were reported. Compared to the previous year, incidence did not change. In total, 36 malaria cases were notified who were infected abroad while visiting malaria endemic areas. PMID- 26233072 TI - Measles in Poland in 2013. AB - BACKGROUND: Since 1998, Poland has been actively participating in the Measles Elimination Program, coordinated by the World Health Organization (WHO). It requires achieving and maintaining very high vaccine coverage (>95%), recording all cases and suspected cases of measles, and laboratory testing of all suspected measles cases in the WHO Reference Laboratory. In Poland it is a Laboratory of Department of Virology, NIPH-NIH. In order to confirm or exclude the case of measles specific measles IgM antibodies should be measured using Elisa test, or molecular testing (PCR) should be performed to detect the presence measles virus RNA in biological material. AIM: To assess epidemiological situation of measles in Poland in 2013, including vaccination coverage in Polish population, and Measles Elimination Program implementation status. METHODS: The descriptive analysis was based on data retrieved from routine mandatory surveillance system and published in the annual bulletins "Infectious diseases and poisonings in Poland in 2013" and "Vaccinations in Poland in 2013", and measles case-based reports from 2013 sent to the Department of Epidemiology NIPH-NIH by Sanitary Epidemiological Stations. RESULTS: In total, there were 84 measles cases registered in Poland in 2013 (incidence 0.22 per 100,000). The highest incidence rate was observed among infants (2.18 per 100,000) and children aged 1 year (1.27 per 100,000). In 2013, 56 cases (66.7%) were hospitalized due to measles. No deaths from measles were reported. Vaccination coverage of children and youth aged 2-11 years ranged from 82.8% do 99.5% (primary vaccination in children born in 2012-2007) and from 73.6% to 93.2% (booster dose in children born in 2004 2001). In 2013, 127 measles-compatible cases were reported (67% of expected reports). Two hundred seven cases (80%) were confirmed by IgM ELISA test. SUMMARY AND CONCLUSIONS: In 2013, the epidemiological situation of measles deteriorated in comparison to proceding year. The sensitivity of measles surveillance improved but is still insufficient. It is necessary to further promote Measles Elimination Program in Poland, to improve measles surveillance system and to maintain the high immunisation coverage. PMID- 26233073 TI - Mumps in Poland in 2013. AB - BACKGROUND: Vaccination against mumps from 2003 is mandatory in Poland and given as two dose scheme with MMR vaccine (mumps, measles, and rubella). Earlier this vaccination was only recommended. Despite observed decline in mumps incidence for over a decade which is a result of conducted vaccinations, mumps is still a common childhood disease. AIM: To assess epidemiological situation of mumps in Poland in 2013, including vaccination coverage in Polish population, in comparison to previous years. METHODS: The descriptive analysis was based on data retrieved from routine mandatory surveillance system and published in the annual bulletins "Infectious diseases and poisonings in Poland in 2013" and "Vaccinations in Poland in 2013" (Czarkowski MP i in., Warszawa 2013, NIZP-PZH i GIS). Mumps cases were classified according to the criteria of surveillance case definition implemented in the European Union (Commission Decision of 28 April 2008 amending Decision 2002/253/EC). National Immunisation Programme for year 2013 was also used. RESULTS: In total, there were 2 436 mumps cases registered in Poland in 2013. Incidence of mumps was 6.3 per 100,000 and it was lower by 12.5% in comparison with 2012 and lower by 18.2% in comparison with median for the years 2007-2010. The highest incidence rate was observed among children aged 5 years (54.0 per 100,000). Incidence in men (7.5) was higher than in women (5.2). In 2013, 38 people were hospitalized due to mumps. Vaccination coverage of children aged 3 years in Poland in 2013 was 97.5% and it was lower by 0.4% in comparison with year 2012. CONCLUSIONS: Systematic execution of mumps vaccination in accordance with the National Immunisation Programme resulted in a significant decrease in the number of registered cases. Due to the high vaccination coverage further decline in the number of cases is expected. PMID- 26233074 TI - Rubella in Poland in 2013. AB - BACKGROUND: In 2004, Poland has adopted the WHO goal of rubella elimination and congenital rubella syndrome prevention. The main target of the Programme is to stop transmission of the virus in the environment and prevention of congenital rubella in children. This can be achieved by carrying out the vaccination. Participation in the rubella elimination program requires clinical diagnosis of rubella cases and their confirmation with laboratory test. In Poland, until 2003, national vaccination recommendation included a dose of rubella vaccine only for girls aged 13 years. Among men, the incidence of measles remained high creating a risk of infection of non-immune pregnant women which may lead to the development of congenital rubella syndrome in the child. AIM: To assess epidemiological situation of rubella in Poland in 2013, including vaccination coverage in Polish population. METHODS: The descriptive analysis was based on data retrieved from routine mandatory surveillance system and published in the annual bulletins "Infectious diseases and poisonings in Poland in 2013" and "Vaccinations in Poland in 2013" (MP. Czarkowski, Warszawa 2014, NIZP-PZH, GIS). RESULTS: In 2013, there was big epidemic of rubella in Poland--with 38,548 registered cases (6 times more than in 2012), incidence 84.4 per 100,000 (5 times higher than in the previous year). The highest incidence rate, regardless of gender and the environment, was observed among adolescents aged 15-19 years (911.6 per 100,000). The incidence of rubella in boys and men was significantly higher than the incidence in girls and women (181.4 versus 23.9). In 2013, two cases of congenital rubella syndrome were registered. SUMMARY AND CONCLUSIONS: Rubella epidemic which occurred in Poland in 2013 was the result of use in the past vaccination against rubella only for girls 13 years of age. The proportion of laboratory tests confirming/excluding rubella infection is still very low in Poland. In 2013, only 0.2% of rubella cases were laboratory confirmed. PMID- 26233075 TI - Chickenpox in Poland in 2013. AB - BACKGROUND: A large number of chickenpox cases, occurring especially in children, indicates the rationale for the use of chickenpox vaccinations. In Poland since 2002, chickenpox vaccination is included in the National Immunisation Programme as recommended. AIM: To assess epidemiological situation of chickenpox in Poland in 2013 in comparison to previous years. METHODS: The descriptive analysis was based on data retrieved from routine mandatory surveillance system and published in the annual bulletins "Infectious diseases and poisonings in Poland in 2013" and "Vaccinations in Poland in 2013" (Czarkowski MP i in., Warszawa 2014, NIZP PZH i GIS). National Immunisation Programme for year 2013 was also used. RESULTS: In 2013, 178 501 cases of chickenpox were registered in Poland. The incidence was 463.6 and was lower than in 2012 (540.5). The highest number of cases was reported in mazowieckie voivodeship, the lowest in podlaskie voivodeship. The highest incidence was recorded in children aged 4 years (6 545.1 per 100,000). The chickenpox incidence among men (491.7) was higher by 12.4% comparing to women (437.3). The incidence among rural residents (497.2) was higher than among urban residents (441.7). Number of cases hospitalized due to mumps was 1 184. Number of people vaccinated against chickenpox was 57 168. SUMMARY: In 2013, there was decrease in the incidence of chickenpox [corrected] in Poland with small fluctuations. Since 2002 the number of people vaccinated against chickenpox increased. The increase in the number of people vaccinated against chickenpox would help maintain the downward trend in subsequent years. PMID- 26233076 TI - Scarlet fever in Poland in 2013. AB - OBJECTIVE: Assessment of the epidemiological situation of scarlet fever in Poland in 2013 in comparison with previous years. MATERIALS AND MATHODS. The evaluation was performed by reviewing surveillance data published in the bulletin, "Infectious diseases and poisonings in Poland in 2013" (Warsaw 2014, NIPH-NIH, CSI) and also in bulletins from previous years, and unpublished data collected under Statistical survey program of official statistics. RESULTS: In 2013 did not change the general view of the epidemiological situation of scarlet fever in Poland. Analysed data did not indicate the possibility of shortening an epidemic cycle of scarlet fever, nor suggest growing rate of epidemic curve or increase of average annual incidence which was observed in last twenty years. In 2013, in the country a total of 25 115 cases were registered with corresponding incidence 65.2 per 100,000 population (in voivodeships: from 22.9 in Lodzkie to 111.1 in Pomorskie). The highest incidence was notified in 5-year-old (949.2) and 4-year old children (916.6), and the cases among children and young people up to 15 years accounted for 87.0% of all cases. The incidence among men (78.8) was higher over 50% than incidence among women (52.5). The incidence was higher in urban areas than in rural areas and was 68.7 (in rural area 59.9). 1.04% of patients were hospitalized. No deaths related to this disease were reported. SUMMARY: A sudden increasing incidence among men, especially in the 15-19 age group and growing proportion of cases among adults in comparison to the notified in previous years, according to authors' opinion, can be associated with compensatory epidemic of rubella (!). It is estimated, that about 10% scarlet fever cases reported to surveillance in a year are misclassified and could be unrecognized cases of rubella. Therefore, it is important to enhance specificity of epidemiological surveillance of scarlet fever. Additionally, it will give a better opportunity to monitor and supervise measles and rubella elimination program. PMID- 26233077 TI - Meningitis and encephalitis in Poland in 2013. AB - AIM OF THE STUDY: The aim of this study was to assess the epidemiology of meningitis and/or encephalitis in Poland in 2013. INTRODUCTION: In the last three years in Poland, about 3000 cases of meningitis and/or encephalitis of viral or bacterial etiology were recorded annually. MATERIALS AND METHODS: Assessment of the epidemiological situation of meningitis and/or encephalitis in Poland in 2013, was based on the results of the analysis of epidemiological reports sent to the NIZP-PZH by the Regional Sanitary-Epidemiological Stations published in the annual bulletin "Infectious diseases and poisonings in Poland in 2013" and "Preventive immunizations in Poland in 2013". RESULTS: In 2013 in Poland 3,116 cases of bacterial meningitis and/or encephalitis were recorded. Almost 50% of these were viral infections. SUMMARY AND CONCLUSIONS: The epidemiological situation of meningitis and/or encephalitis in Poland in 2013 compared to 2012 did not change significantly. PMID- 26233078 TI - Legionellosis in Poland in 2013. AB - OBJECTIVE: The objective of the article is to assess the epidemiological situation of legionellosis in Poland in 2013 in comparison to the preceding years. MATERIAL AND METHODS. The analysis of epidemiological situation was based on the data published in the annual bulletin: "Infectious diseases and poisonings in Poland in 2013" and its prior versions as well as the legionellosis case reports sent to the Department of Epidemiology of NIPH-NIH. RESULTS: In Poland, all cases of legionellosis, including Legionnaires' disease--a form of disease accompanied by pneumonia and mild, influenza-like form of infection--Pontiac fever are routinely reported to the surveillance. In 2013, a total of 11 legionellosis cases were reported (all 11 were cases of Legionnaires' disease and no one case of Pontiac fever); the incidence was 0.029 per 100,000 population which was a bit higher compared to the previous year but was 40 % lower from the median incidence for 2007-2011. The infections were reported in 7 provinces. The incidence in males (0.04 per 100,000) was slightly higher compared to females (0.02). No legionellosis outbreaks were registered--all infections were of sporadic nature. All cases were hospitalized., of these, seven were infected in the country, including three hospital acquired infections. Four infections were associated with travels abroad (one to Austria, one to Bulgaria, one to Germany and one to Italy). All the four cases connected with travel abroad survived., but 5 cases from 7 infected in Poland were fatal. The sanitary inspection reported that four fatal cases were over the age of 50, but one girl was 14 years old CONCLUSIONS: In 2013, no changes of fundamental features of legionellosis epidemiological situation in Poland were observed. It is recommended to enhance the surveillance for legionellosis, with emphasis on conducting environmental investigation in areas where infections have occurred. PMID- 26233079 TI - Yersiniosis in Poland in 2013. AB - AIM: The aim of this paper was to assess the epidemiological situation of yersiniosis in Poland in 2013 against previous years. MATERIALAND METHODS: We reviewed surveillance data published in the annual bulletin "Infectious diseases and poisonings in Poland" from 2008 to 2013 (MP Czarkowski et al., NIH and GIS) and individual yersiniosis case reports from 2013 sent by the Sanitary Epidemiological Stations. Additionally, we use data from the Department of Demographic Surveys in Central Statistical Office. RESULTS: A total of 219 yersiniosis cases were reported in Poland in 2013, including 199 cases of intestinal and 20 cases of extraintestinal yersiniosis. Among those were infections caused by Y. enterocolitica, and Y. pseudotuberculosis--217 and 2 cases, respectively. The incidence rate was 0.57 per 100,000 inhabitants. Hospitalization required 54,8% of cases. Deaths related to the disease were not reported. Intestinal yersiniosis was manifested mostly by following symptoms: diarrhoea (91%), fever (74%), abdominal pain (49%) and vomiting (21%). The most affected group in intestinal infections were children younger than 4 years--126 cases (63% of all cases). There were less extraintestinal infections in comparison to 2012 (30 cases), manifested mainly by symptoms from the osteoarticular system, presented in 80% of patients. Similarly to 2012, the most cases of intestinal yersiniosis reported from Mazowieckie province (123 cases). Serotypes of isolated Y. enterocolitica strains were identified in 115 cases (53%), including serotypes: O3 (88.7%), O8 (8.7%) and O9 (2.6%). One household outbreak caused by Y. enterocolitica O3 occurred. In 2013 identified 10 infections with serotype O8. CONCLUSIONS: Occurrence of a significantly higher number of yersiniosis cases during the third and fourth quarter of 2013 suggests the changes in seasonal distribution of infections in comparison to previous years. This may be related to a very low number of infections caused by serotype O8, reported in past years within the first half of the year. Maintaining a high percentage (47%) of a non-serotyped strains of Yersinia isolated from patients points to lack of serotyping in routine laboratory diagnostics. Reporting cases of extraintestinal yersiniosis from only few provinces may suggest that the real number of infections remains underreported. PMID- 26233080 TI - Foodborne botulism in Poland in 2013. AB - OBJECTIVES: The aim of the study is to assess the epidemiology of foodborne botulism in Poland in 2013. MATERIALS AND METHODS: We reviewed surveillance data published in the annual bulletin "Infectious diseases and poisonings in Poland in 2013" and in previous publications, and botulism case reports for 2013 sent to the Department of Epidemiology NIPH-NIH by Sanitary-Epidemiological Stations. RESULTS: In 2013, a total of 24 foodborne botulism cases (including 8 laboratory confirmed cases) was reported, corresponding to the lowest annual incidence rate (0.06 per 100,000 population) since the introduction of botulism as mandatory notifiable disease. The highest incidence in the country was reported in Kujawsko Pomorskie (0.19). Incidence in rural areas (0.09 per 100,000 population) was more than 2-fold higher than the incidence in urban areas (0.04). Men, had more than 3 times higher incidence than women; the highest incidence rate (0.29 per 100,000 population) was observed among men in the age group of 40-49 years. Most cases were associated with consumption of different types of commercially canned meat. Commercially canned fish was also a common vehicle. All cases were hospitalized. No deaths related to the disease were reported. CONCLUSIONS: In 2013, in Poland a downward trend in the incidence of foodborne botulism was maintained. Insufficient laboratory capacity remains a major weakness in national surveillance resulting in disproportionate reporting of cases meeting only clinical criteria and an epidemiological link. This situation clearly speaks for the need to improve laboratory capacity for surveillance. PMID- 26233081 TI - Hepatitis A in Poland in 2013. AB - OBJECTIVE: The aim of the study is to assess the epidemiological situation of hepatitis A in Poland in 2013 compared to previous years. MATERIAL AND METHODS: The evaluation was carried out on the basis of the results of the analysis of data from the annual bulletin "Infectious diseases and poisonings in Poland in 2013" and "Vaccinations in Poland in 2013", the information from individual diseases forms and epidemiological investigations forms for hepatitis A outbreaks, sent by sanitary-epidemiological stations to the Department of Epidemiology of NIZP-PZH. RESULTS: In 2013, 48 cases of hepatitis A were registered in Poland. The incidence per 100,000 inhabitants was 0.12, and in particular provinces it ranged from 0.05 in the Kujawsko-Pomorskie province to 0.26 in the Wielkopolska province. The incidence of hepatitis A for men and women was at a similar level and amounted to 0.13 and 0.12/100,000. In 2013 imported cases accounted for 45.8% of the total number of hepatitis A cases. There were three outbreaks, where the total of 13 people fell ill. SUMMARY AND CONCLUSIONS: 2013 saw a slight decrease in the number of cases compared to the previous year. Besides, there were no significant changes in the hepatitis A epidemiological situation. In Poland, there is still very low endemicity. Since several years, there has been a decline in the number of people vaccinated against hepatitis A. All of this affects the accumulation of a fairly large population of people susceptible to the infection, which may increase incidence. Although the current hepatitis A epidemiological situation in Poland is good, it still requires monitoring, analysis and constant observation within the structured epidemiological surveillance. PMID- 26233082 TI - Hepatitis B in Poland in 2013. AB - OBJECTIVE: Evaluation of the epidemiological situation of hepatitis B in Poland in 2013 in comparison with the previous years. MATERIAL AND METHODS: Epidemiological situation of hepatitis B in Poland in 2013 was evaluated on a basis of individual reports on acute and chronic hepatitis B cases registered by sanitary and epidemiological stations and aggregated data derived from annual bulletins "Infectious diseases and poisonings in Poland". RESULTS: In 2013, a total of 1,541 hepatitis B cases were reported, including 36 co-infections with HBV and HCV. Compared to the previous year, incidence slightly decreased and amounted to 4.0 per 100,000 population. Acute stage accounted for 5.3% of all HBV infections (incidence--0.21 per 100,000 population). Having compared to 2012, there was a slight increase in the incidence and share of acute stage in all HBV infections. The total number of acute hepatitis B cases, however, remained low. The highest incidence was reported in mazowieckie province for both acute (0.45 per 100,000) and chronic (7.40 per 100,000) hepatitis B. Similar to the previous year, males and urban population were the most affected group. Acute HBV infections were not identified in the age group 0-24 years which is subject to mandatory vaccination in neonatal period or at the age of 14 years. Acute and chronic stages of hepatitis B were most commonly diagnosed in persons aged 65-74 years (incidence--0.44 per 100,000) and 40-44 years (incidence--13.3 per 100,000), respectively. According to the CSO data, a total of 7 and 38 fatal cases were registered in 2013 due to acute and chronic HBV infection, respectively. CONCLUSIONS: In 2013, a decreasing trend of hepatitis B incidence was discontinued. Thus, it is important to monitor whether this situation would not be reverted in the successive years. Hepatitis B incidence, which is slightly lower compared to the previous year, suggested that the incidence is relatively stable. In case of acute infections, medical procedures remained to be the most commonly listed exposure. Having considered a higher number of infections, sanitary conditions in health care units should be improved. PMID- 26233083 TI - Hepatitis C in Poland in 2013. AB - INTRODUCTION: Since 1997, hepatitis C (HCV infection) is registered separately in epidemiological surveillance in Poland. Having considered the predominance of chronic infections of long-term asymptomatic course, the number of infections detected in successive years and registered in surveillance system does not reflect the actual dynamics of hepatitis C epidemiological situation. To a large extent, it is dependent on current HCV testing practices. Furthermore, it may also result from modifications introduced to the regulations of HCV case notification. OBJECTIVE: This article aims at evaluating the epidemiological situation of hepatitis C in Poland in 2013 with the reference to the data from previous years. MATERIALAND METHODS: Epidemiological situation of hepatitis C in Poland was analyzed on a basis of aggregated data from routine surveillance system published in annual bulletin "Infectious diseases and poisonings in Poland in 2013"(Czarkowski MP et al. Warsaw: NIPH-NIH and CSI, 2013). Data on hepatitis C mortality was derived from the Demographic Surveys and Labour Market Department of the Central Statistical Office. RESULTS: In 2013, a total of 2,705 (incidence 7.03 per 100,000) HCV infections meeting 2005 definition were reported in Poland, including 35 co-infections with HCV and HBV (1.3%). Having compared to 2012, there was an increase in incidence by 15% (2,359; 6.12). In 2013, 2,641 cases (6,86) meeting 2009 definition were registered. Compared to 2012, it was an increase by 16% (2,268; 5.89). In 2013, 175 HCV fatal cases were reported, of whom only 2 were due to the acute stage of disease. CONCLUSIONS: In recent years, a societal burden resulting from undiagnosed or untreated chronic HCV infections is on the increase. It is demonstrated by high HCV mortality and increasing trend of incidence of symptomatic chronic hepatitis C (2005 definition) and hospitalizations. PMID- 26233084 TI - Tetanus in Poland in 2013. AB - Tetanus is an infectious disease which, despite the small number of cases is a permanent risk to unvaccinated people. The severity of disease is associated with high mortality especially in older age groups. PURPOSE OF THE STUDY: The aim of the paper is to present epidemiological surveillance data tetanus in 2013. MATERIAL AND METHODS: The source of the data are the individual case reports of tetanus sent to the Department of Epidemiology, NIPH-NIH and bulletin data "Infectious diseases and poisonings in Poland in 2013. RESULTS: In 2013 number of recorded cases of tetanus was 14. Four cases of disease occurred in men and 10 in women. Among cases 13 people were over 69 years of age and among them 7 people died. SUMMARY AND CONCLUSIONS: Severity of tetanus, despite the small number of annual cases leads to several deaths each year, particularly in the older age groups. This deaths could be prevented by vaccination. PMID- 26233085 TI - HIV and AIDS in Poland in 2013. AB - AIM: The aim is to analyze the epidemiological situation of newly diagnosed HIV infections and AIDS cases in Poland in 2013 and years earlier. MATERIALS AND METHODS: Descriptive analysis of newly detected HIV cases and incident AIDS cases was performed based on routine notifications by clinicians and laboratories. Data on the number of HIV tests were derived from annual survey among laboratories. RESULTS: In 2013 there were 1,098 HIV cases diagnosed in Poland (detection rate 2.85 per 100,000 population), including 23 among non-Polish citizens. The rate remained at the same level as in 2011, but 14.7% higher than median in 2007-2011. The total number of AIDS cases was 163 (incidence 0.42 per 100,000) and 46 AIDS patients died (0.12 per 100,00). HIV infection is mainly detected among people aged 20 to 39 years (73.3%) and among males (85.6%). Aproximately 68.4% of newly diagnosed infections with known transmission category were acquired by homosexual contacts (MSM). The number of infections in this group decreased by 2.2% compared to previous year. The percentage of late presenters (defined by the time between HIV and AIDS diagnoses of less than 3 months) increased in comparison with year 2012 (8.4% of newly diagnosed HIV infections). CONCLUSIONS: HIV epidemic continues to develop among MSM in Poland. However, assessment of epidemiological situation is limited by the missing data on the probable transmission route in a large percentage of reported newly detected cases of HIV infection. PMID- 26233086 TI - Malaria in Poland in 2013. AB - OBJECTIVE: Evaluation of the epidemiological situation of imported malaria in Poland in 2013 compared to the data from previous years. MATERIAL AND METHODS: The assessment was performed based on the results of the analysis of individual reports sent to the NIPH-NIH by sanitary-epidemiological stations and aggregated data published in the annual bulletins "Infectious diseases and poisonings in Poland". Cases were registered according to the case definition criteria applicable in the EU countries. RESULTS: In 2013, a total of 36 imported malaria cases were registered in Poland, 15 more than in 2012. No deaths were recorded. As much as 80% of all cases were imported from African countries, of whom the majority came from Nigeria, 14% from Asia and 6% from South America. Concurrent infection with dengue virus was confirmed in one person coming back from Philippines. Plasmodium species was determined in 35 of 36 cases by blood film or PCR test. Invasion with P. falciparum and P. vivax was found in 23 (66%) and 9 (26%) cases, respectively. There was also one case of each of the following: P. ovale, P. malariae and mixed invasion. As in previous years, in most cases, the invasion was associated with tourist trips (47%) or work-related travels (36%). Immigrants or students visiting the country of origin accounted for 11% of patients, in two cases (6%) purpose of the journey was not determined. As many as 7 patients used chemoprophylaxis, including two persons who took drugs in compliance with the recommendations. CONCLUSIONS: Despite a significant increase in the number of cases compared to previous years, the total number of imported malaria remains low. Persistent large number of delays in the diagnosis and a high percentage of severe malaria cases indicate the need to raise doctors awareness of the possibility of malaria incidence. Travelers should be also constantly reminded of the need to inform their GPs about the stay in the malaria endemic areas in the event of fever after returning. PMID- 26233087 TI - Tuberculosis in Poland in 2013. AB - AIM OF THE STUDY: To evaluate the main features of TB epidemiology in 2013 in Poland and to compare with the corresponding EU/EEA data. METHODS: Analysis of case- based clinical and demographic data on TB patients from Central TB Register, of data submitted by laboratories on anti-TB drug susceptibility testing results in cases notified in 2013, data from National Institute of Public Health- National Institute of Hygiene on cases of tuberculosis as AIDS-defining disease, from Central Statistical Office on deaths from tuberculosis based on death certificates, data from ECDC report "European Centre for Disease Prevention and Control/WHO Regional Office for Europe. Tuberculosis surveillance and monitoring in Europe 2015. Stockholm: European Centre for Disease Prevention and Control, 2015". RESULTS: 7250 TB cases were reported in Poland in 2013. The incidence rate was 18.8 cases per 100 000, with large variability between voivodships from 9.9 to 27.4. The mean annual decrease of TB incidence in 2009 2013 was 2.0%. 6403 cases had no history of previous treatment (rate 16.6). The number of all notified pulmonary tuberculosis cases was 6835; 17.8 per 100 000. The proportion of extrapulmonary tuberculosis among all registered cases was 5.7% (415 cases). In 2013, 34 patients had fibrous-cavernous pulmonary tuberculosis (0.5% of all cases of pulmonary tuberculosis). TB was diagnosed in 116 children (1.6% of all cases, incidence 2.0). The incidence of tuberculosis increased progressively with age to 33.7 among patients 65 years old and older. The mean age of new TB cases was 53.5 years. The incidence among men (26.8) was more than two times higher than among women (11.4). The incidence rate in rural population was lower than in urban areas; 17.1 vs. 20.0. Bacteriologically confirmed pulmonary cases (4825) constituted 68,2% of all pulmonary TB cases. The number of smear positive pulmonary TB cases was 2859 (61.3% of culture confirmed pulmonary cases). There were 52 foreigners registered among all cases of tuberculosis in Poland (0.7%) and 250 cases registered among prisoners (rate 298.0). There were 40 patients with MDR-TB (0.8% of cases with known DST results). TB was AIDS indicative disease in 35 cases. There were 630 deaths due to tuberculosis in 2012 (1.6 TB deaths per 100 000). Mortality among males--2.6--was more than 3 times higher than among females--0.8. CONCLUSIONS: In Poland in 2013 the incidence of tuberculosis was higher than the average in EU/EEA countries. The highest incidence rates occurred in older age groups. The incidence in men was more than 2 times higher than in women. The incidence of tuberculosis in children and the percentage of patients with drug- resistant tuberculosis are lower than average in the EU/EEA and that is favorable for epidemiological situation of tuberculosis in our country. PMID- 26233089 TI - Recommendations for the management of symptomatic Clostridium difficile infection (CDI). PMID- 26233088 TI - Occurrence and maintenance of hantavirus infections among rodent populations in their natural habitat--results of a field study from Podkarpackie province, Poland 2010-2012. AB - Human cases of hantavirus infection have been reported annually in Poland's Podkarpackie province, since 2007. In 2014 the number of cases reported significantly increased prompting a rise in studies focusing on the infection. OBJECTIVE: The purpose of this study was to evaluate the prevalence, maintenance and the dynamics of hantavirus infection among rodent species, including the bank vole (Myodes glareolus) and yellow-necked mouse (Apodemus flavicollis) which act as reservoirs of hantavirus in the environment. MATERIAL AND METHODS: Rodent capture was carried out on seven research grids in the Podkarpackie province, from summer 2010 to spring 2012. They were caught in live-capture traps used in accordance with the protocol CMR (Catch-Mark-Release). The population was estimated as MNA (Minimum Number Alive). Blood samples were collected for serological testing on live animals by puncture of saphenous vein. In order to determine the hantavirus infection we used ReaScan Ab-Dect Puumala IgG- Reagena(r) for bank voles, and for mice ELISA--Mouse Hanta Virus Test ELISA Kit (Version with Control Antigen Wells)--BioCat GmbH(r). The relationship between age, gender, seasons, population size and prevalence of hantavirus infection was tested by Pearson's chi-squared test or Fisher's exact test and by calculating the Pearson's correlation coefficient. RESULTS: A total of 854 rodents were captured: 222 bank voles, 592 yellow-necked mice, 4 common voles and 36 striped field mice. Of these, 564 were tested. The presence of specific anti-hantavirus was found in 9.7% of bank voles and 9.5% of yellow-necked mice. There was a statistically significant difference in the frequency of infection between the groups of male and female yellow-necked mice as well as in the groups of adult group in both species. The dynamics of spread of hantavirus infection was clearly evident in the studied area of Sanok. The correlation coefficient between the number of individuals caught and the prevalence of hantavirus infection in yellow necked mice was -0,87 but for the bank vole it was 0,76. SUMMARY AND CONCLUSIONS: The results of the study indicate that hantavirus infection among yellow-necked mice and bank voles are unevenly distributed in certain hot spots, vary over time, and are most in the spring season. In addition, differences observed in the dynamics of infection depended on the species of animal hosts. It would be advisable to conduct long-term study, which would allow for a risk assessment of the possibility of turning the spot located outbreaks into endemic area of hantavirus occurrence. PMID- 26233090 TI - Recommended management of Toxoplasma gondii infection in pregnant women and their children. AB - Aforesaid recommendations for the management of T.gondii infection, elaborated by the group of experts, are intended for physicians of various specialties in order to standardize and facilitate diagnostic and therapeutic management. Early diagnosis of congenital toxoplasmosis, both symptomatic and asymptomatic, in neonatal period, initiation of adequate treatment and long-term, multispecialist monitoring, including multi-organ rehabilitation of children may prevent or reduce the complications of congenital toxoplasmosis. Health education, whose role is often underestimated, should be targeted mainly on girls and women at reproductive age as to prevent from infection during pregnancy. PMID- 26233091 TI - Recommendations for the management of rickettsioses. PMID- 26233092 TI - Principles of diagnosis and treatment of bacterial purulent meningoencephalitis in adults. PMID- 26233093 TI - Diagnosis and treatment of tick-borne diseases recommendations of the Polish Society of Epidemiology and Infectious Diseases. PMID- 26233094 TI - Recommendations for elastography-based imaging of liver. PMID- 26233095 TI - Perspective: Electrospray photoelectron spectroscopy: From multiply-charged anions to ultracold anions. AB - Electrospray ionization (ESI) has become an essential tool in chemical physics and physical chemistry for the production of novel molecular ions from solution samples for a variety of spectroscopic experiments. ESI was used to produce free multiply-charged anions (MCAs) for photoelectron spectroscopy (PES) in the late 1990 s, allowing many interesting properties of this class of exotic species to be investigated. Free MCAs are characterized by strong intramolecular Coulomb repulsions, which create a repulsive Coulomb barrier (RCB) for electron emission. The RCB endows many fascinating properties to MCAs, giving rise to meta-stable anions with negative electron binding energies. Recent development in the PES of MCAs includes photoelectron imaging to examine the influence of the RCB on the electron emission dynamics, pump-probe experiments to examine electron tunneling through the RCB, and isomer-specific experiments by coupling PES with ion mobility for biological MCAs. The development of a cryogenically cooled Paul trap has led to much better resolved PE spectra for MCAs by creating vibrationally cold anions from the room temperature ESI source. Recent advances in coupling the cryogenic Paul trap with PE imaging have allowed high-resolution PE spectra to be obtained for singly charged anions produced by ESI. In particular, the observation of dipole-bound excited states has made it possible to conduct vibrational autodetachment spectroscopy and resonant PES, which yield much richer vibrational spectroscopic information for dipolar free radicals than traditional PES. PMID- 26233096 TI - Communication: The performance of non-iterative coupled cluster quadruples models. AB - We compare the numerical performance of various non-iterative coupled cluster (CC) quadruples models. The results collectively show how approaches that attempt to correct the CC singles and doubles energy for the combined effect of triple and quadruple excitations all fail at recovering the correlation energy of the full CC singles, doubles, triples, and quadruples (CCSDTQ) model to within sufficient accuracy. Such a level of accuracy is only achieved by models that make corrections to the full CC singles, doubles, and triples (CCSDT) energy for the isolated effect of quadruple excitations of which the CCSDT(Q-3) and CCSDT(Q 4) models of the Lagrangian-based CCSDT(Q-n) perturbation series are found to outperform alternative models that add either of the established [Q] and (Q) corrections to the CCSDT energy. PMID- 26233097 TI - Communication: Vibrational and vibronic coherences in the two dimensional spectroscopy of coupled electron-nuclear motion. AB - We theoretically investigate the photon-echo spectroscopy of coupled electron nuclear quantum dynamics. Two situations are treated. In the first case, the Born Oppenheimer (adiabatic) approximation holds. It is then possible to interpret the two-dimensional (2D) spectra in terms of vibrational motion taking place in different electronic states. In particular, pure vibrational coherences which are related to oscillations in the time-dependent third-order polarization can be identified. This concept fails in the second case, where strong non-adiabatic coupling leads to the breakdown of the Born-Oppenheimer-approximation. Then, the 2D-spectra reveal a complicated vibronic structure and vibrational coherences cannot be disentangled from the electronic motion. PMID- 26233098 TI - Communication: UV photoionization of cytosine catalyzed by Ag(+). AB - The photo-induced damages of DNA in interaction with metal cations, which are found in various environments, still remain to be characterized. In this paper, we show how the complexation of a DNA base (cytosine (Cyt)) with a metal cation (Ag(+)) changes its electronic properties. By means of UV photofragment spectroscopy of cold ions, it was found that the photoexcitation of the CytAg(+) complex at low energy (315-282) nm efficiently leads to ionized cytosine (Cyt(+)) as the single product. This occurs through a charge transfer state in which an electron from the p orbital of Cyt is promoted to Ag(+), as confirmed by ab initio calculations at the TD-DFT/B3LYP and RI-ADC(2) theory level using the SV(P) basis set. The low ionization energy of Cyt in the presence of Ag(+) could have important implications as point mutation of DNA upon sunlight exposition. PMID- 26233099 TI - Communication: Non-monotonic evolution of dynamical heterogeneity in unfreezing process of metallic glasses. AB - The relaxation dynamics in unfreezing process of metallic glasses is investigated by the activation-relaxation technique. A non-monotonic dynamical microstructural heterogeneities evolution with temperature is discovered, which confirms and supplies more features to flow units concept of glasses. A flow unit perspective is proposed to microscopically describe this non-monotonic evolution of the dynamical heterogeneities as well as its relationship with the deformation mode development of metallic glasses. PMID- 26233100 TI - Communication: Classical threshold law for ion-neutral-neutral three-body recombination. AB - A very recently method for classical trajectory calculations for three-body collision [Perez-Rios et al., J. Chem. Phys. 140, 044307 (2014)] has been applied to describe ion-neutral-neutral ternary processes for low energy collisions: 0.1 mK-10 mK. As a result, a threshold law for the three-body recombination cross section is obtained and corroborated numerically. The derived threshold law predicts the formation of weakly bound dimers, with binding energies comparable to the collision energy of the collisional partners. In this low energy range, this analysis predicts that molecular ions should dominate over molecular neutrals as the most products formed. PMID- 26233101 TI - Sculpting bespoke mountains: Determining free energies with basis expansions. AB - The intriguing behavior of a wide variety of physical systems, ranging from amorphous solids or glasses to proteins, is a direct manifestation of underlying free energy landscapes riddled with local minima separated by large barriers. Exploring such landscapes has arguably become one of statistical physics's great challenges. A new method is proposed here for uniform sampling of rugged free energy surfaces. The method, which relies on special Green's functions to approximate the Dirac delta function, improves significantly on existing simulation techniques by providing a boundary-agnostic approach that is capable of mapping complex features in multidimensional free energy surfaces. The usefulness of the proposed approach is established in the context of a simple model glass former and model proteins, demonstrating improved convergence and accuracy over existing methods. PMID- 26233102 TI - A Gaussian wave packet phase-space representation of quantum canonical statistics. AB - We present a mapping of quantum canonical statistical averages onto a phase-space average over thawed Gaussian wave-packet (GWP) parameters, which is exact for harmonic systems at all temperatures. The mapping invokes an effective potential surface, experienced by the wave packets, and a temperature-dependent phase-space integrand, to correctly transition from the GWP average at low temperature to classical statistics at high temperature. Numerical tests on weakly and strongly anharmonic model systems demonstrate that thermal averages of the system energy and geometric properties are accurate to within 1% of the exact quantum values at all temperatures. PMID- 26233104 TI - Using an iterative eigensolver to compute vibrational energies with phase-spaced localized basis functions. AB - Although phase-space localized Gaussians are themselves poor basis functions, they can be used to effectively contract a discrete variable representation basis [A. Shimshovitz and D. J. Tannor, Phys. Rev. Lett. 109, 070402 (2012)]. This works despite the fact that elements of the Hamiltonian and overlap matrices labelled by discarded Gaussians are not small. By formulating the matrix problem as a regular (i.e., not a generalized) matrix eigenvalue problem, we show that it is possible to use an iterative eigensolver to compute vibrational energy levels in the Gaussian basis. PMID- 26233105 TI - Monte Carlo simulation of dense polymer melts using event chain algorithms. AB - We propose an efficient Monte Carlo algorithm for the off-lattice simulation of dense hard sphere polymer melts using cluster moves, called event chains, which allow for a rejection-free treatment of the excluded volume. Event chains also allow for an efficient preparation of initial configurations in polymer melts. We parallelize the event chain Monte Carlo algorithm to further increase simulation speeds and suggest additional local topology-changing moves ("swap" moves) to accelerate equilibration. By comparison with other Monte Carlo and molecular dynamics simulations, we verify that the event chain algorithm reproduces the correct equilibrium behavior of polymer chains in the melt. By comparing intrapolymer diffusion time scales, we show that event chain Monte Carlo algorithms can achieve simulation speeds comparable to optimized molecular dynamics simulations. The event chain Monte Carlo algorithm exhibits Rouse dynamics on short time scales. In the absence of swap moves, we find reptation dynamics on intermediate time scales for long chains. PMID- 26233103 TI - A new smoothing function to introduce long-range electrostatic effects in QM/MM calculations. AB - A new method to account for long range electrostatic contributions is proposed and implemented for quantum mechanics/molecular mechanics long range electrostatic correction (QM/MM-LREC) calculations. This method involves the use of the minimum image convention under periodic boundary conditions and a new smoothing function for energies and forces at the cutoff boundary for the Coulomb interactions. Compared to conventional QM/MM calculations without long-range electrostatic corrections, the new method effectively includes effects on the MM environment in the primary image from its replicas in the neighborhood. QM/MM LREC offers three useful features including the avoidance of calculations in reciprocal space (k-space), with the concomitant avoidance of having to reproduce (analytically or approximately) the QM charge density in k-space, and the straightforward availability of analytical Hessians. The new method is tested and compared with results from smooth particle mesh Ewald (PME) for three systems including a box of neat water, a double proton transfer reaction, and the geometry optimization of the critical point structures for the rate limiting step of the DNA dealkylase AlkB. As with other smoothing or shifting functions, relatively large cutoffs are necessary to achieve comparable accuracy with PME. For the double-proton transfer reaction, the use of a 22 A cutoff shows a close reaction energy profile and geometries of stationary structures with QM/MM-LREC compared to conventional QM/MM with no truncation. Geometry optimization of stationary structures for the hydrogen abstraction step by AlkB shows some differences between QM/MM-LREC and the conventional QM/MM. These differences underscore the necessity of the inclusion of the long-range electrostatic contribution. PMID- 26233106 TI - Using multi-dimensional Smolyak interpolation to make a sum-of-products potential. AB - We propose a new method for obtaining potential energy surfaces in sum-of products (SOP) form. If the number of terms is small enough, a SOP potential surface significantly reduces the cost of quantum dynamics calculations by obviating the need to do multidimensional integrals by quadrature. The method is based on a Smolyak interpolation technique and uses polynomial-like or spectral basis functions and 1D Lagrange-type functions. When written in terms of the basis functions from which the Lagrange-type functions are built, the Smolyak interpolant has only a modest number of terms. The ideas are tested for HONO (nitrous acid). PMID- 26233107 TI - Theoretically informed Monte Carlo simulation of liquid crystals by sampling of alignment-tensor fields. AB - A theoretically informed coarse-grained Monte Carlo method is proposed for studying liquid crystals. The free energy functional of the system is described in the framework of the Landau-de Gennes formalism. The alignment field and its gradients are approximated by finite differences, and the free energy is minimized through a stochastic sampling technique. The validity of the proposed method is established by comparing the results of the proposed approach to those of traditional free energy minimization techniques. Its usefulness is illustrated in the context of three systems, namely, a nematic liquid crystal confined in a slit channel, a nematic liquid crystal droplet, and a chiral liquid crystal in the bulk. It is found that for systems that exhibit multiple metastable morphologies, the proposed Monte Carlo method is generally able to identify lower free energy states that are often missed by traditional approaches. Importantly, the Monte Carlo method identifies such states from random initial configurations, thereby obviating the need for educated initial guesses that can be difficult to formulate. PMID- 26233108 TI - Kinetic Monte Carlo simulations of surface reactions on supported nanoparticles: A novel approach and computer code. AB - So far most kinetic Monte Carlo (kMC) simulations of heterogeneously catalyzed gas phase reactions were limited to flat crystal surfaces. The newly developed program MoCKA (Monte Carlo Karlsruhe) combines graph-theoretical and lattice based principles to be able to efficiently handle multiple lattices with a large number of sites, which account for different facets of the catalytic nanoparticle and the support material, and pursues a general approach, which is not restricted to a specific surface or reaction. The implementation uses the efficient variable step size method and applies a fast update algorithm for its process list. It is shown that the analysis of communication between facets and of (reverse) spillover effects is possible by rewinding the kMC simulation. Hence, this approach offers a wide range of new applications for kMC simulations in heterogeneous catalysis. PMID- 26233109 TI - Noise analysis of genome-scale protein synthesis using a discrete computational model of translation. AB - Noise in genetic networks has been the subject of extensive experimental and computational studies. However, very few of these studies have considered noise properties using mechanistic models that account for the discrete movement of ribosomes and RNA polymerases along their corresponding templates (messenger RNA (mRNA) and DNA). The large size of these systems, which scales with the number of genes, mRNA copies, codons per mRNA, and ribosomes, is responsible for some of the challenges. Additionally, one should be able to describe the dynamics of ribosome exchange between the free ribosome pool and those bound to mRNAs, as well as how mRNA species compete for ribosomes. We developed an efficient algorithm for stochastic simulations that addresses these issues and used it to study the contribution and trade-offs of noise to translation properties (rates, time delays, and rate-limiting steps). The algorithm scales linearly with the number of mRNA copies, which allowed us to study the importance of genome-scale competition between mRNAs for the same ribosomes. We determined that noise is minimized under conditions maximizing the specific synthesis rate. Moreover, sensitivity analysis of the stochastic system revealed the importance of the elongation rate in the resultant noise, whereas the translation initiation rate constant was more closely related to the average protein synthesis rate. We observed significant differences between our results and the noise properties of the most commonly used translation models. Overall, our studies demonstrate that the use of full mechanistic models is essential for the study of noise in translation and transcription. PMID- 26233110 TI - Analytical gradients of the state-average complete active space self-consistent field method with density fitting. AB - An efficient implementation of the state-averaged complete active space self consistent field (SA-CASSCF) gradients employing density fitting (DF) is presented. The DF allows a reduction both in scaling and prefactors of the different steps involved. The performance of the algorithm is demonstrated on a set of molecules ranging up to an iron-Heme b complex which with its 79 atoms and 811 basis functions is to our knowledge the largest SA-CASSCF gradient computed. For smaller systems where the conventional code could still be used as a reference, both the linear response calculation and the gradient formation showed a clear timing reduction and the overall cost of a geometry optimization is typically reduced by more than one order of magnitude while the accuracy loss is negligible. PMID- 26233111 TI - Diffusion approximations to the chemical master equation only have a consistent stochastic thermodynamics at chemical equilibrium. AB - The stochastic thermodynamics of a dilute, well-stirred mixture of chemically reacting species is built on the stochastic trajectories of reaction events obtained from the chemical master equation. However, when the molecular populations are large, the discrete chemical master equation can be approximated with a continuous diffusion process, like the chemical Langevin equation or low noise approximation. In this paper, we investigate to what extent these diffusion approximations inherit the stochastic thermodynamics of the chemical master equation. We find that a stochastic-thermodynamic description is only valid at a detailed-balanced, equilibrium steady state. Away from equilibrium, where there is no consistent stochastic thermodynamics, we show that one can still use the diffusive solutions to approximate the underlying thermodynamics of the chemical master equation. PMID- 26233112 TI - Spin orbit coupling for molecular ab initio density matrix renormalization group calculations: Application to g-tensors. AB - Spin Orbit Coupling (SOC) is introduced to molecular ab initio density matrix renormalization group (DMRG) calculations. In the presented scheme, one first approximates the electronic ground state and a number of excited states of the Born-Oppenheimer (BO) Hamiltonian with the aid of the DMRG algorithm. Owing to the spin-adaptation of the algorithm, the total spin S is a good quantum number for these states. After the non-relativistic DMRG calculation is finished, all magnetic sublevels of the calculated states are constructed explicitly, and the SOC operator is expanded in the resulting basis. To this end, spin orbit coupled energies and wavefunctions are obtained as eigenvalues and eigenfunctions of the full Hamiltonian matrix which is composed of the SOC operator matrix and the BO Hamiltonian matrix. This treatment corresponds to a quasi-degenerate perturbation theory approach and can be regarded as the molecular equivalent to atomic Russell Saunders coupling. For the evaluation of SOC matrix elements, the full Breit Pauli SOC Hamiltonian is approximated by the widely used spin-orbit mean field operator. This operator allows for an efficient use of the second quantized triplet replacement operators that are readily generated during the non relativistic DMRG algorithm, together with the Wigner-Eckart theorem. With a set of spin-orbit coupled wavefunctions at hand, the molecular g-tensors are calculated following the scheme proposed by Gerloch and McMeeking. It interprets the effective molecular g-values as the slope of the energy difference between the lowest Kramers pair with respect to the strength of the applied magnetic field. Test calculations on a chemically relevant Mo complex demonstrate the capabilities of the presented method. PMID- 26233113 TI - Reliable prediction of three-body intermolecular interactions using dispersion corrected second-order Moller-Plesset perturbation theory. AB - Three-body and higher intermolecular interactions can play an important role in molecular condensed phases. Recent benchmark calculations found problematic behavior for many widely used density functional approximations in treating 3 body intermolecular interactions. Here, we demonstrate that the combination of second-order Moller-Plesset (MP2) perturbation theory plus short-range damped Axilrod-Teller-Muto (ATM) dispersion accurately describes 3-body interactions with reasonable computational cost. The empirical damping function used in the ATM dispersion term compensates both for the absence of higher-order dispersion contributions beyond the triple-dipole ATM term and non-additive short-range exchange terms which arise in third-order perturbation theory and beyond. Empirical damping enables this simple model to out-perform a non-expanded coupled Kohn-Sham dispersion correction for 3-body intermolecular dispersion. The MP2 plus ATM dispersion model approaches the accuracy of O(N(6)) methods like MP2.5 or even spin-component-scaled coupled cluster models for 3-body intermolecular interactions with only O(N(5)) computational cost. PMID- 26233114 TI - A multi-agent quantum Monte Carlo model for charge transport: Application to organic field-effect transistors. AB - We have developed a multi-agent quantum Monte Carlo model to describe the spatial dynamics of multiple majority charge carriers during conduction of electric current in the channel of organic field-effect transistors. The charge carriers are treated by a neglect of diatomic differential overlap Hamiltonian using a lattice of hydrogen-like basis functions. The local ionization energy and local electron affinity defined previously map the bulk structure of the transistor channel to external potentials for the simulations of electron- and hole conduction, respectively. The model is designed without a specific charge transport mechanism like hopping- or band-transport in mind and does not arbitrarily localize charge. An electrode model allows dynamic injection and depletion of charge carriers according to source-drain voltage. The field-effect is modeled by using the source-gate voltage in a Metropolis-like acceptance criterion. Although the current cannot be calculated because the simulations have no time axis, using the number of Monte Carlo moves as pseudo-time gives results that resemble experimental I/V curves. PMID- 26233115 TI - Density perturbation theory. AB - Despite the fundamental importance of electron density in density functional theory, perturbations are still usually dealt with using Hartree-Fock-like orbital equations known as coupled-perturbed Kohn-Sham (CPKS). As an alternative, we develop a perturbation theory that solves for the perturbed density directly, removing the need for CPKS. This replaces CPKS with a true Hohenberg-Kohn density perturbation theory. In CPKS, the perturbed density is found in the basis of products of occupied and virtual orbitals, which becomes ever more over-complete as the size of the orbital basis set increases. In our method, the perturbation to the density is expanded in terms of a series of density basis functions and found directly. It is possible to solve for the density in such a way that it makes the total energy stationary even if the density basis is incomplete. PMID- 26233116 TI - Interaction picture density matrix quantum Monte Carlo. AB - The recently developed density matrix quantum Monte Carlo (DMQMC) algorithm stochastically samples the N-body thermal density matrix and hence provides access to exact properties of many-particle quantum systems at arbitrary temperatures. We demonstrate that moving to the interaction picture provides substantial benefits when applying DMQMC to interacting fermions. In this first study, we focus on a system of much recent interest: the uniform electron gas in the warm dense regime. The basis set incompleteness error at finite temperature is investigated and extrapolated via a simple Monte Carlo sampling procedure. Finally, we provide benchmark calculations for a four-electron system, comparing our results to previous work where possible. PMID- 26233117 TI - Stimulated Raman signals at conical intersections: Ab initio surface hopping simulation protocol with direct propagation of the nuclear wave function. AB - Femtosecond Stimulated Raman Spectroscopy (FSRS) signals that monitor the excited state conical intersections dynamics of acrolein are simulated. An effective time dependent Hamiltonian for two C-H vibrational marker bands is constructed on the fly using a local mode expansion combined with a semi-classical surface hopping simulation protocol. The signals are obtained by a direct forward and backward propagation of the vibrational wave function on a numerical grid. Earlier work is extended to fully incorporate the anharmonicities and intermode couplings. PMID- 26233118 TI - Collective aspects of singlet fission in molecular crystals. AB - We present a model to describe collective features of singlet fission in molecular crystals and analyze it using many-body theory. The model we develop allows excitonic states to delocalize over several chromophores which is consistent with the character of the excited states in many molecular crystals, such as the acenes, where singlet fission occurs. As singlet states become more delocalized and triplet states more localized, the rate of singlet fission increases. We also determine the conditions under which the two triplets resulting from fission are correlated. Using the Bethe Ansatz and an entanglement measure for indistinguishable bipartite systems, we calculate the triplet-triplet entanglement as a function of the biexciton interaction strength. The biexciton interaction can produce bound biexciton states and provides a source of entanglement between the two triplets even when the triplets are spatially well separated. Significant entanglement between the triplet pair occurs well below the threshold for bound pair formation. Our results paint a dynamical picture that helps to explain why fission has been observed to be more efficient in molecular crystals than in their covalent dimer analogues and have consequences for photovoltaic efficiency models that assume that the two triplets can be extracted independently. PMID- 26233120 TI - Non-equilibrium reaction and relaxation dynamics in a strongly interacting explicit solvent: F + CD3CN treated with a parallel multi-state EVB model. AB - We describe a parallelized linear-scaling computational framework developed to implement arbitrarily large multi-state empirical valence bond (MS-EVB) calculations within CHARMM and TINKER. Forces are obtained using the Hellmann Feynman relationship, giving continuous gradients, and good energy conservation. Utilizing multi-dimensional Gaussian coupling elements fit to explicitly correlated coupled cluster theory, we built a 64-state MS-EVB model designed to study the F + CD3CN -> DF + CD2CN reaction in CD3CN solvent (recently reported in Dunning et al. [Science 347(6221), 530 (2015)]). This approach allows us to build a reactive potential energy surface whose balanced accuracy and efficiency considerably surpass what we could achieve otherwise. We ran molecular dynamics simulations to examine a range of observables which follow in the wake of the reactive event: energy deposition in the nascent reaction products, vibrational relaxation rates of excited DF in CD3CN solvent, equilibrium power spectra of DF in CD3CN, and time dependent spectral shifts associated with relaxation of the nascent DF. Many of our results are in good agreement with time-resolved experimental observations, providing evidence for the accuracy of our MS-EVB framework in treating both the solute and solute/solvent interactions. The simulations provide additional insight into the dynamics at sub-picosecond time scales that are difficult to resolve experimentally. In particular, the simulations show that (immediately following deuterium abstraction) the nascent DF finds itself in a non-equilibrium regime in two different respects: (1) it is highly vibrationally excited, with ~23 kcal mol(-1) localized in the stretch and (2) its post-reaction solvation environment, in which it is not yet hydrogen bonded to CD3CN solvent molecules, is intermediate between the non-interacting gas-phase limit and the solution-phase equilibrium limit. Vibrational relaxation of the nascent DF results in a spectral blue shift, while relaxation of the post reaction solvation environment results in a red shift. These two competing effects mean that the post-reaction relaxation profile is distinct from what is observed when Franck-Condon vibrational excitation of DF occurs within a microsolvation environment initially at equilibrium. Our conclusions, along with the theoretical and parallel software framework presented in this paper, should be more broadly applicable to a range of complex reactive systems. PMID- 26233119 TI - Markov state modeling and dynamical coarse-graining via discrete relaxation path sampling. AB - A method is derived to coarse-grain the dynamics of complex molecular systems to a Markov jump process (MJP) describing how the system jumps between cells that fully partition its state space. The main inputs are relaxation times for each pair of cells, which are shown to be robust with respect to positioning of the cell boundaries. These relaxation times can be calculated via molecular dynamics simulations performed in each cell separately and are used in an efficient estimator for the rate matrix of the MJP. The method is illustrated through applications to Sinai billiards and a cluster of Lennard-Jones discs. PMID- 26233121 TI - Copper ESEEM and HYSCORE through ultra-wideband chirp EPR spectroscopy. AB - The main limitation of pulse electron paramagnetic resonance (EPR) spectroscopy is its narrow excitation bandwidth. Ultra-wideband (UWB) excitation with frequency-swept chirp pulses over several hundreds of megahertz overcomes this drawback. This allows to excite electron spin echo envelope modulation (ESEEM) from paramagnetic copper centers in crystals, whereas up to now, only ESEEM of ligand nuclei like protons or nitrogens at lower frequencies could be detected. ESEEM spectra are recorded as two-dimensional correlation experiments, since the full digitization of the electron spin echo provides an additional Fourier transform EPR dimension. Thus, UWB hyperfine-sublevel correlation experiments generate a novel three-dimensional EPR-correlated nuclear modulation spectrum. PMID- 26233122 TI - Simple expressions of the nuclear relaxation rate enhancement due to quadrupole nuclei in slowly tumbling molecules. AB - For slowly tumbling entities or quasi-rigid lattices, we derive very simple analytical expressions of the quadrupole relaxation enhancement (QRE) of the longitudinal relaxation rate R1 of nuclear spins I due to their intramolecular magnetic dipolar coupling with quadrupole nuclei of arbitrary spins S >= 1. These expressions are obtained by using the adiabatic approximation for evaluating the time evolution operator of the quantum states of the quadrupole nuclei S. They are valid when the gyromagnetic ratio of the spin S is much smaller than that of the spin I. The theory predicts quadrupole resonant peaks in the dispersion curve of R1 vs magnetic field. The number, positions, relative intensities, Lorentzian shapes, and widths of these peaks are explained in terms of the following properties: the magnitude of the quadrupole Hamiltonian and the asymmetry parameter of the electric field gradient (EFG) acting on the spin S, the S-I inter-spin orientation with respect to the EFG principal axes, the rotational correlation time of the entity carrying the S-I pair, and/or the proper relaxation time of the spin S. The theory is first applied to protein amide protons undergoing dipolar coupling with fast-relaxing quadrupole (14)N nuclei and mediating the QRE to the observed bulk water protons. The theoretical QRE agrees well with its experimental counterpart for various systems such as bovine pancreatic trypsin inhibitor and cartilages. The anomalous behaviour of the relaxation rate of protons in synthetic aluminium silicate imogolite nano-tubes due to the QRE of (27)Al (S = 5/2) nuclei is also explained. PMID- 26233123 TI - Graph theoretical enumeration of topology-distinct structures for hydrogen fluoride clusters (HF)n (n <= 6). AB - A graph theoretical procedure to generate all the possible topology-distinct structures for hydrogen fluoride (HF) clusters is presented in this work. The hydrogen bond matrix is defined and used to enumerate the topology-distinct structures of hydrogen fluoride (HF)n (n = 2-8) clusters. From close investigation of the structural patterns obtained, several restrictions that should be satisfied for a structure of the HF clusters to be stable are found. The corresponding digraphs of generated hydrogen bond matrices are used as the theoretical framework to obtain all the topology-distinct local minima for (HF)n (n <= 6), at the level of MP2/6-31G**(d, p) of ab initio MO method and B3LYP/6 31G**(d, p) of density functional theory method. For HF clusters up to tetramers, the local minimum structures that we generated are same as those in the literature. For HF pentamers and hexamers, we found some new local minima structures which had not been obtained previously. PMID- 26233124 TI - Spectroscopic and theoretical studies of the low-lying states of BaO(+). AB - The BaO(+) cation is of interest from the perspectives of electronic structure and the potential for cooling to ultra-cold temperatures. Spectroscopic data for the ion have been obtained using a two-color photoionization technique. The ionization energy for BaO was found to be 6.8123(3) eV. The ground state of BaO(+) was identified as X(2)Sigma(+), and both vibrational and rotational constants were determined. Vibrationally resolved spectra were recorded for A(2)Pi, the first electronically excited state. These data yielded the term energy, vibrational frequency, and the spin-orbit interaction constant. Relativistic electronic structure calculations were carried out using multi reference configuration interaction (MRCI), coupled cluster and density functional theory methods. Transition moments for the pure vibrational and A(2)Pi X(2)Sigma(+) transitions were predicted using the MRCI method. PMID- 26233125 TI - Flowing-afterglow study of electron-ion recombination of para-H3(+) and ortho H3(+) ions at temperatures from 60 K to 300 K. AB - Detailed measurements employing a combination of a cryogenic flowing afterglow with Langmuir probe (Cryo-FALP II) and a stationary afterglow with near-infrared absorption spectroscopy (SA-CRDS) show that binary electron recombination of para H3(+) and ortho-H3(+) ions occurs with significantly different rate coefficients, (p)alphabin and (o)alphabin, especially at very low temperatures. The measurements cover temperatures from 60 K to 300 K. At the lowest temperature of 60 K, recombination of para-H3(+) is at least three times faster than that of ortho-H3(+) ((p)alphabin=(1.8+/-0.4)*10(-7) cm(3) s(-1) vs. (o)alphabin=(0-0 (+5))*10(-8) cm(3) s(-1)). PMID- 26233126 TI - Spin-torsion effects in the hyperfine structure of methanol. AB - The magnetic hyperfine structure of the non-rigid methanol molecule is investigated experimentally and theoretically. 12 hyperfine patterns are recorded using molecular beam microwave spectrometers. These patterns, along with previously recorded ones, are analyzed in an attempt to evidence the effects of the magnetic spin-torsion coupling due to the large amplitude internal rotation of the methyl group [J. E. M. Heuvel and A. Dymanus, J. Mol. Spectrosc. 47, 363 (1973)]. The theoretical approach setup to analyze the observed data accounts for this spin-torsion in addition to the familiar magnetic spin-rotation and spin spin interactions. The theoretical approach relies on symmetry considerations to build a hyperfine coupling Hamiltonian and spin-rotation-torsion wavefunctions compatible with the Pauli exclusion principle. Although all experimental hyperfine patterns are not fully resolved, the line position analysis yields values for several parameters including one describing the spin-torsion coupling. PMID- 26233127 TI - Photo-assisted intersystem crossing: The predominant triplet formation mechanism in some isolated polycyclic aromatic molecules excited with pulsed lasers. AB - Naphthalene, anthracene, and phenanthrene are shown to have very long-lived triplet lifetimes when the isolated molecules are excited with nanosecond pulsed lasers resonant with the lowest singlet state. For naphthalene, triplet state populations are created only during the laser pulse, excluding the possibility of normal intersystem crossing at the one photon level, and all molecules have triplet lifetimes greater than hundreds of microseconds, similar to the behavior previously reported for phenylacetylene. Although containing 7-12 thousand cm(-1) of vibrational energy, the triplet molecules have ionization thresholds appropriate to vibrationless T1 states. The laser power dependences (slopes of log-log power plots) of the excited singlet and triplet populations are about 0.7 for naphthalene and about 0.5 for anthracene. Kinetic modeling of the power dependences successfully reproduces the experimental results and suggests that the triplet formation mechanism involves an enhanced spin orbit coupling caused by sigma character in states at the 2-photon level. Symmetry adapted cluster configuration interaction calculations produced excited state absorption spectra to provide guidance for estimating kinetic rates and the sigma character present in higher electronic states. It is concluded that higher excited state populations are significant when larger molecules are excited with pulsed lasers and need to be taken into account whenever discussing the molecular photodynamics. PMID- 26233128 TI - Photoelectron spectra and structure of the Mnn(-) anions (n = 2-16). AB - Photoelectron spectra of the Mnn(-) anion clusters (n = 2-16) are obtained by anion photoelectron spectroscopy. The electronic and geometrical structures of the anions are computed using density functional theory with generalized gradient approximation and a basis set of triple-zeta quality. The electronic and geometrical structures of the neutral Mnn clusters have also been computed to estimate the adiabatic electron affinities. The average absolute difference between the computed and experimental vertical detachment energies of an extra electron is about 0.2 eV. Beginning with n = 6, all lowest total energy states of the Mnn(-) anions are ferrimagnetic with the spin multiplicities which do not exceed 8. The computed ionization energies of the neutral Mnn clusters are in good agreement with previously obtained experimental data. According to the results of our computations, the binding energies of Mn atoms are nearly independent on the cluster charge for n > 6 and possess prominent peaks at Mn13 and Mn13(-) in the neutral and anionic series, respectively. The density of states obtained from the results of our computations for the Mnn(-) anion clusters show the metallic character of the anion electronic structures. PMID- 26233129 TI - Structures of the 2-nitrophenol alkali complexes in solution and the solid state. AB - The materials studied in this investigation were aqueous solutions (0.02-25.0 mM) of the salts of alkali metal ion (Me(+)) and 2-nitrophenol (2-NP). In the investigation, small-angle X-ray scattering, wide-angle X-ray scattering, and membrane-pressure osmometry were used to study the 2-NP-Me(+) molecular salt structures and the onset of crystallization as a function of concentration and temperature. The experimental methods used to examine the 2-NP-Me(+) molecular salt complexes provided corroborative evidence for the existence of spherical clusters with hydrodynamic diameters between ~12 A (Li) and 14 A (Cs). Guinier plots of the zero-angle scattering peak were characteristic of the scattering from lamellae-like shapes with thicknesses of ~290 A. Tetramer and pentamer 2-NP Me(+) molecular clusters for Me(+) = Li, Na, K, and Rb were assembled from four or five 2-NP molecules bound to a central alkali metal ion. The coordination symmetry around the six coordinated Li(+), Na(+), and K(+) ions was that of a trigonal prism (D3h), with an octahedral arrangement (D2h). The Rb(+) also revealed six-coordinate geometry and the central Rb(+) ion adopted an octahedral arrangement (D2h). The eight-coordinated Cs(+) ions with six 2-NP ligands were characteristic of a square antiprism (D4d). The square antiprism was the outcome of leaving two o-nitro groups and two phenolic oxygens being left intermolecularly uncoordinated to the Cs(+) ion. The 2-NP residues were strictly planar and contained short non-bonded intramolecular distances. van der Waals forces were present between the adjacently stacked phenyl rings. No water molecules were involved as ligands for any of the 2-nitrophenol-Me(+) complexes. PMID- 26233130 TI - High-lying electronic states of the rubidium dimer-Ab initio predictions and experimental observation of the 5(1)Sigmau(+) and 5(1)Piu states of Rb2 by polarization labelling spectroscopy. AB - Two-colour polarization labelling experiments have been used to explore the excitation spectrum of the rubidium dimer in the region 25,500-27,000 cm(-1), probing two mutually interacting states, identified from ab initio calculations as the 5(1)Sigmau(+) and 5(1)Piu states whose atomic dissociation products are Rb(5s) + Rb(5d). Treating the rather irregular progressions observed in the excitation spectra as transitions to single states with (numerous) local perturbations, we propose spectroscopic parameters and potential energy curves to describe the investigated levels. Observations cover more than 20 vibrational levels in the inner minima of both the 5(1)Piu and 5(1)Sigmau(+) states. Analysis was guided by ab initio calculations performed to describe the (1,3)Lambdag,u electronic states of Rb2 up to the Rb(5s) + Rb(5f) atomic asymptote. The theoretical potential energy curves are given in ASCII format in an electronic supplement to this paper. PMID- 26233131 TI - Isotopic fractionation in proteins as a measure of hydrogen bond length. AB - If a deuterated molecule containing strong intramolecular hydrogen bonds is placed in a hydrogenated solvent, it may preferentially exchange deuterium for hydrogen. This preference is due to the difference between the vibrational zero point energy for hydrogen and deuterium. It is found that the associated fractionation factor Phi is correlated with the strength of the intramolecular hydrogen bonds. This correlation has been used to determine the length of the H bonds (donor-acceptor separation) in a diverse range of enzymes and has been argued to support the existence of short low-barrier H-bonds. Starting with a potential energy surface based on a simple diabatic state model for H-bonds, we calculate Phi as a function of the proton donor-acceptor distance R. For numerical results, we use a parameterization of the model for symmetric O-H?O bonds [R. H. McKenzie, Chem. Phys. Lett. 535, 196 (2012)]. We consider the relative contributions of the O-H stretch vibration, O-H bend vibrations (both in plane and out of plane), tunneling splitting effects at finite temperature, and the secondary geometric isotope effect. We compare our total Phi as a function of R with NMR experimental results for enzymes, and in particular with an earlier model parametrization Phi(R), used previously to determine bond lengths. PMID- 26233133 TI - Investigation on ultracold RbCs molecules in (2)0(+) long-range state below the Rb(5S1/2) + Cs(6P1/2) asymptote by high resolution photoassociation spectroscopy. AB - We present high resolution photoassociation spectroscopy of RbCs molecules in (2)0(+) long-range state below the Rb(5S1/2) + Cs(6P1/2) asymptote and derive the corresponding C6 coefficient, which is used to revise the potential energy curves. The excited state molecules are produced in a dual-species dark spontaneous force optical trap and detected by ionizing ground state molecules after spontaneous decay, using a high sensitive time-of-flight mass spectrum. With the help of resonance-enhanced two-photon ionization technique, we obtain considerable high resolution photoassociation spectrum with rovibrational states, some of which have never been observed before. By applying the LeRoy-Bernstein method, we assign the vibrational quantum numbers and deduce C6 coefficient, which agrees with the theoretical value of A(1)Sigma(+) state correlated to Rb(5S1/2) + Cs(6P1/2) asymptote. The obtained C6 coefficient is used to revise the long-range potential energy curve for (2)0(+) state, which possesses unique A - b mixing characteristic and can be a good candidate for the production of absolutely ground state molecule. PMID- 26233132 TI - Effect of kinetic energy on the doping efficiency of cesium cations into superfluid helium droplets. AB - We present an experimental investigation of the effect of kinetic energy on the ion doping efficiency of superfluid helium droplets using cesium cations from a thermionic emission source. The kinetic energy of Cs(+) is controlled by the bias voltage of a collection grid collinearly arranged with the droplet beam. Efficient doping from ions with kinetic energies from 20 eV up to 480 V has been observed in different sized helium droplets. The relative ion doping efficiency is determined by both the kinetic energy of the ions and the average size of the droplet beam. At a fixed source temperature, the number of doped droplets increases with increasing grid voltage, while the relative ion doping efficiency decreases. This result implies that not all ions are captured upon encountering with a sufficiently large droplet, a deviation from the near unity doping efficiency for closed shell neutral molecules. We propose that this drop in ion doping efficiency with kinetic energy is related to the limited deceleration rate inside a helium droplet. When the source temperature changes from 14 K to 17 K, the relative ion doping efficiency decreases rapidly, perhaps due to the lack of viable sized droplets. The size distribution of the Cs(+)-doped droplet beam can be measured by deflection and by energy filtering. The observed doped droplet size is about 5 * 10(6) helium atoms when the source temperature is between 14 K and 17 K. PMID- 26233134 TI - Resonances in rotationally inelastic scattering of NH3 and ND3 with H2. AB - We present theoretical studies on the scattering resonances in rotationally inelastic collisions of NH3 and ND3 molecules with H2 molecules. We use the quantum close-coupling method to compute state-to-state integral and differential cross sections for the NH3/ND3-H2 system for collision energies between 5 and 70 cm(-1), using a previously reported potential energy surface [Maret et al., Mon. Not. R. Astron. Soc. 399, 425 (2009)]. We identify the resonances as shape or Feshbach resonances. To analyze these, we use an adiabatic bender model, as well as examination at the scattering wave functions and lifetimes. The strength and width of the resonance peaks suggest that they could be observed in a crossed molecular beam experiment involving a Stark-decelerated NH3 beam. PMID- 26233135 TI - Torsion-vibration coupling in S1 toluene: Implications for IVR, the torsional barrier height, and rotational constants. AB - We have examined the S1<-S0 transition of toluene in the region from the 0(0)(0) band to ~210 cm(-1) above it. The spectrum reveals methyl rotor levels of 0(0) toluene up to m = 6 and of the lowest frequency vibration, 20(1), up to m = 4. The rotor levels of both 20(1) and 0(0) are perturbed by torsion-vibration coupling. The inclusion of torsion-vibration coupling leads to the S1 torsional barrier, V6, being revised from -26.376 cm(-1) to -5.59 cm(-1). The torsion vibration coupling constant is determined to be 21.1 cm(-1). This situation is the S1 analogue of that recently reported for S0 toluene [Gascooke et al., J. Chem. Phys. 142, 024315 (2015)]. Torsion-vibration coupling alters both the rotor band positions and the rotational contours, which particularly affects the rotational constants associated with motion around the a-axis, about which the methyl group rotates. Every vibrational state (indicated generically by X) will be involved in the corresponding X - X20(1) torsion-vibration coupling; so, this interaction permeates the vib-rotor manifold, providing a mechanism to enhance intramolecular vibrational energy redistribution. PMID- 26233136 TI - Isomeric signatures in the fragmentation of pyridazine and pyrimidine induced by fast ion impact. AB - We present fast proton impact induced fragmentations of pyrimidine and pyridazine as an experimental resource to investigate isomeric signatures. Major isomeric imprints are identified for few fragment ions and differences of more than an order of magnitude for the cross sections of fragments of the same mass were measured. The observation of the molecular structure of these isomers gives no apparent indication for the reasons for such substantial differences. It is verified that the simple displacement of the position of one nitrogen atom strongly inhibits or favors the production of some ionic fragment species. The dependency of the fragmentation cross sections on the proton impact energy, investigated by means of time of flight mass spectroscopy and of a model calculation based in first order perturbation theory, allows us to disentangle the complex collision dynamics of the ionic fragments. The proton-induced fragmentation discriminates rather directly the association between a molecular orbital ionization and the fragment-ions creation and abundance, as well as how the redistribution of the energy imparted to the molecules takes place, triggering not only single but also double vacancy and leads to specific fragmentation pathways. PMID- 26233137 TI - New potential energy surface for the HCS(+)-He system and inelastic rate coefficients. AB - A new high quality potential energy surface is calculated at a coupled-cluster single double triple level with an aug-cc-pV5Z basis set for the HCS(+)-He system. This potential energy surface is used in low energy quantum scattering calculations to provide a set of (de)-excitation cross sections and rate coefficients among the first 20 rotational levels of HCS(+) by He in the range of temperature from 5 K to 100 K. The paper discusses the impact of the new ab initio potential energy surface on the cross sections at low energy and provides a comparison with the HCO(+)-He system. The HCS(+)-He rate coefficients for the strongest transitions differ by factors of up to 2.5 from previous rate coefficients; thus, analysis of astrophysical spectra should be reconsidered with the new rate coefficients. PMID- 26233138 TI - Effect of CH stretching excitation on the reaction dynamics of F + CHD3 -> DF + CHD2. AB - The vibrationally excited reaction of F + CHD3(nu1 = 1) -> DF + CHD2 at a collision energy of 9.0 kcal/mol is investigated using the crossed-beams and time sliced velocity map imaging techniques. Detailed and quantitative information of the CH stretching excitation effects on the reactivity and dynamics of the title reaction is extracted with the help of an accurate determination of the fraction of the excited CHD3 reagent in the crossed-beam region. It is found that all vibrational states of the CHD2 products observed in the ground-state reaction, which mainly involve the excitation of the umbrella mode of the CHD2 products, are severely suppressed by the CH stretching excitation. However, there are four additional vibrational states of the CHD2 products appearing in the excited-state reaction which are not presented in the ground-state reaction. These vibrational states either have the CH stretching excitation retained or involve one quantum excitation in the CH stretching and the excitation of the umbrella mode. Including all observed vibrational states, the overall cross section of the excited-state reaction is estimated to be 66.6% of that of the ground-state one. Experimental results also show that when the energy of CH stretching excitation is released during the reaction, it is deposited almost exclusively as the rovibrational energy of the DF products, with little portion in the translational degree of freedom. For vibrational states of the CHD2 products observed in both ground- and excited-state reactions, the CH stretching excitation greatly suppresses the forward scattered products, causing a noticeable change in the product angular distributions. PMID- 26233139 TI - How to predict the ideal glass transition density in polydisperse hard-sphere packings. AB - The formula for the entropy s of the accessible volume of the phase space for frictionless hard spheres is combined with the Boublik-Mansoori-Carnahan-Starling Leland (BMCSL) equation of state for polydisperse three-dimensional packings to obtain an analytical expression for s as a function of packing density phi. Polydisperse hard-sphere packings with log-normal, Gaussian, and Pareto particle diameter distributions are generated to estimate their ideal glass transition densities phig. The accessible entropy s at phig is almost the same for all investigated particle diameter distributions. We denote this entropy as sg and can predict phig for an arbitrary particle diameter distribution through an equation s(phi) = sg. If the BMCSL equation of state is used for s(phi), then phig is found to depend only on the first three moments of a particle diameter distribution. PMID- 26233140 TI - Theoretical study on the hydrophobic and hydrophilic hydration on large solutes: The case of phthalocyanines in water. AB - A theoretical study on the hydration phenomena of three representative Phthalocyanines (Pcs): the metal-free, H2Pc, and the metal-containing, Cu phthalocyanine, CuPc, and its soluble sulphonated derivative, [CuPc(SO3)4](4-), is presented. Structural and dynamic properties of molecular dynamics trajectories of these Pcs in solution were evaluated. The hydration shells of the Pcs were defined by means of spheroids adapted to the solute shape. Structural analysis of the axial region compared to the peripheral region indicates that there are no significant changes among the different macrocycles, but that of [CuPc(SO3)4](4-), where the polyoxoanion presence induces a typically hydrophilic hydration structure. The analyzed water dynamic properties cover mean residence times, translational and orientational diffusion coefficients, and hydrogen bond network. These properties allow a thorough discussion about the simultaneous existence of hydrophobic and hydrophilic hydration in these macrocycles, and indicate the trend of water structure to well define shells in the environment of hydrophobic solutes. The comparison between the structural and dynamical analysis of the hydration of the amphipathic [CuPc(SO3)4](4-) and the non-soluble Cu-Pc shows a very weak coupling among the hydrophilic and hydrophobic fragments of the macrocycle. Quantitative results are employed to revisit the iceberg model proposed by Frank and Evans, leading to conclude that structure and dynamics support a non-strict interpretation of the iceberg view, although the qualitative trends pointed out by the model are supported. PMID- 26233141 TI - The nature of geometric frustration in the Kob-Andersen mixture. AB - Geometric frustration is an approach to the glass transition based upon the consideration of locally favoured structures (LFS), which are geometric motifs which minimise the local free energy. Geometric frustration proposes that a transition to a crystalline state is frustrated because these LFS do not tile space. However, this concept is based on icosahedra which are not always the LFS for a given system. The LFS of the popular Kob-Andersen (KA) model glassformer are the bicapped square antiprism, which does tile space. Such a LFS-crystal is indeed realised in the Al2Cu structure, which is predicted to be a low energy state for the KA model with a 2:1 composition. We, therefore, hypothesise that upon changing the composition in the KA model towards 2:1, geometric frustration may be progressively relieved, leading to larger and larger domains of LFS which would ultimately correspond to the Al2Cu crystal. Remarkably, rather than an increase, upon changing composition we find a small decrease in the LFS population, and the system remains impervious to nucleation of LFS crystals. We suggest that this may be related to the composition of the LFS, as only a limited subset is compatible with the crystal. We further demonstrate that the Al2Cu crystal will grow from a seed in the KA model with 2:1 composition and identify the melting temperature to be 0.447(2). PMID- 26233142 TI - Eighth to sixteenth virial coefficients of the Lennard-Jones model. AB - We calculated virial coefficients BN, 8 <= N <= 16, of the Lennard-Jones (LJ) model using both the Mayer-sampling Monte Carlo method and direct generation of configurations, with Wheatley's algorithm for summation of clusters. For N = 8, 24 values are reported, and for N = 9, 12 values are reported, both for temperatures T in the range 0.6 <= T <= 40.0 (in LJ units). For each N in 10 <= N <= 16, one to four values are reported for 0.6 <= T <= 0.9. An approximate functional form for the temperature dependence of BN was developed, and fits of LJ BN(T) based on this form are presented for each coefficient, 4 <= N <= 9, using new and previously reported data. PMID- 26233143 TI - Temperature-dependent solubilities and mean ionic activity coefficients of alkali halides in water from molecular dynamics simulations. AB - The mean ionic activity coefficients of aqueous KCl, NaF, NaI, and NaCl solutions of varying concentrations have been obtained from molecular dynamics simulations following a recently developed methodology based on gradual insertions of salt molecules [Z. Mester and A. Z. Panagiotopoulos, J. Chem. Phys. 142, 044507 (2015)]. The non-polarizable ion models of Weerasinghe and Smith [J. Chem. Phys. 119, 11342 (2003)], Gee et al. [J. Chem. Theory Comput. 7, 1369 (2011)], Reiser et al. [J. Chem. Phys. 140, 044504 (2014)], and Joung and Cheatham [J. Phys. Chem. B 112, 9020 (2008)] were used along with the extended simple point charge (SPC/E) water model [Berendsen et al., J. Phys. Chem. 91, 6269 (1987)] in the simulations. In addition to the chemical potentials in solution used to obtain the activity coefficients, we also calculated the chemical potentials of salt crystals and used them to obtain the solubility of these alkali halide models in SPC/E water. The models of Weerasinghe and Smith [J. Chem. Phys. 119, 11342 (2003)] and Gee et al. [J. Chem. Theory Comput. 7, 1369 (2011)] provide excellent predictions of the mean ionic activity coefficients at 298.15 K and 1 bar, but significantly underpredict or overpredict the solubilities. The other two models generally predicted the mean ionic activity coefficients only qualitatively. With the exception of NaF for which the solubility is significantly overpredicted, the model of Joung and Cheatham predicts salt solubilities that are approximately 40% 60% of the experimental values. The models of Reiser et al. [J. Chem. Phys. 140, 044504 (2014)] make good predictions for the NaCl and NaI solubilities, but significantly underpredict the solubilities for KCl and NaF. We also tested the transferability of the models to temperatures much higher than were used to parametrize them by performing simulations for NaCl at 373.15 K and 1 bar, and at 473.15 K and 15.5 bar. All models overpredict the drop in the values of mean ionic activity coefficients with increased temperature seen in experiments. The present results, together with earlier calculations for a number of models for NaCl aqueous solutions at 298.15 K, point to the strong need for development of improved intermolecular potential models for classical simulations of electrolyte solutions. PMID- 26233144 TI - Distinct dissociation kinetics between ion pairs: Solvent-coordinate free-energy landscape analysis. AB - Different ion pairs exhibit different dissociation kinetics; however, while the nature of this process is vital for understanding various molecular systems, the underlying mechanism remains unclear. In this study, to examine the origin of different kinetic rate constants for this process, molecular dynamics simulations were conducted for LiCl, NaCl, KCl, and CsCl in water. The results showed substantial differences in dissociation rate constant, following the trend kLiCl < kNaCl < kKCl < kCsCl. Analysis of the free-energy landscape with a solvent reaction coordinate and subsequent rate component analysis showed that the differences in these rate constants arose predominantly from the variation in solvent-state distribution between the ion pairs. The formation of a water bridging configuration, in which the water molecule binds to an anion and a cation simultaneously, was identified as a key step in this process: water-bridge formation lowers the related dissociation free-energy barrier, thereby increasing the probability of ion-pair dissociation. Consequently, a higher probability of water-bridge formation leads to a higher ion-pair dissociation rate. PMID- 26233145 TI - Extension of the BMCSL equation of state for hard spheres to the metastable disordered region: Application to the SAFT approach. AB - A simple modification of the Boublik-Mansoori-Carnahan-Starling-Leland equation of state is proposed for an application to the metastable disordered region. The new model has a positive pole at the jamming limit and can accurately describe the molecular simulation data of pure hard in the stable fluid region and along the metastable branch. The new model has also been applied to binary mixtures hard spheres, and an excellent description of the fluid and metastable branches can be obtained by adjusting the jamming packing fraction. The new model for hard sphere mixtures can be used as the repulsive term of equations of state for real fluids. In this case, the modified equations of state give very similar predictions of thermodynamic properties as the original models, and one can remove the multiple liquid density roots observed for some versions of the Statistical Associating Fluid Theory (SAFT) at low temperature without any modification of the dispersion term. PMID- 26233146 TI - Origin of abnormally sharp features in collision-induced spectra of cryosolutions. AB - A weak, paradoxically narrow resonance feature (shortly, the r-line) near the O2 fundamental frequency in the collision-induced absorption spectrum of oxygen dissolved in liquid argon and liquid nitrogen (T = 89 K) is resolved for the first time. An accurate band shape fitting routine to separate the r-line from the by-far more intense diffuse background and to study its behavior versus the oxygen mole fraction x which ranged from 0.03 up to 0.23 has been elaborated. At small x (?0.07), the r-line intensity was found to scale as x(2) leaving no doubt that it is due to the solute-solute (O2-O2) interactions. In line with our results on the pH2-LNe cryosystem [Herrebout, Phys. Rev. Lett. 101, 093001 (2008)], the Lorentzian r-line shape and its extraordinary sharpness (half width at half height ~ 1 cm(-1)) are indicative of the motional narrowing of the relative solute-solute translational spectrum. As x is further raised, ternary solute-solute interactions impede the r-line growth in the O2-LAr spectrum because of the cancellation effect [J. Van Kranendonk, Physica 23, 825 (1957)]. Theoretical arguments are given that multiple interactions between the solutes should finally destroy the solute-solute induced r-line when the mixed solution approaches the limit of the pure liquid (x = 1). Interestingly, the nonbinary effects are too weak to appreciably affect the quadratic r-line scaling in the O2 LN2 cryosystem which persists up to x = 0.23. It is emphasized that studies of the resonant features in the collision-induced spectra of binary cryosolutions open up unique opportunities to spectroscopically trace the microscopic-scale diffusion. PMID- 26233147 TI - Intermediate-range chemical ordering of cations in molten RbCl-AgCl. AB - A first sharp diffraction peak (FSDP) is observed in the X-ray total structure factor of a molten mixture of RbCl-AgCl, while both pure melts of RbCl and AgCl do not exhibit FSDP individually. Molecular dynamics simulations were performed to investigate the origin of the FSDP with the polarizable ion model (PIM). Coexistence of covalent Ag-Cl and ionic Rb-Cl bonds leads the system to evolve intermediate range ordering, which is simulated by introducing the induced polarization in different ways between Ag-Cl with fully polarizable treatment based on Vashishta-Raman potential and Rb-Cl with suppression over-polarization in the nearest neighbor contribution based on Born-Meyer potential. The partial structure factors for both the Ag-Ag and Rb-Rb correlations, SAgAg(Q) and SRbRb(Q), show a positive contribution to the FSDP, while SAgRb(Q) for the Ag-Rb correlation exhibits a negative contribution, indicating that Ag and Rb ions are distributed in an alternating manner within the intermediate-range length scale. The origin of the intermediate-range chemical ordering of cations can be ascribed to the preferred direction of the dipole moments of anions in the PIM. PMID- 26233148 TI - Thermodynamic nature of vitrification in a 1D model of a structural glass former. AB - We propose a new spin-glass model with no positional quenched disorder which is regarded as a coarse-grained model of a structural glass-former. The model is analyzed in the 1D case when the number N of states of a primary cell is large. For N -> infinity, the model exhibits a sharp freezing transition of the thermodynamic origin. It is shown both analytically and numerically that the glass transition is accompanied by a significant growth of a static length scale xi pointing to the structural (equilibrium) nature of dynamical slowdown effects in supercooled liquids. PMID- 26233149 TI - Free energy of ion hydration: Interface susceptibility and scaling with the ion size. AB - Free energy of solvation of a spherical ion in a force-field water is studied by numerical simulations. The focus is on the linear solvation susceptibility connecting the linear response solvation free energy to the squared ion charge. Spherical hard-sphere solutes, hard-sphere ions, and Kihara solutes (Lennard Jones modified hard-sphere core) are studied here. The scaling of the solvation susceptibility with the solute size significantly deviates from the Born equation. Using empirical offset corrections of the solute size (or the position of the first peak of the solute-solvent distribution function) do not improve the agreement with simulations. We advance a new perspective on the problem by deriving an exact relation for the radial susceptibility function of the interface. This function yields an effective cavity radius in the Born equation calculated from the solute-solvent radial distribution function. We find that the perspective of the local response, assuming significant alteration of the solvent structure by the solute, is preferable compared to the homogeneous approximation assuming intact solvent structure around the solute. The model finds a simple explanation of the asymmetry of hydration between anions and cations in denser water shells around anions and smaller cavity radii arising from the solute solvent density profiles. PMID- 26233150 TI - Lattice Boltzmann simulations of a viscoelastic shear-thinning fluid. AB - We present a hybrid lattice Boltzmann algorithm for the simulation of flow glass forming fluids, characterized by slow structural relaxation, at the level of the Navier-Stokes equation. The fluid is described in terms of a nonlinear integral constitutive equation, relating the stress tensor locally to the history of flow. As an application, we present results for an integral nonlinear Maxwell model that combines the effects of (linear) viscoelasticity and (nonlinear) shear thinning. We discuss the transient dynamics of velocities, shear stresses, and normal stress differences in planar pressure-driven channel flow, after switching on (startup) and off (cessation) of the driving pressure. This transient dynamics depends nontrivially on the channel width due to an interplay between hydrodynamic momentum diffusion and slow structural relaxation. PMID- 26233151 TI - Solute location in a nanoconfined liquid depends on charge distribution. AB - Nanostructured materials that can confine liquids have attracted increasing attention for their diverse properties and potential applications. Yet, significant gaps remain in our fundamental understanding of such nanoconfined liquids. Using replica exchange molecular dynamics simulations of a nanoscale, hydroxyl-terminated silica pore system, we determine how the locations explored by a coumarin 153 (C153) solute in ethanol depend on its charge distribution, which can be changed through a charge transfer electronic excitation. The solute position change is driven by the internal energy, which favors C153 at the pore surface compared to the pore interior, but less so for the more polar, excited state molecule. This is attributed to more favorable non-specific solvation of the large dipole moment excited-state C153 by ethanol at the expense of hydrogen bonding with the pore. It is shown that a change in molecule location resulting from shifts in the charge distribution is a general result, though how the solute position changes will depend upon the specific system. This has important implications for interpreting measurements and designing applications of mesoporous materials. PMID- 26233152 TI - Hydrated proton and hydroxide charge transfer at the liquid/vapor interface of water. AB - The role of the solvated excess proton and hydroxide ions in interfacial properties is an interesting scientific question with applications in a variety of aqueous behaviors. The role that charge transfer (CT) plays in interfacial behavior is also an unsettled question. Quantum calculations are carried out on clusters of water with an excess proton or a missing proton (hydroxide) to determine their CT. The quantum results are applied to analysis of multi-state empirical valence bond trajectories. The polyatomic nature of the solvated excess proton and hydroxide ion results in directionally dependent CT, depending on whether a water molecule is a hydrogen bond donor or acceptor in relation to the ion. With polyatomic molecules, CT also depends on the intramolecular bond distances in addition to intermolecular distances. The hydrated proton and hydroxide affect water's liquid/vapor interface in a manner similar to monatomic ions, in that they induce a hydrogen-bonding imbalance at the surface, which results in charged surface waters. This hydrogen bond imbalance, and thus the charged waters at the surface, persists until the ion is at least 10 A away from the interface. PMID- 26233153 TI - Wettability of graphitic-carbon and silicon surfaces: MD modeling and theoretical analysis. AB - The wettability of graphitic carbon and silicon surfaces was numerically and theoretically investigated. A multi-response method has been developed for the analysis of conventional molecular dynamics (MD) simulations of droplets wettability. The contact angle and indicators of the quality of the computations are tracked as a function of the data sets analyzed over time. This method of analysis allows accurate calculations of the contact angle obtained from the MD simulations. Analytical models were also developed for the calculation of the work of adhesion using the mean-field theory, accounting for the interfacial entropy changes. A calibration method is proposed to provide better predictions of the respective contact angles under different solid-liquid interaction potentials. Estimations of the binding energy between a water monomer and graphite match those previously reported. In addition, a breakdown in the relationship between the binding energy and the contact angle was observed. The macroscopic contact angles obtained from the MD simulations were found to match those predicted by the mean-field model for graphite under different wettability conditions, as well as the contact angles of Si(100) and Si(111) surfaces. Finally, an assessment of the effect of the Lennard-Jones cutoff radius was conducted to provide guidelines for future comparisons between numerical simulations and analytical models of wettability. PMID- 26233154 TI - Graphene oxide as an optimal candidate material for methane storage. AB - Methane, the primary constituent of natural gas, binds too weakly to nanostructured carbons to meet the targets set for on-board vehicular storage to be viable. We show, using density functional theory calculations, that replacing graphene by graphene oxide increases the adsorption energy of methane by 50%. This enhancement is sufficient to achieve the optimal binding strength. In order to gain insight into the sources of this increased binding, that could also be used to formulate design principles for novel storage materials, we consider a sequence of model systems that progressively take us from graphene to graphene oxide. A careful analysis of the various contributions to the weak binding between the methane molecule and the graphene oxide shows that the enhancement has important contributions from London dispersion interactions as well as electrostatic interactions such as Debye interactions, aided by geometric curvature induced primarily by the presence of epoxy groups. PMID- 26233156 TI - Phases, phase equilibria, and phase rules in low-dimensional systems. AB - We present a unified approach to thermodynamic description of one, two, and three dimensional phases and phase transformations among them. The approach is based on a rigorous definition of a phase applicable to thermodynamic systems of any dimensionality. Within this approach, the same thermodynamic formalism can be applied for the description of phase transformations in bulk systems, interfaces, and line defects separating interface phases. For both lines and interfaces, we rigorously derive an adsorption equation, the phase coexistence equations, and other thermodynamic relations expressed in terms of generalized line and interface excess quantities. As a generalization of the Gibbs phase rule for bulk phases, we derive phase rules for lines and interfaces and predict the maximum number of phases than may coexist in systems of the respective dimensionality. PMID- 26233155 TI - Adsorption of biomedical coating molecules, amino acids, and short peptides on magnetite (110). AB - Superparamagnetic iron oxide nanoparticles for biomedical applications are usually coated with organic molecules to form a steric barrier against agglomeration. The stability of these coatings is well established in the synthesis medium but is more difficult to assess in physiological environment. To obtain a first theoretical estimate of their stability in such an environment, we perform density functional theory calculations of the adsorption of water, polyvinyl alcohol (PVA) and polyethylene glycol (PEG) coating molecules, as well as the monomer and dimer of glycine as a prototype short peptide, on the (110) surface of magnetite (Fe3O4) in vacuo. Our results show that PVA binds significantly stronger to the surface than both PEG and glycine, while the difference between the latter two is quite small. Depending on the coverage, the water adsorption strength is intermediate between PVA and glycine. Due to its strongly interacting OH side groups, PVA is likely to remain bound to the surface in the presence of short peptides. This stability will have to be further assessed by molecular dynamics in the solvated state for which the present work forms the basis. PMID- 26233157 TI - Effect of water on the local electric potential of simulated ionic micelles. AB - Ionic micelles in an aqueous solution containing single-charged counter-ions have been simulated by molecular dynamics. For both cationic and anionic micelles, it has been demonstrated that explicit description of solvent has strong effect on the micelle's electric field. The sign of the local charge alters in the immediate vicinity of the micellar crown and the electric potential varies nonmonotonically. Two micelle models have been examined: the hybrid model with a rigid hydrocarbon core and the atomistic model. For three molecular models of water (Simple Point Charge model (SPC), Transferable Intermolecular Potential 5- Points (TIP5P) and two-centered S2), the results have been compared with those for the continuum solvent model. The orientational ordering of solvent molecules has strong effect on the local electric field surprisingly far from the micelle surface. PMID- 26233158 TI - Percolation in suspensions of polydisperse hard rods: Quasi universality and finite-size effects. AB - We present a study of connectivity percolation in suspensions of hard spherocylinders by means of Monte Carlo simulation and connectedness percolation theory. We focus attention on polydispersity in the length, the diameter, and the connectedness criterion, and we invoke bimodal, Gaussian, and Weibull distributions for these. The main finding from our simulations is that the percolation threshold shows quasi universal behaviour, i.e., to a good approximation, it depends only on certain cumulants of the full size and connectivity distribution. Our connectedness percolation theory hinges on a Lee Parsons type of closure recently put forward that improves upon the often-used second virial approximation [T. Schilling, M. Miller, and P. van der Schoot, e print arXiv:1505.07660 (2015)]. The theory predicts exact universality. Theory and simulation agree quantitatively for aspect ratios in excess of 20, if we include the connectivity range in our definition of the aspect ratio of the particles. We further discuss the mechanism of cluster growth that, remarkably, differs between systems that are polydisperse in length and in width, and exhibits non-universal aspects. PMID- 26233159 TI - Study of translational and rotational dynamics of birefringent colloidal particles by depolarized light scattering in the far- and near-field regimes. AB - We characterize the translational and rotational dynamics of birefringent spherical colloidal particles by depolarized light scattering in the far- and near-field regimes. For this purpose, we use depolarized dynamic light scattering and propose an extension of dynamic heterodyne near-field light scattering that takes into account the polarization state of the light. Such a combination of methods allows to access colloidal dynamics in an extended q-range and permits to evaluate different modes of particles motion in suspension. Furthermore, we obtain a good agreement between results from the far- and near-field approaches thus validating our proposal and opening the possibility to investigate simultaneously the subtle interplay between translational and rotational motions of anisotropic colloidal particles in length-scales from the order of the particle size to several interparticle distances. PMID- 26233160 TI - Depolarized light scattering from prolate anisotropic particles: The influence of the particle shape on the field autocorrelation function. AB - We provide a theoretical analysis for the intermediate scattering function typically measured in depolarized dynamic light scattering experiments. We calculate the field autocorrelation function g1(VH)(Q,t) in dependence on the wave vector Q and the time t explicitly in a vertical-horizontal scattering geometry for differently shaped solids of revolution. The shape of prolate cylinders, spherocylinders, spindles, and double cones with variable aspect ratio is expanded in rotational invariants flm(r). By Fourier transform of these expansion coefficients, a formal multipole expansion of the scattering function is obtained, which is used to calculate the weighting coefficients appearing in the depolarized scattering function. In addition to translational and rotational diffusion, especially the translational-rotational coupling of shape-anisotropic objects is considered. From the short-time behavior of the intermediate scattering function, the first cumulants Gamma(Q) are calculated. In a depolarized scattering experiment, they deviate from the simple proportionality to Q(2). The coefficients flm(Q) strongly depend on the geometry and aspect ratio of the particles. The time dependence, in addition, is governed by the translational and rotational diffusion tensors, which are calculated by means of bead models for differently shaped particles in dependence on their aspect ratio. Therefore, our analysis shows how details of the particle shape--beyond their aspect ratio--can be determined by a precise scattering experiment. This is of high relevance in understanding smart materials which involve suspensions of anisotropic colloidal particles. PMID- 26233161 TI - Inverse patchy colloids with two and three patches. Analytical and numerical study. AB - We propose an analytical solution of the multi-density Ornstein-Zernike equation supplemented by the associative Percus-Yevick closure relations specifically designed to describe the equilibrium properties of the novel class of patchy colloidal particles represented by the inverse patchy colloids with arbitrary number of patches. Using Baxter's factorization method, we reduce solution of the problem to the solution of one nonlinear algebraic equation for the fraction of the particles with one non-bonded patch. We present closed-form expressions for the structure (structure factor) and thermodynamic (internal energy) properties of the system in terms of this fraction (and parameters of the model). We perform computer simulation studies and compare theoretical and computer simulation predictions for the pair distribution function, internal energy, and number of single and double bonds formed in the system, for two versions of the model, each with two and three patches. We consider the models with formation of the double bonds blocked by the patch-patch repulsion and the models without patch-patch repulsion. In general very good agreement between theoretical and computer simulation results is observed. PMID- 26233162 TI - Design strategies for self-assembly of discrete targets. AB - Both biological and artificial self-assembly processes can take place by a range of different schemes, from the successive addition of identical building blocks to hierarchical sequences of intermediates, all the way to the fully addressable limit in which each component is unique. In this paper, we introduce an idealized model of cubic particles with patterned faces that allows self-assembly strategies to be compared and tested. We consider a simple octameric target, starting with the minimal requirements for successful self-assembly and comparing the benefits and limitations of more sophisticated hierarchical and addressable schemes. Simulations are performed using a hybrid dynamical Monte Carlo protocol that allows self-assembling clusters to rearrange internally while still providing Stokes-Einstein-like diffusion of aggregates of different sizes. Our simulations explicitly capture the thermodynamic, dynamic, and steric challenges typically faced by self-assembly processes, including competition between multiple partially completed structures. Self-assembly pathways are extracted from the simulation trajectories by a fully extendable scheme for identifying structural fragments, which are then assembled into history diagrams for successfully completed target structures. For the simple target, a one-component assembly scheme is most efficient and robust overall, but hierarchical and addressable strategies can have an advantage under some conditions if high yield is a priority. PMID- 26233163 TI - Orientational ordering and phase behaviour of binary mixtures of hard spheres and hard spherocylinders. AB - We study the structure and fluid-phase behaviour of binary mixtures of hard spheres (HSs) and hard spherocylinders (HSCs) in isotropic and nematic states using the NPnAT ensemble Monte Carlo (MC) approach in which the normal component of the pressure tensor is fixed in a system confined between two hard walls. The method allows one to estimate the location of the isotropic-nematic phase transition and to observe the asymmetry in the composition between the coexisting phases, with the expected enhancement of the HSC concentration in the nematic phase. This is in stark contrast with the previously reported MC simulations where a conventional isotropic NPT ensemble was used. We further compare the simulation results with the theoretical predictions of two analytic theories that extend the original Parsons-Lee theory using the one-fluid and the many-fluid approximations [Malijevsky et al., J. Chem. Phys. 129, 144504 (2008)]. In the one fluid version of the theory, the properties of the mixture are related to an effective one-component HS system, while in the many-fluid theory, the components of the mixtures are represented as separate effective HS particles. The comparison reveals that both the one- and the many-fluid approaches provide a reasonably accurate quantitative description of the mixture including the predictions of the isotropic-nematic phase boundary and degree of orientational order of the HSC-HS mixture. PMID- 26233164 TI - Multiple folding pathways of proteins with shallow knots and co-translational folding. AB - We study the folding process in the shallowly knotted protein MJ0366 within two variants of a structure-based model. We observe that the resulting topological pathways are much richer than identified in previous studies. In addition to the single knot-loop events, we find novel, and dominant, two-loop mechanisms. We demonstrate that folding takes place in a range of temperatures and the conditions of most successful folding are at temperatures which are higher than those required for the fastest folding. We also demonstrate that nascent conditions are more favorable to knotting than off-ribosome folding. PMID- 26233165 TI - Spontaneous emergence of autocatalytic information-coding polymers. AB - Self-replicating systems based on information-coding polymers are of crucial importance in biology. They also recently emerged as a paradigm in material design on nano- and micro-scales. We present a general theoretical and numerical analysis of the problem of spontaneous emergence of autocatalysis for heteropolymers capable of template-assisted ligation driven by cyclic changes in the environment. Our central result is the existence of the first order transition between the regime dominated by free monomers and that with a self sustaining population of sufficiently long chains. We provide a simple, mathematically tractable model supported by numerical simulations, which predicts the distribution of chain lengths and the onset of autocatalysis in terms of the overall monomer concentration and two fundamental rate constants. Another key result of our study is the emergence of the kinetically limited optimal overlap length between a template and each of its two substrates. The template-assisted ligation allows for heritable transmission of the information encoded in chain sequences thus opening up the possibility of long-term memory and evolvability in such systems. PMID- 26233166 TI - The regulation mechanism of yitJ and metF riboswitches. AB - Riboswitches which function at the transcriptional level are sensitive to cotranscriptional folding. Based on the recently proposed theory of cotranscriptional folding, we developed a transition node approximation method to effectively decrease the conformation space of long RNA chains. Our results indicate that this approximation is reliable for calculating the cotranscriptional folding kinetics of long mRNA chains. We theoretically studied the cotranscriptional folding behavior of the yitJ and metF riboswitches in the absence/presence of S-adenosylmethionine. Although the two S-box riboswitches have similar OFF-state structures and share common features of riboswitches operated at the transcriptional level, their regulation mechanisms are different. The yitJ riboswitch is regulated by a combination of thermodynamic and kinetic mechanisms, while the metF riboswitch is solely kinetically controlled. For the yitJ riboswitch, transcriptional pausing at the U-stretch directly following the terminator decreases the amount of ligand required to trigger the switch. The different regulation mechanisms and binding affinities of the two riboswitches result from the different lengths of the anti-terminator helix, which in yitJ is short and only disrupts helix P1 of the riboswitch aptamer, but in metF is long and breaks both the helices P1 and P4. PMID- 26233167 TI - Computation of the binding free energy of peptides to graphene in explicit water. AB - The characteristic properties of graphene make it useful in an assortment of applications. One particular application--the use of graphene in biosensors- requires a thorough understanding of graphene-peptide interactions. In this study, the binding of glycine (G) capped amino acid residues (termed GXG tripeptides) to trilayer graphene surfaces in aqueous solution was examined and compared to results previously obtained for peptide binding to single-layer free standing graphene [A. N. Camden, S. A. Barr, and R. J. Berry, J. Phys. Chem. B 117, 10691-10697 (2013)]. In order to understand the interactions between the peptides and the surface, binding enthalpy and free energy values were calculated for each GXG system, where X cycled through the typical 20 amino acids. When the GXG tripeptides were bound to the surface, distinct conformations were observed, each with a different binding enthalpy. Analysis of the binding energy showed the binding of peptides to trilayer graphene was dominated by van der Waals interactions, unlike the free-standing graphene systems, where the binding was predominantly electrostatic in nature. These results demonstrate the utility of computational materials science in the mechanistic explanation of surface biomolecule interactions which could be applied to a wide range of systems. PMID- 26233168 TI - Rate turnover in mechano-catalytic coupling: A model and its microscopic origin. AB - A novel aspect in the area of mechano-chemistry concerns the effect of external forces on enzyme activity, i.e., the existence of mechano-catalytic coupling. Recent experiments on enzyme-catalyzed disulphide bond reduction in proteins under the effect of a force applied on the termini of the protein substrate reveal an unexpected biphasic force dependence for the bond cleavage rate. Here, using atomistic molecular dynamics simulations combined with Smoluchowski theory, we propose a model for this behavior. For a broad range of forces and systems, the model reproduces the experimentally observed rates by solving a reaction diffusion equation for a "protein coordinate" diffusing in a force-dependent effective potential. The atomistic simulations are used to compute, from first principles, the parameters of the model via a quasiharmonic analysis. Additionally, the simulations are also used to provide details about the microscopic degrees of freedom that are important for the underlying mechano catalysis. PMID- 26233169 TI - Dynamics of water around the complex structures formed between the KH domains of far upstream element binding protein and single-stranded DNA molecules. AB - Single-stranded DNA (ss-DNA) binding proteins specifically bind to the single stranded regions of the DNA and protect it from premature annealing, thereby stabilizing the DNA structure. We have carried out atomistic molecular dynamics simulations of the aqueous solutions of two DNA binding K homology (KH) domains (KH3 and KH4) of the far upstream element binding protein complexed with two short ss-DNA segments. Attempts have been made to explore the influence of the formation of such complex structures on the microscopic dynamics and hydrogen bond properties of the interfacial water molecules. It is found that the water molecules involved in bridging the ss-DNA segments and the protein domains form a highly constrained thin layer with extremely retarded mobility. These water molecules play important roles in freezing the conformational oscillations of the ss-DNA oligomers and thereby forming rigid complex structures. Further, it is demonstrated that the effect of complexation on the slow long-time relaxations of hydrogen bonds at the interface is correlated with hindered motions of the surrounding water molecules. Importantly, it is observed that the highly restricted motions of the water molecules bridging the protein and the DNA components in the complexed forms originate from more frequent hydrogen bond reformations. PMID- 26233170 TI - Publisher's Note: "Communication: Saturated CO2 absorption near 1.6 MUm for kilohertz-accuracy transition frequencies" [J. Chem. Phys. 142, 191103 (2015)]. PMID- 26233171 TI - Point/Counterpoint. Proton therapy is the most cost-effective modality for partial breast irradiation. PMID- 26233172 TI - Technical Note: Impact on detective quantum efficiency of edge angle determination method by International Electrotechnical Commission methodology for cardiac x-ray image detectors. AB - PURPOSE: Cardiac x-ray detectors are used to acquire moving images in real-time for angiography and interventional procedures. Detective quantum efficiency (DQE) is not generally measured on these dynamic detectors; the required "for processing" image data and control of x-ray settings have not been accessible. By 2016, USA hospital physicists will have the ability to measure DQE and will likely utilize the International Electrotechnical Commission (IEC) standard for measuring DQE of dynamic x-ray imaging devices. The current IEC standard requires an image of a tilted tungsten edge test object to obtain modulation transfer function (MTF) for DQE calculation. It specifies the range of edge angles to use; however, it does not specify a preferred method to determine this angle for image analysis. The study aimed to answer the question "will my choice in method impact my results?" Four different established edge angle determination methods were compared to investigate the impact on DQE. METHODS: Following the IEC standard, edge and flat field images were acquired on a cardiac flat-panel detector to calculate MTF and noise power spectrum, respectively, to determine DQE. Accuracy of the methods in determining the correct angle was ascertained using a simulated edge image with known angulations. Precision of the methods was ascertained using variability of MTF and DQE, calculated via bootstrapping. RESULTS: Three methods provided near equal angles and the same MTF while the fourth, with an angular difference of 6%, had a MTF lower by 3% at 1.5 mm(-1) spatial frequency and 8% at 2.5 mm(-1); corresponding DQE differences were 6% at 1.5 mm(-1) and 17% at 2.5 mm(-1); differences were greater than standard deviations in the measurements. CONCLUSIONS: DQE measurements may vary by a significant amount, depending on the method used to determine the edge angle when following the IEC standard methodology for a cardiac x-ray detector. The most accurate and precise methods are recommended for absolute assessments and reproducible measurements, respectively. PMID- 26233173 TI - Semiautomated head-and-neck IMRT planning using dose warping and scaling to robustly adapt plans in a knowledge database containing potentially suboptimal plans. AB - PURPOSE: Prior work by the authors and other groups has studied the creation of automated intensity modulated radiotherapy (IMRT) plans of equivalent quality to those in a patient database of manually created clinical plans; those database plans provided guidance on the achievable sparing to organs-at-risk (OARs). However, in certain sites, such as head-and-neck, the clinical plans may not be sufficiently optimized because of anatomical complexity and clinical time constraints. This could lead to automated plans that suboptimally exploit OAR sparing. This work investigates a novel dose warping and scaling scheme that attempts to reduce effects of suboptimal sparing in clinical database plans, thus improving the quality of semiautomated head-and-neck cancer (HNC) plans. METHODS: Knowledge-based radiotherapy (KBRT) plans for each of ten "query" patients were semiautomatically generated by identifying the most similar "match" patient in a database of 103 clinical manually created patient plans. The match patient's plans were adapted to the query case by: (1) deforming the match beam fluences to suit the query target volume and (2) warping the match primary/boost dose distribution to suit the query geometry and using the warped distribution to generate query primary/boost optimization dose-volume constraints. Item (2) included a distance scaling factor to improve query OAR dose sparing with respect to the possibly suboptimal clinical match plan. To further compensate for a component plan of the match case (primary/boost) not optimally sparing OARs, the query dose volume constraints were reduced using a dose scaling factor to be the minimum from either (a) the warped component plan (primary or boost) dose distribution or (b) the warped total plan dose distribution (primary + boost) scaled in proportion to the ratio of component prescription dose to total prescription dose. The dose-volume constraints were used to plan the query case with no human intervention to adjust constraints during plan optimization. RESULTS: KBRT and original clinical plans were dosimetrically equivalent for parotid glands (mean/median doses), spinal cord, and brainstem (maximum doses). KBRT plans significantly reduced larynx median doses (21.5 +/- 6.6 Gy to 17.9 +/- 3.9 Gy), and oral cavity mean (32.3 +/- 6.2 Gy to 28.9 +/- 5.4 Gy) and median (28.7 +/- 5.7 Gy to 23.2 +/- 5.3 Gy) doses. Doses to ipsilateral parotid gland, larynx, oral cavity, and brainstem were lower or equivalent in the KBRT plans for the majority of cases. By contrast, KBRT plans generated without the dose warping and dose scaling steps were not significantly different from the clinical plans. CONCLUSIONS: Fast, semiautomatically generated HNC IMRT plans adapted from existing plans in a clinical database can be of equivalent or better quality than manually created plans. The reductions in OAR doses in the semiautomated plans, compared to the clinical plans, indicate that the proposed dose warping and scaling method shows promise in mitigating the impact of suboptimal clinical plans. PMID- 26233174 TI - Methods, software and datasets to verify DVH calculations against analytical values: Twenty years late(r). AB - PURPOSE: The authors designed data, methods, and metrics that can serve as a standard, independent of any software package, to evaluate dose-volume histogram (DVH) calculation accuracy and detect limitations. The authors use simple geometrical objects at different orientations combined with dose grids of varying spatial resolution with linear 1D dose gradients; when combined, ground truth DVH curves can be calculated analytically in closed form to serve as the absolute standards. METHODS: dicom RT structure sets containing a small sphere, cylinder, and cone were created programmatically with axial plane spacing varying from 0.2 to 3 mm. Cylinders and cones were modeled in two different orientations with respect to the IEC 1217 Y axis. The contours were designed to stringently but methodically test voxelation methods required for DVH. Synthetic RT dose files were generated with 1D linear dose gradient and with grid resolution varying from 0.4 to 3 mm. Two commercial DVH algorithms-pinnacle (Philips Radiation Oncology Systems) and PlanIQ (Sun Nuclear Corp.)-were tested against analytical values using custom, noncommercial analysis software. In Test 1, axial contour spacing was constant at 0.2 mm while dose grid resolution varied. In Tests 2 and 3, the dose grid resolution was matched to varying subsampled axial contours with spacing of 1, 2, and 3 mm, and difference analysis and metrics were employed: (1) histograms of the accuracy of various DVH parameters (total volume, Dmax, Dmin, and doses to % volume: D99, D95, D5, D1, D0.03 cm(3)) and (2) volume errors extracted along the DVH curves were generated and summarized in tabular and graphical forms. RESULTS: In Test 1, pinnacle produced 52 deviations (15%) while PlanIQ produced 5 (1.5%). In Test 2, pinnacle and PlanIQ differed from analytical by >3% in 93 (36%) and 18 (7%) times, respectively. Excluding Dmin and Dmax as least clinically relevant would result in 32 (15%) vs 5 (2%) scored deviations for pinnacle vs PlanIQ in Test 1, while Test 2 would yield 53 (25%) vs 17 (8%). In Test 3, statistical analyses of volume errors extracted continuously along the curves show pinnacle to have more errors and higher variability (relative to PlanIQ), primarily due to pinnacle's lack of sufficient 3D grid supersampling. Another major driver for pinnacle errors is an inconsistency in implementation of the "end-capping"; the additional volume resulting from expanding superior and inferior contours halfway to the next slice is included in the total volume calculation, but dose voxels in this expanded volume are excluded from the DVH. PlanIQ had fewer deviations, and most were associated with a rotated cylinder modeled by rectangular axial contours; for coarser axial spacing, the limited number of cross-sectional rectangles hinders the ability to render the true structure volume. CONCLUSIONS: The method is applicable to any DVH-calculating software capable of importing dicom RT structure set and dose objects (the authors' examples are available for download). It includes a collection of tests that probe the design of the DVH algorithm, measure its accuracy, and identify failure modes. Merits and applicability of each test are discussed. PMID- 26233175 TI - Proton dose calculation on scatter-corrected CBCT image: Feasibility study for adaptive proton therapy. AB - PURPOSE: To demonstrate the feasibility of proton dose calculation on scatter corrected cone-beam computed tomographic (CBCT) images for the purpose of adaptive proton therapy. METHODS: CBCT projection images were acquired from anthropomorphic phantoms and a prostate patient using an on-board imaging system of an Elekta infinity linear accelerator. Two previously introduced techniques were used to correct the scattered x-rays in the raw projection images: uniform scatter correction (CBCTus) and a priori CT-based scatter correction (CBCTap). CBCT images were reconstructed using a standard FDK algorithm and GPU-based reconstruction toolkit. Soft tissue ROI-based HU shifting was used to improve HU accuracy of the uncorrected CBCT images and CBCTus, while no HU change was applied to the CBCTap. The degree of equivalence of the corrected CBCT images with respect to the reference CT image (CTref) was evaluated by using angular profiles of water equivalent path length (WEPL) and passively scattered proton treatment plans. The CBCTap was further evaluated in more realistic scenarios such as rectal filling and weight loss to assess the effect of mismatched prior information on the corrected images. RESULTS: The uncorrected CBCT and CBCTus images demonstrated substantial WEPL discrepancies (7.3 +/- 5.3 mm and 11.1 +/- 6.6 mm, respectively) with respect to the CTref, while the CBCTap images showed substantially reduced WEPL errors (2.4 +/- 2.0 mm). Similarly, the CBCTap-based treatment plans demonstrated a high pass rate (96.0% +/- 2.5% in 2 mm/2% criteria) in a 3D gamma analysis. CONCLUSIONS: A priori CT-based scatter correction technique was shown to be promising for adaptive proton therapy, as it achieved equivalent proton dose distributions and water equivalent path lengths compared to those of a reference CT in a selection of anthropomorphic phantoms. PMID- 26233177 TI - A multicenter study to quantify systematic variations and associated uncertainties in source positioning with commonly used HDR afterloaders and ring applicators for the treatment of cervical carcinomas. AB - PURPOSE: The reconstruction of radiation source position in the treatment planning system is a key part of the applicator reconstruction process in high dose rate (HDR) brachytherapy treatment of cervical carcinomas. The steep dose gradients, of as much as 12%/mm, associated with typical cervix treatments emphasize the importance of accurate and precise determination of source positions. However, a variety of methodologies with a range in associated measurement uncertainties, of up to +/-2.5 mm, are currently employed by various centers to do this. In addition, a recent pilot study by Awunor et al. ["Direct reconstruction and associated uncertainties of (192)Ir source dwell positions in ring applicators using gafchromic film in the treatment planning of HDR brachytherapy cervix patients," Phys. Med. Biol. 58, 3207-3225 (2013)] reported source positional differences of up to 2.6 mm between ring sets of the same type and geometry. This suggests a need for a comprehensive study to assess and quantify systematic source position variations between commonly used ring applicators and HDR afterloaders across multiple centers. METHODS: Eighty-six rings from 20 European brachytherapy centers were audited in the form of a postal audit with each center collecting the data independently. The data were collected by setting up the rings using a bespoke jig and irradiating gafchromic films at predetermined dwell positions using four afterloader types, MicroSelectron, Flexitron, GammaMed, and MultiSource, from three manufacturers, Nucletron, Varian, and Eckert & Ziegler BEBIG. Five different ring types in six sizes (O25 O35 mm) and two angles (45 degrees and 60 degrees ) were used. Coordinates of irradiated positions relative to the ring center were determined and collated, and source position differences quantified by ring type, size, and angle. RESULTS: The mean expanded measurement uncertainty (k = 2) along the direction of source travel was +/-1.4 mm. The standard deviation associated with the source position reproducibility was within +/-1.0 mm for all afterloaders. Maximum source positional variations of 2.1 and 3.9, 1.8 and 5.4, and 2.3 and 3.4 mm were observed at standard treatment positions for the O26, O30, and O32 mm sized 45 degrees and 60 degrees rings, respectively. Mean positional differences between a majority of the rings were within +/-1.0 mm. Mean positional differences between a majority of the intracenter ring sets were within the expanded measurement uncertainty. When comparing the 45 degrees -60 degrees source paths, mean differences of 1.6, 0.9, and 0.9 mm were observed across the O26, O30 (MicroSelectron), and O32 mm (GammaMed) rings, respectively. When comparing to manufacturer source path models, maximum offsets of 1.9 and 2.1, 2.6 and 2.3, and 0.8 and 1.6 mm were observed for the O26, O30 (MicroSelectron), and O30 mm (Flexitron) sized 45 degrees and 60 degrees rings, respectively. When comparing the audit to ring commissioning data of participating centers, mean differences of up to 2.4 mm were observed. CONCLUSIONS: A majority of the audited rings showed a good degree of manufacturer consistency; however, substantial positional variation observed between some rings emphasizes the importance of commissioning each ring before clinical use. Differences observed between audit and commissioning data also indicate some variation in source treatment positions across centers. PMID- 26233176 TI - T2-weighted four dimensional magnetic resonance imaging with result-driven phase sorting. AB - PURPOSE: T2-weighted MRI provides excellent tumor-to-tissue contrast for target volume delineation in radiation therapy treatment planning. This study aims at developing a novel T2-weighted retrospective four dimensional magnetic resonance imaging (4D-MRI) phase sorting technique for imaging organ/tumor respiratory motion. METHODS: A 2D fast T2-weighted half-Fourier acquisition single-shot turbo spin-echo MR sequence was used for image acquisition of 4D-MRI, with a frame rate of 2-3 frames/s. Respiratory motion was measured using an external breathing monitoring device. A phase sorting method was developed to sort the images by their corresponding respiratory phases. Besides, a result-driven strategy was applied to effectively utilize redundant images in the case when multiple images were allocated to a bin. This strategy, selecting the image with minimal amplitude error, will generate the most representative 4D-MRI. Since we are using a different image acquisition mode for 4D imaging (the sequential image acquisition scheme) with the conventionally used cine or helical image acquisition scheme, the 4D dataset sufficient condition was not obviously and directly predictable. An important challenge of the proposed technique was to determine the number of repeated scans (NR) required to obtain sufficient phase information at each slice position. To tackle this challenge, the authors first conducted computer simulations using real-time position management respiratory signals of the 29 cancer patients under an IRB-approved retrospective study to derive the relationships between NR and the following factors: number of slices (NS), number of 4D-MRI respiratory bins (NB), and starting phase at image acquisition (P0). To validate the authors' technique, 4D-MRI acquisition and reconstruction were simulated on a 4D digital extended cardiac-torso (XCAT) human phantom using simulation derived parameters. Twelve healthy volunteers were involved in an IRB-approved study to investigate the feasibility of this technique. RESULTS: 4D data acquisition completeness (Cp) increases as NR increases in an inverse-exponential fashion (Cp = 100 - 99 * exp(-0.18 * NR), when NB = 6, fitted using 29 patients' data). The NR required for 4D-MRI reconstruction (defined as achieving 95% completeness, Cp = 95%, NR = NR,95) is proportional to NB (NR,95 ~ 2.86 * NB, r = 1.0), but independent of NS and P0. Simulated XCAT 4D-MRI showed a clear pattern of respiratory motion. Tumor motion trajectories measured on 4D-MRI were comparable to the average input signal, with a mean relative amplitude error of 2.7% +/- 2.9%. Reconstructed 4D-MRI for healthy volunteers illustrated clear respiratory motion on three orthogonal planes, with minimal image artifacts. The artifacts were presumably caused by breathing irregularity and incompleteness of data acquisition (95% acquired only). The mean relative amplitude error between critical structure trajectory and average breathing curve for 12 healthy volunteers is 2.5 +/- 0.3 mm in superior-inferior direction. CONCLUSIONS: A novel T2-weighted retrospective phase sorting 4D-MRI technique has been developed and successfully applied on digital phantom and healthy volunteers. PMID- 26233178 TI - A hybrid approach for fusing 4D-MRI temporal information with 3D-CT for the study of lung and lung tumor motion. AB - PURPOSE: Accurate visualization of lung motion is important in many clinical applications, such as radiotherapy of lung cancer. Advancement in imaging modalities [e.g., computed tomography (CT) and MRI] has allowed dynamic imaging of lung and lung tumor motion. However, each imaging modality has its advantages and disadvantages. The study presented in this paper aims at generating synthetic 4D-CT dataset for lung cancer patients by combining both continuous three dimensional (3D) motion captured by 4D-MRI and the high spatial resolution captured by CT using the authors' proposed approach. METHODS: A novel hybrid approach based on deformable image registration (DIR) and finite element method simulation was developed to fuse a static 3D-CT volume (acquired under breath hold) and the 3D motion information extracted from 4D-MRI dataset, creating a synthetic 4D-CT dataset. RESULTS: The study focuses on imaging of lung and lung tumor. Comparing the synthetic 4D-CT dataset with the acquired 4D-CT dataset of six lung cancer patients based on 420 landmarks, accurate results (average error <2 mm) were achieved using the authors' proposed approach. Their hybrid approach achieved a 40% error reduction (based on landmarks assessment) over using only DIR techniques. CONCLUSIONS: The synthetic 4D-CT dataset generated has high spatial resolution, has excellent lung details, and is able to show movement of lung and lung tumor over multiple breathing cycles. PMID- 26233179 TI - Three dimensional dose distribution comparison of simple and complex acquisition trajectories in dedicated breast CT. AB - PURPOSE: A novel breast CT system capable of arbitrary 3D trajectories has been developed to address cone beam sampling insufficiency as well as to image further into the patient's chest wall. The purpose of this study was to characterize any trajectory-related differences in 3D x-ray dose distribution in a pendant target when imaged with different orbits. METHODS: Two acquisition trajectories were evaluated: circular azimuthal (no-tilt) and sinusoidal (saddle) orbit with +/-15 degrees tilts around a pendant breast, using Monte Carlo simulations as well as physical measurements. Simulations were performed with tungsten (W) filtration of a W-anode source; the simulated source flux was normalized to the measured exposure of a W-anode source. A water-filled cylindrical phantom was divided into 1 cm(3) voxels, and the cumulative energy deposited was tracked in each voxel. Energy deposited per voxel was converted to dose, yielding the 3D distributed dose volumes. Additionally, three cylindrical phantoms of different diameters (10, 12.5, and 15 cm) and an anthropomorphic breast phantom, initially filled with water (mimicking pure fibroglandular tissue) and then with a 75% methanol 25% water mixture (mimicking 50-50 fibroglandular-adipose tissues), were used to simulate the pendant breast geometry and scanned on the physical system. Ionization chamber calibrated radiochromic film was used to determine the dose delivered in a 2D plane through the center of the volume for a fully 3D CT scan using the different orbits. RESULTS: Measured experimental results for the same exposure indicated that the mean dose measured throughout the central slice for different diameters ranged from 3.93 to 5.28 mGy, with the lowest average dose measured on the largest cylinder with water mimicking a homogeneously fibroglandular breast. These results align well with the cylinder phantom Monte Carlo studies which also showed a marginal difference in dose delivered by a saddle trajectory in the central slice. Regardless of phantom material or filled fluid density, dose delivered by the saddle scan was negligibly different than the simple circular, no-tilt scans. The average dose measured in the breast phantom was marginally higher for saddle than the circular no tilt scan at 3.82 and 3.87 mGy, respectively. CONCLUSIONS: Not only does nontraditional 3D trajectory CT scanning yield more complete sampling of the breast volume but also has comparable dose deposition throughout the breast and anterior chest volume, as verified by Monte Carlo simulation and physical measurements. PMID- 26233180 TI - Selecting registration schemes in case of interstitial lung disease follow-up in CT. AB - PURPOSE: Primary goal of this study is to select optimal registration schemes in the framework of interstitial lung disease (ILD) follow-up analysis in CT. METHODS: A set of 128 multiresolution schemes composed of multiresolution nonrigid and combinations of rigid and nonrigid registration schemes are evaluated, utilizing ten artificially warped ILD follow-up volumes, originating from ten clinical volumetric CT scans of ILD affected patients, to select candidate optimal schemes. Specifically, all combinations of four transformation models (three rigid: rigid, similarity, affine and one nonrigid: third order B spline), four cost functions (sum-of-square distances, normalized correlation coefficient, mutual information, and normalized mutual information), four gradient descent optimizers (standard, regular step, adaptive stochastic, and finite difference), and two types of pyramids (recursive and Gaussian-smoothing) were considered. The selection process involves two stages. The first stage involves identification of schemes with deformation field singularities, according to the determinant of the Jacobian matrix. In the second stage, evaluation methodology is based on distance between corresponding landmark points in both normal lung parenchyma (NLP) and ILD affected regions. Statistical analysis was performed in order to select near optimal registration schemes per evaluation metric. Performance of the candidate registration schemes was verified on a case sample of ten clinical follow-up CT scans to obtain the selected registration schemes. RESULTS: By considering near optimal schemes common to all ranking lists, 16 out of 128 registration schemes were initially selected. These schemes obtained submillimeter registration accuracies in terms of average distance errors 0.18 +/- 0.01 mm for NLP and 0.20 +/- 0.01 mm for ILD, in case of artificially generated follow-up data. Registration accuracy in terms of average distance error in clinical follow-up data was in the range of 1.985-2.156 mm and 1.966-2.234 mm, for NLP and ILD affected regions, respectively, excluding schemes with statistically significant lower performance (Wilcoxon signed-ranks test, p < 0.05), resulting in 13 finally selected registration schemes. CONCLUSIONS: Selected registration schemes in case of ILD CT follow-up analysis indicate the significance of adaptive stochastic gradient descent optimizer, as well as the importance of combined rigid and nonrigid schemes providing high accuracy and time efficiency. The selected optimal deformable registration schemes are equivalent in terms of their accuracy and thus compatible in terms of their clinical outcome. PMID- 26233181 TI - Optical delay encoding for fast timing and detector signal multiplexing in PET. AB - PURPOSE: The large number of detector channels in modern positron emission tomography (PET) scanners poses a challenge in terms of readout electronics complexity. Multiplexing schemes are typically implemented to reduce the number of physical readout channels, but often result in performance degradation. Novel methods of multiplexing in PET must be developed to avoid this data degradation. The preservation of fast timing information is especially important for time-of flight PET. METHODS: A new multiplexing scheme based on encoding detector interaction events with a series of extremely fast overlapping optical pulses with precise delays is demonstrated in this work. Encoding events in this way potentially allows many detector channels to be simultaneously encoded onto a single optical fiber that is then read out by a single digitizer. A two channel silicon photomultiplier-based prototype utilizing this optical delay encoding technique along with dual threshold time-over-threshold is demonstrated. RESULTS: The optical encoding and multiplexing prototype achieves a coincidence time resolution of 160 ps full width at half maximum (FWHM) and an energy resolution of 13.1% FWHM at 511 keV with 3 * 3 * 5 mm(3) LYSO crystals. All interaction information for both detectors, including timing, energy, and channel identification, is encoded onto a single optical fiber with little degradation. CONCLUSIONS: Optical delay encoding and multiplexing technology could lead to time-of-flight PET scanners with fewer readout channels and simplified data acquisition systems. PMID- 26233182 TI - Technical Note: Automatic real-time ultrasound tracking of respiratory signal using selective filtering and dynamic template matching. AB - PURPOSE: In respiratory motion modeling for liver interventions, the respiratory signal is usually obtained by using special tracking devices to monitor external skin. However, due to intrinsic limits and cost consideration of these tracking devices, a purely ultrasound image-based approach to tracking the signal is a more feasible option. METHODS: In this study, a novel image-based method is proposed to obtain the respiratory signal directly from 2D ultrasound images by automatically identifying and tracking the liver boundary. The boundary identification is a multistage process, which is the key to utilize a Hessian matrix-based 2D filter to enhance the line-like liver boundary and weaken other liver tissues. For tracking the identified boundary, a new dynamic template matching technique is first applied to estimate 2D displacements, and a boundary specific selection mechanism is then introduced to extract the respiratory signal from the 2D displacements. RESULTS: The experiments demonstrate that their method can obtain accurate breathing signals, which are in key phases comparable to the manually annotation and highly consistent to the electromagnetic-tracked ground truth signals (average correlation coefficients 0.9209 and statistically significant p < 0.01). Meanwhile, the experiments also prove their method can achieve high real-time performance of about 80-160 Hz. CONCLUSIONS: This method provides a good alternative to traditional external-landmark-based tracking methods and may be widely applied for respiratory compensation in ultrasound guided liver interventions. PMID- 26233183 TI - Impact of different meander sizes on the RF transmit performance and coupling of microstrip line elements at 7 T. AB - PURPOSE: In this work, the transmit performance and interelement coupling characteristics of radio frequency (RF) antenna microstrip line elements are examined in simulations and measurements. METHODS: The initial point of the simulations is a microstrip line element loaded with a phantom. Meander structures are then introduced at the end of the element. The size of the meanders is increased in fixed steps and the magnetic field is optimized. In continuative simulations, the coupling between identical elements is evaluated for different element spacing and loading conditions. Verification of the simulation results is accomplished in measurements of the coupling between two identical elements for four different meander sizes. Image acquisition on a 7 T magnetic resonance imaging (MRI) system provides qualitative and quantitative comparisons to confirm the simulation results. RESULTS: Simulations point out an optimum range of meander sizes concerning coupling in all chosen geometric setups. Coupling measurement results are in good agreement with the simulations. Qualitative and quantitative comparisons of the acquired MRI images substantiate the coupling results. CONCLUSIONS: The coupling between coil elements in RF antenna arrays consisting of the investigated element types can be optimized under consideration of the central magnetic field strength or efficiency depending on the desired application. PMID- 26233184 TI - Automated cortical bone segmentation for multirow-detector CT imaging with validation and application to human studies. AB - PURPOSE: Cortical bone supports and protects human skeletal functions and plays an important role in determining bone strength and fracture risk. Cortical bone segmentation at a peripheral site using multirow-detector CT (MD-CT) imaging is useful for in vivo assessment of bone strength and fracture risk. Major challenges for the task emerge from limited spatial resolution, low signal-to noise ratio, presence of cortical pores, and structural complexity over the transition between trabecular and cortical bones. An automated algorithm for cortical bone segmentation at the distal tibia from in vivo MD-CT imaging is presented and its performance and application are examined. METHODS: The algorithm is completed in two major steps-(1) bone filling, alignment, and region of-interest computation and (2) segmentation of cortical bone. After the first step, the following sequence of tasks is performed to accomplish cortical bone segmentation-(1) detection of marrow space and possible pores, (2) computation of cortical bone thickness, detection of recession points, and confirmation and filling of true pores, and (3) detection of endosteal boundary and delineation of cortical bone. Effective generalizations of several digital topologic and geometric techniques are introduced and a fully automated algorithm is presented for cortical bone segmentation. RESULTS: An accuracy of 95.1% in terms of volume of agreement with manual outlining of cortical bone was observed in human MD-CT scans, while an accuracy of 88.5% was achieved when compared with manual outlining on postregistered high resolution micro-CT imaging. An intraclass correlation coefficient of 0.98 was obtained in cadaveric repeat scans. A pilot study was conducted to describe gender differences in cortical bone properties. This study involved 51 female and 46 male participants (age: 19-20 yr) from the Iowa Bone Development Study. Results from this pilot study suggest that, on average after adjustment for height and weight differences, males have thicker cortex (mean difference 0.33 mm and effect size 0.92 at the anterior region) with lower bone mineral density (mean difference -28.73 mg/cm(3) and effect size 1.35 at the posterior region) as compared to females. CONCLUSIONS: The algorithm presented is suitable for fully automated segmentation of cortical bone in MD-CT imaging of the distal tibia with high accuracy and reproducibility. Analysis of data from a pilot study demonstrated that the cortical bone indices allow quantification of gender differences in cortical bone from MD-CT imaging. Application to larger population groups, including those with compromised bone, is needed. PMID- 26233185 TI - Quantitative analysis of breast echotexture patterns in automated breast ultrasound images. AB - PURPOSE: Breast tissue composition is considered to be associated with breast cancer risk. This study aimed to develop a computer-aided classification (CAC) system to automatically classify echotexture patterns as heterogeneous or homogeneous using automated breast ultrasound (ABUS) images. METHODS: A CAC system was proposed that can recognize breast echotexture patterns in ABUS images. For each case, the echotexture pattern was assessed by two expert radiologists and classified as heterogeneous or homogeneous. After neutrosophic image transformation and fuzzy c-mean clusterings, the lower and upper boundaries of the fibroglandular tissues were defined. Then, the number of hypoechoic regions and histogram features were extracted from the fibroglandular tissues, and the support vector machine model with the leave-one-out cross-validation method was utilized as the classifier. The authors' database included a total of 208 ABUS images of the breasts of 104 females. RESULTS: The accuracies of the proposed system for the classification of heterogeneous and homogeneous echotexture patterns were 93.48% (43/46) and 92.59% (150/162), respectively, with an overall Az (area under the receiver operating characteristic curve) of 0.9786. The agreement between the radiologists and the proposed system was almost perfect, with a kappa value of 0.814. CONCLUSIONS: The use of ABUS and the proposed method can provide quantitative information on the echotexture patterns of the breast and can be used to evaluate whether breast echotexture patterns are associated with breast cancer risk in the future. PMID- 26233187 TI - A generalized reconstruction framework for unconventional PET systems. AB - PURPOSE: Quantitative estimation of the radionuclide activity concentration in positron emission tomography (PET) requires precise modeling of PET physics. The authors are focused on designing unconventional PET geometries for specific applications. This work reports the creation of a generalized reconstruction framework, capable of reconstructing tomographic PET data for systems that use right cuboidal detector elements positioned at arbitrary geometry using a regular Cartesian grid of image voxels. METHODS: The authors report on a variety of design choices and optimization for the creation of the generalized framework. The image reconstruction algorithm is maximum likelihood-expectation maximization. System geometry can be specified using a simple script. Given the geometry, a symmetry seeking algorithm finds existing symmetry in the geometry with respect to the image grid to improve the memory usage/speed. Normalization is approached from a geometry independent perspective. The system matrix is computed using the Siddon's algorithm and subcrystal approach. The program is parallelized through open multiprocessing and message passing interface libraries. A wide variety of systems can be modeled using the framework. This is made possible by modeling the underlying physics and data correction, while generalizing the geometry dependent features. RESULTS: Application of the framework for three novel PET systems, each designed for a specific application, is presented to demonstrate the robustness of the framework in modeling PET systems of unconventional geometry. Three PET systems of unconventional geometry are studied. (1) Virtual-pinhole half-ring insert integrated into Biograph-40: although the insert device improves image quality over conventional whole-body scanner, the image quality varies depending on the position of the insert and the object. (2) Virtual-pinhole flat-panel insert integrated into Biograph-40: preliminary results from an investigation into a modular flat-panel insert are presented. (3) Plant PET system: a reconfigurable PET system for imaging plants, with resolution of greater than 3.3 mm, is shown. Using the automated symmetry seeking algorithm, the authors achieved a compression ratio of the storage and memory requirement by a factor of approximately 50 for the half-ring and flat panel systems. For plant PET system, the compression ratio is approximately five. The ratio depends on the level of symmetry that exists in different geometries. CONCLUSIONS: This work brings the field closer to arbitrary geometry reconstruction. A generalized reconstruction framework can be used to validate multiple hypotheses and the effort required to investigate each system is reduced. Memory usage/speed can be improved with certain optimizations. PMID- 26233186 TI - Image-based reconstruction of three-dimensional myocardial infarct geometry for patient-specific modeling of cardiac electrophysiology. AB - PURPOSE: Accurate three-dimensional (3D) reconstruction of myocardial infarct geometry is crucial to patient-specific modeling of the heart aimed at providing therapeutic guidance in ischemic cardiomyopathy. However, myocardial infarct imaging is clinically performed using two-dimensional (2D) late-gadolinium enhanced cardiac magnetic resonance (LGE-CMR) techniques, and a method to build accurate 3D infarct reconstructions from the 2D LGE-CMR images has been lacking. The purpose of this study was to address this need. METHODS: The authors developed a novel methodology to reconstruct 3D infarct geometry from segmented low-resolution (Lo-res) clinical LGE-CMR images. Their methodology employed the so-called logarithm of odds (LogOdds) function to implicitly represent the shape of the infarct in segmented image slices as LogOdds maps. These 2D maps were then interpolated into a 3D image, and the result transformed via the inverse of LogOdds to a binary image representing the 3D infarct geometry. To assess the efficacy of this method, the authors utilized 39 high-resolution (Hi-res) LGE-CMR images, including 36 in vivo acquisitions of human subjects with prior myocardial infarction and 3 ex vivo scans of canine hearts following coronary ligation to induce infarction. The infarct was manually segmented by trained experts in each slice of the Hi-res images, and the segmented data were downsampled to typical clinical resolution. The proposed method was then used to reconstruct 3D infarct geometry from the downsampled images, and the resulting reconstructions were compared with the manually segmented data. The method was extensively evaluated using metrics based on geometry as well as results of electrophysiological simulations of cardiac sinus rhythm and ventricular tachycardia in individual hearts. Several alternative reconstruction techniques were also implemented and compared with the proposed method. RESULTS: The accuracy of the LogOdds method in reconstructing 3D infarct geometry, as measured by the Dice similarity coefficient, was 82.10% +/- 6.58%, a significantly higher value than those of the alternative reconstruction methods. Among outcomes of electrophysiological simulations with infarct reconstructions generated by various methods, the simulation results corresponding to the LogOdds method showed the smallest deviation from those corresponding to the manual reconstructions, as measured by metrics based on both activation maps and pseudo-ECGs. CONCLUSIONS: The authors have developed a novel method for reconstructing 3D infarct geometry from segmented slices of Lo-res clinical 2D LGE-CMR images. This method outperformed alternative approaches in reproducing expert manual 3D reconstructions and in electrophysiological simulations. PMID- 26233188 TI - CT perfusion analysis by nonlinear regression for predicting hemorrhagic transformation in ischemic stroke. AB - PURPOSE: Intravenous thrombolysis can improve clinical outcome in acute ischemic stroke patients but increases the risk of hemorrhagic transformation (HT). Blood brain barrier damage, which can be quantified by the vascular permeability for contrast agents, is a potential predictor for HT. This study aimed to assess whether this prediction can be improved by measuring vascular permeability using a novel fast nonlinear regression (NLR) method instead of Patlak analysis. METHODS: From a prospective ischemic stroke multicenter cohort study, 20 patients with HT on follow-up imaging and 40 patients without HT were selected. The permeability transfer constant K(trans) was measured in three ways; using standard Patlak analysis, Patlak analysis with a fixed offset, and the NLR method. In addition, the permeability-surface (PS) area product and the conventional perfusion parameters (blood volume, flow, and mean transit time) were measured using the NLR method. Relative values were calculated in two ways, i.e., by dividing the average in the infarct core by the average in the contralateral hemisphere, and by dividing the average in the ipsilateral hemisphere by the average in the contralateral hemisphere. Mann-Whitney U tests and receiver operating characteristic (ROC) analyses were performed to assess the discriminative power of each of the relative parameters. RESULTS: Both the infarct-core and whole-hemisphere averaged relative K(trans) (rK(trans)) values, measured with the NLR method, were significantly higher in the patients who developed HT as compared with those who did not. The rK(trans) measured with standard Patlak analysis was not significantly different. The relative PS (rPS), measured with NLR, had the highest discriminative power (P = 0.002). ROC analysis of rPS showed an area under the curve (AUC) of 0.75 (95% confidence interval: 0.62-0.89) and a sensitivity of 0.75 at a specificity of 0.75. The AUCs of the Patlak rK(trans), the Patlak rK(trans) with fixed offset, and the NLR rK(trans) were 0.58, 0.66, and 0.67, respectively. CONCLUSIONS: CT perfusion analysis may aid in predicting HT, but standard Patlak analysis did not provide estimates for rK(trans) that were significantly higher in the HT group. The rPS, measured in the infarct core with NLR, had superior discriminative power compared with K(trans) measured with either Patlak analysis with a fixed offset or NLR, and conventional perfusion parameters. PMID- 26233189 TI - Phase-based vascular input function: Improved quantitative DCE-MRI of atherosclerotic plaques. AB - PURPOSE: Quantitative pharmacokinetic modeling of dynamic contrast-enhanced (DCE) MRI can be used to assess atherosclerotic plaque microvasculature, which is an important marker of plaque vulnerability. Purpose of the present study was (1) to compare magnitude- versus phase-based vascular input functions (m-VIF vs ph-VIF) used in pharmacokinetic modeling and (2) to perform model calculations and flow phantom experiments to gain more insight into the differences between m-VIF and ph-VIF. METHODS: Population averaged m-VIF and ph-VIFs were acquired from 11 patients with carotid plaques and used for pharmacokinetic analysis in another 17 patients. Simulations, using the Bloch equations and the MRI scan geometry, and flow phantom experiments were performed to determine the effect of local blood velocity on the magnitude and phase signal enhancement. RESULTS: Simulations and flow phantom experiments revealed that flow within the lumen can lead to severe underestimation of m-VIF, while this is not the case for the ph-VIF. In line, the peak concentration of the m-VIF is significantly lower than ph-VIF (p < 0.001), in vivo. Quantitative model parameters for m- and ph-VIF differed in absolute values but were moderate to strongly correlated with each other [K(trans) Spearman's rho > 0.93 (p < 0.001) and vp Spearman's rho > 0.58 (p < 0.05)]. CONCLUSIONS: m-VIF is strongly influenced by local blood velocity, which leads to underestimation of the contrast medium concentration. Therefore, it is advised to use ph-VIF for DCE-MRI analysis of carotid plaques for accurate quantification. PMID- 26233190 TI - A multi-institutional study to assess adherence to lung stereotactic body radiotherapy planning goals. AB - PURPOSE: A multi-institutional planning study was performed to evaluate the frequency that current guidelines established by Radiation Therapy Oncology Group (RTOG) protocols and other literature for lung stereotactic body radiotherapy (SBRT) treatments are followed. METHODS: A total of 300 patients receiving lung SBRT treatments in four different institutions were retrospectively reviewed. The treatments were delivered using Linac based SBRT (160 patients) or image guided robotic radiosurgery (140). Most tumors were located peripherally (250/300). Median fractional doses and ranges were 18 Gy (8-20 Gy), 12 Gy (6-15 Gy), and 10 Gy (5-12 Gy) for three, four, and five fraction treatments, respectively. The following planning criteria derived from RTOG trials and the literature were used to evaluate the treatment plans: planning target volumes, PTVV 100 >= 95% and PTVV 95 >= 99%; conformality indices, CI100% < 1.2 and CI50% range of 2.9-5.9 dependent on PTV; total lung-ITV: V20Gy < 10%, V12.5Gy < 15%, and V5Gy < 37%; contralateral lung V5Gy < 26%; and maximum doses for spinal cord, esophagus, trachea/bronchus, and heart and great vessels. Populations were grouped by number of fractions, and dosimetric criteria satisfaction rates (CSRs) were reported. RESULTS: Five fraction regimens were the most common lung SBRT fractionation (46%). The median PTV was 27.2 cm(3) (range: 3.8-419.5 cm(3)). For all plans: mean PTVV 100 was 94.5% (+/-5.6%, planning CSR: 69.8%), mean PTVV 95 was 98.1% (+/-4.1%, CSR: 69.5%), mean CI100% was 1.14 (+/-0.21, CSR: 79.1%, and 16.5% within minor deviation), and mean CI50% was 5.63 (+/-2.8, CSR: 33.0%, and 28.0% within minor deviation). When comparing plans based on location, peripherally located tumors displayed higher PTVV 100 and PTVV 95 CSR (71.5% and 71.9%, respectively) than centrally located tumors (61.2% and 57.1%, respectively). Overall, the planning criteria were met for all the critical structure such as lung, heart, spinal cord, esophagus, and trachea/bronchus for at least 85% of the patients. CONCLUSIONS: Among the various parameters that were used to evaluate the SBRT plans, the CI100% and CI50% were the most challenging criteria to meet. Although the CSRs of organs at risk were higher among all cases, their proximity to the PTV was a significant factor. PMID- 26233191 TI - A novel synthetic single crystal diamond device for in vivo dosimetry. AB - PURPOSE: Aim of the present work is to evaluate the synthetic single crystal diamond Schottky photodiode developed at the laboratories of "Tor Vergata" University in Rome in a new dosimeter configuration specifically designed for offline wireless in vivo dosimetry (IVD) applications. METHODS: The new diamond based dosimeter, single crystal diamond detector (SCDD-iv), consists of a small unwired detector and a small external reading unit that can be connected to commercial electrometers for getting the detector readout after irradiation. Two nominally identical SCDD-iv dosimeter prototypes were fabricated and tested. A basic dosimetric characterization of detector performances relevant for IVD application was performed under irradiation with (60)Co and 6 MV photon beams. Preirradiation procedure, response stability, short and long term reproducibility, leakage charge, fading effect, linearity with dose, dose rate dependence, temperature dependence, and angular response were investigated. RESULTS: The SCDD-iv is simple, with no cables linked to the patient and the readout is immediate. The range of response with dose has been tested from 1 up to 12 Gy; the reading is independent of the accumulated dose and dose rate independent in the range between about 0.5 and 5 Gy/min; its temperature dependence is within 0.5% between 25 and 38 degrees C, and its directional dependence is within 2% from 0 degrees to 90 degrees . The combined relative standard uncertainty of absorbed dose to water measurements is estimated lower than the tolerance and action level of 5%. CONCLUSIONS: The reported results indicate the proposed novel offline dosimeter based on a synthetic single crystal diamond Schottky photodiode as a promising candidate for in vivo dosimetry applications with photon beams. PMID- 26233192 TI - Noise reduction for curve-linear structures in real time fluoroscopy applications using directional binary masks. AB - PURPOSE: Recent efforts in the reconstruction of interventional devices from two distinct views require the segmentation of the object in both fluoroscopic images. Noise might decrease the quality of the segmentation and cause artifacts in the reconstruction. The noise level depends on the x-ray dose the patient is exposed to. The proposed algorithm reduces the noise and enhances the separability of curvilinear devices in background subtracted fluoroscopic images to allow a more accurate segmentation. METHODS: The algorithm uses a set of binary masks to estimate a line conformity measure that determines the best direction for a directional filter kernel. If the calculated value exceeds a certain threshold, the directional kernel is used to obtain the filtered value. Otherwise, an isotropic filter kernel is used. RESULTS: The evaluation was performed on a set of 36 fluoroscopic images using a vascular head phantom with three different guidewires and nine different x-ray dosages from 6 nGy/pulse to 45 nGy/pulse as well as a clinical data set containing ten images. Compared with wavelet shrinkage and the bilateral filter, the proposed algorithm increased the average contrast to noise ratio by at least 17.8% for the phantom and 68.9% for the clinical images. The accuracy of the device segmentation was improved on average by at least 17.3% and 14.0%, respectively. CONCLUSIONS: The proposed algorithm was able to significantly reduce the amount of noise in the images and therefore increase the quality of the device segmentations compared to both the bilateral filter and the wavelet thresholding approach for all acquired noise levels using rotating directional filter kernels near line structures and isotropic kernels for the background. The application of the proposed algorithm for the 3D reconstruction of curvilinear devices from two views would allow a more accurate reconstruction of the device. PMID- 26233193 TI - Generation of hybrid sinograms for the recovery of kV-CT images with metal artifacts for helical tomotherapy. AB - PURPOSE: The overall goal of this study is to restore kilovoltage computed tomography (kV-CT) images which are disfigured by patients' metal prostheses. By generating a hybrid sinogram that is a combination of kV and megavoltage (MV) projection data, the authors suggest a novel metal artifact-reduction (MAR) method that retains the image quality to match that of kV-CT and simultaneously restores the information of metal prostheses lost due to photon starvation. METHODS: CT projection data contain information about attenuation coefficients and the total length of the attenuation. By normalizing raw kV projections with their own total lengths of attenuation, mean attenuation projections were obtained. In the same manner, mean density projections of MV-CT were obtained by the normalization of MV projections resulting from the forward projection of density-calibrated MV-CT images with the geometric parameters of the kV-CT device. To generate the hybrid sinogram, metal-affected signals of the kV sinogram were identified and replaced by the corresponding signals of the MV sinogram following a density calibration step with kV data. Filtered backprojection was implemented to reconstruct the hybrid CT image. To validate the authors' approach, they simulated four different scenarios for three heads and one pelvis using metallic rod inserts within a cylindrical phantom. Five inserts describing human body elements were also included in the phantom. The authors compared the image qualities among the kV, MV, and hybrid CT images by measuring the contrast-to-noise ratio (CNR), the signal-to-noise ratio (SNR), the densities of all inserts, and the spatial resolution. In addition, the MAR performance was compared among three existing MAR methods and the authors' hybrid method. Finally, for clinical trials, the authors produced hybrid images of three patients having dental metal prostheses to compare their MAR performances with those of the kV, MV, and three existing MAR methods. RESULTS: The authors compared the image quality and MAR performance of the hybrid method with those of other imaging modalities and the three MAR methods, respectively. The total measured mean of the CNR (SNR) values for the nonmetal inserts was determined to be 14.3 (35.3), 15.3 (37.8), and 25.5 (64.3) for the kV, MV, and hybrid images, respectively, and the spatial resolutions of the hybrid images were similar to those of the kV images. The measured densities of the metal and nonmetal inserts in the hybrid images were in good agreement with their true densities, except in cases of extremely low densities, such as air and lung. Using the hybrid method, major streak artifacts were suitably removed and no secondary artifacts were introduced in the resultant image. In clinical trials, the authors verified that kV and MV projections were successfully combined and turned into the resultant hybrid image with high image contrast, accurate metal information, and few metal artifacts. The hybrid method also outperformed the three existing MAR methods with regard to metal information restoration and secondary artifact prevention. CONCLUSIONS: The authors have shown that the hybrid method can restore the overall image quality of kV-CT disfigured by severe metal artifacts and restore the information of metal prostheses lost due to photon starvation. The hybrid images may allow for the improved delineation of structures of interest and accurate dose calculations for radiation treatment planning for patients with metal prostheses. PMID- 26233195 TI - Calibration of GafChromic EBT3 for absorbed dose measurements in 5 MeV proton beam and (60)Co gamma-rays. AB - PURPOSE: To study EBT3 GafChromic film in low-energy protons, and for comparison purposes, in a reference (60)Co beam in order to use it as a calibrated dosimetry system in the proton irradiation facility under construction within the framework of the Oncological Therapy with Protons (TOP)-Intensity Modulated Proton Linear Accelerator for RadioTherapy (IMPLART) Project at ENEA-Frascati, Italy. METHODS: EBT3 film samples were irradiated at the Istituto Nazionale di Fisica Nucleare Laboratori Nazionali di Legnaro, Italy, with a 5 MeV proton beam generated by a 7 MV Van de Graaff CN accelerator. The nominal dose rates used were 2.1 Gy/min and 40 Gy/min. The delivered dose was determined by measuring the particle fluence and the energy spectrum in air with silicon surface barrier detector monitors. A preliminary study of the EBT3 film beam quality dependence in low-energy protons was conducted by passively degrading the beam energy. EBT3 films were also irradiated at ENEA-National Institute of Ionizing Radiation Metrology with gamma radiation produced by a (60)Co source characterized by an absorbed dose to water rate of 0.26 Gy/min as measured by a calibrated Farmer type ionization chamber. EBT3 film calibration curves were determined by means of a set of 40 film pieces irradiated to various doses ranging from 0.5 Gy to 30 Gy absorbed dose to water. An EPSON Expression 11000XL color scanner in transmission mode was used for film analysis. Scanner response stability, intrafilm uniformity, and interfilm reproducibility were verified. Optical absorption spectra measurements were performed on unirradiated and irradiated EBT3 films to choose the most sensitive color channel to the dose range used. RESULTS: EBT3 GafChromic films show an under response up to about 33% for low-energy protons with respect to (60)Co gamma radiation, which is consistent with the linear energy transfer dependence already observed with higher energy protons, and a negligible dose-rate dependence in the 2-40 Gy/min range. Short- and long-term scanner stabilities were 0.5% and 1.5%, respectively; film uniformity and reproducibility were better than 0.5%. CONCLUSIONS: The main purpose of this study was to implement EBT3 dosimetry in the proton low-energy radiobiology line of the TOP-IMPLART accelerator, having a maximum energy of 7 MeV. Low-energy proton and (60)Co calibrated sources were used to investigate the behavior of film response vs to be written in italicum dose. The calibration in 5 MeV protons is currently used for dose assessment in the radiobiological experiments at the TOP-IMPLART accelerator carried out at that energy value. PMID- 26233194 TI - Accurate body composition measures from whole-body silhouettes. AB - PURPOSE: Obesity and its consequences, such as diabetes, are global health issues that burden about 171 * 10(6) adult individuals worldwide. Fat mass index (FMI, kg/m(2)), fat-free mass index (FFMI, kg/m(2)), and percent fat mass may be useful to evaluate under- and overnutrition and muscle development in a clinical or research environment. This proof-of-concept study tested whether frontal whole body silhouettes could be used to accurately measure body composition parameters using active shape modeling (ASM) techniques. METHODS: Binary shape images (silhouettes) were generated from the skin outline of dual-energy x-ray absorptiometry (DXA) whole-body scans of 200 healthy children of ages from 6 to 16 yr. The silhouette shape variation from the average was described using an ASM, which computed principal components for unique modes of shape. Predictive models were derived from the modes for FMI, FFMI, and percent fat using stepwise linear regression. The models were compared to simple models using demographics alone [age, sex, height, weight, and body mass index z-scores (BMIZ)]. RESULTS: The authors found that 95% of the shape variation of the sampled population could be explained using 26 modes. In most cases, the body composition variables could be predicted similarly between demographics-only and shape-only models. However, the combination of shape with demographics improved all estimates of boys and girls compared to the demographics-only model. The best prediction models for FMI, FFMI, and percent fat agreed with the actual measures with R(2) adj. (the coefficient of determination adjusted for the number of parameters used in the model equation) values of 0.86, 0.95, and 0.75 for boys and 0.90, 0.89, and 0.69 for girls, respectively. CONCLUSIONS: Whole-body silhouettes in children may be useful to derive estimates of body composition including FMI, FFMI, and percent fat. These results support the feasibility of measuring body composition variables from simple cameras such as those found in cell phones. PMID- 26233196 TI - Intercostal high intensity focused ultrasound for liver ablation: The influence of beam shaping on sonication efficacy and near-field risks. AB - PURPOSE: One of the major issues in high intensity focused ultrasound ablation of abdominal lesions is obstruction of the ultrasound beam by the thoracic cage. Beam shaping strategies have been shown by several authors to increase focal point intensity while limiting rib exposure. However, as rib obstruction leaves only part of the aperture available for energy transmission, conserving total emitted acoustic power, the intensity in the near-field tissues inherently increases after beam shaping. Despite of effective rib sparing, those tissues are therefore subjected to increased risk of thermal damage. In this study, for a number of clinically representative intercostal sonication geometries, modeling clinically available hardware, the effect of beam shaping on both the exposure of the ribs and near-field to acoustic energy was evaluated and the implications for the volumetric ablation rate were addressed. METHODS: A relationship between rib temperature rise and acoustic energy density was established by means of in vivo MR thermometry and simulations of the incident acoustic energy for the corresponding anatomies. This relationship was used for interpretation of rib exposure in subsequent numerical simulations in which rib spacing, focal point placement, and the focal point trajectory were varied. The time required to heat a targeted region to 65 degrees C was determined without and with the application of beam shaping. The required sonication time was used to calculate the acoustic energy density at the fat-muscle interface and at the surface of the ribs. At the fat-muscle interface, exposure was compared to available literature data and rib exposure was interpreted based on the earlier obtained relation between measured temperature rise and simulated acoustic energy density. To estimate the volumetric ablation rate, the cool-down time between periods of energy exposure was estimated using a time-averaged power limit of 100 kJ/h. RESULTS: At the level of the ribs, the temperature rise-energy density proportionality constant was estimated to be 6.0-7.6 degrees C/(J/mm(2)). Beam shaping by the geometric shadow method typically reduces the acoustic intensity a factor of 2, considering the 1 cm(2) with the highest exposure. For a 4 mm diameter circular sonication trajectory, the near-field energy limit of 2.5 J/mm(2) was exceeded for all considered geometries. The estimated rib temperature was in all but one (sonication 50 mm behind the ribs, with 15 mm rib spacing and a 4 mm diameter circular sonication trajectory) of the considered scenarios within acceptable limits. For those sonication scenarios where a single sonication is considered safe both in terms of near-field as well as rib heating, volumetric ablation rates in the order of 1 ml/h are estimated. CONCLUSIONS: Intercostal sonication is associated with an increased risk of near-field overheating. This risk is strongly dependent on the considered rib spacing, the placement of the focus behind the ribs, and the selected sonication trajectory. For the hardware under simulation, obstruction by the thoracic cage renders ablations of clinically relevant volumes within a practical time-frame unfeasible in a large part of the liver. Improvements maybe expected from transducer designs with a larger active surface and/or nonlinear sonication strategies. PMID- 26233197 TI - Synchronized multiartifact reduction with tomographic reconstruction (SMART RECON): A statistical model based iterative image reconstruction method to eliminate limited-view artifacts and to mitigate the temporal-average artifacts in time-resolved CT. AB - PURPOSE: In x-ray computed tomography (CT), a violation of the Tuy data sufficiency condition leads to limited-view artifacts. In some applications, it is desirable to use data corresponding to a narrow temporal window to reconstruct images with reduced temporal-average artifacts. However, the need to reduce temporal-average artifacts in practice may result in a violation of the Tuy condition and thus undesirable limited-view artifacts. In this paper, the authors present a new iterative reconstruction method, synchronized multiartifact reduction with tomographic reconstruction (SMART-RECON), to eliminate limited view artifacts using data acquired within an ultranarrow temporal window that severely violates the Tuy condition. METHODS: In time-resolved contrast enhanced CT acquisitions, image contrast dynamically changes during data acquisition. Each image reconstructed from data acquired in a given temporal window represents one time frame and can be denoted as an image vector. Conventionally, each individual time frame is reconstructed independently. In this paper, all image frames are grouped into a spatial-temporal image matrix and are reconstructed together. Rather than the spatial and/or temporal smoothing regularizers commonly used in iterative image reconstruction, the nuclear norm of the spatial-temporal image matrix is used in SMART-RECON to regularize the reconstruction of all image time frames. This regularizer exploits the low-dimensional structure of the spatial temporal image matrix to mitigate limited-view artifacts when an ultranarrow temporal window is desired in some applications to reduce temporal-average artifacts. Both numerical simulations in two dimensional image slices with known ground truth and in vivo human subject data acquired in a contrast enhanced cone beam CT exam have been used to validate the proposed SMART-RECON algorithm and to demonstrate the initial performance of the algorithm. Reconstruction errors and temporal fidelity of the reconstructed images were quantified using the relative root mean square error (rRMSE) and the universal quality index (UQI) in numerical simulations. The performance of the SMART-RECON algorithm was compared with that of the prior image constrained compressed sensing (PICCS) reconstruction quantitatively in simulations and qualitatively in human subject exam. RESULTS: In numerical simulations, the 240(?) short scan angular span was divided into four consecutive 60(?) angular subsectors. SMART-RECON enables four high temporal fidelity images without limited-view artifacts. The average rRMSE is 16% and UQIs are 0.96 and 0.95 for the two local regions of interest, respectively. In contrast, the corresponding average rRMSE and UQIs are 25%, 0.78, and 0.81, respectively, for the PICCS reconstruction. Note that only one filtered backprojection image can be reconstructed from the same data set with an average rRMSE and UQIs are 45%, 0.71, and 0.79, respectively, to benchmark reconstruction accuracies. For in vivo contrast enhanced cone beam CT data acquired from a short scan angular span of 200(?), three 66(?) angular subsectors were used in SMART RECON. The results demonstrated clear contrast difference in three SMART-RECON reconstructed image volumes without limited-view artifacts. In contrast, for the same angular sectors, PICCS cannot reconstruct images without limited-view artifacts and with clear contrast difference in three reconstructed image volumes. CONCLUSIONS: In time-resolved CT, the proposed SMART-RECON method provides a new method to eliminate limited-view artifacts using data acquired in an ultranarrow temporal window, which corresponds to approximately 60(?) angular subsectors. PMID- 26233198 TI - Angular independent silicon detector for dosimetry in external beam radiotherapy. AB - PURPOSE: In this work, the "edgeless" silicon detector technology is investigated, in combination with an innovative packaging solution, to manufacture silicon detectors with negligible angular response. The new diode is also characterized as a dosimeter for radiotherapy with the aim to verify its suitability as a single detector for in vivo dosimetry as well as large area 2D array that does not require angular correction to their response. METHODS: For the characterisation of the "edgeless-drop-in" detector technology, a set of samples have been manufactured with different sensitive areas (1 * 1 and 0.5 * 0.5 mm(2)) and different thicknesses (0.1 and 0.5 mm) in four different combinations of top and peripheral p-n junction fabricated on p-type and n-type silicon substrates. The diode probes were tested in terms of percentage depth dose (PDD), dose rate, and linearity and compared to ion chambers. Measurements of the output factor have been compared to film. The angular response of the diodes probes has been tested in a cylindrical PMMA phantom, rotated with bidirectional accuracy of 0.25 degrees under 10 * 10 cm(2) 6 MV Linac photon beam. The radiation hardness has been investigated as well as the effect of radiation damage on the angular and dose rate response of the diode probes when irradiated with photons from a Co-60 gamma source up to dose of 40 kGy. RESULTS: The PDDs measured by the edgeless detectors show an agreement with the data obtained using ion chambers within +/-2%. The output factor measured with the smallest area edgeless diodes (0.5 * 0.5 mm(2)-0.1 and 0.5 mm thick) matches EBT3 film to within 2% for square field size from 10 to 0.5 cm side equivalent distance. The dose rate dependence in a dose per pulse range of 0.9 * 10(-5)-2.7 * 10(-4) Gy/pulse was less than -7% and +300% for diodes fabricated on p-type and n-type substrates, respectively. The edgeless diodes fabricated on the p-type substrate demonstrated degradation of the response as a function of the irradiation dose within 5%-15%, while diodes on the n-type substrate show a variation of approximately 30% after 40 kGy. The angular response of all probes is minimal (within 2%) but the N on N and P on P configurations show the best performances with an angular dependence of +/-1.0% between 0 degrees and 180 degrees in the transversal direction. In this configuration, the space charge region of the passive diode extends from the behind and sidewall toward the anode on the top providing beneficial electric field distribution in the peripheral area of the diode. Such performance has also been tested after irradiation by Co 60 up to 40 kGy with no measurable change in angular response. CONCLUSIONS: A new edgeless-drop-in silicon diode fabrication and packaging technology has been used to develop detectors that show no significant angular dependence in their response for dosimetry in radiation therapy. From the characterisation of the diodes, proposed in a wide range of different geometries and configurations, the authors recommend the P-on-P detectors in conjunction with "drop in" packaging technology as the candidate for further development as single diode probe or 2D diode array for dosimetry in radiotherapy. PMID- 26233199 TI - The development of a population of 4D pediatric XCAT phantoms for imaging research and optimization. AB - PURPOSE: We previously developed a set of highly detailed 4D reference pediatric extended cardiac-torso (XCAT) phantoms at ages of newborn, 1, 5, 10, and 15 yr with organ and tissue masses matched to ICRP Publication 89 values. In this work, we extended this reference set to a series of 64 pediatric phantoms of varying age and height and body mass percentiles representative of the public at large. The models will provide a library of pediatric phantoms for optimizing pediatric imaging protocols. METHODS: High resolution positron emission tomography-computed tomography data obtained from the Duke University database were reviewed by a practicing experienced radiologist for anatomic regularity. The CT portion of the data was then segmented with manual and semiautomatic methods to form a target model defined using nonuniform rational B-spline surfaces. A multichannel large deformation diffeomorphic metric mapping algorithm was used to calculate the transform from the best age matching pediatric XCAT reference phantom to the patient target. The transform was used to complete the target, filling in the nonsegmented structures and defining models for the cardiac and respiratory motions. The complete phantoms, consisting of thousands of structures, were then manually inspected for anatomical accuracy. The mass for each major tissue was calculated and compared to linearly interpolated ICRP values for different ages. RESULTS: Sixty four new pediatric phantoms were created in this manner. Each model contains the same level of detail as the original XCAT reference phantoms and also includes parameterized models for the cardiac and respiratory motions. For the phantoms that were 10 yr old and younger, we included both sets of reproductive organs. This gave them the capability to simulate both male and female anatomy. With this, the population can be expanded to 92. Wide anatomical variation was clearly seen amongst the phantom models, both in organ shape and size, even for models of the same age and sex. The phantoms can be combined with existing simulation packages to generate realistic pediatric imaging data from different modalities. CONCLUSIONS: This work provides a large cohort of highly detailed pediatric phantoms with 4D capabilities of varying age, height, and body mass. The population of phantoms will provide a vital tool with which to optimize 3D and 4D pediatric imaging devices and techniques in terms of image quality and radiation-absorbed dose. PMID- 26233200 TI - The value of nodal information in predicting lung cancer relapse using 4DPET/4DCT. AB - PURPOSE: There is evidence that computed tomography (CT) and positron emission tomography (PET) imaging metrics are prognostic and predictive in nonsmall cell lung cancer (NSCLC) treatment outcomes. However, few studies have explored the use of standardized uptake value (SUV)-based image features of nodal regions as predictive features. The authors investigated and compared the use of tumor and node image features extracted from the radiotherapy target volumes to predict relapse in a cohort of NSCLC patients undergoing chemoradiation treatment. METHODS: A prospective cohort of 25 patients with locally advanced NSCLC underwent 4DPET/4DCT imaging for radiation planning. Thirty-seven image features were derived from the CT-defined volumes and SUVs of the PET image from both the tumor and nodal target regions. The machine learning methods of logistic regression and repeated stratified five-fold cross-validation (CV) were used to predict local and overall relapses in 2 yr. The authors used well-known feature selection methods (Spearman's rank correlation, recursive feature elimination) within each fold of CV. Classifiers were ranked on their Matthew's correlation coefficient (MCC) after CV. Area under the curve, sensitivity, and specificity values are also presented. RESULTS: For predicting local relapse, the best classifier found had a mean MCC of 0.07 and was composed of eight tumor features. For predicting overall relapse, the best classifier found had a mean MCC of 0.29 and was composed of a single feature: the volume greater than 0.5 times the maximum SUV (N). CONCLUSIONS: The best classifier for predicting local relapse had only tumor features. In contrast, the best classifier for predicting overall relapse included a node feature. Overall, the methods showed that nodes add value in predicting overall relapse but not local relapse. PMID- 26233201 TI - MRI reconstruction of multi-image acquisitions using a rank regularizer with data reordering. AB - PURPOSE: To improve rank constrained reconstructions for undersampled multi-image MRI acquisitions. METHODS: Motivated by the recent developments in low-rank matrix completion theory and its applicability to rapid dynamic MRI, a new reordering-based rank constrained reconstruction of undersampled multi-image data that uses prior image information is proposed. Instead of directly minimizing the nuclear norm of a matrix of estimated images, the nuclear norm of reordered matrix values is minimized. The reordering is based on the prior image estimates. The method is tested on brain diffusion imaging data and dynamic contrast enhanced myocardial perfusion data. RESULTS: Good quality images from data undersampled by a factor of three for diffusion imaging and by a factor of 3.5 for dynamic cardiac perfusion imaging with respiratory motion were obtained. Reordering gave visually improved image quality over standard nuclear norm minimization reconstructions. Root mean squared errors with respect to ground truth images were improved by ~18% and ~16% with reordering for diffusion and perfusion applications, respectively. CONCLUSIONS: The reordered low-rank constraint is a way to inject prior image information that offers improvements over a standard low-rank constraint for undersampled multi-image MRI reconstructions. PMID- 26233202 TI - Development of a video image-based QA system for the positional accuracy of dynamic tumor tracking irradiation in the Vero4DRT system. AB - PURPOSE: To develop and evaluate a new video image-based QA system, including in house software, that can display a tracking state visually and quantify the positional accuracy of dynamic tumor tracking irradiation in the Vero4DRT system. METHODS: Sixteen trajectories in six patients with pulmonary cancer were obtained with the ExacTrac in the Vero4DRT system. Motion data in the cranio-caudal direction (Y direction) were used as the input for a programmable motion table (Quasar). A target phantom was placed on the motion table, which was placed on the 2D ionization chamber array (MatriXX). Then, the 4D modeling procedure was performed on the target phantom during a reproduction of the patient's tumor motion. A substitute target with the patient's tumor motion was irradiated with 6 MV x-rays under the surrogate infrared system. The 2D dose images obtained from the MatriXX (33 frames/s; 40 s) were exported to in-house video-image analyzing software. The absolute differences in the Y direction between the center of the exposed target and the center of the exposed field were calculated. Positional errors were observed. The authors' QA results were compared to 4D modeling function errors and gimbal motion errors obtained from log analyses in the ExacTrac to verify the accuracy of their QA system. The patients' tumor motions were evaluated in the wave forms, and the peak-to-peak distances were also measured to verify their reproducibility. RESULTS: Thirteen of sixteen trajectories (81.3%) were successfully reproduced with Quasar. The peak-to-peak distances ranged from 2.7 to 29.0 mm. Three trajectories (18.7%) were not successfully reproduced due to the limited motions of the Quasar. Thus, 13 of 16 trajectories were summarized. The mean number of video images used for analysis was 1156. The positional errors (absolute mean difference + 2 standard deviation) ranged from 0.54 to 1.55 mm. The error values differed by less than 1 mm from 4D modeling function errors and gimbal motion errors in the ExacTrac log analyses (n = 13). CONCLUSIONS: The newly developed video image-based QA system, including in house software, can analyze more than a thousand images (33 frames/s). Positional errors are approximately equivalent to those in ExacTrac log analyses. This system is useful for the visual illustration of the progress of the tracking state and for the quantification of positional accuracy during dynamic tumor tracking irradiation in the Vero4DRT system. PMID- 26233203 TI - Age at exposure and attained age variations of cancer risk in the Japanese A-bomb and radiotherapy cohorts. AB - PURPOSE: Phenomenological risk models for radiation-induced cancer are frequently applied to estimate the risk of radiation-induced cancers at radiotherapy doses. Such models often include the effect modification, of the main risk to radiation dose response, by age at exposure and attained age. The aim of this paper is to compare the patterns in risk effect modification by age, between models obtained from the Japanese atomic-bomb (A-bomb) survivor data and models for cancer risks previously reported for radiotherapy patients. Patterns in risk effect modification by age from the epidemiological studies of radiotherapy patients were also used to refine and extend the risk effect modification by age obtained from the A-bomb survivor data, so that more universal models can be presented here. METHODS: Simple log-linear and power functions of age for the risk effect modification applied in models of the A-bomb survivor data are compared to risks from epidemiological studies of second cancers after radiotherapy. These functions of age were also refined and fitted to radiotherapy risks. The resulting age models provide a refined and extended functional dependence of risk with age at exposure and attained age especially beyond 40 and 65 yr, respectively, and provide a better representation than the currently available simple age functions. RESULTS: It was found that the A-bomb models predict risk similarly to the outcomes of testicular cancer survivors. The survivors of Hodgkin's disease show steeper variations of risk with both age at exposure and attained age. The extended models predict solid cancer risk increase as a function of age at exposure beyond 40 yr and the risk decrease as a function of attained age beyond 65 yr better than the simple models. CONCLUSIONS: The standard functions for risk effect modification by age, based on the A-bomb survivor data, predict second cancer risk in radiotherapy patients for ages at exposure prior to 40 yr and attained ages before 55 yr reasonably well. However, for larger ages, the refined and extended models can be applied to predict the risk as a function of age. PMID- 26233205 TI - A method for evaluating image quality of monochrome and color displays based on luminance by use of a commercially available color digital camera. AB - PURPOSE: The aim of this study is to propose a method for the quantitative evaluation of image quality of both monochrome and color liquid-crystal displays (LCDs) using a commercially available color digital camera. METHODS: The intensities of the unprocessed red (R), green (G), and blue (B) signals of a camera vary depending on the spectral sensitivity of the image sensor used in the camera. For consistent evaluation of image quality for both monochrome and color LCDs, the unprocessed RGB signals of the camera were converted into gray scale signals that corresponded to the luminance of the LCD. Gray scale signals for the monochrome LCD were evaluated by using only the green channel signals of the camera. For the color LCD, the RGB signals of the camera were converted into gray scale signals by employing weighting factors (WFs) for each RGB channel. A line image displayed on the color LCD was simulated on the monochrome LCD by using a software application for subpixel driving in order to verify the WF-based conversion method. Furthermore, the results obtained by different types of commercially available color cameras and a photometric camera were compared to examine the consistency of the authors' method. Finally, image quality for both the monochrome and color LCDs was assessed by measuring modulation transfer functions (MTFs) and Wiener spectra (WS). RESULTS: The authors' results demonstrated that the proposed method for calibrating the spectral sensitivity of the camera resulted in a consistent and reliable evaluation of the luminance of monochrome and color LCDs. The MTFs and WS showed different characteristics for the two LCD types owing to difference in the subpixel structure. The MTF in the vertical direction of the color LCD was superior to that of the monochrome LCD, although the WS in the vertical direction of the color LCD was inferior to that of the monochrome LCD as a result of luminance fluctuations in RGB subpixels. CONCLUSIONS: The authors' method based on the use of a commercially available color camera is useful to evaluate and understand the display performances of both monochrome and color LCDs in radiology departments. PMID- 26233204 TI - Quantitative correlational study of microbubble-enhanced ultrasound imaging and magnetic resonance imaging of glioma and early response to radiotherapy in a rat model. AB - PURPOSE: Radiotherapy remains a major treatment method for malignant tumors. Magnetic resonance imaging (MRI) is the standard modality for assessing glioma treatment response in the clinic. Compared to MRI, ultrasound imaging is low-cost and portable and can be used during intraoperative procedures. The purpose of this study was to quantitatively compare contrast-enhanced ultrasound (CEUS) imaging and MRI of irradiated gliomas in rats and to determine which quantitative ultrasound imaging parameters can be used for the assessment of early response to radiation in glioma. METHODS: Thirteen nude rats with U87 glioma were used. A small thinned skull window preparation was performed to facilitate ultrasound imaging and mimic intraoperative procedures. Both CEUS and MRI with structural, functional, and molecular imaging parameters were performed at preradiation and at 1 day and 4 days postradiation. Statistical analysis was performed to determine the correlations between MRI and CEUS parameters and the changes between pre- and postradiation imaging. RESULTS: Area under the curve (AUC) in CEUS showed significant difference between preradiation and 4 days postradiation, along with four MRI parameters, T2, apparent diffusion coefficient, cerebral blood flow, and amide proton transfer-weighted (APTw) (all p < 0.05). The APTw signal was correlated with three CEUS parameters, rise time (r = - 0.527, p < 0.05), time to peak (r = - 0.501, p < 0.05), and perfusion index (r = 458, p < 0.05). Cerebral blood flow was correlated with rise time (r = - 0.589, p < 0.01) and time to peak (r = - 0.543, p < 0.05). CONCLUSIONS: MRI can be used for the assessment of radiotherapy treatment response and CEUS with AUC as a new technique and can also be one of the assessment methods for early response to radiation in glioma. PMID- 26233206 TI - Dosimetric verification of lung cancer treatment using the CBCTs estimated from limited-angle on-board projections. AB - PURPOSE: Lung cancer treatment is susceptible to treatment errors caused by interfractional anatomical and respirational variations of the patient. On-board treatment dose verification is especially critical for the lung stereotactic body radiation therapy due to its high fractional dose. This study investigates the feasibility of using cone-beam (CB)CT images estimated by a motion modeling and free-form deformation (MM-FD) technique for on-board dose verification. METHODS: Both digital and physical phantom studies were performed. Various interfractional variations featuring patient motion pattern change, tumor size change, and tumor average position change were simulated from planning CT to on-board images. The doses calculated on the planning CT (planned doses), the on-board CBCT estimated by MM-FD (MM-FD doses), and the on-board CBCT reconstructed by the conventional Feldkamp-Davis-Kress (FDK) algorithm (FDK doses) were compared to the on-board dose calculated on the "gold-standard" on-board images (gold-standard doses). The absolute deviations of minimum dose (DeltaDmin), maximum dose (DeltaDmax), and mean dose (DeltaDmean), and the absolute deviations of prescription dose coverage (DeltaV100%) were evaluated for the planning target volume (PTV). In addition, 4D on-board treatment dose accumulations were performed using 4D-CBCT images estimated by MM-FD in the physical phantom study. The accumulated doses were compared to those measured using optically stimulated luminescence (OSL) detectors and radiochromic films. RESULTS: Compared with the planned doses and the FDK doses, the MM-FD doses matched much better with the gold-standard doses. For the digital phantom study, the average (+/- standard deviation) DeltaDmin, DeltaDmax, DeltaDmean, and DeltaV100% (values normalized by the prescription dose or the total PTV) between the planned and the gold-standard PTV doses were 32.9% (+/-28.6%), 3.0% (+/-2.9%), 3.8% (+/-4.0%), and 15.4% (+/-12.4%), respectively. The corresponding values of FDK PTV doses were 1.6% (+/-1.9%), 1.2% (+/-0.6%), 2.2% (+/-0.8%), and 17.4% (+/-15.3%), respectively. In contrast, the corresponding values of MM-FD PTV doses were 0.3% (+/-0.2%), 0.9% (+/-0.6%), 0.6% (+/-0.4%), and 1.0% (+/-0.8%), respectively. Similarly, for the physical phantom study, the average DeltaDmin, DeltaDmax, DeltaDmean, and DeltaV100% of planned PTV doses were 38.1% (+/-30.8%), 3.5% (+/-5.1%), 3.0% (+/-2.6%), and 8.8% (+/ 8.0%), respectively. The corresponding values of FDK PTV doses were 5.8% (+/ 4.5%), 1.6% (+/-1.6%), 2.0% (+/-0.9%), and 9.3% (+/-10.5%), respectively. In contrast, the corresponding values of MM-FD PTV doses were 0.4% (+/-0.8%), 0.8% (+/-1.0%), 0.5% (+/-0.4%), and 0.8% (+/-0.8%), respectively. For the 4D dose accumulation study, the average (+/- standard deviation) absolute dose deviation (normalized by local doses) between the accumulated doses and the OSL measured doses was 3.3% (+/-2.7%). The average gamma index (3%/3 mm) between the accumulated doses and the radiochromic film measured doses was 94.5% (+/-2.5%). CONCLUSIONS: MM-FD estimated 4D-CBCT enables accurate on-board dose calculation and accumulation for lung radiation therapy. It can potentially be valuable for treatment quality assessment and adaptive radiation therapy. PMID- 26233208 TI - Liver 4DMRI: A retrospective image-based sorting method. AB - PURPOSE: Four-dimensional magnetic resonance imaging (4DMRI) is an emerging technique in radiotherapy treatment planning for organ motion quantification. In this paper, the authors present a novel 4DMRI retrospective image-based sorting method, providing reduced motion artifacts than using a standard monodimensional external respiratory surrogate. METHODS: Serial interleaved 2D multislice MRI data were acquired from 24 liver cases (6 volunteers + 18 patients) to test the proposed 4DMRI sorting. Image similarity based on mutual information was applied to automatically identify a stable reference phase and sort the image sequence retrospectively, without the use of additional image or surrogate data to describe breathing motion. RESULTS: The image-based 4DMRI provided a smoother liver profile than that obtained from standard resorting based on an external surrogate. Reduced motion artifacts were observed in image-based 4DMRI datasets with a fitting error of the liver profile measuring 1.2 +/- 0.9 mm (median +/- interquartile range) vs 2.1 +/- 1.7 mm of the standard method. CONCLUSIONS: The authors present a novel methodology to derive a patient-specific 4DMRI model to describe organ motion due to breathing, with improved image quality in 4D reconstruction. PMID- 26233207 TI - Review of SPECT collimator selection, optimization, and fabrication for clinical and preclinical imaging. AB - In single photon emission computed tomography, the choice of the collimator has a major impact on the sensitivity and resolution of the system. Traditional parallel-hole and fan-beam collimators used in clinical practice, for example, have a relatively poor sensitivity and subcentimeter spatial resolution, while in small-animal imaging, pinhole collimators are used to obtain submillimeter resolution and multiple pinholes are often combined to increase sensitivity. This paper reviews methods for production, sensitivity maximization, and task-based optimization of collimation for both clinical and preclinical imaging applications. New opportunities for improved collimation are now arising primarily because of (i) new collimator-production techniques and (ii) detectors with improved intrinsic spatial resolution that have recently become available. These new technologies are expected to impact the design of collimators in the future. The authors also discuss concepts like septal penetration, high resolution applications, multiplexing, sampling completeness, and adaptive systems, and the authors conclude with an example of an optimization study for a parallel-hole, fan-beam, cone-beam, and multiple-pinhole collimator for different applications. PMID- 26233210 TI - Evaluation of diffusion models in breast cancer. AB - PURPOSE: The purpose of this study is to investigate whether the microvascular pseudodiffusion effects resulting with non-monoexponential behavior are present in breast cancer, taking into account tumor spatial heterogeneity. Additionally, methodological factors affecting the signal in low and high diffusion-sensitizing gradient ranges were explored in phantom studies. METHODS: The effect of eddy currents and accuracy of b-value determination using a multiple b-value diffusion weighted MR imaging sequence were investigated in test objects. Diffusion model selection and noise were then investigated in volunteers (n = 5) and breast tumor patients (n = 21) using the Bayesian information criterion. RESULTS: 54.3% of lesion voxels were best fitted by a monoexponential, 26.2% by a stretched exponential, and 19.5% by a biexponential intravoxel incoherent motion (IVIM) model. High correlation (0.92) was observed between diffusion coefficients calculated using mono- and stretched-exponential models and moderate (0.59) between monoexponential and IVIM (medians: 0.96/0.84/0.72 * 10(-3) mm(2)/s, respectively). Distortion due to eddy currents depended on the direction of the diffusion gradient and displacement varied between 1 and 6 mm for high b-value images. Shift in the apparent diffusion coefficient due to intrinsic field gradients was compensated for by averaging diffusion data obtained from opposite directions. CONCLUSIONS: Pseudodiffusion and intravoxel heterogeneity effects were not observed in approximately half of breast cancer and normal tissue voxels. This result indicates that stretched and IVIM models should be utilized in regional analysis rather than global tumor assessment. Cross terms between diffusion-sensitization gradients and other imaging or susceptibility-related gradients are relevant in clinical protocols, supporting the use of geometric averaging of diffusion-weighted images acquired with diffusion-sensitization gradients in opposite directions. PMID- 26233209 TI - Framework for 3D histologic reconstruction and fusion with in vivo MRI: Preliminary results of characterizing pulmonary inflammation in a mouse model. AB - PURPOSE: Pulmonary inflammation is associated with a variety of diseases. Assessing pulmonary inflammation on in vivo imaging may facilitate the early detection and treatment of lung diseases. Although routinely used in thoracic imaging, computed tomography has thus far not been compellingly shown to characterize inflammation in vivo. Alternatively, magnetic resonance imaging (MRI) is a nonionizing radiation technique to better visualize and characterize pulmonary tissue. Prior to routine adoption of MRI for early characterization of inflammation in humans, a rigorous and quantitative characterization of the utility of MRI to identify inflammation is required. Such characterization may be achieved by considering ex vivo histology as the ground truth, since it enables the definitive spatial assessment of inflammation. In this study, the authors introduce a novel framework to integrate 2D histology, ex vivo and in vivo imaging to enable the mapping of the extent of disease from ex vivo histology onto in vivo imaging, with the goal of facilitating computerized feature analysis and interrogation of disease appearance on in vivo imaging. The authors' framework was evaluated in a preclinical preliminary study aimed to identify computer extracted features on in vivo MRI associated with chronic pulmonary inflammation. METHODS: The authors' image analytics framework first involves reconstructing the histologic volume in 3D from individual histology slices. Second, the authors map the disease ground truth onto in vivo MRI via coregistration with 3D histology using the ex vivo lung MRI as a conduit. Finally, computerized feature analysis of the disease extent is performed to identify candidate in vivo imaging signatures of disease presence and extent. RESULTS: The authors evaluated the framework by assessing the quality of the 3D histology reconstruction and the histology-MRI fusion, in the context of an initial use case involving characterization of chronic inflammation in a mouse model. The authors' evaluation considered three mice, two with an inflammation phenotype and one control. The authors' iterative 3D histology reconstruction yielded a 70.1% +/- 2.7% overlap with the ex vivo MRI volume. Across a total of 17 anatomic landmarks manually delineated at the division of airways, the target registration error between the ex vivo MRI and 3D histology reconstruction was 0.85 +/- 0.44 mm, suggesting that a good alignment of the ex vivo 3D histology and ex vivo MRI had been achieved. The 3D histology-in vivo MRI coregistered volumes resulted in an overlap of 73.7% +/- 0.9%. Preliminary computerized feature analysis was performed on an additional four control mice, for a total of seven mice considered in this study. Gabor texture filters appeared to best capture differences between the inflamed and noninflamed regions on MRI. CONCLUSIONS: The authors' 3D histology reconstruction and multimodal registration framework were successfully employed to reconstruct the histology volume of the lung and fuse it with in vivo MRI to create a ground truth map for inflammation on in vivo MRI. The analytic platform presented here lays the framework for a rigorous validation of the identified imaging features for chronic lung inflammation on MRI in a large prospective cohort. PMID- 26233211 TI - Selective robust optimization: A new intensity-modulated proton therapy optimization strategy. AB - PURPOSE: To develop a new robust optimization strategy for intensity-modulated proton therapy as an important step in translating robust proton treatment planning from research to clinical applications. METHODS: In selective robust optimization, a worst-case-based robust optimization algorithm is extended, and terms of the objective function are selectively computed from either the worst case dose or the nominal dose. Two lung cancer cases and one head and neck cancer case were used to demonstrate the practical significance of the proposed robust planning strategy. The lung cancer cases had minimal tumor motion less than 5 mm, and, for the demonstration of the methodology, are assumed to be static. RESULTS: Selective robust optimization achieved robust clinical target volume (CTV) coverage and at the same time increased nominal planning target volume coverage to 95.8%, compared to the 84.6% coverage achieved with CTV-based robust optimization in one of the lung cases. In the other lung case, the maximum dose in selective robust optimization was lowered from a dose of 131.3% in the CTV based robust optimization to 113.6%. Selective robust optimization provided robust CTV coverage in the head and neck case, and at the same time improved controls over isodose distribution so that clinical requirements may be readily met. CONCLUSIONS: Selective robust optimization may provide the flexibility and capability necessary for meeting various clinical requirements in addition to achieving the required plan robustness in practical proton treatment planning settings. PMID- 26233212 TI - A general framework of noise suppression in material decomposition for dual energy CT. AB - PURPOSE: As a general problem of dual-energy CT (DECT), noise amplification in material decomposition severely reduces the signal-to-noise ratio on the decomposed images compared to that on the original CT images. In this work, the authors propose a general framework of noise suppression in material decomposition for DECT. The method is based on an iterative algorithm recently developed in their group for image-domain decomposition of DECT, with an extension to include nonlinear decomposition models. The generalized framework of iterative DECT decomposition enables beam-hardening correction with simultaneous noise suppression, which improves the clinical benefits of DECT. METHODS: The authors propose to suppress noise on the decomposed images of DECT using convex optimization, which is formulated in the form of least-squares estimation with smoothness regularization. Based on the design principles of a best linear unbiased estimator, the authors include the inverse of the estimated variance covariance matrix of the decomposed images as the penalty weight in the least squares term. Analytical formulas are derived to compute the variance-covariance matrix for decomposed images with general-form numerical or analytical decomposition. As a demonstration, the authors implement the proposed algorithm on phantom data using an empirical polynomial function of decomposition measured on a calibration scan. The polynomial coefficients are determined from the projection data acquired on a wedge phantom, and the signal decomposition is performed in the projection domain. RESULTS: On the Catphan((r))600 phantom, the proposed noise suppression method reduces the average noise standard deviation of basis material images by one to two orders of magnitude, with a superior performance on spatial resolution as shown in comparisons of line-pair images and modulation transfer function measurements. On the synthesized monoenergetic CT images, the noise standard deviation is reduced by a factor of 2-3. By using nonlinear decomposition on projections, the authors' method effectively suppresses the streaking artifacts of beam hardening and obtains more uniform images than their previous approach based on a linear model. Similar performance of noise suppression is observed in the results of an anthropomorphic head phantom and a pediatric chest phantom generated by the proposed method. With beam hardening correction enabled by their approach, the image spatial nonuniformity on the head phantom is reduced from around 10% on the original CT images to 4.9% on the synthesized monoenergetic CT image. On the pediatric chest phantom, their method suppresses image noise standard deviation by a factor of around 7.5, and compared with linear decomposition, it reduces the estimation error of electron densities from 33.3% to 8.6%. CONCLUSIONS: The authors propose a general framework of noise suppression in material decomposition for DECT. Phantom studies have shown the proposed method improves the image uniformity and the accuracy of electron density measurements by effective beam-hardening correction and reduces noise level without noticeable resolution loss. PMID- 26233213 TI - Robust PET-guided intensity-modulated radiation therapy. AB - PURPOSE: Functional image guided intensity-modulated radiation therapy has the potential to improve cancer treatment quality by basing treatment parameters such as heterogeneous dose distributions information derived from imaging. However, such heterogeneous dose distributions are subject to imaging uncertainty. In this paper, the authors develop a robust optimization model to design plans that are desensitized to imaging uncertainty. METHODS: Starting from the pretreatment fluorodeoxyglucose-positron emission tomography scans, the authors use the raw voxel standard uptake values (SUVs) as input into a series of intermediate functions to transform the SUV into a desired dose. The calculated desired doses were used as an input into a robust optimization model to generate beamlet intensities. For each voxel, the authors assume that the true SUV cannot be observed but instead resides in an interval centered on the nominal (i.e., observed) SUV. Then the authors evaluated the nominal and robust solutions through a simulation study. The simulation considered the effect of the true SUV being different from the nominal SUV on the quality of the treatment plan. Treatment plans were compared on the metrics of objective function value and tumor control probability (TCP). RESULTS: Computational results demonstrate the potential for improvements in tumor control probability and deviation from the desired dose distribution compared to a nonrobust model while maintaining acceptable tissue dose. CONCLUSIONS: Robust optimization can help design treatment plans that are more stable in the presence of image value uncertainties. PMID- 26233214 TI - Effective noise-suppressed and artifact-reduced reconstruction of SPECT data using a preconditioned alternating projection algorithm. AB - PURPOSE: The authors have recently developed a preconditioned alternating projection algorithm (PAPA) with total variation (TV) regularizer for solving the penalized-likelihood optimization model for single-photon emission computed tomography (SPECT) reconstruction. This algorithm belongs to a novel class of fixed-point proximity methods. The goal of this work is to investigate how PAPA performs while dealing with realistic noisy SPECT data, to compare its performance with more conventional methods, and to address issues with TV artifacts by proposing a novel form of the algorithm invoking high-order TV regularization, denoted as HOTV-PAPA, which has been explored and studied extensively in the present work. METHODS: Using Monte Carlo methods, the authors simulate noisy SPECT data from two water cylinders; one contains lumpy "warm" background and "hot" lesions of various sizes with Gaussian activity distribution, and the other is a reference cylinder without hot lesions. The authors study the performance of HOTV-PAPA and compare it with PAPA using first order TV regularization (TV-PAPA), the Panin-Zeng-Gullberg one-step-late method with TV regularization (TV-OSL), and an expectation-maximization algorithm with Gaussian postfilter (GPF-EM). The authors select penalty-weights (hyperparameters) by qualitatively balancing the trade-off between resolution and image noise separately for TV-PAPA and TV-OSL. However, the authors arrived at the same penalty-weight value for both of them. The authors set the first penalty weight in HOTV-PAPA equal to the optimal penalty-weight found for TV-PAPA. The second penalty-weight needed for HOTV-PAPA is tuned by balancing resolution and the severity of staircase artifacts. The authors adjust the Gaussian postfilter to approximately match the local point spread function of GPF-EM and HOTV-PAPA. The authors examine hot lesion detectability, study local spatial resolution, analyze background noise properties, estimate mean square errors (MSEs), and report the convergence speed and computation time. RESULTS: HOTV-PAPA yields the best signal-to-noise ratio, followed by TV-PAPA and TV-OSL/GPF-EM. The local spatial resolution of HOTV-PAPA is somewhat worse than that of TV-PAPA and TV OSL. Images reconstructed using HOTV-PAPA have the lowest local noise power spectrum (LNPS) amplitudes, followed by TV-PAPA, TV-OSL, and GPF-EM. The LNPS peak of GPF-EM is shifted toward higher spatial frequencies than those for the three other methods. The PAPA-type methods exhibit much lower ensemble noise, ensemble voxel variance, and image roughness. HOTV-PAPA performs best in these categories. Whereas images reconstructed using both TV-PAPA and TV-OSL are degraded by severe staircase artifacts; HOTV-PAPA substantially reduces such artifacts. It also converges faster than the other three methods and exhibits the lowest overall reconstruction error level, as measured by MSE. CONCLUSIONS: For high-noise simulated SPECT data, HOTV-PAPA outperforms TV-PAPA, GPF-EM, and TV OSL in terms of hot lesion detectability, noise suppression, MSE, and computational efficiency. Unlike TV-PAPA and TV-OSL, HOTV-PAPA does not create sizable staircase artifacts. Moreover, HOTV-PAPA effectively suppresses noise, with only limited loss of local spatial resolution. Of the four methods, HOTV PAPA shows the best lesion detectability, thanks to its superior noise suppression. HOTV-PAPA shows promise for clinically useful reconstructions of low dose SPECT data. PMID- 26233215 TI - A level set method for cupping artifact correction in cone-beam CT. AB - PURPOSE: To reduce cupping artifacts and improve the contrast-to-noise ratio in cone-beam computed tomography (CBCT). METHODS: A level set method is proposed to reduce cupping artifacts in the reconstructed image of CBCT. The authors derive a local intensity clustering property of the CBCT image and define a local clustering criterion function of the image intensities in a neighborhood of each point. This criterion function defines an energy in terms of the level set functions, which represent a segmentation result and the cupping artifacts. The cupping artifacts are estimated as a result of minimizing this energy. RESULTS: The cupping artifacts in CBCT are reduced by an average of 90%. The results indicate that the level set-based algorithm is practical and effective for reducing the cupping artifacts and preserving the quality of the reconstructed image. CONCLUSIONS: The proposed method focuses on the reconstructed image without requiring any additional physical equipment, is easily implemented, and provides cupping correction through a single-scan acquisition. The experimental results demonstrate that the proposed method successfully reduces the cupping artifacts. PMID- 26233216 TI - Frequency considerations for deep ablation with high-intensity focused ultrasound: A simulation study. AB - PURPOSE: The objective of this study was to explore frequency considerations for large-volume, deep thermal ablations with focused ultrasound. Though focal patterns, focal steering rate, and the size of focal clusters have all been explored in this context, frequency studies have generally explored shallower depths and hyperthermia applications. This study examines both treatment efficiency and near-field heating rate as functions of frequency and depth. METHODS: Flat, 150 mm transducer arrays were simulated to operate at frequencies of 250, 500, 750, 1000, 1250, and 1500 kHz. Each array had lambda2 interelement spacing yielding arrays of 2000-70 000 piston-shaped elements arranged in concentric rings. Depths of 50, 100, and 150 mm were explored, with attenuation (alpha) values of 2.5-10 (Np/m)/MHz. Ultrasound propagation was simulated with the Rayleigh-Sommerfeld integral over a volume of homogeneous simulated tissue. Absorbed power density was determined from the acoustic pressure which, in turn, was modeled with the Pennes bioheat transfer equation. Using this knowledge of temperature over time, thermal dose function of Sapareto and Dewey was used to model the resulting bioeffect of each simulated sonication. Initially, single foci at each depth, frequency, and alpha were examined with either fixed peak temperatures or fixed powers. Based on the size of the resulting, single foci lesions, larger compound sonications were designed with foci packed together in multiple layers and rings. For each depth, focal patterns were chosen to produce a similar total ablated volume for each frequency. These compound sonications were performed with a fixed peak temperature at each focus. The resulting energy efficiency (volume ablated per acoustic energy applied), near-field heating rate (temperature increase in the anterior third of the simulation space per unit volume ablated), and near- and far-field margins were assessed. RESULTS: Lesions of comparable volume were created with different frequencies at different depths. The results reflect the interconnected nature of frequency as it effects focal size (decreasing with frequency), peak pressure (generally increasing with frequency), and attenuation (also increasing with frequency). The ablation efficiency was the highest for alpha = 5 (Np/m)/MHz at a frequency of 750 kHz at each depth. For alpha = 10 (Np/m)/MHz, efficiency was the highest at 750 kHz for a depth of 50 mm, and 500 kHz at depths of 100 and 150 mm. At all sonication depths, near-field heating was minimized with lower frequencies of 250 and 500 kHz. CONCLUSIONS: Large-volume ablations are most efficient at frequencies of 500 750 kHz at depths of 100-150 mm. When one considers that near-field heat accumulation tends to be the rate limiting factor in large-volume ablations like uterine fibroid surgery, the results show that frequencies as low as 500 kHz are favored for their ability to reduce heating in the near-field. PMID- 26233217 TI - A contactless approach for respiratory gating in PET using continuous-wave radar. AB - PURPOSE: Respiratory gating is commonly used to reduce motion artifacts in positron emission tomography (PET). Clinically established methods for respiratory gating in PET require contact to the patient or a direct optical line between the sensor and the patient's torso and time consuming preparation. In this work, a contactless method for capturing a respiratory signal during PET is presented based on continuous-wave radar. METHODS: The proposed method relies on the principle of emitting an electromagnetic wave and detecting the phase shift of the reflected wave, modulated due to the respiratory movement of the patient's torso. A 24 GHz carrier frequency was chosen allowing wave propagation through plastic and clothing with high reflections at the skin surface. A detector module and signal processing algorithms were developed to extract a quantitative respiratory signal. The sensor was validated using a high precision linear table. During volunteer measurements and [(18)F] FDG PET scans, the radar sensor was positioned inside the scanner bore of a PET/computed tomography scanner. As reference, pressure belt (one volunteer), depth camera-based (two volunteers, two patients), and PET data-driven (six patients) signals were acquired simultaneously and the signal correlation was quantified. RESULTS: The developed system demonstrated a high measurement accuracy for movement detection within the submillimeter range. With the proposed method, small displacements of 25 MUm could be detected, not considerably influenced by clothing or blankets. From the patient studies, the extracted respiratory radar signals revealed high correlation (Pearson correlation coefficient) to those derived from the external pressure belt and depth camera signals (r = 0.69-0.99) and moderate correlation to those of the internal data-driven signals (r = 0.53-0.70). In some cases, a cardiac signal could be visualized, due to the representation of the mechanical heart motion on the skin. CONCLUSIONS: Accurate respiratory signals were obtained successfully by the proposed method with high spatial and temporal resolution. By working without contact and passing through clothing and blankets, this approach minimizes preparation time and increases the convenience of the patient during the scan. PMID- 26233218 TI - Practical dose point-based methods to characterize dose distribution in a stationary elliptical body phantom for a cone-beam C-arm CT system. AB - PURPOSE: To propose new dose point measurement-based metrics to characterize the dose distributions and the mean dose from a single partial rotation of an automatic exposure control-enabled, C-arm-based, wide cone angle computed tomography system over a stationary, large, body-shaped phantom. METHODS: A small 0.6 cm(3) ion chamber (IC) was used to measure the radiation dose in an elliptical body-shaped phantom made of tissue-equivalent material. The IC was placed at 23 well-distributed holes in the central and peripheral regions of the phantom and dose was recorded for six acquisition protocols with different combinations of minimum kVp (109 and 125 kVp) and z-collimator aperture (full: 22.2 cm; medium: 14.0 cm; small: 8.4 cm). Monte Carlo (MC) simulations were carried out to generate complete 2D dose distributions in the central plane (z = 0). The MC model was validated at the 23 dose points against IC experimental data. The planar dose distributions were then estimated using subsets of the point dose measurements using two proposed methods: (1) the proximity-based weighting method (method 1) and (2) the dose point surface fitting method (method 2). Twenty-eight different dose point distributions with six different point number cases (4, 5, 6, 7, 14, and 23 dose points) were evaluated to determine the optimal number of dose points and their placement in the phantom. The performances of the methods were determined by comparing their results with those of the validated MC simulations. The performances of the methods in the presence of measurement uncertainties were evaluated. RESULTS: The 5-, 6-, and 7-point cases had differences below 2%, ranging from 1.0% to 1.7% for both methods, which is a performance comparable to that of the methods with a relatively large number of points, i.e., the 14- and 23-point cases. However, with the 4-point case, the performances of the two methods decreased sharply. Among the 4-, 5-, 6-, and 7 point cases, the 7-point case (1.0% [+/-0.6%] difference) and the 6-point case (0.7% [+/-0.6%] difference) performed best for method 1 and method 2, respectively. Moreover, method 2 demonstrated high-fidelity surface reconstruction with as few as 5 points, showing pixelwise absolute differences of 3.80 mGy (+/-0.32 mGy). Although the performance was shown to be sensitive to the phantom displacement from the isocenter, the performance changed by less than 2% for shifts up to 2 cm in the x- and y-axes in the central phantom plane. CONCLUSIONS: With as few as five points, method 1 and method 2 were able to compute the mean dose with reasonable accuracy, demonstrating differences of 1.7% (+/-1.2%) and 1.3% (+/-1.0%), respectively. A larger number of points do not necessarily guarantee better performance of the methods; optimal choice of point placement is necessary. The performance of the methods is sensitive to the alignment of the center of the body phantom relative to the isocenter. In body applications where dose distributions are important, method 2 is a better choice than method 1, as it reconstructs the dose surface with high fidelity, using as few as five points. PMID- 26233219 TI - Influence of source batch S dispersion on dosimetry for prostate cancer treatment with permanent implants. AB - PURPOSE: In clinical practice, specific air kerma strength (SK) value is used in treatment planning system (TPS) permanent brachytherapy implant calculations with (125)I and (103)Pd sources; in fact, commercial TPS provide only one SK input value for all implanted sources and the certified shipment average is typically used. However, the value for SK is dispersed: this dispersion is not only due to the manufacturing process and variation between different source batches but also due to the classification of sources into different classes according to their SK values. The purpose of this work is to examine the impact of SK dispersion on typical implant parameters that are used to evaluate the dose volume histogram (DVH) for both planning target volume (PTV) and organs at risk (OARs). METHODS: The authors have developed a new algorithm to compute dose distributions with different SK values for each source. Three different prostate volumes (20, 30, and 40 cm(3)) were considered and two typical commercial sources of different radionuclides were used. Using a conventional TPS, clinically accepted calculations were made for (125)I sources; for the palladium, typical implants were simulated. To assess the many different possible SK values for each source belonging to a class, the authors assigned an SK value to each source in a randomized process 1000 times for each source and volume. All the dose distributions generated for each set of simulations were assessed through the DVH distributions comparing with dose distributions obtained using a uniform SK value for all the implanted sources. The authors analyzed several dose coverage (V100 and D90) and overdosage parameters for prostate and PTV and also the limiting and overdosage parameters for OARs, urethra and rectum. RESULTS: The parameters analyzed followed a Gaussian distribution for the entire set of computed dosimetries. PTV and prostate V100 and D90 variations ranged between 0.2% and 1.78% for both sources. Variations for the overdosage parameters V150 and V200 compared to dose coverage parameters were observed and, in general, variations were larger for parameters related to (125)I sources than (103)Pd sources. For OAR dosimetry, variations with respect to the reference D0.1cm(3) were observed for rectum values, ranging from 2% to 3%, compared with urethra values, which ranged from 1% to 2%. CONCLUSIONS: Dose coverage for prostate and PTV was practically unaffected by SK dispersion, as was the maximum dose deposited in the urethra due to the implant technique geometry. However, the authors observed larger variations for the PTV V150, rectum V100, and rectum D0.1cm(3) values. The variations in rectum parameters were caused by the specific location of sources with SK value that differed from the average in the vicinity. Finally, on comparing the two sources, variations were larger for (125)I than for (103)Pd. This is because for (103)Pd, a greater number of sources were used to obtain a valid dose distribution than for (125)I, resulting in a lower variation for each SK value for each source (because the variations become averaged out statistically speaking). PMID- 26233220 TI - Characteristic image quality of a third generation dual-source MDCT scanner: Noise, resolution, and detectability. AB - PURPOSE: The purpose of this work was to assess the inherent image quality characteristics of a new multidetector computed tomography system in terms of noise, resolution, and detectability index as a function of image acquisition and reconstruction for a range of clinically relevant settings. METHODS: A multisized image quality phantom (37, 30, 23, 18.5, and 12 cm physical diameter) was imaged on a SOMATOM Force scanner (Siemens Medical Solutions) under variable dose, kVp, and tube current modulation settings. Images were reconstructed with filtered back projection (FBP) and with advanced modeled iterative reconstruction (ADMIRE) with iterative strengths of 3, 4, and 5. Image quality was assessed in terms of the noise power spectrum (NPS), task transfer function (TTF), and detectability index for a range of detection tasks (contrasts of approximately 45, 90, 300, 900, and 1000 HU, and 2-20 mm diameter) based on a non-prewhitening matched filter model observer with eye filter. RESULTS: Image noise magnitude decreased with decreasing phantom size, increasing dose, and increasing ADMIRE strength, offering up to 64% noise reduction relative to FBP. Noise texture in terms of the NPS was similar between FBP and ADMIRE (<5% shift in peak frequency). The resolution, based on the TTF, improved with increased ADMIRE strength by an average of 15% in the TTF 50% frequency for ADMIRE-5. The detectability index increased with increasing dose and ADMIRE strength by an average of 55%, 90%, and 163% for ADMIRE 3, 4, and 5, respectively. Assessing the impact of mA modulation for a fixed average dose over the length of the phantom, detectability was up to 49% lower in smaller phantom sections and up to 26% higher in larger phantom sections for the modulated scan compared to a fixed tube current scan. Overall, the detectability exhibited less variability with phantom size for modulated scans compared to fixed tube current scans. CONCLUSIONS: Image quality increased with increasing dose and decreasing phantom size. The CT system exhibited nonlinear noise and resolution properties, especially at very low-doses, large phantom sizes, and for low-contrast objects. Objective image quality metrics generally increased with increasing dose and ADMIRE strength, and with decreasing phantom size. The ADMIRE algorithm could offer comparable image quality at reduced doses or improved image quality at the same dose. The use of tube current modulation resulted in more consistent image quality with changing phantom size. PMID- 26233221 TI - Comparison and uncertainty evaluation of different calibration protocols and ionization chambers for low-energy surface brachytherapy dosimetry. AB - PURPOSE: A surface electronic brachytherapy (EBT) device is in fact an x-ray source collimated with specific applicators. Low-energy (<100 kVp) x-ray beam dosimetry faces several challenges that need to be addressed. A number of calibration protocols have been published for x-ray beam dosimetry. The media in which measurements are performed are the fundamental difference between them. The aim of this study was to evaluate the surface dose rate of a low-energy x-ray source with small field applicators using different calibration standards and different small-volume ionization chambers, comparing the values and uncertainties of each methodology. METHODS: The surface dose rate of the EBT unit Esteya (Elekta Brachytherapy, The Netherlands), a 69.5 kVp x-ray source with applicators of 10, 15, 20, 25, and 30 mm diameter, was evaluated using the AAPM TG-61 (based on air kerma) and International Atomic Energy Agency (IAEA) TRS-398 (based on absorbed dose to water) dosimetry protocols for low-energy photon beams. A plane parallel T34013 ionization chamber (PTW Freiburg, Germany) calibrated in terms of both absorbed dose to water and air kerma was used to compare the two dosimetry protocols. Another PTW chamber of the same model was used to evaluate the reproducibility between these chambers. Measurements were also performed with two different Exradin A20 (Standard Imaging, Inc., Middleton, WI) chambers calibrated in terms of air kerma. RESULTS: Differences between surface dose rates measured in air and in water using the T34013 chamber range from 1.6% to 3.3%. No field size dependence has been observed. Differences are below 3.7% when measurements with the A20 and the T34013 chambers calibrated in air are compared. Estimated uncertainty (with coverage factor k = 1) for the T34013 chamber calibrated in water is 2.2%-2.4%, whereas it increases to 2.5% and 2.7% for the A20 and T34013 chambers calibrated in air, respectively. The output factors, measured with the PTW chambers, differ by less than 1.1% for any applicator size when compared to the output factors that were measured with the A20 chamber. CONCLUSIONS: Measurements using both dosimetric protocols are consistent, once the overall uncertainties are considered. There is also consistency between measurements performed with both chambers calibrated in air. Both the T34013 and A20 chambers have negligible stem effect. Any x-ray surface brachytherapy system, including Esteya, can be characterized using either one of these calibration protocols and ionization chambers. Having less correction factors, lower uncertainty, and based on measurements, performed in closer to clinical conditions, the TRS-398 protocol seems to be the preferred option. PMID- 26233222 TI - Assessment of tumor response to radiation and vascular targeting therapy in mice using quantitative ultrasound spectroscopy. AB - PURPOSE: It is now recognized that the tumor vasculature is in part responsible for regulating tumor responses to radiation therapy. However, the extent to which radiation-based vascular damage contributes to tumor cell death remains unknown. In this work, quantitative ultrasound spectroscopy (QUS) methods were used to investigate the acute responses of tumors to radiation-based vascular treatments. METHODS: Tumor xenografts (MDA-MB-231) were treated with single radiation doses of 2 or 8 Gy alone, or in combination with pharmacological agents that modulate vascular radiosensitivity. The midband fit, the slope, and the 0-MHz intercept QUS parameters were obtained from a linear-regression fit to the averaged power spectrum of frequency-dependent ultrasound backscatter and were used to quantify acute tumor responses following treatment administration. Power spectrums were extracted from raw volumetric radio-frequency ultrasound data obtained before and 24 h following treatment administration. These parameters have previously been correlated to tumor cell death. Staining using in situ end labeling, carbonic anhydrase 9 and cluster of differentiation 31 of tumor sections were used to assess cell death, oxygenation, and vasculature distributions, respectively. RESULTS: Results indicate a significant midband fit QUS parameter increases of 3.2 +/- 0.3 dBr and 5.4 +/- 0.5 dBr for tumors treated with 2 and 8 Gy radiation combined with the antiangiogenic agent Sunitinib, respectively. In contrast, tumors treated with radiation alone demonstrated a significant midband fit increase of 4.4 +/- 0.3 dBr at 8 Gy only. Preadministration of basic fibroblast growth factor, an endothelial radioprotector, acted to minimize tumor response following single large doses of radiation. Immunohistochemical analysis was in general agreement with QUS findings; an R(2) of 0.9 was observed when quantified cell death was correlated with changes in midband fit. CONCLUSIONS: Results from QUS analysis presented in this study confirm that acute tumor response is linked to a vascular effect following high doses of radiation therapy. Overall, this is in agreement with previous reports suggesting that acute tumor radiation response is regulated by a vascular-driven response. Data also suggest that Sunitinib may enhance tumor radiosensitivity through a vascular remodeling process, and that QUS may be sensitive to changes in tissue properties associated with vascular remodeling. Finally, the work also demonstrates the ability of QUS methods to monitor response to radiation-based vascular strategies. PMID- 26233223 TI - Generation of brain pseudo-CTs using an undersampled, single-acquisition UTE mDixon pulse sequence and unsupervised clustering. AB - PURPOSE: MR-based pseudo-CT has an important role in MR-based radiation therapy planning and PET attenuation correction. The purpose of this study is to establish a clinically feasible approach, including image acquisition, correction, and CT formation, for pseudo-CT generation of the brain using a single-acquisition, undersampled ultrashort echo time (UTE)-mDixon pulse sequence. METHODS: Nine patients were recruited for this study. For each patient, a 190-s, undersampled, single acquisition UTE-mDixon sequence of the brain was acquired (TE = 0.1, 1.5, and 2.8 ms). A novel method of retrospective trajectory correction of the free induction decay (FID) signal was performed based on point spread functions of three external MR markers. Two-point Dixon images were reconstructed using the first and second echo data (TE = 1.5 and 2.8 ms). R2(*) images (1/T2(*)) were then estimated and were used to provide bone information. Three image features, i.e., Dixon-fat, Dixon-water, and R2(*), were used for unsupervised clustering. Five tissue clusters, i.e., air, brain, fat, fluid, and bone, were estimated using the fuzzy c-means (FCM) algorithm. A two-step, automatic tissue-assignment approach was proposed and designed according to the prior information of the given feature space. Pseudo-CTs were generated by a voxelwise linear combination of the membership functions of the FCM. A low-dose CT was acquired for each patient and was used as the gold standard for comparison. RESULTS: The contrast and sharpness of the FID images were improved after trajectory correction was applied. The mean of the estimated trajectory delay was 0.774 MUs (max: 1.350 MUs; min: 0.180 MUs). The FCM-estimated centroids of different tissue types showed a distinguishable pattern for different tissues, and significant differences were found between the centroid locations of different tissue types. Pseudo-CT can provide additional skull detail and has low bias and absolute error of estimated CT numbers of voxels (-22 +/- 29 HU and 130 +/- 16 HU) when compared to low-dose CT. CONCLUSIONS: The MR features generated by the proposed acquisition, correction, and processing methods may provide representative clustering information and could thus be used for clinical pseudo CT generation. PMID- 26233224 TI - External validation of a publicly available computer assisted diagnostic tool for mammographic mass lesions with two high prevalence research datasets. AB - PURPOSE: Lesions detected at mammography are described with a highly standardized terminology: the breast imaging-reporting and data system (BI-RADS) lexicon. Up to now, no validated semantic computer assisted classification algorithm exists to interactively link combinations of morphological descriptors from the lexicon to a probabilistic risk estimate of malignancy. The authors therefore aim at the external validation of the mammographic mass diagnosis (MMassDx) algorithm. A classification algorithm like MMassDx must perform well in a variety of clinical circumstances and in datasets that were not used to generate the algorithm in order to ultimately become accepted in clinical routine. METHODS: The MMassDx algorithm uses a naive Bayes network and calculates post-test probabilities of malignancy based on two distinct sets of variables, (a) BI-RADS descriptors and age ("descriptor model") and (b) BI-RADS descriptors, age, and BI-RADS assessment categories ("inclusive model"). The authors evaluate both the MMassDx (descriptor) and MMassDx (inclusive) models using two large publicly available datasets of mammographic mass lesions: the digital database for screening mammography (DDSM) dataset, which contains two subsets from the same examinations a medio-lateral oblique (MLO) view and cranio-caudal (CC) view dataset-and the mammographic mass (MM) dataset. The DDSM contains 1220 mass lesions and the MM dataset contains 961 mass lesions. The authors evaluate discriminative performance using area under the receiver-operating-characteristic curve (AUC) and compare this to the BI-RADS assessment categories alone (i.e., the clinical performance) using the DeLong method. The authors also evaluate whether assigned probabilistic risk estimates reflect the lesions' true risk of malignancy using calibration curves. RESULTS: The authors demonstrate that the MMassDx algorithms show good discriminatory performance. AUC for the MMassDx (descriptor) model in the DDSM data is 0.876/0.895 (MLO/CC view) and AUC for the MMassDx (inclusive) model in the DDSM data is 0.891/0.900 (MLO/CC view). AUC for the MMassDx (descriptor) model in the MM data is 0.862 and AUC for the MMassDx (inclusive) model in the MM data is 0.900. In all scenarios, MMassDx performs significantly better than clinical performance, P < 0.05 each. The authors furthermore demonstrate that the MMassDx algorithm systematically underestimates the risk of malignancy in the DDSM and MM datasets, especially when low probabilities of malignancy are assigned. CONCLUSIONS: The authors' results reveal that the MMassDx algorithms have good discriminatory performance but less accurate calibration when tested on two independent validation datasets. Improvement in calibration and testing in a prospective clinical population will be important steps in the pursuit of translation of these algorithms to the clinic. PMID- 26233225 TI - Erratum: "Exploitation of temporal redundancy in compressed sensing reconstruction of fMRI studies with a prior-based algorithm (PICCS)" [Med. Phys. 42, 3814-3821 (2015)]. PMID- 26233226 TI - Erratum: "Three-dimensional texture analysis of contrast enhanced CT images for treatment response assessment in Hodgkin lymphoma: Comparison with F-18-FDG PET" [Med. Phys. 41(12), 121904 (2014)]. PMID- 26233229 TI - Biomechanics of high-grade spondylolisthesis with and without reduction. AB - The clinical advantages of reducing spondylolisthesis over fusion in situ have several intuitive reasons such as restore the spinal column into a more anatomic relationship and alignment. However, there is only little evidence in the literature supporting the theoretical advantages of reduction, and its effect on spinopelvic alignment remains poorly defined. In this study, a comprehensive finite element model was developed to analyze the biomechanics of the spine after spinal fusion at L5-S1 in both types of high-grade spondylolisthesis (balanced and unbalanced pelvis). The relevant clinical indices (i.e. spondylolisthesis grade and Dubousset lumbosacral angle), the displacement of L4-L5, pressure within the annulus and nucleus, and stress at L4-L5 were evaluated and compared. The model can well predict the changes of the important clinical indices during the surgery. For a balanced pelvis, the reduction has a minimal effect on the biomechanical conditions at the adjacent level during postsurgical activities. In the unbalanced case, reduction induced larger deformation in the lumbosacral region and a higher stress concentration at adjacent level. Whether such a stress concentration can lead to long-term disc degeneration is not known. The results provide additional information for the clinician considering reduction of high grade spondylolisthesis. PMID- 26233231 TI - No association between ApoE polymorphism and febrile seizures. AB - Seizures associated with fever are a common pediatric problem, affecting about 2 7 % of children between 3 months and 5 years of age. Differentiation of febrile seizures from acute symptomatic seizures secondary to central nervous system infections or seizures associated with fever in children with epilepsy is essential to provide appropriate treatment and follow-up care. Here, we tested the hypothesis that children who exhibit simple febrile seizures during early childhood, but do not develop epileptic seizures later in life, might preferentially carry the ApoE2 allele of the gene coding for the apolipoprotein E. We did not find any differences in the distribution of ApoE alleles or genotypes between individuals who exhibited simple febrile seizures (n = 93) and age-matched, typically developing subjects (n = 80). We found that the observed allele and genotype frequencies did not deviate from Hardy-Weinberg equilibrium, which suggests that the frequencies of ApoE alleles and genotypes are stable in the Swiss population from which our samples were derived. Across both groups of subjects (n = 173), we found an ApoE2 allele frequency of 0.064, an ApoE3 frequency of 0.829 and an ApoE4 frequency of 0.107. Our findings are consistent with previous reports of the distribution of ApoE polymorphism for European subjects free of any neurological disorders, and show that the different alleles of the gene coding for the apolipoprotein E are not associated with the occurrence of simple febrile seizures. PMID- 26233230 TI - Identification of neuromotor deficits common to autism spectrum disorder and attention deficit/hyperactivity disorder, and imitation deficits specific to autism spectrum disorder. AB - Deficits in motor and imitation abilities are a core finding in autism spectrum disorders (ASD), but impaired motor functions are also found in attention deficit/hyperactivity disorder (ADHD). Given recent theorising about potential aetiological overlap between the two disorders, the present study aimed to assess difficulties in motor performance and imitation of facial movements and meaningless gestures in a sample of 24 ADHD patients, 22 patients with ASD, and 20 typically developing children, matched for age (6-13 years) and similar in IQ (>80). Furthermore, we explored the impact of comorbid ADHD symptoms on motor and imitation performance in the ASD sample and the interrelationships between the two groups of variables in the clinical groups separately. The results show motor dysfunction was common to both disorders, but imitation deficits were specific to ASD. Together with the pattern of interrelated motor and imitation abilities, which we found exclusively in the ASD group, our findings suggest complex phenotypic, and possibly aetiological, relationships between the two neurodevelopmental conditions. PMID- 26233232 TI - Diagnostic delay and prognosis in primary central nervous system lymphoma compared with glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) and primary central nervous system lymphoma (PCNSL) are malignant cerebral neoplasms associated with poor prognosis. Early diagnosis and subsequent planning of adequate treatment strategy are relevant to improve survival and reduce neurological deficit. Two groups of patients affected by GBM and PCNSL were compared to identify: (1) factors influencing the time necessary to obtain a correct diagnosis; (2) the influence of the interval time from clinical onset to diagnosis on the prognosis. Fifty-six patients (28 PCNSL and 28 GBM, 23 females and 33 males) referred to the same hospital setting were retrospectively evaluated. The mean age at diagnosis was 61 years. The two groups were comparable in terms of age, sex, clinical symptoms at onset and performance status. There was no relevant difference in time span from clinical onset to first neuroimaging examination, while time span from first neuroimaging to final morphological diagnosis was much longer in PCNSL patients (p = 0.008). Multivariate Cox regression analysis, including both PCNSL and GBM cases, showed a significant association of the overall survival with: time to diagnosis (HR 0.06), age at onset (HR 1.04). Our results show a significant diagnostic delay in PCNSL cases. Age at onset of disease and time to diagnosis emerge as clinical factors affecting overall survival in both groups. Stereotactic-guided biopsy should be chosen as routine method to early diagnose PCNSL. The clinical relevance of early diagnosis in GBM and PCNSL needs to be emphasized to maximize the overall survival in both neoplasms. PMID- 26233233 TI - Light-induced inhibition of laccase in Pycnoporus sanguineus. AB - The aim was to determine which specific regions of the visible light spectrum were responsible for the induction or inhibition of laccase in Pycnoporus sanguineus. Cultures were exposed to various bandwidth lights: blue (460 nm), green (525 nm), white (a combination of 460 and 560 nm), red (660 nm), and darkness. The results indicate that short wavelengths strongly inhibit the production of laccase: green (3.76 +/- 1.12 U/L), blue (1.94 +/- 0.36 U/L), and white (1.05 +/- 0.21 U/L) in proportions of 85.8, 92.6, and 96.0%, respectively; whereas long wavelengths inhibit laccase production only partially i.e., red light (14.05 +/- 4.79 U/L) in a proportion of 46.8%. Maximum activity was induced in absence of visible light (30 degrees C, darkness), i.e., 30.76 +/- 4.0 U/L. It is concluded that the production of laccase in P. sanguineus responds to light stimuli [measured as wavelengths and lx] and that it does so inversely. This can be explained as an ecological mechanism of environmental recognition, given that P. sanguineus develops inside lignocellulose structures in conditions of darkness. The presence of short wavelength light (460-510 nm) would indicate that the organism finds itself in an external environment, unprovided of lignin, and that it is therefore unnecessary to secrete laccase. This possible new regulation in the laccase production in P. sanguineus has important biotechnological implications, for it would be possible to control the production of laccase using light stimuli. PMID- 26233234 TI - The time-course of distractor processing in auditory spatial negative priming. AB - The spatial negative priming effect denotes slowed-down and sometimes more error prone responding to a location that previously contained a distractor as compared with a previously unoccupied location. In vision, this effect has been attributed to the inhibition of irrelevant locations, and recently, of their task-assigned responses. Interestingly, auditory versions of the task did not yield evidence for inhibitory processing of task-irrelevant events which might suggest modality specific distractor processing in vision and audition. Alternatively, the inhibitory processes may differ in how they develop over time. If this were the case, the absence of inhibitory after-effects might be due to an inappropriate timing of successive presentations in previous auditory spatial negative priming tasks. Specifically, the distractor may not yet have been inhibited or inhibition may already have dissipated at the time performance is assessed. The present study was conducted to test these alternatives. Participants indicated the location of a target sound in the presence of a concurrent distractor sound. Performance was assessed between two successive prime-probe presentations. The time between the prime response and the probe sounds (response-stimulus interval, RSI) was systematically varied between three groups (600, 1250, 1900 ms). For all RSI groups, the results showed no evidence for inhibitory distractor processing but conformed to the predictions of the feature mismatching hypothesis. The results support the assumption that auditory distractor processing does not recruit an inhibitory mechanism but involves the integration of spatial and sound identity features into common representations. PMID- 26233235 TI - Psychosocial predictors of emotional eating and their weight-loss treatment induced changes in women with obesity. AB - PURPOSE: This study aimed at assessing whether psychosocial predictors of controlled eating and weight loss also predict emotional eating, and how differing weight-loss treatment methods affect those variables. METHODS: Women with obesity (M = 47.8 +/- 7.9 years; BMI = 35.4 +/- 3.3 kg/m(2)) were randomized into groups of either phone-supported self-help (Self-Help; n = 50) or in-person contact (Personal Contact; n = 53) intended to increase exercise, improve eating behaviors, and reduce weight over 6 months. RESULTS: A multiple regression analysis indicated that at baseline mood, self-regulating eating, body satisfaction, and eating-related self-efficacy significantly predicted emotional eating (R (2) = 0.35), with mood and self-efficacy as independent predictors. Improvements over 6 months on each psychosocial measure were significantly greater in the Personal Contact group. Changes in mood, self-regulation, body satisfaction, and self-efficacy significantly predicted emotional eating change (R (2) = 0.38), with all variables except self-regulation change being an independent predictor. Decreased emotional eating was significantly associated with weight loss. CONCLUSION: Findings suggest that weight-loss interventions should target specific psychosocial factors to improve emotional eating. The administration of cognitive-behavioral methods through personal contact might be more beneficial for those improvements than self-help formats. PMID- 26233236 TI - First-episode psychotic disorder improving after immunotherapy. PMID- 26233237 TI - Potentially Beneficial Effect of Hydroxychloroquine in a Patient with a Novel Mutation in Protein Kinase Cdelta Deficiency. AB - Protein kinase C delta (PRKCD) has essential functions in controlling B-cell proliferation and apoptosis, development of B-cell tolerance and NK-cell cytolitic activity. Human PRKCD deficiency was recently identified to be causative for an autoimmune lymphoproliferative syndrome like disorder with significant B-cell proliferation particularly of immature B cells. Here we report a child with a novel mutation in PRKCD gene who presented with CMV infection and an early onset SLE-like disorder which was successfully treated with hydroxychloroquine. PMID- 26233238 TI - Severe and Rapid Progression in Very Early-Onset Chronic Granulomatous Disease Associated Colitis. AB - PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency disease that leads to recurrent infection and hyper-inflammation, occasionally represented by CGD-associated colitis (CGD colitis). Although clinical symptoms of CGD colitis mimic those of ulcerative colitis (UC), there is no reliable standard measurement of disease activity or standard therapeutic strategy for CGD colitis. Here, we examined the clinical manifestation of CGD colitis based on severity using a noninvasive measure of disease activity, the Pediatric Ulcerative Colitis Activity Index (PUCAI), which has been validated and widely used for pediatric UC. METHODS: Sixteen of 35 CGD patients, who were diagnosed with CGD colitis based on colonoscopic and histological findings, were examined using the PUCAI. Both the PUCAI and the physician global assessment (PGA) tool were retrospectively scored by reviewing medical records. RESULTS: Disease activity defined by PUCAI was correlated with PGA, and increased at diagnosis of CGD colitis, especially in patients who were younger than 6 years of age (very early-onset CGD colitis: VEO-CGD colitis) when diagnosed with CGD colitis. All severe patients had a more progressive form of VEO-CGD colitis. Unlike mild and moderate patients, severe patients required multidrug therapy of corticosteroids and immunomodulator/immunosuppressants, and some were eventually treated with hematopoietic stem cell transplantation. CONCLUSIONS: Although the validation of PUCAI in CGD colitis should be considered for future use, our results indicate that noninvasive measures could be effective to measure disease activity and help to determine suitable treatment for CGD colitis. In patients with VEO-CGD colitis, multidrug therapy would need to be considered at an early stage on the basis of disease activity. PMID- 26233239 TI - Apoptotic Effect of Geniposide on Fibroblast-Like Synoviocytes in Rats with Adjuvant-Induced Arthritis via Inhibiting ERK Signal Pathway In Vitro. AB - Stimulating fibroblast-like synoviocyte (FLS) apoptosis in rheumatoid arthritis (RA) is a promising strategy for clinical treatment. Previous studies have confirmed that geniposide shows a certain anti-arthritic effect in vivo. However, whether geniposide can induce RA FLS apoptosis and the underlying mechanisms has not been elucidated. Herein, adjuvant-induced arthritis (AIA) in rat was induced and FLS was isolated from synovial tissues by tissue explant cultivation method. MTT assay, Hoechst staining, and flow cytometric apoptosis assay were applied to evaluate apoptotic effect of geniposide on AIA FLS. Bcl-2, Bax, and caspase 3 messenger RNA (mRNA) levels, and extracellular-signal-regulated kinases (ERKs) and phosphorylated ERK protein levels were examined by real-time PCR and western blot, respectively. We found that geniposide dose-dependently inhibited AIA FLS proliferation in vitro. AIA FLS treated with geniposide displayed typical apoptotic morphological characteristics including nuclear shrinkage and chromatin condensation. Flow cytometric apoptosis assay indicated that geniposide significantly increased the apoptosis rate of AIA FLS. Additionally, geniposide treatment on AIA FLS decreased Bcl-2 mRNA level and increased Bax and caspase 3 mRNA levels, accompanied by reduced protein levels of phosphorylated-ERK1/2, without affecting total ERK1/2. In conclusion, geniposide effectively induces AIA FLS apoptosis through regulating the apoptosis-related gene expressions and inhibiting ERK signal pathway. PMID- 26233240 TI - Locally Advanced Non-Small Cell Lung Cancer: Optimal Chemotherapeutic Agents and Duration. AB - OPINION STATEMENT: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the USA. The treatment of locally advanced NSCLC (LA NSCLC) is challenging and must be individualized. For patients with completely resected stage III NSCLC, adjuvant cisplatin-based chemotherapy for 4 cycles is recommended. For patients with inoperable or unresectable stage III NSCLC, chemoradiation is the preferred treatment. Patients with a good performance status, minimal or no weight loss, and adequate pulmonary function should be offered concurrent chemoradiation. The optimal chemotherapeutic agents to be used concurrently with radiation remain undefined. In the USA, cisplatin plus etoposide or carboplatin plus paclitaxel are the most commonly used regimens. In addition, the optimal duration of therapy remains undefined, including the role of consolidation chemotherapy. Thus far, randomized phase III trials have failed to identify a survival advantage for administering chemotherapy beyond that delivered during radiation therapy. Molecularly targeted agents, angiogenesis inhibitors, and immunotherapy have a defined role for patients with metastatic disease. The role, if any, of these new classes of agents is undergoing investigation for patients with earlier stage disease, including stage III disease. PMID- 26233241 TI - The dorsal premotor cortex exerts a powerful and specific inhibitory effect on the ipsilateral corticofacial system: a dual-coil transcranial magnetic stimulation study. AB - A rich pattern of connectivity is present in non-human primates between the dorsal premotor cortex (PMCd) and the motor cortex (M1). By analogy, similar connections are hypothesized in humans between the PMCd and the ipsilateral hand related M1. However, the technical difficulty of applying transcranial magnetic stimulation (TMS) with a dual-coil paradigm to two cortical regions in such close spatial proximity renders their in vivo demonstration difficult. The present work aims at assessing in humans the existence of short-latency influences of the left PMCd on the ipsilateral corticofacial system by means of TMS. A dual-coil TMS paradigm was used with 16 participants. Test TMS pulses were applied to the left orofacial M1, and conditioning TMS pulses were applied to three distinct points of the ipsilateral PMCd along the caudal part of the superior frontal sulcus. The inter-stimulus interval (ISI) between condTMS and testTMS varied in 2-ms steps between 2 and 8 ms. Motor evoked potentials (MEPs) in the active orbicularis oris muscle were recorded. CondTMS exerted a robust effect on the corticofacial system only when applied to one specific portion of the PMCd and only at one specific ISI (6 ms). The effect consisted in a systematic suppression of facial MEPs compared to those obtained by testTMS alone. No other effect was found. We provide evidence for a specific short-latency inhibitory effect of the PMCd on the ipsilateral M1, likely witnessing direct corticocortical connectivity in humans. We also describe a novel paradigm to test ipsilateral PMCd-M1 in humans. PMID- 26233242 TI - Effects of New Antiplatelet Agents and Aldosterone Receptor Antagonists on Mortality in Patients with Myocardial Infarction. PMID- 26233243 TI - Biomechanical testing of circumferential instrumentation after cervical multilevel corpectomy. AB - STUDY DESIGN: Biomechanical investigation. PURPOSE: This study describes ex vivo evaluation of the range of motion (ROM) to characterize the stability and need for additional dorsal fixation after cervical single-level, two-level or multilevel corpectomy (CE) to elucidate biomechanical differences between anterior-only and supplemental dorsal instrumentation. METHODS: Twelve human cervical cadaveric spines were loaded in a spine tester with pure moments of 1.5 Nm in lateral bending (LB), flexion/extension (FE), and axial rotation (AR), followed by two cyclic loading periods for three-level corpectomies. After each cyclic loading session, flexibility tests were performed for anterior-only instrumentation (group_1, six specimens) and circumferential instrumentation (group_2, six specimens). RESULTS: The flexibility tests for all circumferential instrumentations showed a significant decrease in ROM in comparison with the intact state and anterior-only instrumentations. In comparison with the intact state, supplemental dorsal instrumentation after three-level CE reduced the ROM to 12% (+/-10%), 9% (+/-12%), and 22% (+/-18%) in LB, FE, and AR, respectively. The anterior-only construct outperformed the intact state only in FE, with a significant ROM reduction to 57% (+/-35 %), 60% (+/-27%), and 62% (+/-35%) for one-, two- and three-level CE, respectively. CONCLUSIONS: The supplemental dorsal instrumentation provided significantly more stability than the anterior-only instrumentation regardless of the number of levels resected and the direction of motion. After cyclic loading, the absolute differences in stability between the two instrumentations remained significant while both instrumentations showed a comparable increase of ROM after cyclic loading. The large difference in the absolute ROM of anterior-only compared to circumferential instrumentations supports a dorsal support in case of three-level approaches. PMID- 26233244 TI - Carotid body tumor: a 25-year experience. AB - Carotid body tumor is an uncommon hypervascular benign tumor in the head and neck region. It usually presents as a slow growing mass at the carotid bifurcation. Because of the high rate of neurovascular complications, resection of this tumor is considered challenging for otolaryngologists. Between 1988 and 2013, 40 carotid body tumors from 38 patients were diagnosed and underwent resection at Siriraj Hospital (25 female and 13 male patients). Their age ranged from 15 to 59 years. Seven patients had bilateral tumors simultaneously whereas six cases had familial history of carotid body tumor. Carotid angiography was performed in 29 cases; other additional diagnostic studies included CT scan, MRI, and MRA to detect the widening of carotid bifurcation, its extension, and multifocal tumors. All diagnosed tumors were successfully removed. However, internal carotid artery and carotid bifurcation were injured in 11 cases (27.5 %). Shamblin class III and previous biopsy history were considered risk factors for vascular injury. Postoperative cranial nerves deficit was found in 20 % of the cases and CNS complication occurred in two patients (5 %). There was no surgical mortality. Additionally, upon the mean follow-up period of 36 months, no recurrence or malignant transformation was detected in this study. Multidisciplinary approach, early tumor detection, meticulous preoperative evaluation, and modern vascular surgical technique are the key success factors for tumor removal. PMID- 26233245 TI - Malignant otitis externa in a healthy non-diabetic patient. AB - A healthy 60-year-old male was initially treated for external otitis, and subsequently received multiple surgeries including abscess drainage, temporal bone debridement, canaloplasty of the external auditory meatus, and fistula excision and was treated with numerous antibiotics at another hospital over a 1 year period. He was seen at our hospital on February 14, 2014 with a complaint of a non-healing wound behind the left ear and drainage of purulent fluid. He had no history of diabetes mellitus or compromised immune function. Computed tomography (CT) and magnetic resonance imaging (MRI) studies at our hospital showed osteomyelitis involving the left temporal, occipital, and sphenoid bones, the mandible, and an epidural abscess. Routine blood testing and tests of immune function were normal, and no evidence of other infectious processes was found. He was diagnosed with malignant otitis externa (MOE). Bone debridement and incision and drainage of the epidural abscess were performed, and vancomycin was administered because culture results revealed Corynebacterium jeikeium, Corynebacterium xerosis, and Enterococcus faecalis. MOE should be considered in healthy patients with external otitis who fail initial treatment. PMID- 26233246 TI - Contrast-enhanced MRI of the knee in children unaffected by clinical arthritis compared to clinically active juvenile idiopathic arthritis patients. AB - OBJECTIVES: To evaluate enhancing synovial thickness upon contrast-enhanced magnetic resonance imaging (MRI) of the knee in children unaffected by clinical arthritis compared with clinically active juvenile idiopathic arthritis (JIA) patients. A secondary objective was optimization of the scoring method based on maximizing differences on MRI between these groups. METHODS: Twenty-five children without history of joint complaints nor any clinical signs of joint inflammation were age/sex-matched with 25 clinically active JIA patients with arthritis of at least one knee. Two trained radiologists, blinded for clinical status, independently evaluated location and extent of enhancing synovial thickness with the validated Juvenile Arthritis MRI Scoring system (JAMRIS) on contrast-enhanced axial fat-saturated T1-weighted MRI of the knee. RESULTS: Enhancing synovium (>=2 mm) was present in 13 (52 %) unaffected children. Using the total JAMRIS score for synovial thickening, no significant difference was found between unaffected children and active JIA patients (p = 0.091). Additional weighting of synovial thickening at the JIA-specific locations enabled more sensitive discrimination (p = 0.011). CONCLUSIONS: Mild synovial thickening is commonly present in the knee of children unaffected by clinical arthritis. The infrapatellar and cruciate ligament synovial involvement were specific for JIA, which-in a revised JAMRIS increases the ability to discriminate between JIA and unaffected children. KEY POINTS: * Synovial inflammation is the primary disease feature in juvenile idiopathic arthritis (JIA). * Appearance of the synovium on contrast-enhanced MRI in unaffected children is unknown. * Validation of existing scoring methods requires comparison between JIA and unaffected children. * Mild enhancing synovial thickening was detected in half of the unaffected children. * Location weighting for JIA-specific locations increased discriminative value of the scoring methods (p = 0.011). PMID- 26233247 TI - Control of brain metastases from radioresistant tumors treated by stereotactic radiosurgery. AB - Renal cell carcinoma, sarcoma, and melanoma are considered to be "radioresistant" tumor histologies. Brain metastases (BM) from these tumors are considered unlikely to be controlled using the relatively low doses used in whole brain radiotherapy (WBRT). Our objective was to analyze the efficacy of stereotactic radiosurgery (SRS) on local control and overall survival of BM from radioresistant primary tumors. We reviewed all patients who received Gamma Knife Radiosurgery (GKRS) for BM at Columbia University Medical Center between January 2009 and April 2014. All patients were treated using the Gamma Knife Perfexion System. Dosimetric data was collected from treatment plans and metastases were categorized as radioresistant or not. Response was assessed by reviewing follow up brain imaging studies and classified according to RECIST. Local control and median overall survival were calculated using the Kaplan-Meier method. In total, 373 tumors were analyzed from 126 patients. Of these tumors, 49 (13.1 %) originated from radioresistant cancers. The overall local control rate in the radioresistant cohort was 89.8 and 90.1 % in the non-radioresistant cohort. Univariate and multivariate analyses demonstrated that radioresistance status of the primary tumor had no statistically significant effect on local control with hazard ratios of 1.0 (p = 1.0, 95 % CI 0.388-2.576) and 0.954 (p = 0.926, 95 % CI 0.349-2.603) respectively. Median overall survival for both radioresistant and non-radioresistant cohorts was 20.0 months, with a p value of 0.926. There was no significant difference in local control of BM from radioresistant and non radioresistant primary tumors treated with GKRS. Both cohorts showed excellent response and local control, suggesting that SRS upfront or in addition to WBRT may be an appropriate strategy in the treatment of BM from radioresistant cancers. Median overall survival for both cohorts was equal, suggesting that improved local control may be associated with an improvement in long-term survival. PMID- 26233248 TI - Current status of intratumoral therapy for glioblastoma. AB - With emerging drug delivery technologies becoming accessible, more options are expected to become available to patients with glioblastoma (GBM) in the near future. It is important for clinicians to be familiar with the underlying mechanisms and limitations of intratumoral drug delivery, and direction of recent research efforts. Tumor-adjacent brain is an extremely complex living matrix that creates challenges with normal tissue intertwining with tumor cells. For convection-enhanced delivery (CED), the role of tissue anisotropy for better predicting the biodistribution of the infusate has recently been studied. Computational predictive methods are now available to better plan CED therapy. Catheter design and placement-in addition to the agent being used-are critical components of any protocol. This paper overviews intratumoral therapies for GBM, highlighting key anatomic and physiologic perspectives, selected agents (especially immunotoxins), and some new developments such as the description of the glymphatic system. PMID- 26233250 TI - Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration. AB - AIM/HYPOTHESIS: Mitochondria and the endoplasmic reticulum (ER) physically interact by close structural juxtaposition, via the mitochondria-associated ER membrane. Inter-organelle communication between the ER and mitochondria has been shown to regulate energy metabolism and to be central to the modulation of various key processes such as ER stress. We aimed to clarify the role of mitochondrial fission in this communication. METHODS: We generated mice lacking the mitochondrial fission protein dynamin-related protein 1 (DRP1) in the liver (Drp1LiKO mice). RESULTS: Drp1LiKO mice showed decreased fat mass and were protected from high-fat diet (HFD)-induced obesity. Analysis of liver gene expression profiles demonstrated marked elevation of ER stress markers. In addition, we observed increased expression of the fibroblast growth factor 21 (FGF21) gene through induction of activating transcription factor 4, master regulator of the integrated stress response. CONCLUSIONS/INTERPRETATION: Disruption of mitochondrial fission in the liver provoked ER stress, while inducing the expression of FGF21 to increase energy expenditure and protect against HFD-induced obesity. PMID- 26233251 TI - Liquid hot water pretreatment of energy grasses and its influence of physico chemical changes on enzymatic digestibility. AB - Pennisetum hybrid I, II and switchgrass were pretreated with liquid hot water to enhance the release of sugars. The optimum hydrolysis factor for three energy grasses was 5.98, and the total xylose yield was 88.4%, 98.1% and 83.6% for grass I, II and S. It was indicated that the ratio of syringyl and guaiacyl units of lignin played an important role on the hemicellulose hydrolysis in LHW than branch degree, but latter contributed more on the characterization of xylooligomers degree of polymerization. Moreover, the analysis of multi-scale changes of substrate suggested that cellulose crystallinity index and degree of polymerization seemed no direct relationships for increase of enzymatic digestibility. While lignin barrier was the main factor limiting efficiency of sugar release, and Pennisetum hybrid with low lignin content and high sugar recovery was proved to be a prospective plant feedstock for cellulosic ethanol production. PMID- 26233252 TI - Combining asymmetrical flow field-flow fractionation with on- and off-line fluorescence detection to examine biodegradation of riverine dissolved and particulate organic matter. AB - This study demonstrated that asymmetrical flow field-flow fractionation (AF4) coupled with on-line UV and fluorescence detection (FLD) and off-line excitation emission matrix (EEM) fluorescence spectroscopy can be employed to analyze the influence of microbial metabolic activity on the consumption and production of freshwater organic matter. With the AF4 system, organic matter is on-line enriched during a focusing/relaxation period, which is an essential process prior to separation. Size-fractionated chromophoric and fluorophoric organic materials were simultaneously monitored during the 30-min AF4 separation process. Two fractions of different sizes (dissolved organic matter (DOM) and particulate organic matter (POM)) of freshwater samples from three locations (up-, mid-, and downstream) along the Han River basin of Korea were incubated with the same inoculum for 14 days to analyze fraction-specific alterations in optical properties using AF4-UV-FLD. A comparison of AF4 fractograms obtained from pre- and post-incubation samples revealed that POM-derived DOM were more susceptible to microbial metabolic activity than was DOM. Preferential microbial consumption of protein-like DOM components concurred with enhanced peaks of chromophoric and humic-like fluorescent components, presumably formed as by-products of microbial processing. AF4-UV-FLD combined with off-line identification of microbially processed components using EEM fluorescence spectroscopy provides a powerful tool to study the relationship between microbial activity and composition as well as biodegradability of DOM and POM-derived DOM from different origins, especially for the analysis of chromophoric and fluorophoric organic matter that are consumed and produced by microbial metabolic activity. The proposed AF4 system can be applied to organic matter in freshwater samples having low concentration range (0.3-2.5ppm of total organic carbon) without a pre-concentration procedure. PMID- 26233253 TI - Chromatographic efficiency comparison of polyhedral oligomeric silsesquioxanes containing hybrid monoliths via photo- and thermally-initiated free-radical polymerization in capillary liquid chromatography for small molecules. AB - Monolithic poly(methacrylate epoxy cyclosiloxane-co-polyhedral oligomeric silsesquioxanes) (epoxy-MA-POSS) capillary columns have been prepared via either photo- or thermally-initiated polymerization of the corresponding monomers using a 1-propanol/PEG 400 mixture as porogens. Photochemical polymerization was accomplished by irradiation of the UV-transparent capillary for 10min at room temperature, while thermal polymerization was performed at 55 degrees C, 60 degrees C or 65 degrees C for 18h. The evaluation of chromatographic property for two hybrid epoxy-MA-POSS monoliths was carried out. The results indicate that hybrid monoliths fabricated by photochemical initiation exhibit higher column efficiency (97,000-98,400plates/m) than those synthesized by thermal polymerization (41,100-48,000plates/m) in cLC. The higher efficiency of photo initiated hybrid monoliths is closely related to lower eddy dispersion (A-term) and mass transfer resistance (C-term). PMID- 26233254 TI - Labeling and label free shotgun proteomics approaches to characterize muscle tissue from farmed and wild gilthead sea bream (Sparus aurata). AB - The proteome characterization of fish muscle tissues, together with the relative expression of each individual protein, provides knowledge on the biochemical response of the organisms and allows to assess the effect of different types of feeding, growth site and nutritional quality of the investigated species. This type of study is usually performed by gel-based proteomics approaches, however shotgun proteomics can serve as well, reducing analysis time and improving sample high-throughput. In this work, a shotgun proteomics method was thus developed and then applied to the characterization of gilthead sea bream edible muscle. The sarcoplasmic protein fraction was extracted, in-solution digested by trypsin and finally analyzed by nanoHPLC high resolution tandem mass spectrometry. Two different quantification strategies were also tested. One was based on chemical dimethyl labeling and the other one on label free quantification. A comparison between these two analytical workflows was performed, to evaluate their individual performance in the analysis of fish samples and assess the differences induced by farming practice on the final commercial product with respect to wild gilthead sea bream. Quantitative differences were detected, and the most relevant one regarded the common fish allergen parvalbumin, found overexpressed in farmed fish samples. PMID- 26233255 TI - Capillary electrophoresis determination of non-protein amino acids as quality markers in foods. AB - Non-protein amino acids mainly exist in food as products formed during food processing, as metabolic intermediates or as additives to increase nutritional and functional properties of food. This fact makes their analysis and determination an attractive field in food science since they can give interesting information on the quality and safety of foods. This article presents a comprehensive review devoted to describe the latest advances in the development of (achiral and chiral) analytical methodologies by capillary electrophoresis and microchip capillary electrophoresis for the analysis of non-protein amino acids in a variety of food samples. Most relevant information related to sample treatment, experimental separation and detection conditions, preconcentration strategies and limits of detection will be provided. PMID- 26233256 TI - Characterization of large surface area polymer monoliths and their utility for rapid, selective solid phase extraction for improved sample clean up. AB - While polymer monoliths are widely described for solid phase extraction (SPE), appropriate characterization is rarely provided to unravel the links between physical characteristics and observed advantages and disadvantages. Two known approaches to fabricate large surface area polymer monoliths with a bimodal pore structure were investigated. The first incorporated a high percentage of divinyl benzene (PDVB) and the second explored hypercrosslinking of pre-formed monoliths. Adsorption of probe analytes; anisole, benzoic acid, cinnamic acid, ibuprofen and cortisone were investigated using frontal analysis and the SPE performance was compared with particulate adsorbents. Frontal analysis of anisole described maximum adsorption capacities of 164mgg(-1) and 298mgg(-1) for hypercrosslinked and PDVB adsorbents, respectively. The solvated state specific surface area was calculated to be 341 and 518m(2)g(-1) respectively. BET revealed a hypercrosslinked surface area of 817m(2)g(-1), 2.5 times greater than in the solvated state. The PDVB BET surface area was 531m(2)g(-1), similar to the solvated state. Micropores of 1nm provided the enhanced surface area for hypercrosslinked adsorbents. PDVB displayed a pore size distribution of 1-6nm. Frontal analysis demonstrated the micropores present size exclusion for the larger probes. Recovery of anisole was determined by SPE using 0.4 and 1.0mLmin( 1). Recovery for PDVB remained constant at 90%+/-0.103 regardless of the extraction flow rate suggesting extraction performance is independent of flow rate. A more efficient sample purification of saccharin in urine was yielded by PDVB due to selective permeation of the small pores. PMID- 26233257 TI - Targeted Treatments for Pulmonary Arterial Hypertension: Interpreting Outcomes by Network Meta-analysis. AB - BACKGROUND: No meta-analysis for indirect comparisons has been conducted to study the effectiveness of treatments for pulmonary arterial hypertension (PAH). METHODS: Our search covered the literature up to December 2014. The following five classes of agents indicated for PAH were evaluated: 1) oral endothelin receptor antagonists (ERAs); 2) oral phosphodiesterase type 5 inhibitors (PDE 5Is); 3) prostanoids administered by oral, intravenous, subcutaneous or inhalatory route; 4) selective non-prostanoid prostacyclin receptor (IP receptor) agonists (sPRAs); 5) soluble guanylate cyclase stimulators (sGCSs). Our methodology was based on standard models of Bayesian network meta-analysis. The end-point of our analysis was clinical worsening. Odds ratio was the outcome measure along with 95% credible intervals. RESULTS: Our search identified 17 randomised controlled trials (4,465 patients). There were 15 head-to-head comparisons (five direct, 10 indirect). As expected, nearly all values of odds ratio estimated for the direct comparisons versus placebo favoured the treatment arm at levels of statistical significance. More interestingly, none of the 10 head-to-head indirect comparisons between active agents showed any statistically significant difference. CONCLUSION: Our results indicate that these five classes of agents for PAH are more effective than placebo and show no significant difference in effectiveness from one another. In this context, choosing the treatment for an individual patient is a quite difficult task. PMID- 26233258 TI - A comparison of public datasets for acceleration-based fall detection. AB - Falls are one of the leading causes of mortality among the older population, being the rapid detection of a fall a key factor to mitigate its main adverse health consequences. In this context, several authors have conducted studies on acceleration-based fall detection using external accelerometers or smartphones. The published detection rates are diverse, sometimes close to a perfect detector. This divergence may be explained by the difficulties in comparing different fall detection studies in a fair play since each study uses its own dataset obtained under different conditions. In this regard, several datasets have been made publicly available recently. This paper presents a comparison, to the best of our knowledge for the first time, of these public fall detection datasets in order to determine whether they have an influence on the declared performances. Using two different detection algorithms, the study shows that the performances of the fall detection techniques are affected, to a greater or lesser extent, by the specific datasets used to validate them. We have also found large differences in the generalization capability of a fall detector depending on the dataset used for training. In fact, the performance decreases dramatically when the algorithms are tested on a dataset different from the one used for training. Other characteristics of the datasets like the number of training samples also have an influence on the performance while algorithms seem less sensitive to the sampling frequency or the acceleration range. PMID- 26233259 TI - High prevalence of Takotsubo syndrome in patients admitted to the Medical Intensive Care Unit with mon-cardiac illnesses. PMID- 26233260 TI - Bioaggregate Inhibits Osteoclast Differentiation, Fusion, and Bone Resorption In Vitro. AB - INTRODUCTION: Several bioactive bioceramics with osteoconductive effects can inhibit osteoclast formation and bone resorption in vitro, but the exact underlying mechanism has not been fully elucidated. Bioaggregate (BA), a novel calcium silicate nanoparticulate bioceramic, significantly induces bone and periodontal regeneration. In this study, we aimed to explore the effect of BA extracts on osteoclastogenesis and bone resorption. METHODS: The RAW264.7 cells were treated with soluble receptor activator of nuclear factor kappa B ligand to osteoclastogenesis. BA extracts were used to investigate the effect of BA on osteoclast differentiation, fusion, and bone resorption. Furthermore, the ions in BA extracts were quantitatively analyzed. Finally, the key molecules in the receptor activator of nuclear factor kappa B ligand-RANK signaling pathway, including receptor activator of nuclear factor kappaB (RANK), tumor necrosis factor receptor associated factor 6 (TRAF6), nuclear factor-kappa B (NF-kappaB), and nuclear factor of activated T cells c1 (NFATc1), were explored. RESULTS: BA suppressed osteoclastogenesis and bone resorption in vitro. BA releases Si ions and a small amount of Sr ions and provides alkalinity. Treatment with BA extracts decreased the migration ability and fusion of RAW264.7 cells. We also observed that BA causes a significantly decreased expression of RANK, TRAF6, NF-kappaB, and NFATc1. CONCLUSIONS: Our study provides further insight into the mechanism by which calcium silicate-based bioceramics inhibit osteoclastogenesis and bone resorption and also suggests that BA is a useful material for several clinical situations because it both stimulates osteoblast differentiation and inhibits osteoclast formation. PMID- 26233261 TI - PsbS protein modulates non-photochemical chlorophyll fluorescence quenching in membranes depleted of photosystems. AB - Plants with varying levels of PsbS protein were grown on lincomycin. Enhanced levels of non-photochemical fluorescence quenching (NPQ) in over-expressers of the protein have been observed. This was accompanied by increased amplitude of the irreversible NPQ component, qI, previously considered to reflect mainly photoinhibition of PSII reaction centres (RCII). However, since RCIIs were largely absent the observed qI is likely to originate from the LHCII antenna. In chloroplasts of over-expressers of PsbS grown on lincomycin an abnormally large NPQ (~7) was characterised by a 0.34 ns average chlorophyll fluorescence lifetime. Yet the lifetime in the Fm state was similar to that of wild-type plants. 77K fluorescence emission spectra revealed a specific 700 nm peak typical of LHCII aggregates as well as quenching of the PSI fluorescence at 730 nm. The aggregated state manifested itself as a clear change in the distance between LHCII complexes detected by freeze-fracture electron microscopy. Grana thylakoids in the quenched state revealed 3 times more aggregated LHCII particles compared to the dark-adapted state. Overall, the results directly demonstrate the importance of LHCII aggregation in the NPQ mechanism and show that the PSII supercomplex structure plays no role in formation of the observed quenching. PMID- 26233262 TI - Disruption of cholinergic neurotransmission exacerbates Abeta-related cognitive impairment in preclinical Alzheimer's disease. AB - Disruption in cholinergic neurotransmission is one of the earliest neuropathological changes in preclinical Alzheimer's disease (AD) and may be associated with abnormal beta-amyloid (Abeta) accumulation. Therefore, disruption of cholinergic neurotransmission with scopolamine may unmask otherwise undetectable cognitive deficits in preclinical AD. To compare the effects of low dose (0.20 mg s.c.) scopolamine on cognition between Abeta+ and Abeta- cognitively normal (CN) older adults using the Groton Maze Learning Test (GMLT). CN older adults completed the GMLT predose and then received scopolamine (0.20 mg) subcutaneously. Participants were reassessed 1-, 3-, 5-, 7-, and 8-hours post dose. All participants underwent positron emission tomography neuroimaging for Abeta using (18)F-florbetapir within 6 weeks of their baseline visit. Rhode Island Hospital Clinical Research Center, Providence, USA. CN older adults (n = 63), with a family history of AD and subjective memory complaints were enrolled (15 were classified as Abeta+ and 48 were classified as Abeta-). Cognition was assessed using the computerized GMLT at all predose and post-dose time points. At 5-hours post dose, the Abeta+ group performed significantly worse than the Abeta- group on all measures of learning efficiency and working memory and/or executive function (Cohen's d = 1.13-1.56). When participants were classified as having an abnormal response to scopolamine (based on change score at 5-hours post dose >0), 100% were correctly classified as Abeta+ and 67% as Abeta-. The results of this study suggest that diminished cholinergic tone likely occurs in preclinical AD, and as such, the use of a cholinergic stress test to perturb an already compromised neurotransmitter system may be an effective way of identifying CN older adults who are in this preclinical stage of AD. PMID- 26233263 TI - RUNX3 gene polymorphisms are associated with clinical features of systemic lupus erythematosus in Chinese Han population. PMID- 26233264 TI - Systematic Review of Cognitive Dysfunction in Pediatric and Juvenile Multiple Sclerosis. AB - BACKGROUND: Cognitive dysfunction is a common finding in individuals with multiple sclerosis at all ages. Cognitive impairment may drastically affect the life of younger patients with multiple sclerosis who are still undergoing education and schooling. METHODS: We carried out a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations to assess the published data on multiple sclerosis and cognition in pediatric or juvenile patients. Only articles presenting original data on patients with multiple sclerosis diagnosed before age 18 years of age were included. RESULTS: Thirty-two articles fulfilled the inclusion criteria for this systematic review. The conclusion from all articles was that cognitive dysfunction in multiple sclerosis starting before the age of 18 years is both significant and disruptive and must be routinely assessed. However, assessment methods were heterogeneous and often very expensive to perform, whereas proposals for treatment were virtually absent in the literature. CONCLUSION: Cognitive dysfunction can be a significant symptom of multiple sclerosis of early onset, but its impact and management needs to be better assessed. A task force should be created to study and manage cognitive dysfunction in pediatric and juvenile multiple sclerosis. PMID- 26233265 TI - Clinical image in gastroenterology. Anatomic variation of the left hepatic artery. PMID- 26233266 TI - Resolution of complex choledocholithiasis with removable metal stent. A case report. PMID- 26233267 TI - Lights and shadows in the diagnosis and surveillance of a young asymptomatic patient with Peutz-Jeghers syndrome. PMID- 26233268 TI - Differentiation of lipid-poor adrenal adenomas from non-adenomas with magnetic resonance imaging: Utility of dynamic, contrast enhancement and single-shot T2 weighted sequences. AB - PURPOSE: To evaluate the utility of dynamic, contrast-enhanced magnetic resonance imaging (MRI) in combination with single-shot T2-weighted (ssT2) sequences in the differentiation of lipid-poor adrenal adenomas from non-adenomas. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and is HIPAA compliant. Between January 2007 and December 2010, 46 patients with MRI demonstrating a lipid-poor adrenal lesion who underwent either surgical resection or a minimum of 24 months of imaging follow-up were identified retrospectively. All images were retrospectively reviewed in blinded fashion by two radiologists. Each adrenal lesion was categorized by dynamic enhancement features and qualitative signal on ssT2 images and was categorized as an adenoma if it demonstrated homogenous enhancement in the arterial phase, washout with capsule enhancement in the delayed phase, and T2 signal isointense to normal adrenal tissue. Any lesion that did not fulfill all the criteria was classified as a non-adenoma. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for characterization of adenoma were calculated for each reader with 95% confidence intervals. A kappa test assessed level of agreement between readers. RESULTS: Application of our criteria lead to an MRI diagnosis of lipid-poor adrenal adenoma with a sensitivity of 84.2-89.5% (16/19 17/19), specificity of 96.3% (26/27), positive predictive value of 94.1-94.4% (16/17-17/18), negative predictive value of 89.7-92.9% (26/29-26/28), and accuracy of 91.3-93.5% (42/46-43/46). Agreement between the two readers showed substantial kappa agreement for the differentiation of adenoma from non-adenoma. CONCLUSIONS: Dynamic, contrast-enhanced T1-weighted three-dimensional gradient echo sequences in combination with ssT2 images can accurately differentiate lipid poor adrenal adenomas from non-adenomas. PMID- 26233269 TI - Eccrine Carcinoma: The Role of Mohs Micrographic Surgery and a Review of the Literature. PMID- 26233270 TI - Concomitant Hip Arthroscopy and Periacetabular Osteotomy. AB - PURPOSE: To detail our early experience using concomitant hip arthroscopy and periacetabular osteotomy (PAO) for the treatment of acetabular dysplasia. METHODS: We prospectively collected and retrospectively reviewed the surgical and outcome data of 17 patients who underwent concomitant hip arthroscopy and PAO between October 2010 and July 2013. Preoperative and postoperative range of motion, outcome and pain scores, and radiographic data were collected. Intraoperative arthroscopic findings and postoperative complications were recorded. RESULTS: The group consisted of 3 male and 14 female patients with a mean follow-up period of 2.4 years. Three patients had undergone previous surgery on the affected hip. Chondrolabral pathology was identified in all 17 patients. Twelve patients underwent labral repair, and five patients underwent partial labral debridement. No patient was converted to total hip arthroplasty or required revision surgery at short-term follow-up. All 4 patient-reported outcome scores showed statistically significant changes from baseline to latest follow-up (P < .001). An excellent outcome was obtained in 82% of patients (13 of 16). The lateral center-edge angle averaged 11 degrees preoperatively and 29 degrees postoperatively. The acetabular inclination averaged 18 degrees preoperatively and 3 degrees postoperatively. The anterior center-edge angle averaged 7 degrees preoperatively and 27 degrees postoperatively. At most recent radiographic follow-up, 1 patient had progression of arthritic changes but remained asymptomatic. No other patient showed any radiographic evidence of progression of arthritis. Complications included 3 superficial wound infections, 1 pulmonary embolism, and 1 temporary sciatic neurapraxia. CONCLUSIONS: Our initial experience with concomitant hip arthroscopy and PAO has been favorable. We noted that all our patients have evidence of chondrolabral damage at the time of PAO when the joint is distracted and evaluated. All patients in this series had intra articular pathology treated arthroscopically and showed satisfactory mean clinical improvement. Hip arthroscopy with PAO did not appear to introduce complications beyond the PAO alone. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26233271 TI - Regulation causes nitrogen cycling discontinuities in Mediterranean rivers. AB - River regulation has fundamentally altered large sections of the world's river networks. The effects of dams on the structural properties of downstream reaches are well documented, but less is known about their effect on river ecosystem processes. We investigated the effect of dams on river nutrient cycling by comparing net uptake of total dissolved nitrogen (TDN), phosphorus (TDP) and organic carbon (DOC) in river reaches located upstream and downstream from three reservoir systems in the Ebro River basin (NE Iberian Peninsula). Increased hydromorphological stability, organic matter standing stocks and ecosystem metabolism below dams enhanced the whole-reach net uptake of TDN, but not that of TDP or DOC. Upstream from dams, river reaches tended to be at biogeochemical equilibrium (uptake~release) for all nutrients, whereas river reaches below dams acted as net sinks of TDN. Overall, our results suggest that flow regulation by dams may cause relevant N cycling discontinuities in rivers. Higher net N uptake capacity below dams could lead to reduced N export to downstream ecosystems. Incorporating these discontinuities could significantly improve predictive models of N cycling and transport in complex river networks. PMID- 26233272 TI - Macroscopic findings during endoscopic sinus surgery for chronic rhinosinusitis in children. AB - AIM: Endeavor to intraoperative macroscopic evaluation of changes in children with CRSs. Analysis of the type and incidence of pathological changes observed macroscopically during FESS was undertaken as well as an parallel attempt to correlate the level of inflammation markers with severity of disease. MATERIALS AND METHODS: Retrospective analysis of case records of 153 patients of the Department of Pediatric Otolaryngology, Medical University of Warsaw, hospitalized between 2010 and 2013. During that time 106 patients with a diagnosis of chronic maxillary sinusitis required surgical intervention. 102 children (avg-aged 11.5 years) were qualified to functional endoscopic surgery. The youngest patient was 3 years old and the oldest 18. 26 patients presented the polypoid lesions of sinuses or nasals. At 19 confirmed the coexistence of sinus polyps with nasal polyps. RESULTS: 76 patients had oedematous-inflammatory lesions and 26 polypoid. Among the group of listed above 26 children, 19 had either sinuses or nasal polyps. 15% children with polyps were diagnosed with cystic fibrosis and 8.0% with asthma. A common deviation in the results of morphology in children with CRSs is higher level of monocytes. Inflammation markers within the population of FESS qualified children were low. CONCLUSIONS: (1) Oedematous-inflammatory lesions are frequently intraoperatively identified. (2) The CRSs without polyps is the common type of chronic sinusitis in children. (3) Nasal polyps often coexist with sinus polyps. (4) If nasal polyps are found in pediatric population then diagnosis of CF, allergy and GERD should be considered. (5) Markers of inflammation in CRSs are low. PMID- 26233273 TI - Moderate Versus Deep Hypothermia With Unilateral Selective Antegrade Cerebral Perfusion for Acute Type A Dissection. AB - BACKGROUND: Despite improved results with surgical therapy for acute type A aortic dissection (ATAAD), there remains a lack of consensus regarding the optimal method of cerebral protection and circulation management during ATAAD. The purpose of this study is to determine whether in the setting of antegrade cerebral perfusion, moderate hypothermic circulatory arrest (MHCA) provides equivalent cerebral and visceral protection as deep hypothermic circulatory arrest (DHCA) for patients undergoing emergent ATAAD repair. METHODS: A review of the Emory aortic surgery database from 2004 to 2014 identified 288 patients who underwent ATAAD with right axillary artery cannulation, unilateral selective antegrade cerebral perfusion (uSACP), and hypothermic circulatory arrest (HCA). In all, 88 patients underwent HCA at 24 degrees C or lower (DHCA), and 206 patients underwent HCA at more than 24 degrees C (MHCA). Major adverse outcomes of death, stroke, temporary neurologic dysfunction, and dialysis-dependent renal failure were examined. RESULTS: The groups were well matched for age and major comorbidities. The DHCA patients underwent HCA at lower temperatures (DHCA 21.6 +/- 3.1 degrees C vs MHCA 27.4 +/- 1.6 degrees C, p < 0.01). There were no significant differences in cardiopulmonary bypass, cross-clamp, or HCA times. Mortality was 14.6% for DHCA patients, and 9.2% for MHCA patients (p = 0.17). There was no significant difference in stroke, temporary neurologic dysfunction, or dialysis-dependent renal failure. There was no association with either MHCA plus uSACP or DHCA plus uSACP and any of the major adverse outcomes (p > 0.05). CONCLUSIONS: Moderate HCA with uSACP is an effective circulation management strategy that provides excellent cerebral and visceral protection during emergent ATAAD repair. In the setting of antegrade cerebral perfusion, deep hypothermia does not provide any additional benefit. PMID- 26233274 TI - Endoscopic Ultrasound Estimates for Tumor Depth at the Gastroesophageal Junction Are Inaccurate: Implications for the Liberal Use of Endoscopic Resection. AB - BACKGROUND: Endoscopic resection is increasingly utilized for treating early stage esophageal cancer, and endoscopic ultrasound (EUS) frequently guides treatment selection. Studies report greater than 80% sensitivity and 90% specificity, but our experience suggests less accuracy at the gastroesophageal (GE) junction. The objective of this study is to determine the accuracy of EUS for depth of GE junction cancer and the potential treatment implications. METHODS: A retrospective review of a prospective database was performed for patients from 1995 to 2014 with GE junction esophageal cancer that underwent EUS staging and resection (surgical or endoscopic) without neo-adjuvant therapy. Patient, tumor, EUS, and pathologic characteristics were examined. RESULTS: For the 181 patients that met criteria, the median age was 66 years, 17% were female, 91% white, and 98% had adenocarcinoma. Concordance between EUS (u) T and pathologic (p) T was 48%, with 23% under-staged and 29% over-staged. The EUS was accurate in the following: uT0 6% (1 of 18); uT1a 56% (23 of 41); uT1b 58% (41 of 71); uT2 10% (2 of 21); and uT3 70% (21 of 30). Inaccurate EUS depth had potential to lead to over-treatment in 38% (27 of 71) of uT1b and 76% (16 of 21) of uT2. In 50% of pT1a tumors, EUS depth was T1b or greater. Logistic regression revealed tumor length (continuous variable) to be associated with inaccurate uT (p = 0.016). Accurately staged tumors were significantly longer than inaccurately staged tumors (2.7 vs 1.7 cm, p = 0.011). CONCLUSIONS: Early to intermediate GE junction tumors are frequently over-staged. This highlights the importance of diagnostic endoscopic resection for determining accurate tumor depth and selecting correct therapy. PMID- 26233275 TI - Influence of Morphology and Initial Surgical Strategy on Survival of Infants With Tricuspid Atresia. AB - BACKGROUND: Tricuspid atresia (TA) is a heterogeneous single-ventricle anomaly in which initial presentation and, consequently, timing and mode of palliation vary based on morphology and degree of pulmonary or systemic outflow obstruction. We report current era palliation outcomes and examine whether morphologic and, subsequently, surgical factors influence survival. METHODS: From 2002 to 2012, 105 infants with TA underwent surgical palliation. Competing risks analyses modeled events after first-stage surgery (Glenn versus death) and after Glenn (Fontan versus death) and examined risk factors affecting outcomes. RESULTS: Seventy-eight patients (74%) required neonatal first-stage palliation, including modified Blalock-Taussig shunt (n = 46, 44%), Norwood (n = 18, 17%), and pulmonary artery band (n = 14, 13%), whereas 27 (26%) received primary Glenn as their initial surgery. Hospital mortality was 5 patients (4.8%). Competing risks models showed that by 1 year after first-stage surgery, 15% of patients had died and 83% had undergone Glenn. By 5 years after Glenn, 2% of patients had died and 80% had undergone Fontan. Overall 8-year survival was 84%. On multivariable analysis, risk factors for mortality were genetic/extracardiac anomalies (hazard ratio 7.0, 95% confidence interval: 2.4 to 20.6, p < 0.001) and pulmonary atresia (hazard ratio 4.4, 95% confidence interval: 1.6 to 12.2, p = 0.004). Survival was not affected by initial palliation type (p = 0.36), ventriculoarterial discordance (p = 0.25), systemic outflow obstruction (p = 0.84), or arch obstruction (p = 0.62). CONCLUSIONS: Despite morphologic and physiologic variations necessitating different palliative sequences, multistage palliation outcomes of various TA subtypes are comparable and generally good, with the exception of patients with associated genetic/extracardiac anomalies. The bulk of mortality is interstage, indicating continued opportunity for improvement in monitoring and managing patients during this critical period. PMID- 26233277 TI - Clinical Experience With Sternotomy Versus Subcostal Approach for Exchange of HeartMate II Left Ventricular Assist Device. AB - BACKGROUND: The safety and efficacy of exchanging the HeartMate II (Thoratec Corp, Pleasanton, CA) left ventricular assist device (LVAD) through a less invasive subcostal approach remains unclear. METHODS: We reviewed the records of 17 patients who underwent exchange of their HeartMate II device at our institution since 2007. We divided the cohort into devices exchanged through a subcostal (SC) approach versus a median sternotomy (MS) approach and obtained data pertaining to the short- and long-term outcomes. RESULTS: Nine patients had pump exchange through an MS approach versus 8 patients who underwent an SC approach. The mean duration of support with the first pump was 540 +/- 450 days. The reason for exchange was electromechanical failure (7 patients), thrombosis (8 patients), and infection (2 patients). There were no 30-day perioperative deaths with either approach. Compared with sternotomy, patients who underwent an SC approach had significantly shorter operative times (131 vs 222 minutes; p = 0.001) and lower reoperation rates for bleeding (0 vs 44.4%; P = 0.05) and required fewer transfused blood products (packed red cells, 3.5 units vs 7.1 units; p < 0.05; cryoprecipitate, 50.7 mL vs 209.3 mL; p = 0.01; and platelets, 292 mL versus 762 mL; p < 0.05). Additionally, patients who underwent an SC approach had shorter postoperative stays in the intensive care unit (ICU) (5 days vs 13.8 days; p < 0.05) and shorter total hospital stays (16.4 days vs 27.2 days; p < 0.05). Long-term survival after mean follow-up of 260 days for the SC group and 232 days for the sternotomy group was 75% and 33%, respectively. CONCLUSIONS: Exchange of the HeartMate II pump can be accomplished with low morbidity and mortality and good long-term outcomes through a less invasive SC approach. PMID- 26233276 TI - Transapical and Transaortic Transcatheter Aortic Valve Replacement in the United States. AB - BACKGROUND: When transcatheter aortic valve replacement (TAVR) cannot be carried out through transfemoral access, alternative access TAVR is indicated. The purpose of this study was to explore inhospital and 1-year outcomes of patients undergoing alternative access TAVR through the transapical (TA) or transaortic (TAo) techniques in the United States. METHODS: Clinical records of 4,953 patients undergoing TA (n = 4,085) or TAo (n = 868) TAVR from 2011 to 2014 in The Society of Thoracic Surgeons (STS)/American College of Cardiology Transcatheter Valve Therapy Registry were linked to Centers for Medicare and Medicaid Services hospital claims. Inhospital and 1-year clinical outcomes were stratified by operative risk; and the risk-adjusted association between access route and mortality, stroke, and heart failure repeat hospitalization was explored. RESULTS: Mean age for all patients was 82.8 +/- 6.8 years. The median STS predicted risk of mortality was significantly higher among patients undergoing TAo (8.8 versus 7.4, p < 0.001). When compared with TA, TAo was associated with an increased risk of unadjusted 30-day mortality (10.3% versus 8.8%) and 1-year mortality (30.3% versus 25.6%, p = 0.006). There were no significant differences between TAo and TA for inhospital stroke rate (2.2%), major vascular complications (0.3%), and 1-year heart failure rehospitalizations (15.7%). Examination of high-risk and inoperable subgroups showed that 1-year mortality was significantly higher for TAo patients classified as inoperable (p = 0.012). CONCLUSIONS: Patients undergoing TAo TAVR are older, more likely female, and have significantly higher STS predicted risk of mortality scores than patients operated on by TA access. There were no risk-adjusted differences between TA and TAo access in mortality, stroke, or readmission rates as long as 1 year after TAVR. PMID- 26233278 TI - Human Lung Fibroblasts Inhibit Non-Small Cell Lung Cancer Metastasis in Ex Vivo 4D Model. AB - BACKGROUND: We determined the effect of human lung fibroblasts (LFs) in metastatic lesion formation in a four-dimensional (4D) lung cancer model. METHODS: Human cancer-associated fibroblasts (CAFs) were isolated from the primary tumor, and normal LFs were isolated from adjacent lung using fluorescence activated cell sorting. The 4D metastatic lung cancer model was seeded with the human lung cancer cell lines (H460, A549, and H1299) alone or was seeded with CAFs or LFs. In addition, the 4D model seeded with human lung cancer cell lines was also treated with conditioned media of LFs or CAFs grown on the 4D model. We determined the number of metastatic tumor cells per high-power field on the model. RESULTS: There were significantly fewer metastatic lesions per high-power field in the 4D model seeded with the H460 cell line and LFs compared with H460 alone on day 15 (p = 0.008) or compared with H460 and CAFs (p = 0.002). This relationship was also seen with A549 and H1299 tumor cells. Moreover, the H460 cell line treated with conditioned media from the 4D model seeded with LFs had significantly fewer metastatic lesions than the 4D model seeded with CAFs. This was also seen with two other pairs of human fibroblasts obtained from patients. CONCLUSIONS: The secreted factor from LFs grown on the 4D model inhibits the formation of metastatic lesions. The 4D model may be used to determine the role of different components of the tumor's microenvironment in metastatic lesion formation, and this secreted factor may provide a novel therapy for treatment of cancer metastasis. PMID- 26233279 TI - Evaluation of The Society of Thoracic Surgeons Online Risk Calculator for Assessment of Risk in Patients Presenting for Aortic Valve Replacement After Prior Coronary Artery Bypass Graft: An Analysis Using the STS Adult Cardiac Surgery Database. AB - BACKGROUND: Accurate risk assessment in patients presenting for aortic valve replacement (AVR) after prior coronary artery bypass grafting (CABG) is essential for appropriate selection of surgical versus percutaneous therapy. METHODS: We included 6,534 patients in The Society for Thoracic Surgeons (STS) Adult Cardiac Surgery Database (October 2009 through December 2013) who underwent elective, isolated reoperative AVR for aortic stenosis after prior CABG. Case-specific PROM was calculated and observed-to-expected ratios were inspected across the spectrum of risk. A cohort-specific recalibration equation was derived using logistic regression: = expit(-0.6453+0.6147*logit(PROM) -0.0709*logit(PROM)(^)2), where PROM is the predicted risk of mortality. The proportion of patients reclassified as low (PROM < 4%), intermediate (4% to < 8%), high (8% to < 12%), and very high risk (>= 12%) was calculated using the recalibration equation. The performance of the cohort-specific recalibration equation was then compared with the generic recalibration for quarterly STS reports. RESULTS: The STS online risk calculator overestimates risk for low, intermediate, and high risk categories. Using the recalibrated risk equation, a substantial proportion of patients were reclassified as the following: 25.5% from intermediate to low risk; 39.7% from high to intermediate risk; and 41.5% from very high to high risk. Comparison of the cohort-specific recalibration equation to the generic quarterly STS recalibration demonstrated very similar results. CONCLUSIONS: In patients presenting for AVR after prior CABG, the STS online risk calculator overestimates risk for all but the highest risk patients. Using a cohort-specific recalibration equation, a substantial proportion of patients would be downgraded to lower risk categories. The cohort-specific recalibration correlates well with the existing generic quarterly STS recalibration. The findings of this study support recommendations for periodic recalibration of the online risk calculator in order to facilitate clinical decision making in real time. PMID- 26233280 TI - Treatment of venous lesions of the lips and perioral area with a long-pulsed Nd:YAG laser. AB - The conventional treatments for venous lesions of the lip have been excision, cryotherapy, infrared coagulation, and sclerotherapy. We report the use of a long pulsed Nd:YAG laser in 31 consecutive patients. At a mean follow up of 12 months (6 weeks to 3 years), 27 (87%) had no evidence of recurrence and one had a small contracted scar. The treatment is effective for both small and large lesions, and operation or other ablative techniques are no longer indicated, or considerably less relevant. PMID- 26233282 TI - One year of anaesthesia in France: A comprehensive survey based on the national medical information (PMSI) database. Part 2: Out-hospital patients. AB - INTRODUCTION: Epidemiological data on French ambulatory anaesthesias are restricted. The aim of this study was to perform an epidemiological analysis of this activity for the year 2010. METHODS: Using the national database program for medical information systems (the PMSI), we have listed all institutions in France and her overseas territories performing ambulatory anaesthesia. We have assessed the number and nature of anaesthetic procedures, in terms of type of institution, age and surgeries. These results were correlated with French general demographics. RESULTS: Ambulatory anaesthetic procedures represented 44.4% of all anaesthesias, excluding childbirth, (n=4644,791 ambulatory acts), among which 88% were performed on adults and 12% on minors. The "65-74 years" age group had the highest annual relative rate of ambulatory anaesthesia. Rate of ambulatory anaesthesia was higher in children compared to adults (60% versus 42.8%, respectively). Outpatient surgery was mainly developed in Private Clinics as compared to public institutions. CONCLUSION: Ambulatory anaesthesia has dramatically increased over fourteen years. It represents almost half of all anaesthetic acts, and its development is promising, especially in University Hospitals and adult populations. PMID- 26233281 TI - Increased cardiovascular disease risk in the HIV-positive population on ART: potential role of HIV-Nef and Tat. AB - With effective antiretroviral therapy (ART), many HIV-infected people die of diseases other than acquired immune deficiency syndrome (AIDS). In particular, coronary artery disease has emerged as one of most critical complications of HIV infection and a major cause of morbidity and mortality. Although reportedly antiretroviral combination therapy itself may accelerate atherosclerosis by enhancing dyslipidemia, most recent epidemiological studies support the notion that HIV infection itself contributes to cardiovascular disease. However, it is still a mystery how the virus can contribute to cardiovascular disease development even while suppressed by ARTs. This review discusses the current understanding of interactions between HIV infection and cardiovascular diseases in both clinical and experimental studies with special focus on those viral proteins that are still produced by HIV. This will help infectious disease/vascular biology experts to gain insights into the pathophysiological mechanisms of HIV-associated cardiovascular disease and new trends to treat and prevent cardiovascular disease in the HIV-infected population. PMID- 26233283 TI - Adult neurogenesis and brain remodelling after brain injury: From bench to bedside? AB - OBJECTIVE: Brain trauma and stroke cause important disabilities. The mechanisms involved are now well described, but all therapeutics developed thus far for neuro-protection are currently unsuccessful at improving neurologic prognosis. The recently studied neuro-restorative time following brain injury may point towards a promising therapeutic approach. The purpose of this paper is to explain the mechanisms of this revolutionary concept, give an overview of related knowledge and discuss its transfer into clinical practice. DATA SOURCES AND SYNTHESIS: An overview of the neurogenesis concept using MEDLINE, EMBASE and CENTRAL databases was carried out in May 2014. The clinicaltrials.gov registry was used to search for ongoing clinical trials in this domain. CONCLUSION: The concept of brain remodelling upset fundamental ideas concerning the neurologic system and opened new fields of research. Therapies currently under evaluation hold promising results and could have a real prognostic impact in future years, but the translation of these therapies from the laboratory to the clinic is still far from completion. PMID- 26233284 TI - The Role of Peripheral Nociceptive Neurons in the Pathophysiology of Osteoarthritis Pain. AB - Knee osteoarthritis is characterized by progressive damage and remodeling of all tissues in the knee joint. Pain is the main symptom associated with knee osteoarthritis. Recent clinical and pre-clinical studies have provided novel insights into the mechanisms that drive the pain associated with joint destruction. In this narrative review, we describe current knowledge regarding the changes in the peripheral and central nervous systems that occur during the progression of osteoarthritis and discuss how therapeutic interventions may provide pain relief. PMID- 26233285 TI - Risk Assessment Tools for Osteoporosis Screening in Postmenopausal Women: A Systematic Review. AB - Osteoporotic fractures are common in postmenopausal women. Tools are available to estimate the risk of low bone mineral density (BMD) or fracture. This systematic review retrieved articles that evaluated osteoporosis risk assessment tools among postmenopausal women in North America. For identifying BMD T-score <=-2.5, most studies of the Simple Calculated Osteoporosis Risk Estimation tool (SCORE) and Osteoporosis Risk Assessment Instrument (ORAI) reported sensitivity >=90 %. Area under the receiver operating characteristic curve (AUC) was usually <0.75 for SCORE and >=0.75 for ORAI. Among women 50-64 years old, a Fracture Risk Assessment Tool (FRAX) threshold >=9.3 % had a sensitivity of 33 % for identifying BMD T-score <=-2.5 and 26 % for predicting major osteoporotic fracture (MOF). For predicting MOF, sensitivity was higher for SCORE and Osteoporosis Self-assessment Tool equation (OST), and higher in women >=65 years old. For predicting BMD T-score <=-2.5 in women >=65 years old, the sensitivities of SCORE; ORAI; and Age, Body Size, No Estrogen (ABONE) were very high. No optimal osteoporosis risk assessment tool is available for identifying low BMD and MOF risk. PMID- 26233286 TI - Plain or decorated? Object visual features matter in infant spatial categorization. AB - The current study investigated infant spatial categorization of a support relation across differences in the perceptual features of the objects. Infants of 8 and 14 months (N = 67) were habituated to dynamic support events with objects that were plain and monochromatic or those that were embellished with decorations (e.g., polka dots, feathers). Infants were then tested with events that presented a novel pair of objects, a novel spatial relation (i.e., containment), or both. Infants, particularly those of 8 months, formed an abstract categorical representation of a support relation when habituated with the decorated objects but not the plain objects. The results suggest that the perceptual features of objects can facilitate infants' categorization of spatial relations, at least in some learning settings and especially with younger infants. PMID- 26233287 TI - The Effect of Centering Pregnancy versus Traditional Prenatal Care Models on Improved Adolescent Health Behaviors in the Perinatal Period. AB - STUDY OBJECTIVE: To determine if the CenteringPregnancy model of prenatal care improves maternal health behaviors in adolescent pregnancy. DESIGN: We conducted a retrospective chart review comparing 150 pregnant adolescents who received prenatal care between 2008 to 2012 with CenteringPregnancy to those receiving care in traditional prenatal care models with either multiprovider or single provider visits. Outcome measures included weight gain during pregnancy, compliance to prenatal care appointments, infant feeding method, postpartum follow up and contraceptive use postpartum. A chi(2) analysis was used to compare outcomes between the 3 groups at a 2-tailed alpha of .05. RESULTS: Fifty individuals were evaluated in each group. Adolescents in the CenteringPregnancy group were more likely to comply with prenatal and postpartum visits and to meet the 2009 Institute of Medicine gestational weight guidelines for weight gain in pregnancy than were adolescents in either multiprovider (62.0% vs 38.0%, P = .02) or single-provider (62.0% vs 38.0%, P = .02) groups. The CenteringPregnancy group was also more likely to solely breastfeed compared with adolescents in the multiprovider group (40.0% vs 20.0%, P = .03) and include breastfeeding in addition to bottle-feeding compared with both multiprovider (32.0% vs 14.0%, P = .03) and single-provider (32.0% vs 12.0%, P = .03) patient groups. Additionally, the CenteringPregnancy group had increased uptake of long-acting reversible contraception and were less likely to suffer from postpartum depression. CONCLUSIONS: CenteringPregnancy Prenatal Care program aids in compliance to prenatal visits, appropriate weight gain, increased uptake of highly effective contraception, and breastfeeding among adolescent mothers. PMID- 26233288 TI - Regression of Adenomyosis on Magnetic Resonance Imaging after a Course of Hormonal Suppression in Adolescents: A Case Series. AB - STUDY OBJECTIVE: To demonstrate that adenomyosis is a rare cause of dysmenorrhea or chronic pelvic pain (CPP) in the adolescent population that can be identified with magnetic resonance imaging (MRI) and to report resolution of adenomyosis by MRI after a course of hormonal suppression in 4 adolescents. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series of 4 adolescents with adenomyosis on pelvic MRI at Texas Children's Hospital. INTERVENTIONS: Continuous oral contraceptive (COC) therapy or leuprolide acetate. MAIN OUTCOME MEASURES: Lesions on pelvic MRI after treatment. METHODS: We reviewed medical records of 4 adolescents with CPP and adenomyosis on T2-weighted pelvic MRI. All patients had initial diagnostic pelvic MRI and then definitive hormonal intervention. Repeat imaging was obtained after a symptom-free interval. RESULTS: Patient ages ranged from 12 to 16 years. One patient had resolution of symptoms with COC therapy. MRI performed 3 years later showed no adenomyosis. Three patients failed COC therapy. All were symptomatically improved after therapy with a gonadotropin-releasing hormone agonist. Follow-up MRI performed at intervals between 6 months and 3 years showed resolution of adenomyosis. CONCLUSION: MRI can raise suspicion for the diagnosis of adenomyosis in adolescents with refractory CPP. Subsequent MRI can show regression of lesions after symptom resolution with hormonal therapy. PMID- 26233289 TI - Effectiveness of the Association N-Palmitoylethanolamine and Transpolydatin in the Treatment of Primary Dysmenorrhea. AB - STUDY OBJECTIVE: To evaluate the effectiveness and safety of the combination of N palmitoylethanolamine (PEA) and transpolydatin vs placebo in the treatment of primary dysmenorrhea in adolescents and young women. DESIGN, SETTING, AND PARTICIPANTS: Randomized treatment and follow-up of 220 cases of primary dysmenorrhea in the Department of Medicine and Health Sciences, Institute of Gynecology and Obstetrics, University of Molise, Italy. METHODS: Between February 2013 and February 2014, we treated 220 young women aged 16 to 24 years who had primary dysmenorrhea: 110 patients were treated with the oral combination of PEA transpolydatin: 400 mg + 40 mg (1 tablet a day for 10 days from the 24th day of cycle) and 110 patients with placebo (1 tablet a day for 10 days from the 24th day of cycle). A follow-up was performed after treatment, and all girls were seen at this time. A 10-point visual analog scale was used to measure the improvement of pelvic pain. For categorical variables, the chi(2) test and analysis of variance were performed to value the significance of differences between groups. A value of P < .05 was considered statistically significant. RESULTS: An improvement of pelvic pain was seen in 98.18% (95% confidence interval 97.64% to 98.60%) of cases in group 1 vs 56.36% (95% confidence interval 48.62% to 63.81%) in group 2 (P < .001). The combination of PEA and transpolydatin was more effective than placebo (P < .001). CONCLUSION: The combination of PEA and transpolydatin shows promise as a valid adjuvant therapy in the medical treatment of primary dysmenorrhea in adolescents and young women. PMID- 26233290 TI - Frequency and Determinants of Urinary Incontinence in Adolescent and Young Nulliparous Women. AB - STUDY OBJECTIVE: To investigate the rate of urinary incontinence (UI) in a sample of young nulligravid women and its potential risk factors and consequences on life habits. DESIGN AND PARTICIPANTS: The study is based on an online self administered questionnaire taken by nulligravid women aged 15 to 25 years. MEASUREMENTS: The Questionnaire for Urinary Incontinence Diagnosis and part of The King's Health Questionnaire. Demographics and general characteristics are also recorded. RESULTS: We collected 1936 questionnaires (mean age of participants, 21 years); 12.4% of the sample reported any UI (95% confidence interval [CI] 10.9% to 13.9%). The estimated incidence of UI subtypes was 7.2% (95% CI 6.0% to 8.4%) stress UI, 3.4% (95% CI 2.6% to 4.3%) urge UI, and 1.9% (95% CI 1.3% to 2.6%) mixed UI. Age younger than 19 years and body mass index of 30 kg/m(2) or greater were associated in the multivariate analysis with an increased risk of UI. A self-reported history of psychological disorders increased the risk of UI (adjusted odds ratio [AOR] 1.4 and 95% CI 1.1% to 1.9%), without significant differences among the UI subtypes. A current history of constipation (AOR 1.9 and 95% CI 1.3% to 2.6%) and enuresis after the age of 5 also increased the risk of UI (AOR 2.9 and 95% CI 2.0% to 4.3%). CONCLUSION: In a sample of young nulligravid women, UI was not associated with any chronic risk factor known for elder age, but a prevention program may be proposed to women because of their young age (eg, educational session to promote the proper functioning of the pelvic floor). More detailed analyses are needed to better assess the prevalence of UI and risk factors in young nulligravid women. PMID- 26233292 TI - Menstrual Cycle and the Prevalence of Premenstrual Syndrome/Premenstrual Dysphoric Disorder in Adolescent Athletes. AB - STUDY OBJECTIVE: The purpose of this study was to assess the menstrual cycle, menstrual disorders and premenstrual syndrome/premenstrual dysphoric disorder (PMS/PMDD) in girls and young women participating in competitive sports. The impact of PMS/PMDD symptoms on the quality of life was also analyzed. DESIGN: The prospective study encompassed 125 girls and young women with the aim to determine the presence of menstrual disorders and the prevalence of PMS/PMDD. PARTICIPANTS: The studied group was composed of 75 female athletes aged 16 to 22 years. The control group included 50 healthy girls and young women who did not practice competitive sports. SETTING: The studied athletes and the controls prospectively evaluated their 2 consecutive menstrual cycles by using a questionnaire. INTERVENTIONS: The research tools were a purpose-built questionnaire, a daily log of PMS symptoms according to the American College of Obstetricians and Gynecologists' guidelines, and a daily log of PMDD symptoms based on the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnostic criteria. MAIN OUTCOME MEASURES: To determine the impact of competitive sports on the menstrual cycle, menstrual disorders, and the prevalence of PMS/PMDD in girls and young women. RESULTS: Intensive physical exercise delayed menarche. PMDD was diagnosed in 8% and PMS in 42.4% of all respondents. The prevalence of PMDD did not differ significantly between the groups (9.33% versus 6.00%). PMS was significantly more frequent among athletes than among controls (49.33% versus 32%, P = .045). The prevalence of PMS correlated significantly with mean age (P = .00001) and age at menarche (P = .03) in athletes. PMS was more frequent in older athletes and in girls with older age at menarche. CONCLUSION: Competitive sports, older mean age, older age at menarche, length of sporting career, and intensity of training are conducive to PMS. The prevalence of PMS increases with the duration and intensification of competitive exercises. PMID- 26233291 TI - Preconception Nutrition, Physical Activity, and Birth Outcomes in Adolescent Girls. AB - STUDY OBJECTIVE: Recommendations for preconception care usually include optimal nutrition and physical activity, but these have not been tested extensively for their relationship with birth outcomes such as low birth weight and preterm birth. DESIGN: Data from Waves I, II, and IV of the National Longitudinal Study of Adolescent Health (Add Health) contractual dataset were used. METHODS: In Wave I in-home interview, participants were asked to recall their frequency of having 5 types of food on the previous day, including milk, fruit, vegetables, grains, and sweets. At Wave II, participants reported the previous day's intake of 55 items, and results were categorized into high-calorie sweet, high-calorie nonsweet, and low-calorie food. At Wave I in-home interview, participants were also asked how many times in a week or during the past week they were involved in types of physical activity. At Wave IV, female participants reported pregnancies and birth outcomes. Multivariable linear regression analysis with survey weighting was used to predict birth weight and gestational age. RESULTS: There were no associations between reported food intake and birth outcomes. Girls who engaged in more episodes of active behavior had higher birth weights (P < .01), but hours of sedentary behavior was not associated with birth weight. Multivariable analysis also indicated a U-shaped association between BMI and birth weight (P for quadratic term = .01). CONCLUSION: Adolescents who are more physically active before pregnancy have more positive birth outcomes as represented by birth weight. PMID- 26233293 TI - Pregnant Adolescents Admitted to an Inpatient Child and Adolescent Psychiatric Unit: An Eight-Year Review. AB - STUDY OBJECTIVE: To assess patient outcomes and describe demographic data of pregnant adolescents admitted to an inpatient child and adolescent psychiatric unit, as well as to determine if it is safe to continue to admit pregnant adolescents to such a unit. DESIGN, SETTING, AND PARTICIPANTS: A descriptive retrospective chart review conducted at a free-standing pediatric hospital in northeast Ohio of all pregnant adolescents aged 13 to 17 years admitted to the inpatient child and adolescent psychiatric unit from July 2005 to April 2013. MAIN OUTCOME MEASURES: Data collection included details on demographic, pregnancy status, and psychiatric diagnoses. RESULTS: Eighteen pregnant adolescents were admitted to the psychiatric unit during the time frame. Sixteen of those were in the first trimester of pregnancy. Pregnancy was found to be a contributing factor to the adolescent's suicidal ideation and admission in 11 of the cases. Admission to an inpatient psychiatric facility did not lead to adverse effects in pregnancy. CONCLUSION: Pregnant adolescents did not have negative pregnancy outcomes related to admission to an inpatient psychiatric unit. Results of this study suggest that it is safe to continue to admit uncomplicated pregnant adolescents in their first trimester to an inpatient child and adolescent psychiatric unit for an acute stay. PMID- 26233294 TI - Is there any role of latent toxoplasmosis in schizophrenia disease? AB - BACKGROUND: A large number of studies have hypothesized that Toxoplasma gondii is a potentially relevant etiological factor in some cases of schizophrenia. By contrast, some studies have disproved this association. The aim of this study was to investigate whether latent toxoplasmosis has any role in schizophrenia disease. Additionally, the association between T. gondii and subtypes of schizophrenia, and the impacts of toxoplasmosis on psychopathology were examined in the study. METHODS: A total of 85 patients with schizophrenia and 60 healthy volunteers were included in this prospective study. Immunoglobulin G (IgG) antibody to T. gondii was examined by enzyme-linked immune-sorbent assay method. RESULTS: Seropositivity rates were 43.5% for the patients with schizophrenia and 43.3% for the healthy controls (odds ratio: 1.008, 95% confidence interval: 0.517 1.964, p = 0.981).There was no significant difference in T. gondii IgG positivity between the schizophrenia and control groups with respect to sex and age. The difference in seroprevalence of T. gondii IgG antibodies among the schizophrenia subtypes was not statistically significant (p = 0.934). No significant difference was found in Positive and Negative Syndrome Subscales between Toxoplasma-infected and Toxoplasma-free patients. CONCLUSION: In the study area with a high prevalence of T. gondii, no association between toxoplasmosis and schizophrenia was detected. These findings showed that toxoplasmosis has no role in the risk of schizophrenia disease. PMID- 26233295 TI - The precariousness of the franchise state: Voluntary sector health services and international NGOs in Tanzania, 1960s - mid-1980s. AB - This paper challenges conventional narratives on the role of international non governmental organisations (INGOs) in the delivery of health services in Tanzania. Adopting an historical gaze which focuses on the 1960s to mid-1980s the paper argues that the 'franchise state' in the Tanzanian health system was not created by collusion between international donors and INGOs, underpinned by a set of health sector reforms that advocated the use of non-state actors; but was rather the legacy of the colonial health system bequeathed to the post independence state. It was a system in which voluntary non-state actors (but, importantly, not INGOs) were already entrenched as key providers; and in which many of the features of the franchise state - fragmentation, structural weaknesses, lack of accountability to users - were already long established. But if INGOs did not create these features, as their critics attest, they did contribute to the maintenance and extension of these features. The short-term perspectives of NGOs, their small-scale piecemeal engagement, and the extra demands they placed upon their voluntary actor partners, left little scope for the development of sustainable, national and accountable solutions to the health needs of the country. In exploring these ideas, the paper contributes to a more nuanced understanding of the path dependency that created Tanzania's health system. The analysis also contributes to a deepening of the understanding of the make-up of the voluntary sector beyond a narrow gaze on the institution of the INGO. PMID- 26233296 TI - 'High profile health facilities can add to your trouble': Women, stigma and un/safe abortion in Kenya. AB - Public health discourses on safe abortion assume the term to be unambiguous. However, qualitative evidence elicited from Kenyan women treated for complications of unsafe abortion contrasted sharply with public health views of abortion safety. For these women, safe abortion implied pregnancy termination procedures and services that concealed their abortions, shielded them from the law, were cheap and identified through dependable social networks. Participants contested the notion that poor quality abortion procedures and providers are inherently dangerous, asserting them as key to women's preservation of a good self, management of stigma, and protection of their reputation, respect, social relationships, and livelihoods. Greater public health attention to the social dimensions of abortion safety is urgent. PMID- 26233297 TI - Prenatal diagnosis: From policy to practice. Two distinct ways of managing prognostic uncertainty and anticipating disability in Brazil and in France. AB - Prenatal diagnosis (PND) has gradually established itself as part of the pregnancy monitoring process, with a view to reducing the number of births of children exposed to disability by combining the use of biomedical tools with laws that authorise abortion in cases of foetal pathology. This article looks at how laws which vary from one country to another modulate the way in which PND practices are organised on a daily basis, determine the discourse of practitioners and lead them to adopt specific stances during prenatal consultations with couples coping with a foetal anomaly. We present a comparative ethnographic study, which took place between 2009 and 2011 in France and Brazil, in reference units, based on observation of consultations, professional meetings, and interviews with health practitioners. The fact that access to abortion due to foetal pathology is possible in France, and criminalised in Brazil, conditions how doctors analyse the framework of their medical practice and approach the issue of disability with couples during consultations. In France, practitioners would appear to be satisfied with a professional framework that they themselves created. Faced with prognostic uncertainty, the legal obligation to inform encourages them to discuss all of the potential complications of the diagnosed anomalies and leads them to provide probabilistic information about the life of the child to be, supported by evidence-based medicine. In Brazil, in the public service, the lack of access to abortion has created a malaise among practitioners who criticise this impediment to the objective nature of their practice and to the quality of the information that they provide. Some use prognostic uncertainty to direct the thoughts of women and couples towards the dynamics proper to each individual human trajectory within a given family and a specific social environment. PMID- 26233298 TI - Impact of growth temperature and surface type on the resistance of Pseudomonas aeruginosa and Staphylococcus aureus biofilms to disinfectants. AB - Biofilm formation of Pseudomonas aeruginosa and Staphylococcus aureus on food contact-surfaces represents a significant risk for the public health. In this context, the present study investigates the relationship between the environmental conditions of biofilm formation and the resistance to disinfectants. Therefore, a static biofilm reactor, called NEC-Biofilm System, was established in order to study the effect of growth temperature (20, 30 and 37 degrees C), and of the surface type (stainless steel and polycarbonate), on biofilm resistance to disinfectants. These conditions were selected to mimic the biofilm formation on abiotic surfaces of food processing industries. The antibiofilm assays were performed on biofilms grown during 24 h. The results showed that the growth temperature influenced significantly the biofilm resistance to disinfectants. These data also revealed that the growth temperature has a significant effect on the biofilm structure of both bacteria. Furthermore, the increase of the biofilm growth temperature increased significantly the algD transcript level in sessile P. aeruginosa cells, whereas the icaA one was not affected in S. aureus cells. Overall, our findings show that the biofilm structure and matrix cannot fully explain the biofilm resistance to disinfectant agents. Nevertheless, it underlines the intimate link between environmental conditions, commonly met in food sectors, and the biofilm resistance to disinfectants. PMID- 26233299 TI - Global longitudinal two-dimensional systolic strain is associated with hemodynamic alterations in arterial hypertension. AB - Arterial hypertension can lead to the progressive deterioration of the left ventricular (LV) performance. The aim of this study was to estimate the relation of global longitudinal systolic strain (GLSS) with central and systemic hemodynamics assessed by applanation tonometry and impedance cardiography in 125 hypertensive patients. Those with more impaired GLSS characterized with 1/worse diastolic function (mitral inflow early phase (E) to mitral septal annulus early diastolic velocity (e') ratio, 8.0 vs. 7.0, P = .014); 2/lower LV performance (cardiac index, 3.14 vs. 3.64 l/min/m(2); P = .007), and 3/higher afterload (systemic vascular resistance index, 2506 vs. 2107 dyn s m(2)/cm(5); P = .008). No relevant differences in, that is, gender, age, blood pressure, LV mass index, left chambers dimensions, and central blood pressure characteristics were identified. The results revealed that impaired GLSS is related to LV diastolic dysfunction and altered hemodynamics which may be markers of early systolic LV dysfunction related to arterial hypertension. PMID- 26233300 TI - A proactive system for maritime environment monitoring. AB - The ability to remotely detect and monitor oil spills is becoming increasingly important due to the high demand of oil-based products. Indeed, shipping routes are becoming very crowded and the likelihood of oil slick occurrence is increasing. In this frame, a fully integrated remote sensing system can be a valuable monitoring tool. We propose an integrated and interoperable system able to monitor ship traffic and marine operators, using sensing capabilities from a variety of electronic sensors, along with geo-positioning tools, and through a communication infrastructure. Our system is capable of transferring heterogeneous data, freely and seamlessly, between different elements of the information system (and their users) in a consistent and usable form. The system also integrates a collection of decision support services providing proactive functionalities. Such services demonstrate the potentiality of the system in facilitating dynamic links among different data, models and actors, as indicated by the performed field tests. PMID- 26233301 TI - Trace metals in the surface sediments of the eastern continental shelf of Hainan Island: Sources and contamination. AB - Major (Al) and trace metal (Cu, Pb, Zn, Cr, Ni, Cd, and As) concentrations in 29 surface sediment samples from the eastern continental shelf of Hainan Island were evaluated to determine the level of contamination. A multivariate analysis indicated that the sources of Cd, As, and Pb were primarily anthropogenic, whereas the sources of Cu, Zn, Cr, and Ni were primarily natural and/or partially anthropogenic. Enrichment factor (EF) and geoaccumulation index (Igeo) values were calculated to assess the anthropogenic contamination in the region. Both the EF and Igeo values indicated relatively elevated Cd and As concentrations. This study provides a useful aid for sustainable marine management in the region. PMID- 26233302 TI - Quantitative distribution and functional groups of intertidal macrofaunal assemblages in Fildes Peninsula, King George Island, South Shetland Islands, Southern Ocean. AB - To evaluate spatial distribution pattern of intertidal macrofauna, quantitative investigation was performed in January to February, 2013 around Fildes Peninsula, King George Island, South Shetland Islands. A total of 34 species were identified, which were dominated by Mollusca, Annelida and Arthropoda. CLUSTER analysis showed that macrofaunal assemblages at sand-bottom sites belonged to one group, which was dominated by Lumbricillus sp. and Kidderia subquadrata. Macrofaunal assemblages at gravel-bottom sites were divided into three groups while Nacella concinna was the dominant species at most sites. The highest values of biomass and Shannon-Wiener diversity index were found in gravel sediment and the highest value of abundance was in sand sediment of eastern coast. In terms of functional group, detritivorous and planktophagous groups had the highest values of abundance and biomass, respectively. Correlation analysis showed that macrofaunal abundance and biomass had significant positive correlations with contents of sediment chlorophyll a, phaeophorbide and organic matter. PMID- 26233303 TI - Sedimentary organic and inorganic records of eutrophication and hypoxia in and off the Changjiang Estuary over the last century. AB - Organic and inorganic sedimentary parameters in and off the Changjiang Estuary have been analyzed to reconstruct historical trends in eutrophication and hypoxia over the last century. The lipid biomarker concentrations in the Changjiang Estuary mud area (CEMA) indicated eutrophication accelerated after the 1970s. Meanwhile, Mo/Al indicated hypoxia has increased since 1960s. Eutrophication and hypoxia in the CEMA are primarily a result of the dramatically increased load of terrestrial nutrients from the Changjiang to the East China Sea. The lipid biomarker concentrations in the southwest Cheju Island mud area (SCIMA) showed primary production is controlled mainly by changes in regional climate and marine current. No significant hypoxia occurred in the SCIMA over the past century as indicated by Mo/Al. Therefore, geochemical indicators of eutrophication and hypoxia revealed different patterns between the CEMA and SCIMA, suggesting the role of river-derived nutrients in sustaining eutrophication and hypoxia in the CEMA since the 1960s. PMID- 26233304 TI - Assessment of metal contamination in coastal sediments of the Maluan Bay (China) using geochemical indices and multivariate statistical approaches. AB - Total concentrations and chemical forms of heavy metals in surface sediments of Maluan Bay were determined and multiple geochemical indices and guidelines were applied to assess potential contamination and environmental risks. Metal concentrations exhibited significant spatial variation and the speciation of Cr was presented dominantly in the residual fraction, while Cd was found mostly in the non-residual fraction and thus of high potential bioavailability. Cluster analysis separated four subgroups of sampling sites with different levels of contamination. Further, a multivariate method offered the specific interpretation of possible contaminant sources and/or pathways. Factor scores characterized the sampling locations and elucidated the pollution status, pointing out the impact of multiple "hidden hotspots" of contaminants and providing further evidence of the existence of clear pollution-risk gradients in lagoon areas. The study supports the integrative approach as powerful tool to diagnose the pollution status scientifically for management decisions in coastal sediment of complex environment. PMID- 26233305 TI - Hong Kong at the Pearl River Estuary: A hotspot of microplastic pollution. AB - Large plastic (>5mm) and microplastic (0.315-5mm) debris were collected from 25 beaches along the Hong Kong coastline. More than 90% consisted of microplastics. Among the three groups of microplastic debris, expanded polystyrene (EPS) represented 92%, fragments represented 5%, and pellets represented 3%. The mean microplastic abundance for Hong Kong was 5595items/m(2). This number is higher than international averages, indicating that Hong Kong is a hotspot of marine plastic pollution. Microplastic abundance was significantly higher on the west coast than on the east coast, indicating that the Pearl River, which is west of Hong Kong, may be a potential source of plastic debris. The amounts of large plastic and microplastic debris of the same types (EPS and fragments) were positively correlated, suggesting that the fragmentation of large plastic material may increase the quantity of beach microplastic debris. PMID- 26233306 TI - A review of the status and development of Kuwait's fisheries. AB - The status of Kuwait's fisheries landings and relative abundance for major species was reviewed using research data from Kuwait Institute for Scientific Research and landing data from the Kuwait's Central Statistical Bureau. Landing data showed significant decreases for major commercial species such as zobaidy (Pampus argenteus), suboor (Tenualosa ilisha), hamoor (Epinephelus coioides), newaiby (Otolithes ruber) and hamra (Lutjanus malabaricus) while abundance data for the shrimp Penaeus semisulcatus showed significant reduction in the recent years mainly because of overfishing. The catch-rate data showed continuous decline for major species such as zobaidy, newaiby and hamoor, which indicate that stock abundances of these species are low. The reduction in stock abundance in context with changes in habitat quality, particularly the effects of reduced discharge of the Shatt Al-Arab, is discussed. PMID- 26233307 TI - Identification of Heat Shock Protein families and J-protein types by incorporating Dipeptide Composition into Chou's general PseAAC. AB - Heat Shock Proteins (HSPs) are the substantial ingredients for cell growth and viability, which are found in all living organisms. HSPs manage the process of folding and unfolding of proteins, the quality of newly synthesized proteins and protecting cellular homeostatic processes from environmental stress. On the basis of functionality, HSPs are categorized into six major families namely: (i) HSP20 or sHSP (ii) HSP40 or J-proteins types (iii) HSP60 or GroEL/ES (iv) HSP70 (v) HSP90 and (vi) HSP100. Identification of HSPs family and sub-family through conventional approaches is expensive and laborious. It is therefore, highly desired to establish an automatic, robust and accurate computational method for prediction of HSPs quickly and reliably. Regard, a computational model is developed for the prediction of HSPs family. In this model, protein sequences are formulated using three discrete methods namely: Split Amino Acid Composition, Pseudo Amino Acid Composition, and Dipeptide Composition. Several learning algorithms are utilized to choice the best one for high throughput computational model. Leave one out test is applied to assess the performance of the proposed model. The empirical results showed that support vector machine achieved quite promising results using Dipeptide Composition feature space. The predicted outcomes of proposed model are 90.7% accuracy for HSPs dataset and 97.04% accuracy for J-protein types, which are higher than existing methods in the literature so far. PMID- 26233308 TI - miRNA-regulated gene expression differs in celiac disease patients according to the age of presentation. AB - Celiac disease is an intestinal disease which shows different symptoms and clinical manifestations among pediatric and adult patients. These variations could be imputable to age-related changes in gut architecture and intestinal immune system, which could be characterized by gene expression differences possibly regulated by miRNAs. We analyzed a panel of miRNAs and their target genes in duodenal biopsies of Marsh 3AB and 3C pediatric celiac patients, compared to controls. Moreover, to assess variation of expression in plasma samples, we evaluated circulating miRNA levels in controls and patients at diagnosis or on gluten-free diet. We detected a decreased miR-192-5p expression in celiac patients, but no variations in NOD2 and CXCL2, targets previously identified in adults. Conversely, we detected a significant increase in mRNA and protein levels of another target, MAD2L1, protein related to cell cycle control. miR-31-5p and miR-338-3p were down-regulated and their respective targets, FOXP3 and RUNX1, involved in Treg function, resulted up-regulated in celiac patients. Finally, we detected, in celiac patients, an increased expression of miR-21-5p, possibly caused by a regulatory loop with its putative target STAT3, which showed an increased activation in Marsh 3C patients. The analysis of plasma revealed a trend similar to that observed in biopsies, but in presence of gluten-free diet we could not detect circulating miRNAs values comparable to controls. miRNAs and their gene targets showed an altered expression in duodenal mucosa and plasma of celiac disease pediatric patients, and these alterations could be different from adult ones. PMID- 26233309 TI - Use of miRNAs in biofluids as biomarkers in dietary and lifestyle intervention studies. AB - The selection of biomarkers in nutrigenomics needs to reflect subtle changes in homoeostasis representing the relation between nutrition and health, or nutrition and disease. It is believed that noncoding RNAs, such as circulating microRNAs (miRNAs), may represent such a new class of integrative biomarkers. Until now, the most relevant body fluids for miRNA quantification in response to nutrition have not been clearly defined, but recent studies listed in this review indicate that miRNAs from plasma or serum, PBMC and faeces might be relevant biomarkers to quantify the physiological impacts of dietary or lifestyle intervention studies. In addition, a number of recent studies also indicate that miRNAs could permit to monitor the impact of diet on gut microbiota. We also discuss the main preanalytical considerations that are important to take into account before miRNA screening which can affect the reproducibility of the data. PMID- 26233311 TI - Theoretical Approaches for Understanding the Interplay Between Stress and Chemical Reactivity. AB - The use of mechanical stresses to induce chemical reactions has attracted significant interest in recent years. Computational modeling can play a significant role in developing a comprehensive understanding of the interplay between stresses and chemical reactivity. In this review, we discuss techniques for simulating chemical reactions occurring under mechanochemical conditions. The methods described are broadly divided into techniques that are appropriate for studying molecular mechanochemistry and those suited to modeling bulk mechanochemistry. In both cases, several different approaches are described and compared. Methods for examining molecular mechanochemistry are based on exploring the force-modified potential energy surface on which a molecule subjected to an external force moves. Meanwhile, it is suggested that condensed phase simulation methods typically used to study tribochemical reactions, i.e., those occurring in sliding contacts, can be adapted to study bulk mechanochemistry. PMID- 26233310 TI - Involvement of polyphosphate kinase in virulence and stress tolerance of uropathogenic Proteus mirabilis. AB - Proteus mirabilis (P. mirabilis), a gram-negative enteric bacterium, frequently causes urinary tract infections. Many virulence factors of uropathogenic P. mirabilis have been identified, including urease, flagella, hemolysin and fimbriae. However, the functions of polyphosphate kinase (PPK), which are related to the pathogenicity of many bacteria, remain entirely unknown in P. mirabilis. In this study, a ppk gene encoding the PPK insertional mutant in P. mirabilis strain HI4320 was constructed, and its biological functions were examined. The results of survival studies demonstrated that the ppk mutant was deficient in resistance to oxidative, hyperosmotic and heat stress. The swarming and biofilm formation abilities of P. mirabilis were also attenuated after the ppk interruption. In vitro and in vivo experiments suggested that ppk was required for P. mirabilis to invade the bladder. The negative phenotypes of the ppk mutant could be restored by ppk gene complementation. Furthermore, two-dimensional gel electrophoresis and liquid chromatography-mass spectrometry were used to analyze the proteomes of the wild-type strain and the ppk mutant. Compared with the wild type strain, seven proteins including TonB-dependent receptor, universal stress protein G, major mannose-resistant/Proteus-like fimbrial protein (MR/P fimbriae), heat shock protein, flagellar capping protein, putative membrane protein and multidrug efflux protein were down-regulated, and four proteins including exported peptidase, repressor protein for FtsI, FKBP-type peptidyl-prolyl cis trans isomerase and phosphotransferase were up-regulated in the ppk mutant. As a whole, these results indicate that PPK is an important regulator and plays a crucial role in stress tolerance and virulence in uropathogenic P. mirabilis. PMID- 26233312 TI - Ligand-Controlled Site-Selective Cross-Coupling. AB - Site-selective mono-cross-coupling reactions involving dichloro- or dibromo(hetero)aryl substrates are utilized to prepare substituted monochloro- or monobromo(hetero)arenes, which are used as drug components and synthetic precursors. In these reactions, selectivity toward the preferred reaction site of a dihalo(hetero)arene can vary depending on the ancillary ligand of the transition metal catalyst. This review summarizes the examples of ligand controlled site-selective cross-coupling reactions, specifically those mediated by Pd complexes. PMID- 26233313 TI - Beneficial effects of a cardiac support device on left ventricular remodeling after posterior myocardial infarction: an evaluation by echocardiography, pressure-volume curves and ventricular histology. AB - PURPOSE: Posterior myocardial infarction (MI) can induce LV remodeling and ischemic mitral regurgitation (IMR). The protective effects of a cardiac support device (CSD) against LV remodeling and IMR after posterior MI have been poorly documented. METHODS: Posterior MI was induced by ligation of the left circumflex coronary artery in beagle dogs. After 7 days, the dogs were randomized to a CSD placement (CSD group, n = 8) or no treatment (CTL group, n = 8). RESULTS: At 3 months after MI, the LV remodeling was less marked and the LV and RV systolic functions were better in the CSD group than in the CTL group. Neither the RV nor LV diastolic function (min dP/dt, Tau and EDPVR) was disturbed by the CSD. IMR was consistently prevented in our canine model. CONCLUSION: Early application of a CSD after posterior MI can attenuate LV remodeling without causing any deterioration of the biventricular diastolic function. PMID- 26233314 TI - Forensic and medico-legal radiology: challenges, issues and new perspectives. PMID- 26233315 TI - Biosynthetic enhancement of single-stage Poly(3-hydroxybutyrate-co-4 hydroxybutyrate) production by manipulating the substrate mixtures. AB - Two-stage fermentation was normally employed to achieve a high poly(3 hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-4HB)] productivity with higher 4HB molar fraction. Here, we demonstrated single-stage fermentation method which is more industrial feasible by implementing mixed-substrate cultivation strategy. Studies on bioreactor scale show a remarkably high PHA accumulation of 73 wt%, contributing to a high PHA concentration and product yield of 8.6 g/L and 2.7 g/g, respectively. This fermentation strategy has resulted in copolymers with wider range of 4HB monomer composition, which ranges from 12 to 55 mol%. These copolymers show a broad range of weight average molecular weight (M w ) from 119.5 to 407.0 kDa. The copolymer characteristics were found to be predominantly affected by the nature of the substrates and the mixture strategies, regardless of the 4HB monomer compositions. This was supported by the determination of copolymer randomness using (13)C-NMR analysis. The study warrants significantly in the copolymer scale-up and modeling at industrial level. PMID- 26233316 TI - Functional manipulations of the tetramycin positive regulatory gene ttmRIV to enhance the production of tetramycin A and nystatin A1 in Streptomyces ahygroscopicus. AB - A putative regulatory gene ttmRIV located in the tetramycin biosynthetic gene cluster was found in Streptomyces ahygroscopicus. In-frame deletion of ttmRIV led to abolishment of tetramycin and significant enhancement of nystatin A1, whose production reached 2.1-fold of the H42 parental strain. Gene complementation by an integrative plasmid carrying ttmRIV restored tetramycin biosynthesis revealed that ttmRIV was indispensable to tetramycin biosynthesis. Gene expression analysis of the H42 strain and its mutant strain DeltattmRIV via reverse transcriptase-PCR of the tetramycin gene cluster demonstrated that the expression levels of most biosynthetic genes were reduced in DeltattmRIV. Results of electrophoretic mobility shift assays showed that TtmRIV bound the putative promoters of several genes in the tetramycin pathway. Thus, TtmRIV is a pathway specific positive regulator activating the transcription of the tetramycin gene cluster in S. ahygroscopicus. Providing an additional copy of ttmRIV under the control of the ermEp* promoter in the H42 strain boosted tetramycin A production to 3.3-fold. PMID- 26233317 TI - The modeling of ethanol production by Kluyveromyces marxianus using whey as substrate in continuous A-Stat bioreactors. AB - We investigated the kinetics of whey bioconversion into ethanol by Kluyveromyces marxianus in continuous bioreactors using the "accelerostat technique" (A-stat). Cultivations using free and Ca-alginate immobilized cells were evaluated using two different acceleration rates (a). The kinetic profiles of these systems were modeled using four different unstructured models, differing in the expressions for the specific growth (MU) and substrate consumption rates (r s), taking into account substrate limitation and product inhibition. Experimental data showed that the dilution rate (D) directly affected cell physiology and metabolism. The specific growth rate followed the dilution rate (MU~D) for the lowest acceleration rate (a = 0.0015 h(-2)), condition in which the highest ethanol yield (0.52 g g(-1)) was obtained. The highest acceleration rate (a = 0.00667 h( 2)) led to a lower ethanol yield (0.40 g g(-1)) in the system where free cells were used, whereas with immobilized cells ethanol yields increased by 23 % (0.49 g g(-1)). Among the evaluated models, Monod and Levenspiel combined with Ghose and Tyagi models were found to be more appropriate for describing the kinetics of whey bioconversion into ethanol. These results may be useful in scaling up the process for ethanol production from whey. PMID- 26233318 TI - Disclosure during prenatal mental health screening. AB - BACKGROUND: While women and healthcare providers have generally viewed perinatal mental health screening favorably, some qualitative studies suggest that some women intentionally decide not to reveal their symptoms during screening. PURPOSE: The purpose of this study was to describe women's reported willingness to disclose mental health concerns during screening and factors associated with this. METHODS: This cross-sectional study included pregnant women who were >16 years of age and could speak/read English. Women were recruited from five maternity clinics and two community hospitals in Alberta, Canada (May-December, 2013). Eligible women completed the online Barriers and Facilitators of Mental Health Screening Questionnaire on recruitment. The primary outcome for this analysis was women's level of honesty about mental health concerns (completely vs somewhat/not at all honest) during screening. Analyses included descriptive statistics and multivariable logistic regressions to identify factors associated with honesty. RESULTS: Participation rate was 92% (460/500). Seventy-nine percent of women indicated that they could be 'completely honest' during screening. Women who feared their provider would view them as bad mothers were less likely to be honest. We found a significant association between 'less anonymous' modes of screening and honesty. LIMITATIONS: Over eighty percent of women in this study were well-educated, partnered, Caucasian women. As such, generalizability of the study findings may be limited. CONCLUSIONS: Most women indicated they could be honest during screening. Stigma-related factors and screening mode influenced women's willingness to disclose. Strategies to reduce stigma during screening are warranted to enhance early detection of prenatal mental illness. PMID- 26233319 TI - Hippocampal glutamate is increased and associated with risky drinking in young adults with major depression. AB - BACKGROUND: Risky drinking in young people is harmful, highly prevalent and often complicated by comorbid mental health problems that compound alcohol-induced impairment. The hippocampus and the glutamate system have been implicated in the pathophysiology of alcoholism and depression. This study aimed to determine whether risky drinking is associated with glutamate levels recorded within the hippocampus of young adults with major depression. METHODS: Sixty-three young persons with major depression (22.1+/-3.1 years; 65% female) and 38 healthy controls were recruited. Participants completed the alcohol use disorder identification test and underwent proton magnetic resonance spectroscopy to measure in vivo glutamate levels within the hippocampus following a period of at least 48h of abstinence. RESULTS: Young adults with depression had significantly increased hippocampal glutamate levels and a positive association between the level of alcohol use and glutamate. Regression analysis revealed that higher levels of hippocampal glutamate were predicted by having increased levels of risky drinking and depression. LIMITATIONS: Small sample sizes for testing diagnosis by risky drinking interaction and use of creatine ratios rather than the absolute concentrations of glutamate. DISCUSSION: The hippocampus is a critical region; given its role in learning and memory as well as mood regulation, and the neurochemical changes observed in this study may precede structural changes, which are commonly observed in both depression and alcohol misuse. These findings suggest that young adults with major depression who engage in risky drinking may be at increased risk of glutamate excitotoxicity. PMID- 26233320 TI - The prevalence and predictors of comorbid bipolar disorder and obsessive compulsive disorder: A systematic review and meta-analysis. AB - BACKGROUND: Although some authors have recently investigated the co-occurrence of anxiety and bipolar disorders, the topic remains insufficiently studied. Defining the prevalence and predictors of BD-OCD comorbidity has important nosological, clinical and therapeutic implications. METHODS: A systematic review and meta analysis was conducted on the prevalence and predictors of comorbid BD-OCD. Relevant papers published through March 30th, 2015 were identified searching the electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Library. RESULTS: 46 articles met inclusion criteria. The pooled prevalence of OCD in BD was 17.0% (95% CI 12.7-22.4%), which was comparable to the results reported by the pooled prevalence of BD in OCD (18.35%, 95% CI 13.2-24.8%). With regard to OCD-BD predictors, a higher mean age predicted a lower prevalence of OCD in BD patients. Sub group meta-analyses reported higher OCD prevalence rates in BD children and adolescents (24.2%, compared to 13.5% in adults), in BD-I patients (24.6%, compared to 13.6% in mixed BD patients), and among population-based studies (22.2%, compared to 13.2% in hospital-based studies). LIMITATIONS: Most studies use retrospective assessment scales with low sensitivity in discriminating true ego-dystonic obsessions from depressive ruminations that may bias results towards an overestimation of obsessive symptom prevalence. CONCLUSIONS: This first systematic review and meta-analysis of the prevalence and predictors of comorbid BD-OCD confirms that BD-OCD comorbidity is a common condition in psychiatry with children and adolescents and BD-I patients as the most affected subgroups. PMID- 26233321 TI - Neuroanatomical correlates of genetic risk for bipolar disorder: A voxel-based morphometry study in bipolar type I patients and healthy first degree relatives. AB - BACKGROUND: Bipolar disorder (BD) is a highly heritable mental illness which is associated with neuroanatomical abnormalities. Investigating healthy individuals at high genetic risk for bipolar disorder may help to identify neuroanatomical markers of risk and resilience without the confounding effects of burden of illness or medication. METHODS: Structural magnetic resonance imaging scans were acquired from 30 euthymic patients with BD-I (BP), 28 healthy first degree relatives of BD-I patients (HR), and 30 healthy controls (HC). Data was analyzed using DARTEL for voxel based morphometry in SPM8. RESULTS: Whole-brain analysis revealed a significant main effect of group in the gray matter volume in bilateral inferior frontal gyrus, left parahippocampal gyrus, left lingual gyrus and cerebellum, posterior cingulate gyrus, and supramarginal gyrus (alphasim corrected (<=0.05 FWE)). Post-hoc t-tests showed that inferior frontal gyrus volumes were bilaterally larger both in BP and HR than in HC. BP and HR also had smaller cerebellar volume compared with HC. In addition, BP had smaller left lingual gyrus volume, whereas HR had larger left parahippocampal and supramarginal gyrus volume compared with HC. LIMITATIONS: This study was cross sectional and the sample size was not large. All bipolar patients were on medication, therefore we were not able to exclude medication effects in bipolar group in this study. CONCLUSIONS: Our findings suggest that increased inferior frontal gyrus and decreased cerebellar volumes might be associated with genetic predisposition for bipolar disorder. Longitudinal studies are needed to better understand the predictive and prognostic value of structural changes in these regions. PMID- 26233322 TI - The variable heart: High frequency and very low frequency correlates of depressive symptoms in children and adolescents. AB - BACKGROUND: Work examining the link between lower heart rate variability (HRV) and depression in children and adolescents is lacking, especially in light of the physiological changes that occur during pubertal development. METHOD: We investigated the association between spectral measures of resting HRV and depressive symptoms among 127 children and adolescents, ages 10-17. Using spectral analysis, we evaluated (1) the association between relative high frequency (HF) HRV and depressive symptoms; (2) the predictive power of relative HF HRV for depressive symptoms in the context of relative low frequency (LF) and relative very low frequency (VLF) HRV; and (3) the relationship between relative HF, LF, and VLF band activity, age and pubertal maturation. RESULTS: Consistent with previous work, results revealed that relative HF HRV was negatively associated with self-reported depressive symptoms. As well, relative VLF HRV was positively associated with depressive symptoms. Regression analyses revealed that relative HF HRV and relative VLF HRV significantly predicted self-report depressive symptoms while controlling for age, sex and pubertal maturation, with relative VLF HRV emerging as the strongest indicator of depressive symptoms. Developmental findings also emerged. Age and pubertal maturation were negatively associated with relative HF HRV and positively correlated with relative VLF HRV. CONCLUSIONS: Results provide support for the relationship between HRV and depression and suggest that both HF and VLF HRV are relevant to depression symptom severity. Findings also reinforce the importance of considering pubertal development when investigating HRV-depression associations in children and adolescents. LIMITATIONS: Influences on cardiac control including physical activity levels and exercise patterns could be controlled in future work. Our data speak to a depressive symptom dimension and relative spectral power HRV. Thus, we cannot make strong claims about relative spectral power HRV and clinical depression. PMID- 26233324 TI - Imaging predictors of remission to anti-depressant medications in major depressive disorder. AB - BACKGROUND: We review what is currently known about neuroimaging predictors of remission in major depressive disorder (MDD) after antidepressant medication (ADM) treatment. METHODS: A systematic literature search found a total of twenty seven studies comparing baseline neuroimaging findings in depressed patients who achieved remission with non-remitters following treatment with ADMs. RESULTS: Eighteen of these studies utilised structural magnetic resonance imaging (MRI). These studies associated larger hippocampal (four studies) and cingulate volume (two studies) with remission. Two diffusion MRI studies identified a positive relationship between the fractional anisotropy of the cingulum bundle and remission. White matter signal hyperintensities were quantified in two papers - both observing decreased remission rates with increasing lesion burden. Nine studies on functional imaging met inclusion criteria - three using functional MRI, one with single photon emission computed tomography (SPECT), and five which evaluated patients with positron emission tomography (PET). These findings were not convergent, with different regions of interest interrogated. LIMITATIONS: The studies were generally underpowered. Overall these data were heterogeneous with only a small number identifying concordant findings. CONCLUSIONS: At present, the data remains inconsistent. The more promising biomarker of remission to ADMs appears to be hippocampal size, although this marker also has conflicting reports. Given remission should be the primary end-point of treatment, and that ADMs are the front-line treatment type for MDD, more focussed research is required to focus specifically on the imaging correlates of remission to ADMs. PMID- 26233323 TI - Identifying differences between depressed adolescent suicide ideators and attempters. AB - BACKGROUND: Adolescent depression and suicide are pressing public health concerns, and identifying key differences among suicide ideators and attempters is critical. The goal of the current study is to test whether depressed adolescent suicide attempters report greater anhedonia severity and exhibit aberrant effort-cost computations in the face of uncertainty. METHODS: Depressed adolescents (n=101) ages 13-19 years were administered structured clinical interviews to assess current mental health disorders and a history of suicidality (suicide ideators=55, suicide attempters=46). Then, participants completed self report instruments assessing symptoms of suicidal ideation, depression, anhedonia, and anxiety as well as a computerized effort-cost computation task. RESULTS: Compared with depressed adolescent suicide ideators, attempters report greater anhedonia severity, even after concurrently controlling for symptoms of suicidal ideation, depression, and anxiety. Additionally, when completing the effort-cost computation task, suicide attempters are less likely to pursue the difficult, high value option when outcomes are uncertain. Follow-up, trial-level analyses of effort-cost computations suggest that receipt of reward does not influence future decision-making among suicide attempters, however, suicide ideators exhibit a win-stay approach when receiving rewards on previous trials. LIMITATIONS: Findings should be considered in light of limitations including a modest sample size, which limits generalizability, and the cross-sectional design. CONCLUSIONS: Depressed adolescent suicide attempters are characterized by greater anhedonia severity, which may impair the ability to integrate previous rewarding experiences to inform future decisions. Taken together, this may generate a feeling of powerlessness that contributes to increased suicidality and a needless loss of life. PMID- 26233325 TI - Circulating microRNA-203 predicts metastases, early recurrence, and poor prognosis in human gastric cancer. AB - BACKGROUND: Metastasis is a major cause of death in patients with gastric cancer (GC). MicroRNAs (miRNAs) relating to the epithelial-mesenchymal transition (EMT) control GC progression and metastasis. The aim of this study was to evaluate serum EMT-associated miRNAs for metastatic and prognostic noninvasive biomarkers in GC. METHODS: In the first step of this study (preliminary experiments), we selected candidate miRNAs associated with metastasis by analyzing the expression of the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141, and miR-429) and miR-203 in serum samples from stage I (n = 12) and stage IV (n = 12) GC patients. The second phase involved the independent validation of candidate miRNAs in serum specimens from 130 patients with GC and 22 controls. RESULTS: Based on the preliminary experiments, miR-203 was selected as the candidate serum miRNA that was most closely associated with metastasis. Validation analysis revealed that serum miR-203 levels were significantly lower in stage IV than stage I-III GC patients. Serum miR-203 expression was significantly lower in GC patients with a higher T stage, vessel invasion, and lymph node, peritoneal, and distant metastases. Low expression of serum miR-203 was significantly associated with poor disease-free and overall survival. Multivariate analysis revealed that low serum miR-203 expression was an independent predictive marker for lymph node, peritoneal, and distant metastases and a poor prognosis in patients with GC. CONCLUSIONS: Serum miR-203 has the potential to serve as a noninvasive biomarker for prognosis and to predict metastasis in patients with GC. PMID- 26233327 TI - Impact of butyric acid on butanol formation by Clostridium pasteurianum. AB - The butanol yield of the classic fermentative acetone-butanol-ethanol (ABE) process has been enhanced in the past decades through the development of better strains and advanced process design. Nevertheless, by-product formation and the incomplete conversion of intermediates still decrease the butanol yield. This study demonstrates the potential of increasing the butanol yield from glycerol though the addition of small amounts of butyric acid. The impact of butyric acid was investigated in a 7L stirred tank reactor. The results of this study show the positive impact of butyric acid on butanol yield under pH controlled conditions and the metabolic stages were monitored via online measurement of carbon dioxide formation, pH value and redox potential. Butyric acid could significantly increase the butanol yield at low pH values if sufficient quantities of primary carbon source (glycerol) were present. PMID- 26233326 TI - CD97 promotion of gastric carcinoma lymphatic metastasis is exosome dependent. AB - BACKGROUND: CD97 knockdown impairs the metastatic capacity of SGC-7901 gastric cancer cells. However, the role of CD97 in the distant lymphatic premetastatic niche formation of gastric cancer remains unknown. METHODS: Exosomes and the soluble fraction were isolated from SGC-L (an SGC-7901-cell-derived highly lymphatic metastatic cell line) and CD97-knockdown (SGC-L/CD97-kd) cells, and were co-cultured with gastric cancer cells. The metastatic capacity of the two cell lines was evaluated in vitro and in a footpad lymph node metastasis mouse model. Premetastatic-niche-formation-related proteins were examined immunohistochemically. RESULTS: CD97 expression was ninefold higher in SGC-L cells than in SGC-7901 cells. In vitro, exosomes or conditioned medium from the SGC-L cells enhanced cell proliferation (20 % increase) and invasion (30 % increase) as compared with that from SGC-L/CD97-kd cells (p < 0.01). Intrafootpad injections of SGC-L, but not SGC-L/CD97-kd exosomes or conditioned medium, strongly promoted SGC-L and SGC-L/CD97-kd cell accumulation in the draining lymph nodes (p < 0.01) and increased CD55, CD44v6, alpha5beta1, CD31, epithelial cell adhesion molecule, and CD151 expression. Although the SGC-L/CD97-kd exosomes alone were insufficient for promotion of metastasis, they were partly aided by the SGC-L-cell-derived soluble fraction. CONCLUSIONS: The CD97 small isoform promotes SGC-L cell lymphatic metastasis exosome dependently, and aided by the soluble fraction, the exosome-dependent CD97 plays a pivotal role in premetastatic niche formation. PMID- 26233328 TI - Maximizing biomass concentration in baker's yeast process by using a decoupled geometric controller for substrate and dissolved oxygen. AB - Biomass production by baker's yeast in a fed-batch reactor depends on the metabolic regime determined by the concentration of glucose and dissolved oxygen in the reactor. Achieving high biomass concentration in turn is dependent on the dynamic interaction between the glucose and dissolved oxygen concentration. Taking this into account, we present in this paper the implementation of a decoupled input-output linearizing controller (DIOLC) for maximizing biomass in a fed-batch yeast process. The decoupling is based on the inversion of 2*2 input output matrix resulting from global linearization. The DIOLC was implemented online using a platform created in LabVIEW employing a TCP/IP protocol via the reactor's built-in electronic system. An improvement in biomass yield by 23% was obtained compared to that using a PID controller. The results demonstrate superior capability of the DIOLC and that the cumulative effect of smoother control action contributes to biomass maximization. PMID- 26233329 TI - Treatment of petrochemical wastewater by microaerobic hydrolysis and anoxic/oxic processes and analysis of bacterial diversity. AB - Microaerobic hydrolysis-acidification (MHA)-anoxic-oxic (A/O) processes were developed to treat actual petrochemical wastewater. The results showed that the overall COD removal efficiency was 72-79% at HRT=20h, and MHA accounted for 33 42% of COD removal, exhibiting good efficiency of acidogenic fermentation. Ammonium removal was more than 94%. The main pollutants in the influent were identified to be benzene, ketone, alcohols, amine, nitrile and phenols by GC-MS, and the majority of pollutants could be removed by MHA-A/O treatment. Proteobacteria was the most dominant bacteria in the system, accounting for more than 55% of the reads. The predominant genera in MHA, anoxic and oxic reactors were Anaerolineaceae and Sulfuritalea, Lactococcus and Blastocatella, and Saprospiraceae uncultured and Nitrosomonadaceae, respectively. This treatment system exhibited good performance in degrading the complex compounds in the petrochemical wastewater. PMID- 26233330 TI - Extracellular expression of natural cytosolic arginine deiminase from Pseudomonas putida and its application in the production of L-citrulline. AB - The Pseudomonas putida arginine deiminase (ADI), a natural cytosolic enzyme, and Thermobifida fusca cutinase were co-expressed in Escherichia coli, and the optimized cutinase gene was used for increasing its expression level. 90.9% of the total ADI protein was released into culture medium probably through a nonspecific leaking mechanism caused by the co-expressed cutinase. The enzymatic properties of the extracellular ADI were found to be similar to those of ADI prepared by conventional cytosolic expression. Extracellular production of ADI was further scaled up in a 3-L fermentor. When the protein expression was induced by IPTG (25.0MUM) and lactose (0.1gL(-1)h(-1)) at 30 degrees C, the extracellular ADI activity reached 101.2UmL(-1), which represented the highest ADI production ever reported. In addition, the enzymatic synthesis of l-citrulline was performed using the extracellularly expressed ADI, and the conversion rate reached 100% with high substrate concentration at 650gL(-1). PMID- 26233331 TI - Attitudes Toward Genetic Testing for Celiac Disease. AB - HLA molecular typing for celiac disease (CD) is a genetic test with a high negative predictive value. The aim of this study is to explore knowledge of and attitudes towards genetic testing (GT). A 25-item questionnaire was developed by a multidisciplinary team and distributed to members of CD support groups across the United States. Respondents (n = 1835) were mainly female (88 %), married (76 %), and college-educated (55 %), with a median age range of 31-50 years. Those who were married (82 vs 75 %, p = 0.002), had children (82 vs 74 %, p < 0.001), and had pursued education beyond high school (81 vs 68 %, p = 0.004) were more likely to be aware of the availability of GT. On multivariable analysis, adjusting for age, sex, education, marital status, region of residence, and having children, college-education (OR 2.05, 95 % CI: 1.33-3.16) and having children (OR 1.56, 95 % CI: 1.15-2.11) remained significant predictors of GT awareness. A majority of patients with a personal or family history of CD planned GT for their children, and the most common concerns regarding GT were cost and impact on health care and/or insurance. In conclusion, awareness of GT is high among CD support group members. Efforts should be made to increase knowledge of GT in those with a lower educational level, and healthcare professionals should attempt to address concerns regarding GT cost and the impact of results on health care and insurance status. PMID- 26233332 TI - Is there a link between preoperative fluoroscopic cough stress testing and synthetic midurethral tape outcome? AB - OBJECTIVES: The primary aim of our study was to assess the utility of fluoroscopic cough stress testing as a predictor of synthetic midurethral tape (MUT) outcome. The secondary aim was to examine whether baseline demographics, clinical symptoms and urodynamic variables could predict MUT success. STUDY DESIGN: We carried out a retrospective study including women with stress urinary incontinence (SUI) who underwent retropubic MUT in a tertiary referral urogynaecology unit. We excluded cases where concurrent pelvic organ prolapse surgery was performed. Patients were subdivided into groups based on the pre operative fluoroscopic cough stress testing, using Blaivas and Versi classifications. Subjective outcome was evaluated at 6 weeks based on self reported SUI in the symptom domain of the King's Health Questionnaire. Logistic regression models were used to identify predictors of treatment success. RESULTS: 143 patients were included in the study. Blaivas and Versi classifications were not useful in predicting subjective success (p=0.44 and p=0.40, respectively). Baseline demographics, clinical and other urodynamic variables failed to predict subjective outcome. CONCLUSIONS: Fluoroscopic cough stress testing is not a useful predictor of MUT outcome. No preoperative variables have been found to predict MUT success. PMID- 26233333 TI - Suppression of lung metastases by the CD26/DPP4 inhibitor Vildagliptin in mice. AB - Metastases rather than primary cancers determine nowadays the survival of patients. One of the most common primary malignancies is colorectal cancer and this type of tumor is characterized by a high tendency to spread metastases to the lung and liver. CD26/DPP4 is a transmembrane molecule with enzymatic functions which cleaves biologically active peptides. Recently, CD26/DPP4 has become the focus of cancer research and it was shown that CD26/DPP4-positive cancer cells display increased metastatic activity. Here, we tested if the CD26/DPP4-inhibitor Vildagliptin suppresses the development and growth of mouse colorectal lung metastases. This inhibitor of CD26/DPP4 was employed on mouse (C57BL/6) colorectal lung metastases, established by intravenous injection of the syngeneic cell line MC38. For mechanistic analysis, a subcutaneous tumor model was used. The treatment with Vildagliptin significantly suppressed both, the incidence and growth of lung metastases. Autophagy markers (LC3, p62, and ATF4) decreased, apoptosis increased (TUNEL, pH3/Ki-76), and the cell cycle regulator pCDC2 was inhibited. In conclusion, we here showed an anti-tumor effect of Vildagliptin via downregulation of autophagy resulting in increased apoptosis and modulation of the cell cycle. We therefore propose Vildagliptin for the evaluation as a new therapeutic approach for the treatment of colorectal cancer lung metastases. PMID- 26233334 TI - Lower CYP2C9 activity in Turkish patients with Behcet's disease compared to healthy subjects: a down-regulation due to inflammation? AB - BACKGROUND: We previously reported on a Swedish patient with Behcet's disease (BD) who was an ultra-rapid metaboliser of drugs catalysed by CYP2C9. Was this extreme metabolism caused by the disease? AIM: This study aims to compare the genotype/phenotype of CYP2C9 in patients with BD and healthy subjects. As the occurrence of BD is high in Turkey, all subjects were recruited from this country. METHODS: Genotyping of CYP2C9 was performed using standard PCR-RFLP and allele-specific PCR methods. Phenotyping of CYP2C9 was performed by administration of a 50-mg single oral dose of losartan and by calculating the urinary metabolic ratio (MR) of probe drug to its metabolite E-3174. Quantitation was performed by HPLC. RESULTS: The frequency of CYP2C9*2 and *3 was not significantly different between the Behcet's disease patients (12.5 and 8.7%) and the healthy subjects (8.9 and 8.2%). The geometric mean losartan MR was higher in the 52 patients (1.75) than in the 96 healthy subjects (1.02) (p = 0.002; t test). Within the genotypes *1/*1, there was a significant difference of MR between patients and healthy subjects (P = 0.006). All but three of the Behcet's disease patients were treated with colchicine. In nine subsequent patients, we found no significant effect of 2 weeks of treatment with colchicine on the CYP2C9 MR. CONCLUSION: Contrary to expectation, the CYP2C9 activity was lower in Turkish BD patients compared to healthy subjects. As this seems not to be due to colchicine treatment, our hypothesis is that inflammation related to BD might have caused the down-regulation of the CYP2C9 activity due to immune cytokine reactions. The ultra-rapid metabolism of CYP2C9 substrate drugs in the Swedish patient was not due to her BD. PMID- 26233335 TI - Mechanism-based population pharmacokinetic and pharmacodynamic modeling of intravenous and intranasal dexmedetomidine in healthy subjects. AB - PURPOSE: Dexmedetomidine is an alpha2-adrenoceptor agonist used for perioperative and intensive care sedation. This study develops mechanism-based population pharmacokinetic-pharmacodynamic models for the cardiovascular and central nervous system (CNS) effects of intravenously (IV) and intranasally (IN) administered dexmedetomidine in healthy subjects. METHOD: Single doses of 84 MUg of dexmedetomidine were given once IV and once IN to six healthy men. Plasma dexmedetomidine concentrations were measured for 10 h along with plasma concentrations of norepinephrine (NE) and epinephrine (E). Blood pressure, heart rate, and CNS drug effects (three visual analog scales and bispectral index) were monitored to assess the pharmacological effects of dexmedetomidine. PK-PD modeling was performed for recently published data (Eur J Clin Pharmacol 67: 825, 2011). RESULTS: Pharmacokinetic profiles for both IV and IN doses of dexmedetomidine were well fitted using a two-compartment PK model. Intranasal bioavailability was 82%. Dexmedetomidine inhibited the release of NE and E to induce their decline in blood. This decrease in NE was captured with an indirect response model. The concentrations of the mediator NE served via a biophase/transduction step and nonlinear pharmacologic functions to produce reductions in blood pressure and heart rate, while a direct effect model was used for the CNS effects. CONCLUSION: The comprehensive panel of two biomarkers and seven response measures were well captured by the population PK/PD models. The subjects were more sensitive to the CNS (lower EC 50 values) than cardiovascular effects of dexmedetomidine. PMID- 26233336 TI - Diabetic neuropathy is not associated with homocysteine, folate, vitamin B12 levels, and MTHFR C677T mutation in type 2 diabetic outpatients taking metformin. AB - BACKGROUND: Hyperhomocysteinemia and vitamin B12 deficiency may be involved in the development of diabetic peripheral neuropathy (DPN). Metformin therapy may reduce vitamin B12 plasma levels, thus contributing to DPN. AIM AND METHODS: The purposes of this cross-sectional study were to assess (1) the potential associations of DPN with serum levels of homocysteine (tHcy), B-vitamins, and/or the common methylenetetrahydrofolate reductase (MTHFR) C677T mutation; (2) the influence of chronic treatment with metformin on tHcy and B-vitamins concentrations and, finally, (3) to evaluate whether, by this influence, metformin is a risk factor for DPN in a group of type 2 diabetic outpatients. RESULTS: Our data showed that fasting tHcy, folate, and vitamin B12 levels and the MTHFR C677T genotype distribution were comparable between subjects with (n = 79, 30 %) and without DPN (n = 184, 70 %). Metformin-treated subjects (n = 124, 47 %) showed significantly lower levels of vitamin B12 (P < 0.001), but the prevalence of DPN was not different when compared to those not treated with this drug (33 vs. 27 %, P = NS). At univariate regression analysis, DPN was associated with age, duration of diabetes, HbA1c, creatinine levels, and the presence of coronary heart disease (CHD), and negatively with HDL-C concentrations (P < 0.05 all), but at multivariate regression analysis, high creatinine levels (P = 0.06), low HDL-C levels (P = 0.013), and a higher prevalence of CHD (P = 0.001) were the only variables independently associated with DPN in this population. CONCLUSIONS: In conclusion, in these type 2 diabetic outpatients circulating levels of tHcy, folate, and the MTHFR C677T mutation are not associated with DPN, which was predicted by creatinine levels, CHD, and dyslipidemia. Metformin therapy is associated with a mild vitamin B12 level reduction, but not with DPN. PMID- 26233339 TI - Invited Article: First flight in space of a wide-field-of-view soft x-ray imager using lobster-eye optics: Instrument description and initial flight results. AB - We describe the development, launch into space, and initial results from a prototype wide field-of-view soft X-ray imager that employs lobster-eye optics and targets heliophysics, planetary, and astrophysics science. The sheath transport observer for the redistribution of mass is the first instrument using this type of optics launched into space and provides proof-of-concept for future flight instruments capable of imaging structures such as the terrestrial cusp, the entire dayside magnetosheath from outside the magnetosphere, comets, the Moon, and the solar wind interaction with planetary bodies like Venus and Mars [Kuntz et al., Astrophys. J. (in press)]. PMID- 26233337 TI - Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations. AB - PURPOSE: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease characterized by impaired adrenal steroidogenesis and most often caused by CYP21A2 gene mutations. For the first time, we reported complete spectrum and frequency of CYP21A2 gene mutations in 61 unrelated patients with classical and non-classical CAH from Serbia. METHODS: Direct DNA sequencing of whole CYP21A2 gene and polymerase chain reaction with sequence-specific primers for detection of CYP21A1P/CYP21A2 chimeras were combined. RESULTS: We identified 18 different pathogenic alleles-two of them novel. Mutation detection rate was highest in patients with salt-wasting form of CAH (94.7%). The most prevalent mutation was intron 2 splice site mutation, c.290-13A/C>G (18.5%). Other mutation frequencies were: CYP21A1P/CYP21A2 chimeras (13%), p.P30L (13%), p.R356W (11.1%), p.G110fs (7.4%), p.Q318X (4.6%), p.V281L (4.6%), p.I172N (2.8%), p.L307fs (2.8%), p.P453S (1.9%), etc. Mainly, frequencies were similar to those in Slavic populations and bordering countries. However, we found 6.5% of alleles with multiple mutations, frequently including p.P453S. Effects of novel mutations, c.386T>C (p.Leu129Pro) and c.493T>C (p.Ser165Pro), were characterized in silico as deleterious. The effect of well-known mutations on Serbian patients' phenotype was as expected. CONCLUSIONS: The first comprehensive molecular genetic study of Serbian CAH patients revealed two novel CYP21A2 mutations. This study will enable genetic counseling in our population and contribute to better understanding of molecular landscape of CAH in Europe. PMID- 26233340 TI - Preface: High-pressure studies with x-rays. PMID- 26233338 TI - Expanding the therapeutic spectrum of metformin: from diabetes to cancer. AB - INTRODUCTION: Metformin, an oral hypoglycemic agent, was introduced in the clinical practice for the treatment of type 2 diabetes mellitus more than a half century ago. Over the years, several studies demonstrated that diabetic patients treated with metformin have a lower incidence of cancer, raising the hypothesis that the spectrum of clinical applications of the drug could be expanded also to cancer therapy. Following these initial findings, a large number of studies were performed aimed at elucidating the effects of metformin on different types of tumor, at explaining its direct and indirect anti-cancer mechanisms and at identifying the molecular pathways targeted by the drug. Several clinical trials were also performed aimed at evaluating the potential anti-cancer effect of metformin among diabetic and non-diabetic patients affected by different types of cancer. While the results of several clinical studies are encouraging, a considerable number of other investigations do not support a role of metformin as an anti-cancer agent, and highlight variables possibly accounting for discrepancies. AIM: We hereby review the results of in vitro and in vivo studies addressing the issue of the anti-cancer effects of metformin. CONCLUSIONS: If in vitro data appear solid, the results provided by in vivo studies are somehow controversial. In this view, larger studies are needed to fully elucidate the role of metformin on cancer development and progression, as well as the specific clinical settings in which metformin could become an anti-cancer drug. PMID- 26233341 TI - New developments in laser-heated diamond anvil cell with in situ synchrotron x ray diffraction at High Pressure Collaborative Access Team. AB - An overview of the in situ laser heating system at the High Pressure Collaborative Access Team, with emphasis on newly developed capabilities, is presented. Since its establishment at the beamline 16-ID-B a decade ago, laser heated diamond anvil cell coupled with in situ synchrotron x-ray diffraction has been widely used for studying the structural properties of materials under simultaneous high pressure and high temperature conditions. Recent developments in both continuous-wave and modulated heating techniques have been focusing on resolving technical issues of the most challenging research areas. The new capabilities have demonstrated clear benefits and provide new opportunities in research areas including high-pressure melting, pressure-temperature-volume equations of state, chemical reaction, and time resolved studies. PMID- 26233342 TI - The laser micro-machining system for diamond anvil cell experiments and general precision machining applications at the High Pressure Collaborative Access Team. AB - We have designed and constructed a new system for micro-machining parts and sample assemblies used for diamond anvil cells and general user operations at the High Pressure Collaborative Access Team, sector 16 of the Advanced Photon Source. The new micro-machining system uses a pulsed laser of 400 ps pulse duration, ablating various materials without thermal melting, thus leaving a clean edge. With optics designed for a tight focus, the system can machine holes any size larger than 3 MUm in diameter. Unlike a standard electrical discharge machining drill, the new laser system allows micro-machining of non-conductive materials such as: amorphous boron and silicon carbide gaskets, diamond, oxides, and other materials including organic materials such as polyimide films (i.e., Kapton). An important feature of the new system is the use of gas-tight or gas-flow environmental chambers which allow the laser micro-machining to be done in a controlled (e.g., inert gas) atmosphere to prevent oxidation and other chemical reactions in air sensitive materials. The gas-tight workpiece enclosure is also useful for machining materials with known health risks (e.g., beryllium). Specialized control software with a graphical interface enables micro-machining of custom 2D and 3D shapes. The laser-machining system was designed in a Class 1 laser enclosure, i.e., it includes laser safety interlocks and computer controls and allows for routine operation. Though initially designed mainly for machining of the diamond anvil cell gaskets, the laser-machining system has since found many other micro-machining applications, several of which are presented here. PMID- 26233343 TI - Focusing polycapillary to reduce parasitic scattering for inelastic x-ray measurements at high pressure. AB - The double-differential scattering cross-section for the inelastic scattering of x-ray photons from electrons is typically orders of magnitude smaller than that of elastic scattering. With samples 10-100 MUm size in a diamond anvil cell at high pressure, the inelastic x-ray scattering signals from samples are obscured by scattering from the cell gasket and diamonds. One major experimental challenge is to measure a clean inelastic signal from the sample in a diamond anvil cell. Among the many strategies for doing this, we have used a focusing polycapillary as a post-sample optic, which allows essentially only scattered photons within its input field of view to be refocused and transmitted to the backscattering energy analyzer of the spectrometer. We describe the modified inelastic x-ray spectrometer and its alignment. With a focused incident beam which matches the sample size and the field of view of polycapillary, at relatively large scattering angles, the polycapillary effectively reduces parasitic scattering from the diamond anvil cell gasket and diamonds. Raw data collected from the helium exciton measured by x-ray inelastic scattering at high pressure using the polycapillary method are compared with those using conventional post-sample slit collimation. PMID- 26233344 TI - High pressure Laue diffraction and its application to study microstructural changes during the alpha -> beta phase transition in Si. AB - An approach using polychromatic x-ray Laue diffraction is described for studying pressure induced microstructural changes of materials under pressure. The advantages of this approach with respect to application of monochromatic x-ray diffraction and other techniques are discussed. Experiments to demonstrate the applications of the method have been performed on the alpha -> beta phase transition in Si at high pressures using a diamond anvil cell. We present the characterization of microstructures across the alpha-beta phase transition, such as morphology of both the parent and product phases, relative orientation of single-crystals, and deviatoric strains. Subtle inhomogeneous strain of the single-crystal sample caused by lattice rotations becomes detectable with the approach. PMID- 26233345 TI - New developments in micro-X-ray diffraction and X-ray absorption spectroscopy for high-pressure research at 16-BM-D at the Advanced Photon Source. AB - The monochromator and focusing mirrors of the 16-BM-D beamline, which is dedicated to high-pressure research with micro-X-ray diffraction (micro-XRD) and X-ray absorption near edge structure (XANES) (6-45 keV) spectroscopy, have been recently upgraded. Monochromatic X-rays are selected by a Si (111) double-crystal monochromator operated in an artificial channel-cut mode and focused to 5 MUm * 5 MUm (FWHM) by table-top Kirkpatrick-Baez type mirrors located near the sample stage. The typical X-ray flux is ~5 * 10(8) photons/s at 30 keV. The instrumental resolution, Deltaq/qmax, reaches to 2 * 10(-3) and is tunable through adjustments of the detector distance and X-ray energy. The setup is stable and reproducible, which allows versatile application to various types of experiments including resistive heating and cryogenic cooling as well as ambient temperature compression. Transmission XANES is readily combined with micro-XRD utilizing the fixed-exit feature of the monochromator, which allows combined XRD-XANES measurements at a given sample condition. PMID- 26233346 TI - New developments in high pressure x-ray spectroscopy beamline at High Pressure Collaborative Access Team. AB - The 16 ID-D (Insertion Device - D station) beamline of the High Pressure Collaborative Access Team at the Advanced Photon Source is dedicated to high pressure research using X-ray spectroscopy techniques typically integrated with diamond anvil cells. The beamline provides X-rays of 4.5-37 keV, and current available techniques include X-ray emission spectroscopy, inelastic X-ray scattering, and nuclear resonant scattering. The recent developments include a canted undulator upgrade, 17-element analyzer array for inelastic X-ray scattering, and an emission spectrometer using a polycapillary half-lens. Recent development projects and future prospects are also discussed. PMID- 26233347 TI - X-ray imaging for studying behavior of liquids at high pressures and high temperatures using Paris-Edinburgh press. AB - Several X-ray techniques for studying structure, elastic properties, viscosity, and immiscibility of liquids at high pressures have been integrated using a Paris Edinburgh press at the 16-BM-B beamline of the Advanced Photon Source. Here, we report the development of X-ray imaging techniques suitable for studying behavior of liquids at high pressures and high temperatures. White X-ray radiography allows for imaging phase separation and immiscibility of melts at high pressures, identified not only by density contrast but also by phase contrast imaging in particular for low density contrast liquids such as silicate and carbonate melts. In addition, ultrafast X-ray imaging, at frame rates up to ~10(5) frames/second (fps) in air and up to ~10(4) fps in Paris-Edinburgh press, enables us to investigate dynamics of liquids at high pressures. Very low viscosities of melts similar to that of water can be reliably measured. These high-pressure X-ray imaging techniques provide useful tools for understanding behavior of liquids or melts at high pressures and high temperatures. PMID- 26233348 TI - Developments in time-resolved high pressure x-ray diffraction using rapid compression and decompression. AB - Complementary advances in high pressure research apparatus and techniques make it possible to carry out time-resolved high pressure research using what would customarily be considered static high pressure apparatus. This work specifically explores time-resolved high pressure x-ray diffraction with rapid compression and/or decompression of a sample in a diamond anvil cell. Key aspects of the synchrotron beamline and ancillary equipment are presented, including source considerations, rapid (de)compression apparatus, high frequency imaging detectors, and software suitable for processing large volumes of data. A number of examples are presented, including fast equation of state measurements, compression rate dependent synthesis of metastable states in silicon and germanium, and ultrahigh compression rates using a piezoelectric driven diamond anvil cell. PMID- 26233349 TI - Online remote control systems for static and dynamic compression and decompression using diamond anvil cells. AB - The ability to remotely control pressure in diamond anvil cells (DACs) in accurate and consistent manner at room temperature, as well as at cryogenic and elevated temperatures, is crucial for effective and reliable operation of a high pressure synchrotron facility such as High Pressure Collaborative Access Team (HPCAT). Over the last several years, a considerable effort has been made to develop instrumentation for remote and automated pressure control in DACs during synchrotron experiments. We have designed and implemented an array of modular pneumatic (double-diaphragm), mechanical (gearboxes), and piezoelectric devices and their combinations for controlling pressure and compression/decompression rate at various temperature conditions from 4 K in cryostats to several thousand Kelvin in laser-heated DACs. Because HPCAT is a user facility and diamond cells for user experiments are typically provided by users, our development effort has been focused on creating different loading mechanisms and frames for a variety of existing and commonly used diamond cells rather than designing specialized or dedicated diamond cells with various drives. In this paper, we review the available instrumentation for remote static and dynamic pressure control in DACs and show some examples of their applications to high pressure research. PMID- 26233350 TI - Velocity map imaging with non-uniform detection: Quantitative molecular axis alignment measurements via Coulomb explosion imaging. AB - We present a method for inverting charged particle velocity map images which incorporates a non-uniform detection function. This method is applied to the specific case of extracting molecular axis alignment from Coulomb explosion imaging probes in which the probe itself has a dependence on molecular orientation which often removes cylindrical symmetry from the experiment and prevents the use of standard inversion techniques for the recovery of the molecular axis distribution. By incorporating the known detection function, it is possible to remove the angular bias of the Coulomb explosion probe process and invert the image to allow quantitative measurement of the degree of molecular axis alignment. PMID- 26233351 TI - High-gain cryogenic amplifier assembly employing a commercial CMOS operational amplifier. AB - We have developed a cryogenic amplifier for the measurement of small current signals (10 fA-100 nA) from cryogenic optical detectors. Typically operated with gain near 10(7) V/A, the amplifier performs well from DC to greater than 30 kHz and exhibits noise level near the Johnson limit. Care has been taken in the design and materials to control heat flow and temperatures throughout the entire detector-amplifier assembly. A simple one-board version of the amplifier assembly dissipates 8 mW to our detector cryostat cold stage, and a two-board version can dissipate as little as 17 MUW to the detector cold stage. With current noise baseline of about 10 fA/(Hz)(1/2), the cryogenic amplifier is generally useful for cooled infrared detectors, and using blocked impurity band detectors operated at 10 K, the amplifier enables noise power levels of 2.5 fW/(Hz)(1/2) for detection of optical wavelengths near 10 MUm. PMID- 26233352 TI - A source for microhydrated biomolecules. AB - We describe the construction of an apparatus for the production of a molecular jet of microhydrated biomolecules. Our design uses a water reservoir producing water vapour, which then passes through a separate reservoir containing a vapour of a sublimated biomolecule. The mixture coexpands into a molecular beam apparatus through a conical nozzle. Mass spectra showing water-adenin and water uracil complexes are shown as typical examples. Suitable expansion conditions are reached without the use of an inert carrier gas. PMID- 26233353 TI - Long-term laser frequency stabilization using fiber interferometers. AB - We report long-term laser frequency stabilization using only the target laser and a pair of 5 m fiber interferometers, one as a frequency reference and the second as a sensitive thermometer to stabilize the frequency reference. When used to stabilize a distributed feedback laser at 795 nm, the frequency Allan deviation at 1000 s drops from 5.6 * 10(-8) to 6.9 * 10(-10). The performance equals that of an offset lock employing a second, atom-stabilized laser in the temperature control. PMID- 26233354 TI - Development of two-band infrared radiometer for irradiance calibration of target simulators. AB - A detector-based spectral radiometer has been developed for the calibration of target simulator. Unlike the conventional spectral irradiance calibration method based on radiance and irradiance, the new radiometer is calibrated using image space temperature based method. The image-space temperature based method improves the reproducibility in the calibration of radiometer and reduces the uncertainties existing in the conventional calibration methods. The calibrated radiometer is then used to establish the irradiance transfer standard for the target simulator. With the designed radiometer in this paper, a highly accurate irradiance calibration for target simulators of wavelength from 2.05 to 2.55 MUm and from 3.7 to 4.8 MUm can be performed with an expanded uncertainty (k = 2) of calibration of 2.18%. Last but not least, the infrared radiation of the target simulator was measured by the infrared radiometer, the effectiveness and capability of which are verified through measurement of temperature and irradiance and a comparison with the thermal imaging camera. PMID- 26233355 TI - Experimental station for laser-based picosecond time-resolved x-ray absorption near-edge spectroscopy. AB - We present an experimental station designed for time-resolved X-ray Absorption Near-Edge Spectroscopy (XANES). It is based on ultrashort laser-plasma x-ray pulses generated from a table-top 100 mJ-class laser at 10 Hz repetition rate. A high transmission (10%-20%) x-ray beam line transport using polycapillary optics allows us to set the sample in an independent vacuum chamber, providing high flexibility over a wide spectral range from 0.5 up to 4 keV. Some XANES spectra are presented, demonstrating 1% noise level in only ~1 mn and ~100 cumulated laser shots. Time-resolved measurements are reported, indicating that the time resolution of the entire experimental station is 3.3 +/- 0.6 ps rms. PMID- 26233356 TI - A sensitive Faraday rotation setup using triple modulation. AB - The utilization of polarized targets in scattering experiments has become a common practice in many major accelerator laboratories. Noble gases are especially suitable for such applications, since they can be easily hyper polarized using spin exchange or metastable pumping techniques. Polarized helium 3 is a very popular target because it often serves as an effective polarized neutron due to its simple nuclear structure. A favorite cell material to generate and store polarized helium-3 is GE-180, a relatively dense aluminosilicate glass. In this paper, we present a Faraday rotation method, using a new triple modulation technique, where the measurement of the Verdet constants of SF57 flint glass, pyrex glass, and air was tested. The sensitivity obtained shows that this technique may be implemented in future cell wall characterization and thickness measurements. We also discuss the first ever extraction of the Verdet constant of GE-180 glass for four wavelength values of 632 nm, 773 nm, 1500 nm, and 1547 nm, whereupon the expected 1/lambda(2) dependence was observed. PMID- 26233357 TI - Attenuated total reflectance Fourier-transform infrared spectroscopic investigation of silicon heterojunction solar cells. AB - Silicon heterojunction solar cells critically depend on the detailed properties of their amorphous/crystalline silicon interfaces. We report here on the use of attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy to gain precise insight into the vibrational properties of the surfaces and ultrathin layers present in such solar cells. We fabricate ATR prisms from standard silicon wafers similar to those used for device fabrication. In this fashion, we acquire very-high sensitivity FTIR information on device-relevant structures. Our method has no requirement for minimum layer thickness, enabling the study of the impact of the different fabrication process steps on the film microstructure. We discuss the necessary requirements for the method implementation and give a comprehensive overview of all observed vibration modes. In particular, we study vibrational signatures of Si-H(X), Si-H(X)(Si(Y)O(Z)), B H, hydroxyl groups, and hydrocarbons on the Si(111) surface. We observe subtle effects in the evolution of the chemical state of the surface during sample storage and process-related wafer handling and discuss their effect on the electronic properties of the involved interfaces. PMID- 26233358 TI - Matrix isolation sublimation: An apparatus for producing cryogenic beams of atoms and molecules. AB - We describe the apparatus to generate cryogenic beams of atoms and molecules based on matrix isolation sublimation. Isolation matrices of Ne and H2 are hosts for atomic and molecular species which are sublimated into vacuum at cryogenic temperatures. The resulting cryogenic beams are used for high-resolution laser spectroscopy. The technique also aims at loading atomic and molecular traps. PMID- 26233359 TI - Injection locking of a high power ultraviolet laser diode for laser cooling of ytterbium atoms. AB - We developed a high-power laser system at a wavelength of 399 nm for laser cooling of ytterbium atoms with ultraviolet laser diodes. The system is composed of an external cavity laser diode providing frequency stabilized output at a power of 40 mW and another laser diode for amplifying the laser power up to 220 mW by injection locking. The systematic method for optimization of our injection locking can also be applied to high power light sources at any other wavelengths. Our system does not depend on complex nonlinear frequency-doubling and can be made compact, which will be useful for providing light sources for laser cooling experiments including transportable optical lattice clocks. PMID- 26233360 TI - A compact ultranarrow high-power laser system for experiments with 578 nm ytterbium clock transition. AB - In this paper, we present the realization of a compact, high-power laser system able to excite the ytterbium clock transition at 578 nm. Starting from an external-cavity laser based on a quantum dot chip at 1156 nm with an intra-cavity electro-optic modulator, we were able to obtain up to 60 mW of visible light at 578 nm via frequency doubling. The laser is locked with a 500 kHz bandwidth to an ultra-low-expansion glass cavity stabilized at its zero coefficient of thermal expansion temperature through an original thermal insulation and correction system. This laser allowed the observation of the clock transition in fermionic (173)Yb with a <50 Hz linewidth over 5 min, limited only by a residual frequency drift of some 0.1 Hz/s. PMID- 26233361 TI - XeCl excimer laser with new prism resonator configurations and its performance characteristics. AB - New resonator cavity configurations, namely, the prism resonator and unstable prism resonator, are demonstrated for the first time in an excimer (XeCl) laser with interesting and novel results. High misalignment tolerance ~50 mrad is achieved with considerably reduced beam divergence of less than ~1 mrad without reduction in output power capabilities of the laser. The misalignment tolerance of ~50 mrad is a dramatic improvement of ~25 times compared to ~2 mrad normally observed in standard excimer laser with plane-plane cavity. Increase in depth of focus from 3 mm to 5.5 mm was also achieved in case of prism resonator configuration with an improvement of about 60%. Unstable prism resonator configuration is demonstrated here in this paper with further reduction in beam divergence to about 0.5 mrad using plano-convex lens as output coupler. The misalignment tolerance in case of unstable prism resonator was retained at about 30 mrad which is a high value compared to standard unstable resonators. The output beam spot was completely filled with flat-top profile with prism resonator configurations, which is desired for various material processing applications. Focusing properties and beam divergence in case of prism resonator have been investigated using SEM (scanning electron microscope) images. SEM images of the focused spot size (~20 MUm holes) on metal sheet indicate beam divergence of about 0.05 mrad which is about 1.5 times diffraction limit. Energy contained in this angle is thus sufficient for micro-machining applications. Clean and sharp edges of the micro-holes show high pointing stability with multiple shot exposures. Such characteristics of the excimer laser system will be extremely useful in micro-machining and other field applications. PMID- 26233362 TI - High-speed quantum-random number generation by continuous measurement of arrival time of photons. AB - We demonstrate a novel high speed and multi-bit optical quantum random number generator by continuously measuring arrival time of photons with a common starting point. To obtain the unbiased and post-processing free random bits, the measured photon arrival time is converted into the sum of integral multiple of a fixed period and a phase time. Theoretical and experimental results show that the phase time is an independent and uniform random variable. A random bit extraction method by encoding the phase time is proposed. An experimental setup has been built and the unbiased random bit generation rate could reach 128 Mb/s, with random bit generation efficiency of 8 bits per detected photon. The random numbers passed all tests in the statistical test suite. PMID- 26233364 TI - Dual-axis vapor cell for simultaneous laser frequency stabilization on disparate optical transitions. AB - We have developed a dual-axis ytterbium (Yb) vapor cell and used it to simultaneously address the two laser cooling transitions in Yb at wavelengths 399 nm and 556 nm, featuring the disparate linewidths of 2pi * 29 MHz and 2pi * 182 KHz, respectively. By utilizing different optical paths for the two wavelengths, we simultaneously obtain comparable optical densities suitable for saturated absorption spectroscopy for both the transitions and keep both the lasers frequency stabilized over several hours. We demonstrate that by appropriate control of the cell temperature profile, two atomic transitions differing in relative strength across a large range of over three orders of magnitude can be simultaneously addressed, making the device adaptable to a variety of spectroscopic needs. We also show that our observations can be understood with a simple theoretical model of the Yb vapor. PMID- 26233363 TI - An array of virtual Frisch-grid CdZnTe detectors and a front-end application specific integrated circuit for large-area position-sensitive gamma-ray cameras. AB - We developed a robust and low-cost array of virtual Frisch-grid CdZnTe detectors coupled to a front-end readout application-specific integrated circuit (ASIC) for spectroscopy and imaging of gamma rays. The array operates as a self-reliant detector module. It is comprised of 36 close-packed 6 * 6 * 15 mm(3) detectors grouped into 3 * 3 sub-arrays of 2 * 2 detectors with the common cathodes. The front-end analog ASIC accommodates up to 36 anode and 9 cathode inputs. Several detector modules can be integrated into a single- or multi-layer unit operating as a Compton or a coded-aperture camera. We present the results from testing two fully assembled modules and readout electronics. The further enhancement of the arrays' performance and reduction of their cost are possible by using position sensitive virtual Frisch-grid detectors, which allow for accurate corrections of the response of material non-uniformities caused by crystal defects. PMID- 26233365 TI - Study of the operation temperature in the spin-exchange relaxation free magnetometer. AB - We study the influence of the cell temperature on the sensitivity of the spin exchange relaxation free (SERF) magnetometer and analyze the possibility of operating at a low temperature. Utilizing a 25 * 25 * 25 mm(3) Cs vapor cell with a heating temperature of 85 degrees C, which is almost half of the value of potassium, we obtain a linewidth of 1.37 Hz and achieve a magnetic field sensitivity of 55 fT/Hz(1/2) in a single channel. Theoretical analysis shows that fundamental sensitivity limits of this device with an active volume of 1 cm(3) could approach 1 fT/Hz(1/2). Taking advantage of the higher saturated vapor pressure, SERF magnetometer based on Cs opens up the possibility for low cost and portable sensors and is particularly appropriate for lower temperature applications. PMID- 26233366 TI - Novel schemes for the optimization of the SPARC narrow band THz source. AB - A pulsed, tunable, narrow band radiation source with frequency in the THz region can be obtained collecting the coherent transition radiation produced by a train of ultra-short electron bunches having picosecond scale inter-distance. In this paper, we review the techniques feasible at the SPARC_LAB test facility to produce and manipulate the requested train of electron bunches and we examine the dynamics of their acceleration and compression. In addition, we show how the performances of the train compression and the radiation intensity and bandwidth can be significantly improved through the insertion of a fourth order harmonic cavity, working in the X-band and acting as a longitudinal phase space linearizer. PMID- 26233367 TI - Design of in-flight fragment separator using high-power primary beams in the energy of a few hundred MeV/u. AB - An in-flight fragment separator usually requires large acceptance and high momentum resolution to minimize the loss of a rare isotope beam of interest produced at a thin target, which is especially important when (238)U fission reactions in the energy of 200 MeV/u are used. The production target and beam dump are located in the pre-separator, where a beam power of up to 400 kW is dissipated. The area is surrounded by thick radiation shielding walls, which result in long drift spaces between adjacent magnetic components at various locations and an asymmetrical layout. Efforts have been made to minimize non linear effects in the pre-separator beam optics with trials of different separator configurations and correction schemes using COSY Infinity and GICOSY. The main separator is configured to be mirror symmetric such that correction with hexapole and octupole coils can be more readily applied. The separator configuration was finalized to allow the facility design to proceed and the key components including superconducting magnets have been designed and prototyped. In addition, the separator design has been evaluated using LISE++ including a set of wedge degraders at dispersive focal planes to improve the yield and purity of selected isotope beam. PMID- 26233368 TI - Microwave induced plasma discharge in multi-cell superconducting radio-frequency cavity. AB - A R&D effort for in situ cleaning of 1.5 GHz Superconducting Radio Frequency (SRF) cavities at room temperature using the plasma processing technique has been initiated at Jefferson Lab. This is a step toward the cleaning of cryomodules installed in the Continuous Electron Beam Accelerator Facility (CEBAF). For this purpose, we have developed an understanding of plasma discharge in a 5-cell CEBAF type SRF cavity having configurations similar to those in the main accelerator. The focus of this study involves the detailed investigations of developing a plasma discharge inside the cavity volume and avoids the breakdown condition in the vicinity of the ceramic RF window. A plasma discharge of the gas mixture Ar O2 (90%:10%) can be established inside the cavity volume by the excitation of a resonant 4pi/5 TM010-mode driven by a klystron. The absence of any external magnetic field for generating the plasma is suitable for cleaning cavities installed in a complex cryomodule assembly. The procedures developed in these experimental investigations can be applied to any complex cavity structure. Details of these experimental measurements and the observations are discussed in the paper. PMID- 26233369 TI - Spark discharge coupled laser multicharged ion source. AB - A spark discharge is coupled to a laser multicharged ion source to enhance ion generation. The laser plasma triggers a spark discharge with electrodes located in front of the ablated target. For an aluminum target, the spark discharge results in significant enhancement in the generation of multicharged ions along with higher charge states than observed with the laser source alone. When a Nd:YAG laser pulse (wavelength 1064 nm, pulse width 7.4 ns, pulse energy 72 mJ, laser spot area on target 0.0024 cm(2)) is used, the total multicharged ions detected by a Faraday cup is 1.0 nC with charge state up to Al(3+). When the spark amplification stage is used (0.1 MUF capacitor charged to 5.0 kV), the total charge measured increases by a factor of ~9 with up to Al(6+) charge observed. Using laser pulse energy of 45 mJ, charge amplification by a factor of ~13 was observed for a capacitor voltage of 4.5 kV. The spark discharge increases the multicharged ion generation without increasing target ablation, which solely results from the laser pulse. This allows for increased multicharged ion generation with relatively low laser energy pulses and less damage to the surface of the target. PMID- 26233370 TI - Generation and diagnostics of pulsed intense ion beams with an energy density of 10 J/cm2. AB - The paper presents the results of a study on transportation and focusing of a pulsed ion beam at gigawatt power level, generated by a diode with explosive emission cathode. The experiments were carried out with the TEMP-4M accelerator operating in double-pulse mode: the first pulse is of negative polarity (500 ns, 100-150 kV), and this is followed by a second pulse of positive polarity (120 ns, 200-250 kV). To reduce the beam divergence, we modified the construction of the diode. The width of the anode was increased compared to that of the cathode. We studied different configurations of planar and focusing strip diodes. It was found that the divergence of the ion beam formed by a planar strip diode, after construction modification, does not exceed 3 degrees (half-angle). Modification to the construction of a focusing diode made it possible to reduce the beam divergence from 8 degrees to 4 degrees -5 degrees , as well as to increase the energy density at the focus up to 10-12 J/cm(2), and decrease the shot to shot variation in the energy density from 10%-15% to 5%-6%. When measuring the ion beam energy density above the ablation threshold of the target material (3.5-4 J/cm(2)), we used a metal mesh with 50% transparency to lower the energy density. The influence of the metal mesh on beam transport has been studied. PMID- 26233372 TI - Design of post linac to driver linac transport beam line in rare isotope accelerator. AB - We investigated the design of a beam transport line connecting the post linac to the driver linac (P2DT) in the Rare Isotope Accelerator (RAON). P2DT beam line is designed by 180 degrees bending scheme to send the radioactive isotope separation on-line (ISOL) beams accelerated in the Linac-3 to Linac-2. The beam line is designed as a 180 degrees bend for the transport of a multi-charge state (132)Sn(+45,+46,+47) beam. We used the TRACE 3-D, TRACK, and ORBIT codes to design the optics system, which also includes two bunchers and ten sextupole magnets for chromaticity compensation. The transverse emittance growth is minimized by adopting mirror symmetric optics and by correcting second-order aberrations using sextupoles. We report on the multi-charge state beam transport performance of the designed beam line. The main characteristics of the P2DT line are to minimize beam loss and the growth of emittance, and for charge stripping. Beam optics for P2DT is optimized for reducing beam loss and charge stripping. As Linac-3 may accelerate the stable beam and radioactive beam simultaneously, P2DT line also transports the stable beam and radioactive beam simultaneously. Thus, we need a RF switchyard to send the stable beam to the ISOL target and the radioactive beam to the high-energy experimental area in Linac-2 end. PMID- 26233371 TI - Beam emittance measurements and simulations of injector line for radio frequency quadrupole. AB - A 400 keV deuteron (D(+)) radio frequency quadrupole (RFQ) accelerator has been designed, built, and commissioned at the Bhabha Atomic Research Centre, India. A beam line has been developed for injecting deuterons into the 400 keV RFQ. This comprises of a RF plasma ion source and a low energy beam transport (LEBT) system, consisting of two solenoid magnets and two steerer magnets. The ion source is characterized in terms of transverse beam emittance. A slit-wire scanner based emittance measurement setup has been developed for the transverse emittance measurements of H(+) and D(+) beams. The measured emittance values are found to be well within the acceptance value for the RFQ. These measured emittance parameters are used to optimize the solenoid fields in LEBT to match the beam from the ion source to RFQ. TRACEWIN simulation code is used for the beam transport simulations. The simulations show 99% transmission of D(+) beam through the RFQ, while 95% transmission has been measured experimentally. PMID- 26233373 TI - Calibration of time of flight detectors using laser-driven neutron source. AB - Calibration of three scintillators (EJ232Q, BC422Q, and EJ410) in a time-of flight arrangement using a laser drive-neutron source is presented. The three plastic scintillator detectors were calibrated with gamma insensitive bubble detector spectrometers, which were absolutely calibrated over a wide range of neutron energies ranging from sub-MeV to 20 MeV. A typical set of data obtained simultaneously by the detectors is shown, measuring the neutron spectrum emitted from a petawatt laser irradiated thin foil. PMID- 26233374 TI - Review and demonstration of ultra-low-emittance photocathode measurements. AB - This paper reports the development of a simple and reliable apparatus for measuring ultra-low emittance, or equivalently the mean transverse energy from cryogenically cooled photocathodes. The existing methods to measure ultra-low emittance from photocathodes are reviewed. Inspired by the available techniques, we have implemented two complementary methods, the waist scan and voltage scan, in one system giving consistent results. Additionally, this system is capable of measuring the emittance at electric fields comparable to those obtained in DC photoinjectors. PMID- 26233375 TI - Rayleigh scattering of linear alkylbenzene in large liquid scintillator detectors. AB - Rayleigh scattering poses an intrinsic limit for the transparency of organic liquid scintillators. This work focuses on the Rayleigh scattering length of linear alkylbenzene (LAB), which will be used as the solvent of the liquid scintillator in the central detector of the Jiangmen Underground Neutrino Observatory. We investigate the anisotropy of the Rayleigh scattering in LAB, showing that the resulting Rayleigh scattering length will be significantly shorter than reported before. Given the same overall light attenuation, this will result in a more efficient transmission of photons through the scintillator, increasing the amount of light collected by the photosensors and thereby the energy resolution of the detector. PMID- 26233376 TI - Enhancement of beam pulse controllability for a single-pulse formation system of a cyclotron. AB - The single-pulse formation technique using a beam chopping system consisting of two types of high-voltage beam kickers was improved to enhance the quality and intensity of the single-pulse beam with a pulse interval over 1 MUs at the Japan Atomic Energy Agency cyclotron facility. A contamination rate of neighboring beam bunches in the single-pulse beam was reduced to less than 0.1%. Long-term purification of the single pulse beam was guaranteed by the well-controlled magnetic field stabilization system for the cyclotron magnet. Reduction of the multi-turn extraction number for suppressing the neighboring beam bunch contamination was achieved by restriction of a beam phase width and precise optimization of a particle acceleration phase. In addition, the single-pulse beam intensity was increased by a factor of two or more by a combination of two types of beam bunchers using sinusoidal and saw-tooth voltage waveforms. Provision of the high quality intense single-pulse beam contributed to improve the accuracy of experiments for investigation of scintillation light time-profile and for neutron energy measurement by a time-of-flight method. PMID- 26233377 TI - Combined hydrogen and lithium beam emission spectroscopy observation system for Korea Superconducting Tokamak Advanced Research. AB - A novel beam emission spectroscopy observation system was designed, built, and installed onto the Korea Superconducting Tokamak Advanced Research tokamak. The system is designed in a way to be capable of measuring beam emission either from a heating deuterium or from a diagnostic lithium beam. The two beams have somewhat complementary capabilities: edge density profile and turbulence measurement with the lithium beam and two dimensional turbulence measurement with the heating beam. Two detectors can be used in parallel: a CMOS camera provides overview of the scene and lithium beam light intensity distribution at maximum few hundred Hz frame rate, while a 4 * 16 pixel avalanche photo-diode (APD) camera gives 500 kHz bandwidth data from a 4 cm * 16 cm region. The optics use direct imaging through lenses and mirrors from the observation window to the detectors, thus avoid the use of costly and inflexible fiber guides. Remotely controlled mechanisms allow adjustment of the APD camera's measurement location on a shot-to-shot basis, while temperature stabilized filter holders provide selection of either the Doppler shifted deuterium alpha or lithium resonance line. The capabilities of the system are illustrated by measurements of basic plasma turbulence properties. PMID- 26233378 TI - Analysis of Wien filter spectra from Hall thruster plumes. AB - A method for analyzing the Wien filter spectra obtained from the plumes of Hall thrusters is derived and presented. The new method extends upon prior work by deriving the integration equations for the current and species fractions. Wien filter spectra from the plume of the NASA-300M Hall thruster are analyzed with the presented method and the results are used to examine key trends. The new integration method is found to produce results slightly different from the traditional area-under-the-curve method. The use of different velocity distribution forms when performing curve-fits to the peaks in the spectra is compared. Additional comparison is made with the scenario where the current fractions are assumed to be proportional to the heights of peaks. The comparison suggests that the calculated current fractions are not sensitive to the choice of form as long as both the height and width of the peaks are accounted for. Conversely, forms that only account for the height of the peaks produce inaccurate results. Also presented are the equations for estimating the uncertainty associated with applying curve fits and charge-exchange corrections. These uncertainty equations can be used to plan the geometry of the experimental setup. PMID- 26233379 TI - Two dimensional triangulation of breakdown in a high voltage coaxial gap. AB - We describe a technique by which magnetic field probes are used to triangulate the exact position of breakdown in a high voltage coaxial vacuum gap. An array of three probes is placed near the plane of the gap with each probe at 90 degrees intervals around the outer (anode) electrode. These probes measure the azimuthal component of the magnetic field and are all at the same radial distance from the cylindrical axis. Using the peak magnetic field values measured by each probe, the current carried by the breakdown channel, and Amperes law we can calculate the distance away from each probe that the breakdown occurred. These calculated distances are then used to draw three circles each centered at the centers of the corresponding magnetic probes. The common intersection of these three circles then gives the predicted azimuthal location of the center of the breakdown channel. Test results first gathered on the coaxial gap breakdown device (240 A, 25 kV, 150 ns) at the University of California San Diego and then on COBRA (1 MA, 1 MV, 100 ns) at Cornell University indicate that this technique is relatively accurate and scales between these two devices. PMID- 26233380 TI - Compact, battery powered, wireless digitizers for in situ data acquisitions in the sino-united spherical tokamak. AB - Potential isolation and long cable drive are very important in acquiring certain signals from tokamak diagnostics. Compact, battery powered, wireless digitizers for in situ data acquisition have been developed and routinely used in the sino united spherical tokamak to solve the problems of isolation and long cables. The wireless digitizers utilize the integrated analog to digital converters and the static random access memory of microcontrollers but transfer data wirelessly. They consist of simple and concise circuits but have considerable performances of 12-16 bit in resolution and 500-1000 kS/s in sample rate. Wireless triggering and energy saving are two major challenges of the wireless digitizers. Wireless transceivers in the data link layer are used as trigger and can reduce the trigger jitters to be smaller than 1 MUs. In order to reduce the energy consumption, the wireless digitizers are waken only when the tokamak is about to discharge. After discharges, they turn to a periodic checking mode with current consumption smaller than 200 MUA. Because of low duty cycle, the wireless digitizers have a battery life of up to four weeks. In general, the wireless digitizers have better performance than normal isolation amplifiers and can greatly simplify the cable connections. They are very suitable for the data acquisition of dangerous and/or susceptible analog signals in tokamaks. PMID- 26233381 TI - Instrument for precision long-term beta-decay rate measurements. AB - We describe an experimental setup for making precision measurements of relative beta-decay rates of (22)Na, (36)Cl, (54)Mn, (60)Co, (90)Sr, (133)Ba, (137)Cs, (152)Eu, and (154)Eu. The radioactive samples are mounted in two automated sample changers that sequentially position the samples with high spatial precision in front of sets of detectors. The set of detectors for one sample changer consists of four Geiger-Muller (GM) tubes and the other set of detectors consists of two NaI scintillators. The statistical uncertainty in the count rate is few times 0.01% per day for the GM detectors and about 0.01% per hour on the NaI detectors. The sample changers, detectors, and associated electronics are housed in a sealed chamber held at constant absolute pressure, humidity, and temperature to isolate the experiment from environmental variations. The apparatus is designed to accumulate statistics over many years in a regulated environment to test recent claims of small annual variations in the decay rates. We demonstrate that absent this environmental regulation, uncontrolled natural atmospheric pressure variations at our location would imprint an annual signal of 0.1% on the Geiger Muller count rate. However, neither natural pressure variations nor plausible indoor room temperature variations cause a discernible influence on our NaI scintillator detector count rate. PMID- 26233382 TI - Battery-powered pulsed high density inductively coupled plasma source for pre ionization in laboratory astrophysics experiments. AB - An electrically floating radiofrequency (RF) pre-ionization plasma source has been developed to enable neutral gas breakdown at lower pressures and to access new experimental regimes in the Caltech laboratory astrophysics experiments. The source uses a customized 13.56 MHz class D RF power amplifier that is powered by AA batteries, allowing it to safely float at 3-6 kV with the electrodes of the high voltage pulsed power experiments. The amplifier, which is capable of 3 kW output power in pulsed (<1 ms) operation, couples electrical energy to the plasma through an antenna external to the 1.1 cm radius discharge tube. By comparing the predictions of a global equilibrium discharge model with the measured scalings of plasma density with RF power input and axial magnetic field strength, we demonstrate that inductive coupling (rather than capacitive coupling or wave damping) is the dominant energy transfer mechanism. Peak ion densities exceeding 5 * 10(19) m(-3) in argon gas at 30 mTorr have been achieved with and without a background field. Installation of the pre-ionization source on a magnetohydrodynamically driven jet experiment reduced the breakdown time and jitter and allowed for the creation of hotter, faster argon plasma jets than was previously possible. PMID- 26233383 TI - Measurement of reflectivity of spherically bent crystals using Kalpha signal from hot electrons produced by laser-matter interaction. AB - In an experiment at the laser facility ECLIPSE of the CELIA laboratory, University of Bordeaux, we measure the reflectivity of spherically bent crystals that are commonly used to investigate the propagation of fast electrons through the Kalpha radiation they generate in matter. The experimental reflectivity compares well with predictions from a ray-tracing code that takes into account the specific geometry, although the crystals seem to suffer from aging problems. PMID- 26233384 TI - A new compact solid-state neutral particle analyser at ASDEX Upgrade: Setup and physics modeling. AB - At ASDEX Upgrade (AUG), a new compact solid-state detector has been installed to measure the energy spectrum of fast neutrals based on the principle described by Shinohara et al. [Rev. Sci. Instrum. 75, 3640 (2004)]. The diagnostic relies on the usual charge exchange of supra-thermal fast-ions with neutrals in the plasma. Therefore, the measured energy spectra directly correspond to those of confined fast-ions with a pitch angle defined by the line of sight of the detector. Experiments in AUG showed the good signal to noise characteristics of the detector. It is energy calibrated and can measure energies of 40-200 keV with count rates of up to 140 kcps. The detector has an active view on one of the heating beams. The heating beam increases the neutral density locally; thereby, information about the central fast-ion velocity distribution is obtained. The measured fluxes are modeled with a newly developed module for the 3D Monte Carlo code F90FIDASIM [Geiger et al., Plasma Phys. Controlled Fusion 53, 65010 (2011)]. The modeling allows to distinguish between the active (beam) and passive contributions to the signal. Thereby, the birth profile of the measured fast neutrals can be reconstructed. This model reproduces the measured energy spectra with good accuracy when the passive contribution is taken into account. PMID- 26233385 TI - Silicon detectors for monitoring neutron beams in n-TOF beamlines. AB - During 2014, the second experimental area (EAR2) was completed at the n-TOF neutron beam facility at CERN (n-TOF indicates neutron beam measurements by means of time of flight technique). The neutrons are produced via spallation, by means of a high-intensity 20 GeV pulsed proton beam impinging on a thick target. The resulting neutron beam covers the energy range from thermal to several GeV. In this paper, we describe two beam diagnostic devices, both exploiting silicon detectors coupled with neutron converter foils containing (6)Li. The first one is based on four silicon pads and allows monitoring of the neutron beam flux as a function of the neutron energy. The second one, in beam and based on position sensitive silicon detectors, is intended for the reconstruction of the beam profile, again as a function of the neutron energy. Several electronic setups have been explored in order to overcome the issues related to the gamma flash, namely, a huge pulse present at the start of each neutron bunch which may blind the detectors for some time. The two devices were characterized with radioactive sources and also tested at the n-TOF facility at CERN. The wide energy and intensity range they proved capable of sustaining made them attractive and suitable to be used in both EAR1 and EAR2 n-TOF experimental areas, where they became immediately operational. PMID- 26233386 TI - A modified Katsumata probe--Ion sensitive probe for measurement in non-magnetized plasmas. AB - A modified Katsumata probe has been developed for measurement of ion velocity distribution function (IVDF) in technological non-magnetized plasmas. A simple construction of the modified Katsumata probe consists of adding a pair of permanent Sm-Co magnets in front of Katsumata probe. A comparative study regarding IVDF measurement in a high power impulse magnetron sputtering system operating in pure argon atmosphere by means of developed modified Katsumata probe and commercially available gridded retarding field analyzer (RFA) has been carried out. A time-resolved measurement of IVDF for two different pressures whilst other plasma conditions have been kept unchanged has revealed that the main advantage of the modified Katsumata probe compared to the RFA consists in significantly smaller angular aperture of entrance orifice of modified Katsumata probe being approximately 15 degrees in comparison with a commercial RFA having angular aperture more than 160 degrees . It leads in much better velocity resolution in measured IVDF since the transversal part of velocity vector is much more suppressed compared to RFA. Furthermore, the modified Katsumata probe less suffers from collisions of ions in the space charge sheath in front or inside of the probe compared to the RFA. PMID- 26233387 TI - Assessment of the accuracy of plasma shape reconstruction by the Cauchy condition surface method in JT-60SA. AB - For the purpose of stable plasma equilibrium control and detailed analysis, it is essential to reconstruct an accurate plasma boundary on the poloidal cross section in tokamak devices. The Cauchy condition surface (CCS) method is a numerical approach for calculating the spatial distribution of the magnetic flux outside a hypothetical surface and reconstructing the plasma boundary from the magnetic measurements located outside the plasma. The accuracy of the plasma shape reconstruction has been assessed by comparing the CCS method and an equilibrium calculation in JT-60SA with a high elongation and triangularity of plasma shape. The CCS, on which both Dirichlet and Neumann conditions are unknown, is defined as a hypothetical surface located inside the real plasma region. The accuracy of the plasma shape reconstruction is sensitive to the CCS free parameters such as the number of unknown parameters and the shape in JT 60SA. It is found that the optimum number of unknown parameters and the size of the CCS that minimizes errors in the reconstructed plasma shape are in proportion to the plasma size. Furthermore, it is shown that the accuracy of the plasma shape reconstruction is greatly improved using the optimum number of unknown parameters and shape of the CCS, and the reachable reconstruction errors in plasma shape and locations of strike points are within the target ranges in JT 60SA. PMID- 26233388 TI - A high time resolution x-ray diagnostic on the Madison Symmetric Torus. AB - A new high time resolution x-ray detector has been installed on the Madison Symmetric Torus (MST) to make measurements around sawtooth events. The detector system is comprised of a silicon avalanche photodiode, a 20 ns Gaussian shaping amplifier, and a 500 MHz digitizer with 14-bit sampling resolution. The fast shaping time diminishes the need to restrict the amount of x-ray flux reaching the detector, limiting the system dead-time. With a much higher time resolution than systems currently in use in high temperature plasma physics experiments, this new detector has the versatility to be used in a variety of discharges with varying flux and the ability to study dynamics on both slow and fast time scales. This paper discusses the new fast x-ray detector recently installed on MST and the improved time resolution capabilities compared to the existing soft and hard x-ray diagnostics. In addition to the detector hardware, improvements to the detector calibration and x-ray pulse identification software, such as additional fitting parameters and a more sophisticated fitting routine are discussed. Finally, initial data taken in both high confinement and standard reversed-field pinch plasma discharges are compared. PMID- 26233389 TI - Velocimetry of cathode particles in a magnetoplasmadynamic thruster discharge plasma. AB - With high-speed imaging, it is possible to directly observe the time-evolution of the macroscopic behavior of the discharge plasma in a magnetoplasmadynamic thruster (MPDT). By utilizing direct high-speed imaging capable of capturing many images over the course of a single discharge, the velocity of the cathode erosion particles can be measured, opening the possibility of a novel, noninvasive technique for discharge plasma flow field velocimetry. In this work, an 8 kA argon MPDT discharge is imaged at 26 173 fps utilizing a 0.9 neutral density filter. The camera is aligned with thruster centerline 4 m downstream of the thruster exit plane. By tracking visible particles appearing in the multiple images, the particle motion in the radial and azimuthal directions is directly imaged. Through the use of traditional techniques in digital particle image velocimetry, the cathode particles emanating from the discharge are measured to have a mean radial velocity of 44.6 +/- 6.0 m/s with a 95% confidence interval and a statistically insignificant azimuthal velocity. The setup and analysis employed permits measurement of the particle velocity in orthogonal direction to the image sensor plane using a single camera. By combining a background removal subtraction technique and knowledge of the optical focal plane, the estimated mean axial velocity of the particles is 1.59 km/s. This investigation ends with a discussion of important factors to consider for future MPDT high-speed imaging particle velocimetry, such as frame-rate, image size, spatial resolution, optics, and data handling selections. PMID- 26233390 TI - Analysis system of submicron particle tracks in the fine-grained nuclear emulsion by a combination of hard x-ray and optical microscopy. AB - Analyses of nuclear emulsion detectors that can detect and identify charged particles or radiation as tracks have typically utilized optical microscope systems because the targets have lengths from several MUm to more than 1000 MUm. For recent new nuclear emulsion detectors that can detect tracks of submicron length or less, the current readout systems are insufficient due to their poor resolution. In this study, we developed a new system and method using an optical microscope system for rough candidate selection and the hard X-ray microscope system at SPring-8 for high-precision analysis with a resolution of better than 70 nm resolution. Furthermore, we demonstrated the analysis of submicron-length tracks with a matching efficiency of more than 99% and position accuracy of better than 5 MUm. This system is now running semi-automatically. PMID- 26233392 TI - Modular apparatus for electrostatic actuation of common atomic force microscope cantilevers. AB - Piezoelectric actuation of atomic force microscope (AFM) cantilevers often suffers from spurious mechanical resonances in the loop between the signal driving the cantilever and the actual tip motion. These spurious resonances can reduce the accuracy of AFM measurements and in some cases completely obscure the cantilever response. To address these limitations, we developed a specialized AFM cantilever holder for electrostatic actuation of AFM cantilevers. The holder contains electrical contacts for the AFM cantilever chip, as well as an electrode (or electrodes) that may be precisely positioned with respect to the back of the cantilever. By controlling the voltages on the AFM cantilever and the actuation electrode(s), an electrostatic force is applied directly to the cantilever, providing a near-ideal transfer function from drive signal to tip motion. We demonstrate both static and dynamic actuations, achieved through the application of direct current and alternating current voltage schemes, respectively. As an example application, we explore contact resonance atomic force microscopy, which is a technique for measuring the mechanical properties of surfaces on the sub micron length scale. Using multiple electrodes, we also show that the torsional resonances of the AFM cantilever may be excited electrostatically, opening the door for advanced dynamic lateral force measurements with improved accuracy and precision. PMID- 26233391 TI - Mega-electron-volt ultrafast electron diffraction at SLAC National Accelerator Laboratory. AB - Ultrafast electron probes are powerful tools, complementary to x-ray free electron lasers, used to study structural dynamics in material, chemical, and biological sciences. High brightness, relativistic electron beams with femtosecond pulse duration can resolve details of the dynamic processes on atomic time and length scales. SLAC National Accelerator Laboratory recently launched the Ultrafast Electron Diffraction (UED) and microscopy Initiative aiming at developing the next generation ultrafast electron scattering instruments. As the first stage of the Initiative, a mega-electron-volt (MeV) UED system has been constructed and commissioned to serve ultrafast science experiments and instrumentation development. The system operates at 120-Hz repetition rate with outstanding performance. In this paper, we report on the SLAC MeV UED system and its performance, including the reciprocal space resolution, temporal resolution, and machine stability. PMID- 26233393 TI - Simultaneous measurement of all thermoelectric properties of bulk materials in the temperature range 300-600 K. AB - Thermoelectric materials can directly convert heat into electrical energy. The characterization of different materials is an important part in thermoelectric materials research to improve their properties. Usually, different methods and setups are combined for the temperature dependent determination of all thermoelectric key quantities - Seebeck coefficient, electrical conductivity, and thermal conductivity. Here, we present a measurement system for the simultaneous determination of all of these quantities plus the direct determination of the figure of merit by means of the Harman method (zT)H in a temperature range from room temperature up to 600 K. A simultaneous measurement saves time and reduces the measurement error, and the change of all material properties can be monitored even for unstable materials. Thermal conductivity measurements are inherently affected by undesired thermal losses, in particular, through radiation at higher temperatures. We show a simple experimental approach to measure radiation losses and correct for those. Comparative measurements on traditional systems show good agreement for all measured quantities. PMID- 26233394 TI - A large electrochemical setup for the anodization of aluminum towards highly ordered arrays of cylindrical nanopores. AB - A new electrochemical setup and the associated procedures for growing ordered anodic aluminum oxide pore arrays on large surfaces are presented. The typical size of the samples is 14 * 14 cm(2). The most crucial experimental parameters that allow for the stabilization of the high-field procedures are a very efficient cooling of sample and electrolyte, as well as the initial ramping up of the voltage at an accurately defined rate. The morphology of the cylindrical, parallel alumina pores is similar to those obtained on smaller scales with standard setups. Our setup facilitates the availability of porous anodic alumina as a template system for a number of applications. PMID- 26233395 TI - Advanced in-situ electron-beam lithography for deterministic nanophotonic device processing. AB - We report on an advanced in-situ electron-beam lithography technique based on high-resolution cathodoluminescence (CL) spectroscopy at low temperatures. The technique has been developed for the deterministic fabrication and quantitative evaluation of nanophotonic structures. It is of particular interest for the realization and optimization of non-classical light sources which require the pre selection of single quantum dots (QDs) with very specific emission features. The two-step electron-beam lithography process comprises (a) the detailed optical study and selection of target QDs by means of CL-spectroscopy and (b) the precise retrieval of the locations and integration of target QDs into lithographically defined nanostructures. Our technology platform allows for a detailed pre-process determination of important optical and quantum optical properties of the QDs, such as the emission energies of excitonic complexes, the excitonic fine structure splitting, the carrier dynamics, and the quantum nature of emission. In addition, it enables a direct and precise comparison of the optical properties of a single QD before and after integration which is very beneficial for the quantitative evaluation of cavity-enhanced quantum devices. PMID- 26233396 TI - 3D printer generated thorax phantom with mobile tumor for radiation dosimetry. AB - This article describes the design, construction, and properties of an anthropomorphic thorax phantom with a moving surrogate tumor. This novel phantom permits detection of dose both inside and outside a moving tumor and within the substitute lung tissue material. A 3D printer generated the thorax shell composed of a chest wall, spinal column, and posterior regions of the phantom. Images of a computed tomography scan of the thorax from a patient with lung cancer provided the template for the 3D printing. The plastic phantom is segmented into two materials representing the muscle and bones, and its geometry closely matches a patient. A surrogate spherical plastic tumor controlled by a 3D linear stage simulates a lung tumor's trajectory during normal breathing. Sawdust emulates the lung tissue in terms of average and distribution in Hounsfield numbers. The sawdust also provides a forgiving medium that permits tumor motion and sandwiching of radiochromic film inside the mobile surrogate plastic tumor for dosimetry. A custom cork casing shields the film and tumor and eliminates film bending during extended scans. The phantom, lung tissue surrogate, and radiochromic film are exposed to a seven field plan based on an ECLIPSE plan for 6 MV photons from a Trilogy machine delivering 230 cGy to the isocenter. The dose collected in a sagittal plane is compared to the calculated plan. Gamma analysis finds 8.8% and 5.5% gamma failure rates for measurements of large amplitude trajectory and static measurements relative to the large amplitude plan, respectively. These particular gamma analysis results were achieved using parameters of 3% dose and 3 mm, for regions receiving doses >150 cGy. The plan assumes a stationary detection grid unlike the moving radiochromic film and tissues. This difference was experimentally observed and motivated calculated dose distributions that incorporated the phase of the tumor periodic motion. These calculations modestly improve agreement between the measured and intended doses. PMID- 26233397 TI - Versatile common instrumentation for optical detection of pH and dissolved oxygen. AB - The recent trend toward use of disposable and miniature bioreactors requires the use of appropriate sensors. pH and dissolved oxygen (DO) are often measured using optical chemical sensors due to their small form factor and convenience in use. These sensors are often interrogated using a specialized opto-electronic transducer that is designed around the optical sensor. In this contribution, we are presenting a new class of opto-electronic transducers that are usable with several different chemical sensors without the need to switch the optics or hardware when changing the type of the chemical sensor. This allows flexibility closer to the lab-grade devices while the size is closer to a dedicated sensor. This versatile instrumentation is capable of seamlessly switching between the pH and DO measurement modes and is capable of auto recognition of the sensor type. The principle of ratiometric fluorescence is used for pH measurements, and that of fluorescence lifetime for DO measurements. An approach to obtain identical calibrations between several devices is also presented. The described hardware constitutes common instrumentation for measuring either pH or DO and has been tested in actual bioprocesses. It has been found adequate for continuous bioprocess monitoring. PMID- 26233398 TI - Readout for intersatellite laser interferometry: Measuring low frequency phase fluctuations of high-frequency signals with microradian precision. AB - Precision phase readout of optical beat note signals is one of the core techniques required for intersatellite laser interferometry. Future space based gravitational wave detectors like eLISA require such a readout over a wide range of MHz frequencies, due to orbit induced Doppler shifts, with a precision in the order of MUrad/?Hz at frequencies between 0.1 mHz and 1 Hz. In this paper, we present phase readout systems, so-called phasemeters, that are able to achieve such precisions and we discuss various means that have been employed to reduce noise in the analogue circuit domain and during digitisation. We also discuss the influence of some non-linear noise sources in the analogue domain of such phasemeters. And finally, we present the performance that was achieved during testing of the elegant breadboard model of the LISA phasemeter, which was developed in the scope of a European Space Agency technology development activity. PMID- 26233399 TI - Determining the microwave coupling and operational efficiencies of a microwave plasma assisted chemical vapor deposition reactor under high pressure diamond synthesis operating conditions. AB - The microwave coupling efficiency of the 2.45 GHz, microwave plasma assisted diamond synthesis process is investigated by experimentally measuring the performance of a specific single mode excited, internally tuned microwave plasma reactor. Plasma reactor coupling efficiencies (eta) > 90% are achieved over the entire 100-260 Torr pressure range and 1.5-2.4 kW input power diamond synthesis regime. When operating at a specific experimental operating condition, small additional internal tuning adjustments can be made to achieve eta > 98%. When the plasma reactor has low empty cavity losses, i.e., the empty cavity quality factor is >1500, then overall microwave discharge coupling efficiencies (eta(coup)) of >94% can be achieved. A large, safe, and efficient experimental operating regime is identified. Both substrate hot spots and the formation of microwave plasmoids are eliminated when operating within this regime. This investigation suggests that both the reactor design and the reactor process operation must be considered when attempting to lower diamond synthesis electrical energy costs while still enabling a very versatile and flexible operation performance. PMID- 26233400 TI - High repetition rate multi-channel source of high-power rf-modulated pulses. AB - This paper presents the results of testing a high voltage pulse generator based on parallel gyromagnetic nonlinear transmission lines filled with saturable ferrite. The generator is capable of producing almost identical stable rf modulated nanosecond high voltage pulses in each of the two, or four, parallel output channels. The output voltage amplitude in each channel can reach -285 or 180 kV, respectively, with a rf modulation depth of up to 60%. Drive pulses were produced as the packets of duration 1-5 s at a pulse repetition frequency of 800 Hz using a driver equipped with all-solid-state switches. Splitting the driver pulse provided electric field strengths in the channels which were below the breakdown field strength of the transmission lines. As a result, the use of nonlinear transmission lines of reduced diameter made it possible to increase the center frequency of the excited rf oscillations to ~2 GHz. PMID- 26233401 TI - A 16 MJ compact pulsed power system for electromagnetic launch. AB - This paper has established a compact pulsed power system (PPS) of 16 MJ for electromagnetic rail gun. The PPS consists of pulsed forming network (PFN), chargers, monitoring system, and current junction. The PFN is composed of 156 pulse forming units (PFUs). Every PFU can be triggered simultaneously or sequentially in order to obtain different total current waveforms. The whole device except general control table is divided into two frameworks with size of 7.5 m * 2.2 m * 2.3 m. It is important to estimate the discharge current of PFU accurately for the design of the whole electromagnetic launch system. In this paper, the on-state characteristics of pulse thyristor have been researched to improve the estimation accuracy. The on-state characteristics of pulse thyristor are expressed as a logarithmic function based on experimental data. The circuit current waveform of the single PFU agrees with the simulating one. On the other hand, the coaxial discharge cable is a quick wear part in PFU because the discharge current will be up to dozens of kA even hundreds of kA. In this article, the electromagnetic field existing in the coaxial cable is calculated by finite element method. On basis of the calculation results, the structure of cable is optimized in order to improve the limit current value of the cable. At the end of the paper, the experiment current wave of the PPS with the load of rail gun is provided. PMID- 26233402 TI - Design of a novel integrated position sensor based on Hall effects for linear oscillating actuator. AB - Linear oscillating actuator provides linear reciprocate motion directly without other auxiliary components, which is suitable for high integration applications in aerospace industry. Accurate position control is essential for linear oscillating motor and relies on concise measurement of mover position. However, most position measurements are dependent on external complicated sensors, which hinders further integration of linear oscillating actuation system. In this paper, a novel position sensing system for linear oscillating actuator based on Hall effects is proposed to achieve accurate and high integration measurement simultaneously. Axial sensing magnetic field with approximately linear relationship with position is created for direct and convenient measurement. Analytical model of sensing magnetic field is set up for optimization and validated by finite element method and experimental results. Finally, sensing magnets are integrated into motor prototype for experiments. Dynamic position results are tested in experiments and prove to be effective and accurate for position sensing with short-stroke. PMID- 26233403 TI - ZnO thin film piezoelectric MEMS vibration energy harvesters with two piezoelectric elements for higher output performance. AB - Zinc oxide (ZnO) thin film piezoelectric microelectromechanical systems (MEMS) based vibration energy harvesters with two different designs are presented. These harvesters consist of a silicon cantilever, a silicon proof mass, and a ZnO piezoelectric layer. Design I has a large ZnO piezoelectric element and Design II has two smaller and equally sized ZnO piezoelectric elements; however, the total area of ZnO thin film in two designs is equal. The ZnO thin film is deposited by means of radio-frequency magnetron sputtering method and is characterized by means of XRD and SEM techniques. These ZnO energy harvesters are fabricated by using MEMS micromachining. The natural frequencies of the fabricated ZnO energy harvesters are simulated and tested. The test results show that these two energy harvesters with different designs have almost the same natural frequency. Then, the output performance of different ZnO energy harvesters is tested in detail. The effects of series connection and parallel connection of two ZnO elements on the load voltage and power are also analyzed. The experimental results show that the energy harvester with two ZnO piezoelectric elements in parallel connection in Design II has higher load voltage and higher load power than the fabricated energy harvesters with other designs. Its load voltage is 2.06 V under load resistance of 1 MOmega and its maximal load power is 1.25 MUW under load resistance of 0.6 MOmega, when it is excited by an external vibration with frequency of 1300.1 Hz and acceleration of 10 m/s(2). By contrast, the load voltage of the energy harvester of Design I is 1.77 V under 1 MOmega resistance and its maximal load power is 0.98 MUW under 0.38 MOmega load resistance when it is excited by the same vibration. PMID- 26233404 TI - A flexible tactile sensor calibration method based on an air-bearing six dimensional force measurement platform. AB - A number of common issues related to the process of flexible tactile sensor calibration are discussed in this paper, and an estimate of the accuracy of classical calibration methods, as represented by a weight-pulley device, is presented. A flexible tactile sensor calibration method that is based on a six dimensional force measurement is proposed on the basis of a theoretical analysis. A high-accuracy flexible tactile sensor calibration bench based on the air bearing six-dimensional force measurement principle was developed to achieve a technically challenging measurement accuracy of 2% full scale (FS) for three dimensional (3D) flexible tactile sensor calibration. The experimental results demonstrate that the accuracy of the air-bearing six-dimensional force measurement platform can reach 0.2% FS. Thus, the system satisfies the 3D flexible tactile sensor calibration requirement of 2% FS. PMID- 26233405 TI - Proof-of-principle demonstration of a virtual flow meter-based transducer for gaseous helium monitoring in particle accelerator cryogenics. AB - A transducer based on a virtual flow meter is proposed for monitoring helium distribution and consumption in cryogenic systems for particle accelerators. The virtual flow meter allows technical and economical constraints, preventing installation of physical instruments in all the needed measurement points, to be overcome. Virtual flow meter performance for the alternative models of Samson [ http://www.samson.de (2015)] and Sereg-Schlumberger [ http://www.slb.com/ (2015)] is compared with the standard IEC 60534-2-1 [Industrial-process control valves Part 2-1: Flow capacity-sizing equations for fluid flow under installed conditions (2011), https://webstore.iec.ch/publication/2461], for a large temperature range, for both gaseous and liquid helium phases, and for different pressure drops. Then, the calibration function of the transducer is derived. Finally, the experimental validation for the helium gaseous state on the test station for superconducting magnets in the laboratory SM18 [Pirotte et al., AIP Conf. Proc. 1573, 187 (2014)] at CERN is reported. PMID- 26233407 TI - Fast and sensitive method for detecting volatile species in liquids. AB - This paper presents a novel apparatus for extracting volatile species from liquids using a "sniffer-chip." By ultrafast transfer of the volatile species through a perforated and hydrophobic membrane into an inert carrier gas stream, the sniffer-chip is able to transport the species directly to a mass spectrometer through a narrow capillary without the use of differential pumping. This method inherits features from differential electrochemical mass spectrometry (DEMS) and membrane inlet mass spectrometry (MIMS), but brings the best of both worlds, i.e., the fast time-response of a DEMS system and the high sensitivity of a MIMS system. In this paper, the concept of the sniffer-chip is thoroughly explained and it is shown how it can be used to quantify hydrogen and oxygen evolution on a polycrystalline platinum thin film in situ at absolute faradaic currents down to ~30 nA. To benchmark the capabilities of this method, a CO-stripping experiment is performed on a polycrystalline platinum thin film, illustrating how the sniffer-chip system is capable of making a quantitative in situ measurement of <1% of a monolayer of surface adsorbed CO being electrochemically stripped off an electrode at a potential scan-rate of 50 mV s(-1). PMID- 26233406 TI - A portable blood plasma clot micro-elastometry device based on resonant acoustic spectroscopy. AB - Abnormal blood clot stiffness is an important indicator of coagulation disorders arising from a variety of cardiovascular diseases and drug treatments. Here, we present a portable instrument for elastometry of microliter volume blood samples based upon the principle of resonant acoustic spectroscopy, where a sample of well-defined dimensions exhibits a fundamental longitudinal resonance mode proportional to the square root of the Young's modulus. In contrast to commercial thromboelastography, the resonant acoustic method offers improved repeatability and accuracy due to the high signal-to-noise ratio of the resonant vibration. We review the measurement principles and the design of a magnetically actuated microbead force transducer applying between 23 pN and 6.7 nN, providing a wide dynamic range of elastic moduli (3 Pa-27 kPa) appropriate for measurement of clot elastic modulus (CEM). An automated and portable device, the CEMport, is introduced and implemented using a 2 nm resolution displacement sensor with demonstrated accuracy and precision of 3% and 2%, respectively, of CEM in biogels. Importantly, the small strains (<0.13%) and low strain rates (<1/s) employed by the CEMport maintain a linear stress-to-strain relationship which provides a perturbative measurement of the Young's modulus. Measurements of blood plasma CEM versus heparin concentration show that CEMport is sensitive to heparin levels below 0.050 U/ml, which suggests future applications in sensing heparin levels of post-surgical cardiopulmonary bypass patients. The portability, high accuracy, and high precision of this device enable new clinical and animal studies for associating CEM with blood coagulation disorders, potentially leading to improved diagnostics and therapeutic monitoring. PMID- 26233408 TI - A new potentiometric SO2 sensor based on Li3PO4 electrolyte film and its response characteristics. AB - A potentiometric SO2 gas sensor based on Li3PO4 solid electrolyte has been developed using Au as the reference electrode and Li2SO4/V2O5 as the sensing electrode. The Li3PO4 film was deposited on Al2O3 substrate by resistance heating evaporation. Two Au films with designed patterns were formed on the Li3PO4 film by micro-fabrication technologies. The sensing electrode covers one electrode partly using thick-film technology. The electromotive force values between the sensing electrode and the reference electrode were measured and various characteristics were studied including sensitivity, response characteristics, and stability and selectivity. According to the results, we conclude that an optimal working temperature of the SO2 sensor is 500 degrees C, the measurement range is 0-100 ppm, the sensitivity is about 32.47 mV/dec, the response and the recovery time is about 5 min and 10 min, respectively. And the stability and the selectivity of the sensor are good, making it have potential in SO2 measurement of living environment. PMID- 26233410 TI - Pasted type distributed two-dimensional fiber Bragg grating vibration sensor. AB - A pasted type distributed two-dimensional fiber Bragg grating (FBG) vibration sensor has been proposed and studied in this paper. The optical fiber is directly considered as an elastomer. The two-dimensional vibration can be separated by subtraction/addition of two FBGs' center wavelength shift. The principle of the sensor as well as numerical simulation and experimental analyses are presented. Experimental results show that the resonant frequencies of the sensor x/y main vibration direction are separately 1300/20.51 Hz, which are consistent with the numerical simulation analysis result. The flat frequency range resides in 10-750 Hz and 3-12 Hz, respectively; dynamic range is 28.63 dB; in the x main vibration direction, the sensor's sensitivity is 32.84 pm/g, with linearity 3.91% in the range of 10-60 m/s(2), while in the y main vibration direction, the sensor's sensitivity is 451.3 pm/g, with linearity 1.92% in the range of 1.5-8 m/s(2). The cross sensitivity is 3.91%. Benefitting from the two dimensional sensing properties, it can be used in distributed two-dimensional vibration measurement. PMID- 26233409 TI - Desktop aligner for fabrication of multilayer microfluidic devices. AB - Multilayer assembly is a commonly used technique to construct multilayer polydimethylsiloxane (PDMS)-based microfluidic devices with complex 3D architecture and connectivity for large-scale microfluidic integration. Accurate alignment of structure features on different PDMS layers before their permanent bonding is critical in determining the yield and quality of assembled multilayer microfluidic devices. Herein, we report a custom-built desktop aligner capable of both local and global alignments of PDMS layers covering a broad size range. Two digital microscopes were incorporated into the aligner design to allow accurate global alignment of PDMS structures up to 4 in. in diameter. Both local and global alignment accuracies of the desktop aligner were determined to be about 20 MUm cm(-1). To demonstrate its utility for fabrication of integrated multilayer PDMS microfluidic devices, we applied the desktop aligner to achieve accurate alignment of different functional PDMS layers in multilayer microfluidics including an organs-on-chips device as well as a microfluidic device integrated with vertical passages connecting channels located in different PDMS layers. Owing to its convenient operation, high accuracy, low cost, light weight, and portability, the desktop aligner is useful for microfluidic researchers to achieve rapid and accurate alignment for generating multilayer PDMS microfluidic devices. PMID- 26233411 TI - Fluidized bed coupled rotary reactor for nanoparticles coating via atomic layer deposition. AB - A fluidized bed coupled rotary reactor has been designed for coating on nanoparticles (NPs) via atomic layer deposition. It consists of five major parts: reaction chamber, dosing and fluidizing section, pumping section, rotary manipulator components, as well as a double-layer cartridge for the storage of particles. In the deposition procedure, continuous fluidization of particles enlarges and homogenizes the void fraction in the particle bed, while rotation enhances the gas-solid interactions to stabilize fluidization. The particle cartridge presented here enables both the fluidization and rotation acting on the particle bed, demonstrated by the analysis of pressure drop. Moreover, enlarged interstitials and intense gas-solid contact under sufficient fluidizing velocity and proper rotation speed facilitate the precursor delivery throughout the particle bed and consequently provide a fast coating process. The cartridge can ensure precursors flowing through the particle bed exclusively to achieve high utilization without static exposure operation. By optimizing superficial gas velocities and rotation speeds, minimum pulse time for complete coating has been shortened in experiment, and in situ mass spectrometry showed the precursor usage can reach 90%. Inductively coupled plasma-optical emission spectroscopy results suggested a saturated growth of nanoscale Al2O3 films on spherical SiO2 NPs. Finally, the uniformity and composition of the shells were characterized by high angle annular dark field-transmission electron microscopy and energy dispersive X ray spectroscopy. PMID- 26233412 TI - Accurate three-dimensional shape and deformation measurement at microscale using digital image correlation. AB - Based on stereomicroscope and three-dimensional (3D) digital image correlation (DIC) method, a non-contact measurement technique is presented to measure the 3D shape and deformation data on miniature specimens and the corresponding microscopic measurement system is developed. A pair of cameras is mounted on a binocular stereo light microscope to acquire pairing micrographs from two different optical paths of a specimen surface spraying with speckle pattern. Considering complex optical paths and high magnification, an accurate equivalent relative calibration method, combining a priori warping functions, is proposed to correct image distortions and optimize the intrinsic and extrinsic parameters of stereomicroscope. Then, a fast one-dimensional synchronous stereo matching method, based on the DIC method and image rectification technique, is proposed to search for discontinuous corresponding points in the pairing micrographs. Finally, the 3D shape is reconstructed from the corresponding points, while the temporal micrographs acquired before and after deformation are employed to determine the full-field deformation. The effectiveness and accuracy of the presented microscale measurement technique are verified by a series of experiments. PMID- 26233413 TI - Time-resolved fast-neutron radiography of air-water two-phase flows in a rectangular channel by an improved detection system. AB - In a previous work, we have demonstrated the feasibility of high-frame-rate, fast neutron radiography of generic air-water two-phase flows in a 1.5 cm thick, rectangular flow channel. The experiments have been carried out at the high intensity, white-beam facility of the Physikalisch-Technische Bundesanstalt, Germany, using an multi-frame, time-resolved detector developed for fast neutron resonance radiography. The results were however not fully optimal and therefore we have decided to modify the detector and optimize it for the given application, which is described in the present work. Furthermore, we managed to improve the image post-processing methodology and the noise suppression. Using the tailored detector and the improved post-processing, significant increase in the image quality and an order of magnitude lower exposure times, down to 3.33 ms, have been achieved with minimized motion artifacts. Similar to the previous study, different two-phase flow regimes such as bubbly slug and churn flows have been examined. The enhanced imaging quality enables an improved prediction of two phase flow parameters like the instantaneous volumetric gas fraction, bubble size, and bubble velocities. Instantaneous velocity fields around the gas enclosures can also be more robustly predicted using optical flow methods as previously. PMID- 26233414 TI - Reliable measurement of the Seebeck coefficient of organic and inorganic materials between 260 K and 460 K. AB - A new experimental setup for reliable measurement of the in-plane Seebeck coefficient of organic and inorganic thin films and bulk materials is reported. The system is based on the "Quasi-Static" approach and can measure the thermopower in the range of temperature between 260 K and 460 K. The system has been tested on a pure nickel bulk sample and on a thin film of commercially available PEDOT: PSS deposited by spin coating on glass. Repeatability within 1.5% for the nickel sample is demonstrated, while accuracy in the measurement of both organic and inorganic samples is guaranteed by time interpolation of data and by operating with a temperature difference over the sample of less than 1 K. PMID- 26233415 TI - Note: Vibration energy harvesting based on a round acoustic fence. AB - An energy harvester based on a round acoustic fence (RAF) has been proposed and studied. The RAF is composed of cylindrical stubs stuck in a circular array on a thin metal plate, which can confine the acoustic energy efficiently. By removing one stub and thus opening a small gap in the RAF, acoustic leakage with larger intensity can be produced at the gap opening. With the vibration source surrounded by the RAF, the energy harvesting at the gap opening has a wide bandwidth and is insensitive to the position of the vibration source. The results may have potential applications in harvesting the energy of various vibration sources in solid structure. PMID- 26233416 TI - Note: Direct piezoelectric effect microscopy. AB - An alternative method for investigating piezoelectric surfaces is suggested, exploiting the direct piezoeffect. The technique relies on acoustic (ultrasonic) excitation of the imaged surface and mapping of the resulting oscillatory electric potential. The main advantages arise from the spatial resolution of the conductive scanning probe microscopy in combination with the relatively large magnitude of the forward piezo signal Upf, which can be of the order of tens of mV even for non-ferroelectric piezoelectric materials. The potency of this experimental strategy is illustrated with measurements on well-crystallized quartz surfaces, where Upf ~ 50 mV, for a piezoelectric coefficient of d33 = - 2.27 * 10(-12) m/V, and applied stress of about T3 ~ 5.7 kPa. PMID- 26233417 TI - Note: Electrochemical etching of cylindrical nanoprobes using a vibrating electrolyte. AB - An electrochemical etching process using a vibrating electrolyte of potassium hydroxide to prepare tungsten cylindrical nanotips is developed. The vibrating electrolyte eases the effects of a diffusion layer and extends the etching area, which aid in the production of cylindrical nanotips. Larger amplitudes and a vibration frequency of 35 Hz are recommended for producing cylindrical nanotips. Nanotips with a tip radius of approximately 43 nm and a conical angle of arctan 0.0216 are obtained. PMID- 26233418 TI - Note: Precise radial distribution of charged particles in a magnetic guiding field. AB - Current high precision beta decay experiments of polarized neutrons, employing magnetic guiding fields in combination with position sensitive and energy dispersive detectors, resulted in a detailed study of the mono-energetic point spread function (PSF) for a homogeneous magnetic field. A PSF describes the radial probability distribution of mono-energetic electrons at the detector plane emitted from a point-like source. With regard to accuracy considerations, unwanted singularities occur as a function of the radial detector coordinate which have recently been investigated by subdividing the radial coordinate into small bins or employing analytical approximations. In this note, a series expansion of the PSF is presented which can numerically be evaluated with arbitrary precision. PMID- 26233419 TI - Note: Radiochemical measurement of fuel and ablator areal densities in cryogenic implosions at the National Ignition Facility. AB - A new radiochemical method for determining deuterium-tritium (DT) fuel and plastic ablator (CH) areal densities (rhoR) in high-convergence, cryogenic inertial confinement fusion implosions at the National Ignition Facility is described. It is based on measuring the (198)Au/(196)Au activation ratio using the collected post-shot debris of the Au hohlraum. The Au ratio combined with the independently measured neutron down scatter ratio uniquely determines the areal densities rhoR(DT) and rhoR(CH) during burn in the context of a simple 1 dimensional capsule model. The results show larger than expected rhoR(CH) values, hinting at the presence of cold fuel-ablator mix. PMID- 26233420 TI - Note: Design and development of wireless controlled aerosol sampling network for large scale aerosol dispersion experiments. AB - Wireless based custom built aerosol sampling network is designed, developed, and implemented for environmental aerosol sampling. These aerosol sampling systems are used in field measurement campaign, in which sodium aerosol dispersion experiments have been conducted as a part of environmental impact studies related to sodium cooled fast reactor. The sampling network contains 40 aerosol sampling units and each contains custom built sampling head and the wireless control networking designed with Programmable System on Chip (PSoCTM) and Xbee Pro RF modules. The base station control is designed using graphical programming language LabView. The sampling network is programmed to operate in a preset time and the running status of the samplers in the network is visualized from the base station. The system is developed in such a way that it can be used for any other environment sampling system deployed in wide area and uneven terrain where manual operation is difficult due to the requirement of simultaneous operation and status logging. PMID- 26233421 TI - Note: Upgrade of electron cyclotron emission imaging system and preliminary results on HL-2A tokamak. AB - The electron cyclotron emission imaging system on the HL-2A tokamak has been upgraded to 24 (poloidally) * 16 (radially) channels based on the previous 24 * 8 array. The measurement region can be flexibly shifted due to the independence of the two local oscillator sources, and the field of view can be adjusted easily by changing the position of the zoom lenses. The temporal resolution is about 2.5 MUs and the achievable spatial resolution is 1 cm. After laboratory calibration, it was installed on HL-2A tokamak in 2014, and the local 2D mode structures of MHD activities were obtained for the first time. PMID- 26233422 TI - Note: Improved technique for ultrashort lasers pulse width stabilization. AB - We have developed an improved pulse width stabilization method based on the second harmonic generation (SHG) technique using the relationship between pulse width, input intensity, and SHG intensity. On the basis of an analysis of the improved method accuracy, we then proposed a novel processing algorithm, which allowed us to increase the accuracy of pulse width stabilization to 1.2%. We applied this method to a picosecond Yb-doped fiber laser, which offers pulse widths ranging from 10 to 14 ps. We have demonstrated, for what is believed to be the first time, pulse width stabilization of this laser with an absolute error of less than 200 fs. PMID- 26233423 TI - Comment on "Calibration-independent measurement of complex permittivity of liquids using a coaxial transmission line" [Rev. Sci. Instrum. 86, 014704 (2015)]. AB - In this letter, we comment on the applicability of the derived characteristic equation (Eq. (7)) in a recently published article of Guoxin [Rev. Sci. Instrum. 86, 014704 (2015)]. To validate our comment, we first derive another characteristic function for determination of complex permittivity of dielectric materials for the configurations considered in the above article using calibration-independent uncorrected S-parameters for transmission-line measurements (coaxial-line, waveguide, free-space, etc). Unlike the characteristic equation in this article, the characteristic equation derived here for determination of the complex permittivity of liquid samples does not require any knowledge about the complex permittivity of plugs, used for holding liquid samples in place. We then performed 3-D full-wave simulations for the measurement configurations presented in Guoxin's article for substantiation of the characteristic equation derived in this letter. PMID- 26233425 TI - Autoimmunity and Immune Dysregulation in Primary Immune Deficiency Disorders. AB - Primary immune deficiencies are often associated with autoimmune disease due to the dysregulation of the immune system as a whole. In many immune deficiencies, lymphocytes may be present but dysfunctional, allowing for the development of excessive autoreactivity and resultant autoimmune disease. Autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy, autoimmune lymphoproliferative syndrome, immunodyregulation polyendocrinopathy enteropathy X linked, IL-10/IL-10 receptor deficiencies, and PLCG2-associated antibody deficiency and immune dysregulation are disorders in which autoimmunity is a hallmark of the clinical disease presentation. In contrast, adaptive and innate immune deficiencies, which are typically defined by their infectious susceptibilities, can be associated with variable rates of autoimmune manifestations, predominantly autoimmune cytopenias. This review describes the immune dysregulation and autoimmune manifestations that may be encountered in various immune deficiencies. PMID- 26233426 TI - Allergen Component Testing in the Diagnosis of Food Allergy. AB - IgE-mediated food allergies are an important public health problem, affecting 5 % of adults and 8 % of children, with numerous studies indicating that the prevalence is increasing. Food allergic reactions can range in severity from mild to severe and life threatening. Accurate diagnosis of food allergy is necessary not only to provide appropriate and potentially life-saving preventive measures but also to prevent unwarranted dietary restrictions. The diagnosis of food allergy has traditionally been based on clinical history and food specific IgE (sIgE) testing, including skin prick testing (SPT), serum tests, or both. These tests tend to be extremely sensitive, but positive test results to foods that are tolerated are common. Studies of allergen component-resolved diagnostics (CRD) show that adjuvant use of this modality may provide a more accurate assessment in the diagnosis of food allergy, though the reported benefits are questionable for a number of major allergens. Furthermore, diagnostic cutoff values have been difficult to determine for allergens where component testing has been demonstrated to be beneficial. PMID- 26233427 TI - The Prevalence of Tree Nut Allergy: A Systematic Review. AB - Tree nuts are one of the most common foods causing acute allergic reactions and nearly all tree nuts have been associated with fatal allergic reactions. Despite their clinical importance, tree nut allergy epidemiology remains understudied and the prevalence of tree nut allergy in different regions of the world has not yet been well characterised. We aimed to systematically review the population prevalence of tree nut allergy in children and adults. We searched three electronic databases (OVID MEDLINE, EMBASE and PubMed) from January 1996 to December 2014. Eligible studies were categorised by age, region and method of assessment of tree nut allergy. Of the 36 studies identified most were in children (n = 24) and from Europe (n = 18), UK (n = 8) or USA (n = 5). Challenge confirmed IgE-mediated tree nut allergy prevalence was less than 2 % (although only seven studies used this gold standard) while probable tree nut allergy prevalence ranged from 0.05 to 4.9 %. Prevalence estimates that included oral allergy syndrome (OAS) reactions to tree nut were significantly higher (8-11.4 %) and were predominantly from Europe. Prevalence of individual tree nut allergies varied significantly by region with hazelnut the most common tree nut allergy in Europe, walnut and cashew in the USA and Brazil nut, almond and walnut most commonly reported in the UK. Monitoring time trends of tree nut allergy prevalence (both overall and by individual nuts) as well as the prevalence of OAS should be considered given the context of the overall recent rise in IgE-mediated food allergy prevalence in the developed world. PMID- 26233428 TI - Molecular Allergy Diagnostics: Analytical Features That Support Clinical Decisions. AB - Application of purified native and recombinant allergenic molecules into IgE antibody assays can improve analytical sensitivity and specificity for selected allergen specificities. They enhance analytical sensitivity by allowing assays to detect IgE antibodies with a lower limit of quantification (LoQ) to missing or poorly represented allergens in diagnostic extracts that are commonly used in vivo and in vitro. Use of selected allergenic molecules can help improve the clinician's prediction of the risk of a serious allergic reaction to stable allergens. They can provide diagnostic information to determine if a provocation challenge (e.g., oral food challenge) is indeed mandatory or not necessarily needed to support the final diagnostic decision. Suspected cross-reactivity based on the clinical history can be adjudicated by analyzing IgE antibodies to allergenic molecules from cross-reactive protein families. Finally, genuine primary sensitization can be identified by IgE antibody responses that are measured to selected allergenic molecules which are present in only one particular allergen source. After allergen-specific IgE detection, careful interpretation is required by the physician who knows the patient's history. Applying single allergen molecules, positive IgE antibody results are still only relevant in the case of corresponding objective symptoms. Subsequently, clinical relevance of such an IgE antibody test result must be determined by the clinician and not by the test itself. Because of their comprehensive nature, allergen extracts will remain the principal allergen source for diagnostic in vivo and in vitro assays of IgE antibody for many years. Judicious use of individual allergenic molecules in serum IgE assays may provide their most cost effective and efficient application for establishing a definitive diagnosis of human allergic disease. PMID- 26233429 TI - Applications of Molecular Diagnostic Testing in Food Allergy. AB - IgE-mediated food allergy is a relevant health problem inducing symptoms ranging from mild local reactions up to severe life-threatening situations. Currently, no immunotherapy is available and avoidance of the incriminating food is the method of choice. Therefore, reliable diagnostic tools to formulate dietary recommendations and to avoid unnecessary exclusion diets for the individual patient are urgently needed. This review provides an update on the current knowledge on food allergens and their application in various diagnostic approaches such as skin prick test, basophil activation test, and serum IgE testing. Furthermore, these new approaches are discussed and compared to conventional extract-based assays and correlated to the gold standard of food allergy diagnosis, the double-blind placebo-controlled food challenge. Finally, the application of food allergens for preventive measurements such as allergen detection assays and the determination of threshold levels for allergen levels are discussed. PMID- 26233431 TI - Neural systems for social cognition: gray matter volume abnormalities in boys at high genetic risk of autism symptoms, and a comparison with idiopathic autism spectrum disorder. AB - Klinefelter syndrome (47, XXY) is associated with several physical, cognitive, and behavioral consequences. In terms of social development, there is an increased risk of autism symptomatology. However, it remains unclear how social deficits are related to abnormal brain development and to what degree underlying mechanisms of social dysfunction in 47, XXY are similar to, or different from, those in idiopathic autism (ASD). This study was aimed at investigating the neural architecture of brain structures related to social information processing in boys with 47, XXY, also in comparison with boys with idiopathic ASD. MRI scans of 16 boys with 47, XXY, 16 with ASD, and 16 nonclinical, male controls were analyzed using voxel-based morphometry (VBM). A region of interest mask containing the superior temporal cortex, amygdala, orbitofrontal cortex (OFC), insular cortex, and medial frontal cortex was used. The Social Responsiveness Scale (SRS) was used to assess degree of autism spectrum symptoms. The 47, XXY group could not be distinguished from the ASD group on mean SRS scores, and their scores were significantly higher than in controls. VBM showed that boys with 47, XXY have significant gray matter volume reductions in the left and right insula, and the left OFC, compared with controls and boys with ASD. Additionally, boys with 47, XXY had significantly less gray matter in the right superior temporal gyrus than controls. These results imply social challenges associated with 47, XXY may be rooted in neural anatomy, and autism symptoms in boys with 47, XXY and boys with ASD might have, at least partially, different underlying etiologies. PMID- 26233430 TI - Eosinophilic Esophagitis and Gastroenteritis. AB - Eosinophilic gastrointestinal disease (EGID) can be classified as eosinophilic esophagitis (EoE) when the eosinophilia is limited to the esophagus or as eosinophilic gastritis (EG) if it is limited to the gastric tract, eosinophilic colitis (EC) if it is limited to the colon, and eosinophilic gastroenteritis (EGE) if the eosinophilia involves one or more parts of the gastrointestinal tract. EoE is by far the most common EGID. It is a well-defined chronic atopic disease due to a T helper type 2 (Th2) inflammation triggered often by food allergens. EoE diagnosis is done if an esophageal biopsy shows at least 15 eosinophils per high power field (eos/hpf). Globally accepted long-term therapies for EoE are the use of swallowed inhaled steroids or food antigen avoidance. The treatment of EoE is done not only to control symptoms but also to prevent complications such as esophageal stricture and food impaction. EGE cause non specific gastrointestinal (GI) symptoms and are diagnosed if esophagogastroduodenoscopy (EGD)/colonoscopy show eosinophilia in one or more parts of the GI tract. They are rare diseases with an unclear pathogenesis, and they are poorly defined in terms of diagnostic criteria and treatment. Before initiating treatment of any EGE, it is imperative to conduct a differential diagnosis to exclude other causes of hypereosinophilia with GI localization. EGE are often poorly responsive to therapy and there is no commonly accepted long term treatment. EG has many characteristics similar to EoE, including the fact that it is often due to a food allergen-driven Th2 inflammation; transcriptome analysis however shows that it is more a systemic disease and has a different gene signature than EoE. EC is a benign form of delayed food allergy in infant and is instead a difficult-to-treat severe inflammatory condition in older children and adults. EC in the latter groups can be a manifestation of drug allergy or autoimmune disease. Overall EGE, EC, and EG are rare and are a diagnosis of exclusion until more common causes of eosinophilia have been excluded. PMID- 26233432 TI - Smaller than expected cognitive deficits in schizophrenia patients from the population-representative ABC catchment cohort. AB - Most neuropsychological studies on schizophrenia suffer from sample selection bias, with male and chronic patients being overrepresented. This probably leads to an overestimation of cognitive impairments. The present study aimed to provide a less biased estimate of cognitive functions in schizophrenia using a population representative catchment area sample. Schizophrenia patients (N = 89) from the prospective Mannheim ABC cohort were assessed 14 years after disease onset and first diagnosis, using a comprehensive neuropsychological test battery. A healthy control group (N = 90) was carefully matched according to age, gender, and geographic region (city, rural surrounds). The present sample was representative for the initial ABC cohort. In the comprehensive neuropsychological assessment, the schizophrenia patients were only moderately impaired as compared to the healthy control group (d = 0.56 for a general cognitive index, d = 0.42 for verbal memory, d = 0.61 for executive functions, d = 0.69 for attention). Only 33 % of the schizophrenia patients scored one standard deviation unit below the healthy control group in the general cognitive index. Neuropsychological performance did not correlate with measures of the clinical course including age at onset, number of hospital admissions, and time in paid work. Thus, in this population-representative sample of schizophrenia patients, neuropsychological deficits were less pronounced than expected from meta-analyses. In agreement with other epidemiological studies, this suggests a less devastating picture of cognition in schizophrenia. PMID- 26233433 TI - MAP1B and NOS1 genes are associated with working memory in youths with attention deficit/hyperactivity disorder. AB - Diverse efforts have been done to improve the etiologic understanding of mental disorders, such as attention-deficit/hyperactivity disorder (ADHD). It becomes clear that research in mental disorders needs to move beyond descriptive syndromes. Several studies support recent theoretical models implicating working memory (WM) deficits in ADHD complex neuropsychology. The aim of this study was to examine the association between rs2199161 and rs478597 polymorphisms at MAP1B and NOS1 genes with verbal working memory in children and adolescents with ADHD. A total of 253 unrelated ADHD children/adolescents were included. The sample was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria. Digit Span from the Wechsler Intelligence Scale for Children-Third Edition was used to assess verbal WM. The raw scores from both forward and backward conditions of Digit Span were summed and converted into scaled scores according to age. The means of scaled Digit Span were compared according to genotypes by ANOVA. Significant differences in Digit Span scores between MAP1B genotype groups (rs2199161: F = 5.676; p = 0.018) and NOS1 (rs478597: F = 6.833; p = 0.009) genes were detected. For both polymorphisms, the CC genotype carriers showed a worse performance in WM task. Our findings suggest possible roles of NOS1 and MAP1B genes in WM performance in ADHD patients, replicating previous results with NOS1 gene in this cognitive domain in ADHD children. PMID- 26233434 TI - Design, synthesis and biological characterization of selective LIMK inhibitors. AB - Inhibitors of LIM kinases are considered of interest for several indications, including elevated intraocular pressure (IOP), cancer, or infection by HIV-1. LX 7101 (Lexicon Pharmaceuticals) was advanced to Phase-I clinical trials as an IOP lowering agent for treatment of glaucoma. We here discuss the design, synthesis and evaluation of LIMK inhibitors based on a pyrrolopyrimidine scaffold, which represent close analogs of LX-7101. Exploration of structure-activity relationships revealed that many of such compounds, including LX-7101, cause potent inhibition of LIMK1 and LIMK2, and also ROCK2 and PKA. Molecular variations around the various structural elements of LX-7101 were attempted. Substitution on position 6 of the pyrrolopyrimidine scaffold led to the identification of LX-7101 analogs displaying good selectivity versus ROCK, PKA and Akt. PMID- 26233435 TI - Synthesis of sulfonamides incorporating piperazinyl-ureido moieties and their carbonic anhydrase I, II, IX and XII inhibitory activity. AB - By using SLC-0111 (4-fluorophenylureido-benzenesulfonamide), a sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in Phase I clinical trials as an antitumor agent as lead molecule, a series of benzenesulfonamide derivatives incorporating ureido moieties was synthesized. The new compounds contain a 4-N substituted piperazine fragment in which the ureido linker has been included, and were tested as inhibitors of the cytosolic human (h) hCA I and II isoforms, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. Depending on the substitution pattern at the piperazine ring, low nanomolar inhibitors were detected against all four isoforms, making the new class of sulfonamides of interest for various pharmacologic applications. PMID- 26233436 TI - Psychometric properties of the RCMAS-2 in pediatric cancer patients. AB - PURPOSE OF THE RESEARCH: The Revised Children's Manifest Anxiety Scale, second edition (RCMAS-2) is widely used internationally to assess anxiety. However, there is little data regarding its validity for pediatric cancer patients. This study evaluated the psychometric properties of the RCMAS-2 in pediatric cancer patients. METHODS AND SAMPLE: This cross-sectional study included 370 pediatric cancer patients (aged 6-19 years) that were recruited from three medical centers between August 2008 and March 2011 in Taiwan. Reliability was evaluated by internal consistency. Confirmatory factor analysis was performed to examine the factor structure. Construct validity was examined by known-groups analyses. KEY RESULTS: The internal consistency of the full scale was good (alpha = 0.90) but the scores of Physiological Anxiety subscale was low (alpha = 0.65). Using known groups validity, significant differences in anxiety were observed between genders and between patients that were on and off treatment. The hypothesized three factor model did not adequately fit (chi(2)/d.f = 2.4; p < 0.01, GFI = 0.80, CFI = 0.71, RMSEA = 0.06, SRMR = 0.01). CONCLUSIONS: The RCMAS-2 demonstrated reliability and validity for use with pediatric cancer patients aged 6 and 19 years. Further structure evaluation of the RCMAS-2 in pediatric oncology population is needed, and the scores of the Physiological Anxiety subscale should be interpreted with caution. PMID- 26233437 TI - Clostridium difficile Diarrhea in the Elderly: Current Issues and Management Options. AB - Clostridium difficile infection (CDI) is the most common cause of infectious diarrhea in healthcare settings. Along with antimicrobial exposure, advanced age has been shown to be a significant risk factor for the development and recurrence of, and mortality from, CDI. The substantial burden of CDI in the elderly may be related to frequent healthcare exposure, the necessity for more medications, altered intestinal microbiota, and complicated comorbidities. A diagnosis of CDI is based on evidence of toxin, or the C. difficile organism itself, in a stool sample in the presence of clinical signs and symptoms. Only symptomatic patients should be tested for CDI, and routine surveillance or repeat testing on asymptomatic patients as a test of cure is discouraged. Antibiotic discontinuation alone can improve or resolve CDI in some patients, and concomitant use of antibiotics is associated with decreased response to CDI treatment. Metronidazole, vancomycin, and fidaxomicin are the therapeutic agents currently available for CDI, with the selection of these agents being based on disease severity, history of recurrence, and cost. The recurrence rate after initial treatment is 20-30%. The first recurrence can be treated with the same therapeutic agent and, for subsequent recurrences, vancomycin in a tapered and/or pulsed regimen is recommended. Fecal microbiota transplantation has shown remarkable effectiveness for recurrent anti-refractory CDI, although caution is advised in treating immunocompromised hosts and those with toxic megacolon. C. difficile can be transmitted directly and indirectly via contact with patients or their environment; therefore, isolation precautions should be initiated at the first suspicion of CDI. C. difficile spores can survive for a long time on environmental surfaces, and the patient's room and all equipment used in the room should be disinfected. In order to manage CDI in the elderly, timely diagnosis, appropriate treatment based on severity of illness, and effective infection control are essential. PMID- 26233439 TI - Bootstrap study of genome-enabled prediction reliabilities using haplotype blocks across Nordic Red cattle breeds. AB - This study compared the accuracy of genome-enabled prediction models using individual single nucleotide polymorphisms (SNP) or haplotype blocks as covariates when using either a single breed or a combined population of Nordic Red cattle. The main objective was to compare predictions of breeding values of complex traits using a combined training population with haplotype blocks, with predictions using a single breed as training population and individual SNP as predictors. To compare the prediction reliabilities, bootstrap samples were taken from the test data set. With the bootstrapped samples of prediction reliabilities, we built and graphed confidence ellipses to allow comparisons. Finally, measures of statistical distances were used to calculate the gain in predictive ability. Our analyses are innovative in the context of assessment of predictive models, allowing a better understanding of prediction reliabilities and providing a statistical basis to effectively calibrate whether one prediction scenario is indeed more accurate than another. An ANOVA indicated that use of haplotype blocks produced significant gains mainly when Bayesian mixture models were used but not when Bayesian BLUP was fitted to the data. Furthermore, when haplotype blocks were used to train prediction models in a combined Nordic Red cattle population, we obtained up to a statistically significant 5.5% average gain in prediction accuracy, over predictions using individual SNP and training the model with a single breed. PMID- 26233438 TI - Utility of the combination of DAT SPECT and MIBG myocardial scintigraphy in differentiating dementia with Lewy bodies from Alzheimer's disease. AB - PURPOSE: (123)I-2beta-Carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ((123)I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT SPECT) and (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy can be used to assist in the diagnosis of patients with dementia with Lewy bodies (DLB). We compared the diagnostic value of these two methods in differentiating DLB from Alzheimer's disease (AD). Furthermore, we evaluated whether a combination of DAT SPECT and MIBG myocardial scintigraphy would provide a more useful means of differentiating between DLB and AD. METHODS: Patients with AD (n = 57) and patients with DLB (n = 76) who underwent both DAT SPECT and MIBG myocardial scintigraphy were enrolled. The sensitivity, specificity, and accuracy of both methods as well as their combination for differentiating DLB from AD were calculated. Moreover, we examined whether symptoms of the patients with DLB were associated with the patterns of the abnormalities displayed on DAT SPECT and MIBG myocardial scintigraphy. RESULTS: The sensitivity and specificity of differentiating DLB from AD were 72.4 and 94.4 % by the heart to mediastinum ratio of MIBG uptake, 88.2 and 88.9 % by the specific binding ratio on DAT SPECT, and 96.1 and 90.7 % by their combination, respectively. The combined use of DAT SPECT and MIBG myocardial scintigraphy enabled more accurate differentiation between DLB and AD compared with either DAT SPECT or MIBG myocardial scintigraphy alone. There was a significantly higher frequency of parkinsonism in the abnormal DAT SPECT group than the normal DAT SPECT group. On the other hand, there was a higher frequency of the appearance of rapid eye movement (REM) sleep behavior disorder in the abnormal MIBG uptake group than the normal MIBG uptake group. CONCLUSION: These results suggested that using a combination of these scintigraphic methods is a useful and practical approach to differentiate DLB from AD. PMID- 26233440 TI - Characterization of peripartum rumination and activity of cows diagnosed with metabolic and uterine diseases. AB - The objectives of the current experiment were to characterize the correlation among total serum Ca, nonesterified fatty acids (NEFA), beta-hydroxybutyrate (BHBA), and haptoglobin concentrations and daily rumination time (DRT) and activity of periparturient cows and to determine the association between periparturient events and peripartum DRT and activity. Holstein animals (nulliparous = 77, parous = 219) were enrolled in the experiment approximately 21 d before expected calving date. Cows were fitted with individual Heat Rumination Long Distance collars (HRLD, SCR Engineers Ltd., Netanya, Israel) from enrollment until approximately 21 +/- 3 d postpartum. Blood samples collected weekly from enrollment to 21 d postpartum were used to determine concentrations of NEFA, BHBA, and haptoglobin. Blood samples collected within 72 h after calving were used to determine total serum Ca concentration. Subclinical ketosis was characterized by BHBA > 1,000 umol/L in any sample, and subclinical hypocalcemia was characterized by Ca < 8.55 ng/dL within 72 h after calving. Cows were examined 1, 7 +/- 3, and 14 +/- 3 d postpartum for diagnosis of retained fetal membrane and metritis. Total Ca (r = 0.15), NEFA (r = -0.27), and haptoglobin (r = -0.18) concentrations were weakly correlated with DRT. Concentration of BHBA (r = -0.14) was weakly correlated with activity. Postpartum DRT was reduced among cows that delivered twins compared with cows that delivered singletons (437.9 +/- 4.8 vs. 385.9 +/- 17.1 min/d). Prepartum (465.8 +/- 4.1 vs 430.8 +/- 14.9 arbitrary units) and postpartum (536.5 +/- 5.5 vs. 480.3 +/- 19.4 arbitrary units) activity were reduced among cows that delivered twins compared with cows that delivered singletons. Delivery of stillborn calves was associated with reduced DRT prepartum (478.0 +/- 5.9 vs. 417.0 +/- 23.4 min/d) and postpartum (437.2 +/- 4.8 vs. 386.5 +/- 19.3 min/d). On the other hand, cows delivering stillborn calves had increased activity prepartum compared with cows delivering live calves (499.3 +/- 16.2 vs. 461.3 +/- 4.1 arbitrary unit). Occurrence of retained fetal membrane tended to and was associated with reduced prepartum (444.3 +/- 11.0 vs. 466.5 +/- 4.3 arbitrary unit) and postpartum (488.2 +/- 14.5 vs. 538.8 +/- 5.7 arbitrary unit) activity, respectively. Cows diagnosed with metritis had reduced postpartum DRT (415.9 +/- 10.1 vs. 441.0 +/- 5.2 min/d) and activity (512.5 +/- 11.5 vs. 539.2 +/- 6.0 arbitrary unit). Postpartum activity was reduced among cows that were diagnosed with subclinical ketosis (502.20 +/- 16.5 vs. 536.6 +/- 6.2 arbitrary unit). Although differences in DRT and activity between populations of cows that developed periparturient diseases and healthy cows were observed, further experiments are necessary to determine how DRT and activity data may be used to precociously diagnose individuals that will develop such periparturient diseases. PMID- 26233441 TI - Cooling cows efficiently with sprinklers: Physiological responses to water spray. AB - Dairies in the United States commonly cool cattle with sprinklers mounted over the feed bunk that intermittently spray the cows' backs. These systems use potable water-an increasingly scarce resource--but there is little experimental evidence about how much is needed to cool cows or about droplet size, which is thought to affect hair coat penetration. Our objectives were to determine how sprinkler flow rate and droplet size affect physiological measures of heat load in a hot, dry climate, and to evaluate cooling effectiveness against water use. The treatments were an unsprayed control and 6 soaker nozzles that delivered four 3-min spray applications of 0.4, 1.3, or >= 4.5 L/min (with 2 droplet sizes within each flow rate) and resulting in 30 to 47% of spray directly wetting each cow. Data were collected from high-producing lactating Holsteins (n = 19) tested individually in ambient conditions (air temperature = 31.2 +/- 3.8 degrees C, mean +/- standard deviation). Cows were restrained in headlocks for 1h and received 1 treatment/d for 3d each, with order of exposure balanced in a crossover design. When cows were not sprayed, physiological measures of heat load increased during the 1-h treatment. All measures responded rapidly to spray: skin temperature decreased during the first water application, and respiration rate and body temperature did so before the second. Droplet size had no effect on cooling, but flow rate affected several measures. At the end of 1h, 0.4 L/min resulted in lower respiration rate and skin temperature on directly sprayed body parts relative to the control but not baseline values, and body temperature increased to 0.2 degrees C above baseline. When 1.3 or >= 4.5 L/min was applied, respiration rate was lower than the control and decreased relative to baseline, and body temperature stayed below baseline for at least 30 min after treatment ended. The treatment that best balanced cooling effectiveness against water usage was 1.3 L/min: although >= 4.5 L/min reduced respiration rate relative to baseline by 4 more breaths/min than 1.3 L/min did (-13 vs. -9 breaths/min, respectively), each additional liter of water decreased this measure by only <= 0.1 breaths/min (<= 1% of the total reduction achieved using 1.3 L/min). We found similar water efficiency patterns for skin temperature and the amount of time that body temperature remained below baseline after treatment ended. Thus, when using this intermittent spray schedule in a hot, dry climate, applying at least 1.3 L/min improved cooling, but above this, additional physiological benefits were relatively minor. PMID- 26233442 TI - Late-gestation heat stress abatement on performance and behavior of Holstein dairy cows. AB - The objective of this study was to evaluate cooling to lessen the effects of heat stress during the last 3 wk of gestation on performance and behavior of multiparous Holstein cows. Twenty nonlactating cows were randomly assigned to treatments approximately 21 d before their expected calving date based on mature equivalent milk production and parity. Treatments were only imposed during the last 3 wk of gestation and included heat stress (HT; n=10) and cooling (CL; n=10), both under a similar photoperiod (14 h of light and 10 h of dark). Dry cows were housed in a sand-bedded stall with the stall areas for CL cows equipped with sprinklers and fans that were on from 0700 to 1900 h, whereas those for the HT cows were not. After parturition, all cows were housed in a barn with cooling devices. Rectal temperatures were measured daily at 1400 h and respiration rates were recorded by counting the flank movements for 1 min at 1500 h on odd days over the last 3 wk of gestation to calving. Daily dry matter intake was measured from -21 d relative to expected calving to 21 d after calving and milk production was recorded daily up to 180 d in milk. Behavioral changes of dry cows were studied continuously for 24 h at -10 d relative to expected calving. The average temperature-humidity index during the last 3 wk of gestation was 69.7 and was not significantly different between treatments. Heat-stressed cows exhibited greater rectal temperatures (39.5 vs. 39.2 degrees C), greater respiration rates (70.4 vs. 63.3 breaths/min), and decreased dry matter intake (13.7 vs. 15.5 kg/d) compared with CL cows. Compared with HT cows, CL cows produced more milk during 180 d in milk (40.5 vs. 44.6 kg/d). Heat stress decreased ruminating (243.2 vs. 282.5 min/d) and chewing times (390.6 vs. 448.7 min/d) at -10 d before calving. The CL cows had shorter standing times than their HT counterparts (390.4 vs. 474.0 min/d). These results confirm that heat stress abatement in the late gestation period improves performance of dairy cows in subsequent lactation. PMID- 26233443 TI - Molecular epidemiology and strain-specific characteristics of Streptococcus agalactiae at the herd and cow level. AB - Host-adaptation of Streptococcus agalactiae subpopulations has been described whereby strains that are commonly associated with asymptomatic carriage or disease in people differ phenotypically and genotypically from those causing mastitis in dairy cattle. Based on multilocus sequence typing (MLST), the most common strains in dairy herds in Denmark belong to sequence types (ST) that are also frequently found in people. The aim of this study was to describe epidemiological and diagnostic characteristics of such strains in relation to bovine mastitis. Among 1,199 cattle from 6 herds, cow-level prevalence of S. agalactiae was estimated to be 27.4% based on PCR and 7.8% based on bacteriological culture. Quarter-level prevalence was estimated at 2.8% based on bacteriological culture. Per herd, between 2 and 26 isolates were characterized by pulsed-field gel electrophoresis (PFGE) and MLST. Within each herd, a single PFGE type and ST predominated, consistent with a contagious mode of transmission or point source infection within herds. Evidence of within-herd evolution of S. agalactiae was detected with both typing methods, although ST belonged to a single clonal complex (CC) per herd. Detection of CC23 (3 herds) was associated with significantly lower approximate count (colony-forming units) at the quarter level and significantly lower cycle threshold value at the cow level than detection of CC1 (2 herds) or CC19 (1 herd), indicating a lower bacterial load in CC23 infections. Median values for the number of infected quarters and somatic cell count (SCC) were numerically but not significantly lower for cows infected with CC23 than for cows with CC1 or CC19. For all CC, an SCC threshold of 200,000 cells/mL was an unreliable indicator of infection status, and prescreening of animals based on SCC as part of S. agalactiae detection and eradication campaigns should be discouraged. PMID- 26233444 TI - Energy content of reduced-fat dried distillers grains with solubles for lactating dairy cows. AB - Eight Holstein and 8 Jersey multiparous, lactating cows were used to complete 56 energy balances to determine the energy content of reduced-fat dried distillers grains with solubles (RFDDGS). A repeated switchback design was used to compare treatments with and without RFDDGS. Diets consisted of 24.2% corn silage, 18.4% alfalfa hay, 6.94% brome hay with either 22.9% rolled corn or 14.8% soybean meal (control), or 8.95% rolled corn, 28.8% RFDDGS, and 0% soybean meal [Co-P; dry matter (DM) basis]. The inclusion of RFDDGS did not affect DM intake, averaging 21.4 +/- 0.53 kg of DM for all cows, but milk production tended to increase from 29.8 to 30.9 +/- 1.46 kg/d for control and Co-P treatments, respectively. Milk fat percentage and energy-corrected milk did not differ between treatments, averaging 4.33 +/- 0.14% and 34.1 kg/d, respectively. Milk protein was significantly decreased by the Co-P treatment (3.56 and 3.41 +/- 0.08% for control and Co-P treatments), but protein yield was not affected. Milk energies were 1.40 Mcal/d greater with Co-P. Energy lost as methane was reduced by 0.31 Mcal/d with the addition of RFDDGS to the diet. Heat loss averaged 29.9 +/- 0.55 Mcal/d and was not different between diets. Average energy retained as tissue energy was -2.99 +/- 0.93 Mcal/d and did not differ between treatments. Intake of digestible and metabolizable energy were not different between the control and Co P treatments, averaging 2.68 and 2.31 Mcal/kg of DM, respectively. The net energy of lactation values of control and Co-P diets were calculated to be 1.43 and 1.47 Mcal/kg of DM, respectively. These energy estimates suggest greater energy content of diets containing RFDDGS than diets containing a mixture of corn and soybean meal in lactating dairy cows. PMID- 26233445 TI - Short communication: Streptococcus canis is able to establish a persistent udder infection in a dairy herd. AB - Bovine mastitis caused by Streptococcus canis is relatively rare. Consequently, many epidemiologic aspects of the infection, including factors that mediate crossing of host species barriers by the pathogen, infectiousness of the microorganism to the mammary gland, and the course of the disease within a herd, are still not elucidated. Therefore, the aim of the present study was to describe results of a 15-mo observation of subclinical Strep. canis mastitis on a dairy farm housing 76 lactating Holstein-Friesian cows. Upon 3 visits to the farm during a period between April 2013 and June 2014, Strep. canis was cultured from milk samples of 17 (22.4% of the herd), 7 (9.6%), and 8 (11.3%) cows, respectively. The isolates obtained were characterized phenotypically by means of the API Strep identification kit (bioMerieux, Marcy l'Etoile, France), as well as genetically by using random amplified polymorphic DNA and macrorestriction analysis of the chromosomal DNA by pulsed-field gel electrophoresis. All strains displayed the same biochemical features, and the molecular methods revealed that the isolates belonged to a single clone or were very closely related. Results of the study indicate that Strep. canis is capable of causing intramammary infections of long duration, behaving in a contagious manner. Because a persistently infected cow may serve as the source of Strep. canis infection for other animals, effective control of this type of udder infection within a herd may require similar measures to those adopted in Streptococcus agalactiae eradication programs. PMID- 26233446 TI - Associations between hepatic metabolism of propionate and palmitate in liver slices from transition dairy cows. AB - Multiparous Holstein cows (n=95) were used to evaluate changes in hepatic propionate and palmitate metabolism and liver composition over time during the transition period, along with the relationships of these variables with cumulative increases in nonesterified fatty acids and beta-hydroxybutyrate during the periparturient period. Data from 3 previous experiments were used to address the study objectives, accounting for a total of 95 multiparous Holstein cows. Liver slices from biopsies on d -21, 1, and 21 relative to parturition were used to determine conversion of [1-(14)C]palmitate to CO2 and esterified products (EP) and the conversion of [1-(14)C]propionate to CO2 and glucose. Hepatic glycogen content was highest on d -21 and was 26.9 and 36.5% of prepartum values on d 1 and 21, respectively. Liver triglyceride content was lowest at d -21 and was 271 and 446% of prepartum values on d 1 and 21, respectively. We detected no difference in the capacity for the liver to oxidize [1-(14)C]palmitate to CO2 between d -21 and d 1; however, on d 21, oxidation was 84% of prepartum values. The capacity of the liver to convert [1-(14)C]palmitate to EP was 148 and 139% of prepartum values on d 1 and 21, respectively. The capacity of liver to convert [1 (14)C]propionate to CO2 was 127 and 83% of prepartum values on d 1 and 21, and the capacity of liver to convert [1-(14)C]propionate to glucose was 126 and 85% of prepartum values on d 1 and 21, respectively. Correlation relationships suggest that overall, cows with elevated prepartum liver triglyceride content had elevated triglycerides throughout the transition period along with increased [1 (14)C]palmitate oxidation and conversion to EP and a decreased propensity to convert [1-(14)C]propionate to glucose. Cows with increased [1-(14)C]propionate oxidation had increased conversion of [1-(14)C]propionate to glucose throughout the transition period. Overall, conditions that lead to impairments in fatty acid metabolism during the transition period appear to be associated with impaired postpartum hepatic propionate metabolism. PMID- 26233447 TI - Effects of partly replacing dietary starch with fiber and fat on milk production and energy partitioning. AB - The effects of partly replacing dietary starch with fiber and fat to provide a diet with similar net energy for lactation (NEL) density on yields of milk and milk components and on energy partitioning were evaluated in a crossover design experiment. Holstein cows (n = 32; 109 +/- 22 d in milk, mean +/- standard deviation) were randomly assigned to treatment sequence. Treatments were a high starch diet containing 33% corn grain (mixture of dry ground and high-moisture corn; HS) or a high-fiber, high-fat diet containing 2.5% palmitic acid-enriched fatty acid (FA) supplement (HFF). Diets contained corn silage, alfalfa silage, and wheat straw as forage sources; HS contained 32% starch, 3.2% FA, and 25% neutral detergent fiber, whereas HFF contained 16% starch, 5.4% FA, and 33% neutral detergent fiber. Compared with HS, the HFF treatment reduced milk yield, milk protein concentration, and milk protein yield, but increased milk fat concentration, milk fat yield, milk energy output, and milk to feed ratio (energy corrected milk/dry matter intake). The HFF treatment reduced the yield of de novo synthesized (< 16-carbon) milk FA and increased the yield of 16-carbon milk FA. Yield of preformed (> 16-carbon) milk FA was not different. The HFF treatment increased plasma concentrations of triglycerides and nonesterified fatty acids, but decreased plasma concentration of insulin. Compared with HS, the HFF treatment reduced body weight gain, change in body condition score, and fat thickness over the rump and rib. Calculated body energy gain, as a fraction of NEL use, was less for HFF than HS, whereas milk energy as a fraction of NEL use was increased for HFF. We concluded that the 2 treatments resulted in similar apparent NEL densities and intakes, but the HS treatment partitioned more energy toward body gain whereas the HFF treatment partitioned more energy toward milk. A high-fiber, high-fat diet might diminish the incidence of over conditioning in mid-lactation cows while maintaining high milk production. PMID- 26233448 TI - Parameterization of a ruminant model of phosphorus digestion and metabolism. AB - The objective of the current work was to parameterize the digestive elements of the model of Hill et al. (2008) using data collected from animals that were ruminally, duodenally, and ileally cannulated, thereby providing a better understanding of the digestion and metabolism of P fractions in growing and lactating cattle. The model of Hill et al. (2008) was fitted and evaluated for adequacy using the data from 6 animal studies. We hypothesized that sufficient data would be available to estimate P digestion and metabolism parameters and that these parameters would be sufficient to derive P bioavailabilities of a range of feed ingredients. Inputs to the model were dry matter intake; total feed P concentration (fPtFd); phytate (Pp), organic (Po), and inorganic (Pi) P as fractions of total P (fPpPt, fPoPt, fPiPt); microbial growth; amount of Pi and Pp infused into the omasum or ileum; milk yield; and BW. The available data were sufficient to derive all model parameters of interest. The final model predicted that given 75 g/d of total P input, the total-tract digestibility of P was 40.8%, Pp digestibility in the rumen was 92.4%, and in the total-tract was 94.7%. Blood P recycling to the rumen was a major source of Pi flow into the small intestine, and the primary route of excretion. A large proportion of Pi flowing to the small intestine was absorbed; however, additional Pi was absorbed from the large intestine (3.15%). Absorption of Pi from the small intestine was regulated, and given the large flux of salivary P recycling, the effective fractional small intestine absorption of available P derived from the diet was 41.6% at requirements. Milk synthesis used 16% of total absorbed P, and less than 1% was excreted in urine. The resulting model could be used to derive P bioavailabilities of commonly used feedstuffs in cattle production. PMID- 26233449 TI - Effects of precalving body condition score and prepartum feeding level on production, reproduction, and health parameters in pasture-based transition dairy cows. AB - Precalving feeding level alters postcalving energy balance, dry matter intake, the liver and adipose tissue transcriptome, hepatic lipidosis, and the risk of metabolic diseases in both high-production cows consuming total mixed rations and moderate-production cows grazing pasture. We hypothesized that the reported benefits of a controlled restriction before calving are dependent on precalving body condition score (BCS): low BCS animals would not benefit from reduced feeding levels precalving, but high BCS cows would have metabolic and immunomodulatory profiles indicative of an improved health status. One hundred sixty-one days before calving, 150 cows were allocated randomly to 1 of 6 treatment groups (n = 25) in a 2 * 3 factorial arrangement: 2 precalving BCS categories (4.0 and 5.0; based on a 10-point scale: BCS4 and BCS5, respectively) and 3 levels of energy intake during the 3 wk preceding calving (75, 100, and 125% of estimated requirements). Cows in the BCS4 and BCS5 groups were managed through late lactation to ensure that target calving BCS was achieved at dry off. Cows were then fed to maintain this BCS target until 3 wk before expected calving date, at which point they were managed within their allotted precalving energy intake treatments by offering different allowances of fresh pasture/cow per day. Milk production, body weight, and BCS were measured weekly; blood was sampled weekly before and after calving and on d 0, 1, 2, 3, and 4 relative to calving. Aspirated plasma was assayed for nonesterified fatty acids, beta-hydroxybutyrate, total protein, albumin, cholesterol, haptoglobin, IL-1beta, IL-6, total antioxidant capacity, and reactive oxygen species. Liver was sampled wk 1, 2, and 4 postcalving for triacylglycerol analysis. Results confirm that precalving BCS and precalving feeding level have both independent and interdependent effects on production and health characteristics of transition dairy cows. Irrespective of precalving BCS, a controlled restriction precalving reduced the net release of nonesterified fatty acids from adipose tissue postpartum and increased plasma calcium concentrations, reducing the risk of milk fever. Fatter cows produced more milk but lost more BCS postcalving and had greater blood beta hydroxybutyrate concentrations and increased hepatic lipidosis. In comparison, after calving, indicators of reduced immune competence were accentuated in BCS4 cows subjected to a feed restriction before calving, probably increasing the risk of infectious diseases. It would appear from these results that optimally conditioned cows will benefit from a short-term (2-3 wk) controlled feed restriction (75-90% of requirements), whereas cows in less than optimal condition should be fed to requirements before calving. PMID- 26233450 TI - Short communication: Arcobacter butzleri and Arcobacter cryaerophilus survival and growth in artisanal and industrial ricotta cheese. AB - Ricotta cheese is a ready-to-eat product with properties (pH >6.0, aw >0.98-0.99) and moisture content (75-80%) that may pose a risk to public health due to postprocess contamination by several bacterial pathogens, including Arcobacters. The objective of the study was to evaluate the behavior of Arcobacter butzleri and Arcobacter cryaerophilus in ricotta cheese during its shelf life assuming postprocessing contamination. Two types of ricotta cheese, artisanal water buffalo (WB) and industrial cow milk ricotta cheese, were experimentally contaminated with A. butzleri and A. cryaerophilus and the count was monitored at 2 different temperatures (6 degrees C and 12 degrees C) during shelf life of 5 d for WB cheese and 22 d for industrial ricotta cheese. In WB ricotta cheese the A. butzleri count remained stable during the 5 d of storage at 6 degrees C, whereas a moderate but significant decrease was observed in A. cryaerophilus count. The counts of both species increased when WB ricotta cheese was stored at 12 degrees C. In industrial ricotta cheese stored at 6 degrees C, a significant reduction was observed both in A. butzleri and A. cryaerophilus counts during the 22-d storage period; at 12 degrees C storage, a count increase was observed for both Arcobacter species up to d 14 of storage after which the log cfu/g count resulted constant until d 22 of storage. The ability of A. butzleri and A. cryaerophilus to survive at 6 degrees C and to grow at 12 degrees C in ricotta cheese has significant food safety implications. PMID- 26233451 TI - A stochastic estimate of the economic impact of oral calcium supplementation in postparturient dairy cows. AB - The objective was to develop stochastic models to estimate the economic impact in the first 30 d in milk of oral calcium supplementation to multiparous postparturient dairy cows using 4 different strategies: (1) supplementation of cows with a high previous lactation mature-equivalent milk yield, (2) supplementation of lame cows, (3) supplementation of both cows that have a high previous lactation mature-equivalent milk yield and cows that are lame, and (4) supplementation of all cows. Data from current literature were used to model input variables associated with the costs and risks related to milk production, postparturient disease, and culling. The mean net herd impact per 1,000 calvings for each of the 4 supplementation strategies was $4,425, $5,812, $8,313, and $3,065, respectively. Postpartum supplementation of multiparous lame cows had the highest return on investment at 6.5 to 1, followed by supplementation of multiparous high milk yield and lame cows, multiparous high milk yield cows only, and supplementation of all multiparous postpartum cows with returns of 1.8 to 1, 1.1 to 1, and 0.3 to 1, respectively. A herd's average milk yield at first test had the highest influence on the net impact of oral calcium supplementation to all multiparous cows and accounted for 30% of the variation, followed by the decrease in risk of health events in lame cows given oral calcium at 22%, a herd's prevalence of lameness at calving at 13%, and the price of milk at 10%. Each of the remaining stochastic variables contributed to less than 5% of the variation in net herd financial impact of oral calcium administration. Whereas supplementation of all postpartum multiparous cows returned a positive net herd impact approximately 80% of the time, if a herd was willing to devote time to mature-equivalent milk yield calculations and locomotion scoring, supplementation of this subpopulation of postpartum cows with oral calcium was estimated to have a positive economic impact in all iterations. Depending on the supplementation strategy chosen and baseline milk yield and immediate postpartum lameness prevalence in a herd, a herd with 1,000 calvings per year can expect to see an average net impact ranging from approximately $3,000 to $8,000 after postpartum supplementation of oral calcium in multiparous animals. PMID- 26233452 TI - Yogurt made from milk heated at different pH values. AB - Milk for yogurt manufacture is subjected to high heat treatment to denature whey proteins. Low milk pH values (<= 6.5) at heating result in most denatured whey proteins becoming associated with casein micelles, whereas high milk pH values (>= 7.0) at heating result in the formation of mostly soluble (nonmicellar) denatured whey protein complexes. There are conflicting reports on the relative importance of soluble and casein-bound whey protein aggregates on the properties of acid gels. Prior studies investigating the effect of pH of milk at heating used model gels in which milk was acidified by glucono-delta-lactone; in this study, we prepared yogurt gels using commercial starter cultures. Model acid gels can have very different texture and physical properties from those made by fermentation with starter cultures. In this study, we investigated the effects of different pH values of milk at heating on the rheological, light backscatter, and microstructural properties of yogurt gels. Reconstituted skim milk was adjusted to pH values 6.2, 6.7, and 7.2 and heated at 85 degrees C for 30 min. A portion of the heated milk samples was readjusted back to pH 6.7 after heating. Milks were inoculated with 3% (wt/wt) yogurt starter culture and incubated at 40 degrees C until pH 4.6. Gel formation was monitored using dynamic oscillatory rheology, and parameters measured included the storage modulus (G') and loss tangent (LT) values. Light-backscattering properties, such as the backscatter ratio (R) and the first derivative of light backscatter ratio (R'), were also monitored during fermentation. Fluorescence microscopy was used to observe gel microstructure. The G' values at pH 4.6 were highest in gels made from milk heated at pH 6.7 and lowest in milk heated at pH 6.2, with or without pH adjustment after heating. The G' values at pH 4.6 were lower in samples after adjustment back to pH 6.7 after heating. No maximum in the LT parameter was observed during gelation for yogurts made from milk heated at pH 6.2; a maximum in LT was observed at pH ~4.8 for samples heated at pH 6.7 or 7.2, with or without pH adjustment after heating. Higher R-values were observed with an increase in pH of heating, with or without pH adjustment after heating. The sample heated at pH 6.2 had only one major peak in its R' profile during acidification, whereas samples heated at pH 6.7 and 7.2 had 2 large peaks. The lack of a maximum in LT parameter and the presence of a single peak in the R' profile for the samples heated at pH 6.2 were likely due to the partial solubilization of insoluble calcium phosphate when milk was acidified to this lower pH value. No clear differences were observed in the microstructures of gels between the different treatments. This study indicates that heating milk at the natural pH (~6.7) created an optimum balance of casein-bound and soluble denatured whey proteins, which resulted in yogurt with the highest gel stiffness. PMID- 26233453 TI - Resource recovery using whey permeate to cultivate Phellinus linteus mycelium: Solid-state and submerged liquid fermentation. AB - The growth characteristics of Phellinus linteus mycelium were assessed and compared under solid-state fermentation (SSF) and submerged liquid fermentation (SLF) systems on whey permeate medium. Response surface methodology was used to investigate the growth rates of mycelia under various conditions of operating temperature (TO), initial pH, and substrate concentration ([S]). The optimal growth conditions of P. linteus mycelium were determined to be 26.1 degrees C, pH 4.6, and 60.3g of lactose/L in the SSF system, and 29.0 degrees C, pH 5.0, and 65.3g of lactose/L in the SLF system. The maximum growth rates were predicted to be 1.92 +/- 0.01 mm/d in SSF and 192.1 +/- 0.0mg/L per day in SLF. Random trials were conducted to experimentally validate the evaluated optimal conditions. The differences between the modeled and observed values were only 5.3% in the SSF system and 6.1% in the SLF system. Significant engineering factors differed between the fermentation techniques; TO was significant in both cultivation systems, whereas initial pH was significant in SSF but [S] was significant in SLF. Our findings can be used to guide the operation of the bioconversion process for cultivating P. linteus mycelium using whey permeate wastewater. PMID- 26233454 TI - Colostrum quality affects immune system establishment and intestinal development of neonatal calves. AB - The first meal of a neonatal calf after birth is crucial for survival and health. The present experiment was performed to assess the effects of colostrum quality on IgG passive transfer, immune and antioxidant status, and intestinal morphology and histology in neonatal calves. Twenty-eight Holstein neonatal male calves were used in the current study, 24 of which were assigned to 1 of 3 treatment groups: those that received colostrum (GrC), transitional milk (GrT, which was obtained after the first milking on 2-3 d after calving), and bulk tank milk (GrB) only at birth. The 4 extra neonatal calves who were not fed any milk were assigned to the control group and were killed immediately after birth to be a negative control to small intestinal morphology and histology detection. Calves in GrC gained more body weight than in GrT, whereas GrB calves lost 0.4 kg compared with the birth weight. Serum total protein, IgG, and superoxide dismutase concentrations were highest in GrC, GrT was intermediate, whereas GrB was the lowest on d 2, 3, and 7. Apparent efficiency of absorption at 48 h, serum complement 3 (C3), and complement 4 (C4) on d 2, 3, and 7 in GrB was low compared with GrC and GrT. On the contrary, malondialdehyde on d 7 increased in GrB. Calves in GrC had better villus length and width, crypt depth, villus height/crypt depth (V/C) value, and mucosal thickness in the duodenum, jejunum, and ileum, whereas GrT calves had lower villus length and width, crypt depth, and mucosal thickness than those fed colostrum. Villi of calves in GrB were nonuniform, sparse, severely atrophied, and apically abscised, and Peyer's patches and hydroncus were detected. Overall, colostrum is the best source for calves in IgG absorption, antioxidant activities, and serum growth metabolites, and promoting intestinal development. The higher quality of colostrum calves ingested, the faster immune defense mechanism and the more healthy intestinal circumstances they established. PMID- 26233455 TI - Hepatic metabolic response of Holstein cows in early and mid lactation is altered by nutrient supply and lipopolysaccharide in vitro. AB - The metabolic response of the liver during periods of inflammation is poorly understood. The objective of this study was to characterize the effects of nutrient supply and lipopolysaccharide (LPS) challenge on hepatic intermediate metabolism of early- and mid-lactation cows by employing gas chromatography-mass spectrometry with stable isotope tracer. Twelve multiparous Holstein-Friesian cows in early (n = 6; 12 +/- 4.2 d in milk) and mid (n = 6; 115 +/- 13.5 d in milk) lactation were used for this study. Liver biopsies were performed on all cows. Liver slices (40-60 mg) were incubated in a 37 degrees C water bath for 2 h with either control (phosphate buffered saline), pyruvate (PYR; 1mM unlabeled pyruvate and 1mM [(13)C3]pyruvate), pyruvate + propionate (PYR+PRO; 1mM unlabeled pyruvate, 1mM [(13)C3]pyruvate, and 2mM sodium propionate), or pyruvate + AA (PYR+AA; 1mM unlabeled pyruvate, 1mM [(13)C3]pyruvate, and 2mM AA solution), and LPS (0.0 or 0.2 MUg/mL) was added to flasks per treatment. Enrichment of isotopomers in metabolic equilibrium with Krebs cycle intermediates was assessed. Pyruvate fluxes and the enzymatic activity of pyruvate carboxylase (PC) versus pyruvate dehydrogenase (PDH) and phosphoenol pyruvate carboxykinase (PEPCK) were calculated. Media were analyzed for concentrations of tumor necrosis factor-alpha (TNF-alpha), glucose, and haptoglobin. Data were analyzed as randomized block (stage of lactation) design in a factorial arrangement of nutrient treatments by LPS dose. Challenge with LPS increased the mRNA abundance of TNF-alpha, haptoglobin, and serum amyloid A 2, and the concentration of TNF-alpha in media. Challenge with LPS increased mRNA abundance of PC but reduced the enrichment of (13)C1[M1] and (13)C2[M2]alanine and tended to reduce the enzymatic activity of PEPCK. Incubation with PYR+PRO and PYR+AA increased the flux of pyruvate to acetyl CoA. However, only PYR+PRO increased the enzymatic activity of PEPCK and PDH versus PC and decreased the mRNA abundance of PC. Cows in early lactation tended to receive a greater contribution of pyruvate to the oxaloacetate flux via the lower PDH versus PC activity and a higher mRNA abundance of PC than cows in mid lactation. Our results suggest that regardless of stage of lactation and nutrient supplement, hepatic gluconeogenesis was impaired during inflammation. Further research examining how various nutrients support liver function and improve the immunometabolic response of liver during inflammation is warranted. PMID- 26233456 TI - Screening of Lactobacillus strains for their ability to produce conjugated linoleic acid in milk and to adhere to the intestinal tract. AB - Conjugated linoleic acid (CLA) has been shown to provide beneficial effects on health; however, the amount consumed in food is far from that required for the desired effects. Thus, increasing the CLA content in dairy foods through milk fermentation with specific lactic acid bacteria (LAB) offers an interesting alternative. Moreover, some LAB may be able to adhere to the intestinal mucosa and produce CLA through endogenous synthesis. Therefore, the objective of this study was to screen LAB isolates for their ability to produce CLA in skim milk and in simulated gastrointestinal conditions. Additionally, the ability of selected CLA-producing LAB to adhere to the intestinal mucosa in a murine model was assessed. Results showed that of 13 strains of Lactobacillus tested, only 4 were able to produce CLA in skim milk supplemented with linoleic acid (13.44 +/- 0.78 to 50.9 +/- 0.26 ug/mL). Furthermore, these 4 Lactobacillus strains were able to survive and produce CLA in simulated gastrointestinal conditions and to adhere to the intestinal mucosa of Wistar rats after 7 d of oral inoculation with fluorescently labeled bacteria. Accordingly, these 4 Lactobacillus strains may be used to manufacture fermented dairy foods to increase CLA content, and consumption of these fermented milks may result in CLA produced endogenously by these LAB. PMID- 26233457 TI - Genomic characteristics of Staphylococcus aureus strains associated with high within-herd prevalence of intramammary infections in dairy cows. AB - Staphylococcus aureus is one of the most important causes of mastitis in dairy cattle. Based on previous research, Staph. aureus genotypes with different pathogenic and contagious properties can cause intramammary infection (IMI) and coexist in the same herd. Our study aimed to compare Staph. aureus strains from herds that differed in IMI prevalence using different molecular approaches such as ribosomal spacer (RS)-PCR, multilocus sequence typing (MLST), spa typing, ribotyping, pulsed-field gel electrophoresis (PFGE), and multiplex PCR. For this purpose, 31 dairy herds with Staph. aureus IMI were selected, and 16 of these were chosen for a comparison study: the 8 high-prevalence (HP) herds had Staph. aureus IMI prevalence >28% and the 8 low-prevalence (LP) herds had an IMI prevalence <4%. A total of 650 isolates of Staph. aureus from mammary quarters of all positive cows were genotyped with RS-PCR, a technique based on amplification of a portion of the intergenic spacer 16S-23S rRNA, and a subset of 54 strains was also analyzed by multiplex PCR, ribotyping, PFGE, MLST, and spa typing. The RS-PCR analysis revealed 12 different profiles. Staphylococcus aureus strains isolated from 5 out of 8 HP herds showed a profile identical to the genotype B (GTB), described in previous studies as being strongly associated with high within-herd prevalence of Staph. aureus mastitis and the presence of the genes coding for enterotoxins sea, sed, and sej, a long x-region of spa gene, and 3 lukE fragments. Moreover, all strains isolated in the HP herds possessed genes coding for staphylococcal enterotoxins. In LP herds, a limited number of strains of 6 genotypes, different from those isolated in HP herds, were identified and GTB was not found. Within these genotypes, 4 strains were positive for the mecA gene. Preliminary results and comparison with other genotyping methods confirmed that genotyping by RS-PCR is an accurate, rapid, and inexpensive tool for future field studies on Staph. aureus mastitis strains and generates clinically relevant results. PMID- 26233458 TI - Application of the Welfare Quality protocol to dairy buffalo farms: Prevalence and reliability of selected measures. AB - Within the general aim of developing a Welfare Quality system for monitoring dairy buffalo welfare, this study focused on prevalence and interobserver reliability of the animal-related variables to be included in the scheme. As most of the measures were developed for cattle, the study also aimed to verify their prevalence for buffaloes. Thirty animal-based measures (22 clinical and 8 behavioral measurements) and 20 terms used for qualitative behavior assessment were assessed in 42 loose-housed buffalo farms. All farms were located in central southern Italy. Two assessors were used (1 male and 1 female). The time needed to record all measures (animal-, resource-, and management-based) was 5.47 +/- 0.48 h (mean +/- SD). Interobserver reliability of animal-based measures was evaluated using Spearman rank correlation coefficient test (rs). If 0.7 is considered as threshold for high interobserver reliability, all animal-based measures were above this level. In particular, most of the coefficients were above 0.85, with higher values observed for prevalence of animals that can be touched (rs = 0.99) and prevalence of animals with iatrogenic abscess (rs = 0.97), whereas lower coefficients were found for the prevalence of vulvar discharge (rs = 0.74) and dewlap edema (rs = 0.73). Twelve out of the 20 terms used for the qualitative behavior assessment reached a satisfactory interobserver reliability (rs = 0.65). Principal component analysis of qualitative behavior assessment scores was conducted for each assessor. Both principal component 1 and principal component 2 showed high interobserver reliability (rs = 0.80 and 0.79, respectively). In addition, relevant proportions of animals were affected by welfare issues specific to buffaloes, such as overgrown claws (median = 34.1%), withers hygroma (median = 13.3%), and vulvar or uterine prolapse (median = 9.3%). We concluded that most of the investigated measures could be reliably included in the final scheme, which can be used as such to monitor buffalo welfare. However, to inform consumers about the welfare status of the animals, the data should be integrated into a single overall assessment of animal welfare, as already performed in the Welfare Quality project for dairy cattle. PMID- 26233459 TI - Animal health and welfare planning improves udder health and cleanliness but not leg health in Austrian dairy herds. AB - Animal health and welfare planning is considered an important tool for herd management; however, its effectiveness is less well known. The aim of this study was to conduct animal health and welfare planning on 34 Austrian dairy farms and to evaluate changes in health and welfare after 1 yr. After an initial assessment using the Welfare Quality protocol (Welfare Quality Consortium, Lelystad, the Netherlands), results were reported back to the farmers. Health and welfare area(s) in which both the farmer and the researcher regarded improvement as important were discussed. Management practices and husbandry measures were chosen according to the respective farm situation. One year after interventions had been initiated, farms were reassessed, and the degree of implementation of improvement measures was recorded. The average implementation rate was 57% and thus relatively high when compared with other studies. High degrees of implementation were achieved related to cleanliness and udder health, at 77 and 63%, respectively. Intervention measures addressing udder health were mostly easy to incorporate in the daily routine and led to a reduced somatic cell score, whereas this score increased in herds without implementation of measures. The decrease in cows with dirty teats was more pronounced when measures were implemented compared with control farms. The implementation rate regarding leg health (46%) was comparably low in the present study, and leg health did not improve even when measures were implemented. Lying comfort, social behavior, and human-animal relationship did not require interventions and were therefore seldom chosen by farmers as part of health and welfare plans. In conclusion, the structured, participatory process of animal health and welfare planning appears to be a promising way to improve at least some animal health and welfare issues. PMID- 26233460 TI - Effect of beta-hydroxybutyric acid, parity, and body condition score on phenotype and proliferative capacity of colostral mononuclear leukocytes of high-yielding dairy cows. AB - In neonatal calves, the ingestion of colostrum is imperative for preventing infectious diseases. Investigations into the transfer of passive immunity of cattle have primarily focused on the importance of colostral immunoglobulins, with a recent increase in focus on understanding the role of colostral leukocytes. The main objective of the present study was to measure the influence of parity, body condition score, serum nonesterified fatty acids, and serum beta hydroxybutyrate concentrations of periparturient cows on phenotype and mitogen- and antigen-induced proliferative capacity of bovine colostral leukocytes. Holstein-Friesian cows (n=141) were intramuscularly vaccinated at 60 and 30 d before the expected parturition date with a tetanus toxoid vaccine. Of these 141 animals, 28 primiparous and 72 multiparous cows were sampled immediately after parturition. Colostrum mononuclear cell populations were identified by flow cytometry using bovine cluster of differentiation markers, and the proliferative capacity of these cells was determined using a (3)H-thymidine proliferation assay. Under-conditioned cows had a significantly higher percentage of colostral macrophages than normal-conditioned animals, whereas over-conditioned cows had significantly more colostral B-lymphocytes. Serum beta-hydroxybutyrate was significantly associated with higher numbers of colostral T-lymphocytes and macrophages. Heifers had significantly higher mitogen- and antigen-induced proliferation of their colostral leukocytes than third parity or older cows. In conclusion, body condition score, parity, and serum beta-hydroxybutyrate concentration of periparturient high-yielding dairy cows were shown to influence the number of colostral macrophages or the mitogen- and antigen-induced proliferation of colostral leukocytes, possibly influencing the cellular immunity of the newborn calf. PMID- 26233461 TI - Quality characteristics and plasmin activity of thermosonicated skim milk and cream. AB - The shelf life of pasteurized milk is limited by heat-stable proteases, which cause gelation and bitter taste upon extended storage of milk. Ultra-high temperature processing inactivates proteases but detrimentally affects milk's sensory quality. An adjunct to pasteurization is desired to extend milk's shelf life while maintaining quality characteristics. In this study, the effects of combined heat and ultrasound (thermosonication) on total plasmin activity and various quality characteristics of skim milk and cream were studied. Thermosonication, at an average power of 115 W (152 ump-p, where p-p=peak-to-peak amplitude) for 3 min, decreased the total plasmin activity (i.e., plasmin- and plasminogen-derived activity) by nearly 94% in fresh skim milk and cream. Enzyme activity in thermosonicated skim milk samples measured at the end of 30 d was 5- to 10-fold higher than on d 0, but remained stable in thermosonicated cream. Descriptive analysis of odor attributes was conducted for up to 4 wk with 8 trained panelists. No significant differences were observed between the intensities of offensive "eggy" and "rubbery" odor attributes of thermosonicated skim milk and pasteurized commercial skim milk and cream. In addition, lightness (L*) values and viscosity were not adversely affected by thermosonication. Thermosonication decreased the fat globule size in skim milk and cream, and the homogenizing effect increased with treatment time. Thermosonication at average powers of 104 W (133 ump-p) and 115 W (152 ump-p) for 1 and 3 min destroyed coliforms and over 99% of the total aerobic bacteria. The total aerobic bacteria counts of thermosonicated skim milk and cream samples were less than 20,000 cfu/mL on d 30. Because thermosonication did not induce off-aromas or viscosity changes but did inactivate microorganisms and protease enzymes, thermosonication may be an appropriate adjunct to pasteurization to extend milk shelf life. PMID- 26233462 TI - Effect of commercial hauling practices and tanker cleaning treatments on raw milk microbiological quality. AB - Consolidation of the US milk industry has led to use of tankers for up to 24 h in between thorough cleanings. As the heavy use of tankers has not been previously studied, the effect of this form of hauling on raw milk quality is unknown. This study focused on the effect of frequent tanker use during hauling on raw milk quality at a commercial facility. Standard tanker use (cleaned-in-place once per 24 h) served as our control and incremental cleaning treatments (water rinse after each load, water rinse after each load with a sanitizer treatment after 12 h, and 12 h of sanitizer treatment) were added to the study to understand if any effect could be mitigated by more frequent cleaning. Producer samples were collected from the farm before loading milk into the tanker as well as sampling the same milk directly out of the tanker truck before unloading at the manufacturer. The study was repeated at 2 different dairy manufacturing facilities, once during the summer and once during the winter. Milk quality was quantified through industry-relevant microbiological tests: individual bacteria count, thermophilic spore count, and preliminary incubation count. Within the study we defined a negative effect on milk quality as a statistically significant difference between the tanker and producer samples in any of the 3 microbial tests conducted between treatments. Results from the study showed no clear effect due to hauling in individual bacteria count, thermophilic spore count, or preliminary incubation counts. There was also no difference in milk quality between the 2 plants, suggesting that neither season nor location affected our results in the standard use variable. As we did not see a negative effect on milk quality in the standard use variable, the addition of cleaning treatments did not appear to provide any clear benefit. Tanker surface swabs and ATP swabs were also used to monitor tanker sanitation and the efficacy of cleaning treatments. Both surface and ATP swabs revealed differences between cleaning efficacy at the 2 facilities. Although the differences in efficacy did not influence tanker milk quality within our study, variability in sanitation may provide a source of contamination that could negatively affect raw milk quality in other areas. Based on this study, current hauling practices appear to be effective in mitigating any measurable effect on raw milk quality; however, further investigation is needed before making industry-wide recommendations. PMID- 26233463 TI - Comparison of the nutritional regulation of milk fat secretion and composition in cows and goats. AB - A study with 2 ruminant species (goats and cows) with inherent differences in lipid metabolism was performed to test the hypothesis that milk fat depression (MFD) due to marine lipid supplements or diets containing high amounts of starch and plant oil is caused by different mechanisms and that each ruminant species responds differently. Cows and goats were allocated to 1 of 3 groups (4 cows and 5 goats per group) and fed diets containing no additional oil (control) or supplemented with fish oil (FO) or sunflower oil and wheat starch (SOS) according to a 3 * 3 Latin square design with 26-d experimental periods. In cows, milk fat content was lowered by FO and SOS (-31%), whereas only FO decreased milk fat content in goats (-21%) compared with the control. Furthermore, FO and SOS decreased milk fat yield in cows, but not in goats. In both species, FO and SOS decreased the secretion of C16 FA output. However, SOS increased milk secretion of >C16 FA in goats. Compared with the control, SOS resulted in similar increases in milk trans-10,cis-12 conjugated linoleic acid (CLA) in both species, but caused a 2-fold larger increase in trans 10 18:1 concentration in cows than for goats. Relative to the control, responses to FO in both species were characterized by a marked decrease in milk concentration of 18:0 (-74%) and cis-9 18:1 (-62%), together with a ~5-fold increase in total trans 18:1, but the proportionate changes in trans-10 18:1 were lower for goats. Direct comparison of animal performance and milk FA responses to FO and SOS treatments demonstrated interspecies differences in mammary lipogenesis, suggesting a lower sensitivity to the inhibitory effects of trans 10,cis-12 CLA in goats and that ruminal biohydrogenation pathways are more stable and less prone to diet-induced shifts toward the formation of trans-10-containing intermediates in goats compared with cows. Even though a direct cause and effect could not be established, results suggest that regulation of milk fat synthesis during FO-induced MFD may be related to a shortage of 18:0 for endogenous mammary cis-9 18:1 synthesis, increase in the incorporation of trans FA in milk triacylglycerols, and limitations in the synthesis of FA de novo to maintain milk fat melting point. However, the possible contribution of biohydrogenation intermediates with putative antilipogenic effects in the mammary gland, including trans-9,cis-11 CLA, trans-10 18:1, or cis-11 18:1 to FO-induced MFD cannot be excluded. PMID- 26233464 TI - Critical Evaluation of the Changes in Glutamine Synthetase Activity in Models of Cerebral Stroke. AB - The following article addresses some seemingly paradoxical observations concerning cerebral glutamine synthetase in ischemia-reperfusion injury. In the brain, this enzyme is predominantly found in astrocytes and catalyzes part of the glutamine-glutamate cycle. Glutamine synthetase is also thought to be especially sensitive to inactivation by the oxygen- and nitrogen-centered radicals generated during strokes. Despite this apparent sensitivity, glutamine synthetase specific activity is elevated in the affected tissues during reperfusion. Given the central role of the glutamine-glutamate cycle in the brain, we sought to resolve these conflicting observations with the view of providing an alternative perspective for therapeutic intervention in stroke. PMID- 26233465 TI - Effects of ATP and NGF on Proliferation and Migration of Neural Precursor Cells. AB - Purinergic receptors belong to the most ancient neurotransmitter system. While their relevance in neurotransmission is well characterized, it has become clear that they have many other cellular functions. During development, they participate in regulation of proliferation and differentiation of stem cells. Here, we used rat embryonic telencephalon neurosphere cultures to detect purinergic P2 receptor subtype expression and possible synergistic actions of these receptors with NGF. Neurospheres proliferate in the presence of EGF and FGF 2; however, upon depletion of these growth factors, they migrate and differentiate into neurons and glial phenotypes. Expression patterns of P2X and P2Y receptors changed along neural differentiation. Gene expression of P2X2-7 and P2Y1,2,4,6,12,14 receptors was confirmed in undifferentiated and neural differentiated neurospheres, with an up-regulation of P2X2 and P2X6 subtypes, together with a down-regulation of P2X4, P2X7 and P2Y subtypes upon induction to differentiation. BrdU-labeling and subsequent flow cytometry analysis was used to measure cell proliferation, which was increased by chronic exposure to NGF and increasing concentrations of ATP, in line with the expression levels of PCNA. Furthermore, a synergistic effect on proliferation was observed in conditions of co-incubation with ATP and NGF. While ATP and NGF independently promoted neural migration, no inter-relation between these factors was detected for this cellular process. As conclusion, an unknown synergism of ATP and NGF in proliferation is described. Future efforts may elucidate the underlying mechanisms of the interrelationship of ATP and NGF during neurogenesis. PMID- 26233466 TI - Vascular Endothelial Growth Factor Enhanced the Angiogenesis Response of Human Umbilical Cord-Derived Mesenchymal Stromal Cells in a Rat Model of Radiation Myelopathy. AB - The present study was designed to examine a synergistic role for VEGF and human umbilical cord-derived MSCs (UC-MSCs) therapy in a rat model of radiation myelopathy. UC-MSCs and VEGF were injected through the tail vein at 90, 97, 104 and 111 days post-irradiation. Behavioral tests were performed, and histological damage was examined. The microcirculation in the spinal cord was assessed using von Willebrand factor immunohistochemical analysis and laser-Doppler flowmetry. The microenvironment in the spinal cord was determined by measuring the pro inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha in the serum and the anti-inflammatory cytokines brain-derived neurotrophic factor and glial cell-derived neurotrophic factor in the spinal cord. The UC-MSCs processed with VEGF, including VEGF165-induced UC-MSC (iUC), VEGF and UC-MSCs (VEGF-UC), increased the endothelial cell density and the microvessel density in the white matter and gray matter of the spinal cord, raised the relative magnitude of spinal cord blood flow compared to UC-MSCs treatment alone. Our data provided the first evidence that vascular endothelial growth factor enhanced the angiogenesis response of human umbilical cord-derived mesenchymal stromal cells in a rat model of radiation myelopathy. PMID- 26233467 TI - [Treatment of Fallot tetralogy with a transannular patch. Six years follow-up]. AB - BACKGROUND: Primary repair of Fallot tetralogy has been performed successfully for the last 45 years. It has low surgical mortality (< 5%), with excellent long term results. However, there are delayed adverse effects: progressive right ventricular dilation and dysfunction, arrhythmia, and sudden death. In our centre, Fallot tetralogy is the most common form of cyanotic congenital heart disease (including transannular patch) and accounts for 7.5% of all cardiovascular surgical procedures. The mid-term follow-up results are reported. MATERIAL AND METHODS: Case series. The study included patients who had complete repair of Fallot tetralogy with transannular patch from January 2000 to December 2009. An analysis was performed on the clinical variables, morbidity and mortality. RESULTS: There were 52 patients in the study, with mean age 4 +/- 2 years. Perioperative mortality in 6 patients, with 5 associated with residual right ventricular obstruction and, 1 associated with further surgery. The survival rate was 88% (46) patients, with a follow-up 75 +/- 26 months. Late morbidity occurred in 14, due to right ventricular dysfunction in 11, recurrent distal obstruction in 2, and residual ventricular septal defect in 1. Associated risk factors were severe pulmonary insufficiency (p=0.001); QRS > 160 ms, p=0.001); cardiothoracic > 0.60 index, (p=0.048), and tricuspid regurgitation (p=0.001). CONCLUSIONS: There was reasonable long-term survival and excellent quality of life after total correction of Fallot tetralogy; however, progressive right ventricular dysfunction requires continuous monitoring, as well as the choice of optimal timing of pulmonary valve replacement. PMID- 26233468 TI - Men, hearts and minds: developing and piloting culturally specific psychometric tools assessing psychosocial stress and depression in central Australian Aboriginal men. AB - PURPOSE: The health inequalities experienced by Aboriginal and Torres Strait Islander Australians are well documented but there are few empirical data outlining the burden, consequences, experience and expression of depressive illness. This paper seeks to address the lack of accessible, culturally specific measures of psychosocial stress, depression or quality of life developed for, and validated within, this population. METHODS: Building on an extensive qualitative phase of research, a psychosocial questionnaire comprising novel and adapted scales was developed and piloted with 189 Aboriginal men across urban and remote settings in central Australia. With a view to refining this tool for future use, its underlying structure was assessed using exploratory factor analysis, and the predictive ability of the emergent psychosocial constructs assessed with respect to depressive symptomatology. RESULTS: The latent structure of the psychosocial questionnaire was conceptually aligned with the components of the a priori model on which the questionnaire was based. Regression modelling indicated that depressive symptoms were driven by a sense of injury and chronic stress and had a non-linear association with socioeconomic position. CONCLUSIONS: This represents the first community-based survey of psychosocial stress and depression in Aboriginal men. It provides both knowledge of, and an appropriate process for, the further development of psychometric tools, including quality of life, in this population. Further research with larger and more diverse samples of Aboriginal people is required to refine the measurement of key constructs such as chronic stress, socioeconomic position, social support and connectedness. The further refinement, validation against criterion-based methods and incorporation within primary care services is essential. PMID- 26233469 TI - A fractographic study of clinically retrieved zirconia-ceramic and metal-ceramic fixed dental prostheses. AB - OBJECTIVES: A recent 3-year randomized controlled trial (RCT) of tooth supported three- to five-unit zirconia-ceramic and metal-ceramic posterior fixed dental prostheses (FDPs) revealed that veneer chipping and fracture in zirconia-ceramic systems occurred more frequently than those in metal-ceramic systems [1]. This study seeks to elucidate the underlying mechanisms responsible for the fracture phenomena observed in this RCT using a descriptive fractographic analysis. METHODS: Vinyl-polysiloxane impressions of 12 zirconia-ceramic and 6 metal ceramic FDPs with veneer fractures were taken from the patients at the end of a mean observation of 40.3+/-2.8 months. Epoxy replicas were produced from these impressions [1]. All replicas were gold coated, and inspected under the optical microscope and scanning electron microscope (SEM) for descriptive fractography. RESULTS: Among the 12 zirconia-ceramic FDPs, 2 had small chippings, 9 had large chippings, and 1 exhibited delamination. Out of 6 metal-ceramic FDPs, 5 had small chippings and 1 had large chipping. Descriptive fractographic analysis based on SEM observations revealed that fracture initiated from the wear facet at the occlusal surface in all cases, irrespective of the type of restoration. SIGNIFICANCE: Zirconia-ceramic and metal-ceramic FDPs all fractured from microcracks that emanated from occlusal wear facets. The relatively low fracture toughness and high residual tensile stress in porcelain veneer of zirconia restorations may contribute to the higher chipping rate and larger chip size in zirconia-ceramic FDPs relative to their metal-ceramic counterparts. The low veneer/core interfacial fracture energy of porcelain-veneered zirconia may result in the occurrence of delamination in zirconia-ceramic FDPs. PMID- 26233472 TI - Access to Clinical Therapeutics. PMID- 26233470 TI - Efficacy of Fluoroquinolone/Probiotic Combination Therapy for Recurrent Urinary Tract Infection in Children: A Retrospective Analysis. AB - PURPOSE: Children with normal urinary tract anatomy and function and highly recurrent urinary tract infection (rUTI) may have a lack of alternatives when antibiotic prophylaxis and "watchful waiting" approaches fail. This retrospective review reports the outcomes in children who received a fluoroquinolone/probiotic combination in an attempt to quantify a reduction in rUTI that was perceived by both clinicians and patients' families. METHODS: Data from all children with rUTIs previously managed with a fluoroquinolone/probiotic combination at the Pediatric Infectious Diseases Clinic at Duke University Medical Center (Durham, North Carolina) were identified and analyzed. FINDINGS: Data from 10 children were eligible for inclusion. Compared with before therapy initiation, total UTI episodes were significantly fewer after therapy initiation (57 vs 4; P = 0.0001). Seven (70%) were free of rUTIs during the follow-up period. Of the 8 patients with known compliance, 7 (88%) were free of rUTIs. IMPLICATIONS: Given the chronic nature of these patients' symptoms, the significant decrease in UTI after the initiation of therapy, and the increase in the interval without an infection and/or its symptoms, this treatment regimen has the potential to improve overall quality of life, decrease antibiotic courses, and decrease health care costs in children with rUTI. These results will be validated with a larger cohort of patients in a prospective, randomized trial. PMID- 26233471 TI - Medication Extraction from Electronic Clinical Notes in an Integrated Health System: A Study on Aspirin Use in Patients with Nonvalvular Atrial Fibrillation. AB - PURPOSE: The purpose of this study was to investigate whether aspirin use can be captured from the clinical notes in a nonvalvular atrial fibrillation population. METHODS: A total of 29,507 patients with newly diagnosed nonvalvular atrial fibrillation were identified from January 1, 2006, through December 31, 2011, and were followed up through December 31, 2012. More than 3 million clinical notes were retrieved from electronic medical records. A training data set of 2949 notes was created to develop a computer-based method to automatically extract aspirin use status and dosage information using natural language processing (NLP). A gold standard data set of 5339 notes was created using a blinded manual review. NLP results were validated against the gold standard data set. The aspirin data from the structured medication databases were also compared with the results from NLP. Positive and negative predictive values, along with sensitivity and specificity, were calculated. FINDINGS: NLP achieved 95.5% sensitivity and 98.9% specificity when compared with the gold standard data set. The positive predictive value was 93.0%, and the negative predictive value was 99.3%. NLP identified aspirin use for 83.8% of the study population, and 70% of the low dose aspirin use was identified only by the NLP method. IMPLICATIONS: We developed and validated an NLP method specifically designed to identify low dose aspirin use status from the clinical notes with high accuracy. This method can be a valuable tool to supplement existing structured medication data. PMID- 26233473 TI - Changing the Management of Paracetamol Poisoning. AB - PURPOSE: The management of paracetamol poisoning was revolutionized after use of acetylcysteine in the 1970s. The protocol used, 3 weight-related infusions, requires almost 24 hours in hospital. It is associated with adverse events in treated patients, particularly anaphylactoid reactions and vomiting. Present treatment nomograms were based on a small series of untreated patients: only 5 of 22 (23%) and 6 of 25 (24%) between the 100 to 200 mg/L and 200 to 300 mg/L nomogram lines, respectively, developed liver injury (alanine transaminase >1000 IU/L). Many patients treated today are unlikely to be at actual risk for major hepatotoxicity. This article discusses the background to future prospects in this area. METHODS: The history behind approaches to the use of acetylcysteine is presented briefly. The rationale for, and key findings of, a new 12-hour antidote regimen for paracetamol poisoning are detailed. Newer markers of hepatotoxicity, such as miR-122, HMGB1, and necrosis K18, which predict patients at risk more reliably and earlier than existing tests, are discussed. FINDINGS: A 2-phase 12 hour acetylcysteine infusion protocol (100 mg/kg over 2 hours: 200 mg/kg over 10 hours) was studied in a formal factorial design against the traditional 3-phase 20.25-hour infusion protocol, with and without pretreatment with ondansetron or placebo. The 12-hour regimen was associated with very significant reductions in anaphylactoid reactions (odds ratio = 0.23; 95% CI, 0.12-0.43; P < 0.0001) and vomiting (odds ratio = 0.37; 95% CI, 0.18-0.79; P = .003) compared with the 20.25 hour infusion protocol. There were few withdrawals from the clinical trial, indicating the feasibility of conducting such studies in Europe. IMPLICATIONS: Novel proteomic markers are better than existing standard tests (alanine transaminase and international normalized ratio) early in the course of paracetamol poisoning. Together with these new biomarkers of hepatotoxicity, a 12 hour acetylcysteine protocol offers clinicians and patients the possibility for better targeting of therapy, fewer adverse effects, a simpler dosing regimen, and shorter hospital stay. PMID- 26233476 TI - CXCL7-induced macrophage infiltration in lung tumor is independent of CXCR2 expression: CXCL7-induced macrophage chemotaxis in LLC tumors. AB - Chemokines play diverse roles in modulating the immune response during tumor development. Levels of CXC chemokine ligand 7 (CXCL7) protein vary during tumorigenesis, and the evidence suggests that this chemokine serves as a novel biomarker of early-stage lung cancer. We investigated the effect of CXCL7 gene expression on the infiltration of myeloid cells into the tumor microenvironment in Lewis lung carcinoma (LLC). Tumors established from LLC cells overexpressing CXCL7 (CXCL7-LLC tumors) increased the infiltration of CD206(+) M2 macrophages at the early stages of tumorigenesis. This infiltration was independent of CXCR2 expression on either tumor cells or macrophages. CXCL7-LLC tumors developed faster than control-LLC tumors (IRES-LLC tumor) did. The extent of CD4(+) T cell, CD8(+) T cell, and natural killer T cell infiltration was similar between the two tumor groups. Our findings suggest that CXCL7 attracts macrophages especially at the tumor site and may accelerate lung tumor development in the early stages. PMID- 26233474 TI - Function of insulin in snail brain in associative learning. AB - Insulin is well known as a hormone regulating glucose homeostasis across phyla. Although there are insulin-independent mechanisms for glucose uptake in the mammalian brain, which had contributed to a perception of the brain as an insulin insensitive organ for decades, the finding of insulin and its receptors in the brain revolutionized the concept of insulin signaling in the brain. However, insulin's role in brain functions, such as cognition, attention, and memory, remains unknown. Studies using invertebrates with their open blood-vascular system have the promise of promoting a better understanding of the role played by insulin in mediating/modulating cognitive functions. In this review, the relationship between insulin and its impact on long-term memory (LTM) is discussed particularly in snails. The pond snail Lymnaea stagnalis has the ability to undergo conditioned taste aversion (CTA), that is, it associatively learns and forms LTM not to respond with a feeding response to a food that normally elicits a robust feeding response. We show that molluscan insulin related peptides are up-regulated in snails exhibiting CTA-LTM and play a key role in the causal neural basis of CTA-LTM. We also survey the relevant literature of the roles played by insulin in learning and memory in other phyla. PMID- 26233477 TI - Association of interleukin-6 gene polymorphism (rs1800796) with severity and functional status of osteoarthritis in elderly individuals. AB - Osteoarthritis (OA) is the most prevalent disease of the musculoskeletal system and it has an important genetic component. Despite several reports have shown the involvement of pro-inflammatory cytokine such as interleukin-1beta and TNF-alpha, the role of interleukin-6 (IL-6) in osteoarthritis is still unclear. Thus, this study aimed to analyze the relationship between the single nucleotide polymorphism in the portion -572 of the promoter region of the IL6 gene (SNP 572G/C) with hip and knee OA in the elderly. In this case-control study, 257 physically independent elderly were recruited (case group: 92 individuals with osteoarthritis and control group: 165 individuals with no osteoarthritis). Blood samples were collected from patients for the DNA fragments extraction and amplification by real-time polymerase chain reaction (PCR) by TaqMan system for subsequent genotyping of IL6 gene. The degree of joint damage was assessed by radiographic classification based on the criteria of Kellgren and Lawrence. The functional status was evaluated by Lequesne and WOMAC questionnaires. It was observed that individuals carrying the C allele have lower susceptibility to osteoarthritis (OR=0.51, 95% CI: 0.32-0.80, p=0.004) and less radiological impairment for both hip (Fisher-Freeman-Halton test=4.2 and p=0.04) and knee joints (Fisher-Freeman-Halton test=4.7 and p=0.03). Regarding functional status, individuals carrying the C allele has a lower degree of functional impairment assessed by WOMAC (Mann-Whitney test, p=0.04), although no difference was observed in the Lequesne questionnaire (p>0.05). Additionally, it was observed a marked reduction in IL-6 serum levels in individuals with GC and CC genotypes when compared to individuals harboring GG genotype. In conclusion, the polymorphism -572G/C IL6 is a protective factor for the presence and severity of hip and knee osteoarthritis in the elderly. Further prospective studies with large sample size and methods (e.g. effect of this polymorphism on gene expression, haplotype analysis for IL-6 promoter polymorphism) are needed to validate this study findings. PMID- 26233478 TI - Urinary incontinence in gynaecological consultations. Do all women with symptoms wish to be treated? AB - OBJECTIVE: To determine the prevalence and symptom severity of urinary incontinence (UI) in women who attend primary care gynaecological consultations, as well as the proportion of women with UI symptoms who wish to be studied and treated. MATERIALS AND METHODS: A multicentre, observational, descriptive cross sectional study was conducted of women who visit the 8 specialised consultations for sexual and reproductive health (SRH) in the 4 Catalan provinces for any reason (except UI, pregnancy and postpartum). We employed the ICQ-UI-SF questionnaire to detect UI symptoms. Women with UI symptoms (ICI-Q-SF>0) were asked whether they wanted specific care for their UI problem. Those who answered "no" were asked why. RESULTS: The study included 2840 women, 41.8% of whom reported urine losses, especially mild to moderate symptoms. Some 53.62% of the women with UI responded that they did not wish to be treated. Of these, 75% had mild symptoms, 45% had moderate symptoms, and only 16% and 5% had severe or very severe symptoms, respectively. Fifty-three percent of the women did not want treatment because the UI was not a significant problem for them. CONCLUSIONS: Almost half of the women who attended a specialised consultation for SRH for any reason reported UI symptoms, especially mild and moderate. More than half of the patients with UI symptoms did not want to start a diagnostic and treatment process for their problem. Symptom severity is associated with the willingness to be treated. PMID- 26233479 TI - Holmium laser enucleation versus laparoscopic simple prostatectomy for large adenomas. AB - OBJECTIVE: The aim of this study is to compare Holmium laser enucleation of the prostate with another minimally invasive technique, the laparoscopic simple prostatectomy. MATERIALS AND METHODS: We compared outcomes of a series of 40 patients who underwent laparoscopic simple prostatectomy (n=20) with laser enucleation of the prostate (n=20) for large adenomas (>100 grams) at our institution. Study variables included operative time and catheterization time, hospital stay, pre- and post-operative International Prostate Symptom Score and maximum urinary flow rate, complications and economic evaluation. Statistical analyses were performed using the Student t test and Fisher test. RESULTS: There were no significant differences in patient age, preoperative prostatic size, operating time or specimen weight between the 2 groups. Duration of catheterization (P=.0008) and hospital stay (P<.0001) were significantly less in the laser group. Both groups showed a statistically significant improvement in functional variables at 3 months post operatively. The cost utility analysis for Holmium per case was 2589 euros versus 4706 per laparoscopic case. In the laser arm, 4 patients (20%) experienced complications according to the modified Clavien classification system versus 5 (25%) in the laparoscopic group (P>.99). CONCLUSION: Holmium enucleation of the prostate has similar short term functional results and complication rates compared to laparoscopic simple prostatectomy performed in large glands with the advantage of less catheterization time, lower economic costs and a reduced hospital stay. PMID- 26233480 TI - Towards greater involvement of the urologist in smoking prevention. PMID- 26233482 TI - Epilithonimonas psychrotolerans sp. nov., isolated from alpine permafrost. AB - A bacterial strain, designated TSBY 57T, was isolated during a study on the phylogenetic diversity of culturable bacteria from alpine permafrost in Tianshan Mountains, China, and was classified by means of a polyphasic taxonomic approach. The novel strain was found to belong to the genus Epilithonimonas and was distinguished from recognized species of this genus. Strain TSBY 57T grew aerobically, at 0-30 degrees C, with 0-1.5% (w/v) NaCl and at pH 6-8.Cells were Gram-stain-negative, non-motile, non-spore-forming rods. Compared with the reference strains, the novel strain was psychrotolerant. The predominant fatty acids were summed feature 3 (consisting of C16:1omega7c and/or C16:1omega6c), anteiso-C15:0 and iso-C15:0.The sole respiratory quinone was MK 6.Phosphatidylethanolamine was predominant in the polar lipid profile of strain TSBY 57T. These chemotaxonomic traits were in good agreement with the characteristics of the genus Epilithonimonas. On the basis of 16S rRNA gene sequence similarity, strain TSBY 57T was a member of the genus Epilithonimonas and was closely related to Epilithonimonas tenax DSM 16811T (99.0%), Epilithonimonas ginsengisoli DCY78T (98.6%) and Epilithonimonas lactis H1T (98.5%). However, DNA-DNA reassociation values between strain TSBY 57T and E. tenax DSM 16811T, E. ginsengisoli DCY78T and E. lactis H1T were 39.5 +/- 2.6, 37.7 +/- 1.0 and 37.3 +/- 1.1%, respectively. The G+C content of the DNA was 34.4 +/- 0.2 mol%. Based on data from this polyphasic taxonomic study, strain TSBY 57T represents a novel species of the genus Epilithonimonas, for which the name Epilithonimonas psychrotolerans sp. nov. is proposed. The type strain is TSBY 57T ( = NRRL B-51307T=CCTCC AB 207182T). PMID- 26233481 TI - Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT). AB - BACKGROUND: The combination of aclidinium bromide, a long-acting anticholinergic, and formoterol fumarate, a long-acting beta2-agonist (400/12 MUg twice daily) achieves improvements in lung function greater than either monotherapy in patients with chronic obstructive pulmonary disease (COPD), and is approved in the European Union as a maintenance treatment. The effect of this combination on symptoms of COPD and exacerbations is less well established. We examined these outcomes in a pre-specified analysis of pooled data from two 24-week, double blind, parallel-group, active- and placebo-controlled, multicentre, randomised Phase III studies (ACLIFORM and AUGMENT). METHODS: Patients >=40 years with moderate to severe COPD (post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity <70 % and FEV1 >=30 % but <80 % predicted normal) were randomised (ACLIFORM: 2:2:2:2:1; AUGMENT: 1:1:1:1:1) to twice-daily aclidinium/formoterol 400/12 MUg or 400/6 MUg, aclidinium 400 MUg, formoterol 12 MUg or placebo via GenuairTM/Pressair(r). Dyspnoea (Transition Dyspnoea Index; TDI), daily symptoms (EXAcerbations of Chronic pulmonary disease Tool [EXACT] Respiratory Symptoms [E-RS] questionnaire), night-time and early-morning symptoms, exacerbations (Healthcare Resource Utilisation [HCRU] and EXACT definitions) and relief-medication use were assessed. RESULTS: The pooled intent to-treat population included 3394 patients. Aclidinium/formoterol 400/12 MUg significantly improved TDI focal score versus placebo and both monotherapies at Week 24 (all p < 0.05). Over 24 weeks, significant improvements in E-RS total score, overall night-time and early-morning symptom severity and limitation of early-morning activities were observed with aclidinium/formoterol 400/12 MUg versus placebo and both monotherapies (all p < 0.05). The rate of moderate or severe HCRU exacerbations was significantly reduced with aclidinium/formoterol 400/12 MUg compared with placebo (p < 0.05) but not monotherapies; the rate of EXACT-defined exacerbations was significantly reduced with aclidinium/formoterol 400/12 MUg versus placebo (p < 0.01) and aclidinium (p < 0.05). Time to first HCRU or EXACT exacerbation was longer with aclidinium/formoterol 400/12 MUg compared with placebo (all p < 0.05) but not the monotherapies. Relief-medication use was reduced with aclidinium/formoterol 400/12 MUg versus placebo and aclidinium (p < 0.01). CONCLUSIONS: Aclidinium/formoterol 400/12 MUg significantly improves 24-hour symptom control compared with placebo, aclidinium and formoterol in patients with moderate to severe COPD. Furthermore, aclidinium/formoterol 400/12 MUg reduces the frequency of exacerbations compared with placebo. TRIAL REGISTRATION: NCT01462942 and NCT01437397 (ClinicalTrials.gov). PMID- 26233483 TI - The history and evolution of outpatient parenteral antibiotic therapy (OPAT). AB - Outpatient parenteral antibiotic therapy (OPAT) is now a widely accepted and safe therapeutic option for carefully selected patients. Benefits include cost savings and improved patient satisfaction; risks include failure to adhere to care, unexpected changes in the underlying infection, and adverse drug and intravenous access events. We report on our 40-year experience with OPAT in a single healthcare system in the USA and highlight OPAT developments in several countries. We compared data on patients treated in our programme over two time periods: Period 1 from 1978 to 1990; and Period 2, calendar year 2014. In Period 2 paediatric patients were excluded. Between Periods 1 and 2, changes included an almost three-fold increase in the number of patients treated per year (80 vs. 229), treatment of more patients with severe orthopaedic-related infections (20% vs. 38%), a marked increase in the use of peripherally inserted central catheters to administer antibiotics (20% vs. 98%), a shorter duration of inpatient stay and a longer duration of OPAT (13 days vs. 24 days). Other changes in Period 2 included treatment of 20% of patients without antecedent hospitalisation, and use of carbapenems rather than cephalosporins as the most frequently administered agents. OPAT was safe, with rehospitalisation rates of 6% and 1% in Periods 1 and 2, respectively. We recommend increased access to structured OPAT teams and the development of standard definitions and criteria for important outcome measures (e.g. clinical 'cure' and unplanned hospital re-admissions). These steps are critical for patient safety and financial stewardship of resources. PMID- 26233484 TI - Cigarette craving is associated with blunted reward processing in nicotine dependent smokers. AB - BACKGROUND: Dysfunctional reward processing leading to the undervaluation of non drug rewards is hypothesized to play a crucial role in nicotine dependence. However, it is unclear if blunted reward responsivity and the desire to use nicotine are directly linked after a brief period of abstinence. Such an association would suggest that individuals with reduced reward responsivity may be at increased risk to experience nicotine craving. METHODS: Reward function was evaluated with a probabilistic reward task (PRT), which measures reward responsivity to monetary incentives. To identify whether smoking status influenced reward function, PRT performance was compared between non-depressed, nicotine-dependent smokers and non-smokers. Within smokers, correlations were conducted to determine if blunted reward responsivity on the PRT was associated with increased nicotine craving. Time since last nicotine exposure was standardized to 4h for all smokers. RESULTS: Smokers and non-smokers did not differ in reward responsivity on the PRT. However, within smokers, a significant negative correlation was found between reward responsivity and intensity of nicotine craving. CONCLUSIONS: The current findings show that, among smokers, the intensity of nicotine craving is linked to lower sensitivity to non-drug rewards. This finding is in line with prior theories that suggest reward dysfunction in some clinical populations (e.g., depressive disorders, schizophrenia) may facilitate nicotine use. The current study expands on such theories by indicating that sub-clinical variations in reward function are related to motivation for nicotine use. Identifying smokers who show blunted sensitivity to non-drug rewards may help guide treatments aimed at mitigating the motivation to smoke. PMID- 26233485 TI - Multiple substance use patterns in adolescents-A multilevel latent class analysis. AB - BACKGROUND: Multiple substance use among adolescents is associated with a number of negative consequences. Therefore, we aim to investigate multiple substance use patterns among young adolescents and identify possible multilevel predictors. METHODS: We analyzed a longitudinal sample of 2490 German students (51% male; Mage=13.32, SD=0.57) at 45 schools in four German states (Bremen, Hesse, North Rhine-Westphalia, Schleswig-Holstein), who completed two assessments in fall, 2010 and fall, 2013. We conducted multilevel latent class analysis for follow-up data on a variety of outcomes, and tested our final 3-class-model for possible baseline predictors. Follow-up substance use measures included lifetime use, current use, and amount of substance for cigarettes and alcohol. Baseline covariates comprised age, gender, socio-economic status, bullying, victimization, peer and parental use, type of school, and health certification of school. RESULTS: We identified three latent classes: non-users (n=1541; 61.9%), experimenters (n=722; 29.0%), and multiusers (n=227; 9.1%). Experimental consumption was predicted by higher baseline age (OR=1.71; 1.31-2.24), paternal drinking (OR=2.89; 1.23-6.79), and school type (OR=2.57; 1.83-3.61), while multiuse was predicted by peer smoking (OR=2.94; 1.80-4.80) and drinking (OR=2.13; 1.32-3.44), maternal drinking (OR=6.26; 2.02-19.43), bullying (OR=1.69; 1.15-2.48), higher age (OR=1.92; 1.40-2.62), and school type (OR=4.76; 2.75-8.24) compared to the non-users class. CONCLUSIONS: Prevention and further research on multiple substance use need to concentrate on social influence models and behavior-related interventions, especially at schools without a college preparatory track. PMID- 26233487 TI - Alterations to antigen-specific immune responses before and after multidrug therapy of leprosy. AB - This study evaluated the impact of leprosy multidrug therapy (MDT) on cell mediated immunity (CMI) and antibody responses at diagnosis in untreated paucibacillary (PB) (n=15) and multibacillary (MB) patients (n=15) using a panel of Mycobacterium leprae recombinant antigens (rMLs) (CMI: 46f, ML0276, ML2055, leprosy IDRI diagnostic 1 [LID-1], and ML2629, as negative control; serology: LID 1, 46f, 92f, and 33f, as negative control, and phenolic glycolipid I [PGL-I]) and at 2 time points after MDT (PB: 8-20months; MB: 4-22months). At diagnosis, PB patients produced interferon gamma (IFNgamma), and MB patients exhibited low/absent response. Shortly after MDT, IFNgamma production in PB patients declined except for LID-1; MB patients produced IFNgamma to LID-1. Almost 2years after MDT, IFNgamma levels declined in PB and MB patients. Most untreated PB patients were seronegative to PGL-I and rML, remaining so after MDT. Most untreated MB patients were seropositive to all antigens, and IgG to rMLs declined after MDT. Reduction in antigen-specific CMI in PB and in antibody response in MB patients may help monitor MDT effectiveness. PMID- 26233486 TI - Variations in opioid receptor genes in neonatal abstinence syndrome. AB - BACKGROUND: There is significant variability in the severity of neonatal abstinence syndrome (NAS) due to in-utero opioid exposure. We wanted to determine if single nucleotide polymorphisms (SNPs) in key candidate genes contribute to this variability. METHODS: Full-term opioid-exposed newborns and their mothers (n=86 pairs) were studied. DNA was genotyped for 80 SNPs from 14 genes utilizing a custom designed microarray. The association of each SNP with NAS outcomes was evaluated. RESULTS: SNPs in two opioid receptor genes in the infants were associated with worse NAS severity: (1) The PNOC rs732636 A allele (OR=3.8, p=0.004) for treatment with 2 medications and a longer hospital stay (LOS) of 5.8 days (p=0.01), and (2) The OPRK1 rs702764 C allele (OR=4.1, p=0.003) for treatment with 2 medications. The OPRM1 rs1799971 G allele (beta=-6.9 days, p=0.02) and COMT rs740603 A allele (beta=-5.3 days, p=0.01) were associated with shorter LOS. The OPRD1 rs204076 A allele in the mothers was associated with a longer LOS by 6.6 days (p=0.008). Results were significant point-wise but did not meet the experiment-wide significance level. CONCLUSIONS: These findings suggest that SNPs in opioid receptor and the PNOC genes are associated with NAS severity. However, further testing in a large sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants at highest risk for severe NAS. PMID- 26233488 TI - Depression moderates between physical activity and quality of life in low-income children. AB - PURPOSE: This study investigated the relationship between physical activity and health-related quality of life (HRQoL) as moderated by depression in low-income children. METHODS: A cross-sectional study was conducted with 149 children ages 10-12 whose families' monthly incomes were at or below 150% of Korea's minimum cost of living. Children's physical activity, depression, and HRQoL were measured with self-administered questionnaires. Multiple regression and simple slope analysis examined the moderating effect of depression between physical activity and HRQoL. RESULTS: Physical activity was significantly positively correlated with HRQoL while depression was significantly negatively correlated with physical activity and HRQoL. Physical activity, depression, and their interaction explained 39.3% of variance in low-income children's HRQoL. Simple slope analysis showed that increased physical activity was related to higher QoL among children without depressive symptoms but not significantly related to QoL for children with depressive symptoms. CONCLUSION: The moderating effect of depression between physical activity and QoL was confirmed in children from low-income families. To improve HRQoL through physical activity interventions, depression screening and symptom management should be performed so that strategies to promote QoL can be effectively applied consistent with depression screening results. PMID- 26233489 TI - Chiral Separation of Ormeloxifene Hydrochloride, a Non-steroidal Contraceptive Agent. AB - Ormeloxifene hydrochloride (Centchroman) is once-a-week non-steroidal oral contraceptive agent marketed in India and other countries. In this study, we report a validated isocratic high-performance liquid chromatographic (HPLC) method for chiral separation of D- and L-ormeloxifene hydrochloride. This method is capable of baseline separation of its D- and L-isomers. HPLC separation was achieved on a Lux 5u cellulose-1 with a mobile phase comprising hexane, isopropanol, methanol and triethylamine (90:10:1:0.5). Validation parameters such as limit of detection, limit of quantitation, linearity, precision, accuracy, specificity and preformulation studies were conducted according to new guidelines of International Conference on Harmonization. PMID- 26233490 TI - Evaluation of ultraviolet irradiation efficacy in an automated system for the aseptic compounding using challenge test. AB - OBJECTIVE: Ultraviolet (UV) irradiation efficacy in the intravenous compounding robot APOTECAchemo was evaluated to define the best operative conditions in terms of sterility and time optimization. DESIGN: The challenge test was used against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Bacillus subtilis spores and Candida albicans. Inoculated plates were placed inside the robot and irradiated for different times. Microbial air and surface quality inside the equipment were monitored utilizing settle and contact plates, swabs. RESULTS: After 4 h, no microorganisms were viable with killing rates ranging from 5- to 7-log for different microorganisms after 1 h of exposition. In confirmation of the efficacy of the UV irradiation program adopted, the microbial monitoring inside the equipment always gave negative results. CONCLUSIONS: This is the first exhaustive investigation of UV irradiation efficacy in the aseptic pharmaceutical production. We demonstrated that UV irradiation plays an essential role in maintaining the sterility condition of the workplace inside the APOTECAchemo and assuring the standards for aseptic manufacturing of medicinal drugs, as required for Class A clean areas. A 4-h UV irradiation also ensures sterility in the case of very resistant microorganisms and in the presence of high microbial charge (10(8) CFU/ml), but a killing rate of 5 or more is already recorded after the first hour of exposition. The results provide useful information for the best operative conditions in terms of both sterility and time optimization, not only for the automated compounding, but also for the traditional aseptic manufacturing processes. PMID- 26233491 TI - Design and real time implementation of fuzzy switched controller for single phase active power filter. AB - This paper proposes a novel fuzzy switched controller (FSC) integrated in direct current control (DCC) algorithm for single phase active power filter (SPAPF). The controller under study consists of conventional PI controller, fractional order PI controller (FO-PI) and fuzzy decision maker (FDM) that switches between them using reduced fuzzy logic control. The proposed controller offers short response time with low damping and deals efficiently with the external disturbances while preserving the robustness properties. To fulfill the requirements of power quality, unity power factor and harmonics limitations in active power filtering an experimental test bench has been built using dSPACE 1104 to demonstrate the feasibility and effectiveness of the proposed controller. The obtained results present high performance in steady and transient states. PMID- 26233492 TI - Long-term outcome of children with patent processus vaginalis incidentally diagnosed by laparoscopy. AB - INTRODUCTION: Patent processus vaginalis (PPV) might be incidentally diagnosed during laparoscopy. The aims of this study were to determine the prevalence and the natural history of PPV, i.e. its possible development into symptomatic inguinal hernia. PATIENTS AND METHODS: INCLUSION CRITERIA: children <16years undergoing laparoscopy for pathologies other than processus vaginalis (PV) related, from 10/2000-10/2005. EXCLUSION CRITERIA: past or present history of PV related pathologies. The internal inguinal rings were documented during laparoscopy. Follow-up was provided by phone inquiry and clinical examination if needed. Median follow-up was 10.5years (range 7.1-12.8). RESULTS: 416 patients were included. Median age at laparoscopy was 12.4years (range 3days-18.1years). Forty-three PPV (33 unilateral, 5 bilateral) were found in 38 patients (9.1%). Four children with PPV presented later with an ipsilateral inguinal hernia (10.5%, 95%CI [3%; 25%]), at a median age of 16.0years (range 11.8-17.3), at a median of 22.5months (range 12-50) after initial laparoscopy, as compared to no patient in the population with obliterated PV (0%, 95%CI [0%; 1%]). CONCLUSION: 9.1% of the observed pediatric population showed an asymptomatic PPV, and 10.5% of these children later developed an inguinal hernia. None of the children with obliterated PV developed a hernia. PMID- 26233493 TI - Formation, characterization and stability of oil nanodroplets on immersed substrates. AB - Nanoscale oil droplets locating at solid-liquid interfaces significantly impact the interfacial properties, which are concerned in both industry applications and fundamental studies. This review article presents an overview of the current progress in nanodroplet research. We will start from the characterization of interfacial nanodroplets and the formation of interfacial nanodroplets by direct adsorption from emulsions and by the solvent exchange protocol. Then we will review the experimental and theoretical studies on the evolution of oil nanodroplets including spreading, dissolution, and detachment. We will also cover the emerging applications of the interfacial nanodroplets in the fields of surface functionalization and nanostructure engineering, and particularly, highlight the potential application as capping agents to obtain architectures on microparticle surface. Finally we propose the challenges and the opportunities in this area. In our opinion, the nanodroplets have not only of high relevance to practical applications, but also serve as a model system for understanding many interfacial phenomena, such as phase separation and wetting on a microscopic scale. PMID- 26233494 TI - Structure and energy of liquid foams. AB - We present an overview of recent advances in the understanding of foam structure and energy and their dependence on liquid volume fraction. We consider liquid foams in equilibrium for which the relevant energy is surface energy. Measurements of osmotic pressure can be used to determine this as a function of liquid fraction in good agreement with results from computer simulations. This approach is particularly useful in the description of foams with high liquid content, so-called wet foams. For such foams X-ray tomography proves to be an important technique in analysing order and disorder. Much of the discussion in this article is also relevant to bi-liquid foams, i.e. emulsions, and to solid foams, provided that the solidification preserves the structure of the initially liquid foam template. PMID- 26233495 TI - Heteroaggregation of nanoparticles with biocolloids and geocolloids. AB - The application of nanoparticles has raised concern over the safety of these materials to human health and the ecosystem. After release into an aquatic environment, nanoparticles are likely to experience heteroaggregation with biocolloids, geocolloids, natural organic matter (NOM) and other types of nanoparticles. Heteroaggregation is of vital importance for determining the fate and transport of nanoparticles in aqueous phase and sediments. In this article, we review the typical cases of heteroaggregation between nanoparticles and biocolloids and/or geocolloids, mechanisms, modeling, and important indicators used to determine heteroaggregation in aqueous phase. The major mechanisms of heteroaggregation include electric force, bridging, hydrogen bonding, and chemical bonding. The modeling of heteroaggregation typically considers DLVO, X DLVO, and fractal dimension. The major indicators for studying heteroaggregation of nanoparticles include surface charge measurements, size measurements, observation of morphology of particles and aggregates, and heteroaggregation rate determination. In the end, we summarize the research challenges and perspective for the heteroaggregation of nanoparticles, such as the determination of alphahetero values and heteroaggregation rates; more accurate analytical methods instead of DLS for heteroaggregation measurements; sensitive analytical techniques to measure low concentrations of nanoparticles in heteroaggregation systems; appropriate characterization of NOM at the molecular level to understand the structures and fractionation of NOM; effects of different types, concentrations, and fractions of NOM on the heteroaggregation of nanoparticles; the quantitative adsorption and desorption of NOM onto the surface of nanoparticles and heteroaggregates; and a better understanding of the fundamental mechanisms and modeling of heteroaggregation in natural water which is a complex system containing NOM, nanoparticles, biocolloids and geocolloids. PMID- 26233496 TI - [Exophthalmos]. PMID- 26233497 TI - Does Rheumatoid Cachexia Predispose Patients with Rheumatoid Arthritis to Osteoporosis and Vertebral Fractures? AB - OBJECTIVE: To assess the prevalence and risk factors of rheumatoid cachexia (RC) and evaluate its relationship with osteoporosis and vertebral fractures (VF) in patients with rheumatoid arthritis (RA). METHODS: We enrolled into a cross sectional study 178 consecutive patients with RA (82.6% women) with a mean age of 54.1 +/- 11.5 years (25-82) and who fulfilled the American College of Rheumatology criteria for the classification of RA. Body composition, lateral VF assessment images, and scans of the lumbar spine and proximal femur were obtained using dual-energy x-ray absorptiometry. RC was defined by a fat-free mass index below the 10th percentile and a fat mass index above the 25th percentile compared with a reference population. VF were defined using Genant semiquantitative approach. RESULTS: RC was observed in 96 patients (53.9%) and osteoporosis in 52 patients (29.2%). Comparison between women with and without RC showed that women with RC had a longer disease duration, higher disease activity variables, higher steroid cumulative dose, and higher proportion of patients with erosive arthritis. Women with RC had lower total hip bone mineral density (BMD) and T score than women without RC, while comparison in men found only body mass index to be significantly lower in men with RC. Regression logistic analysis showed an independent and significant association between RC and age and disease activity in women. CONCLUSION: Our study showed that half of the patients with RA may have RC, a condition that was significantly associated with disease activity and low hip BMD, but not with VF. PMID- 26233498 TI - Clinical Features and Outcomes of Takayasu Arteritis with Neurological Symptoms in China: A Retrospective Study. AB - OBJECTIVE: To describe the clinical features and longterm outcomes of patients with Takayasu arteritis (TA) in China who experienced neurological symptoms. METHODS: A retrospective study was undertaken of patients with TA who attended a single study center from 2002 to 2013, who also exhibited neurological symptoms (n = 274). Clinical and imaging features were analyzed, as well as longterm outcomes. RESULTS: The mean age at disease onset was 28.2 +/- 11.2 years, with a female-to-male ratio of 4.3:1. The most common neurological manifestation was dizziness (214, 78.1%), the most frequent type of TA was type III (112, 40.9%), and the most common affected artery was the left subclavian (147, 53.6%). Involvement of 3 or 4 branches of the aortic arch was observed in 28% of patients. Among 30 patients experiencing a stroke (10.9%), steno-occlusive lesions of the subclavian artery and common carotid artery were frequently observed in patients with ischemic stroke, while steno-occlusive lesions of the descending aorta, abdominal aorta, and/or renal arteries were more frequently observed with hemorrhagic stroke. Heart failure was the most common cardiovascular event in those who died (n = 6) and in surviving cohorts. CONCLUSION: Neurological features in patients with TA were variable, and correlated with the number of arteries and the site of artery involvement. Resistant hypertension was one of the most important risk factors for hemorrhagic stroke in patients with TA. PMID- 26233499 TI - Comparison of 2 Dosages of Intraarticular Triamcinolone for the Treatment of Knee Arthritis: Results of a 12-week Randomized Controlled Clinical Trial. AB - OBJECTIVE: To determine whether a double dose of intraarticular triamcinolone acetonide is more effective for knee arthritis than a 40-mg dose. METHODS: In this 12-week randomized controlled clinical trial, 40 mg and 80 mg of intraarticular triamcinolone acetonide were compared in patients with knee arthritis. Evaluated variables included a Likert burden scale, visual analog scale pain scale, degree of arthritis activity, presence of swelling, and presence of functional limitation. RESULTS: Ninety-seven patients were randomized. No significant differences were observed between the groups regarding any outcomes. CONCLUSION: An 80-mg dose of triamcinolone acetonide had no additional benefit compared with 40 mg as treatment for knee arthritis. TRIAL REGISTRATION: Nederlands Trial Register; trial registration number: NTR2298. PMID- 26233500 TI - Autoantibodies against Endothelin 1 Type A Receptor Are Strong Predictors of Digital Ulcers in Systemic Sclerosis. AB - OBJECTIVE: To determine the predictive value of functional autoantibodies against vascular receptors for the development of ischemic digital ulcers (DU) in patients with systemic sclerosis (SSc). METHODS: Angiotensin II Type 1 receptor (AT1R) and endothelin 1 Type A receptor (ETAR) autoantibodies were measured at baseline in a prospective cohort of 90 patients with SSc together with 5 validated angiogenic markers. The primary outcome was the occurrence of at least 1 new ischemic DU during the 5-year followup. RESULTS: Twenty-four patients developed at least 1 new DU during the followup period. Univariate Cox analysis revealed that concentrations above the median value of anti-AT1R and anti-ETAR antibodies were predictive of the occurrence of ischemic DU (HR 2.85, 95% CI 1.19 6.84 and HR 3.39, 95% CI 1.35-8.50, respectively). A first multivariate Cox analysis including functional autoantibodies and clinical predictors of new DU confirmed anti-ETAR autoantibodies as independent predictors of the occurrence of new ischemic DU (HR 3.15, 95% CI 1.22-8.13) together with a history of DU at baseline. In a second model implemented with angiogenic markers, anti-ETAR autoantibodies remained an independent predictor of the occurrence of new ischemic DU (HR 9.59, 95% CI 1.75-52.64) together with the presence at baseline of active DU or history of DU. CONCLUSION: Anti-ETAR autoantibodies can be used together with the presence of current or past DU to identify patients with SSc who are at risk for the development of subsequent DU. These autoantibodies may allow for earlier management and therapeutic intervention. PMID- 26233501 TI - Effectiveness of Triamcinolone Hexacetonide Intraarticular Injection in Interphalangeal Joints: A 12-week Randomized Controlled Trial in Patients with Hand Osteoarthritis. AB - OBJECTIVE: To evaluate the effectiveness and tolerance of intraarticular injection (IAI) of triamcinolone hexacetonide (TH) for the treatment of osteoarthritis (OA) of hand interphalangeal (IP) joints. METHODS: Sixty patients who underwent IAI at the most symptomatic IP joint were randomly assigned to receive TH/lidocaine (LD; n = 30) with TH 20 mg/ml and LD 2%, or just LD (n = 30). The injected joint was immobilized with a splint for 48 h in both groups. Patients were assessed at baseline and at 1, 4, 8, and 12 weeks by a blinded observer. The following variables were assessed: pain at rest [visual analog scale (VAS)r], pain at movement (VASm), swelling (physician VASs), goniometry, grip and pinch strength, hand function, treatment improvement, daily requirement of paracetamol, and local adverse effects. The proposed treatment (IAI with TH/LD) was successful if statistical improvement (p < 0.05) was achieved in at least 2 of 3 VAS. Repeated-measures ANOVA test was used to analyze intervention response. RESULTS: Fifty-eight patients (96.67%) were women, and the mean age was 60.7 years (+/- 8.2). The TH/LD group showed greater improvement than the LD group for VASm (p = 0.014) and physician VASs (p = 0.022) from the first week until the end of the study. In other variables, there was no statistical difference between groups. No significant adverse effects were observed. CONCLUSION: The IAI with TH/LD has been shown to be more effective than the IAI with LD for pain on movement and joint swelling in patients with OA of the IP joints. Regarding pain at rest, there was no difference between groups. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT02102620). PMID- 26233502 TI - Work Disability in Early Systemic Sclerosis: A Longitudinal Population-based Cohort Study. AB - OBJECTIVE: To study work disability (WD) with reference to levels of sick leave and disability pension in early systemic sclerosis (SSc). METHODS: Patients with SSc living in the southern part of Sweden with onset of their first non-Raynaud symptom between 2003 and 2009 and with a followup of 36 months were included in a longitudinal study. Thirty-two patients (26 women, 24 with limited SSc) with a median age of 47.5 years (interquartile range 43-53) were identified. WD was calculated in 30-day intervals from 12 months prior to disease onset until 36 months after, presented as the prevalence of WD per year (0-3) and as the period prevalence of mean net days per month (+/- SD). Comparisons were made between patients with different disease severity and sociodemographic characteristics, and between patients and a reference group (RG) from the general population. RESULTS: Seventy-eight percent had no WD 1 year prior to disease onset, which decreased to 47% after 3 years. The relative risk for WD in patients with SSc compared with RG was 0.95 (95% CI 0.39-2.33) at diagnosis, and increased to 2.41 (1.28-4.55) after 3 years. There were no significant correlations between WD and disease severity, but between WD and years at workplace (rs = -0.72; p = 0.002), education (rs = -0.51; p = 0.004), and sickness absence the month before disease onset (rs = 0.58; p = 0.001), respectively. CONCLUSION: Considerable increase in WD was noted 3 years after disease onset. Limited education, fewer years at workplace, and sickness absence before disease onset may be risk factors for sustained WD. PMID- 26233503 TI - The Detection of Rheumatic Disease through Hospital Diagnoses with Examples of Rheumatoid Arthritis and Giant Cell Arteritis: What Are We Missing? AB - OBJECTIVE: We examined hospitalizations for patients with known rheumatoid arthritis (RA) or giant cell arteritis (GCA) to evaluate whether hospitalization related diagnoses accurately identified patients with rheumatologic diseases. METHODS: Diagnosis codes for hospitalizations in 1996-2012 among previously identified population-based cohorts of patients with RA or GCA were examined for RA or GCA mentions. RESULTS: RA or GCA mention occurred in only 55% of 2407 hospitalizations among patients with RA and 31% of 502 hospitalizations among patients with GCA. RA or GCA was mentioned more often in recent years, younger patients, and rheumatic medication users. CONCLUSION: Coding for RA or GCA during hospitalizations was often missed. Research using hospital diagnoses alone could be biased. PMID- 26233504 TI - Patient Expectations and Perceptions of Goal-setting Strategies for Disease Management in Rheumatoid Arthritis. AB - OBJECTIVE: To identify how patients perceive the broad effect of active rheumatoid arthritis (RA) on their daily lives and indicate how RA disease management could benefit from the inclusion of individual goal-setting strategies. METHODS: Two multinational surveys were completed by patients with RA. The "Good Days Fast" survey was conducted to explore the effect of disease on the daily lives and relationships of women with RA. The "Getting to Your Destination Faster" survey examined RA patients' treatment expectations and goal setting practices. RESULTS: Respondents from all countries agreed that RA had a substantial negative effect on many aspects of their lives (work productivity, daily routines, participation in social and leisure activities) and emotional well-being (loss of self-confidence, feelings of detachment, isolation). Daily pain was a paramount issue, and being pain- and fatigue-free was considered the main indicator of a "good day." Setting personal, social, and treatment goals, as well as monitoring disease progress to achieve these, was considered very beneficial by patients with RA, but discussion of treatment goals seldom appeared to be a part of medical appointments. CONCLUSION: Many patients with RA feel unable to communicate their disease burden and treatment goals, which are critically important to them, to their healthcare provider (HCP). Insights gained from these 2 surveys should help to guide patients and HCP to better focus upon mutually defined goals for continued improvement of management and achievement of optimal care in RA. PMID- 26233506 TI - Comparison of Photo Optical Imaging with Musculoskeletal Ultrasound and Clinical Examination in the Assessment of Inflammatory Activity in Proximal Interphalangeal Joints in Rheumatoid Arthritis and Osteoarthritis. AB - OBJECTIVE: Lightscan is a novel, rapid, low-cost, easily operated and noninvasive imaging technology used to assess inflammatory activity in proximal interphalangeal (PIP) joints. The results are calculated automatically. To our knowledge, this is the first comparative study of photo optical imaging (POI), with clinical examination (CE), disease activity score at 28 joints (DAS28) erythrocyte sedimentation rate (ESR), and musculoskeletal ultrasonography (US) in healthy subjects and patients with rheumatoid arthritis (RA) or osteoarthritis (OA). METHODS: There were 688 PIP joints of both hands examined in 87 subjects (38 RA, 21 OA, 28 healthy) by Lightscan and compared with CE for clinically swollen and tender joints, DAS28-ESR (only RA), and US. RESULTS: With US as reference, POI had a sensitivity of 74% and a specificity of 93%. In the receiver operating curve (ROC) analysis, the Lightscan showed a higher sensitivity and specificity [area under the curve (AUC) 0.879] for the distinction of healthy subjects versus patients (OA, RA) than US in greyscale (GSUS; AUC 0.797) and power Doppler (PDUS; AUC 0.67). POI correlated significantly with GSUS (r 0.473, p < 0.01) and PDUS (r 0.486, p < 0.01). The agreement rates between POI and GSUS were up to 79%, between POI and PDUS up to 92%, and between POI and CE up to 66%. POI did not correlate with DAS28-ESR. CONCLUSION: The Lightscan is a new technology offering sensitive imaging detection of inflammatory changes in subjects with RA and OA with PIP arthritis. POI was more sensitive than CE and correlated significantly to GSUS and PDUS, while presenting a higher sensitivity and specificity for the detection of healthy subjects versus patients (RA, OA) based on the ROC analysis. PMID- 26233505 TI - Utility of Select Plasma MicroRNA for Disease and Cardiovascular Risk Assessment in Patients with Rheumatoid Arthritis. AB - OBJECTIVE: MicroRNA (miRNA) are small noncoding RNA that posttranscriptionally regulate gene expression and serve as potential mediators and markers of disease. Recently, plasma miR-24-3p and miR-125a-5p concentrations were shown to be elevated in rheumatoid arthritis (RA) and useful for RA diagnosis. We assessed the utility of 7 candidate plasma miRNA, selected for biological relevance, for RA diagnosis and use as markers of disease activity and subclinical atherosclerosis in RA. METHODS: The cross-sectional study included 168 patients with RA and 91 control subjects of similar age, race, and sex. Plasma concentrations of miR-15a-5p, miR-24-3p, miR-26a-5p, miR-125a-5p, miR-146a-5p, miR-155-5p, and miR-223-3p were measured by quantitative PCR. Utility of plasma miRNA concentrations for RA diagnosis was assessed by area under the receiver operating characteristic curve (AUROC). Associations between plasma miRNA concentrations and RA disease activity and coronary artery calcium score were assessed by Spearman correlations. RESULTS: Plasma concentrations of miR-15a-5p, miR-24-3p, miR-26a-5p, miR-125a-5p, miR-146a-5p, miR-155-5p, and miR-223-3p were significantly increased in patients with RA. The highest AUROC for diagnosis of RA (AUROC = 0.725) was found in miR-24-3p, including among rheumatoid factor negative patients (AUROC = 0.772). Among all patients with RA, the combination of miR-24-3p, miR-26a-5p, and miR-125a-5p improved the model modestly (AUROC = 0.747). One miRNA, miR-155-5p, was weakly inversely associated with swollen joint count (p = 0.024), but no other miRNA were associated with disease activity or coronary artery calcium score. CONCLUSION: The combination of miR-24-3p, miR-26a 5p, and miR-125a-5p had the strongest diagnostic accuracy for RA. Candidate miRNA had little or no association with RA disease activity or subclinical atherosclerosis. PMID- 26233507 TI - Impaired Antiatherogenic Functions of High-density Lipoprotein in Patients with Ankylosing Spondylitis. AB - OBJECTIVE: Ankylosing spondylitis (AS) is a chronic inflammatory disease associated with increased risk of cardiovascular disease (CVD). High-density lipoprotein (HDL) exerts a series of antiatherogenic properties and protects from CVD. We evaluated whether HDL antiatherogenic properties are impaired in patients with AS. METHODS: HDL (apoB-depleted serum) was isolated from 35 patients with AS and 35 age- and sex-matched controls. We measured the antioxidant capacity of HDL, the ability of HDL to induce cholesterol efflux, the activity of HDL associated enzymes paraoxonase-1 (PON1) and myeloperoxidase (MPO), as well as the ability of HDL to induce Akt kinase activation. RESULTS: HDL from patients with AS had decreased antioxidant capacity and decreased ability to promote cholesterol efflux from macrophages compared to controls. HDL-associated PON1 activity was lower and HDL-associated MPO activity higher in patients with AS compared to controls. Higher MPO activity correlated positively with lower antioxidant capacity of HDL in patients with AS. In addition, HDL from patients with AS had impaired endothelial Akt kinase activating properties that were inversely correlated with the MPO/PON1 ratio and positively correlated with the cholesterol efflux capacity of HDL. CONCLUSION: HDL from patients with AS displays impaired antiatherogenic properties. Attenuation of HDL properties may constitute a link between AS and CVD. PMID- 26233508 TI - Harmonizing Pain Outcome Measures: Results of the Pre-OMERACT Meeting on Partnerships for Consensus on Patient-important Pain Outcome Domains Between the Cochrane Musculoskeletal Group and OMERACT. AB - OBJECTIVE: A variety of authorities in pain measurement and outcome methodology met prior to the Outcome Measures in Rheumatology (OMERACT) 12 meeting in May 2014 to develop partnerships for consensus on pain outcomes. METHODS: Following overview presentations, discussion centered on pain-specific and global constructs in the domain of chronic pain. Practical issues for clinical trial implementation were also discussed. Breakout sessions were completed regarding additional details of domain constructs. A nominal group process involving all workshop participants confirmed that chronic pain outcome measures encompass a broad range of constructs and that existing scales may be inadequate for assessment in clinical trials. RESULTS: Participants endorsed that both pain intensity and pain interference are important constructs to be measured in clinical trials of chronic pain as it pertains to rheumatologic diagnoses. CONCLUSION: Further work is needed on inclusion of the patient perspective in the development of pain domains as well as Cochrane Collaboration summary of findings tables. PMID- 26233509 TI - Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy. AB - OBJECTIVE: To assess the efficacy and safety of JNJ-40346527, a selective inhibitor of colony-stimulating factor-1 (CSF-1) receptor kinase that acts to inhibit macrophage survival, proliferation, and differentiation in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) therapy. METHODS: In this randomized, double-blind, placebo-controlled, parallel group study, adults were randomized (2:1) to receive oral JNJ-40346527 100 mg or placebo twice daily through Week 12. Patients with RA had disease activity [>= 6 swollen/>= 6 tender joints, C-reactive protein (CRP) >= 0.8 mg/dl] despite DMARD therapy for >= 6 months. The primary endpoint was change from baseline at Week 12 in the 28-joint Disease Activity Score with CRP (DAS28-CRP). Pharmacokinetic/pharmacodynamic analyses were also performed, and safety was assessed through Week 16. RESULTS: Ninety-five patients were treated (63 JNJ 40346527, 32 placebo); 8 patients discontinued treatment (6 JNJ-40346527, 2 placebo) through Week 12. Mean improvements in DAS28-CRP from baseline to Week 12 were 1.15 for the JNJ-40346527 group and 1.42 for the placebo group (p = 0.30); thus, a statistically significant difference was not observed for the primary endpoint. Pharmacokinetic exposure to JNJ-40346527 and its active metabolites was above the projected concentration needed for pharmacologic activity, and effective target engagement and proof of activity were demonstrated by increased levels of CSF-1 and decreased CD16+ monocytes in JNJ-40346527-treated, but not placebo-treated, patients. Thirty-seven (58.7%) JNJ-40346527-treated and 16 (50.0%) placebo-treated patients reported >= 1 adverse event (AE); 1 (1.6%) JNJ 40346527-treated and 3 (9.4%) placebo-treated patients reported >= 1 serious AE. CONCLUSION: Although adequate exposure and effective peripheral target engagement were evident, JNJ-40346527 efficacy was not observed in patients with DMARD refractory active RA. ClinicalTrials.gov identifier: NCT01597739. EudraCT Number: 2011-004529-28. PMID- 26233510 TI - Health Literacy Rates in a Population of Patients with Rheumatoid Arthritis in Southwestern Ontario. AB - OBJECTIVE: To determine the rate of low health literacy in the rheumatoid arthritis (RA) population in southwestern Ontario. METHODS: For the study, 432 patients with RA were contacted, and 311 completed the assessment. The health literacy levels of the participants were estimated using 4 assessment tools administered in the following order: the Single Item Literacy Screener (SILS), the Medical Term Recognition Test (METER), the Rapid Estimate of Adult Literacy in Medicine (REALM), and the Shortened Test of Functional Health Literacy in Adults (STOFHLA). RESULTS: The rates of low literacy as estimated by STOFHLA, REALM, METER, and SILS were 14.5%, 14.8%, 14.1%, and 18.6%, respectively. All 4 assessment tools were statistically significantly correlated. STOFHLA, REALM, and METER were strongly correlated with each other (r = 0.59-0.79), while SILS only demonstrated moderate correlations with the other assessment tools (r = 0.33 0.45). Multiple linear regression and binary logistic regression analyses revealed that low levels of education and a lack of daily reading activity were common predictors of low health literacy. Using a non-English primary language at home was found to be a strong predictor of low health literacy in STOFHLA, REALM, and METER. Male sex was found to be a significant predictor of poor performance in REALM and METER, but not STOFHLA. CONCLUSION: Low health literacy is an important issue in the southwestern Ontario RA population. About 1 in 7 patients with RA may not have the necessary skills to become involved in making decisions regarding their personal health. Rheumatologists should be aware of the low health literacy levels of patients with RA and should consider identifying patients at risk of low health literacy. PMID- 26233511 TI - Discordance of Global Assessments by Patient and Physician Is Higher in Female than in Male Patients Regardless of the Physician's Sex: Data on Patients with Rheumatoid Arthritis, Axial Spondyloarthritis, and Psoriatic Arthritis from the DANBIO Registry. AB - OBJECTIVE: To assess the frequency of discordance in patient's (PtGA) and physician's (PGA) global assessment, and to investigate whether higher discordance in female patients compared with male patients is associated with the physician's sex in patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), and psoriatic arthritis (PsA). METHODS: PtGA, PGA, and other patient-related variables were retrieved from the Danish DANBIO registry, used nationwide to monitor patients with RA, axSpA, and PsA. A questionnaire was sent to all physicians registering in DANBIO (n = 265) regarding individual physician characteristics including sex and age. Discordance was defined as PtGA > 20 mm higher (or lower) than PGA. First encounters between patients and physicians were analyzed using descriptive statistics and mixed model regression analysis. RESULTS: Ninety physicians (34%) returned the questionnaire and were pairwise matched with 10,282 first patient encounters (8300 patients with RA, 524 axSpA, and 1458 PsA). The frequency of discordant (PtGA > PGA) encounters (not including PGA > PtGA seen in < 2%) in RA, axSpA, and PsA was 49.0%, 48.3%, and 56.5%, respectively. Discordance was more common in female patients with high scores on functional disability, pain, and fatigue across the 3 diseases, whereas it was independent of the physician's sex. CONCLUSION: In this study on Danish patients with RA, axSpA, and PsA, the PtGA was > 20 mm higher than the PGA in about half of the encounters, and more common in female patients of both female and male physicians. This finding highlights one of the challenges in shared decision making. PMID- 26233512 TI - Pronounced Risk of Fractures among Elderly Men Affected by Granulomatosis with Polyangiitis. AB - OBJECTIVE: It is unknown whether patients affected by granulomatosis with polyangiitis (GPA) are at increased risk of fractures, and whether the fracture risk in GPA varies with age and sex. The aim of the present study was to compare the fracture risk among patients with GPA with that among age- and sex-matched population controls. METHODS: We established a monocentric cohort of patients treated for GPA at a Danish tertiary care center from 1995 to 2010 (n = 159) and a register-derived GPA cohort identified from the Danish National Hospital Register (n = 402). Each patient was matched with 7 population controls. The occurrence of fractures among patients was compared with that among controls by calculation of incidence rate ratios (IRR). RESULTS: In the monocentric cohort, an increased fracture risk was observed among men aged >= 55 years at the time of first hospitalization for GPA (IRR 3.5, 95% CI 1.6-7.6), but not among men < 55 years (IRR 0.3, 95% CI 0.04-2.1) or women (IRR women >= 55 yrs: 1.0, 95% CI 0.4 2.7 and IRR for women < 55 yrs: 0.7, 95% CI 0.2-2.4). In the register-derived cohort, an increased fracture risk was also observed among men aged >= 55 years at study baseline (IRR 2.0, 95% CI 1.2-3.5), whereas the incidence rate of fractures was not significantly increased among younger men or women (IRR for men < 55 yrs: 1.0, 95% CI 0.4-2.3; IRR for women >= 55 yrs: 0.9, 95% CI 0.5-1.5; IRR for women < 55 yrs: 1.6, 95% CI 0.7-3.6). CONCLUSION: Elderly male patients with GPA have a pronounced risk of developing fractures. This finding is of relevance for the clinical management of patients with GPA. PMID- 26233513 TI - An Observational Study of Gout Prevalence and Quality of Care in a National Australian General Practice Population. AB - OBJECTIVE: The central strategy for effective gout management is longterm urate lowering therapy to maintain the serum urate at a level below 0.36 mmol/l. We sought to determine the prevalence of gout and the quality of care in a national Australian general practice population. METHODS: Data were from general practice point-of-care electronic records over a 5-year period (n = 1,479,449). Information was collected on patients with gout according to a validated definition. All patients who visited the same general practices over the study period formed the denominator group. We determined the estimated prevalence of gout, the frequency of allopurinol prescription, and serum urate testing, and the percentage of patients achieving a target serum urate level. RESULTS: The crude prevalence of gout in this general practice population was 1.54% (95% CI 1.52 1.56). Prevalence in men was 2.67% and in women 0.53%. Prevalence increased with age in both men and women (4.90%, 95% CI 4.82-4.99, in men > 65 yrs). Allopurinol was prescribed to 57% of patients with gout during the 5 years of the study. Only 55% of patients with gout had their serum urate tested at any time during the 5 year study period. A target serum urate concentration of < 0.36 mmol/l at any time during the 5-year study period was documented in 22.4% of all people with gout. CONCLUSION: Gout is managed poorly in Australian primary care, with low levels of allopurinol prescribing and serum urate testing. Collectively, these factors probably contribute to low achievement of serum urate targets. PMID- 26233514 TI - [Percutaneous treatment of mitral valve regurgitation: Initial experience with the MitraClip device]. AB - INTRODUCTION: Mitral regurgitation (MR) is the most common valvular disease and has recently become the target of a number of percutaneous approaches. The MitraClip is virtually the only device for which there is considerable experience, with more than 20,000 procedures performed worldwide. OBJECTIVE: To describe our initial experience of the percutaneous treatment of MR with the MitraClip device. METHODS: We describe the first six MitraClip cases performed in this institution (mean age 58.5 +/- 13.1 years), with functional MR grade 4+ and New York Heart Association (NYHA) heart failure class III or IV (n=3), with a mean follow-up of 290 +/- 145 days. RESULTS: Procedural success (MR <= 2+) was 100%. Total procedure time was 115.8 +/- 23.7 min, with no in-hospital adverse events and discharge between the fourth and eighth day, and consistent improvement in the six-minute walk test (329.8 +/- 98.42 vs. 385.33 +/- 106.95 m) and in NYHA class (three patients improved by two NYHA classes). During follow-up there were two deaths, in two of the four patients who had been initially considered for heart transplantation. CONCLUSION: In patients with functional MR the MitraClip procedure is safe, with both a high implantation and immediate in hospital success rate. A longer follow-up suggests that the clinical benefit decreases or disappears completely in patients with more advanced heart disease, namely those denied transplantation or on the heart transplant waiting list. PMID- 26233515 TI - The specifics of vector transmission of arboviruses of vertebrates and plants. AB - Blood-feeding or sap-feeding arthropods, principally in the taxa Acarina and Insecta are major vectors of viruses of plants and vertebrates. The enormous associated literature suggests that the virus-vector interaction can be of distinct types, some adopted specifically by plant viruses and others by vertebrate viruses. Based on emblematic examples of poxviruses and orthomyxoviruses of vertebrates and of luteovirus, geminivirus, and nanovirus of plants, we here discuss the possibility that the current restriction of certain transmission modes to a given host type may simply reflect limited knowledge. Particularly, we question the absence of a specific relationship in some cases of 'mechanical' transmission of viruses of vertebrates and challenge the so-called 'circulative non-propagative' transmission as a discrete concept specific to plant viruses. PMID- 26233517 TI - Proposal for creation of a new genus Neomicrococcus gen. nov. to accommodate Zhihengliuella aestuarii Baik et al. 2011 and Micrococcus lactis Chittpurna et al. 2011 as Neomicrococcus aestuarii comb. nov. and Neomicrococcus lactis comb. nov. AB - Micrococcus lactis and Zhihengliuella aestuarii were described independently in 2011. Their type strains showed high levels of 16S rRNA gene sequence similarity (99.3%). Phylogenetic analysis revealed that M. lactis MCC 2278T and Z. aestuarii JCM 16166T formed a monophyletic group and showed distant relationships to other members of closely related genera such as Micrococcus, Zhihengliuella, Arthrobacter and Citricoccus. The presence of large proportions of iso-C14:0 and iso-C16:0 with small amounts of iso-C15:0 distinguished M. lactis MCC 2278T and Z. aestuarii JCM 16166T from other members of the genera Micrococcus and Zhihengliuella. Unlike other members of the genera Zhihengliuella and Micrococcus, M. lactis MCC 2278T and Z. aestuarii JCM 16166T showed growth at low concentrations of NaCl. Thus, based on distinctive phylogenetic, chemotaxonomic and physiological features of these two organisms in comparison with other members of the genera Micrococcus and Zhihengliuella, it is clear that they do not fit within the existing classification and deserve separate status. DNA-DNA hybridization between the two type strains was 63%, indicating that they represent separate species. In this study, we propose the creation of a novel genus, Neomicrococcus gen. nov., to accommodate the two species with Neomicrococcus aestuarii gen. nov., comb. nov. (type strain JCM 16166T = KCTC 19557T) as the type species. Neomicrococcus lactis comb. nov. (type strain MCC 2278T = DSM 23694T) is also proposed. PMID- 26233518 TI - [Systematic vaccination: Convinced, hesitants and radicals]. PMID- 26233519 TI - Devastating recurrent brain ischemic infarctions and retinal disease in pediatric patients with CD59 deficiency. AB - Identification of CD59 p.Cys89Tyr mutation in 5 patients from North-African Jewish origin presenting with chronic inflammatory demyelinating polyradiculoneuropathy like disease and chronic hemolysis, led us to reinvestigate an unsolved disease in 2 siblings from the same origin who died 17 years ago. The two patients carried the same CD59 gene mutation previously described by our group. These children had quiet similar disease course but in addition developed devastating recurrent brain infarctions, retinal and optic nerve involvement. Revising the brain autopsy of one of these patients confirmed the finding of multiple brain infarctions of different ages. CD59 protein expression was missing on brain endothelial cells by immunohistochemical staining. This new data expands the clinical spectrum of CD59 mutations and further emphasizes the need for its early detection and treatment. PMID- 26233520 TI - Utilization of cardiac computed tomography angiography and outpatient invasive coronary angiography in Ontario, Canada. AB - BACKGROUND: Cardiac computed tomography angiography (coronary CTA) has emerged as a non-invasive method of diagnosing coronary artery disease. The extent of utilization and uptake of this technology since initiation of its funding by the government of Ontario is unknown. OBJECTIVES: The aim of our study was to examine coronary CTA utilization and the rates of elective invasive coronary angiography and revascularization before and after funding initiation. METHODS: We studied all coronary CTAs performed on adults in Ontario after initiation of funding. We also used an interrupted time series analysis to compare the average monthly rates of invasive angiography and revascularization before and after initiation of funding. RESULTS: There was an initial steep increase in age-and sex standardized rates of coronary CTA from 5.0 to 11.4/100,000 over the first two quarters after funding initiation. Afterwards, there was a gradual increase in utilization from 11.4 to 17.1/100,000 over two subsequent calendar years. There was a significant reduction in both the mean monthly outpatient invasive coronary angiography (from 20.7 to 19.9 per 100,000 (p = 0.0004)) and revascularization (from 4.9 to 4.4 per 100,000 (p < 0.0001)) rates in the three years following introduction of the coronary CTA billing code as compared to the three prior to its introduction. CONCLUSIONS: Since the introduction of coronary CTA funding in Ontario, there has been a steady and controlled increase in its utilization. The increasing use of coronary CTA was associated with a reduction in both the rates of invasive angiography and revascularization. PMID- 26233521 TI - Frontal-posterior theta oscillations reflect memory retrieval during sentence comprehension. AB - Successful working-memory retrieval requires that items be retained as distinct units. At the neural level, it has been shown that theta-band oscillatory power increases with the number of to-be-distinguished items during working-memory retrieval. Here we hypothesized that during sentence comprehension, verbal working-memory retrieval demands lead to increased theta power over frontal cortex, supposedly supporting the distinction amongst stored items during verbal working-memory retrieval. Also, synchronicity may increase between the frontal cortex and the posterior cortex, with the latter supposedly supporting item retention. We operationalized retrieval by using pronouns, which refer to and trigger the retrieval of antecedent nouns from a preceding sentence part. Retrieval demand was systematically varied by changing the pronoun antecedent: Either, it was non-embedded in the preceding main clause, and thus easy-to retrieve across a single clause boundary, or embedded in the preceding subordinate clause, and thus hard-to-retrieve across a double clause boundary. We combined electroencephalography (EEG), scalp-level time-frequency analysis, source localization, and source-level coherence analysis, observing a frontal midline and broad left-hemispheric theta-power increase for embedded-antecedent compared to non-embedded-antecedent retrieval. Sources were localized to left frontal, left-parietal, and bilateral-inferior-temporal cortices. Coherence analyses suggested synchronicity between left-frontal and left-parietal and between left-frontal and right-inferior-temporal cortices. Activity of an array of left-frontal, left-parietal, and bilateral-inferior-temporal cortices may thus assist retrieval during sentence comprehension, potentially indexing the orchestration of item distinction, verbal working memory, and long-term memory. Our results extend prior findings by mapping prior knowledge on the functional role of theta oscillations onto processes genuine to human sentence comprehension. PMID- 26233523 TI - Bodystorming: effects of collaboration and familiarity on improvising contemporary dance. AB - In contemporary dance, cognitive events are not necessarily restricted "to the skin or skull of an individual" (Hutchins in Int Encycl Soc Behav Sci 2068-2072, 2001) but distributed across dancers during collaborative improvisation. There is some experimental evidence of greater output when people perform problem-solving tasks alone. However, when a task is challenging and paired participants are familiar with each other, pairwise and emergent outcomes are more plentiful than solo outcomes. We investigate these factors in the context of dance with the broad hypothesis that innovation is enhanced when dancers improvise together compared with when they improvise alone. Dancers (N = 10) in a professional company improvised for 2 min alone and then with another dancer. Dancer familiarity (familiar, unfamiliar) and task (expressive, non-expressive) were crossed (within-subjects). The improvisations were video-recorded over 2 h in the dancers' usual improvisation space. After each improvisation, the dancers: stated the number of movement ideas expressed and rated task ease, satisfaction, interest, novelty, originality and clarity. In both tasks, there was a tendency for self-report of a greater number of movement ideas expressed in familiar and unfamiliar pairs than alone. Ratings of task ease, satisfaction, interest, clarity, etc. were slightly higher in the unfamiliar pair condition. In the non expressive task, ratings of the task were higher in pairs (M = 3.02, SD 0.82) than in the solo (M = 2.67, SD 0.96) condition. Distributed creativity, relational cognition and social facilitation are used to interpret the results. PMID- 26233522 TI - Coexpression of cyclin D1 and alpha-internexin in oligodendroglial tumors. AB - Oligodendroglial tumors with neuronal differentiation cases have been reported in recent studies. Oligodendrocyte precursor cells (OPCs) give rise to both oligodendrocytes and neurons; however, little is known about the association between OPCs and oligodendroglial tumors with neuronal differentiation. Previously, we observed the coexpression of cyclin D1, one of the OPC markers, and alpha-internexin (INA) in oligodendroglial tumor cells. INA is a neuronal marker, and has been indicated as an immunohistochemical surrogate of chromosome 1p/19q co-deletion in oligodendroglial tumors. In this study, we investigated the expression status in 83 gliomas immunohistochemically, and found that cyclin D1 positive cells were commonly detected in gliomas. There was no correlation between the cyclin D1 and Ki-67 labeling indices, suggesting an unrecognized role of cyclin D1 other than a cell cycle regulator in gliomas. Cyclin D1/INA double positive cells were consistently observed in oligodendroglial tumors regardless of histological grade. In 2 cases of oligodendroglioma with neuronal differentiation, the tumor cells of neuronal morphology showed higher expression of INA, suggesting INA expression may be associated with a bona fide neuronal phenotype. The prevalence of cyclin D1/INA double-positive cells is a distinct feature of oligodendroglial tumors. This new characteristic finding may have practical utility in glioma classification. PMID- 26233524 TI - Movement specific reinvestment and allocation of attention by older adults during walking. AB - Older repeat fallers have previously been shown to have a higher propensity to consciously monitor and control their movements (i.e. reinvestment) than non fallers, yet to direct their attention equally between their limb movements and the external environment during locomotion (Wong et al. in J Am Geriatr Soc 57: 920-922, 2009). Whether increased attention to their movements is a result of falling or originates from a prior inclination to reinvest remains unclear. In order to better understand the interaction between reinvestment and attention during locomotion, this study examined the allocation of attention by older adults who had not fallen but displayed a high or low inclination for reinvestment. Twenty-eight low and twenty-eight high reinvestors were required to perform 30 walking trials. Their allocation of attention during walking was evaluated by asking tone-related attentional focus questions shortly after finishing each walking trial. High reinvestors were found to be more aware of their limb movements and less aware of the external environment. Low reinvestors, on the contrary, were more aware of the surrounding environment and less aware of their movement mechanics. Given that focusing internally to body movements has been proposed to utilise working memory capacity, the ability of high reinvestors to pick up all the environmental information necessary for successful locomotion might be compromised and requires further examination. PMID- 26233525 TI - Subjective present: a window of temporal integration indexed by mismatch negativity. AB - It has been proposed that temporal perception is implemented in a "time window" of approximately 3 s which we experience as "present". Using mismatch negativity (MMN), we tested the hypothesis whether a time window of 3 s is selective for pre attentively detecting the violation of regularity in a stimulus sequence by employing different interstimulus intervals. Our results showed that in frontal midline areas, the amplitudes of MMN were significantly larger for the shorter interstimulus intervals up to 3 s than for the longer ones. In lateralized frontal areas, male subjects seemed to have a stronger effect in the temporal modulation of the MMN, which might deserve further investigation. We conclude that a time window of 3 s is selective for neuronal mechanisms to process deviant stimuli and that information processing is temporally segmented, creating a "subjective present" in discrete sequential steps. PMID- 26233526 TI - An implicit spatial memory alignment effect. AB - The memory alignment effect is the advantage of reasoning from a perspective which is aligned with the frame of reference used to encode an environment in memory. It usually occurs when participants have to consciously take a perspective to perform a spatial memory task. The present experiment assesses whether the memory alignment effect can occur without requiring to consciously take a given perspective, when the misaligned perspective is only perceptively provided. In others words, does the memory alignment effect still arise when it is only implicitly prompted? Thirty participants learned a sequence of four objects' positions in a room from a north-as-up survey perspective. During the testing phase, they had to point to the direction of a target object from another object ('the reference') with a fixed north-up orientation. The background behind the reference object displayed either a uniform color (control condition) or a misaligned ground-level perspective. The latter displayed a reference object's position information which was either congruent with the studied environment (congruent misaligned condition) or incongruent (incongruent misaligned condition). Mean pointing errors were higher in the congruent misaligned condition than in the control condition, whereas the incongruent misaligned condition did not differ from the control one. The present study shows that the memory alignment effect can arise without requiring a conscious misaligned perspective taking. Moreover, the perceived misaligned perspective must share the same spatial content as the memorized spatial representation in order to induce an alignment effect. PMID- 26233527 TI - How language impacts memory of motion events in English and French. AB - This paper examines whether cross-linguistic differences in motion encoding affect event processing, specifically memory performance. We compared speakers of two languages which differ strikingly in how they habitually encode MANNER and PATH of motion (Talmy in Toward a cognitive semantics: typology and process in concept structuring, 2nd edn, vol 2. MIT Press, Cambridge, 2000). We tested French and English adult native speakers across three tasks that recruited and/or suppressed verbal processing to different extents: verbal event descriptions elicited on the basis of dynamic motion stimuli, a verbal memory task testing the impact of prior verbalisation on target recognition, and a non-verbal memory task, using a dual-task paradigm to suppress internal verbalisation. Results showed significant group differences in the verbal description task, which mirrored expected typological tendencies. English speakers more frequently expressed both MANNER and PATH information than French speakers, who produced more descriptions encoding either PATH or MANNER alone. However, these differences in linguistic encoding did not significantly affect speakers' memory performance in the memory recognition tasks, neither in the verbal nor in the non verbal condition. The findings contribute to current debates regarding the conditions under which language effects occur and the relative weight of language specific and universal constraints on spatial cognition. PMID- 26233528 TI - To fly or not to fly? The automatic influence of negation on language-space associations. AB - Embodied models of language understanding propose a close association between language comprehension and sensorimotor processes. Specifically, they suggest that meaning representation is grounded in modal experiences. Converging evidence suggests that words automatically activate spatial processing. For example, words such as 'sky' ('ground') facilitate motor and visual processing associated with upper (lower) space. However, very little is known regarding the influence of linguistic operators such as negation on these language-space associations. If these associations play a crucial role for language understanding beyond the word level, one would expect linguistic operators to automatically influence or modify these language-space associations. Participants read sentences describing an event implying an upward or a downward motion in an affirmative or negated version (e.g. The granny looks to the sky/ground vs. The granny does not look to the sky/ground). Subsequently, participants responded with an upward or downward arm movement according to the colour of a dot on the screen. The results showed that the motion direction implied in the sentences influenced subsequent spatially directed motor responses. For affirmative sentences, arm movements were faster if they matched the movement direction implied in the sentence. This language-space association was modified by the negation operator. Our results show that linguistic operators--such as negation--automatically modify language space associations. Thus, language-space associations seem to reflect language processes beyond pure word-based activations. PMID- 26233529 TI - Intersection of reality and fiction in art perception: pictorial space, body sway and mental imagery. AB - BACKGROUND: The thesis of embodied cognition claims that perception of the environment entails a complex set of multisensory processes which forms a basis for the agent's potential and immediate actions. However, in the case of artworks, an agent becomes an observer and action turns into a reaction. This raises questions about the presence of embodied or situated cognition involved in art reception. AIMS: The study aimed to assess the bodily correlates of perceiving fictional pictorial spaces in the absence of a possibility of an actual physical immersion or manipulation of represented forms. METHOD: The subjects were presented with paintings by Vermeer and De Hooch, whilst their body sway and eye movements were recorded. Moreover, test and questionnaires on mental imagery (MRT, VVIQ and OSIQ) were administered. RESULTS: Three major results were obtained: (1) the degree of pictorial depth did not influence body sway; (2) fixations to distant elements in paintings (i.e. backgrounds) were accompanied by an increase in body sway; and (3) mental rotation test scores correlated positively with body sway. CONCLUSIONS: Our results suggest that in certain cases -despite the fictional character of art--observers' reactions resemble reactions to real stimuli. It is proposed that these reactions are mediated by mental imagery (e.g. mental rotation) that contributes to the act of representing alternative to real artistic spaces. PMID- 26233530 TI - Reversing the affordance effect: negative stimulus-response compatibility observed with images of graspable objects. AB - Responses are faster when the task-irrelevant orientation of a graspable object's handle corresponds to the location of the response hand. Over the past decade, research has focused on dissociating between two competing accounts of this effect: One rooted in motoric object affordances and the other resting on attentional mechanisms (i.e., Simon effect). Following this avenue of inquiry, we conducted three experiments, in which subjects had to respond bimanually to grayscale photographs of frying pans and saucepans. In addition to horizontal orientation (control/leftward/rightward handles), Experiments 1 and 2 also manipulated the direction of exogenous attentional shifts (left/right) using laterally placed, colored markers within the objects. Both experiments yielded regular Simon effects based on the location of the colored markers. However, in stark contrast to previous research, a negative stimulus-response compatibility effect was obtained with regard to the orientation of the graspable handles. This reversed affordance effect was also observed using the original, unedited grayscale photographs (Experiment 3), which suggested that its occurrence cannot be attributed to the use of colored markers. These unexpected findings appear to support the idea that Simon effects result from automatic and exogenous attentional orienting mechanisms, whereas affordances arise from controlled and endogenous attentional processes. Such a top-down attentional account of affordance can accommodate the observed reversal of the effect in the context of task characteristics. PMID- 26233531 TI - On the relevance of Gibson's affordance concept for geographical information science (GISc). AB - J. J. Gibson's concept of affordances has provided a theoretical basis for various studies in geographical information science (GISc). This paper sets out to explain its popularity from a GISc perspective. Based on a short review of previous work, it will be argued that its main contributions to GISc are twofold, including an action-centered view of spatial entities and the notion of agent environment mutuality. Using the practical example of pedestrian behavior simulation, new potentials for using and extending affordances are discussed. PMID- 26233532 TI - Preliminary testing of a novel bilateral plating technique for treating periprosthetic fractures of the distal femur. AB - BACKGROUND: Current stabilization methods for periprosthetic fractures of the distal femur are inadequate in achieving fracture fixation, with complication rates as high as 29%. A major contributor to poor outcomes is that these methods rely only on screw purchase in the bone to maintain fracture reduction. We designed, manufactured and evaluated a novel plating method that utilizes the femoral prosthesis to enhance stability for treatment of distal femoral periprosthetic fractures. METHODS: Medial and lateral plates were designed and manufactured based on geometry of a synthetic femur and femoral prosthesis. The two plates were linked via a compression screw and a small tab on each plate that inserted into pre-existing slots on the prosthesis. Mechanical tests (500N compression or 250N anterior directed cantilever bending), were performed on synthetic femurs with simple transverse fractures (3mm gap) just superior to the distal femoral prosthesis that were stabilized using either the prototype plates or a single lateral plate. Translational movements of the fracture site during loading were measured using 3D motion tracking. FINDINGS: With the single lateral plate, the distal fragment experienced a resultant displacement of 0.40mm under cantilever bending and 0.61mm under compression (13% and 20% respectively of fracture gap width). With the bilateral plates, fracture gap motion was significantly reduced to 0.13mm under bending and compression (4.3% of the fracture gap). INTERPRETATION: Our results indicate that a bilateral plating method is capable of improving stabilization of periprosthetic fractures compared to the traditional lateral plating technique. PMID- 26233533 TI - Reply to Masaki Shiota and Akira Yokomizo's Letter to the Editor re: Robert J. van Soest, Ellen S. de Morree, Charlotte F. Kweldam, et al. Targeting the Androgen Receptor Confers In Vivo Cross-resistance Between Enzalutamide and Docetaxel, But Not Cabazitaxel, in Castration-resistant Prostate Cancer. Eur Urol 2015;67:981-5. PMID- 26233535 TI - Identifying the Optimal Role for Pharmacists in Care Transitions: A Systematic Review. AB - BACKGROUND: A transition from one health care setting to another increases the risk of medication errors. Several strategies have been applied to improve care transitions and reduce adverse clinical outcomes. Pharmacist intervention during and after hospitalization has been frequently studied and show a variable effect on these outcomes. OBJECTIVE: To identify the components of pharmacist intervention that improve clinical outcomes during care transitions. METHODS: MEDLINE, EMBASE, International Pharmaceutical Abstracts, and Web of Science databases were searched for randomized controlled trials (RCTs) that studied pharmacist intervention with regard to hospitalization. Two reviewers independently screened all references published from inception to November 2014, extracted data, and assessed risk of bias. RESULTS: A total of 30 studies met the inclusion criteria. A model was created to categorize and cluster components of pharmacist intervention. The average number of components deployed, stages of hospitalization covered, and intervention targets were equally distributed between effective and ineffective studies. A best evidence synthesis of 15 studies revealed strong evidence for a clinical medication review in multifaceted programs (5 effective vs. 0 ineffective studies). Conflicting evidence was found for an isolated postdischarge intervention, admission medication reconciliation, combining postdischarge interventions with in-hospital interventions, and covering of multiple stages. Closely collaborating with other health care providers enhanced the effectiveness. CONCLUSIONS: Although there is a need for well-designed and well-reported RCTs, the study heterogeneity enabled a best evidence synthesis to elucidate effective components of pharmacist intervention. In isolated postdischarge intervention programs, evidence tends towards collaborating with nurses and tailoring to individual patient needs. In multifaceted intervention programs, performing medication reconciliation alone is insufficient in reducing postdischarge clinical outcomes and should be combined with active patient counseling and a clinical medication review. Furthermore, close collaboration between pharmacists and physicians is beneficial. Finally, it is important to secure continuity of care by integrating pharmacists in these multifaceted programs across health care settings. Ultimately, pharmacists need to know patient clinical background and previous hospital experience. PMID- 26233534 TI - The pepper phosphoenolpyruvate carboxykinase CaPEPCK1 is involved in plant immunity against bacterial and oomycete pathogens. AB - Phosphoenolpyruvate carboxykinase, a member of the lyase family, is involved in the metabolic pathway of gluconeogenesis in organisms. Although the major function of PEPCK in gluconeogenesis is well established, it is unclear whether this enzyme is involved in plant immunity. Here, we isolated and identified the pepper (Capsicum annuum) PEPCK (CaPEPCK1) gene from pepper leaves infected with Xanthomonas campestris pv. vesicatoria (Xcv). CaPEPCK1 was strongly expressed in pepper leaves during the incompatible interaction with avirulent Xcv and in response to environmental stresses, especially salicylic acid (SA) treatment. PEPCK activity was low in healthy leaves but dramatically increased in avirulent Xcv-infected leaves. Knock-down expression of CaPEPCK1 by virus-induced gene silencing resulted in high levels of susceptibility to both virulent and avirulent Xcv infection. CaPEPCK1 silencing in pepper compromised induction of the basal defense-marker genes CaPR1 (pathogenesis-related 1 protein), CaPR10 (pathogenesis-related 10 protein) and CaDEF1 (defensin) during Xcv infection. SA accumulation was also significantly suppressed in the CaPEPCK1-silenced pepper leaves infected with Xcv. CaPEPCK1 in an Arabidopsis overexpression (OX) line inhibited the proliferation of Pseudomonas syringae pv. tomato (Pst) and Hyaloperonospora arabidopsidis (Hpa). CaPEPCK1-OX plants developed more rapidly, with enlarged leaves, compared to wild-type plants. The T-DNA insertion Arabidopsis orthologous mutants pck1-3 and pck1-4 were more susceptible to the bacterial Pst and oomycete Hpa pathogens than the wild type. Taken together, these results suggest that CaPEPCK positively contributes to plant innate immunity against hemibiotrophic bacterial and obligate biotrophic oomycete pathogens. PMID- 26233536 TI - Factors Associated with Failure to Achieve SVR in Hepatitis C Genotype 3 Patients Within an Integrated Care Delivery System. AB - BACKGROUND: Achievement of sustained virologic response (SVR) and factors associated with treatment failure in hepatitis C virus (HCV) genotype 3 have been described in tertiary and referral care settings, with rates of SVR reported to range between 72% and 89%. Fewer data exist on SVR outside of these settings. OBJECTIVE: To describe rates of SVR and characterize factors associated with achievement of SVR within an integrated health care delivery system. METHODS: A retrospective cohort study of genotype 3 HCV patients treated with dual therapy (pegylated interferon-alpha plus ribavirin) was conducted at Kaiser Permanente Southern California. Adult patients diagnosed with HCV and testing positive for HCV-RNA genotype 3 were identified from electronic medical records. Data were collected on patient demographics, baseline health status, and comorbid conditions. A multivariate logistic regression model was used to determine the association between baseline patient factors and SVR. RESULTS: A total of 484 HCV genotype 3 patients met the eligibility criteria. The median age was 49 years, and 65.7% were male. Overall, 252 (52.1%) achieved SVR. Aged >= 45 years and male gender were associated with lower rates of SVR; cirrhosis and chronic diseases (diabetes and chronic obstructive pulmonary disease) were also associated with lower rates of SVR. CONCLUSIONS: SVR was lower in patients within an integrated care delivery system than in those in tertiary and referral centers. Males and older patients had lower rates of SVR, as well as patients with cirrhosis, diabetes, and chronic obstructive pulmonary disease. PMID- 26233537 TI - Postmarketing Safety Profile of Subcutaneous Interferon Beta-1a Given 3 Times Weekly: A Retrospective Administrative Claims Analysis. AB - BACKGROUND: Health insurance administrative claims databases represent a valuable source of information regarding the safety profile of marketed products as used in actual clinical practice in a broader range of patients than that assessed in clinical trials. Interferon beta-1a administered subcutaneously 3 times weekly (IFN beta-1a SC tiw), which was approved in 2002 by the FDA for the treatment of relapsing-remitting multiple sclerosis (MS), has over a decade of postmarketing experience. To date, however, its postmarketing safety profile has not been described using a real-world evidence source such as administrative claims data. OBJECTIVE: To describe the safety profile of IFN beta-1a SC tiw as presented in its U.S. prescribing information (PI) for patients with MS initiating IFN beta-1a SC tiw therapy using data from U.S. health care administrative claims databases. METHODS: This study featured an observational and retrospective "new start" cohort design using data from the Truven MarketScan Commercial and Medicare Supplemental health care administrative claims databases. Patients were eligible for inclusion if they were aged >= 18 years; had >= 1 diagnosis for MS recorded between January 1, 2006, and December 31, 2012; had >= 2 prescriptions for IFN beta-1a SC tiw; and had >= 90 days of continuous eligibility pre-index date and >= 180 days of continuous eligibility post-index date. Patients with a prescription for IFN beta-1a SC tiw without a MS diagnosis were excluded. Patients were followed from first prescription for IFN beta-1a SC tiw (index date) until date of therapy switch or discontinuation, end of insurance eligibility, or end of observation period. Adverse events (AEs) examined were those listed in the Warnings and Precautions, Adverse Reactions, and Postmarketing Experience sections of the 2014 U.S. PI. Outcomes of interest were identified at the Medical Dictionary for Regulatory Activities (version 17.1) Preferred Term level and then coded to the corresponding ICD-9-CM criteria. Descriptive analyses of patient demographic, health status, health care utilization, and adherence status were performed, and incidence rates (IRs) per 100 person-years of labeled AEs with corresponding 95% CIs were calculated. The IR calculation was based on events that presented after therapy initiation and that were not present in the 90-day pre-index period. RESULTS: The top 6 AEs included influenza-like symptoms (IR = 15.65, 95% CI = 14.96-16.36); malaise (IR = 15.33, 95% CI = 14.65-16.04; fatigue (IR = 15.02, 95% CI = 14.35-15.72); abdominal pain (IR = 10.18, 95% CI = 9.67-10.70); chest pain (IR = 8.48, 95% CI = 8.03-8.95); and depression (IR = 7.75, 95% CI = 7.32-8.20). In contrast, the 6 lowest IRs were for maculo-papular rash (IR = 0.01, 95% CI = 0.00-0.04; injection site necrosis (IR = 0.01, 95% CI = 0.00-0.03); erythema multiforme (IR = 0.01, 95% CI = 0.00-0.04); hypoesthesia (IR = 0.00, 95% CI = 0.00-0.02); Stevens Johnson Syndrome (IR = 0.00, 95% CI = 0.00-0.02); and xerophthalmia (IR = 0.00, 95% CI = 0.00-0.02). CONCLUSIONS: Study results show strong convergence between the real-world safety profile of IFN beta-1a SC tiw and its U.S. label. Our findings demonstrate the value of using real-world evidence obtained from administrative claims to complement clinical trial and postmarketing surveillance data in order to characterize the safety profile of established products, such as IFN beta-1a SC tiw, in the postmarketing context. PMID- 26233538 TI - Impact of Appointment-Based Medication Synchronization on Existing Users of Chronic Medications. AB - BACKGROUND: Appointment-based medication synchronization (ABMS) has been associated with greater patient adherence and persistence when patients begin taking chronic medications. It is not known whether similar results will be seen for patients who have been taking chronic medications for 6 months or more. OBJECTIVE: To compare the impact of a community pharmacy chain's ABMS program on medication adherence and persistence of existing users of chronic medications with individuals who are not enrolled in the program. METHODS: A retrospective cohort study compared patients receiving ABMS with matched comparison groups receiving usual care. ABMS consisted of synchronizing a patient's medications to be dispensed on a single appointment day every month, a call to the patient prior to the appointment day to address any prescription changes and to remind the patient, and a patient visit to the pharmacy to pick up the medications. Outcomes were 1-year adherence rates using proportion of days covered (PDC) and 1-year nonpersistence rates. Data for this study came from prescription claims records of patients taking 1 of 6 chronic medication classes during the period of December 1, 2011, to February 28, 2014. ABMS patients were matched with comparison groups according to prior adherence behavior, medication class, age, gender, and geographic region. RESULTS: Mean PDC scores ranged from 0.73 to 0.91 for ABMS patients (n = 205 to 716) and from 0.57 to 0.71 for usual care depending on the medication class. The percentage of adherent individuals (i.e., PDC >= 0.80) was 55% to 84% for ABMS participants and 37% to 62% for usual care. Odds of adherence was 2.3 to 3.6 times greater with ABMS. Usual care patients became nonpersistent (61% to 74%) more often than ABMS patients (33% to 44%) with hazard ratios of nonpersistence being 0.39 to 0.67 for individuals in the program. CONCLUSIONS: An ABMS program in a community pharmacy setting was associated with higher rates of adherence and persistence for patients who had been taking chronic medications for at least 6 months. Approximately 18 to 35 additional ABMS participants were adherent for every 100 patients enrolled when compared with usual care. For every 100 patients receiving usual care, 17 to 40 additional patients in the ABMS group were persistent. This study shows that ABMS programs can improve medication adherence and persistence for patients who are newly prescribed or currently taking chronic medications. PMID- 26233539 TI - Impact of Employer-Sponsored Onsite Pharmacy and Condition Management Programs on Medication Adherence. AB - BACKGROUND: Poor medication adherence is associated with worsened health outcomes and higher health care expenditures. An increasing number of employers are sponsoring wellness initiatives designed to support healthy lifestyles, improve productivity, and offer a return on investment. Onsite pharmacies may facilitate higher medication adherence rates by providing employees a convenient, low-cost option for filling prescriptions that is integrated with other onsite health services. OBJECTIVES: To (a) assess the impact of an employer's onsite pharmacy on health plan members' medication adherence using multiple measures of medication adherence and persistence, including medication possession ratio (MPR), average number of days until discontinuation (60-day gap in coverage), and percentage of members without a 30-day gap in coverage, and (b) evaluate these outcomes between those members who participated in condition management programs and those who did not. METHODS: A retrospective analysis of a self-insured employer's claims data was undertaken. Medication adherence was assessed among the self-insured employer's health plan members, which included subscribers and their dependents who filled an asthma, depression, diabetes, hypertension, or hyperlipidemia medication at an onsite pharmacy, compared with those who used a community pharmacy. Multiple standard measures of medication adherence were considered. These measures included MPR, which was assessed for 1- and 2-year time periods. MPR was chosen because it is one of the most commonly referenced formulas in the literature and represents adherence over a fixed period of time. In addition, medication persistence was estimated by 30-day gaps in coverage and discontinuation of treatment. To assess the impact of onsite pharmacy use and account for covariate effects, the linear mixed model approach was applied with the logit transformed MPR as the response variable. An analysis of MPR among condition management participants was also performed. RESULTS: In total, 2,498 subscribers and their dependents were included in the analysis. The average MPR at 365 days was significantly higher (P < 0.0001) among onsite pharmacy users for all medication types, ranging from 13% higher for depression medications to 20% higher for hypertension medications. This trend persisted at 730 days (P < 0.001), with average MPRs ranging from 6% higher for hyperlipidemia medications to 11% higher for hypertension medications. A mixed model analysis indicated that members who used the onsite pharmacy were 3.44 times more likely to demonstrate medication adherence (95% CI = 2.84-4.16; P < 0.0001) at 365 days. Likewise, at 180 and 365 days, onsite pharmacy users were less likely to have 30-day gaps in treatment. The average number of days until discontinuation (defined as a 60-day gap) was also significantly longer (P < 0.0001) among onsite pharmacy users, ranging from an average of 56 additional days for depression medications to 105 additional days for hypertension medications. While the average MPR tended to be higher among those subscribers and their dependents who participated in condition management programs, this trend was not statistically significant for all medication types. CONCLUSIONS: Based on multiple measures, onsite pharmacy use was associated with higher medication adherence, while the results were inconclusive for condition management participation. PMID- 26233540 TI - The Effects of Cost Sharing on Adherence to Medications Prescribed for Concurrent Use: Do Definitions Matter? AB - BACKGROUND: Accurate estimates of the effects of cost sharing on adherence to medications prescribed for use together, also called concurrent adherence, are important for researchers, payers, and policymakers who want to reduce barriers to adherence for chronic condition patients prescribed multiple medications concurrently. But measure definition consensus is lacking, and the effects of different definitions on estimates of cost-related nonadherence are unevaluated. OBJECTIVES: To (a) compare estimates of cost-related nonadherence using different measure definitions and (b) provide guidance for analyses of the effects of cost sharing on concurrent adherence. METHODS: This is a retrospective cohort study of Medicare Part D beneficiaries aged 65 years and older who used multiple oral antidiabetics concurrently in 2008 and 2009. We compared patients with standard coverage, which contains cost-sharing requirements in deductible (100%), initial (25%), and coverage gap (100%) phases, to patients with a low-income subsidy (LIS) and minimal cost-sharing requirements. Data source was the IMS Health Longitudinal Prescription Database. Patients with standard coverage were propensity matched to controls with LIS coverage. Propensity score was developed using logistic regression to model likelihood of Part D standard enrollment, controlling for sociodemographic and health status characteristics. For analysis, 3 definitions were used for unadjusted and adjusted estimates of adherence: (1) patients adherent to All medications; (2) patients adherent on Average; and (3) patients adherent to Any medication. Analyses were conducted using the full study sample and then repeated in analytic subgroups where patients used (a) 1 or more costly branded oral antidiabetics or (b) inexpensive generics only. RESULTS: We identified 12,771 propensity matched patients with Medicare Part D standard (N = 6,298) or LIS (N = 6,473) coverage who used oral antidiabetics in 2 or more of the same classes in 2008 and 2009. In this sample, estimates of the effects of cost sharing on concurrent adherence varied by measure definition, coverage type, and proportion of patients using more costly branded drugs. Adherence rates ranged from 37% (All: standard patients using 1+ branded) to 97% (Any: LIS using generics only). In adjusted estimates, standard patients using branded drugs had 0.63 (95% CI = 0.57-0.70) and 0.70 (95% CI = 0.63-0.77) times the odds of concurrent adherence using All and Average definitions, respectively. The Any subgroup was not significant (OR = 0.89, 95% CI = 0.87-1.17). Estimates also varied in the full-study sample (All: OR = 0.79, 95% CI = 0.74-0.85; Average: OR = 0.83, 95% CI = 0.77-0.89) and generics-only subgroup, although cost-sharing effects were smaller. The Any subgroup generated no significant estimates. CONCLUSIONS: Different concurrent adherence measure definitions lead to markedly different findings of the effects of cost sharing on concurrent adherence, with All and Average subgroups sensitive to these effects. However, when more study patients use inexpensive generics, estimates of these effects on adherence to branded medications with higher cost-sharing requirements may be diluted. When selecting a measure definition, researchers, payers, and policy analysts should consider the range of medication prices patients face, use a measure sensitive to the effects of cost sharing on adherence, and perform subgroup analyses for patients prescribed more medications for which they must pay more, since these patients are most vulnerable to cost-related nonadherence. PMID- 26233541 TI - Reach and Validity of an Objective Medication Adherence Measure Among Safety Net Health Plan Members with Diabetes: A Cross-Sectional Study. AB - BACKGROUND: With the expansion of Medicaid and low-cost health insurance plans among diverse patient populations, objective measures of medication adherence using pharmacy claims could advance clinical care and translational research for safety net care. However, safety net patients may experience fluctuating prescription drug coverage, affecting the performance of adherence measures. OBJECTIVE: To evaluate the performance of continuous medication gap (CMG) for diverse, low-income managed care members with diabetes. METHODS: We conducted this cross-sectional analysis using administrative and clinical data for 680 members eligible for a self-management support trial at a nonprofit, government sponsored managed care plan. We applied CMG methodology to cardiometabolic medication claims for English- , Cantonese- , or Spanish-speaking members with diabetes. We examined inclusiveness (the proportion with calculable CMG) and selectivity (sociodemographic and medical differences from members without CMG). For validity, we examined unadjusted associations of suboptimal adherence (CMG > 20%) with suboptimal cardiometabolic control. RESULTS: 429 members (63%) had calculable CMG. Compared with members without CMG, members with CMG were younger, more likely employed, and had poorer glycemic control but had better blood pressure and lipid control. Suboptimal adherence occurred more frequently among members with poor cardiometabolic control than among members with optimal control (28% vs. 12%, P = 0.02). CONCLUSIONS: CMG demonstrated acceptable inclusiveness and validity in a diverse, low-income safety net population, comparable with its performance in studies among other insured populations. CMG may provide a useful tool to measure adherence among increasingly diverse Medicaid populations, complemented by other strategies to reach those not captured by CMG. PMID- 26233542 TI - Improving the Efficiency and Quality of the Value Assessment Process for Companion Diagnostic Tests: The Companion test Assessment Tool (CAT). AB - BACKGROUND: Companion diagnostic tests (CDTs) have emerged as a vital technology in the effective use of an increasing number of targeted drug therapies. Although CDTs can offer a multitude of potential benefits, assessing their value within a health technology appraisal process can be challenging because of a complex array of factors that influence clinical and economic outcomes. OBJECTIVE: To develop a user-friendly tool to assist managed care and other health care decision makers in screening companion tests and determining whether an intensive technology review is necessary and, if so, where the review should be focused to improve efficiency. METHODS: First, we conducted a systematic literature review of CDT cost-effectiveness studies to identify value drivers. Second, we conducted key informant interviews with a diverse group of stakeholders to elicit feedback and solicit any additional value drivers and identify desirable attributes for an evidence review tool. A draft tool was developed based on this information that captured value drivers, usability features, and had a particular focus on practical use by nonexperts. Finally, the tool was pilot tested with test developers and managed care evidence evaluators to assess face-validity and usability. The tool was also evaluated using several diverse examples of existing companion diagnostics and refined accordingly. RESULTS: We identified 65 cost effectiveness studies of companion diagnostic technologies. The following factors were most commonly identified as value drivers from our literature review: clinical validity of testing; efficacy, safety, and cost of baseline and alternative treatments; cost and mortality of health states; and biomarker prevalence and testing cost. Stakeholders identified the following additional factors that they believed influenced the overall value of a companion test: regulatory status, actionability, utility, and market penetration. These factors were used to maximize the efficiency of the evidence review process. Stakeholders also stated that a tool should be easy to use and time efficient. Cognitive interviews with stakeholders led to minor changes in the draft tool to improve usability and relevance. The final tool consisted of 4 sections: (1) eligibility for review (2 questions), (2) prioritization of review (3 questions), (3) clinical review (3 questions), and (4) economic review (5 questions). CONCLUSIONS: Although the evaluation of CDTs can be challenging because of limited evidence and the added complexity of incorporating a diagnostic test into drug treatment decisions, using a pragmatic tool to identify tests that do not need extensive evaluation may improve the efficiency and effectiveness of CDT value assessments. PMID- 26233543 TI - Appointment-Based Models and Medication Synchronization: Silver Bullet for Adherence or One Piece of the Puzzle? PMID- 26233544 TI - MiR-141 Inhibits Gastric Cancer Proliferation by Interacting with Long Noncoding RNA MEG3 and Down-Regulating E2F3 Expression. AB - BACKGROUND: MiR-141 and long noncoding RNA MEG3 have been independently reported to be tumor suppressor genes in various cancers. However, their expression has never been previously associated with gastric cancer (GC). AIMS: To investigate the interaction of miR-141 and MEG3 in GC. METHODS: QRT-PCR was used to detect miR-141, MEG3, and E2F3 in gastric tissues and cells. CCK-8 and flow cytometry analysis were used to detect cell functions. Western blot and luciferase activity were used to identify E2F3 as one of the direct targets of miR-141. RESULTS: We found that expression of both miR-141 and MEG3 was significantly reduced in GC compared with levels in matched nonmalignant tissues. Positive correlation between miR-141 and MEG3 was found in both tumor tissues and control tissues. Furthermore, the over-expression of either miR-141 or MEG3 in 7901 and MKN45 cells inhibited cell proliferation and cell cycle progression and promoted cell apoptosis. E2F3 was identified as a target of miR-141, and its inhibition significantly reduced MEG3 expression. E2F3 expression was also found to be negatively associated with both MEG3 and miR-141. E2F3 over-expression partly reversed the changes caused by transfection of miR-141 mimic, and inhibition of miR-141 or MEG3 overrides MEG3- or miR-141-induced modulation of cell growth in GC. CONCLUSIONS: These findings together suggested that miR-141 could be interacting with MEG3 and targeting E2F3, and these factors may play important anti-tumor effects in GC pathogenesis and provide therapeutic targets in the clinics. PMID- 26233546 TI - Novel Use of Long, Large-Caliber, Fenestrated Stents for Endoscopic Transpapillary Gallbladder Stenting for Therapy of Symptomatic Gallbladder Disease. PMID- 26233545 TI - Protective Effect of Peroxiredoxin 6 in Ischemia/Reperfusion-Induced Damage of Small Intestine. AB - BACKGROUND: Strong oxidative stress starting in the epithelium upon restoration of blood cell circulation is a major cause of necrosis of the intestinal epithelium in ischemia/reperfusion-induced damage. AIM: The purpose of this study was to investigate the tissue-protective effect of exogenous peroxiredoxin 6 (Prx6) in ischemia/reperfusion-induced damage of small intestine. METHODS: The research was carried out using a model of acute superior mesenteric artery occlusion in Wistar male rats. Exogenous Prx6 was administrated intravenously 15 min prior to small intestine ischemia. The distribution of endogenous Prx6 in the small intestine was determined by immunohistochemical analysis. The expression level of antioxidant enzymes was evaluated by RT-PCR in real time. RESULTS: Exogenous Prx6 injected to animals intravenously was detected in blood vessel lumens, and its diffuse distribution was subsequently confirmed in the intestinal epithelium. Expression analysis of genes coding for major antioxidant enzymes demonstrated a significant activation of SOD 1, SOD 3, Prx6, GPx2, GPx7 expression during I/R-induced damage of the small intestine. Injection of exogenous Prx6 prior to induced ischemia resulted in minimization of oxidative injury by reducing necrosis and apoptosis, by normalization of gene activity of antioxidant enzyme. It eventually led to a reduction of epithelium destruction in the small intestine. By contrast, administration of a purified mutant form of Prx6 (Prx6C47S) without peroxidase activity had no protective effect. CONCLUSION: The application of exogenous Prx6 enables normalization of the antioxidant status of the small intestine and reduction of cell destruction upon I/R-induced organ damage. PMID- 26233548 TI - Double Rarities, Double Challenges: Extra-Mammary Paget's Disease and Anal Adenocarcinoma. PMID- 26233549 TI - Protease-Activated Receptor-2 Up-Regulates Transient Receptor Potential Vanilloid 4 Function in Mouse Esophageal Keratinocyte. AB - BACKGROUND: The reflux of pancreatic-duodenal fluids is implicated in the pathophysiology of proton-pump inhibitor-resistant gastroesophageal reflux disease (GERD). Protease-activated receptor-2 (PAR-2) is activated by proteases, the pancreatic enzyme, trypsin, and the activated PAR-2 enhances transient receptor potential vanilloid 4 (TRPV4) function in neurons. TRPV4 stimulates ATP exocytosis in conjunction with the vesicular nucleotide transporter, which mediates mechano-transduction and vagal stimulation. The aim of the present study was to verify whether the activated PAR-2 up-regulates TRPV4 function in mouse esophageal keratinocytes, which may link to the pathophysiology in PPI-resistant GERD. METHODS: TRPV4 and PAR-2 expressions were detected by RT-PCR, immunostaining, and western blotting in mouse esophageal keratinocytes. The functional response of TRPV4 to esophageal keratinocytes was analyzed using a Ca(2+) imaging system. Cellular ATP release was examined by luciferase-luciferin reaction. TRPV4 phosphorylation was studied by immunoprecipitation and western blotting. RESULTS: PAR-2 and TRPV4 mRNAs and proteins were expressed in esophageal keratinocytes. Pre-treatment with trypsin significantly increased the responses to TRPV4 activator in esophageal keratinocytes, probably via the phosphorylation of serine residue of TRPV4 by protein kinase C and resulted in cellular ATP release from the cells. CONCLUSIONS: Activated PAR-2 with trypsin exposure up-regulated TRPV4 function and increased ATP release in mouse esophageal keratinocytes. This mechanism might be related to the pathophysiology of GERD, especially non-erosive GERD. PMID- 26233551 TI - Erratum to: Trimethylamine-N-oxide: A Novel Biomarker for the Identification of Inflammatory Bowel Disease. PMID- 26233550 TI - Serum 25-Hydroxyvitamin D Levels and the Risk of Dysplasia and Esophageal Adenocarcinoma in Patients with Barrett's Esophagus. AB - BACKGROUND: To date, there are no studies reporting an association between vitamin D and Barrett's esophagus (BE), the precursor for esophageal adenocarcinoma (EAC). AIMS: Our aim was to study the association between serum 25 hydroxyvitamin D (25(OH)D) levels and prevalence and incidence of dysplasia/EAC in BE. METHODS: Patients from our BE Registry cohort seen between 2000 and 2012 who had serum 25(OH)D levels measured were included. Age, gender, race, BE length, hiatal hernia size, and histological findings were recorded. Patients without high-grade dysplasia (HGD)/EAC at or within 1 year of index biopsy and who had follow-up endoscopies and 25(OH)D levels were studied for incidence of dysplasia/EAC. RESULTS: Among 429 patients with BE, the mean 25(OH)D level was 72 +/- 31.2 nmol/L. Hundred and one (23.6 %) patients had deficiency (<50 nmol/L), 149 (34.7 %) had insufficiency (50-74.9 nmol/L), and 179 (41.7 %) had normal levels of 25(OH)D. There was no association between serum 25(OH)D levels and dysplasia (p = 0.90). In the incidence cohort of 246 patients with median follow up of 46 months, there were 34 cases of low-grade dysplasia, 12 of HGD, and 5 of EAC. Change in 25(OH)D levels did not impact progression to dysplasia/EAC (every 5 nmol/L increase from baseline, hazard ratio 0.98; p = 0.62). CONCLUSIONS: Serum 25(OH)D levels were low in 58.3 % of our BE cohort. There was no association between 25(OH)D levels and prevalence or incidence of HGD/EAC in patients with BE. Further long-term studies are needed to study the association between vitamin D status and progression of dysplasia in BE. PMID- 26233552 TI - Probe-Based Confocal Endomicroscopy in Primary Sclerosing Cholangitis: Not All Inflammatory Strictures Are the Same. AB - BACKGROUND AND STUDY AIMS: Primary sclerosing cholangitis (PSC) frequently causes inflammatory strictures (IS). The Paris Classification (PC) for probe-based confocal laser endomicroscopy (pCLE) identifies four descriptive criteria of IS. We aim to compare the pCLE findings of IS in PSC and non-PSC patients. PATIENTS AND METHODS: This is a single-center, retrospective review of all histologically proven IS evaluated with pCLE with at least 6 months of follow-up. All pCLE images were reviewed for each criteria of the PC: (1) vascular congestion, (2) dark granular pattern, (3) increased inter-glandular space, and (4) thickened reticular structures (TRS). The clinical status (PSC vs. non-PSC) was blinded to the reviewer. Univariate, multivariate, and stepwise logistic regression analyses were conducted. The primary outcome was the number of PC criteria present in PSC versus non-PSC. RESULTS: A total of 35 patients (13 PSC, 22 non-PSC) were included (mean age 59.1 years, 25.7 % male). Each of the PC criteria was present more frequently in non-PSC patients. The presence of TRS was significantly different (95 vs. 62 %, p = 0.01). All patients had at least two criteria present, but non-PSC patients had a significantly higher frequency of three criteria (95 vs. 38 %, p < 0.001) and four criteria (55 vs. 23 %, respectively, one-tailed p = 0.03) present. CONCLUSION: In patients with IS, the individual and combined components of the PC are present in higher frequency in non-PSC patients. The presence of TRS is 13 times more likely to predict non-PSC etiologies. Refined pCLE criteria may be required to evaluate IS in patients with PSC. CLINICAL TRIAL REGISTRATION NUMBER: NCT02166086. PMID- 26233553 TI - Non-absorbable sutures are associated with lower recurrence rates in laparoscopic percutaneous inguinal hernia ligation. AB - INTRODUCTION: Laparoscopic hernia repair with percutaneous ligation of the patent processes vaginalis is a minimally invasive alternative to open inguinal herniorrhaphy in children. With the camera port concealed at the umbilicus, this technique offers an excellent cosmetic result. It is also faster than the traditional laparoscopic repair with no differences in complication rates or hospital stay. The goal of this study was to describe a series of consecutive patients, emphasizing the impact of suture materials (absorbable vs. non absorbable) on hernia recurrences. METHODS: A retrospective review was performed of consecutive transperitoneal laparoscopic subcutaneous ligations of a symptomatic hernia and/or communicating hydrocele by 4 surgeons. Patients > Tanner 2 or with prior hernia repair were excluded. The success of the procedure and number of sutures used was compared between cases performed with absorbable vs. non-absorbable suture. Risk factors for surgical failure (age, weight, number of sutures used, suture type) were assessed with logistic regression. RESULTS: 94 patients underwent laparoscopic percutaneous hernia ligation at a mean age of 4.9 years. Outcomes in 85 (90%) patients with 97 hernia repairs at a mean of 8 months after surgery revealed 26% polyglactin vs 4% polyester recurrences (p = 0.004) which occurred at mean of 3.6 months after surgery, Table 1. Repairs performed with non-absorbable suture required only 1 suture more often than those performed with absorbable suture (76% vs 60%, p = 0.163). Logistic regression revealed suture type was an independent predictor for failure (p = 0.017). Weight (p = 0.249), age (p = 0.055), and number of sutures (p = 0.469) were not significantly associated with recurrent hernia. DISCUSSION: Our review of consecutive hernia repairs using the single port percutaneous ligation revealed a significantly higher recurrent hernia rate with absorbable (26%) versus non-absorbable (4%) suture. This finding remained significant in a logistic regression model irregardless of number of sutures placed, age, and weight. Though the authors acknowledge the drawback of the potential for learning curve to confound our data, we still feel these findings are clinically important as this analysis of outcomes has changed our surgical practice as now all providers involved perform this procedure with exclusively non-absorbable suture. We thus suggest that surgeons who perform this technique, especially those newly adopting it, use non absorbable suture for optimal patient outcomes. CONCLUSIONS: Recurrent hernia after laparoscopic percutaneous hernia ligation was significantly lower in repairs performed with non-absorbable suture. Based on this data, we recommend the use of non-absorbable suture during laparoscopic ligation of inguinal hernias in children. PMID- 26233554 TI - Laparoscopic treatment of ureteropelvic junction obstruction in five pediatric cases of pelvic kidneys. AB - OBJECTIVE: Ectopic kidney is a rare urologic condition and may be revealed by ureteropelvic junction obstruction (UPJO) in children, with pelvic kidney being the most common location. Our experience using a minimally invasive approach to treat UPJO by dismembered pyeloplasty led us to report five cases of UPJO with pelvic kidney operated on by transperitoneal laparoscopy, focusing on medium-term follow-up results and surgical technique. PATIENTS AND METHODS: From 1999 to 2010, we reviewed all cases of UPJO managed in our center, a total of 391 patients. Among those, 125 patients were operated on via a minimal invasive approach, 104 by retroperitoneoscopy, and 21 by transperitoneal laparoscopy. Five patients presented ectopic pelvic kidney and were retrospectively reviewed. US scan and uro-MRI were done preoperatively in all cases for anatomic and functional evaluation. Peri-operative data such as operative time, transfusion, and complications were reported. At last clinic, sonographic and functional evaluation was noted. Focusing on surgical technique, we reported the tips and tricks to successfully and easily perform the dismembered pyeloplasty: optimization of the trocars' location according to the kidney location and use of a transparietal stay stitch to stabilize the suture line of the pyeloplasty. RESULTS: All five patients underwent dismembered pyeloplasty, at a mean age of 8 years and a mean weight of 23.4 kg. Mean operative time was 213 min (min-max: 180 245). One case of giant hydronephrosis and megacalicosis required conversion at the beginning of the learning curve. None of the patients required blood transfusion. Mean hospital stay was 2.4 days (range: 1-4). All the patients had an uneventful postoperative recovery and good postoperative functional results, with either stable or improved pelvic dilatation and renal function at a mean follow-up of 3.3 years (range: 2-5.6). DISCUSSION: This small series of five ectopic kidneys reflects the surgical challenge for the pediatric surgeon to perform reconstructive surgery on an abnormal anatomy. However, increasing experience in robotics in urologic pediatric surgery may lead to shortening of operative time and facilitate both dissection and suturing. CONCLUSION: Dismembered pyeloplasty by transperitoneal laparoscopy is a feasible although technically demanding, safe and effective approach in the management of ureteropelvic junction obstruction in pelvic kidney in children. PMID- 26233555 TI - Human biomonitoring of multiple mycotoxins in the Belgian population: Results of the BIOMYCO study. AB - Mycotoxins are important food contaminants responsible for health effects such as cancer, nephrotoxicity, hepatotoxicity or immunosuppression. The assessment of mycotoxin exposure is often based on calculations combining mycotoxin occurrence data in food with population data on food consumption. Because of limitations inherent to that approach, the direct measurement of biomarkers of exposure in biological fluids has been proposed as a suitable alternative to perform an accurate mycotoxin exposure assessment at individual level. For this reason, the BIOMYCO study was designed to assess mycotoxin exposure in Belgian adults and children using urinary biomarkers of exposure. Morning urine was gathered in a representative part of the Belgian population according to a standardised study protocol, whereby 155 children (3-12 years old) and 239 adults (19-65 years old) were selected based on random cluster sampling. These urine samples were analysed for the presence of 33 potential biomarkers with focus on aflatoxins, citrinin (CIT), fumonisins, trichothecenes, ochratoxin A (OTA), zearalenone and their metabolites using two validated LC-MS/MS methods. Nine out of the 33 analysed mycotoxins were detected whereby deoxynivalenol (DON), OTA, CIT and their metabolites were the most frequently detected. Deoxynivalenol-15-glucuronide was the main urinary DON biomarker and was found in all urine samples in the ng/mL range. Furthermore deoxynivalenol-3-glucuronide was quantified in 91% of the urine samples collected from children and in 77% of the samples collected from adults. Deoxynivalenol was detected in 70% and 37% of the samples of children and adults respectively. For the first time deepoxy-deoxynivalenol-glucuronide was detected in children's urine (17%). In the samples collected by adults, the prevalence was 22%. Whereas all these mycotoxins contaminated the urine samples in the ng/mL range, CIT and OTA were present in much lower concentrations (pg/mL). OTA contaminated 51% and 35% of the samples collected by children and adults respectively. CIT and its metabolite were present in 72% and 6% of children's urine, whereas they contaminated 59% and 12% of adult's urine. Finally, alpha-zearalenol and beta-zearalenol-14-glucuronide were found in respectively one and two samples from adults. The exposure to DON, OTA and CIT was compared between subgroups and urinary mycotoxin concentrations differed significantly among age and gender. Based on the urinary levels, the daily intake of DON and OTA was estimated and evaluated whereby, depending on the used method, 16-69% of the population possibly exceeded the tolerable daily intake for DON and 1% for OTA. The BIOMYCO study is the first study whereby a multi-toxin approach was applied for mycotoxin exposure assessment in adults and children on a large scale. Moreover, it is the first study that described the exposure to an elaborated set of mycotoxins in the Belgian population. Biomarker analysis showed a clear exposure of a broad segment of the Belgian population to DON, OTA and CIT. The risk assessment based on these data indicates a potential concern for a number of individuals whereby young children need special attention because of the relatively higher food intake per kg body weight. PMID- 26233556 TI - Assessing correlations between geological hazards and health outcomes: Addressing complexity in medical geology. AB - BACKGROUND: The field of medical geology addresses the relationships between exposure to specific geological characteristics and the development of a range of health problems: for example, long-term exposure to arsenic in drinking water can result in the development of skin conditions and cancers. While these relationships are well characterised for some examples, in others there is a lack of understanding of the specific geological component(s) triggering disease onset, necessitating further research. OBJECTIVES: This paper aims to highlight several important complexities in geological exposures and the development of related diseases that can create difficulties in the linkage of exposure and health outcome data. Several suggested approaches to deal with these complexities are also suggested. DISCUSSION: Long-term exposure and lengthy latent periods are common characteristics of many diseases related to geological hazards. In combination with long- or short-distance migrations over an individual's life, daily or weekly movement patterns and small-scale spatial heterogeneity in geological characteristics, it becomes problematic to appropriately assign exposure measurements to individuals. The inclusion of supplementary methods, such as questionnaires, movement diaries or Global Positioning System (GPS) trackers can support medical geology studies by providing evidence for the most appropriate exposure measurement locations. CONCLUSIONS: The complex and lengthy exposure-response pathways involved, small-distance spatial heterogeneity in environmental components and a range of other issues mean that interdisciplinary approaches to medical geology studies are necessary to provide robust evidence. PMID- 26233557 TI - Induced growth of dendrite gold nanostructure by controlling self-assembly aggregation dynamics. AB - Self-assembly of gold nanoparticles (AuNPs) is an important growth mode for fabricating functional materials. In this work we report a dendrite structure formed by slowing down the aggregation dynamics of AuNPs self-assembly. The obtained results show that the aggregation dynamics is dominated by the Reaction Limited Aggregation Model (RLA) more than the Diffusion Limited Aggregation Model (DLA). In which the repulsion due to electrostatic forces is dominant by the Van Der Walls attraction forces, and low sticking probability of nanoparticles. The aggregation dynamics of AuNPs can be slowed down if the water evaporation of the drop casted colloidal AuNPs on a quartz substrate is slowed. Slowing down the evaporation allows electrostatic repulsion forces to decrease gradually. At certain point, the attraction forces become higher than the electrostatic repulsion and hence cluster aggregation take place slowly. The slow aggregation dynamics allows the nanoparticles to sample all possible orientation in the sticking site, searching for the lowest energy configuration. The size distribution of the nanoparticles in liquid is confirmed using dynamic light scattering based on Stokes-Einstein equation for diffusion coefficient in water. X-ray and photoluminescence (PL) spectra of the sample after aggregation showed a shift which is related to the aggregation compared with non-aggregated colloidal nanoparticles in the solution. The study shows that dendrite self similar structure can be formed by slowing down the aggregation dynamics of nanoparticles as a result of minimizing the Helmholtz free surface energy of the system. PMID- 26233558 TI - Influence of steric interactions on the dielectric and electrokinetic properties in colloidal suspensions. AB - One of the main assumptions of the standard electrokinetic model is that ions behave as point like entities. In this work we remove this assumption and analyze the main consequences of finite ionic size on the dielectric and electrokinetic properties of colloidal suspensions. We represent the steric interactions by means of the Bikerman and the Carnahan-Starling equations and solve numerically the standard linearized electrokinetic equations in the stationary and the frequency domains, for surface charge density and electrolyte solution concentration values typically encountered in colloidal suspensions. In all cases the steric interactions improve upon the predictions of the standard model since the surface potential, the electrophoretic mobility, and the conductivity and permittivity increments increase. However, the corrections introduced by the Bikerman equation are generally small: less than 10% as compared to the standard model. On the contrary, the Carnahan-Starling equation leads to corrections to the surface potential versus surface charge and the electrophoretic mobility values that easily surpass 10% and can attain values as high as 50%. Corrections to the conductivity and permittivity increments are smaller but still non negligible. PMID- 26233559 TI - Effects of the non-steroidal anti-inflammatory drug(NSAID) naproxen on gene expression of antioxidant enzymes in zebrafish (Danio rerio). AB - The aim of this study was to investigate the effects of naproxen on the gene expression of antioxidant enzymes in adult zebrafish. Surprisingly, after 2 weeks exposure no significant effect on the mRNA expression of the target genes was found in the liver. However, mRNA levels of three genes were altered significantly in the intestine. The expression of Ucp-2 decreased at the environmental concentration of 1MUg/L while mRNA expression of GST p2 increased at the concentration of 100MUg/L. The mRNA level for the antioxidant enzyme CAT was up-regulated significantly at both the concentrations used. Exposure to naproxen caused only moderate effects on the expression of antioxidant genes in the intestine rather than in the liver, which demonstrates that the intestine is more sensitive to waterborne naproxen exposure than the liver. Interestingly, the adverse side effects of NSAIDs occur in the gastrointestinal tract of humans. To our knowledge, this is the first study that has focused on transcriptional effects of naproxen on zebrafish. PMID- 26233560 TI - Influence of dioxin on the daily variation of insulin sensitivity in mice. AB - To evaluate an influence of dioxin on a daily variation of insulin sensitivity, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (100ng/kg) was given for 3 weeks in mice. Insulin tolerance test and oral glucose tolerance test were performed. TCDD decreased insulin sensitivity at an active period, but not at a rest period. TCDD elevated plasma TNF-alpha, and the value was significantly higher during an active period than during a rest period. These data suggest that TCDD blunts insulin sensitivity, mainly during an active period. Higher elevation in plasma TNF-alpha during an active period might be involved in this phenomenon. PMID- 26233561 TI - Functional characterization of CYP1A9 and CYP1C1 from Anguillus japonica. AB - We evaluated the metabolism of several herbicides and progesterone by two P450 proteins (CYP1A9 and CYP1C1) from Japanese eel (Anguilla japonica). Expression vectors harboring CYP1A9 and CYP1C1 sequences were introduced into Escherichia coli. E. coli membrane fractions were incubated with each substrate, and the metabolites were analyzed. CYP1A9 and CYP1C1 deethylated 7-ethoxycoumarin and phenacetin, and demethylated chlorotoluron, diuron, and linuron. CYP1C1 specifically hydroxlyated progesterone at the 6beta and 16alpha positions. Five amino acids of CYP1A9 related to substrate binding were selected for mutation analyses [CYP1A9(F128A), CYP1A9(F229A), CYP1A9(F263A), CYP1A9(V387A), and CYP1A9(I391A)]. Two variants, CYP1A9(F229A) and CYP1A9(F128A), changed the ratio of 16alpha hydroxyprogesterone to 6beta hydroxyprogesterone. Among all the variants, CYP1A9(F263A) showed the highest activity towards substrates used. CYP1A9(V387A) and CYP1A9(I391A) showed higher activities than that of CYP1A9 toward progesterone. The substrate specificity of CYP1A9 may be altered by replacing an amino acid related to substrate binding. PMID- 26233562 TI - Developmental exposure to paracetamol causes biochemical alterations in medulla oblongata. AB - The effect and safety of prenatal and early life administration of paracetamol - routinely used over-the-counter antipyretic and analgesic medication on monoamines content and balance of amino acids in the medulla oblongata is still unknown. In this study we have determined the level of neurotransmitters in this structure in two-month old Wistar male rats exposed to paracetamol in the dose of 5 (P5, n=10) or 15mg/kg b.w. (P15, n=10) during prenatal period, lactation and till the end of the second month of life. Control group received drinking water (Con, n=10). Monoamines, their metabolites and amino acids concentration in medulla oblongata of rats were determined using high performance liquid chromatography (HPLC) in 60 postnatal day (PND60). This experiment shows that prenatal and early life paracetamol exposure modulates neurotransmission associated with serotonergic, noradrenergic and dopaminergic system in medulla oblongata. Reduction of alanine and taurine levels has also been established. PMID- 26233563 TI - Current source density analysis of resting state EEG in depression: a review. AB - Electroencephalography (EEG) has been widely used in the neurophysiological investigation of major depressive disorder (MDD) during past decades. An approach that has attracted particular interest over the past 20 years is current source density (CSD) that assesses current source in extracellular spaces, which are the local generators of the field potentials caused by the activation of neurones. Our aim was to review the current literature regarding resting state CSD analysis in MDD patients. To date, the most prominent aspects in such studies comprise the identification of clinical endophenotypes on the basis of resting state CSD, and the investigation of CSD with respect to treatment outcome prediction. Increased alpha band resting state CSD in frontal regions is typical for MDD, while increased theta band activity in the rostral anterior cingulate gyrus (rACC) has been found to be a good predictor of better antidepressant response. However, differences in the methods used in different studies could be responsible for some contradictions in reported findings. Further research is needed for better distinction of depressive patients from patients with other psychiatric disorders, as well as from healthy subjects. PMID- 26233564 TI - Is nocturnal eating in restless legs syndrome linked to a specific psychopathological profile? A pilot study. AB - The purpose of the study was to evaluate psychological comorbidity in drug-naive or drug-free primary restless legs syndrome (p-RLS) patients with nocturnal eating disorder (NED), and to analyze the association of comorbid p-RLS and NED with obsessive-compulsive, mood and anxiety symptoms, and personality. Participants comprised 20 consecutive female outpatients with p-RLS, 10 without NED and 10 with NED, and 10 female controls matched for age. Both patients and controls were evaluated by the Hamilton Depression and the Anxiety Rating Scales, the State-Trait Anxiety Inventory, the Maudsley Obsessive Compulsive Inventory and the temperament and character inventory-revised. Compared to controls, p-RLS patients without and with NED had higher trait anxiety and current anxiety and obsessive-compulsive symptoms. p-RLS patients with NED also had significantly higher doubting compared to p-RLS patients without NED. Furthermore, groups differed for harm avoidance (HA), with p-RLS patients with and without NED having higher scores than controls. Untreated p-RLS patients, particularly those with nocturnal eating, report anxiety and obsessive-compulsive symptoms, perceive stressful situations as dangerous and threatening and tend to respond with anxiety to such situations. They have higher tendency to respond intensely to aversive stimuli, inhibiting behavior to avoid punishment, novelty, and frustrative omission of expected rewards. We hypothesize that higher levels of HA, a biologically determined personality trait, might constitute a diathesis predisposing individuals to display obsessive-compulsive symptoms, namely increasingly severe compulsive nocturnal eating. PMID- 26233566 TI - Trehalose-Induced Variation in Mechanical Properties of Vesicles in Aqueous Solution. AB - The effect of the trehalose incorporation on the nanomechanical properties of dipalmitoylphosphatidylcholine vesicles was studied using atomic force microscope (AFM) on mica surface. The vesicles were prepared only with the variation in the trehalose concentration and adsorbed on the mica surface. After the morphology of the adsorbed vesicles was characterized, the behavior of an AFM tip into the vesicle was monitored using the plot of the tip displacement versus the tip deflection. It was observed that the breakthrough of the tip into the vesicles occurred two times. Each breakthrough represented each penetration of the tip into each layer. Force data prior to the first breakthrough fitted well with the Hertzian model to estimate Young's modulus and bending modulus of the vesicles. It was found that the Young's modulus and bending modulus decreased proportionally to the increase in the trehalose concentration up to 0.5 of trehalose to lipid. However, above 0.5, the moduli were a little varied with the increase. In the identical measurements at glucose, just a slight change in the moduli was observed with the increase in the glucose composition from 0 % glucose up to even 2:1 ratio of glucose:lipid. These results in the mechanical properties seem attributable to the osmotic and volumetric effects on the headgroup packing disruption. PMID- 26233565 TI - Down-Regulation of Excitatory Amino Acid Transporters EAAT1 and EAAT2 by the Kinases SPAK and OSR1. AB - SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress responsive kinase 1) are cell volume-sensitive kinases regulated by WNK (with-no K[Lys]) kinases. SPAK/OSR1 regulate several channels and carriers. SPAK/OSR1 sensitive functions include neuronal excitability. Orchestration of neuronal excitation involves the excitatory glutamate transporters EAAT1 and EAAT2. Sensitivity of those carriers to SPAK/OSR1 has never been shown. The present study thus explored whether SPAK and/or OSR1 contribute to the regulation of EAAT1 and/or EAAT2. To this end, cRNA encoding EAAT1 or EAAT2 was injected into Xenopus oocytes without or with additional injection of cRNA encoding wild-type SPAK or wild-type OSR1, constitutively active (T233E)SPAK, WNK insensitive (T233A)SPAK, catalytically inactive (D212A)SPAK, constitutively active (T185E)OSR1, WNK insensitive (T185A)OSR1 or catalytically inactive (D164A)OSR1. The glutamate (2 mM)-induced inward current (I Glu) was taken as a measure of glutamate transport. As a result, I Glu was observed in EAAT1- and in EAAT2 expressing oocytes but not in water-injected oocytes, and was significantly decreased by coexpression of SPAK and OSR1. As shown for EAAT2, SPAK, and OSR1 decreased significantly the maximal transport rate but significantly enhanced the affinity of the carrier. The effect of wild-type SPAK/OSR1 on EAAT1 and EAAT2 was mimicked by (T233E)SPAK and (T185E)OSR1, but not by (T233A)SPAK, (D212A)SPAK, (T185A)OSR1, or (D164A)OSR1. Coexpression of either SPAK or OSR1 decreased the EAAT2 protein abundance in the cell membrane of EAAT2-expressing oocytes. In conclusion, SPAK and OSR1 are powerful negative regulators of the excitatory glutamate transporters EAAT1 and EAAT2. PMID- 26233567 TI - Breath carbonyl compounds as biomarkers of lung cancer. AB - OBJECTIVE: Lung cancer dysregulations impart oxidative stress which results in important metabolic products in the form of volatile organic compounds (VOCs) in exhaled breath. The objective of this work is to use statistical classification models to determine specific carbonyl VOCs in exhaled breath as biomarkers for detection of lung cancer. MATERIALS AND METHODS: Exhaled breath samples from 85 patients with untreated lung cancer, 34 patients with benign pulmonary nodules and 85 healthy controls were collected. Carbonyl compounds in exhaled breath were captured by silicon microreactors and analyzed by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). The concentrations of carbonyl compounds were analyzed using a variety of statistical classification models to determine which compounds best differentiated between the patient sub-populations. Predictive accuracy of each of the models was assessed on a separate test data set. RESULTS: Six carbonyl compounds (C(4)H(8)O, C(5)H(10)O, C(2)H(4)O(2), C(4)H(8)O(2), C(6)H(10)O(2), C(9)H(16)O(2)) had significantly elevated concentrations in lung cancer patients vs. CONTROLS: A model based on counting the number of elevated compounds out of these six achieved an overall classification accuracy on the test data of 97% (95% CI 92%-100%), 95% (95% CI 88%-100%), and 89% (95% CI 79%-99%) for classifying lung cancer patients vs. non smokers, current smokers, and patients with benign nodules, respectively. These results were comparable to benchmarking based on established statistical and machine-learning methods. The sensitivity in each case was 96% or higher, with specificity ranging from 64% for benign nodule patients to 86% for smokers and 100% for non-smokers. CONCLUSION: A model based on elevated levels of the six carbonyl VOCs effectively discriminates lung cancer patients from healthy controls as well as patients with benign pulmonary nodules. PMID- 26233568 TI - Genomic variations in plasma cell free DNA differentiate early stage lung cancers from normal controls. AB - OBJECTIVES: Cell free tumor DNA (cfDNA) circulating in blood has a great potential as biomarker for cancer clinical management. The objective of this study is to evaluate if cfDNA in blood plasma is detectable in early stage lung cancer patients. MATERIALS AND METHODS: We extracted cfDNAs and tumor tissue DNAs from 8 lung adenocarcinoma patients. We also extracted cfDNAs from 8 normal controls. To evaluate copy number variations (CNV) and identify potential mutations, we performed low pass whole genome sequencing and targeted sequencing of 50 cancer genes. To accurately reflect the tumor-associated genomic abnormality burden in plasma, we developed a new scoring algorithm, plasma genomic abnormality (PGA) score, by summarizing absolute log2 ratios in most variable genomic regions. We performed digital PCR and allele-specific PCR to validate mutations detected by targeted sequencing. RESULTS AND CONCLUSIONS: The median yield of cfDNA in 400 ul plasma was 4.9 ng (range 2.25-26.98 ng) in patients and 2.32 ng (range 1.30-2.81 ng) in controls (p=0.003). The whole genome sequencing generated approximately 20 million mappable sequence reads per subject and 5303 read counts per 1Mb genomic region. Log2 ratio-based CNV analysis showed significant chromosomal abnormality in cancer tissue DNAs and subtle but detectable differences in cfDNAs between patients and controls. Genomic abnormality analysis showed that median PGA score was 9.28 (7.38-11.08) in the 8 controls and 19.50 (5.89-64.47) in the 8 patients (p=0.01). Targeted deep sequencing in tumor tissues derived from the 8 patients identified 14 mutations in 12 different genes. The PCR-based assay confirmed 3 of 6 selected mutations in cfDNAs. These results demonstrated that the PGA score and cfDNA mutational analysis could be useful tool for the early detection of lung cancer. These blood based genomic and genetic assays are noninvasive and may sensitively distinguish early stage disease when combined with other existing screening strategies including low-dose CT scanning. PMID- 26233569 TI - Comparative effectiveness of 3- versus 4-factor prothrombin complex concentrate for emergent warfarin reversal. AB - INTRODUCTION: Three- and 4-factor prothrombin complex concentrates (PCC) are routinely administered for emergent reversal of warfarin, but direct comparisons of clinical outcomes are lacking. The purpose of this study was to compare the safety and effectiveness of 3- and 4-PCC in patients requiring emergent warfarin reversal. MATERIALS AND METHODS: This was a single-center retrospective study in adult patients requiring administration of either 3-PCC or 4-PCC for emergent reversal of warfarin. RESULTS: One hundred sixty-five patients were included (3 PCC, n=109; 4-PCC, n=56). The most frequent indications for PCC were intracranial and gastrointestinal bleeding. Baseline median INR was 2.5 (2.0-3.2) and 2.4 (2.0 4.2) in the 3-PCC and 4-PCC groups. Thirty minutes after PCC administration, median INR decreased to 1.3 in both groups (p<0.001), and 87 (80%) versus 47 (84%) of patients had INR values<=1.5 (p=0.52) in the 3-PCC group versus the 4 PCC group. Thromboembolic events occurred in 7 patients (4%) and were similar between the 3-PCC (n=3, 3%) and 4-PCC (n=4, 7%) groups (p=0.23). Thirty-four (31%) patients in the 3-PCC group died compared to 5 patients (9%) in the 4-PCC group (p=0.001). INR>1.5 thirty minutes after PCC was associated with increased mortality (OR 4.3; 95% CI 1.8-10.4, p=0.001), and administration of a 4-PCC was associated with decreased mortality (OR 0.19; 95% CI 0.06-0.54, p=0.002). CONCLUSION: Patients who received 4-PCC, and those with INR<=1.5 regardless of type of PCC received were more likely to survive. Thromboembolic events were low in both groups and similar to previous studies. PMID- 26233570 TI - Association between genetic polymorphisms and deep vein thrombosis in a Chinese population. PMID- 26233571 TI - A novel method for the quantification of key components of manual dexterity after stroke. AB - BACKGROUND: A high degree of manual dexterity is a central feature of the human upper limb. A rich interplay of sensory and motor components in the hand and fingers allows for independent control of fingers in terms of timing, kinematics and force. Stroke often leads to impaired hand function and decreased manual dexterity, limiting activities of daily living and impacting quality of life. Clinically, there is a lack of quantitative multi-dimensional measures of manual dexterity. We therefore developed the Finger Force Manipulandum (FFM), which allows quantification of key components of manual dexterity. The purpose of this study was (i) to test the feasibility of using the FFM to measure key components of manual dexterity in hemiparetic stroke patients, (ii) to compare differences in dexterity components between stroke patients and controls, and (iii) to describe individual profiles of dexterity components in stroke patients. METHODS: 10 stroke patients with mild-to-moderate hemiparesis and 10 healthy subjects were recruited. Clinical measures of hand function included the Action Research Arm Test and the Moberg Pick-Up Test. Four FFM tasks were used: (1) Finger Force Tracking to measure force control, (2) Sequential Finger Tapping to measure the ability to perform motor sequences, (3) Single Finger Tapping to measure timing effects, and (4) Multi-Finger Tapping to measure the ability to selectively move fingers in specified combinations (independence of finger movements). RESULTS: Most stroke patients could perform the tracking task, as well as the single and multi-finger tapping tasks. However, only four patients performed the sequence task. Patients showed less accurate force control, reduced tapping rate, and reduced independence of finger movements compared to controls. Unwanted (erroneous) finger taps and overflow to non-tapping fingers were increased in patients. Dexterity components were not systematically related among each other, resulting in individually different profiles of deficient dexterity. Some of the FFM measures correlated with clinical scores. CONCLUSIONS: Quantifying some of the key components of manual dexterity with the FFM is feasible in moderately affected hemiparetic patients. The FFM can detect group differences and individual profiles of deficient dexterity. The FFM is a promising tool for the measurement of key components of manual dexterity after stroke and could allow improved targeting of motor rehabilitation. PMID- 26233572 TI - Zinc supplementation and the effects on metabolic status in gestational diabetes: A randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: To the best of our knowledge, no reports are available indicating the effects of zinc supplementation on metabolic status in women with gestational diabetes (GDM). This study was designed to determine the effects of zinc supplementation on glucose homeostasis parameters and lipid concentrations in GDM women. METHODS: This randomized, double-blind, placebo-controlled trial was performed among 58 women diagnosed with GDM, primigravida and aged 18-40years old. Patients were randomly divided into two groups to receive 233mg zinc gluconate (containing 30mg zinc) supplements (n=29) or placebo (n=29) per day for 6weeks. Fasting blood samples were taken at the beginning and end of the trial to quantify glucose, insulin and lipid concentrations. RESULTS: Patients who received zinc supplements had significantly higher serum zinc concentrations (+6.9+/-13.2 vs. -1.5+/-16.5mg/dL, P=0.03) than those received the placebo. In addition, zinc-supplemented patients had reduced fasting plasma glucose (FPG) ( 6.6+/-11.2 vs. +0.6+/-6.7mg/dL, P=0.005), serum insulin levels (-1.3+/-6.6 vs. +6.6+/-12.2MUIU/mL, P=0.003), homeostasis model of assessment-insulin resistance (HOMA-IR) (-0.5+/-1.6 vs. +1.5+/-2.7, P=0.001), homeostatic model assessment-Beta cell function (HOMA-B) (-0.7+/-25.0 vs. +26.5+/-49.5, P=0.01) and increased quantitative insulin sensitivity check index (QUICKI) (+0.01+/-0.01 vs. -0.01+/ 0.02, P=0.004) compared with the placebo. Additionally, significant differences in serum triglycerides (+13.6+/-61.4 vs. +45.9+/-36.5mg/dL, P=0.01) and VLDL cholesterol concentrations (+2.7+/-12.3 vs. +9.2+/-7.3mg/dL, P=0.01) were observed following the administration of zinc supplements compared with the placebo.We did not observe any significant effects of taking zinc supplements on other lipid profiles. CONCLUSIONS: Taken together, 30mg zinc supplementation per day for 6weeks among GDM women had beneficial effects on metabolic profiles. PMID- 26233573 TI - The association of antidepressant medications and diabetic retinopathy among people with diabetes. AB - OBJECTIVE: To determine if the use of antidepressants was associated with lower odds of diabetic retinopathy and if so, to determine if this association was mediated by decreased inflammation as measured by C-reactive protein (CRP). DESIGN: This was a cross sectional study of 1,041 participants with type 2 diabetes 40-85years old from the 2005-2008 National Health and Nutrition Examination Survey (NHANES). Multiple logistic regression was used to examine the association between the outcome of diabetic retinopathy and the primary exposure of antidepressant medication usage. We also determined whether CRP meets standard criteria as a mediator between antidepressant use and diabetic retinopathy. RESULTS: Participants using antidepressants were less likely to have diabetic retinopathy (OR 0.50, 95% CI: 0.31-0.82). CRP did not meet one of the criteria for mediation. However, CRP was an effect modifier such that the association of antidepressant use and diabetic retinopathy was only present among participants with CRP >=0.3mg/dl. Among the antidepressant drug classes, selective serotonin reuptake inhibitor (SSRI) users had significantly lower odds of developing diabetic retinopathy compared to non-users of antidepressants. CONCLUSIONS: Using representative survey data of US adults with type-2 diabetes, this study found that antidepressant use was associated with lower odds of diabetic retinopathy. Further longitudinal and experimental studies are necessary to confirm this finding and to determine if there is a role for antidepressants in preventing diabetic retinopathy in select patient populations. PMID- 26233574 TI - Association between comorbidities and dementia in diabetes mellitus patients: population-based retrospective cohort study. AB - AIMS: Most diabetes mellitus (DM) patients have several comorbidities; the correlation of these comorbidities with dementia in DM requires clarification. METHODS: Using claims data from Taiwan National Health Insurance, we identified 33,709 DM adults before the year 2000 and randomly selected 67,066 non-DM patients matched by sex and age. Subjects were followed until diagnosis with dementia, excluded due to death/withdrawal from the insurance program, or followed until 2011. We compared the incidence and hazard ratio (HR) for dementia in both cohorts. RESULTS: Comorbidities were more prevalent in DM patients, including hypertension, hyperlipidemia, stroke, coronary artery and/or kidney disease. The HR was higher for the DM cohort with comorbidities than those without: 1.88 vs. 1.46 with hypertension; 1.56 vs. 1.39 with hyperlipidemia; 1.73 vs. 1.37 with coronary artery disease; 2.36 vs. 2.29 with stroke and 1.88 vs. 1.50 with kidney disease. The HR for dementia in diabetics rose from 1.41 in those without comorbidities to 2.49 in those with >=4 comorbidities. In the DM cohort, HR was 1.22 for non-insulin-users and 1.41 for insulin-users, and 1.49 for type 1 DM and 1.23 for type 2 DM. CONCLUSION: Diabetic patients have an elevated risk of dementia, and comorbidity increases this risk. PMID- 26233575 TI - Contemporary Outcome in Patients With Idiopathic Dilated Cardiomyopathy. AB - Outcome is better in patients with idiopathic dilated cardiomyopathy (IDC) than in ischemic heart failure (HF), but morbidity and mortality are nevertheless presumed to be substantial. Most data on the prognosis in IDC stem from research performed before the widespread use of current evidence-based treatment, including implantable devices. We report outcome data from a cohort of patients with IDC treated according to current HF guidelines and compare our results with previous figures: 102 consecutive patients referred to our tertiary care hospital with idiopathic IDC and a left ventricular ejection fraction <40% were included in a prospective cohort study. After extensive baseline work-up, follow-up was performed after 6 and 13 months. Vital status and heart transplantation were recorded. Over the first year of follow-up, the patients were on optimal pharmacological treatment, and 24 patients received implantable devices. Left ventricular ejection fraction increased from 26 +/- 10% to 41 +/- 11%, peak oxygen consumption increased from 19.5 +/- 7.1 to 23.4 +/- 7.8 ml/kg/min, and functional class improved substantially (all p values <0.001). After a median follow-up of 3.6 years, 4 patients were dead, and heart transplantation had been performed in 9 patients. According to our literature search, survival in patients with IDC has improved substantially over the last decades. In conclusion, patients with IDC have a better outcome than previously reported when treated according to current guidelines. PMID- 26233576 TI - Antithrombotic and Antiplatelet Therapy in Patients Requiring Oral Anticoagulation After Percutaneous Coronary Intervention. PMID- 26233577 TI - Transcriptome-based discovery of AP2/ERF transcription factors related to temperature stress in tea plant (Camellia sinensis). AB - Tea plant (Camellia sinensis) is an important natural resource for the global supply of non-alcoholic beverage production. The extension of tea plant cultivation is challenged by biotic and abiotic stresses. Transcription factors (TFs) of the APETALA 2 (AP2)/ethylene-responsive factor (ERF) family are involved in growth and anti-stresses through multifaceted transcriptional regulation in plants. This study comprehensively analyzed AP2/ERF family TFs from C. sinensis on the basis of the transcriptome sequencing data of four tea plant cultivars, namely, 'Yunnanshilixiang', 'Chawansanhao', 'Ruchengmaoyecha', and 'Anjibaicha'. A total of 89 putative AP2/ERF transcription factors with full-length AP2 domain were identified from C. sinensis and classified into five subfamilies, namely, AP2, dehydration-responsive-element-binding (DREB), ERF, related to ABI3/VP (RAV), and Soloist. All identified CsAP2/ERF genes presented relatively stable expression levels in the four tea plant cultivars. Many groups also showed cultivar specificity. Five CsAP2/ERF genes from each AP2/ERF subfamily (DREB, ERF, AP2, and RAV) were related to temperature stresses; these results indicated that AP2/ERF TFs may play important roles in abnormal temperature stress response in C. sinensis. PMID- 26233578 TI - Efficacy of Ozurdex implant in recalcitrant diabetic macular edema--a single center experience. AB - The purpose of this study is to report the efficacy of intravitreal Ozurdex implant in managing recalcitrant diabetic macular edema. Retrospective interventional non-randomized study of patients with recalcitrant diabetic macular edema who received intravitreal Ozurdex implant. Main outcome measures were change in the central macular thickness, visual acuity, and intraocular pressure. Sixty-seven eyes of 52 patients with recalcitrant diabetic macular edema with a mean duration of 45.4 +/- 22.5 months (range 6-96 months) were studied. Mean central macular thickness decreased from 514.2 +/- 177.8 um at baseline to 394.3 +/- 152.2 um (p = 0.007), 301.8 +/- 93.0 um (p < 0.000), 316.4 +/- 115.6 um (p < 0.000), and 419.9 +/- 186.3 u (p = 0.03) at 1, 6, 12, and 24 weeks, respectively. Mean best corrected visual acuity changed from 0.82 +/- 0.46 log MAR to 0. 69 +/- 0.44 log MAR (p = 0.122), 0.61 +/- 0.40 log MAR (p = 0.007), 0.65 +/- 0.37 log MAR (p = 0.024), and 0.68 +/- 0.49 log MAR (p = 0.091) at 1, 6, 12, and 24 weeks, respectively. Single injection of intravitreal Ozurdex implant led to progressive decrease in central macular thickness with maximum percentage decrease at 6 weeks (41.2 %) from the baseline which was maintained up to 12 weeks. Eight eyes showed transient rise in intraocular pressure at 2 months which was controlled by antiglaucoma medications. PMID- 26233580 TI - Balance function in patients who had undergone allogeneic hematopoietic stem cell transplantation. AB - A previous study reported a 45% incidence of falling among allogeneic haematopoietic stem cell transplantation (allo-HSCT) patients during hospitalisation. We investigated balance and physical function in allo-HSCT patients. Thirty patients (18 men and 12 women) who underwent allo-HSCT between February 2013 and September 2014 were included in this study. Patients were evaluated for up to 3 weeks before and 7 weeks after transplantation. Balance was evaluated using the Timed Up and Go test (TUG) and length of centre of pressure (CoP). Physical function was assessed using hand-grip strength, knee-extensor strength tests, and the 6 min walk test (6MWT). TUG and length of CoP were significantly increased following HSCT (P<0.01). Hand-grip strength, knee extensor strength, and the 6MWT score decreased significantly after allo-HSCT (P<0.01). TUG and length of CoP were negatively correlated with hand grip and knee-extensor strength (P<=0.05). The allo-HSCT patients in this study had worsened dynamic and static movements of the CoP after transplantation as well as decline of physical function. Rehabilitation staff, nurses, and physicians should recognize the decreased balance function of patients who have undergone allo HSCT. PMID- 26233579 TI - The prognostic value of pSTAT3 in gastric cancer: a meta-analysis. AB - INTRODUCTION: The prognostic value of pSTAT3 in gastric cancer has been assessed for years while the results remain controversial and heterogeneous. Therefore, we conducted this meta-analysis to determine the prognostic effect of pSTAT3 in gastric cancer patients. METHODS: We searched PubMed, Embase and Web of Science and eight studies comprising 1314 gastric cancer patients were included in our meta-analysis. Hazard ratios (HRs) with 95 % confidence interval (95 % CI) were extracted to perform meta-analysis on the overall survival. Subgroup analysis according to study location, publication year, number of patients and quality score of studies were also investigated. RESULTS: Our results revealed that pSTAT3-positive patients had a significant increase in mortality risk as compared to pSTAT3-negative patients in the random-effects model (combined HR 1.87, 95 % CI 1.28-2.74). However, our result showed no statistically significant association between pSTAT3 and clinicopathological characteristics (TMN stage, lymph node metastasis, grade of differentiation, Lauren classification and distant metastasis) of gastric cancer. CONCLUSION: In conclusion, our meta analysis suggests that positive expression of pSTAT3 is associated with poor prognosis in gastric cancer patients. PMID- 26233581 TI - Gait variability in healthy old adults is more affected by a visual perturbation than by a cognitive or narrow step placement demand. AB - Gait variability measures have been linked to fall risk in older adults. However, challenging walking tasks may be required to elucidate increases in variability that arise from subtle age-related changes in cognitive processing and sensorimotor function. Hence, the study objective was to investigate the effects of visual perturbations, increased cognitive load, and narrowed step width on gait variability in healthy old and young adults. Eleven old (OA, 71.2+/-4.2 years) and twelve young (YA, 23.6+/-3.9 years) adults walked on a treadmill while watching a speed-matched virtual hallway. Subjects walked: (1) normally, (2) with mediolateral visual perturbations, (3) while performing a cognitive task (serial seven subtractions), and (4) with narrowed step width. We computed the mean and variability of step width (SW and SWV, respectively) and length (SL, SLV) over one 3-min trial per condition. Walking normally, old and young adults exhibited similar SWV and SLV. Visual perturbations significantly increased gait variability in old adults (by more than 100% for both SWV and SLV), but not young adults. The cognitive task and walking with narrowed step width did not show any effect on SWV or SLV in either group. The dramatic increase in step width variability when old adults were subjected to mediolateral visual perturbations was likely due to increased reliance on visual feedback for assessing whole-body position. Further work is needed to ascertain whether these findings may reflect sub-clinical balance deficits that could contribute to the increased fall risk seen with advancing age. PMID- 26233582 TI - Collective physician perspectives on non-oral medication approaches for the management of clinically relevant unresolved issues in Parkinson's disease: Consensus from an international survey and discussion program. AB - Navigate PD was an educational program established to supplement existing guidelines and provide recommendations on the management of Parkinson's disease (PD) refractory to oral/transdermal therapies. It involved 103 experts from 13 countries overseen by an International Steering Committee (ISC) of 13 movement disorder specialists. The ISC identified 71 clinical questions important for device-aided management of PD. Fifty-six experts responded to a web-based survey, rating 15 questions as 'critically important;' these were refined to 10 questions by the ISC to be addressed through available evidence and expert opinion. Draft guidance was presented at international/national meetings and revised based on feedback. Key take-home points are: * Patients requiring levodopa >5 times daily who have severe, troublesome 'off' periods (>1-2 h/day) despite optimal oral/transdermal levodopa or non-levodopa-based therapies should be referred for specialist assessment even if disease duration is <4 years. * Cognitive decline related to non-motor fluctuations is an indication for device-aided therapies. If cognitive impairment is mild, use deep brain stimulation (DBS) with caution. For patients who have cognitive impairment or dementia, intrajejunal levodopa infusion is considered as both therapeutic and palliative in some countries. Falls are linked to cognitive decline and are likely to become more frequent with device-aided therapies. * Insufficient control of motor complications (or drug resistant tremor in the case of DBS) are indications for device-aided therapies. Levodopa-carbidopa intestinal gel infusions or subcutaneous apomorphine pump may be considered for patients aged >70 years who have mild or moderate cognitive impairment, severe depression or other contraindications to DBS. PMID- 26233583 TI - Bioenergy from stillage anaerobic digestion to enhance the energy balance ratio of ethanol production. AB - The challenges associated with the availability of fossil fuels in the past decades intensified the search for alternative energy sources, based on an ever increasing demand for energy. In this context, the application of anaerobic digestion (AD) as a core treatment technology in industrial plants should be highlighted, since this process combines the pollution control of wastewaters and the generation of bioenergy, based on the conversion of the organic fraction to biogas, a methane-rich gaseous mixture that may supply the energetic demands in industrial plants. In this context, this work aimed at assessing the energetic potential of AD applied to the treatment of stillage, the main wastewater from ethanol production, in an attempt to highlight the improvements in the energy balance ratio of ethanol by inserting the heating value of methane as a bioenergy source. At least 5-15% of the global energy consumption in the ethanol industry could be supplied by the energetic potential of stillage, regardless the feedstock (i.e. sugarcane, corn or cassava). The association between bagasse combustion and stillage anaerobic digestion in sugarcane-based distilleries could provide a bioenergy surplus of at least 130% of the total fossil fuel input into the ethanol plant, considering only the energy from methane. In terms of financial aspects, the economic gains could reach US$ 0.1901 and US$ 0.0512 per liter of produced ethanol, respectively for molasses- (Brazil) and corn-based (EUA) production chains. For large-scale (~1000 m(3)EtOH per day) Brazilian molasses-based plants, an annual economic gain of up to US$ 70 million could be observed. Considering the association between anaerobic and aerobic digestion, for the scenarios analyzed, at least 25% of the energetic potential of stillage would be required to supply the energy consumption with aeration, however, more suitable effluents for agricultural application could be produced. The main conclusion from this work indicates that anaerobic processes should be considered the core technology to treat stillage, based mainly on the attractive relation energy generation-financial return and on the possibility to keep the advantages inherent to the common fertigation when using the treated effluent in agriculture. PMID- 26233584 TI - Influence of an aniline supplement on the stability of aerobic granular sludge. AB - In order to evaluate the stability of aerobic granules in a toxic environment, this study discussed the influence of an aniline supplement on the properties and microbial community of aerobic granules. In the early stages of sequencing batch reactor (SBR) operation, an aniline supplement slightly affected the properties of the aerobic granules (strength, growth rate, SVI and so on). This effect was thereafter removed because of a change in the microbial community and the structure of aerobic granules: with the present of aniline, microbes with biodegradation ability appeared and gathered in the aerobic granules and the aerobic granules densified and settled faster as their SVI decreased to 35 mL/g and settling velocity increased to 41.56 m/h. When a synthetic waste water containing acetate as carbon source was used as influent, aniline (10-500 mg/L) could be degraded in 6 h, at a rate as high as 37.5 mg aniline/(L.h), with a removal rate in excess of 90%, while the effluent COD fell below 100 mg/L from the initial about 2000 mg/L. The aerobic granules cultured by acetate were compact, stable and resistant to aniline. PMID- 26233585 TI - Production of activated carbon from biodiesel solid residues: An alternative for hazardous metal sorption from aqueous solution. AB - In this study, the potential for the sorption of Pb(2+) and Cd(2+) from aqueous solutions using HNO3-treated activated carbon (TAC) obtained from radish press cake (Raphanus sativus L.), a solid residue from biodiesel production, was investigated. Activated carbon (AC) was obtained by physical activation with CO2(g). Chemical modification with HNO3 was employed to increase the sorption capability of the AC. The sorption of Pb(2+) and Cd(2+) was studied in monometallic systems in equilibrium with different metal-ion concentrations (10 400 mg L(-1)). The experimental sorption equilibrium data were fit to the Langmuir and Freundlich isotherm models. The maximum sorption capacity (qmax) obtained for AC from the Langmuir isotherm was 45.5 mg g(-1) for Cd(2+) and 250 mg g(-1) for Pb(2+). Moreover, TAC presented qmax of 166.7 mg g(-1) (1.48 mmol g( 1)) for Cd(2+) and 500.0 mg g(-1) (2.41 mmol g(-1)) for Pb(2+)showing the effect of chemical modification. Sorption-desorption studies showed that the interaction between metals and TAC is reversible and this sorbent can be reused for several consecutive cycles. Furthermore, the sorption of Cd(2+) and Pb(2+) by TAC was not affected by the presence of competing ions. The experimental data obtained in this study indicated that this solid residue is viable for the production of sorbents that remove metals, such as cadmium and lead, from wastewaters and thereby contribute to the sustainable development of the production of biodiesel. PMID- 26233586 TI - Treatment of sewage sludge in a thermophilic membrane reactor (TMR) with alternate aeration cycles. AB - The management of sewage sludge is becoming a more and more important issue, both at national and international level, in particular due to the uncertain recovery/disposal future options. Therefore, it is clear that the development of new technologies that can mitigate the problem at the source by reducing sludge production is necessary, such as the European Directive 2008/98/EC prescribes. This work shows the results obtained with a thermophilic membrane reactor, for processing a biological sludge derived from a wastewater treatment plant (WWTP) that treats urban and industrial wastewater. Sewage sludge was treated in a thermophilic membrane reactor (TMR), at pilot-scale (1 m(3) volume), with alternate aeration cycles. The experimentation was divided into two phases: a "startup phase" during which, starting with a psychrophilic/mesophilic biomass, thermophilic conditions were progressively reached, while feeding a highly biodegradable substrate; the obtained thermophilic biomass was then used, in the "regime phase", to digest biological sludge which was fed to the plant. Good removal yields were observed: 64% and 57% for volatile solids (VS) and total COD (CODtot), respectively, with an average hydraulic retention time (HRT) equal to 20 d, an organic loading rate (OLR) of about 1.4-1.8 kg COD m(-3) d(-1) and aeration/non aeration cycles alternated every 4 h. PMID- 26233587 TI - Early and adequate empirical antibiotic treatment in sepsis saves lives, but how should it be provided? PMID- 26233588 TI - Multidisciplinary consensus document on the management of massive haemorrhage (HEMOMAS document). AB - Massive haemorrhage is common and often associated with high morbidity and mortality. We perform a systematic review of the literature, with extraction of the recommendations from the existing evidences because of the need for its improvement and the management standardization. From the results we found, we wrote a multidisciplinary consensus document. We begin with the agreement in the definitions of massive haemorrhage and massive transfusion, and we do structured recommendations on their general management (clinical assessment of bleeding, hypothermia management, fluid therapy, hypotensive resuscitation and damage control surgery), blood volume monitoring, blood products transfusion (red blood cells, fresh frozen plasma, platelets and their best transfusion ratio), and administration of hemostatic components (prothrombin complex, fibrinogen, factor VIIa, antifibrinolytic agents). PMID- 26233589 TI - Late proliferating and inflammatory effects on murine microvascular heart and lung endothelial cells after irradiation. AB - BACKGROUND AND PURPOSE: Radiotherapy of thoracic tumors increases the risk to develop cardiac diseases at later time-points. We compared time kinetics of radiation-induced changes of surface markers related to proliferation, progenitor cell development and inflammation in lung and heart microvascular endothelial cells (ECs). MATERIAL AND METHODS: Mice received local thorax irradiation with a single dose of 0, 2 or 8 Gy. Following magnetic bead separation and biotin streptavidin competition, cell surface markers of isolated ECs from the lung and heart were analyzed 5, 10, 15 and 20 weeks after irradiation by flow cytometry. RESULTS: Irradiation with 8 Gy resulted in a temporary and differential up regulation of proliferation markers (HCAM, Integrin beta-3, Endoglin, VE cadherin, VEGFR-2) on ECs. Mucosialin a progenitor marker increased in lung ECs 15-20 weeks and inflammatory markers (PECAM-1, ICAM-1, ICAM-2, VCAM-1) started to increase 10 weeks after thorax irradiation with 8 Gy. Interestingly, ICAM-1 and VCAM-1 remained up-regulated 20 weeks after irradiation in heart and lung ECs. CONCLUSIONS: The persistently elevated expression density of ICAM-1 and VCAM-1 on ECs may suggest that an irradiation at 8 Gy induces late inflammatory responses in heart and lung ECs. PMID- 26233590 TI - Clinical efficacy and failure pattern in patients with cervical esophageal cancer treated with definitive chemoradiotherapy. AB - BACKGROUND: Data on cervical esophageal cancer (CEC) based on modern radiotherapy technique are rare. We aimed to analyze the clinical efficacy and failure pattern of patients with CEC who underwent definitive chemoradiotherapy. METHODS: Between February 2002 and October 2013, 102 patients with CEC treated with definitive chemoradiotherapy were retrospectively analyzed. All patients received concurrent platinum-based chemotherapy with conformal radiotherapy (50-70 Gy in 25-35 fractions, 5 fractions per week over 5-7 weeks). Overall survival (OS), progression-free survival (PFS) and loco-regional failure-free survival (LRFFS) were calculated. RESULTS: The 3-year OS, PFS and LRFFS rates for the entire sample were 39.3%, 33.6% and 35.3%, respectively. During follow-up, 32, 26, and 41 patients had developed local, regional, and distant failure, respectively. Sex and hoarseness were independent prognostic indicators for OS (P=0.011, P<0.001; respectively) and PFS (P=0.008, P=0.001; respectively). Hoarseness was the only independent prognostic factor for LRFFS (P=0.002). CONCLUSIONS: Distant metastasis was the most common failure pattern in CEC patients undergoing definitive chemoradiotherapy. Hoarseness was an independent prognostic factor for OS, PFS, and LRFFS. PMID- 26233591 TI - Phase I study of stereotactic body radiation therapy for peripheral T2N0M0 non small cell lung cancer with PTV<100 cc using a continual reassessment method (JCOG0702). AB - PURPOSE: To estimate the maximum tolerated dose (MTD) and to determine the recommended dose (RD) of stereotactic body radiation therapy (SBRT) for peripheral T2N0M0 non-small cell carcinoma (NSCLC) with target volume (PTV) < 100 cc. MATERIALS AND METHODS: The continual reassessment method (CRM) was used to determine the dose level that patients should be assigned to and to estimate the MTD. Dose limiting toxicity (DLT) was grade 3 radiation pneumonitis (RP) within 180 days after the start of SBRT, grade 2 RP was used as a surrogate DLT. The RD was equal to the MTD. The dose was prescribed at D95 of the PTV. RESULTS: Fifteen patients were accrued. Only 1 experienced grade 2 RP at 60 Gy in 4 fractions. It was difficult to fulfill the dose constraints at 60 Gy in 4 fractions, and the maximum dose level assigned by CRM was changed to 55 Gy in 4 fractions. The lower limit of 95% of the credible interval exceeded the adjacent level, and the RD was determined as 55 Gy in 4 fractions. CONCLUSIONS: The RD of SBRT for peripheral T2N0M0 NSCLC with PTV<100 cc was determined to be 55 Gy in 4 fractions. PMID- 26233592 TI - What morphological pattern of "impressio ligamenti costoclavicularis" is the most predominant? PMID- 26233593 TI - Clinical anatomy of the orbitomeningeal foramina: variational anatomy of the canals connecting the orbit with the cranial cavity. AB - PURPOSE: In addition to the optic canal and the superior orbital fissure, orbits are connected with the cranial cavity via inconstant canals including the orbitomeningeal foramen. This study has been carried out in order to define many anatomical and radiological details of the orbitomeningeal foramen that are relevant in the clinical practice. METHODS: Almost 1000 skulls and 50 computerized tomographies were examined to determine incidence, number, length, and caliber of the orbitomeningeal foramen as well as the topography of their orbital and cranial openings. A retrospective study of angiographies carried out on more than 100 children was performed to look for arteries candidate to run through the orbitomeningeal foramen. RESULTS: Orbitomeningeal foramina were detected in 59.46% of skulls and in 54% of individuals by computerized tomography. Orbits with two to five foramina were found. Canals were classified as M-subtype or A-subtype depending on their cranial opening. Large foramina, with the caliber ranging between 1 and 3 mm, were found in 12.17% of orbitomeningeal foramen-bearing orbits. By computed tomography the average caliber measured 1.2 +/- 0.3 and 1.5 +/- 0.5 mm (p < 0.005) at the orbital and cranial openings, respectively (p < 0.005). Angiographies showed meningo-lacrimal and meningo-ophthalmic arteries, meningeal branches of the lacrimal and supraorbital arteries, and some unidentified arteries that could pass through the orbitomeningeal foramina. CONCLUSIONS: Orbitomeningeal foramina are a common occurrence. When large they may house important arteries that can be the source of severe bleedings during deep dissection of the lateral wall of the orbit. Orbital surgeons should be aware of their existence. PMID- 26233594 TI - Multiple PRP injections are more effective than single injections and hyaluronic acid in knees with early osteoarthritis: a randomized, double-blind, placebo controlled trial. AB - PURPOSE: To compare the effectiveness of intraarticular (IA) multiple and single platelet-rich plasma (PRP) injections as well as hyaluronic acid (HA) injections in different stages of osteoarthritis (OA) of the knee. METHODS: A total of 162 patients with different stages of knee OA were randomly divided into four groups receiving 3 IA doses of PRP, one dose of PRP, one dose of HA or a saline injection (control). Then, each group was subdivided into two groups: early OA (Kellgren-Lawrence grade 0 with cartilage degeneration or grade I-III) and advanced OA (Kellgren-Lawrence grade IV). The patients were evaluated before the injection and at the 6-month follow-ups using the EuroQol visual analogue scale (EQ-VAS) and International Knee Documentation Committee (IKDC) subjective scores. Adverse events and patient satisfaction were recorded. RESULTS: There was a statistically significant improvement in the IKDC and EQ-VAS scores in all the treatment groups compared with the control group. The knee scores of patients treated with three PRP injections were significantly better than those patients of the other groups. There was no significant difference in the scores of patients injected with one dose of PRP or HA. In the early OA subgroups, significantly better clinical results were achieved in the patients treated with three PRP injections, but there was no significant difference in the clinical results of patients with advanced OA among the treatment groups. CONCLUSION: The clinical results of this study suggest IA PRP and HA treatment for all stages of knee OA. For patients with early OA, multiple (3) PRP injections are useful in achieving better clinical results. For patients with advanced OA, multiple injections do not significantly improve the results of patients in any group. LEVEL OF EVIDENCE: I. PMID- 26233595 TI - A novel technique for combined medial collateral ligament and posterior oblique ligament reconstruction: technical note. AB - PURPOSE: In the last year, we have performed a new technique for combined medial collateral ligament (MCL) and posterior oblique ligament (POL) reconstruction in chronic setting of anterior cruciate ligament and MCL complex deficiency. Autogenous semitendinosus tendon with the tibial attachment preserved has been used for the medial/posteromedial compartment reconstruction. We describe the operative technique. METHODS: Between January and December 2014, 12 consecutive patients with multiligamentous injuries underwent concomitant MCL/POL using a novel technique. The usefulness of the novel technique is the semitendinosus sling on the semimembranosus tendon and the POL fixation with the knee in full extension. RESULTS: An ideal anteroposterior and rotational stability avoiding the medial compartment over constraint was achieved, in the immediate after surgery, due to the sequence of the bundle fixations and to the semitendinosus sling below the semimembranosus tendon. CONCLUSIONS: This technique is easily reproducible and useful and restores the medial stability immediately after surgery. PMID- 26233596 TI - Are severe musculoskeletal injuries associated with symptoms of common mental disorders among male European professional footballers? AB - PURPOSE: To explore the associations of severe musculoskeletal injuries (joint and muscles) and surgeries with symptoms of common mental disorders (distress, anxiety/depression, sleeping disturbance, adverse alcohol behaviour , smoking, adverse nutrition behaviour) among male European professional footballers. METHODS: Cross-sectional analyses were conducted on electronic questionnaires completed by professional footballers recruited from the national players' unions of Finland, France, Norway, Spain or Sweden. The number of severe (time loss of more than 28 days) musculoskeletal injuries (total, joint, muscle) and surgeries during a professional football career was examined through four questions, while symptoms of common mental disorders were evaluated through validated scales. RESULTS: A total of 540 professional footballers (mean age of 27 years; 54 % playing in the highest leagues) participated in the study. Sixty-eight per cent of the participants had already incurred one or more severe joint injuries and 60 % one or more severe muscle injuries. Prevalence of symptoms of common mental disorders ranged from 3 % for smoking to 37 % for anxiety/depression and 58 % for adverse nutrition behaviour. The number of severe musculoskeletal injuries during a football career was positively correlated with distress, anxiety and sleeping disturbance, while the number of surgeries was correlated with adverse alcohol behaviour and smoking. Professional footballers who had sustained one or more severe musculoskeletal injuries during their career were two to nearly four times more likely to report symptoms of common mental disorders than professional footballers who had not suffered from severe musculoskeletal injuries. CONCLUSION: It can be concluded that the number of severe musculoskeletal injuries and surgeries during a career is positively correlated and associated with symptoms of common mental disorders among male European professional footballers. This study emphasises the importance of applying a multidisciplinary approach to the clinical care and support of professional footballers, especially when a player faces lengthy periods without training and competition as a consequence of recurrent severe joint or muscle injuries. LEVEL OF EVIDENCE: III. PMID- 26233597 TI - Evaluation of pivot shift phenomenon while awake and under anaesthesia by different manoeuvres using triaxial accelerometer. AB - PURPOSE: Evaluating pivot shift phenomenon is difficult due to its subjectivity, wide variation of testing manoeuvres, and difficulty in evaluating patients while awake. The purpose of this study was to evaluate the pivot shift phenomenon using a triaxial accelerometer by two different manoeuvres, the pivot shift test as representative of flexion manoeuvre and N test as a representative of extension manoeuvre, and in two different conditions, awake and under anaesthesia. METHODS: Twenty-nine patients with unilateral anterior cruciate ligament (ACL)-injured knee were included. Pivot shift test and N test were performed for both injured and uninjured legs while awake and under anaesthesia, with the acceleration measurements using a triaxial accelerometer (KiRA). The tests were also subjectively graded on a scale of 0-6 based on the modification of IKDC criteria. RESULTS: Under anaesthesia, acceleration of ACL-injured knees was greater than that of uninjured knees in both pivot shift test (P < 0.001) and N test (P < 0.001) , whereas the acceleration value was greater in the N test. Furthermore, there were significant positive correlations between the acceleration and subjective grading in both tests, whereas the N test was more significant than the pivot shift test. On the other hand, there was no statistical significance in acceleration between ACL-injured and uninjured knees in either test while the patient was awake. CONCLUSION: The triaxial accelerometer was useful to objectively detect and quantitatively evaluate the pivot shift phenomenon by both the pivot shift test and N test under anaesthesia. The acceleration of ACL injured knees was greater than that of uninjured knees, and the acceleration was correlated with the subjective manual grading, especially in the N test. On the other hand, its use while the patient was awake was likely limited. LEVELS OF EVIDENCE: Diagnostic study of non-consecutive patients without a universally applied gold standard, Level III. PMID- 26233598 TI - Acute Anterior Uveitis and Spondyloarthritis: More Than Meets the Eye. AB - Ankylosing spondylitis (AS) and related forms of spondyloarthritis (SpA) are associated with some extra-articular features, and the most common symptomatic association is with acute anterior uveitis (AAU). Thus, approximately 40 % of patients with AS will experience a sudden onset of a unilateral anterior uveitis sometime during the course of their disease. Patients with AAU, especially those who are HLA-B27 positive, should be questioned about inflammatory low back pain and also evaluated for other clinical features of SpA. Since a prolonged delay in diagnosis is common among SpA patients and occurrence of AAU may be the reason for their first interaction with medical care, occurrence of AAU presents a unique opportunity for identifying such undiagnosed SpA patients. Therefore, a novel evidence-based algorithm called Dublin Uveitis Evaluation Tool (DUET) has been proposed to guide ophthalmologists and primary care physicians to refer appropriate AAU patients to rheumatologists. In a large two-phase study, approximately 40 % of patients presenting with idiopathic AAU were noted to have undiagnosed SpA, and DUET algorithm was noted to have excellent sensitivity (96 %) and specificity (97 %). It has a positive likelihood ratio (LR) 41.5 and negative LR 0.03. In most instances, the eye inflammation responds well to corticosteroid and mydriatic eye drops and without the need for additional therapy. Use of oral corticosteroids is reserved for patients, especially with associated chronic inflammatory bowel disease or psoriatic arthritis presenting with bilateral, chronic, anterior, and/or intermediate uveitis, and this treatment is rarely needed for more than a couple of weeks. A very small percentage may be more refractory to such treatment and require potential novel therapies, including the use of tumor necrosis factor blockers. PMID- 26233600 TI - 50 years of Medicare. PMID- 26233601 TI - Can we model a cognitive footprint of interventions and policies to help to meet the global challenge of dementia? PMID- 26233599 TI - Bone Homeostasis and Repair: Forced Into Shape. AB - Mechanical loading is a potent anabolic regulator of bone mass, and the first line of defense for bone loss is weight-bearing exercise. Likewise, protected weight bearing is the first prescribed physical therapy following orthopedic reconstructive surgery. In both cases, enhancement of new bone formation is the goal. Our understanding of the physical cues, mechanisms of force sensation, and the subsequent cellular response will help identify novel physical and therapeutic treatments for age- and disuse-related bone loss, delayed- and nonunion fractures, and significant bony defects. This review highlights important new insights into the principles and mechanisms governing mechanical adaptation of the skeleton during homeostasis and repair and ends with a summary of clinical implications stemming from our current understanding of how bone adapts to biophysical force. PMID- 26233602 TI - The Use of Magnetic Resonance Imaging Screening for Optic Pathway Gliomas in Children with Neurofibromatosis Type 1. AB - OBJECTIVE: To evaluate the utility of screening brain/orbital magnetic resonance imaging (MRI) in a large population of children with neurofibromatosis type 1 (NF1) over a 20-year period. STUDY DESIGN: A retrospective analysis of clinical and imaging data from children with NF1 seen at a single center between 1990 and 2010 was performed. RESULTS: During the 20-year study period, 826 individuals with NF1 (402 females, 424 males) ages 1-9 years were screened for optic pathway gliomas (OPGs) using brain/orbital MRI; 18% were identified with OPGs with a median age at detection of 3 years. Fifteen percent of patients with OPGs had radiologic or clinical progression requiring therapy. Children with chiasmatic and postchiasmatic tumors were more likely to require therapy compared with patients with prechiasmatic OPGs (P < .0001). Patients with visual deficits at the time of diagnosis were more likely to experience visual decline despite therapy when compared with patients treated based on radiologic progression (P < .012). CONCLUSIONS: Our findings confirm that chiasmatic and postchiasmatic OPG in children with NF1 have the highest risk for progression and vision loss. Early identification of OPG by screening MRI prior to the development of vision loss may lead to improved visual outcomes. Children with negative brain and orbital MRI screening at age 15 months or later did not develop symptomatic OPGs. PMID- 26233603 TI - Variation in Computed Tomography Imaging for Pediatric Injury-Related Emergency Visits. AB - OBJECTIVE: To assess variation in the use of computed tomography (CT) for pediatric injury-related emergency department (ED) visits. STUDY DESIGN: This was a retrospective cohort study of visits to 14 network-affiliated EDs from November 2010 through February 2013. Visits were identified by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Primary outcome was CT use. We used descriptive statistics and performed multivariable logistic regression to evaluate the association of patient and ED covariates on any and body region-specific CT use. RESULTS: Of the 80 868 injury related visits, 11.4% included CT, and 28.4% of those involved more than 1 CT. Across EDs, CT use ranged from 7.6% to 25.5% of visits and did not correlate with institutional Injury Severity Score (P = .33) or admission/transfer rates (P = .07). In multivariable analysis of nonpediatric EDs, trauma centers and nonacademic EDs were associated with CT use. Higher pediatric volume was associated with any CT use; however, there was an inverse relationship between volume and nonhead CT use. When the pediatric ED was included in multivariable modeling, the effect of level 1-3 trauma center designation remained, and the pediatric level 1 trauma center was less likely to use most body region-specific CTs. CONCLUSION: There is wide variation in CT imaging for pediatric injury related visits not attributable solely to case mix. Future work to optimize CT utilization should focus on additional factors contributing to imaging practices and interventions. PMID- 26233605 TI - Sigmoid Volvulus: An Underestimated Cause of Intestinal Obstruction in Cornelia de Lange Syndrome. PMID- 26233604 TI - Severe Congenital Heart Defects Are Associated with Global Reduction of Neonatal Brain Volumes. AB - OBJECTIVES: To determine neonatal global and regional brain volumes in infants with congenital heart disease (CHD) in comparison with healthy controls and to determine brain growth. STUDY DESIGN: Prospective cohort study in infants undergoing open-heart surgery for complex CHD. Global and regional volumetric measurements on preoperative cerebral magnetic resonance imaging were manually segmented in children without overt brain lesions. RESULTS: Preoperative brain volumetry of 19 patients demonstrates reduction in total and regional brain volumes, without any specific regional predilection compared with 19 healthy control infants (total brain volume reduction: 21%, regional brain volume reduction 8%-28%, all P < .001). CONCLUSIONS: Infants with CHD undergoing bypass surgery have smaller brain volumes prior to surgery without a specific regional predilection. This suggests a fetal origin of reduced brain growth. PMID- 26233606 TI - Ketamine-like effects of a combination of olanzapine and fluoxetine on AMPA and NMDA receptor-mediated transmission in the medial prefrontal cortex of the rat. AB - Preclinical studies indicate that the rapid antidepressant effect of ketamine is dependent on activation of AMPA receptors in the medial prefrontal cortex (mPFC) resulting in a prolonged enhancement of glutamatergic transmission in the mPFC. In similarity, addition of atypical antipsychotic drugs (APDs) to SSRIs has also been found to induce a rapid and potent antidepressant effect. Using intracellular recordings in layer V/VI pyramidal cells of the rat mPFC in vitro, we found that a combination of low, clinically relevant concentrations of the atypical APD olanzapine and the SSRI fluoxetine facilitated NMDA and AMPA-induced currents in pyramidal cells via activation of dopamine D1 receptors. A single ketamine injection (10mg/kg, 24h before the experiment) enhanced AMPA-and apparently to some extent also NMDA-induced currents. Our results propose that the rapid and potent antidepressant effects of both treatments may be related to a common mechanism of action, namely facilitation of glutamatergic, in particular AMPA receptor-mediated transmission, in the mPFC. PMID- 26233607 TI - Long-term use of antipsychotics among community-dwelling persons with Alzheimer's disease: A nationwide register-based study. AB - Antipsychotics are recommended only for short-term treatment of severe behavioral and psychological symptoms of dementia. Our objective was to study the duration of antipsychotic use and factors associated with long-term use (365 days or over) among community-dwelling persons with Alzheimer's disease (AD) during a 7-year follow-up. This was a nationwide register-based cohort study including all community-dwelling residents in Finland diagnosed with AD in 2005 (n=7217). The follow-up for antipsychotic use started 3 years before the diagnosis of AD and we applied a 7-year washout period to ascertain truly incident antipsychotic use. Follow-up ended on institutionalization, death or at the end of study period (December 31, 2009). Duration of antipsychotic use was modeled from individual purchase histories recorded in the Finnish Prescription Register. During the 7 year follow-up, 34% (2287/6740) of persons initiated antipsychotic use. Median duration of the first antipsychotic use period was 219 (interquartile range 85 583) days. Of those who discontinued antipsychotic use (n=1303), 44% restarted use later. Among users with at least one year of follow-up time after initiating antipsychotic use, prevalence of long-term use was 57% (893/1563). Long-term use was associated with initiation of use after AD diagnosis and choice of antipsychotic. Duration of use was more likely to be shorter among haloperidol users and longer among quetiapine users compared with risperidone users. In conclusion, long-term use of antipsychotics is frequent among community-dwelling persons with AD. Duration of use is not in line with the guidelines recommending time-limited use of antipsychotics. PMID- 26233608 TI - Stress induced risk-aversion is reverted by D2/D3 agonist in the rat. AB - Stress exposure triggers cognitive and behavioral impairments that influence decision-making processes. Decisions under a context of uncertainty require complex reward-prediction processes that are known to be mediated by the mesocorticolimbic dopamine (DA) system in brain areas sensitive to the deleterious effects of chronic stress, in particular the orbitofrontal cortex (OFC). Using a decision-making task, we show that chronic stress biases risk based decision-making to safer behaviors. This decision-making pattern is associated with an increased activation of the lateral part of the OFC and with morphological changes in pyramidal neurons specifically recruited by this task. Additionally, stress exposure induces a hypodopaminergic status accompanied by increased mRNA levels of the dopamine receptor type 2 (Drd2) in the OFC; importantly, treatment with a D2/D3 agonist quinpirole reverts the shift to safer behaviors induced by stress on risky decision-making. These results suggest that the brain mechanisms related to risk-based decision-making are altered after chronic stress, but can be modulated by manipulation of dopaminergic transmission. PMID- 26233609 TI - Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. AB - BACKGROUND: Small cell lung cancer (SCLC) is a very fast growing form of cancer and is characterised by early metastasis. As a result, chemotherapy is the mainstay of treatment. A number of different platinum-based chemotherapy regimens and non-platinum-based chemotherapy regimens have been used for the treatment of SCLC, with varying results. This review was conducted to analyse the data from these studies in order to compare their effectiveness. OBJECTIVES: To determine the effectiveness of platinum chemotherapy regimens compared with non-platinum chemotherapy regimens in the treatment of SCLC with respect to survival, tumour response, toxicity and quality of life. SEARCH METHODS: We searched the biomedical literature databases CENTRAL (TheCochrane Library 2014, Issue 7), MEDLINE, EMBASE and CINAHL from 1966 to August 2014. In addition, we handsearched reference lists from relevant resources. SELECTION CRITERIA: All randomised controlled trials involving patients with pathologically confirmed SCLC (including both limited-stage disease and extensive-stage disease) and the use of a platinum-based chemotherapy regimen in at least one treatment arm and a non platinum-based chemotherapy regimen in a separate arm. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. Two authors independently assessed search results. We assessed included studies for methodological quality and recorded the following outcome data: survival, tumour response, toxicity and quality of life. We combined the results of the survival, tumour response and toxicity data in a meta-analysis. Quality-of-life data were analysed individually. MAIN RESULTS: A total of 32 studies involving 6075 patients with SCLC were included in this systematic review. The majority of studies were multi-centre randomised controlled trials conducted throughout Europe, North America and Asia with the earliest study publishing data in 1981 and the latest in 2014. The duration of studies ranged from 12 to 72 months with a median of 32 months. The median age of patients in the vast majority of studies was between 60 and 65 years of age. Eighteen studies presented data on extensive-stage disease. Nine studies presented data on limited stage disease. Eleven studies did not present data based on the disease stage. These data were analysed separately in subgroup analyses. Sixteen (50%) studies were of good quality with a low risk of bias and the data from these studies were analysed separately in a heterogeneity analysis.There was no statistically significant difference between treatment groups in terms of survival at 6 months, 12 months and 24 months. There was also no statistically significant difference in terms of overall tumour response. However, platinum-based treatment regimens did have a significantly higher rate of complete response. Platinum-based chemotherapy regimens had significantly higher rates of nausea and vomiting and thrombocytopenia toxicity. Four trials presented quality-of-life data, but, due to the different systems used to measure quality of life this data could not be combined in a meta-analysis. AUTHORS' CONCLUSIONS: Platinum-based chemotherapy regimens did not offer a statistically significant benefit in survival or overall tumour response compared with non-platinum-based regimens. However, platinum based chemotherapy regimens did increase complete response rates, at the cost of higher adverse events including nausea and vomiting, anaemia and thrombocytopenia toxicity. These data suggest non-platinum chemotherapy regimens have a more advantageous risk-benefit profile. This systematic review highlights the lack of quality-of-life data in trials involving chemotherapy treatment for SCLC. With poor long-term survival associated with both treatment groups, the issue of the quality of the survival period takes on even more significance. It would be beneficial for future trials in this area to include a quality-of-life assessment. PMID- 26233610 TI - Postmortem serum protein growth arrest-specific 6 levels in sepsis-related deaths. AB - Growth arrest-specific 6 (Gas6) is widely expressed in leukocytes, platelets, endothelial cells, and monocytes. It regulates various processes including granulocyte adhesion to the endothelium, cell migration, thrombus stabilization, and cytokine release. In humans, increased plasma Gas6 levels have been described in patients with sepsis and septic shock. In this study, Gas6 concentrations were measured in postmortem serum from femoral blood in a series of sepsis-related fatalities and control cases. The aims were twofold: first, to determine whether Gas6 can be reliably determined in postmortem serum; and second, to assess its diagnostic potential in identifying sepsis-related deaths. Two study groups were prospectively formed, a sepsis-related fatalities group (24 cases) and a control group (24 cases) including cases of deep vein thrombosis and fatal pulmonary embolism, cases of systemic inflammatory response syndrome in severe trauma, cases of end-stage renal failure, and cases of hanging (non-septic, non-SIRS, non end stage renal failure cases). The preliminary results of this study seem to indicate that Gas6 can be effectively measured in postmortem serum. However, Gas6 levels in sepsis-related fatalities do not appear to be clearly distinguishable from concentrations in pulmonary embolism, severe trauma, and end-stage renal failure cases. These findings tend to support previous reports that indicated that Gas6 behaves as an acute phase reactant and can be considered a general marker of inflammation rather than a specific biomarker of sepsis. PMID- 26233611 TI - Enlarged parietal foramina: a rare forensic autopsy finding. AB - Enlarged parietal foramina (EPF) are a quite rare developmental defect of the parietal bone which has to be distinguished from the normal small parietal foramina. We report a forensic case of an individual found in an advanced state of putrefaction in his own house with an undetermined cause of death. No evidence of trauma was observed, and the toxicological exam was negative. The victim was a 40-year-old man with a history of epilepsy. The large biparietal foramina, a rare anatomical variation and unusual autopsy finding, were observed at autopsy. The recognition of anatomical variations is important to avoid false interpretations and conclusions and has a significant potential as an identity factor, thus contributing to positive identification. PMID- 26233612 TI - Rapid elimination of Carboxy-THC in a cohort of chronic cannabis users. AB - Urinary 11-nor-Delta(9)-tetrahydrocannabinol-9-carboxylic acid (Carboxy-THC) concentrations, normalised to creatinine output, have been demonstrated to be a useful tool in the interpretation of the results of a series of urine tests for cannabis. These tests, often termed historical data, can be used to identify potential chronic cannabis users who may present occupational health and safety risks within the workplace. Conversely, the data can also be used to support employee claims of previous regular, rather than recent, cannabis use. This study aimed at examining the mean elimination of Carboxy-THC in 37 chronic users undergoing voluntary abstinence over a 2-week period. Urine specimens were collected prior to the study and after 1 and 2 weeks of abstinence. Carboxy-THC levels in urine were measured by gas chromatography-mass spectrometry (GC-MS) following alkaline hydrolysis, organic solvent extraction and derivatisation to form its pentafluoropropionic derivative. The creatinine-normalised Carboxy-THC concentrations declined rapidly over the 2 weeks of abstinence period and the majority of chronic cannabis users (73%) reduced their urinary Carboxy-THC levels to below the 15-MUg/L confirmatory cutoff within that time. The study further highlights the value of historical urinary Carboxy-THC data as a means of identifying potential occupational health and safety risks among chronic cannabis users. PMID- 26233613 TI - Forensic parameters of the Investigator DIPplex kit (Qiagen) in six Mexican populations. AB - Allele frequencies and statistical parameters of forensic efficiency for 30 deletion-insertion polymorphisms (DIPs) were estimated in six Mexican populations. For this purpose, 421 unrelated individuals were analyzed with the Investigator DIPplex kit. The Hardy-Weinberg and linkage equilibrium was demonstrated for this 30-plex system in all six populations. We estimated the combined power of discrimination (PD >= 99.999999%) and combined power of exclusion (PE >= 98.632705%) for this genetic system. A low but significant genetic structure was demonstrated among these six populations by pairwise comparisons and AMOVA (F ST >= 0.7054; p <= 0.0007), which allows clustering populations in agreement with geographical criteria: Northwest, Center, and Southeast. PMID- 26233615 TI - Diagnostic value of lead aVR in acute coronary syndrome. PMID- 26233614 TI - Impact of cannabis use on prefrontal and parietal cortex gyrification and surface area in adolescents and emerging adults. AB - BACKGROUND: Regions undergoing maturation with CB1 receptors may be at increased risk for cannabis-induced alterations. Here, we examine the relationships between cannabis use and prefrontal (PFC) and inferior parietal gyrification and surface area (SA) in youth. METHODS: Participants included 33 cannabis users and 35 controls (ages 18-25). Exclusions included co-morbid psychiatric/neurologic disorders and heavy other drug use. Multiple regressions and Pearson r correlations examined the effects of cannabis use on gyrification, SA and cognition. RESULTS: Cannabis use was associated with decreased gyrification in: ventral-medial PFC (RH: [FDR corrected p=.02], LH: [FDR corrected p=.02]); medial PFC (RH: [FDR corrected p=.02], LH: [FDR corrected p=.02]); and frontal poles (RH: [FDR corrected p=.02], LH: [FDR corrected p=.02]). No differences were observed in bilateral hemispheres, PFC, dorsolateral, ventrolateral, or inferior parietal ROIs. Cannabis use was associated with marginally decreased SA in left: medial PFC [FDR corrected p=.09], and ventral lateral PFC: [FDR corrected p=.09]. In cannabis users, increased gyrification was associated with improved working memory performance in right medial (p=.003), ventral-medial (p=.03), and frontal pole ROIs (p=.007). CONCLUSIONS: Cannabis use was associated with reduced gyrification in PFC regions implicated in self-referential thought and social cognition. Results suggest that these gyrification characteristics may have cognitive implications. PMID- 26233616 TI - Fecal calprotectin: can be used to distinguish between bacterial and viral gastroenteritis in children? AB - OBJECTIVE: Fecal calprotectin is used as a good indicator of intestinal mucosal inflammation. The aim of this study is to evaluate the diagnostic value of fecal calprotectin (f-CP) for the etiology of acute gastroenteritis in children. MATERIALS AND METHODS: All patients presenting with acute diarrhea (<18 years) who had 3 or more soft or watery stools per day were enrolled in this study. Stool microscopic examination and cultures for bacteria and parasites were performed. Polymerase chain reaction test was also applied to stool samples for viruses (Rotavirus, Adenovirus, Norwalk, and Astrovirus). The level of f-CP was carried out by using enzyme-linked immunosorbent assay test. RESULTS: Eighty-four patients with diarrhea were enrolled. The f-CP level was higher in patients with microscopic examination positive (n=17) (median with interquartile range, 1610.0 [908.8-2100] mg/L) than in patients with microscopic examination negative (n=67) (123.8 [25.0-406.3] mg/L) (P<.001). Concentrations of f-CP in patients with stool culture positive (1870.0 [822.5-2100] mg/L) were significantly elevated compared with the concentrations of the patient with virus detected in stool (95.0 [21.3 240.9] mg/L) (P<.001). In the diagnosis for bacterial acute gastroenteritis, the area under the receiver operating characteristic curve for f-CP was 0.867 (95% confidence interval, 0.763-0.971), sensitivity was 88.9%, and specificity was 76.0% if the threshold was taken as 710 mg/L. CONCLUSION: We conclude that f-CP, which is useful, valuable, noninvasive, easily and rapidly measured laboratory test along with simple microscopic examination of stool, can be used as an indicator of intestinal inflammation and to distinguish the bacterial gastroenteritis from the viral gastroenteritis. PMID- 26233617 TI - High serum cancer antigen 125 level indicates perforation in acute appendicitis. AB - BACKGROUND: The diagnosis of acute appendicitis is sometimes challenging, and prompt evaluation is required because of the risk of complications if not treated appropriately. AIM: We aimed to evaluate whether cancer antigen 125 (CA-125) has diagnositic accuracy and predictor of the severity in acute appendicitis. RESULTS: Sixty patients with acute appendicitis were recruited prospectively in this study between May 2014 and March 2015. Blood samples were obtained to measure CA-125 levels before appendectomy. Of the 57 patients, 10 had perforated or gangrenous appendicitis intraoperatively. The CA-125 levels were significantly higher in patients with perforated or gangrenous appendicitis than patients with uncomplicated appendicitis (49.9 vs 10.5 U/mL, P=.000). CONCLUSIONS: Cancer antigen 125 levels in patients with highly suspected or confirmed appendicitis could help clinicians determine the severity of the disease. PMID- 26233618 TI - The pathophysiologies of asphyxial vs dysrhythmic cardiac arrest: implications for resuscitation and post-event management. AB - BACKGROUND: Cardiac arrest is not a uniform condition and significant heterogeneity exists within all victims with regard to the cause of cardiac arrest. Primary cardiac (dysrhythmic) and asphyxial causes together are responsible for most cases of cardiac arrest at all age groups. The purpose of this article is to review the pathophysiologic differences between dysrhythmic and asphyxial cardiac arrest in the prearrest period, during the no-flow state, and after successful cardiopulmonary resuscitation. METHODS: The electronic databases of PubMed/Medline, Scopus, and Cochrane were searched for relevant literature and studies. RESULTS/DISCUSSION: Significant differences exist between dysrhythmic and asphyxial cardiac arrest regarding their pathophysiologic pathways and affect consequently the postresuscitation period. Laboratory data indicate that asphyxial cardiac arrest leads to more widespread postresuscitation brain damage compared with dysrhythmic cardiac arrest. Regarding postresuscitation myocardial dysfunction, few studies have addressed a comparison of the 2 conditions with controversial results. CONCLUSIONS: Asphyxial cardiac arrest differs significantly from dysrhythmic cardiac arrest with regard to pathophysiologic mechanisms, neuropathologic damage, postresuscitation organ dysfunction, and response to therapy. Both conditions should be considered and treated in a different manner. PMID- 26233619 TI - Assessment of acute asthma severity in the ED: are heart and respiratory rates relevant? AB - BACKGROUND: Assessment of acute asthma severity in the emergency department (ED) determines the appropriate initial therapy. The aim of this study was to evaluate the usefulness of heart and respiratory rates as determinants of severity of asthma exacerbations. METHODS: It was a pooled analysis of individual patient data from different controlled clinical trials performed over a 9-year period. The sample was characterized by patients with a diagnosis of asthma, age 18 to 50 years, and a forced expiratory volume in the first second (FEV1) or a peak expiratory flow less than or equal to 50% of predicted at ED presentation. RESULTS: One thousand one hundred ninety-two severe acute asthmatics (age 33.9 +/ 10.3 years and FEV1 = 27.4% +/- 9.7%) were enrolled. Two-thirds of patients were categorized as having severe acute asthma (FEV1, 31%-50% of predicted) and the remaining third as life-threatening asthma (FEV1, <=30% of predicted). There were no relationships between the intensity of airway obstruction as measured by the FEV1 and the degree of tachycardia (r = 0.05, P > .1) or tachypnea (r = 0.06, P > .1). Only 22% and 19% of the patients, respectively, met the heart rate and respiratory rate requirements for acute severe asthma (>=120/min and >=25/min, respectively). In contrast to FEV1 and arterial oxygen saturation, baseline heart and respiratory rates did not predict admissions of patients at the end of treatment. CONCLUSIONS: This pooled analysis suggests a poor performance of heart and respiratory rates as determinants of acute asthma severity in the ED. PMID- 26233620 TI - Child endotracheal intubation with a Clarus Levitan fiberoptic stylet vs Macintosh laryngoscope during resuscitation performed by paramedics: a randomized crossover manikin trial. AB - INTRODUCTION: The main cause of cardiac arrest in pediatric patients is respiratory failure. OBJECTIVE: To test the ability of paramedics to intubate the trachea of a child by means of the standard Macintosh [MAC] laryngoscope vs the Clarus Leviatan fiberoptic stylet (FPS) during 3-airway scenarios. METHODS: This was a randomized crossover manikin study involving 89 paramedics. The participants performed tracheal intubations using the MAC laryngoscope and the Clarus Leviatan FPS in 3 pediatric airway scenarios: scenario A, normal airway without chest compression (CC); scenario B, normal airway with CC; and scenario C, difficult airway with CC. RESULTS: A total of 89 paramedics participated in this study. In scenario A, the FPS maintained a better success rate at first attempt (97.8% vs 88.9%; P=.73) and time required to intubate (17 [interquartile range, 15-21) seconds vs 18 [interquartile range, 16-22] seconds; P=.67) when compared with MAC. In scenarios B and C, the results with FPS were significantly better than those with MAC (P<.05) for all analyzed variables. CONCLUSIONS: This study suggested that the FPS could be used as an option for airway management even for paramedics with little experience. Future studies should explore the efficacy of FPS in pediatric clinical emergency settings. PMID- 26233621 TI - A cost-effective surgical navigation solution for periacetabular osteotomy (PAO) surgery. AB - PURPOSE: To evaluate a low-cost, inertial sensor-based surgical navigation solution for periacetabular osteotomy (PAO) surgery without the line-of-sight impediment. METHODS: Two commercial inertial measurement units (IMU, Xsens Technologies, The Netherlands), are attached to a patient's pelvis and to the acetabular fragment, respectively. Registration of the patient with a pre operatively acquired computer model is done by recording the orientation of the patient's anterior pelvic plane (APP) using one IMU. A custom-designed device is used to record the orientation of the APP in the reference coordinate system of the IMU. After registration, the two sensors are mounted to the patient's pelvis and acetabular fragment, respectively. Once the initial position is recorded, the orientation is measured and displayed on a computer screen. A patient-specific computer model generated from a pre-operatively acquired computed tomography scan is used to visualize the updated orientation of the acetabular fragment. RESULTS: Experiments with plastic bones (eight hip joints) performed in an operating room comparing a previously developed optical navigation system with our inertial based navigation system showed no statistically significant difference on the measurement of acetabular component reorientation. In all eight hip joints the mean absolute difference was below four degrees. CONCLUSION: Using two commercially available inertial measurement units we show that it is possible to accurately measure the orientation (inclination and anteversion) of the acetabular fragment during PAO surgery and therefore to successfully eliminate the line-of-sight impediment that optical navigation systems have. PMID- 26233622 TI - Improving workflows of neuro-interventional procedures with autostereoscopic 3D visualization of multi-modality imaging in hybrid interventional suites. AB - PURPOSE: Recent developments in interventional neuroradiology techniques, medical imaging modalities, endovascular stenting and embolization materials lead to an increasing number of patients with cerebral aneurysms and arteriovenous malformations that are eligible for endovascular treatment and have opened new perspectives for novel ways for patient treatment in general. In this paper, we describe a software tool for 3D image fusion of multi-modal acquisitions to assist endovascular treatment of cerebral malformations. The software and an autostereoscopic 3D display were implemented and tested in clinical applications in a hybrid interventional suite that is used for radio-interventional as well as neurosurgical procedures. Our hypothesis is that fusion of image data acquired prior to intervention procedures with images acquired during those procedures should allow better visualizing and navigating through complex cerebral vasculature. This should also improve workflows of neuro-interventional procedures. METHODS: Preoperative and intra-operative acquisitions of vascular images of the brain were performed and transferred to a dedicated imaging workstation to be processed with our image fusion and visualization software tool. The tool was developed as a plugin extension to the open-source DICOM viewer OsiriX and is based on a modular and scalable architecture. Several processing modules were implemented to allow spatial co-registration and fusion of preoperative and intra-operative modalities. A special extension was also implemented for interactive autostereosopic, glass-free 3D visualization of fused results. RESULTS: The software platform was validated and evaluated in nine in vivo procedures by expert users. All patient cases were related to interventional treatment of neuro-vascular diseases. The emphasis was laid on the added value of spatial co-registration and fusion of preoperative and intra-operative modalities, as well as the overall impact on workflow during the intervention. The co-registered and fused images were visualized on an autostereoscopic 3D monitor installed in hybrid interventional suite. All experiments were evaluated and scored by interventional physicians and technicians. CONCLUSIONS: Displaying 3D-4D representations of brain vascular anomalies based on multi-modal acquisitions on a 3D autostereoscopic display is beneficial for the workflow and efficiency of interventional radiologists. The implemented software tool fulfills the premise of applicability of an open-source platform for more advanced, multi modal visualization and processing of brain vascular structures for image-guided therapeutic interventions. PMID- 26233623 TI - Shading correction for endoscopic images using principal color components. AB - PURPOSE: Inhomogeneous illumination often causes significant shading and vignetting effects in images captured by an endoscope. Most of the established shading correction methods are designed for gray-level images. Only few papers have been published about how to compensate for shading in color images. For endoscopic images with a distinct red coloring, these methods tend to produce color artifacts. METHOD: A color shading correction algorithm for endoscopic images is proposed. Principal component analysis is used to calculate an appropriate estimate of the shading effect so that a one-channel shading correction can be applied without producing undesired artifacts. RESULTS: The proposed method is compared to established YUV and HSV color-conversion-based approaches. It produces superior results both on simulated and on real endoscopic images. Example images of using the proposed shading correction for endoscopic image mosaicking are presented. CONCLUSION: A new method for shading correction is presented which is tailored to images with distinct coloring. It is beneficial for the visual impression and further image analysis tasks. PMID- 26233624 TI - Budget impact analysis of CYP2C19-guided voriconazole prophylaxis in AML. AB - OBJECTIVES: The objective of this study was to determine the economic impact of proactive, CYP2C19 genotype-guided voriconazole prophylaxis in AML. METHODS: An Excel-based model was created to project the cost of treating a simulated cohort of severely neutropenic AML patients undergoing antifungal prophylaxis. The model compares (i) standard prophylactic dosing with voriconazole and (ii) CYP2C19 genotyping of all AML patients to guide voriconazole dosing and prescribing. RESULTS: Based on the model, genotype-guided dosing of voriconazole conservatively spares 2.3 patients per year from invasive fungal infections. Implementing proactive genotyping of all AML patients in a simulated 100 patient cohort is expected to save a total of $41467 or $415 per patient. CONCLUSIONS: The model, based on the robust literature of clinical and economic data, predicts that proactive genotype-guided voriconazole prophylaxis is likely to yield modest cost savings while improving patient outcomes. The primary driver of savings is the avoidance of expensive antifungal treatment and extended hospital stays, costing $30 952 per patient, in patients succumbing to fungal infection. PMID- 26233625 TI - Modeling of protein-anion exchange resin interaction for the human growth hormone charge variants. AB - Modeling ion exchange chromatography (IEC) behavior has generated significant interest because of the wide use of IEC as an analytical technique as well as a preparative protein purification process; indeed there is a need for better understanding of what drives the unique behavior of protein charge variants. We hypothesize that a complex protein molecule, which contains both hydrophobic and charged moieties, would interact strongly with an in silico designed resin through charged electrostatic patches on the surface of the protein. In the present work, variants of recombinant human growth hormone that mimic naturally occurring deamidation products were produced and characterized in silico. The study included these four variants: rhGH, N149D, N152D, and N149D/N152D. Poisson Boltzmann calculations were used to determine surface electrostatic potential. Metropolis Monte Carlo simulations were carried out with the resulting variants to simulate IEC systems, examining the free energy of the interaction of the protein with an in silico anion exchange column represented by polylysine polypeptide. The results show that the charge variants have different average binding energies and the free energy of interaction can be used to predict the retention time for the different variants. PMID- 26233627 TI - Clinical and Imaging Features of Lacrimal Gland Involvement in Granulomatosis with Polyangiitis. AB - PURPOSE: Lacrimal gland involvement in granulomatosis with polyangiitis (GPA) commonly accompanies orbital disease, but occasionally may be the sole presentation preceding any other organ manifestation or systemic disease. Diagnosis of orbital GPA, especially in patients with lacrimal involvement as the initial presentation, can be difficult because of nonspecific clinical features and lack of diagnostic specificity on histologic and antineutrophilic cytoplasmic antibody (ANCA) testing. Orbital GPA can be associated with a high morbidity from potential visual loss or rapid progression of latent systemic disease, making early diagnosis important. The purpose of this study was to describe the clinical and imaging features of patients with lacrimal gland involvement secondary to GPA and to compare them with those of other orbital inflammatory conditions in the lacrimal gland fossa. DESIGN: Retrospective, noninterventional comparative case series. PARTICIPANTS: Two hundred forty-seven patients who had undergone orbital biopsy over a 21-year period were identified from the Institute of Ophthalmology Pathology database. Sixty-nine patients were found to have orbital inflammatory disease with lacrimal gland involvement, of whom 7 had a final diagnosis of GPA. METHODS: Clinical and imaging features of patients with GPA were analyzed and compared with those of the non-GPA group. MAIN OUTCOME MEASURES: Features associated with GPA. RESULTS: The median age at presentation for GPA patients was 30 years (mean +/- standard deviation, 36.7+/-16.7 years; range, 14-57 years). The interval from presentation to definitive diagnosis of GPA ranged from 3 to 20 months (mean, 12.1 months; median, 12 months). Sinonasal involvement was demonstrated in 43% and bony changes were demonstrated in 29% of patients with GPA. A higher proportion of patients with GPA demonstrated sinonasal involvement (P = 0.011) and bony destruction (P = 0.048) compared with non-GPA patients. CONCLUSIONS: Associated sinonasal involvement and bony changes on imaging are highly suggestive of GPA and should prompt a full diagnostic workup. A high index of suspicion should be maintained, with repeated ANCA testing, biopsy, and imaging where indicated, especially in the younger age group. PMID- 26233626 TI - The Risk of Intraocular Pressure Elevation in Pediatric Noninfectious Uveitis. AB - PURPOSE: To characterize the risk and risk factors for intraocular pressure (IOP) elevation in pediatric noninfectious uveitis. DESIGN: Multicenter retrospective cohort study. PARTICIPANTS: Nine hundred sixteen children (1593 eyes) younger than 18 years at presentation with noninfectious uveitis followed up between January 1978 and December 2007 at 5 academic uveitis centers in the United States. METHODS: Medical records review by trained, certified experts. MAIN OUTCOME MEASURES: Prevalence and incidence of IOP of 21 mmHg or more and 30 mmHg or more and incidence of a rise in IOP by 10 mmHg or more. To avoid underascertainment, outcomes were counted as present when IOP-lowering therapies were in use. RESULTS: Initially, 251 (15.8%) and 46 eyes (2.9%) had IOP >=21 mmHg and >=30 mmHg, respectively. Factors significantly associated with presenting IOP elevation included age of 6 to 12 years (versus other pediatric ages), prior cataract surgery, pars plana vitrectomy, duration of uveitis >=6 months, contralateral IOP elevation, presenting visual acuity worse than 20/40, and topical corticosteroid use (in a dose-response relationship). The median follow up was 1.25 years (interquartile range, 0.4-3.66). The estimated incidence of any observed IOP elevation to >=21 mmHg, to >=30 mmHg, and increase in IOP by >=10 mmHg was 33.4%, 14.8%, and 24.4%, respectively, within 2 years. Factors associated with IOP elevation included pars plana vitrectomy, contralateral IOP elevation (adjusted hazard ratio [aHR], up to 9.54; P < 0.001), and the use of topical (aHR, up to 8.77 that followed a dose-response relationship; P < 0.001), periocular (aHR, up to 7.96; P < 0.001), and intraocular (aHR, up to 19.7; P < 0.001) corticosteroids. CONCLUSIONS: Intraocular pressure elevation affects a large minority of children with noninfectious uveitis. Statistically significant risk factors include IOP elevation or use of IOP-lowering treatment in the contralateral eye and local corticosteroid use that demonstrated a dose-and route of administration-dependent relationship. In contrast, use of immunosuppressive drug therapy did not increase such risk. Pediatric eyes with noninfectious uveitis should be followed up closely for IOP elevation, especially when strong risk factors such as the use of local corticosteroids and contralateral IOP elevation are present. PMID- 26233628 TI - The Effect of Cataract Surgery on Circadian Photoentrainment: A Randomized Trial of Blue-Blocking versus Neutral Intraocular Lenses. AB - PURPOSE: Cataract decreases blue light transmission. Because of the selective blue light sensitivity of the retinal ganglion cells governing circadian photoentrainment, cataract may interfere with normal sleep-wake regulation and cause sleep disturbances. The purpose was to investigate the effect of cataract surgery on circadian photoentrainment and to determine any difference between blue-blocking and neutral intraocular lenses (IOLs). DESIGN: The study was a single-center, investigator-driven, double-masked, block-randomized clinical trial. PARTICIPANTS: One eye in 76 patients with bilateral age-related cataract eligible for cataract surgery was included. METHODS: Intervention was cataract surgery by phacoemulsification. Patients were randomized to receive a blue blocking or neutral IOL. MAIN OUTCOME MEASURES: Primary outcome was activation of intrinsic photosensitive ganglion cells using post-illumination pupil response (PIPR) to blue light from 10 to 30 seconds after light exposure as a surrogate measure. Secondary outcomes were circadian rhythm analysis using actigraphy and 24-hour salivary melatonin measurements. Finally, objective and subjective sleep quality were determined by actigraphy and the Pittsburgh Sleep Quality Index. RESULTS: The blue light PIPR increased 2 days (17%) and 3 weeks (24%) after surgery (P < 0.001). The majority of circadian and sleep-specific actigraphy parameters did not change after surgery. A forward shift of the circadian rhythm by 22 minutes (P = 0.004) for actigraphy and a tendency toward an earlier melatonin onset (P = 0.095) were found. Peak salivary melatonin concentration increased after surgery (P = 0.037). No difference was detected between blue blocking and neutral IOLs, whereas low preoperative blue light transmission was inversely associated with an increase in PIPR (P = 0.021) and sleep efficiency (P = 0.048). CONCLUSIONS: Cataract surgery increases photoreception by the photosensitive retinal ganglion cells. Because of inconsistency between the significant findings and the many parameters that were unchanged, we can conclude that cataract surgery does not adversely affect the circadian rhythm or sleep. Longer follow-up time and fellow eye surgery may reveal the significance of the subtle changes observed. We found no difference between blue-blocking and neutral IOLs, and, because of the minor effect of surgery in itself, an effect of IOL type seems highly unlikely. PMID- 26233629 TI - Next-generation Sequencing in the Diagnosis of Metabolic Disease Marked by Pediatric Cataract. PMID- 26233630 TI - Choice of injury scoring system in low- and middle-income countries: Lessons from Mumbai. AB - INTRODUCTION: Injury is a major cause of morbidity and mortality in low- and middle-income countries. Effective trauma surveillance is imperative to guide research and quality improvement interventions, so an accurate metric for quantifying injury severity is crucial. The objectives of this study are (1) to assess the feasibility of calculating five injury scoring systems--ISS (injury severity score), RTS (revised trauma score), KTS (Kampala trauma score), MGAP (mechanism, GCS (Glasgow coma score), age, pressure) and GAP (GCS, age, pressure) -with data from a trauma registry in a lower middle-income country and (2) to determine which of these scoring systems most accurately predicts in-hospital mortality in this setting. PATIENTS AND METHODS: This is a retrospective analysis of data from an institutional trauma registry in Mumbai, India. Values for each score were calculated when sufficient data were available. Logistic regression was used to compare the correlation between each score and in-hospital mortality. RESULTS: There were sufficient data recorded to calculate ISS in 73% of patients, RTS in 35%, KTS in 35%, MGAP in 88% and GAP in 92%. ISS was the weakest predictor of in-hospital mortality, while RTS, KTS, MGAP and GAP scores all correlated well with in-hospital mortality (area under ROC (receiver operating characteristic) curve 0.69 for ISS, 0.85 for RTS, 0.86 for KTS, 0.84 for MGAP, 0.85 for GAP). Respiratory rate measurements, missing in 63% of patients, were a major barrier to calculating RTS and KTS. CONCLUSIONS: Given the realities of medical practice in low- and middle-income countries, it is reasonable to modify the approach to characterising injury severity to favour simplified injury scoring systems that accurately predict in-hospital mortality despite limitations in trauma registry datasets. PMID- 26233631 TI - Investigating the relationship between weather and violence in Baltimore, Maryland, USA. AB - BACKGROUND: It is a common refrain at major urban trauma centers that caseloads increase in the heat of the summer. Several previous studies supported this assertion, finding trauma admissions and crime to correlate positively with temperature. We examined links between weather and violence in Baltimore, MD, through trauma presentation to Johns Hopkins Hospital and crime reports filed with the Baltimore Police Department. METHODS: Crime data were obtained from the Baltimore City Police Department from January 1, 2008 to March 31, 2013. Trauma data were obtained from a prospectively collected registry of all trauma patients presenting to Johns Hopkins Hospital from January 1, 2007 to March 31, 2013. Weather data were obtained from the National Climatic Data Center. Correlation coefficients were calculated and negative binomial regression was used to elucidate the independent associations of weather and temporal variables with the trauma and crime data. RESULTS: When adjusting for temporal and meteorological factors, maximum daily temperature was positively associated with total trauma, intentional injury, and gunshot wounds presenting to Johns Hopkins Hospital along with total crime, violent crime, and homicides in Baltimore City. Associations of average wind speed, daily precipitation, and daily snowfall with trauma and crime were far weaker and, when significant, nearly universally negative. CONCLUSION: Maximum daily temperature is the most important weather factor associated with violence and trauma in our study period and location. Our findings suggest potential implications for hospital staffing to be explored in future studies. PMID- 26233632 TI - Pharmacological Management of Pediatric Patients with Comorbid Attention-Deficit Hyperactivity Disorder Oppositional Defiant Disorder. AB - Attention-deficit hyperactivity disorder (ADHD) is a common developmental neurobiological condition of childhood characterized by age-inappropriate degrees of hyperactivity/impulsivity and inattention to tasks requiring sustained vigilance. Oppositional defiant disorder (ODD) is an externalizing behavior disorder characterized by difficulties with emotional and behavioral regulation that frequently brings the child into conflict with authority figures. In the clinical setting, ODD is the most common ADHD comorbidity. The combination portends more severe symptom severity, daily impairment, and a more at-risk prognosis than either disorder alone. We briefly review the literature on the characteristics and treatment of the ADHD and ODD child. A clinical approach to evaluation and treatment of ADHD and ODD is then presented. This approach emphasizes the importance of child and parent psychoeducation about the two disorders alone and in combination, the importance of behavioral management therapy approaches, the possible need for school and academic supports, and the decision to use evidence-based stimulant or non-stimulant ADHD medications depending on symptom severity combined with child and parental wishes and choice. PMID- 26233633 TI - A Review on Carotid Ultrasound Atherosclerotic Tissue Characterization and Stroke Risk Stratification in Machine Learning Framework. AB - Cardiovascular diseases (including stroke and heart attack) are identified as the leading cause of death in today's world. However, very little is understood about the arterial mechanics of plaque buildup, arterial fibrous cap rupture, and the role of abnormalities of the vasa vasorum. Recently, ultrasonic echogenicity characteristics and morphological characterization of carotid plaque types have been shown to have clinical utility in classification of stroke risks. Furthermore, this characterization supports aggressive and intensive medical therapy as well as procedures, including endarterectomy and stenting. This is the first state-of-the-art review to provide a comprehensive understanding of the field of ultrasonic vascular morphology tissue characterization. This paper presents fundamental and advanced ultrasonic tissue characterization and feature extraction methods for analyzing plaque. Additionally, the paper shows how the risk stratification is achieved using machine learning paradigms. More advanced methods need to be developed which can segment the carotid artery walls into multiple regions such as the bulb region and areas both proximal and distal to the bulb. Furthermore, multimodality imaging is needed for validation of such advanced methods for stroke and cardiovascular risk stratification. PMID- 26233635 TI - Implementation of a Transdisciplinary Team for the Transition Support of Medically and Socially Complex Youth. AB - PURPOSE: This article reports the ongoing work of a statewide transition support program which serves youth ages 11 to 22 with medically complex conditions and socially complex lives. METHODS: Seven years of transition support services have led to program evolution demonstrated via a descriptive summary of the patients along with both families' and primary care providers' responses to satisfaction surveys. An illustrative case is used to highlight the types of expertise needed in specialized transition service delivery for patients with significant complexity. The team's analysis of their transdisciplinary work processes further explains the work. RESULTS: Nearly three hundred youth with complex needs are served yearly. Families and primary care providers express high satisfaction with the support of the services. The case example shows the broad array of transition specific services engaged beyond the usual skill set of pediatric or adult care coordination teams. Transdisciplinary team uses skills in collaboration, support, learning, and compromise within a trusting and respectful environment. They describe the shared responsibility and continuous learning of the whole team. CONCLUSIONS: Youth with complex medical conditions and complex social situations are at higher risk for problems during transition. Serving this population with a transdisciplinary model is time consuming and requires advanced expertise but, with those investments, we can meet the expectations of the youth, their families and primary care providers. Successful transdisciplinary teamwork requires sustained and focused investment. Further work is needed to describe the complexity of this service delivery along with distinct transition outcomes and costs comparisons. PMID- 26233634 TI - How Durable Are the Effects After Metabolic Surgery? AB - Bariatric surgery was initially developed as a tool for weight reduction only, but it is gaining popularity because of its remarkable effect on glucose metabolism in morbidly obese and less obese patients. Recent publications have shown the superiority of metabolic surgery over medical treatment for diabetes, creating a new field of clinical research that is currently overflowing in the medical community with outstanding high-quality data. Metabolic surgery is effective in treating diabetes, even in non-morbidly obese patients. PMID- 26233636 TI - Antioxidant status in women who have had a miscarriage. AB - PURPOSE: During normal pregnancy there is an oxido-reductive balance between action of pro-oxidative factors. The aim of this study was to evaluate the total antioxidant status (TAS) and glutathione peroxidase (GSH-Px) activity, and the content of selenium (Se), zinc (Zn), copper (Cu) and manganese (Mn) in women who have had a miscarriage. PATIENTS AND METHODS: The study group consisted of 83 women who had had miscarriages. The control group included 35 women in the first trimester of pregnancy, and 35 pregnant women after childbirth. RESULTS: TAS activity and Cu concentration in serum in women who experienced a miscarriage were significantly lower, but Mn level - higher, than in women in the first trimester of pregnancy. The content of Se, Cu and Mn in placental tissue in patients who have had a miscarriage was significantly higher, while Zn content was lower than in pregnant women at full-term delivery. CONCLUSIONS: Our findings, provided in the research, enable us to claim that the total antioxidative status is significantly lower in women who have had a miscarriage. Low level of Zn but high of Mn in the examined biological material may be indicative to the incidence of miscarriage. PMID- 26233637 TI - Copeptin: Pathophysiology and potential clinical impact. AB - Copeptin, a C-terminal part of the precursor pre-provasopressin is a novel biomarker of arginine-vasopressin (AVP) system. Measurements of AVP concentration are not used in clinical practice because of technical difficulties. Copeptin is synthesized in stoichiometric ratio with AVP, hence it reflects vasopressin concentration in human plasma and serum. This review outlines current research concerning the role of copeptin as a prognostic marker in different diseases and its potential clinical value. PMID- 26233638 TI - A 64-year old woman with right hand swelling and paresthesia. PMID- 26233639 TI - A young woman with a heart attack? PMID- 26233640 TI - An ultrasensitive label-free immunosensor based on CdS sensitized Fe-TiO2 with high visible-light photoelectrochemical activity. AB - An ultrasensitive label-free immunosensor was developed for the detection of squamous cell carcinoma antigen (SCCA) based on CdS sensitized Fe-TiO2 nanocomposites with high visible-light photoelectrochemical (PEC) activity. In this protocol, ascorbic acid was used as an efficient electron donor for scavenging photogenerated holes. The Fe-doped TiO2 improved the absorption of TiO2 in the visible light region and promoted the photocurrent production distinctly. Especially, 0.1% Fe-TiO2 showed the highest photocurrent, which was 7.4 times that of pure TiO2. Carboxyl functionalized CdS nanoparticles (CdS NPs) were bonded onto Fe-TiO2 composite through interactions between carboxyl groups and TiO2, which further enhanced the PEC signal strength by approximately 2.9 fold compared with 0.1% Fe-TiO2. The specific binding between SCCA and antibody resulted in a decrease in photocurrent intensity and the intensity decreased linearly with the logarithm of SCCA concentration in the range of 0.001-75 ng mL( 1) with a detection limit of 0.22 pg mL(-1). The developed CdS enhanced Fe-TiO2 PEC immunosensor exhibited high sensitivity, good reproducibility, and low cost, which may have potential applications in clinical diagnosis of cancers, aptasensors, photocatalysis, and other related fields. PMID- 26233641 TI - Comprehensive detection of diverse exon 19 deletion mutations of EGFR in lung Cancer by a single probe set. AB - Detection of exon 19 deletion mutation of EGFR, one of the most frequently occurring mutations in lung cancer, provides the crucial information for diagnosis and treatment guideline in non-small-cell lung cancer (NSCLC). Here, we demonstrate a simple and efficient method to detect various exon 19 deletion mutations of EGFR using a single probe set comprising of an oligo-quencher (oligo Q) and a molecular beacon (MB). While the MB hybridizes to both the wild and mutant target DNA, the oligo-Q only binds to the wild target DNA, leading to a fluorescent signal in case of deletion mutation. This enables the comprehensive detection of the diverse exon 19 deletion mutations using a single probe set. We demonstrated the utility and efficiency of the approach by detecting the frequent exon 19 deletion mutations of EGFR through a real-time PCR and in situ fluorescence imaging. Our approach enabled the detection of genomic DNA as low as 0.02 ng, showing a detection limit of 2% in a heterogeneous DNA mixture, and could be used for detecting mutations in a single cell level. The present MB and oligo-Q dual probe system can be used for diagnosis and treatment guideline in NSCLC. PMID- 26233642 TI - Molecularly imprinted polymers as recognition materials for electronic tongues. AB - For over three decades now, molecularly imprinted polymers (MIPs) have successfully been used for selective chemical sensing because the shape and size of their imprinted molecular cavities perfectly matched those of the target analyte molecules. Moreover, orientation of recognizing sites of these cavities corresponded to those of the binding sites of the template molecules. In contrast, electronic tongue (e-tongue) is usually an array of low-affinity recognition units. Its selectivity is based on recognition pattern or multivariate analysis. Merging these two sensing devices led to a synergetic hybrid sensor, an MIP based e-tongue. Fabrication of these e-tongues permitted simultaneous sensing and discriminating several analytes in complex solutions of many components so that these arrays compensated for limitation in cross reactivity of MIPs. Apparently, analytical signals generated by MIP-based e tongues, compared to those of ordinary sensor arrays, were more reliable where a unique pattern or 'fingerprint' for each analyte was generated. Additionally, several transduction platforms (from spectroscopic to electrochemical) engaged in constructing MIP-based e-tongues, found their broad and flexible applications. The present review critically evaluates achievements in recent developments of the MIP based e-tongues for chemosensing. PMID- 26233643 TI - A rapid MZI-IDA sensor system for EGFR mutation testing in non-small cell lung cancer (NSCLC). AB - Epidermal growth factor receptor (EGFR) is a non-small-cell lung cancer biomarker, based on which several near-patient-testing methods have been developed and applied to predict treatment response on individual patients. Existing methods for detection of EGFR mutation are costly, labor-intensive and time-consuming. In this paper, we report a novel EGFR mutation testing system, which is based on Mach-Zehnder Interferometer (MZI) sensor and isothermal solid phase DNA amplification (IDA) technique, called MZI-IDA sensor system. The system can deliver results within 30 min and shows high sensitivity to detect trace amounts of genomic DNA (<1 copy). In addition, the system is able to detect a L858R mutation in a 99:1 mixture of wild-type and mutant cells. In a pilot clinical study, the system is compared with conventional methods (PCR and direct sequencing) by using tissue biopsy samples from NSCLC patients. The MZI-IDA sensor system is proved to be capable of fast and accurate detection of the L858R mutation of EGFR gene in clinical samples. This may greatly help the clinicians develop an appropriate treatment plan. PMID- 26233644 TI - Aberrant serum polyunsaturated fatty acids profile is relevant with acute coronary syndrome. AB - Although a robust relationship between aberrant serum polyunsaturated fatty acids (PUFAs) profile and coronary artery disease (CAD) has been reported, the details concerning the association between aberrant PUFAs profile and clinical feature of CAD are not fully discovered. Therefore, we investigated the relationship between serum PUFAs and clinical profiles in CAD patients. We classified 595 consecutive CAD patients, who underwent coronary angiography into 3 groups according to the clinical profiles of CAD (group A: early phase ACS, n = 96; group B: stable CAD with previous history of ACS, n = 259; group C: stable CAD without previous history of ACS, n = 240) and measured serum n-3 [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)] and n-6 [arachidonic acid (AA)] PUFAs. Serum EPA, DHA, and EPA/AA ratio were significantly low in the order of group A < B < C [EPA; 48.1 (34.1-60.3) MUg/ml, 61.7 (41.2-94.5) MUg/ml, and 74.4 (52.7-104.9) MUg/ml, DHA; 113.1 (92.8-135.1) MUg/ml, 125.8 (100.4-167.2) MUg/ml, and 140.1 (114.7-177.0) MUg/ml, EPA/AA ratio; 0.31 (0.22-0.45), 0.39 (0.26-0.62), and 0.44 (0.31-0.69), medians with interquartile range, p < 0.01]. Multiple regression analysis revealed that EPA (p = 0.009) and EPA/AA ratio (p = 0.023), but not DHA and DHA/AA ratio, were negatively associated with clinical profiles of ACS in CAD patients. Significant correlation was not observed between PUFAs profile and severity of coronary stenosis. Low serum EPA and EPA/AA ratio correlates with clinical profiles of ACS in patients with CAD, regardless of the extent and severity of coronary artery stenosis. PMID- 26233646 TI - The long-term prognostic value of the Q wave criteria for prior myocardial infarction recommended in the universal definition of myocardial infarction. AB - BACKGROUND: We sought to characterize the prognostic value of the third universal definition of myocardial infarction (UDMI) and >=40msec Q wave criteria. METHODS: We evaluated hazard ratios (HR) with 95% confidence intervals (CI) for cardiovascular (CV) death for computerized Q wave measurements from the electrocardiograms of 43,661 patients collected from 1987 to 1999 at the Palo Alto VA. There were 3929 (9.0%) CV deaths over a mean follow-up of 7.6 (+/-3.8) years. RESULTS: The risk of CV death for Q waves >=40msec in any two contiguous leads in any lead group was equivalent to or higher than that for contiguous UDMI Q waves, with HR 2.44 (95% CI 2.15-4.11) and HR 2.42 (95% CI (2.18-3.42), respectively. CONCLUSIONS: The UDMI Q wave criteria do not provide an advantage over >=40msec Q waves at predicting CV death. PMID- 26233645 TI - Video Lottery is the Most Harmful Form of Gambling in Canada. AB - This paper summarizes the degree to which different forms of legal gambling contribute to Problem and Pathological Gambling (PPG) in Canada. Legal gambling activities were compared using meta-analysis of publicly available data concerning Canada's legal gambling industry. The majority of revenues in the decade spanning 2002-2012 were drawn from Video Lottery Terminals and casino slot machines. Population surveys indicated that three quarters of Canadians reported some form of past-year gambling participation, but most did not play Electronic Gambling Machines. Annual revenues divided by estimated numbers of participants in various gambling activities showed that Video Lottery players spent more money on average than did participants in other forms of gambling. The relative risk of PPG was higher among Video Lottery players than it was for other common forms of gambling. Results from a community study of frequent Video Lottery players showed that the risk of frequent players reporting symptoms of PPG was elevated if they reported playing weekly, spending $50 or more per session, or playing for more than an hour per session. These studies provide converging evidence that Video Lottery is more hazardous to consumers than other forms of gambling that are commonly practised in Canada. PMID- 26233647 TI - New strict left bundle branch block criteria reflect left ventricular activation differences. AB - AIMS: Pacing lead electrical delays and strict left bundle branch block (LBBB) criteria were assessed against cardiac resynchronization therapy (CRT) outcome. METHODS: Forty-nine patients with LBBB and QRS duration >130 milliseconds underwent CRT-implantation. Sensed right ventricular to left ventricular electrical delay (RV-LV-IED) was measured. Response to CRT was defined as >=15% decrease in left ventricular end-systolic volume. RESULTS: Eighteen of 20 (90%) patients with non-ischemic dilated cardiomyopathy (DCM) and 18 of 29 (62%) with ischemic heart disease (IHD) responded to CRT, p<0.01. When applying new strict ECG criteria subsequent rates of response in DCM were 18/19 (95%) and in IHD of 18/23 (78%) respectively, p<0.05 between IHD groups. Correspondingly, RV-LV-IED was longer in DCM compared to IHD patients and in responders compared to non responders, p=0.017 and p<0.001, respectively. CONCLUSION: Interventricular electrical delay predicts left ventricular remodeling after CRT and new, strict ECG criteria of LBBB are superior in predicting remodeling. PMID- 26233649 TI - The configuration of job placement for people with disabilities in the current economic contingencies in Italy: Social and clinical implications for health. AB - BACKGROUND: In current socioeconomic conditions, working occupies a key role in people's lives, from both practical and existential perspectives. The absence of work can produce a considerable impact on the identity of individuals and entire communities. This emphasis on work is even more important for some groups in society, particularly for people with disabilities. In the Italian context, despite the existence of legislation on the subject, only 16% of people with disabilities have a job. This study was conducted to understand how people with disabilities become included in companies. OBJECTIVE: This research proposes to highlight the ways in which corporate bodies' roles relate to people with disabilities' work in order to assess related theories, beliefs and critical aspects. METHODS: Using the M.A.D.I.T. (Methodology of Textual Analysis of Computerized Data), some companies' placement managers for people with disabilities were interviewed. RESULTS: This analysis highlights conditions explaining current difficulties, especially in the absence of agreed upon criteria and a delegation. CONCLUSION: This research highlights the need to carry out a structural reorganization for the relationship between companies and employment agencies to avoid the risk that the lack of communication between the involved parties and the lack of support in the employment process may force companies to consider people with disabilities as an obstacle rather than a resource. PMID- 26233648 TI - The prognostic value of discordant T waves in lead aVR: A simple risk marker of sudden cardiac arrest in ischemic cardiomyopathy. AB - BACKGROUND: Simple and reliable ECG marker(s) for sudden cardiac arrest (SCA) could be very useful in assessing high-risk populations. Since ischemic repolarization abnormalities in the left ventricular (LV) apex are strongly correlated with discordant T waves in lead aVR, we sought to evaluate the clinical and prognostic significance of this feature in ischemic cardiomyopathy. METHODS: The PAREPET trial enrolled patients with ischemic cardiomyopathy eligible for a primary prevention implantable cardiac defibrillator (ICD). Those with persistent pacing or left bundle branch block were excluded. Amplitudes of T/aVR were automatically computed from median ECG beats at enrollment and endpoints were blindly adjudicated. RESULTS: The sample was mainly composed of older men (n=138, age 65+/-12, 91% male, EF 29+/-9%). At enrollment, amplitude of T/aVR significantly correlated with EF, indexed LV end-diastolic volume, B-type natriuretic peptide (BNP), regional scar volume, and PET-quantified denervated myocardium. After a median follow up of 4.2years, there were 23 (17%) adjudicated SCA. In multivariate analysis, the presence of discordant T/aVR (>0mm, n=42, 30%) was a significant and independent predictor of SCA (hazard ratio 2.0 [95% CI 1.0 4.9]) and cardiac death (hazard ratio 1.9 [95% CI 1.0-3.7]). CONCLUSIONS: In subjects with ischemic cardiomyopathy, discordant T waves in lead aVR are associated with high-risk clinical parameters including lower ejection fraction, greater ventricular volume, higher BNP, and more denervated myocardium. Furthermore, discordant T/aVR remained an independent predictor of SCA and cardiovascular mortality even after accounting for these prognostic factors. PMID- 26233650 TI - Land application of mine water causes minimal uranium loss offsite in the wet-dry tropics: Ranger Uranium Mine, Northern Territory, Australia. AB - Ranger Uranium Mine (RUM) is situated in the wet-dry tropics of Northern Australia. Land application (irrigation) of stockpile (ore and waste) runoff water to natural woodland on the mine lease is a key part of water management at the mine. Consequently, the soil in these Land Application Areas (LAAs) presents a range of uranium (U) and other metals concentrations. Knowledge of seasonal and temporal changes in soil U and physicochemical parameters at RUM LAAs is important to develop suitable management and rehabilitation strategies. Therefore, soil samples were collected from low, medium, high and very high U sites at RUM LAAs for two consecutive years and the effect of time and season on soil physicochemical parameters particularly U and other major solutes applied in irrigation water was measured. Concentrations of some of the solutes applied in the irrigation water such as sulphur (S), iron (Fe) and calcium (Ca) showed significant seasonal and temporal changes. Soil S, Fe and Ca concentration decreased from year 1 to year 2 and from dry to wet seasons during both years. Soil U followed the same pattern except that we recorded an increase in soil U concentrations at most of the RUM LAAs after year 2 wet season compared to year 2 dry season. Thus, these sites did not show a considerable decrease in soil U concentration from year 1 to year 2. Sites which contained elevated U after wet season 2 also had higher moisture content which suggests that pooling of U containing rainwater at these sites may be responsible for elevated U. Thus, U may be redistributed within RUM LAAs due to surface water movement. The study also suggested that a decrease in U concentrations in LAA soils at very high U (>900 mg kg(-1)) sites is most likely due to transport of particulate matter bound U by surface runoff and U may not be lost from the surface soil due to vertical movement through the soil profile. Uranium attached to particulate matter may reduce its potential for environmental impact. These findings suggest that U is effectively adsorbed by the soils and thus land application may serve as a useful tool for U management in the wet-dry tropics of northern Australia. PMID- 26233651 TI - Error-control and processes optimization of (223/224)Ra measurement using Delayed Coincidence Counter (RaDeCC). AB - RaDeCC has proved to be a precise and standard way to measure (224)Ra and (223)Ra in water samples and successfully made radium a tracer of several environmental processes. In this paper, the relative errors of (224)Ra and (223)Ra measurement in water samples via a Radium Delayed Coincidence Count system are analyzed through performing coincidence correction calculations and error propagation. The calculated relative errors range of 2.6% ~ 10.6% for (224)Ra and 9.6% ~ 14.2% for (223)Ra. For different radium activities, effects of decay days and counting time on final radium relative errors are evaluated and the results show that these relative errors can decrease by adjusting the two measurement factors. Finally, to minimize propagated errors in Radium activity, a set of optimized RaDeCC measurement parameters are proposed. PMID- 26233653 TI - Development of an in vivo tissue-engineered valved conduit (type S biovalve) using a slitted mold. AB - In autologous valved conduits (biovalves) using in-body tissue architecture, the limited area available for leaflet formation is a concern. In this study, we designed a novel biovalve mold with slits to enhance in vivo cell migration, regardless of size. As a control, the original mold without slits was used. When both types of molds were embedded into subcutaneous pouches in beagle dogs for 8 weeks, the outer surfaces of all molds were completely covered with connective tissue to form conduit tissue. In the molds without slits, the leaflet size was limited to half of the design. In contrast, in the mold with slits, the complete leaflet area was formed. Upon trimming excess peripheral tissues, removing the mold, and cutting the connective tissue formed at the slits, completely autologous connective tissue biovalves with the designed leaflet area were obtained as type S (diameter, 6-28 mm) biovalves. The slit structure customized to the mold was effective for allowing cells to enter, thereby facilitating cell migration and contributing to the successful preparation of reliable biovalves of various physiological sizes suitable for all clinical uses. PMID- 26233654 TI - Effectiveness of oral litholysis therapy for improving glucose intolerance and malnutrition in patients with poor results following endoscopic therapy and extracorporeal shock wave lithotripsy for calcified pancreatic stones. AB - We report a case of pancreatolithiasis in which glucose intolerance and malnutrition were significantly improved after starting oral litholysis therapy (OLT) with use of trimethadione. A 43-year-old female with multiple calcified stones in the main and peripheral pancreatic ducts had experienced recurrent and severe attacks of pain for 7 years (from 21 to28 years of age). Impaired glucose tolerance was first noted at the age of 32 years. We started OLT after interventional endoscopic therapy combined with extracorporeal shock wave lithotripsy failed because of kink and stenosis of the main pancreatic duct (MPD). Over the next 9 years, a significant decrease in total pancreatic calcified stone volume was shown by computer analysis of follow-up computed tomography images. Larger stones completely disappeared without attacks of pain. In addition, both glucose intolerance and insulin secretion were significantly ameliorated, followed by improvement of malnutrition. OLT may induce intraductal decompression by dissolving stones in the peripheral ducts as well as the MPD, with resulting preservation of endocrine function and improvement of malnutrition. Since the present results were obtained in a single case, further clinical trials are necessary to evaluate the value of performing OLT under various conditions to eliminate stones. PMID- 26233655 TI - Amycolatopsis flava sp. nov., a halophilic actinomycete isolated from Dead Sea. AB - A novel halophilic, filamentous actinomycete, designated strain AFM 10111(T), was isolated from a sediment sample collected from the Dead Sea of Israel and its taxonomic position was established by using a polyphasic taxonomic approach. The isolate grew at 20-35 degrees C, pH 5-12 and with 1-30 % NaCl. The substrate mycelium is white or yellow, well developed, branched and fragments into squarish, rod-like elements. The isolate contained meso-diaminopimelic acid as cell-wall diamino acid, and arabinose and galactose as whole-cell sugars. The major menaquinone was MK-9(H4). The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine phosphatidylmethylethanolamine and one unidentified phospholipid. Major fatty acids were iso-C16:0, iso-C16:1 H, C17:1 omega6c. The DNA G + C content was 67.7 mol %. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain AFM 10111(T) belongs to the genus Amycolatopsis, and formed a distinct clade with Amycolatopsis marina CGMCC 4.3568(T) and Amycolatopsis palatopharyngis CGMCC 4.1729(T), with the sequence similarity 98.4 and 98.6 %. The level of DNA-DNA relatedness between the strain AFM 10111(T) and A. marina CGMCC 4.3568(T) and A. palatopharyngis CGMCC 4.1729(T) were 46.9 +/- 3.08 and 49.4 +/- 1.25 %. The combined genotypic and phenotypic data indicate that strain AFM 10111(T) represents a novel species of the genus Amycolatopsis, for which the name Amycolatopsis flava sp. nov. is proposed. The type strain is AFM 10111(T) (= DSM 46658(T) = CGMCC 4.7123(T)). PMID- 26233656 TI - Calcium effect on the metabolic pathway of phosphorus accumulating organisms in enhanced biological phosphorus removal systems. AB - Phosphorus accumulating organisms (PAOs) have been found to act as glycogen accumulating organisms (GAOs) under certain conditions, thus, the deterioration in the performance of enhanced biological phosphorus removal systems is not always attributed to the proliferation of GAOs. In this work, the effects of calcium on the metabolic pathway of PAOs were explored. It was found that when the influent Ca(2+) concentration was elevated, the tendency and extent of extracellular calcium phosphate precipitation increased, and the intracellular inert Ca-bound polyphosphate was synthesized, while the microbial population remained almost unchanged. The changes in the ratios of phosphorus released/acetate uptaken, the glycogen degraded/acetate uptaken and the poly-beta hydroxyalkanoates synthesized/acetate uptaken during the anaerobic period confirm that, as the influent Ca(2+) concentration was increased, the polyphosphate accumulating metabolism was partially shifted to the glycogen-accumulating metabolism. At an influent Ca(2+) around 50 mg/L, in addition to the extracellular calcium phosphate precipitation, the intracellular inert Ca-bound polyphosphate synthesis might also be involved in the metabolic change of PAOs. The results of the present work would be beneficial to better understand the biochemical metabolism of PAOs in enhanced biological phosphorus removal systems. PMID- 26233657 TI - Characterization of the dissolved phosphorus uptake kinetics for the effluents from advanced nutrient removal processes. AB - Given the importance of the watershed protection plans, direct determination of phosphorus (P) mineralization rates in advanced wastewater treatment facility effluents is crucial for developing the most protective strategies minimiz eutrophication in receiving surface waters. In this study, algal bioassays were used to determine the uptake rate of dissolved P in effluents from a broad range of advanced nutrient removal technologies (e.g., membrane biological reactor, traditional biological, tertiary membrane, Blue PROTM, etc.). Dissolved P uptake kinetics were fit to a gamma model and three first-order decay models. A traditional one-pool model correlated poorly with the experimental data (i.e., r(2) = 0.73 +/- 0.09), whereas two-pool model and three-pool models performed much better (i.e., r(2) > 0.9). These models also provided strong evidence for the existence of recalcitrant P in the effluents from these tertiary facilities. The Gamma model showed the mineralization of organic P followed a reactive continuum and further suggested the partitioning of P loads with different bioavailability levels should be accounted for the future modeling practices. From a modeling perspective, the Gamma model should be considered to be the theoretically best model as it gave the most parsimonious fit to the data using the fewest terms. Our study suggested that the current Total Maximum Daily Load (TMDL) model could be easily modified with the updated mineralization kinetics, which should lead to both ecological and economic benefits. PMID- 26233658 TI - Modelling combined effect of chloramine and copper on ammonia-oxidizing microbial activity using a biostability approach. AB - Continuous and batch laboratory experiments were used to evaluate the combined effects of copper and chloramine on ammonia oxidizing microbes present in otherwise high nitrifying water samples. The experimental data were analyzed using a biostability concept and quantified with the biostable residual concentratrion (BRC) of monochloramine, or the concentration that prevents the onset of nitrification. In the batch experiments, copper dosing >=0.25 mg-Cu L( 1) resulted in complete inhibition of nitrification, and a lower copper dosing (0.1 mg-Cu L(-1)) delayed nitrification. The BRC was systematically lowered with the addition of copper. For example, a free-ammonium concentration of 0.1 mg-N L( 1) had a BRC of 0.73 mg-Cl2 L(-1) with no Cu, but addition of 0.1 mg-Cu L(-1) lowered the BRC to 0.16 mg-Cl2 L(-1), while addition of 0.25 mg-Cu L(-1) eliminated the need to add chloramine (BRC = 0). A non-competitive inhibition model fit the experimental data well with a copper threshold of 0.044 mg-Cu L(-1) and can be used to estimate Cu doses needed to prevent nitrification based on the chloramine concentration. Full scale systems applications need further study. PMID- 26233659 TI - Subcellular mechanism of Escherichia coli inactivation during electrochemical disinfection with boron-doped diamond anode: A comparative study of three electrolytes. AB - Although the identification of effective oxidant species has been extensively studied, yet the subcellular mechanism of bacterial inactivation has never been clearly elucidated in electrochemical disinfection processes. In this study, subcellular mechanism of Escherichia coli inactivation during electrochemical disinfection was revealed in terms of comprehensive factors such as cell morphology, total organic components, K(+) leakage, membrane permeability, lipid peroxidation, membrane potential, membrane proteins, intracellular enzyme, cellular ATP level and DNA. The electrolysis was conducted with boron-doped diamond anode in three electrolytes including chloride, sulfate and phosphate. Results demonstrated that cell inactivation was mainly attributed to damage to the intracellular enzymatic systems in chloride solution. In sulfate solution, certain essential membrane proteins like the K(+) ion transport systems were eliminated. Thus, the pronounced K(+) leakage from cytosol resulted in gradual collapse of the membrane potential, which would hinder the subcellular localization of cell division-related proteins as well as ATP synthesis and thereby lead to the bacterial inactivation. Remarkable lipid peroxidation was observed, while the intracellular damage was negligible. In phosphate solution, the cells sequentially underwent overall destruction as a whole cell with no captured intermediate state, during which the organic components of the cells were mostly subjected to mineralization. This study provided a thorough insight into the bacterial inactivation mechanism on the subcellular level. PMID- 26233660 TI - Full scale performance of the aerobic granular sludge process for sewage treatment. AB - Recently, aerobic granular sludge technology has been scaled-up and implemented for industrial and municipal wastewater treatment under the trade name Nereda((r)). With full-scale references for industrial treatment application since 2006 and domestic sewage since 2009 only limited operating data have been presented in scientific literature so far. In this study performance, granulation and design considerations of an aerobic granular sludge plant on domestic wastewater at the WWTP Garmerwolde, the Netherlands were analysed. After a start up period of approximately 5 months, a robust and stable granule bed (>8 g L(-1)) was formed and could be maintained thereafter, with a sludge volume index after 5 min settling of 45 mL g(-1). The granular sludge consisted for more than 80% of granules larger than 0.2 mm and more than 60% larger than 1 mm. Effluent requirements (7 mg N L(-1) and 1 mg P L(-1)) were easily met during summer and winter. Maximum volumetric conversion rates for nitrogen and phosphorus were respectively 0.17 and 0.24 kg (m(3) d)(-1). The energy usage was 13.9 kWh (PE150.year)(-1) which is 58-63 % lower than the average conventional activated sludge treatment plant in the Netherlands. Finally, this study demonstrated that aerobic granular sludge technology can effectively be implemented for the treatment of domestic wastewater. PMID- 26233661 TI - Temporal variability of urinary concentrations of phthalate metabolites, parabens and benzophenone-3 in a Belgian adult population. AB - In the present study, we investigated the temporal within-person variability of the exposure biomarker for phthalates, parabens and benzophenone-3 (BP3) in 32 Belgian adults, each providing 11 urine spots during 4 months. We calculated the intraclass coefficient correlation (ICC), the sensitivity and the specificity to assess the temporal reproducibility and to investigate the predictive ability of the spot measurements for these classes of chemicals. Additionally, we explored the temporal variability of the estimation of the cumulative risk of exposure to phthalates (hazard index; HI). We observed fair ICC ranging from 0.55 to 0.68 for parabens, monoethyl phthalate (MEP), mono-iso-butyl phthalate (MiBP) and BP3, but lower ICC, from 0.20 to 0.49, for monobenzyl phthalate (MBzP), mono-n-butyl phthalate (MnBP), mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxo-hexyl phthalate (5-oxo-MEHP) and mono-2-ethyl-5-hydroxy-hexyl phthalate (5-OH-MEHP). The ICC estimated for HI (0.49) reflected a moderate reproducibility. The measurements in spot samples were moderate to good predictor of the 4-month level of exposure for parabens, MEP, MnBP, MiBP, BP3 and HI (sensitivity ranging from 0.67 to 0.77), but lower predictor for MEHP, 5-oxo-MEHP, 5-OH-MEHP and MBzP (sensitivity ranging from 0.58 to 0.63). The sensitivity could be increased when several spot urinary levels were averaged to predict the long-term level of exposure. Globally, our results indicate that a single spot measurement seems to correctly represent the long-term exposure for parabens, BP3, MEP, MiBP and HI. Additional spot samples seemed to be needed for the proper exposure assessment of the other target compounds. PMID- 26233662 TI - Current standings in diagnostic management of acute venous thromboembolism: Still rough around the edges. AB - Signs and symptoms of acute deep vein thrombosis (DVT) and pulmonary embolism (PE) are notoriously non-specific. Therefore, diagnostic management algorithms have been developed, consisting of a clinical decision rule (CDR), D-dimer testing and an imaging test, that allow safe diagnostic management and the exclusion of VTE in clinical practice. However, several challenges still remain: adherence to the diagnostic algorithms, accurate diagnosis of recurrent VTE and reducing the radiation exposure associated with computed tomography pulmonary angiography for suspected PE. In this clinically oriented review, we will provide an overview of current diagnostic algorithms for suspected DVT and PE and focus on recent advances including strategies to improve adherence to recommended algorithms, age-dependent D-dimer threshold and novel imaging techniques. PMID- 26233663 TI - Comparative analysis of virulence determinants, antibiotic susceptibility patterns and serogrouping of atypical enteropathogenic Escherichia coli versus typical enteropathogenic E. coli in India. AB - The epidemiology of enteropathogenic Escherichia coli (EPEC) and the significance of isolation of atypical EPEC (aEPEC) in childhood diarrhoea have not been well studied in an Indian context. A comparative study was undertaken to investigate virulence determinants, antibiotic susceptibility patterns and serogrouping of typical EPEC (tEPEC) versus aEPEC causing diarrhoea in children. A total of 400 prospective and 500 retrospective E. coli isolates were included. PCR was performed for eae, bfpA, efa, nleB, nleE, cdt, ehxA and paa genes. The Clinical and Laboratory Standards Institute's disc diffusion test was used to determine the antimicrobial susceptibility. Phenotypic screening of extended spectrum beta lactamases (ESBLs), AmpC and Klebsiella pneumoniae carbapenemase (KPC) production, and molecular detection of bla(NDM-1), bla(VIM), bla(CTX-M-15), bla(IMP) and bla(KPC) were performed. aEPEC (57.6 %) were more common as compared with tEPEC (42.3 %). The occurrence of virulence genes was observed to be three times higher in aEPEC as compared with tEPEC, efa1 (14.7 % of aEPEC, 4 % of tEPEC) being the most common. Most of the isolates did not belong to the classical EPEC O-serogroups. The highest resistance was observed against amoxicillin (93.22 %) followed by quinolones (83 %), cephalosporins (37.28 %), cotrimoxazole (35.59 %) and carbapenems (30.5 %). Overall equal numbers of aEPEC (41.17 %) and tEPEC (40 %) were observed to be multidrug-resistant. Fifteen EPEC strains demonstrated presence of ESBLs, five produced AmpC and four each produced metallo-beta-lactamases and KPC-type carbapenemases; eight, seven and one isolate(s) each were positive for bla(VIM), bla(CTX-M-15) and bla(NDM-1), respectively. Here, to the best of our knowledge, we report for the first time on carbapenem resistance and the presence of bla(NDM-1) and bla(CTX-M-15) in EPEC isolates from India. PMID- 26233664 TI - Distribution of arbuscular mycorrhizal fungi associated with different land use systems of Arunachal Pradesh of Eastern Himalayan region. AB - Arbuscular mycorrhizal fungi are the main component of soil microbial population in most agroecosystems. They forms a close association with more than 80% of the plant species making immobilized mineral nutrients available to the plants in order to sustain normal growth and reproduction. In this study the diversity of mycorrhizal fungi has been examined in seven land use ecosystems of Arunachal Pradesh in Eastern Himalayan region. A total of 24 species of AM fungi belonging to 4 genera viz., Glomus, Scutellospora, Aculospora and Gigaspora were isolated from the soil samples collected from different land use systems. Glomus was the dominant genera and Glomus occulatum was the most abundant species in all the seven land use systems. Total spore number was highly variable among all the land use systems. Species richness was recorded highest in natural forest that maintains a faster nutrient cycle with the highest diversity index. The Jhum fallow land and tea garden has the least number of AM fungal species due to high disturbance of fire and application of fungicides and inorganic fertilizer. Further the plant species composition, particularly the ground vegetation coverage and disturbance level affects the distribution of the AM fungal species. In our study it has been shown that AMF diversity is significantly affected by the land use practices practiced by the people. Hence, the AM fungi isolated from different land use system may be useful in improving the agriculture practices particularly the plantation crops in the region. PMID- 26233665 TI - Anomalous equivalent potential temperature: an atmospheric feature predicting days with higher risk for fatal outcome in acute ischemic stroke-a preliminary study. AB - Acute stroke is a life-threatening condition. Fatal outcome is related to risk factors, some of these affected by climatic changes. Forecasting potentially harmful atmospheric processes may therefore be of practical importance in the acute care of stroke patients. We analyzed the history of all patients with acute ischemic stroke (N = 184) confirmed by neuroimaging including those who died (N = 35, 15 males) at our hospital department in the winter months of 2009. Patient data were anonymized, and the human meteorologists were only aware of patients' age, gender, and exact time of death. Of the meteorological parameters, equivalent potential temperature (EPT) has been chosen for analysis. EPT is generally used for forecasting thunderstorms, but in the case of synoptic scale airflow (10(6) m), it is suitable for characterizing the air mass inflowing from different regions. The behavior of measured EPT values was compared to the climatic (30 years) averages. We developed meteorological criteria for anomalous periods of EPT and tested if such periods are associated with higher rate of fatal outcome. The duration of anomalous and non-anomalous periods was nearly equal during the studied 3 months. Stroke onset distributed similarly between anomalous and non-anomalous days; however, of the 35 deaths, 27 occurred during anomalous periods: on average, 0.56 deaths occurred on anomalous days and 0.19 on non-anomalous days. Winter periods meeting the criteria of anomalous EPT may have a significant adverse human-meteorological impact on the outcome in acute ischemic stroke. PMID- 26233666 TI - Assessment of surface water quality using multivariate statistical techniques: case study of the Nampong River and Songkhram River, Thailand. AB - Multivariate statistical techniques such as cluster analysis (CA), principal component analysis (PCA), factor analysis (FA), and discriminant analysis (DA) were applied for the assessment of spatial and temporal variations of a large complex water quality data set of the Nampong River and Songkhram River, generated for more than 10 years (1996-2012) by monitoring of 16 parameters at different sites. According to the water quality characteristics, hierarchical CA grouped 13 sampling sites of the Nampong River into two clusters, i.e., upper stream (US) and lower stream (LS) sites, and five sampling sites of the Songkhram River into three clusters, i.e., upper stream (US), middle stream (MS) and lower stream (LS) sites. PCA/FA applied to the data sets thus obtained five latent factors explaining 69.80 and 69.32 % of the total variance in water quality data sets of LS and US areas, respectively, in the Nampong River and six latent factors explaining 80.80, 73.95, and 73.78 % of the total variance in water quality data sets of LS, MS, and US areas, respectively, in the Songkhram River. This study highlights the usefulness of multivariate statistical assessment of complex databases in the identification of pollution sources to better comprehend the spatial and temporal variations for effective river water quality management. PMID- 26233667 TI - Stormwater runoff to an impaired lake: impacts and solutions. AB - Stormwater runoff can represent a significant source of pollutants to downstream water bodies. An integrated assessment was conducted for the Spring Lake watershed in western Michigan because of concerns that increased impervious land cover in the watershed, especially in sub-basins adjacent to Spring Lake, would result in greater stormwater runoff and pollutant loads. Spring Lake has a history of high total phosphorus (TP) concentrations and cyanobacterial blooms. An alum treatment, paid for by an assessment, was applied to Spring Lake in 2005 to control internal phosphorus loading; hence, there was an economic incentive for stakeholders to limit new phosphorus from entering the lake, which otherwise would reduce the long-term efficacy of the alum treatment. This study provides a novel six-step process that identifies priority areas and optimally reduces nonpoint sources of pollution. We identified a suite of best management practices to be placed in the watershed, assessed their optimal locations based on pollutant sources, and modeled the degree to which their implementation would reduce TP and total suspended solids. Application of the modeled best management practices (BMPs) resulted in a 15 % reduction in TP load and a 17 % reduction in total suspended solid load. Reductions were not uniform throughout the watershed, with the greatest reductions closest to Spring Lake. We also developed a flow chart for BMP selection, which may be transferable to other watersheds with similar issues. PMID- 26233668 TI - Analysis of mercury and methylmercury concentrations, and selenium:mercury molar ratios for a toxicological assessment of sperm whales (Physeter macrocephalus) in the most recent stranding event along the Adriatic coast (Southern Italy, Mediterranean Sea). AB - Mass stranding of sperm whales (Physeter macrocephalus) is a rare event in the Mediterranean Sea. In September 2014, a pod of seven sperm whales became stranded along the Adriatic coast of Southern Italy. This is the seventh occurrence of this type since 1555 in this sea basin. Total concentrations of mercury (T-Hg), methylmercury (MeHg) and selenium (Se) were measured from brain, muscle, liver and kidney of three female sperm whales, which died in this event. Analyses showed considerable, age-dependent variations in Hg and Se concentrations in the different organs. The contamination levels of T-Hg in the liver (up to 200 mg kg( 1)) and brain (up to 21 mg kg(-1)) samples were markedly higher than those in the kidney and muscle samples. The liver and brain also showed the highest Se levels. Se:Hg molar ratios ?1 were observed in all the organs of the three sperm whales, suggesting that Se could protect the animals from Hg toxicity. The risk of Hg associated neurotoxicity was assessed by comparing our values to thresholds set for neurotoxicity in mammals, and the role of Se in the detoxification process of T-Hg/MeHg is discussed herein. PMID- 26233670 TI - Evidence of apoptosis induced by viral protein 2 of chicken anaemia virus. AB - Although viral protein 3 (VP3) of chicken anaemia virus (CAV) has been well recognised as an inducer of apoptosis, viral protein 2 (VP2) of the virus has only been speculated to have apoptotic activity. This has not been verified because the open reading frame (ORF) encoding VP2 completely encompasses that encoding VP3, and thus the possibility of expression of VP3 cannot be excluded. The aim of this study was to elucidate the potential role of VP2 as an inducer of apoptosis. Site-directed mutagenesis was used to generate a point mutation that knocked out VP3 by early termination of its translation with a stop codon without imposing any change in the amino acid sequence of VP2. The mutated sequence was inserted into the pCAT plasmid preceded by a favorable Kozak's consensus sequence to create pCAT-VP2(+)VP3(-). The absence of VP3 expression in MSB1 cells transfected with this plasmid was confirmed using Western blotting, and DNA strand breaks and nuclear morphological changes were assessed to detect apoptosis. There was an increased level of apoptotic death in cells transfected with pCAT-VP2(+)VP3(-) compared to those transfected with the vector alone. This provides evidence that CAV VP2 can induce apoptosis. PMID- 26233669 TI - Diversity of Synechococcus at the Martha's Vineyard Coastal Observatory: Insights from Culture Isolations, Clone Libraries, and Flow Cytometry. AB - The cyanobacterium Synechococcus is a ubiquitous, important phytoplankter across the world's oceans. A high degree of genetic diversity exists within the marine group, which likely contributes to its global success. Over 20 clades with different distribution patterns have been identified. However, we do not fully understand the environmental factors that control clade distributions. These factors are likely to change seasonally, especially in dynamic coastal systems. To investigate how coastal Synechococcus assemblages change temporally, we assessed the diversity of Synechococcus at the Martha's Vineyard Coastal Observatory (MVCO) over three annual cycles with culture-dependent and independent approaches. We further investigated the abundance of both phycoerythrin (PE)-containing and phycocyanin (PC)-only Synechococcus with a flow cytometric setup that distinguishes PC-only Synechococcus from picoeukaryotes. We found that the Synechococcus assemblage at MVCO is diverse (13 different clades identified), but dominated by clade I representatives. Many clades were only isolated during late summer and fall, suggesting more favorable conditions for isolation at this time. PC-only strains from four different clades were isolated, but these cells were only detected by flow cytometry in a few samples over the time series, suggesting they are rare at this site. Within clade I, we identified four distinct subclades. The relative abundances of each subclade varied over the seasonal cycle, and the high Synechococcus cell concentration at MVCO may be maintained by the diversity found within this clade. This study highlights the need to understand how temporal aspects of the environment affect Synechococcus community structure and cell abundance. PMID- 26233671 TI - Immune-spaying as an alternative to surgical spaying in Iberian * Duroc females: Effect on the VOC profile of dry-cured shoulders and dry-cured loins as detected by PTR-ToF-MS. AB - Immunocastration in pigs has been proposed as a cruelty-free alternative to surgical castration. In this work the effect of immune-spaying of female pigs on the volatile compound profile of Iberian dry-cured products was evaluated. The head-space volatile compound of dry-cured shoulders and loins from surgically spayed, immune-spayed and entire Iberian * Duroc females was characterized by proton transfer reaction-time of flight-mass spectrometry. It was not possible to identify a significant effect of the castration modality on dry-cured shoulders, probably because of the heterogeneity of samples. Contrarily, Principal Component Analysis of dry-cured loins indicates a better homogeneity of samples and the separation of loins from surgically spayed and immune-spayed females. Some mass peaks tentatively identified as important flavor compounds in dry-cured products, 3-methylbutanal, 2,3-butanedione and 3-methylbutanoic acid, were significantly higher in the immune-spayed females. Therefore, immune-spaying seems to have a negligible effect on the volatile compound profile of dry-cured shoulders, whereas it could affect the VOC profile in the case of dry-cured loins. PMID- 26233672 TI - Data-driven risk identification in phase III clinical trials using central statistical monitoring. AB - Our interest lies in quality control for clinical trials, in the context of risk based monitoring (RBM). We specifically study the use of central statistical monitoring (CSM) to support RBM. Under an RBM paradigm, we claim that CSM has a key role to play in identifying the "risks to the most critical data elements and processes" that will drive targeted oversight. In order to support this claim, we first see how to characterize the risks that may affect clinical trials. We then discuss how CSM can be understood as a tool for providing a set of data-driven key risk indicators (KRIs), which help to organize adaptive targeted monitoring. Several case studies are provided where issues in a clinical trial have been identified thanks to targeted investigation after the identification of a risk using CSM. Using CSM to build data-driven KRIs helps to identify different kinds of issues in clinical trials. This ability is directly linked with the exhaustiveness of the CSM approach and its flexibility in the definition of the risks that are searched for when identifying the KRIs. In practice, a CSM assessment of the clinical database seems essential to ensure data quality. The atypical data patterns found in some centers and variables are seen as KRIs under a RBM approach. Targeted monitoring or data management queries can be used to confirm whether the KRIs point to an actual issue or not. PMID- 26233673 TI - Local and Global Visual Processing in Autism Spectrum Disorders: Influence of Task and Sample Characteristics and Relation to Symptom Severity. AB - Local and global visual processing abilities and processing style were investigated in individuals with autism spectrum disorder (ASD) versus typically developing individuals, children versus adolescents and boys versus girls. Individuals with ASD displayed more attention to detail in daily life, while laboratory tasks showed slightly reduced global processing abilities, intact local processing abilities, and a more locally oriented processing style. However, the presence of these group differences depended on particular task and sample (i.e., age and gender) characteristics. Most measures of local and global processing did not correlate with each other and were not associated with processing style. Significant associations between local-global processing and ASD symptom severity were observed, but the causality of these associations remains unclear. PMID- 26233675 TI - Femoral fixation strength following soft-tissue posterolateral corner reconstruction using fibular-based technique: Biomechanical analysis of four techniques in normal and low-density synthetic bone. AB - BACKGROUND: Optimal femoral fixation of soft-tissue grafts has been described for anterior cruciate ligament reconstruction. Posterolateral corner reconstruction differs from ACL reconstruction in two ways: (a) soft-tissue fixation into the femur requires two tails and (b) the line of force is different. Our purpose was to determine the optimal femoral fixation of soft-tissue grafts during posterolateral corner reconstructions. We hypothesized that interference screw fixation is the strongest technique in normal-density lateral femoral condyle, whereas, cortically-based fixation techniques are stronger methods in low-density lateral femoral condyle. METHODS: We evaluated elongation during cyclic loading, yield load, peak load-to-failure, and stiffness of four soft-tissue graft femoral fixation methods during posterolateral corner reconstruction. Our model included bovine flexor tendons and contoured synthetic bones. Grafts were secured to the lateral epicondyle in normal- or low-density bone models using spiked washer, button, interference screw, or button and interference screw. Five specimens for each were tested in each bone density. Analysis of variance using Tukey-Kramer adjustment for multiple hypothesis testing was used. Six cadaver bones whose density was analyzed using computerized tomography scan quantitation were tested using interference screw fixation. RESULTS: No method produced significantly stronger yield load or peak load-to-failure in normal-density bone. In low density bone, cortically-based methods produced significantly higher yield load or peak load-to-failure. Yield load or peak load-to-failure was significantly higher in normal-density bone when using spiked washer or interference screw fixation. CONCLUSION: No femoral fixation method tested produced superior yield load or peak load-to-failure. Spiked washer and interference screw fixation are inferior fixation methods in low-density bone. CLINICAL RELEVANCE: For fibular based posterolateral corner reconstructions, all fixation methods tested are acceptable in high-density bone, while cortical fixation methods should be considered in low-density bone. PMID- 26233674 TI - From video recordings to whisker stable isotopes: a critical evaluation of timescale in assessing individual foraging specialisation in Australian fur seals. AB - Estimating the degree of individual specialisation is likely to be sensitive to the methods used, as they record individuals' resource use over different time periods. We combined animal-borne video cameras, GPS/TDR loggers and stable isotope values of plasma, red cells and sub-sampled whiskers to investigate individual foraging specialisation in female Australian fur seals (Arctocephalus pusillus doriferus) over various timescales. Combining these methods enabled us to (1) provide quantitative information on individuals' diet, allowing the identification of prey, (2) infer the temporal consistency of individual specialisation, and (3) assess how different methods and timescales affect our estimation of the degree of specialisation. Short-term inter-individual variation in diet was observed in the video data (mean pairwise overlap = 0.60), with the sampled population being composed of both generalist and specialist individuals (nested network). However, the brevity of the temporal window is likely to artificially increase the level of specialisation by not recording the entire diet of seals. Indeed, the correlation in isotopic values was tighter between the red cells and whiskers (mid- to long-term foraging ecology) than between plasma and red cells (short- to mid-term) (R(2) = 0.93-0.73 vs. 0.55-0.41). delta(13)C and delta(15)N values of whiskers confirmed the temporal consistency of individual specialisation. Variation in isotopic niche was consistent across seasons and years, indicating long-term habitat (WIC/TNW = 0.28) and dietary (WIC/TNW = 0.39) specialisation. The results also highlight time-averaging issues (under-estimation of the degree of specialisation) when calculating individual specialisation indices over long time-periods, so that no single timescale may provide a complete and accurate picture, emphasising the benefits of using complementary methods. PMID- 26233676 TI - Knowing hypertension and diabetes: Conditions of treatability in Uganda. AB - In Uganda, hypertension and diabetes have only recently been included in the health policy agenda. As they become treatable disorders, they take on more distinct contours in people's minds. This article relates knowledge about these two conditions to health institutions and technology for diagnosing and treating them. The response to the AIDS epidemic in Uganda provides an important context for, and contrast with, the emergence of hypertension and diabetes as social phenomena. Ethnographic fieldwork shows the interplay between experience of these conditions and the political economy of treatability. PMID- 26233677 TI - Clinical feasibility of interactive motion-controlled games for stroke rehabilitation. AB - BACKGROUND: Active gaming technologies, including the Nintendo Wii and Xbox Kinect, have become increasingly popular for use in stroke rehabilitation. However, these systems are not specifically designed for this purpose and have limitations. The aim of this study was to investigate the feasibility of using a suite of motion-controlled games in individuals with stroke undergoing rehabilitation. METHODS: Four games, which utilised a depth-sensing camera (PrimeSense), were developed and tested. The games could be played in a seated or standing position. Three games were controlled by movement of the torso and one by upper limb movement. Phase 1 involved consecutive recruitment of 40 individuals with stroke who were able to sit unsupported. Participants were randomly assigned to trial one game during a single session. Sixteen individuals from Phase 1 were recruited to Phase 2. These participants were randomly assigned to an intervention or control group. Intervention participants performed an additional eight sessions over four weeks using all four game activities. Feasibility was assessed by examining recruitment, adherence, acceptability and safety in both phases of the study. RESULTS: Forty individuals (mean age 63 years) completed Phase 1, with an average session time of 34 min. The majority of Phase 1 participants reported the session to be enjoyable (93 %), helpful (80 %) and something they would like to include in their therapy (88 %). Sixteen individuals (mean age 61 years) took part in Phase 2, with an average of seven 26 min sessions over four weeks. Reported acceptability was high for the intervention group and improvements over time were seen in several functional outcome measures. There were no serious adverse safety events reported in either phase of the study; however, a number of participants reported minor increases in pain. CONCLUSIONS: A post-stroke intervention using interactive motion-controlled games shows promise as a feasible and potentially effective treatment approach. This paper presents important recommendations for future game development and research to further explore long-term adherence, acceptability, safety and efficacy. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ( ACTRN12613000220763 ). PMID- 26233678 TI - The impact of structural empowerment and psychological capital on competence among Chinese baccalaureate nursing students: A questionnaire survey. AB - BACKGROUND: Competence in nursing has been increasingly addressed. However, studies from the international literature have demonstrated that graduate nurses are not ready and they are not competent to provide safe and effective nursing care. Therefore, it is important to assess nursing students' competence and to explore the relevant factors for improving nursing students' competence and the quality of nursing care. OBJECTIVES: The purpose of this paper is to investigate the influence of structural empowerment (an environmental resource) and psychological capital (an intrapersonal resource) on baccalaureate nursing students' competence. DESIGN AND METHODS: The study was designed as a cross sectional survey. A total of 300 senior baccalaureate nursing students in China practicing in five major tertiary teaching hospitals were invited to participate in the current survey. A total of 286 students completed the survey and were evaluated statistically. Thus, the response rate was 95.3%. RESULTS: The results of the study indicate that nursing students have medium-high levels of competence, and medium-high levels of structural empowerment and psychological capital. Students with perceived higher levels of structure empowerment and psychological capital were more likely to achieve higher levels of competence. CONCLUSIONS: Structural empowerment and psychological capital were significantly and positively correlated with students' competence. The findings implicate that nursing managers and educators should not only promote interventions to enhance competence of baccalaureate nursing students but also focus on creating a supportive clinical learning environment and strengthen their positive intrapersonal resource. PMID- 26233679 TI - Genetic characteristics of canine bocaviruses in Korean dogs. AB - To survey for canine bocavirus (CBoV) infection, 83 Korean dogs showing several clinical signs were collected in different provinces from January 2013 to July 2014. Using polymerase chain reaction (PCR) and in situ hybridization, CBoVs were detected in intestine and/or lung samples of 8 dogs (9.6%). To reveal the genetic characteristics of CBoVs, partial or complete regions of CBoVs were sequenced. In phylogenetic trees, 8 CBoVs fell into three clusters. The CBoV strains 13D226-1, 13D250, and 14Q216 were closely related to the CBoV HK831F strain, and the CBoV 14D142 strain was related to the CBoV HK882F strain. Lastly, CBoV 13D003, 13D095, 14D193, and 14Q209 strains were related to CBoV Dis-023, Dis-040, and Dis-046 strains. Interestingly, no canine pathogens were found in dogs in which four CBoVs (13D003, 13D0095, 14D142, and 14D193 strains) were detected and three of them (13D003, 13D095, and 14D193 strains) had a unique deletion (18 nucleotides) in the VP2 gene. Further, the open reading frame 4 (ORF4) region was absent in these 4CBoVs, but found in the other strains, which indicates that the absence of the ORF4 region rather than a unique deletion may have an influence on the pathogenesis of CBoV in dogs. PMID- 26233680 TI - Use of proteomics in the study of microbial diseases of small ruminants. AB - Objective of the paper is to review potential applications of proteomics methodologies in the study of microbial diseases of small ruminants. Proteomics has been employed for the elucidation of pathogenesis of various diseases, i.e., in the study of determinants of microbial agents and the study of host-pathogen interactions, as well as in improved disease diagnosis by the identification of biomarkers. Extensive uses of proteomics in sheep and goat diseases have been applied primarily in mastitis, in reproductive infections, in paratuberculosis, in respiratory infections and in scrapie. Mining deeper into the various proteomes and application of new methodological strategies in clinical studies will provide information about disease processes. Improvement of diagnostic techniques, development of vaccines against diseases and establishment of tools for optimum animal production are key-areas for targeted research. PMID- 26233681 TI - Influence of menopausal status on diagnostic accuracy of myometrial invasion in endometrial cancer: diffusion-weighted and dynamic contrast-enhanced MRI at 3 T. AB - AIM: To assess the influence of menopausal status on the diagnostic accuracy of diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for evaluating myometrial invasion in patients diagnosed with endometrial cancer. MATERIALS AND METHODS: In this prospective study, 91 consecutive female patients diagnosed with endometrial cancer were enrolled for preoperative evaluation using 3 T MRI. Two radiologists interpreted myometrial invasion depth on DW (b=1000 s/mm(2)) and DCE MRI images, with surgical histopathology as the reference standard. Statistical methods included kappa statistics for evaluating reader agreement and diagnostic performance analysis between pre- and postmenopausal groups. RESULTS: Reader agreement of DW MRI was poor (kappa=0.20) for premenopausal patients. The diagnostic accuracy of DW MRI in detecting myometrial involvement was significantly lower in premenopausal compared with postmenopausal patients (0.42 versus 0.73, p=0.006). There was no difference in the diagnostic accuracy of DW MRI in detecting deep myometrial invasion between premenopausal and postmenopausal groups (0.94 versus 0.95, p>0.99). CONCLUSION: For premenopausal patients who plan to receive fertility preserving treatment for endometrial cancer, DCE MRI is superior to DW MRI in excluding any possible myometrial invasion. For preoperative assessment of deep myometrial invasion, DW MRI can be a legitimate alternative to DCE MRI regardless of menopausal status and is particularly beneficial for patients at risk of nephrogenic systemic fibrosis. PMID- 26233682 TI - Azacitidine is effective for the treatment of myelodysplastic syndrome and accompanied Sweet syndrome. PMID- 26233683 TI - Synergistic effect of sorafenib and cGvHD in patients with high-risk FLT3-ITD+AML allows long-term disease control after allogeneic transplantation. AB - The multikinase inhibitor sorafenib has shown a strong anti-leukemic effect in FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML); however, remission is often transient. To better understand the role of sorafenib, we performed a retrospective analysis of all patients who received sorafenib in combination with allogeneic hematopoietic stem cell transplantation (HSCT) at our center. Seventeen patients with FLT3-ITD positive AML were treated with sorafenib in combination with allogeneic HSCT. Seven patients received sorafenib therapy pre- and posttransplant, and 10 patients were given sorafenib only posttransplant. Median duration of sorafenib treatment was 13 months (range 1 42); median dose was 600 mg (range 100-1200). Fourteen patients (82 %) achieved a complete remission (CR), while 5 patients (29 %) eventually developed progressive disease. Developing chronic graft-versus-host disease (GvHD) had a strong protective influence on the risk of sorafenib resistance (p = 0.028, HR 0.08, 95 % CI 0.01-0.76). In a total of 8 patients, sorafenib had to be stopped, paused or dose-reduced due to toxicity. In 5 patients with pronounced toxicity, we switched to an alternating dosing schedule with 1 month on/1 month off sorafenib. These patients subsequently remained in sustained complete molecular remission, with a median follow-up of 20 months. Our data indicate that sorafenib can achieve high rates of sustained remission in high-risk patients treated in combination with HSCT. PMID- 26233685 TI - Nucleolipid bilayers: A quartz crystal microbalance and neutron reflectometry study. AB - POP-Ade (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidyladenosine) is a biocompatible anionic nucleolipid with the DNA nucleoside, Adenosine, in the polar headgroup. We have studied the affinity of nucleic acids of different contour length, composition and structure toward supported lipid bilayers (SLB) composed of POP-Ade mixed with the zwitterionic phospholipid POPC (1-palmitoyl-2 oleoyl-sn-glycero-3-phosphocholine) using quartz crystal microbalance with dissipation monitoring (QCM-D) and neutron reflectometry (NR). In order to highlight the specificity of the nucleic acid interaction, the results were compared with data obtained for SLB containing the anionic phospholipid POPG (1 palmitoyl-2-oleoyl-sn-phosphatidyl-glycerol) replacing POP-Ade. Our results demonstrate that the presence of a nucleobase headgroup provides the bilayers with the ability to bind single stranded nucleic acids in a selective fashion, according to a Watson-Crick pattern. In addition the interaction with double stranded nucleic acids was strengthened. Overall, these findings represent fundamental information for the design of biocompatible DNA vectors with DNA-RNA based amphiphiles. PMID- 26233684 TI - Effect of sitagliptin on epicardial fat thickness in subjects with type 2 diabetes and obesity: a pilot study. AB - The aim of the study was to assess the effect of sitagliptin addition on the epicardial adipose tissue (EAT) thickness in subjects with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. This was a 24-week interventional pilot study in 26 consecutive type 2 diabetic patients, 14 females and 12 males average age of 43.8 +/- 9.0 years, with Hemoglobin A1c (HbA1c) >= 7% on metformin monotherapy. Subjects who met the inclusion criteria were added on sitagliptin and started on sitagliptin/metformin combination at the dosage of 50 mg/1000 mg twice daily. EAT and visceral and total body fat were measured, respectively, with echocardiography and bioelectrical impedance analysis at baseline and after 24 weeks of sitagliptin/metformin treatment in each subject. HbA1c and plasma lipids were also measured. EAT decreased significantly from 9.98 +/- 2.63 to 8.10 +/- 2.11 mm, p = 0.001, accounting for a percentage of reduction (?%) of -15% after 24 weeks of sitagliptin addition, whereas total body fat percentage, visceral fat, and body mass index (BMI), decreased by 8, 12, and 7%, respectively (p = 0.001 for all). After 6 month, EAT ?% was significantly correlated with ?% of visceral fat (r = 0.456; p = 0.01), whereas no correlation with either BMI ?% (r = 0.292; p = 0.147) or HbA1c ?% was found. The addition of Sitagliptin produced a significant and rapid reduction of EAT, marker of organ specific visceral fat, in overweight/obese individuals with type 2 diabetes inadequately controlled on metformin monotherapy. EAT as measured with ultrasound can serve as no invasive and accurate marker of visceral fat changes during pharmaceutical interventions targeting the fat. PMID- 26233686 TI - Human metabolism and excretion kinetics of aniline after a single oral dose. AB - Aniline is an important source material in the chemical industry (e.g., rubber, pesticides, and pharmaceuticals). The general population is known to be ubiquitously exposed to aniline. Thus, assessment of aniline exposure is of both occupational and environmental relevance. Knowledge on human metabolism of aniline is scarce. We orally dosed four healthy male volunteers (two fast and two slow acetylators) with 5 mg isotope-labeled aniline, consecutively collected all urine samples over a period of 2 days, and investigated the renal excretion of aniline and its metabolites by LS-MS/MS and GC-MS. After enzymatic hydrolysis of glucuronide and sulfate conjugates, N-acetyl-4-aminophenol was the predominant urinary aniline metabolite representing 55.7-68.9 % of the oral dose, followed by the mercapturic acid conjugate of N-acetyl-4-aminophenol accounting for 2.5-6.1 %. Acetanilide and free aniline were found only in minor amounts accounting for 0.14-0.36 % of the dose. Overall, these four biomarkers excreted in urine over 48 h post-dose represented 62.4-72.1 % of the oral aniline dose. Elimination half times were 3.4-4.3 h for N-acetyl-4-aminophenol, 4.1-5.5 h for the mercapturic acid conjugate, and 1.3-1.6 and 0.6-1.2 h for acetanilide and free aniline, respectively. Urinary maximum concentrations of N-acetyl-4-aminophenol were reached after about 4 h and maximum concentrations of the mercapturic acid conjugate after about 6 h, whereas concentrations of acetanilide and free aniline peaked after about 1 h. The present study is one of the first to provide reliable urinary excretion factors for aniline and its metabolites in humans after oral dosage, including data on the predominant urinary metabolite N-acetyl-4 aminophenol, also known as an analgesic under the name paracetamol/acetaminophen. PMID- 26233687 TI - RNAi in murine hepatocytes: the agony of choice--a study of the influence of lipid-based transfection reagents on hepatocyte metabolism. AB - Primary hepatocyte cell cultures are widely used for studying hepatic diseases with alterations in hepatic glucose and lipid metabolism, such as diabetes and non-alcoholic fatty liver disease. Therefore, small interfering RNAs (siRNAs) provide a potent and specific tool to elucidate the signaling pathways and gene functions involved in these pathologies. Although RNA interference (RNAi) in vitro is frequently used in these investigations, the metabolic alterations elucidated by different siRNA delivery strategies have hardly been investigated in transfected hepatocytes. To elucidate the influence of the most commonly used lipid-based transfection reagents on cultured primary hepatocytes, we studied the cytotoxic effects and transfection efficiencies of INTERFERin((r)), Lipofectamine((r))RNAiMAX, and HiPerFect((r)). All of these transfection agents displayed low cytotoxicity (5.6-9.0 +/- 1.3-3.4%), normal cell viability, and high transfection efficiency (fold change 0.08-0.13 +/- 0.03-0.05), and they also favored the satisfactory down-regulation of target gene expression. However, when effects on the metabolome and lipidome were studied, considerable differences were observed among the transfection reagents. Cellular triacylglycerides levels were either up- or down-regulated [maximum fold change: INTERFERin((r)) (48 h) 2.55 +/- 0.34, HiPerFect((r)) (24 h) 0.79 +/- 0.08, Lipofectamine((r))RNAiMAX (48 h) 1.48 +/- 0.21], and mRNA levels of genes associated with lipid metabolism were differentially affected. Likewise, metabolic functions such as amino acid utilization from were perturbed (alanine, arginine, glycine, ornithine, and pyruvate). In conclusion, these findings demonstrate that the choice of non-viral siRNA delivery agent is critical in hepatocytes. This should be remembered, especially if RNA silencing is used for studying hepatic lipid homeostasis and its regulation. PMID- 26233688 TI - Sentinel lymph node mapping for 385 gastric cancer patients. AB - BACKGROUND: The objectives were to investigate the accuracy of sentinel lymph node (SLN) biopsy, detect the predictors for undetected or false-negative cases, evaluate the indications for SLN-navigated gastrectomy, and characterize the problems of SLN mapping in gastric cancer. The SLN concept may be applicable to early gastric cancer, particularly clinical T1N0M0 or T2N0M0 with tumor diameter <=4 cm. METHODS: A total of 385 consecutive patients diagnosed with cT1N0M0 or cT2aN0M0 operable gastric cancer from April 1999 to December 2007 underwent radical gastrectomy with SLN mapping. SLNs were identified using radio-guided and dye-guided methods. Predictors for undetected or false-negative cases on SLN mapping were examined by multivariate regression analysis. RESULTS: The detection rate of hot and/or blue nodes was 96.6% (372 of 385). The accuracy of metastatic status based on SLNs was 98.9% (368 of 372) for all cases in whom SLNs could be detected. Furthermore, the accuracy of metastatic status based on SLNs was 99.1% (344 of 347) in cT1 gastric cancer and 96.0% (24 of 25) in cT2 gastric cancer. Pathologically, the tumors invaded to the muscularis propria or deeper in three of four false-negative cases. All but one case had metastatic lymph nodes within the sentinel basins. In terms of 5-y recurrence free survival, positive SLN cases (SLN(+)) had a worse prognosis than negative SLN cases (SLN(-); P = 0.008). Moreover, SLN(+) and non-SLN(-) cases (SLN(+)/non-SLN(-)) had a similar prognosis as SLN(+) and non-SLN(+) cases (SLN(+)/non-SLN(+)) (P = 0.511). On multivariate regression analysis, undetected or false-negative cases were significantly associated with the time period. CONCLUSIONS: The present results appeared to validate the SLN concept for untreated cT1 gastric cancer with tumor diameter <=4 cm. SLN mapping may provide an effective method of staging the lymph node status of patients undergoing minimized gastrectomy. Sentinel basin dissection guards against the possibility of leaving positive lymph nodes. Stabilization of the procedure and experience with SLN mapping in gastric cancer might decrease undetected or false-negative cases. PMID- 26233689 TI - The effect of pH versus base deficit on organ failure in trauma patients. AB - BACKGROUND: Base deficit (BD) calculations are affected by trauma-related changes in circulating concentrations of anions after injury. In contrast, pH is a direct measurement that corresponds to hypoperfusion. We hypothesized that changes in pH would more closely correspond to organ dysfunction compared with changes in BD. MATERIALS AND METHODS: BD and pH values were collected for the first 48 h after injury from a retrospective cohort of 74 multiply injured adult patients who were admitted to the surgical intensive care unit for a minimum of 1 wk. Mean and extreme (minimum pH and maximum BD) values of pH and BD were determined for day 1 (0-24 h) and for day 2 (24-48 h) after injury. Organ dysfunction was measured by averaging daily sequential organ failure assessment scores over the entire duration of intensive care unit admission. BD and pH values were compared with mean modified sequential organ failure assessment scores by univariate and multivariate linear regression. RESULTS: Organ dysfunction corresponded more closely with changes in pH compared with those in BD. Minimum pH and maximum BD showed better correspondence to organ dysfunction compared with mean values. Minimum pH values at 24-48 h had the highest univariate (r(2) = 0.43) correspondence to organ dysfunction. In contrast, mean BD values at 24-48 h showed no correspondence (r(2) = 0.07) to organ dysfunction. Multivariate analysis demonstrated that 24-48 h of minimum pH had the highest numerical effect on organ dysfunction. CONCLUSIONS: Correspondence between organ dysfunction and BD deteriorated in contrast to increasing correspondence between organ dysfunction and pH measured within 48 h after injury. PMID- 26233690 TI - An inflammatory myopathy unmasks a case of leprosy in an Italian patient. PMID- 26233691 TI - Fall risk is associated with amplified functional connectivity of the central executive network in patients with Parkinson's disease. AB - Falls are debilitating problems that markedly impact the health-related quality of life of many patients with Parkinson's disease (PD). Numerous studies point to the role of executive function and attention in falls; however, the brain mechanisms underlying these relationships are less clear. Here, we aim to evaluate the brain mechanisms underlying the role of executive function in falls. Patients with PD who were fallers (n = 27) or non-fallers (n = 53) and 27 healthy older adults were examined in a cross-sectional study. Gray matter volumes of the caudate head and posterior putamen were evaluated, as these striatal regions play a role in the executive and the sensorimotor cortico-striatal networks, respectively. The functional connectivity of the central executive network and of the sensorimotor network was measured using intrinsic brain connectivity during resting state functional magnetic resonance imaging. Compared to non-fallers and healthy controls, fallers had lower gray matter volume in the caudate head, but not in the posterior putamen, and increased connectivity between posterior partial regions of the central executive network, with no difference within the sensorimotor network. Mediation analysis demonstrated that the relationships between caudate head gray matter volume and fall history and risk were mediated by increased connectivity within the central executive network, apparently via attentional changes. The above findings provide additional converging evidence for the involvement of executive-related brain changes in falls in PD and support the important role of attention and executive function in fall risk. PMID- 26233692 TI - The Alzheimer disease BIN1 locus as a modifier of GBA-associated Parkinson disease. AB - GBA mutations are among the most common genetic risk factors for Parkinson disease (PD) worldwide. We aimed to identify genetic modifiers of the age at onset (AAO) in GBA-associated PD. The study included a genome-wide discovery phase, including a cohort of 79 patients with the GBA p.N370S mutation, and candidate validation and replication analyses of 8 SNPs in patients with mild (n = 113) and severe (n = 41) GBA mutations. Genotyping was performed using the Affymetrix human SNP 6.0 array and TaqMan assays. In the genome-wide phase, none of the SNPs passed the genome-wide significance threshold. Eight SNPs were selected for further analysis from the top hits. In all GBA-associated PD patients (n = 153), the BIN1 rs13403026 minor allele was associated with an older AAO (12.4 +/- 5.9 years later, p = 0.0001), compared to patients homozygous for the major allele. Furthermore, the AAO was 10.7 +/- 6.8 years later in patients with mild GBA mutations, (p = 0.005, validation group), and 17.1 +/- 2.5 years later in patients with severe GBA mutations (p = 0.01, replication). Our results suggest that alterations in the BIN1 locus, previously associated with Alzheimer disease, may modify the AAO of GBA-associated PD. More studies in other populations are required to examine the role of BIN1-related variants in GBA associated PD. PMID- 26233693 TI - Optical coherence tomography findings in Huntington's disease: a potential biomarker of disease progression. AB - Previous reports of ocular abnormalities in Huntington's disease (HD) have detailed eye movement disorders. The objective of this case-control study was to investigate optic nerve and macular morphology in HD using optical coherence tomography (OCT). A total of 26 HD patients and 29 controls underwent a thorough ophthalmic examination including spectral domain OCT scans of the macula and peripapillary retinal nerve fibre layer (RNFL). Genetic testing results, disease duration, HD disease burden scores and Unified HD Rating Scale motor scores were acquired for HD patients. Temporal RNFL thickness was significantly reduced in the HD group (62.3 vs. 69.8 MUm, p = 0.005), and there was a significant negative correlation between temporal RNFL thickness and disease duration (R (2) = -0.51, p = 0.04). Average peripapillary RNFL thickness was not significantly different between the HD and control groups. There was a significant negative correlation between macular volume and disease duration (R (2) = -0.71, p = 0.002), and motor scores (R (2) = -0.56, p = 0.01). Colour vision was significantly poorer in the HD group. Temporal RNFL is preferentially thinned in HD patients, possibly implicating mitochondrial dysfunction as the temporal RNFL is reduced in the patients with some mitochondrial disorders, including Leber's hereditary optic neuropathy. The correlation between the decrease in macular volume and temporal RNFL, and increasing disease severity suggests that OCT may be a useful biomarker for disease progression in HD. Larger, longitudinal studies are required. PMID- 26233694 TI - Are We Following the Recommendations of the Clinical Guidelines? Another Point of View. PMID- 26233695 TI - Comparative study of image quality between axial T2-weighted BLADE and turbo spin echo MRI of the upper abdomen on 3.0 T. AB - OBJECTIVE: To compare image quality of turbo spin-echo (TSE) with BLADE [which is also named periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER)] on magnetic resonance imaging (MRI) for upper abdomen. MATERIALS AND METHODS: This study involved the retrospective evaluation of 103 patients (63 males, 40 females; age range 19-76 years; median age 53.8 years) who underwent 3.0 T MRI with both conventional TSE T2-weighted imaging (T2WI) and BLADE TSE T2WI. Two radiologists assessed respiratory motion, gastrointestinal peristalsis, and vascular pulsation artifacts, as well as the sharpness of the liver and pancreas edges. Scores for all magnetic resonance (MR) images were recorded. Wilcoxon's rank test was used to compare hierarchical data. Cohen's kappa coefficient was adopted to analyze interobserver consistency. RESULTS: Compared to TSE T2WI, BLADE TSE T2WI reduced all of the examined motion artifacts and increased the sharpness of the liver and pancreas edges (all P < 0.05). Medium to good interobserver consistency was obtained for evaluating these indicators. The scanning time of BLADE TSE T2WI was 4-16 s shorter than that of conventional TSE T2WI. CONCLUSION: Compared to TSE sequence, the BLADE technique can reduce the respiratory motion, gastrointestinal peristalsis, and vascular pulsation artifacts, while decreasing the scanning time and improving the anatomic detail and image quality. PMID- 26233696 TI - Low empathy is associated with problematic use of the Internet: Empirical evidence from China and Germany. AB - As empathy has not been investigated in the context of problematic use of the Internet, we conducted a study to test for a potential link. In samples from China (N=438) and Germany (N=202), two self-report measures for empathic behavior and one self-report measure for problematic Internet use (PIU) were administered in adolescents/students. Across both cultures lower empathy was associated with more PIU. The present study underlines the importance to take into account empathy related questionnaires for a better understanding of Internet overuse in the future. PMID- 26233697 TI - Implementing Effective Substance Abuse Treatments in General Medical Settings: Mapping the Research Terrain. AB - The National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute on Drug Abuse (NIDA), and Veterans Health Administration (VHA) share an interest in promoting high quality, rigorous health services research to improve the availability and utilization of evidence-based treatment for substance use disorders (SUD). Recent and continuing changes in the healthcare policy and funding environments prioritize the integration of evidence-based substance abuse treatments into primary care and general medical settings. This area is a prime candidate for implementation research. Recent and ongoing implementation projects funded by these agencies are reviewed. Research in five areas is highlighted: screening and brief intervention for risky drinking; screening and brief intervention for tobacco use; uptake of FDA-approved addiction pharmacotherapies; safe opioid prescribing; and disease management. Gaps in the portfolios, and priorities for future research, are described. PMID- 26233698 TI - Office-Based Opioid Treatment with Buprenorphine (OBOT-B): Statewide Implementation of the Massachusetts Collaborative Care Model in Community Health Centers. AB - We describe a Massachusetts Bureau of Substance Abuse Services' (BSAS) initiative to disseminate the office-based opioid treatment with buprenorphine (OBOT-B) Massachusetts Model from its development at Boston Medical Center (BMC) to its implementation at fourteen community health centers (CHCs) beginning in 2007. The Massachusetts Collaborative Care Model for the delivery of opioid agonist therapy with buprenorphine, in which nurses working with physicians play a central role in the evaluation and monitoring of patients, holds promise for the effective expansion of treatment for opioid use disorders. The training of and technical assistance for the OBOT nurses as well as a limited program assessment are described. Data spanning 6years (2007-2013) report patient demographics, prior treatment for opioid use disorders, history of overdose, housing, and employment. The expansion of OBOT to the fourteen CHCs increased the number of physicians who were "waivered" (i.e., enabling their prescribing of buprenorphine) by 375%, from 24 to 114, within 3years. During this period the annual admissions of OBOT patients to CHCs markedly increased. Dissemination of the Massachusetts Model of the Office-Based Opioid Treatment with Buprenorphine employing a collaborative care model with a central role for nursing enabled implementation of effective treatment for patients with an opioid use disorder at community health centers throughout Massachusetts while effectively engaging primary care physicians in this endeavor. PMID- 26233699 TI - Characteristics, management, and outcomes of repair of rectovaginal fistula among 1100 consecutive cases of female genital tract fistula in Ethiopia. AB - OBJECTIVE: To characterize the incidence, presentation, management, and outcomes of rectovaginal fistula (RVF) in Ethiopia. METHODS: In a retrospective study, demographic and clinical data were obtained for all women with genital tract fistulas admitted to the Barhirdar Hamlin Fistula Hospital, Ethiopia, for fistula repair surgery between January 2005 and October 2008. RESULTS: Of 1100 cases, 1057 were suitable for analysis. Vesicovaginal fistula (VVF) without RVF was present in 933 (88.3%) cases, combined VVF and RVF in 79 (7.5%), and isolated RVF in 45 (4.3%). Only 4 (0.4%) women had isolated RVFs that could be attributed to prolonged obstructed labor; the remaining 41 RVFs were due to trauma (including sexual trauma), iatrogenic causes, infection, perineal tears, or previous failed repairs. All RVFs were managed with a flap-splitting operative technique, without grafts or diverting colostomies. Overall, 120 (98.4%) of 122 RVFs repaired at the study hospital remained closed at discharge. Combined VVF and RVF was associated with a longer labor (P<0.001), more stillbirths (P=0.028), a larger and lower VVF (P<0.001 for both), and more vaginal scarring than was isolated VVF (P<0.001). CONCLUSION: An obstetric RVF represents a more severe injury process than does a VVF. RVFs rarely occur without a VVF if due to obstructed labor. However, they can be managed successfully without diverting colostomies or grafts. PMID- 26233700 TI - Leadless Cardiac Pacemakers: Pacing Paradigm Change. AB - Traditional transvenous approach for permanent cardiac pacing can be associated with significant acute and chronic complications related partly to either the insertion of transvenous lead or subcutaneous placement of pacemaker device. We summarize the current status of a novel self-contained leadless cardiac pacemaker in the first-in-human and subsequent series of feasibility studies in patients indicated for ventricular rate-responsive pacing (VVI). Using a femoral venous approach, the device is implanted at the right ventricular apical septum region. We describe the technical and clinical characterization of this innovative technology. Two different systems of leadless pacemakers are currently implanted to the patients. Up to now, the electrical parameters, such as pacing thresholds, sensing parameters, and pacing impedances, either improved or remained stable within the accepted range. In this chapter, we also discuss the potential benefit for the future, but in summary, all available data demonstrate the feasibility of leadless cardiac pacing. PMID- 26233701 TI - Accuracy of Proximal Tibial Bone Cut Using Anterior Border of Tibia as Bony Landmark in Total Knee Arthroplasty. AB - The purpose of our study was to evaluate the accuracy of the tibial bone cut in total knee arthroplasty using the anterior tibial border as a guide compared to using bony and soft tissue landmarks of the ankle joint. The extramedullary alignment guide was set parallel to a line connecting the proximal and distal one thirds of the anterior border of the tibia while the rotational direction of the distal end of the guide was adjusted to the anteroposterior axis of the proximal tibia. Significant differences were detected in the ideal coronal tibial component angles with improvements from 87.2% to 95.9%. The anterior tibial border was a reliable landmark in total knee arthroplasty in clinical practice, as shown by our previous computer simulation. PMID- 26233702 TI - Reduced SIRT1 expression correlates with enhanced oxidative stress in compensated and decompensated heart failure. AB - Sirtuin-1 (SIRT1) is a longevity factor in mammals initiating the cell survival mechanisms, and preventing ischemic injury in heart. In the etiopathogenesis of heart failure (HF), impairment in cardiomyocyte survival is a notable factor. Oxidative stress comprises a critical impact on cardiomyocyte lifespan in HF. The aim of the present study was to investigate SIRT1 expression in patients with compensated (cHF) and decompensated HF (dHF), and its correlation with oxidative stress. SIRT1 expression in peripheral leukocytes was examined using quantitative RT-PCR in 163 HF patients and 84 controls. Serum total oxidant status (TOS) and total antioxidant status (TAS) were measured via colorimetric assays, and oxidative stress index (OSI) was calculated. Lipid parameters were also determined by routine laboratory methods. SIRT1 mRNA expression was significantly downregulated in HF with more robust decrease in dHF (p=0.002, control vs cHF; p<0.001, control vs dHF). Markedly increased oxidative stress defined as elevated TOS, OSI and low TAS levels were detected in HF patients comparing with the controls (TAS; p=0.010, control vs cHF, p=0.045 control vs dHF, TOS; p=0.004 control vs cHF; p<0.001 control vs dHF, OSI; p<0.001 for both comparisons, respectively). With SIRT1 expression levels, TAS, TOS, OSI, and high density lipoprotein levels in cHF and dHF were determined correlated. SIRT1 expression were significantly reduced in both HF subtypes, particularly in dHF. SIRT1 expression was correlated with the oxidant levels and antioxidant capacity. Data suggest that SIRT1 may have a significant contribution in regulation of oxidant/antioxidant balance in HF etiology and compensation status. PMID- 26233705 TI - Transition thoughts. PMID- 26233706 TI - Clinical Relevance Commentary in Response to: The diagnostic accuracy of five tests for diagnosing partial-thickness tears of the supraspinatus tendon: A cohort study. PMID- 26233703 TI - Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells. AB - Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 uM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells. PMID- 26233707 TI - Establishing normative nasal nitric oxide values in infants. AB - INTRODUCTION: Primary ciliary dyskinesia (PCD), a disease of impaired respiratory cilia motility, is often difficult to diagnose. Recent studies show low nasal nitric oxide (nNO) is closely linked to PCD, allowing the use of nNO measurement for PCD assessments. Nasal NO cutoff values for PCD are stratified by age, given nNO levels normally increase with age. However, normative values for nNO have not been established for infants less than 1 year old. In this study, we aim to establish normative values for nNO in infants and determine their utility in guiding infant PCD assessment. METHODS AND RESULTS: We obtained 42 nNO values from infants less than 1 year old without a history of PCD or recurrent sinopulmonary disease. Using regression analysis, we estimated the mean age adjusted nNO values and established a 95% prediction interval (PI) for normal nNO. Using these findings, we were able to show 14 of 15 infant PCD patients had abnormally low nNO with values below the 95% PI. CONCLUSIONS: In this study we determined a regression model that best fits normative nNO values for infants less than 1 year old. This model identified the majority of PCD infants as having abnormally low nNO. These findings suggest nNO measurement can help guide PCD assessment in infants, and perhaps other pulmonary diseases with a link to low nNO. With early assessments, earlier clinical intervention may be possible to slow disease progression and help reduce pulmonary morbidity. PMID- 26233708 TI - The effects of anti-DNA topoisomerase II drugs, etoposide and ellipticine, are modified in root meristem cells of Allium cepa by MG132, an inhibitor of 26S proteasomes. AB - DNA topoisomerase II (Topo II), a highly specialized nuclear enzyme, resolves various entanglement problems concerning DNA that arise during chromatin remodeling, transcription, S-phase replication, meiotic recombination, chromosome condensation and segregation during mitosis. The genotoxic effects of two Topo II inhibitors known as potent anti-cancer drugs, etoposide (ETO) and ellipticine (EPC), were assayed in root apical meristem cells of Allium cepa. Despite various types of molecular interactions between these drugs and DNA-Topo II complexes at the chromatin level, which have a profound negative impact on the genome integrity (production of double-strand breaks, chromosomal bridges and constrictions, lagging fragments of chromosomes and their uneven segregation to daughter cell nuclei), most of the elicited changes were apparently similar, regarding both their intensity and time characteristics. No essential changes between ETO- and EPC-treated onion roots were noticed in the frequency of G1-, S , G2-and M-phase cells, nuclear morphology, chromosome structures, tubulin microtubule systems, extended distribution of mitosis-specific phosphorylation sites of histone H3, and the induction of apoptosis-like programmed cell death (AL-PCD). However, the important difference between the effects induced by the ETO and EPC concerns their catalytic activities in the presence of MG132 (proteasome inhibitor engaged in Topo II-mediated formation of cleavage complexes) and relates to the time-variable changes in chromosomal aberrations and AL-PCD rates. This result implies that proteasome-dependent mechanisms may contribute to the course of physiological effects generated by DNA lesions under conditions that affect the ability of plant cells to resolve topological problems that associated with the nuclear metabolic activities. PMID- 26233709 TI - Role of phytosterols in drought stress tolerance in rice. AB - Phytosterols are integral components of the membrane lipid bilayer in plants. They regulate membrane fluidity to influence its properties, functions and structure. An increase in accumulation of phytosterols namely campesterol, stigmasterol and beta-sitosterol was observed in rice as seedlings matured. The levels of the major phytosterol, beta-sitosterol in N22 (drought tolerant) rice seedlings was found to increase proportionately with severity of drought stress. Its levels were 145, 216, 345 and 364 MUg/g FW after subjecting to water stress for 3, 6, 9 and 12 days respectively, while for IR64 (drought susceptible), levels were 137, 198, 227 and 287 MUg/g FW at the same stages. Phytosterols were also found to increase with maturity as observed at 30, 50 and 75 days after planting. The activity of HMG-CoA reductase (EC 1.1.1.34) which is considered to be a key limiting enzyme in the biosynthesis of phytosterols was 0.55, 0.56, 0.78 and 0.85 MUmol/min/L at 3, 6, 9 and 12 days of water stress in N22 and 0.31, 0.50, 0.54 and 0.65 MUmol/min/L in case of IR64 respectively. The elevation in the levels of phytosterols as well as the activity of HMG-CoA reductase during drought stress indicates the role of phytosterols in providing tolerance to stress. PMID- 26233704 TI - Antioxidant responses and cellular adjustments to oxidative stress. AB - Redox biological reactions are now accepted to bear the Janus faceted feature of promoting both physiological signaling responses and pathophysiological cues. Endogenous antioxidant molecules participate in both scenarios. This review focuses on the role of crucial cellular nucleophiles, such as glutathione, and their capacity to interact with oxidants and to establish networks with other critical enzymes such as peroxiredoxins. We discuss the importance of the Nrf2 Keap1 pathway as an example of a transcriptional antioxidant response and we summarize transcriptional routes related to redox activation. As examples of pathophysiological cellular and tissular settings where antioxidant responses are major players we highlight endoplasmic reticulum stress and ischemia reperfusion. Topologically confined redox-mediated post-translational modifications of thiols are considered important molecular mechanisms mediating many antioxidant responses, whereas redox-sensitive microRNAs have emerged as key players in the posttranscriptional regulation of redox-mediated gene expression. Understanding such mechanisms may provide the basis for antioxidant-based therapeutic interventions in redox-related diseases. PMID- 26233710 TI - Protective effect of UV-A radiation during acclimation of the photosynthetic apparatus to UV-B treatment. AB - We examined the acclimation response of the photosynthetic apparatus of barley (Hordeum vulgare L.) to a combination of UV-A and UV-B radiation (UVAB) and to UV B radiation alone. Our aim was to evaluate whether UV-A radiation prevents UV-B induced damage to the photosynthetic apparatus and whether UV-A pre-acclimation is required to mitigate the negative influence of UV-B radiation. Barley plants were grown from seeds under low photosynthetically active radiation (50 MUmol m( 2) s(-1)) either in the absence or presence of UV-A radiation (UVA- and UVA+ plants, respectively). After 8 days of development, plants were exposed simultaneously to UV-A and UV-B radiation for the next 6 days. Additionally, UVA- plants were exposed to UV-B radiation alone. The UVA+ plants had a higher CO2 assimilation rate near the light-saturation region (A(N)) and a higher content of both total chlorophylls (Chls) and total carotenoids than the UVA- plants. Chls content, A(N), the potential quantum yield of photosystem II (PSII) photochemistry (F(V)/F(M)), the capacity of light-induced thermal energy dissipation and the efficiency of excitation energy transfer within PSII remained the same or even increased in both UVA+ and UVA- plants after UVAB treatment. On the contrary, exposure of UVA- plants to UV-B radiation itself led to a reduction in all these characteristics. We revealed that the presence of UV-A radiation during UVAB treatment not only mitigated but completely eliminated the negative effect of UV-B radiation on the functioning of the photosynthetic apparatus and that UV-A pre-acclimation was not crucial for development of this UV-A-induced resistance against UV-B irradiation. PMID- 26233711 TI - Phyto mediated biogenic synthesis of silver nanoparticles using leaf extract of Andrographis echioides and its bio-efficacy on anticancer and antibacterial activities. AB - The present study reveals the efficiency of Andrographis echioides for green synthesis of silver nanoparticles (AgNPs). The leaf aqueous extract of A. echioides was used for the synthesis of AgNPs and they were characterized by UV visible, High Resonance Scanning Electron Microscope (HRSEM), Energy-Dispersive X ray Spectroscopy (EDX), Atomic Force Microscope (AFM), X-ray Diffraction (XRD) and Fourier Transform Infrared Spectroscopy (FTIR) analysis. The toxicity of AgNPs was evaluated by using MTT assay. Our present study showed that biosynthesized AgNPs inhibited proliferation of human breast adenocarcinoma cancer cell line (MCF-7) with 31.5 MUg/mL at 24h incubation. Results suggest that AgNPs may exert its anticancer activity on MCF-7 cell line by suppressing its growth. The silver nanoparticles was studied against Gram positive and Gram negative bacteria. The highest antibacterial activity was found against Escherichia coli (28 mm) and Staphylococcus aureus (23 mm) respectively. PMID- 26233712 TI - The Forced Surrender of Infants Born to Unwed Mothers in Southern Italy. A Case Study of Late Nineteenth Century Practices in the Town of Forio d'Ischia. AB - For many centuries, unwed mothers in southern Italy were forced to surrender their infants because of a number of social, religious, economic, and political pressures. This study focuses on the policies and practices that were in place in southern Italy regarding illegitimate infants in the late nineteenth century. A detailed analysis of the policies and practices present in the town of Forio d'Ischia during the 20-year period 1880-1899 is also presented. During these two decades, there were 37 illegitimate live births representing 0.70% of the 5249 live births recorded in this town. Although small in number, these illegitimate births, referred to as spuri in Italian, from the Latin spurius, meaning bastard, were managed by standard predetermined procedures. These included anonymity for the parents, the transfer of such infants to an official town receiver of foundlings, and their transport to Naples' orphanage, the Real Casa Santa dell'Annunziata. This orphanage maintained fairly detailed records about the children who were delivered to it. After a few days at the orphanage, infants were often entrusted to the care of external wet nurses, preferably outside of Naples. This was done in the belief that infant survival was better assured in more rural environments. The case of an illegitimate infant, Antonino Spinalbese, is presented in detail. Born on 14 February 1882 in the town of Forio d'Ischia, he was brought to the orphanage 4 days later. Following a two-day stay at the orphanage, he was entrusted to an external wet nurse, Michele Mondella, and her husband, Ciro Fiscale di Felice, a mariner in the town of Torre del Greco. The available evidence indicates that Antonino Spinalbese became a mariner like his stepfather. As a crew member of the passenger ship, Vulcano, he made three trips from Naples to New York City in 1922 and 1923. PMID- 26233713 TI - The Role of Condom Use Self-Efficacy on Intended and Actual Condom Use Among University Students in Ghana. AB - Little attention has been paid to the dimensions that help to predict and understand condom use among university students within an African context. A cross-sectional study involving 518 university students in Accra, Ghana was conducted to determine how the Condom Use self-Efficacy Scale-Ghana (CUSES-G) can predict both actual condom use and future condom use. Of all the participants, 84% were sexually active but less than half of the sample (48%) reported to have used condom during their last sexual intercourse. A hierarchical regression analysis showed that components of the Condom Use Self-Efficacy Scale (CUESE-G) such as appropriation, assertiveness, pleasure and intoxication, and STDs predicted condom use and condom use intentions. Behavioural change campaigns targeting university students should encourage condom use self-efficacy, as this would strengthen condom use, which is economically cheap and practically effective means of preventing STIs including HIV. PMID- 26233714 TI - Long-term follow-up of subcutaneous ICD systems in patients with hypertrophic cardiomyopathy: a single-center experience. AB - BACKGROUND: The totally subcutaneous implantable defibrillator (S-ICD) was introduced as a new alternative to conventional implantable defibrillators and is employed worldwide. This system is especially attractive for young patients. However, in patients with hypertrophic cardiomyopathy (HCM), T-wave oversensing may occur. To address the question whether the S-ICD system is suitable for HCM patients, the data of a standard of care prospective single-center S-ICD registry were evaluated. METHODS AND RESULTS: In the present study, 18 HCM patients who received an S-ICD for primary (n = 14) or secondary prevention (n = 4) and a minimal follow-up duration of 6 months were analyzed. The mean follow-up duration was 31.7 +/- 15.4 months. Ventricular arrhythmias were adequately detected in 4 patients (22%). In 7 patients (39%), T-wave oversensing was noticed and led to at least one inappropriate shock in 4 patients (22%). Further adverse events included surgical revision due to a mobile sensing electrode and resulting noise detection as well as one case of early battery failure requiring pulse generator change. CONCLUSION: Patients with HCM and S-ICD systems have an increased risk of T-wave oversensing and inappropriate shock delivery. Thorough monitoring as well as exercise tests may help to improve device settings and thereby prevent T-wave oversensing. PMID- 26233715 TI - Clinical outcomes of three different types of hardware for the treatment of mandibular angle fractures: a comparative retrospective study. AB - A retrospective study was conducted to compare the clinical outcomes of three different types of hardware that are used in mandibular angle fracture fixation. Thirty patients were selected from the hospital database. The patients were categorized into the following groups: group A, in which a single 2.0-mm locking miniplate was used; group B, in which a single rigid 2.3-mm plate was used; and group C, in which a single lag screw was inserted. All patients were followed for 6 months. With regard to intraoperative variables, significant differences were found among the groups in the duration of surgery and cost. Group C had the shortest surgical time, followed by group A and then group B. Two patients, one in group A and one in group B, suffered an occlusal discrepancy after surgery. Of the group A patients, two exhibited wound dehiscence and one had an infection. One patient in group B had an exposed plate. Sensory nerve involvement was noted in three group C patients and one group B patient. The lag screw was associated with the fewest complications and exhibited all of the advantages of plating systems in the treatment of angle fracture. The lag screw involved the least hardware and a short operating time, however the differences were not significant. PMID- 26233716 TI - Carnosine markedly ameliorates H9N2 swine influenza virus-induced acute lung injury. AB - Oxidative stress injury is an important pathogenesis of influenza virus in critically ill patients. The present study investigated the efficacy of carnosine, an antioxidant and free radical scavenger, on a model of acute lung injury (ALI) induced by H9N2 swine influenza virus. Female specific-pathogen-free BALB/c mice were randomized into four groups and treated as follows: (1) H9N2 group, (2) mock control group, (3) H9N2+carnosine group and (4) carnosine control group. The H9N2 group mice were inoculated intranasally with A/Swine/Hebei/012/2008/ (H9N2) virus (100 MUl) in allantoic fluid (AF), whilst mock-infected animals were intranasally inoculated with non-infectious AF. Carnosine [10 mg (kg body mass)- 1] was administered orally (100 MUl) for 7 days consecutively. The survival rate, lung water content, TNF-alpha and IL-1beta levels, lung histopathology, myeloperoxidase (MPO) activity, and Toll-like receptor (TLR)-4 levels were determined at 2, 4, 6, 8 and 14 days after inoculation. Carnosine treatment effectively decreased the mortality (43 versus 75 %, P < 0.05), significantly ameliorated pathological lesions in lungs and decreased the lung wet/dry mass ratio (P < 0.05). It also inhibited MPO activity, suppressed TNF-alpha and IL-1beta release, decreased the H9N2 viral titre, and markedly inhibited levels of TLR-4 mRNA and protein in the lungs of infected mice (P < 0.05), which supported the use of carnosine for managing severe influenza cases. PMID- 26233717 TI - Bilateral chronic compartment syndrome of the thenar muscles: A case report. AB - This case report features a patient with chronic bilateral compartment syndrome of the thenar muscles, which had appeared spontaneously 8 years earlier. The condition was progressive and symptoms recently had become worse. Pressure measurements were performed three times to establish the diagnosis: before, immediately after and 10 minutes after hand exertion. Pain relief was achieved by performing a fasciotomy of the right thenar compartment. PMID- 26233718 TI - Integrated CLL Scoring System, a New and Simple Index to Predict Time to Treatment and Overall Survival in Patients With Chronic Lymphocytic Leukemia. AB - INTRODUCTION: Several prognostic factors have been identified to predict the outcome of patients with chronic lymphocytic leukemia (CLL), but only a few studies analyzed more markers together. PATIENTS AND METHODS: Taking advantage of a population of 608 patients, we identified the strongest prognostic markers of survival and, subsequently, in a cohort of 212 patients we integrated data of cytogenetic lesions, IGHV mutational status, and CD38 expression in a new and easy scoring system we called the integrated CLL scoring system (ICSS). ICSS defines 3 groups of risk: (1) low risk (patients with 13q(-) or normal fluorescence in-situ hybridization analysis results, mutated IGHV, and CD38) (2) high risk (all 11q(-) or 17p(-) patients and/or all unmutated IGHV and CD38(+) patients); and (3) intermediate risk (all remaining patients). RESULTS: Using only these 3 already available prognostic factors, we were able to properly redefine patients and better predict the clinical course of the disease. CONCLUSION: ICSS could become a useful tool for CLL patients' management. PMID- 26233721 TI - Association of the IRF5 rs2070197 polymorphism with systemic lupus erythematosus: a meta-analysis. AB - The aim of this study was to explore whether the interferon regulatory factor 5 (IRF5) gene rs2070197 polymorphism was associated with systemic lupus erythematosus (SLE) in multiple ethic populations. A meta-analysis was conducted on the C allele of the IRF5 rs2070197 polymorphism. A total of 7 published case control studies with 12 comparisons involving 8171 SLE patients and 8904 controls were available for this meta-analysis. This meta-analysis demonstrated the IRF5 rs2070197 polymorphism conferred susceptibility to SLE in all subjects (odds ratio (OR) = 2.128, 95 % confidence interval (CI): 1.856-2.441, P < 0.001) without inter-study heterogeneity. The IRF5 rs2070197 polymorphism was identified as risk factors for SLE in Caucasian populations (OR 1.82, 95 % CI 1.70-1.96), but it had no effects (monomorphic) in Asians. Large-scale multicenter epidemiological studies in selected populations with other risk factors were urgently required. PMID- 26233720 TI - Enthesitis-related arthritis. AB - Juvenile idiopathic arthritis (JIA) is the most common chronic arthritis of childhood. Currently, it is characterized by seven categories. The enthesitis related arthritis (ERA) category usually affects boys older than 6 years and presents with lower limb asymmetrical arthritis associated with enthesitis. Later, these children can develop inflammatory lumbosacral pain (IBP). These children are at risk of developing acute anterior uveitis. A recently devised disease activity index, Juvenile Spondyloarthropathy Disease Activity Index (JSpADA), has been validated in retrospective cohorts. The corner stone of treatment is NSAIDs, local corticosteroid injections, and exercise. Methotrexate and sulfasalazine can be used for peripheral arthritis while anti-tumor necrosis factor (TNF) agents are sometimes used to treat refractory enthesitis and sacroiliitis. Almost two third of patients with ERA have persistent disease and often have impairments in their quality of life. The presence of hip or ankle arthritis and a family history of spondyloarthropathy or polyarticular joint involvement at onset are associated with poorer prognosis. PMID- 26233722 TI - Hyperferritinemic syndrome: Still's disease and catastrophic antiphospholipid syndrome triggered by fulminant Chikungunya infection: a case report of two patients. AB - There are four medical conditions characterized by high levels of ferritin, the macrophage activation syndrome (MAS), adult onset Still' s disease (AOSD), catastrophic antiphospholipid syndrome (CAPS), and septic shock, that share similar clinical and laboratory features, suggesting a common pathogenic mechanism. This common syndrome entity is termed "the hyperferritinemic syndrome." Here, we describe two different cases of hyperferritinemic syndrome triggered by Chikungunya fever virus infection: a 21-year-old female with SLE and a 32-year-old male patient who developed AOSD after the coinfection of dengue and Chikungunya viruses. PMID- 26233723 TI - Policies, Guidelines and Consensus Statements: Pharmacologic Management of Type 2 Diabetes-2015 Interim Update. PMID- 26233724 TI - New Insulins and New Aspects in Insulin Delivery. AB - The major abnormality in both type 1 and type 2 diabetes is insulin deficiency. The methods of replacing insulin have improved throughout the decades, but hypoglycemia is still the limiting factor for many individuals with diabetes, and it prevents them from achieving ideal glycemic targets. New insulin and newer delivery systems are being developed that can improve some of the limitations of current insulins or make the delivery of insulins more acceptable for some patients. Extending the duration of action of basal insulins and shortening the peak of fast-acting insulins may have advantages for individuals with diabetes. Different delivery systems may make insulin more acceptable to patients and may have other advantages, which may aid in attaining better glycemic control. PMID- 26233725 TI - The development of non-toxic ionic-crosslinked chitosan-based microspheres as carriers for the controlled release of silk sericin. AB - Silk sericin is recently shown to possess various biological activities for biomedical applications. While various sericin carriers were developed for drug delivery system, very few researches considered sericin as a bioactive molecule itself. In this study, sericin incorporated in the chitosan-based microspheres was introduced as a bioactive molecule and bioactive carrier at the same time. The chitosan/sericin (CH/SS) microspheres at different composition (80/20, 70/30, 60/40, and 50/50) were successfully fabricated using anhydroustri-polyphosphate (TPP) as a polyanionic crosslinker. The microspheres with an average size of 1-4 MUm and narrow size distribution were obtained. From FT-IR spectra, the presence of both chitosan and sericin in the microspheres confirmed the occurrence of ionic interaction that crosslink them within the microspheres. We also found that the CH/SS microspheres prepared at 50/50 could encapsulate sericin at the highest percentage (37.28%) and release sericin in the most sustained behavior, possibly due to the strong ionic interaction of the positively charged chitosan and the negatively charged sericin. On the other hand, the composition of CH/SS had no effect on the degradation rate of microspheres. All microspheres continuously degraded and remained around 20% after 14 days of enzymatic degradation. This explained that the ionic crosslinkings between chitosan and sericin could be demolished by the enzyme and hydrolysis. Furthermore, we have verified that all CH/SS microspheres at any concentrations showed non-toxicity to L929 mouse fibroblast cells. Therefore, we suggested that the non-toxic ionic-crosslinked CH/SS microspheres could be incorporated in wound dressing material to achieve the sustained release of sericin for accelerated wound healing. PMID- 26233726 TI - NMR-Based Metabolic Profiling Reveals Neurochemical Alterations in the Brain of Rats Treated with Sorafenib. AB - Sorafenib, an active multi-kinase inhibitor, has been widely used as a chemotherapy drug to treat advanced clear-cell renal cell carcinoma patients. In spite of the relative safety, sorafenib has been shown to exert a negative impact on cognitive functioning in cancer patients, specifically on learning and memory; however, the underlying mechanism remains unclear. In this study, an NMR-based metabolomics approach was applied to investigate the neurochemical effects of sorafenib in rats. Male rats were once daily administrated with 120 mg/kg sorafenib by gavage for 3, 7, and 28 days, respectively. NMR-based metabolomics coupled with histopathology examinations for hippocampus, prefrontal cortex (PFC), and striatum were performed. The (1)H NMR spectra data were analyzed by using multivariate pattern recognition techniques to show the time-dependent biochemical variations induced by sorafenib. Excellent separation was obtained and distinguishing metabolites were observed between sorafenib-treated and control rats. A total of 36 differential metabolites in hippocampus of rats treated with sorafenib were identified, some of which were significantly changed. Furthermore, these modified metabolites mainly reflected the disturbances in neurotransmitters, energy metabolism, membrane, and amino acids. However, only a few metabolites in PFC and striatum were altered by sorafenib. Additionally, no apparent histological changes in these three brain regions were observed in sorafenib-treated rats. Together, our findings demonstrate the disturbed metabonomics pathways, especially, in hippocampus, which may underlie the sorafenib-induced cognitive deficits in patients. This work also shows the advantage of NMR-based metabolomics over traditional approach on the study of biochemical effects of drugs. PMID- 26233729 TI - Embodying animals: Body-part compatibility in mammalian, reptile and aves classes. AB - The purpose of the present study was to determine how humans code homologous body parts of nonhuman mammal, reptilian, and aves animals with respect to the representation of the human body. To this end, participants completed body-part compatibility tasks in which responses were executed to colored targets that were superimposed over the upper limbs, lower limbs or head of different animals in different postures. In Experiment 1, the images were of meekats and lizards in bipedal and quadrupedal postures. In Experiment 2, the images were of a human, a penguin, and an owl in a bipedal posture with upper limbs stretched out. Overall, the results revealed that the limbs of nonhuman mammals (meerkat and human) were consistently mapped onto the homologous human body parts only when the mammals were in a bipedal posture. Specifically, body-part compatibility effects emerged for the human and the meerkat in a bipedal posture, but not the meerkat in the quadrupedal posture. Further, consistent body-part compatibility effects were not observed for the lizard in the quadrupedal posture or for the lizard, penguin, or owl in a bipedal posture. The pattern of results suggests that the human bipedal body representation may distinguish taxonomical classes and is most highly engaged when viewing homologous body parts of mammalian animals. PMID- 26233727 TI - A Novel Compound ITC-3 Activates the Nrf2 Signaling and Provides Neuroprotection in Parkinson's Disease Models. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder accompanied by a selective loss of the dopamine(DA)ergic neurons residing in the substantia nigra. There is ample evidence that neuroinflammation and oxidative stress are involved in the pathogenesis of PD. In the present study, we aimed at protecting the DAergic neurons by suppressing these cellular events and generated a novel synthetic isothiocyanate ITC-3. The compound led to elevation of nuclear and total levels of the transcription factor Nrf2 and interacted with its binding protein Keap1 with high affinity, suggesting Nrf2 activation. ITC-3 was able to suppress production of the proinflammatory mediators in lipopolysaccharide activated BV-2 microglial cells. It also increased mRNA and protein levels of the Nrf2-dependent antioxidant enzymes NAD(P)H quinone oxidoreductase, heme oxygenase 1, and glutamylcysteine ligase in both BV-2 and DAergic neuronal CATH.a cells. The compound protected the DAergic cells against oxidative stress. In vivo, ITC-3 attenuated the loss of tyrosine hydroxylase-immunopositive nigrostriatal DAergic neurons, suppressed microglial activation, and abolished PD-associated motor deficits in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-elicited animal model of PD. Taken together, ITC-3 may be useful toward development of neuroprotective therapy for PD. PMID- 26233728 TI - Procedural Performance Benefits after Excitotoxic Hippocampal Lesions in the Rat Sequential Reaction Time Task. AB - It is widely agreed upon that hippocampal function is linked to episodic-like and spatial memory across various species, for example, rodents. However, the interplay between hippocampal function and other types of learning and memory, like procedural stimulus-response or sequential learning, is less clear. Recently (Eckart et al. in Hippocampus 22:1202-1214, 2012), we showed that excitotoxic hippocampal lesions, which mainly affected its dorsal part, led not only to the expected deficits in a spatial and episodic-like memory task, namely the object place recognition test, but also to substantial improvements in terms of speed and accuracy in a rat adaption of the human sequential reaction time task (SRTT). The design of that experiment, however, which included fixed test durations per training day, led to the fact that lesioned animals gained more instrumental experience, which may partly have accounted for their enhanced performance. In order to rule out such a potential confound, we performed the present experiment on rats with similar ibotenic lesions aiming at the dorsal hippocampus, but we now kept the amount of correct instrumental responses and reinforcements on the same level as in controls. Our data revealed that lesioned animals were still able to complete the SRTT in a substantially smaller amount of time, when compared to control and sham-operated animals, although no differences were observable in terms of speed or accuracy. Also, the animals with lesions showed impaired extinction in a subsequent test where rewards were omitted. The former effect can primarily be attributed to shorter post-reinforcement pauses in the lesioned animals, and the possible mechanisms of this and the extinction effect will be addressed in the discussion. PMID- 26233730 TI - Post-learning stress enhances long-term memory and differentially influences memory in females depending on menstrual stage. AB - Most work has shown that post-learning stress enhances long-term memory; however, there have been recent inconsistencies in this literature. The purpose of the present study was to examine further the effects of post-learning stress on long term memory and to explore any sex differences that may exist. Male and female participants learned a list of 42 words that varied in emotional valence and arousal level. Following encoding, participants completed a free recall assessment and then submerged their hand into a bath of ice cold (stress) or lukewarm (no stress) water for 3 min. The next day, participants were given free recall and recognition tests. Stressed participants recalled more words than non stressed participants 24h after learning. Stress also enhanced female participants' recall of arousing words when they were in the follicular, but not luteal, phase. These findings replicate previous work examining post-learning stress effects on memory and implicate the involvement of sex-related hormones in such effects. PMID- 26233731 TI - In vitro effects of Eucalyptus staigeriana nanoemulsion on Haemonchus contortus and toxicity in rodents. AB - Strategies for controlling gastrointestinal nematodes have been developed based on the use of numerous alternative methods, including the use of phytotherapy. New formulations of essential oils with anthelmintic activity have been proposed as a means to optimize their biological effects. Thus, the objective of this study was to formulate a nanoemulsion to optimize the nematicide effect of Eucalyptus staigeriana essential oil (EsEO). Initially, physico-chemical analyses were performed to verify the stability of the E. staigeriana nanoemulsion (EsNano). In vitro tests were conducted to evaluate the ovicidal and larvicidal activities of both EsNano and EsEO against Haemonchus contortus, and toxicology tests were then performed on rodents. The EsEO content in the nanoemulsion was 36.4% (v/v), and the mean particle size was 274.3 nm. EsNano and EsEO inhibited larval hatching by 99% and 96.3% at 1 and 2mg/ml concentrations, respectively, and inhibited larval development by 96.3% and 97.3% at 8 mg/ml concentrations. The acute toxicity test revealed that the EsNano and EsEO doses required to kill 50% of the mice (LD50) were 1,603.9 and 3,495.9 mg/ml, respectively. EsNano did not alter the hematological parameters in the rats after treatment. PMID- 26233732 TI - Efficacy of Febuxostat for Slowing the GFR Decline in Patients With CKD and Asymptomatic Hyperuricemia: A 6-Month, Double-Blind, Randomized, Placebo Controlled Trial. AB - BACKGROUND: Hyperuricemia is a putative risk factor for the progression of chronic kidney disease (CKD). We hypothesized that control of asymptomatic hyperuricemia may slow disease progression in CKD. STUDY DESIGN: This was a single-center, double-blind, randomized, parallel-group, placebo-controlled study. SETTING & PARTICIPANTS: Eligible participants were adults from Eastern India aged 18 to 65 years with CKD stages 3 and 4, with asymptomatic hyperuricemia. INTERVENTION: The intervention group received febuxostat, 40mg, once daily for 6 months, while the placebo group received placebo; both groups were followed up for 6 months. OUTCOMES: The primary outcome was the proportion of patients showing a >10% decline in estimated glomerular filtration rate (eGFR) from baseline in the febuxostat and placebo groups. Secondary outcomes included changes in eGFRs in the 2 groups from baseline and at the end of the study period. RESULTS: 45 patients in the febuxostat group and 48 in the placebo group were analyzed. Mean eGFR in the febuxostat group showed a nonsignificant increase from 31.5+/-13.6 (SD) to 34.7+/-18.1mL/min/1.73m(2) at 6 months. With placebo, mean eGFR decreased from a baseline of 32.6+/-11.6 to 28.2+/-11.5mL/min/1.73m(2) (P=0.003). The difference between groups was 6.5 (95% CI, 0.08-12.81) mL/min/1.73m(2) at 6 months (P=0.05). 17 of 45 (38%) participants in the febuxostat group had a >10% decline in eGFR over baseline compared with 26 of 48 (54%) from the placebo group (P<0.004). LIMITATIONS: Limitations of this study included small numbers of patients and short follow-up, and ~10% of the randomly assigned population dropped out prior to completion. CONCLUSIONS: Febuxostat slowed the decline in eGFR in CKD stages 3 and 4 compared to placebo. PMID- 26233733 TI - Factors associated with women's entry into the sex industry: findings from interviews conducted with female sex workers in Chinese detention centres. AB - BACKGROUND: To date, limited research has been conducted to identify the personal and contextual factors that contribute to women's entry into the sex industry in China. METHODS: The reasons for and factors associated with voluntary entry into the sex industry were explored through in-depth interviews conducted with 38 Chinese women who were held in detention centres for selling sex. RESULTS: Women's personal accounts reveal that entry into sex work is influenced by life aspirations, family responsibilities and social connections, which facilitate mobility to a new urban environment in which they encounter opportunities and challenges. Findings highlight the complex interactions between individual and contextual factors in relation to women's entry into sex work. CONCLUSIONS: In a rapidly developing country such as China, entry into sex work may appeal to women of low socioeconomic status, particularly young women who have recently migrated to urban areas. For members of this mobile and relatively disadvantaged population, comprehensive social services and support are urgently needed. PMID- 26233734 TI - Evaluating exposure of pedestrians to airborne contaminants associated with non potable water use for pavement cleaning. AB - Climate change and increasing demography press local authorities to look after affordable water resources and replacement of drinking water for city necessities like street and pavement cleaning by more available raw water. Though, the substitution of drinking by non-drinking resources demands the evaluation of sanitary hazards. This article aims therefore to evaluate the contribution of cleaning water to the overall exposure of city dwellers in case of wet pavement cleaning using crossed physical, chemical and biological approaches. The result of tracer experiments with fluorescein show that liquid water content of the cleaning aerosol produced is about 0.24 g m(-3), rending possible a fast estimation of exposure levels. In situ analysis of the aerosol particles indicates a significant increase in particle number concentration and particle diameter, though without change in particle composition. The conventional bacterial analysis using total coliforms as tracer suggests that an important part of the contamination is issued from the pavement. The qPCR results show a more than 20-fold increase of background genome concentration for Escherichia coli and 10-fold increase for Enterococcus but a negligible contribution of the cleaning water. The fluorescence analysis of the cleaning aerosol confirms the above findings identifying pavement surface as the major contributor to aerosol organic load. The physical, chemical and microbiological approaches used make it possible to describe accurately the cleaning bioaerosol and to identify the existence of significantly higher levels of all parameters studied during the wet pavement cleaning. Though, the low level of contamination and the very short time of passage of pedestrian in the zone do not suggest a significant risk for the city dwellers. As the cleaning workers remain much longer in the impacted area, more attention should be paid to their chronic exposure. PMID- 26233735 TI - Formaldehyde exposure in gross anatomy laboratory of Suranaree University of Technology: a comparison of area and personal sampling. AB - Cadavers are usually preserved by embalming solution which is composed of formaldehyde (FA), phenol, and glycerol. Therefore, medical students and instructors have a higher risk of exposure to FA inhalation from cadavers during dissection. Therefore, the objective of this study was to evaluate the FA exposure in indoor air and breathing zone of medical students and instructors during dissection classes in order to investigate the relationship between them. The indoor air and personal air samples in breathing zone were collected three times during anatomy dissection classes (in January, August, and October of 2014) with sorbent tubes, which were analyzed by high-performance liquid chromatography (HPLC). The air cleaner machines were determined by weight measurement. Pulmonary function tests and irritation effects were also investigated. The mean of FA concentrations ranged from 0.117 to 0.415 ppm in the indoor air and from 0.126 to 1.176 ppm in the breathing zone of students and instructors. All the personal exposure data obtained exceeded the threshold limit of NIOSH and WHO agencies. The air cleaner machines were not significant difference. The pulmonary function of instructors showed a decrease during attention of classes and statistically significant decreasing in the instructors more than those of the students. Clinical symptoms that were observed in nose and eyes were irritations with general fatigue. We suggested that the modified exhaust ventilation and a locally ventilated dissection work table were considered for reducing FA levels in the gross anatomy dissection room. PMID- 26233737 TI - The energetic characterization of pineapple crown leaves. AB - Energetic characterization of biomass allows for assessing its energy potential for application in different conversion processes into energy. The objective of this study is to physicochemically characterize pineapple crown leaves (PC) for their application in energy conversion processes. PC was characterized according to ASTM E871-82, E1755-01, and E873-82 for determination of moisture, ash, and volatile matter, respectively; the fixed carbon was calculated by difference. Higher heating value was determined by ASTM E711-87 and ash chemical composition was determined by XRF. The thermogravimetric and FTIR analyses were performed to evaluate the thermal decomposition and identify the main functional groups of biomass. PC has potential for application in thermochemical processes, showing high volatile matter (89.5%), bulk density (420.8 kg/m(3)), and higher heating value (18.9 MJ/kg). The results show its energy potential justifying application of this agricultural waste into energy conversion processes, implementing sustainability in the production, and reducing the environmental liabilities caused by its disposal. PMID- 26233736 TI - Heavy metals and polycyclic aromatic hydrocarbons in surface sediments of Karoon River, Khuzestan Province, Iran. AB - Karoon is the longest river in Iran and provides water for industries located along its banks, such as metal, petrochemical, and oil industries. It is also the source of drinking water for cities such as Ahwas, Abadan, and Khorramshahr. In this study, 34 and 18 surface sediment samples were collected and analyzed for heavy metals (Al, As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn) and polycyclic aromatic hydrocarbons (PAHs). The measured concentrations of heavy metals were compared with US EPA sediment quality guidelines, and the results showed that Cu concentration was above the threshold effect level (TEL) in 65.67% of the samples and Hg concentration was above the effect range median (ERM) in some samples. The results revealed that Hg was severely enriched (5 < enrichment factor < 20) and classified in very high ecological risk index category. It is the major metallic contaminant in the study area. The total PAH concentrations ranged from 11.54 117,730 MUg/kg, with the mean value of 7034.55 MUg/kg dominated by lower molecular weight (LMW) PAHs. The total potentially carcinogenic PAHs (?cPAHs) in sediment samples ranged from 2.09 to 31,930 MUg/kg, indicating high carcinogenic potential of sediments in the study area. The total toxic equivalent (TEQ) values ranged from 1.06 to 7228.7 MUg/kg. Maximum TEQ occurred in Abadan oil refinery station followed by Khorramshahr soap factory and Abadan petrochemical complex. Principal component analysis and cluster analysis also revealed the relationships between the studied parameters and identified their probable sources. PMID- 26233738 TI - IgE antibodies and urinary trimethylarsine oxide accounted for 1-7% population attributable risks for eczema in adults: USA NHANES 2005-2006. AB - Population attributable risks from serum IgE and dust miteallergen concentrations and environmental chemicals for eczema are unclear. Therefore, it was aimed to examine serum IgE and allergen concentrations and environmental chemicals for eczema in adults and to calculate population attributable risks in a national and population-based setting. Data retrieved from the National Health and Nutrition Examination Survey, 2005-2006, was analyzed. Information on demographics and self reported ever eczema was obtained by household interview. Bloods and urines (sub sample) were also collected during the interview. Adults aged 20-85 were included. Statistical analyses were using chi-square test, t test, survey weighted logistic regression modeling, and population attributable risk (PAR) estimation. Of all the included American adults (n = 4979), 310 (6.2%) reported ever eczema. Moreover, more eczema cases were observed in female adults but fewer cases in people born in Mexico. There were no significant associations observed between commonly known biomarkers (including vitamin D) and eczema or between dust mite allergens and eczema. Serum D. Farinae (PAR 1.0%), D. Pteronyssinus (PAR 1.1%), cat (PAR 1.8%), dog (PAR 1.6%), and muse (PAR 3.2%) IgE antibodies were associated with eczema. Adults with ever eczema were found to have higher levels of urinary trimethylarsine oxide concentrations (PAR 7.0%) but not other speciated arsenic concentrations. There were no clear associations between other environmental chemicals including heavy metals, phthalates, phenols, parabens, pesticides, nitrate, perchlorate, polycyclic hydrocarbons and eczema as well. Elimination of environmental risks might help delay or stop eczema up to 7% in the adult population. PMID- 26233739 TI - Protective effect of Crocin against zearalenone-induced oxidative stress in liver and kidney of Balb/c mice. AB - Zearalenone (ZEN) is a mycotoxin from Fusarium species commonly found in many food commodities and known to cause reproductive disorders. Several studies have shown that ZEN is hematotoxic and hepatotoxic and causes several alterations of immunological parameters. In the present study, we aimed to evaluate the protective effect of Crocin (CRO), a natural carotenoid, against ZEN-induced toxicity in both renal and hepatic tissues of Balb/c mice. We demonstrated that ZEN (40 mg/kg body weight (b.w.)) induced oxidative stress in both kidney and liver as monitored by measuring the malondialdehyde (MDA) level, the protein carbonyl generation, the catalase and superoxide dismutase activity, and the expression of the heat shock proteins (Hsp70). However, combined treatment of ZEN with different doses of CRO (50, 100, and 250 mg/kg b.w.) significantly reduced ZEN-induced alterations in all tested oxidative stress markers. It could be concluded that CRO was effective in the protection against ZEN-induced toxicity in the liver and kidney of Balb/c mice. PMID- 26233740 TI - Utilization of air pollution control residues for the stabilization/solidification of trace element contaminated soil. AB - The aim of this study was to evaluate the stabilization/solidification (S/S) of trace element-contaminated soil using air pollution control residues (APCRs) prior to disposal in landfill sites. Two soil samples (with low and moderate concentrations of organic matter) were stabilized using three APCRs that originated from the incineration of municipal solid waste, bio-fuels and a mixture of coal and crushed olive kernels. Two APCR/soil mixtures were tested: 30% APCR/70% soil and 50% APCR/50% soil. A batch leaching test was used to study immobilization of As and co-occurring metals Cr, Cu, Pb and Zn. Solidification was evaluated by measuring the unconfined compression strength (UCS). Leaching of As was reduced by 39-93% in APCR/soil mixtures and decreased with increased amounts of added APCR. Immobilization of As positively correlated with the amount of Ca in the APCR and negatively with the amount of soil organic matter. According to geochemical modelling, the precipitation of calcium arsenate (Ca3(AsO4)2/4H2O) and incorporation of As in ettringite (Ca6Al2(SO4)3(OH)12 . 26H2O) in soil/APCR mixtures might explain the reduced leaching of As. A negative effect of the treatment was an increased leaching of Cu, Cr and dissolved organic carbon. Solidification of APCR/soil was considerably weakened by soil organic matter. PMID- 26233741 TI - Soil microbial respiration and PICT responses to an industrial and historic lead pollution: a field study. AB - We performed a field investigation to study the long-term impacts of Pb soil contamination on soil microbial communities and their catabolic structure in the context of an industrial site consisting of a plot of land surrounding a secondary lead smelter. Microbial biomass, catabolic profiles, and ecotoxicological responses (PICT) were monitored on soils sampled at selected locations along 110-m transects established on the site. We confirmed the high toxicity of Pb on respirations and microbial and fungal biomasses by measuring positive correlations with distance from the wall factory and negative correlation with total Pb concentrations. Pb contamination also induced changes in microbial and fungal catabolic structure (from carbohydrates to amino acids through carboxylic malic acid). Moreover, PICT measurement allowed to establish causal linkages between lead and its effect on biological communities taking into account the contamination history of the ecosystem at community level. The positive correlation between qCO2 (based on respiration and substrate use) and PICT suggested that the Pb stress-induced acquisition of tolerance came at a greater energy cost for microbial communities in order to cope with the toxicity of the metal. In this industrial context of long-term polymetallic contamination dominated by Pb in a field experiment, we confirmed impacts of this metal on soil functioning through microbial communities, as previously observed for earthworm communities. PMID- 26233742 TI - Recent trends in chloride and sodium concentrations in the deep subalpine lakes (Northern Italy). AB - A growing concern exists about the effects of chloride (Cl) on freshwater systems. Increasing Cl concentrations have been observed in the last few decades in several rivers and lakes, mainly in northern countries. In Italy, present levels and temporal changes of sodium (Na) and Cl in water bodies have rarely been assessed. Based on long-term data for the lakes of the subalpine district in Italy (Maggiore, Lugano, Como, Iseo, Garda), we analyzed trends affecting Cl and Na concentrations during the last 25 years, with the aim of identifying temporal changes and assessing possible causes. An in-depth analysis is presented for Lake Maggiore. Positive temporal Na and Cl trends were evident in all studied lakes, with the trends increasing since early 2000s. Data for Lake Maggiore tributaries showed a clear seasonality (higher values in winter and early spring). The NaCl used as road de-icing agent, together with Cl discharge from wastewater treatment plants, were identified as the main causes for the observed trends. Chloride concentrations in the lakes are below the threshold limit for reduced water quality and below concentrations known to harm aquatic biota. However, considering the relevance of deep subalpine lakes, representing almost 80% of the total freshwater volume in Italy, these trends indicate an important chemical change, which warrants further analysis. PMID- 26233743 TI - Adsorbed poly(aspartate) coating limits the adverse effects of dissolved groundwater solutes on Fe0 nanoparticle reactivity with trichloroethylene. AB - For in situ groundwater remediation, polyelectrolyte-modified nanoscale zerovalent iron particles (NZVIs) have to be delivered into the subsurface, where they degrade pollutants such as trichloroethylene (TCE). The effect of groundwater organic and ionic solutes on TCE dechlorination using polyelectrolyte modified NZVIs is unexplored, but is required for an effective remediation design. This study evaluates the TCE dechlorination rate and reaction by-products using poly(aspartate) (PAP)-modified and bare NZVIs in groundwater samples from actual TCE-contaminated sites in Florida, South Carolina, and Michigan. The effects of groundwater solutes on short- and intermediate-term dechlorination rates were evaluated. An adsorbed PAP layer on the NZVIs appeared to limit the adverse effect of groundwater solutes on the TCE dechlorination rate in the first TCE dechlorination cycle (short-term effect). Presumably, the pre-adsorption of PAP "trains" and the Donnan potential in the adsorbed PAP layer prevented groundwater solutes from further blocking NZVI reactive sites, which appeared to substantially decrease the TCE dechlorination rate of bare NZVIs. In the second and third TCE dechlorination cycles (intermediate-term effect), TCE dechlorination rates using PAP-modified NZVIs increased substantially (~100 and 200%, respectively, from the rate of the first spike). The desorption of PAP from the surface of NZVIs over time due to salt-induced desorption is hypothesized to restore NZVI reactivity with TCE. This study suggests that NZVI surface modification with small, charged macromolecules, such as PAP, helps to restore NZVI reactivity due to gradual PAP desorption in groundwater. PMID- 26233744 TI - Influence of road traffic, residential heating and meteorological conditions on PM10 concentrations during air pollution critical episodes. AB - The importance of road traffic, residential heating and meteorological conditions as major drivers of urban PM10 concentrations during air pollution critical episodes has been assessed in the city of Florence (Italy) during the winter season. The most significant meteorological variables (wind speed and atmospheric stability) explained 80.5-85.5% of PM10 concentrations variance, while a marginal role was played by major emission sources such as residential heating (12.1%) and road traffic (5.7%). The persistence of low wind speeds and unstable atmospheric conditions was the leading factor controlling PM10 during critical episodes. A specific PM10 critical episode was analysed, following a snowstorm that caused a "natural" scenario of 2-day dramatic road traffic abatement (-43%), and a massive (up to +48%) and persistent (8 consecutive days) increase in residential heating use. Even with such a strong variability in local PM10 emissions, the role of meteorological conditions was prominent, revealing that short-term traffic restrictions are insufficient countermeasures to reduce the health impacts and risks of PM10 critical episodes, while efforts should be made to anticipate those measures by linking them with air quality and weather forecasts. PMID- 26233745 TI - Anaerobic degradation of increased phenol concentrations in batch assays. AB - Phenol is a wastewater contaminant depicting an environmental hazard. It can be found in effluents from various industrial processes and becomes even more common as a waste by-product of biomass-based bioenergy concepts. Because of its toxicity to anaerobic microorganisms, it can be recalcitrant during biogas production and anaerobic wastewater treatment. This study tested increased phenol loads (100 to 5000 mg L(-1)) as the sole carbon source in a semi-continuous mesophilic anaerobic adaption experiment using an unadapted microbial community from a standard biogas plant. Phenol was completely degraded at starting concentrations of up to 2000 mg L(-1). At 5000 mg L(-1), complete inhibition of the anaerobic community was observed. Lag times were reduced down to less than a day treating 2000 mg L(-1) after 16 weeks of adaption to gradually increased phenol concentrations. Specific degradation rates increased consecutively up to 7.02 mg gVS (-1) day(-1) at 2000 mg L(-1). This concentration was completely degraded within less than 12 days. The microbial community composition was assessed using 16S rRNA gene-based terminal restriction fragment length polymorphism (T-RFLP) analysis. In the bacterial community, no clear shift was visible. Clostridia were with the highest relative abundance of 27 %, the most prominent bacterial class. T-RFs representing Clostridia, Anaerolinaceae, Flavobacteria, and Bacteroidea appeared at similar relative abundance level throughout the experiment. The archaeal community, however, changed from a Methanosarcinales-dominated community (57%) to a community with a nearly even distribution of Methanobacteriales (21%) and Methanosarcinales (34%) with increasing starting phenol concentration. PMID- 26233746 TI - Emission factor and balance of mercury in fish farms in an artificial reservoir in NE Brazil. AB - This paper estimated the mercury (Hg), emission factor, and mass balance from caged fish farming in the Castanhao Reservoir, NE Brazil, based on monitoring of a typical farm of Nile tilapia (Oreochromis niloticus). The total Hg input to the farm reached 1.45 gHg ha(-1) year(-1), from which 0.21 gHg ha(-1) year(-1) was exported out as fish biomass, ultimately resulting in an emission factor of 1.24 gHg ha(-1) year(-1) for the reservoir or approximately 8.27 mgHg ton fish(-1) year(-1) produced. Most of the input came from aquafeeds with concentrations varying from 1.4 to 31.1 ng g(-1), depending on the type of aquafeed. The Hg concentrations in fish were very low and varied from 1.0 to 2.9 ng g(-1). These values are two orders of magnitude lower than the legal limit for human consumption. The estimated total annual discharge of Hg from farming into the reservoir is 174 g for 18,000 tons of fish produced and may reach 387 g when the reservoir reaches its total capacity (40,000 tons), which is expected to occur in 2020. The mass balance, considering the deposition and accumulation rates, showed that approximately 40% of the total Hg input accumulate in farm sediments (0.72 g ha(-1) year(-1)), which is approximately 60% of the deposition rate estimated through the sediment traps and suggests that 0.54 gHg ha(-1) year(-1) could eventually be transported out of the farm to the reservoir. Notwithstanding these facts, the total annual input of Hg from fish farming to the Castanhao Reservoir is less than 1.0% of the total input from anthropogenic sources. PMID- 26233747 TI - Study on the release routes of allelochemicals from Pistia stratiotes Linn., and its anti-cyanobacteria mechanisms on Microcystis aeruginosa. AB - Allelochemicals in Pistia stratiotes Linn. have a strong anti-cyanobacteria effect on Microcystis aeruginosa. To further determine the release routes of allelochemicals in P. stratiotes and understand their anti-cyanobacteria mechanisms, we aimed to systematically investigate the allelopathic effects of leaf leachates, leaf volatilization, root exudates, and residue decomposition of P. stratiotes on M. aeruginosa. The influences of P. stratiotes allelochemicals on the physiological properties of M. aeruginosa were also studied. Root exudates of P. stratiotes exhibited the strongest inhibitory effect on M. aeruginosa growth. The residue decomposition and leaf leachates exhibited a relatively strong inhibitory effect on M. aeruginosa growth. By contrast, the leaf volatilization stimulated M. aeruginosa growth. Therefore, root exudation was determined to be the main release route of allelochemicals from P. stratiotes. The mixed culture experiment of P. stratiotes root exudates and M. aeruginosa showed that the allelochemicals released from root exudation had no effect on the electron transfer of M. aeruginosa photosynthetic system II. However, it reduced the phycocyanin (PC) content and phycocyanin to allophycocyanin (PC/APC) ratio in the photosynthetic system. As the root exudates concentration increased, the electrical conductivity (EC) and superoxide anion radical (O2(*-)) values in the M. aeruginosa culture fluid increased significantly, indicating that the allelochemicals released from the root of P. stratiotes inhibited algae growth by affecting the PC and PC/APC levels in photosynthesis, destroying the cell membrane, and increasing O2(*-) content to result in oxidative damage of M. aeruginosa. PMID- 26233748 TI - The effect of Beauveria bassiana infection on cell mediated and humoral immune response in house fly, Musca domestica L. AB - Entomopathogenic fungi that manifest infections by overcoming insect's immune response could be a successful control agent for the house fly, Musca domestica L. which is a major domestic, medical, and veterinary pest. In this study, the immune response of house fly to Beauveria bassiana infection was investigated to reveal fundamental aspects of house fly hemocyte biology, such as hemocyte numbers and size, which is poorly understood. The total hemocyte counts (THCs) in B. bassiana-infected house fly showed an initial increase (from 6 to 9 h), followed by subsequent decrease (9 to 12 h) with increase in time of infection. The THCs was slightly greater in infected flies than the non-infected ones. Insight into relative hemocyte counts depicted a significant increase in prohemocyte (PR) and decrease in granulocyte (GR) in infected house flies compared to non-infected ones. The relative cell area of hemocyte cells showed a noticeable increase in PR and intermediate cells (ICs), while a considerable reduction was observed for plasmatocyte (PL) and GR. The considerable variation in relative cell number and cell area in the B. bassiana-infected house flies indicated stress development during infection. The present study highlights changes occurring during B. bassiana invasion to house fly leading to establishment of infection along with facilitation in understanding of basic hemocyte biology. The results of the study is expected to help in better understanding of house fly immune response during fungal infection, so as to assist production of more efficient mycoinsecticides for house fly control using B. bassiana. PMID- 26233749 TI - Response of wheat and pea seedlings on increase of bromine concentration in the growth medium. AB - Biogeochemical cycles of bromine (Br) and its quantitative requirements for different plant species are still studied poorly. There is a need to examine Br pathways in plants and evaluate the factors important for Br accumulation in a plant. In the present work, the effects of different Br compounds on an uptake of Br by two plant species (wheat and pea) that tolerate Br differently (pea is more sensitive to Br compared with wheat) have been studied. The growth medium was spiked with either KBr or NaBr at concentrations 0, 10, 50 and 100 mg/L. Elemental analysis of the plants was performed using inductively coupled plasma optical emission spectrometry (ICP-OES) and ICP-MS analytical techniques after leaching of the samples with tetramethyl ammonium hydroxide at mild temperature (60 degrees C). The experimental results have shown that wheat and pea seedlings can accumulate rather large amounts of Br. An increase of Br concentration in a plant was not always directly proportional to the variations in the Br concentration in the growth medium. In wheat, the greater part of Br was accumulated during first 7 days. In pea, the uptake of Br lasted until the end of the experiment. Certain differences in the ability of plants to accumulate Br were observed when the plants were grown in a medium spiked with different Br compounds. In most cases, Br accumulation was higher in the leaves of the plants grown in the medium spiked with KBr. The same tendency was observed for another halogen, chlorine (Cl). PMID- 26233750 TI - The pollution intensity of Australian power stations: a case study of the value of the National Pollutant Inventory (NPI). AB - This paper presents a comprehensive analysis of the pollutant emissions from electrical generation facilities reported to Australia's National Pollutant Inventory (NPI). The data, in terms of pollutant intensity with respect to generation capacity and fuel source, show significant variability. Based on reported data, the dominant pathway and environmental segment for emissions is point-source air emissions. Surprisingly, pollutant emissions from power stations are generally a very small fraction of Australia's facility and diffuse emissions, except for F, HCl, NO(x), PM2.5, SO2 and H2SO4 (where it constitutes between 30 and 90% of emissions). In general, natural gas and diesel facilities have higher organic pollutant intensities, while black and brown coal have higher metal/metalloid pollutant intensities and there is a wide variability for inorganic pollutant intensities. When examining pollutant intensities with respect to capacity, there is very little evidence to show that increased scale leads to more efficient operation or lower pollutant intensity. Another important finding is that the pollutant loads associated with transfers and reuse are substantial, and often represent most of the reported pollutants from a given generation facility. Finally, given the issues identified with the NPI data and its use, some possible improvements include the following: (i) linking site generation data to NPI data (especially generation data, i.e., MWh); (ii) better validation and documentation of emissions factors, especially the methods used to derive and report estimates to the NPI; (iii) using NPI data to undertake comparative life cycle impact assessment studies of different power stations and fuel/energy sources, or even intensive industrial regions (especially from a toxicity perspective) and (iv) linking NPI data in a given region to ongoing environmental monitoring, so that loads can be linked to concentrations for particular pollutants and the relevant guidelines (e.g., air, water, human health). Pollutant inventory systems are clearly valuable tools in understanding pollution burdens and ongoing analysis of the growing body of data should help to further improve environmental and public health outcomes. Overall, this study provides a valuable insight into the current status of pollutant intensities from Australia's electrical generation facilities and should be a valuable benchmark for future studies and international comparisons. PMID- 26233751 TI - Hydrogen production using thermocatalytic decomposition of methane on Ni30/activated carbon and Ni30/carbon black. AB - Hydrogen is an energy carrier of the future need. It could be produced from different sources and used for power generation or as a transport fuel which mainly in association with fuel cells. The primary challenge for hydrogen production is reducing the cost of production technologies to make the resulting hydrogen cost competitive with conventional fuels. Thermocatalytic decomposition (TCD) of methane is one of the most advantageous processes, which will meet the future demand, hence an attractive route for COx free environment. The present study deals with the production of hydrogen with 30 wt% of Ni impregnated in commercially available activated carbon and carbon black catalysts (samples coded as Ni30/AC and Ni30/CB, respectively). These combined catalysts were not attempted by previous studies. Pure form of hydrogen is produced at 850 degrees C and volume hourly space velocity (VHSV) of 1.62 L/h g on the activity of both the catalysts. The analysis (X-ray diffraction (XRD)) of the catalysts reveals moderately crystalline peaks of Ni, which might be responsible for the increase in catalytic life along with formation of carbon fibers. The activity of carbon black is sustainable for a longer time compared to that of activated carbon which has been confirmed by life time studies (850 degrees C and 54 sccm of methane). PMID- 26233752 TI - Thermal desorption of PCBs from contaminated soil with copper dichloride. AB - Copper dichloride is an important catalyst both in the dechlorination of chlorinated aromatic compounds and the formation of PCDD/Fs. The effect of copper dichloride on polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) was studied in treated soil and off gas after thermal desorption of PCB-contaminated soil at 300, 400, 500, 600 degrees C. The presence of copper dichloride clearly enhances thermal desorption by promoting PCBs removal, destruction, and dechlorination. After thermal treatment at 600 degrees C for 1 h, the removal efficiency and destruction efficiency for PCBs reached 98.1 and 93.9%, respectively. Compared with the positive influence on PCBs, copper dichloride catalyzed large amount of PCDFs formation at 300 degrees C, with the concentration ratio of 2.35. The effect of CuCl2 on PCDFs formation weakened with the rising temperature since PCDFs destruction became dominant under higher temperature. Different from PCDFs, PCDDs concentration in treated soil and off gas decreased continuously with the increasing temperature. PMID- 26233753 TI - The roles of methanogens and acetogens in dechlorination of trichloroethene using different electron donors. AB - We evaluated the effects of methanogens and acetogens on the function and structure of microbial communities doing reductive dechlorination of trichloroethene (TCE) by adding four distinct electron donors: lactate, a fermentable organic; acetate, a non-fermentable organic; methanol, a fermentable 1-C (carbon) organic; and hydrogen gas (H2), the direct electron donor for reductive dechlorination by Dehalococcoides. The fermentable electron donors had faster dechlorination rates, more complete dechlorination, and higher bacterial abundances than the non-fermentable electron donors during short-term tests. Phylotypes of Dehalococcoides were relatively abundant (>=9%) for the cultures fed with fermentable electron donors but accounted for only ~1-2% of the reads for the cultures fed by the non-fermentable electron donors. Routing electrons to methanogenesis and a low ratio of Dehalococcoides/methanogenesis (Dhc/mcrA) were associated with slow and incomplete reductive dechlorination with methanol and H2. When fermentable substrates were applied as electron donors, a Dhc/mcrA ratio >=6.4 was essential to achieve fast and complete dechlorination of TCE to ethene. When methanogenesis was suppressed using 2-bromoethanesulfonate (BES), achieving complete dechlorination of TCE to ethane required a minimum abundance of the mcrA gene. Methanobacterium appeared to be important for maintaining a high dechlorination rate, probably by providing Dehalococcoides with cofactors other than vitamin B12. Furthermore, the presence of homoacetogens also was important to maintain a high dechlorination rate, because they provided acetate as Dehalococcoides's obligatory carbon source and possibly cofactors. PMID- 26233754 TI - The effect of lead on the growth, content of primary metabolites, and antioxidant response of green alga Acutodesmus obliquus (Chlorophyceae). AB - Green unicellular alga Acutodesmus obliquus (Turpin) Hegewald et Hanagata (SAG strain no. 276-6) (Chlorophyceae) was used for determination of phytotoxicity of lead (Pb) at the range of concentrations 0.01-500 MUM during 7 days of culture. The accumulation of Pb in algal cells was found to be increased in a concentration- and duration-dependent manner. The highest Pb uptake value was obtained in response to 500 MUM Pb on the seventh day of cultivation. The decrease in the number and the size of cells and the contents of selected primary metabolites (photosynthetic pigments, monosaccharides, and proteins) in A. obliquus cells were observed under Pb stress. Heavy metal stimulated also formation of reactive oxygen species (hydrogen peroxide) and oxidative damage as evidenced by increased lipid peroxidation. On the other hand, the deleterious effects of Pb resulting from the cellular oxidative state can be alleviated by enzymatic (superoxide dismutase, catalase, ascorbate peroxidase, and glutathione reductase) and non-enzymatic (ascorbate, glutathione) antioxidant systems. These results suggest that A. obliquus is a promising bioindicator of heavy metal toxicity in aquatic environment, and it has been identified as good scavenger of Pb from aqueous solution. PMID- 26233755 TI - Assessment of silver nanoparticle toxicity for common carp (Cyprinus carpio) fish embryos using a novel method controlling the agglomeration in the aquatic media. AB - Formation of agglomerates and their rapid sedimentation during aquatic ecotoxicity testing of nanoparticles is a major issue with a crucial influence on the risk assessment of nanomaterials. The present work is aimed at developing and testing a new approach based on the periodic replacement of liquid media during an ecotoxicological experiment which enabled the efficient monitoring of exposure conditions. A verified mathematical model predicted the frequencies of media exchanges which checked for formation of agglomerates from silver nanoparticles AgNP with 50 nm average size of the original colloid. In the model experiments, embryos of common carp Cyprinus carpio were exposed repeatedly for 6 h to AgNPs (5-50 MUm Ag L(-1)) either under semistatic conditions (exchange of media after 6 h) or in variants with frequent media exchanges (varying from 20 to 300 min depending on the AgNP colloid concentration and the desired maximum agglomerate size of 200 or 400 nm). In contrast to other studies, where dissolved free metals are usually responsible for toxic effects, our 144-h experiments demonstrated the importance of AgNP agglomerates in the adverse effects of nanosilver. Direct adsorption of agglomerates on fish embryos locally increased Ag concentrations which resulted in pronounced toxicity particularly in variants with larger 400 nm agglomerates. The present study demonstrates the suitability of the novel methodology in controlling the conditions during aquatic nanomaterial toxicity testing. It further provided insights into the mechanisms underlying the effects of AgNP, which rank on a global scale among the most widely used nanomaterials. PMID- 26233756 TI - Lipo-chitooligosaccharidic nodulation factors and their perception by plant receptors. AB - Lipo-chitooligosaccharides produced by nitrogen-fixing rhizobia are signaling molecules involved in the establishment of an important agronomical and ecological symbiosis with plants. These compounds, known as Nod factors, are biologically active on plant roots at very low concentrations indicating that they are perceived by specific receptors. This article summarizes the main strategies developed for the syntheses of bioactive Nod factors and their derivatives in order to better understand their mode of perception. Different Nod factor receptors and LCO-binding proteins identified by genetic or biochemical approaches are also presented, indicating perception mechanisms that seem to be more complicated than expected, probably involving multi-component receptor complexes. PMID- 26233757 TI - Effect of 21-Gene RT-PCR Assay on Adjuvant Therapy and Outcomes in Patients With Stage I Breast Cancer. AB - BACKGROUND: Recurrence score (RS) derived from a 21-gene reverse transcriptase polymerase chain reaction assay is used to stratify patients with early-stage estrogen receptor-positive, HER2-normal breast cancer into 3 groups on the basis of 10-year distant metastasis risk: low, intermediate, and high. Published data are limited regarding the effect of RS on choice of adjuvant therapy for T1 breast cancer. We investigated the relationship between RS and choice of adjuvant therapy, prognosis, and benefit of chemotherapy (CT) in stage I breast cancer. MATERIALS AND METHODS: We reviewed the records of 1030 patients with estrogen receptor-positive, HER2-normal stage I breast cancer and RS available. RSs were correlated with clinicopathologic characteristics, treatment, and outcome. RESULTS: Patients with pathologic (p)T1a, pT1b, and pT1c disease did not differ in distribution of low, intermediate, and high RS (P = .673). Overall, fewer than 10% of patients had a high RS. Histologic grade 1, nuclear grade 1, and low Ki-67 expression had only 1%, 0%, and 6% of high RSs, respectively. Among patients with intermediate RSs, 41% with pT1b and 46% with pT1c disease received CT. Among patients with intermediate RSs, for pT1b disease, distant disease-free survival (DDFS) did not differ between hormonal therapy (HT) alone and CT with HT (P = .752); for pT1c, DDFS was superior for CT with HT (P = .020). Histologic grade was the only independent prognostic factor of DDFS (P = .0007, 1 vs. 3; P = .035, 2 vs. 3); RS did not predict DDFS (P = .083, high vs. low; P = .066, intermediate vs. low). CONCLUSION: The added value of RS to known prognostic factors appears limited to patients with pT1b breast cancer. However, this study lacked long-term follow-up. PMID- 26233758 TI - Hidden Markov analysis of improved bandwidth mechanosensitive ion channel data. AB - The gating behaviour of a single ion channel can be described by hidden Markov models (HMMs), forming the basis for statistical analysis of patch clamp data. Extensive improved bandwidth (25 kHz, 50 kHz) data from the mechanosensitive channel of large conductance in Escherichia coli were analysed using HMMs, and HMMs with a moving average adjustment for filtering. The aim was to determine the number of levels, and mean current, mean dwell time and proportion of time at each level. Parameter estimates for HMMs with a moving average adjustment for low pass filtering were obtained using an expectation-maximisation algorithm that depends on a generalisation of Baum's forward-backward algorithm. This results in a simpler algorithm than those based on meta-states and a much smaller parameter space; hence, the computational load is substantially reduced. In addition, this algorithm maximises the actual log-likelihood rather than that for a related meta state process. Comprehensive data analyses and comparisons across all our data sets have consistently shown five subconducting levels in addition to the fully open and closed levels for this channel. PMID- 26233759 TI - Functional similarities between heterogeneously and homogenously expressed MscL constructs. AB - The mechanosensitive channel of large conductance MscL is a well-characterized mechanically gated non-selective ion channel, which often serves as a prototype mechanosensitive channel for mechanotransduction studies. However, there are some discrepancies between MscL constructs used in these studies, most notably unintended heterogeneous expression from some MscL expression constructs. In this study we investigate the possible cause of this expression pattern, and compare the original non-homogenously expressing constructs with our new homogeneously expressing one to confirm that there is little functional difference between them. In addition, a new MscL construct has been developed with an improved molar extinction coefficient at 280 nm, enabling more accurate protein quantification. PMID- 26233760 TI - Molecular dynamics study on protein-water interplay in the mechanogating of the bacterial mechanosensitive channel MscL. AB - One of the goals of mechanosensitive channel (MSC) studies is to understand the underlying molecular and biophysical mechanisms of the mechano-gating process from force sensing to gate opening. We focus on the latter process and investigate the role of water in the bacterial MSC MscL, which is activated by membrane tension. We analyze the interplay between water and the gate constituting amino acids, Leu19-Gly26, through molecular dynamics simulations. To highlight the role of water, specifically hydration of the gate, in MscL gating, we restrain lateral movements of the water molecules along the water-vapor interfaces at the top and bottom of the vapor bubble, plugging the closed gate. The gating behaviors in this model and the normal MscL model, in which water movements are unrestrained, are compared. In the normal model, increased membrane tension breaks the hydrogen bond between Leu19 and Val 23 of the inner helix, exposing the backbone carbonyl oxygen of Leu19 to the water-accessible lumen side of the gate. Associated with this activity, water comes to access the vapor region and stably interacts with the carbonyl oxygen to induce a dewetting to wetting transition that facilitates gate expansion toward channel opening. By contrast, in the water-restrained model, carbonyl oxygen is also exposed, but no further conformational changes occur at the gate. This suggests that gate opening relies on a conformational change initiated by wetting. The penetrated water weakens the hydrophobic interaction between neighboring transmembrane inner helices called the "hydrophobic lock" by wedging into the space between their interacting portions. PMID- 26233761 TI - PECAS: prokaryotic and eukaryotic classical analysis of secretome. AB - Full sets of proteins that are transported to the extracellular space, called secretomes, have been studied for a variety of organisms to understand their potential role in crucial metabolic pathways and complex health conditions. However, there is a lack of tools for integrative classical analysis of secretomes that consider all the data sources available nowadays. Thus, PECAS (Prokaryotic and Eukaryotic Classical Analysis of Secretome) has been developed to provide a well-established prediction pipeline on secreted proteins for prokaryote and eukaryote species. PMID- 26233762 TI - Computerized trainings in four groups of struggling readers: Specific effects on word reading and comprehension. AB - Four groups of poor readers were identified among a population of students with learning disabilities attending a special class in secondary school: normal readers; specific poor decoders; specific poor comprehenders, and general poor readers (deficits in both decoding and comprehension). These students were then trained with a software program designed to encourage either their word decoding skills or their text comprehension skills. After 5 weeks of training, we observed that the students experiencing word reading deficits and trained with the decoding software improved primarily in the reading fluency task while those exhibiting comprehension deficits and trained with the comprehension software showed improved performance in listening and reading comprehension. But interestingly, the latter software also led to improved performance on the word recognition task. This result suggests that, for these students, training interventions focused at the text level and its comprehension might be more beneficial for reading in general (i.e., for the two components of reading) than word-level decoding trainings. PMID- 26233763 TI - Effect of learning disabilities on academic self-concept in children with epilepsy and on their quality of life. AB - Academic self-concept could significantly affect academic achievement and self confidence in children with epilepsy. However, limited attention has been devoted to determining factors influencing academic self-concept of children with epilepsy. We aimed to analyze potentially significant variables (gender, frequency of seizures, duration of epilepsy, intellectual disability, learning disability and attention deficit hyperactivity disorder) in relation to academic self-concept in children with epilepsy and to additional domains of their quality of life. The study group consisted of 182 children and adolescents aged 9-14 years who completed the SPAS (Student's Perception of Ability Scale) questionnaire determining their academic self-concept and the modified Czech version of the CHEQOL-25 (Health-Related Quality of Life Measure for Children with Epilepsy) questionnaire evaluating their health-related quality of life. Using regression analysis, we identified learning disability as a key predictor for academic-self concept of children with epilepsy. While children with epilepsy and with no learning disability exhibited results comparable to children without epilepsy, participants with epilepsy and some learning disability scored significantly lower in almost all domains of academic self-concept. We moreover found that children with epilepsy and learning disability have significantly lower quality of life in intrapersonal and interpersonal domains. In contrast to children with epilepsy and with no learning disability, these participants have practically no correlation between their quality of life and academic self concept. Our findings suggest that considerable attention should be paid to children having both epilepsy and learning disability. It should comprise services of specialized counselors and teaching assistants with an appropriate knowledge of epilepsy and ability to empathize with these children as well as educational interventions focused on their teachers and classmates. PMID- 26233764 TI - Numerical skills in children with Down syndrome. Can they be improved? AB - The present study aims to explore the impact of a numerical skills training program on the basic mathematical skills and logical thinking in children with Down syndrome (DS). The training program was built specifically for children with DS, bearing the strengths and weaknesses of their particular cognitive profile in mind. Two groups of children with DS took part in the study. All children were tested before and after the training on measures of numerical skills and logical thinking. One group of 27 children was trained in numerical skills twice a week for 2 months, for about 30min per session. A control group of 9 children was not involved in any training session. After training, children in the intervention group performed better in numerical tests, while those in the control group did not. These results suggest that our training program is both feasible and effective for children with Down syndrome. PMID- 26233765 TI - Proxy and self-reported Quality of Life in adults with intellectual disabilities: Impact of psychiatric symptoms, problem behaviour, psychotropic medication and unmet needs. AB - Proxies often underestimate the subjective Quality of Life (QoL) of adults with intellectual disability (ID). However, little is known about the reasons for these differences. Accordingly, the purpose of the present study is to, firstly, compare the self-reported QoL of adults with ID with proxy reports from staff of sheltered working and housing facilities, and, secondly, to identify possible differences of the impact of four potential predictor variables. Data of 102 adults with ID were collected as part of the MEMENTA study ('Mental health care provision for adults with ID and a mental disorder'). Results show that self report QoL scores ranged from 72.6 to 86.8. Both proxies consistently reported lower QoL scores and agreement between self and proxy ratings was predominantly poor. Unmet needs and psychotropic medication were identified as the most important predictors of reduced self-rated QoL, whereas an increase of psychiatric symptoms, problem behaviours, and psychotropic medication best predicted the reduced QoL proxy ratings. To conclude, proxies still have to strive for a more holistic approach in surrogate QoL assessments and according to adults with ID, service providers should focus on a reduction of unmet needs and psychotropic medication to further improve QoL. PMID- 26233766 TI - Development of predicted no effect concentration (PNEC) for TCS to terrestrial species. AB - Triclosan (TCS) is an important broad-spectrum antimicrobial agent widely utilized in a range of personal care products, and is therefore commonly found in the environment. A few studies have been conducted to investigate predicted no effect concentration (PNEC) for TCS on terrestrial organisms. This could be due to lack of toxicity data especially chronic toxicity data for species on various taxonomic levels. In the present study, chronic toxicity of TCS on 6 terrestrial species (3 dicotyledonous plants, 2 monocotyledonous plants and 1 terrestrial invertebrate) were tested. PNEC values of TCS based on toxicity data of 14 terrestrial species (5 dicotyledonous plants, 4 monocotyledonous plants and 5 terrestrial invertebrates) from 4 Phyla and 11 Families were calculated using the log-logistic species sensitivity distribution (SSD) method. The result of our toxicity tests showed that the dicotyledonous plant Lactuca sativa was the most sensitive species to TCS exposure. The PNEC value for TCS was derived to be 0.04 0.21mgkg(-1) when using the log-logistic SSD method. The use of toxicity data from various taxonomic levels is recommended in deriving the PNEC value in the terrestrial environment. PMID- 26233767 TI - Contribution of the Endothelin System to the Genesis and Maintenance of Atrial Fibrillation: Review of the Literature and Clinical Implications. PMID- 26233768 TI - Clinical Assessment in Acute Heart Failure. PMID- 26233769 TI - Validation of the HellenicSCORE (a Calibration of the ESC SCORE Project) Regarding 10-Year Risk of Fatal Cardiovascular Disease in Greece. AB - INTRODUCTION: There is increasing interest in indexes that estimate the individual risk of developing a cardiovascular disease (CVD) event; the European Society of Cardiology (ESC), in the latest guidelines (2012) for CVD prevention, acknowledged the importance of risk evaluation through risk scores, i.e. the ESC SCORE (Systematic COronary Risk Estimation). However, there has been much discussion about the reliability of such CVD risk scores among different populations. The ESC SCORE is a CVD risk-specific tool for Europe, based on datasets from 12 European countries (Greece did not participate). In the mid 2000s the HellenicSCORE, a calibration of the ESC SCORE based on national mortality data and prevalence regarding risk factors as reported by the ATTICA study, was proposed for the Greek population and became a part of daily clinical practice. This validation of the HellenicSCORE was performed using the 10-year follow-up examination of the ATTICA study participants. METHODS: Of the 3042 participants of the ATTICA study (enrolment 2001-2002), 2583 were contacted in the 10-year follow-up (2011-2012). The HellenicSCORE as calculated using participants' baseline characteristics was tested against the 10-year CVD event rates. RESULTS: The 10-year fatal or non-fatal CVD incidence rate was 15.7% (19.7% in men and 11.7% in women). The HellenicSCORE correctly predicted 95.6% of fatal CVD cases and 93.2% of the fatal and non-fatal CVD cases. No interactions with sex, age group or comorbidities were observed. CONCLUSION: The HellenicSCORE is a valid tool for CVD risk estimation in Greek subjects. The present work suggests a calibration methodology that could be used by other nations for CVD risk estimation. PMID- 26233770 TI - Are Cardiac Risk Scores Useful in Daily Clinical Practice? PMID- 26233771 TI - Predictive Value of the No-Reflow Phenomenon and Epicardial Adipose Tissue for Clinical Outcomes After Primary Percutaneous Coronary Intervention. AB - INTRODUCTION: The determinants of clinical outcomes in patients with acute ST elevation myocardial infarction (STEMI) are still being debated. The aim of this study was to investigate the prognostic value of the no-reflow phenomenon and epicardial adipose tissue (EAT) thickness for clinical outcomes in patients undergoing primary percutaneous coronary intervention (pPCI) for STEMI. METHODS: The present study prospectively included 114 consecutive patients (mean age 54 +/ 10 years, 15 women) who underwent successful pPCI. Patients were divided into two groups according to the occurrence of the no-reflow phenomenon and further subdivided according to the tertile of EAT thickness (Group I <5.1 mm, Group II >=5.1 mm). We assessed the composite and separate occurrence of major adverse cardiac events. RESULTS: Throughout the 3-year follow up, the number of admissions for heart failure was significantly higher in patients with no-reflow (n=5 [20%] vs. n=1 [1%], p=0.003) and in female patients (n=4 [26%] vs. n=2 [2%], p=0.004). In the subgroup analysis, group I patients with no-reflow showed a higher frequency of admission for heart failure (n=4 [44%] vs. n=1 [6%], p=0.04). However, multivariate logistic regression analysis demonstrated that only no reflow and female sex independently predicted admission for heart failure (OR: 19.3, 95%CI: 1.4-269.7, p=0.03, and OR: 24.9, 95%CI: 2.2-288.8, p=0.01, respectively). CONCLUSION: No-reflow and female sex are independent predictors of admission for heart failure in the longterm follow up of patients with STEMI. However, EAT thickness is not associated with clinical outcomes after pPCI. PMID- 26233772 TI - Epicardial Adipose Tissue and No-Reflow Phenomenon: Adipokines as Regulators of Coronary Microcirculation? PMID- 26233773 TI - Acute Exacerbation Impairs Right Ventricular Function in COPD Patients. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) may impair right ventricular (RV) function. Tissue Doppler imaging (TDI) is helpful in the noninvasive evaluation of RV longitudinal function. The aim of this study was to assess the impact of acute COPD exacerbation on RV function assessed by TDI. METHODS: The study included 30 COPD patients who had acute exacerbation and 30 controls. RV function was assessed echocardiographically during acute exacerbation and after recovery. In addition to conventional echocardiographic parameters, tricuspid annular plane systolic excursion, tricuspid annulus peak systolic velocity (Sa), and TDI-derived isovolumic myocardial acceleration (IVA) were determined. RESULTS: During exacerbation, COPD patients had a significantly larger RV and higher pulmonary artery systolic pressure, with significantly lower IVA, Sa and tricuspid annular plane systolic excursion compared to controls. After recovery, IVA and Sa significantly increased, while RV diameter and pulmonary artery systolic pressure significantly decreased to levels similar to controls. There were statistically significant, but modest correlations between IVA and Sa (r=0.441, p=0.003), tricuspid annular plane systolic excursion (r=0.628, p<0.001), pulmonary artery systolic pressure (r=-0.391, p=0.002) and RV diameter (r=-0.309, p=0.018). Sa correlated with pulmonary artery systolic pressure (r=-0.350, p=0.007) and RV diameter (r=-0.344, p=0.008). CONCLUSIONS: COPD exacerbations have a negative impact on RV function. TDI-derived IVA and Sa may be used in the assessment of subclinical RV dysfunction in COPD patients with exacerbation. PMID- 26233774 TI - Enterovirus Causing Progression of Heart Failure in a Patient with a History of Myocardial Infarction. AB - Human enteroviruses (HEV) are an important cause of myocarditis and are associated with the pathogenesis of dilated cardiomyopathy (DCM). Current polymerase chain reaction studies in human myocardium have provided evidence that HEV are present in acute and chronic myocarditis as well as in DCM. To our knowledge, the presence of the HEV genome in the myocardium of human patients with heart failure (HF) after myocardial infarction (MI) has not been reported, nor have HEV been implicated as a factor affecting HF progression in patients after MI. Information about the presence of HEV in the heart tissue seems to be clinically important, since HEV infection is a frequent cause of HF and increased mortality. We present the case of a 54-year-old woman with a history of MI and HF progression. Our investigations suggested HEV as a possible cause of HF progression. Successful treatment with interferon- improved the patient's clinical status, apparently confirming our hypothesis. PMID- 26233775 TI - First in Greece Transcatheter Aortic Valve Implantation using the CoreValve Evolut-R Retrievable and Repositionable Bioprosthesis with the InLine Sheath and the EnVeo Loading Guiding Catheter: A Major Advantage for SmallDiameter Access Vessels. AB - We report the first TAVI procedure in Greece to use the CoreValve Evolut-R (23 mm profile) bioprosthesis with the InLine sheath and the EnVeo loading guiding catheter in a patient with small anatomical characteristics (aortic annulus, access vessel) and severe comorbidities. The procedure was successfully conducted under general anesthesia through a surgically prepared, extensively calcified, left femoral artery. PMID- 26233776 TI - Ruptured Sinus of Valsalva: Not Always an Aneurysm. PMID- 26233777 TI - Treatment of a Severely Degenerated Mitral Bioprosthesis with Transcatheter Valve In-Valve Implantation. PMID- 26233778 TI - Acute Coronary Syndromes and Comorbidities. PMID- 26233779 TI - Letter from the New Editor. PMID- 26233780 TI - Antimicrobial-related medication safety incidents: a regional retrospective study in West of Scotland hospitals. AB - BACKGROUND: Medication-related incidents are an important consideration in enhancing patient safety in hospital care. The wide use of antimicrobial therapy in this population renders these medications particularly vulnerable to errors and adverse events. AIM: To analyse the characteristics of antimicrobial-related incident reports across a group of secondary care hospitals. METHODS: Reports for antimicrobial-related incidents from April 2010 to December 2013 were obtained from a regional area of hospitals in National Health Service Scotland. Reports were analysed as a full set, and with subset analyses of incidents resulting in patient harm/injury and those included in a multi-variable regression adjusted by occupied bed-days and defined daily doses to better ascertain areas to target for antimicrobial safety. FINDINGS: In total, 1345 incidents were reported at a crude rate of 0.98 reports/day [95% confidence interval (CI) 0.93-1.03 reports/day]. Penicillins (371 reports; 27.6%), aminoglycosides (358; 26.6%) and glycopeptides (210; 15.6%) were the most commonly involved classes of medications. Most incidents involved no injury/harm (514; 38.2%), but 72 reports (5.4%) did result in patient harm. The rehabilitation/assessment [relative rate (RR) 2.61, 95% CI 1.70-4.03] and women/childrens (RR 2.04, 95% CI 1.39-2.99) directorates had higher incident reporting rates compared with other directorates, likely as a function of at-risk patient populations. Among the types of incidents reported, those involving issues with administration/supply were most common (RR 2.07, 95% CI 1.51-2.84). CONCLUSION: Incident reporting for antimicrobials identified several key areas for quality improvement in the hospital setting, which can guide safety efforts. PMID- 26233781 TI - Analysis of shared miRNAs of different species using ensemble CCA and genetic distance. AB - MicroRNA is a type of single stranded RNA molecule and has an important role for gene expression. Although there have been a number of computational methodologies in bioinformatics research for miRNA classification and target prediction tasks, analysis of shared miRNAs among different species has not yet been addressed. In this article, we analyzed miRNAs that have the same name and function but have different sequences and belong to different (but closely related) species which are constructed from the online miRBase database. We used sequence-driven features and performed the standard and the ensemble versions of Canonical Correlation Analysis (CCA). However, due to its sensitivity to noise and outliers, we extended it using an ensemble approach. Using linear combinations of dimer features, the proposed Ensemble CCA (ECCA) method has identified higher test-set-correlations than CCA. Moreover, our analysis reveals that the Redundancy Index of ECCA applied to a pair of species has correlation with their genetic distance. PMID- 26233782 TI - Fate of cadmium in the rhizosphere of Arabidopsis halleri grown in a contaminated dredged sediment. AB - In regions impacted by mining and smelting activities, dredged sediments are often contaminated with metals. Phytotechnologies could be used for their management, but more knowledge on the speciation of metals in the sediment and on their fate after colonization by plant roots is needed. This work was focused on a dredged sediment from the Scarpe river (North of France), contaminated with Zn and Cd. Zn, Cd hyperaccumulating plants Arabidopsis halleri from metallicolous and non-metallicolous origin were grown on the sediment for five months in a pot experiment. The nature and extent of the modifications in Cd speciation with or without plant were determined by electron microscopy, micro X-ray fluorescence and bulk and micro X-ray absorption spectroscopy. In addition, changes in Cd exchangeable and bioavailable pools were evaluated, and Cd content in leachates was measured. Finally, Cd plant uptake and plant growth parameters were monitored. In the original sediment, Cd was present as a mixed Zn, Cd, Fe sulfide. After five months, although pots still contained reduced sulfur, Cd bearing sulfides were totally oxidized in vegetated pots, whereas a minor fraction (8%) was still present in non-vegetated ones. Secondary species included Cd bound to O-containing groups of organic matter and Cd phosphates. Cd exchangeability and bioavailability were relatively low and did not increase during changes in Cd speciation, suggesting that Cd released by sulfide oxidation was readily taken up with strong interactions with organic matter and phosphate ligands. Thus, the composition of the sediment, the oxic conditions and the rhizospheric activity (regardless of the plant origin) created favorable conditions for Cd stabilization. However, it should be kept in mind that returning to anoxic conditions may change Cd speciation, so the species formed cannot be considered as stable on the long term. PMID- 26233783 TI - Effects of heavy metal pollution from mining and smelting on enchytraeid communities under different land management and soil conditions. AB - We studied enchytraeid communities in several habitats polluted by heavy metals from Zn-Pb mining and smelting activities. We sampled 41 sites that differed in the type of substratum (carbonate rock, metal-rich carbonate mining waste, siliceous sand) and land management (planting Scots pine, topsoiling, leaving to natural succession), and the distance from the smelter. Our main aims were to determine which pollution variables and natural factors most influenced enchytraeid species composition, richness and density, and examine what was the effect of planting Scots pine (reclamation) on enchytraeid communities. The soils harboured on average 1 to 5 enchytraeid species and 700 to 18,300 individuals per square metre, depending on the habitat. These figures were generally lower than those reported from unpolluted regions. Redundancy and multiple regression analyses confirmed the negative impact of heavy metal pollution on both enchytraeid community structure and abundance. Among pollution variables, the distance from the smelter best explained the variation in enchytraeid communities. The concentrations of heavy metals in the soil had less (e.g. total Pb and exchangeable Zn) or negligible (water-soluble forms) explanatory power. Natural soil properties were nearly irrelevant for enchytraeids, except for soil pH, which determined the species composition. Plant species richness was an important explanatory variable, as it positively affected most parameters of enchytraeid community. The results of two-by-two factorial comparisons (planting Scots pine vs. natural succession; carbonate mining waste vs. siliceous sand) suggest that reclamation can improve soil quality for biota, since it increased the diversity and abundance of enchytraeids; this effect was not dependent on the type of substratum. In conclusion, enchytraeids responded negatively to heavy metal pollution and their response was consistent and clear. These animals can be used as indicators of metal toxicity even in the presence of high natural variability, but it is recommended to study their species composition. PMID- 26233784 TI - Intraosseous concentration and inhibitory effect of different intravenous cefazolin doses used in preoperative prophylaxis of total knee arthroplasty. AB - BACKGROUND: The aim of this study was to compare the intraosseous concentrations and the inhibitory effects on the growth of Staphylococcus aureus of 1 g versus 2 g of intravenous (IV) prophylactic cefazolin in total knee arthroplasty (TKA). MATERIALS AND METHODS: Eighteen patients (21 knees) with primary knee osteoarthritis were divided into two groups receiving 1 g (12 patients: 14 knees) versus 2 g (six patients: seven knees) IV prophylactic cefazolin prior to the incision in TKA. Subchondral bone samples (proximal tibia, distal femur) were taken during the operation. These samples were analyzed for intraosseous concentration of cefazolin and their inhibitory effects on the growth of S. aureus, using high-performance liquid chromatography (HPLC) and agar disc diffusion bioassays. RESULTS: The mean intraosseous concentration in the 2 g dose group was significantly higher than in the 1 g dose group in the proximal tibia (p = 0.007) and distal femur (p = 0.016). There were no significant differences between the two groups in terms of mean inhibitory effects in the proximal tibia or distal femur (p > 0.05). No significant correlations were found between the intraosseous concentrations and inhibitory effects in the proximal tibia (r = 0.18, p = 0.52) and distal femur (r = -0.29, p = 0.30). CONCLUSION: IV cefazolin at a dose of 2 g produced greater intraosseous concentrations overall than a dose of 1 g. However, the higher intraosseous concentrations did not correlate with higher inhibitory effects. PMID- 26233785 TI - Visualization of multi-property landscapes for compound selection and optimization. AB - Compound optimization generally requires considering multiple properties in concert and reaching a balance between them. Computationally, this process can be supported by multi-objective optimization methods that produce numerical solutions to an optimization task. Since a variety of comparable multi-property solutions are usually obtained further prioritization is required. However, the underlying multi-dimensional property spaces are typically complex and difficult to rationalize. Herein, an approach is introduced to visualize multi-property landscapes by adapting the concepts of star and parallel coordinates from computer graphics. The visualization method is designed to complement multi objective compound optimization. We show that visualization makes it possible to further distinguish between numerically equivalent optimization solutions and helps to select drug-like compounds from multi-dimensional property spaces. The methodology is intuitive, applicable to a wide range of chemical optimization problems, and made freely available to the scientific community. PMID- 26233787 TI - Surfactant induced aggregation behavior of Merocyanine-540 adsorbed on polymer coated positively charged gold nanoparticles. AB - Surfactant induced aggregation behavior of Merocyanine 540 adsorbed on polymer (PDD) coated gold nanoparticles (AuNP) is reported. The absorption band of the dye shifts to higher energy in the presence of free polymer and polymer coated AuNP implying aggregation. Addition of a negatively charged surfactant (SDS) induces multiple bands in the extinction spectrum of the dye adsorbed on nanoparticle surface. The highest (460nm) and lowest (564nm) energy bands of the dye become prominent at 10 and >50MUM SDS concentrations respectively (dye: 10MUM; AuNP: 100-200pM). Based on earlier results the high energy band is likely to originate from dye aggregates and the low energy band is likely to originate from dye monomers. This is attributed to the interplay between polymer-surfactant and polymer-dye interactions at the AuNP surface. The extinction spectra of dye adsorbed at AuNP surface remain unaffected in the presence of a positively charged (CTAB) or a neutral surfactant (Tx-100), at low surfactant concentrations. However at higher surfactant concentrations (>60MUM) dye aggregation takes place which is attributed to dye-surfactant interactions. The fluorescence intensity of the dye quenched significantly but its lifetime increased in the presence of polymer coated AuNP. This is attributed to aggregation and reduction in the photoisomerization rate of the dye adsorbed on AuNP surface. PMID- 26233788 TI - Determination of polycyclic aromatic hydrocarbons by four-way parallel factor analysis in presence of humic acid. AB - There is not effective method to solve the quenching effect of quencher in fluorescence spectra measurement and recognition of polycyclic aromatic hydrocarbons in aquatic environment. In this work, a four-way dataset combined with four-way parallel factor analysis is used to identify and quantify polycyclic aromatic hydrocarbons in the presence of humic acid, a fluorescent quencher and an ubiquitous substance in aquatic system, through modeling the quenching effect of humic acid by decomposing the four-way dataset into four loading matrices corresponding to relative concentration, excitation spectra, emission spectra and fluorescence quantum yield, respectively. It is found that Phenanthrene, pyrene, anthracene and fluorene can be recognized simultaneously with the similarities all above 0.980 between resolved spectra and reference spectra. Moreover, the concentrations of them ranging from 0 to 8MUgL(-1) in the test samples prepared with river water could also be predicted successfully with recovery rate of each polycyclic aromatic hydrocarbon between 100% and 120%, which were higher than those of three-way PARAFAC. These results demonstrate that the combination of four-way dataset with four-way parallel factor analysis could be a promising method to recognize the fluorescence spectra of polycyclic aromatic hydrocarbons in the presence of fluorescent quencher from both qualitative and quantitative perspective. PMID- 26233789 TI - Geographical traceability of Marsdenia tenacissima by Fourier transform infrared spectroscopy and chemometrics. AB - A combination of Fourier transform infrared spectroscopy with chemometrics tools provided an approach for studying Marsdenia tenacissima according to its geographical origin. A total of 128 M. tenacissima samples from four provinces in China were analyzed with FTIR spectroscopy. Six pattern recognition methods were used to construct the discrimination models: support vector machine-genetic algorithms, support vector machine-particle swarm optimization, K-nearest neighbors, radial basis function neural network, random forest and support vector machine-grid search. Experimental results showed that K-nearest neighbors was superior to other mathematical algorithms after data were preprocessed with wavelet de-noising, with a discrimination rate of 100% in both the training and prediction sets. This study demonstrated that FTIR spectroscopy coupled with K nearest neighbors could be successfully applied to determine the geographical origins of M. tenacissima samples, thereby providing reliable authentication in a rapid, cheap and noninvasive way. PMID- 26233790 TI - Contemporary Surgical Management of Early Glottic Cancer. AB - For early-stage T1-T2 glottic squamous cell carcinoma, transoral laser microsurgery (TLM) is the main surgical modality, with rates of local control and laryngeal preservation ranging from 85% to 100% and low morbidity. For extensive lesions, open conservation laryngeal surgery may enable wider resections than TLM but at costs of longer hospital stay and higher postoperative morbidity. Surgery provides results that are comparable to nonsurgical treatment options while reserving radiation therapy for recurrences or second primary cancers, particularly in younger patients. In the future, transoral robot-assisted surgery may enable more extensive transoral resections than laser alone, decreasing further the indications for open surgery. PMID- 26233791 TI - Salvage Conservation Laryngeal Surgery After Radiation Therapy Failure. AB - Conservation laryngeal surgery (CLS) includes time-honored approaches such as the vertical partial laryngectomy and the open horizontal supraglottic laryngectomy, as well as the supracricoid partial laryngectomy and transoral laser microsurgery. Carefully selected patients can undergo transoral endoscopic or open CLS for early to intermediate stage recurrent tumors of the glottic and supraglottic larynx. Patient factors, such as comorbid pulmonary disease, are essential in selecting patients for CLS, especially after previous radiation therapy. This article reviews the preoperative indications and postoperative management of salvage CLS after radiation therapy for laryngeal cancer. PMID- 26233792 TI - Transoral and Transcervical Surgical Innovations in the Treatment of Glottic Cancer. AB - Transoral and transcervical surgery to treat glottic cancer has advanced substantially over the past decade. There have been considerable innovations that enhance vocal function for early disease and airway function for advanced disease. The fiber-based angiolytic 532 nm potassium titanyl phosphate laser has provided a new foundational strategy to maintain high cure rates with enhanced vocal outcomes for the treatment of early glottic disease. For advanced glottic cancer, transplanting cryopreserved aortic homograft to reconstruct wide-field laryngotracheal airway defects can provide an adequate airway caliber such that a long-term tracheotomy can frequently be avoided. PMID- 26233793 TI - Transcervical Conservation Laryngeal Surgery: An Anatomic Understanding to Enhance Functional and Oncologic Outcomes. AB - The goal of this review is to facilitate an improved understanding of the indications and contraindications to transcervical conservation laryngeal surgery in the treatment of glottic and supraglottic carcinoma. An overview of seminal anatomic principles is presented to provide guidance for clinicians contemplating open partial laryngectomy options. PMID- 26233794 TI - Function Preservation in Laryngeal Cancer. PMID- 26233795 TI - Dual inhibitors of the dengue and West Nile virus NS2B-NS3 proteases: Synthesis, biological evaluation and docking studies of novel peptide-hybrids. AB - Dengue virus (DENV) and West Nile virus (WNV) are mosquito-borne arboviruses responsible for causing acute systemic diseases and severe health conditions in humans. The discovery of therapies capable to prevent infections or treat infected individuals remains an important challenge, since no vaccine or specific efficient treatment could be developed so far. In this context, we present herein the synthesis, characterization, biological evaluation and docking studies of novel peptide-hybrids based on 2,4-thiazolidinedione scaffolds containing non polar groups. The most promising compound has an IC50 of 0.75 MUM against WNV protease, which represents a seventyfold improvement in activity compared to our previously reported compounds. Experimental results and docking studies are in agreement with the hypothesis that a non-polar group in the scaffold is important to obtain interactions between the inhibitors and a hydrophobic pocket in the substrate recognition region of the DENV and WNV NS2B-NS3 serine proteases. PMID- 26233796 TI - Synthesis and carbonic anhydrase I, II, IX and XII inhibitory activity of sulfamates incorporating piperazinyl-ureido moieties. AB - A series of sulfamates were synthesized using as lead compound SLC-0111, a sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in Phase I clinical trials. The new derivatives incorporated ureido moieties as spacers between the benzene sulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor, but the urea moieties were part of a substituted piperazine ring system. The derivatives (and some of their phenol precursors) were tested for the inhibition of the cytosolic, hCA I and II (off target isoforms) and the trans-membrane, tumor-associated hCA IX and XII enzymes (anticancer drug targets). Generally hCA I was not effectively inhibited, whereas many low nanomolar inhibitors were evidenced against hCA II (KIs in the range of 1.0-94.4 nM), IX (KIs in the range of 0.91-36.9 nM), and XII (KIs in the range of 1.0-84.5 nM). The best substitution fragments at the piperazine ring included the following moieties: 3-methylphenyl, 2,3-dimethylphenyl, 4-methoxyphenyl, 6 arylpyrimidine-2-yl. PMID- 26233797 TI - Identification of 2-aminopyrimidine derivatives as inhibitors of the canonical Wnt signaling pathway. AB - The canonical Wnt signaling pathway plays a fundamental role in embryonic as well as in adult development. Consequently, dysregulation of the pathway has been linked to a wide spectrum of pathological conditions. In a program aimed at the identification of small molecule inhibitors of the canonical Wnt pathway we identified a series of 2-aminopyrimidine derivatives which specifically inhibited the pathway with minimal or no sign of cellular toxicity. The hit molecules 1 and 2 showed promising inhibitory activity with IC50 values of approximately 10 MUM, but low solubility and metabolic stability. During the early stage of the hit series exploration, the pyrimidine core was variously decorated to obtain active compounds with a better physico-chemical profile. In particular, compound 13 showed Wnt inhibition activity comparable to hit molecules 1 and 2, with improved physico-chemical properties. Therefore, this series of compounds may be considered a promising starting point for the design of novel small molecule inhibitors of the canonical Wnt pathway. PMID- 26233798 TI - Optimization of permethyl ningalin B analogs as P-glycoprotein inhibitors. AB - In the present study, a total of 9 novel permethyl ningalin B analogs have been synthesized and evaluated for their P-gp modulating activity in a P-gp overexpressed breast cancer cell line LCC6MDR. Among these derivatives, compound 12 with dimethoxy groups at rings A and B and tri-substitution at ring C with ortho-methoxyethylmorpholine, meta-bromo and para-benzyloxy groups displays the most potent P-gp modulating activity with EC50 of 423 nM to reverse paclitaxel resistance. It is non-toxic towards L929 fibroblast with IC50 greater than 100 MUM and with selective index greater than 236. Its mechanism to reverse P-gp mediated drug resistance is by virtue of inhibiting transport activity of P-gp, restoring intracellular drug accumulation and eventually chemosensitizing the cancer cells to anticancer drug again. Moreover, compound 12 showed better solubility (405 ng/mL) than hit compound 1 in phosphate buffer (pH 4.0). In summary, our study demonstrates that permethyl ningalin B derivative 12 is non toxic and efficient P-gp inhibitor that is a potential candidate to be used clinically to reverse P-gp mediated cancer drug resistance. PMID- 26233799 TI - Ethylenedioxy homologs of N-methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) and its corresponding cathinone analog methylenedioxymethcathinone: Interactions with transporters for serotonin, dopamine, and norepinephrine. AB - N-Methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; 'Ecstasy'; 1) and its beta-keto analog methylone (MDMC; 2) are popular drugs of abuse. Little is known about their ring-expanded ethylenedioxy homologs. Here, we prepared N-methyl-(3,4 ethylenedioxyphenyl)-2-aminopropane (EDMA; 3), both of its optical isomers, and beta-keto EDMA (i.e., EDMC; 4) to examine their effects at transporters for serotonin (SERT), dopamine (DAT), and norepinephrine (NET). In general, ring expansion of the methylenedioxy group led to a several-fold reduction in potency at all three transporters. With respect to EDMA (3), S(+)3 was 6-fold, 50-fold, and 8-fold more potent than its R(-) enantiomer at SERT, DAT, and NET, respectively. Overall, in the absence of a beta-carbonyl group, the ethylenedioxy (i.e., 1,4-dioxane) substituent seems better accommodated at SERT than at DAT and NET. PMID- 26233800 TI - Synthesis, nicotinic acetylcholine receptor binding, in vitro and in vivo pharmacology properties of 3'-(substituted pyridinyl)-deschloroepibatidine analogs. AB - Over the last several years we have synthesized and studied the in vitro and in vivo nAChR pharmacological properties of epibatidine (4) analogs. In this study we report the synthesis, nAChR in vitro and in vivo pharmacological properties of 3'-(substituted pyridinyl)-deschloroepibatidine analogs (5a-e and 6a-e). All of the analogs had high binding affinity for alpha4beta2(*)-nAChRs. Several of the analogs were potent antagonists of alpha4beta2-nAChRs in in vitro efficacy tests and were potent antagonists of nicotine-induced antinociception in the mouse tail flick test. Compound 6b had a Ki = 0.13 nM in the binding assay, 25- and 46-fold selectivity for the alpha4beta2(*)-nAChR relative to the alpha3beta4- and alpha7 nAChR, respectively, in the in vitro efficacy test and an AD50 = 0.13 MUg/kg in the tail-flick test. Combined with favorable calculated physiochemical properties compared to varenicline, our findings suggest that 6b should be considered for development as a potential pharmacotherapy for treating nicotine addiction and other CNS disorders. PMID- 26233801 TI - Synthesis and structure-activity relationship of uracil nucleotide derivatives towards the identification of human P2Y6 receptor antagonists. AB - P2Y6 receptor (P2Y6-R) is involved in various physiological and pathophysiological events. With a view to set rules for the design of UDP-based reversible P2Y6-R antagonists as potential drugs, we established structure activity relationship of UDP analogues, bearing modifications at the uracil ring, ribose moiety, and the phosphate chain. For instance, C5-phenyl- or 3-NMe-uridine 5'-alpha,beta-methylene-diphosphonate, 16 and 23, or lack of 2'-OH, in 12-15, resulted in loss of both agonist and antagonist activity toward hP2Y6-R. However, uridylyl phosphosulfate, 19, selectively inhibited hP2Y6-R (IC50 112 MUM) versus P2Y2/4-Rs. In summary, we have established a comprehensive SAR for hP2Y6-R ligands towards the development of hP2Y6-R antagonists. PMID- 26233802 TI - Identification and comparison of the predictors of maximal inspiratory force and handgrip in a healthy elderly population. The proof study. AB - BACKGROUND: A severe weakness of peripheral muscles occurs in half of the persons aged 80 years or older. The common factors between muscle depletion and reduced respiratory strength have not yet been established. OBJECTIVE: In the subjects of the Proof cohort, we aimed to identify, among body composition, pulmonary function and energy expenditure parameters, the predictors of maximal inspiratory pressure (MIP) as an index of respiratory muscle strength and handgrip (HG) as an index of peripheral muscle strength. SUBJECTS AND METHODS: In 375 healthy elderly subjects aged 72 +/- 1 years, fat mass (FM) and fat free mass (FFM) were assessed by DEXA, the last being also indexed to height (FFMI). Spirometry was performed and daily energy expenditure (DEE) was estimated by a questionnaire. After three years, MIP and HG of the dominant arm were determined and the predicting value of pulmonary function tests, body composition and DEE on these parameters was tested. RESULTS: Mean MIP and HG were 77 +/- 26% and 106 +/- 19% of the predicted value (%pred) with 90 (24%) and 30 (8%) subjects below standards, respectively. There was a significant but weak correlation between MIP%pred and HG%pred (r = 0.175, p < 0.001). Logistic regression showed that low MIP was predicted by trunk FFM and FFMI in women, and DEE in men. Low HG was predicted by trunk FM in men only. CONCLUSIONS: The predictors of a reduction of MIP in the elderly differ from those of HG, suggesting a differential regulation of respiratory muscle and arm strength. PMID- 26233803 TI - Phase I dose-finding and pharmacokinetic study of docetaxel and gefitinib in patients with advanced or metastatic non-small-cell lung cancer: evaluation of drug-drug interaction. AB - PURPOSE: Docetaxel and gefitinib play key roles in the treatment of non-small cell lung cancer (NSCLC), and their combination could be of interest. Both drugs are mainly metabolized by CYP3A4, and drug-drug interactions are a major concern. This phase I dose-finding study was designed to assess the tolerability and drug drug interactions in this combination using full pharmacokinetic (PK) samplings. METHODS: Docetaxel was intravenously administered on days 1 and 22 at a dose of 45 or 60 mg/m(2). Gefitinib (250 mg/day) was orally administrated starting on day 2. Ten PK samplings of docetaxel were performed on days 1 and 22. Seven PK samplings of gefitinib were performed on day 18 +/- 3 and on day 22. RESULTS: Twelve patients with advanced or metastatic NSCLC were enrolled without considering EGFR mutation status. The major toxicity was neutropenia. Two patients withdrew from this study due to dose-limiting toxicities; however, the toxicity profiles in this combination were generally acceptable. The docetaxel AUC0-24 and C max did not differ whether administered alone or with gefitinib, and the geometric mean ratios (GMRs) of AUC0-24 and C max (co administrated/administrated alone) were 0.95 (90 % CI 0.85-1.06) and 0.95 (90 % CI 0.85-1.05), respectively. Furthermore, the GMRs of the steady state gefitinib AUC0-24 and C max were 0.93 (90 % CI 0.84-1.03) and 0.98 (90 % CI 0.88-1.09), respectively. CONCLUSION: The tolerability of 60 mg/m(2) docetaxel with 250 mg/day gefitinib was confirmed, and we observed no drug-drug interaction in this combination. PMID- 26233804 TI - [Psychological distress of children with progressive diseases and multiple disabilities: A crossed analysis]. AB - INTRODUCTION: In this paper, we present the results of research conducted on the psychological distress of lysosomal-disease-affected children. Lysosomal diseases are rare genetic diseases most often leading to severe disabilities, both psychological and physiological. As frequently reported by their relatives, affected children experience nervous breakdowns, which are sometimes treated with antidepressant prescriptions. However, mental impairment as well physical disabilities can prevent children from making their pain noticed and identified by their relatives. This raises a new research question: when disabilities are severe, how should the psychological distress of affected children be identified? METHOD AND POPULATION: Recent studies on the care of children with multiple disabilities (San Salavadour 2000; Scelles 2003; Camelio 2006; Pautrel, 2009) have used the children's family and caregivers to access their feelings, considered to be translators of children's feelings because they understand their nonverbal language (Camelio, 2006). Using this methodology, four parents from the French not-for-profit association called "VML" (Vaincre les maladies lysosomales) and four professionals were involved in semi-structured interviews. The goal of these interviews was to identify signs of possible psychological suffering, the context in which those signs were expressed, the meaning and the value attributed to it by the family and caregivers, and the reaction as well as an evaluation of that reaction. Thirteen children were involved, 12 of whom were described as having shown signs of psychological distress. Six lysosomal diseases were represented. RESULTS: Two types of signs were reported: active signs (e.g., agitation, screaming, crying) and passive signs (e.g., no communication, withdrawal, lack of facial expression). Most of the time, passive signs were interpreted by the family and caregivers as evidence of deep psychological distress. The meanings of both types of sign were the following: fear, anxiety, distress, sadness, depression, stress, anger, and frustration. The family and caregivers responded by socializing with the child, providing him with comfort, assisting him in meeting his basic needs, administering medication, etc. Loneliness, disease-progression-related loss of abilities, physical pain, and epilepsy were the main factors of psychological distress. Three children were prescribed an antidepressant, two with an anticonvulsive effect. DISCUSSION: The results of this research depend on the difficulty making a distinction between physical and psychological pain and the interpretation of the child's relatives remains an imperfect translation of what the child feels. Further research to overcome these shortcomings is currently under consideration. Moreover, quantitative analysis is needed to make this research more robust. PMID- 26233806 TI - Lack of association between mitochondrial DNA G15257A and G15812A variations and multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a debilitating disease of the central nervous system for which no definitive therapy has yet been developed. The etiology remains uncertain, but there is evidence of genetic susceptibility to the disease, including contributions from mitochondrial DNA (mtDNA) variations to the pathogenesis of MS. G15257A and G15812A are variations of the mtDNA tRNA(Thr) gene in MS sufferers of different populations. The present study tested the hypothesis of an association of the G15257A and G15812A variations of the mtDNA tRNA(Thr) gene to the susceptibility to MS in an Iranian population. MATERIAL AND METHODS: Two hundred subjects included 100 MS patients and 100 unrelated healthy controls. DNA was extracted from blood samples by means of a salting-out method. The mtDNA fragment was amplified by polymerase chain reaction (PCR). Restriction fragment length polymorphism (RFLP) analysis was done by digestion of the PCR products with Acc I and Rsa I restriction endonuclease enzymes for mtDNA G15257A and G15812A variations, respectively. Afterwards, the restriction products were visualized by electrophoresis using 3% Agarose gel and safe DNA gel staining. To confirm the accuracy of genotyping procedure, sequencing of the mtDNA fragments was carried out in randomly selected samples. RESULTS: The mtDNA G15257A variation was found in one of the 100 patients and one of the 100 controls (P=0.637) (odds ratio [OR]=1, 95% confidence interval [95% CI]=0.0-79.2). The mtDNA G15812A variation was not found in any of the 100 patients or 100 controls (0%) (P=1) (OR=1, 95% CI=0.0-79.2). CONCLUSION: The evidence from the present study is inconsistent with the hypothesis that the G15257A and G15812A variations in the mtDNA tRNA(Thr) gene are associated with susceptibility to MS in the selected population. PMID- 26233805 TI - A genetic association study of two genes linked to neurodegeneration in a Sardinian multiple sclerosis population: the TARDBP Ala382Thr mutation and C9orf72 expansion. AB - Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by inflammation and accompanied and followed by neurodegeneration. Missense mutations of the TAR DNA Binding Protein gene (TARDBP) located in the chromosome 1p36.22 region, and the hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) are pathogenic in other neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Assuming that TARDBP Ala382Thr mutation and C9orf72 expansion may underlie MS, we evaluated their frequency in a large cohort of MS patients and controls from Sardinia, an island characterized by a very high frequency of MS and an unusual genetic background. Genomic DNA was extracted from peripheral blood and analyzed for the presence of a TARDBP Ala382Thr mutation and C9orf72 expansion. Difference in the frequency of these mutations between MS patients and controls was calculated using the chi(2) test with a standard 2*2 table. The Ala382Thr mutation in its heterozygous state was found in 27/1833 patients (1.4%) and 20/1475 controls (1.3%), whereas C9orf72 pathogenic repeat expansion was found in 6/1014 MS patients (0.6%) and 2/333 controls (0.6%). Individuals carrying the mutations did not present with other neurodegenerative conditions and any differences were reported between groups. TARDBP Ala382Thr mutation and C9orf72 expansion do not play a major role in MS pathogenesis in the Sardinian population. Further analyses on larger samples of MS patients from other populations are needed to better define the possible role of these genes in the complex interplay between neuroinflammation and neurodegeneration in MS. PMID- 26233807 TI - Pain perception in major depressive disorder: a neurophysiological case-control study. AB - BACKGROUND: Depression and pain may sometimes be related conditions. Occasionally, depression may be associated with physical symptoms, such as back pain and headache. Moreover, depression may impair the subjective response to pain and is likely to influence the pain feeling. Conversely, chronic pain may represent an emotional condition as well as physical sensation, and can influence both the mood and behaviour. AIM: To better understand the relationship between pain and depression, we therefore assessed the pain threshold and the tolerance pain threshold in patients with depressive disorders. MATERIALS AND METHODS: We conducted a case-control study and selected patients who had recently received a diagnosis of major depression (DSM-IV), before treatment, and without any significant pain complaints. Age- and sex-matched healthy controls were also included. Tactile and pain thresholds were assessed in all subjects through an electrical stimulation test. All results were compared between the groups. RESULTS: 27 patients and 27 age-matched healthy controls were included in the study. Tactile, pain and tolerance thresholds were evaluated in all subjects. The pain threshold and pain tolerance were lower in patients with major depression than controls. All differences were statistically significant (p<0.05). CONCLUSION: These results suggest the abnormal processing of pain stimuli in depressive disorders. PMID- 26233808 TI - Efficacy and safety of NABOTA in post-stroke upper limb spasticity: a phase 3 multicenter, double-blinded, randomized controlled trial. AB - Botulinum toxin A is widely used in the clinics to reduce spasticity and improve upper limb function for post-stroke patients. Efficacy and safety of a new botulinum toxin type A, NABOTA (DWP450) in post-stroke upper limb spasticity was evaluated in comparison with Botox (onabotulinum toxin A). A total of 197 patients with post-stroke upper limb spasticity were included in this study and randomly assigned to NABOTA group (n=99) or Botox group (n=98). Wrist flexors with modified Ashworth Scale (MAS) grade 2 or greater, and elbow flexors, thumb flexors and finger flexors with MAS 1 or greater were injected with either drug. The primary outcome was the change of wrist flexor MAS between baseline and 4weeks post-injection. MAS of each injected muscle, Disability Assessment Scale (DAS), and Caregiver Burden Scale were also assessed at baseline and 4, 8, and 12weeks after the injection. Global Assessment Scale (GAS) was evaluated on the last visit at 12weeks. The change of MAS for wrist flexor between baseline and 4weeks post-injection was -1.44+/-0.72 in the NABOTA group and -1.46+/-0.77 in the Botox group. The difference of change between both groups was 0.0129 (95% confidence interval -0.2062-0.2319), within the non-inferiority margin of 0.45. Both groups showed significant improvements regarding MAS of all injected muscles, DAS, and Caregiver Burden Scale at all follow-up periods. There were no significant differences in all secondary outcome measures between the two groups. NABOTA demonstrated non-inferior efficacy and safety for improving upper limb spasticity in stroke patients compared to Botox. PMID- 26233809 TI - Do additional imaging studies change operative management in patients undergoing adrenalectomy? AB - BACKGROUND: The purpose of this study is to determine the incidence of a secondary imaging modality (SIM) in the workup of adrenal masses and the usefulness of this additional imaging in changing surgical management. METHODS: A retrospective analysis of our adrenalectomy database was performed on adult patients who underwent >=1 imaging study before surgery. A multivariate logistic regression model was then constructed to identify patient factors that predisposed SIM. RESULTS: From February 2001 to August 2014, 264 cases met inclusion criteria, of which 98 (37%) were identified to have SIM. Patients with cancer (P = .001), incidentaloma (P = .002), and pheochromocytoma (P < .0001) were more likely to undergo additional imaging. MRI was the most commonly obtained SIM. In addition, 90 of the 98 cases (92%) met indications for adrenalectomy with primary imaging study and biochemical screening alone. Of the remaining 8 cases, in only 4 instances (4%) did SIM modify surgical decision making. CONCLUSION: The high incidence of unnecessary additional imaging performed in patients undergoing adrenalectomy is counterproductive to efforts toward cost-conscious, high-quality health care. Patients with adrenal tumors would benefit from early surgical referral to allow the surgeon to help guide clinical decision making and to avoid the use of excessive imaging. PMID- 26233810 TI - Modified laparoscopic Sugarbaker repair decreases recurrence rates of parastomal hernia. AB - BACKGROUND: Parastomal hernia (PH) is a frequent complication of stoma formation, and recurrence after repair is common. A laparoscopic modified Sugarbaker technique (SB) may decrease the recurrence of PH compared with other methods. METHODS: A retrospective review, approved by the institutional review board, of patients who underwent PH repair between 2004 and 2014 was performed. Demographics, factors for ostomy formation, hernia risk factors, intraoperative and postoperative information, and recurrence data were compared among SB and other techniques. Time to recurrence was compared between SB versus other techniques with the Kaplan-Meier method and adjusted Cox proportional hazards regression modeling. RESULTS: Sixty-two PH repairs were performed: 39 (61%) paraileostomy and 23 (39%) paracolostomy. Repairs included 25 laparoscopic modified SB and 37 from other techniques. There was no difference in demographics. Postoperative complication rate was lesser in SB versus all other groups (40% vs 76%, P = .02). Recurrence rates were lesser for SB versus all others (16% vs 60%, P < .001). Follow-up was similar among all groups. After adjustment, SB was found to be protective of recurrences (hazard ratio = .28, 95% confidence interval = 0.09-0.82). CONCLUSION: A laparoscopic modified SB technique provides decreased rates of recurrence and postoperative complications compared with other approaches. PMID- 26233813 TI - Child maltreatment and risk behaviors: The roles of callous/unemotional traits and conscientiousness. AB - Child maltreatment poses significant risk to the development of callous/unemotional traits as well as risk behaviors such as engaging in violence, having sex with strangers, and binge drinking. In the current study, the indirect pathway from child maltreatment to risk behaviors was examined via callous/unemotional traits; whereas the conscientious personality trait was tested as a moderator of this indirect pathway. Young adults and parents (N=361; Mage=19.14, SD=1.44) completed questionnaires on child maltreatment histories, callousness/unemotional traits, personality characteristics, and risk behaviors. Structural equation modeling was used to examine the hypothesized direct, indirect and conditional indirect effects. Findings showed indirect links between the child maltreatment latent factor and physical fighting, having sex with strangers, and binge drinking via callous/unemotional traits. Furthermore, the conscientiousness personality type significantly buffered the connection between callous/unemotional traits and physical fighting, supporting a conditional indirect effects. Callous/unemotional traits are important factors in the underlying mechanism between child maltreatment and risk behaviors among young adults, and conscientiousness serves as a protective factor against violence. Preventive intervention programs and clinicians may benefit from focusing in addressing callous/unemotional traits among youth who report childhood maltreatment experiences as well as targeting conscientiousness as a protective factor. PMID- 26233814 TI - [SECOT-GEIOS guidelines in osteoporosis and fragility fracture. An update]. PMID- 26233815 TI - Fatty Acid and Lipid Profiles with Emphasis on n-3 Fatty Acids and Phospholipids from Ciona intestinalis. AB - In order to establish Ciona intestinalis as a new bioresource for n-3 fatty acids rich marine lipids, the animal was fractionated into tunic and inner body tissues prior to lipid extraction. The lipids obtained were further classified into neutral lipids (NL), glycolipids (GL) and phospholipids (PL) followed by qualitative and quantitative analysis using GC-FID, GC-MS, (1)H NMR, 2D NMR, MALDI-TOF-MS and LC-ESI-MS methods. It was found that the tunic and inner body tissues contained 3.42-4.08% and 15.9-23.4% of lipids respectively. PL was the dominant lipid class (42-60%) irrespective of the anatomic fractions. From all lipid fractions and classes, the major fatty acids were 16:0, 18:1n-9, C20:1n-9, C20:5n-3 (EPA) and C22:6n-3 (DHA). The highest amounts of long chain n-3 fatty acids, mainly EPA and DHA, were located in PL from both body fractions. Cholestanol and cholesterol were the dominant sterols together with noticeable amounts of stellasterol, 22 (Z)-dehydrocholesterol and lathosterol. Several other identified and two yet unidentified sterols were observed for the first time from C. intestinalis. Different molecular species of phosphatidylcholine (34 species), sphingomyelin (2 species), phosphatidylethanolamine (2 species), phosphatidylserine (10 species), phosphatidylglycerol (9 species), ceramide (38 species) and lysophospholipid (5 species) were identified, representing the most systematic PL profiling knowledge so far for the animal. It could be concluded that C. intestinalis lipids should be a good alternative for fish oil with high contents of n-3 fatty acids. The lipids would be more bioavailable due to the presence of the fatty acids being mainly in the form of PL. PMID- 26233816 TI - Microwave Energy Increases Fatty Acid Methyl Ester Yield in Human Whole Blood Due to Increased Sphingomyelin Transesterification. AB - Dried blood spots (DBS) by fingertip prick collection for fatty acid profiling are becoming increasingly popular due to ease of collection, minimal invasiveness and its amenability to high-throughput analyses. Herein, we assess a microwave assisted direct transesterification method for the production of fatty acid methyl esters (FAME) from DBS. Technical replicates of human whole blood were collected and 25-MUL aliquots were applied to chromatography strips prior to analysis by a standard 3-h transesterification method or microwave-assisted direct transesterification method under various power (variable vs constant), time (1-5 min) and reagent (1-10% H2SO4 in methanol) conditions. In addition, a standard method was compared to a 5-min, 30-W power microwave in 1% H2SO4 method for FAME yield from whole blood sphingomyelin, and sphingomyelin standards alone and spiked in whole blood. Microwave-assisted direct transesterification yielded no significant differences in both quantitative (nmol/100 uL) and qualitative (mol%) fatty acid assessments after as little as 1.5- and 1-min reaction times, respectively, using the variable power method and 5% H2SO4 in methanol. However, 30-W power for 5 min increased total FAME yield of the technical replicates by 14%. This increase appears largely due to higher sphingomyelin-derived FAME yield of up to 109 and 399% compared to the standard method when determined from whole blood or pure standards, respectively. In conclusion, microwave-assisted direct transesterification of DBS achieved in as little as 1-min, and 5-min reaction times increase total fatty acids primarily by significantly improving sphingomyelin-derived fatty acid yield. PMID- 26233817 TI - Milk Phospholipids Enhance Lymphatic Absorption of Dietary Sphingomyelin in Lymph Cannulated Rats. AB - Supplementation with sphingomyelin has been reported to have beneficial effects on disease prevention and health maintenance. However, compared with glycerolipids, intact sphingomyelin and ceramides are poorly absorbed. Therefore, if the bioavailability of dietary sphingomyelin is increased, then the dose administered can be reduced. This study was designed to identify molecular species of ceramide in rat lymph after the ingestion of milk sphingomyelin, and to compare the effect of purified sphingomyelin with milk phospholipids concentrate (MPL, 185 mg sphingomyelin/g) on lymphatic absorption of milk sphingomyelin. Lymph was collected hourly for 6 h from lymph-cannulated rats (n = 8/group) after the administration of a control emulsion (triolein, bovine serum albumin, and sodium taurocholate), a sphingomyelin emulsion (control + purified sphingomyelin), or a MPL emulsion (control + MPL). Molecular species of ceramide in lymph were analyzed using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Molecular species of ceramide, containing not only d18:1, but also d17:1 and d16:1 sphingosine with 16:0, 22:0, 23:0, and 24:0 fatty acids (specific to milk sphingomyelin), were increased in rat lymph after the administration of milk sphingomyelin. Their molecular species were similar to those of dietary milk sphingomyelin. Recovery of ceramide moieties from dietary sphingomyelin was 1.28- to 1.80-fold significantly higher in the MPL group than in the sphingomyelin group. Our results demonstrated that dietary sphingomyelin from milk was transported to lymph as molecular species of ceramide hydrolyzed from milk sphingomyelin and co-ingestion of sphingomyelin with glycerophospholipids enhanced the bioavailability of dietary sphingomyelin. PMID- 26233818 TI - Mass Spectrometric Confirmation of gamma-Linolenic Acid Ester-Linked Ceramide 1 in the Epidermis of Borage Oil Fed Guinea Pigs. AB - Ceramide 1 (Cer1), a Cer species with eicosasphingenine (d20:1) amide-linked to two different omega-hydroxy fatty acids (C30wh:0:C32wh:1), which are, in turn, ester-linked to linoleic acid (LNA; 18:2n-6), plays a critical role in maintaining the structural integrity of the epidermal barrier. Prompted by the recovery of a disrupted epidermal barrier with dietary borage oil [BO: 36.5% LNA and 23.5% gamma-linolenic acid (GLA; 18:3n-6)], in essential fatty acid (EFA) deficient guinea pigs, we further investigated the effects of BO on the substitution of ester-linked GLA for LNA in these two epidermal Cer1 species by LC-MS in positive and negative modes. Dietary supplementation of BO for 2 weeks in EFA-deficient guinea pigs increased LNA ester-linked to C32wh:1/d20:1 and C30wh:0/d20:1 of Cer1. Moreover, GLA ester-linked to C32wh:1/d20:1, but not to C30wh:0/d20:1, of Cer1 was detected, which was further confirmed by the product ions of m/z 277.2 for ester-linked GLA and m/z 802.3 for the deprotonated C32wh:1/d20:1. C20-Metabolized fatty acids of LNA or GLA were not ester-linked to these Cer1 species. Dietary BO induced GLA ester-linked to C32wh:1/d20:1 of epidermal Cer1. PMID- 26233819 TI - Modulation of the Expression of Components of the Stress Response by Dietary Arachidonic Acid in European Sea Bass (Dicentrarchus labrax) Larvae. AB - This study reports for the first time on European sea bass, Dicentrarchus labrax (L.), larvae, the effect of different levels of dietary arachidonic acid (ARA; 20:4n-6) on the expression of genes related to the fish stress response. Copies of mRNA from genes related to steroidogenesis [StAR (steroidogenic acute regulatory protein), c-Fos, and CYP11beta (11beta-hydroxylase gene)], glucocorticoid receptor complex [GR (glucocorticoid receptor) and HSP (heat shock proteins) 70 and 90) and antioxidative stress (catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase] were quantified. Eighteen day-old larvae were fed for 14 days with three experimental diets with increasing levels of ARA (0.3, 0.6 and 1.2% d.w.) and similar levels of docosahexaenoic (22:6n-3) and eicosapentaenoic (20:5n-3) acids (5 and 3%, respectively). The quantification of stress-related genes transcripts was conducted by One-Step TaqMan real time RT PCR with the standard curve method (absolute quantification). Increase dietary levels of ARA induced a significantly (p < 0.05) down-regulation of genes related to cortisol synthesis, such as StAR and CYP11beta and up-regulated genes related to glucocorticoid receptor complex, such as HSP70 and GR. No effects were observed on antioxidant enzymes gene expression. These results revealed the regulatory role of dietary ARA on the expression of stress-related genes in European sea bass larvae. PMID- 26233820 TI - Reply to: "Gallbladder cancer: Nihilism abates, optimism prevails". PMID- 26233821 TI - Gallbladder cancer: Nihilism abates, optimism prevails. PMID- 26233822 TI - FDES, a GPU-based multislice algorithm with increased efficiency of the computation of the projected potential. AB - While the computational complexity of calculation of the projected potential in the multislice algorithm through reciprocal space scales quadratically with the number of atoms A per slice, a pure real-space calculation scales linearly with A. A hybrid strategy is introduced that has a theoretical complexity of O(AlogA), but that, when measured, outperforms both the reciprocal-space and the real-space approach by approximately an order in A and a large factor, respectively. This strategy is implemented in a new program, dubbed forward dynamical electron scattering (FDES), which simulates high resolution transmission electron microscopy images, diffraction patterns and convergent beam electron diffraction patterns. FDES attains a further increase in speed by running on a graphics processing unit and is made available to the community as open software. PMID- 26233823 TI - High contrast 3D imaging of surfaces near the wavelength limit using tabletop EUV ptychography. AB - Scanning electron microscopy and atomic force microscopy are well-established techniques for imaging surfaces with nanometer resolution. Here we demonstrate a complementary and powerful approach based on tabletop extreme-ultraviolet ptychography that enables quantitative full field imaging with higher contrast than other techniques, and with compositional and topographical information. Using a high numerical aperture reflection-mode microscope illuminated by a tabletop 30 nm high harmonic source, we retrieve high quality, high contrast, full field images with 40 nm by 80 nm lateral resolution (~1.3 lambda), with a total exposure time of less than 1 min. Finally, quantitative phase information enables surface profilometry with ultra-high, 6 A axial resolution. In the future, this work will enable dynamic imaging of functioning nanosystems with unprecedented combined spatial (<10 nm) and temporal (<10 fs) resolution, in thick opaque samples, with elemental, chemical and magnetic sensitivity. PMID- 26233824 TI - Predicting the future in schizophrenia: The discrepancy between anticipatory and consummatory pleasure. AB - When predicting future emotions we use inaccurate biases which rely on our most salient and recent experiences. In schizophrenia, there appears to be a specific deficit in this anticipatory process which is associated with reduced motivation and engagement. The nature of this deficit and how it differs to the general population is unclear. This study introduces a new task examining the discrepancy between anticipated and experienced pleasure and investigates its potential usefulness to characterise the pleasure deficit in people with schizophrenia. Forty-eight healthy controls and 50 individuals with schizophrenia completed the Components of Pleasure Task (COP) which uses a range of images to generate anticipatory and experiential ratings. Participants also completed measures of mood and symptoms. Individuals with schizophrenia had a larger anticipatory consummatory discrepancy score. This was due to under-anticipating highly pleasant stimuli and over-anticipating low pleasantness stimuli. People with schizophrenia are blunted compared to controls when anticipating stimuli, considering highly and lowly rated stimuli alike. A greater discrepancy between anticipated and experienced pleasure may contribute to negative symptoms such as poor motivation and social withdrawal. Reducing the discrepancy between experienced and anticipated pleasure may be a target for interventions aiming to reduce negative symptoms. PMID- 26233825 TI - Depressed older adults may be less cared for than depressed younger ones. AB - The aim of the study was to investigate depression treatment use, either psychotherapy (PT) or antidepressant drugs (ADT) in the older and younger depressed population. Cohorts of 6316 elderly (>=65 year-old) and 25,264 matched non-elderly (25-64 year-old) depressed patients were created from a large national claims database of managed care plans from 2003 to 2006. Factors associated with ADT or PT were assessed using multivariate logistic models. During the 120 days following the depression diagnosis, the elderly persons were less often treated than the younger adults either by ADT (25.6% vs. 33.8%) or by PT (13.0% vs. 34.4%). ADT dispensing occurred later in the elderly group (51 vs. 14 days). ADT was associated with comorbid chronic conditions or polypharmacy in the elderly and younger adults. The selection of treatment (ADT or PT) was associated with the history of treated depression using the same type of treatment, in both groups. Thus, depression goes commonly untreated. Comorbidity was associated with higher ADT dispensing rates. However, although depressed elderly commonly presented with comorbidity, this age group was at higher risk of untreated illness or later treatment. PMID- 26233826 TI - Theory of mind in Koreans with schizophrenia: A meta-analysis. AB - Previous meta-analytic studies conducted in Western countries have consistently revealed impairments in theory of mind (ToM) in schizophrenia. However, there is no systematic meta-analytic review of ToM deficits in individuals with schizophrenia in non-Western countries. In addition, ToM impairments in individuals with schizophrenia have not been investigated in the distinctive domains (i.e., verbal vs. visual, or affective vs. cognitive). The current meta analytic study systematically synthesized 13 studies comparing ToM performance of adults with schizophrenia (n=377) and that of healthy controls (n=386) in Korea. The results indicate that Koreans with schizophrenia showed overall large ToM impairments (d=-1.273) but intact performance in control tasks that require a similar amount of cognitive demand as ToM tasks do. Large impairments in affective and cognitive ToM (d=-1.445 and -1.202, respectively) and verbal and visual ToM (d=-1.239 and -1.221, respectively) were found in Koreans with schizophrenia. There were no differences in magnitude between affective and cognitive ToM or between verbal and visual ToM. These results suggest that Koreans with schizophrenia experience substantial impairments in various ToM domains. Comprehensive multi-modality-based assessment targeting various ToM domains should be considered for treatment planning of individuals with schizophrenia. PMID- 26233827 TI - Does smoking abstinence influence distress tolerance? An experimental study comparing the response to a breath-holding test of smokers under tobacco withdrawal and under nicotine replacement therapy. AB - Distress tolerance has been operationalized as task persistence in stressful behavioral laboratory tasks. According to the distress tolerance perspective, how an individual responds to discomfort/distress predicts early smoking lapses. This theory seems weakly supported by experimental studies since they are limited in number, show inconsistent results, do not include control conditions. We tested the response to a stressful task in smokers under abstinence and under no abstinence to verify if tobacco abstinence reduces task persistence, thus distress tolerance. A placebo-controlled, double-blind, randomized, cross-over design was used. Twenty smokers underwent a breath holding test after the administration of nicotine on one test day and a placebo on another test day. Physiological and psychological variables were assessed at baseline and directly before and after each challenge. Abstinence induced a statistically significant shorter breath holding duration relative to the nicotine condition. No different response to the breath holding test was observed when nicotine and placebo conditions were compared. No response to the breath holding test was found when pre- and post-test values of heart rate, blood pressure, Visual Analogue Scale for fear or discomfort were compared. In brief, tobacco abstinence reduces breath holding duration but breath holding test does not influence discomfort. PMID- 26233828 TI - Cognitive structure from childhood to adulthood in kindreds densely affected by schizophrenia and bipolar disorder. AB - The developmental aspects of cognitive structures from childhood until adulthood and across different levels of risk for psychopathology have been little studied. The aim of the current study was to explore the cognitive factorial structure in subsamples from highly familial and densely affected kindreds of schizophrenia and bipolar disorder - i.e. affected adult members, non-affected adult members and high-risk youth. The same neuropsychological battery was administered in a sample of 480 participants: schizophrenia and bipolar patients (n=51), young high risk offspring (n=61), non-affected adult relatives of patients (n=96), and controls (n=272). Exploratory Factorial Analysis was performed in the control sample and yielded a 5-factor solution: verbal comprehension, processing speed/working memory, visual learning and memory, verbal learning and memory, reasoning and problem solving. Confirmatory factor analysis indicated that the hierarchical 5-factor solution was well suited for the young high-risk offspring, the non-affected adult relatives of patient and the patients. A hierarchical model with a "g" factor was a good fit for all subsamples. These results suggest that cognitive impairments may aggregate in highly familial individuals. PMID- 26233829 TI - Juvenile sex offenders: Personality profile, coping styles and parental care. AB - In recent years, there has been an increasing interest in juvenile sex offenders showing that this population is highly heterogeneous. The aim of the present study was to identify possible different profiles that could help understand the motivation behind offending, comparing 31 Juvenile Sexual Offenders (JSOs), 31 Juvenile Sexual Non Offenders (JSNOs) and 31 Juvenile Non Offenders (Control Group). A data collection form, the Minnesota Multiphasic Personality Inventory Adolescent (MMPI-A) or Minnesota Multiphasic Personality Inventory-2 (MMPI-2), the Coping Inventory for Stressful Situations (CISS) and the Parental Bonding Inventory (PBI) were administered to all participants. The results show that JSOs differs from JNSOs in some domains, such as living in single-parent homes, while maintain some common aspects such as academic failure and previous sexual intercourse. Moreover, JNSOs showed more abnormal personality traits, such as Authority Problems, MacAndrew Alcoholism, Acknowledgement and Alcohol-Drug Problem Proneness compared to JSOs and the Control Group, while JSOs and JNSOs use a coping strategy more oriented to Avoidance and Distraction compared to the Control group. Finally, JSOs described the relationships with fathers characterized by higher care and protection than JNSOs. These findings provide additional evidence with respect the prevention and treatment of criminal sexual behavior in adolescent. PMID- 26233830 TI - The mental illness microaggressions scale-perpetrator version (MIMS-P): Reliability and validity. AB - The study objective was to develop a new measure for use in the empirical measurement of microaggression behaviors perpetrated towards persons with mental illness and examine its psychometric properties. Following development of an initial item pool, 505 participants (students at a large college in New York City and community members recruited through Amazon's Mechanical Turk program) completed an online survey including a 20-item measure of microaggression behaviors. Exploratory factor analysis revealed three subscales: Assumption of Inferiority (alpha=0.81), Patronization (alpha=0.78), and Fear of Mental Illness (alpha=0.63). Additional analyses supported convergent validity of the measure with two widely used measures of mental illness stigma. The MIMS-P is the first instrument to measure microaggressions endorsed by perpetrators against a socially marginalized group and demonstrates strong psychometric properties. Inclusion of this scale in future research can help facilitate understanding of perpetrator perspectives and assist with intervention development. PMID- 26233831 TI - Influence of the leptin and cortisol levels on craving and smoking cessation. AB - Leptin inhibits cortisol release and may increase the craving for cigarettes, hindering the process of smoking cessation. We evaluate the influence of the initial concentration of cortisol and serum leptin on craving and smoking status in individuals after one month of treatment for smoking cessation. The leptin concentration was adjusted by the Initial Body Mass Index (BMI) (leptin/BMI) and the initial percentage of body fat (%BF) (leptin/%BF). The craving was assessed using the Questionnaire of Smoking Urges-Brief (QSU-Brief). The QSU-Brief was assessed about a score of factor 1 (positive reinforcement by tobacco), and factor 2 (negative reinforcement by tobacco). Correlation was found between QSU Brief (Factor 1 and 2) with the initial concentration of leptin/BF% among those who continued to smoke. There was a negative correlation between cortisol levels and leptin/%BF in individuals who remained smokers after 1 month. There was a positive correlation between leptin/BMI and leptin/%BF with the QSU-Brief (Factor 2) of 1 month in women who remained smokers (r=0.565; p=0.023) and the QSU-Brief (Factor 2) initial among the abstinent women (r=0.551; p=0.033). The highest concentrations of leptin were associated with greater craving and difficulty in achieve abstinence. PMID- 26233832 TI - Immediate Effect of Stimulability Assessment on Acoustic, Aerodynamic, and Patient-Perceptual Measures of Voice. AB - OBJECTIVES: The purpose of the present study was to determine if patients with voice disorders could achieve immediate improvements in acoustic and aerodynamic parameters and patient's perception of the sound and feel of voice following instructions to use clear speech. STUDY DESIGN: This is a retrospective study. METHODS: A total of 114 patients underwent acoustic and aerodynamic analyses of voice before and after instructions to use "clear speech," while reading a standardized passage. The patient's and speech-language pathologist's (SLP) judgments of voice change were also measured. RESULTS: An increase (improvement) in average vocal intensity (P < 0.001), average airflow (P < 0.001), total breaths taken (P < 0.001), total reading time (P < 0.001), and breaths/second (P < 0.001) was observed as a function of "clear speech" intervention. No change in acoustic analyses was observed. Most patients reported an improvement in the sound or feel of voice immediately after the assessment. CONCLUSIONS: This study is the first to quantify acoustic and aerodynamic parameters and clinician's and patient's perceptions of a standardized stimulability test for voice change in the voice laboratory. These results are potentially paradigm shifting in the role of the SLP in the evaluative clinic setting. PMID- 26233833 TI - Optimizing Global Health Electives Through Partnerships: A Pilot Study of Pediatric Residents. PMID- 26233834 TI - Pediatric Environmental Health Specialty Units: An Analysis of Operations. AB - BACKGROUND: In 1998 the Agency for Toxic Substances and Disease Registry (ATSDR) secured the first federal funding to develop an innovative network of public health-oriented entities: Pediatric Environmental Health Specialty Units (PEHSUs). PEHSU goals were to provide pediatric and environmental health education to health care providers and health profession students, to offer consultation to health care professionals, parents, and others regarding environmental health exposures, and to provide referrals to specialized medical resources when necessary. This report analyzes the productivity of US PEHSUs from 1999 to 2014. METHODS: This was a retrospective analysis of federally mandated quarterly reports filed by each PEHSU. These reports document specific goal related deliverables outlined under cooperative agreements awarded to the Association of Occupational and Environmental Clinics (AOEC) with funding from the Environmental Protection Agency (EPA) and ATSDR. Costs were obtained from grant budget information available from the administrator of the grants, AOEC. RESULTS: Total EPA/ATSDR funding for PEHSUs paid to AOEC during 1999-2014 was $23,847,452. The average cost to the EPA/ATSDR of running each PEHSU in 2014 was $169,256. Through over 8000 consultations and educational activities, PEHSUs reached 702,506 people: 298,936 health professionals, 61,947 health professional trainees, 323,817 members of the public, and 17,806 public health officials and others. CONCLUSIONS: PEHSUs have grown into an established, productive network of clinical and educational centers whose expertise and activities have benefited both the public and health care professionals alike. The federal contributions to the cost of operating these centers have been more than offset by the benefits PEHSUs have conferred on the communities they serve. PMID- 26233835 TI - Reliability of student midwives' visual estimate of blood loss in the immediate postpartum period: a cross-sectional study. AB - BACKGROUND: In France, postpartum hemorrhage (blood loss>=500mL in the first 24h postpartum) is the leading direct obstetric cause of maternal mortality. In French practice, PPH is mainly diagnosed by a quantitative assessment of blood loss, performed by subjective methods such as visual estimates. Various studies have concluded that visual estimates are imprecise, tend to underestimate blood loss, and thus to delay diagnosis of PPH. OBJECTIVES: The principal objective of this study was to assess the accuracy of visual estimates of blood loss by student midwives. The secondary objectives were to study intraobserver agreement of these assessments, to assess the accuracy of visual estimates for threshold values, and to look for a region effect. DESIGN: A cross-sectional multicentre study. SETTING: All French midwifery schools (n=35). PARTICIPANTS: Volunteer French student midwives at their fifth (final) year (n=463). METHODS: The online questionnaire contained 16 photographs (8 different, each presented twice) of simulated volumes of blood loss (100, 150, 200, 300, 500, 850, 1000, and 1500mL). A 50-mL reference standard for calibration accompanied each photograph. Only one answer could be selected among the 7 choices offered for each photograph. Comparisons used chi(2) and Kappa tests. RESULTS: The participation rate was 48.43% (463/956), and 7.408 visual estimates were collected. Estimates were accurate for 35.34% of the responses. The reproducibility rate for the visual estimates (0.17<=k<=0.48) and for the accurate visual estimates (0.11<=k<=0.55) were moderate for 4 of the 8 volumes (100, 300, 1000, and 1500mL). The percentage of accurate responses was significantly higher for volumes<=300mL than for those >=500mL (52.94% vs. 17.17%, p<0.0001) and those >=1000mL (52.94% vs. 18.30%, p<0.0001). The percentage of accurate responses varied between the regions (p=0.042). CONCLUSION: Despite the help of a visual aid, both the accuracy and reproducibility of the visual estimates were low. PMID- 26233836 TI - Economic and Quality-of-Life Implications of Non-Alcoholic Fatty Liver Disease. AB - Non-alcoholic fatty liver disease (NAFLD) is a very common chronic liver disease worldwide, is on the rise following the trend of increasing prevalence of obesity, is the second most common indication for liver transplantation, and is an important cause for hepatocellular carcinoma. Despite the increasing recognition of NAFLD as an important chronic liver disease, little has been published on the economic and health-related quality of life (HR-QOL) impact of NAFLD. We reviewed the current literature related to the economics and HR-QOL of NAFLD and found that increased costs and decreased HR-QOL were associated with NAFLD. PMID- 26233837 TI - Celect Inferior Vena Cava Wall Strut Perforation Begets Additional Strut Perforation. AB - PURPOSE: To identify risk factors for strut perforation following Celect inferior vena cava (IVC) filter (IVCF) placement and to use finite element modeling to predict the mechanical impact of long-dwelling filters. MATERIALS AND METHODS: Ninety-one patients with three computed tomography (CT) studies were evaluated following Celect IVCF placement (2007-2013). Three-dimensional finite element models of the Celect IVCF were developed to simulate mechanical deformation of the IVCF encountered in vivo. Simulated forces applied by the primary struts on the IVC wall were measured as a function of luminal area and tilt angle. RESULTS: Although 33 patients (36%) showed primary strut perforation on initial follow-up CT, 60 patients (66%) showed progressive perforation over time (P < .0001), with 72 patients (79%) showing primary strut perforation on the final CT (average, 554 d). Female patients (P = .004) and those with malignancy history (P = .01) had significantly higher perforation rates at a given time. Caval area also decreased after primary filter strut perforation, and we therefore proposed that this was the mechanism for progressive perforation. Consistent with this mechanism, three dimensional finite element modeling demonstrated increasing strut force with decreasing IVC diameter. CONCLUSIONS: Celect IVCF primary strut perforation is progressive over time and is more common in female patients and those with a history of malignancy. In addition, this progressive perforation may be predicted by three-dimensional finite element modeling. These patient populations may require closer follow-up after IVCF placement to prevent or reduce the risk for filter complication or worsening perforation. PMID- 26233839 TI - The role of vitamin D in cancer prevention. AB - Vitamin D, also known as cholecalciferol, is the precursor to the active steroid hormone 1, 25-dihydroxyvitamin D3 (calcitriol; 1, 25(OH)2D3). The main physiological role for 1, 25(OH)2D3 is to regulate calcium and inorganic phosphate homeostasis for bone health. More recently, vitamin D has been investigated for its effects in the prevention and treatment of a variety of diseases such as cancer, autoimmune disorders, and cardiovascular disease. Preclinical data strongly support a role for vitamin D in the prevention of cancer through its anti-proliferative, pro-apoptotic, and anti-angiogenic effects on cells. Epidemiologic and clinical studies have shown mixed data on the correlation between serum vitamin D levels and cancer risk. This report seeks to outline results from the most recent preclinical and clinical studies investigating the potential role of vitamin D in cancer prevention. PMID- 26233838 TI - Quantitative Assessment of Iron-Labeled Stem-Cell Adhesion at the Vessel Wall in a Vascular Flow Model: Correlation of T2*-Weighted Imaging at 3 T and Histology. AB - PURPOSE: To evaluate the distribution of superparamagnetic iron oxide (SPIO) labeled cells in a perfused segment of a porcine artery and to estimate the number of adherent cells by means of magnetic resonance (MR) imaging. MATERIALS AND METHODS: Six vessel specimens (diameters between 0.8 and 1.2 cm) were placed in a bioreactor system, and 2 * 10(4) to 1 * 10(6) SPIO-labeled endothelial colony-forming cells were injected into the artery within the perfused reactor. The area of resulting signal extinctions at the inner wall of the vessels was quantified on MR images by using a high-resolution T2*-weighted sequence with a slice-by-slice approach. After imaging, the labeled cells were quantified histologically. RESULTS: The total iron load of each cell was 56.5 pg +/- 14.4. In the applied range of 2 * 10(4) to 1 * 10(6) cells per vessel, the area of iron induced signal extinction at the vessel wall on T2*-weighted imaging corresponded to the histologically detected cell number (r = 0.98, P < .001). CONCLUSIONS: A correlation between the area of signal extinction and the number of labeled cells at the vessel wall was found. This might help to evaluate dose rates in further clinical applications of intravascular cell-based therapies. PMID- 26233840 TI - Guidelines and strategy of the International Conference of Harmonization (ICH) and its member states to overcome existing impurity control problems for antibiotics in China. AB - In the present report, we review the technical guidelines and principles on impurity research and control for antibiotics established by various agencies, including the International Conference of Harmonization (ICH), the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the China Food and Drug Administration (CFDA). Progresses with the US Pharmacopoeia (USP), the European Pharmacopoeia (EP) and the Chinese Pharmacopoeia (ChP) to control impurities in antibiotics are also presented. Next, our discussion is focused on analyzing the CFDA's requirements on impurity research and control for antibiotics, and the implementation of ICH, FDA and other technical guidelines for generic drugs impurity control in China. Existing problems are further reviewed, in order to improve the overall process for the control of antibiotic purity. PMID- 26233841 TI - Mining chemodiversity from biodiversity: pharmacophylogeny of medicinal plants of Ranunculaceae. AB - This paper reports a pharmacophylogenetic study of a medicinal plant family, Ranunculaceae, investigating the correlations between their phylogeny, chemical constituents, and pharmaceutical properties. Phytochemical, ethnopharmacological, and pharmacological data were integrated in the context of the systematics and molecular phylogeny of the Ranunculaceae. The chemical components of this family included several representative metabolic groups: benzylisoquinoline alkaloids, ranunculin, triterpenoid saponin, and diterpene alkaloids, among others. Ranunculin and magnoflorine were found to coexist in some genera. The pharmacophylogenetic analysis, integrated with therapeutic information, agreed with the taxonomy proposed previously, in which the family Ranunculaceae was divided into five sub-families: Ranunculoideae, Thalictroideae, Coptidoideae, Hydrastidoideae, and Glaucidioideae. It was plausible to organize the sub-family Ranunculoideae into ten tribes. The chemical constituents and therapeutic efficacy of each taxonomic group were reviewed, revealing the underlying connections between phylogeny, chemical diversity, and clinical use, which should facilitate the conservation and sustainable utilization of the pharmaceutical resources derived from the Ranunculaceae. PMID- 26233842 TI - Preventive effects of the polysaccharide of Larimichthys crocea swim bladder on carbon tetrachloride (CCl4)-induced hepatic damage. AB - The aim of the present study was to determine the preventive effects of the polysaccharide of Larimichthys crocea swim bladder (PLCSB) on CCl4-induced hepatic damage in ICR mice. The in vitro preventive effects of PLCSB on CCl4 induced liver cytotoxic effect were evaluated in BRL 3A rat liver cells using the MTT assay. The serum levels of AST, ALT, and LDH in mice were determined using commercially available kits. The levels of IL-6, IL-12, TNF-alpha, and IFN-gamma were determined using ELISA kits. The pathological analysis of hepatic tissues was performed with H and E staining, and the gene and protein expressions were determined by RT-PCR and Western blotting, respectively. PLCSB (20 MUg.mL(-1)) could increase the growth of BRL 3A rat liver cells treated with CCl4. The serum levels of AST, ALT, and LDH were significantly decreased when the mice were treated with two doses of PLCSB, compared with the control mice (P < 0.05). PLCSB treated groups also showed reduced levels of the serum pro-inflammatory cytokines IL-6, IL-12, TNF-alpha, and IFN-gamma. PLCSB could decrease the liver weight, compared to the CCl4-treated control mice. The histopathology sections of liver tissues in the 100 mg.kg(-1) PLCSB group indicated that the animals were recovered well from CCl4 damage, but the 50 mg.kg(-1) PLCSB group showed necrosis to a more serious extent. The 100 mg.kg(-1) PLCSB group showed significantly decreased mRNA and protein expression levels of NF-kappaB, iNOS, and COX-2, and increased expression of IkappaB-alpha compared with the CCl4-treated control group. In conclusion, PLCSB prevented from CCl4-induced hepatic damage in vivo. PMID- 26233843 TI - Asiatic acid mitigates hyperglycemia and reduces islet fibrosis in Goto-Kakizaki rat, a spontaneous type 2 diabetic animal model. AB - The Goto-Kakizaki (GK) rat is a spontaneous type 2 diabetic animal model, which is characterized by a progressive loss of beta islet cells with fibrosis. In the present study, the hypoglycemic effect of asiatic acid (AA) in GK rats was examined. GK rats receiving AA at a daily dose of 25 mg.kg(-1) for four weeks showed a significant reduction in blood glucose levels. Age-matched normal Wistar rats were given 0.5% sodium carboxymethyl cellulose (CMC-Na) solution for the same periods and used as control. Compared to the normal Wistar rats, GK rats treated with AA showed improvement in insulin resistance partially through decreasing glucose level (P < 0.01) and insulin level (P < 0.05). Furthermore, the results of immunohistochemistry indicate that AA treatment reduced islet fibrosis in GK rats. Fibronectin, a key protein related to islet fibrosis, was over-expressed in GK rats, which was reversed significantly by AA treatment (P < 0.05). These findings suggest that AA has a beneficial effect on lowering blood glucose levels in GK rats and improves fibrosis of islets in diabetes, which may play a role in the prevention of islets dysfunction. PMID- 26233844 TI - Pharmacokinetics and tissue distributions of veratric acid after intravenous administration in rats. AB - The present study was designed to investigate the pharmacokinetics and tissue distributions of veratric acid following intravenous administration in rats. The concentrations of veratric acid in rat plasma at various times after administrated at doses of 2.5, 5, and 10 mg.kg(-1) were quantified by HPLC. The tissue distributions of veratric acid at various times after a single intravenous dose of 2.5 mg.kg(-1) were also analyzed. The plasma pharmacokinetic parameters at the three doses were as follows: t(1/2), (86.23 +/- 6.83), (72.66 +/- 4.10) and (71.20 +/- 2.90) min; C0, (11.10 +/- 1.47), (23.67 +/- 1.24) and (39.17 +/- 3.90) MUg.mL(-1); and AUC(0->infinity), (1 240.90 +/- 129.14), (2 273.84 +/- 132.47) and (3 516.4 +/- 403.37) min.MUg.mL(-1), respectively. The compound was distributed into tissues rapidly and extensively after intravenous administration and was mainly distributed into the liver, heart and kidneys. PMID- 26233845 TI - Laminaria japonica increases plasma exposure of glycyrrhetinic acid following oral administration of Liquorice extract in rats. AB - The present study was designed to investigate the effects of Laminaria japonica (Laminaria) on pharmacokinetics of glycyrrhetinic acid (GA) following oral administration of Liquorice extract in rats. Following oral administrations of single-dose and multi-dose Liquorice extract and Liquorice-Laminaria extract, respectively, plasma samples were obtained at various times and the concentrations of GA, liquiritigenin, and isoliquiritigenin were measured by LC MS. The effects of Laminaria extract on pharmacokinetics of GA were also investigated, following single-dose and multidose of glycyrrhizic acid (GL). The effects of Laminaria extract on intestinal absorption of GA and GL were studied using the in situ single-pass intestinal perfusion model. The metabolism of GL to GA in the contents of small and large intestines was also studied. The results showed Liquorice-Laminaria extract markedly increased the plasma concentration of GA, accompanied by a shorter Tmax. Similar alteration was observed following multidose administration. However, pharmacokinetics of neither liquiritigenin nor isoliquiritigenin was affected by Laminaria. Similarly, Laminaria markedly increased concentration and decreased Tmax of GA following oral GL were observed. The data from the intestinal perfusion model showed that Laminaria markedly increased GL absorption in duodenum and jejunum, but did not affect the intestinal absorption of GA. It was found that Laminaria enhanced the metabolism of GL to GA in large intestine. In conclusion, Laminaria increased plasma exposures of GA following oral administration of liquorice or GL, which partly resulted from increased intestinal absorption of GL and metabolism of GL to GA in large intestine. PMID- 26233846 TI - A new biflavone glucoside from the roots of Stellera chamaejasme. AB - The present study investigated the chemical constituents of the roots of Stellera chamaejasme (Thymelaeaceae). One new biflavone glucoside (1), along with other thirteen known compounds (2-14), was isolated by repeated column chromatographic methods and their structures were elucidated on the basis of spectral analyses. The cytotoxic activities of selected compounds were evaluated against four human cancer cell lines (A549, BEL-7402, HCT-116, and MDA-MB-231) by the SRB assay method. Compound 9 showed remarkable cytotoxicity against BEL-7402 with IC50 value being 0.65 MUg.mL(-1); compounds 7, 8, and 12 exhibited significant cytotoxic activity against A549 with IC50 values being 2.38, 1.57, and 2.35 MUg.mL(-1), respectively. PMID- 26233848 TI - Causes of "ischemic electrocardiogram changes" in near drowning: Myocardial ischemia from coronary artery disease vs coronary vasospasm vs Takotsubo syndrome. PMID- 26233847 TI - Development and validation of an HPLC-MS/MS analytical method for quantitative analysis of TCBA-TPQ, a novel anticancer makaluvamine analog, and application in a pharmacokinetic study in rats. AB - We have recently designed and synthesized several novel iminoquinone anticancer agents that have entered preclinical development for the treatment of human cancers. Herein we developed and validated a quantitative HPLC-MS/MS analytical method for one of the lead novel anticancer makaluvamine analog, TCBA-TPQ, and conducted a pharmacokinetic study in laboratory rats. Our results indicated that the HPLC-MS/MS method was precise, accurate, and specific. Using this method, we carried out in vitro and in vivo evaluations of the pharmacological properties of TCBA-TPQ and plasma pharmacokinetics in rats. Our results provide a basis for future preclinical and clinical development of this promising anticancer marine analog. PMID- 26233849 TI - Takotsubo cardiomyopathy is the main explanation for ischemic electrocardiographic changes in near drowning. PMID- 26233850 TI - Management and outcomes in patients with moderate or severe functional mitral regurgitation and severe left ventricular dysfunction. AB - AIMS: The management and outcomes of patients with functional moderate/severe mitral regurgitation and severe left ventricular (LV) systolic dysfunction are not well defined. We sought to determine the characteristics, management strategies, and outcomes of patients with moderate or severe mitral regurgitation (MR) and LV systolic dysfunction. METHODS AND RESULTS: For the period 1995-2010, the Duke Echocardiography Laboratory and Duke Databank for Cardiovascular Diseases databases were merged to identify patients with moderate or severe functional MR and severe LV dysfunction (defined as LV ejection fraction <= 30% or LV end-systolic diameter > 55 mm). We examined treatment effects in two ways. (i) A multivariable Cox proportional hazards model was used to assess the independent relationship of different treatment strategies and long-term event (death, LV assist device, or transplant)-free survival among those with and without coronary artery disease (CAD). (ii) To examine the association of mitral valve (MV) surgery with outcomes, we divided the entire cohort into two groups, those who underwent MV surgery and those who did not; we used inverse probability weighted (IPW) propensity adjustment to account for non-random treatment assignment. Among 1441 patients with moderate (70%) or severe (30%) MR, a significant history of hypertension (59%), diabetes (28%), symptomatic heart failure (83%), and CAD (52%) was observed. Past revascularization in 26% was noted. At 1 year, 1094 (75%) patients were treated medically. Percutaneous coronary intervention was performed in 114 patients, coronary artery bypass graft (CABG) surgery in 82, CABG and MV surgery in 96, and MV surgery alone in 55 patients. Among patients with CAD, compared with medical therapy alone, the treatment strategies of CABG surgery [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.42-0.76] and CABG with MV surgery (HR 0.58, 95% CI 0.44-0.78) were associated with long-term, event-free survival benefit. Percutaneous intervention treatment produced a borderline result (HR 0.78, 95% CI 0.61-1.00). However, the relationship with isolated MV surgery did not achieve statistical significance (HR 0.64, 95% CI 0.33-1.27, P = 0.202). Among those with CAD, following IPW adjustment, MV surgery was associated with a significant event-free survival benefit compared with patients without MV surgery (HR 0.71, 95% CI 0.52 0.95). In the entire cohort, following IPW adjustment, the use of MV surgery was associated with higher event-free survival (HR 0.69, 95% CI 0.53-0.88). CONCLUSION: In patients with moderate or severe MR and severe LV dysfunction, mortality was substantial, and among those selected for surgery, MV surgery, though performed in a small number of patients, was independently associated with higher event-free survival. PMID- 26233851 TI - Paroxysmal atrial fibrillation originating from giant right atrial appendage aneurysm. PMID- 26233852 TI - Platelet progenitors: the hidden drug target. PMID- 26233855 TI - Letter From the Guest Editor. Imaging of Functional and Dysfunctional Neurologic Systems. PMID- 26233853 TI - Determined to Fail--the Role of Genetic Mechanisms in Heart Failure. AB - Genetic variants contribute to several steps during heart failure pathophysiology. The mechanisms include frequent polymorphisms that increase the susceptibility to heart failure in the general population and rare variants as causes of an underlying cardiomyopathy. In this review, we highlight recent discoveries made by genetic approaches and provide an outlook onto the role of epigenetic modifiers of heart failure. PMID- 26233854 TI - Chronic pain acceptance incrementally predicts disability in polytrauma-exposed veterans at baseline and 1-year follow-up. AB - War veterans are at increased risk for chronic pain and co-occurring neurobehavioral problems, including posttraumatic stress disorder (PTSD), depression, alcohol-related problems, and mild traumatic brain injury (mTBI). Each condition is associated with disability, particularly when co-occurring. Pain acceptance is a strong predictor of lower levels of disability in chronic pain. This study examined whether acceptance of pain predicted current and future disability beyond the effects of these co-occurring conditions in war veterans. Eighty trauma-exposed veterans with chronic pain completed a PTSD diagnostic interview, clinician-administered mTBI screening, and self-report measures of disability, pain acceptance, depression, and alcohol use. Hierarchical regression models showed pain acceptance to be incrementally associated with disability after accounting for symptoms of PTSD, depression, alcohol-related problems, and mTBI (total adjusted R(2) = .57, p < .001, DeltaR(2) = .03, p = .02). At 1-year follow-up, the total variance in disability accounted for by the model decreased (total adjusted R(2) = .29, p < .001), whereas the unique contribution of pain acceptance increased (DeltaR(2) = .07, p = .008). Pain acceptance remained significantly associated with 1-year disability when pain severity was included in the model. Future research should evaluate treatments that address chronic pain acceptance and co-occurring conditions to promote functional recovery in the context of polytrauma in war veterans. PMID- 26233856 TI - Rise of Functional Neuroradiologists in Clinical Care. AB - Recent translational advances in neuroimaging herald a fundamental shift in the practice of Neuroradiology. Biological, physiological, microstructural, metabolic, and functional imaging techniques have bridged the gaps between clinical imaging and the clinical neurosciences. These advancements are guiding the transition of neuroradiology from traditional pattern-based, image-centric toward knowledge-based, patient-centric practice strategies. The willingness of the neuroradiologist to embrace this shift is critical to the process. The chapter highlights the expanding role and importance of the functional neuroradiologist in clinical care. PMID- 26233857 TI - Functional and Dysfunctional Sensorimotor Anatomy and Imaging. AB - The sensorimotor system of the human brain and body is fundamental only in its central role in our daily lives. On further examination, it is a system with intricate and complex anatomical, physiological, and functional relationships. Sensorimotor areas including primary sensorimotor, premotor, supplementary motor, and higher order somatosensory cortices are critical for function and can be localized at routine neuroimaging with a familiarity of sulcal and gyral landmarks. Likewise, a thorough understanding of the functions and dysfunctions of these areas can empower the neuroradiologist and lead to superior imaging search patterns, diagnostic considerations, and patient care recommendations in daily clinical practice. Presurgical functional brain mapping of the sensorimotor system may be necessary in scenarios with distortion of anatomical landmarks, multiplanar localization, homunculus localization, congenital brain anomalies, informing diffusion tensor imaging interpretations, and localizing nonvisible targets. PMID- 26233859 TI - Imaging of Cortical and White Matter Language Processing. AB - Although investigations into the functional and anatomical organization of language within the human brain began centuries ago, it is recent advanced imaging techniques including functional magnetic resonance imaging and diffusion tensor imaging that have helped propel our understanding forward at an unprecedented rate. Important cortical brain regions and white matter tracts in language processing subsystems including semantic, phonological, and orthographic functions have been identified. An understanding of functional and dysfunctional language anatomy is critical for practicing radiologists. This knowledge can be applied to routine neuroimaging examinations as well as to more advanced examinations such as presurgical brain mapping. PMID- 26233858 TI - Imaging of the Functional and Dysfunctional Visual System. AB - Functional magnetic resonance imaging (fMRI) is used clinically to map the visual cortex before brain surgery or other invasive treatments to achieve an optimal balance between therapeutic effect and the avoidance of postoperative vision deficits. Clinically optimized stimuli, analyses, and displays permit identification of cortical subregions supporting high-acuity central vision that is critical for reading and other essential visual functions. A novel data display permits instant appreciation of the functional relationship between the pattern of fMRI brain activation and the pattern of vision loss and preservation within the patient's field of view. Neurovascular uncoupling and its detection in the visual cortex are key issues for the interpretation of fMRI results in patients with existing brain pathology. PMID- 26233860 TI - Imaging of Functional and Dysfunctional Episodic Memory. AB - A foundational framework for understanding functional and dysfunctional imaging of episodic memory emerges from the last 3 decades of human and animal research. This comprehensive review is presented from the vantage point of the fornix, a white matter bridge that occupies a central position in this functional network. Salient insights are identified, spanning topics such as hippocampal efferent and afferent networks, input and processing streams, hemispheric specialization, dysfunctional effects of pathologic and surgical injury, optimization of functional magnetic resonance imaging design and neuropsychological tests, and rehabilitation strategies. Far-reaching implications are considered for radiologists, whose clinical effect stretches beyond imaging and interfaces with neurosurgeons, neuropsychologists, and other neurospecialists. PMID- 26233861 TI - Cortical and Subcortical Substrates of Cranial Nerve Function. AB - The pivotal role of cranial nerves in a wholesome life experience cannot be overemphasized. Research has opened new avenues to understand cranial nerve function. Classical concept of strict bilateral cortical control of cranial nerves has given way to concepts of hemispheric dominance and hemispheric lateralization. An astute Neuroradiologist should keep abreast of these concepts and help patients and referring physicians by applying this knowledge in reading images. This chapter provides an overview of cranial nerve function and latest concepts pertaining to their cortical and subcortical control. PMID- 26233862 TI - Eloquent Brain, Ethical Challenges: Functional Brain Mapping in Neurosurgery. AB - Functional brain mapping is an increasingly relied upon tool in presurgical planning and intraoperative decision making. Mapping allows personalization of structure-function relationships when surgical or other treatment of pathology puts eloquent functioning like language or vision at risk. As an innovative technology, functional brain mapping holds great promise but also raises important ethical questions. In this article, recent work in neuroethics on functional imaging and functional neurosurgery is explored and applied to functional brain mapping. Specific topics discussed in this article are incidental findings, responsible innovation, and informed consent. PMID- 26233863 TI - Effects of supplementation with green tea catechins on plasma C-reactive protein concentrations: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Promising experimental and clinical trials suggest that green tea decreases the inflammatory process in cardiometabolic diseases, but evidence from epidemiologic studies about the effects on plasma C-reactive protein (CRP) seems inconsistent and ambiguous. Therefore, the aim of this meta-analysis was to evaluate the effects of green tea supplementation on plasma CRP concentrations. METHODS: We searched selected database up to October 26, 2014 to identify randomized controlled trials (RCTs) investigating the effects of green tea supplementation on plasma CRP concentrations. Two independent reviewers extracted data on study characteristics, methods, and outcomes. RESULTS: Meta-analysis of data from 11 RCTs arms did not indicate a significant effect of supplementation with green tea catechins on plasma CRP concentrations (weighted mean difference [WMD], 0.085 mg/L; 95% confidence interval [CI], -0.225 to 0.395; P = 0.592). This effect size was robust in sensitivity analysis and omission of each individual study did not have a significant effect. The nonsignificant effects of green tea catechins on plasma CRP concentrations were also observed in subgroups of studies with green tea supplementation with a duration of <8 wk (WMD, 0.029 mg/L; 95% CI, -0.229 to 0.286; P = 0.828) and >=8 wk (WMD, 0.099 mg/L; 95% CI, 0.555 to 0.754; P = 0.766). Likewise, there was no significant effect in subgroups of studies with total catechins doses <400 mg/d (WMD, 0.073 mg/L; 95% CI, -0.251 to 0.398; P = 0.658) and >=400 mg/d (WMD, 0.213 mg/L; 95% CI, -0.148 to 0.574; P = 0.247). The effect sizes were not significant after stratification of studies to those recruiting healthy subjects (WMD, -0.028 mg/L; 95% CI, -0.216 to 0.160; P = 0.769), and those recruiting participants with cardiometabolic diseases (WMD, 0.260 mg/L; 95% CI, -0.815 to 1.334; P = 0.636). CONCLUSIONS: This meta-analysis of data from 11 RCT arms did not indicate a significant effect of supplementation with green tea catechins on plasma CRP concentrations. Furthermore, well-designed trials are necessary to validate these results. PMID- 26233864 TI - Benefits of dietary phytochemical supplementation on eccentric exercise-induced muscle damage: Is including antioxidants enough? AB - The purpose of this review was to critically discuss studies that investigated the effects of supplementation with dietary antioxidant phytochemicals on recovery from eccentric exercise-induced muscle damage. The performance of physical activities that involve unaccustomed eccentric muscle actions-such as lowering a weight or downhill walking-can result in muscle damage, oxidative stress, and inflammation. These events may be accompanied by muscle weakness and delayed-onset muscle soreness. According to the current evidences, supplementation with dietary antioxidant phytochemicals appears to have the potential to attenuate symptoms associated with eccentric exercise-induced muscle damage. However, there are inconsistencies regarding the relationship between muscle damage and blood markers of oxidative stress and inflammation. Furthermore, the effectiveness of strategies appear to depend on a number of aspects inherent to phytochemical compounds as well as its food matrix. Methodological issues also may interfere with the proper interpretation of supplementation effects. Thus, the study may contribute to updating professionals involved in sport nutrition as well as highlighting the interest of scientists in new perspectives that can widen dietary strategies applied to training. PMID- 26233865 TI - Cytokines, angiogenic, and antiangiogenic factors and bioactive lipids in preeclampsia. AB - Preeclampsia is a low-grade systemic inflammatory condition in which oxidative stress and endothelial dysfunction occurs. Plasma levels of soluble receptor for vascular endothelial growth factor (VEGFR)-1, also known as sFlt1 (soluble fms like tyrosine kinase 1), an antiangiogenic factor have been reported to be elevated in preeclampsia. It was reported that pregnant mice deficient in catechol-O-methyltransferase (COMT) activity show a preeclampsia-like phenotype due to a deficiency or absence of 2-methoxyoestradiol (2-ME), a natural metabolite of estradiol that is elevated during the third trimester of normal human pregnancy. Additionally, autoantibodies (AT1-AAs) that bind and activate the angiotensin II receptor type 1 a (AT1 receptor) also have a role in preeclampsia. None of these abnormalities are consistently seen in all the patients with preeclampsia and some of them are not specific to pregnancy. Preeclampsia could occur due to an imbalance between pro- and antiangiogenic factors. VEGF, an angiogenic factor, is necessary for the transport of polyunsaturated fatty acids (PUFAs) to endothelial cells. Hence reduced VEGF levels decrease the availability of PUFAs to endothelial cells. This leads to a decrease in the formation of anti-inflammatory and angiogenic factors: lipoxins, resolvins, protectins, and maresins from PUFAs. Lipoxins, resolvins, protectins, maresins, and PUFAs suppress insulin resistance; activation of leukocytes, platelets, and macrophages; production of interleukin-6 and tumor necrosis factor alpha; and oxidative stress and endothelial dysfunction; and enhance production of prostacyclin and nitric oxide (NO). Estrogen enhances the formation of lipoxin A4 and NO. PUFAs also augment the production of NO and inhibit the activity of angiotensin-converting enzyme and antagonize the actions of angiotensin II. Thus, PUFAs can prevent activation of angiotensin II receptor type 1 a (AT1 receptor). Patients with preeclampsia have decreased plasma phospholipid concentrations of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), the precursors of lipoxins (from AA), resolvins (from EPA and DHA), and protectins (from DHA) and prostaglandin E1 (PGE1 from DGLA: dihomo-gamma linolenic acid) and prostacyclin (PGI2 derived from AA). Based on these evidences, it is proposed that preeclampsia may occur due to deficiency of PUFAs and their anti-inflammatory products: lipoxins, resolvins, protectins, and maresins. PMID- 26233866 TI - PREDyCES study: The cost of hospital malnutrition in Spain. AB - OBJECTIVES: The aim of this study was to analyze the economic effects of hospital malnutrition and the cost of longer hospital stays according to the Prevalence of Hospital Malnutrition and Associated Costs in Spain (PREDyCES) study data. METHODS: This was a nested case-control study in a prospective cohort of patients (n = 114) who were at nutritional risk at admission and controls (n = 354) who were not at risk at admission. The total cost of hospital stay was the cost of the bed plus the cost of drugs administered during the stay. Hospital costs were extrapolated to Spanish National Health System admissions for 2009. RESULTS: The mean hospital length of stay for patients at risk (cases) was significantly longer (11.5 +/- 7.5 versus 8.5 +/- 5.8 d; P < 0.001) than for the controls. The cost of patients at risk at admission was significantly higher than that of those not at risk (?8590 +/- ?6127 versus ?7085 +/- ?5625; P = 0.015). The most significant difference in the cost of the hospital stay was observed between controls at nutritional risk at discharge and controls who remained not at risk throughout the hospital stay (?13 013 +/- ?9086 versus ?6665 +/- ?5091; P < 0.001). Extrapolation of the study findings to Spanish National Health System hospital admissions showed that the potential cost of hospital malnutrition in Spain was at least ?1.143 billion per year. CONCLUSION: Hospital malnutrition in Spain is associated with substantial costs, suggesting the need to establish procedures for screening, diagnosing, and treating malnutrition. PMID- 26233867 TI - Factors associated with maternal serum C-reactive protein throughout pregnancy: A longitudinal study in women of Rio de Janeiro, Brazil. AB - OBJECTIVES: The aim of this study was to evaluate the longitudinal changes of C reactive protein (CRP) concentrations during pregnancy and to assess whether socioeconomic, anthropometric, dietary, behavioral, and biochemical factors are associated with these changes. METHODS: This was a prospective cohort study of 115 adult pregnant women, followed at gestational weeks 5 to 13, 20 to 26, and 30 to 36. Serum concentrations of CRP (mg/L) were measured by the immunoturbidimetric method with ultrasensitive kits (sensitivity 0.05 mg/dL). The statistics included descriptive analysis (mean + SD) and longitudinal linear mixed-effects models, reporting the beta coefficient and 95% confidence intervals (CI). RESULTS: Serum CRP concentrations progressively increased throughout pregnancy (beta = 0.121; 95% CI, 0.071-0.171). Parity (beta = 1.579; 95% CI, 0.731-2.427) and prepregnancy body mass index (BMI) (beta = 0.316; 95% CI, 0.053 0.587) were positively associated and dietary glycemic load was negatively associated (beta = -0.203; 95% CI, -0.380 to -0.026) with CRP concentrations in the multiple model. Prepregnancy obese women presented a more pronounced increase of CRP concentrations compared with normal weight women (beta = 0.210; 95% CI, 0.059-0.360 versus 0.115, respectively; 95% CI, 0.049-0.181). A statistically significant interaction was observed between parity and gestational age (beta = 0.045; 95% CI, -0.084 to -0.005), indicating that the variation of CRP throughout pregnancy differed according to parity categories. CONCLUSION: CRP concentrations increased throughout pregnancy. Parity and prepregnancy BMI were positively associated and dietary glycemic load was negatively associated with concentrations of CRP. PMID- 26233868 TI - Impact of intravenous lipid emulsions on liver function tests: Contribution of parenteral fish oil. AB - OBJECTIVE: Lipids in parenteral nutrition (PN) have been linked to liver damage. The aim of this study is to 1) determine whether the incidence of alterations in liver function tests (LFTs) changes over time among hospitalized adult patients receiving PN; 2) evaluate whether the alteration in LFTs varies with the pattern of lipid administration; and 3) study the relationship between LFT alterations and fish oil (FO) emulsions. METHODS: Patients treated with PN over 4 y were included. Demographic, clinical, nutritional, and analytical variables were collected. LFTs (gamma-glutamyl transferase [GGT], alkaline phosphatase [AP], alanine aminotransferase [ALT], and total bilirubin [BIL]) were collected during PN treatment. Differences in LFTs were studied with t tests for paired samples. To match the type of lipid with each of the LFTs studied, four multivariate statistical models were performed. Significance was reported with the 95% confidence interval (CI) at p < 0.05 (two-tailed). RESULTS: We studied 1555 patients. LFT alterations at baseline were high and increased during PN treatment except ALT. GGT and AP showed significant increases from baseline values. In the multivariate study, daily dose of FO (g.kg(-1).d(-1)) was associated with a significant decrease in GGT (B = -11.189; 95% CI, -19.799 to -2.578) and in AP (B = -5.250; 95% CI, -10.263 to -0.237). Daily dose of vegetal oil (g/kg) had a tendency for a significant increase in GGT (B = 0.441; 95% CI, -0.107 to 1.039) and AP (B = 0.312; 95% CI, -0.023 to 0.648). CONCLUSIONS: GGT and AP increased throughout the clinical course of PN administration. These alterations had a multifactorial component. The administration of FO was associated with a significant decrease in the levels of GGT and AP. PMID- 26233869 TI - Potential contribution of African green leafy vegetables and maize porridge composite meals to iron and zinc nutrition. AB - OBJECTIVES: The aim of this study was to determine the mineral nutritive value of different traditional African green leafy vegetable (GLV) dishes and their composite meals with fortified and unfortified maize porridge. METHODS: The mineral (iron, zinc, and calcium) and antinutrient (phytate, total phenolics, and tannins) contents and in vitro bioaccessibility of iron and zinc were analyzed. The iron and zinc contents and bioaccessibilities were used to calculate contribution these dishes and meals could make toward the recommended daily requirements and absolute requirements of vulnerable populations. RESULTS: It was found that the GLV dishes contained average amounts of zinc (2.8-3.2 mg/100 g, dry base [db]), but were high in both iron (12.5-23.4 mg/100 g, db) and antinutrients (phytate 1420-2089 mg/100 g, db; condensed tannins 105-203 mg/100 g, db). The iron bioaccessibility and amount of bioaccessible iron ranged between 6.7% and 45.2% and 0.9 and 5.11 mg/100 g, db, respectively. The zinc bioaccessibility and amount of bioaccessible zinc ranged between 6.4% and 12.7% and 0.63 and 1.63 mg/100 g, db, respectively. CONCLUSION: Importantly, although compositing the GLV dishes with fortified maize porridges decreases the iron and zinc contents, because of the low antinutrient content of the maize meal, the amount of bioaccessible iron and zinc in the meal increases. PMID- 26233870 TI - Low-carbohydrate-diet score and metabolic syndrome: An epidemiologic study among Iranian women. AB - OBJECTIVE: Epidemiologic studies linking carbohydrate consumption and risk for metabolic syndrome (MetS) are limited. The association between low-carbohydrate diet score and MetS has not been investigated. The aim of this study was to investigate low-carbohydrate-diet score in relation to MetS among a group of Iranian women. METHOD: This cross-sectional study was conducted with 442 Iranian female teachers >20 y of age. Usual dietary intakes were assessed using a validated, dish-based semiquantitative food frequency questionnaire. Metabolic syndrome was defined according to the American Heart Association/National Heart, Lung, and Blood Institute/International Diabetes Federation definition guidelines. RESULTS: The prevalence of MetS in the lowest and highest quintile of low-carbohydrate-diet score was 17.5% and 18.8%, respectively (P = 0.97). There was no statistically significant difference in the prevalence between extreme quartiles low-carbohydrate-diet score and MetS (odds ratio, 0.93; 95% confidence interval, 0.38-2.28). After controlling for age, energy intake, and other potential confounders, low-carbohydrate-diet score was not significantly associated with MetS. A significant association was observed between this score and abnormal fasting plasma glucose. We failed to find a significant relationship between this score and other components of MetS. CONCLUSIONS: Diets with lower amounts of carbohydrate and higher contents of fat and protein were not significantly associated with the risk for MetS in a cross-sectional study with a group of Iranian women. More longitudinal studies are needed to confirm these results. PMID- 26233871 TI - Effect of onion peel extract on endothelial function and endothelial progenitor cells in overweight and obese individuals. AB - OBJECTIVES: Acute or chronic intake of polyphenol-rich foods has been reported to improve endothelial function. Quercetin, found abundantly in onion, is a potent antioxidant flavonoid. The aim of this study was to investigate whether consumption of onion peel extract (OPE) improves endothelial function in healthy overweight and obese individuals. METHODS: This was a randomized double-blind, placebo-controlled study. Seventy-two healthy overweight and obese participants were randomly assigned to receive a red, soft capsule of OPE (100 mg quercetin/d, 50 mg quercetin twice daily; n = 36 participants) or an identical placebo capsule (n = 36) for 12 wk. Endothelial function, defined by flow-mediated dilation (FMD), circulating endothelial progenitor cells (EPCs) by flow cytometry, and laboratory test were determined at baseline and after treatment. RESULTS: Baseline characteristics and laboratory findings did not significantly differ between the two groups. Compared with baseline values, the OPE group showed significantly improved FMD at 12 wk (from 12.5 +/- 5.2 to 15.2 +/- 6.1; P = 0.002), whereas the placebo group showed no difference. Nitroglycerin-mediated dilation did not change in either group. EPC counts (44.2 +/- 25.6 versus 52.3 +/ 18.6; P = 0.005) and the percentage of EPCs were significantly increased in the OPE group. When FMD was divided into quartiles, rate of patients with endothelial dysfunction defined as lowest quartile (cutoff value, 8.6%) of FMD improved from 26% to 9% by OPE. CONCLUSION: Medium-term administration of OPE an improvement in FMD and circulating EPCs. PMID- 26233872 TI - Association of the leptin receptor Gln223 Arg polymorphism with lipid profile in obese Pakistani subjects. AB - OBJECTIVE: Leptin receptor gene (LEPR) encodes a receptor for leptin hormone expressed in hypothalamus and single nucleotide polymorphisms in LEPR may have a considerable effect on obesity phenotype. The aim of this study was to investigate an extensively studied LEPR polymorphism Gln223 Arg in a Pakistani study group and its association patterns with different serum biochemical parameters. METHODS: The study included 250 obese and 225 nonobese subjects. Gln223 Arg polymorphism was genotyped by polymerase chain reaction restriction fragment-length polymorphism. Anthropometric parameters and plasma glucose, total cholesterol, triacylglycerols, high density lipoprotein cholesterol, low density lipoprotein cholesterol, leptin, and insulin were measured. RESULTS: The Gln223 Arg polymorphism was found to be significantly associated with body mass index, systolic and diastolic blood pressure, and weight only in obese subjects, and with all lipid parameters in both obese and nonobese subjects when Gln/Gln or Gln/Arg genotypes were compared with Arg/Arg genotype. CONCLUSIONS: The LEPR Gln223 is associated with obesity, lipid parameters, and plasma glucose in all subjects, with weight, body mass index, and systolic and diastolic blood pressure only in obese subjects, but showed no association with leptin, insulin, and HOMA IR in a Pakistani study group. PMID- 26233873 TI - Soluble arabinoxylan alters digesta flow and protein digestion of red meat containing diets in pigs. AB - OBJECTIVES: The aim of this study was to investigate how a moderate increase in dietary meat content combined (or not) with soluble fibre would influence protein digestion as well as digesta characteristics and flow. METHODS: Four groups of pigs were fed Western-style diets (high-protein/high-fat) containing two types of barbecued red meat, one with and one without a wheat arabinoxylan-rich fraction. After 4 wk, digesta samples were collected from small and large intestinal sites and analyzed for protein, amino acids, dry matter, and acid-insoluble ash. Tissue samples were also collected from each site. RESULTS: Arabinoxylan consumption led to somewhat lower apparent protein digestibility within the small and large intestines as well as shorter mean retention times. This suggests that the lowered protein digestibility is due, at least partly, to shorter access time to digestive proteases and absorptive surfaces. Additionally, digesta mass was higher in pigs fed arabinoxylan while dry matter (%) was lower, indicating an increased digesta water-holding capacity due to the presence of a soluble dietary fiber. CONCLUSION: Data showed that solubilized wheat arabinoxylan provides potential health benefits through decreased protein digestibility, increased digesta mass, and reduced mean retention time, even for diets with a moderately higher protein content. These factors are associated with efficiency of digestion and satiety, both of which have implications for prevention of obesity and other health disorders. PMID- 26233874 TI - Dietary silicon-enriched spirulina improves early atherosclerosis markers in hamsters on a high-fat diet. AB - OBJECTIVE: The aim of this study was to investigate the effects of dietary silicon-enriched spirulina (SES) on atherosclerosis. METHODS: Hamsters (six per group) on a high-fat (HF) diet received SES or non-enriched spirulina (both at 57 mg/kg body weight) daily. This corresponded to 0.57 mg silicon/kg body weight daily. RESULTS: The HF diet induced dyslipidemia, insulin resistance, oxidative stress, and vascular dysfunction. Compared with the HF group, SES attenuated increases of lipemia and prevented insulin resistance (IR) (P = 0.001). SES protected against oxidative stress through a reduction of heart (P = 0.006) and liver (P < 0.0001) nicotinamide adenine dinucleotide phosphate-oxidase activity and by sparing the activity of superoxide dismutase (P = 0.0017) and glutathione peroxidase (P = 0.01861). SES decreased inflammation, lowering tumor necrosis factor-alpha (P = 0.0006) and interleukin-6 levels (P = 0.0112), decreasing polymorphonuclear cells and preventing nuclear factor-kappaB activity (P = 0.0259). SES corrected plasma level of monocyte chemoattractant protein-1 (P = 0.0380), which was increased by the HF diet. Finally, SES supplementation prevented vascular and endothelial functions assessed respectively by the contractile response to the agonist phenylephrine and the relaxation induced by acetylcholine. CONCLUSION: SES protects against metabolic imbalance, inflammation, oxidative stress, and vascular dysfunction induced by an HF diet, and could prevent the atherogenic processes. Synergistic effects between spirulina and silicon were observed. PMID- 26233875 TI - Preparation of iron-enriched baker's yeast and its efficiency in recovery of rats from dietary iron deficiency. AB - OBJECTIVES: Iron is an important mineral, essential for the health and function of mammalian cells. Despite its key role, iron deficiency in humans is common worldwide, often leading to significant health issues within the population. The aim of this study was to evaluate the potential of using iron-enriched baker's yeast as a source of iron, especially for the protection and recovery from conditions related to anemia. METHODS: Iron-enriched yeast was prepared by cultivating cells on basal medium comprising different iron concentrations. The effects of iron supplementation on animal health were assessed by feeding anemic rats with a variety of diets containing either inorganic iron or iron-enriched yeast. Body weight, iron bioavailability, blood parameters, and the activity of iron-containing enzymes (catalase) were studied. RESULTS: Iron accumulation in yeast cells increased with iron concentration, reaching a maximum of 15 mg/g when 32 mM iron was applied. Rat groups fed iron-enriched yeast had the highest feed efficiency, iron bioavailability, and hemoglobin concentration. The source of iron supplementation influenced catalase activity in kidney tissues, increasing from 70 U/g tissue in anemic rats to 90 U/g tissue (inorganic iron salt), 110 U/g tissue (inorganic iron salt and non-enriched dry yeast), 145 U/g tissue (iron enriched yeast 15 mg/g iron) and 115 U/g tissue (iron-enriched yeast 30 mg/g iron). The histologic study of tissues from liver, kidney, heart, and spleen of rats from different groups showed that the damage observed in tissues of anemic rats, was not observed after feeding with iron-enriched yeasts. CONCLUSION: The results demonstrated that ingestion of iron-enriched yeast is more efficient than inorganic treatment in recovery from iron deficiency, including tissue recovery in rats. PMID- 26233876 TI - Percutaneous transhepatic duodenostomy for a gastrectomy case with CT guidance and real-time visualization by an ultrasound and endoscopy. AB - After gastrectomy, the remnant stomach, a small stomach behind the lateral segment of the liver, is thought to be a relative contraindication to receiving a percutaneous endoscopy-guided gastrostomy (PEG). We successfully performed a percutaneous duodenostomy in a case with remnant stomach. We used a transhepatic pull method with computed tomography (CT) guidance and real-time visualization by using ultrasound (US) and an endoscopy. The procedure was as follows: 1. Full stretching of the remnant stomach; 2. Insertion of a fine injection needle into the duodenal lumen through the lateral segment of the liver without an intrahepatic vascular and biliary injury using real-time visualization through US; 3. Confirmation of the location of the fine needle using abdominal CT, which showed the fine needle penetrating through the lateral segment and the duodenal lumen; 4. Insertion of the thick needle of the PEG kit just laterally of the fine needle; 5. Confirmation of the location of the thick needle using a repeated CT; 6. Endoscopic confirmation of the location of the two needles; 7. Changing the direction of the thick needle using guidance with endoscopy, inserting the thick needle into the duodenal lumen, and removing the fine needle; 8. Insertion of the guide wire through the thick needle; and 9. Placement of the PEG tube using the pull method. Using a real-time US scan, we detected the puncture of the anterior wall of the duodenum or stomach and avoided intrahepatic major vascular and biliary injuries. PMID- 26233877 TI - Change in skeletal muscle mass after administering entecavir in patients with hepatitis B. AB - OBJECTIVE: Cachexia, or disease-related loss of muscle mass, is a complication of chronic liver disease that modifies its clinical course. The aim of this study was to determine whether improvement in liver function and cachexia through control of the hepatitis B virus (HBV) increases skeletal muscle mass. METHODS: The blood tests and cross-sectional area (mm(2)) of the psoas major muscle on computed tomography were measured before and after long-term entecavir therapy (median, 39 mo; range, 14-76 mo) in patients with hepatitis B (17 men, 13 women; mean age, 63 +/- 13 y). RESULTS: The anti-HBV effect was good in 30 patients given entecavir, and most patients had undetectable serum HBV-DNA levels (93%) and alanine aminotransferase normalization (83%) within a median of 32 mo. Overall, no significant change in the area of the psoas major muscle was seen in any of the patients, although a significant increase was seen when limited to cases of protein malnutrition defined as serum albumin (Alb) <4 g/dL. A positive correlation was seen for the amount of change (Delta) in the psoas major muscle and the amount of change (Delta) in Alb. CONCLUSIONS: The present findings suggest that skeletal muscle mass may fluctuate in parallel with Alb levels. An improvement in low muscle mass may thus be expected from antiviral therapy for viral liver disease, especially in patients with cachexia. PMID- 26233878 TI - Preeclampsia in the 21st century: Unresolved questions concerning etiology. PMID- 26233879 TI - Nutritional issues in obese patients submitted to bariatric surgery. Re. "Bariatric surgery may not achieve intended outcomes in all patients". PMID- 26233880 TI - Re: "Dietary fatty acids intake and mortality in patients with heart failure". PMID- 26233881 TI - Source segregation and food waste prevention activities in high-density households in a deprived urban area. AB - A waste audit and a household questionnaire survey were conducted in high-density housing estates in one of the most economically and socially deprived areas of England (Haringey, London). Such areas are under-represented in published research. The study examined source segregation, potential participation in a food waste segregation scheme, and food waste prevention activities in five estates (1034 households). The results showed that: contamination of recyclables containers was low; ca. 28% of the mixed residual waste's weight was recyclable; food waste comprised a small proportion of the waste from these residents, probably because of their relatively disadvantaged economic circumstances; and the recycling profile reflected an intermittent pattern of behaviour. Although the majority of respondents reported that they would participate in a food waste separation scheme, the response rate was low and many responses of "don't know" were recorded. Municipalities committed to foster improved diversion from landfill need to recognise that there is no "quick and easy fix", regardless of local or national aspirations. Lasting and sustained behaviour change requires time and the quality of service provision and associated infrastructure play a fundamental role in facilitating residents to participate effectively in waste management activities that maximise capture of source-segregated materials. Populations in deprived areas that reside in high-rise, high-density dwellings are "hard-to-reach" in terms of participation in recycling schemes and exceptional efforts and additional resources are usually required to improve performance. PMID- 26233882 TI - Numerical study of radiation effect on the municipal solid waste combustion characteristics inside an incinerator. AB - Due to its advantages of high degree volume reduction, relatively stable residue, and energy reclamation, incineration becomes one of the best choices for Municipal Solid Waste (MSW) disposal. However, detailed measurements of temperature and gas species inside a furnace are difficulty by conventional experimental techniques. Therefore, numerical simulation of MSW incineration in the packed bed and gas flow field was applied. In this work, a three dimensional (3-D) model of incinerator system, including flow, heat transfer, detailed chemical mechanisms, and non-gray gas models, was developed. Radiation from the furnace wall and the flame formed above the bed is of importance for drying and igniting the waste. The preheated air with high temperature is used for the MSW combustion. Under the conditions of high temperature and high pressure, MSW combustion produces a variety of radiating gases. The wavelength-depend radiative properties of flame adopted in non-gray radiation model were obtained from a statistical narrow-band model. The influence of radiative heat transfer on temperature, flow field is researched by adiabatic model (without considering radiation), gray radiation model, and non-gray radiation model. The simulation results show that taking into account the non-gray radiation is essential. PMID- 26233883 TI - Prevalence and lifestyle determinants of central obesity in children. AB - PURPOSE: Central obesity is a strong risk factor for metabolic disorders and cardiometabolic diseases in children and adolescents. The aim of the present study was to evaluate the prevalence of central obesity and to determine its cross-sectional association with lifestyle habits in a sample of school-aged children in Greece. METHODS: The study sample consisted of 124,113 children (9.9 +/- 1.1 years old, 51 % boys) attending the third and fifth grade of primary school. Anthropometric measurements were performed by trained physical education teachers, and central obesity was defined as waist-to-height ratio >=0.5. Children's lifestyle habits were assessed through 7-day recall questionnaires. RESULTS: Of the participating children, 33.4 % were classified as centrally obese. Central obesity was significantly more prevalent in boys than in girls (36.0 vs. 30.7 %, P < 0.001) and was present in 95 % of obese children, as well as in a significant percentage of overweight (69.5 %) and normal-weight ones (12.0 %). Children with central obesity, compared to their non-centrally obese counterparts, reported poorer dietary habits and were less physically active. According to multiple logistic regression analysis, frequent breakfast (OR 0.72, 95 % CI 0.69-0.75) and snack consumption (OR 0.70, 95 % CI 0.67-0.74), as well as frequent participation in sedentary activities (OR 1.10, 95 % CI 1.07-1.14), were the strongest lifestyle determinants of central obesity. CONCLUSION: Strategies for the prevention of central obesity and associated comorbidities are urgently needed, for both obese and non-obese children. Our results suggest the need for a shift towards a healthier environment for our children, with emphasis on specific lifestyle habits, such as regular meal consumption and low sedentariness. PMID- 26233884 TI - Age-related changes in basal substrate oxidation and visceral adiposity and their association with metabolic syndrome. AB - PURPOSE: Ageing is directly associated with visceral fat (VAT) deposition and decline of metabolically active cellular mass, which may determine age-related shifts in substrate oxidation and increased cardiometabolic risk. We tested whether VAT and fasting respiratory quotient (RQ, an index of macronutrient oxidation) changed with age and if they were associated with increased risk of metabolic syndrome (MetSyn). METHODS: A total of 2819 adult participants (age range: 18-81 years; men/women: 894/1925) were included; we collected history, anthropometric measures, biochemistry, smoking habits, and physical activity. The body mass index range was 18.5-60.2 kg/m(2). Gas exchanges (VO2 and VCO2) were measured by indirect calorimetry in fasting conditions, and RQ was calculated. Body composition was measured by bioelectrical impedance. Abdominal subcutaneous fat and VAT were measured by ultrasonography. MetSyn was diagnosed using harmonised international criteria. Multivariate linear and logistic regression models were utilised. RESULTS: VAT increased with age in both men (r = 0.31, p < 0.001) and women (r = 0.37, p < 0.001). Basal RQ was not significantly associated with age (p = 0.49) and VAT (p = 0.20); in addition, basal RQ was not a significant predictor of MetSyn (OR 3.31, 0.57-19.08, p = 0.27). VAT was the primary predictor of MetSyn risk in a fully adjusted logistic model (OR 4.25, 3.01-5.99, p < 0.001). CONCLUSIONS: Visceral adiposity remains one of the most important risk factors for cardiometabolic risk and is a significant predictor of MetSyn. Post-absorptive substrate oxidation does not appear to play a significant role in age-related changes in body composition and cardiometabolic risk, except for a correlation with triglyceride concentration. PMID- 26233885 TI - Comparative effectiveness of antiarrhythmic drugs for rhythm control of atrial fibrillation. AB - INTRODUCTION: Although there are many different antiarrhythmic drugs (AADs) approved for rhythm management of atrial fibrillation (AF), little comparative effectiveness data exist to guide drug selection. METHODS: We followed 5952 consecutive AF patients who were prescribed amiodarone (N=2266), dronedarone (N=488), dofetilide (N=539), sotalol (N=1718), or class 1C agents (N=941) to the primary end point of AF recurrence. RESULTS: Median follow-up time was 18.2 months (range 0.1-101.6 months). Patients who were prescribed amiodarone had the highest, while patients on class 1C agents had the lowest baseline CHA2DS2-VASc score, Charlson comorbidity index, and burden of comorbid illnesses including coronary artery disease, congestive heart failure, diabetes mellitus, hyperlipidemia, chronic obstructive lung disease, chronic kidney disease, or cancer (p<0.05 for all comparisons). After adjusting for baseline characteristics, using dronedarone as benchmark, amiodarone [hazard ratio (HR) 0.58, p<0.001], class 1C agents (HR 0.70, p<0.001), and sotalol (HR 0.79, p=0.008), but not dofetilide (HR 0.87, p=0.178) were associated with less AF recurrence. In addition, compared to dronedarone, amiodarone and class 1C agents were associated with lower rates of admissions for AF (HR 0.55, p<0.001 for amiodarone; HR 0.71, p=0.021 for class 1C agents) and all-cause mortality was lowest in patients treated with class 1C agents (HR 0.42, p=0.018). The risk of stroke was similar among all groups. CONCLUSION: Compared with dronedarone, amiodarone, class 1C agents, and sotalol are more effective for rhythm control, while dofetilide had similar efficacy. These findings have important implications for clinical practice. PMID- 26233886 TI - Correlation between UGT1A1 polymorphisms and raltegravir plasma trough concentrations in Japanese HIV-1-infected patients. AB - Raltegravir (RAL), an HIV integrase inhibitor, is metabolized mainly by UDP glucuronosyltransferase 1A1 (UGT1A1). Polymorphisms in UGT1A1 may cause alterations in the pharmacodynamics of RAL, which is taken twice daily with no dietary restrictions. We compared the effect of two polymorphic alleles in this gene, UGT1A1*6 and UGT1A1*28 on plasma RAL concentrations in Japanese HIV-1 infected patients. Of 114 Japanese HIV-1-infected patients who received RAL, the frequencies of UGT1A1*6 and UGT1A1*28 were 18% and 13%, respectively. The percentage of homozygotes for UGT1A1*6 and UGT1A1*28 was 6% and 4%, respectively, the percentage of compound heterozygotes for UGT1A1*6 and UGT1A1*28 was 2%, and that of heterozygotes for UGT1A1*6 and UGT1A1*28 was 22% and 17%, respectively. RAL plasma trough concentrations were compared for each polymorphism. Significantly higher levels of RAL were observed with patients who were homozygous for UGT1A1*6 (median: 1.0 MUg/mL) than for the normal allele (median: 0.11 MUg/mL; p = 0.021). Multivariate logistic regression analysis showed that the presence of one or two alleles of UGT1A1*6 or two alleles of UGT1A1*28 were independent factors associated with high RAL plasma trough concentrations (>= 0.17 MUg/mL). These results indicated that UGT1A1*6 and UGT1A1*28 are both factors influencing the RAL plasma trough concentrations in Japanese HIV-1 infected patients. PMID- 26233887 TI - Environmental Considerations for Improving Nutritional Status in Older Adults with Dementia: A Narrative Review. AB - As the number of older adults in the United States continues to grow, the American health care system will face the unique challenge of providing care for these individuals, including many who will be diagnosed with some form of dementia. As dementia progresses, patients require increasing amounts of care and nutrient intake usually declines. This tends to result in weight loss, malnutrition, and increased morbidity and mortality. Various interventions have been developed with the goal of improving meal intake and reducing unintentional weight loss in patients with dementia. Several studies have shown that meal intake improves with the provision of adequate assistance, either from staff members or from volunteer feeding assistants. Some studies have focused on the method of meal service and its influence on meal intake and nutrition status. Both buffet-style and family-style dining have shown promising results in terms of improving meal intake and quality of life among older adults in long-term-care settings. Other environment-related interventions include improving lighting and visual contrast, altering the dining room to more closely resemble a home-style setting, using the aroma of food to stimulate appetite, using routine seating arrangements, and using relaxing or familiar music in the dining room to provide a calmer environment. The purpose of this review is to evaluate the research on environment-based interventions to improve nutritional status among older adults with dementia, to describe potential for practical applications, and to identify gaps in the existing literature whereon further research is warranted. PMID- 26233888 TI - Stories to Tell: Conducting a Nutrition Assessment with the Use of Narrative Medicine. PMID- 26233893 TI - TCP1 Modulates DWF4 Expression via Directly Interacting with the GGNCCC Motifs in the Promoter Region of DWF4 in Arabidopsis thaliana. AB - Our previous studies indicated that TCP1 is a positive regulator of the brassinosteroid (BR) biosynthesis pathway by mediating the transcription of DWF4, one of the key BR biosynthetic genes in Arabidopsis thaliana. Whether TCP1 can directly bind to the promoter region of DWF4, however, has not been experimentally demonstrated. Here we provide our biochemical and genetic evidence that TCP1 mediates the expression of DWF4 by directly associating with the two GGNCCC motifs in the promoter region of DWF4. The expression levels of DWF4 are positively correlated to TCP1 abundance in planta. Electrophoretic mobility shift assays (EMSAs) using various synthetic DNA fragments suggest that the GGNCCC core sequence is critical for TCP1 binding. DNA sequences flanking the GGNCCC motifs are less important for the association of TCP1. Using DWF4p-GUS transgenic plants as an assay system, it is clearly indicated that these motifs are required for the positive regulation of DWF4 transcription by TCP1. More significantly, whole genome microarray analyses indicate that TCP1 can directly or indirectly regulate the expression of many other genes known to be important for normal plant growth and development. PMID- 26233890 TI - The PI3K/AKT Pathway and Renal Cell Carcinoma. AB - The phosphatidylinositol 3 kinase (PI3K)/AKT pathway is genetically targeted in more pathway components and in more tumor types than any other growth factor signaling pathway, and thus is frequently activated as a cancer driver. More importantly, the PI3K/AKT pathway is composed of multiple bifurcating and converging kinase cascades, providing many potential targets for cancer therapy. Renal cell carcinoma (RCC) is a high-risk and high-mortality cancer that is notoriously resistant to traditional chemotherapies or radiotherapies. The PI3K/AKT pathway is modestly mutated but highly activated in RCC, representing a promising drug target. Indeed, PI3K pathway inhibitors of the rapalog family are approved for use in RCC. Recent large-scale integrated analyses of a large number of patients have provided a molecular basis for RCC, reiterating the critical role of the PI3K/AKT pathway in this cancer. In this review, we summarize the genetic alterations of the PI3K/AKT pathway in RCC as indicated in the latest large-scale genome sequencing data, as well as treatments for RCC that target the aberrant activated PI3K/AKT pathway. PMID- 26233891 TI - Identification of Global DNA Methylation Signatures in Glioblastoma-Derived Cancer Stem Cells. AB - Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. The existence of a small population of stem-like tumor cells that efficiently propagate tumors and resist cytotoxic therapy is one proposed mechanism leading to the resilient behavior of tumor cells and poor prognosis. In this study, we performed an in-depth analysis of the DNA methylation landscape in GBM-derived cancer stem cells (GSCs). Parallel comparisons of primary tumors and GSC lines derived from these tumors with normal controls (a neural stem cell (NSC) line and normal brain tissue) identified groups of hyper- and hypomethylated genes that display a trend of either increasing or decreasing methylation levels in the order of controls, primary GBMs, and their counterpart GSC lines, respectively. Interestingly, concurrent promoter hypermethylation and gene body hypomethylation were observed in a subset of genes including MGMT, AJAP1 and PTPRN2. These unique DNA methylation signatures were also found in primary GBM-derived xenograft tumors indicating that they are not tissue culture related epigenetic changes. Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate tumor suppressor genes that are frequently down-regulated in GBMs such as SPINT2, NEFM and PENK. Forced re-expression of SPINT2 reduced glioma cell proliferative capacity, anchorage independent growth, cell motility, and tumor sphere formation in vitro. The results from this study demonstrate that GSCs possess unique epigenetic signatures that may play important roles in the pathogenesis of GBM. PMID- 26233894 TI - Identification and Characterization of ABA-Responsive MicroRNAs in Rice. AB - MicroRNAs (miRNAs) are endogenous non-coding small RNAs that silence genes through mRNA degradation or translational inhibition. The phytohormone abscisic acid (ABA) is essential for plant development and adaptation to abiotic and biotic stresses. In Arabidopsis, miRNAs are implicated in ABA functions. However, ABA-responsive miRNAs have not been systematically studied in rice. Here high throughput sequencing of small RNAs revealed that 107 miRNAs were differentially expressed in the rice ABA deficient mutant, Osaba1. Of these, 13 were confirmed by stem-loop RT-PCR. Among them, miR1425-5P, miR169a, miR169n, miR390-5P, miR397a and miR397b were up-regulated, but miR162b reduced in expression in Osaba1. The targets of these 13 miRNAs were predicted and validated by gene expression profiling. Interestingly, the expression levels of these miRNAs and their targets were regulated by ABA. Cleavage sites were detected on 7 of the miRNA targets by 5'-Rapid Amplification of cDNA Ends (5'-RACE). Finally, miR162b and its target OsTRE1 were shown to affect rice resistance to drought stress, suggesting that miR162b increases resistance to drought by targeting OsTRE1. Our work provides important information for further characterization and functional analysis of ABA responsive miRNAs in rice. PMID- 26233892 TI - Additive Effect of Zfhx3/Atbf1 and Pten Deletion on Mouse Prostatic Tumorigenesis. AB - The phosphatase and tensin homolog (PTEN) and the zinc finger homeobox 3 (ZFHX3)/AT-motif binding factor 1 (ATBF1) genes have been established as tumor suppressor genes in prostate cancer by their frequent deletions and mutations in human prostate cancer and by the formation of mouse prostatic intraepithelial neoplasia (mPIN) or tumor by their deletions in mouse prostates. However, whether ZFHX3/ATBF1 deletion together with PTEN deletion facilitates prostatic tumorigenesis is unknown. In this study, we simultaneously deleted both genes in mouse prostatic epithelia and performed histological and molecular analyses. While deletion of one Pten allele alone caused low-grade (LG) mPIN as previously reported, concurrent deletion of Zfhx3/Atbf1 promoted the progression to high grade (HG) mPIN or early carcinoma. Zfhx3/Atbf1 and Pten deletions together increased cell proliferation, disrupted the smooth muscle layer between epithelium and stroma, and increased the number of apoptotic cells. Deletion of both genes also accelerated the activation of Akt and Erk1/2 oncoproteins. These results suggest an additive effect of ZFHX3/ATBF1 and PTEN deletions on the development and progression of prostate neoplasia. PMID- 26233895 TI - Convergence of Y Chromosome STR Haplotypes from Different SNP Haplogroups Compromises Accuracy of Haplogroup Prediction. PMID- 26233896 TI - Behavioral Switch of Food Preference upon Sugar Deficiency Is Regulated by GPCRs in Drosophila. PMID- 26233897 TI - An evaluation of different steam disinfection protocols for cystic fibrosis nebulizers. AB - BACKGROUND: Contamination is a key element in cystic fibrosis. For this reason, nebulizer hygiene is an important, but complex and time-consuming task for cystic fibrosis patients. The aim of this study was to compare different steam disinfection and drying protocols. METHODS: One hundred nebulizer parts were inoculated with cystic fibrosis-related bacteria in high concentrations (Burkholderia multivorans 3.9 * 10(10)/ml, Staphylococcus aureus 8.9 * 10(8/)ml and Pseudomonas aeruginosa 2.1 * 10(9)/ml). Tubes with Mycobacterium abscessus complex were additionally tested. Six steam disinfectors were compared. Different methods of drying were examined. RESULTS: All tested bacteria were efficiently killed by the different steam disinfectors tested. The risk of contamination depended on the method of drying. CONCLUSIONS: Steam disinfection is a safe disinfection method. It is better to leave the nebulizers wet after steam disinfection than to manipulate them by active drying, which seems to be a source of recontamination. PMID- 26233898 TI - A tribute to Cicero Parker Meek. AB - Cicero Parker Meek (1914-1979) was working as a general practitioner at the Aiken County Hospital in South Carolina, USA, and had a special interest in the treatment of burn patients. The procedure first presented in 1958 by Meek for a device-based expansion of split-skin (micrografting), which was invented before the mesh technique, is a milestone in the history of burns surgery. The method was forgotten until well into the 90s of the last century, and was only readopted and improved by no longer identifiable physicians at the Red Cross Hospital in Beverwijk. The Meek translation procedure was subsequently modified through the innovations of Kreis and Raff. With increased survival of massively burned patients, mesh grafting fell short of requirements. Mesh grafts of 1:9 expansion are difficult to handle and are vulnerable to dislodgement on the wound bed. Kreis and Raff showed in 1994 that 1:9 expanded mesh grafts did not achieve a true 1:9 expansion on the wound surface, in contrast to 1:9 expanded Meek grafts. Thus Meek grafts provided a highly effective autograft expansion in very large burns. Cicero Parker Meek was an exceptional person in the history of burn therapy. PMID- 26233899 TI - Towards more efficient burn care: Identifying factors associated with good quality of life post-burn. AB - BACKGROUND: As minor burn patients constitute the vast majority of a developed nation case-mix, streamlining care for this group can promote efficiency from a service-wide perspective. This study tested the hypothesis that a predictive nomogram model that estimates likelihood of good long-term quality of life (QoL) post-burn is a valid way to optimise patient selection and risk management when applying a streamlined model of care. METHOD: A sample of 224 burn patients managed by the Burn Service of Western Australia who provided both short and long term outcomes was used to estimate the probability of achieving a good QoL defined as 150 out of a possible 160 points on the Burn Specific Health Scale Brief (BSHS-B) at least six months from injury. A multivariate logistic regression analysis produced a predictive model provisioned as a nomogram for clinical application. A second, independent cohort of consecutive patients (n=106) was used to validate the predictive merit of the nomogram. RESULTS AND DISCUSSION: Male gender (p=0.02), conservative management (p=0.03), upper limb burn (p=0.04) and high BSHS-B score within one month of burn (p<0.001) were significant predictors of good outcome at six months and beyond. A Receiver Operating Curve (ROC) analysis demonstrated excellent (90%) accuracy overall. At 80% probability of good outcome, the false positive risk was 14%. The nomogram was validated by running a second ROC analysis of the model in an independent cohort. The analysis confirmed high (86%) overall accuracy of the model, the risk of false positive was reduced to 10% at a lower (70%) probability. This affirms the stability of the nomogram model in different patient groups over time. An investigation of the effect of missing data on sample selection determined that a greater proportion of younger patients with smaller TBSA burns were excluded due to loss to follow up. CONCLUSION: For clinicians managing comparable burn populations, the BSWA burns nomogram is an effective tool to assist the selection of patients to a streamlined care pathway with the aim of improving efficiency of service delivery. PMID- 26233900 TI - Machine learning in burn care and research: A systematic review of the literature. AB - BACKGROUND: To date, there are no reviews on machine learning (ML) in burn care. Considering the growth of ML in medicine and the complexities and challenges of burn care, this review specializes on ML applications in burn care. The objective was to examine the features and impact of applications in targeting various aspects of burn care and research. METHODS: MEDLINE, the Cochrane Database of Systematic Reviews, ScienceDirect, and citation review of relevant primary and review articles were searched for studies involving burn care/research and machine learning. Data were abstracted on study design, study size, year, population, application of burn care/research, ML technique(s), and algorithm performance. RESULTS: 15 retrospective observational studies involving burn patients met inclusion criteria. In total 5105 patients with acute thermal injury, 171 clinical burn wounds, 180 9-mer peptides, and 424 12-mer peptides were included in the studies. Studies focused on burn diagnosis (n=5), aminoglycoside response (n=3), hospital length of stay (n=2), survival/mortality (n=4), burn healing time (n=1), and antimicrobial peptides in burn patients (n=1). Of these 15 studies, 11 used artificial neural networks. Importantly, all studies demonstrated the benefits of ML in burn care/research and superior performance over traditional statistical methods. However, algorithm performance was assessed differently by different authors. Feature selection varied among studies, but studies with similar applications shared specific features including age, gender, presence of inhalation injury, total body surface area burned, and when available, various degrees of burns, infections, and previous histories/conditions of burn patients. CONCLUSION: A common feature base may be determined for ML in burn care/research, but the impact of ML will require further validation in prospective observational studies and randomized clinical trials, establishment of common performance metrics, and high quality evidence about clinical and economic impacts. Only then can ML applications be advanced and accepted widely in burn care/research. PMID- 26233901 TI - Fractional flow reserve, an effective preoperative guideline to a patient with a huge coronary artery fistula and tandem stenosis. PMID- 26233902 TI - Role of Cytochrome P450 Monooxygenase in Carcinogen and Chemotherapeutic Drug Metabolism. AB - The purpose of this chapter is to provide insight into which human cytochromes P450 (CYPs) may be involved in metabolism of chemical carcinogens and anticancer drugs. A historical overview of this field and the development of literature using relevant animal models and expressed human CYPs have provided information about which specific CYPs may be involved in carcinogen metabolism. Definition of the biochemical properties of CYP activity came from several groups who studied the reaction stoichiometry of butter yellow and benzo[alpha]pyrene, including their role in induction of these enzyme systems. This chapter will list as much as is known about the human CYPs involved in carcinogen and anticancer drug metabolism, as well as summarize studies with rodent CYPs. A review of three major classes of anticancer drugs and their metabolism in humans is covered for cyclophosphamide, procarbazine, and anthracycline antibiotics, cancer chemotherapeutic compounds extensively metabolized by CYPs. The emerging information about human CYP gene polymorphisms as well as other enzymes involved in foreign compound metabolism provides considerable information about how these genetic variants affect carcinogen and anticancer drug metabolism. With information available from individual's genomic sequences, consideration of populations who may be at risk due to environmental exposure to carcinogens or how to optimize their cancer therapy regimens to enhance efficacy of the anticancer drugs appears to be an important field of study to benefit individuals in the future. PMID- 26233903 TI - Involvement of Cytochrome P450 in Reactive Oxygen Species Formation and Cancer. AB - This review examines the involvement of cytochrome P450 (CYP) enzymes in the formation of reactive oxygen species in biological systems and discusses the possible involvement of reactive oxygen species and CYP enzymes in cancer. Reactive oxygen species are formed in biological systems as byproducts of the reduction of molecular oxygen and include the superoxide radical anion (?O2-), hydrogen peroxide (H2O2), hydroxyl radical (?OH), hydroperoxyl radical (HOO?), singlet oxygen ((1)O2), and peroxyl radical (ROO?). Two endogenous sources of reactive oxygen species are the mammalian CYP-dependent microsomal electron transport system and the mitochondrial electron transport chain. CYP enzymes catalyze the oxygenation of an organic substrate and the simultaneous reduction of molecular oxygen. If the transfer of oxygen to a substrate is not tightly controlled, uncoupling occurs and leads to the formation of reactive oxygen species. Reactive oxygen species are capable of causing oxidative damage to cellular membranes and macromolecules that can lead to the development of human diseases such as cancer. In normal cells, intracellular levels of reactive oxygen species are maintained in balance with intracellular biochemical antioxidants to prevent cellular damage. Oxidative stress occurs when this critical balance is disrupted. Topics covered in this review include the role of reactive oxygen species in intracellular cell signaling and the relationship between CYP enzymes and cancer. Outlines of CYP expression in neoplastic tissues, CYP enzyme polymorphism and cancer risk, CYP enzymes in cancer therapy and the metabolic activation of chemical procarcinogens by CYP enzymes are also provided. PMID- 26233904 TI - Polymorphic Variants of Cytochrome P450: Relevance to Cancer and Other Diseases. AB - Associations of cytochrome P450 (CYP) polymorphisms with risk of disease development have been reported widely. For lung cancer, a large number of studies on CYP1A1, CYP2D6, and CYP2A6 polymorphisms have been performed. However, recent studies, including meta-analyses and genome-wide association studies, suggest that only the CYP2A6 association, where genotypes associated with low activity decrease susceptibility possibly due to slower nicotine metabolism, appears significant. Associations with lung cancer susceptibility have also been reported for CYP1A2, CYP1B1, and CYP2E1 polymorphisms but these, though biologically plausible, have not been well replicated. For cancers where exposure to xenobiotics other than tobacco smoke affects risk, CYP polymorphisms may also be relevant. Examples include CYP3A for hepatocellular carcinoma due to aflatoxin exposure, CYP1A2 for colon cancer associated with heterocyclic arylamine exposure and CYP2E1 for nitrosamine-related nasopharyngeal cancer. For other diseases, a well-established example relates to CYP1B1 where homozygosity for rare mutations occurs in primary congenital glaucoma. Rare CYP1B1 mutations and possibly polymorphisms may also contribute to risk for more common forms of glaucoma. CYP2C isoforms and CYP2J2 contribute to extrahepatic metabolism of arachidonic acid to epoxyeicosanoic acids which have effects in the cardiovascular system. Genotype for these isoforms may be relevant to risk of cardiovascular disease but evidence is still lacking. CYP2C19 poor metabolizers may be at increased risk of endometriosis, and CYP2E1 genotype may modulate risk of development of alcoholic liver disease. In conclusion, CYP polymorphisms are relevant to risk for some diseases but this may have been overstated in earlier studies. PMID- 26233905 TI - Personalized Cancer Therapy Considering Cytochrome P450 Variability. AB - The individual variability of pharmacokinetics is underestimated and few systematic studies exist in this field. In most cases, this leads to unwanted side effects or toxicity. In polychemotherapy, prodrugs (like ifosfamide), which have to be activated by cytochrome P450 enzymes (CYPs), play an important role. If patients are poor metabolizers for these drugs, the therapy will be ineffective. Furthermore, CYPs and transporters can be (over)expressed in target tissues, which is also not examined and considered in clinical routine. Here, we present a body map showing relevant enzymes in some organs and tissues. Finally, a typical case of a Caucasian chemotherapy patient with breast cancer is presented and discussed regarding a personalized cancer therapy considering the single nucleotide polymorphisms found via genotyping. PMID- 26233907 TI - Role of Cytochrome P450s in Inflammation. AB - Cytochrome P450 epoxygenases and hydroxylases play a regulatory role in the activation and suppression of inflammation by generating or metabolizing bioactive mediators. CYP2C and CYP2J epoxygenases convert arachidonic acid to anti-inflammatory epoxyeicosatrienoic acids, which have protective effects in a variety of disorders including cardiovascular disease and metabolic syndrome. CYP4A and CYP4F hydroxylases have the ability to metabolize multiple substrates related to the regulation of inflammation and lipid homeostasis, and it is a challenge to determine which substrates are physiologically relevant for each enzyme; the best-characterized activities include generation of 20 hydroxyeicosatetraenoic acid and inactivation of leukotriene B4. The expression of hepatic drug-metabolizing cytochrome P450s is modulated by cytokines during inflammation, resulting in changes to the pharmacokinetics of prescribed medications. Cytochrome P450s are therefore the focus of intersecting challenges in the pharmacology of inflammation: not only do they represent targets for development of new anti-inflammatory drugs but they also contribute to variability in drug efficacy or toxicity in inflammatory disease. Animal models and primary hepatocytes have been used extensively to study the effects of cytokines on cytochrome P450 expression and activity. However, it is difficult to predict changes in drug exposure in patients because the response to inflammation varies depending on the disease state, its time course, and the cytochrome P450 involved. In these circumstances, the development of endogenous markers of cytochrome P450 metabolism might provide a useful tool to reevaluate drug dosage and choice of therapy. PMID- 26233908 TI - Cytochrome P450-CYP2 Family-Epoxygenase Role in Inflammation and Cancer. AB - Arachidonic acids are converted to eicosanoid mediators by different enzyme systems: cyclooxygenase, lipoxygenase, and cytochrome P450 (CYP) monooxygenase pathways (omega/omega-1-hydroxylases and epoxygenases). Of 57 putatively functional human CYPs, only about a dozen enzymes are responsible for xenobiotic metabolism. CYP2 family is the predominant epoxygenase isoform abundantly expressed in the endothelium, myocardium, and kidney in humans. Numerous studies have demonstrated the cardiovascular protective effects of CYP epoxygenases and eicosatrienoic acids ranging from vasodilation, antihypertensive, proangiogenesis, antiatherosclerosis, and cardiac protection. The roles of CYP2 family and their metabolites in inflammation and cancer biology have recently attracted great attention. Here, we review the recent progress on polymorphisms, distribution and function of CYP2 family, and their roles in inflammation and cancer. PMID- 26233906 TI - Xenobiotic and Endobiotic Mediated Interactions Between the Cytochrome P450 System and the Inflammatory Response in the Liver. AB - The liver is a unique organ in the body as it has significant roles in both metabolism and innate immune clearance. Hepatocytes in the liver carry a nearly complete complement of drug metabolizing enzymes, including numerous cytochrome P450s. While a majority of these enzymes effectively detoxify xenobiotics, or metabolize endobiotics, a subportion of these reactions result in accumulation of metabolites that can cause either direct liver injury or indirect liver injury through activation of inflammation. The liver also contains multiple populations of innate immune cells including the resident macrophages (Kupffer cells), a relatively large number of natural killer cells, and blood-derived neutrophils. While these cells are primarily responsible for clearance of pathogens, activation of these immune cells can result in significant tissue injury during periods of inflammation. When activated chronically, these inflammatory bouts can lead to fibrosis, cirrhosis, cancer, or death. This chapter will focus on interactions between how the liver processes xenobiotic and endobiotic compounds through the cytochrome P450 system, and how these processes can result in a response from the innate immune cells of the liver. A number of different clinically relevant diseases, as well as experimental models, are currently available to study mechanisms related to the interplay of innate immunity and cytochrome P450-mediated metabolism. A major focus of the chapter will be to evaluate currently understood mechanisms in the context of these diseases, as a way of outlining mechanisms that dictate the interactions between the P450 system and innate immunity. PMID- 26233909 TI - Cytochrome P450 omega-Hydroxylases in Inflammation and Cancer. AB - Cytochrome P450-dependent omega-hydroxylation is a prototypic metabolic reaction of CYP4 family members that is important for the elimination and bioactivation of not only therapeutic drugs, but also endogenous compounds, principally fatty acids. Eicosanoids, derived from arachidonic acid, are key substrates in the latter category. Human CYP4 enzymes, mainly CYP4A11, CYP4F2, and CYP4F3B, hydroxylate arachidonic acid at the omega position to form 20-HETE, which has important effects in tumor progression and on angiogenesis and blood pressure regulation in the vasculature and kidney. CYP4F3A in myeloid tissue catalyzes the omega-hydroxylation of leukotriene B4 to 20-hydroxy leukotriene B4, an inactivation process that is critical for the regulation of the inflammatory response. Here, we review the enzymology, tissue distribution, and substrate selectivity of human CYP4 omega-hydroxylases and their roles as catalysts for the formation and termination of the biological effects of key eicosanoid metabolites in inflammation and cancer progression. PMID- 26233911 TI - Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease. AB - Fat accumulation (hepatic steatosis) in alcoholic and nonalcoholic fatty liver disease is a potentially pathologic condition which can progress to steatohepatitis (inflammation), fibrosis, cirrhosis, and carcinogenesis. Many clinically used drugs or some alternative medicine compounds are also known to cause drug-induced liver injury, which can further lead to fulminant liver failure and acute deaths in extreme cases. During liver disease process, certain cytochromes P450 such as the ethanol-inducible cytochrome P450-2E1 (CYP2E1) and CYP4A isozymes can be induced and/or activated by alcohol and/or high-fat diets and pathophysiological conditions such as fasting, obesity, and diabetes. Activation of these P450 isozymes, involved in the metabolism of ethanol, fatty acids, and various drugs, can produce reactive oxygen/nitrogen species directly and/or indirectly, contributing to oxidative modifications of DNA/RNA, proteins and lipids. In addition, aldehyde dehydrogenases including the mitochondrial low Km aldehyde dehydrogenase-2 (ALDH2), responsible for the metabolism of acetaldehyde and lipid aldehydes, can be inactivated by various hepatotoxic agents. These highly reactive acetaldehyde and lipid peroxides, accumulated due to ALDH2 suppression, can interact with cellular macromolecules DNA/RNA, lipids, and proteins, leading to suppression of their normal function, contributing to DNA mutations, endoplasmic reticulum stress, mitochondrial dysfunction, steatosis, and cell death. In this chapter, we specifically review the roles of the alcohol-metabolizing enzymes including the alcohol dehydrogenase, ALDH2, CYP2E1, and other enzymes in promoting liver disease. We also discuss translational research opportunities with natural and/or synthetic antioxidants, which can prevent or delay the onset of inflammation and liver disease. PMID- 26233913 TI - Cytochrome P450 Vitamin D Hydroxylases in Inflammation and Cancer. AB - Vitamin D insufficiency correlates with increased incidence of inflammatory disorders and cancer of the colon, breast, liver, and prostate. Preclinical studies demonstrated that the hormonally active form of vitamin D, 1,25(OH)2D3, has antiproliferative, proapoptotic, anti-inflammatory, and immunomodulatory effects. Tissue levels of 1,25(OH)2D3 are determined by expression and activity of specific vitamin D hydroxylases expressed at renal and extrarenal sites. In order to understand how perturbations in the vitamin D system affect human health, we need to understand the steps involved in the synthesis and catabolism of the active metabolite. This review provides an overview about recent findings on the altered vitamin D metabolism in inflammatory conditions and carcinogenesis. We will summarize existing data on the pathophysiological regulation of vitamin D hydroxylases and outline the role of adequate levels of 1,25(OH)2D3 on tissue homeostasis. PMID- 26233914 TI - Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer. Preface. PMID- 26233910 TI - Bile Acid Metabolism and Signaling in Cholestasis, Inflammation, and Cancer. AB - Bile acids are synthesized from cholesterol in the liver. Some cytochrome P450 (CYP) enzymes play key roles in bile acid synthesis. Bile acids are physiological detergent molecules, so are highly cytotoxic. They undergo enterohepatic circulation and play important roles in generating bile flow and facilitating biliary secretion of endogenous metabolites and xenobiotics and intestinal absorption of dietary fats and lipid-soluble vitamins. Bile acid synthesis, transport, and pool size are therefore tightly regulated under physiological conditions. In cholestasis, impaired bile flow leads to accumulation of bile acids in the liver, causing hepatocyte and biliary injury and inflammation. Chronic cholestasis is associated with fibrosis, cirrhosis, and eventually liver failure. Chronic cholestasis also increases the risk of developing hepatocellular or cholangiocellular carcinomas. Extensive research in the last two decades has shown that bile acids act as signaling molecules that regulate various cellular processes. The bile acid-activated nuclear receptors are ligand-activated transcriptional factors that play critical roles in the regulation of bile acid, drug, and xenobiotic metabolism. In cholestasis, these bile acid-activated receptors regulate a network of genes involved in bile acid synthesis, conjugation, transport, and metabolism to alleviate bile acid-induced inflammation and injury. Additionally, bile acids are known to regulate cell growth and proliferation, and altered bile acid levels in diseased conditions have been implicated in liver injury/regeneration and tumorigenesis. We will cover the mechanisms that regulate bile acid homeostasis and detoxification during cholestasis, and the roles of bile acids in the initiation and regulation of hepatic inflammation, regeneration, and carcinogenesis. PMID- 26233915 TI - Chronic intermittent mental stress promotes atherosclerotic plaque vulnerability, myocardial infarction and sudden death in mice. AB - Vulnerable atherosclerotic plaques are prone to plaque rupture leading to acute cardiovascular syndromes and death. Elucidating the risk of plaque rupture is important to define better therapeutic or preventive strategies. In the present study, we investigated the effect of chronic intermittent mental stress on atherosclerotic plaque stability and cardiovascular mortality in apolipoprotein E deficient (ApoE(-/-)) mice with a heterozygous mutation in the fibrillin-1 gene (Fbn1(C1039G+/)(-)). This mouse model displays exacerbated atherosclerosis with spontaneous plaque ruptures, myocardial infarction and sudden death, when fed a Western-type diet (WD). Female ApoE(-/-)Fbn1(C1039G+/-) mice were fed a WD for up to 25 weeks. After 10 weeks WD, mice were divided in a control (n = 27) and mental stress (n = 29) group. The chronic intermittent mental stress protocol consisted of 3 triggers: water avoidance, damp bedding and restraint stress, in a randomly assigned order lasting 6 h every weekday for 15 weeks. Chronic intermittent mental stress resulted in a significant increase in the amount of macrophages in atherosclerotic plaques of the proximal ascending aorta, whereas type I collagen and fibrous cap thickness were decreased. The coronary arteries of mental stress-treated mice showed larger plaques, more stenosis, and an increased degree of perivascular fibrosis. Moreover, myocardial infarctions occurred more frequently in the mental stress group. As compared to the control group, the survival of stressed ApoE(-/-)Fbn1(C1039G+/-) mice decreased from 67% to 52% at 25 weeks WD, presumably due to myocardial infarctions. In conclusion, chronic intermittent mental stress promotes plaque instability, myocardial infarctions, and mortality of ApoE(-/-)Fbn1(C1039G+/-) mice. PMID- 26233912 TI - Role of Retinoic Acid-Metabolizing Cytochrome P450s, CYP26, in Inflammation and Cancer. AB - Vitamin A (retinol) and its active metabolite, all-trans-retinoic acid (atRA), play critical roles in regulating the differentiation, growth, and migration of immune cells. Similarly, as critical signaling molecules in the regulation of the cell cycle, retinoids are important in cancers. Concentrations of atRA are tightly regulated in tissues, predominantly by the availability of retinol, synthesis of atRA by ALDH1A enzymes and metabolism and clearance of atRA by CYP26 enzymes. The ALDH1A and CYP26 enzymes are expressed in several cell types in the immune system and in cancer cells. In the immune system, the ALDH1A and CYP26 enzymes appear to modulate RA concentrations. Consequently, alterations in the activity of ALDH1A and CYP26 enzymes are expected to change disease outcomes in inflammation. There is increasing evidence from various disease models of intestinal and skin inflammation that treatment with atRA has a positive effect on disease markers. However, whether aberrant atRA concentrations or atRA synthesis and metabolism play a role in inflammatory disease development and progression is not well understood. In cancers, especially in acute promyelocytic leukemia and neuroblastoma, increasing intracellular concentrations of atRA appears to provide clinical benefit. Inhibition of the CYP26 enzymes to increase atRA concentrations and combat therapy resistance has been pursued as a drug target in these cancers. This chapter covers the current knowledge of how atRA and retinol regulate the immune system and inflammation, how retinol and atRA metabolism is altered in inflammation and cancer, and what roles atRA metabolizing enzymes have in immune responses and cancers. PMID- 26233916 TI - Fenofibrate effects on arterial endothelial function in adults with type 2 diabetes mellitus: A FIELD substudy. AB - OBJECTIVE: Dislipidaemia in type 2 diabetes mellitus contributes to arterial endothelial dysfunction and an increased risk of cardiovascular disease. Fenofibrate, a lipid-regulating peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist, has been shown to reduce vascular complications in adults with type 2 diabetes. However, the mechanisms for such benefit are not well understood. We examined the effects of fenofibrate on brachial artery endothelial function in adults with type 2 diabetes. METHODS: In a prospectively designed substudy of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, we assessed arterial flow-mediated dilatation (FMD; endothelium-dependent dilatation) and dilator responses to glyceryl trinitrate (GTN, an endothelium independent dilator) in a subset of 193 representative adults. Traditional risk factors were assessed at baseline, 4 months and 2 years after randomised treatment allocation to fenofibrate (200 mg daily) or placebo. The prespecified primary study endpoint was the difference in FMD between treatment groups at 4 months. RESULTS: Fenofibrate was associated with a significant improvement at 4 months compared with placebo (+1.05% (absolute); P=0.03); GTN-dilator responses were unchanged (P=0.77). After 2 years, FMD was similar in both groups (P=0.46). In multivariable models, none of the fenofibrate-related changes in lipoproteins and lipids were significantly associated with improved FMD on fenofibrate at 4 months. CONCLUSION: Treatment with fenofibrate significantly improved arterial endothelial function after 4 months. However, the effect was no longer apparent after 2 years. The long-term beneficial vascular effects of fenofibrate in type 2 diabetes are likely to be mediated via mechanisms other than improvement in endothelium-dependent dilatation of conduit arteries, and may differ for the microcirculation. PMID- 26233918 TI - B lymphocytes in abdominal aortic aneurysms. AB - Abdominal aortic aneurysm (AAA) is a progressive inflammatory disease of the artery walls. Immune cells, including B lymphocytes, are implicated in the pathogenesis of AAA through interconnected mechanisms. Many studies have shown that compared with normal abdominal aortic tissue, the amount of B lymphocytes that infiltrate the adventitia of AAAs was significantly higher. Activated B lymphocytes promote AAA by producing immunoglobulins, cytokines, and matrix metalloproteinases (MMPs), resulting in the activation of macrophages, mast cells (MCs) and complement pathways. Finally, all of these factors lead to the degradation of collagen and matrix proteins and to aortic wall remodeling, which are hallmarks of AAA. However, few studies focus on the relative function of B cells, and their precise mechanisms in AAA remain unclear. Thus, we summarize the current knowledge on the role of B cells in AAA and offer recommendations for further investigation of preventing the progression of AAA. PMID- 26233919 TI - Sexually transmissible infections and characteristics of men aged 60 years and over attending a public sexually transmitted diseases (STD) clinic in South Australia. AB - Background With society ageing, sexually transmissible infections (STIs) in the older population are of interest from an economic, health-related and social burden perspective. Few studies on STIs in men older than 60 years of age exist. METHODS: A retrospective study was performed looking at characteristics of, and STIs in, 29106 men (of which 689 were older than 60 years of age), at first presentation, visiting the only South Australian public sexually transmitted diseases (STD) clinic over a 13-year period. RESULTS: Older men [men who have sex with men (MSM) and men who have sex with women (MSW)] were less likely than younger men to have been tested for HIV. CONCLUSION: There is a need for increased HIV testing in older men. PMID- 26233917 TI - Mycobacterial heat shock protein 65 (mbHSP65)-induced atherosclerosis: Preventive oral tolerization and definition of atheroprotective and atherogenic mbHSP65 peptides. AB - OBJECTIVE: The aim of this study was to identify atherogenic and atheroprotective peptides of bacterial HSP60 [taking mycobacterial HSP65 (mbHSP65) as a potent paradigmatic representative] that could be used as candidates for an orally applied tolerizing vaccine against atherosclerosis. METHODS: ApoE(-/-) mice were immunized with mbHSP65 protein or peptides, given mbHSP65 orally and then kept either on chow or high cholesterol diet. Atherosclerosis was assessed by en face and immunohistological analysis. Anti-HSP autoantibodies were detected by ELISA. The number and in vitro suppressive function of splenic and lymph node regulatory T cells (Tregs) were analyzed by flow cytometry. Specific T cell reactivity against mbHSP65 protein or peptides was assessed by proliferation assay. RESULTS: Decreased lesion size was accompanied by (a) increased splenic Treg numbers; (b) increased interleukin (IL)-10 mRNA levels in the aorta; (c) increased levels of anti-mbHSP65 and anti-mouse HSP60 antibodies pointing to pro-eukaryotic HSP60 humoral crossreaction, not curtailed by oral tolerization; (d) most importantly, we identified and functionally characterized novel atherogenic and atheroprotective mbHSP65 epitopes. CONCLUSION: Atheroprotective mbHSP65 peptides may be considered as potential candidates for the development of a tolerizing vaccine to prevent and treat atherosclerosis, while keeping protective immunity to non-atherogenic domains of mbHSP65 intact. PMID- 26233920 TI - Low salinity enhances NI-mediated oxidative stress and sub-lethal toxicity to the green shore crab (Carcinus maenas). AB - Nickel (Ni) is a metal of environmental concern, known to cause toxicity to freshwater organisms by impairing ionoregulation and/or respiratory gas exchange, and by inducing oxidative stress. However, little is known regarding how nickel toxicity is influenced by salinity. In the current study we investigated the salinity-dependence and mechanisms of sub-lethal Ni toxicity in a euryhaline crab (Carcinus maenas). Crabs were acclimated to three experimental salinities--20, 60 and 100% seawater (SW)--and exposed to 3mg/L Ni for 24h or 96 h. Tissues were dissected for analysis of Ni accumulation, gills were taken for oxidative stress analysis (catalase activity and protein carbonyl content), haemolymph ions were analysed for ionoregulatory disturbance, and oxygen consumption was determined in exercised crabs after 96 h of Ni exposure. Total Ni accumulation was strongly dependant on salinity, with crabs from 20% SW displaying the highest tissue Ni burdens after both 24 and 96-h exposures. After 96 h of exposure, the highest accumulation of Ni occurred in the posterior (ionoregulatory) gills at the lowest salinity, 20% SW. Posterior gill 8 exhibited elevated protein carbonyl levels and decreased catalase activity after Ni exposure, but only in 20% SW. Similarly, decreased levels of haemolymph Mg and K and an increased level of Ca were recorded but only in crabs exposed to Ni for 96 h in 20% SW. Oxygen consumption after exercise was also inhibited in crabs exposed to Ni in 20% SW. These data show for the first time the simultaneous presence of all three modes of sub lethal Ni toxicity in exposed animals, and indicate a strong salinity dependence of sub-lethal Ni toxicity to the euryhaline crab, C. maenas, a pattern that corresponded to tissue Ni accumulation. PMID- 26233921 TI - Thresholds of copper phytotoxicity in field-collected agricultural soils exposed to copper mining activities in Chile. AB - It has been argued that the identification of the phytotoxic metal thresholds in soil should be based on field-collected soil rather than on artificially contaminated soils. However, the use of field-collected soils presents several difficulties for interpretation because of mixed contamination and unavoidable covariance of metal contamination with other soil properties that affect plant growth. The objective of this study was to estimate thresholds of copper phytotoxicity in topsoils of 27 agricultural areas historically contaminated by mining activities in Chile. We performed emergence and early growth (21 days) tests (OECD 208 and ISO 11269-2) with perennial ryegrass (Lolium perenne L.). The total Cu content in soils was the best predictor of plant growth and shoot Cu concentrations, while soluble Cu and pCu(2+) did not well correlate with these biological responses. The effects of Pb, Zn, and As on plant responses were not significant, suggesting that Cu is a metal of prime concern for plant growth in soils exposed to copper mining activities in Chile. The effects of soil nutrient availability and shoot nutrient concentrations on ryegrass response were not significant. It was possible to determine EC10, EC25 and EC50 of total Cu in the soil of 327 mg kg(-1), 735 mg kg(-1) and 1144 mg kg(-1), respectively, using the shoot length as a response variable. However, the derived 95% confidence intervals for EC10, EC25 and EC50 values of total soil Cu were wide, and thus not allowing a robust assessment of metal toxicity for agricultural crops, based on total soil Cu concentrations. Thus, plant tests might need to be performed for metal toxicity assessment. This study suggests shoot length of ryegrass as a robust response variable for metal toxicity assessment in contaminated soils with different nutrient availability. PMID- 26233922 TI - Efficient TpV minimization for circular, cone-beam computed tomography reconstruction via non-convex optimization. AB - An efficient iterative algorithm, based on recent work in non-convex optimization and generalized p-shrinkage mappings, is proposed for volume image reconstruction from circular cone-beam scans. Conventional total variation regularization makes use of L1 norm of gradient magnitude images (GMI). However, this paper utilizes a generalized penalty function, induced by p-shrinkage, of GMI which is proven to be a better measurement of its sparsity. The reconstruction model is formed using generalized total p-variation (TpV) minimization, which differs with the state of the art methods, with the constraint that the estimated projection data is within a specified tolerance of the available data and that the values of the volume image are non-negative. Theoretically, the proximal mapping for penalty functions induced by p-shrinkage has an exact and closed-form expression; thus, the constrained optimization can be stably and efficiently solved by the alternating direction minimization (ADM) scheme. Each sub-problem decoupled by variable splitting is minimized by explicit and easy-to-implement formulas developed by ADM. The proposed algorithm is efficiently implemented using a graphics processing unit and is referred to as "TpV-ADM." This method is robust and accurate even for very few view reconstruction datasets. Verifications and comparisons performed using various datasets (including ideal, noisy, and real projections) illustrate that the proposed method is effective and promising. PMID- 26233923 TI - The Prevalence of Bruising Among Infants in Pediatric Emergency Departments. AB - STUDY OBJECTIVE: Bruising can indicate abuse for infants. Bruise prevalence among infants in the pediatric emergency department (ED) setting is unknown. Our objective is to determine prevalence of bruising, associated chief complaints, and frequency of abuse evaluations in previously healthy infants presenting to pediatric EDs. METHODS: We conducted a prospective, observational, multicenter study of infants aged 12 months or younger presenting to pediatric EDs. Structured sampling was used. Pediatric emergency medicine clinicians performed complete skin examinations to screen for bruising. Study investigators documented skin findings, date of visit, patient's age, chief complaint, and abuse evaluation. The primary outcome was prevalence of bruising. Secondary outcomes were prevalence of bruising based on chief complaint and frequency of abuse evaluation. Point estimates of bruise prevalence and differences in bruise prevalence between patient subgroups were calculated with 95% confidence intervals (CIs). RESULTS: Bruising was identified in 88 of 2,488 infants (3.5%; 95% CI 2.9% to 4.4%). Rates of bruising for infants 5 months and younger and older than 5 months were 1.3% and 6.4%, respectively (difference 5.1%; 95% CI 3.6% to 6.8%). For infants 5 months and younger, 83% of bruising was associated with a trauma chief complaint and only 0.2% of infants presenting with a medical chief complaint had bruising. Pediatric emergency medicine clinicians obtained abuse evaluations on 23% of infants with bruising, and that rate increased to 50% for infants 5 months and younger. CONCLUSION: Bruising prevalence in children 12 months and younger who were evaluated in pediatric EDs was low, increased within age strata, and was most often associated with a trauma chief complaint. Most bruised infants did not undergo an abuse evaluation. PMID- 26233924 TI - Health Information Exchange in Emergency Medicine. AB - Emergency physicians often must make critical, time-sensitive decisions with a paucity of information with the realization that additional unavailable health information may exist. Health information exchange enables clinician access to patient health information from multiple sources across the spectrum of care. This can provide a more complete longitudinal record, which more accurately reflects the way most patients obtain care: across multiple providers and provider organizations. This information article explores various aspects of health information exchange that are relevant to emergency medicine and offers guidance to emergency physicians and to organized medicine for the use and promotion of this emerging technology. This article makes 5 primary emergency medicine-focused recommendations, as well as 7 additional secondary generalized recommendations, to health information exchanges, policymakers, and professional groups, which are crafted to facilitate health information exchange's purpose and demonstrate its value. PMID- 26233925 TI - Radiofrequency-oxidation treatment of sewage sludge. AB - A novel thermal-chemical treatment technology using radiofrequency heating and oxidants (hydrogen peroxide, ozone and a combination of both) was used for the treatment of sewage sludge. This was to evaluate the process effectiveness on cell disintegration and nutrient release of sludge, physical property changes such as particle size distribution, dewaterability and settleability, and their inter-relationships. The effectiveness of treatment processes was in the following order, from the most to least: thermal-oxidation process, oxidation process and thermal process. The thermal-oxidation process greatly increased cell disintegration and nutrient release, improved settleability, and decreased particle sizes. The treatment scheme involving ozone addition followed by hydrogen peroxide and radiofrequency heating yielded the highest soluble chemical oxygen demand, volatile fatty acids, ammonia and metals, while proffering the shortest capillary suction time and excellent settling properties. PMID- 26233927 TI - Decreased IgM, IgA, and IgG response to pneumococcal vaccine in children with transient hypogammaglobulinemia of infancy. PMID- 26233926 TI - Long-term assessment of esophageal remodeling in patients with pediatric eosinophilic esophagitis treated with topical corticosteroids. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic TH2 inflammatory disease characterized by tissue remodeling that leads to esophageal strictures and food impactions. Effects of therapy on long-term remodeling in patients with pediatric eosinophil-associated diseases have not been previously described. OBJECTIVE: We sought to understand the long-term control of esophageal remodeling in patients with EoE. METHODS: We assessed endoscopic and histologic remodeling and TGF-beta1 expression in esophageal biopsy specimens from children (n = 32) with EoE treated with topical corticosteroids (TCSs) over 10 years (mean, 4.5 years). We used standardized EoE scoring tools to gauge endoscopic and symptom features. RESULTS: Seven hundred thirty-eight biopsy specimens from 246 endoscopic procedures were evaluated over 10 years. Four hundred eighty-six biopsy specimens had adequate lamina propria for evaluation of subepithelial remodeling. The severity of epithelial esophageal eosinophilia correlated with epithelial remodeling (basal zone hyperplasia, desquamation, and dilated intercellular spaces; P < .0001), lamina propria eosinophilia (P < .0001), and fibrosis (P < .0001). Sixteen subjects were initial responders (<15 eosinophils/high-power field) to TCSs. Responders and nonresponders spent 54% and 97% of their total disease duration with active EoE (P < .001) and 23% and 53% (P < .02) with maximal fibrosis scores, respectively. Responders had lower endoscopy scores during their disease duration (P = .013). Having less than 15 eosinophils/high-power field at any time correlated with lower fibrosis and endoscopic severity. TGF-beta1(+) cell counts decreased in responders at the first biopsy, but this was not sustained. Symptoms did not correlate with other disease features. CONCLUSIONS: Children with EoE have substantial esophageal remodeling, which associates with inflammation and can improve in a sustainable manner with TCSs. Although endoscopic features correspond to histologic features, symptoms did not correlate with inflammation or fibrosis. PMID- 26233929 TI - Impaired microbial killing by neutrophils from patients with protein kinase C delta deficiency. PMID- 26233930 TI - A Meta-Analysis Investigating Falls in Older Adults Taking Selective Serotonin Reuptake Inhibitors Confirms an Association but by No Means Implies Causation. PMID- 26233928 TI - Group 2 innate lymphocytes (ILC2) are enriched in active eosinophilic esophagitis. PMID- 26233932 TI - Identification of an AVP-NPII mutation within the AVP moiety in a family with neurohypophyseal diabetes insipidus: review of the literature. AB - Familial neurohypophyseal diabetes insipidus (FNDI) is a disorder characterized by excess excretion of diluted urine (polyuria) and increased uptake of fluids (polydipsia). The disorder is caused by mutations affecting the AVP-NPII gene, resulting in absent or deficient secretion of the antidiuretic hormone arginine vasopressin (AVP) by the neurohypophysis. In this study we examined a three generation Cypriot kindred suspected to have FNDI. Direct sequencing analysis of AVP-NPII identified a missense mutation (NM_000490.4:c.61T>C; p.Tyr21His; rs121964893) within the AVP moiety on exon 1 of the gene in all affected family members. So far, only three studies have reported mutations within the AVP moiety of AVP-NPIIas being associated with FNDI, with the vast majority of identified FNDI mutations being located within the signalling peptide or the neurophysis II (NPII) moiety of the gene. The mutation within the AVP moiety identified here had been reported previously in a Turkish kindred with FNDI. Consequently, the findings of this study confirm the causal role of mutations within the AVP moiety in FNDI. Herein we review reported mutations within the AVP moiety of AVP-NPII and their contribution to FNDI. PMID- 26233931 TI - The effects of sleep and light at night on melatonin in adolescents. AB - OBJECTIVE: The circadian hormone melatonin has wide-reaching effects on human physiology. In adolescents, the impact of nighttime light exposure and other modifiable behavioral factors on melatonin levels is poorly understood. DESIGN: We cross-sectionally examined the influence of nighttime behaviors on melatonin levels in 100 adolescents (average age: 15.7; 55 female, 45 male), who completed a self-administered questionnaire and provided a first morning urine sample to assay for urinary 6-sulfatoxymelatonin (aMT6s) levels. We used mixed-effects regression models to test for differences in aMT6s levels by categories of covariates. RESULTS: Self-reported sleep duration, ambient light levels during sleep, and use of electronics after turning off lights did not significantly predict aMT6s levels. Compared to those who reported weekend bedtimes before 11 pm, urinary aMT6s levels were significantly lower among participants reporting weekend bedtimes after midnight (52.5 vs. 38.0 ng/mg creatinine, P trend=0.007). Sleep interruption also appeared to be significantly associated with lower urinary aMT6s levels, but only if lights were turned on during sleep interruption (43.0 ng/mg creatinine for participants with sleep interruption but not turning lights on, vs. 24.6 ng/mg creatinine for participants reporting that they turned on the light when their sleep was interrupted P difference=0.032). CONCLUSIONS: Our study suggests that self-reported sleep-related behaviors have little to no effect on adolescent circadian systems, though larger studies are needed to confirm our findings. PMID- 26233933 TI - Factors associated with adherence to oral antihyperglycemic monotherapy in patients with type 2 diabetes mellitus in the United Kingdom. AB - To evaluate adherence to oral antihyperglycemic monotherapy, we conducted a retrospective cohort study of a UK clinical database. The mean proportion of days covered was 73.5%, and 60.1% of patients were adherent. Younger age and fewer concomitant medications were negatively associated with the likelihood of being adherent. PMID- 26233935 TI - Superficial vein thrombosis: differential diagnosis of circumscribed skin discolorations at autopsy. PMID- 26233934 TI - Effects of three injectable antidiabetic agents on glycaemic control, weight change and drop-out in type 2 diabetes suboptimally controlled with metformin and/or a sulfonylurea: A network meta-analysis. AB - AIMS: The objective of this review was to assess glucagon-like peptide-1 receptor agonists (GLP-1 RAs), basal insulin, and premixed insulin among participants with type 2 diabetes inadequately controlled with metformin and/or a sulfonylurea. METHODS: We searched PubMed, EmBase, and the Cochrane Library to identify eligible randomized controlled trials (RCTs) for a network meta-analysis. RESULTS: A total of 17 RCTs involving 5874 adult individuals were included. Compared with placebo, all three therapies showed a significant effect on achieving target glycated hemoglobin (HbA1c) (GLP-1 RAs: 31.7%, 95% CI, 24.7 38.6%; premixed insulin: 31.1%, 95% CI, 20.4-41.8%; basal insulin: 26.0%, 95% CI, 16.4-35.7%). However, there was no significant difference between the three therapies. A similar result was found in HbA1c reduction. The use of GLP-1 RAs resulted in significant body weight loss (-3.73 kg, 95% CI, -4.52 to -2.95 kg vs. basal insulin and -5.27 kg, 95% CI, -6.17 to -4.36 kg vs. premixed insulin) but there was a higher drop-out rate of participants. Premixed insulin seemed associated with more severe hypoglycemic episodes. CONCLUSIONS: The three injectables had similar impact on glycemic control but other differentiating features relevant to the management of type 2 diabetes with GLP-1 RAs having the most favorable profile. PMID- 26233936 TI - Prescription opioid related deaths in New York City: a 2 year retrospective analysis prior to the introduction of the New York State I-STOP law. AB - The United States is in the midst of an unprecedented drug epidemic. Illicit use of prescription medicine, predominantly opioids, has become one of the nation's fastest-growing drug problems. We have conducted a retrospective review of prescription opioid fatalities in New York City (NYC) prior to the introduction of a 2013 law intended to curtail prescription drug abuse. Over the 2 years of our study, there were 1286 chemical intoxication fatalities in NYC. Of these, 547 (42.5%) were associated with prescription opioids (6.5/100,000 population). Methadone was most frequently encountered followed by oxycodone. Only 36.7% of decedents had a valid opioid prescription. Of non-opioid medications associated with the prescription opiate deaths, benzodiazepines were the most frequently encountered (68.4%), and alprazolam (35.1%) was most common. Though prescribers have no control over drug diversion they should be cognizant of the urgent public health concern regarding prescription opioid abuse and associated fatalities and attempt to identify doctor shoppers and limit prescription of these potent drugs to those with a legitimate need for pain control. They also need to be aware of the high incidence of fatalities due to combined opioid and benzodiazepine use/abuse and refrain from prescribing them in tandem. PMID- 26233938 TI - New approaches for automatic threedimensional source localization of acoustic emissions--Applications to concrete specimens. AB - The task of locating a source in space by measuring travel time differences of elastic or electromagnetic waves from the source to several sensors is evident in varying fields. The new concepts of automatic acoustic emission localization presented in this article are based on developments from geodesy and seismology. A detailed description of source location determination in space is given with the focus on acoustic emission data from concrete specimens. Direct and iterative solvers are compared. A concept based on direct solvers from geodesy extended by a statistical approach is described which allows a stable source location determination even for partly erroneous onset times. The developed approach is validated with acoustic emission data from a large specimen leading to travel paths up to 1m and therefore to noisy data with errors in the determined onsets. The adaption of the algorithms from geodesy to the localization procedure of sources of elastic waves offers new possibilities concerning stability, automation and performance of localization results. Fracture processes can be assessed more accurately. PMID- 26233937 TI - A case of suicide by self-injection of adrenaline. AB - Adrenaline (epinephrine) auto-injectors provide life-saving pre-hospital treatment for individuals experiencing anaphylaxis in a community setting. Errors in handling adrenaline auto-injectors, particularly by children and healthcare professionals, have been reported. Reports of adrenaline overdoses are limited in the medical literature. In most of these cases, accidental adrenaline administration results from medical error. Exogenous administration of catecholamine is responsible for cardiovascular and metabolic responses, which may cause supraventricular tachycardia, ventricular dysrhythmias and myocardial ischemia. The authors present a unique autopsy case involving a 34 year-old woman who intentionally self-injected adrenaline using an adrenaline auto-injector as part of a suicide plan. Catecholamines and metanephrines were measured in peripheral and cardiac blood as well as urine and vitreous humor. Based on the results of all postmortem investigations, the cause of death was determined to be cardiac dysrhythmia and cardiac arrest following adrenaline self-injection. PMID- 26233939 TI - Tobacco and alcohol use in pregnancy in France: the role of migrant status: the nationally representative ELFE study. AB - INTRODUCTION: Tobacco and alcohol use in pregnancy are modifiable yet frequent risk factors of poor perinatal outcomes. We examined whether characteristics associated with substance use in pregnancy vary between native and migrant women, who often differ in terms of socio-demographic characteristics. METHODS: Data come from a nationally representative sample of children born in France in 2011 (ELFE study, n=18,014). Maternal substance use in pregnancy (tobacco: >=1 cigarette/day, alcohol: >=1 time, binge drinking: >=3 units of alcohol on one occasion) was assessed using survey methodology by a) trained interviewers and b) self-reports. Migration status was determined based on country of birth (native born vs. migrant). The sample included 2330 migrant women, predominantly from North Africa (35.4% - primarily Algeria and Morocco), Sub-Saharan Africa (27.3% - primarily Senegal, Ivory Coast, the Congo and Cameroun), Europe (20.2% - primarily Portugal and Germany) and Asia (10.2% - primarily Turkey). Characteristics potentially associated with substance use included socio demographics (maternal age, number of children, relationship status, educational attainment, employment status), health (psychological difficulties, incomplete prenatal care) and partner's characteristics (migration status, employment). RESULTS: Compared to the native-born, migrant women had lower levels of tobacco smoking (8.8 vs. 21.9%) and alcohol use (23.4 vs. 40.7%), but not binge drinking (2.9 vs. 3.3%). Unfavorable socioeconomic circumstances were associated with tobacco smoking in native-born women only. Single parenthood was associated with alcohol use only in migrant women. In migrant women, co-occurring use of another substance and psychological difficulties were more strongly associated with use of tobacco, alcohol or binge drinking than in native-born women. CONCLUSIONS: Migrant women have less favorable socioeconomic characteristics than native women but are generally less likely to use tobacco and alcohol in pregnancy. However those who experience single-parenthood need special attention, as they are disproportionately likely to use psychoactive substances which put them and their children at risk of poor health outcomes. PMID- 26233940 TI - Osteopathology and selenium deficiency co-occurring in a population of endangered Patagonian huemul (Hippocamelus bisulcus). AB - BACKGROUND: About 1,000 endangered Patagonian huemul deer (Hippocamelus bisulcus) remain in Chile and 350-500 in Argentina. Most groups (>100) are not recovering, and prevalence of osteopathology in Argentina was at least 57%. Here I describe relevant cases of osteopathology from a Chilean population which, however, recently also provided data on trace mineral status, supporting the initial hypothesis that nutrition may be a primary etiologic factor. Additionally, recent data on bone chemical composition of Argentine cases and soil analyses are discussed. RESULTS: Fluoride levels in Argentine cases with osteopathology were low and fluorosis was discarded as an etiological factor. Selenium deficiency occurred in 73% of huemul from the Chilean population which exhibited several cases with osteopathology. The pathophysiognomy included extensive erosion; tooth loss; porosification; perforations of palate, maxillar and mandibular bone with frequent exposure of tooth roots; and fractured mandibula. Areas currently used by remaining huemul have mainly acidic volcanic soils, which reduces selenium bioavailability: mean soil selenium levels from areas typically used by extant huemul were very deficient (0.19 ppm), corroborating documented overt selenium deficiency in local livestock and plants. The area of extant huemul is known to result in primary iodine deficiency in livestock which is aggravated by selenium deficiency. CONCLUSIONS: Currently the most parsimonious explanation for frequent osteopathology and lack of numerical recovery are the combined effects of selenium and iodine deficiencies based on: osteopathology in a population of selenium deficient huemul; selenium deficient livestock, plants and soils; acidic soils; and regional primary iodine deficiency. The nexus between mineral nutrition and population dynamics of huemul may be due to constraints on their movements to fertile lowlands, including the elimination of historic migratory traditions, and concomitant elimination of source populations. PMID- 26233941 TI - Effect of aquatic interval training with Mediterranean diet counseling in obese patients: results of a preliminary study. AB - BACKGROUND: No previous studies have investigated a high-intensity interval training program (HIIT) with an immersed ergocycle and Mediterranean diet counseling (Med) in obese patients. We aimed to compare the effects of an intensive lifestyle intervention, Med and HIIT with a water-immersed versus dryland ergocycle, on cardiometabolic and exercise parameters in obese patients. METHODS: We retrospectively identified 95 obese patients at their entry into a 9 month Med and HIIT program: 21 were trained on a water-immersed ergocycle and 74 on a standard dryland ergocycle. Body composition, cardiometabolic and exercise parameters were measured before and after the program. RESULTS: For obese patients performing water- and dryland-exercise (mean age 58+/-9 years versus 55+/-7 years), BMI was higher for the water- than dryland-exercise group (39.4+/ 8.3kg/m(2) versus 34.7+/-5.1kg/m(2), P<0.05), and total fat mass, fasting glycemia and triglycerides level were higher (P<0.05). Both groups showed similarly improved body composition variables (body mass, waist circumference, fat mass, P<0.001), fasting glycemia and triglycerides level (P<0.05). Initial maximal aerobic capacity (metabolic equivalents [METs]) and maximal heart rate (HRmax) were lower for the water- than dryland-exercise group (P<0.05). For both groups, METs, resting HR, resting blood pressure, abdominal and leg muscle endurance were similarly improved (P<0.05). CONCLUSIONS: A long-term Mediterranean diet and HIIT program with water-cycling is as effective as a dryland program in improving body composition, fasting glucose, triglycerides level, blood pressure and fitness in obese patients. A Mediterranean diet combined with water-cycling HIIT may be efficient for severely obese patients at high risk of musculoskeletal conditions. PMID- 26233942 TI - User-centred design in brain-computer interface research and development. PMID- 26233943 TI - Tumours of the foot and ankle. AB - Sarcomas are rare tumours and particularly rarer in the foot and ankle region. The complex anatomy of the foot and ankle makes it unique and hence poses a challenge to the surgeon for limb salvage surgery. Other lesions found in the foot and ankle region are benign bone and soft tissue tumours, metastasis and infection. The purpose of this article is to discuss the relevance of the complex anatomy of the foot and ankle in relation to tumours, clinical features, their general management principles and further discussion about some of the more common bone and soft tissue lesions. Discussion of every single bone and soft tissue lesion in the foot and ankle region is beyond the scope of this article. PMID- 26233945 TI - [Good news for Spanish neonates]. PMID- 26233944 TI - Antithrombotic strategy after bioprosthetic aortic valve replacement in patients in sinus rhythm: evaluation of guideline implementation. AB - OBJECTIVES: After elective aortic valve replacement, patients are at risk of developing valve thrombosis and systemic arterial thromboembolism. Current guidelines recommend antithrombotic therapy with aspirin or vitamin K antagonists (VKAs) during the first 3 months after the procedure, but have level 2 or 3 evidence. As a consequence, the most appropriate antithrombotic therapy is still a matter of debate. This retrospective study analysed all thromboembolic and bleeding complications in patients with either antiplatelet or anticoagulation therapy 1 year after bioprosthetic aortic valve replacement. METHODS: A total of 402 patients undergoing bioprosthetic aortic valve implantation at the VU University Medical Centre and subsequently treated at three regional hospitals were included. The individual duration of either VKAs (acenocoumarol) or aspirin was determined and related to thrombotic and bleeding events. Patients were followed and censored at 1 year postoperatively for survival, cerebral ischaemia, myocardial infarction, peripheral arterial embolism, and minor and major haemorrhages. RESULTS: A total of 24 thromboembolic complications and 31 bleeding episodes occurred. Multivariable analyses revealed that acenocoumarol caused more bleeding episodes (risk ratio [RR]: 8.41, 95% CI: 3.58-19.79) and a similar amount of thromboembolic events (RR: 1.2, 95% CI: 0.47-3.02) compared with aspirin. Prior use of acenocoumarol was found to be a risk factor for thromboembolic events (RR: 3.1, 95% CI: 1.31-7.19). Gender, dyslipidaemia, prior percutaneous coronary intervention, prior use of acenocoumarol and concomitant coronary artery bypass grafting were found to be predictors for bleeding events. CONCLUSIONS: In patients 1 year following bioprosthetic aortic valve replacement, acenocoumarol therapy was associated with a significant increased risk of bleeding events and no reduction in thromboembolic events compared with antiplatelet therapy. These findings support the recommendations of aspirin over VKAs as postoperative thromboprophylaxis. PMID- 26233946 TI - Pakistan: the final frontier for global polio eradication. PMID- 26233947 TI - Pregnancy: Data, Outcomes, and Treatment Paradigms in Rheumatology. PMID- 26233948 TI - The Contributions of Whole-body Magnetic Resonance Imaging for the Diagnosis and Management of Chronic Recurrent Multifocal Osteomyelitis. PMID- 26233949 TI - Silent Joint in Dispute. Is Intraarticular Treatment of Temporomandibular Joint Questionable? PMID- 26233950 TI - A Critical Examination of the Polysymptomatic Distress Scale Construct as a Symptom Severity Questionnaire. PMID- 26233951 TI - Polyarticular Severe Tophaceous Gout Secondary to Limited Medication Access. PMID- 26233952 TI - Finger Flexion Deformity and Carpal Tunnel Syndrome Caused by Gouty Tophus. PMID- 26233953 TI - A Case Series of Adenosine Deaminase 2-deficient Patients Emphasizing Treatment and Genotype-phenotype Correlations. PMID- 26233954 TI - TNFRSF1A Gene Causing Tumor Necrosis Factor Receptor-associated Periodic Syndrome in 2 Siblings Displaying Variable Disease Severity and Discordant Heterozygosity for an MEFV E148Q Variant. PMID- 26233955 TI - Orbital Myositis and Primary Sjogren Syndrome. PMID- 26233956 TI - Regularized Regression Versus the High-Dimensional Propensity Score for Confounding Adjustment in Secondary Database Analyses. AB - Selection and measurement of confounders is critical for successful adjustment in nonrandomized studies. Although the principles behind confounder selection are now well established, variable selection for confounder adjustment remains a difficult problem in practice, particularly in secondary analyses of databases. We present a simulation study that compares the high-dimensional propensity score algorithm for variable selection with approaches that utilize direct adjustment for all potential confounders via regularized regression, including ridge regression and lasso regression. Simulations were based on 2 previously published pharmacoepidemiologic cohorts and used the plasmode simulation framework to create realistic simulated data sets with thousands of potential confounders. Performance of methods was evaluated with respect to bias and mean squared error of the estimated effects of a binary treatment. Simulation scenarios varied the true underlying outcome model, treatment effect, prevalence of exposure and outcome, and presence of unmeasured confounding. Across scenarios, high dimensional propensity score approaches generally performed better than regularized regression approaches. However, including the variables selected by lasso regression in a regular propensity score model also performed well and may provide a promising alternative variable selection method. PMID- 26233957 TI - Removal of growth hormone receptor (GHR) in muscle of male mice replicates some of the health benefits seen in global GHR-/- mice. AB - Global disruption of the GH receptor in mice (GHR-/-) produces a large and reproducible extension in lifespan. Since lack of GH action in muscle resulting in improved glucose homeostasis is potentially a mechanism by which GHR-/- mice are long-lived, and since no information on muscle-specific GHR disruption in females is available, we generated and characterized a line of muscle-specific GHR disrupted (MuGHRKO) mice. As expected, male MuGHRKO mice had improved fasting blood glucose, insulin, c-peptide, and glucose tolerance. In contrast, female MuGHRKO mice exhibited normal glucose, insulin, and glucose tolerance. Body weight was mildly but significantly altered in opposite directions in males (decreased) and females (increased) compared to controls. Grip strength and treadmill endurance were unchanged with advanced age in both sexes, suggesting that the direct action of GH on muscle has minimal effect on age-related musculoskeletal frailty. Longevity was unchanged in both sexes at Ohio University and significantly increased for males at University of Michigan. These data suggest that removal of GHR in muscle of male MuGHRKO mice replicates some of the health benefits seen in global GHR-/- mice including improvements to glucose homeostasis and smaller body weight in males, which may explain the trends observed in lifespan. PMID- 26233960 TI - [To fight against obesity, France bans use of soda fountain]. PMID- 26233961 TI - [An immunochromatographic device for rapid detection of ribosomal protein L7/L12 as a diagnostic test for Mycoplasma pneumonia]. PMID- 26233958 TI - MiR-17-92 cluster promotes hepatocarcinogenesis. AB - MiR-17-92 cluster is an oncogenic miRNA cluster that is implicated in several cancers, although its role in hepatocarcinogenesis has not been clearly defined. In this study, we show that the miR-17-92 cluster is highly expressed in human hepatocellular carcinoma (HCC) tissues compared to the non-tumorous liver tissues by RT-PCR and in situ hybridization analyses. Increased miR-17-92 cluster expression in HCC tissues was further confirmed by analysis of the RNA-sequencing data of 319 patients available from the Cancer Genome Atlas (TCGA) Data Portal (https://tcga-data.nci.nih.gov/tcga/). To create an animal model that resembles enhanced miR-17-92 in the liver, we developed liver-specific miR-17-92 transgenic mice and the animals were treated with the hepatic carcinogen, diethylnitrosamine (DEN). We observed that the liver-specific miR-17-92 transgenic mice showed significantly increased hepatocellular cancer development compared to the matched wild-type control mice. Forced overexpression of the miR-17-92 cluster in cultured human hepatocellular cancer cells enhanced tumor cell proliferation, colony formation and invasiveness in vitro, whereas inhibition of the miR-17-92 cluster reduced tumor cell growth. By analyzing the miRNA and mRNA sequencing data from the 312 hepatocellular cancer patients available from the TCGA database, we observed that the expression levels of the miR-17-92 cluster members and host gene in the tumor tissues are negatively correlated with several target genes, including CREBL2, PRRG1, NTN4. Our findings demonstrate an important role of the miR-17-92 cluster in hepatocarcinogenesis and suggest the possibility of targeting this pivotal miRNA cluster for potential therapy. PMID- 26233959 TI - Distinct genotype-dependent differences in transcriptome responses in humans exposed to environmental carcinogens. AB - Considering genetic variability in population studies focusing on the health risk assessment of exposure to environmental carcinogens may provide improved insights in individual environmental cancer risks. Therefore, the current study aims to determine the impact of genetic polymorphisms on the relationship between exposure and gene expression, by identifying exposure-dependently coregulated genes and genetic pathways. Statistical analysis based on mixed models, was performed to relate gene expression data from 134 subjects to exposure measurements of multiple carcinogens, 28 polymorphisms, age, sex and biomarkers of cancer risk. We evaluated the combined exposure to cadmium, lead, polychlorinated biphenyls, p,p'-dichlorodiphenyldichloroethylene, hexachlorobenzene and 1-OH-pyrene, and the outcome was biologically interpreted by using ConsensusPathDB, thereby focusing on carcinogenesis-related pathways. We found generic and carcinogenesis-related pathways deregulated in both sexes, but males showed a stronger transcriptome response than females. We highlighted NOTCH1, CBR1, ITGB3, ITGA4, ADI1, HES1, NCOA2 and SMARCA2 in view of their direct link with cancer development. Two of these, NOTCH1 and ITGB3, are also known to respond to PCBs and cadmium chloride exposure in rodents and to lead in humans. Subjects carrying a high number of risk alleles appear more responsive to combined carcinogen exposure with respect to the induced expression of some of these cancer-related genes, which may be indicative of increased cancer risk as a consequence of environmental factors. PMID- 26233962 TI - Health conditions for travelers to Saudi Arabia for the pilgrimage to Mecca (Hajj), 2015. PMID- 26233963 TI - Meeting of the International Task Force for Disease Eradication, April 2015. PMID- 26233964 TI - [In Process Citation]. PMID- 26233965 TI - Roundabout to remission. PMID- 26233966 TI - Six Prominent WOMEN SCIENTISTS Making a Difference in the AIDS Fight. PMID- 26233967 TI - Studies Showcase Advances in Designing Antibody-inducing Antigens. PMID- 26233968 TI - Evaluation of Platform Switching on Crestal Bone Stress in Tapered and Cylindrical Implants: A Finite Element Analysis. AB - PURPOSE: To analyze and compare the stress distribution around tapered and cylindrical implants and investigate how different abutment diameters influence crestal bone stress levels. MATERIALS AND METHODS: Six finite element models of an abutment (5 mm, 4.3 mm, and 3.5 mm in diameter) and supporting implants (tapered and cylindrical) were designed. A vertical force of 100 N and a 15 degree oblique force of 100 N were applied separately on the occlusal surface, and von Misses stresses were evaluated in the cortical and cancellous bone. RESULTS: Higher stress was observed under oblique loading than under vertical loading of both tapered and cylindrical implants. Tapered implants demonstrated more stress under both vertical and oblique loading. Platform switching reduced peri-implant crestal bone stress in all models under vertical and oblique forces. The peri-implant crestal bone around tapered implants experienced 4.8% more stress under vertical loading and 35% more stress under oblique loading in comparison to bone around cylindrical implants (2.62 MPa with vertical loading, 8.11 MPa under oblique loading). Oblique loads resulted in much higher stress concentrations in the peri-implant crestal bone than vertical loads (238% in cylindrical and 308% in tapered implants). When the abutment diameter decreased, both models showed reductions of stress in the crestal bone under both types of loading. CONCLUSION: In this finite element analysis, tapered implants increased crestal bone stress upon loading, and platform switching minimized the stress transmitted to the crestal bone in both tapered and parallel wall implants. PMID- 26233969 TI - Gingival Cysts of Adults: Retrospective Analysis from Two Centers in South Brazil and a Review of the Literature. AB - Gingival cysts of adults are rare developmental cysts, with an incidence of 0.3% among all odontogenic cysts. They are benign, well-defined nodules located on the attached gingiva with a fluid-filled appearance. The aim of the present study was to perform an analysis of gingival cysts in adults diagnosed at an oral pathology laboratory and a hospital pathology service in order to determine the frequency of occurrence of this lesion, and to perform a literature review to correlate the present findings with those described in the literature. This study emphasizes the low frequency of gingival cysts in adults and the importance of gathering clinical, radiographic and histopathological information to define the final diagnosis. PMID- 26233971 TI - [Some views about the method of selection of participants to a scientific meeting]. PMID- 26233970 TI - A Novel Surgical Approach for Treatment of Class II Furcation Defects Using Marginal Periosteal Membrane. AB - OBJECTIVES: This study was designed to describe and evaluate the use of a vascularized marginal periosteal barrier membrane (MPM) harvested by a semilunar incision, alone or combined with a bone graft, in treatment of class II furcation defects in mandibular molars, compared to open flap debridement (OFD). METHODS: Thirty class II furcation defects in mandibular molars were randomly assigned into three equal groups: Group I included OFD, Group II included defects treated with MPM, and Group III consisted of defects treated with MPM after applying demineralized freeze-dried bone allograft (DFDBA). At baseline and 6-month follow up, vertical probing depth (VPD), clinical attachment level (CAL) measurements, along with a radiographic measurement of bone height (BH), were obtained for each defect. Transmission electron microscopy (TEM) was used for further evaluation of the histological changes associated with gingival samples related to each line of treatment. RESULTS: Both Groups II and III reflected significant favorable outcomes in all the assessed parameters compared to OFD. A non-significant difference was found between both groups regarding VPD, while significant improvement in CAL and BH were detected in Group III (p <= 0.05). Favorable histological findings were also noticed in the test groups, with more improvement in Group III. CONCLUSION: Placement of a vascularized MPM as a barrier membrane, using a semilunar incision, demonstrated a significant improvement in both clinical and histological outcomes of class II furcation defects in lower molars. When it was combined with DFDBA, a meaningful difference was found with regard to early wound healing and gain in CAL and BH. PMID- 26233972 TI - [Prenatal screening for anueploidies in the first trimester: Audit to a Fetal Medicine Centre with specialized Laboratory in Mexico]. AB - BACKGROUND: Screening for aneuploidies using ultrasound and biochemical first trimester markers has an expected performance if the qualification requirements are fulfilled. OBJECTIVE: To describe the first trimester markers in Mexico through the audit to a Fetal Medicine Centre and Laboratory. MATERIAL AND METHOD: Descriptive study conducted with the audit method of ultrasound and biochemical markers in pregnancies that prenatal screening tests in the first quarter were made between 11 + 1 and 14 + 1 weeks pregnant patients who came to the Laboratorio del Centro Medico para Atencion Fetal Especializada. RESULTS: In 17 months n=1020 pregnancies, 962 (94.3%) single, 55 (5.4%) doubles, and 3 (0.3%) triplets. Median maternal age of 33.8 years (16-52), 413 (40.5%) > or = 35 years. 1080 foetuses with 1009 valid measurements of nuchal translucency (29.8% at external cabinets), 54% >p50; 7.3% >p95, and 1.6% > p99. Out of 1555 sera processed at the Laboratory (f-beta-hCG and PAPP-A, Roche), 641 (41.2%) were interpreted at external centres. In 914 sera the f-beta-hCG MoM were p50 = 0.72, 3.2% >p95; for PAPP-A, p50 = 0.89, 9.0% < p5. There were 850 combined tests, and in 745 an additional marker was added; the IP ductus venosus median was 0.99 MoM. A risk > or =1 in 100 resulted in 50 foetuses (4.6%); 27 underwent invasive procedure at our Centre, 19 normal karyotypes, and 8 abnormal as: 3 trisomy 21 and 5 diverse aneuploidies. CONCLUSIONS: The qualification requirements are fulfilled for nuchal translucency, ductus venosus, and the combined test; 1 out of 3 invasive procedures resulted an aneuploidy; the estimated false positive rate is 3.9%. The Laboratory will adjust the median values of the biochemical markers. A cohort study has begun. PMID- 26233973 TI - [Non invasive prenatal test (NIPT) in maternal blood by parallel massive sequencing. Initial experience in Mexican women and literature review]. AB - BACKGROUND: Discovery of cell-free fetal DNA (cffDNA) in maternal blood in 1997 by Lo et al. has opened the possibility of a noninvasive prenatal test (NIPT). Currently, it is employed in the analysis of aneuploidies and fetal sex determination. Massive parallel sequencing (MPS) detects the origin of each amplified sequence, and analyses over-representation of sequences or any decrease in the fetal chromosomes in maternal plasma. This technique has been validated and allows assessment of trisomies 13, 18 and 21, obtaining the result in about a week from 10-weeks of gestational age. By using NIPT, we expect a reduction in the number of invasive studies and the risk of fetal loss. OBJECTIVE: To communicate the experience obtained at Genetics Clinic of the Hospital Angeles Lomas, in the use of NIPT by MPS as a method of prenatal screening for aneuploidies and fetal sex determination. MATERIAL AND METHODS: A prospective, observational and descriptive study was carried out in order to develop a database of patients who underwent NIPT (Harmony test) from August 2013 to date. Maternal blood samples were analyzed at Ariosa Diagnostics Inc. at San Jose California, USA. RESULTS: Noninvasive prenatal test was applied to 42 patients, with average maternal age of 37.1 years. The percentage of gestational age was 13.3 weeks and of fetal fraction was 12.7%. Two cases of high risk of trisomy 18 and two cases with high risk for X monosomy were obtained. In only one case the test was used for fetal determination, because of a story of Wiskott-Aldrich (W A) disease. In all cases of low risk, the result was confirmed at birth and fetal sex was consistent with reports of literature. CONCLUSIONS: NIPT is currently the screening test with the highest detection rate (greater than 98%, with a false negative rate lesser than 0.5% and a sensitivity and specificity close to 100%), although it can vary from one chromosome to another. It is indicated for women with a result of high risk for trisomy 13, 18 and 21. This test has not been validated for low risk women or multiple pregnancies. In our series, the most frequent indication was advanced maternal age. The weight of the patients is important because it is a factor related to the percentage of fetal DNA. In cases with high risk for X monosomy in which the cytogenetic result was 46, XX, it is important to consider as much causes as possible, such as uniparental disomy (UPD), mosaicism and maternal contamination. Only in a case with W-A story the test was conducted specifically for fetal sex determination and confirmed by amniocentesis. In the cases of high-risk results, confirmation by an invasive method, before an obstetric decision, is indispensable. Further studies are still needed to continue the validation of this test by different molecular techniques and in other groups of patients. PMID- 26233974 TI - [Uterine artery embolization as palliative treatment in cervical cancer]. AB - OBJECTIVE: To describe intractable bleeding in cases of end-stage cervical cancer that required uterine artery embolization (UAE) as a palliative treatment, evaluating the effectiveness of the technique and its success rate. MATERIAL AND METHODS: Retrospective study performed from January 2001 to May 2014, that included patients diagnosed with cervical carcinoma stage IV bleeding, who required uterine artery embolization as palliative treatment in the General Hospital of Albacete. RESULTS: Six patients had symptoms of moderate to severe bleeding and anemia. After the UAE, it was possible to offer a proper management of bleeding and successful stabilization of the patients, improving their quality of life. The success of the technique was complete (100%). CONCLUSION: Uterine artery embolization can be an effective technique in women with advanced cancers, which are not amenable to other treatments. PMID- 26233975 TI - [Teenage pregnancy]. AB - In Mexico, 20% of the annual births are presented in women younger than 20 years old. Pregnancy in adolescents puts at risk mother and child health. This risk is major while the woman is younger, especially when the social and economic conditions are not favorable, which is decisive in later psychosocial development. It has been pointed out that the youths with low education, with minor academic and laboral expectations, with low self-esteem and assertiveness, tend to begin early their active sexual life, to use less frequently contraceptives, and in the case of younger women, to be pregnant, with the risk of abortion because they cannot to make the best decision. It is important to take into account the social context and the special characteristics of the family to understand situation of adolescent at risk of pregnancy. PMID- 26233976 TI - [Cervical ectopic pregnancy. Hysteroscopy treatment, case report]. AB - The cervical ectopic pregnancy is extremely rare accounting for approximately 0.1% of all ectopic pregnancies. The incidence is estimated at 1:2500-1:98,000 pregnancies. Before the decade of the 80s, the diagnosis is usually performed to made curettage for incomplete abortion likely secondary to uncontrollable bleeding culminating in hysterectomy, is extremely dangerous, as the trophoblast uterine vessels can reach through the thin wall cervical and cause serious and intractable bleeding that usually ends even today in mutilating surgeries to limit future playback. Currently exist no clear criteria in the literature to help decision-making. We report a case of cervical pregnancy successfully treated by operative hysteroscopy ablation and proposes criteria that could help in the future to address this devastating disease. PMID- 26233977 TI - [Neonatal Dengue. Presentation of clinical cases]. AB - Dengue is an infectious disease caused by a flavivirus, with four serotypes, transmitted by the mosquito Aedes aegypti. In Mexico it is a public health problem, especially in the region of central and southeast of the country. The disease can be asymptomatic or present serious forms and even death. It is confirmed by detection of the NS1 Antigen; IgM antibodies, polymerase chain reaction and virus isolation. The vertical transmission to de newborn has been little studied. 7 cases in neonates from November to December 2011 are reported. All patients were male, obtained by caesarean section between 34 and 40 weeks of gestation, whose mothers were enrolled with fever and symptoms associated with dengue disease and serology positive for dengue. Six with positive AgNS1 and one positive IgM; one mother died. All the newborns had positive serology for dengue, 4 with positive AgNS1 and 3 positive IgM. The clinical features of the newborn ranged from asymptomatic to one serious dengue fever, shock and hemorrhage. The symptomatic 6 attended with thrombocytopenia, changes in temperature and unspecific disturbance. The severity of mothers conditioned disrepair product at birth, but not with subsequent gravity of the new born. Vertical trasmission of dengue should be suspected in risk areas, to maintain vigilance and to give early treatment. Also is neccesary promote the realization of specific diagnostic and therapeutic guidelines to the neonatal period. PMID- 26233978 TI - [Cervical ectopic pregnancy of 16 weeks gestation. Block with preventive hysterectomy surgical technique for massive pelvic hemorrhage. Case report]. AB - Obstetric hemorrhage remains the leading cause of maternal death, we continue to insist on preventive management of patients at high risk of massive pelvic bleeding, uterine dearterialization selective, significantly reduces the morbidity and mortality of the patient, on this ocassion we report the case of a 33-year-old with a diagnosis of cervical ectopic pregnancy of 13 gestational weeks, treated with selective dearterialization of hypogastric arteries with excellent results, without postoperative complications. PMID- 26233979 TI - [Congenital cystic adenomatoid malformation of the lung, intrauterine diagnostic and treatment. A case report and literature review]. AB - The use of prenatal ultrasonography has improve the detection of fetal abnormalities, which affects the perception about the natural history and evolution of them, changing the management of the fetus and neonate. Today, it is possible to perform an early prenatal diagnosis, and be treated even intrauterine with high rates of success. Such is the case of Congenital Cystic Adenomatoid Malformation (CCAM), characterized by abnormal proliferation and dilatation of the terminal structures of the airway, generating multiple cysts of diferent sizes and locations. The CCAM can be asymptomatic until adulthood, but sometimes it is presented as an adverse perinatal outcome, manifested with ascites, hydrothorax, hydrops and hypoplasia of the affected lung. We report a case of a pregnant women, 32-year-old, diagnosed on the 18 week pregnancy by ultrasound Type 3 Congenital Cystic Adenomatoid Malformation disease. Treated with an intrauterine intervention percutaneous fetal sclerotherapy successfully. PMID- 26233980 TI - [Immunological tolerance]. AB - Immunological tolerance refers to the ability of not reacting by immunological defense reactions when they are not needed. It does not mean a mere lack of response but rather continuous active controlling and modifying of initiated responses towards tolerance. While tolerance is primarily a property of the adaptive immune system, it is also influenced by the innate immune system. The importance of tolerance is emphasized in the intestinal immune system, where foreign structures are present in abundance. In fact, orally administered antigens may in the future hopefully be utilized for the treatment of diseases caused by harmful immune responses. PMID- 26233981 TI - [Treatment of venous thrombosis in a cancer patient]. AB - One out of five cancer patients develop venous thrombosis, the risk thereof being 4-7-fold in cancer patients compared with the normal population. Venous thromboses in cancer patients are associated with a higher mortality than in other thrombotic patients. Early detection, effective treatment of venous thrombosis along with sufficiently long and appropriately planned post-thrombotic prophylaxis will improve the prognosis. The treatment of venous thrombosis in a cancer patient differs from that in other patients, as prolonged treatment with low molecular weight heparins has been shown to be more effective than other treatments and is likely to be accompanied by favorable effects as regards cancer biology. PMID- 26233982 TI - [Adolescents engaging in sexually offending behavior]. AB - Sexually offending behavior by adolescents may be directed towards children, age mates and adults. Neurocognitive and psychiatric disorders and the associated inability to age-related interpersonal relationships and inability to control the sexual desires activated during adolescence may lead a young person to seek inappropriate sexual satisfaction from children. Sometimes the offenses are part of antisocial development. Interventions should be focused on the distorted cognitions and attitudes maintaining the injurious sexual behavior, and on the risk of criminal behavior in general. Pharmacological therapy, mainly with SSRI drugs, has also been tested in adolescents. PMID- 26233983 TI - [Endoscopic surgery accelerates recovery from empyema]. AB - The incidence of thoracic empyema is increasing. Early treatment of empyema should focus on optimal drainage and antibiotics. If conventional therapy fails, surgical intervention has to be considered and approximately 30% of all patients require surgery. In a three-year period (2011-2013), 182 patients were operated at Helsinki University Hospital due to pleural empyema. Thoracoscopic decortication was performed on 44% of the patients and 56% underwent open surgery. After thoracoscopy, the patients had a shorter hospital stay and fewer reoperations. Thoracoscopic decortication should therefore be the first-line procedure in the surgical treatment of pleural empyema. PMID- 26233984 TI - [External regulation of clinical research requires a change]. AB - Key findings and recommendations from a study comparing clinical research regulation in Finland with those in England, Canada (Ontario) and USA are presented. Data were collected with various methods, including interviewing key experts. While the norms and ethical codes were similar, the interpretation partly differed. In each country there were various actors in regulation and practical arrangements differed. Research ethics committees (REC) were crucial, as well as drug authorities in research with drugs. Recommendations include reforming the medical research law, widening the dimensions of ethics judgment, restricting the REC tasks, including a central committee, and introducing quality assurance and restricting the drug control authority tasks. PMID- 26233985 TI - [Hemolysis and metastatic cancer in an elderly man]. AB - Sometimes correct diagnoses is reached after many years and even after decades. Our patient had for decades suffered from a hemolytic disease, life-threatening, metastatic cancer at the age of almost 90 years was also suspected. The patient was finally diagnosed as having mild hereditary spherocytosis and the associated paraspinal extramedullar hematopoiesis as well as an osteoporotic vertebral fracture caused by osteoporosis. PMID- 26233986 TI - [Blessing in disguise: a favorable consequence of a resuscitation trauma]. AB - Powerful resuscitation may save the life of a person having cardiac arrest. Resuscitation measures may, however, cause injuries as well. We describe a patient, in whom a perforation of the gastric wall as a complication of resuscitation was detected, and upon imaging of the perforation, renal cell carcinoma was detected as an incidental finding. The resuscitation was successful, and the complication of resuscitation led to early diagnosis and treatment of the cancer. PMID- 26233987 TI - [Postpartum cerebral sinus thrombosis leading to death of a young woman]. AB - Of all cerebral sinus thromboses, 5 to 20% occur in connection with pregnancy or childbirth, or during the puerperium. The risk is highest during the first month following delivery. Approximately half of the women developing sinus thrombosis possess several concomitant risk factors predisposing to venous thrombosis, and about a fifth of them have a trombophilic disorder. We describe a postpartum cerebral sinus thrombosis leading with the associated complications to the patient's death. The patient was afterwards shown to possess the most common factor predisposing to venous thrombosis, the factor V Leiden mutation. PMID- 26233988 TI - [Update on Current Care Guideline: Food allergy (children)]. AB - This guideline, targeted to healthcare workers dealing with food-allergic children, provides a review on the clinical aspects of pediatric food allergy. The main updates include: elimination diets are not recommended for breast feeding mothers; probiotics are not recommended for allergy prevention or treatment; food challenges are the basis of the diagnosis, but it can be improved by IgE component diagnostics. The treatment for severe symptoms is specific food avoidance, mildly symptomatic children should continue with versatile diet. Specific oral tolerance induction is a safe and effective treatment in most of the pediatric patients. PMID- 26233990 TI - When Humanitarianism Trumps Politics. PMID- 26233989 TI - Provision of Private Care by Doctors Employed in Public Health Institutions: Ethical Considerations and Implications for Clinical Training. AB - This paper summarizes the difficulties that may emerge when the same care provider attends to private and public patients within the same or different clinical settings. First, I argue that blurring the boundaries between public and private care may start a slippery slope leading to "black" under-the-table payments for preferential patient care. Second, I question whether public hospitals that allow their doctors to attend to private patients provide an appropriate learning environment for medical students and residents. Finally, I propose a way to both maintain the advantages of private care and avoid its negative consequences: complete separation between the public and the private health care systems. PMID- 26233991 TI - Long-Term Outcomes Following Reduction and Fixation of Displaced Subcapital Hip Fractures in the Young Elderly. AB - BACKGROUND: The surgical treatment of hip fractures remains controversial especially when considering age. OBJECTIVES: To investigate the long-term functional outcomes of displaced subcapital hip fractures that were reduced and surgically fixed using parallel cannulated screws in patients aged 60 years and younger. METHODS: During the period 1996-2005, 27 patients under age 60 with displaced subcapital hip fractures classified as Garden III or IV were treated with fracture reduction and surgical internal fixation using cannulated screws. Patient outcomes were assessed using the Harris Hip Score (HHS) and physical examination. RESULTS: During a follow-up period of 8-17 years 4 of the 27 patients (14.8%) developed non-union/femoral head avascular necrosis and had undergone hip arthroplasty. All reoperations were performed within the first year after fracture fixation, all in the 50-60 year old age group. The revision rate among patients 50-60 years old was significantly higher than that of patients 50 years and younger (40% vs. 0%, P = 0.037). Mean HHS was higher for patients not requiring revision surgery (85.4) than for patients with revision surgery (75.5), but this difference was not significant. CONCLUSIONS: Internal fixation using fracture reduction and cannulated screw fixation is a successful treatment modality for displaced subcapital hip fractures in patients under 50 years old. Patients aged 50-60 may have a higher risk of avascular necrosis or non-union and require arthroplasty, often within the first year after fracture fixation. The long-term outcome following these fractures is good when excluding patients who had early complications. PMID- 26233992 TI - Tuberculosis during Pregnancy in Northern Israel, 2002-2012: Epidemiology and Clinical Practices. AB - BACKGROUND: Atypical presentation of tuberculosis (TB) during pregnancy may cause diagnostic delay and adversely influence pregnancy outcome. OBJECTIVES: To examine the incidence and clinical and epidemiological features of TB during pregnancy and investigate infection control measures at delivery and during the postpartum period. METHODS: We retrospectively evaluated all reported cases of TB diagnosed during pregnancy to 6 months postpartum in Israel's Northern Health District (2002-2012). RESULTS: Active TB was detected in six patients; all were negative for human immunodeficiency virus (HIV). Two patients were diagnosed in the postpartum period, and four had pulmonary involvement. The average incidence during this period (3.9 per 100,000 pregnancies) was similar to that in the general population. Five patients were at high risk of contracting TB due to either recent immigration from a high-burden country or being in contact with another individual with active TB. Patients with pleuropulmonary involvement had prolonged cough and abnormal chest X-rays, without fever. Diagnosis was delayed for 3 to 7 months from symptom onset. Investigation of the newborn to rule out intrauterine infection was conducted in only one of four relevant cases. All patients were infected with organisms susceptible to all first-line drugs, and all were cured with standard therapy. CONCLUSIONS: There was a considerable delay in the diagnosis of TB among pregnant women, and investigation of the newborn upon delivery to rule out TB infection was routinely omitted. Effective management of TB during pregnancy and the postpartum period requires a multidisciplinary approach including an obstetrician, pediatrician, TB specialist, and public health physician. PMID- 26233993 TI - Effects of Sacral Neuromodulation on Urinary and Fecal Incontinence. AB - BACKGROUND: Fecal incontinence is defined as involuntary passage of stool through the anus. It may vary from soiling to complete evacuation. This involuntary loss of feces, flatus or urge incontinence adversely affects quality of life. Urinary urge incontinence is characterized by symptoms of frequency, urgency and urge incontinence (either alone or in combination). Urgency frequency syndrome is defined as symptoms of frequency and urgency without incontinence episodes. OBJECTIVES: To evaluate the efficacy of sacral neuromodulation on these pathologies. METHODS: Following a detailed investigation, 51 patients with either urinary or fecal incontinence, or both, who did not respond to medical and behavioral treatment were offered the temporary implant. Of the 51 patients 40 showed improvement and advanced for a permanent device. RESULTS: After a mean follow-up of 5 years (range 1-8), there was a significant reduction in the number of incontinence episodes (P < 0.0001), and the number of pads used also declined significantly (P < 0.0001). A marked improvement in quality of life was reported by 71.4% of the women and 58.3% of the men. CONCLUSIONS: Sacral neuromodulation as shown in this study appears to be a promising treatment for urinary and fecal incontinence and can dramatically improve patients' quality of life. PMID- 26233994 TI - QT Interval Length in Elderly Prostatic Cancer Patients on Anti-Testosterone Treatment. AB - Background: QT segment prolongation is a high risk factor for fatal arrhythmias. Several studies have indicated a possible relation between low testosterone levels and QT interval prolongation. OBJECTIVES: To compare the QT interval length in elderly patients with prostate carcinoma who were on anti-testosterone treatment and those who were not. METHODS: We screened the electrocardiograms (ECGs) of 100 prostate cancer patients divided into two groups: 50 patients on anti-testosterone drug treatment and 50 patients not. QT interval length was measured according to the accepted methods. RESULTS: The mean QTc 12 leads in the entire group was 0.45 +/- 0.04 sec, which is close to the upper limit. Mean QTc was actually longer in the control group and there was no QTc difference between the groups after adjustment for possible confounders. Prolonged QTc 12-lead ECG (48% in treated and 54% in non-treated) and lead L2 QT interval (50% in treated and 56% in non-treated) did not differ significantly between the groups. The analysis of QTc 12-lead ECG indicated no significant effects of anti-testosterone drug treatment. Only the use of furosemide was associated with QT prolongation. CONCLUSIONS: The results of this preliminary study do not support our initial concern of an alarmingly prolonged QT interval in the anti-testosterone treated group. However, further prospectively designed studies are needed. In the meanwhile we call for a close follow-up of the QT interval length in patients receiving anti-testosterone treatment. PMID- 26233995 TI - A Comparative Matched Analysis of Clinical Outcomes between Transradial versus Transfemoral Percutaneous Coronary Intervention. AB - BACKGROUND: Several trials support the transradial route of percutaneous coronary intervention (PCI) since it reduces access-site vascular complications and bleeding. OBJECTIVES: To examine the effects of transradial interventions (TRI) on clinical outcomes in a 'real-world' cohort of patients undergoing PCI. METHODS: We analyzed 4873 consecutive patients who underwent PCI at a tertiary center and identified 373 patients who underwent TRI. Patients (radial vs. femoral) were compared using a propensity score analysis to best match between groups. Outcome parameters included total mortality, myocardial infarction (MI), repeat target vessel revascularization (TVR) rates, length of hospitalization and AHt/Hb/creatinine values during hospitalization. These were evaluated at 6 months and 1 to 3 years after PCI. RESULTS: The rates of major adverse cardiovascular event (MACE) and its constituents were similar in the transradial vs. transfemoral groups at all time intervals: 6.7% vs. 5.5% at 6 months, 10.3% vs. 10% at 1 year, 15.7% vs. 15% at 2 years, 15.7% vs. 16% at 3 years, respectively (P = 0.6). The length of hospitalization was shorter in the TRI group (2.87 days +/- 2.04 vs. 3.3 days +/- 3.12, P = 0.023). We did not find significant differences between the groups in the mean AHt/Hb/creatinine values during the hospitalization course. CONCLUSIONS: In a real-world setting of PCI, the TRI route of PCI is as safe and efficient as the femoral approach. TRI is associated with shorter duration of hospitalization. PMID- 26233996 TI - Deceased Organ Donor Characteristics and Organ Utilization in Israel, 2004-2013. AB - BACKGROUND: The number of patients awaiting organ transplantation continues to exceed the number of available organs. OBJECTIVES: To document changes in the demographic characteristics of brain-dead, heart-beating organ donors over the past 10 years which may impact on organ utilization. METHODS: Data were extracted from the Israel Transplant Registry and the Donor Action database for the 10 year period 2004-2013, inclusive. RESULTS: The median age of the donors increased from 44 (range 3-73 years) to 53.5 years (range 1-79 years) (P < 0.001). There was a significant increase in the median age of donors of kidneys (33 to 51 years, P < 0.001), livers (41 to 53 years, P < 0.001) and lungs (40 to 49.5 years, P < 0.001). The number of donors dying from trauma decreased (34.5% to 20%, P < 0.001), while those with anoxic brain damage increased (14.5% to 25%, P < 0.001). The percent of male donors decreased over the study period, from 63% to 53%. An increase was noted in the mean number of organs transplanted per donor, from 3.29 to 3.82 per donor, due mainly to a significant increase in the utilization of lungs (31.5% to 51.3%, P < 0.001) and livers (76.3% to 82.4%, P < 0.001) while heart utilization decreased significantly since 2006 (40.9% to 17.5%, P < 0.001). CONCLUSION: Trends in the heart-beating, brain-dead organ donor pool in Israel over the past 10 years reveal significant changes in demographic characteristics which in the future will impact on the number of organs available for transplantation. PMID- 26233997 TI - Cholesterol Levels Decrease soon after Acute Myocardial Infarction. AB - BACKGROUND: While earlier studies indicated that cholesterol levels decrease significantly after an acute myocardial infarction (MI), a more recent study refuted this observation. OBJECTIVES: To assess changes in plasma lipid levels after onset of acute MI, and determine important predictors of lipid dynamics. METHODS: We prospectively measured lipid levels of patients who presented with an acute MI. Blood samples were drawn on admission to the hospital (day 1), after fasting at least 12 hours overnight (day 2), and on the 4th day of hospitalization (day 4). RESULTS: Of 67 acute MI patients, 30 were admitted for ST elevation MI (STEMI) and 37 for non-STEMI. Both total cholesterol and low density lipoprotein cholesterol (LDL-C) levels decreased significantly (by 9%) in the 24 hours after admission and by 13% and 17% respectively on day 4. High density lipoprotein cholesterol (HDL-C) levels as well as triglycerides did not change significantly. Independent predictors of LDL-C decrease were the presence of diabetes mellitus [odds ratio (OR) 6.73, P = 0.01), and elevated cardiac troponin T (cTnT) levels (OR 1.81, P < 0.04). CONCLUSIONS: LDL-C levels decrease significantly after an acute MI. The reduction is correlated with cTnT levels. Diabetes is a strong independent predictor of LDL-C decrease. In acute MI patients only measurements taken within 24 hours of onset should be used to guide selection of lipid-lowering medication. PMID- 26233998 TI - Estimating the Burden of Fungal Diseases in Israel. AB - Fungal diseases affect a large proportion of the population, ranging in severity from mild superficial infections to life-threatening invasive diseases. Estimates of disease burden are needed to inform public health policies. We estimated the incidence of fungal diseases in Israel based on published surveillance data and risk-based calculations using previously established models. Deaths associated with fungal diseases were estimated from local surveillance data (candidemia) and published reports (invasive aspergillosis). Candidemia was estimated in 649 persons/year and invasive aspergillosis in 254 persons/year; the associated mortality was 2.75 and 0.96 per 100,000 population/year, respectively. Recurrent Candida vulvovaginitis occurs in 130,440 women annually. National incidence rates of cryptococcosis, pneumocystis pneumonia and mucormycosis could not be reliably estimated. Single-center data-derived estimates yielded 24, 26 and 20 cases/year, respectively. Allergic bronchopulmonary aspergillosis, asthma with fungal sensitization and allergic fungal sinusitis affect 8297 (range 2323-11,615), 14,372 (14,372-17,965) and 39,922 (15,969-183,643) persons, respectively. In Israel, candidemia and invasive aspergillosis rank high among infection-related causes of mortality. Allergic fungal diseases cause chronic or recurrent symptoms in a large population and may contribute to asthma-related hospitalization and death. These general estimates should serve as a primer for future efforts to study fungal epidemiology. PMID- 26233999 TI - Surgical Treatment of Femoral Neck Fractures in Young Adults. PMID- 26234000 TI - Tuberculosis Diagnosis in Israel: Don't Forget Pregnant Women. PMID- 26234001 TI - A Creative Approach to Mycotic Abdominal Aortic Aneurysm Secondary to Coxiella burnetii Infection. PMID- 26234002 TI - Thoracoscopic Azygos Vein Lobe Resection in a Patient with Synchronous Right and Left Lung Cancer. PMID- 26234003 TI - Successful Treatment of CINCA/NOMID Syndrome with Interleukin-1 Blockade. PMID- 26234004 TI - Amaurosis Fugax, Anterior Ischemic Optic Neuropathy and Cilioretinal Artery Occlusion Secondary to Giant Cell Arteritis. PMID- 26234005 TI - Systemic Lupus Erythematosus with Stage IV Nephritis in an African Girl. PMID- 26234006 TI - PAGET'S DISEASE AND MALE BREAST CANCER. PMID- 26234007 TI - To the Editor. PMID- 26234008 TI - HELICOBACTER PYLORI AND ATHEROSCLEROSIS. PMID- 26234009 TI - President's Perspective. PMID- 26234010 TI - CAT OF THE MONTH. Critically Appraised Topics. Time of Post Space Preparation Affects the Amount of Coronal Microleakage in Endodontically Treated Teeth When a Resin Sealer Is Used (UT CAT #2773). PMID- 26234011 TI - Oral and Maxillofacial Pathology. Case of month. Neurofibroma. PMID- 26234012 TI - Inflammatory Paradental Cyst in the Mandibular Region: A Report of Two Cases. AB - A distinctive form of paradental cyst can occur on the buccal and apical aspects of erupted mandibular molars. This cyst has peculiar clinical and radiographic features, although the microscopic findings are the same as those of odontogenic inflammatory cysts. Diagnostic and therapeutic problems can occur when this lesion is misinterpreted as a radicular cyst. The purpose of this paper is to present two additional cases of a paradental cyst in the buccal and mesial aspects of a mandibular first molar involving the apical area. The difficulty of diagnosis, treatment, and controversies regarding terminology are also discussed. PMID- 26234013 TI - The Essential Types of Insurance for New Dentists. AB - Although these insurance options may seem overwhelming and expensive, consider the cost of not having proper coverage in place if something catastrophic happens, such as a disability or lawsuit early in your career. Being a dentist is one of the best occupations there is. The future of dentistry is bright and new dentists can make a great living with a successful career that lasts as long as they want. Part of that successful career is being sure you have the right type of coverage in place so that if something catastrophic happens the insurance company takes the risk rather than your practice, your professional reputation, or your pocket book. PMID- 26234014 TI - President's Perspective. PMID- 26234015 TI - In memoriam David H. McCarley, DDS, FAGD, 1953-2015. PMID- 26234016 TI - CAT OF THE MONTH. Critically Appraised Topics. Gabapentin Is as Effective as an Occlusal Appliance in Controlling Nighttime Masticatory EMG Activity (UT CAT #2762). PMID- 26234017 TI - Oral and Maxillofacial Pathology. Case of the Month. Adenomatoid Odontogenic Tumor. PMID- 26234018 TI - Dentists' use of caries risk assessment and individualized caries prevention for their adult patients: Findings from The Dental Practice-Based Research Network. AB - OBJECTIVES: Few studies have examined dentists' subjective ratings of importance of caries risk factors or tested whether dentists use this information in treatment planning. This study tested several hypotheses related to caries risk assessment (CRA) and individualized caries prevention (ICP). METHODS: Data were collected as part of a questionnaire entitled 'Assessment of Caries Diagnosis and Caries Treatment' completed by 547 practitioners who belong to The Dental Practice-Based Research Network (DPBRN), a consortium of participating practices and dental organizations. RESULTS: Sixty-nine percent of DPBRN dentists perform CRA on their patients. Recently graduated dentists, dentists with busier practices, and those who believe a dentist can predict future caries were the most likely to use CRA. The association between CRA and individualized prevention was weaker than expected (r = 0.21). Dentists who perform CRA provide ICP to 57% of their patients, compared with 42% for dentists who do not perform CRA. Based on their responses to radiographic and clinical scenarios in the questionnaire, dentists who use CRA appear to use this information in restorative decisions. CONCLUSION: A substantial percentage of DPBRN dentists do not perform CRA, and there is not a strong linkage between its use and use of individualized preventive regimens for adult patients. More progress in the implementation of current scientific evidence in this area is warranted. PMID- 26234019 TI - The Role of the Dentist in Sleep Medicine. PMID- 26234020 TI - Ebola Protection for Dental Offices. PMID- 26234021 TI - HISTORY OF THE SURGERY FOR OTOSCLEROSIS AND COCHLEAR IMPLANTS. PMID- 26234022 TI - DATA MINING APPROACH FOR IN-HOSPITAL TREATMENT OUTCOME IN PATIENTS WITH ACUTE CORONARY SYNDROME. AB - INTRODUCTION: Risk stratification is nowadays crucial when estimating the patient's prognosis in terms of treatment outcome and it also helps in clinical decision making. Several risk assessment models have been developed to predict short-term outcomes in patients with acute coronary syndrome. This study was aimed at developing an outcome prediction model for patients with acute coronary syndrome submitted to percutaneus coronary intervention using data mining approach. MATERIAL AND METHODS: A total of 2030 patients hospitalized for acute coronary syndrome and treated with percutaneous coronary intervention from December 2008 to December 2011 were assigned to a derivation cohort. Demographic and anamnestic data, clinical characteristics on admission, biochemical analysis of blood parameters on admission, and left ventricular ejection fraction formed the basis ofthe study. A number of machine learning algorithms available within Waikato Environment for Knowledge Discovery had been evaluated and the most successful was chosen. The predictive model was subsequently validated in a different population of 931 patients (validation cohort), hospitalized during 2012. RESULTS: The best prediction results were achieved using Alternating Decision Tree classifier, which was able to predict in-hospital mortality with 89% accuracy, and preserved good performance on validation cohort with 87% accuracy. Alternating Decision Tree classifier identified a subset of 6 attributes most relevant to mortality prediction: systolic and diastolic blood pressure, heart rate, left ventricular ejection fraction, age, and troponin value. CONCLUSION: Data mining approach enabled the authors to develop a model capable of predicting the in-hospital outcome following percutaneous coronary intervention. The model showed excellent sensitivity and specificity during internal validation. PMID- 26234023 TI - MENTAL HEALTH PROBLEMS AND SPEECH DEVELOPMENT IN TODDLERS WITH PHYSICAL ILLNESSES. AB - INTRODUCTION: Mental health problems develop more and more frequently in children and adolescents. Children with physical ill- nesses are at a particular risk of developing associated mental health problems and it is important to study this association in order to detect and treat these problems on time. This study was aimed at determining whether there were differences in the presence of mental health problems and delayed speech development in children with physical illnesses between 18 and 36 months of age compared to the presence of these problems in healthy children. MATERIAL AND METHODS: The study was carried out as an observational cross-sectional study. It included 100 children, of both sexes, aged up to 3 years. The first group consisted of 50 children with physical illnesses that were hospitalized at the Institute for Child and Youth Health Care of Vojvodina, and the control group consisted of 50 healthy children of the same age who attended kindergarten "Radosno detinjstvo" inNovi Sad. The instrument of the study was "A checklist of child behavior for children aged 1.5 to 5 years". The hypothesis was checked with t-test for independent samples. "A survey of language development for children aged 18 to 35 months" was used for assessing the language development. The second part of the hypothesis was checked with chi square test. RESULTS: A statistically significant difference was detected in the following dimensions of the questionnaire: emotional reactivity, anxiety / depression, withdrawal, aggression, stress, internalization, externalization, and total problems. A statistically significant difference was also found in the area of language delay. CONCLUSION: It has been concluded that mental health problems, as well as the language delay, are more pronounced among the children with physical illnesses than in the control group of children. PMID- 26234024 TI - ARTICULATION DISORDERS IN SERBIAN LANGUAGE IN CHILDREN WITH SPEECH PATHOLOGY. AB - INTRODUCTION: Articulation is the result of speech organs and it means clean, clear and distinct pronunciation of voices in words. MATERIAL AND METHODS: A prospective study included 24 children between 5 and 15 years of age, of both sexes. All children were monolingual, Serbian being their native language. The quality of articulation was tested with Triage articulation test. RESULTS: Neither omission nor distortion of plosives was observed in any of them, whereas substitution of plosives occurred in 12% of patients. Omission of affricates was not observed in any of the subjects, but substitution and distortion occurred in 29%, and 76% of subjects, respectively. Omission of fricatives was found in 29% subjects, substitution in 52%, and distortion in 82% of subjects. Omission and distortion of nasals was not recorded in any of the subjects, and substitution occurred in 6% of children. Omission of laterals was observed in 6%, substitution in 46% and distortion in 52% of subjects with articulation disorders. Discussion and CONCLUSION: Articulation disorders were observed not only in children diagnosed with dyslalia but in those with dysphasia and stuttering as well. Children with speech disorders articulate vowels best, then nasals and plosives. Articulation of fricatives and laterals was found to be most severely deviated, including all three disorders, i.e. substitution, omission and distortion. Spasms of speech muscles and vegetative reactions were also observed in this study, but only in children with stuttering. PMID- 26234025 TI - CYSTATIN C - MORE THAN THE MARKER OF THE GLOMERULAR FILTRATION RATE. AB - INTRODUCTION: Cystatin C is one of biomarkers that meet the conditions necessary for an endogenous substance to be a marker of the glomerular filtration rate. Cystatin c - properties. Cystatin C is produced in the nucleated cells in a constant amount, and its serum concentration does not depend on muscle mass and protein intake. The catabolism of cystatin C is mostly done in the kidneys. Determination of cystatin c level. Cystatin C may be determined in the serum, plasma, capillary blood and urine. The laboratory methods which are mainly used to determine its level are neplielometric and turbidimetric immunoassays. Cystatin c as a marker of glomerular filtration rate. Cystatin C is superior to creatinine as a marker of kidney function, especially in the early stages of chronic kidney disease. Several formulas are available for calculating the glomerular filtration rate from serum cystatin C. Cystatin c in various physiological/pathophysiological conditions. The level of cystatin C should be interpreted carefully because there are factors that can affect its level regardless of the renal function (thyroid dysfunction, glucocorticoids use, malignancies etc.). Higher cystatin C concentrations in general population are associated with an increased cardiovascular risk, as well as with preecampsia in pregnant women. CONCLUSION: The significant advantages of cystatin C as a kidney function marker are its use in the creatinine "blind" area, in pediatric and the elderly population. In addition, cystatin C could be used as a marker for cardiovascular risk assessment, in predicting and detecting preeclampsia, in patients with malignant diseases, etc. PMID- 26234026 TI - FUNCTIONAL STATUS OF PATIENTS AFTER STROKE. AB - INTRODUCTION: Patients who have suffered from stroke become disabled and have specific problems due to the physical and mental disability that requires the implementation of rehabilitation and the creation of conditions for independent living, economic and social reintegration. The aim of this study was to evaluate the functional recovery of patients after ischemic stroke, during the subacute phase of medical rehabilitation. MATERIAL AND METHODS: The study was organized as a prospective study, which included 74 patients (44 men, 30 women) treated after stroke at the Department of Medical Rehabilitation, Clinical Center of Vojvodina during 2013. Motor recovery was assessed by Signe-Brunnstrom scale, and Barthel Index, Rivermead Mobility Index, and modified Rankin scale were applied to assess the function. RESULTS: The average age of patients after stroke was 66.59 +/- 9.607 years. The mean hospital stay was 34.35 days. The majority of patients in this study had right-hand hemiparesis 47 (63.5%), and 27 (36.5%) had left-hand hemiparesis. By analyzing the average valueof motor recovery of the affected limb by S.Brunnstrom's scale during rehabilitation at the Department of Medical Rehabilitation, it was found that the value at the end of subacute rehabilitation phase was significantly increased (p<0.01). The results of this testing showed a statistically significant improvement (p<0.0l) in the average values of Barthel Index, Rivermead Mobility Index and modified Rankin scale during the rehabilitation treatment of stroke patients. CONCLUSION: The obtained results showed that the rehabilitation treatment resulted in better functional and motor recovery in the patients who had had ischemic stroke. PMID- 26234027 TI - BACTERIAL INFECTIONS IN PATIENTS WITH LIVER CIRRHOSIS. AB - INTRODUCTION: Liver cirrhosis is characterized by a reduced defensive reaction to bacterial infections and patients with cirrhosis are at increased risk of developing infections, sepsis and death. The most common bacterial infections in these patients are spontaneous bacterial peritonitis, urinary tract infection, pneumonia, skin and soft tissue infection and bacteremia. The most common causes are Gram negative bacteria. The aim of this study was to determine the prevalence, localization and etiology of bacterial infections in hospitalized patients with liver cirrhosis. MATERIAL AND METHODS: This retrospective study included 401 patients with liver cirrhosis hospitalized at the Department of Infectious Diseases, Clinical Center of Vojvodina Novi Sad in the period from 2006 to 2010. Bacterial infection was diagnosed according to clinical examination, laboratory findings, radiological examination and bacterial positive culture. RESULTS: The prevalence of bacterial infection was 38.15% (153/401). The most common infections were pneumonia (21.56%), urinary tract infection (20.91%), and spontaneous bacterial peritonitis (18.95%). Localization of infection remained undetermined in as many as 37 patients (24.18%). Bacterial cultures were positive in 32 patients (20.91%), Gram negative bacteria were commonly isolated, mostly Escherichia coli (71.87%). The mortality rate among patients with bacterial infections was 31.37% (48/153). CONCLUSION: Bacterial infections are often found in patients with liver cirrhosis, the most frequent being pneumonia, urinary tract infection and spontaneous bacterial peritonitis. Gram negative bacteria, especially Escherichia coli were predominant in the etiology. The extent to which bacterial infections are taken into consideration in cases with liver cirrhosis is rather high; however, they are not proved etiologically to the satisfactory level. PMID- 26234028 TI - RISK FACTORS FOR BILATERAL ANTERIOR CRUCIATE LIGAMENT INJURIES. AB - INTRODUCTION: The aim of this study has been to identify which risk factors can influence bilateral anterior cruciate ligament injury. MATERIAL AND METHODS: Thirty-two operated patients took part in this survey during the period of ten years. There were 5 women and 27 men, with average age of 30.46 years (19-55). The respondents filled in the questionnaire by answering the questions regarding the time when getting injured and operated, mechanism of injuries, genetic and anthropometric data, characteristics of sports and every day activities. RESULTS: The incidence of reconstructed bilateral injuries in relation to unilateral ones was 2.3% (50/2168). The age of respondents and side of the injured knee did not correlate significantly with the achieved subjective physical activity level after the second knee surgery. The average time from the first injury to operation was 10 months and 4.3 years since that moment up to the injury of the other knee. It took more than 9 months on average until the reconstruction of contralateral anterior cruciate ligament. The most of athletes were injured in football matches. Three-quarters of athletes returned to competition activities after the first operation, which caused the same injury of the contralateral knee. DISCUSSION AND CONCLUSION: Anterior cruciate ligament rupture of the contralateral knee most often occurs in young active athletes within the first four years after the initial reconstruction. Its frequency is not affected by sex, side of extremity, genetic predisposition, type of sport, concomitant injuries and the choice of graft. Returning to the same or higher level of sports activities after the first reconstruction is one of the preconditions for injuring the other knee in the same way. PMID- 26234029 TI - DEVELOPMENT OF PLASTIC SURGERY. AB - INTRODUCTION: Plastic surgery is a medical specialty dealing with corrections of defects, improvements in appearance and restoration of lost function. Ancient times. The first recorded account of reconstructive plastic surgery was found in ancient Indian Sanskrit texts, which described reconstructive surgeries of the nose and ears. In ancient Greece and Rome, many medicine men performed simple plastic cosmetic surgeries to repair damaged parts of the body caused by war mutilation, punishment or humiliation. In the Middle Ages, the development of all medical braches, including plastic surgery was hindered. New age. The interest in surgical reconstruction of mutilated body parts was renewed in the XVIII century by a great number of enthusiastic and charismatic surgeons, who mastered surgical disciplines and became true artists that created new forms. Modern era. In the XX century, plastic surgery developed as a modern branch in medicine including many types of reconstructive surgery, hand, head and neck surgery, microsurgery and replantation, treatment of burns and their sequelae, and esthetic surgery. Contemporary and future plastic surgery will continue to evolve and improve with regenerative medicine and tissue engineering resulting in a lot of benefits to be gained by patients in reconstruction after body trauma, oncology amputation, and for congenital disfigurement and dysfunction. PMID- 26234030 TI - DR AVRAM JOZEF VINAVER (1862-1915) - PIONEER OF RADIOLOGY IN SERBIA. AB - INTRODUCTION: Dr Abraham Joseph Vinaver (1862-1915), a Jew from Poland, was a pioneer of radiology in Serbia. He graduated from the Faculty of Medicine in Warsaw (1887), but lived and worked in abac (the Kingdom of Serbia) since 1890. Dr Abraham Joseph Vinarev - Career Development. He procured the first X-ray machine and developed radiological service in Sabac five years after the discovery of X-rays. These were the beginnings of radiology in Serbia. He introduced the application of artesian wells. Dr Abraham Joseph Vinarev - a Participant at the First Congress of Serbian Physicians and Naturalists, Belgrade 1904. "The diagnostic importance of X-rays in lung disease, especially in initial tuberculosis" and "Five Years of Treatment by X-Ray Machines" were the first works in the field of radiology in Serbia by this author. Dr Abraham Joseph Vinaver - Reserve Medical Officer in the Serbian Army. During the Balkan Wars, he was a volunteer with the rank of major engaged in military corps and he participated in the First World War as well. He died of malaria in 1915 in Gevgelija. "Dr Avram Vinaver"- Stanislav Vinarev. His dedication to work during the typhus epidemics was put into verses of a poem by his son Stanislav Vinarev. CONCLUSION: Dr Avram Vinaver Joseph was a noble man with a great heart, who selflessly sacrificed himself for the Serbian people and Serbia. He gave his contribution to the development of health services in Serbia, both in peacetime and wartime conditions. Dr Abraham Joseph Vinaver laid the foundations for today's radiology in Serbia. PMID- 26234031 TI - A maternal bond the story of the infinite loop of iron deficiency anemia. PMID- 26234032 TI - [REORGANIZATION OF THE ULTRASTRUCTURE OF NEOCORTICAL NEURONS IN RATS TREATED WITH CELL-FREE DNA]. AB - Neuron ultrastructure was studied in layers III-V of rat brain neocortex 24 hours after intraperitoneal (n=3) or intravenous (n=3) injection of cell-free DNA (7.7x10(-5) g/kg body weight). A plastic restructuring of nuclear chromatin, nucleolar hypertrophy, deep invaginations of nuclear envelope, hyperplasia of mito- chondria and their close contact with other organelles and the nucleus, formation of cytoplasmic tubulovesicular bodies which may promote enhanced synaptic vesicle transport to presynaptic axonal terminals, activation of astrocyte glia were found. The data obtained suggest that injection of cell-free DNA lead to pronounced ultrastructural reorganization in neocortical neurons directed to protein synthesis activation, enhancement of synaptic transmission efficiency, as well as intensification of energy metabolism, that may contribute to reparative and compensatory restorative processes in cerebral ischemic pathology. PMID- 26234033 TI - [LAMINAR LOCATION OF NEURONS PROVIDING INTERHEMISPHERIC CONNECTIONS IN THE VISUAL CORTEX IN CATS WITH IMPAIRMENTS OF BINOCULAR VISION]. AB - The distributio of cells in the visual cortical layers of intact cats (n=7) and cats with experimentally induced strabismus (n=10) and monocular deprivation (n=5) was studied after microiontophoretic injection of horseradish peroxidase into the ocular-dominance columns in areas 17, 18 and the transition zone 17/18. It was found that in cats with impaired binocular vision, the callosal cells were located deeper in layers of I/II, and higher - in layer IV, as compared to those in intact cats. Also in cats with impaired binocular vision, the proportion of callosal cells in layer IV was increased, while in layers II/III it was reduced as compared to intact cats. The most pronounced changes were noted in monocular deprived animals. These findings suggest an important role of sensory input in the formation of the callosal neurons layer distribution. PMID- 26234034 TI - [PECULIARITIES OF STRUCTURAL ORGANIZATION OF AMYGDALA BASOLATERAL NUCLEUS IN THE BRAIN OF MEN AND WOMEN]. AB - Using the morphometric method, neuron profile field areas and the density of neurons and gliocytes were measured in amygdala basolateral nucleus in left and right hemispheres of the brain in 6 men and 6 women aged 19 to 55 years. Women showed a tendency towards hemispheric asymmetry of the indices studied with their greater values found in left hemisphere. In the group of men, the opposite tendency to hemispheric asymmetry was found: greater values of the indices studied were detected in right hemisphere. PMID- 26234035 TI - [ULTRASTRUCTURE OF MOTOR NEURONS AND SYNAPSES IN THE OCULOMOTOR NERVE NUCLEI IN MICE]. AB - Motor neuron and synapse ultrastructure in the somatic area of oculomotor nerve nuclei (cranial nerve III nuclei) was studied in C57 Black/6 mice. It was shown that that axodendritic and axosomatic synapses were characterized by rounded subjunctional bodies, located at the postsynaptic side of the synaptic contact at some distance from postsynaptic density. At the site of the subjunctional densities, the synaptic gap was expanded to 30 um. In the same synapse, the synaptic gap could be reduced twice or more. Axosomatic and axodendritic synapses occured on spines. On the soma and dendrites of motoneurons, en passant type of synapses were found. No gap junctions were observed. PMID- 26234036 TI - [A COMPARATIVE STUDY OF CATECHOLAMINERGIC AND NITROXIDERGIC VASOMOTOR NEURONS IN THE NUCLEI OF THE CAUDAL PART OF THE BRAINSTEM OF THE RAT]. AB - Immunohistochemical methods for the demonstration of tyrosine hydrolase (TH) and neuronal form of nitric oxide synthase (nNOS) were used to study the distribution of catecholaminergic and nitroxidergic vasomotor neurons respectively, in the nuclei of the medulla oblongata and the pons of 12 Wistar rats. Most often the expression of TG was found in neurons located in the nucleus and several reticular nuclei (gigantocellular, paragigantocellular, caudal pons nucleus), but the proportion of immunoreactive neurons did not exceed 8-14%. In the other nuclei (reticular parvocellular nucleus and oral pons nucleus, spinal nucleus of the trigeminal nerve) the value of this parameter ranged from 1 to 3%. In a large group of nuclei with proven vasomotor function such neurons were constantly not detected. In the structures with high content of catecholaminergic neurons, nNOS positive cells were found, as a rule, in fewer numbers than in the nuclei with a limited number of TH-positive neurons. PMID- 26234037 TI - [THE DISTRIBUTION OF CHOLINERGIC AND NITROXIDERGIC NEURONS IN THE SPINAL CORD OF NEWBORN AND ADULT RATS]. AB - The aim of this study was to examine the distribution of cholinergic and nitroxidergic neurons in the spinal cord (SC) of adult and newborn rats. Using immunohistochemical demonstration of choline acetyltransferase (ChAT) and nitric oxide synthase (NOS), cervical portions of SC were studied in newborn (n=5) and adult (n=5) Wistar rats. It was found that ChAT-positive neurons were localized in the anterior horns of the SC, while individual cells were located in of SC posterior horns, in the central gray matter and at the boundary of VI-VII Rexed laminae. Nitroxidergic neurons were located in the superficial layers of SC posterior horns of grey matter, in the central gray matter and in the area of VI VII Rexed laminae. It is found that SC of newborn and adult rats contained cholinergic neurons expressing NOS. Detection of cells containing both enzymes already at postnatal Day 1, suggests that they were formed in rat SC during prenatal ontogenesis PMID- 26234038 TI - [VARIANT ANATOMY OF SPLENIC LIGAMENTS AND ARTERIES PASSING THROUGH THEM]. AB - The research was performed on 15 non embalmed bodies and 32 abdominal complexes of adult individuals. The comparative study of variant anatomy of splenic ligaments and architectonics of arteries passing through them was carried out to substantiate the mobilization of splenopancreatic complex. Anatomical and angiographic restudied were carried out using preparation, morphometry, injection of gastric, pancreatic and splenic vascular bed with red lead suspension. It was established that the form and sizes of splenic ligaments and their interrelation with the branches of the splenic artery were variable. The minimal and maximal sizes of gastrolienal, phrenicosplenic and splenocolic ligaments differed 2-3 times. In most cases, spleen was fixed in abdominal cavity by many short ligaments. It was shown that architectonics and topography of main branches of spleen artery were determined by morphometric characteristics of the spleen proper and its ligaments. The knowledge of splenic ligament variant anatomy allows a new perspective to approach to substantiate different methods of the mobilization of spleno-pancreatic complex during surgical operations on organs of the upper part of the peritoneal cavity and organ-preserving surgery of the spleen. PMID- 26234039 TI - [INTERSTRAIN AND SEASONAL DIFFERENCES IN THE RESPONSE OF BLOOD AND ORGANS OF THE IMMUNE SYSTEM TO ROUND-THE-CLOCK ILLUMINATION OF CBA AND C57/BL6 MICE]. AB - The study of the immune system of mice of CBA (n=7) and C57BL/6 (n=7) strains was performed during a 12-hour photoperiod (12:12) and round-the-clock illumination (RI) in December and March. The numbers of CD3+, CD4+8-, CD4-8-, CD4+8+, CD19+, CD3+hi lymphocyte subpopulations in the thymus and spleen, as well as the proliferative activity of thymocytes and splenocytes were measured by flow cytometry. It was found that the most pronounced. interstrain differences in the cellular composition of the thymus were observed in March, while those in the cellular composition of the spleen were detected in December. Overall, in C57BL/6 mice as compared with CBA mice, the number and proliferative activity of the cells of lymphoid organs was increased. In December, the influence of RI on the cellular composition of the thymus was more pronounced in C57BL/6 mice, while the effect on cellular composition of the spleen was greater in CBA nice. In March, after exposure to RI, a number of CD3+, CD19+ and CD4+8-splenocytes was increased in CBA mice, while it was decreased in C57BL/6 mice. In C57BL/6 mice, after exposure to RI, the proliferative activity of thymocytes decreased in winter and increased in spring . Interstrain and seasonal differences in the cellular composition of lymphoid organs in CBA and C57BL/6 mice, with a photoperiod of 12:12 and RI should be taken into account in experimental work with aninials of different genotypes in different seasons of the year. PMID- 26234040 TI - [THE PECULIARITIES OF UTERINE STRUCTURE AFTER DELIVERY IN RATS WITH THE MYOMETRIAL SCAR]. AB - The uterine tissues of female rats (n=30) with a scarred myometrium were examined by methods of light microscopy after the delivery. 1.5-2 months after the delivery no significant differences in the parameters of blood and lymph flow in the deep layers of the endometrium, myometrium and the myometrial scar tissue were found between the intact rats, nulliparous rats with a scarred uterus, rats that gave birth after laparotomy only and those that gave birth under the conditions of myometrial scar. In the course of pregnancy and labor activity, the damage of the tissues was observed not in the uterine scar proper, but at its borders with the myometrium. This is supported by the old hemorrhages and lymphostasis phenomena, greater number of lymphocytes, neutrophils, monocytes, macrophages and erythrocytes. In determining the indications and contraindications to vaginal childbirth in women with scarred uterus it is necessary to examine not only the scar proper, but also its border with the myometrium. The myometrial scar by itself, is not an absolute contraindication to vaginal delivery, the natural delivery is feasible in the absence of cavities with liquid and hemorrhages in the tissues of the uterine scar and at its border with myometrium. PMID- 26234041 TI - [DYNAMICS OF CHANGES IN THE NUMERICAL DENSITY OF PLACENTAL MACROPHAGES DURING UROGENITAL INFECTION IN EARLY PREGNANCY]. AB - The changes in the numerical density of macrophages of maternal (basal decidua) and fetal (Kashchenko-Hofbauer cells) origin were studied in the placenta of women with opportunistic (Ureaplasma urealyticum and Mycoplasma hominis) and pathogenic (Chlamydia trachomatis) urogenital microflora. Histological study of placenta was performed and CD68-immunoreactive cells were detected immunohistochemically in the basal decidua and in the chorionic villi obtained during artificial abortions for non-medical reasons in the 6-8th week of pregnancy (n=136). The results showed no changes in the numerical density of macrophages of maternal origin and a significant decrease in the numerical density of macrophages in the stroma of the chorionic villi, which was associated in Chlamydial infection with a delayed, and in Ureaplasma and Mycoplasma infection - with an accelerated development of the villous tree. PMID- 26234042 TI - [STRUCTURE OF PARAPATELLAR CARTILAGES IN CANIDS]. AB - The aim of the study was to establish general patterns and morphological characteristics of the parapatellar structures of the knee joint in canids: dogs of factory breeding - Caucasian shepherd dog (n=15), Central Asian shepherd dog (n=14), poodle (n=9), the toy Terrier (n=13), Yorkshire Terrier (n=14) and Steppenwolf (n=17) and foxes (n=7) obtained from natural biocenoses. Subtle anatomical dissection was conducted and macroscopic evaluation of the structures was performed together with light microscopic analysis of serial histological sections stained with hematoxylin-eosin and picrofuchsin-fuchselin. Comparative analysis of the parapatellar cartilages allowed to establish both common regularities and breed-specific signs of their structure, that resulted from the impact of biomechanics of the locomotor behavior of the animals. In all the investigated canids parapatellar cartilages were formed by fibrous cartilaginous tissue with a predominance of fibrous structures over the cellular component and they could be divided into 3 zones - superficial, medial and deep. The peculiarities of the fibroarchitectonics of collagen bundles in each of them correspond to the nature of the pattern of biomechanical loads applied. Micromorphological studies performed show that parapatellar cartilages can act as compensatory devices, leveling functional overload of the quadriceps femoris in the extension phase of the knee joint. PMID- 26234043 TI - [STUDY OF CHONDROCYTE PROLIFERATIVE ACTIVITY IN THE CANINE ARTICULAR CARTILAGE DURING LENGTHENING OF THE ADJACENT LIMB SEGMENT]. AB - To assess the effect of orthopedic lengthening on proliferative activity of chondrocytes in the articular cartilage, dosed tibial lengthening by 28 mm was performed in 15 dogs at the rate of I mm/day divided into 4 sessions. Experiment time-points - 28 days of distraction, 30 days of fixation in the apparatus and 30 days after the apparatus removal. Methods of light microscopy of paraffin sections, immunohistochemistry, histomorphometry of semithin epoxide sections were used. At the end of distraction, the preferential concentration of Ki-67 marker was detected in the upper layers of the intermediate zone, while focal distribution was noted in the superficial and deep zones of articular cartilage of femoral condyles. Upon completion of lengthening, a stable increase in the number of chondrocytes was noted in the superficial and intermediate zones but not in the deep cartilage zone as com ared with the intact group (n=5). PMID- 26234044 TI - [PECULIARITIES OF BONE TISSUE MORPHOGENESIS DURING SHIN LENGTHENING USING THE METHOD OF TRANSOSSEOUS DISTRACTION OSTEOSYNTHESIS WITH THE INCREASED DAILY RATE]. AB - Histogenesis of bone tissue was studied in 25 adult mongrel dogs under conditions of automatic shin lengthening by the technique of transosseous distraction osteosynthesis with the daily rate of 3 mm in 120 repeats using the methods of light, scanning electron microscopy, electron probe microanalysis, immunohistochemistry and morphometry. During the distraction period, cellular heteromorphism and proliferative activity of the cells of connective tissue interlayer and periosteum were clearly detected in the interfragmental diastasis. In the post-distraction period, the reduction of cellular heteromorphism and the increase of the biosynthetic activity of the osteoblastic cells were observed while the provisional endosteal bone regenerate of normotrophic type with the signs of organotypic reorganization was formed. Intramembranous osteogenesis was noted at all the stages of the experiment. The organ-specific nature of the newly formed bone occured by 30 days after the apparatus removal. Bone tissue plasticity and the conditions of high-fractional distraction allow to increase the daily rate of leg lengthening up to 3 mm, as well as to provide the formation of weight-bearing bone part during 45 days, thereby reducing by 31% the duration of the period of fixator use for shin lengthening in comparison with that one adopted in classic technique with the daily rate not exceeding 1 mm. PMID- 26234045 TI - [SOMATOTYPOLOGICAL CHARACTERISTICS OF THE DEVELOPMENT OF RURAL SCHOOLCHILDREN IN NIZHNIY NOVGOROD REGION]. AB - The aim of this study was to determine somatotypological characteristics of 4619 rural schoolchildren (RSC) aged 7-17 years, resulting from the rate of biological development and conditions of residence. It was found that most RSC had age appropriate rate of development. Among the extreme variants most frequently recorded were: retarded rate of maturation in boys and anticipatory rate of maturation rate in girls. RSC of asthenoid somatotype were characterized by the lag of biological age from the calendar age, while RSC of muscular and digestive body types, on the contrary, had an accelerated development. RSC had somatotypological characteristics that distinguished them from the urban schoolchildren, which is due to the specific conditions of life, in particular, agricultural activity that promotes physical activity and prevalence of schoolchildren with muscular somatotype among both boys and girls. However, equal proportions of children with digestive constitution among urban and RSC highlight the negative impact of factor of nutrition. PMID- 26234046 TI - [HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL IDENTIFICATION OF HUMAN MYOCARDIAL MAST CELLS]. AB - This paper compares the results of application of various methods of histochemical and immunohistochemical staining of mast cells (MC) in human myocardium after formalin fixation and paraffin embedding of the material. It was shown that the optimal methods for description of their structure were toluidine blue staining and and Giemsa stain, while alcian blue staining represented the most suitable histochemical method for MC counting. In combination with immunohistochemical detection of synaptophysin, it could be used for identification of co-localization of MC and nerve terminals in the myocardium. Combined staining of MC with alcian blue and safranin is not suitable for human formalin-fixed myocardial MC. Immunohistochemical techniques of MC tryptase and chymase demonstration appear to be more sensitive when compared with histochemical methods, and allow the most comprehensive quantitative description of human myocardial MC population. PMID- 26234047 TI - [Scientific-research work of students as a basis for the development of cognitive activity, of interest in the specialty, creative independence and professionally relevant competences]. PMID- 26234048 TI - [Experimental and histological analysis of connective tissue and blood (to the 140th anniversary of Professor A. A. Maksimov)]. PMID- 26234049 TI - [Alexander Lyubishev (1890-1972) and the development of national morphology]. PMID- 26234050 TI - [XVII International Conference on Plastination (July, 14-18, 2014, St. Petersburg)]. PMID- 26234051 TI - [<> - International Scientific-Practical Conference devoted to the 100 anniversary of birthday of Professor Zoya Izmailovna Ibragimova (September, 25 26, 2014, Vitebsk, Belarus)]. PMID- 26234052 TI - [To the Jubilee of Valentina Vitaliyevna MOLCHANOVA]. PMID- 26234053 TI - [Rudolf Pavlovich SAMUSEV (to 75th birthday)]. PMID- 26234054 TI - [Vagif Bilas ogly SHADLINSKiY (to 75th birthday)]. PMID- 26234055 TI - [Victor Vasiliyevich BANIN (to 70th birthday)]. PMID- 26234056 TI - [First Russian Surgical Journal (to 130th anniversary of foundation of the journal "Vestnik Khirurgii named after I. I. Grekov")]. PMID- 26234057 TI - [Nikoai Nilovich Burdenko (1876-1946)]. PMID- 26234058 TI - [DIRECT REVASCULIZATION OF THE MYOCARDIUM FROM LEFT-SIDE MINITHORACOTOMY - MODERN PERFORMANCE OF THE OPERATION NAMED AFTER V.I. KOLESOV]. AB - The article provides the results of minimally invasive direct revasculization of myocardium at the period from 2012 to 2014. Given method was used in 49 interventions. There weren't any lethal cases or myocardial infarctions. A mean hospital stay consisted of 8,6+/-2,7. Computer thomographic coronary bypass angiography was carried out after operation in terms of 6-48 months. The occlusion of mammary coronary shunt was revealed in 3 patients with minimally invasive revasculization of the myocardium in terms up to 48 months. There were noted a decrease' of hospital stay, bleeding during surgery and in early postoperative period, duration of artificial pulmonary ventilation, length of stay in intensive care unit for this group of patients. PMID- 26234059 TI - [ENDOVASCULAR ABDOMINAL AORTIC ANEURISM REPAIR]. AB - The authors analyzed the single-center experience of treatment of 72 patients with abdominal aortic aneurisms and severe accompanied pathology. The aneurisms were repaired by stent-grafts. All the patients had abdominal aortic aneurisms with the diameters from 41 to 84 mm against the background of severe somatic pathology. It was a contraindication to planned open surgery. An installation of stent-graft was successful in all 72 follow-ups. It wasn't necessary to use a conversion to open surgery. The follow-up period consisted of 44,6?2,1 months. Control ultrasound and computer tomography studies hadn't revealed an increase of aneurism sack sizes or "eakages". A reduction of abdominal aortic aneurism sizes was noted in 37 patients on 4-5% during first year after operation. The stent graft implantation extends the possibilities of abdominal aortic aneurism treatment for patients from a high surgical risk group. PMID- 26234060 TI - [VALUE OF ANATOMICAL INTRACRANIAL RESERVE IN SURGICAL TREATMENT OF INJURIES AND DISEASES OF THE BRAIN]. AB - The authors proposed to evaluate the quantity of anatomical intracranial reserve according to morphometric measurements in axial projection by means of helical computer tomography data of bitemporal distance, width of the tentorial opening, diameter of the foramen magnum and mutual correlation of these parameters in points. This method showed a high accuracy (92%) and predictive value (85%) in determination of terms and volume of complex treatment of 140 victims with craniocerebral injury, 120 patients with primary tumors of the brain and 110 patients with acute disorder of cerebral circulation. PMID- 26234061 TI - [POSSIBILITIES OF ENDOVASCULAR INTERVENTIONS IN TREATMENT OF BUDD-CHIARI SYNDROME]. AB - The article presents the results of endovascular treatment of 35 patients with Budd-Chiari syndrome. An analysis of efficacy of modern interventions was made. There were shown the. possibilities of balloon dilatation of stenosis of renal veins, the balloon dilatation and stenting with metal self-expansible stents of stenosis an occlusion of intrahepatic section of the postcava and results of transhepatic portsystemic bypass surgery. PMID- 26234062 TI - [TREATMENT OF COLORECTAL CANCER COMPLICATED BY INTESTINAL OBSTRUCTION USING THE METHOD OF <> RECOVERY]. AB - A medical trend which is currently gaining strength includes the complex treatment based on the concept of "fast-track" recovery in oncology. An application of modem high-tech approaches allowed minimizing the terms of treatment, shortening economic costs and getting the highest final results. It provides a high quality treatment. Given method could exclude an interim treatment stages, sufficiently reduces terms of general treatment and rehabilitation of patients and could succeed in high quality of life for the patients in short- and long-term period. The authors present the results of successful clinical surgery of 78 patients using this method in public health. PMID- 26234063 TI - [SIDE-TO-END ANASTOMOSIS IN LOW ANTERIOR RECTAL RESECTION]. AB - The authors have launched a prospective randomized study aimed to make a comparison of functional results of formation of straight coloanal (control group) and side-to end (main group) anastomosis in case of low anterior rectal resection since 2012. Each group consisted of 40 patients undergoing operation concerning uncomplicated rectal cancer of medium-ampullar section of rectum. It was noted that patients of the main group had lower stool frequency in postoperative period. A function of the interior sphincter was less damaged and the rate of compliance of rectum was high. PMID- 26234064 TI - [WAYS OF IMPROVEMENT OF LOOP ENDARTERECTOMY RESULTS FROM ILIAC-FEMORAL SEGMENT]. AB - The article presents an analysis of treatment results of 91 patients with iliac femoral segment artery occlusion at the period from 2008 to 2014. Patients were divided into 2 groups: main group (n=30) consisted of patients who undergoing a half-closed loop endarterectomy with following implantation of stent-grafts in this area and control group (n=61) had patients whom were performed routine half closed loop endarterectomy. The II degree of ischemia of lower extremities was in 88 (96,7%) patients and III degree had 3 (3,3%) patients. The areas of abnormalities of intravascular pattern were detected in 100% of cases in intraoperative angiography. They were modified using stent-grafts. A primary vascular patency was 100% in the first group and it numbered 65% in the second group during 5 years. The intraoperative angiography control with stent-graft implantation to the area of endarterectomy allowed reliable improvement of treatment results. PMID- 26234065 TI - [APPLICATION OF COMPRESSION MINI-SCREWS IN TREATMENT OF PATIENTS WITH INJURY OF ELBOW JOINT BONES]. AB - A case report presents the experience of application of compression pileateless mini-screws (Gerbert's screws) in treatment of intra-articular fractures, which formed the elbow joint (44 cases). There were performed 32 operations concerning fracture of head of radius, 10 operations on the occasion of fractures of distal section of the humerus and 2 operations on the coronoid process. Long-term treatment results were followed-up in 31 patients during more than 6 months. On basis of analysis of treatment results the authors made a conclusion that the application of mini-screws in case of bone fractures, which formed the elbow joint, allowed realization of stable osteosynthesis after anatomic reposition of articular surfaces, obtaining good anatomical and functional result and shortened the terms of patient's treatment. PMID- 26234066 TI - [OBJECTIVE CRITERIA OF PATIENT'S READINESS TO FREE AUTOPLASTY IN CASE OF GRANULATING WOUNDS (CRITERIA OF READINESS OF GRANULATING WOUNDS TO OPERATION)]. AB - The article based on the analysis of 84 follow-up of the patients. The authors suggested using the indices of microbiological and immunological investigations and data of laser Doppler ultrasonography to determine the readiness of granulating wound to free autoplasty. The data obtained allowed developing an algorithm of treatment, patient's preparation to surgery and determination of operation terms. PMID- 26234067 TI - [EMBOLIZATION OF BRONCHIAL ARTERIES IN ACUTE PULMONARY BLEEDING IN CHILDREN]. AB - Children with acute pulmonary bleeding (8 cases) due to different pathology of trancheobronchial tree were followed-up at the period from 2008 to 2014. Diagnostic angiography and X-ray endovascular occlusion of bronchial arteries were performed in the case of insufficiency of conservative and endoscopic methods of hemostasis. Microembolic spheres were used for embolization of distal vessels. The embolization coils and micro-coils were applied for occlusion of great vessels. Children (5 cases) were discharged from the hospital after embolization at the terms of 6-12 months. They hadn't any ischemic complications associated with bronchial artery occlusion. The sequelae of main disease caused deaths of 3 other kids. The X-ray occlusion is a low-invasive and highly effective method of arrest of all types of bleeding from pool of bronchial arteries. The method could be applied even in extremely severe condition of the patients. PMID- 26234068 TI - [PRIMARY-MULTIPLE TUMORS IN PATIENTS WITH NEOPLASMS OF THYROID GLAND]. AB - The authors studied the long-term results of surgical treatment of 949 patients with thyroid carcinoma. The malignant tumors of other organs were revealed in 55 (5,8%) cases during 20 years of follow-up. It was stated that patients with thyroid carcinoma had a higher risk of developing other malignant tumors than in population. A typical background for onset of other neoplasms was a latent hypothyroidism, hyperlipidemia, hypersecretion of gonadotropins, an influence of occupational hazard of chemical nature and hereditary load of oncology. PMID- 26234069 TI - [DIAGNOSTIC AND TREATMENT STRATEGY IN FOLLICULAR TUMOR OF THYROID GLAND]. AB - The article is based on the treatment results of 44 patients with follicular tunor of thyroid gland. A staged morphological assessment of thyroid nodes was performed for all patients: in case of preoperative fine-needle biopsy, urgent intraoperative study and according to results of final histological research. The urgent histological study of surgical material was conducted for 44 patients with diagnosis "follicular tumor" according to fine-needle biopsy. The data of final histological study were matched with findings of intraoperative research. A micro follicular adenoma was detected in 22 patients (50%) and 6 (13,6%) patients had this diagnosis combined with autoimmune thyroiditis. The general part of patients didn't changed in final study, but the rate of diagnosis "micro-follicular adenoma against the background of autoimmune thyroiditis" increased. Papillary carcinoma was revealed in 5 (11,4%) patients and follicular cancer had 4 (9,1%) patients detected in intraoperative study and 3 (6,8%) more patients according to data of final research. The histopathologic feature of colloid goiter was observed in 7 (15,9%) cases and a part of such patients reduced to 6,8% during final study. One of the patients (2,3%) had final diagnosis "oncocytoma". In case of thyroid nodules detection the needle biopsy should be carried out regardless to the size of nodule. The authors recommended performing the surgery with the urgent histological study in case of undetermined histological report. The following surgical strategy was specified by the results of the urgent histological report. PMID- 26234070 TI - [RESULTS OF RESEARCH OF GALECTIN-3 AND THYROGLOBULIN IN PATIENTS WITH THYROID NODULES]. AB - An investigation of galectin-3 and thyroglobulin using IFA was conducted in 80 patients. A lavage of aspirate from the thyroid gland was obtained by fine-needle aspiration biopsy. It was stated that significant increase of galectin-3 and thyroglobulin was noted in case of high differentiated thyroid carcinoma in comparison with benign nodules. Galectin-3 and thyroglobulin from the lavage of thyroid gland aspirate could be used as an oncological marker for complex differentiated diagnostics of high differentiated thyroid carcinoma and benign nodules. PMID- 26234071 TI - [REMOTE 3-YEAR RESULTS OF APPLICATION OF <> WAYS OF REVASCULARIZATION IN PATIENTS WITH CHRONIC ISCHEMIA OF LOWER EXTREMITIES]. AB - There are several ways of <> revascularization such as revascularizated osteotrepanation of shinbone and lumbar sympathectomy (LS) for treatment of patients with chronic ischemia of lower extremities. They appeared to be sufficiently effective for the patients with II stage of the disease. Patients with critical ischemia (III stage) had persistent positive results after lumbar sympathectomy during 3-year period only in 33% of cases and using revacularized osteotrepnation - 46%. The difference in efficacy of treatment using LS and standard conservative therapy is statistically low significant, so that isn't allowed.recommending the sympathectomy for treatment of III stage ischemia. The method of revascularizated osteotrepanation of shinbone showed a reliably better result, therefore this way is reasonable to apply in surgery in case of III stage ischemia. PMID- 26234072 TI - [RESULTS OF RESTORATIVE OPERATIONS USING MODIFIED METHOD OF FORMATION OF TEMPORARY LOOP INTESTINAL STOMAS]. AB - The article estimated the results of excision of temporary loop colo- and ileostomas using method of their formation with erfixation of parietal peritoneum to aponeurosis of abdominal external oblique muscle in 18 patients. The authors concluded that the formation of temporary loop stoma with fixation of parietal peritoneum to aponeurosis had many advantages and could ter mprve he rsuls of the resoraive operation. PMID- 26234073 TI - [Successful treatment of pyloric stenosis by ionized argon plasma in case of gastric ulcer against the background of brain tumor]. PMID- 26234074 TI - [Surgery of patient with primary-multiple synchronous cancer of the stomach and colon combined with visceral vessels anomaly]. PMID- 26234075 TI - [Successful treatment of patient with recurrent hepatocellular carcinoma]. PMID- 26234076 TI - [Restoration of renal blood flow and excretory function after successful revascularization in chronic renal artery occlusion]. PMID- 26234078 TI - [THE ALTERNATIVE MODEL IN TRAINING FOR OPERATION MANAGEMENT ON LUMBAR SPINE]. AB - The authors proposed to use a lumbar part of calf carcass as a new biological model for training of basic practical skills in order to perform the neurosurgical operative interventions on the spine. The proximity of anatomico surgical parameters of given model and human cavader lumbar spine was estimated. The study proved the possibility of use of lumbar part of calf carcass for training techniques of transpedicular fixation and microdiskectomy in lumbar part. PMID- 26234077 TI - [Intrapartum invasive fetal interventions and postnatal surgical treatment of giant teratomas of different location]. PMID- 26234079 TI - [OPTIMIZATION OF THE METHOD OF SUPRAPANCREATIC LYMPH NODE DISSECTION IN LAPAROSCOPY-ASSISTED GASTRECTOMY (IN THE FINAL ANALYSIS OF INTERNATIONAL CONFERENCES <>)]. AB - The article analyzed the methods of suprapancretic lymph node dissection in laparoscopic gastrectomy which were devel- oped and applied in Japan. The authors described the details of operation technique. There were noted the advantages of medial approach for suprapancreatic lymph node dissection. PMID- 26234080 TI - [First female surgeon in Russia]. PMID- 26234081 TI - [Application of new hardware mechatronic means of external compression of human thorax in performance of cardio-pulmonary resuscitation]. PMID- 26234082 TI - [Relevance of normothermic ex-vivo perfusion of the liver in transplantation]. PMID- 26234083 TI - [Endoscopic treatment of gastro-intestinal neoplasia - evolution of the method]. PMID- 26234084 TI - [Nozological Heterogeneity, Molecular Genetics and Immunology of Autoimmune Diabetes Mellitus]. AB - Article is devoted to the review of literature data, and also the analysis of results of own researches concerning genetics, molecular genetics and immunological violations at various forms of the autoimmune diabetes (DM) including classical T1DM, LADA type and an autoimmune polyglandular syndrome of 1 type (APS1). In case of T1DM more than 80% of patients are carriers of one or two strongest predisposing haplotypes: DRB1*04-DQA1*0301-DQB1*0302 and DRB1*03 DQA1*0501-DQB1*0201 designated as DQ2 and DQ8. HLA genes can model a clinical features of disease. In Russian population, the children with diabetes manifestation up to 5-year age has significantly often high risk genotypes (DQ2/ DQ8) and significantly less the low risk genotypes in comparison with children, who had manifestation of T1DMin 10 years and later. The long-term 16-yearsfamily studies showed the maximum frequency of TJDMin high risk group, constantly accruing in process of increase in term of supervision, and in groups of an average and low risk lower and invariable. The highest risk of T1DM manifestation, reaching 90% at 10 years of supervision is defined by existence of HLA high risk genotypes and many antibodies, revealedfrom early age. LADA - the hybridform of autoimmune DM having signs of T1DM and T2DM in the basis. The development of autoimmune process against beta-cells can be caused by only gene mutation (APS1). The part of T1DM cases which doesn't have the contributing HLA genes and autoimmune markers in process of studying of the importance of various genes and their biological value can be attributed to new, yet unknown forms of DM. PMID- 26234085 TI - [Autoimmune Diseases of Digestive System]. AB - Autoimmune diseases of digestive system refer to pathological conditions, caused by autoimmune mechanisms, and their etiology remains unknown. This is a group of relatively rare diseases, however, during the last years a marked tendency towards the raise in incidence andprevalence is observed, which led to an increase in number of clinical investigations on etiology, pathogenesis, and, accordingly, development of new diagnostic methods and therapies. Results of such trials shown, for example, that the pathogenesis of chronic cholestatic liver diseases is associated with nuclear receptors function, while the main etiological and pathogenic factor of inflammatory bowel diseases represents gut microbiota. Despite new achievements in autoinmune diseases of digestive system research, therapies are low effective and are accompanied by a huge number of adverse events. The fact that these diseases may lead to malignant tumors is also worth noting. For example, patients with primary sclerosing cholangitis have a 160 times higher risk of cholangiocellular carcinoma, while 10-14% ofpatients with celiac disease may develop malignancies of esophagus, small and large intestine. Thus, these diseases require further investigation with a purpose of more accurate diagnostic methods for the detection of disease at early stages and new effective and safe therapies development. PMID- 26234086 TI - [The Experimental Model of Autoimmune Process: the Role of Epigenetic Variation in the Population of Mice Hybrids]. AB - BACKGROUND: At the development of graft versus host disease in genetically homogeneous population of (C57BI/6 x DBA/2) Fl mice two clinical phenotypes of SLE-like disease were revealed: lupus+ (immune complex glomerulonephritis and hemnolytic anemia) and lupus - (hemolytic anemia). The GvHD phenotypic heterogeneity is determined by the Th2-polarization: Th2 lymphocyte predominant activity, leads to the lupus+development, or prevalence activity of Th1 cells, leads to the lupus- development. OBJECTIVE: Our aim was to evaluate the possibility of using an experimental model of autoimmnune disease for studying and testing of epigenetic modifications, shifting Th1/Th2 balance in vivo. METHODS: Chronic GVHD was induced in B6D2F1 mice by the transplantation of 130x10(6) parental DBA/2 splenocytes. Anti-ds-DNA, total IgG and IgGI, IgG2a Abs were measured by ELISA. RESULTS: Six- to 8-week-old female DBA/2 and B6D2F1 mice were obtained from Biological Research Laboratory (Novosibirsk). It was established that regular moderate physical activity (unladed swimming) shifted Th1/Th2 balance towards Th1. This leads to a decrease in a population of recipients the lupus+ mice from 57 to 26% (p <0,001) with significantly reduced hypergammaglobulinemia (IgG from 2,8 to 2,0 mg/ml; p <0,047) and DNA antibodies titer from 0,18 to 0,12 OD (p =0,05). Administration of epigenetic modificator bisphenol A at low doses, which mimicking estrogen effects, enhances the proportion of lupus+ mice in experimental groups from 33 to 64% (p <0,001) and impairs their clinical status by the increasing the urine protein level from 2.8 to 4,2 mg/ml (p <0,001) in animals. CONCLUSION: Th1/Th2 - balance presumably is determined by the immune system epigenetic modification in experimental mice, formed on the previous stages of ontogeny and defines the direction of immune processes development in individual animal. PMID- 26234087 TI - [Future Therapeutic Targets in Management of Autoimmune Skin Diseases]. AB - Pemphigus is a severe, potentially fatal bullous skin disease, caused by desmoglein autoantibody production and immune-mediated regulation of T-cells subsets. Conventional therapy including systemic corticosteroids with or without other immunosupressants causes numerous adverse effects and becomes inefficient in refractory patients. In this work, the authors showed a modern view on the pathogenesis ofpemphigus. This article describes the detailed action mechanism of rituximab, a chimeric monoclonal antibody directed against CD20 antigen of B cells. The authors conduct the results of meta-analyses of rituximab's efficiency in pemphigus patients. Moreover, in this article, the authors consider new promising treatment tions and potential targets for biological therapy of pemphigus diseases. PMID- 26234088 TI - [Innovative Methods of Some Systemic Autoimmune Diseases Treatment]. AB - In the present paper we consider the problem of innovative treatment of systemic autoiminune diseases for example, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The use of biological therapy is suitable for severe rheumatoid arthritis and promotes remission in 25-30% of cases. Application biological therapy (as anti-B cell therapy) in cases of systemic lupus erythematosus severe forms can reduce the immuno activity level, and also leads to the regression of secondary vasculitis in lung tissue and renal parenchyma. The analysis of drugs and principles of treatment of rheumatoid arthritis and systemic lupus erythematosus was done. Particular attention is paid to the safety and efficacy of biological agents and synthetic base anti-inflammatory drugs. PMID- 26234089 TI - [Autoimmune Rheumatic Diseases - Problems of Immunopathology and Personalized Treatment]. AB - By current standards autoimmunity is a complex pathological process based on a violation of tolerance and, consequently, the pathological immune response against its own tissues components (autoantigens) leading to the development of a wide range of autoimmune diseases in humans. In recent years, multiple immune disorders both acquired and/ or congenital (associated with polymorphisms of genes that regulate immune response) have been transcribed. These disorders occur at the cellular and humoral levels: thymus, intestines, peripheral blood immune cells, including T and B lymphocytes, macrophages, dendritic cells, Treg-cells (Treg), components of complement system, cytokines and others. The interaction between the development of autoimmune rheumatic (ARD) and autoinflammatory diseases and syndromes is detected; a classification of immune-inflammatory diseases is designed. The article describes the results of our studies on the treatment of ARD using innovative genetically engineered biological agents and on the research ofpathogenetic mechanisms and diagnostics of ARD based on immunological and molecular biological diagnostic techniques of a wide range of molecular and cellular biomarkers (autoantibodies, inflammatory acute phase proteins, cytokines, chemokines, markers of activation of the vascular endothelium, the components of the complement system, lymphocyte subpopulations, products of metabolism of bone and cartilage tissue, genetic, epigenetic, transcriptomic markers). The approaches to personalized treatment of ARD are presented. PMID- 26234090 TI - [Autoimmune Diseases of the Nervous System: Problem Statement and Prospects]. AB - This review highlights the achievements in the field of autoimmune diseases of the nervous system over the last 15 years. It became possible to deepen the understanding of medical and social significance of these diseases, form the concept of nosologic unit heterogeneity, describe new and atypical forms ofdemyelinating diseases of the central and peripheral nervous system, autoimmune diseases of the neuromuscular synapse. Also, it is important to mention, that the new antigens were identified, the diagnostic panel of autoantibodies was developed and put into practice. Furthermore, the dinical practice guidelinesfor the diagnosis and management of patients were developed, the new drugs were tested and included in these guidelines. The scientists of the biggest Russian neurological centre, Research Centre of Neurology (Moscow), developed a <> for immunotherapy of multiple sclerosis, studied pathomorphosis of Guillain-Barre syndrome, specified the components of its pathogenesis, improved the programs of pathogenetic therapy, which led to the decrease in mortality from 30 to 3%, helped to decrease the A VL period by 2 times, hasten the recovery of independent walking by 2.5 times. Nowadays different biomarkers of diseases of the central and peripheral nervous system are studied and modern technologies in neurorehabilitation are applied. PMID- 26234091 TI - [Role of Bradikynin in the Mechanism of Ischemic Preconditioning of the Heart. Prospects of Bradykinin Application in Cardiosurgical Praxis]. AB - Bradykinin level is increased in myocardium in response to short-term ischemia/reperfusion that is one of the evidences of its trigger role in ischemic preconditioning (IP). Pharmacological induced increase of endogenous bradykinin and kallidin-like peptide levels in myocardium enhances cardiac tolerance to impact of ischemia/reperfusion. Experiments with genetically modified mice indicate that kinins are involved in preconditioning but they are not the only trigger of IP. The B2-receptor blocking abolishes antiarrhythmic, infarct reducing effects ofpreconditioning, eliminates IP-induced cardiac tolerance to oxidative stress. Exogenous bradykinin mimics inotropic and cardioprotective effects of IP but does not mimic antiarrhythmic effect of preconditioning. The intracoronary or intravenous bradykinin infusion enhances human heart resistance to ischemia/reperfusion. Implementation of the cardioprotective effect of IP is provided by the activation of multiple signaling pathways that involve: B2 receptor, calcitonin gene-related peptide, NO-synthase, guanylyl cyclase, cGMP, protein kinase G, mitochondrial KATP channels, reactive oxygen species, kinases C, ERK andAkt. To increase of the human heart tolerance to ischemia/reperfusion is necessary to develop B2-receptor agonists devoid hypotensive and pro inflammatory properties. PMID- 26234092 TI - [Characteristics of Left Ventricular Diastolic Function in Patients before and after Coronary Artery Bypass Grafting]. AB - Diastolic heart dysfunction occurs essentially in patients who suffer from chronic heart failure. In this context an investigation and application of different methods for diastolic function improvement remain a priority in the therapy of cardiovascular diseases. OBJECTIVE: Our ain was to estimate coronary artery bypass grafting effect on the left ventricularfunctionality in patients with coronaty heart disease. METHODS: Patients (30 men without myocardial infarction and 44 - with myocardial infarction) were investigated by Doppler Echocardiography before and after coronary artery bypass grafting for left ventricular diastolic function assessment. In addition, during the year after operation examinations were carried out. Analysis of the data allowed detecting two types of disorders of transmitral flow: rigid and pseudononnal. RESULTS: Our investigation showed that transinitral parameters improved in patients after operation. Patients without myocardial infarction in anamnesis had a myocardium cell relaxation improvement (IVRT decreasing; p =0,046), but an active myocardium relaxation turned for the better (increasing of E/A (p <0,001) by component A lowering (p =0, 003). Changes of pulmonary veins parameters were followed by the improvement of left heart ventricle relaxation: active - PVD decreasing, p =0,051; and passive - PVA decreasing, p =0,028. Patients with myocardial infarction in anamnesis had an IVRT decreasing (p =0,040) and A decreasing (p =0,041). In addition, in this group left atrial function improved (PVS decreasing; p =0,037). CONCLUSION: Coronary artery bypass grafting is effective in left ventricular diastolic function improvement and Doppler Echocardiography method can become an important criterion to estimate the treatment adequacy. PMID- 26234093 TI - [The Relationship of the Degree of Impairment of the Structure and Function of the Liver with its Chronic Illnesses in Children]. AB - OBJECTIVE: Our aim was to on the basis of determining the degree of violation of the structure and function of the liver establish their relationships and to assess the dynamics of liver disease in its chronic illnesses in children. METHODS: With the help of the developed scoring systems were used to assess the degree of liver dysfunction and the degree of disruption of the structure of the liver and the severity of portal hypertension. RESULTS: The results of the diagnostic methods 252 children aged 1 to 17 years (mean age of 11.8+/-3,5) with Wilson disease (WD), autoimmune hepatitis (AIH), chronic hepatitis C (CHC) were analyzed; 48 patients underwent liver transplantation. In children with WD, AIHand CHC liverfunction reduced by 41.3+/-12.9% to 28.8+/-12.5% and 19.1+/-7.8% respectively. Structure of the liver in children with WD, AIH and CHC was disturbed by 25.0+/-8.1% to 20.4+/-9.2% and 6.8+/-4.4% respectively. Thefunction and structure violations of the liver more pronounced in liver cirrhosis. The use of the developed scoring systems to monitor the severity of liver damage in the dynamics and evaluation of the effectiveness of the therapy is demonstrated. The degree of liver dysfunction is directly dependent on the degree of its structure. Abnormal liverfunction >=40% and >=40% of its structure with treatment failure can be used as a criterion of indicationsfor elective liver transplantation with its chronic diseases in children. CONCLUSION: Developed a point system to determine liver function and a point system to determine disruption of the structure of the liver and the severity of portal hypertension in children can serve as an objective criterion for assessing the severity of liver disease, monitoring their changes in the dynamics with the assessment of the effectiveness of the therapy and making decisions about the need for routine liver transplantation in its chronic illnesses in children. PMID- 26234094 TI - [Hygienic Assesment of Educational Texts: Methodical Approaches and Evaluation of Difficulties for Children of Secondary Textbooks]. AB - BACKGROUND: The understandability and readability of the text are significant indicators of evaluation of textbooks. OBJECTIVE: The aim of the study - rationale of improving the readability and understandability of textbooks. METHODS: 60 modern textbooks for 5-11th classes on History, Physics, Biology and 23 textbooks of 1960-1980's edition. Flesch index was used to assess the readability, Fogh index - to evaluate understandability. RESULTS: The readability and understandability of texts in textbooks of 1960-1980's and modern editions have no differences and show the same complexity of old and modern textbooks for students. The indicator of understandability of textbooks for primary classes corresponds to age norm and is 4.4+/-0.2 points. The indicator of readability for these books is less age norm and is 53.8+/-2.9 points, which increases the physiological cost of educational activities of children of primary school age. Children's readability and understandability of school textbooks are a significant factor of intensity of training activities and can be objectively assessed by Flesch and Fogh indices, that it is appropriate for an objective hygienic assessment of the tension of the educational activities for children. CONCLUSION: The main direction of optimization of the tension of educational activity is to reduce the intellectual and emotional loads in children by increasing the easiness of reading textbooks due to their compliance with the age peculiarities of students. PMID- 26234095 TI - [Features of Autonomic Response in Children with Bronchial Asthma in the Period of Exacerbation]. AB - BACKGROUND: Asthma is one of the urgent problems of modern pediatrics, but neuroregulation mechanisms underlying this disease have not been fully disclosed so far. The autonomic interaction assessment in patients with bronchial asthma is important to understand the pathogenesis and prognosis of the disease. OBJECTIVE: The aim of this study was to investigate features of autonomic response in children with asthma in the period of exacerbation. METHODS: The autonomic nervous system ANS) of 82 children aged 6 to 18 years old with asthma in the period of exacerbation were investigated. The spectral analysis of the heart rate variability and the correlation rhythmography method (skaterography) were used to assess the ANS state. Investigations were carried out at rest and after clinoorthostatic test. RESULTS: Non-respiratory (slow) waves reflecting (be degree of activity of humoral and neural canals of heart rate central regulation were dominated at the spectrogram of 72 (87.80%) children experiencing asthma attack; more than half of patients (58.53%) had predominantly very low-frequency component (VLF%) in the range of fluctuation rate that indicated (the influence of neurohumoral regulation. A significant increase in vagosympathetic balance coefficient (LE/HF) was recorded after clinoorthostatic test indicating the activation of the sympathetic nervous system. According to the correlation rhytlimnography data, a considerable scattering of scattergraphy points was detected in patients in (the baseline state that indicated the predominant influence of parasympathetic nervous system. After the clinoorthostatic test, on the contrary, we observed the <> of the scattergraphy cloud that could indicate sympathicotonia. CONCLUSION: The imbalance of the autonomic nervous system in the form of activation of the sympathetic amid neurohumoral regulation department was found in children with asthma. PMID- 26234096 TI - [Modern Views on Children's Interstitial Lung Disease]. AB - Interstitial lung diseases (ILD, diffuse lung diseases) are a heterogeneous group of diseases in which a pathological process primarily involved alveoli and perialveolar interstitium, resulting in impaired gas exchange, restrictive changes of lung ventilation function and diffuse interstitial changes detectable by X-ray. Children's interstitial lung diseases is an topical problem ofpediatricpulmonoogy. The article presents current information about classification, epidemiology, clinical presentation, diagnostics, treatment and prognosis of these rare diseases. The article describes the differences in the structure, pathogenesis, detection of various histological changes in children's ILD compared with adult patients with ILD. Authors cite an instance of registers pediatric patients with ILD. The clinical semiotics of ILD, the possible results of objective research, the frequency of symptoms, the features of medical history, the changes detected on chest X-rays, CT semiotics described in detail. Particular attention was paid to interstitial lung diseases, occurring mainly in newborns and children during the first two years of life, such as congenital deficiencies of surfactant proteins, neuroendocrine cell hyperplasia of infancy, pulmonary interstitial glycogenosis. The diagnostic program for children's ILD, therapy options are presented in this article. PMID- 26234097 TI - [Hydrogen Sulfide as a Third Essential Gas Molecule in Living Tissues]. AB - The data offoreign studies over the last 15 years devoted to endogenous synthesis and biological role of hydrogen sulfide in micromolar quantities which complemented the already two well-known gas transmitters - OH and NO are presented in this review. Despite the short period since the physiological properties of hydrogen sulfide were opened (about 20 years) it was found that this gas transmitter plays a key role in the regulation of nerve (neural signal transmission), cardiovascular (relaxation of smooth muscles), immune (antinflammatory and cytoprotective agent) sensory, gastrointestinal (output of insulin) systems and in the metabolism of various organs. Currently the role of H2S in the pathogenesis of different diseases, neurodegenerative diseases, diabetes, heart failure) is being studying. The developments of drugs that act as either exogenous donors H2S or blockers of the biosynthesis of H2S are promising. With consideration the fact that H2S is a representative of non-synaptic way of intercellular communication based on diffusion of molecules of inorganic compounds in the intercellular space in all directions and effect on distant from their place offormation non- synaptic receptors it is suggested to use exogenous H2S in strict proportion for the treatment of a number of human diseases. PMID- 26234098 TI - [Liver and Its Lymph Region at Benzo[a]pyrene Effects in an Experiment]. AB - BACKGROUND: Benzo[a]pyrene (BaP) is the widespread environmental toxicant with carcinogenic activity. BaP undergoes metabolic activation in the liver microsomal monooxygenase system, and its regional lymph nodes act as peripheral filters, purifying lymph formed in the liver. It remains an open question about the significance of the integral liver and lymphatic system work in supporting processes of adaptation and resistance to the BaP effects. OBJECTIVE: The purpose of our investigation was to study structural and metabolic changes in the liver and its lymph region in males Wistar rats weighing 180-220g. METHODS: Animals of the experimental group (n =20) daily for 3 days was performed BaP injections: intraperitoneal with 2 mg per 100g of body weight in 0.2-0.3 ml of olive oil. Rats in the control group (n =20) received in the same mode of injection of olive oil. The light and electron microscopy morphometric study of the liver and its regional lymph nodes morphometric analysis were performed. The intensity of lipid peroxidation in the liver was measured by the number of diene conjugates (DC), ketotriene conjugates (KC) and malondialdehyde (MDA). RESULTS: Simultaneous increase of the hepatic sinusoids relative area and the specific area of the regional lymph nodes sinus system under the BaP effect was found. At ultrastructural level dilatation of the Disse spaces, filling of cell detritus and collagen fibers bundles of these spaces were noted. Damage of nuclear apparatus, balloon transformation of granular endoplasmic reticulum profiles were found in hepatocytes, condensation of the mitochondrial matrix was observed. The relative squares of B-dependent zones increased and T-dependentparacortical zone reduced in the regional lymph nodes. The increase in the content of KC and MDA in liver was identified. CONCLUSION: benzo[a]pyrene causes interrelated cascade of reactions in the liver and in its lymphatic region: a disturbance of the blood lymph barrier morphological organization, and so obstruction of the lymphatic drainagefrom the organ. These promotes development of tissue hypoxia and apoptosis, protein synthesizing and energy cell apparatus disruptions, formation of lymphoid tissue temporary infiltrates in the liver. PMID- 26234099 TI - [Epidemiological Surveillance of Cholera in Russia During the Period of the Seventh Pandemic]. AB - In this work basic stages of formation of the epidemiological surveillance of cholera in Russia are described. In 1990-s for the first time zoning by epidemic manifestations of cholera was carried out at the level of subjects forming parts of Russia and other Republics of the Soviet Union with the introduction of differential tactics of epidemiological surveillance. Improvement of epidemiological surveillance of cholera was aimed at harmonization with the IHR (2005), integration of epidemiological surveillance of cholera and social hygienic monitoring of water objects of I and II categories. Characterization of isolated Vibrio cholerae strains (1990-2014) on the genomic basis determined the emergence of new VNTR-genotypes of V. cholerae O1 ctxAB+ tcpA+, responsible for outbreaks, simultaneously with isolation of V. cholerae 01 ctxAB-tcpA-strains during monitoring of environmental objectsfor cholera. A viewpoint is considered of the beginning of the eighth cholera pandemic in the context of emergence of V. cholerae El Tor strains with CTXphi prophage carrying ctxB gene of cholera toxin of classical biovar. Main directions offurther enhancement ofepidemiological surveillance include the study of basic data structures used in the epidemiological surveillance system, the use of zoning of municipal units offederal subjects with corresponding surveillance tactics and expected economic effect. PMID- 26234100 TI - [Current Concepts of Human Microsporidiosis]. AB - Microsporidiosis is an ubiquitous opportunistic disease that usually appears in immunocompromised patients: AIDS patients or organ-transplant recipients. The infectious agents of disease are fungi-related obligate intracellular parasites - microsporidia. Alongside with Cryptosporidium and Cytomegalovirus, these parasites are the most common causative agents of diarrhea in HIV-infected patients. Intestinalform of microsporidiosis has been mostfrequently observed, but microsporidia can affect almost any organs of the human body, eyes, lungs, muscles, organs of the nervous system. The present paper overviews the current data on the etiology, pathogenesis, epidemiology, clinical presentation, diagnosis and treatment methods of microsporidiosis. PMID- 26234101 TI - [L.A. Iakovleva]. PMID- 26234102 TI - Staying Current. PMID- 26234103 TI - CAT OF THE MONTH. Critically Appraised Topics. Occlusal Overload May Contribute to Late Implant Failure in Patients with Anterior Dental Implants (UT CAT #2647). PMID- 26234104 TI - Oral and Maxillofacial Pathology. Case of the Month. Antral Pseudocyst. PMID- 26234105 TI - Digital Devices and Distracted Doctoring. AB - During the past twenty years a digital sea change has affected our world. Digital devices have changed the way we live and especially the way we work in our professions. As dentists, we are able to work with far greater accuracy and precision than ever before; we would be foolish not to embrace these advances. But, as is often the case with rapid cultural changes, we need to be aware of the possibility of unintended consequences that may accompany this revolution. Sound scientific studies are beginning to warn of the psychological and physiological problems of overuse of digital devices in our daily lives. We should remember that these devices are neutral. It is up to each of us to use them in ways that enhance patient care. PMID- 26234106 TI - Guided Surgery in Pre-doctorate Clinic: A Case Study. PMID- 26234107 TI - Risks Associated with Cosmetic Procedures. PMID- 26234108 TI - Something to Smile About. PMID- 26234109 TI - CAT OF THE MONTH. Critically Appraised Topics. Replacing Missing Molars with Removable Prosthesis Does Not Reduce or Prevent TMD Pain (UT CAT #2806). PMID- 26234110 TI - Oral and Maxillofacial Pathology. Case of the Month. Actinic prurigo. PMID- 26234111 TI - Analysis of Texas State Board of Dental Examiners Practice Survey and the Number and Location of Dental Service Organizations in Texas. PMID- 26234112 TI - 2014/2015 Financial Report Texas Dental Association. PMID- 26234113 TI - Practice Profits Suffering? Here's Why. PMID- 26234114 TI - Are You Protecting Your Patients from Identity Theft? PMID- 26234115 TI - African Journal of Medicine and Medical Sciences--A New Beginning. PMID- 26234116 TI - Blood platelet: a review of its characteristics and function in acute malaria infection. AB - BACKGROUND: The role of the circulating platelet has until in relatively recent times, been mainly considered in terms of cellular mediators of thrombohaemorrhagic activities. It has most recently also been shown to play important role in modulating host immune response to infections such as malaria infection, both in the early and later phases of the infection. Data on the role that platelets play in early malaria infection is relatively scanty. This review highlights changes in platelet characteristics and function that have been reported in acute malaria infection. METHODS: Literature from Pubmed (MEDLINE), Google Scholar, Google search, textbooks and Cochrane Library were reviewed covering the period RESULTS: It is observed that Thrombocytopenia which had hitherto been considered as the hallmark of the complication of acute malaria infection, occurs in 40-80% of human acute malaria infection and in 100% of murine models. It results from platelet activation mechanism. The evidence in support of this view includes associated findings of elevated plasma concentrations of Beta-thromboglobulin (BTG) and Platelet Factor 4 (PF4) as well as enhanced production of Thromboxane A2 (TXA2) and 6-keto prostaglandin F1alpha (6-KPF1alpha). There is also loss of total platelet sialic acid associated with reduction of platelet life span. A more recent finding of platelet killing of the parasite inside the infected red cell has revealed a hitherto little known potential which shows that early interaction between circulating platelets and the malaria parasite in the course of infection may result in reduction of parasitaemia thus mediating host survival to malaria infection. The mechanism(s) of platelet protective activity in early acute malaria is/are yet to be fully clarified in order to provide better understanding of the phenomenon. Clinically, it has also been reported that in acute malaria infection, the severity of clinical manifestations correlates closely with the parasite load. CONCLUSION: Reported changes of platelet/malaria parasite interactions highlighted in this review bring to the fore the need for more research activities to be undertaken in this area. PMID- 26234117 TI - Effects of vitamin E and melatonin on serum testosterone level in sleep deprived Wistar rats. AB - BACKGROUND: Sleep deprivation affects a significant proportion of the global population. It has been reported to induce oxidative stress in the testes and reduce serum testosterone levels. Exogenous anti-oxidants have been known to prevent damages and diseases associated with oxidative stress but there is dearth of knowledge on their effectiveness during sleep deprivation. AIM: This study was designed to investigate the effects of two anti-oxidants; melatonin and vitamin E on serum testosterone concentration in sleep deprived male Wistar rats. METHODS: Thirty (30) male Wistar rats were used for this study. Animals were divided into six (6) groups (n = 5). Group 1 was the control, group 2 rats were sleep deprived, group 3 received vitamin E (200 mg/ kg bwt) only, group 4 rats received vitamin E and were sleep deprived, group 5 received melatonin only (10 mg/kg bwt), and group 6 rats received melatonin (10 mg/kg bwt) and were sleep deprived. Sleep deprivation was induced using the modified multiple platform technique. Body weights were taken on days 7, 14 and 21. Blood was collected at sacrifice and serum was obtained for analyses of testosterone, corticosterone and melatonin. Testicular malondialdehyde, superoxide dismutase and catalase levels were determined by the methods of Adam-Vizi and Seregi (1982), Misra and Fridovich (1972), and Sinha, (1972) respectively. Data obtained were analyzed using one way ANOVA and p < 0.05 was considered significant. RESULTS: Serum testosterone (nmol/l) of the sleep deprived animals (0.6 +/- 0.3) reduced significantly (p < 0.05) compared with control group (3.3 +/- 0.04), sleep deprived+vitamin E group (2.8 +/- 0.5) and sleep deprived+melatonin group (2.0 +/ 0.3). Also, melatonin+sleep deprived group had reduced testosterone compared with control. There were no significant changes in the serum corticosterone (nmol/l) and melatonin levels in all the groups compared with the sleep deprived group. However, corticosterone was increased in the sleep deprived+Vitamin E group (51.6 +/- 20.5) compared with control (6.3 +/- 0.6) Sleep deprived group had increased testicular malondialdehyde (MDA) (1.6 +/- 0.1 unit/mg), superoxide dismutase (SOD) (3.2 +/- 0.2 unit/mg), and catalasel evels (44.3 +/- 1.1 unit/ mg) compared with control (0.9 +/- 0.0 MUmg). MDA, and catalase were significantly reduced in sleep deprived+vitamin E (1.1 +/- 0.2, 2.4 +/- 0.3, 39 +/- 1.0 unit/ mg) compared with sleep deprived while melatonin alone had increased MDA. level (1.7 +/- 0.2unit/mg) compared with control. SOD in the sleep deprived+melatonin group (2.7 +/- 0.2 MU/mg) as compared with control increased (p < 0.05) while MDA and catalase levels as compared with control and sleep deprived groups showed no difference. Histological findings showed that the pathology in the testes of sleep deprived rats was ameliorated by vitamin E. CONCLUSION: Vitamin E had a more potent effect than melatonin in maintaining testosterone level in sleep deprived Wistar rat. PMID- 26234118 TI - Cocos nucifera L. water improves reproductive indices in Wistar Rats. AB - BACKGROUND: This study explored the effects of Cocos nucifera L. water (CW) on the hypothalamo-pituitary-gonadal axis (HPG) and fertility in Wistar rats. METHODS: Adult male and female Wistar rats were treated orally as follows; Study 1: Group 1: control (distilled water), group 2: 20 ml/kg corn oil (danazol vehicle), group 3: 20 ml/kg CW, group 4: 40 ml/kg CW, group 5: danazol, group 6: danazol + 20 ml/kg CW and group 7: danazol + 40 ml/kg CW. 200 mg/ kg danazol was administered. Serum levels of LH, FSH, estradiol and testosterone; gonadal weights and sperm indices were assessed. Study 2: Group 1: control (distilled water), group 2: 20 ml/kg CW, group 3: 40 ml/kg CW for 6 and 2 weeks prior to mating in male and female rats respectively. RESULTS: Significant (p < 0.05) increases in estradiol concentration were observed in groups 3, 4, 6 and 7. Significant reductions in LH, FSH, estradiol and testosterone levels were observed in group 5 which were ameliorated in groups 6 and 7. Males showed significant increases in sperm count and motility in groups 3, 4, 6 and 7, and reductions in these variables along with viability in group 5. CW pre-treatment increased fecundity index and proportion of female pups from dams, while the pups from sires showed higher birth weights. CONCLUSIONS: CW acts on the HPG to positively influence reproductive function in both males and females and may aid in maternal preconception sex selection of female offspring. PMID- 26234119 TI - Tobacco smoking and medical co-morbidities among patients with schizophrenia in a Nigerian clinical setting. AB - BACKGROUND: Smoking is highly prevalent in patients living with schizophrenia and is associated with medical and psychiatric morbidities METHODS: In this descriptive, consecutive patients with schizophrenia (368) were interviewed at State Hospital Ibadan between January and December 2008. Information on demography and tobacco smoking, medication adherence and self reports of chronic common health conditions were obtained. The PANSS was used to determine level of psychopathology. Univariate associations were determined using Chi square statistics and multivariate analysis was used for further exploration of variables that were significant during univariate analysis. All analyses were performed using the SPSS (17.0). RESULTS: Prevalence of lifetime tobacco use was 198 (53.8%), current use 122 (33.1%). Current use was highest in respondents less than 25 years of age X2 = 11.8, p = 0.003 and reduced with increasing education, X2 = 21.6, p = 0.00, higher in non medication adherent patients, X2 = 19.9, p = 0.00 and was associated with health conditions such as haemopoetic diseases X2 = 6.8, p = 0.01 and respiratory diseases. Mean score of positive, negative, general psychopathology, total psychopathology subscales of PANSS were respectively significantly higher among current user, compared with abstainers, t = 6.7, p = 0.00, t = 5.1, p = 0.00, t 6.2, p.= 0.00, t 6.7, p = 0.00. Only general psychopathology subscale of PANSS, OR = 3.5, 95% CI (1.2-6.5), p = 0.02 remained associated with current tobacco use after adjusting for gender. CONCLUSION: The present study demonstrates high rate of tobacco use in patients with schizophrenia. Thus, such patients require additional screening for tobacco and tobacco cessation program. PMID- 26234120 TI - Attitudes towards abortion law reforms in Nigeria and factors influencing its social acceptance among female undergraduates in a Nigerian university. AB - BACKGROUND: Unsafe abortion is one of the causes of maternal morbidity and mortality globally and it is still a burden in Nigeria. Restriction laws have been blamed for the recurrent vulnerability of women including female adolescents to unsafe abortions. METHODS: A cross-sectional, semi-structured, self administered questionnaire was administered to 407 first year female undergraduates in the three female halls of residence of the University of Ibadan, Nigeria in February 2012 to determine their attitudes to abortion laws and the social acceptance of abortion laws in Nigeria. RESULTS: A vast majority (96.1%) knew what an abortion was and barely half were aware of the grounds in which it may be legal. Only 84 (20.6%) of the respondents knew that there were 2 abortion laws in operation in Nigeria. One hundred and thirteen (27.8%) wanted the current abortion law to be reformed and thirteen (3.2%) admitted that they had had an abortion in the past. More than half of them, 212 (52.1%) would support an abortion if pregnancy followed rape/ incest and 201(49.4%) if there was fetal abnormality. Religious reasons influenced the social opinions on abortion laws in most of the students (73%). CONCLUSION: The study showed some awareness towards abortion law reforms and we advocate that sexually active young individuals should be encouraged to adopt effective dual protection against unwanted pregnancy and STIs. Efforts should also be made at imparting reproductive health education to youths, especially girls. PMID- 26234121 TI - Radiation therapy interruption in a poor resource setting: causes and management.. AB - BACKGROUND: Treatment interruption is the failure to execute approved treatment plan of a patient. This adversely affects treatment outcomeif not properly managed. This retrospective study causes and management of radiation treatment interruptions during High Dose Rate Brachytherapy(HDRB) for carcinoma of the cervix in a teaching hospital in Nigeria. METHODS: Five hundred patients with cervical carcinoma, who received HDRB, post external beam radiotherapy, between August, 2008 and July, 2013 were assessed. They were grouped into (A): those who experienced treatment interruption and (B): those who did not. Each patient was scheduled to receive three fractions of HDRB over 3 weeks. Those in groups A were assessed for the exact treatment fraction missed, the cause and duration of treatment interruption and the actions taken to compensate for non-execution of treatment. RESULTS: A total of 90 patients fall into group A and most (41) of them experienced interruptions in the third fraction of their treatment. The most frequent (44%) causes of treatment interruptions observed among them were patient related. Record of compensation for treatment interruption was not found in patients' treatment folders. This action may be due to lack of functional procedures for managing treatment interruptions and insufficient follow-up of patients, who never came back for consideration for compensation. CONCLUSION: This study showed that radiation oncology centres need to review their policies for managing treatment interruptions and documentation. Also, the mechanism for patients' follow-up should be strengthened to a reasonable extent to achieve better radiotherapy care. PMID- 26234122 TI - Pattern of skin sensitivity to various aeroallergens in bronchial asthmatic patients in Lagos, Nigeria. AB - Background: Skin prick testing is an established way of investigating respiratory allergic diseases to determine the allergen or allergens responsible for clinical symptoms as well as degree of reactivity in the individual cases. OBJECTIVE: To study the skin sensitivity to various aeroallergens by skin prick test in selected asthmatic patients (with and without concurrent Allergic Rhinitis). DESIGN: A prospective case-control study. SETTING: Tertiary Health Institution. SUBJECTS: Cases were 160 adult patients with confirmed bronchial asthma and controls were 160 subjects without bronchial asthma. METHODS: Skin prick test was performed with a panel of allergens which included house dust mites, cockroach, cat, dog, moulds, and aspergillus fumigatus on all subjects. RESULTS: Amongst the asthmatic patients 148 (92%) had positive skin tests to the allergens, this is higher than findings from previous studies carried out on asthmatics in Lagos. The house dust mite (Dermatophagoides pteronyssimus) had the highest proportion of reactions among the study group. There is a higher incidence of severe reactions to other allergens (grass mix, dog skin, cat skin, aspergillus, cockroach) in the asthmatics than the control. CONCLUSION: The skin test is a valuable diagnostic tool in detecting the presence and degree of allergy in asthmatics in our environment. However, the house dust mite was allergen that most of the subjects reacted to. PMID- 26234123 TI - Pregnancy related changes in human salivary secretion and composition in a Nigerian population. AB - BACKGROUND: A variety of physiological changes occurring during pregnancy has been shown to affect the oral health. Saliva is critical for preserving and maintaining the health of oral tissues and has been used as a source of non invasive investigation of different conditions in human and animal studies. AIM: This study was designed to evaluate changes in secretion and composition of saliva in pregnant women in a Nigerian population. METHODS: This was a descriptive cross-sectional study using purposive sampling technique. Saliva samples were collected from 50 pregnant and age matched 50 non-pregnant women. Salivary flow rate, pH, total protein and concentrations of sodium, potassium, calcium, phosphate and bicarbonate were determined and compared using paired independent sample t test. RESULTS: Salivary pH,mean concentrations of potassium and bicarbonate were significantly reduced while mean concentrations of salivary sodium and phosphate were significantly elevated in pregnant women compared to non-pregnant women (P < 0.05). However, there was no significant difference in the salivary flow rate, concentrations of total protein and calcium. CONCLUSION: Salivary pH, bicarbonate and potassium concentrations were reduced while sodium and phosphate concentrations were elevated in pregnant women. These findings suggest that pregnant women may be predisposed to higher caries incidence. PMID- 26234124 TI - Evaluation of pedestrian road traffic maxillofacial injuries in a Nigerian tertiary hospital. AB - Background: Walking is the most basic form of mobility and forms an important part of daily activities; however, walking could often be associated with risks. This is more so when pedestrians share a common space with motorized vehicles especially in developing countries. Despite the frequency of road traffic crashes (RTC) related pedestrian injuries in many developing countries, there is a dearth of documentation of maxillofacial injuries in victims of pedestrian road traffic crashes. The aim of this study was to determine the causes, frequency, pattern, severity, concomitant injuries and outcome of pedestrian maxillofacial injuries observed at a tertiary trauma centre in Nigeria. METHOD: Pedestrian victims of RTC were prospectively recruited from among all maxillofacial trauma patients seen at the Accident and Emergency department and the Department of Oral and Maxillofacial Surgery of the University College Hospital, Ibadan between April 2011 and November 2011. Ethical approval was obtained from the UI/UCH Joint Ethics Review Board before the commencement of the study and informed consent was obtained from participants. Patients' demography, the crash events, types of maxillofacial injuries, and concomitant injuries were recorded. Severity of maxillofacial injury was estimated based on the Maxillofacial Injury Severity Scale (MFISS). RESULTS: Forty-six participants (22.9% of all victims of road traffic crashes seen within the study period) were victims of pedestrian RTC. Pedestrian RTC occurred in all age groups with almost 40% of the victims in their 1st and 2nd decades of life. The most severe MFISS was observed in the 21 - 30 year age group while the least severe injury observed was in the 71 - 80 years age group. Thirty participants (65.2%) were hit by a car or minibus while fourteen (30.4%) were knocked down by a motorcycle. Two (4.4%) were hit by a truck. Soft tissue injury was the most common maxillofacial injury and head injury was the commonest concomitant injury observed. The median MFISS score of victims of motorcycle was 4.0 while the median scores for victims of car/minibus pedestrian RTC was 9.0. The most severe maxillofacial injury was seen in victim of car/minibus pedestrian crashes. Seventeen percent (8) of the victims had a fatal outcome. Conclusion: Pedestrian RTC resulting in maxillofacial injuries are common in the studied environment. It is particularly common among the 11 -20 year age group and victims are usually hit by cars/minibuses. These injuries are often severe and fatal outcome is not infrequent. Therefore, definitive preventive measures are imperative. PMID- 26234125 TI - Cervical ectopic pregnancy managed with methotrexate and tranexamic acid: A case report. AB - BACKGROUND: Cervical pregnancy is a rare life-threatening form of ectopic pregnancy and when it occurs, it is challenging to decide the management options. Surgical intervention has been documented to be complicated by intractable haemorrhage and most often necessitating hysterectomy. We hereby report a case of cervical pregnancy managed conservatively with medical agents prior to surgical intervention. CASE PRESENTATION AND MANAGEMENT: A 29 year old primiparous woman with gestational diabetes mellitus who presented at 10 weeks gestation with 5 days history of brownish vaginal discharge and 2 days history of painless vaginal bleeding. On pelvic examination the cervix was disproportionately larger than the uterus with a closed internal os. Transvaginal and abdominal ultrasound scanning confirmed a live cervical pregnancy. She had intramuscular methotrexate and tranexamic acid followed by suction evacuation combined with balloon tamponade. Examination at 6 weeks post procedure revealed a normal cervix. CONCLUSION: Cervical pregnancy still occurs in this environment despite its rarity. Surgical intervention usually results in hysterectomy and adopting medical management as a first line treatment option offers the benefit of uterine preservation. PMID- 26234126 TI - Retained surgical needle post myomectomy, an uncommon mishap. AB - BACKGROUND: Retained foreign bodies are relatively uncommon and probably underreported in the tropics. Largely preventable errors, they cause harm to both the patient and the medical practitioner. CASE PRESENTATION AND MANAGEMENT: A 32 year old primigravida with recurrent lower abdominal pain in pregnancy. She had myomectomy a year earlier at a private hospital in which the endometrium was inadvertently breached. She subsequently had an elective caesarean section at 38 weeks and 2 days gestational age. Intra-operative findings were adhesive bands between the uterus and loops of bowel and a round bodied surgical needle attached by adhesions anteriorly to the lower segment. Her post operative care was uneventful and she was discharged home on the 3rd day post operation. CONCLUSION: Retained surgical foreign body (RSFB) could pose a diagnostic dilemma as in the case of this patient with recurrent lower abdominal pain in pregnancy. Meticulous instrument count should include sutures and needles. PMID- 26234127 TI - Professor Effiong Essien Udo Akang, MBBS, FMCPath, FWACP. PMID- 26234128 TI - [The newest developments of the study on anti-HIV drugs]. AB - Besides 36 (28 single-tablets and 8 fixed-dose combinations) used antiretroviral drugs clinically, there are a number of investigational antiretroviral agents currently in phase 2-3 clinical trial. Tenofoviralafenamidefumarate (TAF) is a novel nucleoside analogue reverse transcriptase inhibitor that is potent and less toxicity than tenofovir (TDF). Doravirine is a non-nucleoside analogue reverse transcriptase inhibitor that demonstrates activity against NNRTI-resistant viral strains. GSK744 is an integrase inhibitor with a long acting preparation. In addition, several drugs with new mechanisms are also noted, for example, BMS-663 068 is a small molecule CD4 attachment inhibitors and cenicriviroc is a novel CCR5/CCR2 antagonist with antiretroviral activity and anti-inflammatory effects. Several drug classes that target known pathways in HIV latency have being developed, and leading the list are histone deacetylase inhibitors. Other agents include protein kinase C activators, positive transcription elongation factor activators, DNA methyl-transferase inhibitors and histone methyl-transferase inhibitors and so on. This review is focused on the above-mentioned drug candidates that may be used in clinical in next couple of years and those compounds that can reverse latent HIV infections. PMID- 26234129 TI - [Progress in the study of Her2-targeted cancer therapeutic antibodies]. AB - Tumor surface antigen human epidermal growth factor receptor 2 (Her2) is a type I receptor tyrosine kinase, which belongs to human epidermal growth factor receptor family. Her2-overexpression is associated with tumorigenesis and metastasis. Due to significant clinical effects, Her2-targeted cancer therapy especially therapeutic antibody has become the hot spot in the field of cancer treatment. Anti-Her2 antibody drugs include monoclonal antibodies, antibody-drug conjugates, bispecific antibodies and emerging "two in one" antibody. Based on structure and function of Her2, this review focuses on recent advances in active mechanisms and clinical researches of these antibodies. PMID- 26234130 TI - [Polymorph transformation of solid drugs]. AB - For the minimized phase transtorming risk, the most stable polymorph is generally considered as the desirable solid form for pharmaceutical applications. However, occasionally, the stable form may have some shortcomings such as low solubility, dissolution rate and bioavailability, etc. In that case, the metastable form which is kinetically stable at room or lower temperature could be selected. Using metastable form may result in polymorph transformation in pharmaceutical manufacture and storage. Hence, the knowledge of the transformation between solid forms is essential to the development of the drug materials. In this paper, we will review the recent studies in the area of crystal conversion of polymorphs and hydrates, to illustrate some cases to introduce the types, conditions and mechanisms of the crystalline solid transformation. PMID- 26234131 TI - [Progress in the study of near-infrared fluorescent probes for the detection of beta-amyloid deposition in Alzheimer's disease]. AB - Alzheimer's disease (AD) is the most common cause of cognitive impairment in older people. With the aging of society is more and more serious, AD caused great burden to patients and society. A beta is a classical biomarker of AD, which has been widely used in clinical diagnosis of AD patients. Compared with positron emission tomography (PET) and single photon emission computed tomography (SPECT), near infrared fluorescence imaging has many advantages including highly sensitive, non-invasive, safety and inexpensive. Therefore, many research groups have focused on developing the molecular probes of near-infrared fluorescence (NIRF) imaging. In this article, we will review the progress of the probes of NIRF. PMID- 26234132 TI - [Targeting angiogenesis and vascular remodeling as a novel therapeutic approach to liver fibrosis]. AB - Development of liver fibrosis is closely associated with angiogenesis and abnormal vascular remodeling. Recent studies have highlighted the importance of angiogenesis and vascular remodeling in fibrogenesis, the results that inhibition of angiogenesis is effective in suppression of liver fibrosis demonstrate that therapies with several molecular targets against angiogenesis, inflammation and fibrosis might be beneficial for the treatment of cirrhosis. However, there is some evidence that inhibition of angiogenesis can even worsen fibrosis. This article outlines recent advances regarding the interplay between inflammation, angiogenesis and fibrogenesis in terms of cellular and molecular mechanisms, and suggests a requirement of greater understanding to intervene in these key processes, such as liver sinusoidal endothelial cell fenestration and impact distinct chemokine actions driving monocyte migration and differentiation, for therapeutic benefit in the future. PMID- 26234133 TI - [Interaction of butylphthalide with rat and human liver CYP450 isoenzymes]. AB - The work aims to study the drug metabolizing enzymes involved in the metabolism of butylphthalide and evaluate the induction and inhibition activities of butylphthalide on CYP450 isoenzymes by using in vitro (liver microsome incubation system of rats and human) and in vivo (CYP induced model of rats) method. Butylphthalide was incubated with selective inhibitors of CYP450, and its metabolic rate was determined to identify the metabolizing isoenzymes of NBP in rat (normal and induced rats) and human liver microsomes. The in vitro inhibition effect of butylphthalide on 6 main liver microsomal CYP450 isoenzymes was evaluated by using probe drugs; the induction and inhibition activities in vivo of butylphthalide on CYP450 isoenzymes were evaluated by NBP ig dosing (160 mg x kg(-1)) and iv dosing (20 mg x kg(-1)) in rats. After adding the specific inhibitors of CYP2C11, 2E1 and 3A 1/2 for rat, CYP2C19, 2E1 and 3A4/5 for human, the metabolism of NBP in rat and human liver microsomes were reduced 38.8%, 86.2%, 78.4% and 51.0%, 92.0%, 58.9% of control, respectively. The metabolic rates of NBP in CYP2E1 and 3A 1/2 induced rat liver microsomes were increased 25.5% and 68.9%. High concentration of NBP (>= 200 MUmol x L(-1), in vitro) could inhibit the activities of CYP1A2, 2C6, 2C11 and 2D2 in rats, and high concentration of NBP ( >= 15 MUmol x L(-1), in vitro) could inhibit the activity of CYP2C19 in human. All the results indicated that NBP should be mainly metabolized by CYP2E1, 2C11 and 3A 1/2 in rats and CYP2E1, 2C19 and 3A4/5 in human. High concentration of NBP could inhibit human CYP2C19 in vitro. No significant induction/inhibition effects of NBP were observed on rat liver CYP450 isoforms after ig 160 mg x kg(-1) NBP or iv 20 mg x kg(-1) NBP. PMID- 26234134 TI - [Effects of Hemerocallis citrine baroni flavonids on CCl4-induced liver fibrosis of rats]. AB - This study is designed to explore the possible effects of Hemerocallis citrina baroni flavonids (HCBF) on liver fibrosis induced by CCl4 in rats. The liver fibrosis model was induced by CCl4, and HCBF were administered by gastric perfusion at 25 and 50 mg x kg(-1) qd for 50 days, while the contents of alanine transaminase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), superoxide dismutase (SOD), maleic dialdehyde (MDA) and transforming growth factor-beta1 (TGF-beta1) were measured and the contents of PINP were measured in liver tissue, and the expression of TGF-beta1 were observed by immunohistochemisty and Western blot. The pathological changes of liver tissue were examined by HE. The results showed that HCBF (25, 50 mg x kg(-1)) improved the liver function significantly through reducing the level of ALT, AST, GGT and ALP (P < 0.05 or P < 0.01), and increasing the content of SOD (P < 0.01), while reducing the content of MDA (P < 0.05 or P < 0.01), the expression of TGF-beta1 (P < 0.05) and the content of PINP (P < 0.05). The results suggest that HCBF (25, 50 mg x kg(-1)) may inhibit the liver injury induced by CCl4 by decreasing the oxidative stress. PMID- 26234135 TI - [Expression and antitumor activity of fusion protein RGD-TRAIL in Pichia pastoris]. AB - To compare the activity of RGD-TRAIL in different expression systems, RGD-TRAIL in both Escherichia coli (E.coli) and Pichia pastoris was constructed and expressed. In vitro activity of RGD-TRAIL from Pichia pastoris expression system was also analyzed. Genetic engineering techniques were used to construct recombinant plasmid pET30-rgd-trail and pHBM-rgd-trail. The recombinant protein RGD-TRAIL was purified with Ni ion affinity chromatography after induction. MTT assay, ELISA, scratch wound healing, transwell migration assay and Hoechst 33342 staining were performed to detect the effects of RGD-TRAIL on proliferation, binding activity, migration and apoptosis. The expression of apoptosis-associated proteins was detected by Western blotting. Recombinant protein RGD-TRAIL was successfully expressed in a form of inclusion body in E.coli, while expressed secretorily in Pichia pastoris. It possessed more potent cytotoxicity than RGD TRAIL in E.coli by MTT assay. The RGD-TRAIL expressed by Pichia pastoris showed powerful binding affinity with cancer cells expressing alpha(v), DR4, DR5 and highly potent cytotoxicity through inducing apoptosis of cancer cells. Nuclear fragmentation was examined by Hoechst 33342 staining. Cleaved PARP and caspase-3 were also detected after incubation with RGD-TRAIL. Additionally, RGD-TRAIL inhibited migration significantly in A549 and HT1080 cells. The results demonstrate that Pichia pastoris expression system is more suitable for the recombinant protein RGD-TRAIL. Its binding affinity and antitumor activity might make RGD-TRAIL a promising candidate for cancer therapy. PMID- 26234136 TI - [Determination of serum acetaminophen based on the diazo reaction and its application in the evaluation of gastric emptying]. AB - This study aims to establish a method to determine the serum acetaminophen concentration based on diazo reaction, and apply it in the gastric emptying evaluation. Theoretically, acetaminophen could take hydrolysis reaction in hydrochloric acid solution to produce p-aminophenol, which could then take diazo reaction resulting in a product with special absorption peak at 312 nm. Then the serum acetaminophen concentration and recovery rate were calculated according to the standard curve drawn with absorbance at 312 nm. ICR mice were given a dose of acetaminophen (500 mg x kg(-1)) by gavage and the serum acetaminophen was dynamically measured through the diazo reaction. Besides, ICR mice were subcutaneously injected with the long-acting GLP-1 analog GW002 before the gavage of acetaminophen, and serum acetaminophen concentration was measured as above to study how GW002 could influence the gastric emptying. The data showed acetaminophen ranging from 0 to 160 MUg x mL(-1) could take diazo reaction with excellent linear relationship, and the regression equation was y = 0.0181 x +0.0104, R2 = 0.9997. The serum acetaminophen was also measured with good linear relationship (y = 0.0045 x + 0.0462, R = 0.9982) and the recovery rate was 97.4% 116.7%. The serum concentration of acetaminophen reached peak at about 0.5 h after gavage, and then gradually decreased. GW002 could significantly lower the serum acetaminophen concentration and make the area under the concentration-time curve (AUC) decrease by 28.4%. In conclusion, a method for the determination of serum acetaminophen based on the diazo reaction was established with good accuracy and could be used in the evaluation of gastric emptying. PMID- 26234137 TI - [Radiosynthesis and preliminary evaluation of 5-([11C]methyloxy)-L-tryptophan as PET tumor imaging]. AB - The PET tracer 5-([11C]methyloxy)-L-tryptophan (5-(11)CMTP) was prepared by nucleophilic fluorination and alkylation reaction via a two-step procedure in order to develop specific tumor probe. The biodistribution and microPET imaging of 5-(11)CMTP were executed. The results unveiled that the overall radiochemical yield with no decay correction was (14.6 +/-7.2) %, the radiochemical purity was more than 95% and high uptake and long retention time of 5-(11)CMTP in liver, kidney and blood were observed but low uptake in brain and muscle were found, furthermore, high uptake of 5-(11)CMTP in tumor tissue was observed. It seems that 5-(11)CMTP will be a potential amino acid tracer for tumors imaging with PET. PMID- 26234138 TI - [Synthesis and anti-proliferative activity of fluoroquinolone C-3 fused heterocyclic alpha,beta-unsaturated ketones derived from ciprofloxacin]. AB - To discover novel antitumor fluoroquinolone lead compounds from a rational modification for antibacterial fluoroquinolones, a fused heterocyclic ketone corresponding to thiazolo[2,3- b][1,2,4]triazolone used as a bioisosteric replacement of the C-3 carboxylic acid group of ciprofloxacin 1, and further modification by a Claisen condensation reaction with substituted benzaldehydes formed novel fluoroquinolone C-3 fuse heterocyclic alpha, beta-unsaturated ketones as the title compounds (6a-6r), separately. The structures of eighteen title compounds were characterized by elemental analysis, 1H NMR and MS, and the in vitro anti-proliferative activity against human hepatoma Hep-3B cells, pancreatic Capan-1 cells and leukemia HL60 cells was evaluated by a MTT assay. The preliminary results showed that the title compounds not only had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin 1, but also exhibited the highest activity against Capan-1 cells. In particular, compounds carrying an electron-withdrawing carboxyl (6k, 6m) or sulfonamide substituent (6q, 6r) attached to benzene ring were comparable to or better than constractive drug doxorubicin against Capan-1 cells. As such, it suggests that it is favorable for a fused heterocyclic alpha, beta-unsaturated ketone scaffold instead of the C-3 carboxylic acid group to improve the antitumor activity of fluoroquinolones. PMID- 26234139 TI - [Novel hybrids of (phenylsulfonyl)furoxan and N-benzyl matrinol as anti hepatocellular carcinoma agents]. AB - N-Benzyl matrinol was obtained by hydrolysis, benzylation and reduction reaction from matrine. A series of hybrids (8a-8n) from (phenylsulfonyl)furoxan and N benzyl matrinol were synthesized and biologically evaluated as anti hepatocellular carcinoma agents. All target compounds were evaluated for anti proliferative activity against human hepatocellular Bel-7402, SMMC-7721, Bel 7404, and HepG2 cells in vitro by MTT method. The results indicated that all of these compounds had potent anti-proliferative activity which were more potent than their parent compound and 5-FU, especially 8a-8h and 8j showed the strongest anti-HCC HepG2 cell activity with IC50 values of 0.12-0.93 MUmol x L(-1). PMID- 26234140 TI - [Chemical constituents from Morus notabilis and their cytotoxic effect]. AB - Une new flavonoids named as notabilisin K (1), together with four known compounds, morusin (2), mulberrofuran A (3), neocyclomorusin (4) and mornigrol F (5) are separated from 95% ethanol extracts of the twigs of Morus notabilis. Compounds 2-5 are separated from this plant for the first time. Notabilisin I, notabilisin J exhibits certain effect against cells of HCT-116, HepG2 and A2780 with IC50 values ranging from 1.47 MUmol x L(-1) to 5.46 MUmol x L(-1). Morusin exhibits strong effect against five kinds of human cancer cells (BGC823, A2780, HCT-116, HepG2 and NCI-H1650) with IC50 values ranging from 0.74 MUmol x L(-1) to 1.58 MUmol x L(-1). PMID- 26234141 TI - [Rapid determination of ATP, ADP, AMP and phosphate in drug by 31P NMR spectroscopy]. AB - The content of ATP, ADP, AMP, sodium phosphate and sodium pyrophosphate were determined by 31P NMR, the linear range of ATP, ADP and AMP were found to be 0.004-0.080 mol x L(-1), sodium phosphate and sodium pyrophosphate were 0.005 0.100 mol x L(-1). The RSD were 0.40%-1.30%, the recovery were 96.9% - 105.2%. The method has been applied to the determination of ATP injection. The impurities of ATP injection were ADP and sodium phosphate. The content of ATP is in line with the requirement of the pharmacopoeia. The results indicated that the method is of good reproducibility, high accuracy, rapid and simple operation, without pretreatment and interference of other elements, 31P NMR is a new and reliable method of analyzing ATP, ADP, AMP and phosphate. PMID- 26234142 TI - [Identification of liposoluble constituents in Yushu tablets by UPLC-ESI-IT TOF/MS]. AB - In order to identify the chemical constituents of Yushu tablets comprehensively, we studied the chemical constituents of CHCl3 extract from Yushu tablets by the ultra performance liquid chromatography-electrospray ionization-ion trap-time of flight mass spectrometry (UPLC-ESI-IT-TOF/MS). It showed that there were more than 100 compounds separated, and forty-nine peaks among these were identified on the basis of high resolution mass spectrometry data and literature data reported. Determination of twelve peaks was further confirmed by standard substances. These components assigned to the different plant sources mainly included phenylpropanoids, triterpenoids, quinones and m-trihydroxybenzene compounds. By analyzing the chemical components of CHCl3 extract from compound Chinese medicine Yushu tablets comprehensively, this study provided the foundation for studying chemical components, pharmacodynamic substance and quality control of Yushu tablets. PMID- 26234143 TI - [Analysis and identification of water soluble components of water buffalo horn]. AB - This study is to analyze and identify the water soluble components of water buffalo horn (Bubali Cornu, WBH), and also establish a method for investigating these components. Shotgun proteomic analysis identified proteins in WBH aqueous extraction: keratin, collagen, desmoglein, etc. Ultrafiltration and LC-MS/MS were used to separate and identify the peptides in WBH aqueous extract, as a result, identified peptides were mainly derived from nonspecific degradation products of keratin and collagen, which including C-terminal peptides and non C-terminal peptides. Hypoxanthine, uridine, guanosine, and adenosine were identified by comparing with the standards. The strategy in present study could be used in analyzing water soluble components of animal horn derived TCM. It provides a reference for investigation of the material basis of animal horn derived TCM. PMID- 26234144 TI - [Chemical comparison of different Farfarae Flos by NMR-based metabolomic approaches]. AB - 1H NMR-based metabolomic approach combined with multivariate statistical analysis was used to evaluate the quality of 21 Farfarae Flos (FF) samples from different growth regions. Principal component analysis showed that wild and cultivated FF could be separated clearly, suggesting a big chemical difference existed between them. Supervised PLS-DA analysis indicated that the wild samples showed higher levels of secondary metabolites, such as bauer-7-ene-3beta, 16alpha-diol, chlorogenic acid, rutin, 7-(3'-ethylcrotonoyloxy)-1alpha-(2'-methyl-butyryloxy) 3, 14-dehydro-Z-notonipetranone (EMDNT), tussilagone, beta-sitosterol and sitosterone. This is consistent with traditional experience that the quality of wild samples are better than that of cultivated ones. The content of pyrrolizidine alkaloids senkirkine also differed greatly among samples from different habitats. The Pearson correlation analysis showed that senkirkine is positively correlated with 4, 5-O-dicaffeoylquinic acid, 3,5-O-dicaffeoylquinic acid, 3,4-O-dicaffeoylquinic acid, rutin, kampferol analogues, to a statistically significant extent. The correlation between the toxic compounds and the bioactive components in FF should be further studied. PMID- 26234145 TI - [Therapeutic efficacy of pegylated polymyxin E in the treatment of infection induced by gramnegative bacteria and the effect of reducing nephrotoxicity]. AB - Polymyxin E shows effective treatment of the infection induced by resistant gramnegative bacteria, but its nephrotoxicity severely limits the clinical application of this drug. In this work, methoxypolyethylene glycols 2000 (mPEG2K) polymyxin E (PME) was synthesized via chemical grafting reaction and had been characterized. The antimicrobial activity and cytotoxicity of mPEG2K-PME in vitro were investigated on Escherichia coli and HK-2 cells, separately. Intra-abdominal infection model was further established in order to study the therapeutic effect and the toxic effect on kidney of mice. The results showed that mPEG2K-PME exhibited significant inhibitory effect on Escherichia coli and had a lower toxicity on HK-2 cells in vitro. At the same time, mPEG2K-PME had a good efficacy in the treatment of Escherichia coli infected mice in vivo. Moreover, nephrotoxicity caused by mPEG2K-PME was significantly reduced compared to free PME. mPEG2K-PME is promising in development of new preparations with high efficiency and low toxicity. PMID- 26234146 TI - [The molecular mechanism between baicalin metal complexes and bovin serum album]. AB - In this paper, the new carbon nanotube modified glassy carbon electrode (F CNTs/GCE) was prepared to establish a new method for studying the molecular interaction mechanism between baicalin metal complexes (BMC) and bovine serum album (BSA), and the principle of this method was discussed deeply. Under the physiological condition, the thermodynamics and kinetics properties of interaction between BMC and BSA were studied by cyclic voltammetry (CV) to inference their molecular effective mechanism. The results show that the presence of F-CNTs can accelerate the electron transfer, and better response signal was showed in the BMC/BMC-BSA system. The detection of interaction of BMC-BSA used new method show that BMC-BSA generates stable thermodynamically non-covalent compounds, and the obtained average binding sites of BMC-BSA were 1.7; the number of electron transfer in BMC/BMC-BSA reaction process was 2, and non electroactive supramolecular compounds of BMC-BSA were generated by this interacting reaction. The relevant research work provides a new way to study the molecular mechanism for the interaction of drugs with protein, and with a certain reference value for discussion on the non covalent interactions. PMID- 26234147 TI - [Cloning and functional characterization of a cDNA encoding isopentenyl diphosphate isomerase involved in taxol biosynthesis in Taxus media]. AB - Taxol is one of the most potent anti-cancer agents, which is extracted from the plants of Taxus species. Isopentenyl diphosphate isomerase (IPI) catalyzes the reversible transformation between IPP and DMAPP, both of which are the general 5 carbon precursors for taxol biosynthesis. In the present study, a new gene encoding IPI was cloned from Taxus media (namely TmIPI with the GenBank Accession Number KP970677) for the first time. The full-length cDNA of TmIPI was 1 232 bps encoding a polypeptide with 233 amino acids, in which the conserved domain Nudix was found. Bioinformatic analysis indicated that the sequence of TmIPI was highly similar to those of other plant IPI proteins, and the phylogenetic analysis showed that there were two clades of plant IPI proteins, including IPIs of angiosperm plants and IPIs of gymnosperm plants. TmIPI belonged to the clade of gymnosperm plant IPIs, and this was consistent with the fact that Taxus media is a plant species of gymnosperm. Southern blotting analysis demonstrated that there was a gene family of IPI in Taxus media. Finally, functional verification was applied to identify the function of TmIPI. The results showed that biosynthesis of beta-carotenoid was enhanced by overexpressing TmIPI in the engineered E. coli strain, and this suggested that TmIPI might be a key gene involved in isoprenoid/terpenoid biosynthesis. PMID- 26234148 TI - [Enzymatic cyclization of peptides using immobilized sortase A]. AB - Peptide cyclization, a pivotal approach to modifying linear precursors of proteins and pepticles, has been used to enhance their biological activities and serum stabilities. Recently, sortase A (SrtA) from Staphyloccus aureus becomes a promising new technology for efficiently incorporating site specific modifications into proteins, conjugating the cell surface and cyclizing the linear peptides. In this study, we constructed two recombinant expression systems, one with chitin binding domain and the other with six-histidine tag and chitin binding domain on the N-terminal of SrtA, separately. The results of enzymatic kinetics indicate that the two recombinant tags do not impair the transpeptidase activity of SrtA compared with the standard reaction reported under the same reaction condition. The two synthesized peptides with N-ternimal three glycines and C-terminal penta-amino acid motif, LPETG, were cyclized using immobilized and recycled SrtA. The SrtA-based cyclization promises to represent a simple method for easy and efficient enzymatic synthesis of large cyclic peptides. PMID- 26234150 TI - Mature. PMID- 26234149 TI - Validation and acceptability of double-blind, placebo-controlled food challenges in children. PMID- 26234151 TI - Follicular size and stage and gonadotropin concentration affect alginate encapsulated in vitro growth and survival of pre- and early antral dog follicles. AB - Understanding stage-specific requirements of mammalian folliculogenesis is limited in the domestic dog. The present study examined the effects of two potential regulators of dog follicle growth and survival in vitro, namely the original stage of the follicle (i.e. preantral (<=230um diameter) vs early antral (diameter from >230 to <=330um) and FSH and/or LH concentrations. After isolation and alginate encapsulation, follicles were cultured in 0, 1, 10 or 100ugmL-1 FSH and 0, 1 or 10ngmL-1 LH for 20 days. Regardless of stage, FSH promoted growth, but LH did the same only in the absence of FSH. Production of 17beta-oestradiol and progesterone was detectable, indicating theca cell activity. The greatest growth occurred in preantral (mean (+/- s.d.) 61.4+/-25.9%) versus antral (42.6+/ 20.3%) follicles, but neither developmental stage nor gonadotropin affected survival. Antrum detection was minimal due, in part, to antral collapse, and oocytes exhibited an increasingly pale appearance and chromatin degeneration over time. The results demonstrate that pre- and early antral stage dog follicles encapsulated in alginate grow significantly in vitro. However, because FSH and LH alone or in combination fail to promote antrum development, the next step is identifying factors that enhance antral expansion. PMID- 26234152 TI - Long-term outcome for Down syndrome patients with hematopoietic disorders. AB - BACKGROUND/PURPOSE: Although Down syndrome (DS) patients have a higher risk of developing transient myeloproliferative disorder (TMD) and acute leukemia, very little data is available on long-term outcome in Taiwanese patients. The current study was designed to determine the clinical characteristics and treatment outcome of DS patients with TMD or acute leukemia (AL). METHODS: In 25 consecutive DS patients with TMD or AL enrolled from 1990 to 2012, clinical manifestations and treatment protocols were investigated and GATA1 (GATA binding protein 1) mutations were identified. Among 16 DS-acute myeloid leukemia (DS-AML) patients, clinical outcomes were compared between survivors and nonsurvivors. RESULTS: Most of our DS patients had TMD (32%), acute megakaryoblastic leukemia (24%), or acute erythromegakaryoblastic leukemia (16%). The median follow-up time was 22.5 months (1-230 months). The age was younger and the hemoglobin (Hb) level and platelet count were higher in TMD patients than in leukemia patients. Among DS-AML patients, the Hb level was higher in survivors than nonsurvivors (8.8 +/- 2.7 g/dL vs. 5.8 +/- 2.4 g/dL; p = 0.044) and the age was older in relapsed patients than in nonrelapsed patients (43.8 +/- 18 months old vs. 21.6 +/- 8.6 months old; p = 0.025). The 3-year overall survival (OS) rate was 44%, higher in patients receiving appropriate chemotherapy than in those receiving inadequate treatment (63.6% vs. 0%, p = 0.001), and higher in those diagnosed with TMD or AL after 2008 than before 2008 (33.3% vs. 75%; p = 0.119). CONCLUSION: Outcome in DS AML patients is optimal if appropriate treatment is provided. With modification of the treatment strategy in 2008, OS increased in Taiwan. PMID- 26234153 TI - Antidepressant-like effects of quercetin in diabetic rats are independent of hypothalamic-pituitary-adrenal axis. AB - OBJECTIVE: Quercetin, one of the most potent flavonol in the family of flavonoids, has been shown to have benefits against diabetes and its complications. In the present study, we investigated effects of quercetin on depression-like behaviours and hypothalamic-pituitary-adrenal (HPA) axis in diabetic rats. METHODS: Experimental diabetes was induced by using streptozotocin, and either 50 or 100 mg/kg quercetin was intraperitoneally administered for 21 days. Following the last treatment, animals were subjected to the forced swim test, and subsequently, the blood was obtained by cardiac puncture to measure plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels. RESULTS: A significant increase of the total immobile time, accompanied by a decrease in the immobility latency, which suggests a depressive status, was observed in diabetic animals that was reversed by the treatment of 50 mg/kg quercetin. However, the higher dose of quercetin (100 mg/kg) was ineffective in alleviating depression-like behaviours. The plasma concentrations of ACTH, and total- and free-CORT were not affected by both doses of quercetin. CONCLUSION: Therefore, we concluded that the antidepressant-like effects of quercetin in diabetes are independent of the HPA axis. PMID- 26234154 TI - Circadian Rhythms in Rho1 Activity Regulate Neuronal Plasticity and Network Hierarchy. AB - Neuronal plasticity helps animals learn from their environment. However, it is challenging to link specific changes in defined neurons to altered behavior. Here, we focus on circadian rhythms in the structure of the principal s-LNv clock neurons in Drosophila. By quantifying neuronal architecture, we observed that s LNv structural plasticity changes the amount of axonal material in addition to cycles of fasciculation and defasciculation. We found that this is controlled by rhythmic Rho1 activity that retracts s-LNv axonal termini by increasing myosin phosphorylation and simultaneously changes the balance of pre-synaptic and dendritic markers. This plasticity is required to change clock network hierarchy and allow seasonal adaptation. Rhythms in Rho1 activity are controlled by clock regulated transcription of Puratrophin-1-like (Pura), a Rho1 GEF. Since spinocerebellar ataxia is associated with mutations in human Puratrophin-1, our data support the idea that defective actin-related plasticity underlies this ataxia. PMID- 26234155 TI - Mechanistic Origin of Microtubule Dynamic Instability and Its Modulation by EB Proteins. AB - Microtubule (MT) dynamic instability is driven by GTP hydrolysis and regulated by microtubule-associated proteins, including the plus-end tracking end-binding protein (EB) family. We report six cryo-electron microscopy (cryo-EM) structures of MTs, at 3.5 A or better resolution, bound to GMPCPP, GTPgammaS, or GDP, either decorated with kinesin motor domain after polymerization or copolymerized with EB3. Subtle changes around the E-site nucleotide during hydrolysis trigger conformational changes in alpha-tubulin around an "anchor point," leading to global lattice rearrangements and strain generation. Unlike the extended lattice of the GMPCPP-MT, the EB3-bound GTPgammaS-MT has a compacted lattice that differs in lattice twist from that of the also compacted GDP-MT. These results and the observation that EB3 promotes rapid hydrolysis of GMPCPP suggest that EB proteins modulate structural transitions at growing MT ends by recognizing and promoting an intermediate state generated during GTP hydrolysis. Our findings explain both EBs end-tracking behavior and their effect on microtubule dynamics. PMID- 26234157 TI - Exaggerated Blood Pressure Response to Exercise: Will It Ever Be Ready for Prime Time? PMID- 26234158 TI - Heart failure and chemotherapeutic agents. AB - Advances in chemotherapeutic agents over the past two decades have resulted in significantly improved cancer survival rates. Cardiac toxicity, however, has emerged as a leading cause of morbidity, both during and years after treatment. One of the most common manifestations of cardiotoxicity is that of heart failure and left ventricular systolic dysfunction. Consequently, the field of cardio oncology is a rapidly emerging field of sub-specialty, with growing research interests in all aspects of management. In this review, current opinions and guidelines in this field are discussed, with particular focus on the most common culprits, the anthracyclines and the monoclonal antibody, trastuzumab. PMID- 26234156 TI - RAG Represents a Widespread Threat to the Lymphocyte Genome. AB - The RAG1 endonuclease, together with its cofactor RAG2, is essential for V(D)J recombination but is a potent threat to genome stability. The sources of RAG1 mis targeting and the mechanisms that have evolved to suppress it are poorly understood. Here, we report that RAG1 associates with chromatin at thousands of active promoters and enhancers in the genome of developing lymphocytes. The mouse and human genomes appear to have responded by reducing the abundance of "cryptic" recombination signals near RAG1 binding sites. This depletion operates specifically on the RSS heptamer, whereas nonamers are enriched at RAG1 binding sites. Reversing this RAG-driven depletion of cleavage sites by insertion of strong recombination signals creates an ectopic hub of RAG-mediated V(D)J recombination and chromosomal translocations. Our findings delineate rules governing RAG binding in the genome, identify areas at risk of RAG-mediated damage, and highlight the evolutionary struggle to accommodate programmed DNA damage in developing lymphocytes. PMID- 26234159 TI - Analysis of clinical features and lifestyle in Korean senile gluteal dermatosis patients. AB - BACKGROUND: Senile gluteal dermatosis (SGD) is characterized by hyperkeratotic lichenified skin lesions on the superior part and both sides of the anal cleft. These lesions are particularly prevalent in sedentary and elderly patients. OBJECTIVES: The purpose of this study was to investigate the prevalence, clinical manifestations, and other clinical characteristics of SGD in elderly Korean individuals. METHODS: A total of 280 subjects aged >60 years identified through the outpatient department at our hospital were included in this study. Basic clinical information was collected, and the subjects were evaluated clinically for gluteal lesions. Skin biopsies were performed in eight of the patients diagnosed with SGD. RESULTS: Among a total of 280 subjects, 37 were diagnosed with SGD. Their mean age was 70.4 years. The prevalence of SGD was found to increase with age. In addition, there was a significant positive correlation between SGD and lower lean body mass, longer period of a sedentary lifestyle, use of a Korean-style mattress, and diabetes mellitus. Most patients had either mild symptoms or were asymptomatic. Skin biopsies showed hyperkeratosis, acanthosis, follicular plugging, and meandering superficial vessel proliferation with mild lymphohistiocytic infiltration. None of the biopsy specimens exhibited amyloid deposition. CONCLUSIONS: Our findings suggest that SGD is a common disorder in elderly Korean individuals and is associated with prolonged periods of rest such as those occurring in a highly sedentary lifestyle and with sleeping on a Korean style mattress. PMID- 26234160 TI - Parental buffering of fear and stress neurobiology: Reviewing parallels across rodent, monkey, and human models. AB - It has been long recognized that parents exert profound influences on child development. Dating back to at least the seventeenth-century Enlightenment, the ability for parents to shape child behavior in an enduring way has been noted. Twentieth-century scholars developed theories to explain how parenting histories influence psychological development, and since that time, the number of scientific publications on parenting influences in both human and nonhuman animal fields has grown at an exponential rate, reaching numbers in the thousands by 2015. This special issue describes a symposium delivered by Megan Gunnar, Regina Sullivan, Mar Sanchez, and Nim Tottenham in the Fall of 2014 at the Society for Social Neuroscience. The goal of the symposium was to describe the emerging knowledge on neurobiological mechanisms that mediate parent-offspring interactions across three different species: rodent, monkey, and human. The talks were aimed at designing testable models of parenting effects on the development of emotional and stress regulation. Specifically, the symposium aimed at characterizing the special modulatory (buffering) effects of parental cues on fear- and stress-relevant neurobiology and behaviors of the offspring and to discuss examples of impaired buffering when the parent-infant relationship is disrupted. PMID- 26234162 TI - Recurrent Spontaneous Paresthesia in the Upper Limb Could Be Due to Migraine: A Case Series. AB - Transient neurologic dysfunction is a characteristic feature of migraine. About 20% of migraineurs may experience various symptoms in the absence of any headache at one time or another. Visual auras are the most common auras of migraine, and migraine is considered as the most common cause of transient vision loss in young patients. Sensory auras are the second most common migrainous auras. However, the literature is silent for isolated sensory aura as a migraine equivalent. Herein we report 14 patients with recurrent episodic paresthesia in the limbs and other body parts. All patients fulfilled the diagnostic criteria of "typical aura without headache" of ICHD-3beta. All patients were subjected to various investigations to rule out secondary causes. Ten patients received antimigraine drugs and all showed a positive response to therapy. Recurrent spontaneous paresthesia is quite common in the general population and many patients remain undiagnosed. We speculate that a subset of patients might be related to migrainous sensory auras. PMID- 26234161 TI - Suspected myofibrillar myopathy in Arabian horses with a history of exertional rhabdomyolysis. AB - REASONS FOR PERFORMING STUDY: Although exertional rhabdomyolysis (ER) is common in Arabian horses, there are no dedicated studies describing histopathological characteristics of muscle from Arabian horses with ER. OBJECTIVES: To prospectively identify distinctive histopathological features of muscle from Arabian endurance horses with a history of ER (pro-ER) and to retrospectively determine their prevalence in archived samples from Arabian horses with exertional myopathies (retro-ER). STUDY DESIGN: Prospective and retrospective histopathological description. METHODS: Middle gluteal muscle biopsies obtained from Arabian controls (n = 14), pro-ER (n = 13) as well as archived retro-ER (n = 25) muscle samples previously classified with type 2 polysaccharide storage myopathy (15/25), recurrent exertional rhabdomyolysis (7/25) and no pathology (3/25) were scored for histopathology and immunohistochemical staining of cytoskeletal proteins. Glutaraldehyde-fixed samples (2 pro-ER, one control) were processed for electron microscopy. Pro-ER and retro-ER groups were compared with controls using Mann-Whitney U and Fisher's exact tests. RESULTS: Centrally located myonuclei in mature myofibres were found in significantly more (P<0.05) pro-ER (12/13) and retro-ER (21/25) horses than controls (4/14). Degenerating myofibres were not evident in any biopsies. Retro-ER horses had amylase-resistant polysaccharide (6/25, P<0.05) and higher scores for cytoplasmic glycogen, rimmed vacuoles and rod-like bodies. A few control horses (3/14) and significantly (P<0.05) more pro-ER (12/13) and retro-ER (18/25) horses had disrupted myofibrillar alignment and large desmin and alphabeta-crystallin positive cytoplasmic aggregates. Prominent Z-disc degeneration and focal myofibrillar disruption with regional accumulation of beta-glycogen particles were identified on electron microscopy of the 2 pro-ER samples. CONCLUSIONS: In a subset of Arabian horses with intermittent episodes of exertional rhabdomyolysis, ectopic accumulation of cytoskeletal proteins and Z-disc degeneration bear a strong resemblance to a myofibrillar myopathy. While many of these horses were previously diagnosed with type 2 polysaccharide storage myopathy, pools of glycogen forming within disrupted myofibrils appeared to give the false appearance of a glycogen storage disorder. PMID- 26234163 TI - Electron Localization of Anions Probed by Nitrile Vibrations. AB - Localization and delocalization of electrons is a key concept in chemistry, and is one of the important factors determining the efficiency of electron transport through organic conjugated molecules, which have potential to act as "molecular wires". This, in turn, substantially influences the efficiencies of organic solar cells and other molecular electronic devices. It is also necessary to understand the electronic energy landscape and the dynamics that govern electron transport capabilities in one-dimensional conjugated chains so that we can better define the design principles for conjugated molecules for their applications. We show that nitrile nu(C=N) vibrations respond to the degree of electron localization in nitrile-substituted organic anions by utilizing time-resolved infrared detection combined with pulse radiolysis. Measurements of a series of aryl nitrile anions allow us to construct a semiempirical calibration curve between the changes in the nu(C=N) infrared (IR) shifts and the changes in the electronic charges from the neutral to the anion states in the nitriles; more electron localization in the nitrile anion results in larger IR shifts. Furthermore, the IR line width in anions can report a structural change accompanying changes in the electronic density distribution. Probing the shift of the nitrile nu(C=N) IR vibrational bands enables us to determine how the electron is localized in anions of nitrile functionalized oligofluorenes, considered as organic mixed-valence compounds. We estimate the diabatic electron transfer distance, electronic coupling strengths, and energy barriers in these mixed-valence compounds. The analysis reveals a dynamic picture, showing that the electron is moving back and forth within the oligomers with a small activation energy of <=kBT, likely controlled by the movement of dihedral angles between monomer units. Implications for the electron transport capability in molecular wires are discussed. PMID- 26234164 TI - A Comparison of AV Nodal Reentrant Tachycardia in Young Children and Adolescents: Electrophysiology, Ablation, and Outcomes. AB - BACKGROUND: Atrioventricular nodal reentrant tachycardia (AVNRT) typically occurs in adolescents and adults with limited data regarding AVNRT in young children. METHODS: All patients with AVNRT who underwent electrophysiology study and ablation between 2005 and 2012 were retrospectively studied. Patients were stratified by age <10 years (young AVNRT) or >=10 years (older AVNRT). Young AVNRT patients were also compared to age-matched patients with orthodromic reentrant tachycardia (ORT). RESULTS: A total of 275 studies in 272 patients were evaluated including 38 young AVNRT patients (7.7 +/- 1.5 years) and 202 older AVNRT patients (14.9 +/- 2.1 years). An atrial-His jump >=50 ms was demonstrated in 56% of young and 64% of older patients. Slow pathway modification was attempted in all but one older patient with acute ablation success achieved in all. RF ablation was the primary ablation modality with cryoablation used in 10 patients (three young and seven older). Recurrences were rare (zero young and three older patients) despite residual AVNRT echo beats postablation in 34% of young and 40% of older patients. One older AVNRT patient (0.5%) required a pacemaker for heart block while no complications occurred in the young patients. Electrophysiologic parameters were comparable to the 35 age-matched young ORT group (7.7 +/-1.7 years) in whom supraventricular tachycardia was more inducible. CONCUSIONS: Slow pathway modification for AVNRT in children resulted in high success and low complication rates, regardless of age. Recurrence of tachycardia was infrequent despite persistence of AVNRT echo beats in 34-40% of patients following slow pathway modification. PMID- 26234165 TI - Chromosomal polymorphism in mammals: an evolutionary perspective. AB - Although chromosome rearrangements (CRs) are central to studies of genome evolution, our understanding of the evolutionary consequences of the early stages of karyotypic differentiation (i.e. polymorphism), especially the non-meiotic impacts, is surprisingly limited. We review the available data on chromosomal polymorphisms in mammals so as to identify taxa that hold promise for developing a more comprehensive understanding of chromosomal change. In doing so, we address several key questions: (i) to what extent are mammalian karyotypes polymorphic, and what types of rearrangements are principally involved? (ii) Are some mammalian lineages more prone to chromosomal polymorphism than others? More specifically, do (karyotypically) polymorphic mammalian species belong to lineages that are also characterized by past, extensive karyotype repatterning? (iii) How long can chromosomal polymorphisms persist in mammals? We discuss the evolutionary implications of these questions and propose several research avenues that may shed light on the role of chromosome change in the diversification of mammalian populations and species. PMID- 26234166 TI - Educating Jurors about Forensic Evidence: Using an Expert Witness and Judicial Instructions to Mitigate the Impact of Invalid Forensic Science Testimony. AB - Invalid expert witness testimony that overstated the precision and accuracy of forensic science procedures has been highlighted as a common factor in many wrongful conviction cases. This study assessed the ability of an opposing expert witness and judicial instructions to mitigate the impact of invalid forensic science testimony. Participants (N = 155) acted as mock jurors in a sexual assault trial that contained both invalid forensic testimony regarding hair comparison evidence, and countering testimony from either a defense expert witness or judicial instructions. Results showed that the defense expert witness was successful in educating jurors regarding limitations in the initial expert's conclusions, leading to a greater number of not-guilty verdicts. The judicial instructions were shown to have no impact on verdict decisions. These findings suggest that providing opposing expert witnesses may be an effective safeguard against invalid forensic testimony in criminal trials. PMID- 26234167 TI - Characterization of a porcine model for associating liver partition and portal vein ligation for a staged hepatectomy. AB - BACKGROUND: Publications using the ALPPS (associating liver partition and portal vein ligation for a staged hepatectomy) procedure have demonstrated a future liver remnant growth of 40-160% in only 6-9 days. The present study aimed to develop and describe the first large animal model of ALPPS that can be used for future studies. METHODS: A total of 13 female domestic pigs underwent ALPPS stage 1 (portal vein division and parenchymal transection) followed by ALPPS stage 2 (completion left-extended hepatectomy) 7 days later. An abdominal computed tomography (CT) scan was performed immediately prior to ALPPS stage 1 surgery and again 7 days later to assess hypertrophy immediately prior to ALPPS stage 2 surgery. Blood samples, as well as tissue analysis for Ki-67, were performed. RESULTS: On CT volumetric analysis, the mean size of the future liver remnant (FLR) prior to ALPPS stage 1 was 21 +/- 2% and 40 +/- 6% prior to ALPPS stage 2. The median degree of growth was 75% with a mean kinetic growth rate of 11% per day. Liver weights at autopsy correlated well with CT volumetric analysis (r = 0.87). There was no significant difference in mean lab values [asparate aminotransferase (AST), alanine aminotransferase (ALT), ammonia, International Normalized Ratio (INR) or bilirubin] from baseline until immediately prior to ALPPS stage 2. Post ALPPS stage 2 there was a significant increase in INR from baseline 1.1 to 1.6 (P = 0.012). No post-operative deaths secondary to liver failure were observed. CONCLUSION: The present study describes the first reproducible large animal model of the ALPPS procedure. The degree of liver growth and the kinetic rate of growth were similar to that which has been demonstrated in human publications. This model will be valuable as future laboratory studies are performed. PMID- 26234168 TI - Finite lattice model for molecular aggregation equilibria. Boolean statistics, analytical approximations, and the macroscopic limit. AB - Molecular processes, ranging from hydrophobic aggregation and protein binding to mesoscopic self-assembly, are typically driven by a delicate balance of energetic and entropic non-covalent interactions. Here, we focus on a broad class of such processes in which multiple ligands bind to a central solute molecule as a result of solute-ligand (direct) and/or ligand-ligand (cooperative) interaction energies. Previously, we described a weighted random mixing (WRM) mean-field model for such processes and compared the resulting adsorption isotherms and aggregate size distributions with exact finite lattice (FL) predictions, for lattices with up to n = 20 binding sites. Here, we compare FL predictions obtained using both Bethe-Guggenheim (BG) and WRM approximations, and find that the latter two approximations are complementary, as they are each most accurate in different aggregation regimes. Moreover, we describe a computationally efficient method for exhaustively counting nearest neighbors in FL configurations, thus making it feasible to obtain FL predictions for systems with up n = 48 binding sites, whose properties approach the thermodynamic (infinite lattice) limit. We further illustrate the applicability of our results by comparing lattice model and molecular dynamics simulation predictions pertaining to the aggregation of methane around neopentane. PMID- 26234169 TI - Controversies in Robotics: Open Versus Robotic Radical Cystectomy. AB - Open radical cystectomy (ORC) remains the gold standard for treatment of muscle invasive bladder cancer and certain cases of high-risk noninvasive bladder cancer. However, ORC is associated with significant morbidity, and there is promise of improved outcomes with the emergence of minimally invasive surgery. Because of the increased adoption of robotic radical cystectomy (RRC), we sought to review the current literature on the robotic approach. We explored the surgical techniques, perioperative and postoperative complications, oncologic and functional outcomes, and quality of life of patients with RRC versus ORC. Current data appear to favor RRC in perioperative outcomes and patient recovery, although RRC continues to be associated with longer surgical times and higher costs. Oncologic data are also promising, however data on long-term oncologic outcomes are insufficient. To date, there is evidence of similar functional outcomes between RRC and ORC continence, but there is a paucity of rigorous, standardized studies on health-related quality of life for continent versus incontinent diversion. Even as use of RRC steadily grows, there is a lack of consensus on the type of approach and urinary diversion that is optimal. We assessed the influence of surgeon experience on the totally intracorporeal urinary diversion and its feasibility to be widely adopted. We aimed to answer the question of whether there are significant benefits to RRC, and furthermore, of the effect of the approach on the choice of urinary diversion. PMID- 26234171 TI - Nodal radiation in breast cancer does not improve survival. PMID- 26234170 TI - Potency trends of Delta9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005-15. AB - BACKGROUND AND AIMS: Between 2000 and 2005 the average percentage of Delta(9) tetrahydrocannabinol (THC) in marijuana as sold in Dutch coffeeshops has increased substantially; the potency of domestic products (Nederwiet and Nederhasj) has particularly increased. In contrast with imported marijuana, Nederwiet hardly contained any cannabidiol (CBD), a cannabinoid that is thought to offset some of the adverse effects of THC. In 2005, the THC content in Nederwiet was significantly lower than in 2004. This study investigates the further decrease or increase of cannabinoids in these cannabis products. METHODS: From 2005 to 2015 five different cannabis products were bought anonymously in 50 coffeeshops that were selected randomly each year from all coffeeshops in the Netherlands. A total of 2126 cannabis samples were bought, consisting of 664 Nederwiet samples (most popular), 537 Nederwiet samples (supposed strongest varieties), 183 imported herbal cannabis samples, 140 samples of cannabis resin made of Nederwiet and 602 samples of imported cannabis resin. All samples were analysed chemically for their THC, CBD and cannabinol (CBN) content. RESULTS: Between 2005 and 2015, the mean potencies of the most popular and the strongest Nederwiet and of imported cannabis resin were 16.0+/-4.0%, 17.0+/-3,9% and 16.5+/ 6.3%, respectively. Imported herbal cannabis (6.5+/-3.5%) and cannabis resin made from Nederwiet (30.2+/-16.4%) contained, respectively, less (beta=-10.0, P<0.001) and more (beta=13.7, P<0.001) THC than imported cannabis resin. Linear regression models were used to study the trends in THC of the different cannabis products over time. A marginal, but significant (P<0.001), overall decline of THC per year of 0.22% was found in all cannabis products. However, no significant difference was found between the five products in the THC linear trajectories across time. Of all the cannabis products, only imported cannabis resin contained a relatively high CBD/THC ratio (median 0.42). CONCLUSION: The average tetrahydrocannabinol (THC) content of the most popular herbal cannabis products in the Netherlands has decreased slightly since 2005. The popular Nederwiet type still has a relatively high THC to cannabidiol ratio. PMID- 26234172 TI - EMA paediatric medicine waivers. PMID- 26234173 TI - Vosaroxin in acute myeloid leukaemia. PMID- 26234175 TI - Genetic testing for patients with colorectal cancer. PMID- 26234176 TI - A metabolomics approach to studying the effects of Jinxin oral liquid on RSV infected mice using UPLC/LTQ-Orbitrap mass spectrometry. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Jinxin oral liquid (JOL) is a traditional Chinese medicine (TCM) formula modified from ma-xing-shi-gan-tang, an ancient formula widely used in the treatment of respiratory diseases such as bronchitis, pneumonia, and asthma. In our previous studies, JOL was shown to safely and effectively treat viral pneumonia, especially that involving respiratory syncytial virus (RSV). AIM OF THE STUDY: To investigate the mechanism of the effect of JOL in RSV infected mice, using a metabolomics approach based on ultra performance liquid chromatography coupled with linear ion trap quadrupole Orbitrap mass spectrometry (UPLC/LTQ-Orbitrap-MS). MATERIALS AND METHODS: BALB/c mice were divided into four groups, the control group (saline inoculation/no treatment), RSV group (RSV inoculation/saline treatment), RSV+JOL group (RSV inoculation/JOL treatment), and RSV+Riba group (RSV inoculation/ribavirin treatment). Plasma and lung tissue samples were collected 7 days after the inoculation/treatment protocols, and UPLC/LTQ-Orbitrap-MS method based on metabolomics was developed. Principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were utilized to identify biomarkers potentially associated with the anti-RSV activity of JOL. RESULTS: JOL was associated with reduced inflammatory responses in RSV-infected lung tissue. The combination of PCA and OPLS-DA revealed deviations in 11 biomarkers in plasma, and 16 biomarkers in lung tissue induced by RSV that were corrected with JOL treatment. These biomarkers were primarily components of metabolic pathways involving glycerophosphocholines, sphingolipids, and glycerolipids. JOL was able to restore the abnormal levels of these biomarkers detected in the plasma and lung tissue of RSV-infected mice to approximately normal levels. CONCLUSIONS: This study suggested that JOL can treat RSV pneumonia effectively, partially by ameliorating the associated disturbances to lipid metabolism. The results provided insight into the anti-RSV mechanism of JOL, and also demonstrated that metabolomics is a valuable tool for investigating the efficacy of TCM treatment for RSV pneumonia, and the associated biomarkers involved. PMID- 26234177 TI - Ethnobotanical study of medicinal plants by population of Valley of Juruena Region, Legal Amazon, Mato Grosso, Brazil. AB - ETHNOPHARMACOLOGICAL IMPORTANCE: The use of medicinal plants for treatment, cure and prevention of diseases has been described by many people since time immemorial. Because of this use, commercial and scientific interests have emerged, making it necessary to realize ethnobotanical surveys of medicinal plants species, which is important for subsequent chemical and pharmacological bioprospections. AIM OF THE STUDY: This study aimed at surveying, identifying, cataloging and documenting the medicinal plants species used in the Valley of Juruena, Northwestern Mato Grosso, Legal Amazon Brazil for the treatment of various human diseases, as well as assessed the species of interest for bioprospecting potential. MATERIALS AND METHODS: Informants were interviewed using semi-structured form to capture information on socio-demographic and ethnopharmacological data of medicinal plants such as vernacular name, uses, geographic origin, habit, form of preparation and part used. Results were analyzed using descriptive and quantitative means: indices of use-report (Ur) and informant consensus factor (ICF), for the selection of plant species with therapeutic potential. RESULTS: Three hundred and thirty two (332) plants species belonging to 90 families were reported for medicinal purposes and totaling 3973 use-reports were reported by 365 (92.9%) of the people interviewed. Asteraceae (32.2%), Fabaceae (26.7%) and Lamiaceae (24.4%) families were the most represented, with majority being species native (64.45%) to Brazil. Leaves (64.5%) were the part of the plant most used and infusion (45.7%) was the most utilized form. Gastrointestinal disorders followed by respiratory complaints topped the list of use-reports. The native or naturalized plants with the highest use reports in the order of decreasing absolute frequency per each emic-category are Cymbopogon citratus (DC.) Stapfc (104), Mentha pulegium L. (94), Arrabidaea chica (Humb. & Bonpl.) B. Verl. (97), Alternanthera brasiliana (L.) Kuntze (71), Baccharis crispa Spreng (57), Phyllanthus niruri L. (48), Gossypium barbadense L. (44), Solidago microglossa DC. (40) and Bauhinia forficata L. (20). And the most cited exotics are: Chenopodium ambrosioides L. (151), Aloe vera (L.) Burm. f., (89) and Rosmarinus officinalis L. (72). In some cases, high ICF values were found, which reflects high degree of homogeneity of consensus among informants in this region on medicinal plants. CONCLUSION: The population of Valle of Juruena makes use of a wide array of medicinal plants distributed in all use categories with predominance of those use in the treatments of gastrointestinal and respiratory ailments. The therapeutic potential of some of the species of medicinal importance extensively utilized by the population of the region have been scientifically validated, and are therefore promising prototype of new drugs. However, there are some of these species whose ethnomedicinal uses are yet to be scientifically verified and thus constitute an unexplored terrain for future biological/pharmacological studies. PMID- 26234178 TI - Weathering the empire: meteorological research in the early British Straits Settlements. AB - This article explores meteorological interest and experimentation in the early history of the Straits Settlements. It centres on the establishment of an observatory in 1840s Singapore and examines the channels that linked the observatory to a global community of scientists, colonial officers and a reading public. It will argue that, although the value of overseas meteorological investigation was recognized by the British government, investment was piecemeal and progress in the field often relied on the commitment and enthusiasm of individuals. In the Straits Settlements, as elsewhere, these individuals were drawn from military or medical backgrounds, rather than trained as dedicated scientists. Despite this, meteorology was increasingly recognized as of fundamental importance to imperial interests. Thus this article connects meteorology with the history of science and empire more fully and examines how research undertaken in British dependencies is revealing of the operation of transnational networks in the exchange of scientific knowledge. PMID- 26234174 TI - Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. AB - BACKGROUND: Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia. METHODS: This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801. FINDINGS: Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7.5 months (95% CI 6.4-8.5) in the vosaroxin plus cytarabine group and 6.1 months (5.2-7.1) in the placebo plus cytarabine group (hazard ratio 0.87, 95% CI 0.73-1.02; unstratified log-rank p=0.061; stratified p=0.024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p<0.0001). Early mortality was similar between treatment groups (30-day: 28 [8%] of 355 patients in the vosaroxin plus cytarabine group vs 23 [7%] of 350 in the placebo plus cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus cytarabine and in eight (2%) of 350 patients given placebo plus cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]). INTERPRETATION: Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia. FUNDING: Sunesis Pharmaceuticals. PMID- 26234179 TI - Vertical stratification of matrix production is essential for physical integrity and architecture of macrocolony biofilms of Escherichia coli. AB - Bacterial macrocolony biofilms grow into intricate three-dimensional structures that depend on self-produced extracellular polymers conferring protection, cohesion and elasticity to the biofilm. In Escherichia coli, synthesis of this matrix - consisting of amyloid curli fibres and cellulose - requires CsgD, a transcription factor regulated by the stationary phase sigma factor RpoS, and occurs in the nutrient-deprived cells of the upper layer of macrocolonies. Is this asymmetric matrix distribution functionally important or is it just a fortuitous by-product of an unavoidable nutrient gradient? In order to address this question, the RpoS-dependent csgD promoter was replaced by a vegetative promoter. This re-wiring of csgD led to CsgD and matrix production in both strata of macrocolonies, with the lower layer transforming into a rigid 'base plate' of growing yet curli-connected cells. As a result, the two strata broke apart followed by desiccation and exfoliation of the top layer. By contrast, matrix free cells at the bottom of wild-type macrocolonies maintain colony contact with the humid agar support by flexibly filling the space that opens up under buckling areas of the macrocolony. Precisely regulated stratification in matrix-free and matrix-producing cell layers is thus essential for the physical integrity and architecture of E. coli macrocolony biofilms. PMID- 26234180 TI - Nonenzymatic Glycation and Degree of Mineralization Are Higher in Bone From Fractured Patients With Type 1 Diabetes Mellitus. AB - Low-energy fractures are frequent complications in type 1 diabetes mellitus patients (T1DM). Modifications of bone intrinsic composition might be a potential cause of fragility observed in diabetic subjects. Advanced glycation end products (AGEs) were found in numerous connective tissues from T1DM patients. However, whether AGEs are present at high levels in bone matrix from diabetic subjects is unknown. Moreover, whether elevated AGEs in the bone matrix impair mineralization has not been addressed in humans. The purposes of this study were 1) to determine whether bone matrix from fracturing and nonfracturing T1DM contained more AGEs than bone from healthy patients (CTL), and 2) to compare the degree of mineralization of bone and hardness between fracturing and nonfracturing T1DM versus CTL. We analyzed iliac crest bone biopsies from 5 fracturing T1DM patients, 5 nonfracturing T1DM patients, and 5 healthy subjects, all age- and sex matched. AGEs (pentosidine) in bone matrix was measured by high-performance liquid chromatography separately in trabecular and cortical bone. The degree of mineralization of bone (DMB) was assessed by digitized microradiography, and mechanical properties by micro- and nanohardness tests. Trabecular bone from fracturing T1DM exhibited significantly higher levels of pentosidine than CTL (p = 0.04) and was more mineralized than nonfracturing T1DM (p = 0.04) and CTL (p = 0.04). Trabecular bone was not significantly different in pentosidine between nonfracturing T1DM and CTL. Cortical bone from nonfracturing T1DM was not significantly different from CTL. Positive correlations were found between HbA1c and pentosidine (r' = 0.79, p < 0.003) and between HbA1c and DMB (r' = 0.64, p < 0.02). Both modifications could lead to less flexible bone (reduced modulus of elasticity) and a tendency toward low-energy fractures in T1DM patients. PMID- 26234181 TI - Clinicopathological and phenotypic features of chronic NK cell lymphocytosis identified among patients with asymptomatic lymphocytosis. AB - INTRODUCTION: Chronic natural killer (NK) cell lymphocytosis is currently a provisional entity. This study demonstrated NK cell lymphocytosis in patients with asymptomatic lymphocytosis and presented the hematological and phenotypic findings. METHODS: Flow cytometry analysis was performed for investigation of unexplained peripheral lymphocytosis. NK cells were determined by the phenotype of CD3-/CD16+/CD56+. Chronic NK cell lymphocytosis was defined by a NK cell count of >= 2 * 10(9)/L, persistent for over 6 months, no evidence of B- or T-cell clonality and no hematologic disorders. RESULTS: Among 190 patients with peripheral lymphocytosis, 15(7.9%) patients, age 42-72 years, were identified to have NK cell lymphocytosis, with a median NK cell count of 3.1 * 10(9)/L (range 2.1-7.3 * 10(9)/L). Persistent NK cell lymphocytosis was confirmed with a median follow-up of 18 months. CD56(bright) NK cell populations were seen in eight patients and CD56(dim) NK cells in seven patients. CD57 co-expression was seen in both CD56(dim) and CD56(bright) cells. CD7, CD2, or CD8 expression was seen in some of the NK populations. The NK cell lymphocytosis appeared stable and no progression to NK cell leukemia during the follow-up period. CONCLUSION: This study demonstrated that chronic NK cell lymphocytosis, similar to monoclonal B lymphocytosis or T-cell clones, may account for asymptomatic lymphocytosis. There were no identifiable causes of the NK cell expansion. The variable phenotype may represent the heterogeneity and pathological features of NK lymphocytosis. PMID- 26234183 TI - Genomic characterization of a novel avian arthritis orthoreovirus variant by next generation sequencing. AB - By using next-generation sequencing (NGS) technology, we have identified a divergent avian orthoreovirus (ARV) field variant (Reo/PA/Broiler/15511/13, or PA15511), isolated from broiler chickens with viral arthritis in Pennsylvania in 2013. The complete genome of the PA15511 field strain was 23,495 bp in length with 10 dsRNA segments encoding 12 viral proteins. The lengths of the genomic segments ranged from 1192 bp (S4) to 3958 bp (L1). Genomic analysis has revealed that this virus is distinct from reference ARV strains and meets criteria for a new or novel strain. PMID- 26234182 TI - An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer. AB - High-grade serous ovarian cancers (HGSCs) are deadly malignancies that relapse despite carboplatin chemotherapy. Here we show that 16 independent primary HGSC samples contain a CA125-negative population enriched for carboplatin-resistant cancer initiating cells. Transcriptome analysis reveals upregulation of homologous recombination DNA repair and anti-apoptotic signals in this population. While treatment with carboplatin enriches for CA125-negative cells, co-treatment with carboplatin and birinapant eliminates these cells in HGSCs expressing high levels of the inhibitor of apoptosis protein cIAP in the CA125 negative population. Birinapant sensitizes CA125-negative cells to carboplatin by mediating degradation of cIAP causing cleavage of caspase 8 and restoration of apoptosis. This co-therapy significantly improves disease-free survival in vivo compared with either therapy alone in tumour-bearing mice. These findings suggest that therapeutic strategies that target CA125-negative cells may be useful in the treatment of HGSC. PMID- 26234184 TI - Complete genome sequence analysis and identification of putative metallo-beta lactamase and SpoIIIE homologs in Bacillus cereus group phage BCP8-2, a new member of the proposed Bastille-like group. AB - Bacillus cereus group-specific bacteriophage BCP8-2 exhibits a broad lysis spectrum among food and human isolates (330/364) of B. cereus while not infecting B. subtilis (50) or B. licheniformis (12) strains. Its genome is 159,071 bp long with 220 open reading frames, including genes for putative methyltransferases, metallo-beta-lactamase, and a sporulation-related SpoIIIE homolog, as wells as 18 tRNAs. Comparative genome analysis showed that BCP8-2 is related to the recently proposed Bastille-like phages, but not with either SPO1-like or Twort-like phages of the subfamily Spounavirinae. PMID- 26234185 TI - Genetic variability and evolutionary analysis of parietaria mottle virus: role of selection and genetic exchange. AB - The genetic variability and evolution of parietaria mottle virus (PMoV) of the genus Ilarvirus was studied by analyzing nucleotide sequences of 2b and CP genes from isolates collected in different countries. Phylogenetic analysis showed that PMoV isolates clustered in different clades: one (clade I) composed of only Italian isolates and three clades (clades II-IV) including the Spanish isolates. The Greek isolate GrT-1 used in this study was in clade IV for the CP phylogenetic tree whereas it formed a separate branch in the 2b phylogenetic tree. The nucleotide sequence diversity of both the 2b and CP genes was low (0.062 +/- 0.006 and 0.063 +/- 0.006 for 2b and CP, respectively) but higher than those of other ilarviruses. Distribution of synonymous and nonsynonymous substitutions revealed that 2b and CP proteins are under purifying selection, with some positions under diversifying selection. Genetic exchange among Spanish isolates was also detected. PMID- 26234187 TI - Dr. Alan Yagoda and the Development of Systemic Therapy for Advanced Bladder Cancer. PMID- 26234186 TI - Copy number variation-based genome wide association study reveals additional variants contributing to meat quality in Swine. AB - Pork quality is important both to the meat processing industry and consumers' purchasing attitude. Copy number variation (CNV) is a burgeoning kind of variants that may influence meat quality. In this study, a genome-wide association study (GWAS) was performed between CNVs and meat quality traits in swine. After false discovery rate (FDR) correction, a total of 8 CNVs on 6 chromosomes were identified to be significantly associated with at least one meat quality trait. All of the 8 CNVs were verified by next generation sequencing and six of them were verified by qPCR. Only the haplotype block containing CNV12 is adjacent to significant SNPs associated with meat quality, suggesting the effects of those CNVs were not likely captured by tag SNPs. The DNA dosage and EST expression of CNV12, which overlap with an obesity related gene Netrin-1 (Ntn1), were consistent with Ntn1 RNA expression, suggesting the CNV12 might be involved in the expression regulation of Ntn1 and finally influence meat quality. We concluded that CNVs may contribute to the genetic variations of meat quality beyond SNPs, and several candidate CNVs were worth further exploration. PMID- 26234188 TI - Re-focusing risk assessment in forensic mental health nursing. PMID- 26234189 TI - The journey of positioning self as both mental health nurse and qualitative researcher: a critical reflection. AB - This paper discusses the development of a mental health nurse clinician to a mental health nurse researcher. Understanding the theoretical and professional drives that shape mental health nurses clinical practice and how that links to becoming a researcher is discussed. Mental health nurses who conduct research have to often move between their clinical roles and that of the researcher, doing this safely using a reflective supervision approach enables the nurse to conduct the research from a stronger professional and ethical standpoint. The intention of the paper is to encourage mental health nurses to engage in research and development. Shifting between the positions of a mental health nurse clinician and a qualitative researcher has some parallels to the processes in the nurse service user relationship. This paper addresses this development from practitioner to researcher in one mental health nurse's journey through a PhD study using constructivist grounded theory. The paper examines theoretical and professional drives that have shaped my clinical practice and the role of the researcher in constructivist grounded theory, the notion of the researcher shifting between insider and outsider status, and the importance of reflexivity in conducting research. These influences will be discussed in the context of the development of a constructivist grounded theory study of the delivery of health care to service users with a mental illness in general hospital wards. PMID- 26234190 TI - Recovery from psychosis: physical health, antipsychotic medication and the daily dilemmas for mental health nurses. PMID- 26234192 TI - Causation, Confounding, and Contrast-Enhanced Computed Tomography. PMID- 26234193 TI - Does Albumin Infusion Reduce Renal Impairment and Mortality in Patients With Spontaneous Bacterial Peritonitis? PMID- 26234194 TI - Osteochondral allograft transplantation in cartilage repair: Graft storage paradigm, translational models, and clinical applications. AB - The treatment of articular cartilage injury and disease has become an increasingly relevant part of orthopaedic care. Articular cartilage transplantation, in the form of osteochondral allografting, is one of the most established techniques for restoration of articular cartilage. Our research efforts over the last two decades have supported the transformation of this procedure from experimental "niche" status to a cornerstone of orthopaedic practice. In this Kappa Delta paper, we describe our translational and clinical science contributions to this transformation: (1) to enhance the ability of tissue banks to process and deliver viable tissue to surgeons and patients, (2) to improve the biological understanding of in vivo cartilage and bone remodeling following osteochondral allograft (OCA) transplantation in an animal model system, (3) to define effective surgical techniques and pitfalls, and (4) to identify and clarify clinical indications and outcomes. The combination of coordinated basic and clinical studies is part of our continuing comprehensive academic OCA transplant program. Taken together, the results have led to the current standards for OCA processing and storage prior to implantation and also novel observations and mechanisms of the biological and clinical behavior of OCA transplants in vivo. Thus, OCA transplantation is now a successful and increasingly available treatment for patients with disabling osteoarticular cartilage pathology. PMID- 26234195 TI - Perfluorinated chemicals, PFOS and PFOA, enhance the estrogenic effects of 17beta estradiol in T47D human breast cancer cells. AB - Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are the two most popular surfactants among perfluorinated compounds (PFCs), with a wide range of uses. Growing evidence suggests that PFCs have the potential to interfere with estrogen homeostasis, posing a risk of endocrine-disrupting effects. This in vitro study aimed to investigate the estrogenic effect of these compounds on T47D hormone-dependent breast cancer cells. PFOS and PFOA (10(-12) to 10(-4) M) were not able to induce estrogen response element (ERE) activation in the ERE luciferase reporter assay. The ERE activation was induced when the cells were co incubated with PFOS (10(-10) to 10(-7) M) or PFOA (10(-9) to 10(-7) M) and 1 nM of 17beta-estradiol (E2). PFOS and PFOA did not modulate the expression of estrogen-responsive genes, including progesterone (PR) and trefoil factor (pS2), but these compounds enhanced the effect of E2-induced pS2 gene expression. Neither PFOS nor PFOA affected T47D cell viability at any of the tested concentrations. In contrast, co-exposure with PFOS or PFOA and E2 resulted in an increase of E2-induced cell viability, but no effect was found with 10 ng ml(-1) EGF co-exposure. Both compounds also intensified E2-dependent growth in the proliferation assay. ERK1/2 phosphorylation was increased by co-exposure with PFOS or PFOA and E2, but not with EGF. Collectively, this study shows that PFOS and PFOA did not possess estrogenic activity, but they enhanced the effects of E2 on estrogen-responsive gene expression, ERK1/2 activation and the growth of the hormone-deprived T47D cells. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26234196 TI - A careful look at ECG sampling frequency and R-peak interpolation on short-term measures of heart rate variability. AB - As the literature on heart rate variability (HRV) continues to burgeon, so too do the challenges faced with comparing results across studies conducted under different recording conditions and analysis options. Two important methodological considerations are (1) what sampling frequency (SF) to use when digitizing the electrocardiogram (ECG), and (2) whether to interpolate an ECG to enhance the accuracy of R-peak detection. Although specific recommendations have been offered on both points, the evidence used to support them can be seen to possess a number of methodological limitations. The present study takes a new and careful look at how SF influences 24 widely used time- and frequency-domain measures of HRV through the use of a Monte Carlo-based analysis of false positive rates (FPRs) associated with two-sample tests on independent sets of healthy subjects. HRV values from the first sample were calculated at 1000 Hz, and HRV values from the second sample were calculated at progressively lower SFs (and either with or without R-peak interpolation). When R-peak interpolation was applied prior to HRV calculation, FPRs for all HRV measures remained very close to 0.05 (i.e. the theoretically expected value), even when the second sample had an SF well below 100 Hz. Without R-peak interpolation, all HRV measures held their expected FPR down to 125 Hz (and far lower, in the case of some measures). These results provide concrete insights into the statistical validity of comparing datasets obtained at (potentially) very different SFs; comparisons which are particularly relevant for the domains of meta-analysis and mobile health. PMID- 26234197 TI - Reformulating the Quantum Uncertainty Relation. AB - Uncertainty principle is one of the cornerstones of quantum theory. In the literature, there are two types of uncertainty relations, the operator form concerning the variances of physical observables and the entropy form related to entropic quantities. Both these forms are inequalities involving pairwise observables, and are found to be nontrivial to incorporate multiple observables. In this work we introduce a new form of uncertainty relation which may give out complete trade-off relations for variances of observables in pure and mixed quantum systems. Unlike the prevailing uncertainty relations, which are either quantum state dependent or not directly measurable, our bounds for variances of observables are quantum state independent and immune from the "triviality" problem of having zero expectation values. Furthermore, the new uncertainty relation may provide a geometric explanation for the reason why there are limitations on the simultaneous determination of different observables in N dimensional Hilbert space. PMID- 26234198 TI - An optimized polyamine moiety boosts the potency of human type II topoisomerase poisons as quantified by comparative analysis centered on the clinical candidate F14512. AB - Combined computational-experimental analyses explain and quantify the spermine vectorized F14512's boosted potency as a topoII poison. We found that an optimized polyamine moiety boosts drug binding to the topoII/DNA cleavage complex, rather than to the DNA alone. These results provide new structural bases and key reference data for designing new human topoII poisons. PMID- 26234199 TI - High diversity of Bradyrhizobium strains isolated from several legume species and land uses in Brazilian tropical ecosystems. AB - The genus Bradyrhizobium stands out among nitrogen-fixing legume-nodulating bacteria because it predominates among the efficient microsymbionts of forest, forage, and green manure legume species, as well as important species of grain legumes, such as soybean, cowpea, and peanut. Therefore, the diversity of Bradyrhizobium strains is a relevant resource from environmental and economic perspectives, and strains isolated from diverse legume species and land uses in Brazilian tropical ecosystems were assessed in this study. To accomplish this, sequences of four housekeeping genes (atpD, dnaK, gyrB, and recA) were individually analysed, with the first three also being considered using multilocus sequence analysis (MLSA). The sensitivity of the strains to different antibiotics, their tolerance to different levels of salinity, and their ability to nodulate soybean plants were also measured. The phylogenetic trees based on each individual gene, and on the concatenated housekeeping genes, revealed several strain clusters separated from any currently described species. The Bradyrhizobium strains studied were generally resistant to antibiotics. All strains were able to grow at salinity levels of up to 0.5% NaCl, whereas only strains UFLA03-142, UFLA03-143, UFLA03-145, and UFLA03-146 grew in the presence of 1% NaCl. Together, the results indicated that some of the strains studied were potential novel species, indicating that the various soils and ecosystems in Brazil may harbour an as yet unknown diversity of rhizobia. PMID- 26234200 TI - The electronic properties of impurities (N, C, F, Cl, and S) in Ag3PO4: A hybrid functional method study. AB - The transition energies and formation energies of N, C, F, Cl, and S as substitutional dopants in Ag3PO4 are studied using first-principles calculations based on the hybrid Hartree-Fock density functional, which correctly reproduces the band gap and thus provides the accurate defect states. Our results show that NO and CO act as deep acceptors, FO, ClO, and SP act as shallow donors. NO and CO have high formation energies under O-poor condition therefore they are not suitable for p-type doping Ag3PO4. Though FO, ClO, and SP have shallow transition energies, they have high formation energies, thus FO, ClO, and SP may be compensated by the intrinsic defects (such as Ag vacancy) and they are not possible lead to n-type conductivity in Ag3PO4. PMID- 26234201 TI - Effect of protein or energy restriction during late gestation on hormonal and metabolic status in pregnant goats and postnatal male offspring. AB - The objective of this study was to investigate the effects of maternal protein or energy restriction on hormonal and metabolic status of pregnant goats during late gestation and their postnatal male kids. Forty-five pregnant goats were fed a control (CON), 40% protein-restricted (PR) or 40% energy-restricted (ER) diet from 90 days of gestation until parturition. Plasma of mothers (90, 125 and 145 days of gestation) and kids (6 weeks of age) were sampled to determine metabolites and hormones. Glucose concentration for pregnant goats subjected to PR or ER was less (P < 0.001) than that of CON goats at 125 and 145 days of gestation. However, plasma nonesterified fatty acids concentration was greater (P < 0.01) at 125 and 145 days for PR and ER than CON. Protein restriction increased (P < 0.01) maternal cortisol concentration by 145 days of gestation, and ER decreased (P < 0.01) maternal insulin concentration at 125 days of gestation. Moreover, maternal amino acid (AA) concentrations were affected by nutritional restriction, with greater (P < 0.05) total AA (TAA) and nonessential AA (NEAA) for PR goats but less (P < 0.05) TAA and NEAA for ER goats at 125 days of gestation. After 6 weeks of nutritional recovery, plasma concentrations of most metabolic and hormonal parameters in restricted kids were similar to CON kids, except for reduced (P < 0.05) insulin concentration in ER, and reduced (P < 0.05) Asp concentration in PR and ER kids. These results provide information on potential metabolic mechanisms responsible for fetal programming. PMID- 26234202 TI - Cu-Catalyzed Cyanation of Arylboronic Acids with Acetonitrile: A Dual Role of TEMPO. AB - The cyanation of arylboronic acids by using acetonitrile as the "CN" source has been achieved under a Cu(cat.)/TEMPO system (TEMPO=2,2,6,6-tetramethylpiperidine N-oxide). The broad substrate scope includes a variety of electron-rich and electron-poor arylboronic acids, which react well to give the cyanated products in high to excellent yields. Mechanistic studies reveal that TEMPO-CH2 CN, generated in situ, is an active cyanating reagent, and shows high reactivity for the formation of the CN(-) moiety. Moreover, TEMPO acts as a cheap oxidant to enable the reaction to be catalytic in copper. PMID- 26234203 TI - Giant uterine fibroids: consequences of delay in presentation. PMID- 26234205 TI - Multiple shape memory polymers based on laminates formed from thiol-click chemistry based polymerizations. AB - This investigation details the formation of polymer network trilayer laminates formed by thiol-X click chemistries, and their subsequent implementation and evaluation for quadruple shape memory behavior. Thiol-Michael addition and thiol isocyanate-based crosslinking reactions were employed to fabricate each of the laminate's layers with independent control of the chemistry and properties of each layer and outstanding interlayer adhesion and stability. The characteristic features of step-growth thiol-X reactions, such as excellent network uniformity and narrow thermal transitions as well as their stoichiometric nature, enabled fabrication of trilayer laminates with three distinctly different glass transition temperatures grouped within a narrow range of 100 degrees C. Through variations in the layer thicknesses, a step-wise modulus drop as a function of temperature was achieved. This behavior allowed multi-step programming and the demonstration and quantification of quadruple shape memory performance. As is critical for this performance, the interface connecting the layers was evaluated in stoichiometric as well as off-stoichiometric systems. It was shown that the laminated structures exhibit strong interfacial binding and hardly suffer any delamination during cyclic material testing and deformation. PMID- 26234206 TI - Mechanochemistry of lithium nitride under hydrogen gas. AB - Hydrogen uptake during the mechanochemistry of lithium nitride under 9 MPa hydrogen pressure has been analyzed by means of in situ solid-gas absorption and ex situ X-ray diffraction (XRD) measurements. In situ hydrogenation curves show two H-sorption steps leading to an overall hydrogen uptake of 9.8 wt% H after 3 hours of milling. The milled end-products consist of nanocrystalline (~10 nm) LiNH2 and LiH phases. The first reaction step comprises the transformation of the polymorph alpha-Li3N (S.G. P6/mmm) into the beta-Li3N (S.G. P63/mmc) metastable phase and the reaction of the latter with hydrogen to form lithium imide: beta Li3N + H2-> Li2NH + LiH. Reaction kinetics of the first step is zero-order. Its rate-limiting control is assigned to the collision frequency between milling balls and Li3N powder. In the second absorption step, lithium imide converts to lithium amide following the reaction scheme Li2NH + H2-> LiNH2 + LiH. Reaction kinetics is here limited by one-dimensional nucleation and the growth mechanism, which, in light of structural data, is assigned to the occurrence of lithium vacancies in the imide compound. This study provides new insights into the reaction paths and chemical kinetics of light hydrogen storage materials during their mechanochemical synthesis. PMID- 26234207 TI - Specificity of the mammalian glycolipid transfer proteins. AB - Structurally the glycolipid transfer protein (GLTP) fold differs from other proteins that recognize glycolipids, such as non-specific lipid transfer proteins and lysosomal lipid degradation assisting proteins, even though they act on the same class of lipids. Proteins with glycan binding domains, such as lectins and pulmonary surfactant proteins share no structural similarity with the GLTP family either. Currently the unique GLTP-fold specific for binding glycosphingolipids is found only in the founding member GLTP and the phosphoinositol 4-phosphate adapter protein 2, FAPP2. FAPP2 was originally characterized as a member eight of the pleckstrin homology domain-containing family A (PLEKHA8). This review summarizes what is structurally required by the glycosphingolipids in order for them to be transported by the GLTPs. PMID- 26234208 TI - Protein structure refinement via molecular-dynamics simulations: What works and what does not? AB - Protein structure refinement during CASP11 by the Feig group was described. Molecular dynamics simulations were used in combination with an improved selection and averaging protocol. On average, modest refinement was achieved with some targets improved significantly. Analysis of the CASP submission from our group focused on refinement success versus amount of sampling, refinement of different secondary structure elements and whether refinement varied as a function of which group provided initial models. The refinement of local stereochemical features was examined via the MolProbity score and an updated protocol was developed that can generate high-quality structures with very low MolProbity scores for most starting structures with modest computational effort. Proteins 2016; 84(Suppl 1):282-292. (c) 2015 Wiley Periodicals, Inc. PMID- 26234209 TI - Charge optimized many-body (COMB) potential for dynamical simulation of Ni-Al phases. AB - An interatomic potential for the Ni-Al system is presented within the third generation charge optimized many-body (COMB3) formalism. The potential has been optimized for Ni3Al, or the gamma' phase in Ni-based superalloys. The formation energies predicted for other Ni-Al phases are in reasonable agreement with first principles results. The potential further predicts good mechanical properties for Ni3Al, which includes the values of the complex stacking fault (CSF) and the anti phase boundary (APB) energies for the (1 1 1) and (1 0 0) planes. It is also used to investigate dislocation propagation across the Ni3Al (1 1 0)-Ni (1 1 0) interface, and the results are consistent with simulation results reported in the literature. The potential is further used in combination with a recent COMB3 potential for Al2O3 to investigate the Ni3Al (1 1 1)-Al2O3 (0 0 01) interface, which has not been modeled previously at the classical atomistic level due to the lack of a reactive potential to describe both Ni3Al and Al2O3 as well as interactions between them. The calculated work of adhesion for this interface is predicted to be 1.85 J m(-2), which is in agreement with available experimental data. The predicted interlayer distance is further consistent with the available first-principles results for Ni (1 1 1)-Al2O3 (0 0 0 1). PMID- 26234210 TI - Lycaenid Caterpillar Secretions Manipulate Attendant Ant Behavior. AB - Mutualistic interactions typically involve the exchange of different commodities between species. Nutritious secretions are produced by a number of insects and plants in exchange for services such as defense. These rewards are valuable metabolically and can be used to reinforce the behavior of symbiotic partners that can learn and remember them effectively. We show here novel effects of insect exocrine secretions produced by caterpillars in modulating the behavior of attendant ants in the food-for-defense interaction between lycaenid butterflies and ants. Reward secretions from the dorsal nectary organ (DNO) of Narathura japonica caterpillars function to reduce the locomotory activities of their attendant ants, Pristomyrmex punctatus workers. Moreover, workers that feed from caterpillar secretions are significantly more likely to show aggressive responses to eversion of the tentacle organs of the caterpillars. Analysis of the neurogenic amines in the brains of workers that consumed caterpillar secretions showed a significant decrease in levels of dopamine compared with controls. Experimental treatments in which reserpine, a known inhibitor of dopamine in Drosophila, was fed to workers similarly reduced their locomotory activity. We conclude that DNO secretions of lycaenid caterpillars can manipulate attendant ant behavior by altering dopaminergic regulation and increasing partner fidelity. Unless manipulated ants also receive a net nutritional benefit from DNO secretions, this suggests that similar reward-for-defense interactions that have been traditionally considered to be mutualisms may in fact be parasitic in nature. PMID- 26234211 TI - Genome-wide Evidence Reveals that African and Eurasian Golden Jackals Are Distinct Species. AB - The golden jackal of Africa (Canis aureus) has long been considered a conspecific of jackals distributed throughout Eurasia, with the nearest source populations in the Middle East. However, two recent reports found that mitochondrial haplotypes of some African golden jackals aligned more closely to gray wolves (Canis lupus), which is surprising given the absence of gray wolves in Africa and the phenotypic divergence between the two species. Moreover, these results imply the existence of a previously unrecognized phylogenetically distinct species despite a long history of taxonomic work on African canids. To test the distinct-species hypothesis and understand the evolutionary history that would account for this puzzling result, we analyzed extensive genomic data including mitochondrial genome sequences, sequences from 20 autosomal loci (17 introns and 3 exon segments), microsatellite loci, X- and Y-linked zinc-finger protein gene (ZFX and ZFY) sequences, and whole-genome nuclear sequences in African and Eurasian golden jackals and gray wolves. Our results provide consistent and robust evidence that populations of golden jackals from Africa and Eurasia represent distinct monophyletic lineages separated for more than one million years, sufficient to merit formal recognition as different species: C. anthus (African golden wolf) and C. aureus (Eurasian golden jackal). Using morphologic data, we demonstrate a striking morphologic similarity between East African and Eurasian golden jackals, suggesting parallelism, which may have misled taxonomists and likely reflects uniquely intense interspecific competition in the East African carnivore guild. Our study shows how ecology can confound taxonomy if interspecific competition constrains size diversification. PMID- 26234212 TI - Functional Specialization of Neural Input Elements to the Drosophila ON Motion Detector. AB - Detecting the direction of visual movement is fundamental for every sighted animal in order to navigate, avoid predators, or detect conspecifics. Algorithmic models of correlation-type motion detectors describe the underlying computation remarkably well. They consist of two spatially separated input lines that are asymmetrically filtered in time and then interact in a nonlinear way. However, the cellular implementation of this computation remains elusive. Recent connectomic data of the Drosophila optic lobe has suggested a neural circuit for the detection of moving bright edges (ON motion) with medulla cells Mi1 and Tm3 providing spatially offset input to direction-selective T4 cells, thereby forming the two input lines of a motion detector. Electrophysiological characterization of Mi1 and Tm3 revealed different temporal filtering properties and proposed them to correspond to the delayed and direct input, respectively. Here, we test this hypothesis by silencing either Mi1 or Tm3 cells and using electrophysiological recordings and behavioral responses of flies as a readout. We show that Mi1 is a necessary element of the ON pathway under all stimulus conditions. In contrast, Tm3 is specifically required only for the detection of fast ON motion in the preferred direction. We thereby provide first functional evidence that Mi1 and Tm3 are key elements of the ON pathway and uncover an unexpected functional specialization of these two cell types. Our results thus require an elaboration of the currently prevailing model for ON motion detection and highlight the importance of functional studies for neural circuit breaking. PMID- 26234213 TI - EXO70I Is Required for Development of a Sub-domain of the Periarbuscular Membrane during Arbuscular Mycorrhizal Symbiosis. AB - In eukaryotic cells, polarized secretion mediated by exocytotic fusion of membrane vesicles with the plasma membrane is essential for spatially restricted expansion of the plasma membrane and for the delivery of molecules to specific locations at the membrane and/or cell surface. The EXOCYST complex is central to this process, and in yeast, regulation of the EXO70 subunit influences exocytosis and cargo specificity. In contrast to yeast and mammalian cells, plants have upwards of 23 EXO70 genes with largely unknown roles. During arbuscular mycorrhizal (AM) symbiosis, deposition of the plant periarbuscular membrane (PAM) around the fungal arbuscule creates an intracellular membrane interface between the symbionts. The PAM has two major membrane sub-domains, and symbiosis-specific transporter proteins are localized in the branch domain. Currently, the mechanisms and cellular machinery involved in biogenesis of the PAM are largely unknown. Here, we identify an EXO70I protein present exclusively in plants forming AM symbiosis. Medicago truncatula exo70i mutants are unable to support normal arbuscule development, and incorporation of two PAM-resident ABC transporters, STR and STR2, is limited. During arbuscule branching, EXO70I is located in spatially restricted zones adjacent to the PAM around the arbuscule hyphal tips where it interacts with Vapyrin, a plant-specific protein required for arbuscule development. We conclude that EXO70I provides a specific exocytotic capacity necessary for development of the main functional sub-domain of the PAM. Furthermore, in contrast to other eukaryotes, plant EXO70s have evolved distinct specificities and interaction partners to fulfill their specialized secretory requirements. PMID- 26234215 TI - Mitochondrial Proteostatic Collapse Leads to Hypoxic Injury. AB - Hypoxic injury is a key pathological event in a variety of diseases. Despite the clinical importance of hypoxia, modulation of hypoxic injury mechanisms for therapeutic benefit has not been achieved, suggesting that critical features of hypoxic injury have not been identified or fully understood. Because mitochondria are the main respiratory organelles of the cell, they have been the focus of much research into hypoxic injury. Previous research has focused on mitochondria as effectors of hypoxic injury, primarily in the context of apoptosis activation and calcium regulation; however, little is known about how mitochondria themselves are injured by hypoxia. Maintenance of protein folding is essential for normal mitochondrial function, whereas failure to maintain protein homeostasis (proteostasis) appears to be a component of aging and a variety of diseases. Previously, it has been demonstrated that mitochondria possess their own unfolded protein response that is activated in response to mitochondrial protein folding stress, a response that is best understood in C. elegans. Because hypoxia has been shown to disrupt ATP production and translation of nuclear encoded proteins- both of which are shown to disrupt mitochondrial proteostasis in other contexts we hypothesized that failure to maintain mitochondrial proteostasis may play a role in hypoxic injury. Utilizing C. elegans models of global, focal, and cell non-autonomous hypoxic injury, we have found evidence of mitochondrial protein misfolding post-hypoxia and have found that manipulation of the mitochondrial protein folding environment is an effective hypoxia protective strategy. PMID- 26234214 TI - Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2. AB - The RNA-processing protein TDP-43 is central to the pathogenesis of amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron (MN) disease. TDP-43 is conserved in Drosophila, where it has been the topic of considerable study, but how TDP-43 mutations lead to age-dependent neurodegeneration is unclear and most approaches have not directly examined changes in MN morphology with age. We used a mosaic approach to study age-dependent MN loss in the adult fly leg where it is possible to resolve single motor axons, NMJs and active zones, and perform rapid forward genetic screens. We show that expression of TDP 43(Q331K) caused dying-back of NMJs and axons, which could not be suppressed by mutations that block Wallerian degeneration. We report the identification of three genes that suppress TDP-43 toxicity, including shaggy/GSK3, a known modifier of neurodegeneration. The two additional novel suppressors, hat-trick and xmas-2, function in chromatin modeling and RNA export, two processes recently implicated in human ALS. Loss of shaggy/GSK3, hat-trick, or xmas-2 does not suppress Wallerian degeneration, arguing TDP-43(Q331K)-induced and Wallerian degeneration are genetically distinct processes. In addition to delineating genetic factors that modify TDP-43 toxicity, these results establish the Drosophila adult leg as a valuable new tool for the in vivo study of adult MN phenotypes. PMID- 26234216 TI - Restoration of Vision with Ectopic Expression of Human Rod Opsin. AB - Many retinal dystrophies result in photoreceptor loss, but the inner retinal neurons can survive, making them potentially amenable to emerging optogenetic therapies. Here, we show that ectopically expressed human rod opsin, driven by either a non-selective or ON-bipolar cell-specific promoter, can function outside native photoreceptors and restore visual function in a mouse model of advanced retinal degeneration. Electrophysiological recordings from retinal explants and the visual thalamus revealed changes in firing (increases and decreases) induced by simple light pulses, luminance increases, and naturalistic movies in treated mice. These responses could be elicited at light intensities within the physiological range and substantially below those required by other optogenetic strategies. Mice with rod opsin expression driven by the ON-bipolar specific promoter displayed behavioral responses to increases in luminance, flicker, coarse spatial patterns, and elements of a natural movie at levels of contrast and illuminance (~50-100 lux) typical of natural indoor environments. These data reveal that virally mediated ectopic expression of human rod opsin can restore vision under natural viewing conditions and at moderate light intensities. Given the inherent advantages in employing a human protein, the simplicity of this intervention, and the quality of vision restored, we suggest that rod opsin merits consideration as an optogenetic actuator for treating patients with advanced retinal degeneration. PMID- 26234218 TI - AHRQ's Safety Program for Ambulatory Surgery. PMID- 26234217 TI - Zeta-Tubulin Is a Member of a Conserved Tubulin Module and Is a Component of the Centriolar Basal Foot in Multiciliated Cells. AB - There are six members of the tubulin superfamily in eukaryotes. Alpha- and beta tubulin form a heterodimer that polymerizes to form microtubules, and gamma tubulin nucleates microtubules as a component of the gamma-tubulin ring complex. Alpha-, beta-, and gamma-tubulin are conserved in all eukaryotes. In contrast, delta- and epsilon-tubulin are conserved in many, but not all, eukaryotes and are associated with centrioles, although their molecular function is unclear. Zeta tubulin is the sixth and final member of the tubulin superfamily and is largely uncharacterized. We find that zeta-, epsilon-, and delta-tubulin form an evolutionarily co-conserved module, the ZED module, that has been lost at several junctions in eukaryotic evolution and that zeta- and delta-tubulin are evolutionarily interchangeable. Humans lack zeta-tubulin but have delta-tubulin. In Xenopus multiciliated cells, zeta-tubulin is a component of the basal foot, a centriolar appendage that connects centrioles to the apical cytoskeleton, and co localizes there with epsilon-tubulin. Depletion of zeta-tubulin results in disorganization of centriole distribution and polarity in multiciliated cells. In contrast with multiciliated cells, zeta-tubulin in cycling cells does not localize to centrioles and is associated with the TRiC/CCT cytoplasmic chaperone complex. We conclude that zeta-tubulin facilitates interactions between the centrioles and the apical cytoskeleton as a component of the basal foot in differentiated cells and propose that the ZED tubulins are important for centriole functionalization and orientation of centrioles with respect to cellular polarity axes. PMID- 26234219 TI - Persistent contamination on colonoscopes and gastroscopes detected by biologic cultures and rapid indicators despite reprocessing performed in accordance with guidelines. AB - BACKGROUND: Pathogens have been transmitted via flexible endoscopes that were reportedly reprocessed in accordance with guidelines. METHODS: Researchers observed reprocessing activities to ensure guideline compliance in a large gastrointestinal endoscopy unit. Contamination was assessed immediately after bedside cleaning, manual cleaning, high-level disinfection, and overnight storage via visual inspection, aerobic cultures, and tests for adenosine triphosphate (ATP), protein, carbohydrate, and hemoglobin. RESULTS: All colonoscopes and gastroscopes were reprocessed in accordance with guidelines during the study. Researchers collected and tested samples during 60 encounters with 15 endoscopes. Viable microbes were recovered from bedside-cleaned (92%), manually cleaned (46%), high-level disinfected (64%), and stored (9%) endoscopes. Rapid indicator tests detected contamination (protein, carbohydrate, hemoglobin, or ATP) above benchmarks on bedside-cleaned (100%), manually cleaned (92%), high-level disinfected (73%), and stored (82%) endoscopes. Visible residue was never observed on endoscopes, but it was often seen on materials used to sample endoscopes. Seven endoscopes underwent additional reprocessing in response to positive rapid indicators. Control endoscope channels were free of biologic residue and viable microbes. CONCLUSION: Despite reprocessing in accordance with US guidelines, viable microbes and biologic debris persisted on clinically used gastrointestinal endoscopes, suggesting current reprocessing guidelines are not sufficient to ensure successful decontamination. PMID- 26234220 TI - Diabetes mellitus is associated with increased risk of surgical site infections: A meta-analysis of prospective cohort studies. AB - BACKGROUND AND OBJECTIVE: Observational studies have suggested an association between diabetes mellitus and the risk of surgical site infections (SSIs), but the results remain inconclusive. We conducted a meta-analysis of prospective cohort studies to elucidate the relationship between diabetes mellitus and SSIs. METHODS: We searched PubMed, Embase, and Web of Science databases and reviewed the reference lists of the retrieved articles to identify relevant studies. Associations were tested in subgroups representing different patient characteristics and study quality criteria. The random-effect model was used to calculate the overall relative risk (RR). RESULTS: Fourteen prospective cohort studies (N = 91,094 participants) were included in this meta-analysis, and the pooled crude RR was 2.02 (95% confidence interval, 1.68-2.43) with significant between-study heterogeneity observed (I(2) = 56.50%). Significant association was also detected after we derived adjusted RRs for studies not reporting the adjusted RRs and calculated the combined adjusted RR of the 14 studies (RR, 1.69; 95% confidence interval, 1.33-2.13). Results were consistent and statistically significant in all subgroups. Stratified analyses found the number of confounders adjusted for, sample size, and method of diabetes case ascertainment might be the potential sources of heterogeneity. Sensitivity analysis further demonstrated the robustness of the result. CONCLUSIONS: This meta-analysis suggests diabetes mellitus is significantly associated with increased risk of SSIs. Future studies are encouraged to reveal the mechanisms underlying this association. PMID- 26234221 TI - Occupational exposure to bloodborne pathogens in a specialized care service in Brazil. AB - In a retrospective study about the epidemiology of exposure to bloodborne pathogens among health care providers, 71.10% of the analyzed events occurred among health professionals, mainly auxiliary nurses. Percutaneous exposure (83.04%) was the most frequent. Greater advances are necessary in the development of public policies for this issue in terms of inspection of regulatory norms and raising the professionals' awareness through policy and education. PMID- 26234222 TI - Pericardial Effusion and Multiple Organ Involvement Are Independent Predictors of Mortality in Patients with Systemic Light Chain Amyloidosis. AB - OBJECTIVE: Left ventricular (LV) functions assessed by echocardiography and cardiac biomarkers are strong predictors of mortality in patients with systemic light chain (AL) amyloidosis. However, most previous studies have been conducted in Western countries, and the predictors of mortality in Asian patients with AL amyloidosis have not been characterized. To address this issue, we aimed to determine the predictors of mortality in Asian patients with biopsy-confirmed AL amyloidosis. METHODS: We retrospectively enrolled 31 patients (59+/-11 years, 55% men) in whom AL amyloidosis was confirmed by biopsies from cardiac or non-cardiac tissues. Of these patients, 15 (48%) met the international echocardiographic criteria for cardiac amyloidosis (mean LV wall thickness >12 mm without other causes of LV hypertrophy). RESULTS: During a mean follow-up period of 21+/-20 months, 15 patients died. Non-survivors had a higher number of involved organs, lower e', and higher rates of E/e' >15, pericardial effusion (PE), low voltage on an electrocardiogram and a New York Heart Association (NYHA) functional class >= III, compared with survivors. In multivariate analysis, a NYHA functional class >= III (p=0.024) and cardiac involvement (p=0.032) were independent predictors of PE in patients with AL amyloidosis. Multivariate Cox proportional hazard analysis indicated that PE (hazard ratio: 21.9, p=0.025) and the number of involved organs (hazard ratio: 2.8, p=0.015), but not LV diastolic parameters of tissue Doppler echocardiography, independently predict mortality in patients with AL amyloidosis. CONCLUSION: PE and multiple organ involvement, compared with e' and E/e', are stronger predictors of mortality in patients with AL amyloidosis. The advanced disease stage of AL amyloidosis might underlie the strong association between PE and a poor outcome. PMID- 26234224 TI - Serum Adiponectin Levels and Changes in Glucose Metabolism before and after Treatment for Thyroid Dysfunction. AB - OBJECTIVE: Adiponectin is an adipokine which is known to decrease in individuals associated with obesity and insulin resistance. In this study, we aimed to investigate the serum adiponectin levels and glucose metabolism in patients with thyroid dysfunction before and after treatment. METHODS: Newly diagnosed overt hypothyroid (n=20) and thyrotoxic (n=23) patients and healthy controls (n=20) with a body mass index of <30 kg/m(2) were evaluated prospectively. Patients with a known state of insulin resistance, including prediabetes and overt diabetes, and individuals with chronic diseases were excluded. Thyroid function and fasting plasma glucose (FPG), insulin, homeostatic model assessment (HOMA) insulin resistance (HOMA-IR) and HOMA-beta cell function (HOMA-beta), lipid and adiponectin levels were investigated in the basal state and after the restoration of euthyroidism. RESULTS: The basal fasting FPG levels were lower in the hypothyroid patients than the control subjects (p=0.02) and similar between the thyrotoxic patients and control subjects (p=0.127). The basal HOMA-beta levels were higher in the patients with hypothyroidism than in those with thyrotoxicosis (p=0.015). Following the restoration of euthyroidism, the FPG levels significantly increased in the hypothyroid patients (p=0.002) and decreased in the thyrotoxic (p=0.001) patients. The basal plasma adiponectin levels were 14.55+/-8.4 mcg/mL, 13.79+/-9.13 mcg/mL and 11.68+/-6.0 mcg/mL in the hypothyroid and thyrotoxic patients and healthy controls, respectively (p=0.503). The adiponectin levels decreased significantly in the patients with hypothyroidism (p=0.047), whereas they did not change in the patients with thyrotoxicosis (p=0.770) after achieving euthyroidism. CONCLUSION: In this study, following the restoration of euthyroidism, the FPG levels increased in the hypothyroidism patients and decreased in the thyrotoxicosis patients, despite the lack of changes in the HOMA-IR and HOMA-beta levels. Meanwhile, the hypothyroid, thyrotoxic and euthyroid subjects had similar basal adiponectin levels, and a significant decrease in the adiponectin levels was observed after treatment for hypothyroidism, despite the absence of changes after treatment for thyrotoxicosis, indicating the need for further studies with a larger sample size. PMID- 26234223 TI - Effects of Cardiac Hemodynamics on Agreement in the pH, HCO3- and Lactate Levels between Arterial and Venous Blood Samples in Patients with Known or Suspected Chronic Heart Failure. AB - OBJECTIVE: Analyses of arterial blood gas parameters, including pH, HCO3- and lactate, play an important role in assessing the clinical status of patients with heart failure. In the present study, we evaluated the degree of agreement in the pH, HCO3- and lactate levels between arterial and venous blood samples according to the subset of the Forrester classification. METHODS: The study population consisted of 128 patients with known or suspected heart failure. The subjects were divided into four groups based on the Forrester classification. Arterial blood samples were drawn from the radial or brachial artery, and venous blood samples were drawn from the pulmonary artery. RESULTS: There were 59 patients with a Forrester subset I status, 32 patients with a subset II status, 21 patients with a subset III status and 16 patients with a subset IV status. The pH and HCO3- levels were similar between the four subsets. In all subsets, the pH values were significantly higher and the HCO3- values were significantly lower in the arterial blood samples than in the venous blood samples. There was good correlation and agreement in the pH and HCO3- levels between the arterial and venous blood samples. In contrast, there was a significant difference in the lactate levels in both the arterial and venous blood samples between the four subsets, and the lactate levels were highest in subset IV. In all subsets, there was good correlation and agreement in the lactate levels between the arterial and venous blood samples. CONCLUSION: These data suggest that the venous pH, HCO3- and lactate levels are acceptable substitutes for arterial parameters, regardless of the cardiac hemodynamics. PMID- 26234225 TI - Study on the Effectiveness of Cardiopulmonary Resuscitation in Elderly Patients Presenting with Cardiopulmonary Arrest on Arrival. AB - OBJECTIVE: This study was conducted to determine whether a policy of not attempting to resuscitate patients who are 80 years of age and older with cardiopulmonary arrest on arrival is justifiable. METHODS: The protocol of this study was approved without the need for informed consent by the research ethics board of Gunma University Hospital. We prospectively analyzed patients with cardiopulmonary arrest on arrival that was due to an intrinsic reason who were taken to Gunma University Hospital between January 2013 and March 2014. The patients were divided into two groups: patients who were less than 80 years of age (L group) and those aged 80 years and older (H group). We compared the patients' characteristics, including the etiology of cardiac arrest, and the prognosis between the two groups. RESULTS: A total of 103 patients with cardiopulmonary arrest on arrival were enrolled. There were no significant differences in the patients' characteristics, such as age, sex, witness and bystander cardiopulmonary resuscitation, and transportation time between the two groups. The return of spontaneous circulation was obtained in 14 patients (25.5%) in the L group and in 9 patients (18.8%) in the H group; however, no significant difference was seen between the two groups. Two patients in the L group were in good neurological condition when they were discharged; however, the other patients did not survive. CONCLUSION: Even patients 80 years of age and older can be resuscitated to spontaneous circulation. We do not endorse a policy that recommends not performing cardiopulmonary resuscitation based solely on the age of the patient. PMID- 26234226 TI - Asymptomatic Free Air Caused by Mallory-Weiss Tears during Endoscopy. AB - An 80-year-old woman was referred to our hospital for the treatment of advanced gastric cancer which extended from the antrum to the bulbus of the duodenum. Although the patient did not struggle or retch during endoscopy, multiple mucosal lacerations were observed in the proximal stomach by Mallory-Weiss tears. No evidence of perforation was identified at the sites. The day after endoscopy, computed tomography revealed free air close to the gastric cardia, but the patient did not complain of any symptoms; she was able to consume a normal diet and did not require any treatment. PMID- 26234227 TI - Localized IgG4-related Cholecystitis Mimicking Gallbladder Cancer. AB - We encountered a case of localized IgG4-cholecystitis mimicking gallbladder cancer with focal/segmental type1 autoimmune pancreatitis (AIP). In this case, we were unable to exclude a diagnosis of gallbladder cancer and thus performed radical cholecystectomy. Type1 AIP is often associated with gallbladder lesions, accompanied by generally diffuse, circumferential thickening of the gallbladder wall. Although localized IgG4-related cholecystitis is extremely rare, differentiating this condition from gallbladder cancer is often very difficult. PMID- 26234228 TI - Acute Pulmonary Embolism due to Paget-Schroetter Syndrome. AB - A 17-year-old Japanese male athlete presented to the emergency department at our hospital with a chief complaint of exertional dyspnea. Although there were no significant findings in the right and left upper extremities on a physical examination, a chest computed tomography scan showed bilateral multiple thrombosis in the pulmonary arteries, indicating pulmonary thromboembolism, and deep vein thrombosis in the left subclavian vein. Upper limb venography showed interruption of the left subclavian vein (so-called Paget-Schroetter syndrome; PSS). We herein report this rare case of PSS that led to pulmonary thromboembolism in a young, male field athlete. PMID- 26234229 TI - Hyperglycemia-associated Hemichorea-hemiballism: The Spectrum of Clinical Presentation. AB - Hyperglycemia rarely manifests as hemichorea-hemiballism (HH), which is characterized by simple partial motor seizures. One of the difficulties in the management of hyperglycemia-induced HH is the failure to recognize this entity due to its relatively uncommon presentation. We herein present a case series of hyperglycemia-associated dyskinesias, highlighting the different possible clinical presentations of this entity. Both hyperglycemia and hyperosmolality are probable predisposing factors, while ketoacidosis has a protective role in preventing the dyskinesias. One of our patients had ketotic hyperglycemia leading to HH, a previously unreported finding. Early recognition of this entity is crucial as prompt glycemic control leads to the resolution of symptoms and signs. PMID- 26234230 TI - Delayed Development of Primary Biliary Cirrhosis in a Patient with Acute Glomerulonephritis: A Possible Pitfall of a Self-limiting Disease. AB - Acute poststreptococcal glomerulonephritis (APSGN) is a well-established disease. Although various immune responses are thought to be involved in the pathogenesis of APSGN, the disease has a self-limiting nature in clinical practice, despite the presence of severe acute symptoms. We herein report the case of a 78-year-old woman with APSGN who developed primary biliary cirrhosis (PBC) after achieving remission of renal manifestations, including anasarca and elevation of serum creatinine, indicating that persistent alterations in the immune system can cause extrarenal disorders. This case provides insights into the appropriate clinical management of ASPGN and pathogenesis of PBC. PMID- 26234231 TI - Hepatocellular Carcinoma in a Patient with Polycystic Liver Disease. AB - A 49-year-old Japanese woman with polycystic liver disease (PLD) was admitted for right hypochondrial pain. CT showed a huge enhancing mass in the liver. She tested negative for other liver diseases, such as hepatitis B and C and alcoholic liver disease. After the patient expired due to hepatic failure, an autopsy revealed poorly differentiated hepatocellular carcinoma (HCC) surrounded by multiple hepatic cysts. The small amount of residual hepatic parenchyma showed nonalcoholic fatty liver disease (NAFLD) with severe steatosis. Severe emaciation was also apparent. This case suggests that malnutrition in patients with symptomatic PLD may contribute to the development of HCC via NAFLD. PMID- 26234232 TI - IgG4-related Disease: A Mass Lesion in the Intrarenal Sinus near the Renal Pelvis. AB - A 52-year-old Japanese woman was admitted to our hospital with the renal pelvic mass lesion detected on a health screening examination. The surgical specimen contained a mass exhibiting the histological features of immunoglobulin (Ig)G4 related disease, including lymphoplasmacytic infiltration and sclerosis with numerous IgG4-producing plasma cells. Postoperatively, an elevation of the serum IgG4 level was confirmed at 403 mg/dL; however, there was no evidence of tubulointerstitial nephritis or glomerulopathy, including membranous nephropathy, and the urothelium of the renal pelvis was intact without inflammation. We herein report this case in which IgG4-related disease of the renal pelvic region presented with a mass lesion in the intrarenal sinus near the renal pelvis, not 'pyelitis' (as described by Stone). PMID- 26234233 TI - High Anion Gap Metabolic Acidosis after a Suicide Attempt with Cyanide: The Rebirth of Cyanide Poisoning. AB - A 33-year-old woman was admitted to our emergency department in a state of unconsciousness after attempting suicide with unknown substances. Severe metabolic acidosis (pH: 6.81), with a high anion gap (36.2) and high lactate level (20.2 mmol/L), was observed. After four hours of intensive medical treatment, the patient regained consciousness, with a return of the arterial pH to 7.42. Finally, cyanide intoxication was diagnosed based on the detection of a serum cyanide level of 3.5 mg/L. The presence of a high anion gap associated with severe lactic acidosis is a clue for making a rapid differential diagnosis of acute cyanide intoxication. Providing intensive and immediate supportive management is also crucial, even in cases without obtainable specific antidotes. PMID- 26234234 TI - Lung Carcinosarcoma Masked by Tracheobronchial Aspergillosis. AB - Tracheobronchial aspergillosis is a form of invasive aspergillosis limited to the airways. Its presence usually indicates an immunocompromised status or local dysfunction of airway immunity. We herein report a case of lung carcinosarcoma masked by tracheobronchial aspergillosis and discuss the clinical manifestations, diagnostic procedures and treatment of such cases. Tracheobronchial aspergillosis may also mask endobronchial carcinoma, leading to difficulties in determining the diagnosis and selecting subsequent treatment. Bronchoscopy is crucial for obtaining a definitive diagnosis and confirming the treatment. In particular, the combination of intravenous antifungal drug administration, localized antifungal application and interventional bronchoscopy is effective. Nevertheless, clinicians should always investigate the underlying disease carefully, including the potential occurrence of lung malignancy. PMID- 26234235 TI - Mediastinal Seminoma with an Elevated Level of Serum Angiotensin-converting Enzyme. AB - A 22-year-old man was admitted following the detection of right hilar enlargement during a medical checkup. The patient's serum angiotensin-converting enzyme (ACE) level was abnormally high, and a needle aspiration biopsy showed non-caseating epithelioid cell granulomas. Surgical resection was performed, and the resected specimens showed irregularly shaped seminoma nests with intervening stroma consisting of epithelioid cell granulomas. Furthermore, immunohistochemistry demonstrated ACE expression in the epithelioid cells and some tumor cells. The patient's serum ACE level declined after the surgery and subsequent systemic chemotherapy, indicating the presence of tumor-induced sarcoid-like reactions rather than the coexistence of seminoma and sarcoidosis. PMID- 26234236 TI - Post-irradiation Skin Changes Associated with Lumbosacral Radiculopathy. AB - We herein describe the cases of two patients with post-irradiation lumbosacral radiculopathy. The patients underwent postoperative radiation therapy to the abdomen due to testicular neoplasms 20 and 25 years prior to the onset of weakness, respectively. On physical examinations, asymmetric lower limb weakness and areflexia without apparent sensory loss were observed in both patients. Interestingly, artificial and squared atrophy of the skin and subcutaneous tissue, thought to correspond to the radiation fields, were observed in the lower back, and electromyography revealed selective motor axon loss localized to the lower extremities. The detection of skin changes in the area being irradiated is a valuable clue for diagnosing post-irradiation lumbosacral radiculopathy. PMID- 26234237 TI - Parasympathetic Dominant Autonomic Dysfunction in Charcot-Marie-Tooth Disease Type 2J with the MPZ Thr124Met Mutation. AB - We herein report the case of a 69-year-old woman with Charcot-Marie-Tooth Disease type 2J (CMT2J) who presented with Adie's pupil, deafness, and urinary disturbance in addition to motor symptoms. On autonomic investigation, the coefficient of variation of the R-R intervals was decreased, and a urodynamic analysis showed a hypotonic bladder. A heart rate variability analysis revealed a decreased high frequency component and low frequency/high frequency ratio. Orthostatic hypotension was not present, and the sympathetic skin response and cardiac scintigraphy using (123)I-metaiodobenzylguanidine were normal. A gene analysis showed a known heterozygous mutation associated with CMT2J in myelin protein zero exon 3, resulting in the substitution of threonine to methionine at position 124. Our case suggests that mainly the parasympathetic autonomic function is disturbed in CMT2J. PMID- 26234238 TI - Idiopathic Hypertrophic Spinal Pachymeningitis. AB - A 63-year-old man revealed a four-month history of muscle weakness of the lower limbs, hypoesthesia of the L5 and S1 area and ischuria. On MRI, the spinal cord was compressed by an encircled mass, which showed hypointensity on T1- and T2 weighted images with gadolinium enhancement at the Th11 to Th12 vertebra. Because of the rapid progression of myelopathy, posterior decompression was performed and idiopathic hypertrophic spinal pachymeningitis (HSP) was finally diagnosed. The patient's neurological signs markedly improved with postoperative corticosteroid treatment. Idiopathic HSP is a clinical emergency and early surgical intervention is essential to prevent irreversible damage to the nervous system. PMID- 26234239 TI - An Atypical Case of Anti-NMDA Receptor Encephalitis: Predominant Parkinsonism and Persisting Micrographia without Oro-facial Dyskinesia. AB - We describe the case of a 46-year-old man with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis with prominent parkinsonism. The patient presented with psychiatric symptoms followed by epileptic seizure and parkinsonism including micrographia. Magnetic resonance imaging (MRI) revealed lesions in the bilateral medial temporal lobes and basal ganglia on fluid-attenuated inversion recovery images. His symptoms and MRI findings were ameliorated by immunotherapy but then relapsed. After retreatment, his parkinsonism gradually improved except for the micrographia. This is an atypical case of anti-NMDAR encephalitis in that the patient showed prominent and refractory parkinsonism, thus indicating that the clinical diversity of anti-NMDAR encephalitis is greater than expected. PMID- 26234240 TI - Observation of Angiolymphoid Hyperplasia with Eosinophilia (ALHE) at Three Arterial Sites and Its Association with Membranous Nephropathy. AB - We herein report a case involving the systemic presentation of angiolymphoid hyperplasia with eosinophilia (ALHE) in association with membranous nephropathy (MN). A 34-year-old Japanese man presented with leg edema and bilateral temporal nodules. He had a history of Buerger's disease and recurrent coronary stenosis. A renal biopsy performed to assess nephrotic syndrome revealed MN. Furthermore, a temporal nodule was excised, and ALHE was diagnosed. We reevaluated the coronary and posterior tibial artery specimens obtained in his twenties and presumed that these lesions were also vascular tumors arising from ALHE. The association of ALHE and MN is quite rare. PMID- 26234241 TI - Iris Metastasis of Esophageal Cancer. PMID- 26234242 TI - Endoscopic Findings of Ischemic Enteritis. PMID- 26234243 TI - Simultaneously Acquired Myocardial Perfusion, Metabolism and Function after ACS. PMID- 26234244 TI - Ultra-Rapid and Massive Thrombus Formation in Cardiac Chambers. PMID- 26234245 TI - A Long-term, Uneventful Case of Bilateral Lucite-ball Plombage. PMID- 26234246 TI - Nodular Cytomegalovirus Pneumonia. PMID- 26234247 TI - Peripheral Sympathetic Nerve Dysfunction in Adolescent Japanese Girls Following Immunization with the Human Papillomavirus Vaccine. PMID- 26234248 TI - Peripheral Sympathetic Nerve Dysfunction in Adolescent Japanese Girls Following Immunization with the Human Papillomavirus Vaccine. PMID- 26234250 TI - SnO2(beta-Bi2O3)/Bi2Sn2O7 nanohybrids doped with Pt and Pd nanoparticles: applications in visible light photocatalysis, electrical conductivity and dye sensitized solar cells. AB - Bi2O3-SnO2 nanocomposites formed at a nominal molar ratio of 3 : 1 and loaded with Pd/Pt nanoparticles synthesized by a sol gel-hydrothermal method with the aid of a template were thoroughly characterized by X-ray diffraction, TEM-EDX, N2 sorptiometry, diffuse reflectance UV-Vis, FTIR, photoluminescence and electrical conductivity. It has been shown that Pd and Pt stimulate the existence of beta Bi2O3 and SnO2, respectively together with the key component Bi2Sn2O7. The photocatalytic results indicate that Pd/beta-Bi2O3-Bi2Sn2O7 revealed a remarkable performance for the degradation of methylene blue (MB) dye as compared to the Pt/SnO2-Bi2Sn2O7 and Bi2O3-SnO2 samples in both the UV and visible regions. The enhanced photocatalytic activity of the Pd/beta-Bi2O3-Bi2Sn2O7 nanocomposite is primarily attributed to the broad contact between the beta-Bi2O3 and Bi2Sn2O7 phases, which indicates high mesoporosity and heterojunction structures resulting in separation efficacy between photo-induced electron-hole pairs. Specifically, the photosensitive beta-Bi2O3 is easily excited and released electrons to be accepted by Bi2Sn2O7 and Pd that might be deposited in the interlayer between beta-Bi2O3 and Bi2Sn2O7. The degradation mechanism of MB over Pd/beta-Bi2O3 Bi2Sn2O7 in the visible region showed that the dye degradation proceeds through evolution of O2(-) and OH radicals as evaluated using photoluminescence and free radical trapping experiments. An insight into the electrical properties including the dielectric constant and impedance of the materials indicates that Pd/beta Bi2O3-Bi2Sn2O7 has the highest conductivity based on increasing the ionic transport and defects at the beta-Bi2O3/Bi2Sn2O7 heterojunction. This material displayed an improved photocurrent response of a higher power conversion efficiency, exceeding that of Pt/SnO2-Bi2Sn2O7 and SnBi3 by 50% and 250%, respectively, in dye-sensitized solar cells. Picosecond-resolved photoluminescence (PL) and polarization gated PL anisotropy measurements were combined to clarify the process of FRET from the excited Pd/beta-Bi2O3-Bi2Sn2O7 to SD N719. This indicates that the latter structure can be proposed as a multifunctional candidate for use in dye-sensitized solar cells, as an electrical material and as an efficient photocatalyst based on its versatile structure. PMID- 26234249 TI - Graphene-like two-dimensional layered nanomaterials: applications in biosensors and nanomedicine. AB - The development of nanotechnology provides promising opportunities for various important applications. The recent discovery of atomically-thick two-dimensional (2D) nanomaterials can offer manifold perspectives to construct versatile devices with high-performance to satisfy multiple requirements. Many studies directed at graphene have stimulated renewed interest on graphene-like 2D layered nanomaterials (GLNs). GLNs including boron nitride nanosheets, graphitic-carbon nitride nanosheets and transition metal dichalcogenides (e.g. MoS2 and WS2) have attracted significant interest in numerous research fields from physics and chemistry to biology and engineering, which has led to numerous interdisciplinary advances in nano science. Benefiting from the unique physical and chemical properties (e.g. strong mechanical strength, high surface area, unparalleled thermal conductivity, remarkable biocompatibility and ease of functionalization), these 2D layered nanomaterials have shown great potential in biochemistry and biomedicine. This review summarizes recent advances of GLNs in applications of biosensors and nanomedicine, including electrochemical biosensors, optical biosensors, bioimaging, drug delivery and cancer therapy. Current challenges and future perspectives in these rapidly developing areas are also outlined. It is expected that they will have great practical foundation in biomedical applications with future efforts. PMID- 26234251 TI - Palladium(II)-catalyzed allylic C-H oxidation of hindered substrates featuring tunable selectivity over extent of oxidation. AB - The use of Oxone and a palladium(II) catalyst enables the efficient allylic C?H oxidation of sterically hindered alpha-quaternary lactams which are unreactive under known conditions for similar transformations. This simple, safe, and effective system for C?H activation allows for unusual tunable selectivity between a two-electron oxidation to the allylic acetates and a four-electron oxidation to the corresponding enals, with the dominant product depending on the presence or absence of water. The versatile synthetic utility of both the allylic acetate and enal products accessible through this methodology is also demonstrated. PMID- 26234253 TI - Supplemental use of an interferon-gamma release assay in a state-wide tuberculosis contact tracing program in Victoria: a six-year review. AB - INTRODUCTION: Tuberculin skin testing (TST) has been the accepted Australian standard for investigating contacts following exposure to infectious tuberculosis (TB). In recent years, the availability of the interferon-gamma release assays (IGRA) has introduced a potential alternative test but data on its use in this context are limited. METHODS: A prospective longitudinal cohort study was conducted from 2008-2013 to review the use of IGRA and subsequent TB disease following testing in a state-wide contact tracing program. Additional information on the experience and acceptability of IGRA in this context was also obtained through program staff surveys following implementation. RESULTS: IGRA testing was performed on 643 contacts, with a mean follow-up of 3.7 years. IGRA was primarily used to supplement TST, most commonly due to borderline TST reactivity in individuals who had bacille Calmette-Guerin vaccination. Where both TST and IGRA were performed, correlation of test results was poor (kappa=0.35). The negative predictive value for later development of active TB was 99.5%. CONCLUSIONS: Our experience suggests that IGRA are able to be incorporated safely and effectively as a supplement to TST-based contact tracing. PMID- 26234255 TI - Legionella pneumophila: probable transmission from a contaminated respiratory device. PMID- 26234254 TI - Interim estimates of male human papillomavirus vaccination coverage in the school based program in Australia. PMID- 26234256 TI - Influenza outbreak preparedness: lessons from outbreaks in residential care facilities in 2014. AB - This report describes 6 influenza outbreaks in residential care facilities during the 2014 influenza season in the Sydney Local Health District. Vaccination rates were high among residents (95%) and low among staff (39%). The majority of residents with laboratory confirmed influenza (67%) did not meet the influenza like illness case definition.Positive influenza specimens were subtyped as H3N2 (40%), H1N1 (5%) or not subtyped (55%). We illustrate the implications of low vaccine effectiveness and antigenic drift, and provide recommendations for the effective management of future influenza outbreaks. PMID- 26234252 TI - From sauropsids to mammals and back: New approaches to comparative cortical development. AB - Evolution of the mammalian neocortex (isocortex) has been a persisting problem in neurobiology. While recent studies have attempted to understand the evolutionary expansion of the human neocortex from rodents, similar approaches have been used to study the changes between reptiles, birds, and mammals. We review here findings from the past decades on the development, organization, and gene expression patterns in various extant species. This review aims to compare cortical cell numbers and neuronal cell types to the elaboration of progenitor populations and their proliferation in these species. Several progenitors, such as the ventricular radial glia, the subventricular intermediate progenitors, and the subventricular (outer) radial glia, have been identified but the contribution of each to cortical layers and cell types through specific lineages, their possible roles in determining brain size or cortical folding, are not yet understood. Across species, larger, more diverse progenitors relate to cortical size and cell diversity. The challenge is to relate the radial and tangential expansion of the neocortex to the changes in the proliferative compartments during mammalian evolution and with the changes in gene expression and lineages evident in various sectors of the developing brain. We also review the use of recent lineage tracing and transcriptomic approaches to revisit theories and to provide novel understanding of molecular processes involved in specification of cortical regions. PMID- 26234257 TI - Australian National Enterovirus Reference Laboratory annual report, 2013. AB - Australia conducts surveillance for cases of acute flaccid paralysis (AFP) in children less than 15 years of age as the main method to monitor its polio-free status in accordance with the World Health Organization (WHO) recommendations. Cases of AFP in children are notified to the Australian Paediatric Surveillance Unit or the Paediatric Active Enhanced Disease Surveillance System and faecal specimens are referred for virological investigation to the National Enterovirus Reference Laboratory. In 2013, no cases of poliomyelitis were reported from clinical surveillance and Australia reported 1.4 non-polio AFP cases per 100,000 children, meeting the WHO performance criterion for a sensitive surveillance system. Non-polio enteroviruses can also be associated with AFP and enterovirus A71 was identified from nine of the 61 cases classified as non-polio AFP in 2013, which was part of a larger outbreak associated with this virus. A Sabin poliovirus was detected in an infant recently returned from Pakistan and who had been vaccinated while abroad. Globally, 416 cases of polio were reported in 2013, with the 3 endemic countries: Afghanistan; Nigeria; and Pakistan, accounting for 38% of the cases. To safeguard the progress made towards polio eradication, in May 2014, WHO recommended travellers from the 10 countries that are currently reporting wild poliovirus transmission have documented evidence of recent polio vaccination before departure. PMID- 26234259 TI - Monitoring the incidence and causes of diseases potentially transmitted by food in Australia: Annual report of the OzFoodNet network, 2011. AB - This report summarises the incidence of diseases potentially transmitted by food in Australia and details outbreaks associated with food in 2011. OzFoodNet sites reported 30,957 notifications of 9 diseases or conditions that may be transmitted by food. The most commonly notified infections were Campylobacter (17,733 notifications) followed by Salmonella (12,271 notifications). The most frequently notified Salmonella serotype was Salmonella Typhimurium, accounting for 48% of all Salmonella notifications. OzFoodNet sites also reported 1,719 outbreaks of gastrointestinal illness affecting 29,839 people and resulting in 872 people being hospitalised and 103 associated deaths. The majority of outbreaks (79% 1,352/1,719) were due to person-to-person transmission, 9% (151/1,719) were suspected or confirmed to be foodborne, 11% (192/1,719) were due to an unknown mode of transmission, 19 were due to community based Salmonella clusters, four were due to waterborne or suspected waterborne transmission and 1 outbreak was due to animal-to-person transmission. Foodborne and suspected foodborne outbreaks affected 2,104 persons and included 231 hospitalisations. There were 5 deaths reported during these outbreaks. Salmonella was the most common aetiological agent identified in foodborne outbreaks and restaurants were the most frequently reported food preparation setting. A single food source of infection was identified for 49 outbreaks, 26 of which were associated with the consumption of dishes containing raw or minimally cooked eggs and all of these outbreaks were due to S. Typhimurium. These data assist agencies to document sources of foodborne disease, develop food safety policies, and prevent foodborne illness. PMID- 26234258 TI - Tuberculosis notifications in Australia, 2012 and 2013. AB - The National Notifiable Diseases Surveillance System received 1,317 tuberculosis (TB) notifications in 2012 and 1,263 notifications in 2013. This represents a rate of 5.8 per 100,000 population in 2012 and 5.5 per 100,000 population in 2013 and a reversal of the upward trend in TB incidence reported since 2007. In 2012 and 2013, Australia's overseas-born population continued to represent the majority of TB notifications with an incidence rate of 19.5 per 100,000 and 18.4 per 100,000 respectively. The incidence of TB in the Australian-born Indigenous population has fluctuated over the last decade; however, it remained reasonably steady in 2012 and 2013 with an incidence rate of 4.5 per 100,000 and 4.6 per 100,000 respectively. The incidence of TB in the Australian-born non-Indigenous population has continued to remain low at 0.7 per 100,000 in 2012 and 0.8 per 100,000 in 2013. Australia continued to record only a small number of multi-drug resistant TB cases nationally (2012: n=20; 2013: n=22) of which nearly all were identified in the overseas-born population. This report demonstrates excellent and sustained control of TB in Australia and reflects Australia's commitment to reducing the global burden of TB. PMID- 26234260 TI - Invasive pneumococcal disease in Australia, 2009 and 2010. AB - Enhanced surveillance for invasive pneumococcal disease (IPD) was conducted in all Australian states and territories in 2009 and 2010 with comprehensive comparative data available since 2002. There were 1,556 cases of IPD notified to the National Notifiable Diseases Surveillance System in Australia in 2009, a notification rate of 7.2 cases per 100,000 population. In 2010 there were 1,640 cases, a notification rate of 7.4 cases per 100,000. The overall rate of IPD in Indigenous Australians was almost 6 times the rate in non-Indigenous Australians in both 2009 and 2010. In 2009 and 2010, notification rates of IPD caused by serotypes included in the 7-valent pneumococcal conjugate vaccine (7vPCV) continued to decrease across all age groups. Rates of IPD caused by non-7vPCV serotypes continued to show an increasing trend in both Indigenous and non Indigenous children aged less than 5 years. In Indigenous adults (>=50 years), rates of IPD caused by both 23-valent pneumococcal polysaccharide vaccine (23vPPV) serotypes and non-23vPPV serotypes continued to show an overall increase, particularly in 2010. There were 110 deaths attributed to IPD in 2009 and 137 in 2010, although it should be noted that deaths may be under-reported. The number of invasive pneumococcal isolates with reduced penicillin susceptibility remained low and reduced susceptibility to third generation cephalosporins was rare. PMID- 26234261 TI - OzFoodNet quarterly report, 1 July to 30 September 2013. PMID- 26234262 TI - National Notifiable Diseases Surveillance System, 1 January to 31 March 2015. PMID- 26234263 TI - Australian childhood immunisation coverage, 1 July to 30 September cohort, assessed as at December 2014. PMID- 26234264 TI - Australian Gonococcal Surveillance Programme, 1 July to 30 September 2014. PMID- 26234265 TI - Australian Gonococcal Surveillance Programme, 1 January to 31 March 2015. PMID- 26234266 TI - Australian Meningococcal Surveillance Programme quarterly report, 1 January to 31 March 2015. PMID- 26234267 TI - Australian Sentinel Practices Research Network, 1 January to 31 March 2015. PMID- 26234268 TI - Invasive pneumococcal disease surveillance Australia, 1 October to 31 December 2014. PMID- 26234270 TI - New surveillance case definition: Highly pathogenic avian influenza. PMID- 26234269 TI - Invasive pneumococcal disease surveillance Australia, 1 January to 31 March 2015. PMID- 26234271 TI - Revised surveillance case definitions. PMID- 26234272 TI - Multiple origins of Heliozoa from flagellate ancestors: New cryptist subphylum Corbihelia, superclass Corbistoma, and monophyly of Haptista, Cryptista, Hacrobia and Chromista. AB - Heliozoan protists have radiating cell projections (axopodia) supported by microtubular axonemes nucleated by the centrosome and bearing granule-like extrusomes for catching prey. To clarify previously confused heliozoan phylogeny we sequenced partial transcriptomes of two tiny naked heliozoa, the endohelean Microheliella maris and centrohelid Oxnerella marina, and the cercozoan pseudoheliozoan Minimassisteria diva. Phylogenetic analysis of 187 genes confirms that all are chromists; but centrohelids (microtubules arranged as hexagons and triangles) are not sisters to Endohelea having axonemes in transnuclear cytoplasmic channels (triangular or square microtubular arrays). Centrohelids are strongly sister to haptophytes (together phylum Haptista); we explain the common origins of their axopodia and haptonema. Microheliella is sister to new superclass Corbistoma (zooflagellate Telonemea and Picomonadea, with asymmetric microfilamentous pharyngeal basket), showing that these axopodial protists evolved independently from zooflagellate ancestors. We group Corbistoma and Endohelea as new cryptist subphylum Corbihelia with dense fibrillar interorganellar connections; endohelean axopodia and Telonema cortex are ultrastructurally related. Differently sampled trees clarify why corticate multigene eukaryote phylogeny is problematic: long-branch artefacts probably distort deep multigene phylogeny of corticates (Plantae, Chromista); basal radiations may be contradictorily reconstructed because of their extreme closeness and the Bayesian star-tree paradox. Haptista and Hacrobia are holophyletic, and Chromista probably are. PMID- 26234273 TI - Molecular phylogenetics and historical biogeography amid shifting continents in the cockles and giant clams (Bivalvia: Cardiidae). AB - Reconstructing historical biogeography of the marine realm is complicated by indistinct barriers and, over deeper time scales, a dynamic landscape shaped by plate tectonics. Here we present the most extensive examination of model-based historical biogeography among marine invertebrates to date. We conducted the largest phylogenetic and molecular clock analyses to date for the bivalve family Cardiidae (cockles and giant clams) with three unlinked loci for 110 species representing 37 of the 50 genera. Ancestral ranges were reconstructed using the dispersal-extinction-cladogenesis (DEC) method with a time-stratified paleogeographic model wherein dispersal rates varied with shifting tectonics. Results were compared to previous classifications and the extensive paleontological record. Six of the eight prior subfamily groupings were found to be para- or polyphyletic. Cardiidae originated and subsequently diversified in the tropical Indo-Pacific starting in the Late Triassic. Eastern Atlantic species were mainly derived from the tropical Indo-Mediterranean region via the Tethys Sea. In contrast, the western Atlantic fauna was derived from Indo-Pacific clades. Our phylogenetic results demonstrated greater concordance with geography than did previous phylogenies based on morphology. Time-stratifying the DEC reconstruction improved the fit and was highly consistent with paleo-ocean currents and paleogeography. Lastly, combining molecular phylogenetics with a rich and well-documented fossil record allowed us to test the accuracy and precision of biogeographic range reconstructions. PMID- 26234274 TI - Molecular phylogenetics and biogeography of the Neotropical skink genus Mabuya Fitzinger (Squamata: Scincidae) with emphasis on Colombian populations. AB - Understanding the phylogenetic and geographical history of Neotropical lineages requires having adequate geographic and taxonomic sampling across the region. However, Colombia has remained a geographical gap in many studies of Neotropical diversity. Here we present a study of Neotropical skinks of the genus Mabuya, reptiles that are difficult to identify or delimit due to their conservative morphology. The goal of the present study is to propose phylogenetic and biogeographic hypotheses of Mabuya including samples from the previously under studied territory of Colombia, and address relevant biogeographic and taxonomic issues. We combined molecular and morphological data sampled densely by us within Colombia with published data representing broad sampling across the Neotropical realm, including DNA sequence data from two mitochondrial (12S rRNA and cytochrome b) and three nuclear genes (Rag2, NGFB and R35). To evaluate species boundaries we employed a general mixed Yule-coalescent (GMYC) model applied to the mitochondrial data set. Our results suggest that the diversity of Mabuya within Colombia is higher than previously recognized, and includes lineages from Central America and from eastern and southern South America. The genus appears to have originated in eastern South America in the Early Miocene, with subsequent expansions into Central America and the Caribbean in the Late Miocene, including at least six oceanic dispersal events to Caribbean Islands. We identified at least four new candidate species for Colombia and two species that were not previously reported in Colombia. The populations of northeastern Colombia can be assigned to M. zuliae, while specimens from Orinoquia and the eastern foothills of the Cordillera Oriental of Colombia correspond to M. altamazonica. The validity of seven species of Mabuya sensu lato was not supported due to a combination of three factors: (1) non-monophyly, (2) <75% likelihood bootstrap support and <0.95 Bayesian posterior probability, and (3) GMYC analysis collapsing named species. Finally, we suggest that Mabuya sensu stricto may be regarded as a diverse monophyletic genus, widely distributed throughout the Neotropics. PMID- 26234275 TI - The next frontier: Fostering innovation by improving health data access and utilization. PMID- 26234276 TI - Botulinum toxin A for treating spasticity in adults: costly for French hospitals? AB - INTRODUCTION: Intramuscular injection of botulinum toxin (BoNTA) is one of the primary treatments for focal spasticity. This treatment is considered costly and the level of reimbursement by health insurance has been decreasing in many countries for several years. The aim of this study was to determine the real cost of treating spasticity with BoNTA and to compare this with the level of reimbursement by the national health insurance in France in 2008 and with a new fee, specific to the injection of BoNTA in ambulatory services. METHOD: A single center, retrospective study using the 2008 database from a French secondary-care day-hospital unit (treating spasticity in adults with sequelae of stroke, multiple sclerosis or traumatic brain injuries). The level of reimbursement by the French ministry of health for BoNTA treatment for adults with spasticity constituted the "calculated cost" and corresponded to the hospital's "budget". The "real cost" (incurred by the hospital) included the sum of staffing and material costs as well as the number of toxin vials used. The calculated costs for 2009 and 2013 were based on the levels of reimbursement during those years. The difference between real and calculated cost for 2009 and 2013 was estimated considering that the real cost of 2008 was stable. RESULTS: In 2008, 364 patients received BoNTA, resulting in 870 day-hospital admissions. The calculated cost was 459,056?/year and the real cost was 567,438?/year (equivalent to 4.27?/day/patient). The total budget deficit (hospital income minus hospital costs) was 108,383?. The deficit was estimated at 222,892? in 2009 and 241,188? in 2013. CONCLUSION: The daily cost of BoNTA treatment for spasticity is reasonable; however, because of the level of reimbursement by the national health insurance in France, the treatment is costly for French hospitals. PMID- 26234277 TI - The cough reflex is upregulated by lisinopril microinjected into the caudal nucleus tractus solitarii of the rabbit. AB - We have previously shown that cough potentiation induced by intravenous administration of the AT1 receptor antagonist losartan is lower than that induced by the ACE inhibitor lisinopril in anesthetized and awake rabbits. Since losartan and lisinopril cross the blood-brain barrier, their central action on the cough reflex can be hypothesized. Mechanical stimulation of the tracheobronchial tree and citric acid inhalation were used to induce cough reflex responses in pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bilateral microinjections (30-50 nl) of losartan (5mM), lisinopril (1mM), bradykinin (0.05 mM), HOE-140 (0.2mM, a bradykinin B2 receptor antagonist) and CP-99,994 (1mM, an NK1 receptor antagonist) were performed into the caudal nucleus tractus solitarii, the predominant site of termination of cough-related afferents. Lisinopril, but not losartan increased the cough number. This effect was reverted by HOE-140 or CP-99,994. Cough potentiation was also induced by bradykinin. The results support for the first time a central protussive action of lisinopril mediated by an accumulation of bradykinin and substance P. PMID- 26234279 TI - Prevalence of Gout in the Adult Population of France. AB - OBJECTIVE: To estimate adult gout prevalence in France. METHODS: We used a previously established phone questionnaire that allowed for classifying patients as gouty or nongouty by 2 logistic regression models and 1 classification and regression tree (CART) model, the sensitivity and specificity of which were all more than 80%. The full questionnaire was administered by phone to subjects who acknowledged present or past nontraumatic acute pain in a peripheral joint, the others being classified as nongouty. A random sample of adults residing in France was derived from the national telephone directory (home and mobile) by the quota method and further redressed to match the French population. The target size for the interview survey conducted in March and June 2013 was 10,000 participants. RESULTS: We interviewed 10,026 participants. All 3 models (2 logistic regression models and a CART model) converged to an estimated gout prevalence of 0.9%. This prevalence was lower than that estimated by self-reporting only (3.7% [95% confidence interval 3.3-4.1]). The prevalence was higher for men than women and increased with age but did not differ by area of France. CONCLUSION: Gout prevalence in the adult population of France in 2013 was estimated at 0.9%. Studies using self-reporting only might overestimate the prevalence. PMID- 26234280 TI - Comparison of upright balance in stroke, Parkinson and multiple sclerosis. AB - OBJECTIVE: Multiple sclerosis (MS), Parkinson's disease (PD) and stroke (ST) subjects show balance impairments due to damage of the balance control system. The objective of the study was to assess the impact of MS, PD and ST on upright posture in eyes open condition and when visual and/or proprioceptive inputs are altered. MATERIALS AND METHODS: A total of 188 subjects with MS (n = 80), PD (n = 58) and ST (n = 50), mean age (SD), 57.9 (14.6) years, and 32 healthy subjects (HS) aged 53.7 (15.7) years were assessed by a stabilometric platform in a cross sectional study. RESULTS: Compared to HS, MS showed large deviations from normal performances with respect to magnitude (P < 0.001) and regularity (P < 0.05) of body sway irrespective of the altered sensory information. Similarly to MS, PD showed large and abnormal levels of body sway (P < 0.001) and postural tremor (P < 0.05), while ST was the least impaired except for an asymmetrical distribution of body weight between legs (P < 0.001). Finally, the MS group compared to PD and ST showed the largest body instability after eye closure (P < 0.05) and when visual and proprioceptive inputs were removed (P < 0.05). PD showed instability mainly after the alteration of proprioceptive inputs (P < 0.05), while ST showed the smallest increase of body instability when sensory inputs were reduced. DISCUSSION: Objective assessment revealed pathology-specific balance disorders and showed the differential impact of MS, PD and ST on the ability to use sensory information for balance control. PMID- 26234281 TI - Interaction of water with a benzimidazole derivative: fluorescence and colorimetric recognition of trace level water involving intra-molecular charge transfer process. AB - Benzimidazole-derived ICT-based probe, DFPBEN is developed for trace level determination of water. In presence of water, the naked eye color of DFPBEN changes from red to yellow, while it turns to green from red under UV light. Upon addition of water, DFPBEN shows a ratiometric absorbance change in methanol. PMID- 26234282 TI - Evaluation of a Weight-based Rabbit Anti-thymocyte Globulin Induction Dosing Regimen for Kidney Transplant Recipients. AB - STUDY OBJECTIVE: Although rabbit anti-thymocyte globulin (rATG) is commonly used as induction therapy for kidney transplantation, dosing is not standardized. Recently available findings suggest that even subtle differences in the cumulative dose of rATG induction may have an impact on acute rejection rates for patients receiving steroid-minimization maintenance immunosuppression. This investigation evaluated the potential consequences of rounding and capping rATG doses in patients receiving steroid-containing maintenance immunosuppression when calculating the dose based on actual body weight. DESIGN: Single-center retrospective cohort study. SETTING: A large academic medical center. PATIENTS: A total of 261 adult kidney transplant recipients between July 1, 2010, and December 31, 2012, who received rATG induction and were maintained on tacrolimus, mycophenolate, and prednisone. METHODS AND MEASUREMENTS: Incidences of biopsy confirmed acute rejection, opportunistic infections and hematologic effects within 12 months posttransplant were assessed for patients receiving a cumulative rATG dose of 5 mg/kg or higher (5.2 +/- 0.2 mg/kg, n=138) compared with those who received a cumulative rATG dose lower than 5 mg/kg (4.5 +/- 0.6 mg/kg, n=123). The groups had similar baseline characteristics, immunologic risk, and indications for rATG induction. The incidence of clinically relevant biopsy confirmed acute rejection was low and similar between the groups (8.7% for rATG of 5 mg/kg or higher vs 8.9% for rATG lower than 5 mg/kg, p=0.944). Patient survival, all-cause graft survival, and graft function did not differ between the groups. Incidences of cytomegalovirus and BK virus infection as well as the extent and duration of lymphopenia were also similar between the groups. CONCLUSIONS: In combination with triple maintenance immunosuppression consisting of tacrolimus, mycophenolate, and prednisone, modest differences in the cumulative rATG dose were not associated with increased risk of acute rejection. Measures to optimize rATG utilization present opportunities for cost-saving without sacrificing efficacy in this patient population. PMID- 26234283 TI - Shape-controlled synthesis of mesoporous iron phosphate materials with crystallized frameworks. AB - Herein, we report the preparation of crystalline mesoporous iron phosphate (FePO4, hereafter abbreviated as FeP) materials with 2D-plates and 1D-rods in the presence of an amphiphilic block copolymer (F127), iron nitrate, and phosphoric acid. The dimensionality of mesoporous FeP can be switched by changing the polarity of the synthetic medium. PMID- 26234284 TI - Mesenchymal stromal cells improve cardiac function and left ventricular remodeling in a heart transplantation model. AB - BACKGROUND: Ischemia/reperfusion (I/R) injury is an inevitable consequence of organ transplantation and a major determinant of patient and graft survival in heart transplantation. Bone marrow-mesenchymal stromal cell (BM-MSC) treatment is a potentially effective cell therapy for cardiac disease. We investigated the effects of intravenous delivery of BM-MSCs in the acute phase post-transplant in a heterotopic heart transplantation (HHT) model associated with I/R injury. METHODS: Hearts of wild-type Lewis (WT LEW) rats were harvested and transplanted heterotopically into the necks of recipient WT LEW rats. Forty-eight hours after HHT, BM-MSCs were injected intravenously into animals in the experimental group, whereas controls received normal saline (NS). RESULTS: Eight days after BM-MSC injection, fractional shortening of transplanted hearts was significantly higher and left ventricular systolic diameter was lower in the BM-MSC group compared with controls, whereas no differences were found 28 days after infusion. A reduction in ventricular remodeling and cardiac fibrosis was observed by histochemical analysis and confirmed by cardiac magnetic resonance imaging in the BM-MSC group. The perivascular stromal cells' density and the number of capillaries were increased whereas the number of apoptotic cells decreased significantly in transplanted hearts in the BM-MSC group compared with the NS group. CONCLUSIONS: We showed early improvement in cardiac function and subsequent enhanced ventricular remodeling, reduced cardiac fibrosis, augmented neo-vascularization and decreased cardiomyocyte apoptosis of the transplanted heart in a heterotopic transplantation model after intravenous infusion of BM derived MSCs. Our data suggest that clinical studies with BM-MSCs are warranted to understand their effects on cardiac graft and transplant recipient survival. PMID- 26234295 TI - Rate of tuberculosis infection in children and adolescents with household contact with adults with active pulmonary tuberculosis as assessed by tuberculin skin test and interferon-gamma release assays. AB - Tuberculosis (TB) infection was evaluated in Brazilian immunocompetent children and adolescents exposed and unexposed (control group) to adults with active pulmonary TB. Both groups were analysed by clinical and radiological assessment, TST, QFT-IT and T-SPOT.TB. The three tests were repeated after 8 weeks in the TB exposed group if results were initially negative. Individuals with latent tuberculosis infection (LTBI) were treated and tests were repeated after treatment. Fifty-nine TB-exposed and 42 controls were evaluated. Rate of infection was 69.5% and 9.5% for the exposed and control groups, respectively. The exposed group infection rate was 61% assessed by TST, 57.6% by T-SPOT.TB, and 59.3%, by QFT-IT. No active TB was diagnosed. Agreement between the three tests was 83.1% and 92.8% in the exposed and control groups, respectively. In the exposed group, T-SPOT.TB added four TB diagnoses [16%, 95% confidence interval (CI) 1.6-30.4] and QFT-IT added three TB diagnoses (12%, 95% CI 0-24.7) in 25 individuals with negative tuberculin skin test (TST). Risk factors associated to TB infection were contact with an adult with active TB [0-60 days: odds ratio (OR) 6.9; >60 days: OR 27.0] and sleeping in the same room as an adult with active TB (OR 5.2). In Brazilian immunocompetent children and adolescents, TST had a similar performance to interferon-gamma release assays and detected a high rate of LTBI. PMID- 26234296 TI - Effect of increasing dietary calcium through supplements and dairy food on body weight and body composition: a meta-analysis of randomised controlled trials. AB - This meta-analysis of randomised controlled trials assessed the effect of Ca on body weight and body composition through supplementation or increasing dairy food intake. Forty-one studies met the inclusion criteria (including fifty-one trial arms; thirty-one with dairy foods (n 2091), twenty with Ca supplements (n 2711). Ca intake was approximately 900 mg/d higher in the supplement groups compared with control. In the dairy group, Ca intake was approximately 1300 mg/d. Ca supplementation did not significantly affect body weight (mean change ( - 0.17, 95% CI - 0.70, 0.37) kg) or body fat (mean change ( - 0.19, 95% CI - 0.51, 0.13) kg) compared to control. Similarly, increased dairy food intake did not affect body weight ( - 0.06, 95% CI - 0.54, 0.43) kg or body fat change ( - 0.36, 95% CI - 0.80, 0.09) kg compared to control. Sub-analyses revealed that dairy supplementation resulted in no change in body weight (nineteen studies, n 1010) ( - 0.32, 95% CI - 0.93, 0.30 kg, P= 0.31), but a greater reduction in body fat (thirteen studies, n 564) ( - 0.96, 95% CI - 1.46, - 0.46 kg, P < 0.001) in the presence of energy restriction over a mean of 4 months compared to control. Increasing dietary Ca intake by 900 mg/d as supplements or increasing dairy intake to approximately 3 servings daily (approximately 1300 mg of Ca/d) is not an effective weight reduction strategy in adults. There is, however, an indication that approximately 3 servings of dairy may facilitate fat loss on weight reduction diets in the short term. PMID- 26234285 TI - Neutrophil-lymphocyte and platelet-lymphocyte ratio as predictors of disease specific survival after resection of adrenocortical carcinoma. AB - BACKGROUND: The systemic inflammatory response may be associated with tumor progression. We sought to analyze the impact of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) on recurrence-free survival (RFS) and disease specific survival (DSS) among patients who underwent surgery for adrenocortical carcinoma (ACC). METHODS: Patients undergoing surgery for ACC were identified from a multi-center database. Cut-off values of 5 and 190 were defined as elevated NLR and PLR, respectively, and long-term outcome was assessed. RESULTS: Among 84 patients with ACC, 29 (34.%) had NLR > 5 while 32 (40.5%) had PLR > 190. NLR and PLR were associated with larger tumors (NLR > 5: <= 5 cm, 0% vs. >5 cm, 39.7%; PLR > 190: <= 5cm, 0% vs. >5 cm, 45.7%), as well as need to resect of other organs (NLR > 5: other organ resected 48.8% vs. not resected 20.9%; PLR > 190: other organ resected 25.0% vs. not resected 56.4%)(all P < 0.05). Five-year RFS was associated with an elevated NLR (NLR <= 5, 14.2% vs. NLR> 5, 10.5%) and PLR (PLR <= 190: 19.4% vs. PLR > 190: 5.2%) (both P < 0.05). On multivariate survival analyses, PLR remained a predictor of RFS (HR 1.72), while NLR was associated with both DSS (HR 2.21) and RFS (HR 1.99) (both P < 0.05). CONCLUSIONS: Immune markers such as NLR and PLR may be useful to stratify patients with regards to prognosis following surgery for ACC. PMID- 26234297 TI - Direct Carbonization of Cyanopyridinium Crystalline Dicationic Salts into Nitrogen-Enriched Ultra-Microporous Carbons toward Excellent CO2 Adsorption. AB - A family of nitrogen-enriched ultramicroporous carbon materials was prepared by direct carbonization of task-specifically designed molecular carbon precursors of cyanopyridinium-based crystalline dicationic salts (CISs). Varying the molecular structure of CISs, large surface area (918 m(2) g(-1)), high N content (20.10 wt %), and narrow distributed ultramicropores (0.59 nm) can be simultaneously achieved on the sample PCN-14 derived from methyl-linked 4-cyanopyridinium D[4 CNPyMe]Tf2N. It therefore exhibited exceptional performance in greenhouse gas CO2 capture, i.e., simultaneously possessing (1) high CO2 adsorption uptakes: 5.33 mmol g(-1) at 273 K, and 3.68 mmol g(-1) at 298 K (both at 1.0 bar); (2) unprecedented selectivity of CO2 versus N2: 156; and (3) a high adsorption ratio of CO2 to N2: 148 (at 1.0 bar). This is the first time such a high selectivity and adsorption ratio over carbon materials has been achieved, which is among the highest values over solid adsorbents. PMID- 26234298 TI - Lameness detection in dairy cattle: single predictor v. multivariate analysis of image-based posture processing and behaviour and performance sensing. AB - The objective of this study was to evaluate if a multi-sensor system (milk, activity, body posture) was a better classifier for lameness than the single sensor-based detection models. Between September 2013 and August 2014, 3629 cow observations were collected on a commercial dairy farm in Belgium. Human locomotion scoring was used as reference for the model development and evaluation. Cow behaviour and performance was measured with existing sensors that were already present at the farm. A prototype of three-dimensional-based video recording system was used to quantify automatically the back posture of a cow. For the single predictor comparisons, a receiver operating characteristics curve was made. For the multivariate detection models, logistic regression and generalized linear mixed models (GLMM) were developed. The best lameness classification model was obtained by the multi-sensor analysis (area under the receiver operating characteristics curve (AUC)=0.757+/-0.029), containing a combination of milk and milking variables, activity and gait and posture variables from videos. Second, the multivariate video-based system (AUC=0.732+/ 0.011) performed better than the multivariate milk sensors (AUC=0.604+/-0.026) and the multivariate behaviour sensors (AUC=0.633+/-0.018). The video-based system performed better than the combined behaviour and performance-based detection model (AUC=0.669+/-0.028), indicating that it is worthwhile to consider a video-based lameness detection system, regardless the presence of other existing sensors in the farm. The results suggest that Theta2, the feature variable for the back curvature around the hip joints, with an AUC of 0.719 is the best single predictor variable for lameness detection based on locomotion scoring. In general, this study showed that the video-based back posture monitoring system is outperforming the behaviour and performance sensing techniques for locomotion scoring-based lameness detection. A GLMM with seven specific variables (walking speed, back posture measurement, daytime activity, milk yield, lactation stage, milk peak flow rate and milk peak conductivity) is the best combination of variables for lameness classification. The accuracy on four-level lameness classification was 60.3%. The accuracy improved to 79.8% for binary lameness classification. The binary GLMM obtained a sensitivity of 68.5% and a specificity of 87.6%, which both exceed the sensitivity (52.1%+/-4.7%) and specificity (83.2%+/-2.3%) of the multi-sensor logistic regression model. This shows that the repeated measures analysis in the GLMM, taking into account the individual history of the animal, outperforms the classification when thresholds based on herd level (a statistical population) are used. PMID- 26234299 TI - A mathematical model of heat flow in a thermopile for measuring muscle heat production: implications for design and signal analysis. AB - Contracting muscles produce heat which largely arises from the biochemical reactions that provide the energy for contraction. Measurements of muscle heat production have made, and continue to make, important contributions to our understanding of the bases of contraction. Most measurements of muscle heat production are made using a thermopile, consisting of a series of thermocouples arranged so that alternate thermocouples are in thermal contact with the muscle and with an isothermal reference. In this study, a mathematical model was constructed of a muscle lying on a thermopile consisting of antimony-bismuth thermocouples sandwiched between polymer sheets. The validity of the model was demonstrated by its ability to accurately predict thermopile outputs in response to applying heat to the thermopile surface, to generating heat in the thermocouples using the Peltier effect and to adding heat capacity on the thermopile surface. The model was then used to show how practical changes to thermopile construction could minimise response time and thermopile heat capacity and allow measurement of very low rates of heat production. The impulse response of a muscle-thermopile system was generated using the model and used to illustrate how a measured signal can be deconvolved with the impulse response to correct for lag introduced by the thermopile. PMID- 26234300 TI - Optically bright p-excitons indicating strong Coulomb coupling in transition metal dichalcogenides. AB - It is shown that the strong Coulomb coupling in intrinsic suspended semiconducting transition metal dichalcogenides can exceed the critical value needed for an excitonic ground state. The dipole-allowed optical excitations then correspond to intra-excitonic transitions such that the optically bright excitonic transitions near the Dirac points have a p-like symmetry, whereas the s like states are dipole forbidden. The large intrinsic coupling strength seems to be a generic property of the semiconducting transition metal dichalcogenides and strong Coulomb-coupling signatures in the form of the optical selection rules can be observed even in samples grown on typical substrates like SiO2. For the examples of WS2 and WSe2, excellent agreement of the computed excitonic resonance energies with recent experiments is demonstrated. PMID- 26234301 TI - Stability of Aluminum-Doped Copper Cluster Cations and Their Reactivity toward NO and O2. AB - Aluminum-doped copper cluster cations, CunAl(+), were produced via an ion sputtering method and analyzed by mass spectrometry. The measured size distributions show that Cu6Al(+) and Cu18Al(+) are highly stable species, which can be understood in terms of the electronic subshell 1P and 2S closings, respectively. Furthermore, the reactions of size-selected CunAl(+) (n = 4-6 and 8 16) with NO and O2 were studied at near thermal energies by using a tandem-type mass spectrometer. The doping of an Al atom improves the reactivity of the clusters toward NO in particular for n = 9, 11, 13, and 15, whereas it does not change the reactivity toward O2 significantly. Consequently, it was found that CunAl(+) (n = 9, 11, 13 and 15) are more reactive toward NO than toward O2. The high reactivity of Cu9Al(+) toward NO compared to that of Cu10(+) is explained in terms of the increase of the adsorption energy and the lowering of the barrier to dissociative adsorption, with the aid of calculations based on density functional theory. Moreover, the multiple-collision reactions of CunAl(+) (n = 9, 11, and 13) with NO result in the production of cluster dioxides, Cun-3AlO2(+), (i.e., release of N2), which clearly indicates that NO decomposition proceeds on these clusters. PMID- 26234304 TI - Blood Pressure, Heart Rate Variability, and Renal Function in Nonsmoker and Smoker Hypertensive Patients. PMID- 26234303 TI - Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer. AB - In response to the rapid and wide acceptance and use of endoscopic treatments for early gastric cancer, the Japan Gastroenterological Endoscopy Society (JGES), in collaboration with the Japanese Gastric Cancer Association (JGCA), has produced 'Guidelines for ESD and EMR for Early Gastric Cancer', as a set of basic guidelines in accordance with the principles of evidence-based medicine. These Guidelines cover the present state of knowledge and are divided into the following seven categories: Indications, Preoperative diagnosis, Techniques, Evaluation of curability, Complications, Long-term postoperative surveillance, and Histology. Twenty-three statements were finally accepted as guidelines, and the majority of these were obtained from descriptive studies with lower evidence levels. A number of statements had to be created by consensus (the lowest evidence level), as evidence levels remain low for many specific areas in this field. PMID- 26234305 TI - Tricuspid Regurgitation Following Implantation of Endocardial Leads: Incidence and Predictors. AB - BACKGROUND: Endocardial leads, permanent pacemaker (PPM), or implantable cardioverter defibrillator (ICD) placed across the tricuspid valve can lead to tricuspid regurgitation (TR). The reported incidence of this complication has varied widely. There are limited data predicting which patients will develop this complication. This study sought to describe the incidence of worsening TR post PPM or ICD and to identify patient-specific predictors of increased TR following lead placement. METHODS: Patients (N = 382) who received a PPM or ICD from January 1, 2006 to December 31, 2010 and had echocardiograms both within 365 days prior to and up to 1,200 days after device placement were studied. TR was assessed on a 6-point scale (none/trace, mild, mild to moderate, moderate, moderate to severe, severe). Primary outcome was a two-grade increase in the severity of TR. Echocardiographic and clinical predictors of worsening TR were examined using multivariate regression. RESULTS: A two-grade increase in TR occurred in 10.0% of our patient population. Age, lead position, atrial fibrillation, right atrial (RA) area, right ventricular systolic pressure (RVSP), left atrial area, and severity of mitral regurgitation were univariate predictors of worsening TR post lead placement. In the multivariate analysis, predevice RA area and RVSP were associated with increased TR after endocardial lead placement. Percentage of time spent pacing did not appear to be associated with increased TR. CONCLUSION: The incidence of increased TR postendocardial lead placement was 10.0%; this is lower than prior estimates. Predevice RA area and RVSP are predictors of increased TR after lead placement. PMID- 26234306 TI - Adaptive and acclimative responses of cyanobacteria to far-red light. AB - Cyanobacteria use three major photosynthetic complexes, photosystem (PS) I, PS II and phycobilisomes, to harvest and convert sunlight into chemical energy. Until recently, it was generally thought that cyanobacteria only used light between 400 nm and 700 nm to perform photosynthesis. However, the discovery of chlorophyll (Chl) d in Acaryochloris marina and Chl f in Halomicronema hongdechloris showed that some cyanobacteria could utilize far-red light. The synthesis of Chl f (and Chl d) is part of an extensive acclimation process, far-red light photoacclimation (FaRLiP), which occurs in many cyanobacteria. Organisms performing FaRLiP contain a conserved set of 17 genes encoding paralogous subunits of the three major photosynthetic complexes. Far-red light photoacclimation leads to substantial remodelling of the photosynthetic apparatus and other changes in cellular metabolism through extensive changes in transcription. Far-red light photoacclimation appears to be controlled by a red/far-red photoreceptor, RfpA, as well as two response regulators (RfpB and RfpC), one of which is a DNA-binding protein. The remodelled photosynthetic complexes, including novel phycobiliproteins, absorb light above 700 nm and enable cells to grow in far-red light. A much simpler acclimation response, low light photoacclimation (LoLiP), occurs in some cyanobacteria that contain the apcD4-apcB3-isiX cluster, which allows cells to grow under low light conditions. PMID- 26234308 TI - [Short history of laboratory diagnostics of allergy in Hungary, current possibilities and future perspectives]. AB - Up to know the indications for the optimal applications of laboratory diagnosis of allergic diseases have become widely known. Measurements of allergy specific IgE and various tests of cell mediated immunity are included in the practice. It can be stated that measurements of total serum IgE and allergen specific IgE (kU/l and RAST classes) can be maintained further in the Hungarian practice with the expected continuous participation of all laboratories in the external quality control program (QualiCont). However, it is also apparent that regional introduction of the urgent "molecular (component) based allergy diagnostics" has become necessary for efficient allergen specific immunotherapy in Hungary. In cases of the allergen specific cell mediated immunologic reactions, allergen induced cell proliferation and cytokine release measurements are recommended. However, it is also obvious that application of these measurements in clinical practice need correct financial support from health care authorities. PMID- 26234307 TI - Total cholesterol, lipoprotein, and triglyceride levels in tumor necrosis factor inhibitor-treated patients with psoriasis, psoriatic arthritis, or rheumatoid arthritis. PMID- 26234309 TI - [Drug compliance of patients on anticoagulant treatment]. AB - Despite several therapeutic possibilities the morbidity and mortality of thromboembolic disorders remain high. Improving drug compliance - i. e. keeping up the doctor's prescriptions - may be an effective tool to reach better results. To improve patients' compliance, the risk factors of non-compliance should be recognized. Among these patients' fear of adverse effects of drugs, their lack of knowledge about their illness and medication, forgetfulness, and other social, economic factors may be the most important. Furthermore, adherence may be worsened when the patient feels that the decision has been made over his/her head. Sustained medical adherence is important because anticoagulation may be a life-long treatment. The new oral anticoagulants make the matter of compliance to be current. These new type of drugs do not need regular laboratory monitoring and, therefore, compliance cannot be strictly followed. There are several studies concerning drug compliance to anticoagulant medications. Improvement of adherence is based on regular patient education after reviewing the factors of non compliance, which needs teamwork with important roles of doctors, pharmacists, dietetics and nurses. Careful and accurate work of the participants of primary care might be complemented by the activity of anticoagulant clinics. PMID- 26234311 TI - [How to rank if you must? Reflections on the book of Amy N. Langville and Carl D. Meyer]. AB - More than ever, our life is permeated by rankings. This is true also in the world of scientific research. The responsibility of the producers of such rankings is significant, since their results may influence decisions determining human fates and careers. The reviewed book - in a rather special area of ranking only - exemplifies how a set of methodologies can be systematically compiled, and how various methods can be combined into comprehensive, multidimensional rating and ranking systems. PMID- 26234310 TI - [Facilitating the diagnosis of depression and burnout by identifying demographic and work-related risk and protective factors among nurses]. AB - INTRODUCTION: Depression and burnout are frequent comorbidities among nurses. Despite similar symptoms, their management differ. Therefore, their timely diagnosis is essential. AIM: To identify demographic and work-related risk and protective factors of burnout and depression, and facilitate their diagnosis. METHOD: A cross-sectional study among 1,713 nurses was carried out. Depression and burnout were assessed by the shortened Beck Depression Questionnaire and Maclach Burnout Inventory, respectively. Risk and protective factors were explored using t-tests and analysis of variance. RESULTS: The prevalence of depression and moderate-to-high burnout was 35.1% and 34-74%, respectively. Having a partner/child and longer employment in the outpatient setting protected from burnout. Lack of a partner and male sex emerged as risk factors of depression and depersonalisation, respectively. CONCLUSIONS: High prevalence of depression and burnout among nurses poses a significant public health issue. Familiarity with the disease-specific risk and protective factors identified in this research may facilitate timely diagnosis and effective disease management. PMID- 26234312 TI - [Professor Zoltan Alfoldy at the helm of the Hungarian Institute of Microbiology for 25 years (1950-1974)]. PMID- 26234314 TI - Influence of metamizole on 1) minimal alveolar concentration of sevoflurane in dogs and 2) on thermal and mechanical nociception in conscious dogs. AB - OBJECTIVE: To determine the acute anti-nociceptive and the minimal alveolar concentration (MAC) sparing effects of metamizole sodiummonohydrate (dipyrone) in dogs for possible perioperative analgesia. STUDY DESIGN: Two groups of seven adult dogs were used in two separate randomised, blinded, controlled, cross-over studies. In each study, each dog received metamizole 50 mg kg(-1) intravenously (IV) and placebo (saline 0.9%) IV. METHODS: Sevoflurane MAC was determined using the bracketing technique and electrical stimulation (50 V, 50 Hz, 10 milliseconds) at a thoracic limb, before treatment and 1 and 4 hours post treatment. In conscious dogs, thermal thresholds were determined by ramped contact heat at the thoracic wall. Mechanical thresholds (MTs) were measured by constantly rising force pressing against the radial bone. Thresholds were determined pre and 45, 75, 105, 135, 165, 195, 225, 255, 285, 315, 345, 375, 435, 495, 555, 615, 675, 735 minutes and 24 hours post treatment. Parametric data were analyzed by analysis of variance for repeated measurements and paired t-tests. Friedman test was used for nonparametric data. Level of significance was set to <5%. RESULTS: Metamizole did not change MAC of sevoflurane significantly compared to baseline values [mean +/- SD Vol%; 2.7 +/- 0.5 (BL); 2.8 +/- 0.6 (1 hour); 2.8 +/- 0.4 (4 hours)] and placebo [2.8 +/- 0.5 (BL); 2.9 +/- 0.5 (1 hour); 2.9 +/- 0.4 (4 hour)]. Metamizole caused a significant rise in % TE up to 105 minutes (66.5 +/- 12.1%) and in MT up to 75 minutes (12.7 +/- 5.0 N) compared to baseline (55 +/- 10%; 7.9 +/- 1.8 N). There were no significant differences between treatments. CONCLUSION AND CLINICAL RELEVANCE: Metamizole did not induce an anaesthetic sparing effect. In awake dogs metamizole induced only mild and short cutaneous anti-nociception. Metamizole as the sole analgesic drug in the perioperative periode is not recommended. PMID- 26234315 TI - New Investigator and Trainee Task Force Survey on the Recruitment and Retention of Headache Specialists. AB - OBJECTIVES: We sought to survey the New Investigators and Trainees Section (NITS) members of the American Headache Society (AHS) to better understand their exposure to headache medicine during training and to determine their perceptions and attitudes about the field and the future of headache medicine. BACKGROUND: Despite the high prevalence of headache disorders in the general population, only about 2% of neurology residents pursue headache medicine fellowships. Furthermore, there is a paucity of United Council of Neurologic Subspecialties headache specialists in the country to meet the population demands. Thus, there needs to be a focus on how to recruit and retain more headache specialists. METHODS: A survey was distributed via SurveyMonkey to the NITS listserv. It remained online for 60 days, during which reminder emails were sent to members of the listserv. In addition, the survey was available on laptops at NITS-related events at an annual AHS meeting. Descriptive analyses were then conducted using SurveyMonkey and Excel. RESULTS: Of the 93 members of NITS, 64 of the 96 (68.8%) clicked to initiate the survey and 52.7% successfully completed it. Attendings made up the majority of respondents (62.5%), followed by fellows (10.9%), and residents (7.8%). Key highlights of the survey included the following: just under 10% reported no exposure to a headache center during any time in their training (medical school, residency, or fellowship); less than 2% had exposure to a headache center during medical school; less than half of participants reported exposure to a headache center in residency (45.3%) and during fellowship (43.4%). Having a mentor in the field, liking the patient population, and working in a headache center, 64.7%, 52.9%, and 41.2%, respectively, were the top ways in which participants became interested in headache. The journal Headache (56.9%), attendings (56.3%), and the AHS/American Academy of Neurology guidelines for migraine management (52.0%) are the resources cited as being used all/most of the time. About 82.4% strongly agree that there needs to be improved headache education for physicians of all specialties (primary care, emergency department, psychiatry); 84.4% feel that they are appreciated by their patients; 68.6% feel that there is strong support in their departments for headache; 56.9% believe that their work schedule leaves enough time for personal and family life; and 60.8% agreed that their professional life will improve in years to come. Participants agreed/strongly agreed that they like to treat the following diseases/symptoms: migraine headache (98.0%), cluster headache (92%), chronic daily headache (84%), and post-concussive syndrome (71.4%). Participants disagreed/strongly disagreed that they like to treat the following comorbid conditions/symptoms: low back pain (66.6%), dizziness (42.9%), sleep apnea (36.7%), depression (32.0%), and anxiety (32.0%). CONCLUSIONS: In this detailed survey on the recruitment and retention of headache specialists, the following themes emerged: mentorship and exposure to a headache center are key foundations in the young investigator/trainee experience. Young headache specialists appear positive about their field of medicine. These specialists like to treat various headache types but not necessarily some of the related comorbidities (sleep disorders, depression, anxiety, back pain, and dizziness). Finally, there was strong agreement that there needs to be improved headache education for physicians of other medical specialties. PMID- 26234317 TI - Variety of gambling activities from adolescence to age 30 and association with gambling problems: a 15-year longitudinal study of a general population sample. AB - AIMS: To estimate trajectories of gambling variety from mid-adolescence to age 30 years, and compare the different trajectory groups with regard to the type and the frequency of gambling activities practiced and gambling-related problems. DESIGN: Prospective longitudinal cohort study. SETTING: Province of Quebec, Canada. PARTICIPANTS: A mixed-gender general population cohort assessed at ages 15 (n=1882), 22 (n=1785) and 30 (n=1358). MEASUREMENTS: Adolescent and adult versions of the South Oaks Gambling Screen (SOGS). FINDINGS: Group-based trajectory analysis identified three distinct trajectories: a late-onset low trajectory (26.7% of sample) initiating gambling at age 22, an early-onset low trajectory (64.8% of sample), characterized by one to two different activities from age 15 onwards and a high trajectory (8.4% of sample), with an average of four to five different activities from age 15 to 30. Males (14.2%) were four times more likely to be on a high trajectory than females (3.5%) (P<0.001). Preferred types of gambling activities were similar across the three trajectories. Participants on a high trajectory reported higher gambling frequency at ages 15 and 30, and were more likely to experience problem gambling at age 30: 3.09 [95% confidence interval (CI)=1.66, 5.75] and 2.26 (95% CI=1.27, 4.04) times more, respectively, than late-onset low and early-onset low participants, even when socio-economic status (SES), frequency of gambling and problem gambling in adolescence, gender, age 30 education, SES and frequency of gambling were controlled. CONCLUSIONS: Engaging in several different types of gambling in early adulthood appears to be a risk factor for emergence of problem gambling. PMID- 26234318 TI - Association between Left Ventricular Postsystolic Shortening and Diastolic Relaxation in Asymptomatic Patients with Systemic Hypertension. AB - BACKGROUND: Few data have existed on myocardial postsystolic shortening (PSS) accounting for left ventricular (LV) diastolic dysfunction in systemic hypertension. We examined this relationship, along with clinical and other cardiac parameters, in asymptomatic patients with hypertension. METHODS: We analyzed 104 patients on pharmacological treatment for hypertension who had no signs or symptoms of heart failure for conventional and speckle tracking echocardiography. The sum of the postsystolic index for multiple LV segments (total PSI) and global longitudinal strain (GLS) was computed and used as measures for global PSS and myocardial systolic function, respectively. The tissue Doppler e' and the speckle tracking-derived global strain rate during early diastole (e'sr) were obtained as indicators of LV relaxation. The circumferential end-systolic stress was also determined noninvasively and substituted for a measure of myocardial afterload. RESULTS: Main variables that correlated with the e' and e'sr were shown to be age, LV mass index, left atrial volume index, GLS, and the total PSI. Multivariate analysis including gender, circumferential end-systolic stress, and the use of calcium channel blockers as possible covariates revealed that age (beta = -0.29, P = 0.002), total PSI (beta = -0.26, P = 0.008), and LV mass index (beta = -0.25, P = 0.017) were significant independent determinants of e' and that age (beta = -0.34, P < 0.001) and GLS (beta = -0.28, P = 0.006) were of e'sr. CONCLUSIONS: Our findings indicate that while depending on the degree of GLS, PSS may affect diastolic relaxation in patients with asymptomatic, but treated, hypertensive patients. PMID- 26234319 TI - Cannabinoids: is there a potential treatment role in epilepsy? AB - Cannabinoids have been used medicinally for centuries, and in the last decade, attention has focused on their broad therapeutic potential particularly in seizure management. While some cannabinoids have demonstrated anticonvulsant activity in experimental studies, their efficacy for managing clinical seizures has not been fully established. This commentary will touch on our understanding of the brain endocannabinoid system's regulation of synaptic transmission in both physiological and pathophysiological conditions, and review the findings from both experimental and clinical studies on the effectiveness of cannabinoids to suppress epileptic seizures. At present, there is preliminary evidence that non psychoactive cannabinoids may be useful as anticonvulsants, but additional clinical trials are needed to fully evaluate the efficacy and safety of these compounds for the treatment of epilepsy. PMID- 26234320 TI - Cognitive impairments associated with morphological changes in cortical and subcortical structures in multiple system atrophy of the cerebellar type. AB - BACKGROUND AND PURPOSE: Patients with the cerebellar variant of multiple system atrophy (MSA-C) often show cognitive deficits in various cognitive domains. The association between morphometric changes in cortical and subcortical structures and cognitive impairments in MSA-C were investigated to explore the neural correlates responsible for cognitive deficits in MSA-C patients. METHODS: Using surface-based morphometry, region-of-interest cortical thickness and the volumes and shapes of subcortical structures were examined in 18 patients who fulfilled the criteria of probable MSA-C and were compared to 50 healthy controls. The association between regional changes and cognitive functions in MSA-C were investigated by applying linear regression analyses after controlling for confounding factors. RESULTS: Compared with controls, the patients with MSA-C showed significant cortical thinning in the fronto-temporo-parietal regions and volume reduction in subcortical structures with shape changes. Cerebellar volume had no significant effect on cortical and subcortical volumes. The severity of atrophic changes in the bilateral thalamus, the left cerebellum and the left pericalcarine gyrus were significantly correlated with attentional, executive and visuospatial dysfunctions. CONCLUSION: Cognitive impairment in MSA-C might result from functional disruption of the corticostriatal and pontocerebellar circuit mediated by primary cortical, cerebellar or thalamic pathology. PMID- 26234321 TI - Chemical Differentiation of Osseous and Nonosseous Materials Using Scanning Electron Microscopy-Energy-Dispersive X-Ray Spectrometry and Multivariate Statistical Analysis. AB - Identification of osseous materials is generally established on gross anatomical features. However, highly fragmented or taphonomically altered materials may be problematic and may require chemical analysis. This research was designed to assess the use of scanning electron microscopy-energy-dispersive X-ray spectrometry (SEM/EDX), elemental analysis, and multivariate statistical analysis (principal component analysis) for discrimination of osseous and nonosseous materials of similar chemical composition. Sixty samples consisting of osseous (human and nonhuman bone and dental) and non-osseous samples were assessed. After outliers were removed a high overall correct classification of 97.97% was achieved, with 99.86% correct classification for osseous materials. In addition, a blind study was conducted using 20 samples to assess the applicability for using this method to classify unknown materials. All of the blind study samples were correctly classified resulting in 100% correct classification, further demonstrating the efficiency of SEM/EDX and statistical analysis for differentiation of osseous and nonosseous materials. PMID- 26234322 TI - ASXL1 single nucleotide polymorphisms rs62206933, rs117901891, and rs74638057 identify a subgroup of acquired aplastic anemia in Chinese Han patients. PMID- 26234323 TI - National trends with a laparoscopic liver resection: results from a population based analysis. AB - BACKGROUND: Interest in laparoscopic liver resection (LLR) has grown since the International 'Louisville Statement' regarding laparoscopic liver surgery was published in 2009. However, limited population-based data on LLR utilization patterns and outcomes are available. METHODS: LLR data from the Nationwide Inpatient Sample (NIS, 2000-2012) and the National Surgical Quality Improvement Project (NSQIP, 2005-2012) were compared before and after the Louisville Statement in 2009. RESULTS: In total, 1131 and 642 LLR were identified from NIS and NSQIP, respectively. Three-quarters of patients underwent LLR for a malignant indication (NIS primary malignancy, 29.6% versus metastasis, 45.1%; NSQIP primary malignancy, 35.5% versus metastasis, 46.1%). The annual volume of LLR increased from 2000-2008 versus 2009-2012 (NIS: 63 versus 168, P < 0.001; NSQIP: 52 versus 127; both P = 0.001). The peri-operative mortality associated with LLR was 2.8% in NIS and 2.2% in NSQIP. The morbidity was 38.1% in NIS and 30.7% in NSQIP. Mortality and morbidity did not change over time (both P > 0.050). After 2009, LLR was associated with a shorter length of stay (LOS) (NIS: 5 versus 6 days, P = 0.007). CONCLUSION: Since the Louisville Statement in 2009, utilization of LLR has increased. LLR is associated with a modest decrease in LOS and appears to be safe with mortality and morbidity similar to open surgery. PMID- 26234324 TI - Epidemiological data on airborne contact dermatitis - results of the IVDK. AB - BACKGROUND: Airborne contact dermatitis (AirbCD) is not uncommon, according to a large number of published case reports and review articles. Epidemiological data on AirbCD based on larger clinical samples have not yet been published. OBJECTIVES: To investigate demographic characteristics and patch test reactivity in patients diagnosed with both occupational and non-occupational AirbCD. METHODS: A retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 1994-2013, including 201 344 consecutively patch tested patients, was performed. RESULTS: One thousand two hundred and three patients (0.6%) were diagnosed with AirbCD, 421 (35.0%) of these with an occupational background. Occupational dermatitis and face involvement were more prevalent than in patients without AirbCD (n = 200 141). Sensitization to epoxy resin and sensitization to methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) were significantly associated with AirbCD, and there was a trend for sensitization to Compositae mix and/or sesquiterpene lactone mix to be associated with AirbCD. Adhesives, plastics, construction materials, paints and varnishes in occupational cases, and plants in non occupational cases, were the most commonly documented culprit product categories. CONCLUSIONS: AirbCD is more common in patients with occupational dermatitis than in patients with non-occupational dermatitis. In our clinical sample, components of epoxy resin systems, MCI/MI and Compositae allergens were the most important contact allergens associated with AirbCD. Patch testing with additional allergens is important. PMID- 26234326 TI - Perceived Barriers to Treatment for Alcohol Problems: A Latent Class Analysis. AB - OBJECTIVE: Low rates of alcohol treatment seeking have been shown to be associated with perceived barriers to treatment, but heterogeneity in patterns of perceived barriers has not been explored. The study analyzed data from a population-based sample of adults with alcohol abuse and dependence in order to describe latent classes of individuals who reported one or more of 15 perceived barriers to seeking alcohol treatment and to identify characteristics associated with class membership. METHODS: Data were from the National Epidemiologic Survey on Alcohol and Related Conditions (2001-2002). Analyses were restricted to treatment-naive adults with alcohol abuse or dependence who reported a perceived treatment need (N=1,053). Latent class analysis was performed to identify subgroups with respect to barriers to treatment. Latent class regression identified variables associated with each subgroup. RESULTS: Two subgroups emerged: the low-barriers class (87%), characterized primarily by attitudinal barriers, and the high-barriers class (13%), characterized by significant attitudinal, financial, stigma, and readiness-for-change barriers. In both classes, the most frequently endorsed barrier was the attitudinal belief that "I should be strong enough" to handle the problem without treatment. Univariate analyses showed strong associations between membership in the high-barriers class and comorbid psychiatric disorders, alcohol dependence (compared with abuse), and a family history of alcohol problems. Multivariate analyses found significant associations with a lifetime anxiety disorder and with education level. CONCLUSIONS: Attitudinal barriers were most prevalent. Findings revealed a notable subgroup with multiple barriers, including financial and stigma-related barriers. This subgroup may require additional resources and support to enter treatment. PMID- 26234327 TI - Brief Critical Time Intervention to Reduce Psychiatric Rehospitalization. AB - OBJECTIVE: The study investigated the association between implementation of a brief critical time intervention (BCTI) model and occurrence of early and long term psychiatric readmission of adults with serious mental illness. METHODS: A sample of 149 adults with a psychiatric inpatient readmission within 30 days of a prior psychiatric hospitalization was referred to an acute level of service coordination (ASC) available at six provider organizations implementing BCTI. Activities important to the delivery of BCTI were monitored and supported. A comparison cohort of 224 adults served by ASC at the same organizations before implementation of BCTI was derived from administrative data. Frequencies of behavioral health service utilization and readmission rates for the intervention and comparison cohorts within 30 and up to 180 days of the prior readmission were compared. RESULTS: Utilization rates of mental health and substance use disorder services were similar for both cohorts postdischarge. The proportion of individuals readmitted within 30 days of a discharge was lower for the BCTI cohort (28%) than the comparison cohort (47%) (p<.001). Longer-term readmission rates also were lower in the BCTI cohort but were not significantly different from the comparison cohort (44% versus 52%). With analyses controlling for patient characteristics and service utilization, individuals in the comparison cohort were 2.83 times more likely to be readmitted within 30 days than those who received BCTI (p<.001). CONCLUSIONS: BCTI was associated with decreased early readmission rates, suggesting that this model may be an effective approach to improve continuity of care for this population. PMID- 26234325 TI - Modulation of cardiovascular toxicity in Hodgkin lymphoma: potential role and mechanisms of aerobic training. AB - Hodgkin lymphoma (HL) outcomes have improved due to advances in cancer treatment. However, HL survivors remain at increased risk for cardiovascular (CV) morbidity and mortality related to the long-term cardiotoxicity of HL treatment, particularly anthracycline chemotherapy and mediastinal radiotherapy. The role of aerobic training for the prevention of CV disease in the general population has been well established. However the safety and efficacy of aerobic training on CV outcomes has not been well studied in HL survivors. The purpose of this paper is to provide an up-to-date summary of the treatment-related adverse CV effects in HL survivors, review the CV benefits of exercise and review the limited evidence on the potential CV benefit of aerobic training in HL survivors. PMID- 26234329 TI - Relationship Between Seclusion and Restraint Reduction and Assaults in Pennsylvania's Forensic Services Centers: 2001-2010. AB - OBJECTIVE: This prospective study assessed the use of seclusion and restraint in Pennsylvania forensic centers from 2001 through 2010. It also examined the correlation between declining use of containment procedures and patient-to patient and patient-to-staff assaults. METHODS: The 2,741 episodes of restraint or seclusion involving 801 unique individuals served in state forensic centers during the study period were entered into a uniform database. Included in this data set were demographic and diagnostic data as well as the causes and injuries associated with each use of these procedures. These data were correlated with rates of patient-to-patient and patient-to-staff assaults with any injury for each month of this study. RESULTS: From 2001 to 2010, the rate of use of mechanical restraint significantly declined from 1.63 to .04 episodes per 1,000 days (p<.001), and the rate of use of seclusion significantly declined from .89 to .04 episodes per 1,000 days (p<.001). There was a nonsignificant decline in the use of physical restraint during this span. During this decade, the rate of patient-to-staff assaults declined, and the rate of patient-to-patient assaults was unaffected. CONCLUSIONS: Decreasing the use of containment procedures had a positive effect on reducing assaults. Leadership, data transparency, use of clinical alerts, workforce development, policy changes, and discontinuation of psychiatric use of PRN orders were all contributing factors. A philosophical change toward a recovery model of psychiatric care and services was the driving force behind this transformation. PMID- 26234328 TI - Associations Between Quality of Life and Functioning in an Assertive Community Treatment Population. AB - OBJECTIVE: Level of functioning is positively associated with subjective quality of life for people with severe mental illness, but a detailed relationship between functioning and satisfaction with various life domains is largely unknown, and this gap prompted this study. METHODS: Demographic and clinical data were obtained from 149 patients engaged with 12 assertive community treatment teams in Norway. Multivariate regression analyses were used to explore associations between subjective quality of life and patient characteristics. RESULTS: Analyses confirmed positive associations between quality of life and age, functioning, and weekly contact with family and friends and a negative association with anxiety and depressive symptoms. Positive associations between several areas of practical and social functioning and satisfaction with related life domains also were found. CONCLUSIONS: Although a causal direction of the associations between functioning and life satisfaction has not been determined in this study, the positive findings might indicate that programs aiming to improve functioning could affect patients' quality of life. PMID- 26234330 TI - Financial Health and Mental Health Among Clients of a Community Mental Health Center: Making the Connections. AB - OBJECTIVES: This study evaluated financial challenges, satisfaction with financial-management supports, and interest in additional or alternative supports among clients of a mental health center. METHODS: Six focus groups were held with 39 clients of an urban community mental health center who reported having difficulty with their finances. Five focus groups were held with direct-care staff who provided services to the clients. Investigators used an inductive analytical approach to distill themes from notes taken during the focus groups. RESULTS: Clients emphasized the challenges of living in poverty and described using complex strategies to sustain themselves, including negotiating benefits systems, carefully planning purchases, and developing and relying on social relationships. They spoke of having uneven access to tools and services for managing their money, such as advice from direct-care staff, representative payees, and bank accounts, and had varying opinions about their value. Noting concerns similar to those of clients, direct-care staff expressed frustration at the lack of support services for helping clients manage their finances. Both clients and staff expressed the need for more services to help clients with their finances. CONCLUSIONS: Findings suggest a need for more services to support people with mental illness to manage their finances, particularly a more flexible and broader range of options than are provided by current representative-payee mechanisms. PMID- 26234331 TI - Female Veterans in Jail Diversion Programs: Differences From and Similarities to Their Male Peers. AB - OBJECTIVE: This study compared the demographic, behavioral health, criminal justice, and military characteristics and experiences of female and male veterans participating in criminal justice diversion programs funded under the Substance Abuse and Mental Health Services Administration Jail Diversion and Trauma Recovery program. METHODS: Data on program participants were collected as part of a national cross-site evaluation. Baseline interview data from 1,025 program participants were analyzed. RESULTS: For the most part, there were few statistically significant differences between female and male veterans with criminal justice involvement. However, females reported significantly more sexual trauma, more females had PTSD, and females had more severe PTSD symptoms. In contrast, males reported earlier criminal justice involvement, more males served in military combat, and males had higher rates of substance use. CONCLUSIONS: Although male and female veterans involved in jail diversion programs share many characteristics, the differences in types of trauma exposure and rates of substance use suggest that programs should include attention to gender in planning program services. PMID- 26234332 TI - Medicaid, Private Insurance, and the Availability of Smoking Cessation Interventions in Substance Use Disorder Treatment. AB - OBJECTIVE: Integration of smoking cessation services in substance use disorder treatment would benefit many patients. Although prior studies have identified organizational characteristics associated with delivery of these services, less is known regarding associations between financial factors and the availability of smoking cessation services. This study examined whether reliance on Medicaid and private insurance revenues is associated with the availability of a formal counseling-based smoking cessation program and medications (sustained-release bupropion, varenicline, and nicotine replacement) within U.S. specialty treatment organizations. METHODS: Administrators of a national sample of 372 treatment organizations participated in face-to-face structured interviews from October 2011 to December 2013. Participants provided data regarding smoking cessation services, revenue sources, and other organizational characteristics. Multiple imputation was used to address missing data, and models were estimated by using logistic regression with adjustment for clustering of organizations within states. RESULTS: Greater reliance on Medicaid revenues was positively associated with the odds of offering counseling-based smoking cessation programs, sustained release bupropion, varenicline, and nicotine replacement. For example, a 10 percentage point increase in Medicaid revenues was associated with a 12% increase in the odds of offering a smoking cessation program. Reliance on private insurance revenues was positively associated with the odds of offering the three medications. CONCLUSIONS: The findings point to future potential increases in the availability of smoking cessation services in the context of expanding insurance coverage under health care reform. Longitudinal research will be needed to examine whether this impact is realized. PMID- 26234333 TI - Hospital Costs Associated With Agitation in the Acute Care Setting. AB - OBJECTIVE: The study determined hospital costs associated with a diagnosis of agitation among patients at 14 general hospitals in Spain. METHODS: Data from discharge records of adult patients (2008-2012) with a diagnosis of agitation (ICD-9-CM code 293.0) were analyzed. Incremental hospital costs for agitated patients and a control group of patients without agitation were quantified, and the adjusted cost and incremental cost for both groups were compared by use of a recycled-predictions approach. RESULTS: The analysis included 355,496 hospital discharges, 5,334 of which were of patients with a diagnosis of agitation. Among patients with a diagnosis of agitation, hospital stays were significantly longer (12 days versus nine days). A significant difference in mean costs of ?472 (95% confidence interval [CI]=?351-?593) was noted between patients with agitation and those in the control group. A recycled-predictions approach showed a difference of ?1,593(CI=?1,556-?1,631). CONCLUSIONS: Findings indicate that agitation increased the use of hospital resources by at least 8%. PMID- 26234334 TI - Risk of Dementia Among Elderly Nursing Home Patients Using Paroxetine and Other Selective Serotonin Reuptake Inhibitors. AB - OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) are the first line of treatment for depression. Among the SSRIs, paroxetine has strong anticholinergic properties and may lead to increased risk of adverse cognitive outcomes among elderly patients. This study evaluated the comparative risk of dementia associated with use of paroxetine and other SSRIs among elderly nursing home patients. METHODS: A retrospective cohort study using propensity score matching was conducted with 2007-2010 Minimum Data Set-linked Medicare data. The study population included elderly nursing home patients with depression who were new users of SSRIs. Patients were followed for a maximum of two years after index SSRI use. The risk of dementia was modeled by using a robust Cox proportional hazards model to account for clustering within matched users of paroxetine and other SSRIs. RESULTS: The unmatched cohort included 19,952 new users of SSRIs; 1,898 used paroxetine, and 18,054 used other SSRIs. In the propensity-matched cohort of 3,796 patients, the unadjusted incidence of dementia was 7.5% for users of paroxetine and 8.6% for users of other SSRIs. There was no difference in the risk of dementia for users of paroxetine or other SSRIs. These study findings remained robust in multiple sensitivity analyses involving various measures of dementia. CONCLUSIONS: Compared with use of other SSRIs, use of paroxetine was not associated with higher risk of dementia among elderly nursing home patients with depression. Future studies are needed to evaluate the impact of paroxetine on other cognition measures. PMID- 26234335 TI - Supportive Versus Demanding Intervention Programs for Young Adults With Severe Mental Illness. AB - Two rehabilitation programs for young adults ages 18 to 30 with severe mental illness were launched in Israel in 2009. Both programs adhered to the Illness Management and Recovery approach, but one emphasized emotional support and containment (supportive model program), and the other emphasized practical support to promote independence (demanding model program). A formative and developmental evaluation of both programs was conducted. Qualitative and quantitative findings indicated that both programs have merits, suggesting that they could be combined to formulate a best practice tailored for the unique needs of this population. PMID- 26234336 TI - Memantine and reduced time with dyskinesia in Parkinson's Disease. AB - OBJECTIVES: The partial glutamate antagonist amantadine is currently used in clinical practice, to reduce dyskinesia developing as a side-effect of levodopa treatment in patients suffering from Parkinson's disease (PD). This study was aimed at evaluating the antidyskinetic effect of another glutamate antagonist, memantine. METHODS AND MATERIALS: We performed a randomized, double-blind and placebo-controlled crossover clinical trial of memantine (20 mg), with a 3-week treatment period, and 15 patients completed the study. RESULTS: The primary outcome measure, a change in observed dyskinesia ratings, did not reach significance. Seven of the 15 patients reduced the L-dopa-induced dyskinesias by 32%, whereas for three patients, they increased by 33%, and for five patients, they did not change. Data from the self-administered diaries, as a secondary outcome measure, did show a significant 35% reduction in the percentage of time of the day spent with dyskinesia, from 25% (placebo) to 16% (memantine). Memantine was well tolerated, without any serious adverse events, or worsening in the parkinsonian motor score. CONCLUSION: The results suggest that memantine may be a useful antidyskinetic drug, and a larger clinical study is warranted. PMID- 26234343 TI - Application of the multifactor dimensionality reduction method in evaluation of the roles of multiple genes/enzymes in multidrug-resistant acquisition in Pseudomonas aeruginosa strains. AB - Multidrug-resistant Pseudomonas aeruginosa (MDRPA) infections are major threats to healthcare-associated infection control and the intrinsic molecular mechanisms of MDRPA are also unclear. We examined 348 isolates of P. aeruginosa, including 188 MDRPA and 160 non-MDRPA, obtained from five tertiary-care hospitals in Guangzhou, China. Significant correlations were found between gene/enzyme carriage and increased rates of antimicrobial resistance (P < 0.01). gyrA mutation, OprD loss and metallo-beta-lactamase (MBL) presence were identified as crucial molecular risk factors for MDRPA acquisition by a combination of univariate logistic regression and a multifactor dimensionality reduction approach. The MDRPA rate was also elevated with the increase in positive numbers of those three determinants (P < 0.001). Thus, gyrA mutation, OprD loss and MBL presence may serve as predictors for early screening of MDRPA infections in clinical settings. PMID- 26234344 TI - Psychological distress of children with early-onset type 1 diabetes and their mothers' well-being. AB - AIM: Few studies have focused on the psychological adjustment of pre-adolescent children with type 1 diabetes. This study examined psychosocial functioning in nine- and 10-year-old children with early-onset type 1 diabetes, and their mothers, and associations between psychosocial functioning and diabetes management. METHODS: The mothers of 63 children with early-onset diabetes and 86 healthy children evaluated their own psychosocial functioning, and their child's, with standardised rating scales. We used general linear models to analyse the children's behaviour problems and the mothers' well-being. Associations between the children's behaviour problems, diabetes-related measures and the mothers' well-being were studied with partial correlations. RESULTS: Children with diabetes had more internalising problems than the controls (p = 0.001), and these were associated with poor glycaemic control at the early stage of the illness (p = 0.033) and the use of insulin pumps in girls (p = 0.004). Mothers in the diabetes group had more child-related stress than the controls (p < 0.001), and poorer well-being was associated with the children's behavioural problems (p < 0.024). CONCLUSION: Children with early-onset diabetes faced an increased risk of internalising problems in middle childhood. The mothers' psychological distress was associated with children's behaviour problems rather than their diabetes. PMID- 26234345 TI - Bioactive Core-Shell Nanofiber Hybrid Scaffold for Efficient Suicide Gene Transfection and Subsequent Time Resolved Delivery of Prodrug for Anticancer Therapy. AB - Nanofiber scaffold's ability to foster seemingly nonexistent interface with the cells enables them to effectively deliver various bioactive molecules to cells in the vicinity. Among such bioactive molecules, therapeutically active nucleic acid has been the most common candidate. In spite of such magnanimous efforts in this field, it remains a paradox that suicide gene delivery by nanofibers has never been sought for anticancer application. To investigate such a possibility, in the present work, a composite core-shell nanofiberous scaffold has been realized which could efficiently transfect suicide gene into cancer cells and simultaneously deliver prodrug, 5-Fluorocytosine (5-FC) in a controlled and sustained manner. The scaffold's ability to instigate apoptosis by suicide gene therapy in nonsmall lung cancer cells (A549) was ascertained at both phenotypic and genotypic levels. A cascade of events starting from suicide gene polyplex release from nanofibers, transfection, and expression of cytosine deaminase uracil phosphoribosyltransferase (CD::UPRT) suicide gene by A549; subsequent prodrug release; and its metabolic conversion into toxic intermediates which finally culminates in host cells apoptosis has been monitored in a time-dependent manner. This work opens up new application avenues for nanofiber-based scaffolds which can effectively manage cancer prognosis. PMID- 26234346 TI - Effects of arachidonic acid intake on inflammatory reactions in dextran sodium sulphate-induced colitis in rats. AB - The aim of this study was to investigate the effects of the administration of oral arachidonic acid (AA) in rats with or without dextran sulphate sodium (DSS) induced inflammatory bowel disease. Male Wistar rats were administered AA at 0, 5, 35 or 240 mg/kg daily by gavage for 8 weeks. Inflammatory bowel disease was induced by replacing drinking water with 3 % DSS solution during the last 7 d of the AA dosing period. These animals passed loose stools, diarrhoea and red stained faeces. Cyclo-oxygenase-2 concentration and myeloperoxidase activity in the colonic tissue were significantly increased in the animals given AA at 240 mg/kg compared with the animals given AA at 0 mg/kg. Thromboxane B2 concentration in the medium of cultured colonic mucosae isolated from these groups was found to be dose-dependently increased by AA, and the increase was significant at 35 and 240 mg/kg. Leukotriene B4 concentration was also significantly increased and saturated at 5 mg/kg. In addition, AA at 240 mg/kg promoted DSS-induced colonic mucosal oedema with macrophage infiltration. In contrast, administration of AA for 8 weeks, even at 240 mg/kg, showed no effects on the normal rats. These results suggest that in rats with bowel disease AA metabolism is affected by oral AA, even at 5 mg/kg per d, and that excessive AA may aggravate inflammation, whereas AA shows no effects in rats without inflammatory bowel disease. PMID- 26234347 TI - Environmental impact of replacing soybean meal with rapeseed meal in diets of finishing pigs. AB - The major impact of the livestock sector on the environment may be reduced by feeding agricultural co-products to animals. Since the last decade, co-products from biodiesel production, such as rapeseed meal (RSM), became increasingly available in Europe. Consequently, an increase in RSM content in livestock diets was observed at the expense of soybean meal (SBM) content. Cultivation of SBM is associated with high environmental impacts, especially when emissions related to land use change (LUC) are included. This study aims to assess the environmental impact of replacing SBM with RSM in finishing pig diets. As RSM has a lower nutritional value, we assessed the environmental impact of replacing SBM with RSM using scenarios that differed in handling changes in nutritional level. Scenario 1 (S1) was the basic scenario containing SBM. In scenario 2 (S2), RSM replaced SBM based on CP content, resulting in reduced energy and amino acid content, and hence an increased feed intake to realize the same growth rate. The diet of scenario 3 (S3) was identical to S2; however, we assumed that pigs were not able to increase their feed intake, leading to reduced growth performance. In scenario 4 (S4), the energy and amino acid content were increased to the same level of S1. Pig performances were simulated using a growth model. We analyzed the environmental impact of each scenario using life-cycle assessment, including processes of feed production, manure management, piglet production, enteric fermentation and housing. Results show that, expressed as per kg of BW, replacing SBM with RSM in finishing pig diets marginally decreased global warming potential (GWP) and energy use (EU) but decreased land use (LU) up to 12%. Between scenarios, S3 had the maximum potential to reduce the environmental impact, due to a lower impact per kg of feed and an increased body protein-to-lipid ratio of the pigs, resulting in a better feed conversion ratio. Optimization of the body protein-to-lipid ratio, therefore, might result in a reduced environmental impact of pig production. Furthermore, the impact of replacing SBM with RSM changed only marginally when emissions related to direct (up to 2.9%) and indirect LUC (up to 2.5%) were included. When we evaluated environmental impacts of feed production only, which implies excluding other processes along the chain as is generally found in the literature, GWP decreased up to 10%, including LUC, EU up to 5% and LU up to 16%. PMID- 26234348 TI - [Hospital Preparations Supporting the Medication--Status Quo and Challenges in the Future]. PMID- 26234349 TI - [Indomethacin Spray Preparation for the Control of Pain Associated with Stomatitis Caused by Chemotherapy and Radiotherapy in Cancer Patients]. AB - Severe stomatitis caused by chemotherapy and radiotherapy is accompanied by severe pain and results in a poor quality of life. We used a spray preparation of indomethacin (IM; 0.25% IM dissolved in phosphate buffer, pH 7.4), a nonsteroidal anti-inflammatory drug (NSAID) to control the pain associated with stomatitis at the University of Tsukuba Hospital. This review specifically aimed to collect information on the use of the IM spray preparation, from our previous studies, to facilitate its proper use in a hospital setting. On studying the stability of the IM spray preparation, we concluded that the preparation should be kept in the refrigerator for daily use, and that it can be stored for at least 2 months at 4 degrees C, and for 24 months at -20 degrees C. To evaluate the efficacy of the IM spray preparation, we retrospectively surveyed its analgesic effects. Using the 10-grade Visual Analogue Scale in 23 patients, we found that pain associated with stomatitis was reduced from 10 to 4.7 after application of the spray. In conclusion, our study results on the stability and efficacy of the IM spray preparation have led to the proper use of the spray in cancer patients with stomatitis caused by chemotherapy and radiotherapy. PMID- 26234350 TI - [Efficacy of Rebamipide Gargle against Chemotherapy-induced Oral Mucositis]. AB - Chemotherapy-induced oral mucositis (CIOM) is a severe adverse event resulting from cancer chemotherapy. Toxic free radicals and pro-inflammatory cytokines produced by anticancer drugs have been reported to be associated with CIOM. Rebamipide has been shown to increase gastric endogenous prostaglandin E2 and I2, to promote gastric epithelial mucin, and to behave as an oxygen free-radical scavenger in addition to other anti-inflammatory actions. We developed a gargle solution of rebamipide, adding ultrahydrogel for mucosal protection and to maintain rebamipide on the oral mucosa. A 300 mL rebamipide gargle solution combines 600 mg rebamipide, 3 g high molecular-weight polyethylene oxide, 1.2 g carrageenan, pineapple flavoring, and water. The efficacy of the rebamipide gargle was evaluated in 175 patients with CIOM from November 2009 to December 2012, each instructed to use the rebamipide gargle 5-6 times daily. The severity of CIOM was assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). Their CTCAE scores (3/2/1/0) changed from n=13/64/98/0 to 0/10/103/62, respectively, after initiation of the rebamipide gargle (p<0.01; paired t-test). The median duration to best response was 14 days (range: 1-49). CTCAE scores decreased in 132 patients (75.4%), including 62 (35.4%) who achieved grade 0. There were no unexpected safety events. Rebamipide gargle was well tolerated and demonstrated to have significant therapeutic efficacy against CIOM. PMID- 26234351 TI - [The Contribution of GMP-grade Hospital Preparation to Translational Research]. AB - Translational research is important for applying the outcomes of basic research studies to practical medical treatments. In exploratory early-phase clinical trials for an innovative therapy, researchers should generally manufacture investigational agents by themselves. To provide investigational agents with safety and high quality in clinical studies, appropriate production management and quality control are essential. In the Department of Pharmacy of Kyoto University Hospital, a manufacturing facility for sterile drugs was established, independent of existing manufacturing facilities. Manuals on production management and quality control were developed according to Good Manufacturing Practices (GMP) for Investigational New Drugs (INDs). Advanced clinical research has been carried out using investigational agents manufactured in our facility. These achievements contribute to both the safety of patients and the reliability of clinical studies. In addition, we are able to do licensing-out of our technique for the manufacture of investigational drugs. In this symposium, we will introduce our GMP grade manufacturing facility for sterile drugs and discuss the role of GMP grade hospital preparation in translational research. PMID- 26234352 TI - [Research on Molecular Mechanisms of Engulfment of Apoptotic Cells]. AB - Apoptotic cells generated during development and immune responses in animals are rapidly engulfed by phagocytes, such as macrophages and dendritic cells. When the engulfment process malfunctions, the apoptotic cells undergo secondary necrosis, which results in the release of noxious cellular components into the extracellular space. Thus, the efficient clearance of apoptotic cells is indispensable for the maintenance of tissue homeostasis; however, the molecular mechanisms underlying the engulfment of apoptotic cells remain largely unknown. To identify the molecules that are involved in this process, we developed a functional screening strategy using a retrovirus cDNA library. Using this assay, we isolated cDNA clones encoding RhoG and Rab5 which enhanced the engulfment of apoptotic cells. In addition, we found that Rac1, which is very similar to RhoG, and Rab5 are necessary for engulfment; their activities were successfully visualized by a combination of fluorescence resonance energy transfer technology with time-lapse imaging techniques. We further determined that G protein-coupled receptor kinase 6 (GRK6), originally identified as a kinase responsible for the desensitization and downregulation of G-protein-coupled receptors, activates Rac1 independent of the two known intracellular engulfment pathways in phagocytes. GRK6-deficient macrophages exhibited impaired phagocytosis of apoptotic cells. Consequently, GRK6-deficient mice developed autoimmune phenotypes such as an increase in the amount of anti-dsDNA in serum and the deposition of immune complexes in the kidney. Thus, our findings contributed to the understanding of the molecular mechanisms that regulate apoptotic engulfment in phagocytes. PMID- 26234353 TI - [Development of Efficient Separation and Sensitive Analytical Methods for Biological Compounds and Their Application]. AB - Measurement of biological compounds is important for the clarification of biological phenomena. For the quantification of trace amounts of biological compounds, efficient separation and sensitive analytical methods are necessary. The present author developed HPLC-fluorescence and chemiluminescence detection methods for biological compounds such as catecholamines, amino acids, and thiols. In this review article, two studies are summarized: one on the development of an on-chip liquid chromatography method using pillar array columns with low dispersion turns; and another on the development of simultaneous analytical method of biothiols by HPLC with fluorescence detection under hydrophilic interaction chromatography conditions. PMID- 26234354 TI - [The Role of GRK2 and Its Potential as a New Therapeutic Target in Diabetic Vascular Complications]. AB - A decrease in nitric oxide (NO) production may induce pathological conditions associated with endothelial dysfunction and diabetes. Although a decrease in NO production caused by impaired Akt/endothelial nitric oxide synthesis (eNOS) signaling has been demonstrated at the aorta in the presence of diabetic vascular complications, little is known regarding the details of the mechanism. We identified G-protein-coupled receptor kinase 2 (GRK2) as a critical factor in diabetic endothelial dysfunction. GRK2 plays a role in many physiological functions including regulation of G-protein-coupled receptors (GPCRs). We found that the vasculature affected by type 2 diabetes expresses high levels of GRK2, which may induce endothelial dysfunction caused by impaired Akt/eNOS signaling. GRK2 activation also induces changes in the subcellular localization of GRK2 and beta-arrestin 2, a downstream protein, from the cytosol to membrane. In mouse aorta GRK2 may be, on translocation, a key negative regulator and an important regulator of beta-arrestin 2/Akt/eNOS signaling, which has been implicated in diabetic endothelial dysfunction. Furthermore, in the aortic membrane of type 2 diabetic model mice under insulin stimulation, the impaired Akt/eNOS signaling was improved by a selective GRK2 inhibitor. These results suggest that in diabetes the GRK2 inhibitor ameliorates vascular endothelial dysfunction via Akt/eNOS signaling by inhibiting GRK2 activity and enhancing beta-arrestin 2 translocation to the membrane under GPCR or non-GPCR stimulation, thereby contributing to blood pressure- and blood glucose-lowering effects. We propose that the GRK2 inhibitor may be a promising therapeutic target for cardiovascular complications in type 2 diabetes. PMID- 26234355 TI - [Expected Duties of Pharmacists and Potential Needs of Physicians and Nurses on a Kaifukuki Rehabilitation Ward]. AB - This study investigated the required duties of pharmacists in a kaifukuki rehabilitation ward from the viewpoint of the ward physicians and nurses. A questionnaire survey was distributed to 27 facilities with kaifukuki rehabilitation wards. The questionnaire examined which duties the physicians and nurses expected from pharmacists while on the ward (4 areas, 10 items), as well as the time required for pharmacists to carry out those duties. Multivariate analysis was used to investigate which types of work took the most time for pharmacists on kaifukuki rehabilitation wards. Responses were received from 43 physicians and 184 nurses who worked on the kaifukuki rehabilitation wards of 19 facilities. The results revealed that the essential duties performed by pharmacists were the management of medical supplies, instruction on the use of self-medicating drugs at the time of introduction, and monitoring drug side effects. Furthermore, some duties, such as the distribution of medicines and changing or suggesting new drugs, required pharmacists to spend extended time on the ward. The responses indicated that physicians and nurses recognized the necessity for pharmacists to perform ward duties along with their routine work. This study shows that physicians and nurses working in kaifukuki rehabilitation wards demand proactive participation from pharmacists in appropriate medical therapy, such as instruction in the administration of medications and assessment at the time of prescription changes. PMID- 26234356 TI - [Effect of Adhesives on the Properties of Adhesion, Drug Release and Skin Permeation of Lidocaine Tapes]. AB - A generic drug is defined as a drug product that is comparable to a brand name drug in terms of dosage, form, strength, route of administration, quality, performance characteristics, and indicated use. Generic drugs for topical use, in the case of sheet-like products, are required to be the same as the original drug in terms of application area and dosage form. The composition of such generic drug formulations may differ from that of the original product. The adhesive of any pharmaceutically-active tape that directly contacts the skin plays a role in delivering the active ingredient into the skin, and affects the sensation and ease of handling. Therefore, adhesives are an important ingredient in these products. Thus, the aim of this study was to characterize original and generic lidocaine tape products, and to evaluate the adhesive properties of each. The tack force, peel strength and shear adhesion were measured as adhesive properties. In addition, in vitro drug releasing profiles and skin permeation profiles of the products were evaluated. In vivo transdermal absorption was also evaluated to predict the possibility of adverse effects. Adhesive properties differed among the three analyzed products. These differences may have been caused by differences in the adhesives. Drug-releasing profiles and skin permeation profiles also differed among the three products, even though the pharmacokinetics were not significantly different. By obtaining an adequate understanding of the characteristics of original and generic products, we will be able to provide better tailor-made medications for drug therapies for patients. PMID- 26234357 TI - [Investigation of Intravenous Azithromycin Treatment Safety When Reducing Solvent for Intensive Care Unit Patients]. AB - Intravenous azithromycin (AZM) was approved for use in December 2011 in Japan. In general, intravenous AZM injections are diluted to 1 mg/mL, with a total infusion volume of 500 mL to avoid phlebitis. Patients in intensive care units (ICUs) require small infusion volumes. We retrospectively evaluated the total AZM infusion volume in 65 ICU patients receiving AZM treatment from December 2011 to August 2014. Thirteen patients (20.0%) received a reduced volume [100 mL (5 mg/mL) or 250 mL (2 mg/mL)] using an infusion pump over 2 h. No peripheral phlebitis was observed in any patient. Based on this result, it is assumed that AZM can be safely administered to ICU patients even though the volume of solvent is reduced. AZM is widely recommended for the treatment of community-acquired respiratory infections and is used in patients with severe infections. Further investigation is required in additional patients to understand the effects of AZM volume reduction in greater detail. PMID- 26234358 TI - [Adverse Event Trends Associated with Over-the-counter Drugs: Data Mining of the Japanese Adverse Drug Event Report Database]. AB - Over-the-counter (OTC) drugs play an important role in self-medication. To ensure patient safety, pharmacists should ask patients to pay attention to possible adverse events (AE) associated with OTC drugs and educate patients about the symptoms related to those AEs. The aims of the present study were as follows: (1) to assess the tendency of AEs to occur with OTC drug use in Japan; (2) to detect a safety signal for OTC drugs using the reporting odds ratio (ROR); and (3) to evaluate clustery features, which include suspected drugs and therapeutic classifications, and safety signal indices (number of reports and the ROR), using cluster analysis. The number of reports of AEs following use of combination cold remedy, antipyretic and analgesic remedy, and herbal medicine was 1007, 566, and 221, respectively. We set the cluster number at five; clustery features obtained were as follows: (1) high reporting rate for skin and subcutaneous tissue disorder AEs was the largest group related to combination cold remedy; (2) high reporting rate for nervous system disorder AEs including dizziness was the second largest group. The same medicinal ingredient may demonstrate similar tendencies of the occurrence of AEs and similar clustery features in the Japanese Adverse Drug Event Report database. Our analysis of AEs associated with OTC drugs may be useful for pharmacists and patients alike. Further studies are required to draw better-informed conclusions. PMID- 26234359 TI - Mechanisms of Resistance to Chemotherapy in Gastric Cancer. AB - Although surgical resection is the standard curative therapy for gastric cancer, these tumors are often diagnosed at an advanced stage, when surgery is not recommended. Alternative treatments such as radiotherapy and chemotherapy achieve only very modest results. There is therefore an urgent need to advance in this field of oncologic gastroenterology. The poor response of gastric cancer to chemotherapy is usually due to a combination of mechanisms of chemoresistance (MOC), which may include a reduction in drug uptake (MOC-1a), enhanced drug efflux (MOC-1b), a reduced proportion of active agents in tumor cells due to a reduction in pro-drug activation or an enhancement in drug inactivation (MOC-2), changes in the expression/function of the molecular targets of anticancer drugs (MOC-3), an enhanced ability of cancer cells to repair anticancer drug-induced DNA damage (MOC-4), and decreased expression/function of pro-apoptotic factors or up-regulation of anti-apoptotic genes (MOC-5). Two major goals of modern pharmacology aimed at overcoming this situation are the prediction of a lack of response to chemotherapy and the identification of the underlying mechanisms accounting for primary or acquired refractoriness to anticancer drugs. These are important issues if we are to select the best pharmacological regime for each patient and develop novel strategies to overcome chemoresistance. The present review reports updated information regarding the mechanisms of chemoresistance (from MOC-1 to MOC-5) in gastric cancer, the advances made in the prediction of the failure of chemotherapeutic treatment, and novel strategies based on gene therapy currently being developed to treat these tumors. PMID- 26234360 TI - Design, Synthesis and Biological Evaluation of Thiohydantoin Derivatives as Novel Anti-prostate Cancer Agents. AB - A series of novel thiohydantoin derivatives were synthesized and evaluated for the abilities of inhibiting cell proliferation and prostate specific antigen (PSA) expression in prostate cancer cells. These derivatives selectively inhibited proliferation of AR positive LNCaP cells and PSA expression except compounds 5i and 5j. Compound 5t was approximately 15-fold more potent than MDV3100 to inhibit LNCaP cell proliferation. Compounds 5i and 5j inhibited cell growth of both AR positive LNCaP cells and AR negative PC-3 cells with potential to be developed as novel agents to treat antiandrogen resistant prostate cancer. PMID- 26234361 TI - Based on Nucleotides Analysis of Tumor Cell Lines to Construct and Validate a Prediction Model of Mechanisms of Chemotherapeutics. AB - Cancer is one of the diseases that seriously threaten to human life worldwide. Up to now, chemotherapy remains to be a critical means of cancer treatment, thus the development of chemotherapeutical drugs has become a top priority. An ion pair high performance liquid chromatography (ion pair RP-HPLC) was established for analyzing intracellular nucleotides of tumor cell lines. In this article, a partial least-squares discriminant analysis (PLS-DA) prediction model of mechanisms of chemotherapeutics was established based on four types of drugs with different mechanisms, including antimetabolic agents, antineoplastic agents that affect protein synthesis, agents directly acting on DNA, and RNA interference agents. Then four anti-tumor agents commonly used in clinical were used to validate the availability of the prediction model. Three natural compounds, including 16- dehydropregnenolone (16-DHP), apigenin (API) and diosgenin (DIO), were reported to display anti-tumor effect with unclear mechanisms. The three components were applied to this prediction model firstly. In conclusion, the recognition model was proved to be accurate and feasible to some degree and might become a promising auxiliary method in the process of chemotherapeutic drugs development. PMID- 26234362 TI - Role of Genetics and Epigenetics in Mucosal, Uveal, and Cutaneous Melanomagenesis. AB - Melanoma prevalently occurs on parts of the body that have been overexposed to the sun. However, it can also originate in the nervous system, eye and mucous membranes. Melanoma has been thought for a long time to arise through a series of genetic mechanisms involving numerous irreversible changes within the human genome. However, recently, "epimutations" have attracted considerable attention owing to their high prevalence rate and reversible nature. These observations opened up new perspectives in the use of epidrugs with the potential for restoring the "correct" control of neoplastic genomes. Here, we focused on the common consensus on genetics and epigenetics in melanoma. We also discussed the clinical applications of regulators of epigenetic enzymes able to revert the epigenetic and metabolic hallmarks of melanoma cells. Such anti-neoplastic agents affect the expression profile of antioncogenes, proto-oncogenes, and microRNAs resulting in enhanced differentiation, apoptosis, and growth inhibition. PMID- 26234363 TI - Dominant structural defects in amorphous silicon. AB - The nature of disorder in amorphous silicon (a-Si) is explored by investigating the spatial arrangement and energies of coordination defects in a numerical model. Spatial correlations between structural defects are examined on the basis of a parameter that quantifies the probability for two sites to share a bond. Pentacoordinated atoms are found to be the dominant coordination defects. They show a tendency to cluster, and about 17% of them are linked through three membered rings. As for tricoordinated sites, they are less numerous, and tend to be distant by at least two bond lengths. Typical local geometries associated to under and overcoordinated atoms are extracted from the model and described using partial bond angle distributions. An estimate of the formation energies of structural defects is provided. Using molecular-dynamics calculations, we simulate the implantation of high-energy atoms in the initial structure in order to study the effect of relaxation on the coordination defects and their environments. PMID- 26234364 TI - Integrating biologically inspired nanomaterials and table-top stereolithography for 3D printed biomimetic osteochondral scaffolds. AB - The osteochondral interface of an arthritic joint is notoriously difficult to regenerate due to its extremely poor regenerative capacity and complex stratified architecture. Native osteochondral tissue extracellular matrix is composed of numerous nanoscale organic and inorganic constituents. Although various tissue engineering strategies exist in addressing osteochondral defects, limitations persist with regards to tissue scaffolding which exhibit biomimetic cues at the nano to micro scale. In an effort to address this, the current work focused on 3D printing biomimetic nanocomposite scaffolds for improved osteochondral tissue regeneration. For this purpose, two biologically-inspired nanomaterials have been synthesized consisting of (1) osteoconductive nanocrystalline hydroxyapatite (nHA) (primary inorganic component of bone) and (2) core-shell poly(lactic-co glycolic) acid (PLGA) nanospheres encapsulated with chondrogenic transforming growth-factor beta1 (TGF-beta1) for sustained delivery. Then, a novel table-top stereolithography 3D printer and the nano-ink (i.e., nHA + nanosphere + hydrogel) were employed to fabricate a porous and highly interconnected osteochondral scaffold with hierarchical nano-to-micro structure and spatiotemporal bioactive factor gradients. Our results showed that human bone marrow-derived mesenchymal stem cell adhesion, proliferation, and osteochondral differentiation were greatly improved in the biomimetic graded 3D printed osteochondral construct in vitro. The current work served to illustrate the efficacy of the nano-ink and current 3D printing technology for efficient fabrication of a novel nanocomposite hydrogel scaffold. In addition, tissue-specific growth factors illustrated a synergistic effect leading to increased cell adhesion and directed stem cell differentiation. PMID- 26234365 TI - Trauma or growth after a natural disaster? The mediating role of rumination processes. AB - The aim of this study was to test a cognitive model of posttraumatic symptoms (PTS) and posttraumatic growth (PTG) after exposure to a natural disaster. It was hypothesized that although subjective severity of trauma would be related to the severity of PTS, this relation would be mediated by brooding and cognitive strategies related to the presence of repetitive negative content in thoughts. Furthermore, the relation between severity and PTG would be fully mediated by deliberate rumination (DR), cognitive strategies related to conscious efforts focused on handling the event. To evaluate the cognitive model, adults (N=351) who lost their homes as a result of the earthquake and tsunami that occurred in Chile on February 27, 2010, were selected. Structural equation modeling was used to analyze the data. The resulting model had adequate indices of goodness adjustment and showed that brooding completely mediated the relation between subjective severity and PTS, and DR completely mediated the relation between subjective severity, brooding, and PTG. These results highlight the role of both the content and process of rumination in mediating the association between subjective severity of trauma, PTS, and PTG. The implications of these results for a more comprehensive model of symptom severity that occurs after trauma are discussed. PMID- 26234366 TI - Toughened hydrogels inspired by aquatic caddisworm silk. AB - Aquatic caddisworm silk is a tough adhesive fiber. Part of the toughening mechanism resides in serial, Ca(2+)-phosphate crosslinked nano-domains that comprise H-fibroin, the major structural protein. To mimic the toughening mechanism, a synthetic phosphate-graft-methacrylate prepolymer, as a simple H fibroin analog, was copolymerized within a covalent elastic network of polyacrylamide. Above a critical phosphate sidechain density, hydrogels equilibrated with Ca(2+) or Zn(2+) ions displayed greatly increased initial stiffness, strain-rate dependent yield behavior, and required 100 times more work to fracture than hydrogels equilibrated with Mg(2+) or Na(+) ions. Conceptually, the enhanced toughness is attributed to energy-dissipating, viscous unfolding of clustered phosphate-metal ion crosslinks at a critical stress. The toughness of the bioinspired hydrogels exceeds the toughness of cartilage and meniscus suggesting potential application as prosthetic biomaterials. The tough hydrogels also provide a simplified model to test hypotheses about caddisworm silk architecture, phosphate metal ion interactions, and mechanochemical toughening mechanisms. PMID- 26234367 TI - Electronic properties of free-standing TiO2 nanotube arrays fabricated by electrochemical anodization. AB - Nanotubular TiO2 has attracted considerable attention owing to its unique functional properties, including high surface area and vectorial charge transport along the nanotube, making it a good photocatalytic material. Anodic TiO2 nanotube (TiNT) arrays on a Ti foil substrate were prepared by electrochemical anodic oxidation and SEM/HRTEM/XRD analyses have suggested that the walls of TiO2 tubes are formed from stacked [101] planes (anatase). Both HRTEM and XRD indicate an interplanar spacing of d101 = 0.36 nm in the wall structure. Despite the large amount of work done on nanotube synthesis, a thorough investigation of the electronic and atomic structures of free-standing TiNT arrays has not yet been carried out. X-ray absorption spectroscopy (XAS), resonant inelastic X-ray scattering (RIXS) and scanning photoelectron microscopy (SPEM) are employed herein to examine the electronic and atomic structures at the top and bottom of TiNT arrays. These analyses demonstrate the presence of mixed valence states of the Ti ions (Ti(3+) and Ti(4+)) and a structural distortion at the bottom cap region of the TiNT. Additionally, the results obtained herein suggest the formation of a defective anatase phase at the bottom cap barrier layer between the Ti foil substrate and TiNT during the growth of electrochemically anodized nanotubes. PMID- 26234368 TI - Binder-free three-dimensional high energy density electrodes for ionic-liquid supercapacitors. AB - We demonstrate a facile methodology to fabricate binder-free porous carbon nanofiber electrodes for room temperature ionic-liquid supercapacitors. The device provides an energy density of 80 W h kg(-1) based on the mass of two electrodes while retaining the high rate capability of supercapacitors with near ideal CV curves at a high scan rate of 200 mV s(-1). PMID- 26234369 TI - Unraveling the complexity of protein backbone dynamics with combined (13)C and (15)N solid-state NMR relaxation measurements. AB - Typically, protein dynamics involve a complex hierarchy of motions occurring on different time scales between conformations separated by a range of different energy barriers. NMR relaxation can in principle provide a site-specific picture of both the time scales and amplitudes of these motions, but independent relaxation rates sensitive to fluctuations in different time scale ranges are required to obtain a faithful representation of the underlying dynamic complexity. This is especially pertinent for relaxation measurements in the solid state, which report on dynamics in a broader window of time scales by more than 3 orders of magnitudes compared to solution NMR relaxation. To aid in unraveling the intricacies of biomolecular dynamics we introduce (13)C spin-lattice relaxation in the rotating frame (R1rho) as a probe of backbone nanosecond microsecond motions in proteins in the solid state. We present measurements of (13)C'R1rho rates in fully protonated crystalline protein GB1 at 600 and 850 MHz (1)H Larmor frequencies and compare them to (13)C'R1, (15)N R1 and R1rho measured under the same conditions. The addition of carbon relaxation data to the model free analysis of nitrogen relaxation data leads to greatly improved characterization of time scales of protein backbone motions, minimizing the occurrence of fitting artifacts that may be present when (15)N data is used alone. We also discuss how internal motions characterized by different time scales contribute to (15)N and (13)C relaxation rates in the solid state and solution state, leading to fundamental differences between them, as well as phenomena such as underestimation of picosecond-range motions in the solid state and nanosecond-range motions in solution. PMID- 26234372 TI - Reciprocal hybridization of MoO2 nanoparticles and few-layer MoS2 for stable lithium-ion batteries. AB - The reciprocal hybridization of MoO2 nanoparticles and few-layer MoS2 has been realized via a facile hydrothermal reaction. The resulting MoO2/MoS2 hybrids exhibit a high reversible specific capacity of 1103 mA h g(-1) at 0.2 A g(-1) with a high rate performance (273 mA h g(-1) at 6.4 A g(-1)) and an excellent cycling stability (~92% capacity retention after 800 cycles) mainly due to the strong synergistic effect between them. PMID- 26234370 TI - New insights into the formation mechanism of Ag, Au and AgAu nanoparticles in aqueous alkaline media: alkoxides from alcohols, aldehydes and ketones as universal reducing agents. AB - In this report we present new insights into the formation mechanism of Ag, Au and AgAu nanoparticles with alcohols, aldehydes and ketones in alkaline medium at room temperature. We selected methanol, ethanol, glycerol, formaldehyde, acetaldehyde and acetone to demonstrate their capability of reducing gold and silver ions under the above-mentioned conditions. We showed that the particles are also formed with potassium tert-butoxide in the absence of hydroxides. Our results strongly suggest that alkoxides, formed from any molecule containing a hydroxyl or a functional group capable of generating them in alkaline medium, are the actual and universal reducing agent of silver and gold ions, in opposition to the currently accepted mechanisms. The universality of the reaction mechanism proposed in this work may impact on the production of noble nanoparticles with simple chemicals normally found in standard laboratories. PMID- 26234373 TI - Regulatory T Cells in Kidney Transplantation: New Directions? AB - The contribution of regulatory T cells in the maintenance of kidney graft survival is of major interest. Although many experimental models suggest a role in the induction of graft tolerance, reproducing these findings in clinic is less clear. While modulation of the regulatory T cell response is a promising therapeutic concept in transplantation, a better understanding of function, phenotype and biology is needed to be able to optimally exploit these cells in order to induce graft tolerance. With this in mind, we review here the current understanding of the phenotypic-functional delineation of Tregs and how Tregs can contribute to graft survival. We highlight their potential role in long-term graft survival and kidney operational tolerance. We also discuss the mechanisms needed for the molecular development of regulatory T cells: A combination of FOXP3 molecular partners, epigenetic, metabolic, and posttranslational modifications are necessary to generate well-functioning regulatory T cells and maintain their core identify. We discuss how an improved understanding of these mechanisms will permit the identification of new potent therapeutic strategies to improve kidney graft survival. PMID- 26234374 TI - Diabetes and Hypertension: A Comparative Review of Current Guidelines. AB - Cardiovascular disease plays a major role in the morbidity and mortality of patients with diabetes mellitus. In turn, hypertension is a major risk factor for cardiovascular disease, and its prevalence is increased in diabetes mellitus. Therefore, the detection and management of elevated blood pressure (BP) is a critical component of the comprehensive clinical management of diabetics. Despite significant advances in our understanding of the pathogenesis and treatment of hypertension, there continues to be debate regarding the pharmacologic treatment of hypertension, especially in high-risk groups such as in patients with diabetes mellitus with and without chronic kidney disease (CKD). This debate largely involves at what BP (ie, treatment threshold BP) to initiate pharmacologic antihypertensive therapy and subsequently what treatment target BP should be achieved (ie, goal BP). Presently, there are several guidelines that address hypertension in diabetes mellitus, including the recently released guideline from the Eighth Report of the Joint National Committee (JNC 8). Therefore, this review will compare and contrast these current guidelines, as they relate to the management and treatment of hypertension in diabetes mellitus. Since diabetes mellitus and CKD are significantly inter-related, the presence of CKD as it relates to patients with diabetes mellitus will also be addressed. PMID- 26234375 TI - Refusing Implantable Cardioverter Defibrillator (ICD) Replacement in Elderly Persons-The Same as Giving Up Life: A Qualitative Study. AB - BACKGROUND: More than 20% of implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy (CRT) devices are implanted in the elderly population aged 80 years or older. In recent scientific literature it is suggested to consider termination of ICD therapy, rather than ICD replacement, in this patient group. The aim of this study was to explore the experiences of persons above 80 years of age concerning replacement of the ICD battery, and the shared communication and decision making with healthcare professionals. METHODS: We performed a qualitative, explorative study, inspired by Ricoeur's narrative, with a phenomenological-hermeneutic approach, involving 11 ICD patients older than 80 years. The study period was 2011-2012. RESULTS: The meaning of the patients' experiences of living with an ICD was formulated into two themes: (1) "Feeling safe with the ICD" with the subthemes: "The ICD-a life keeper," "The battery level is important," "ICD shock-no problem." (2) "The physician is an authority" with the subthemes: "Being trustful," "Feeling fine knowing nothing," "Criminal act to deactivate the ICD." CONCLUSION: The elderly ICD recipients tended not to be aware of the option of declining replacement of their ICD. They tended to expect to have their ICD replaced and not to be involved actively in decision making concerning this. Healthcare professionals have an obligation to discuss options and ensure that every patient understands these. More research is needed to change practices and create more realistic, person-centered, ethically acceptable, and constructive healthcare for elderly persons with an ICD. PMID- 26234376 TI - Automated and manual sperm analysis: united we stand, divided we fall. PMID- 26234377 TI - Value of spectral Doppler indices in the assessment of semen parameter deterioration and infertility. PMID- 26234379 TI - betaKlotho expression is reduced in human non-melanoma skin cancer. PMID- 26234378 TI - Clinicopathological description of two cases with SQSTM1 gene mutation associated with frontotemporal dementia. AB - There is a strong genetic influence on the clinicopathological phenotypes associated with frontotemporal lobar degeneration (FTLD) and frontotemporal dementia (FTD). Intracellular deposition of TDP-43 is the phenotypical hallmark of a frequent subgroup of cases. Mutations in the sequestosome 1 (SQSTM1) gene have rarely been found in individuals with FTD. Here we provide a comprehensive clinicopathological description of two cases with a SQSTM1 mutation. The clinical phenotype of patient 1 (mutation p.Glu396*) was compatible with the behavioural variant (bv) of FTD. TDP-43 pathology was consistent with the features of type B of FTLD-TDP pathology. However, prominent neuronal granular cytoplasmic TDP-43 immunoreactivity and abundant oligodendroglial inclusions, proven by colocalization with the oligodendroglial-marker TPPP/p25, were also seen. The clinical phenotype of patient 2 was compatible with bvFTD associated with parkinsonism and bulbar symptoms in the later stage. Genetic testing of patient 2 identified a C9orf72 repeat expansion mutation together with a missense mutation (p.Arg212Cys) in SQSTM1. TDP-43 pathology was characterized by neuritic profiles compatible mostly with type A. In contrast to patient 1, p62 pathology was seen to a greater extent as TDP-43 immunoreactivity in neurons. Using an antibody that detects poly(GP) peptides produced via repeat associated non-ATG translation associated with expanded hexanucleotide repeat in the C9orf72 gene, we confirmed the presence of pathognomonic inclusions. The present study supports previous observations on amyotrophic lateral sclerosis (ALS) that SQSTM1 mutations consistently associate with TDP-43 pathology. The co-presence of C9orf72 mutation may influence the phenotype, thus finding one FTLD (or ALS) related mutation does not exclude the presence of further influential genetic alterations. Oligodendroglial TDP-43 pathology is considerable in some forms of FTLD-TDP, thus their evaluation might be considered to be included in classification systems. PMID- 26234380 TI - Episodic Syndromes That May Be Associated With Migraine: A.K.A. "the Childhood Periodic Syndromes". AB - Previously called "childhood periodic syndromes that are commonly precursors of migraine" in International Headache Classification of Headache Disorders (ICHD) II, these disorders were renamed "episodic syndromes that may be associated with migraine" in ICHD-III beta. The specific disorders reviewed in this article include: benign paroxysmal torticollis, benign paroxysmal vertigo, abdominal migraine, and cyclical vomiting syndrome, as well as infantile colic, which was recently added under the appendix section in ICHD-III beta. PMID- 26234381 TI - Overexpression of a novel cold-responsive transcript factor LcFIN1 from sheepgrass enhances tolerance to low temperature stress in transgenic plants. AB - As a perennial forage crop broadly distributed in eastern Eurasia, sheepgrass (Leymus chinensis (Trin.) Tzvel) is highly tolerant to low-temperature stress. Previous report indicates that sheepgrass is able to endure as low as -47.5 degrees C,allowing it to survive through the cold winter season. However, due to the lack of sufficient studies, the underlying mechanism towards the extraordinary low-temperature tolerance is unclear. Although the transcription profiling has provided insight into the transcriptome response to cold stress, more detailed studies are required to dissect the molecular mechanism regarding the excellent abiotic stress tolerance. In this work, we report a novel transcript factor LcFIN1 (L. chinensis freezing-induced 1) from sheepgrass. LcFIN1 showed no homology with other known genes and was rapidly and highly induced by cold stress, suggesting that LcFIN1 participates in the early response to cold stress. Consistently, ectopic expression of LcFIN1 significantly increased cold stress tolerance in the transgenic plants, as indicated by the higher survival rate, fresh weight and other stress-related indexes after a freezing treatment. Transcriptome analysis showed that numerous stress-related genes were differentially expressed in LcFIN1-overexpressing plants, suggesting that LcFIN1 may enhance plant abiotic stress tolerance by transcriptional regulation. Electrophoretic mobility shift assays and CHIP-qPCR showed that LcCBF1 can bind to the CRT/DRE cis-element located in the promoter region of LcFIN1, suggesting that LcFIN1 is directly regulated by LcCBF1. Taken together, our results suggest that LcFIN1 positively regulates plant adaptation response to cold stress and is a promising candidate gene to improve crop cold tolerance. PMID- 26234382 TI - Genetic and non-genetic factors related to the success of artificial insemination in dairy goats. AB - The objective of this study was to evaluate genetic and non-genetic factors influencing artificial insemination (AI) success in French dairy goats. Data analysis, on a total of 584 676 and 386 517 AI records for Alpine and Saanen breed, respectively, collected from 1992 to 2009, was conducted separately on each breed. We used a linear simple repeatability animal model which combined male and female random effect and environmental fixed effects. The most important environmental factor identified was the period within year effect due to the European heat wave of 2003. The estimated values of the annual fertility exhibited a negative trend of 1% loss of AI success per 10 years for Alpine breed only. The range of variation for the flock*within years random effect was 70% and 65% for Alpine and Saanen breeds. The negative effect on AI success of antibody production after repetitive hormonal treatment was confirmed. We observed an important positive relationship between fertility and protein yield expressed as quartile within flock*years of protein 250-day yield for female with lactation number over 1, while this trend was negative for primiparous females. We detected a negative effect of the duration of conservation of semen with a difference of about 4% of AI success between extreme values (2 to 8+ or 9+ years). Heritability estimates for male fertility were 0.0037 and 0.0043 for Alpine and Saanen breed respectively, while estimates for female fertility was 0.040 and 0.049. Repeatability estimates for males were 0.008 and 0.010 for Alpine and Saanen, respectively, and 0.097 and 0.102 for females. With such low values of heritability, selection can hardly affect fertility. PMID- 26234383 TI - Direct Transfer, Shorter Onset-to-Balloon Time, and Better Clinical Outcome in ST Segment Elevation Myocardial Infarction. PMID- 26234384 TI - Can We Predict or Prevent Progression of Aortic Stenosis? PMID- 26234385 TI - Budesonide inhaler device switch patterns in an asthma population in Swedish clinical practice (ASSURE). AB - BACKGROUND: Dry powder inhaler (DPI) device switch in asthma treatment could potentially increase with the entrance of new devices. We examined the switch patterns of budesonide (BUD) DPI analogues available in Sweden. METHODS: This observational real-life study linked primary healthcare medical records data from the Vastra Gotaland region to national Swedish registries, and included asthma patients (ICD-10-CM J45) prescribed BUD in a multidose DPI. Index date: first dispense of BUD DPI. Switch date: prescription of another BUD DPI device. Study outcomes (switch vs. non-switch) were exacerbations and prescription of short acting beta2 -agonists. Study period was 1 July 2005 to 31 October 2013. RESULTS: Overall, 15,169 asthma patients were on treatment with BUD DPI; 1178 (7.35%) switched to another BUD DPI during the study. Pair-wise 1:1 matching of switchers vs. non-switchers resulted in two groups of 463 patients each (mean age 36 years, 55% female patients). A 25% higher exacerbation rate was seen postswitch (0.40 vs. 0.32; p = 0.047). Switchers were 4.5 year younger and had lower medication possession rate than non-switchers. Switch without primary healthcare visit did not differ between groups regarding consultations and exacerbations (no visit 4.96 and 0.90; visit 4.29 and 0.77, respectively). However, patients without primary healthcare visit at switch had significantly more outpatient hospital visits (2.01 vs. 0.81; p < 0.001). CONCLUSIONS: Considering the low switch rate, asthma patients and physicians in Swedish general practice seem reluctant to switch to another BUD DPI device. Switch, especially without primary healthcare visit, was associated with decreased asthma control resulting in higher exacerbation rate and more outpatient hospital visits. PMID- 26234386 TI - Histone H3K4 methylation regulates hyphal growth, secondary metabolism and multiple stress responses in Fusarium graminearum. AB - Histone H3 lysine 4 methylation (H3K4me) is generally associated with actively transcribed genes in a variety of eukaryotes. The function of H3K4me in phytopathogenic fungi remains unclear. Here, we report that FgSet1 is predominantly responsible for mono-, di- and trimethylation of H3K4 in Fusarium graminearum. The FgSET1 deletion mutant (DeltaFgSet1) was crippled in hyphal growth and virulence. H3K4me is required for the active transcription of genes involved in deoxynivalenol and aurofusarin biosyntheses. Unexpectedly, FgSet1 plays an important role in the response of F. graminearum to cell wall-damaging agents via negatively regulating phosphorylation of FgMgv1, a core kinase in the cell wall integrity pathway. In addition, DeltaFgSet1 exhibited increased resistance to the transcription elongation inhibitor mycophenolic acid. Yeast two hybrid assays showed that FgSet1 physically interacts with multiple proteins including FgBre2, FgSpp1 and FgSwd2. FgBre2 further interacts with FgSdc1. Western blotting analyses showed that FgBre2 and FgSdc1 are associated with H3K4me. Both proteins are also involved in regulating deoxynivalenol biosynthesis and in responses to mycophenolic acid and cell wall-damaging agents. Taken together, these data indicate that H3K4me plays critical roles not only in regulation of fungal growth and secondary metabolism but also in multiple stress responses in F. graminearum. PMID- 26234387 TI - Functional lateralization of temporoparietal junction - imitation inhibition, visual perspective-taking and theory of mind. AB - Although neuroimaging studies have consistently identified the temporoparietal junction (TPJ) as a key brain region involved in social cognition, the literature is far from consistent with respect to lateralization of function. For example, during theory-of-mind tasks bilateral TPJ activation is found in some studies but only right hemisphere activation in others. Visual perspective-taking and imitation inhibition, which have been argued to recruit the same socio-cognitive processes as theory of mind, are associated with unilateral activation of either left TPJ (perspective taking) or right TPJ (imitation inhibition). The present study investigated the functional lateralization of TPJ involvement in the above three socio-cognitive abilities using transcranial direct current stimulation. Three groups of healthy adults received anodal stimulation over right TPJ, left TPJ or the occipital cortex prior to performing three tasks (imitation inhibition, visual perspective-taking and theory of mind). In contrast to the extant neuroimaging literature, our results suggest bilateral TPJ involvement in imitation inhibition and visual perspective-taking, while no effect of anodal stimulation was observed on theory of mind. The discrepancy between these findings and those obtained using neuroimaging highlight the efficacy of neurostimulation as a complementary methodological tool in cognitive neuroscience. PMID- 26234388 TI - Dihydroxydiphenyl - a historical rubber contact allergen? PMID- 26234389 TI - Risk of mortality on and off methadone substitution treatment in primary care: a national cohort study. AB - AIM: To assess whether risk of death increases during periods of treatment transition, and investigate the impact of supervised methadone consumption on drug-related and all-cause mortality. DESIGN: National Irish cohort study. SETTING: Primary care. PARTICIPANTS: A total of 6983 patients on a national methadone treatment register aged 16-65 years between 2004 and 2010. MEASUREMENT: Drug-related (primary outcome) and all-cause (secondary outcome) mortality rates and rate ratios for periods on and off treatment; and the impact of regular supervised methadone consumption. RESULTS: Crude drug-related mortality rates were 0.24 per 100 person-years on treatment and 0.39 off treatment, adjusted mortality rate ratio 1.63 [95% confidence interval (CI) = 0.66-4.00]. Crude all cause mortality rate per 100 person-years was 0.51 on treatment versus 1.57 off treatment, adjusted mortality rate ratio 3.64 (95% CI = 2.11-6.30). All-cause mortality off treatment was 6.36 (95% CI = 2.84-14.22) times higher in the first 2 weeks, 9.12 (95% CI = 3.17-26.28) times higher in weeks 3-4, compared with being 5 weeks or more in treatment. All-cause mortality was lower in those with regular supervision (crude mortality rate 0.60 versus 0.81 per 100 person-years) although, after adjustment, insufficient evidence exists to suggest that regular supervision is protective (mortality rate ratio = 1.23, 95% CI = 0.67-2.27). CONCLUSIONS: Among primary care patients undergoing methadone treatment, continuing in methadone treatment is associated with a reduced risk of death. Patients' risk of all-cause mortality increases following treatment cessation, and is highest in the initial 4-week period. PMID- 26234390 TI - 3D-QSAR Selectivity Analysis of 1-Adamantyl-3-Heteroaryl Urea Analogs as Potent Inhibitors of Mycobacterium tuberculosis. AB - A 3D-QSAR selectivity analysis of 53 adamantyl heteroaryl urea derivatives active against M. tuberculosis is reported. These analogs inhibit Mycobacterial Membrane Protein Large 3 (MmpL3), a proposed transporter for cell wall mycolic acids. However, these analogs also exhibit affinity towards human soluble epoxide hydrolase (sEH) enzyme, making them pharmacologically undesirable. Thus, COMFA and CoMSIA selective studies viz ligand and receptor-based alignment has been described to evaluate key pharmacophoric structural features that may possibly play a crucial role for selective inhibition. This hypothesis was experimentally validated and successfully tested on four novel adamantyl urea based derivatives with known biological activity. Therefore, this approach may pave way to novel specific inhibitors in tuberculosis drug discovery process. PMID- 26234391 TI - Clients' Perception of Outcome of Team-Based Prenatal and Reproductive Genetic Counseling in Serbian Service Using the Perceived Personal Control (PPC) Questionnaire. AB - This is the first study in Serbia and the region of South-East Europe dedicated to clients' perception of outcome and efficiency of prenatal and reproductive genetic counseling. The primary aim of this study was to assess overall value and success of genetic counseling in prenatal and reproductive care with regard to perceived personal control of clients, reflecting also in a part patient comprehension, knowledge retention, and empowerment in decision-making. The standardized Perceived Personal Control questionnaire (PPC) was used for the assessment of 239 female participants. First, we performed a complete validation of the psychometric characteristics of the Serbian-language version of the PPC questionnaire. The validation of the questionnaire permits other researchers from Serbian-speaking regions of South-East Europe to use this standard instrument to assess the effectiveness of prenatal genetic counseling in their communities and analyze advantages and disadvantages of their counseling models. We also measured social and demographic characteristics of participants. Further, we analyzed effects of our team-based prenatal and reproductive genetic counseling model through (a) calculation of PPC scores at three different stages (before initial, after initial, and before second counseling session), and (b) by assessing participants' responses by indication for referral (advanced maternal age, abnormal biochemical screening, family history of hereditary disorders, maternal exposure to drugs, exposure to radiation, exposure to infective agents, infertility or recurrent abortions, and miscellaneous). The results indicate that participants' knowledge after initial counseling increased significantly and after that remained stable and sustainable. A satisfactory level of confidence among participants had been achieved, in that many felt an increased sense of control over their situation and emotional response to it. Indirectly, these results indicate the success of a team-based prenatal genetic counseling model, which has not been assessed in the literature to date. PMID- 26234392 TI - Accufix Atrial J Lead Retention Wire Protrusion Resulting in Aortic Perforation and Cardiac Tamponade More Than Two Decades after Implantation. PMID- 26234393 TI - Characterisation of genetic structure of the Mayan population in Guatemala by autosomal STR analysis. AB - BACKGROUND: Currently, the Guatemalan population comprises genetically isolated groups due to geographic, linguistic and cultural factors. For example, Mayan groups within the Guatemala population have preserved their own language, culture and religion. These practices have limited genetic admixture and have maintained the genetic identity of Mayan populations. AIM: This study is designed to define the genetic structure of the Mayan-Guatemalan groups Kaqchiquel, K'iche', Mam and Q'eqchi' through autosomal short tandem repeat (STR) polymorphisms and to analyse the genetic relationships between them and with other Mayan groups. SUBJECTS AND METHODS: Fifteen STR polymorphisms were analysed in 200 unrelated donors belonging to the Kaqchiquel (n = 50), K'iche' (n = 50), Mam (n = 50) and Q'eqchi' (n = 50) groups living in Guatemala. Genetic distance, non-metric MDS and AMOVA were used to analyse the genetic relationships between population groups. RESULTS: Within the Mayan population, the STRs D18S51 and FGA were the most informative markers and TH01 was the least informative. AMOVA and genetic distance analyses showed that the Guatemalan-Native American populations are highly similar to Mayan populations living in Mexico. CONCLUSIONS: The Mayan populations from Guatemala and other Native American groups display high genetic homogeneity. Genetic relationships between these groups are more affected by cultural and linguistic factors than geographical and local flow. This study represents one of the first steps in understanding Mayan-Guatemalan populations, the associations between their sub-populations and differences in gene diversity with other populations. This article also demonstrates that the Mestizo population shares most of its ancestral genetic components with the Guatemala Mayan populations. PMID- 26234394 TI - A new approach for breeding low-temperature-resistant Volvariella volvacea strains: Genome shuffling in edible fungi. AB - Volvariella volvacea is difficult to store fresh because of the lack of low temperature resistance. Many traditional mutagenic strategies have been applied in order to select out strains resistant to low temperature, but few commercially efficient strains have been produced. In order to break through the bottleneck of traditional breeding and significantly improve low-temperature resistance of the edible fungus V. volvacea, strains resistant to low temperature were constructed by genome shuffling. The optimum conditions of V. volvacea strain mutation, protoplast regeneration, and fusion were determined. After protoplasts were treated with 1% (v/v) ethylmethylsulfonate (EMS), 40 Sec of ultraviolet (UV) irradiation, 600 Gy electron beam implantation, and 750 Gy60 Co-gamma irradiation, separately, the lethality was within 70%-80%, which favored generating protoplasts being used in following forward mutation. Under these conditions, 16 strains of V. volvacea mutated by EMS, electron beam, UV irradiation, and 60 Co-gamma irradiation were obtained. The 16 mutated protoplasts were selected to serve as the shuffling pool based on their excellent low-temperature resistance. After four rounds of genome shuffling and low temperature resistance testing, three strains (VF1 , VF2 , and VF3 ) with high genetic stability were screened. VF1 , VF2 , and VF3 significantly enhanced fruit body shelf life to 20, 28, and 28 H at 10 degrees C, respectively, which exceeded 25%, 75%, and 75%, respectively, compared with the storage time of V23, the most low-temperature-resistant strain. Genome shuffling greatly improved the low-temperature resistance of V. volvacea, and shortened the course of screening required to generate desirable strains. To our knowledge, this is the first paper to apply genome shuffling to breeding new varieties of mushroom, and offers a new approach for breeding edible fungi with optimized phenotype. PMID- 26234395 TI - Clinical assessment and prevalence of parkinsonism in Japanese elderly people. AB - BACKGROUND: Parkinsonism is often observed in the elderly. To clarify the prevalence of parkinsonism-associated diseases and conditions, we conducted a population-based study in a rural island town in western Japan, Ama-cho. METHODS: Participants included 924 subjects aged 65 years or older residing in the town. Between 2008 and 2011, participants were assessed via standardized neurological examination scales, and Brain MRIs were carried out in 2010. Based on the results of assessment using the modified Unified Parkinson's Disease Rating Scale and a standardized neurological examination, participants were diagnosed as having parkinsonism or mild parkinsonian signs (MPS), or as displaying normal motor conditions (M-normal). RESULTS: Of the 729 participants screened, 70 subjects were diagnosed as having parkinsonism, corresponding to a crude prevalence rate of 9.6% (95% CI, 7.9-11.3%), while 167 MPS subjects (22.9%) and 492 subjects experiencing M-normal (67.5%) were observed. Parkinsonism was found in association with various diseases such as Vascular parkinsonism, Lewy body disease, Alzheimer's disease (AD), and idiopathic normal-pressure hydrocephalus. Among the subjects with dementia, the proportion with parkinsonism was higher in the non-AD dementia group. CONCLUSION(S): Parkinsonism occurs in association with several diseases in elderly people. Parkinsonism was also found to be commonly associated with cognitive impairment. PMID- 26234396 TI - Heart failure years after cancer treatment. AB - Progress in cancer treatment has significantly improved survival of patients with cancer. However, the incidence of cardiovascular diseases such as left ventricular dysfunction (LVD) and chronic heart failure (HF) is increasing due to the long-term toxic effects of chemotherapy and radiotherapy. Cardio-oncology teams are necessary to ensure the implementation of primary prevention strategies and screening protocols for early recognition of LVD. Moreover, early administration of advanced treatment for HF is crucial to achieve left ventricular recovery. In this article we will focus on the prevalence of chronic HF among cancer survivors, the main risk factors of LVD and chronic HF, the prevention strategies and management based on the current evidence and, finally, the future perspectives in this field. PMID- 26234397 TI - Energetics and dynamics in organic-inorganic halide perovskite photovoltaics and light emitters. AB - The rapid transcendence of organic-inorganic metal halide perovskite solar cells to above the 20% efficiency mark has captivated the broad photovoltaic community. As the efficiency race continues unabated, it is essential that fundamental studies keep pace with these developments. Further gains in device efficiencies are expected to be increasingly arduous and harder to come by. The key to driving the perovskite solar cell efficiencies towards their Shockley-Queisser limit is through a clear understanding of the interfacial energetics and dynamics between perovskites and other functional materials in nanostructured- and heterojunction type devices. In this review, we focus on the current progress in basic characterization studies to elucidate the interfacial energetics (energy-level alignment and band bending) and dynamical processes (from the ultrafast to the ultraslow) in organic-inorganic metal halide perovskite photovoltaics and light emitters. Major findings from these studies will be distilled. Open questions and scientific challenges will also be highlighted. PMID- 26234398 TI - Contribution of lone-pairs to birefringence affected by the Pb(II) coordination environment: a DFT investigation. AB - Pb(II) cations have long been associated with lone-pairs which can help to enhance the optical anisotropic birefringence. In this paper, the contribution of lead cations to birefringence has been investigated using first-principles and real-space atom-cutting methods. The results show that the contribution of lead cations to birefringence is determined by the degree of stereochemical activity, which is affected by the coordination environment of lead cations. PMID- 26234400 TI - Evaluation of nanoparticle delivered cisplatin in beagles. AB - Intracranial neoplasia is a significant cause of morbidity and mortality in both human and veterinary patients, and is difficult to treat with traditional therapeutic methods. Cisplatin is a platinum (Pt)-containing chemotherapeutic agent approved by the Food and Drug Administration; however, substantial limitations exist for its application in canine brain tumor treatment due to the difficulty in crossing the blood-brain barrier (BBB), development of resistance, and toxicity. A modified Pt(iv)-prodrug of cisplatin, Platin-M, was recently shown to be deliverable to the brain via a biocompatible mitochondria-targeted lipophilic polymeric nanoparticle (NP) that carries the drug across the BBB and to the mitochondria. NP mediated controlled release of Platin-M and subsequent reduction of this prodrug to cisplatin allowed cross-links to be formed with the mitochondrial DNA, which have no nucleotide excision repair system, forcing the overactive cancer cells to undergo apoptosis. Here, we report in vitro effects of targeted Platin-M NPs (T-Platin-M-NPs) in canine glioma and glioblastoma cell lines with results indicating that this targeted NP formulation is more effective than cisplatin. In both the cell lines, T-Platin-M-NP was significantly more efficacious compared to carboplatin, another Pt-based chemotherapy, which is used in the settings of recurrent high-grade glioblastoma. Mitochondrial stress analysis indicated that T-Platin-M-NP is more effective in disrupting the mitochondrial bioenergetics in both the cell types. A 14-day distribution study in healthy adult beagles using a single intravenous injection at 0.5 mg kg(-1) (with respect to Platin-M) of T-Platin-M-NPs showed high levels of Pt accumulation in the brain, with negligible amounts in the other analyzed organs. Safety studies in the beagles monitoring physical, hematological, and serum chemistry evaluations were within the normal limits on days 1, 7, and 14 after injection of either 0.5 mg kg(-1) or 2 mg kg(-1) or 2.2 mg kg(-1) (with respect to Platin-M) of T-Platin-M-NPs. At all doses over the 14-day period, no neurotoxicity was observed based upon periodic neurological examinations and cerebrospinal fluid analysis. These studies demonstrated the translational nature of T-Platin-M-NPs for applications in the treatment of brain tumors. PMID- 26234401 TI - The dysregulation of endoplasmic reticulum stress response in acute-on-chronic liver failure patients caused by acute exacerbation of chronic hepatitis B. AB - Although endoplasmic reticulum (ER) stress is critical in various liver diseases, its role in acute-on-chronic liver failure (AoCLF) caused by acute exacerbation of chronic hepatitis B (CHB) is still elusive. This study aimed to analyse ER stress responses in the progression of HBV-related AoCLF. Normal liver tissues (n = 10), liver tissues of CHB (n = 12) and HBV-related patients with AoCLF (n = 19) were used. Electron microscopy of the ultrastructure of the ER was carried out on liver specimens. The gene and protein expression levels of ER stress-related genes were measured. We further analysed the correlation between the expression levels of ER stress-related molecules and liver injury. Electron microscopy identified typical features of the ER microstructure in AoCLF subjects. Among the three pathways of unfolded protein responses, the PKR-like ER kinase and inositol requiring enzyme 1 signalling pathway were activated in CHB subjects and inactivated in AoCLF subjects, while the activating transcription factor 6 signalling pathway was sustained in the activated form during the progression of AoCLF; the expression of glucose-regulated protein (Grp)78 and Grp94 was gradually decreased in AoCLF subjects compared to healthy individuals and CHB subjects, showing a negative correlation with serum ALT, AST and TBIL; moreover, the ER stress-related apoptosis molecules were activated in the progression of acute exacerbation of CHB. The dysregulated ER stress response may play a complicated role in the pathogenesis of AoCLF, and a severe ER stress response may predict the occurrence of AoCLF caused by acute exacerbation of CHB. PMID- 26234404 TI - Relatively Permanent Pigmented or Vascular Skin Marks for Identification: A Pilot Reliability Study. AB - In child sexual exploitation offenses, the collected evidence images often show the skin of nonfacial body parts of the criminals and victims. For identification in this scenario, "relatively permanent pigmented or vascular skin marks," abbreviated as RPPVSM, were recently introduced as the basis for a novel biometric trait. This pilot study evaluated the interexaminer variability of RPPVSM identification. Four dermatology physicians were recruited to examine RPPVSM from 75 skin images collected from a total of 51 Caucasian and Asian subjects. The images were separated into 50 reference ("suspect") images and 25 evaluation ("evidence") images. The examiners were asked to perform identification by annotating RPPVSM in each of the 25 evaluation images and matching them with the reference images. The rate of misidentification was 0% while the mean rate at which examiners failed to find a match was 6%, indicating the potential of dermatology physicians performing the role of RPPVSM examiners. PMID- 26234405 TI - Correlation of 24-Hour Blood Pressure and Heart Rate Variability to Renal Function Parameters in Hypertensive Patients. The Effect of Smoking. AB - Intrarenal hemodynamics depend on blood pressure (BP), heart rate (HR), and smoking. Although BP levels have been associated with kidney function, the effect of HR levels, BP, and HR variability on renal function are less well clarified. This cross-sectional study sought to determine the association of 24-hour BP and HR variability with kidney function in hypertensive patients, stratified by smoking. The study comprised 9600 nondiabetic, never-treated hypertensive individuals without evident renal impairment examined from 1985 to 2014 (aged 53.3+/-13.4 years, 55.3% males). The 24-hour systolic BP (SBP) and HR variability were estimated via their coefficient of variation (CV =standard deviation*100/mean value) derived from ambulatory recording. The CV SBP-to-CV HR ratio (CV R) was used as a marker of the interplay between 24-hour SBP and HR variability. Renal function was estimated via 24-hour urine creatinine clearance (CrCl), estimated glomerular filtration rate (eGFR), albumin-to-creatinine ratio (ACR), and 24-hour urine alpha1 -microglobulin. After adjustment for age, sex, and smoking, CV SBP was found to be weakly correlated to eGFR (r=-0.017, P=.1) and somewhat more strongly to CrCl, ACR, and alpha1 -microglobulin (r=-0.032, 0.072, and 0.065; P=.002, <.001 and <.001, respectively). CV HR was much better related to renal function, with stronger adjusted correlations to CrCl, eGFR, ACR, and alpha1 -microglobulin (r=0.185, 0.134, -0.306, -0.247; all P<.001, respectively). CV R also showed equally good adjusted correlations (r=-0.175, 0.125, 0.336, 0.262; all P<.001, respectively). Most adjusted correlations for CV HR and CV R were even better in smokers (r=0.213, 0.158, -0.332, -0.272 and 0.183, -0.118, 0.351, 0.275, respectively; all P<.001). CV HR and CV R emerge as better related to kidney function than CV SBP, especially in smokers. The correlation of CV HR and CV SBP to renal function is inverse to each other. ACR and alpha1 -microglobulin are better related to variability indices than CrCl and eGFR. However, causal relations cannot be proved. PMID- 26234406 TI - Thearubigins protect against acetaminophen-induced hepatic and renal injury in mice: biochemical, histopathological, immunohistochemical, and flow cytometry study. AB - CONTEXT: Acetaminophen toxicity is used as a model for studying chemical toxicity. N-acetylcysteine (NAC) is used for the treatment of hepatotoxicity; however, there is no specific therapy for nephrotoxicity. OBJECTIVE: This study was designed to investigate the potential protective effect of black tea extract (BTE) and its main phenolic pigment, thearubigins (TRs), against acetaminophen (APAP)-induced hepatic and renal injury in mice. MATERIALS AND METHODS: Besides control groups, six groups (n = 8) were given intraperitoneally APAP (300 mg/kg) and then after 1.5 hours were treated intraperitoneally as follows: NAC (318 mg/kg), BTE (3%, 4.5%), and TRs (50, 60, and 70 mg/kg). Six hours post-APAP injection, blood was collected for biochemical measurements. Later, liver and kidneys were removed for histopathological, immunohistochemical, and flow cytometry studies. RESULTS: APAP increased alanine aminotransferase and malondialdehyde and decreased glutathione levels in blood. Treatments significantly reversed these changes mostly with NAC and TRs70. TRs showed dose dependent significant differences. The APAP-induced central lobular hepatic necrosis and increased TUNEL positivity were mild with co-administration of NAC and TRs (60, 70) while moderate with co-administration of BTE (3, 4.5) and TRs50. The APAP-increased serum creatinine level was significantly reversed by treatments (mostly TRs60, 70). The APAP-induced renal tubular epithelial degeneration and necrosis were mild with co-administration of TRs (60, 70) while moderate with co-administration of NAC, BTE (3, 4.5), and TRs50. The APAP accumulated apoptotic cells in sub-G1 phase were significantly decreased by treatments, mostly by NAC and TRs70 in the liver and TRs (60, 70) in kidneys. CONCLUSION: Thearubigins protected against acetaminophen-induced hepatotoxicity and nephrotoxicity in mice possibly through their antioxidant activity. PMID- 26234408 TI - Self-Assembled Nanoparticles Based on Amphiphilic Anticancer Drug-Phospholipid Complex for Targeted Drug Delivery and Intracellular Dual-Controlled Release. AB - Integrating advantages of mitomycin C (MMC)-phospholipid complex for increased drug encapsulation efficiency and reduced premature drug release, DSPE-PEG-folate (DSPE-PEG-FA) for specific tumor targeting, we reported a simple one-pot self assembly route to prepare the MMC-phospholipid complex-loaded DSPE-PEG-based nanoparticles (MP-PEG-FA NPs). Both confocal imaging and flow cytometry demonstrated that MMC was distributed into nuclei after cellular uptake and intracellular drug delivery. More importantly, the systemically administered MP PEG-FA NPs led to increased blood persistence and enhanced tumor accumulation in HeLa tumor-bearing nude mice. This study introduces a simple and effective strategy to design the anticancer drug-phospholipid complex-based targeted drug delivery system for sustained/controlled drug release. PMID- 26234407 TI - Effects of oral intake of plasmacytoid dendritic cells-stimulative lactic acid bacterial strain on pathogenesis of influenza-like illness and immunological response to influenza virus. AB - Lactococcus lactis ssp. lactis JCM5805 has been shown to be a rare lactic acid bacterium that can activate plasmacytoid dendritic cells in both murine and human species. In this study, we carried out a randomised placebo-controlled double blind experiment to evaluate its effect on the pathogenesis of influenza-like illness during the winter season. A total of 213 volunteers were divided into two groups, which received either yogurt made with L. lactis JCM5805 or a placebo beverage daily for 10 weeks. In the JCM5805 group, the cumulative incidence days of 'cough' and 'feverishness', which are defined as major symptoms of an influenza-like illness, were significantly decreased compared with the placebo group. In addition, peripheral blood mononuclear cells prepared from volunteers were cultured in the presence of inactivated human influenza virus A/H1N1 (A/PR/8/34). IFN-alpha elicited by A/H1N1 tended to be higher in the JCM5805 group compared with the placebo group, and an IFN-alpha-inducible antiviral factor, interferon-stimulated gene 15 (ISG15), elicited by A/H1N1 was significantly higher in the JCM5805 group compared with the placebo group after the intake period. These results suggest that intake of JCM5805 is able to prevent the pathogenesis of an influenza-like illness via enhancement of an IFN alpha-mediated response to the influenza virus. PMID- 26234409 TI - AIE luminogen-functionalised mesoporous nanomaterials for efficient detection of volatile gases. AB - Mesoporous silica nanoparticles functionalised with aggregation-induced emission (AIE) luminogen via a carbon-nitrogen double bond are fabricated into films by a dip-coating method. The as-made films can serve as efficient fluorescent sensors for the naked-eye detection of volatile acid gases by colour and emission changes, as well as for the detection of 2,4-dinitrotoluene vapours by fluorescence quenching. PMID- 26234410 TI - Impact of the 13-valent pneumococcal conjugate vaccine on the incidence of pneumococcal meningitis in children. AB - The impact of the 13-valent pneumococcal conjugate vaccine (PCV13) on the incidence of pneumococcal meningitis (PM) in children is unknown. To determine this impact, a descriptive multicentre retrospective cohort study was conducted from 2008 to 2013 in northern France. All laboratory-confirmed PM in children aged <18 years in all hospitals of the area with paediatric units were included. Two independent databases were used for exhaustive identification of cases: medical plus laboratory records at each hospital and discharge codes. The corrected incidence of PM was determined by a capture-recapture analysis using these two databases. Sixty-two cases were found over the 6-year period. A decrease of the PM corrected incidence was observed in the global population (P = 0.07), significant only for children aged <2 years, from 11.9/100 000 in 2008 in 1.9/100 000 in 2013 [6.4 fold-decrease, 95% confidence interval (CI) 1.4-41, P = 0.01] between years 2008 and 2013. When comparing the pre- and post-PCV13 periods, this decrease was still statistically significant for children aged <2 years [7.32/100 000 (95% CI 4.39-10.25) to 2.78/100 000 (95% CI 0.96-4.60), P = 0.01]. Only three (5%) cases of PM caused by vaccine serotypes could have been prevented. After the introduction of the PCV13 vaccine, a decrease in the incidence of PM cases in children in northern France was observed. PMID- 26234411 TI - Long-Term Exercise and Bone Mineral Density Changes in Postmenopausal Women--Are There Periods of Reduced Effectiveness? AB - There is increasing evidence that physical exercise can prevent fractures in postmenopausal women. However, even with careful adaptation of the exercise program to subjects' changing bone, health, and fitness status, effectivity may still decrease over the time. This could be specifically the case where the limitations of higher age collide with the specification of the exercise program. Thus, the aim of this study was to monitor bone mineral density (BMD) changes over a 16-year period of supervised exercise. Our hypothesis was that BMD differences at lumbar spine (LS) and femoral neck (FN) between exercisers (EG) and nontraining controls (CG) increased throughout the intervention with significant differences for each of the four 4-year observation periods. Sixty seven (EG, n = 39 versus CG, n = 28) initially early-postmenopausal osteopenic women of the Erlangen Fitness and Osteoporosis Prevention Study (EFOPS) with complete BMD data sets for baseline (1998) and 4-, 8-, 12-, and 16-year follow-up were included in the analysis. The exercise protocol initially focused on a high intensity strategy that addressed bone but increasingly shifted to a more comprehensive intervention. LS-BMD differences between the EG and CG continuously increased (year 4: 2.4% (95%- Confidence Interval 1.0% to 3.8%), year 8: 3.1% (1.6% to 4.7%), year 12: 3.9% (1.9% to 5.8), year 16: 4.5% (2.5% to 6.6%). Correspondingly, rising differences for FN-BMD (0.9% (-0.2% to 2.1%) versus 1.9% (0.4% to 3.3%) versus 2.0% (0.5% to 3.8%) versus 3.0% (1.0% to 5.0%)) were observed. However, in contrast to our hypothesis, group differences within the four 4-year periods were not consistently significant (LS, p = 0.001 to 0.097; FN, p = 0.026 to 0.673); further, BMD kinetics among the groups varied between LS and FN. Of particular importance, significant differences (p <= 0.030) for both regions were still found in the final period. We conclude that exercise-even when adapted for subjects' decreasing bone, health, and fitness status-is consistently effective in favorably affecting BMD in (initially) early-postmenopausal osteopenic women without any leveling-off effect after 16 years of exercise. PMID- 26234412 TI - Using Evidence to Influence Policy and Improve Practice. PMID- 26234414 TI - On the Employment of Persons With Mental Health Issues. PMID- 26234417 TI - A neutral low-coordinate heterocyclic bismuth-tin species. AB - The reaction of distannadiazane bearing bulky (R)Ar*-groups ((R)Ar* = C6H2{C(H)Ph2}2R-2,6,4; R = iPr, tBu) with ECl3 (E = Sb, Bi) was studied resulting in the isolation of previously unknown N,N-bis(dichloropnictino)amines (3) and a novel heterocyclic carbenoid bismuth species (4) bearing a Bi((III)) and a Sn((IV)) center. The structure and bonding was investigated by means of X-ray structure elucidations and DFT calculations. PMID- 26234416 TI - Label-free single-cell protein quantification using a drop-based mix-and-read system. AB - Quantitative protein analysis of single cells is rarely achieved due to technical difficulties of detecting minute amounts of proteins present in one cell. We develop a mix-and-read assay for drop-based label-free protein analysis of single cells. This high-throughput method quantifies absolute, rather than relative, amounts of proteins and does not involve antibody labeling or mass spectrometry. PMID- 26234419 TI - Corrigendum: Grb2 monomer-dimer equilibrium determines normal versus oncogenic function. PMID- 26234421 TI - A Simple and Efficient Preparation of High-Purity Hydrogen Trioxide (HOOOH). AB - A simple and efficient method allows the synthesis of solutions of high-purity hydrogen trioxide (HOOOH), released in the low-temperature methytrioxorhenium(VII) (MTO)-catalyzed transformation of the ozonized polystyrene-supported dimethylphenylsilane. High-purity hydrogen trioxide solutions in diethyl ether, separated from the polymer and free of any reactants and by-products, can be stored at -20 degrees C for weeks. By removing the solvent in vacuo, HOOOH could be isolated in highly pure form or transferred to other solvents, thus significantly extending the research perspectives of HOOOH for novel applications. PMID- 26234418 TI - Energy coupling mechanisms of MFS transporters. AB - Major facilitator superfamily (MFS) is a large class of secondary active transporters widely expressed across all life kingdoms. Although a common 12 transmembrane helix-bundle architecture is found in most MFS crystal structures available, a common mechanism of energy coupling remains to be elucidated. Here, we discuss several models for energy-coupling in the transport process of the transporters, largely based on currently available structures and the results of their biochemical analyses. Special attention is paid to the interaction between protonation and the negative-inside membrane potential. Also, functional roles of the conserved sequence motifs are discussed in the context of the 3D structures. We anticipate that in the near future, a unified picture of the functions of MFS transporters will emerge from the insights gained from studies of the common architectures and conserved motifs. PMID- 26234423 TI - Formation of bcc and fcc during the coalescence of free and supported Fe and Ni clusters. AB - The formation of bcc and fcc during the coalescence of free and supported Fe and Ni clusters has been studied by molecular dynamics simulation using an embedded atom method. Structural evolution of the clusters, coalesced under varying temperature, Ni content and substrate conditions, was explored by interatomic energy, snapshots, pair distribution functions and bond order parameters. The results show that the formation of bcc and fcc is strongly related to Ni content, substrate and coalescence temperature. Free clusters coalesced at 1200 K form bcc at lower Ni contents with fcc forming at higher Ni concentrations and no observable coexistence of bcc and fcc. Differences in coalescence at 1000 K result from the coexistence of bcc and fcc within the Ni range of 50-70%. Free clusters supported on disordered Ni substrates were shown to transform from spherical morphology to islands of supported clusters with preferred epitaxial orientation. The Ni content required to form bcc and fcc coexistence on supported clusters at 1000 K decreased to 30-50% Ni. Free clusters possessing bcc and fcc generally stacked along the bcc (110) and fcc (111) facets, whereas supported clusters stacked along the (111) bcc and (100) fcc planes. Structural transformation was induced by clusters containing greater numbers of atoms. Spread over the substrate enhanced interatomic energy, order substrates affect the epitaxial growth direction and increase the melting points of the supported clusters. This study can be used to predict the nature of fcc and bcc formation in Fe-Ni films. PMID- 26234422 TI - Differential effects of central administration of relaxin-3 on food intake and hypothalamic neuropeptides in male and female rats. AB - Relaxin-3 (RLN3) is an orexigenic neuropeptide that produces sex-specific effects on food intake by stronger stimulation of feeding in female compared with male rats. This study determined which hypothalamic nuclei and associated neuropeptides may be involved in the sex-specific orexigenic effects of RLN3. Relaxin-3 (800 pmol) or vehicle was injected into the lateral ventricle of female and male rats. Food and water intake were measured after the first injection, and rats were euthanized after the second injection to determine the mRNA expression of the hypothalamic neuropeptides. Food but not water intake showed sex-specific effects of RLN3. Stimulation of food intake by RLN3 was significantly higher in female than in male rats. No effect of RLN3 injection was found on c-fos mRNA expression in the arcuate, dorsomedial and ventromedial hypothalamic nuclei. Increased c-fos mRNA expression was observed in the paraventricular hypothalamic nucleus (PVN) in both sexes and in the lateral hypothalamic area (LHA) in female rats. Relaxin-3 injections led to a sex-nonspecific increase in the expression of oxytocin mRNA in the magnocellular PVN. Conversely, RLN3-induced expression of anorexigenic neuropeptide arginine vasopressin (AVP) was significantly higher in the parvocellular PVN in male compared with female rats. Finally, RLN3 administration significantly increased the expression of orexin (ORX) mRNA in the LHA in female but not in male rats. Stronger expression of anorexigenic AVP in the PVN in male rats and increased expression of ORX in the LHA in female rats may contribute to stronger orexigenic effects of RLN3 in female rats compared with male rats. PMID- 26234424 TI - Glancing angle metal evaporation synthesis of catalytic swimming Janus colloids with well defined angular velocity. AB - The ability to control the degree of spin, or rotational velocity, for catalytic swimming devices opens up the potential to access well defined spiralling trajectories, enhance cargo binding rate, and realise theoretically proposed behaviour such as chiral diffusion. Here we assess the potential to impart a well defined spin to individual catalytic Janus swimmers by using glancing angle metal evaporation onto a colloidal crystal to break the symmetry of the catalytic patch due to shadowing by neighbouring colloids. Using this approach we demonstrate a well-defined relationship between the glancing angle and the ratio of rotational to translational velocity. This allows batches of colloids with well-defined spin rates in the range 0.25 to 2.5 Hz to be produced. With reference to the shape and thickness variations across the catalytically active shapes, and their propulsion mechanism we discuss the factors that can lead to the observed variations in rotational propulsion. PMID- 26234425 TI - Three-Dimensional Porous Copper-Graphene Heterostructures with Durability and High Heat Dissipation Performance. AB - Porous materials have historically been of interest for a wide range of applications in thermal management, for example, in heat exchangers and thermal barriers. Rapid progress in electronic and optoelectronic technology necessitates more efficient spreading and dissipation of the heat generated in these devices, calling for the development of new thermal management materials. Here, we report an effective technique for the synthesis of porous Cu-graphene heterostructures with pores of about 30 MUm and a porosity of 35%. Graphene layers were grown on the surfaces of porous Cu, which was formed via the coalescence of molten Cu microparticles. The surface passivation with graphene layers resulted in a thermal conductivity higher than that of porous Cu, especially at high temperatures (approximately 40% at 1173 K). The improved heat dissipation properties of the porous structures were demonstrated by analysis of the thermal resistance and temperature distribution of LED chips mounted on the structures. The effective combination of the structural and material properties of porous Cu graphene heterostructures provides a new material for effective thermal management of high-power electronic and optoelectronic devices. PMID- 26234426 TI - [Risk Management of Teratogenic Drugs ~The Current States of Practice in Europe, US and Japan~]. AB - Thalidomide was approved for the treatment of multiple myeloma in Japan under a risk management program, named TERMS, in 2008. Since then, we have been conducting a survey of the stakeholders to assess the effectiveness of TERMS. These surveys showed patients had enough knowledge of the risks of thalidomide. In the USA, legislation in 2007 granted its U.S. Food and Drug Administration (FDA) the authority to require Risk Evaluation and Mitigation Strategies (REMS) when necessary to ensure that a drug's benefits outweigh its risks. As of 2015, more than 70 drugs, including thalidomide, have REMS programs. In Germany, in the early 1960s, over 5000 children were born with deformities. Therefore, the safety regulations in Germany go far beyond the European Medicines Agency (EMA) safety regulations at the time of thalidomide re-approval; thalidomide can be prescribed by a special prescribing form, including both proof of the patients' awareness of information about the risks, and participation in a pregnancy prevention program. While Japan has taken similar safety measures, a portion of thalidomide is still privately imported there. By March 2013, 594 patients have been registered to Japan's Safety Management System for Unapproved Drugs (SMUD), which was introduced by the Ministry of Health, Labour and Welfare (MHLW) in 2009. The number of females of child bearing potential (FCBPs) was 33 and the fraction (33/594=5.6%) was higher than that (48/7370=0.7%) in the case of TERMS. Risk management of thalidomide is described in this review. PMID- 26234427 TI - Learning and teaching clinical communication in the clinical workplace. AB - BACKGROUND: Clinical communication teaching and learning has become increasingly separate from the clinical workplace over the last 20 years in the UK, and in many medical schools is front-loaded to the early years of the curriculum. Many reasons exist to explain this separation, including the increasing use of simulation. However, learning by simulation alone is not ideal, and the literature now points towards a new direction that blends simulation with authentic experiences in the clinical workplace to aid the transition to clinical life. CONTEXT: This article presents a practical example of collaboration between a London medical school and a hospital trust to provide an integrated clinical communication learning experience for students by situating teaching on the clinical wards for senior medical students. Clinical communication teaching and learning has become increasingly separate from the clinical workplace INNOVATION: We outline a new teaching initiative, the 'Communication on the wards' pilot project, that blends clinical communication teaching with ward-based learning in an authentic environment, with patients, medical students and teachers working together. IMPLICATIONS: This teaching initiative was a practical attempt to bridge the theory-practice gap in clinical communication education, and to place learning in the clinical workplace for students. As such, it was enjoyed by all those who took part, and may be the way forward for clinical communication teaching and learning in the future. PMID- 26234428 TI - When does pleasure start after the end of pain? The time course of relief. AB - Painful events are suggested to elicit two opponent responses: a negatively valenced and a positively valenced process triggered by their onset and termination, respectively. Consequently, stimuli (conditioned stimulus, CS) associated with pain onset (unconditioned stimulus, US) provoke defensive responses like startle potentiation, while stimuli associated with pain termination elicit appetitive responses like startle attenuation. Here we summarize four studies elucidating the time course of the relief following the termination of a painful US. In these studies, the timing of a relief-associated stimulus (reliefCS) presented after a painful US was varied from immediately (Study1), 3 seconds (Study4), or 6 seconds (Study2 and 3) after the US. Responses to these relief CSs were compared also with responses to a stimulus presented before the US (fearCS), and a third stimulus (safetyCS) that was never associated with the US. The synopsis of these studies reveals that the timing of the reliefCS is crucial to turn a defensive response into an appetitive response. Namely, the reliefCS immediately following the US-induced startle potentiation and negative valence (Study1); 3 seconds later, the startle response was slightly less potentiated and the ratings a little less negative (Study4); finally, the reliefCS presented 6 seconds after the US caused startle attenuation (Study2 and 3) and positively valenced ratings (Study3). In sum, the observed time course of relief closely follows the predictions of opponent process theory. This means that relief may be a reinforcer that elicits conditioned appetitive behavior, but its reinforcing properties strongly depend on its temporal relation to the aversive event. PMID- 26234429 TI - PAX1 methylation as an auxiliary biomarker for cervical cancer screening: a meta analysis. AB - OBJECTIVE: Several studies have implicated PAX1 epigenetic regulation in cervical neoplasia. The aim of this meta-analysis was to assess PAX1 gene methylation as a potential biomarker in cervical cancer screening. METHODS: A systematical search of all major databases was performed, in order to include all relevant publications in English until December 31(st) 2014. Studies with insufficient data, conducted in experimental models or associated with other comorbidities were excluded from the meta-analysis. Summary receiver operating characteristics (SROC) for Cervical Intraepithelial Neoplasia grade 2 or worse (CIN2(+)) versus normal, and CIN grade 3 or worse (CIN3(+)) versus normal, were estimated using the bivariate model. RESULTS: Out of the 20 initially included studies, finally 7 (comprising of 1385 subjects with various stages of CIN and normal cervical pathology) met the inclusion criteria. The sensitivity of CIN2(+) versus normal was estimated to be 0.66 (CI 95%, 0.46-0.81) and the specificity 0.92 (CI 95%, 0.88-0.95). On the other hand, the sensitivity of CIN3(+) versus normal was 0.77 (CI 95%, 0.58-0.89) and the specificity 0.92 (CI 95%, 0.88-0.94). Moreover, the area under the curve (AUC) in the former case was 0.923, and in the latter 0.931. CONCLUSION: The results of this meta-analysis support the utility of PAX1 methylation as an auxiliary biomarker in cervical cancer screening. PAX1 could be used effectively to increase the specificity of HPV DNA by detecting women with more advanced cervical abnormalities. PMID- 26234430 TI - Manipulating the Coffee-Ring Effect: Interactions at Work. AB - The evaporation of a drop of colloidal suspension pinned on a substrate usually results in a ring of particles accumulated at the periphery of the initial drop. Intense research has been devoted to understanding, suppressing and ultimately controlling this so-called coffee-ring effect (CRE). Although the crucial role of flow patterns in the CRE has been thoroughly investigated, the effect of interactions on this phenomenon has been largely neglected. This Concept paper reviews recent works in this field and shows that the interactions of colloids with (and at) liquid-solid and liquid-gas interfaces as well as bulk particle particle interactions drastically affect the morphology of the deposit. General rules are established to control the CRE by tuning these interactions, and guidelines for the rational physicochemical formulation of colloidal suspensions capable of depositing particles in desirable patterns are provided. This opens perspectives for the reliable control of the CRE in real-world formulations and creates new paradigms for flexible particle patterning at all kinds of interfaces as well for the exploitation of the CRE as a robust and inexpensive diagnostic tool. PMID- 26234431 TI - Stochastic resonance is a method to improve the biosynthetic response of chondrocytes to mechanical stimulation. AB - Cellular mechanosensitivity is an important factor during the mechanical stimulation of tissue engineered cartilage. While the application of mechanical stimuli improves tissue growth and properties, chondrocytes also rapidly desensitize under prolonged loading thereby limiting its effectiveness. One potential method to mitigate load-induced desensitization is by superimposing noise on the loading waveforms ("stochastic resonance"). Thus, the purpose of this study was to investigate the effects of stochastic resonance on chondrocyte matrix metabolism. Chondrocyte-seeded agarose gels were subjected to dynamic compressive loading, with or without, superimposed vibrations of different amplitudes and frequency bandwidths. Changes in matrix biosynthesis were determined by radioisotope incorporation and subsequent effects on intracellular calcium signaling were evaluated by confocal microscopy. Although dependent on the duration of loading, superimposed vibrations improved cellular sensitivity to mechanical loading by further increasing matrix synthesis between 20-60%. Stochastic resonance also appeared to limit load-induced desensitization by maintaining sensitivity under desensitized loading conditions. While superimposed vibrations had little effect on the magnitude of intracellular calcium signaling, recovery of mechanosensitivity after stimulation was achieved at a faster rate suggesting that less time may be required between successive loading applications. Thus, stochastic resonance appears to be a valuable tool during the mechanical stimulation of cartilage constructs, even when suboptimal stimulation conditions are used. PMID- 26234432 TI - Fabrication of Micro/Nanoscale Motors. PMID- 26234433 TI - Production of Limonoids with Insect Antifeedant Activity in a Two-Stage Bioreactor Process with Cell Suspension Culture of Azadirachta indica. AB - Neem tree (Azadirachta indica) cell suspension culture is an alternative for the production of limonoids for insect control that overcomes limitations related to the supply of neem seeds. To establish conditions for cell growth and azadiracthin-related limonoid production, the effect of different sucrose concentrations, nitrate and phosphate in Murashige and Skoog (MS) medium, and the addition of one precursor and three elicitors was evaluated in shake flasks. The process was scaled up to a 3-l stirred tank bioreactor in one- and two-stage batch cultivation. In shake flasks, more than fivefold increase in the production of limonoids with the modified MS medium was observed (increase from 0.77 to 4.52 mg limonoids/g dry cell weight, DCW), while an increase of more than fourfold was achieved by adding the elicitors chitosan, salicylic acid, and jasmonic acid together (increase from 1.03 to 4.32 mg limonoids/g DCW). In the bioreactor, the volumetric production of limonoids was increased more than threefold with a two stage culture in day 18 (13.82 mg limonoids/l in control single-stage process and 41.44 mg/l in two-stage process). The cultivation and operating mode of the bioreactor reported in this study may be adapted and used in optimization and process plant development for production of insect antifeedant limonoids with A. indica cell suspension cultures. PMID- 26234434 TI - Quantitative Evaluation of Myostatin Gene in Stably Transfected Caprine Fibroblast Cells by Anti-Myostatin shRNA. AB - Skeletal muscle is the major component of lean tissue that is used for consumption, and myostatin is a negative regulator of skeletal muscle growth. Downregulation of this gene therefore offers a strategy for developing superior animals with enhanced muscle growth. Knockdown of myostatin was achieved by RNA interference technology. The anti-myostatin shRNA were designed and stably transfected in caprine fibroblast cells. The reduced expression of target gene was achieved and measured in clonal fibroblast cells by real-time PCR. Two single cell clones induced significant decrease of myostatin gene expression by 73.96 and 72.66 %, respectively (P < 0.05). To ensure the appropriate growth of transfected cell, seven media were tested. The best suited media was used for transfected fibroblast cell proliferation. The findings suggest that shRNA provides a novel potential tool for gene knockdown and these stably transfected cells can be used as the donor cells for animal cloning. PMID- 26234435 TI - Heterologous Expression and Characterization of a GH3 beta-Glucosidase from Thermophilic Fungi Myceliophthora thermophila in Pichia pastoris. AB - A novel beta-glucosidase of glycoside hydrolase (GH) family 3 from Myceliophthora thermophila (mtbgl3b) was successfully expressed in Pichia pastoris. The full length gene consists of 2613 bp nucleotides encoding a protein of 870 amino acids. MtBgl3b showed maximum activity at pH 5.0 and remained more than 70 % relative activity at 3.5-6.0. The enzyme displayed the highest activity at 60 degrees C and kept about 90 % relative activity for 50-65 degrees C; besides, the enzyme showed psychrophilic trait and remains 51 % relative activity at 40 degrees C. MtBgl3b exhibited good stability over a wide pH range of 3.0-10.0 and was thermostable at 60 and 65 degrees C. The enzyme displayed highest activity towards p-nitrophenyl-beta-D-glucopyranoside (pNPG), followed by p-nitrophenyl-D cellobioside (pNPC), cellotetraose, cellotriose, cellobiose, and gentiobiose. When using 10 % cellobiose (w/v) as the substrate, the enzyme showed transglycosylation activity to produce the cellotriose. The kinetic parametric of K m and V max were 2.78 mM and 927.9 MUM mg(-1) min(-1), respectively. Finally, the reaction mode of the enzyme and the substrates were analyzed by molecular docking approach. PMID- 26234436 TI - Mechanism of Adsorptive Removal of Methylene Blue Using Dried Biomass of Rhizopus oryzae. AB - Adsorption is an efficient way to remove synthetic dyes from industrial effluent. Here, we show mechanism of adsorptive removal of cationic dye methylene blue (MB) from its aqueous solution using dried biomass of Rhizopus oryzae as a biosorbent. The optimum pH and temperature for adsorption was found to be 7.0 and 28 degrees C, respectively. Scanning electron microscopy (SEM) of the biomass suggested distinct changes in surface topology post-MB adsorption, while Fourier transform infrared (FTIR) study indicated chemical interaction between the surface of the biomass and MB. Chemical modification of -OH and -C=O groups of biomass reduced the MB adsorption and corroborated with the FTIR analyses. Kinetics study revealed that the adsorption rate was fast initially and reached equilibrium at 4 h following a pseudo-second-order-kinetics. The adsorption isotherm followed Freundlich isotherm model with n value of 1.1615.The dried biomass of R. oryzae can be used as a potent biosorbent for the removal of MB. PMID- 26234437 TI - Investigating Cellular Responses During Photohydrogen Production by the Marine Microalga Tetraselmis subcordiformis by Quantitative Proteome Analysis. AB - The marine microalga Tetraselmis subcordiformis could photoproduce hydrogen under the regulation of carbonyl cyanide m-chlorophenylhydrazone (CCCP), and a hydrogen production process kinetic analysis was characterized by two peaks, suggesting that two distinct mechanisms might exist in this alga. Therefore, 2D nanoliquid chromatography-tandem mass spectrometry (LC-MS/MS) was introduced to analyze the proteome of samples from different time points. A total of 912 proteins were identified, providing a global view of the cellular responses at the proteomic level. These proteins can be divided into multiple functional groups including stress responses, energy metabolism and redox homeostasis. The quantitative proteomic data provided more details on the electron donors for hydrogen production. During the first stage, photosystem II produced electrons for hydrogen production; during the second stage, metabolites were the major electron donors via nonphotochemical plastoquinone reduction by NADH dehydrogenase. PMID- 26234439 TI - Unveiling the relationships among the viscosity equations of glass liquids and colloidal suspensions for obtaining universal equations with the generic free volume concept. AB - The underlying relationships among viscosity equations of glass liquids and colloidal suspensions are explored with the aid of free volume concept. Viscosity equations of glass liquids available in literature are focused and found to have a same physical basis but different mathematical expressions for the free volume. The glass transitions induced by temperatures in glass liquids and the percolation transition induced by particle volume fractions in colloidal suspensions essentially are a second order phase transition: both those two transitions could induce the free volume changes, which in turn determines how the viscosities are going to change with temperatures and/or particle volume fractions. Unified correlations of the free volume to both temperatures and particle volume fractions are thus proposed. The resulted viscosity equations are reducible to many popular viscosity equations currently widely used in literature; those equations should be able to cover many different types of materials over a wide temperature range. For demonstration purpose, one of the simplified versions of those newly developed equations is compared with popular viscosity equations and the experimental data: it can well fit the experimental data over a wide temperature range. The current work reveals common physical grounds among various viscosity equations, deepening our understanding on viscosity and unifying the free volume theory across many different systems. PMID- 26234438 TI - Lipid Production of Heterotrophic Chlorella sp. from Hydrolysate Mixtures of Lipid-Extracted Microalgal Biomass Residues and Molasses. AB - This study investigated the feasibility of lipid production of Chlorella sp. from waste materials. Lipid-extracted microalgal biomass residues (LMBRs) and molasses were hydrolyzed, and their hydrolysates were analyzed. Five different hydrolysate mixture ratios (w/w) of LMBRs/molasses (1/0, 1/1, 1/4, 1/9, and 0/1) were used to cultivate Chlorella sp. The results showed that carbohydrate and protein were the two main compounds in the LMBRs, and carbohydrate was the main compound in the molasses. The highest biomass concentration of 5.58 g/L, Y biomass/sugars of 0.59 g/g, lipid productivity of 335 mg/L/day, and Y lipids/sugars of 0.25 g/g were obtained at the hydrolysate mixture ratio of LMBRs/molasses of 1/4. High C/N ratio promoted the conversion of sugars into lipids. The lipids extracted from Chlorella sp. shared similar lipid profile of soybean oil and is therefore a potential viable biodiesel feedstock. These results showed that Chlorella sp. can utilize mixed sugars and amino acids from LMBRs and molasses to accumulate lipids efficiently, thus reducing the cost of microalgal biodiesel production and improving its economic viability. PMID- 26234440 TI - How many markers are enough? Factors influencing parentage testing in different livestock populations. AB - Reliability of parentage test panels is usually based on its power to exclude wrong parentage assignments based on allele frequencies. We evaluated the rates of false exclusions and inclusions in parentage assignments, and how these results are affected by allele frequencies, panel sizes and the number of allowed mismatches. We also evaluated the reliability of parentage testing by comparing populations with distinct genetic backgrounds using pure and composite families of cattle and sheep. Allowing for 1% genotype mismatches in true parent-offspring relations provided the best compromise between false-positive and false-negative assignments. Pure breeds needed at least 200-210 single-nucleotide polymorphism (SNP) markers to correctly assign relations, but between 700 and 890 markers to avoid assigning incorrect relationships. Composite breeds needed between 220 (sheep) and 500 (cattle) markers for correct assignment; 680 (cattle) to 4400 (sheep) SNPs were needed to eliminate false-positive assignments. Allowing 0% genotype mismatches decreased false-positive but increased false-negative assignments, whilst a higher threshold of 2% showed the opposite effects. Panels with high minor allele frequencies (0.35-0.45) provided the best chance for correct parentage resolutions requiring fewer markers. Further, we propose that a dynamic threshold would allow adapting to population specific error rates. A comparison to the performance of the official International Society for Animal Genetics SNP panel for cattle and a recently published SNP panel for sheep showed that randomly selected markers performed only slightly worse for the applied parentage test based on opposing homozygotes. This suggests that even with carefully selected panels, only marginal assignment improvements are obtainable for a particular number of SNPs. The main point for improvement is the number of markers used. We recommend using at least 200 SNP markers for parentage testing if the aim is to reduce false-negative results. To fully exclude false positives at least 700 markers are required. PMID- 26234441 TI - Thermal Imaging of Body Surface Temperature Distribution in Women with Anorexia Nervosa. AB - The drastic reduction in body weight observed in anorexia nervosa (AN) leads to various endocrine changes and consequently to disturbance in thermoregulation mechanisms and body temperature. Thermography allows for a noninvasive diagnosis of the distribution of skin surface temperatures, which is especially important for difficult patients such as women with AN, who are often very sensitive and difficult to treat. The main aim of this study was to measure the mean temperatures (Tmean ) of selected body areas in young women diagnosed with AN and identify those areas where the temperature differences were particularly significant between healthy women and them. Additionally, we determined the relationships between body mass index, body composition (especially subcutaneous and VFM) and the value of mean surface temperature (Tmean ) in AN woman. In the subjects with AN, Tmean of the abdomen, lower back and thighs were significantly higher than in the reference group, while Tmean of the hands were significantly lower. Among other things, analysis showed a significant negative correlation between Tmean of the abdomen, lower back and thighs, and the mass of subcutaneous and visceral fat. The lower Tmean of the hand was directly proportional to the reduced anthropomorphic parameters. The direct evaluation of body surface temperature distribution could provide clinical implications for the treatment of anorexic patients, including the potential use of thermotherapy in stimulating the circulatory system, especially in hypothermia, bradycardia and hypotension. PMID- 26234442 TI - Effect of a new insulin treatment regimen on glycaemic control and quality of life of Muslim patients with type 2 diabetes mellitus during Ramadan fast - an open label, controlled, multicentre, cluster randomised study. AB - We performed a non-inferiority trial comparing insulin detemir (Levemir) and biphasic insulin (NovoMix70) to standard care during Ramadan fast in insulin treated type 2 diabetes mellitus (T2DM) patients. This was an open label, controlled, multicentre, cluster randomised non-inferiority study. Insulin treated T2DM patients from 12 randomly selected primary clinics received Levemir and NovoMix 70 (intervention, n = 127) or standard care according to the American Diabetes Association recommendations (control, n = 118). Insulin dose (intervention) was 60% of the usual, of this 40% was dosed as Levemir at sunrise and 60% as NovoMix 70 before dinner. Insulin was titrated according to daily 4 point self-measured blood glucose (4P-SMBG) levels. The primary outcome was the difference in mean daily 4P-SMBG during days 23-30 of treatment. Mean age was 60.1 (SD 8.9) and 59.4 (SD 10.1) years in the intervention and control respectively. Mean HbA1c was 8.38% (68 mmol/mol) (SD 0.96) and 8.45% (69 mmol/mol) (SD 1.08). Mean BMI was 32.99 (SD 7.05) and 33.08 (SD 7.24), respectively. The intervention was non-inferior to standard care as assessed by mean 4P-SMBG during days 23-30 of treatment [155 (SD 30.76) mg% and 159 (SD 33.24) mg% respectively, p = 0.269]. Adverse event rate was significantly lower in the intervention group [0.04 (SD 0.06) vs. 0.07 (SD 0.11), p = 0.010]. In particular, hypoglycaemia event rate was lower in the intervention group [0.00 (SD 0.01) vs. 0.01 (SD 0.03), p <= 0.001]. To conclude, treatment with Levemir and NovoMix 70 was non-inferior to standard care in this heterogeneous group of patients and was associated with less adverse events. PMID- 26234443 TI - In memoriam. Herwig Thoma, PhD: Pioneer in Artificial Heart and Functional Electrical Stimulation. PMID- 26234444 TI - A Look Back at the ISRBP 2014 Congress to Move Forward in 2015 and Beyond. PMID- 26234445 TI - Welcome to the 23rd Annual Congress of the International Society for Rotary Blood Pumps. PMID- 26234446 TI - Welcome From the President of the International Society for Rotary Blood Pumps. PMID- 26234447 TI - Numerical Analysis of Blood Damage Potential of the HeartMate II and HeartWare HVAD Rotary Blood Pumps. AB - Implantable left ventricular assist devices (LVADs) became the therapy of choice in treating end-stage heart failure. Although survival improved substantially and is similar in currently clinically implanted LVADs HeartMate II (HM II) and HeartWare HVAD, complications related to blood trauma are frequently observed. The aim of this study was to compare these two pumps regarding their potential blood trauma employing computational fluid dynamics. High-resolution structured grids were generated for the pumps. Newtonian flow was calculated, solving Reynolds-averaged Navier-Stokes equations with a sliding mesh approach and a k omega shear stress transport turbulence model for the operating point of 4.5 L/min and 80 mm Hg. The pumps were compared in terms of volumes subjected to certain viscous shear stress thresholds, below which no trauma was assumed (von Willebrand factor cleavage: 9 Pa, platelet activation: 50 Pa, and hemolysis: 150 Pa), and associated residence times. Additionally, a hemolysis index was calculated based on a Eulerian transport approach. Twenty-two percent of larger volumes above 9 Pa were observed in the HVAD; above 50 Pa and 150 Pa the differences between the two pumps were marginal. Residence times were higher in the HVAD for all thresholds. The hemolysis index was almost equal for the HM II and HVAD. Besides the gap regions in both pumps, the inlet regions of the rotor and diffuser blades have a high hemolysis production in the HM II, whereas in the HVAD, the volute tongue is an additional site for hemolysis production. Thus, in this study, the comparison of the HM II and the HVAD using numerical methods indicated an overall similar tendency to blood trauma in both pumps. However, influences of turbulent shear stresses were not considered and effects of the pivot bearing in the HM II were not taken into account. Further in vitro investigations are required. PMID- 26234448 TI - Animal Experiments of the Helical Flow Total Artificial Heart. AB - Severe cardiac failure patients require a total artificial heart (TAH) to save life. To realize a TAH that can fit a body of small stature and has high performance, high durability, good anatomical fitting, good blood compatibility, and physiological control, we have been developing the helical flow TAH (HFTAH) with two helical flow pumps with hydrodynamic levitation impeller. Animal experiments of the HFTAH were conducted to perform in vivo studies. The HFTAH was implanted in 13 adult female goats weighing 45.0-64.0 kg. After surgery, neither anti-coagulant nor anti-platelet medication was given systemically. The HFTAH was usually driven with a quasi-pulsatile mode. The 1/R control or DeltaP control was applied to control the circulation. The DeltaP control is a new method using simplified equation of the 1/R control. The HFTAH could be implanted in all goats with good anatomical fitting. Two goats survived for a long time (100 and 68 days). Major causes of termination were device failure and surgical complications. In the device failure, trouble with hydrodynamic bearing was conspicuous. In the two long-term survived goats, experiments were terminated with bearing instability that was probably caused by the suction effect. In these goats, hemolysis occurred on postoperative day 88 and 44, which was considered to be relevant to the bearing trouble. Thrombus was found at the broken right bearing of the 100-day survived goat. However, antithrombogenicity of the pump is expected to be good unless bearing trouble occurs. In two long-term survived goats, the 1/R control or DeltaP control worked appropriately to prevent the elevation of right atrial pressure. In both goats, hemodynamic parameters changed with the condition of the animals, liver and kidney functions remained almost normal except when recovering from surgery and during hemolysis, and total protein recovered 2 weeks after surgery. Although instability of the hydrodynamic bearing should be improved, performance of the HFTAH with physiological control could be demonstrated. PMID- 26234449 TI - Initial Acute Animal Experiment Using a New Miniature Axial Flow Pump in Series With the Natural Heart. AB - We have advocated an axial flow blood pump called "valvo pump" that is implanted at the aortic valve position, and we have developed axial flow blood pumps to realize the concept of the valvo pump. The latest model of the axial flow blood pump mainly consists of a stator, a directly driven impeller, and a hydrodynamic bearing. The axial flow blood pump has a diameter of 33 mm and length of 74 mm, and the length of anatomical occupation is 33 mm. The axial flow blood pump is anastomosed to the aorta with polytetrafluoroethylene (PTFE) cuffs worn on the inflow and outflow ports. Dp-Q curves of the axial flow blood pump are flatter than those of ordinary axial flow pumps, and pump outflow of 5 L/min was obtained against a pressure difference of 50 mm Hg at a rotational speed of 9000 rpm in vitro. The axial flow blood pump was installed in a goat by anastomosing with the thoracic descending aorta using PTFE cuffs, and it was rotated at a rotational speed of 8000 rpm. Unlike in case of the ventricular assistance in parallel with the natural heart, pulsatilities of aortic pressure and aortic flow were preserved even when the pump was on, and mean aortic flow was increased by 1.5 L/min with increase in mean aortic pressure of 30 mm Hg. In conclusion, circulatory assistance in series with the natural heart using the axial flow blood pump was able to improve hemodynamic pulsatility, and it would contribute to improvement of end-organ circulation. . PMID- 26234450 TI - Pump Speed Waveform Analysis to Detect Aortic Valve Opening in Patients on Ventricular Assist Device Support. AB - As the aortic valve (AV) opens, the pump pressure head remains constant, which is reflected as a "notch/plateau" in pump pressure and flow signals. However, instantaneous flow estimation may be influenced by friction and is particularly difficult in axial pumps. Therefore, a new method to determine the duration of AV opening based on the area under the curve (AUC) of the power spectral density analysis of pump speed signal was developed. Data from patients implanted with HeartWare HVAD left ventricular assist device were studied at different pump speeds, with simultaneous transthoracic echocardiography in two cohorts. In the first group, pump data of 15 patients were used to investigate the ability to discriminate between an open and closed AV. In the second cohort of a further 13 patients, the duration of AV opening was measured from digitized M-mode images, and the relationship between the AV opening time and the new method assessed. In 14 of the initial 15 patients, AV status could be discriminated using only one threshold for all patients. In the second cohort, gradual speed reduction resulted in aortic valve opening in 12 of the 13 patients. The correlation between AV opening duration and AUC was 0.96 +/- 0.03. Regression analysis indicated a linear relationship in each of the patients with a small error between the fit and the measured opening time (root mean square error = 11.0 +/- 7.6 ms). However, the slopes (69.0 +/- 52.8) and intercepts (-31.4 +/- 78.0) varied widely between patients. The sensitivity and specificity for the new method using AUC threshold of 0.95 for aortic valve closure was 95% and 91%, respectively. The newly developed method to detect AV opening not only provides information on the AV status during LVAD support (open/closed) but also gives insight into the duration of AV opening. Because the slope of the relationship varies from patient to patient, initial training and adaptation of the method to each patient seems to be required. PMID- 26234451 TI - Real-Time Observation of Thrombus Growth Process in an Impeller of a Hydrodynamically Levitated Centrifugal Blood Pump by Near-Infrared Hyperspectral Imaging. AB - Understanding the thrombus formation in cardiovascular devices such as rotary blood pumps is the most important issue in developing more hemocompatible devices. The objective of this study was to develop a hyperspectral imaging (HSI) method to visualize the thrombus growth process within a rotary blood pump and investigate the optical properties of the thrombus. An in vitro thrombogenic test was conducted using fresh porcine blood and a specially designed hydrodynamically levitated centrifugal blood pump with a transparent bottom. The pump rotating at 3000 rpm circulated the blood at 1.0 L/min. The bottom surface of the pump was illuminated with white light pulsed at the same frequency as the pump rotation, and the backward-scattered light was imaged using the HSI system. Using stroboscopic HSI and an image construction algorithm, dynamic spectral imaging at wavelengths ranging from 608 to 752 nm within the rotating pump was achieved. After completing the experiment, we collected the red thrombus formed in the pump impeller and quantified the thrombus hemoglobin concentration (Hbthrombus ). The spectrum changed around the center of the impeller, and the area of change expanded toward the impeller flow path. The shape corresponded approximately to the shape of the thrombus. The spectrum change indicated that the light scattering derived from red blood cells decreased. The Hbthrombus was 4.7 +/- 1.3 g/dL versus a total hemoglobin of 13 +/- 0.87 g/dL. The study revealed that Hbthrombus was reduced by the surrounding blood flow. PMID- 26234452 TI - Hemocompatibility of Axial Versus Centrifugal Pump Technology in Mechanical Circulatory Support Devices. AB - The hemocompatible properties of rotary blood pumps commonly used in mechanical circulatory support (MCS) are widely unknown regarding specific biocompatibility profiles of different pump technologies. Therefore, we analyzed the hemocompatibility indicating markers of an axial flow and a magnetically levitated centrifugal device within an in vitro mock loop. The HeartMate II (HM II; n = 3) device and a CentriMag (CM; n = 3) adult pump were investigated in a human whole blood mock loop for 360 min using the MCS devices as a driving component. Blood samples were analyzed by enzyme-linked immunosorbent assay for markers of coagulation, complement system, and inflammatory response. There was a time-dependent activation of the coagulation (thrombin-antithrombin complexes [TAT]), complement (SC5b-9), and inflammation system (polymorphonuclear [PMN] elastase) in both groups. The mean value of TAT (CM: 4.0 MUg/L vs. 29.4 MUg/L, P < 0.001; HM II: 4.5 MUg/L vs. 232.2 MUg/L, P < 0.05) and PMN elastase (CM: 53.4 ng/mL vs. 253.8 ng/mL, P < 0.05; HM II: 28.0 ng/mL vs. 738.8 ng/mL, P < 0.001) significantly increased from baseline until the end of the experiments (360 min). After 360 min, TAT and PMN values were significantly higher in the HM II group compared with the values in the CM adult group. The values of SC5b-9 increased from baseline to 360 min in the CM group (CM: 141.8 ng/mL vs. 967.9 ng/mL, P < 0.05) and the HM II group. However, the increase within the HM II group (97.3 vs. 2462.0, P = 0.06) and the comparison of the 360-min values between CM group and HM II group did not reach significance (P = 0.18). The activation of complement, coagulation, and inflammation system showed a time-dependent manner in both devices. The centrifugal CM device showed significantly lower activation of coagulation and inflammation than that of the HM II axial flow pump. Both HM II and CM have demonstrated an acceptable hemocompatibility profile in patients. However, there is a great opportunity to gain a clinical benefit by developing techniques to lower the blood surface interaction within both pump technologies and a magnetically levitated centrifugal pump design might be superior. PMID- 26234453 TI - Interventional Occlusion of Left Ventricular Assist Device Outflow Graft After Pump Thrombosis and Partial Myocardial Recovery. PMID- 26234455 TI - In-transit metastasis of advanced eccrine porocarcinoma. PMID- 26234456 TI - Contemporary outcomes of surgery for aortic root aneurysms: A propensity-matched comparison of valve-sparing and composite valve graft replacement. AB - OBJECTIVE: The study objective was to give an overview of the current state of the art of the surgical treatment of aortic root pathologies in a high-volume center. METHODS: From May 1997 to January 2014, aortic root replacement was performed in 890 consecutive patients; 289 received a mechanical composite valved graft, 421 received a biologic composite valved graft, and 180 received a valve sparing reconstruction. Propensity matching analysis was used to neutralize the differences in baseline characteristics between patients assigned to the different procedures. RESULTS: Operative mortality was 0.2% (0% in the valve sparing reconstruction group); the incidence of major postoperative complications was less than 0.5%. Predictors of adverse in-hospital outcome were age, nonelective operation, renal status, reoperation, New York Heart Association class, ejection fraction, and concomitant procedures. Five-year survival was 89.4%. Previous myocardial infarction, preoperative renal status, redo operation, and concomitant procedures were significantly associated with follow-up death. In the propensity-matched groups, the type of operation performed did not affect in hospital and late outcome. Aortic reintervention rates at 5 years were 0% for the mechanical composite valved graft group, 2.4% for the biologic composite valved graft group, and 7.3% for the valve-sparing reconstruction series. CONCLUSIONS: In the current era, aortic root replacement can be performed with low perioperative risk in high-volume aortic centers. The type of operation performed does not affect early or late survival. Although the mechanical composite valved graft remains the gold standard for durability, the biologic composite valved graft and valve-sparing reconstruction are excellent options for those who cannot take or want to avoid long-term anticoagulation. PMID- 26234457 TI - The quest toward the Holy Grail of mechanical circulatory support. PMID- 26234458 TI - The Surgical Apgar Score in esophagectomy. AB - OBJECTIVE: The Surgical Apgar Score is a validated prognostic tool that is based on select intraoperative variables (heart rate, mean arterial pressure, and blood loss). It has been shown to be a strong predictor of morbidity and mortality in a variety of surgical populations. Esophagectomy for malignancy represents a unique subset of patients at high risk for postoperative complications. This study assessed the ability of a modified esophagectomy Surgical Apgar Score (eSAS) to predict 30-day major morbidity. METHODS: A retrospective review included 168 patients who underwent elective esophagectomy for malignant disease at the University of Wisconsin from January 2009 through July 2013. Preoperative patient characteristics, intraoperative details, and short-term outcomes were recorded. Primary outcome was 30-day major morbidity. Univariate and multivariate analyses were performed to determine associations between predictive variables, eSAS, and major morbidity. RESULTS: Major morbidity occurred in 35% of cases. Univariate analysis showed that eSAS of 6 or less was strongly associated with major morbidity (unadjusted odds ratio, 2.55; 95% confidence interval, 1.32-4.91; P = .005). Other risk factors included transhiatal technique, body mass index less than 20 or greater than 35 kg/m(2), and history of diabetes mellitus. In multivariate analysis, eSAS of 6 or less remained a strong predictor of postoperative complications (adjusted odds ratio, 3.75; 95% confidence interval, 1.70-8.26; P = .001). CONCLUSIONS: The eSAS was strongly associated with 30-day major morbidity after esophagectomy. Prospective studies are needed to determine whether improved outcomes can be achieved with the eSAS for risk-stratified triage and postoperative care modification. PMID- 26234459 TI - Successful thoracoscopic resection of large symptomatic mediastinal lymphatic malformations: Report of 3 cases. PMID- 26234460 TI - Chlorobaculum tepidum growth on biogenic S(0) as the sole photosynthetic electron donor. AB - The green sulfur bacteria, the Chlorobi, are phototrophic bacteria that oxidize sulfide and deposit extracellular elemental sulfur globules [S(0)]. These are subsequently consumed after sulfide is exhausted. S(0) globules from a Chlorobaculum tepidum mutant strain were purified and used to show that the wild type strain of Cba. tepidum can grow on biogenic S(0) globules as the sole photosynthetic electron donor, i.e. in medium with no other source of reducing power. Growth yields and rates on biogenic S(0) are comparable with those previously determined for Cba. tepidum grown on sulfide as the sole electron donor. Contact between cells and S(0) was required for growth. However, only a fraction of the cell population was firmly attached to S(0) globules. Microscopic examination of cultures growing on S(0) demonstrated cell-S(0) attachment and allowed for the direct observation of S(0) globule degradation. Bulk chemical analysis, scanning electron microscopy, secondary ion mass spectrometry and SDS PAGE indicate that Cba. tepidum biogenic S(0) globules contain carbon, oxygen and nitrogen besides S and may be associated with specific proteins. These observations suggest that current models of S(0) oxidation in the Chlorobi need to be revised to take into account the role of cell-S(0) interactions in promoting S(0) degradation. PMID- 26234461 TI - Sex ratio of equine offspring is affected by the ages of the mare and stallion. AB - The aim of this study was to determine the influence of parental age on the sex ratio of offspring in horses. Two trials were performed. In the first trial, the data from a randomly obtained population with a 1:1 sex ratio of 59,950 Mangalarga Marchador horses born in Brazil from 1990 to 2011 were analyzed. The sex ratios of the offspring were compared among groups according to the mare and the stallion ages (from 3 to 25 years). In the first step of the analysis, the mares and stallions were grouped according to age in 5-year intervals. In the second step, the groups were based on the parental age gap at conception. In the third step, the group of the mares and stallions with similar ages from the second step was subdivided, and the different parental age subgroups that were divided into 5-year intervals were compared. In the fourth step, the sex ratio of the offspring was determined according to the ages of the mares and the stallions at conception. The second trial was based on the data from 253 horses of several breeds that were born after natural gestation into a herd from 1989 to 2010, and the offspring of groups that were younger or older than 15 years were compared. The data from both trials were analyzed using a chi-square test (P <= 0.01 for the first trial; and P <= 0.05 for the second trial) for the comparisons of the sex ratios. In the first trial, the Spearman test (P <= 0.01) was used to verify the correlations between the parental age and the offspring sex ratio. In the first trial, the offspring sex ratio decreased as the mare or stallion age increased, and the decrease was more marked for the mares than for the stallions. In the second trial, the mares older than 15 years had more fillies than the younger mares, but the stallion age had no effect on the sex of the offspring. The first trial, with a large number of horses, revealed the pattern of the distribution of the sex ratios of offspring according to the parental age in horses, whereas the second trial, with a more restricted number of horses, confirmed the influence of the age of the mare on the offspring sex ratio. We concluded that the parental age affected the offspring sex ratio in horses and that this effect was stronger for the mares than for the stallions. PMID- 26234462 TI - Optimization of conditions for long-term prefreezing storage of brown bear sperm before cryopreservation. AB - Brown bear ejaculates are usually collected in field conditions and may need to be shipped to a laboratory for the application of reproductive biotechnologies before cryopreservation. The aim of this study was to extend the prefreezing step to 48 hours (1 hour vs. long-term storage [LS] to 24 and 48 hours) to enable the sample to be transported. The effects of storage temperature (experiment 1), glycerol concentration (experiment 2), and dilution rate (experiment 3) on sperm were evaluated. Electroejaculates from brown bears were stored under different experimental conditions and cryopreserved. The sperm motility and viability, apoptotic status, and acrosomal status of sperm were assessed before freezing (prefreezing), after thawing, and after 2-hour incubation at 37 degrees C (thermal stress test). In all experiments, one control sample was frozen using a standard protocol (control). In experiment 1, three temperatures during LS with 6% glycerol were tested: 5 degrees C (T5), 15 degrees C (T15), and room temperature (RT). The LS-T5 sample yielded the highest postthawing results for viability (42.4%), progressive motility (15.6%), and intact acrosome (83.1%) after 24 hours in comparison with the other temperatures (P < 0.05); for 48 hours, the LS-T5 sample reached higher total and progressive motility (25.9% and 9%, respectively) and nonapoptotic values (36.5%). Recovery rates revealed susceptibility to freezing at LS-15 or LS-RT samples at 24 hours (viability) or 48 hours (viability and motility). In experiment 2, samples were stored at 5 degrees C up to 48 hours and three glycerol concentrations were evaluated: 0% (0Gly), 3% (3Gly), and 6% (6Gly). Postthawing viability and motility increased progressively with the percentage of glycerol for 24 hours at 5 degrees C; 6% glycerol during 48-hour storage had beneficial effects on sperm cryopreservation. Besides, 6% glycerol had a clearly superior freezability for viability (42.7% and 40.8% for 24 hours and 48 hours, respectively) and motility (24 hours: total, 44.1%; progressive, 17.1%; 48 hours: total, 38.4%; progressive, 16%). In experiment 3, samples were stored up to 48 hours at 5 degrees C with 6% of glycerol and two dilution methods were evaluated: dilution 1:1 (average: 1782 * 10(6) sperm/mL; low) or final dilution (100 * 10(6) sperm/mL; high). Both dilution rates showed similar postthawing and postincubation results within 24 hours of long-term storage. After 48 hours, high dilution supported better postthawing quality. Both dilutions showed similar resistance to cryopreservation, except after 48 hours, when the high dilution reached a higher percent recovery rate of viability (38.8% vs. 21.6%, P < 0.05). In conclusion, our results suggested that the best conditions for long-term prefreezing storage (up to 48 hours) of brown bear electroejaculates are at 5 degrees C, at a concentration of 100 * 10(6) sperm/mL, and with 6% glycerol. PMID- 26234463 TI - Effects of intrauterine infusion of Trueperella pyogenes on endometrial mRNA expression of proinflammatory cytokines and luteolytic cascade genes and their association with luteal life span in dairy cows. AB - Objectives were to determine the effects of intrauterine infusion (IUI) of Trueperella pyogenes on endometrial expression of proinflammatory cytokines and luteal life span. Holstein cows (n = 32) were allocated randomly, in two replicates (15 then 17 cows), to receive one of three treatments on Day 5 of the estrous cycle: TP (n = 13), IUI containing 10(9) colony-forming units/mL of T. pyogenes; tumor necrosis factor (TNF; n = 9), IUI containing 1 MUg of TNFalpha; and control (n = 10), IUI of saline solution. Five cows per treatment had uterine biopsies collected at 6, 12, and 24 hours after treatment to evaluate the endometrial messenger RNA expression of TNFalpha (TNF), interleukin-1beta (IL1B), IL6, IL8, prostaglandin E synthase (PGES), prostaglandin F synthase (PGFS), and oxytocin receptor (OXR), and histologic evidence of inflammation. Messenger RNA expression was measured using quantitative reverse transcription polymerase chain reaction. The remaining cows had ovaries scanned and blood collected for progesterone evaluation; however, only seven, four, and three cows in the TP, TNF, and control groups were used for comparison in replicate 2. The GLIMMIX procedure of SAS was used for statistical analysis. All TP and TNF cows had moderate to severe endometrial inflammation, whereas only one control had mild inflammation. Premature luteolysis occurred in three, one, and zero cows in the TP, TNF and control groups, respectively. Delayed luteolysis occurred in one TP and one TNF cow. Interleukin-1beta expression was greater in the TP cows than in the TNF cows at 24 hours after IUI. Moreover, IL6 expression tended to be greater for the TP cows than for the control cows at 12 hours after IUI. Interleukin 8 expression was greater in the TP cows than in the control and TNF cows at 24 hours after IUI. Oxytocin receptor expression tended to be greater for the TP cows and was greater for the TNF cows than for the control cows at 12 hours. The messenger RNA expressions of TNF, PGES, and PGFS were not affected by treatment, time, or their interaction. In conclusion, IUI of T. pyogenes or TNFalpha led to histologic evidence of inflammation and early luteolysis in some cows, which may have been caused by increased endometrial expression of proinflammatory cytokines (i.e., IL1B, IL6), chemokines (i.e., IL8), and luteolytic cascade factors (i.e., OXR). PMID- 26234464 TI - Synthesis of a high resolution social contact network for Delhi with application to pandemic planning. AB - OBJECTIVE: We aim to understand quantitatively how targeted-layered containment (TLC) strategies contain an influenza pandemic in a populous urban area such as Delhi, India using networked epidemiology. METHODS: A key contribution of our work is a methodology for the synthesis of a realistic individual-based social contact network for Delhi using a wide variety of open source and commercial data. New techniques were developed to infer daily activities for individuals using aggregate data published in transportation science literature in combination with human development surveys and targeted local surveys. The resulting social contact network is the first such network constructed for any urban region of India. This time varying, spatially explicit network has over 13 million people and more than 200 million people-people contacts. The network has several interesting similarities and differences when compared with similar networks of US cities. Additionally, we use a high performance agent-based modeling environment to study how an influenza-like illness would spread over Delhi. We also analyze well understood pharmaceutical and non-pharmaceutical containment strategies, or a combination thereof (also known as TLCs), to control a pandemic outbreak. RESULTS: (i) TLC strategies produce the mildest and most delayed epidemic out-break than any of the individual interventions; (ii) the epidemic dynamics of Delhi appear to be strongly influenced by the activity patterns and the demographic structure of its local residents; and (iii) a high resolution social contact network helps in analyzing effective public health policies. CONCLUSION: A high resolution synthetic network is constructed based on surveyed data. It captures the underlying contact structure of a certain population and can be used to quantitatively analyze public health policy effectiveness. To the best of our knowledge, this study is the first of its kind in the Indian sub-continent. PMID- 26234465 TI - Vector promoters used in Klebsiella pneumoniae. AB - Much effort has been devoted to the metabolic engineering of Klebsiella pneumoniae; however, our knowledge of the actual expression level of promoters used in K. pneumoniae is limited. In this study, the expression levels of three promoters were compared systematically by using the lacZ reporter gene with different carbon sources in K. pneumoniae. The results showed that, although promoters PT5 and Ptac designed for Escherichia coli were functional, PT5 appeared more efficient and the induction/repression ratio of Ptac was decreased extremely in K. pneumoniae. The basal level of Ptac for lacZ expression reached 396.5 U/mg, which was 9.5-fold higher compared with PT5 in LB medium, indicating Ptac can be used as an efficient "constitutive" promoter as well as an efficient induced promoter in K. pneumoniae. In different carbon sources medium, a newly constructed endogenous constitutive Pbud proved to be a stable and weak promoter. On the basis of our data, a set of Pbud and Ptac promoters could meet the broad range (about 1,000 orders of magnitude) of gene expression needed for engineered K. pneumoniae in glycerol-based medium. PMID- 26234466 TI - Generation of a Homozygous Transgenic Rat Strain Stably Expressing a Calcium Sensor Protein for Direct Examination of Calcium Signaling. AB - In drug discovery, prediction of selectivity and toxicity require the evaluation of cellular calcium homeostasis. The rat is a preferred laboratory animal for pharmacology and toxicology studies, while currently no calcium indicator protein expressing rat model is available. We established a transgenic rat strain stably expressing the GCaMP2 fluorescent calcium sensor by a transposon-based methodology. Zygotes were co-injected with mRNA of transposase and a CAG-GCaMP2 expressing construct, and animals with one transgene copy were pre-selected by measuring fluorescence in blood cells. A homozygous rat strain was generated with high sensor protein expression in the heart, kidney, liver, and blood cells. No pathological alterations were found in these animals, and fluorescence measurements in cardiac tissue slices and primary cultures demonstrated the applicability of this system for studying calcium signaling. We show here that the GCaMP2 expressing rat cardiomyocytes allow the prediction of cardiotoxic drug side-effects, and provide evidence for the role of Na(+)/Ca(2+) exchanger and its beneficial pharmacological modulation in cardiac reperfusion. Our data indicate that drug-induced alterations and pathological processes can be followed by using this rat model, suggesting that transgenic rats expressing a calcium-sensitive protein provide a valuable system for pharmacological and toxicological studies. PMID- 26234468 TI - Feasibility and efficacy of gemcitabine plus cisplatin combination therapy after curative resection for biliary tract cancer. AB - BACKGROUND: The aim of this multi-institutional study was to assess the feasibility and the efficacy of gemcitabine plus cisplatin (CDDP) combination therapy (GC therapy) for biliary tract cancer (BTC) in the adjuvant setting. METHODS: Eligible patients identified between January 2008 and January 2013 were enrolled. GC therapy at 1,000 mg/m(2) of gemcitabine and 25 mg/m(2) of CDDP on days 1 and 8 repeated every 3 weeks was performed for 6 months. The primary endpoint was the feasibility and the adverse events, and the secondary endpoint was recurrence-free survival (RFS) and overall survival (OS). RESULTS: Among 29 evaluable patients, the protocol was completed in 21 (72%) patients. Relative dose intensity (RDI) of gemcitabine and CDDP was 77% and 81%, respectively. There was no difference in the completion rate and the RDI between patients who underwent resection with vs. without major hepatectomy. Grade 3-4 toxicities included leukopenia (14%) and neutropenia (27%). Two-year RFS and 2-year OS was 59% and 90%, respectively. CONCLUSIONS: Standard dose of GC therapy is tolerable in patients with BTC who underwent curative resection either with or without major hepatectomy. The survival effect of this regimen is promising, but further comparative study is needed. PMID- 26234469 TI - Offspring's hydromineral adaptive responses to maternal undernutrition during lactation. AB - Early development, throughout gestation and lactation, represents a period of extreme vulnerability during which susceptibility to later metabolic and cardiovascular injuries increases. Maternal diet is a major determinant of the foetal and newborn developmental environment; maternal undernutrition may result in adaptive responses leading to structural and molecular alterations in various organs and tissues, such as the brain and kidney. New nephron anlages appear in the renal cortex up to postnatal day 4 and the last anlages to be formed develop into functional nephrons by postnatal day 10 in rodents. We used a model of undernutrition in rat dams that were food-restricted during the first half of the lactation period in order to study the long-term effects of maternal diet on renal development, behaviour and neural hydromineral control mechanisms. The study showed that after 40% food restriction in maternal dietary intake, the dipsogenic responses for both water and salt intake were not altered; Fos expression in brain areas investigated involved in hydromineral homeostasis control was always higher in the offspring in response to isoproterenol. This was accompanied by normal plasma osmolality changes and typical renal histology. These results suggest that the mechanisms for the control of hydromineral balance were unaffected in the offspring of these 40% food-restricted mothers. Undernutrition of the pups may not be as drastic as suggested by dams' restriction. PMID- 26234467 TI - IgG Antibody Responses to Recombinant gp120 Proteins, gp70V1/V2 Scaffolds, and a CyclicV2 Peptide in Thai Phase I/II Vaccine Trials Using Different Vaccine Regimens. AB - RV144 correlates of risk analysis showed that IgG antibodies to gp70V1V2 scaffolds inversely correlated with risk of HIV acquisition. We investigated IgG antibody responses in RV135 and RV132, two ALVAC-HIV prime-boost vaccine trials conducted in Thailand prior to RV144. Both trials used ALVAC-HIV (vCP1521) at 0, 1, 3, and 6 months and HIV-1 gp120MNgD and gp120A244gD in alum (RV135) or gp120SF2 and gp120CM235 in MF59 (RV132) at 3 and 6 months. We assessed ELISA binding antibodies to the envelope proteins (Env) 92TH023, A244gD and MNgD, cyclicV2, and gp70V1V2 CaseA2 (subtype B) and 92TH023 (subtype CRF01_AE), and Env specific IgG1 and IgG3. Antibody responses to gp120 A244gD, MNgD, and gp70V1V2 92TH023 scaffold were significantly higher in RV135 than in RV132. Antibodies to gp70V1V2 CaseA2 were detected only in RV135 vaccine recipients and IgG1 and IgG3 antibody responses to A244gD were significantly higher in RV135. IgG binding to gp70V1V2 CaseA2 and CRF01_AE scaffolds was higher with the AIDSVAX((r))B/E boost but both trials showed similar rates of antibody decline post-vaccination. MF59 did not result in higher IgG antibody responses compared to alum with the antigens tested. However, notable differences in the structure of the recombinant proteins and dosage used for immunizations may have contributed to the magnitude and specificity of IgG induced by the two trials. PMID- 26234470 TI - R-phenibut binds to the alpha2-delta subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects. AB - Phenibut is clinically used anxiolytic, mood elevator and nootropic drug. R phenibut is responsible for the pharmacological activity of racemic phenibut, and this activity correlates with its binding affinity for GABAB receptors. In contrast, S-phenibut does not bind to GABAB receptors. In this study, we assessed the binding affinities of R-phenibut, S-phenibut, baclofen and gabapentin (GBP) for the alpha2-delta subunit of the voltage-dependent calcium channel (VDCC) using a subunit-selective ligand, radiolabelled GBP. Binding experiments using rat brain membrane preparations revealed that the equilibrium dissociation constants (Kis) for R-phenibut, S-phenibut, baclofen and GBP were 23, 39, 156 and 0.05MUM, respectively. In the pentylenetetrazole (PTZ)-induced seizure test, we found that at doses up to 100mg/kg, R-phenibut did not affect PTZ-induced seizures. The anti-nociceptive effects of R-phenibut were assessed using the formalin-induced paw-licking test and the chronic constriction injury (CCI) of the sciatic nerve model. Pre-treatment with R-phenibut dose-dependently decreased the nociceptive response during both phases of the test. The anti-nociceptive effects of R-phenibut in the formalin-induced paw-licking test were not blocked by the GABAB receptor-selective antagonist CGP35348. In addition, treatment with R- and S-phenibut alleviated the mechanical and thermal allodynia induced by CCI of the sciatic nerve. Our data suggest that the binding affinity of R-phenibut for the alpha2-delta subunit of the VDCC is 4 times higher than its affinity for the GABAB receptor. The anti-nociceptive effects of R-phenibut observed in the tests of formalin-induced paw licking and CCI of the sciatic nerve were associated with its effect on the alpha2-delta subunit of the VDCC rather than with its effects on GABAB receptors. In conclusion, our results provide experimental evidence for GBP-like, anti-nociceptive properties of R-phenibut, which might be used clinically to treat neuropathic pain disorders. PMID- 26234472 TI - Effects of constrained arm swing on vertical center of mass displacement during walking. AB - The purpose of this study was to determine the effects of constraining arm swing on the vertical displacement of the body's center of mass (COM) during treadmill walking and examine several common gait variables that may account for or mask differences in the body's COM motion with and without arm swing. Participants included 20 healthy individuals (10 male, 10 female; age: 27.8 +/- 6.8 years). The body's COM displacement, first and second peak vertical ground reaction forces (VGRFs), and lowest VGRF during mid-stance, peak summed bilateral VGRF, lower extremity sagittal joint angles, stride length, and foot contact time were measured with and without arm swing during walking at 1.34 m/s. The body's COM displacement was greater with the arms constrained (arm swing: 4.1 +/- 1.2 cm, arm constrained: 4.9 +/- 1.2 cm, p < 0.001). Ground reaction force data indicated that the COM displacement increased in both double limb and single limb stance. However, kinematic patterns visually appeared similar between conditions. Shortened stride length and foot contact time also were observed, although these do not seem to account for the increased COM displacement. However, a change in arm COM acceleration might have contributed to the difference. These findings indicate that a change in arm swing causes differences in vertical COM displacement, which could increase energy expenditure. PMID- 26234471 TI - Improved gait in persons with knee related mobility limitations by a rosehip food supplement: A randomized, double-blind, placebo-controlled trial. AB - PURPOSE: To evaluate the efficacy of a specialized rosehip powder nutraceutical on the biomechanical function of the knee joint during walking in individuals with knee-related walking limitations. METHODS: Randomized, participant and outcome assessor blinded trial. Participants with self-reported knee-related walking limitations were randomized (1:1) to receive three capsules/day of either rosehip powder or identically appearing placebo capsules for 12 weeks. At baseline and the 12 weeks follow-up, 3-dimensional gait analyses were performed from which the peak resultant knee moment was selected as primary outcome. Secondary outcomes included sagittal and frontal plane knee joint moments, knee joint kinematics, peaks in the vertical ground reaction forces, and self-selected walking speeds. Analyses were based on ANCOVA with the 'Intention-To-Treat' (ITT) population, defined as all randomized participants using last observation carried forward imputation for missing data. RESULTS: 100 participants were randomized to rosehip (n=50) or placebo (n=50) and defined the ITT population. Of these 94 completed the study (47 in each group). There were statistically significant group differences in the change from baseline in the primary outcome: the resultant knee moment (0.06 nm/kg, 95%CI: 0.00-0.12; P=0.039) and in the peaks in the sagittal plane moments and kinematics during the stance phase of walking with the rosehip group exhibiting greater joint moments and more knee joint flexion during walking than the placebo group. CONCLUSION: A daily intake of rosehip powder for 12 weeks improved important indices of knee joint function and dynamics during walking compared to placebo in persons with knee-related walking limitations. PMID- 26234473 TI - Bioceramic fabrics improve quiet standing posture and handstand stability in expert gymnasts. AB - Bioceramic fabrics have been claimed to improve blood circulation, thermoregulation and muscle relaxation, thereby also improving muscular activity. Here we tested whether bioceramic fabrics have an effect on postural control and contribute to improve postural stability. In Experiment 1, we tested whether bioceramic fabrics contribute to reduce body-sway when maintaining standard standing posture. In Experiment 2, we measured the effect of bioceramic fabrics on body-sway when maintaining a more instable posture, namely a handstand hold. For both experiments, postural oscillations were measured using a force platform with four strain gauges that recorded the displacements of the center of pressure (CoP) in the horizontal plane. In half of the trials, the participants wore a full-body second skin suit containing a bioceramic layer. In the other half of the trials, they wore a 'placebo' second skin suit that had the same cut, appearance and elasticity as the bioceramic suit but did not contain the bioceramic layer. In both experiments, the surface of displacement of the CoP was significantly smaller when participants were wearing the bioceramic suit than when they were wearing the placebo suit. The results suggest that bioceramic fabrics do have an effect on postural control and improve postural stability. PMID- 26234474 TI - Injectable sodium pentobarbital: Stability at room temperature. AB - INTRODUCTION: Sodium pentobarbital (Nembutal) is a barbiturate used in research as an anesthetic in many animal models. The injectable form of this drug has lately become difficult to procure and prohibitively expensive. Due to this lack of availability, researchers have begun to compound injectable sodium pentobarbital from so-called "nonpharmaceutical" pentobarbital. Some oversight agencies have objected to this practice, claiming a lack of quality control and degradation of the drug. We sought with this study to establish both: 1) a protocol for the preparation of injectable sodium pentobarbital, and 2) standard operating procedures to monitor the quality of the preparation and degradation of the drug over time. METHODS: Our preparation consists of a mixture of sodium pentobarbital in alkaline aqueous solution, propylene glycol, and ethanol. Pentobarbital content in this preparation was assayed by high-pressure liquid chromatography (HPLC). We also assayed pentobarbital content over time in preparations of various ages up to 6 years old. RESULTS: We determined that the drug degraded at a maximum of 0.5% per year in our preparation (alkaline water/propylene glycol/ethanol) when stored in the dark at room temperature. A yellow discoloration developed after about 2 years, which we have arbitrarily determined disqualifies the preparation from use as an anesthetic. Attempts to spectroscopically assay this discoloration were not successful. CHEMICALS: Pentobarbital sodium (CID: 14075609). PMID- 26234475 TI - O2 and H2O2 transformation steps for the oxygen reduction reaction catalyzed by graphitic nitrogen-doped carbon nanotubes in acidic electrolyte from first principles calculations. AB - It is highly challenging but extremely desirable to develop carbon catalysts with high oxygen reduction reaction (ORR) activity and stability in acidic medium for commercial application. In this paper, based on density functional theory (DFT) calculations with long range interaction correction and solvation effects, the elementary transformations of all the probable intermediates in the ORR and the hydrogen peroxide reduction reaction (HPRR) over graphitic nitrogen-doped carbon nanotubes (NCNTs) in acidic medium were evaluated, and it was found that all the rate determining steps are related to the bonding hydroxyl group because of the strong interaction between the hydroxyl group and carbon. Thus, it is hard for the direct four-electron ORR and the two-electron HPRR to proceed. Together with hydrogen peroxide disproportionation (HPD), a mixed mechanism for the ORR in acidic electrolyte was proposed, where the two-electron and three-electron ORRs and HPD dominate the electrode reaction. The experimental result for the ORR catalyzed by NCNTs in acidic electrolyte also well illustrated the rationality of the theoretical calculations. This study not only gives new insights into the effect of graphitic nitrogen doping on the ORR catalyzed by carbon, but also provides a guide to design carbon catalysts with high ORR activity in acidic electrolyte. PMID- 26234476 TI - Should recent experiences with CVOTs for oral hypoglycemic drugs allow us to rethink the regulatory paradigm? AB - In response to a meta-analysis raising significant concerns over the cardiovascular safety of rosiglitazone, the US Food and Drug Administration (FDA) issued a draft guidance directing sponsors of novel diabetes drugs to address cardiovascular risk, including large outcomes trials. Regulatory experience supports that outcomes trials, absent a clear signal of risk, may add reassurance, but also have significant consequences. The FDA should finalize this guidance, taking into account the regulatory experience since 2008. PMID- 26234477 TI - Energy harvesting performance of piezoelectric ceramic and polymer nanowires. AB - Energy harvesting from ubiquitous ambient vibrations is attractive for autonomous small-power applications and thus considerable research is focused on piezoelectric materials as they permit direct inter-conversion of mechanical and electrical energy. Nanogenerators (NGs) based on piezoelectric nanowires are particularly attractive due to their sensitivity to small-scale vibrations and may possess superior mechanical-to-electrical conversion efficiency when compared to bulk or thin-film devices of the same material. However, candidate piezoelectric nanowires have hitherto been predominantly analyzed in terms of NG output (i.e. output voltage, output current and output power density). Surprisingly, the corresponding dynamical properties of the NG, including details of how the nanowires are mechanically driven and its impact on performance, have been largely neglected. Here we investigate all realizable NG driving contexts separately involving inertial displacement, applied stress T and applied strain S, highlighting the effect of driving mechanism and frequency on NG performance in each case. We argue that, in the majority of cases, the intrinsic high resonance frequencies of piezoelectric nanowires (~tens of MHz) present no barrier to high levels of NG performance even at frequencies far below resonance (<1 kHz) typically characteristic of ambient vibrations. In this context, we introduce vibrational energy harvesting (VEH) coefficients etaS and etaT, based on intrinsic materials properties, for comparing piezoelectric NG performance under strain-driven and stress-driven conditions respectively. These figures of merit permit, for the first time, a general comparison of piezoelectric nanowires for NG applications that takes into account the nature of the mechanical excitation. We thus investigate the energy harvesting performance of prototypical piezoelectric ceramic and polymer nanowires. We find that even though ceramic and polymer nanowires have been found, in certain cases, to have similar energy conversion efficiencies, ceramics are more promising in strain-driven NGs while polymers are more promising for stress-driven NGs. Our work offers a viable means of comparing NG materials and devices on a like-for-like basis that may be useful for designing and optimizing nanoscale piezoelectric energy harvesters for specific applications. PMID- 26234478 TI - MLVF analysis of anginosus (milleri) group streptococci. AB - We developed a new method of typing for anginosus group streptococci (SAG). It is the first SAG-dedicated, PCR-based method, which allows to determine the relationship between strains. The method is based on the detection of tandem repeats among 9 genomic loci and is classified as multilocus variable number tandem repeats fingerprint (MLVF) type of analysis. Using the described method, it is possible to detect over half million MLVF patterns, which correlate with pulsed-field gel electrophoresis profiles. The other advantage of the method is relatively short time from "cell to data", low costs, and easy application for epidemiological and evolutionary studies. PMID- 26234479 TI - High prevalence of fluoroquinolone-nonsusceptible Streptococcus pyogenes emm12 in Taiwan. AB - Fluoroquinolone-nonsusceptible Streptococcus pyogenes has rapidly emerged in several countries. The aim of this study was to survey the epidemiology and molecular characteristics of fluoroquinolone-nonsusceptible S. pyogenes in Taiwan. A total of 350 consecutive S. pyogenes isolates were collected between January 2005 and December 2012, including 152 (43.4%) invasive and 198 (56.6%) noninvasive isolates. Thirty-nine isolates (11.1%) of S. pyogenes were nonsusceptible to fluoroquinolones, including one emm1/ST28, 4 emm4/ST39, 33 emm12/ST36, and 1 emm87/ST62. Of all the isolates, emm12 (50%) demonstrated the highest prevalence of fluoroquinolone nonsusceptibility. Alterations of Ser79Phe and Ala12Val in ParC were the most frequently mutations in fluoroquinolone nonsusceptible S. pyogenes isolates. There were no amino acid substitutions in GyrB, and 1 emm87 isolate exhibited 3 nonsynonymous mutations in ParE. Our study reveals the emergence of fluoroquinolone-nonsusceptible S. pyogenes emm12/ST36 in Taiwan. Regular surveillance of fluoroquinolone susceptibility in S. pyogenes is suggested. PMID- 26234480 TI - Are repeated assisted reproductive technology treatments and an unsuccessful outcome risk factors for unipolar depression in infertile women? AB - INTRODUCTION: Previous studies have shown conflicting results as to whether unsuccessful medically assisted reproduction is a risk factor for depression among women. This study therefore investigated if women with no live birth after assisted reproductive technology (ART) treatment had a higher risk of unipolar depression compared with women with a live birth after ART treatment. MATERIAL AND METHODS: The Danish National ART-Couple (DANAC) Cohort is a national register based cohort study that consists of women who received ART treatment from 1 January 1994 to 30 September 2009, in Denmark (n = 41 050). Information on unipolar depression was obtained from the Danish Psychiatric Central Research Register. The analyses were conducted in Cox regression analysis. RESULTS: During the 308 494 person-years of follow up, 552 women were diagnosed with unipolar depression. A Cox proportional hazards model showed that women in ART treatment, with no live birth yet, had a lower risk of unipolar depression compared with women with a live birth. Women had the highest risk of unipolar depression 0-42 days after a live birth (adjusted hazard ratio 5.08, 95% CI 3.11-8.29) compared with women with no live birth. A lower, but still increased, risk of unipolar depression, was found in women 43 days to 1 year and >1 year after a live birth compared with women with no live birth yet. CONCLUSIONS: Motherhood is an important trigger of unipolar depression in women conceiving after ART treatment. PMID- 26234481 TI - External Nasal Neuralgia: A Neuropathic Pain Within the Territory of the External Nasal Nerve. AB - BACKGROUND: Nasal pain is a challenging diagnosis and very little has been reported in the neurological literature. The nose is a sophisticated structure regarding its innervation, which is supplied by the first and second divisions of the trigeminal nerve. Painful cranial neuropathies are an important group in the differential diagnosis, although they have been described only scarcely. Here, we report a case that can conform a non-traumatic external nasal nerve neuralgia. CASE: A 76-year-old woman was referred to our office due to pain in her left nose. She was suffering from daily excruciating attacks, which were strictly limited to the territory supplied by her left external nasal nerve (left ala nasi and apex nasi). She denied previous traumatisms and the ancillary tests did not yield any underlying pathology. An anesthetic blockade of her left external nasal nerve achieved a marked reduction of the number of episodes as well as their intensity. CONCLUSION: External nasal neuralgia seems a specific neuralgia causing nasal pain. Anesthetic blockades of the external nasal nerve may be a valid treatment for this condition. PMID- 26234482 TI - Au nanoparticle scaffolds modulating intermolecular interactions among the conjugated azobenzenes chemisorbed on curved surfaces: tuning the kinetics of cis trans isomerisation. AB - pi-pi Intermolecular interactions among adjacent conjugated azobenzenes chemisorbed on (non-)flat Au surfaces can be tuned by varying the curvature of the Au nanoparticles. Here we show that such interactions rule the thermal cis trans isomerization kinetics, towards a better control on the azobenzene bistability for its optimal integration as a responsive material. PMID- 26234483 TI - Afferent fibers involved in the bradykinin-induced cardiovascular reflexes from the ovary in rats. AB - Bleeding or rupture of the ovary often accompanies ovarian cysts and causes severe pain and autonomic responses such as hypotension. It would be expected that ovarian afferents contribute to cardiovascular responses induced by ovarian failure. The present study examined cardiovascular responses to noxious chemical stimulation of the ovary by bradykinin, an algesic substance released by tissue damage, and explored the role of ovarian afferents in the ovarian-cardiovascular responses in anesthetized rats. Non-pregnant adult rats were anesthetized with pentobarbital and artificially ventilated. The carotid artery was cannulated to monitor blood pressure and heart rate. Noxious chemical stimulation was achieved by applying a small piece of cotton soaked with bradykinin to the surface of the ovary for 30s. Application of bradykinin (10(-4) M) to the ovary decreased heart rate and blood pressure. These cardiovascular responses were not significantly influenced by severance of the vagal nerves or the superior ovarian nerve, but were abolished by severance of the ovarian nerve plexus (ONP). Application of bradykinin (10(-4) M) to the ovary evoked afferent activity of the ONP both in vivo and in vitro preparations. These results indicate that the decreases in heart rate and blood pressure following chemical noxious stimulation of the ovary with bradykinin are reflex responses, whose afferent nerve pathway is mainly through afferent fibers in the ONP. PMID- 26234484 TI - Discordant Electrocardiogram Left Ventricular Wall Thickness and Strain Findings in Influenza Myocarditis. AB - A 42-year-old man presented with a viral prodrome and tested positive for influenza A. He rapidly deteriorated developing cardiogenic shock, rhabdomyolysis, and acute kidney injury. Patient improved 1 week later with supportive measures including vasopressors, inotropes, and an intraaortic balloon pump. We report this case as it highlights the discordance between echocardiographic ventricular wall thickening as a result of myocardial edema, and electrocardiographic findings at presentation, with a reversal in findings at time of resolution. Additionally, there was some suggestion of a regional pattern to the reduced longitudinal strain. PMID- 26234485 TI - The risks of planned vaginal breech delivery versus planned caesarean section for term breech birth: a meta-analysis including observational studies. AB - BACKGROUND: The mode of delivery in term singleton breech presentation has been debated for more than half a century and has been examined in both randomised and observational studies. OBJECTIVE: To determine the absolute and relative risks of perinatal mortality and morbidity in planned vaginal breech delivery. SEARCH STRATEGY: A computer-based literature search was conducted mainly in the databases of HINARI, PubMed and Google scholar for studies comparing planned vaginal delivery and planned caesarean section. SELECTION CRITERIA: Studies that assessed the perinatal mortality and morbidity in relation to the term singleton breech mode of delivery between 1993 and 2014 were included. DATA COLLECTION AND ANALYSIS: In this meta-analysis, 27 articles with a total sample size of 258 953 women were included. Relative and absolute risks of perinatal mortality and morbidity in relation to mode of delivery were determined. MAIN RESULTS: The relative risk of perinatal mortality and morbidity was about two- to five-fold higher in the planned vaginal than in the planned caesarean delivery group. The absolute risks of perinatal mortality, fetal neurologic morbidity, birth trauma, 5-minute Apgar score <7 and neonatal asphyxia in the planned vaginal delivery group were 0.3, 0.7, 0.7, 2.4 and 3.3%, respectively. CONCLUSION: Perinatal mortality and morbidity in the planned vaginal breech delivery were significantly higher than with planned caesarean delivery. Even taking into account the relatively low absolute risks of vaginal breech delivery, the current study substantiates the practice of individualised decision-making on the route of delivery in a term breech presentation. TWEETABLE ABSTRACT: Although vaginal breech delivery is controversial, this review has shown low absolute risk. PMID- 26234486 TI - Implementation strategies to enhance management of heavy alcohol consumption in primary health care: a meta-analysis. AB - BACKGROUND AND AIMS: Screening and brief interventions (SBI) delivered in primary health care (PHC) are cost-effective in decreasing alcohol consumption; however, they are underused. This study aims to identify implementation strategies that focus on SBI uptake and measure impact on: (1) heavy drinking and (2) delivery of SBI in PHC. METHODS: Meta-analysis was conducted of controlled trials of SBI implementation strategies in PHC to reduce heavy drinking. Key outcomes included alcohol consumption, screening, brief interventions and costs in PHC. Predictor measures concerned single versus multiple strategies, type of strategy, duration and physician-only input versus that including mid-level professionals. Standardized mean differences (SMD) were calculated to indicate the impact of implementation strategies on key outcomes. Effect sizes were aggregated using meta-regression models. RESULTS: The 29 included studies were of moderate methodological quality. Strategies had no overall impact on patients' reported alcohol consumption [SMD=0.07; 95% confidence interval (CI)=-0.02 to 0.16], despite improving screening (SMD=0.53; 95% CI=0.28-0.78) and brief intervention delivery (SMD=0.64;95% CI=0.27-1.02). Multi-faceted strategies, i.e. professional and/or organizational and/or patient-orientated strategies, seemed to have strongest effects on patients' alcohol consumption (P<0.05, compared with professional-orientated strategies alone). Regarding SBI delivery, combining professional with patient-orientated implementation strategies had the highest impact (P<0.05). Involving other staff besides physicians was beneficial for screening (P<0.05). CONCLUSIONS: To increase delivery of alcohol screening and brief interventions and decrease patients' alcohol consumption, implementation strategies should include a combination of patient-, professional- and organizational-orientated approaches and involve mid-level health professionals as well as physicians. PMID- 26234487 TI - Preformed gelatin microcryogels as injectable cell carriers for enhanced skin wound healing. AB - Wound dressings of cell-laden bulk hydrogel or scaffold were mainly applied for enhanced cell engraftment in contrast to free cell injection. However, dressing of cells laden in biomaterials on wound surface might not effectively and timely exert functions on deep or chronic wounds where insufficient blood supply exists. Previously, we developed injectable gelatin microcryogels (GMs) which could load cells for enhanced cell delivery and cell therapy. In this study, biological changes of human adipose-derived stem cells (hASCs) laden in GMs were compared in varied aspects with traditional two dimensional (2D) cell culture, such as cell phenotype markers, stemness genes, differentiation, secretion of growth factors, cell apoptosis and cell memory by FACS, QRT-PCR and ELISA, that demonstrated the priming effects of GMs on upregulation of stemness genes and improved secretion of growth factors of hASCs for potential augmented wound healing. In a full thickness skin wound model in nude mice, multisite injection and dressing of hASCs-laden GMs could significantly accelerate the healing compared to free cell injection. Bioluminescence imaging and protein analysis indicated improved cell retention and secretion of multiple growth factors. Our study suggests that GMs as primed injectable 3D micro-niches represent a new cell delivery methodology for skin wound healing which could not only benefit on the recovery of wound bed but also play direct effects on wound basal layer for healing enhancement. Injectable GMs as facile multisite cell delivery approach potentially provide new minimally-invasive therapeutic strategy for refractory wounds such as diabetic ulcer or radiative skin wound. STATEMENT OF SIGNIFICANCE: This work applied a type of elastic micro-scaffold (GMs) to load and prime hMSCs for skin wound healing. Due to the injectability of GMs, the 3D cellular micro-niches could simply realize minimally-invasive and multisite cell delivery approach for accelerating the wound healing process superior to free cell injection. The biological features of MSCs has been thoroughly characterized during 3D culture in GMs (i.e. cell proliferation, characterization of cell surface markers, stemness of MSCs in GMs, differentiation of MSCs in GMs, secretion of MSCs in GMs, induced apoptosis of MSCs in GMs). Multiple methods such as bioluminescent imaging, immunohistochemistry, immunofluorescence, qRT-PCR, ELSA and western blot were used to assess the in vivo results between groups. PMID- 26234489 TI - Strontium-containing apatite/polylactide composites enhance bone formation in osteopenic rabbits. AB - Strontium (Sr) has been shown to favor bone formation and is used clinically to treat osteoporosis. We have previously reported that Sr addition in apatite/polylactide composites could enhance the BMP-induced bone formation around implants at ectopic site in healthy animals. In this study we aimed to investigate the effectiveness of Sr addition on the local bone formation in osteoporosis. Apatite/polylactide composite granules with different Sr content were loaded with equal amount of rhBMP-2 and implanted intramuscularly in healthy rabbits (Con) and rabbits that received bilateral ovariectomy and daily injection of glucocorticoid (OP) for 12 weeks. The potential effect of Sr on the final volume of BMP-induced bone in both groups was investigated histologically and histomorphometrically. The de novo bone formed in OP implants was significantly less than in Con group when the implants contained no Sr, indicating that the BMP induced osteogenesis was impaired in OP animals. Sr substitution as low as 0.5 mol% in apatite increased the bone volume in OP implants to levels comparable to that in the Con group, indicating a positive effect of Sr addition on the local bone formation in OP animals. In addition, more adipose tissue formed in parallel with the appearance of cartilage tissue in OP implants, suggesting that the differentiation potential of stem cell in OP animals may have shifted towards adipogenesis and chondrogenesis. From these results, we conclude that the use of Sr addition to enhance the bone growth surrounding implants in osteoporosis merits further study. STATEMENT OF SIGNIFICANCE: The impaired bone healing capacity of osteoporotic patients might result in poor osteointegration and surgical failure in case implants are placed. In this study we aimed to enhance the bone formation around implants under such scenario by adding strontium as the stimulus. Different from other studies, the samples were loaded with rhBMP-2 and implanted at an ectopic site (spinal muscles of New Zealand rabbits) to exclude the influence of conductive bone repair. The results showed that the addition of strontium could enhance the BMP-2-induced bone formation on implants in osteopenic rabbits to levels comparable to that in healthy rabbits. Secondarily, we observed more adipose tissue and cartilage tissue in osteopenic implants, suggesting the role of adipogenesis and chondrogenesis in osteopenia/osteoporosis. PMID- 26234488 TI - Surface-mediated delivery of siRNA from fibrin hydrogels for knockdown of the BMP 2 binding antagonist noggin. AB - Antagonists and inhibitory molecules responsible for maintaining tissue homeostasis can present a significant barrier to healing when tissue engineering/regenerative medicine strategies are employed. One example of this situation is the up-regulation of antagonists such as noggin in response to increasing concentrations of bone morphogenetic protein-2 (BMP-2) present from endogenous bone repair processes or delivered exogenously from biomaterials (synthetic bone grafts). While recombinant human (rh)BMP-2 delivered from synthetic bone grafts has been shown to be an effective alternative to autografts and allografts, the supraphysiological doses of rhBMP-2 have led to clinically adverse side effects. The high rhBMP-2 dosage may be required, in part, to overcome the presence of antagonists such as noggin. Small interfering RNA (siRNA) is an appealing approach to overcome this problem because it can knock down antagonists or inhibitory molecules in a temporary manner. Here, we conducted fundamental studies on the delivery of siRNA from material surfaces as a means to knock-down antagonists like noggin. Non-viral cationic lipid (Lipofectamine)-siRNA complexes were delivered from a fibrin hydrogel surface to MC3T3-E1 preosteoblasts that were treated with a supraphysiological dose of rhBMP 2 to achieve noggin mRNA expression levels higher than cells naive to rhBMP-2. Confocal microscopy and flow cytometry showed intracellular uptake of siRNA in over 98% of MC3T3-E1 cells after 48 h. Doses of 0.5 and 1 MUg noggin siRNA were able to significantly reduce noggin mRNA to levels equivalent to those in MC3T3 E1 cells not exposed to rhBMP-2 with no effects on cell viability. STATEMENT OF SIGNIFICANCE: Small interfering RNA (siRNA) has been considered for treatment of diseases ranging from Alzheimer's to cancer. However, the ability to use siRNA in conjunction with biomaterials to direct tissue regeneration processes has received relatively little attention. Using the bone morphogenetic protein 2 antagonist, noggin, as a model, this research describes an approach to knock-down molecules that are inhibitory to desired regenerative pathways at the mRNA level via siRNA delivery from a hydrogel surface. Interactions between the material (fibrin) surface and polycation-siRNA complexes, release of the siRNA from the material surface, high levels of cellular uptake/internalization of siRNA, and significant knockdown of the targeting (noggin) mRNA are demonstrated. Broader future applications include those to nerve regeneration, cardiovascular tissue engineering, directing (stem) cell behavior, and mitigating inflammatory responses to materials. PMID- 26234490 TI - Improved burn wound healing by the antimicrobial peptide LLKKK18 released from conjugates with dextrin embedded in a carbopol gel. AB - Antimicrobial peptides (AMPs) are good candidates to treat burn wounds, a major cause of morbidity, impaired life quality and resources consumption in developed countries. We took advantage of a commercially available hydrogel, Carbopol(r), a vehicle for topical administration that maintains a moist environment within the wound site. We hypothesized that the incorporation of LLKKK18 conjugated to dextrin would improve the healing process in rat burns. Whereas the hydrogel improves healing, LLKKK18 released from the dextrin conjugates further accelerated wound closure, and simultaneously improving the quality of healing. Indeed, the release of LLKKK18 reduced oxidative stress and inflammation (low neutrophil and macrophage infiltration and pro-inflammatory cytokines levels). Importantly, it induced a faster resolution of the inflammatory stage through early M2 macrophage recruitment. In addition, LLKKK18 stimulated angiogenesis (increased VEGF and microvessel development in vivo). Moreover, collagen staining evaluated by Masson's Trichrome was visually much more intense after treatment with LLKKK18, suggesting higher collagen deposition. Overall, we generated an effective, safe and inexpensive formulation that maintains a moist environment in the wound, easy to apply and remove, and with potential to prevent infection due to the presence of an antimicrobial peptide. These findings propel us to further study this LLKKK18-containing formulation, setting the foundations towards a potential therapeutic approach for burn wound treatment. STATEMENT OF SIGNIFICANCE: This work presents a newly developed formulation that holds great potential as a therapeutic approach for burn treatment. It is based on the sustained delivery of an antimicrobial peptide - LLKKK18 - from conjugates with dextrin, after degradation of dextrin backbone upon exposure to wound alpha amylases. Conjugates were further embedded in Carbopol(r), a commercially available hydrogel, suitable for topical administration and that provides a moist environment to the wound. Overall, we obtained an efficient, safe and non expensive formulation that improves burn wound healing, maintains a moist environment within the wound, is easy to apply-and-remove, and has potential to prevent infection due to the presence of an antimicrobial peptide. Importantly, this is the first time the wound healing ability of LLKKK18 is demonstrated and that its main mechanisms of action are identified. PMID- 26234491 TI - Dual functional core-sheath electrospun hyaluronic acid/polycaprolactone nanofibrous membranes embedded with silver nanoparticles for prevention of peritendinous adhesion. AB - Peritendinous adhesions, one of the common complications after tendon injury and subsequent surgery, could be minimized by directly placing a physical barrier between the injured site and the surrounding tissue. We used silver (Ag) nanoparticles embedded in electrospun hyaluronic acid (HA)/polycaprolactone (PCL) nanofibrous membranes (NFMs) (HA/PCL+Ag NFMs) to prevent peritendinous adhesions and bacterial infection after tendon surgery. HA was used for effective lubrication, and Ag provided antibacterial activity. A dual functional anti adhesion barrier with core-sheath nanofibrous architecture was made from an HA core solution and a photo-reduced silver nitrate/PCL sheath solution. Polycaprolactone NFMs (PCL NFMs), hyaluronic acid/polycaprolactone core-sheath NFMs (HA/PCL NFMs) and HA/PCL+Ag NFMs with comparable fiber diameters and pore sizes were prepared and analyzed. The microporous structure of NFMs is expected to effectively block the penetration of adhesion-forming fibroblasts during tendon healing. The release of Ag from HA/PCL+Ag NFMs plateaued after 4 days, which confirmed the short-term anti-bacterial effect, and this result was verified with agar diffusion tests. In contrast, the release of HA was extended up to 21 days to simulate the lubrication effect offered by HA in the synovial fluid of the tendon sheath. In vitro cell culture experiments revealed that HA/PCL+Ag NFMs exhibited the highest inhibition of fibroblast attachment and proliferation without significant cytotoxicity due to the synergistic effect of Ag and HA. In vivo studies with a rabbit flexor tendon model further confirmed the efficacy of HA/PCL+Ag NFMs in reducing peritendinous adhesion as determined by gross observation, histology, joint range-of-motion, tendon gliding and biomechanical tests. PMID- 26234492 TI - Cardiotoxicity from the cardiologist's perspective. AB - Screening programs and contemporary multidisciplinary management of oncologic patients have resulted in lower mortality and improved outcomes. Nevertheless, treatment-related cardiac toxicity has been recognized as a major side effect, negatively affecting quality of life and prognosis in cancer survivors. Physicians involved in the care of these patients should be familiar with the effects of chemotherapy and radiotherapy on the heart, as well as the tests that may facilitate early diagnosis and prompt referral to cardiology units with expertise in the management of oncologic patients. This special report focuses on the mechanisms of cardiotoxicity and the techniques (including basic and advanced imaging and biomarkers) used in the cardiac evaluation of cancer patients. PMID- 26234497 TI - Programmed cell removal biomarkers calreticulin and CD47 implicated in oral lichen planus. AB - OBJECTIVES: To investigate the expression of the programmed cell removal markers, calreticulin (CRT) and CD47, known to be involved in various autoimmune diseases, in patients with oral lichen planus (OLP), and to investigate the association with clinical behavior. MATERIALS AND METHODS: Biopsies of 78 patients with OLP were included. The clinical data were collected from patients' charts. The expression of CRT and CD47 was immunomorphometrically analyzed in the epithelial (CRTep, CD47ep) and inflammatory cells (CRTinf, CD47inf), and the results were correlated with the clinical presentation. RESULTS: The epithelial and inflammatory cells expressed CRT (2.83 +/- 6.62 and 5.13 +/- 3.72) and CD47 (7.92 +/- 4.6 and 10.7 +/- 7.16). The expressions of CD47ep and CD47inf were associated (R = 0.64, P < 0.0005) with one another. The expressions of CRTinf and CD47ep were higher in atrophic erosive forms (A/ELP) than in the keratotic form of patients with OLP (6.46 +/- 0.76 and 9.38 +/- 0.87 vs 4.2 +/- 0.61 and 6.84 +/- 0.91, respectively, P = 0.002 and P = 0.021). The expression of CRTep was associated with more localized lesions (P < 0.009) and more abundant in males (P = 0.049), and the expression of CRTinf was associated with the presence of skin lesions and symptoms (P < 0.034 and P = 0.047, respectively). Only in A/ELP patients, the expression of CRTep was associated with high expression of CD47ep (R = 0.6, P = 0.004), where both CD47ep and CD47inf were associated with lower age of the patients (R = -0.48, P = 0.03 and R = -0.54, P = 0.01). CONCLUSIONS: The pattern of expression of CRT and CD47 in OLP suggests a general programmed cell removal response in OLP. Symptomatic patients may benefit from CRT/CD47 targeted therapy in the future. PMID- 26234498 TI - Serum bilirubin concentration is associated with eGFR and urinary albumin excretion in patients with type 1 diabetes mellitus. AB - AIMS: Although relationships of serum bilirubin concentration with estimated glomerular filtration rate (eGFR) and urinary albumin excretion (UAE) in patients with type 2 diabetes have been reported, whether such relationships exist in patients with type 1 diabetes is unknown. METHODS: A total of 123 patients with type 1 diabetes were investigated in this cross-sectional study. The relationship between bilirubin (total and indirect) concentrations and log(UAE) as well as eGFR was examined by Pearson's correlation analyses. Multivariate regression analyses were used to assess the association of bilirubin (total and indirect) with eGFR as well as log(UAE). RESULTS: A positive correlation was found between serum bilirubin concentration and eGFR; total bilirubin (r=0.223, p=0.013), indirect bilirubin (r=0.244, p=0.007). A negative correlation was found between serum bilirubin concentration and log(UAE); total bilirubin (r=-0.258, p=0.005), indirect bilirubin (r=-0.271, p=0.003). Multivariate regression analyses showed that indirect bilirubin concentration was an independent determinant of eGFR and log(UAE). CONCLUSIONS: Bilirubin concentration is associated with both eGFR and log(UAE) in patients with type 1 diabetes. Bilirubin might have a protective role in the progression of type 1 diabetic nephropathy. PMID- 26234499 TI - Global signal regression has complex effects on regional homogeneity of resting state fMRI signal. AB - Regional homogeneity (ReHo) quantifies spatially local synchronization of resting state fMRI signal and has been applied to lots of clinic studies. Accumulating evidences demonstrated that the synchronization between spatially distinct brain regions, i.e. functional connectivity, can be remarkably influenced if the global mean time course is regressed out, namely global signal regression (GSR). Very recently, it was reported GSR reduces the test-retest reliability of ReHo, and reduces the positive correlation between ReHo and head motion. In this study, we were interested in two questions: 1) how GSR affects the raw ReHo values and its spatial distribution over the brain; 2) how GSR affects the differences of ReHo between two resting states, eyes open (EO) and eyes closed (EC), in healthy individuals. We found that the ReHo values were reduced by GSR but the spatial distribution of ReHo was not changed remarkably. In addition, split-half reproducibility analysis showed reproducible ReHo difference between EO and EC in some areas (e.g., thalamus and caudate) only with GSR, but showed reproducible ReHo difference in some other area (right temporal pole) only without GSR. The effects of GSR were almost independent of regression of other nuisance covariates. Our results suggest that the influences of GSR on ReHo are remarkable, reliable and complex. For the between-condition comparison, the GSR effects are region specific. We suggest that, for application studies using ReHo approach, it would be helpful to report results both with and without GSR. PMID- 26234500 TI - Analysis of kinetic curve and model-based perfusion parameters on dynamic contrast enhanced MRI in breast cancer patients: Correlations with dominant stroma type. AB - OBJECTIVE: Our purpose was to evaluate imaging findings of breast cancers according to the dominant stroma type by using kinetic curve analysis and model based perfusion parameters from dynamic contrast-enhanced magnetic resonance imaging. METHODS: From March 2011 to September 2011, 64 cancers in 64 patients were included for data analysis. Kinetic curve analysis and model based perfusion parameters (Ktrans, Kep and Ve) were obtained using dynamic contrast-enhanced magnetic resonance imaging and post-processing software. Imaging characteristics were analyzed according to the tumor-stroma ratio and dominant stroma type. RESULTS: Ve values were significantly lower in tumors with more than 50% cellularity (0.44 vs. 0.29, p=0.008). Histologic grade, estrogen receptor status and subtype of cancer (triple negative versus non-triple negative) were significantly different (p=0.009, p=0.019 and p=0.03, respectively). Median Kep values were different between collagen dominant, fibroblast dominant and lymphocyte dominant groups. By post hoc comparisons, mean Kep values were significantly higher in lymphocyte dominant group than collagen dominant group (p=0.003). Ktrans and Ve values were not significantly different according to dominant stroma type (p=0.351 and p=0.257, respectively). In multivariate regression analysis, nuclear grade (p=0.021) and dominant stroma type (collagen dominant, p=0.017) were independently correlated with Kep values. In terms of the dominant stroma type, the collagen dominant type showed a decrease of 0.247 in Kep values, compared with the fibroblast-dominant type (p=0.017). CONCLUSIONS: Ve values were significantly lower in tumors with high tumor-stroma ratio. Kep values were significantly lower in breast cancers with dominant collagen type and higher in cancers with high nuclear grade. PMID- 26234501 TI - Balanced MR cholangiopancreatography with motion-sensitized driven-equilibrium (MSDE) preparation: Feasibility and optimization of imaging parameters. AB - PURPOSE: To show the feasibility of motion-sensitized driven-equilibrium-balanced magnetic resonance cholangiopancreatography and to determine the optimal velocity encoding (VENC) value. MATERIALS AND METHODS: Sixteen healthy volunteers underwent MRI study using a 1.5-T clinical unit and a 32-channel body array coil. For each volunteer, images were obtained using the following seven respiratory triggered sequences: (1) balanced magnetic resonance cholangiopancreatography without motion-sensitized driven-equilibrium, and (2)-(7) balanced magnetic resonance cholangiopancreatography with motion-sensitized driven-equilibrium, with VENC=1, 3, 5, 7, 9 and infinitycm/s for the x-, y-, and z-directions, respectively. Quantitative evaluation was obtained by measuring the maximum signal intensity of the common hepatic duct, portal vein, liver tissue including visible peripheral vessels, and liver tissue excluding visible peripheral vessels that were evaluated. We compared the contrast ratios of portal vein/common hepatic duct, liver tissue including visible peripheral vessels/common hepatic duct and liver tissue excluding visible peripheral vessels/common hepatic duct among the five finite sequences (VENC=1, 3, 5, 7, and 9cm/s). Statistical comparisons were performed using the t-test for paired data with the Bonferroni correction. RESULTS: Suppression of blood vessel signals was achieved with motion sensitized driven-equilibrium sequences. We found the optimal VENC values to be either 3 or 5cm/s with the best suppression of relative vessel signals to bile ducts. At a lower VENC value (1cm/s), the bile duct signal was reduced, presumably due to minimal biliary flow. CONCLUSION: The feasibility of motion sensitized driven-equilibrium-balanced magnetic resonance cholangiopancreatography was suggested. The optimal VENC value was considered to be either 3 or 5cm/s. The clinical usefulness of this new magnetic resonance cholangiopancreatography sequence needs to be verified by further studies. PMID- 26234503 TI - Immunomodulatory role of IL-33 counteracts brain inflammation in stroke. PMID- 26234504 TI - Superparamagnetic iron oxide nanoparticles for direct labeling of stem cells and in vivo MRI tracking. AB - To develop effective stem cell therapies, it is important to track therapeutic cells non-invasively and monitor homing to areas of pathology. The purpose of this study was to design and evaluate the labeling efficiency of commercially available dextran-coated superparamagnetic iron oxide nanoparticles, FeraTrack Direct (FTD), in various stem and immune cells; assess the cytotoxicity and tolerability of the FTD in stem cells; and monitor stem cell homing using FTD labeled bone-marrow-derived mesenchymal stromal cells (BMSCs) and neural stem cells (NSCs) in a tumor model by in vivo MRI. BMSCs, NSCs, hematopoietic stem cells (HSCs), T-lymphocytes, and monocytes were labeled effectively with FTD without the need for transfection agents, and Prussian blue (PB) staining and transmission electron microscopy (TEM) confirmed intracellular uptake of the agent. The viability, proliferation, and functionality of the labeled cells were minimally or not affected after labeling. When 10(6) FTD-labeled BMSCs or NSCs were injected into C6 glioma bearing nude mice, the cells homing to the tumors were detected as hypointense regions within the tumor using 3 T clinical MRI up to 10 days post injection. Histological analysis confirmed the homing of injected cells to the tumor by the presence of PB positive cells that are not macrophages. Labeling of stem cells or immune cells with FTD was non-toxic, and should facilitate the translation of this agent to clinical trials for evaluation of trafficking of cells by MRI. PMID- 26234506 TI - QSAR Analysis of Some Antagonists for p38 map kinase Using Combination of Principal Component Analysis and Artificial Intelligence. AB - Quantitative relationships between structures of a set of p38 map kinase inhibitors and their activities were investigated by principal component regression (PCR) and principal componentartificial neural network (PC-ANN). Latent variables (called components) generated by principal component analysis procedure were applied as the input of developed Quantitative structure- activity relationships (QSAR) models. An exact study of predictability of PCR and PC-ANN showed that the later model has much higher ability to calculate the biological activity of the investigated molecules. Also, experimental and estimated biological activities of compounds used in model development step have indicated a good correlation. Obtained results show that a non-linear model explaining the relationship between the pIC50s and the calculated principal components (that extract from structural descriptors of the studied molecules) is superior than linear model. Some typical figures of merit for QSAR studies explaining the accuracy and predictability of the suggested models were calculated. Therefore, to design novel inhibitors of p38 map kinase with high potency and low undesired effects the developed QSAR models were used to estimate biological pIC50 of the studied compounds. PMID- 26234507 TI - Application of Multivariate Linear and Nonlinear Calibration and Classification Methods in Drug Design. AB - Data manipulation and maximum efficient extraction of useful information need a range of searching, modeling, mathematical, and statistical approaches. Hence, an adequate multivariate characterization is the first necessary step in investigation and the results are interpreted after multivariate analysis. Multivariate data analysis is capable of not only large dataset management but also interpret them surely and rapidly. Application of chemometrics and cheminformatics methods may be useful for design and discovery of new drug compounds. In this review, we present a variety of information sources on chemometrics, which we consider useful in different fields of drug design. This review describes exploratory analysis (PCA), classification and multivariate calibration (PCR, PLS) methods to data analysis. It summarizes the main facts of linear and nonlinear multivariate data analysis in drug discovery and provides an introduction to manipulation of data in this field. It handles the fundamental aspects of basic concepts of multivariate methods, principles of projections (PCA and PLS) and introduces the popular modeling and classification techniques. Enough theory behind these methods, more particularly concerning the chemometrics tools is included for those with little experience in multivariate data analysis techniques such as PCA, PLS, SIMCA, etc. We describe each method by avoiding unnecessary equations, and details of calculation algorithms. It provides a synopsis of the method followed by cases of applications in drug design (i.e., QSAR) and some of the features for each method. PMID- 26234505 TI - A HER2-specific Modified Fc Fragment (Fcab) Induces Antitumor Effects Through Degradation of HER2 and Apoptosis. AB - FS102 is a HER2-specific Fcab (Fc fragment with antigen binding), which binds HER2 with high affinity and recognizes an epitope that does not overlap with those of trastuzumab or pertuzumab. In tumor cells that express high levels of HER2, FS102 caused profound HER2 internalization and degradation leading to tumor cell apoptosis. The antitumor effect of FS102 in patient-derived xenografts (PDXs) correlated strongly with the HER2 amplification status of the tumors. Superior activity of FS102 over trastuzumab or the combination of trastuzumab and pertuzumab was observed in vitro and in vivo when the gene copy number of HER2 was equal to or exceeded 10 per cell based on quantitative polymerase chain reaction (qPCR). Thus, FS102 induced complete and sustained tumor regression in a significant proportion of HER2-high PDX tumor models. We hypothesize that the unique structure and/or epitope of FS102 enables the Fcab to internalize and degrade cell surface HER2 more efficiently than standard of care antibodies. In turn, increased depletion of HER2 commits the cells to apoptosis as a result of oncogene shock. FS102 has the potential of a biomarker-driven therapeutic that derives superior antitumor effects from a unique mechanism-of-action in tumor cells which are oncogenically addicted to the HER2 pathway due to overexpression. PMID- 26234508 TI - 3D-QSAR analysis of MCD inhibitors by CoMFA and CoMSIA. AB - Three-dimensional quantitative structure-activity relationship was developed for the series of compounds as malonyl-CoA decarboxylase antagonists (MCD) using the CoMFA and CoMSIA methods. The statistical parameters for CoMFA (q(2)=0.558, r(2)=0.841) and CoMSIA (q(2)= 0.615, r(2) = 0.870) models were derived based on 38 compounds as training set in the basis of the selected alignment. The external predictive abilities of the built models were evaluated by using the test set of nine compounds. From obtained results, the CoMSIA method was found to have highly predictive capability in comparison with CoMFA method. Based on the given results by CoMSIA and CoMFA contour maps, some features that can enhance the activity of compounds as MCD antagonists were introduced and used to design new compounds with better inhibition activity. PMID- 26234509 TI - Acute and subchronic toxicity studies on safety assessment of Paecilomyces tenuipes N45 extracts. AB - Paecilomyces tenuipes, one of the commonly used Chinese medicinal fungus, has received much attention over the world, which possesses various active compounds and biological activities. However, little toxicological information is available. Therefore, the present study evaluated the potential toxicity of aqueous and ethanol extracts of Paecilomyces tenuipes N45 via acute and subchronic administration in mouse and rat, respectively. For improving the extraction rate of aqueous extract, response surface methodology (RSM) was employed to optimize the extraction condition first in this paper. The obtained optimal extract conditions were temperature 80 degrees C, liquid-solid ratio 50 mL.g-1 and time 3 h. In the acute toxicity test, aqueous and ethanol extracts caused neither mortality nor toxicological signs, and the maximum tolerance dose was estimated over 15 g/kg. No mortality or adverse effects was observed in subchronic toxicity studies. No significant difference in bodyweight, relative organ weight or hematological parameters was noted during the experiment. Comparing with nontreated rats, ALT, K and BUN levels were changed in experimental group detecting via biochemical analysis. No abnormality of internal organs was noted between treatment and control groups in gross and histopathological examinations. Our present study suggested that the tolerance dose of the Paecilomyces tenuipes N45 extracts were more than 15 g/kg and no observed-adverse-effect level (NOAEL) of the extracts for both male and female rats after 90-day adminstation. Additionally, the extracts may possess renal protective and hepato-protective effects. PMID- 26234510 TI - Artificial Neural Network Methods Applied to Drug Discovery for Neglected Diseases. AB - Among the chemometric tools used in rational drug design, we find artificial neural network methods (ANNs), a statistical learning algorithm similar to the human brain, to be quite powerful. Some ANN applications use biological and molecular data of the training series that are inserted to ensure the machine learning, and to generate robust and predictive models. In drug discovery, researchers use this methodology, looking to find new chemotherapeutic agents for various diseases. The neglected diseases are a group of tropical parasitic diseases that primarily affect poor countries in Africa, Asia, and South America. Current drugs against these diseases cause side effects, are ineffective during the chronic stages of the disease, and are often not available to the needy population, have relative high toxicity, and face developing resistance. Faced with so many problems, new chemotherapeutic agents to treat these infections are much needed. The present review reports on neural network research, which studies new ligands against Chagas' disease, sleeping sickness, malaria, tuberculosis, and leishmaniasis; a few of the neglected diseases. PMID- 26234511 TI - Bio-AIMS Collection of Chemoinformatics Web Tools based on Molecular Graph Information and Artificial Intelligence Models. AB - The molecular information encoding into molecular descriptors is the first step into in silico Chemoinformatics methods in Drug Design. The Machine Learning methods are a complex solution to find prediction models for specific biological properties of molecules. These models connect the molecular structure information such as atom connectivity (molecular graphs) or physical-chemical properties of an atom/group of atoms to the molecular activity (Quantitative Structure - Activity Relationship, QSAR). Due to the complexity of the proteins, the prediction of their activity is a complicated task and the interpretation of the models is more difficult. The current review presents a series of 11 prediction models for proteins, implemented as free Web tools on an Artificial Intelligence Model Server in Biosciences, Bio-AIMS (http://bio-aims.udc.es/TargetPred.php). Six tools predict protein activity, two models evaluate drug - protein target interactions and the other three calculate protein - protein interactions. The input information is based on the protein 3D structure for nine models, 1D peptide amino acid sequence for three tools and drug SMILES formulas for two servers. The molecular graph descriptor-based Machine Learning models could be useful tools for in silico screening of new peptides/proteins as future drug targets for specific treatments. PMID- 26234512 TI - Chemometrics-assisted Spectrofluorimetric Determination of Two Co-administered Drugs of Major Interaction, Methotrexate and Aspirin, in Human Urine Following Acid-induced Hydrolysis. AB - Methotrexate (MTX) is widely used to treat rheumatoid arthritis (RA), mostly along with non-steroidal anti-inflammatory drugs (NSAIDs), the most common of which is aspirin or acetyl salicylic acid (ASA). Since NSAIDs impair MTX clearance and increase its toxicity, it was necessary to develop a simple and reliable method for the monitoring of MTX levels in urine samples, when coadministered with ASA. The method was based on the spectrofluorimetric measurement of the acid-induced hydrolysis product of MTX, 4-amino-4-deoxy-10 methylpteroic acid (AMP), along with the strongly fluorescent salicylic acid (SA), a product of acid-induced hydrolysis of aspirin and its metabolites in urine. The overlapping emission spectra were resolved using the derivative method (D method). In addition, the corresponding derivative emission spectra were convoluted using discrete Fourier functions, 8-points sin xi polynomials, (D/FF method) for better elimination of interferences. Validation of the developed methods was carried out according to the ICH guidelines. Moreover, the data obtained using derivative and convoluted derivative spectra were treated using the non-parametric Theil's method (NP), compared with the least-squares parametric regression method (LSP). The results treated with Theil's method were more accurate and precise compared with LSP since the former is less affected by the outliers. This work offers the potential of both derivative and convolution using discrete Fourier functions in addition to the effectiveness of using the NP regression analysis of data. The high sensitivity obtained by the proposed methods was promising for measuring low concentration levels of the two drugs in urine samples. These methods were efficiently used to measure the drugs in human urine samples following their co-administration. PMID- 26234513 TI - Classification of natural estrogen-like isoflavonoids and diphenolics by QSAR tools. AB - This work reports a detailed study of the ability of linear and non-linear classification methods to estimate the estrogenic activities of a series of 55 natural estrogen-like isoflavonoid and diphenolic compounds. In doing so, we examined the use of linear discriminant analysis (LDA) and nonlinear support vector machines (SVMs) techniques along with feature selection algorithms. The structural characteristics of each of the studied compounds were calculated from the optimized molecular geometries. Both the LDA and SVMs models contain four descriptors, however, the SVMs model (total accuracy 89.1%) was found to be superior to the LDA model (total accuracy 80.0%). The analysis of molecular descriptors within our models provided essential insights towards a better understanding of the estrogenic mechanisms of natural estrogen-like phytoestrogens. Furthermore, the derived models can be applied in the future screening of other natural estrogen-like compounds. PMID- 26234514 TI - Near Infrared Spectroscopic Combined with Partial Least Squares and Radial Basis Function Neural Network to Analyze Paclitaxel Concentration in Rat Plasma. AB - Paclitaxel is known as one of the most effective anticancer drugs. Near Infrared Spectroscopy (NIRS), a rapid, precise and non-destructive approach of analysis, has been widely used for qualitative and quantitative detection. The present study aims to analyze the plasma paclitaxel concentration with NIRS. Various batches of plasma samples were prepared and the concentration of paclitaxel was determined via high performance liquid chromatography tandem mass spectrometry (LC-MS/MS). The outliers and the number of calibration set were confirmed by Monte Carlo algorithm combined with partial least squares (MCPLS). Since NIR spectra may be contaminated by signals from background and noise, a series of preprocessing were performed to improve signal resolution. Moving window PLS and radical basis function neural network (RBFNN) methods were applied to establish calibration model. Although both PLS and RBFNN models are well-fitting, RBFNN established model displayed better qualities on stability and predictive ability. The correlation coefficients of calibration curve and prediction set (Rc(2) and Rp(2)) are 0.9482 and 0.9544, respectively. Moreover, independent verification test with 20 samples confirmed the well predictive ability of RBFNN model. PMID- 26234515 TI - RepurposeVS: A Drug Repurposing-Focused Computational Method for Accurate Drug Target Signature Predictions. AB - We describe here RepurposeVS for the reliable prediction of drug-target signatures using X-ray protein crystal structures. RepurposeVS is a virtual screening method that incorporates docking, drug-centric and protein-centric 2D/3D fingerprints with a rigorous mathematical normalization procedure to account for the variability in units and provide high-resolution contextual information for drug-target binding. Validity was confirmed by the following: (1) providing the greatest enrichment of known drug binders for multiple protein targets in virtual screening experiments, (2) determining that similarly shaped protein target pockets are predicted to bind drugs of similar 3D shapes when RepurposeVS is applied to 2,335 human protein targets, and (3) determining true biological associations in vitro for mebendazole (MBZ) across many predicted kinase targets for potential cancer repurposing. Since RepurposeVS is a drug repurposing-focused method, benchmarking was conducted on a set of 3,671 FDA approved and experimental drugs rather than the Database of Useful Decoys (DUDE) so as to streamline downstream repurposing experiments. We further apply RepurposeVS to explore the overall potential drug repurposing space for currently approved drugs. RepurposeVS is not computationally intensive and increases performance accuracy, thus serving as an efficient and powerful in silico tool to predict drug-target associations in drug repurposing. PMID- 26234516 TI - Synthesis, aromaticity and photophysical behaviour of ferrocene- and ruthenocene appended semisynthetic chlorin derivatives. AB - Two novel synthetic strategies to covalently link a metallocene electron-donor unit to a chlorin ring are presented. In one approach, pyropheophorbide a is readily converted into its 13(1) -ferrocenyl dehydro derivative by nucleophilic addition of the ferrocenyl anion to the 13(1) -carbonyl group. In another approach, the corresponding 13(1) -pentamethylruthenocenyl derivative is synthesised from 13(1) -fulvenylchlorin by a facile ligand exchange/deprotonation reaction with the [RuCp*(cod)Cl] (Cp*=pentamethylcyclopentadienyl; cod=1,5 cyclooctadiene) complex. The resulting metallocene-chlorins exhibit reduced aromaticity, which was unequivocally supported by ring-current calculations based on the gauge-including magnetically induced current (GIMIC) method and by calculated nucleus-independent chemical shift (NICS) values. The negative ring current in the isocyclic E ring suggests the antiaromatic character of this moiety and also clarifies the spontaneous reactivity of the complexes with oxygen. The oxidation products were isolated and their electrochemical and photophysical properties were studied. The ruthenocene derivatives turned out to be stable under light irradiation and showed photoinduced charge transfer with charge-separation lifetimes of 152-1029 ps. PMID- 26234517 TI - Disrupted causal connectivity anchored on the anterior cingulate cortex in first episode medication-naive major depressive disorder. AB - In recent years, major depressive disorder (MDD) has been demonstrated to be associated with abnormalities in neural networks, particularly the prefrontal limbic network (PLN). However, there are few current studies that have examined information flow in the PLN. In this study, Granger causality analysis (GCA), based on signed regression coefficient, was used to explore changes in causal connectivity in resting-state PLNs of MDD patients. A total of 23 first-episode medication-naive MDD patients and 20 normal control participants were subjected to resting-state functional magnetic resonance imaging (RS-fMRI) scans. Increased causal effects of the right insular cortex, right putamen and right caudate on the rostral anterior cingulate cortex (rACC) and reduced causal effects of bilateral dorsolateral prefrontal cortex (DLPFC) and left orbitofrontal cortex (OFC) on the rACC were found in MDD patients compared to normal controls. The extensive reduction in the causal effect of the prefrontal cortex (PFC) demonstrates impaired top-down cognitive control in MDD patients. Changes in the causal relationship between the right insula and rACC suggest problems in coordination of the default mode network by the right anterior insular cortex (rAI). These findings provide valuable insight into MDD-related neural network disorders reported in previous RS-fMRI studies and may potentially guide clinical treatment of MDD in the future. PMID- 26234518 TI - Perception of emotion in facial stimuli: The interaction of ADRA2A and COMT genotypes, and sex. AB - Emotional facial stimuli are important social signals that are essential to be perceived and recognized in order to make appropriate decisions and responses in everyday communication. The ability to voluntarily guide attention to perceive and recognize emotions, and react to them varies largely across individuals, and has a strong genetic component (Friedman et al., 2008). Two key genetic variants of the catecholamine system that have been related to emotion perception and attention are the catechol-O-methyl transferase genetic variant (COMT Val158Met) and the alpha2A-receptor gene promoter polymorphism (ADRA2A C-1291G) accordingly. So far, the interaction of the two with sex in emotion perception has not been studied. Multilevel modeling method was applied to study how COMT Val158Met, ADRA2A C-1291G and sex are associated with measures of emotion perception in a large sample of young adults. Participants (n=506) completed emotion recognition and behavioral emotion detection tasks. It was found that COMT Val158Met genotype in combination with the ADRA2A C-1291G and sex predicts emotion detection, and perception of valence and arousal. In simple visual detection, the ADRA2A C-1291G G-allele leads to slower detection of a highly arousing face (scheming), which is modulated by each additional COMT Val158Met Met-allele and male sex predicting faster responses. The combination of G-allele, Met-allele and male sex also predicts higher perceived negativity in sad faces. No effects of C-1291G, Val158Met, and sex were found on verbal emotion recognition. Applying the findings to study the interplay between catecholamine-O-methyl transferase activity and alpha2A-receptors in emotion perception disorders (such as ADHD, autism and schizophrenia) in men and women would be the next step towards understanding individual differences in emotion perception. PMID- 26234519 TI - Glycoxidation of histone proteins in autoimmune disorders. AB - Post translational modifications (PTMs) alter the characteristic properties of proteins by influencing the spatial orientation of amino acid residues leading to a variety of pathological complications. Among the large number of PTMs, much attention has focused on non-enzymatic glycation and oxidation of proteins that form advanced glycation end products and generate autoantibodies. Histone proteins are essential components of chromatin structure and have role in its higher order structural formation. They have abundance of lysine and arginine residues and thus are prone to glyoxidation reactions. Glyoxidation causes structural alterations in histones and consequently leads to a variety of modifications in their amino acid sequence and the secondary and tertiary structure producing new antigenic determinants that may result in cause an aggressive autoimmune response. Here we review and evaluate the field of histone glyoxidation and its role in autoimmune disorders. We explore their structural alterations and immunogenicity of histones after glycation and oxidation reactions, and their role in autoimmune disease such as systemic lupus erythematosus, rheumatoid arthritis and diabetes. PMID- 26234520 TI - Improved Multiplex Ligation-dependent Probe Amplification (i-MLPA) for rapid copy number variant (CNV) detection. AB - BACKGROUND: In Multiplex Ligation-dependent Probe Amplification (MLPA), copy number variants (CNVs) for specific genes are identified after normalization of the amounts of PCR products from ligated reference probes hybridized to genomic regions that are ideally free from normal variation. However, we observed ambiguous calls for two reference probes in an investigation of the human 15q11.2 region by MLPA among 20 controls, due to the presence of single nucleotide polymorphisms (SNPs) in the probe-binding regions. Further in silico analysis revealed that 18 out of 19 reference probes hybridize to regions subject to variation, underlining the requirement for designing new reference probes against variation-free regions. METHODS: An improved MLPA (i-MLPA) method was developed by generating a new set of reference probes to reduce the chances of ambiguous calls and new reagents that reduce hybridization times to 30 min from 16h to obtain MLPA ratio data within 6h. Using i-MLPA, we screened 240 schizophrenia patients for CNVs in 15q11.2 region. CONCLUSION: Three deletions and two duplications were identified among the 240 schizophrenia patients. No variation was observed for the new reference probes. Taken together, i-MLPA procedure helps obtaining non-ambiguous CNV calls within 6h without compromising accuracy. PMID- 26234521 TI - Does Renal Denervation Fit All Resistant Hypertension? The Role of Genetics. PMID- 26234522 TI - Influenza vaccination of health care personnel: Experiences with the first year of a national data collection effort. AB - BACKGROUND: The purpose of this project was to evaluate a standardized measure of health care personnel (HCP) influenza vaccination during the first year of implementation. The measure requires acute care hospitals to gather vaccination status data from employees, licensed independent practitioners (LIPs), and adult students/trainees and volunteers. The evaluation included a hospital sampling frame stratified by 4 United States Census Bureau Regions and hospital bed count. The hospitals were selected within strata using simple random sampling and the probability proportional to size method, without replacement. METHODS: Semi structured telephone interviews were conducted. Two qualitative data analysts independently coded each interview, and data were synthesized using a thematic analysis. This evaluation took place at hospitals reporting HCP influenza vaccination data as part of the Centers for Medicare & Medicaid Services Hospital Inpatient Quality Reporting (IQR) Program. Participants included the staff at 46 hospitals who were knowledgeable about data collection to fulfill IQR program requirements. RESULTS: Facilitators of data collection included having a small number of HCP, having a data collection system already in place, and providing HCP with advance notice of data collection. Major challenges included the absence of an established tracking process and monitoring HCP not regularly working in the facility, particularly LIPs. More than half of the facilities noted the time- and/or resource-intensive nature of data collection. Most facilities used data collected to meet other reporting requirements beyond the IQR Program. CONCLUSIONS: Hospitals implemented a range of data collection methods to comply with reporting requirements. Lessons learned from the first year of measure implementation can be used to enhance data collection practices across HCP groups for future influenza seasons. PMID- 26234523 TI - Allergic perioral contact dermatitis caused by rubber chemicals during dental treatment. PMID- 26234524 TI - Pharmacological stimulation of serotonin 5-HT1B receptors enhances increases in plasma active glucagon-like peptide-1 levels induced by dipeptidyl peptidase-4 inhibition independently of feeding in mice. AB - AIM: Glucagon-like peptide-1 (GLP-1), an incretin hormone, is released from intestinal L cells in response to nutrient ingestion. Dipeptidyl peptidase-4 (DPP 4) rapidly degrades the active form of GLP-1 to an inactive form in the bloodstream. The present study aimed to investigate the role of serotonin (5 HT)1B receptors in the regulation of plasma active GLP-1 levels and glucose tolerance under DPP-4 inhibition. METHODS: C57BL6J mice treated with or without alogliptin, a highly selective DPP-4 inhibitor, for 4 days were intraperitoneally injected with either saline, the 5-HT1B/2C receptor agonist meta chlorophenylpiperazine (mCPP) at 2.5mg/kg and 5mg/kg or the selective 5-HT1B receptor agonist CP94253 at 2.5mg/kg and 5mg/kg, and food-deprived after treatment. An hour later, plasma active GLP-1 levels were determined. Also, a glucose tolerance test was done by injecting D-glucose (2g/kg) following the injection of saline or CP94253 (5mg/kg) in mice treated with alogliptin. RESULTS: Intraperitoneal injection of mCPP (2.5 and 5mg/kg) or CP94253 (2.5 and 5mg/kg) in mice treated with alogliptin for 4 days significantly increased plasma active GLP 1 levels compared with saline controls in mice that were food-deprived after the injections. While intraperitoneal injection of either mCPP or CP94253 alone had no significant effect on plasma active GLP-1 levels, the injection of CP94253 improved glucose tolerance in mice treated with alogliptin compared with saline. CONCLUSION: These findings suggest that pharmacological stimulation of 5-HT1B receptors enhances the increases in plasma active GLP-1 induced by DPP-4 inhibition independently of feeding and also improves glucose tolerance in mice. PMID- 26234526 TI - The effects of resveratrol supplementation on cardiovascular risk factors in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled study. AB - Non-alcoholic fatty liver disease (NAFLD) is usually associated with insulin resistance, central obesity, reduced glucose tolerance, type 2 diabetes mellitus and hypertriacylglycerolaemia. The beneficial effects of resveratrol on metabolic disorders have been shown previously. The aim of this study was to evaluate the effects of resveratrol supplementation on cardiovascular risk factors in patients with NAFLD. In this randomised double-blinded placebo-controlled clinical trial, fifty NAFLD patients were supplemented with either a 500-mg resveratrol capsule or a placebo capsule for 12 weeks. Both groups were advised to follow an energy balanced diet and physical activity recommendations. resveratrol supplementation reduced alanine aminotransferase (ALT) and hepatic steatosis significantly more than placebo (P0.05). There were no significant changes in blood pressure, insulin resistance markers and TAG in either group (P>0.05). Our data have shown that 12-week supplementation of 500 mg resveratrol does not have any beneficial effect on anthropometric measurements, insulin resistance markers, lipid profile and blood pressure; however, it reduced ALT and hepatic steatosis in patients with NAFLD. PMID- 26234527 TI - Solid-state NMR: An emerging technique in structural biology of self-assemblies. AB - Protein self-assemblies are ubiquitous biological systems involved in many cellular processes, ranging from bacterial and viral infection to the propagation of neurodegenerative disorders. Studying the atomic three-dimensional structures of protein self-assemblies is a particularly demanding task, as these systems are usually insoluble, non-crystalline and of large size. Solid-state NMR (ssNMR) is an emerging method that can provide atomic-level structural data on intact macromolecular assemblies. We here present recent progress in magic-angle spinning ssNMR to study protein assemblies and give an overview on its combination with complementary techniques such as cryo-EM, mass-per-length measurements, SAXS and X-ray diffraction. Applications of ssNMR on its own and in hybrid approaches have revealed precious atomic details and first high-resolution structures of complex biological assemblies, including amyloid fibrils, bacterial filaments, phages or virus capsids. PMID- 26234525 TI - The heat shock response restricts virus infection in Drosophila. AB - Innate immunity is the first line of defence against pathogens and is essential for survival of the infected host. The fruit fly Drosophila melanogaster is an emerging model to study viral pathogenesis, yet antiviral defence responses remain poorly understood. Here, we describe the heat shock response, a cellular mechanism that prevents proteotoxicity, as a component of the antiviral immune response in Drosophila. Transcriptome analyses of Drosophila S2 cells and adult flies revealed strong induction of the heat shock response upon RNA virus infection. Dynamic induction patterns of heat shock pathway components were characterized in vitro and in vivo following infection with different classes of viruses. The heat shock transcription factor (Hsf), as well as active viral replication, were necessary for the induction of the response. Hsf-deficient adult flies were hypersensitive to virus infection, indicating a role of the heat shock response in antiviral defence. In accordance, transgenic activation of the heat shock response prolonged survival time after infection and enabled long-term control of virus replication to undetectable levels. Together, our results establish the heat shock response as an important constituent of innate antiviral immunity in Drosophila. PMID- 26234528 TI - GATA1 directly mediates interactions with closely spaced pseudopalindromic but not distantly spaced double GATA sites on DNA. AB - The transcription factor GATA1 helps regulate the expression of thousands of genes involved in blood development, by binding to single or double GATA sites on DNA. An important part of gene activation is chromatin looping, the bringing together of DNA elements that lie up to many thousands of basepairs apart in the genome. It was recently suggested, based on studies of the closely related protein GATA3, that GATA-mediated looping may involve interactions of each of two zinc fingers (ZF) with distantly spaced DNA elements. Here we present a structure of the GATA1 ZF region bound to pseudopalindromic double GATA site DNA, which is structurally equivalent to a recently-solved GATA3-DNA complex. However, extensive analysis of GATA1-DNA binding indicates that although the N-terminal ZF (NF) can modulate GATA1-DNA binding, under physiological conditions the NF binds DNA so poorly that it cannot play a direct role in DNA-looping. Rather, the ability of the NF to stabilize transcriptional complexes through protein-protein interactions, and thereby recruit looping factors such as Ldb1, provides a more compelling model for GATA-mediated looping. PMID- 26234529 TI - Human Identification via Lateral Patella Radiographs: A Validation Study. AB - This research examines the utility of patella outline shape for matching 3D scans of patellae to knee radiographs using elliptical Fourier analysis and subjective methods of human visual comparison of patellae across radiographs for identification purposes. Repeat radiographs were captured of cadaver's knees for visual comparison before patellae were extracted and skeletonized for quantitative comparisons. Quantitative methods provided significant narrowing down of the candidate pool to just a few potential matches (<5% of original sample), while the human analysts showed high capacity for correctly matching radiographs, irrespective of educational level (positive predictive value = 99.8%). The successful computerized matching based on a single quantified patella trait (outline shape) helps explain the potency achieved by subjective visual examination. This work adds to a growing body of studies demonstrating the value of single isolated infracranial bones for human identification via radiographic comparison. PMID- 26234530 TI - Insights into relevant mechanistic aspects about the induction period of Cu(0)/Me(6)TREN-mediated reversible-deactivation radical polymerization. AB - There is a controversial debate about the mechanism of the Cu(0)-catalyzed radical polymerization. Herein, a comparative analysis of a series of reactions catalyzed by different valent copper shows that the induction period and the subsequent autoaccelerated polymerization of a Cu(0)/Me6TREN-catalyzed system originate from the accumulation of soluble copper species, and Cu(I) is still a powerful activator under its disproportionation favored conditions. PMID- 26234532 TI - Falls in older adults with major depressive disorder (MDD): a systematic review and exploratory meta-analysis of prospective studies. AB - BACKGROUND: Depressive symptomology is now widely recognized as a key risk factor for falls. The evidence regarding the impact of major depressive disorder (MDD) on falls is unclear. A systematic review and exploratory meta-analysis was undertaken to explore the relationship between MDD and falls. METHODS: Major electronic database were searched from inception till April 2015. Studies that defined MDD and measured falls prospectively in older adults (>=60 years) were included. Studies relying on depressive symptomology alone were excluded. The methodological quality of included articles was assessed and study findings were synthesized using an exploratory meta-analysis. RESULTS: From a potential of 415 articles, only three studies met the inclusion criteria. This included 976 unique older adults with a range of mean age from >=65 to 83 years. The methodological quality of included studies was satisfactory. None of the included studies' primary aim was to investigate the relationship between MDD and falls. The exploratory meta-analysis demonstrated older adults with MDD are at increased risk of falling compared to non-depressed older adults (odds ratio (OR) 4.0, 95% CI 2.0-8.1, I(2) = 60%, n = 976). CONCLUSION: There is a paucity of research considering falls in older adults with MDD. Our results demonstrate that the odds of falling appear to be greater among people with MDD (OR 4.0) than in previous meta-analyses that have only considered subthreshold depressive symptoms. Given the distinct nature and challenges with MDD, more research is required to better understand the falls risk in this group. PMID- 26234531 TI - A systematic review of Rift Valley Fever epidemiology 1931-2014. AB - BACKGROUND: Rift Valley Fever (RVF) is a mosquito-borne viral zoonosis that was first isolated and characterized in 1931 in Kenya. RVF outbreaks have resulted in significant losses through human illness and deaths, high livestock abortions and deaths. This report provides an overview on epidemiology of RVF including ecology, molecular diversity spatiotemporal analysis, and predictive risk modeling. METHODOLOGY: Using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched for relevant RVF publications in repositories of the World Health Organization Library and Information Networks for Knowledge (WHOLIS), U.S Centers for Disease Control and Prevention (CDC), and Food and Agricultural Organization (FAO). Detailed searches were performed in Google Scholar, SpringerLink, and PubMed databases and included conference proceedings and books published from 1931 up to 31st January 2015. RESULTS AND DISCUSSION: A total of 84 studies were included in this review; majority (50%) reported on common human and animal risk factors that included consumption of animal products, contact with infected animals and residing in low altitude areas associated with favorable climatic and ecological conditions for vector emergence. A total of 14 (16%) of the publications described RVF progressive spatial and temporal distribution and the use of risk modeling for timely prediction of imminent outbreaks. Using distribution maps, we illustrated the gradual spread and geographical extent of disease; we also estimated the disease burden using aggregate human mortalities and cumulative outbreak periods for endemic regions. CONCLUSION: This review outlines common risk factors for RVF infections over wider geographical areas; it also emphasizes the role of spatial models in predicting RVF enzootics. It, therefore, explains RVF epidemiological status that may be used for design of targeted surveillance and control programs in endemic countries. PMID- 26234533 TI - Comparing alpha7 nicotinic acetylcholine receptor binding, amyloid-beta deposition, and mitochondria complex-I function in living brain: A PET study in aged monkeys. AB - This study was aimed to assess the correlations among alpha7 nicotinic acetylcholine receptor (alpha7-nAChR) binding, amyloid-beta (Abeta) deposition, and mitochondrial complex I (MC-I) activity in the brain of aged monkeys (Macaca mulatta). Positron emission tomography (PET) measurements with [(11) C](R)-MeQAA, [(11) C]PIB, and [(18) F]BCPP-EF were conducted in monkeys in a conscious condition. [(11) C](R)-MeQAA binding was analyzed by a simplified reference tissue model to calculate nondisplaceable binding potential (BPND), [(11) C]PIB uptake was calculated by standard uptake value ratio (SUVR), and [(18) F]BCPP-EF binding was determined by Logan graphical analysis to calculate total distribution volume (VT) with arterial blood sampling. Higher brain uptake was determined in the thalamus, hippocampus, striatum, and cortical regions for [(11) C](R)-MeQAA, while being lower in the cerebellum. Significant age-related reduction of [(11) C](R)-MeQAA binding to alpha7-nAChR was determined only in the occipital cortex. The plot of Vt of [(18) F]BCPP-EF against BPND of [(11) C](R) MeQAA indicated a significant negative correlation in the hippocampus and cortical regions in aged animals. Plotting of SUVR of [(11) C]PIB against BPND of [(11) C](R)-MeQAA showed a positive correlation. The in vivo binding of [(11) C](R)-MeQAA could reflect the upregulation of alpha7-nAChR induced by neurodegenerative damage determined by Abeta deposition as well as impaired MC-I activity in living brain. PMID- 26234534 TI - The length-dependent activation of contraction is equally impaired in impuberal male and female rats in monocrotaline-induced right ventricular failure. AB - The length-dependent activation of contraction is attenuated in the failing myocardium of adult male rats. This pathological change is not seen in adult female rats, possibly because of a protective effect of sex hormones. The present study evaluated length-dependent changes in isometric twitch, Ca(2+) transient (CaT) and action potential (AP) in the right ventricular myocardium of impuberal healthy male and female rats (control) and in rats treated with a single injection of 50 mg/kg monocrotaline (MCT). Compared with sex-matched control rats, MCT-treated male and female rats exhibited increased right ventricular weight (134% and 142% of control, respectively), decreased left ventricular weight (72% and 79%), twitch attenuation (48.8 +/- 2.7% and 57.5 +/- 1.2%) and prolongation (125 +/- 3% and 127 +/- 2%), CaT attenuation (37.8 +/- 0.4% and 39.1 +/- 1.1%) and prolongation (114 +/- 1% and 116 +/- 1%) and AP prolongation at 90% repolarization (195 +/- 2% and 203 +/- 1%). The MCT-treated male rats exhibited a 50% lower integral magnitude and an approximately 25% larger time-to-peak 'bump' compared with control male rats. These parameters in MCT-treated female rats tended to show similar changes to those seen in the control female rats, with no significant difference between the two groups. In all groups, integral magnitude and time-to-peak 'bump' increased with length. In conclusion, the length dependent activation of contraction was equally blunted in the failing right ventricular myocardium of impuberal male and female rats. This was related to changes in CaT and AP, which were similar between male and female rats. Therefore, puberty is necessary for manifestation of the protective effects of sex hormones on this remodelling. PMID- 26234535 TI - Lateral teleradiography of the head as a diagnostic tool used to predict obstructive sleep apnea. AB - OBJECTIVES: To (1) assess the relationship between obstructive sleep apnea (OSA) and craniofacial, pharyngeal anatomy and (2) to submit the recommendations for clinicians for increasing the sensitivity in the diagnostics of OSA. METHODS: A review of the relevant literature linking OSA in adults with cephalometric analysis was performed. In total, 11 articles with similar procedural criteria were selected. The data were analysed using the Comprehensive Meta-Analysis Software (Biostat Inc., Englewood, NJ) and Statistica 12.0 (StatSoft Inc., Dell Software, Tulsa, OK). RESULTS: Adults with OSA did not show statistically significant differences in the sagittal and vertical skeletal planes in comparison with the controls (p > 0.05). The patients with OSA had soft palate length, width and area increased accordingly by 4.21, 1.99 mm and 0.86 cm(2), tongue area increased by 2.02 cm(2), the upper posterior pharyngeal space (SPAS) and lower posterior pharyngeal space reduced accordingly by 4.53 and 1.32 mm, mandibular plane to the hyoid bone (MP-H) distance increased by 4.14 mm compared with the controls (p < 0.05). The SPAS parameter of the patients with OSA did not show statistically significant differences between the studies, with the mean value being 5.69 mm. CONCLUSIONS: Analysed cephalometric data totally supported the concept of soft-tissue abnormalities in subjects with OSA, skeletal-only halfway; MP-H and SPAS being the most reliable parameters. Increased MP-H may serve as a predictor when differentiating normal subjects and patients with OSA. Reduced SPAS width could be a prognostic parameter for suspecting OSA. These two values should be kept in mind by dentists and can also be used as a simple auxiliary method by physicians; nevertheless, it is still underestimated and more studies are needed. PMID- 26234536 TI - Effect of display type, DICOM calibration and room illuminance in bitewing radiographs. AB - OBJECTIVES: To compare observer performance in the detection of both anatomical structures and caries in bitewing radiographs using consumer grade displays with and without digital imaging and communications in medicine (DICOM) calibration, tablets (third generation iPad; Apple, Cupertino, CA) and 6-megapixel (MP) displays under different lighting. METHODS: 30 bitewing radiographs were blindly evaluated on four displays under bright (510 lx) and dim (16 lx) ambient lighting by two observers. The dentinoenamel junction, enamel and dentinal caries, and the cortical border of the alveolar crests were evaluated. Consensus was considered as reference. Intraobserver agreement was determined. The proportion of equivalent ratings and weighted kappa were used to assess reliability. RESULTS: The proportion of equivalent ratings with consensus differed significantly between uncalibrated and DICOM-calibrated consumer grade display in enamel caries in upper and lower molars in bright (p = 0.013 and p = 0.003) lighting, and in dentinal caries in lower molars in both bright (p = 0.022) and dim (p = 0.004) lighting. The proportion also differed significantly between DICOM-calibrated consumer grade and 6-MP display in dentinal caries in lower molars in bright lighting (p = 0.039), tablet and consumer grade display in enamel caries in upper molars (p = 0.017) in bright lighting, tablet and 6-MP display in dentinal caries in lower molars (p = 0.003) in bright lighting and in enamel caries in lower molars (p = 0.012) in dim lighting. CONCLUSIONS: DICOM calibration improves the detection of enamel and dentinal caries in bitewing radiographs, particularly in bright lighting. Therefore, a calibrated consumer grade display can be recommended as a diagnostic tool for viewing bitewing radiographs. PMID- 26234538 TI - Self-assembly of the decagonal quasicrystalline order in simple three-dimensional systems. AB - Using molecular dynamics simulations we show that a one-component system can be driven to a three-dimensional decagonal (10-fold) quasicrystalline state just by purely repulsive, isotropic and monotonic interaction pair potential with two characteristic length scales; no attraction is needed. We found that self assembly of a decagonal quasicrystal from a fluid can be predicted by two dimensionless effective parameters describing the fluid structure. We demonstrate stability of the results under changes of the potential by obtaining the decagonal order for three particle systems with different interaction potentials, both purely repulsive and attractive, but with the same values of the effective parameters. Our results suggest that soft matter quasicrystals with decagonal symmetry can be experimentally observed for the same systems demonstrating the dodecagonal order for an appropriate tuning of the effective parameters. PMID- 26234537 TI - Neuropeptide F neurons modulate sugar reward during associative olfactory learning of Drosophila larvae. AB - All organisms continuously have to adapt their behavior according to changes in the environment in order to survive. Experience-driven changes in behavior are usually mediated and maintained by modifications in signaling within defined brain circuits. Given the simplicity of the larval brain of Drosophila and its experimental accessibility on the genetic and behavioral level, we analyzed if Drosophila neuropeptide F (dNPF) neurons are involved in classical olfactory conditioning. dNPF is an ortholog of the mammalian neuropeptide Y, a highly conserved neuromodulator that stimulates food-seeking behavior. We provide a comprehensive anatomical analysis of the dNPF neurons on the single-cell level. We demonstrate that artificial activation of dNPF neurons inhibits appetitive olfactory learning by modulating the sugar reward signal during acquisition. No effect is detectable for the retrieval of an established appetitive olfactory memory. The modulatory effect is based on the joint action of three distinct cell types that, if tested on the single-cell level, inhibit and invert the conditioned behavior. Taken together, our work describes anatomically and functionally a new part of the sugar reinforcement signaling pathway for classical olfactory conditioning in Drosophila larvae. PMID- 26234539 TI - Multifunctional nanoparticles: recent progress in cancer therapeutics. AB - Although much progress has been made in treating cancers, cancer death rates in and around the United States are still high. Current treatments are either ineffective against some cancers or detrimental to patients, which decreases their quality of life. The use of nanotechnology in cancer therapy can potentially increase patient survival, reduce side effects, and reduce mortality rates because nanoparticles (NPs) have the potential to target only tumors and bypass healthy cells. NPs possess many features, including size, shape, charge, and composition, which allow them to carry chemotherapeutics to cancer cells. NPs can also be used in radiotherapy as radiosensitizers and in imaging as contrast agents. Many studies have performed in vitro and/or in vivo experiments on these particles in human and animal cell lines. This review discusses recent studies on different NPs and their potential use in cancer therapy. PMID- 26234540 TI - Improving Photovoltaic Performance of the Linear A-Ar-A-type Small Molecules with Diketopyrropyrrole Arms by Tuning the Linkage Position of the Anthracene Core. AB - Two isomeric A-Ar-A-type small molecules of DPP2An(9,10) and DPP2An(2,6), were synthesized with two acceptor arms of diketopyrropyrroles (DPP) and a planar aryl hydrocarbon core of the different substituted anthracene (An), respectively. Their thermal stability, crystallinity, optoelectronic, and photovoltaic performances were investigated. Significantly red-shifted absorption profile and higher HOMO level were observed for the DPP2An(2,6) with 2,6-substituted anthracene relative to the DPP2An(9,10) with 9,10-substituted anthracene, as the former exhibited better planarity and a larger conjugate system. As a result, the solution-processing solar cells based on DPP2An(2,6) and PC71BM (w/w,1:1) displayed remarkably increased power conversion efficiency of 5.44% and short circuit current density (Jsc) of 11.90 mA/cm(2) under 1% 1,8-diiodooctane additive. The PCE and Jsc values were 3.7 and 2.9 times those of the optimized DPP2An(9,10)-based cells, respectively. This work demonstrates that changing the linkage position of the anthracene core in the A-Ar-A-type SMs can strongly improve the photovoltaic properties in organic solar cells. PMID- 26234541 TI - Intraosseous Non-Hodgkin Lymphoma Mimicking a Periapical Lesion. AB - Non-Hodgkin lymphomas are a group of disorders involving malignant monoclonal proliferation of lymphoid cells, which appear at extranodal sites in approximately 40% of the cases, particularly in the gastrointestinal tract. Intraosseous lymphomas of the head and neck region are extremely rare and can mimic other diseases such as periodontitis or periapical pathologies. This report presents an additional case of intraosseous lymphoma that was previously misdiagnosed as periapical disease. In addition, a literature review was made based on PubMed, and all cases of periapical lymphoma were analyzed. After the diagnosis of lymphoma, the current patient was treated with 6 cycles of chemotherapy and showed satisfactory outcome. The literature review displayed 29 cases of lymphoma affecting the periapical region, and in 51.7% of them endodontic treatment was performed previously to the diagnosis of lymphoma. Although lymphoma is uncommon in the oral cavity, some symptoms can assist the dentist to suspect malignant conditions, mainly in cases presenting numb chin syndrome. PMID- 26234542 TI - Cyclic Fatigue of ProFile Vortex and Vortex Blue Nickel-Titanium Files in Single and Double Curvatures. AB - INTRODUCTION: The aims of this study were to determine the flexibility of ProFile Vortex (VX) and Vortex Blue (VB) files (Dentsply Tulsa Dental Specialties, Tulsa, OK) and then to evaluate and compare their fatigue resistance in artificial single curvature and 2 different artificial double curvature canals. METHODS: Flexibility of the files (size 25/.04) in bending was assessed according to ISO 3630-1. Both files were subjected to fatigue tests inside artificial canals with a single curvature (group 1: 60 degrees curvature, 5-mm radius) and with 2 different double curvatures (group 2: first [coronal] curve of 60 degrees curvature and 5-mm radius and the second one [apical] of 30 degrees curvature and 2-mm radius and group 3: first curve of 60 degrees curvature and 5-mm radius and the second one of 60 degrees curvature and 2-mm radius). The number of cycles to fracture (NCF) was recorded, and the fracture surface of all fragments was examined with a scanning electron microscope. RESULTS: The bending load was significantly lower for VB files than VX files (P < .05), and the 2 types of files followed different trajectories in identical canals. In group 1, the 2 files had significantly higher NCF than in groups 2 and 3 (P < .05). Both files had significantly higher NCF in group 2 than in group 3 (P < .05). In group 1, VB files had fatigue resistance superior to VX files (P < .05), whereas in groups 2 and 3 their fatigue resistance was not statistically different from each other. The crack initiation of a vast majority of files that fractured in double curvature canals (groups 2 and 3) was localized on either 1 of 2 of the 3 cutting edges. CONCLUSIONS: Double curvature canals represent a much more stressful and challenging anatomy than single curvature canals, and, in them, fatigue resistance may be affected by the degrees and the radii of curvatures as well as by the bending properties of the files. PMID- 26234543 TI - Infection Control in Retreatment Cases: In Vivo Antibacterial Effects of 2 Instrumentation Systems. AB - INTRODUCTION: This in vivo study compared the antibacterial effects of 2 instrumentation systems in root canal-treated teeth with apical periodontitis. METHODS: Forty-eight teeth with a single root and a single canal showing post treatment apical periodontitis were selected for this study. For retreatment, teeth were randomly divided into 2 groups according to the instrumentation system used: Self-Adjusting File (SAF; ReDent-Nova, Ra'anana, Israel) and Twisted File Adaptive (TFA; SybronEndo, Orange, CA). In both groups, 2.5% sodium hypochlorite was the irrigant. Bacteriological samples were taken before (S1) and after chemomechanical preparation (S2). In the TFA group, passive ultrasonic irrigation (PUI) was performed after instrumentation, and samples were also taken after this supplementary step (S2b). DNA was extracted from the clinical samples and subjected to quantitative real-time polymerase chain reaction to evaluate the levels of total bacteria, streptococci, and Enterococcus faecalis. Statistical analyses from quantitative real-time polymerase chain reaction data were performed within groups using the Wilcoxon matched pairs test and between groups using the Mann-Whitney U test and the Fisher exact test with the significance level set at P < .05. RESULTS: Bacteria were detected in S1 samples from 43 teeth, which were then included in the antibacterial experiment. Both SAF and TFA instrumentation protocols showed a highly significant intracanal bacterial reduction (P < .001). Intergroup quantitative comparisons disclosed no significant differences between TFA with or without PUI and SAF (P > .05). PUI did not result in significant improvement in disinfection (P > .05). CONCLUSIONS: Both instrumentation systems/treatment protocols were highly effective in significantly reducing the intracanal bacterial counts. No significant difference was observed between the 2 systems in disinfecting the canals of teeth with post treatment apical periodontitis. PMID- 26234544 TI - Reliability and Reproducibility of Manual and Automated Volumetric Measurements of Periapical Lesions. AB - INTRODUCTION: The present study aimed to test the reliability and reproducibility of 2 methods: manual and automated segmentation (using a threshold-based region growing algorithm) for measuring the volume of periapical lesions. METHODS: A total of 43 cone-beam computed tomographic scans (14 men and 29 women, mean age of 54.6 +/- 8.5 years) were analyzed by 3 observers. Intraobserver reproducibility and interobserver reliability were assessed using the intraclass correlation coefficient. Parametric correlation between manual and automated volumetric measurements was performed. In addition, the Student t test was also used to compare the mean time required for manual and automated volumetric measurements. RESULTS: Automated segmentation showed slightly higher intraclass correlation coefficient values for all observers. A strong significant correlation was found between manual and automated volumetric measurements performed by the 3 observers. A significant difference in the mean procedure time was also found between both methods (P = .001). CONCLUSIONS: Within the limitations of this study, the present results suggest that automated segmentation with a region growing algorithm is faster and slightly more reliable to calculate the volume of periapical lesions. PMID- 26234545 TI - Noninvasive Assessment of Skeletal Microstructure and Estimated Bone Strength in Hypoparathyroidism. AB - In hypoparathyroidism, areal bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) is above average, and skeletal indices by bone biopsy are abnormal. We used high-resolution peripheral quantitative computed tomography (HRpQCT) and finite element analyses (FEA) to further investigate skeletal microstructure and estimated bone strength. We studied 60 hypoparathyroid subjects on conventional therapy using DXA, HRpQCT, and FEA of the distal radius and tibia compared with normative controls from the Canadian Multicentre Osteoporosis Study. In hypoparathyroid women and men, areal BMD was above average at the lumbar spine and hip sites by DXA; radial BMD was also above average in hypoparathyroid women. Using HRpQCT, cortical volumetric BMD was increased in the hypoparathyroid cohort compared with controls at both the radius and tibia. Cortical porosity was reduced at both sites in pre- and postmenopausal women and at the tibia in young men with a downward trend at the radius in men. At the tibia, trabecular number was increased in premenopausal women and men and trabecular thickness was lower in women. Ultimate stress and failure load at both sites for the hypoparathyroid subjects were similar to controls. Using a linear regression model, at both radius and tibia, each increment in age decreased ultimate stress and failure load, whereas each increment in duration of hypoparathyroidism increased these same indices. These results provide additional evidence for the critical role of parathyroid hormone in regulating skeletal microstructure. Longer disease duration may mitigate the adverse effects of age on estimated bone strength in hypoparathyroidism. PMID- 26234546 TI - Cloning and functional characterization of an isopentenyl diphosphate isomerase gene from Tripterygium wilfordii. AB - Tripterygium wilfordii Hook.F. is one of the most valuable medicinal plants because it contains a large variety of active terpenoid compounds, including triptolide, celastrol, and wilforlide. All of the pharmacologically active secondary metabolites are synthesized from the 2-C-methyl-d-erythritol 4 phosphate and mevalonate pathway in the isoprenoid biosynthetic system. The key step in this pathway is the isomerization of dimethylallyl diphosphate and isopentenyl diphosphate, which is catalyzed by isopentenyl diphosphate isomerase (IPI). In the present study, a full-length cDNA encoding IPI (designate as TwIPI, GenBank accession no.KT279355) was cloned from a suspension of cultured cells from T. wilfordii. The full-length cDNA of TwIPI was 1,564 bp and encoded a polypeptide of 288 amino acids. The bioinformatics analysis showed that the deduced TwIPI sequence contained the TNTCCSHPL and WGEHELDY motif. The transcription level of the TwIPI in the suspension cells increased almost fivefold after treatment with methyl jasmonate as an elicitor. A functional color assay in Escherichia coli indicated that TwIPI could promote the accumulation of lycopene and encoded a functional protein. PMID- 26234547 TI - Career satisfaction of Jordanian dental hygienists. AB - AIM: The aim of this study was to determine the factors that affect Jordanian dental hygienists with their career satisfaction including financial issues, employment settings and policies. MATERIALS AND METHODS: Randomized sample of 102 dental hygienists with a bachelor's degree were selected from the entire population of Jordanian dental hygienists. Participants received a cover letter with a questionnaire. Findings were analysed using descriptive data techniques. Chi-square test was used to determine the statistically significant differences across demographic variables and career satisfaction's factors. RESULTS: About 22.5% of the participants are not working as dental hygienist. Dental hygiene profession in Jordan includes predominantly (74.0%) females. Majority of them (51.9%) were employed in JUST, and minority (6.3%) in MOH. Most of them (56.4%) were aged 24-29 years old, and mostly 62.2% with <=1 child. About 53.1% employed by general dentist. Almost 35.3% had >=4 years' job experience. Majority (47.6%) expressed high level of satisfaction with dental materials and equipment to practice work; however, only 2.0% expressed very high level of satisfaction with employment policies. Almost 32.4% expressed low level of satisfaction with salary level. Minority (2.0%) expressed dissatisfaction with quality of dentist's work. Statistically significant association was found between workplace, and dental materials and equipment to practice work, salary level, employment policies (P = 0.003, P = 0.003, P = 0.026), and number of children with flexibility in work hours (P = 0.001). CONCLUSION: Jordanian dental hygienists' workplacesatisfaction w as significantly associated with dental materials and equipment to practice work, salary level, and employment policies. Understanding the working patterns of dental hygienists in Jordan is important to increase their career satisfaction levels. PMID- 26234548 TI - Luminescence and X-ray absorption studies on 0.5% Ce(3+) doped BaCa2MgSi2O8 phosphor. AB - 0.5% Ce(3+) doped BaCa2MgSi2O8 phosphor was prepared by a conventional solid state reaction method. Luminescence spectra as well as fluorescence decay were monitored in the VUV-UV range. Ce(3+) emissions are assigned to cerium ions on a Ba(2+) site, and the five 4f-5d excitation bands of Ce(3+) were determined at low temperature. The light yield is estimated to be around 10,600 ph MeV(-1) under X ray excitation. X-ray absorption near-edge structure (XANES) was explored to study the energy transfer efficiency to optical centers from each element in the phosphor; the results show that the contributions to luminescence are not identical for each element. PMID- 26234549 TI - Reply: To PMID 25892127. PMID- 26234550 TI - Reply: To PMID 25892127. PMID- 26234551 TI - Fabrication of poly hydroxybutyrate-polyethylene glycol-folic acid nanoparticles loaded by paclitaxel. AB - In this study drug (paclitaxel)-loaded nanoparticles of poly hydroxybutyrate polyethylene glycol-folic acid (PHB-PEG-FOL) were prepared by using an oil-in water (O/W) emulsion-solvent evaporation method. The functionalization and conjugation steps in the chemical synthesis were confirmed using Fourier transform infrared (FTIR) and nuclear magnetic resonance tests ((1)H NMR). Morphology of nanoparticles was evaluated by scanning electron microscopy (SEM). Nanoparticles were characterized by particle size analyzer. Between two samples containing drug, the lower doses showed more homogeneous distribution, and the lowest aggregation. The drug release profiles showed a two-phase release including initial rapid release and a continuous release. MG63 cells were used to evaluate cytotoxicity. The cytotoxicity of PHB-PEG-FOL nanoparticles with drug against cancer cells was much higher and longer than free drug sample. These nanoparticles were successfully synthesized as a novel system for targeted drug delivery against cancer cells. PMID- 26234553 TI - Non-invasive ventilation and diaphragmatic pacing in ALS. PMID- 26234554 TI - Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to amyotrophic lateral sclerosis (DiPALS): a multicentre, open label, randomised controlled trial. AB - BACKGROUND: Non-invasive ventilation is part of the standard of care for treatment of respiratory failure in patients with amyotrophic lateral sclerosis (ALS). The NeuRx RA/4 Diaphragm Pacing System has received Humanitarian Device Exemption approval from the US Food and Drug Administration for treatment of respiratory failure in patients with ALS. We aimed to establish the safety and efficacy of diaphragm pacing with this system in patients with respiratory muscle weakness due to ALS. METHODS: We undertook a multicentre, open-label, randomised controlled trial at seven specialist ALS and respiratory centres in the UK. Eligible participants were aged 18 years or older with laboratory supported probable, clinically probable, or clinically definite ALS; stable riluzole treatment for at least 30 days; and respiratory insufficiency. We randomly assigned participants (1:1), via a centralised web-based randomisation system with minimisation that balanced patients for age, sex, forced vital capacity, and bulbar function, to receive either non-invasive ventilation plus pacing with the NeuRx RA/4 Diaphragm Pacing System or non-invasive ventilation alone. Patients, carers, and outcome assessors were not masked to treatment allocation. The primary outcome was overall survival, defined as the time from randomisation to death from any cause. Analysis was by intention to treat. This trial is registered, ISRCTN number 53817913. FINDINGS: Between Dec 5, 2011, and Dec 18, 2013, we randomly assigned 74 participants to receive either non-invasive ventilation alone (n=37) or non-invasive ventilation plus diaphragm pacing (n=37). On Dec 18, 2013, the Data Monitoring and Ethics Committee (DMEC) recommended suspension of recruitment on the basis of overall survival figures. Randomly assigned participants continued as per the study protocol until June 23, 2014, when the DMEC advised discontinuation of pacing in all patients. Follow-up assessments continued until the planned end of the study in December, 2014. Survival was shorter in the non-invasive ventilation plus pacing group than in the non-invasive ventilation alone group (median 11.0 months [95% CI 8.3-13.6] vs 22.5 months [13.6-not reached]; adjusted hazard ratio 2.27, 95% CI 1.22-4.25; p=0.009). 28 (76%) patients died in the pacing group and 19 (51%) patients died in the non-invasive ventilation alone group. We recorded 162 adverse events (5.9 events per person-year) in the pacing group, of which 46 events were serious, compared with 81 events (2.5 events per person-year) in the non-invasive ventilation alone group, of which 31 events were serious. INTERPRETATION: Addition of diaphragm pacing to standard care with non-invasive ventilation was associated with decreased survival in patients with ALS. Our results suggest that diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure. FUNDING: The National Institute for Health Research Health Technology Assessment Programme; the Motor Neurone Disease Association of England, Wales, and Northern Ireland. PMID- 26234555 TI - Experimental approach to prezygotic chromosome screening using only a single pair of gametes in mice. AB - During in vitro embryo production, chromosome screening is essential to prevent pregnancy losses caused by embryonic chromosome aberrations. When the chromosome screening is completed before fertilization, gametes are effectively utilized as genetic resources. The aim of this study was to investigate whether chromosome screening of gametes accompanied by fertilization would be feasible using a single mouse spermatozoon and oocyte. Metaphase II oocytes were divided into a cytoplast and a karyoplast. For genome cloning of the gametes, androgenic and gynogenic embryos were produced by microinjection of sperm into cytoplasts and parthenogenetic activation of karyoplasts, respectively. Pairs of blastomeres from androgenic and gynogenic embryos were fused electrically to produce diploid embryos, which were transferred into pseudopregnant surrogate mothers to examine fetal development. Blastomeres from androgenic and gynogenic embryos were individually treated with calyculin A-a specific inhibitor of type 1 and 2A protein phosphatases-for 2 h to induce premature chromosome condensation. Thereafter, chromosome analysis of blastomeres, reflecting the genetic constitution of individual spermatozoa and oocytes, was performed, and we confirmed that most of the androgenic and gynogenic 2-cell embryos had a haploid set of chromosomes in their sister blastomeres. The reconstructed embryos from blastomeres of androgenic and gynogenic 2-cell embryos could be implanted and develop into live fetuses, albeit at low efficiency. This study indicates that prezygotic chromosome screening and embryo production using a single pair of gametes may be practicable. PMID- 26234557 TI - Use of non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients: insights from a specialist atrial fibrillation clinic. AB - BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) are broadly preferable to vitamin K antagonists (VKAs) for stroke prevention in non-valvular atrial fibrillation (AF) given their overall net clinical benefit. We report an audit of the profile of OAC usage and adverse events in patients attending a specialist AF clinic. METHODS: Patients attending our specialist AF clinic who were commenced on NOACs for SPAF between January 2013 and August 2014 were included and electronic medical records were retrospectively reviewed between August 2014 and November 2014, to collect demographic, clinical and outcome data. Outcomes included cerebrovascular and bleeding events, death, switching between NOACs or to VKA, dose changes, cessation of NOACs and the reasons for these. To provide perspective, descriptive comparisons were made with a historical cohort of warfarin users attending the specialist AF clinic prior to the introduction of NOACs. RESULTS: We report data on 813 patients as follows: (i) 233 consecutive patients (mean (standard deviation) age 74 (10) years, 45.1% female) initiated on NOACs, with median (interquartile range) CHA2 DS2 -VASc score 3 (2-5) and HAS BLED score 1 (1-2); and (ii) a historical cohort of 580 patients on warfarin (mean (SD) age 75 (10) years, 42.1% female) with broadly similar demographics. Overall, 54.5% (127/233) were started on rivaroxaban, 22.7% (53/233) on dabigatran and 22.7% on apixaban. Two patients experienced a transient ischaemic attack; 31 patients (13%) contributed to 37 documented bleeding events of which five bleeds (in four patients, 1.7%) were classified as major. There were seven deaths; cause of death was not available for three and the others were not related to NOACs. Eighteen (7.7%) patients switched NOACs, 2 (0.9%) patients switched to warfarin and 8 (3.4%) had their NOACs stopped. There were no ischaemic strokes in the NOAC cohort, compared with nine in the warfarin cohort, with a similar rate of major bleeding (1.7% for NOACs and 1.6% for warfarin). There were more gastrointestinal haemorrhages in the NOAC cohort (3.4% vs. 0.7% with warfarin). CONCLUSION: In this specialist AF clinic, patients prescribed NOACs had a favourable adverse event profile with good efficacy for stroke prevention, with a low rate of cessation or switch to warfarin. PMID- 26234558 TI - Diabetes and Age-Related Differences in Vascular Function of Renal Artery: Possible Involvement of Endoplasmic Reticulum Stress. AB - To study the time-course relationship between vascular functions and endoplasmic reticulum (ER) stress in type 2 diabetes, we investigated vascular function and associated protein expression, including cyclo-oxygenase (COX), ER stress, and apoptotic markers, in renal arteries (RA) from type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats at the young adult (4 months old) and aged (18 months old) stages. In the RA of aged OLETF (vs. young OLETF), we found: (1) Increased contractions induced by uridine adenosine tetraphosphate (Up4A) and phenylephrine, (2) decreased relaxation and increased contraction induced by acetylcholine (ACh) at lower and higher concentrations, respectively, and (3) increased expression of COX-1 and C/EBP-homologous protein (CHOP, a pro-apoptotic protein). In aged rats, the expression of COX-1, COX-2, PDI (an ER protein disulfide isomerase), Bax (a proapoptotic marker), and CHOP were increased in RA from OLETF rats (vs. age-matched control Long-Evans Tokushima Otsuka [LETO] rats). Up-regulation of PDI and Bax were seen in the RA from young OLETF (vs. young LETO) rats. No age-related alterations were apparent in the above changes in RA from LETO rats, excluding ACh-induced contraction. Short-term treatment with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 100 mg/kg per day, intraperitoneally for 1 week) to OLETF rats at the chronic stage of the disease (12 months old) could suppress renal arterial contractions induced by Up4A and ACh. These results suggest that a long-term duration of disease may be important for the development of vascular dysfunction rather than aging per se. The early regulation of ER stress may be important against the development of diabetes associated vascular dysfunction. PMID- 26234559 TI - Effect of Nitrogen Substitution in V2 O3 on the Metal-Insulator Transition. AB - The effect of N-doping on the paramagnetic-antiferromagnetic transition associated with the metal-insulator (M-I) transition of V2 O3 at 150 K has been studied in bulk samples as well as in nanosheets. The magnetic transition temperature of V2 O3 is lowered to ~120 K in the N-doped samples. Electrical resistivity data also indicate a similar lowering of the M-I transition temperature. First-principles DFT calculations reveal that anionic (N) substitution and the accompanying oxygen vacancies reduce the energy of the high temperature metallic corundum phase relative to the monoclinic one leading to the observed reduction in Neel temperature. In the electronic structure of N substituted V2 O3 , a sub-band of 2p states of trivalent anion (N) associated with its strong bond with the vanadium cation appears at the top of the band of O(2p) states, the 3d-states of V being slightly higher in energy. Its band gap is thus due to crystal field splitting of the degenerate d-orbitals of vanadium and superexchange interaction, which reduces notably (DeltaEg =-0.4 eV) due to their hybridization with the 2p states of nitrogen. A weak magnetic moment arises in the monoclinic phase of N-substituted V2 O3 with O-vacancies, with a moment of -1 MUB /N localized on vanadium atoms in the vicinity of oxygen vacancies. PMID- 26234560 TI - A Toll-Like Receptor 1/2 Agonist Augments Contractility in Rat Corpus Cavernosum. AB - INTRODUCTION: Activation of the innate immune Toll-like receptor 2 (TLR2) initiates inflammation and has been implicated in vascular dysfunction. Increased contraction and decreased relaxation responses in the penile vasculature lead to erectile dysfunction, a condition associated with inflammation. However, whether TLR2 activation plays a role in penile vascular function has not been established. AIM: We hypothesized that activation of the TLR 1/2 heterodimer (TLR1/2) augments contractile and impairs relaxation responses of corpus cavernosum and that these perturbations of vascular function are mediated by low nitric oxide (NO) availability and enhanced activity of the RhoA/Rho-kinase pathway. METHODS: Contraction and relaxation responses were measured in rat cavernosal strips using a myograph after incubation with a TLR1/2-activating ligand Pam3 CSK4 (Pam3), the TLR1/2 inhibitor CuCPT 22 (CuCPT), and inhibitors of NO synthase (LNAME) and Rho-kinase (Y27632). TLR2 protein expression was assessed by immunohistochemistry. MAIN OUTCOME MEASURES: Cumulative concentration response curves, sensitivity (pEC50), and maximal response (Emax ) of cavernosal strips to vasodilatory and vasocontractile agonists were compared between treatments. RESULTS: Pam3-treated cavernosal strips exhibited greater pEC50 and higher Emax to phenylephrine (PE) than control tissues. Inhibition of NO synthase increased Emax to PE in Pam3-treated cavernosal strips. Pam3 treatment reduced relaxation to Y27632 compared with control tissues. Inhibition of TLR1/2 activation with CuCPT returned the augmented contraction to PE and the decreased relaxation to Y27632 of Pam3-treated cavernosal strips to control values. CONCLUSIONS: The TLR1/2 heterodimer mediates augmented contraction and reduced relaxation in rat cavernosal strips. Thus, TLR1/2 activation antagonizes vascular responses crucial for normal erectile function and implicates immune activation in vasculogenic erectile dysfunction. Immune signaling via TLR2 may offer novel targets for treating inflammation-mediated vascular dysfunction in the penis. PMID- 26234561 TI - The dual transcriptional regulator RovM regulates the expression of AR3- and T6SS4-dependent acid survival systems in response to nutritional status in Yersinia pseudotuberculosis. AB - Coordinated regulation of various acid survival systems in response to environmental stimuli is crucial for the adaptation of enteropathogenic bacteria to acidic environments such as the stomach. In this study, we demonstrated that the RovM protein, a central regulator of the CsrABC-RovM-RovA cascade, conversely regulates the expression of two acid survival systems in Yersinia pseudotuberculosis by acting as a dual transcriptional regulator. RovM activated the expression of T6SS4, which is essential for bacterial survival under mild acidic conditions, by binding upstream of the T6SS4 promoter. On the contrary, RovM repressed the expression of a functional arginine-dependent acid resistance system (AR3), which is crucial for bacterial survival under strong acidic conditions, by directly binding to the -35 element in the AR3 promoter. Consistent with previous findings that rovM expression responds to the availability of nutrients, the expression of T6SS4 and AR3 was differentially regulated by nutritional status. Based on these results, a dynamic model whereby RovM coordinately regulates the expression of AR3 and T6SS4 in response to the availability of nutrients in the environment was proposed. PMID- 26234563 TI - Electrochemical 'bubble swarm' enhancement of ultrasonic surface cleaning. AB - An investigation of surface cleaning using a swarm of gas bubbles within an acoustically activated stream is presented. Electrolysis of water at Pt microwires (100 MUm diameter) to produce both hydrogen and oxygen bubbles is shown to enhance the extent of ultrasonic surface cleaning in a free flowing water stream containing an electrolyte (0.1 M Na2SO4) and low surfactant concentration (2 mM SDS). The surfactant was employed to allow control of the average size of the bubble population within the swarm. The electrochemical bubble swarm (EBS) is shown to perturb acoustic transmission through the stream. To optimise the cleaning process both the ultrasonic field and the electrochemical current are pulsed and synchronized but with different duty cycles. Cleaning action is demonstrated on structured surfaces (porcine skin and finger mimics) loaded with fluorescent particles. This action is shown to be significantly enhanced compared to that found with an inherent bubble population produced by the flow and acoustic regime alone under the same conditions. PMID- 26234562 TI - Knockdown of PFTK1 Inhibits the Migration of Glioma Cells. AB - The prognosis of glioma patients is generally poor, so it is urgent to find out the underlying molecular mechanisms. PFTK1 is a member of cyclin-dependent kinases (Cdks) family and has been reported to contribute to tumor migration and invasion. In this study, we aimed to explore the expression and function in human glioma. Western blot and immunohistochemistry were used to evaluate the expression of PFTK1. PFTK1 expression was higher in glioma tissues compared with normal brain tissues, and its level was associated with the WHO grade in Western blot analysis. The suppression of PFTK1 expression by RNA interference was shown to inhibit the migration of glioma cells. Knockdown of PFTK1 increases E-cadherin expression and decreases vimentin expression. These data show that PFTK1 may participate in the pathogenic process of glioma, suggesting that PFTK1 can become a potential therapeutic strategy for gastric cancer. PMID- 26234564 TI - Women's Perception of Transvaginal Natural Orifice Transluminal Endoscopic Surgery (NOTES): Results of a Survey of Female Medical Staff and Literature Review. AB - OBJECTIVE: Over the past 8 years, natural orifice transluminal endoscopic surgery (NOTES) has developed from preclinical to routine clinical practice. However, there are still concerns regarding the transvaginal approach. In our survey, we were interested in females with a professional medical background, thus having at least a basic medical understanding, which might discriminate between objective and subjective concerns. MATERIAL AND METHODS: A questionnaire with 14 items was distributed among 1895 female physicians and nursing and administration staff of the University Medical Center Hamburg-Eppendorf. In addition, a qualitative literature review was performed. Data analysis was carried out using statistical package R version 2.15.0. RESULTS: The questionnaire was answered anonymously by 553 employees (29%). Fifty-seven percent were nurses, 18.6% belonged to administration, and 17% were physicians. A total of 63.1% of our respondents would choose the transvaginal NOTES technique for an assumed ovariectomy, while only 30.4% would choose this access for cholecystectomy. Doubts regarding transvaginal NOTES were related to sexual dysfunction (44.8%), its experimental nature (43.8%), future pregnancies (36.8%), and ethical reasons (30.3%). The literature review showed that women's perception of the transvaginal access is documented very heterogeneously and therefore difficult to compare. CONCLUSIONS: Despite the good reported results of NOTES and the medical background of the surveyed female employees, our study and the literature review clearly shows that there are fears regarding the transvaginal access, which might be a result of limited information. More accurate explanation of the available methods by the attending surgeon can lead to a better choice of the patient's preferred method. PMID- 26234565 TI - Carotid artery stiffness is related to hyperinsulinemia and insulin-resistance in middle-aged, non-diabetic hypertensive patients. AB - BACKGROUND AND AIMS: Glycometabolic abnormalities are frequently found in hypertension and could affect the mechanical properties of carotid arteries. The aim of the study was to investigate the relationship of glucose tolerance, plasma insulin, and insulin sensitivity with carotid distensibility in middle-aged, non diabetic hypertensive patients free of cardiac and vascular complications. METHOD AND RESULTS: In 93 patients with grade 1-2, uncomplicated, primary hypertension and 68 matched normotensive controls we measured plasma glucose and insulin at fast and after an oral glucose load (OGTT), calculated the HOMA-index as a marker of insulin sensitivity, and assessed distensibility of common carotid arteries by B-mode ultrasonography. Hypertensive patients were hyperinsulinemic and insulin resistant as compared to normotensive controls. Hypertensive patients with impaired fasting glucose and/or impaired glucose tolerance had comparable distensibility of carotid arteries. Patients with decreased carotid distensibility were older and had higher body mass, fasting and post-OGTT plasma insulin, HOMA-index, and carotid IMT than the remaining patients, but no differences in glycated hemoglobin, and fasting or post-OGTT plasma glucose. Carotid coefficient of distensibility was inversely related and beta-stiffness directly related with fasting and post-OGTT plasma insulin, and HOMA-index. Multivariate logistic regression showed that age and post-OGTT plasma insulin levels predicted carotid artery stiffening independent of body mass index, sex, blood pressure, and plasma glucose levels. CONCLUSIONS: The study demonstrates that decreased insulin sensitivity and the related hyperinsulinemia but not hyperglycemia could contribute to carotid artery stiffening in middle-aged, non diabetic hypertensive patients free of cardiovascular complications. PMID- 26234566 TI - Early gene-diet interaction between glucokinase regulatory protein (GCKR) polymorphism, vegetable and fish intakes in modulating triglyceride levels in healthy adolescents. AB - BACKGROUND AND AIMS: The benefits of dietary vegetable and fish consumptions on improving glucose and lipid metabolism have been well established. Recently, the T-allele of a common genetic variant rs780094 at glucokinase regulatory protein (GCKR) was reported to be associated with elevated triglyceride (TG) levels but reduced fasting plasma glucose (FPG) and type 2 diabetes risk. However, the dietary modulation on genetic risk is not clearly understood. METHODS AND RESULTS: A cohort of 2095 Chinese adolescents (mean age 15.6 +/- 2.0 years, 45.3% male) recruited from a population-based school survey for cardiovascular risk factor assessment, with dietary data including weekly vegetable and fish consumptions as well as clinical data were genotyped for the GCKR rs780094 polymorphism. In the linear regression analysis with adjustment for sex, age, body mass index, and socioeconomic status (school banding, paternal and maternal education levels), the frequency of vegetable intake per week was inversely associated with FPG (P = 0.044). Individuals with low fish intake generally had elevated TG levels but reduced TC, HDL-C and LDL-C (0.006 < P < 0.029). We also observed significant associations of the minor T-allele of GCKR rs780094 with decreased FPG (P = 0.013) and increased TG levels (P = 2.7 * 10(-8)). There were significant gene-diet interactions between rs780094 and vegetable consumption (P(interaction) = 0.009), and between rs780094 and fish consumption (P(interaction) = 0.031) in modulating TG levels. The T-allele of GCKR locus was associated with higher TG levels amongst individuals with >=7 vegetable meals per week (P = 6.4 * 10(-9)), and among individuals with <7 fish meals per week (P = 0.020 and 7.0 * 10(-7) for 4-6 and <=3 meals per week, respectively). High intake of vegetable exerted a reduction in TG levels only among CC genotype carriers (Ptrend = 0.020), while high intake of fish was associated with reduced TG levels only among TT genotype carriers (Ptrend = 0.026). CONCLUSIONS: In summary, our data indicated that the favorable associations of higher vegetable and fish intakes on TG levels are dependent on the genetic background of an individual. In particular, at-risk TT- genotype carriers of the GCKR variant may derive more benefits from a high fish intake, while the CC-genotype carriers may find further benefits from a high consumption of vegetable. PMID- 26234567 TI - IR spectroscopy of protonated leu-enkephalin and its 18-crown-6 complex embedded in helium droplets. AB - Ultracold IR spectra of the protonated five amino acid peptide leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) embedded in superfluid helium droplets have been recorded using a free-electron laser as radiation source. The results show resolved spectra, which are in good agreement with theoretical calculations, as well as with the available gas-phase data indicating that the helium environment does not induce a significant matrix-shift. In addition, the effect of the interaction between the charge and the peptide backbone has been further investigated by complexing protonated leu-enkephalin with one 18-crown-6 molecule. Good agreement between the experimental and theoretical results allow for an assignment of a preferred molecular structure. PMID- 26234568 TI - Tips and tricks for DIEP flap breast reconstruction in patients with previous abdominal scar. AB - The aim of this study was to analyze outcomes of patients who had prior abdominal operations and underwent DIEP flap breast reconstruction and to describe technical strategies to insure well-vascularized flap-harvest minimizing abdominal donor-site complications. All patients who underwent DIEP flap breast reconstruction between 2004 and 2014 were reviewed and divided into a control group (CG) and a scar group (SG). Patient demographics, operative details, flap and donor-site complications were analyzed and compared. For all of the scars, DIEP flap design was not modified, but a standardized approach was developed according to the type and location of the scar, available vascular pedicle, perforator locations, and the required flap tissue for breast reconstruction. Two hundred and eighty patients underwent 292 flaps in CG and 107 underwent 111 flaps in SG. Pfannenstiel, McBurney, laparoscopic, midline and subcostal were the most common previous incisions. There were no significant differences between groups regarding demographics, flap and mastectomy weight, active smoking, or radiation status (P > 0.05). No significant differences were observed in DIEP flap loss (P = 0.909), partial flap loss (P=0.799), or fat necrosis (P=0.871) and in the rate of abdominal donor-site complications between groups (P > 0.05). SG had a significantly higher mean operative time than CG (P=0.034). Medial raw was a negative risk-factor for flap complications, while BMI (>25.1 kg/m2 ) and smoking history were significant predictors for donor-site complications. With careful preoperative planning and appropriate technical strategies, successfully DIEP flap breast reconstruction can be performed without increased flap and donor-site complications in patients with preexisting abdominal scars. (c) 2015 Wiley Periodicals, Inc. Microsurgery 37:282-292, 2017. PMID- 26234569 TI - Ultrafast Spreading Effect Induced Rapid Cell Trapping into Porous Scaffold with Superhydrophilic Surface. AB - In this contribution, superhydrophilic chitosan-based scaffolds with ultrafast spreading property were fabricated and used to improve the trapped efficiency of cells. The ultrafast spreading property allowed cells to be trapped into the internal 3D porous structures of the prepared scaffolds more quickly and effectively. Cell adhesion, growth, and proliferation were also improved, which could be attributed to the combination of UV irradiation and ultrafast spreading property. The construction of ultrafast spreading property on the scaffold surface will offer a novel way to design more effective scaffold in tissue engineering that could largely shorten the therapeutic time for patients. PMID- 26234570 TI - Neuroscience and the future for mental health? AB - Psychiatry is in one of its regular crises. It is a crisis of its diagnostic systems despite - perhaps because - of the recurrent claims about the extent of diagnosable 'brain disorders'. It is a crisis of its explanatory systems despite perhaps because - of its current wager on the brain as the ultimate locus for explanations of mental disorders. It is a crisis of its therapeutic capacities despite - perhaps because - more and more people are making use of its primary mode of intervention focussed on the brain - psychiatric drugs. In this editorial, I will suggest that this triple crisis of diagnosis, explanation and therapeutics arises from the dominant reductionist approaches to the role of neurobiology in psychiatry that priorities the analysis of brain mechanisms, at the expense of an understanding of the whole living organism in its milieu, and the processes which social experience shapes neurobiology from the moment of conception if not before. I shall suggest a different approach that starts from the experience of persons coping with adversity in their forms of life. This approach does not require giving up on our search for plausible explanations of mental health problems that engage neurobiological mechanisms, but it begins from a commitment to understanding, and hence intervening in, the ways in which social adversity shapes and blights the lives of so many of our fellow citizens. PMID- 26234572 TI - Communal farmers' perceptions of tick-borne diseases affecting cattle and investigation of tick control methods practiced in Zimbabwe. AB - Tick borne diseases (TBDs) are responsible for huge economic losses in cattle production in most African countries where the majority of cattle owners are the resource poor communal farmers. Governments have initiated and co-ordinate tick control programs with farmers required to contribute funds for their sustenance. The success of these programs will hinge upon the involvement of communal farmers in their design, implementation and evaluation. To this end, 313 communal farmers (approximately 8.4% response rate) were interviewed and 3 focus group discussions were carried out in the southern low-veld part of Zimbabwe with the objectives of investigating communal farmers' perceptions on TBDs affecting cattle, level of participation in government initiated tick control programs, other tick control methods practiced, types of acaricides used and their perceived effectiveness. There was a general awareness of TBDs with 67.7% (n=212) farmers being able to describe tick diseases with names or clinical and post-mortem signs. The diseases or problems frequently associated with ticks were cowdriosis (38%, n=119), mastitis (36.7%, n=115), anaplasmosis (36.1%, n=113), body damage (28.4%, n=89), babesiosis (24.6%, n=77) and poor body condition (16.6%, n=52). Cattle mortalities due to TBDs were reported by 23.8% (n=74) of the farmers. The plunge dip was consistently used by farmers (70.3%, n=220) to control ticks. Other tick control methods practiced were the hand spraying (67.4%, n=211), hand dressing (16.6%, n=52), traditional methods (5.4%, n=17), use of pour-ons (4.5%, n=14) and smearing (2.2%, n=7). The formamidines were the most common class of acaricide used (59.4%, n=186), followed by synthetic pyrethroids (29.1%, n=91), macro cyclic lactones (12.8%, n=40) and organophosphates (4.5%, n=14). Most farmers (75.2%, n=231) perceived these acaricides to be effective in controlling ticks. The results of focus group discussions showed that a number of factors influenced the success of government initiated tick control programs and these included inconsistent supply of acaricides, unaffordable dipping fees, lack of water, long distance to the dip tank, lack of information on dipping procedures and lack of knowledge on strategies for delaying acaricide resistance. This study demonstrates that while farmers can be a valuable source of information with regards to the epidemiology of tick borne diseases affecting their cattle, there is still need for further training in understanding the TBDs and strategies for their control. PMID- 26234571 TI - Immunoproteomic profiling of Rickettsia parkeri and Rickettsia amblyommii. AB - Rickettsia parkeri is an Amblyomma-associated, spotted fever group Rickettsia species that causes an eschar-associated, febrile illness in multiple countries throughout the Western Hemisphere. Many other rickettsial species of known or uncertain pathogenicity have been detected in Amblyomma spp. ticks in the Americas, including Rickettsia amblyommii, "Candidatus Rickettsia andeanae" and Rickettsia rickettsii. In this study, we utilized an immunoproteomic approach to compare antigenic profiles of low-passage isolates of R. parkeri and R. amblyommii with serum specimens from patients with PCR- and culture-confirmed infections with R. parkeri. Five immunoreactive proteins of R. amblyommii and nine immunoreactive proteins of R. parkeri were identified by matrix-assisted laser desorption ionization tandem time-of-flight mass spectrometry. Four of these, including the outer membrane protein (Omp) A, OmpB, translation initiation factor IF-2, and cell division protein FtsZ, were antigens common to both rickettsiae. Serum specimens from patients with R. parkeri rickettsiosis reacted specifically with cysteinyl-tRNA synthetase, DNA-directed RNA polymerase subunit alpha, putative sigma (54) modulation protein, chaperonin GroEL, and elongation factor Tu of R. parkeri which have been reported as virulence factors in other bacterial species. Unique antigens identified in this study may be useful for further development of the better serological assays for diagnosing infection caused by R. parkeri. PMID- 26234573 TI - Chemokine MCP1/CCL2 gene polymorphism influences Henoch-Schonlein purpura susceptibility in Iranian Azeri-Turkish patients. AB - BACKGROUND: Henoch-Schonlein purpura (HSP) is the most common small-vessel vasculitis and mainly affects children. Although its pathophysiology is unknown, several studies have indicated the possible involvement of infections and genetic factors in the development of HSP. The human leukocyte antigen (HLA) gene family and several other genes involved in the inflammatory system have been studied. The CCL2 gene, encoding chemokine monocyte chemo-attractant protein 1 (MCP 1/CCL2), is one of several cytokine genes clustered on chromosome 17. The encoded protein displays chemotactic activity for monocytes. METHODS: This is a case control study comparing 36 children diagnosed with HSP within the Iranian Azeri Turkish ethnic population and 50 healthy adults from the same ethnic group. CCL2, C-2518T polymorphism genotypes were determined by polymerase chain reaction and by PVUII restriction enzyme analysis and subsequent agarose gel electrophoresis. RESULTS: Our results showed a significant association between the allelic and genotypic frequency of this gene and HSP disease in this cohort. The results of this study indicate that frequencies of the T allele of CCL2 (P = 0.015) and the TT genotype (P = 0.004) are significantly higher in HSP patients. A comparison of clinical symptoms and laboratory data with CCL2 C-2518T polymorphism showed that patients with the TT genotype presented a higher clinical score and more severe clinical features. CONCLUSIONS: MCP1/CCL2 C-2518T gene polymorphism is associated with susceptibility to HSP. This is the first study to report a significant association between MCP1/CCL2 C-2518T and a susceptibility to HSP in this population. PMID- 26234574 TI - Enhanced antibacterial activity of NR latex gloves with raspberry-like PMMA-N,N,N trimethyl chitosan particles. AB - Raspberry-like poly(methyl methacrylate) (PMMA) latex particles stabilized with silica nanoparticles (SiNPs) were prepared via the Pickering emulsion polymerization for use as substrate of N,N,N-trimethyl chitosan (TMC) adsorption. With the aims to simultaneously reduce the surface friction and improve the antibacterial activity of rubber gloves, the synthesized PMMA-SiNPs(TMC) particles were electrostatically deposited onto a sulphur prevulcanized natural rubber (SPNR) latex film. From SEM and AFM analyses, the results showed the highest surface coverage of PMMA-SiNPs(TMC) particles on the surface of SPNR film of 41% and the surface roughness of 69nm. The coated SPNR film exhibited effective antibacterial activity especially against S. aureus. Therefore, this investigation would be useful for fabrication of special gloves with antibacterial properties. PMID- 26234575 TI - Facile fabrication of magnetic carboxymethyl starch/poly(vinyl alcohol) composite gel for methylene blue removal. AB - This study presents a simple method to fabricate magnetic carboxymethyl starch/poly(vinyl alcohol) (mCMS/PVA) composite gel. The obtained mCMS/PVA was characterized by Fourier transform infrared (FTIR) spectra, vibrating-sample magnetometer (VSM) and scanning electron microscopy (SEM) measurements. The application of mCMS/PVA as an adsorbent for removal of cationic methylene blue (MB) dye from water was investigated. Benefiting from the combined merits of carboxymethyl starch and magnetic gel, the mCMS/PVA simultaneously exhibited excellent adsorption property toward MB and convenient magnetic separation capability. The effects of initial dye concentration, contact time, pH and ionic strength on the adsorption performance of mCMS/PVA adsorbent were investigated systematically. The adsorption process of mCMS/PVA for MB fitted pseudo-second order model and Freundlich isotherm. Moreover, desorption experiments revealed that the mCMS/PVA adsorbent could be well regenerated in ethanol solution without obvious compromise of removal efficiency even after eight cycles of desorption/adsorption. Considering the facile fabrication process and robust adsorption performance, the mCMS/PVA composite gel has great potential as a low cost adsorbent for environmental decontamination. PMID- 26234576 TI - Peroxynitrite and fibrinolytic system-The effects of peroxynitrite on t-PA induced plasmin activity. AB - The aim of the present study was the investigation of peroxynitrite (ONOO(-)) effects on fibrinolysis in vitro and in silico. The exposure of human plasminogen to ONOO(-) (10-1000MUM) resulted in a decrease of t-PA-induced amidolytic activity of plasmin; the inhibitory effect was associated with the increasing level of 3-nitrotyrosine in plasminogen/plasmin molecule. Furthermore, ONOO(-) displayed both the ability to impair the t-PA-induced activation of plasminogen to plasmin, and to reduce the rate of fibrin lysis by plasmin. The susceptibility of plasminogen in blood plasma to nitrative action of ONOO(-) was revealed by the immunoprecipitation technique. To confirm the hypothesis that 3-nitrotyrosine generation is crucial for the impairment of plasmin activity, (-)-epicatechin, a polyphenolic antioxidant that selectively prevents tyrosine nitration, was used both for in vitro experiments as well as for in silico studies on ONOO(-), ONOOH and (-)-epicatechin binding and plasminogen nitration. (-)-Epicatechin effectively protected plasminogen against ONOO(-)-induced inactivation and significantly reduced the level of 3-nitrotyrosine. The obtained results revealed tyrosine nitration as the most likely mechanism of the inhibitory effect of ONOO( ) on plasmin(ogen) functions. The possible role of tyrosine modifications was additionally confirmed by bioinformatics calculations with indication of nitration susceptible tyrosine residues. PMID- 26234577 TI - Partial replacement effect of montmorillonite with cellulose nanowhiskers on polylactic acid nanocomposites. AB - In this study, hybrid montmorillonite/cellulose nanowhiskers (MMT/CNW) reinforced polylactic acid (PLA) nanocomposites were produced through solution casting. The CNW filler was first isolated from microcrystalline cellulose by chemical swelling technique. The partial replacement of MMT with CNW in order to produce PLA/MMT/CNW hybrid nanocomposites was performed at 5 parts per hundred parts of polymer (phr) fillers content, based on highest tensile strength values as reported in our previous study. MMT were partially replaced with various amounts of CNW (1, 2, 3, 4 and 5phr). The tensile, thermal, morphological and biodegradability properties of PLA hybrid nanocomposites were investigated. The highest tensile strength of hybrid nanocomposites was obtained with the combination of 4phr MMT and 1phr CNW. Interestingly, the ductility of hybrid nanocomposites increased significantly by 79% at this formulation. The Young's modulus increased linearly with increasing CNW content. Thermogravimetric analysis illustrated that the partial replacement of MMT with CNW filler enhanced the thermal stability of the PLA. This is due to the relatively good dispersion of fillers in the hybrid nanocomposites samples as revealed by transmission electron microscopy. Interestingly, partial replacements of MMT with CNW improved the biodegradability of hybrid nanocomposites compared to PLA/MMT and neat PLA. PMID- 26234578 TI - The Arabian camel Camelus dromedarius heat shock protein 90alpha: cDNA cloning, characterization and expression. AB - Heat shock protein 90 (Hsp90) is a highly conserved ubiquitous molecular chaperone contributing to assisting folding, maintenance of structural integrity and proper regulation of a subset of cytosolic proteins. In the present study, a heat shock protein 90alpha full length coding cDNA was isolated and cloned from the Arabian one-humped camel by reverse transcription polymerase chain reaction (RT-PCR). The full length cDNA sequence was submitted to NCBI GeneBank under the accession number KF612338. The sequence analysis of the Arabian camel Hsp90alpha cDNA showed 2202bp encoding a protein of 733 amino acids with estimated molecular mass of 84.827kDa and theoretical isoelectric point (pI) of 5.31. Blast search analysis revealed that the C. dromedarius Hsp90alpha shared high similarity with other known Hsp90alpha. Comparative analyses of camel Hsp90alpha protein sequence with other mammalian Hsp90s showed high identity (85-94%). Heterologous expression of camel Hsp90alpha cDNA in E. coli JM109 (DE3) gave a fusion protein band of 86.0kDa after induction with IPTG for 4h. PMID- 26234579 TI - Cloning and expression of low temperature active endoglucanase EG5C from Paenibacillus sp. IHB B 3084. AB - The endoglucanase gene designated as EG5C encoding cold active endoglucanase produced by Paenibacillus sp. IHB B 3084 was cloned and expressed in Escherichia coli BL21(DE3). The gene consisting of 1719bp open reading frame encoded a protein of 573 amino acids with a predicted molecular weight of 63.5kDa. The presence of N-terminal catalytic domain of the glycosyl hydrolase family 5 (GH5) and C-terminal carbohydrate binding X2 domain suggested the modular nature of the enzyme. The native signal peptide of EG5C was capable of efficiently secreting the enzyme with near equal activities in the cytoplasmic and extracellular fractions. The recombinant enzyme purified 9.46 fold to homogeneity with 22.33% yield gave 7.758IU/mg specific activity. The enzyme was stable over the broad pH range of 4-12 with more than 50% residual activity. The optimal activity was at 40 degrees C with 70% relative activity at 5 degrees C. The low temperature activity despite the shorter linker region suggested a novel cold adaptation mechanism by the enzyme. The enzyme displayed higher activity on carboxymethylcellulose than avicel which is useful in maintaining the tensile strength of fiber. The efficient secretion and low temperature activity offer prospect for large-scale production and industrial application of the endoglucanase. PMID- 26234580 TI - Thermal stress resistance and aging effects of Panax notoginseng polysaccharides on Caenorhabditis elegans. AB - Panax notoginseng attract public attention due to their potential biomedical properties and corresponding health benefits. The present study investigated the anti-aging and thermal stress resistance effects of polysaccharides from P. notoginseng on Caenorhabditis elegans. Results showed polysaccharides had little scavenging ability of reactive oxygen species (ROS) in vitro, but significantly extended lifespan of C. elegans, especially the main root polysaccharide (MRP) which prolongs the mean lifespan of wild type worms by 21%. Further study demonstrated that the heat stress resistance effect of polysaccharides on C. elegans might be attributed to the elevation of antioxidant enzyme activities (both superoxide dismutase (SOD) and catalase (CAT)) and the reduction lipid peroxidation of malondialdehyde (MDA) level. Taken together, the results provided a scientific basis for the further exploitation of the mechanism of longer lifespan controlled by P. notoginseng polysaccharides on C. elegans. The P. notoginseng polysaccharides might be considered as a potential source to delay aging. PMID- 26234581 TI - Chemical and rheological properties of exopolysaccharides produced by four isolates of rhizobia. AB - The rheological, physicochemical properties, emulsification and stability of exopolysaccharides (EPSs) from four rhizobia isolates (LBMP-C01, LBMP-C02, LBMP C03 and LBMP-C04) were studied. The EPS yields of isolates under these experimental conditions were in the range of 1.5-6.63gL(-1). The LBMP-C04 isolate, which presented the highest EPS production (6.63gL(-1)), was isolated from Arachis pintoi and was identified as a Rhizobium sp. strain that could be explored as a possible potential source for the production of extracellular heteropolysaccharides. All polymers showed a pseudoplastic non-Newtonian fluid behavior or shear thinning property in aqueous solutions. Among the four EPS tested against hydrocarbons, EPS LBMP-C01 was found to be more effective against hexane, olive and soybean oils (89.94%, 82.75% and 81.15%, respectively). Importantly, we found that changes in pH (2-11) and salinity (0-30%) influenced the emulsification of diesel oil by the EPSs. EPSLBMP-C04 presented optimal emulsification capacity at pH 10 (E24=53%) and 30% salinity (E24=27%). These findings contribute to the understanding of the influence of the chemical composition, physical properties and biotechnology applications of rhizobial EPS solutions their bioemulsifying properties. PMID- 26234582 TI - Interplay of strain and indium incorporation in InGaN/GaN dot-in-a-wire nanostructures by scanning transmission electron microscopy. AB - The interplay between strain and composition is at the basis of heterostructure design to engineer new properties. The influence of the strain distribution on the incorporation of indium during the formation of multiple InGaN/GaN quantum dots (QDs) in nanowire (NW) heterostructures has been investigated, using the combined techniques of geometric phase analysis of atomic-resolution images and quantitative elemental mapping from core-loss electron energy-loss spectroscopy within scanning transmission electron microscopy. The variation in In-content between successive QDs within individual NWs shows a dependence on the magnitude of compressive strain along the growth direction within the underlying GaN barrier layer, which affects the incorporation of In-atoms to minimize the local effective strain energy. Observations suggest that the interfacial misfit between InGaN/GaN within the embedded QDs is mitigated by strain partitioning into both materials, and results in normal stresses inflicted by the presence of the surrounding GaN shell. These experimental measurements are linked to the local piezoelectric polarization fields for individual QDs, and are discussed in terms of the photoluminescence from an ensemble of NWs. PMID- 26234583 TI - The impact of osteopontin on prognosis and clinicopathology of colorectal cancer patients: a systematic meta-analysis. AB - Colorectal cancer (CRC) is one of the most frequent malignant neoplasms worldwide. Up to now, no biomarker has been used to predict the prognosis and surveillance of patients with CRC. Recently, the association between osteopontin (OPN) overexpression and the prognosis of CRC was investigated widely, but the results were inconsistent. Therefore, the aim of present meta-analysis was to assess the prognostic effect of osteopontin in patients with CRC. PubMed, EMBASE, Web of Science, Scopus and Chinese Medical Database were systematically searched. A total of 15 studies containing 1698 patients were included in our meta analysis. The pooled data of studies showed that high OPN expression was significantly associated with high tumor grades (OR = 2.24, 95% CI 1.55-3.23), lymph node metastasis (OR = 2.36, 95% CI 1.71-3.26) and tumor distant metastasis (OR = 2.38, 95% CI 1.01-5.60). Moreover, high OPN expression was significantly associated with the 2-year (HR 1.97, 95% CI 1.30-3.00), 3-year (HR 1.82, 95% CI 1.24-2.68), 5 year (HR 1.53, 95% CI 1.28-1.82) survival rates and overall survival (OS, HR 1.70, 95% CI 1.12-2.60), respectively. These results indicated that OPN could serve as a prognostic biomarker and as a potential therapeutic target for CRC. PMID- 26234584 TI - A mixed effect model for bivariate meta-analysis of diagnostic test accuracy studies using a copula representation of the random effects distribution. AB - Diagnostic test accuracy studies typically report the number of true positives, false positives, true negatives and false negatives. There usually exists a negative association between the number of true positives and true negatives, because studies that adopt less stringent criterion for declaring a test positive invoke higher sensitivities and lower specificities. A generalized linear mixed model (GLMM) is currently recommended to synthesize diagnostic test accuracy studies. We propose a copula mixed model for bivariate meta-analysis of diagnostic test accuracy studies. Our general model includes the GLMM as a special case and can also operate on the original scale of sensitivity and specificity. Summary receiver operating characteristic curves are deduced for the proposed model through quantile regression techniques and different characterizations of the bivariate random effects distribution. Our general methodology is demonstrated with an extensive simulation study and illustrated by re-analysing the data of two published meta-analyses. Our study suggests that there can be an improvement on GLMM in fit to data and makes the argument for moving to copula random effects models. Our modelling framework is implemented in the package CopulaREMADA within the open source statistical environment R. PMID- 26234585 TI - Preferences of air-blood-saline sonographic microbubble contrast agents among emergency medicine resident physicians. AB - INTRODUCTION: The placement of a central venous catheter (CVC) remains an important intervention in the care of critically ill patients in the emergency department, and bedside ultrasound can be used for procedural guidance as well as conformation of placement. Microbubble contrast-enhanced ultrasound may facilitate CVC tip position localization, and the addition of autologous blood can significantly increase its echogenicity. The purpose of this study was to describe the preferences of a group of resident physicians regarding the performance of various concentrations of air-blood-saline sonographic microbubble contrast agents. METHODS: Institutional Animal Care and Use Committee approved prospective study. A CVC was inserted into the right internal jugular vein of a 20-kg Yorkshire swine under general anesthesia. Contrast mixtures were created with air, saline, and varying amounts of blood and were injected while echocardiographic video clips were recorded and reviewed by 25 physician sonographers. RESULTS: All reading physicians reported increased overall echogenicity, a higher peak echogenicity, and greater personal preference for blood containing solutions. Nearly all reading physicians preferred the lower percentage blood containing mixtures over the higher percentage blood containing mixture. CONCLUSION: The inclusion of 1 to 3 parts of 10 of the patient's blood in the preparation of a sonographic contrast mixture increased the echogenicity of the contrast, resulted in better visualization of both the contrast and the endocardial border and was the preferred mixture among the resident physicians studied. PMID- 26234586 TI - Transient sampling of aggregation-prone conformations causes pathogenic instability of a parkinsonian mutant of DJ-1 at physiological temperature. AB - Various missense mutations in the cytoprotective protein DJ-1 cause rare forms of inherited parkinsonism. One mutation, M26I, diminishes DJ-1 protein levels in the cell but does not result in large changes in the three-dimensional structure or thermal stability of the protein. Therefore, the molecular defect that results in loss of M26I DJ-1 protective function is unclear. Using NMR spectroscopy near physiological temperature, we found that the picosecond-nanosecond dynamics of wild-type and M26I DJ-1 are similar. In contrast, elevated amide hydrogen/deuterium exchange rates indicate that M26I DJ-1 is more flexible than the wild-type protein on longer timescales and that hydrophobic regions of M26I DJ-1 are transiently exposed to solvent. Tryptophan fluorescence spectroscopy and thiol crosslinking analyzed by mass spectrometry also demonstrate that M26I DJ-1 samples conformations that differ from the wild-type protein at 37 degrees C. These transiently sampled conformations are unstable and cause M26I DJ-1 to aggregate in vitro at physiological temperature but not at lower temperatures. M26I DJ-1 aggregation is correlated with pathogenicity, as the structurally similar but non-pathogenic M26L mutation does not aggregate at 37 degrees C. The onset of dynamically driven M26I DJ-1 instability at physiological temperature resolves conflicting literature reports about the behavior of this disease associated mutant and illustrates the pitfalls of characterizing proteins exclusively at room temperature or below, as key aspects of their behavior may not be apparent. PMID- 26234587 TI - Extinction learning is slower, weaker and less context specific after alcohol. AB - Alcohol is frequently involved in psychological trauma and often used by individuals to reduce fear and anxiety. We examined the effects of alcohol on fear acquisition and extinction within a virtual environment. Healthy volunteers were administered alcohol (0.4g/kg) or placebo and underwent acquisition and extinction from different viewpoints of a virtual courtyard, in which the conditioned stimulus, paired with a mild electric shock, was centrally located. Participants returned the following day to test fear recall from both viewpoints of the courtyard. Skin conductance responses were recorded as an index of conditioned fear. Successful fear acquisition under alcohol contrasted with impaired extinction learning evidenced by persistent conditioned responses (Experiment 1). Participants' impairments in extinction under alcohol correlated with impairments in remembering object-locations in the courtyard seen from one viewpoint when tested from the other viewpoint. Alcohol-induced extinction impairments were overcome by increasing the number of extinction trials (Experiment 2). However, a test of fear recall the next day showed persistent fear in the alcohol group across both viewpoints. Thus, alcohol impaired extinction rather than acquisition of fear, suggesting that extinction is more dependent than acquisition on alcohol-sensitive representations of spatial context. Overall, extinction learning under alcohol was slower, weaker and less context-specific, resulting in persistent fear at test that generalized to the extinction viewpoint. The selective effect on extinction suggests an effect of alcohol on prefrontal involvement, while the reduced context-specificity implicates the hippocampus. These findings have important implications for the use of alcohol by individuals with clinical anxiety disorders. PMID- 26234589 TI - Clinically Useful Genetic Markers of Antidepressant Response: How Do We Get There From Here? PMID- 26234590 TI - A New Role for Clonidine in Addictions: Catching Relapses Before They Happen. PMID- 26234588 TI - Contribution of N-methyl-D-aspartate receptors to attention and episodic spatial memory during senescence. AB - A decrease in N-methyl-D-aspartate receptor (NMDAR) function is associated with age-related cognitive impairments. However, NMDAR antagonists are prescribed for cognitive decline associated with age-related neurodegenerative disease, raising questions as to the role of NMDAR activity in cognitive function during aging. The current studies examined effects of NMDAR blockade on cognitive task that are sensitive to aging. Young and middle-age rats were trained on the five-choice serial reaction time task (5-CSRTT) and challenged with MK-801 (0.025, 0.05, and 0.1mg/kg or vehicle). Attention deficits were apparent in middle-age and performance of young and middle-age rats was enhanced for low doses of MK-801 (0.025 and 0.05). The beneficial effects on attention were reversed by the highest dose of MK-801. Older animals exhibited a delay-dependent impairment of episodic spatial memory examined on a delayed-matching to place water maze task. Similarly, a low dose of MK-801 (0.05mg/kg) impaired performance with increasing delay and aged animals were more susceptible to disruption by NMDAR blockade. Despite MK-801 impairment of episodic spatial memory, MK-801 had minimal effects on spatial reference memory. Our results confirm that NMDARs contribute to rapidly acquired and flexible spatial memory and support the idea that a decline in NMDAR function contributes to the age-related impairments in cognition. PMID- 26234591 TI - Gene and Environment Interactions in the Brain: A Pathway to ADHD? PMID- 26234592 TI - Amygdala on the Lookout. PMID- 26234593 TI - Ethics, Interrogation, and the American Psychiatric Association. PMID- 26234594 TI - Are We Turning Our Backs on Our Patients? Training Psychiatrists in the Era of the Electronic Health Record. PMID- 26234595 TI - John and Alicia Nash: A Beautiful Love Story. PMID- 26234596 TI - The Long View. PMID- 26234597 TI - Response to the Presidential Address. PMID- 26234598 TI - Paul Summergrad, M.D., 141st President, 2014-2015. PMID- 26234599 TI - Integrating Primary Care and Behavioral Health: The Role of the Psychiatrist in the Collaborative Care Model. PMID- 26234600 TI - Goldwater v. Ginzburg. PMID- 26234601 TI - Clinical Trials for Treatment of Borderline Personality Disorder. PMID- 26234602 TI - IQ as a Cognitive Marker of Genetic Liability in Relatives of Schizophrenia Patients. PMID- 26234603 TI - Response to Buoli et al. PMID- 26234604 TI - In the Wake of National Trauma: Psychological Reactions Following the Charlie Hebdo Terror Attack. PMID- 26234605 TI - Depression and Insulin Resistance: Additional Support for the Novel Heuristic Model in Perimenopausal Depression. PMID- 26234607 TI - The American Psychiatric Association Practice Guidelines for the Psychiatric Evaluation of Adults. PMID- 26234606 TI - Response to Eskola et al. PMID- 26234608 TI - Reports to the Membership. AB - The following are edited/abbreviated versions of the annual reports of the APA Secretary-Treasurer, CEO and Medical Director, Speaker, and Speaker-Elect and the chairpersons of the APA Committee on Bylaws, Membership Committee, Committee of Tellers, and Elections Committee. The full reports were presented at the APA Annual Business Meeting in Toronto, May 17th, 2015. PMID- 26234611 TI - Increased risk of exposure to microcystins in the scum of the filamentous cyanobacterium Aphanizomenon flos-aquae accumulated on the western shoreline of the Curonian Lagoon. AB - Concentration of toxic cyanobacteria blooms on the downwind shore of high recreational amenity water bodies with largely increases the risk of exposure to cyanotoxins. In this study analysis of phytoplankton structure, cyanotoxin composition and concentration was performed on cyanobacteria scum material, high- and low-density bloom samples in the Curonian Lagoon. We found that the concentration of cyanotoxins in the scum material increased from ~30 to ~300-fold compared to bloom samples. In Microcystis aeruginosa dominated samples microcystin-LR was present at the highest concentration, while the dominance of Planktothrix agardhii was associated with the occurrence of dmMC-RR as the major microcystin variant. The toxicological potential of cyanobacterial scums in the Curonian Lagoon is emphasized, and management by removal of these scums is proposed. PMID- 26234610 TI - Establishment of a new OSCC cell line derived from OLK and identification of malignant transformation-related proteins by differential proteomics approach. AB - Oral squamous cell carcinoma (OSCC) is usually preceded by the oral premalignant lesions, mainly oral leukoplakia (OLK) after repeated insults of carcinogens, tobacco. B(a)P and DMBA are key carcinogens in tobacco smoke. In the present study, for the first time we established the cancerous cell line OSCC-BD induced by B(a)P/DMBA mixture and transformed from dysplastic oral leukoplakia cell line DOK. Cell morphology, proliferation ability, migration ability, colony formation, and tumorigenicity were studied and confirmed the malignant characteristics of OSCC-BD cells. We further identified the differential proteins between DOK and OSCC-BD cells by stable isotope dimethyl labeling based quantitative proteomic method, which showed 18 proteins up-regulated and 16 proteins down-regulated with RSD < 8%. Differential proteins are mainly related to cell cycle, cell proliferation, DNA replication, RNA splicing and apoptosis. Abberant binding function, catalysis activity and transportor activity of differential proteins might contribute to the malignant transformation of OLK. Of the 34 identified differential proteins with RSD < 8%, 13 novel cancer-related proteins were reported in the present study. This study might provide a new insight into the mechanism of OLK malignant transformation and the potent biomarkers for early diagnosis, meanwhile further facilitate the application of the quantification proteomics to carcinogenesis research. PMID- 26234612 TI - Characterisation, quantity and sorptive properties of microplastics extracted from cosmetics. AB - Cosmetic products, such as facial scrubs, have been identified as potentially important primary sources of microplastics to the marine environment. This study characterises, quantifies and then investigates the sorptive properties of plastic microbeads that are used as exfoliants in cosmetics. Polyethylene microbeads were extracted from several products, and shown to have a wide size range (mean diameters between 164 and 327 MUm). We estimated that between 4594 and 94,500 microbeads could be released in a single use. To examine the potential for microbeads to accumulate and transport chemicals they were exposed to a binary mixture of (3)H-phenanthrene and (14)C-DDT in seawater. The potential for transport of sorbed chemicals by microbeads was broadly similar to that of polythene (PE) particles used in previous sorption studies. In conclusion, cosmetic exfoliants are a potentially important, yet preventable source of microplastic contamination in the marine environment. PMID- 26234613 TI - Assessment of organotin and tin-free antifouling paints contamination in the Korean coastal area. AB - Twelve organotins (methyl-, octyl-, butyl-, and phenyl-tin), and eight tin-free antifouling paints and their degradation products were measured in marine sediments from the Korean coastal area, and Busan and Ulsan bays, the largest harbor area in Korea. The total concentration of tin-free antifouling paints was two- to threefold higher than the total concentration of organotins. Principal component analysis was used to identify sites with relatively high levels of contamination in the inner bay area of Busan and Ulsan bays, which were separated from the coastal area. In Busan and Ulsan bays, chlorothalonil and DMSA were more dominant than in the coastal area. However, Sea-Nine 211 and total diurons, including their degradation products, were generally dominant in the Korean coastal area. The concentrations of tin and tin-free compounds were significantly different between the east and west coasts. PMID- 26234614 TI - Chattonella (Raphidophyceae) bloom spatio-temporal variations in Tachibana Bay and the southern area of Ariake Sea, Japan: Interregional displacement patterns with Skeletonema (Bacillariophyceae). AB - In 2010, a massive bloom of the raphidophycean flagellate Chattonella occurred in the Ariake Sea and Tachibana Bay. Bloom dynamics and hydrographical conditions were examined by field survey. The development and decline of the bloom occurred three times in Tachibana Bay. First and third bloom developments synchronized with precipitation, and the second bloom developed in synchronization with a salinity decrease which occurred in relation to an increase of river discharge from the Chikugo River which takes several days to flow from the Ariake Sea. These results imply that the bloom was transported with the low salinity water from the Ariake Sea to Tachibana Bay. During blooms along the northern coast of Shimabara Peninsula, the predominant phytoplankton species changed from Chattonella to Skeletonema. Low salinity water intrusion induced an interregional difference of the Chattonella and Skeletonema bloom spatially-differentiated by the salinity in the Ariake Sea and Tachibana Bay. PMID- 26234615 TI - Bioremediation of diesel from a rocky shoreline in an arid tropical climate. AB - A non invasive sampling and remediation strategy was developed and implemented at shoreline contaminated with spilt diesel. To treat the contamination, in a practical, cost-effective, and safe manner (to personnel working on the stockpiles and their ship loading activity), a non-invasive sampling and remediation strategy was designed and implemented since the location and nature of the impacted geology (rock fill) and sediment, precluded conventional ex-situ and any in-situ treatment where drilling is required. A bioremediation process using surfactant, and added N & P and increased aeration, increased the degradation rate allowing the site owner to meet their regulatory obligations. Petroleum hydrocarbons decreased from saturation concentrations to less than detectable amounts at the completion of treatment. PMID- 26234616 TI - Seasonal oxygen depletion in the North Sea, a review. AB - Seasonal mean oxygen depletion in offshore and coastal North Sea bottom waters was shown to range between 0.9 and 1.8 mg/L, corresponding to 95-83% saturation, between July and October over a 30-year assessment period (1980-2010). The magnitude of oxygen depletion was controlled by thermal stratification, modulated by water depth and nitrogen availability. Analyses were based on about 19,000 combined data sets. Eutrophication problem areas were identified mainly in coastal waters by oxygen minima, the lower 10th percentile of oxygen concentrations, and deviations of oxygen depletion from correlated stratification values. Connections between oxygen consumption and nitrogen sources and conversion, including denitrification, were indicated by correlations. Mean oxygen consumption reflected a minimum seasonal turnover of 3.1 g N/m(2) in the south-eastern North Sea, including denitrification of 1 g N/m(2). Oxygen depletion was underestimated in shallow coastal waters due to repeated erosion of stratification as indicated by local high variability. PMID- 26234617 TI - Metabolic fate (absorption, beta-oxidation and deposition) of long-chain n-3 fatty acids is affected by sex and by the oil source (krill oil or fish oil) in the rat. AB - The effects of krill oil as an alternative source of n-3 long-chain PUFA have been investigated recently. There are conflicting results from the few available studies comparing fish oil and krill oil. The aim of this study was to compare the bioavailability and metabolic fate (absorption, beta-oxidation and tissue deposition) of n-3 fatty acids originating from krill oil (phospholipid-rich) or fish oil (TAG-rich) in rats of both sexes using the whole-body fatty acid balance method. Sprague-Dawley rats (thirty-six male, thirty-six female) were randomly assigned to be fed either a krill oil diet (EPA+DHA+DPA=1.38 mg/g of diet) or a fish oil diet (EPA+DHA+DPA=1.61 mg/g of diet) to constant ration for 6 weeks. The faeces, whole body and individual tissues were analysed for fatty acid content. Absorption of fatty acids was significantly greater in female rats and was only minimally affected by the oil type. It was estimated that most of EPA (>90 %) and more than half of DHA (>60 %) were beta-oxidised in both diet groups. Most of the DPA was beta-oxidised (57 and 67 % for female and male rats, respectively) in the fish oil group; however, for the krill oil group, the majority of DPA was deposited (82-83 %). There was a significantly greater deposition of DPA and DHA in rats fed krill oil compared with those fed fish oil, not due to a difference in bioavailability (absorption) but rather due to a difference in metabolic fate (anabolism v. catabolism). PMID- 26234618 TI - Frost Grape Polysaccharide (FGP), an Emulsion-Forming Arabinogalactan Gum from the Stems of Native North American Grape Species Vitis riparia Michx. AB - A new arabinogalactan is described that is produced in large quantity from the cut stems of the North American grape species Vitis riparia (Frost grape). The sugar composition consists of l-arabinofuranose (l-Araf, 55.2%) and d galactopyranose (d-Galp 30.1%), with smaller components of d-xylose (11.2%), d mannose (3.5%), and glucuronic acid (GlcA, ~2%), the latter linked via a galactosyl residue. Permethylation identified 3-linked Galp residues, some substituted at the 2-position with Galp or Manp, terminal Araf and Xylp, and an internal 3-substituted Araf. NMR (HSQC, TOCSY, HMBC, DOSY) identified betaGalp and three alphaAraf spin systems, in an Araf-alpha1,3-Araf-alpha1,2-Araf-alpha1,2 Galp structural motif. Diffusion-ordered NMR showed that the FGP has a molecular weight of 1-10 MDa. Unlike gum arabic, the FGP does not contain a hydroxyproline rich protein (HPRP). FGP forms stable gels at >15% w/v and at 1-12% solutions are viscous and are excellent emulsifiers of flavoring oils (grapefruit, clove, and lemongrass), giving stable emulsions for >=72 h. Lower concentrations (0.1% w/v) were less viscous, yet still gave stable grapefruit oil/water emulsions. Hence, FGP is a beta1,3-linked arabinogalactan with potential as a gum arabic replacement in the food and beverage industries. PMID- 26234619 TI - The Initial Slope of the Variogram, Foundation of the Trabecular Bone Score, Is Not or Is Poorly Associated With Vertebral Strength. AB - Trabecular bone score (TBS) rests on the textural analysis of dual-energy X-ray absorptiometry (DXA) to reflect the decay in trabecular structure characterizing osteoporosis. Yet, its discriminative power in fracture studies remains incomprehensible because prior biomechanical tests found no correlation with vertebral strength. To verify this result possibly owing to an unrealistic setup and to cover a wide range of loading scenarios, the data from three previous biomechanical studies using different experimental settings were used. They involved the compressive failure of 62 human lumbar vertebrae loaded 1) via intervertebral discs to mimic the in vivo situation ("full vertebra"); 2) via the classical endplate embedding ("vertebral body"); or 3) via a ball joint to induce anterior wedge failure ("vertebral section"). High-resolution peripheral quantitative computed tomography (HR-pQCT) scans acquired from prior testing were used to simulate anterior-posterior DXA from which areal bone mineral density (aBMD) and the initial slope of the variogram (ISV), the early definition of TBS, were evaluated. Finally, the relation of aBMD and ISV with failure load (F(exp)) and apparent failure stress (sigmaexp) was assessed, and their relative contribution to a multilinear model was quantified via ANOVA. We found that, unlike aBMD, ISV did not significantly correlate with F(exp) and sigmaexp , except for the "vertebral body" case (r(2) = 0.396, p = 0.028). Aside from the "vertebra section" setup where it explained only 6.4% of sigmaexp (p = 0.037), it brought no significant improvement to aBMD. These results indicate that ISV, a replica of TBS, is a poor surrogate for vertebral strength no matter the testing setup, which supports the prior observations and raises a fortiori the question of the deterministic factors underlying the statistical relationship between TBS and vertebral fracture risk. PMID- 26234621 TI - Dyslexia: Creating impact through innovation. PMID- 26234622 TI - Metacognition and Reading: Comparing Three Forms of Metacognition in Normally Developing Readers and Readers with Dyslexia. AB - Metacognition refers to 'cognition about cognition' and includes metacognitive knowledge, strategies and experiences (Efklides, 2008; Flavell, 1979). Research on reading has shown that better readers demonstrate more metacognitive knowledge than poor readers (Baker & Beall, 2009), and that reading ability improves through strategy instruction (Gersten, Fuchs, Williams, & Baker, 2001). The current study is the first to specifically compare the three forms of metacognition in dyslexic (N = 22) versus normally developing readers (N = 22). Participants read two factual texts, with learning outcome measured by a memory task. Metacognitive knowledge and skills were assessed by self-report. Metacognitive experiences were measured by predictions of performance and judgments of learning. Individuals with dyslexia showed insight into their reading problems, but less general knowledge of how to approach text reading. They more often reported lack of available reading strategies, but groups did not differ in the use of deep and surface strategies. Learning outcome and mean ratings of predictions of performance and judgments of learning were lower in dyslexic readers, but not the accuracy with which metacognitive experiences predicted learning. Overall, the results indicate that dyslexic reading and spelling problems are not generally associated with lower levels of metacognitive knowledge, metacognitive strategies or sensitivity to metacognitive experiences in reading situations. PMID- 26234623 TI - A randomized controlled clinical trial of 3-unit posterior zirconia-ceramic fixed dental prostheses (FDP) with layered or pressed veneering ceramics: 3-year results. AB - OBJECTIVES: The aim of the present pilot study was to test whether or not posterior zirconia-ceramic fixed dental prostheses (FDPs) with pressed veneering ceramic exhibit less chipping than FDPs with layered veneering ceramics. METHODS: Forty patients (13 female, 27 male; mean age 54 years (range 26.1-80.7 years) in need of one maxillary or mandibular three-unit FDP in the second premolar or molar region were recruited and treated at two separate centers at the University of Zurich according to the same study protocol. The frameworks were made out of zirconia using a CAD/CAM system (Cerec Sirona, Bensheim, Germany). The patients were randomly assigned to either the test group (zirconia frameworks veneered with pressed ceramic; IPS e.max ZirPress, Ivoclar Vivadent AG, Schaan, Liechtenstein; n=20) or the control group (layered veneering ceramic; IPS e.max Ceram, Ivoclar Vivadent AG, Schaan, Liechtenstein; n=20). All FDPs were adhesively cemented and evaluated at baseline (i.e., cementation), at 6 months and at 1 and 3 years of clinical service. The survival of the reconstruction was recorded. The technical outcome was assessed using modified United States Public Health Services (USPHS) criteria. The biologic parameters analyzed at abutment teeth and analogous non-restored teeth included probing pocket depth (PPD), plaque control record (PCR), bleeding on probing (BOP), and tooth vitality (CO2). Data was descriptively analyzed and survival was calculated using Kaplan-Meier statistics. RESULTS: 36 patients (25 female, 11 male; mean age 52.3 years) with 18 test and 18 control FDPs were examined after a mean follow-up of 36 months (95% CI: 32.6-39.1 months). Comparison of groups was done by Crosstabulation showing even distribution of the respective restored teeth amidst the groups. Survival rate was 100% for both test and control FDPs. Chipping of the veneering ceramic tended to occur more frequently in test (n=8; 40%) than in control (n=4; 20%) FDPs, albeit not significantly (p=0.3). No further differences of the technical outcomes of test and control FDPs occurred.In both test and control group healthy conditions and no difference of the biologic parameters at the abutment and un-restored teeth was found. CONCLUSION: Zirconia FDPs with pressed and layered veneering ceramics exhibited similar outcomes at 3 years. A trend to more chipping of the pressed veneering ceramic, however, was observed. CLINICAL SIGNIFICANCE: Posterior restorations with zirconia frameworks are a viable treatment method. When restoring posterior teeth with all-ceramic restorations, care providers should be aware of the higher rate of chipping compared to the published data on conventional metal-ceramic restorations. PMID- 26234624 TI - Three-year outcomes of apicectomy (apicoectomy): Mining an insurance database. AB - OBJECTIVES: The outcome of apicectomy in clinical reality is supposed to be different compared to outcomes reported from clinical trials. The objective of this study was to measure the outcome of apicectomies under practice conditions by mining an insurance data base. METHODS: This retrospective study was based on claims data of a major German national health insurance company (BARMER GEK). Through the company's data warehouse fee codes and treatment dates were accessible and allowed the tracing of clinical courses. Kaplan-Meier survival analyses for the target event 'extraction' were conducted for all teeth that underwent apicectomies within a 3 year period. Testing for differences among survival rates across groups was performed with the Log-Rank-test. RESULTS: A total of 93,797 teeth in 77,636 patients could be traced after apicectomy. The cumulative 3-year survival rate was 81.6%. Anterior teeth showed a significantly higher survival rate of 84.0% compared to premolars (80.4%) and molars (80.2%). The survival rate in men (83.5%) was significantly higher than in women (80.6%). Analysis of survival by age revealed continuously declining survival rates with age (93.3% for subjects under 18 years of age to 75.6% for subjects over 84 years of age). CONCLUSIONS: The 3-year outcomes of apicectomy were still acceptable for an intervention that is mostly conducted as a retreatment after failure of a preceding measure. However at a population level, the question remains to be answered whether other treatment options would potentially be more effective. PMID- 26234625 TI - Additional disinfection with a modified salt solution in a root canal model. AB - OBJECTIVES: The aim of this study is to investigate the disinfecting properties of a modified salt solution (MSS) and calcium hydroxide (Ca(OH)2) in a non-direct contact ex-vivo model. METHODS: Seventy-four single-canal roots infected with Enterococcus faecalis were treated with 1% sodium hypochlorite (NaOCl) irrigation or with NaOCl irrigation with subsequent dressing with MSS or Ca(OH)2. After removal of the dressings, the roots were filled with bacterial growth medium and incubated for seven days to enable the surviving bacteria to repopulate the root canal lumen. Growth was determined by sampling the root canals with paper points before treatment (S1), after treatment (S2) and incubation after treatment (S3). The colony forming units were counted at S1 and S2. At S3, growth was determined as no/yes regrowth. The Kruskal-Wallis, McNemar and chi(2) test were used for statistical analyses. RESULTS: At S2, in the NaOCl group, growth was found in 5 of 19 root canals. After the removal of MSS or Ca(OH)2 bacteria were retrieved from one root canal in both groups. At S3, repopulation of the root canals had occurred in 14 of 19 roots after sole NaOCl irrigation, 6 of 20 roots after MSS dressing and in 14 of 20 roots after Ca(OH)2-dressing. MSS was more effective in preventing regrowth than Ca(OH)2 (P=0.009). CONCLUSIONS: The modified salt solution prevented regrowth in roots which indicates that it can eliminate persistent bacteria. Dressing the root canals with Ca(OH)2 did not provide additional disinfection after NaOCl irrigation. PMID- 26234626 TI - Analysis of L-type amino acid transporter in canine hepatocellular carcinoma. AB - p. 527, lines 5 to 1 from the bottom in the right column. While Kadosawa et al. reported the LAT1 expression in the canine mammary gland tumor and melanoma in the veterinary clinic [9-11], little information is available concerning LAT expression in hepatocellular carcinoma cells (HCCs) of dog; should have been While Fukumoto et al. reported the LAT1 expression in the canine mammary gland tumor and melanoma in the veterinary clinic [9-11], little information is available concerning LAT expression in hepatocellular carcinoma cells (HCCs) of dog. PMID- 26234627 TI - The effect of RE substitution in layered REO(0.5)F(0.5)BiS2: chemical pressure, local disorder and superconductivity. AB - We have studied the effect of RE substitution on the structure and the local atomic disorder in REO0.5F0.5BiS2 (RE = rare-earth) to understand their correlation with the bulk superconductivity in these materials. The mean RE size, affecting the chemical pressure, has been varied in two series namely Ce1 xNdxO0.5F0.5BiS2 and Nd1-ySmyO0.5F0.5BiS2. The lattice parameters evolve anomalously, showing an anisotropic shrinkage (elongation) of the c-axis (a-axis) to an isotropic expansion of the lattice with increasing mean RE size. The Bi L3 edge extended X-ray absorption fine structure (EXAFS) measurements are performed to investigate local displacements in the BiS2 lattice, revealing a large disorder and a sharp boundary between the Ce-containing and Sm-containing series with a distinct local structure. The results suggest that the bulk superconductivity in REO0.5F0.5BiS2 is correlated with anomalous atomic displacements in the Bi-S1 network, likely to be a combined effect of active Bi 6s electronic states and a possible Jahn-Teller-like instability of the Bi 6px/6py electrons. PMID- 26234629 TI - Innovative community-based educational face-to-face intervention to reduce HIV, hepatitis C virus and other blood-borne infectious risks in difficult-to-reach people who inject drugs: results from the ANRS-AERLI intervention study. AB - AIMS: To study the effectiveness of an educational intervention on risks associated with drug injection, comparing primary [unsafe HIV-hepatitis C virus (HCV) practices] and secondary (local complications at injecting site) end-points in harm reduction (HR) programmes offering this intervention versus HR programmes not offering it. DESIGN: This non-random clustered intervention study was conducted in nine intervention groups (programmes offering the intervention) and eight control groups (programmes not offering it). Each participant was followed up through a telephone interview at enrolment and at 6 and 12 months. SETTING: The study took place in 17 cities throughout France. PARTICIPANTS: Of the 271 participants, 144 were enrolled into the intervention group and 127 in the control group. Of the latter, 113 received at least one educational session. INTERVENTION: A series of participant-centred face-to-face educational sessions. Each session included direct observation by trained non-governmental organization (NGO) staff or volunteers of participants' self-injecting the psychoactive product they used habitually; analysis by the trained NGO staff or volunteers of the participant's injecting practices, identification of injection-related risks and explanation of safer injecting practices; and an educational exchange on the individual participant's injection practices and the questions he or she asked. MEASUREMENTS: Primary and secondary outcomes were 'at least one unsafe HIV-HCV practice' and at least one injection-related complication (derived from a checklist). FINDINGS: The proportion of participants with at least one unsafe HIV HCV practice in the intervention group decreased significantly, from 44% at M0 to 25% at M6, as well as complications at the injection site (from 66 to 39% at M12), while in the control group it remained mainly stable. Multivariate probit analyses showed that the intervention group experienced a significant reduction in unsafe HIV-HCV practices at M6 [coefficient, 95% confidence interval (CI) = 0.73 (-1.47 to 0.01)] and in injection-related complications at M12 [coefficient, 95% CI = -1.01 (-1.77 to -0.24)], compared with the control group. CONCLUSIONS: An inexpensive and easily implemented educational intervention on risks associated with drug injection reduces significantly unsafe HIV-HCV transmission practices and injection-related complications. PMID- 26234630 TI - Dual Effect of (LK)nL Peptides on the Onset of Insulin Amyloid Fiber Formation at Hydrophobic Surfaces. AB - Soluble proteins are constantly in contact with material or cellular surfaces, which can trigger their aggregation and therefore have a serious impact on the development of stable therapeutic proteins. In contact with hydrophobic material surfaces, human insulin aggregates readily into amyloid fibers. The kinetics of this aggregation can be accelerated by small peptides, forming stable beta-sheets on hydrophobic surfaces. Using a series of (LK)nL peptides with varying length, we show that these peptides, at low, substoichiometric concentrations, have a positive, cooperative effect on insulin aggregation. This effect is based on a cooperative adsorption of (LK)nL peptides at hydrophobic surfaces, where they form complexes that help the formation of aggregation nuclei. At higher concentrations, they interfere with the formation of an aggregative nucleus. These effects are strictly dependent on the their adsorption on hydrophobic material surfaces and highlight the importance of the impact of materials on protein stability. (LK)nL peptides prove to be valuable tools to investigate the mechanism of HI aggregation nuclei formation on hydrophobic surfaces. PMID- 26234632 TI - Insights into the UDP-sugar selectivities of human UDP-glycosyltransferases (UGT): a molecular modeling perspective. AB - Enzymes of the human uridine diphosphate (UDP)-glycosyltransferase (UGT) superfamily typically catalyze the covalent addition of a sugar from UDP-sugar cofactors to relatively small lipophilic compounds. The sugar conjugates are often biologically less active with improved water-solubility, facilitating more effective elimination from the body. Experimental data indicate that UGT proteins exhibit differing selectivities toward various UDP-sugars. Although, three dimensional (3D) structures of UGT proteins are required to provide insights into the UDP-sugar selectivities observed for the various UGT proteins, there are currently, no experimental structures available for human UGTs bound to UDP sugar(s). Thus, the absence of 3D structures poses a major challenge for analyzing UDP-sugar selectivity at an atomic level. In this commentary, we highlight the application of comparative homology modeling for understanding the UDP-sugar selectivities of UGT proteins. Homology models of the C-terminal (CT) domain indicate a highly conserved structural fold across the UGT family with backbone root mean-squared deviations (rmsds) between 0.066 and 0.079 A with respect to the UGT2B7-CT X-ray crystal structure. The models show that four residues in the terminal portion of the CT signature sequence play an important role in UDP-sugar selectivity. The N-terminal domain is less likely to be associated with UDP-sugar selectivity, although, a conserved residue, Arg-259 (UGT2B7 numbering) in the UGT 1 and 2 families may influence UDP-sugar selectivity. Overall, the models demonstrate excellent agreement with experimental observations in predicting the key residues that influence the selectivity of UDP-sugar binding. PMID- 26234631 TI - Cinnamaldehyde inhibits inflammation and brain damage in a mouse model of permanent cerebral ischaemia. AB - BACKGROUND AND PURPOSE: Recent findings suggest the importance of inflammation in the pathogenesis of cerebral ischaemia and its potential as a therapeutic target. Cinnamaldehyde is a diterpene with a wide range of anti-inflammatory effects thus may be advantageous in the treatment of cerebral ischaemia. The present study examined the potential therapeutic effects of cinnamaldehyde on cerebral ischaemia using a mouse model with permanent middle cerebral artery occlusion. EXPERIMENTAL APPROACH: Male CD-1 mice, which had the middle cerebral artery occluded, were treated (i.p.) with cinnamaldehyde. Neuroprotection by cinnamaldehyde was analysed by evaluating neurological deficit scores, brain oedema and infarct volume. Expressions of signal transduction molecules and inflammatory mediators were measured by Western blotting, qRT-PCR and immunohistochemical staining. Activation of NF-kappaB was assessed by Western blotting, immunohistochemistry and immunofluorescence. KEY RESULTS: Cinnamaldehyde reduced the neurological deficit scores, brain oedema and infarct volume. Cinnamaldehyde suppressed the activation of signal transduction molecules including toll-like receptor 4, tumour necrosis receptor-associated factor 6 and NF-kappaB, attenuated the increased levels of TNF-alpha, IL-1beta, CCL2 and endothelial-leukocyte adhesion molecule-1 and ultimately reduced leukocyte infiltration into the ischaemic brain areas after cerebral ischaemia. CONCLUSIONS AND IMPLICATIONS: Cinnamaldehyde protects against cerebral ischaemia injury by inhibiting inflammation, partly mediated by reducing the expression of toll-like receptor 4, tumour necrosis receptor-associated factor 6 and the nuclear translocation of NF-kappaB. Our findings suggest that cinnamaldehyde may serve as a new candidate for further development as a treatment for stroke. PMID- 26234633 TI - Lumbar spinal atypical teratoid rhabdoid tumor. AB - We describe a pediatric patient with an atypical teratoid rhabdoid tumor (AT/RT) exclusively of the lumbar spine, with a different presentation from the two previously reported pediatric lumbar AT/RT. AT/RT are rare pediatric tumors of the central nervous system, with a dismal prognosis. Although there is sufficient literature on brain AT/RT, spinal AT/RT continues to be a rare entity, with a lumbar location even less frequently reported. A 30-month-old African American boy with multiple comorbidities presented with the inability to ambulate, encopresis and urinary dribbling. The MRI showed an intradural extramedullary mass extending downwards from the L3-4 level. He underwent an L3-S2 laminoplasty. The surgically resected mass was marked by sheets of cells with large nuclei and prominent nucleoli. The tumor cells stained with antibodies to synaptophysin and CAM5.2, and showed no immunoreactivity to INI-1 antibody. He was diagnosed with a World Health Organization Grade IV AT/RT. There was no mutation detected in the SMARCB1 gene on a comprehensive analysis of his blood. The boy is currently being treated according to the Medical University of Vienna AT/RT protocol, with no evidence of tumor recurrence 8 months after surgery. To our knowledge, this is the only report of a lumbar AT/RT in an African American child. PMID- 26234634 TI - Interhemispheric approach for endoscopic ligation of an anterior cranial fossa dural arteriovenous fistula. AB - We describe the endoscopic ligation of an anterior cranial fossa (ACF) dural arteriovenous fistula (DAVF) through an interhemispheric approach. Intracranial DAVF of the ACF are rare and associated with an aggressive natural history, due to their ubiquitous direct cortical venous drainage and frequent coincidence of venous ectasia. Although surgical ligation is the preferred treatment for ACF DAVF, the role of endoscopy in the surgical management of DAVF is undefined. A 53 year-old woman was incidentally diagnosed with an ACF DAVF. Cerebral angiography showed a Borden type III, Cognard type IV left sided ACF DAVF, supplied by ethmoidal branches of the bilateral ophthalmic arteries and draining directly into an enlarged and ectatic left inferior frontal cortical vein, with a venous varix distal to the point of fistulization. An initial attempt at endovascular treatment from a transvenous approach was unsuccessful, due to significant stenosis of the left cavernous sinus. Therefore, we elected to proceed with surgical ligation. From an interhemispheric approach and under the guidance of frameless stereotactic neuronavigation, a 0 degrees endoscope was advanced into the interhemispheric fissure until the arterialized draining vein was visualized. After dissecting along the draining vein to the point of fistulization, the proximal portion of the draining vein was ligated. Intraoperative angiography confirmed complete obliteration of the DAVF, and the patient was asymptomatic at the 6 week postoperative follow-up. Endoscopy provides excellent visualization of ACF DAVF and can safely facilitate surgical treatment in appropriately selected patients with these lesions. PMID- 26234635 TI - Progression free survival and functional outcome after surgical resection of intramedullary ependymomas. AB - We present a 15 year institutional analysis of the factors affecting progression free survival (PFS) and overall survival (OS) in patients undergoing attempted resection of adult intramedullary spinal cord ependymomas. Intramedullary spinal cord tumors are rare but important clinical entities, and ependymomas are the most commonly encountered intramedullary tumor. In total, 53 adult patients over the span of 15 years were analyzed for OS, PFS, and the effects of plane of dissection (POD) and gross total resection (GTR) on functional and long term outcomes. The mean age was 45 years and median follow-up was 54 months. The follow-up neurological outcome and modified McCormick scale were used to determine the functional outcome. Kaplan-Meier curves were used to calculate progression and survival. The overall ability to achieve GTR was significantly correlated to identification of an intraoperative POD (p<0.001). There was a trend towards increased PFS with the ability to achieve a GTR. There was no significant difference in the pre- and postoperative functional outcome scores. The ability to achieve a GTR is strongly correlated to the identification of a POD in ependymomas. There is a trend towards an increased probability of PFS in intramedullary spinal cord tumors when GTR is achieved. The resection of these tumors is likely to halt, but not reverse, neurological deterioration. PMID- 26234636 TI - Design of Highly Photofunctional Porous Polymer Films with Controlled Thickness and Prominent Microporosity. AB - Porous organic polymers allow the integration of various pi-units into robust porous pi-networks, but they are usually synthesized as unprocessable solids with poor light-emitting performance as a result of aggregation-related excitation dissipation. Herein, we report a general strategy for the synthesis of highly emissive photofunctional porous polymer films on the basis of a complementary scheme for the structural design of aggregation-induced-emissive pi-systems. We developed a high-throughput and facile method for the direct synthesis of large area porous thin films at the liquid-electrode interface. The approach enables the preparation of microporous films within only a few seconds or minutes and allows precise control over their thickness with sub-nanometer precision. By virtue of rapid photoinduced electron transfer, the thin films can detect explosives with enhanced sensitivity to low parts-per-million levels in a selective manner. PMID- 26234637 TI - Irisin levels in the progression of diabetes in sedentary women. AB - CONTEXT: The recently discovered peptide irisin has been hypothesized to be a regulator of body metabolism. However, studies ended up with controversial results. In the present study, we aimed to investigate irisin levels in sedentary women at different stages of prediabetes. DESIGN, SETTING, AND SUBJECTS: We performed a cross-sectional analysis of circulating levels of irisin in 263 females similar for age and body mass index (BMI) and the groups included 52 normal glucose tolerance (NGT), 60 isolated impaired fasting glucose (IFG), 36 isolated impaired glucose tolerance (IGT), 65 both IFG and IGT and 50 type 2 diabetic patients. All patients were exercising less than 150 min/week. RESULTS: Plasma irisin levels were significantly lower in IFG+IGT (2.86 +/- 0.6 MUg/mL, p: 0.019) and T2DM (2.83 +/- 0,5 MUg/mL, p: 0.005) patients compared to NGT (3.16 +/ 0.3 MUg/mL) patients. After age adjustment there was a negative correlation between irisin and BMI (r: -0.141; p: 0.031), postprandial glucose (PPG) (r: 0.142; p: 0.030), low density lipoprotein-cholesterol (LDL-C) (r: -0.138; p: 0.035) and triglyceride (TG) (r: -0.214; p: 0.001) and a positive correlation between irisin and high density lipoprotein-cholesterol (HDL-C) (r:.142; p: 0.030). After adjustment for age and BMI; PPG (r: -0. 137; p: 0.037), LDL-C (r: 0. 143; p: 0.029) and TG (r: -0.203; p: 0.002) were considered to correlate with irisin levels. Subgroup analysis revealed that TG levels were correlated with irisin levels in IFG (r: -0.347; p: 0.014) and IGT (r: -0.397; p: 0.030) patients. CONCLUSION: In our cohort of sedentary women, irisin levels were lower in patients with IFG+IGT and with diabetes than in patients with NGT. There is no correlation between irisin levels and BMI. Irisin is a myokine decreasing gradually with the progression of glucose intolerance and T2DM and is not correlated with BMI in sedentary women. PMID- 26234638 TI - Pleural fluid cell-free DNA in parapneumonic pleural effusion. AB - OBJECTIVES: To measure the accuracy of pleural fluid cell-free DNA (cfDNA) concentration for diagnosis of parapneumonic pleural effusions (PPE). DESIGN AND METHODS: We studied pleural fluids obtained by thoracocentesis in patients with pleural effusion. DNA was automatically extracted from pleural fluid using the MagNa Pure Compact instrument (Roche Diagnostics), and was measured by a real time quantitative PCR assay for the beta-globin gene using a Light-Cycler 480 Real-Time PCR instrument (Roche Diagnostics). Patients were classified into two groups according to the etiology of pleural effusion: PPE and NOT PPE. The diagnostic accuracy was determined using receiver operating characteristic (ROC) techniques by analyzing the area under the ROC curve (AUC). RESULTS: We studied 78 patients with ages between 1 and 86 years old (median=64). Sixteen patients were PPE and 62 were NOT PPE (24 transudative, 30 malignant and 8 other etiology). Pleural fluid cfDNA concentration was higher in patients with PPE (median=46,240 ng/mL) than in those with NOT PPE (median=224 ng/mL). The AUC value was 0.907 (p<0.0001) and the optimal cut-off value was 6740 ng/mL exhibiting 87.5% sensitivity and 80.6% specificity. Also, there were significant differences between transudative and exudative effusions according to pleural fluid cfDNA concentration (p<0.0001). The AUC value was 0.994 and the optimal cut off value was 162ng/mL exhibiting 100% sensitivity and 96.3% specificity. CONCLUSIONS: Pleural fluid cfDNA concentration showed high accuracy for diagnosis of PPE and to discriminate between transudative and exudative effusions. PMID- 26234640 TI - Undetermined Manner of Death: An Autopsy Series. AB - A manner of death may be ruled undetermined by the forensic pathologist when there is insufficient information about the circumstances surrounding the death to make a ruling. The aim of our study was to retrospectively analyze a series of autopsy cases that were classified as undetermined manner of death after complete investigations. In all, 48 cases were examined. In 23 cases (48%), the cause of death was determined. The most frequent cause of death was toxic death (n = 11). More than one manner of death was deemed conceivable for most cases (n = 39). The most frequent and the most probable manner of death was accident (n = 37). Homicide was not excluded in about 23% of the cases. Our study showed that the manner of death may remain undetermined despite an established cause of death, and even when two or more conceivable causes of death are considered. Our study pointed out that undetermined manner of death covers a wide range of situations and that homicide may be underestimated. PMID- 26234639 TI - Comparison of cell stabilizing blood collection tubes for circulating plasma tumor DNA. AB - OBJECTIVES: Circulating plasma DNA is being increasingly used for biomedical and clinical research as a substrate for genetic testing. However, cell lysis can occur hours after venipuncture when using standard tubes for blood collection, leading to an increase in contaminating cellular DNA that may hinder analysis of circulating plasma DNA. Cell stabilization agents can prevent cellular lysis for several days, reducing the need for immediate plasma preparation after venipuncture, thereby facilitating the ease of blood collection and sample preparation for clinical research. However, the majority of cell stabilizing reagents have not been formally tested for their ability to preserve circulating plasma tumor DNA. DESIGN & METHODS: In this study, we compared the properties of two cell stabilizing reagents, the cell-free DNA BCT tube and the PAXgene tube, by collecting blood samples from metastatic breast cancer patients and measuring genome equivalents of plasma DNA by droplet digital PCR. We compared wild type PIK3CA genome equivalents and also assayed for two PIK3CA hotspot mutations, E545K and H1047R. RESULTS: Our results demonstrate that blood stored for 7 days in BCT tubes did not show evidence of cell lysis, whereas PAXgene tubes showed an order of magnitude increase in genome equivalents, indicative of considerable cellular lysis. CONCLUSIONS: We conclude that BCT tubes can prevent lysis and cellular release of genomic DNA of blood samples from cancer patients when stored at room temperature, and could therefore be of benefit for blood specimen collections in clinical trials. PMID- 26234641 TI - Nursing discharge planning for older medical inpatients in Switzerland: A cross sectional study. AB - Nursing discharge planning for elderly medical inpatients is an essential element of care to ensure optimal transition to home and to reduce post-discharge adverse events. The objectives of this cross-sectional study were to investigate the association between nursing discharge planning components in older medical inpatients, patients' readiness for hospital discharge and unplanned health care utilization during the following 30 days. Results indicated that no patients benefited from comprehensive discharge planning but most benefited from less than half of the discharge planning components. The most frequent intervention recorded was coordination, and the least common was patients' participation in decisions regarding discharge. Patients who received more nursing discharge components felt significantly less ready to go home and had significantly more readmissions during the 30-day follow-up period. This study highlights large gaps in the nursing discharge planning process in older medical inpatients and identifies specific areas where improvements are most needed. PMID- 26234642 TI - Facing the Adversity: the Role of Internal Assets on Well-Being in Adolescents with Special Needs. AB - Negative life events are one of the major threats to well-being. Some adolescents are more vulnerable, namely adolescents with special needs that face special challenges for growing up healthy and happy. Nevertheless, internal assets can act as protective factors. The aim of this study is to analyze the factors that moderate the impact of negative life events, among adolescents with special needs, on well-being. The sample included 472 adolescents with special needs, mean age 14 years old. Pupils attended 77 public schools in Portugal. Sample was collected within the HBSC (Health Behavior in School aged Children) Portuguese survey. Questions used in this study, covered well-being, internal assets and life events. Results showed that the well-being of adolescents with special needs who had a set of internal assets (personal and social competences) was protected, even when they faced negative life events. However when several negative life events were present, the assets that continued to be protective were problem solving, F(4, 383) = 3.79, p = .005, eta2 = .04, and self-efficacy, F(4, 377) = 3.39, p = .010, eta2 = .04, suggesting the resilience properties of these factors. PMID- 26234643 TI - Genomic and transcriptomic insights into the cytochrome P450 monooxygenase gene repertoire in the rice pest brown planthopper, Nilaparvata lugens. AB - The cytochrome P450 monooxygenase (P450) gene family is one of the most abundant eukaryotic gene families that encode detoxification enzymes. In this study, we identified an abundance of P450 gene repertoire through genome- and transcriptome wide analysis in the brown planthopper (Nilaparvata lugens), the most destructive rice pest in Asia. Detailed gene information including the exon-intron organization, size, transcription orientation and distribution in the genome revealed that many P450 loci were closely situated on the same scaffold, indicating frequent occurrence of gene duplications. Insecticide-response expression profiling revealed that imidacloprid significantly increased NlCYP6CS1v2, NLCYP4CE1v2, NlCYP4DE1, NlCYP417A1v2 and NlCYP439A1 expression; while triazophos and deltamethrin notably enhanced NlCYP303A1 expression. Expression analysis at the developmental stage showed the egg-, nymph-, male- and female-specific expression patterns of N. lugens P450 genes. These novel findings will be helpful for clarifying the P450 functions in physiological processes including development, reproduction and insecticide resistance in this insect species. PMID- 26234644 TI - Medically important fungi respond to azole drugs: an update. AB - The increased numbers of patients with compromised immune systems in the last three decades have increased the chances of life-threatening fungal infections. Numerous antifungal drugs have been developed in the last 20 years to treat these infections. The largest group, the azoles, inhibits the synthesis of fungal sterols. The use of these fungistatic azoles has subsequently led to the emergence of acquired azole resistance. The most common mechanisms that result in azole resistance include the overexpression or mutation of the azole target enzyme, and overexpression of drug transporters that are responsible for azole efflux from cells. Additional, less-frequent mechanisms have also been identified. Understanding azole resistance mechanisms is crucial for current antifungal treatment and for the future development of new treatment strategies. PMID- 26234645 TI - Direct and positive regulation of Caenorhabditis elegans bed-3 by PRDM1/BLIMP1 ortholog BLMP-1. AB - Caenorhabditis elegans BLMP-1 is the homolog of mammalian PRDM1/BLIMP1 transcriptional repressor and a component of the heterochronic pathway regulating developmental timing. We found that BLMP-1 positively and directly regulates the bed-3 gene required for vulval cell division and molting. blmp-1 mutation or RNAi reduces bed-3 reporter expression and causes phenotype similar to bed-3 mutations. We mapped an enhancer element responsible for bed-3 expression in the vulva and the hypodermis to a 200 bp region in the third intron. Using EMSA, we identified BLMP-1 binding sites within this region. Mutating these sites abolished both in vitro BLMP-1 binding and in vivo enhancer activity. Thus, BLMP 1 directly and positively regulates bed-3 transcription, connecting the heterochronic pathway to regulation of vulval cell division and molting. Recently, C. elegans blmp-1 was found to act as a transcriptional repressor. Thus, C. elegans BLMP-1 acts as a transcriptional activator or a repressor depending on the context. PMID- 26234647 TI - Competitive Halide Binding by Halogen Versus Hydrogen Bonding: Bis-triazole Pyridinium. AB - The binding of F(-) , Cl(-) , Br(-) , and I(-) anions by bis-triazole-pyridine (BTP) was examined by quantum chemical calculations. There is one H atom on each of the two triazole rings that chelate the halide via H bonds. These H atoms were replaced by halogens Cl, Br, and I, thus substituting H bonds by halogen bonds. I substitution strongly enhances the binding; Br has a smaller effect, and Cl weakens the interaction. The strength of the interaction is sensitive to the overall charge on the BTP, rising as the binding agent becomes singly and then doubly positively charged. The strongest preference of a halide for halogenated as compared to unsubstituted BTP, as much as several orders of magnitude, is observed for I(-) . Both unsubstituted and I-substituted BTP could be used to selectively extract F(-) from a mixture of halides. PMID- 26234646 TI - Asiatic acid alleviates cardiovascular remodelling in rats with L-NAME-induced hypertension. AB - A previous study demonstrated the antihypertensive effect of asiatic acid. The current study investigates the effect of asiatic acid on cardiovascular remodelling and possible mechanisms involved in Nomega -nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Male Sprague-Dawley rats were treated with L-NAME (40 mg/kg per day) for 3 weeks in order to induce hypertension. Hypertensive rats were administered asiatic acid (20 mg/kg per day) or vehicle for a further 2 weeks. It was found that hypertensive rats showed high systolic blood pressure, left ventricular (LV) hypertrophy, increases in LV fibrosis, aortic wall thickness and aortic collagen deposition (P < 0.05). Moreover, decreased plasma nitrate and nitrite (NOx) and increased plasma tumor necrosis factor alpha (TNF-alpha) were observed in hypertensive rats (P < 0.05). This was consistent with downregulation of endothelial nitric oxide synthase (eNOS) expression and upregulation of inducible nitric oxide synthase (iNOS) expression in heart and aortic tissues (P < 0.05). Levels of malondialdehyde (MDA) in plasma, aortic and heart tissues were significantly increased in hypertensive rats (P < 0.05). Asiatic acid markedly reduced blood pressure, alleviated cardiovascular remodelling, and restored plasma NOx and TNF-alpha as well as eNOS/iNOS expression in heart and aortic tissues (P < 0.05). Additionally, there was a significant reduction of MDA levels in the tissues of treated hypertensive rats. In conclusion, this study demonstrates the therapeutic effects of asiatic acid on blood pressure and cardiovascular remodelling, which is possibly related to the restoration of eNOS/iNOS expression, and the resulting anti-inflammatory and antioxidant activities. PMID- 26234648 TI - Akt2 knock-down reveals its contribution to human lung cancer cell proliferation, growth, motility, invasion and endothelial cell tube formation. AB - The Akt/PKB serine/threonine protein kinase consists of three isoforms: Akt-1, -2 and -3. Their overexpression has been detected in human cancers, but their roles in cancer progression are unclear. We investigated the impact of specific silencing of Akt1 and Akt2 on human lung cancer cell proliferation, colony growth, motility, and invasion in vitro as well as tumor growth in vivo using human Non-Small Cell Lung Cancer cells LNM35, and on the vascular tube formation using HUVEC cells. Although silencing of Akt1 decreased cellular invasion at least in part via COX-2 inhibition, it had almost no effect on cell motility, proliferation, colony formation, and angiogenesis. Transient as well as stable silencing of Akt2 resulted in a strong inhibition of Rb phosphorylation associated with a decrease in cellular proliferation and colony formation, leading to the inhibition of tumor growth in the xenograft model. Silencing of Akt2 also reduced cellular motility and invasion in vitro, presumably via COX-2 inhibition. Moreover, silencing of Akt2 in the HUVEC cells resulted in the inhibition of their spontaneous angiogenic phenotype. Altogether, these results indicate that Akt2 plays an important role in lung cancer progression and can be a promising target for lung cancer therapy. PMID- 26234649 TI - IgE responses to exogenous and endogenous allergens in atopic dermatitis patients under long-term systemic cyclosporine A treatment. AB - Atopic dermatitis (AD) patients mount IgE antibody responses to a variety of environmental allergens and also to autoantigens. We analyzed serum samples from four AD patients who had received oral cyclosporine A (CyA) treatment for up to 17 months regarding IgE autoreactivity to nitrocellulose-blotted human epithelial cell extracts and IgE levels to environmental allergens by quantitative ImmunoCap measurements. Skin inflammation was assessed by SCORAD. During full-dose treatment, a strong reduction in T-cell-mediated skin symptoms was observed which reappeared when CyA treatment was reduced or stopped. The intensity of IgE autoreactivity seemed to follow skin inflammation as it was reduced during full dose treatment and increased upon inflammation. Interestingly, IgE levels to exogenous allergens were boosted by allergen exposure, declined thereafter, and seemed to be unaffected by CyA. Our data thus indicate that allergen-specific IgE production is boosted by allergen contact and cannot be reduced by CyA-mediated T cell suppression. PMID- 26234650 TI - Prostate Cancer on the Web-Expedient Tool for Patients' Decision-Making? AB - Many patients diagnosed with cancer search for health information on the Web. We aimed to assess the quality and reliability of online health information on prostate cancer. Google, Yahoo, and Bing were searched for the term "prostate cancer." After selecting the most frequented websites, quality was measured by DISCERN score, JAMA benchmark criteria, and presence of HONcode certification. Popularity was assessed by Alexa tool, while accessibility, usability, and reliability were investigated by LIDA tool. Readability was analyzed by Flesch Kincaid Reading Grade Level and Automated Readability Index. All 13 selected websites were rated as being of high quality according to the DISCERN instrument (76.5 +/- 2.6 out of 80 points). JAMA benchmark criteria were fulfilled by 87 % of websites, whereas only 37 % were certified by the HONcode. Median Alexa Traffic Rank was 2718 ranging from 7 to 679,038. Websites received 2.3 +/- 0.5 daily pageviews per visitor and users spent an average of 2 min 58 s +/- 39 sec on the website. Accessibility (92 +/- 5 %) and usability (92 +/- 3 %) scores were high and reliability (88 +/- 8 %) moderate according to the LIDA tool. Flesch Kincaid Grade Level was 7.9 +/- 2.2, and Automated Readability Index was 7.5 +/- 2.4, rating the websites as fairly difficult to read. In conclusion, quality, accessibility, and usability of websites on prostate cancer provided a high rating in the current analysis. These findings are encouraging in view of the growing frequency of patients' access of health information online. PMID- 26234651 TI - Reference Values for Echocardiography in Middle-Aged Population: The Cardiovascular Risk in Young Finns Study. AB - BACKGROUND: Population and sex-specific reference limits produced with modern ultrasound equipment are needed for accurate clinical echocardiography diagnostics. We report a comprehensive set of reference limits of cardiac function and dimensions in a group of young and middle-aged Finnish men and women produced by the recommendations of European Society of Echocardiography and American Society of Cardiology. METHODS AND RESULTS: Cardiac structure and function was studied in a standardized comprehensive echocardiographic examination in 1,079 healthy volunteers without cardiovascular diseases or major known risk factors participating in the population-based Young Finns study (444 men and 635 women, age range 34 and 49 years). We present sex-specific reference values for echocardiographic parameters reflecting cardiac structure (ventricular and atrial dimensions and volumes, left ventricular wall thickness and mass, aortic root) and function. From the 86 measured parameters, only 7 were not statistically significantly different between sexes. CONCLUSION: The Young Finns study provides echocardiographic reference ranges for cardiac structure and function quantification that can be utilized to enhance the accuracy or echocardiography diagnostics. The results emphasize the need for sex-specific assessment for most echocardiographic parameters. PMID- 26234652 TI - Sutureless Valve Implantation in Sievers Type 0 Bicuspid Annuli: A Word of Caution. AB - AIM: We describe a series of 3f Enable sutureless prostheses implanted in bicuspid valves. METHODS: Between March 2011 and April 2014, five patients with Sievers type 0 bicuspid valves were selected to receive the sutureless 3f Enable prosthesis . Exclusion criteria were: intraoperative calibration of the aortic annulus >27 mm, left ventricle ejection fraction <50%, age <70 years. RESULTS: All the implantations could be performed without the necessity to re-deploy the prosthesis . The perioperative transesophageal echocardiogragram detected two moderate paravalvular leakages (PVL) in two patients who received a large size of prosthesis (25 and 27 mm, respectively). The two leakages, at a follow-up of 32 and 24 months, respectively, increased to grade II and II +. No PVL appeared in the other three patients. CONCLUSION: This experience should warn about the inadequate performance of the 3f Enable valve in Sievers type 0 large aortic bicuspid annuli. In this subset any minor intraoperative residual leakage should not be accepted. PMID- 26234653 TI - mRIN for direct assessment of genome-wide and gene-specific mRNA integrity from large-scale RNA-sequencing data. AB - The volume of RNA-Seq data sets in public repositories has been expanding exponentially, providing unprecedented opportunities to study gene expression regulation. Because degraded RNA samples, such as those collected from post mortem tissues, can result in distinct expression profiles with potential biases, a particularly important step in mining these data is quality control. Here we develop a method named mRIN to directly assess mRNA integrity from RNA-Seq data at the sample and individual gene level. We systematically analyse large-scale RNA-Seq data sets of the human brain transcriptome generated by different consortia. Our analysis demonstrates that 3' bias resulting from partial RNA fragmentation in post-mortem tissues has a marked impact on global expression profiles, and that mRIN effectively identifies samples with different levels of mRNA degradation. Unexpectedly, this process has a reproducible and gene-specific component, and transcripts with different stabilities are associated with distinct functions and structural features reminiscent of mRNA decay in living cells. PMID- 26234654 TI - The Effect of Depressive Symptoms and Antidepressant Use on Subsequent Physical Decline and Number of Hospitalizations in Nursing Home Residents: A 9-Year Longitudinal Study. AB - OBJECTIVE: To investigate whether depressive symptoms and antidepressant use at baseline predict the subsequent decline in physical functioning and number of hospitalizations in nursing home residents. DESIGN: Observational study based on Minimum Data Set (MDS) 2.0. SETTING: Six nursing homes in Hong Kong. PARTICIPANTS: All nursing home residents (n = 1076) assessed with the MDS 2.0 in 2005 followed until 2013. MEASUREMENTS: Outcome variables included annual performance in activities of daily living (ADLs) and number of hospitalizations within 90 days before each assessment. The presence of depressive symptoms at baseline was measured by the Resident Assessment Protocol triggered from the MDS 2.0 assessment. Records of antidepressant use and other control variables were exacted directly from the MDS 2.0 assessment. RESULTS: The presence of baseline depressive symptoms did not have significant association with baseline ADLs and number of hospitalizations according to the multilevel mixed-effect model. However, it was associated with a faster deterioration of physical functioning (coefficient 0.03; 95% confidence interval [CI] 0.00-0.07) and an increase in the number of hospitalizations (coefficient 0.05; 95% CI 0.03-0.07). No significant difference between elders using antidepressants and elders who were free from depressive symptoms was observed. If depressive symptoms were presented but antidepressants were not used, a much sharper decline was evident (coefficient 0.06; 95% CI 0.02-0.09). CONCLUSIONS: This study provided evidence that the presence of depressive symptoms is associated with more utilization of health care services. However, the use of antidepressants may play a significant role in altering the trajectory. The presence of depressive symptoms is a worrisome but treatable condition. Effective intervention/treatment should be called on. PMID- 26234655 TI - Validation of analytical procedures using HPLC-ELSD to determine six sesquiterpene lactones in Eremanthus species. AB - Eremanthus species display sesquiterpene lactones with therapeutic potential. We are proposing the development of a new analytical method that has been completely validated to qualify Eremanthus species and its main lactones in raw material using HPLC-ELSD. For the sample preparation, 10.0 mg of powdered Eremanthus leaves was extracted with a 5 mL MeOH/H2 O (9:1 v/v) solution containing scopoletin at 140 ug/mL as the internal standard. For the separation of eight compounds, six of which were lactones, one internal (IS) and one secondary standard were performed utilizing monolithic columns with a nonlinear gradient. The selectivity, stability, precision and matrix effects parameters showed values of RSD of <10%. The six lactones and scopoletin (IS) were recovered with a proportion between 74 and 90% with accuracy represented by error at -25.41%. The linear dynamic range was obtained between 10.0 and 310.0 ug/mL for all compounds with r(2) > 0.9987. The limits of detection and quantitation ranged from 2.00 to 6.79 ug/mL and from 6.00 to 20.40 ug/mL, respectively. Assessing the robustness study, this method can be used in inter-laboratory studies. Using the HPLC-ELSD method, six sesquiterpene lactones including 4beta,5-dihydro-2',3'-dihydroxy-15 deoxy-goyazensolide, goyazensolide, 4beta,5-dihydro-2',3'-epoxy-15-deoxy goyazensolide, centratherin, 4beta,5-dihydro-15-deoxy-goyazensolide and lychnofolide, were detected and quantified from distinct Eremanthus species, which were collected in different regions. PMID- 26234656 TI - TNF-alpha Has Not Been Shown to Be Elevated in Headache Patients: A Response. PMID- 26234657 TI - Cd59a deficiency in mice leads to preferential innate immune activation in the retinal pigment epithelium-choroid with age. AB - Dysregulation of the complement system has been implicated in the pathogenesis of age-related macular degeneration. To investigate consequences of altered complement regulation in the eye with age, we examined Cd59a complement regulator deficient (Cd59a(-/-)) mice between 4 and 15 months. In vivo imaging revealed an increased age-related accumulation of autofluorescent spots in Cd59a(-/-) mice, a feature that reflects accumulation of subretinal macrophages and/or microglia. Despite this activation of myeloid cells in the eye, Cd59a(-/-) mice showed normal retinal histology and function as well as normal choroidal microvasculature. With age, they revealed increased expression of activators of the alternative complement pathway (C3, Cfb, Cfd), in particular in the retinal pigment epithelium (RPE)-choroid but less in the retina. This molecular response was not altered by moderately-enhanced light exposure. Cd59a deficiency therefore leads to a preferential age-related dysregulation of the complement system in the RPE-choroid, that alone or in combination with light as a trigger, is not sufficient to cause choroidal vascular changes or retinal degeneration and dysfunction. This data emphasizes the particular vulnerability of the RPE choroidal complex to dysregulation of the alternative complement pathway during aging. PMID- 26234658 TI - General Life and Diabetes-Related Stressors in Early Adolescents With Type 1 Diabetes. AB - INTRODUCTION: To examine general and diabetes-related stressors in early adolescents with type 1 diabetes (T1D). METHOD: Data were from 205 participants (58% female; 33% minority; 11-14 years) enrolled in a clinical trial. Teens identified their top 3 stressors and responded to open-ended questions. A content analysis method was used to identify themes across stressor categories. RESULTS: Eight-two percent of teens reported that school was a top stressor, followed by social life (49%) and diabetes (48%). We identified 5 themes of general life stressors (fitting in, having friends, balancing competing demands, living with family, and feeling pressure to do well) and 3 themes of diabetes-specific stressors (just having diabetes, dealing with emotions, and managing diabetes). DISCUSSION: Though teens with T1D experienced stressors specific to T1D, they perceived stress related to normal adolescent growth and development more frequently. Teens with T1D may need psychosocial support that holistically addresses both typical developmental and diabetes-related stressors. PMID- 26234659 TI - Impact of Total Arterial Reconstruction on Long-Term Mortality and Morbidity: Off Pump Total Arterial Reconstruction Versus Non-Total Arterial Reconstruction. AB - BACKGROUND: We were interested in how favorable an influence total arterial reconstruction has on the clinical outcome of patients undergoing off-pump coronary artery bypass graft surgery. METHODS: From January 2002 to December 2013, a total of 1,064 patients underwent isolated off-pump coronary artery bypass graft surgery at our institution. Of these 1,064 patients, 763 underwent total arterial revascularization (AR) and 301 underwent a combination of artery and vein revascularization (AVR). We compared the clinical results between the two groups using the propensity score matching technique. RESULTS: In all, 260 cases from the AVR group and 520 from the AR group were successfully matched. All procedures were performed using the off-pump technique without conversion to on pump. Eight patients in the AVR group (3.1%) and 5 in the AR group (1.0%) died in hospital. Multivariate analysis revealed that chronic kidney disease (odds ratio 6.9, p < 0.001), urgency (odds ratio 7.3, p < 0.001), and body mass index (odds ratio 1.3, p = 0.02) were independent risk factors for hospital death. Follow-up was complete for 97.6% of the patients to a maximum of 13 years. According to the Kaplan-Meier method, the rate of 12-year freedom from all causes of death was 69.7% for the AVR group and 72.6% for the AR group (p = 0.002), and the corresponding rates for major adverse cardiac events were 83.9% and 87.7% (p = 0.009). By multivariate Cox regression analysis, total arterial reconstruction was identified as a preventive factor for late cardiac events. CONCLUSIONS: Total arterial revascularization has some degree of favorable effect on the long-term clinical outcome of patients undergoing off-pump coronary artery bypass graft surgery. PMID- 26234660 TI - Echocardiographic Guided Closure of Perimembranous Ventricular Septal Defects. AB - BACKGROUND: Transesophageal echocardiogram-guided minimally invasive periventricular device closure of perimembranous ventricular septal defects (pmVSDs) without cardiopulmonary bypass is a treatment option for pmVSDs. We introduce our improvements to this technique and mid-term follow-up results. METHODS: From May 2011 to May 2014, 187 patients with pmVSDs aged 6 months to 31 years (8.2 +/- 10.2 years) were enrolled in this study. The procedure was performed through a new transthoracic approach of 1 to 2 cm without sternotomy. Device selection and the operative procedure were monitored by transesophageal echocardiogram. The patients underwent follow-up examinations of echocardiography and electrocardiogram at 1 month, 3 months, 6 months, and 1 year after the operation and annually thereafter. RESULTS: The defects were closed successfully in 179 patients (95.7%), and in 8 patients the operation was converted to conventional surgical repair. Six patients (3.4%) had an incomplete right bundle branch block. One patient experienced an intermittent complete atrioventricular block on the fourth day after the operation, and sinus rhythm was restored by corticosteroid therapy after 5 days. A trivial residual shunt was observed in 8 patients (4.5%) during the procedure. The average hospital stay was 3.1 +/- 0.9 days. Follow-up in all patients ranged from 1 month to 36 months (median, 12.6 months), and aortic regurgitation, malignant arrhythmia, and device dislocation were not observed in any patients. However, 3 patients (1.7%) still had a trivial residual shunt at their last follow-up. CONCLUSIONS: Periventricular device closure through a modified transthoracic approach without sternotomy is a potentially safe and effective treatment option for pmVSDs. Controlled studies with long-term follow-up are necessary. PMID- 26234661 TI - Pyromellitic dithioimides: thionation improves air-stability and electron mobility of N-type organic field-effect transistors. AB - Thionation and fluorination of pyromellitic diimides (PyDIs) increased the electron mobility and on/off ratio of the original diimides by two orders of magnitude and improved the threshold voltage and air-stability of diimide compounds. PMID- 26234662 TI - Lengthening of the subscapularis tendon as a sign of partial tearing in continuity. AB - BACKGROUND: The quantification of a subscapularis tendon lesion may be difficult on magnetic resonance imaging, as well as during arthroscopic inspection. Consequently, the surgical decision of whether to only debride a degenerated tendon or to lateralize the more intact tendon portion may be arbitrary. This study aims to quantify the length of the subscapularis tendon as a sign of partial tendon tearing. METHODS: We retrospectively identified 92 magnetic resonance arthrography studies of suspected rotator cuff lesions obtained 3 months before shoulder arthroscopy. The myotendinous junction was identified, and the subscapularis tendon and muscle lengths were measured. Findings on arthroscopy performed later were used as the diagnostic gold standard for tendon integrity and compared with the magnetic resonance data. RESULTS: Arthroscopy showed an intact subscapularis tendon in 43 patients, tendinopathy in 21 patients, and a partial rupture in 28 patients. The mean subscapularis tendon lengths were 40 mm in cases of intact subscapularis musculotendinous units, 45 mm in cases of tendinopathy, and 53 mm in cases of partial tears, whereas the mean subscapularis muscle lengths were 105 mm, 94 mm, and 95 mm, respectively, in these groups. CONCLUSION: Partial tears of the subscapularis tendon lead to muscle shortening by approximately 10% and elongation of the tendon by approximately 32%, which may be interpreted as muscle retraction and a tendon rupture in continuity. If the subscapularis tendon has an apparent length of greater than 60 mm, the probability of a tear is 98%. Determination of the tendon length may therefore be a useful additional tool to quantify the integrity of the subscapularis tendon and degree of myotendinous retraction. PMID- 26234663 TI - In vivo kinetic evaluation of an adhesive capsulitis model in rats. AB - BACKGROUND AND HYPOTHESIS: We hypothesized that extra-articular, internal fixation of the shoulder in rats would result in a subsequent decrease in rotational range of motion (ROM) and an increase in joint stiffness. We further hypothesized that residual kinematic changes would still be present at 8 weeks after immobilization. Extra-articular, internal fixation of the shoulder has been used to induce adhesive capsulitis in rats; however, the effects on in vivo kinematics have not been assessed. METHODS: Baseline measurements of rotational torque and ROM were acquired (n = 10 rats), and the left forelimb of each animal was immobilized with sutures passed between the scapula and the humeral shaft. After 8 weeks, the sutures were removed, and changes in kinematics and kinetics were longitudinally quantified in the follow-up period. Changes in stiffness, defined as the area under the angle-torque curve, were also quantified. RESULTS: Immediately after suture removal, there was a 63% decrease in total ROM compared with baseline (51 degrees +/- 10 degrees vs. 136 degrees +/- 0 degrees ; P < .001). Similarly, total torque was found to increase 13.4 N.mm compared with baseline (22.6 +/- 5.9 N.mm vs. 9.2 +/- 2.6 N.mm; P = .002). Residual total ROM restrictions and an increased torque in internal rotation were still evident at 8 weeks of follow-up (113 degrees +/- 8 degrees vs. 137 degrees +/- 0 degrees , P < .001 and 3.5 +/- 0.4 N.mm vs. 2.7 +/- 0.7 N.mm, P = .036). Stiffness also increased after suture removal and at 8 weeks of follow-up compared with baseline. CONCLUSION: This animal model of adhesive capsulitis rendered lasting effects on in vivo kinematics of the shoulder. PMID- 26234664 TI - Functional outcome of reverse shoulder tumor prosthesis in the treatment of proximal humerus tumors. AB - BACKGROUND: The treatment of proximal humerus tumors with reverse shoulder arthroplasty with allograft augmentation is still controversial. A tumor prosthesis represents a proven solution for such osseous defects. We investigated the functional results of patients who underwent reverse shoulder tumor prosthesis (RSTP) without the use of allograft after resection of a proximal humerus tumor. METHODS: We retrospectively evaluated 10 patients with malignant proximal humerus tumors who had undergone RSTP, with a mean follow-up period of 18.2 months (range, 6-27 months). The average age of the patients was 49.4 years. The mean resection length was 10.2 cm (range, 6-16 cm). The tumor prosthesis was preferred for the humeral component. Released rotator cuff muscles were reattached to the prosthesis with nonabsorbable sutures. RESULTS: The mean active forward flexion was 96 degrees (range, 30 degrees -160 degrees ), the mean active abduction was 88 degrees (range, 30 degrees -160 degrees ), and the mean active external rotation was 13 degrees (range, 0 degrees -20 degrees ). The mean Constant-Murley score was 53.7%. The mean Disabilities of the Arm, Shoulder, and Hand score was 26.2. The mean visual analog scale score was 1.3. The mean Musculoskeletal Tumor Society score was 78.1%. None of our patients have shown local recurrence or infection signs in the follow-up period. CONCLUSIONS: Functionally satisfying results and a stable shoulder can be achieved by reverse shoulder arthroplasty without the need for an allograft. An intact abductor mechanism with a shorter resection humerus length produced good results. The treatment of malignant proximal humerus tumors with RSTP is an alternative that minimizes surgery time and complexity. PMID- 26234665 TI - Assessment of painful total shoulder arthroplasty using computed tomography arthrography. AB - BACKGROUND: This study assessed the accuracy of computed tomography (CT) arthrography when evaluating glenoid component stability in the setting of postarthroplasty shoulder pain. METHODS: We retrospectively reviewed all patients presenting to the clinic during a 5.5-year period to identify those with a painful shoulder arthroplasty more than 1 year after the index procedure. We excluded reverse and hemiarthroplasty procedures, patients with a clearly identifiable cause for pain, such as rotator cuff insufficiency or gross component loosening as seen on plain radiographs, and those with culture-positive aspiration. There were 14 patients with suspected glenoid component loosening but inconclusive plain radiographs. Each of the 14 patients underwent a CT arthrogram that was evaluated by the senior author (J.J.P.W.) for the presence or absence of contrast material underneath the polyethylene component. Operative reports and surgical videos from subsequent arthroscopy were reviewed to assess glenoid component stability as determined by direct arthroscopic visualization. RESULTS: CT arthrography suggested glenoid component loosening in 8 of 14 patients (57.1%), and arthroscopic inspection identified loosening in 10 of 14 patients (71.4%). In 3 of 10 patients (30%), CTA suggested a well-fixed glenoid component, but gross loosening was identified during arthroscopy. In this study, CTA yielded a sensitivity of 70%, a specificity of 75%, a positive predictive value of 87.5%, and a negative predictive value of 50.0%. CONCLUSION: CTA had a low negative predictive value (50%), and therefore, the prediction of component stability based on the absence of contrast between the glenoid component and the bone cement interface does not always reflect true stability. PMID- 26234666 TI - Outcomes of arthroscopic treatment of osteochondritis dissecans of the capitellum and description of the technique. AB - HYPOTHESIS: We hypothesize that a technique for all-arthroscopic fixation of capitellum osteochondritis dissecans (OCD) lesions using suture fixation and autogenous iliac crest bone grafting offers a successful alternative to open internal fixation techniques as shown by 2-year validated patient-reported outcomes. METHODS: Our technique uses arthroscopic all-inside suture fixation with iliac crest autogenous bone grafting. The procedure was performed on 4 elite level, adolescent athletes presenting with 5 unstable capitellum OCD lesions resulting in elbow pain, limited range of motion, and decreased ability to play. Magnetic resonance imaging showed an unstable OCD lesion, which was correlated with arthroscopy. Postoperatively, patients were evaluated by the short version of the Disabilities of the Arm, Shoulder and Hand questionnaire; Oxford Elbow and Mayo Elbow scores; visual analog scale; postoperative range of motion; and return to play. RESULTS: Three female patients and one male patient aged 13 to 15 years underwent the procedure. The mean final follow-up period was 2.8 years. Union was achieved in all patients, as seen on magnetic resonance imaging at a mean of 3 months. At follow-up, the mean loss of extension was 2 degrees . Mean flexion was 153 degrees . There was no loss of supination or pronation. The mean score on the short version of the Disabilities of the Arm, Shoulder and Hand questionnaire was 11. The mean Mayo Elbow score was 88. The mean Oxford Elbow score was 42. The mean visual analog scale score was 2. The mean time to return to play was 4 months. All patients continued to compete at an elite level. There were no infections or cases of fixation failure, and no patients required conversion to open surgery or needed revision surgery. CONCLUSION: Arthroscopic all-inside fixation of unstable OCD lesions is a successful technique, facilitating athletes to return to an elite level of play. PMID- 26234667 TI - In vivo 3-dimensional analysis of scapular and glenohumeral kinematics: comparison of symptomatic or asymptomatic shoulders with rotator cuff tears and healthy shoulders. AB - BACKGROUND: Alteration in shoulder kinematics has been suggested as one cause of symptoms in shoulders with rotator cuff tears (RCTs). However, only a few studies comparing symptomatic and asymptomatic RCTs using kinematic analysis have been performed. The purpose of this study was to compare 3-dimensional (3D) scapular and glenohumeral kinematics during scapular-plane abduction among symptomatic RCTs, asymptomatic RCTs, and healthy shoulders. METHODS: This study included 7 healthy shoulders in subjects with a mean age of 62 years, 5 symptomatic RCTs in subjects with a mean age of 70 years, and 7 asymptomatic RCTs in subjects with a mean age of 67 years. All shoulders with RCTs had medium-sized tears (1-3 cm in the coronal plane) that were confirmed with magnetic resonance imaging. Biplane fluoroscopic images during scapular-plane abduction were recorded, and computed tomography-derived 3D bone models were matched with the silhouettes of the bones on the fluoroscopic images using 3D/2-dimensional model-image registration techniques. Angular values of the scapula and glenohumeral kinematics were compared among the 3 groups. RESULTS: Posterior tilt of the scapula was significantly smaller in the symptomatic RCTs (3.1 degrees +/- 1.8 degrees ) than in healthy shoulders (10.4 degrees +/- 0.8 degrees ) (P = .049). The humerus of the symptomatic shoulders was less externally rotated relative to the scapula throughout the activity than the healthy shoulders and asymptomatic RCTs (P = .006 and P = .028 respectively). However, there were no kinematic differences between the asymptomatic RCTs and healthy shoulders. CONCLUSION: Kinematic changes in symptomatic RCTs might be associated with development of symptoms. Improvement of these kinematic changes may be a key to successful conservative treatment for symptomatic RCTs. PMID- 26234668 TI - How to discriminate between acute traumatic and chronic degenerative rotator cuff lesions: an analysis of specific criteria on radiography and magnetic resonance imaging. AB - BACKGROUND: Discrimination between acute traumatic and chronic degenerative rotator cuff lesions (RCLs) is an important aid to decision making in therapeutic management. To date, no clinical signs or radiologic findings that enable confident differentiation between these distinct etiologic entities have been identified. The purpose of this investigation was to perform a systematic analysis of known radiographic and magnetic resonance imaging (MRI) features of RCLs and of further, not yet accurately described parameters. The hypothesis was that there are specific radiologic features that allow reliable discrimination between traumatic and nontraumatic RCLs. METHODS: Fifty consecutive patients with RCLs confirmed by MRI were enrolled in this study. Group A was made up of 25 patients with a history of trauma within the previous 6 weeks and no pre-existing shoulder pain, whereas group B comprised 25 patients with shoulder pain for not more than 12 months and no history of relevant trauma. Radiographs and magnetic resonance images were analyzed in a standardized protocol. RESULTS: No radiographic features were found to differ significantly between the 2 groups. On MRI, edema in the injured muscle was more common in group A (37.5% vs 4%, P = .04). A characteristic feature in traumatic RCLs was a wavelike appearance (kinking) of the central tendon (64% vs 32%, P = .03). In group B, more muscular atrophy was found (29.2% vs 60%, P = .02). Thinning and retraction did not differ between the groups. CONCLUSION: MRI, but not radiography, can be used to help discriminate between traumatic and nontraumatic RCLs. Although no absolute distinguishing feature was found, edema, kinking, and muscular atrophy are positive criteria for differentiation. PMID- 26234669 TI - Gadolinium-complexed Abeta-binding contrast agents for MRI diagnosis of Alzheimer's Disease. AB - MRI contrast agents, containing peptide sequences that bind beta-amyloid and gadolinium ions ligated to DOTA have been synthesized for evaluation in early diagnosis of Alzheimer's Disease in transgenic mice models. A number of brain penetration modifications were incorporated and sufficient amounts of contrast agent in the brain were achieved only by addition of a cationic cell penetration sequence along with the use of microparticle assisted ultrasound activation. In the T1 mode of a MRI scan, the peptide (R2) illuminated areas of brain rich in amyloid plaques. PMID- 26234670 TI - Nomenclature for factors of the HLA system, update April 2015. PMID- 26234671 TI - Brainstem system of hippocampal theta induction: The role of the ventral tegmental area. AB - This article summarizes the results of studies concerning the influence of the ventral tegmental area (VTA) on the hippocampal theta rhythm. Temporary VTA inactivation resulted in transient loss of the hippocampal theta. Permanent destruction of the VTA caused a long-lasting depression of the power of the theta and it also had some influence on the frequency of the rhythm. Activation of glutamate (GLU) receptors or decrease of GABAergic tonus in the VTA led to enhancement of dopamine release and increased hippocampal theta power. High time and frequency cross-correlation was detected for the theta band between the VTA and hippocampus during paradoxical sleep and active waking. Thus, the VTA may belong to the broad network involved in theta rhythm regulation. This article also presents a model of brainstem-VTA-hippocampal interactions in the induction of the hippocampal theta rhythm. The projections from the VTA which enhance theta rhythm are incorporated into the main theta generation pathway, in which the septum acts as the central node. The neuronal activity that may be responsible for the ability of the VTA to regulate theta probably derives from the structures associated with rapid eye movement (sleep) (REM) sleep or with sensorimotor activity (i.e., mainly from the pedunculopontine and laterodorsal tegmental nuclei and also from the raphe). PMID- 26234672 TI - Palladium(II)-catalysed regioselective synthesis of 3,4-disubstituted quinolines and 2,3,5-trisubstituted pyrroles from alkenes via anti-Markovnikov selectivity. AB - A novel strategy has been identified for the regioselective synthesis of 3,4 disubstituted quinolines and 2,3,5-trisubstituted pyrroles from simple alkenes via anti-Markovnikov selectivity under palladium catalysis. The salient features are synthesis of two different heterocycles, readily available starting materials, broad substrate scope, moderate to good yields and use of molecular oxygen as a terminal oxidant. PMID- 26234673 TI - Chronic Liver Disease Questionnaire would be a primary screening tool of neuropsychiatric test detecting minimal hepatic encephalopathy of cirrhotic patients. AB - AIM: The neuropsychiatric test (NP test) is a clinically available modality to confirm minimal hepatic encephalopathy (MHE), but it takes at least 30 min for outpatients to complete. An easier primary screening tool of the NP test would be helpful to predict MHE in routine testing on the public. METHODS: We performed a prospective cohort study on 59 cirrhotic outpatients at Kobe University Hospital. Laboratory measurements, the NP test and the Chronic Liver Disease Questionnaire (CLDQ) were performed. As an indicator of MHE, cases with and without two abnormal subsets or more in the NP test were compared, and the independent risk factors were statistically examined. Predictive scoring systems of the risk of MHE were established using multivariate logistic regression. RESULTS: CLDQ worry (WO) was the best predictive factor of MHE diagnosed by the NP test (P = 0.006). The predictive model using CLDQ WO discriminated well between patients with and without MHE (area under the curve, 0.714; 95% confidence interval, 0.582-0.824). The predictive scores of MHE enable the patient-specific probability to be easily looked up. CONCLUSION: CLDQ WO was shown to be an independent factor associated with the NP test to diagnose MHE in cirrhotic patients. The easy predictive scoring system of the risk of MHE using CLDQ WO could become a primary screening tool before performing the NP test in a social setting. PMID- 26234674 TI - Overexpression of miR-214-3p in esophageal squamous cancer cells enhances sensitivity to cisplatin by targeting survivin directly and indirectly through CUG-BP1. AB - Based on its marked overexpression in multiple malignancies and its roles in promoting cell survival and proliferation, survivin is an attractive candidate for targeted therapy. Toward this end, a detailed understanding of the mechanisms regulating survivin expression in different cancer cells will be critical. We have previously shown that the RNA-binding protein (RBP) CUG-BP1 is overexpressed in esophageal cancer cells and post-transcriptionally regulates survivin in these cells. The objective of this study was to investigate the role of microRNAs (miRs) in regulating survivin expression in esophageal cancer cells. Using miR expression profiling analysis, we found that miR-214-3p is one of the most markedly downregulated miRs in two esophageal squamous cancer cell lines compared with esophageal epithelial cells. Interestingly, using miR target prediction programs, both survivin and CUG-BP1 mRNA were found to contain potential binding sites for miR-214-3p. Forced expression of miR-214-3p in esophageal cancer cells leads to a decrease in the mRNA and protein levels of both survivin and CUG-BP1. This effect is due to decreased mRNA stability of both targets. By contrast, silencing miR-214-3p in esophageal epithelial cells leads to an increase in both survivin and CUG-BP1 mRNA and protein. To determine whether the observed effect of miR-214-3p on survivin expression was direct, mediated through CUG-BP1, or both, binding studies utilizing biotin pull-down assays and heterologous luciferase reporter constructs were performed. These demonstrated that the mRNA of survivin and CUG-BP1 each contain two functional miR-214-3p-binding sites as confirmed by mutational analysis. Finally, forced expression of miR-214-3p enhances the sensitivity of esophageal cancer cells to cisplatin-induced apoptosis. This effect is abrogated with rescue expression of survivin or CUG BP1. These findings suggest that miR-214-3p acts as a tumor suppressor and that its downregulation contributes to chemoresistance in esophageal cancer cells by targeting both survivin and CUG-BP1. PMID- 26234675 TI - JAK2V617F mediates resistance to DNA damage-induced apoptosis by modulating FOXO3A localization and Bcl-xL deamidation. AB - The JAK2V617F mutation is found in most patients with a myeloproliferative neoplasm (MPN). This gain-of-function mutation dysregulates cytokine signaling and is associated with increased accumulation of DNA damage, a process likely to drive disease evolution. JAK2V617F inhibits NHE-1 upregulation in response to DNA damage and consequently represses Bcl-xL deamidation and apoptosis, thus giving rise to inappropriate cell survival. However, the mechanism whereby NHE-1 expression is inhibited by JAK2V617F is unknown. In this study, we demonstrate that the accumulation of reactive oxygen species (ROS) in cells expressing JAK2V617F compromises the NHE-1/Bcl-xL deamidation pathway by repressing NHE-1 upregulation in response to DNA damage. In JAK2V617F-positive cells, increased ROS levels results from aberrant PI3K signaling, which decreases nuclear localization of FOXO3A and decreases catalase expression. Furthermore, when compared with autologous control erythroblasts, clonally derived JAK2V617F positive erythroblasts from MPN patients displayed increased ROS levels and reduced nuclear FOXO3A. However, in hematopoietic stem cells (HSCs), FOXO3A is largely localized within the nuclei despite the presence of JAK2V617F mutation, suggesting that JAK2-FOXO signaling has a different effect on progenitors compared with stem cells. Inactivation of FOXO proteins and elevation of intracellular ROS are characteristics common to many cancers, and hence these findings are likely to be of relevance beyond the MPN field. PMID- 26234676 TI - TRM6/61 connects PKCalpha with translational control through tRNAi(Met) stabilization: impact on tumorigenesis. AB - Accumulating evidence suggests that changes of the protein synthesis machinery alter translation of specific mRNAs and participate in malignant transformation. Here we show that protein kinase C alpha (PKCalpha) interacts with TRM61, the catalytic subunit of the TRM6/61 tRNA methyltransferase. The TRM6/61 complex is known to methylate the adenosine 58 of the initiator methionine tRNA (tRNAi(Met)), a nuclear post-transcriptional modification associated with the stabilization of this crucial component of the translation-initiation process. Depletion of TRM6/61 reduced proliferation and increased death of C6 glioma cells, effects that can be partially rescued by overexpression of tRNAi(Met). In contrast, elevated TRM6/61 expression regulated the translation of a subset of mRNAs encoding proteins involved in the tumorigenic process and increased the ability of C6 cells to form colonies in soft agar or spheres when grown in suspension. In TRM6/61/tRNAi(Met)-overexpressing cells, PKCalpha overexpression decreased tRNAi(Met) expression and both colony- and sphere-forming potentials. A concomitant increase in TRM6/TRM61 mRNA and tRNAi(Met) expression with decreased expression of PKCalpha mRNA was detected in highly aggressive glioblastoma multiforme as compared with Grade II/III glioblastomas, highlighting the clinical relevance of our findings. Altogether, we suggest that PKCalpha tightly controls TRM6/61 activity to prevent translation deregulation that would favor neoplastic development. PMID- 26234677 TI - RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression. AB - RNF126 is an E3 ubiquitin ligase. The deletion of RNF126 gene was observed in a wide range of human cancers and is correlated with improved disease-free and overall survival. These data highlight the clinical relevance of RNF126 in tumorigenesis and cancer therapy. However, the specific functions of RNF126 remain largely unknown. Homologous recombination (HR)-mediated DNA double-strand break repair is important for tumor suppression and cancer therapy resistance. Here, we demonstrate that RNF126 facilitates HR by promoting the expression of BRCA1, in a manner independent of its E3 ligase activity but depending on E2F1, a well-known transcription factor of BRCA1 promoter. In support of this result, RNF126 promotes transactivation of BRCA1 promoter by directly binding to E2F1. Most importantly, an RNF126 mutant lacking 11 amino acids that is responsible for the interaction with E2F1 has a dominant-negative effect on BRCA1 expression and HR by suppressing E2F1-mediated transactivation of BRCA1 promoter and blocking the enrichment of E2F1 on BRCA1 promoter. Lastly, RNF126 depletion leads to the increased sensitivity to ionizing radiation and poly (ADP-ribose) polymerase inhibition. Collectively, our results suggest a novel role of RNF126 in promoting HR-mediated repair through positive regulation on BRCA1 expression by direct interaction with E2F1. This study not only offers novel insights into our current understanding of the biological functions of RNF126 but also provides a potential therapeutic target for cancer treatment. PMID- 26234678 TI - E3 ligase EDD1/UBR5 is utilized by the HPV E6 oncogene to destabilize tumor suppressor TIP60. AB - Tat-interacting protein of 60 kDa (TIP60) is an essential lysine acetyltransferase implicated in transcription, DNA damage response and apoptosis. TIP60 protein expression is reduced in cancers. In cervical cancers, human papillomavirus (HPV) E6 oncogene targets cellular p53, Bak and some of the PDZ domain-containing proteins for proteasome-mediated degradation through E6AP ligase. Recently, E6 oncogene from high-risk and low-risk categories was also shown to target TIP60. However, the molecular mechanisms and whether destabilization of TIP60 contributes to HPV E6-mediated transformation remain unanswered. Our proteomic analyses revealed EDD1 (E3 identified by differential display), an E3 ligase generally overexpressed in cancers as a novel interacting partner of TIP60. By investigating protein turnover and ubiquitination assays, we show that EDD1 negatively regulates TIP60's stability through the proteasome pathway. Strikingly, HPV E6 uses this function of EDD1 to destabilize TIP60. Colony-formation assays and soft agar assays show that gain of function of TIP60 or depletion of EDD1 in HPV-positive cervical cancer cells significantly inhibits cell growth in vitro. This phenotype is strongly supported by the in-vivo studies where re-activation of TIP60 in cervical cancer cells dramatically reduces tumor formation. In summary, we have discovered a novel ligase through which E6 destabilizes TIP60. Currently, in the absence of an effective therapeutic vaccine for malignant cervical cancers, cervical cancer still remains to be a major disease burden. Hence, our studies implying a distinct tumor suppressor role for TIP60 in cervical cancers show that reactivation of TIP60 could be of therapeutic value. PMID- 26234679 TI - Functional features of EVI1 and EVI1Delta324 isoforms of MECOM gene in genome wide transcription regulation and oncogenicity. AB - The MDS1 and ecotropic viral integration site 1 (EVI1) complex locus (MECOM) gene encodes several transcription factor variants including MDS1-EVI1, EVI1 and EVI1Delta324. Although MDS1-EVI1 has been associated with tumor-suppressing activity, EVI1 is a known oncogene in various cancers, whose expression is associated with poor patient survival. Although EVI1Delta324 is co-transcribed with EVI1, its activity in cancer cells is not fully understood. Previous reports described that unlike EVI1, EVI1Delta324 protein cannot transform fibroblasts because of its disrupted N-terminal zinc finger (ZNF) domain. To better understand EVI1Delta324 biology and function, we obtained genome-wide binding occupancies and expression data in ovarian cancer cells. We characterized its DNA binding sites, binding motif and target genes. Comparative analyses with previous study show that EVI1 and EVI1Delta324 share similar transcriptional activities linked to their common C-terminus ZNF domain. They bind to an E-twenty-six family (ETS)-like motif, target to a large extent the same genes and cooperate with AP1 transcription factor. EVI1Delta324-occupied genes were 70.7% similar to EVI1 bound genes. More strikingly, EVI1 and EVI1Delta324 differentially expressed genes were 99.87% identical, indicating comparable transcriptional regulatory functions. Consistently with gene ontologies linked to these target genes, EVI1Delta324 expression in HeLa cells could enhance anchorage-independent growth, such as EVI1, showing that EVI1Delta324 expression also lead to pro-oncogenic effects. The main specific feature of EVI1 variant is its N-terminus ZNF domain that binds DNA through GATA-like motif. We found that most GATA-like EVI1 chromatin immunoprecipitation sequencing peaks are far from genes and are not involved in transcriptional regulation. These genomic regions were enriched in simple sequence repeats and displayed high meiotic recombination rates. Overall, our genomics analyses uncovered common and specific features of two major MECOM isoforms. Their influence on transcription and downstream cell proliferation was comparable. However, EVI1-specific GATA-like binding sites, from its N-terminus ZNF domain, associated with high recombination rates, suggesting possible additional oncogenic potential for EVI1 in modulating genomic stability. PMID- 26234680 TI - Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells. AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and incurable disease. Poor prognosis is due to multiple reasons, including acquisition of resistance to gemcitabine, the first-line chemotherapeutic approach. Thus, there is a strong need for novel therapies, targeting more directly the molecular aberrations of this disease. We found that chronic exposure of PDAC cells to gemcitabine selected a subpopulation of cells that are drug-resistant (DR-PDAC cells). Importantly, alternative splicing (AS) of the pyruvate kinase gene (PKM) was differentially modulated in DR-PDAC cells, resulting in promotion of the cancer related PKM2 isoform, whose high expression also correlated with shorter recurrence-free survival in PDAC patients. Switching PKM splicing by antisense oligonucleotides to favor the alternative PKM1 variant rescued sensitivity of DR PDAC cells to gemcitabine and cisplatin, suggesting that PKM2 expression is required to withstand drug-induced genotoxic stress. Mechanistically, upregulation of the polypyrimidine-tract binding protein (PTBP1), a key modulator of PKM splicing, correlated with PKM2 expression in DR-PDAC cell lines. PTBP1 was recruited more efficiently to PKM pre-mRNA in DR- than in parental PDAC cells. Accordingly, knockdown of PTBP1 in DR-PDAC cells reduced its recruitment to the PKM pre-mRNA, promoted splicing of the PKM1 variant and abolished drug resistance. Thus, chronic exposure to gemcitabine leads to upregulation of PTBP1 and modulation of PKM AS in PDAC cells, conferring resistance to the drug. These findings point to PKM2 and PTBP1 as new potential therapeutic targets to improve response of PDAC to chemotherapy. PMID- 26234681 TI - Myogenic transcription factors regulate pro-metastatic miR-182. AB - Approximately 30% of patients with soft-tissue sarcoma die from pulmonary metastases. The mechanisms that drive sarcoma metastasis are not well understood. Recently, we identified miR-182 as a driver of sarcoma metastasis in a primary mouse model of soft-tissue sarcoma. We also observed elevated miR-182 in a subset of primary human sarcomas that metastasized to the lungs. Here, we show that myogenic differentiation factors regulate miR-182 levels to contribute to metastasis in mouse models. We find that MyoD directly binds the miR-182 promoter to increase miR-182 expression. Furthermore, mechanistic studies revealed that Pax7 can promote sarcoma metastasis in vivo through MyoD-dependent regulation of pro-metastatic miR-182. Taken together, these results suggest that sarcoma metastasis can be partially controlled through Pax7/MyoD-dependent activation of miR-182 and provide insight into the role that myogenic transcription factors have in sarcoma progression. PMID- 26234683 TI - Resident Macrophages and Lymphocytes in the Canine Endometrium. AB - Resident immune cells play a major role in endometrial immunity and in tissue homoeostasis. This study aimed to analyse the distribution of macrophages, B and T lymphocytes (respectively, Mo, B-Lym and T-Lym) in the canine endometrium throughout the oestrous cycle and in late involution (at the proestrus stage post parturition). An immunohistochemistry technique was used on samples from 50 post pubertal healthy female dogs, of which five in late post-partum. The distribution of resident immune cells was analysed in three endometrial layers (superficial, intermediate and basal areas). Mo, B-Lym and T-Lym were demonstrated to reside in the endometrium in all the stages of the canine cycle; their numbers being considerably higher during late involution. T-Lym were scattered in the stroma or amidst the glandular epithelium, constituting the predominant immune cell population in anestrus and proestrus, but decreased in number at all other stages. Endometrial B-Lym remained fairly constant during the canine cycle, although its numbers were higher in late involution. Mo counts were higher during anestrus compared to the other stages, the cells being displaced into the superficial endometrial layer. Mo demonstrated the highest level in late involution samples, forming small aggregates below the surface epithelium. The number of immune cells was not normally distributed, suggesting the influence of individual factors, such as age or parity, not explored herein due to limited sample availability. Still, this study provides important information for the interpretation of endometrial biopsies in dogs and for the understanding of the increased susceptibility to uterine infection during dioestrus found in the bitch. PMID- 26234682 TI - The EGF receptor ligand amphiregulin controls cell division via FoxM1. AB - Epidermal growth factor receptor (EGFR) is central to epithelial cell physiology, and deregulated EGFR signaling has an important role in a variety of human carcinomas. Here we show that silencing of the EGF-related factor amphiregulin (AREG) markedly inhibits the expansion of human keratinocytes through mitotic failure and accumulation of cells with ? 4n DNA content. RNA-sequencing-based transcriptome analysis revealed that tetracycline-mediated AREG silencing significantly altered the expression of 2331 genes, 623 of which were not normalized by treatment with EGF. Interestingly, genes irreversibly upregulated by suppression of AREG overlapped with genes involved in keratinocyte differentiation. Moreover, a significant proportion of the irreversibly downregulated genes featured upstream binding sites recognized by forkhead box protein M1 (FoxM1), a key transcription factor in the control of mitosis that is widely dysregulated in cancer. The downregulation of FoxM1 and its target genes preceded mitotic arrest. Constitutive expression of FoxM1 in AREG knockdown cells normalized cell proliferation, reduced the number of cells with ? 4n DNA content and rescued expression of FoxM1 target genes. These results demonstrate that AREG controls G2/M progression and cytokinesis in keratinocytes via activation of a FoxM1-dependent transcriptional program, suggesting new avenues for treatment of epithelial cancer. PMID- 26234684 TI - Plasmids from the gut microbiome of cabbage root fly larvae encode SaxA that catalyses the conversion of the plant toxin 2-phenylethyl isothiocyanate. AB - Cabbage root fly larvae (Delia radicum) cause severe crop losses (>= 50%) of rapeseed/ canola and cabbages used in the food and biofuel industries. These losses occur despite the fact that cabbages produce insecticidal toxins such as isothiocyanates. Here we describe the cabbage root fly larval gut microbiome as a source of isothiocyanate degrading enzymes. We sequenced the microbial gut community of the larvae and analysed phylogenetic markers and functional genes. We combined this with the isolation of several microbial strains representing the phylogenetic distribution of the metagenome. Eleven of those isolates were highly resistant towards 2-phenylethyl isothiocyanate, a subset also metabolized 2 phenylethyl isothiocyanate. Several plasmids appeared to be shared between those isolates that metabolized the toxin. One of the plasmids harboured a saxA gene that upon transformation gave resistance and enabled the degradation of 2 phenylethyl isothiocyanate in Escherichia coli. Taken together, the results showed that the cabbage root fly larval gut microbiome is capable of isothiocyanate degradation, a characteristic that has not been observed before, and may help us understand and design new pest control strategies. PMID- 26234685 TI - [Preterm labor: Reproducibility of detection test of PAMG-1 before and after digital examination, and transvaginal ultrasound cervical length]. AB - OBJECTIVES: With current diagnostic resources, it is impossible to predict if a patient consulting in the obstetrics emergencies with symptoms of preterm labor, preterm delivery or not. A novel test for the detection of time to spontaneous preterm delivery was developed and would predict imminent delivery in 7 or 14 days from the time of testing. The diagnostic performances of detection test of PAMG-1 have been validated before digital examination. However digital examination is usually made in first line. The objective of this study was to assess the reproducibility of these diagnostic performances after digital examination and transvaginal ultrasound cervical length. METHODS: A prospective and observational study was conducted in a level 3 maternity (University Hospital of Saint-Etienne), from June 2013 to January 2014. Patients consulted in the obstetrics emergencies for threatened preterm birth between 24-34 weeks were enrolled with written and signed consent. Reproducibility of this test was assessed after digital examination, transvaginal ultrasound cervical length and a long time after all investigations. RESULTS: Forty-one patients were included in our study. Average gestational age was 29 weeks, digital examination was changed in 36 patients, whereas cervical length was less than 26mm for only 17 patients. In our study, 100% of tests results remain negative or positive after digital examination and 95,1% after transvaginal ultrasound. Our results confirmed this excellent specificity (97.5% [IC 95%; 86.8-99.9]) and negative predictive value (97.5% [IC 95%; 86.8-99.9]). CONCLUSION: This work allowed to demonstrate the reproducibility of detection test of PAMG-1 after a digital examination. An initial management with detection test of PAMG-1 could allow reducing the rate of unnecessary hospitalization. PMID- 26234686 TI - Improvement of digestive complaints in women with severe colorectal endometriosis benefiting from continuous amenorrhoea triggered by triptorelin. A prospective pilot study. AB - OBJECTIVE: To assess the impact of therapeutic amenorrhoea triggered by triptorelin in the digestive complaints of women with deep endometriosis infiltrating the rectum. DESIGN: Prospective series of consecutive patients with deep endometriosis of the rectum enrolled over a period of 17 consecutive months. SETTING: University tertiary referral center. PATIENTS: Seventy patients. INTERVENTIONS: Medical therapy (triptorelin 11.25 mg and add-back therapy using estradiol) administered for 3.4+/-1.8months before surgery. MAIN OUTCOME MEASURES: Gastrointestinal standardised questionnaires before beginning medical treatment and the day before surgery. RESULTS: The most frequent digestive complaints at baseline were: defecation pain in 77.1% of patients, bloating in 60%, diarrhoea in 54.3% and constipation in 50%. The largest diameter of the rectal area infiltrated by the disease was <1cm in 12.2% of women, 1 to 2.9 cm in 34.3% and >=3cm in 51.4%. Multiple colorectal nodules were found in 32.9%. Medical treatment led to disappearance of cyclic defecation pain in 78.6%, dyschesia in 58.3%, diarrhoea in 58.3% and bloating in 50%. Relieving digestive complaints was not significantly related to either length of triptorelin administration or size of rectal infiltration by deep endometriosis. CONCLUSION: Therapeutic amenorrhoea averaging 3 months allowed complete improvement of various cyclic digestive complaints in more than half of patients. In selected patients, continuous therapeutic amenorrhoea could compensate for the lack of complete resection of deep infiltrating endometriosis of the rectum, when this latter is likely to result in a high rate of postoperative morbidity. PMID- 26234687 TI - [How I perform...a rescue cervical cerclage]. PMID- 26234688 TI - Angiographic factors associated with haemorrhagic presentation of brain arteriovenous malformation in a Chinese paediatric population. AB - OBJECTIVE: To identify specific angiographic factors associated with haemorrhagic presentation of brain arteriovenous malformation in Chinese paediatric patients. DESIGN: Retrospective cross-sectional observational study. SETTING: Four locoregional tertiary neurosurgical centres in Hong Kong: Queen Elizabeth Hospital, Tuen Mun Hospital, Kwong Wah Hospital, and Pamela Youde Nethersole Eastern Hospital. PATIENTS: Patients aged 18 years or younger who underwent pretreatment digital subtraction angiography for brain arteriovenous malformation between 1 January 2005 and 31 July 2013 were included. Patients were divided into haemorrhagic and non-haemorrhagic groups based on the initial presentation. Pretreatment digital subtraction angiographies were independently reviewed by two experienced neuroradiologists. MAIN OUTCOME MEASURES: The following parameters were evaluated for their association with haemorrhagic presentation by univariate and multivariate analyses: nidus location, nidus size, nidus morphology (diffuse or compact); origin and number of arterial feeders; venous drainage; number of draining veins; presence of aneurysms, venous varices, and venous stenosis. RESULTS: A total of 67 children and adolescents (28 male, 39 female) with a mean age of 12 years were included. Of them, 52 (78%) presented with haemorrhage. Arteriovenous malformation size (P=0.004) and morphology (P=0.05) were found to be associated with haemorrhagic presentation by univariate analysis. Small arteriovenous malformation nidus size and diffuse nidal morphology were identified as independent risk factors for haemorrhage by multivariate analysis. CONCLUSION: Smaller arteriovenous malformation size and diffuse nidal morphology are angiographic factors independently associated with haemorrhagic presentation. Bleeding risk is important in determining the therapeutic approach (aggressive vs conservative) and timeframe, particularly in paediatric patients. PMID- 26234690 TI - A novel single walled carbon nanotube (SWCNT) functionalization agent facilitating in vivo combined chemo/thermo therapy. AB - Carbon nanotubes (CNTs) have shown intriguing applications in biotechnological and biomedical fields due to their unique shape and properties. However, the fact that unmodified CNTs are prone to aggregation, stunts CNTs applications under physiological conditions. In this research, we found that as little as 1/5th the single walled carbon nanotube (SWCNT) weight of Evans Blue (EB) is capable of dispersing SWCNT as well as facilitating SWCNT functionalization. In view of the binding between EB and albumin, the yielding product (SWCNT/EB) demonstrated extreme stability for weeks under physiological conditions and it can be endowed with a therapeutic ability by simply mixing SWCNT/EB with an albumin based drug. Specifically, the formed SWCNT/EB/albumin/PTX nanocomplex exhibits strong near infrared (NIR) absorbance, and can serve as an agent for chemo/thermal therapeutic purposes. Our in vivo result reveals that SWCNT/EB/albumin/PTX after being administered into the MDA-MB-435 tumor would effectively ablate the tumor by chemo and photothermal therapy. Such a combined treatment strategy provides remarkable therapeutic outcomes in restraining tumor growth compared to chemo or photothermal therapy alone. Overall, our strategy of dispersing SWCNTs by EB can be used as a platform for carrying other drugs or functional genes with the aid of albumin to treat diseases. The present study opens new opportunities in surface modification of SWCNTs for future clinical disease treatment. PMID- 26234689 TI - Paracetamol overdose in Hong Kong: is the 150-treatment line good enough to cover patients with paracetamol-induced liver injury? AB - OBJECTIVES: To evaluate the failure rate of the 150-treatment line for paracetamol overdose in Hong Kong, and the impact if the treatment threshold was lowered. SETTING: Public hospitals, Hong Kong. PATIENTS: All patients with acute paracetamol overdose reported to the Hong Kong Poison Information Centre from 1 January 2011 to 31 December 2013 were studied and analysed for the timed serum paracetamol concentration and their relationship to different treatment lines. Presence of significant liver injury following paracetamol overdose was documented. The potential financial burden of different treatment lines implemented locally was estimated. RESULTS: Of 893 patients, 187 (20.9%) had serum paracetamol concentration above the 150-treatment line, 112 (12.5%) had serum paracetamol concentration between the 100- and 150-treatment lines, and 594 (66.5%) had serum paracetamol level below the 100-treatment line. Of the 25 (2.8%) patients who developed significant liver injury, two were between the 100- and 150-treatment lines, and the other two were below the 100-treatment line. The failure rate of the 150-treatment line was 0.45%. Lowering the treatment threshold to the 100-treatment line might lower the failure rate of the treatment nomogram to 0.22% but approximately 37 more patients per year would need to be treated. It would incur an additional annual cost of HK$189 131 (US$24 248), and an additional 1.83 anaphylactoid reactions per year. The number needed-to-treat to potentially reduce one significant liver injury is 112. CONCLUSIONS: Lowering the treatment threshold of paracetamol overdose may reduce the treatment-line failure rate. Nonetheless such a decision must be balanced against the excess in treatment complications and health care resources. PMID- 26234691 TI - Mentoring health researchers globally: Diverse experiences, programmes, challenges and responses. AB - Mentoring experiences and programmes are becoming increasingly recognised as important by those engaged in capacity strengthening in global health research. Using a primarily qualitative study design, we studied three experiences of mentorship and eight mentorship programmes for early career global health researchers based in high-income and low- and middle-income countries. For the latter, we drew upon programme materials, existing unpublished data and more formal mixed-method evaluations, supplemented by individual email questionnaire responses. Research team members wrote stories, and the team assembled and analysed them for key themes. Across the diverse experiences and programmes, key emergent themes included: great mentors inspire others in an inter-generational cascade, mentorship is transformative in personal and professional development and involves reciprocity, and finding the right balance in mentoring relationships and programmes includes responding creatively to failure. Among the challenges encountered were: struggling for more level playing fields for new health researchers globally, changing mindsets in institutions that do not have a culture of mentorship and building collaboration not competition. Mentoring networks spanning institutions and countries using multiple virtual and face-to face methods are a potential avenue for fostering organisational cultures supporting quality mentorship in global health research. PMID- 26234692 TI - Reconstructing facial contour deformities using stereoscopic thoracodorsal artery perforator adipofascial flaps. AB - PURPOSE: Correcting facial contour deformities is a challenge, as it demands thoughtful planning on design, composition of flap, and secondary procedures. The thoracodorsal artery perforator (TDAP) flap has become a workhorse flap for various reconstructions. In this report, we present our experience of reconstructing facial contour deformities using the free TDAP adipofascial flap, focusing on its customized design. PATIENTS AND METHOD: Sixteen patients underwent correction of a facial contour deformity with free TDAP adipofascial flaps from 2002 to 2012. The causes of defects were Romberg disease (n = 7), oncological defects (n = 5), craniofacial microsomia (n = 3), and trauma (n = 1). The flaps were three-dimensionally designed in a contour map fashion to have different thickness according to the defects by adjusting the height of adipose tissue and varying tissue composition. Customized dimension of flaps having reliable perfusion were harvested with minimized sacrifice of overlying skin. RESULTS: Flap size ranged from 6 * 3 cm to 25 * 25 cm. Six flaps were based on two perforators and the other 10 on one. Five flaps were harvested in a chimeric fashion. All flaps survived completely. No donor morbidity developed in any case. Seven patients underwent secondary corrections including fat injection or liposuction. Improved contour and symmetry were achieved in all patients and was confirmed by a photographic evaluation. Mean follow-up period was 37.8months. CONCLUSIONS: Our results suggest that the stereoscopic TDAP adipofascial flaps with diligent secondary approaches may be a reliable alternative for aesthetic reconstruction of facial contour deformities. (c) 2015 Wiley Periodicals, Inc. Microsurgery 37:300-306, 2017. PMID- 26234693 TI - Agreement of site and central readings of ileocolonoscopic scores in Crohn's disease: comparison using data from the EXTEND trial. AB - BACKGROUND AND AIMS: Centralized endoscopic scoring may reduce variability, but evidence is lacking in patients with Crohn's disease. We assessed the agreement of endoscopic scorings between site endoscopists and one central reader by using data from the adalimumab Crohn's disease clinical trial EXTEND. METHODS: Agreement between readers for Crohn's Disease Endoscopic Index of Severity (CDEIS)-scored endoscopies from 6 sites and Simple Endoscopic Score for Crohn's Disease (SES-CD)-scored endoscopies from 19 sites in EXTEND was evaluated at baseline and weeks 12 and 52. Agreement on total scores was calculated by using intraclass correlation coefficient (ICC). Kappa statistic or Spearman correlation coefficient measured the agreement between readers for each ileocolonic segment on CDEIS variables including deep ulceration, surface involved, and ulcerated surface and SES-CD variables including ulcerated surface, size of ulcers, and affected surface. RESULTS: ICCs on mean scores at baseline and weeks 12 and 52 were 0.78, 0.92, and 0.86 (CDEIS), and 0.77, 0.86, and 0.82 (SES-CD), respectively. Site endoscopists consistently reported higher scores. High agreement was observed for most segments and all time points for CDEIS variables and SES-CD large ulcers. Weak agreement occurred for the right side of the colon at all time points for CDEIS deep ulceration and SES-CD large ulcers and at baseline and week 12 for CDEIS ulcerated surface. Fair/moderate agreement occurred for SES-CD ulcerated surface and moderate/high agreement for affected surface for all segments and time points. CONCLUSIONS: Site and central readers showed high agreement on total CDEIS and SES-CD scores overall, whereas variability for individual segments was observed. Weakest agreement occurred at baseline, with a greater difference for SES-CD than for CDEIS score. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00348283.). PMID- 26234694 TI - Significance of a white opaque substance under magnifying narrow-band imaging colonoscopy for the diagnosis of colorectal epithelial neoplasms. AB - BACKGROUND AND AIMS: The aim of this study was to examine the significance of a white opaque substance (WOS) found on magnifying narrow-band imaging (M-NBI) for the diagnosis of colorectal neoplastic lesions. METHODS: We retrospectively reviewed colonoscopy records from 2006 to 2012 at our institution and identified cases of endoscopically or surgically resected colorectal epithelial neoplasms observed by M-NBI colonoscopy. The colonoscopic and histologic characteristics of the lesions were compared between WOS-positive and WOS-negative lesions. We further classified the WOS as regular or irregular and compared the histologic characteristics between the two types of lesions. RESULTS: There were 105 WOS positive lesions and 451 WOS-negative lesions. The former were subdivided into lesions with regular and irregular WOS. The incidence of high-grade dysplasia or carcinoma was significantly higher in WOS-positive lesions (61.9%) than in WOS negative lesions (28.6%) (P < .05). Among the WOS-positive lesions, massive submucosal invasion was more frequent in lesions with irregular WOS (82.4%) than in those with regular WOS (1.4%) (P < .05). Among cancers with massive submucosal invasion, lymph node metastasis was more frequent in cancers with irregular WOS (17.4%) than in those with regular WOS or without the WOS (0%) (P < .05). CONCLUSIONS: A WOS in colorectal neoplasms may be an optical marker for high grade dysplasia and cancer. An irregular WOS may be indicative of massive submucosal invasion and lymph node metastasis. PMID- 26234695 TI - A new duodenal rendezvous technique for biliary cannulation in patients with T tube after orthotopic liver transplantation (with video). AB - BACKGROUND AND AIMS: Because a traditional rendezvous (RV) technique implies stretching of the papilla, possibly leading to post-ERCP pancreatitis, an alternative duodenal RV technique was evaluated. The aim was to assess the effectiveness, safety, and amount of time spent performing duodenal RV versus traditional RV cannulation in orthotopic liver transplantation patients with a T tube. METHODS: We retrospectively reviewed data from a prospective ERCP database held by our university hospital. Twenty patients with a T-tube who had undergone ERCP for biliary adverse events after orthotopic liver transplantation were included. The successful cannulation rate, the amount of time spent performing cannulation, the post-ERCP pancreatitis rate, and hyperamylasemia 24 hours after the procedure were recorded. RESULTS: Successful cannulation was achieved by the duodenal RV technique in 9 of 10 patients (90%), taking 146 seconds (interquartile range 63-341 seconds) with a short learning curve effect. An unsuccessful duodenal RV procedure occurred because of the angulation of the hydrophilic tip of the guidewire while crossing the papilla, thus preventing cannulation. Successful cannulation was achieved by the traditional RV technique in all cases (N = 11), including the failed duodenal RV technique, taking 374 seconds (interquartile range 320-410 seconds) (P < .05 vs duodenal RV). However, no post-ERCP pancreatitis occurred after using the duodenal RV technique compared with 2 episodes of mild pancreatitis after using the traditional RV technique. Twenty-four hours after the procedure, the median amylasemia level was 84 IU/L (interquartile range 49-105 IU/L) and 265 IU/L (interquartile range 73-2945 IU/L) for the duodenal versus traditional RV techniques, respectively (P = not significant). CONCLUSIONS: In patients with a T-tube after liver transplantation, the duodenal RV technique was not associated with post-ERCP pancreatitis, presumably because of the reduction of stress on the major papilla. Cannulation by using the duodenal RV technique was faster compared with the traditional RV technique. These preliminary data point out the use of the duodenal RV technique as the first option to choose in case of failed cannulation before attempting the traditional RV technique. PMID- 26234696 TI - Endoscopic submucosal dissection as minimally invasive treatment for superficial pharyngeal cancer: a phase II study (with video). AB - BACKGROUND AND AIMS: Although endoscopic submucosal dissection (ESD) has been applied for superficial pharyngeal cancer, no prospective trials have been reported. To investigate the efficacy and safety of ESD for superficial pharyngeal cancer, we conducted a prospective phase II trial. METHODS: Fifty-four patients with 73 lesions were enrolled from September 2010 to August 2014, and ESD was performed. The primary endpoint was the complete resection rate. Secondary endpoints were safety, recurrence-free survival, overall survival, and incidence of metachronous pharyngeal cancer. RESULTS: Fifty-four patients had stage 0-III cancer: stage 0, n = 22; stage I, n = 14; stage II, n = 17; and stage III, n = 1. The en bloc resection rate was 100%, and the complete resection rate was 79.5% (58/73 lesions; 95% confidence interval, 68%-88%). No serious adverse events related to ESD were encountered. Four patients required nasogastric intubation and feeding. No patients required percutaneous endoscopic gastrostomy and tracheotomy. Swallowing, speech, and airway functions were preserved in all patients. One of the 54 patients died of an unrelated illness. Median follow-up was 27 months (range 6-55 months). Local cervical lymph node metastasis was observed in 1 patient, and the case was salvaged successfully with lymph node dissection. The 3-year overall and recurrence-free survival rates were 97.7% and 98.1%, respectively. Cumulative development of multiple cancers of the pharynx at 3 years was 18.4%. CONCLUSIONS: ESD appears to be a safe and effective minimally invasive treatment in patients with superficial pharyngeal cancer. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000003623.). PMID- 26234697 TI - Balloon enteroscopy-assisted ERCP in patients with Roux-en-Y gastrectomy and intact papillae (with videos). AB - BACKGROUND AND AIMS: Balloon enteroscopy-assisted ERCP has provided a marked improvement in the success rate of reaching the papilla and consecutive ERCP procedures in patients with surgically altered anatomy in the Roux-en-Y reconstruction setting. However, limited data are available on the outcome of balloon enteroscopy-assisted ERCP in patients with Roux-en-Y anatomy who have naive papillae. We retrospectively evaluated the feasibility of balloon enteroscopy-assisted ERCP in Roux-en-Y reconstruction after total or subtotal gastrectomy (RYG) with native papillae. METHODS: We performed 123 ERCP procedures in 109 patients with RYG. Among these patients, 90 consecutive ERCPs in 90 patients with native papillae were included. When selective biliary cannulation failed, the double-guidewire technique, the precut technique, or the rendezvous technique were performed as advanced cannulation methods. RESULTS: The overall success rate of reaching the papilla was 93.5% (115/123). The total procedure success rate was 88.1% (96/109). The adverse event rate was 7.3% (8/109). The success rate of the standard cannulation of the intact papilla was 67.8% (61/90). The final cannulation success rate was 95.6% (86/90) by using advanced cannulation methods. CONCLUSIONS: Standard cannulation of the intact papilla in RYG cases remains challenging and uncertain. The use of various advanced cannulation methods improves the deep cannulation rate. Once selective cannulation succeeds, the treatment success rate is very high. PMID- 26234698 TI - Notes on the history of the Dr. Senckenbergische Anatomie in Frankfurt/Main. Part I. Development of student numbers, body procurement, and gross anatomy courses from 1914 to 2013. AB - Until recently, it was believed that all internal documentation regarding student affairs and body procurement of the Dr. Senckenbergische Anatomie concerning the time before March 1944 - when the building was destroyed during an Allied air raid - was lost. A few years ago, however, we discovered stacks of old documents in the current anatomy building. These documents permitted a reconstruction (1) of the history of body procurement, student numbers and course management from 1914 to 1944, as well as (2) some aspects of the building's history in the time immediately after its destruction that have hitherto not been documented. In this paper (Part I), we will deal with the organizational history of the Dr. Senckenbergische Anatomie from 1914 to 2013, placing special emphasis on the development of the student population and body procurement, as well as on the major changes that occurred in the gross anatomy labs of the last century. More than 30,000 students were trained in the Dr. Senckenbergische Anatomie over the last 100 years, and more than 3000 bodies have been received. The number of incoming bodies has remained quite stable in all these years and is, on average, approximately 32 per year. The number of students entering the gross anatomy lab during that period, however, rose from less than 100 to more than 600. A companion paper (Part II) deals with the years of the Third Reich (1933-1945) in more detail. PMID- 26234699 TI - Carbazole-functionalized polyphenylene-decorated solid state emissive D-A-D molecules: reduced donor-acceptor interaction and enhanced emission in the solid state. AB - A new series of D-A-D molecules (1-3) with carbazole as a donor and 2,5-diaryl 1,3,4-oxadiazole, dibenzothiophene-S,S-dioxide and benzo[1,2,5]thiadiazole as acceptors have been synthesized. Polyphenylene dendrons have also been incorporated to prevent the face to face pi-pi stacking in aggregates. Unlike traditional D-A systems, which show ACQ problems and large red shifts in the solid state, these derivatives (1-3) exhibit good solid state luminescence behavior without undergoing a red shift or fluorescence quenching. The present results indicate that just the combination of a donor-acceptor system with bulkier dendrons is not enough to generate efficient solid state emissions but the prevention of co-facial interaction between donors and acceptors in aggregates is more important. In the case of derivative 3, restriction of complete molecular planarization and steric hindrance near the acceptor can effectively prevent intermolecular donor-acceptor interactions, thus leading to enhanced emission in aggregates. While in the case of derivative 1, a sterically unhindered acceptor is easily approached by a donor due to close molecular packing in aggregates forming weakly luminescent species. PMID- 26234700 TI - Supramolecular oligothiophene microfibers spontaneously assembled on surfaces or coassembled with proteins inside live cells. AB - During the last few decades, multifunctional nano- and microfibers made of semiconducting pi-conjugated oligomers and polymers have generated much interest because of a broad range of applications extending from sensing to bioelectronic devices and (opto)electronics. The simplest technique for the fabrication of these anisotropic supramolecular structures is to let the molecules do the work by spontaneous organization driven by the information encoded in their molecular structure. Oligothiophenes-semiconducting and fluorescent compounds that have been extensively investigated for applications in thin-film field-effect transistors and solar cells and to a lesser extent as dyes for fluorescent labeling of proteins, DNA, and live cells-are particularly suited as building blocks for supramolecular architectures because of the peculiar properties of the thiophene ring. Because of the great polarizability of sulfur outer-shell electrons and the consequent facile geometric deformability and adaptability of the ring to the environment, thiophene can generate multiple nonbonding interactions to promote non-covalent connections between blocks. Furthermore, sulfur can be hypervalent, i.e., it can accommodate more than the eight electrons normally associated with s and p shells. Hypervalent oligothiophene-S,S-dioxides whose oxygen atoms can be involved in hydrogen bonding have been synthesized. These compounds are amphiphilic, and some of them are able to spontaneously cross the membrane of live cells. Hypervalent nonbonding interactions of divalent sulfur, defined as weak coordination to a proximate nitrogen or oxygen, have also been invoked in the solid-state packing of many organic molecules and in the architecture of proteins. In this Account, we describe two different types of thiophene-based building blocks that can induce the spontaneous formation of nanostructured microfibers in very different environments. The first, based on the synthesis of "sulfur-overrich" hexamers and octamers, leads to surface independent self-assembly of microfibers-helical or rodlike depending on the groups attached to the same identical inner core-that are crystalline, fluorescent, and conductive and display chirality despite the lack of chiral carbon atoms on the building blocks. Supramolecular polymorphic microfibers are also formed, and they are characterized by very different functional properties. The second, based on a rigid oligothiophene-S,S-dioxide, leads to coassembled protein-oligothiophene microfibers that are physiologically formed inside live cells. The oligothiophene-S,S-dioxide can indeed spontaneously cross the membrane of live cells and be directed toward the perinuclear region, where it is recognized and incorporated by specific peptides during the formation of fibrillar proteins without being harmful to the cells. Coassembled oligothiophene protein microfibers are progressively formed through a cell-mediated physiological process. Thanks to the oligothiophene blocks, the microfibers possess fluorescence and charge-conduction properties. By means of fluorescence imaging, we demonstrated that various types of live cells seeded on these microfibers were able to internalize and degrade them, experiencing in turn different effects on their morphology and viability, suggesting a possible use of the microfibers as multiscale biomaterials to direct cell behavior. On the whole, our results show the great versatility of oligothiophene building blocks and allow us to foresee that their capabilities of spontaneous assembly in the most different environments could be exploited in much more exciting research fields than those explored to date. PMID- 26234702 TI - Functional and clinical insights from neuroimaging studies in childhood-onset schizophrenia. AB - Childhood-onset schizophrenia is a rare pediatric onset psychiatric disorder continuous with and typically more severe than its adult counterpart. Neuroimaging research conducted on this population has revealed similarly severe neural abnormalities. When taken as a whole, neuroimaging research in this population shows generally decreased cortical gray matter coupled with white matter connectivity abnormalities, suggesting an anatomical basis for deficits in executive function. Subcortical abnormalities are pronounced in limbic structures, where volumetric deficits are likely related to social skill deficits, and cerebellar deficits that have been correlated to cognitive abnormalities. Structures relevant to motor processing also show a significant alteration, with volumetric increase in basal ganglia structures likely due to antipsychotic administration. Neuroimaging of this disorder shows an important clinical image of exaggerated cortical loss, altered white matter connectivity, and differences in structural development of subcortical areas during the course of development and provides important background to the disease state. PMID- 26234704 TI - A cocatalyst-free Eosin Y-sensitized p-type of Co3O4 quantum dot for highly efficient and stable visible-light-driven water reduction and hydrogen production. AB - Owing to the effect of energy band bending, p-type Co3O4 quantum dots sensitized by Eosin Y showed a high and stable photocatalytic activity (~13,440 MUmol h(-1) g(-1)(cat)) for water reduction and hydrogen production under visible-light irradiation without any cocatalyst. PMID- 26234705 TI - Hepatocyte growth factor-expressing adenovirus upregulates matrix metalloproteinase-1 expression in keloid fibroblasts. AB - BACKGROUND: Keloids are marked by an overabundance of extracellular matrix. The antifibrotic effect of hepatocyte growth factor (HGF) is achieved by increasing the expression of matrix metalloproteinases (MMPs) that drive extracellular matrix catabolism. As such, we cultivated an RGD-modified HGF-expressing adenovirus (dE1-RGD/lacZ/HGF) for introduction into keloid fibroblasts (KFs), looking at the subsequent impact on MMP-1 expression. METHODS: KFs infected with either test virus as experimental group (dE1-RGD/lacZ/HGF) or its counterpart (dE1-RGD/lacZ) as control group were examined for HGF protein expression using an enzyme-linked immunosorbent assay (ELISA). Collagen (types I and III) and MMP-1 mRNA levels were also determined by reverse transcriptase-polymerase chain reaction, and ELISA was used to monitor MMP-1 protein expression. RESULTS: In KFs harboring the test virus, high levels of HGF were induced at a multiplicity of infection ratio of 50 (3260.6 +/- 162.7 pg/ml) after 72 hours of incubation. Furthermore, reverse transcriptase-polymerase chain reaction and ELISA confirmed that MMP-1 mRNA and protein expression rose significantly in KFs after transduction by the test virus (P < 0.05). However, mRNA levels of collagen were unaffected by the experimental group. CONCLUSION: These results suggest that an HGF-expressing adenovirus may be therapeutic for keloids by increasing MMP-1 expression. PMID- 26234701 TI - Neuroimaging endophenotypes in autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder that has a strong genetic basis, and is heterogeneous in its etiopathogenesis and clinical presentation. Neuroimaging studies, in concert with neuropathological and clinical research, have been instrumental in delineating trajectories of development in children with ASD. Structural neuroimaging has revealed ASD to be a disorder with general and regional brain enlargement, especially in the frontotemporal cortices, while functional neuroimaging studies have highlighted diminished connectivity, especially between frontal-posterior regions. The diverse and specific neuroimaging findings may represent potential neuroendophenotypes, and may offer opportunities to further understand the etiopathogenesis of ASD, predict treatment response, and lead to the development of new therapies. PMID- 26234706 TI - The Arabidopsis vacuolar sugar transporter SWEET2 limits carbon sequestration from roots and restricts Pythium infection. AB - Plant roots secrete a significant portion of their assimilated carbon into the rhizosphere. The putative sugar transporter SWEET2 is highly expressed in Arabidopsis roots. Expression patterns of SWEET2-beta-glucuronidase fusions confirmed that SWEET2 accumulates highly in root cells and thus may contribute to sugar secretion, specifically from epidermal cells of the root apex. SWEET2-green fluorescent protein fusions localized to the tonoplast, which engulfs the major sugar storage compartment. Functional analysis of SWEET2 activity in yeast showed low uptake activity for the glucose analog 2-deoxyglucose, consistent with a role in the transport of glucose across the tonoplast. Loss-of-function sweet2 mutants showed reduced tolerance to excess glucose, lower glucose accumulation in leaves, and 15-25% higher glucose-derived carbon efflux from roots, suggesting that SWEET2 has a role in preventing the loss of sugar from root tissue. SWEET2 root expression was induced more than 10-fold during Pythium infection. Importantly, sweet2 mutants were more susceptible to the oomycete, showing impaired growth after infection. We propose that root-expressed vacuolar SWEET2 modulates sugar secretion, possibly by reducing the availability of glucose sequestered in the vacuole, thereby limiting carbon loss to the rhizosphere. Moreover, the reduced availability of sugar in the rhizosphere due to SWEET2 activity contributes to resistance to Pythium. PMID- 26234707 TI - Drug metabolism and pharmacokinetic diversity of ranunculaceae medicinal compounds. AB - The wide-reaching distributed angiosperm family Ranunculaceae has approximately 2200 species in around 60 genera. Chemical components of this family include several representative groups: benzylisoquinoline alkaloid (BIA), ranunculin, triterpenoid saponin and diterpene alkaloid, etc. Their extensive clinical utility has been validated by traditional uses of thousands of years and current evidence-based medicine studies. Drug metabolism and pharmacokinetic (DMPK) studies of plant-based natural products are an indispensable part of comprehensive medicinal plant exploration, which could facilitate conservation and sustainable utilization of Ranunculaceae pharmaceutical resources, as well as new chemical entity development with improved DMPK parameters. However, DMPK characteristics of Ranunculaceaederived medicinal compounds have not been summarized. Black cohosh (Cimicifuga) and goldenseal (Hydrastis) raise concerns of herbdrug interaction. DMPK studies of other Ranunculaceae genera, e.g., Nigella, Delphinium, Aconitum, Trollius, and Coptis, are also rapidly increasing and becoming more and more clinically relevant. In this contribution, we highlight the up-to-date awareness, as well as the challenges around the DMPK related issues in optimization of drug development and clinical practice of Ranunculaceae compounds. Herb-herb interaction of Ranunculaceae herb-containing traditional Chinese medicine (TCM) formula could significantly influence the in vivo pharmacokinetic behavior of compounds thereof, which may partially explain the complicated therapeutic mechanism of TCM formula. Although progress has been made on revealing the absorption, distribution, metabolism, excretion and toxicity (ADME/T) of Ranunculaceae compounds, there is a lack of DMPK studies of traditional medicinal genera Aquilegia, Thalictrum and Clematis. Fluorescent probe compounds could be promising substrate, inhibitor and/or inducer in future DMPK studies of Ranunculaceae compounds. A better understanding of the important herb-drug/herb-herb interactions, bioavailability and metabolomics aspects of Ranunculaceae compounds will bolster future natural product-based drug design and the comprehensive investigation of inter-individual inconsistency of drug metabolism. PMID- 26234708 TI - Molecular Scanning of beta-Thalassemia in the Southern Region of Central Java, Indonesia; a Step Towards a Local Prevention Program. AB - Thalassemia is the most prevalent genetic blood disorder worldwide, and particularly prevalent in Indonesia. The purpose of this study was to determine the spectrum of beta-thalassemia (beta-thal) mutations found in the southern region of Central Java, Indonesia. The subjects of the study included 209 beta thal Javanese patients from Banyumas Residency, a southwest region of Central Java Province. DNA analysis was performed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), amplification refractory mutation system (ARMS), and the direct sequencing method. The results showed that 14 alleles were found in the following order: IVS-I-5 (G > C) (HBB: c.92 + 5G > C) 43.5%, codon 26 (Hb E; HBB: c.79G > A) 28.2%, IVS-I-1 (G > A) (HBB: c.92 + 1G > A) 5.0%, codon 15 (TGG > TAG) (HBB: c.47G > A) 3.8%, IVS-I-1 (G > T) (HBB: c.92 + 1G > T) 3.1%, codon 35 (-C) (HBB: c.110delC) 2.4%. The rest, including codons 41/42 (-TTCT) (HBB: c.126_129delCTTT), codons 8/9 (+G) (HBB: c.27_28insG), codon 19 (AAC > AGC) (HBB: c.59A > G), codon 17 (AAG > TAG) (HBB: c.52A > T), IVS-I-2 (T > C) (HBB: c.92 + 2T > C), codons 123/124/125 (-ACCCCACC) (HBB: c.370_378delACCCCACCA), codon 40 (-G) (HBB: c.123delG) and Cap +1 (A > C) (HBB: c.-50A > C), accounted for up to 1.0% each. The most prevalent alleles would be recommended to be used as part of beta-thal screening for the Javanese, one of the major ethnic groups in the country. PMID- 26234709 TI - The mathematics of a quantum Hamiltonian computing half adder Boolean logic gate. AB - The mathematics behind the quantum Hamiltonian computing (QHC) approach of designing Boolean logic gates with a quantum system are given. Using the quantum eigenvalue repulsion effect, the QHC AND, NAND, OR, NOR, XOR, and NXOR Hamiltonian Boolean matrices are constructed. This is applied to the construction of a QHC half adder Hamiltonian matrix requiring only six quantum states to fullfil a half Boolean logical truth table. The QHC design rules open a nano architectronic way of constructing Boolean logic gates inside a single molecule or atom by atom at the surface of a passivated semi-conductor. PMID- 26234710 TI - Tamoxifen persistently disrupts the humoral adaptive immune response of gilthead seabream (Sparus aurata L.). AB - There is increasing concern about the possible effect of pharmaceutical compounds may have on the fish immune system. Bath exposition of 17alpha-ethynylestradiol (EE2), a synthetic estrogen used in oral contraceptives, altered the immune response of the gilthead seabream (Sparus aurata L.), a marine hermaphrodite teleost. Tamoxifen (Tmx) is a selective estrogen-receptor modulator used in hormone replacement therapy, the effects of which are unknown in fish immunity. This study aims to investigate the effects of dietary administration of EE2 (5 MUg/g food) and Tmx (100 MUg/g food) on the immune response of gilthead seabream, and the capacity of the immune system to recover its functionality after a recovery period. The results show for the first time the reversibility of the effect of EE2 and Tmx on the fish immune response. Tmx promoted a transient alteration in hepatic vitellogenin gene expression of a different magnitude to that produced by EE2. Both, EE2 and Tmx inhibited the induction of interleukin 1beta gene expression while reversed the inhibition of ROI production in leukocytes following vaccination. However, none of these effects were observed after ceasing EE2 and Tmx exposure. EE2 and Tmx stimulated the antibody response of vaccinated fish although Tmx, but not EE2, altered the antibody response and modulated the percentage of IgM(+) B lymphocytes of vaccinated fish during the recovery phase. Taken together, our results suggest that EE2 and Tmx might alter the capacity of fish to appropriately respond to infection and show that Tmx has a long-lasting effect on humoral adaptive immunity. PMID- 26234711 TI - The capacity of mid-pregnancy cervical length to predict preterm birth in low risk women: a national cohort study. AB - INTRODUCTION: We investigated the predictive capacity of mid-trimester cervical length (CL) measurement for spontaneous and iatrogenic preterm birth. MATERIAL AND METHODS: We performed a prospective observational cohort study in nulliparous women and low-risk multiparous women with a singleton pregnancy between 16(+0) and 21(+6) weeks of gestation. We assessed the prognostic capacity of transvaginally measured mid-trimester CL for spontaneous and iatrogenic preterm birth (<37 weeks) using likelihood ratios (LR) and receiver-operating characteristic analysis. We calculated numbers needed to screen to prevent one preterm birth assuming different treatment effects. Main outcome measures were preterm birth <32, <34 and <37 weeks. RESULTS: We studied 11,943 women, of whom 666 (5.6%) delivered preterm: 464 (3.9%) spontaneous and 202 (1.7%) iatrogenic. Mean CL was 44.1 mm (SD 7.8 mm). In nulliparous women, the LRs for spontaneous preterm birth varied between 27 (95% CI 7.7-95) for a CL <= 20 mm, and 2.0 (95% CI 1.6-2.5) for a CL between 30 and 35 mm. For low-risk multiparous women, these LRs were 37 (95% CI 7.5-182) and 1.5 (95% CI 0.97-2.2), respectively. Using a cut off for CL <= 30 mm, 28 (6.0%) of 464 women with spontaneous preterm birth were identified. The number needed to screen to prevent one case of preterm birth was 618 in nulliparous women and 1417 for low-risk multiparous women (40% treatment effect, cut-off 30 mm). CONCLUSION: In women at low risk of preterm birth, CL predicts spontaneous preterm birth. However, its isolated use as a screening tool has limited value due to low sensitivity. PMID- 26234712 TI - A computer-designed scaffold for bone regeneration within cranial defect using human dental pulp stem cells. AB - A computer-designed, solvent-free scaffold offer several potential advantages such as ease of customized manufacture and in vivo safety. In this work, we firstly used a computer-designed, solvent-free scaffold and human dental pulp stem cells (hDPSCs) to regenerate neo-bone within cranial bone defects. The hDPSCs expressed mesenchymal stem cell markers and served as an abundant source of stem cells with a high proliferation rate. In addition, hDPSCs showed a phenotype of differentiated osteoblasts in the presence of osteogenic factors (OF). We used solid freeform fabrication (SFF) with biodegradable polyesters (MPEG-(PLLA-co-PGA-co-PCL) (PLGC)) to fabricate a computer-designed scaffold. The SFF technology gave quick and reproducible results. To assess bone tissue engineering in vivo, the computer-designed, circular PLGC scaffold was implanted into a full-thickness cranial bone defect and monitored by micro-computed tomography (CT) and histology of the in vivo tissue-engineered bone. Neo-bone formation of more than 50% in both micro-CT and histology tests was observed at only PLGC scaffold with hDPSCs/OF. Furthermore, the PLGC scaffold gradually degraded, as evidenced by the fluorescent-labeled PLGC scaffold, which provides information to tract biodegradation of implanted PLGC scaffold. In conclusion, we confirmed neo-bone formation within a cranial bone defect using hDPSCs and a computer-designed PLGC scaffold. PMID- 26234714 TI - Anticoagulation Reversal with Prothrombin Complex Concentrate in Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Intracerebral hemorrhage is a well-recognized complication of anticoagulation therapy. However, there are only a few reports that address the management of aneurysmal subarachnoid hemorrhage (aSAH) in anticoagulated patients. OBJECTIVE: We report on our experiences with the use of prothrombin complex concentrate (PCC) for rapid anticoagulation reversal in aSAH. METHODS: We retrospectively analyzed our institutional database of consecutive patients who received PCC between February 2006 and August 2014 (n > 1000). Data from all anticoagulated patients referred to our hospital for aSAH and those who received PCC were included in this analysis. Patient characteristics as well as treatment modalities were analyzed, with specific focus on results of laboratory examination, PCC administration and bleeding, and thromboembolic complications during the later course. RESULTS: In total, only 9 patients (< 1% of all aSAH patients treated at our institution during the study period) had been anticoagulated at admission. Median international normalized ratio (INR) of patients at admission was 2.31 (interquartile range [IQR] 1.83-2.97) and after median administration of 2500 IU (IQR 2000-3000 IU) PCC, median INR significantly decreased to 1.15 (IQR 1.07-1.19). Surgical and interventional procedures were initiated within a median of 3.9 h (IQR 1.7-9.3 h) after admission. No hemorrhagic or thromboembolic events occurred later in the course. A favorable outcome according to the Glasgow Outcome Scale (scores of 4 and 5) was achieved in 6 patients (67%). CONCLUSIONS: Aneurysmal SAH in anticoagulated patients is a rare condition. PCC is an effective option to rapidly reverse anticoagulation in aSAH and might facilitate achieving a favorable outcome in these patients. PMID- 26234715 TI - Intra-Abdominal Radiopacities after Arsenic Intoxication. PMID- 26234713 TI - Evidence for early and progressive ultrasonic vocalization and oromotor deficits in a PINK1 gene knockout rat model of Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disease that leads to a wide range of motor and nonmotor deficits. Specifically, voice and swallow deficits manifest early, are devastating to quality of life, and are difficult to treat with standard medical therapies. The pathological hallmarks of PD include accumulation of the presynaptic protein alpha-synuclein (alphaSyn) as well as degeneration of substantia nigra dopaminergic neurons. However, there is no clear understanding of how or when this pathology contributes to voice and swallow dysfunction in PD. The present study evaluates the effect of loss of function of the phosphatase and tensin homolog-induced putative kinase 1 gene in rats (PINK1( /-) ), a model of autosomal recessive PD in humans, on vocalization, oromotor and limb function, and neurodegenerative pathologies. Behavioral measures include ultrasonic vocalizations, tongue force, biting, and gross motor performance that are assayed at 2, 4, 6, and 8 months of age. Aggregated alphaSyn and tyrosine hydroxylase immunoreactivity (TH-ir) were measured at 8 months. We show that, compared with wild-type controls, PINK1(-/-) rats develop (1) early and progressive vocalization and oromotor deficits, (2) reduced TH-ir in the locus coeruleus that correlates with vocal loudness and tongue force, and (3) alphaSyn neuropathology in brain regions important for cranial sensorimotor control. This novel approach of characterizing a PINK1(-/-) genetic model of PD provides the foundational work required to define behavioral biomarkers for the development of disease-modifying therapeutics for PD patients. PMID- 26234716 TI - Emergency Physician Utilization of Alcohol/Substance Screening, Brief Advice and Discharge: A 10-Year Comparison. AB - BACKGROUND: In 2007, of the 130 million emergency department (ED) visits, ~ 38 million were due to injury, and of those, 1.9 million involved alcohol. The emergency department is a pivotal place to implement Screening, Brief Intervention, and Referral to Treatment (SBIRT) due to the high number of patients presenting with alcohol/substance abuse risk factors or related injuries. STUDY OBJECTIVE: This study compares two surveys, approximately 11 years apart, of emergency physicians nationwide which assesses the use of validated screening tools, the availability of community resources for alcohol/substance abuse treatment, and the prevailing attitudes of emergency physicians regarding Screening and Brief Intervention for alcohol/substance abuse. METHODS: We performed cross-sectional anonymous surveys of 1500 emergency physicians drawn from American College of Emergency Physicians members. The survey results were compared for time interval change. RESULTS: The two surveys had comparable response rates. The median percentage of patients screened for alcohol/substance abuse in 1999 was 15%, vs. 20% in 2010. In 2010, 26% of emergency physicians had a formal screening tool, and the majority used Cut-down, Annoyed, Guilty, Eye-opener (85%). In 2010, a statistically significant increase in the number of emergency physicians said they would "always" or "almost always" use discharge instructions that were specific for alcohol/substance abuse, if available, vs. 1999. CONCLUSION: Few emergency physicians screen for alcohol/substance abuse despite evidence that screening and brief intervention is effective. Emergency physicians are receptive to the use of discharge material. PMID- 26234717 TI - Resident Supervision and Patient Safety: Do Different Levels of Resident Supervision Affect the Rate of Morbidity and Mortality Cases? AB - BACKGROUND: In our academic emergency department, our senior residents lead their own patient care team, known as the red team (RT). Attending physicians are responsible for managing their own team (AT) and precepting the senior resident's cases. OBJECTIVE: We hypothesized that the RT would have the same number of morbidity and mortality (M&M) cases and similar numbers of adverse outcomes as the AT. We also hypothesized that there would be no increase in M&M cases during the first quarter of every academic year. METHODS: We obtained data from M&M cases from 2009-2013, including month and year of patient visit, standard of care code (SoCC), and whether the patient was seen by the RT or an AT. Data were analyzed using a chi(2) test comparing expected outcomes with observed outcomes. RESULTS: There was a total of 117 M&M cases during the study period with a SoCC >= 3; 76 cases were AT and 41 cases were RT. There was no statistically significant difference between expected and observed number of cases. Mean RT and AT SoCCs were 4.03 and 4.23, respectively. There was no statistically significant difference between the two groups for SoCC. Mean SoCC was not significantly different for the first quarter of the year. CONCLUSIONS: We found that our patient care model did not lead to an increased number of M&M cases and RT cases were not associated with worse outcomes overall. Additionally, there was no increased rate of M&M cases in the beginning of the academic year. PMID- 26234718 TI - Exploring the Nature of the Intention, Meaning and Perception Process of the Neuro-occupation Model to Understand Adaptation to Change. AB - The theoretical model of neuro-occupation, intention, meaning and perception, sought to describe the symbiotic relationship between occupation and the brain, as a chaotic, self-organized, complex system. Lack of evidence has limited its applicability to practice. The aim of this study was to track the postulates of the model within the daily experiences of subjects. Structured matrices were created for content analysis, using a qualitative multiple-case-study design, typically used for testing models. An underpinning principle of the model, defined a circular causality feedback process, which was confirmed as described through tracing the repetitive processes within the lived experience of two Iranian men. The process suggested that continual adaptation occurred in lives interrupted by cerebrovascular accident, which enabled the subjects to return to expression of meaning through purposeful occupation and continually re-shaped their perceptions. The primary limitation of this study was that it was the earliest attempt to test the model and to substantiate the process by comparing the similarities and differences between too few subjects. Future research should identify the same process in more subjects and validate a practical assessment tool for clients. These findings may inform practitioners about intentional use of occupational challenges to elicit adaptive behaviours in clients. PMID- 26234720 TI - BCRP and P-gp relay overexpression in triple negative basal-like breast cancer cell line: a prospective role in resistance to Olaparib. AB - The triple negative basal-like (TNBL) breast carcinoma is an aggressive and unfavorable prognosis disease. Inhibitors of poly(ADP-ribose) polymerase such as Olaparib could represent a promising targeted therapy but their sensitivity against Multidrug Resistance proteins (MDR), which causes resistance, is not well defined. Thus, our work focused on the analysis of P-gp and BCRP coexpression in the SUM1315 TNBL human cell line, in correlation with Olaparib intracellular concentration. Western blot analyses showed a clear coexpression of P-gp and BCRP in SUM1315 cells. A low cytotoxic Olaparib treatment clearly led to an increased expression of both BCRP and P-gp in these cells. Indeed, after 1.5 h of treatment, BCRP expression was increased with a 1.8 fold increase rate. Then, P gp took over from 3 h to 15 h with an average increase rate of 1.8 fold, and finally returned to control value at 24 h. HPLC-UV analyses showed that, in the same treatment conditions, the intracellular Olaparib concentration increased from 1 h to 3 h and remained relatively stable until 24 h. Results suggest that the resistance mechanism induced by Olaparib in TNBL SUM1315 cell line may be overpassed if a cytotoxic and stable intracellular level of the drug can be maintained. PMID- 26234721 TI - Use of Prosthetic Replacement of the Ocular Surface Ecosystem Scleral Lenses in Patients with Ocular Chronic Graft-versus-Host Disease. AB - The purpose of this study was to evaluate the impact of prosthetic replacement of the ocular surface ecosystem (BostonSight PROSE, Boston Foundation for Sight, Needham, MA) treatment, utilizing customized scleral devices, on visual acuity, visual function, and ocular surface changes in patients with ocular chronic graft versus-host disease (cGVHD). A retrospective analysis was performed on 79 eyes of 40 patients with cGVHD referred to the University of Southern California department of ophthalmology between November 2009 and July 2013 for PROSE treatment. This analysis included an assessment of ocular symptoms and visual function before and after treatment using the Ocular Surface Disease Index (OSDI) survey. Pre- and post-treatment visual acuity and clinical data were also compared. Twenty-eight male patients and 12 female patients were included in this study. The average age was 56.1 years (range, 27 to 74). Of the 79 eyes treated, 71 (90%) showed improved visual acuity with PROSE treatment. Fifty-seven eyes (72%) experienced a 2- or greater line visual acuity improvement and 14 eyes (18%) experienced a 1-line improvement. Average logarithm of the minimal angle of resolution improved from .49 +/- .52 to .16 +/- .44 (P < .0001), which correlates to a Snellen score improvement of approximately 20/60 to 20/30. Sixty-six of 79 eyes (84%) showed decreased corneal staining after treatment. All 9 eyes presenting with filamentary keratitis and 3 eyes with epithelial defects demonstrated complete healing of the epithelial surface after PROSE fitting. At post-treatment follow-up, 8 patients had died and 3 stopped wearing their devices. Of the remaining 29 patients, average OSDI scores improved from 72.6 +/- 20.1 to 21.1 +/- 14.9 (P < .0001). PROSE therapy, utilizing customized scleral lenses, can reduce ocular symptoms, improve visual acuity, and improve ocular surface integrity or appearance in patients with ocular cGVHD. PMID- 26234719 TI - Interaction of MIF Family Proteins in Myocardial Ischemia/Reperfusion Damage and Their Influence on Clinical Outcome of Cardiac Surgery Patients. AB - AIMS: Cardiac surgery involves myocardial ischemia/reperfusion (I/R) with potentially deleterious consequences. Macrophage migration inhibitory factor (MIF) is a stress-regulating chemokine-like cytokine that protects against I/R damage, but functional links with its homolog, d-dopachrome tautomerase (MIF-2), and the circulating soluble receptor CD74 (sCD74) are unknown. In this study, we investigate the role of MIF, MIF-2, sCD74, and MIF genotypes in patients scheduled for elective single or complex surgical procedures such as coronary artery bypass grafting or valve replacement. RESULTS: MIF and MIF-2 levels significantly increased intraoperatively, whereas measured sCD74 decreased correspondingly. Circulating sCD74/MIF complexes were detectable in 50% of patients and enhanced MIF antioxidant activity. Intraoperative MIF levels were independently associated with a reduced risk for the development of atrial fibrillation (AF) (odds ratio 0.99 [0.98-1.00]; p=0.007). Circulating levels of MIF-2, but not MIF, were associated with an increased frequency of organ dysfunction and predicted the occurrence of AF (area under the curve [AUC]=0.663; p=0.041) and pneumonia (AUC=0.708; p=0.040). Patients with a high-expression MIF genotype exhibited a reduced incidence of organ dysfunction compared with patients with low-expression MIF genotypes (3 vs. 25; p=0.042). INNOVATION: The current study comprehensively highlights the kinetics and clinical relevance of MIF family proteins and the MIF genotype in cardiac surgery patients. CONCLUSION: Our findings suggest that increased MIF levels during cardiac surgery feature organ-protective properties during myocardial I/R, while the soluble MIF receptor, sCD74, may enhance MIF antioxidant activity. In contrast, high MIF-2 levels are predictive of the development of organ dysfunction. Importantly, we provide first evidence for a gene-phenotype relationship between variant MIF alleles and clinical outcome in cardiac surgery patients. PMID- 26234722 TI - DNMT3A R882 Mutation with FLT3-ITD Positivity Is an Extremely Poor Prognostic Factor in Patients with Normal-Karyotype Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation. AB - The prognostic relevance of epigenetic modifying genes (DNMT3A, TET2, and IDH1/2) in patients with acute myeloid leukemia (AML) has been investigated extensively. However, the prognostic implications of these mutations after allogeneic hematopoietic cell transplantation (HCT) have not been evaluated comprehensively in patients with normal-karyotype (NK)-AML. A total of 115 patients who received allogeneic HCT for NK-AML were retrospectively evaluated for the FLT3-ITD, NPM1, CEBPA, DNMT3A, TET2, IDH1/2, WT1, NRAS, ASXL2, FAT1, DNAH11, and GATA2 mutations in diagnostic samples and analyzed for long-term outcomes after allogeneic HCT. The prevalence rates for the mutations were as follows: FLT3-ITD positivity (FLT3 ITD(pos)) (32.2%), NPM1 mutation (43.5%), CEBPA mutation (double) (24.6%), DNMT3A mutation (DNMT3A(mut)) (31.3%), DNMT3A R882(mut) (18.3%), TET2 mutation (8.7%), and IDH1/2 mutation (16.5%). The 5-year overall survival (OS) and event-free survival (EFS) rates were 57.3% and 58.1%, respectively. A multivariate analysis revealed that FLT3-ITD(pos) (hazard ratio, [HR], 2.23; P = .006) and DNMT3A R882(mut) (HR, 2.74; P = .002) were unfavorable prognostic factors for OS. In addition, both mutations were significant risk factors for EFS and relapse. People with DNMT3A R882(mut) accompanied by FLT3-ITD(pos) had worse OS and EFS, and higher relapse rates than those with the other mutations, which were confirmed in a propensity score 1:2 matching analysis. These results suggest that DNMT3A R882(mut), particularly when accompanied by FLT3-ITD(pos), is a significant prognostic factor for inferior transplantation survival outcome by increasing relapse risk, even after allogeneic HCT. PMID- 26234723 TI - Long-Term Morbidity and Mortality in Children with Chronic Graft-versus-Host Disease Classified by National Institutes of Health Consensus Criteria after Allogeneic Hematopoietic Stem Cell Transplantation. AB - We report the long-term morbidity and mortality of 105 pediatric patients who developed chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). According to the consensus criteria of the National Institutes of Health, the global severity of cGVHD was mild in 26 patients (25%), moderate in 30 patients (29%), and severe in 49 patients (47%). Patients with severe cGVHD had a significantly lower cumulative incidence of cGVHD remission and higher probability of continuing cGVHD at 8 years from cGVHD diagnosis compared with those with mild or moderate cGVHD. The 10-year cumulative incidence of nonrelapse mortality in severe cGVHD patients was significantly higher and the probability of disease-free survival was significantly lower than those among patients with mild and moderate cGVHD. Of the 59 patients who survived for more than 5 years, 20 (34%) (4 with moderate and 16 with severe cGVHD) had persistent functional impairment caused by cGVHD with a Karnofsky/Lansky performance score of 90% in 3 patients, 80% in 4 patients, and below 70% in 13 patients at the time of relapse, death, or last follow-up. Better therapeutic strategies are needed to lower the incidence of severe cGVHD, considering the longer life expectancy of pediatric HSCT survivors. PMID- 26234724 TI - Engagement: Looking beyond the mirror to understand action understanding. AB - In this paper, we argue that the current focus on mirroring as the route to explaining the development of action understanding is misleading and problematic. It facilitates a fundamentally spectatorial stance, ignoring engagement and dialogue; it focuses on similarity between self and other and neglects difference; and it succumbs to the static terminology of mechanism rather than a dynamic language of process. Contrary to this view, dialogic exchanges are evident from the start of life, revealing infants' ability to engage with and respond appropriately to actions that are outside their own motor repertoire. We suggest that engagement rather than mirroring better accounts for many current findings in action understanding. The neurological evidence to date shows that action perception involves a process of continuous synchronization and change, suggesting that it might be more fruitful for research and theory to look beyond mirroring and instead adopt dynamic processual explanations of action understanding within interaction. PMID- 26234725 TI - Cryptic laminar and columnar organization in the dorsolateral pallium of a weakly electric fish. AB - In the weakly electric gymnotiform fish, Apteronotus leptorhynchus, the dorsolateral pallium (DL) receives diencephalic inputs representing electrosensory input utilized for communication and navigation. Cell counts reveal that, similar to thalamocortical projections, many more cells are present in DL than in the diencephalic nucleus that provides it with sensory input. DL is implicated in learning and memory and considered homologous to medial and/or dorsal pallium. The gymnotiform DL has an apparently simple architecture with a random distribution of simple multipolar neurons. We used multiple neurotracer injections in order to study the microcircuitry of DL. Surprisingly, we demonstrated that the intrinsic connectivity of DL is highly organized. It consists of orthogonal laminar and vertical excitatory synaptic connections. The laminar synaptic connections are symmetric sparse, random, and drop off exponentially with distance; they parcellate DL into narrow (60 MUm) overlapping cryptic layers. At distances greater than 100 MUm, the laminar connections generate a strongly connected directed graph architecture within DL. The vertical connectivity suggests that DL is also organized into cryptic columns; these connections are highly asymmetric, with superficial DL cells preferentially projecting towards deeper cells. Our experimental analyses suggest that the overlapping cryptic columns have a width of 100 MUm, in agreement with the minimal distance for strong connectivity. The architecture of DL and the expansive representation of its input, taken together with the strong expression of N-methyl-D-aspartate (NMDA) receptors by its cells, are consistent with theoretical ideas concerning the cortical computations of pattern separation and memory storage via bump attractors. PMID- 26234726 TI - Magnetophoresis of superparamagnetic nanoparticles at low field gradient: hydrodynamic effect. AB - Convective current driven by momentum transfer between magnetic nanoparticles (MNPs) and their surrounding fluid during magnetophoresis process under a low gradient magnetic field (<100 T m(-1)) is presented. This magnetophoresis induced convective flow, which imposed direct hydrodynamic effects onto the separation kinetics of the MNPs under low gradient magnetic separation (LGMS), is analogous to the natural convection found in heat transportation. Herein, we show the significance of the induced convection in controlling the transport behavior of MNPs, even at a very low particle concentration of 5 mg L(-1), and this feature can be characterized by the newly defined magnetic Grashof number. By incorporating fluid flow equations into the existing magnetophoresis model, we reveal two unique features of this convective flow associated with low gradient magnetophoresis, namely, (1) the continuous homogenization of the MNPs solution and (2) accompanying sweeping flow that accelerates the collection of MNPs. According to both simulation and experimental data, the induced convection boosts the magnetophoretic capture of MNPs by approximately 30 times compared to the situation with no convection. PMID- 26234727 TI - Nonalcoholic fatty liver disease and statins. AB - OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of elevated transaminase levels and affects approximately one third of the general population. Patients with NAFLD are at increased risk for cardiovascular events, which represent the leading cause of death in this population. We discuss the safety and efficacy of statins in this population. MATERIALS/METHODS: We reviewed the most recent literature on the safety of statins in patients with NAFLD and on their effects on liver histology and cardiovascular events. RESULTS: It appears that statins can be safely administered to patients with NAFLD, including those with elevated transaminase levels (<3 times the upper limit of normal). Post-hoc analyses of randomized controlled trials also suggest that statins might reduce cardiovascular morbidity in this population. On the other hand, there are few and controversial data on the effects of statins on liver histology in patients with NAFLD. CONCLUSIONS: Statins appear to be safe and might also reduce cardiovascular events in patients with NAFLD. Ongoing and future studies will clarify whether statins might also have a role in the treatment of NAFLD. PMID- 26234728 TI - Supplementary heat-killed Lactobacillus reuteri GMNL-263 ameliorates hyperlipidaemic and cardiac apoptosis in high-fat diet-fed hamsters to maintain cardiovascular function. AB - Obesity and hyperlipidaemia increase the risk of CVD. Some strains of probiotics have been suggested to have potential applications in cardiovascular health by lowering serum LDL-cholesterol. In this work, high-fat diet-induced hyperlipidaemia in hamsters was treated with different doses (5*108 and 2.5*109 cells/kg per d) of heat-killed Lactobacillus reuteri GMNL-263 (Lr263) by oral gavage for 8 weeks. The serum lipid profile analysis showed that LDL-cholesterol and plasma malondialdehyde (P-MDA) were reduced in the GMNL-263 5*108 cells/kg per d treatment group. Total cholesterol and P-MDA were reduced in the GMNL-263 2.5*109 cells/kg per d treatment group. In terms of heart function, the GMNL-263 2.5*109 cells/kg per d treatments improved the ejection fraction from 85.71 to 91.81 % and fractional shortening from 46.93 to 57.92 % in the high-fat diet-fed hamster hearts. Moreover, the GMNL-263-treated, high-fat diet-fed hamster hearts exhibited reduced Fas-induced myocardial apoptosis and a reactivated IGF1R/PI3K/Akt cell survival pathway. Interestingly, the GMNL-263 treatments also enhanced the heat-shock protein 27 expression in a dose-dependent manner, but the mechanism for this increase remains unclear. In conclusion, supplementary heat killed L. reuteri GMNL-263 can slightly reduce serum cholesterol. The anti hyperlipidaemia effects of GMNL-263 may reactivate the IGF1R/PI3K/Akt cell survival pathway and reduce Fas-induced myocardial apoptosis in high-fat diet-fed hamster hearts. PMID- 26234729 TI - Bridging the gap: functional healing of embryonic small intestine ex vivo. AB - The ability to grow embryonic organs ex vivo provides an opportunity to follow their differentiation in a controlled environment, with resulting insights into normal development. Additionally, similar strategies can be used to assess effects on organogenesis of physical and chemical manipulations. This study aimed to create an organ culture model with which to test physical manipulations to enhance healing of gut segments, thus generating a single functional organ. Embryonic mouse jejunum was isolated and cut into 2-3 mm tubes, which were placed in pairs, separated by a small gap, on semi-permeable supports. Each pair was linked by a nylon suture threaded through their lumens. After 3 days in organ culture fed by defined serum-free media, the rudiments differentiated to form tubes of smooth muscle surrounding a core of rudimentary villi. Of 34 such pairs, 74% had touching and well aligned proximate ends. Of these joined structures, 80% (59% of the total pairs) had a continuous lumen, as assessed by observing the trajectories of fluorescent dextrans injected into their distal ends. Fused organ pairs formed a single functional unit, as assessed by spontaneous contraction waves propagated along their lengths. In these healed intestines, peripherin(+) neurons formed a nexus in the zone of fusion, linking the rudiment pairs. In future, this system could be used to test whether growth factors enhance fusion. Such results should in turn inform the design of novel treatments for short bowel syndrome, a potentially fatal condition with a currently limited and imperfect range of therapies. PMID- 26234730 TI - Clinicopathological characteristics of freezing of gait in autopsy-confirmed Parkinson's disease. AB - BACKGROUND: Twenty-five percent to sixty percent of Parkinson's disease (PD) patients reportedly have freezing of gait, leading to impaired mobility, falls, and decreased quality of life. Several factors have been associated with gait freezing in PD patients. We analyze for these factors in autopsy-proven PD patients. METHODS: We performed a chart review of 58 patients with pathologically confirmed PD based on substantia nigra Lewy bodies. Freezing of gait was defined as a score of 1 or more on Item 14 of the Unified Parkinson's Disease Rating Scale or if documented on examination. Serial office notes and scales were used to determine onset and progression of motor and non-motor symptoms. RESULTS: Patients had been followed up for an average of 20 visits over 9 y. The mean onset of gait freezing was 9.3 y from initial motor symptoms. Patients with earlier gait freezing more commonly had initial gait difficulties and developed postural instability, dyskinesias, memory impairment, hallucinations, and vivid dreams earlier during the disease course. Early onset of hallucinations was correlated with more rapid progression of gait freezing. Maximal equivalent levodopa dose was not correlated with earlier onset or progression of gait freezing. Progressive and more severe gait freezing trended toward higher severity Lewy body disease on postmortem examination. CONCLUSIONS: Early onset and rapid progression of freezing of gait in this cohort were correlated with early cognitive impairment and hallucinations that are potential clinical hallmarks of cortical Lewy bodies. The gradual worsening and severity of gait freezing correlated with the density of cortical Lewy body-containing neurons. PMID- 26234731 TI - Protective Effects of Catechin against Monosodium Urate-Induced Inflammation through the Modulation of NLRP3 Inflammasome Activation. AB - Gouty inflammation results from the stimulation of monosodium urate (MSU). Interleukin-1beta (IL-1beta) secretion is the primary clinical manifestation of MSU attack, and MSU activates IL-1beta through a nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome. This study investigated the protective effect and underlying mechanism of naturally occurring phenolic compounds on MSU-induced inflammation in vivo and in vitro. A screening of phenolic compounds revealed that gallic acid and catechin exhibited the most potent free radical scavenging activities. Subcutaneous injection of gallic acid or catechin significantly reduced MSU induced IL-1beta and IL-6 secretion in C57BL/6 mice. However, only catechin inhibited MSU-induced IL-1beta secretion and NLRP3 inflammasome activation in MSU challenged THP-1 cells. MSU-triggered mitochondrial reactive oxygen species (MtROS) production and intracellular calcium levels were significantly decreased by treatment with catechin in THP-1 cells. Catechin treatment also up-regulated Bcl-2 levels and restored MSU-induced mitochondrial transmembrane potential impairment. These results indicate that the protective effects of catechin on MSU induced IL-1beta secretion are associated with modulation of mitochondrial damage. It also suggests that catechin has the potential to protect gout attack by modulation of NLRP3 inflammasome activation. PMID- 26234733 TI - Medical mirroring: granulomatosis with polyangiitis (formerly Wegener's) mimicking immunoglobulin-G4 related disease. AB - Granulomatosis with polyangiitis (GPA; formerly Wegener's) can present with clinical and histopathological features similar to those of immunoglobulin-G4 related disease (IgG4-RD), a recently described fibro-inflammatory condition. The ability of these two distinct entities to mimic each other closely creates significant pitfalls in diagnosis. We present a unique case in which GPA presented as a peri-aortic fibrotic mass in the retroperitoneum. The patient's other clinical features also overlapped with classic IgG4-RD disease manifestations, but the histopathology in two organs and the serological data confirmed the diagnosis of GPA. Rigorous histopathological review remains the gold standard for the diagnosis of GPA and the distinction of this entity from IgG4-RD and other mimickers. PMID- 26234735 TI - The phylogenomics of protein structures: The backstory. AB - In this introductory retrospective, evolution as viewed through gene trees is inspected through a lens compounded from its founding operational assumptions. The four assumptions of the gene tree culture that are singularly important to evolutionary interpretations are: a. that protein-coding sequences are molecular fossils; b. that gene trees are equivalent to species trees; c. that the tree of life is assumed to be rooted in a simple akaryote cell implying that akaryotes are primitive, and d. that the notion that all or most incongruities between alignment-based gene trees are due to horizontal gene transfer (HGT), which includes the endosymbiotic models postulated for the origins of eukaryotes. What has been unusual about these particular assumptions is that though each was taken on board explicitly, they are defended in the face of factual challenge by a stolid disregard for the conflicting observations. The factual challenges to the mainstream gene tree-inspired evolutionary view are numerous and most convincingly summarized as: Genome trees tell a very different story. Phylogeny inferred from genomic assortments of homologous protein structural-domains does not support any one of the four principle evolutionary interpretations of gene trees: a. 3D protein domain structures are the molecular fossils of evolution, while coding sequences are transients; b. Species trees are very different from gene trees; c. The ToL is rooted in a surprisingly complex universal common ancestor (UCA) that is distinct from any specific modern descendant and d. HGT including endosymbiosis is a negligible player in genome evolution from UCA to the present. PMID- 26234734 TI - Sulfur vesicles from Thermococcales: A possible role in sulfur detoxifying mechanisms. AB - The euryarchaeon Thermococcus prieurii inhabits deep-sea hydrothermal vents, one of the most extreme environments on Earth, which is reduced and enriched with heavy metals. Transmission electron microscopy and cryo-electron microscopy imaging of T. prieurii revealed the production of a plethora of diverse membrane vesicles (MVs) (from 50 nm to 400 nm), as is the case for other Thermococcales. T. prieurii also produces particularly long nanopods/nanotubes, some of them containing more than 35 vesicles encased in a S-layer coat. Notably, cryo electron microscopy of T. prieurii cells revealed the presence of numerous intracellular dark vesicles that bud from the host cells via interaction with the cytoplasmic membrane. These dark vesicles are exclusively found in conjunction with T. prieurii cells and never observed in the purified membrane vesicles preparations. Energy-Dispersive-X-Ray analyses revealed that these dark vesicles are filled with sulfur. Furthermore, the presence of these sulfur vesicles (SVs) is exclusively observed when elemental sulfur was added into the growth medium. In this report, we suggest that these atypical vesicles sequester the excess sulfur not used for growth, thus preventing the accumulation of toxic levels of sulfur in the host's cytoplasm. These SVs transport elemental sulfur out of the cell where they are rapidly degraded. Intriguingly, closely related archaeal species, Thermococcus nautili and Thermococcus kodakaraensis, show some differences about the production of sulfur vesicles. Whereas T. kodakaraensis produces less sulfur vesicles than T. prieurii, T. nautili does not produce such sulfur vesicles, suggesting that Thermococcales species exhibit significant differences in their sulfur metabolic pathways. PMID- 26234736 TI - Global inequities between polluters and the polluted: climate change impacts on coral reefs. AB - For many ecosystem services, it remains uncertain whether the impacts of climate change will be mostly negative or positive and how these changes will be geographically distributed. These unknowns hamper the identification of regional winners and losers, which can influence debate over climate policy. Here, we use coral reefs to explore the spatial variability of climate stress by modelling the ecological impacts of rising sea temperatures and ocean acidification, two important coral stressors associated with increasing greenhouse gas (GHG) emissions. We then combine these results with national per capita emissions to quantify inequities arising from the distribution of cause (CO2 emissions) and effect (stress upon reefs) among coral reef countries. We find pollution and coral stress are spatially decoupled, creating substantial inequity of impacts as a function of emissions. We then consider the implications of such inequity for international climate policy. Targets for GHG reductions are likely to be tied to a country's emissions. Yet within a given level of GHG emissions, our analysis reveals that some countries experience relatively high levels of impact and will likely experience greater financial cost in terms of lost ecosystem productivity and more extensive adaptation measures. We suggest countries so disadvantaged be given access to international adaptation funds proportionate with impacts to their ecosystem. We raise the idea that funds could be more equitably allocated by formally including a metric of equity within a vulnerability framework. PMID- 26234737 TI - The high prevalence of hepatitis E virus infection in wild boars in Ibaraki Prefecture, Japan. AB - Hepatitis E virus (HEV) is known as a causative agent of zoonosis and food poisoning. Pigs and some species of wild animals, including wild boar, are known to be a reservoir of HEV. In this study, we investigated the situation regarding HEV infection in wild boars in Ibaraki Prefecture, Japan. Serum, liver and feces samples from 68 animals were collected, and the presence or absence of HEV genomic RNA and HEV antibodies were analyzed. The viral genome was detected in samples from 7 (10.3%) animals, with all HEVs classified as genotype 3, subtype 3b. HEV antibodies were detected in samples from 28 (41%) animals. This report demonstrates for the first time the high prevalence of HEV infection in wild boars in Ibaraki Prefecture. PMID- 26234738 TI - Synovial fluid total protein concentration as a possible marker for canine idiopathic polyarthritis. AB - Idiopathic polyarthritis (IPA) is a very common inflammatory arthropathy in the dog. Canine IPA is diagnosed mainly by detecting increased number of leukocytes in the synovial fluid (SF), which is easily influenced by glucocorticoid therapy. We obtained 31 SF samples from 24 IPA dogs prior to (n=19) and/or after (n=12) 1 to 10 weeks of glucocorticoid therapy. The SF total protein concentrations of IPA dogs were significantly higher than those of dogs with non-arthritis diseases (n=34) and healthy controls (n=10). Our data revealed that the SF total protein concentrations are not influenced by several weeks of glucocorticoid therapy. Hence, the SF total protein concentration is applicable as a diagnostic marker of canine IPA even when the patients are receiving glucocorticoid therapy. PMID- 26234739 TI - Therapeutic effects of vitamin E supplementation in 4 dogs with poor semen quality and low superoxide dismutase activity in seminal plasma. AB - Four dogs with poor semen quality, low seminal plasma superoxide dismutase (SOD) activity and low blood plasma testosterone (T) levels were orally administered one vitamin E tablet containing 50 mg alpha-tocopheryl acetate per dog daily for 4 weeks. The mean values of semen quality were temporarily improved after the start of vitamin E treatment and the values of 4, and 5 weeks after that were significantly different from those before the treatment (P<0.05-0.001). The mean blood plasma T and seminal plasma SOD activity values slightly increased in the 4 dogs after the treatment. The results of the present study indicate that poor semen quality in dogs with low seminal plasma SOD can be improved by vitamin E treatment. PMID- 26234740 TI - Intravenous Ketamine for Rapid Opioid Dose Reduction, Reversal of Opioid-Induced Neurotoxicity, and Pain Control in Terminal Care: Case Report and Literature Review. AB - OBJECTIVE: We report a case of opioid-induced neurotoxicity (OIN) in an actively dying hospice patient, its reversal and improved analgesia that followed opioid dosage reduction made possible after addition of IV ketamine. We briefly review the diagnosis and treatment of OIN. SETTING: OIN, particularly when associated with high dose opioid therapy in palliative care, may pose difficult diagnostic and treatment challenges. Few publications from end-of-life settings provide systematic approaches to management of OIN. PATIENTS: We describe a case of OIN in a hospice patient receiving medical care at home while actively dying. INTERVENTION: Addition of IV ketamine and reduction of the patient's high-dose opioid regimen. RESULTS: The patient's pain was controlled within 24 hours of initiation of IV ketamine while the total opioid dose was reduced. His symptoms of OIN (delirium, tremor, myoclonus, and hallucinations) also rapidly subsided. CONCLUSION: OIN should be considered as an etiology of CNS dysfunction occurring with prolonged, high-dose opioid therapy. This case highlights the opioid-sparing and analgesic properties of low-dose ketamine, allowing reversal of OIN in the home hospice setting. PMID- 26234741 TI - A first-principles examination of conducting monolayer 1T'-MX2 (M = Mo, W; X = S, Se, Te): promising catalysts for hydrogen evolution reaction and its enhancement by strain. AB - We investigated the application of 1T'-MX2 (M = Mo, W; X = S, Se, Te) 2D materials as hydrogen evolution reaction (HER) catalysts using density functional theory. Our results show that 1T'-MX2 have lower energies and are dynamically more stable than their 1T counterparts, therefore likely more relevant to previous experimental findings and applications. We found that sulfides are better catalysts, followed by selenides and tellurides. Specifically, 1T'-MoS2 and WS2 are the best HER catalysts among MX2. We proposed a mechanism, rather than the metallicity surmised previously, based on the calculated density of states. On the other hand, the effectively stretched (compressed) X site on the 1T' 2 * 1 reconstruction from 1T is shown to be more (less) active for the HER. We further exploited the application of external strain to tune and boost the HER performance. Our findings are of significance in the elucidation of previous experimental studies and exploration of potential materials for clean energy applications. PMID- 26234742 TI - Mast cells control insulitis and increase Treg cells to confer protection against STZ-induced type 1 diabetes in mice. AB - Quantitative alterations in mast cell numbers in pancreatic lymph nodes (PLNs) have been reported to be associated with type 1 diabetes (T1D) progression, but their potential role during T1D remains unclear. In this study, we evaluated the role of mast cells in T1D induced by multiple low-dose streptozotocin (MLD-STZ) treatments, using two strains of mast cell-deficient mice (W/W(v) or Wsh/Wsh) and the adoptive transfer of mast cells. Mast cell deficient mice developed severe insulitis and accelerated hyperglycemia, with 100% of mice becoming diabetic compared to their littermates. In parallel, these diabetic mice had decreased numbers of T regulatory (Treg) cells in the PLNs. Additionally, mast cell deficiency caused a significant reduction in IL-10, TGF-beta, and IL-6 expression in the pancreatic tissue. Interestingly, IL-6-deficient mice are more susceptible to T1D associated with reduced Treg-cell numbers in the PLNs, but mast cell transfer from wild-type mice induced protection to T1D in these mice. Finally, mast cell adoptive transfer prior to MLD-STZ administration conferred resistance to T1D, promoted increased Treg cells, and decreased IL-17-producing T cells in the PLNs. Taken together, our results indicate that mast cells are implicated in resistance to STZ-induced T1D via an immunological tolerance mechanism mediated by Treg cells. PMID- 26234743 TI - Proteomic Techniques and Management of Flooding Tolerance in Soybean. AB - Climate change is considered a major threat to world agriculture and food security. To improve the agricultural productivity and sustainability, the development of high-yielding stress-tolerant, and climate-resilient crops is essential. Of the abiotic stresses, flooding stress is a very serious hazard because it markedly reduces plant growth and grain yield. Proteomic analyses indicate that the effects of flooding stress are not limited to oxygen deprivation but include many other factors. Although many flooding response mechanisms have been reported, flooding tolerance mechanisms have not been fully clarified for soybean. There were limitations in soybean materials, such as mutants and varieties, while they were abundant in rice and Arabidopsis. In this review, plant proteomic technologies are introduced and flooding tolerance mechanisms of soybeans are summarized to assist in the improvement of flooding tolerance in soybeans. This work will expedite transgenic or marker-assisted genetic enhancement studies in crops for developing high-yielding stress-tolerant lines or varieties under abiotic stress. PMID- 26234744 TI - On the Meanings of Self-Regulation: Digital Humanities in Service of Conceptual Clarity. AB - Self-regulation is of interest both to psychologists and to teachers. But what the word means is unclear. To define it precisely, two studies examined the American Psychological Association's system of controlled vocabulary specifically, the 447 associated terms it presents-and used techniques from the Digital Humanities to identify 88 closely related concepts and six broad conceptual clusters. The resulting analyses show how similar ideas are interrelated: self-control, self-management, self-observation, learning, social behavior, and the personality constructs related to self-monitoring. A full-color network map locates these concepts and clusters relative to each other. It also highlights some of the interests of different audiences, which can be described heuristically using two axes that have been labeled abstract versus practical and self-oriented versus other-oriented. PMID- 26234747 TI - Utility of the Community Integration Questionnaire in a sample of adults with neurological and neuropsychiatric disorders receiving prevocational training. AB - PURPOSE: To investigate utility of the Community Integration Questionnaire (CIQ) in a mixed sample of adults with neurological and neuropsychiatric disorders. METHOD: Cross-sectional, interview-based study. Participants were community dwelling adults with disabilities resulting from neurological and neuropsychiatric disorders (N = 54), who participated in a pre-vocational readiness and social skills training program. Psychometric properties of the Community Integration Questionnaire (CIQ) were assessed and validated against Mayo-Portland Adaptability Inventory (MPAI) and The Problem Checklist from the New York University Head Injury Family Interview (PCL). RESULTS: Based on the revised scoring procedures, psychometric properties of the CIQ Home Competency scale were excellent, followed by the Total score and Social Integration scale. Productive Activity scale had low content validity and a weak association with the total score. Convergent and discriminant validity of the CIQ were demonstrated by correlation patterns with MPAI scales in the expected direction. Significant relationship was found with PCL Physical/Dependency scale. Significant associations were found with sex, living status, and record of subsequent employment. CONCLUSIONS: The results provide support for the use of the CIQ as a measure of participation in individuals with neurological and neuropsychiatric diagnoses and resulting disabilities. Implications for Rehabilitation An important goal of rehabilitation and training programs for individuals with dysfunction of the central nervous system is to promote their participation in social, vocational, and domestic activities. The Community Integration Questionnaire (CIQ) is a brief and efficient instrument for measuring these participation domains. This study demonstrated good psychometric properties and high utility of the CIQ in a sample of 54 individuals participating in a prevocational training program. PMID- 26234746 TI - Time-driven activity based costing of total knee replacement surgery at a London teaching hospital. AB - INTRODUCTION: The aim of this study was to conduct a time-driven activity based costing (TDABC) analysis of the clinical pathway for total knee replacement (TKR) and to determine where the major cost drivers lay. METHODS: The in-patient pathway was prospectively mapped utilising a TDABC model, following 20 TKRs. The mean age for these patients was 73.4 years. All patients were ASA grade I or II and their mean BMI was 30.4. The 14 varus knees had a mean deformity of 5.32 degrees and the six valgus knee had a mean deformity of 10.83 degrees . Timings were prospectively collected as each patient was followed through the TKR pathway. RESULTS: Pre-operative costs including pre-assessment and joint school were L 163. Total staff costs for admission and the operating theatre were L 658. Consumables cost for the operating theatre were L 1862. The average length of stay was 5.25 days at a total cost of L 910. Trust overheads contributed L 1651. The overall institutional cost of a 'noncomplex' TKR in patients without substantial medical co-morbidities was estimated to be L 5422, representing a profit of L 1065 based on a best practice tariff of L 6487. CONCLUSIONS: The major cost drivers in the TKR pathway were determined to be theatre consumables, corporate overheads, overall ward cost and operating theatre staffing costs. Appropriate discounting of implant costs, reduction in length of stay by adopting an enhanced recovery programme and control of corporate overheads through the use of elective orthopaedic treatment centres are proposed approaches for reducing the overall cost of treatment. PMID- 26234745 TI - Under pressure: adolescent substance users show exaggerated neural processing of aversive interoceptive stimuli. AB - AIMS: Adolescents with substance use disorders (SUD) exhibit hyposensitivity to pleasant internally generated (interoceptive) stimuli and hypersensitivity to external rewarding stimuli. It is unclear whether similar patterns exist for aversive interoceptive stimuli. We compared activation in the insular cortex and other brain regions during the anticipation and experience of aversive stimuli between adolescents with SUD and those without. DESIGN: Cross-sectional experimental study with two groups. PARTICIPANTS: Adolescents (ages 15-17 years) with an alcohol or marijuana SUD (n=18) and healthy comparison subjects (CON, n=15). Participants were recruited by distributing flyers at local high schools. SETTING: Keck Imaging Center, University of California San Diego, CA, USA. MEASUREMENTS: Behavioral and neural responses to a continuous performance task with inspiratory breathing load recorded during an fMRI session. Questionnaires assessed life-time drug use, anxiety, sensation-seeking, impulsivity, affect and bodily awareness. Visual analog scales assessed drug craving and breathing load responses. FINDINGS: Across subjects, experience of breathing load elicited greater bilateral anterior and posterior insula (AI and PI, respectively) activation than anticipation (F(1,31)=4.16, P<0.05). SUD exhibited greater left AI and bilateral PI activation during breathing load than anticipation, compared with CON (F(1,31)=4.16, P<0.05). In contrast, CON showed greater activation during anticipation than breathing load in left PI, compared with SUD (F(1,31)=4.16, P<0.05). CONCLUSIONS: Adolescents with alcohol and marijuana substance use disorders may be hypersensitive to aversive interoceptive stimuli. PMID- 26234749 TI - Highly ordered nanoporous films from supramolecular diblock copolymers with hydrogen-bonding junctions. AB - We designed efficient precursors that combine complementary associative groups with exceptional binding affinities and thiocarbonylthio moieties enabling precise RAFT polymerization. Well defined PS and PMMA supramolecular polymers with molecular weights up to 30 kg mol(-1) are synthesized and shown to form highly stable supramolecular diblock copolymers (BCPs) when mixed, in non-polar solvents or in the bulk. Hierarchical self-assembly of such supramolecular BCPs by thermal annealing affords morphologies with excellent lateral order, comparable to features expected from covalent diblock copolymer analogues. Simple washing of the resulting materials with protic solvents disrupts the supramolecular association and selectively dissolves one polymer, affording a straightforward process for preparing well-ordered nanoporous materials without resorting to crosslinking or invasive chemical degradations. PMID- 26234750 TI - Integration of vascular systems between the brain and spinal cord in zebrafish. AB - Cerebral and spinal vascular systems are organized individually, and they then conjugate at their border, through the integration of basilar artery and vertebral arteries. Zebrafish (Danio rerio) is an ideal organism for studying early vascular development, and the precise procedure of cranial and truncal vascular formation has been previously demonstrated using this model. However, the stepwise process of the integration between the brain and spinal cord has not been clearly elucidated. In this study, we describe the integration of the independent vascular systems for the brain and spinal cord, using transgenic zebrafish expressing enhanced green fluorescent protein in endothelial cells. Initially, basilar artery and primordial hindbrain channels, into which internal carotid arteries supplied blood, were connected with dorsal longitudinal anastomose vessels, via the first intersegmental artery. This initial connection was not influenced by flow dynamics, suggesting that vascular integration in this region is controlled by genetic cues. Vertebral arteries were formed individually as longitudinal vessels beneath the spinal cord, and became integrated with the basilar artery during subsequent remodeling. Furthermore, we confirmed the basal vasculature was well conserved in adult zebrafish. Observations of vascular integration presented herein will contribute to an understanding of regulatory mechanisms behind this process. PMID- 26234751 TI - Discovery and characterization of spontaneous mouse models of craniofacial dysmorphology. AB - Craniofacial abnormalities are among the most common features of human genetic syndromes and disorders. The etiology of these conditions is often complex, influenced by both genetic context and the environment. Frequently, craniofacial abnormalities present as part of a syndrome with clear comorbid phenotypes, providing additional insight into mechanisms of the causative gene or pathway. The mouse has been a key tool in our understanding of the genetic mechanisms of craniofacial development and disease, and can provide excellent models for human craniofacial abnormalities. While powerful genetic engineering tools in the mouse have contributed significantly our understanding of craniofacial development and dysmorphology, forward genetic approaches provide an unbiased means to identify new genes and pathways. Moreover, spontaneous mutations can occur on any number of genetic backgrounds, potentially revealing critical genes that require a specific genetic context. Here we report discovery and phenotyping of 43 craniofacial mouse models, derived primarily from a screen for spontaneous mutations in production colonies at the Jackson Laboratory. We identify the causative gene for 33 lines, including novel genes in pathways not previously connected to craniofacial development, and novel alleles of known genes that present with unique phenotypes. Together with our detailed characterization, this work provides a valuable gene discovery resource for the craniofacial community, and a rich source of mouse models for further investigation. PMID- 26234752 TI - Fertilization stimulates 8-hydroxy-2'-deoxyguanosine repair and antioxidant activity to prevent mutagenesis in the embryo. AB - Oxidative DNA damage harbored by both spermatozoa and oocytes at the time of fertilization must be repaired prior to S-phase of the first mitotic division to reduce the risk of transversion mutations occurring in the zygote and subverting the normal patterns of cell differentiation and development. Of the characterised oxidative DNA lesions, 8-hydroxy-2'-deoxyguanosine (8OHdG) is particularly mutagenic. The current study reveals for the first time a marked acceleration of 8OHdG repair in the mouse oocyte/zygote by the base excision repair (BER) pathway following fertilization. Specifically, fertilization initiates post-translational modification to BER enzymes such as OGG1 and XRCC1, causing nuclear localisation and accelerated 8OHdG excision. Additionally, both the nuclear and mitochondrial genomes appear to benefit from increased protection against further 8OHdG formation by a fertilization-associated increase in glutathione peroxidase activity. The major limitation of the characterised 8OHdG repair system is the relatively low level of OGG1 expression in the oocyte, in contrast to the male germ line where it is the only constituent of the BER pathway. The male and female germ lines therefore collaborate in the repair of oxidative DNA damage, and oocytes are vulnerable to high levels of 8OHdG being carried into the zygote by the fertilizing spermatozoon. PMID- 26234753 TI - LRRK2 A419V variant is a risk factor for Parkinson's disease in Asian population. AB - Recently, LRRK2 A419V (rs34594498) was reported associating with Parkinson's disease (PD) in Asian population; yet the conclusion is still unobvious. We conducted a case-control study to determine the potential associations between A419V and PD in Chinese population. Five hundred PD patients and 574 health controls were genotyped. Our results showed, A419V has a significantly higher frequency among PD patients than the controls (p = 0.025, odds ratio [OR] = 2.57, 95% confidence interval [CI] [1.13-5.86]), especially in early-onset PD (p = 0.027, OR = 10.40, 95% CI [1.31-82.89]). And PD patients who carried A419V have a lower Minimum-Mental State Examination scores than PD patients who did not (p = 0.04). We also conducted a meta-analysis on A419V. In Asian population, A419V was detected at a significantly higher frequency among PD patients in contrast to controls: Z = 2.47, p = 0.01, OR = 2.11, 95% CI [1.17-3.82]. When only considering the Chinese population, the difference was more obvious with Z = 3.41, p = 0.0007, OR = 2.07, 95% CI [1.36-3.14]. The results suggest LRRK2 A419V appears to be a risk factor for PD in Asian, especially in early-onset patients. Finally, larger sample with centering on young or cognitive impairment PD patients in Asian would be preferable for further confirmation. PMID- 26234754 TI - The relation of structural integrity and task-related functional connectivity in the aging brain. AB - The relations among structural integrity, functional connectivity (FC), and cognitive performance in the aging brain are still understudied. Here, we used multimodal and multivariate approaches to specifically examine age-related changes in task-related FC, gray-matter volumetrics, white-matter integrity, and performance. Our results are two-fold, showing (i) age-related differences in FC of the working memory network and (ii) age-related recruitment of a compensatory network associated with better accuracy on the task. Increased connectivity in the compensatory network correlates positively with preserved white-matter integrity in bilateral frontoparietal tracks and with larger gray-matter volume of right inferior parietal lobule. These findings demonstrate the importance of structural integrity and FC in working memory performance associated with healthy aging. PMID- 26234755 TI - Plasma amyloid beta-quo vadis? PMID- 26234756 TI - PCC characteristics at rest in 10-year memory decliners. AB - The present research sought to characterize the intrinsic functional networks associated with a 10-year episodic memory decline in elderly using data from a longitudinal population-based cohort (Bordeaux-3City). Complementary measures of whole-brain resting-state functional magnetic resonance imaging investigations were combined to compare functional architecture of brain networks both at connectional and topological levels in 22 decliners to 22 nondecliners; episodic memory decline being assessed through a multiple time point Free and Cued Selective Reminding Test. The decliners presented differences in functional architecture centered on the posterior cingulate cortex, characterized by a significant decrease of connectivity intensity, a significant increased centrality. In accordance, a decrease of the functional connectivity inside the default mode network was observed in the decliners. Our results highlight the central role of the posterior cingulate cortex in a slow but reliable memory decline in elderly. Because functional alterations of this region are currently described in Alzheimer's disease, this functional signature could constitute a risk for Alzheimer's disease. PMID- 26234757 TI - Neural Underpinnings of Working Memory in Adult Survivors of Childhood Brain Tumors. AB - Adult survivors of childhood brain tumors are at risk for cognitive performance deficits that require the core cognitive skill of working memory. Our goal was to examine the neural mechanisms underlying working memory performance in survivors. We studied the working memory of adult survivors of pediatric posterior fossa brain tumors using a letter n-back paradigm with varying cognitive workload (0-, 1-, 2-, and 3-back) and functional magnetic resonance imaging as well as neuropsychological measures. Survivors of childhood brain tumors evidenced lower working memory performance than demographically matched healthy controls. Whole brain analyses revealed significantly greater blood-oxygen level dependent (BOLD) activation in the left superior / middle frontal gyri and left parietal lobe during working memory (2-back versus 0-back contrast) in survivors. Left frontal BOLD response negatively correlated with 2- and 3-back working memory performance, Auditory Consonant Trigrams (ACT), and Digit Span Backwards. In contrast, parietal lobe BOLD response negatively correlated with 0-back (vigilance task) and ACT. The results revealed that adult survivors of childhood posterior fossa brain tumors recruited additional cognitive control resources in the prefrontal lobe during increased working memory demands. This increased prefrontal activation is associated with lower working memory performance and is consistent with the allocation of latent resources theory. PMID- 26234758 TI - Sleep assessment for better understanding skin composition. PMID- 26234759 TI - Sleep and skin composition. PMID- 26234760 TI - Gut permeability, its interaction with gut microflora and effects on metabolic health are mediated by the lymphatics system, liver and bile acid. AB - There is evidence to link obesity (and metabolic syndrome) with alterations in gut permeability and microbiota. The underlying mechanisms have been questioned and have prompted this review. We propose that the gut barrier function is a primary driver in maintaining metabolic health with poor health being linked to 'gut leakiness'. This review will highlight changes in intestinal permeability and how it may change gut microflora and subsequently affect metabolic health by influencing the functioning of major bodily organs/organ systems: the lymphatic system, liver and pancreas. We also discuss the likelihood that metabolic syndrome undergoes a cyclic worsening facilitated by an increase in intestinal permeability leading to gut dysbiosis, culminating in ongoing poor health leading to further exacerbated gut leakiness. PMID- 26234761 TI - The natural history and prognosis of epilepsy. AB - Epilepsy is a brain condition characterized by the recurrence of unprovoked seizures. Generally, prognosis refers to the probability of attaining seizure freedom on treatment and little is known about the natural history of the untreated condition. Here, we summarize aspects of the prognosis and prognostic predictors of treated and untreated epilepsy and of its different syndromes. Usually, epilepsy is a fairly benign condition. Most epilepsies have a good prognosis for full seizure control and eventual discontinuation of AEDs, but epilepsy syndromes have differing outcomes and responses to treatment. Prognostic factors include aetiology, EEG abnormalities, type of seizures and the number of seizures experienced before treatment onset, and poor early effects of drugs. Early response to treatment is an important positive predictor of long-term prognosis, while the history of a high number of seizures at the time of diagnosis, intellectual disability, and symptomatic aetiology are negative predictors. Different prognostic patterns can be identified, suggesting that the epileptogenic process is not static. Epilepsy carries a greater than expected risk of premature death. Aetiology is the single most important risk factor for premature death. PMID- 26234762 TI - Angiotensin and mineralocorticoid receptor antagonism attenuates cardiac oxidative stress in angiotensin II-infused rats. AB - Angiotensin II (Ang II) and aldosterone contribute to hypertension, oxidative stress and cardiovascular damage, but the contributions of aldosterone during Ang II-dependent hypertension are not well defined because of the difficulty to assess each independently. To test the hypothesis that during Ang II infusion, oxidative and nitrosative damage is mediated through both the mineralocorticoid receptor (MR) and angiotensin type 1 receptor (AT1), five groups of Sprague Dawley rats were studied: (i) control; (ii) Ang II infused (80 ng/min * 28 days); (iii) Ang II + AT1 receptor blocker (ARB; 10 mg losartan/kg per day * 21 days); (iv) Ang II + mineralocorticoid receptor (MR) antagonist (Epl; 100 mg eplerenone/day * 21 days); and (v) Ang II + ARB + Epl (Combo; * 21 days). Both ARB and combination treatments completely alleviated the Ang II-induced hypertension, whereas eplerenone treatment only prolonged the onset of the hypertension. Eplerenone treatment exacerbated the Ang II-mediated increase in plasma and heart aldosterone 2.3- and 1.8-fold, respectively, while ARB treatment reduced both. Chronic MR blockade was sufficient to ameliorate the AT1-mediated increase in oxidative damage. All treatments normalized protein oxidation (nitrotyrosine) levels; however, only ARB and Combo treatments completely reduced lipid peroxidation (4-hydroxynonenal) to control levels. Collectively, these data suggest that receptor signalling, and not the elevated arterial blood pressure, is the principal culprit in the oxidative stress-associated cardiovascular damage in Ang II-dependent hypertension. PMID- 26234764 TI - Cutting stems before relaxing xylem tension induces artefacts in Vitis coignetiae, as evidenced by magnetic resonance imaging. AB - It was recently reported that cutting artefacts occur in some species when branches under tension are cut, even under water. We used non-destructive magnetic resonance imaging (MRI) to investigate the change in xylem water distribution at the cellular level in Vitis coignetiae standing stems before and after relaxing tension. Less than 3% of vessels were cavitated when stems under tension were cut under water at a position shorter than the maximum vessel length (MVL) from the MRI point, in three of four plants. The vessel contents remained at their original status, and cutting artefact vessel cavitation declined to <1% when stems were cut at a position farther than the MVL from the MRI point. Water infiltration into the originally cavitated vessels after cutting the stem, i.e. vessel refilling, was found in <1% of vessels independent of cutting position on three of nine plants. The results indicate that both vessel cavitation and refilling occur in xylem tissue under tension following stem cutting, but its frequency is quite small, and artefacts can be minimized altogether if the distance between the monitoring position and the cutting point is longer than the MVL. PMID- 26234763 TI - Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers. AB - Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. However, the role of autophagy factors in cancer progression and their effect in treatment response remain largely elusive. Recent studies have shown that UVRAG, a key autophagic tumour suppressor, is mutated in common human cancers. Here we demonstrate that the cancer-related UVRAG frameshift (FS), which does not result in a null mutation, is expressed as a truncated UVRAG(FS) in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAG(FS) abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAG(FS) can trigger CRC metastatic spread through Rac1 activation and epithelial-to mesenchymal transition, independently of autophagy. Interestingly, UVRAG(FS) expression renders cells more sensitive to standard chemotherapy regimen due to a DNA repair defect. These results identify UVRAG as a new MSI target gene and provide a mechanism for UVRAG participation in CRC pathogenesis and treatment response. PMID- 26234765 TI - Myocyte enhancer factor 2D promotes tumorigenicity in malignant glioma cells. AB - The prognosis of patients with malignant glioma is always quite poor, and this poor prognosis is probably due to our incomplete understanding of the molecular mechanisms underlying malignant glioma. It is known that myocyte enhancer factor 2D (MEF2D) plays an oncogenic role in hepatocellular carcinoma and promotes the survival of various types of cells. However, little is known about the expression profile and function of MEF2D in malignant glioma. In this study, we investigated the function and expression of MEF2D in malignant glioma. We found that in malignant glioma, there is an aberrantly high expression of MEF2D, which leads to poor prognosis of malignant glioma. The downregulation of MEF2D suppresses the proliferation of malignant glioma cell lines by inducing delay of S and G2/M phases of cell cycle and promoting apoptosis. Furthermore, the overexpression of MEF2D in astrocytes accelerates cell proliferation by regulating cell cycle progression. Furthermore, a mouse malignant glioma model demonstrated that MEF2D deficiency blocks malignant glioma formation in vivo. We conclude that MEF2D may act as a potential oncogene in malignant glioma and thus serve as a candidate target for malignant glioma therapy. PMID- 26234767 TI - PP2A inhibition as a novel therapeutic target in castration-resistant prostate cancer. AB - Protein phosphatase 2A (PP2A) is a well-known tumor suppressor frequently inhibited in human cancer. Alterations affecting PP2A subunits together with the deregulation of endogenous PP2A inhibitors such as CIP2A and SET have been described as contributing mechanisms to inactivate PP2A in prostate cancer. Moreover, recent findings highlight that functional inactivation of PP2A could represent a key event in the acquisition of castration-resistant phenotype and a novel molecular target with high impact at both clinical and therapeutic levels in prostate cancer. PMID- 26234766 TI - PDGF-D promotes dermal fibroblast invasion in 3-dimensional extracellular matrix via Snail-mediated MT1-MMP upregulation. AB - Increasing attention has been focused on the malignant tumor microenvironment, which plays important roles in tumor occurrence, progression and metastasis. Fibroblasts are recruited by platelet-derived growth factor (PDGFs) and invade the tumor microenvironment. In the PDGF family, PDGF-B has been reported to play an important role in the recruitment and invasion programs. However, whether PDGF D plays a role in these programs remains unclear. We generated a recombinant plasmid expressing human PDGF-D and transfected the plasmid to dermal fibroblasts to examine the effects on cell invasive activities in 3D type I collagen gels. PDGF-D plasmid transfection enhanced fibroblast invasive activities both in invasive cell numbers and invasion depth in 3D collagen gels. These effects were blocked by Snail-specific siRNA transfection. PDGF-D transfection significantly induced Snail expression at both mRNA and protein levels. PDGF-D further upregulated MT1-MMP mRNA and protein expressions and this was inhibited when Snail was knocked down by siRNA. Both Snail and MT1-MMP expressions in fibroblasts and cellular invasive activities in 3D collagen induced by PDGF-D were inhibited by LY294002, SP600125, and U1026, the inhibitors of PI3K, JNK, and ERK1/2 signaling pathways, respectively. However, no effects were observed in response to the P38MAPK signaling pathway inhibitor SB203580. These effects of PDGF-D were confirmed by using the culture supernatants of the transfectants. Taken together, these data demonstrate that PDGF-D plays important roles in the recruitment and invasion programs of fibroblasts via the activation of PI3K, JNK and ERK1/2 signaling pathways, and upregulation of Snail and downstream effecter MT1-MMP. These findings indicate that PDGF-D is an important player in the tumor microenvironment for fibroblast recruitment. PMID- 26234768 TI - Extinction in a hyperdiverse endemic Hawaiian land snail family and implications for the underestimation of invertebrate extinction. AB - The International Union for Conservation of Nature (IUCN) Red List includes 832 species listed as extinct since 1600, a minuscule fraction of total biodiversity. This extinction rate is of the same order of magnitude as the background rate and has been used to downplay the biodiversity crisis. Invertebrates comprise 99% of biodiversity, yet the status of a negligible number has been assessed. We assessed extinction in the Hawaiian land snail family Amastridae (325 species, IUCN lists 33 as extinct). We did not use the stringent IUCN criteria, by which most invertebrates would be considered data deficient, but a more realistic approach comparing historical collections with modern surveys and expert knowledge. Of the 325 Amastridae species, 43 were originally described as fossil or subfossil and were assumed to be extinct. Of the remaining 282, we evaluated 88 as extinct and 15 as extant and determined that 179 species had insufficient evidence of extinction (though most are probably extinct). Results of statistical assessment of extinction probabilities were consistent with our expert evaluations of levels of extinction. Modeling various extinction scenarios yielded extinction rates of 0.4-14.0% of the amastrid fauna per decade. The true rate of amastrid extinction has not been constant; generally, it has increased over time. We estimated a realistic average extinction rate as approximately 5%/decade since the first half of the nineteenth century. In general, oceanic island biotas are especially susceptible to extinction and global rate generalizations do not reflect this. Our approach could be used for other invertebrates, especially those with restricted ranges (e.g., islands), and such an approach may be the only way to evaluate invertebrates rapidly enough to keep up with ongoing extinction. PMID- 26234769 TI - Case Report of Debilitating Headaches and a Coexisting Ophthalmic Artery Aneurysm: An Indication for Treatment? AB - OBJECTIVE: We present a case of a patient who had severe unilateral headaches related to a small, unruptured ophthalmic artery aneurysm, who experienced complete headache cessation following endovascular coiling. BACKGROUND: Small unruptured intracranial aneurysms are generally managed and followed conservatively due to minimal risk of rupture. Headaches are frequently reported in patients with intracranial aneurysms, but these aneurysms are typically considered incidental and unrelated, given the undefined association between headaches and most aneurysms. CONCLUSION: There may be some unruptured intracranial aneurysms that can cause intractable headaches and warrant interventional treatment. Future prospective studies are needed that compare pre- and post-procedure headache character and diagnosis, aneurysm characteristics such as size, location, orientation, and shape, type of aneurysm repair with materials used, and other potential risk factors for worsening post-procedure headache in order to better predict headache association to aneurysms, as well as outcomes following endovascular aneurysm treatment. PMID- 26234770 TI - Few-layer, large-area, 2D covalent organic framework semiconductor thin films. AB - In this work, we synthesize large-area thin films of a conjugated, imine-based, two-dimensional covalent organic framework at the solution/air interface. Thicknesses between ~2-200 nm are achieved. Films can be transferred to any desired substrate by lifting from underneath, enabling their use as the semiconducting active layer in field-effect transistors. PMID- 26234771 TI - Case-finding for cognitive impairment among people with Type 2 diabetes in primary care using the Test Your Memory and Self-Administered Gerocognitive Examination questionnaires: the Cog-ID study. AB - AIM: To evaluate two cognitive tests for case-finding for cognitive impairment in older patients with Type 2 diabetes. METHODS: Of 1243 invited patients with Type 2 diabetes, aged >=70 years, 228 participated in a prospective cohort study. Exclusion criteria were: diagnosis of dementia; previous investigation at a memory clinic; and inability to write or read. Patients first filled out two self administered cognitive tests (Test Your Memory and Self-Administered Gerocognitive Examination). Secondly, a general practitioner, blinded to Test Your Memory and Self-Administered Gerocognitive Examination scores, performed a structured evaluation using the Mini-Mental State Examination. Subsequently, patients suspected of cognitive impairment (on either the cognitive tests or general practitioner evaluation) and a random sample of 30% of patients not suspected of cognitive impairment were evaluated at a memory clinic. Diagnostic accuracy and area under the curve were determined for the Test Your Memory, Self Administered Gerocognitive Examination and general practitioner evaluation compared with a memory clinic evaluation to detect cognitive impairment (mild cognitive impairment or dementia). RESULTS: A total of 44 participants were diagnosed with cognitive impairment. The Test Your Memory and Self-Administered Gerocognitive Examination questionnaires had negative predictive values of 81 and 85%, respectively. Positive predictive values were 39 and 40%, respectively. The general practitioner evaluation had a negative predictive value of 83% and positive predictive value of 64%. The area under the curve was ~0.70 for all tests. CONCLUSIONS: Both the tests evaluated in the present study can easily be used in case-finding strategies for cognitive impairment in patients with Type 2 diabetes in primary care. The Self-Administered Gerocognitive Examination had the best diagnostic accuracy and therefore we would have a slight preference for this test. Applying the Self-Administered Gerocognitive Examination would considerably reduce the number of patients in whom the general practitioner needs to evaluate cognitive functioning to tailor diabetes treatment. PMID- 26234772 TI - A rapid UPLC-MS/MS method for the determination of oleanolic acid in rat plasma and liver tissue: application to plasma and liver pharmacokinetics. AB - A reliable high-throughput ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for oleanolic acid (OA) determination in rat plasma and liver tissue using glycyrrhetic acid as the internal standard (IS). Plasma and liver homogenate samples were prepared using solid-phase extraction. Chromatographic separation was achieved on a C18 column using an isocratic mobile phase system. The detection was performed by multiple reaction monitoring mode via positive electrospray ionization interface. The calibration curves showed good linearity (R(2) > 0.9997) within the tested concentration ranges. The lower limit of quantification for plasma and liver tissue was <=0.75 ng/mL. The intra- and inter-day precision and accuracy deviations were within +/-15% in plasma and liver tissue. The mean extraction recoveries ranged from 80.8 to 87.0%. In addition, the carryover, matrix effect, stability and robustness involved in the method were also validated. The method was successfully applied to the plasma and hepatic pharmacokinetics of OA after oral administration to rats. PMID- 26234777 TI - Microfluidic Single-Cell Analysis with Affinity Beads. PMID- 26234773 TI - Formulation of Biologically-Inspired Silk-Based Drug Carriers for Pulmonary Delivery Targeted for Lung Cancer. AB - The benefits of using silk fibroin, a major protein in silk, are widely established in many biomedical applications including tissue regeneration, bioactive coating and in vitro tissue models. The properties of silk such as biocompatibility and controlled degradation are utilized in this study to formulate for the first time as carriers for pulmonary drug delivery. Silk fibroin particles are spray dried or spray-freeze-dried to enable the delivery to the airways via dry powder inhalers. The addition of excipients such as mannitol is optimized for both the stabilization of protein during the spray-freezing process as well as for efficient dispersion using an in vitro aerosolisation impactor. Cisplatin is incorporated into the silk-based formulations with or without cross-linking, which show different release profiles. The particles show high aerosolisation performance through the measurement of in vitro lung deposition, which is at the level of commercially available dry powder inhalers. The silk-based particles are shown to be cytocompatible with A549 human lung epithelial cell line. The cytotoxicity of cisplatin is demonstrated to be enhanced when delivered using the cross-linked silk-based particles. These novel inhalable silk-based drug carriers have the potential to be used as anti-cancer drug delivery systems targeted for the lungs. PMID- 26234778 TI - Anionic Lipid, pH-Sensitive Liposome-Gold Nanoparticle Hybrids for Gene Delivery Quantitative Research of the Mechanism. PMID- 26234783 TI - Advances in nowcasting influenza-like illness rates using search query logs. AB - User-generated content can assist epidemiological surveillance in the early detection and prevalence estimation of infectious diseases, such as influenza. Google Flu Trends embodies the first public platform for transforming search queries to indications about the current state of flu in various places all over the world. However, the original model significantly mispredicted influenza-like illness rates in the US during the 2012-13 flu season. In this work, we build on the previous modeling attempt, proposing substantial improvements. Firstly, we investigate the performance of a widely used linear regularized regression solver, known as the Elastic Net. Then, we expand on this model by incorporating the queries selected by the Elastic Net into a nonlinear regression framework, based on a composite Gaussian Process. Finally, we augment the query-only predictions with an autoregressive model, injecting prior knowledge about the disease. We assess predictive performance using five consecutive flu seasons spanning from 2008 to 2013 and qualitatively explain certain shortcomings of the previous approach. Our results indicate that a nonlinear query modeling approach delivers the lowest cumulative nowcasting error, and also suggest that query information significantly improves autoregressive inferences, obtaining state-of the-art performance. PMID- 26234784 TI - Childhood adversity and behavioral health outcomes for youth: An investigation using state administrative data. AB - This study aimed to measure the relative contribution of adverse experiences to adolescent behavioral health problems using administrative data. Specifically, we sought to understand the predictive value of adverse experiences on the presence of mental health and substance abuse problems for youth receiving publicly funded social and health services. Medicaid claims and other service records were analyzed for 125,123 youth age 12-17 and their biological parents. Measures from administrative records reflected presence of parental domestic violence, mental illness, substance abuse, criminal justice involvement, child abuse and/or neglect, homelessness, and death of a biological parent. Mental health and substance abuse status of adolescents were analyzed as functions of adverse experiences and other youth characteristics using logistic regression. In multivariate analyses, all predictors except parental domestic violence were statistically significant for substance abuse; parental death, parental mental illness, child abuse or neglect and homelessness were statistically significant for mental illness. Odds ratios for child abuse/neglect were particularly high in both models. The ability to identify risks during childhood using administrative data suggests the potential to target prevention and early intervention efforts for children with specific family risk factors who are at increased risk for developing behavioral health problems during adolescence. This study illustrates the utility of administrative data in understanding adverse experiences on children and the advantages and disadvantages of this approach. PMID- 26234785 TI - Possible involvement of the Sigma-1 receptor chaperone in chemotherapeutic induced neuropathic pain. AB - Previous studies have shown that ligands of the sigma-1 receptor chaperone (Sig 1R) regulate pain-related behaviors. Clinical use of chemotherapeutics is often compromised due to their adverse side effects, particularly those related to neuropathy. Previous studies have shown that repeated administration of oxaliplatin and paclitaxel produces neuropathy in rodents. Therefore, the aim of the present study was to clarify the involvement of the Sig-1R in chemotherapeutic-induced neuropathy by examining the effects of oxaliplatin and paclitaxel on the Sig-1R levels in the spinal cord, and by examining the effects of Sig-1R agonist and antagonist on oxaliplatin- and paclitaxel-induced neuropathy in rats. Chemotherapeutic-induced neuropathic pain was accompanied by a significant reduction of the Sig-1R level in the spinal cord. Furthermore, the administration of paclitaxel to CHO cells that stably overexpressed Sig-1Rs induced the clustering of Sig-1Rs. We also found that the Sig-1R agonist SA4503 potently inhibited the neuropathy induced by oxaliplatin- and paclitaxel, whereas this action was abolished by the Sig-1R antagonist NE-100. These results suggest that the reduction of Sig-1R activity is involved in chemotherapeutic-induced neuropathy, and the Sig-1R agonist SA4503 could serve as a potential candidate for the treatment of chemotherapeutic-induced neuropathy. PMID- 26234786 TI - Simulated soil crust conditions in a chamber system provide new insights on cyanobacterial acclimation to desiccation. AB - Environmental research often faces two major hurdles: (i) fluctuating spatial and temporal conditions and consequently large variability in the organisms' abundance and performance, and (ii) complex, costly logistics involved in field experiments. Measurements of physiological parameters or molecular analyses often represent single shot experiments. To study desiccation acclimation of filamentous cyanobacteria, the founders and main primary producers in desert biological soil crusts (BSC), we constructed an environmental chamber that can reproducibly and accurately simulate ambient conditions and measure microorganism performance. We show that recovery from desiccation of BSC cyanobacteria and Leptolyngbya ohadii isolated thereof are strongly affected by dehydration rate following morning dew. This effect is most pronounced in cells exposed to high light and temperature in the dry phase. Simultaneous measurements of water content, gas exchange and fluorescence were performed during dehydration. Photosynthetic performance measured by fluorescence begins declining when light intensity reaches values above 100 MUmol photons m(-2) s(-1), even in fully hydrated cells. In contrast, photosynthetic rates measured using O2 evolution and CO2 uptake increased during rising irradiance to the point where the water content declined below ~ 50%. Thus, fluorescence cannot serve as a reliable measure of photosynthesis in desert cyanobacteria. The effects of drying on gas exchange are discussed. PMID- 26234787 TI - Computational design of faster rotating second-generation light-driven molecular motors by control of steric effects. AB - We report a systematic computational investigation of the possibility to accelerate the rate-limiting thermal isomerizations of the rotary cycles of synthetic light-driven overcrowded alkene-based molecular motors through modulation of steric interactions. Choosing as a reference system a second generation motor known to accomplish rotary motion in the MHz regime and using density functional theory methods, we propose a three-step mechanism for the thermal isomerizations of this motor and show that variation of the steric bulkiness of the substituent at the stereocenter can reduce the (already small) free-energy barrier of the rate-determining step by a further 15-17 kJ mol(-1). This finding holds promise for future motors of this kind to reach beyond the MHz regime. Furthermore, we demonstrate and explain why one particular step is kinetically favored by decreasing and another step is kinetically favored by increasing the steric bulkiness of this substituent, and identify a possible back reaction capable of impeding the rotary rate. PMID- 26234788 TI - Predictors of progression into acute-on-chronic liver failure from acute deterioration of pre-existing chronic liver disease. AB - AIM: To compare the prognosis between the patients with progression into acute-on chronic liver failure (ACLF) from acute deterioration of pre-existing chronic liver disease and patients without this progression, and to determine predictors of this disease progression. METHODS: We retrospectively analyzed clinical data from 285 patients admitted with acute worsening of pre-existing chronic liver disease within 4 weeks characterized by total bilirubin (TBIL) of 51 MUM/L or more and prothrombin activity (PTA) of more than 40% but less than 70%, which did not meet the Asia-Pacific Association for the Study of the Liver criteria for ACLF. Patient survival was estimated by Kaplan-Meier analysis and subsequently compared by log-rank test. Independent predictors of disease progression were determined using univariate analysis and multivariate Cox regression analysis. RESULTS: The 90-day survival rates significantly worsened in patients with progression into ACLF compared with those without this progression. Baseline TBIL, baseline Model for End-Stage Liver Disease (MELD) score, and the maximum changing rates of PTA level and Child-Turcotte-Pugh (CTP) score were independently associated with progression into ACLF in patients with acute deterioration of pre-existing chronic liver disease. CONCLUSION: Patients with acute worsening of pre-existing chronic liver disease characterized by TBIL of 51 MUM/L or more and PTA of more than 40% but less than 70% should receive aggressive prediction and prevention of ACLF development. Baseline TBIL, baseline MELD score, and the maximum changing rates of PTA level and CTP score may early predict the progression into ACLF. PMID- 26234789 TI - Synthesis and characterization of a polyborosilazane/Cp2ZrCl2 hybrid precursor for the Si-B-C-N-Zr multinary ceramic. AB - A novel zirconium-contained polyborosilazane (PBSZ-Zr) was synthesized by chemical modification of a liquid polyborosilazane (LPBSZ) with Cp2ZrCl2. A Si-B C-N-Zr multinary ceramic was prepared via pyrolysis of PBSZ-Zr. The properties and the ceramization process of PBSZ-Zr, as well as the microstructural development and properties of the derived SiBCN-Zr ceramic, were well studied. The active Si-H and N-H groups in LPBSZ react with Zr-Cl in Cp2ZrCl2 to form PBSZ Zr polymers. The Zr content of the SiBCN-Zr ceramic was 3.39 wt% when the weight ratio of Cp2ZrCl2 to LPBSZ was 20 : 100. The SiBCN-Zr ceramic remains amorphous when pyrolyzed below 1600 degrees C, but the crystal phases of Zr2CN, ZrC, BN, SiC, and Si3N4 were detected from a 1600 degrees C treated sample. Due to the low activity of free carbon at the interface of the SiBCN-Zr ceramic, the oxidation resistance of the SiBCN-Zr ceramic under air was improved compared with the SiBCN ceramic. PMID- 26234790 TI - Electrochemical, Spectroscopic, and Density Functional Theory Characterization of Redox Activity in Nickel-Substituted Azurin: A Model for Acetyl-CoA Synthase. AB - Nickel-containing enzymes are key players in global hydrogen, carbon dioxide, and methane cycles. Many of these enzymes rely on Ni(I) oxidation states in critical catalytic intermediates. However, due to the highly reactive nature of these species, their isolation within metalloenzymes has often proved elusive. In this report, we describe and characterize a model biological Ni(I) species that has been generated within the electron transfer protein, azurin. Replacement of the native copper cofactor with nickel is shown to preserve the redox activity of the protein. The Ni(II/I) couple is observed at -590 mV versus NHE, with an interfacial electron transfer rate of 70 s(-1). Chemical reduction of Ni(II)Az generates a stable species with strong absorption features at 350 nm and a highly anisotropic, axial EPR signal with principal g-values of 2.56 and 2.10. Density functional theory calculations provide insight into the electronic and geometric structure of the Ni(I) species, suggesting a trigonal planar coordination environment. The predicted spectroscopic features of this low-coordinate nickel site are in good agreement with the experimental data. Molecular orbital analysis suggests potential for both metal-centered and ligand-centered reactivity, highlighting the covalency of the metal-thiolate bond. Characterization of a stable Ni(I) species within a model protein has implications for understanding the mechanisms of complex enzymes, including acetyl coenzyme A synthase, and developing scaffolds for unique reactivity. PMID- 26234791 TI - Nano-constructed Carriers Loaded With Antioxidant: Boon For Cardiovascular System. AB - In the last couple of decades antioxidant agents have entered the health market as an easy and attractive means of managing diseases. These agents are of enormous interest for an increasingly health-concerned society, and may be particularly relevant for prophylaxis of a number of diseases i.e. arthritis, cancer, metabolic and cardiovascular diseases, osteoporosis, cataracts, brain disorders, etc. Antioxidants are also favorable to vascular healthiness and symbolize useful compounds because they are able to diminish overall cardiovascular risk by acting analogous to first line therapy or as adjuvants in case of failure or in situations where first line therapy cannot be used. Furthermore, well-designed trials are indeed needed to improve the therapeutic efficacy and health benefits of antioxidants. Numerous in vivo proof-of-concepts studies are offered to underline the feasibility of nanostructure system in order to optimizing the delivery of cardiovascular drugs. The present review highlights the recent approaches for management of cardiovascular disease using different vesicular and particulate carriers, including liposomes, nanoparticles, and nanoemulsions, with a primary emphasis on those which are expected to enhance the antioxidants level. PMID- 26234792 TI - Role of Antioxidants for the Treatment of Cardiovascular Diseases: Challenges and Opportunities. AB - Cardiovascular disorders or cardiovascular diseases (CVD) are major illness associated with heart and blood vessels. Reactive oxygen species (ROS), generated during excessive oxidative stress, are responsible for the pathophysiology of various cardiovascular disorders including atherosclerosis, cardiac hypertrophy, cardiomyopathy, heart failure, ventricular remodeling, ischemia/reperfusion injury and myocardial infarction. Cellular "redox homeostasis" generally maintains the healthy physiology in cardiac myocytes and endothelial cells. However, during excessive oxidative stress body's endogenous system fails to maintain normal physiology hence antioxidant supplementation is necessary, which could scavenge the free radicals and other toxic radicals. Several antioxidants such as CoQ10, beta carotene, lycopene, quercetin, reserveterol, vitamin C and vitamin E have shown preventive and therapeutic benefits in different forms of CVD. However, poor biopharmaceutical properties and variable pharmacokinetics of several antioxidants limits their use as therapeutic agents. Hence delivery of stable antioxidants at their site of action is a need of current scenario. Several novel carriers based approaches have shown considerable benefits for the systemic and site specific delivery of antioxidants for the preventive and therapeutic treatment of several cardiovascular diseases. In the present review, conventional as well as novel antioxidants have been discussed with special emphasis for the treatment of CVD. Further, the current review also highlights the critical challenges for antioxidant delivery and various novel carriers (nanoformulations) including, liposomes and nanoparticles explored for their efficient delivery in the therapeutic management of CVD. PMID- 26234793 TI - Antisense Therapy for Cardiovascular Diseases. AB - Antisense oligonucleotide therapy is a growing field in cardiac, metabolic, and muscular diseases. This precision therapy allows for treatment of diseases due to specific genetic defects. Antisense has few side effects and is relatively long lasting. Some major targets for antisense therapy include hyperglycemia, hyperlipidemia, and hypercholesterolemia. ISIS Pharmaceuticals recently commercialized antisense therapy with Kynamro (Mipomersen) for homozygous familial hypercholesterolemia, opening the door for other antisense oligonucleotides for lowering proteins. Antisense can also be used to increase proteins that are inhibited by mutant exons. Sarepta is testing exon 51 skipping in the mutated dystrophin gene, which if successful will help affected individuals walk, and may help restore some cardiac function. These antisense techniques also could be applied as antisense therapies to overcome gene defects in hypertension, heart disease, muscular defects and metabolic syndrome. PMID- 26234794 TI - Exercise as a platform for pharmacotherapy development in cardiac diseases. AB - Moderate exercise is an effective and economic way to prevent and treat cardiovascular diseases. Unlike pathological cardiac growth, exercise-induced cardiac growth, excluding extreme strenuous exercise, does not cause cardiac cell death, fibrosis, and cardiac dysfunction. The balanced cardiomyogenesis (cardiomyocyte hypertrophy and hyperplasia) and neo-angiogenesis are essential determinants for exercise-induced cardiac growth. In particular, exercise leads to physiological cardiac growth through regulating the IGF-1-PI3K-Akt, nitric oxide (NO), C/EBPbeta, and PGC-1alpha signaling pathways, which might be novel therapeutic targets for cardiac diseases. The formation of new cardiomyocytes in response to exercise suggests that exercise might be a useful tool to enhance cardiac regenerative capacity. Exercise also exerts its protective effects against cardiac aging and cardiac metabolic derangement. Moreover, growing evidence reveals the regulation of cardiac and circulating microRNAs in response to exercise. A better understanding of the mechanisms underlying exercise-induced cardioprotection will lead to the development of innovative pharmacotherapies for cardiac diseases. PMID- 26234795 TI - Vernakalant as a Novel Anti-Arrhythmic Agent for Converting of Atrial Fibrillation, Molecular Mechanism, Updated Clinical Efficacy, and Future Development. AB - The rising incidence of atrial fibrillation (AF) has stimulated researches to identify novel therapeutic options for such most common and refractory cardiac arrhythmia in clinical practice. Rhythm control strategy is shown to be associated with a lower risk of progression to permanent AF and greater clinical benefit as compared with rate control. Remarkable progress has been witnessed in rhythm control strategy particularly along with the development of mapping and ablation technology, while still should pharmacological cardioversion serve as an integrated approach for the management of AF especially in the emergency department or centers not equipped with ablation professionals. Concerns regarding the safety and efficacy of existing conventional antiarrhythmic drugs (AADs) limit their clinical use. Vernakalant, with its relatively atrial selective antiarrhythmic profile, is developed as a novel AAD for pharmacological cardioversion of AF. Its mechanisms involve potassium and sodium channels blocking effects during atrial action potential. A series of clinical trials have demonstrated the rapid, efficacious and safe effect of vernakalant over placebo or conventional AADs in terminating recent-onset AF among patients with structurally normal or minimal heart disease; but current evidence does not show a superior role of vernakalant in treating long-duration AF or atrial flutter. More evidence with respect to comparisons of vernakalant with conventional AADs as well as their synergic effects is needed. Cost-effectiveness analyses of vernakalant applied in prospective and "real world" practice remain to be assessed. PMID- 26234796 TI - Role of the heme oxygenase-adiponectin-atrial natriuretic peptide axis in renal function. AB - The incidence of renal complications including kidney failure is on the rise. Moreover, with aging of the population and the high incidence of diabetes, hypertension and obesity, this trend may prevail. An important cytoprotective enzyme that has been shown to improve renal function is heme-oxygenase (HO). HO is known to abate apoptosis and necrosis, and improves cell vitality, which in turn, may enhance tissue regeneration. Consistently, HO has been shown to restore tissue morphology by potentiating potentiate proteins of repair/regeneration and promoting neovascularization. The formation of new tissue may replace damaged or dysfunctional tissue to preserve cellular integrity and function after injury. Emerging evidence indicate that HO-inducers improve kidney function in several models including, (i) streptozotocin-induced diabetic rats, (ii) Zucker-diabetic fatty rats, (iii) Zucker-fatty rats, (iii) spontaneously hypertensive rats, (iv) uninephrectomized deoxycorticosterone-acetate hypertensive rats, (v) N(omega) nitro-l-arginine-methyl ester (L-NAME)-induced hypertensive rats, (vi) glycerol induced renal failure, (vii) nephrotoxic nephritis, (viii) sepsis-induced kidney injury, (ix) cystic renal disease, (x) cisplatin-mediated acute kidney injury, and (xi) rhabdomyolysis-induced renal injury. The mechanisms underlying the HO mediated reno-protection include: (i) the restoration of renal morphology by enhancing proteins of regeneration, (ii) the potentiation of the HO-adiponectin atrial natriuretic peptide axis, with corresponding suppression of oxidative/inflammatory insults and extracellular matrix/profibrotic factors, and (iii) the potentiation of podocyte cytoskeletal proteins such as nephrin, podocin, podocalyxin and CD2-associated-protein, which are fundamental for forming the glomerular filtration barrier that selectively allows small molecules to pass through but not large protein molecules. Thus, this review highlights the HO-adiponectin-atrial natriuretic peptide axis in renoprotection. PMID- 26234797 TI - Toxics of Tobacco Smoke and Cardiovascular System: From Functional to Cellular Damage. AB - Manufactured tobacco contains over 4, 000 toxic substances, but only a few exert adverse cardiovascular effects. Nicotine and its metabolites, carbon monoxide, thiocyanate and some aromatic amines play a strong, although different, role to determine cardiovascular damage. Of these substances, however, nicotine, acting by the double mechanism of addiction and receptor-binding, and carbon monoxide by increasing the production of carboxyhemoglobin and hypoxia, are the main determinants of the damage. The development of the alterations of heart and blood vessels follows a typical way, initially consisting of functional responses that become irreversible pathological lesions at the time. Myocardium and endothelial cells are the targets where cigarette smoking exerts its effects. The first displays functional and pathological disorders primarily related to ischemic heart disease, cardiomyopathy, including experimental cardiomyopathy from smoking, and heart failure, while the second should be interpreted as a structure, which shows early alterations caused by smoking as clearly evident, repeatable and typically depending on smoking toxicity. Cardiovascular damage has a functional onset, which, at the time, leads to irreversible morphological damage of myocardial and endothelial cells. PMID- 26234798 TI - Nomenclature for factors of the HLA system, update May 2015. PMID- 26234799 TI - Secular trends of pregnancies in women with inflammatory connective tissue disease. AB - INTRODUCTION: This study examined secular trends in reproductive outcome in women with inflammatory connective tissue disease compared with reference deliveries from the general population. MATERIAL AND METHODS: Historical cohort study based on data registered in the Medical Birth Register of Norway from 1967 to 2009. The study included singleton births in women recorded with connective tissue disease (n = 851) and reference deliveries from the general population (n = 2 437 110). Births were stratified in four periods, 1967-1979, 1980-1989, 1990-1999 and 2000 2009. Associations between connective tissue disease and maternal and perinatal outcomes by decade were assessed in logistic regression analyses and adjusted for maternal age at delivery and parity. RESULTS: In the 1970s, around 2.7 deliveries/year were registered for women with connective tissue disease (0.004% of all deliveries). This increased to 42 deliveries/year (0.07% of all deliveries) after 2000. Adjusted odds ratios (aOR) for cesarean section were 5.0 (95% CI 2.1-11.9) in the first and 1.8 (95% CI 1.4-2.3) in the last period. For preterm delivery the aOR decreased from 4.9 (95% CI 2.1-11.4) to 3.1 (95% CI 2.3 4.2) and the aOR for birthweight <2500 g changed from 7.3 (95% CI 3.3-16.3) to 4.1 (95% CI 3.0-5.6). CONCLUSIONS: An increasing number of births were observed over time among women with connective tissue disease. Adverse pregnancy outcomes were more common among women with connective tissue disease but risks have decreased over time. PMID- 26234801 TI - Predictors of outcome of an Internet-based cognitive-behavioural therapy for post traumatic stress disorder in older adults. AB - OBJECTIVES: The aim of this study was to evaluate the role of resource-oriented variables such as self-efficacy, locus of control (LOC) and post-traumatic growth (PTG) in predicting treatment response in older adults with post-traumatic stress. METHODS: Fifty-eight older adults with subsyndromal or greater severity of war-associated post-traumatic stress disorder (PTSD) symptoms completed a randomized controlled Internet-based cognitive-behavioural therapy (CBT) with immediate and delayed treatment groups. Assessments of PTSD severity and resource oriented variables of self-efficacy, LOC and PTG were conducted at baseline, post treatment and at a 6-month follow-up. RESULTS: Results revealed that pre treatment scores on measures of internal LOC and PTG predicted PTSD symptom severity at post-treatment, even after controlling for initial PTSD. At a 6-month follow-up, internal LOC continued to predict PTSD symptom severity. In addition, repeated-measures analyses of variance revealed that, relative to older adults with low internal LOC and PTG, older adults with high internal LOC and PTG, respectively, did not differ with respect to initial PTSD severity, but they showed a more pronounced response to treatment. CONCLUSION: These findings suggest that greater locus of control and post-traumatic growth is associated with greater improvement in PTSD symptoms following Internet-based CBT. Assessment of these constructs may be useful in identifying trauma survivors who are most likely to respond to CBT. PRACTITIONER POINTS: Greater internal locus of control and post-traumatic growth is associated with greater improvement in PTSD symptoms following Internet-based CBT. Older adults with initial high internal locus of control and post-traumatic growth, respectively, did not differ with respect to initial PTSD severity, but they showed a more pronounced response to treatment. It could be assumed that patients with initial functional appraisals could benefit easier and faster from a trauma-focused cognitive-behavioural therapy compared to individuals with lower internal locus of control and post traumatic growth. PMID- 26234802 TI - Further improvement on delay-range-dependent robust absolute stability for Lur'e uncertain systems with interval time-varying delays. AB - This paper investigates improved delay-range-dependent robust absolute stability criteria for a class of Lur'e uncertain systems with interval time-varying delays. By using delayed decomposition approach (DDA), a tighter upper bound of the derivative of Lyapunov functional can be obtained, and thus the proposed criteria give results with less conservatism compared with some previous ones. An integral inequality approach (IIA) is proposed to reduce the conservativeness in computing the allowable maximum admissible upper bound (MAUB) of the time-delay. The developed stability condition is expressed in terms of linear matrix inequality (LMI) that manipulates fewer decision variables and requires reduced computational load. Finally, three numerical examples are given to show the effectiveness of the proposed stability criteria. PMID- 26234800 TI - Do pre-existing diabetes social support or depressive symptoms influence the effectiveness of a diabetes management intervention? AB - OBJECTIVE: Examine influences of diabetes-specific social support (D-SS) and depressive symptoms on glycemic control over time, among adults randomized to a diabetes self-management education and support (DSME/S) intervention or usual care. METHODS: Data were from 108 African-American and Latino participants in a 6 month intervention trial. Multivariable linear regression models assessed associations between baseline D-SS from family and friends and depressive symptoms with changes in HbA1c. We then examined whether baseline D-SS or depression moderated intervention-associated effects on HbA1c. RESULTS: Higher baseline D-SS was associated with larger improvements in HbA1c (adjusted DeltaHbA1c -0.39% for each +1-point D-SS, p=0.02), independent of intervention associated HbA1c decreases. Baseline depressive symptoms had no significant association with subsequent HbA1c change. Neither D-SS nor depression moderated intervention-associated effects on HbA1c. CONCLUSIONS AND PRACTICE IMPLICATIONS: Diabetes self-management education and support programs have potential to improve glycemic control for participants starting with varying levels of social support and depressive symptoms. Participants starting with more support for diabetes management from family and friends improved HbA1c significantly more over 6 months than those with less support, independent of additional significant DSME/S intervention-associated HbA1c improvements. Social support from family and friends may improve glycemic control in ways additive to DSME/S. PMID- 26234803 TI - Investigating virtual reality navigation in amnestic mild cognitive impairment using fMRI. AB - Spatial navigation requires a well-established network of brain regions, including the hippocampus, caudate nucleus, and retrosplenial cortex. Amnestic Mild Cognitive Impairment (aMCI) is a condition with predominantly memory impairment, conferring a high predictive risk factor for dementia. aMCI is associated with hippocampal atrophy and subtle deficits in spatial navigation. We present the first use of a functional Magnetic Resonance Imaging (fMRI) navigation task in aMCI, using a virtual reality analog of the Radial Arm Maze. Compared with controls, aMCI patients showed reduced activity in the hippocampus bilaterally, retrosplenial cortex, and left dorsolateral prefrontal cortex. Reduced activation in key areas for successful navigation, as well as additional regions, was found alongside relatively normal task performance. Results also revealed increased activity in the right dorsolateral prefrontal cortex in aMCI patients, which may reflect compensation for reduced activations elsewhere. These data support suggestions that fMRI spatial navigation tasks may be useful for staging of progression in MCI. PMID- 26234804 TI - Controllable Growth of Vertical Heterostructure GaTe(x)Se(1-x)/Si by Molecular Beam Epitaxy. AB - Two dimensional (2D) alloys, especially transition metal dichalcogenides, have attracted intense attention owing to their band-gap tunability and potential optoelectrical applications. Here, we report the controllable synthesis of wafer scale, few-layer GaTexSe1-x alloys (0 <= x <= 1) by molecular beam epitaxy (MBE). We achieve a layer-by-layer growth mode with uniform distribution of Ga, Te, and Se elements across 2 in. wafers. Raman spectroscopy was carried out to explore the composition-dependent vibration frequency of phonons, which matches well with the modified random-element-isodisplacement model. Highly efficient photodiode arrays were also built by depositing few-layer GaTe0.64Se0.36 on n-type Si substrates. These p-n junctions have steady rectification characteristics with a rectifying ratio exceeding 300 and a high external quantum efficiency around 50%. We further measured more devices on MBE-grown GaTexSe1-x/Si heterostructures across the full range to explore the composition-dependent external quantum efficiency. Our study opens a new avenue for the controllable growth of 2D alloys with wafer-scale homogeneity, which is a prominent challenge in 2D material research. PMID- 26234805 TI - Accelerating peroxidase mimicking nanozymes using DNA. AB - DNA-capped iron oxide nanoparticles are nearly 10-fold more active as a peroxidase mimic for TMB oxidation than naked nanoparticles. To understand the mechanism, the effect of DNA length and sequence is systematically studied, and other types of polymers are also compared. This rate enhancement is more obvious with longer DNA and, in particular, poly-cytosine. Among the various polymer coatings tested, DNA offers the highest rate enhancement. A similar acceleration is also observed for nanoceria. On the other hand, when the positively charged TMB substrate is replaced by the negatively charged ABTS, DNA inhibits oxidation. Therefore, the negatively charged phosphate backbone and bases of DNA can increase TMB binding by the iron oxide nanoparticles, thus facilitating the oxidation reaction in the presence of hydrogen peroxide. PMID- 26234807 TI - SUMOylation: A link to future therapeutics. AB - SUMOylation, much of a similar process like ubiquitination catches attention across various research groups as a potential therapeutic target to fight various infectious and cancerous diseases. This idea take its strength from recent reports which unearth the molecular mechanisms of SUMOylation and its involvement in important diseases distributed across various kingdoms. At the beginning SUMOylation was considered a process affected only by viral diseases but subsequent reports enlighten its role in diseases caused by bacteria as well. This enhances the SUMOylation canvas and demanded more in-depth study of the process. The present review is an attempt to study the regulatory mechanism of genes when the natural SUMOylation pathway is disturbed, the cross-talk among SUMOylation and other post translational modifications, the role of miRNAs in controlling the function of transcripts, loading of RNA species into exosomes and the possible SUMOylation related therapeutic targets. PMID- 26234806 TI - Attention network functioning in children with anxiety disorders, attention deficit/hyperactivity disorder and non-clinical anxiety. AB - BACKGROUND: Research with adults suggests that anxiety is associated with poor control of executive attention. However, in children, it is unclear (a) whether anxiety disorders and non-clinical anxiety are associated with deficits in executive attention, (b) whether such deficits are specific to anxiety versus other psychiatric disorders, and (c) whether there is heterogeneity among anxiety disorders (in particular, specific phobia versus other anxiety disorders). METHOD: We examined executive attention in 860 children classified into three groups: anxiety disorders (n = 67), attention-deficit/hyperactivity disorder (ADHD; n = 67) and no psychiatric disorder (n = 726). Anxiety disorders were subdivided into: anxiety disorders excluding specific phobia (n = 43) and specific phobia (n = 21). The Attention Network Task was used to assess executive attention, alerting and orienting. RESULTS: Findings indicated heterogeneity among anxiety disorders, as children with anxiety disorders (excluding specific phobia) showed impaired executive attention, compared with disorder-free children, whereas children with specific phobia showed no executive attention deficit. Among disorder-free children, executive attention was less efficient in those with high, relative to low, levels of anxiety. There were no anxiety related deficits in orienting or alerting. Children with ADHD not only had poorer executive attention than disorder-free children, but also higher orienting scores, less accurate responses and more variable response times. CONCLUSIONS: Impaired executive attention in children (reflected by difficulty inhibiting processing of task-irrelevant information) was not fully explained by general psychopathology, but instead showed specific associations with anxiety disorders (other than specific phobia) and ADHD, as well as with high levels of anxiety symptoms in disorder-free children. PMID- 26234808 TI - Comparison of treatment with continuous subcutaneous insulin infusion versus multiple daily insulin injections with bolus calculator in patients with type 1 diabetes. AB - OBJECTIVES: A study of the glycemic control, quality of life, and fear and perception of hypoglycemia by comparing continuous subcutaneous insulin infusion (CSII) group with multiple daily inyections (MDI) with bolus calculator group. MATERIAL AND METHODS: This is a retrospective cohort study with following up during the first 12 months that CSII group (n=30) begins the use of "bolus wizard" and the MDI-calculator (n=30) group begins the use of the bolus calculator (Accu-Chek((r)) Aviva Expert). PRIMARY OUTCOME: HbA1c (3, 6 and 12 months). Questionnaires used: EsDQOL (quality of life), FH-15 (fear of hypoglycemia), and Clarke (perception of hypoglycemia). STATISTICAL ANALYSIS: T Student and nonparametric tests. RESULTS: The average reduction in HbA1c during the study was significantly higher in CSII group (-0.56+/-0.84%) compared with the MDI group (0.097+/-0.94%), P=.028. The average basal insulin dose was significantly higher in the MDI group (at baseline, 6 and 12 months). No significant differences were found between the 2 treatment groups after analyzing the EsDQOL, FH-15 and Clarke questionnaires. In the CSII group, perceived quality of life assessed by the EsDQOL questionnaire was found to be better at the end of the study than at the beginning of using the insulin pump. CONCLUSIONS: The average reduction in HbA1c was significantly higher in the CSII group. In the CSII group, perceived quality of life was better at the end of the study than at the beginning. PMID- 26234809 TI - With reference to the paper by Hubig et al. entitled 'Temperature based forensic death time estimation: The standard model in experimental test' (Legal Med 2015 XX). PMID- 26234810 TI - A Cu(111) supported h-BN nanosheet: a potential low-cost and high-performance catalyst for CO oxidation. AB - A Cu(111) supported h-BN nanosheet (h-BNNS) has been systematically investigated by first-principles DFT using dispersion corrections. During the interaction between Cu and h-BNNS, the electrons migrate from the metal to the h-BNNS, leading to the formation of gap states above and under the Fermi level. Significant electrons are observed to migrate from the supported h-BNNS to the O2 molecule, resulting in the activation of the adsorbed O2. While for the unsupported h-BNNS, the absorbed O2 is almost intact with a very weak binding energy. CO oxidation is chosen as a benchmark probe reaction to better understand the enhanced catalytic activity induced by the Cu(111) metal substrate. The calculated energy barrier of the reaction CO + O2* -> CO2* + O* is found to be only 0.51 eV with a large exothermicity of -2.93 eV. Even for the process of CO reacting with the residual atomic O* to generate CO2*, the barrier is found to be nearly null, helping the catalyst to facilely recover itself. Our calculation results suggest that the Cu(111) supported h-BNNS is a potential low cost and high activity catalyst for CO oxidation. PMID- 26234811 TI - A perforator from the ulnar artery and cutaneous nerve of the hypothenar area: An anatomical study for clinical application. AB - PURPOSE: The hypothenar perforator flap is a recently introduced method for fingertip reconstruction, which offers excellent results but lacks adequate anatomic studies. The present study is aimed to clarify the anatomic characteristics of the hypothenar area to analyze the potential clinical application of sensate flaps and to access the reliability of hypothenar perforator arteries. MATERIALS AND METHODS: A total of 26 amputated forearms were used, and a percentage scattergram using an x-y-axis was created. The y-axis was a vertical line from the midpoint of pisiform base (0%) to the midvolar crease of the metacarpophalangeal joint (100%). The x-axis was a line perpendicular to the y-axis, and was quantified as a percentage value. We then studied the number of perforators, the diameter and length of the pedicle, and evaluated the differences between the zones and sexes. RESULTS: A reliable region for the hypothenar perforator flap, including more than two perforator arteries with an average diameter of over 1 mm, was mapped as 5%-20% on the x-axis and 10%-50% on the y-axis. The nerves appeared to occur more densely than the arteries, with 5% 15% on the x-axis and 25%-60% on the y-axis. CONCLUSION: The most consistent area for sensate flap elevation was the region around 5%-15% on the x-axis and 25%-50% on the y-axis. We expect that our data concerning perforator artery and cutaneous nerve branches in the hypothenar area of the hand will aid in establishing appropriate clinical usage of the hypothenar perforator flap. (c) 2014 Wiley Periodicals, Inc. Microsurgery 37:49-56, 2017. PMID- 26234812 TI - A prospective case series evaluating efficacy and safety of combination of itraconazole and potassium iodide in rhinofacial conidiobolomycosis. AB - BACKGROUND: Rhinofacial conidiobolomycosis (RFC) is an uncommon subcutaneous fungal infection producing painless swelling with grotesque deformity of the face. Although there are case reports and small case series; there are very few prospective studies evaluating treatment outcome and long-term follow-up. OBJECTIVE: To evaluate the safety and efficacy of combination of itraconazole (200 mg twice daily) and saturated solution of potassium iodide (SSKI) in patients with RFC. METHODS: Ten patients of RFC were studied over a period of 5 years. Diagnosis was confirmed by clinical, histopathological, and microbiological evaluation. Conidiobolus was cultured in four cases and in the rest of the cases, the histopathology was suggestive of RFC. They were treated with itraconazole (200 mg twice daily) and SSKI and followed up for a minimum of 1 year after stopping treatment. RESULTS: The mean age was 38.7 years and the mean duration of symptoms was 22.4 months. Males were predominantly involved (9 : 1). Seven patients responded to the combination treatment, five had complete resolution and two had good improvement (50-75%); however, in two patients the response was minimal (<25% regression of the swelling) and one patient did not show any improvement after 6 months of treatment. CONCLUSION: Combination of itraconazole and SSKI is an effective treatment modality for RFC with relatively faster onset of action, low relapse rates, and minimal adverse effects. It can be considered as first-line treatment in patients with RFC. PMID- 26234814 TI - Lack of language skills and knowledge of local culture in international medical graduates: Implications for the NHS. AB - International Medical Graduates (IMGs) form a coherent part of the National Health Service (NHS). Nearly 25% of the doctors working in the NHS are IMGs who obtained their primary medical degree from outside the EU. Moving to a different country that holds a different set of values and belief systems can be very challenging for IMGs, which in turn could have a significant effect on the service provided to NHS patients. This article will address the issue of effective communication skills within the IMG population and will explore the underlying issues behind this problem. PMID- 26234813 TI - Csk-Induced Phosphorylation of Src at Tyrosine 530 is Essential for H2O2-Mediated Suppression of ERK1/2 in Human Umbilical Vein Endothelial Cells. AB - Mitogen-activated protein kinases (MAPKs) are key signal transducers involved in various cellular events such as growth, proliferation, and differentiation. Previous studies have reported that H2O2 leads to phosphorylation of extracellular signal-regulated kinase (ERK), one of the MAPKs in endothelial cells. The current study shows that H2O2 suppressed ERK1/2 activation and phosphorylation at specific concentrations and times in human umbilical vein endothelial cells but not in immortalized mouse aortic endothelial cells or human astrocytoma cell line CRT-MG. Phosphorylation of other MAPK family members (i.e., p38 and JNK) was not suppressed by H2O2. The decrease in ERK1/2 phosphorylation induced by H2O2 was inversely correlated with the level of phosphorylation of Src tyrosine 530. Using siRNA, it was found that H2O2-induced suppression of ERK1/2 was dependent on Csk. Physiological laminar flow abrogated, but oscillatory flow did not affect, the H2O2-induced suppression of ERK1/2 phosphorylation. In conclusion, H2O2-induced Csk translocation to the plasma membrane leads to phosphorylation of Src at the tyrosine 530 residue resulting in a reduction of ERK1/2 phosphorylation. Physiological laminar flow abrogates this effect of H2O2 by inducing phosphorylation of Src tyrosine 419. These findings broaden our understanding of signal transduction mechanisms in the endothelial cells against oxidative stress. PMID- 26234815 TI - Should we implement mealtime assistance in the hospital setting? A systematic literature review with meta-analyses. AB - AIMS AND OBJECTIVES: This review aimed to determine the effect of mealtime assistance provided to hospitalised patients (>=65 years) by nurses, trained staff or volunteers on nutritional and anthropometric outcomes. BACKGROUND: Malnutrition is a critical issue in hospitals with a reported prevalence of 20 50%. Nutritional supplementation has been associated with increased weight gain, improved function and decreased mortality; however, other system approaches including mealtime assistance may also contribute to improving nutritional intake. DESIGN: A systematic literature review. METHODS: Six electronic databases (CINAHL Plus, Cochrane Library, ProQuest Nursing and Allied Health Source, Scopus, PsycINFO and MEDLINE) were searched from their inception to August 2014. Inclusion criteria were hospitalised patients >=65 years, provided mealtime assistance by nurses, volunteers or trained staff. Studies were examined for quality and risk of bias. Outcome data were combined narratively and by meta analyses. RESULTS: From 5458 publications, five studies met the inclusion criteria. Studies were rated neutral and positive according to the Academy of Nutrition and Dietetics Quality Checklist. Adherence to study protocols was not always reported. Meta-analyses demonstrated significantly greater daily energy and protein intake where mealtime assistance was provided. Anthropometric outcomes generally did not differ significantly with mealtime assistance. Observation and sampling bias were noted in several studies. CONCLUSIONS: There is evidence that mealtime assistance increases daily energy and protein intake in hospitalised patients (>=65 years). More robust research is needed to elucidate whether this strategy may be an effective means of addressing the high prevalence of malnutrition in hospitals. RELEVANCE TO CLINICAL PRACTICE: The evidence identified suggests that mealtime assistance provided to hospitalised older patients (>=65 years) leads to a statistically significant increase in energy and protein intake. For many patients, this increase in both energy and protein intake will be clinically significant, reducing the gap between requirements and actual intake. PMID- 26234816 TI - Pax factors in transcription and epigenetic remodelling. AB - The nine Pax transcription factors that constitute the mammalian family of paired domain (PD) factors play key roles in many developmental processes. As DNA binding transcription factors, they exhibit tremendous variability and complexity in their DNA recognition patterns. This is ascribed to the presence of multiple DNA binding structural domains, namely helix-turn-helix (HTH) domains. The PD contains two HTH subdomains and four of the nine Pax factors have an additional HTH domain, the homeodomain (HD). We now review these diverse DNA binding modalities together with their properties as transcriptional activators and repressors. The action of Pax factors on gene expression is also exerted through recruitment of chromatin remodelling complexes that introduce either activating or repressive chromatin marks. Interestingly, the recent demonstration that Pax7 has pioneer activity, the unique property to "open" chromatin, further underlines the mechanistic versatility and the developmental importance of these factors. PMID- 26234817 TI - ArsP: a methylarsenite efflux permease. AB - Trivalent organoarsenic compounds are far more toxic than either pentavalent organoarsenicals or inorganic arsenite. Many microbes methylate inorganic arsenite (As(III)) to more toxic and carcinogenic methylarsenite (MAs(III)). Additionally, monosodium methylarsenate (MSMA or MAs(V)) has been used widely as an herbicide and is reduced by microbial communities to MAs(III). Roxarsone (3 nitro-4-hydroxybenzenearsonic acid) is a pentavalent aromatic arsenical that is used as antimicrobial growth promoter for poultry and swine, and its active form is the trivalent species Rox(III). A bacterial permease, ArsP, from Campylobacter jejuni, was recently shown to confer resistance to roxarsone. In this study, C. jejuni arsP was expressed in Escherichia coli and shown to confer resistance to MAs(III) and Rox(III) but not to inorganic As(III) or pentavalent organoarsenicals. Cells of E. coli expressing arsP did not accumulate trivalent organoarsenicals. Everted membrane vesicles from those cells accumulated MAs(III) > Rox(III) with energy supplied by NADH oxidation, reflecting efflux from cells. The vesicles did not transport As(III), MAs(V) or pentavalent roxarsone. Mutation or modification of the two conserved cysteine residues resulted in loss of transport activity, suggesting that they play a role in ArsP function. Thus, ArsP is the first identified efflux system specific for trivalent organoarsenicals. PMID- 26234818 TI - Dioxin risk reduction programme at the most severe dioxin hot spot in Vietnam: Residual knowledge, attitude and practices five years post intervention. AB - Bien Hoa Airbase was one of the bulk storage and supply facilities for defoliants during the Vietnam War. Environmental and biological samples taken around the airbase have elevated levels of dioxin. In 2007, a pre-intervention knowledge, attitude and practice (KAP) survey of local residents living in Trung Dung and Tan Phong wards was undertaken regarding appropriate strategies to reduce dioxin exposure. A risk reduction programme was implemented in 2008 and post intervention KAP surveys were undertaken in 2009 and 2013 to evaluate the longer term impacts. Quantitative assessment was undertaken via a KAP survey in 2013 among 600 local residents randomly selected from the two intervention wards and one control ward (Buu Long). Eight in-depth interviews and two focus group discussions were also undertaken for qualitative assessment. Most programme activities had ceased and dioxin risk communication activities had not been integrated into local routine health education programmes; however, main results generally remained and were better than that in Buu Long. In total, 48.2% of households undertook measures to prevent exposure, higher than those in pre- and post-intervention surveys (25.8% and 39.7%) and the control ward (7.7%). Migration and the sensitive nature of dioxin issues were the main challenges for the programme's sustainability. PMID- 26234819 TI - Resting-state functional connectivity in major depressive disorder: A review. AB - Major depressive disorder (MDD) affects multiple large-scale functional networks in the brain, which has initiated a large number of studies on resting-state functional connectivity in depression. We review these recent studies using either seed-based correlation or independent component analysis and propose a model that incorporates changes in functional connectivity within current hypotheses of network-dysfunction in MDD. Although findings differ between studies, consistent findings include: (1) increased connectivity within the anterior default mode network, (2) increased connectivity between the salience network and the anterior default mode network, (3) changed connectivity between the anterior and posterior default mode network and (4) decreased connectivity between the posterior default mode network and the central executive network. These findings correspond to the current understanding of depression as a network based disorder. PMID- 26234820 TI - Urchin-like Au@CdS/WO3 micro/nano heterostructure as a visible-light driven photocatalyst for efficient hydrogen generation. AB - Urchin-like micro/nano heterostructure Au@CdS/WO3 was synthesized by using a facile photodeposition method with no need for an additional stabilizer, which can be used as an efficient all-solid Z-scheme visible-light photocatalyst for H2 generation with a high H2 evolution rate. PMID- 26234822 TI - Individual differences in neural mechanisms of selective auditory attention in preschoolers from lower socioeconomic status backgrounds: an event-related potentials study. AB - Selective attention, the ability to enhance the processing of particular input while suppressing the information from other concurrent sources, has been postulated to be a foundational skill for learning and academic achievement. The neural mechanisms of this foundational ability are both vulnerable and enhanceable in children from lower socioeconomic status (SES) families. In the current study, we assessed individual differences in neural mechanisms of this malleable brain function in children from lower SES families. Specifically, we investigated the extent to which individual differences in neural mechanisms of selective auditory attention accounted for variability in nonverbal cognitive abilities in lower SES preschoolers. We recorded event-related potentials (ERPs) during a dichotic listening task and administered nonverbal IQ tasks to 124 lower SES children (77 females) between the ages of 40 and 67 months. The attention effect, i.e., the difference in ERP mean amplitudes elicited by identical probes embedded in stories when attended versus unattended, was significantly correlated with nonverbal IQ scores. Larger, more positive attention effects over the anterior and central electrode locations were associated with superior nonverbal IQ performance. Our findings provide initial evidence for prominent individual differences in neural indices of selective attention in lower SES children. Furthermore, our results indicate a noteworthy relationship between neural mechanisms of selective attention and nonverbal IQ performance in lower SES preschoolers. These findings provide the basis for future research to identify the factors that contribute to such individual differences in neural mechanisms of selective attention. PMID- 26234821 TI - Sodium butyrate alleviates adipocyte inflammation by inhibiting NLRP3 pathway. AB - Insulin resistance (IR) is a common feature of Type II diabetes, metabolic disorders, hypertension and other vascular diseases. Recent studies showed that obesity-induced inflammation may be critical for IR. To investigate the anti inflammatory effect of sodium butyrate (NaB) on obesity-induced inflammation, the db/db mice were intraperitoneally injected with NaB for 6 weeks. Glucose control was evaluated by glucose tolerance test (GTT) and insulin tolerance test (ITT). Adipose tissue was harvested for gene expression analysis. 3T3-L1 adipocytes were treated with Tnf-alpha to mimic the inflammatory state and gene expression was detected by realtime PCR and Western blotting. Our results showed that NaB treatment improved glucose control in db/db mice as determined by GTT and ITT tests. Gene expression analysis showed that NaB inhibited cytokines and immunological markers including CD68, Interferon-gamma and Mcp in adipose tissues in db/db mice. Moreover, NaB inhibited cytokine releasing in 3T3-L1 adipocytes treated with TNF-alpha. Further analysis of inflammation pathway showed that NLRP3 was activated in db/db mice, which was efficiently inhibited by NaB treatment. Our data suggest that inhibition of obesity-induced inflammation alleviates IR, and NaB might be a potential anti-inflammatory agent for obesity. PMID- 26234824 TI - Engineering topological superconductors using surface atomic-layer/molecule hybrid materials. AB - Surface atomic-layer (SAL) superconductors consisting of epitaxially grown metal adatoms on a clean semiconductor surface have been recently established. Compared to conventional metal thin films, they have two important features: (i) space inversion symmetry-breaking throughout the system and (ii) high sensitivity to surface adsorption of foreign species. These potentially lead to manifestation of the Rashba effect and a Zeeman field exerted by adsorbed magnetic organic molecules. After introduction of the archetypical SAL superconductor Si(111)-(?7 * ?3)-In, we describe how these features are utilized to engineer a topological superconductor with Majorana fermions and discuss its promises and expected challenges. PMID- 26234823 TI - The adaptive statistical iterative reconstruction-V technique for radiation dose reduction in abdominal CT: comparison with the adaptive statistical iterative reconstruction technique. AB - OBJECTIVE: To investigate whether reduced radiation dose abdominal CT images reconstructed with adaptive statistical iterative reconstruction V (ASIR-V) compromise the depiction of clinically competent features when compared with the currently used routine radiation dose CT images reconstructed with ASIR. METHODS: 27 consecutive patients (mean body mass index: 23.55 kg m(-2) underwent CT of the abdomen at two time points. At the first time point, abdominal CT was scanned at 21.45 noise index levels of automatic current modulation at 120 kV. Images were reconstructed with 40% ASIR, the routine protocol of Dong-A University Hospital. At the second time point, follow-up scans were performed at 30 noise index levels. Images were reconstructed with filtered back projection (FBP), 40% ASIR, 30% ASIR-V, 50% ASIR-V and 70% ASIR-V for the reduced radiation dose. Both quantitative and qualitative analyses of image quality were conducted. The CT dose index was also recorded. RESULTS: At the follow-up study, the mean dose reduction relative to the currently used common radiation dose was 35.37% (range: 19-49%). The overall subjective image quality and diagnostic acceptability of the 50% ASIR-V scores at the reduced radiation dose were nearly identical to those recorded when using the initial routine-dose CT with 40% ASIR. Subjective ratings of the qualitative analysis revealed that of all reduced radiation dose CT series reconstructed, 30% ASIR-V and 50% ASIR-V were associated with higher image quality with lower noise and artefacts as well as good sharpness when compared with 40% ASIR and FBP. However, the sharpness score at 70% ASIR-V was considered to be worse than that at 40% ASIR. Objective image noise for 50% ASIR-V was 34.24% and 46.34% which was lower than 40% ASIR and FBP. CONCLUSION: Abdominal CT images reconstructed with ASIR-V facilitate radiation dose reductions of to 35% when compared with the ASIR. ADVANCES IN KNOWLEDGE: This study represents the first clinical research experiment to use ASIR-V, the newest version of iterative reconstruction. Use of the ASIR-V algorithm decreased image noise and increased image quality when compared with the ASIR and FBP methods. These results suggest that high-quality low-dose CT may represent a new clinical option. PMID- 26234825 TI - Temperature Management Guidelines. PMID- 26234826 TI - 50th Anniversary Landmark Commentary on Cosgrove DM, Thurer RL, Lytle BW, Gill CG, Peter M, Loop FD. Blood conservation during myocardial revascularization. Ann Thorac Surg 1979;28:184-9. PMID- 26234827 TI - 50th Anniversary Landmark Commentary on Bove EL, Behrendt DM. Open-heart surgery in the first week of life. Ann Thorac Surg 1980;29:130-4. PMID- 26234828 TI - 50th Anniversary Landmark Commentary on Deslauriers J, Beaulieu M, Benazera A, McClish A. Sleeve pneumonectomy for bronchogenic carcinoma. Ann Thorac Surg 1979;28:465-74. PMID- 26234829 TI - Should a Thoracic Surgeon Transfer a Complicated Case to a Competing Medical Center Against the Hospital's Order? PMID- 26234830 TI - Invited Commentary. PMID- 26234831 TI - Invited Commentary. PMID- 26234832 TI - Invited Commentary. PMID- 26234833 TI - Invited Commentary. PMID- 26234834 TI - Invited Commentary. PMID- 26234835 TI - Invited Commentary. PMID- 26234836 TI - Invited Commentary. PMID- 26234837 TI - Invited Commentary. PMID- 26234838 TI - Intraaortic Protection From Embolization in Patients Undergoing Transaortic Transcatheter Aortic Valve Implantation. AB - PURPOSE: Transcatheter aortic valve implantation (TAVI) results in the dislodgement of debris with risk of cerebral lesions or stroke. The EMBOL-X protection device (Edwards Lifesciences, Irvine, CA) is positioned within the ascending aorta to capture such debris. DESCRIPTION: Between July 2012 and April 2014 we randomly assigned 30 high-risk patients to undergo transaortic TAVI with the SAPIEN XT prosthesis (Edwards Lifesciences) combined with either the EMBOL-X device (group-1, n = 14) or without (group-2, n = 16). Periprocedural cerebral lesions were assessed by diffusion-weighted magnetic resonance imaging (DW-MRI) at baseline and within 7 days post-procedurally. EVALUATION: New foci of restricted diffusion on cerebral DW-MRI were found in 69% in group-2 and 50% in group-1. Lesion size was smaller in patients treated with the EMBOL-X device than in those without (88 +/- 60 vs 168 +/- 217 mm(3), p = 0.27, t = 1.2, degrees of freedom = 10). Transaortic TAVI patients treated with the EMBOL-X device had significantly smaller lesion volumes in the supply region of the middle cerebral artery (33 +/- 29 vs 76 +/- 67 mm(3), p = 0.04). There were no neurologic events after transaortic TAVI. CONCLUSIONS: The intraaortic protection device seems to reduce both the incidence and the volume of new cerebral lesions (ClinicalTrials.gov number, NCT01735513). PMID- 26234839 TI - Individualizing Management of Complex Esophageal Pathology Using Three Dimensional Printed Models. AB - PURPOSE: In complex esophageal cases, conventional two-dimensional imaging is limited in demonstrating anatomic relationships. We describe the utility of three dimensional (3D) printed models for complex patients to individualize care. DESCRIPTION: Oral effervescent agents, with positive enteric contrast, distended the esophagus during computed tomography (CT) scanning to facilitate segmentation during post-processing. The CT data were segmented, converted into a stereolithography file, and printed using photopolymer materials. EVALUATION: In 1 patient with a left pneumonectomy, aortic bypass, and esophageal diversion, 3D printing enabled visualization of the native esophagus and facilitated endoscopic mucosal resection, followed by hiatal dissection and division of the gastroesophageal junction as treatment. In a second patient, 3D printing allowed enhanced visualization of multiple esophageal diverticula, allowing for optimization of the surgical approach. CONCLUSIONS: Printing of 3D anatomic models in patients with complex esophageal pathology facilitates planning the optimal surgical approach and anticipating potential difficulties for the multidisciplinary team. These models are invaluable for patient education. PMID- 26234840 TI - Successful Resection of Giant Mediastinal Lipofibroadenoma of the Thymus by Video Assisted Thoracoscopic Surgery. AB - We report the case of a 20-year-old man who presented with a large heterogeneous mass incidentally found on a chest roentgenogram performed in the context of acute onset of fever and cough. A chest computed tomography scan showed a large heterogenous mass in the anterior mediastinum. The patient underwent surgical resection by a right video-assisted thoracoscopic approach. The resected mass was completely encapsulated and was histologically determined to be a lipofibroadenoma. Complete resection is curative. This is the sixth reported case of lipofibroadenoma of the thymus in the English literature and the first reported case of video-assisted thoracoscopic resection of a lipofibroadenoma. PMID- 26234841 TI - Rare Pulmonary Metastasis From Thyroid Mucosa-Associated Lymphoid Tissue Lymphoma. AB - Primary pulmonary lymphomas constitute up to 1% of all pulmonary malignancies. Patients with mucosa-associated lymphoid tissue (MALT) lymphoma represent approximately 90% of patients with primary pulmonary lymphoma. Most pulmonary MALT lymphomas are primary tumors. Pulmonary metastasis is extremely rare. A 65 year-old woman was diagnosed with a thyroid MALT lymphoma in 2008 and underwent total thyroidectomy, followed by chemotherapy. After 5 years of follow-up, she referred to our hospital with an abnormal shadow on a chest roentgenogram. She underwent video-assisted thoracoscopic surgery and was diagnosed with metastatic thyroid MALT lymphoma. Postoperatively, she was treated with chemotherapy, including rituximab, and is alive without recurrence. PMID- 26234842 TI - Rare Middle Mediastinal Paraganglioma Mimicking Metastatic Neuroendocrine Tumor. AB - Mediastinal paragangliomas are rare neural crest derived tumors that may produce symptoms of excess catecholamine production or mass effect. Paragangliomas can histologically mimic neuroendocrine tumors. Further, both can arise in similar locations. We report a patient who presented with a right upper lobe as well as middle mediastinal lesion. Preoperative biopsy as well as intraoperative frozen section of these lesions failed to distinguish between paraganlioma or neuroendocrine tumor, necessitating a right upper lobectomy and complete mediastinal lymphadenectomy. Final pathology revealed carcinoid tumorlets in the right upper lobe and a middle mediastinal paraganglioma. PMID- 26234843 TI - Preoperative Embolization of a Posterior Mediastinal Lipid-Poor Angiolipoma Mimicking a Paravertebral Nerve Sheath Tumor. AB - Mediastinal angiolipomas are extremely rare tumors within the thorax, and only 6 cases have been previously reported in the literature. We describe the case of a lipid-poor angiolipoma within the posterior mediastinum of a 63-year-old man who complained of chest pain. Interestingly, initial imaging of the posterior mediastinal mass of our patient suggested a nerve sheath tumor. A specimen from a percutaneous transthoracic core needle biopsy confirmed an angiolipoma. We decided to preoperatively embolize the posterior mediastinal mass to reduce intraoperative bleeding and to facilitate the excision of the tumor. PMID- 26234844 TI - Feasibility and Complications in Concomitant Lung Resection With Minimally Invasive Repair of Pectus Excavatum. AB - Minimally invasive repair of pectus excavatum (MIRPE) is the procedure of choice in experienced centers and can be offered in combination with other thoracic procedures. Between 2001 and 2013, 3 cases involving MIRPE and lung surgery were done in our clinic. While postoperative course of 2 procedures (MIRPE and video assisted thoracoscopic surgery [VATS] segmentectomy and MIRPE and VATS bullectomy) were uncomplicated, the MIRPE and VATS lung biopsy patient developed major complications arising from prolonged air leak and was ultimately managed with an Eloesser flap. In carefully selected cases, simultaneous lung surgery and MIRPE can be done safely but problems of lung reexpansion, long-term drainage, and infection should be kept in mind. PMID- 26234845 TI - Interatrial Bronchogenic Cyst Resection. AB - Interatrial bronchogenic cysts are rare entities, and the long-term clinical sequelae are unknown. This case report details the removal of a large (>4 cm) interatrial bronchogenic cyst that had been present for more than 10 years. Surgical resection remains the current standard of therapy when encountering an interatrial mass. PMID- 26234846 TI - Gene Mutation Analysis in Determining Late Recurrence of Adenocarcinoma of the Lung. AB - A patient was found to have a new pleural lesion 14 years after undergoing complete resection of primary lung cancer. Histologic and genetic analysis of the previously resected specimen and the samples obtained of a newly performed biopsy confirmed that the tumors were identical, and the recurrence of lung cancer was determined. This case is instructive because of the rather long interval between the resection of the initial tumor and the recurrence and because of the presence of validated proof of recurrence by both clinical features and genetic analysis. PMID- 26234847 TI - First-in-Man, Mitral Valve-in-Valve Transcatheter Implantation Through an Innovative Minimally Invasive Surgical Approach. AB - Degeneration of a surgically implanted valve bioprosthesis may occur in elderly, frail patients with an extremely high risk to undergo redo cardiac surgery. Transapical or fully percutaneous transseptal approaches have been described in order to treat degenerated aortic and mitral bioprosthesis. We performed the first-in-man successful mitral transcatheter valve delivery with a valve-in-valve technique through an innovative route; ie, a video-assisted endoscopic direct access to the left atrium, in an 82-year-old patient who previously underwent surgical replacement of the mitral valve and with a prohibitive surgical risk. PMID- 26234848 TI - Late Cardiac Tamponade as a Result of Parietal Pericardium Erosion. AB - Late onset cardiac tamponade is a rare and particularly challenging (both from diagnostic and management perspectives) complication of intracardiac lead implantation. We present a case of a late tamponade leading to cardiogenic shock, which occurred 1,164 days after implantable cardioverter-defibrillator (ICD) implantation. Open repair revealed unusual and, to our knowledge, not yet reported mechanism of the disease. A pressure sore caused by an ICD lead was found in the parietal layer of pericardium with no visible damage to the visceral layer. Conservative management in the described clinical scenario could be fatal, thus awareness of this pathomechanism of tamponade is critical. PMID- 26234849 TI - Infected False Aneurysm of the Aortic Arch After Endoscopic Transurethral Instillation of Bacillus Calmette-Guerin. AB - The case of an 81-year-old male operated on for an infected false aneurysm of the aortic arch by Mycobacterium bovis (M. bovis) is described. Arch reconstruction with cryopreserved aortic patch was successfully performed under hypothermic circulatory arrest. Antituberculous chemotherapy was given for 12 months and presently the patient is leading a normal life. Vascular infection after bacillus Calmette-Guerin bladder therapy is uncommon and aortic arch involvement near exceptional. This diagnosis has to be considered in patients with such previous urologic interventions. PMID- 26234850 TI - Left Ventricular Assist Device Implantation After Intracardiac Parachute Device Removal. AB - Left ventricular assist device implantation is a proven and efficient modality for the treatment of end-stage heart failure. Left ventricular assist device versatility as a bridge to heart transplantation or destination therapy has led to improved patient outcomes with a concomitant rise in its overall use. Other less invasive treatment modalities are being developed to improve heart function and morbidity and mortality for the heart failure population. Percutaneous ventricular restoration is a new investigational therapy that deploys an intracardiac parachute to wall off damaged myocardium in patients with dilated left ventricles and ischemic heart failure. Clinical trials are under way to test the efficacy of percutaneous ventricular restoration using the parachute device. This review describes our encounter with the parachute device, its explantation due to refractory heart failure, and surgical replacement with a left ventricular assist device. PMID- 26234851 TI - Deep Hypothermic Circulatory Arrest in a Patient With Cold-Induced Urticaria. AB - Acquired cold urticaria is a condition characterized by the onset of pruritic hives, swelling, and occasional severe systemic reactions, during the rewarming phase, after cold exposure. Pulmonary thromboendarterectomy (PTE) is a cardiac surgical procedure where organized thrombus is excised from the pulmonary vasculature in order to improve pulmonary blood flow and relieve pressure on the right ventricle. A PTE requires institution of deep hypothermic circulatory arrest (DHCA) in order to reduce blood flow from collateral vessels during thrombus excision. We describe a case of PTE performed under DHCA in a patient with ACU. PMID- 26234852 TI - Combined Transcatheter Aortic Valve Replacement and Thoracic Endovascular Aortic Repair Using Transapical Access. AB - Vascular complications remain an important consideration when selecting access for delivery of large endovascular devices. With the advent of transcatheter aortic valve replacement, transapical access has become an acceptable technique when transfemoral or direct transaortic access is contraindicated. We report the use of the transapical approach during thoracic aortic endovascular repair in 2 patients, one of which included concomitant delivery of a transcatheter aortic valve replacement device. To our knowledge, this is the first reported case of a hybrid single-stage transcatheter aortic valve replacement and thoracic aortic endovascular repair using transapical access. PMID- 26234853 TI - Recurrent Primary Cardiac Sarcoma Managed With Radical Cardiac Resection and Pneumonectomy. AB - Primary cardiac tumors are extremely rare. Although complete surgical resection of malignant primary cardiac tumors results in an improved survival compared with no intervention, the overall prognosis is generally poor, with treatable recurrent primary cardiac sarcomas being extremely rare. We report a patient with a recurrent primary cardiac sarcoma obstructing the left atrium managed with radical cardiac resection, including right pneumonectomy, with 21-month postprocedural survival. PMID- 26234854 TI - An Extensively Calcified Right Atrial Myxoma. PMID- 26234855 TI - Ortner's Syndrome Secondary to a Huge Left Atrium. PMID- 26234856 TI - Calcified Ascending Aortic Aneurysm. PMID- 26234857 TI - Giant Pseudoaneurysm of Reconstructed Right Ventricular Outflow Tract. PMID- 26234858 TI - Bovine Pericardial Wrap for Intractable Bleeding After Graft Replacement of the Ascending Aorta. AB - Bleeding after ascending aortic graft replacement or aortic root replacement is a well-known adverse event and is an important cause of morbidity and mortality after operations on the aorta. After a long pump run, the need of the hour is to achieve hemostasis expeditiously. We have used bovine pericardium as a wrap, which is useful in preventing bleeding from anastomotic suture lines. PMID- 26234859 TI - Novel Approach to Construct Absent Intrapericardial Branch Pulmonary Arteries. AB - Unilateral or bilateral absence of branch pulmonary arteries is a rare congenital heart defect. Various reconstructive techniques have been previously described, each with its inherent limitations. We present a novel technique of constructing a branch pulmonary artery that maintains potential for growth. PMID- 26234860 TI - Three-Sinus Repair of Elastin Arteriopathy Associated Supravalvar Pulmonary Stenosis With Bilateral Branch Pulmonary Artery Involvement. AB - Elastin arteriopathy-associated supravalvar pulmonary stenosis is characterized by a thick intraluminal ringlike obstruction at the sinotubular junction of the pulmonary valve. Extension of disease into the branch pulmonary arteries is common. A three-sinus pulmonary trunk augmentation combined with bilateral branch pulmonary augmentation is presented. This approach normalizes the pulmonary trunk and allows optimal augmentation of the central pulmonary arteries. PMID- 26234861 TI - Chest Wall Reconstruction Using a Methyl Methacrylate Neo-Rib and Mesh. AB - Prosthetic reconstruction of the chest wall after oncologic resection is performed by means of various techniques using different materials. We describe a new technique of chest wall reconstruction that includes the use of Marlex mesh and the creation of a neo-rib from a Steinmann pin and methyl methacrylate. PMID- 26234862 TI - The Society of Thoracic Surgeons, The Society of Cardiovascular Anesthesiologists, and The American Society of ExtraCorporeal Technology: Clinical Practice Guidelines for Cardiopulmonary Bypass--Temperature Management During Cardiopulmonary Bypass. AB - In order to improve our understanding of the evidence-based literature supporting temperature management during adult cardiopulmonary bypass, The Society of Thoracic Surgeons, the Society of Cardiovascular Anesthesiology and the American Society of ExtraCorporeal Technology tasked the authors to conduct a review of the peer-reviewed literature, including: 1) optimal site for temperature monitoring, 2) avoidance of hyperthermia, 3) peak cooling temperature gradient and cooling rate, and 4) peak warming temperature gradient and rewarming rate. Authors adopted the American College of Cardiology/American Heart Association method for development clinical practice guidelines, and arrived at the following recommendations: No Recommendation No recommendation for a guideline is provided concerning optimal temperature for weaning from CPB due to insufficient published evidence. PMID- 26234863 TI - Therapeutic Pneumothorax and the Nobel Prize. AB - At the turn of the 20th century, the epidemic proportions of tuberculosis puzzled great parts the scientific community. Thus it is not surprising that well-known scholars who worked on particularly promising solutions to fight the disease were nominated for the Nobel Prize for Physiology or Medicine, perhaps the most prestigious benchmark of scientific excellence. The authors have gathered files on the Italian phtisiologist Carlo Forlanini (1847 to 1918) at the Nobel Prize archive for Physiology or Medicine in Solna, Sweden. Drawing on these files and contemporary publications, the authors discuss the origin of artificial pneumothorax for treating pulmonary tuberculosis, show how it became an international gold standard operation, and trace why the Nobel committee finally chose not to award Forlanini. Twenty Nobel Prize nominations for Forlanini were submitted from 1912 to 1919 exclusively by Italian scholars. In 1913 and 1914, Forlanini was on the shortlist of the Nobel Committee and thus one of the prime candidates for the prestigious prize. Important aspects of the rise, fall, and revival of the artificial pneumothorax from 1815 to 2015 are highlighted along with its benefits and risks. PMID- 26234864 TI - Is Endurance of Homografts Affected by End-Stage Renal Disease in Patients With Aortic Valve Endocarditis? PMID- 26234865 TI - Near-Infrared Spectroscopy in Adult Patients Receiving Extracorporeal Membrane Oxygenation. PMID- 26234866 TI - Reply: To PMID 25661581. PMID- 26234868 TI - Reply: To PMID 25193209. PMID- 26234869 TI - Reply: To PMID 25530090. PMID- 26234867 TI - Easier and Quicker Surgical Solution for Destructive Aortic Endocarditis. PMID- 26234870 TI - Quality of Lymphadenectomy in Lung Cancer. PMID- 26234871 TI - Surgical Strategy for Malignant Pleural Mesothelioma: Where Are We Going and What Are We Missing? PMID- 26234872 TI - Reply: To PMID 24726598. PMID- 26234873 TI - About Chimney Technique for Mitral Valve Replacement. PMID- 26234874 TI - Reply: To PMID 24182489. PMID- 26234875 TI - Acute Lung Injury After Bilateral Lung Transplantation Due to Contralateral Pulmonary Arterial Anastomotic Obstruction. AB - Acute lung injury after lung transplantation is usually due to reperfusion injury and can severely affect outcome. Unilateral lung injury is usually due to obstruction of the pulmonary venous/left atrial anastomosis. We present the successful treatment of a patient with unilateral acute lung injury unusually caused by contralateral pulmonary artery anastomotic obstruction. The detection and management of this clinical situation is discussed. PMID- 26234876 TI - Corrective Operation in an Intramyocardial Dissecting Hemorrhage After Subacute Anterior Myocardial Infarction. AB - Intramyocardial dissecting hemorrhage is a very rare and potentially lethal complication of myocardial infarction. The diagnosis is typically made by echocardiography, by cardiac magnetic resonance imaging, at operation, or during postmortem examination. Medical treatment is most often associated with high mortality, and surgical treatment is required. We report a 53-year old man admitted to the urology department with a large left-sided kidney infarction. A subacute myocardial infarction by electrocardiogram, elevated troponin T level, and typical clinical signs of an acute coronary syndrome 5 days and 2 weeks before admission were also evident. Intramyocardial dissecting hemorrhage with an adjacent thrombotic formation was suspected by echocardiography and cardiac computed tomography and confirmed by magnetic resonance imaging. The patient underwent successful surgical correction and was discharged in good clinical condition. PMID- 26234877 TI - Endovascular Repair of Ascending Aortic Pseudoaneurysm With Custom-Designed Endograft. AB - Open repair of ascending aortic pseudoaneurysm (AscAP) carries high risks and mortality rate. Previous papers reported the off-label use of standard thoracic or abdominal endograft in very selected cases. We present the case of a 57-year old man with an AscAP successfully managed with a new custom-designed endograft. PMID- 26234878 TI - Pulmonary Artery Band Reduces Left Atrial Pressure in Dilated Cardiomyopathy. AB - We describe a case of pulmonary artery band placement in a 2-month-old infant with dilated cardiomyopathy and moderate mitral regurgitation in impending need of ventricular assist device. Despite minimal change in echocardiographic appearance, pulmonary artery band placement resulted in significantly reduced left atrial pressure and unchanged right atrial pressure. Improved cardiac output has enabled weaning from ventilator support and favorable somatic growth with enteral feeding. The patient has been stable on milrinone for 3 months, awaiting cardiac transplantation on a regular ward. This therapy represents a potential alternative in small children, who are deemed high-risk candidates for mechanical circulatory support. PMID- 26234879 TI - An Unusual Subcutaneous Mass After Cardiac Surgery: Do Not Forget Ventricular Pseudoaneurysms. PMID- 26234880 TI - Left Main Bronchial Stenosis Mimicking Congenital Lobar Emphysema in an 8-Month Old Child. PMID- 26234881 TI - Precise De Vega Annuloplasty Using Tricuspid Valve Gauges. AB - Simple tricuspid annuloplasty gauges are described that simulate normal tricuspid valve annular geometry and enable the surgeon to perform precise De Vega tricuspid annuloplasties, with restoration of normal tricuspid valve configuration and function. PMID- 26234882 TI - The effect of pH on the rheology of mixed gels containing whey protein isolate and xanthan-curdlan hydrogel. AB - The ultimate goal of this work was to examine the effect of xanthan-curdlan hydrogel complex (XCHC) on the rheology of whey protein isolate (WPI) within the pH range of 4-7 upon heating and cooling. Dynamic rheological properties of WPI and XCHC were studied individually and in combination, as a function of time or temperature. For pure WPI, gels were pH-dependent, and in all pH values except 7, gels formed upon first heating from 40 to 90 degrees C. At pH 7, WPI did not form gel upon first heating, and the storage modulus (G') started to increase during the holding time at 90 degrees C. The onset of gelation temperature of WPI was lower in acidic pH ranges compared to the neutral pH. In mixed gels, the presence of XCHC increased the G' of the gels. The rheological behaviour was pH dependent and initially was controlled by XCHC; however, after the consolidation of WPI network, the behaviour was led by the whey protein isolate. Results showed that XCHC had a synergistic effect on enhancing the elastic modulus of the gels after the consolidation of WPI network. Based on the results of this study, it is possible to use these biopolymers in the formulation of frozen dairy-based products and enable food manufactures to improve the textural and physicochemical properties, and as a result the consumer acceptance of the food product. PMID- 26234883 TI - Unravelling caesarean delivery as a risk factor for antepartum stillbirth. PMID- 26234885 TI - Fezf2 expression in layer 5 projection neurons of mature mouse motor cortex. AB - The mature cerebral cortex contains a wide diversity of neuron phenotypes. This diversity is specified during development by neuron-specific expression of key transcription factors, some of which are retained for the life of the animal. One of these key developmental transcription factors that is also retained in the adult is Fezf2, but the neuron types expressing it in the mature cortex are unknown. With a validated Fezf2-Gfp reporter mouse, whole-cell electrophysiology with morphology reconstruction, cluster analysis, in vivo retrograde labeling, and immunohistochemistry, we identify a heterogeneous population of Fezf2(+) neurons in both layer 5A and layer 5B of the mature motor cortex. Functional electrophysiology identified two distinct subtypes of Fezf2(+) neurons that resembled pyramidal tract projection neurons (PT-PNs) and intratelencephalic projection neurons (IT-PNs). Retrograde labeling confirmed the former type to include corticospinal projection neurons (CSpPNs) and corticothalamic projection neurons (CThPNs), whereas the latter type included crossed corticostriatal projection neurons (cCStrPNs) and crossed-corticocortical projection neurons (cCCPNs). The two Fezf2(+) subtypes expressed either CTIP2 or SATB2 to distinguish their physiological identity and confirmed that specific expression combinations of key transcription factors persist in the mature motor cortex. Our findings indicate a wider role for Fezf2 within gene expression networks that underpin the diversity of layer 5 cortical projection neurons. PMID- 26234884 TI - Correlating antimicrobial activity and model membrane leakage induced by nylon-3 polymers and detergents. AB - Most antimicrobial peptides act upon target microorganisms by permeabilizing their membranes. The mode of action is often assessed by vesicle leakage experiments that use model membranes, with the assumption that biological activity correlates with the permeabilization of the lipid bilayer. The current work aims to extend the interpretation of vesicle leakage results and examine the correlation between vesicle leakage and antimicrobial activity. To this end, we used a lifetime-based leakage assay with calcein-loaded vesicles to study the membrane permeabilizing properties of a novel antifungal polymer poly-NM, two of its analogs, and a series of detergents. In conjunction, the biological activities of these compounds against Candida albicans were assessed and correlated with data from vesicle leakage. Poly-NM induces all-or-none leakage in polar yeast lipid vesicles at the polymer's MIC, 3 MUg mL(-1). At this and higher concentrations, complete leakage after an initial lag time was observed. Concerted activity tests imply that this polymer acts independently of the detergent octyl glucoside (OG) for both vesicle leakage and activity against C. albicans spheroplasts. In addition, poly-NM was found to have negligible activity against zwitterionic vesicles and red blood cells. Our results provide a consistent, detailed picture of the mode of action of poly-NM: this polymer induces membrane leakage by electrostatic lipid clustering. In contrast, poly MM:CO, a nylon-3 polymer comprised of both cationic and hydrophobic segments, seems to act by a different mechanism that involves membrane asymmetry stress. Vesicle leakage for this polymer is transient (limited to <100%) and graded, non specific among zwitterionic and polar yeast lipid vesicles, additive with detergent action, and correlates poorly with biological activity. Based on these results, we conclude that comprehensive leakage experiments can provide a detailed description of the mode of action of membrane permeabilizing compounds. Without this thorough approach, it would have been logical to assume that the two nylon-3 polymers we examined act via similar mechanisms; it is surprising that their mechanisms are so distinct. Some, but not all mechanisms of vesicle permeabilization allow for antimicrobial activity. PMID- 26234886 TI - Post-Natal Persistent Infection With Classical Swine Fever Virus in Wild Boar: A Strategy for Viral Maintenance? AB - In this study, fifteen wild boar piglets were intranasally inoculated <10 h after birth with the moderately virulent classical swine fever virus (CSFV) strain Catalonia 01. At 5 days post-inoculation, seven other animals within 48 h of birth were put in contact with them. Viral replication and innate and specific immune responses were evaluated. Of the inoculated animals, 46.67% remained post natally persistently infected and were apparently healthy with neither humoral nor cellular immunological responses specific to CSFV and with high viral loads in their blood, organs and body secretions. Moreover, the present data extend the time period to 48 h after birth when a moderately virulent CSFV strain could lead to post-natal persistent infection given the generation of persistently infected wild boars in the contact group (33.33%). The innate immune response to the virus, as measured by type I IFN-alpha in serum, was mostly not impaired in the persistently infected wild boars. Interestingly, a decrease and lack of IFN-gamma producing cells against CSFV and PHA was observed. In endemic countries where wild swine species are increasing and low and moderate virulence CSFV strains are prevalent, the possible generation of this form of disease cannot be ruled out. PMID- 26234887 TI - Cumulative genetic risk and age at onset in Parkinson's disease. PMID- 26234888 TI - Dimensional ultrasonographic relationship of the right lobe of pancreas with associated anatomic landmarks in clinically normal dogs. AB - The purpose of this prospective study was to establish the ultrasonographic characteristics of the dimension of the right pancreatic lobe with that of the associated anatomic landmarks in healthy dogs. Ultrasonographic examinations were performed on 25 dogs. The thickness of the right pancreatic lobe was compared with that of mural thickness of duodenum, diameter of duodenum, pancreatic duct, abdominal aorta, portal vein, caudal vena cava, and length and width of the right kidney and right adrenal gland. The correlation between each pancreatic parameter and the dimensions of the anatomical landmarks were assessed using linear regression analysis and Pearson's correlation coefficient (r) test. Significant, but weak linear correlations were observed between thickness of right pancreatic lobe with that of duodenum mural thickness (r=0.605, R(2)=0.339, P=0.001); duodenum diameter (r=0.573, R(2)=0.299, P=0.003); and right adrenal gland length (r=0.508, R(2)=0.052, P=0.01). There was no significant dimensional relationship with other selected anatomic landmarks. The ratio between the thickness of right pancreatic lobe and the mural thickness of duodenum, diameter of duodenum and length of right adrenal gland were 2.88 +/- 0.53, 1.27 +/- 0.27 and 0.81 +/- 0.15, respectively. Calculating the ratio of thickness of the right pancreatic lobe with the dimension of significantly correlated anatomic landmarks is a useful and simple method for evaluating the size of the right pancreatic lobe in dogs in clinical practice. PMID- 26234889 TI - GM1 gangliosidosis in a Japanese domestic cat: a new variant identified in Hokkaido, Japan. AB - A male Japanese domestic cat with retarded growth in Hokkaido, Japan, showed progressive motor dysfunction, such as ataxia starting at 3 months of age and tremors, visual disorder and seizure after 4 months of age. Finally, the cat died of neurological deterioration at 9 months of age. Approximately half of the peripheral blood lymphocytes had multiple abnormal vacuoles. Magnetic resonance imaging showed bisymmetrical hyperintensity in the white matter of the parietal and occipital lobes in the forebrain on T2-weighted and fluid-attenuated inversion recovery images, and mild encephalatrophy of the olfactory bulbs and temporal lobes. The activity of lysosomal acid beta-galactosidase in leukocytes was negligible, resulting in the biochemical diagnosis of GM1 gangliosidosis. Histologically, swollen neurons characterized by accumulation of pale, slightly granular cytoplasmic materials were observed throughout the central nervous system. Dysmyelination or demyelination and gemistocytic astrocytosis were observed in the white matter. Ultrastructually, membranous cytoplasmic bodies were detected in the lysosomes of neurons. However, genetic analysis did not identify the c.1448G>C mutation, which is the single known mutation of feline GM1 gangliosidosis, suggesting that the cat was affected with a new variant of the feline disease. PMID- 26234891 TI - Outcomes for out-of-hospital cardiac arrests across 7 countries in Asia: The Pan Asian Resuscitation Outcomes Study (PAROS). AB - BACKGROUND: The Pan Asian Resuscitation Outcomes Study (PAROS) Clinical Research Network (CRN) was established in collaboration with emergency medical services (EMS) agencies and academic centers in Japan, Singapore, South Korea, Malaysia, Taiwan, Thailand, and UAE-Dubai and aims to report out-of-hospital cardiac arrests (OHCA) and provide a better understanding of OHCA trends in Asia. METHODS AND RESULTS: This is a prospective, international, multi-center cohort study of OHCA across the Asia-Pacific. Each participating country provided between 1.5 and 2.5 years of data from January 2009 to December 2012. All OHCA cases conveyed by EMS or presenting at emergency departments were captured. 66,780 OHCA cases were submitted to the PAROS CRN; 41,004 cases were presumed cardiac etiology. The mean age OHCA occurred varied from 49.7 to 71.7 years. The proportion of males ranged from 57.9% to 82.7%. Proportion of unwitnessed arrests ranged from 26.4% to 67.9%. Presenting shockable rhythm rates ranged from 4.1% to 19.8%. Bystander cardiopulmonary resuscitation (CPR) rates varied from 10.5% to 40.9%, however <1.0% of these arrests received bystander defibrillation. For arrests that were with cardiac etiology, witnessed arrest and VF, the survival rate to hospital discharge varied from no reported survivors to 31.2%. Overall survival to hospital discharge varied from 0.5% to 8.5%. Survival with good neurological function ranged from 1.6% to 3%. CONCLUSIONS: Survival to hospital discharge for Asia varies widely and this may be related to patient and system differences. This implies that survival may be improved with interventions such as increasing bystander CPR, public access defibrillation and improving EMS. PMID- 26234892 TI - An investigation of thrust, depth and the impedance cardiogram as measures of cardiopulmonary resuscitation efficacy in a porcine model of cardiac arrest. AB - OBJECTIVE: Optimising the depth and rate of applied chest compressions following out of hospital cardiac arrest is crucial in maintaining end organ perfusion and improving survival. The impedance cardiogram (ICG) measured via defibrillator pads produces a characteristic waveform during chest compressions with the potential to provide feedback on cardiopulmonary resuscitation (CPR) and enhance performance. The objective of this pre-clinical study was to investigate the relationship between mechanical and physiological markers of CPR efficacy in a porcine model and examine the strength of correlation between the ICG amplitude, compression depth and end-tidal CO2 (ETCO2). METHODS: Two experiments were performed using 24 swine (12 per experiment). For experiment 1, ventricular fibrillation (VF) was induced and mechanical CPR commenced at varying thrusts (0 60 kg) for 2 min intervals. Chest compression depth was recorded using a Philips QCPR device with additional recording of invasive physiological parameters: systolic blood pressure, ETCO2, cardiac output and carotid flow. For experiment 2, VF was induced and mechanical CPR commenced at varying depths (0-5 cm) for 2 min intervals. The ICG was recorded via defibrillator pads attached to the animal's sternum and connected to a Heartsine 500 P defibrillator. ICG amplitude, chest compression depth, systolic blood pressure and ETCO2 were recorded during each cycle. In both experiments the within-animal correlation between the measured parameters was assessed using a mixed effect model. RESULTS: In experiment 1 moderate within-animal correlations were observed between physiological parameters and compression depth (r=0.69-0.77) and thrust (r=0.66 0.82). A moderate correlation was observed between compression depth and thrust (r=0.75). In experiment 2 a strong within-animal correlation and moderate overall correlations were observed between ICG amplitude and compression depth (r=0.89, r=0.79) and ETCO2 (r=0.85, r=0.64). CONCLUSION: In this porcine model of induced cardiac arrest moderate within animal correlations were observed between mechanical and physiological markers of chest compression efficacy demonstrating the challenge in utilising a single mechanical metric to quantify chest compression efficacy. ICG amplitude demonstrated strong within animal correlations with compression depth and ETCO2 suggesting its potential utility to provide CPR feedback in the out of hospital setting to improve performance. PMID- 26234893 TI - Public Access Defibrillation: Great benefit and potential but infrequently used. AB - BACKGROUND: In Copenhagen, a volunteer-based Automated External Defibrillator (AED) network provides a unique opportunity to assess AED use. We aimed to determine the proportion of Out-of-Hospital Cardiac Arrest (OHCA) where an AED was applied before arrival of the ambulance, and the proportion of OHCA-cases where an accessible AED was located within 100 m. In addition, we assessed 30-day survival. METHODS: Using data from the Mobile Emergency Care Unit and the Danish Cardiac Arrest Registry, we identified 521 patients with OHCA between October 1, 2011 and September 31, 2013 in Copenhagen, Denmark. RESULTS: An AED was applied in 20 cases (3.8%, 95% CI [2.4 to 5.9]). Irrespective of AED accessibility, an AED was located within 100 m of a cardiac arrest in 23.4% (n=102, 95% CI [19.5 to 27.7]) of all OHCAs. However, at the time of OHCA, an AED was located within 100 m and accessible in only 15.1% (n=66, 95% CI [11.9 to 18.9]) of all cases. The 30 day survival for OHCA with an initial shockable rhythm was 64% for patients where an AED was applied prior to ambulance arrival and 47% for patients where an AED was not applied. CONCLUSIONS: We found that 3.8% of all OHCAs had an AED applied prior to ambulance arrival, but 15.1% of all OHCAs occurred within 100 m of an accessible AED. This indicates the potential of utilising AED networks by improving strategies for AED accessibility and referring bystanders of OHCA to existing AEDs. PMID- 26234894 TI - Two minutes CPR versus five cycles CPR prior to reanalysis of the cardiac rhythm: A prospective, randomized simulator-based trial. AB - AIM OF THE STUDY: While the 2005 cardiopulmonary resuscitation (CPR) guidelines recommended to provide CPR for five cycles before the next cardiac rhythm check, the current 2010 guideline now recommend to provide CPR for 2 min. Our aim was to compare adherence to both targets in a simulator-based randomized trial. METHODS: 119 teams, consisting of three to four physicians each, were randomized to receive a graphical display of the simplified circular adult BLS algorithm with the instruction to perform CPR for either 2 min or five cycles 30:2. Subsequently teams had to treat a simulated unwitnessed cardiac arrest. Data analysis was performed using video-recordings obtained during simulations. The primary endpoint was adherence, defined as being within +/-20% of the instructed target (i.e. 96-144s in the 2 min teams and 4-6 cycles in the fivex30:2 teams). RESULTS: 22/62 (35%) of the "two minutes" teams and 48/57 (84%) of the "five*30:2" teams provided CPR within a range of +/- 20% of their instructed target (P<0.0001). The median time of CPR prior to rhythm check was 91s and 87s, respectively, (P=0.59) with a significant larger variance (P=0.023) in the "two minutes" group. CONCLUSIONS: This randomized simulator-based trial found better adherence and less variance to an instruction to continue CPR for five cycles before the next cardiac rhythm check compared to continuing CPR for 2 min. Avoiding temporal targets whenever possible in guidelines relating to stressful events appears advisable. PMID- 26234895 TI - Clarifying the design of the PARAMEDIC trial. PMID- 26234897 TI - Macro- and microclimatic interactions can drive variation in species' habitat associations. AB - Many species are more restricted in their habitat associations at the leading edges of their range margins, but some species have broadened their habitat associations in these regions during recent climate change. We examine the effects of multiple, interacting climatic variables on spatial and temporal patterns of species' habitat associations, using the speckled wood butterfly, Pararge aegeria, in Britain, as our model taxon. Our analyses reveal that this species, traditionally regarded as a woodland-dependent insect, is less restricted to woodland in regions with warmer winters and warmer and wetter summers. In addition, over the past 40 years of climate change, the species has become less restricted to woodland in locations where temperature and summer rainfall have increased most. We show that these patterns arise mechanistically because larval growth rates are slower in open (i.e. nonwoodland) habitats associated with colder microclimates in winter and greater host plant desiccation in summer. We conclude that macro- and microclimatic interactions drive variation in species' habitat associations, which for our study species resulted predominantly in a widening of habitat associations under climate change. However, species vary in their climatic and nonclimatic requirements, and so complex spatial and temporal patterns of changes in habitat associations are likely to be observed in future as the climate changes. PMID- 26234896 TI - Carotid Doppler blood flow measurement during cardiopulmonary resuscitation is feasible: A first in man study. AB - OBJECTIVE: High quality chest compressions are the cornerstone of effective cardiopulmonary resuscitation (CPR). There is no available method of real time noninvasive hemodynamic measurement and feedback to inform rescuers of the efficacy of compressions. Ultrasound-based measures of blood flow may provide immediate, noninvasive hemodynamic information. Our objective was to determine the feasibility and safety of using ultrasound to measure blood flow on patients with cardiac arrest. METHODS: Study design This was a prospective cohort study in an emergency department setting. Subjects Included were patients receiving ongoing manual chest compressions for cardiac arrest. Excluded were those less than 18 years of age, incarcerated, pregnant, with neck injury, or obvious traumatic cause of arrest. Scan protocol Physicians recorded blood flow over the common carotid arteries during chest compressions with transverse and longitudinal color flow and Doppler using a portable ultrasound machine (CX30, Philips Healthcare., Andover, MA). Measurements Duration of scan time, and the median values for peak systolic (PSV), end-diastolic (EDV) and mean diastolic (MDV) carotid blood flow velocities were captured. Feasibility was defined as the proportion of eligible subjects upon whom ultrasound was initiated Safety was defined as availability of at least 5 min of scanning time. RESULTS: Nineteen patients (56% of eligible) where enrolled and had ultrasound measurements attempted during manual compressions. In one patient, scanning was not initiated because ongoing CPR efforts were terminated. Three patients were enrolled but had no images available for review. A total of 15 patients (78% of attempted) had ultrasound imaging saved. Most (n=10, 66%) had scanning times greater than 5 min (median 5 min 59s, interquartile range 3 min 15s to 8 min 25s), median PSV was 67 cms(-1) (IQR 55-106), median EDV was 18 cms(-1) (IQR 12-27), and median MDV was 14 cms(-1) (IQR 9-18). CONCLUSIONS: Ultrasound measurement of common carotid artery blood flow during CPR is feasible. Further studies are necessary to correlate carotid blood flow to other hemodynamic measures and its effects on patient outcomes. PMID- 26234898 TI - Fasciola hepatica: Specificity of a coproantigen ELISA test for diagnosis of fasciolosis in faecal samples from cattle and sheep concurrently infected with gastrointestinal nematodes, coccidians and/or rumen flukes (paramphistomes), under field conditions. AB - Chronic fasciolosis is often diagnosed by faecal egg counting (FEC), following concentration of the eggs in the sample by a zinc sulphate floatation method. However, concentration by a sedimentation technique gives improved sensitivity. Interpretation of FEC results for fasciolosis is complicated by factors such as the long pre-patent period and irregular egg shedding. Thus, FEC reduction tests (FECRT), when used alone, are not completely reliable for diagnosis of anthelmintic susceptibility or resistance in local fluke populations, especially when parasite burdens are small. A Fasciola hepatica coproantigen ELISA test has been introduced which more accurately reflects the presence of flukes in the host bile ducts in late pre-patent infections, and absence of flukes following successful chemotherapeutic intervention. The aim of the present study was to elucidate the specificity of the F. hepatica coproantigen ELISA technique, particularly regarding potential cross-reactivity with rumen fluke (paramphistome), gastrointestinal nematode and coccidian infections. The method involved parallel testing of a large battery of faecal samples from field infected cattle and sheep using floatation and sedimentation FECs and coproantigen analysis. No evidence was found for significant false positivity in the F. hepatica coproantigen ELISA due to paramphistome, coccidian and/or gastrointestinal nematode co-infections. With sedimentation FECs less than 10 F. hepatica eggs per gram (epg), the likelihood of a positive coproantigen result for the sample progressively decreased. Diagnosis of fasciolosis should be based on consideration of both FEC and coproantigen ELISA findings, to ensure optimum sensitivity for pre-patent and low-level infections. PMID- 26234901 TI - [Lack of knowledge about the specialty of Intensive Medicine in Spain]. PMID- 26234900 TI - The Efficacy of Lumbosacral Spine Phantom to Improve Resident Proficiency in Performing Ultrasound-Guided Spinal Procedure. AB - OBJECTIVE: To evaluate the efficacy of a lumbosacral spine phantom to improve novices' proficiency in performing ultrasound-guided facet joint injection and medial branch block. DESIGN AND SETTING: Prospective study in a university hospital. SUBJECTS: In total, 30 participants with no experience of spinal ultrasonography were included and were allocated to one of two groups (control group, N = 10 and training group, N = 20). METHODS: A lumbosacral spine phantom was prepared using a lumbosacral spine model embedded in a mixture of gelatin and psyllium husk. All participants were tested (test-1) following a basic education introductory program. Participants in the control group were then tested again after 1 week (test-2). Those in the training group received a further 3-h training, individually, and were tested again after 1 week (test-2). RESULTS: The mean performance scores on test-1 were 57.6 +/- 6.0 in the control group and 57.3 +/- 6.7 in the training group; and at test-2, 61.0 +/- 8.6 and 91.7 +/- 4.9 (P < 0.001), respectively. The median time of performance at test-1 was 158.3 +/- 41.9 seconds in the control group and 185.3 +/- 68.1 seconds in the training group; and at test-2, 146.9 +/- 38.9 seconds and 69.9 +/- 22.0 seconds (P < 0.001), respectively. In the training group, the mean self-rating level of proficiency scores were 2.2 +/- 1.0 at pretraining, and 6.8 +/- 0.8 at post-training, respectively (P < 0.001). CONCLUSION: Training using a gelatin-based spine phantom helped novices to acquire the skills necessary to perform ultrasound guided lumbar facet joint injections and medial branch blocks. PMID- 26234899 TI - Therapeutic effect for liver-metastasized tumor by sequential intravenous injection of anionic polymer and cationic lipoplex of siRNA. AB - Previously, we developed a novel siRNA transfer method to the liver by sequential intravenous injection of anionic polymer and cationic liposome/siRNA complex (cationic lipoplex). In this study, we investigated whether siRNA delivered by this sequential injection could significantly suppress mRNA expression of the targeted gene in liver metastasis and inhibit tumor growth. When cationic lipoplex was intravenously injected into mice bearing liver metastasis of human breast tumor MCF-7 at 1 min after intravenous injection of chondroitin sulfate C (CS) or poly-l-glutamic acid (PGA), siRNA was accumulated in tumor-metastasized liver. In terms of a gene silencing effect, sequential injections of CS or PGA plus cationic lipoplex of luciferase siRNA could reduce luciferase activity in liver MCF-7-Luc metastasis. Regarding the side effects, sequential injections of CS plus cationic lipoplex did not exhibit hepatic damage or induction of inflammatory cytokines in serum after repeated injections, but sequential injections of PGA plus cationic lipoplex did. Finally, sequential injections of CS plus cationic lipoplex of protein kinase N3 siRNA could suppress tumor growth in the mice bearing liver metastasis. From these findings, sequential injection of CS and cationic lipoplex of siRNA might be a novel systemic method of delivering siRNA to liver metastasis. PMID- 26234902 TI - Rheb signaling and tumorigenesis: mTORC1 and new horizons. AB - Rheb is a conserved small GTPase that belongs to the Ras superfamily, and is mainly involved in activation of cell growth through stimulation of mTORC1 activity. Because deregulation of the Rheb/mTORC1 signaling is associated with proliferative disorders and cancer, inhibition of mTORC1 has been therapeutically approached. Although this therapy has proven antitumor activity, its efficacy is not as expected. Here, we will review the main work on the identification of the role of Rheb in cell growth, and on the relevance of Rheb in proliferative disorders, including cancer. We will also review the Rheb functions that could explain tumor resistance to therapies with mTORC1 inhibitors, and will mainly focus our discussion on mTORC1-independent Rheb functions that could also be implicated in cancer cell survival and tumorigenesis. The current progress on the understanding of the noncanonical Rheb functions prompts future studies to establish their relevance in cancer and in the context of current cancer therapies. PMID- 26234903 TI - Design, synthesis and immunological evaluation of 1,2,3-triazole-tethered carbohydrate-Pam3Cys conjugates as TLR2 agonists. AB - Novel triazolyl Pam3Cys conjugates encompassing various carbohydrate entities have been synthesized by copper mediated azide-alkyne click chemistry protocol with a view to probe the SAR pertaining to their adjuvant activity in conjunction with OVA as antigen. The preliminary ex vivo cytokine profiling revealed optimal Th1 activation and the in vivo adjuvant studies of ribose derived hybrid (6 e) revealed a marked improvement in the OVA specific antibody IgG response and Th1 cytokine expressions. The triazolyl Pam3Cys carbohydrate conjugates were found to be the hTLR2 agonists as revealed by their SEAP activity due to NFKB activation. The described protocol is the first successful attempt of the amalgamation of carbohydrate-Pam3Cys motifs tethered to a triazole linker as a peptide free adjuvant. PMID- 26234905 TI - A P450 fusion library of heme domains from Rhodococcus jostii RHA1 and its evaluation for the biotransformation of drug molecules. AB - The actinomycete Rhodococcus jostii RHA1 contains a multitude of oxygenase enzymes, consonant with its remarkable activities in the catabolism of hydrophobic xenobiotic compounds. In the interests of identifying activities for the transformation of drug molecules, we have cloned genes encoding 23 cytochrome P450 heme domains from R. jostii and expressed them as fusions with the P450 reductase domain (RhfRED) of cytochrome P450Rhf from Rhodococcus sp. NCIMB 9784. Fifteen of the fusions were expressed in the soluble fraction of Escherichia coli Rosetta (DE3) cells. Strains expressing the fusions of RhfRED with genes ro02604, ro04667, ro11069, ro11320, ro11277, ro08984 and ro04671 were challenged with 48 commercially available drugs revealing many different activities commensurate with P450-catalyzed hydroxylation and demethylation reactions. One recombinant strain, expressing the fusion of P450 gene ro11069 (CYP257A1) with RhfRED, and named Ro07-RhfRED, catalyzed the N-demethylation of diltiazem and imipramine. This observation was in accord with previous reports of this enzyme's activity as a demethylase of alkaloid substrates. Ro07-RhfRED was purified and characterised, and applied in cell-free biotransformations of imipramine (7 MUM) giving a 63% conversion to the N-desmethyl product. PMID- 26234904 TI - Optimization of 3-aryl-3-ethoxypropanoic acids and discovery of the potent GPR40 agonist DS-1558. AB - GPR40 agonists stimulate insulin secretion only under the presence of high glucose concentration. Based on this mechanism, GPR40 agonists are believed to be promising novel insulin secretagogues with low risk of hypoglycemia. The optimizations of 3-aryl-3-ethoxypropanoic acids were performed to improve in vitro activity. We discovered compound 29r (DS-1558), (3S)-3-ethoxy-3-(4-{[(1R)-4 (trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, which was confirmed to have an enhancing effect on glucose-dependent insulin secretion after intravenous glucose injection in SD rats. PMID- 26234906 TI - Synthesis and biological evaluation of 9-N-oxamyl sialosides as Siglec-7 ligands. AB - Siglecs (sialic acid recognizing immunoglobulin like lectins) are a family of lectins with specificity for sialic acid containing carbohydrates. Synthetic sialic acid derivatives with high affinity proved useful to unravel the biological role of the ligand binding domain, although many of their functions in immunity remain unknown. Here we present design, synthesis, affinity evaluation and molecular modeling of novel 9-N-oxamoyl modified sialosides as Siglec-7 ligands. PMID- 26234907 TI - Addition of niclosamide to palladium(II) saccharinate complex of terpyridine results in enhanced cytotoxic activity inducing apoptosis on cancer stem cells of breast cancer. AB - Wnt signaling is one of the core signaling pathways of cancer stem cells (CSCs). It is re-activated in CSCs and plays essential role in the survival, self-renewal and proliferation of these cells. Therefore, we aimed to evaluate the cytotoxic effects of palladium(II) complex which is formulated as [PdCl(terpy)](sac)2H2O and its combination with niclosamide which is an inhibitor of Wnt signaling pathway associated with breast cancer stem cells. Characteristic cell surface markers (CD44(+)/CD24(-)) were determined by flow cytometry in CSCs. ATP viability assay was used to determine the cytotoxic activity. The mode of cell death was evaluated morphologically using fluorescence microscopy and biochemically using M30 ELISA assay as well as performing qPCR. Our study demonstrated that the combination of niclosamide (1.5 MUM) and Pd(II) complex (12.5, 25 and 50 MUM) at 48 h has enhanced cytotoxic activity resulted from the induction of apoptosis (indicated by the presence of pyknotic nuclei, increments in M30 and over expression of proapoptotic genes of TNFRSF10A and FAS). Importantly, the addition of niclosamide resulted in the suppression of autophagy (proved by the decrease in ATG5 gene levels) that might have contributed to the enhanced cytotoxicity. In conclusion, the application of this combination may be regarded as a novel and effective approach for the treatment of breast cancer due to its promising cytotoxic effect on cancer stem cells that cause recurrence of the disease. PMID- 26234908 TI - CH3NH3PbI(3-x)Cl(x) films with coverage approaching 100% and with highly oriented crystal domains for reproducible and efficient planar heterojunction perovskite solar cells. AB - Depositing pinhole-free perovskite films is of vital importance for achieving high performance perovskite solar cells, especially in a planar heterojunction device. Here, perovskite films with coverage approaching 100% and with highly oriented crystal domains were obtained by carefully controlling the annealing temperature and duration. Perovskite solar cells with an average efficiency of 12% and a maximum efficiency of 15.17% were achieved in a planar heterojunction structure. Comprehensive characterization and analysis showed that appropriate annealing temperature and duration allowed the perovskite crystals to grow slowly, resulting in highly oriented crystal domains without any internal voids or pinholes. The anisotropic transport properties of perovskite crystals ensure efficient electron and hole transport to their corresponding electrodes. PMID- 26234909 TI - Recombinant Newcastle disease virus-vectored vaccines against human and animal infectious diseases. AB - Recent advances in recombinant genetic engineering techniques have brought forward a leap in designing new vaccines in modern medicine. One attractive strategy is the application of reverse genetics technology to make recombinant Newcastle disease virus (rNDV) deliver protective antigens of pathogens. In recent years, numerous studies have demonstrated that rNDV-vectored vaccines can induce quicker and better humoral and mucosal immune responses than conventional vaccines and are protective against pathogen challenges. With deeper understanding of NDV molecular biology, it is feasible to develop gene-modified rNDV vaccines accompanied by good safety, high efficacy, low toxicity and better immunogenicity. This review summarizes the development of reverse genetics technology in using NDV as a promising vaccine vector to design new vaccines for human and animal use. PMID- 26234910 TI - Delivery of Highly Active Noble-Metal Nanoparticles into Microspherical Supports by an Aerosol-Spray Method. AB - Noble metal nanoparticles (NPs) with 1-5 nm diameter obtained from NaHB4 reduction possess high catalytic activity. However, they are rarely used directly. This work presents a facile, versatile, and efficient aerosol-spray approach to deliver noble-metal NPs into metal oxide supports, while maintaining the size of the NPs and the ability to easily adjust the loading amount. In comparison with the conventional spray approach, the size of the loaded noble metal nanoparticles can be significantly decreased. An investigation of the 4 nitrophenol hydrogenation reaction catalyzed by these materials suggests that the NPs/oxides catalysts have high activity and good endurance. For 1 % Au/CeO2 and Pd/Al2 O3 catalysts, the rate constants reach 2.03 and 1.46 min(-1) , which is much higher than many other reports with the same noble-metal loading scale. Besides, the thermal stability of catalysts can be significantly enhanced by modifying the supports. Therefore, this work contributes an efficient method as well as some guidance on how to produce highly active and stable supported noble metal catalysts. PMID- 26234911 TI - Primary and Secondary Stabbing Headache: A Response. PMID- 26234912 TI - Are GLP-1 receptor agonists useful against traumatic brain injury? AB - This Editorial highlights a study by Li et al. (2015) in the current issue of J. Neurochem. The image depicts the hypothesized neuroprotective pathway that is proposed by the authors. Using a combination of SH-SY5Y and primary rat neuron cultures the GLP-1R agonist, Liraglutide, was shown to increase SH-SY5Y proliferation and CREB phosphorylation correlating with reduced toxicity, preservation of Bcl2 protein levels, and decreased caspase 3 activity following glutamate or H2 O2 stimulations. These in vitro observations correlated with a Liraglutide-dependent improvement in memory performance in mice subjected to a mild TBI. Bcl2, B-cell lymphoma 2; CREB, cAMP-response element binding protein; GLP-1R, glucagon-like peptide 1 receptor; TBI, traumatic brain injury; PKA, protein kinase A. PMID- 26234913 TI - Climate-mediated diversification of turtles in the Cretaceous. AB - Chelonians are ectothermic, with an extensive fossil record preserved in diverse palaeoenvironmental settings: consequently, they represent excellent models for investigating organismal response to long-term environmental change. We present the first Mesozoic chelonian taxic richness curve, subsampled to remove geological/collection biases, and demonstrate that their palaeolatitudinal distributions were climate mediated. At the Jurassic/Cretaceous transition, marine taxa exhibit minimal diversity change, whereas non-marine diversity increases. A Late Cretaceous peak in 'global' non-marine subsampled richness coincides with high palaeolatitude occurrences and the Cretaceous thermal maximum (CTM): however, this peak also records increased geographic sampling and is not recovered in continental-scale diversity patterns. Nevertheless, a model detrended richness series (insensitive to geographic sampling) also recovers a Late Cretaceous peak, suggesting genuine geographic range expansion among non marine turtles during the CTM. Increased Late Cretaceous diversity derives from intensive North American sampling, but subsampling indicates that Early Cretaceous European/Asian diversity may have exceeded that of Late Cretaceous North America. PMID- 26234914 TI - Improvement of Bell's palsy associated with resolution of acute hepatitis B infection. PMID- 26234916 TI - Information/Education Page. Spasticity and Traumatic Brain Injury. PMID- 26234915 TI - Hairless mice as an experimental model of infection with Leishmania (Leishmania) amazonensis. AB - HRS/J Hairless mice have been investigated as an experimental model in cutaneous leishmaniasis induced by Leishmania (Leishmania) amazonensis. The animals were inoculated with 10(6) promastigotes into the right hind footpad and the course of infection was followed up for 30, 60 and 90 days. BALB/c mice were infected and used as control. Hairless mice were susceptible to L. (L.) amazonensis infection and a progressive increase in number of parasites and footpad thickness was detected over time. Signals of dissemination and visceralization were confirmed by the presence of parasite in the draining lymph node of lesion and spleen, at different times post infection. IL-10 gene expression evaluated by RT-PCR was significantly higher in Hairless mice at 60 days post infection, corroborating the pattern of susceptibility. These results point this inbred strain as a promising susceptible model for the study of experimental infection induced by L. (L.) amazonensis. This model would allow the use of other infection sites that minimize secondary interference and best monitoring the skin lesion, as in the case of in vivo assays of potential drugs for LT. PMID- 26234917 TI - Normative Values and Interrelationship of MDVP Voice Analysis Parameters Before and After Endotracheal Intubation. AB - PURPOSE: The Multi-Dimensional Voice Program (MDVP) is used for assessment of voice quality. A simple procedure for MDVP recordings was used in a randomized clinical trial (RCT) on induced vocal fold trauma due to intubation. This secondary study compares the common MDVP parameters with other normative values for adults and investigates the correlation between these MDVP parameters in relation to the "standardized" trauma of endotracheal intubation. METHODS: Preoperative and postoperative assessments of vocal fold pathology with flexible videolaryngoscopy and voice analysis with MDVP using the best-of-three standardized recording were performed in 121 patients with normal voices included consecutively in the RCT. The procedures of anesthesia were standardized. RESULTS: The normative MDVP values of this study are consistently lower compared with most normative values presented in other studies. The preoperative to postoperative differences in jitter values (jitter and relative average perturbation) were closely correlated to the shimmer values for patients with postoperative vocal fold edemas. In the patients with edema, the preoperative to postoperative differences in jitter had a correlation coefficient of 0.95 (P < 0.0001) to the difference in shimmer, compared with a correlation coefficient of 0.39 (P < 0.0001) in the patients without edema. CONCLUSIONS: This study supports the use of the "Best-of-Three" procedures for precise and relevant MDVP parameter calculations. The MDVP parameters, with closely correlated changes in jitter and shimmer values, accurately reflect the induced vocal fold edema when using the preoperative to postoperative changes. PMID- 26234918 TI - Reliable Change on Neuropsychological Tests in the Uniform Data Set. AB - Longitudinal normative data obtained from a robust elderly sample (i.e., believed to be free from neurodegenerative disease) are sparse. The purpose of the present study was to develop reliable change indices (RCIs) that can assist with interpretation of test score changes relative to a healthy sample of older adults (ages 50+). Participants were 4217 individuals who completed at least three annual evaluations at one of 34 past and present Alzheimer's Disease Centers throughout the United States. All participants were diagnosed as cognitively normal at every study visit, which ranged from three to nine approximately annual evaluations. One-year RCIs were calculated for 11 neuropsychological variables in the Uniform Data Set by regressing follow-up test scores onto baseline test scores, age, education, visit number, post-baseline assessment interval, race, and sex in a linear mixed effects regression framework. In addition, the cumulative frequency distributions of raw score changes were examined to describe the base rates of test score changes. Baseline test score, age, education, and race were robust predictors of follow-up test scores across most tests. The effects of maturation (aging) were more pronounced on tests related to attention and executive functioning, whereas practice effects were more pronounced on tests of episodic and semantic memory. Interpretation of longitudinal changes on 11 cognitive test variables can be facilitated through the use of reliable change intervals and base rates of score changes in this robust sample of older adults. A Web-based calculator is provided to assist neuropsychologists with interpretation of longitudinal change. PMID- 26234919 TI - HypoAware: development and pilot study of a brief and partly web-based psychoeducational group intervention for adults with Type 1 and insulin-treated Type 2 diabetes and problematic hypoglycaemia. AB - AIM: Our aim was to study the feasibility and acceptability of our partly online psychoeducational group intervention HypoAware targeted at adults with insulin treated diabetes and hypoglycaemia problems in an uncontrolled multi-centre pilot study. METHODS: We developed a 4-week, party online, group intervention, based on key elements of the evidence-based Blood Glucose Awareness Training (BGAT) and with input from diabetes healthcare professionals and people with diabetes. We recruited adults with Type 1 and insulin-treated Type 2 diabetes with impaired hypoglycaemia awareness, frequent hypoglycaemic episodes and/or fear of hypoglycaemia. Feasibility was assessed by means of self-report questionnaires. Pre-post outcomes included self-reported frequency of mild hypoglycaemia, fear of hypoglycaemia, confidence in diabetes self-care, subjective health status, diabetes-specific and general psychological distress and emotional well-being. RESULTS: Organization, recruitment, delivery of HypoAware, retention and compliance yielded no major problems, and both trainers and participants were very satisfied with the programme. The intervention materials required only minor changes. We obtained pre-post intervention measurements in 37 participants from eight hospitals with three drop-outs. Worries about hypoglycaemia, diabetes distress and confidence in self-care improved significantly (P < 0.05), although frequency of hypoglycaemia and hypoglycaemia awareness did not. CONCLUSIONS: HypoAware is a new, feasible and acceptable intervention including online modules aimed to help adults with Type 1 and insulin-treated Type 2 diabetes reduce hypoglycaemia and related problems. A cluster-randomized controlled trial is planned to test effectiveness, combined with an economic evaluation. PMID- 26234920 TI - Tailored delivery of analgesic ziconotide across a blood brain barrier model using viral nanocontainers. AB - The blood brain barrier (BBB) is often an insurmountable obstacle for a large number of candidate drugs, including peptides, antibiotics, and chemotherapeutic agents. Devising an adroit delivery method to cross the BBB is essential to unlocking widespread application of peptide therapeutics. Presented here is an engineered nanocontainer for delivering peptidic drugs across the BBB encapsulating the analgesic marine snail peptide ziconotide (Prialt(r)). We developed a bi-functional viral nanocontainer based on the Salmonella typhimurium bacteriophage P22 capsid, genetically incorporating ziconotide in the interior cavity, and chemically attaching cell penetrating HIV-Tat peptide on the exterior of the capsid. Virus like particles (VLPs) of P22 containing ziconotide were successfully transported in several BBB models of rat and human brain microvascular endothelial cells (BMVEC) using a recyclable noncytotoxic endocytic pathway. This work demonstrates proof in principle for developing a possible alternative to intrathecal injection of ziconotide using a tunable VLP drug delivery nanocontainer to cross the BBB. PMID- 26234921 TI - Enhancing the child survival agenda to promote, protect, and support early child development. AB - High rates of child mortality and lost developmental potential in children under 5 years of age remain important challenges and drivers of inequity in the developing world. Substantive progress has been made toward Millennium Development Goal (MDG) 4 to improve child survival, but as we move into the post 2015 sustainable development agenda, much more work is needed to ensure that all children can realize their full and holistic physical, cognitive, psychological, and socio-emotional development potential. This article presents child survival and development as a continuous and multifaceted process and suggests that a life course perspective of child development should be at the core of future policy making, programming, and research. We suggest that increased attention to child development, beyond child survival, is key to operationalize the sustainable development goals (SDGs), address inequities, build on the demographic dividend, and maximize gains in human potential. An important step toward implementation will be to increase integration of existing interventions for child survival and child development. Integrated interventions have numerous potential benefits, including optimization of resource use, potential additive impacts across multiple domains of health and development, and opportunity to realize a more holistic approach to client-centered care. However, a notable challenge to integration is the continued division between the health sector and other sectors that support child development. Despite these barriers, empirical evidence is available to suggest that successful multisectoral coordination is feasible and leads to improved short- and long-term outcomes in human, social, and economic development. PMID- 26234922 TI - Tissue plasminogen activator treatment of bilateral pulmonary emboli in a pediatric patient supported with a ventricular assist device. AB - Bleeding and thrombosis are well-known potential complications of VAD support. We present a pediatric patient who developed massive bilateral pulmonary emboli while on BiVAD support that was successfully treated with intravenous tPA and bridged to heart transplant. PMID- 26234923 TI - Pre-deamidation of soy protein isolate exerts impacts on transglutaminase-induced glucosamine glycation and cross-linking as well as properties of the products. AB - BACKGROUND: Transglutaminase (TGase) induces protein glycation and cross-linking, but results in lower solubility and digestibility due to excessive cross-linking. Deamidation of soy protein isolate (SPI) by HCl converts glutamine residues, and provides less opportunity for the two reactions. Two deamidated SPI products (DSPI1 and DSPI2) were thus glucosamine-glycated and cross-linked, to clarify the effects of pre-deamidation on the two reactions and properties of the products. RESULTS: DSPI1 and DSPI2 had respective degrees of deamidation of 12.2% and 27.4%. They and SPI were used to generate three glycated and cross-linked products (GC-DSPI1, GC-DSPI2 and GC-SPI) containing glucosamine of 12.0, 4.4 and 19.7 g kg(-1) protein, respectively, which were reflected in their infrared spectra at two regions. These three (especially GC-SPI) had higher water-binding than SPI (8.2-12.6 versus 6.2 g g(-1) protein). GC-DSPI1 and GC-DSPI2 showed better enzymatic digestion than GC-SPI. Thermogravimetric and circular dichroism analyses verified that GC-DSPI1 and GC-DSPI2 had maximum degradation rates at temperatures 12-14 degrees C lower than GC-SPI, and possessed a more open secondary structure. CONCLUSION: SPI deamidation decreases forthcoming glycation and cross-linking, and gives the products higher digestibility, less increased hydration, lower thermal stability, and a more open secondary structure. Pre deamidation is applicable to control the properties of GC-proteins. (c) 2015 Society of Chemical Industry. PMID- 26234924 TI - Treatment of Foot Degloving Injury With Aid of Negative Pressure Wound Therapy and Dermal Regeneration Template. AB - Degloving injury of the foot continues to be a challenging condition to treat. Despite current advancements in reconstructive options, most of these injuries can result in amputations, causing physical and emotional impairment. Few reports have been published on the management of these complex traumatic injuries. Typical reconstruction options have included skin grafting and reattachment of the avulsed skin. Many treating physicians have encountered challenging issues in predicting tissue viability, knowing the extent of the injury, and making a logical decision for limb salvage procedures. The present report provides an algorithm of our approach in managing degloving injuries. A case of foot degloving injury, treated by serial surgical operations with the dominant aim of salvaging the avulsed tissue, is presented. The avulsed portion of the foot, with no identifiable vessels for microsurgical reattachment, was defatted and used as a full-thickness skin graft. Negative pressure wound therapy and a dermal regeneration template were used as adjunct techniques to help obtain good soft tissue coverage. The traditional treatment methods for degloving injuries and the applications of new wound care technologies are discussed. PMID- 26234925 TI - Long-Term Fever After Hallux Valgus Surgery Secondary to Titanium Allergy: A Case Report and Review of the Literature. AB - We present the case of a patient who had experienced a fever of unknown cause for >7 months after surgical treatment for hallux valgus. A patch test revealed a positive reaction to a titanium alloy. All symptoms subsequently disappeared after we removed the implanted titanium screws. Histopathologic examination of the tissue surrounding the screws showed macrophage infiltration in the tissue. For >1 year after removal of the titanium screws, the patient's body temperature remained <37 degrees C. These results support a diagnosis of titanium allergy in our patient. To the best of our knowledge, a long-term fever caused by an allergic reaction to mini-titanium screws of such a small size has not been reported. A review of 16 cases of titanium allergy reported in the published data confirmed that titanium allergy is extremely rare and that the clinical symptoms can vary. Titanium allergy should be suspected when a patient presents with a fever of unknown cause, delayed wound healing, dermatitis, or impaired fracture healing after internal fixation with titanium materials. A patch test for titanium or the lymphocyte transformation test could offer guidance for the clinical diagnosis of titanium allergy. Finally, we recommend that all patients should be asked whether they have a history of an allergy to any metal before surgery. PMID- 26234926 TI - Locating the nucleation sites for protein encapsulated gold nanoclusters: a molecular dynamics and fluorescence study. AB - Fluorescent gold nanoclusters encapsulated by proteins have attracted considerable attention in recent years for their unique properties as new fluorescence probes for biological sensing and imaging. However, fundamental questions, such as the nucleation sites of gold nanoclusters within proteins and the fluorescence mechanism remain unsolved. Here we present a study of the location of gold nanoclusters within bovine serum albumin (BSA) combining both fully atomistic molecular dynamic (MD) simulations and fluorescence spectroscopic studies. The MD simulations show gold clusters growing close to a number of cysteine sites across all three domains of BSA, although just two major sites in domains IIB and IA were found to accommodate large clusters comprising more than 12 atoms. The dependence of the fluorescence on pH is found to be compatible with possible nucleation sites in domains IIB and IA. Furthermore, the energy transfer between tryptophan and gold nanoclusters reveals a separation of 29.7 A, further indicating that gold nanoclusters were most likely located in the major nucleation site in domain IIB. The disclosure of the precise location of the gold nanoclusters and their surrounding amino acid residues should help better understanding of their fluorescence mechanism and aid their optimization as fluorescent nanoprobes. PMID- 26234928 TI - Investigation of 5-HT2A gene expression in PBMCs of patients with allergic asthma. AB - BACKGROUND: Asthma is an inflammatory airway disorder in which different immune cells in the blood and lungs play a fundamental role. In asthma condition, the airway inflammation accompanied by bronchial smooth muscle spasm cause airway obstruction. A study showed that high concentration of blood serotonin is associated with the intensity and exacerbation of asthma disease. Other studies showed that a subtype of serotonin receptor called 5-Hydroxytriptamine 2A receptor (5- HT2A) can enhance T-cell blastogenesis and production of pro inflammatory cytokines such as IFNgamma. OBJECTIVE: The objective of this study was to assess the level of 5-HT2A in peripheral blood mononuclear cells (PBMCs) of asthmatic patients. METHODS: PBMCs were extracted from blood of 30 patients with asthma and 30 normal people. After synthesizing cDNAs from total mRNAs, real time PCR was performed to amplify 5-HT2A and beta-actin (as an internal control). The expression ratios were analyzed in patients with asthma in comparison with normal group. RESULTS: The results indicated that gene expression is significantly increased in peripheral blood mononuclear cells (PBMCs) of asthma patients in comparison with normal group (P = 0.003). CONCLUSION: The results of this study can suggest designing a protocol by using of the 5-HT2A receptor expression in PBMCs as a biomarker of asthma, but this requires further studies on a larger number of patients. In addition, the potential role of this receptor in bronchoconstriction can lead us to use its antagonists as a new treatment in asthma. PMID- 26234927 TI - Transient postnatal fluoxetine decreases brain concentrations of 20-HETE and 15 epi-LXA4, arachidonic acid metabolites in adult mice. AB - BACKGROUND: Transient postnatal exposure of rodents to the selective serotonin (5 HT) reuptake inhibitor (SSRI) fluoxetine alters behavior and brain 5-HT neurotransmission during adulthood, and also reduces brain arachidonic (ARA) metabolic consumption and protein level of the ARA metabolizing enzyme, cytochrome P4504A (CYP4A). HYPOTHESIS: Brain 20-hydroxyeicosatetraenoic acid (20 HETE), converted by CYP4A from ARA, will be reduced in adult mice treated transiently and postnatally with fluoxetine. METHODS: Male mice pups were injected i.p. daily with fluoxetine (10mg/kg) or saline during P4-P21. At P90 their brain was high-energy microwaved and analyzed for 20-HETE and six other ARA metabolites by enzyme immunoassay. RESULTS: Postnatal fluoxetine vs. saline significantly decreased brain concentrations of 20-HETE (-70.3%) and 15-epi lipoxin A4 (-60%) in adult mice, but did not change other eicosanoid concentrations. CONCLUSIONS: Behavioral changes in adult mice treated postnatally with fluoxetine may be related to reduced brain ARA metabolism involving CYP4A and 20-HETE formation. PMID- 26234929 TI - Quasi-Static Magnetic Field Shielding Using Longitudinal Mu-Near-Zero Metamaterials. AB - The control of quasi-static magnetic fields is of considerable interest in applications including the reduction of electromagnetic interference (EMI), wireless power transfer (WPT), and magnetic resonance imaging (MRI). The shielding of static or quasi-static magnetic fields is typically accomplished through the use of inherently magnetic materials with large magnetic permeability, such as ferrites, used sometimes in combination with metallic sheets and/or active field cancellation. Ferrite materials, however, can be expensive, heavy and brittle. Inspired by recent demonstrations of epsilon-, mu- and index-near-zero metamaterials, here we show how a longitudinal mu-near-zero (LMNZ) layer can serve as a strong frequency-selective reflector of magnetic fields when operating in the near-field region of dipole-like sources. Experimental measurements with a fabricated LMNZ sheet constructed from an artificial magnetic conductor - formed from non-magnetic, conducting, metamaterial elements - confirm that the artificial structure provides significantly improved shielding as compared with a commercially available ferrite of the same size. Furthermore, we design a structure to shield simultaneously at the fundamental and first harmonic frequencies. Such frequency selective behavior can be potentially useful for shielding electromagnetic sources that may also generate higher order harmonics, while leaving the transmission of other frequencies unaffected. PMID- 26234930 TI - Identification and characterization of naturally occurring DSF-family quorum sensing signal turnover system in the phytopathogen Xanthomonas. AB - Molecules of the diffusible signal factor (DSF)-family are a class of quorum sensing (QS) signals used by the phytopathogens Xanthomonas. Studies during the last decade have outlined how Xanthomonas cells enter the QS phase. However, information on the mechanism underlying its exit from the QS phase is limited. RpfB has recently been reported as a fatty acyl-CoA ligase (FCL) that activates a wide range of fatty acids to their CoA esters in vitro. Here, we establish an improved quantification assay for DSF-family signals using liquid chromatography mass spectrometry in X. campestris pv. campestris (Xcc). We first demonstrated that RpfB represents a naturally occurring DSF-family signal turnover system. RpfB effectively turns over DSF-family signals DSF and BDSF in vivo. RpfB FCL enzymatic activity is required for DSF and BDSF turnover. Deletion of rpfB slightly increased Xcc virulence in the Chinese radish and overexpression of rpfB significantly decreased virulence. We further showed that the expression of rpfB is growth phase-dependent, and its expression is significantly enhanced when Xcc cells enter the stationary phase. DSF regulates rpfB expression in a concentration-dependent manner. rpfB expression is also negatively regulated by the DSF signalling components RpfC, RpfG and Clp. The global transcription factor Clp directly binds to the AATGC-tgctgc-GCATC motif in the promoter region of rpfB to repress its expression. Finally, RpfB-dependent signal turnover system was detected in a wide range of bacterial species, suggesting that it is a conserved mechanism. PMID- 26234931 TI - The acute impact of polyphenols from Hibiscus sabdariffa in metabolic homeostasis: an approach combining metabolomics and gene-expression analyses. AB - We explored the acute multifunctional effects of polyphenols from Hibiscus sabdariffa in humans to assess possible consequences on the host's health. The expected dynamic response was studied using a combination of transcriptomics and metabolomics to integrate specific functional pathways through network-based methods and to generate hypotheses established by acute metabolic effects and/or modifications in the expression of relevant genes. Data were obtained from healthy male volunteers after 3 hours of ingestion of an aqueous Hibiscus sabdariffa extract. The data were compared with data obtained prior to the ingestion, and the overall findings suggest that these particular polyphenols had a simultaneous role in mitochondrial function, energy homeostasis and protection of the cardiovascular system. These findings suggest beneficial actions in inflammation, endothelial dysfunction, and oxidation, which are interrelated mechanisms. Among other effects, the activation of the heme oxygenase-biliverdin reductase axis, the systemic inhibition of the renin-angiotensin system, the inhibition of the angiotensin-converting enzyme, and several actions mirroring those of the peroxisome proliferator-activated receptor agonists further support this notion. We also found concordant findings in the serum of the participants, which include a decrease in cortisol levels and a significant increase in the active vasodilator metabolite of bradykinin (des-Arg(9)-bradykinin). Therefore, our data support the view that polyphenols from Hibiscus sabdariffa play a regulatory role in metabolic health and in the maintenance of blood pressure, thus implying a multi-faceted impact in metabolic and cardiovascular diseases. PMID- 26234932 TI - Administration of naloxone in combination with recombinant Plasmodium vivax AMA-1 in BALB/c mice induces mixed Th1/Th2 immune responses. AB - Naloxone (NLX) has the ability to shift the immune response to a Th1 profile. Therefore, the adjuvant efficacy of NLX with recombinant P. vivax apical membrane antigen-1(rPvAMA-1) in BALB/c mice was evaluated. Mice were immunized subcutaneously with purified rPvAMA-1 formulated with NLX (doses of 5 mg/kg body weight) alone or in combination with IFA. A significant increase in anti-PvAMA-1 IgG antibody after the second boost (mean OD490 = 2.08 and 2.17, in groups received, rPvAMA-1/NLX and rPvAMA-1/NLX/IFA, respectively) was detected. IgG1 and IgG2b were the predominant isotypes in all immunized mouse groups. In immunized mice with rPvAMA-1/NLX (mean: 1036 pg/mL) and with rPvAMA-1/NLX/IFA (mean: 1024 pg/mL), IFN-gamma was elicited in response to rPvAMA-1 after the second boost. No detectable IL-4 secretion was determined in all tested groups. In conclusion, the administration of NLX alone or NLX/IFA with rPvAMA-1 in BALB/c mice, which induced mixed Th1/Th2 immune responses, was comparable with that of the same recombinant antigen with CFA/IFA adjuvant. The results indicate that NLX alone may possibly not be considered as a potent Th1 adjuvant in PvAMA-1-based vaccine. However, in order to modulate immune responses from mixed Th1/Th2 to strong and protective Th1 response, further study is warranted on combination of NLX with other adjuvants such as CpG motifs or MPL in proper vaccine formulation. Additionally, dose-response study is necessary to determine the effect of different doses of antigen combined with NLX (at various doses) in Balb/c mice. PMID- 26234933 TI - Treatable newborn and infant seizures due to inborn errors of metabolism. AB - About 25% of seizures in the neonatal period have causes other than asphyxia, ischaemia or intracranial bleeding. Among these are primary genetic epileptic encephalopathies with sometimes poor prognosis and high mortality. In addition, some forms of neonatal infant seizures are due to inborn errors of metabolism that do not respond to common AEDs, but are amenable to specific treatment. In this situation, early recognition can allow seizure control and will prevent neurological deterioration and long-term sequelae. We review the group of inborn errors of metabolism that lead to newborn/infant seizures and epilepsy, of which the treatment with cofactors is very different to that used in typical epilepsy management. PMID- 26234934 TI - Rotational spectroscopy of methyl benzoylformate and methyl mandelate: structure and internal dynamics of a model reactant and product of enantioselective reduction. AB - Pure rotational spectra of a prototypical prochiral ester, methyl benzoylformate (MBF), and the product of its enantioselective reduction, (R)-(-)-methyl mandelate (MM), were measured in the range of 5-16 GHz, using a cavity-based molecular beam Fourier-transform microwave spectrometer. Potential conformers were located using density functional theory calculations, and one conformer of each species was identified experimentally. The minimum energy conformer of MBF, in which the ester group is in a Z orientation, was observed for the first time. Based on an atoms-in-molecules analysis, MBF contains a weak CH...O=C hydrogen bond between the carbonyl oxygen atom of the ester group and the nearest hydrogen atom of the aromatic ring. In the minimum energy conformer of MM, the ester group is oriented to accommodate a hydrogen bond between the hydrogen atom of the hydroxyl group and the carbonyl oxygen atom (OH...O=C), rather than the sp(3) oxygen atom (OH...O-C). For both species, splittings of the rotational transitions were observed, which are attributed to methyl internal rotation, and the orientations and barrier heights of the methyl tops were determined precisely. The barrier heights for MBF and MM are 4.60(2) and 4.54(3) kJ mol(-1), respectively, which are consistent with values predicted by high-level wavefunction-based calculations. On the basis of an atoms-in-molecules analysis, we propose that destabilization of the sp(3) oxygen atom of the ester group most directly dictates the barrier height. PMID- 26234935 TI - Predictors of hospitalization and quality of life in heart failure: A model of comorbidity, self-efficacy and self-care. AB - BACKGROUND: Comorbidity is associated with decreased confidence or self-efficacy to perform self-care in heart failure patients which, in turn, impairs self-care behaviors. Comorbidity is also associated with increased hospitalization rates and poorer quality of life. Yet the manner in which comorbidity and self-efficacy interact to influence self-care, hospitalization, and quality of life remains unclear. OBJECTIVES: The purpose of this study was to test an explanatory model. The research questions were (1) What is the contribution of comorbidity to heart failure self-care behaviors and outcomes (i.e. hospitalization, quality of life)? and (2) Is comorbidity a moderator of the relationship between self-efficacy and heart failure self-care behaviors? DESIGN: This was an analysis of an existing dataset of 628 symptomatic, older (mean age=73, standard deviation (SD)=11) male (58%) Italian heart failure patients using structural equation modeling and simple slope analysis. RESULTS: Higher levels of self-care maintenance were associated with higher quality of life and lower hospitalization rates. Higher levels of comorbidity were associated with lower levels of self-care management. Comorbidity moderated the relationship between self-efficacy and self-care maintenance, but not self-care management. Post hoc simple slopes analysis showed significantly different slope coefficients (pdiff<.05). Specifically, in patients with less comorbidity, the relationship between self-efficacy and self-care was significantly stronger than in patients with higher comorbidity. CONCLUSIONS: Self-efficacy is important in the self-care maintenance process at each level of comorbidity. Because higher comorbidity weakens the strength of the relationship between self-efficacy and self-care maintenance, tailoring interventions aimed at improving self-efficacy to different levels of comorbidity may be key to impacting hospitalization and quality of life. PMID- 26234936 TI - Assessing measurement in health: Beyond reliability and validity. AB - BACKGROUND: Psychometric concepts have undergone a transformation in health fields, as articulated in a consensus report by an international panel of health measurement experts: COSMIN, the COnsensus-based Standards for the selection of health Measurement INstruments. OBJECTIVES: The aims of this paper are to describe emerging ideas relating to the development and testing of new measures in health fields, to present a revised measurement taxonomy that builds upon COSMIN, and to explore the extent to which the new measurement concepts have played a role in psychometric assessments in nursing. DESIGN: A descriptive analysis of a sample of psychometric papers published in three major nursing journals was undertaken. METHODS: A new measurement taxonomy is presented and explained. A sample of 105 studies, representing a consecutive sample of psychometric studies published in the International Journal of Nursing Studies, Nursing Research, and Research in Nursing & Health between 2010 and 2014 was reviewed to ascertain the extent to which psychometric assessments in nursing map onto the new taxonomy. RESULTS: Most nursing studies reviewed adhered to traditional concepts of psychometric assessment, which focus on reliability and validity. The studies in the sample rarely involved assessments of longitudinal measurement aspects, namely the reliability and validity of change scores (responsiveness). CONCLUSIONS: Many constructs of interest to nurse researchers are amenable to change-and these constructs are frequently the target of nursing interventions designed to foster change. Future psychometric work by nurse researchers would benefit from assessments of the psychometric adequacy of change scores. PMID- 26234937 TI - The relationship between workplace learning and midwives' and nurses' self reported competence: a cross-sectional survey. AB - BACKGROUND: Nurses have to maintain and improve their nursing competence in order to provide the best patient care possible. Workplace learning has the potential to improve nursing competence. Previous studies have examined the effect of training on competence development. However, the effects of other aspects of learning, such as learning from practice, feedback, reflection, and from others have not been investigated previously. Furthermore, it is uncertain what methods of learning nurses with different clinical experience adopt and how these learning methods relate to their self-reported competence. OBJECTIVES: The objectives of this study were to identify the methods of learning used by less and more experienced nurses, and to explore what methods of workplace learning would be associated with the self-reported competence of both groups of nurses. DESIGN: A cross-sectional survey design was utilised. SETTINGS: The study was conducted at two university-affiliated hospitals in Japan. PARTICIPANTS: A convenience sample of 954 nurses/midwives (hereafter referred to as nurses), who were involved in direct patient care, were recruited and 494 nurses returned usable questionnaires. METHODS: A survey method was used to collect data. The Holistic Nursing Competence Scale, the Learning Experience Scale and the Japanese version of Rosenberg's Self-esteem Scale, along with demographic questions, were included in the questionnaire. Hierarchical regression analysis was conducted to investigate the relationship between learning and nurses' self-evaluation of competence. This analysis was carried out for less experienced nurses (<=5 years of clinical experience) and experienced nurses (>5 years of experience). RESULTS: The results showed that learning was correlated with the levels of competence that nurses considered they had. When the specific types of learning were examined in relation to self-reported competence, there were a similarity and differences between less and more experienced nurses. For both groups of nurses, learning through reflection was found to relate to their self-reported competence. In addition, learning through practice and learning from others were positively correlated with the self-reported competence of less experienced nurses, while learning from feedback and training were positively associated with the self-reported competence of experienced nurses. CONCLUSION: Learning from reflection may be useful for both less and more experienced nurses by allowing them to embrace a positive view of their competence. Moreover, creating opportunities to experiment and observe others' practice can be profitable for less experienced nurses, while offering training opportunities and feedback can be beneficial for experienced nurses. PMID- 26234938 TI - An MRI Method To Map Tumor Hypoxia Using Red Blood Cells Loaded with a pO2 Responsive Gd-Agent. AB - Hypoxia is a typical hallmark of many solid tumors and often leads to therapy resistance and the development of a more aggressive cancer phenotype. Oxygen content in tissues has been evaluated using numerous different methods for several imaging modalities, but none has yet reached the required standard of spatial and temporal resolution. Magnetic Resonance Imaging (MRI) appears to be the technique of choice and several pO2-responsive probes have been designed for it over the years. In vivo translation is often hampered in Gd-relaxation agents as it is not possible to separate effects that arise from changes in local concentration from those associated with responsive properties. A novel procedure for the MRI based assessment of hypoxia is reported herein. The method relies on the combined use of Gd-DOTP- and Gd-HPDO3A-labeled red blood cells (RBCs) where the first probe acts as a vascular oxygenation-responsive agent, while the second reports the local labeled RBC concentration in a transplanted breast tumor mouse model. The MRI assessment of oxygenation state has been validated by photoacoustic imaging and ex vivo immunofluorescence. The method refines tumor staging in preclinical models and makes possible an accurate monitoring of the relationship between oxygenation and tumor growth. PMID- 26234939 TI - Using Post-Traumatic Amnesia To Predict Outcome after Traumatic Brain Injury. AB - Duration of post-traumatic amnesia (PTA) has emerged as a strong measure of injury severity after traumatic brain injury (TBI). Despite the growing international adoption of this measure, there remains a lack of consistency in the way in which PTA duration is used to classify severity of injury. This study aimed to establish the classification of PTA that would best predict functional or productivity outcomes. We conducted a cohort study of 1041 persons recruited from inpatient admissions to a TBI rehabilitation center between 1985 and 2013. Participants had a primary diagnosis of TBI, emerged from PTA before discharge from inpatient hospital, and engaged in productive activities before injury. Eight models that classify duration of PTA were evaluated-six that were based on the literature and two that were statistically driven. Models were assessed using area under the receiver operating characteristic curve (AUC) as well as model based Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC) statistics. All categorization models showed longer PTA to be associated with a greater likelihood of being nonproductive at 1 year after TBI. Classification systems with a greater number of categories performed better than two-category systems. The dimensional (continuous) form of PTA resulted in the greatest AUC, and lowest AIC as well as BIC, of the classification systems examined. This finding indicates that the greatest accuracy in prognosis is likely to be achieved using PTA as a continuous variable. This enables the probability of productive outcomes to be estimated with far greater precision than that possible using a classification system. Categorizing PTA to classify severity of injury may be reducing the precision with which clinicians can plan the treatment of patients after TBI. PMID- 26234941 TI - Two Novel NYX Gene Mutations in the Chinese Families with X-linked Congenital Stationary Night Blindness. AB - Mutations in NYX and CACNA1F gene are responsible for the X-linked congenital stationary night blindness (CSNB). In this study, we described the clinical characters of the two Chinese families with X-linked CSNB and detected two novel mutations of c. 371_377delGCTACCT and c.214A>C in the NYX gene by direct sequencing. These two mutations would expand the mutation spectrum of NYX. Our study would be helpful for further studying molecular pathogenesis of CSNB. PMID- 26234942 TI - Against the mainstream: the membrane-associated type I toxin BsrG from Bacillus subtilis interferes with cell envelope biosynthesis without increasing membrane permeability. AB - Toxin-antitoxin loci, which encode a toxic protein alongside with either RNA or a protein able to counteract the toxicity, are widespread among archaea and bacteria. These loci are implicated in persistence, and as addiction modules to ensure stable inheritance of plasmids and phages. In type I toxin-antitoxin systems, a small RNA acts as an antitoxin, which prevents the synthesis of the toxin. Most type I toxins are small hydrophobic membrane proteins generally assumed to induce pores, or otherwise permeabilise the cytoplasmic membrane and, as a result, induce cell death by energy starvation. Here we show that this mode of action is not a conserved property of type I toxins. The analysis of the cellular toxicity caused by Bacillus subtilis prophage SPbeta-encoded toxin BsrG revealed that, surprisingly, it neither dissipates membrane potential nor affects cellular ATP-levels. In contrast, BsrG strongly interferes with the cell envelope biosynthesis, causes membrane invaginations together with delocalisation of the cell wall synthesis machinery and triggers autolysis. Furthermore, efficient inhibition of protein biosynthesis is observed. These findings question the simplistic assumption that small membrane targeting toxins generally act by permeabilising the membrane. PMID- 26234940 TI - Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer. AB - BACKGROUND: The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance. METHODS: We integrated reverse phase protein array (RPPA) and gene expression data from patients with HER2-positive breast cancer treated with trastuzumab in the adjuvant setting. RESULTS: We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02). This suggests that STAT3 induces a characteristic set of gene expression changes in HER2-positive cancers. Tumors characterized as high pSTAT3-GS were associated with trastuzumab resistance (log rank P = 0.049). These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02). Of interest, constitutively activated pSTAT3 tumors were associated with loss of PTEN, elevated IL6, and stromal reactivation. CONCLUSIONS: This study provides compelling evidence for a link between pSTAT3 and trastuzumab resistance in HER2 positive primary breast cancers. Our results suggest that it may be valuable to add agents targeting the STAT3 pathway to trastuzumab for treatment of HER2 positive breast cancer. PMID- 26234944 TI - Genetic influence on age at first birth of female twins born in the UK, 1919-68. AB - Using a sample of monozygotic (945, 42 per cent) and dizygotic (1,329, 58 per cent) twin pairs born 1919-68 in the UK, we applied innovative tobit models to investigate genetic and environmental influences on age at first birth (AFB). We found that a substantial part (40 per cent) of the variation in AFB is caused by latent family characteristics. Genetic dispositions (26 per cent) play a more important role than the shared environment of siblings (14 per cent), with the non-shared environment/measurement error having the strongest influence (60 per cent). Like previous studies, this study reveals marked changes in estimates over time, and supports the idea that environmental constraints (war or economic crisis) suppress and normative freedom (sexual revolution) promotes the activation of genetic predispositions that affect fertility. We show that the exclusion of censored information (i.e., on the childless) by previous studies biased their results. PMID- 26234943 TI - Synthetic heparan sulfate dodecasaccharides reveal single sulfation site interconverts CXCL8 and CXCL12 chemokine biology. AB - The multigram-scale synthesis of a sulfation-site programmed heparin-like dodecasaccharide is described. Evaluation alongside dodecasaccharides lacking this single glucosamine O6-sulfation, or having per-O6-sulfation, shows that site specific modification of the terminal glucosamine dramatically interconverts regulation of in vitro and in vivo biology mediated by the two important chemokines, CXCL12 (SDF1alpha) or CXCL8 (IL-8). PMID- 26234947 TI - Basic nutrition knowledge of recent medical graduates entering a pediatric residency program. AB - OBJECTIVE: This study assesses the basic nutritional knowledge of fourth year medical/osteopathic school graduates entering a pediatric residency program and compares the knowledge of the medical students to that of the patients and parents who completed the same survey previously. METHODS: Medical and osteopathic school graduates entering a pediatric residency program completed an 18-question nutrition survey during resident orientation in June of 2011 and 2012. RESULTS: The incoming interns averaged answering 52% of the questions correctly. Interns did better than both groups but the only statistically significant difference was between the interns and the non-eating disorder adolescents and their parents (p<0.001). CONCLUSION: Incoming residents to a pediatric residency program appear to be deficient in basic nutritional knowledge. With the ever increasing burden of obesity and its associated co morbidities on society, it is imperative that medical education focuses on preparing physicians to appropriately counsel all populations on proper nutrition. PMID- 26234945 TI - Weight Loss Associated with Cholinesterase Inhibitors in Individuals with Dementia in a National Healthcare System. AB - OBJECTIVES: To determine whether initiation of cholinesterase inhibitors is associated with significant weight loss in a real-word clinical setting. DESIGN: Retrospective cohort study from 2007 to 2010 comparing weight loss in individuals with dementia newly prescribed cholinesterase inhibitors and those newly prescribed other chronic medications. SETTING: National Veterans Affairs data. PARTICIPANTS: Individuals aged 65 and older with a diagnosis of dementia who received a new prescription for a cholinesterase inhibitor or other new chronic medication. MEASUREMENTS: The primary outcome was time to 10-pound weight loss over 12 months. Propensity score matching was used to control for the likelihood of receiving a cholinesterase inhibitor based on baseline characteristics. Data were analyzed in a priori defined subgroups according to age, comorbid burden, and initial weight. RESULTS: Of 6,504 individuals that met study criteria, 1,188 started on cholinesterase inhibitors were matched to 2,189 started on other medications. The propensity-matched cohorts were well balanced on baseline covariates. Participants initiated on cholinesterase inhibitors had a higher risk of weight loss than matched controls at 12 months (hazard ratio = 1.23, 95% confidence interval (CI) = 1.07-1.41). At 12 months, 29.3% of participants taking cholinesterase inhibitors had experienced weight loss, compared with 22.8% of nonusers, corresponding to a number needed to harm of 21.2 (95% CI = 12.5-71.4) over 1 year. There were no significant differences in the risk of weight loss within subgroups. CONCLUSION: These results are consistent with the available data from randomized controlled trials. Clinicians should consider the risk of weight loss when prescribing cholinesterase inhibitors. PMID- 26234946 TI - Identification of a DYRK1A Inhibitor that Induces Degradation of the Target Kinase using Co-chaperone CDC37 fused with Luciferase nanoKAZ. AB - The protein kinase family includes attractive targets for drug development. Methods for screening of kinase inhibitors remain largely limited to in vitro catalytic assays. It has been shown that ATP-competitive inhibitors antagonize interaction between the target kinase and kinase-specific co-chaperone CDC37 in living cells. Here we show a cell-based method to screen kinase inhibitors using fusion protein of CDC37 with a mutated catalytic 19-kDa component of Oplophorus luciferase, nanoKAZ (CDC37-nanoKAZ). A dual-specificity kinase DYRK1A, an importance of which has been highlighted in Alzheimer's disease, was targeted in this study. We established 293T cells stably expressing CDC37-nanoKAZ, and analyzed interaction between CDC37-nanoKAZ and DYRK1A. We revealed that DYRK1A interacted with CDC37-nanoKAZ. Importantly, point mutations that affect autophosphorylation strengthened the interaction, thus improving signal/noise ratio of the interaction relative to non-specific binding of CDC37-nanoKAZ. This high signal/noise ratio enabled screening of chemical library that resulted in identification of a potent inhibitor of DYRK1A, named CaNDY. CaNDY induced selective degradation of DYRK1A, and inhibited catalytic activity of recombinant DYRK1A with IC50 value of 7.9 nM by competing with ATP. This method based on a mutant target kinase and a bioluminescence-eliciting co-chaperone CDC37 could be applicable to evaluation and development of inhibitors targeting other kinases. PMID- 26234948 TI - Prevalence and incidence of mental health problems among Dutch medical students and the study-related and personal risk factors: a longitudinal study. AB - BACKGROUND: A high prevalence of mental health problems (i.e. depression and/or anxiety) has been found in medical students in comparison with the general population. Therefore, the objective was first to study the prevalence and 1-year incidence of symptoms of depression, anxiety and any mental health problems among Dutch medical students and, second, to study which study-related and personal factors present a risk of these mental health problems. METHODS: A 1-year prospective longitudinal study was performed among medical students of two medical faculties in the Netherlands (n=951). Health problems and study-related and personal factors were measured with an online questionnaire. Mental health problems were assessed by depression and/or anxiety symptoms (BSI-DEP and BSI ANG). Univariate and multivariate hierarchical logistic regression analyses were performed to examine which of the study-related and personal factors predict mental health problems. RESULTS: At follow-up, 36%, 28% and 48% of the medical students reported symptoms of depression, anxiety and mental health problems, respectively. The incidence between 2010 and 2011 for depression was 20%, 17% for anxiety and 25% for mental health problems. Students who are worried about their own health during medical education are at an increased risk of future mental health problems (OR 2.0 [1.3-2.9], p=0.00). Excessive drinking behavior is a protective factor in this study (OR 0.7 [0.5-0.9], p=0.02). CONCLUSION: This study shows that only two out of nine factors are significantly associated with mental health problems among Dutch medical students, one risk factor and one protective factor. PMID- 26234949 TI - Influence Re-weighted G-Estimation. AB - Individualized medicine is an area that is growing, both in clinical and statistical settings, where in the latter, personalized treatment strategies are often referred to as dynamic treatment regimens. Estimation of the optimal dynamic treatment regime has focused primarily on semi-parametric approaches, some of which are said to be doubly robust in that they give rise to consistent estimators provided at least one of two models is correctly specified. In particular, the locally efficient doubly robust g-estimation is robust to misspecification of the treatment-free outcome model so long as the propensity model is specified correctly, at the cost of an increase in variability. In this paper, we propose data-adaptive weighting schemes that serve to decrease the impact of influential points and thus stabilize the estimator. In doing so, we provide a doubly robust g-estimator that is also robust in the sense of Hampel (15). PMID- 26234950 TI - Student Engagement: A Principle-Based Concept Analysis. AB - A principle-based concept analysis of student engagement was used to examine the state of the science across disciplines. Four major perspectives of philosophy of science guided analysis and provided a framework for study of interrelationships and integration of conceptual components which then resulted in formulation of a theoretical definition. Findings revealed student engagement as a dynamic reiterative process marked by positive behavioral, cognitive, and affective elements exhibited in pursuit of deep learning. This process is influenced by a broader sociocultural environment bound by contextual preconditions of self investment, motivation, and a valuing of learning. Outcomes of student engagement include satisfaction, sense of well-being, and personal development. Findings of this analysis prove relevant to nursing education as faculty transition from traditional teaching paradigms, incorporate learner-centered strategies, and adopt innovative pedagogical methodologies. It lends support for curricula reform, development of more accurate evaluative measures, and creation of meaningful teaching-learning environments within the discipline. PMID- 26234952 TI - The impact of HIV-related stigma on the lives of HIV-positive women: an integrated literature review. AB - AIMS AND OBJECTIVES: To critically explore how Human Immunodeficiency Virus related stigma impacts on the lives of Human Immunodeficiency Virus-positive women through an integrative review of the literature. BACKGROUND: Throughout history Human Immunodeficiency Virus infection has been associated with sex trade, injecting drug use and other deviant behaviours within society. These historical associations can lead to the generation of negative perceptions of Human Immunodeficiency Virus-positive women. As such, women who contract Human Immunodeficiency Virus infection can be susceptible to societal stigma. DESIGN: An integrative literature review. METHODS: To identify the publications on the impact of Human Immunodeficiency Virus-related stigma among women, a search was performed using the following databases: CINAHL, Medline, PsycINFO, EMBASE, and Applied Social Sciences Index and Abstract covering the period from 2000-2014. The following key words were included in the search: 'women', 'Human Immunodeficiency Virus', and 'stigma'. RESULTS: Twenty-six articles were retrieved and reviewed. From the results, four key themes merged in relation to the impact of Human Immunodeficiency Virus-related stigma on Human Immunodeficiency Virus-positive women's lives: the individual, relationships, work and the community. CONCLUSIONS: Despite great advances in the management and treatment of those who are Human Immunodeficiency Virus positive, it appears the lives of many women living with Human Immunodeficiency Virus remain greatly affected by their Human Immunodeficiency Virus infection with gender-specific stigma and stereotypes. Having a holistic understanding of this impact offers the potential for those responsible for the funding and draws the attention of researchers and policy makers on promoting medical services specifically for Human Immunodeficiency Virus-positive women, minimising social stigmatisation towards this client group, and optimising their health outcomes. RELEVANCE TO CLINICAL PRACTICE: In an attempt to amplify Human Immunodeficiency Virus-positive women's ability to resist social injustice, obtain support and optimise their health outcomes, nurses should expand their roles and work with professionals from different sectors to ensure the provision of comprehensive care to women with Human Immunodeficiency Virus infection. PMID- 26234951 TI - Delayed Match Retrieval: a novel anticipation-based visual working memory paradigm. AB - We tested 8- and 10-month-old infants' visual working memory (VWM) for object location bindings - what is where - with a novel paradigm, Delayed Match Retrieval, that measured infants' anticipatory gaze responses (using a Tobii T120 eye tracker). In an inversion of Delayed-Match-to-Sample tasks and with inspiration from the game Memory, in test trials, three face-down virtual 'cards' were presented. Two flipped over sequentially (revealing, e.g. a swirl pattern and then a star), and then flipped back face-down. Next, the third card was flipped to reveal a match (e.g. a star) to one of the previously seen, now face down cards. If infants looked to the location where the (now face-down) matching card had been shown, this was coded as a correct response. To encourage anticipatory looks, infants subsequently received a reward (a brief, engaging animation) presented at that location. Ten-month-old infants performed significantly above chance, showing that their VWM could hold object-location information for the two cards. Overall, 8-month-olds' performance was at chance, but they showed a robust learning trend. These results corroborate previous findings (Kaldy & Leslie, 2005; Oakes, Ross-Sheehy & Luck, 2006) and point to rapid development of VWM for object-location bindings. However, compared to previous paradigms that measure passive gaze responses to novelty, this paradigm presents a more challenging, ecologically relevant test of VWM, as it measures the ability to make online predictions and actively localize objects based on VWM. In addition, this paradigm can be readily scaled up to test toddlers or older children without significant modification. PMID- 26234953 TI - Long-term evaluation of impedance levels and clinical development in subthalamic deep brain stimulation for Parkinson's disease. AB - BACKGROUND: This study was conducted to better understand the development of clinical efficacy and impedance levels in the long-term course of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD). METHODS: In this retrospective study of twenty PD patients, the motor part of the Unified Parkinson's Disease Rating Scale was periodically assessed i) after withdrawal of medication and inactivated stimulation, ii) after withdrawal of medication with activated stimulation and iii) after challenge with l-Dopa during activated stimulation up to 13 years after surgery. RESULTS: STN-DBS with or without medication significantly improved motor function up to 13 years after surgery. The contribution of axial symptoms increased over time. While the stimulation parameters were kept constant, the therapeutic impedances progressively declined. CONCLUSION: STN-DBS in PD remains effective in the long term course of the disease. Constant current stimulation might be preferable over voltage-controlled stimulation, as it would alleviate the impact of impedance changes on the volume of tissue activated. PMID- 26234954 TI - Ionothermal Synthesis and Structure of a New Layered Zirconium Phosphate. AB - A new layered zirconium phosphate material has been synthesized ionothermally using N-ethylpyridinium (Epy) bromide as both the solvent and the template, and its structure has been solved from synchrotron X-ray powder diffraction data using the charge-flipping routine implemented in Superflip. Rietveld refinement coupled with difference electron density map analysis was used to locate the organic cations between the layers. In the final stages of refinement, it became clear that not only ethylpyridinium but also pyridinium ions were present between the zirconium phosphate layers. These findings were then corroborated using elemental analysis, TGA, and solid-state (13)C CP/MAS NMR data. PMID- 26234956 TI - Exposure to Childhood Poverty and Mental Health Symptomatology in Adolescence: A Role of Coping Strategies. AB - Childhood poverty is associated with stress dysregulation which contributes to psychological illness in later ages. The adverse effects of childhood poverty on stress regulation may be mediated in part by the use of disengaging strategies to cope with stress. However, the relations among childhood poverty, coping strategies and psychopathology throughout childhood to adolescence have not been explored. This prospective, longitudinal study included 185 low- and middle income adolescents at age 17. Chronic exposure to poverty from birth to early adolescence (age 13) was prospectively associated with increases in the use of disengagement versus engagement coping four years later. Increased use of disengagement coping between the ages of 13 and 17 explained the indirect link between poverty exposure since birth and both externalizing and internalizing symptoms at age 17. The findings provide evidence for a coping pathway underlying the link between prolonged exposure to childhood poverty and mental health sequelae. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26234957 TI - Low-rise scar deep inferior epigastric artery perforator flap for breast reconstruction. AB - BACKGROUND: To achieve an unnoticeable postoperative scar in patients with little abdominal skin laxity for breast reconstruction by deep inferior epigastric artery perforator (DIEP) flap, we devised a new design called the low-rise scar DIEP flap; the skin paddle of this flap is located lower with a smaller vertical width, and more adipose tissue is elevated to obtain enough volume. The purpose of this report is to evaluate the utility of the low-rise scar DIEP flap compared with that of the conventionally designed flap. METHODS: Twelve patients who underwent low-rise scar DIEP flaps (study group) and 11 patients who underwent conventionally-designed DIEP flaps (control group) were included in the present study. The distance from the umbilicus to horizontal scar was divided by the patient's height. The length of the scar was divided by the abdominal circumference. These ratios were compared between groups. RESULTS: All flaps survived completely and no recipient site complication was observed, except for one case in the control group with small-range fat necrosis. No donor site complication was observed in either group. The distance ratio was significantly larger in study group (<0.01, 0.049 +/- 0.004, and 0.028 +/- 0.005, respectively). The length ratio was significantly smaller in the study group <0.01, 0.42 +/- 0.02 and 0.36 +/- 0.02, respectively). The weight of the flap used for reconstruction was 338.8 +/- 127.7 g in the study group and 320.5 +/- 63.0 g in the control group CONCLUSIONS: A low-rise scar DIEP flap leaves a lower and shorter postoperative scar. PMID- 26234955 TI - Peer Network Counseling with Urban Adolescents: A Randomized Controlled Trial with Moderate Substance Users. AB - Close peer networks can affect adolescents' health behaviors by altering their social environments, and thus their risk for and protection against substance use involvement. We tested a 20 minute intervention named Peer Network Counseling that integrates motivational interviewing and peer network strategies with 119 urban adolescents who reported occasional or problem substance use. Adolescents presenting at primary care clinic were randomized to intervention or control conditions and followed for 6 months. Mixed-effect latent growth models were used to evaluate intervention effects on trajectories of alcohol and marijuana use, offers to use substances, and moderation models to test for interactions between intervention condition and peer network characteristics. A significant intervention effect was found for boys for offers to use alcohol from friends (p<.05), along with a trend significant effect for alcohol use (p<.08). Intervention was more effective in reducing marijuana use, vs. control, for participants with more peer social support (p<.001) and with more peer encouragement for prosocial behavior (school, clubs, sports, religious activities); however, intervention did not affect these network characteristics. Results provide support to continue this line of research to test brief interventions that activate protective peer network characteristics among at-risk adolescents, while also raising some interesting gender-based intervention questions for future research. PMID- 26234958 TI - Total synthesis of astrosterioside A, an anti-inflammatory asterosaponin. AB - Astrosterioside A, a sulfated steroidal hexasaccharide isolated from starfish Astropecten monacanthus showing potent anti-inflammatory activity, was synthesized in a convergent linear sequence of 24 steps and in 6.8% overall yield from adrenosterone. PMID- 26234959 TI - Does iodinated contrast medium amplify DNA damage during exposure to radiation. AB - There is a recognized increased risk of cancer following exposure of humans to ionizing radiation; this is felt to be most likely due to damage to DNA strands during exposure. Damage to DNA strands can be demonstrated microscopically following exposure to X-rays, and new evidence is emerging that this effect may be compounded by administration of iodinated contrast agents. PMID- 26234960 TI - Relational learning and transitive expression in aging and amnesia. AB - Aging has been associated with a decline in relational memory, which is critically supported by the hippocampus. By adapting the transitivity paradigm (Bunsey and Eichenbaum (1996) Nature 379:255-257), which traditionally has been used in nonhuman animal research, this work examined the extent to which aging is accompanied by deficits in relational learning and flexible expression of relational information. Older adults' performance was additionally contrasted with that of amnesic case DA to understand the critical contributions of the medial temporal lobe, and specifically, the hippocampus, which endures structural and functional changes in healthy aging. Participants were required to select the correct choice item (B versus Y) based on the presented sample item (e.g., A). Pairwise relations must be learned (A->B, B->C, C->D) so that ultimately, the correct relations can be inferred when presented with a novel probe item (A >C?Z?). Participants completed four conditions of transitivity that varied in terms of the degree to which the stimuli and the relations among them were known pre-experimentally. Younger adults, older adults, and DA performed similarly when the condition employed all pre-experimentally known, semantic, relations. Older adults and DA were less accurate than younger adults when all to-be-learned relations were arbitrary. However, accuracy improved for older adults when they could use pre-experimentally known pairwise relations to express understanding of arbitrary relations as indexed through inference judgments. DA could not learn arbitrary relations nor use existing knowledge to support novel inferences. These results suggest that while aging has often been associated with an emerging decline in hippocampal function, prior knowledge can be used to support novel inferences. However, in case DA, significant damage to the hippocampus likely impaired his ability to learn novel relations, while additional damage to ventromedial prefrontal and anterior temporal regions may have resulted in an inability to use prior knowledge to flexibly express indirect relational knowledge. PMID- 26234962 TI - Paying attention to my voice or yours: An ERP study with words. AB - Self-related stimuli-such as one's own face or name-seem to be processed differently from non-self stimuli and to involve greater attentional resources, as indexed by larger amplitude of the P3 event-related potential (ERP) component. Nonetheless, the differential processing of self-related vs. non-self information using voice stimuli is still poorly understood. The present study investigated the electrophysiological correlates of processing self-generated vs. non-self voice stimuli, when they are in the focus of attention. ERP data were recorded from twenty right-handed healthy males during an oddball task comprising pre recorded self-generated (SGV) and non-self (NSV) voice stimuli. Both voices were used as standard and deviant stimuli in distinct experimental blocks. SGV was found to elicit more negative N2 and more positive P3 in comparison with NSV. No association was found between ERP data and voice acoustic properties. These findings demonstrated an earlier and later attentional bias to self-generated relative to non-self voice stimuli. They suggest that one's own voice representation may have a greater affective salience than an unfamiliar voice, confirming the modulatory role of salience on P3. PMID- 26234961 TI - Present self, past self and close-other: Event-related potential study of face and name detection. AB - A growing body of evidence suggests that information regarding the past self and other people is processed similarly. However, there is not much evidence supporting this notion at the neural level. In this event-related potential (ERP) study we examined processing of one's own marital and family name (i.e., present and past self-name, respectively) and images of present and past self-face in comparison to names and faces of others (the close-other, famous and unknown person). Amplitudes of P300 (a late ERP component associated with attention, emotion, and autobiographical memory) to self-face and self-name, either present or past, was enhanced in comparison to famous and unknown faces and names. No differences, however, were observed between the past and present self-names as well as between past and present self-faces. Moreover, P300 amplitude to the past self-face was enhanced in the right hemisphere in comparison to the close-other's face, whereas P300 amplitudes to the past self-name and the close-other's name did not differ. Thus, our results indicated that information related to non physical aspects of the past self were processed similarly to the close-other. PMID- 26234963 TI - [Bioethics destiny]. AB - The paper is about the links between ethics and science, at a time (1974-2014) when the life sciences expanded rapidly. First (1974-1994), the development of a principlist ethics, set out by philosophers, sustained the research, and the scientists, expected to behave responsibly, felt like they could easily converge towards impeccable and consensual solutions to any problem arising from scientific innovations. Later on (1994-2014), however, while yielding ground to social sciences and ground work, bioethics took an empirical turn; then it became clear that behaving responsibly was compatible with a plurality of divergent normative convictions. Ethics crumbled. Local or national policies restored order, so-called bioethical laws short-circuited ethical reflection. And far from being respected as the wise men, apt to recommend the very best solutions to problems raised by new scientific advances, researchers happened to be deemed irresponsible, as some of them were suspected of lacking intellectual integrity. PMID- 26234964 TI - Indigenous Knowledge of Herbal Medicines among Adolescents in Amassoma, Bayelsa State, Nigeria. AB - BACKGROUND: The use of herbal medicines in Nigeria is on the increase. Documented Population based data on the use of herbal medicinal products and indigenous knowledge among the younger generations are lacking in Nigeria and Africa at large. AIM: The aim of this study is to investigate the extent of use and general knowledge of herbal medicines among adolescents in the Niger Delta Region of Nigeria. METHODS: The study covered a total of Two hundred and twenty-eight adolescents randomly selected in Senior Secondary Schools (SSS 1-3) in Amassoma using a semi structured questionnaire/Interview and informal conversation on the respondents. FINDINGS: Nearly all (97%) the respondents have had contact with herbs. Less than 1% had contact with herbs through formal education (teachers/literatures). Stimulation of interest was majorly through parents (53%). Grandparents were the highest (46%) of custodian of indigenous knowledge. Parents were the next (39.7%). Only 39% of the respondents would prefer the use of herbal medicine to modern medicine. Fever was the main ailment mentioned followed by eye ailment and stomach ache. Vernonia amygdalina was the main plant for the treatment of fever. CONCLUSION: The study revealed that parents are the major custodians of knowledge being transferred to the younger generation and little or none is learnt from Schools. There is therefore the need to include the study of herbal medicines in School's curricula especially at SS 2 and SS 3 since they are matured enough to appreciate the importance of Herbal medicine so as to prepare them for the promotion of herbal medicine in future and to preserve our indigenous knowledge. PMID- 26234965 TI - Social Cognitive Predictors of Breakfast Consumption in Primary School's Male Students. AB - PURPOSE: This study aimed to test the usefulness of social cognitive theory (SCT) in explaining breakfast consumption in a sample of primary male students. METHODS: Participants in this cross-sectional study were 358 male students (3rd, 4th and 5th grades) from eight public primary schools of Ilam city. Data were collected by a self-administered questionnaire based on components of SCT. Bivariate correlations and multiple logistic regression analysis using an Enter method were used to identify social cognitive correlates and determinants of breakfast consumption. RESULTS: A total of 358 participants ranging in age from 8 12 years (M=10.06) were studied. The result of the study showed that the SCT significantly predicted breakfast consumption. SCT variables explained 41.4% of the variance in breakfast consumption behaviors, though, self-regulation was found to be the strongest predictor of breakfast consumption behaviors. There was the strongest correlation between behaviors and self-regulation, (r=0.561; P<0.001). CONCLUSION: The findings support the usefulness of SCT in explaining breakfast consumption behaviors. These results suggest an essential role for self regulation, self-efficacy and social support in the breakfast consumption behaviors of primary male students. PMID- 26234966 TI - Multiple Imputation to Correct for Nonresponse Bias: Application in Non communicable Disease Risk Factors Survey. AB - BACKGROUND: This study was carried out to use multiple imputation (MI) in order to correct for the potential nonresponse bias in measurements related to variable fasting blood glucose (FBS) in non-communicable disease risk factors survey conducted in Iran in 2007. METHODS: Five multiple imputation methods as bootstrap expectation maximization, multivariate normal regression, univariate linear regression, MI by chained equation, and predictive mean matching were applied to impute variable fasting blood sugar. To make FBS consistent with normality assumption natural logarithm (Ln) and Box-Cox (BC) transformations were used prior to imputation. Measurements from which we intended to remove nonresponse bias included mean of FBS and percentage of those with high FBS. RESULTS: For mean of FBS results didn't considerably change after applying MI methods. Regarding the prevalence of high blood sugar all methods on original scale tended to increase the estimates except for predictive mean matching that along with all methods on BC or Ln transformed data didn't change the results. CONCLUSIONS: FBS related measurements didn't change after applying different MI methods. It seems that nonresponse bias was not an important challenge regarding these measurements. However use of MI methods resulted in more efficient estimations. Further studies are encouraged on accuracy of MI methods in these settings. PMID- 26234967 TI - Comparing the Effects of Two Feeding Methods on Metabolic Bone Disease in Newborns with Very Low Birth Weights. AB - INTRODUCTION: Bone metabolic disease is an important issue in newborns with very low birth weight. The 80 percent of the transport of calcium (Ca) and phosphor (P) from mother to fetus takes place in the third trimester of pregnancy. This transport process is impaired with the preterm delivery of the newborn. On the other side, breast milk and formula are not competent resources to supply sufficient amounts of Ca and P to meet the requirements of the preterm newborn, thereby a greater reduction in the storage of these minerals. The current study has been done with the purpose of comparing the effects of two feeding methods on the indices of metabolic bone disease in newborns with very low birth weights (VLBW). MATERIALS & METHODS: The study design was cohort and the study was done on a total of 58 newborns with very low birth weights in Kashan Shahid Beheshti Hospital. The newborns were divided into two groups with 29 placed in the group of alternate feeding on preterm formula (preNan) and the other 29 placed in the group of breast milk and preterm formula (preNan). Eventually, the indices of bone metabolic disease were measured in both groups and were statistically analyzed. RESULTS: The difference between the mean serum levels of Ca in different weeks and also between the two groups were significant (p=0.001). However, the changes in mean serum level of P in the two groups were not significant (P=0.151). The comparison of serum levels of alkaline phosphatase between the two groups indicated that their difference was significant and that they had been influenced by the feeding method (P=0.001). The serum level of bicarbonate, when compared between the two groups, was found to make a significant difference (P=0.001). The difference between the two feeding methods in precipitating rickets and osteopenia was not significant. CONCLUSION: According to the findings of current study, feeding on preterm formula (preNan) is associated with better and more desirable results, though the occurrence of rickets in the two groups had no significant difference. PMID- 26234968 TI - Structured Walking and Chronic Institutionalized Schizophrenia Inmates: A pilot RCT Study on Quality of Life. AB - BACKGROUND: Lifestyle moderate-intensity physical activity can lower the risk of over twenty chronic health conditions, whilst inactivity reduces daily functioning and physical health of individuals living with schizophrenia. This study conducted in 2014 examines the effect of structured walking participation on QOL, psychosocial functioning and symptoms in Hospital Permai, one of the largest psychiatry institution in Asia METHOD: Chronic patients with schizophrenia (n=104) who met inclusion criteria were randomised to either a 3 month structured walking intervention or a treatment-as-usual arm. The Positive and Negative Syndrome Scale (PANSS), global functioning (PSP) and QOL (SF-36) were measured at baseline and after the 3-month interval. RESULTS: At 3 month follow-up, there were significant within group differences in QOL (SF-36), psychiatric symptoms (PANSS), and personal and social performance (PSP). There were statistically significant increase in the median SF-36 scores, with increases shown in physical functioning (p<.001), physical role limitations (p<.05), social functioning (p<.01) in the intervention group compared to treatment-as-usual group. Statistically significant reduction of median PANSS score of the intervention group were noted in positive (p<0.001) and negative (p<0.01) symptom, and general psychopathology (p<0.01) scales. Statistically significant increase in the median PSP score (p<0.01) was found in the intervention group compared with the treatment-as-usual group. Between-group differences at post intervention (favouring Intervention) were significant for PANSS positive and SF36 Physical CONCLUSION: In long stayed chronic inmates, a simple but consistent, organized walking intervention has the potential to bring improvement in functioning, reduction in psychiatric symptoms and quality of Life. The emphasis of rehabilitation should target at lifestyle redesign intervention. PMID- 26234970 TI - The Effect of Metacognitive Instruction on Problem Solving Skills in Iranian Students of Health Sciences. AB - BACKGROUND: Learning requires application of such processes as planning, supervision, monitoring and reflection that are included in the metacognition. Studies have shown that metacognition is associated with problem solving skills. The current research was conducted to investigate the impact of metacognitive instruction on students' problem solving skills. METHODS: The study sample included 40 students studying in the second semester at Kermanshah University of Medical Sciences, 2013-2014. They were selected through convenience sampling technique and were randomly assigned into two equal groups of experimental and control. For the experimental group, problem solving skills were taught through metacognitive instruction during ten two-hour sessions and for the control group, problem solving skills were taught via conventional teaching method. The instrument for data collection included problem solving inventory (Heppner, 1988), which was administered before and after instruction. The validity and reliability of the questionnaire had been previously confirmed. The collected data were analyzed by descriptive statistics, mean and standard deviation and the hypotheses were tested by t-test and ANCOVA. RESULTS: The findings of the posttest showed that the total mean scores of problem solving skills in the experimental and control groups were 151.90 and 101.65, respectively, indicating a significant difference between them (p<0.001). This difference was also reported to be statistically significant between problem solving skills and its components, including problem solving confidence, orientation-avoidance coping style and personal control (p<0.001). No significant difference, however, was found between the students' mean scores in terms of gender and major. CONCLUSION: Since metacognitive instruction has positive effects on students' problem solving skills and is required to enhance academic achievement, metacognitive strategies are recommended to be taught to the students. PMID- 26234969 TI - Measuring and Analyzing Waiting Time Indicators of Patients' Admitted in Emergency Department: A Case Study. AB - BACKGROUND & AIMS: Measuring and analyzing of provided services times in Emergency Department is the way to improves quality of hospital services. The present study was conducted with aim measuring and analyzing patients waiting time indicators in Emergency Department in a general hospital in Iran. MATERIAL & METHODS: This cross-sectional, observational study was conducted during April to September 2012. The study population consisted of 72 patients admitted to the Emergency Department at Baharlo hospital. Data collection was carried out by workflow forms. Data were analyzed by t. test and ANOVA. RESULTS: The average waiting time for patients from admission to enter the triage 5 minutes, the average time from triage to physician visit 6 minute and the average time between examinations to leave ED was estimated 180 minutes. The total waiting time in the emergency department was estimated at about 210 minutes. The significant correlation between marital status of patients (P=0.03), way of arrive to ED (P=0.02) and type of shift work (P=0.01) with studied time indicators were observed. CONCLUSION: According to results and comparing with similar studies, the average waiting time of patients admitted to the studied hospital is appropriate. Factors such as: Utilizing clinical governance system and attendance of resident Emergency Medicine Specialist have performed an important role in reducing of waiting times in ED. PMID- 26234971 TI - Iranian Clinical Nurses' Readiness for Self-Directed Learning. AB - INTRODUCTION: Clinical nurses are in need of being able to adapt to the ever changing environment of clinical settings. The prerequisite for their successful adaptation is to be lifelong learners. An approach for making nurses lifelong learners is self-directed learning. AIMS: This study was undertaken to evaluate a group of Iranian clinical nurses' readiness for self-directed learning and its relationship with some of their personal characteristics. METHODS: This cross sectional descriptive study was conducted in 2014. A random sample of 314 nurses working in three hospitals affiliated to Isfahan Social Security Organization, Isfahan, Iran, was recruited to complete the Fisher's Self-directed Learning Readiness Scale. FINDINGS: In total, 279 nurses filled the scale completely. The mean of their readiness for self-directed learning was 162.50+/-14.11 (120-196). The correlation of self-directed learning readiness with age, gender, marital status, and university degree was not statistically significant. CONCLUSION: Most nurses had great readiness for self-directed learning. Accordingly, nursing policy-makers need to develop strategies for promoting their self-directed learning. Moreover, innovative teaching methods such as problem solving and problem-based learning should be employed to prepare nurses for effectively managing the complexities of their ever-changing work environment. PMID- 26234972 TI - Diseases Burden of Chronic Obstructive Pulmonary Disease (COPD) Attributable to Ground-Level Ozone in Thailand: Estimates Based on Surface Monitoring Measurements Data. AB - BACKGROUND: Ambient ozone (O3) pollution has increased globally since preindustrial times. At present, O3 is one of the major air pollution concerns in Thailand, and is associated with health impacts such as chronic obstructive pulmonary disease (COPD). The objective of our study is to estimate the burden of disease attributed to O3 in 2009 in Thailand based on empirical evidence. METHODS: We estimated disability-adjusted life years (DALYs) attributable to O3 using the comparative risk assessment framework in the Global Burden of Diseases (GBD) study. We quantified the population attributable fraction (PAF), integrated from Geographic Information Systems (GIS)-based spatial interpolation, the population distribution of exposure, and the exposure-response coefficient to spatially characterize exposure to ambient O3 pollution on a national scale. Exposure distribution was derived from GIS-based spatial interpolation O3 exposure model using Pollution Control Department Thailand (PCD) surface air pollution monitor network sources. Relative risk (RR) and population attributable fraction (PAF) were determined using health impact function estimates for O3. RESULT: PAF (%) of COPD attributable to O3 were determined by region: at approximately, Northern=2.1, Northeastern=7.1, Central=9.6, Eastern=1.75, Western=1.47 and Southern=1.74. The total COPD burden attributable to O3 for Thailand in 2009 was 61,577 DALYs. Approximately 0.6% of the total DALYs in Thailand is male: 48,480 DALYs; and female: 13,097 DALYs. CONCLUSION: This study provides the first empirical evidence on the health burden (DALYs) attributable to O3 pollution in Thailand. Varying across regions, the disease burden attributable to O3 was 0.6% of the total national burden in 2009. Better empirical data on local specific sites, e.g. urban and rural areas, alternative exposure assessment, e.g. land use regression (LUR), and a local concentration response coefficient are required for future studies in Thailand. PMID- 26234973 TI - Effect of Percutaneous Coronary Intervention on Left Ventricular Diastolic Function in Patients With Coronary Artery Disease. AB - BACKGROUND: There is considerable disagreement over the effects of percutaneous coronary intervention (PCI) on left ventricular diastolic function that has necessitated the investigation of diastolic indices. The present study was conducted to evaluate left ventricular diastolic function and its indices, three months after performing the PCI procedure in patients with coronary artery disease (CAD). METHODS: In a quasi-experimental clinical trial study (before and after), 51 patients with CAD scheduled for elective PCI were investigated provided that their Ejection Fraction (EF) was > 30%. Before and three months after PCI, echocardiography was carried out to evaluate left ventricular diastolic indices including the E/Ea as the most important criteria for diagnosis of diastolic heart failure (DHF). RESULTS: Based on the E/Ea indices and after PCI, the number of patients with DHF decreased significantly: 40 patients (78.4%) before PCI versus 28 patients (54.9%) after PCI (p<0.05). The Mean and Standard error of deceleration time (DT), isovolumic relaxation time (IVRT), early diastolic mitral annulus velocity; Ea (E'), E/Ea and left ventricular ejection function (LVEF) indices underwent significant changes. In addition, MVA dur/PVA dur, PVs/PVd, and E/Ea indices had changed significantly after PCI in both genders. However, no significant difference was reported for the other indices. CONCLUSION: The E/Ea ratio as an important criterion for diagnosis of DHF was improved after PCI. Improvement of several other diastolic indices was observed after the PCI procedure. It can be concluded that PCI can be an effective treatment modality in patients with left ventricular diastolic indices. PMID- 26234974 TI - Application of the Activity-Based Costing Method for Unit-Cost Calculation in a Hospital. AB - BACKGROUND: Choosing an appropriate accounting system for hospital has always been a challenge for hospital managers. Traditional cost system (TCS) causes cost distortions in hospital. Activity-based costing (ABC) method is a new and more effective cost system. OBJECTIVE: This study aimed to compare ABC with TCS method in calculating the unit cost of medical services and to assess its applicability in Kashani Hospital, Shahrekord City, Iran. METHODS: This cross-sectional study was performed on accounting data of Kashani Hospital in 2013. Data on accounting reports of 2012 and other relevant sources at the end of 2012 were included. To apply ABC method, the hospital was divided into several cost centers and five cost categories were defined: wage, equipment, space, material, and overhead costs. Then activity centers were defined. ABC method was performed into two phases. First, the total costs of cost centers were assigned to activities by using related cost factors. Then the costs of activities were divided to cost objects by using cost drivers. After determining the cost of objects, the cost price of medical services was calculated and compared with those obtained from TCS. RESULTS: The Kashani Hospital had 81 physicians, 306 nurses, and 328 beds with the mean occupancy rate of 67.4% during 2012. Unit cost of medical services, cost price of occupancy bed per day, and cost per outpatient service were calculated. The total unit costs by ABC and TCS were respectively 187.95 and 137.70 USD, showing 50.34 USD more unit cost by ABC method. ABC method represented more accurate information on the major cost components. CONCLUSION: By utilizing ABC, hospital managers have a valuable accounting system that provides a true insight into the organizational costs of their department. PMID- 26234975 TI - Personality Traits and Identity Styles in Methamphetamine-Dependent Women: A Comparative Study. AB - BACKGROUND: Studies over the past two decades have shown that various personality traits of substance-dependent men measure differently than compared to normal individuals. However fewer studies have addressed the role of identity as an influential factor in the onset and continuation of drug dependency. METHODS: The objective of this study was to compare the Big Five personality factors and identity styles in methamphetamine dependent women and non-user group. Forty eight methamphetamine dependent women under treatment in Welfare Organization's residential centers filled out the NEO Five-Factor Inventory (NEO-FFI) and the Berzonsky's Identity Style Inventory. They were compared with 48 non-dependent women who were matched in terms of age, education, marital status, and occupation. Data was analyzed with t student test. Statistical analyses were performed using the SPSS V.16 software. Differences were considered significant at P<0.05. RESULTS: Results found that methamphetamine dependent woman had significantly higher levels of neuroticism and lower levels of conscientiousness, agreeableness and openness to experience compared to normative sample of female respondents .In addition, mean scores of diffuse/avoidant identity style in methamphetamine user women was significantly higher than non-user group. This is while non-user women had a significantly higher mean in normative identity style. CONCLUSION: Identity styles along with personality traits can be a key role in drug use in women in this study. Therefore, enhancing understanding about the role of identity can be helpful in treatment programs especially in harm reduction approaches. PMID- 26234976 TI - Emotion Risk-Factor in Patients with Cardiac Diseases: The Role of Cognitive Emotion Regulation Strategies, Positive Affect and Negative Affect (A Case Control Study). AB - Application of psychological interventions is essential in classic treatments for patient with cardiac diseases. The present study compared cognitive emotion regulation strategies, positive affect, and negative affect for cardiac patients with healthy subjects. This study was a case-control study. Fifty subjects were selected using convenient sampling method from cardiac (coronary artery disease) patients presenting in Imam Ali medical center of Kermanshah, Iran in the spring 2013. Fifty subjects accompanied the patients to the medical center, selected as control group, did not have any history of cardiac diseases. For collecting data, the cognitive emotion regulation questionnaire and positive and negative affect scales were used. For data analysis, multivariate analysis of variance (MANOVA) Was applied using the SPSS statistical software (ver. 19.0). In all cognitive emotion regulation strategies, there was a significant difference between the two groups. A significant difference was also detected regarding positive affect between the two groups, but no significant difference was found regarding negative affect. We found as a result that, having poor emotion regulation strategies is a risk factor for developing heart diseases. PMID- 26234977 TI - Acoustic Performance of 3D Printed Nanocomposite Earmuff. AB - INTRODUCTION: Hearing protection devices are one of the primary noise reduction tools in developing countries. This study is intended to produce and apply acrylonitrile butadiene styrene (ABS)/clay nanocomposites to fabricate a laboratory single cup earmuffs and then compare it with double cup and single cup pure ABS earmuffs in terms of noise attenuation performance and comfort. In addition, the noise attenuation performance of single cup pure ABS earmuffs is compared with double cup pure ABS earmuffs. METHODS: ABS/nanoclay filament was fabricated using a twin screw extruder. A three dimensional (3D) printing machine and a 3D model of earcup, designed by solid work software, were applied to print single and double cup earmuffs using ABS/nanoclay composite and pure ABS filaments. Finally, using an acoustic test fixture, objective noise attenuation test was performed on three different types of earmuffs, including with and without nano material and a secondary cup. Moreover, earmuffs weight was measured as a comfort component. RESULTS: Insertion loss and calculated noise reduction rating (NRR) of single cup ABS/nanoclay earmuffs (NRR=19.4 dB) and double cup pure ABS earmuffs (NRR=18.93 dB) were improved in comparison with single cup pure ABS earmuffs (NRR=15.7 dB). Additionally, both single cup earmuffs were significantly lighter than double cup earmuffs. Although single cup nano and double cup earmuffs had nearly the same attenuation performance, single cup nano earmuffs were 74 gr lighter than double cup earmuffs, so with reference to comfort, single cup nano earmuffs will probably be more acceptable. CONCLUSIONS: From this survey it might be concluded that, even though single cup ABS/nanoclay earmuffs was lighter than double cup pure ABS earmuffs, it had approximately more attenuation performance in comparison with double cup pure ABS earmuffs. Consequently, users are probably more prone to wear light- weight single cup ABS/nanoclay earmuffs as a result of improved comfort. In short, ABS/nanoclay composite can be considered a good choice in products with the necessity of high acoustic performance and low weight. PMID- 26234978 TI - "I rarely read the label": Factors that Influence Thai Consumer Responses to Nutrition Labels. AB - BACKGROUND: This qualitative study employed the Knowledge-Attitude-Behaviour (KAB) model and Health Belief Model (HBM) to investigate factors influencing Thai consumer decision making about use of nutrition labels. Labels include both Nutrition Information Panels (1998-) and Guideline Daily Amounts labels (2011-). METHOD: In-depth interviews were conducted with 34 participants representing two socio-demographic extremes in Thailand--"urban Bangkok" (university educated consumers) and "provincial Ranong" (non-university educated consumers). An integrated KAB-HBM model was used to devise in-depth interviews for a qualitative study using 20 open-ended questions and samples of food package labels. Additional questions arose from the interviews and they lasted 30-45 minutes and were video recorded. The analysis identified recurring themes using Atlas.ti software. RESULTS: Most participants (n=25) were aware of nutrition labels but a much smaller number (n=10) used and derived any benefit from them. Nutrition label users were classified into 4 groups: A) competent user; B) confused user; C) aware non-user; D) unaware non-user. Better educated participants were better at understanding nutrition labels but not more likely to use labels. Belief that nutrition influences health increased likelihood of using nutrition labels to make decisions about food. Being well-educated and motivated by health concerns increased likelihood of attention to nutrition labels. CONCLUSION: Results are discussed with a view to increasing the use of nutrition labels by Thai consumers. Our findings, drawing on a combination of the KAB and HBM models, can contribute to strategies motivating consumers to use nutrition labels and can provide useful insights for developing promotional strategies. PMID- 26234979 TI - Prescription, Dispensation, and Generic Medicine Replacement Ratios: Influence on Japanese Medicine Costs. AB - This study used publicly available data to examine the effect of the separation of dispensing and prescribing medicines between pharmacists in pharmacies and doctors in medical institutions (the separation system) and the generic medicine replacement ratio on the cost of various medicines in Japanese prefectures. For Japanese medical institutions, participation in the separation system is optional. Consequently, the expansion rate of the separation system for each administrative district is highly variable. In our multiple regression analysis, the dependent variables were the costs of daily medicines, specifically, total, internal, external, and injection medicines, as well as medical devices, and the independent variables were the expansion rate of the separation system and generic medicine replacement ratio. The expansion rate of the separation system showed a significant negative partial correlation with the daily costs of total, internal, and injection medicines as well as medical devices. Moreover, the rate of replacing brand name medicines with generic medicines showed a significant negative partial correlation with the daily costs of total and internal medicines. However, external and injection medicines and medical devices did not because only a few or no generic products of these types were sold in the Japanese market. Otherwise, expansion of the separation system was effective in reducing medicine costs, except in the case of external medicines. This suggests that the cost efficiency effect of the separation system does not function all the time. PMID- 26234980 TI - Epidemiology and Trend of Head and Neck Cancers in Iran. AB - INTRODUCTION: Head and neck cancers are the sixth common cancer worldwide. It is necessary to inform the trend of incidence for health planning. This study aimed to investigate the trend of head and neck cancers in Iran. METHODS: This study was carried out based on national report on cancer registry in Iran. The crude incidence rate was calculated as per 100,000 people, and Age Standardized incidence Rate (ASR) was estimated using direct standardization and the standard population of World Health Organization (W.H.O). Data was analyzed using the Cochran-Armitage test for linear trend and software of WinPepi 2.1. RESULTS: A total of 25,952 cases of cancers of the head and neck have been registered between 2003 and 2009. The age-standardized incidence rate reached from 4.8 cases per 100,000 in 2003 to 8.5 and 7.4 in 2008 and 2009, respectively, which revealed significantly increasing trends. CONCLUSIONS: According to increasing trend age standardized rate of head and neck cancer in Iran, it is recommended to identify risk factors and vulnerable groups in order to reduce the burden of this type of cancers. PMID- 26234981 TI - The Relationship Between Hope and Religious Coping Among Patients With Type 2 Diabetes. AB - BACKGROUND & PURPOSE: Globally, diabetes is one of the most common non-contagious diseases resulting in severe complications. Fostered hope facilitates coping and improves self-care and one of the Factors affecting hope is religious beliefs. This research investigated the level of hope and its relationship with religious coping among Type 2 diabetes patients. MATERIAL & METHODS: This correlation, cross-sectional study was conducted on 150 patients with Type 2 diabetes, who had been referred to the Karaj Diabetes Association during the period, March-June 2011, and selected through purposive sampling. A three-part questionnaire including demographic data, the Herth Hope Index, and a short form of religious coping, was used for data collection. The data were analyzed using descriptive and analytic statistics, including Pearson's correlation coefficient, the t-test, a one-way ANOVA, and a multiple regression analysis. The set significance level was p<0.05. RESULTS: The mean hope score was 34.89 (SD+/-8.75); most of the subjects (46.7%) showed high levels of hope. Positive religious coping, marital status, and social support significantly affected hope fostering(r=0.897, p =0.000). A significant negative relationship was found between hope and age (r= 0.373, p=0.000), and between hope and negative religious coping (r=-0.749, p=0.000). CONCLUSION: Positive religious coping, married life, and social support significantly affected the development of hope. Moreover, there was a significant positive relationship between positive religious coping and social support. So, strengthening social support could lead to increased levels of positive religious coping and fostering of hope. PMID- 26234982 TI - Relationship Between Ischemic Heart Disease and Sexual Satisfaction. AB - AIM: Ischemic heart disease is a life-threatening condition. Considerable doubts exist over the effects of this disease on patients' sexual activity and satisfaction. The aim of this study was to evaluate the relationship between ischemic heart disease and sexual satisfaction. METHODS: In a retrospective cohort study, the convenience sample of 150 patients exposure with ischemic heart disease and 150 people without exposure it was drawn from Shahid Beheshti hospital, Kashan, Iran. Sampling was performed from March to September 2014. We employed the Larson's Sexual Satisfaction Questionnaire for gathering the data. Data were analyzed using descriptive statistics and Chi-square, t-test and linear regression analysis. RESULTS: The means of sexual satisfaction in patients exposure with ischemic heart disease and among the subjects without exposure it were 101.47+/-13.42 and 100.91+/-16.52, respectively. There was no significant difference between the two groups regarding sexual satisfaction. However, sexual satisfaction was significantly correlated with gender and the use of cardiac medications (P value<0.05). CONCLUSION: The level of sexual satisfaction in patients with exposure ischemic heart disease is similar to the people without exposure it. Moreover, the men and the patients who do not receive cardiac medications have higher levels of sexual satisfaction. Nurses who are providing care to patients with ischemic heart disease need to pay closer attention to patient education about sexual issues. PMID- 26234983 TI - Relative Contribution of Obesity, Sedentary Behaviors and Dietary Habits to Sleep Duration Among Kuwaiti Adolescents. AB - The aim of this study was to investigate whether body mass index (BMI), eating habits and sedentary behaviours were associated with sleep duration among Kuwaiti adolescents. The study is part of the Arab Teens Lifestyle Study (ATLS), which is a school-based cross-sectional multi-center collaborative study. A sample of 906 adolescents (boys and girls) aged 14-19 years was randomly selected from 6 Kuwaiti Governances using a multistage stratified cluster sampling technique. The findings revealed that the prevalence of overweight and obesity was 50.5% in boys and 46.5% in girls. The majority of boys (76%) and of girls (74%) fell into the short sleep duration category (6 hours/day or less). Sleep duration were found to be negatively associated with BMI (girls only). Watching television (boys and girls) and working on computers (boys only) were also negatively associated with sleep duration. While the consumption of breakfast (both genders) and milk (boys only) was positively associated with sleep duration (p<0.05). In contrast, the consumption of fast foods (both genders), sugar-sweetened drinks and sweets (boys only) potatoes (girls only) were negatively associated with sleep duration (p<0.05). It can be concluded that the majority of Kuwaiti adolescents exhibit insufficient sleep duration which was associated with obesity measure, a combination of poor eating habits and more sedentary behaviors. The findings also suggest gender differences in these associations. Therefore, adequate sleep is an important modifiable risk factor to prevent obesity and was positively associated with some unhealthy lifestyle habits. PMID- 26234984 TI - Model of Providing Assistive Technologies in Special Education Schools. AB - Most students diagnosed with disabilities in Thai special education schools received assistive technologies, but this did not guarantee the greatest benefits. The purpose of this study was to survey the provision, use and needs of assistive technologies, as well as the perspectives of key informants regarding a model of providing them in special education schools. The participants were selected by the purposive sampling method, and they comprised 120 students with visual, physical, hearing or intellectual disabilities from four special education schools in Chiang Mai, Thailand; and 24 key informants such as parents or caregivers, teachers, school principals and school therapists. The instruments consisted of an assistive technology checklist and a semi-structured interview. Results showed that a category of assistive technologies was provided for students with disabilities, with the highest being "services", followed by "media" and then "facilities". Furthermore, mostly students with physical disabilities were provided with assistive technologies, but those with visual disabilities needed it more. Finally, the model of providing assistive technologies was composed of 5 components: Collaboration; Holistic perspective; Independent management of schools; Learning systems and a production manual for users; and Development of an assistive technology center, driven by 3 major sources such as Government and Private organizations, and Schools. PMID- 26234985 TI - The Dependence on Smokeless Tobacco in the South Asian Communities in East London. AB - BACKGROUND & OBJECTIVE: The purpose of the study was to understand the dependency on smokeless tobacco. METHODS: The major aspect of the interview was to study the type of chewing tobacco used, frequency of purchase of chewing tobacco, change in attitude and behavior after the use of chewing tobacco. This study was done in 2005 in London. Of the 110 respondents interviewed 88 were used for the data analysis. STUDY DESIGN: An exploratory study was conducted in East London, United Kingdom. The selected sample was interviewed through a questionnaire, based on the Severson Smokeless Tobacco Dependence Scale. RESULTS: Cross tabulations report that in a sample of 88 South Asian UK resident men 46.6% used leaf (paan), 43.2% used processed form of chewing tobacco and 10.2% used gutka. Older age (67%) respondents were more likely than the younger age (30%) respondents to chew tobacco. The frequency of purchase of chewing tobacco is reported high (67.2%) in the older age group than the younger age group (50%). CONCLUSION: This current study used an amended form of the Severson Smokeless Tobacco Scale questionnaire to study the dependency on smokeless tobacco. The study could be developed in the selection of the sample, which would include both males and females to study the dependency on smokeless tobacco. PMID- 26234986 TI - The Impact of Anxiety and Depression on the Quality of Life of Hemodialysis Patients. AB - PURPOSE: This study was to explore the impact of anxiety and depression on the quality of life of hemodialysis patients. MATERIAL & METHODS: The sample studied consisted of 395 hemodialysis patients. Data was collected by the completion of a specially designed questionnaire for the needs of the present study which apart from socio-demographic and clinical, it also included HADS scale to assess the level of anxiety and depression as well as the scale Missoula-VITAS Quality of Life Index (MVQOLI) to assess patients' quality of life. RESULTS: The results of this study showed that 47.8% had high anxiety levels and 38.2% had high levels of depression. The average total score of quality of life was found to be 17.14. It was also shown that the total score of quality of life presented statistically significant association with family status (p=0.007), educational level (p<0.001), the number of children (p=0.001), patients' adherence to doctors' orders (p=0.003) and proposed diet (p=0.002) and the relations of patients with healthcare professionals and the other patients (p<0.001). The multiple linear regression showed that the overall quality of life score was statistically associated with the levels of depression after adjusted for possible confounders. More specifically, it was found that total score of quality of life was 2.5 and 4.4 points lower for patients with moderate and high levels of depression, respectively, compared to patients with low levels of depression (p<0.001). CONCLUSIONS: Evaluation of anxiety and depression in conjunction with quality of life in hemodialysis patients should be an integral part of the therapeutic regimen. PMID- 26234987 TI - A "Healthy" Color: Information About Healthy Eating Attenuates the "Red Effect". AB - The influence of the color red on our evaluative processes and psychological, emotional, and cognitive decision making is known as the "red effect." The present study tested the hypothesis that this "red effect" could be attenuated by information about the healthfulness of an individual's diet. To test this hypothesis 122 participants rated the attractiveness and healthfulness of a picture of the same female wearing a red or white (neutral color) shirt who was described as eating a healthy or unhealthy food. Results showed that participants did rate the female wearing the red shirt as more attractive (evidence of the "red effect"). However, when the female was described as eating an unhealthy food, the red effect was not significant. These findings suggest that the red effect is robust, but can be attenuated by manipulating the perceptions of health. PMID- 26234988 TI - Multiple Risk Factors of Alcoholic and Non-Alcoholic Myocardial Infarction Patients. AB - BACKGROUND: Myocardial infarction (MI) is one of the most critical medical emergency and contributor to morbidity and mortality worldwide. Myocardial infarction is the most common form of coronary heart disease and leading cause of premature death. Past century has seen substantial advancement in the field of medical sciences but still mortality trends due to myocardial infarction is increasing in developing countries including India. We have conducted this study to compare the Sociodemographic characteristics of alcoholic and non alcoholic MI patients admitted in coronary care unit of Saveetha Medical College, Chennai, India. METHODS: An exploratory cross sectional study was performed by enrolling a convenient sample of 100 Myocardial Infarction patients. Information about Sociodemographic characteristics, past medical history, alcohol and tobacco intake, physical activity, psychological stress and biochemical measurements was gathered. RESULTS: The mean age of the respondents was 46 (SD=6) years and majority of them were male i.e. 82%. 100% married and 89% literate, there were 24% past and 22% present alcoholics. Consumption of alcohol on a monthly, weekly and daily basis was 8%, 11% and 5% respectively. Preference to brandy was 67%, rum was 21% and that the beer was 12%. Current smoker were 20% and former were 11%. 93% and 52% respondents were under medication of beta blocker and angiotensin-converting-enzyme (ACE) inhibitors respectively. CONCLUSION: Worldwide, MI is the most common cause of mortality and morbidity and hence early diagnosis and management is most essential. Results from our study revealed that, participants had sedentary lifestyles where risk factors of MI such as alcohol consumption, and smoking does existed. PMID- 26234989 TI - Contraception Use among Iranian Women With HIV: A Qualitative Study. AB - BACKGROUND: The application of family planning methods to people with HIV not only prevents unwanted pregnancy, but also leads to a reduction in the possibility of transmission of the virus from the patient to the sexual partner and the fetus. In order to prevent the spread of HIV and enhance reproductive rights, it is necessary to inform women with HIV of the contraception methods. OBJECTIVE: The aim of this study was to explore experiences of HIV positive women about contraception use. METHOD: This qualitative study was conducted on 18 women with HIV who were at reproductive age and had referred the Center for clients with Risky Behavior in Imam Khomeini Hospital. Data were analyzed using the conventional content analysis method in MAXQDA 10. RESULTS: The following two themes were derived from descriptions of the use of contraception methods by women with HIV: 1) Contraception is the forgotten component of reproductive health services; 2) inconsistent condom use. Each theme also contained three sub themes. CONCLUSION: Results of investigations showed that Risky Behavior consultation Centers mostly stress the use of condom for husband/sexual partners without HIV. In addition, since health care practitioners play an important role in provision of reproductive health services, their lack of knowledge and cooperation considerably contribute to the spread of the disease and violation of patient rights. PMID- 26234990 TI - Ebola Outbreak in Nigeria: Increasing Ebola Knowledge of Volunteer Health Advisors. AB - In many low-income countries, volunteer health advisors (VHAs) play an important role in disseminating information, especially in rural or hard-to-reach locations. When the world's largest outbreak of Ebola virus disease (EVD) occurred in 2014, a majority of cases were concentrated in the West African countries of Guinea, Liberia, and Sierra Leone. Twenty cases were reported in Nigeria initially and there was a need to rapidly disseminate factual information on Ebola virus. In southeast Nigeria, a group of VHAs was being used to implement the Healthy Beginning Initiative [HBI], a congregation based intervention to increase HIV testing among pregnant women and their male partners. The purpose of this study was to assess the baseline and post EVD training knowledge of VHAs during the outbreak in Nigeria. In September 2014, 59 VHAs attending a HBI training workshop in the Enugu State of Nigeria participated in an Ebola awareness training session. Participants completed a 10-item single-answer questionnaire that assessed knowledge of Ebola epidemiology, symptoms, transmission, prevention practices, treatment and survival prior to the Ebola awareness training. After the training, the VHAs repeated the questionnaire. Answers to pre and post questionnaires were analyzed using paired t-tests. Multiple linear regression was used to examine the relationship between pre and post total questionnaire scores and age, education, current location and employment. The average pre-test score was 7.3 and average post-test score was 7.8 which was a significant difference (t=-2.5, p=0.01). Prior to the training, there was a significant difference in Ebola knowledge based on the VHAs education only (p<0.01). After training, education was no longer significant for Ebola knowledge. Existing community health programs can be used as a platform to train VHAs in times of epidemics for quick dissemination of vital health information in areas lacking adequate health infrastructure and personnel. PMID- 26234991 TI - Outcome Measures in Tele-Rehabilitation and Virtual Reality for Stroke Survivors: Protocol for a Scoping Review. AB - Despite the increased interest about tele-rehabilitation, virtual reality and outcome measures for stroke rehabilitation, surprisingly little research has been done to map and summarize the most common outcome measures used in tele rehabilitation. For this review, we propose to conduct a systematic search of the literature that reports outcome measures used in tele-rehabilitation or virtual reality for stroke rehabilitation. Specific objectives include: 1) to identify the outcome measures used in tele-rehabilitation studies; 2) to describe the psychometric properties of the outcome measures in the included studies; 3) to describe which parts of the International Classification of Functioning are measured in the studies. METHODS: we will conduct a comprehensive search of relevant electronic databases (e.g., PUBMED, CINAHL, EMBASE, PSYCOINFO, Cochrane Central Register of Controlled Trial and PEDRO). The scoping review will include all study designs. Two reviewers will pilot-test the data extraction forms and will independently screen all the studies and extract the data. Disagreements about inclusion or exclusion will be resolved by consensus or by consulting a third reviewer. The results will be synthesized and reported considering the implications of the findings within the clinical practice and policy context. Dissemination: we anticipate that this scoping review will contribute to inform researchers and end-users (ie, clinicians and policy-makers), regarding the most appropriate outcome measures for tele-rehabilitation or virtual reality as well as help to identify gaps in current measures. Results will be disseminated through reports and open access journals, conference presentations, as well as newsletters, podcasts and meetings targeting all the relevant stakeholders. PMID- 26234992 TI - Increasing Knowledge and Health Literacy about Preterm Births in Underserved Communities: An Approach to Decrease Health Disparities, a Pilot Study. AB - INTRODUCTION: Health disparities can negatively impact subsets of the population who have systematically experienced greater socioeconomic obstacles to health. For example, health disparities between ethnic and racial groups continue to grow due to the widening gap in large declines in infant and fetal mortality among Caucasians compared to Black non-Hispanic or African Americans. According to the American Congress of Obstetricians and Gynecologists, preterm birth remains a leading cause of infant morbidity and mortality. The purpose of our study is to determine if the computer-based educational modules related to preterm birth health literacy and health disparity with a pre-test and post-test can effectively increase health knowledge of our participants in targeted underserved communities within the Richmond-metro area. METHODS: This was a pilot study in the Richmond-Metro area. Participants were required to be over the age of 18, and had to electronically give consent. Descriptive statistics, means and standard deviations, and Paired t-tests were conducted in SPSS 22.0. RESULTS: There were 140 participants in the pilot study. P<.05 was set as significant and all four modules had a P<.000. The males were not significant with modules: Let's Talk Patient & Provider Communication P<.132 and It Takes a Village P<.066. Preterm birth status yes all of the findings were statistically significant P<.000. Preterm birth status no Let's Talk Patients & Provider Communication was not significant P<.106. CONCLUSION: Overall, researchers found that with a strong research methodology and strong content relevant to the community, the participants demonstrated an increase in their knowledge in health literacy and preterm birth. PMID- 26234993 TI - Utilization of the Emergency Department and Predicting Factors Associated With Its Use at the Saudi Ministry of Health General Hospitals. AB - Overuse of emergency rooms (ER) is a public health problem. To investigate this issue, a cross-sectional survey was conducted at the ERs of King Abdul-Aziz Hospital, King Fahd Hospital, and Al-Thaghor Hospital in November 2013 with the aims of estimating emergency service utilization for non-urgent cases, identifying the predictors of ER utilization for non-urgent cases, and measuring patients' knowledge of primary healthcare centers (PHCCs). Patients were interviewed using a structured questionnaire and the data were analyzed using the Statistical Package for the Social Sciences. We recruited 300 patients; males comprised 50.7% of the sample. A higher proportion of patients with non-urgent cases visited the ER three to four times a year (P=0.001). A higher proportion of patients without emergencies had not attempted to visit an outpatient clinic before the ER (P=0.003). Most patients without emergencies thought the ER was the first place to consult in case of illness. Most patients who visited the ER were single, <15 years, and had lower incomes. Patients requested ER services for primary care-treatable conditions because of limited services and resources as well as limited working hours at PHCCs. Most patients (90.0%) were knowledgeable about PHCCs, with those of lower education being more knowledgeable. Patients reported long ER waiting times (>=3 hours), no organization (85.9%), and lack of medical staff. Overall, overuse of ER services is high at the Ministry of Health hospitals in Jeddah. The risk factors for ER overuse are age<15 years, singlehood, and low incomes. Policy makers and health providers have a challenging task to control ER overuse. We recommend developing strategies to implement policies aimed at reducing non-urgent ER use as well as making healthcare services more available to the population. PMID- 26234994 TI - Factors Affecting Response to Infertility Treatment: Case of Iran. AB - INTRODUCTION: Infertility affects both women and men in all the countries. Infertility often has profound long-term or short-term impacts on the people involved and puts them at risk of familial and social pressures. According to WHO estimates, between 8% and 12% of all the couples worldwide experience some form of infertility during their reproductive life, i.e. 50-80 million people are affected. The aim of this study was to evaluate the response to infertility treatment by taking into account factors such as age, hirsutism, menstruation and galactose among women in Kerman. METHODOLOGY: Of a total of 300 patient files evaluated 220 cases were flawless, of which the study factors were recorded. These data were estimated by Logit model. The dependent variable was the response to treatment (0 and 1) and the independent variables included age of men and women, hirsutism, menstruation, galactose, duration of the period no preventive measures were used and body mass index. After entering the data, model output was analyzed by using the STATA software. RESULTS: The results showed that of all the model variables, female age (prob=0.0065), menstruation (prob=0.04), hirsutism (prob=0.02), marriage age (in months) (prob=0.02) and BMI were significant and other variables were not significant. McFadden analysis for goodness of fit was 0.92. CONCLUSION: The study results showed that women should pay more attention to variables such as BMI, menstruation quality (regular and irregular) and aging because clinical disregard of any of the above can have a significant impact on the individual's fertility. PMID- 26234995 TI - Assessment of Risk Factors in Patients With Myocardial Infarction. AB - BACKGROUND: Coronary artery diseases (CAD) are one of the important health problems in the world, although considerable progresses have been made to decrease the mortality, they are still the first cause of death in many countries. Hence, the necessity of examining effective factors and risk factors on CAD can be one of the most important health priorities in many countries like Iran. OBJECTIVE: This study was performed to assess the risk factors in patients with myocardial infarction (MI) in Zahedan. MATERIALS & METHODS: This is a cross sectional study in which 213 patients were examined. They had been diagnosed to have heart failure. Data gathering took 18 months. Data gathering tool was a designed checklist which was filled up by an experienced nurse during interview. Obtained results were recorded in files and analyzed in SPSS 21. RESULTS: Results showed that 70% of patients were women and only 30% were men. 48% of them were illiterate and patients mean age was 58.3. SD had been 12.6. The mean of pain onset time till referring to hospital was 11 hours with SD of 2.1. 17% of patients (coronary artery diseases history), 25.5% (hypertension history), 26% (diabetes history), 15.5% (cholesterol history), 13% (smoking) and 3% have reported CABG history. The majority of people who referred had inferior MI (40.4%). 67.1% normal rhythm, 2.8% atrial fibrillation and 16% had ventricular tachycardia. Statistical tests showed a significant correlation between sex and the mean of referring time (p<0.05) but the relation between age and referring time was not significant. CONCLUSION: Effective risk factors on MI were recognized in this study. Some of them such as age, sex and education cannot be modified but many are controllable such as hypertension, diabetes, cholesterol, and smoking and on time referring after pain onset. Having considered the results of this study health promotion for society and especially vulnerable people can be provided by omitting or reducing risk factors. PMID- 26234996 TI - Insufficient Knowledge of Breast Cancer Risk Factors Among Malaysian Female University Students. AB - BACKGROUND: Despite continuous argument about the efficacy of breast self examination; it still could be a life-saving technique through inspiring and empowering women to take better control over their body/breast and health. This study investigated Malaysian female university students' knowledge about breast cancer risk factors, signs, and symptoms and assessed breast self-examination frequency among students. METHOD: A cross-sectional survey was conducted in 2013 in nine public and private universities in the Klang Valley and Selangor. 842 female students were respondents for the self-administered survey technique. Simple descriptive and inferential statistics were employed for data analysis. RESULTS: The uptake of breast self-examination (BSE) was less than 50% among the students. Most of students had insufficient knowledge on several breast cancer risk factors. CONCLUSION: Actions and efforts should be done to increase knowledge of breast cancer through the development of ethnically and traditionally sensitive educational training on BSE and breast cancer literacy. PMID- 26234997 TI - Long-term Follow-up After Transcatheter Aortic Valve Implantation for Severe Aortic Stenosis. AB - INTRODUCTION AND OBJECTIVES: Transcatheter aortic valve implantation is used as an alternative to surgical valve replacement in patients with severe aortic stenosis who are considered high-surgical-risk or inoperable. Two of the main areas of uncertainty in this field are valve durability and long-term survival. METHODS: This prospective single-center registry study from a tertiary hospital included all consecutive patients who underwent percutaneous aortic valve implantation between 2008 and 2012. Clinical follow-up lasted a minimum of 2.5 years and a maximum of 6.5 years. Valve Academic Research Consortium-2 definitions were used. RESULTS: Seventy-nine patients were included, with an immediate success rate of 94.9%. The median survival was 47.6 months (95% confidence intervals, 37.4-57.9 months), ie, 4 years. One quarter of deaths occurred in the first month, and most were of cardiovascular cause. After the first month, most deaths were due to noncardiovascular causes. The mean values of valve gradients did not increase during follow-up. The cumulative rate of prosthetic valve dysfunction was 15.3%, with no cases of repeat valve replacement. CONCLUSIONS: Half of the patients with aortic stenosis who underwent transcatheter aortic valve implantation were alive 4 years after the procedure. There was a 15.3% prosthetic valve dysfunction rate in cumulative follow-up, with no cases of repeat valve replacement. PMID- 26234998 TI - Parasitic myoma after laparoscopic morcellation: a systematic review of the literature. AB - BACKGROUND: Laparoscopic morcellation is frequently used for tissue removal after laparoscopic hysterectomy or myomectomy and may result in parasitic myomas, due to seeding of remained tissue fragments in the abdominal cavity. However, little is known about the incidence and risk factors of this phenomenon. OBJECTIVES: To identify the incidence and risk factors for the development of parasitic myoma after laparoscopic morcellation. SEARCH STRATEGY: A systematic review of the literature in Pubmed (MEDLINE) and Embase was conducted. Reference lists of identified relevant articles were checked for missing case reports. SELECTION CRITERIA: Studies reporting on incidence or cases of parasitic myoma diagnosed after laparoscopic morcellation were selected. Studies were excluded when history of laparoscopic morcellation was lacking or final pathology demonstrated a malignancy or endometriosis. DATA COLLECTION AND ANALYSIS: Data were extracted and analysed on incidence of parasitic myomas and characteristics of case reports. MAIN RESULTS: Fourty-four studies were included. Sixty-nine women diagnosed with parasitic myomas after laparoscopic morcellation were identified. Mean age was 40.8 (+/- 7.5) years (range 24-57), median time between surgery and diagnosis was 48.0 months (range 1-192) and mean number of parasitic myomas was 2.9 (+/- 3.3) (range 1-16). The overall incidence of parasitic myomas after laparoscopic morcellation was 0.12-0.95%. CONCLUSION: Although the incidence is relatively low, it is important to discuss the risk of parasitic myoma after laparoscopic morcellation with women and balance towards alternative treatment options. The duration of steroid exposure after laparoscopic morcellation might be a risk factor for development of parasitic myomas. TWEETABLE ABSTRACT: Systematic review on the incidence and risk factors for parasitic myoma after laparoscopic morcellation. PMID- 26234999 TI - The present situation of echinococcoses in Mongolia. AB - This review presents the historical and current situation of echinococcoses in Mongolia. Since the collapse of the Soviet Union in 1991, Mongolia's health surveillance infrastructure has been very poor, especially as it pertains to chronic diseases, including neglected zoonotic diseases (NZDs). Although there is anecdotal evidence of people dying from hepatic disease due to infection with the larval stage of Echinococcus spp., there are very few published reports. All confirmed cases of echinococcoses in Mongolia are from hospitals located in the capital city of Ulaanbaatar. Cases of cystic echinococcosis (CE), caused by either Echinococcus granulosus sensu stricto or Echinococcus canadensis are believed to be relatively common throughout Mongolia. In contrast, cases of alveolar echinococcosis (AE), caused by Echinococcus multilocularis, are believed to be rare. Recent wild-animal surveys have revealed that wolves (Canis lupus) are the major definitive hosts of E. canadensis, whereas both wolves and red foxes (Vulpes vulpes) are the primary definitive hosts of E. multilocularis. Although wild-animal surveys have begun to elucidate the transmission of Echinococcus spp. in Mongolia, there have yet to be large-scale studies conducted in domestic dogs and livestock. Therefore, further epidemiological studies, in addition to education-based control campaigns, are needed to help combat this NZD. PMID- 26235000 TI - Polymer-mediated nanorod self-assembly predicted by dissipative particle dynamics simulations. AB - Self-assembly of nanoparticles in polymer matrices is an interesting and growing subject in the field of nanoscience and technology. We report herein on modelling studies of the self-assembly and phase behavior of nanorods in a homopolymer matrix, with the specific goal of evaluating the role of deterministic entropic and enthalpic factors that control the aggregation/dispersion in such systems. Grafting polymer brushes from the nanorods is one approach to control/impact their self-assembly capabilities within a polymer matrix. From an energetic point of view, miscible interactions between the brush and the matrix are required for achieving a better dispersibility; however, grafting density and brush length are the two important parameters in dictating the morphology. Unlike in previous computational studies, the present Dissipative Particle Dynamics (DPD) simulation framework is able to both predict dispersion or aggregation of nanorods and determine the self-assembled structure, allowing for the determination of a phase diagram, which takes all of these factors into account. Three types of morphologies are predicted: dispersion, aggregation and partial aggregation. Moreover, favorable enthalpic interactions between the brush and the matrix are found to be essential for expanding the window for achieving a well-dispersed morphology. A three-dimensional phase diagram is mapped on which all the afore mentioned parameters are taken into account. Additionally, in the case of immiscibility between brushes and the matrix, simulations predict the formation of some new and tunable structures. PMID- 26235001 TI - The alpha-Glucosidase and alpha-Amylase Enzyme Inhibitory of Hydroxytyrosol and Oleuropein. AB - To date, numerous studies have reported on the antidiabetic properties of various plant extracts through inhibition of carbohydrate-hydrolysing enzymes. The objective of this research was to evaluate the inhibitory effect of the hydroxytyrosol and the oleuropein against alpha-amylase and alpha-glucosidase. The hydroxytyrosol was purified from olive leaves. The result shows that the hydroxytyrosol had the strongest alpha-glucosidase inhibitory effect with IC50 values of 150 MUM with mild inhibition against alpha-amylase. The enzyme kinetic studies, using Lineweaver-Burk indicated that, in the presence of the hydroxytyrosol, the Michaelis-Menton constant (Km) remained constant but the maximal velocity (Vmax) decreased, revealing a non-competitive type of inhibition with inhibition constants; Ki for the formation of the inhibitor-enzyme complex and Kis for the formation of the inhibitor-enzyme-substrate complex of 104.3 and 150.1 MUM, respectively. On the other hand, oleuropein showedan uncompetitive inhibition. The concentrations used in this work were below cytotoxic levels observed at 400 MUM. However, at 600 MUM, the hydroxytyrosol significantly decreased viability of the Caco-2 cells (p < 0.05) and in the case of the oleuropein, there's an increase in cell number compared to control (p < 0.05). These results suggest that the hydroxytyrosol and oleuropein are two potential effective alpha-glucosidase inhibitors for management of postprandial hyperglycemia. PMID- 26235002 TI - Repellent and Fumigant Activities of Tanacetum nubigenum Wallich. ex DC Essential Oils against Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae). AB - The repellent and fumigant toxicity of essential oils of Tanacetum nubigenum Wallich. ex DC collected from three different habitats (Gothing, Burphu and Glacier) of Uttarakhand Himalayas, India named as TNG, TNB and TNM respectively, were investigated against the adults of red flour beetle Tribolium castaneum (Herbst). Among the three samples tested, TNG was found to more potent exhibiting more repellent effect towards the insects and with LC50 values by fumigant bioassay were 13.23 and 8.32 ul per 0.25 L air at 24 and 48 h exposure of insects to the essential oil respectively. In between other two oil samples, TNM was superior in potency showed LC50 value of 14.22 (24 h) & 8.82 ul per 0.25 L air (48 h). During in vivo study all the essential oil samples significantly protected 500 g of wheat grains for 6 months from insect infestation as compared to non fumigated grains and order of efficacy was TNG>TNM>TNB. There were no side effects of essential oils on germination rate of grains (<85%) exposed for 6 months after fumigation. The present study suggests that essential oil of T. nubigenum can be explored as novel natural fumigants for the control of stored product insects. PMID- 26235003 TI - To Reinforce Oleo Science Research. Preface. PMID- 26235005 TI - [Use of tranexamic acid in primary total knee replacement: effects on perioperative blood loss]. AB - BACKGROUND AND OBJECTIVES: The use of tranexamic acid in primary total knee replacement surgeries has been the subject of constant study. The strategies to reduce bleeding are aimed at reducing the need for blood transfusion due to the risks involved. In this study we evaluated the use of tranexamic acid in reducing bleeding, need for blood transfusion, and prevalence of postoperative deep vein thrombosis (DVT) in primary total knee replacement. METHOD: 62 patients undergoing primary total knee replacement were enrolled in the study, from June 2012 to May 2013, and randomized to receive a single dose of 2.5g of intravenous tranexamic acid (Group TA) or saline (Group GP), 5minutes before opening the pneumatic tourniquet, respectively. Hemoglobin, hematocrit, and blood loss were recorded 24hours after surgery. DVT was investigated during patient's hospitalization and 15 and 30 days after surgery in review visits. RESULTS: There was no demographic difference between groups. Group TA had 13.89% decreased hematocrit (p=0.925) compared to placebo. Group TA had a decrease of 12.28% (p=0.898) in hemoglobin compared to Group GP. Group TA had a mean decrease of 187.35mL in blood loss (25.32%) compared to group GP (p=0.027). The number of blood transfusions was higher in Group GP (p=0.078). Thromboembolic events were not seen in this study. CONCLUSION: Tranexamic acid reduced postoperative bleeding without promoting thromboembolic events. PMID- 26235007 TI - Introduction: Intradural spinal tumors. PMID- 26235006 TI - Prospective, longitudinal assessment of quality of life in children from diagnosis to 3 months off treatment for standard risk acute lymphoblastic leukemia: Results of Children's Oncology Group study AALL0331. AB - Standard risk acute lymphoblastic leukemia (SR-ALL) has high cure rates, but requires 2-3 years of therapy. We aimed to (i) prospectively evaluate health related quality of life (HRQOL) during and after SR-ALL therapy, and (ii) identify associated predictors. Parents of 160 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (physical, emotional and social functioning) and Family Assessment Device-General Functioning (FAD-GF) at 1, 6 and 12 months after diagnosis, and 3 months post therapy. Mean PedsQL scores in physical, emotional and social functioning were impaired 1 month after diagnosis but steadily improved. Three months post therapy, impaired physical and social functioning was observed in 27.8 and 25.8% of patients, respectively. In repeated-measures analysis, problematic family functioning predicted emotional (OR = 1.85, 95% CI 1.03-3.34) and social (OR = 1.99, 95% CI 1.21-3.27) impairment. Larger household size was associated with social impairment (OR = 1.21, 95% CI 1.02-1.45). Adverse neurological event(s) during therapy predicted post-therapy physical (OR = 5.17, 95% CI 1.61-16.63) and social (OR = 8.17, 95% CI 1.19-56.16) impairment. HRQOL 1 month after diagnosis was not predictive of HRQOL 3 months after therapy completion. In conclusion, children with SR-ALL experience considerable impairment in HRQOL at the end of induction, but rapidly improve. However, many still experience physical and social impairment 3 months post-therapy, suggesting a role for continued family and physical functioning support. Longer follow-up is needed to determine if post therapy deficits change over time. PMID- 26235008 TI - Minimally invasive removal of lumbar intradural extramedullary lesions using the interlaminar approach. AB - OBJECT Posterior midline laminectomy or hemilaminectomy has been successfully applied as the standard microsurgical technique for the treatment of spinal intradural pathologies. However, the associated risks of postoperative spinal instability increase the need for subsequent fusion surgery to prevent potential long-term spinal deformity. Continuous efforts have been made to minimize injuries to the surrounding tissue resulting from surgical manipulations. The authors report here their experiences with a novel minimally invasive surgical approach, namely the interlaminar approach, for the treatment of lumbar intraspinal tumors. METHODS A retrospective review was conducted of patients at the Second Affiliated Hospital of Zhejiang University School of Medicine who underwent minimally invasive resection of lumbar intradural-extramedullary tumors. By using an operative microscope, in addition to an endoscope when necessary, the authors were able to treat all patients with a unilateral, paramedian, bone-sparing interlaminar technique. Data including preoperative neurological status, tumor location, size, pathological diagnosis, extension of resections, intraoperative blood loss, length of hospital stay, and clinical outcomes were obtained through clinical and radiological examinations. RESULTS Eighteen patients diagnosed with lumbar intradural-extramedullary tumors were treated from October 2013 to March 2015 by this interlaminar technique. A microscope was used in 15 cases, and the remaining 3 cases were treated using a microscope as well as an endoscope. There were 14 schwannomas, 2 ependymomas, 1 epidermoid cyst, and 1 enterogenous cyst. Postoperative radiological follow-up revealed complete removal of all the lesions and no signs of bone defects in the lamina. At clinical follow-up, 14 of the 18 patients had less pain, and patients' motor/sensory functions improved or remained normal in all cases except 1. CONClUSIONS When meeting certain selection criteria, intradural-extramedullary lumbar tumors, especially schwannomas, can be completely and safely resected through a less-invasive interlaminar approach using a microscope, or a microscope in addition to an endoscope when necessary. This approach was advantageous because it caused even less bone destruction, resulting in better postoperative spinal stability, no need for facetectomy and fusion, and quicker functional recovery for the patients. Individualized surgical planning according to preoperative radiological findings is key to a successful microsurgical resection of these lesions through the interlaminar space. PMID- 26235009 TI - Comparison of open and minimally invasive surgery for intradural-extramedullary spine tumors. AB - OBJECT Patients with symptomatic intradural-extramedullary (ID-EM) tumors may be successfully treated with resection of the lesion and decompression of associated neural structures. Studies of patients undergoing open resection of these tumors have reported high rates of gross-total resection (GTR) with minimal long-term neurological deficit. Case reports and small case series have suggested that these patients may be successfully treated with minimally invasive surgery (MIS). These studies have been limited by small patient populations. Moreover, there are no studies directly comparing perioperative outcomes between patients treated with open resection and MIS. The objective of this study was to compare perioperative outcomes in patients with ID-EM tumors treated using open resection or MIS. METHODS A retrospective review was performed using data collected from 45 consecutive patients treated by open resection or MIS for ID-EM spine tumors. These patients were treated over a 9-year period between April 2003 and October 2012 at Northwestern University and the University of Chicago. Statistical analysis was performed to compare perioperative outcomes between the two groups. RESULTS Of the 45 patients in the study, 27 were treated with the MIS approach and 18 were treated with the open approach. Operative time was similar between the two groups: 256.3 minutes in the MIS group versus 241.1 minutes in the open group (p = 0.55). Estimated blood loss was significantly lower in the MIS group (133.7 ml) compared with the open group (558.8 ml) (p < 0.01). A GTR was achieved in 94.4% of the open cases and 92.6% of the MIS cases (p = 0.81). The mean hospital stay was significantly shorter in the MIS group (3.9 days) compared with the open group (6.1 days) (p < 0.01). There was no significant difference between the complication rates (p = 0.32) and reoperation rates (p = 0.33) between the two groups. Multivariate analysis demonstrated an increased rate of complications in cervical spine tumors (OR 15, p = 0.05). CONCLUSIONS Thoracolumbar ID-EM tumors may be safely and effectively treated with either the open approach or an MIS approach, with an equivalent rate of GTR, perioperative complication rate, and operative time. Patients treated with an MIS approach may benefit from a decrease in operative blood loss and shorter hospital stays. PMID- 26235010 TI - Comparison of minimally invasive transspinous and open approaches for thoracolumbar intradural-extramedullary spinal tumors. AB - OBJECT Spinal tumor resection has historically been performed via open approaches, although minimally invasive approaches have recently been found to be effective in small cohort series. The authors compare surgical characteristics and clinical outcomes of surgery in patients undergoing mini-open and open approaches for intradural-extramedullary tumor resection. METHODS The authors retrospectively reviewed 65 consecutive intradural-extramedullary tumor resections performed at their institution from 2007 to 2014. Patients with cervical tumors or pathology demonstrating neurofibroma were excluded (n = 14). The nonparametric Mann-Whitney U-test and Pearson chi-square test were used to compare continuous and categorical variables, respectively. Statistical analyses were performed using SPSS, with significance set at p < 0.05. RESULTS Fifty-one thoracolumbar intradural-extramedullary tumor resections were included; 25 were performed via the minimally invasive transspinous approach. There were no statistically significant differences in age, sex, body mass index, preoperative American Spinal Injury Association (ASIA) score, preoperative symptom duration, American Society of Anesthesiologists (ASA) physical status class, tumor size, or tumor location. There was no statistically significant difference between groups with respect to the duration of the operation or extent of resection, but the mean estimated blood loss was significantly lower in the minimally invasive surgery (MIS) cohort (142 vs 320 ml, p < 0.05). In each group, the 2 most common tumor pathologies were schwannoma and meningioma. There were no statistically significant differences in length of hospitalization, ASIA score improvement, complication rate, or recurrence rate. The mean duration of follow-up was 2 years for the MIS group and 1.6 years for the open surgery group. CONCLUSIONS This is one of the largest comparisons of minimally invasive and open approaches to the resection of thoracolumbar intradural-extramedullary tumors. With well-matched cohorts, the minimally invasive transspinous approach appears to be as safe and effective as the open technique, with the advantage of significantly reduced intraoperative blood loss. PMID- 26235011 TI - Management of cervical spine deformity after intradural tumor resection. AB - Management of intradural spinal tumors requires posterior decompressive techniques. Cervical spine deformity secondary to sagittal and/or coronal imbalance after a laminectomy may result in significant cervical pain and functional deterioration, as well as neurological deficits in the most severe cases. In this paper, the authors discuss the management of cervical spine deformity after intradural tumor resection, with emphasis on the surgical strategies required to reestablish acceptable cervical spine alignment and to correct postoperative deformity. In general, after an oncological evaluation, assessing the alignment, extent, and flexibility of the deformity is mandatory before surgical planning. Rigid deformities require an osteotomy and, most often, combined approaches to restore cervical alignment. Flexible deformities can often be treated with a single approach, although a circumferential approach has its advantages. PMID- 26235012 TI - Intramedullary spinal cord tumors: a review of current and future treatment strategies. AB - Intramedullary spinal cord tumors have low incidence rates but are associated with difficult treatment options. The majority of patients with these tumors can be initially treated with an attempted resection. Unfortunately, those patients who cannot undergo gross-total resection or have subtotal resection are left with few treatment options, such as radiotherapy and chemotherapy. These adjuvant treatments, however, are associated with the potential for significant adverse side effects and still leave patients with a poor prognosis. To successfully manage these patients and improve both their quality of life and prognosis, novel treatment options must be developed to supplement subtotal resection. New research is underway investigating alternative therapeutic approaches for these patients, including directed, localized drug delivery and nanomedicine techniques. These and other future investigations will hopefully lead to promising new therapies for these devastating diseases. PMID- 26235013 TI - Intramedullary spinal cord metastases: an increasingly common diagnosis. AB - OBJECT Intramedullary spinal cord metastases (ISCM) represent a small proportion of intramedullary tumors. However, with the lifespans of patients with malignant tumors increasing, incidents of ISCM are on the rise. Due to threateningly severe disabilities in patients, accompanied by limited life expectancy, every attempt should be made to treat these tumors the same way as metastases elsewhere in the CNS, with the goal of complete removal of the ISCM and preservation of neurological functions. The object of this study is to retrospectively analyze the experiences of 22 patients who were surgically treated for ISCM over a 22 year period. METHODS Hospital charts of 22 patients, who were surgically treated for ISCM between 1992 and 2014, were reviewed retrospectively. Demographic data, histopathological diagnoses of primary cancer, chronological sequence of the disease, and neurological status using the simplified McCormick functional classification were collected and reanalyzed. RESULTS The most frequent histology was metastasis of lung cancer, followed by brain and breast cancers. The time span from primary cancer diagnosis to the development of symptomatic spinal metastases ranged from 0 to 285 months, with a mean interval of 38 months. The leading presenting sign was dysesthesia (77% of the population), followed by paresis (68%). Only 5 patients (23%) showed urinary retention. Initial performance status represented by the McCormick Scale was on average 2.47. Total or near-total removal was achieved in 87% of cases. Compared with the clinical status 1-2 days after surgery, there was an improvement in the McCormick Scale grade at the last follow-up from 2.47 to 2.12 (p = 0.009). Likewise, an improvement was detected when comparing the preoperative status with the last follow-up (from 2.45 to 2.12; p = 0.029). The mean survival time after surgery was 11.6 months. CONCLUSIONS These results suggest that surgery for intramedullary metastases-with all of the challenges of a rare and potentially risky procedure-can be beneficial to patients with advanced stages of cancer. Surgery can be performed with minimal new morbidity and results in maintaining neurological performance status. PMID- 26235014 TI - Imaging diagnosis and the role of endovascular embolization treatment for vascular intraspinal tumors. AB - Intraspinal tumors comprise a large spectrum of neoplasms, including hemangioblastomas, paragangliomas, and meningiomas. These tumors have several common characteristic imaging features, such as highly vascular mass appearance in angiography, hypointense rim and serpentine flow voids in MRI, and intense enhancement after intravenous contrast administration. Due to their rich vascularity, these tumors represent a special challenge for surgical treatment. More recently, the surgical treatment of intraspinal vascular tumors has benefited from the combination of endovascular techniques used to better delineate these lesions and to promote preoperative reduction of volume and tissue blood flow. Endovascular embolization has been proven to be a safe procedure that facilitates the resection of these tumors; hence, it has been proposed as part of the standard of care in their management. PMID- 26235016 TI - Intramedullary hemangioblastomas: surgical results in 16 patients. AB - OBJECT Hemangioblastomas are rare, benign, highly vascularized tumors that can be found throughout the neuraxis but are mainly located in the cerebellum and in the spinal cord. Spinal hemangioblastomas can present with motor and sensory deficits, whose severity varies according to the size and location of the tumor. Resection is the best treatment option to avoid neurological deterioration. The authors report surgical results in the treatment of intramedullary hemangioblastomas and discuss the technical nuances important to achieving total resection without adding new deficits. METHODS A consecutive series of patients with intramedullary hemangioblastomas operated on between 2000 and 2014 by the senior author (H.T.) is presented. The functional scale proposed by McCormick was used to evaluate the patients' neurological status before and after surgery. RESULTS Sixteen patients were included in the study and underwent 17 surgeries. Follow-up was at least 6 months. Age at presentation varied from 13 to 58 years (mean 33.8 years). Ten patients (62.5%) were males and 6 patients (37.5%) were females. Seven (43.75%) of the 16 patients had associated von Hippel-Lindau syndrome, with hemangioblastomas also presenting in other locations. Three patients had multiple tumors in the same segment in the spinal cord, and 10 patients (62.5%) presented with cysts. According to the site of presentation, 11 tumors (68.75%) were localized at the cervical region (including the cervicomedullary junction) and 5 tumors (31.25%) at the thoracic level. Total resection was achieved in all cases, evidenced by postoperative MRI. Four patients had some functional worsening immediately after surgery. After 6 months, 1 patient had functional worsening compared with preoperative status, and 2 patients had clinical improvement. The majority of the patients remained clinically stable postoperatively. CONCLUSIONS Adequate knowledge of anatomy and the correct use of microsurgical techniques allowed total resection of these tumors, with minimal morbidity and maximum functional recovery. Outcome seems to be directly related to the neurological status before surgery. PMID- 26235015 TI - Discrete or diffuse intramedullary tumor? Contrast-enhanced intraoperative ultrasound in a case of intramedullary cervicothoracic hemangioblastomas mimicking a diffuse infiltrative glioma: technical note and case report. AB - Hemangioblastomas are benign, highly vascularized intramedullary lesions that may also extend into the intradural space. Surgery represents the standard therapy, with the goal of obtaining complete resection even at the risk of neurological morbidity. MRI is the gold standard for diagnosis and assessment of intramedullary tumors. Nevertheless, sometimes MRI may not accurately differentiate between different types of intramedullary tumors, in particular if they are associated with syringes or intra- and peritumoral cysts. This could subsequently affect surgical strategies. Intraoperative ultrasound (ioUS) has become in the last few years a very useful tool for use during neurosurgical procedures. Various ioUS modalities such as B-mode and Doppler have been applied during neurosurgical procedures. On the other hand, the use of contrast-enhanced ultrasound (CEUS) is not yet well defined and standardized in this field. We report a case of a young patient harboring a cervicothoracic intramedullary tumor, for which the preoperative neuroradiologi-cal diagnosis was in favor of a diffuse astrocytoma with nodular components whereas ioUS demonstrated 3 distinct intramedullary nodules. CEUS showed highly vascularized lesions, compatible with hemangioblastomas. These findings, particularly those obtained with CEUS, allowed better definition of the lesions for diagnosis, enhanced understanding of the physiopathological aspects, and permitted the localization of all 3 nodules, thus limiting spinal cord manipulation and allowing complete resection of the lesions, with an uneventful postoperative neurological course. To the best of our knowledge, this is the first report of the use of intraoperative CEUS in a case of intramedullary hemangioblastoma. PMID- 26235017 TI - Intramedullary spinal cavernoma: clinical presentation, microsurgical approach, and long-term outcome in a cohort of 48 patients. AB - OBJECT Intramedullary spinal cavernoma (ISC) is a rare entity and accounts for approximately 5%-12% of all spinal vascular pathologies. The purpose of the present study was to examine the influence of clinical presentation, localization, and different surgical approaches on long-term outcome in patients treated for ISC. METHODS The authors performed a retrospective single-center study of 48 cases of ISC treated microsurgically over the past 28 years. Analyzed factors included preoperative clinical history, microsurgical strategies, neurological outcome (American Spinal Injury Association [ASIA] grade, Epstein and Cooper grade), and the occurrence of postoperative spinal ataxia. Univariate analysis was performed to identify factors influencing long-term outcome. RESULTS Preoperatively, 18.8% of all patients experienced a slow, progressive decline in neurological function and 33.3% suffered repetitive episodes of acute neurological deterioration over a time frame of months to years. Moreover, 16.7% noted the sudden onset of a severe neurological deficit, whereas 25% experienced the sudden onset of symptoms with a subsequent gradually progressive decline in neurological function. On long-term follow-up after treatment (mean +/- SD, 79.3 +/- 35.2 months), 70.8% of patients showed no change in neurological function, 6.3% suffered from a decline, and 22.9% improved neurologically. Thoracolumbar localization (p = 0.043), low preoperative Epstein and Cooper grade for the lower extremities (p < 0.001), and a low preoperative ASIA grade (p < 0.001) were identified as factors associated with an unfavorable outcome (ASIA Grade A-C). The rate of spinal ataxia related to surgical approach was 16.7%. CONCLUSION Postoperative neurological function in ISC patients is determined by the preoperative neurological status. On long-term follow-up after microsurgical treatment, 93.7% of patients presented with a stable or improved condition (ASIA grade); thus, definite microsurgical treatment should be considered as long as patients present with only mild symptoms after the diagnosis of symptomatic ISC. PMID- 26235018 TI - Assessment of outcome in patients undergoing surgery for intradural spinal tumor using the multidimensional patient-rated Core Outcome Measures Index and the modified McCormick Scale. AB - OBJECT The aim of this study was to evaluate outcome in patients undergoing surgical treatment for intradural spinal tumor using a patient-oriented, self rated, outcome instrument and a physician-based disease-specific instrument. METHODS Prospectively collected data from 63 patients with intradural spinal tumor were analyzed in relation to scores on the multidimensional patient-rated Core Outcome Measures Index (COMI) and the physician-rated modified McCormick Scale, before and at 3 and 12 months after surgery. RESULTS There was no statistically significant difference between the scores on the modified McCormick Scale preoperatively and at the 3-month follow-up, though there was a trend for improvement (p = 0.073); however, comparisons between the scores determined preoperatively and at the 12-month follow-up, as well as 3- versus 12-month follow-ups, showed a statistically significant improvement in each case (p < 0.004). The COMI scores for axial pain, peripheral pain, and back-related function showed a significant reduction (p < 0.001) from before surgery to 3 months after surgery, and thereafter showed no further change (p > 0.05) up to 12 months postoperatively. In contrast, the overall COMI score, "worst pain," quality of life, and social disability not only showed a significant reduction from before surgery to 3 months after surgery (p < 0.001), but also a further significant reduction up to 12 months postoperatively (p < 0.001). The scores for work disability showed no significant improvement from before surgery to the 3 month follow-up (p > 0.05), but did show a significant improvement (p = 0.011) from 3 months to 12 months after surgery. At the 3- and 12-month follow-ups, 85.2% and 83.9% of patients, respectively, declared that the surgical procedure had helped/helped a lot; 95.1% and 95.2%, respectively, declared that they were satisfied/very satisfied with their care. CONCLUSIONS COMI is a feasible tool to use in the evaluation of baseline symptoms and outcome in patients undergoing surgery for intradural spinal tumor. COMI was able to detect changes in outcome at 3 months after surgery (before changes were apparent on the modified McCormick Scale) and on later postoperative follow-up. The COMI subdomains are valuable for monitoring the patient's reintegration into society and the work environment. The addition of an item that specifically covers neurological deficits may further increase the value of COMI in patients with spinal tumors. PMID- 26235019 TI - Letter to the Editor: Stereotactic laser ablation of high-grade gliomas. PMID- 26235021 TI - Association of risk factors with unfavorable outcomes after resection of adult benign intradural spine tumors and the effect of hospital volume on outcomes: an analysis of 18, 297 patients across 774 US hospitals using the National Inpatient Sample (2002-2011). AB - OBJECT Because of the limited data available regarding the associations between risk factors and the effect of hospital case volume on outcomes after resection of intradural spine tumors, the authors attempted to identify these associations by using a large population-based database. METHODS Using the National Inpatient Sample database, the authors performed a retrospective cohort study that involved patients who underwent surgery for an intradural spinal tumor between 2002 and 2011. Using national estimates, they identified associations of patient demographics, medical comorbidities, and hospital characteristics with inpatient postoperative outcomes. In addition, the effect of hospital volume on unfavorable outcomes was investigated. Hospitals that performed fewer than 14 resections in adult patients with an intradural spine tumor between 2002 and 2011 were labeled as low-volume centers, whereas those that performed 14 or more operations in that period were classified as high-volume centers (HVCs). These cutoffs were based on the median number of resections performed by hospitals registered in the National Inpatient Sample during the study period. RESULTS Overall, 18,297 patients across 774 hospitals in the United States underwent surgery for an intradural spine tumor. The mean age of the cohort was 56.53 +/- 16.28 years, and 63% were female. The inpatient postoperative risks included mortality (0.3%), discharge to rehabilitation (28.8%), prolonged length of stay (> 75th percentile) (20.0%), high-end hospital charges (> 75th percentile) (24.9%), wound complications (1.2%), cardiac complications (0.6%), deep vein thrombosis (1.4%), pulmonary embolism (2.1%), and neurological complications, including durai tears (2.4%). Undergoing surgery at an HVC was significantly associated with a decreased chance of inpatient mortality (OR 0.39; 95% CI 0.16-0.98), unfavorable discharge (OR 0.86; 95% CI 0.76-0.98), prolonged length of stay (OR 0.69; 95% CI 0.62-0.77), high-end hospital charges (OR 0.67; 95% CI 0.60-0.74), neurological complications (OR 0.34; 95% CI 0.26-0.44), deep vein thrombosis (OR 0.65; 95% CI 0.45-0.94), wound complications (OR 0.59; 95% CI 0.41-0.86), and gastrointestinal complications (OR 0.65; 95% CI 0.46-0.92). CONCLUSIONS The results of this study provide individualized estimates of the risks of postoperative complications based on patient demographics and comorbidities and hospital characteristics and shows a decreased risk for most unfavorable outcomes for those who underwent surgery at an HVC. These findings could be used as a tool for risk stratification, directing presurgical evaluation, assisting with surgical decision making, and strengthening referral systems for complex cases. PMID- 26235020 TI - The genetic basis of intradural spinal tumors and its impact on clinical treatment. AB - Genetic alterations in the cells of intradural spinal tumors can have a significant impact on the treatment options, counseling, and prognosis for patients. Although surgery is the primary therapy for most intradural tumors, radiochemothera-peutic modalities and targeted interventions play an ever evolving role in treating aggressive cancers and in addressing cancer recurrence in long-term survivors. Recent studies have helped delineate specific genetic and molecular differences between intradural spinal tumors and their intracranial counterparts and have also identified significant variation in therapeutic effects on these tumors. This review discusses the genetic and molecular alterations in the most common intradural spinal tumors in both adult and pediatrie patients, including nerve sheath tumors (that is, neurofibroma and schwannoma), meningioma, ependymoma, astrocytoma (that is, low-grade glioma, anaplastic astrocytoma, and glioblastoma), hemangioblastoma, and medulloblastoma. It also examines the genetics of metastatic tumors to the spinal cord, arising either from the CNS or from systemic sources. Importantly, the impact of this knowledge on therapeutic options and its application to clinical practice are discussed. PMID- 26235022 TI - Association of tumor location, extent of resection, and neurofibromatosis status with clinical outcomes for 221 spinal nerve sheath tumors. AB - OBJECT Intradural extramedullary spine tumors represent two-thirds of all primary spine neoplasms. Approximately half of these are peripheral nerve sheath tumors, mainly neurofibromas and schwannomas. Given the rarity of this disease and, thus, the limited analyses of clinical outcomes, the authors examined the association of tumor location, extent of resection, and neurofibromatosis (NF) status with clinical outcomes. METHODS Patients were identified through a search of the University of California, San Francisco, neuropathology database and a separate review of current procedural terminology codes. Data recorded included patient age, patient sex, clinical presentation, presence of NF, tumor type, tumor location, extent of resection (gross-total resection [GTR] or subtotal resection [STR]), and clinical follow-up. RESULTS Of 221 tumors in 199 patients (mean age 45 years), 53 were neurofibromas, 163 were schwannomas, and 5 were malignant peripheral nerve sheath tumors. The most common presenting symptom was spinal pain (76%), followed by weakness (36%) and sensory abnormalities (34%). Mean symptom duration was 16 months. In terms of spinal location, neurofibromas were more common in the cervical spine (74% vs 27%, p < 0.001), and schwannomas were more common in the thoracic and lumbosacral spine (73% vs 26%, p < 0.001). Rates of GTR were lower for neurofibromas than schwannomas (51% vs 83%, p < 0.001), regardless of location. Rates of GTR were lower for cervical (54%) than thoracic (90%) and lumbosacral (86%) lesions (p < 0.001). NF was associated with lower rates of GTR among all tumors (43% vs 86%, p < 0.001). The mean follow-up time was 32 months. Recurrence/progression was more common for neurofibromas than schwannomas (17% vs 7%, p = 0.03), although the mean time to recurrence/progression did not differ according to tumor type (45 vs 53 months, p = 0.63). As expected, GTR was associated with lower recurrence rates (4% vs 22%, p < 0.001). According to multivariate analysis, cervical location (OR 0.239, 95% CI 0.110-0.520) and presence of NF (OR 0.166, 95% CI 0.054-0.507) were associated with lower rates of GTR. In a separate model, only GTR (OR 0.141, 95% CI 0.046 0.429) was associated with tumor recurrence. CONCLUSIONS Resection is an effective treatment for spinal nerve sheath tumors. Neurofibromas were found more commonly in the cervical spine than in other regions of the spine and were associated with higher rates of recurrence and lower rates of GTR than other tumor types, particularly in patients with NF Types 1 or 2. According to multivariate analysis, both cervical location and presence of NF were associated with lower rates of GTR. According to a second multivariate model, the only variable associated with tumor recurrence was extent of resection. Maximal safe resection remains ideal for these lesions; however, patients with cervical tumors or NF should be counseled about their increased risk for recurrence. PMID- 26235023 TI - Spinal ependymomas. Part 1: Intramedullary ependymomas. AB - OBJECT Ependymomas represent the most common intramedullary tumor in adults. Despite their usually well-defined dissection plane, surgical morbidity has been documented to be considerably higher compared with other intramedullary entities. This study presents an analysis of risk factors for surgical morbidity and data on long-term results for intramedullary ependymomas. METHODS Among 1447 patients with tumors of the spinal canal treated between 1980 and 2014, 309 patients presented with intramedullary tumors. One hundred patients with intramedullary ependymomas underwent 102 operations. Mean age was 44 +/- 15 years (range 8-74 years). Patients were followed by outpatient visits and questionnaires, with a mean follow-up of 77 +/- 91 months. Short-term results were determined for individual symptoms and the McCormick Scale, whereas tumor recurrence rates were calculated with Kaplan-Meier statistics. RESULTS Compared with cervical ependymomas, those of the thoracic spine were associated with more severe motor deficits and gait problems at presentation. A total of 86.3% of patients with intramedullary ependymomas underwent gross-total resection (GTR). A low preoperative McCormick grade and first surgery were the strongest predictors for a GTR. Postoperatively, 67.6% of patients demonstrated a worse neurological state at discharge from the hospital. This deterioration was transient for 40.1% of the patients and permanent for 27.5%. In the long term, the McCormick grade remained unchanged from the preoperative grade in 74.5% of patients, while it was improved in 5.9% of patients and increased after surgery in 19.6% of patients. According to a multivariate analysis, the risk of permanent morbidity increased with a thoracic level of the ependymoma, advanced age, a long clinical history, presence of a tumor hemorrhage, and surgery on a recurrent tumor. In the long term, tumor recurrence rates correlated significantly with the amount of resection (4.2% and 18.5% in 20 years after GTR and partial resections, respectively). Postoperative neuropathic pain syndromes affected 37.0% of patients, whereas 4% demonstrated a postoperative myelopathy related to cord tethering at the level of surgery. CONCLUSIONS Intramedullary ependymomas are tumors best treated surgically. A complete resection indicates cure for the overwhelming majority of these patients. Surgery should be performed early by neurosurgeons who deal with these lesions on a regular basis to achieve high GTR rates. Permanent surgical morbidity varies most according to tumor location and patient age. PMID- 26235024 TI - Spinal ependymomas. Part 2: Ependymomas of the filum terminale. AB - OBJECT Ependymomas of the filum terminale provide specific surgical challenges due to their often enormous size, contact with nerve roots of the cauda equina and conus, and potential for subarachnoid dissemination. This study presents treatment results for these tumors over a 30-year period. METHODS Among 1447 patients with tumors of the spinal canal treated between 1980 and 2014, 618 patients presented with extramedullary tumors. Of these, 42 patients (25 males, 17 females) demonstrated a myxopapillary ependymoma in the lumbosacral region. Thirty-four patients underwent 36 operations for 39 such tumors. The mean patient age was 38 +/- 14 years (range 11-73 years), with an average clinical history of 37 +/- 67 months. Patients were followed through outpatient visits and questionnaires, with a mean follow-up of 10 years (127 +/- 100 months). Twenty seven operations were performed to treat de novo tumors and the remainder were undertaken on recurrent tumors. Short-term results were determined for individual symptoms, and tumor recurrence rates were calculated with Kaplan-Meier statistical analyses. RESULTS Subarachnoid dissemination was observed in 11 patients and was related to previous surgery in 9 patients and associated with extensive tumors in 2 patients. Gross-total resections (GTR) were achieved in 28 operations (77.7%) and subtotal resections in the remainder. Subtotal resections were restricted to unencapsulated ependymomas (61.5%). Radiotherapy was employed after 6 operations on unencapsulated tumors, with 5 of these also demonstrating subarachnoid seeding. Permanent surgical morbidity affected 3 patients who experienced permanent worsening of bladder function, while 7 patients showed no postoperative changes, and the remaining 26 operations were followed by improvements. Long-term outcome depended on the amount of resection and the presence of a tumor capsule. Eight of 9 tumor recurrences affected unencapsulated tumors, of which 3 had undergone GTR. The overall recurrence rates were 6.6%, 19.0%, and 37.0% after 1, 10, and 20 years, respectively. For unencapsulated ependymomas, the corresponding rates were 15.6%, 32.5%, and 66.2% after 1, 10, and 20 years, respectively, with significantly lower rates of 9.1% after 10 and 20 years for encapsulated tumors. Postoperative radiotherapy tended to prolong the recurrence-free interval for patients with unencapsulated tumors. Five patient deaths occurred during follow-up, of which 2 deaths were tumor related and occurred at 216 and 287 months after surgery. CONCLUSION Extramedullary ependymomas are slow-growing tumors in the lumbosacral region, sometimes with an indolent course for long periods of time. Despite their delicate location and often enormous size, surgical morbidity in experienced hands is low, with good chances for postoperative clinical improvements and very low recurrence rates after GTR for encapsulated tumors. The role of postoperative radiotherapy remains controversial. Radiotherapy may be considered after incomplete resections of unencapsulated tumors and/or for patients with subarachnoid dissemination. PMID- 26235025 TI - Outcomes following myxopapillary ependymoma resection: the importance of capsule integrity. AB - OBJECT While extent of resection has been shown to correlate with outcomes after myxopapillary ependymoma (MPE) resection, the effect of capsular violation has not been well studied. The role of adjuvant radiation also remains controversial. In this paper the authors' goals were to evaluate outcomes following resection of MPE based on intraoperative capsular violation and to explore the role of adjuvant radiotherapy in cases of capsular violation. METHODS A retrospective review of patients undergoing resection of MPE at 2 academic institutions between 1990 and 2013 was performed. Cases with dissemination at presentation, less than 12 months of follow-up, or incomplete records were excluded. Extent of resection was defined as en bloc if all visible tumor was removed without capsular violation, gross-total resection (GTR) if all visible tumor was removed, but with capsular violation, and subtotal resection (STR) if a known residual was left at the time of surgery. Postoperative MR images were reviewed to confirm the extent of resection. Primary outcomes were progression-free survival (PFS) and overall recurrence rates. The effects of extent of resection, capsular violation, and adjuvant radiotherapy on recurrence rates and PFS were analyzed using Kaplan Meier statistics. Associations between recurrence and preoperative variables were evaluated using Fisher exact methods and t-tests where appropriate. RESULTS Of the 107 patients reviewed, 58 patients (53% were male) met inclusion criteria. The mean age at surgery was 40.8 years (range 7-68 years). The median follow-up was 51.5 months (range 12-243 months). Extent of resection was defined as en bloc in 46.5% (n = 27), GTR in 34.5% (n = 20), and STR in 18.9% (n = 11). No recurrences were noted in the en bloc group, compared with 15% (n = 3) and 45% (n = 5) in the GTR and STR groups. En bloc resection was achieved most frequently in tumors involving the conus. Twelve patients (20%) underwent adjuvant radiotherapy following either STR or GTR. The overall recurrence rate was 13.8% (n = 8), and the 5-year PFS was 81%. Capsular violation was associated with a higher recurrence rate (p = 0.005). Adjuvant radiotherapy showed a nonsignificant trend of lower recurrence rates (16.7% vs 31.6%, p = 0.43) and longer PFS at 5 years (83.3% vs 49.9%, p = 0.16) in cases of capsular violation. CONCLUSIONS A strong correlation between capsular violation and recurrence was found following removal of MPE and should be assessed when defining extent of resection in future studies. Although the use of adjuvant radiotherapy in cases of capsular violation showed a trend toward improved PFS, further investigation is needed to establish its role as salvage therapy also appears to be effective at halting disease progression. PMID- 26235026 TI - Hemilaminectomy approach for intradural extramedullary spinal tumors: an analysis of 164 patients. AB - OBJECT The authors report their experience with the use of a minimally invasive hemilaminectomy approach for the excision of intradural extramedullary (IDEM) tumors of the spinal cord. METHODS Included were 164 consecutive patients (167 tumors in total), treated between January 2004 and December 2014, in whom the hemilaminectomy approach for IDEM spinal cord tumors was planned. The clinicoradiological data of patients presenting to Christian Medical College were analyzed retrospectively using a computerized chart-review method. Preoperative MRI localization was used in 51 cases. RESULTS The mean age (+/- SD) of the patients was 42.6 +/- 16.6 years, and the mean duration of symptoms was 20.8 +/- 27.8 months. The average tumor size was 2.4 +/- 1.7 cm. Forty-four tumors were cervical, 5 were cervicothoracic, 72 were thoracic, 7 were thoracolumbar, and 39 were lumbar. Forty-two tumors were ventrally located, whereas 11 were ventrolateral; the rest were either dorsal or dorsolateral. The most common pathologies were schwannoma (110 cases) and meningioma (31 cases). Total excision was achieved for 93% of the tumors. The average duration of surgery was 1.6 +/- 0.6 hours. CONCLUSIONS The hemilaminectomy approach to the removal of intradural tumors was quick and safe and resulted in minimal morbidity and no mortality. Preoperative MRI localization improved accuracy and reduced operating time by eliminating the need for intraoperative fluoroscopy. PMID- 26235027 TI - Enhanced photon absorption in spiral nanostructured solar cells using layered 2D materials. AB - Recent investigations of semiconducting two-dimensional (2D) transition metal dichalcogenides have provided evidence for strong light absorption relative to its thickness attributed to high density of states. Stacking a combination of metallic, insulating, and semiconducting 2D materials enables functional devices with atomic thicknesses. While photovoltaic cells based on 2D materials have been demonstrated, the reported absorption is still just a few percent of the incident light due to their sub-wavelength thickness leading to low cell efficiencies. Here we show that taking advantage of the mechanical flexibility of 2D materials by rolling a molybdenum disulfide (MoS(2))/graphene (Gr)/hexagonal boron nitride stack to a spiral solar cell allows for optical absorption up to 90%. The optical absorption of a 1 MUm long hetero-material spiral cell consisting of the aforementioned hetero stack is about 50% stronger compared to a planar MoS(2) cell of the same thickness; although the volumetric absorbing material ratio is only 6%. A core-shell structure exhibits enhanced absorption and pronounced absorption peaks with respect to a spiral structure without metallic contacts. We anticipate these results to provide guidance for photonic structures that take advantage of the unique properties of 2D materials in solar energy conversion applications. PMID- 26235028 TI - Structure and Assembly Mechanism of the Signaling Complex Mediated by Human CSF 1. AB - Human colony-stimulating factor 1 receptor (hCSF-1R) is unique among the hematopoietic receptors because it is activated by two distinct cytokines, CSF-1 and interleukin-34 (IL-34). Despite ever-growing insights into the central role of hCSF-1R signaling in innate and adaptive immunity, inflammatory diseases, and cancer, the structural basis of the functional dichotomy of hCSF-1R has remained elusive. Here, we report crystal structures of ternary complexes between hCSF-1 and hCSF-1R, including their complete extracellular assembly, and propose a mechanism for the cooperative human CSF-1:CSF-1R complex that relies on the adoption by dimeric hCSF-1 of an active conformational state and homotypic receptor interactions. Furthermore, we trace the cytokine-binding duality of hCSF 1R to a limited set of conserved interactions mediated by functionally equivalent residues on CSF-1 and IL-34 that play into the geometric requirements of hCSF-1R activation, and map the possible mechanistic consequences of somatic mutations in hCSF-1R associated with cancer. PMID- 26235029 TI - Structure of a Bacterial ABC Transporter Involved in the Import of an Acidic Polysaccharide Alginate. AB - The acidic polysaccharide alginate represents a promising marine biomass for the microbial production of biofuels, although the molecular and structural characteristics of alginate transporters remain to be clarified. In Sphingomonas sp. A1, the ATP-binding cassette transporter AlgM1M2SS is responsible for the import of alginate across the cytoplasmic membrane. Here, we present the substrate-transport characteristics and quaternary structure of AlgM1M2SS. The addition of poly- or oligoalginate enhanced the ATPase activity of reconstituted AlgM1M2SS coupled with one of the periplasmic solute-binding proteins, AlgQ1 or AlgQ2. External fluorescence-labeled oligoalginates were specifically imported into AlgM1M2SS-containing proteoliposomes in the presence of AlgQ2, ATP, and Mg(2+). The crystal structure of AlgQ2-bound AlgM1M2SS adopts an inward-facing conformation. The interaction between AlgQ2 and AlgM1M2SS induces the formation of an alginate-binding tunnel-like structure accessible to the solvent. The translocation route inside the transmembrane domains contains charged residues suitable for the import of acidic saccharides. PMID- 26235030 TI - Structural Basis of Latrophilin-FLRT-UNC5 Interaction in Cell Adhesion. AB - Fibronectin leucine-rich repeat transmembrane proteins (FLRTs) are cell-adhesion molecules with emerging functions in cortical development and synapse formation. Their extracellular regions interact with latrophilins (LPHNs) to mediate synapse development, and with Uncoordinated-5 (UNC5)/netrin receptors to control the migration of neurons in the developing cortex. Here, we present the crystal structures of FLRT3 in isolation and in complex with LPHN3. The LPHN3/FLRT3 structure reveals that LPHN3 binds to FLRT3 at a site distinct from UNC5. Structure-based mutations specifically disrupt LPHN3/FLRT3 binding, but do not disturb their interactions with other proteins or their cell-membrane localization. Thus, they can be used as molecular tools to dissect the functions of FLRTs and LPHNs in vivo. Our results suggest that UNC5 and LPHN3 can simultaneously bind to FLRT3, forming a trimeric complex, and that FLRT3 may form transsynaptic complexes with both LPHN3 and UNC5. These findings provide molecular insights for understanding the role of cell-adhesion proteins in synapse function. PMID- 26235033 TI - Syntheses and in Vitro Antiplasmodial Activity of Aminoalkylated Chalcones and Analogues. AB - A series of readily synthesized and inexpensive aminoalkylated chalcones and diarylpropane analogues (1-55) were synthesized and tested against chloroquinone sensitive (D10 and NF54) and -resistant (Dd2 and K1) strains of Plasmodium falciparum. Hydrogenation of the enone to a diarylpropane moiety increased antiplasmodial bioactivity significantly. The influence of the structure of the amine moiety, A-ring substituents, propyl vs ethyl linker, and chloride salt formation on further enhancing antiplasmodial activity was investigated. Several compounds have IC50 values similar to or better than chloroquine (CQ). The most active compound (26) had an IC50 value of 0.01 MUM. No signs of resistance were detected, as can be expected from compounds with structures unrelated to CQ and other currently used antimalarial drugs. Toxicity tests (in vitro CHO cell assay) gave high SI indices. PMID- 26235031 TI - Structural and Mechanistic Insights into the Latrophilin3-FLRT3 Complex that Mediates Glutamatergic Synapse Development. AB - Latrophilins (LPHNs) are adhesion-like G-protein-coupled receptors implicated in attention-deficit/hyperactivity disorder. Recently, LPHN3 was found to regulate excitatory synapse number through trans interactions with fibronectin leucine rich repeat transmembrane 3 (FLRT3). By isothermal titration calorimetry, we determined that only the olfactomedin (OLF) domain of LPHN3 is necessary for FLRT3 association. By multi-crystal native single-wavelength anomalous diffraction phasing, we determined the crystal structure of the OLF domain. This structure is a five-bladed beta propeller with a Ca(2+) ion bound in the central pore, which is capped by a mobile loop that allows the ion to exchange with the solvent. The crystal structure of the OLF/FLRT3 complex shows that LPHN3-OLF in the closed state binds with high affinity to the concave face of FLRT3-LRR with a combination of hydrophobic and charged residues. Our study provides structural and functional insights into the molecular mechanism underlying the contribution of LPHN3/FLRT3 to the development of glutamatergic synapses. PMID- 26235034 TI - The impact of the CYP2D6 gene polymorphism on the risk of pemphigoid. AB - BACKGROUND: Studies concerning the etiopathogenesis of numerous diseases emphasize the involvement of genetically determined impairments of xenobiotic metabolism. Nowadays, more attention has been drawn to the role of cytochrome P450 and its isoenzymes in the course of dermatological diseases, including pemphigoid, the most frequently occurring autoimmune bullous disease, whose etiopathogenesis has not been completely elucidated. AIM: The aim of the study was to find out whether there was any relationship between the CYP2D6 gene polymorphism and the development of bullous pemphigoid (BP). MATERIAL AND METHODS: The study included 221 subjects, 71 patients with BP, and 150 healthy volunteers constituting a control group. The identification of CYP2D6 (CYP2D6*1, CYP2D6*3, CYP2D6*4) gene alleles was performed using the polymerase chain reaction-fragment length polymorphism method. RESULTS: A higher frequency of the CYP2D6*3/CYP2D6*4 genotype was observed in patients with BP (P = 0.0033) than in controls. The relative risk of developing BP expressed with the odds ratio was nearly four times higher in subjects in whom the presence of the CYP2D6*3 allele was detected (odds ratio 3.8; P = 0.0234). CONCLUSION: The study results may suggest the impact of CYP2D6 gene polymorphism (A2637 deletion) on a higher prevalence of bullous pemphigoid. PMID- 26235032 TI - Role of the Fourth Transmembrane alpha Helix in the Allosteric Modulation of Pentameric Ligand-Gated Ion Channels. AB - The gating of pentameric ligand-gated ion channels is sensitive to a variety of allosteric modulators that act on structures peripheral to those involved in the allosteric pathway leading from the agonist site to the channel gate. One such structure, the lipid-exposed transmembrane alpha helix, M4, is the target of lipids, neurosteroids, and disease-causing mutations. Here we show that M4 interactions with the adjacent transmembrane alpha helices, M1 and M3, modulate pLGIC function. Enhanced M4 interactions promote channel function while ineffective interactions reduce channel function. The interface chemistry governs the intrinsic strength of M4-M1/M3 inter-helical interactions, both influencing channel gating and imparting distinct susceptibilities to the potentiating effects of a lipid-facing M4 congenital myasthenic syndrome mutation. Through aromatic substitutions, functional studies, and molecular dynamics simulations, we elucidate a mechanism by which M4 modulates channel function. PMID- 26235035 TI - Advances in Respiratory and Nasal Drug Delivery. PMID- 26235036 TI - STMN1 overexpression correlates with biological behavior in human cutaneous squamous cell carcinoma. AB - Stathmin 1 (STMN1) is an important molecule in regulating cellular microtubule dynamics and promoting microtubule depolymerization in interphase and late mitosis. Evidences showed that STMN1 was up-regulated in many cancers, but there was no report about the roles of STMN1 in human cutaneous squamous cell carcinoma (cSCC). Here, we confirmed significant upregulation of STMN1 in cSCC tissues and cell lines compared with non-tumor counterparts. STMN1 upregulation was associated with the proliferation, migration, invasion and apoptosis of cSCC cells. The results suggested that STMN1 may play an important role in the development and tumor progression of cSCC. PMID- 26235037 TI - Trophic mismatch and its effects on the growth of young in an Arctic herbivore. AB - In highly seasonal environments, timing of breeding of organisms is typically set to coincide with the period of highest resource availability. However, breeding phenology may not change at a rate sufficient to keep up with rapid changes in the environment in the wake of climate change. The lack of synchrony between the phenology of consumers and that of their resources can lead to a phenomenon called trophic mismatch, which may have important consequences on the reproductive success of herbivores. We analyzed long-term data (1991-2010) on climate, plant phenology and the reproduction of a long-distance Arctic migrant, the greater snow goose (Chen caerulescens atlantica), in order to examine the effects of mismatched reproduction on the growth of young. We found that geese are only partially able to adjust their breeding phenology to compensate for annual changes in the timing of high-quality food plants, leading to mismatches of up to 20 days between the two. The peak of nitrogen concentration in plants, an index of their nutritive quality for goslings, occurred earlier in warm springs with an early snow melt. Likewise, mismatch between hatch dates of young and date of peak nitrogen was more important in years with early snow melt. Gosling body mass and structural size at fledging was reduced when trophic mismatch was high, particularly when the difference between date of peak nitrogen concentration and hatching was >9 days. Our results support the hypothesis that trophic mismatch can negatively affect the fitness of Arctic herbivores and that this is likely to be exacerbated by rising global temperatures. PMID- 26235038 TI - Preperitoneal Continuous Infusion of Local Anesthetics: What Is the Impact on Surgical Wound Infections in Humans? AB - OBJECTIVE: Continuous surgical wound infusion with local anesthetics is an effective and widely used technique in postoperative pain management. Some aspects of this technique, however, require further investigation. The aim of this study was to retrospectively assess whether continuous infusion of ropivacaine delays the process of wound healing, with an increased incidence of infection. DESIGN: In total, 244 patients aged between 18 and 75 years, American society of anesthesiology II-III, underwent hepatobiliary pancreatic surgery, were classified into two groups and retrospectively analyzed: group R (Ropivacaine) included 152 patients whose surgical incision was fitted with a preperitoneal catheter continuously infusing ropivacaine. Group C (Control) included 92 patients receiving a total intravenous postoperative analgesia. The evaluation forms of the surgical wound according to the Southampton wound assessment scale (SWAS) were collected at three time points. The main outcome was the rate of patients with surgical site infection within 30 days postoperatively. RESULTS: Twenty-one patients (13.8%) in group R and 9 patients (9.8%) in group C (P = 0.35) presented wound infection. The rate of patients with a wound evaluation of a SWAS grade IV or V in three time frames in Group R and Group C was T0, 1 (0.7%) and 1 (1.08%) (P = 0.72); T1, 25 (16.4%) and 7 (7.6%) (P = 0.04); T2, 8 (5.3%) and 5 (5.4%) (P = 0.53), respectively.onclusions. The incidence of infection in the surgical site according to the centers for disease control definition was comparable in both groups. The description of the wound healing process according to the SWAS scale shows an initial and temporary decrease in maturation in group R which does not persist in the long-term. PMID- 26235039 TI - Carbon dioxide fixation and sulfate sequestration by a supramolecular trigonal bipyramid. AB - The subcomponent self-assembly of a bent dialdehyde ligand and different cationic and anionic templates led to the formation of two new metallosupramolecular architectures: a Fe(II) 4 L6 molecular rectangle was isolated following reaction of the ligand with iron(II) tetrafluoroborate, and a M5 L6 trigonal bipyramidal structure was constructed from either zinc(II) tetrafluoroborate or cadmium(II) trifluoromethanesulfonate. The spatially constrained arrangement of the three equatorial metal ions in the M5 L6 structures was found to induce small-molecule transformations. Atmospheric carbon dioxide was fixed as carbonate and bound to the equatorial metal centers in both the Zn5 L6 and Cd5 L6 assemblies, and sulfur dioxide was hydrated and bound as the sulfite dianion in the Zn5 L6 structure. Subsequent in situ oxidation of the sulfite dianion resulted in a sulfate dianion bound within the supramolecular pocket. PMID- 26235041 TI - Evolving targeted therapies for right ventricular failure. AB - INTRODUCTION: Although right and left ventricular embryological origins, morphology and cardiodynamics differ, the notion of selectively targeted right ventricular therapies remains controversial. AREAS COVERED: This review focuses on both the currently evolving pharmacologic agents targeting right ventricular failure (metabolic modulators, phosphodiesterase type V inhibitors) and future therapeutic approaches including epigenetic modulation by miRNAs, chromatin binding complexes, long non-coding RNAs, genomic editing, adoptive gene transfer and gene therapy, cell regeneration via cell transplantation and cell reprogramming and cardiac tissue engineering. EXPERT OPINION: Strategies for adult right ventricular regeneration will require a more holistic approach than strategies for adult left ventricular failure. Instances of right ventricular failure requiring global reconstitution of right ventricular myocardium, attractive approaches include: i) myocardial patches seeded with cardiac fibroblasts reprogrammed into cardiomyocytes in vivo by small molecules, miRNAs or other epigenetic modifiers; and ii) administration of miRNAs, lncRNAs or small molecules by non-viral vector delivery systems targeted to fibroblasts (e.g., episomes) to stimulate in vivo reprogramming of fibroblasts into cardiomyocytes. For selected heritable genetic myocardial diseases, genomic editing affords exciting opportunities for allele-specific silencing by site-specific directed silencing, mutagenesis or gene excision. Genomic editing by adoptive gene transfer affords similarly exciting opportunities for restoration of myocardial gene expression. PMID- 26235042 TI - Relationship Reciprocation Modulates Resource Allocation in Adolescent Social Networks: Developmental Effects. AB - Adolescence is characterized as a period of social reorientation toward peer relationships, entailing the emergence of sophisticated social abilities. Two studies (Study 1: N = 42, ages 13-17; Study 2: N = 81, ages 13-16) investigated age group differences in the impact of relationship reciprocation within school based social networks on an experimental measure of cooperation behavior. Results suggest development between mid- and late adolescence in the extent to which reciprocation of social ties predicted resource allocation. With increasing age group, investment decisions increasingly reflected the degree to which peers reciprocated feelings of friendship. This result may reflect social-cognitive development, which could facilitate the ability to navigate an increasingly complex social world in adolescence and promote positive and enduring relationships into adulthood. PMID- 26235043 TI - UDP-glucose pyrophosphorylase influences polysaccharide synthesis, cell wall components, and hyphal branching in Ganoderma lucidum via regulation of the balance between glucose-1-phosphate and UDP-glucose. AB - UDP-glucose pyrophosphorylase (UGP) is a key enzyme involved in carbohydrate metabolism, but there are few studies on the functions of this enzyme in fungi. The ugp gene of Ganoderma lucidum was cloned, and enzyme kinetic parameters of the UGP recombinant protein were determined in vitro, revealing that this protein was functional and catalyzed the reversible conversion between Glc-1-P and UDP Glc. ugp silencing by RNA interference resulted in changes in the levels of the intermediate metabolites Glc-1-P and UDP-Glc. The compounds and structure of the cell wall in the silenced strains were also altered compared with those in the wild-type strains. Moreover, the number of hyphal branches was also changed in the silenced strains. To verify the role of UGP in hyphal branching, a ugp overexpressing strain was constructed. The results showed that the number of hyphal branches was influenced by UGP. The mechanism underlying hyphal branching was further investigated by adding exogenous Glc-1-P. Our results showed that hyphal branching was regulated by a change in the cytosolic Ca(2+) concentration, which was affected by the level of the intermediate metabolite Glc-1-P, in G. lucidum. Our findings indicate the existence of an interaction between carbon metabolism and Ca(2+) signaling in this fungus. PMID- 26235044 TI - VdCrz1 is involved in microsclerotia formation and required for full virulence in Verticillium dahliae. AB - Calcium signaling plays crucial roles in ion stress tolerance, sporulation and pathogenicity in fungi. Although the signaling pathway mediated by calcineurin and the calcineurin-responsive zinc finger transcription factor Crz1 is well characterized in other fungi, this pathway is not well characterized in the phytopathogenic fungus, Verticillium dahliae. To better understand the role of this calcineurin-dependent transcription factor in V. dahliae, an ortholog of CRZ1, VdCrz1, was identified and characterized functionally. Transcriptional analysis of VdCrz1 and GFP expression driven by the VdCrz1 promoter indicated that VdCrz1 was involved in microsclerotia development. After targeted deletion of VdCrz1, microsclerotia formation and melanin accumulation were impaired. Furthermore, the DeltaVdCrz1 mutants were hypersensitive to high concentrations of Ca(2+) and cell wall-perturbing agents, such as sodium dodecyl sulfate. The addition of Mg(2+) to the medium restores the microsclerotia formation in DeltaVdCrz1 mutants. The DeltaVdCrz1 mutants exhibited delayed Verticillium wilt symptoms on smoke tree. These results suggest that VdCrz1 plays important roles in Ca(2+) signaling, cell wall integrity, microsclerotia development and full virulence in V. dahliae. PMID- 26235045 TI - Assessing new dimensions of attentional functions in children prenatally exposed to environmental contaminants using an adapted Posner paradigm. AB - Chronic exposure to methylmercury (MeHg), lead (Pb) and polychlorinated biphenyls (PCBs) has been associated with a range of attention deficits in children, but it is not known whether selective spatial attention is also altered. We modified the classic Posner paradigm, which assesses visuospatial attention, to also assess vigilance and impulsivity. This paradigm is based on the well-documented findings that a target will be detected more quickly if a visual cue indicates beforehand where it will appear, and more slowly if the cue indicates a false spatial location. In our task, visual distractors were introduced, in addition to the classic Posner trials, to assess impulsivity, and a central smiley face, whose eye-movement cued the location of the targets, to measure spatial attention. This task was administered to 27 school-age Inuit children (mean age = 11.2 years) from Nunavik (Arctic Quebec, Canada), in which pre- and postnatal exposures to environmental contaminants had been documented from birth. After controlling for the impact of confounding variables, multivariable regressions revealed that prenatal exposures to PCBs and Pb were significantly associated with greater inattention and impulsivity, respectively, while current exposure to Pb was significantly associated with longer reaction times. Although a significant correlation was observed between cord blood PCB concentration and decreased visuospatial performance, no significant association was found after adjustment for confounders. No effect was found for Hg exposures. These results suggest that our adapted Posner paradigm is sensitive in detecting a range of attention deficits in children exposed to environmental contaminants; implications for future studies are discussed. PMID- 26235046 TI - Cadherin Switch during EMT in Neural Crest Cells Leads to Contact Inhibition of Locomotion via Repolarization of Forces. AB - Contact inhibition of locomotion (CIL) is the process through which cells move away from each other after cell-cell contact, and it contributes to malignant invasion and developmental migration. Various cell types exhibit CIL, whereas others remain in contact after collision and may form stable junctions. To investigate what determines this differential behavior, we study neural crest cells, a migratory stem cell population whose invasiveness has been likened to cancer metastasis. By comparing pre-migratory and migratory neural crest cells, we show that the switch from E- to N-cadherin during EMT is essential for acquisition of CIL behavior. Loss of E-cadherin leads to repolarization of protrusions, via p120 and Rac1, resulting in a redistribution of forces from intercellular tension to cell-matrix adhesions, which break down the cadherin junction. These data provide insight into the balance of physical forces that contributes to CIL in cells in vivo. PMID- 26235047 TI - Crumbs3-Mediated Polarity Directs Airway Epithelial Cell Fate through the Hippo Pathway Effector Yap. AB - Epithelial cells undergo dynamic polarity changes as organs pattern, but the relationship between epithelial polarity and cell fate is poorly understood. Using the developing lung as a model, we found that distinct alterations in apical-basal polarity dictate airway epithelial differentiation. We demonstrate that Crb3, a Crumbs isoform that determines epithelial apical domain identity, is required for airway differentiation by controlling the localization of the transcriptional regulator Yap. We show that Crb3 promotes the interaction between Yap and the Hippo pathway kinases Lats1/2 at apical cell junctions to induce Yap phosphorylation and cytoplasmic retention, which drive cell differentiation. Loss of Crb3 in developing mouse airways or isolated adult airway progenitors results in unrestricted nuclear Yap activity and consequent cell differentiation defects. Our findings demonstrate that polarity-dependent cues control airway cell differentiation, offering important molecular insights into organ patterning. PMID- 26235048 TI - Direct Microtubule-Binding by Myosin-10 Orients Centrosomes toward Retraction Fibers and Subcortical Actin Clouds. AB - Positioning of centrosomes is vital for cell division and development. In metazoan cells, spindle positioning is controlled by a dynamic pool of subcortical actin that organizes in response to the position of retraction fibers. These actin "clouds" are proposed to generate pulling forces on centrosomes and mediate spindle orientation. However, the motors that pull astral microtubules toward these actin structures are not known. Here, we report that the unconventional myosin, Myo10, couples actin-dependent forces from retraction fibers and subcortical actin clouds to centrosomes. Myo10-mediated centrosome positioning requires its direct microtubule binding. Computational image analysis of large microtubule populations reveals a direct effect of Myo10 on microtubule dynamics and microtubule-cortex interactions. Myo10's role in centrosome positioning is distinct from, but overlaps with, that of dynein. Thus, Myo10 plays a key role in integrating the actin and microtubule cytoskeletons to position centrosomes and mitotic spindles. PMID- 26235049 TI - [Management of venous thromboembolism: A 2015 update]. AB - Deep venous thrombosis (DVT) and pulmonary embolism (PE) constitute venous thromboembolic disease (VTE). Venous thromboembolic disease is a common, serious, and multifactorial disease, the incidence of which increases with age. Risk factors, whether transient (surgery, plaster immobilization, bed rest/hospitalization) or chronic/persistent (age, cancer, clinical or biological thrombophilia, etc.), modulate the duration of treatment. In the absence of pathognomonic clinical sign or symptom, diagnostic management relies in the evaluation of the clinical pre-test probability followed by a laboratory or an imaging testing. So far, compression ultrasound and multidetector computed tomography angiography are the best diagnostic tests to make a positive diagnosis of DVT or PE, respectively. Anticoagulants at therapeutic dose for at least 3months constitute the cornerstone of VTE management. Availability of new direct oral anticoagulants, which have recently been shown to be as effective and as safe as vitamin K antagonist in clinical trials, should facilitate ambulatory management of VTE and favour extended treatments for individuals with unprovoked VTE or VTE provoked by a chronic/persistent risk factor. PMID- 26235051 TI - Response to 'Tacrolimus pharmacokinetics after kidney transplantation--Influence of changes in haematocrit and steroid dose'. PMID- 26235052 TI - Hail formation triggers rapid ash aggregation in volcanic plumes. AB - During explosive eruptions, airborne particles collide and stick together, accelerating the fallout of volcanic ash and climate-forcing aerosols. This aggregation process remains a major source of uncertainty both in ash dispersal forecasting and interpretation of eruptions from the geological record. Here we illuminate the mechanisms and timescales of particle aggregation from a well characterized 'wet' eruption. The 2009 eruption of Redoubt Volcano, Alaska, incorporated water from the surface (in this case, a glacier), which is a common occurrence during explosive volcanism worldwide. Observations from C-band weather radar, fall deposits and numerical modelling demonstrate that hail-forming processes in the eruption plume triggered aggregation of ~95% of the fine ash and stripped much of the erupted mass out of the atmosphere within 30 min. Based on these findings, we propose a mechanism of hail-like ash aggregation that contributes to the anomalously rapid fallout of fine ash and occurrence of concentrically layered aggregates in volcanic deposits. PMID- 26235050 TI - Bioluminescent imaging of vaccinia virus infection in immunocompetent and immunodeficient rats as a model for human smallpox. AB - Due to the increasing concern of using smallpox virus as biological weapons for terrorist attack, there is renewed interest in studying the pathogenesis of human smallpox and development of new therapies. Animal models are highly demanded for efficacy and safety examination of new vaccines and therapeutic drugs. Here, we demonstrated that both wild type and immunodeficient rats infected with an engineered vaccinia virus carrying Firefly luciferase reporter gene (rTV-Fluc) could recapitulate infectious and clinical features of human smallpox. Vaccinia viral infection in wild type Sprague-Dawley (SD) rats displayed a diffusible pattern in various organs, including liver, head and limbs. The intensity of bioluminescence generated from rTV-Fluc correlated well with viral loads in tissues. Moreover, neutralizing antibodies had a protective effect against virus reinfection. The recombination activating gene 2 (Rag2) knockout rats generated by transcription activator-like effector nucleases (TALENs) technology were further used to examine the infectivity of the rTV-Fluc in immunodeficient populations. Here we demonstrated that Rag2-/- rats were more susceptible to rTV Fluc than SD rats with a slower virus clearance rate. Therefore, the rTV-Fluc/SD rats and rTV-Fluc/Rag2-/- rats are suitable visualization models, which recapitulate wild type or immunodeficient populations respectively, for testing human smallpox vaccine and antiviral drugs. PMID- 26235053 TI - Connecting Self-Awareness and Error-Awareness in Patients with Traumatic Brain Injury. AB - Impaired self-awareness after traumatic brain injury (TBI) is often seen in stark contrast to the observations of significant-others, who are acutely aware of the difficulties experienced by patients. Our objective was to investigate the relationship between metacognitive knowledge in daily life and emergent awareness of errors during laboratory tasks, since the breakdown of error detection mechanisms may impose limitations on the recovery of metacognitive knowledge after TBI. We also examined the extent to which these measures of awareness can predict dysexecutive behaviors. A sample of TBI patients (n=62) and their significant-others, provided reports of daily functioning post injury. In addition, patients underwent a neuropsychological assessment and were instructed to signal their errors during go/no-go tests. Interrelationships between metacognitive and emergent levels of awareness were examined, after controlling for the influence of secondary cognitive variables. Significant-other ratings correlated with errors made by the patients on neuropsychological tests but not with their premorbid function. Patients who under-reported daily life difficulties or over-reported their competency, compared to significant-other reports, were less likely to show awareness of laboratory errors. Emergent awareness was also identified as the sole predictor of performance on the modified six-element test, an ecologically valid test of multitasking. The online breakdown of error awareness after brain injury is related to difficulties with metacognitive awareness as reported in daily life, and is also predictive of dysexecutive behaviors. These findings are discussed in the context of multidimensional and neural models of awareness and error monitoring. PMID- 26235054 TI - Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity. AB - Apoptotic resistance is becoming a significant obstacle for cancer therapy as the majority of treatment takes the route of apoptotic induction. It is of great importance to develop an alternative strategy to induce cancer cell death. We previously reported that autophagic cell death mediated by nuclear receptor TR3 and driven by a chemical agonist, 1-(3,4,5-trihydroxyphenyl)nonan-1-one (THPN), is highly effective in the therapy of melanoma but not any other cancer types. Here, we discovered that the insensitivity of cancer cells to THPN originated from a high cellular Akt2 activity. Akt2 phosphorylation interferes with TR3 export to cytoplasm and targeting to mitochondria, which lead to the autophagic induction. Therefore, the TR3-mediated autophagy could be effectively induced in the otherwise insensitive cells by downregulating Akt2 activity. Highly effective antineoplastic compounds are developed through optimizing the structure of THPN. This study implicates a general strategy for cancer therapy by the induction of autophagic cell death. PMID- 26235055 TI - Comprehensive Structural and Biochemical Analysis of the Terminal Myxalamid Reductase Domain for the Engineered Production of Primary Alcohols. AB - The terminal reductase (R) domain from the non-ribosomal peptide synthetase (NRPS) module MxaA in Stigmatella aurantiaca Sga15 catalyzes a non-processive four-electron reduction to produce the myxalamide family of secondary metabolites. Despite widespread use in nature, a lack of structural and mechanistic information concerning reductive release from polyketide synthase (PKS) and NRPS assembly lines principally limits our ability to redesign R domains with altered or improved activity. Here we report crystal structures for MxaA R, both in the absence and, for the first time, in the presence of the NADPH cofactor. Molecular dynamics simulations were employed to provide a deeper understanding of this domain and further identify residues critical for structural integrity, substrate binding, and catalysis. Aggregate computational and structural findings provided a basis for mechanistic investigations and, in the process, delivered a rationally altered variant with improved activity toward highly reduced substrates. PMID- 26235056 TI - Giving credence to controls: Avoiding the false phenotype. PMID- 26235058 TI - Alzheimer's as a Systems-Level Disease Involving the Interplay of Multiple Cellular Networks. AB - Alzheimer's disease (AD), and many neurodegenerative disorders, are multifactorial in nature. They involve a combination of genomic, epigenomic, interactomic and environmental factors. Progress is being made, and these complex diseases are beginning to be understood as having their origin in altered states of biological networks at the cellular level. In the case of AD, genomic susceptibility and mechanisms leading to (or accompanying) the impairment of the central Amyloid Precursor Protein (APP) processing and tau networks are widely accepted as major contributors to the diseased state. The derangement of these networks may result in both the gain and loss of functions, increased generation of toxic species (e.g., toxic soluble oligomers and aggregates) and imbalances, whose effects can propagate to supra-cellular levels. Although well sustained by empirical data and widely accepted, this global perspective often overlooks the essential roles played by the main counteracting homeostatic networks (e.g., protein quality control/proteostasis, unfolded protein response, protein folding chaperone networks, disaggregases, ER-associated degradation/ubiquitin proteasome system, endolysosomal network, autophagy, and other stress-protective and clearance networks), whose relevance to AD is just beginning to be fully realized. In this chapter, an integrative perspective is presented. Alzheimer's disease is characterized to be a result of: (a) intrinsic genomic/epigenomic susceptibility and, (b) a continued dynamic interplay between the deranged networks and the central homeostatic networks of nerve cells. This interplay of networks will underlie both the onset and rate of progression of the disease in each individual. Integrative Systems Biology approaches are required to effect its elucidation. Comprehensive Systems Biology experiments at different 'omics levels in simple model organisms, engineered to recapitulate the basic features of AD may illuminate the onset and sequence of events underlying AD. Indeed, studies of models of AD in simple organisms, differentiated cells in culture and rodents are beginning to offer hope that the onset and progression of AD, if detected at an early stage, may be stopped, delayed, or even reversed, by activating or modulating networks involved in proteostasis and the clearance of toxic species. In practice, the incorporation of next-generation neuroimaging, high-throughput and computational approaches are opening the way towards early diagnosis well before irreversible cell death. Thus, the presence or co occurrence of: (a) accumulation of toxic Abeta oligomers and tau species; (b) altered splicing and transcriptome patterns; (c) impaired redox, proteostatic, and metabolic networks together with, (d) compromised homeostatic capacities may constitute relevant 'AD hallmarks at the cellular level' towards reliable and early diagnosis. From here, preventive lifestyle changes and tailored therapies may be investigated, such as combined strategies aimed at both lowering the production of toxic species and potentiating homeostatic responses, in order to prevent or delay the onset, and arrest, alleviate, or even reverse the progression of the disease. PMID- 26235057 TI - There and back again: Iterating between population-based modeling and experiments reveals surprising regulation of calcium transients in rat cardiac myocytes. AB - While many ion channels and transporters involved in cardiac cellular physiology have been identified and described, the relative importance of each in determining emergent cellular behaviors remains unclear. Here we address this issue with a novel approach that combines population-based mathematical modeling with experimental tests to systematically quantify the relative contributions of different ion channels and transporters to the amplitude of the cellular Ca(2+) transient. Sensitivity analysis of a mathematical model of the rat ventricular cardiomyocyte quantified the response of cell behaviors to changes in the level of each ion channel and transporter, and experimental tests of these predictions were performed to validate or invalidate the predictions. The model analysis found that partial inhibition of the transient outward current in rat ventricular epicardial myocytes was predicted to have a greater impact on Ca(2+) transient amplitude than either: (1) inhibition of the same current in endocardial myocytes, or (2) comparable inhibition of the sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA). Experimental tests confirmed the model predictions qualitatively but showed some quantitative disagreement. This guided us to recalibrate the model by adjusting the relative importance of several Ca(2+) fluxes, thereby improving the consistency with experimental data and producing a more predictive model. Analysis of human cardiomyocyte models suggests that the relative importance of outward currents to Ca(2+) transporters is generalizable to human atrial cardiomyocytes, but not ventricular cardiomyocytes. Overall, our novel approach of combining population-based mathematical modeling with experimental tests has yielded new insight into the relative importance of different determinants of cell behavior. PMID- 26235059 TI - Application of Systems Theory in Longitudinal Studies on the Origin and Progression of Alzheimer's Disease. AB - This chapter questions the prevailing "implicit" assumption that molecular mechanisms and the biological phenotype of dominantly inherited early-onset alzheimer's disease (EOAD) could serve as a linear model to study the pathogenesis of sporadic late-onset alzheimer's disease (LOAD). Now there is growing evidence to suggest that such reductionism may not be warranted; these suppositions are not adequate to explain the molecular complexities of LOAD. For example, the failure of some recent amyloid-centric clinical trials, which were largely based on the extrapolations from EOAD biological phenotypes to the molecular mechanisms in the pathogenesis of LOAD, might be due to such false assumptions. The distinct difference in the biology of LOAD and EOAD is underscored by the presence of EOAD cases without evidence of familial clustering or Mendelian transmission and, conversely, the discovery and frequent reports of such clustering and transmission patterns in LOAD cases. The primary thesis of this chapter is that a radically different way of thinking is required for comprehensive explanations regarding the distinct complexities in the molecular pathogenesis of inherited and sporadic forms of Alzheimer's disease (AD). We propose using longitudinal analytical methods and the paradigm of systems biology (using transcriptomics, proteomics, metabolomics, and lipidomics) to provide us a more comprehensive insight into the lifelong origin and progression of different molecular mechanisms and neurodegeneration. Such studies should aim to clarify the role of specific pathophysiological and signaling pathways such as neuroinflammation, altered lipid metabolism, apoptosis, oxidative stress, tau hyperphosphorylation, protein misfolding, tangle formation, and amyloidogenic cascade leading to overproduction and reduced clearance of aggregating amyloid beta (Abeta) species. A more complete understanding of the distinct difference in molecular mechanisms, signaling pathways, as well as comparability of the various forms of AD is of paramount importance. The development of knowledge and technologies for early detection and characterization of the disease across all stages will improve the predictions regarding the course of the disease, prognosis, and response to treatment. No doubt such advances will have a significant impact on the clinical management of both EOAD and LOAD patients. The approach propped here, combining longitudinal studies with the systems biology paradigm, will create a more effective and comprehensive framework for development of prevention therapies in AD. PMID- 26235060 TI - The APP Proteolytic System and Its Interactions with Dynamic Networks in Alzheimer's Disease. AB - Diseases of aging are often complex and multifactorial, involving many genetic and life course modifiers. Systems biology is becoming an essential tool to investigate disease initiation and disease progression. Alzheimer's disease (AD) can be used as a case study to investigate the application of systems biology to complex disease. Here we describe approaches to capturing biological data, representing data in terms of networks and interpreting their meaning in relation to the human population. We highlight issues that remain to be addressed both in terms of modeling disease progression and in relating findings to the current understanding of human disease. PMID- 26235061 TI - Effects of Mild and Severe Oxidative Stress on BACE1 Expression and APP Amyloidogenic Processing. AB - This chapter describes methods for establishing oxidative stress conditions that do not induce cell death in a neuronal cell culture model. We termed these conditions "mild oxidative stress," as opposed to "severe oxidative stress," which results in significant cell loss. Mild oxidative stress resembles more closely what happens in the aging brain than severe oxidative stress. The protocols we have delineated include the preparation and maintenance of mouse primary cortical cultures, the induction of oxidative stress by treatment with hydrogen peroxide, the assessment of cell viability by the 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the measurement of free radical production by the 2',7'-dichlorofluorescein (DCF) assay, and western blot analysis of the amyloid precursor protein (APP) and beta-site APP cleaving enzyme, BACE1, two key proteins associated with Alzheimer's disease pathology and oxidative stress. PMID- 26235062 TI - Advanced Assay Monitoring APP-Carboxyl-Terminal Fragments as Markers of APP Processing in Alzheimer Disease Mouse Models. AB - The 99-amino-acid-long APP-carboxy-terminal fragment, named C99, is a membrane bound peptide generated from the amyloid precursor protein (APP) by beta secretase cleavage and is the direct precursor of amyloid beta (Abeta). Here we describe a method for the quantification of C99. The amount of C99 is an indicative value of the amyloid pathology in an Alzheimer's disease (AD) model, and could be used as a marker to study AD progression in comprehensive experiments, including screening for new compounds and repurposing of drugs to treat AD. PMID- 26235063 TI - Optical Super-Resolution Imaging of beta-Amyloid Aggregation In Vitro and In Vivo: Method and Techniques. AB - Super-resolution microscopy has emerged as a powerful and non-invasive tool for the study of molecular processes both in vitro and in live cells. In particular, super-resolution microscopy has proven valuable for research studies in protein aggregation. In this chapter we present details of recent advances in this method and the specific techniques, enabling the study of amyloid beta aggregation optically, both in vitro and in cells. First, we show that variants of optical super-resolution microscopy provide a capability to visualize oligomeric and fibrillar structures directly, providing detailed information on species morphology in vitro and even in situ, in the cellular environment. We focus on direct Stochastic Optical Reconstruction Microscopy, dSTORM, which provides morphological detail on spatial scales below 20 nm, and provide detailed protocols for its implementation in the context of amyloid beta research. Secondly, we present a range of optical techniques that offer super-resolution indirectly, which we call multi-parametric microscopy. The latter offers molecular scale information on self-assembly reactions via changes in protein or fluorophore spectral signatures. These techniques are empowered by our recent discovery that disease related amyloid proteins adopt intrinsic energy states upon fibrilisation. We show that fluorescence lifetime imaging provides a particularly sensitive readout to report on the aggregation state, which is robustly quantifiable for experiments performed either in vitro or in vivo. PMID- 26235064 TI - Protocols for Monitoring the Development of Tau Pathology in Alzheimer's Disease. AB - The microtubule-associated protein tau plays a critical role in the pathogenesis of Alzheimer's disease (AD) and several related disorders collectively known as tauopathies. Development of tau pathology is associated with progressive neuronal loss and cognitive decline. In the brains of AD patients, tau pathology spreads following a predictable, anatomically defined progression pattern that can be followed by immunohistochemistry looking at brain post-mortem samples from Alzheimer patients at different stages of the disease. Furthermore, since it has been proposed that AD may be a synaptopathy and dendritic spines of pyramidal neurons are the major targets of cortical synapses, the analysis of dendritic spines is a useful tool to study the correlation between tau phosphorylation at specific sites, synaptopathy and cognitive impairment. Finally, characterization of phosphorylated tau in detergent-insoluble protein aggregates could also be an indication of the neuropathological staging in AD. Here, we describe these three complementary protocols to follow the development of tau pathology in Alzheimer's disease. PMID- 26235065 TI - LC3-II Tagging and Western Blotting for Monitoring Autophagic Activity in Mammalian Cells. AB - The autophagosome-associated protein LC3-II is commonly used as a marker of autophagic activity within cells, but its levels are affected by both formation and degradation of autophagosomes. This can make the significance of altered LC3 II levels ambiguous. Here we describe the method of Bafilomycin A1 blotting, in which the degradation of autophagosomes is prevented in cultured cells, allowing the causes of altered LC3-II levels to be determined. PMID- 26235066 TI - Advanced Mitochondrial Respiration Assay for Evaluation of Mitochondrial Dysfunction in Alzheimer's Disease. AB - Alzheimer's disease (AD) is characterized by the presence of amyloid plaques (aggregates of amyloid-beta [Abeta]) and neurofibrillary tangles (aggregates of tau) in the brain, but the underlying mechanisms of the disease are still partially unclear. A growing body of evidence supports mitochondrial dysfunction as a prominent and early, chronic oxidative stress-associated event that contributes to synaptic abnormalities, and, ultimately, selective neuronal degeneration in AD. Using a high-resolution respirometry system, we shed new light on the close interrelationship of this organelle with Abeta and tau in the pathogenic process underlying AD by showing a synergistic effect of these two hallmark proteins on the oxidative phosphorylation capacity of mitochondria isolated from the brain of transgenic AD mice. In the present chapter, we first introduce the principle of the Abeta and tau interaction on mitochondrial respiration, and secondly, we describe in detail the used respiratory protocol. PMID- 26235067 TI - Analysis of Microglial Proliferation in Alzheimer's Disease. AB - The expansion and activation of the microglial population is a hallmark of many neurodegenerative diseases. Despite this fact, little quantitative information is available for specific neurodegenerative disorders, particularly for Alzheimer's disease (AD). Determining the degree of local proliferation will not only open avenues into understanding the dynamics of microglial proliferation, but also provide an effective target to design strategies with therapeutic potential. Here we describe immunohistochemical methods to analyse microglial proliferation in both transgenic murine models of AD and in human post-mortem samples, to provide a broad picture of the microglial response at the different experimental levels. The application of a common and universal method to analyse the microglial dynamics across different laboratories will help to understand the contribution of these cells to the pathology of AD and other neurodegenerative diseases. PMID- 26235068 TI - Yeast as a Model for Alzheimer's Disease: Latest Studies and Advanced Strategies. AB - The yeast Saccharomyces cerevisiae, a unicellular eukaryotic model, has enabled major breakthroughs in our understanding of a plethora of cellular and molecular processes. Today, a 're-invention' of its use in fundamental and applied research is paving the way for a better understanding of the mechanisms causing neurodegeneration. The increasing emergence of neurodegenerative disorders is becoming more and more problematic in our ageing society. Most prevalent is Alzheimer's disease (AD), affecting more than 35 million people worldwide (Abbott, Nature 475, S2-S4, 2011) and causing an enormous burden on a personal and communal level. The disease is characterized by two major pathological hallmarks: extracellular amyloid plaques consisting mainly of deposits of amyloid beta (Abeta) peptides, and intracellular neurofibrillary tangles (NFTs), consisting mainly of aggregates of hyperphosphorylated tau protein. Despite the huge importance of thoroughly understanding the underlying molecular mechanisms of neurodegeneration, progress has been slow. However, multiple complementary research methods are proving their value, particularly with the work done with S. cerevisiae, which combines well-established, fast genetic and molecular techniques with the ability to faithfully capture key molecular aspects of neurodegeneration. In this review chapter, we focus on the considerable progress made using S. cerevisiae as a model system for Alzheimer's disease. PMID- 26235069 TI - Yeast as a Model for Studies on Abeta Aggregation Toxicity in Alzheimer's Disease, Autophagic Responses, and Drug Screening. AB - The Abeta peptide is widely considered a major cause of Alzheimer's disease since it causes neuronal death in an oligomerisation-dependent manner. In order to identify new inhibitors of Abeta that may be chemo preventative for Alzheimer's disease, a yeast assay that qualitatively determines the amounts and state of the human Abeta42 peptide has been developed. Yeast assays such as this can be applied to studies on aggregation toxicity, autophagic responses and drug screening in Alzheimer's disease. PMID- 26235070 TI - Drosophila melanogaster as a Model for Studies on the Early Stages of Alzheimer's Disease. AB - Fruit flies (Drosophila melanogaster) have been widely used to study the cellular and molecular basis of human neurodegenerative disease. The biological similarities between the human and the fly have been explored successfully to further investigate the pathological basis of Alzheimer's disease (AD). Here, we discuss transgenic Drosophila models systems and the methodologies that have been employed in the study of AD. PMID- 26235071 TI - Chronic Mild Stress Assay Leading to Early Onset and Propagation of Alzheimer's Disease Phenotype in Mouse Models. AB - A comprehensive chronic mild stress (CMS) procedure is presented, which consists in the application of unpredictable mild stressors to animal models in a random order for several weeks. This assay can be applied to Alzheimer's disease (AD) mouse models, leading to accelerated onset and increased severity of AD phenotypes and signs, including memory deficits and the accumulation of amyloid beta and phospho-tau. These assays open the way towards advanced studies on the influence of sustained mild stress, stress responses and pathways on the onset and propagation of Alzheimer's disease. PMID- 26235072 TI - Gene Expression Studies on Human Trisomy 21 iPSCs and Neurons: Towards Mechanisms Underlying Down's Syndrome and Early Alzheimer's Disease-Like Pathologies. AB - The cause of Alzheimer disease (AD) is not well understood and there is no cure. Our ability to understand the early events in the course of AD is severely limited by the difficulty of identifying individuals who are in the early, preclinical stage of this disease. Most individuals with Down's syndrome (DS, trisomy 21) will predictably develop AD and that they will do so at a young age makes them an ideal population in which to study the early stages of AD. Several recent studies have exploited induced pluripotent stem cells (iPSCs) generated from individuals with familial AD, spontaneous AD and DS to attempt to identify early events and discover novel biomarkers of disease progression in AD. Here, we summarize the progress and limitations of these iPSC studies with a focus on iPSC derived neurons. Further, we outline the methodology and results for comparing gene expression between AD and DS iPSC-derived neurons. We highlight differences and commonalities in these data that may implicate underlying genes and pathways that are causative for AD. PMID- 26235073 TI - Cortical Differentiation of Human Pluripotent Cells for In Vitro Modeling of Alzheimer's Disease. AB - Stem cell models of Alzheimer's disease provide an opportunity to study the mechanisms underlying disease pathology at a resolution that is not possible in animal models. Furthermore, the ability to reprogram patient somatic cells to a pluripotent state ensures that the disease can be investigated in the correct genetic context. Here, we describe the directed differentiation of human pluripotent cells to cortical progenitors by recapitulating key developmental signaling events in vitro. Over a timeframe that mirrors human development, these progenitors give rise to functional lower and upper layer neurons. We also describe biochemical and imaging based methods to analyse key APP and Tau phenotypes in neurons generated from pluripotent stem cells from individuals with either monogenic familial Alzheimer's disease or Down's syndrome. PMID- 26235074 TI - Next Generation Sequencing in Alzheimer's Disease. AB - For the first time in the history of human genetics research, it is now both technically feasible and economically affordable to screen individual genomes for novel disease-causing mutations at base-pair resolution using "next-generation sequencing" (NGS). One popular aim in many of today's NGS studies is genome resequencing (in part or whole) to identify DNA variants potentially accounting for the "missing heritability" problem observed in many genetically complex traits. Thus far, only relatively few projects have applied these powerful new technologies to search for novel Alzheimer's disease (AD) related sequence variants. In this review, I summarize the findings from the first NGS-based resequencing studies in AD and discuss their potential implications and limitations. Notable recent discoveries using NGS include the identification of rare susceptibility modifying alleles in APP, TREM2, and PLD3. Several other large-scale NGS projects are currently underway so that additional discoveries can be expected over the coming years. PMID- 26235075 TI - Pooled-DNA Sequencing for Elucidating New Genomic Risk Factors, Rare Variants Underlying Alzheimer's Disease. AB - Analyses of genome-wide association studies (GWAS) for complex disorders usually identify common variants with a relatively small effect size that only explain a small proportion of phenotypic heritability. Several studies have suggested that a significant fraction of heritability may be explained by low-frequency (minor allele frequency (MAF) of 1-5 %) and rare-variants that are not contained in the commercial GWAS genotyping arrays (Schork et al., Curr Opin Genet Dev 19:212, 2009). Rare variants can also have relatively large effects on risk for developing human diseases or disease phenotype (Cruchaga et al., PLoS One 7:e31039, 2012). However, it is necessary to perform next-generation sequencing (NGS) studies in a large population (>4,000 samples) to detect a significant rare variant association. Several NGS methods, such as custom capture sequencing and amplicon-based sequencing, are designed to screen a small proportion of the genome, but most of these methods are limited in the number of samples that can be multiplexed (i.e. most sequencing kits only provide 96 distinct index). Additionally, the sequencing library preparation for 4,000 samples remains expensive and thus conducting NGS studies with the aforementioned methods are not feasible for most research laboratories.The need for low-cost large scale rare variant detection makes pooled-DNA sequencing an ideally efficient and cost effective technique to identify rare variants in target regions by sequencing hundreds to thousands of samples. Our recent work has demonstrated that pooled DNA sequencing can accurately detect rare variants in targeted regions in multiple DNA samples with high sensitivity and specificity (Jin et al., Alzheimers Res Ther 4:34, 2012). In these studies we used a well-established pooled-DNA sequencing approach and a computational package, SPLINTER (short indel prediction by large deviation inference and nonlinear true frequency estimation by recursion) (Vallania et al., Genome Res 20:1711, 2010), for accurate identification of rare variants in large DNA pools. Given an average sequencing coverage of 30* per haploid genome, SPLINTER can detect rare variants and short indels up to 4 base pairs (bp) with high sensitivity and specificity (up to 1 haploid allele in a pool as large as 500 individuals). Step-by-step instructions on how to conduct pooled-DNA sequencing experiments and data analyses are described in this chapter. PMID- 26235076 TI - New Genome-Wide Methods for Elucidation of Candidate Copy Number Variations (CNVs) Contributing to Alzheimer's Disease Heritability. AB - The complexity of human genetic variation has been extended by the observation of abundant and widespread variation in the copy number of submicroscopic DNA segments. The discovery of this novel level of genome organization opened new possibilities concerning the genetic variation that may confer susceptibility to or cause disease. Copy number variants (CNVs) influence gene expression, phenotypic variation and adaptation by altering gene dosage and genome organization. Concordant with the common disease common variant hypothesis these structural variants are now subject to interrogation for disease association. Alzheimer's disease (AD) is a progressive neurodegenerative disease with an estimated heritability of 60-80 %. Large scale genome-wide association studies (GWAS) using high frequency single nucleotide polymorphism (SNP) variants identified ten loci which do not account for the measured heritability. To find the missing heritability systematic assessment of all mutational mechanisms needs to be performed. Between the powerful SNP-GWAS studies and the planned Whole Genome Sequencing projects the contribution of copy number variation (CNV) to the genetic architecture of AD needs to be studied fully. PMID- 26235077 TI - RNA-Sequencing to Elucidate Early Patterns of Dysregulation Underlying the Onset of Alzheimer's Disease. AB - With its ability to perform rapid transcriptome profiling and profound transcriptomic analysis powered by high-throughput sequencing at a high resolution with deep coverage, the advent of RNA sequencing technology, RNA-Seq, outperforms other methods in the field, such as microarrays, and has changed our way of performing transcriptomic investigation. Protocols for preparing libraries for RNA-Seq using the Illumina and Roche 454 sequencing platforms are included in this chapter. Common steps for library preparation in both platforms include RNA fragmentation, cDNA synthesis, adaptor ligation, and PCR amplification of cDNA strands. Illumina adopts solid-phase bridge PCR amplification, while 454 uses water-in-oil emulsion-based PCR amplification. Despite differences in the PCR amplification step, both platforms employ the same sequencing-by-synthesis technology for the sequencing process. Application of the RNA-Seq technique in the context of dysregulation of the transcriptome in Alzheimer's disease is also discussed. PMID- 26235078 TI - Systems Biology Approaches to the Study of Biological Networks Underlying Alzheimer's Disease: Role of miRNAs. AB - MicroRNAs (miRNAs) are emerging as significant regulators of mRNA complexity in the human central nervous system (CNS) thereby controlling distinct gene expression profiles in a spatio-temporal manner during development, neuronal plasticity, aging and (age-related) neurodegeneration, including Alzheimer's disease (AD). Increasing effort is expended towards dissecting and deciphering the molecular and genetic mechanisms of neurobiological and pathological functions of these brain-enriched miRNAs. Along these lines, recent data pinpoint distinct miRNAs and miRNA networks being linked to APP splicing, processing and Abeta pathology (Lukiw et al., Front Genet 3:327, 2013), and furthermore, to the regulation of tau and its cellular subnetworks (Lau et al., EMBO Mol Med 5:1613, 2013), altogether underlying the onset and propagation of Alzheimer's disease. MicroRNA profiling studies in Alzheimer's disease suffer from poor consensus which is an acknowledged concern in the field, and constitutes one of the current technical challenges. Hence, a strong demand for experimental and computational systems biology approaches arises, to incorporate and integrate distinct levels of information and scientific knowledge into a complex system of miRNA networks in the context of the transcriptome, proteome and metabolome in a given cellular environment. Here, we will discuss the state-of-the-art technologies and computational approaches on hand that may lead to a deeper understanding of the complex biological networks underlying the pathogenesis of Alzheimer's disease. PMID- 26235079 TI - The Emerging Role of Metalloproteomics in Alzheimer's Disease Research. AB - Metals are increasingly recognized to have an important role in molecular processes underlying Alzheimer's disease (AD). This chapter discusses the current role of metals in AD and expands on the development of metalloproteomics and how the recent advances in analytical technology will allow detailed investigation of metalloproteins. Investigation of individual metalloproteins will yield new mechanistic details about the role of metals in AD. PMID- 26235080 TI - Redox Proteomics in Human Biofluids: Sample Preparation, Separation and Immunochemical Tagging for Analysis of Protein Oxidation. AB - Proteomics offers the simultaneous detection of a large number of proteins in a single experiment and can provide important information regarding crucial aspects of specific proteins, particularly post-translational modifications (PTMs). Investigations of oxidative PTMs are currently performed using focused redox proteomics techniques, which rely on gel electrophoresis separations of intact proteins with the final detection of oxidative PTMs being performed by mass spectrometry (MS) analysis. The application of this technique to human biofluids is being subject of increasing investigation and is expected to provide new insights on the oxidative status of the peripheral proteome in neurological diseases such as Alzheimer's disease, towards purposes of early diagnosis and prognosis. This chapter describes all the experimental steps to perform redox proteomics analysis of cerebrospinal fluid and plasma/serum samples. PMID- 26235082 TI - AlzPathway, an Updated Map of Curated Signaling Pathways: Towards Deciphering Alzheimer's Disease Pathogenesis. AB - Alzheimer's disease (AD) is a complex neurodegenerative disorder in which loss of neurons and synaptic function causes dementia in the elderly. To clarify AD pathogenesis and develop drugs for AD, thousands of studies have elucidated signaling pathways involved. However, knowledge of AD signaling pathways has not been compiled as a pathway map. In this chapter, we introduce the manual construction of a pathway map in AD which we call "AlzPathway", that comprehensively catalogs signaling pathways in the field of AD. We have collected and manually curated over 100 review articles related to AD, and have built the AD pathway map. AlzPathway is currently composed of thousands of molecules and reactions in neurons, brain blood barrier, presynaptic, postsynaptic, astrocyte, and microglial cells, with their cellular localizations. AlzPathway provides a systems-biology platform of comprehensive AD signaling and related pathways which is expected to contribute to clarification of AD pathogenesis and AD drug development. PMID- 26235083 TI - A Computational Network Biology Approach to Uncover Novel Genes Related to Alzheimer's Disease. AB - Recent advances in the fields of genetics and genomics have enabled the identification of numerous Alzheimer's disease (AD) candidate genes, although for many of them the role in AD pathophysiology has not been uncovered yet. Concomitantly, network biology studies have shown a strong link between protein network connectivity and disease. In this chapter I describe a computational approach that, by combining local and global network analysis strategies, allows the formulation of novel hypotheses on the molecular mechanisms involved in AD and prioritizes candidate genes for further functional studies. PMID- 26235081 TI - Advanced Shotgun Lipidomics for Characterization of Altered Lipid Patterns in Neurodegenerative Diseases and Brain Injury. AB - Multi-dimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) is a powerful technology platform among current lipidomics practices due to its high efficiency, sensitivity, and reproducibility, as well as its broad coverage. This platform has been widely used to determine the altered lipid profiles induced by diseases, injury, genetic manipulations, drug treatments, and aging, among others. Herein, we summarize the principles underlying this platform and present a protocol for analysis of many of the lipid classes and subclasses covered by MDMS-SL directly from lipid extracts of brain samples. We believe that this protocol can aid researchers in the field to determine altered lipid patterns in neurodegenerative diseases and brain injury. PMID- 26235084 TI - Network Approaches to the Understanding of Alzheimer's Disease: From Model Organisms to Humans. AB - It is becoming increasingly evident that Alzheimer's disease cannot be considered as the outcome of a single pathway, but rather we should view it as a system, that is, a network of interactions between large numbers of different protein molecules. In the last few years, probably because of the inherent limitations of traditional methods and because of the great increase in availability of sequencing data, this type of approach is being used more and more. In the following, we will discuss what constitutes a "network approach," what are its pros and cons, a number of recent case studies and finally what are the future perspectives of this type of analysis. PMID- 26235085 TI - Characterization of Genetic Networks Associated with Alzheimer's Disease. AB - At the molecular level, the genetics of complex disease such as Alzheimer's disease (AD) manifests itself as series of alterations in the molecular interactions in pathways and networks that define biological processes underlying the pathophysiological states of disease. While large-scale genome-wide association (GWA) studies of late-onset alzheimer's disease (LOAD) have uncovered prominent genomic regions linked to the disease, the cause for the vast majority of LOAD cases still remains unknown. Increasingly available large-scale genomic and genetic data related to LOAD has made it possible to comprehensively uncover the mechanisms causally lined to LOAD in a completely data-driven manner. Here we review the various aspects of systems/network biology approaches and methodology in constructing genetic networks associated with AD from large sampling of postmortem brain tissues. We describe in detail a multiscale network modeling approach (MNMA) that integrates interaction and causal gene networks to analyze large-scale DNA, gene expression and pathophysiological data from multiple post mortem brain regions of LOAD patients as well non-demented normal controls. MNMA first employs weighted gene co-expression network analysis (WGCNA) to construct multi-tissue networks that simultaneously capture intra-tissue and inter-tissue gene-gene interactions and then quantifies the change in connectivity among highly co-expressed genes in LOAD with respect to the normal state. Co-expressed gene modules are then rank ordered by relevance to pathophysiological traits and enrichment of genes differentially expressed in LOAD. Causal regulatory relationships among the genes in each module are then determined by a Bayesian network inference framework that is used to formally integrate genetic and gene expression information. MNMA has uncovered a massive remodeling of network structures in LOAD and identified novel subnetworks and key regulators that are causally linked to LOAD. In the end, we will outline the challenges in systems/network approaches to LOAD. PMID- 26235086 TI - Network-Based Analysis for Uncovering Mechanisms Underlying Alzheimer's Disease. AB - Alzheimer's disease (AD) is known to be a multifactorial neurodegenerative disorder, and is one of the main causes of dementia in the elderly. Many studies have demonstrated molecules involved in the pathogenesis of AD, however its underlying mechanisms remain obscure. It may be simplistic to try to explain the disease based on the role of a few genes only. Accumulating new, huge amount of information from e.g. genome, proteome and interactome datasets and new knowledge, we are now able to clarify and characterize diseases essentially as a result of dysfunction of molecular networks. Recent studies have indicated that relevant genes affected in human diseases concentrate in a part of the network, often called as "disease module." In the case of AD, some disease-associated pathways seem different, but some of them are clearly disease-related and coherent. This suggests the existence of a common pathway that negatively drives from healthy state to disease state (i.e., the disease module(s)). Additionally, such disease modules should dynamically change through AD progression. Thus, network-level approaches are indispensable to address unknown mechanisms of AD. In this chapter, we introduce network strategies using gene co-expression and protein interaction networks. PMID- 26235087 TI - The SDREM Method for Reconstructing Signaling and Regulatory Response Networks: Applications for Studying Disease Progression. AB - The Signaling and Dynamic Regulatory Events Miner (SDREM) is a powerful computational approach for identifying which signaling pathways and transcription factors control the temporal cellular response to a stimulus. SDREM builds end-to end response models by combining condition-independent protein-protein interactions and transcription factor binding data with two types of condition specific data: source proteins that detect the stimulus and changes in gene expression over time. Here we describe how to apply SDREM to study human diseases, using epidermal growth factor (EGF) response impacting neurogenesis and Alzheimer's disease as an example. PMID- 26235088 TI - Advanced Neuroimaging Methods Towards Characterization of Early Stages of Alzheimer's Disease. AB - In the past 5 years, imaging network properties in the brain of patients with Alzheimer's disease (AD) has revolutionized our understanding of this disorder. Postmortem data had already suggested that the damage spreads along functional neural networks, but postmortem studies do not provide information on the temporal evolution of the damage in the same patient, essential to determine spreading. These data can be provided by functional and structural neuroimaging, which allow for the visualization over time of the progressive damage inflicted by AD. Functional networks can be mapped by determining the synchrony across brain regions of the blood oxygenation level dependence (BOLD) signal on functional magnetic resonance imaging (MRI) during quiet wakefulness. Other less extensively used techniques are also useful. For instance, amyloid deposition can be imaged and its progression mapped to determine whether it follows brain networks, and, if so, which are affected earliest. Network patterns of neurobiological changes, including tau deposition, may prove critical to our understanding of the neurobiology of AD and therefore open the way for therapeutic interventions. PMID- 26235089 TI - Plasma Proteomics Biomarkers in Alzheimer's Disease: Latest Advances and Challenges. AB - The recent paradigm shift towards a more biologically oriented definition of Alzheimer's disease (AD) in clinical settings increases the need for sensitive biomarkers that can be applied in population-based settings. Blood plasma is easily accessible and contains a large number of proteins related to cerebral processes. It is therefore an ideal candidate for AD biomarker discovery. The present chapter provides an overview of the current research landscape in relation to blood-based AD biomarkers. Both clinical and methodological issues are covered. A brief summary is given on two relevant laboratory techniques to ascertain blood biomarker changes due to AD; methodological and clinical challenges in the field are also discussed. PMID- 26235090 TI - A Practical Guide for Exploring Opportunities of Repurposing Drugs for CNS Diseases in Systems Biology. AB - Systems biology has shown its potential in facilitating pathway-focused therapy development for central nervous system (CNS) diseases. An integrated network can be utilized to explore the multiple disease mechanisms and to discover repositioning opportunities. This review covers current therapeutic gaps for CNS diseases and the role of systems biology in pharmaceutical industry. We conclude with a Multiple Level Network Modeling (MLNM) example to illustrate the great potential of systems biology for CNS diseases. The system focuses on the benefit and practical applications in pathway centric therapy and drug repositioning. PMID- 26235091 TI - An Unusual Case of Preexcitation: Where Is the Accessory Pathway? PMID- 26235092 TI - Gaining control over breast cancer risk: Transforming vulnerability, uncertainty, and the future through clinical trial participation - a qualitative study. AB - Concepts of disease risk and its management are central to processes of medicalisation and pharmaceuticalisation. Through a narrative perspective, this paper aims to understand how such macro-level developments may (or may not) be experienced individually, and how an algorithm that is used for recruitment into a clinical trial may structure individual notions of being 'at risk' and 'in need of treatment'. We interviewed 31 women participating in the Study of Tamoxifen and Raloxifene (STAR), a chemoprevention trial conducted in the US between 1999 and 2006. Interviews were thematically analysed. Women in the study had experienced the threat of breast cancer and felt vulnerable to developing the disease prior to STAR participation. The diagnosis of 'being at risk' for cancer through an algorithm that determined risk-eligibility for STAR, opened up the possibility for the women to heal. The trial became a means to recognise and collectivise the women's experiences of vulnerability. Through medication intake, being cared for by study coordinators, and the sense of community with other STAR participants, trial participation worked to transform women's lives. Such transformative experiences may nevertheless have been temporary, enduring only as long as the close links to the medical institution through trial participation lasted. PMID- 26235093 TI - Studies on Antifungal Potential, Primary Characterization and Mode of Action of a De Novo Cytoplasmic Protein (EAF) from Human Commensal Escherichia coli Against Aspergillus spp. AB - A de novo protein named as EAF (Escherichia antifungal protein) from the cytoplasmic pool of an Escherichia coli strain (MTCC 1652), has been purified to homogeneity using anion exchange (Q-XL Sepharose) and cation exchange (SP Sepharose) chromatography. The MIC (minimum inhibitory concentration) values of purified protein against A. fumigatus (the major pathogenic species) were found to be comparable with standard drugs i.e. 3.90 ug/ml, 3.90 ug/ml and 1.25 ug/disc via microbroth dilution assay (MDA), percentage spore germination inhibition (PSGI) and disc diffusion assay (DDA) respectively. Toxicity results confirmed that it causes no haemolysis against human RBCs upto a concentration of 1000.0 ug/ml as compared to Amphotericin B (conventional antifungal drug) that causes hundred percent haemolysis at a concentration of 37.50 ug/ml only.The purified protein demonstrated a molecular mass of 28 kDa on SDS-PAGE which was further authenticated by MALDI-TOF. Proteomic and bioinformatics studies deciphered its significant homology (72 %) with chain A-D-ribose binding protein (cluster 2 sugar binding periplasmic proteins; sequence homologues of transcription regulatory proteins) from E. coli. Single dimensional page analysis of A. fumigatusproteins with due effect of EAF (at MIC50) revealed the inhibition of two major proteins; a heat shock protein 70-Hsp70 (68 kDa); having role in protein folding and functioning andphenylanalyl-t RNA synthetase PodG subunit protein (74 kDa); involved in growth polarity in fungi. Scanning electron microscopic studies depicted homologous results. We suggest that EAF most likely belongs to a new group of proteins with potent antifungal characteristics, negligible toxicity and targeting vital proteins of fungal metabolism. PMID- 26235095 TI - Timing of mammalian peripheral trigeminal system development relative to body size: A comparison of metatherians with rodents and monotremes. AB - Specializations of the trigeminal sensory system are present in all three infraclasses of mammals (metatheria, eutheria, prototheria or monotremata). The trigeminal sensory system has been suggested as a critically important modality for sampling the path to the pouch and detecting the nipple or milk patch, but the degree to which that system may be required to function at birth varies significantly. Archived sections of the snout and brainstem of embryonic and postnatal mammals were used to test the relationship between structural maturity of the two ends of the trigeminal nerve pathway and the body size of mammalian young in metatherians, rodents and monotremes. A system for staging different levels of structural maturity of the vibrissae and trigeminal sensory was applied to embryos, pouch young and hatchlings and correlated with body length. Dasyurids are born at the most immature state with respect to vibrissal and trigeminal sensory nucleus development of any available metatherian, but these components of the trigeminal system are also developmentally advanced relative to body size when dasyurids are compared to other metatherians. Vibrissal and trigeminal sensory nucleus development is at a similar stage of development at birth and for a given body size in non-dasyurid metatherians; and trigeminal sensory nucleus development in monotremes is at a similar stage at birth to metatherians. Rodents reach a far more advanced stage of vibrissal and trigeminal sensory nucleus development at birth than do metatherians, and in the case of the mouse have a more developmentally advanced trigeminal system than all available metatherians at any given body length. Precocious development of the trigeminal sensory pathway relative to body size is evident in dasyurids, as might be expected given the small birth size of those metatherians. Nevertheless, the trigeminal sensory system in metatherians in general is not precocious relative to body size when these species are considered alongside the pace of trigeminal somatosensory development in rodents. PMID- 26235094 TI - Intracellular levels of glutamate in swollen astrocytes are preserved via neurotransmitter reuptake and de novo synthesis: implications for hyponatremia. AB - Hyponatremia and several other CNS pathologies are associated with substantial astrocytic swelling. To counteract cell swelling, astrocytes lose intracellular osmolytes, including l-glutamate and taurine, through volume-regulated anion channel. In vitro, when swollen by exposure to hypo-osmotic medium, astrocytes lose endogenous taurine faster, paradoxically, than l-glutamate or l-aspartate. Here, we explored the mechanisms responsible for differences between the rates of osmolyte release in primary rat astrocyte cultures. In radiotracer assays, hypo osmotic efflux of preloaded [(14) C]taurine was indistinguishable from d-[(3) H]aspartate and only 30-40% faster than l-[(3) H]glutamate. However, when we used HPLC to measure the endogenous intracellular amino acid content, hypo-osmotic loss of taurine was approximately fivefold greater than l-glutamate, and no loss of l-aspartate was detected. The dramatic difference between loss of endogenous taurine and glutamate was eliminated after inhibition of both glutamate reuptake [with 300 MUM dl-threo-beta-benzyloxyaspartic acid (TBOA)] and glutamate synthesis by aminotransferases [with 1 mM aminooxyacetic acid (AOA)]. Treatment with TBOA+AOA made reductions in the intracellular taurine and l-glutamate levels approximately equal. Taken together, these data suggest that swollen astrocytes actively conserve intracellular glutamate via reuptake and de novo synthesis. Our findings likely also explain why in animal models of acute hyponatremia, extracellular levels of taurine are dramatically elevated with minimal impact on extracellular l-glutamate. We identified mechanisms that allow astrocytes to conserve intracellular l-glutamate (Glu) upon exposure to hypo-osmotic environment. Cell swelling activates volume-regulated anion channel (VRAC) and triggers loss of Glu, taurine (Tau), and other cytosolic amino acids. Glu is conserved via reuptake by Na(+) -dependent transporters and de novo synthesis in the reactions of mitochondrial transamination (TA). These findings explain why, in acute hyponatremia, extracellular levels of Tau can be dramatically elevated with minimal changes in extracellular Glu. PMID- 26235096 TI - The incremental prognostic value of the incorporation of myocardial perfusion assessment into clinical testing with stress echocardiography study. AB - BACKGROUND: The authors recently demonstrated that simultaneous assessment of myocardial perfusion (MP) and wall motion (WM) by myocardial contrast echocardiography (MCE) is feasible and accurate when incorporated into a clinical stress echocardiography (SE) service. However, it is unknown whether the incremental prognostic value of MP beyond WM, previously shown in research studies, is reproducible when MCE is performed in the clinical arena. METHODS: In this prospective study, MCE was performed by multiple operators during routine clinical SE, whose results were classified as normal WM and MP, abnormal WM and MP, or normal WM but abnormal MP. Patients were followed for the prospectively determined combined primary outcome of all-cause mortality, nonfatal myocardial infarction, and late revascularization. Cox regression analyses were performed to identify predictors of outcome. RESULTS: Of 220 patients undergoing simultaneous MCE during SE, 197 patients (90%) with interpretable WM and MP images were available for follow-up at a mean time period of 17 +/- 7 months. There were 35 events (six deaths, six myocardial infarctions, and 23 revascularizations). Among prognostic clinical variables, resting left ventricular function, and WM and MP data, abnormal MP at peak stress was the only independent predictor of primary outcome (hazard ratio, 4.41; 95% confidence interval, 1.37-14.20; P = .02). Sequential Cox regression models showed that abnormal MP also carried incremental prognostic value over clinical variables, resting left ventricular function and abnormal WM. CONCLUSIONS: In keeping with previous research studies, this prospective study demonstrates the incremental prognostic benefit of MP assessment beyond WM when MCE is incorporated into a clinical SE service. PMID- 26235097 TI - Chemokine (C-X-C motif) receptor 3-positive B cells link interleukin-17 inflammation to protumorigenic macrophage polarization in human hepatocellular carcinoma. AB - B cells consistently represent abundant cellular components in tumors; however, direct evidence supporting a role for B cells in the immunopathogenesis of human cancers is lacking, as is specific knowledge of their trafficking mechanisms. Here, we demonstrate that chemokine (C-X-C motif) receptor 3-positive (CXCR3(+)) B cells constitute approximately 45% of B-cell infiltrate in human hepatocellular carcinoma (HCC) and that their levels are positively correlated with early recurrence of HCC. These cells selectively accumulate at the invading edge of HCC and undergo further somatic hypermutation and immunoglobulin G-secreting plasma cell differentiation. Proinflammatory interleukin-17(+) cells are important for the induction of epithelial cell-derived CXCR3 ligands CXCL9, CXCL10, and CXCL11, which subsequently promote the sequential recruitment and further maturation of CXCR3(+) B cells. More importantly, we provide evidence that CXCR3(+) B cells, but not their CXCR3(-) counterparts, may operate in immunoglobulin G-dependent pathways to induce M2b macrophage polarization in human HCC. Depletion of B cells significantly suppresses M2b polarization and the protumorigenic activity of tumor-associated macrophages and restores the production of antitumorigenic interleukin-12 by those cells in vivo. CONCLUSION: Selective recruitment of CXCR3(+) B cells bridges proinflammatory interleukin-17 response and protumorigenic macrophage polarization in the tumor milieu, and blocking CXCR3(+) B-cell migration or function may help defeat HCC. PMID- 26235098 TI - Effect of sample preservation on stress softening and permanent set of porcine skin. AB - Skin is a composite material with a complex structure which exhibits a wide range of behaviours such as anisotropy, viscoelasticity, hyperelasticity, plasticity etc. Indeed it remains a great challenge to understand its behaviour as it is involved in many consumer and medical applications. In most studies, experiments are performed in situ or in vitro on fresh tissues but most of the time samples are preserved before testing (fridge, freezer, saline solution etc.). In this paper, the impact of samples conservation on the softening behaviour and on the permanent set is studied in order to select the appropriate conservation protocol. Samples are extracted from several pigs' abdomens (direction parallel to spine) and the mechanical testing consists in loading-unloading uniaxial tension tests instrumented with digital image correlation inducing thus reliable strain measurements in a chosen region of interest. The results of this study revealed that preservation conditions must be carefully chosen; conservation in a saline solution and freezing without any caution alter the irreversible part of the global mechanical behaviour of the tissues. PMID- 26235100 TI - [Hidradenoma papilliferum or anogenital mammary-like gland adenoma]. PMID- 26235099 TI - Voice and respiratory outcomes after permanent transoral surgery of bilateral vocal fold paralysis. AB - OBJECTIVES/HYPOTHESIS: Bilateral vocal fold paralysis (BVFP) is a rare but life threatening condition mostly caused by iatrogenic damage to the peripheral recurrent laryngeal nerve. Endoscopic enlargement techniques have been the standard treatment for decades. However, prospective studies using internationally accepted phoniatric and respiratory evaluation guidelines are rare. STUDY DESIGN: Prospective observational multicenter study. METHODS: Twelve clinical centers screened 61 patients, of whom 36 were eligible according to the study protocol. Subjects were assessed with specific phoniatric and respiratory tests preoperatively and at 1 and 6 months postoperatively. RESULTS: Important respiratory parameters improved significantly 6 months postoperatively (peak expiratory and expiratory flow), confirming that a glottal enlargement effectively reduced the obstruction. Objective parameters dealing with voice quality worsened significantly (maximum phonation time, voice range profile, hoarseness), whereas subjective voice assessment (VHI-12) did not change significantly. CONCLUSION: Endoscopic glottal enlargement is an effective method for relieving symptoms of dyspnea due to BVFP. Postoperatively, voice quality objectively worsened; however, this was not perceived by the patients themselves. Laryngostroboscopic findings did not correlate strongly with voice and respiratory outcomes. LEVEL OF EVIDENCE: 2b. PMID- 26235101 TI - Focal inhibitory seizure with prolonged deficit in adult Sturge-Weber syndrome. AB - Sturge-Weber syndrome is a sporadic congenital neurocutaneous disorder often related to varying degrees of motor impairment. The phenomenon of prolonged ictal paresis is a rare seizure sign that can be due to lesions affecting the centro parietal lobe. Focal inhibitory motor seizures can be difficult to differentiate from other clinical entities such as stroke, migraine or postictal paresis. We describe the case of a 40-year-old patient suffering from Sturge-Weber syndrome, admitted due to prolonged right-sided hemiparesis following a usual seizure. Repeated EEGs during the prolonged deficit showed only intermittent left fronto parietal sharp waves. (99m)Tc HMPAO-brain SPECT performed seven days after the last seizure showed a vast area of parieto-occipital hyperperfusion in the left hemisphere. Aggressive antiepileptic therapy dramatically improved the clinical symptoms and scintigraphic images, which corroborated the diagnosis of ictal paresis. This case highlights the role of SPECT in the evaluation of Sturge-Weber syndrome, not only to investigate progressive neurological deterioration, but also exacerbation of seizures or prolonged neurological deficits. In fact, it may be possible to document ongoing epileptic activity using SPECT, despite a non contributory EEG, which may be of help in adapting a therapeutic strategy. PMID- 26235102 TI - Maternal exercise before and during pregnancy does not impact offspring exercise or body composition in mice. AB - BACKGROUND: The genome, the environment, and their interactions simultaneously regulate complex traits such as body composition and voluntary exercise levels. One such environmental influence is the maternal milieu (i.e., in utero environment or maternal care). Variability in the maternal environment may directly impact the mother, and simultaneously has the potential to influence the physiology and/or behavior of offspring in utero, post birth, and into adulthood. Here, we utilized a murine model to examine the effects of the maternal environment in regard to voluntary exercise (absence of wheel running, wheel running prior to gestation, and wheel running prior to and throughout gestation) on offspring weight and body composition (% fat tissue and % lean tissue) throughout development (~3 to ~9 weeks of age). Additionally, we examined the effects of ~6 weeks of maternal exercise (prior to and during gestation) on offspring exercise levels at ~9 weeks of age. RESULTS: We observed no substantial effects of maternal exercise on subsequent male or female offspring body composition throughout development, or on the propensity of offspring to engage in voluntary wheel running. At the level of the individual, correlational analyses revealed some statistically significant relationships between maternal and offspring exercise levels, likely reflecting previously known heritability estimates for such traits. CONCLUSIONS: The current results conflict with previous findings in human and mouse models demonstrating that maternal exercise has the potential to alter offspring phenotypes. We discuss our negative findings in the context of the timing of the maternal exercise and the level of biological organization of the examined phenotypes within the offspring. PMID- 26235104 TI - Institutional factors in the management of adults with diabetic ketoacidosis in the UK: results of a national survey. PMID- 26235103 TI - Detection and Differentiation of Threonine- and Tyrosine-Monophosphorylated Forms of ERK1/2 by Capillary Isoelectric Focusing-Immunoassay. AB - The extracellular signal regulated kinases ERK1/2 play important roles in the regulation of diverse cellular functions and have been implicated in several human diseases. In addition to the fully activated, diphosphorylated ERK1/2 protein, monophosphorylated forms of ERK1/2 have been observed, which may have distinct biological functions. We report here on the highly sensitive detection and differentiation of unphosphorylated, threonine-phosphorylated (pT), tyrosine phosphorylated (pY) and diphosphorylated ERK1 and ERK2 by capillary isoelectric focusing followed by immunological detection (CIEF-immunoassay). Eight different phosphorylated and unphosphorylated forms of ERK1/2 were resolved according to charge. The unequivocal identification and differentiation of ERK1 and ERK2 forms monophosphorylated at either threonine or tyrosine was achieved by competitive blocking with specific phospho-peptides and different phosphorylation-sensitive antibodies. The suitability of the additional pT-ERK1/2 and pY-ERK1/2 differentiation for the time-resolved in-depth study of phospho-form distribution in response to specific stimuli is demonstrated in human neuroblastoma SH-SY5Y and monocytic THP-1 cell lines, and in human peripheral blood mononuclear cells. PMID- 26235105 TI - Predicting near-UV electronic circular dichroism in nucleosomal DNA by means of DFT response theory. AB - It is demonstrated that time-dependent density functional theory (DFT) calculations can accurately predict changes in near-UV electronic circular dichroism (ECD) spectra of DNA as the structure is altered from the linear (free) B-DNA form to the supercoiled N-DNA form found in nucleosome core particles. At the DFT/B3LYP level of theory, the ECD signal response is reduced by a factor of 6.7 in going from the B-DNA to the N-DNA form, and it is illustrated how more than 90% of the individual base-pair dimers contribute to this strong hypochromic effect. Of the several inter-base pair parameters, an increase in twist angles is identified as to strongly contribute to a reduced ellipticity. The present work provides first evidence that first-principles calculations can elucidate changes in DNA dichroism due to the supramolecular organization of the nucleoprotein particle and associates these changes with the local structural features of nucleosomal DNA. PMID- 26235106 TI - Images of flight nursing in Australia: A study using institutional ethnography. AB - Pictures speak a thousand words. The traditional romantic image of an Australian aeromedical service is a male doctor and male pilot, out to rescue the male stockman from the red dust of the Australian outback. However, the reality is considerably different, particularly in the current context of the Australian healthcare system. This paper examines the images of flight nursing using a critical lens. The images are derived from popular literature sources from the early 1940s through to the present. A textual analysis of the images of flight nursing using the methodology of institutional ethnography reveals a number of themes including the glamorous, the romantic, and the heroic nurse. This study illustrates that the way these nurses are portrayed within popular literature mirrors the Australian cultural ethic of heroic bush pioneer, yet at the same time the work these nurses do is undervalued by various omissions and misrepresentations. The results from this study have the potential to significantly improve recognition of the work performed by flight nurses and to challenge incorrect cultural myths. PMID- 26235107 TI - Phosphatase-mediated bioprecipitation of lead by soil fungi. AB - Geoactive soil fungi were examined for their ability to release inorganic phosphate (Pi ) and mediate lead bioprecipitation during growth on organic phosphate substrates. Aspergillus niger and Paecilomyces javanicus grew in 5 mM Pb(NO3)2-containing media amended with glycerol 2-phosphate (G2P) or phytic acid (PyA) as sole P sources, and liberated Pi into the medium. This resulted in almost complete removal of Pb from solution and extensive precipitation of lead containing minerals around the biomass, confirming the importance of the mycelium as a reactive network for biomineralization. The minerals were identified as pyromorphite (Pb5(PO4)3Cl), only produced by P. javanicus, and lead oxalate (PbC2O4), produced by A. niger and P. javanicus. Geochemical modelling of lead and lead mineral speciation as a function of pH and oxalate closely correlated with experimental conditions and data. Two main lead biomineralization mechanisms were therefore distinguished: pyromorphite formation depending on organic phosphate hydrolysis and lead oxalate formation depending on oxalate excretion. This also indicated species specificity in biomineralization depending on nutrition and physiology. Our findings provide further understanding of lead geomycology and organic phosphates as a biomineralization substrate, and are also relevant to metal immobilization biotechnologies for bioremediation, metal and P biorecovery, and utilization of waste organic phosphates. PMID- 26235109 TI - Charge carrier mobilities in organic semiconductors: crystal engineering and the importance of molecular contacts. AB - We have conducted a combined experimental and theoretical study on the optimization of hexa-peri-hexabenzocoronene (HBC) as organic semiconductor. While orientations with high electronic coupling are unfavorable in the native liquid crystalline phase of HBC, we enforced such orientations by applying external constraints. To this end, self-assembled monolayers (SAMs) were formed by a non conventional preparation method on an Au-substrate using electrochemical control. Within these SAMs the HBC units are forced into favorable orientations that cannot be achieved by unconstrained crystallization. For simulating the charge transport we applied a recently developed approach, where the molecular structure and the charge carrier are propagated simultaneously during a molecular dynamics simulation. Experiments as well as simulations are mutually supportive of an improved mobility in these novel materials. The implication of these findings for a rational design of future organic semiconductors will be discussed. PMID- 26235108 TI - Right radial artery pulse loss after transesophageal echocardiography probe insertion in an infant with an aberrant right subclavian artery. PMID- 26235110 TI - Effects of local application of methylprednisolone delivered by the C/GP-hydrogel on the recovery of facial nerves. AB - CONCLUSIONS: Local administration of MP delivered by the C/GP-MP-hydrogel can improve the recovery of facial nerve following crush injury. The findings suggested that locally injected MP delivered by C/GP-hydrogel might be a promising treatment for facial nerve damage. OBJECTIVES: In this study, the aim is to assess the effectiveness of locally administrating methylprednisolone(MP) loaded by chitosan-beta-glycerophosphate hydrogel (C/GP-hydrogel) on the regeneration of facial nerve crush injury. METHODS: After the crush of left facial nerves, Wistar rats were randomly divided into four different groups. Then, four different therapies were used to treat the damaged facial nerves. At the 1(st), 2(nd), 3(rd), and 4(th) week after injury, the functional recovery of facial nerves and the morphological changes of facial nerves were assessed. The expression of growth associated protein-43 (GAP-43) protein in the facial nucleus were also evaluated. RESULTS: Locally injected MP delivered by C/GP-hydrogel effectively accelerated the facial functional recovery. In addition, the regenerated facial nerves in the C/GP-MP group were more mature than those in the other groups. The expression of GAP-43 protein was also improved by the MP, especially in the C/GP-MP group. PMID- 26235111 TI - Enantioselective comprehensive two-dimensional gas chromatography. A route to elucidate the authenticity and origin of Rosa damascena Miller essential oils. AB - The analysis of Bulgarian and Turkish Rosa damascena Miller essential oils was performed by flow-modulated comprehensive two-dimensional gas chromatography using simultaneous detection of the second column effluent by flame ionization and quadrupole mass spectrometric detection. Enantioselective separations were obtained by running the samples on 2,3-di-O-ethyl-6-O-tert-butyldimethylsilyl beta-cyclodextrin column as the first column and on polyethylene glycol as the second column. The determination of enantiomeric or diastereomeric excess of some terpenoic solutes is a possible route for quality or authenticity control as well as for the elucidation of the country of origin. PMID- 26235112 TI - Generation of catalytically active materials from a liquid metal precursor. AB - A facile route to prepare catalytically active materials from a galinstan liquid metal alloy is introduced. Sonicating liquid galinstan in alkaline solution or treating it in reducing media results in the creation of solid In/Sn rich microspheres that show catalytic activity toward both potassium ferricyanide and 4-nitrophenol reduction. PMID- 26235115 TI - Surgical simulation stimulation. PMID- 26235116 TI - How it so? PMID- 26235117 TI - Re. Shining light in dark corners: Diagnosis and management of late-onset fetal growth restriction. ANZJOG 2015; 55(1):3-10. Author response (I). PMID- 26235118 TI - Re: Diagnosis and management of late-onset fetal growth restriction. PMID- 26235119 TI - Re. Shining light in dark corners: Diagnosis and management of late-onset fetal growth restriction. ANZJOG 2015; 55(1):3-10. Author response (II). PMID- 26235120 TI - Theory of Kerr and Faraday rotations and linear dichroism in Topological Weyl Semimetals. AB - We consider the electromagnetic response of a topological Weyl semimetal (TWS) with a pair of Weyl nodes in the bulk and corresponding Fermi arcs in the surface Brillouin zone. We compute the frequency-dependent complex conductivities sigmaalphabeta(omega) and also take into account the modification of Maxwell equations by the topological theta-term to obtain the Kerr and Faraday rotations in a variety of geometries. For TWS films thinner than the wavelength, the Kerr and Faraday rotations, determined by the separation between Weyl nodes, are significantly larger than in topological insulators. In thicker films, the Kerr and Faraday angles can be enhanced by choice of film thickness and substrate refractive index. We show that, for radiation incident on a surface with Fermi arcs, there is no Kerr or Faraday rotation but the electric field develops a longitudinal component inside the TWS, and there is linear dichroism signal. Our results have implications for probing the TWS phase in various experimental systems. PMID- 26235122 TI - Corrigendum: Cu/Fe-Cocatalyzed Formation of beta-Ketophosphonates by a Domino Knoevenagel-Decarboxylation-Oxyphosphorylation Sequence from Aromatic Aldehydes and H-Phosphonates. PMID- 26235126 TI - Apoptosis progression studied using parallel dielectrophoresis electrophysiological analysis and flow cytometry. AB - Apoptosis is characterised by many cellular events, but the standard Annexin-V assay identifies two; the transfer of the phospholipid phosphatidylserine (PS) from inner to outer leaflets of the plasma membrane, acting as an "eat me" signal to macrophages, and the permeabilisation of the plasma membrane. In this paper we compare the results from the Annexin-V assay with electrophysiology data obtained in parallel using dielectrophoresis, which highlights two changes in cell electrophysiology; a change in cytoplasmic conductivity which correlates with PS expression, and a membrane conductance spike that correlates with permeabilisation. Combining results from both methods shows a strong inverse relationship between conductivity and PS externalisation. One mechanism which may explain this correlation is related to intracellular Ca(2+), which is known to increase early in apoptosis. PS expression occurs when enzymes called scramblases swap external and internal phospholipids, and which are usually activated by Ca(2+), whilst the change in cytoplasmic conductivity may be due to K(+) efflux from intermediate conductance (IK) ion channels that are also activated by Ca(2+). PMID- 26235127 TI - Characterization of Porous Materials by Fluorescence Correlation Spectroscopy Super-resolution Optical Fluctuation Imaging. AB - Porous materials such as cellular cytosol, hydrogels, and block copolymers have nanoscale features that determine macroscale properties. Characterizing the structure of nanopores is difficult with current techniques due to imaging, sample preparation, and computational challenges. We produce a super-resolution optical image that simultaneously characterizes the nanometer dimensions of and diffusion dynamics within porous structures by correlating stochastic fluctuations from diffusing fluorescent probes in the pores of the sample, dubbed here as "fluorescence correlation spectroscopy super-resolution optical fluctuation imaging" or "fcsSOFI". Simulations demonstrate that structural features and diffusion properties can be accurately obtained at sub-diffraction limited resolution. We apply our technique to image agarose hydrogels and aqueous lyotropic liquid crystal gels. The heterogeneous pore resolution is improved by up to a factor of 2, and diffusion coefficients are accurately obtained through our method compared to diffraction-limited fluorescence imaging and single particle tracking. Moreover, fcsSOFI allows for rapid and high-throughput characterization of porous materials. fcsSOFI could be applied to soft porous environments such hydrogels, polymers, and membranes in addition to hard materials such as zeolites and mesoporous silica. PMID- 26235128 TI - Magnetic mediation effect of a C impurity in a Mn-doped Zn12O12 nanocluster: a case of multiple exchange interactions. AB - The stability and exchange interaction mechanism of a doped Zn12O12 cluster with Mn and C atoms were investigated by first-principles calculations. For the Mn doped Zn12O12 cluster, it is identified that a superexchange interaction deriving the hybridization between the Mn 3d(2/x)-2/y and O 2p(xy) orbitals dominates the Mn(?)-Mn(?) antiferromagnetic coupling, although a direct exchange interaction deriving the Mn-Mn bonding is also found. In order to turn the Mn spin state in the Mn-doped Zn12O12 cluster, C doping is undertaken to change the magnetic interactions of these impurities. It is proved that the C incorporation into the Mn-doped Zn12O12 cluster destroys the short-ranged antiferromagnetic coupling, where multiple exchange interactions take over, including the direct exchange interaction and the kinetic p-d exchange interaction partially due to the geometric distortion and surface effect with dangling bonds (sp(2)-like hybrids). It is concluded that the kinetic p-d exchange interaction plays a dominant role in Mn/C-doped Zn12O12 clusters. PMID- 26235130 TI - Live cell imaging of SOS and prophage dynamics in isogenic bacterial populations. AB - Almost all bacterial genomes contain DNA of viral origin, including functional prophages or degenerated phage elements. A frequent but often unnoted phenomenon is the spontaneous induction of prophage elements (SPI) even in the absence of an external stimulus. In this study, we have analyzed SPI of the large, degenerated prophage CGP3 (187 kbp), which is integrated into the genome of the Gram-positive Corynebacterium glutamicum ATCC 13032. Time-lapse fluorescence microscopy of fluorescent reporter strains grown in microfluidic chips revealed the sporadic induction of the SOS response as a prominent trigger of CGP3 SPI but also displayed a considerable fraction (~30%) of RecA-independent SPI. Whereas approx. 20% of SOS-induced cells recovered from this stress and resumed growth, the spontaneous induction of CGP3 always led to a stop of growth and likely cell death. A carbon source starvation experiment clearly emphasized that SPI only occurs in actively proliferating cells, whereas sporadic SOS induction was still observed in resting cells. These data highlight the impact of sporadic DNA damage on the activity of prophage elements and provide a time-resolved, quantitative description of SPI as general phenomenon of bacterial populations. PMID- 26235131 TI - Convergent validity of the Timed Up and Go Test and Ten-metre Timed Walk Test in pregnant women with pelvic girdle pain. AB - Pregnant women with pelvic girdle pain (PGP) often experience functional difficulties, in particular walking difficulties. Currently, however, there is a lack of validated performance-orientated outcome measures available for use in this population. The Timed Up and Go (TUG) test and Ten-metre Timed Walk Test (10 mTWT) are two short-distance walking tests that have demonstrated reliability in pregnant women with PGP, but as yet have no established validity. The aim of the present study was to evaluate the convergent validity of the TUG and 10 mTWT by comparing performances on these two walking tests with scores achieved on the Active Straight Leg Raise (ASLR) test and the Pelvic Girdle Questionnaire (PGQ). Eighteen pregnant women with PGP aged 31.4 years (SD = 2.7) and 28.9 weeks pregnant (SD = 7.3) were included. Spearman rank correlation coefficient (rs) was used to determine convergent validity. Strong correlations were found between the TUG and ASLR (rs = 0.73, p = 0.001), and the 10 mTWT and ASLR (rs = -0.65, p = 0.003). Relationships between the TUG and PGQ were moderate (rs = 0.41 to 0.52) and between the 10 mTWT and PGQ low to moderate (rs = -0.25 to -0.56). The strong relationships between the walking tests and the ASLR may suggest these tests all assess the same construct. The weaker relationships found between the walking tests and the PGQ may be related to the self-report and multiple functional activities nature of the questionnaire. This study found both the TUG and 10 mTWT to be valid weight-bearing physical performance measures, although more research is warranted due to the small study sample. PMID- 26235132 TI - Lipid A-activated inducible nitric oxide synthase expression via nuclear factor kappaB in mouse choroid plexus cells. AB - Choroid plexus (CP) which is responsible for the inflammatory mediators including nitric oxide (NO) are thought to play a crucial role in the process of bacterial meningitis. The present study investigated the mechanisms regulating inducible nitric oxide synthase (iNOS) expression in the choroid plexus epithelium (CPe) in mice. Initially, the expression of iNOS in mouse CPe was strengthened by intracerebroventriclar (i.c.v.) administration of lipid A, which is part of a Gram-negative bacterial endotoxin located at one end of the lipopolysaccharide (LPS) molecule. Next, the expression of iNOS in the CP epithelial cell line ECPC 4 cells was increased from 24 to 48h after lipid A treatment, although mRNA and proteins of toll-like receptor (TLR)-2 and -4 expressed in ECPC-4 cells were not changed by lipid A. The expression of total nuclear factor kappaB (NFkappaB), an inflammatory transcriptional factor, in ECPC-4 cells was not changed for 72 h after lipid A treatment, while cytoplasmic NFkappaB was decreased and nuclear NFkappaB was increased from 1 to 2 h. In addition, the phosphorylation of inhibitor kappaB (IkappaB) was peaked at 10 min, and the level of IkappaB was attenuated from 10 to 45 min after lipid A treatment. Moreover, the RNA interference (RNAi) of NFkappaB suppressed the expression of iNOS induced by lipid A. We demonstrated that lipid A-induced iNOS expression in ECPC-4 cells was mainly regulated by the activation of NFkappaB-IkappaB intracellular signaling pathway. Thus, we propose that the CPe plays a pivotal role in innate immunity responses of the brain, that is, the signal pathway TLRs on the CPe following inflammatory stimulation such as meningitis is activated, leading to iNOS expression through NFkappaB. PMID- 26235133 TI - Chlorisondamine, a sympathetic ganglionic blocker, moderates the effects of whole body irradiation (WBI) on early host defense to a live bacterial challenge. AB - There is a growing consensus that long-term deficits in the brain are due to dynamic interactions between multiple neural and immune cell types. Specifically, radiation induces an inflammatory response, including changes in neuromodulatory pro- and anti-inflammatory cytokine secretion. The purpose of this study was to establish that there is sympathetic involvement in radiation-induced decrements early in in vivo immune function host defense. Female, 8-9 week-old C57BL/6J mice were exposed to whole-body irradiation (WBI). There were 8 groups with radiation (0 vs. 3 Gy protons), immune challenge (Escherichia coli) and exposure to the sympathetic ganglionic blocker, chlorisondamine (1 mg/kg weight, i.p.), as independent variables. Ten days post-irradiation, mice were inoculated with E. coli intraperitoneally and sacrificed 90-120 min later. The data suggest that radiation-induced changes in immune function may in part be mediated by the sympathetic nervous system. Briefly, we found that radiation augments the bacteria-induced inflammatory cytokine response, particularly those cytokines involved in innate immunity. However, this augmentation can be reduced by the ganglionic blockade. PMID- 26235134 TI - The ultrasonographic evaluation of hemodynamic changes in patients with diabetic polyneuropathy after tarsal tunnel decompression. AB - BACKGROUND: Nerve decompression procedures have shown to have promising roles in patients with diabetic polyneuropathy. It is known that not only nerves but also arteries pass through the same compressed anatomical tunnels. The aim of the study is to reveal whether the surgical decompression procedures have a positive effect on hemodynamic and morphological parameters of the arterial structures passing through these anatomic tunnels. METHODS: Twenty-seven patients who underwent posterior and anterior tarsal tunnel release procedures were retrospectively scanned for preoperative and 3 months postoperative arterial Doppler ultrasound imaging. The preoperative and third month postoperative measurements were compared for flow pattern of artery, flow lumen diameter, pulsatility index (PI), resistance index (RI), and flow volumes by evaluating the hemodynamic and morphological parameters of dorsalis pedis (DPA) and tibialis posterior arteries (TPA). RESULTS: For TPA, mean PI values were 5.76 +/- 2.78 preoperatively, 7.17 +/- 3.08 postoperatively. Mean RI values were 0.94 +/- 0.04 preoperatively and 0.89 +/- 0.05 postoperatively. For DPA, mean PI values were 5.06 +/- 2.14 preoperatively and 6.35 +/- 2.31 postoperatively. Mean RI values were 0.93 +/- 0.05 preoperatively and 0.86 +/- 0.06 postoperatively. When the results are analyzed for both of the arteries, PI values were significantly increased; RI values were significantly decreased when the preoperative measurements were compared with the postoperative measurements (P < 0.05). CONCLUSION: According to these results, it can be suggested that the nerve release procedures have a positive effect on the hemodynamic and morphological parameters of the arteries as they pass through the anatomical tunnels as well as its positive effects on the neurological functions of the entrapped nerves. PMID- 26235135 TI - Bioassay case study applying the maximin D-optimal design algorithm to the four parameter logistic model. AB - Cell-based potency assays play an important role in the characterization of biopharmaceuticals but they can be challenging to develop in part because of greater inherent variability than other analytical methods. Our objective is to select concentrations on a dose-response curve that will enhance assay robustness. We apply the maximin D-optimal design concept to the four-parameter logistic (4 PL) model and then derive and compute the maximin D-optimal design for a challenging bioassay using curves representative of assay variation. The selected concentration points from this 'best worst case' design adequately fit a variety of 4 PL shapes and demonstrate improved robustness. PMID- 26235136 TI - Innate positive chemotaxis to pollen from crops and banker plants in predaceous biological control agents: towards new field lures? AB - Predator-prey interactions form the core of biological control of arthropod pests. Which tools can be used to monitor and collect carnivorous arthropods in natural habitats and targeted crops? Eco-friendly and effective field lures are urgently needed. In this research, we carried out olfactometer experiments assess innate positive chemotaxis to pollen of seven crop and banker plant by two important predatory biological control agents: the coccinellid Propylea japonica (Thunberg) and the anthocorid Orius sauteri (Poppius). We compared the attractiveness of pollens from crops and banker plants to that of common prey homogenates (aphids and thrips, respectively). Attractiveness of the tested odor sources was checked via field trapping experiments conducted in organic apple orchards and by release-recapture assays in organic greenhouse tomato crops. Maize and canola pollen were attractive to both P. japonica and O. sauteri, in laboratory and field assays. P. japonica was highly attracted by balm mint pollen, whereas O. sauteri was attracted by alfalfa pollen. Our results encourage the use of pollen from crops and banker plants as low-cost and eco-friendly attractors to enhance the monitoring and attraction of arthropod predators in biological control programs. PMID- 26235137 TI - A squaraine-based colorimetric and F(-) dependent chemosensor for recyclable CO2 gas detection: highly sensitive off-on-off response. AB - An unsymmetrical squaraine-based chemosensor SH2 has been synthesized, and its sensing behavior towards CO2 gas was described in detail by UV-vis and (1)H NMR spectroscopies in DMSO. The results indicated that the extremely sensitive "naked eye" CO2 gas detection can be operated in the presence of excess [Bu4N]F (TBAF) and the sensor is easy to recycle. These properties enable SH2 to act as a CO2 and F(-) controlled "OFF-ON-OFF" switch. Combining theoretical analyses, a plausible sensing mechanism was proposed to illustrate how the receptor SH2 works as a CO2 sensitive and selective colorimetric probe in the present system. PMID- 26235138 TI - A new metric for centralization of ruptured abdominal aortic aneurysm repair in large territories. AB - OBJECTIVE: This study proposes the DEDE (Door-from-Emergency to Door-to-EVAR [endovascular aneurysm repair]) time as a new metric for ruptured abdominal aortic aneurysm (RAAA) delay time to surgery, permitting coherent centralization in large territories. It demonstrates how the DEDE time can be applied, using data from the province of Quebec, and looks at its potential effect on 30-day mortality. METHODS: We used the Quebec Integrated Chronic Disease Surveillance System (QICDSS), the linkage of five health administrative databases, to build a retrospective cohort of RAAA patients repaired operatively between April 1, 2006, and March 31, 2013. A validated algorithm was used to identify open surgical repair (OSR) and EVAR patients. Hospitals performing these operations were further characterized according to their location, volume of RAAA, types of surgeries (OSR vs EVAR), and surgeon's volume. Logistic and log-binomial regression analyses identified the risk of 30-day mortality with age, sex, hospital volume, and surgical groups as variables. Using the DEDE 90 metric and the attributable fraction, we projected how centralization and increasing the number of EVAR would affect the 30-day mortality. RESULTS: Among patients aged >=65 years, 895 RAAAs were identified. OSR was performed in 839 patients (93.7%) and EVAR in 56 (6.3%). The overall 30-day mortality was 34.4%, and more specifically, was 35.5% for OSR compared with 17.9% for EVAR (P = .0046). RAAAs were treated in 39 hospitals, including 16 centers averaging less than one RAAA repair per year. Low-volume (39.4%) vs high-volume centers (32.5%) had similar 30 day mortality (P = .2198). In the multivariate analysis, the relative risk for OSR was 1.95 (P = .0211) and was not significant for hospital volume. Applying the DEDE 90 metric and increasing access to EVAR to 50% of patients, the overall 30-day mortality would be 26.8%. CONCLUSIONS: DEDE 90 is a new metric for a coherent centralization model, particularly in large territories, where transport time is crucial. Increasing access to EVAR performed in high-volume centers, with consideration to transport time, could improve the 30-day mortality after a RAAA repair. PMID- 26235140 TI - Dietary flavonoid fisetin binds to beta-tubulin and disrupts microtubule dynamics in prostate cancer cells. AB - Microtubule targeting based therapies have revolutionized cancer treatment; however, resistance and side effects remain a major limitation. Therefore, novel strategies that can overcome these limitations are urgently needed. We made a novel discovery that fisetin, a hydroxyflavone, is a microtubule stabilizing agent. Fisetin binds to tubulin and stabilizes microtubules with binding characteristics far superior than paclitaxel. Surface plasmon resonance and computational docking studies suggested that fisetin binds to beta-tubulin with superior affinity compared to paclitaxel. Fisetin treatment of human prostate cancer cells resulted in robust up-regulation of microtubule associated proteins (MAP)-2 and -4. In addition, fisetin treated cells were enriched in alpha-tubulin acetylation, an indication of stabilization of microtubules. Fisetin significantly inhibited PCa cell proliferation, migration, and invasion. Nudc, a protein associated with microtubule motor dynein/dynactin complex that regulates microtubule dynamics, was inhibited with fisetin treatment. Further, fisetin treatment of a P-glycoprotein overexpressing multidrug-resistant cancer cell line NCI/ADR-RES inhibited the viability and colony formation. Our results offer in vitro proof-of-concept for fisetin as a microtubule targeting agent. We suggest that fisetin could be developed as an adjuvant for treatment of prostate and other cancer types. PMID- 26235141 TI - Wakeful rest promotes the integration of spatial memories into accurate cognitive maps. AB - Flexible spatial navigation, e.g. the ability to take novel shortcuts, is contingent upon accurate mental representations of environments-cognitive maps. These cognitive maps critically depend on hippocampal place cells. In rodents, place cells replay recently travelled routes, especially during periods of behavioural inactivity (sleep/wakeful rest). This neural replay is hypothesised to promote not only the consolidation of specific experiences, but also their wider integration, e.g. into accurate cognitive maps. In humans, rest promotes the consolidation of specific experiences, but the effect of rest on the wider integration of memories remained unknown. In the present study, we examined the hypothesis that cognitive map formation is supported by rest-related integration of new spatial memories. We predicted that if wakeful rest supports cognitive map formation, then rest should enhance knowledge of overarching spatial relations that were never experienced directly during recent navigation. Forty young participants learned a route through a virtual environment before either resting wakefully or engaging in an unrelated perceptual task for 10 min. Participants in the wakeful rest condition performed more accurately in a delayed cognitive map test, requiring the pointing to landmarks from a range of locations. Importantly, the benefit of rest could not be explained by active rehearsal, but can be attributed to the promotion of consolidation-related activity. These findings (i) resonate with the demonstration of hippocampal replay in rodents, and (ii) provide the first evidence that wakeful rest can improve the integration of new spatial memories in humans, a function that has, hitherto, been associated with sleep. PMID- 26235139 TI - Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth. AB - The bone morphogenetic protein (BMP) pathway belonging to the Transforming Growth Factor beta (TGFbeta) family of secreted cytokines/growth factors is an important regulator of cancer. BMP ligands have been shown to play both tumor suppressive and promoting roles in human cancers. We have found that BMP ligands are amplified in human ovarian cancers and that BMP receptor expression correlates with poor progression-free-survival (PFS). Furthermore, active BMP signaling has been observed in human ovarian cancer tissue. We also determined that ovarian cancer cell lines have active BMP signaling in a cell autonomous fashion. Inhibition of BMP signaling with a small molecule receptor kinase antagonist is effective at reducing ovarian tumor sphere growth. Furthermore, BMP inhibition can enhance sensitivity to Cisplatin treatment and regulates gene expression involved in platinum resistance in ovarian cancer. Overall, these studies suggest targeting the BMP pathway as a novel source to enhance chemo-sensitivity in ovarian cancer. PMID- 26235142 TI - Volumetric-modulated arc stereotactic body radiotherapy for prostate cancer: dosimetric impact of an increased near-maximum target dose and of a rectal spacer. AB - OBJECTIVE: In volumetric-modulated arc therapy (VMAT) prostate stereotactic body radiotherapy (SBRT), dose coverage of the planning target volume (PTV) becomes challenging when the sparing of rectum, bladder and urethra is strictly pursued. Our current 35-Gy-in-five-fraction plans only assure 33.2 Gy to >=95% PTV ([Formula: see text] >= 95%). Looking for an improved [Formula: see text], increased near-maximum target dose (D2%) and prostate-rectum spacer insertion were tested. METHODS: For 11 patients, two VMAT plans, with D2% <= 37.5 Gy (Hom) or D2% <= 40.2 Gy (Het), on each of two CT studies, before or after spacer insertion, were computed. All plans assured [Formula: see text] >=95%, and <1 cm(3) of rectum, bladder and urethra receiving >=35 Gy. By hypothesis testing, several dose-volume metrics for target coverage and rectal sparing were compared across the four groups of plans. The impact of spacer insertion on the fractions of rectum receiving more than 18, 28 and 32 Gy ([Formula: see text]) was further tested by linear correlation analysis. RESULTS: By hypothesis testing, the increased D2% was associated with improvements in target coverage, whereas spacer insertion was associated with improvements in both target coverage and rectal [Formula: see text]. By linear correlation analysis, spacer insertion was related to the reductions in rectal [Formula: see text] for X >= 28 Gy. CONCLUSION: A slightly increased D2% or the use of spacer insertion was each able to improve [Formula: see text]. Their combined use assured [Formula: see text] >= 98% to all our patients. Spacer insertion was further causative for improvements in rectal sparing. ADVANCES IN KNOWLEDGE: For VMAT plans in prostate SBRT, the distinct dosimetric usefulness of increased D2% and of the use of spacer insertion were validated in terms of target coverage and rectal sparing. PMID- 26235143 TI - A comparison of high b-value vs standard b-value diffusion-weighted magnetic resonance imaging at 3.0 T for medulloblastomas. AB - OBJECTIVE: To investigate the utility of diffusion-weighted (DW) MRI using high b value vs standard b-value for patients with medulloblastoma (MB). Minimum apparent diffusion coefficient (ADCMIN) values were also compared with tumour cellularity. METHODS: High and standard b-value DW images were obtained for 17 patients with MB. The number and location of the lesions, signal intensities (SIs), signal-to-noise ratios (SNRs), contrast-to-noise ratios, contrast ratios (CRs) and ADCs of the lesions were compared. Tumour cellularity was also measured and compared with ADCMIN values. RESULTS: All 20 lesions were hyperintense on the DW MR images with high and standard b-values. Four additional lesions were revealed on high b-value, and all 24 lesions were more conspicuous at high b value. SI, SNR and ADC values for the lesions were lower in the high b-value images than in the standard b-value images. The ADCMIN value at b = 3000 s mm(-2) was more significantly associated with tumour cellularity than that at b = 1000 s mm(-2). CR values were significantly higher in the high b-value images than in the standard b-value images. CONCLUSION: DW imaging using high b-value may be beneficial for detecting additional, less prominent lesions and may improve the contrast between MB lesions and normal tissue. A stronger inverse correlation with tumour cellularity was identified using the ADCMIN values at high b-value. ADVANCES IN KNOWLEDGE: This study demonstrates the superiority of high b-value DW imaging compared with standard b-value imaging for the detection of MB lesions, especially those with subtle foci. PMID- 26235145 TI - McArdle disease: 2 case reports. AB - A high serum level of creatine kinase (CK) is a common reason for referring to medical specialities. Myopathies are one of the causes of elevated levels of CK. McArdle disease is the most common disorder of skeletal muscle carbohydrate metabolism. The cases are presented on 2 patients who were referred to our medical consultation to study the cause of their increased CK levels: a 72 year old asymptomatic man with high levels of CK detected by chance in a routine analysis, and a 30 year old woman with very few symptoms, apart from slight muscle pain and tiredness. Electromyography was normal in both patients. There was null activity of myophosphorylase in muscle biopsy of both cases, so a diagnosis of McArdle disease was made. PMID- 26235144 TI - Paediatric musculoskeletal interventional radiology. AB - Interventional radiology technique is now well established and widely used in the adult population. Through minimally invasive procedures, it increasingly replaces surgical interventions that involve higher percentages of invasiveness and, consequently, of morbidity and mortality. For these advantageous reasons, interventional radiology in recent years has spread to the paediatric age as well. The aim of this study was to review the literature on the development, use and perspectives of these procedures in the paediatric musculoskeletal field. Several topics are covered: osteomuscle neoplastic malignant and benign pathologies treated with invasive diagnostic and/or therapeutic procedures such as radiofrequency ablation in the osteoid osteoma; invasive and non-invasive procedures in vascular malformations; treatment of aneurysmal bone cysts; and role of interventional radiology in paediatric inflammatory and rheumatic inflammations. The positive results that have been generated with interventional radiology procedures in the paediatric field highly encourage both the development of new ad hoc materials, obviously adapted to young patients, as well as the improvement of such techniques, in consideration of the fact that childrens' pathologies do not always correspond to those of adults. In conclusion, as these interventional procedures have proven to be less invasive, with lower morbidity and mortality rates as well, they are becoming a viable and valid alternative to surgery in the paediatric population. PMID- 26235146 TI - Reliability of ultrasound texture measures of Biceps Brachialis and Gastrocnemius Lateralis muscles' images. AB - Ultrasound (US) is an important tool for diagnosing of many musculoskeletal tissue conditions. Image texture analysis can be used to characterize this tissue. The complexity curve (CC) is a technique commonly used to characterize the number of grey-level transitions in an image. Variability and reliability of US texture measures in the muscle tissue are unavailable in the literature. The aim of this study was to determine the variability and reliability of five CC texture parameters from US images of healthy Biceps Brachialis and Gastrocnemius Lateralis (GL) muscles, with longitudinal and transversal orientations of the probe. Eight images per subject were obtained for 30 men in 2 days. Mean, standard deviation, coefficient of variation and intraclass correlation coefficient for the five parameters were calculated for regions of interest. Results showed that the variability was similar for both muscles and most of the parameters showed satisfactory reliability (r > 0.7) for the Biceps Brachialis with the transverse scan and for the GL with the longitudinal scan. PMID- 26235147 TI - STING Activation by Translocation from the ER Is Associated with Infection and Autoinflammatory Disease. AB - STING is an ER-associated membrane protein that is critical for innate immune sensing of pathogens. STING-mediated activation of the IFN-I pathway through the TBK1/IRF3 signaling axis involves both cyclic-dinucleotide binding and its translocation from the ER to vesicles. However, how these events are coordinated, and the exact mechanism of STING activation, remain poorly understood. Here, we found that the Shigella effector protein IpaJ potently inhibits STING signaling by blocking its translocation from the ER to ERGIC, even in the context of dinucleotide binding. Reconstitution using purified components revealed STING translocation as the rate-limiting event in maximal signal transduction. Furthermore, STING mutations associated with autoimmunity in humans were found to cause constitutive ER exit and to activate STING independent of cGAMP binding. Together, these data provide compelling evidence for an ER retention and ERGIC/Golgi-trafficking mechanism of STING regulation that is subverted by bacterial pathogens and is deregulated in human genetic disease. PMID- 26235148 TI - Views of general practitioners and head and neck surgeons on the referral system for suspected cancer: a survey. AB - BACKGROUND: The two-week wait referral system for suspected cancer was introduced in the National Health Service in 2000. This study aimed to identify areas for improvement to the two-week wait system by seeking the opinions of doctors working in primary and secondary care. METHOD: A questionnaire was distributed to general practitioners and head and neck surgeons within North West England with ethical consent. RESULTS: Twenty-seven general practitioners and 15 head and neck surgeons responded. Of the general practitioners, 59.3 per cent declared that they never attend training on referrals in this specialty. Overall, 59.3 per cent of general practitioners and 86.7 per cent of head and neck surgeons felt that the two-week wait system could be improved. CONCLUSION: The main areas for further work are development of pre-referral communication between primary and secondary care along with development of practical educational measures for general practitioners. PMID- 26235149 TI - Structural evolution analysis and cold-crystallization kinetics of spherical crystals in poly(trimethylene terephthalate) film using Raman spectroscopy. AB - Dynamic processes and the structural evolution of cold-crystallized poly(trimethylene terephthalate) (PTT) film were investigated using Raman spectroscopy. Raman scattering of C[double bond, length as m-dash]O stretching vibration was related to the molecular chain movement and structure evolution in PTT during cold crystallization. In particular, information about each phase of crystallization, including induction, nucleation, nucleus growth, and secondary crystallization, was thoroughly revealed. The experimental results indicated that the kinetic parameters measured by the Raman method were in good agreement with those obtained by differential scanning calorimetry (DSC) and infrared spectroscopy. The blue-shifted C[double bond, length as m-dash]O stretching vibration resulting from the crystallization process is a popular phenomenon and may therefore have many potential applications in a wide range of areas. PMID- 26235150 TI - Facilitators and Barriers to Noninvasive Ventilation Adherence in Youth with Nocturnal Hypoventilation Secondary to Obesity or Neuromuscular Disease. AB - OBJECTIVE: Many youth struggle with adherence to bilevel noninvasive ventilation (NIV), often shortly after initiation of treatment. Anecdotal evidence suggests youths with comorbid obesity struggle with adherence while youths with comorbid neuromuscular disease demonstrate better adherence rates. The objective of this study was to explore factors relating to bilevel NIV adherence, and to compare these between youths with underlying obesity or neuromuscular disease. METHODS: An exploratory qualitative approach was used to examine youth and caregivers' experiences with and perceptions of bilevel NIV. Semi-structured interviews (n = 16) of caregivers and youths were conducted. Youths 12 years and older with nocturnal hypoventilation diagnosed on polysomnography and managed with bilevel NIV, with either concurrent obesity or neuromuscular disease were included. Thematic analysis of interview data was conducted using qualitative analysis software. RESULTS: Factors associated with positive bilevel NIV adherence included previous encouraging experiences with therapy; subjective symptom improvement; familiarity with medical treatments; understanding of nocturnal hypoventilation and its consequences; family and health-care team support; and early adaptation to treatments. Factors associated with poor bilevel NIV adherence included previous negative experiences with therapy, negative attitude towards therapy; difficulty adapting; perceived lack of support from family or health-care team; fear/embarrassment regarding treatment; caregivers not being health-minded; technical issues; side effects; and a lack of subjective symptom improvement. CONCLUSIONS: The dimensions which most affect adherence to bilevel NIV are those which contribute to youths' conception of feeling "well" or "unwell." Adherence to treatment may hinge largely on the way in which NIV is initially experienced and framed. COMMENTARY: A commentary on this article appears in this issue on page 1355. PMID- 26235151 TI - Evidence Supports No Relationship between Obstructive Sleep Apnea and Premolar Extraction: An Electronic Health Records Review. AB - OBJECTIVE: A controversy exists concerning the relationship, if any, between obstructive sleep apnea (OSA) and the anatomical position of the anterior teeth. Specifically, there has been speculation that extraction orthodontics and retraction of the anterior teeth contributes to OSA by crowding the tongue and decreasing airway space. This retrospective study utilized electronic medical and dental health records to examine the association between missing premolars and OSA. METHODS: The sample (n = 5,584) was obtained from the electronic medical and dental health records of HealthPartners in Minnesota. Half of the subjects (n = 2,792) had one missing premolar in each quadrant. The other half had no missing premolars. Cases and controls were paired in a 1:1 match on age range, gender, and body mass index (BMI) range. The outcome was the presence or absence of a diagnosis of OSA confirmed by polysomnography. RESULTS: Of the subjects without missing premolars, 267 (9.56%) had received a diagnosis of OSA. Of the subjects with four missing premolars, 299 (10.71%) had received a diagnosis of OSA. The prevalence of OSA was not significantly different between the groups (OR = 1.14, p = 0.144). CONCLUSION: The absence of four premolars (one from each quadrant), and therefore a presumed indicator of past "extraction orthodontic treatment," is not supported as a significant factor in the cause of OSA. PMID- 26235152 TI - Comparative Capabilities of Clinical Assessment, Diagnostic Criteria, and Polysomnography in Detecting Sleep Bruxism. AB - OBJECTIVE: To evaluate the diagnostic capability of signs and symptoms of sleep bruxism (SB) as per the American Academy of Sleep Medicine (AASM) criteria and a diagnostic grading system proposed by international experts for assessing SB. METHODS: The study was conducted in three phases (interview, physical examination, and sleep studies). Subjects were asked about self-reported tooth grinding sounds occurring during sleep, muscle fatigue, temporal headaches, jaw muscle pain, and jaw locking. A visual examination was conducted to check for presence of abnormal tooth wear. A full-night polysomnography (PSG) was performed. After three phases, the subjects were divided into two groups matched by age and gender: Case Group, 45 SB subjects, and Control Group, 45 non-SB subjects. Diagnostic accuracy measurements were calculated for each sign or symptom individually and for the two diagnostic criteria analyzed. RESULTS: Muscle fatigue, temporal headaches, and AASM criteria were associated with highest sensitivity (78%, 67%, 58%, respectively) and also with highest diagnostic odds ratio (OR = 9.63, 9.25, 6.33, respectively). Jaw locking, muscle pain, and the criterion of "probable SB" were associated with the worst sensitivity (16%, 18%, 22%, respectively). CONCLUSIONS: Presence of muscle fatigue and temporal headaches can be considered good tools to screen SB patients. None of the diagnostic criteria evaluated was able to accurately identify patients with SB. AASM criteria had the strongest diagnostic capabilities and--although they do not attain diagnostic values high enough to replace the current gold standard (PSG)--should be used as a screening tool to identify SB. PMID- 26235154 TI - Actigraphy as a "Truth-Buster". PMID- 26235153 TI - A Comparison of Different Success Definitions in Non-Continuous Positive Airway Pressure Treatment for Obstructive Sleep Apnea Using Cardiopulmonary Coupling. AB - STUDY OBJECTIVES: The definition and the criteria for the successful treatment of obstructive sleep apnea vary, depending on the study. This study aimed to compare different success criteria of non-continuous positive airway pressure (non-CPAP) treatment for obstructive sleep apnea in terms of sleep quality by using cardiopulmonary coupling. METHODS: We included 98 patients who had been treated with sleep surgery or with a mandibular advancement device at our sleep clinic from January 2011 to March 2013. The success and failure groups were divided by 6 criteria that have been used in the literature. The validity of each of the 6 criteria was evaluated by cardiopulmonary coupling-based sleep quality. RESULTS: The parameters of cardiopulmonary coupling indicated that sleep quality improved with non-CPAP treatment: low-frequency coupling decreased from 57.4% +/- 17.7% to 46.9% +/- 16.5%, whereas high-frequency coupling increased from 30.2% +/- 17.1% to 37.4% +/- 16.7%. In multiple regression analysis, only the criterion of a reduction in the apnea-hypopnea index greater than 50% was significantly associated with sleep quality improvement (p = 0.016; 95% confidence interval, 1.008-1.076 in the high-frequency coupling increment; p = 0.001; 95% confidence interval, 1.025-1.099 in the low-frequency coupling decrement). CONCLUSIONS: Cardiopulmonary coupling analysis showed that a reduction in the apnea-hypopnea index of more than 50% might be the optimal criterion to determine the success or failure of non-CPAP treatment in terms of sleep quality. PMID- 26235155 TI - Association between 25-Hydroxyvitamin D and Obstructive Sleep Apnea: A Systematic Review and Meta-Analysis. PMID- 26235157 TI - Evaluation of Bone Mineral Density by Computed Tomography in Patients with Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: Clinical studies have investigated whether obstructive sleep apnea (OSA) can modulate bone metabolism but data are conflicting. Bone mineral density (BMD) measured by dual-energy x-ray absorptiometry is the standard technique for quantifying bone strength but has limitations in overweight patients (body mass index [BMI] >= 25 kg/m(2)). The aim of this study was to examine the association between OSA and BMD by examining CT images that allow true volumetric measurements of the bone regardless of BMI. METHODS: Lumbar vertebrae BMD was evaluated in 234 persons (180 males and 54 females) by CT scan. The method was calibrated by a phantom containing a known concentration of hydroxyapatite. RESULTS: BMD was lower in male patients with severe OSA (apnea hypopnea index [AHI] >= 30/h) than non OSA (AHI < 5; p < 0.05), while OSA and BMD had no association in females. Linear and multiple regression analyses revealed that age (p < 0.0001, beta = -0.52), hypertension (p = 0.0068, beta = -0.17), and the alveolar-arterial oxygen pressure difference (A-aDO2) (p = 0.012, beta = 0.15) in males were associated with BMD, while only age (p < 0.0001, beta = 0.68) was associated with BMD in females. CONCLUSION: Males with severe OSA had a significantly lower BMD than non OSA participants. Age, hypertension, and elevation of A-aDO2 were significant factors for BMD by CT imaging. The usefulness of measuring BMD in OSA patients by CT scanning should be studied in future. PMID- 26235158 TI - Upper Airway Stimulation for Obstructive Sleep Apnea: Self-Reported Outcomes at 24 Months. AB - OBJECTIVES: To evaluate the long-term (24-mo) effect of cranial nerve upper airway stimulation (UAS) therapy on patient-centered obstructive sleep apnea (OSA) outcome measures. METHODS: Prospective, multicenter, cohort study of 126 patients with moderate to severe OSA who had difficulty adhering to positive pressure therapy and received the surgically implanted UAS system. Outcomes were measured at baseline and postoperatively at 12 mo and 24 mo, and included self- and bedpartner-report of snoring intensity, Epworth Sleepiness Scale (ESS), and Functional Outcomes of Sleep Questionnaire (FOSQ). Additional analysis included FOSQ subscales, FOSQ-10, and treatment effect size. RESULTS: Significant improvement in mean FOSQ score was observed from baseline (14.3) to 12 mo (17.3), and the effect was maintained at 24 mo (17.2). Similar improvements and maintenance of effect were seen with all FOSQ subscales and FOSQ-10. Subjective daytime sleepiness, as measured by mean ESS, improved significantly from baseline (11.6) to 12 mo (7.0) and 24 mo (7.1). Self-reported snoring severity showed increased percentage of "no" or "soft" snoring from 22% at baseline to 88% at 12 mo and 91% at 24 mo. UAS demonstrated large effect size (> 0.8) at 12 and 24 mo for overall ESS and FOSQ measures, and the effect size compared favorably to previously published effect size with other sleep apnea treatments. CONCLUSIONS: In a selected group of patients with moderate to severe OSA and body mass index <= 32 kg/m2, hypoglossal cranial nerve stimulation therapy can provide significant improvement in important sleep related quality-of-life outcome measures and the effect is maintained across a 2-y follow-up period. PMID- 26235156 TI - Development of the National Healthy Sleep Awareness Project Sleep Health Surveillance Questions. AB - OBJECTIVES: For the first time ever, as emphasized by inclusion in the Healthy People 2020 goals, sleep health is an emphasis of national health aims. The National Healthy Sleep Awareness Project (NHSAP) was tasked to propose questions for inclusion in the next Behavioral Risk Factor Surveillance System (BRFSS), a survey that includes a number of questions that target behaviors thought to impact health, as a means to measure community sleep health. The total number of questions could not exceed five, and had to include an assessment of the risk for obstructive sleep apnea (OSA). METHODS: An appointed workgroup met via teleconference and face-to-face venues to develop an inventory of published survey questions being used to identify sleep health, to develop a framework on which to analyze the strengths and weaknesses of current survey questions concerning sleep, and to develop recommendations for sleep health and disease surveillance questions going forward. RESULTS: The recommendation was to focus on certain existing BRFSS questions pertaining to sleep duration, quality, satisfaction, daytime alertness, and to add to these other BRFSS existing questions to make a modified STOP-BANG questionnaire (minus the N for neck circumference) to assess for risk of OSA. CONCLUSIONS: Sleep health is an important dimension of health that has previously received less attention in national health surveys. We believe that 5 questions recommended for the upcoming BRFSS question banks will assist as important measures of sleep health, and may help to evaluate the effectiveness of interventions to improve sleep health in our nation. PMID- 26235160 TI - Frequencies and Associations of Narcolepsy-Related Symptoms: A Cross-Sectional Study. AB - OBJECTIVES: Narcolepsy is a disabling disease with a delayed diagnosis. At least 3 years before the disorder identification, several comorbidities can be observed in patients with narcolepsy. The early recognition of narcolepsy symptoms may improve long-term prognosis of the patients. Thus, we aimed to investigate the prevalence of the symptoms associated with narcolepsy and its social and psychological association in a sample of Sao Paulo city inhabitants. METHODS: We performed a cross-sectional evaluation with 1,008 individuals from the Sao Paulo Epidemiologic Sleep Study (EPISONO). Excessive daytime sleepiness (EDS) was assessed by the Epworth Sleepiness Scale. Volunteers were also asked about the occurrence of cataplectic-like, hypnagogic or hypnopompic hallucinations, and sleep paralysis symptoms. The participants underwent a full-night polysomnography and completed questionnaires about psychological, demographic, and quality of life parameters. RESULTS: We observed a prevalence of 39.2% of EDS, 15.0% of cataplectic-like symptom, 9.2% of hypnagogic or hypnopompic hallucinations, and 14.9% of sleep paralysis in Sao Paulo city inhabitants. A frequency of 6.9% was observed when EDS and cataplectic-like symptoms were grouped. The other associations were EDS + hallucinations (4.7%) and EDS + sleep paralysis (7.5%). Symptomatic participants were predominantly women and younger compared with patients without any narcolepsy symptom (n = 451). Narcolepsy symptomatology was also associated with a poor quality of life and symptoms of depression, anxiety, and fatigue. CONCLUSIONS: Narcolepsy-related symptoms are associated with poor quality of life and worse psychological parameters. PMID- 26235161 TI - Technology Use and Sleep Quality in Preadolescence and Adolescence. AB - STUDY OBJECTIVES: The purpose of this study was to analyze differences between preadolescents and adolescents on the use of technology and to test the contribution of using Internet and mobile phone, and circadian preference on sleep quality. METHODS: We recruited a sample of 850 (364 males) preadolescents and adolescents. Self-report questionnaires about sleep schedule, sleep wake behavior problems, circadian preferences, and the use of technology (e.g., Internet and mobile phone) were administered. Students were asked to fill out the School Sleep Habits Survey, a self-report questionnaire on the use of technology, the Mobile Phone Involvement Questionnaire (MPIQ), and the Shorter Promis Questionnaire (SPQ). RESULTS: Adolescents reported more sleep problems, a tendency toward eveningness, and an increase of Internet and phone activities, as well as social network activities, while preadolescents were more involved in gaming console and television viewing. The regression analysis performed separately in the two age groups showed that sleep quality was affected by the circadian preference (eveningness) in both groups. Adolescents' bad sleep quality was consistently associated with the mobile phone use and number of devices in the bedroom, while in preadolescents, with Internet use and turning-off time. CONCLUSIONS: The evening circadian preference, mobile phone and Internet use, numbers of other activities after 21:00, late turning off time, and number of devices in the bedroom have different negative influence on sleep quality in preadolescents and adolescents. PMID- 26235162 TI - Excessive Dynamic Airway Collapse of the Lower Airway: A Cause for Persistent Sleep Disordered Breathing after Tracheostomy. AB - ABSTRACT: Tracheostomy has demonstrated effectiveness in the control of obstructive sleep apnea (OSA) in most patients; however, current evidence suggests significant sleep disordered breathing may persist, particularly in morbidly obese individuals. While several mechanisms have been proposed to explain this phenomenon, we demonstrate evidence of a previously unidentified pathophysiology: excessive dynamic airway collapse (EDAC) of the lower airway. We present the case of a 62-year-old woman status post tracheostomy with persistent dyspnea in the supine position. Both radiographic and bronchoscopic images demonstrate prolapse of the posterior membranous trachea at the level of the trachea and mainstem bronchi with partial or complete obstruction. The prolapse was completely relieved with upright positioning or positive airway pressure. This case illustrates a novel mechanism of post-tracheostomy sleep disordered breathing in obese individuals and emphasizes the need to consider follow-up polysomnography after tracheostomy in this patient population, especially those with persistent symptoms related to sleep or the supine position. PMID- 26235163 TI - Obstructive Sleep Apnea and Osteoporosis Risk. PMID- 26235164 TI - Radical-Mediated Three-Component Reaction: A Study toward the Total Synthesis of Resiniferatoxin. AB - This review summarizes the efforts to develop a radical-mediated three-component reaction and its application to a convergent approach to synthesize the 5/7/6 tricyclic framework (ABC-rings) of the densely functionalized dephnane diterpene, resiniferatoxin. The alpha-alkoxy bridgehead radical species, which was designed as the radical donor of the three-component reaction, was generated from O,Se- and O,Te-acetals under two different conditions. The generated alpha-alkoxy bridgehead radical effectively underwent the three-component reaction with alpha,beta-unsaturated ketones and allyltributyltin/aldehyde under each of the conditions, giving rise to a wide variety of multiply functionalized 2,3-trans disubstituted cyclopentenone moieties. One of the established reactions was utilized as the key assembling reaction of the ABC-tricyclic framework of resiniferatoxin. The reaction of the bridgehead radical of the highly functionalized 6-membered C-ring, the 5-membered A-ring, and an allyltributyltin derivative effectively produced the C4-branched AC-rings. The last B-ring was constructed from the coupling adduct in two steps through the 7-endo cyclization, delivering the tricyclic framework possessing the correct C8 and 9-stereocenters of resiniferatoxin. The present methods demonstrate the power of the three component reaction using an alpha-alkoxy bridgehead radical in a convergent approach to the complex architectures of daphnane diterpenes. PMID- 26235166 TI - Synthesis of Novel Pyrido[1,2-a]pyrimidine-3-carboxamide Derivatives and Their Anticancer Activity. AB - A series of novel pyrido[1,2-a]pyrimidine-3-carboxamide derivatives 6a-n were prepared starting from 2(1H) pyridone 1 via hydrolysis, de-carboxylation, selective O-alkylation followed by rearrangement to give pyridine-2-amine 3. Compound 3 on reaction with ethoxy methylene malonic diethyl ester (EMME) under a conventional method followed by cyclization under micro wave irradiation (MWI) conditions resulted in product 5. Compound 5 on coupling with diverse substituted aliphatic amines formed title compounds 6a-n. All the products 6a-n were screened against four human cancer cell lines and compounds 6h-k and n which showed promising anticancer activity have been identified. PMID- 26235165 TI - Eleven Microbial Metabolites of 6-Hydroxyflavanone. AB - 6-Hydroxyflavanone (1) when fermented with fungal culture Cunninghamella blakesleeana (ATCC 8688a) yielded flavanone 6-O-beta-D-glucopyranoside (2), flavanone 6-sulfate (3), and 6-hydroxyflavanone 7-sulfate (4). Aspergillus alliaceus (ATCC 10060) also transformed 1 to metabolite 3 as well as 4' hydroxyflavanone 6-sulfate (5) and 6,4'-dihydroxyflavanone (6). Beauveria bassiana (ATCC 7159) metabolized 1 to 6 and flavanone 6-O-beta-D-4-O methyglucopyranoside (7). Mucor ramannianus (ATCC 9628) transformed 1 to 2,4-cis 6-hydroxyflavan-4-ol (8), 2,4-trans-6-hydroxyflavan-4-ol (9), 2,4-trans-6,4' dihydroxyflavan-4-ol 5-sulfate (10), 1,3-cis-1-methoxy-1-(2,5-dihydroxyphenyl)-3 phenylpropane (11) and 2,4-trans-flavan-4-ol 6-sulfate (12). Structures of the metabolic products were elucidated by means of spectroscopic data. None of the metabolites tested showed antibacterial, antifungal and antimalarial activities against selected organisms. However, weak antileishmanial activity was observed for metabolite 11 when tested against Leishmania donovani. PMID- 26235167 TI - Synthesis and Structure-Activity Relationships of 2-Aminoacetamide Derivatives as Peroxisome Proliferator-Activated Receptor alpha/gamma Dual Agonists. AB - We describe the design, syntheses, and structure-activity relationships of novel zwitterionic compounds as nonthiazolidinedion-based peroxisome proliferator activated receptor (PPAR) alpha/gamma dual agonists. In our previous report, we obtained compound 1 showing potent PPARalpha/gamma dual agonistic activities, together with a sufficient glucose-lowering effect in db/db mice. However, this compound possessed an issue, i.e., the 1,3,4-oxadiazole ring was not stable in acidic conditions. Thus, we carried out further optimization to improve the stability while maintaining the other favorable profile features including potent PPARalpha/gamma dual agonistic activity. We addressed the issue by changing the oxadiazole ring to a bioisostere amide group. These amide derivatives were stable in acidic conditions and decreased plasma glucose and plasma triglyceride levels significantly without marked weight gain. PMID- 26235159 TI - Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion. AB - The American Academy of Sleep Medicine and Sleep Research Society recently released a Consensus Statement regarding the recommended amount of sleep to promote optimal health in adults. This paper describes the methodology, background literature, voting process, and voting results for the consensus statement. In addition, we address important assumptions and challenges encountered during the consensus process. Finally, we outline future directions that will advance our understanding of sleep need and place sleep duration in the broader context of sleep health. PMID- 26235168 TI - Megastigmane Glucosides and Megastigmanes from the Leaves of Meliosma lepidota ssp. squamulata. AB - From the leaves of Meliosma lepidota ssp. squamulata, megastigmane glucosides with spiro-structures and megastigmanes were isolated. Their structures were determined by X-ray crystallographic analyses and spectroscopic investigation. The absolute structures of the megastigmanes were determined by the modified Mosher's method. PMID- 26235169 TI - Identification of Furosemide Photodegradation Products in Water-Acetonitrile Mixture. AB - The aim of this study was to identify the chemical structure of the photodegradation products of furosemide in a water-acetonitrile mixture (1 : 1). Furosemide solution was irradiated with a D65 fluorescent lamp and the products were isolated by preparative HPLC. The fractions were evaporated to dryness in vacuo. The purity of the photodegradation products was measured by HPLC. The purity of products 1, 3, and 4 was greater than 90%, whereas that of product 2 was 13%, therefore, photodegradation product 2 was unstable. We identified photodegradation products 1 and 3 as 4-chloro-5-sulfamoylanthranilic acid and 4 hydroxy-N-furfuryl-5-sulfamoylanthranilic acid, respectively, by LC/MS and NMR. Additionally, we assumed that photodegradation product 4 was methyl 2-((furan-2 ylmethyl)amino)-4-hydroxy-3-(methyleneamino)-5-sulfamoylbenzoate by LC/MS and NMR. This showed that furosemide underwent hydrolysis and substitution, and reacted with the acetonitrile under the light of a D65 fluorescent lamp. We were furthermore able to determine the elution times of the photodegradation products of furosemide by applying the Japanese Pharmacopoeia chromatographic method for related substances to the isolated products. PMID- 26235170 TI - Cytotoxic Biscembranoids from the Soft Coral Sarcophyton pauciplicatum. AB - Ten biscembranoids (1-10), including the two new compounds sarcophytolides M and N (1 and 2), were isolated from the methanol extract of the Vietnamese soft coral Sarcophyton pauciplicatum. Their structures were elucidated by spectroscopic methods including one dimensional (1D)- and 2D-NMR, high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), and circular dichroism (CD). The in vitro cytotoxic activity of all isolated compounds against a panel of eight human cancer cell lines including HepG2 (hepatoma cancer), HL-60 (acute leukemia), KB (epidermoid carcinoma), LNCaP (prostate cancer), LU-1 (lung cancer), MCF7 (breast cancer), SK-Mel2 (melanoma), and SW480 (colon adenocarcinoma) was evaluated using the sulforhodamine B colorimetric assay. Among the isolated biscembranoids, 1, 3, 4, 7, 9, and 10 exhibited significant cytotoxic effects and may be selected for further studies of their anticancer activity. PMID- 26235171 TI - Antiviral Activity of Four New Resin Glycosides Calysolins XIV-XVII from Calystegia soldanella against Herpes Simplex Virus. AB - Four new resin glycosides, named calysolins XIV (1), XV (2), XVI (3), and XVII (4) were isolated from the leaves, stems, and roots of Calystegia soldanella ROEM.. et SCHULT. (Convolvulaceae). Their structures were determined based on spectroscopic and chemical evidence, and consisted of two different types: those (1) with a macrolactone structure and those (2-4) with a non-macrolactone structure. Their sugar moieties were partially acylated by specific organic acids, including tiglic, 2S-methylbutyric, and 2S,3S-nilic acids. Additionally, evaluation of the antiviral activity of 1-4 revealed effects against the herpes simplex virus type 1. PMID- 26235172 TI - [Catecholamine-secreting paraganglioma in a patient with Eisenmenger syndrome and a single ventricle. Nitric oxide administration and minimally invasive haemodynamic monitoring]. AB - Surgery for catecholamine-secreting neuroendocrine tumours poses a high anaesthetic risk that might increase due to coexisting congenital heart diseases, such as a single ventricle and Eisenmenger syndrome. This report emphasises the usefulness of pulse range haemodynamic monitoring over thermodilution in a patient with a single ventricle. In addition, the importance of nitric oxide is stressed in the management of respiratory problems associated to surgical-related pulmonary hypertension. As to the anaesthetic techniques, none is preferred as long as the one chosen has no haemodynamic repercussions. PMID- 26235174 TI - Application of data science tools to quantify and distinguish between structures and models in molecular dynamics datasets. AB - Structure quantification is key to successful mining and extraction of core materials knowledge from both multiscale simulations as well as multiscale experiments. The main challenge stems from the need to transform the inherently high dimensional representations demanded by the rich hierarchical material structure into useful, high value, low dimensional representations. In this paper, we develop and demonstrate the merits of a data-driven approach for addressing this challenge at the atomic scale. The approach presented here is built on prior successes demonstrated for mesoscale representations of material internal structure, and involves three main steps: (i) digital representation of the material structure, (ii) extraction of a comprehensive set of structure measures using the framework of n-point spatial correlations, and (iii) identification of data-driven low dimensional measures using principal component analyses. These novel protocols, applied on an ensemble of structure datasets output from molecular dynamics (MD) simulations, have successfully classified the datasets based on several model input parameters such as the interatomic potential and the temperature used in the MD simulations. PMID- 26235173 TI - Mesenchymal stem cells regulate melanoma cancer cells extravasation to bone and liver at their perivascular niche. AB - Skeleton and liver are preferred organs for cancer dissemination in metastatic melanoma negatively impacting quality of life, therapeutic success and overall survival rates. At the target organ, the local microenvironment and cell-to-cell interactions between invading and resident stromal cells constitute critical components during the establishment and progression of metastasis. Mesenchymal stem cells (MSCs) possess, in addition to their cell progenitor function, a secretory capacity based on cooperativity with other cell types in injury sites including primary tumors (PT). However, their role at the target organ microenvironment during cancer dissemination is not known. We report that local MSCs, acting as pericytes, regulate the extravasation of melanoma cancer cells (MCC) specifically to murine bone marrow (BM) and liver. Intra-arterially injected wild-type MCC fail to invade those selective organs in a genetic model of perturbed pericyte coverage of the vasculature (PDGF-B(ret/ret)), similar to CD146-deficient MCC injected into wild type mice. Invading MCC interact with resident MSCs/pericytes at the perivascular space through co-expressed CD146 and Sdf-1/CXCL12-CXCR4 signaling. Implanted engineered bone structures with MSCs/pericytes deficient of either Sdf-1/CXCL12 or CD146 become resistant to invasion by circulating MCC. Collectively, the presence of MSCs/pericytes surrounding the target organ vasculature is required for efficient melanoma metastasis to BM and liver. PMID- 26235175 TI - Hypofractionated radiation therapy versus conventionally fractionated radiation therapy for early-stage breast cancer: how do we choose? PMID- 26235176 TI - How can we identify new biomarkers for patients with for lung metastasectomy in colorectal cancer. PMID- 26235177 TI - How can we decrease suicide risk in cases of genitourinary cancer? PMID- 26235178 TI - Targeting aggressive cancers with an artificial sweetener: could saccharin be a lead compound in anticancer therapy? PMID- 26235180 TI - Bleomycin pulmonary toxicity in adult Saudi patients with Hodgkin's lymphoma. AB - BACKGROUND: Bleomycin pulmonary toxicity (BPT) has been described in Hodgkin's lymphoma (HL) patients treated with bleomycin-containing chemotherapy regimens. METHODOLOGY: We reviewed the records of 164 consecutive HL patients. RESULTS: BPT was observed in 24 of 164 patients (15%). Older age and history of concomitant lung disease were significantly associated with approximately threefold (odds ratio: 3.38; 95% CI: 1.25-9.13; p = 0.02) and sevenfold (odds ratio: 7.19; 95% CI: 2.64-19.54; p < 0.0001) increase in BPT risk, respectively. The actuarial 5 year progression-free and overall survival for BPT and non-BPT groups, were not significantly different. CONCLUSION: In Saudi Arabian HL patients, the risk of BPT and its effect on survival outcome were comparable to that reported from developed countries. PMID- 26235181 TI - Functional genetic variants in pre-miR-146a and 196a2 genes are associated with risk of lung cancer in North Indians. AB - OBJECTIVE: To find the association of two pre-miRNA polymorphisms with risk of lung cancer in North Indians. MATERIALS & METHODS: Genotyping of 250 cases and 255 controls for miR-146a and miR-196a2 using PCR-RFLP. RESULTS: Heterozygous subjects showed a risk toward lung cancer (LC), especially for adenocarcinoma (OR: 1.82; 95% CI: 1.04-3.20; p = 0.03) in miR-146a gene. TT genotype for miR 196a2 gene also showed 3.2-fold risk toward LC and the risk was fivefold higher for squamous cell carcinoma. Survival rate was significantly lower in subjects with TT genotype as compared with the CC genotype in miR-196a2. CONCLUSION: Both the single nucleotide polymorphism variants showed a positive association toward risk of lung cancer. PMID- 26235179 TI - Development of PROSTVAC immunotherapy in prostate cancer. AB - PROSTVAC immunotherapy is a heterologous prime-boost regimen of two different recombinant pox-virus vectors; vaccinia as the primary immunotherapy, followed by boosters employing fowlpox, to provoke immune responses against prostate-specific antigen. Both vectors contain transgenes for prostate-specific antigen and a triad of T-cell costimulatory molecules (TRICOM). In a placebo-controlled Phase II trial of men with minimally symptomatic, chemotherapy-naive metastatic castration-resistant prostate cancer, PROSTVAC was well tolerated and associated with a 44% reduction in death. With a novel mechanism of action, and excellent tolerability, PROSTVAC has the potential to dramatically alter the treatment landscape of prostate cancer, not only as a monotherapy, but also in combination with other novel agents, such as immune check point inhibitors and novel androgen receptor blockers. A Phase III trial recently completed accrual. PMID- 26235182 TI - The diverse roles of adiponectin in non-small-cell lung cancer: current data and future perspectives. AB - In recent years, there is growing research interest for the biological role of adipose tissue-derived bioactive factors, mainly including adipokines, in various forms of cancer. Adiponectin (APN) is the most abundant circulating adipokine, and a key mediator of several cancer-related processes, such as cell proliferation, apoptosis, regulation of tumor cell invasion and angiogenesis. In this review we summarize and critically discuss the published literature on the diverse roles of APN in non-small-cell lung cancer, including its implication in lung cancer development, its use as a diagnostic and prognostic biomarker, and its correlation with cancer-related cachexia. The main challenges and future perspectives, mainly with regard to the potential development of APN-targeted therapeutic agents in cancer therapeutics, are also briefly presented and discussed. PMID- 26235183 TI - Next revolution in molecular theranostics: personalized medicine for urologic cancers. AB - Extensive lists of molecular biomarkers are currently evaluated as potential targets for directed cancer therapies. We reviewed three potential candidate biomarkers to play a role in the near future as molecular theranostics for urologic malignancies. Carbonic anhydrase type IX is a surrogate marker of hypoxia highly expressed in cancer cells. Their expression and clinical significance in kidney and urothelial bladder cancer are discussed as well as the main therapeutic approaches that are currently under evaluation. For prostate cancer, available evidence on the use of prostate-specific membrane antigen and neuropeptide receptors radiolabeled analog and the undergoing clinical studies are also analyzed and discussed at different stages of prostate cancer. PMID- 26235184 TI - Biomarkers to detect Wilms tumors in pediatric patients: where are we now? AB - Wilms tumor (WT) is the most common pediatric renal tumor. Survival rates are high, whether treated according to the European protocols (SIOP-RTSG) that use prenephrectomy chemotherapy or the Children's Oncology Group (COG) protocols, with immediate nephrectomy. However, the more intensive treatment given to higher risk subgroups may result in late effects. Current risk stratification does not identify all tumors that relapse and loss of heterozygosity of 16q and 1p are the only molecular biomarkers used in risk stratification. In this review we describe recent new genetic and epigenetic findings in WT and discuss their potential use as biomarkers. We discuss approaches to ensure representative sampling of WTs including the potential for 'liquid biopsy' to circumvent intratumoral heterogeneity. PMID- 26235185 TI - Global health from a cancer care perspective. AB - Cancer is now recognized as one of the four leading causes of morbidity and mortality worldwide, and incidence is expected to rise significantly in the next two decades. Unfortunately, low- and middle-income countries (LMIC) suffer disproportionately from the world's cancer cases. The growing burden of cancer and maldistribution of cancer care resources in LMIC warrant a massive re evaluation of the structural inequalities that produce global oncological disparities and a worldwide commitment to improve both prevention and treatment strategies. Efforts to improve cancer care capacity should focus on horizontal strengthening of healthcare systems that provide safe, affordable, effective and sustainable care. In response to current deficiencies, many international organizations have started to partner with LMIC to create solutions. Telemedicine and international collaboration are also promising ways to effect change and improve global oncological care. PMID- 26235186 TI - Optimum design and criticality safety of a beam-shaping assembly with an accelerator-driven subcritical neutron multiplier for boron neutron capture therapies. AB - The beam-shaping assembly for boron neutron capture therapies with a compact accelerator-driven subcritical neutron multiplier was designed so that an epithermal neutron flux of 1.9*10(9) cm(-2) s(-1) at the treatment position was generated by 5 MeV protons in a beam current of 2 mA. Changes in the atomic density of (135)Xe in the nuclear fuel due to the operation of the beam-shaping assembly were estimated. The criticality safety of the beam-shaping assembly in terms of Xe poisoning is discussed. PMID- 26235187 TI - Near threshold 7Li(p,n) 7Be reaction as neutron source for BNCT. AB - (7)Li(p,n)(7)Be is an endothermic reaction and working near its threshold (1.88 MeV) has the advantage of neutron spectra with maximum energies of about 100 keV, considerably lower than at higher beam energies, or than using other neutron producing reactions or as for the uranium fission spectrum, relevant for BNCT based on nuclear reactors. With this primary energy it is much easier to obtain the energies needed for treating deep seated tumors by BNCT (about 10 keV). This work studies bombarding energies up to 2.05 MeV, different beam incidence angles and the effect of the undesirable gamma production via the (7)Li(p,gammap') (7)Li reaction. PMID- 26235188 TI - Frontoparietal Bone in Extinct Palaeobatrachidae (Anura): Its Variation and Taxonomic Value. AB - Palaeobatrachidae are extinct frogs from Europe closely related to the Gondwanan Pipidae, which includes Xenopus. Their frontoparietal is a distinctive skeletal element which has served as a basis for establishing the genus Albionbatrachus. Because little was known about developmental and individual variation of the frontoparietal, and its usefulness in delimiting genera and species has sometimes been doubted, we investigate its structure in Palaeobatrachus and Albionbatrachus by means of X-ray high resolution computer tomography (micro-CT). To infer the scope of variation present in the fossil specimens, we also examined developmental and interspecific variation in extant Xenopus. In adults of extinct taxa, the internal structure of the frontoparietal bone consists of a superficial and a basal layer of compact bone, with a middle layer of cancellous bone between them, much as in early amphibians. In Albionbatrachus, the layer of cancellous bone, consisting of small and large cavities, was connected with the dorsal, sculptured surface of the bone by a system of narrow canals; in Palaeobatrachus, the layer of cancellous bone and the canals connecting this layer with the dorsal surface of the frontoparietal were reduced. The situation in Palaeobatrachus robustus from the lower Miocene of France is intermediate-while external features support assignment to Palaeobatrachus, the inner structure is similar to that in Albionbatrachus. It may be hypothesized that sculptured frontoparietals with a well-developed layer of cancellous (i.e., vascularized) bone may indicate adaptation to a more terrestrial way of life, whereas a reduced cancellous layer might indicate a permanent water dweller. PMID- 26235189 TI - An unknown mass: the differential diagnosis of digit tumors. AB - There is little discussion of tumors arising in the digits in the dermatology literature. The patient with an undifferentiated mass of the finger is frequently encountered in the clinic, and variances in presentation of common and uncommon entities pose a challenge that may prompt further investigation for proper diagnosis and treatment. In this review, the authors illustrate the approach and work-up of an unknown digit mass of a 45-year-old female patient. They go on to discuss the presentation and treatment of common tumor lesions of the finger likely to be encountered in the dermatologist's clinic including: ganglion cyst/mucous cyst, giant-cell tumor, verruca vulgaris, epidermal inclusion cyst, poroma, porocarcinoma, squamous cell carcinoma, basal cell carcinoma, melanoma, infantile digital fibromatosis, acquired digital fibrokeratoma, Koenen's tumor, schwannoma, cutaneous neurofibroma, pyogenic granuloma, hemangioma, glomus tumor, epithelioid sarcoma, and metastatic disease. PMID- 26235190 TI - Randainins A-D, Based on Unique Diterpenoid Architectures, from Callicarpa randaiensis. AB - Four new compounds, randainins A-D (1-4), were isolated from the leaves and twigs of Callicarpa randaiensis, which is an endemic species in Taiwan. Compounds 1 and 2 are diterpenoids with an unusual trans-7/5 ring system, whereas compounds 3 and 4 are diterpenoids possessing a trans-5/7 ring scaffold. The structures of the new compounds were established based on NMR and MS data analyses. Anti inflammatory activities and cytotoxicity were tested and evaluated for these compounds. Compound 4 exhibited moderate inhibition of superoxide-anion generation with an IC50 value of 21.5 +/- 2.5 MUM. PMID- 26235191 TI - Complications Within 30 Days of Hand Surgery: An Analysis of 10,646 Patients. AB - PURPOSE: The American College of Surgeons Surgical Quality Improvement Program database collects detailed and validated data on demographics, comorbidities, and 30-day postoperative outcomes of patients undergoing operations in most subspecialties. This dataset has been previously used to quantify complications and identify risk factors in other surgical subspecialties. We sought to determine the incidence of postoperative complications following hand surgery and to identify factors associated with increased risk of complications in order to focus preventive strategies. METHODS: National Surgical Quality Improvement Program data from 2006 to 2011 were queried using 302 hand-specific Current Procedural Technology codes. Descriptive statistics were calculated for the population, and potential risk factors and patient characteristics were analyzed for their association with complications in the 30-day postoperative period using both univariate and multivariate analyses. RESULTS: There were 208 hand-specific Current Procedural Technology codes represented in the data, and of these, 84 were associated with at least 1 complication. The overall incidence of complications within 30 days of hand surgery was 2.5% (95% confidence interval, 2.2%-2.8%). In univariate analysis, older age, diabetes, chronic obstructive pulmonary disease, congestive heart failure, atherosclerosis, steroids, bleeding disorder, increasing American Society of Anesthesiologists class, increasing wound class, emergency procedure, longer operative time, and preoperative transfusion were associated with significantly higher risk of complications, and local anesthesia and outpatient surgery were associated with lower risk. In the multivariate model, male sex, increasing American Society of Anesthesiologists class, wound class 4, and preoperative transfusion were associated with significantly higher risk, and outpatient surgery was associated with significantly lower risk. The most common complication was surgical-site infection (1.2%). CONCLUSIONS: The incidence of complications was low, with overall health status being more important than specific comorbidities in predicting complication risk. This information may be valuable in counseling patients before surgery and in identifying patients at higher risk for complications following hand surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 26235192 TI - In-hospital worsening heart failure. AB - Acute worsening heart failure (WHF) is seen in a sizable portion of patients hospitalized for heart failure, and is increasingly being recognized as an entity that is associated with an adverse in-hospital course. WHF is generally defined as worsening heart failure symptoms and signs requiring an intensification of therapy, and is reported to be seen in anywhere from 5% to 42% of heart failure admissions. It is difficult to ascertain the exact epidemiology of WHF due to varying definitions used in the literature. Studies indicate that WHF cannot be precisely predicted on the basis of baseline variables assessed at the time of admission. Recent data suggest that some experimental therapies may reduce the risk of development of WHF among hospitalized heart failure patients, and this is associated with a reduction in risk of subsequent post-discharge cardiovascular mortality. In this respect, WHF holds promise as a endpoint for acute heart failure clinical trials to better elucidate the benefit of targeted novel therapies. Better understanding of the pathophysiology and a consensus on the definition of WHF will further improve our epidemiological and clinical understanding of this entity. PMID- 26235193 TI - Response to comments on "Vagally Mediated Analgesia: Breath-Holding During Exhalation as a Simple Manipulation to Reduce Pain Perception". PMID- 26235195 TI - Anti-angiogenic drugs for second-line treatment of NSCLC patients: just new pawns on the chessboard? AB - Tumor angiogenesis is one of the main pathways targeted to treat cancer. Bevacizumab added survival benefit when combined with platinum-based chemotherapy in NSCLC. Recently, Phase III trials showed survival benefit when anti-angiogenic drugs are added to docetaxel as second-line treatment for NSCLC. These anti angiogenic agents include nintedanib and ramucirumab, a tyrosine-kinase inhibitor and a monoclonal antibody, respectively, which target receptors involved in angiogenesis. These studies have some similarities and differences. We propose a new algorithm for treatment sequences in performance status 0-1 patients with non oncogene-addicted NSCLC type adenocarcinoma. Indeed clearer scientific evidences are available for this subgroup of patients. PMID- 26235196 TI - Impact of urinary tract infections on short-term kidney graft outcome. AB - Urinary tract infections (UTIs) are frequent after renal transplantation, but their impact on short-term graft outcome is not well established. All kidney transplants performed between July 2003 and December 2010 were investigated to evaluate the impact of UTI on graft function at 1 year after transplantation. Of 867 patients who received a kidney transplant, 184 (21%) developed at least one episode of UTI, at a median of 18 days after transplantation. The prevalence of acute graft pyelonephritis (AGP) was 15%. The most frequent pathogens identified were Escherichia coli, Klebsiella species, and Pseudomonas aeruginosa, 37% of which were considered to be multidrug-resistant strains. Thirty-eight patients (4%) lost their grafts, 225 patients (26%) had graft function impairment and the 1-year mortality rate was 3%; however, no patient died as a consequence of a UTI. Surgical re-intervention and the development of at least one episode of AGP were independently associated with 1-year graft function impairment. Moreover, the development of at least one episode of AGP was associated with graft loss at 1 year. Patients with AGP caused by a resistant strain had graft function impairment more frequently, although this difference did not reach statistical significance (53% vs. 36%, p 0.07). Neither asymptomatic bacteriuria nor acute uncomplicated UTI were associated with graft function impairment in multivariate analysis. To conclude, UTIs are frequent in kidney transplant recipients, especially in the early post-transplantation period. Although AGP was significantly associated with kidney graft function impairment and 1-year post transplantation graft loss, lower UTIs did not affect graft function. PMID- 26235197 TI - Phylogenetic characterization of Central/Southern European lineage 2 West Nile virus: analysis of human outbreaks in Italy and Greece, 2013-2014. AB - In recent years, West Nile virus (WNV) lineage 2 has been spreading and causing disease outbreaks in humans and animals in Europe. In order to characterize viral diversity, we performed full-length genome sequencing of WNV lineage 2 from human samples collected during outbreaks in Italy and Greece in 2013 and 2014. Phylogenetic analysis showed that these WNV lineage 2 genomes belonged to a monophyletic clade derived from a single introduction into Europe of the prototype Hungarian strain. Correlation of phylogenetic data with geospatial information showed geographical clustering of WNV genome sequences both in Italy and in Greece, indicating that the virus had evolved and diverged during its dispersal in Europe, leading to the emergence of novel genotypes, as it adapted to local ecological niches. These genotypes carried divergent conserved amino acid substitutions, which might have been relevant for viral adaptation, as suggested by selection pressure analysis and in silico and experimental modelling of sequence changes. In conclusion, the results of this study provide further information on WNV lineage 2 transmission dynamics in Europe, and emphasize the need for WNV surveillance activities to monitor viral evolution and diversity. PMID- 26235198 TI - Virus isolation, genetic characterization and seroprevalence of Toscana virus in Algeria. AB - Toscana virus (TOSV; Bunyaviridae, Phlebovirus) is transmitted by sandflies of the genus Phlebotomus in the Mediterranean area. One strain of TOSV was isolated from a total of almost 23 000 sandflies collected in Kabylia, Algeria. The complete genome was sequenced, and phylogenetic studies indicated that it was most closely related with TOSV strain from Tunisia within lineage A, which also includes Italian, French and Turkish strains. A seroprevalence study performed on 370 sera collected from people living in the same area showed that almost 50% possessed neutralizing antibodies against TOSV, a rate much higher than that observed in Southern Europe. Sandfly species distribution in the study area suggests that the vector of TOSV in this region belongs to the subgenus Larroussius. These data support the rapid implementation of the diagnosis of TOSV in clinical microbiology laboratories to estimate the burden in patients presenting with neuroinvasive infections and febrile illness. PMID- 26235199 TI - Rab27a GTPase modulates L-type Ca2+ channel function via interaction with the II III linker of CaV1.3 subunit. AB - In a variety of cells, secretory processes require the activation of both Rab27a and L-type channels of the Ca(V)1.3 subtype. In the retinal pigment epithelium (RPE), Rab27a and Ca(V)1.3 channels regulate growth-factor secretion towards its basolateral side. Analysis of murine retina sections revealed a co-localization of both Rab27a and Ca(V)1.3 at the basolateral membrane of the RPE. Heterologously expressed Ca(V)1.3/beta3/alpha2delta1 channels showed negatively shifted voltage-dependence and decreased current density of about 70% when co expressed with Rab27a. However, co-localization analysis using alpha(5)beta(1) integrin as a membrane marker revealed that Rab27a co-expression reduced the surface expression of Ca(V)1.3 only about 10%. Physical binding of heterologously expressed Rab27a with Ca(V)1.3 channels was shown by co-localization in immunocytochemistry as well as co-immunoprecipitation which was abolished after deletion of a MyRIP-homologous amino acid sequence at the II-III linker of the Ca(V)1.3 subunit. Rab27a over-expression in ARPE-19 cells positively shifted the voltage dependence, decreased current density of endogenous Ca(V)1.3 channels and reduced VEGF-A secretion. We show the first evidence of a direct functional modulation of an ion channel by Rab27a suggesting a new mechanism of Rab and ion channel interaction in the control of VEGF-A secretion in the RPE. PMID- 26235200 TI - Rebuttal to Drs. Hussein and Cooperberg. PMID- 26235201 TI - Phase I/II prospective trial of cancer-specific imaging using ultrasound spectrum analysis tissue-type imaging to guide dose-painting prostate brachytherapy. AB - PURPOSE: To assess the technical feasibility, toxicity, dosimetry, and preliminary efficacy of dose-painting brachytherapy guided by ultrasound spectrum analysis tissue-type imaging (TTI) in low-risk, localized prostate cancer. METHODS AND MATERIALS: Fourteen men with prostate cancer who were candidates for brachytherapy as sole treatment were prospectively enrolled. Treatment planning goal was to escalate the tumor dose to 200% with a modest de-escalation of dose to remaining prostate compared with our standard. Primary end points included technical feasibility of TTI-guided brachytherapy and equivalent or better toxicity compared with standard brachytherapy. Secondary end points included dose escalation to tumor regions and de-escalated dose to nontumor regions on the preimplant plan, negative prostate biopsy at 2 years, and freedom from biochemical failure. RESULTS: Thirteen of fourteen men successfully completed the TTI-guided brachytherapy procedure for a feasibility rate of 93%. A software malfunction resulted in switching one patient from TTI-guided to standard brachytherapy. An average of 2.7 foci per patient was demonstrated and treated with an escalated dose. Dosimetric goals on preplan were achieved. One patient expired from unrelated causes 65 days after brachytherapy. Toxicity was at least as low as standard brachytherapy. Two-year prostate biopsies were obtained from six men; five (83%) were definitively negative, one showed evidence of disease with treatment effect, and none were positive. No patients experienced biochemical recurrence after a median followup of 31.5 (24-52) months. CONCLUSIONS: We have demonstrated that TTI-guided dose-painting prostate brachytherapy is technically feasible and results in clinical outcomes that are encouraging in terms of low toxicity and successful biochemical disease control. PMID- 26235202 TI - Using an integrated teaching and learning approach to deliver inter-professional practice in Public Health. AB - In order to address health inequalities an interprofessional approach is required. To recreate this experience for pre-registration healthcare students an innovative model utilising integrated approaches to teaching and learning was developed. This incorporated interprofessional education, threshold concepts, virtual learning and narrative pedagogy. PMID- 26235203 TI - Tacrolimus pharmacokinetics after kidney transplantation--Influence of changes in haematocrit and steroid dose. PMID- 26235204 TI - Engineering Cyclodextrin Clicked Chiral Stationary Phase for High-Efficiency Enantiomer Separation. AB - The separation of racemic molecules is of crucial significance not only for fundamental research but also for technical application. Enantiomers remain challenging to be separated owing to their identical physical and chemical properties in achiral environments. Chromatographic techniques employing chiral stationary phases (CSPs) have been developed as powerful tools for the chiral analysis and preparation of pure enantiomers, most of which are of biological and pharmaceutical interests. Here we report our efforts in developing high performance phenylcarbamated cyclodextrin (CD) clicked CSPs. Insights on the impact of CD functionalities in structure design are provided. High-efficiency enantioseparation of a range of aryl alcohols and flavanoids with resolution values (Rs) over 10 were demonstrated by per(3-chloro-4-methyl)phenylcarbamated CD clicked CSP. Comparison study and molecular simulations suggest the improved enantioselectivity was attributed to higher interactions energy difference between the complexes of enantiomers and CSPs with phenylcarbamated CD bearing 3 chloro and 4-methyl functionalities. PMID- 26235205 TI - Flexible lithium-oxygen battery based on a recoverable cathode. AB - Although flexible power sources are crucial for the realization next-generation flexible electronics, their application in such devices is hindered by their low theoretical energy density. Rechargeable lithium-oxygen (Li-O2) batteries can provide extremely high specific energies, while the conventional Li-O2 battery is bulky, inflexible and limited by the absence of effective components and an adjustable cell configuration. Here we show that a flexible Li-O2 battery can be fabricated using unique TiO2 nanowire arrays grown onto carbon textiles (NAs/CT) as a free-standing cathode and that superior electrochemical performances can be obtained even under stringent bending and twisting conditions. Furthermore, the TiO2 NAs/CT cathode features excellent recoverability, which significantly extends the cycle life of the Li-O2 battery and lowers its life cycle cost. PMID- 26235206 TI - Relative validity of a semi-quantitative, web-based FFQ used in the 'Snart Foraeldre' cohort - a Danish study of diet and fertility. AB - OBJECTIVE: To assess the relative validity of a semi-quantitative, web-based FFQ completed by female pregnancy planners in the Danish 'Snart Foraeldre' study. DESIGN: We validated a web-based FFQ based on the FFQ used in the Danish National Birth Cohort against a 4 d food diary (FD) and assessed the relative validity of intakes of foods and nutrients. We compared means and medians of intakes, and calculated Pearson correlation coefficients and de-attenuated coefficients to assess agreement between the two methods. We also calculated the proportion correctly classified based on the same or adjacent quintile of intake and the proportion of grossly misclassified (extreme quintiles). SETTING: Participants (n 128) in the 'Snart Foraeldre' study who had completed the web-based FFQ were invited to participate in the validation study. SUBJECTS: Participants in the 'Snart Foraeldre' study, in total ninety-seven women aged 20-42 years. RESULTS: Reported intakes of dairy products, vegetables and potatoes were higher in the FFQ compared with the FD, whereas reported intakes of fruit, meat, sugar and beverages were lower in the FFQ than in the FD. Overall the de-attenuated correlation coefficients were acceptable, ranging from 0.33 for energy to 0.93 for vitamin D. The majority of the women were classified in the same or adjacent quintile and few women were misclassified (extreme quintiles). CONCLUSION: The web-based FFQ performs well for ranking women of reproductive age according to high or low intake of foods and nutrients and, thus, provides a solid basis for investigating associations between diet and fertility. PMID- 26235207 TI - Central venous catheter thrombosis and the fibrin sleeve: unraveling the mystery. PMID- 26235208 TI - Comparison of Glioblastomas and Brain Metastases using Dynamic Contrast-Enhanced Perfusion MRI. AB - PURPOSE: To compare glioblastoma and brain metastases using T1-weighted dynamic contrast-enhanced (DCE)-MRI perfusion technique. METHODS: 26 patients with glioblastoma and 32 patients with metastatic brain lesions with no treatment who underwent DCE-MRI were, retrospectively, analyzed. DCE perfusion parameters K(trans) and Vp were calculated for the whole tumor. Signal intensity time curves were quantified by calculating the area under the curve (AUC) and the logarithmic slope of the washout phase to explore the heterogeneous tumor characteristics. RESULTS: Glioblastoma did not differ from all brain metastases in K(trans) (P = .34) or Vp (P = .47). Glioblastoma and melanoma metastases differed from hypovascular metastases in AUC and log slope of the washout phase of the signal intensity time curve (P < .05); however, glioblastoma and melanoma metastases did not differ from each other (AUC: P = .78, Log slope: P = .77). Glioblastoma and melanoma metastases differed from hypovascular metastases in the ratio of Voxelneg /Voxelpos (P< .03); however, they did not differ from each other. Glioblastoma and melanoma metastases differed from each other in Voxelneg_threshold at higher negative log slope threshold. CONCLUSION: DCE-MRI showed that it has a potential to differentiate glioblastomas, melanoma metastases and hypovascular brain tumors. Logarithmic slope of the washout phase and AUC of the signal intensity time curve were shown to be the best discriminator between hypervascular and hypovascular neoplasms. PMID- 26235209 TI - Reverse remodeling and the mechanism of mitral regurgitation improvement in patients with dilated cardiomyopathy. AB - BACKGROUND: Functional mitral regurgitation (MR) is a common finding in dilated cardiomyopathy. Left ventricular (LV) reverse remodeling with LV size reduction and improvement in LV function is a well recognized phenomenon. We aimed to evaluate the impact of LV remodeling on the mechanism leading to functional MR. METHODS: Among 188 patients with non-ischemic dilated cardiomyopathy, 10 patients significantly improved their LV function, reduced LV size and MR severity during follow-up (RRMR). A comparison was made between their baseline and follow-up echocardiographic examinations and to a matched-control group of patients who did not improve (no RRMR). LV and left atrium (LA) dimensions and volumes, LV mass (LVM), LV ejection fraction (LVEF) (Simpsons), sphericity index (SI), mitral valve tenting area (TA) coaptation distance (CD), effective regurgitant orifice (ERO), and regurgitant volume were calculated. Multivariable analysis was performed in order to evaluate which echocardiographic parameters related to MR improvement in reverse remodeling. RESULTS: LV and LA dimensions and volumes, LVM, SI, TA, CD, ERO and right ventricle, in the RRMR group significantly decreased at follow-up (p < 0.04 for all). When compared to no RRMR, despite a similar ERO (0.2 +/- 0.05 vs. 0.2 +/- 0.08, p = 0.13) and a larger regurgitant volume (38 +/- 9 vs. 29 +/- 8 mL, p = 0.05) and despite similar clinical characteristics and medical treatment we found significantly higher LVEF, smaller LV dimensions and volumes, smaller LVM and SI in the RRMR group (p < 0.05 for all). On multivariable analysis the SI was the sole predictor of RRMR (p = 0.04, OR = 0.76, CI 0.58-0.99). CONCLUSIONS: Reverse remodeling characterized by improvement in LV function, reduction in LV size and an associated reduction in MR severity is related to LV SI at baseline. PMID- 26235211 TI - Meeting pragmatism halfway: making a pragmatic clinical trial protocol. AB - Pragmatic clinical trials (PCTs) are today an increasingly prominent means of measuring the 'effectiveness' of healthcare interventions in 'real world' clinical settings, in order to produce evidence on which to base regulatory and clinical decision-making. Although several sociological studies have shown persuasively how PCTs are co-constructed within particular healthcare systems in which they are based, they have tended to focus on relatively later stages in careers of trials. The paper contributes to literature by considering how the 'real world' of the UK National Health Service (NHS) is incorporated into the design of a research protocol. Drawing on a meeting held just prior to patient recruitment for a PCT in maternal health, the paper analyses a trial collective's efforts to purify the messy domain of NHS clinical care into the orderly confines of the protocol (Law 2004), which meant satisfying demands for both scientific and social robustness (c.f. Nowotny et al. 2001). The findings show how efforts to inscribe robustness into the PCT protocol were themselves mediated through epistemic and regulatory conventions surrounding protocols as devices in healthcare research. Finally it is argued that meetings constitute an important epistemic instrument through which to settle various emerging tensions in PCT protocol design. PMID- 26235212 TI - Palladium-Catalyzed Zinc-Amide-Mediated C-H Arylation of Fluoroarenes and Heteroarenes with Aryl Sulfides. AB - C-H arylation of polyfluoroarenes and heteroarenes with aryl sulfides proceeds smoothly with the aid of a palladium-N-heterocyclic carbene catalyst. A bulky zinc amide, TMPZnCl?LiCl, plays a key role as an effective base to generate the corresponding arylzinc species in situ. This arylation protocol is practically much easier to perform than our previous method, which necessitates preparation of the arylzinc reagents in advance from the corresponding aryl halides. Aryl sulfides that are prepared through sulfur-specific reactions, such as SN Ar sulfanylation and extended Pummerer reactions, undergo this direct arylation, offering interesting transformations that are otherwise difficult to achieve with conventional halogen-based organic synthesis. PMID- 26235210 TI - Critical roles of co-activation receptor DNAX accessory molecule-1 in natural killer cell immunity. AB - Natural killer (NK) cells, which can exert early and powerful anti-tumour and anti-viral responses, are important components of the innate immune system. DNAX accessory molecule-1 (DNAM-1) is an activating receptor molecule expressed on the surface of NK cells. Recent findings suggest that DNAM-1 is a critical regulator of NK cell biology. DNAM-1 is involved in NK cell education and differentiation, and also plays a pivotal role in the development of cancer, viral infections and immune-related diseases. However, tumours and viruses have developed multiple mechanisms to evade the immune system. They are able to impair DNAM-1 activity by targeting the DNAM-1 receptor-ligand system. We have reviewed the roles of DNAM 1, and its biological functions, with respect to NK cell biology and DNAM-1 chimeric antigen receptor-based immunotherapy. PMID- 26235213 TI - Temoporfin photodynamic therapy in advanced hilar ductal carcinoma: A promising endoscopic modality. PMID- 26235214 TI - Toward point-of-care testing for JAK2 V617F mutation on a microchip. AB - Molecular genetics now plays a crucial role in diagnosis, the identification of prognostic markers, and monitoring of hematological malignancies. Demonstration of acquired changes such as the JAK2 V617F mutation within myeloproliferative neoplasms (MPN) has quickly moved from a research setting to the diagnostic laboratory. Microfluidics-based assays can reduce the assay time and sample/reagent consumption and enhance the reaction efficiency; however, no current assay has integrated isothermal amplification for point-of-care MPN JAK2 V617F mutation testing with a microchip. In this report, an integrated microchip that performs the whole human blood genomic DNA extraction, loop-mediated isothermal nucleic acid amplification (LAMP) and visual detection for point-of care genetic mutation testing is demonstrated. This method was validated on DNA from cell lines as well as on whole blood from patients with MPN. The results were compared with those obtained by unlabeled probe melting curve analysis. This chip enjoys a high accuracy, operability, and cost/time efficiency within 1h. All these benefits provide the chip with a potency toward a point-of-care genetic analysis. All samples identified as positive by unlabeled probe melting curve analysis (n=27) proved positive when tested by microchip assay. None of the 30 negative controls gave false positive results. In addition, a patient with polycythemia vera diagnosed as being JAK2 V617F-negative by unlabeled probe melting curve analysis was found to be positive by the microchip. This microchip would possibly be very attractive in developing a point-of-care platform for quick preliminary diagnosis of MPN or other severe illness in resource-limited settings. PMID- 26235215 TI - The reaction of a platinated methionine motif of CTR1 with cysteine and histidine is dependent upon the type of precursor platinum complex. AB - The human copper protein (hCTR1) is believed to facilitate the cellular uptake of cisplatin. Cisplatin likely binds to the methionine (Met)-rich motifs located in the N-terminus of hCTR1, and ligand exchange would be essential if cisplatin has to pass through the hCTR1 channel. In this work, we investigated the reaction between platinated adducts of a methionine-rich motif of yeast CTR1 (Mets7) and N acetyl-cysteine (AcCys) or N-acetyl-histidine (AcHis), mimicking metal-binding residues downstream the CTR1 channel. Platination involved two cis-compounds, cisplatin and oxaliplatin, and one monofunctional complex, cis diammine(pyridine)chloridoplatinum(II) (cDPCP). The reactions were monitored by HPLC and the products were characterized by ESI-MS. The results indicate different reactivities depending upon the platinum complex. The cisplatin/Mets7 adduct reacts readily with both cysteine and histidine (t1/2<2min). In contrast, the oxaliplatin/Mets7 adduct reacts with cysteine but not with histidine, whereas cDPCP/Mets7 adduct reacts with histidine but not with cysteine. Hence, Mets7 adducts of these platinum complexes exhibit different reactivities towards downstream coordinating amino acids. These results suggest that each platinum complex possesses different reactivities and consequently may lead to differences in their cellular distribution and bioactivity. PMID- 26235216 TI - Multiphasic presentation of Rasmussen's encephalitis. AB - Rasmussen's encephalitis is a rare, chronic inflammatory disorder of unknown cause, characterised by drug-resistant focal epilepsy that may rarely present in adolescence or adulthood. We present a case of Rasmussen's encephalitis with prominent recurrent fluctuation in symptoms and well-documented fluctuating changes on MRI, adding to the spectrum of diversity of Rasmussen's encephalitis. PMID- 26235217 TI - A Novel Advanced Laboratory Diagnosis to Guide Tuberculosis Drug Therapy. PMID- 26235218 TI - GRK5 Polymorphisms and Postoperative Atrial Fibrillation following Coronary Artery Bypass Graft Surgery. AB - Postoperative atrial fibrillation (POAF) is a serious yet common complication after coronary artery bypass grafting (CABG) surgery. Previous study have identified multiple genetic susceptibility loci for POAF susceptibility after CABG, although some studies are under-powered. However, none of these studies have been conducted among Asians. In current study, we aim to systematically evaluated the previous positive findings for POAF susceptibility after CABG among Chinese population, using a large population-based, two-stage, case-cohort study. From a discovery cohort of 1,348 patients, a total of nine independent loci were evaluated. Six significant SNPs were then assessed in a separately collected validation cohort of 2,000 patients. After adjustment for clinical predictors of POAF, two variants in GRK5 gene (rs4752292, and rs11198893) were replicated with significance were replicated in the validation cohort. The ORs for each additional copy of minor allele were 1.32 (95% CI: 1.15-1.50, P = 5.82 * 10(-5)) and 1.47 (95% CI: 1.28-1.69, P = 1.16 * 10(-7)), respectively. In this two-stage independently collected cardiac surgery cohorts, genetic variations in the GRK5 gene are independently associated with POAF risk in patients who undergo CABG surgery in Asians. PMID- 26235219 TI - Drawing dependent structures, mechanical properties and cyclization behaviors of polyacrylonitrile and polyacrylonitrile/carbon nanotube composite fibers prepared by plasticized spinning. AB - Drawing to change the structural properties and cyclization behaviors of the polyacrylonitrile (PAN) chains in crystalline and amorphous regions is carried out on PAN and PAN/carbon nanotube (CNT) composite fibers. Various characterization methods including Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and thermal gravimetric analysis are used to monitor the structural evolution and cyclization behaviors of the fibers. With an increase of the draw ratio during the plasticized spinning process, the structural parameters of the fibers, i.e. crystallinity and planar zigzag conformation, are decreased at first, and then increased, which are associated with the heat exchange rate and the oriented-crystallization rate. A possible mechanism for plasticized spinning is proposed to explain the changing trends of crystallinity and planar zigzag conformation. PAN and PAN/CNT fibers exhibit various cyclization behaviors induced by drawing, e.g., the initiation temperature for the cyclization (Ti) of PAN fibers is increased with increasing draw ratio, while Ti of PAN/CNT fibers is decreased. Drawing also facilitates cyclization and lowers the percentage of beta-amino nitrile for PAN/CNT fibers during the stabilization. PMID- 26235220 TI - Changes in the management of liver trauma leading to reduced mortality: 15-year experience in a major trauma centre. AB - BACKGROUND: Worldwide, the evolution of management of liver injury has resulted in improved outcomes. The aim of this study was to examine the trend in the management and outcomes of patients with liver injury. Primary outcomes were defined as mortality and hospital length of stay. The secondary aim was to identify independent predictors of mortality. METHODS: This study utilized hospital trauma registry data of all trauma patients with liver injuries admitted from 1999 to 2013. Patients in this 15-year period were divided into three periods of 5 years each and compared in terms of demographics, management and outcomes. RESULTS: A total of 725 patients with hepatic trauma were included. Patient demographics were similar, except for an increase in patient transfers from rural locations. Non-operative management increased significantly. There was a significant increase in the use of damage control surgery with perihepatic packing in high-grade liver injuries managed operatively. Hepatic angioembolization commenced midway through the study period. The overall mortality decreased by approximately threefold (P < 0.001) and mortality within 24 h of arrival to hospital by approximately fivefold (P < 0.001). Controlling for independent predictive factors of mortality, the mortality within 24 h reduced from 18.8% in period 1 to 3.6% in period 3 (P = 0.001). CONCLUSIONS: At this institution, an integrated trauma service has led to an evolution in the management of hepatic trauma, favouring non-operative management, damage control surgery and the use of hepatic angioembolization. We experienced a significantly improved mortality within 24 h of arrival to hospital in patients with liver trauma. PMID- 26235222 TI - Long-term adherence to inhaled corticosteroids in children with asthma: Observational study. AB - INTRODUCTION: Non-adherence to daily controller medication in childhood asthma is strongly dependent on potentially modifiable factors such as parental illness perceptions and medication beliefs. The extent to which adherence in children can be improved by addressing modifiable determinants of non-adherence has not been studied to date, however. We assessed long-term adherence and its determinants in children with asthma enrolled in a comprehensive asthma care program employing shared decision making with parents. METHODS: Observational study in 135 children 2-12 years of age with asthma attending a hospital-based outpatient clinic. One year adherence to inhaled corticosteroids was measured by electronic devices. Parental illness perceptions and medication beliefs, and asthma control were assessed by validated questionnaires. RESULTS: Median (interquartile range) adherence was 84% (70-92%). 55 children (41%) did not achieve the pre-defined level of good adherence (>=80%) and this was associated with poorer asthma control. Parental perceived medication necessity was high, with a median (interquartile range) BMQ necessity score of 17 (16-20). Parents' replies to the five key questions on the core issues of the program showed high concordance of their illness perceptions and medication beliefs with the medical model of asthma and its treatment. Differences in these perceptions between adherent and non adherent families were small and non-significant. CONCLUSIONS: Poor adherence may persist in children despite a high level of concordance between medical team and parents on illness perceptions and medication beliefs, even in the absence of socio-economic barriers to good adherence. Achieving good adherence in all children is a complex task, requiring interventions not covered in current guidelines of managing asthma in children. PMID- 26235221 TI - Fungi associated with rocks of the Atacama Desert: taxonomy, distribution, diversity, ecology and bioprospection for bioactive compounds. AB - This study assessed the diversity of cultivable rock-associated fungi from Atacama Desert. A total of 81 fungal isolates obtained were identified as 29 Ascomycota taxa by sequencing different regions of DNA. Cladosporium halotolerans, Penicillium chrysogenum and Penicillium cf. citrinum were the most frequent species, which occur at least in four different altitudes. The diversity and similarity indices ranged in the fungal communities across the latitudinal gradient. The Fisher-alpha index displayed the higher values for the fungal communities obtained from the siltstone and fine matrix of pyroclastic rocks with finer grain size, which are more degraded. A total of 23 fungal extracts displayed activity against the different targets screened. The extract of P. chrysogenum afforded the compounds alpha-linolenic acid and ergosterol endoperoxide, which were active against Cryptococcus neoformans and methicillin resistance Staphylococcus aureus respectively. Our study represents the first report of a new habitat of fungi associated with rocks of the Atacama Desert and indicated the presence of interesting fungal community, including species related with saprobes, parasite/pathogen and mycotoxigenic taxa. The geological characteristics of the rocks, associated with the presence of rich resident/resilient fungal communities suggests that the rocks may provide a favourable microenvironment fungal colonization, survival and dispersal in extreme conditions. PMID- 26235223 TI - Novel flexible belt-shaped coaxial microcables with tunable multicolor luminescence, electrical conductivity and magnetism. AB - A novel type of flexible [Fe3O4/PANI/PMMA]@{[Eu(BA)3phen + Tb(BA)3phen]/PMMA} (PMMA = polymethyl methacrylate, BA = benzoic acid, phen = phenanthroline, PANI = polyaniline) belt-shaped coaxial microcable possessing electrical conductivity, magnetism and color-tunable photoluminescence has been successfully fabricated by electrospinning technology using a specially designed coaxial spinneret. Every strip of belt-shaped coaxial microcable is assembled with a Fe3O4/PANI/PMMA electrically conductive -magnetic bifunctional core and a [Eu(BA)3phen + Tb(BA)3phen]/PMMA insulative and photoluminescence-tunable shell. The conductivity of the core of belt-shaped coaxial microcables reaches up to the order of 10(-2) S cm(-1) and all belt-shaped coaxial microcables are insulated from each other. The tuning of emission color is possible by changing the Eu(3+)/Tb(3+) molar ratio of the belt-shaped coaxial microcables. The electrical conductivity, magnetic and photoluminescence properties of belt-shaped coaxial microcables can be tuned by adjusting the content of PANI, Fe3O4 nanoparticles (NPs) and rare earth complexes. More importantly, the proposed design idea and the construction technique are universal regarding the preparation of other multifunctional one-dimensional micromaterials. PMID- 26235225 TI - Quality-by-design-based ultra high performance liquid chromatography related substances method development by establishing the proficient design space for sumatriptan and naproxen combination. AB - Quality-by-design-based methods hold greater level of confidence for variations and greater success in method transfer. A quality-by-design-based ultra high performance liquid chromatography method was developed for the simultaneous assay of sumatriptan and naproxen along with their related substances. The first screening was performed by fractional factorial design comprising 44 experiments for reversed-phase stationary phases, pH, and organic modifiers. The results of screening design experiments suggested phenyl hexyl column and acetonitrile were the best combination. The method was further optimized for flow rate, temperature, and gradient time by experimental design of 20 experiments and the knowledge space was generated for effect of variable on response (number of peaks >= 1.50 - resolution). Proficient design space was generated from knowledge space by applying Monte Carlo simulation to successfully integrate quantitative robustness metrics during optimization stage itself. The final method provided the robust performance which was verified and validated. Final conditions comprised Waters(r) Acquity phenyl hexyl column with gradient elution using ammonium acetate (pH 4.12, 0.02 M) buffer and acetonitrile at 0.355 mL/min flow rate and 30 degrees C. The developed method separates all 13 analytes within a 15 min run time with fewer experiments compared to the traditional quality-by testing approach. PMID- 26235226 TI - TFA-promoted direct C-H sulfenylation at the C2 position of non-protected indoles. AB - A simple, efficient and practical metal-free C-H sulfenylation process at the C2 position of non-protected indoles has been developed. 2-Thioindoles were obtained in moderate to high yields using stable and readily available N (thio)succinimides at room temperature in the presence of TFA. PMID- 26235224 TI - Dynamics of gene silencing during X inactivation using allele-specific RNA-seq. AB - BACKGROUND: During early embryonic development, one of the two X chromosomes in mammalian female cells is inactivated to compensate for a potential imbalance in transcript levels with male cells, which contain a single X chromosome. Here, we use mouse female embryonic stem cells (ESCs) with non-random X chromosome inactivation (XCI) and polymorphic X chromosomes to study the dynamics of gene silencing over the inactive X chromosome by high-resolution allele-specific RNA seq. RESULTS: Induction of XCI by differentiation of female ESCs shows that genes proximal to the X-inactivation center are silenced earlier than distal genes, while lowly expressed genes show faster XCI dynamics than highly expressed genes. The active X chromosome shows a minor but significant increase in gene activity during differentiation, resulting in complete dosage compensation in differentiated cell types. Genes escaping XCI show little or no silencing during early propagation of XCI. Allele-specific RNA-seq of neural progenitor cells generated from the female ESCs identifies three regions distal to the X inactivation center that escape XCI. These regions, which stably escape during propagation and maintenance of XCI, coincide with topologically associating domains (TADs) as present in the female ESCs. Also, the previously characterized gene clusters escaping XCI in human fibroblasts correlate with TADs. CONCLUSIONS: The gene silencing observed during XCI provides further insight in the establishment of the repressive complex formed by the inactive X chromosome. The association of escape regions with TADs, in mouse and human, suggests that TADs are the primary targets during propagation of XCI over the X chromosome. PMID- 26235227 TI - Uterine papillary serous carcinoma pre-operatively diagnosed as endometrioid carcinoma: Is omentectomy necessary? AB - BACKGROUND: Uterine papillary serous carcinoma (UPSC) is a relatively rare but aggressive uterine malignancy comprising approximately 10% of endometrial cancers. Many women pre-operatively misdiagnosed as having endometrioid carcinoma have ultimately UPSC on final pathology. These women receive inadequate surgical staging without omentectomy. AIM: To assess the value of omentectomy on disease free interval and overall survival in women with UPSC who had an initial diagnosis of endometrioid carcinoma. METHODS: This retrospective study included all women treated for the final diagnosis of UPSC in our centre from January 2007 to December 2012. Data regarding patient demographics, staging procedures, histology results, adjuvant therapy and follow-up outcomes were recorded. RESULTS: Of the 52 women with a final diagnosis of UPSC, more than 45% had an initial diagnosis of endometrioid carcinoma. All women underwent hysterectomy and removal of the adnexa. Lymph node evaluation was performed in 75% of women. Omentectomy was performed in 30/52 women (58%). Of those, three women (10%) had omental involvement. Mean disease-free interval with omentectomy was 24.5 months versus 30.5 months without (P = 0.29). Mean overall survival was 33 months with an omentectomy and 29 months without (P = 0.32). Recurrence patterns did not differ between groups. CONCLUSION: Women diagnosed pre-operatively with endometrioid carcinoma and eventually found to have UPSC can expect no change in prognosis despite not having undertaken a full staging procedure. Repeat surgery for omentectomy is probably of no benefit. PMID- 26235228 TI - Eyes on words: A fixation-related fMRI study of the left occipito-temporal cortex during self-paced silent reading of words and pseudowords. AB - The predominant finding of studies assessing the response of the left ventral occipito-temporal cortex (vOT) to familiar words and to unfamiliar, but pronounceable letter strings (pseudowords) is higher activation for pseudowords. One explanation for this finding is that readers automatically generate predictions about a letter string's identity - pseudowords mismatch these predictions and the higher vOT activation is interpreted as reflecting the resultant prediction errors. The majority of studies, however, administered tasks which imposed demands above and beyond the intrinsic requirements of visual word recognition. The present study assessed the response of the left vOT to words and pseudowords by using the onset of the first fixation on a stimulus as time point for modeling the BOLD signal (fixation-related fMRI). This method allowed us to assess the neural correlates of self-paced silent reading with minimal task demands and natural exposure durations. In contrast to the predominantly reported higher vOT activation for pseudowords, we found higher activation for words. This finding is at odds with the expectation of higher vOT activation for pseudowords due to automatically generated predictions and the accompanying elevation of prediction errors. Our finding conforms to an alternative explanation which considers such top-down processing to be non-automatic and task-dependent. PMID- 26235229 TI - Characterization of Paramagnetic Reactive Intermediates: Predicting the NMR Spectra of Iron(IV)-Oxo Complexes by DFT. AB - The relative energies of spin states of several iron(IV)-oxo complexes and related species have been calculated with DFT methods by employing the B3LYP* functional. We show that such calculations can predict the correct ground spin state of Fe(IV) complexes and can then be used to determine the (1) H NMR spectra of all spin states; the spectral features are remarkably different, hence calculated paramagnetic (1) H NMR spectra can be used to support the structure elucidation of numerous paramagnetic complexes. Applications to a number of stable and reactive iron(IV)-oxo species are described. PMID- 26235231 TI - Palladium-catalyzed arylation of 2H-chromene: a new entry to pyrano[2,3 c]carbazoles. AB - Pyrano[2,3-c]carbazoles which are biologically valuable and synthetically challenging frameworks are synthesized in high yields over five steps from commercially available resorcinol. Palladium-catalyzed arylation remains a key step in this novel strategy. The versatility of this protocol has been demonstrated by the synthesis of naturally occurring alkaloid clauraila C and 7 methoxyglycomaurin. The anti-proliferative activity of these designed compounds (5a, 5f, and 5l) has been evaluated in a cancer cell line (MOLT-4). The molecular docking study revealed that this pyrano[2,3-c]carbazole class of molecules selectively occupies the colchicine binding site of the tubulin-polymer. PMID- 26235230 TI - Interstitial flows promote amoeboid over mesenchymal motility of breast cancer cells revealed by a three dimensional microfluidic model. AB - Malignant tumors are often associated with an elevated fluid pressure due to the abnormal growth of vascular vessels, and thus an increased interstitial flow out of the tumors. Recent in vitro works revealed that interstitial flows critically regulated tumor cell migration within a three dimensional biomatrix, and breast cancer cell migration behavior depended sensitively on the cell seeding density, chemokine availability and flow rates. In this paper, we focus on the role of interstitial flows in modulating the heterogeneity of cancer cell motility phenotype within a three dimensional biomatrix. Using a newly developed microfluidic model, we show that breast cancer cells (MDA-MB-231) embedded in a 3D type I collagen matrix exhibit both amoeboid and mesenchymal motility, and interstitial flows promote the cell population towards the amoeboid motility phenotype. Furthermore, the addition of exogenous adhesion molecules (fibronectin) within the extracellular matrix (type I collagen) partially rescues the mesenchymal phenotype in the presence of the flow. Quantitative analysis of cell tracks and cell shapes shows distinct differential migration characteristics of amoeboid and mesenchymal cells. Notably, the fastest moving cells belong to the subpopulation of amoeboid cells. Together, these findings highlight the important role of biophysical forces in modulating tumor cell migration heterogeneity and plasticity, as well as the suitability of microfluidic models in interrogating tumor cell dynamics at single-cell and subpopulation level. PMID- 26235232 TI - Post-Translational Modification of Bionanoparticles as a Modular Platform for Biosensor Assembly. AB - Context driven biosensor assembly with modular targeting and detection moieties is gaining significant attentions. Although protein-based nanoparticles have emerged as an excellent platform for biosensor assembly, current strategies of decorating bionanoparticles with targeting and detection moieties often suffer from unfavorable spacing and orientation as well as bionanoparticle aggregation. Herein, we report a highly modular post-translational modification approach for biosensor assembly based on sortase A-mediated ligation. This approach enables the simultaneous modifications of the Bacillus stearothermophilus E2 nanoparticles with different functional moieties for antibody, enzyme, DNA aptamer, and dye decoration. The resulting easy-purification platform offers a high degree of targeting and detection modularity with signal amplification. This flexibility is demonstrated for the detection of both immobilized antigens and cancer cells. PMID- 26235233 TI - "Family reunion"--A structured view on the composition of the receptor complexes of interleukin-6-type and interleukin-12-type cytokines. PMID- 26235235 TI - Cooperative effects of lattice and spin-orbit coupling on the electronic structure of orthorhombic SrIrO3. AB - Orthorhombic SrIrO3 subjected to strain shows tunable transport properties. With underlying symmetry remaining invariant, these properties are associated with IrO6 octahedral tilting. Adopting first-principles methods, the effects of crystal field, spin-orbit coupling (SOC), and Coulomb correlations, on comparable interaction length scales, are discussed. While tilting induces a t(2g) - e(g) crystal-field splitting and band narrowing, SOC induces a partial splitting of the J(eff) bands rendering SrIrO3 a semi-metallic ground state. The SOC enhanced hybridization of Ir-O orbitals serves as an explanation as to why the critical Hubbard correlation strength increases with increasing SOC strength in SrIrO3 to induce an insulating phase. PMID- 26235236 TI - Isolation and propagation of the animal rotaviruses in MA-104 cells--30 years of practical experience. AB - A total of 136 rotavirus positive samples from diarrhoeic animals of different species were submitted for isolation and cultural propagation of rotavirus on MA 104 cells. The samples were collected from animals with diarrhoea, between 1980 and 2010, originating from herds or farms located in several parts of Germany. Rotaviruses of species A were isolated from 102 faecal samples in cultures of MA 104 cells under the following conditions: pre-treatment of virus with trypsin, incorporation of trypsin into culture medium, use of roller cultures, and centrifugation of the samples on the cells. The cell culture adapted viruses produced a cytopathic effect, accompanied by the release of cells from the glass surface of the cultivation vessels. After 10 passages the virus isolates yielded titres between 10(5.5) and 10(7.5)ml(-1) TCID50. Isolation and serial propagation of the virus in MA-104 cells was confirmed by immunofluorescence assay, transmission electron microscopy, and polyacrylamide-gel electrophoresis of viral dsRNA. Eight (5.9%) of the electrophoretic profiles were characteristic of species B or D rotaviruses, which were not replicated in MA-104 cells. PMID- 26235234 TI - tRNA-dependent alanylation of diacylglycerol and phosphatidylglycerol in Corynebacterium glutamicum. AB - Aminoacyl-phosphatidylglycerol synthases (aaPGSs) are membrane proteins that utilize aminoacylated tRNAs to modify membrane lipids with amino acids. Aminoacylation of membrane lipids alters the biochemical properties of the cytoplasmic membrane and enables bacteria to adapt to changes in environmental conditions. aaPGSs utilize alanine, lysine and arginine as modifying amino acids, and the primary lipid recipients have heretofore been defined as phosphatidylglycerol (PG) and cardiolipin. Here we identify a new pathway for lipid aminoacylation, conserved in many Actinobacteria, which results in formation of Ala-PG and a novel alanylated lipid, Alanyl-diacylglycerol (Ala DAG). Ala-DAG formation in Corynebacterium glutamicum is dependent on the activity of an aaPGS homolog, whereas formation of Ala-PG requires the same enzyme acting in concert with a putative esterase encoded upstream. The presence of alanylated lipids is sufficient to enhance the bacterial fitness of C. glutamicum cultured in the presence of certain antimicrobial agents, and elucidation of this system expands the known repertoire of membrane lipids acting as substrates for amino acid modification in bacterial cells. PMID- 26235237 TI - Local-scale Partitioning of Functional and Phylogenetic Beta Diversity in a Tropical Tree Assemblage. AB - The relative degree to which stochastic and deterministic processes underpin community assembly is a central problem in ecology. Quantifying local-scale phylogenetic and functional beta diversity may shed new light on this problem. We used species distribution, soil, trait and phylogenetic data to quantify whether environmental distance, geographic distance or their combination are the strongest predictors of phylogenetic and functional beta diversity on local scales in a 20-ha tropical seasonal rainforest dynamics plot in southwest China. The patterns of phylogenetic and functional beta diversity were generally consistent. The phylogenetic and functional dissimilarity between subplots (10 * 10 m, 20 * 20 m, 50 * 50 m and 100 * 100 m) was often higher than that expected by chance. The turnover of lineages and species function within habitats was generally slower than that across habitats. Partitioning the variation in phylogenetic and functional beta diversity showed that environmental distance was generally a better predictor of beta diversity than geographic distance thereby lending relatively more support for deterministic environmental filtering over stochastic processes. Overall, our results highlight that deterministic processes play a stronger role than stochastic processes in structuring community composition in this diverse assemblage of tropical trees. PMID- 26235238 TI - Impact of inflammation-based prognostic score on survival after curative thoracoscopic esophagectomy for esophageal cancer. AB - BACKGROUND: Despite recent improvements in early detection, progress in surgical techniques, and development of chemoradiation therapies, prognosis of esophageal cancer remains poor. The aim of the present study was to assess whether Glasgow Prognostic Score (GPS), an inflammation-based prognostic score, has prognostic value independent of conventional clinicopathological criteria in patients undergoing curative resection for esophageal cancer, even in elderly patients. METHODS: We retrospectively reviewed the database of 141 consecutive patients with histologically verified esophageal squamous cell carcinoma who underwent potentially curative surgery in our institute, between January 2006 and December 2014. GPS and neutrophil lymphocyte ratio (NLR) were calculated. RESULTS: On multivariate analysis, TNM stage (p < 0.0001) and GPS (p = 0.041) were independently associated with worse prognosis in overall patients with esophageal cancer. Multivariate analysis evaluated the prognostic factors in two different patient groups: patients younger than 70 years (non-elderly) and those aged 70 years or more (elderly). Multivariate analysis demonstrated that TNM stage (p = 0.0003) was an only independent risk factor for a worse prognosis among non elderly group. Meanwhile, multivariate analysis demonstrated that TNM stage (p = 0.001) and GPS (p = 0.043) were the independent risk factor for a worse prognosis among elderly group. CONCLUSION: The present study demonstrated that GPS is associated with prognosis and can be considered as an independent prognostic marker in patients who underwent esophagectomy. Moreover, the GPS has the advantage of being simple to measure, routinely available and well standardized. But the present study failed to confirm the NLR as a significant predictor of survival following resection for esophageal cancer. PMID- 26235239 TI - Effects of low- and high-frequency repetitive magnetic stimulation on neuronal cell proliferation and growth factor expression: A preliminary report. AB - Repetitive magnetic stimulation is a neuropsychiatric and neurorehabilitation tool that can be used to investigate the neurobiology of sensory and motor functions. Few studies have examined the effects of repetitive magnetic stimulation on the modulation of neurotrophic/growth factors and neuronal cells in vitro. Therefore, the current study examined the differential effects of repetitive magnetic stimulation on neuronal cell proliferation as well as various growth factor expression. Immortalized mouse neuroblastoma cells were used as the cell model in this study. Dishes of cultured cells were randomly divided into control, sham, low-frequency (0.5Hz, 1Tesla) and high-frequency (10Hz, 1Tesla) groups (n=4 dishes/group) and were stimulated for 3 days. Expression of neurotrophic/growth factors, Akt and Erk was investigated by Western blotting analysis 3 days after repetitive magnetic stimulation. Neuroblastoma cell proliferation was determined with a cell counting assay. There were differences in cell proliferation based on stimulus frequency. Low-frequency stimulation did not alter proliferation relative to the control, while high-frequency stimulation elevated proliferation relative to the control group. The expression levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) and platelet-derived growth factor (PDGF) were elevated in the high-frequency magnetic stimulation group. Akt and Erk expression was also significantly elevated in the high-frequency stimulation group, while low-frequency stimulation decreased the expression of Akt and Erk compared to the control. In conclusion, we determined that different frequency magnetic stimulation had an influence on neuronal cell proliferation via regulation of Akt and ERK signaling pathways and the expression of growth factors such as BDNF, GDNF, NT-3 and PDGF. These findings represent a promising opportunity to gain insight into how different frequencies of repetitive magnetic stimulation may mediate cell proliferation. PMID- 26235240 TI - Conformation driven in situ interlock: from discrete metallocycles to infinite polycatenanes. AB - A novel conformation driven self-assembly system, where four metallocycles with different conformations have been in situ self-assembled, has been reported. Interestingly, only square metallocycles can further interlock into polycatenanes. However, rectangular and rhombus metallocycles fail to overcome such an entropically unfavourable process, which constitutes an obstacle to the formation of polycatenanes. PMID- 26235242 TI - alpha-Lipoic acid as a triglyceride-lowering nutraceutical. AB - Considering the current obesity epidemic in the United States (>100 million adults are overweight or obese), the prevalence of hypertriglyceridemia is likely to grow beyond present statistics of ~30% of the population. Conventional therapies for managing hypertriglyceridemia include lifestyle modifications such as diet and exercise, pharmacological approaches, and nutritional supplements. It is critically important to identify new strategies that would be safe and effective in lowering hypertriglyceridemia. alpha-Lipoic acid (LA) is a naturally occurring enzyme cofactor found in the human body in small quantities. A growing body of evidence indicates a role of LA in ameliorating metabolic dysfunction and lipid anomalies primarily in animals. Limited human studies suggest LA is most efficacious in situations where blood triglycerides are markedly elevated. LA is commercially available as dietary supplements and is clinically shown to be safe and effective against diabetic polyneuropathies. LA is described as a potent biological antioxidant, a detoxification agent, and a diabetes medicine. Given its strong safety record, LA may be a useful nutraceutical, either alone or in combination with other lipid-lowering strategies, when treating severe hypertriglyceridemia and diabetic dyslipidemia. This review examines the current evidence regarding the use of LA as a means of normalizing blood triglycerides. Also presented are the leading mechanisms of action of LA on triglyceride metabolism. PMID- 26235241 TI - Glial alterations from early to late stages in a model of Alzheimer's disease: Evidence of autophagy involvement in Abeta internalization. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease without effective therapy. Brain amyloid deposits are classical histopathological hallmarks that generate an inflammatory reaction affecting neuronal and glial function. The identification of early cell responses and of brain areas involved could help to design new successful treatments. Hence, we studied early alterations of hippocampal glia and their progression during the neuropathology in PDAPP-J20 transgenic mice, AD model, at 3, 9, and 15 months (m) of age. At 3 m, before deposits formation, microglial Iba1+ cells from transgenic mice already exhibited signs of activation and larger soma size in the hilus, alterations appearing later on stratum radiatum. Iba1 immunohistochemistry revealed increased cell density and immunoreactive area in PDAPP mice from 9 m onward selectively in the hilus, in coincidence with prominent amyloid Congo red + deposition. At pre plaque stages, GFAP+ astroglia showed density alterations while, at an advanced age, the presence of deposits was associated with important glial volume changes and apparently being intimately involved in amyloid degradation. Astrocytes around plaques were strongly labeled for LC3 until 15 m in Tg mice, suggestive of increased autophagic flux. Moreover, beta-Amyloid fibrils internalization by astrocytes in in vitro conditions was dependent on autophagy. Co-localization of Iba1 with ubiquitin or p62 was exclusively found in microglia contacting deposits from 9 m onward, suggesting torpid autophagy. Our work characterizes glial changes at early stages of the disease in PDAPP-J20 mice, focusing on the hilus as an especially susceptible hippocampal subfield, and provides evidence that glial autophagy could play a role in amyloid processing at advanced stages. PMID- 26235243 TI - Comment to the article 'A physiologically based model for spirometric reference equations in adults'. PMID- 26235244 TI - Chronic Alcoholism and the Danger of Profound Hypomagnesemia. PMID- 26235245 TI - Palindromic Rheumatism: An Unusual Cause of Chronic Intermittent Arthritis. PMID- 26235246 TI - Artificial Hyperparathyroidism--Think Twice Before Taking Your Blood Sample. PMID- 26235247 TI - Occam's Razor and the Diagnosis of Mantle Cell Lymphoma. PMID- 26235248 TI - Renal Failure due to Excessive Intake of Almonds in the Absence of Oxalobacter formigenes. PMID- 26235249 TI - Investigation of the relationship between neutrophil-to-lymphocyte ratio and obstructive sleep apnoea syndrome. AB - OBJECTIVE: To investigate the neutrophil-to-lymphocyte ratio and sleep apnoea severity relationship. METHODS: Patients (n = 178) were assigned to five groups according to apnoea-hypopnea indices and continuous positive airway pressure use. White blood cell, neutrophil, lymphocyte and neutrophil-to-lymphocyte ratio values were compared for each group. RESULTS: The neutrophil-to-lymphocyte ratio values of severe obstructive sleep apnoea syndrome patients (group 4) were significantly higher than those of: control patients (group 1), mild obstructive sleep apnoea syndrome patients (group 2) and patients treated with continuous positive airway pressure (group 5) (p = 0.008, p = 0.008 and p = 0.003). Minimum oxygen saturation values of group 4 were significantly lower than those of groups 1, 2 and 5 (p = 0.0005, p = 0.011 and p = 0.001). There was a positive correlation between apnoea-hypopnea index and neutrophil-to-lymphocyte ratio (r = 0.758, p = 0.034), and a negative correlation between apnoea-hypopnea index and minimum oxygen saturation (r = -0.179, p = 0.012). CONCLUSION: Neutrophil-to lymphocyte ratio may be used to determine disease severity, complementing polysomnography. PMID- 26235250 TI - PAH/DAS covalently cross-linked layer-by-layer multilayers: a "nano-net" superstratum immobilizes nanoparticles and remains permeable to small molecules. AB - A "nano-net" superstratum strategy is developed to stabilize layer-by-layer (LbL) films that incorporate nanoparticles. The superstratum immobilizes silica, gold, or magnetic nanoparticles and at the same time is permeable to small molecules. Unlike most strategies to stabilize LbL multilayers reported in the literature, our strategy does not directly cross-link the nanoparticles and polymers in the adjacent layer, thus circumventing the tedious processes of (surface) modification of the nanoparticles or polymers. The unique advantage of our strategy is further employed in the preparation of a model functional device, where mesoporous silica nanoparticles are held in the composite multilayers with enhanced stabilities. A model drug, methylene blue, is then loaded in large amounts due to the porous structure of the silica particles, and could be released in a delayed manner up to 55 h. PMID- 26235251 TI - First Synthesis of Novel Aminophenyl Pyridinium-5-(hydroxybenzoyl) hydrazonomethyl-2-oxothiazol-3-ide Derivatives and Evaluation of Their Anticancer Activities. AB - The first total synthesis for large-scale production and anticancer activity of novel aminophenylpyridinium-5-(hydroxybenzoyl)hydrazonomethyl-2-oxothiazol-3-ide (PBHT) (1) and its derivatives are reported. The chemical structure of PBHT was unambiguously determined by utilization of the two-dimensional nuclear Overhauser effect (NOE) technique. The anticancer activity against human colon adenocarcinoma (HCT15) cells of all synthesized compounds was approximately four fold greater than that of 5-fluorouracil, with IC50 values ranging from 10.1 to 14.2 uM. The three structural determinants of hydroxybenzoyl, hydrazinylidene, and pyridinium oxothiazole in the synthesized compounds could be indispensable for exhibiting anticancer activity. PMID- 26235252 TI - Model of care for a changing healthcare system: are there foundational pillars for design? AB - Currently, healthcare organisations are being challenged to provide optimal clinical services within budget limitations while simultaneously being confronted by aging consumers and labour and skill shortages. Within this dynamic and changing environment, the ability to remain responsive to patient needs while managing these issues poses further challenges. Development or review of the model of care (MOC) may provide a possible solution to support efficiencies in service provision. Although MOC are not readily understood or appreciated as an efficiency strategy, they can be more easily explained by considering several recurring pillars when developing or redesigning an MOC. Generic and recurring foundational pillars include integrated care models, team functioning and communication, leadership, change management and lean thinking. These foundational pillars should be incorporated into the development and application of MOC in order to achieve desired outcomes. However, sustainability requires continuous review to enable improvement and must be integrated into routine business. Moreover, successful review of MOC requires collaboration and commitment by all stakeholders. Leaders are critical to motivating clinicians and stakeholders in the review process. Further, it is imperative that leaders engage stakeholders to commit to support the agreed strategies designed to provide efficient and comprehensive healthcare services. Redesign of MOC can significantly improve patient care by applying the agreed strategies. In the current healthcare environment, these strategies can favourably affect healthcare expenditure and, at the same time, improve the quality of interprofessional health services. PMID- 26235253 TI - Neurotoxicological effects of nicotine on the embryonic development of cerebellar cortex of chick embryo during various stages of incubation. AB - Long-acting nicotine is known to exert pathological effects on almost all tissues including the cerebellar cortex. The present work was designed to elucidate the effect of nicotine on the development of cerebellar cortex of chick embryo during incubation period. The fertilized eggs of hen (Gallus gallus domesticus) were injected into the air space by a single dose of long acting nicotine (1.6 mg/kg/egg) at the 4th day of incubation. The embryos were taken out of the eggs on days 8, 12 and 16 of incubation. The cerebellum of the control and treated embryos at above ages were processed for histopathological examination. The TEM were examined at 16th day of incubation. The results of the present study revealed that, exposure to long-acting nicotine markedly influence the histogenesis of cerebellar cortex of chick embryo during the incubation period. At 8th day of incubation, nicotine delayed the differentiation of the cerebellar analge; especially the external granular layer (EGL) and inner cortical layer (ICL). Furthermore, at 12th day of incubation, the cerebellar foliation was irregular and the Purkinje cells not recognized. By 16th day of incubation, the cerebellar foliations were irregular with interrupted cerebellar cortex and irregular arrangement of Purkinje cells. Immunohistochemical analysis for antibody P53 protein revealed that the cerebellar cortex in all stages of nicotine treated groups possessed a moderate to weak reaction for P53 protein however; this reaction was markedly stronger in the cerebellar cortex of control groups. Moreover, the flow cytometric analysis confirmed that the percentage of apoptosis in control group was significantly higher compared with that of nicotine treated group. At the TEM level, the cerebellar Purkinje cells of 16th day of treated groups showed multiple subcellular alterations in compared with those of the corresponding control group. Such changes represented by appearing of vacuolated mitochondria, cisternal fragmentation of RER, irregular grooves of Golgi tubules. Also, multiple cytoplasmic vacuoles and aggregation of Nissl granules were recorded around pyknotic nucleus. PMID- 26235254 TI - Potential roles of matrix metalloproteinases and characteristics of ovarian development in neonatal guinea pigs. AB - The present study was conducted to investigate expression of matrix metalloproteinases (MMPs) and early ovarian development in neonatal guinea pigs. Thirty neonatal guinea pigs at 3 or 8 days of age were administrated 5IU equine chorionic gonadotropin (eCG) or saline, and the ovaries were collected after 2 days of eCG. Serum concentrations of estradiol and progesterone were determined, and ovarian localization of StAR, MMP-2 and MMP-9 were analyzed by immunohistochemical staining. Results indicate that injection of eCG sensitized the neonatal ovary and elevated serum concentrations of estradiol and progesterone, but not enough to stimulate ovarian follicular development in the ovaries. MMP-2 and MMP-9 were both immunolocalized to the surface of granulosa cells of primary and secondary follicles, and high MMP-2 expression was accompanied by low StAR expression in eCG-treated ovaries. Collectively, we hypothesize that MMP-2, -9 and StAR are both involved in follicular atresia through their participation in cell proliferation and tissue remodeling. PMID- 26235255 TI - A prospective cohort study on poor oral hygiene and pancreatic cancer risk. AB - Poor oral hygiene has been proposed to increase the risk for pancreatic cancer. We aim to assess this hypothesis, using number of teeth, dental plaque and oral mucosal lesions examined at baseline as a proxy for oral hygiene. During 1973-74 a population-based prevalence study of oral mucosal lesions was carried out in Uppsala County in central Sweden. We followed the study population through linkages with the Swedish Cancer and Total Population registers. A total of 19,924 participants were included, and 126 pancreatic cancer cases were identified during an average of 28.7 years of follow-up. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) for pancreatic cancer were estimated using Cox proportional hazards regression models. Overall, subjects with fewer teeth at baseline tended to have an increased risk for pancreatic cancer, although the estimates were not statistically significant. Among subjects with more than 10 teeth, those with unacceptable dental plaque had an HR of 2.1 (95% CI: 1.0, 4.7), compared with those without dental plaque after adjustment for potential confounding factors. Individuals with Candida-related or denture related oral mucosal lesions, or tongue lesions, compared with those without any of the three studied lesions, had a 70, 30 and 80% excess risk of developing pancreatic cancer, respectively. Presence of more than one type of studied lesions further increased the risk for pancreatic cancer. In conclusion, our findings provide evidence to support the hypothesis that poor oral hygiene plays an important role in the development of pancreatic cancer. PMID- 26235256 TI - Enhanced light emission from carbon nanotubes integrated in silicon micro resonator. AB - Single-walled carbon nanotubes are considered a fascinating nanomaterial for photonic applications and are especially promising for efficient light emitters in the telecommunication wavelength range. Furthermore, their hybrid integration with silicon photonic structures makes them an ideal platform to explore their intrinsic properties. Here we report on the strong photoluminescence enhancement from carbon nanotubes integrated in silicon ring resonator circuits under two pumping configurations: surface-illuminated pumping at 735 nm and collinear pumping at 1.26 MUm. Extremely efficient rejection of the non-resonant photoluminescence was obtained. In the collinear approach, an emission efficiency enhancement by a factor of 26 has been demonstrated in comparison with the classical pumping scheme. This demonstration paves the way for the development of integrated light sources in silicon based on carbon nanotubes. PMID- 26235257 TI - Eribulin in 'field practice': an overview of the Italian experience. PMID- 26235258 TI - Long response to eribulin in breast cancer: a case report. AB - No definitive cure is available for metastatic breast cancer and current therapies mainly focus on symptom control and minimization of adverse events to extend survival and maintain a good quality of life. Current treatment options include hormonal and chemotherapeutic agents which are characterized by different toxicity profiles and are selected based on patients' performance status and prior therapies. Eribulin is a microtubule dynamic inhibitor which acts by sequestering tubulin molecules into aggregates, thus preventing microtubule growth and causing apoptosis. Many studies show that heavily pretreated metastatic breast cancer patients benefit from eribulin treatment both in terms of efficacy and for the favorable toxicity profile. In the Phase III EMBRACE study, eribulin treatment resulted in a significant improvement in overall survival. We report here the case of a patient who experienced a time to progression of several months with eribulin after three lines of chemotherapy and two lines of hormonal therapy. PMID- 26235259 TI - Benefit of eribulin in a patient with HER2(+) breast cancer who progressed after trastuzumab and lapatinib: a case report. AB - We report the case of a HER2(+) breast cancer patient, with early relapse, refractory to HER2-targeted therapy and treated with eribulin mesylate. The patient progressed during two different HER2 target therapies: trastuzumab as adjuvant/first-line treatment and lapatinib as second-line treatment. The patient underwent nine cycles of eribulin (1.23 mg/m(2) days 1-8 every 3 weeks). The therapy was well tolerated. Restaging with computed tomography after the second cycle of treatment demonstrated stable disease. After nine cycles of eribulin therapy the patient experienced disease progression and she died 6 months later. This case report provides further insights regarding the use of eribulin mesylate as third-line treatment in a HER2(+) breast cancer patient. PMID- 26235260 TI - Retinal metastasis regression with eribulin in a heavily pretreated breast cancer patient. AB - The authors present the case of a heavily pretreated young woman with retinal and brain metastases from breast cancer who was successfully treated with eribulin. Eribulin was given at 1.1 mg/m(2) on day 1 and 8, every 3 weeks for a total of 12 courses. A significant reduction in the size of brain and retinal lesions was achieved after three cycles. The treatment was continued for 12 cycles, with a good profile of tolerability. In this clinical case, eribulin demonstrated to be active on brain and retinal metastases from breast cancer, although preclinical data showed limited ability to cross the blood-brain barrier. PMID- 26235261 TI - Long-lasting control with eribulin in a taxane pretreated metastatic breast cancer patient. AB - Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Moreover, many chemotherapeutic agents need to be interrupted due to toxicity. Here we report an extremely long duration of chemotherapy with eribulin (11 courses) in a taxane-pretreated metastatic breast cancer patient. Therapy was well tolerated with no worsening of pre existing neuropathy, achieving excellent outcomes and a good quality of life. This report adds to the pool of knowledge regarding the use of this important new metastatic breast cancer chemotherapeutic agent. PMID- 26235262 TI - Response to eribulin in a difficult-to-treat, heavily pretreated breast cancer patient: a case report. AB - In this short paper, we report our experience with eribulin mesylate in a heavily pretreated breast cancer patient with multiple bone metastases. The patient had been treated with doxorubicin, cyclophosphamide, methotrexate, fluorouracil, tamoxifen, letrozole, LH-RH analogs, fulvestrant, bevacizumab and paclitaxel and liposomal doxorubicin. In November 2013 treatment with eribulin ready to use solution (1.23 mg/m(2) days 1 and 8 of a 21-day cycle) was started and administered for a total of 14 courses. After six cycles of eribulin, evaluation with MRI showed a marked decrease in neoplastic involvement and replacement of osteolytic lesions with osteoblastic ones. No unexpected acute toxicity was observed. Although with all the limitations of any anecdotal report, our experience documents the efficacy and safety of eribulin in this difficult-to treat patient who had been treated with multiple lines of chemotherapy. PMID- 26235263 TI - Eribulin mesylate in advanced breast cancer: retrospective review of a single institute experience. AB - AIM: EMA licensed eribulin mesylate in 2011 for women with advanced breast cancer already treated with at least two lines of chemotherapy, including anthracyclines and taxanes. Azienda Sanitaria Firenze experience is reported to assess the efficacy and safety of eribulin in the real-life setting. PATIENTS & METHODS: Eribulin was infused as per indication. All women treated in the last 2 years were reviewed. RESULTS: A total of 27 women received eribulin. All but one was pretreated with anthracyclines, 97% with taxanes and 87% with capecitabine. Median age was 63 years (range: 27-80). A median of four cycles of eribulin were infused (range: 2-10). Overall response rate was 30% with a 45% of clinical benefit (response plus stable disease for at least 24 weeks). Toxicities have been as expected. Severe toxicities were rare, with one patient experiencing sepsis and 18% developing grade 3 asthenia. CONCLUSION: Eribulin maintains its activity out of clinical trials, without unexpected toxicities. PMID- 26235264 TI - Epidermal growth factor receptor mutation status in cell-free DNA supernatant of bronchial washings and brushings. AB - BACKGROUND: The aim of the current study was to examine whether it would be possible to detect epidermal growth factor receptor (EGFR) mutations in cytology cell-free DNA (ccfDNA) from the supernatant fluids of bronchial cytology samples. METHODS: This study investigated cell damage via immunostaining with a cleaved caspase 3 antibody and the quantity of cell-free DNA in supernatant fluid from 2 cancer cell lines, and the EGFR mutation status was evaluated via polymerase chain reaction (PCR) analysis. EGFR mutations were also evaluated via PCR analysis in 74 clinical samples of ccfDNA from bronchial washing samples with physiological saline or from bronchial brushing liquid-based cytology samples with CytoRich Red. RESULTS: The quantity and fragmentation of cell-free DNA in the supernatant fluid and the cell damage and cleaved caspase 3 expression in the sediment gradually increased in a time-dependent manner in the cell lines. In the 74 clinical samples, the quantity of ccfDNA extracted from the supernatant was adequate to perform the PCR assay, whereas the quality of ccfDNA in physiological saline was often decreased. The detection of EGFR mutations with ccfDNA showed a sensitivity of 88.0%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 89.7%, and an accuracy of 94.1% in samples with malignant or atypical cells. CONCLUSIONS: These results suggest that activating EGFR mutations can be detected with ccfDNA extracted from the supernatant fluid of liquid-based samples via a PCR assay. This could be a rapid and sensitive method for achieving a parallel diagnosis by both morphology and DNA analysis in non-small cell lung cancer patients. PMID- 26235265 TI - Association between genetic variants in NOD2, C13orf31, and CCDC122 genes and leprosy among the Chinese Yi population. AB - BACKGROUND: A significant association between single nucleotide polymorphisms in NOD2, C13orf31, and CCDC122 genes and leprosy has been reported in a previous genome-wide association study of leprosy in the Chinese Han population. However, it remains unknown whether this association exists among the Chinese Yi population. The aim of this study was to investigate whether single nucleotide polymorphisms in NOD2, C13orf31, and CCDC122 genes are associated with leprosy among the Chinese Yi population in China. METHODS: We genotyped rs9302752, rs7194886, rs8057341, and rs3135499 in the NOD2 gene; rs3764147 and rs10507522 in the C13orf31 gene; and rs3088362 and rs9533634 in the CCDC122 gene in a Chinese Yi cohort comprised of 319 patients with leprosy and 355 ethnic-matched controls. The differences between the patients and healthy controls were analyzed using chi squared analysis. RESULTS: Significant differences of rs3135499 in NOD2, rs3764147 and rs10507522 in C13orf31, and rs3088362 and rs9533634 in CCDC122 were observed between the patients and the healthy control groups in the cohort. The allelic P values and odd ratios were as follows: rs3135499, 1.0 * 10(-8) and 2.55; rs3764147, 1.7 * 10(-7) and 1.88; rs10507522, 1.16 * 10(-5) and 1.95; rs3088362, 8.2 * 10(-4) and 1.51; rs9533634, 5.34 * 10(-5) and 1.73. No significant differences were found in the distributions of rs9302752, rs7194886, and rs8057341 between the patients and healthy controls. CONCLUSIONS: We demonstrated that genetic variants in the NOD2, C13orf31, and CCDC122 genes are closely associated with leprosy among the Chinese Yi population, which implicates the pathogenic role of NOD2, C13orf31, and CCDC122 genes in a different ethnicity. PMID- 26235266 TI - Preparation and evaluation of an astatine-211-labeled sigma receptor ligand for alpha radionuclide therapy. AB - INTRODUCTION: Sigma receptors are overexpressed in a variety of human tumors, making them potential targets for radionuclide receptor therapy. We have previously synthesized and evaluated (131)I-labeled (+)-2-[4-(4 iodophenyl)piperidino]cyclohexanol [(+)-[(131)I]pIV], which has a high affinity for sigma receptors. Therefore, (+)-[(131)I]pIV significantly inhibited tumor cell proliferation in tumor-bearing mice. In the present study, we report the synthesis and the in vitro and in vivo characterization of (+)-[(211)At]pAtV, an (211)At-labeled sigma receptor ligand, that has potential use in alpha radionuclide receptor therapy. METHODS: The radiolabeled sigma receptor ligand (+)-[(211)At]pAtV was prepared using a standard halogenation reaction generating a 91% radiochemical yield with 98% purity after HPLC purification. The partition coefficient of (+)-[(211)At]pAtV was measured. Cellular uptake experiments and in vivo biodistribution experiments were performed using a mixed solution of (+) [(211)At]pAtV and (+)-[(125)I]pIV; the human prostate cancer cell line DU-145, which expresses high levels of the sigma receptors, and DU-145 tumor-bearing mice. RESULTS: The lipophilicity of (+)-[(211)At]pAtV was similar to that of (+) [(125)I]pIV. DU-145 cellular uptake and the biodistribution patterns in DU-145 tumor-bearing mice at 1h post-injection were also similar between (+) [(211)At]pAtV and (+)-[(125)I]pIV. Namely, (+)-[(211)At]pAtV demonstrated high uptake and retention in tumor via binding to sigma receptors. CONCLUSION: These results indicate that (+)-[(211)At]pAtV could function as an new agent for alpha radionuclide receptor therapy. PMID- 26235267 TI - Serotonin promotes acinar dedifferentiation following pancreatitis-induced regeneration in the adult pancreas. AB - The exocrine pancreas exhibits a distinctive capacity for tissue regeneration and renewal following injury. This regenerative ability has important implications for a variety of disorders, including pancreatitis and pancreatic cancer, diseases associated with high morbidity and mortality. Thus, understanding its underlying mechanisms may help in developing therapeutic interventions. Serotonin has been recognized as a potent mitogen for a variety of cells and tissues. Here we investigated whether serotonin exerts a mitogenic effect in pancreatic acinar cells in three regenerative models, inflammatory tissue injury following pancreatitis, tissue loss following partial pancreatectomy, and thyroid hormone stimulated acinar proliferation. Genetic and pharmacological techniques were used to modulate serotonin levels in vivo. Acinar dedifferentiation and cell cycle progression during the regenerative phase were investigated over the course of 2 weeks. By comparing acinar proliferation in the different murine models of regeneration, we found that serotonin did not affect the clonal regeneration of mature acinar cells. Serotonin was, however, required for acinar dedifferentiation following inflammation-mediated tissue injury. Specifically, lack of serotonin resulted in delayed up-regulation of progenitor genes and delayed the formation of acinar-to-ductal metaplasia and defective acinar cell proliferation. We identified serotonin-dependent acinar secretion as a key step in progenitor-based regeneration, as it promoted acinar cell dedifferentiation and the recruitment of type 2 macrophages. Finally, we identified a regulatory Hes1-Ptfa axis in the uninjured adult pancreas, activated by zymogen secretion. Our findings indicated that serotonin plays a critical role in the regeneration of the adult pancreas following pancreatitis by promoting the dedifferentiation of acinar cells. PMID- 26235270 TI - Corrigendum: Induction of a Proton Gradient across a Gold-Supported Biomimetic Membrane by Electroenzymatic H2 Oxidation. PMID- 26235268 TI - [Recombinant tissue plasminogen activator for the management of intracardiac thrombi in newborns]. AB - INTRODUCTION: The incidence of cardiac thrombi in newborns has increased with the use of central venous catheters. Thrombolysis with recombinant tissue plasminogen activator (rTPA) has been used as an alternative to heparin in life threatening giant thrombus and embolization. The aim of this study is to describe the response and complications related to the use of rTPA in the management of life- threatening cardiac thrombi in newborns. PATIENTS AND METHOD: The medical records of 8 newborn were reviewed in a retrospective study, of whom 7 were preterm with cardiac thrombi, and rTPA was used in all of them. RESULTS: The patients included 4 males with a mean weight of 1580 gr. The principal pathology was sepsis (7/8), all of them used venous central catheter. The superior vena cava was the most frequent location, with a mean time of installation before the diagnosis of 12 days. RN 7/8 thrombi were located in the right atrium with a size between 7 to 20 mm. Three patients received low molecular weight heparin prior to using rTPA. They received between 1 to 5 cycles with rTPA. In 4 patients complete resolution of the thrombus was achieved in a mean of 3.5 days. Four patients had intracranial haemorrhage grade I, without sequelae at follow-up. There were no deaths or embolism. CONCLUSION: This study is the first series of infants treated with rTPA in Chile, and where its use has quickly achieved complete resolution of the thrombus in 50% of cases, and partially in the others, thus reducing the secondary life-threatening risk of this disease. PMID- 26235273 TI - Chronic Pelvic Pain Caused by Laxity of the Uterosacral Ligaments: Are the Posterior Fornix Syndrome and the Allen-Masters Syndrome Synonyms? PMID- 26235274 TI - The economic impact of symptomatic menopause among low-socioeconomic women in the United States. AB - BACKGROUND: Menopausal symptoms have a significant negative impact on patient's quality of life and increase healthcare costs among women. METHODS: This retrospective analysis used data from a U.S. national database (01 January 2008 31 December 2010). Patients with a diagnosis of menopause symptoms or a prescription claim for hormone therapy were matched to control patients. Healthcare resource utilization and costs during the 6-month follow-up period were compared. Generalized linear models were used to adjust for differences in baseline and demographic characteristics between the cohorts. RESULTS: A total of 71,076 patients were included in each cohort. Patients with menopausal symptoms were more likely to have depression and anxiety and incurred significantly higher follow-up healthcare costs ($7237 vs $6739, p < 0.001) and healthcare utilization during the 6-month follow-up period. CONCLUSION: Patients diagnosed with menopausal symptoms or treated with hormone therapy incurred significantly higher healthcare costs than those without menopausal symptoms or treatment. PMID- 26235276 TI - Metallic single-unit-cell orthorhombic cobalt diselenide atomic layers: robust water-electrolysis catalysts. AB - The bottleneck in water electrolysis lies in the kinetically sluggish oxygen evolution reaction (OER). Herein, conceptually new metallic non-metal atomic layers are proposed to overcome this drawback. Metallic single-unit-cell CoSe2 sheets with an orthorhombic phase are synthesized by thermally exfoliating a lamellar CoSe2 -DETA hybrid. The metallic character of orthorhombic CoSe2 atomic layers, verified by DFT calculations and temperature-dependent resistivities, allows fast oxygen evolution kinetics with a lowered overpotential of 0.27 V. The single-unit-cell thickness means 66.7 % of the Co(2+) ions are exposed on the surface and serve as the catalytically active sites. The lowered Co(2+) coordination number down to 1.3 and 2.6, gives a lower Tafel slope of 64 mV dec( 1) and higher turnover frequency of 745 h(-1) . Thus, the single-unit-cell CoSe2 sheets have around 2 and 4.5 times higher catalytic activity compared with the lamellar CoSe2 -DETA hybrid and bulk CoSe2 . PMID- 26235277 TI - NAPB - a novel SNARE-associated protein for early-onset epileptic encephalopathy. AB - Next-generation sequencing has accelerated the identification of disease genes in many rare genetic disorders including early-onset epileptic encephalopathies (EOEEs). While many of these disorders are caused by neuronal channelopathies, the role of synaptic and related neuronal proteins are increasingly being described. Here, we report a 6-year-old girl with unexplained EOEE characterized by multifocal seizures and profound global developmental delay. Recessive inheritance was considered due to parental consanguinity and Irish Traveller descent. Exome sequencing was performed. Variant prioritization identified a homozygous nonsense variant in the N-ethylmaleimide-sensitive factor attachment protein, beta (NAPB) gene resulting in a premature stop codon and 46% loss of the protein. NAPB plays a role in soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE)-complex dissociation and recycling (synaptic vesicle docking). Knockout mouse models of the murine ortholog Napb have been previously reported. These mice develop recurrent post-natal epileptic seizures in the absence of structural brain changes. The identification of a disease causing variant in NAPB further recognizes the importance of the SNARE complex in the development of epilepsy and suggests that this gene should be considered in patients with unexplained EOEE. PMID- 26235278 TI - Notch pathway promotes ovarian cancer growth and migration via CXCR4/SDF1alpha chemokine system. AB - Ovarian cancer is the most deadly gynecological malignancy. Understanding the molecular pathogenesis of ovarian cancer is critical to provide new targeted therapeutic strategies. Recent evidence supports a role for Notch in ovarian cancer progression and associates its dysregulation to poor overall survival. Similarly, CXCR4/SDF1alpha signalling correlates with ovarian cancer progression and metastasis. Recent findings indicate that Notch promotes CXCR4/SDF1alpha signalling and its effect on cell growth and migration; nonetheless, up to now, the association between Notch and CXCR4/SDFalpha in ovarian cancer has not been reported. Thereby, the aim of this study was to investigate if Notch and CXCR4/SDF1alpha cooperate in determining ovarian cancer growth, survival and migration. To address this issue, Notch signalling was inhibited by using gamma secretase inhibitors, or upregulated by forcing of Notch1 expression in ovarian cancer cell lines. Our results indicated that Notch activity influenced tumour cell growth and survival and positively regulated CXCR4 and SDF1alpha expression. CXCR4/SDF1alpha signalling mediated the effect of Notch pathway on ovarian cancer cell growth and SDF1alpha-driven migration. Additionally, for the first time, we demonstrated that Notch signalling activation can be detected in ovarian cancer specimens by immunohistochemistry analysis of the Notch transcriptional target, HES6 and is positively correlated with high expression levels of CXCR4 and SDF1alpha. Our results demonstrate that Notch affects ovarian cancer cell biology through the modulation of CXCR4/SDF1alpha signalling and suggest that Notch inhibition may be a rationale therapeutic approach to hamper ovarian cancer progression mediated by the CXCR4/SDF1alpha axis. PMID- 26235279 TI - Sympatho-adrenal morphogenesis regulated by the dorsal aorta. AB - The autonomic nervous system, composed of sympathetic- and para-sympathetic neurons, plays essential roles in a variety of physiological functions including homeostasis and responses to external stimuli. We here present an overview of recent findings concerning how the sympathetic nervous system is formed during the early development, paying particular attention to the morphogenesis of those tissues derived from migrating neural crest cells. Neural crest cells, originally multipotent, are progressively specified to sympathetic ganglia neurons and adrenomedullary cells during their migration through the body. Importantly, the dorsal aorta, the first-forming blood vessel, acts as a signaling center for their migration and differentiation. BMP signals emanating from the dorsal aorta are essential for establishing environmental cues that directly act on the migrating cells. The mechanisms underlying these early neuro-vascular interactions provide insights into understanding diseases caused by malfunctions and malformations of the autonomic nervous system. PMID- 26235280 TI - MoD Special Issue on interactions at the neurovascular interface. PMID- 26235281 TI - Lesson Learned and Practical Advice for Supporting the Pediatric Traveler. PMID- 26235282 TI - Does Reintegration Stress Contribute to Suicidal Ideation Among Returning Veterans Seeking PTSD Treatment? AB - Although posttraumatic stress disorder (PTSD) and other psychiatric symptoms are well-established risk factors for suicidal ideation among returning veterans, less attention has been paid to whether the stress of reintegrating into civilian society contributes to suicidal ideation. Utilizing a sample of 232 returning veterans (95% male, mean age = 33.63 years) seeking PTSD treatment, this study tested whether reintegration difficulties contribute to suicidal ideation over and above the influence of PTSD symptoms, depression symptoms, and potential substance misuse. Logistic regressions indicated that reintegration stress had a unique effect on suicidal ideation over and above PTSD and depression symptoms. Reintegration stress interacted with substance misuse to predict suicidal ideation, such that the effect of reintegration stress on suicidal ideation was much larger for those with potential substance misuse. Exploratory analyses also examined which types of reintegration difficulties were associated with suicidal ideation, and found that difficulty maintaining military friendships, difficulty getting along with relatives, difficulty feeling like you belong in civilian society, and difficulty finding meaning/purpose in life were all significantly associated with suicidal ideation, beyond the effects of psychiatric symptoms and potential substance misuse. Findings highlight the importance of addressing reintegration stress for the prevention of suicide among returning veterans. Implications for treatment are discussed. PMID- 26235283 TI - Ion channel gene expression predicts survival in glioma patients. AB - Ion channels are important regulators in cell proliferation, migration, and apoptosis. The malfunction and/or aberrant expression of ion channels may disrupt these important biological processes and influence cancer progression. In this study, we investigate the expression pattern of ion channel genes in glioma. We designate 18 ion channel genes that are differentially expressed in high-grade glioma as a prognostic molecular signature. This ion channel gene expression based signature predicts glioma outcome in three independent validation cohorts. Interestingly, 16 of these 18 genes were down-regulated in high-grade glioma. This signature is independent of traditional clinical, molecular, and histological factors. Resampling tests indicate that the prognostic power of the signature outperforms random gene sets selected from human genome in all the validation cohorts. More importantly, this signature performs better than the random gene signatures selected from glioma-associated genes in two out of three validation datasets. This study implicates ion channels in brain cancer, thus expanding on knowledge of their roles in other cancers. Individualized profiling of ion channel gene expression serves as a superior and independent prognostic tool for glioma patients. PMID- 26235285 TI - Non-Hodgkin lymphomas: impact of rituximab on overall survival of patients with diffuse large B-cell and follicular lymphoma. AB - BACKGROUND AND AIMS: Information comparing treatment outcome for diffuse large B cell (DLBCL) and follicular (FL) non-Hodgkin lymphoma (NHL) patients treated with schemes with and without rituximab from low- and middle-income countries is scarce. Clinical characteristics, response to therapy and long-term outcome of DLBCL and FL patients were studied. METHODS: Patients with DLBCL and FL diagnosed over 8 years at a reference center in northeast Mexico were included. Kaplan Meier method was used to determine overall survival (OS) and progression-free survival (PFS). Cox regression model was used to evaluate the association between risk factors, rituximab therapy and clinical outcome. RESULTS: One hundred sixteen patients with DLBCL and 65 with FL in advanced stages were included. Median age was 57.8 and 56 years, respectively. Clinical characteristics between groups receiving or not receiving rituximab were comparable. Stages III and IV were found in 63.8% of DLBCL and 84.6% in FL patients, respectively. OS and PFS at 60 months were 63.8 and 51.2% in DLBCL and 70.6 and 33.8% in FL. No difference in OS was found in DLBCL and FL when rituximab-based regimens vs. non rituximab based regimens were compared, but a statistically significant difference was documented in PFS in FL patients. CONCLUSION: Addition of rituximab to CHOP-like regimens did not improve OS in DLBCL and FL NHL subtypes. In comparison to developed countries, diagnosis of NHL was made a decade earlier and in advanced clinical stages. Cost-efficiency of adding rituximab to therapy for these patients should be assessed. PMID- 26235286 TI - Climbing On: Editorial Evolution. PMID- 26235284 TI - The mechanochemistry of copper reports on the directionality of unfolding in model cupredoxin proteins. AB - Understanding the directionality and sequence of protein unfolding is crucial to elucidate the underlying folding free energy landscape. An extra layer of complexity is added in metalloproteins, where a metal cofactor participates in the correct, functional fold of the protein. However, the precise mechanisms by which organometallic interactions are dynamically broken and reformed on (un)folding are largely unknown. Here we use single molecule force spectroscopy AFM combined with protein engineering and MD simulations to study the individual unfolding pathways of the blue-copper proteins azurin and plastocyanin. Using the nanomechanical properties of the native copper centre as a structurally embedded molecular reporter, we demonstrate that both proteins unfold via two independent, competing pathways. Our results provide experimental evidence of a novel kinetic partitioning scenario whereby the protein can stochastically unfold through two distinct main transition states placed at the N and C termini that dictate the direction in which unfolding occurs. PMID- 26235287 TI - Multiscale modelling of palisade formation in gliobastoma multiforme. AB - Palisades are characteristic tissue aberrations that arise in glioblastomas. Observation of palisades is considered as a clinical indicator of the transition from a noninvasive to an invasive tumour. In this paper we propose a computational model to study the influence of the hypoxic switch in palisade formation. For this we produced three-dimensional realistic simulations, based on a multiscale hybrid model, coupling the evolution of tumour cells and the oxygen diffusion in tissue, that depict the shape of palisades during its formation. Our results can be summarized as follows: (1) the presented simulations can provide clinicians and biologists with a better understanding of three-dimensional structure of palisades as well as of glioblastomas growth dynamics; (2) we show that heterogeneity in cell response to hypoxia is a relevant factor in palisade and pseudopalisade formation; (3) we show how selective processes based on the hypoxia switch influence the tumour proliferation. PMID- 26235288 TI - Drafting mechanisms between a dolphin mother and calf. AB - We numerically study the drafting mechanisms between a dolphin mother and her calf swimming near the free surface. Formation locomotion between the cetacean mother-calf pair provides a way for the mother to assist the calf in its locomotion. Depending on the age and size of the calf, it swims at neonate, echelon, and infant positions. At each position, the effects of the calf's size, swimming speed, proximity to the free surface and the formation pattern are investigated and the optimal configurations predicted by the model based on the swimming hydrodynamics are compared with previous observations. It is shown that the neonate position is the optimal formation for controlling the separation of the calf, and the echelon position is the most hydrodynamically efficient position in transferring the thrust force from the mother to the calf. The infant position, on the other hand, avoids the energy loss due to wave generation so that it improves the self-propulsion performance of an older calf. PMID- 26235289 TI - Modeling the formation of cell-matrix adhesions on a single 3D matrix fiber. AB - Cell-matrix adhesions are crucial in different biological processes like tissue morphogenesis, cell motility, and extracellular matrix remodeling. These interactions that link cell cytoskeleton and matrix fibers are built through protein clutches, generally known as adhesion complexes. The adhesion formation process has been deeply studied in two-dimensional (2D) cases; however, the knowledge is limited for three-dimensional (3D) cases. In this work, we simulate different local extracellular matrix properties in order to unravel the fundamental mechanisms that regulate the formation of cell-matrix adhesions in 3D. We aim to study the mechanical interaction of these biological structures through a three dimensional discrete approach, reproducing the transmission pattern force between the cytoskeleton and a single extracellular matrix fiber. This numerical model provides a discrete analysis of the proteins involved including spatial distribution, interaction between them, and study of the different phenomena, such as protein clutches unbinding or protein unfolding. PMID- 26235290 TI - Diamond-Blackfan anemia: death by heme toxicity? PMID- 26235291 TI - Food for thought: obstacles to menu labelling in restaurants and cafeterias. AB - Menu labelling is recommended as a policy intervention to reduce obesity and diet related disease. The present commentary considers the many challenges the restaurant industry faces in providing nutrition information on its menus. Barriers include lack of nutrition expertise, time, cost, availability of nutrition information for exotic ingredients, ability to provide accurate nutrition information, libel risk, customer dissatisfaction, limited space on the menu, menu variations, loss of flexibility in changing the menu, staff training and resistance of employees to change current practice. Health promotion specialists and academics involved in fieldwork must help restaurateurs find solutions to these barriers for menu labelling interventions to be widely implemented and successful. Practical support for small independent restaurants such as free or subsidised nutrition analysis, nutrition training for staff and menu design may also be necessary to encourage voluntary participation. PMID- 26235292 TI - Immunosuppressive agents for treating IgA nephropathy. AB - BACKGROUND: IgA nephropathy (IgAN) is the most common glomerulonephritis world wide and a cause of end-stage kidney disease (ESKD) in 15% to 20% of patients within 10 years and in 30% to 40% of patients within 20 years from the onset of disease. This is an update of a review first published in 2003. OBJECTIVES: To determine the benefits and harms of immunosuppression for the treatment of IgAN. SEARCH METHODS: For this review update we searched the Specialised Register to 19 February 2015 through contact with the Trials Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of treatment for IgAN in adults and children and that compared immunosuppressive agents with placebo, no treatment, or other immunosuppressive or non-immunosuppressive agents. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study risk of bias and extracted data for population characteristics, interventions and outcomes including mortality, infection, hospitalisation, ESKD requiring renal replacement therapy (dialysis or kidney transplantation), doubling of serum creatinine, remission of proteinuria, and end of treatment urinary protein excretion, serum creatinine, and glomerular filtration rate.Estimates of treatment effect and hazards were summarised using random effects meta-analysis. Treatment effects were expressed as relative risk (RR) and 95% confidence intervals (95% CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. MAIN RESULTS: We included 32 studies comprising 1781 participants. Risk of bias within the included studies was generally high: 22 studies (69%) did not describe the method used to generate the randomisation sequence; 24 (75%) did not describe the methods used to conceal allocation; performance bias was not reported or high in 30 studies (94%); detection bias was unclear in 31 studies (97%); attrition bias was low in 14 studies (44%), unclear in eight (25%) and high in 12 studies (38%); reporting bias was low in 21 studies (67%) and high in 10 studies (31%); and four studies received industry funding or were terminated early (13%).Steroids lowered risks of progression to ESKD (6 studies, 341 participants: RR 0.44, 95% CI 0.25 to 0.80), and doubling of serum creatinine (6 studies, 341 participants: RR 0.45, 95% CI 0.29 to 0.69), lowered urinary protein excretion (6 studies, 263 participants: MD -0.49 g/24 h, 95% CI -0.72 to -0.25); and preserved glomerular filtration rate (4 studies, 138 participants: MD 17.87 mL/min/1.73 m(2), 95% CI 4.93 to 30.82) compared to no treatment or placebo. Combining steroids plus renin angiotensin-system (RAS) inhibitors lowered the risk of progression to ESKD (2 studies, 160 participants: RR 0.16, 95% CI 0.04 to 0.59) and reduced urinary protein excretion (1 study, 38 participants: MD -0.20 g/24 h, 95% CI -0.26 to 0.14) compared with RAS inhibitors or steroids alone. Cytotoxic agents (azathioprine) plus steroid regimens plus dipyridamole increased remission of proteinuria (1 study, 78 participants: RR 1.24, 95% CI 1.01 to 1.52) compared to steroids alone but had uncertain effects on other outcomes.Mycophenolate mofetil plus RAS inhibitors lowered the risk of progression to ESKD (1 study, 40 participants: RR 0.22, 95% CI 0.05 to 0.90), improved remission of proteinuria (1 study, 40 participants: RR 2.67, 95% CI 1.32 to 5.39) and reduced urinary protein excretion (1 study, 40 participants: MD -1.26 g/24 h, 95% CI -1.46 to -1.06). Effects of other immunosuppressive regimens (including cyclosporin, leflunomide) were inconclusive primarily due to insufficient data from the individual studies. Subgroup analyses to determine the impact of patient characteristics on treatment effectiveness were not possible. AUTHORS' CONCLUSIONS: The optimal management of IgAN remains uncertain although corticosteroid therapy may lower the risks of kidney disease progression and need for dialysis or transplantation. Evidence for treatment effects of immunosuppressive agents on mortality, infection, and cancer is generally sparse or low-quality and insufficient to guide clinical practice. Available RCTs are few, small, have high risk of bias - particularly selective reporting - and generally do not systematically identify treatment-related harms. Subgroup analyses to identify specific patient characteristics that might predict better response to therapy were not possible. Larger placebo-controlled studies of corticosteroid therapy or mycophenolate mofetil which are sufficiently powered to evaluate patient-relevant end points including adverse events and that examine the optimal duration of treatment are now required in populations with IgAN with a range of kidney function. PMID- 26235293 TI - Educational mismatch and mortality among native-born workers in Sweden. A 19-year longitudinal study of 2.5 million over-educated, matched and under-educated individuals, 1990-2008. AB - This study tests the hypothesis that a disjuncture between an individual's attained level of education and that held by average workers in the individual's occupation leads to higher mortality among those with a prolonged mismatched status. Swedish register data are used in a 19-year longitudinal mortality follow up study of all causes and specific causes of mortality. Participants were all men and women born between 1926 and 1985 who were alive on 1 September 1990, who had concurrent information on their attained level of education and the specific occupation or industry they were employed in during this period for at least a consecutive year. An objective measure of educational and occupational mismatch was constructed from these data. Those with a stable, over-educated matched, or under-educated employment status are included in the final analysis (N = 2,482,696). Independent of social, family, employers' characteristics and prior health problems, the findings from a multivariate, stratified Cox regression analysis suggest there is excessive mortality among the over-educated, and a protective effect of under-education among native-born Swedish men and women. PMID- 26235294 TI - Influence of non-orthodontic intervention on digit sucking and consequent anterior open bite: a preliminary study. AB - OBJECTIVES: This study aimed to assess behavioural and occlusal outcomes of non orthodontic intervention (NOI) in a sample of children, 4-12 years of age, in Australia, in order to establish clinical relevance. MATERIALS AND METHODS: Data from 91 patient records of 4- to 12-year-old children reporting a habit of digit sucking, from two clinics in north-eastern Australia, were de-identified and used. Each patient had been examined at two visits, separated by an interval of 4 months, using standard clinical procedures. RESULTS: Of the 77 children who received a 4-month NOI, 69 (89.6%) had ceased their digit sucking habit by the end of the NOI period [chi2=67.0, degrees of freedom (d.f.)=1, P<0.001]. Of the 72 subjects who had front teeth, the number with anterior open bite decreased from 37 (51.4%) to 12 (16.7%) upon completion of NOI (chi2=21.3, d.f.=1, P<0.001). Among the 32 patients with a measurable overjet, the mean overjet was found to decrease from 4.2+/-2.4 mm to 3.1+/-1.9 mm after implementation of NOI (t=5.8, d.f.=31, P<0.001). Children who received NOI were more likely to quit the digit sucking habit in the 4-month period (P<0.001, OR=51.8, 95% CI: 9.8-273.9) and were more likely to appear without anterior open bite at a 4-month recall (P<0.001, OR=30.0, 95% CI: 5.9-151.6). CONCLUSIONS: This study demonstrated clinical relevance of NOI on the cessation of a digit sucking habit, closure of anterior open bite and reduction of overjet. Further investigations are indicated. PMID- 26235295 TI - Intramolecular Formal anti-Carbopalladation/Heck Reaction: Facile Domino Access to Carbo- and Heterooligocyclic Dienes. AB - An intramolecular domino process consisting of a formal anti-carbopalladation followed by Heck reaction is realized. Complex oligo(hetero)cyclic scaffolds are efficiently obtained in one synthetic step from easily obtainable enyne precursors. In contrast to common syn-carbopalladation reactions of alkyne units, the carbopalladation employed here is designed to afford an anti-arrangement of the two new substituents across the emerging double bond. A prerequisite is that the residues next to the alkyne should lack any beta-hydrogen atoms. The method paves the way to tri- and tetrasubstituted double-bond systems that have not been accessible by conventional Pd catalysis. PMID- 26235296 TI - Editorial. PMID- 26235297 TI - Convergent synthesis of 4,5-branched inner-core oligosaccharides of lipopoly- and lipooligosaccharides. AB - The convergent synthesis of branched inner-core oligosaccharides of lipopoly- and lipooligosaccharide with a 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) disaccharide acceptor was achieved. The l-glycero-d-manno-heptopyranose (Hep) units for the branched core oligosaccharide Galbeta(1-4)Glcbeta(1-4)Hep and Hepalpha(1-3)Hep were prepared from the corresponding Hep building blocks. To obtain 4,5-branched core oligosaccharide structures, the common acceptor Kdoalpha(2-4)Kdo was glycosylated with the Hep units. PMID- 26235298 TI - Patient-centered care: a new paradigm for chronic liver disease. PMID- 26235299 TI - A novel HLA allele, HLA-DQB1*02:57, was identified by polymerase chain reaction sequence-based typing in a Chinese individual. AB - HLA-DQB1*02:57 has one base substitution at position 260 T>C in exon 2 from HLA DQB1*02:01:01. PMID- 26235300 TI - Coarse-grained molecular dynamics studies of the translocation mechanism of polyarginines across asymmetric membrane under tension. AB - Understanding interactions between cell-penetrating peptides and biomembrane under tension can help improve drug delivery and elucidate mechanisms underlying fundamental cellular events. As far as the effect of membrane tension on translocation, it is generally thought that tension should disorder the membrane structure and weaken its strength, thereby facilitating penetration. However, our coarse-grained molecular dynamics simulation results showed that membrane tension can restrain polyarginine translocation across the asymmetric membrane and that this effect increases with increasing membrane tension. We also analyzed the structural properties and lipid topology of the tensed membrane to explain the phenomena. Simulation results provide important molecular information on the potential translocation mechanism of peptides across the asymmetric membrane under tension as well as new insights in drug and gene delivery. PMID- 26235301 TI - Long-lasting seizure-related anxiety in patients with temporal lobe epilepsy and comorbid psychiatric disorders. AB - Ictal anxiety is a frequent epileptic symptom; it is usually brief, associated with objective clinical signs, and is not positively influenced by external factors, in contrast to psychiatric disorders. These criteria can, however, be misleading, especially in patients with psychiatric comorbidities. We report two patients with a history of drug-resistant right temporal lobe epilepsy, who developed long-lasting psychiatric symptoms, suggestive of exacerbation of their comorbid anxiety disorder. However, intracranial EEG data and [(18)F] FDG-PET suggested that these symptoms were related to seizure activity, highlighting the difficulties in differentiating ictal symptoms from psychiatric episodes in some patients with epilepsy and comorbid psychiatric disorders. [Published with video sequence]. PMID- 26235302 TI - Do adsorbed drugs onto P-glycoprotein influence its efflux capability? AB - The membrane biophysical aspects by which multidrug resistance (MDR) relate to the ABC transporter function still remain largely unknown. Notwithstanding the central role that efflux pumps like P-glycoprotein have in MDR onset, experimental studies classified additionally the lipid micro-environment where P gp is inserted as a determinant for the increased efflux capability demonstrated in MDR cell lines. Recently, a nonlinear model for drug-membrane interactions showed that, upon drug adsorption, long-range mechanical alterations are predicted to affect the P-gp ATPase function at external drug concentrations of ~10-100 MUM. However, our results also show that drug adsorption may also occur at P-gp nucleotide-binding domains where conformational changes drive the efflux cycle. Thus, we assessed the effect of drug adsorption to both protein-water and lipid-water interfaces by means of molecular dynamics simulations. The results show that free energies of adsorption are lower for modulators in both lipid/water and protein/water interfaces. Important differences in drug-protein interactions, protein dynamics and membrane biophysical characteristics were observed between the different classes. Therefore, we hypothesize that drug adsorption to the protein and lipid-water interface accounts for a complex network of events that affect the ability of transporters to efflux drugs. PMID- 26235303 TI - Deep Brain Stimulation for Refractory Cocaine Dependence. PMID- 26235304 TI - Gut microbiota richness promotes its stability upon increased dietary fibre intake in healthy adults. AB - Gut microbiota richness and stability are important parameters in host-microbe symbiosis. Diet modification, notably using dietary fibres, might be a way to restore a high richness and stability in the gut microbiota. In this work, during a 6-week nutritional trial, 19 healthy adults consumed a basal diet supplemented with 10 or 40 g dietary fibre per day for 5 days, followed by 15-day washout periods. Fecal samples were analysed by a combination of 16S rRNA gene pyrosequencing, intestinal cell genotoxicity assay, metatranscriptomics sequencing approach and short-chain fatty analysis. This short-term change in the dietary fibre level did not have the same impact for all individuals but remained significant within each individual gut microbiota at genus level. Higher microbiota richness was associated with higher microbiota stability upon increased dietary fibre intake. Increasing fibre modulated the expression of numerous microbiota metabolic pathways such as glycan metabolism, with genes encoding carbohydrate-active enzymes active on fibre or host glycans. High microbial richness was also associated with high proportions of Prevotella and Coprococcus species and high levels of caproate and valerate. This study provides new insights on the role of gut microbial richness in healthy adults upon dietary changes and host microbes' interaction. PMID- 26235305 TI - Stereoselective hydroacylation of bicyclic alkenes with 2-hydroxybenzaldehydes catalyzed by hydroxoiridium/diene complexes. AB - A hydroxoiridium complex coordinated with 1,5-cyclooctadiene efficiently catalyzed the hydroacylation of bicyclic alkenes with 2-hydroxybenzaldehyde and its derivatives in high yields with high stereoselectivity. PMID- 26235306 TI - Removal of multi-substituted nitroaromatic pollutants by zero valent iron: a comparison of performance, kinetics, toxicity and mechanisms. AB - Reductive degradation of three typical multi-substituted nitroaromatic pollutants by zero valent iron was comprehensively compared in terms of performance, kinetics, toxicity and mechanisms in this study. The results showed that 0.5 mM 2,4-dinitrochlorobenzene (DNCB), 2,4-dinitroanisole (DNAN) and 2,4-dinitrophenol (DNP) could be completely removed in the ZVI reduction system within 75 min, 90 min and 210 min, respectively. The pseudo first-order kinetics could well describe the reduction process of the three NACs by ZVI. The reduction rates of the three NACs follow the order of DNCB > DNAN > DNP, which was further confirmed by density functional theory computational analysis. Moreover, the acute toxicity of the three NAC effluents significantly decreased after treatment with ZVI. In addition, the mechanistic investigation revealed that the selective reduction of nitro groups on the three NACs was closely related to the characteristics of the functional groups on the benzene rings. The results of this study would increase the comprehensive understanding in terms of their performance, kinetics, toxicity and mechanisms involved in the reduction of multi-substituted NACs by ZVI, thus benefiting the effective treatment of wastewaters containing multi-substituted nitroaromatic pollutants due to ZVI. PMID- 26235307 TI - Effects of formulation on transport of pyrethroids in residential settings. AB - Washoff of 17 pyrethroid products resulting from a 1-h, 25.4-mm rainfall occurring 24 h after application was measured in indoor studies with concrete slabs. These products included different pyrethroid active ingredients and a range of formulation types. Based on this replicated study, 5 product pairs with contrasting washoff behaviors were chosen for an outdoor study using 6 full-scale house fronts in central California. Products in 4 of these pairs were applied once to different rectangular areas on the driveway (1 product in each pair to 3 house lots and the other to the remaining 3 house lots). The products in the fifth pair were applied 3 times at 2-mo intervals to vertical stucco walls above the driveway. All house lots received natural and simulated rainfall over 7 mo. Indoor studies showed differences up to 170-fold between paired products, whereas the maximum difference between paired products in the field was only 5-fold. In the pair applied to the wall, 1 product had 91 times the washoff of the other in the indoor study, whereas in the field the same product had 15% lower washoff. These results show that, although the formulation may influence washoff under actual use conditions, its influence is complex and not always as predicted by indoor experiments. Because the formulation also affects insect control, washoff research needs to be conducted together with efficacy testing. PMID- 26235308 TI - Synthesis and Atropisomerism of Cascaded Tetraphenylporphyrin-[60]Fullerene Hybrids. AB - Flexible, linked dendritic tetraphenylporphyrin (TPP)-fullerene hybrids were synthesized. They were designed to gain insight into and mimic the primary events in the natural photosynthetic reaction center. These multiporphyrin moieties are based on a light-harvesting concept. Moreover, they incorporate multiple redox components aligned along a redox gradient. Newkome-type dendrons were added to these TPP-fullerene hybrids. In principle they can mediate pH-dependent water solubility, which, however, could not be observed in this case. A protecting group strategy using tert-butyldiphenylsilyl groups allows convergent synthesis of the dendritic compounds. The dendritic multiporphyrins were synthesized separately and can be used as individual building blocks. Atropisomerism was observed in the dendritic compounds, and single atropisomers could be assigned to the corresponding peaks of a characteristic pattern in the NMR spectra. Deprotection of the Newkome-type dendrons was shown to be feasible under mild conditions that leave the redox gradient intact. PMID- 26235309 TI - Neural probes with multi-drug delivery capability. AB - Multi-functional neural probes are promising platforms to conduct efficient and effective in-depth studies of brain by recording neural signals as well as modulating the signals with various stimuli. Here we present a neural probe with an embedded microfluidic channel (chemtrode) with multi-drug delivery capability suitable for small animal experiments. We integrated a staggered herringbone mixer (SHM) in a 3-inlet microfluidic chip directly into our chemtrode. This chip, which also serves as a compact interface for the chemtrode, allows for efficient delivery of small volumes of multiple or concentration-modulated drugs via chaotic mixing. We demonstrated the successful infusion of combinatorial inputs of three chemicals with a low flow rate (170 nl min(-1)). By sequentially delivering red, green, and blue inks from each inlet and conducting visual inspections at the tip of the chemtrode, we measured a short residence time of 14 s which corresponds to a small swept volume of 66 nl. Finally, we demonstrated the potential of our proposed chemtrode as an enabling tool through extensive in vivo mice experiments. Through simultaneous infusions of a chemical (pilocarpine or tetrodotoxin (TTX) at inlet 1), a buffer solution (saline at inlet 2), and 4',6-diamidino-2-phenylindole (DAPI at inlet 3) locally into a mouse brain, we not only modulated the neural activities by varying the concentration of the chemical but also locally stained the cells at our target region (CA1 in hippocampus). More specifically, infusion of pilocarpine with a higher concentration resulted in an increase in neural activities while infusion of TTX with a higher concentration resulted in a distinctive reduction. For each chemical, we acquired multiple sets of data using only one mouse through a single implantation of the chemtrode. Our proposed chemtrode offers 1) multiplexed delivery of three drugs through a compact packaging with a small swept volume and 2) simultaneous recording to monitor near real-time effects on neural signals, which allows for more versatile in vivo experiments with a minimum number of animals to be sacrificed. PMID- 26235310 TI - Mating behavior as an indicator of quality of Drosophila subobscura males? AB - According to current theoretical predictions, any deleterious mutations that reduce nonsexual fitness may have a negative influence on mating success. This means that sexual selection may remove deleterious mutations from the populations. Males of good genetic quality should be more successful in mating, compared to the males of lower genetic quality. As mating success is a condition dependent trait, large fractions of the genome may be a target of sexual selection and many behavioral traits are likely to be condition dependent. We manipulated the genetic quality of Drosophila subobscura males by inducing mutations with ionizing radiation and observed the effects of the obtained heterozygous mutations on male mating behavior: courtship occurrence, courtship latency, mating occurrence, latency to mating and duration of mating. We found possible effects of mutations. Females mated more frequently with male progeny of nonirradiated males and that these males courted females faster compared to the male progeny of irradiated males. Our findings indicate a possible important role of sexual selection in purging deleterious mutations. PMID- 26235312 TI - Calix[4]arene triazole-linked pyrene: click synthesis, assembly on graphene oxide, and highly sensitive carbaryl sensing in serum. AB - A fluorescent calix[4]arene triazole-linked pyrene (CP) was carefully designed and synthesized via click chemistry. The modification of CP with graphene oxide (GO) by a simple non-covalent interaction strategy is presented. Further inspection by electrochemical impedance spectroscopy reveals that the CP-GO could exhibit a very high supramolecular recognition for carbaryl, in particular in serum samples with a nanomolar concentration detection. Additionally, it is easy to directly observe macroscopic recognition by the contact angle, and expand practical applications. PMID- 26235311 TI - Support of positive association in family-based genetic analysis between COL27A1 and Tourette syndrome. AB - Recently, a genome-wide association study has indicated associations between single nucleotide polymorphisms in the Collagen Type XXVII Alpha 1 gene (COL27A1) and Tourette syndrome in several ethnic populations. To clarify the global relevance of the previously identified SNPs in the development of Tourette syndrome, the associations between polymorphisms in COL27A1 and Tourette syndrome were assessed in Chinese trios. PCR-directed sequencing was used to evaluate the genetic contributions of three SNPs in COL27A1(rs4979356, rs4979357 and rs7868992) using haplotype relative risk (HRR) and transmission disequilibrium tests (TDT) with a total of 260 Tourette syndrome trios. The family-based association was significant between Tourette syndrome and rs4979356 (TDT: chi2 = 4.804, P = 0.033; HRR = 1.75, P = 0.002; HHRR = 1.32, P = 0.027), and transmission disequilibrium was suspected for rs4979357 (TDT: chi2 = 3.969, P = 0.053; HRR = 1.84, P = 0.001; HHRR = 1.29, P = 0.044). No statistically significant allele transfer was found for rs7868992 (TDT: chi2 = 2.177, P = 0.158). Although the TDT results did not remain significant after applying the conservative Bonferroni correction (p = 0.005), the significant positive HRR analysis confirmed the possibility of showing transmission disequilibrium, which provides evidence for an involvement of COL27A1in the development of TS. However, these results need to be verified with larger datasets from different populations. PMID- 26235313 TI - Design and Synthesis of Nicotinic Acetylcholine Receptor Antagonists and their Effect on Cognitive Impairment. AB - Structure modification of a lead compound (NSC13378) was accomplished in the present work by an in silico target-based design aimed at ligands acting on the nicotinic acetylcholine receptor (nAChR) for neurodegenerative diseases. A 187 compound focused library derived from the scaffold of the lead compound was screened against acetylcholine-binding proteins (AChBPs). Six compounds were identified and synthesized for binding and biological evaluations. Five compounds were found to bind with AChBPs. Among these compounds, QN1 and BZ1 showed the highest affinity binding with AChBP, with Kd values of 260 and 10 nm, respectively. Functional assays on isolated cell lines containing ligand-gated ion channels revealed that QN1 and BZ1 are a4b2-nAChR antagonists. QN1 and BZ1 significantly alleviated the memory impairment caused by the muscarinic cholinergic antagonist scopolamine (p < 0.05) in mice. Our findings demonstrate the potential of nAChR antagonists in drug development for cognitive impairments. PMID- 26235315 TI - Green functions of interacting systems in the strongly localized regime. AB - We have developed an approach to calculate the single-particle Green function of a one-dimensional many-body system in the strongly localized limit at zero temperature. Our approach sums the contributions of all possible forward scattering paths in configuration space. We demonstrate that for fermions and nearest neighbors interactions the Green function factorizes at every link connecting two sites with the same occupation. As a consequence, the conductance distribution function for interacting systems is log-normal, in the same universality class as non-interacting systems. We have developed a numerical procedure to calculate the ground state and the Green function, generating all possible paths in configuration space. Our results agree with results obtained by exact diagonalization of small systems in the limit of large disorder. PMID- 26235314 TI - Microfluidic Assembly of a Multifunctional Tailorable Composite System Designed for Site Specific Combined Oral Delivery of Peptide Drugs. AB - Multifunctional tailorable composite systems, specifically designed for oral dual delivery of a peptide (glucagon-like peptide-1) and an enzymatic inhibitor (dipeptidyl peptidase 4 (DPP4)), were assembled through the microfluidics technique. Both drugs were coloaded into these systems for a synergistic therapeutic effect. The systems were composed of chitosan and cell-penetrating peptide modified poly(lactide-co-glycolide) and porous silicon nanoparticles as nanomatrices, further encapsulated in an enteric hydroxypropylmethylcellulose acetylsuccinate polymer. The developed multifunctional systems were pH-sensitive, inherited by the enteric polymer, enabling the release of the nanoparticles only in the simulated intestinal conditions. Moreover, the encapsulation into this polymer prevented the degradation of the nanoparticles' modifications. These nanoparticles showed strong and higher interactions with the intestinal cells in comparison with the nonmodified ones. The presence of DPP4 inhibitor enhanced the peptide permeability across intestinal cell monolayers. Overall, this is a promising platform for simultaneously delivering two drugs from a single formulation. Through this approach peptides are expected to increase their bioavailability and efficiency in vivo both by their specific release at the intestinal level and also by the reduced enzymatic activity. The use of this platform, specifically in combination of the two antidiabetic drugs, has clinical potential for the therapy of type 2 diabetes mellitus. PMID- 26235316 TI - Chlamydia-infected cells shed Gp96 to prevent chlamydial re-infection. AB - Chlamydia trachomatis is an obligate intracellular human pathogen with a biphasic developmental life cycle. The infectious elementary bodies (EBs) enter a host cell where they transform into reticulate bodies (RBs) that use cellular metabolites to multiply. Re-infection of an infected cell during the replicative phase of chlamydial development may prevent formation of infectious EBs, interrupting the infectious cycle. Here, we report that Glucose Regulated Protein 96 (Gp96), a chaperone for cell surface receptors, binds to and facilitates adherence and entry of C. trachomatis. Gp96 expression was increased early in infection in a MAP kinase-dependent way, thereby increasing chlamydial adherence and invasion. Gp96 co-precipitated with Protein Disulphide Isomerase (PDI), known to be involved in chlamydial host cell entry. During the replicative phase, Gp96 was depleted from infected cells and shed into the supernatant by activation of metalloproteinase TACE (ADAM17). Loss of Gp96 also reduced the activity of PDI on the cell surface. Reduced surface display of Gp96 prevented chlamydial re infection in a TACE-dependent manner in cell lines but also in primary cells derived from human fimbriae, the natural site of chlamydial infection. Our data suggest a role of infection-induced Gp96 shedding in the protection of the chlamydial replicative niche. PMID- 26235327 TI - Growth hormone (GH) increases cognition and expression of ionotropic glutamate receptors (AMPA and NMDA) in transgenic zebrafish (Danio rerio). AB - The growth hormone/insulin-like factor I (GH/IGF-I) somatotropic axis is responsible for somatic growth in vertebrates, and has important functions in the nervous system. Among these, learning and memory functions related to the neural expression of ionotropic glutamate receptors, mainly types AMPA (alpha-amino 3hydroxy-5methylisoxazole-4propionic) and NMDA (N-methyl-d-aspartate) can be highlighted. Studies on these mechanisms have been almost exclusively conducted on mammal models, with little information available on fish. Consequently, this study aimed at evaluating the effects of the somatotropic axis on learning and memory of a GH-transgenic zebrafish (Danio rerio) model (F0104 strain). Long-term memory (LTM) was tested in an inhibitory avoidance apparatus, and brain expression of igf-I and genes that code for the main subunits of the AMPA and NMDA receptors were evaluated. Results showed a significant increase in LTM for transgenic fish. Transgenic animals also showed a generalized pattern of increase in the expression of AMPA and NMDA genes, as well as a three-fold induction in igf-I expression in the brain. When analyzed together, these results indicate that GH, mediated by IGF-I, has important effects on the brain, with improvement in LTM as a result of increased glutamate receptors. The transgenic strain F0104 was shown to be an interesting model for elucidating the intricate mechanisms related to the effect of the somatotropic axis on learning and memory in vertebrates. PMID- 26235329 TI - Dissociation of the neural substrates of foraging effort and its social facilitation in the domestic chick. AB - The frequency or intensity of behavior is often facilitated by the presence of others. This social facilitation has been reported in a variety of animals, including birds and humans. Based on Zajonc's "drive theory," we hypothesized that facilitation and drive have shared neural mechanisms, and that dopaminergic projections from the midbrain to striatum are involved. As the ascending dopaminergic projections include the mesolimbic and nigrostriatal pathways, we targeted our lesions at the medial striatum (MSt) and substantia nigra (SN). We found that a bilateral electrolytic lesion of the MSt suppressed baseline foraging effort, but social facilitation was intact. Conversely, an electrolytic lesion targeted at the unilateral SN (on the right side) partially suppressed social facilitation, while baseline foraging effort remained unaffected. However, selective depletion of catecholaminergic (thyrosine hydroxylase immunoreactive) terminals by micro-infusion of 6-hydroxydopamine (6-OHDA) to bilateral MSt had no significant effects on foraging behavior, whereas it impaired formation of the association memory reinforced by water reward. Neurochemical assay by high perfromance liquid chromatography also revealed a significant decrease in the dopamine and noradrenaline contents in MSt after 6-OHDA micro-infusion compared with intact control chicks. Thus, we conclude that the neural substrate of social facilitation can be dissociated from that responsible for reward-based foraging effort, and that ascending dopaminergic pathways do not appear to contribute to social facilitation. Based on our detailed analysis of the lesion areas, we discuss fiber tracts or neural components of the midbrain tegmental area that may be responsible for social facilitation. PMID- 26235328 TI - Progestogens' effects and mechanisms for object recognition memory across the lifespan. AB - This review explores the effects of female reproductive hormones, estrogens and progestogens, with a focus on progesterone and allopregnanolone, on object memory. Progesterone and its metabolites, in particular allopregnanolone, exert various effects on both cognitive and non-mnemonic functions in females. The well known object recognition task is a valuable experimental paradigm that can be used to determine the effects and mechanisms of progestogens for mnemonic effects across the lifespan, which will be discussed herein. In this task there is little test-decay when different objects are used as targets and baseline valance for objects is controlled. This allows repeated testing, within-subjects designs, and longitudinal assessments, which aid understanding of changes in hormonal milieu. Objects are not aversive or food-based, which are hormone-sensitive factors. This review focuses on published data from our laboratory, and others, using the object recognition task in rodents to assess the role and mechanisms of progestogens throughout the lifespan. Improvements in object recognition performance of rodents are often associated with higher hormone levels in the hippocampus and prefrontal cortex during natural cycles, with hormone replacement following ovariectomy in young animals, or with aging. The capacity for reversal of age- and reproductive senescence-related decline in cognitive performance, and changes in neural plasticity that may be dissociated from peripheral effects with such decline, are discussed. The focus here will be on the effects of brain derived factors, such as the neurosteroid, allopregnanolone, and other hormones, for enhancing object recognition across the lifespan. PMID- 26235330 TI - Combined effects of exposure to dim light at night and fine particulate matter on C3H/HeNHsd mice. AB - Air and light pollution contribute to fetal abnormalities, increase prevalence of cancer, metabolic and cardiorespiratory diseases, and central nervous system (CNS) disorders. A component of air pollution, particulate matter, and the phenomenon of dim light at night (dLAN) both result in neuroinflammation, which has been implicated in several CNS disorders. The combinatorial role of these pollutants on health outcomes has not been assessed. Male C3H/HeNHsd mice, with intact melatonin production, were used to model humans exposed to circadian disruption by dLAN and contaminated environmental air. We hypothesized exposure to 2.5 MUm of particulate matter (PM2.5) and dLAN (5lx) combines to upregulate neuroinflammatory cytokine expression and alter hippocampal morphology compared to mice exposed to filtered air (FA) and housed under dark nights (LD). We also hypothesized that exposure to PM2.5 and dLAN provokes anxiety-like and depressive like responses. For four weeks, four groups of mice were simultaneously exposed to ambient concentrated PM2.5 or FA and/or dLAN or LD. Following exposure, mice underwent several behavioral assays and hippocampi were collected for qPCR and morphological analyses. Our results are generally comparable to previous PM2.5 and dLAN reports conducted on mice and implicate PM2.5 and dLAN as potential factors contributing to depression and anxiety. Short-term exposure to PM2.5 and dLAN upregulated neuroinflammatory cytokines and altered CA1 hippocampal structural changes, as well as provoked depressive-like responses (anhedonia). However, combined, PM2.5 and dLAN exposure did not have additive effects, as hypothesized, suggesting a ceiling effect of neuroinflammation may exist in response to multiple pollutants. PMID- 26235331 TI - Rats that sign-track are resistant to Pavlovian but not instrumental extinction. AB - Individuals vary in the extent to which they attribute incentive salience to a discrete cue (conditioned stimulus; CS) that predicts reward delivery (unconditioned stimulus; US), which results in some individuals approaching and interacting with the CS (sign-trackers; STs) more than others (goal-trackers; GTs). Here we asked how periods of non-reinforcement influence conditioned responding in STs vs. GTs, in both Pavlovian and instrumental tasks. After classifying rats as STs or GTs by pairing a retractable lever (the CS) with the delivery of a food pellet (US), we introduced periods of non-reinforcement, first by simply withholding the US (i.e., extinction training; experiment 1), then by signaling alternating periods of reward (R) and non-reward (NR) within the same session (experiments 2 and 3). We also examined how alternating R and NR periods influenced instrumental responding for food (experiment 4). STs and GTs did not differ in their ability to discriminate between R and NR periods in the instrumental task. However, in Pavlovian settings STs and GTs responded to periods of non-reward very differently. Relative to STs, GTs very rapidly modified their behavior in response to periods of non-reward, showing much faster extinction and better and faster discrimination between R and NR conditions. These results highlight differences between Pavlovian and instrumental extinction learning, and suggest that if a Pavlovian CS is strongly attributed with incentive salience, as in STs, it may continue to bias attention toward it, and to facilitate persistent and relatively inflexible responding, even when it is no longer followed by reward. PMID- 26235332 TI - Prognostic Role of C-Reactive Protein In Urological Cancers: A Meta-Analysis. AB - Growing evidence suggests serum C-reactive protein (CRP) can serve as a prognostic marker in urological cancers. However, some studies yield contradictory results. Our objective was to determine the relationship between baseline serum CRP and survival outcome in urological cancers. We searched PubMed and EMBASE databases until October 2014 without language restrictions. 44 independent studies investigating the association between baseline serum CRP and cancer-specific survival (CSS) or overall survival (OS) were selected. High CRP yielded a worse survival in renal cell carcinoma, prostate cancer, bladder cancer, and upper urinary tract urothelial carcinoma. Combined results of meta analyses indicated that CRP was a prognostic factor in urological cancers (CSS: p < 0.01; OS: p < 0.01). Subgroup analyses confirmed the significant association between CRP and prognosis, regardless of race and cutoff value of CRP. Specifically, prognostic impact of CRP was also noted in patients with localized RCC treated with nephrectomy (CSS: p < 0.01) and metastatic RCC treated with molecular-targeted therapy (OS: p < 0.01). In conclusion, serum CRP is an independent prognostic factor in urological cancers and risk stratification by serum CRP level could be helpful for prognostic assessment. PMID- 26235333 TI - A Phase 1 Trial of TPI 287 as a Single Agent and in Combination With Temozolomide in Patients with Refractory or Recurrent Neuroblastoma or Medulloblastoma. AB - BACKGROUND: The primary aim of this Phase I study was to determine the maximum tolerated dose (MTD) of TPI 287 and the safety and tolerability of TPI 287 alone and in combination with temozolomide (TMZ) in pediatric patients with refractory or recurrent neuroblastoma or medulloblastoma. The secondary aims were to evaluate the pharmacokinetics of TPI 287 and the treatment responses. PROCEDURE: Eighteen patients were enrolled to a phase I dose escalation trial of weekly intravenous infusion of TPI 287 for two 28-day cycles with toxicity monitoring to determine the MTD, followed by two cycles of TPI 287 in combination with TMZ. Samples were collected to determine the pharmacokinetic parameters C(max), AUC(0 24), t(1/2), CL, and Vd on day 1 of cycles 1 (TPI 287 alone) and 3 (TPI 287 + TMZ) following TPI 287 infusion. Treatment response was evaluated by radiographic (CT or MRI) and radionuclide (MIBG) imaging for neuroblastoma. RESULTS: We determined the MTD of TPI 287 alone and in combination with temozolomide to be 125 mg/m(2). The non-dose-limiting toxicities at this dose were mainly anorexia and pain. The dose-limiting toxicities (DLTs) of two patients at 135 mg/m(2) were grade 3 hemorrhagic cystitis and grade 3 sensory neuropathy. CONCLUSIONS: Overall, TPI 287 was well tolerated by pediatric patients with refractory and relapsed neuroblastoma and medulloblastoma at a dose of 125 mg/m(2) IV on days 1, 8, and 15 of a 28 day cycle. PMID- 26235334 TI - [A rare cause of eosinophilic asthma: Hyper-IgG4 syndrome (IgG4-related sclerosing disease)]. AB - INTRODUCTION: The hyper-IgG4 syndrome is an emerging disease with various thoracic manifestations: eosinophilic asthma, adenomegalies or mediastinal fibrosis, asthma, infiltrative pneumonia, nodules or pseudo-tumors with bronchial and pleural localizations. CASE REPORT: We report the case of a 38-year-old woman who was admitted for acute exacerbation of eosinophilic asthma with high total IgE levels. A medical history of idiopathic acute pancreatitis, associated with sclerosing cholangitis and renal failure, suggested a diagnosis of hyper-IgG4 syndrome in this woman with late-onset severe and non-atopic asthma. A previous hepatic histology and a reinterpretation of renal tomodensitometry have confirmed this hypothesis. CONCLUSION: The hyper-IgG4 syndrome is responsible of different clinico-radiological patterns that should be evoked because of the pejorative evolution of this steroid sensitive disease. PMID- 26235336 TI - Thianthrene-functionalized polynorbornenes as high-voltage materials for organic cathode-based dual-ion batteries. AB - Thianthrene-functionalized polynorbornenes were investigated as high-voltage organic cathode materials for dual-ion cells. The polymers show reversible oxidation reactions in solution and as a solid in composite electrodes. Constant current investigations displayed a capacity of up to 66 mA h g(-1) at a high potential of 4.1 V vs. Li/Li(+). PMID- 26235335 TI - The risk of acute liver injury associated with the use of antibiotics--evaluating robustness of results in the pharmacoepidemiological research on outcomes of therapeutics by a European consortium (PROTECT) project. AB - PURPOSE: To examine the robustness of findings of case-control studies on the association between acute liver injury (ALI) and antibiotic use in the following different situations: (i) Replication of a protocol in different databases, with different data types, as well as replication in the same database, but performed by a different research team. (ii) Varying algorithms to identify cases, with and without manual case validation. (iii) Different exposure windows for time at risk. METHODS: Five case-control studies in four different databases were performed with a common study protocol as starting point to harmonize study outcome definitions, exposure definitions and statistical analyses. RESULTS: All five studies showed an increased risk of ALI associated with antibiotic use ranging from OR 2.6 (95% CI 1.3-5.4) to 7.7 (95% CI 2.0-29.3). Comparable trends could be observed in the five studies: (i) without manual validation the use of the narrowest definition for ALI showed higher risk estimates, (ii) narrow and broad algorithm definitions followed by manual validation of cases resulted in similar risk estimates, and (iii) the use of a larger window (30 days vs 14 days) to define time at risk led to a decrease in risk estimates. CONCLUSIONS: Reproduction of a study using a predefined protocol in different database settings is feasible, although assumptions had to be made and amendments in the protocol were inevitable. Despite differences, the strength of association was comparable between the studies. In addition, the impact of varying outcome definitions and time windows showed similar trends within the data sources. PMID- 26235337 TI - Exogenous control over intracellular acidification: Enhancement via proton caged compounds coupled to gold nanoparticles. AB - The pH regulation has a fundamental role in several intracellular processes and its variation via exogenous compounds is a potential tool for intervening in the intracellular processes. Proton caged compounds (PPCs) release protons upon UV irradiation and may efficiently provoke intracellular on-command acidification. Here, we explore the intracellular pH variation, when purposely synthesized PCCs are coupled to gold nanoparticles (AuNPs) and dosed to HEK-293 cells. We detected the acidification process caused by the UV irradiation by monitoring the intensity of the asymmetric stretching mode of the CO(2) molecule at 2343 cm(-1). The comparison between free and AuNPs functionalized proton caged compound demonstrates a highly enhanced CO(2) yield, hence pH variation, in the latter case. Finally, PCC functionalized AuNPs were marked with a purposely synthesized fluorescent marker and dosed to HEK-293 cells. The corresponding fluorescence optical images show green grains throughout the whole cytoplasm. PMID- 26235339 TI - Inpatient Ophthalmology Consultation for Fungemia: Prevalence of Ocular Involvement and Necessity of Funduscopic Screening. AB - PURPOSE: To determine the generalizability of recent data assessing the necessity of ophthalmic consultation for fungemic patients, we examined the prevalence, microbial profile, and treatment of fungal chorioretinitis and endophthalmitis among patients with positive fungal cultures referred for ophthalmologic consultation at a tertiary care medical center. DESIGN: Retrospective cross sectional study. METHODS: All inpatient ophthalmology consultations from Wills Eye Hospital at Thomas Jefferson University between January 1, 2006 and December 31, 2012 were retrospectively reviewed and cross-referenced to a microbiologic database of positive fungal blood cultures. This included 227 adult consecutive inpatients with positive fungal blood cultures (n = 215) or suspected fungemia (n = 12). Clinical data were extracted from records held by the microbiology laboratory and inpatient records. Patients were deemed to have ocular fungal involvement if dilated fundus examination demonstrated evidence of chorioretinitis or endophthalmitis. RESULTS: Two hundred and twenty-seven consultations were requested to evaluate patients for ocular manifestations of fungemia. Eleven patients (4.8%, 95% CI 2.4%-8.5%) were diagnosed with fungal chorioretinitis or endophthalmitis. Of these 11 patients, 5 had visual symptoms, 2 were asymptomatic, and 4 were unable to communicate. A total of 5 patients (2.2%) received intravitreal injections following funduscopic screening. An additional 11 patients (4.8%) had nonspecific fundus lesions considered to be inconsistent with ocular fungal involvement. The most common fungal species identified were Candida albicans (n = 85), Candida glabrata (n = 63), and Candida parapsilosis (n = 44). CONCLUSIONS: The current study found a low rate of disseminated ocular involvement in patients with positive fungal cultures referred for ophthalmologic consultation. However, 2 patients with ocular fungal involvement denied visual symptoms and over half of affected patients were asymptomatic or unable to communicate. As the presence and severity of ocular involvement in fungemic patients may dictate the mode and duration of antifungal treatment, funduscopic screenings may still have an important role. PMID- 26235340 TI - Ground State Conditions Induce Rapid Reorganization of Core Pluripotency Factor Binding before Global Epigenetic Reprogramming. AB - Mouse embryonic stem cells (mESCs) cultured under serum/LIF conditions exhibit heterogeneous expression of pluripotency-associated factors that can be overcome by two inhibitors (2i) of the MEK and GSK3 pathways. Several studies have shown that the "ground state" induced by 2i is characterized by global hypomethylation and specific transcriptional profiles, but little is known about the contributing effectors. Here we show that 2i conditions rapidly alter the global binding landscape of OCT4, SOX2, and NANOG. The dynamic binding influences enhancer activity and shows enrichment for regulators linked to Wnt and Erk signaling. Epigenomic characterization provided limited insights to the immediate transcriptional dynamics, suggesting that these are likely more secondary effects. Likewise, loss of the PRC2 component EED to prevent H3K27me3 deposition had minimal effect on the transcriptome, implying that it is largely dispensable for continued repression of bivalent genes and de novo silencing in 2i. PMID- 26235341 TI - Single-Cell Transcriptomics Reveals a Population of Dormant Neural Stem Cells that Become Activated upon Brain Injury. AB - Heterogeneous pools of adult neural stem cells (NSCs) contribute to brain maintenance and regeneration after injury. The balance of NSC activation and quiescence, as well as the induction of lineage-specific transcription factors, may contribute to diversity of neuronal and glial fates. To identify molecular hallmarks governing these characteristics, we performed single-cell sequencing of an unbiased pool of adult subventricular zone NSCs. This analysis identified a discrete, dormant NSC subpopulation that already expresses distinct combinations of lineage-specific transcription factors during homeostasis. Dormant NSCs enter a primed-quiescent state before activation, which is accompanied by downregulation of glycolytic metabolism, Notch, and BMP signaling and a concomitant upregulation of lineage-specific transcription factors and protein synthesis. In response to brain ischemia, interferon gamma signaling induces dormant NSC subpopulations to enter the primed-quiescent state. This study unveils general principles underlying NSC activation and lineage priming and opens potential avenues for regenerative medicine in the brain. PMID- 26235342 TI - Reprint of: Extracellular matrix as a biological scaffold material: Structure and function. AB - Biological scaffold materials derived from the extracellular matrix (ECM) of intact mammalian tissues have been successfully used in a variety of tissue engineering/regenerative medicine applications both in preclinical studies and in clinical applications. Although it is recognized that the materials have constructive remodeling properties, the mechanisms by which functional tissue restoration is achieved are not well understood. There is evidence to support essential roles for both the structural and functional characteristics of the biological scaffold materials. This paper provides an overview of the composition and structure of selected ECM scaffold materials, the effects of manufacturing methods upon the structural properties and resulting mechanical behavior of the scaffold materials, and the in vivo degradation and remodeling of ECM scaffolds with an emphasis on tissue function. PMID- 26235343 TI - Reprint of: The history of biodegradable magnesium implants: A review. AB - Today, more than 200 years after the first production of metallic magnesium by Sir Humphry Davy in 1808, biodegradable magnesium-based metal implants are currently breaking the paradigm in biomaterial science to develop only highly corrosion resistant metals. This groundbreaking approach to temporary metallic implants is one of the latest developments in biomaterials science that is being rediscovered. It is a challenging topic, and several secrets still remain that might revolutionize various biomedical implants currently in clinical use. Magnesium alloys were investigated as implant materials long ago. A very early clinical report was given in 1878 by the physician Edward C. Huse. He used magnesium wires as ligature for bleeding vessels. Magnesium alloys for clinical use were explored during the last two centuries mainly by surgeons with various clinical backgrounds, such as cardiovascular, musculoskeletal and general surgery. Nearly all patients benefited from the treatment with magnesium implants. Although most patients experienced subcutaneous gas cavities caused by rapid implant corrosion, most patients had no pain and almost no infections were observed during the postoperative follow-up. This review critically summarizes the in vitro and in vivo knowledge and experience that has been reported on the use of magnesium and its alloys to advance the field of biodegradable metals. PMID- 26235344 TI - Reprint of: Connections between single-cell biomechanics and human disease states: gastrointestinal cancer and malaria. AB - We investigate connections between single-cell mechanical properties and subcellular structural reorganization from biochemical factors in the context of two distinctly different human diseases: gastrointestinal tumor and malaria. Although the cell lineages and the biochemical links to pathogenesis are vastly different in these two cases, we compare and contrast chemomechanical pathways whereby intracellular structural rearrangements lead to global changes in mechanical deformability of the cell. This single-cell biomechanical response, in turn, seems to mediate cell mobility and thereby facilitates disease progression in situations where the elastic modulus increases or decreases due to membrane or cytoskeleton reorganization. We first present new experiments on elastic response and energy dissipation under repeated tensile loading of epithelial pancreatic cancer cells in force- or displacement-control. Energy dissipation from repeated stretching significantly increases and the cell's elastic modulus decreases after treatment of Panc-1 pancreatic cancer cells with sphingosylphosphorylcholine (SPC), a bioactive lipid that influences cancer metastasis. When the cell is treated instead with lysophosphatidic acid, which facilitates actin stress fiber formation, neither energy dissipation nor modulus is noticeably affected. Integrating recent studies with our new observations, we ascribe these trends to possible SPC-induced reorganization primarily of keratin network to perinuclear region of cell; the intermediate filament fraction of the cytoskeleton thus appears to dominate deformability of the epithelial cell. Possible consequences of these results to cell mobility and cancer metastasis are postulated. We then turn attention to progressive changes in mechanical properties of the human red blood cell (RBC) infected with the malaria parasite Plasmodium falciparum. We present, for the first time, continuous force-displacement curves obtained from in-vitro deformation of RBC with optical tweezers for different intracellular developmental stages of parasite. The shear modulus of RBC is found to increase up to 10-fold during parasite development, which is a noticeably greater effect than that from prior estimates. By integrating our new experimental results with published literature on deformability of Plasmodium-harbouring RBC, we examine the biochemical conditions mediating increases or decreases in modulus, and their implications for disease progression. Some general perspectives on connections among structure, single-cell mechanical properties and biological responses associated with pathogenic processes are also provided in the context of the two diseases considered in this work. PMID- 26235345 TI - Reprint of: Development of bioactive peptide amphiphiles for therapeutic cell delivery. AB - There is great clinical interest in cell-based therapies for ischemic tissue repair in cardiovascular disease. However, the regenerative potential of these therapies is limited due to poor cell viability and minimal retention following application. We report here the development of bioactive peptide amphiphile nanofibers displaying the fibronectin-derived RGDS cell adhesion epitope as a scaffold for therapeutic delivery of bone marrow derived stem and progenitor cells. When grown on flat substrates, a binary peptide amphiphile system consisting of 10 wt.% RGDS-containing molecules and 90 wt.% negatively charged diluent molecules was found to promote optimal cell adhesion. This binary system enhanced adhesion 1.4-fold relative to substrates composed of only the non bioactive diluent. Additionally, no enhancement was found upon scrambling the epitope and adhesion was no longer enhanced upon adding soluble RGDS to the cell media, indicating RGDS-specific adhesion. When encapsulated within self-assembled scaffolds of the binary RGDS nanofibers in vitro, cells were found to be viable and proliferative, increasing in number by 5.5 times after only 5 days, an effect again lost upon adding soluble RGDS. Cells encapsulated within a non-bioactive scaffold and those within a binary scaffold with scrambled epitope showed minimal viability and no proliferation. Cells encapsulated within this RGDS nanofiber gel also increase in endothelial character, evident by a decrease in the expression of CD34 paired with an increase in the expression of endothelial-specific markers VE-Cadherin, VEGFR2 and eNOS after 5days. In an in vivo study, nanofibers and luciferase-expressing cells were co-injected subcutaneously in a mouse model. The binary RGDS material supported these cells in vivo, evident by a 3.2-fold increase in bioluminescent signal attributable to viable cells; this suggests the material has an anti-apoptotic and/or proliferative effect on the transplanted bone marrow cells. We conclude that the binary RGDS-presenting nanofibers developed here demonstrate enhanced viability, proliferation and adhesion of associated bone marrow derived stem and progenitor cells. This study suggests potential for this material as a scaffold to overcome current limitations of stem cell therapies for ischemic diseases. PMID- 26235346 TI - Reprint of: Review of bioactive glass: From Hench to hybrids. AB - Bioactive glasses are reported to be able to stimulate more bone regeneration than other bioactive ceramics but they lag behind other bioactive ceramics in terms of commercial success. Bioactive glass has not yet reached its potential but research activity is growing. This paper reviews the current state of the art, starting with current products and moving onto recent developments. Larry Hench's 45S5 Bioglass(r) was the first artificial material that was found to form a chemical bond with bone, launching the field of bioactive ceramics. In vivo studies have shown that bioactive glasses bond with bone more rapidly than other bioceramics, and in vitro studies indicate that their osteogenic properties are due to their dissolution products stimulating osteoprogenitor cells at the genetic level. However, calcium phosphates such as tricalcium phosphate and synthetic hydroxyapatite are more widely used in the clinic. Some of the reasons are commercial, but others are due to the scientific limitations of the original Bioglass 45S5. An example is that it is difficult to produce porous bioactive glass templates (scaffolds) for bone regeneration from Bioglass 45S5 because it crystallizes during sintering. Recently, this has been overcome by understanding how the glass composition can be tailored to prevent crystallization. The sintering problems can also be avoided by synthesizing sol-gel glass, where the silica network is assembled at room temperature. Process developments in foaming, solid freeform fabrication and nanofibre spinning have now allowed the production of porous bioactive glass scaffolds from both melt- and sol-gel-derived glasses. An ideal scaffold for bone regeneration would share load with bone. Bioceramics cannot do this when the bone defect is subjected to cyclic loads, as they are brittle. To overcome this, bioactive glass polymer hybrids are being synthesized that have the potential to be tough, with congruent degradation of the bioactive inorganic and the polymer components. Key to this is creating nanoscale interpenetrating networks, the organic and inorganic components of which have covalent coupling between them, which involves careful control of the chemistry of the sol-gel process. Bioactive nanoparticles can also now be synthesized and their fate tracked as they are internalized in cells. This paper reviews the main developments in the field of bioactive glass and its variants, covering the importance of control of hierarchical structure, synthesis, processing and cellular response in the quest for new regenerative synthetic bone grafts. The paper takes the reader from Hench's Bioglass 45S5 to new hybrid materials that have tailorable mechanical properties and degradation rates. PMID- 26235347 TI - Incremental Prognostic Value of Brachial-Ankle Pulse Wave Velocity to Single Photon Emission Computed Tomography in Patients with Suspected Coronary Artery Disease. AB - AIM: Arterial stiffness assessed by brachial-ankle pulse wave velocity (baPWV) is predictive of cardiovascular events. This study was designed to investigate whether baPWV has an additional prognostic value to single-photon emission computed tomography (SPECT) in patients with suspected coronary artery disease (CAD). METHODS: A total of 350 subjects (age, 66.2 +/- 10.5 years, 53.4% male) with suspected CAD undergoing myocardial SPECT and baPWV within 30 days were retrospectively analyzed. Cardiovascular events, including cardiovascular death, acute coronary syndrome and ischemic stroke, were assessed. Both fixed and reversible perfusion defects on SPECT were considered abnormal myocardial perfusion imaging (MPI) findings. RESULTS: During the median follow-up period of 441 days (interquartile range 169-719 days), cardiovascular events occurred in 21 patients (6.0%). In multivariable Cox regression analysis, abnormal MPI [hazard ratio (HR), 2.67; 95% confidence interval (CI), 1.21-10.37; p=0.024] and high baPWV (>= 1,790 cm/s) (HR, 2.03; 95% CI, 1.08-6.38; p=0.007) were independent predictors of clinical events even after adjusting for possible confounders. Also, high baPWV had an incremental prognostic value to traditional risk factors and abnormal MPI in predicting cardiovascular events (overall Chi-square, from 24.08 to 27.42; p < 0.001). Kaplan-Meier survival curves stratified by baPWV and MPI proved significantly improved prediction of cardiovascular events (log-rank p=0.001). CONCLUSIONS: baPWV has an incremental prognostic value to traditional risk factors and MPI. Therefore, baPWV can be used to identify subjects at higher risk of cardiovascular events in patients undergoing SPECT. PMID- 26235348 TI - Single agent carboplatin for pediatric low-grade glioma: A retrospective analysis shows equivalent efficacy to multiagent chemotherapy. AB - Pediatric low-grade gliomas (LGG) that are unresectable often require adjuvant chemotherapy such as carboplatin/vincristine. Small Phase II studies have suggested equivalent efficacy of single agent 4-weekly carboplatin. A single institution retrospective review captured all patients aged 0 to 18 years diagnosed with LGG between 1996 and 2013 and treated with carboplatin monotherapy. The response and survival according to tumor site was compared to published results for multiagent chemotherapy. Of 268 children diagnosed with LGG diagnosed in this period, 117 received chemotherapy and 104 children received single agent carboplatin as first line chemotherapy. All patients received carboplatin at 560 mg/m(2), four-weekly for a median of 12 courses. The mean age at diagnosis was 5.8 years (range 3m-16y) and 32% had neurofibromatosis type 1. With a mean followup of 54 months, 86% of patients achieved stabilisation or better (SD/PR/CR). 3-year progression free survival (PFS) 66% (95% CI 57-76%), and 5-year PFS was 51% (95% CI 41-63%). 5-year overall survival was 97%. Multivariate analysis showed poorer PFS for those with chiasmatic/hypothalamic tumors. In this retrospective analysis single agent carboplatin shows comparable efficacy to historical multiagent chemotherapy for the treatment of patients with unresectable LGG. Equivalent outcomes are achieved with less chemotherapy, reduced side effects and fewer hospital visits. Further research is required to establish the place of this simplified regimen in the up-front treatment of unresectable LGG. PMID- 26235349 TI - Retinopathy of prematurity and neurodevelopmental disabilities in premature infants. AB - Prematurity is a major global health issue leading to high mortality and morbidity among the survivors. Neurodevelopmental disability (NDD) and retinopathy of prematurity (ROP) are the most common complications of prematurity. In fact, ROP is the second leading cause of childhood blindness in the world. Although there is much information regarding the occurrence of ROP and of NDD in premature infants, there have been few studies on ROP and its association with NDD. The objectives of this article are to review the current literature on the subject and to publish our own findings concerning the association between ROP and NDD in premature infants. The review suggests that although NDDs are related to degree of prematurity, NDD could also be the result of visual impairments resulting from ROP. Our own study shows a close association between NDD and zonal involvement of ROP: higher NDD if zone 1 is involved and less if zone 3 is involved. PMID- 26235350 TI - STED-FLCS: An Advanced Tool to Reveal Spatiotemporal Heterogeneity of Molecular Membrane Dynamics. AB - Heterogeneous diffusion dynamics of molecules play an important role in many cellular signaling events, such as of lipids in plasma membrane bioactivity. However, these dynamics can often only be visualized by single-molecule and super resolution optical microscopy techniques. Using fluorescence lifetime correlation spectroscopy (FLCS, an extension of fluorescence correlation spectroscopy, FCS) on a super-resolution stimulated emission depletion (STED) microscope, we here extend previous observations of nanoscale lipid dynamics in the plasma membrane of living mammalian cells. STED-FLCS allows an improved determination of spatiotemporal heterogeneity in molecular diffusion and interaction dynamics via a novel gated detection scheme, as demonstrated by a comparison between STED-FLCS and previous conventional STED-FCS recordings on fluorescent phosphoglycerolipid and sphingolipid analogues in the plasma membrane of live mammalian cells. The STED-FLCS data indicate that biophysical and biochemical parameters such as the affinity for molecular complexes strongly change over space and time within a few seconds. Drug treatment for cholesterol depletion or actin cytoskeleton depolymerization not only results in the already previously observed decreased affinity for molecular interactions but also in a slight reduction of the spatiotemporal heterogeneity. STED-FLCS specifically demonstrates a significant improvement over previous gated STED-FCS experiments and with its improved spatial and temporal resolution is a novel tool for investigating how heterogeneities of the cellular plasma membrane may regulate biofunctionality. PMID- 26235351 TI - Pulse oximetry in paediatric obstructive sleep apnoea: is it used appropriately? AB - OBJECTIVES: This study assessed the use of pulse oximetry testing in children with suspected obstructive sleep apnoea in a hospital setting. METHODS: A retrospective review of patients who underwent pulse oximetry testing between April 2013 and October 2013 was performed. Primary outcome measures included positive pulse oximetry results, defined as a McGill oximetry score of 2-4. RESULTS: Thirty-seven test results were usable for analysis: from 21 pre- and 16 post-operative tests. Only four patients had positive test results. There was a significant difference between pre- and post-operative quality of life outcome scores in the surgical group (p < 0.0001). CONCLUSION: Pre-operative pulse oximetry should be used as a guide to help triage patients who require specialist paediatric services, such as a paediatric intensive care unit. The use of pulse oximetry, particularly in the post-operative setting, is unlikely to change patient management and can incur unnecessary financial costs to UK National Health Service Hospital Trusts. PMID- 26235352 TI - Sub-100 nm anisotropic gold nanoparticles as surface-enhanced Raman spectroscopy substrates. AB - This study describes a reliable preparation of relatively small Ag/Au-based anisotropic nanostructures possessing tunable absorption bands and their use as surface-enhanced Raman spectroscopy (SERS) substrates. These Au nanostructures were prepared via the seed growth process of small Ag-core-Au-shell-type nanoparticles that were obtained by the subsequent reduction of Ag and Au ions by NaBH(4) and L-ascorbic acid at room temperature. The presence of Ag during the transformation process of the Ag-Au core-shell nanoparticles under light irradiation led to the formation of various small anisotropic Au nanoparticles which clearly exhibited different structural and optical properties from those of nanoparticles prepared from typical Ag-Au alloy or bare Ag or Au seeds. As the optimal size of Au-based substrates for SERS applications was reported to be below 100 nm in diameter under a constant concentration, we tested our moderately small anisotropic nanoparticles (~55 nm in diameter) as a SERS substrate to examine the signal enhancement of 4-nitrobenzenethiol. These nanoparticles exhibited a greatly increased SERS response compared to those of similar sizes of uniform Ag and Au nanoparticles, presumably because of the increased surface area due to the nanoparticles' anisotropic nature (i.e., chemical effect) and partial overlap of their absorption bands with the SERS excitation wavelength (i.e., electromagnetic effect). In addition, these nanoparticles have shown a suitable stability to prevent significant SERS signal fluctuations caused by unpredictable aggregations. Due to our simple synthetic and modification approaches, relatively small Au-based anisotropic nanostructures can be easily designed to serve as attractive SERS templates. PMID- 26235353 TI - Sonodynamic action of chlorin e6 on Staphylococcus aureus and Escherichia coli. AB - Bacteria remain a great threat to human health. In the present study, we examined whether sonodynamic action of chlorin e6 had antibacterial activity on gram positive bacterial strain Staphylococcus aureus (S. aureus) and gram-negative bacterial strain Escherichia coli (E. coli). Colony forming unit (CFU) assay showed that sonodynamic treatment of chlorin e6 induced a 2-log reduction in CFU of E. coli cells, 7-log reduction in CFU of S. aureus. Fluorescent microscopy observed that dead cells remarkably increased whereas live cells decreased after sonodynamic treatment of chlorin e6 on S. aureus cells. We first demonstrated that sonodynamic action of chlorin e6 has antibacterial effect on both gram positive and negative bacteria, more powerful on gram-positive bacteria. PMID- 26235354 TI - Reversal of P-glycoprotein-mediated multidrug resistance by the novel tetrandrine derivative W6. AB - Overexpression of ATP-dependent efflux pump P-glycoprotein (P-gp) is the main cause of multidrug resistance (MDR) and chemotherapy failure in cancer treatment. Inhibition of P-gp-mediated drug efflux is an effective way to overcome cancer drug resistance. The present study investigated the reversal effect of the novel tetrandrine derivative W6 on P-gp-mediated MDR. KBv200, MCF-7/adr and their parental sensitive cell lines KB, MCF-7 were used for reversal study. The intracellular accumulation with P-gp substrates of doxorubicin was determined by flow cytometry. The expression of P-gp and ERK1/2 was investigated by western blot and real-time-PCR (RT-PCR) analysis. ATPase activity of P-gp was performed by P-gp-Glo(TM) assay systems. In comparison with P-gp-negative parental cells, W6 produced a favorable reversal effect in the MDR cells, as determined using the MTT assay. W6 significantly and dose-dependently increased intracellular accumulation of P-gp substrate doxorubicin (DOX) in P-gp overexpressing KBv200 cells, and also inhibited the ATPase activity of P-gp. W6 inhibited P-gp expression in KBv200 cells in a time-dependent manner, but it had no effect on MDR1 expression. In addition, W6 significantly decreased the ERK1/2 activation in KBv200 cells. Our results showed that W6 effectively reversed P-gp-mediated MDR by inhibiting the transport function and expression of P-gp, demonstrating the potential clinical utility of W6. PMID- 26235356 TI - Cdk8 deletion in the Apc(Min) murine tumour model represses EZH2 activity and accelerates tumourigenesis. AB - CDK8 is a dissociable kinase module of the Mediator complex and has been shown to play an important role in transcriptional regulation in organisms as diverse as yeast and humans. Recent studies suggest that CDK8 functions as an oncoprotein in melanoma and colon cancer. Importantly, these studies were conducted using in vitro cell line models and the role of CDK8 in tumourigenesis in vivo has not been explored. We have generated a mouse with a Cdk8 conditional knockout allele and examined the consequences of Cdk8 loss on normal tissue homeostasis and tumour development in vivo. Cdk8 deletion in the young adult mouse did not induce any gross or histopathological abnormalities, implying that Cdk8 is largely dispensable for somatic cellular homeostasis. In contrast, Cdk8 deletion in the Apc(Min) intestinal tumour model shortened the animals' survival and increased tumour burden. Although Cdk8 deletion did not affect tumour initiation, intestinal tumour size and growth rate were significantly increased in Cdk8-null animals. Transcriptome analysis performed on Cdk8-null intestinal cells revealed up-regulation of genes that are governed by the Polycomb group (PcG) complex. In support of these findings, Cdk8-null intestinal cells and tumours displayed a reduction in histone H3K27 trimethylation, both globally and at the promoters of a number of PcG-regulated genes involved in oncogenic signalling. Together, our findings uncover a tumour suppressor function for CDK8 in vivo and suggest that the role of CDK8 activity in driving oncogenesis is context-specific. Sequencing data were deposited at GEO (Accession No. GSE71385). PMID- 26235355 TI - The molecular mechanism of polygalasaponin F-mediated decreases in TNFalpha: emphasizing the role of the TLR4-PI3K/AKT-NF-kappaB pathway. AB - Polygalasaponin F (PS-F), an oleanane-type triterpenoid saponin extracted from Polygala japonica, decreases the release of the inflammatory cytokine tumor necrosis factor alpha (TNFalpha), but the precise molecular mechanisms by which this event occurs are not fully understood. To study the anti-neuroinflammatory mechanisms of PS-F, enzyme-linked immunosorbent assay was used to detect the secretion of TNFalpha from BV-2 microglial cells. Nuclear proteins extracted from BV-2 microglial cells stimulated by lipopolysaccharide (LPS) and pretreated with/without inhibitors were measured by Western blotting, and cell viability was evaluated by MTT analysis. The results indicated that inhibition of toll-like receptor (TLR) 4 (CLI-095 1 MUg/ml), phosphatidylinositol 3-kinase (PI3K) (Ly294002 10 MUM) or IkappaBalpha phosphorylation (Bay11-7082 10 MUM) completely prevents the release of TNFalpha induced by LPS without affecting cell viability and attenuated the nuclear translocation of p65 stimulated by LPS. In addition, PS-F exhibited a similar trend regarding TNFalpha release, AKT phosphorylation and NF-kappaB translocation. These results suggest that PS-F reduces neuroinflammatory cytokine secretion through the regulation of the TLR4-PI3K/AKT NF-kappaB signaling pathway. PMID- 26235357 TI - [Considerations and recommondations for species-appropriate and welfare friendly keeping of ratitae in Germany]. AB - Ostrich farming and keeping in Germany is of increasing interest. Ostrich farming includes keeping the animals as agricultural livestock (production of meat, leather, eggs), for display, hobby farming and keeping in zoological collections. Based on scientific research there is a steady increase in knowledge of keeping ratites according to sophisticated standards in terms of animal welfare legislation. Legislation and recommondations for keeping of ratitae are described. PMID- 26235358 TI - Immobilization of amyloglucosidase onto macroporous cryogels for continuous glucose production from starch. AB - Poly(methyl methacrylate-glycidyl methacrylate) [Poly(MMA-GMA)] cryogels were synthesized using monomers of methylmethacrylic acid and epoxy group bearing GMA via radical cryopolymerization technique. Synthesized cryogels were used for the immobilization of amyloglucosidase to the cryogel surface using epoxy chemistry. Characterizations of the free and immobilized amyloglucosidase were carried out by comparing the optimum and kinetic parameters of enzymes. For this, pH and temperature profiles of free and immobilized preparation were studied and, it was found that, optimum pH of enzyme was not change upon immobilization (pH 5.0), while optimum temperature of the enzyme shifted 10 degrees C to warmer region after immobilization (optimum temperatures for free and immobilized enzyme were 55 and 65 degrees C, respectively). Kinetic parameters of free and immobilized enzyme were also investigated and Km values of free and immobilized amyloglucosidase were found to be 2.743 and 0.865 mg/mL, respectively. Vmax of immobilized amyloglucosidase was found to be (0.496 umol/min) about four times less than that of free enzyme (2.020 umol/min). Storage and operational stabilities of immobilized amyloglucosidase were also studied and it was showed that immobilized preparation had much more stability than free preparation. In the present work, amyloglucosidase immobilized poly(MMA-GMA) cryogels were used for continuous glucose syrup production from starch for the first time. Efficiency of immobilized enzyme was investigated and released amount of glucose was found to be 2.54 mg/mL at the end of the 5 min of hydrolysis. The results indicate that the epoxy functionalized cryogels offer a good alternative for amyloglucosidase immobilization applications with increased operational and thermal stability, and reusability. Also, these cryogels can be used for immobilization of other industrially valuable enzymes beyond amyloglucosidase. PMID- 26235360 TI - Evidence-practice gap for in-office fluoride application in a dental practice based research network. AB - OBJECTIVE: The aims of this study were to examine dentists' recommendations for in-office fluoride to patients and identify dentists' characteristics associated with these recommendations. STUDY DESIGN AND SETTING: The study was conducted using a cross-sectional questionnaire survey in Japan. The survey queried dentists (n = 282) in outpatient dental practices affiliated with the Dental Practice-based Research Network Japan (JDPBRN). This network aims to assist dentists in investigating research questions and sharing their experience and expertise. RESULTS: The responses were obtained by 189 dentists (67 percent). Among valid response, 54 percent of dentists (n = 98) recommend in-office fluoride to more than 50 percent of their patients aged 6-18 years and 15 percent (n = 29) recommended this care to more than 50 percent of their patients aged over 18 years. Multiple logistic regression analysis suggested that factors associated with the percentage of patients who are recommended in-office fluoride included patient's interest in caries prevention and dentist's belief in the effectiveness of caries risk assessment. CONCLUSIONS: Dentist practice patterns for recommending in-office fluoride vary widely. Recommendation was significantly related to having a higher percentage of patients interested in caries prevention and to the dentist's belief about the effectiveness of caries risk assessment. (Clinicaltrials.gov registration number NCT01680848). PMID- 26235361 TI - Microarray-based IgE detection in tears of patients with vernal keratoconjunctivitis. AB - BACKGROUND: A specific allergen sensitization can be demonstrated in approximately half of the vernal keratoconjunctivitis (VKC) patients by conventional allergic tests. The measurement of specific IgE in tears using a multiplex allergen microarray may offer advantages to identify local sensitization to a specific allergen. METHODS: In spring-summer 2011, serum and tears samples were collected from 10 active VKC patients (three females, seven males) and 10 age-matched normal subjects. Skin prick test, symptoms score and full ophthalmological examination were performed. Specific serum and tear IgE were assayed using ImmunoCAP ISAC, a microarray containing 103 components derived from 47 allergens. RESULTS: Normal subjects resulted negative for the presence of specific IgE both in serum and in tears. Of the 10 VKC patients, six resulted positive to specific IgE in serum and/or tears. In three of these six patients, specific IgE was found positive only in tears. Cross-reactivity between specific markers was found in three patients. Grass, tree, mites, animal but also food allergen-specific IgE were found in tears. Conjunctival provocation test performed out of season confirmed the specific local conjunctival reactivity. CONCLUSIONS: Multiple specific IgE measurements with single protein allergens using a microarray technique in tear samples are a useful, simple and non invasive diagnostic tool. ImmunoCAP ISAC detects allergen sensitization at component level and adds important information by defining both cross- and co sensitization to a large variety of allergen molecules. The presence of specific IgE only in tears of VKC patients reinforces the concept of possible local sensitization. PMID- 26235363 TI - Coupling recombinase-mediated cassette exchange with somatic hypermutation for antibody affinity maturation in CHO cells. AB - Heterologous expression of activation-induced cytidine deaminase (AID) can induce somatic hypermutation (SHM) for genes of interest in various cells, and several research groups (including ours) have successfully improved antibody affinity in mammalian or chicken cells using AID-induced SHM. These affinity maturation systems are time-consuming and inefficient. In this study, we developed an antibody affinity maturation platform in Chinese hamster ovary (CHO) cells by coupling recombinase-mediated cassette exchange (RMCE) with SHM. Stable CHO cell clones containing a single copy puromycin resistance gene (PuroR) expression cassette flanked by recombination target sequences (FRT and loxP) being able to highly express a gene of interest placed in the cassette were developed. The PuroR gene was replaced with an antibody gene by RMCE, and the antibody was displayed on the cell surface. Cells displaying antibodies on their membrane were transfected with the AID gene, and mutations of the antibody gene were accumulated by AID-mediated hypermutation during cell proliferation followed by flow cytometric cell sorting for cells bearing antibody mutants with improved affinity. Affinity improvements were detected after only one round of cell sorting and proliferation, mutant clones with 15-fold affinity improvement were isolated within five rounds of maturation (within 2 months). CHO cells are fast growing, stress-resistant and produce antibody with glycosylations suitable for therapy. Our antibody-evolution platform based on CHO cells makes antibody affinity maturation more efficient and is especially convenient for therapeutic antibody affinity improvement. PMID- 26235364 TI - Restoring the SU(4) Kondo regime in a double quantum dot system. AB - We calculate the spectral density and occupations of a system of two capacitively coupled quantum dots, each one connected to its own pair of conducting leads, in a regime of parameters in which the total couplings to the leads for each dot Gamma(i) are different. The system has been used recently to perform pseudospin spectroscopy by controlling independently the voltages of the four leads. For an odd number of electrons in the system, equal coupling to the leads Gamma1 = Gamma2, equal dot levels E1 = E2 and sufficiently large interdot repulsion U12 the system lies in the SU(4) symmetric point of spin and pseudospin degeneracy in the Kondo regime. In the more realistic case Gamma1 ? Gamma2, pseudospin degeneracy is broken and the symmetry is reduced to SU(2). Nevertheless, we find that the essential features of the SU(4) symmetric case are recovered by appropriately tuning the level difference delta = E2 - E1. After this tuning, the system behaves as an SU(4) Kondo one at low energies. Our results are relevant for experiments which look for signatures of SU(4) symmetry in the Kondo regime of similar systems. PMID- 26235362 TI - Histoplasma capsulatum surmounts obstacles to intracellular pathogenesis. AB - The fungal pathogen Histoplasma capsulatum causes respiratory and disseminated disease, even in immunocompetent hosts. In contrast to opportunistic pathogens, which are readily controlled by phagocytic cells, H. capsulatum yeasts are able to infect macrophages, survive antimicrobial defenses, and proliferate as an intracellular pathogen. In this review, we discuss some of the molecular mechanisms that enable H. capsulatum yeasts to overcome obstacles to intracellular pathogenesis. H. capsulatum yeasts gain refuge from extracellular obstacles such as antimicrobial lung surfactant proteins by engaging the beta integrin family of phagocytic receptors to promote entry into macrophages. In addition, H. capsulatum yeasts conceal immunostimulatory beta-glucans to avoid triggering signaling receptors such as the beta-glucan receptor Dectin-1. H. capsulatum yeasts counteract phagocyte-produced reactive oxygen species by expression of oxidative stress defense enzymes including an extracellular superoxide dismutase and an extracellular catalase. Within the phagosome, H. capsulatum yeasts block phagosome acidification, acquire essential metals such as iron and zinc, and utilize de novo biosynthesis pathways to overcome nutritional limitations. These mechanisms explain how H. capsulatum yeasts avoid and negate macrophage defense strategies and establish a hospitable intracellular niche, making H. capsulatum a successful intracellular pathogen of macrophages. PMID- 26235365 TI - Ictal asystole mimicking seizure deterioration in temporal lobe epilepsy. AB - We report on a patient with temporal lobe epilepsy, secondary to a left lateral temporal cavernoma, in whom the change in seizure semiology suggested recurrence of secondary generalized seizures. Anticonvulsive medication previously controlled secondary generalized seizures over a period of years but focal seizures continued at a lower rate. Continuous video-EEG monitoring revealed ictal asystole associated with myoclonic syncope and falls during focal seizures arising from the left temporal lobe. After implantation of a cardiac pacemaker, no more falls occurred during the focal seizures. In conclusion, recurrence of seizure-associated falls is typically attributed to recurrence of secondary generalized seizures, however, ictal asystole should be considered in selected epilepsy patients as a differential diagnosis of falls. [Published with video sequence]. PMID- 26235366 TI - Reply to the Letter to the Editor entitled "Management of prosthetic valve thrombosis in pregnancy". PMID- 26235367 TI - Successful treatment of extramammary Paget's disease of the scalp with photodynamic therapy. PMID- 26235368 TI - A Systematic Review and Meta-Analysis on the Effectiveness of Graded Activity and Graded Exposure for Chronic Nonspecific Low Back Pain. AB - OBJECTIVE: Our aim was to systematically review and meta-analyze the effectiveness of graded activity (GA) or graded exposure (GEXP) for chronic nonspecific low back pain (CNSLBP). METHODS: A literature search of multiple databases (MEDLINE, EMBASE, PEDro, CINAHL, and PsychINFO) was conducted to identify randomized control trials (RCTs). Standardized mean difference (SMD) and 95% confidence intervals (CI) were calculated for relevant outcome measures (pain intensity, disability, quality of life, and catastrophizing). RESULTS: Thirteen RCTs met the inclusion criteria. Only nine studies were included in the meta analysis. GA was significantly more effective than the control group (CG) for improvements in disability in the short term (three studies: n = 254, SMD = -0.3, 95% CI -0.55 to -0.05, P = 0.02) and long term (two studies: n = 238, SMD = 0.53, 95% CI -0.79 to -0.27, P < 0.0001). GA was significantly less effective than GEXP for the improvement of disability in the short term (two studies: n = 105, SMD = 0.39, 95% CI 0.003-0.78, P = 0.048). GA was also significantly less effective than GEXP at improving catastrophizing in the short term (two studies: n = 105, SMD = 0.48, 95% CI 0.09-0.87, P = 0.02). CONCLUSION: Limited evidence has been found to show that GA significantly reduces disability in the short and long term when compared with the CG in CNSLBP. There is moderate evidence that GEXP more effectively decreases catastrophizing than GA in the short term. No difference was found between GA and other exercise for any variable. PMID- 26235369 TI - Diastereo- and Enantioselective Iridium Catalyzed Carbonyl (alpha Cyclopropyl)allylation via Transfer Hydrogenation. AB - The first examples of diastereo- and enantioselective carbonyl alpha (cyclopropyl)allylation are reported. Under the conditions of iridium catalyzed transfer hydrogenation using the chiral precatalyst (R)-Ir-I modified by SEGPHOS, carbonyl alpha-(cyclopropyl)allylation may be achieved with equal facility from alcohol or aldehyde oxidation levels. This methodology provides a conduit to hitherto inaccessible inaccessible enantiomerically enriched cyclopropane containing architectures. PMID- 26235370 TI - Methodological challenges in measuring vaccine effectiveness using population cohorts in low resource settings. AB - Post-licensure real world evaluation of vaccine implementation is important for establishing evidence of vaccine effectiveness (VE) and programme impact, including indirect effects. Large cohort studies offer an important epidemiological approach for evaluating VE, but have inherent methodological challenges. Since March 2012, we have conducted an open prospective cohort study in two sites in rural Malawi to evaluate the post-introduction effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) against all-cause post-neonatal infant mortality and monovalent rotavirus vaccine (RV1) against diarrhoea-related post-neonatal infant mortality. Our study sites cover a population of 500,000, with a baseline post-neonatal infant mortality of 25 per 1000 live births. We conducted a methodological review of cohort studies for vaccine effectiveness in a developing country setting, applied to our study context. Based on published literature, we outline key considerations when defining the denominator (study population), exposure (vaccination status) and outcome ascertainment (mortality and cause of death) of such studies. We assess various definitions in these three domains, in terms of their impact on power, effect size and potential biases and their direction, using our cohort study for illustration. Based on this iterative process, we discuss the pros and cons of our final per-protocol analysis plan. Since no single set of definitions or analytical approach accounts for all possible biases, we propose sensitivity analyses to interrogate our assumptions and methodological decisions. In the poorest regions of the world where routine vital birth and death surveillance are frequently unavailable and the burden of disease and death is greatest We conclude that provided the balance between definitions and their overall assumed impact on estimated VE are acknowledged, such large scale real-world cohort studies can provide crucial information to policymakers by providing robust and compelling evidence of total benefits of newly introduced vaccines on reducing child mortality. PMID- 26235371 TI - Effectiveness of three pneumococcal conjugate vaccines (PCV) to prevent invasive pneumococcal disease in Quebec, Canada. PMID- 26235373 TI - Switching of inherent chirality driven by self-assembly. AB - Dynamic chirality of iminoresorcin[4]arenes that originates from regioselective and diastereoselective keto-enol tautomerisation was switched by non-covalent interactions with achiral molecules, as demonstrated by experimental electronic circular dichroism (ECD) spectra supported by TD DFT calculations. PMID- 26235372 TI - Nationwide population-based surveillance of invasive pneumococcal disease in Japanese children: Effects of the seven-valent pneumococcal conjugate vaccine. AB - BACKGROUND: In Japan, the seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2010. PCV13 has replaced PCV7 since November 2013. METHODS: The effectiveness of PCV7 in protecting against invasive pneumococcal disease (IPD) in children aged <5 years was evaluated in a nationwide active population-based surveillance of IPD in 2008-2013 in 10 prefectures in Japan. RESULTS: 1181 cases were identified; 711 pneumococcal strains were analyzed for serotyping and antimicrobial resistance. Compared with the baseline IPD incidence (25.0 per 100,000), a 98% decline in IPD caused by PCV7 serotypes was found after the introduction of PCV7. This was partially offset by an increased incidence of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes, resulting in a 57% decline in overall IPD incidence. Absolute increases in the incidence rates of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes were 2.1 and 2.8 per 100,000 during the study period, respectively. The proportion of meropenem-nonsusceptible strains, especially with serotypes 19A and 15A, increased significantly after PCV7 introduction. CONCLUSIONS: Our data confirmed a 98% decline in IPD incidence caused by PCV7 serotypes in children aged <5 years and serotype replacement after PCV7 introduction. This shows the importance of continuing surveillance of serotypes responsible for IPD and their antimicrobial resistance in Japan. PMID- 26235374 TI - Hybrid volatolomics and disease detection. AB - This Review presents a concise, but not exhaustive, didactic overview of some of the main concepts and approaches related to "volatolomics"-an emerging frontier for fast, risk-free, and potentially inexpensive diagnostics. It attempts to review the source and characteristics of volatolomics through the so-called volatile organic compounds (VOCs) emanating from cells and their microenvironment. It also reviews the existence of VOCs in several bodily fluids, including the cellular environment, blood, breath, skin, feces, urine, and saliva. Finally, the usefulness of volatolomics for diagnosis from a single bodily fluid, as well as ways to improve these diagnostic aspects by "hybrid" approaches that combine VOC profiles collected from two or more bodily fluids, will be discussed. The perspectives of this approach in developing the field of diagnostics to a new level are highlighted. PMID- 26235375 TI - T-helper 17 cytokines (interleukins 17, 21, 22, and 6, and tumor necrosis factor alpha) in patients with alopecia areata: association with clinical type and severity. AB - BACKGROUND: Alopecia areata (AA) is an organ-specific autoimmune disease characterized by T-cell infiltrates and cytokine production. T-helper 17 (Th17) cells are crucially involved in the pathogenesis of autoimmune diseases. OBJECTIVES: Our aim was to assess the association of Th17 with AA. We examined interleukin (IL)-17, IL-21, IL-22, IL-6, and tumor necrosis factor-alpha (TNF alpha) levels in the serum of patients with AA and studied their association with clinical type and severity of AA. SUBJECTS AND METHODS: The serum concentrations of IL-17, IL-21, IL-22, IL-6, and TNF-alpha were measured in 47 patients with AA and 40 healthy controls. The clinical type of AA was determined, and the severity of hair loss was assessed in accordance with the Alopecia Areata Investigational Assessment Guideline criteria. RESULTS: The serum concentrations of IL-17, IL-21, IL-22, IL-6, and TNF-alpha were significantly higher in patients with AA as compared with healthy controls (mean: IL-17 33.23 +/- 11.58 vs. 4.62 +/- 1.88 pg/ml; P = 0.000, IL-21 62.10 +/- 6.11 vs. 48.38 +/- 3.31 pg/ml; P = 0.000, IL-22 19.27 +/- 3.36 vs. 7.09 +/- 1.62 pg/ml; P = 0.000, IL-6 17.18 +/- 3.08 vs. 4.59 +/- 1.66 pg/ml; P = 0.000, TNF-alpha 19.94 +/- 3.59 vs. 9.95 +/- 2.42 pg/ml; P = 0.000, respectively). There were significant positive correlations between serum IL-17, TNF-alpha, and disease severity. There was also significant positive correlation between serum IL-22 and duration of AA. CONCLUSION: Our results showed high serum levels of Th17 cytokines among patients with AA that may suggest a functional role of these cytokines in the pathogenesis of this important skin disease. It could also provide the rationale for new treatment strategies in AA. PMID- 26235376 TI - Preoperative Patient Reported Mental Health is Associated with High Grade Complications after Radical Cystectomy. AB - PURPOSE: Psychological distress has been associated with an impaired immune response and poor wound healing. We hypothesized that preoperative patient reported mental health would be associated with high grade 30-day complications after radical cystectomy. MATERIALS AND METHODS: We retrospectively identified patients who underwent radical cystectomy for bladder cancer who completed Short Form 12 (SF-12) surveys for self-assessment of health status less than 6 months before surgery. Median physical and mental composite scores were calculated. An expert model including known predictors of postoperative high grade complications was developed, and SF-12 physical composite score and mental composite score were added to determine their association with this end point. RESULTS: From January 2010 to August 2014, 472 patients underwent radical cystectomy for bladder cancer, of whom 274 (58.1%) completed preoperative SF-12 questionnaires. Responders were more likely to be white (p=0.024), have higher preoperative albumin (p=0.037), receive neoadjuvant chemotherapy (p=0.002), have pT3/T4 disease (p=0.044) and have positive soft tissue surgical margins (p=0.006). Median SF-12 physical composite score was 43.1 (IQR 33.0-51.5) and mental composite score was 48.5 (IQR 39.5-54.7) in responders. Overall 46 (16.8%) responders experienced a high grade 30-day complication. Patients with a high grade complication had a lower preoperative median SF-12 mental composite score (44.8 vs 49.8, p=0.004) but no difference in physical composite score (39.2 vs 43.8, p=0.06). SF-12 mental composite score was also a significant predictive variable when added to our expert model (p=0.01). CONCLUSIONS: Preoperative patient reported mental health was independently associated with high grade complications after radical cystectomy. Therefore, patient self-assessment of health status before surgery through validated questionnaires may provide additional information useful in predicting short-term postoperative outcomes. PMID- 26235377 TI - Bladder Cancer Mortality in the United States: A Geographic and Temporal Analysis of Socioeconomic and Environmental Factors. AB - PURPOSE: We assessed the association of temporal, socioeconomic and environmental factors with bladder cancer mortality in the United States. Our hypothesis was that bladder cancer mortality is associated with distinct environmental and socioeconomic factors with effects varying by region, race and gender. MATERIALS AND METHODS: NCI (National Cancer Institute) age adjusted, county level bladder cancer mortality data from 1950 to 2007 were analyzed to identify clusters of increased bladder cancer death using the Getis-Ord Gi* statistic. Socioeconomic, clinical and environmental data were assessed using geographically weighted spatial regression analysis adjusting for spatial autocorrelation. County level socioeconomic, clinical and environmental data were obtained from national databases, including the United States Census, CDC (Centers for Disease Control and Prevention), NCHS (National Center for Health Statistics) and County Health Rankings. RESULTS: Bladder cancer mortality hot spots and risk factors for bladder cancer death differed significantly by gender, race and geographic region. From 1996 to 2007 smoking, unemployment, physically unhealthy days, air pollution ozone days, percent of houses with well water, employment in the mining industry and urban residences were associated with increased rates of bladder cancer mortality (p <0.05). Model fit was significantly improved in hot spots compared to all American counties (R(2) = 0.20 vs 0.05). CONCLUSIONS: Environmental and socioeconomic factors affect bladder cancer mortality and effects appear to vary by gender and race. Additionally there were temporal trends of bladder cancer hot spots which, when persistent, should be the focus of individual level studies of occupational and environmental factors. PMID- 26235379 TI - Evaluation of treatment integrity errors on mand acquisition. AB - Manding allows individuals to access reinforcers in their environment. Caregivers may not implement mand-training programs as designed, which could result in decreased mand proficiency. This study evaluated the effects of delivery of the incorrect item (Experiment 1) and response-independent item delivery (Experiment 2) across 4 levels of treatment integrity (0%, 40%, 70%, and 100%) on mand acquisition with individuals with developmental disabilities. During Experiment 1, 2 of the 3 participants acquired the mand fastest during 100% integrity. Delivery of the incorrect item was detrimental to acquisition, but effects were idiosyncratic. During Experiment 2, all participants acquired the mand trained with 100% integrity fastest, followed by the mand trained with 70% integrity. None of the participants acquired the mands trained with 40% and 0% integrity, suggesting that delivery of the item independent of responding was detrimental to acquisition. For mand training to be most effective, caregivers must implement mand training with high levels of integrity. PMID- 26235378 TI - Specificity of antinuclear autoantibodies recognizing the dense fine speckled nuclear pattern: Preferential targeting of DFS70/LEDGFp75 over its interacting partner MeCP2. AB - Human antinuclear autoantibodies (ANAs) targeting the dense fine speckled (DFS) nuclear protein DFS70, commonly known as lens epithelium derived growth factor p75 (LEDGFp75), present a clinical puzzle since their significance remains elusive. While their frequencies are low in ANA-positive autoimmune rheumatic diseases, they are relatively elevated in clinical laboratory referrals, diverse inflammatory conditions, and 'apparently' healthy individuals. We reported previously that DFS70/LEDGFp75 is an autoantigen in prostate cancer that closely interacts with another 70kD DFS nuclear protein, methyl CpG binding protein 2 (MeCP2). This led us to investigate if anti-DFS sera exclusively target DFS70/LEDGFp75 or also recognize MeCP2. Using several complementary autoantibody detection platforms and cellular/molecular approaches we evaluated 65 human sera producing anti-DFS autoantibodies. Our results show that these antibodies are highly specific for DFS70/LEDGFp75 and do not target MeCP2. Establishing the specificity of anti-DFS autoantibodies has implications for increasing our understanding of their biological significance and clinical utility. PMID- 26235380 TI - Scanning Electron Microscopy Evaluation of Dental Root Resorption Associated With Granuloma. AB - The inflammatory resorption of dental root apex (i.e., the process of removal of cementum and/or dentine through the activity of resorbing cells) may show different configurations and damage the apical root structure. As knowing the morphology of resorption areas of human teeth is essential for the success of endodontic treatments, we investigated the apical resorption by scanning electron microscopy, focusing on roots with granulomas. A total of 30 teeth (with penetrating carious lesions and chronic periapical lesions) were examined, the apical third of the roots were removed and analyzed to estimate periforaminal and foraminal resorption, shape and morphology of foramen resorption, centering of the periforaminal resorption area, and diameters of each apical foramen. Periforaminal resorption was present in all samples, whereas foraminal resorption was present in 92% of cases (mainly funnel shaped). Lacunae were observed in the foraminal resorption area with an average diameter of 35+/-14 MUm. The major and minor diameters of the foramina in teeth with resorption were 443 and 313 MUm, respectively (higher than in healthy teeth). This result indicates an expansion of the apical diameters caused by the pathology, which could encourage a different clinical instrumentation for these teeth. PMID- 26235381 TI - The Arp2/3 inhibitory protein arpin induces cell turning by pausing cell migration. AB - Branched actin networks generated by the Arp2/3 complex provide the driving force for leading edge protrusion in migrating cells. We recently identified Arpin, a protein that inhibits the Arp2/3 complex in lamellipodia. Arpin is activated by the small GTPase Rac, which triggers lamellipodium formation, and thus Arpin renders protrusions unstable. A conserved role of Arpin is to induce migrating cells to turn in different migration models. Here we investigated the mechanism by which Arpin controls directional persistence. For this analysis, we segmented migration trajectories into alternating phases of active migration and pauses, based on a speed threshold. Regardless of the threshold value, Arpin induced more frequent pausing, during which the cell was more likely to change the direction of its migration. Arpin simultaneously acts on cell speed and directional persistence, which are strongly coupled parameters. Induction of frequent pausing by Arpin is consistent with Arpin circuitry: by inhibiting the Arp2/3 complex as a response to Rac activation, Arpin antagonizes a positive feedback loop that sustains protrusions at the leading edge and maintains active migration. We propose the 'duration of active migration' as a useful proxy to measure feedbacks associated with cell migration. PMID- 26235383 TI - Exploring the Effects of Glycosylation and Etherification of the Side Chains of the Anticancer Drug Mitoxantrone. AB - Herein we report the synthesis and biological evaluation of symmetric and asymmetric analogues of the DNA intercalating drug mitoxantrone (MTX) in which the side chains of the parent drug were modified through glycosylation or methyl etherification. Several analogues with glycosylated side chains exhibited higher DNA affinity than the parent MTX. The most potent in vitro cytotoxicity was observed for MTX analogue 8 (1,4-dimethoxy-5,8-bis[2-(2 methoxyethylamino)ethylamino]anthracene-9,10-dione) with methoxy ether containing side chains. Treatment of melanoma-bearing mice with MTX or analogue 8 decreased the intraperitoneal tumor burden relative to untreated mice; the effect of 8 was less pronounced than that of MTX. In vitro metabolism assays of MTX with rabbit liver S9 fraction gave rise to several metabolites; almost no metabolites were detected for MTX analogue 8. The results presented indicate that derivatization of the MTX side chain primary hydroxy groups may result in a significant improvement in DNA affinity and lower susceptibility to the formation of potentially toxic metabolites. PMID- 26235384 TI - Improved canine exome designs, featuring ncRNAs and increased coverage of protein coding genes. AB - By limiting sequencing to those sequences transcribed as mRNA, whole exome sequencing is a cost-efficient technique often used in disease-association studies. We developed two target enrichment designs based on the recently released annotation of the canine genome: the exome-plus design and the exome-CDS design. The exome-plus design combines the exons of the CanFam 3.1 Ensembl annotation, more recently discovered protein-coding exons and a variety of non coding RNA regions (microRNAs, long non-coding RNAs and antisense transcripts), leading to a total size of ~ 152 Mb. The exome-CDS was designed as a subset of the exome-plus by omitting all 3' and 5' untranslated regions. This reduced the size of the exome-CDS to ~ 71 Mb. To test the capturing performance, four exome plus captures were sequenced on a NextSeq 500 with each capture containing four pre-capture pooled, barcoded samples. At an average sequencing depth of 68.3x, 80% of the regions and well over 90% of the targeted base pairs were completely covered at least 5 times with high reproducibility. Based on the performance of the exome-plus, we estimated the performance of the exome-CDS. Overall, these designs provide flexible solutions for a variety of research questions and are likely to be reliable tools in disease studies. PMID- 26235385 TI - Ultra-high-performance core-shell structured Ru@Pt/C catalyst prepared by a facile pulse electrochemical deposition method. AB - Core-shell structured catalysts, made by placing either a monolayer or a thin layer of a noble metal on relatively cheap core-metal nanoparticles, are fascinating and promising fuel cell catalysts due to their high utilization of noble metals. Here, we report our development of a core-shell structured catalyst, Ru@Pt/C, generated by a novel and facile pulse electrochemical deposition (PED) approach. We demonstrate that compared with a commercial Pt/C catalyst, this novel catalyst achieves over four times higher mass activity towards the anodic oxidation of methanol, and 3.6 times higher mass activity towards the cathodic reduction of oxygen. Importantly, we find that the intrinsic activity of Pt in this Ru@Pt/C catalyst is doubled due to the formation of the core-shell structure. The catalyst also shows superior stability: even after 2000 scans, it still retains up to 90% of the peak current. Our findings demonstrate that this novel PED approach is a promising method for preparing high-performance core-shell catalysts for fuel cell applications. PMID- 26235382 TI - Immunogenetics of autoimmune thyroid diseases: A comprehensive review. AB - Both environmental and genetic triggers factor into the etiology of autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT). Although the exact pathogenesis and causative interaction between environment and genes are unknown, GD and HT share similar immune mediated mechanisms of disease. They both are characterized by the production of thyroid autoantibodies and by thyroidal lymphocytic infiltration, despite being clinically distinct entities with thyrotoxicosis in GD and hypothyroidism in HT. Family and population studies confirm the strong genetic influence and inheritability in the development of AITD. AITD susceptibility genes can be categorized as either thyroid specific (Tg, TSHR) or immune-modulating (FOXP3, CD25, CD40, CTLA-4, HLA), with HLA-DR3 carrying the highest risk. Of the AITD susceptibility genes, FOXP3 and CD25 play critical roles in the establishment of peripheral tolerance while CD40, CTLA-4, and the HLA genes are pivotal for T lymphocyte activation and antigen presentation. Polymorphisms in these immune modulating genes, in particular, significantly contribute to the predisposition for GD, HT and, unsurprisingly, other autoimmune diseases. Emerging evidence suggests that single nucleotide polymorphisms (SNPs) in the immunoregulatory genes may functionally hinder the proper development of central and peripheral tolerance and alter T cell interactions with antigen presenting cells (APCs) in the immunological synapse. Thus, susceptibility genes for AITD contribute directly to the key mechanism underlying the development of organ-specific autoimmunity, namely the breakdown in self-tolerance. Here we review the major immune-modulating genes that are associated with AITD and their potential functional effects on thyroidal immune dysregulation. PMID- 26235386 TI - Electrical myotonia in acid maltase deficiency disease. PMID- 26235387 TI - Ultrathin Co3S4 nanosheets that synergistically engineer spin states and exposed polyhedra that promote water oxidation under neutral conditions. AB - Development of efficient and affordable electrocatalysts in neutral solutions is paramount importance for the renewable energy. Herein, we report that the oxygen evolution reaction (OER) performance of Co3 S4 under neutral conditions can be enhanced by exposed octahedral planes and self-adapted spin states in atomically thin nanosheets. A HAADF image clearly confirmed that the active octahedra with Jahn-Teller distortions were exposed exclusively. Most importantly, in the atomically thin nanosheets, the spin states of Co(3+) in the octahedral self adapt from low-spin to high-spin states. As a result, the synergistic effect endow the Co3 S4 nanosheets with superior OER performance, with exceptional low onset overpotentials of circa 0.31 V in neutral solutions, which is state-of-the art among inorganic non-noble metal compounds. PMID- 26235389 TI - Hydrogen-bonded ring closing and opening of protonated methanol clusters H(+)(CH3OH)(n) (n = 4-8) with the inert gas tagging. AB - The preferential hydrogen bond (H-bond) structures of protonated methanol clusters, H(+)(MeOH)n, in the size range of n = 4-8, were studied by size selective infrared (IR) spectroscopy in conjunction with density functional theory calculations. The IR spectra of bare clusters were compared with those with the inert gas tagging by Ar, Ne, and N2, and remarkable changes in the isomer distribution with the tagging were found for clusters with n>= 5. The temperature dependence of the isomer distribution of the clusters was calculated by the quantum harmonic superposition approach. The observed spectral changes with the tagging were well interpreted by the fall of the cluster temperature with the tagging, which causes the transfer of the isomer distribution from the open and flexible H-bond network types to the closed and rigid ones. Anomalous isomer distribution with the tagging, which has been recently found for protonated water clusters, was also found for H(+)(MeOH)5. The origin of the anomaly was examined by the experiments on its carrier gas dependence. PMID- 26235388 TI - Estrogen-induced chromatin decondensation and nuclear re-organization linked to regional epigenetic regulation in breast cancer. AB - BACKGROUND: Epigenetic changes are being increasingly recognized as a prominent feature of cancer. This occurs not only at individual genes, but also over larger chromosomal domains. To investigate this, we set out to identify large chromosomal domains of epigenetic dysregulation in breast cancers. RESULTS: We identify large regions of coordinate down-regulation of gene expression, and other regions of coordinate activation, in breast cancers and show that these regions are linked to tumor subtype. In particular we show that a group of coordinately regulated regions are expressed in luminal, estrogen-receptor positive breast tumors and cell lines. For one of these regions of coordinate gene activation, we show that regional epigenetic regulation is accompanied by visible unfolding of large-scale chromatin structure and a repositioning of the region within the nucleus. In MCF7 cells, we show that this depends on the presence of estrogen. CONCLUSIONS: Our data suggest that the liganded estrogen receptor is linked to long-range changes in higher-order chromatin organization and epigenetic dysregulation in cancer. This may suggest that as well as drugs targeting histone modifications, it will be valuable to investigate the inhibition of protein complexes involved in chromatin folding in cancer cells. PMID- 26235390 TI - Growth kinetics of NaCl crystals in a drying drop of gelatin: transition from faceted to dendritic growth. AB - We report a study on the kinetics of drying of a droplet of aqueous gelatin containing sodium chloride. The process of drying recorded as a video clearly shows different regimes of growth leading to a variety of crystalline patterns. Large faceted crystals of ~mm size form in the early stages of evaporation, followed by highly branched multi-fractal patterns with micron sized features. We simulate the growth using a simple algorithm incorporating aggregation and evaporation, which reproduces the cross-over between the two growth regimes. As evaporation proceeds, voids form in the gel film. The time development of the fluid-void system can be characterized by the Euler number. A minimum in the Euler number marks the transition between the two regimes of growth. PMID- 26235391 TI - Preserved oxygenation in obese patients receiving protective ventilation during laparoscopic surgery: a randomized controlled study. AB - BACKGROUND: Venous admixture from atelectasis and airway closure impedes oxygenation during general anaesthesia. We tested the hypothesis that continuous positive airway pressure (CPAP) during pre-oxygenation and reduced fraction of inspiratory oxygen (FIO2 ) during emergence from anaesthesia can improve oxygenation in patients with obesity undergoing laparoscopic surgery. METHODS: In the intervention group (n = 20, median BMI 41.9), a CPAP of 10 cmH2 O was used during pre-oxygenation and induction of anaesthesia, but no CPAP was used in the control group (n = 20, median BMI 38.1). During anaesthesia, all patients were ventilated in volume-controlled mode with an FIO2 of 0.4 and a positive end expiratory pressure (PEEP) of 10 cmH2 O. During emergence, before extubation, the control group was given an FIO2 of 1.0 and the intervention group was divided into two subgroups, which were given an FIO2 of 1.0 or 0.31. Oxygenation was assessed perioperatively by the estimated venous admixture (EVA). RESULTS: The median EVA before pre-oxygenation was about 8% in both groups. During anaesthesia after intubation, the median EVA was 8.2% in the intervention vs. 13.2% in the control group (P = 0.048). After CO2 pneumoperitoneum, the median EVA was 8.4% in the intervention vs. 9.9% in the control group (P > 0.05). One hour post operatively, oxygenation had deteriorated in patients given an FIO2 of 1.0 during emergence but not in patients given an FIO2 of 0.31. CONCLUSIONS: A CPAP of 10 cmH2 O during pre-oxygenation and induction, followed by PEEP after intubation, seemed to preserve oxygenation during anaesthesia. Post-operative oxygenation depended on the FIO2 used during emergence. PMID- 26235392 TI - PEGylated gamma-tocotrienol isomer of vitamin E: Synthesis, characterization, in vitro cytotoxicity, and oral bioavailability. AB - Vitamin E refers to a family of eight isomers divided into two subgroups, tocopherols and the therapeutically active tocotrienols (T3). The PEGylated alpha tocopherol isomer of vitamin E (vitamin E TPGS) has been extensively investigated for its solubilizing capacity as a nonionic surfactant in various drug delivery systems. Limited information, however, is available about the PEG conjugates of the tocotrienol isomers of vitamin E. In this study two PEGylated gamma-T3 variants with mPEG molecular weights of 350 (gamma-T3PGS 350) and 1000 (gamma T3PGS 1000) were synthesized by a two-step reaction procedure and characterized by (1)H NMR, HPLC, and mass spectroscopy. The physical properties of their self assemblies in water were characterized by zeta, CMC, and size analysis. Similar physical properties were found between the PEGylated T3 and vitamin E TPGS. PEGylated T3 were also found to retain the in vitro cytotoxic activity of the free T3 against the MCF-7 and the triple-negative MDA-MB-231 breast cancer cells. PEGylated gamma-T3 also increased the oral bioavailability of gamma-T3 by threefolds when compared to the bioavailability of gamma-T3 formulated into a self-emulsified drug delivery system. No significant differences in biological activity were found between the PEG 350 and 100 conjugates. Results from this study suggest that PEGylation of gamma-T3 represents a viable platform for the oral and parenteral delivery of gamma-T3 for potential use in the prevention of breast cancer. PMID- 26235393 TI - Bioadhesive vaginal drug delivery of nystatin using a derivatized polymer: Development and characterization. AB - Increasing incidence of resistance to azole antifungals has highlighted the importance of the use of alternative therapeutic agents such as nystatin for the treatment of vulvovaginal candidiasis. The aim of the present study was to develop and characterize locally acting, film formulation for the treatment of candidiasis using a derivatized natural polymer. Derivatization of natural polymer was carried out in order to introduce anionic character to an otherwise neutral polymer, so as to enhance its interaction with vaginal mucous membrane along with inheriting the biocompatibility and nonirritant characteristics of its parent polymer. A carboxymethyl derivative of fenugreek gum (CMFG) was prepared, and characterized by DSC, FTIR and X-ray diffraction studies. The derivatized gum was found to possess bioadhesive and film forming properties. A 3(2) factorial design was employed to formulate vaginal films and a response surface methodological approach was used to study the effect of formulation variables on film properties. Films containing 5% w/v polymer and 2% v/v glycerol exhibited optimum properties in vitro. The optimized drug loaded formulation was able to release 100% drug over a period of 5h and followed Korsmeyer-Peppas kinetics. It was found to be non-irritant and nontoxic to vaginal mucosa and showed appropriate antifungal properties in vivo. PMID- 26235394 TI - Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. AB - Ligand activation of the aryl hydrocarbon (AHR) has profound effects upon the immunological status of the gastrointestinal tract, establishing and maintaining signaling networks, which facilitate host-microbe homeostasis at the mucosal interface. However, the identity of the ligand(s) responsible for such AHR mediated activation within the gut remains to be firmly established. Here, we combine in vitro ligand binding, quantitative gene expression, protein-DNA interaction and ligand structure activity analyses together with in silico modeling of the AHR ligand binding domain to identify indole, a microbial tryptophan metabolite, as a human-AHR selective agonist. Human AHR, acting as a host indole receptor may exhibit a unique bimolecular (2:1) binding stoichiometry not observed with typical AHR ligands. Such bimolecular indole-mediated activation of the human AHR within the gastrointestinal tract may provide a foundation for inter-kingdom signaling between the enteric microflora and the immune system to promote commensalism within the gut. PMID- 26235395 TI - Unlocking the energy capabilities of micron-sized LiFePO4. AB - Utilization of LiFePO4 as a cathode material for Li-ion batteries often requires size nanonization coupled with calcination-based carbon coating to improve its electrochemical performance, which, however, is usually at the expense of tap density and may be environmentally problematic. Here we report the utilization of micron-sized LiFePO4, which has a higher tap density than its nano-sized siblings, by forming a conducting polymer coating on its surface with a greener diazonium chemistry. Specifically, micron-sized LiFePO4 particles have been uniformly coated with a thin polyphenylene film via the spontaneous reaction between LiFePO4 and an aromatic diazonium salt of benzenediazonium tetrafluoroborate. The coated micron-sized LiFePO4, compared with its pristine counterpart, has shown improved electrical conductivity, high rate capability and excellent cyclability when used as a 'carbon additive free' cathode material for rechargeable Li-ion batteries. The bonding mechanism of polyphenylene to LiFePO4/FePO4 has been understood with density functional theory calculations. PMID- 26235409 TI - Seasonal exacerbation of esophageal eosinophilia in children with eosinophilic esophagitis and allergic rhinitis. AB - BACKGROUND: Evidence supports a possible link between eosinophilic esophagitis (EoE) and environmental aeroallergens, which can manifest as seasonal exacerbation of esophageal eosinophilia. Few studies have examined this link in pediatric patients with EoE. OBJECTIVE: To identify the proportion of patients with seasonal induced esophageal eosinophilia. METHODS: A retrospective chart review was conducted of all patients diagnosed with EoE at the authors' institution. Demographic data were collected by chart review. Seasonal variation or flare was defined as a change from fewer than to at least 15 eosinophils per high-power field and a minimum of a 2-fold increase in eosinophil count between 2 consecutive biopsy specimens in different seasons without dietary or medication modifications. RESULTS: Of the 1,180 patients with EoE, 160 (14%) were suspected of having aeroallergen-associated triggers by history. Of these 160 patients, 32 (20%) had biopsy examination-confirmed variation of EoE triggered by aeroallergens. Most of these patients were boys (84%), all had a history or examination consistent with allergic rhinitis, and most had a history of asthma (75%). Thirty-two subjects had obvious seasonal variation, 22 of whom also had known food-induced symptoms. CONCLUSION: Children with EoE and allergic rhinitis might have exacerbations in their esophageal eosinophilia during certain seasons depending on the specific aeroallergens to which they are sensitized. Identification of environmental allergens to sensitized patients is important and can guide therapy. PMID- 26235410 TI - A UK registry study of the effectiveness of a new over-the-counter chronic pain therapy. AB - BACKGROUND: The ActiPatch((r)) (BioElectronics Corporation, MD, USA) pulsed shortwave therapy device has been shown to be clinically effective in three double-blind randomized controlled pain studies. However, the effectiveness of this device in a broader population of chronic musculoskeletal pain sufferers, affected by a variety of etiologies in different regions of the body, has not been studied. AIM: The objective of this registry study was to assess the effectiveness and satisfaction of the ActiPatch device in the general population of chronic pain sufferers. METHODS: A total of 44,000 subjects completed the trial, with 5000 assessments of the device collected. CONCLUSION: The ActiPatch device appears to provide a clinically meaningful reduction of chronic musculoskeletal pain affecting different locations of the body caused by a variety of etiologies. PMID- 26235411 TI - Mitochondrial DNA Fragmentation as a Molecular Tool to Monitor Thermal Processing of Plant-Derived, Low-Acid Foods, and Biomaterials. AB - Cycle threshold (Ct) increase, quantifying plant-derived DNA fragmentation, was evaluated for its utility as a time-temperature integrator. This novel approach to monitoring thermal processing of fresh, plant-based foods represents a paradigm shift. Instead of using quantitative polymerase chain reaction (qPCR) to detect pathogens, identify adulterants, or authenticate ingredients, this rapid technique was used to quantify the fragmentation of an intrinsic plant mitochondrial DNA (mtDNA) gene over time-temperature treatments. Universal primers were developed which amplified a mitochondrial gene common to plants (atp1). These consensus primers produced a robust qPCR signal in 10 vegetables, 6 fruits, 3 types of nuts, and a biofuel precursor. Using sweet potato (Ipomoea batatas) puree as a model low-acid product and simple linear regression, Ct value was highly correlated to time-temperature treatment (R(2) = 0.87); the logarithmic reduction (log CFU/mL) of the spore-forming Clostridium botulinum surrogate, Geobacillus stearothermophilus (R(2) = 0.87); and cumulative F-value (min) in a canned retort process (R(2) = 0.88), all comparisons conducted at 121 degrees C. D121 and z-values were determined for G. stearothermophilus ATCC 7953 and were 2.71 min and 11.0 degrees C, respectively. D121 and z-values for a 174 bp universal plant amplicon were 11.3 min and 9.17 degrees C, respectively, for mtDNA from sweet potato puree. We present these data as proof-of-concept for a molecular tool that can be used as a rapid, presumptive method for monitoring thermal processing in low-acid plant products. PMID- 26235412 TI - An evaluation of current home enteral nutrition services at principal referral hospitals in New South Wales, Australia. AB - OBJECTIVE: This cross-sectional study investigates the home enteral nutrition (HEN) services of public principal referral hospitals in NSW, Australia, comparing their services to best practice guidelines for HEN. METHODS: HEN service processes were investigated using an online questionnaire and telephone interview with the dietitian primarily working with HEN at each hospital. RESULTS: Participating hospitals reported a total of approximately 3200 HEN patients, 76% required oral nutrition support. Only 69% of hospitals had a dietitian allocated to their HEN service and no hospitals had established multidisciplinary teams to manage HEN patients. Post-discharge follow-up, as recommended for tube fed and oral patients, was achieved by 8% and 15% of hospitals respectively. Forty-six per cent of dietitians were satisfied and 46% of dietitians were dissatisfied with current HEN services provided, and reported the following improvements were required: increased clinical resources allocated to HEN dietitian/coordinator; increased outpatient services (home visits, outpatient clinic, multidisciplinary clinic); and an efficient registration process and database. CONCLUSIONS: HEN services among participating hospitals are inconsistent, demonstrating gaps in service provision. Baseline assessment scores varied, with an average of 61% of recommendations currently in use. Best practice guidelines are not firmly adhered to due to limited funding and allocated resources for HEN. PMID- 26235413 TI - [Mobile applications in oncology available for French users: Who's behind?]. PMID- 26235414 TI - [Docetaxel and prostate cancer: Early but not too early]. PMID- 26235415 TI - [Functional iron deficiency, inflammation and fatigue after radiotherapy]. AB - Radiation therapy is associated with a fatigue in the majority of patients with a relative variability according to the type of the tumour, comorbidities, associated treatments and the extent of the irradiation. Its origin is multifactorial. One explanation described is that fatigue could be related to the inflammation caused by irradiation exposure. One of the suspected mechanisms is a functional iron deficiency following pro-inflammatory cytokines synthesis, particularly the interleukins 1 and 6. This phenomenon is accompanied by a reduced availability of iron, while iron reserves are normal or increased. Thus, iron inaccessibility induces lower coefficient of transferrin saturation, which can lead to a non-regenerative normocytic or microcytic anaemia. The availability of iron is controlled by hepcidin that is synthesized in the liver as a response to radiation-induced inflammatory. The presence of hepcidin blocks iron absorption in the intestine and decreases its recycling from senescent red blood cells. A direct relationship between elevated levels of hepcidin, inflammation markers and radiation-induced side effects have been reported. The aim of the article is to review the literature related to fatigue in radiotherapy and understand the mechanisms involved or worsening its occurrence to consider better care and improve patients' quality. PMID- 26235417 TI - Selection of ultimately ill cancer patients able to fulfill a questionnaire: Identification of inherent biases. AB - AIM: Physical or psychological well-being is an essential component of quality care assessment in palliative unit. This assessment is mainly based on self assessment (questionnaires or interviews). The aim of this study is to compare the clinical characteristics of patients able to fulfill a questionnaire and those not able to do that. METHODS: The clinical characteristics of 166 cancer patients admitted in palliative care unit from December 2006 to February 2008 have been collected. Characteristics of patients able to fulfill a questionnaire (80, 48.2%) have been compared to other patients (86, 51.8%). Moreover, functional independence measure (FIM) had been evaluated by nurses. RESULTS: Median age (60 versus 62) and sex ratio (40/40 versus 42/44) are similar in both groups. Lung primaries are significantly less frequent in patients able to fulfill the questionnaire (4% versus 17%, P=0.005). Patients able to fulfill the questionnaire had had better performance status (Karnofsky Index<=30%: 54% versus 21%, P<0.0001). The total score of FIM (56.0 versus 91.5, P<0.00001) and the median overall survivals (2.3 weeks versus 6.6 weeks, P=0.0001) were significantly lower in the group of patients non able to fulfill the questionnaire. CONCLUSIONS: Patients able to fulfill a questionnaire represent only 48.2% of all consecutive admitted patients. These patients are not representative of all patients since they had better performance status, they are less dependent and they display significant better survival. We have to think about new methods to avoid the biases generated by the use of patient-reported outcomes. PMID- 26235418 TI - [Metastatic colonization of the liver by colorectal tumor cells is abolished by two micro-RNAs (miR-483-5p et miR-551a)]. PMID- 26235416 TI - [uPA/PAI-1, Oncotype DXTM, MammaPrint((r)). Prognosis and predictive values for clinical utility in breast cancer management]. PMID- 26235419 TI - [3rd generation's TKI in lung cancer non-small cell EGFR-mutated having acquired a secondary T790M resistance]. AB - Activating EGFR mutations discovery and efficacy of 1st generation tyrosine kinase inhibitors (TKI), such as erlotinib or gefitinib, inaugurated the beginning of personalized medicine in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, all patients showed a tumor progression of 10 to 16 months after the onset of TKI therapy related to molecular resistance mechanisms as T790M mutation. Till now, patients suffering from EGFR-mutated NSCLC with acquired resistance have conventional treatment options. Two new 3rd generations' TKI, AZD9291 and rociletinib, are currently being studied in phases 1-3 studies. Preliminary results show relevant therapeutic properties in patients with T790M mutated-EGFR NSCLC. This review aims to highlight these new molecules, their effectiveness and their clinical toxicities in the treatment of advanced stages of NSCLC expressing the T790M mutation. PMID- 26235420 TI - [Alveolar soft part sarcoma in pediatric patients]. AB - Alveolar soft part sarcoma, ASPS, is a rare malignant tumor, with preferential primary localization in limbs, usually occurring in adolescents and young adults. This sarcoma, well defined histologically and at molecular level, has an indolent course, but a high potential metastatic pulmonary and cerebral evolution, sometimes late. ASPS is characterized by an almost specific translocation t(X, 17)(p11;25) which creates a fusion protein, APSL-TFE3, acting as an aberrant transcription factor. An in-bloc resection of the primary tumor is the treatment of choice in cases of localized disease. Conventional chemotherapy is generally ineffective. The role of radiotherapy is discussed in case of micro- or macroscopical incomplete residue. It seems to reduce local recurrence, but did not influence overall survival. The 5 years survival rate in children, adolescents and young adults is close to 80% in case of localized disease but poorer in presence of metastases. Recently, systemic anti-tumoral treatments have been focused on the use of targeted therapies. Anti-angiogenic drugs and tyrosine kinase inhibitors are the most promising approaches, but require further study. Prognostic risk factors in the literature are age (>10Y), tumor size (>5cm) and presence of metastases. This article reviews the clinical manifestations, diagnosis modalities, radiographic characteristics and therapeutic strategy of this disease in the pediatric population. PMID- 26235421 TI - The Bile Acid Chenodeoxycholic Acid Increases Human Brown Adipose Tissue Activity. AB - The interest in brown adipose tissue (BAT) as a target to combat metabolic disease has recently been renewed with the discovery of functional BAT in humans. In rodents, BAT can be activated by bile acids, which activate type 2 iodothyronine deiodinase (D2) in BAT via the G-coupled protein receptor TGR5, resulting in increased oxygen consumption and energy expenditure. Here we examined the effects of oral supplementation of the bile acid chenodeoxycholic acid (CDCA) on human BAT activity. Treatment of 12 healthy female subjects with CDCA for 2 days resulted in increased BAT activity. Whole-body energy expenditure was also increased upon CDCA treatment. In vitro treatment of primary human brown adipocytes derived with CDCA or specific TGR5 agonists increased mitochondrial uncoupling and D2 expression, an effect that was absent in human primary white adipocytes. These findings identify bile acids as a target to activate BAT in humans. PMID- 26235423 TI - Glial Glycolysis Is Essential for Neuronal Survival in Drosophila. AB - Neuronal information processing requires a large amount of energy, indicating that sugars and other metabolites must be efficiently delivered. However, reliable neuronal function also depends on the maintenance of a constant microenvironment in the brain. Therefore, neurons are efficiently separated from circulation by the blood-brain barrier, and their long axons are insulated by glial processes. At the example of the Drosophila brain, we addressed how sugar is shuttled across the barrier to nurture neurons. We show that glial cells of the blood-brain barrier specifically take up sugars and that their metabolism relies on glycolysis, which, surprisingly, is dispensable in neurons. Glial cells secrete alanine and lactate to fuel neuronal mitochondria, and lack of glial glycolysis specifically in the adult brain causes neurodegeneration. Our work implies that a global metabolic compartmentalization and coupling of neurons and glial cells is a conserved, fundamental feature of bilaterian nervous systems independent of their size. PMID- 26235422 TI - Indoleamine 2,3-Dioxygenase Fine-Tunes Immune Homeostasis in Atherosclerosis and Colitis through Repression of Interleukin-10 Production. AB - Indoleamine 2,3-dioxygenase 1 (Ido1) is a rate-limiting enzyme that catalizes the degradation of tryptophan along the kynurenine pathway. Here, we show that Ido1 activity sustains an immunostimulatory potential through inhibition of interleukin (Il)10. In atherosclerosis, Ido1-dependent inhibition of Il10 translates into disease exacerbation. The resistance of Ido1-deficient mice to enhanced immune activation is broken in Ido1/Il10 double-deficient mice, which show exaggerated immune responses and develop severe spontaneous colitis. We demonstrate that Ido1 activity is required for the regulation of Il10 and that kynurenic acid (Kna), an Ido1-derived metabolite, is responsible for reduced Il10 production through activation of a cAMP-dependent pathway and inhibition of Erk1/2 phosphorylation. Resupplementation of Ido1-deficient mice with Kna limits Il10 expression and promotes atherosclerosis. In human atherosclerotic lesions, increased levels of Kna are associated with an unstable plaque phenotype, and its blood levels predict death and recurrent myocardial infarction in patients with coronary artery disease. PMID- 26235424 TI - Atrial fibrillation in patients with cirrhosis. AB - BACKGROUND & AIMS: Few information is available regarding atrial fibrillation in cirrhotic patients. The aim of this study was to investigate the occurrence and clinical impact of atrial fibrillation in these patients. METHODS: Three hundred and thirty-five cirrhotic patients (219 males; mean age 65 +/- 10.85 years; 196 Child-Pugh class A, 104 class B and 35 class C) were consecutively analysed and followed up for 24 months. Electrocardiograms were available for all patients before starting the study, at basaltime and during the follow-up. Echocardiography was performed in individuals with atrial fibrillation and in 100 randomly chosen patients without it. RESULTS: Atrial fibrillation was observed in 21/335 cirrhotics (mean age 75 +/- 7 years, 13 male), six of whom had permanent and 15 had paroxysmal atrial fibrillation. At univariate analysis, atrial fibrillation significantly correlated with older age, history of coronary heart disease, Child-Pugh score, serum albumin, hepatic encephalopathy, treatment with furosemide, QTc prolongation, atrial section areas, increased PAPs and thickness of interventricular septum. Age [odd ratio 1.12, 95% CI (1.05-1.2), P = 0.001], history of coronary heart disease [odd ratio 4.93, 95% CI (1.04-23.54), P = 0.04] and PAPs [odd ratio 1.12, 95% CI (1.02-1.2), P = 0.01] maintained statistical significance at multivariate analysis. Fifty-one of the 335 patients died during the follow-up. At Cox regression analysis, advanced Child-Pugh score [hazard ratio 1.546, 95% CI (1.357-1.762), P = 0.037] and increased heart rate [hazard ratio 1.117, 95% CI (1.021-1.223), P = 0.016] were significantly associated with mortality which was independent of atrial fibrillation occurrence. CONCLUSIONS: Cirrhosis is not a predisposing factor of atrial fibrillation, which in turn has no impact on mortality in cirrhotic patients. PMID- 26235425 TI - Publication rates in peer-reviewed journals of abstracts presented at the Oral and Maxillofacial Surgery Society of Turkey meetings 2007-2012. AB - The purpose of this study was to find out the rate of peer-reviewed publication of full papers of abstracts presented at the annual meeting of the Oral and Maxillofacial Surgery Society of Turkey, and to identify the time taken for publication, subspecialty, and study design. All abstracts accepted for presentation at the meetings in 2007-12 were identified from the books of abstracts, and evidence of publication was sought from PubMed and Google Scholar. The following variables were evaluated: publication rate, type of presentation (oral or poster), time to publication, subspecialty, study design, name of the journal in which the paper was published, impact factor of the journal, author affiliation, change in number of authors and origin of the study. A total of 1322 abstracts were presented between 2007 and 2012. Of these, 246 (19%) were subsequently published in peer-reviewed journals, including 110/390 oral presentations (28%) and 136/932 poster presentations (15%). Oral presentations were more likely to be published than poster presentations (p=0.000). The mean (SD) time from presentation to publication was 17 (15) months. Anatomical presentations had the highest publication rate (8/11), whereas orthognathic surgery had the lowest (5/67, 7%). Technical notes (5/9) and animal studies (32/70, 46%) were the most common types of publication. Only 246 of the 1322 abstracts (19%) were subsequently published as full papers, which is lower than previously reported in oral and maxillofacial surgery. PMID- 26235426 TI - Re: Empty fenestration of the internal jugular vein: a rare phenomenon. PMID- 26235427 TI - High-dose versus conventional-dose irradiation in cisplatin-based definitive concurrent chemoradiotherapy for esophageal cancer: a systematic review and pooled analysis. AB - We investigate whether high-dose (HD, >=60 Gy) radiotherapy in definitive concurrent chemoradiotherapy (CCRT) based on cisplatin could yield benefits compared to conventional-dose (CD) CCRT. PubMed, Embase and Google Scholar were searched and data were pooled and analyzed for response rate, survival, failure patterns and toxicity. Results showed advantages in response rate, 5-year overall survival rate, local regional recurrence and distant failure rate compared to the CD arm with no difference in Grade >=3 acute and late esophagitis, other toxicities were rare with moderate tolerance, subgroup analysis of squamous cell carcinoma also showed advantages for HD arm. We concluded that >=60 Gy CCRT improved clinical outcomes compared to the CD arm, especially for esophageal squamous cell carcinoma. Our findings may provide a basis for future trials. PMID- 26235428 TI - Density-dependent adjustment of inducible defenses. AB - Predation is a major factor driving evolution, and organisms have evolved adaptations increasing their survival chances. However, most defenses incur trade offs between benefits and costs. Many organisms save costs by employing inducible defenses as responses to fluctuating predation risk. The level of defense often increases with predator densities. However, individual predation risk should not only depend on predator density but also on the density of conspecifics. If the predator has a saturating functional response one would predict a negative correlation between prey density and individual predation risk and hence defense expression. Here, we tested this hypothesis using six model systems, covering a taxonomic range from protozoa to rotifers and crustaceans. In all six systems, we found that the level of defense expression increased with predator density but decreased with prey density. In one of our systems, i.e. in Daphnia, we further show that the response to prey density is triggered by a chemical cue released by conspecifics and congeners. Our results indicate that organisms adjust the degree of defense to the acute predation risk, rather than merely to predators' densities. Our study suggests that density-dependent defense expression reflects accurate predation-risk assessment and is a general principle in many inducible defense systems. PMID- 26235429 TI - Inverse internal conversion in C4(-) below the electron detachment threshold. AB - Inverse internal conversion followed by recurrent fluorescence was observed as a fast decay (10 MUs range) in the time profile of neutral yields from photo excited C4(-) molecular ions. We also elucidated the contribution of such electronic radiative cooling to the C4(-) ions with internal energy far below the detachment threshold by an alternative novel approach, observing the laser wavelength and storage time dependence (ms range) of the total yield of the photo induced neutrals. PMID- 26235430 TI - Rapid and fully automated bacterial pathogen detection on a centrifugal microfluidic LabDisk using highly sensitive nested PCR with integrated sample preparation. AB - Diagnosis of infectious diseases suffers from long turnaround times for gold standard culture-based identification of bacterial pathogens, therefore impeding timely specific antimicrobial treatment based on laboratory evidence. Rapid molecular diagnostics-based technologies enable detection of microorganisms within hours however cumbersome workflows and complex equipment still prevent their widespread use in the routine clinical microbiology setting. We developed a centrifugal-microfluidic "LabDisk" system for rapid and highly-sensitive pathogen detection on a point-of-care analyser. The unit-use LabDisk with pre-stored reagents features fully automated and integrated DNA extraction, consensus multiplex PCR pre-amplification and geometrically-multiplexed species-specific real-time PCR. Processing merely requires loading of the sample and DNA extraction reagents with minimal hands-on time of approximately 5 min. We demonstrate detection of as few as 3 colony-forming-units (cfu) of Staphylococcus warneri, 200 cfu of Streptococcus agalactiae, 5 cfu of Escherichia coli and 2 cfu of Haemophilus influenzae in a 200 MUL serum sample. The turnaround time of the complete analysis from "sample-to-result" was 3 h and 45 min. The LabDisk consequently provides an easy-to-use molecular diagnostic platform for rapid and highly-sensitive detection of bacterial pathogens without requiring major hands on time and complex laboratory instrumentation. PMID- 26235431 TI - Treatment, deterrence or labelling: mentally disordered offenders' perspectives on social control. AB - Mentally disordered offenders are a group of service users who experience substantial amounts of control and supervision. This article uses theories of social control to analyse the way in which mechanisms of control are understood by this group. Semi-structured interviews with mentally disordered offenders in England who were subject to a restriction order under the Mental Health Act 1983 (as amended by the Mental Health Act 2007) provided the empirical basis for this study. The offenders had a number of perspectives on the restriction order. Firstly, it was seen as a mechanism for identifying those suffering from a mental disorder and for providing appropriate treatment. Secondly, the restriction order was viewed as a form of disciplinary control through which societal norms might be internalised. Thirdly, it was seen as labelling offenders in a manner that was experienced as limiting and oppressive. A number of research participants were aware that the order acted to limit staff actions. These participants saw the order as a means by which they might shape the support that they received in order to further their own aims.A video abstract of this article can be found at: https://www.youtube.com/watch?v=qwIwDI2sOTY&feature=youtu.be. PMID- 26235432 TI - The relation between risk-taking behavior and alcohol use in young adults is different for men and women. AB - OBJECTIVE: The present study examined the relationship of risk-taking behavior and alcohol use and the role of sex herein, while adjusting for age, depression, anxiety, stress and lifestyle. METHODS: Participants were 6002 university students. They were classified as either abstinent, drinker but non-binge drinker, or binge drinker based on self-reported alcohol consumption. Risk-taking and risk assessment were evaluated with the RT-18 and depression, anxiety and stress with the DASS-21. RESULTS: The odds of being a binge versus non-binge drinker increased with risk-taking as well as risk assessment for both men and women. The odds being a non-binge drinker versus abstinent were increased by risk taking for women only. For binge drinking versus abstinence, risk-taking had a significant increasing effect for both sexes, but risk assessment was only significant in women. CONCLUSION: These results may assist with alcohol use prevention techniques because risk-taking behavior exerts, even when corrected for age, lifestyle, depression, anxiety, and stress levels, a solid, sex-specific independent effect on alcohol use. PMID- 26235433 TI - An examination of the rapid automatized naming-reading relationship using functional magnetic resonance imaging. AB - Rapid automatized naming (RAN) has been established to be a strong predictor of reading. Yet, the neural correlates underlying the RAN-reading relationship remain unknown. Thus, the purpose of this study was to determine: (a) the extent to which RAN and reading activate similar brain regions (within subjects), (b) whether RAN and reading are directly related in the shared activity network outlined in (a), and (c) to what extent RAN neural activation predicts behavioral reading performance. Using functional magnetic resonance imaging (fMRI), university students (N=15; Mean age=20.6 years) were assessed on RAN (letters and digits) and single-word reading (words and non-words). The results revealed a common RAN-reading network that included regions associated with motor planning (cerebellum), semantic access (middle temporal gyrus), articulation (supplementary motor area, pre-motor), and grapheme-phoneme translation (supramarginal gyrus). We found differences between RAN and reading with respect to percent signal change (PSC) in phonological and orthographic regions, but not in articulatory regions. Significant correlations between the neural RAN and reading parameters were found primarily in motor/articulatory regions. Further, we found a unique relationship between in-scanner reading response time and RAN PSC in the left inferior frontal gyrus. Taken together, these findings support the notion that RAN and reading activate similar neural networks. However, the relationship between RAN and reading is primarily driven by commonalities in the motor-sequencing/articulatory processes. PMID- 26235434 TI - Children with cerebral palsy have uncharacteristic somatosensory cortical oscillations after stimulation of the hand mechanoreceptors. AB - Numerous clinical investigations have reported that children with cerebral palsy (CP) have tactile discrimination deficits that likely limit their ability to plan and manipulate objects. Despite this clinical awareness, we still have a substantial knowledge gap in our understanding of the neurological basis for these tactile discrimination deficits. Previously, we have shown that children with CP have aberrant theta-alpha (4-14 Hz) oscillations in the somatosensory cortices following tactile stimulation of the foot. In this investigation, we evaluated if these aberrant theta-alpha oscillations also extend to the hand. Magnetoencephalography was used to evaluate event-related changes in the theta alpha and beta (18-34 Hz) somatosensory cortical oscillations in groups of children with CP and typically developing (TD) children following tactile stimulation of their hands. Our results showed that the somatosensory theta-alpha oscillations were relatively intact in children with CP, which is in contrast to our previous results for foot tactile stimulations. We suspect that these inter study differences may be related to the higher probability that the neural tracts serving the lower extremities are damaged in children with CP, compared to those serving the upper extremities. This inference is plausible since the participating children with CP had Manual Ability Classification System (MACS) levels between I and II. In contrast to the theta-alpha results, children with CP did exhibit a sharp increase in beta activity during the same time period, which was not observed in TD children. This suggests that children with CP still have deficits in the computational aspect of somatosensory processing. PMID- 26235435 TI - Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer's disease models. AB - Alzheimer's disease (AD) brains exhibit plaques and tangles in association with inflammation. The non-receptor tyrosine kinase Abl is linked to neuro inflammation in AD. Abl inhibition by nilotinib or bosutinib facilitates amyloid clearance and may decrease inflammation. Transgenic mice that express Dutch, Iowa and Swedish APP mutations (TgAPP) and display progressive Abeta plaque deposition were treated with tyrosine kinase inhibitors (TKIs) to determine pre-plaque effects on systemic and CNS inflammation using milliplex(r) ELISA. Plaque Abeta was detected at 4months in TgAPP and pre-plaque intracellular Abeta accumulation (2.5months) was associated with changes of cytokines and chemokines prior to detection of glial changes. Plaque formation correlated with increased levels of pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1alpha, IL-1beta) and markers of immunosuppressive and adaptive immunity, including, IL-4, IL-10, IL-2, IL-3, Vascular Endothelial Growth Factor (VEGF) and IFN-gamma. An inverse relationship of chemokines was observed as CCL2 and CCL5 were lower than WT mice at 2months and significantly increased after plaque appearance, while soluble CX3CL1 decreased. A change in glial profile was only robustly detected at 6months in Tg APP mice and TKIs reduced astrocyte and dendritic cell number with no effects on microglia, suggesting alteration of brain immunity. Nilotinib decreased blood and brain cytokines and chemokines and increased CX3CL1. Bosutinib increased brain and blood IL-10 and CX3CL1, suggesting a protective role for soluble CX3CL1. Taken together these data suggest that TKIs regulate systemic and CNS immunity and may be useful treatments in early AD through dual effects on amyloid clearance and immune modulation. PMID- 26235436 TI - Fibroblast growth factor receptor 3 isoforms: Novel therapeutic targets for hepatocellular carcinoma? AB - Fibroblast growth factor receptors (FGFRs) are frequently up-regulated in subsets of hepatocellular carcinoma (HCC). Here, we provide mechanistic insight that FGFR3 splice variants IIIb and IIIc impact considerably on the malignant phenotype of HCC cells. The occurrence of FGFR3 variants was analyzed in human HCC samples. In hepatoma/hepatocarcinoma cell lines, FGFR3 isoforms were overexpressed by lentiviral constructs or down-modulated by small interfering RNA (siRNA; affecting FGFR3-IIIb and -IIIc) or an adenoviral kinase-dead FGFR3-IIIc construct (kdFGFR3). Elevated levels of FGFR3-IIIb and/or -IIIc were found in 53% of HCC cases. FGFR3-IIIb overexpression occurred significantly more often in primary tumors of large (pT2-4) than of small size (pT1). Furthermore, one or both isoforms were enhanced mostly in cases with early tumor infiltration and/or recurrence at the time of surgery or follow-up examinations. In hepatoma/hepatocarcinoma cells, up-regulated FGFR3-IIIb conferred an enhanced capability for proliferation. Both FGFR3-IIIb and FGFR3-IIIc suppressed apoptotic activity, enhanced clonogenic growth, and induced disintegration of the blood/lymph endothelium. The tumorigenicity of cells in severe combined immunodeficiency mice was augmented to a larger degree by variant IIIb than by IIIc. Conversely, siRNA targeting FGFR3 and kdFGFR3 reduced clonogenicity, anchorage-independent growth, and disintegration of the blood/lymph endothelium in vitro. Furthermore, kdFGFR3 strongly attenuated tumor formation in vivo. CONCLUSIONS: Deregulated FGFR3 variants exhibit specific effects in the malignant progression of HCC cells. Accordingly, blockade of FGFR3-mediated signaling may be a promising therapeutic approach to antagonize growth and malignant behavior of HCC cells. PMID- 26235437 TI - Reconstituting the actin cytoskeleton at or near surfaces in vitro. AB - Actin filament dynamics have been studied for decades in pure protein solutions or in cell extracts, but a breakthrough in the field occurred at the turn of the century when it became possible to reconstitute networks of actin filaments, growing in a controlled but physiological manner on surfaces, mimicking the actin assembly that occurs at the plasma membrane during cell protrusion and cell shape changes. The story begins with the bacteria Listeria monocytogenes, the study of which led to the reconstitution of cellular actin polymerization on a variety of supports including plastic beads. These studies made possible the development of liposome-type substrates for filament assembly and micropatterning of actin polymerization nucleation. Based on the accumulated expertise of the last 15 years, many exciting approaches are being developed, including the addition of myosin to biomimetic actin networks to study the interplay between actin structure and contractility. The field is now poised to make artificial cells with a physiological and dynamic actin cytoskeleton, and subsequently to put these cells together to make in vitro tissues. This article is part of a Special Issue entitled: Mechanobiology. PMID- 26235438 TI - The roles of IP3 receptor in energy metabolic pathways and reactive oxygen species homeostasis revealed by metabolomic and biochemical studies. AB - Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are calcium channels modulating important calcium-mediated processes. Recent studies implicate IP(3)R in cell metabolism, but specific evidence is missing regarding IP(3)R's effects on actual metabolic pathways and key energy metabolites. Here, we applied metabolomics and molecular biology to compare DT40 cell lines devoid of IP(3)R (KO) and its wild type (WT) counterpart. NMR and LC-MS metabolomic data showed that the KO cell line has a very different basic energy metabolism from the WT cell line, showing enhanced Warburg effect. In particular, the KO cells exhibited significant perturbation in energy charge, reduced glutathione and NADPH ratios with slower cellular growth rate. Subsequent flow cytometry results showed that the KO cell line has a higher level of general reactive oxygen species (ROS) but has a lower level of peroxynitrites. This ROS disturbance could be explained by observing lower expression of superoxide dismutase 2 (SOD2) and unchanged expression of catalase. The higher ROS seems to be involved in the slower growth rate of the KO cells, with an ROS scavenger increasing their growth rate. However, the KO and WT cell lines did not show any noticeable differences in AMPK and phosphorylated AMPK levels, suggesting possible saturation of AMPK-mediated metabolic regulatory circuit in both cells. Overall, our study reveals IP3R's roles in ROS homeostasis and metabolic pathways as well as the effects of its KO on cellular phenotypes. PMID- 26235439 TI - The role of FlhF and HubP as polar landmark proteins in Shewanella putrefaciens CN-32. AB - Spatiotemporal regulation of cell polarity plays a role in many fundamental processes in bacteria and often relies on 'landmark' proteins which recruit the corresponding clients to their designated position. Here, we explored the localization of two multi-protein complexes, the polar flagellar motor and the chemotaxis array, in Shewanella putrefaciens CN-32. We demonstrate that polar positioning of the flagellar system, but not of the chemotaxis system, depends on the GTPase FlhF. In contrast, the chemotaxis array is recruited by a transmembrane protein which we identified as the functional ortholog of Vibrio cholerae HubP. Mediated by its periplasmic N-terminal LysM domain, SpHubP exhibits an FlhF-independent localization pattern during cell cycle similar to its Vibrio counterpart and also has a role in proper chromosome segregation. In addition, while not affecting flagellar positioning, SpHubP is crucial for normal flagellar function and is involved in type IV pili-mediated twitching motility. We hypothesize that a group of HubP/FimV homologs, characterized by a rather conserved N-terminal periplasmic section required for polar targeting and a highly variable acidic cytoplasmic part, primarily mediating recruitment of client proteins, serves as polar markers in various bacterial species with respect to different cellular functions. PMID- 26235440 TI - Are Isoursenol and gamma-Amyrin Rare Triterpenes in Nature or Simply Overlooked by Usual Analytical Methods? AB - Among pentacyclic triterpenes commonly found in plants, gamma-amyrin and isoursenol are seldom reported and considered rare in nature. It was hypothesized that these triterpenes are instead routinely overlooked due to inadequate spectral characterization. gamma-Amyrin was prepared by HCOOH isomerization of alpha-amyrin, and isoursenol was isolated from products of a heterologously expressed oxidosqualene cyclase. With precise NMR and GC-MS data, a metabolomics strategy was used to identify isoursenol and gamma-amyrin in a wide range of plants. PMID- 26235442 TI - Insight into the precuneus: a novel seizure semiology in a child with epilepsy arising from the right posterior precuneus. AB - To date, there is limited understanding of the role of the precuneus. fMRI studies have suggested its involvement in a wide spectrum of highly integrated tasks, including spatially-guided behaviour, visuo-spatial imagery, and consciousness. We present a patient with intractable parietal lobe epilepsy arising from a lesion localized to the right precuneus. Two seizure types with distinct semiologies were captured on video-EEG monitoring. The first type consisted of an urge described as a "feeling of wanting to move". On video analysis, the patient is seen to turn his head and body to his left. He remains conscious, he is able to answer questions and when asked, he can look to his right. This seizure was associated with an ictal pattern localized to the right parieto-occipital region. The second seizure type consisted of reading-induced visual distortion with macropsia and micropsia. Interictally, intermittent rhythmic slowing and spikes were seen and localized to the parietal midline and the right parieto-occipital regions. Our patient's seizures are positive phenomena of the right precuneus and its related processing network. They represent unique seizure semiologies that offer further insight into the role of the precuneus in spatial awareness, visuo-spatial processing and consciousness. PMID- 26235443 TI - Biopsy and the diagnostic evaluation of musculoskeletal tumours: critical but often missed in the 21st century. AB - Bone and soft-tissue sarcomas are rare and heterogeneous malignancies arising from tissues of mesenchymal origin. Treatment planning is informed by accurate diagnosis for which biopsy is the diagnostic standard. Biopsy in the setting of suspected malignancy is a technically challenging procedure that should only be performed at specialist institutions. Without the requisite expertise, they can compromise the viability of reconstructive procedures and may make necessary amputation to achieve adequate surgical margins. The risk of complications arising from the procedure must be minimized and therefore biopsy should always be preceded by imaging. There must be no attempt at biopsy or excision prior to referral if there is any suspicion of malignancy. Patients with suspected bone and soft-tissue tumours are best evaluated and treated at specialist sarcoma centres under the care of expert multidisciplinary teams. Prompt referral to a specialist sarcoma centre should always be made prior to biopsy for any suspicious mass that is painful, progressively increasing in size, greater than 5 cm in diameter, deep to deep fascia or recurs following inadvertent excision. PMID- 26235444 TI - Liver injury is associated with mortality in sickle cell disease. AB - BACKGROUND: Increased life expectancy in sickle cell disease (SCD) has resulted in greater recognition of the consequences of repeated intravascular vaso occlusion and chronic haemolysis to multiple organ systems. AIM: To report the long-term consequences of liver dysfunction in SCD. METHODS: A cohort of SCD patients was prospectively evaluated at the National Institutes of Health (NIH) Clinical Center. The association of mortality with liver enzymes, parameters of liver synthetic function and iron overload was evaluated using Cox regression. RESULTS: Exactly, 247 SCD patients were followed up for 30 months of whom 22 (9%) died. After controlling for predictors, increased direct bilirubin (DB), ferritin, alkaline phosphatase and decreased albumin were independently associated with mortality. In a multivariable model, only high DB and ferritin remained significant. Ferritin correlated with hepatic iron content and total blood transfusions but not haemolysis markers. Forty patients underwent liver biopsies and 11 (28%) had fibrosis. Twelve of 26 patients (48%) had portal hypertension by hepatic venous pressure gradient (HVPG) measurements. All patients with advanced liver fibrosis had iron overload; however, most patients (69%) with iron overload were without significant hepatic fibrosis. Ferritin did not correlate with left ventricular dysfunction by echocardiography. DB correlated with bile acid levels suggesting liver pathology. Platelet count and soluble CD14 correlated with HVPG indicating portal hypertension. CONCLUSIONS: Ferritin and direct bilirubin are independently associated with mortality in sickle cell disease. Ferritin likely relates to transfusional iron overload, while direct bilirubin suggests impairment of hepatic function, possibly impairing patients' ability to tolerate systemic insults. PMID- 26235445 TI - Economic evaluations of Internet interventions for mental health: a systematic review. AB - BACKGROUND: Internet interventions are assumed to be cost-effective. However, it is unclear how strong this evidence is, and what the quality of this evidence is. METHOD: A comprehensive literature search (1990-2014) in Medline, EMBASE, the Cochrane Central Register of Controlled Trials, NHS Economic Evaluations Database, NHS Health Technology Assessment Database, Office of Health Economics Evaluations Database, Compendex and Inspec was conducted. We included economic evaluations alongside randomized controlled trials of Internet interventions for a range of mental health symptoms compared to a control group, consisting of a psychological or pharmaceutical intervention, treatment-as-usual (TAU), wait-list or an attention control group. RESULTS: Of the 6587 abstracts identified, 16 papers met the inclusion criteria. Nine studies featured a societal perspective. Results demonstrated that guided Internet interventions for depression, anxiety, smoking cessation and alcohol consumption had favourable probabilities of being more cost-effective when compared to wait-list, TAU, group cognitive behaviour therapy (CBGT), attention control, telephone counselling or unguided Internet CBT. Unguided Internet interventions for suicide prevention, depression and smoking cessation demonstrated cost-effectiveness compared to TAU or attention control. In general, results from cost-utility analyses using more generic health outcomes (quality of life) were less favourable for unguided Internet interventions. Most studies adhered reasonably to economic guidelines. CONCLUSIONS: Results of guided Internet interventions being cost-effective are promising with most studies adhering to publication standards, but more economic evaluations are needed in order to determine cost-effectiveness of Internet interventions compared to the most cost-effective treatment currently available. PMID- 26235446 TI - Beyond land application: Emerging technologies for the treatment and reuse of anaerobically digested agricultural and food waste. AB - Effective treatment and reuse of the massive quantities of agricultural and food wastes generated daily has the potential to improve the sustainability of food production systems. Anaerobic digestion (AD) is used throughout the world as a waste treatment process to convert organic waste into two main products: biogas and nutrient-rich digestate, called AD effluent. Biogas can be used as a source of renewable energy or transportation fuels, while AD effluent is traditionally applied to land as a soil amendment. However, there are economic and environmental concerns that limit widespread land application, which may lead to underutilization of AD for the treatment of agricultural and food wastes. To combat these constraints, existing and novel methods have emerged to treat or reuse AD effluent. The objective of this review is to analyze several emerging methods used for efficient treatment and reuse of AD effluent. Overall, the application of emerging technologies is limited by AD effluent composition, especially the total solid content. Some technologies, such as composting, use the solid fraction of AD effluent, while most other technologies, such as algae culture and struvite crystallization, use the liquid fraction. Therefore, dewatering of AD effluent, reuse of the liquid and solid fractions, and land application could all be combined to sustainably manage the large quantities of AD effluent produced. Issues such as pathogen regrowth and prevalence of emerging organic micro-pollutants are also discussed. PMID- 26235447 TI - Designing Pay-As-You-Throw schemes in municipal waste management services: A holistic approach. AB - Pay-As-You-Throw (PAYT) strategies are becoming widely applied in solid waste management systems; the main purpose is to support a more sustainable - from economic, environmental and social points of view - management of waste flows. Adopting PAYT charging models increases the complexity level of the waste management service as new organizational issues have to be evaluated compared to flat charging models. In addition, innovative technological solutions could also be adopted to increase the overall efficiency of the service. Unit pricing, user identification and waste measurement represent the three most important processes to be defined in a PAYT system. The paper proposes a holistic framework to support an effective design and management process. The framework defines most critical processes and effective organizational and technological solutions for supporting waste managers as well as researchers. PMID- 26235448 TI - Citric acid and ethylene diamine tetra-acetic acid as effective washing agents to treat sewage sludge for agricultural reuse. AB - This paper presents the effects of different concentrations of citric acid (CA) and ethylene diamine tetra-acetic acid (EDTA) when used as additive reagents for the treatment of sewage sludge for agricultural use. Herein, both the retention of nutrients and removal of metals from the sewage sludge are examined. The average removal rate for the metals after treatment by CA decreased in the order Cu>Pb>Cd>Cr>Zn, while the rates after treatment by EDTA decreased in the order of Pb>Cu>Cr>Cd>Zn. After treatment with CA and EDTA, total nitrogen and total phosphorus concentrations in the sludge decreased, while the content of available nitrogen and Olsen-P increased. In addition, a multi-criteria analysis model fuzzy analytic network process method (with 3 main factors and 12 assessment sub factors) was adopted to evaluate the effectiveness of different treatment methods. The results showed that the optimal CA and EDTA concentrations for sewage sludge treatment were 0.60 and 0.125 mol/L, respectively. PMID- 26235449 TI - Circuitry of self-control and its role in reducing addiction. AB - We discuss the idea that addictions can be treated by changing the mechanisms involved in self-control with or without regard to intention. The core clinical symptoms of addiction include an enhanced incentive for drug taking (craving), impaired self-control (impulsivity and compulsivity), negative mood, and increased stress re-activity. Symptoms related to impaired self-control involve reduced activity in control networks including anterior cingulate (ACC), adjacent prefrontal cortex (mPFC), and striatum. Behavioral training such as mindfulness meditation can increase the function of control networks and may be a promising approach for the treatment of addiction, even among those without intention to quit. PMID- 26235450 TI - The Clinical Relevance of Microbleeds in Stroke study (CROMIS-2): rationale, design, and methods. AB - BACKGROUND AND RATIONALE: The increasing use of oral anticoagulants, mostly to prevent ischemic stroke due to atrial fibrillation in an ageing population, has been associated with a fivefold increased incidence of oral anticoagulant associated intracerebral hemorrhage: a rare, serious, and unpredictable complication. We hypothesize that cerebral microbleeds and other markers of cerebral small vessel disease on magnetic resonance imaging, and genetic polymorphisms (e.g. influencing cerebral small vessel integrity or anticoagulation stability), are associated with an increased risk of oral anticoagulant-associated intracerebral hemorrhage, with potential to improve risk prediction. AIMS: (1) To determine the incidence, clinical, radiological, and genetic associations of oral anticoagulant-associated intracerebral hemorrhage in a prospective, multicentre cohort study of patients with atrial fibrillation related ischemic stroke or transient ischemic attack started on oral anticoagulants; (2) To investigate characteristics of oral anticoagulant associated intracerebral hemorrhage compared with non-oral anticoagulants related intracerebral hemorrhage in a prospective study. DESIGN AND METHODS: Study 1: Prospective, multicentre, inception cohort study of 1425 adults started on oral anticoagulants (including vitamin K antagonists and the nonvitamin K oral anticoagulants) after recent ischemic stroke and concurrent atrial fibrillation. Participants will have standardized brain magnetic resonance imaging (including a T2*-weighted gradient-recalled echo sequence) and DNA sample collection at baseline, with two-year follow-up by postal questionnaire and medical records surveillance for symptomatic intracranial hemorrhage, other serious vascular events, and death. We will compare the rates of symptomatic intracranial hemorrhage (primary outcome; subclassified as intracerebral, subdural, extradural, intraventricular), other vascular events, and death (secondary outcomes) in participants with one or more cerebral microbleeds to the rates in those without cerebral microbleeds. STUDY: Prospective case-control study of oral anticoagulant-associated intracerebral hemorrhage compared with non-oral anticoagulant-associated intracerebral hemorrhage to investigate genetic, clinical, and radiological associations with oral anticoagulant-associated intracerebral hemorrhage. In participants with intracerebral hemorrhage (including at least 300 with oral anticoagulant-associated intracerebral hemorrhage), we will collect a DNA sample, standardized clinical data and routine brain imaging (magnetic resonance imaging or computed tomography), and information on functional outcome. EXPECTED OUTCOMES: We will identify the factors associated with increased intracranial hemorrhage risk after oral anticoagulants for secondary prevention after ischemic stroke due to atrial fibrillation. We will determine clinical, radiological and genetic factors, and clinical outcomes associated with oral anticoagulant-associated intracerebral hemorrhage. PMID- 26235451 TI - Flow field thermal gradient gas chromatography. AB - Negative temperature gradients along the gas chromatographic separation column can maximize the separation capabilities for gas chromatography by peak focusing and also lead to lower elution temperatures. Unfortunately, so far a smooth thermal gradient over a several meters long separation column could only be realized by costly and complicated manual setups. Here we describe a simple, yet flexible method for the generation of negative thermal gradients using standard and easily exchangeable separation columns. The measurements made with a first prototype reveal promising new properties of the optimized separation process. The negative thermal gradient and the superposition of temperature programming result in a quasi-parallel separation of components each moving simultaneously near their lowered specific equilibrium temperatures through the column. Therefore, this gradient separation process is better suited for thermally labile molecules such as explosives and natural or aroma components. High-temperature GC methods also benefit from reduced elution temperatures. Even for short columns very high peak capacities can be obtained. In addition, the gradient separation is particularly beneficial for very fast separations below 1 min overall retention time. Very fast measurements of explosives prove the benefits of using negative thermal gradients. The new concept can greatly reduce the cycle time of high-resolution gas chromatography and can be integrated into hyphenated or comprehensive gas chromatography setups. PMID- 26235452 TI - Carboplatin Rechallenge After Hypersensitivity Reactions in Pediatric Patients With Low-Grade Glioma. AB - BACKGROUND: The high prevalence of carboplatin hypersensitivity reactions (HSR) significantly affects the treatment of pediatric patients with low-grade glioma (LGG). Rechallenging patients is an option that must balance the risks of repeat allergic reaction to the benefits of retaining an effective anti-tumor regimen. PROCEDURE: We performed a retrospective review of children with LGG treated with carboplatin and vincristine between October 2000 and April 2013, who had a documented HSR to carboplatin. Patients were re-exposed to carboplatin using either precautionary measures (prolonged infusion time and premedication with H1 antagonists, H2 antagonists, and corticosteroids), a desensitization protocol, or both. RESULTS: We report the results of our institutional experience of carboplatin re-exposure using both premedication with a prolonged infusion time and a desensitization protocol. Overall, 40 of 55 (73%) patients were successfully rechallenged with carboplatin, including 19 of 25 (76%) patients who underwent desensitization. CONCLUSION: Our results demonstrate re-exposure to be a safe alternative to abandoning carboplatin for patients with a hypersensitivity reaction. We propose a clinical algorithm for treatment. PMID- 26235453 TI - Re: Petros P. A critical analysis of the trampoline test for diagnosis of SUI. Re: Rimstad L, Larsen ES, Schiotz HA, Kulseng-Hansen S, Pad tests with increasing load for the diagnosis of stress incontinence, Neurourol Urodyn. 2014;33:1135-39. PMID- 26235454 TI - Using Social Network as a Recruiting Tool for Research on Substance Use in the Taipei Metropolitan Area: Study Design, Implementation, and Epidemiological Estimates. AB - BACKGROUND: This study aimed to evaluate the practical utility of respondent driven sampling (RDS) among regular tobacco and alcohol users in Taipei, Taiwan. METHODS: RDS was implemented from 2007 to 2010 to recruit seed individuals who were 18 to 50 years old, regular tobacco and alcohol users, and currently residing in Taipei. Each respondent was asked to refer up to five friends known to be regular tobacco smokers and alcohol drinkers to participate in the present study. Information pertaining to drug use was collected using an audio computer assisted self-interview instrument. RDSAT software was used for data analyses. RESULTS: The prevalence estimates of illegal-drug-using behaviors attained equilibrium after three to five recruitment waves. Nearly one-fifth of the participants had ever used illegal drugs, of whom over 60% were polydrug users. The RDS-adjusted prevalences of illegal-drug-using behaviors among early-onset smokers were all two or three times higher than those among late-onset smokers. CONCLUSIONS: Our results provided an empirical basis for the practicality and feasibility of using RDS to estimate illegal drug use prevalence among regular tobacco and alcohol users. PMID- 26235457 TI - Lattice dynamics in the paraelectric phase of PbHfO3 studied by inelastic x-ray scattering. AB - We report the results of an inelastic x-ray scattering study of the lattice dynamics in the paraelectric phase of the antiferroelectric lead hafnate PbHfO3. The study reveals an avoided crossing between the transverse acoustic and transverse optic phonon modes propagating along the [1 1 0] direction with [1 -1 0] polarization. The static susceptibility with respect to the generally incommensurate modulations is shown to increase on cooling for the entire Gamma-M direction. We consider different approaches to the data analysis that correspond to different models for the temperature evolution of the dynamic susceptibility function. A number of similarities and differences between the lattice dynamics of PbHfO3 and PbZrO3 are described. PMID- 26235456 TI - Farmers' Cohort for Agricultural Work-Related Musculoskeletal Disorders (FARM) Study: Study Design, Methods, and Baseline Characteristics of Enrolled Subjects. AB - BACKGROUND: The ongoing Farmers' Cohort for Agricultural Work-related Musculoskeletal Disorders (FARM) study was developed to evaluate health status and related factors in farmers. METHODS: Farmers in Kangwon Province, South Korea, were recruited. Baseline characteristics were determined using questionnaires about sociodemographic and health characteristics and agricultural work-related factors. In addition, laboratory examinations (lumbar spinal radiography and serologic testing) were conducted. RESULTS: The FARM study covers eight rural areas and recruited 1013 subjects (534 women; mean [standard deviation {SD}] age, 57.2 [7.5] years). Musculoskeletal pain in multiple areas was reported by 925 subjects (91.3%), and low back pain (63.8%) was the most frequent site of pain. Farmer's Stress Inventory (mean [SD], 77.7 [10.2]; range, 28-112] and subjective stress index (mean [SD], 5.3 [2.4]; range, 0-10) were above median scale values, reflecting a stressful condition, while the EuroQol-5D 3L index and the EuroQol-Visual Analog Scale scores were high (mean [SD], 0.9 [0.1]; range -0.171-1 and mean [SD], 67.7 [18.7]; range 0-100, respectively), reflecting good life quality. In total, 53% of participants had worked in farming for more than 30 years, and workers involved in dry-field farming comprised the largest subgroup (41.5%). Most participants (94.3%) had no more than a high school education, and families with annual income below 20 million won constituted the largest subgroup (36.3%). CONCLUSIONS: The FARM study may provide data on the current health status and related sociodemographic and agricultural work-related risk factors in Korean farmers, with the goal of providing a scientific basis for developing coping interventions and preventive strategies. PMID- 26235455 TI - Prospective Study of Arterial Stiffness and Subsequent Cognitive Decline Among Community-Dwelling Older Japanese. AB - BACKGROUND: Brachial-ankle pulse wave velocity (baPWV) is inversely associated with cognitive function. However, it is not known whether baPWV predicts cognitive decline (CD) in later life. We examined whether or not baPWV is an independent risk marker of subsequent CD in a population of older Japanese. METHODS: Among 982 adults aged 65 years or older who participated in a baseline survey, 526 cognitively intact adults (Mini-Mental State Examination [MMSE] score >=24; mean [SD] age, 71.7 [5.6] years; women, 57.8%) were followed for a period of up to 5 years. Pulse wave velocity was determined using an automated waveform analyser. Cognition was assessed by the MMSE, and CD was defined as a decrease of two points or more on the MMSE. RESULTS: During an average follow-up of 3.4 years, 85 participants (16.2%) developed CD. After controlling for important confounders, the odds ratios for CD in the highest and middle tertiles of baPWV, as compared with the lowest tertile, were 2.95 (95% confidence interval, 1.29 6.74) and 2.39 (95% confidence interval, 1.11-5.15), respectively. CONCLUSIONS: High baPWV was an independent predictor of CD in a general population of older adults and may be useful in the clinical evaluation of elders. PMID- 26235458 TI - Bariatric versus diabetes surgery after five years of follow up. AB - BACKGROUND: Bariatric surgery (BS) is totally different from diabetes surgery (DS) in the patient characters, goals of surgery, and management although similar in surgical procedure. Comparison of BS and DS with long-term data is lacking. MATERIALS AND METHODS: A retrospective review of patients who received BS and patients who received DS at Min-Sheng General Hospital from 2007 to 2013 was designed. All inpatient and outpatient follow-up data were analyzed. Patients undergoing BS for the treatment of morbid obesity were compared with patients undergoing metabolic surgery for the treatment of type 2 diabetes mellitus (T2DM). Patients who received revision surgeries were excluded. The main outcome measures were: (1) operation risk; (2) weight loss; and (3) diabetes remission. RESULTS: Between 2007 and 2013, 2073 patients who received BS and 741 patients who received DS were recruited from both centers. DS patients were older (41.1 +/ 10.9 years vs. 33.1 +/- 9.3 years, p < 0.05) and were more likely to be male (40.2% vs. 28.2%, p < 0.05) and to have diabetes (100% vs. 6.0%, p < 0.05), however, they had similar body mass index (BMI) (37.9 +/- 8.0 vs. 38.5 +/- 9.7, p = 0.78) compared to the BS patients. Surgical procedures are significantly different between the two groups (73.3% of the DS surgeries were gastric bypass procedure, whereas this procedure made up only 47.1% of BS surgeries). Although the major complication rates were similar (2.0% vs. 2.4%), the DS program had a significant higher mortality rate than the BS program (0.54% vs. 0.1%; p < 0.05). At the 5-year follow-up time point, 58.0% of the BS patients had achieved successful results (weight loss > 30%) and 80% of the DS patients had complete remission of their diabetes [hemoglobin A1c (HbA1c) < 6.0%]. Both the DS and the BS group had good results in up to 85% of the patients at the 5-year follow-up time point. CONCLUSION: The clinical profiles were very different between the BS and the DS programs. Both programs achieved the desired outcomes equally well, however, the DS program had a higher risk than the BS program. PMID- 26235459 TI - Concepts as Semantic Pointers: A Framework and Computational Model. AB - The reconciliation of theories of concepts based on prototypes, exemplars, and theory-like structures is a longstanding problem in cognitive science. In response to this problem, researchers have recently tended to adopt either hybrid theories that combine various kinds of representational structure, or eliminative theories that replace concepts with a more finely grained taxonomy of mental representations. In this paper, we describe an alternative approach involving a single class of mental representations called "semantic pointers." Semantic pointers are symbol-like representations that result from the compression and recursive binding of perceptual, lexical, and motor representations, effectively integrating traditional connectionist and symbolic approaches. We present a computational model using semantic pointers that replicates experimental data from categorization studies involving each prior paradigm. We argue that a framework involving semantic pointers can provide a unified account of conceptual phenomena, and we compare our framework to existing alternatives in accounting for the scope, content, recursive combination, and neural implementation of concepts. PMID- 26235460 TI - Extraventricular neurocytoma mimicking bone tumor in thoracic spinal column. PMID- 26235461 TI - Elongation and aberrant articulation of cervical transverse processes mimicking osteochondroma. PMID- 26235462 TI - A rare localization: primary pleomorphic undifferentiated sarcoma. PMID- 26235464 TI - Multiple vertebral dislocation events after fusion for scoliosis in Rett syndrome. PMID- 26235465 TI - Extradural spinal chondromyxoid fibroma mimicking intradural mass lesion: MR and MR myelographic images. PMID- 26235463 TI - Minimally invasive lumbar decompression-the surgical learning curve. AB - BACKGROUND CONTEXT: Minimally invasive spine surgery (MIS) procedures carry an inherently difficult learning curve based upon anecdotal evidence. Few studies have investigated the surgeon's learning curve for MIS lumbar laminectomy or laminotomy with or without discectomy. PURPOSE: To characterize the learning curve of a 1- or 2-level MIS lumbar decompression (LD) based on perioperative and postoperative parameters . STUDY DESIGN/SETTING: Retrospective analysis of a prospectively maintained registry was used for this study. PATIENT SAMPLE: There were 228 consecutive patients who underwent a primary 1- or 2-level MIS LD by a single surgeon for degenerative spinal pathology from 2009 to 2014. From 2005 to 2006, 50 patients underwent 1- or 2-level open LD consecutively. OUTCOME MEASURES: Perioperative and postoperative outcomes (complications, visual analogue scale [VAS] scores, reoperations) were the outcome measures for this study. METHODS: Patients were stratified into first and second groups as determined by the case number at which the procedural time reached a plateau. Demographics, comorbidity, pain scores, and surgical outcomes were compared between the first 50 patients and the subsequent 178 patients. The secondary analysis compared the surgical outcomes between the initial 50 MIS and 50 open LD patients. No funds were received in support of this work. RESULTS: The initial cohort was older with a higher comorbidity burden (p<.05). However, body mass index, gender, smoking status, and ethnicity did not differ between cohorts. The initial cohort incurred a greater procedural time (p<.001) and longer length of hospitalization (p<.05) than the second cohort. Estimated blood loss (EBL), pain scores, complication rates, recurrent herniation rates, and reoperation rates were similar between groups. In the secondary analysis, the open LD patients demonstrated greater procedural time, higher EBL, and longer length of hospital stay than the MIS patients. However, the reoperation rate and 30-day readmission rate were not different between the MIS and open patients. CONCLUSIONS: Continued surgical experience was associated with a reduced operative time, shorter length of hospitalization, and similar blood loss following an MIS LD. Independent of surgical experience, all patients demonstrated similar improvements in clinical outcomes. These findings appear to suggest that although surgical experience may improve perioperative parameters (operative time, length of hospitalization), an MIS LD may initially be performed safely without prior experience. PMID- 26235466 TI - Primary repair of open neural tube defect in adulthood: case example and review of management strategies. AB - BACKGROUND CONTEXT: Neural tube defects are congenital malformations that develop when the neural plate fails to close during embryogenesis. The most common open neural tube defect, myelomeningocele (MMC), is declining in frequency in North America. If identified, an MMC must be closed in the perinatal period to prevent lethal complications. Lesions presenting in older adults are, thus, very uncommon. PURPOSE: The purpose of this study was to describe the surgical management of an adult with an unrepaired ulcerated lumbosacral MMC who presented with persistent cerebrospinal fluid (CSF) leakage and to review the management strategies for adult patients with unrepaired MMC. STUDY DESIGN: A case report was used for this study. METHODS: The patient was a 62-year-old woman with an unrepaired ulcerated lumbosacral MMC and associated lower extremity weakness. She sought medical care for persistent lumbar tenderness and ulceration after sustaining a fall 4 months before admission. Physical and radiological assessment revealed a lumbosacral MMC at the L5 and S1 levels and a tethered cord. Surgical resection of the placode and de-tethering were performed. RESULTS: One week after repair of the lumbosacral MMC, the patient was readmitted for management of continued CSF leakage and hydrocephalus, requiring external ventricular drainage, wound revision, and placement of lumboperitoneal shunt. The patient experienced complete resolution of back pain without additional episodes of CSF leakage. CONCLUSIONS: This rare case and review of management strategies suggests that proper surgical management of open MMC in adulthood can successfully be performed and improve patient symptoms and prevent further complications. PMID- 26235467 TI - Comparative analysis of international standards for the fatigue testing of posterior spinal fixation systems: the importance of preload in ISO 12189. AB - BACKGROUND CONTEXT: Preclinical evaluation of the mechanical reliability of fixation devices is a mandatory activity before their introduction into market. There are two standardized protocols for preclinical testing of spinal implants. The American Society for Testing Materials (ASTM) recommends the F1717 standard, which describes a vertebrectomy condition that is relatively simple to implement, whereas the International Organization for Standardization (ISO) suggests the 12189 standard, which describes a more complex physiological anterior support based setup. Moreover, ASTM F1717 is nowadays well established, whereas ISO 12189 has received little attention: A few studies tried to accurately describe the ISO experimental procedure through numeric models, but these studies totally neglect the recommended precompression step. PURPOSE: This study aimed to build up a reliable, validated numeric model capable of describing the stress on the rods of a spinal fixator assembled according to ISO 12189 standard procedure. Such a model would more adequately represent the in vitro testing condition. STUDY DESIGN: This study used finite element (FE) simulations and experimental validation testing. METHODS: An FE model of the ISO setup was built to calculate the stress on the rods. Simulation was validated by comparison with experimental strain gauges measurements. The same fixator has been previously virtually mounted in an L2-L4 FE model of the lumbar spine, and stresses in the rods were calculated when the spine was subjected to physiological forces and moments. RESULTS: The comparison between the FE predictions and experimental measurements is in good agreement, thus confirming the suitability of the FE method to evaluate the stresses in the device. The initial precompression induces a significant extension of the assembled construct. As the applied load increases, the initial extension is gradually compensated, so that at peak load the rods are bent in flexion: The final stress value predicted is thus reduced to about 50%, if compared with the previous model where the precompression was not considered. CONCLUSIONS: Neglecting the initial preload due to the assembly of the overall construct according to ISO 12189 standard could lead to an overestimation of the stress on the rods up to 50%. To correctly describe the state of stress on the posterior spinal fixator, tested according to the ISO procedure, it is important to take into account the initial preload due to the assembly of the overall construct. PMID- 26235468 TI - Minimally invasive TLIF leads to increased muscle sparing of the multifidus muscle but not the longissimus muscle compared with conventional PLIF-a prospective randomized clinical trial. AB - BACKGROUND CONTEXT: An overload of the paravertebral muscles after surgical intervention is suggested to be the major cause of postoperative pain. In cross sectional area analyses, increased atrophy of the multifidus muscle (MF) after conventional open versus minimally invasive posterior lumbar interbody fusion (PLIF) has been described. The three-dimensional characteristics of the paravertebral muscles and separate evaluation of the longissimus muscle (LS) have not been addressed in analyses thus far. PURPOSE: The purpose of the present study was to compare the MF and LS volume atrophy and fatty degeneration between single-level minimally invasive transforaminal lumbar interbody fusion (miTLIF) and conventional midline approach-based PLIF (coPLIF) of L4/L5 or L5/S1 at the index and superior adjacent segments. DESIGN: This was a prospective, randomized, controlled, non-blinded study. PATIENT SAMPLE: Fifty patients with single-level segment degeneration (Pfirrmann >=III and Modic >=3) of L4/L5 or L5/S1 not requiring decompression were randomly assigned to two groups. OUTCOME MEASURES: Paraspinal lumbar residual muscle tissue volume, change in the relative fat content of MF and LS at the index and superior adjacent segments, and clinical parameters, including a visual analogue scale (VAS) for low back pain and the Oswestry Disability Questionnaire (ODI) were the outcome measures in this study. METHODS: Twenty-five patients were treated with miTLIF, and the remaining patients were treated with coPLIF (both with transpedicular fixation). Clinical scoring was performed preoperatively and at 1 week and 12 months postoperatively, and computed tomography was performed at the latter two follow-ups. RESULTS: The LS damage at the index segment was similar in both groups (3% greater fat content increase in the coPLIF vs. the miTLIF group, p=.032), whereas MF atrophy and degeneration were increased (p<.001) in the coPLIF group. At the adjacent segment, muscle atrophy and increased fatty infiltration (p<.05) were minimal in both muscles but were similar in both groups. Visual analogue scale and ODI scores improved (p<.001), without differences between the groups. CONCLUSIONS: The muscle damage after miTLIF was inferior to that after coPLIF; spatially, however, the muscle sparing was predominantly attributed to the MF and, surprisingly, not to the LS. PMID- 26235469 TI - Preoperative epidural injections are associated with increased risk of infection after single-level lumbar decompression. AB - BACKGROUND CONTEXT: Lumbar epidural steroid injections (LESIs) are often performed as a treatment option for lumbar stenosis and radiculopathy before lumbar decompression surgery. Several case series have reported spinal infections after LESIs. There is lack of literature on the rate of postoperative infections after lumbar decompression in patients who had prior LESIs. PURPOSE: The goal of the present study is to employ a large national database to determine if there is an association between preoperative LESIs at various time intervals before lumbar decompression and the incidence of postoperative infection. STUDY DESIGN/SETTING: Retrospective case control database study, Level III was used in this study. PATIENT SAMPLE: This study comprised Medicare patients over age 65 years who had a LESI within 1 year of single-level lumbar decompression surgery. OUTCOME MEASURES: International Classification of Diseases, 9th Revision diagnosis codes for postoperative infection and Current Procedural Terminology procedure codes for treatment of postoperative infection were the outcome measures for this study. METHODS: The PearlDiver Patient Records Database, an insurance-based database of patient records, was used for this study. The database was queried for LESI and single-level lumbar decompression procedures using Current Procedural Terminology codes. These study patients were then divided into four separate cohorts: (1) lumbar decompression within 1 month following LESI, (2) lumbar decompression between 1 and 3 months following LESI, (3) lumbar decompression between 3 and 6 months following LESI, and (4) lumbar decompression between 6 and 12 months following LESI. Unique control groups for each study cohort were created with patients who underwent single-level lumbar decompression without previous LESI and matched for major risk factors for infection, including age, gender, smoking status, diabetes, and obesity. RESULTS: Overall, the rate of postoperative infection after single-level lumbar decompression after LESI remained relatively low, ranging between 0.8% and 1.7%. The incidence of 90-day postoperative infection after lumbar decompression was significantly higher than matched controls in groups with LESI within 1 month (OR=3.2, p<.0001) and 1-3 months before surgery (OR=1.8, p<.0001). The incidence of 90-day postoperative infection was not significantly different from matched controls in groups with LESI between 3-6 months (OR=1.3, p=.15) and 6-12 months before decompression surgery (OR=1.3, p=.18) CONCLUSIONS: Single-level lumbar decompression within 3 months after LESI may be associated with an increased rate of postoperative infection. Increasing the time interval between LESI and single-level lumbar decompression surgery to at least 3 months may decrease postoperative infection rates. PMID- 26235470 TI - Impact of screw location and endplate preparation on pullout strength for anterior plates and integrated fixation cages. AB - BACKGROUND CONTEXT: Numerous integrated fixation cages (IFCs) have recently been introduced to the market with "zero-profile" designs that incorporate screw fixation through the vertebral endplate. It is unclear whether differences in bone quality and quantity in this insertion location may affect fixation compared with screws used in traditional anterior plate (AP) fixation. Moreover, endplate preparation for IFC implantation may affect fixation strength. PURPOSE: This study aimed to compare pullout strength of screws used in IFCs with screws used for AP implantations. STUDY DESIGN: A biomechanical cadaveric study. METHODS: T12 and L1 vertebrae from 13 human cadaver spines were prepared for pullout testing. End plates in T12 vertebrae were scraped according to surgical practice for fusion procedures. Conversely, endplates in L1 vertebrae were kept intact (unscraped). Integrated fixation cage screws were implanted at a 45 degrees angle into the endplate and AP screws were implanted horizontally into the same vertebral body. Pullout testing was performed on all screws, and peak pullout force (PPF) and work were compared between groups to determine fixation strength. In addition, micro-CT imaging was used to assess bone quantity and quality parameters such as trabecular bone volume fraction, endplate and anterior cortex thickness at screw insertion location, endplate mineralization, and anterior cortex mineralization. RESULTS: Peak pullout force for IFC screws (176+/-68 N) with scraped endplates was similar (p=.26) to AP screws (192+/-84 N). However, PPF for IFC screws (231+/-75 N) with unscraped endplates was significantly greater (p<.01) than AP screws (176+/-50 N). Peak pullout force for IFC screws with scraped endplates was significantly lower (p=.03) than IFC screws with unscraped endplates. Scraped endplates group (0.17+/-0.05 mm) were thinner (p=.05) than unscraped endplates (0.21+/-0.06 mm) by approximately 40 u on average. CONCLUSIONS: These data indicate that IFC and AP screws exhibited similar fixation behavior when the endplate is prepared according to common surgical practices. However, endplate scraping reduces endplate thickness by 20% on average, resulting in a decrease in fixation strength when compared with the unscraped endplates and provides bounds for IFC screw fixation strength. PMID- 26235471 TI - Evaluation of How Depression and Anxiety Mediate the Relationship Between Pain Catastrophizing and Prescription Opioid Misuse in a Chronic Pain Population. AB - OBJECTIVE: We investigated the extent to which anxiety and depression mediate the relationship between pain catastrophizing and the risk of prescription opioid misuse in chronic pain patients. METHODS: 215 patients with chronic occupational musculoskeletal disorders completed self-report measures upon admission to a functional restorational program. A bootstrap multivariate regression analysis was conducted to assess how depression and anxiety mediated the relationship between pain catastrophizing and prescription opioid misuse. RESULTS: Catastrophizing, anxiety, and depression predicted higher risk for prescription opioid misuse. Furthermore, anxiety and depression acted as mediators while controlling for the effects of gender and age. Finally, it was found that the effects of catastrophizing on risk for prescription opioid misuse were completely eliminated by those of depression. CONCLUSION: Due to the partially independent relationship of anxiety and catastrophizing, it is recommended that treatments for chronic pain patients employ techniques addressing both behaviors. The relationship between depression and catastrophizing requires more research since it was observed that their effects were confounded. PMID- 26235472 TI - Correlation of Structural and Macroscopic Properties of Starches with Their Tabletability Using the SM(2) Approach. AB - The effects of PURE-DENT(r) and SPRESS(r) starch properties on their compression behavior was characterized using "SM(2) " approach (structural properties, macroscopic properties, and multivariate analysis). Moisture sorption rate constants, moisture content, amylose and amylopectin degradation enthalpy, percent crystallinity, amylose-amylopectin ratio, and cross-linking degree were used to profile starch structural properties. Particle density, particle size distribution, and Heckel compression descriptors [yield pressure (YP) of plastic deformation, and elastic recovery] were used as macroscopic descriptors. The structural and macroscopic properties were correlated qualitatively [principal component analysis (PCA)] and quantitatively [standard least square regression (SLSR)] with the tablet mechanical strength (TMS). These analyses revealed that the differences correlated with amylose-amylopectin content, particle density, compression mechanisms, and TMS between the starch grades. Univariate analysis proved lacking; however, PCA identified the particle size, moisture content, percent crystallinity, amylose-amylopectin ratio, and YP of plastic deformation and elastic recovery as the main factors influencing the starch TMS. SLSR quantified the positive influence of Fourier transform infrared spectra absorbance ratio at 1022-1003 and YP of the immediate elastic recovery, and the negative contribution of amylopectin content on the TMS. Therefore, starch amylose and amylopectin content, crystallinity, and lower elastic recovery are mainly responsible for better TMS. PMID- 26235473 TI - Empathy costs: Negative emotional bias in high empathisers. AB - Excessive empathy has been associated with compassion fatigue in health professionals and caregivers. We investigated an effect of empathy on emotion processing in 137 healthy individuals of both sexes. We tested a hypothesis that high empathy may underlie increased sensitivity to negative emotion recognition which may interact with gender. Facial emotion stimuli comprised happy, angry, fearful, and sad faces presented at different intensities (mild and prototypical) and different durations (500ms and 2000ms). The parameters of emotion processing were represented by discrimination accuracy, response bias and reaction time. We found that higher empathy was associated with better recognition of all emotions. We also demonstrated that higher empathy was associated with response bias towards sad and fearful faces. The reaction time analysis revealed that higher empathy in females was associated with faster (compared with males) recognition of mildly sad faces of brief duration. We conclude that although empathic abilities were providing for advantages in recognition of all facial emotional expressions, the bias towards emotional negativity may potentially carry a risk for empathic distress. PMID- 26235474 TI - Subjective age moderates the immediate effects of trauma exposure among young adults exposed to rocket attacks. PMID- 26235475 TI - Adult attention deficit hyperactivity symptoms and psychosis: Epidemiological evidence from a population survey in England. AB - Despite both having some shared features, evidence linking psychosis and adult attention deficit hyperactivity disorder (ADHD) is sparse and inconsistent. Hypotheses tested were (1) adult ADHD symptoms are associated with auditory hallucinations, paranoid ideation and psychosis (2) links between ADHD symptoms and psychosis are mediated by prescribed ADHD medications, use of illicit drugs, and dysphoric mood. The Adult Psychiatric Morbidity Survey 2007 (N=7403) provided data for regression and multiple mediation analyses. ADHD symptoms were coded from the ADHD Self-Report Scale (ASRS). Higher ASRS total score was significantly associated with psychosis, paranoid ideation and auditory hallucinations despite controlling for socio-demographic variables, verbal IQ, autism spectrum disorder traits, childhood conduct problems, hypomanic and dysphoric mood. An ASRS score indicating probable ADHD diagnosis was also significantly associated with psychosis. The link between higher ADHD symptoms and psychosis, paranoia and auditory hallucinations was significantly mediated by dysphoric mood, but not by use of amphetamine, cocaine or cannabis. In conclusion, higher levels of adult ADHD symptoms and psychosis are linked and dysphoric mood may form part of the mechanism. Our analyses contradict the traditional clinical view that the main explanation for people with ADHD symptoms developing psychosis is illicit drugs. PMID- 26235477 TI - Adult attachment orientation and automatic processing of emotional information on a semantic level: A masked affective priming study. AB - Early adverse social experiences leading to attachment insecurity could cause heightened sensitivity to emotional information. Automatic processing of emotional stimuli conveys information about positive-negative differentiation and the so-called possessor vs. other-relevance of valence. The aim of the present study was to examine automatic processing of emotional and relevance type information on a semantic level as a function of adult attachment avoidance and anxiety. A masked affective priming task, varying valence and relevance of prime and target adjectives, was presented to a sample of 153 healthy adults. The Experiences in Close Relationships scale was administered to assess attachment orientation. Significant priming effects for valence and relevance were observed. Attachment avoidance, but not attachment anxiety, was significantly related to affective priming independently of trait anxiety and depression. Specifically, attachment avoidance was found to be related to affective priming effects based on other-relevant words. It can be concluded that automatic processing of emotional adjectives used to characterize safe or risky social environments is heightened in avoidant individuals. The avoidantly attached processing style has similarities with repressive coping, which is characterized by an enhanced early response to emotion stimuli followed by avoidant biases at a controlled processing level. PMID- 26235476 TI - Incidence, clinical correlates and treatment effect of rage in anxious children. AB - Episodic rage represents an important and underappreciated clinical feature in pediatric anxiety. This study examined the incidence and clinical correlates of rage in children with anxiety disorders. Change in rage during treatment for anxiety was also examined. Participants consisted of 107 children diagnosed with an anxiety disorder and their parents. Participants completed structured clinical interviews and questionnaire measures to assess rage, anxiety, functional impairment, family accommodation and caregiver strain, as well as the quality of the child's relationship with family and peers. Rage was a common feature amongst children with anxiety disorders. Rage was associated with a more severe clinical profile, including increased anxiety severity, functional impairment, family accommodation and caregiver strain, as well as poorer relationships with parents, siblings, extended family and peers. Rage was more common in children with separation anxiety, comorbid anxiety, attention deficit/hyperactivity disorder and behavioral disorders, but not depressive symptoms. Rage predicted higher levels of functional impairment, beyond the effect of anxiety severity. Rage severity reduced over treatment in line with changes in anxiety symptoms. Findings suggest that rage is a marker of greater psychopathology in anxious youth. Standard cognitive behavioral treatment for anxiety appears to reduce rage without adjunctive treatment. PMID- 26235478 TI - Imagining a brighter future: the effect of positive imagery training on mood, prospective mental imagery and emotional bias in older adults. AB - Positive affect and optimism play an important role in healthy ageing and are associated with improved physical and cognitive health outcomes. This study investigated whether it is possible to boost positive affect and associated positive biases in this age group using cognitive training. The effect of computerised imagery-based cognitive bias modification on positive affect, vividness of positive prospective imagery and interpretation biases in older adults was measured. 77 older adults received 4 weeks (12 sessions) of imagery cognitive bias modification or a control condition. They were assessed at baseline, post-training and at a one-month follow-up. Both groups reported decreased negative affect and trait anxiety, and increased optimism across the three assessments. Imagery cognitive bias modification significantly increased the vividness of positive prospective imagery post-training, compared with the control training. Contrary to our hypothesis, there was no difference between the training groups in negative interpretation bias. This is a useful demonstration that it is possible to successfully engage older adults in computer-based cognitive training and to enhance the vividness of positive imagery about the future in this group. Future studies are needed to assess the longer-term consequences of such training and the impact on affect and wellbeing in more vulnerable groups. PMID- 26235479 TI - Relationship between cannabis and psychosis: Reasons for use and associated clinical variables. AB - The mechanism underneath the relationship between cannabis and psychosis remains controversial, for which several hypotheses have been proposed, including cannabis as self-medication and cannabis as a risk for the development of psychosis. The aim of this work was to study the relationship between cannabis and psychosis in first-episode psychosis cannabis users and non-users, and non psychotic cannabis users. The age at the first psychotic episode, duration of untreated psychosis, psychopathology and reasons for cannabis use were assessed. First-episode psychosis cannabis users showed an earlier age at psychosis onset than non-user patients. No significant differences in symptomatology were found. The distinguishing reasons to use cannabis for patients with first-episode psychosis with respect to non-psychotic users were to arrange their thoughts and deal with hallucinations and suspiciousness. These findings are in agreement with both hypotheses: self-medication and secondary psychosis hypothesis. However, longitudinal prospective cohort studies assessing reasons for cannabis use are needed to investigate both hypotheses and their complementarity. PMID- 26235480 TI - Evidence of rutile-to-anatase photo-induced electron transfer in mixed-phase TiO2 by solid-state NMR spectroscopy. AB - With ethanol as a probe molecule, the surface sites of anatase and rutile can be distinguished using (13)C CP/MAS NMR spectroscopy, which offers an opportunity to investigate the transfer of photo-induced electrons from rutile to anatase in the mixed-phase TiO2. PMID- 26235481 TI - Enabling sense-making for patients receiving outpatient palliative treatment: A participatory action research driven model for person-centered communication. AB - OBJECTIVES: In clinical palliative cancer care, the diversity of patient concerns over time makes information provision a critical issue, the demands of information-seeking patients presenting a challenge to both the communicative and organizational skills of the health provider. This study puts forward a practice model for communication between patients, their family members, and professional health providers during ongoing palliative chemotherapy; a model which supports the providers in enabling person-centered communication. METHOD: A constant comparative analysis adapted to participatory action research was applied. The model was developed step-wise in three interrelated cycles, with results from previous studies from palliative cancer care processed in relation to professional health providers' experience-based clinical knowledge. In doing this, focus group discussions were carried out with providers and patients to develop and revise the model. RESULTS: The Enabling Sense Making model for person centered communication gave rise to three domains (which are also the major communicative actors in palliative care): the patient, the family, and the provider. These actors were placed in the context of a communicative arena. The three respective domains were built up in different layers discriminating between significant aspects of person-centered communication, from the manifest that is most usually explicated in dialogues, to the latent that tends to be implicitly mediated. SIGNIFICANCE OF RESULTS: The model intends to facilitate timely reorientation of care from curative treatment or rehabilitation to palliation, as well as the introduction of appropriate palliative interventions over time during palliative phases. In this way the model is to be regarded a frame for directing the awareness of the professionals, which focuses on how to communicate and how to consider the patient's way of reasoning. The model could be used as a complement to other strategic initiatives for the advancement of palliative care communication. It needs to be further evaluated in regard to practice evidence. PMID- 26235482 TI - Evolution and dispersal of the genus Homo: A landscape approach. AB - The notion of the physical landscape as an arena of ecological interaction and human evolution is a powerful one, but its implementation at larger geographical and temporal scales is hampered by the challenges of reconstructing physical landscape settings in the geologically active regions where the earliest evidence is concentrated. We argue that the inherently dynamic nature of these unstable landscapes has made them important agents of biological change, creating complex topographies capable of selecting for, stimulating, obstructing or accelerating the latent and emerging properties of the human evolutionary trajectory. We use this approach, drawing on the concepts and methods of active tectonics, to develop a new perspective on the origins and dispersal of the Homo genus. We show how complex topography provides an easy evolutionary pathway to full terrestrialisation in the African context, and would have further equipped members of the genus Homo with a suite of adaptive characteristics that facilitated wide-ranging dispersal across ecological and climatic boundaries into Europe and Asia by following pathways of complex topography. We compare this hypothesis with alternative explanations for hominin dispersal, and evaluate it by mapping the distribution of topographic features at varying scales, and comparing the distribution of early Homo sites with the resulting maps and with other environmental variables. PMID- 26235483 TI - Comparison of Dasatinib, Nilotinib, and Imatinib in the Treatment of Chronic Myeloid Leukemia. AB - To overcome the drug resistance phenomenon induced by Imatibib (IM), in clinical practice, are often used second generation of tyrosine kinase inhibitors as Nilotinib (NIL); a such potent inhibitor of the BCR/ABL kinase and Dasatinib (DAS), a inhibitor of BCR/ABL kinase, and inhibitor SrC family kinase. In this study we evaluated the in vivo effect of DAS, NIL, and IM on intracellular calcium concentration, oxidative stress, and apoptosis in peripheral blood leukocytes of 45 newly diagnosed patients with chronic myeloid leukaemia (CML PBM). Our data demonstrated that treatment with DAS and NIL showed an higher modulating potential than IM on intracellular calcium concentration by inhibiting the thapsigargin, a sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor, and Lithium (Li) an inositol 1,4,5-triphosphate (InsP3) receptor inhibitor activities. Moreover our data demonstrated that NIL and DAS have significantly increased apoptosis more than IM by involving both intracellular calcium signaling as well as oxidative stress. The acquisition of the oxidative stress and calcium channels receptors values data could help the hematologist to modulate and improve the treatment of chronic myeloid leukaemia (CML) pathology. PMID- 26235484 TI - Evaluation of ocular findings in patients with vitiligo. AB - In this study, we aimed to investigate ocular manifestations in patients with vitiligo. Sixty-one patients with vitiligo were included in the study. From the patients who referred for examination to the dermatology and ophthalmology clinic, 57 patients without any systemic disease were taken as the control group. In both groups, otorefractometry, keratometry, visual acuity test, intraocular pressure measurement, anterior segment, and fundus examinations of the eye with slit lamp, Schirmer test, and perimetry were carried out. The mean age was 24.54 +/- 11.90 years and 23.03 +/- 8.72 years in the patients and control group, respectively. The mean Schirmer test results were as follows: 16.74 +/- 9.11 mm and 17.64 +/- 9.41 mm for the right and left eyes of the patients, and 21.96 +/- 12.51 mm and 23.42 +/- 12.51 mm for the right and left eyes of controls, respectively. Of the patients, 36 eyes showed lenticular findings. However, only 12 eyes of the controls have some lenticular findings. Twenty-nine eyes in the vitiligo group and four in the controls showed some fundus findings. When the two groups were compared with each other, there was a statistically significant difference between them in terms of Schirmer test results, lens, and fundus findings (P < 0.05 for all). However, there was no significant difference in terms of age, gender, visual acuity, refraction, keratometry, intraocular pressure, perimetry, and corneal findings (P > 0.05 for all). Patients with vitiligo may have more lenticular and retinal findings than normal. They can be more prone to dry eye syndrome as well. PMID- 26235485 TI - Introduction to a Virtual Special Issue on cell biology at the plant-microbe interface. PMID- 26235486 TI - To betalains and back again: a tale of two pigments. PMID- 26235487 TI - Phenotyping in the fields: dissecting the genetics of quantitative traits and digital farming. PMID- 26235488 TI - Dye adsorption mechanisms in TiO2 films, and their effects on the photodynamic and photovoltaic properties in dye-sensitized solar cells. AB - The adsorption mechanism for the N719 dye on a TiO2 electrode was examined by the kinetic and diffusion models (pseudo-first order, pseudo-second order, and intra particle diffusion models). Among these methods, the observed adsorption kinetics are well-described using the pseudo-second order model. Moreover, the film diffusion process was the main controlling step of adsorption, which was analysed using a diffusion-based model. The photodynamic properties in dye-sensitized solar cells (DSSCs) were investigated using time-resolved transient absorption techniques. The photodynamics of the oxidized N719 species were shown to be dependent on the adsorption time, and also the adsorbed concentration of N719. The photovoltaic parameters (Jsc, Voc, FF and eta) of this DSSC were determined in terms of the dye adsorption amounts. The solar cell performance correlates significantly with charge recombination and dye regeneration dynamics, which are also affected by the dye adsorption amounts. Therefore, the photovoltaic performance of this DSSC can be interpreted in terms of the adsorption kinetics and the photodynamics of oxidized N719. PMID- 26235489 TI - Physicochemical constraints of elevated pH affect efficient membrane interaction and arrest an abortive membrane-bound oligomeric intermediate of the beta-barrel pore-forming toxin Vibrio cholerae cytolysin. AB - Vibrio cholerae cytolysin (VCC) is a potent membrane-damaging cytotoxic protein. VCC causes permeabilization of the target cell membranes by forming transmembrane oligomeric beta-barrel pores. Membrane pore formation by VCC involves following key steps: (i) membrane binding, (ii) formation of a pre-pore oligomeric intermediate, (iii) membrane insertion of the pore-forming motifs, and (iv) formation of the functional transmembrane pore. Membrane binding, oligomerization, and subsequent pore-formation process of VCC appear to be facilitated by multiple regulatory mechanisms that are only partly understood. Here, we have explored the role(s) of the physicochemical constraints, specifically imposed by the elevated pH conditions, on the membrane pore formation mechanism of VCC. Elevated pH abrogates efficient interaction of VCC with the target membranes, and blocks its pore-forming activity. Under the elevated pH conditions, membrane-bound fractions of VCC remain trapped in the form of abortive oligomeric species that fail to generate the functional transmembrane pores. Such an abortive oligomeric assembly appears to represent a distinct, more advanced intermediate state than the pre-pore state. The present study offers critical insights regarding the implications of the physicochemical constraints for regulating the efficient membrane interaction and pore formation by VCC. PMID- 26235490 TI - Metabolic biomarkers for chronic kidney disease. AB - Chronic kidney disease (CKD) is an increasingly recognized burden for patients and health care systems with high (and growing) global incidence and prevalence, significant mortality, and disproportionately high treatment costs. Yet, the available diagnostic tools are either impractical in clinical routine or have serious shortcomings impeding a well-informed disease management although optimized treatment strategies with proven benefits for the patients have become available. Advances in bioanalytical technologies have facilitated studies that identified genomic, proteomic, and metabolic biomarker candidates, and confirmed some of them in independent cohorts. This review summarizes the CKD-related markers discovered so far, and focuses on compounds and pathways, for which there is quantitative data, substantiating evidence from translational research, and a mechanistic understanding of the processes involved. Also, multiparametric marker panels have been suggested that showed promising diagnostic and prognostic performance in initial analyses although the data basis from prospective trials is very limited. Large-scale studies, however, are underway and will provide the information for validating a set of parameters and discarding others. Finally, the path from clinical research to a routine application is discussed, focusing on potential obstacles such as the use of mass spectrometry, and the feasibility of obtaining regulatory approval for targeted metabolomics assays. PMID- 26235491 TI - Clinicians' perceptions of the clinical utility of the Multiple Errands Test for adults with neurological conditions. AB - This study examined the clinical utility of the Multiple Errands Test (MET) from the perspective of clinicians. Employing a qualitative descriptive design, in depth semi-structured interviews were conducted with eight occupational therapists. Participants had an average of 12 years clinical experience and their experience using the MET varied. Interviews were transcribed and analysed using framework analysis. Three dominant themes emerged from the data. Theme 1 was that clinicians value the MET because it reflects real-life functioning. Clinicians perceived the MET to be a unique assessment collecting data on functional performance, and sensitive to higher level cognitive deficits. Theme 2 was that the MET could be used flexibly depending on one's rehabilitation goals. Clinicians employed the MET as an assessment to inform the direction of treatment and as a component of their intervention. Theme 3 was that the MET is a challenging assessment requiring buy in and commitment from therapists. This study is the first to report clinicians' perspectives of the clinical utility of the MET. It reinforces the importance of ecologically valid tests, and augments existing research evaluating psychometric properties of the MET by describing how the MET has been employed in rehabilitation settings to improve health outcomes for adults with neurological conditions. PMID- 26235492 TI - 'Newness-struggle-success' continuum: a qualitative examination of the cultural adaptation process experienced by overseas-qualified dentists in Australia. AB - Objectives Overseas-qualified dentists constitute a significant proportion of the Australian dental workforce (approximately one in four). The aim of the present study was to provide a better understanding of the cultural adaptation process of overseas-qualified dentists in Australia, so as to facilitate their integration into the Australian way of life and improve their contribution to Australian healthcare, economy and society. Methods Life stories of 49 overseas-qualified dentists from 22 countries were analysed for significant themes and patterns. We focused on their settlement experience, which relates to their social and cultural experience in Australia. This analysis was consistent with a hermeneutic phenomenological approach to qualitative social scientific research. Results Many participants noted that encounters with 'the Australian accent' and 'slang' influenced their cultural experience in Australia. Most of the participants expressed 'fascination' with the people and lifestyle in Australia, primarily with regard to the relaxed way of life, cultural diversity and the freedom one usually experiences living in Australia. Few participants expressed 'shock' at not being able to find a community of similar religious faith in Australia, as they are used to in their home countries. These issues were analysed in two themes; (1) language and communication; and (2) people, religion and lifestyle. The cultural adaptation process of overseas-qualified dentists in Australia is described as a continuum or superordinate theme, which we have entitled the 'newness-struggle-success' continuum. This overarching theme supersedes and incorporates all subthemes. Conclusion Family, friends, community and organisational structures (universities and public sector) play a vital role in the cultural learning process, affecting overseas-qualified dentist's ability to progress successfully through the cultural continuum. What is known about the topic? Australia is a popular host country for overseas-qualified dentists. Migrant dentists arrive from contrasting social and cultural backgrounds, and these contrasts can be somewhat more pronounced in dentists from developing countries. To date, there is no evidence available regarding the cultural adaptation process of overseas-qualified dentists in Australia or elsewhere. What does this paper add? This study provides evidence to support the argument that the cultural adaptation process of overseas-qualified dentists in Australia can be viewed as a continuum state, where the individual learns to adapt to the people, language and lifestyle in Australia. The ongoing role of family and friends is primary to a successful transition process. Our research also identifies the positive role played by community and organisational structures, such as universities and public sector employment schemes. What are the implications for practitioners? A potential implication for policy makers is to focus on the positive roles played by organisational structures, particularly universities and the public sector. This can inform more supportive migration policy, as well as strengthen the role these organisations play in providing support for overseas-qualified dentists, thus enabling them to integrate more successfully into Australia's health care system, economy and society. PMID- 26235493 TI - Homozygous losses detected by array comparative genomic hybridization in multiplex urothelial carcinomas of the bladder. AB - Urothelial carcinomas (UCs) may present at first as a solitary or multifocal neoplasm. We applied high resolution array comparative genomic hybridization to 24 solitary and 32 multiplex UCs and used the hidden Markov model algorithm to identify the copy number changes at the probe level. Copy number losses and homozygous deletions at the chromosome 9p region affecting the CDKN2A and MTAP genes were the most frequent alterations in both groups of tumors. We have delineated two new tumor suppressor gene regions at chromosome 9p that harbor the PTPRD and BNC2 genes. Copy number losses at chromosomal regions 2q, 8p, and 18p occurred preferentially in solitary UCs, whereas multiplex UCs displayed loss of large chromosomal regions at 9q, 10q, 11q, 18q, and 21q. Homozygous deletions harboring loci of cell adhesion genes such as claudins, desmocollins, and desmogleins were seen exclusively in multiplex UCs. Amplifications occurred only in invasive G3 UCs irrespective of staging. Our study suggests that solitary and multiplex UCs may have divergent genetic pathways. The biallelic inactivation of cellular adhesion genes by homozygous deletions in multiplex UCs may explain the frequent intravesical spreading of tumor cells. . PMID- 26235494 TI - The incidence and prognostic implications of dysphagia in elderly patients institutionalized: A multicenter study in Spain. AB - AIM: Determine the incidence of dysphagia, identify its consequences and objectify related complications and mortality associated with pneumonia, in the institutionalized elderly. METHODS: A prospective observational and multicenter study with a 3-year follow-up period was designed in a cohort of 12 nursing homes within 6 cities in Spain. A total of 2384 patient records were studied. Demographic and clinical data (dementia, cerebrovascular disease), as well as an evaluation of the Barthel Index, dysphagia and aspiration, and mortality at 30 days and 1 year after pneumonia in patients with dysphagia were collected. RESULTS: Of the 2384 patients, 69.6% presented clinical signs of oropharyngeal dysphagia. Patients with dysphagia were older and showed lower functional status and higher prevalence of comorbidities. They had higher mortality as well. CONCLUSIONS: Oropharyngeal dysphagia is a highly prevalent clinical finding in elderly institutionalized patients. Among this population, there is also a higher prevalence of pneumonia, dementia, and cerebrovascular disease and pneumonia is an indicator of mortality. PMID- 26235495 TI - [Blood gas analysis in dogs in veterinary practice. A review]. AB - Blood gas analysis is useful to obtain information about acid-base state and gas exchange of the lung. Interpretation is based on the Henderson-Hasselbalch equation. This approach has its limitations especially in interpretation of complex disturbances of acid-base status and has been complemented by base excess and anion gap. Peter Stewart described a model of quantitative approach to the acid-base disturbances which has been further developed and is known as the strong ion approach. This model differs from the traditional approach in the assessment of metabolic disorders of acid base status. Both models complement each other but also have their advantages and disadvantages. For simple disorders of the acid-base state the Henderson-Hasselbalch approach can be used, however in complex disturbances of acid-base balance, especially with abnormalities of serum albumin and phosphate concentrations, the strong ion approach is recommended. With the understanding of both models and of the clinical presentation of blood gas abnormalities, optimal case management and therapy can be provided. PMID- 26235506 TI - Lack of Correlation Between Liver Tests Abnormalities and Trabectedin Efficacy in the Treatment of Soft Tissue Sarcoma: a Retrospective Study. AB - Elevation in liver transaminases is common in patients treated with the marine antitumor agent trabectedin. However, the impact of trabectedin-related transaminase elevations on treatment outcomes is unclear. This retrospective study investigated the correlation between liver tests abnormalities and treatment outcomes in patients with unresectable advanced or metastatic soft tissue sarcomas (STS) treated with trabectedin 1.5 mg/m(2) once every 3 weeks at three reference centers in Italy. The effect of grade 3/4 elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) during the first two cycles and at any time during trabectedin treatment on progression-free survival (PFS) and overall survival (OS) were analyzed. Liver tests abnormalities during the first two cycles of chemotherapy or at any time during trabectedin treatment did not significantly affect PFS or OS. Nor were survival outcomes significantly different in the subgroups of patients with or without ALT/AST increases or with ALT/AST elevations >= 15 * the upper limit of normal (ULN) versus those with ALT/AST elevation < 15 * ULN. Although liver tests abnormalities are common in patients treated with trabectedin, elevations in ALT and AST are usually transient, occur during the first two cycles of treatment, and do not appear to affect survival. PMID- 26235507 TI - Re: 'The rectus sheath and serratus fascia "reverse" fashion flap for the coverage of the lower pole in immediate implant-based breast reconstruction'. PMID- 26235508 TI - Thumb reconstruction via a pedicled flap based on the superficial palmar branch of the radial artery from the wrist crease area. AB - BACKGROUND: The free flap based on the superficial palmar branch of the radial artery (SPBRA) has been extensively reported. A reversed pedicled flap based on the SPBRA, harvested from the wrist crease area, can be a potential candidate for the reconstruction of the soft-tissue and artery defects in the thumb. METHOD: Between January 2012 and October 2013, this flap was used in seven patients to reconstruct soft-tissue defects in the thumb. In three patients, blood circulation of the thumb was reestablished using flow-through flaps. The Michigan Hand Outcomes Questionnaire was used for patient self-evaluation. RESULTS: In one patient, the surgery was abandoned due to blood vessel variation. All the flaps and thumbs survived in the other six patients. The wounds healed primarily. All patients were followed up for a mean of 16.5 months (range, 12-26 months). At the last follow-up, the mean static two-point discrimination was 7.3 +/- 0.9 mm on the affected side and 4.6 +/- 0.7 on the contralateral side. The range of motion of the metacarpophalangeal joint and the interphalangeal joint were 66.8 +/- 8.4 degrees (contralateral, 85.2 +/- 3.8 degrees ) and 67.0 +/- 6.9 degrees (contralateral, 80.5 +/- 5.0 degrees ), respectively. Patient self-evaluations were good in five cases and fair in one case. CONCLUSION: The reverse island flap based on the SPBRA is feasible for soft-tissue defects and establishing blood circulation in the thumb. The donor site can be closed primarily, and the scar is inconspicuous in the wrist crease. PMID- 26235509 TI - A review of eight unusual pediatric skin and soft-tissue lesions: Diagnosis, workup, and treatment. AB - The spectrum of clinical presentations in pediatric skin and soft-tissue lesions often makes diagnosis challenging. Delays in diagnosis and subsequent treatment can be life threatening, and they can subject patients to more complicated reconstruction. This retrospective case series reviews the presentation, management, and current literature on eight pediatric skin and soft-tissue lesions. For rare lesions and those with unclear pathology, a multidisciplinary approach is strongly advocated for optimal management. PMID- 26235510 TI - A simplified three-dimensional volume measurement technique in keloid scars: Validity and reliability. AB - INTRODUCTION: Effective treatment of keloid scars is important because patients are often confronted with major cosmetic, psychological, and social consequences. Three-dimensional (3D) imaging has been reported for the evaluation of keloid treatment. These techniques were complex to use in clinical practice. In this study, the validity and reliability of a simplified 3D volume measurement technique are defined. METHODS: Thirty-three scars were simulated using deformable modeling compound. The volume of the compound is calculated using the weight and density of the modeling compound, and it is compared with the 3D volume measurement. RESULTS: The mean simulated keloid volume was 2.884 cc. The correlation was very high (r = 0.999), but there was a significant mean difference of 0.252 cc (p < 0.001). This was corrected using a formula, actual volume = 1.072 * measured volume. This formula was validated using a new data set of 33 simulated scars. There was a nonsignificant mean difference of 0.010 cc (p = 0.731). CONCLUSION: This 3D measurement technique combined with the correcting formula is valid and reliable to be used in practice for the evaluation of keloid scar treatment. PMID- 26235511 TI - Clinically focused exome sequencing identifies an homozygous mutation that confers DOCK8 deficiency. PMID- 26235512 TI - Incidence of Merkel cell carcinoma in Olmsted County, Minnesota: a population based study. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive, often cutaneous malignancy. The incidence has been estimated from national registries in the USA and elsewhere, and data indicate variations depending on the region studied. The objective of this study was to determine the incidence of MCC in Olmsted County (MN, USA). METHODS: Using the Rochester Epidemiology Project, which contains health records for all the residents of Olmsted County, we retrospectively reviewed the records for all cases of MCC from 1976 to 2011. RESULTS: The overall annual age- and sex-adjusted incidence of MCC in Olmsted County during 1976-2011 was 0.35 per 100,000 person-years (95% CI, 0.14-0.57). The incidence tended to be higher among men than women with 0.69 per 100,000 (95% CI, 0.24-1.14) and 0.10 per 100,000 (95% CI, 0-0.24), respectively. CONCLUSIONS: These data are within the range of previous MCC incidence reports, and the incidence of MCC in Olmsted County is consistent with rates reported in the remainder of the USA. PMID- 26235513 TI - Structural and mechanistic insights into phospholipid transfer by Ups1-Mdm35 in mitochondria. AB - Eukaryotic cells are compartmentalized into membrane-bounded organelles whose functions rely on lipid trafficking to achieve membrane-specific compositions of lipids. Here we focused on the Ups1-Mdm35 system, which mediates phosphatidic acid (PA) transfer between the outer and inner mitochondrial membranes, and determined the X-ray structures of Mdm35 and Ups1-Mdm35 with and without PA. The Ups1-Mdm35 complex constitutes a single domain that has a deep pocket and flexible Omega-loop lid. Structure-based mutational analyses revealed that a basic residue at the pocket bottom and the Omega-loop lid are important for PA extraction from the membrane following Ups1 binding. Ups1 binding to the membrane is enhanced by the dissociation of Mdm35. We also show that basic residues around the pocket entrance are important for Ups1 binding to the membrane and PA extraction. These results provide a structural basis for understanding the mechanism of PA transfer between mitochondrial membranes. PMID- 26235514 TI - Does increasing applied load lead to contact changes indicative of knee osteoarthritis? A subject-specific FEA study. AB - This study investigated whether increased loading (representing obesity) in the extended knee and flexed knee led to increased stresses in areas of typical medial and lateral osteoarthritis cartilage lesions, respectively. We created two paired sets of subject-specific finite element models; both sets included models of extended knees and of flexed knees. The first set represented normal loading; the second set represented increased loading. All other variables were held constant. The von Mises stresses and contact areas calculated on the tibial cartilage surfaces of the paired models were then compared. In the extended knee models, applying a larger load led to increased stress in the anterior and central regions of the medial tibial cartilage. These are the typical locations of medial osteoarthritis cartilage lesions. Therefore, the results support that increased loading in the extended knee may result in medial osteoarthritis. In the flexed knee models, applying a larger load increased stress in the anterior and central regions of the lateral tibial cartilage. Lateral osteoarthritis cartilage lesions typically occur centrally and posteriorly. Therefore, these results do not support our hypothesis. Shear stress was increased in areas of typical lateral lesions, however, and should be investigated in future studies. PMID- 26235515 TI - Use of tracheal tubes as intercostal catheters. PMID- 26235517 TI - Adaptive noise Wiener filter for scanning electron microscope imaging system. AB - Noise on scanning electron microscope (SEM) images is studied. Gaussian noise is the most common type of noise in SEM image. We developed a new noise reduction filter based on the Wiener filter. We compared the performance of this new filter namely adaptive noise Wiener (ANW) filter, with four common existing filters as well as average filter, median filter, Gaussian smoothing filter and the Wiener filter. Based on the experiments results the proposed new filter has better performance on different noise variance comparing to the other existing noise removal filters in the experiments. PMID- 26235516 TI - Chemokine polyreactivity of IL7Ralpha+CSF-1R+ lympho-myeloid progenitors in the developing fetal liver. AB - In murine ontogeny, fetal liver is the major hemato- and B-lymphopoietic site until birth. Hematopoiesis develops in largely non-hematopoietic niches, which provide contacts, chemokines and cytokines that induce migration, residence, proliferation and differentiation of progenitors. Within early multipotent progenitors an IL7Ralpha(+)CSF-1R(+) subset expressed a mixture of lymphoid- and myeloid-specific genes and differentiated to lymphoid and myeloid lineages in vitro. By contrast, IL7Ralpha(+) cells were lymphoid-committed, and CSF-1R(+) cells were erythro-myeloid-restricted. To respond to a multitude of chemokines single biphenotypic cells expressed CXCR4 and as many as five other chemokine receptors. The monopotent IL7Ralpha(+) and CSF-1R(+)progenitors all expressed CXCR4, and mutually exclusive, more restricted sets of the analysed five chemokine receptors. This study proposes that chemokine polyreactive, cytokine bipotent and monopotent progenitors transmigrate through LYVE-1(high) endothelium, attracted by selected chemokines, and reach the IL7- and CSF-1 producing ALCAM(high) mesenchymal niche, attracted by other sets of chemokines, to differentiate to B-lymphoid respectively myeloid cells. PMID- 26235519 TI - Atomistic modeling of a KRT35/KRT85 keratin dimer: folding in aqueous solution and unfolding under tensile load. AB - We present an atomistic model of a full KRT35/KRT85 dimer, a fundamental building block of human hair. For both monomers initial structures were generated using empirical tools based on homology considerations, followed by the formulation of a naiive dimer model from docking the monomers in vacuum. Relaxation in aqueous solution was then explored from molecular dynamics simulation. Driven by hydrophobic segregation and protein-protein hydrogen bonding relaxation dynamics result in a folded dimer arrangement which shows a striking encounter of cystein groups. Our simulations hence suggests that (i) cystein groups in the coil regions of keratin are well suited to establish disulfide bonds between the two monomers that constitute the dimer, and (ii) the particularly large number of cystein groups in the head and tail regions promotes the connection of dimers to establish meso- to macroscale fibers. Moreover, we show the molecular mechanisms of elastic and plastic deformation under tensile load. Upon elongation beyond the elastic regime, unfolding was identified as the exposure of hydrophobic moieties and the breaking of protein-protein hydrogen bonds. Therein, the step-wise character of the series of unfolding events leads to a broad regime of constant force in response to further elongation. PMID- 26235520 TI - Total Knee Arthroplasty in Patients with Blount Disease or Blount-Like Deformity. AB - Blount disease is associated with complex deformity of the proximal tibia, and some patients will develop knee osteoarthritis. Five patients (eight knees) with Blount disease or Blount-like deformity underwent total knee arthroplasty. Mean proximal tibial metaphyseal-diaphyseal angle was 20.75 degrees . Each patient had substantial posteromedial tibial bony defects and six knees required extensive medial releases. Two knees required increased constraint at index procedure. One patient has undergone bilateral revision surgery with rotating hinge prostheses. Mean WOMAC scores were 13.5 and Knee Society scores were 212.5 at average 75.2 month follow-up. Despite technical challenges, patients with these deformities can have successful outcomes after total knee arthroplasty. Surgeons should be prepared to address posteromedial tibial bony defects and consider constrained arthroplasty at the index procedure. PMID- 26235521 TI - Performance of Non-Cemented, Hemispherical, Rim-Fit, Hydroxyapatite Coated Acetabular Component. AB - The purpose of this study was to assess the durability of a non-cemented, hemispherical rim-fit, hydroxyapatite coated cup with a highly cross-linked polyethylene in 223 total hip arthroplasties. At 6-years follow-up (range, 5-9), there were no cup revisions for osteolysis or loosening. Radiologic evidence of osseointegration was based on presence of Stress Induced Reactive Cancellous Bone and radial trabeculae, seen in 47% and 93% of cups, respectively; both were most prevalent in Zone 1. There was no interference demarcation in any zones. Two cups were revised (0.9%): one for dislocation and another for infection. The Kaplan Meier survivorship for cup revision for any failure (infection, dislocation) was 99% and for mechanical failure (osteolysis, loosening) was 100%. This design has excellent safety, efficacy and durability. PMID- 26235522 TI - Tranexamic Acid Decreases Incidence of Blood Transfusion in Simultaneous Bilateral Total Knee Arthroplasty. AB - Blood management for simultaneous bilateral total knee arthroplasty (TKA) patients is more challenging than in unilateral arthroplasty. We examined if administration of tranexamic acid (TXA) to patients undergoing simultaneous bilateral TKA would reduce blood loss and decrease allogeneic blood transfusion requirements. A retrospective review of 103 patients, 57 in the control and 46 in the TXA group, was performed. There was higher postoperative day 1 hemoglobin in patients receiving TXA (2.95+/-1.33 versus 4.33+/-1.19, P<0.0001). There was also a decrease in the transfusion incidence with administration of TXA (17.4% versus 57.9%, P<0.0001). In conclusion, we have shown that TXA is an effective tool in reducing the transfusion rates by almost 70% in simultaneous bilateral total knee arthroplasty. PMID- 26235523 TI - "Outliers" in Osteoarthritic Knees Concerning Distal Femoral Valgus Angle and Femoral Rotation Angle. PMID- 26235524 TI - Switching Kalman filter based methods for apnea bradycardia detection from ECG signals. AB - Apnea bradycardia (AB) is an outcome of apnea occurrence in preterm infants and is an observable phenomenon in cardiovascular signals. Early detection of apnea in infants under monitoring is a critical challenge for the early intervention of nurses. In this paper, we introduce two switching Kalman filter (SKF) based methods for AB detection using electrocardiogram (ECG) signal.The first SKF model uses McSharry's ECG dynamical model integrated in two Kalman filter (KF) models trained for normal and AB intervals. Whereas the second SKF model is established by using only the RR sequence extracted from ECG and two AR models to be fitted in normal and AB intervals. In both SKF approaches, a discrete state variable called a switch is considered that chooses one of the models (corresponding to normal and AB) during the inference phase. According to the probability of each model indicated by this switch, the model with larger probability determines the observation label at each time instant.It is shown that the method based on ECG dynamical model can be effectively used for AB detection. The detection performance is evaluated by comparing statistical metrics and the amount of time taken to detect AB compared with the annotated onset. The results demonstrate the superiority of this method, with sensitivity and specificity 94.74[Formula: see text] and 94.17[Formula: see text], respectively. The presented approaches may therefore serve as an effective algorithm for monitoring neonates suffering from AB. PMID- 26235525 TI - Quantum and classical dynamics of reactive scattering of H2 from metal surfaces. AB - We review the state-of-the art in dynamics calculations on the reactive scattering of H2 from metal surfaces, which is an important model system of an elementary reaction that is relevant to heterogeneous catalysis. In many applications, quantum dynamics and classical trajectory calculations are performed within the Born-Oppenheimer static surface model. However, ab initio molecular dynamics (AIMD) is finding increased use in applications aimed at modeling the effect of surface phonons on the dynamics. Molecular dynamics with electronic friction has been used to model the effect of electron-hole pair excitation. Most applications are still based on potential energy surfaces (PESs) or forces computed with density functional theory (DFT), using a density functional within the generalized gradient approximation to the exchange correlation energy. A new development is the use of a semi-empirical version of DFT (the specific reaction parameter (SRP) approach to DFT). We also discuss the accurate methods that have become available to represent electronic structure data for the molecule-surface interaction in global PESs. It has now become possible to describe highly activated H2 + metal surface reactions with chemical accuracy using the SRP-DFT approach, as has been shown for H2 + Cu(111) and Cu(100). However, chemical accuracy with SRP-DFT has yet to be demonstrated for weakly activated systems like H2 + Ru(0001) and non-activated systems like H2 + Pd(111), for which SRP DFs are not yet available. There is now considerable evidence that electron-hole pair (ehp) excitation does not need to be modeled to achieve the (chemically) accurate calculation of dissociative chemisorption and scattering probabilities. Dynamics calculations show that phonons can be safely neglected in the chemically accurate calculation of sticking probabilities on cold metal surfaces for activated systems, and in the calculation of a number of other observables. However, there is now sufficient evidence to suggest that the decision on whether or not to neglect phonons should be taken with care, with appropriate consideration of the observable to be computed and of the relevant surface temperature. AIMD calculations have provided valuable insights into the mechanisms that are operative in the dissociative adsorption and absorption of hydrogen on/in precovered metal surfaces. Classical and quantum dynamics calculations have shown that the reaction probability of H2 on Pt surfaces consisting of (100) steps and (111) terraces can to a very good approximation be computed as a weighted average of the reactivities on the steps and terraces. Progress obtained with dynamics calculations on the scattering of H2 from alloys and from simple low index metal surfaces is also reported. Insights that may be obtained on the reactivity of a metal surface from the prominent presence of out of-plane diffraction or, conversely, the complete absence of diffraction, are discussed. A new field has been opened up by experiments on H2 scattering from surfaces at fast grazing incidence, and we discuss new predictions regarding diffraction and dissociative scattering of H2 under such conditions. PMID- 26235526 TI - Screening for gestational diabetes mellitus in Germany: A qualitative study on pregnant women's attitudes, experiences, and suggestions. AB - OBJECTIVE: to explore pregnant women's experiences with the recently implemented screening for gestational diabetes mellitus (GDM). DESIGN: qualitative study. SETTING: Rhine-Neckar Metropolitan region, Germany. PARTICIPANTS: 20 pregnant women aged 27-41 years (mean: 32.6 years) who were at least in gestational week 29, i.e., those who should have already been screened for GDM. MEASUREMENTS AND FINDINGS: semi-structured interviews with open-ended questions were conducted via telephone between November 2013 and February 2014. All interviews were audiotaped, transcribed verbatim and subsequently analyzed using qualitative content analysis according to Mayring. The screening was seen as an important instrument to detect GDM and thus to prevent possible health problems in both mother and child. Some deviations from the recommended screening procedure were reported in the interviews, e.g., collecting capillary blood instead of venous blood during an oral glucose tolerance test (OGTT); offering an OGTT without a prior glucose challenge test (GCT); conducting a GCT after an overnight fast. Two women had to actively ask for the screening to be done. One woman reported that her gynaecologist advised her against the screening. CONCLUSION AND IMPLICATION FOR PRACTICE: this qualitative study reflects the women's experiences with the new screening for GDM. Our findings show that two years after the introduction of universal GDM screening in Germany the screening procedure does not always seem to meet the standards of the German maternity guidelines. PMID- 26235527 TI - Relation between blood flow and tissue blood oxygenation in human fingertip skin. AB - BACKGROUND: Tissue blood flow (BF) is thought to be involved in the regulation of tissue blood oxygenation (StO2). The purpose of the present study was to show the relation between BF and StO2 by measuring them simultaneously under different conditions. METHODS: Twenty-one healthy subjects (age 21-30years) participated in this study. We measured BF and StO2 in a small area of skin (fingertip, palm, forearm) simultaneously using a laser Doppler flowmeter and a tissue oxygenation monitor. Three measurements were made at rest while performing mental arithmetic and during constriction of the ipsilateral upper arm. RESULTS: At rest, BF and StO2 were higher in the fingertip than in the palm or forearm (p<0.01). Performing mental arithmetic produced significant decreases in BF, oxygenated hemoglobin, and StO2 in the fingertip (p<0.05). Constriction of the ipsilateral upper arm produced significant decreases in BF and StO2 (p<0.05) and an increase in oxygenated hemoglobin (p<0.05). Both procedures produced significant increases in deoxygenated hemoglobin (p<0.05), which was in antiphase to the decrease in StO2. CONCLUSIONS: BF decrease produced a significantly decreased StO2 in fingertip skin. The results show that simultaneous measurement of BF and StO2 is beneficial for showing the close relation between them. PMID- 26235530 TI - Magnetic field dependent electro-conductivity of the graphite doped magnetorheological plastomers. AB - In this work we reported a novel graphite doped conductive magnetorheological plastomer (GMRP) with magnetic field dependent electro-conductivity. The conductivity of the GMRPs increased by increasing the content of the graphite particles, while it decreased with the graphite size. When the graphite content reached 15 wt%, the conductivity of GMRPs is approximately 10 000 times higher than the non-doped MRP. Because the iron particles in the GMRPs were magnetic, the conductivity of the GMRPs was magnetically sensitive. Upon applying a 780 mT magnetic field, the electric conductivity could increase about 1000 times larger than the one under zero magnetic field. A particle-particle resistance model was developed to investigate the influence of the magnetic field and graphite doping on the conductivity, and the fitting curve matched the experimental results very well. Finally, a magnetically controllable on-off switch based on GMRPs was proposed and its working mechanism was discussed. PMID- 26235528 TI - Social anxiety, disengagement coping, and alcohol-use behaviors among adolescents. AB - BACKGROUND AND OBJECTIVES: Although research indicates that social anxiety (SA) is associated with problematic drinking, few studies have examined these relations among adolescents, and all alcohol-related assessments have been retrospective. Socially anxious youth may be at risk to drink in an effort to manage negative affectivity, and a proclivity toward disengagement coping (e.g. avoidance of aversive stimuli) may enhance the desire to drink and learning of coping-related use. DESIGN: Adding to research addressing adolescent SA and alcohol use, the current study examined (1) proportional drinking motives (subscale scores divided by the sum of all subscales), (2) current desire to drink in a socially relevant environment (introduction to research laboratory), and (3) the indirect effect of retrospectively reported disengagement in social stress contexts on proportional coping motives and desire to drink. METHOD: Participants were 70 community-recruited adolescents who reported recent alcohol use. Level of SA, disengagement coping, drinking motives, and desire to drink following laboratory introduction were assessed. RESULTS: Proclivity toward disengagement in prior socially stressful contexts accounted for significant variance in the positive relations between SA and both proportional coping motives and current desire to drink. CONCLUSIONS: These data complement existing work. Continued efforts in building developmentally sensitive models of alcohol use are needed. PMID- 26235529 TI - Self-assembled Messenger RNA Nanoparticles (mRNA-NPs) for Efficient Gene Expression. AB - Although mRNA has several advantages over plasmid DNA when delivered into cells for gene expression, mRNA transfection is a very rare occurrence in gene delivery. This is mainly because of the labile nature of RNA, resulting in a low expression level of the desired protein. In this study, self-assembled mRNA nanoparticles (mRNA-NPs) packed with multiple repeats of mRNA were synthesized to achieve efficient gene expression. This approach required only a one-step process to synthesize particles with a minimal amount of plasmid DNA to produce the RNA transcripts via rolling circle transcription. Moreover, there are no concerns for cytotoxicity which can be caused by chemical condensates because mRNA-NPs are made entirely of mRNA. An examination of the cells transfected with the mRNA-NPs encoding the green fluorescence protein (GFP) confirmed that the mRNA-NPs can be used as a novel platform for effective gene delivery. PMID- 26235532 TI - The case for using the correction index obtained from chest radiography for evaluation of pectus excavatum. AB - BACKGROUND: We previously reported the use of a computed tomography (CT)-based Correction Index (CI) as a more accurate assessment of pectus excavatum (PE) severity than the historically used Haller Index (HI). This study examines the diagnostic capabilities of the CI as assessed by lateral chest radiography (CXR). METHODS: A database of PE patients receiving preoperative CXR and CT was created. For each patient, a radiologist calculated a CT-based CI, while two pediatric surgeons independently calculated CXR CIs. RESULTS: The database was composed of 69 patients. Significant correlations were found between CXR CI estimates of the two observers and between the CXR and CT CI for each observer. Per our previous work, CT CIs were used in this study for identifying patients meeting surgical criteria (CT CI>=28%). Observed CXR CIs demonstrated good interrater reliability. The sensitivity (0.83) and specificity (0.77) of CXR in diagnosing severe PE (CT CI>=28%) was high. However, sensitivity (0.89) markedly improved when only considering measured CXR CIs<=26%, and combined specificity rose to 0.86 when only considering measured CXR CIs>=30%. CONCLUSIONS: We recommend the CI as measured by lateral CXR for the preoperative evaluation of PE, with CT used as a confirmatory test in patients measured to have a CXR CI between 26% and 30%. PMID- 26235533 TI - A microfluidic device with focusing and spacing control for resistance-based sorting of droplets and cells. AB - This paper reports a novel hydrodynamic technique for sorting of droplets and cells based on size and deformability. The device comprises two modules: a focusing and spacing control module and a sorting module. The focusing and spacing control module enables focusing of objects present in a sample onto one of the side walls of a channel with controlled spacing between them using a sheath fluid. A 3D analytical model is developed to predict the sheath-to-sample flow rate ratio required to facilitate single-file focusing and maintain the required spacing between a pair of adjacent objects. Experiments are performed to demonstrate focusing and spacing control of droplets (size 5-40 MUm) and cells (HL60, size 10-25 MUm). The model predictions compare well with experimental data in terms of focusing and spacing control within 9%. In the sorting module, the main channel splits into two branch channels (straight and side branches) with the flow into these two channels separated by a "dividing streamline". A sensing channel and a bypass channel control the shifting of the dividing streamline depending on the object size and deformability. While resistance offered by individual droplets of different sizes has been studied in our previous work (P. Sajeesh, M. Doble and A. K. Sen, Biomicrofluidics, 2014, 8, 1-23), here we present resistance of individual cells (HL60) as a function of size. A theoretical model is developed and used for the design of the sorter. Experiments are performed for size-based sorting of droplets (sizes 25 and 40 MUm, 10 and 15 MUm) and HL60 cells (sizes 11 MUm and 19 MUm) and deformability-based sorting of droplets (size 10 +/- 1.0 MUm) and polystyrene microbeads (size 10 +/- 0.2 MUm). The performance of the device for size- and deformability-based sorting is characterized in terms of sorting efficiency. The proposed device could be potentially used as a diagnostic tool for sorting of larger tumour cells from smaller leukocytes. PMID- 26235531 TI - Health care utilization and charges following the enactment of the 2007 Graduated Drivers Licensing Law in Massachusetts. AB - BACKGROUND: Graduated Drivers Licensing (GDL) programs phase in driving privileges for teenagers. In 2007, Massachusetts implemented a stricter version of the 1998 GDL law, with increased fines and education. This study evaluated the impact of the law on motor vehicle crash (MVC)-related health care utilization and charges. METHODS: Massachusetts government and US Census Bureau data were analyzed to compare the rates of MVC-related emergency department (ED) visits and hospital charges before (2002-2006) and after (2007-2011) the 2007 GDL law. Three driver age groups were studied: 16-17 (evaluating the law effect), 18-20 (evaluating the sustainability of the effect), and 25-29 years old (control group). RESULTS: MVC-related ED visits per population decreased after the law for all three age groups (16-17: 2326 to 713; 18-20: 2110 to 1304; 25-29: 1694 to 1228; per 100,000, p<0.001), but the decrease was greater amongst teenagers (16 17: -69%; 18-20: -38%) compared to the control group (-27%); p<0.001. MVC-related hospital charges per population also decreased for teenagers but increased for the control group (16-17: $2.70 m to $1.45 m; 18-20: $3.52 m to $2.26 m; 25-29: $1.86 m to $1.92 m; per 100,000, p<0.001). CONCLUSIONS: The 2007 GDL law in Massachusetts was associated with significant decreases in MVC-related health care utilization and hospital charges among teenage drivers. PMID- 26235534 TI - The role of silicon in physiology of the medicinal plant (Lonicera japonica L.) under salt stress. AB - Silicon(Si) is the only element which can enhance the resistance to multiple stresses. However, the role of silicon in medicinal plants under salt stress is not yet understood. This experiment was conducted to study the effects of silicon addition on the growth, osmotic adjustments, photosynthetic characteristics, chloroplast ultrastructure and Chlorogenic acid (CGA) production of Honeysuckle plant (Lonicera japonica L.) under salt-stressed conditions. Salinity exerted an adverse effect on the plant fresh weight and dry weight, whilst 0.5 g L(-1) K2SiO3 . nH2O addition obviously improved the plant growth. Although Na(+) concentration in plant organs was drastically increased with increasing salinity, higher levels of K(+)/Na(+) ratio was obtained after K2SiO3 . nH2O addition. Salinity stress induced the destruction of the chloroplast envelope; however, K2SiO3 . nH2O addition counteracted the adverse effect by salinity on the structure of the photosynthetic apparatus. K2SiO3 . nH2O addition also enhanced the activities of superoxide dismutase and catalase. To sum up, exogenous Si plays a key role in enhancing its resistance to salt stresses in physiological base, thereby improving the growth and CGA production of Honeysuckle plant. PMID- 26235535 TI - hMSC-Derived VEGF Release Triggers the Chemoattraction of Alveolar Osteoblasts. AB - Human mesenchymal stem cells (hMSCs) are promising candidates for regenerative periodontal strategies, due to the broad spectrum of supportive effects on cells and tissues at the site of application. Although positive effects are visible, the understanding of their underlying mechanisms still requires further elucidation. Recently, we have shown that hMSCs are capable to prompt osteogenic differentiation of alveolar osteoblasts, thereby presumably contributing to alveolar bone regeneration. Another issue that is critical in this context is the attraction of hard tissue-forming cells to regeneration sites, but it is an open question whether hMSCs can afford this. In the present manuscript, we show by life cell imaging that in interactive cocultures, hMSCs successfully trigger osteoblast chemotaxis. Gene expression analysis for hMSC-innate chemoattractive biomolecules, orchestrating this process, revealed vascular endothelial growth factor (VEGF), PgE synthase, osteoprotegerin (OPG), monocyte colony-stimulating factor, and transforming growth factor beta1, which was confirmed for VEGF and OPG on the protein level. Noteworthy, we showed that only corresponding levels of VEGF but not OPG attracted alveolar osteoblasts similar to hMSC coculture, while VEGF inhibitor abolished both the VEGF and the hMSC-triggered chemoattraction. In summary, we have identified secreted OPG and VEGF proteins as potential chemoattractants, of which further characterization yielded VEGF as a causative for hMSC-directed osteoblast chemotaxis. With respect to the better understanding of potential hMSC-based periodontal regeneration strategies, we propose hMSC derived VEGF release as a mechanism in the recruitment of hard tissue-forming cells to alveolar bone sites in need of regeneration. PMID- 26235536 TI - Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi). AB - Haploinsufficiency for the Notch ligand JAG1 in humans results in an autosomal dominant, multisystem disorder known as Alagille syndrome, which is characterized by a congenital cholangiopathy of variable severity. Here, we show that on a C57BL/6 background, jagged1 heterozygous mice (Jag1(+/-) ) exhibit impaired intrahepatic bile duct (IHBD) development, decreased SOX9 expression, and thinning of the periportal vascular smooth muscle cell (VSMC) layer, which are apparent at embryonic day 18 and the first postnatal week. In contrast, mice double heterozygous for Jag1 and the glycosyltransferase, Poglut1 (Rumi), start showing a significant improvement in IHBD development and VSMC differentiation during the first week. At P30, Jag1(+/-) mice show widespread ductular reactions and ductopenia in liver and a mild, but statistically, significant bilirubinemia. In contrast, P30 Jag1/Rumi double-heterozygous mice show well-developed portal triads around most portal veins, with no elevation of serum bilirubin. Conditional deletion of Rumi in VSMCs results in progressive arborization of the IHBD tree, whereas deletion of Rumi in hepatoblasts frequently results in an increase in the number of hepatic arteries without affecting bile duct formation. Nevertheless, removing one copy of Rumi from either VSMCs or hepatoblasts is sufficient to partially suppress the Jag1(+/-) bile duct defects. Finally, all Rumi target sites of the human JAG1 are efficiently glucosylated, and loss of Rumi in VSMCs results in increased levels of full-length JAG1 and a shorter fragment of JAG1 without affecting Jag1 messenger RNA levels. CONCLUSIONS: On a C57BL/6 background, Jag1 haploinsufficiency results in bile duct paucity in mice. Removing one copy of Rumi suppresses the Jag1(+/-) bile duct phenotype, indicating that Rumi opposes JAG1 function in the liver. PMID- 26235537 TI - Pharmaceutical direct-to-consumer advertising and US Hispanic patient-consumers. AB - Hispanic Americans use prescription medications at markedly lower rates than do non-Hispanic whites. At the same time, Hispanics are the largest racial-ethnic minority in the USA. In a recent effort to reach this underdeveloped market, the pharmaceutical industry has begun to create Spanish-language direct-to-consumer advertising (DTCA) campaigns. The substantive content of these campaigns is being tailored to appeal to the purported cultural values, beliefs and identities of Latino consumers. We compare English-language and Spanish-language television commercials for two prescription medications. We highlight the importance of selling medicine to a medically under-served population as a key marketing element of Latino-targeted DTCA. We define selling medicine as the pharmaceutical industry's explicit promotion of medicine's cultural authority as a means of expanding its markets and profits. We reflect on the prospects of this development in terms of promoting medicalisation in a US subgroup that has heretofore eluded the pharmaceutical industry's marketing influence. Our analysis draws on Nikolas Rose's insights concerning variations in the degree to which certain groups of people are more medically made up than others, by reflecting on the racial and ethnic character of medicalisation in the USA and the role DTCA plays in shaping medicalisation trends. A video abstract of this article can be found at: https://www.youtube.com/watch?v=ZabCle9-jHw&feature=youtu.be. PMID- 26235539 TI - Structure, evolution and expression of collagen XXVIII: Lessons from the zebrafish. AB - Collagen XXVIII is the last discovered member of the collagen superfamily and thus has been only sparsely investigated. We studied collagen XXVIII in zebrafish to gain insight into its structure, evolution and expression. In contrast to human and mouse, the zebrafish genome contains four collagen XXVIII genes, col28a1a and -b, and col28a2a and -b. Genomic context and phylogenetic analysis revealed that the a2 branch was lost during evolution of mammals, whereas the duplication of the a1 and a2 branches results from the whole genome duplication in the teleost lineage. Sequence analysis revealed conservation of domain structure and the unique imperfections in the triple helical domain. Two major forms of collagen XXVIII were identified, Col28a1b in adult and Col28a2a in 3 5dpf zebrafish. Composite agarose/polyacrylamide gel electrophoresis revealed that both these chains mainly form dimers of trimers, although Col28a1b appears to be more polydisperse. Homodimers are abundant, although it is possible that complexes consisting of Col28a2a and Col28a1a or -a2b occur. Peptide mass fingerprint analysis revealed that the C-terminal Kunitz domain is often proteolytically processed. In contrast to murine collagen XXVIII, the zebrafish orthologs are widely expressed and not only present in the nervous system. They are differentially expressed in the liver, thymus, muscle, intestine and skin. Altogether our results point to a unique nature of collagen XXVIII within the collagen family. PMID- 26235541 TI - Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with variceal bleeding in liver cirrhosis: outcomes and predictors in a prospective cohort study. AB - BACKGROUND & AIMS: The role of transjugular intrahepatic portosystemic shunt (TIPS) for the secondary prophylaxis of variceal bleeding in cirrhotic patients with portal vein thrombosis (PVT) remains obscure. This prospective cohort study aimed to assess the risk factors associated with TIPS technical success, outcome and prognosis in cirrhotic patients with PVT and a history of variceal bleeding. METHODS: Between May 2009 and April 2011, 51 cirrhotic patients with PVT who attempted TIPS procedures for the prevention of variceal rebleeding were enrolled. RESULTS: TIPS success rate was 84% (43/51). An increased degree of thrombosis within the portal trunk and portal vein branches was inversely associated with TIPS success. Median follow-up time was 40.07 months (range: 0.02 56.87). The cumulative risk of rebleeding was significantly different between TIPS success and failure group (P = 0.002). The univariate analysis also demonstrated that TIPS failure was the only significant predictor associated with rebleeding (hazard ratio [HR] = 4.174, 95% confidence interval [CI]: 1.558 11.186). In TIPS success group, the cumulative rates free of shunt dysfunction at the 6th and 12th month were 79% and 76% respectively. Absence of total superior mesenteric vein (SMV) thrombosis was the only independent predictor (HR = 0.189, 95% CI: 0.047-0.755). In TIPS success group, the 1- and 3-year cumulative survival rates were 77% and 62% respectively. Albumin level was the only independent predictor (HR = 0.877, 95% CI: 0.779-0.986). CONCLUSION: Successful TIPS insertions could effectively prevent from rebleeding in cirrhotic patients with PVT and variceal bleeding. Degree of PVT and SMV thrombosis was associated with TIPS failure and shunt dysfunction respectively. PMID- 26235542 TI - A new potent analgesic agent with reduced liability to produce morphine tolerance. AB - The therapeutic use of opioids is limited by the development of tolerance to the analgesic effect and the cellular and molecular mechanisms underlying this phenomenon are still not completely understood. For this reason the search for new analgesic derivatives, endowed with lower tolerance, is always an active field. The newly synthesized 14-O-Methylmorphine-6-sulfate (14-O-MeM6SU) shows high efficacy in in vitro assays and a strong analgesic action in the rat tail flick test. The aim of present work was to investigate: the analgesic effect of 14-O-MeM6SU in mouse tail-flick test; the tolerance to analgesic effect of 14-O MeM6SU compared to morphine in mice, the effects of test compounds on glutamatergic neurotransmission by measuring spontaneous excitatory postsynaptic currents (sEPSCs) of layer V pyramidal cells from rat prefrontal cortices; and the effect of acute and chronic 14-O-MeM6SU treatments on opioid receptor gene expression in SH-SY5Y neuroblastoma cells expressing MU-opioid (MOP) and nociceptin/opioid receptor-like 1 (NOP) receptors. 14-O-MeM6SU was 17 times more potent than morphine in analgesia and had long duration of action in analgesic dose equipotent to morphine. Mice were treated subcutaneously (s.c.) either with 200 MUmol/kg morphine or with 14-O-MeM6SU (12 MUmol/kg) twice daily for three days. The magnitude of tolerance or cross-tolerance indicated by the shift in antinociceptive ED50 measured was greater for morphine compared to 14-O-MeM6SU. Subsequent to behavioral testing, patch-clamp experiments in layer V pyramidal neurons of rat prefrontal cortical slices in the presence of bicuculline were performed. Both 14-O-MeM6SU (0.1 MUM) and morphine (1 MUM) decreased the frequency of sEPSCs, indicating reduction of glutamate release. The effect of the novel compound was reversed by the opioid receptor antagonist naloxone, indicating an opioid mediated action. In contrast, the amplitude was not affected. Finally, gene expression data showed a dose dependent down-regulation of MOP receptor after 24h and 48 h exposure to 14-O-MeM6SU. Interestingly, no changes were detected for NOP receptor gene expression. The specific lack of this effect could be related to the lower tolerance development to analgesic effect of 14-O-MeM6SU. Furthermore, 14-O-MeM6SU displayed high intrinsic efficacy possibly an important factor in the observed effects. Further, the observed inhibition of glutamatergic signaling might be attributed also to the reduction of opioid tolerance. Based on our results the development of a new clinically important, safe analgesic agent might be possible. PMID- 26235543 TI - Genomes analysis and bacteria identification: The use of overlapping genes as molecular markers. AB - The growing number of available microbial genomes offers the possibility to identify features that could be used for identification. In this work, the possibility to exploit overlapping genes to develop a simple PCR based method of identification, was explored. Using the Burkholderia cepacia complex as a model, genomic analyses were performed to check the phylogenetic distribution of an overlap between marC and hisH genes and then, a PCR specific for Burkholderia was designed, set up and tested on a panel of strains and on DNA extracted from the sputum of cystic fibrosis patients. Results obtained revealed the usefulness of this approach, which could then be used to develop PCR for the identification of specific bacteria species or genera. PMID- 26235544 TI - Sustained biologic-free and drug-free remission in rheumatoid arthritis, where are we now? AB - The advent of new medications and new treatment strategies for rheumatoid arthritis has made it possible to achieve remission in more patients than before. Furthermore, recent clinical trials and register studies suggest that some patients who initially required aggressive therapy may achieve biologic-free remission or even the ultimate goal of therapy, drug-free remission, resembling recovery. Here, we present a discursive review of the most important studies addressing these issues. Based on the overall results, it remains unclear if achieving biologic-free and drug-free remissions are primarily due to the natural course of the disease or to the early therapeutic intervention according to the 'window of opportunity' hypothesis. Although medication-free remission is only achievable in a small subset of patients, characterizing this patient cohort may provide important information about beneficial prognostic factors and the underlying mechanisms. In summary, in a subset of patients biologic-free and even drug-free remission can be achieved; pursuing these possibilities in practice may decrease the risk for long-term side effects and attenuate the economic burden of the disease. PMID- 26235545 TI - Rectal bleeding post the use of the Flexi-Seal faecal management system. PMID- 26235546 TI - PspF-binding domain PspA1-144 and the PspA.F complex: New insights into the coiled-coil-dependent regulation of AAA+ proteins. AB - Phage shock protein A (PspA) belongs to the highy conserved PspA/IM30 family and is a key component of the stress inducible Psp system in Escherichia coli. One of its central roles is the regulatory interaction with the transcriptional activator of this system, the sigma(54) enhancer-binding protein PspF, a member of the AAA+ protein family. The PspA/F regulatory system has been intensively studied and serves as a paradigm for AAA+ enzyme regulation by trans-acting factors. However, the molecular mechanism of how exactly PspA controls the activity of PspF and hence sigma(54) -dependent expression of the psp genes is still unclear. To approach this question, we identified the minimal PspF interacting domain of PspA, solved its structure, determined its affinity to PspF and the dissociation kinetics, identified residues that are potentially important for PspF regulation and analyzed effects of their mutation on PspF in vivo and in vitro. Our data indicate that several characteristics of AAA+ regulation in the PspA.F complex resemble those of the AAA+ unfoldase ClpB, with both proteins being regulated by a structurally highly conserved coiled-coil domain. The convergent evolution of both regulatory domains points to a general mechanism to control AAA+ activity for divergent physiologic tasks via coiled-coil domains. PMID- 26235547 TI - PREFERRED REPORTING ITEMS FOR STUDIES MAPPING ONTO PREFERENCE-BASED OUTCOME MEASURES: THE MAPS STATEMENT. AB - BACKGROUND: "Mapping" onto generic preference-based outcome measures is increasingly being used as a means of generating health utilities for use within health economic evaluations. Despite publication of technical guides for the conduct of mapping research, guidance for the reporting of mapping studies is currently lacking. The MAPS (MApping onto Preference-based measures reporting Standards) statement is a new checklist, which aims to promote complete and transparent reporting of mapping studies. METHODS: In the absence of previously published reporting checklists or reporting guidance documents, a de novo list of reporting items was created by a working group comprised of six health economists and one Delphi methodologist. A two-round, modified Delphi survey with representatives from academia, consultancy, health technology assessment agencies, and the biomedical journal editorial community was used to identify a list of essential reporting items from this larger list. RESULTS: From the initial de novo list of twenty-nine candidate items, a set of twenty-three essential reporting items was developed. The items are presented numerically and categorized within six sections, namely: (i) title and abstract, (ii) introduction, (iii) methods, (iv) results, (v) discussion, and (vi) other. The MAPS statement is best applied in conjunction with the accompanying MAPS explanation and elaboration document. CONCLUSIONS: It is anticipated that the MAPS statement will improve the clarity, transparency. and completeness of reporting of mapping studies. To facilitate dissemination and uptake, the MAPS statement is being co-published by seven health economics and quality of life journals, and broader endorsement is encouraged. The MAPS working group plans to assess the need for an update of the reporting checklist in five years' time. PMID- 26235548 TI - Focal ESES as a selective focal brain dysfunction: a challenge for clinicians, an opportunity for cognitive neuroscientists. PMID- 26235549 TI - Reporting small bowel dose in cervix cancer high-dose-rate brachytherapy. AB - Small bowel (SB) is an organ at risk (OAR) that may potentially develop toxicity after radiotherapy for cervix cancer. However, its dose from brachytherapy (BT) is not systematically reported as in other OARs, even with image-guided brachytherapy (IGBT). This study aims to introduce consideration of quantified objectives for SB in BT plan optimization and to evaluate the feasibility of sparing SB while maintaining adequate target coverage. In all, 13 patients were included in this retrospective study. All patients were treated with external beam radiotherapy (EBRT) 45Gy in 25 fractions followed by high dose rate (HDR)-BT boost of 28Gy in 4 fractions using tandem/ring applicator. Magnetic resonance imaging (MRI) and computed tomographic (CT) images were obtained to define the gross tumor volume (GTV), high-risk clinical target volume (HR-CTV) and OARs (rectum, bladder, sigmoid colon, and SB). Treatment plans were generated for each patient using GEC-ESTRO recommendations based on the first CT/MRI. Treatment plans were revised to reduce SB dose when the [Formula: see text] dose to SB was > 5Gy, while maintaining other OAR constraints. For the 7 patients with 2 sets of CT and MRI studies, the interfraction variation of the most exposed SB was analyzed. Plan revisions were done in 6 of 13 cases owing to high [Formula: see text] of SB. An average reduction of 19% in [Formula: see text] was achieved. Meeting SB and other OAR constraints resulted in less than optimal target coverage in 2 patients (D90 of HR-CTV < 77Gyalphabeta10). The highest interfraction variation was observed for SB at 16 +/- 59%, as opposed to 28 +/- 27% for rectum and 21 +/- 16% for bladder. Prospective reporting of SB dose could provide data required to establish a potential correlation with radiation-induced late complication for SB. PMID- 26235550 TI - Whole-brain hippocampal sparing radiation therapy: Volume-modulated arc therapy vs intensity-modulated radiation therapy case study. AB - The hippocampus is responsible for memory and cognitive function. An ongoing phase II clinical trial suggests that sparing dose to the hippocampus during whole-brain radiation therapy can help preserve a patient's neurocognitive function. Progressive research and advancements in treatment techniques have made treatment planning more sophisticated but beneficial for patients undergoing treatment. The aim of this study is to evaluate and compare hippocampal sparing whole-brain (HS-WB) radiation therapy treatment planning techniques using volume modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT). We randomly selected 3 patients to compare different treatment techniques that could be used for reducing dose to the hippocampal region. We created 2 treatment plans, a VMAT and an IMRT, from each patient's data set and planned on the Eclipse 11.0 treatment planning system (TPS). A total of 6 plans (3 IMRT and 3 VMAT) were created and evaluated for this case study. The physician contoured the hippocampus as per the Radiation Therapy Oncology Group (RTOG) 0933 protocol atlas. The organs at risk (OR) were contoured and evaluated for the plan comparison, which included the spinal cord, optic chiasm, the right and left eyes, lenses, and optic nerves. Both treatment plans produced adequate coverage on the planning target volume (PTV) while significantly reducing dose to the hippocampal region. The VMAT treatment plans produced a more homogenous dose distribution throughout the PTV while decreasing the maximum point dose to the target. However, both treatment techniques demonstrated hippocampal sparing when irradiating the whole brain. PMID- 26235551 TI - A comparison of technologically mediated and face-to-face help-seeking sources. AB - BACKGROUND: Current post-secondary school students have access to multiple help seeking sources. As help-seeking behaviour relates to academic achievement, the provision of preferred help sources would be beneficial to students, instructors, and course designers. AIMS: This study examines whether students prefer and intend to utilize technologically mediated or face-to-face help-seeking sources. SAMPLE: Participants (n = 226) were recruited from two sections of an on campus, introductory, educational psychology class. METHODS: An online survey was distributed containing measures of help-seeking threat, adaptive help-seeking tendencies, avoidant help-seeking tendencies, and the intention to seek help from six sources. Correlations and an ANOVA were calculated to determine whether source preferences differed by self-reported course grade. RESULTS: Help-seeking threat was only negatively associated with sources of help that required face-to face interaction. Despite the threat, students intended to use face-to-face help seeking sources more than technologically mediated sources. Students intended to seek help the most before or after class, via email, or during class. Students intended to seek help the least through the discussion board and during online office hours. Higher performing students preferred face-to-face sources, particularly before or after class and during class, more than lower performing students. Lower performing students intended to use mediated sources especially the discussion board and online office hours more than the higher performing students. CONCLUSIONS: The results provide new insights into the help-seeking process and suggestions for instructors when allocating time and classroom resources. Additionally, the study illustrates the need for continual refinement of a help-seeking source classification system. PMID- 26235562 TI - Regioselective, Molecular Iodine-Mediated C3 Iodination of Quinolines. AB - A novel and convenient method has been developed for the regioselective iodination of quinolines at their C3 position under metal-free conditions. Iodinated quinolines, which are popular building blocks in organic and medicinal chemistry, can be prepared in gram quantities and good yields using this method and further derivatized to give increasingly complex compounds. Preliminary mechanistic studies have shown that this reaction most likely occurs via a radical intermediate. PMID- 26235563 TI - Prevalence of "uncomplicated" stress urinary incontinence in female patients prior to surgery. Re: Norton PA, Nager CW, Brubaker L, Lemack GE, Sirls LT, Holley R, Chai TC, Kraus SR, Zyczynski H, Smith B, Stoddard A; for the Urinary Incontinence Treatment Network. The cost of preoperative urodynamics: A secondary analysis of the ValUE trial. Neurourol Urodyn. 2014 Oct 18. PMID- 26235564 TI - Asymptomatic carotid stenosis is associated with gray and white matter damage. AB - BACKGROUND: Cognitive deficits in patients with asymptomatic carotid stenosis have been reported. The ultimate mechanism of cognitive deficits remains unclear and might be related to subtle structural brain damage. AIMS: The aim of the present study was to evaluate the presence of subtle white and grey matter abnormalities associated with asymptomatic carotid stenosis. METHODS: Twenty-five patients with asymptomatic >=70%/occlusion carotid stenosis and 25 healthy controls, matched for gender and age, underwent 3 Tesla brain magnetic resonance imaging. Gray and white matter macrostructural abnormalities were evaluated with voxel-based morphometry using spm8 software. White matter microstructural abnormalities were evaluated with diffusion tensor images with the Diffusion Toolbox package and tract-based spatial statistics from FMRIB Software Library. RESULTS: We observed significant macro- and microstructural white matter abnormalities, and these findings were diffuse and symmetrical in both hemispheres. In contrast, gray matter atrophy was observed in the areas corresponding to the anterior circulation of the hemisphere ipsilateral to the carotid stenosis. CONCLUSIONS: Patients with asymptomatic carotid stenosis have different patterns of gray and white matter abnormalities. While the white matter damage is diffuse, the gray matter atrophy is localized in the territory of anterior circulation ipsilateral to the stenosis. The role of asymptomatic carotid stenosis in the gray matter damage must be further investigated with longitudinal studies and comparison with neuropsychological evaluation. PMID- 26235565 TI - Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha: 5-year follow-up study. AB - BACKGROUND: Psoriasis is an emerging paradoxical side effect in patients with inflammatory bowel disease (IBD) when treated with anti-TNF alpha. Patients with severe skin lesions unresponsive to topical therapy need to withdraw from treatment. AIM: To estimate the incidence of paradoxical psoriasis in a large cohort of IBD patients treated with anti-TNF alpha and to analyse its clinical correlates. METHODS: A retrospective cohort study on all IBD patients who started anti-TNF alpha at our IBD Centre from January 2008 to December 2013 was performed. Proportional hazards regression models were used to estimate the association between each predictor and time to the development of psoriasis. Time dependent predictors were updated at each available time point. RESULTS: Four hundred and two patients were included. Participants contributed a total of 839 person-years of follow-up, during which 42 incident cases of psoriasis were recorded, with an incidence rate of five per 100 person-years. Cox-regression survival analysis revealed smoking as independent predictor of psoriasis (HR: 2.37, 95% CI: 1.36-4.48; P = 0.008). Conversely, concomitant immunosuppressive therapy was inversely related to psoriasis (HR: 0.33, 95% CI: 0.12-0.92; P = 0.03). CONCLUSIONS: Paradoxical psoriasis is a relevant side effect of anti-TNF alpha therapy, with an incidence rate of five per 100 person-years. Smoking is confirmed as the main risk factor for developing lesions. The combination therapy with anti-TNF alpha plus immunosuppressants is associated with a reduced risk of paradoxical psoriasis. PMID- 26235566 TI - Formal Asymmetric (4+1) Annulation Reaction between Sulfur Ylides and 1,3-Dienes. AB - A highly enantioselective synthesis of functionalized cyclopentanoids by a formal asymmetric (4+1) annulation strategy was developed. The methodology consists of a stereoselective cyclopropanation reaction between chiral sulfur ylides and 1,3 dienes followed by a, in situ, stereospecific MgI2 -catalyzed rearrangement of vinylcyclopropanes. This method is distinguished by a remarkable compatibility with functional groups and a high stereocontrol. PMID- 26235567 TI - Quick serological detection of a cancer biomarker with an agglutinated supramolecular glycoprobe. AB - While serology represents the forefront technique for cancer diagnosis, current clinical methods for the detection of serum biomarkers have flaws in terms of the need of complicated manipulations, long analytical time, and high cost. Here, we develop a supramolecular glycoprobe for the quick serological detection of a cancer biomarker. The probe formed by agglutination between self-assembled glyco gold nanoparticles and a lectin shows subtle optical variations upon the competitive recognition of a glycoprotein biomarker secreted by cancer cells, tumor-bearing mice, as well as clinical cancer patients, with no response to a series of controls including the serum of hepatitis patients. This research provides an insight into the development of effective tools for serological diagnosis of cancer. PMID- 26235568 TI - Band Structure Engineering by Substitutional Doping in Solid-State Solutions of [5-Me-PLY(O,O)]2B(1-x)Be(x) Radical Crystals. AB - We report the substitutional doping of solid-state spiro-bis(5-methyl-1,9-oxido phenalenyl)boron radical ([2]2B) by co-crystallization of this radical with the corresponding spiro-bis(5-methyl-1,9-oxido-phenalenyl)beryllium compound ([2]2Be). The pure compounds crystallize in different space groups ([2]2B, P1, Z = 2; [2]2Be, P21/c, Z = 4) with distinct packing arrangements, yet we are able to isolate crystals of composition [2]2B(1-x)Be(x), where x = 0-0.59. The phase transition from the P1 to the P21/c space group occurs at x = 0.1, but the conductivities of the solid solutions are enhanced and the activation energies reduced for values of x = 0-0.25. The molecular packing is driven by the relative concentration of the spin-bearing ([2]2B) and spin-free ([2]2Be) molecules in the crystals, and the extended Huckel theory band structures show that the progressive incorporation of spin-free [2]2Be in the lattice of the [2]2B radical (overall bandwidth, W = 1.4 eV, in the pure compound) leads to very strong narrowing of the bandwidth, which reaches a minimum at [2]2Be (W = 0.3 eV). The results provide a graphic picture of the structural transformations undergone by the lattice, and at certain compositions we are able to identify distinct structures for the [2]2B and [2]2Be molecules in a single crystalline phase. PMID- 26235569 TI - Mandatory counseling for gamete donation recipients: ethical dilemmas. AB - Mental health professionals have engaged in mandatory pretreatment counseling and assessment of patients seeking treatment at IVF programs in the United States since the 1980s. At present, most recipient patients undergoing IVF with egg or embryo donation in the United States are required to meet with a mental health professional for one pretreatment session. Mandatory counseling of gamete recipients is fraught with ethical questions for the mental health professional. Attention to issues of autonomy, confidentiality, role clarity, along with self evaluation and openness with the patient can help lessen the impact of these ethical challenges. PMID- 26235570 TI - Foreword. PMID- 26235571 TI - Cell Death in the Cardiac Myocyte. AB - Loss of cardiac myocytes plays a critical role in the pathogenesis of cardiovascular disorders. A decrease in the number of cardiac myocytes in cardiac diseases results in sustained, irreversible contractile failure of myocardium. Therefore prevention of cardiac cell death is a potential therapeutic strategy for various heart diseases. It is well accepted that three types of phenomena such as apoptosis, necrosis, and autophagy may be involved in myocardial cell death. Apoptosis is a highly regulated process that is promoted via death receptor pathway in the plasma membrane or via mitochondrial pathway. Necrosis is induced via mitochondrial swelling, cell rupture, and subsequent inflammation. Autophagy is a cell survival mechanism that involves degradation and recycling of cytoplasmic components. As compared with the other two mechanisms, autophagy may mediate cell death under specific conditions. These three types of cell death in the myocardium are discussed in this article. PMID- 26235572 TI - Choose Delicately and Reuse Adequately: The Newly Revealed Process of Autophagy. AB - Autophagy is a degradation system for intracellular components. One of the roles of autophagy is the prompt removal of damaged organelles. Another unique role is to supply resources that maintain metabolism in response to the cellular nutritional state. Precise management of all the components in the autophagic system is essential for cellular health. Especially important are the selectivity of target cargos for autophagy, and the coordination of autophagy with the lysosomal catabolic process. This review outlines our current understanding of autophagy and discusses potential therapeutic perspectives. Emphasis will be given to lysosomal function as a central controller of metabolism, and to selective autophagy as a key mechanism for the efficient removal of dysfunctional organelles. PMID- 26235573 TI - Endogenous Neuroprotective Molecules and Their Mechanisms in the Central Nervous System. AB - Functions of the central nervous system (CNS) are based on a complex neural network. It is believed that the CNS has several neuroprotective mechanisms operated by neurons, glia and other types of cells against various types of neuronal damage. Since mature, differentiated neurons are not able to divide, it is important to protect neurons from damage prior to death. The neuroprotective effects of a number of pharmaceutical agents and natural products against necrosis and apoptosis of the CNS neurons have been reported, thus this review will mainly discuss several endogenous neuroprotectants and their mechanisms. PMID- 26235574 TI - Role of Environmental Chemical Insult in Neuronal Cell Death and Cytoskeleton Damage. AB - Environmental influences, such as chemical exposure, have long been considered potential risk factors for neurodegenerative disorders, including neuromuscular diseases. However, no definitive links between environmental chemical exposure and a pathogenic mechanism of neurodegenerative disease has yet been established. In this study, we describe that exposure to arsenic, an environmental pollutant naturally found in drinking water, induces neuronal cell death and alteration of morphology, particularly neurite outgrowth and in the cytoskeleton of neurons. Since progressive cell loss accompanied by the alteration of neuronal structures and cytoskeleton is considered the major pathologic feature of neurodegenerative disorders, arsenic-induced neurotoxicity might contribute to an etiologic mechanism of some neurodegenerative diseases. Further, we discuss the importance of in vitro assay, particularly an embryonic toxicity test, for assessing the neurotoxicity of chemicals, because most of chemicals found in our environment remain to be evaluated regarding their neurotoxicity risk for neurodegenerative diseases. PMID- 26235575 TI - Cellular Uptake of Decitabine by Equilibrative Nucleoside Transporters in HCT116 Cells. AB - DNA hypermethylation, an epigenetic change that silences gene expression without altering nucleotide sequences, plays a critical role in the formation and progression of colorectal cancers as well as in the acquisition of drug resistance. Decitabine (DAC), a DNA methyltransferase 1 inhibitor of nucleoside analogues, has been shown to restore gene expression silenced by hypermethylation. In the present study, the mechanisms underlying both uridine and DAC uptake were examined in the human colon cancer cell line HCT116. Real time polymerase chain reaction analysis revealed that ENT1 mRNA was the most abundant among the nucleoside transporters examined in HCT116 cells. The ENT1 protein was detected in the membrane fraction, as determined by Western blotting. The uptake of uridine or DAC was time- and concentration-dependent, but also Na(+)-independent. The uptake of these agents was inhibited by S-(4-nitrobenzyl) 6-thioinosine (NBMPR), an inhibitor of equilibrative nucleoside transporters (ENTs), and was also decreased in cells treated with ENT1 small interfering RNA. The uptake of both uridine and DAC was inhibited by uridine, cytidine, adenosine, or inosine, while that of DAC was also inhibited by thymidine. The expression of MAGEA1 mRNA, the DNA of which was methylated in HCT116 cells, was increased by DAC treatment, and this increment was attenuated by concomitant treatment with NBMPR. The IC50 value of DAC was also increased in the presence of NBMPR. These results suggest that DAC is mainly taken up by ENT1 and that this uptake is one of the key determinants of the activity of DAC in HCT116 cells. PMID- 26235576 TI - Positive Regulation of Interleukin-2 Expression by a Pseudokinase, Tribbles 1, in Activated T Cells. AB - Tribbles 1 (TRB1), a member of the Tribbles family, is a pseudokinase that is conserved among species and implicated in various human diseases including leukemia, cardiovascular diseases, and metabolic disorders. However, the role of TRB1 in the immune response is not understood. To evaluate this role, we examined regulation of TRB1 expression and the function of TRB1 in interleukin-2 (IL-2) induction in Jurkat cells, a human acute T cell leukemia cell line. We found that TRB1 was strongly induced by phorbol 12-myristate 13-acetate (PMA) and ionomycin in these cells. IL-2 expression was induced in Jurkat cells activated by PMA and ionomycin; however, knockdown of TRB1 resulted in decreased induction of IL-2. TRB1 null Jurkat cells established using the CRISPR/Cas9 system also showed reduction of IL-2 expression on PMA/ionomycin stimulation. TRB1 knockdown also markedly inhibited IL-2 promoter activation. To determine the mechanism of the stimulatory effect on IL-2 induction, we focused on histone deacetylases (HDACs), and found that HDAC1 preferentially interacts with TRB1. TRB1 suppressed the interaction of HDAC1 with nuclear factor of activated T cells 2 (NFAT2), which is a crucial transcription factor for IL-2 induction. These results indicate that TRB1 is a positive regulator of IL-2 induction in activated T cells. PMID- 26235577 TI - Curcumin Attenuates Hydrogen Peroxide-Induced Premature Senescence via the Activation of SIRT1 in Human Umbilical Vein Endothelial Cells. AB - Endothelial senescence has been proposed to be involved in endothelial dysfunction and atherogenesis. Curcumin, a natural phenol, possesses antioxidant and anti-inflammatory properties. However, the effect of curcumin on endothelial senescence is unclear. This study explores the effect of curcumin on hydrogen peroxide (H2O2)-induced endothelial premature senescence and the mechanisms involved. Human umbilical vein endothelial cells (HUVECs) were cultured, and premature senescence was induced with 100 uM H2O2. Results showed that pretreatment with curcumin significantly attenuated the H2O2-induced HUVECs' premature senescence, which was evidenced by a decreased percentage of senescence associated beta-galactosidase positive cells, improved cell division and decreased expression of senescence-associated protein p21 (all p<0.05). Pretreatment with curcumin decreased oxidative stress and apoptosis in H2O2 treated HUVECs. Treatment of HUVECs with H2O2 also down-regulated the phosphorylation of endothelial nitric oxide synthase (eNOS), decreased the level of nitric oxide in the culture medium, and inhibited the protein expression and enzymatic activity of silent information regulator 1 (SIRT1), while pretreatment with curcumin partly reversed these effects (all p<0.05). Treatment with curcumin alone enhanced the enzymatic activity of SIRT1, but didn't affect cellular senescence, cell growth or apoptosis compared to the Control. The inhibition of SIRT1 using SIRT1 short interfering RNA (siRNA) could decrease the expression and phosphorylation of eNOS and abrogate the protective effect of curcumin on H2O2 induced premature senescence. These findings suggest that curcumin could attenuate oxidative stress-induced HUVECs' premature senescence via the activation of SIRT1. PMID- 26235578 TI - Effect of Piperazine Dithioctate on the Oral Pharmacokinetics of Glimepiride in Rats. AB - The objective of the present work was to investigate the potential for pharmacokinetic drug-drug interactions between glimepiride (GMP) and piperazine dithioctate (PDT) in rats to support the development of an orally combined product of the two drugs. An LC-MS/MS bioanalytical method was developed for simultaneous quantification of GMP and thioctic acid (TA) in rat plasma. The accuracy, precision, linearity, selectivity, and recovery were all within an acceptable range. The oral plasma exposure of the GMP solution was more than 14 times greater than that of the GMP suspension at a dose of 0.5 mg/kg, suggesting a dissolution-limited absorption of the GMP suspension. Oral co-administration of PDT (72 mg/kg) with GMP suspension (0.5 mg/kg) reduced the plasma GMP exposure by approximately 80% without a significant change in t1/2 and tmax. Oral co administration of PDT with GMP solution had no significant effect on the plasma pharmacokinetics of GMP. PDT lowered the pH (from ca. 7 to 5.6) and the dissolved GMP concentration in the GMP suspension. It was also shown that GMP was more soluble at pH 7 than at 5.7 in an aqueous solution, and the oral plasma exposure of a GMP suspension at pH 7.0 was substantially higher than that of a suspension at pH 5.7. These results suggest that the pH-dependent solubility of GMP was likely responsible for PDT's effect on the oral absorption of GMP. In conclusion, the current work suggests a possibility of drug-drug interaction between GMP and PDT upon oral co-administration. PMID- 26235579 TI - Increased Milk Protein Concentration in a Rehydration Drink Enhances Fluid Retention Caused by Water Reabsorption in Rats. AB - A fluid-retention effect is required for beverages that are designed to prevent dehydration. That is, fluid absorbed from the intestines should not be excreted quickly; long-term retention is desirable. Here, we focused on the effect of milk protein on fluid retention, and propose a new effective oral rehydration method that can be used daily for preventing dehydration. We first evaluated the effects of different concentrations of milk protein on fluid retention by measuring the urinary volumes of rats fed fluid containing milk protein at concentrations of 1, 5, and 10%. We next compared the fluid-retention effect of milk protein-enriched drink (MPD) with those of distilled water (DW) and a sports drink (SD) by the same method. Third, to investigate the mechanism of fluid retention, we measured plasma insulin changes in rats after ingesting these three drinks. We found that the addition of milk protein at 5 or 10% reduced urinary volume in a dose dependent manner. Ingestion of the MPD containing 4.6% milk protein resulted in lower urinary volumes than DW and SD. MPD also showed a higher water reabsorption rate in the kidneys and higher concentrations of plasma insulin than DW and SD. These results suggest that increasing milk protein concentration in a beverage enhances fluid retention, which may allow the possibility to develop rehydration beverages that are more effective than SDs. In addition, insulin-modifying renal water reabsorption may contribute to the fluid-retention effect of MPD. PMID- 26235580 TI - Effects of a Tricaprylin Emulsion on Anti-glomerular Basement Membrane Glomerulonephritis in Rats: In Vivo and in Silico Studies. AB - Glomerulonephritis (GN) is a set of pathological conditions that result in the destruction of glomeruli and loss of renal function, commonly leading to the development of end-stage renal disease. Current pharmacotherapy is limited to immunosuppressive therapy. In the present study, we found a novel antinephritic effect of a tricaprylin emulsion in the anti-glomerular basement membrane (anti GBM) GN rat model. We evaluated the treatment in vivo by comparing administration of the emulsion with administration of a casein kinase II (CK2) inhibitor in this rat model, and performed a gene ontology-based microarray analysis to reveal in silico the detailed mechanism of action. Our results showed that administration of the tricaprylin emulsion, or even tricaprylin alone, significantly ameliorated the anti-GBM antibody-induced renal dysfunction in these rats. We believe that tricaprylin is the key active antinephritic component of the emulsion and might be a promising drug for the effective treatment of nephritis. Moreover, with respect to microarray analysis, we developed a generally applicable and rapid method to compare gene expression profile data for multiple models of nephritis and clinical samples from a public domain microarray database. PMID- 26235581 TI - Efficient Packaging of Plasmid DNA Using a pH Sensitive Cationic Lipid for Delivery to Hepatocytes. AB - Plasmid DNA (pDNA) is expected to be a new class of medicine for treating currently incurable diseases. To deliver these nucleic acids, we developed a liposomal delivery system we have called a multifunctional envelope-type nano device (MEND). In this report, we demonstrate that a MEND containing a pH sensitive cationic lipid, YSK05 (YSK-MEND), efficiently delivered pDNA via systemic injection, and that its expression was highly dependent on the encapsulation state of the pDNA. In the preparation, the pH, ionic strength, and sodium chloride (NaCl) concentration of the lipid/pDNA mixture strongly affected the encapsulation efficiency of pDNA. Additionally, the transgene expression of luciferase in the liver by the injected YSK-MEND was dependent on the encapsulation state of pDNA rather than the nature of the YSK-MEND. Confocal laser scanning microscopy findings revealed that injection of the YSK-MEND led to homogenous gene expression in the liver compared to injection via the hydrodynamic tail vein (HTV). Concerning the safety of the YSK-MEND, a transient increase in the activity of liver enzymes was observed. However, no significant adverse events were observed. Taken together, the YSK-MEND represents a potentially attractive therapy for the treatment of various hepatic diseases. PMID- 26235582 TI - Risk Factors for Predicting Severe Neutropenia Induced by Pemetrexed Plus Carboplatin Therapy in Patients with Advanced Non-small Cell Lung Cancer. AB - Pemetrexed plus carboplatin therapy is widely administered to patients with non squamous non-small cell lung cancer. Although severe neutropenia is often observed during this combination therapy, its predictive factors are unknown. Therefore, we investigated the predictive factors for severe neutropenia in 77 patients treated with this combination therapy at the Department of Respiratory Medicine, Kyushu University Hospital, between September 2009 and September 2013. All data were retrospectively collected from the electronic medical record system, and univariate and multivariate logistic regression analyses were performed to identify risk factors for grade 3 or 4 neutropenia. Among the 77 patients, 34 (44%) developed grade 3 or 4 neutropenia. Multivariate analysis revealed that lower baseline hemoglobin values (odds ratio [OR], 1.97 per 1 g/dL decrease; 95% confidence interval [CI], 1.39-2.99, p<0.01) and lower baseline neutrophil counts (OR, 1.71 per 1000/mm(3) decrease; 95% CI, 1.14-2.71, p=0.01) were significantly associated with grade 3 or 4 neutropenia. During 4 courses of pemetrexed plus carboplatin therapy, the incidence of grade 3 or 4 neutropenia in patients with baseline hemoglobin values of <11.6 g/dL was significantly higher than that in patients with values of >=11.6 g/dL [84% (16/19) vs. 31% (18/58), p<0.001]. In conclusion, patients with lower baseline neutrophil counts or lower baseline hemoglobin values, especially those with baseline hemoglobin values of <11.6 g/dL, should be monitored more carefully during pemetrexed plus carboplatin therapy. PMID- 26235583 TI - Biological Effects of the Herbal Plant-Derived Phytoestrogen Bavachin in Primary Rat Chondrocytes. AB - The aim of this study was to examine the anabolic and anticatabolic functions of bavachin in primary rat chondrocytes. With bavachin treatment, chondrocytes survived for 21 d without cell proliferation, and the proteoglycan content and extracellular matrix increased. Short-term monolayer culture of chondrocytes showed that gene induction of both aggrecan and collagen type II, major extracellular matrix components, was significantly upregulated by bavachin. The expression and activities of cartilage-degrading enzymes such as matrix metalloproteinases and a disintegrin and metalloproteinase with thrombospondin motifs were inhibited significantly by bavachin, while tissue inhibitors of metalloprotease were significantly upregulated. Bavachin inhibits the expression of inducible nitric oxide synthase, a representative catabolic factor, and downregulated the expression of nitric oxide, cyclooxygenase-2, and prostaglandin E2 in a dose-dependent manner in chondrocytes. Our results suggest that the bavachin has anabolic and potent anticatabolic biological effects on chondrocytes, which may have considerable promise in treating articular cartilage degeneration in the future. PMID- 26235584 TI - The Effects of the Selective Serotonin Reuptake Inhibitor Fluvoxamine on Voltage Dependent K(+) Channels in Rabbit Coronary Arterial Smooth Muscle Cells. AB - We demonstrated the inhibitory effect of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), on voltage-dependent K(+) (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells using a whole-cell patch clamp technique. Fluvoxamine reduced the amplitude of Kv currents in a concentration-dependent manner with an IC50 value of 3.71+/-1.09 uM and a Hill coefficient of 0.62+/-0.14. Although fluvoxamine did not significantly affect the steady-state activation curve, it shifted the steady-state inactivation curve toward a more negative potential. Pretreatment with another SSRI, paroxetine, did not affect the basal Kv current and did not alter the inhibitory effect of fluvoxamine on Kv channels. We concluded that fluvoxamine inhibits the Kv current in a concentration-dependent manner and in a closed (inactivated) state of the Kv channels independent of serotonin reuptake inhibition. PMID- 26235585 TI - Rapid Fluorescent Detection Assay for Human Parainfluenza Viruses. AB - Human parainfluenza virus type 1 (hPIV1) does not form clear plaque by the conventional plaque formation assay because of slightly a cytopathic effects in many cell lines infected with hPIV1, thus making in virus titration, isolation and inhibitor evaluation difficult. We have succeeded in fluorescent histochemical visualization of sialidase activities of influenza A and B viruses, Newcastle disease virus and Sendai virus by using a novel fluorescent sialidase substrate, 2-(benzothiazol-2-yl)-4-bromophenyl 5-acetamido-3,5-dideoxy-alpha-D glycero-D-galacto-2-nonulopyranosidonic acid (BTP3-Neu5Ac). In this study, we applied the BTP3-Neu5Ac assay for rapid detection of hPIV1 and hPIV type 3. The BTP3-Neu5Ac assay could histochemically visualize dot-blotted hPIVs on a membrane and hPIV-infected cells as local fluorescence under UV irradiation. We succeeded in distinct fluorescent visualization of hPIV1-infected cells in only 3 d using the BTP3-Neu5Ac assay. Due to there being no fixation, hPIV1 was isolated directly from fluorescent stained focus cells by the BTP3-Neu5Ac assay. Establishment of a sensitive, easy, and rapid fluorescent focus detection assay for hPIV, hPIV1 in particular will contribute greatly to progress in hPIV studies. PMID- 26235586 TI - Production and Purification of Secretory Simian Cytidine Monophosphate-N acetylneuraminic Acid Hydroxylase Using Baculovirus-Protein Expression System. AB - Cytidine monophosphate (CMP) N-acetylneuraminic acid (Neu5Ac) hydroxylase (CMAH) is an essential enzyme for N-glycolylneuraminic acid (Neu5Gc) synthesis. In humans, Neu5Gc cannot be synthesized because of a deletion in the CMAH gene. Since Neu5Gc research has not been actively performed in comparison with Neu5Ac research, little is known about the function of Neu5Gc. Possible reasons are that CMAH for controlling Neu5Gc synthesis is not understood well at the molecular level, that commercial Neu5Gc is expensive, and that addition of exogenous Neu5Gc to glycoconjugates is not a general method because of the difficulty in obtaining CMAH. One solution to these problems is to achieve large-scale production of CMAH with enzymatic activity. To produce and purify CMAH as simply as possible, we generated simian CMAH as a secretory protein with a histidine tag using a baculovirus protein expression system. After culture of baculovirus-infected cells in serum-free medium, secretory simian CMAH (approximately 180 ug) was highly purified from the supernatant (150 mL) of cell culture. HPLC analysis showed conversion of CMP-Neu5Ac to CMP-Neu5Gc by the secretory CMAH. We succeeded in producing secretory CMAH with enzymatic activity that is easy to purify. In addition, peptide-N-glycosidase F treatment of CMAH indicated that secretory CMAH was a glycoprotein with N-glycan. It will also contribute to research on Neu5Gc function by easy-to-use methods for controlling Neu5Gc synthesis, for exogenous addition of Neu5Gc to glycoconjugates and by application to industrial Neu5Gc synthesis. PMID- 26235587 TI - (Z)-2-(Benzo[d]thiazol-2-ylamino)-5-(substituted benzylidene)thiazol-4(5H)-one Derivatives as Novel Tyrosinase Inhibitors. AB - Inhibiting tyrosinase is an important goal to prevent melanin accumulation in skin and thereby to inhibit pigmentation disorders. Therefore, tyrosinase inhibitors are an attractive target in cosmetics and treatments for pigmentation disorders. However, only a few tyrosinase inhibitors are currently available because of their toxic effects to skin or lack of selectivity and stability. Here, we newly synthesized thirteen (Z)-2-(benzo[d]thiazol-2-ylamino)-5 (substituted benzylidene)thiazol-4(5H)-one derivatives and examined their effect on melanogenesis. Of these compounds, MHY2081 had the strongest inhibitory effect on tyrosinase without cytotoxicity in B16F10 melanoma cells. Consistently, melanogenesis was notably decreased by MHY2081 treatment. As an underlying mechanism, docking simulation showed that compared to kojic acid, a well-known competitive tyrosinase inhibitor which forms a hydrogen bond and aromatic interaction with tyrosinase, MHY2081 has stronger affinity with tyrosinase by forming three hydrogen bonds and a hydrophobic interaction with residues of tyrosinase. In parallel with this, Lineweaver-Burk plot analysis showed that MHY2081 is a strong competitive inhibitor of tyrosinase. In conclusion, MHY2081 may be a novel tyrosinase inhibitor for prevention and treatment of pigmentation disorders. PMID- 26235588 TI - The 5-Lipoxygenase Inhibitor Zileuton Confers Neuroprotection against Glutamate Oxidative Damage by Inhibiting Ferroptosis. AB - 5-Lipoxygenase (5-LOX) inhibitors have been shown to be protective in several neurodegenerative disease models; however, the underlying mechanisms remain unclear. We investigated whether 5-LOX inhibitor zileuton conferred direct neuroprotection against glutamate oxidative toxicity by inhibiting ferroptosis, a newly identified iron-dependent programmed cell death. Treatment of HT22 mouse neuronal cell line with glutamate resulted in significant cell death, which was inhibited by zileuton in a dose-dependent manner. Consistently, zileuton decreased glutamate-induced production of reactive oxygen species but did not restore glutamate-induced depletion of glutathione. Moreover, the pan-caspase inhibitor Z-Val-Ala-Asp(OMe)-fluoromethyl ketone (ZVAD-fmk) neither prevented HT22 cell death induced by glutamate nor affected zileuton protection against glutamate oxidative toxicity, suggesting that zileuton did not confer neuroprotection by inhibiting caspase-dependent apoptosis. Interestingly, glutamate-induced HT22 cell death was significantly inhibited by the ferroptosis inhibitor ferrostatin-1. Moreover, zileuton protected HT22 neuronal cells from erastin-induced ferroptosis. However, we did not observe synergic protective effects of zileuton and ferrostatin-1 on glutamate-induced cell death. These results suggested that both the 5-LOX inhibitor zileuton and the ferropotosis inhibitor ferrostatin-1 acted through the same cascade to protect against glutamate oxidative toxicity. In conclusion, our results suggested that zileuton protected neurons from glutamate-induced oxidative stress at least in part by inhibiting ferroptosis. PMID- 26235589 TI - Efficient Adenovirus Gene Transfer Methods in Human Colonic Caco-2 Epithelial Cells Using Capric Acid. AB - Adenovirus (Ad) vectors are widely used in gene therapy and in vitro/in vivo gene transfer. However, Ad-mediated gene transfer in epithelial cells shows low efficiency, because Ad fiber cannot bind to the primary receptor, the coxsackievirus and adenovirus receptor (CAR), present in tight junctions. Caco-2 monolayer cells cultured on Transwell-chamber plates for approximately 2 weeks are widely used for drug membrane permeation studies, but Ad-mediated gene transfer is difficult in Caco-2 monolayer cells. First, we examined the efficiency of gene transfer into Caco-2 monolayer cells. Luciferase production in cultured Caco-2 cells transduced with Ad vectors was 20-fold lower on day 12 than on day 1. In contrast, the expression of CAR protein in Caco-2 cells gradually increased along with the duration of culture. For efficient gene transfer into Caco-2 monolayer cells, the binding ability of Ad vectors with CAR was found to be important. Capric acid (C10), a medium-chain fatty acid is a tight-junction modulator used as a pharmaceutical agent. We found that a novel gene transfer method using transduction with Ad vectors in the presence of C10 led more efficiently to LacZ expression in Caco-2 monolayer cells than Ad vectors alone. The results of the present study indicate that C10 could be very useful for Ad mediated gene transfer in human colonic Caco-2 epithelial cells. PMID- 26235590 TI - Evaluation of Duloxetine as Micronuclei Inducer in an Acute and a Subchronic Assay in Mouse. AB - Duloxetine is a widely used antidepressant worldwide. In the present report, we evaluated its capacity to induce micronucleated polychromatic erythrocytes (MNPEs) and micronucleated normochromatic erythrocytes (MNNEs) in mice. Two assays were performed, one with a single chemical administration and the other with daily chemical administration. In the first, we administered the antidepressant once to groups of 5 mice by the intragastric (i.g.) route (2, 20, and 200 mg/kg) and performed the analysis at 24, 48, and 72 h postadministration. A control group administered i.g. distilled water was included in the assay, as well as another treated with the micronuclei-inducing chemical daunorubicin (2.5 mg/kg, injected intraperitoneally (i.p.)). In this assay, we found significant damage induced by duloxetine starting from the first time evaluated, showing the highest MNPE increase at the end of the assay. We observed a saturation effect as well, suggested by a decreasing relative efficiency with respect to each tested dose. In a second assay, we administered the antidepressant i.g. every day for 5 weeks (2, 6, and 12 mg/kg), and micronuclei analysis was performed at the end of each week. In this study, we also found a significant increase in both MNPEs and MNNEs which was clear by the second week of administration. Our results suggest that short-term as well as cumulative damage is produced by duloxetine. Thus, confirmation of the observed genotoxic potential in other models seems advisable, as well as caution when prescribing this antidepressant. PMID- 26235591 TI - Validation of an LC-MS/MS Method for the Determination of Propofol, Midazolam, and Carbamazepine in Rat Plasma: Application to Monitor Their Concentrations Following Co-administration. AB - Propofol (PRO) is a hypnotic used to induce and maintain general anesthesia. A risk of drug-drug interactions exists in cases of clinical co-administration of PRO and midazolam (MDZ) or carbamazepine (CBZ). Therefore a sensitive and rapid assay is needed to monitor these drugs. In this study, a sensitive and selective liquid chromatography-tandem mass spectrometry technique was developed for simultaneous determination of PRO, MDZ, and CBZ in plasma. Simultaneous selected reaction monitoring in the positive and negative ionization modes was used for mass detection. Analytes were isolated from plasma samples by a simple, economic, and rapid solid-phase extraction method. Chromatographic separations were achieved using a Chromolith Performance RP-18e analytical column (100*4.6 mm i.d.) with a mixture of acetonitrile-ammonium acetate buffer (10 mM, pH 3.5) (90 : 10, v/v) as the mobile phase. The method was fully validated for PRO, MDZ, and CBZ over concentrations ranging at 1-100, 2-100, and 7-1000 ng/mL, respectively, with acceptable validation parameters. Furthermore, the method was applied to monitor PRO and MDZ or CBZ following co-administration in rats. PMID- 26235592 TI - Magnetism mediated by a majority of [Fe3+ + VO2-] complexes in Fe-doped CeO2 nanoparticles. AB - We examine the role of Fe(3+) and vacancies (V(O)) on the magnetism of Fe-doped CeO2 nanoparticles. Magnetic nanoparticles of Ce(100-x)Fe(x)O2 (x = 0, 0.26, 1.82, 2.64, 5.26, 6.91, and 7.22) were prepared by a co-precipitation method, and their structural, compositional and magnetic properties were investigated. The CeO2 nanoparticles had a mixed valance of Ce(4+) and Ce(3+) ions, and doping introduced Fe(3+) ions. The decrease in Ce(3+) and increase in Fe(3+) concentrations indicated the presence of more [Fe(3+) + V(O)(2-)] complexes with Fe loading in the particles. Charge neutralization, Fe(3+) + V(O)(2-) + 2Ce(4+) < > 2Ce(3+) + Fe(3+), identified the impact of V(O) on the magnetism, where our results suggest that the Fe-doped CeO2 nanoparticle magnetism is mediated by a majority of [Fe(3+) + V(O)(2-)]-Ce(3+) -[Fe(3+) + V(O)(2-)] complexes. PMID- 26235593 TI - Steam-Assisted Synthesis of an Extra-Stable Polyoxometalate-Encapsulating Metal Azolate Framework: Applications in Reagent Purification and Proton Conduction. AB - Different from the conventional synthesis approaches, such as hydrothermal or solvothermal synthesis, a porous metal azolate framework encapsulating Keggin type [SiW12 O40 ](4-) anions was prepared by an environmentally friendly, low cost, and highly efficient steam-assisted conversion method for the first time. The nanosized polyoxometalates as a template were encapsulated by a zeotype 6(4) 4(8) cage constructed by 28 nuclear zinc atoms connected through 32 Trz ligands. The obtained composite exhibits excellent thermal and chemical stability; meanwhile, its special ability to selectively absorb water from alcohols makes it efficiently separate water from analytically pure ethanol, with the result that water content decreases from 0.23 to 0.05 wt %, which is superior to the standard of chromatographic grade ethanol (<0.1 wt %). Besides, alternating current (ac) impedance experiments also reveal that the hybrid is a kind of proton conductive material. PMID- 26235594 TI - An update on molecular biology and drug resistance mechanisms of multiple myeloma. AB - Multiple myeloma (MM), a neoplasm of plasma cells, is the second most common hematological malignancy. Incidance rates increase after age 40. MM is most commonly seen in men and African-American population. There are several factors to this, such as obesity, environmental factors, family history, genetic factors and monoclonal gammopathies of undetermined significance (MGUS) that have been implicated as potentially etiologic. Development of MM involves a series of complex molecular events, including chromosomal abnormalities, oncogene activation and growth factor dysregulation. Chemotherapy is the most commonly used treatment strategy in MM. However, MM is a difficult disease to treat because of its marked resistance to chemotherapy. MM has been shown to be commonly multidrug resistance (MDR)-negative at diagnosis and associated with a high incidence of MDR expression at relapse. This review deals with the molecular aspects of MM, drug resistance mechanisms during treatment and also possible new applications for overcoming drug resistance. PMID- 26235595 TI - Combination effects of nano-TiO2 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on biotransformation gene expression in the liver of European sea bass Dicentrarchus labrax. AB - The aim of present study was to investigate the influence of titanium dioxide nanoparticles (nano-TiO2, Aeroxide(r) P25) on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) dependent biotransformation gene expression in liver of juvenile European sea bass Dicentrarchus labrax. An in vivo 7day waterborne exposure was performed with nano-TiO2 (1mg/L) and 2,3,7,8-TCDD (46pg/L), singly and in combination. The mRNA expression of aryl hydrocarbon receptor repressor (Ahrr), estrogen receptor (erbeta2), ABC transport proteins as Abcb1, Abcc1-c2-g2, cytochrome P450 (cyp1a), glutathione-s-transferase (gsta), glutathione reductase (gr) and engulfment and motility (ELMO) domain-containing protein 2 (elmod2) was investigated. Ahrr, erbeta2, abcc1 and abcg2 resulted down-regulated with respect to controls in all experimental groups. Co-exposure to nano-TiO2 and 2,3,7,8-TCDD caused a further significant down regulation of ahrr, erbeta2, Abcb1 and Abcc2 compared to single chemical exposure (nano-TiO2 or 2,3,7,8-TCDD alone). No effects were observed for 2,3,7,8-TCDD and nano-TiO2 alone in abcb1 gene, while abcc2 was down-regulated by nano-TiO2 alone. Cyp1a, gst and elmod2 genes were up-regulated by 2,3,7,8-TCDD and to a similar extent after co-exposure. Overall the results indicate that nano TiO2 is unlikely to interfere with 2,3,7,8-TCDD-dependent biotransformation gene expression in the liver of European sea bass, although the effects of co-exposure observed in ABC transport mRNAs might suggest an impact on xenobiotic metabolite disposition and transport in European sea bass liver. PMID- 26235596 TI - A Computational Model of Linguistic Humor in Puns. AB - Humor plays an essential role in human interactions. Precisely what makes something funny, however, remains elusive. While research on natural language understanding has made significant advancements in recent years, there has been little direct integration of humor research with computational models of language understanding. In this paper, we propose two information-theoretic measures ambiguity and distinctiveness-derived from a simple model of sentence processing. We test these measures on a set of puns and regular sentences and show that they correlate significantly with human judgments of funniness. Moreover, within a set of puns, the distinctiveness measure distinguishes exceptionally funny puns from mediocre ones. Our work is the first, to our knowledge, to integrate a computational model of general language understanding and humor theory to quantitatively predict humor at a fine-grained level. We present it as an example of a framework for applying models of language processing to understand higher level linguistic and cognitive phenomena. PMID- 26235597 TI - Adult Patients' Experiences of Nursing Care Dependence. AB - PURPOSE: Care dependence can be associated with suffering and humiliation. Nurses' awareness of patients' perception of care dependence is crucial to enable them in helping the dependent persons. This study aimed to describe adult patients' experience of nursing care dependence. METHOD: A metasynthesis was conducted to integrate qualitative findings from 18 studies published through December 2014 on adult patients' experiences of care dependency. Procedures included the Johanna Briggs Institute approach for data extraction, quality appraisal, and integration of findings. FINDINGS: The experience of dependence revealed the concept of the embodied person, particularly in relation to care of the physical body. The relationship between the individual and nurses within the context of care had a major impact for dependent patients. When the care relation was perceived as positive, the experience led to the development of the person in finding new balances in life, but when it was perceived as negative, it increased patient' suffering. CONCLUSIONS: Care dependence is manifested mostly as bodily dependence and is consistent with its relational nature. The nurse-patient relationship is important to the dependent patients' experience. CLINICAL RELEVANCE: A greater understanding of patients' experiences of dependence is crucial to enable nurses in improving care and decreasing patient suffering. PMID- 26235598 TI - Goats challenged with different members of the Mycobacterium tuberculosis complex display different clinical pictures. AB - Tuberculosis (TB) in goats (Capra hircus) is due to infection with members of the Mycobacterium tuberculosis complex (MTC), mainly Mycobacterium bovis and Mycobacterium caprae. We report a comparative experimental infection of goats with M. bovis, M. caprae and M. tuberculosis strains. We hypothesized that goats experimentally infected with different members of the MTC would display different clinical pictures. Three groups of goats were challenged with either M. bovis SB0134 (group 1, n=5), M. caprae SB0157 (group 2, n=5) and M. tuberculosis SIT58 (group 3, n=4). The highest mean total lesion score was observed in M. bovis challenged goats (mean 15.2, range 9-19), followed by those challenged with M. caprae (10.8, 2-23). The lowest score was recorded in goats challenged with M. tuberculosis (3, 1-6). Culture results coincided with the lesion scores in yielding more positive pools (7/15) in M. bovis challenged goats. By contrast, only three pools were positive from goats challenged M. tuberculosis (3/12) and with M. caprae (3/15), respectively. Differences in the performance of the intradermal and gamma-interferon (IFN-gamma) tests depending of the group were observed since all goats from group 1 were diagnosed using intradermal test and these goats reacted earlier to the IFN-gamma assay in comparison to the other groups. This study confirmed that goats experimentally infected with different members of the MTC display different clinical pictures and this fact may have implications for MTC maintenance and bacterial shedding. PMID- 26235599 TI - Increasing body condition score is positively associated interleukin-6 and monocyte chemoattractant protein-1 in Labrador retrievers. AB - The accumulation of excess body fat is a growing problem in dogs as well as people. Contrary to prior understanding of adipose tissue, fat is now considered to be an active endocrine organ that promotes a chronic low-grade inflammatory state often characterized by an increase in pro-inflammatory cytokines and chemokines. These have been implicated in several obesity-related disorders such as insulin resistance, cardiovascular disease, and neoplasia. The purpose of this study was to characterize fasting plasma cytokine concentrations in ninety-two healthy client-owned Labrador retriever dogs of various ages and body condition scores. The dogs were grouped according to body condition score (BCS) into three categories, lean, overweight and obese. The following cytokines and chemokines were evaluated; tumor necrosis factor-alpha, interleukin-2, interleukin-6, interleukin-8, and monocyte chemotactic protein-1 (TNF-alpha, IL-2, IL-6, IL-8, MCP-1). Our results indicated that fasting plasma IL-6 and MCP-1 concentrations are associated with increasing BCS. This data suggest that certain markers of inflammation increase with increasing body condition score, and that dogs, similar to humans, may be fostering a chronic inflammatory state due to obesity. PMID- 26235600 TI - Three promoters with different tissue specificity and pathogen inducibility express the toll-like-receptor 2 (TLR2)-encoding gene in cattle. AB - Toll-like-receptor 2 (TLR2) is a dominant receptor for perceiving presence of bacterial pathogens. The promoter controlling its tissue specific and infection induced expression in cattle was unknown. We structurally defined with 5'-RACE experiments three promoters (P1-3) controlling TLR2 expression in udder, liver and other tissues of cows suffering from E. coli mastitis. P1 is 5'-adjacent to exon 1 as defined by the prototypical TLR2 cDNA sequence. Exon 1 is spliced to the protein-encoding exon 2. P2 and P3 reside in intron 1, express exon 1A and exon 1B, respectively which are each spliced to exon 2. Infection induced massively (>30-fold) activity of P1 and P2, but not of P3 in udders and also somewhat in liver. However, the GC-rich housekeeping promoter P3 expressed exon1B in many tissues providing the wealth of TLR2-encoding transcripts. Similar induction data were obtained after challenging primary cultures of mammary epithelial cells (pbMEC) with E. coli. Reporter gene analyses in pbMEC and the liver cell line HepG2 collectively validated that P1 and constructs containing segments from P2/P3 are in principle capable to drive gene expression. Our structural data provide the basis for more detailed molecular analyses of the infection and tissue specific regulation of TLR2 expression. PMID- 26235601 TI - Synthesis and EPR/UV/Vis-NIR spectroelectrochemical investigation of a persistent phosphanyl radical dication. AB - The reaction of the bis(imidazoliumyl)-substituted P(I) cation [(2-Im(Dipp) )P(4 Im(Dipp) )](+) (10(+) ) (2-Im=imidazolium-2-yl; 4-Im=imidazolium-4-yl; Dipp=2,6 di-isopropylphenyl) with trifluoromethanesulfonic acid (HOTf) or methyl trifluoromethylsulfonate (MeOTf) yields the corresponding protonated [(2-Im(Dipp) )PH(4-Im(Dipp) )](2+) (11(2+) ) and methylated [(2-Im(Dipp) )PMe(4-Im(Dipp) )](2+) (12(2+) ) dications, respectively. EPR/UV/Vis-NIR spectroelectrochemical investigation of the low-coordinated P(I) cation 10(+) predicted a stable and "bottleable" P-centered radical dication [(2-Im(Dipp) )P(4-Im(Dipp) )](2+.) (13(2+.) ). The reaction of 10(+) with the nitrosyl salt NO[OTf] yields the persistent phosphanyl radical dication 13(2+.) as triflate salt in crystalline form. Quantum chemical investigation revealed an exceptional high spin density at the P atom. PMID- 26235602 TI - A facile phosphine-free colloidal synthesis of Cu2SnS3 and Cu2ZnSnS4 nanorods with a controllable aspect ratio. AB - Cu2SnS3 (CTS) nanorods were synthesized with a controllable aspect ratio via a facile phosphine-free colloidal synthesis. This synthesis can be readily extended to obtain Cu2ZnSnS4 (CZTS) nanorods with tunable Zn content. PMID- 26235603 TI - Assessment of discomfort in patients with cognitive failure in palliative care. AB - OBJECTIVE: When cognitive impairment precludes patients' report of symptoms, it becomes necessary to use other means. The purpose of our study was to evaluate the validity of the method currently in use on our service. METHOD: Two members of the team simultaneously assessed the patient and independently recorded whether the patient showed signs of discomfort, and a third questioned patients with cognitive failure who maintained some ability to respond if something was bothering them. RESULTS: Some 200 assessments were made of 116 patients. The kappa coefficient of agreement was 0.615. The sensitivity was 17% and specificity 99%. The positive predictive value was 88%, and the negative predictive value was 73%. SIGNIFICANCE OF RESULTS: Due to the low sensitivity of this method, it cannot be recommended as a screening tool. PMID- 26235604 TI - Similar Outcomes of Standard Radiotherapy and Hypofractionated Radiotherapy Following Breast-Conserving Surgery. AB - BACKGROUND: Adjuvant radiation therapy is commonly administered to breast cancer patients who received breast-conserving surgery. However, lengthy treatment times of standard radiotherapy pose certain challenges. Here, we performed a prospective controlled study comparing standard radiation to hypofractionated radiotherapy in terms of efficacy and outcome. MATERIAL AND METHODS: Eighty breast cancer patients (tumor stage pT1-2N0-1M0) who had undergone breast conservation surgery were randomly divided into 2 groups (40 patients/group). The experimental group received 43.2 Gy to the whole breast in 18 fractions for 24 days with a concomitant boost (50.4 Gy) to the tumor bed. The control group received 45 Gy to the whole breast in 25 fractions for 44 days with a boost to the tumor bed of 59 Gy. Survival, locoregional recurrence, adverse effects, and aesthetic results were all considered for analysis. RESULTS: The following criteria were included as part of study follow-up: local control, survival, adverse skin reactions, cosmetic outcome, and hematological toxicity. At a median follow-up of 27 months (follow-up rate 100%), there were no statistical differences in any of the categories between the 2 groups. The 2-year survival rate of both groups was 100% without any locoregional recurrence. Although there was some skin toxicity, these instances were not severe and they cleared on their own within 6 weeks. The most common problems encountered by patients were breast fibrosis and altered pigmentation. CONCLUSIONS: A shortened whole-breast hypofractionated irradiation schedule with a concomitant boost is as effective as standard radiation and may be a reasonable alternative following breast conservation surgery. PMID- 26235605 TI - Stagnating crop yields: An overlooked risk for the carbon balance of agricultural soils? AB - The carbon (C) balance of agricultural soils may be largely affected by climate change. Increasing temperatures are discussed to cause a loss of soil organic carbon (SOC) due to enhanced decomposition of soil organic matter, which has a high intrinsic temperature sensitivity. On the other hand, several modeling studies assumed that potential SOC losses would be compensated or even outperformed by an increased C input by crop residues into agricultural soils. This assumption was based on a predicted general increase of net primary productivity (NPP) as a result of the CO2 fertilization effect and prolonged growing seasons. However, it is questionable if the crop C input into agricultural soils can be derived from NPP predictions of vegetation models. The C input in European croplands is largely controlled by the agricultural management and was strongly related to the development of crop yields in the last decades. Thus, a glance at past yield development will probably be more instructive for future estimations of the C input than previous modeling approaches based on NPP predictions. An analysis of European yield statistics indicated that yields of wheat, barley and maize are stagnating in Central and Northern Europe since the 1990s. The stagnation of crop yields can probably be related to a fundamental change of the agricultural management and to climate change effects. It is assumed that the soil C input is concurrently stagnating which would necessarily lead to a decrease of agricultural SOC stocks in the long term given a constant temperature increase. Remarkably, for almost all European countries that are faced with yield stagnation indications for agricultural SOC decreases were already found. Potentially adverse effects of yield stagnation on the C balance of croplands call for an interdisciplinary investigation of its causes and a comprehensive monitoring of SOC stocks in agricultural soils of Europe. PMID- 26235606 TI - Appropriate outcome measurement for children with autism spectrum disorder. PMID- 26235607 TI - Impaired Hematopoiesis and Disrupted Monocyte/Macrophage Homeostasis in Mucopolysaccharidosis Type I Mice. AB - Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disease caused by alpha-L-iduronidase deficiency in which heparan and dermatan sulfate degradation is compromised. Besides primary lysosomal glycosaminoglycan accumulation, further changes in cellular functions have also been described in several murine MPS models. Herein, we evaluated alterations in hematopoiesis and its implications on the production of mature progeny in a MPS I murine model. Despite the significant increase in hematopoietic stem cells, a reduction in common myeloid progenitors and granulocyte-macrophage progenitor cells was observed in Idua -/- mice bone marrow. Furthermore, no alterations in number, viability nor activation of cell death mechanisms were observed in Idua -/- mice mature macrophages but they presented higher sensitivity to apoptotic induction after staurosporine treatment. In addition, changes in Ca(2+) signaling and a reduction in phagocytosis ability were also found. In summary, our results revealed significant intracellular changes in mature Idua -/- macrophages related to alterations in Idua -/- mice hematopoiesis, revealing a disruption in cell homeostasis. These results provide new insights into physiopathology of MPS I. PMID- 26235608 TI - Derivation of coarse-grained simulation models of chlorophyll molecules in lipid bilayers for applications in light harvesting systems. AB - The correct interplay of interactions between protein, pigment and lipid molecules is highly relevant for our understanding of the association behavior of the light harvesting complex (LHCII) of green plants. To cover the relevant time and length scales in this multicomponent system, a multi-scale simulation ansatz is employed that subsequently uses a classical all atomistic (AA) model to derive a suitable coarse grained (CG) model which can be backmapped into the AA resolution, aiming for a seamless conversion between two scales. Such an approach requires a faithful description of not only the protein and lipid components, but also the interaction functions for the indispensable pigment molecules, chlorophyll b and chlorophyll a (referred to as chl b/chl a). In this paper we develop a CG model for chl b and chl a in a dipalmitoylphosphatidyl choline (DPPC) bilayer system. The structural properties and the distribution behavior of chl within the lipid bilayer in the CG simulations are consistent with those of AA reference simulations. The non-bonded potentials are parameterized such that they fit to the thermodynamics based MARTINI force-field for the lipid bilayer and the protein. The CG simulation shows chl aggregation in the lipid bilayer which is supported by fluorescence quenching experiments. It is shown that the derived chl model is well suited for CG simulations of stable, structurally consistent, trimeric LHCII and can in the future be used to study their large scale aggregation behavior. PMID- 26235609 TI - Cueing vocabulary during sleep increases theta activity during later recognition testing. AB - Neural oscillations in the theta band have repeatedly been implicated in successful memory encoding and retrieval. Several recent studies have shown that memory retrieval can be facilitated by reactivating memories during their consolidation during sleep. However, it is still unknown whether reactivation during sleep also enhances subsequent retrieval-related neural oscillations. We have recently demonstrated that foreign vocabulary cues presented during sleep improve later recall of the associated translations. Here, we examined the effect of cueing foreign vocabulary during sleep on oscillatory activity during subsequent recognition testing after sleep. We show that those words that were replayed during sleep after learning (cued words) elicited stronger centroparietal theta activity during recognition as compared to noncued words. The reactivation-induced increase in theta oscillations during later recognition testing might reflect a strengthening of individual memory traces and the integration of the newly learned words into the mental lexicon by cueing during sleep. PMID- 26235610 TI - Selective synthesis of TiO2 single nanocrystals and titanate nanotubes: a controllable atomic arrangement approach via NH4TiOF3 mesocrystals. AB - Nanostructured titania and titanate have been considered as very important materials used in photocatalysis, photovoltaics, gas sensing and other electronic industries. In principle, their common structural feature is that the precursor phase involving TiO6 octahedra or similar building units may be converted to any of the nanostructured titania and titanate forms in a controllable way. Based on the atomic arrangement of ionic liquid-mediated NH4TiOF3 mesocrystals, TiO2 nanocrystals and titanate nanotubes were selectively obtained in H3BO3 and NaOH media, respectively, by using a simple hydrothermal method. Interestingly, the titanate nanotubes were successfully formed by extraction of NH4(+) and F from NH4TiOF3 in a milder alkaline environment as low as 1 M NaOH, rather than conventional treatment of TiO2 in 10 M NaOH. The as-prepared TiO2 nanocrystals with exposed {001} facets exhibit a high photocatalytic activity and sedimentation rate as compared to commercial TiO2. Upon further doping or ion exchange, the newly prepared TiO2 nanocrystals will show potential applications in the environment. PMID- 26235611 TI - Redox regulation of the antimycin A sensitive pathway of cyclic electron flow around photosystem I in higher plant thylakoids. AB - The chloroplast must regulate supply of reducing equivalents and ATP to meet rapid changes in downstream metabolic demands. Cyclic electron flow around photosystem I (CEF) is proposed to balance the ATP/NADPH budget by using reducing equivalents to drive plastoquinone reduction, leading to the generation of proton motive force and subsequent ATP synthesis. While high rates of CEF have been observed in vivo, isolated thylakoids show only very slow rates, suggesting that the activity of a key complex is lost or down-regulated upon isolation. We show that isolation of thylakoids while in the continuous presence of reduced thiol reductant dithiothreitol (DTT), but not oxidized DTT, maintains high CEF activity through an antimycin A sensitive ferredoxin:quinone reductase (FQR). Maintaining low concentrations (~2 mM) of reduced DTT while modulating the concentration of oxidized DTT leads to reversible activation/inactivation of CEF with an apparent midpoint potential of -306 mV (+/-10 mV) and n=2, consistent with redox modulation of a thiol/disulfide couple and thioredoxin-mediated regulation of the plastoquinone reductase involved in the antimycin A-sensitive pathway, possibly at the level of the PGRL1 protein. Based on proposed differences in regulatory modes, we propose that the FQR and NADPH:plastoquinone oxidoreductase (NDH) pathways for CEF are activated under different conditions and fulfill different roles in chloroplast energy balance. PMID- 26235612 TI - Smoking among Aboriginal adults in Sydney, Australia. AB - Issue addressed Tobacco consumption contributes to health disparities among Aboriginal Australians who experience a greater burden of smoking-related death and diseases. This paper reports findings from a baseline survey on factors associated with smoking, cessation behaviours and attitudes towards smoke-free homes among the Aboriginal population in inner and south-western Sydney. Methods A baseline survey was conducted in inner and south-western Sydney from October 2010 to July 2011. The survey applied both interviewer-administered and self administered data collection methods. Multiple logistic regression was performed to determine the factors associated with smoking. Results Six hundred and sixty three participants completed the survey. The majority were female (67.5%), below the age of 50 (66.6%) and more than half were employed (54.7%). Almost half were current smokers (48.4%) with the majority intending to quit in the next 6 months (79.0%) and living in a smoke-free home (70.4%). Those aged 30-39 years (AOR 3.28; 95% CI: 2.06-5.23) and the unemployed (AOR 1.67; 95% CI: 1.11-2.51) had higher odds for current smoking. Participants who had a more positive attitude towards smoke-free homes were less likely to smoke (AOR 0.79; 95% CI: 0.74-.85). Conclusions A high proportion of participants were current smokers among whom intention to quit was high. Age, work status and attitudes towards smoke-free home were factors associated with smoking. So what? The findings address the scarcity of local evidence crucial for promoting cessation among Aboriginal tobacco smokers. Targeted promotions for socio-demographic subgroups and of attitudes towards smoke-free homes could be meaningful strategies for future smoking-cessation initiatives. PMID- 26235613 TI - Onset and durability of pain relief in knee osteoarthritis: pooled results from two placebo trials of naproxen/esomeprazole combination and celecoxib. AB - OBJECTIVE: To further characterize time-to-first pain relief, effect size, correlations between various outcome measures and durability of relief for single tablet naproxen 500 mg/esomeprazole 20 mg (NAP/ESO) given twice daily and celecoxib (CEL) (200 mg) given once daily versus placebo in knee osteoarthritis (OA). METHODS: Unpublished data from two double-blind, double-dummy, placebo controlled trials in which patients aged >=50 years with knee OA were randomized to NAP/ESO (n = 487), CEL (n = 486) or placebo (n = 246) were pooled (NCT00664560 and NCT00665431). Acute response endpoints: 1) Time to first significant pain response, 2) Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain subscale and 3) American Pain Society Patient Outcome Questionnaire (APS-POQ) scores. Sustainability endpoints: 1) Routine Assessment of Patient Index Data (RAPID3) and 2) WOMAC Stiffness, Pain and Total scores; and Patient Global Assessment (PGA) at 6 and 12 weeks. Effect sizes for all measures were calculated. Rescue pain medication use also was analyzed, as was the correlation of WOMAC to RAPID3. RESULTS: NAP/ESO produced statistically significant decreases in WOMAC Pain on Days 2-7 and at Weeks 6 and 12 (all p < 0.05); most APS-POQ pain assessments with NAP/ESO were significantly improved on Days 2-7 compared with placebo (all p < 0.05). A good or excellent response occurred in a median of 6 days. RAPID3 and WOMAC total/stiffness/function/PGA scores decreased significantly at Weeks 6 and 12 (all p < 0.05). Placebo-adjusted WOMAC pain effect sizes were 0.44, 0.34 and 0.25 at Day 7, week 6 and week 12, respectively. RAPID3 to WOMAC total and WOMAC pain to RAPID3: Pain scores were highly correlated at 6 and 12 weeks (correlation coefficients >0.80). No significant differences in overall responses were found between CEL and NAP/ESO. CONCLUSION: Naproxen/esomeprazole produced a significant absolute moderate early pain response, which was maintained for 12 weeks. RAPID3 was found to be highly correlated with the typical OA measure (WOMAC) and might be a useful clinical tool for measuring NSAID response. NCT00664560: https://clinicaltrials.gov/ct2/show/NCT00664560, NCT00665431: https://www.clinicaltrials.gov/ct2/show/NCT00665431. PMID- 26235614 TI - The Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer Associated Fibroblasts. AB - Several questions about the role of the oxygen sensor prolyl-hydroxylase 2 (PHD2) in cancer have not been addressed. First, the role of PHD2 in metastasis has not been studied in a spontaneous tumor model. Here, we show that global PHD2 haplodeficiency reduced metastasis without affecting tumor growth. Second, it is unknown whether PHD2 regulates cancer by affecting cancer-associated fibroblasts (CAFs). We show that PHD2 haplodeficiency reduced metastasis via two mechanisms: (1) by decreasing CAF activation, matrix production, and contraction by CAFs, an effect that surprisingly relied on PHD2 deletion in cancer cells, but not in CAFs; and (2) by improving tumor vessel normalization. Third, the effect of concomitant PHD2 inhibition in malignant and stromal cells (mimicking PHD2 inhibitor treatment) is unknown. We show that global PHD2 haplodeficiency, induced not only before but also after tumor onset, impaired metastasis. These findings warrant investigation of PHD2's therapeutic potential. PMID- 26235615 TI - Impaired Reelin-Dab1 Signaling Contributes to Neuronal Migration Deficits of Tuberous Sclerosis Complex. AB - Tuberous sclerosis complex (TSC) is associated with neurodevelopmental abnormalities, including defects in neuronal migration. However, the alterations in cell signaling mechanisms critical for migration and final positioning of neurons in TSC remain unclear. Our detailed cellular analyses reveal that reduced Tsc2 in newborn neurons causes abnormalities in leading processes of migrating neurons, accompanied by significantly delayed migration. Importantly, we demonstrate that Reelin-Dab1 signaling is aberrantly regulated in TSC mouse models and in cortical tubers from TSC patients owing to enhanced expression of the E3 ubiquitin ligase Cul5, a known mediator of pDab1 ubiquitination. Likewise, mTORC1 activation by Rheb overexpression generates similar neuronal and Reelin Dab1 signaling defects, and directly upregulates Cul5 expression. Inhibition of mTORC1 by rapamycin treatment or by reducing Cul5 largely restores normal leading processes and positioning of migrating neurons. Thus, disrupted Reelin-Dab1 signaling is critically involved in the neuronal migration defects of TSC. PMID- 26235616 TI - c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells. AB - The ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific "client" proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Hsp90 remain unknown. Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity, enhances Hsp90 interaction with kinase clients, and compromises the chaperoning of non-kinase clients such as glucocorticoid receptor and CFTR. Suggesting a regulatory paradigm, we also find that Y223 phosphorylation leads to ubiquitination and degradation of hAha1 in the proteasome. Finally, pharmacologic inhibition of c-Abl prevents hAha1 interaction with Hsp90, thereby hypersensitizing cancer cells to Hsp90 inhibitors both in vitro and ex vivo. PMID- 26235617 TI - Depression of Serotonin Synaptic Transmission by the Dopamine Precursor L-DOPA. AB - Imbalance between the dopamine and serotonin (5-HT) neurotransmitter systems has been implicated in the comorbidity of Parkinson's disease (PD) and psychiatric disorders. L-DOPA, the leading treatment of PD, facilitates the production and release of dopamine. This study assessed the action of L-DOPA on monoamine synaptic transmission in mouse brain slices. Application of L-DOPA augmented the D2-receptor-mediated inhibitory postsynaptic current (IPSC) in dopamine neurons of the substantia nigra. This augmentation was largely due to dopamine release from 5-HT terminals. Selective optogenetic stimulation of 5-HT terminals evoked dopamine release, producing D2-receptor-mediated IPSCs following treatment with L DOPA. In the dorsal raphe, L-DOPA produced a long-lasting depression of the 5 HT1A-receptor-mediated IPSC in 5-HT neurons. When D2 receptors were expressed in the dorsal raphe, application of L-DOPA resulted in a D2-receptor-mediated IPSC. Thus, treatment with L-DOPA caused ectopic dopamine release from 5-HT terminals and a loss of 5-HT-mediated synaptic transmission. PMID- 26235618 TI - Dissection of Axial-Pore Loop Function during Unfolding and Translocation by a AAA+ Proteolytic Machine. AB - In the axial channels of ClpX and related hexameric AAA+ protein-remodeling rings, the pore-1 loops are thought to play important roles in engaging, mechanically unfolding, and translocating protein substrates. How these loops perform these functions and whether they also prevent substrate dissociation to ensure processive degradation by AAA+ proteases are open questions. Using ClpX pore-1-loop variants, single-molecule force spectroscopy, and ensemble assays, we find that the six pore-1 loops function synchronously to grip and unfold protein substrates during a power stroke but are not important in preventing substrate slipping between power strokes. The importance of grip strength is task dependent. ClpX variants with multiple mutant pore-1 loops translocate substrates as well as the wild-type enzyme against a resisting force but show unfolding defects and a higher frequency of substrate release. These problems are magnified for more mechanically stable target proteins, supporting a threshold model of substrate gripping. PMID- 26235619 TI - Functional Redundancy of ERK1 and ERK2 MAP Kinases during Development. AB - ERK1 and ERK2 are the effector kinases of the ERK1/2 MAP-kinase signaling pathway, which plays a central role in transducing signals controlling cell proliferation, differentiation, and survival. Deregulated activity of the ERK1/2 pathway is linked to a group of developmental syndromes and contributes to the pathogenesis of various human diseases. One fundamental question that remains unaddressed is whether ERK1 and ERK2 have evolved unique physiological functions or whether they are used redundantly to reach a threshold of global ERK activity. Here, we show that the extent of development of the mouse placenta and embryo bearing different combinations of Erk1 and Erk2 alleles is strictly correlated with total ERK1/2 activity. We further demonstrate that transgenic expression of ERK1 fully rescues the embryonic and placental developmental defects associated with the loss of ERK2. We conclude that ERK1 and ERK2 exert redundant functions in mouse development. PMID- 26235620 TI - A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation. AB - The mechanistic target of rapamycin complex 2 (mTORC2) regulates cell survival and cytoskeletal organization by phosphorylating its AGC kinase substrates; however, little is known about the regulation of mTORC2 itself. It was previously reported that Akt phosphorylates the mTORC2 subunit SIN1 at T86, activating mTORC2 through a positive feedback loop, though another study reported that S6K phosphorylates SIN1 at the same site, inhibiting mTORC2 activity. We performed extensive analysis of SIN1 phosphorylation upon inhibition of Akt, S6K, and mTOR under diverse cellular contexts, and we found that, in all cell lines and conditions studied, Akt is the major kinase responsible for SIN1 phosphorylation. These findings refine the activation mechanism of the Akt-mTORC2 signaling branch as follows: PDK1 phosphorylates Akt at T308, increasing Akt kinase activity. Akt phosphorylates SIN1 at T86, enhancing mTORC2 kinase activity, which leads to phosphorylation of Akt S473 by mTORC2, thereby catalyzing full activation of Akt. PMID- 26235621 TI - Noncanonical Genomic Imprinting Effects in Offspring. AB - Here, we describe an RNA-sequencing (RNA-seq)-based approach that accurately detects even modest maternal or paternal allele expression biases at the tissue level, which we call noncanonical genomic imprinting effects. We profile imprinting in the arcuate nucleus (ARN) and dorsal raphe nucleus of the female mouse brain as well as skeletal muscle (mesodermal) and liver (endodermal). Our study uncovers hundreds of noncanonical autosomal and X-linked imprinting effects. Noncanonical imprinting is highly tissue-specific and enriched in the ARN, but rare in the liver. These effects are reproducible across different genetic backgrounds and associated with allele-specific chromatin. Using in situ hybridization for nascent RNAs, we discover that autosomal noncanonical imprinted genes with a tissue-level allele bias exhibit allele-specific expression effects in subpopulations of neurons in the brain in vivo. We define noncanonical imprinted genes that regulate monoamine signaling and determine that these effects influence the impact of inherited mutations on offspring behavior. PMID- 26235622 TI - Serine 62-Phosphorylated MYC Associates with Nuclear Lamins and Its Regulation by CIP2A Is Essential for Regenerative Proliferation. AB - An understanding of the mechanisms determining MYC's transcriptional and proliferation-promoting activities in vivo could facilitate approaches for MYC targeting. However, post-translational mechanisms that control MYC function in vivo are poorly understood. Here, we demonstrate that MYC phosphorylation at serine 62 enhances MYC accumulation on Lamin A/C-associated nuclear structures and that the protein phosphatase 2A (PP2A) inhibitor protein CIP2A is required for this process. CIP2A is also critical for serum-induced MYC phosphorylation and for MYC-elicited proliferation induction in vitro. Complementary transgenic approaches and an intestinal regeneration model further demonstrated the in vivo importance of CIP2A and serine 62 phosphorylation for MYC activity upon DNA damage. However, targeting of CIP2A did not influence the normal function of intestinal crypt cells. These data underline the importance of nuclear organization in the regulation of MYC phosphorylation, leading to an in vivo demonstration of a strategy for inhibiting MYC activity without detrimental physiological effects. PMID- 26235623 TI - Obesity Drives Th17 Cell Differentiation by Inducing the Lipid Metabolic Kinase, ACC1. AB - Chronic inflammation due to obesity contributes to the development of metabolic diseases, autoimmune diseases, and cancer. Reciprocal interactions between metabolic systems and immune cells have pivotal roles in the pathogenesis of obesity-associated diseases, although the mechanisms regulating obesity associated inflammatory diseases are still unclear. In the present study, we performed transcriptional profiling of memory phenotype CD4 T cells in high-fat fed mice and identified acetyl-CoA carboxylase 1 (ACC1, the gene product of Acaca) as an essential regulator of Th17 cell differentiation in vitro and of the pathogenicity of Th17 cells in vivo. ACC1 modulates the DNA binding of RORgammat to target genes in differentiating Th17 cells. In addition, we found a strong correlation between IL-17A-producing CD45RO(+)CD4 T cells and the expression of ACACA in obese subjects. Thus, ACC1 confers the appropriate function of RORgammat through fatty acid synthesis and regulates the obesity-related pathology of Th17 cells. PMID- 26235624 TI - In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector. AB - Adeno-associated virus (AAV) vectors have emerged as a gene-delivery platform with demonstrated safety and efficacy in a handful of clinical trials for monogenic disorders. However, limitations of the current generation vectors often prevent broader application of AAV gene therapy. Efforts to engineer AAV vectors have been hampered by a limited understanding of the structure-function relationship of the complex multimeric icosahedral architecture of the particle. To develop additional reagents pertinent to further our insight into AAVs, we inferred evolutionary intermediates of the viral capsid using ancestral sequence reconstruction. In-silico-derived sequences were synthesized de novo and characterized for biological properties relevant to clinical applications. This effort led to the generation of nine functional putative ancestral AAVs and the identification of Anc80, the predicted ancestor of the widely studied AAV serotypes 1, 2, 8, and 9, as a highly potent in vivo gene therapy vector for targeting liver, muscle, and retina. PMID- 26235625 TI - Visual Deprivation Causes Refinement of Intracortical Circuits in the Auditory Cortex. AB - Loss of a sensory modality can lead to functional enhancement of the remaining senses. For example, short-term visual deprivations, or dark exposure (DE), can enhance neuronal responses in the auditory cortex to sounds. These enhancements encompass increased spiking rates and frequency selectivity as well as increased spiking reliability. Although we previously demonstrated enhanced thalamocortical transmission after DE, increased synaptic strength cannot account for increased frequency selectivity or reliability. We thus investigated whether other changes in the underlying circuitry contributed to improved neuronal responses. We show that DE can lead to refinement of intra- and inter-laminar connections in the mouse auditory cortex. Moreover, we use a computational model to show that the combination of increased transmission and circuit refinement can lead to increased firing reliability. Thus cross-modal influences can alter the spectral and temporal processing of sensory stimuli by refinement of thalamocortical and intracortical circuits. PMID- 26235626 TI - Hox5 Genes Regulate the Wnt2/2b-Bmp4-Signaling Axis during Lung Development. AB - Hox genes are required for proper anteroposterior axial patterning and the development of several organ systems. Here, we show that all three Hox5 paralogous genes play redundant roles in the developing lung. Hoxa5;Hoxb5;Hoxc5 triple-mutant embryos develop severely hypoplastic lungs with reduced branching and proximal-distal patterning defects. Hox5 genes are exclusively expressed in the lung mesoderm; however, defects are observed in both lung mesenchyme and endodermally derived epithelium, demonstrating that Hox5 genes act to regulate mesodermal-epithelial crosstalk during development. We show that Hox5 loss of function leads to loss of Wnt2/2b expression in the distal lung mesenchyme and the downregulation of previously identified downstream targets of Wnt2/2b signaling, including Lef1, Axin2, and Bmp4. Wnt2/2b-enriched media rescue proper Sox2/Sox9 patterning and restore Bmp4 expression in Hox5 triple-mutant lung explants. Taken together, these data show that Hox5 genes are key upstream mesenchymal regulators of the Wnt2/2b-Bmp4-signaling axis critical for proper lung patterning. PMID- 26235627 TI - The Placental Gene PEG10 Promotes Progression of Neuroendocrine Prostate Cancer. AB - More potent targeting of the androgen receptor (AR) in advanced prostate cancer is driving an increased incidence of neuroendocrine prostate cancer (NEPC), an aggressive and treatment-resistant AR-negative variant. Its molecular pathogenesis remains poorly understood but appears to require TP53 and RB1 aberration. We modeled the development of NEPC from conventional prostatic adenocarcinoma using a patient-derived xenograft and found that the placental gene PEG10 is de-repressed during the adaptive response to AR interference and subsequently highly upregulated in clinical NEPC. We found that the AR and the E2F/RB pathway dynamically regulate distinct post-transcriptional and post translational isoforms of PEG10 at distinct stages of NEPC development. In vitro, PEG10 promoted cell-cycle progression from G0/G1 in the context of TP53 loss and regulated Snail expression via TGF-beta signaling to promote invasion. Taken together, these findings show the mechanistic relevance of RB1 and TP53 loss in NEPC and suggest PEG10 as a NEPC-specific target. PMID- 26235628 TI - Bone augmentation of the atrophic anterior maxilla for dental implants using rhBMP-2 and titanium mesh: histological and tomographic analysis. AB - The loss of multiple teeth or trauma to the anterior maxilla often results in a deficient ridge width for prosthetic tooth rehabilitation. This study evaluated the use of titanium mesh and recombinant human bone morphogenetic protein 2 (rhBMP-2) for the repair of major bone defects in the alveolar bone. Five patients were enrolled in the study; these patients required implant replacements for two contiguous missing teeth in the anterior maxilla, which lacked sufficient bone. Residual ridges were augmented with rhBMP-2 and titanium mesh to direct the geometry of the newly formed bone. Seven months later, a bone biopsy specimen was removed from the implantation site before osteotomy and insertion of dental implants. Cone beam computed tomography (CBCT) scans were obtained preoperatively, postoperatively (baseline), and 48 months after implantation to evaluate implant healing. All dental implants were placed in the grafted sites without the need for further bone augmentation. The most frequent adverse effects were facial oedema and oral erythema. Biopsy specimens were used to evaluate bone quality. CBCT scans provided a prediction of alveolar restoration and long-term success. The combination of rhBMP-2 and titanium mesh provided effective augmentation of the atrophic anterior maxilla prior to implant placement. PMID- 26235629 TI - Comparison of human mesenchymal stem cells derived from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous tooth pulp. AB - Populations of pluripotent stem cells were isolated from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous teeth and their multipotentiality properties compared. Osteogenic, chondrogenic, adipogenic, and neurogenic differentiation potentials were examined. Bone marrow mesenchymal stem cells (BMMSCs) and synovial fluid-derived cells (SFCs) showed the highest levels of osteogenesis as expressed by alkaline phosphatase (ALP) activity (0.54+/-0.094 U/mg protein and 0.57+/-0.039 U/mg protein, respectively; P=0.60) and by osteocalcin (BGLAP; determined by real-time RT-PCR). SFCs showed the highest levels of chondrogenesis as expressed by ALP activity (1.75+/-0.097 U/mg protein) and of COL2A1 and COL10A1 by real-time PCR. In terms of adipogenesis, lipid vesicles were observed in the BMMSCs and SFCs. Dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) exhibited neurogenesis potential, as shown by increases in expression of class III beta-tubulin (TUBB3) and microtubule-associated protein 2 (MAP2) on RT-PCR. Variability was found in the differentiation potential corresponding to the tendency of the original tissue to differentiate. It is suggested that the cell type should be selected depending on the regenerative treatment regimen. PMID- 26235641 TI - Pancreatic VIPoma visualized by 68Ga DOTA-NOC PET-CT. PMID- 26235642 TI - Calcium Carbonate Mineralized Nanoparticles as an Intracellular Transporter of Cytochrome c for Cancer Therapy. AB - A new intracellular delivery system based on an apoptotic protein-loaded calcium carbonate (CaCO3 ) mineralized nanoparticle (MNP) is described. Apoptosis inducing cytochrome c (Cyt c) loaded CaCO3 MNPs (Cyt c MNPs) were prepared by block copolymer mediated in situ CaCO3 mineralization in the presence of Cyt c. The resulting Cyt c MNPs had a vaterite polymorph of CaCO3 with a mean hydrodynamic diameter of 360.5 nm and exhibited 60% efficiency for Cyt c loading. The Cyt c MNPs were stable at physiological pH (pH 7.4) and effectively prohibited the release of Cyt c, whereas, at intracellular endosomal pH (pH 5.0), Cyt c release was facilitated. The MNPs enable the endosomal escape of Cyt c for effective localization of Cyt c in the cytosols of MCF-7 cells. Flow cytometry showed that the Cyt c MNPs effectively induced apoptosis of MCF-7 cells. These findings indicate that the CaCO3 MNPs can meet the prerequisites for delivery of cell-impermeable therapeutic proteins for cancer therapy. PMID- 26235643 TI - Large-volume en-bloc staining for electron microscopy-based connectomics. AB - Large-scale connectomics requires dense staining of neuronal tissue blocks for electron microscopy (EM). Here we report a large-volume dense en-bloc EM staining protocol that overcomes the staining gradients, which so far substantially limited the reconstructable volumes in three-dimensional (3D) EM. Our protocol provides densely reconstructable tissue blocks from mouse neocortex sized at least 1 mm in diameter. By relaxing the constraints on precise topographic sample targeting, it makes the correlated functional and structural analysis of neuronal circuits realistic. PMID- 26235644 TI - Patterns of inpatient dermatology referral and predictors of diagnostic accuracy in non-dermatologists in a Northern District hospital in Singapore. AB - BACKGROUND: A wide range of dermatological conditions is often encountered in the inpatient setting. Many non-dermatologists experience difficulty in their diagnosis, and referral to a dermatologist is often warranted. In our local setting, this is made through a formal written referral letter, which is usually drafted by the junior doctor on the team. OBJECTIVES: This study was conducted to characterize patterns of inpatient dermatology referral and to investigate whether predictors of diagnostic concordance between the referring non dermatologist and the reviewing dermatologist can be identified. METHODS: A total of 168 inpatient dermatology referrals made between June and September 2013 at a Northern District hospital in Singapore were identified and reviewed. Collated variables were broadly divided into: (i) patient demographic details; (ii) the referring details of non-dermatologists; and (iii) the response details of reviewing dermatologists. RESULTS: No predictors of diagnostic concordance could be identified statistically. A total of 90.5% (n = 152) of referrals were made for both diagnostic and management purposes, whereas 9.5% (n = 16) of referrals were made purely for management purposes. Of the 152 diagnostic and management referrals, a preliminary diagnosis was reflected in 69.1% (n = 105). In 47.6% of all referrals (n = 80), more than one dermatological condition was identified. The fungal smear was the most commonly requested ancillary investigation (22.6%, n = 38/168). Cutaneous skin infections (32.0%, n = 85/266) and endogenous eczema (32.0%, n = 85/266) were by far the two most commonly identified dermatological conditions in our local cohort of patients. CONCLUSIONS: The need for a dedicated inpatient dermatology service is reinforced. However, targeted education may be employed to facilitate the referral process. PMID- 26235646 TI - Proximity-induced magnetism in transition-metal substituted graphene. AB - We investigate the interactions between two identical magnetic impurities substituted into a graphene superlattice. Using a first-principles approach, we calculate the electronic and magnetic properties for transition-metal substituted graphene systems with varying spatial separation. These calculations are compared for three different magnetic impurities, manganese, chromium, and vanadium. We determine the electronic band structure, density of states, and Millikan populations (magnetic moment) for each atom, as well as calculate the exchange parameter between the two magnetic atoms as a function of spatial separation. We find that the presence of magnetic impurities establishes a distinct magnetic moment in the graphene lattice, where the interactions are highly dependent on the spatial and magnetic characteristic between the magnetic and carbon atoms, which leads to either ferromagnetic or antiferromagnetic behavior. Furthermore, through an analysis of the calculated exchange energies and partial density of states, it is determined that interactions between the magnetic atoms can be classified as an RKKY interaction. PMID- 26235647 TI - Quantification of ante-mortem hypoxic ischemic brain injury by post-mortem cerebral magnetic resonance imaging in neonatal encephalopathy. AB - Post-mortem (PM) magnetic resonance imaging (MRI) is increasingly used as an alternative to conventional autopsy in babies dying from neonatal encephalopathy. However, the confounding effect of post-mortem changes on the detection of ante mortem ischemic injury is unclear. We examined whether quantitative MR measurements can accurately distinguish ante-mortem ischemic brain injury from artifacts using post-mortem MRI. METHODS: We compared PM brain MRI (1.5 T Siemens, Avanto) in 7 infants who died with neonatal encephalopathy (NE) of presumed hypoxic-ischemic origin with 7 newborn infants who had sudden unexplained neonatal death (SUND controls) without evidence of hypoxic-ischemic brain injury at autopsy. We measured apparent diffusion coefficients (ADCs), T1 weighted signal intensity ratios (SIRs) compared to vitreous humor and T2 relaxation times from 19 predefined brain areas typically involved in neonatal encephalopathy. RESULTS: There were no differences in mean ADC values, SIRs on T1 weighted images or T2 relaxation times in any of the 19 predefined brain areas between NE and SUND infants. All MRI images showed loss of cortical gray/white matter differentiation, loss of the normal high signal intensity (SI) in the posterior limb of the internal capsule on T1-weighted images, and high white matter SI on T2-weighted images. CONCLUSION: Normal post-mortem changes may be easily mistaken for ante-mortem ischemic injury, and current PM MRI quantitative assessment cannot reliably distinguish these. These findings may have important implications for appropriate interpretation of PM imaging findings, especially in medico-legal practice. PMID- 26235645 TI - The de novo synthesis of ubiquitin: identification of deubiquitinases acting on ubiquitin precursors. AB - Protein ubiquitination, a major post-translational modification in eukaryotes, requires an adequate pool of free ubiquitin. Cells maintain this pool by two pathways, both involving deubiquitinases (DUBs): recycling of ubiquitin from ubiquitin conjugates and processing of ubiquitin precursors synthesized de novo. Although many advances have been made in recent years regarding ubiquitin recycling, our knowledge on ubiquitin precursor processing is still limited, and questions such as when are these precursors processed and which DUBs are involved remain largely unanswered. Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. The identification of these DUBs together with their properties suggests that each ubiquitin precursor can be processed in at least two different manners, explaining the robustness of the ubiquitin de novo synthesis pathway. PMID- 26235648 TI - Interhospital transfer: how can we get it right? PMID- 26235650 TI - Dust mite avoidance for the primary prevention of atopic dermatitis: A systematic review and meta-analysis. AB - BACKGROUND: Dust mite sensitization plays a controversial role in the development of atopic dermatitis. Despite a lack of evidence for its efficacy, dust mite avoidance is commonly recommended for the prevention and treatment of atopic dermatitis. We aimed to evaluate whether dust mite avoidance strategies reduce the risk of developing atopic dermatitis in high-risk infants compared to randomized controls. METHODS: Studies were obtained by searching MEDLINE, PubMed, Scopus, The Cochrane Library, and The Global Resource of Eczema Trials databases. We included randomized, controlled trials of high-risk infants treated with a dust mite avoidance intervention and assessed for atopic dermatitis. Data were extracted independently by two reviewers using predefined criteria. RESULTS: Seven randomized controlled trials met our inclusion criteria (total n = 3040). Studies were largely unblinded but otherwise of reasonable quality. Three trials utilizing a dust mite avoidance approach but not additional interventions were combined in a meta-analysis. Dust mite avoidance provided no benefit in the prevention of atopic dermatitis (relative risk (RR) = 1.08, 95% confidence interval (CI) = 0.78-1.49, I(2) = 73%). CONCLUSIONS: Dust mite avoidance strategies alone or in combination with additional allergen avoidance modalities do not decrease the risk of developing atopic dermatitis and, given the current state of the evidence, should not be recommended for this purpose. The utility of dust mite avoidance for the treatment of atopic dermatitis or for the prevention and treatment of asthma or seasonal rhinoconjunctivitis are outside the scope of this review. PMID- 26235649 TI - IscR of Rhodobacter sphaeroides functions as repressor of genes for iron-sulfur metabolism and represents a new type of iron-sulfur-binding protein. AB - IscR proteins are known as transcriptional regulators for Fe-S biogenesis. In the facultatively phototrophic bacterium, Rhodobacter sphaeroides IscR is the product of the first gene in the isc-suf operon. A major role of IscR in R. sphaeroides iron-dependent regulation was suggested in a bioinformatic study (Rodionov et al., PLoS Comput Biol 2:e163, 2006), which predicted a binding site in the upstream regions of several iron uptake genes, named Iron-Rhodo-box. Most known IscR proteins have Fe-S clusters featuring (Cys)3 (His)1 ligation. However, IscR proteins from Rhodobacteraceae harbor only a single-Cys residue and it was considered unlikely that they can ligate an Fe-S cluster. In this study, the role of R. sphaeroides IscR as transcriptional regulator and sensor of the Fe-S cluster status of the cell was analyzed. A mutant lacking IscR is more impaired in growth under iron limitation than the wild-type and exhibits significantly increased ROS levels in iron-replete and iron-deplete conditions. Expression studies reveal that R. sphaeroides IscR in its cluster-bound form functions as transcriptional repressor of genes involved in iron metabolism by direct binding to the promoter region of genes preceded by the motif. A total of 110 genes are directly or indirectly affected by IscR. Furthermore, IscR possesses a unique Fe S cluster ligation scheme with only a single cysteine involved. PMID- 26235651 TI - Development of a noninvasive electrical impedance probe for minimally invasive tumor localization. AB - Compared with traditional open surgery, minimally invasive surgery (MIS) improves the accuracy and dexterity of a surgeon and minimizes trauma to the patient. However, the lack of significant haptic feedback in MIS can make tumor localization difficult. A noninvasive electrical impedance probe (NEIP), consisting mainly of two spherical electrodes and a constant force generator, has been developed to gently touch or slide over tissue surface and at the same time record impedance values without prior registration of the surface. We prove that there is a linear relationship between the surgical margin width and the recorded conductance. Ex vivo experiments in ten human kidney specimens were performed to demonstrate the feasibility of NEIP. The experimental results verify the linear relationship and indicate that NEIP can provide accurate tumor location while sliding over the tissue surface. PMID- 26235652 TI - Determining comorbidities and quality of life among pediatric survivors of extracorporeal life support. AB - PURPOSE: The purpose of this study is to describe health-related quality of life (HRQoL) and the prevalence of comorbidities in pediatric survivors of extracorporeal life support (ECLS) and to determine risk factors for poor HRQoL. MATERIALS: The study design was a retrospective cohort and prospective follow-up study of patients who received ECLS in the pediatric intensive care unit at Egleston Children's Hospital from 2006 to 2013. Quality of life was measured using the Pediatric Quality of Life Inventory (PedsQL 4.0) completed by either parent proxies or the survivors themselves. Clinical data were obtained via review of electronic medical records. RESULTS: Surveys were sent to 37 parent proxies or survivors with a response rate of 43.2%. Survivors ranged in age from 2 to 21 years with follow-up range of 1 to 7.5 years. Primary respiratory failure due to pneumonia was the reason for ECLS in 81.3%. Mean total PedsQL scores were 73.9 (+/-21.3) with 11 survivors (69.8%) having a normal quality of life. None of the clinical characteristics (including age, ECLS length, or length of stay) correlated with PedsQL scores. The most commonly reported comorbidities included readmission les than 1 year after ECLS (46.7%) and "problems with school" (25%). CONCLUSIONS: Survivors of pediatric extracorporeal membrane oxygenation can exhibit good HRQoL scores yet may be at risk for long-term adverse effects, such as lower psychosocial functioning and problems with school. A rigorous prospective investigation of the long-term follow-up of this patient cohort is needed to further evaluate these conclusions and to work toward the best possible outcomes for recipients of this resource-intensive therapy. PMID- 26235653 TI - Sleep apnea is associated with new-onset atrial fibrillation after coronary artery bypass grafting. AB - PURPOSE: New-onset atrial fibrillation (AF) after coronary artery bypass grafting (CABG) remains a prevalent problem. We investigated the relationship between sleep apnea and new-onset post-CABG AF during inhospital stay. MATERIALS AND METHODS: We prospectively recruited 171 patients listed for an elective CABG for an overnight sleep study. Sleep apnea was defined as apnea-hypopnea index greater than or equal to 5. RESULTS: Among the 160 patients who completed the study, those in the sleep apnea group (n=128; 80%) had larger left atrial diameter (40.4+/-5.4 vs 38.4+/-6.0 mm; P=.03) and left ventricular end-diastolic dimension (52.6+/-7.9 vs 49.2+/-6.8 mm; P=.03) than those in the non-sleep apnea group. The incidence of new-onset post-CABG AF was higher for the sleep apnea than non-sleep apnea groups (24.8% vs 9.7%; P=.07). There was 1 inhospital death and 2 patients with acute renal failure requiring dialysis after CABG in the sleep apnea group. None of the patients developed inhospital stroke. Multiple logistic regression analysis showed that sleep apnea was an independent predictor of post-CABG AF (odds ratio, 4.4; 95% confidence interval, 1.1-18.1; P=.04). CONCLUSION: Sleep apnea is prevalent in patients undergoing CABG. It increases the susceptibility to new-onset AF after CABG, probably related to atrial and ventricular remodeling. PMID- 26235654 TI - Pediatric Early Warning Score and unplanned readmission to the pediatric intensive care unit. AB - BACKGROUND AND OBJECTIVES: Early unplanned Pediatric Intensive Care Unit (PICU) readmission is associated with greater length of stay and mortality. No tools exist to identify children at risk for PICU readmission. The Pediatric Early Warning Score (PEWS) currently identify children at risk for deterioration on the ward. Our primary objective was to evaluate the ability of PEWS to identify children at risk for unplanned PICU readmission. METHODS: A single-center case control study of 189 children (38 cases and 151 age-matched controls) 18years or younger transferred from the PICU to the pediatric ward from January 1, 2010 March 30, 2013, at an urban tertiary care children's hospital was conducted. RESULTS: Thirty-eight cases had unplanned PICU readmission within 48hours of transfer to pediatric ward, whereas 151 controls were not readmitted. The PEWS assigned prior to PICU discharge and first PEWS assigned on the ward were collected for cases and controls. Each 1-point increase in the PEWS score significantly increased risk of PICU readmission (odds ratios [95% confidence intervals], 1.6 [1.12-2.27; P = .009] and 1.89 [1.33-2.69; P < .001], respectively). Discrimination ability of PEWS for PICU readmission improved when chronic diagnoses were included. CONCLUSIONS: Higher PEWS scores were associated with increased risk of unplanned PICU readmission. However, cutoff scores are not sensitive or specific enough to be clinically useful. Adding chronic disease variables may improve the clinical utility of cutoff PEWS scores. PMID- 26235655 TI - Why is the electroanalytical performance of carbon paste electrodes involving an ionic liquid binder higher than paraffinic binders? A simulation investigation. AB - Recently, carbon paste electrodes (CPE) fabricated using an ionic liquid (IL) binder have shown enhanced electroanalytical performance over conventional paraffinic binders. Molecular dynamics (MD) simulations of graphite mixed with ionic liquid and with paraffin binder can unravel the potential atomistic factors responsible for such enhancement. Based on an experimentally optimized binder/graphite mass ratio, which has been reported to be crucial for such a performance, comprehensive simulations (at 323 K) are performed with the ensembles involving an ionic liquid binder (1-butyl-3-methylimidazolium hexafluorophosphate, [C4mim]PF6) and a paraffin binder (n-C20H42) mixed with graphite comprising large-size hexagonal-shaped double graphene plates. Structural analysis indicates both binders form only a monolayer on the graphite surface, covering the surface locally by IL but all-encompassing by paraffin. With charged and uncharged graphite, the IL monolayer tends to cover mainly the graphite center without approaching the edge planes. On the contrary, a monolayer of the paraffin binder covers uniformly the center, near the center, and the edge planes. Cations and anions of the IL form well-defined two dimensional pentagonal matrixes with characteristic high adsorption energy, almost 2.4 times higher than paraffin adsorption. The cation and anion coordination ability of the IL is responsible for such a local distribution. The simulation of these phenomena under experimental conditions unravels strong two-dimensional coordination properties inherent to the ionic liquid when distributed over the graphite surface. This direct MD simulation comparison of the IL properties with an organic liquid counterpart, made for the first time, can be used to explain the high electroanalytical performance (electron transfer) of CPEs involving an IL binder over paraffin binders. PMID- 26235656 TI - Quantum state resolved gas-surface reaction dynamics experiments: a tutorial review. AB - We present a tutorial review of our quantum state resolved experiments designed to study gas-surface reaction dynamics. The combination of a molecular beam, state specific reactant preparation by infrared laser pumping, and ultrahigh vacuum surface analysis techniques make it possible to study chemical reactivity at the gas-surface interface in unprecedented detail. We describe the experimental techniques used for state specific reactant preparation and for detection of surface bound reaction products developed in our laboratory. Using the example of the reaction of methane on Ni and Pt surfaces, we show how state resolved experiments uncovered clear evidence for vibrational mode specificity and bond selectivity, as well as steric effects in chemisorption reactions. The state resolved experimental data provides valuable benchmarks for comparison with theoretical models for gas-surface reactivity aiding in the development of a detailed microscopic understanding of chemical reactivity at the gas-surface interface. PMID- 26235657 TI - Can ultrasound elastography be used as a new technique in the differentiation of undescended testes and reactive lymph nodes in children? AB - AIM: To determine the diagnostic performance of ultrasound elastography in the differentiation of reactive lymph nodes and undescended testes in children. MATERIALS AND METHODS: Seventy-two undescended testes and 34 reactive lymph nodes were prospectively examined with the elastography technique. Four elastographic patterns were used for classification based on the distribution of the blue area. The strain ratios and elasticity patterns of the undescended testes and reactive lymph nodes were evaluated independently by two radiologists. Interobserver agreement and diagnostic performance were analysed. RESULTS: Thirty of the 34 reactive lymph nodes were classified as exhibiting high-strain elastographic patterns (considered Type 1 or Type 2, with blue areas in ?50% of the tissue) by both observers; in contrast, 67 and 71 of 72 undescended testes were classified as exhibiting low-strain elastographic patterns (considered Type 3 or Type 4, with blue areas in >50% of tissue) by radiologists 1 and 2, respectively. The respective mean strain ratios measured by the two radiologists were 0.60+/-0.03 and 0.62+/-0.02 for the reactive lymph nodes and 0.25+/-0.08 and 0.25+/-0.09 for the undescended testes. There were significant differences in the elasticity patterns and strain ratios between the reactive lymph nodes and the undescended testes (p<0.001). The interobserver agreement was excellent for the four elasticity patterns with a weighted kappa coefficient of 0.872. The concordance of the strain ratios between the observers was excellent in the present study (intra-class correlation score: 0.988). CONCLUSIONS: In the majority of cases, conventional two-dimensional ultrasound could be used to differentiate undescended testes from reactive lymph nodes with acceptable accuracy. Although the incremental value of elastography is limited, this technique might have a role in some specific cases. PMID- 26235658 TI - Re: validating a threshold of ocular gaze deviation for the prediction of acute ischaemic stroke. A reply. PMID- 26235660 TI - Association between very small tumour size and increased cancer-specific mortality after radical prostatectomy in lymph node-positive prostate cancer. AB - OBJECTIVE: To determine whether very small prostate cancers present in patients who also have lymph node (LN) metastases represent a particularly aggressive disease variant compared with larger LN-positive tumours. PATIENTS AND METHODS: We identified 37 501 patients diagnosed with prostate cancer between 1988 and 2001 treated with radical prostatectomy within the Surveillance, Epidemiology, and End Results database. The primary study variables were tumour size by largest dimension (stratified into: (i) microscopic focus only or 1 mm; (ii) 2-15 mm; (iii) 16-30 mm; (iv) >30 mm), regional LN involvement, and the corresponding interaction term. We evaluated the risk of 10-year prostate cancer-specific mortality (PCSM) using the Fine and Gray model for competing risks after controlling for race, tumour grade, T stage, receipt of radiation, number of dissected LNs, number of positive LNs, year of diagnosis, and age at diagnosis. RESULTS: The median follow-up was 11.8 years. There was a significant interaction between tumour size and LN involvement (P-interaction <0.001). In the absence of LN involvement (36 561 patients), the risk of 10-year PCSM increased monotonically with increasing tumour size. Among patients with LN involvement (940), those with the smallest tumours had increased 10-year PCSM compared with patients with tumours sized 2-15 mm (24.7% vs 11.8%; adjusted hazard ratio [AHR] 2.84, 95% confidence interval [CI] 1.21-6.71; P = 0.017) or 16-30 mm (24.7% vs 15.5%; AHR 3.12, 95% CI 1.51-6.49; P = 0.002), and similar 10-year PCSM as those with tumours >30 mm (24.7% vs 24.9%; P = 0.156). CONCLUSION: In patients with prostate cancer with LN involvement, very small tumour size may predict for higher PCSM compared with some larger tumours, even after controlling for other prognostic variables. These tumours might be particularly aggressive, beyond what is captured by pathological assessment of tumour grade and stage. PMID- 26235659 TI - Self-help educational booklets for the prevention of smoking relapse following smoking cessation treatment: a randomized controlled trial. AB - AIMS: Most people who quit smoking for a short term will return to smoking again in 12 months. We tested whether self-help booklets can reduce relapse in short term quitters after receiving behavioural and pharmacological cessation treatment. DESIGN: A parallel-arm, pragmatic individually randomized controlled trial. SETTING: Smoking cessation clinics in England. Participants People who stopped smoking for 4 weeks after receiving cessation treatment in stop smoking clinics. INTERVENTION: Participants in the experimental group (n=703) were mailed eight booklets, each of which taught readers how to resist urges to smoke. Participants in the control group (n=704) received a leaflet currently used in practice. MEASUREMENTS: The primary outcome was prolonged, carbon monoxide verified abstinence from months 4 to 12. The secondary outcomes included 7-day self-reported abstinence at 3 and 12 months. Mixed-effects logistic regression was used to estimate treatment effects and to investigate possible effect modifying variables. FINDINGS: There were no statistically significant differences between the groups in prolonged abstinence from months 4 to 12 (36.9% versus 38.6%; odds ratio 0.93, 95% confidence interval 0.75-1.16; P=0.524). In addition, there were no significant differences between the groups in any secondary outcomes. However, people who reported knowing risky situations for relapse and using strategies to handle urges to smoke were less likely to relapse. CONCLUSIONS: In people who stop smoking successfully with behavioural support, a comprehensive self-help educational programme to teach people skills to identify and respond to high-risk situations for return to smoking did not reduce relapse. PMID- 26235661 TI - Relationship between rooftop and on-road concentrations of traffic-related pollutants in a busy street canyon: Ambient wind effects. AB - Rooftop and on-road measurements of O3, NO2, NOx, and CO concentrations were conducted to investigate the relationship between rooftop and on-road concentrations in a busy and shallow street canyon with an aspect ratio of ~0.3 in Seoul, Republic of Korea, from 15 April to 1 May 2014. The median road-to-roof concentration ratios, correlation coefficients between rooftop and on-road concentrations, and temporal variations of rooftop and on-road concentrations are analyzed according to the rooftop wind directions which are two cross-canyon and two along-canyon directions. The analysis results indicate that the relationship is strong when the rooftop is situated on the downwind side rather than on the upwind side. Relative to the cross-canyon wind directions, one of the along canyon wind directions can more enhance the relationship. A conceptual framework is proposed to explain the effect of ambient wind direction on the relationship between rooftop and on-road concentrations in a street canyon. PMID- 26235662 TI - Anticholinesterase, antioxidant activity and phytochemical investigation into aqueous extracts from five species of Agrimonia genus. AB - Aqueous extracts of aerial flowering parts of five Agrimonia species (Rosaceae): Agrimonia coreana Nakai, Agrimonia japonica (Miq.) Koidz, Agrimonia procera Wallr., Agrimonia eupatoria L. and Agrimonia leucantha Kunze were investigated on their antioxidant activity, measured using five different methods; the best was the extract from A. procera with IC50 values from 6 to 29 MUg/mL. All the extracts displayed inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) at the tested concentration of 100 MUg/mL. We found the highest inhibition of cholinesterase in the extract of A. japonica with inhibition 70.4% for AChE and 79.8% for BuChE. These findings are statistically significant in comparison with those of other extracts (p < 0.001). The phytochemical analyses showed that the antioxidant activity of Agrimonia extracts can be affected especially by hexahydroxydiphenoyl (HHDP)-glucose and quercetin glycosides, and inhibition of cholinesterases by apigenin, luteolin and quercetin glycosides. PMID- 26235663 TI - Opinions of Young Adults on Re-Consenting for Biobanking. AB - OBJECTIVE: To evaluate young adult cancer survivor opinions on whether their biobanked tissue and associated de-identified clinical data obtained during their childhood should require re-consent at the age of majority, when parental consent was originally provided. STUDY DESIGN: Thirty young adults (18-34 years old), who were former pediatric oncology patients of The Children's Hospital at Westmead with stored research biospecimens, were recruited. They completed a semistructured interview, which included questions on biobanking re-consent, awareness of biobanked tissue, satisfaction about banked tissue, and independence within the family. Analyses included descriptive and inferential statistics. RESULTS: Sixty percent of participants thought that permission for biobanking should be sought again at adulthood, and the remaining 40% did not think that re consent was necessary. Seventy percent of participants were unaware of their previously banked tissue, which was dependent upon age at diagnosis. When asked whether they granted permission for their tissue to remain in the biobank, all participants agreed. CONCLUSIONS: Although results on whether young adults prefer to re-consent or not for previously biobanked tissue and corresponding clinical data are equivocal, survivors appear to be highly favorable about ongoing biobanking of their childhood specimens for future unspecified research. PMID- 26235664 TI - Postoperative Hyperglycemia and 4-Year Neurodevelopmental Outcome in Children Operated for Congenital Heart Disease. AB - OBJECTIVES: To study the long-term neurodevelopmental effects of hyperglycemia in infant bypass surgery for congenital heart disease (CHD). STUDY DESIGN: Prospective cohort study on neurodevelopmental outcome after infant cardiac bypass surgery. EXCLUSION CRITERIA: age older than 1 year at first surgery, genetic comorbidity, and birth weight <2000 g. Of 167 eligible infants, follow-up examination at 4 years was completed in 150 children (90%). Intraoperative and postoperative highest and lowest glucose levels within 24 hours after bypass surgery were prospectively collected. Neurodevelopmental outcome at 4 years of age was assessed using standardized IQ tests and the Movement Assessment Battery for Children-second version for motor outcome assessment. RESULTS: Mean age at surgery was 2.8 months (0.1-10.7 months), 33% of children had an acyanotic CHD and 67% a cyanotic CHD. Glucose levels were elevated (>8 mmol/L) in 21 (14%) children in the first 24 postoperative hours. Glucose levels normalized in all children within 48 hours, 7 children (4%) received insulin infusions. Mean total IQ was within the normal range, but significantly lower than the normal population (92.5 [SD 15.0], P < .001). Higher postoperative glucose levels were related to better cognitive performance in the univariate analysis (P < .03), but not when other risk factors were taken into account. Independent risk factors for adverse outcome were lower socioeconomic status, higher risk adjustment for congenital heart surgery score, and longer duration of intensive care stay. CONCLUSION: Hyperglycemia is common in the early postoperative course after infant bypass surgery for CHD and normalizes within 48 hours. Hyperglycemia has no adverse effect on long-term neurodevelopmental outcome. PMID- 26235665 TI - Chin Numbness and Pain in a Patient with Burkitt Acute Lymphoblastic Leukemia. PMID- 26235666 TI - Primary Epibulbar Molluscum Contagiosum in an Immunocompetent Child. PMID- 26235667 TI - Celebrating Soft Matter's 10th anniversary: Testing the foundations of classical entropy: colloid experiments. AB - Defining the entropy of classical particles raises a number of paradoxes and ambiguities, some of which have been known for over a century. Several, such as Gibbs' paradox, involve the fact that classical particles are distinguishable, and in textbooks these are often 'resolved' by appeal to the quantum-mechanical indistinguishability of atoms or molecules of the same type. However, questions then remain of how to correctly define the entropy of large poly-atomic particles such as colloids in suspension, of which no two are exactly alike. By performing experiments on such colloids, one can establish that certain definitions of the classical entropy fit the data, while others in the literature do not. Specifically, the experimental facts point firmly to an 'informatic' interpretation that dates back to Gibbs: entropy is determined by the number of microstates that we as observers choose to treat as equivalent when we identify a macrostate. This approach, unlike some others, can account for the existence of colloidal crystals, and for the observed abundances of colloidal clusters of different shapes. We also address some lesser-known paradoxes whereby the physics of colloidal assemblies, which ought to be purely classical, seems to involve quantum mechanics directly. The experimental symptoms of such involvement are predicted to be 'isotope effects' in which colloids with different inertial masses, but otherwise identical sizes and properties, show different aggregation statistics. These paradoxes are caused by focussing one's attention on some classical degrees while neglecting others; when all are treated equally, all isotope effects are found to vanish. PMID- 26235668 TI - Dissociative contributions of the anterior cingulate cortex to apathy and depression: Topological evidence from resting-state functional MRI. AB - Apathy is defined as a mental state characterized by a lack of goal-directed behavior. However, the underlying mechanisms of apathy remain to be fully understood. Apathy shares certain symptoms with depression and both these affective disorders are known to be associated with dysfunctions of the frontal cortex-basal ganglia circuits. It is expected that clarifying differences in neural mechanisms between the two conditions would lead to an improved understanding of apathy. The present study was designed to investigate whether apathy and depression depend on different network properties of the frontal cortex-basal ganglia circuits, by using resting state fMRI. Resting-state fMRI measurement and neuropsychological testing were conducted on middle-aged and older adults (N=392). Based on graph theory, we estimated nodal efficiency (functional integration), local efficiency (functional segregation), and betweenness centrality. We conducted multiple regression analyses for the network parameters using age, sex, apathy, and depression as predictors. Interestingly, results indicated that the anterior cingulate cortex showed lower nodal efficiency, local efficiency, and betweenness centrality in apathy, whereas in depression, it showed higher nodal efficiency and betweenness centrality. The anterior cingulate cortex constitutes the so-called "salience network", which detects salient experiences. Our results indicate that apathy is characterized by decreased salience-related processing in the anterior cingulate cortex, whereas depression is characterized by increased salience-related processing. PMID- 26235669 TI - Performance comparison of four commercial human whole-exome capture platforms. AB - Whole exome sequencing (WXS) is widely used to identify causative genetic mutations of diseases. However, not only have several commercial human exome capture platforms been developed, but substantial updates have been released in the past few years. We report a performance comparison for the latest release of four commercial platforms, Roche/NimbleGen's SeqCap EZ Human Exome Library v3.0, Illumina's Nextera Rapid Capture Exome (v1.2), Agilent's SureSelect XT Human All Exon v5 and Agilent's SureSelect QXT, using the same DNA samples. Agilent XT showed the highest target enrichment efficiency and the best SNV and short indel detection sensitivity in coding regions with the least amount of sequencing. Agilent QXT had slightly inferior target enrichment than Agilent XT. Illumina, with additional sequencing, detected SNVs and short indels at the same quality as Agilent XT, and showed the best performance in coverage of medically interesting mutations. NimbleGen detected more SNVs and indels in untranslated regions than the others. We also found that the platforms, which enzymatically fragment the genomic DNA (gDNA), detected more homozygous SNVs than those using sonicated gDNA. We believe that our analysis will help investigators when selecting a suitable exome capture platform for their particular research. PMID- 26235670 TI - Effect of argan oil on liquid storage of ram semen in Tris or skim milk based extenders. AB - Due to its high antioxidant content, the argan oil could play a beneficial role in liquid storage of ram semen. The aim of this study was to investigate effects of different concentration of argan oil (ARO) on spermatologic parameters, lipid peroxidation and DNA fragmentation during liquid storage of ram semen until 48 h. Also effects of extenders and temperature on same parameters were assessed. For these aims, semen samples were collected from Boujaad rams, extended with Tris egg yolk or skim milk extenders without (control) or supplemented with different concentrations of ARO (1%, 2%, 5% and 10% v/v) at a final concentration of 0.8 * 10(9) sperm/mL and stored until 48 h at 5 degrees C or 15 degrees C. The sperm quality assessments were performed at different intervals during storage (0, 8, 24 and 48 h). Sperm progressive motility started to decrease after 8h of storage in all temperatures--extenders combinations and dropped steadily during the 8-48 h interval. However, sperm viability, progressive motility and membrane integrity were markedly higher in ARO groups (especially in 1% in Tris and 5% in skim milk) until 24h and 48 h storage at both temperatures compared to controls. The argan oil also decreased the level of spontaneous and induced malondialdehyde (MDA) and the sperm DNA fragmentation until 48 h storage. In conclusion, it was determined that addition of argan oil to conventional extenders may improve the quality of ram semen during liquid storage in different temperatures. PMID- 26235671 TI - Suppressed N2O formation during NH3 selective catalytic reduction using vanadium on zeolitic microporous TiO2. AB - Emission of N2O from mobile and off-road engine is now being currently regulated because of its high impact compared to that of CO2, thereby implying that N2O formation from the exhaust gas after-treatment system should be suppressed. Selective catalytic reduction using vanadium supported TiO2 catalyst in mobile and off-road engine has been considered to be major source for N2O emission in the system. Here we have demonstrated that vanadium catalyst supported on zeolitic microporous TiO2 obtained from the hydrothermal reaction of bulk TiO2 at 400 K in the presence of LiOH suppresses significantly the N2O emission compared to conventional VOx/TiO2 catalyst, while maintaining the excellent NOx reduction, which was ascribed to the location of VOx domain in the micropore of TiO2, resulting in the strong metal support interaction. The use of zeolitic microporous TiO2 provides a new way of preparing SCR catalyst with a high thermal stability and superior catalytic performance. It can be also extended further to the other catalytic system employing TiO2-based substrate. PMID- 26235672 TI - Water is Destiny. PMID- 26235673 TI - Autocrine Action of Thrombospondin-2 Determines the Chondrogenic Differentiation Potential and Suppresses Hypertrophic Maturation of Human Umbilical Cord Blood Derived Mesenchymal Stem Cells. AB - Previous studies have shown that mesenchymal stem cell (MSC)-based therapies have varying efficacies for the treatment of various diseases, including cartilage defects. In this study, we demonstrated that the chondrogenic differentiation potential of human umbilical cord blood-derived MSCs (hUCB-MSCs) obtained from different individual donors varies, and we investigated the molecular basis for this variation. Microarray gene expression analysis identified thrombospondin-2 (TSP2) as a candidate gene underlying the interindividual variation in the chondrogenic differentiation potential of hUCB-MSCs. To assess the association between TSP-2 and the differentiation potential, we evaluated chondrogenic differentiation of hUCB-MSCs treated with TSP2 siRNA. In addition, we studied the effect of supplementing exogenous recombinant TSP-2 on TSP2 siRNA-treated hUCB MSCs. We found that TSP-2 autocrinally promoted chondrogenic differentiation of hUCB-MSCs via the Notch signaling pathway, which was confirmed in MSCs from other sources such as bone marrow and adipose tissue. Interestingly, we observed that TSP-2 attenuated hypertrophy, which inevitably occurs during chondrogenic differentiation of hUCB-MSCs. Our findings indicated that the variable chondrogenic differentiation potential of MSCs obtained from different donors is influenced by the TSP-2 level in the differentiating cells. Thus, the TSP-2 level can be used as a marker to select MSCs with superior chondrogenic differentiation potential for use in cartilage regeneration therapy. PMID- 26235674 TI - Context and complexity: the meaning of self-management for older adults with heart disease. AB - Self-management policies have presented opportunities for patients with long-term conditions to take control and actively improve their health. However, the work of self-management appears to be packaged in the form of essential and desirable skills and attributes required for success. This article presents the findings of a qualitative study, employing longitudinal diary interviews with 21 patients aged between 60 and 85 years diagnosed with coronary heart disease from three contrasting general practice areas. Drawing on concepts of the care of the self and the reflexive self, this article presents the diversity of self-management practices by older patients in the context of their lifeworld. Illustrated through individual case studies, it clearly identifies where patients are engaged self-managers with the agency, knowledge and self-discipline to modify their behaviour for an improved health outcome. This study highlights their life and illness perspectives as well as those of patients who are burdened with emotional insecurity, comorbidities and caring responsibilities. It shows the spectrum of relationships with health professionals that influence engaged self-management. We suggest that policy initiatives that favour behavioural change neglect social context and the individualised practices that are a necessary response to structural and psychosocial constraints. PMID- 26235675 TI - Social organization and space use of a wild mandrill (Mandrillus sphinx) group. AB - Mandrills (Mandrillus sphinx) are enigmatic Old World primates whose social organization and ecology remain poorly known. Previous studies indicated, for example, that groups are composed of only adult females and their young or that several units composed of one adult male and several females make up larger permanent social units. Here, we present the first data on group composition and male ranging patterns from the only habituated wild mandrill group and examine how home range size and daily path length varied with environmental and demographic factors over a 15-month period. Our study site is located in southern Gabon where we followed the group on a daily basis, collecting data on presence, ranging, behavior, and parasite load of its individual members. Throughout the study, the group was made up of about 120 individuals, including several non natal and natal adult and sub-adult males. One-male units were never observed. The mandrills traveled an estimated 0.44-6.50 km/day in a home range area of 866.7 ha. Exploratory analyses revealed that precipitation, the number of adult males present, and the richness of protozoan parasites were all positively correlated with daily path length. These results clarify the social system of mandrills and provide first insights into the factors that shape their ranging patterns. PMID- 26235676 TI - Bacterial, fungal and protozoan carbonic anhydrases as drug targets. AB - INTRODUCTION: The carbonic anhydrases (CAs, EC 4.2.1.1), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, as well as in the growth and virulence of pathogens belonging to bacteria, fungi and protozoa. AREAS COVERED: CAs belonging to at least four genetic families, the alpha-, beta-, gamma- and eta-CAs, were discovered and characterized in many pathogens: i) Bacteria encode enzymes from one or more such families, which were investigated as potential drug targets. Inhibition of bacterial CAs by sulfonamides/phenol derivatives lead to inhibition of growth of the pathogen for Helicobacter pylori, Mycobacterium tuberculosis, Brucella suis; ii) Fungi encode for alpha- and beta-CAs, and inhibitors of the sulfonamide, thiol or dithiocarbamate type inhibited the growth of some of them (Malassezia globosa, Candida albicans, Crytpococcus neoformans, etc) in vivo; and iii) Protozoa encode alpha-, beta- or eta-CAs. Sulfonamide, thiols and hydroxamates effectively killed such parasites (Trypanosoma cruzi, Leishmania donovani chagasi, Plasmodium falciparum) in vivo. EXPERT OPINION: None of the microorganism CAs is validated as drug targets as yet, but the inhibitors designed against many such enzymes showed interesting in vitro/in vivo results. By interfering with the activity of CAs from microorganisms, both pH homeostasis as well as crucial biosynthetic reactions are impaired, which lead to significant antiinfective effects, not yet exploited for obtaining pharmacological agents. As resistance to the clinically used antiinfectives is a serious healthcare problem worldwide, inhibition of parasite CAs may constitute an alternative approach for obtaining such agents with novel mechanisms of action. PMID- 26235677 TI - Pharmacogenomics of long-acting beta2-agonists. AB - INTRODUCTION: Long-acting beta2-agonists are an effective class of drugs, when combined with inhaled corticosteroids, for reducing symptoms and exacerbations in patients with asthma that is not adequately controlled by inhaled corticosteroids alone. However, because this class of drugs has been associated with severe adverse events, including hospitalization and death in small numbers of patients, efforts to identify a pharmacogenetic profile for patients at risk has been diligently investigated. AREAS COVERED: The PubMed search engine of the National Library of Medicine was used to identify English-language and non-English language articles published from 1947 to March 2015 pertinent to asthma, pharmacogenomics, and long-acting beta2-agonists. Keywords and topics included: asthma, asthma control, long-acting beta2-agonists, salmeterol, formoterol, pharmacogenetics, and pharmacogenomics. This strategy was also used for the Cochrane Library Database and CINAHL. Reference types were randomized controlled trials, reviews, and editorials. Additional publications were culled from reference lists. The publications were reviewed by the authors and those most relevant were used to support the topics covered in this review. EXPERT OPINION: Children, who carry the ADRB2 Arg16Arg genotype, may be at greater risk than adults for severe adverse events. Rare ADRB2 variants appear to provide better clues for identifying the at-risk population of asthmatics. PMID- 26235678 TI - Alternatively spliced orcokinin isoforms and their functions in Tribolium castaneum. AB - Orcokinin and orcomyotropin were originally described as neuropeptides in crustaceans but have now been uncovered in many species of insects in which they are called orcokinin-A (OK-A) and orcokinin-B (OK-B), respectively. The two groups of mature peptides are products of alternatively spliced transcripts of the single copy gene orcokinin in insects. We investigated the expression patterns and the functions of OK-A and OK-B in the red flour beetle Tribolium castaneum. In situ hybridization and immunohistochemistry using isoform-specific probes and antibodies for each OK-A and OK-B suggests that both peptides are co expressed in 5-7 pairs of brain cells and in the midgut enteroendocrine cells, which contrasts to expression patterns in other insects in which the two peptides are expressed in different cells. We developed a novel behavioral assay to assess the phenotypes of orcokinin RNA interference (RNAi) in T. castaneum. RNAi of ok-a and ok-b alone or in combination resulted in higher frequencies and longer durations of death feigning in response to mechanical stimulation in the adult assay. In the larval behavioral assays, we observed longer recovery times from knockout induced by water submergence in the insects treated with RNAi for ok-a and ok-b alone or in combination. We conclude that both OK-A and OK-B have "awakening" activities and are potentially involved in the control of circadian rhythms. PMID- 26235679 TI - Low air temperature increases the risk of oesophageal variceal bleeding: a population and hospital-based case-crossover study in Taiwan. AB - BACKGROUND & AIMS: Studies concerning seasonal variations and the impact of air temperature on oesophageal variceal bleeding have yielded conflicting results. We aimed to explore the impact of air temperature on the occurrence of variceal bleeding. METHODS: A case-crossover study design was employed, and two cohorts were used, including the NHI-EVB cohort from the National Health Insurance Research Database of Taiwan from 1 January 1999 to 31 December 2010, and the VGH EVB cohort from the Taipei Veterans General Hospital, from 4 May 2002 to 31 December 2010. A conditional logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In total, 2542 cases from the NHI-EVB cohort and 220 cases from the VGH-EVB cohort were analysed. Our analysis showed that low air temperature (LAT) increased the risk of variceal bleeding regardless of age, sex, decompensated cirrhosis, Child-Pugh classification, aetiology of liver disease and concomitant hepatocellular carcinoma; the lag effect was also observed. The ORs per 5 degrees C decrease in daily mean air temperature were 1.144 (95% CI, 1.060-1.235) for the NHI-EVB cohort and 1.307 (95% CI: 1.031-1.658) for the VGH-EVB cohort. Oesophageal variceal bleeding in patients with small varices, end-stage liver disease score ?15 or those using non-selective beta blockers was not influenced by air temperature. CONCLUSIONS: Patients have higher risk of oesophageal variceal bleeding at low air temperature regardless of age, sex, aetiology of cirrhosis, Child-Pugh classification, decompensated cirrhosis and concomitant hepatocellular carcinoma and can be protected by use non-selective beta blockers. PMID- 26235680 TI - De novo transcriptome characterization of the ghost moth, Thitarodes pui, and elevation-based differences in the gene expression of its larvae. AB - Thitarodes pui larvae are the hosts of a medicinal fungus, Ophiocordyceps sinensis, and are naturally distributed at an altitude of 4100-4650 m on Segrila Mountain of the Tibetan Plateau. Here, we conducted transcriptome profiling of T. pui larvae based on the Illumina high-throughput sequencing platform. Subsequently, we explored elevation-based differences of T. pui by comparing gene expression profiles between larvae at high-altitude (natural conditions) and larvae exposed to short-term (2months) low-altitude conditions. A total of 105,935,208 clean reads were assembled into 70,048 unigenes with a mean length of 639 bp. All unigenes were searched against public databases, with 51.26% unigenes being successfully annotated in the NR, SWISS-PROT, EuKaryotic Orthologous Groups (KOG), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genome (KEGG) databases. A total of 11,846 unigenes were functionally classified into 239 KEGG pathways. Metabolism was the most represented pathway, with 4271 unigenes (36.05%). Using the transcriptome data as a reference, 629 (311 up-regulated/318 down-regulated) genes were differentially expressed by low-altitude larvae when compared with those of high-altitude larvae. The most significantly differentially expressed genes were annotated in the processes of carbohydrate metabolism, lipid metabolism, and respiration. This report provides valuable information about the T. pui transcriptome for future genomic studies, including how gene expression is altered in larvae reared at different elevations. PMID- 26235681 TI - Multimodal neuroimaging as a window into the pathological physiology of schizophrenia: Current trends and issues. AB - Visualizing the detailed brain anatomy of individuals with schizophrenia has been made possible by recent advances in magnetic resonance imaging (MRI). Although structural MRI cannot be currently used to diagnose schizophrenia, multimodal MRI can reveal insightful information on key clinical aspects of the pathological physiology of schizophrenia. However, in this regard, the number of multimodal MRI studies is still limited and definitely required. In this review, we discuss how classical and popular theories on the pathological physiology of schizophrenia can be re-examined using neuroimaging studies, and also discuss how multimodal MRI studies may provide additional findings. The pathological hypotheses examined include the "progressive brain disease hypothesis" and "disconnection hypothesis". This article is discussed mainly based on recent findings published by our research group. PMID- 26235683 TI - Recurrence in patients with stage I colorectal cancer. AB - BACKGROUND: Outcomes of patients with stage I colorectal cancer submitted to surgery with curative intent have not been thoroughly explored in contemporary series. METHODS: All patients with colon or rectal adenocarcinoma who underwent resection from the St John of God Hospital (1996-2013) and BioGrid (1991-2013) databases were identified. Patients submitted to local excision, polypectomies or neoadjuvant treatment were excluded. Outcomes included recurrence (combined local and systemic), recurrence-free and overall survival, and survival after recurrence. RESULTS: A total of 1193 patients with stage I disease were included. Median age was 67 (interquartile range 59-75) and median follow-up was 3.2 years (interquartile range 1.4-5.8). Five-year recurrence rate was 7.1% (95% confidence interval (CI) 5.4-9.4%; 5.0% for colon and 11.1% for rectal cancer). Rectal location was an independent predictor of recurrence (hazard ratio (HR) 1.97, 95% CI 1.09-3.55; P = 0.024). Lymphovascular invasion was an independent predictor of recurrence only in patients with rectal cancer (HR 3.0, 95% CI 1.2-7.6; P = 0.018). Five-year recurrence-free survival was 83.2% (95% CI 80.3-85.4%). Age (HR 1.05, 95% CI 1.03-1.07; P < 0.001), elective surgery (HR 0.41, 95% CI 0.21-0.80; P = 0.011) and the American Society of Anesthesiologists (ASA) score (HR 3.08, 95% CI 1.51-6.31; P < 0.001) were independently associated with recurrence-free survival. Median survival after recurrence was 41 months. Resection of recurrence was attempted in 39% of patients. CONCLUSION: Patients with stage I colorectal cancers still have a clinically significant risk of recurrence. Rectal location is independently associated with higher recurrence. Age, elective surgery and ASA are independently associated with recurrence-free survival. A significant proportion of patients with recurrence underwent further resection. PMID- 26235684 TI - [The B side of using beta agonists in children with acute respiratory failure]. PMID- 26235682 TI - Differential activation of the ventromedial prefrontal cortex between male and female givers of social reputation. AB - Accumulating evidence has shown the profound influence of social reputation on human behavior and has implicated the ventromedial prefrontal cortex (vmPFC) in representing subjective values induced by social interaction. However, little is known regarding how the vmPFC encodes subjective pleasantness induced by social reputation received from others. We used functional magnetic resonance imaging (fMRI) to investigate how the vmPFC in males and females encodes the subjective pleasantness of social reputation received from the same gender and from the opposite gender. Behavioral data showed that positive reputation was perceived to be more pleasant than negative reputation. Intriguingly, both male and female subjects showed greater differences in the pleasantness scores between the positive reputation condition and the negative reputation condition from females than between positive and negative reputations from males. Imaging data revealed that the left vmPFC specifically contributed to the processing of positive reputation. The activity patterns of the vmPFC corresponded to the gender differences in behavior during the processing of social reputation. These results indicate that the vmPFC plays a role in representing the subjective value of positive social reputation and that this region might be a final computational site in a stream of value-based decision-making processes. PMID- 26235685 TI - [Genetic predisposition and Pediatric Acute Respiratory Distress Syndrome: New tools for genetic study]. AB - Acute respiratory distress syndrome (ARDS) is the most severe form of respiratory failure. Theoretically, any acute lung condition can lead to ARDS, but only a small percentage of individuals actually develop the disease. On this basis, genetic factors have been implicated in the risk of developing ARDS. Based on the pathophysiology of this disease, many candidate genes have been evaluated as potential modifiers in patient, as well as in animal models, of ARDS. Recent experimental data and clinical studies suggest that variations of genes involved in key processes of tissue, cellular and molecular lung damage may influence susceptibility and prognosis of ARDS. However, the pathogenesis of pediatric ARDS is complex, and therefore, it can be expected that many genes might contribute. Genetic variations such as single nucleotide polymorphisms and copy-number variations are likely associated with susceptibility to ARDS in children with primary lung injury. Genome-wide association (GWA) studies can objectively examine these variations, and help identify important new genes and pathogenetic pathways for future analysis. This approach might also have diagnostic and therapeutic implications, such as predicting patient risk or developing a personalized therapeutic approach to this serious syndrome. PMID- 26235686 TI - [Breath tests in children with suspected lactose intolerance]. AB - INTRODUCTION: Up to 70% of the world population is lactose intolerance. However, there are no epidemiological studies among Chilean pediatric population affected by this condition. OBJECTIVES: Clinical characterization of a series of children who underwent the lactose intolerance breath test for lactose intolerance study, establishing intolerance and malabsorption frequencies, the most frequent symptoms, and test performance depending on the origin. PATIENTS AND METHODS: Patients under 18 years old who took the lactose intolerance breath test in the Gastroenterology Laboratory of the Catholic University of Chile, and who were admitted due to clinically suspected lactose intolerance. Malabsorption was considered when there was as an increase of >=20ppm above the baseline (H2) or >=34ppm of H2 and methane (CH4) combined. Intolerance was considered when the above was associated with a symptom intensity score >=7 during registration. RESULTS: The analysis included194 patients aged 1 to17 years of age. Of these, 102 (53%) presented with malabsorption, and 53 (27%) were intolerant. The frequency of lactose intolerance varied from 7.1 to 45.4%, and it occurred more frequently at older ages. The most common reported symptoms were abdominal pain, bloating and rumbling. DISCUSSION: Lactose malabsorption and intolerance can be investigated from the first years of life using the lactose breath test plus a symptom questionnaire. An increase in the frequency of intolerance with age, and a greater number of positive tests, if they were requested by a gastroenterologist, were observed. PMID- 26235687 TI - [Spirometry interpretation feasibility among pre-school children according to the European Respiratory Society and American Thoracic Society Guidelines]. AB - INTRODUCTION: Spirometry is the most used test to evaluate pulmonary function. Guidelines that defined acceptability and repeatability criteria for its implementation and interpretation among preschoolers were published in 2007. Our objective was to quantify the actual compliance with these criteria among pre school patients. METHODS: A review was performed on the baseline spirometry measured in patients aged 2 to 5 years in the Pediatric Respiratory Laboratory of the Pontificia Universidad Catolica de Chile, who were admitted due to recurrent or persistent coughing or wheezing. Only those results obtained in patients who took the test for the first time were considered. They were analyzed by international standards. RESULTS: A total of 93 spirometry results (mean age 57.4 +/- 8.6 months, 48 males) were obtained, of which 44 (47%) met all acceptable criteria, 87 (93%) obtained expiratory time of >= 0.5seconds, and 67 (72%) of the patients had an end-expiratory flow of <=10% from peak flow. The variation in the measurement of forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) was very low (intraclass correlation coefficient > 0.9). CONCLUSION: It was possible to meet the acceptability and repeatability criteria for spirometry among pre-school children in our Center, which was similar to previous reports. As in older children, this test is fully recommended for pre school children who require lung function studies. PMID- 26235688 TI - [Microalbuminuria in pediatric patients diagnosed with hemolytic uremic syndrome]. AB - INTRODUCTION: Hemolytic uremic syndrome (HUS) is characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney failure. It is the leading cause of acute kidney failure in children under 3 years of age. A variable number of patients develop proteinuria, hypertension, and chronic renal failure. OBJECTIVE: To evaluate the renal involvement in pediatric patients diagnosed with HUS using the microalbumin/creatinine ratio. PATIENTS AND METHODS: Descriptive concurrent cohort study that analyzed the presence of microalbuminuria in patients diagnosed with HUS between January 2001 and March 2012, who evolved without hypertension and normal renal function (clearance greater than 90ml/min using Schwartz formula). Demographic factors (age, sex), clinical presentation at time of diagnosis, use of antibiotics prior to admission, and need for renal replacement therapy were evaluated. RESULTS: Of the 24 patients studied, 54% were male. The mean age at diagnosis was two years. Peritoneal dialysis was required in 45%, and 33% developed persistent microalbuminuria. Antiproteinuric treatment was introduce in 4 patients, with good response. The mean follow-up was 6 years (range 6 months to 11 years). The serum creatinine returned to normal in all patients during follow up. CONCLUSIONS: The percentage of persistent microalbuminuria found in patients with a previous diagnosis of HUS was similar in our group to that described in the literature. Antiproteinuric treatment could delay kidney damage, but further multicenter prospective studies are necessary. PMID- 26235689 TI - [Weight control behaviors in dieting adolescent girls and their relation to body dissatisfaction and obsession with thinness]. AB - INTRODUCTION: Obsession with thinness and body dissatisfaction can lead adolescents to follow unsupervised diets, which could result in risky weight control behaviors such as fasting, vomiting, use of diuretics and laxatives. The aim of the current study is to examine weight control behaviors in dieting adolescents and relate them to body dissatisfaction (BD) and obsession with thinness (OT). METHODS: A cross-sectional study was conducted on 439 adolescents from Valparaiso public schools to investigate risky weight control behaviors due to BD and OT scales from the Eating Disorders Inventory-2 (EDI-2), comparing restrained eaters and non-restrained eaters. RESULTS: A total of 43% adolescents had followed a weight loss diet without medical supervision. The dieters had higher BD and OT values. Moderate to severe food restriction, based on expert judgment, was observed in 29.6%, and differences in the presence and severity of purging behaviors were found between the 2 groups. CONCLUSIONS: One third of the adolescents studied followed diets without professional supervision and had higher BD and OT values, as well as risky weight control behaviors. Overweight and obese adolescents followed more restrictive diets and developed riskier weight control behaviors. PMID- 26235690 TI - [Association between intracellular zinc levels and nutritional status in HIV infected and uninfected children exposed to the virus]. AB - INTRODUCTION: Malnutrition, growth retardation and opportunistic infections outlast the metabolic, immune and gastrointestinal disorders produced by HIV. Zinc deficiency has been associated with deteriorating nutritional status, growth failure, and risk of infection. The aim of this study is to determine the association between zinc levels in peripheral blood mononuclear cells (PBMC) and the nutritional status of HIV-infected and uninfected children exposed to the virus. PATIENTS AND METHODS: An analytical, observational, cross-sectional study was conducted on 17 infected and 17 exposed children, aged 2-10 years. Anthropometric measurements, clinical and nutritional history, 24h recall, measurement of physical activity, and zinc in PBMC by flow cytometry analysis were recorded. RESULTS: Height according to age, energy consumption and adequacy of energy, protein and dietary zinc were significantly higher in children exposed to the virus compared to those infected with HIV (P <.05). No significant differences were found in BMI, levels of zinc in monocytes, CD4 + and CD4- lymphocytes between the two study groups (P >.05). However, the median levels of zinc in monocytes of infected patients was higher (218.6) compared to the control group (217.0). No association was found between zinc intake and levels of intracellular zinc. CONCLUSIONS: The deterioration of nutritional status and growth retardation in children were associated with HIV, but not with the levels of intracellular zinc. The dietary intake of this nutrient was not associated with levels of zinc in monocytes or CD4 + and CD4- lymphocytes. PMID- 26235691 TI - [Chronic granulomatous disease: three cases with different presentations]. AB - INTRODUCTION: Chronic granulomatous disease (CGD) is a rare form of primary immunodeficiency disease, characterized by an abnormal susceptibility to bacterial and fungal infections, and it is caused by a deficit in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex (NADPH), resulting in the inability to generate reactive oxygen species that destroy microorganisms. The diagnosis is based on clinical characteristics and analysis of phagocytes, and later confirmed by molecular studies. Its management should consider antimicrobial prophylaxis, a search for infections and aggressive management of these. OBJECTIVE: To describe three cases of CGD emphasizing their forms of presentation and to conduct a review of the condition. CASE REPORTS: Three case reports, two of them first cousins, are presented. Molecular diagnosis was reached in one of the cases. Recurrent infections, abscesses, adenitis, granulomas and complications are identified to facilitate the suspected diagnosis of CGD, bearing in mind the importance of early diagnosis and genetic counseling. CONCLUSIONS: EGC is a rare congenital primary immunodeficiency disorder, mostly with X-linked inheritance, autosomal recessive form, and a specific presentation form. Its diagnosis should be timely to avoid complications. Prophylaxis and aggressive treatment of infections should be performed, as well as genetic counseling. PMID- 26235692 TI - [Giant paraovarian cyst in childhood - Case report]. AB - INTRODUCTION: Paraovarian cysts are very uncommon in children OBJECTIVE: To present a case of giant paraovarian cyst case in a child and its management using a modified laparoscopic-assisted technique CASE REPORT: A 13-year-old patient with a 15 day-history of intermittent abdominal pain, located in the left hemiabdomen and associated with progressive increase in abdominal volume. Diagnostic imaging was inconclusive, describing a giant cystic formation that filled up the abdomen, but without specifying its origin. Laboratory tests and tumor markers were within normal range. Video-assisted transumbilical cystectomy, a modified laparoscopic procedure with diagnostic and therapeutic intent, was performed with a successful outcome. The histological study reported giant paraovarian cyst. Cytology results were negative for tumor cells. The patient remained asymptomatic during the postoperative follow-up. CONCLUSIONS: The video assisted transumbilical cystectomy is a safe procedure and an excellent diagnostic and therapeutic alternative for the treatment of giant paraovarian cysts. PMID- 26235693 TI - [Pityriasis Lichenoides: Case report and review of the literature]. AB - INTRODUCTION: Pityriasis lichenoides is a benign inflammatory disease of unknown etiology. There are two types of this condition: an acute form (PLEVA = pityriasis lichenoides et varioliformis acuta) and a chronic one (PLC = pityriasis lichenoid chronica). Both are more common in children and young adults. OBJECTIVE: To describe a case of PLC, discuss its clinical presentation, diagnosis, treatment and present a review of the literature. CASE REPORT: A seven year-old child who presented with recurrent oligosymptomatic episodes of bright erythematous papular lesions in centripetal distribution, which subsided and left behind hypopigmented macules. The biopsy of the lesions confirmed chronic pityriasis lichenoid. During the 3 years of follow-up, multiple treatment regimens were used to reduce exacerbations, resulting in a partial response. CONCLUSION: PLC is a rare disease that represents a diagnostic and therapeutic challenge to the physician. The diagnosis of this condition is suspected clinically and confirmed by histology. It does not have specific treatment, but it responds well to corticosteroids, antibiotics, immunosuppressants and phototherapy with UVB narrowband (UVBnb). The latter has given the best results. It is important to monitor patients for risk of developing lymphoproliferative disorders. PMID- 26235694 TI - [Basics of early intervention in children with autism spectrum disorders]. AB - Autism Spectrum Disorders (ASD) are characterized by impairments in communication and social interaction, as well as restricted and repetitive patterns of behavior. They have a prevalence of 0.6% in the general population, although there are no national statistics. Even though their evolution is variable, it has been observed that early intervention is an important factor determining prognosis. The aim of this study is to update concepts regarding the current available evidence on the importance of early intervention. After analyzing the collected information, the importance of early intervention programs for children with ASD is confirmed, as well as the role of pediatricians and other health professionals in the early detection of these disorders. PMID- 26235695 TI - Development and transfer of vocabulary knowledge in Spanish-speaking language minority preschool children. AB - In this study we evaluated the predictive validity of conceptual scoring. Two independent samples of Spanish-speaking language minority preschoolers (Sample 1: N = 96, mean age = 54.51 months, 54.3% male; Sample 2: N = 116, mean age = 60.70 months, 56.0% male) completed measures of receptive, expressive, and definitional vocabulary in their first (L1) and second (L2) languages at two time points approximately 9-12 months apart. We examined whether unique L1 and L2 vocabulary at time 1 predicted later L2 and L1 vocabulary, respectively. Results indicated that unique L1 vocabulary did not predict later L2 vocabulary after controlling for initial L2 vocabulary. An identical pattern of results emerged for L1 vocabulary outcomes. We also examined whether children acquired translational equivalents for words known in one language but not the other. Results indicated that children acquired translational equivalents, providing partial support for the transfer of vocabulary knowledge across languages. PMID- 26235696 TI - Generalized seizure with falling and unresponsive staring provoked by somatosensory stimulation: a video-EEG study. AB - We report a 4-year-old boy with generalized seizures with abrupt falling and unresponsive staring provoked by somatosensory stimuli of the face. Ictal manifestation comprised a sudden fall immediately after wiping the face, followed by unresponsive staring for around 10 seconds, during which time the video-EEG recorded paroxysmal 3-Hz diffuse spike-wave complexes, which were followed by high-voltage 3.5 to 4-Hz delta wave discharges, predominantly appearing in the bilateral frontal areas. Seizures were not controlled by clonazepam, valproate or levetiracetam, but were successfully treated with lamotrigine added to valproate. This type of generalized reflex seizure has so far not been reported in the literature. [Published with video sequence]. PMID- 26235698 TI - Urban-rural disparities in the nutritional status of school adolescent girls in the Mizan district, south-western Ethiopia. AB - INTRODUCTION: Malnutrition that occurs during adolescence has important consequences for the future growth and development of the individual, particularly in girls in developing countries. Besides limiting growth, adolescent malnutrition has important consequences for society. Despite this, there is a lack of information on the nutritional status of adolescent girls in Ethiopia. This study was therefore performed to help redress this lack of data and to provide information for future improvements by health planners and policy makers. METHODS: A comparative cross-sectional study design was employed to determine the urban-rural disparity in nutritional status of adolescent school girls in the Mizan district in south-western Ethiopia. A two-stage sampling procedure was used to randomly select 622 adolescent girls, 311 each from urban and rural locations. Trained field workers used structured questionnaires to obtain the desired information from the respondents. Anthropometric measurements of height and weight were collected using standard procedures and appropriate quality control measures. Height-for-age Z-scores and body mass index (BMI)-for age Z-scores were generated using AnthroPlus software. The independent sample t test and chi2 test were used to determine statistical significance. RESULTS: There were no significant differences in the ages or physical activities of the two populations of girls studied. Consumption of cereal, vegetables, sweets, sugars, fats, meat, and eggs was similar between the two groups, although slight differences were found with regard to legumes, milk, and fruit consumption. No significant differences were found in the prevalence of mild underweight girls and overweight girls in the urban and rural groups (26.5% vs 22.3% and 7.5% vs 5.2%, respectively). Significant stunting was, however, present in the rural population (40.9% vs. 17.8% in the urban group). Although overall lower than the reference data provided by WHO, the mean BMI-for-age Z-scores and height-for-age Z-scores were significantly higher in the urban girls than in their rural counterparts, with mean differences of 0.18 (95% confidence interval (CI) 0.02 0.34) and 0.58 (95% CI 0.45-0.72), respectively. CONCLUSIONS: Malnutrition was present in both urban and rural adolescent girls. The most obvious disparity between the two populations was significant stunting in the rural population. There is therefore an urgent need for strategies to address severe nutritional problems in rural adolescent girls and to improve the nutrition of adolescent girls within the urban environment. PMID- 26235697 TI - Early medication use in new-onset rheumatoid arthritis may delay joint replacement: results of a large population-based study. AB - INTRODUCTION: Use of disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) may prevent joint damage and potentially reduce joint replacement surgeries. We assessed the association between RA drug use and joint replacement in Quebec, Canada. METHODS: A cohort of new-onset RA patients was identified from Quebec's physician billing and hospitalization databases from 2002-2011. The outcome was defined using procedure codes submitted by orthopedic surgeons. Medication use was obtained from pharmacy databases. We used alternative Cox regression models with time-dependent variables measuring the cumulative effects of past use during different time windows (one model focussing on the first year after cohort entry) for methotrexate (MTX), and other DMARDs. Models were adjusted for baseline sociodemographics, co-morbidity and prior health service use, time-dependent cumulative use of other drugs (anti-tumor necrosis factor [anti-TNF] agents, other biologics, cyclooxygenase-2 inhibitors [COXIBs], nonselective nonsteroidal antiinflammatory drugs [NSAIDs], and systemic steroids), and markers of disease severity. RESULTS: During follow-up, 608 joint replacements occurred among 11,333 patients (median follow-up: 4.6 years). The best-fitting model relied on the cumulative early use (within the first year after cohort entry) of MTX and of other DMARDs, with an interaction between MTX and other DMARDs. In this model, greater exposure within the first year, to either MTX (adjusted hazard ratio, HR = 0.95 per 1 month, 95% confidence interval, 95% CI 0.93-0.97) or other DMARDs (HR = 0.97, 95% CI 0.95-0.99) was associated with longer time to joint replacement. CONCLUSIONS: Our results suggest that longer exposure to either methotrexate (MTX) or other DMARDs within the first year after RA diagnosis is associated with longer time to joint replacement surgery. PMID- 26235699 TI - Usefulness of multiple frequency band source localizations in ictal MEG. AB - OBJECTIVE: We evaluated the diagnostic value of multiple frequency band MEG source localization within a wide time window during the preictal period. METHODS: Data for 13 epilepsy patients who showed an ictal event during MEG were analyzed. Several seconds of preictal data were localized in the theta, alpha, beta, and gamma bands by using wavelet transformation and the sLORETA algorithm. The same analysis was performed with narrow time and frequency band. Localization concordances to the surgically resected area were compared. RESULTS: Source localization in the gamma band for a 10s window before ictal onset showed best concordance to the resection cavity. Eight of 13 patients showed sub-lobar concordance in the 10s gamma band localization, whereas 3 showed concordance in the narrow time and frequency analysis. Four of 7 patients with focal cortical dysplasia (FCD) achieved seizure-free outcome, and all 4 showed sub-lobar concordance. CONCLUSIONS: A 10s time window gamma source localization method can be used to delineate the epileptogenic zone. SIGNIFICANCE: The use of a long period during preictal gamma source localization has the potential to become a localizing biomarker of the epileptogenic zone in candidates for surgical intervention, especially in MRI-suspected FCD. PMID- 26235701 TI - Repair of complex vesicovaginal fistulas by combining a rotational bladder flap and full thick vascular peritoneal interposition. AB - PURPOSE: To present the experience of repairing iatrogenic vesicovaginal fistulas (VVFs) using a rotational bladder flap and peritoneal interposition technique. METHODS: Between January 2009 and June 2014, a total of 18 patients (mean age, 44.0 years; age range, 29-51 years) with VVFs were treated using a transperitoneal approach. All VVFs were complications of gynecologic procedures. Twelve patients experienced recurrent VVFs and one patient had a concomitant rectovaginal fistula after radiotherapy. The fistula was approached transabdominally. The peritoneum covering the bladder was isolated to expose the bladder and prepare for the interposition. The bladder was opened along the sagittal plane to the fistula and a bladder flap was rotated downward to fill the fistula defect. The vaginal defect was closed, then a flap using the isolated peritoneum was interposed and fixed between the vagina and bladder. A ureteral re implantation was performed in one patient. All VVF procedures were performed by one urologist (SW). Repair of the rectovaginal fistula was performed by a general surgeon at the same time. RESULTS: Seventeen patients (success rate = 94% [100% for primary cases and 92% for recurrent cases]) had no evidence of recurrent VVF at a mean follow-up of 20 months (range, 6-36 months). The only patient who had previously undergone a repair procedure failed. CONCLUSIONS: A transperitoneal approach with the use of a rotational bladder flap and peritoneal interposition might be a feasible and reliable procedure for surgical management of iatrogenic VVFs, especially in complicated cases. Neurourol. Urodynam. 35:934-938, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26235702 TI - Mouse white adipose tissue-derived mesenchymal stem cells gain pericentral and periportal hepatocyte features after differentiation in vitro, which are preserved in vivo after hepatic transplantation. AB - AIM: Mesenchymal stem cells may differentiate into hepatocyte-like cells in vitro and in vivo. Therefore, they are considered a novel cell resource for the treatment of various liver diseases. Here, the aim was to demonstrate that mesenchymal stem cells may adopt both perivenous and periportal hepatocyte specific functions in vitro and in vivo. METHODS: Adipose tissue-derived mesenchymal stem cells were isolated from immunodeficient C57BL/6 (B6.129S6 Rag2(tm1Fwa) Prf1(tm1Clrk) ) mice and differentiated into the hepatocytic phenotype by applying a simple protocol. Their physiological and metabolic functions were analysed in vitro and after hepatic transplantation in vivo. RESULTS: Mesenchymal stem cells changed their morphology from a fibroblastoid into shapes of osteocytes, chondrocytes, adipocytes and hepatocytes. Typical for mesenchymal stem cells, hematopoietic marker genes were not expressed. CD90, which is not expressed on mature hepatocytes, decreased significantly after hepatocytic differentiation. Markers indicative for liver development like hepatic nuclear factor 4 alpha, or for perivenous hepatocyte specification like cytochrome P450 subtype 3a11, and CD26 were significantly elevated. Periportal hepatocyte-specific markers like carbamoylphosphate synthetase 1, the entry enzyme of the urea cycle, were up-regulated. Consequently, cytochrome P450 enzyme activity and urea synthesis increased significantly to values comparable to cultured primary hepatocytes. Both perivenous and periportal qualities were preserved after hepatic transplantation and integration into the host parenchyma. CONCLUSIONS: Adult mesenchymal stem cells from adipose tissue differentiated into hepatocyte-like cells featuring both periportal and perivenous functions. Hence, they are promising candidates for the treatment of region-specific liver cell damage and may support organ regeneration in acute and chronic liver diseases. PMID- 26235704 TI - Patients' experience of a nurse-led lifestyle clinic at a Swedish health centre. AB - BACKGROUND: In Sweden, 56% of the population aged 16-84 have an unhealthy lifestyle. The primary health care (PHC) has been instructed to offer citizens health promotion and disease-preventive actions. Very few studies have been conducted about how individuals experience interventions from the PHC intended to help them to change lifestyle. AIM: The purpose of the study was to explore patients' experiences of visiting a nurse-led lifestyle clinic. METHODS: Patients (n = 137), who participated in a screening test at a lifestyle clinic, were invited to focus group interviews. Of these, 14 patients agreed to participate. The data were analysed using content analysis. RESULTS: The patients felt that the visit to the lifestyle clinic gave insight into their habits and diminished their fear of not being healthy. Primary health care was seen as a safe provider in this matter. Disappointment was occasioned by the unfulfilled expectations of blood tests, lack of follow-up visit and inconsistencies of approach during the visit to the lifestyle clinic. Personal chemistry was perceived to be crucial for how the encounter with the public health nurse evolved. CONCLUSION: Lifestyle clinics can give patients opportunity to change lifestyle and also to confirm the good habits. It may also be important to have follow-up visits to give the patients' support when changing lifestyle. Nurses counselling patients about lifestyle changes need to have recurrent training in Motivational Interviewing. PMID- 26235703 TI - True Gold or Pyrite: A Review of Reference Point Indentation for Assessing Bone Mechanical Properties In Vivo. AB - Although the gold standard for determining bones' mechanical integrity is the direct measure of mechanical properties, clinical evaluation has long relied on surrogates of mechanical properties for assessment of fracture risk. Nearly a decade ago, reference point indentation (RPI) emerged as an innovative way to potentially assess mechanical properties of bone in vivo. Beginning with the BioDent device, and then followed by the newer generation OsteoProbe, this RPI technology has been utilized in several publications. In this review we present an overview of the technology and some important details about the two devices. We also highlight select key studies, focused specifically on the in vivo application of these devices, as a way of synthesizing where the technology stands in 2015. The BioDent machine has been shown, in two clinical reports, to be able to differentiate fracture versus nonfracture patient populations and in preclinical studies to detect treatment effects that are consistent with those quantified using traditional mechanical tests. The OsteoProbe appears able to separate clinical cohorts yet there exists a lack of clarity regarding details of testing, which suggests more rigorous work needs to be undertaken with this machine. Taken together, RPI technology has shown promising results, yet much more work is needed to determine if its theoretical potential to assess mechanical properties in vivo can be realized. PMID- 26235705 TI - A magnetic resonance imaging family study of cortical thickness in schizophrenia. AB - Schizophrenia is associated with abnormalities in cortical thickness, including both thicker and thinner cortices than controls. Although less reliably than in patients, non-psychotic relatives of schizophrenia patients have also demonstrated both thicker and thinner cortices than controls, suggesting an effect of familial or genetic liability. We investigated cortical thickness in 25 schizophrenia patients, 26 adult non-psychotic first-degree biological relatives, and 23 community controls using the automated program FreeSurfer. Contrary to hypotheses, we found relatives of schizophrenia patients had greater cortical thickness in all lobes compared to patients and controls; however, this finding was not as widespread when compared to controls. In contrast, schizophrenia patients only demonstrated a thinner right fusiform region than controls and relatives. Our finding of greater thickness in adult biological relatives could represent a maladaptive abnormality or alternatively, a compensatory mechanism. Previous literature suggests that the nature of abnormalities in relatives can vary by the age of relatives and change across the developmental period. Abnormalities in patients may depend on lifestyle factors and on current and previous anti-psychotic medication use. Our results speak to the need to study various populations of patients and relatives across the lifespan to better understand different developmental periods and the impact of environmental factors. (c) 2015 Wiley Periodicals, Inc. PMID- 26235706 TI - Bias and imprecision in analysis of real-time quantitative polymerase chain reaction data. AB - Monte Carlo simulations are used to examine the bias and loss of precision that result from experimental error and analysis procedures in real-time quantitative polymerase chain reaction (PCR). In the limit of small copy numbers (N0), Poisson statistics govern the dispersion in estimates of the quantification cycle (Cq) for replicate experiments, permitting the estimation of N0 from the Cq variance, which is inversely proportional to N0. We derive corrections to expressions given previously for this determination. With increasing N0, the Poisson contribution decreases and other effects, like pipet volume uncertainty (typically >3%), dominate. Cycle-to-cycle variability in the amplification efficiency E produces scale dispersion similar to that for variability in the sensitivity of fluorescence detection. When this E variability is proportional to just the amplification (E - 1), there is insignificant effect on Cq if scale-independent definitions are used for this marker. Single-reaction analysis methods based on the exponential growth equation are inherently low-biased in E and high-biased in N0, and these biases can amount to factor-of-4 or greater error in N0. For estimating Cq, their greatest limitation is use of a constant absolute threshold, making them inefficient for data that exhibit scale variability. PMID- 26235708 TI - Stabilization of ferromagnetic ordering in cobaltite double perovskites of La2CoIrO6 and La2CoPtO6. AB - We investigated the local electronic structure and magnetic properties of the cobaltite double perovskites La2CoIrO6 and La2CoPtO6 using Co L2,3-edge x-ray absorption spectroscopy and x-ray magnetic circular dichroism. Despite similarity in the local electronic structure (Co(2+) high-spin states) as well as in the crystal structure (P2(1)/n), only La2CoIrO6 exhibits substantial orbital and spin magnetic moments of Co(2+), whereas they are much weaker in the case of La2CoPtO6. This composition dependence is consistent with the results of magnetization measurements. The details of the mechanism of ferromagnetic ordering in the Co(2+) sublattice in La2CoIrO6 and the lack thereof in La2CoPtO6 are explained in terms of the orbital hybridization of the Co minority-spin t(2g) state and the Ir/Pt j(eff) = 1/2 state. PMID- 26235707 TI - Taurine Boosts Cellular Uptake of Small D-Peptides for Enzyme-Instructed Intracellular Molecular Self-Assembly. AB - Due to their biostability, D-peptides are emerging as an important molecular platform for biomedical applications. Being proteolytically resistant, D-peptides lack interactions with endogenous transporters and hardly enter cells. Here we show that taurine, a natural amino acid, drastically boosts the cellular uptake of small D-peptides in mammalian cells by >10-fold, from 118 MUM (without conjugating taurine) to >1.6 mM (after conjugating taurine). The uptake of a large amount of the ester conjugate of taurine and D-peptide allows intracellular esterase to trigger intracellular self-assembly of the D-peptide derivative, further enhancing their cellular accumulation. The study on the mechanism of the uptake reveals that the conjugates enter cells via both dynamin-dependent endocytosis and macropinocytosis, but likely not relying on taurine transporters. Differing fundamentally from the positively charged cell-penetrating peptides, the biocompatibility, stability, and simplicity of the enzyme-cleavable taurine motif promise new ways to promote the uptake of bioactive molecules for countering the action of efflux pump and contributing to intracellular molecular self-assembly. PMID- 26235709 TI - Influence of the bracket on bonding and physical behavior of orthodontic resin cements. AB - The aim of the study is to determine the influence of the type of bracket, on bond strength, microhardness and conversion degree (CD) of four resin orthodontic cements. Micro-tensile bond strength (uTBS) test between the bracket base and the cement was carried out on glass-hour-shaped specimens (n=20). Vickers Hardness Number (VHN) and micro-Raman spectra were recorded in situ under the bracket base. Weibull distribution, ANOVA and non-parametric test were applied for data analysis (p<0.05). The highest values of eta as well as the beta Weibull parameter were obtained for metallic brackets with TransbondTM plastic brackets with the self-curing cement showing the worst performance. The CD was from 80% to 62.5%. PMID- 26235710 TI - The hydration chemistry of ProRoot MTA. AB - 'Tooth-coloured' ProRoot MTA is an endodontic cement comprising an 80:20 wt% mixture of white Portland cement (WPC) and bismuth oxide. The setting reactions within this cement system are not currently well understood. Accordingly, this research monitors the early hydration chemistry of ProRoot MTA by X-ray diffraction, solid state nuclear magnetic resonance and Fourier transform infrared spectroscopies, and isothermal calorimetry. The initial rate of hydration is rapid with 40% having reacted within the first 24 h; it then slows considerably such that within 3 days the hydration reactions are 58% complete and only increase by a further 1% within one week. The relatively fast reaction of alite to form C-S-H gel and portlandite, and the development of the calcium aluminosulphate phases, are as would be anticipated for the hydration of pure WPC. These findings confirm that bismuth oxide is an inert additive which does not participate in the hydration reactions. PMID- 26235711 TI - Controlled release of simvastatin from biodegradable hydrogels promotes odontoblastic differentiation. AB - The objective of this study was to investigate the odontoblastic differentiation of dental pulp stem cells (DPSC) by biodegradable hydrogels incorporating simvastatin micelles, both in vitro and in vivo. Simvastatin (ST) was incorporated into the micelles of gelatin grafted with L-lactic acid oligomers (LAo) to allow water-solubilization. The simvastatin-LAo-grafted gelatin (LAo-g gelatin) micelles were mixed with gelatin, followed by chemical crosslinking to form gelatin hydrogels (ST Mi/GH). The ST Mi were released from the gelatin hydrogel granules (GH) through enzymatic degradation. The ST Mi enhanced alkaline phosphatase activity, calcium deposition, and bone morphogenic protein-2 secretion of DPSC. When implanted subcutaneously into mice, the ST Mi/GH treated group exhibited increased dentin sialoprotein and calcium deposition, compared with those treated with GH plus free ST. It is possible to achieve odontoblastic differentiation of DPSC through the controlled release of ST from GH. PMID- 26235712 TI - Construction and in vitro characterization of three-dimensional silk fibroinchitosan scaffolds. AB - The objective of this study was to discuss the construction method, characterization, and biocompatibility of three-dimensional silk fibroin-chitosan (SF-CS) scaffolds which met the requirements of bone tissue engineering scaffolds. Silk fibroin (SF) and chitosan (CS) were mixed at different ratios -3 to 7, 5 to 5, and 7 to 3- to fabricate the composite materials. To find out the optimum mixing ratio of SF and CS, parameters such as pore size, porosity, water absorption, and the mechanical properties were evaluated. Osteoblast cells hFOB1.19 were seeded on SF-CS scaffolds and pure CS scaffolds for the first time. Cell adhesion rate, cell proliferation, and cell activity were evaluated, and cell growth and formation of mineralized nodules were observed. Results showed that SF-CS scaffolds are a suitable candidate for bone tissue engineering. PMID- 26235713 TI - Effect of repair resin type and surface treatment on the repair strength of polyamide denture base resin. AB - The purpose of the present study was to evaluate the effects of different repair resins and surface treatments on the repair strength of a polyamide denture base material. Polyamide resin specimens were prepared and divided into nine groups according to the surface treatments and repair materials. The flexural strengths were measured with a 3-point bending test. Data were analyzed with a 2-way analysis of variance, and the post-hoc Tukey test (alpha=0.05). The effects of the surface treatments on the surface of the polyamide resin were examined using scanning electron microscopy. The repair resins and surface treatments significantly affected the repair strength of the polyamide denture base material (p<0.05); however, no significant differences were observed interaction between the factors (p>0.05). The flexural strength of the specimens repaired with the polyamide resin was significantly higher than that of those repaired with the heat-polymerized and autopolymerizing acrylic resins. PMID- 26235714 TI - Push-out bond strength of CPP-ACP-modified calcium silicate-based cements. AB - This study evaluated the push-out bond strength of 0%, 0.5%, 1.0%, 2.0% and 3.0% (w/w) casein phosphopeptide-amorphous calcium phosphate (CPP-ACP)-modified calcium silicate-based cements (CSCs). The push-out bond strength of a trial MTA was also compared with two CSCs (Biodentine(TM) and Angelus((r)) MTA). Three hundred 1 mm thick horizontal root sections were prepared from 60 singlerooted human teeth. The canal space of each section was enlarged and filled with the cements. The sections were stored in a phosphate buffer solution. After incubation for 2 months, the push-out bond strength was measured and the data were analyzed using one way analysis of variance followed by Tukey's test. The addition of CPP-ACP to the test cements increased the push-out bond strength (p<0.05). The push-out bond strength of Biodentine(TM) was higher than the other cements (p<0.05). There was no statistically significant difference between Angelus((r)) MTA and the trial MTA with most of CPP-ACP concentrations. PMID- 26235715 TI - In vitro evaluation of the wear resistance of composite resin blocks for CAD/CAM. AB - The aim of the study was to investigate two- and three-body wear of CAD/CAM blocks. Four composite resins, one hybrid ceramic and one feldspar ceramic block material were examined. Six specimens each were tested in a ball-on-disc wear device fitted with a zirconia ball (50 N load, 1.2 Hz, 50 k cycles) in water for two-body and in poppy seed slurry for three-body wear evaluation. Volume loss after each 10 k cycle was quantified using a digital CCD microscope. STATISTICAL ANALYSIS: ANOVA and Tukey's multiple comparisons (alpha=0.05). Two-body wear for composite resin blocks was small, hybrid ceramic and ceramic blocks showed larger volume loss. Threebody wear was very low for all materials. All CAD/CAM block materials investigated displayed low wear compared to previous data for direct posterior composites carrying out the same wear test. The block materials are considered suitable for fabrication of single full crown restorations on premolar teeth. PMID- 26235716 TI - Mechanical properties of dental Ti-Ag alloys with 22.5, 25, 27.5, and 30 mass% Ag. AB - The mechanical properties -tensile strength, yield strength, elongation after fracture, Vickers hardness, and Young's modulus-and the phases of Ti-Ag alloys were investigated, as prepared with 22.5, 25, 27.5, and 30 mass% Ag. The tensile strength, yield strength, hardness, and Young's modulus of the alloys increase with their Ag content up to 25 mass%, but their breaking elongation decreases. These changes in the mechanical properties are attributed to solid-solution strengthening of the alpha-titanium phase, to Ti2Ag precipitation, and to the formation of eutectic structures composed of alpha+Ti2Ag. The addition of Ag, at 25 mass% in particular, improves the mechanical properties of these alloys, making them suitable for high strength dental prostheses, such as implantretained superstructures and narrow-diameter implants. PMID- 26235718 TI - Interfacial adaptation and thickness of bioceramic-based root canal sealers. AB - This study evaluated and compared the sealer thickness and interfacial adaptation of bioceramic sealers (Sankin Apatite III, MTA Fillapex((r)), EndoSequence((r)) BC) to root dentin against AH Plus((r)) sealer. Sixty extracted single-root premolars were prepared and equally divided into four groups. Sealers were labeled with 0.1% Rhodamine B fluorescent dye. Roots were dissected along the transverse plane at 1 mm (apical), 3 mm (middle), and 6 mm (coronal) levels. Sealer-to-whole canal area ratio was evaluated. Percentage of gap-containing region to canal circumference was calculated using a confocal laser microscope. Sealer thickness was significantly higher at apical and middle levels than at coronal level. EndoSequence BC had the significantly highest thickness compared with MTA Fillapex and AH Plus. The coronal level had significantly less interfacial gaps compared with apical and middle levels. Bioceramic sealers showed more gaps compared with AH Plus, with no significant differences among them. PMID- 26235717 TI - Comparison of peri-implant bone formation around injection-molded and machined surface zirconia implants in rabbit tibiae. AB - The aim of this study was to compare osseointegration and surface characteristics of zirconia implants made by the powder injection molding (PIM) technique against those made by the conventional milling procedure in rabbit tibiae. Surface characteristics of 2 types of implants were evaluated. Sixteen rabbits received 2 types of external hex implants with similar geometry, either machined zirconia implants or PIM zirconia implants, in the tibiae. Removal torque tests and histomorphometric analyses were performed. The roughness of the PIM zirconia implants was higher than that of machined zirconia implants. The PIM zirconia implants exhibited significantly higher bone-implant contact and removal torque values than the machined zirconia implants (p<0.001). The osseointegration of the PIM zirconia implant is promising, and PIM, using the roughened mold etching technique, can produce substantially rougher surfaces on zirconia implants. PMID- 26235719 TI - Gypsum-based biomaterials: Evaluation of physical and mechanical properties, cellular effects and its potential as a pulp liner. AB - This in vitro study aimed to evaluate setting time and compressive strength of gypsum-based chitosan biomaterials and its effect on proliferation of stem cells from human exfoliated deciduous teeth (SHED) and alkaline phosphatase (ALP) activity. Pure-GYP was mixed with water (2.5 g: 1.9 mL); Gyp-CHT was prepared with gypsum, chitosan, and water (2.5 g: 0.285 g: 1.9 mL). Cell viability and ALP activity were assessed at different periods. Data were analyzed using SPSS (p<0.05). The setting times were 2.7 min and 2.8 min for pure-GYP and Gyp-CHT, respectively. Significantly higher compressive strength was observed with Gyp CHT. SHED treatments with both materials were not cytotoxic. ALP was consistently higher in the treated groups compared with the control. Cellular attachments were evident with SEM. Excellent cellular viability with pure-GYP and Gyp-CHT, as well as increased ALP activities, suggested the possibility of tertiary dentin formation. Further studies are necessary to evaluate the biomaterials for its pulp protective potentialities. PMID- 26235720 TI - Cold plasma-induced surface modification of heat-polymerized acrylic resin and prevention of early adherence of Candida albicans. AB - Atmospheric-pressure cold plasma was applied to process the surface of heat polymerized acrylic resin. Changes to the physical properties and early adherence of Candida albicans were investigated. Alternating current cold plasma with Ar/O2 as working gas was used. Scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) were employed to study the possible mechanism. Experimental results showed that after plasma treatment, the contact angle of acrylic resin significantly decreased. There were no significant differences in roughness, flexural strength and elasticity modulus, but microhardness was significant improved in the treated group. More importantly, the early adherence of Candida albicans on the surface was reduced after plasma treatment. Cold plasma seemed to be a promising and convenient strategy of preventing the early adherence of Candida albicans on acrylic resins, which would greatly benefit potential dental applications. PMID- 26235721 TI - NaOCl-mediated biofunctionalization enhances bone-titanium integration. AB - The aim of this study was to examine the effect of NaOCl pretreatment on the biomechanical fixation of implant at the early healing stage of a rat model. Polished titanium cylindrical implants and disks were prepared, and one-half of these samples were dual acidetched. Then, one-half of both surfaces were chemically-cleaned by pretreatment with 5% NaOCl solution for 24 h. Morphological analyses showed that there was no significant difference between before and after NaOCl treatment. The wettability measurement demonstrated that NaOCl treatment secondarily converted both titanium surfaces from hydrophobic to superhydrophilic, accompanied by the removal of hydrocarbons from the titanium surfaces. Biomechanical push-in test indicated that the bone-titanium integration strength of the NaOCl-treated implants were significantly greater than that of the untreated implants (p<0.05). These results showed that NaOCl pretreatment enhanced the osseointegration capability of titanium, indicating its potential for a simple chemical chair-side pretreatment method. PMID- 26235722 TI - Observation of white spot lesions using swept source optical coherence tomography (SS-OCT): in vitro and in vivo study. AB - This study aimed to assess swept source optical coherence tomography (SS-OCT) for in vitro and in vivo detection of enamel white spot lesion (WSL). WSLs without surface breakdown on 33 extracted human posterior teeth were non-invasively scanned using SSOCT. The teeth were then cross-sectioned and imaged under confocal laser scanning microscope (CLSM) and light microscopy (LM). SS-OCT cross sectional images were compared with CLSM and LM. WSL shapes in SS-OCT images closely corresponded to those of LM. There were significant correlations (p<0.001) in WSLs depth between SS-OCT and LM (r=0.92), SS-OCT and CLSM (r=0.80) and CLSM and LM (r=0.85). Six WSLs were also evaluated clinically using SS-OCT; clear in-depth images of these natural WSLs were obtained in vivo. SS-OCT appears to be an effective tool for observation of the internal structure of WSLs, enabling quantitative assessment of WSL depth. Such data can be considered in the clinical management of WSLs. PMID- 26235723 TI - On Structural Features Necessary for Near-IR-Light Photocatalysts. AB - In the search for photocatalysts that can directly utilize near-IR (NIR) light, we investigated three oxides Cu3(OH)4SO4 (antlerite), Cu4(OH)6SO4, and Cu2(OH)3Cl by photodecomposing 2,4-dichlorophenol over them under NIR irradiation and by comparing their electronic structures with that of the known NIR photocatalyst Cu2(OH)PO4. Both Cu3(OH)4SO4 and Cu4(OH)6SO4 are NIR photocatalysts, but Cu2(OH)3Cl is not. Thus, in addition to the presence of two different CuOm and Cu'On polyhedra linked with Cu-O-Cu' bridges, the presence of acceptor groups (e.g., SO4, PO4) linked to the metal oxygen polyhedra is necessary for NIR photocatalysts. PMID- 26235724 TI - The effect of perineural anaesthesia and handler position on limb loading and hoof balance of the vertical ground reaction force in sound horses. AB - REASONS FOR PERFORMING STUDY: The effects of handler position and perineural anaesthesia in sound horses need investigation to facilitate interpretation of pressure plate analysis in lame horses. OBJECTIVES: To evaluate the effect of handler position and perineural anaesthesia on limb loading and particularly hoof balance in sound horses. STUDY DESIGN: Nonrandomised crossover study. METHODS: Six sound horses were walked and trotted over a pressure plate, with the handler on the left and subsequently on the right side, and finally after a bilateral low palmar digital nerve block. One week later this procedure was repeated before and after a bilateral abaxial sesamoidean nerve block. Peak vertical force, vertical impulse and stance time of 5 hoof prints of both forelimbs were obtained (126 Hz), and toe-heel and mediolateral hoof balance curves of the vertical force were plotted throughout stance. Limb-loading and timing data and hoof balance data (beginning, middle and end of the stance phase) were statistically compared (handler left compared with right; before compared with after low palmar digital nerve block and abaxial sesamoidean nerve block; baseline at first measurement session compared with second). RESULTS: There were no significant effects of handler position and perineural anaesthesia on peak vertical force, vertical impulse and stance time. Hoof balance curves were not affected by handler position or perineural anaesthesia. The limb loading data and hoof balance curves were comparable for each horse over the one-week interval. CONCLUSIONS: Handler position and perineural anaesthesia do not have an effect on limb loading and toe heel and mediolateral hoof balance in sound horses, which is of fundamental importance before embarking on pressure plate analysis for lameness diagnosis. PMID- 26235725 TI - Cu-Catalyzed direct cyanation of terminal alkynes with AMBN or AIBN as the cyanation reagent. AB - A Cu-catalyzed direct cyanation of terminal alkynes was reported with broad substrate generality in moderate to high yield, and AMBN (azobisisoamylonitrile)/AIBN (azobisisobutyronitrile) were used as less toxic and effective cyanating sources in open air. Interestingly, addition products were selectively achieved as the major product under the same conditions in argon. PMID- 26235726 TI - Analysing the effects of the aeration pattern and residual ammonium concentration in a partial nitritation-anammox process. AB - A mathematical model was used to evaluate the effect of the aeration pattern and ammonium concentration in a partial nitritation-anammox sequencing batch reactor with granular and flocculent sludge. In the tested conditions, model results indicate that most of the aerobic ammonium oxidation potential would occur in the bulk liquid, with 70% of the ammonium-oxidizing bacteria (AOB) biomass in suspension rather than in granules. The simulated granular sludge consisted predominantly of anammox bacteria with AOB present in the outer layer of the granule (50 MUm AOB layer, accounting for 3% of the granule weight). Simulation results indicated that when granules do not contain any AOB, the amount of granular biomass required to achieve the same level of nitrogen removal would strongly increase (in the simulated conditions, by a factor of three) due to anammox inhibition by oxygen. This underlines the importance of a small fraction of AOB present in the granular anammox sludge. The aeration pattern had an important impact on the nitrogen removal: a better performance was suggested for continuous aeration (90% N-removal) than for intermittent aeration (68-84% N removal). Anammox inhibition during the periods of high oxygen concentration was identified as the main reason for the lower nitrogen removal in the intermittently aerated system. With increasing oxygen concentration, a higher residual (effluent) ammonium concentration was needed to assure nitrite-oxidizing bacteria repression in the system. This study contributes to further understand the complexity of a reactor with both granular and flocculent sludge and the impact of operation conditions on reactor performance. PMID- 26235727 TI - Using baby oil to remove asphalt from burn. PMID- 26235728 TI - Biosynthesis-assisted structural elucidation of the bartolosides, chlorinated aromatic glycolipids from cyanobacteria. AB - The isolation of the bartolosides, unprecedented cyanobacterial glycolipids featuring aliphatic chains with chlorine substituents and C-glycosyl moieties, is reported. Their chlorinated dialkylresorcinol (DAR) core presented a major structural-elucidation challenge. To overcome this, we discovered the bartoloside (brt) biosynthetic gene cluster and linked it to the natural products through in vitro characterization of the DAR-forming ketosynthase and aromatase. Bioinformatic analysis also revealed a novel potential halogenase. Knowledge of the bartoloside biosynthesis constrained the DAR core structure by defining key pathway intermediates, ultimately allowing us to determine the full structures of the bartolosides. This work illustrates the power of genomics to enable the use of biosynthetic information for structure elucidation. PMID- 26235729 TI - Identifying and integrating consumer perspectives in clinical practice guidelines on autosomal-dominant polycystic kidney disease. AB - AIM: This study aimed to identify consumer perspectives on topics and outcomes to integrate in the Kidney Health Australia Caring for Australasians with Renal Impairment (KHA-CARI) clinical practice guidelines on autosomal-dominant polycystic kidney disease (ADPKD). METHODS: A workshop involving three concurrent focus groups with 18 consumers (patients with ADPKD (n = 15), caregivers (n = 3)) was convened. Guideline topics, interventions and outcomes were identified, and integrated into guideline development. Thematic analysis was used to analyse the reasons for their choices. RESULTS: Twenty-two priority topics were identified, with most focussed on non-pharmacological management (diet, fluid intake, physical activity, complementary medicine), pain management and psychosocial care (mental health, counselling, cognitive and behavioural training, education, support groups). They also identified 26 outcomes including quality of life (QoL), progression of kidney disease, kidney function, cyst growth and nephrotoxity. Almost all topics and outcomes suggested were identified by health professionals with the exception of five topics/outcomes. Six themes reflected reasons for their choices: clarifying ambiguities, resolving debilitating pain, concern for family, preparedness for the future, taking control and significance of impact. CONCLUSION: Although there was considerable concordance between the priority topics and outcomes of health professionals and consumers for guidelines of ADPKD, there was also important discordance with consumers focused on fewer issues, but particularly on lifestyle, psychosocial support, pain, and QoL and renal outcomes. Active consumer engagement in guidelines development can help to ensure the inclusion of patient-centred recommendations, which may lead to better management of disease progression, symptoms, complications, and psychosocial impact. PMID- 26235730 TI - Trajectories of Change in Psychotherapy. AB - OBJECTIVE: The current study used multilevel growth mixture modeling to ascertain groups of patients who had similar trajectories in their psychological functioning over the course of short-term treatment. METHOD: A total of 10,854 clients completed a measure of psychological functioning before each session. Psychological functioning was measured by the Behavioral Health Measure, which is an index of well-being, symptoms, and life-functioning. Clients who attended 5 to 25 sessions at 46 different university/college counseling centers and one community mental health center were included in this study. Client diagnoses and the specific treatment approaches were not known. RESULTS: A 3-class solution was a good fit to the data. Clients in classes 1 and 3 had moderate severity in their initial psychological functioning scores, and clients in class 2 had more distressed psychological functioning scores. The trajectory for clients in class 1 was typified by early initial change, followed by a plateau, and then another gain in psychological functioning later in treatment. The trajectory for clients in class 2 demonstrated an initial decrease in functioning, followed by a rapid increase, and then a plateau. Last, the clients in class 3 had a steady increase of psychological functioning, in a more linear manner. CONCLUSION: The trajectories of change for clients are diverse, and they can ebb and flow more than traditional dose-effect and good-enough level models may suggest. PMID- 26235731 TI - Modified functional obturator for the consideration of facial growth in the mucoepidermoid carcinoma pediatric patient. AB - Mucoepidermoid carcinoma (MEC) is a common salivary gland tumor in a adults but is very rare in pediatric patients. The standard treatment of MEC is en bloc resection with wide safety margins and subsequent reconstruction of the jaw, but few surgeons or pediatric specialists have experience with this procedure. An 11 year-old boy received a hemi-maxillectomy with subsequent application of the modified functional obturator (MFO) by the functional matrix concept of Moss. And the patient's face showed normal growth pattern. The purpose of this report is to demonstrate the novel concept of pediatric maxillary reconstruction using MFO for the consideration of facial growth. PMID- 26235732 TI - Systematic review and meta-analysis of randomized controlled trials on the role of mometasone in adenoid hypertrophy in children. AB - OBJECTIVES: Mometasone has been reported to improve the symptoms of nasal obstruction in children with adenoidal hypertrophy. This systematic review and meta-analysis were conducted to evaluate the role of mometasone on different nasal symptoms, otitis media with effusion, adenoid size, and quality of life in children with adenoidal hypertrophy. METHODS: A comprehensive search of MEDLINE, EMBASE, CINAHL and COCHRANE Collaboration databases was undertaken. We identified all the randomized controlled trials (RCTs) in children with adenoidal hypertrophy that compared the effects of mometasone nasal spray and normal saline nasal spray on different outcomes. The deadline of the search was April 2015. The search was supplemented by hand searching of cross-references in the studies and reviews and by contacting the authors of various studies. Only English language RCTs were considered for the systematic review. The primary outcomes were improvement in symptoms of nasal obstruction, mouth breathing, rhinorrhea, snoring, cough, and total nasal symptoms. The secondary outcomes were improvement in otitis media with effusion, quality of life, and size of adenoid. Quality assessment of RCTs was performed using SIGN 50 and Cochrane risk of bias tools. Risk ratio (RR), weighted mean differences (WMD) and their 95% confidence intervals (CI) were calculated for dichotomous and continuous data, respectively. Random effects model was used for the analyses. Heterogeneity was measured by using the I(2) statistics and p value <0.05. RESULTS: Our search generated 87 citations, of which eight RCTs met the inclusion criteria. The methodological quality of all the RCTs was poor. There was no significant difference between mometasone and control groups for the patient's characteristic and grades of different nasal symptoms, otitis media with effusion, obstructive sleep apnea, and quality of life at the basal level. There was also no significant difference in the number of patients with different symptoms at the basal level. After the administration of mometasone, there were significant improvements in grades of nasal obstruction, 0.8+/-0.5 versus 2.0+/-0.6, WMD -1.16 [-2.09, -0.23], snoring 0.3+/-0.4 versus 1.6+/-0.6, WMD -1.07 [-2.09, -0.05], total nasal symptoms 2.9+/ 1.3 versus 6.9+/-1.5, WMD -4.09 [-6.64, -1.53], obstructive sleep apnea, 0.6+/ 0.3 versus 1.4+/-0.4, WMD -0.95 [-1.74, -0.16], as well as the percentage of patients with nasal obstruction, snoring, obstructive sleep apnea, compared to control. There was tendency of improvement in rhinorrhea, and cough with mometasone. Compared to control, mometasone nasal spray significantly improved adenoid size or adenoid/choana ratio 50.9+/-8.8 versus 74.2+/-12.6, WMD -21.2 [ 34.0, -8.4], change in adenoid/choana obstruction from the basal level (p=0.01), and percentage of patients with adenoid hypertrophy, 26% versus 92%, RR 0.29 [0.18, 0.48]. There was improvement in otitis media with effusion, 40% versus 72%, pure tone audiometry 5.2+/-11 versus 11.6+/-11dB, WMD -6.40dB [-12.65, 0.15], and quality of life with mometasone. Subgroup analyses showed that RCTs that followed blinding showed significantly less response compared to RCTs that did not follow it for most of the outcomes. CONCLUSIONS: Mometasone caused improvements in outcomes of nasal obstruction, snoring, total nasal symptoms, pure tune audiometry, otitis media with effusion, adenoid size, and quality of life. The data is based on meta-analysis of RCTs of poor methodological quality. A high methodological quality, placebo controlled RCT of different doses and duration of administration of mometasone is required to evaluate its clear efficacy and safety in children with adenoid hypertrophy. PMID- 26235733 TI - Cytokine Expression in Keratoconus and its Corneal Microenvironment: A Systematic Review. AB - Keratoconus (KC) is a progressive corneal ecstasia characterized by thinning and weakening of the cornea that leads to a cone-like appearance, scarring, and decreased vision. Despite the well-described clinical signs, the cause of KC is unknown. Nevertheless, various genes, proteinases, and environmental factors (eye rubbing, contact lens wear, tear film composition) have been implicated in its etiology. Although classically defined as a predominantly degenerative disease, with mechanically induced trauma accelerating its course, accumulating evidence suggests a pivotal role for inflammation in the pathophysiology of KC. Several reports have linked various inflammatory mediators (cytokines) with KC, but with contradictory findings. The methods and materials used in these studies vary considerably and warrant critical evaluation to decipher the role of inflammatory mediators in KC. We performed a systematic review of current literature on cytokine expression studies in KC and discuss critical soluble and cellular inflammatory mediators that are implicated in its pathogenesis. PMID- 26235734 TI - Indications and expectations for neuropsychological assessment in routine epilepsy care: Report of the ILAE Neuropsychology Task Force, Diagnostic Methods Commission, 2013-2017. PMID- 26235735 TI - In response: Indications and expectations for neuropsychological assessment in routine epilepsy care: Report of the ILAE Neuropsychology Task Force, Diagnostic Methods Commission, 2013-2017. PMID- 26235736 TI - Naming and recognition after laser amygdalohippocampotomy: Is the hippocampus involved? PMID- 26235737 TI - In response: Naming and recognition after laser amygdalohippocampotomy: Is the hippocampus involved? PMID- 26235738 TI - SCN8A mutations in Chinese children with early onset epilepsy and intellectual disability. PMID- 26235739 TI - In response: SCN8A mutations in Chinese children with early onset epilepsy and intellectual disability. PMID- 26235740 TI - In response: Epilepsy surgery trends in the U.S.-Differences between kids and adults. PMID- 26235741 TI - Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid In vitro. AB - AIM: Zoledronic acid (ZA), a bisphosphonate, is currently used in combination with chemotherapeutic agents to suppress breast cancer cell proliferation or breast cancer-induced osteolysis. The aim of this study was to investigate the effects of ZA combined with a natural anticancer compound plumbagin (PL) against human breast cancer cells in vitro. METHODS: Human breast cancer MDA-MB-231SArfp cells were treated with ZA, PL or a combination of ZA and PL. The cell growth, apoptosis and migration were evaluated using CCK-8 assay, flow cytometry and transwell assay, respectively. The expression of apoptosis-related proteins was measured using real-time PCR and Western blotting. Synergism was evaluated using Compusyn software, and the combination index (CI) and drug reduction index (DRI) values were determined. RESULTS: PL or ZA alone caused mild cytotoxicity (the IC50 value at 24 h was 12.18 and above 100 MUmol/L, respectively). However, the combination of ZA and PL caused a synergistic cytotoxicity (CI=0.26). The DRI values also showed a synergistic effect between PL and ZA, with actual values of 5.52 and 3.59, respectively. Furthermore, PL and ZA synergistically induced apoptosis and inhibited migration of the breast cancer cells. Moreover, the combination of ZA and PL decreased the expression of Notch-1, cleaved PARP, Bcl-2 and Bcl-xl, and increased the expression of cleaved caspase-3, CDKN1A and ID1. When the breast cancer cells were transfected with specific siRNA against Notch 1, the combination of ZA and PL markedly increased the expression of Bcl-2. CONCLUSION: Combination of ZA and PL synergistically suppresses human breast cancer MDA-MB-231SArfp cells in vitro. PL can inhibit ZA-induced activation of the Notch-1 signaling pathway and subsequently reduce the expression of Bcl-2, thus potentiating cancer cell apoptosis. PMID- 26235742 TI - JNK is required for maintaining the tumor-initiating cell-like properties of acquired chemoresistant human cancer cells. AB - AIM: Many studies reveal an association between the acquired chemoresistant phenotype of cancer cells and tumor-initiating cell-like properties. The aim of this study was to determine the impact of c-Jun N-terminal kinase (JNK) on the tumor-initiating cell-like properties of acquired chemoresistant human cancer cells. METHODS: Two well-established human acquired chemoresistant cancer cell lines K562/A02 and KB/VCR, as well as their respective parental counterparts K562 and KB were tested. The expression of relevant mRNAs and proteins was detected using qRT-PCR and Western blotting, respectively. Sphere formation and self renewal assays were used to study the tumor-initiating cell-like properties. Soft agar and colony formation assays were used to investigate tumorigenic ability. RESULTS: We observed that suppressing JNK activity by its specific small molecule inhibitor SP600125 or by limiting JNK1/2 expression with JNK1/2 shRNA lentiviruses inhibited the expression of pluripotent stem cell markers such as Oct4, Sox2, and Nanog in KB/VCR cells and K562/A02 cells as well as sphere formation and self-renewal abilities of K562/A02 cells. Additionally, inhibition of JNK activity significantly inhibited the in vitro and in vivo tumor-initiating abilities of KB/VCR cells. Furthermore, our data suggest that blocking JNK activity abundantly inhibited the Hedgehog (Hh) pathway activity, as reflected by reduction of Hedgehog (Hh) pathway target genes Gli1 and ptch1 at the mRNA level as well as Gli-luciferase activity. CONCLUSION: JNK maintains the tumor initiating cell-like properties of acquired chemoresistant K562/A02 and KB/VCR cells potentially through activating the Hedgehog pathway. Thus, disruption of tumor-initiating cell-like properties by targeting JNK may be a new approach to combating acquired chemoresistance. PMID- 26235743 TI - New benzimidazole acridine derivative induces human colon cancer cell apoptosis in vitro via the ROS-JNK signaling pathway. AB - AIM: To investigate the mechanisms underlying anticancer action of the benzimidazole acridine derivative N-{(1H-benzo[d]imidazol-2-yl)methyl}-2 butylacridin-9-amine(8m) against human colon cancer cells in vitro. METHODS: Human colon cancer cell lines SW480 and HCT116 were incubated in the presence of 8m, and then the cell proliferation and apoptosis were measured. The expression of apoptotic/signaling genes and proteins was detected using RT-PCR and Western blotting. ROS generation and mitochondrial membrane depolarization were visualized with fluorescence microscopy. RESULTS: 8m dose-dependently suppressed the proliferation of SW480 and HCT116 cells with IC50 values of 6.77 and 3.33 MUmol/L, respectively. 8m induced apoptosis of HCT116 cells, accompanied by down regulation of Bcl-2, up-regulation of death receptor-5 (DR5), truncation of Bid, cleavage of PARP, and activation of caspases (including caspase-8 and caspase-9 as well as the downstream caspases-3 and caspase-7). Moreover, 8m selectively activated JNK and p38 without affecting ERK in HCT116 cells. Knockout of JNK1, but not p38, attenuated 8m-induced apoptosis. In addition, 8m induced ROS production and mitochondrial membrane depolarization in HCT116 cells. Pretreatment with the antioxidants N-acetyl cysteine or glutathione attenuated 8m induced apoptosis and JNK activation in HCT116 cells. CONCLUSION: The new benzimidazole acridine derivative, 8m exerts anticancer activity against human colon cancer cells in vitro by inducing both intrinsic and extrinsic apoptosis pathways via the ROS-JNK1 pathway. PMID- 26235744 TI - Giant magnetoresistance in the half-metallic double-perovskite ferrimagnet Mn2FeReO6. AB - The first transition-metal-only double perovskite compound, Mn(2+) 2 Fe(3+) Re(5+) O6 , with 17 unpaired d electrons displays ferrimagnetic ordering up to 520 K and a giant positive magnetoresistance of up to 220 % at 5 K and 8 T. These properties result from the ferrimagnetically coupled Fe and Re sublattice and are affected by a two-to-one magnetic-structure transition of the Mn sublattice when a magnetic field is applied. Theoretical calculations indicate that the half metallic state can be mainly attributed to the spin polarization of the Fe and Re sites. PMID- 26235745 TI - Stratification of resectable lung adenocarcinoma by molecular and pathological risk estimators. AB - BACKGROUND: Mortality in early stage, resectable lung cancer is sufficiently high to warrant consideration of post-surgical treatment. Novel markers to stratify resectable lung cancer patients may help with the selection of treatment to improve outcome. METHODS: Primary tumour tissue from 485 patients, surgically treated for stage I-II lung adenocarcinoma, was analysed for the RNA expression of 31 cell cycle progression (CCP) genes by quantitative polymerase chain reaction (PCR). The expression average, the CCP score, was combined with pathological stage into a prognostic score (PS). Cox proportional hazards regression assessed prediction of 5-year lung cancer mortality above clinical variables. The PS threshold was tested for risk discrimination by the Mantel-Cox log-rank test. RESULTS: The CCP score added significant information above clinical markers (all patients, P=0.0029; stage I patients, P=0.013). The prognostic score was a superior predictor of outcome compared to pathological stage alone (PS, P=0.00084; stage, P=0.24). Five-year lung cancer mortality was significantly different between the low-risk (90%, 95% confidence interval (CI) 81-95%), and high-risk groups (65%, 95% CI 57-72%), P=4.2*10(-6)). CONCLUSIONS: The CCP score is an independent prognostic marker in early stage lung adenocarcinoma. The prognostic score provides superior risk estimates than stage alone. The threefold higher risk in the high-risk group defines a subset of patients that should consider therapeutic choices to improve outcome. PMID- 26235746 TI - Differential expression of plasma miRNAs in patients with unprovoked venous thromboembolism and healthy control individuals. AB - BACKGROUND: Venous thromboembolism (VTE) remains the third most common cardiovascular disease with a vague pathogenesis. Circulating miRNAs are small regulatory RNAs found in plasma, serum and other body fluids in an apparently stable form. Although circulating miRNAs, a novel family of regulatory molecules, emerge as a promising class of biomarkers in many cardiovascular diseases and malignancies, knowledge on plasma miRNA levels in VTE remains sparse. AIMS: The present work was conducted as a pilot study in order to estimate the plasma levels of miRNAs in patients with unprovoked VTE and to assess miRNAs as potential novel biomarkers of VTE. METHODS: Twenty patients with a history of unprovoked VTE 1-5 years prior to inclusion in the study and twenty age- and sex matched healthy control participants were enrolled in a case-control study (Tromso IV). Plasma levels of 742 miRNAs were assessed after RNA extraction and reverse transcription. Profiling of miRNA was conducted on the Universal RT microRNA PCR Human panels I and II (Exiqon, Denmark). For normalization of the data, the average of the assays detected in all samples (n=40 samples) was applied. RESULTS: Ninety-seven miRNAs were detected throughout all samples. Of these, miR-10b-5p, -320a, -320b, -424-5p, and -423-5p were upregulated, whereas miR-103a-3p, -191-5p, -301a-3p, and 199b-3p were downregulated in plasmas of VTE patients versus controls (P<=0.05). These miRNAs were confined to the extracellular vesicles-depleted plasma fraction, and yielded clear clustering distinguishing samples from the VTE and control groups. CONCLUSIONS: The results of this pilot study indicate that plasma miRNAs profiling can provide novel biomarkers of unprovoked VTE. PMID- 26235747 TI - Molecular properties of steroids involved in their effects on the biophysical state of membranes. AB - The activity of steroids on membranes was studied in relation to their ordering, rigidifying, condensing and/or raft promoting ability. The structures of 82 steroids were modeled by a semi-empirical procedure (AM1) and 245 molecular descriptors were next computed on the optimized energy conformations. Principal component analysis, mean contrasting and logistic regression were used to correlate the molecular properties with 212 cases of documented activities. It was possible to group steroids based on their properties and activities, indicating that steroids having similar molecular properties have similar activities on membranes. Steroids having high values of area, partition coefficient, volume, number of rotatable bonds, molar refractivity, polarizability or mass displayed ordering, rigidifying, condensing and/or raft promoting activity on membranes higher than those steroids having low values in such molecular properties. After a variable selection procedure circumventing correlation problems among descriptors, area and log P were found as the most relevant properties in governing and predicting the activity of steroids on membranes. A logistic regression model as a function of the area and log P of the steroids is proposed, which is able to predict correctly 92.5% of the cases. A rationale of the findings is discussed. PMID- 26235748 TI - Development of sofosbuvir for the treatment of hepatitis C virus infection. AB - The nucleotide analog NS5B polymerase inhibitor sofosbuvir was approved by the U.S. Food and Drug Administration (FDA) in December 2013 for the treatment of chronic hepatitis C virus (HCV) infection in combination with ribavirin or peginterferon and ribavirin. Sofosbuvir was developed to meet an urgent medical need for shorter, safer, simplified, more effective HCV treatment regimens and to reduce or eliminate the need for peginterferon. New treatment regimens were especially required for patient populations with limited treatment options, including patients who had failed prior HCV therapy, those with compensated and decompensated cirrhosis, and those who were either intolerant of or had contraindications to interferon. Sofosbuvir plus ribavirin for patients with genotype 2 or 3 HCV infection was the first approved all-oral treatment option. Sofosbuvir is also the backbone of the first regimen available for patients awaiting liver transplantation to prevent HCV recurrence, as well as the first oral interferon-free regimen for patients coinfected with HCV and HIV. This paper describes the development of sofosbuvir up to its original FDA approval. PMID- 26235749 TI - Nuclear depolarization and absolute sensitivity in magic-angle spinning cross effect dynamic nuclear polarization. AB - Over the last two decades solid state Nuclear Magnetic Resonance has witnessed a breakthrough in increasing the nuclear polarization, and thus experimental sensitivity, with the advent of Magic Angle Spinning Dynamic Nuclear Polarization (MAS-DNP). To enhance the nuclear polarization of protons, exogenous nitroxide biradicals such as TOTAPOL or AMUPOL are routinely used. Their efficiency is usually assessed as the ratio between the NMR signal intensity in the presence and the absence of microwave irradiation epsilonon/off. While TOTAPOL delivers an enhancement epsilonon/off of about 60 on a model sample, the more recent AMUPOL is more efficient: >200 at 100 K. Such a comparison is valid as long as the signal measured in the absence of microwaves is merely the Boltzmann polarization and is not affected by the spinning of the sample. However, recent MAS-DNP studies at 25 K by Thurber and Tycko (2014) have demonstrated that the presence of nitroxide biradicals combined with sample spinning can lead to a depolarized nuclear state, below the Boltzmann polarization. In this work we demonstrate that TOTAPOL and AMUPOL both lead to observable depolarization at ~110 K, and that the magnitude of this depolarization is radical dependent. Compared to the static sample, TOTAPOL and AMUPOL lead, respectively, to nuclear polarization losses of up to 20% and 60% at a 10 kHz MAS frequency, while Trityl OX63 does not depolarize at all. This experimental work is analyzed using a theoretical model that explains how the depolarization process works under MAS and gives new insights into the DNP mechanism and into the spin parameters, which are relevant for the efficiency of a biradical. In light of these results, the outstanding performance of AMUPOL must be revised and we propose a new method to assess the polarization gain for future radicals. PMID- 26235751 TI - Clinical studies of neuroinflammatory mechanisms in schizophrenia. AB - Schizophrenia is a pervasive neurodevelopmental disorder that appears to result from genetic and environmental factors. Although the dopamine hypothesis is the driving theory behind the majority of translation research in schizophrenia, emerging evidence suggests that aberrant immune mechanisms in the peripheral and central nervous system influence the etiology of schizophrenia and the pathophysiology of psychotic symptoms that define the illness. The initial interest in inflammatory processes comes from epidemiological data and historical observations, dating back several decades. A growing body of research on developmental exposure to infection, stress-induced inflammatory response, glial cell signaling, structural and functional brain changes and therapeutic trials demonstrates the impact that inflammation has on the onset and progression of schizophrenia. Research in animal models of psychosis has helped to advance clinical and basic science investigations of the immune mechanisms disrupted in schizophrenia. However, they are limited by the inability to recapitulate the human experience of hallucinations, delusions and thought disorder that define psychosis. To date, translational studies of inflammatory mechanisms in human subjects have not been reviewed in great detail. Here, we critically review clinical studies that focus on inflammatory mechanisms in schizophrenia. Understanding the neuroinflammatory mechanisms involved in schizophrenia may be essential in identifying potential therapeutic targets to minimize the morbidity and mortality of schizophrenia by interrupting disease development. PMID- 26235752 TI - Rate and risk factors of depressive symptoms in Chinese patients presenting with first-episode non-affective psychosis in Hong Kong. AB - BACKGROUND: Depressive symptoms are a distinct symptom dimension in psychotic disorders and are associated with elevated suicide risk, and poorer clinical and functional outcomes. Previous research on depressive symptoms mainly focused on chronic patients and few studies were conducted to investigate factors associated with depression in the early illness course. We aimed to examine the prevalence and risk factors of depressive symptoms, and their impacts on functioning, subjective quality of life (QoL) and self-efficacy in first-episode non-affective psychosis. METHOD: Three hundred fifty-one Hong Kong Chinese aged 26-55years presenting with first-episode non-affective psychosis to early intervention service were recruited. Assessments encompassing sociodemographics, premorbid adjustment, clinical and treatment profiles, functioning, QoL and perceived self efficacy were conducted. Patients who had Calgary Depression Scale for Schizophrenia (CDSS) total score >=6 were classified as having depressive symptoms. RESULTS: Fifty-three (15.1%) patients exhibited depressive symptoms at entry. Depressed patients had worse functioning, poorer QoL and lower level of self-efficacy than non-depressed counterparts. Multivariate regression analysis showed that previous exposure to stressful life events, unemployment, being married, more severe positive symptoms, higher level of antipsychotic-induced Parkinsonism and negative attitude towards medication treatment were independently associated with depression status. CONCLUSIONS: Depressive symptoms were frequently observed in adult patients with first-episode nonaffective psychosis, and were linked to poor functioning and QoL. Our findings indicated that, aside from social and clinical risk factors, presence of drug-induced Parkinsonism and negative treatment attitude may render patients more vulnerable to developing depression in the early stage of psychotic illness. PMID- 26235753 TI - Social affiliation and negative symptoms in schizophrenia: Examining the role of behavioral skills and subjective responding. AB - Schizophrenia is characterized by profound impairment in the motivation for social affiliation. Negative symptoms are associated with such impairment but the contribution of behavioral skill deficits is unclear. In this study we utilized a novel video paradigm to assess performance-based affiliative behavioral skills in individuals with schizophrenia (N=48) and community controls (N=29). Individuals with schizophrenia displayed significant impairment in behavioral affiliative skills compared to controls; however, in response to the affiliative interaction the groups did not differ on self-reported affective responding, appraisal of the interaction partner, or desire to interact with the partner in the future. Importantly, within the patient group more severe negative symptoms (particularly those related to motivation and pleasure) were associated with poorer affiliative social skills and this relationship was independent of instrumental (non-social) skills, depression or positive symptoms. More severe negative symptoms were also associated with less positive affect in response to the interaction and less positive appraisals of the interaction partner. Self-reported social anhedonia was related to patients' diminished willingness to interact with the partner in the future. These results demonstrate that negative symptoms in schizophrenia are related to both affiliative skill deficits and less affiliative subjective responses to interaction partners. PMID- 26235754 TI - No additive effect of cannabis on cognition in schizophrenia. AB - BACKGROUND: We aimed to examine the association between lifetime cannabis use and estimates of both premorbid and current cognitive function in psychotic disorders in an Australian cohort. METHODS: In an Australian multicenter cohort, 1237 participants with an established ICD-10 diagnosis of psychotic disorder were categorised according to history of lifetime cannabis use (non-users, n=354; cannabis users, n=221; cannabis dependency, n=662). Groups were analyzed according to available indices of cognitive ability: the National Adult Reading Test - Revised (NART-R) for ability prior to illness onset; and the Digit Symbol Coding Test (DSCT) for current ability. Two-way analysis of variance was conducted without any covariate, followed by a two-way analysis of covariance (using age, age at onset of psychiatric illness, premorbid IQ and the Socio Economic Index for Areas (SEIFA) rankings). RESULTS: Whilst there appeared to be a significant association between cannabis use and mean DSCT (higher DSCT scores in cannabis using groups) F(2,1080)=9.478, p<0.001, eta2=0.017), once covariates were used in the analysis there were no significant differences between groups in mean DSCT scores (F(2,1011)=0.929, p=0.395, eta2=0.002). Similarly there were no differences between groups in mean NART scores once, age, age at illness onset and SEIFA rankings were used as covariates (F(2,1032)=1.617, p=0.199, eta2=0.003). CONCLUSIONS: Confounding variables underpin the association between cannabis use and cognitive function in psychotic disorders. Taken together, it would appear that cannabis use or dependence has no additive effect on cognitive dysfunction in these disorders. PMID- 26235765 TI - [Noma]. AB - Noma is a necrotizing ulcerative stomatitis known since Antiquity. It occurs mostly in poor countries, the Sahel countries being the most affected. Each year, several hundred thousand cases are reported. Noma affects especially malnourished children who are less than 6 years old and rarely adults with acquired immunodeficiency (HIV, cancer). Ulcerative lesion is occurring rapidly due to the production of endotoxins by bacteria from oral commensal, telluric and animal origin. Necrotic debridement leads to huge defects: loss of soft tissue (skin, nerves, vessels, eye), bone (maxilla, mandible) and teeth. Death occurs rapidly in a few weeks in 80 % of the cases. In case of survival, the consequences are functional, aesthetic, psychological and social. The goal of the treatment in the acute phase is the patient's survival and the fight against limited mouth opening. The management of the phase of sequela is an anaesthetic, surgical and physiotherapy challenge. Its purpose is the social reintegration of the patient. PMID- 26235766 TI - Reversible and Selective Fluorescence Detection of Histidine Using a Naphthalimide-Based Chemosensing Ensemble. AB - We described a new ensemble-approach-based chemosensor, NCH-Cu(2+), for highly selective and reversible detection of histidine (His) in aqueous solution and live cells. The ligand NCH exhibited specific binding with Cu(2+) ions over other metal ions, accompanied with a 92.2% fluorescence quenching. The decomplexation of NCH-Cu(2+) ensemble by His led to the liberation of the fluorophore, NCH, and thus the fluorescence was recovered. The specific fluorescence enhancement of NCH Cu(2+) towards His showed a good linearity with a detection of limit at 70 nm. Quantification of intracellular His at the single cell level was achieved by microscopy and flow cytometry. Besides the UV/Vis and emission titration, reversibility of the NCH-Cu(2+) towards His was further confirmed by imaging and cytometry analysis. In addition, microscopy studies revealed that NCH-Cu(2+) was distributed in the lysosome of live cells, where it could be employed as a fluorescent biosensor for imaging of His at subcellular level. PMID- 26235767 TI - [In Process Citation]. PMID- 26235768 TI - [In Process Citation]. PMID- 26235769 TI - [In Process Citation]. PMID- 26235770 TI - [In Process Citation]. PMID- 26235771 TI - [Not Available]. PMID- 26235772 TI - Energy contribution from non-breastmilk items in low-income Guatemalan infants in their sixth month of life. AB - OBJECTIVE: To examine the nature and energy contribution of complementary feeding in breastfed infants in their sixth month of life, and the prevalence of the use of bottles as a delivery method. MATERIALS AND METHODS: We recruited 156 breastfeeding infants at a health clinic in metropolitan Quetzaltenango, Guatemala. A previous-day recall was performed. RESULTS: Sixty nine mothers (44%) reported offering items other than breastmilk. The median contribution of energy from complementary foods among infants with mixed feeding (n=66) was 197 kcal/day (interquartile range [IQR] 49-353). The median energy contribution of formula or cow's milk among consumers (n=39) was 212 kcal/day (IQR 84-394). Bottles were used on the previous day by 55 (80%) of the 69 mothers not offering exclusive breastfeeding. CONCLUSIONS: Premature introduction of non-breastmilk items is commonly practiced in feeding Guatemalan infants. Adherence to the internationally recognized guidelines for early infant feeding should be an intervention priority for this population. PMID- 26235773 TI - [Intake of sugar-sweetened non-alcoholic beverages and body mass index: A national sample of Chilean school children]. AB - OBJECTIVE: To estimate the association between the intake of sugar-sweetened non alcoholic beverages and body mass index (BMI) in Chilean school children. MATERIALS AND METHODS: Food consumption frequency data were analyzed for school children aged 6 to 18. The association between consumption of sugar-sweetened beverages and BMI was estimated by multivariate lineal regression models. RESULTS: Sugar-sweetened beverages are consumed on a daily basis by 92% (95%CI:90 94) of subjects with daily intake medians of 424 mL (p25-p75:212-707). Every extra daily portion of sugar-sweetened beverages consumed by school children aged 6 to 13 is associated with 0.13 BMI z-scores (95%CI:0.04-0.2;p=0.01). CONCLUSIONS: School children consume sugar-sweetened beverages daily with intake medians close to 0.5L. There is an association between sugar-sweetened beverage consumption and higher BMI in Chilean school children. PMID- 26235774 TI - [Teen pregnancy and educational gaps: Analysis of a national survey in Mexico]. AB - OBJECTIVE: To characterize female adolescents who have been pregnant, and to analyze the association between adolescent pregnancy and educational gaps. MATERIALS AND METHODS: A cross-sectional study was conducted. Data come from the Encuesta Nacional de Salud y Nutricion (Ensanut 2012), a Mexican representative survey. The set of data used is related to sociodemographic and reproductive characteristics from 1 790 women from 12 to 19 years who had begun their sexual life and had a pregnancy record. Three statistical models were adjusted to observe the association between variables. The dependent variable of the first model was the condition of previous pregnancy, the second to be pregnant at the time of data collection, and the third, educational gap. RESULTS: A 74.9% of the adolescents with history of pregnancy has educational gap. To have the condition of previous pregnancy is associated with living with sexual partner (OR=8.4), educational gap (OR=2.4), low socioeconomical level (OR=2.0) and school assistance (OR=0.5). To be pregnant at the time of data collection has related only to living with sexual partner (OR=9.4). The educational gap shows an association with having more than one pregnancy (OR=2.4), live with sexual partner (OR=1.6), low socioeconomical level (OR=1.8), and school assistance as protective factor (OR=0.3). CONCLUSION: It is necessary to implement effective and efficient educational public politics in order to decrease educational gap. At the same time, to guarantee and improve sexual education in the school system to prevent adolescent pregnancy. PMID- 26235775 TI - [Maternal depressive symptomatology in Mexico: National prevalence, care, and population risk profiles]. AB - OBJECTIVE: This study estimates the prevalence of depressive symptomatology (DS) in women with children younger than five years of age, examines detection and care rates and probabilities of developing DS based on specific risk profiles. MATERIALS AND METHODS: The sample consists of 7 187 women with children younger than five drawn from the Ensanut 2012. RESULTS: DS prevalence is 19.91%, which means at least 4.6 million children live with mothers who experience depressive symptoms indicative of moderate to severe depression. Rates of detection (17.06%) and care (15.19%) for depression are low. DS is associated with violence (OR=2.34; IC95% 1.06-5.15), having >=4 children, having a female baby, older age of the last child, low birth weight, food insecurity, and sexual debut <15 years old (p<0.01). Accumulated probability of DS, taking into consideration all risk factors measured, is 69.76%. It could be reduced to 13.21% through prevention efforts focused on eliminating violence, food insecurity, bias against having a female baby, and low birth weight. CONCLUSIONS: DS is a compelling public health problem in Mexico associated with a well-defined set of risk factors that warrant attention and timely detection at various levels of care. PMID- 26235776 TI - [Living in hemodialysis without social insurance: The voices of renal sick people and their families]. AB - OBJECTIVE: To examine the perspectives and practices of renal sick people and their families without social insurance regarding problems faced while on dialysis treatment. MATERIALS AND METHODS: A qualitative research was developed in Guadalajara, Mexico. Thirty-seven renal sick people on hemodialysis and 50 relatives participated; all affiliated to Seguro Popular. Information was gathered through individual and group interviews. Directed content analysis was carried out. RESULTS: Renal sick people and their families face multiple difficulties while on hemodialysis treatment; nevertheless, economic ones are perceived as a priority due to treatment expenses, lack of financial resources and non-coverage of kidney disease by Seguro Popular. Multiple actions are combined in a circular searching for help process to face the economic burden. CONCLUSION: Hemodialysis treatment is an unbearable economic burden for renal sick people and their families without social insurance. Universal access to renal therapies should be implemented urgently. PMID- 26235777 TI - [Modelling length of hospital stay in motor victims]. AB - OBJECTIVE: To analyze which socio-demographic and other factors related to motor injuries affect the length of hospital recovery stay. MATERIALS AND METHODS: In the study a sample of 17 932 motor accidents was used. All the crashes occurred in Spain between 2000 and 2007. Different regression models were fitted to data to identify and measure the impact of a set of explanatory regressors. RESULTS: Time of hospital stay for men is on average 41% larger than for women. When the victim has a fracture as a consequence of the accident, the mean time of hospital stay is multiplied by five. Injuries located in lower extremities, the head and abdomen are associated with greater hospitalization lengths. CONCLUSIONS: Gender, age and type of victim, as well as the location and nature of injuries, are found to be factors that have significant impact on the expected length of hospital stay. PMID- 26235778 TI - [Nematodes with zoonotic potential in parks of the city of Tunja, Colombia]. AB - OBJECTIVE: To identify the presence of parasites with zoonotic potential in major parks in the city of Tunja, Boyaca. MATERIALS AND METHODS: Twenty eight parks in the city were selected, where 124 samples of feces of dogs and soil were collected with the help of a spatula, gathering approximately 150 g per sample. They were processed by the method of concentration of Ritchie modified making the identification of parasitic forms in an optical microscope. RESULTS: A 60.7% of the parks were positive to nematodes in samples of canine fecal material and 100% on soil. Found nematodes were eggs and larvae of Toxocara spp., Ancylostoma spp., Trichuris vulpis and Strongiloides spp. CONCLUSION: This study demonstrated the potential risk of transmission of zoonoses caused by nematodes in canines and for the need to strengthen public health measures to reduce the risk shows the population exposed to such zoonoses. PMID- 26235779 TI - Primary drug resistance in a region with high burden of tuberculosis. A critical problem. AB - OBJECTIVE: To determine rates of drug resistance in new cases of pulmonary tuberculosis in a region with a high burden of the disease. MATERIALS AND METHODS: New case suspects were referred for drug susceptibility testing. RESULTS: 28.9% of new cases were resistant to at least one first line drug; 3.9% had a multidrug-resistant strain, 15.6% a monoresistant strain and 9.4% a polyresistant strain. CONCLUSION: Our rate of drug resistant tuberculosis in new cases is very high; this has important clinical implications, since even monoresistance can have a negative impact on the outcome of new cases treated empirically with a six month regimen. PMID- 26235780 TI - [Effective access to health services: operationalizing universal health coverage]. AB - The right to health and its operational form, as an organized social response to health: the right to health protection, are the mainstay for the global push towards universal health coverage. The path to achieve this goal is particular to each country and relates to the baseline and specific context in relation to what is feasible. In practical terms, universal coverage involves the correlation between demand and supply of services (promotion, prevention, and care), expressed by the ability for each individual to make use of services when these are required. In those terms universal coverage is then effective access. The objective of the paper is to explore the conceptualization of effective access to health services and propose a definition that allows its operationalization thereof. This definition considers key elements of supply and demand of services, including the availability of resources and adequate provision (quality), as well as barriers to use them. PMID- 26235781 TI - [No time to lose: A life in pursuit of deadly viruses]. PMID- 26235783 TI - Subacute cutaneous lupus erythematosus starting as linear lupus erythematosus. AB - BACKGROUND: Cutaneous lupus in childhood is usually associated with systemic lupus erythematosus (LE). Linear cutaneous LE (LCLE) is an unusual presentation mostly seen in children and young adults. METHODS: We report a rare case of cutaneous subacute LE with a segmentary pattern following the lines of Blaschko in an 18-month-old girl with a 2-month history of persistent, linear, asymptomatic, erythematous lesions along the right arm. The clinical diagnosis at presentation was lichen striatus. RESULTS: A biopsy showed an intense, band-like, inflammatory cell infiltrate with perivascular and periadnexal involvement associated with basal cell liquefactive degeneration. The lesions were treated with topical corticosteroids and healed without scarring. Two months later, new lesions manifested as multiple erythematous, edematous, polycyclic plaques. A new biopsy showed a periadnexal infiltrate, a large amount of mucin, and a thickened basement membrane. Direct immunofluorescence was negative. Our definitive diagnosis was subacute cutaneous LE starting as linear LE. The lesions responded slowly to oral corticosteroids. Six months later, only a mild livedoid skin pattern remained on the patient's legs. CONCLUSIONS: Linear cutaneous LE usually presents with erythematous, atrophic, hyperkeratotic, dyschromic circular lesions arranged in a linear pattern; the main differential diagnosis is lichen striatum. In general, LCLE can be considered as discoid lupus following Blaschko's lines, which correspond to the direction of growth in clones of cutaneous cells that arise during embryogenesis. The present patient represents the first pediatric case of subacute cutaneous LE following Blaschko's lines, with posterior progression to a generalized form of subacute LE. PMID- 26235782 TI - Quantitative interactome analysis reveals a chemoresistant edgotype. AB - Chemoresistance is a common mode of therapy failure for many cancers. Tumours develop resistance to chemotherapeutics through a variety of mechanisms, with proteins serving pivotal roles. Changes in protein conformations and interactions affect the cellular response to environmental conditions contributing to the development of new phenotypes. The ability to understand how protein interaction networks adapt to yield new function or alter phenotype is limited by the inability to determine structural and protein interaction changes on a proteomic scale. Here, chemical crosslinking and mass spectrometry were employed to quantify changes in protein structures and interactions in multidrug-resistant human carcinoma cells. Quantitative analysis of the largest crosslinking-derived, protein interaction network comprising 1,391 crosslinked peptides allows for 'edgotype' analysis in a cell model of chemoresistance. We detect consistent changes to protein interactions and structures, including those involving cytokeratins, topoisomerase-2-alpha, and post-translationally modified histones, which correlate with a chemoresistant phenotype. PMID- 26235784 TI - Realistic sampling of amino acid geometries for a multipolar polarizable force field. AB - The Quantum Chemical Topological Force Field (QCTFF) uses the machine learning method kriging to map atomic multipole moments to the coordinates of all atoms in the molecular system. It is important that kriging operates on relevant and realistic training sets of molecular geometries. Therefore, we sampled single amino acid geometries directly from protein crystal structures stored in the Protein Databank (PDB). This sampling enhances the conformational realism (in terms of dihedral angles) of the training geometries. However, these geometries can be fraught with inaccurate bond lengths and valence angles due to artefacts of the refinement process of the X-ray diffraction patterns, combined with experimentally invisible hydrogen atoms. This is why we developed a hybrid PDB/nonstationary normal modes (NM) sampling approach called PDB/NM. This method is superior over standard NM sampling, which captures only geometries optimized from the stationary points of single amino acids in the gas phase. Indeed, PDB/NM combines the sampling of relevant dihedral angles with chemically correct local geometries. Geometries sampled using PDB/NM were used to build kriging models for alanine and lysine, and their prediction accuracy was compared to models built from geometries sampled from three other sampling approaches. Bond length variation, as opposed to variation in dihedral angles, puts pressure on prediction accuracy, potentially lowering it. Hence, the larger coverage of dihedral angles of the PDB/NM method does not deteriorate the predictive accuracy of kriging models, compared to the NM sampling around local energetic minima used so far in the development of QCTFF. PMID- 26235785 TI - An independent association of prenatal depression with wheezing and anxiety with rhinitis in infancy. AB - BACKGROUND: Different maternal psychological states during pregnancy have been associated with wheeze-rhinitis-eczema symptoms in children. However, previous studies were limited and it was unclear whether the type of prenatal psychological state was associated with a particular symptom. We examined the association of maternal depression and anxiety during pregnancy with wheeze rhinitis-eczema symptoms in infancy. METHODS: In a longitudinal birth cohort (GUSTO) of 1152 mother-child pairs, wheeze-rhinitis-eczema symptoms in the infants during the first year of life were collected by parental report. Maternal depressive and anxiety symptoms were assessed at 26 weeks of gestation using the Edinburgh Postnatal Depression Scale (EPDS) and State Trait Anxiety Inventory (STAI). Logistic regression analyses were performed with adjustment for potential confounders. RESULTS: An increased risk of wheezing was found in infants of pregnant women with probable depression (EPDS >= 15) [odds ratio (OR) = 1.85 (95% confidence interval (CI) 1.10-3.12)], and an increased risk of rhinitis was associated with maternal anxiety [STAI state >= 41: OR = 1.42 (95% CI 1.04-1.93); STAI trait >= 43: OR = 1.38 (95% CI 1.01-1.88)]. After adjusting for known risk factors for the development of allergic disease, these associations remained significant [EPDS >= 15: adjusted OR = 2.09 (95% CI 1.05-4.19); STAI state >= 41: adjusted OR = 1.82 (95% CI 1.17-2.82); STAI trait >= 43: adjusted OR = 1.70 (95% CI 1.10-2.61)]. However, maternal psychological states were not associated with infantile eczema. CONCLUSION: This study suggests that there may be an independent effect of prenatal depression on wheezing and anxiety on rhinitis in infancy. PMID- 26235786 TI - Acceptability of the flipped classroom approach for in-house teaching in emergency medicine. AB - OBJECTIVE: To evaluate the relative acceptability of the flipped classroom approach compared with traditional didactics for in-house teaching in emergency medicine. METHODS: Our department changed its learning model from a 'standard' lecture-based model to a 'flipped classroom' model. The 'flipped classroom' included provided pre-session learning objectives and resources before each 2 h weekly session. In-session activities emphasised active learning strategies and knowledge application. Feedback was sought from all medical staff regarding the acceptability of the new approach using an online anonymous cross-sectional qualitative survey. RESULTS: Feedback was received from 49/57 (86%) medical staff. Ninety-eight per cent (48/49) of respondents preferred the flipped classroom over the traditional approach. Aspects of the flipped classroom learners liked most included case-based discussion, interaction with peers, application of knowledge, self-directed learning and small-group learning. Barriers to pre-session learning include work commitments, 'life', perceived lack of time, family commitments, exam preparation and high volume of learning materials. Reported motivational factors promoting pre-session learning include formal assessment, participation requirements, more time, less material, more clinical relevance and/or more interesting material. Case studies and 'hands-on' activities were perceived to be the most useful in-session activities. CONCLUSION: The flipped classroom shows promise as an acceptable approach to in house emergency medicine teaching. PMID- 26235788 TI - Effectiveness of strabismus surgery on the health-related quality of life assessment of children with intermittent exotropia and their parents: a randomized clinical trial. AB - PURPOSE: To evaluate the ability of strabismus surgery to improve the health related quality of life (HRQOL) assessment scores of children with intermittent exotropia and their parents. METHODS: For this prospective, randomized, parallel group study, 130 children (8-17 year of age) with intermittent exotropia were recruited and randomized to undergo either corrective strabismus surgery or active monitoring without surgery. Each child was accompanied by a parent. HRQOL was assessed with 3 intermittent exotropia questionnaires (IXTQ)--the child self report, parental proxy report, and parental self-report--administered at enrollment and 3 months after intervention. The primary outcome was change in IXTQ score after 3 months for both groups. RESULTS: At enrollment the scores of the surgery group (n = 63) and monitoring group (n = 57) did not differ significantly (P > 0.05). The sex of the reporting parent had no significant influence on the proxy or parental scores at enrollment or at 3 months (P > 0.05, multivariate analysis). Strabismus surgery significantly improved all parts of the IXTQ scores (P < 0.0001, repeated measures analysis of variance). No significant changes were found for the child scores at 3 months in the monitoring group (P = 0.33). However, the parental and proxy scores were significantly decreased (P < 0.0001). CONCLUSIONS: Corrective strabismus surgery significantly improved the HRQOL scores of the children with intermittent exotropia and their parents. PMID- 26235787 TI - Potential Role of Acetyl-CoA Synthetase (acs) and Malate Dehydrogenase (mae) in the Evolution of the Acetate Switch in Bacteria and Archaea. AB - Although many Archaea have AMP-Acs (acetyl-coenzyme A synthetase) and ADP-Acs, the extant methanogenic genus Methanosarcina is the only identified Archaeal genus that can utilize acetate via acetate kinase (Ack) and phosphotransacetylase (Pta). Despite the importance of ack as the potential urkinase in the ASKHA phosphotransferase superfamily, an origin hypothesis does not exist for the acetate kinase in Bacteria, Archaea, or Eukarya. Here we demonstrate that Archaeal AMP-Acs and ADP-Acs contain paralogous ATPase motifs previously identified in Ack, which demonstrate a novel relation between these proteins in Archaea. The identification of ATPase motif conservation and resulting structural features in AMP- and ADP-acetyl-CoA synthetase proteins in this study expand the ASKHA superfamily to include acetyl-CoA synthetase. Additional phylogenetic analysis showed that Pta and MaeB sequences had a common ancestor, and that the Pta lineage within the halophilc archaea was an ancestral lineage. These results suggested that divergence of a duplicated maeB within an ancient halophilic, archaeal lineage formed a putative pta ancestor. These results provide a potential scenario for the establishment of the Ack/Pta pathway and provide novel insight into the evolution of acetate metabolism for all three domains of life. PMID- 26235789 TI - Foveal microanatomy documented by SD-OCT following treatment of advanced retinoblastoma. AB - Progress in the treatment of retinoblastoma has greatly improved patient survival and globe salvage rates. The introduction of intraoperative spectral domain optical coherence tomography (OCT) allows visualization of foveal anatomy and microstructure to predict visual potential and facilitate planning for visual rehabilitation. Eyes with total retinal detachments secondary to exophytic retinoblastoma have OCT findings of absence or disruption of the external limiting membrane and ellipsoid layers. We document the evolution of foveal microanatomy reconstitution following the use of chemotherapy in a 1-year-old boy and illustrate the restoration of the external limiting membrane and ellipsoid layer, thus achieving normal foveal microanatomy. PMID- 26235790 TI - A comparison of Icare PRO and Tono-Pen XL tonometers in anesthetized children. AB - BACKGROUND: Tonometry in the anesthetized child, vital for evaluating known or suspected glaucoma, remains limited to tonometers capable of supine recording. The Icare PRO measures intraocular pressure (IOP) in the sitting or supine patient. The purpose of this study was to compare Icare PRO and Tono-Pen tonometry during examination under anesthesia in eyes of supine children with normal eyes and glaucoma and/or corneal pathology. METHODS: In this prospective study of children undergoing examination under anesthesia, IOP was recorded in both eyes with Icare PRO and Tono-Pen immediately after mask anesthesia induction, with instrument order randomized. RESULTS: A total of 100 eyes of 50 children (median age, 58 months) were included. IOP range was 6-50 mm Hg by Icare PRO and 6-53 mm Hg by Tono-Pen. Mean IOP measured by Tono-Pen (18.9 +/- 7.5) was higher than that measured by Icare PRO (16.7 +/- 7.1 mm Hg) by 2.2 mm Hg (P < 0.001). The presence of corneal edema was associated with IOP measurements higher by Tono-Pen than by Icare PRO (mean difference, 8.4 mm Hg). When eyes with corneal edema were excluded from analysis, there was no correlation between central corneal thickness and the difference in IOP between the two instruments. CONCLUSIONS: IOP in eyes of supine children under anesthesia measured approximately 2 mm Hg higher by Tono-Pen than Icare PRO and this difference was greater in eyes with frank corneal edema. Icare PRO may become a valuable tool for tonometry in supine infants and children, but a confirmatory test should be considered in eyes with corneal edema. PMID- 26235791 TI - The effects of methylphenidate on refraction and anterior segment parameters in children with attention deficit hyperactivity disorder. AB - BACKGROUND: Methylphenidate hydrochloride is used as first-line treatment for attention deficit hyperactivity disorder (ADHD). However, there is concern that this treatment may be associated with increased risk of angle closure glaucoma and disturbance of ocular refraction. The aim of this study was to investigate the effects of methylphenidate treatment on refraction, intraocular pressure, and the anterior chamber in children with ADHD. METHODS: In this prospective pilot study, children diagnosed with ADHD were examined before the start of methylphenidate treatment and again 3 and 9 months after the start of treatment. Ocular examination before and after cycloplegia was performed at each visit, including Pentacam imaging of the anterior chamber. RESULTS: A total of 14 patients (mean age, 11 years) were recruited. The mean visual acuity, sphere, spherical equivalent refraction, intraocular pressure, and cup:disk ratio did not change significantly after the start of treatment. The anterior chamber depth after cycloplegia decreased significantly between baseline and 9 months, from 3.26 +/- 0.22 mm to 3.24 +/- 0.23 mm in the right eye (P = 0.037) and from 3.28 +/- 0.22 mm to 3.25 +/- 0.24 mm in the left eye (P = 0.001). CONCLUSIONS: Methylphenidate does not seem to affect refraction in most children with ADHD. After 9 months of treatment, however, there was a reduction in the anterior chamber depth, which has been described as a powerful predictor of angle closure glaucoma. Further investigation of the potential ocular side effects of methylphenidate treatment is warranted. PMID- 26235792 TI - Filter paper-based insulin-like growth factor assay. AB - This study assessed validity, reliability, and feasibility of a filter paper blood spot insulin-like growth factor 1 (IGF-1) assay for retinopathy of prematurity (ROP) research. Blood samples were collected from 45 healthy children. Half of each sample was spun to obtain serum; half was applied to filter cards and stored for varying times and at different temperatures. IGF-1 assays were performed using a commercially available kit. Intraclass correlation between blood spot and serum IGF-1 values was high (0.97) for validity, and the mean differences were low for test-retest reliability. Time (up to 25 days) and temperature (4 degrees C to 37 degrees C) had no significant effect on sample stability. Feasibility was further assessed in a second cohort study of 74 premature infants being screened for ROP. A total of 817 filter card samples were successfully collected and transported to a central lab, where IGF-1 assays were successfully performed. PMID- 26235793 TI - Plication augmentation of the modified Hummelsheim procedure for treatment of large-angle esotropia due to abducens nerve palsy and type 1 Duane syndrome. AB - BACKGROUND: Multiple procedures have been described to treat a large-angle esodeviation with an associated abduction deficit. We report a plication augmentation of the Hummelsheim procedure for the management of esotropia and severe abduction deficit due to abducens nerve palsy or type 1 Duane syndrome. METHODS: The medical records of patients operated on using the plication augmentation Hummelsheim procedure at two tertiary centers were retrospectively reviewed. The surgery involved ipsilateral lateral rectus plication, half muscle transposition of the vertical rectus muscles to the paralytic plicated lateral rectus, Foster augmentation sutures, and ipsilateral medial rectus recession or botulinum toxin injection if it was found to be tight on intraoperative forced duction testing. Pre- and postoperative deviations, ocular motility findings, and complications were noted. RESULTS: A total of 13 patients were included, all of whom had an esotropia with profound abduction deficit (-4 or more). Postoperative deviations ranged from 14(Delta) of esotropia to 14(Delta) of exotropia, with significant improvement of the abductive motion. No patient developed anterior segment ischemia. CONCLUSIONS: The plication augmentation Hummelsheim procedure resulted in correction of even very large esodeviations and improvement of the abduction force. This procedure may also better preserve the blood supply to the anterior segment compared to other surgical approaches. PMID- 26235794 TI - Goal-determined metrics to assess outcomes of exotropia surgery. AB - PURPOSE: To present a goal-determined methodology for monitoring outcomes after surgery for exotropia. METHODS: The goal-determined metric required surgeons to rank four possible goals preoperatively: (1) binocular potential, (2) restoration of eye contact, (3) diplopia control; and (4) torticollis management. Potential preoperative risk factors were noted. Goal-specific outcomes criteria were applied to the latest sensory-motor examination, 2-6 months after surgery. The medical records of patients who underwent surgery from 2007 to 2012 were retrospectively reviewed with respect to the goal-directed metric. RESULTS: A total of 852 patients were evaluated in the study period: 411 for restoration of eye contact; 347 for binocular potential; 78 for diplopia resolution; and16 for torticollis management. Excellent (62%) or good (16%) outcomes were achieved in 78%. Procedures to resolve diplopia (OR, 6.56; 95% CI, 3.39-12.68) and to restore eye contact (OR, 3.74; 95% CI, 2.65-5.29) were more likely to result in excellent outcomes than procedures to improve binocular potential. Simultaneous surgery for dissociated vertical deviation (OR, 0.38; 95% CI, 0.16-0.92) and preoperative near deviation >=50(Delta) (OR, 0.27; 95% CI, 0.17-0.42) limited likelihood of an excellent outcome. Outcomes monitored by simultaneous rather than alternate prism and cover test were more likely graded excellent (OR, 5.16; 95% CI, 3.50-7.62). Applying motor criteria from the binocular potential goal to the entire cohort diminished putative outcomes (P < 0.001). CONCLUSIONS: Goal-determined metric monitoring outcomes of exotropia surgery provides outcomes germane to the reason for intervention, enables analysis of risk factors affecting outcomes, and facilitates reporting on heterogeneous populations. PMID- 26235795 TI - Outcome of pediatric patients referred for papilledema. AB - PURPOSE: To determine the prevalence of papilledema versus pseudopapilledema among children referred for suspected papilledema and to identify clinical factors differentiating the two diagnoses. METHODS: This is a prospective, cross sectional analysis of patients <18 years old referred to a pediatric ophthalmology clinic for suspected papilledema by ophthalmoscopic examination between April 2012 and February 2014. Patients underwent detailed ophthalmologic and, when indicated, neurologic evaluation to determine the presence or absence of papilledema. RESULTS: A total of 34 patients were identified. Of these, 26 patients were diagnosed with pseudopapilledema or a normal variant; 2, with papilledema; and 6, with unrelated or indeterminate etiology. Headache was a presenting symptom in 25 patients. Five patients complained of additional symptoms suggestive of increased intracranial pressure, of whom 2 were patients diagnosed with papilledema. CONCLUSIONS: The incidence of true papilledema among children referred for suspected papilledema based on fundus examination is very low. Headache is a common nonspecific symptom in most patients, whether or not they have papilledema. If children have no additional signs and/or symptoms suggestive of elevated ICP or vision loss, the need for evaluation of such children is not urgent. A detailed history and examination coupled with noninvasive testing, such as ultrasonography, will generally distinguish pseudopapilledema from other abnormal-appearing optic nerves. PMID- 26235797 TI - Crystallographic transformation of limestone during calcination under CO2. AB - The calcination reaction of limestone (CaCO3) to yield lime (CaO) is at the heart of many industrial applications as well as natural processes. In the recently emerged calcium-looping technology, CO2 capture is accomplished by the carbonation of CaO in a gas-solid reactor (carbonator). CaO is derived by the calcination of limestone in a calciner reactor under necessarily high CO2 partial pressure and high temperature. In situ X-ray diffraction (XRD) has been employed in this work to gain further insight into the crystallographic transformation that takes place during the calcination of limestone under CO2, at partial pressures (P) close to the equilibrium pressure (Peq) and at high temperature. Calcination under these conditions becomes extremely slow. The in situ XRD analysis presented here suggests the presence of an intermediate metastable CaO* phase stemming from the parent CaCO3 structure. According to the reaction mechanism proposed elsewhere, the exothermicity of the CaO* -> CaO transformation and high values of P/Peq inhibit the nucleation of CaO at high temperatures. The wt% of CaO* remains at a relatively high level during slow calcination. Two diverse stages have been identified in the evolution of CaO crystallite size, L. Initially, L increases with CaCO3 conversion, following a logarithmic law. Slow calcination allows the crystallite size to grow up from a few nanometers at nucleation up to around 100 nm near the end of conversion. Otherwise, quick calcination at relatively lower CO2 concentrations limits CaO crystallite growth. Once calcination reaches an advanced state, the presence of CaO* drops to zero and the rate of increase of the CaO crystallite size is significantly hindered. Arguably, the first stage in CaO crystallite growth is driven by aggregation of the metastable CaO* nanocrystals, due to surface attractive forces, whereas the second one is consistent with sintering of the aggregated CaO crystals, and persists with time after full calcination is attained. Our analysis shows that the main mechanism responsible for the increase of CaO crystallite size (and thus for undermining the reactivity of the CaO) under high CO2 partial pressure is enhanced aggregation, whereas CaO sintering is relatively less relevant, as would be expected for calcination temperatures well below the Tamman temperature. PMID- 26235796 TI - Traumatic avulsion of the oculomotor nerve documented by high-resolution magnetic resonance imaging. AB - Autopsy studies have described definitive traumatic avulsion of the oculomotor nerve from the brainstem; however, detailed characterization of mechanisms and localization of traumatic nerve injury has yet to be definitively described in vivo. We report the case of a 13-year-old girl in whom high-resolution magnetic resonance imaging confirmed irreversible injury to the left oculomotor nerve after trauma. PMID- 26235798 TI - Assessment of cardiovascular function from multi-Gaussian fitting of a finger photoplethysmogram. AB - Monitoring of cardiovascular function on a beat-to-beat basis is fundamental for protecting patients in different settings including emergency medicine and interventional cardiology, but still faces technical challenges and several limitations. In the present study, we propose a new method for the extraction of cardiovascular performance surrogates from analysis of the photoplethysmographic (PPG) signal alone.We propose using a multi-Gaussian (MG) model consisting of five Gaussian functions to decompose the PPG pulses into its main physiological components. From the analysis of these components, we aim to extract estimators of the left ventricular ejection time, blood pressure and vascular tone changes. Using a multi-derivative analysis of the components related with the systolic ejection, we investigate which are the characteristic points that best define the left ventricular ejection time (LVET). Six LVET estimates were compared with the echocardiographic LVET in a database comprising 68 healthy and cardiovascular diseased volunteers. The best LVET estimate achieved a low absolute error (15.41 +/- 13.66 ms), and a high correlation (rho = 0.78) with the echocardiographic reference.To assess the potential use of the temporal and morphological characteristics of the proposed MG model components as surrogates for blood pressure and vascular tone, six parameters have been investigated: the stiffness index (SI), the T1_d and T1_2 (defined as the time span between the MG model forward and reflected waves), the reflection index (RI), the R1_d and the R1_2 (defined as their amplitude ratio). Their association to reference values of blood pressure and total peripheral resistance was investigated in 43 volunteers exhibiting hemodynamic instability. A good correlation was found between the majority of the extracted and reference parameters, with an exception to R1_2 (amplitude ratio between the main forward wave and the first reflection wave), which correlated low with all the reference parameters. The highest correlation ([Formula: see text] = 0.45) was found between T1_2 and the total peripheral resistance index (TPRI); while in the patients that experienced syncope, the highest agreement ([Formula: see text] = 0.57) was found between SI and systolic blood pressure (SBP) and mean blood pressure (MBP).In conclusion, the presented method for the extraction of surrogates of cardiovascular performance might improve patient monitoring and warrants further investigation. PMID- 26235799 TI - Age and markers of Leydig cell function, but not of Sertoli cell function predict the success of sperm retrieval in adolescents and adults with Klinefelter's syndrome. AB - Microsurgical testicular sperm extraction (mTESE), combined with intracytoplasmic sperm injection (ICSI) represents a chance for azoospermic men with Klinefelter's syndrome (KS) to father children. The objective of this study was to identify predictive factors for the success of mTESE from adolescents and adults with KS. The clinical data of 50 late pubertal adolescents (13-19 years) and 85 adult patients (20-61 years) with non-mosaic KS, who underwent mTESE, were analysed with respect to factors, potentially predictive of active spermatogenesis; specifically a history of cryptorchidism, age, testicular volumes, serum levels of LH, FSH, testosterone (T) and estradiol at the time of surgery. Inhibin B, AMH and INSL3 were additionally analysed in the adolescents. A younger age and a near compensated Leydig cell function were associated with higher success of sperm retrieval via mTESE: In adolescents >=15-19 years, spermatozoa were retrieved in 45%, compared to 31% in adults; in adolescents aged 13-14 years, spermatozoa were collected in only 10%. Adolescents with an LH <=17.5 U/L, along with a T level >=7.5 nmol/L had the best success rate (54%), which fell to 44% with higher LH, whereas those with low T (<7.5 nmol/L), irrespective of LH had no sperm retrieval. In adults with T levels above and LH below these thresholds, the success rate was 51%, falling to 19%, if LH was higher. When T was lower than threshold, the rate was 17%. No association between testicular volumes, serum levels of FSH, Inhibin B, AMH, estradiol and mTESE success was found. A history of cryptorchidism was associated with lower retrieval rates. A window of opportunity for an approximate 50% chance to retrieve spermatozoa via mTESE exists for young, late pubertal KS patients between age 15 and young adulthood, when Leydig cell function is at its best. In these cases, referral to a centre of expertise should be considered. PMID- 26235800 TI - Faciotopy-A face-feature map with face-like topology in the human occipital face area. AB - The occipital face area (OFA) and fusiform face area (FFA) are brain regions thought to be specialized for face perception. However, their intrinsic functional organization and status as cortical areas with well-defined boundaries remains unclear. Here we test these regions for "faciotopy", a particular hypothesis about their intrinsic functional organisation. A faciotopic area would contain a face-feature map on the cortical surface, where cortical patches represent face features and neighbouring patches represent features that are physically neighbouring in a face. The faciotopy hypothesis is motivated by the idea that face regions might develop from a retinotopic protomap and acquire their selectivity for face features through natural visual experience. Faces have a prototypical configuration of features, are usually perceived in a canonical upright orientation, and are frequently fixated in particular locations. To test the faciotopy hypothesis, we presented images of isolated face features at fixation to subjects during functional magnetic resonance imaging. The responses in V1 were best explained by low-level image properties of the stimuli. OFA, and to a lesser degree FFA, showed evidence for faciotopic organization. When a single patch of cortex was estimated for each face feature, the cortical distances between the feature patches reflected the physical distance between the features in a face. Faciotopy would be the first example, to our knowledge, of a cortical map reflecting the topology, not of a part of the organism itself (its retina in retinotopy, its body in somatotopy), but of an external object of particular perceptual significance. PMID- 26235801 TI - Sex and age differences in the early identification and treatment of alcohol use: a population-based study of patients with alcoholic cirrhosis. AB - AIM: To estimate sex differences in health-care utilization among harmful/hazardous drinkers in the period before alcoholic cirrhosis diagnosis, and estimate sex differences in the extent to which alcohol use and brief alcohol interventions were documented for these individuals compared with a control cohort. DESIGN: Retrospective study using linked general practice and hospital admissions data in England. SETTING: Three hundred and fifty-seven general practitioner (GP) practices in England. PARTICIPANTS: A total of 2479 individuals with alcoholic cirrhosis (mean age at diagnosis=56 years), of whom 67% were men; and 24,790 controls without the disease. MEASUREMENTS: Rates of primary care visits and hospital admissions prior to the diagnosis of alcoholic cirrhosis for men and women, and the proportion of men and women with alcohol consumption and/or alcohol brief intervention documented in their medical record. FINDINGS: Compared with the general population, patients with alcoholic cirrhosis used primary and secondary health-care services more frequently in the years leading up to their diagnosis. In the years prior to diagnosis, men used primary and secondary health-care services more than did women (P for sex interaction P<0.0001). Men were more likely than women to have their alcohol use recorded [odds ratio (OR) men=1.96, 95% confidence interval (CI)=1.7-2.3; women=1.63, 95% CI=1.4-1.8, P for sex interaction P<0.0017]. By contrast, alcohol interventions were recorded more commonly among women (OR men=4.3, 95% CI=3.7-4.9; women=5.8, 95% CI=4.7-6.9, P for sex interaction=0.07), although less common with increasing age (P for age interaction=0.009). CONCLUSIONS: In the United Kingdom, prior to alcoholic cirrhosis diagnosis, excess health-care utilization is higher in men than women and men are more likely than women to have their alcohol use recorded. However, women appear to be more likely than men to receive alcohol brief interventions. PMID- 26235802 TI - Urinary fistula after robot-assisted partial nephrectomy: a multicentre analysis of 1 791 patients. AB - OBJECTIVE: To evaluate the incidence of and risk factors for a urine leak in a large multicentre, prospective database of robot-assisted partial nephrectomy (RPN). PATIENTS AND METHODS: A database of 1 791 RPN from five USA centres was reviewed for urine leak as a complication of RPN. Patient and tumour characteristics were compared between patients with and those without postoperative urine leaks. Fisher's exact test was used for qualitative variables and Wilcoxon sum-rank tests were used for quantitative variables. A review of the literature on PN and urine leak was conducted. RESULTS: Urine leak was noted in 14/1 791 (0.78%) patients who underwent RPN. The mean (sd) nephrometry score of the entire cohort was 7.2 (1.9), and 8.0 (1.9) in patients who developed urine leak. The median (range) postoperative day of presentation was 13 (3-32) days. Patients with urine leak presented in delayed fashion with fever (two of the 14 patients, 14%), gastrointestinal complaints (four patients, 29%), and pain (five patients, 36%). Eight of the 14 patients (57%) required admission, while eight (57%) and nine (64%) had a drain or stent placed, respectively. Drains and stents were removed after a median (range) of 8 (4-13) days and 21 (8-83) days, respectively. Variables associated with urine leak included tumour size (P = 0.021), hilar location (P = 0.025), operative time (P = 0.006), warm ischaemia time (P = 0.005), and pelvicalyceal repair (P = 0.018). Upon literature review, the historical incidence of urine leak ranged from 1.0% to 17.4% for open PN and 1.6-16.5% for laparoscopic PN. CONCLUSION: The incidence of urine leak after RPN is very low and may be predicted by some preoperative factors, affording better patient counselling of risks. The low urinary leak rate may be attributed to the enhanced visualisation and suturing technique that accompanies the robotic approach. PMID- 26235804 TI - Taste Detection Thresholds of Resveratrol. AB - Resveratrol is a polyphenol that is associated with numerous health benefits related to heart disease, cancer, diabetes, and neurological function. The addition of this compound to food products would help to deliver these health benefits to the consumer. However, bitterness associated with resveratrol may impart negative sensory qualities on the food products into which resveratrol is added; thus, decreasing consumer acceptability. This concern may be resolved by encapsulating resveratrol through spray drying, an innovative processing technique. The objectives of this research were to (1) compare taste detection thresholds of unencapsulated resveratrol and encapsulated resveratrol and (2) determine if the inclusion of anhydrous milk fat in the formulation of the encapsulation wall material affects the taste detection threshold of resveratrol within the microcapsules. Resveratrol microcapsules were produced by encapsulating resveratrol in a protein matrix through spray drying. R-index measure by the rating method was used to determine the average taste detection threshold and the pooled group taste detection threshold. The average and pooled group taste detection thresholds of unencapsulated resveratrol, sodium-caseinate based resveratrol microcapsule without fat (SC), and sodium-caseinate-based resveratrol microcapsule with fat (SCAMF) were 90 and 47 mg resveratrol/L (unencapsulated), 313 and 103 mg resveratrol/L (SC), 334 and 108 mg resveratrol/L (SCAMF), respectively. The findings demonstrate that the encapsulation of resveratrol decreased the detection of the compound and provided a means to incorporate resveratrol into food products without imparting negative sensory properties. PMID- 26235806 TI - Success and complications of implant-retained prostheses provided by the Post Doctoral Prosthodontics Program, University of Puerto Rico: a cross-sectional study. AB - STATEMENT OF PROBLEM: The success rate of implant-retained prostheses in a postdoctoral prosthodontics program was unknown and could not be related to any set of potential clinical issues or patient characteristics. PURPOSE: The purpose of this study was to determine the success rate of implant-retained prostheses placed by prosthodontic residents between 1997 and 2012 and to evaluate the associations between patient classifications and specific restoration characteristics as related to prosthesis success or failure. MATERIAL AND METHODS: A total of 272 prostheses in 119 patients were clinically evaluated. Success was defined as the absence of prosthetic complications or any implant related complication that affected prosthesis survival. Logistic regression was used to evaluate associations between prosthesis success/failure and a wide array of study variables, adjusting for patient age, sex, and prosthesis longevity. RESULTS: The overall success rate was 71%, with a mean prosthesis age of 4.5 years (range: 4 months to 16.8 years). Implant single crowns were the most successful prosthesis type (81% success). The most common complications observed were porcelain fractures in fixed dental prostheses (15%) and lack of stability (31%) and retention (29%) in removable dental prostheses. Having a removable prosthesis (versus natural dentition) in the opposing occlusion significantly decreased the odds of success (OR=0.26, 95% CI: 0.11-0.64). Definitively cemented fixed prostheses were more successful than those cemented with an interim cement (OR=4.56, 95% CI: 1.37-15.22). CONCLUSIONS: The overall success rate of the implant-retained prostheses placed in the program was low compared with previously published studies. This study revealed the need for an efficient, comprehensive recall system for patients receiving implant-retained prostheses, either fixed or removable. PMID- 26235805 TI - A new glucosidic phthalide from Helichrysum microphyllum subsp. tyrrhenicum from La Maddalena Island (Sardinia, Italy). AB - In this study, we reported the analysis of the medium polarity fraction obtained from an accession of Helichrysum microphyllum subsp. tyrrhenicum from La Maddalena Island. Besides several compounds already evidenced in this species and related genera, i.e. micropyrone (1), arzanol (2), helipyrone (3), acetyl-bitalin derivatives (4, 5), gnaphaliol (6), caffeic acid (7), ursolic acid (8), 7-O-beta (D-glucopyranosyl)-5-methoxy-1(3H)-isobenzofuranone (9), gnaphaliol-9-O-beta-D glucopyranoside (11) and gnaphaliol-3-O-beta-D-glucopyranoside (12), the presence of a new glycosidic phthalide, 6-O-beta-(D-glucopyranosyl)-4-methoxy-1(3H) benzofuranone (10), was evidenced for the first time, which resulted in a structural isomer of compound (9). The occurrence of this new benzofuranone derivative is an additional evidence of the deep intraspecific variability expressed by this species, which was also stated for the non-volatile components, and may be a distinctive trait of the population growing on La Maddalena Island. PMID- 26235803 TI - Estimation of total kidney volume in autosomal dominant polycystic kidney disease. AB - BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), obtaining measured total kidney volume (mTKV) by magnetic resonance (MR) imaging and manual tracing is time consuming. Two alternative MR imaging methods have recently been proposed to estimate TKV (eTKVellipsoid and eTKVPANK), which require less time. STUDY DESIGN: Cross-sectional and longitudinal diagnostic test study. SETTING & PARTICIPANTS: Patients with ADPKD with a wide range of kidney function and an approved T2-weighted MR image obtained at the University Medical Centers of Groningen, Leiden, Nijmegen, and Rotterdam, the Netherlands, in 2007 to 2014. Test set for assessing reproducibility, n=10; cohort for cross-sectional analyses, n=220; and cohort for longitudinal analyses, n=48. INDEX TESTS: Average times for eTKVellipsoid and eTKVPANK were 5 and 15 minutes, respectively. Bias is defined as (mTKV - eTKV)/mTKV * 100%; precision, as one standard deviation of bias. REFERENCE TESTS: mTKV using manual tracing to calculate the area within kidney boundaries times slice thickness. Average time for mTKV was 55 minutes. RESULTS: In the test set, intra- and intercoefficients of variation for mTKV, eTKVellipsoid, and eTKVPANK were 1.8% and 2.3%, 3.9% and 6.3%, and 3.0% and 3.4%, respectively. In cross-sectional analysis, baseline mTKV, eTKVellipsoid, and eTKVPANK were 1.96 (IQR, 1.28-2.82), 1.93 (IQR, 1.25-2.82), and 1.81 (IQR, 1.17 2.62) L, respectively. In cross-sectional analysis, bias was 0.02% +/- 3.2%, 1.4% +/- 9.2%, and 4.6% +/- 7.6% for repeat mTKV, eTKVellipsoid, and eTKVPANK, respectively. In longitudinal analysis, no significant differences were observed between percentage change in mTKV (16.7% +/- 17.1%) and percentage change in eTKVellipsoid (19.3% +/- 16.1%) and eTKVPANK (17.8% +/- 16.1%) over 3 years. LIMITATIONS: Results for follow-up data should be interpreted with caution because of the limited number of patients. CONCLUSIONS: Both methods for eTKV perform relatively well compared to mTKV and can detect change in TKV over time. Because eTKVellipsoid requires less time than eTKVPANK, we suggest that this method may be preferable in clinical care. PMID- 26235807 TI - 4-Acetylantroquinonol B inhibits colorectal cancer tumorigenesis and suppresses cancer stem-like phenotype. AB - 4-Acetylantroquinonol B (4-AAQB), closely related to the better known antroquinonol, is a bioactive isolate of the mycelia of Antrodia camphorata, a Taiwanese mushroom with documented anti-inflammatory, hypoglycemic, vasorelaxative, and recently demonstrated, antiproliferative activity. Based on its traditional use, we hypothesized that 4-AAQB may play an active role in the suppression of cellular transformation, tumor aggression and progression, as well as chemoresistance in colorectal carcinoma (CRC). In this study, we investigated the antiproliferative role of 4-AAQB and its underlying molecular mechanism. We also compared its anticancer therapeutic potential with that of antroquinonol and the CRC combination chemotherapy of choice - folinic acid, fluorouracil and oxaliplatin (FOLFOX). Our results showed that 4-AAQB was most effective in inhibiting tumor proliferation, suppressing tumor growth and attenuating stemness related chemoresistance. 4-AAQB negatively regulates vital oncogenic and stem cell maintenance signal transduction pathways, including the Lgr5/Wnt/beta catenin, JAK-STAT, and non-transmembrane receptor tyrosine kinase signaling pathways, as well as inducing a dose-dependent downregulation of ALDH and other stemness related factors. These results were validated in vivo, with animal studies showing 4-AAQB possessed comparable tumor-shrinking ability as FOLFOX and potentiates ability of the later to reduce tumor size. Thus, 4-AAQB, a novel small molecule, projects as a potent therapeutic agent for monotherapy or as a component of standard combination chemotherapy. PMID- 26235809 TI - Residual Defect Density in Random Disks Deposits. AB - We investigate the residual distribution of structural defects in very tall packings of disks deposited randomly in large channels. By performing simulations involving the sedimentation of up to 50 * 10(9) particles we find all deposits to consistently show a non-zero residual density of defects obeying a characteristic power-law as a function of the channel width. This remarkable finding corrects the widespread belief that the density of defects should vanish algebraically with growing height. A non-zero residual density of defects implies a type of long-range spatial order in the packing, as opposed to only local ordering. In addition, we find deposits of particles to involve considerably less randomness than generally presumed. PMID- 26235808 TI - Simultaneous morphology manipulation and upconversion luminescence enhancement of beta-NaYF4:Yb3+/Er3+ microcrystals by simply tuning the KF dosage. AB - A strategy has been adopted for simultaneous morphology manipulation and upconversion luminescence enhancement of beta-NaYF4:Yb(3+)/Er(3+) microcrystals by simply tuning the KF dosage. X-ray power diffraction (XRD), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), X ray photoelectron spectroscopy (XPS) and photoluminescence spectra (PL) were used to characterize the samples. The influence of molar ratio of KF to Y(3+) on the crystal phase and morphology has been systematically investigated and discussed. It is found that the molar ratio of KF to Y(3+) can strongly control the morphology of the as-synthesized beta-NaYF4 samples because of the different capping effect of F(-) ions on the different crystal faces. The possible formation mechanism has been proposed on the basis of a series of time-dependent experiments. More importantly, the upconversion luminescence of beta NaYF4:Yb(3+)/Er(3+) was greatly enhanced by increasing the molar ratio of KF to RE(3+) (RE = Y, Yb, Er), which is attributed to the distortion of local crystal field symmetry around lanthanide ions through K(+) ions doping. This synthetic methodology is expected to provide a new strategy for simultaneous morphology control and remarkable upconversion luminescence enhancement of yttrium fluorides, which may be applicable for other rare earth fluorides. PMID- 26235810 TI - Negative Regulation of miR-375 by Interleukin-10 Enhances Bone Marrow-Derived Progenitor Cell-Mediated Myocardial Repair and Function After Myocardial Infarction. AB - Poor survival and function of transplanted cells in ischemic and inflamed myocardium likely compromises the functional benefit of stem cell-based therapies. We have earlier reported that co-administration of interleukin (IL)-10 and BMPAC enhances cell survival and improves left ventricular (LV) functions after acute myocardial infarction (MI) in mice. We hypothesized that IL-10 regulates microRNA-375 (miR-375) signaling in BMPACs to enhance their survival and function in ischemic myocardium after MI and attenuates left ventricular dysfunction after MI. miR-375 expression is significantly upregulated in BMPACs upon exposure to inflammatory/hypoxic stimulus and also after MI. IL-10 knockout mice display significantly elevated miR-375 levels. We report that ex vivo miR 375 knockdown in BMPAC before transplantation in the ischemic myocardium after MI significantly improve the survival and retention of transplanted BMPACs and also BMPAC-mediated post-infarct repair, neovascularization, and LV functions. Our in vitro studies revealed that knockdown of miR-375-enhanced BMPAC proliferation and tube formation and inhibited apoptosis; over expression of miR-375 in BMPAC had opposite effects. Mechanistically, miR-375 negatively regulated 3 phosphoinositide-dependent protein kinase-1 (PDK-1) expression and PDK-1-mediated activation of PI3kinase/AKT signaling. Interestingly, BMPAC isolated from IL-10 deficient mice showed elevated basal levels of miR-375 and exhibited functional deficiencies, which were partly rescued by miR-375 knockdown, enhancing BMPAC function in vitro and in vivo. Taken together, our studies suggest that miR-375 is negatively associated with BMPAC function and survival and IL-10-mediated repression of miR-375 enhances BMPAC survival and function. PMID- 26235814 TI - Exaggerated Exercise Blood Pressure Response and Future Cardiovascular Disease. AB - Exaggerated blood pressure (BP) response to exercise predicts future hypertension. However, there is considerable lack of understanding regarding the mechanism of how this abnormal response is generated, and how it relates to the future establishment of cardiovascular disease. The authors studied 82 healthy male volunteers without cardiovascular risk factors. The participants were categorized into two age-matched groups depending on their exercise systolic BP (ExSBP) rise after 3 minutes of exercise using a submaximal step test: exaggerated ExSBP group (hyper-responders [peak SBP >= 180 mm Hg]) and low ExSBP responder group (hypo-responders [peak SBP <180 mm Hg]). Forearm venous occlusion plethysmography and intra-arterial infusions of acetylcholine (ACh), N(G) monomethyl-L-arginine (L-NMMA), sodium nitroprusside (SNP), and norepinephrine (NE) were used to assess vascular reactivity. Proximal aortic compliance was assessed with ultrasound, and neurohormonal blood sampling was performed at rest and during peak exercise. The hyper-responder group exhibited a significantly lower increase in forearm blood flow (FBF) with ACh compared with the hypo responder group (DeltaFBF 215% [14] vs 332.3% [28], mean [standard error of the mean]; P<.001), as well as decreased proximal aortic compliance. The vasoconstrictive response to L-NMMA was significantly impaired in the hyper responder group in comparison to the hypo-responder group (DeltaFBF -40.2% [1.6] vs -50.2% [2.6]; P<.05). In contrast, the vascular response to SNP and NE were comparable in both groups. Peak exercise plasma angiotensin II levels were significantly higher in the hyper-responder group (31 [1] vs 23 [2] pg/mL, P=.01). An exaggerated BP response to exercise is related to endothelial dysfunction, decreased proximal aortic compliance, and increased exercise-related neurohormonal activation, the constellation of which may explain future cardiovascular disease. PMID- 26235813 TI - Cadmium chloride inhibits lactate gluconeogenesis in mouse renal proximal tubules: An in vitro metabolomic approach with (13)C NMR. AB - Using isolated mouse renal proximal tubules incubated with lactate as substrate, we have found that the addition of 1-50 MUM cadmium chloride (CdCl2) caused a concentration-dependent decrease in lactate utilization, in glucose production and in the cellular level of ATP, coenzyme A, acetyl-coenzyme A and glutathione (reduced and oxidized forms). Combining enzymatic and (13)C NMR measurements in a cellular metabolomic approach, we have shown that, in the presence of 10 MUM CdCl2, fluxes through the key-enzymes of gluconeogenesis, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase were greatly depressed by cadmium. This was accompanied by a reduction in fluxes through the enzymes of the tricarboxylic acid cycle. Comparing the mouse and human renal metabolic responses to cadmium, it is interesting to observe that the mouse renal proximal tubule was much more sensitive than the human renal proximal tubule to the adverse effects of CdCl2. As far as renal gluconeogenesis is concerned, the mouse seems to be an appropriate and convenient animal model to study the mechanism of cadmium nephrotoxicity. However, the data obtained in the mouse should be extrapolated to humans with caution because the inhibition of fluxes through the enzymes of the tricarboxylic acid cycle in mouse tubules were not observed in human tubules. PMID- 26235816 TI - Template-based identification of protein-protein interfaces using eFindSitePPI. AB - Protein-protein interactions orchestrate virtually all cellular processes, therefore, their exhaustive exploration is essential for the comprehensive understanding of cellular networks. A reliable identification of interfacial residues is vital not only to infer the function of individual proteins and their assembly into biological complexes, but also to elucidate the molecular and physicochemical basis of interactions between proteins. With the exponential growth of protein sequence data, computational approaches for detecting protein interface sites have drawn an increased interest. In this communication, we discuss the major features of eFindSite(PPI), a recently developed template-based method for interface residue prediction available at http://brylinski.cct.lsu.edu/efindsiteppi. We describe the requirements and installation procedures for the stand-alone version, and explain the content and format of output data. Furthermore, the functionality of the eFindSite(PPI) web application that is designed to provide a simple and convenient access for the scientific community is presented with illustrative examples. Finally, we discuss common problems encountered in predicting protein interfaces and set forth directions for the future development of eFindSite(PPI). PMID- 26235815 TI - Photo-initiated crosslinking extends mapping of the protein-protein interface to membrane-embedded portions of cytochromes P450 2B4 and b5. AB - Protein-protein interactions play a central role in the regulation of many biochemical processes (e.g. the system participating in enzyme catalysis). Therefore, a deeper understanding of protein-protein interactions may contribute to the elucidation of many biologically important mechanisms. For this purpose, it is necessary to establish the composition and stoichiometry of supramolecular complexes and to identify the crucial portions of the interacting molecules. This study is devoted to structure-functional relationships in the microsomal Mixed Function Oxidase (MFO) complex, which is responsible for biotransformation of many hydrophobic endogenous compounds and xenobiotics. In particular, the cytochrome b5 interaction with MFO terminal oxygenase cytochrome P-450 (P450) was studied. To create photolabile probes suitable for this purpose, we prepared cytochrome b5 which had a photolabile diazirine analog of methionine (pMet) incorporated into the protein sequence, employing recombinant expression in Escherichia coli. In addition to wild-type cytochrome b5, where three methionines (Met) are located at positions 96, 126, and 131, six mutants containing only one Met in the sequence were designed and expressed (see Table 1). In these mutants, a single Met was engineered into the catalytic domain (at positions 23, 41, or 46), into the linker between the protein domains (at position 96), or into the membrane region (at positions 126 or 131). These mutants should confirm or exclude these portions of cytochrome b5 which are involved in the interaction with P450. After UV irradiation, the pMet group(s) in the photolabile cytochrome b5 probe was(were) activated, producing covalent crosslinks with the interacting parts of P450 2B4 in the close vicinity. The covalent complexes were analyzed by the "bottom up" approach with high-accuracy mass spectrometry. The analysis provided an identification of the contacts in the supramolecular complex with low structural resolution. We found that all the above-mentioned cytochrome b5 Met residues can form intermolecular crosslinks and thus participate in the interaction. In addition, our results indicate the existence of at least two P450:cytochrome b5 complexes which differ in the orientation of individual proteins. The results demonstrate the advantages of the photo-initiated crosslinking technique which is able to map the protein-protein interfaces not only in the solvent exposed regions, but also in the membrane-embedded segments (compared to a typical crosslinking approach which generally only identifies crosslinks in solvent exposed regions). PMID- 26235811 TI - Development of a partner preference test that differentiates between established pair bonds and other relationships in socially monogamous titi monkeys (Callicebus cupreus). AB - Partner preference, or the selective social preference for a pair mate, is a key behavioral indicator of social monogamy. Standardized partner preference testing has been used extensively in rodents but a single test has not been standardized for primates. The goal of this study was to develop a partner preference test with socially monogamous titi monkeys (Callicebus cupreus) adapted from the widely used rodent test. In Experiment 1, we evaluated the test with pairs of titi monkeys (N = 12) in a three-chambered apparatus for 3 hr. The subject was placed in the middle chamber, with grated windows separating it from its partner on one side and an opposite sex stranger on the other side. Subjects spent a greater proportion of time in proximity to their partners' windows than the strangers', indicating a consistent preference for the partner over the stranger. Touching either window did not differ between partners and strangers, suggesting it was not a reliable measure of partner preference. Subjects chose their partner more than the stranger during catch and release sessions at the end of the test. In Experiment 2, we compared responses of females with current partners (N = 12) in the preference test with other relationship types representing former attachment bonds (N = 13) and no attachment bond (N = 8). Only females from established pair bonds spent significantly more time near their partner's window compared to the stranger's indicating that this measure of preference was unique to current partners. Other measures of preference did not differentiate behavior toward a current partner and other relationship types. This test reproduces behavioral patterns found in previous studies in titi monkeys highlighting the accuracy of this new partner preference test. This test can be used as a standardized measure of partner preference in titi monkeys to quantitatively study pair bonding and evaluate factors influencing partner preference. PMID- 26235817 TI - Malignant cardiac tumors: diagnosis and treatment. AB - Primary malignant cardiac tumors are represented by sarcomas and non-Hodgkin lymphomas. They are rare, affect mostly patients in the fourth decade of life and have a severe prognosis. Both the diagnosis and the treatment require a multidisciplinary approach, and the cardiologist plays a central role both in the diagnosis and in the follow-up. The prognosis may be improved by a careful planning of surgery and by the use of multimodality treatment, including complementary chemotherapy and radiation therapy. A strict follow-up must be planned even after apparently complete cure. PMID- 26235821 TI - Generalized Keratosis Lichenoides Chronica. PMID- 26235822 TI - Brief rhythmic discharges in neonates: a marker for seizures. AB - Brief rhythmic discharges (BRDs) are paroxysms of rhythmic electrographic activity with an amplitude of >2 MUV and a duration of <10 seconds. Although BRDs are reported in neonates, this electrographic activity contrasts the accepted definition of neonatal seizures (duration of >10 seconds). BRDs are associated with background EEG abnormalities as well as increased morbidity and mortality (Oliveira et al., 2000, Nagarajan et al., 2011), and appear to be more closely related to formal neonatal seizures than post-neonatal epilepsy (Nagarajan et al., 2011). Most neonatal units are restricted to one-hour recordings, and if BRDs are observed without any accompanying electrographic seizures, then the neonate should be regarded as being at high risk of seizures and repeat recordings should be considered. PMID- 26235818 TI - Effects of proton exchange membrane on the performance and microbial community composition of air-cathode microbial fuel cells. AB - This study investigated the effects of proton exchange membranes (PEMs) on performance and microbial community of air-cathode microbial fuel cells (MFCs). Air-cathode MFCs with reactor volume of 1L were constructed in duplicate with or without PEM (designated as ACM-MFC and AC-MFC, respectively) and fed with a mixture of glucose and acetate (1:1, w:w). The maximum power density and coulombic efficiency did not differ between MFCs in the absence or presence of a PEM. However, PEM use adversely affected maximum voltage production and the rate of organic compound removal (p<0.05). Quantitative droplet digital PCR indicated that AC-MFCs had a greater bacterial population than ACM-MFCs (p<0.05). Likewise, ribosomal tag pyrosequencing revealed that the diversity index of bacterial communities was greater for AC-MFCs (p<0.05). Network analysis revealed that the most abundant genus was Enterococcus, which comprised >=62% of the community and was positively associated with PEM and negatively associated with the rate of chemical oxygen demand (COD) removal (Pearson correlation>0.9 and p<0.05). Geobacter, which is known as an exoelectrogen, was positively associated with maximum power density and negatively associated with PEM. Thus, these results suggest that the absence of PEM favored the growth of Geobacter, a key player for electricity generation in MFC systems. Taken together, these findings demonstrate that MFC systems without PEM are more efficient with respect to power production and COD removal as well as exoelectrogen growth. PMID- 26235819 TI - Involvement of a caleosin in lipid storage, spore dispersal, and virulence in the entomopathogenic filamentous fungus, Beauveria bassiana. AB - Eukaryotic cells store lipids in membrane-encased droplets. The entomopathogenic fungus, Beauveria bassiana, initiates infection via attachment of its spores to the epicuticle or waxy layer of target insects, degrading and assimilating host surface hydrocarbons, carbohydrates and proteins. Caleosins are components of the proteinaceous coat of lipid droplets and a single B. bassiana caleosin homologue, Bbcal1, was identified and characterized. The BbCal1 sequence contained an EF hand Ca(2+) binding domain and potential hydrophobic stretches similar to those found in plant caleosins, along with a proline knot motif defined by only two proline residues. Targeted gene inactivation of Bbcal1 did not appear to affect spore germination, growth on lipid substrates or stress response, but changes in lipid, vacuole and endoplasmic reticulum/multilamellar vesicle-like structures, and altered cellular lipid profiles were seen in conidia grown on a variety of substrates including potato dextrose agar, olive oil, glyceride trioleate, oleic acid and the alkane, C16 . The DeltaBbcal1 mutant produced more compact assemblages of conidia, displayed a reduced and delayed spore dispersal phenotype, and showed decreased virulence in insect bioassays using the greater wax moth, Galleria mellonella. Our data indicate novel functions for caleosins in fungal virulence, spore development and the trafficking and/or turnover of lipid related structures. PMID- 26235820 TI - The relationship between teacher burnout and student motivation. AB - BACKGROUND: Teacher burnout is regarded as a serious problem in school settings. To date, studies on teachers' stress and burnout have largely centred on teachers' own characteristics, socialization, and behaviours, but few have explored the connection between teachers' burnout and students' motivation via their own perceptions of teachers' behaviour and emotional well-being. AIMS: This study adopted Maslach et al.'s (2001, Annu. Rev. Psychol., 52, 397) job burnout construct and self-determination theory to investigate the relationships between teachers' burnout and students' autonomous motivation over one-semester physical education classes. SAMPLE: A total of 1,302 high school students and their 33 physical education teachers in 20 high schools from two school districts in a major Midwest metropolitan area in the United States. The two school districts were demographically similar. METHODS: Students and physical education teachers completed questionnaires assessing relevant psychological constructs. There were two time points for collecting students' data. One was at the beginning of a fall semester, and the other was at the end of that semester. Hierarchical linear modelling analyses were conducted. RESULTS: It was revealed that teachers' emotional exhaustion was negatively related to students' perceived teacher autonomy support (TAS); in turn, there was a negative relationship between teachers' feeling of depersonalization and students' autonomous motivation development even when controlling for inadequate TAS. CONCLUSION: The dimensions of teachers' burnout might play different roles in the transmission from teachers to students. Teachers' status of burnout is an important environmental factor associated with students' quality of motivation. PMID- 26235823 TI - Unravelling detrusor underactivity: Development of a bladder outlet resistance Bladder contractility nomogram for adult male patients with lower urinary tract symptoms. AB - AIMS: Voiding dysfunction in adult men may be caused by bladder outlet obstruction (BOO) and/or detrusor underactivity (DU). Until now, it is only possible to classify BOO and DU by pressure-flow analysis. Low values of the maximum Watts factor (Wmax ) indicate DU but thresholds for the diagnosis have not been established. Purpose of this study was to construct a nomogram using bladder outlet resistance and detrusor contractility in order to classify BOO and DU simultaneously. METHODS: Treatment naive men aged >=40 years with uncomplicated lower urinary tract symptoms (LUTS) were prospectively evaluated. Patients were assessed with IPSS, prostate volume, uroflowmetry, post-void residual, and pressure-flow measurement. The bladder outlet obstruction index (BOOI) was used to determine BOO-grade and Wmax to calculate detrusor contractility. Individual BOOI-Wmax values were plotted in a graph. Linear interpolation was applied to determine the 10th, 25th, 50th, 75th, and 90th percentiles. RESULTS: Retrospective analysis of 822 male patients with means of 64 years, IPSS 16, and prostate volume of 40 cc. Patient and clinical parameters of the <25th percentile groups were significantly different compared to the 25th 50th percentiles: age (66 vs. 63 years, P = 0.006), bladder capacity (503 vs. 442 ml, P = 0.009), post-void residual urine (167 vs. 116 ml, P = 0.001), and voiding efficiency (67% vs. 73%, P = 0.015). CONCLUSIONS: The nomogram quantifies the relationship between detrusor contractility and BOO in men with LUTS. A measurement value <25th percentile correlates with clinical indicators of DU and is proposed as a cut-off value for DU-diagnosis. Higher age, bladder capacity, and PVR as well as lower voiding efficiency indicate DU. Neurourol. Urodynam. 35:980-986, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26235824 TI - Two Rare Mutations in the COL1A2 Gene Associate With Low Bone Mineral Density and Fractures in Iceland. AB - We conducted a genome-wide association study of low bone mineral density (BMD) at the hip and spine utilizing sequence variants found through whole-genome sequencing of 2636 Icelanders. We found two rare missense mutations, p.Gly496Ala and p.Gly703Ser, in the COL1A2 gene that associate with measures of osteoporosis in Icelanders. Mutations in COL1A2 are known to cause the autosomal dominant disorder osteogenesis imperfecta. Both variants associate with low BMD and with osteoporotic fractures. p.Gly496Ala (frequency of 0.105%) shows the strongest association with low BMD at the spine (p = 1.8 * 10(-7) , odds ratio [OR] = 4.61 [95% confidence interval (CI) 2.59, 8.18]), whereas p.Gly703Ser (frequency of 0.050%) is most strongly associated with low BMD at the hip (p = 1.9 * 10(-8) , OR = 9.34 [95% CI 4.28, 20.3]). Association with fractures was p = 2.2 * 10(-5) , OR = 3.75 (95% CI 2.03, 6.93) and p = 0.0023, OR = 4.32 (95% CI 1.69, 11.1), respectively. The carriers of these variants do not have signs of osteogenesis imperfecta other than low BMD, demonstrating that similar mutations in COL1A2 can affect skeletal phenotypes in more than one way. PMID- 26235825 TI - How to derive tight-binding spd potentials? Application to zirconium. AB - We propose here a general methodology to derive tight-binding potentials accounting for spd hybridization in transition metals, dealing simultaneously with electronic structure and energy properties. This methodology is illustrated for zirconium which is largely used for technological applications, in particular in the nuclear industry, and whose modelling is known to be complex and challenging. Such potentials are very promising. Their fits have a clear physical meaning with a limited amount of parameters and their complexity can be adjusted as a function of the problem under consideration. PMID- 26235826 TI - Circulating microparticles from diabetic rats impair endothelial function and regulate endothelial protein expression. AB - AIM: Diabetes mellitus increases the risk of cardiovascular disease, which is accompanied by functional and structural changes in the vascular system. Microparticles (MPs) have been described as biological vectors of endothelial dysfunction in other pathologies. However, the molecular mechanisms underlying their formation and signalling are unclear. We investigated the role of MPs derived from streptozotocin (STZ)-induced diabetic rats in endothelial function. METHODS: Male Wistar rats were injected with STZ to induce diabetes, and MPs isolated from control or STZ-induced diabetic rats were characterized by dot blotting (assessed by CD62P detections), flow cytometry (assessed by annexin V detections) and ELISA. Carotid arteries from rats were incubated with MPs, and expressions of enzymes and endothelium-dependent relaxation were analysed. RESULTS: The circulating levels of MPs, particularly the levels of platelet derived microparticles, from diabetic rats were higher than those present in controls. Endothelium-dependent relaxation induced by acetylcholine (ACh) was attenuated in carotid arteries from STZ-induced diabetic rats. Following the incubation of control carotid arteries with MPs isolated from STZ rats, ACh induced endothelium-dependent relaxation was impaired, but MPs isolated from control rats had no such effect. Furthermore, the effect of MPs was mediated by a decrease in expression of endothelial nitric oxide synthase (eNOS) and the overexpression of caveolin-1. CONCLUSION: Circulating MPs isolated from STZ induced diabetic rats induce endothelial dysfunction in carotid arteries and regulate protein expressions of eNOS and caveolin-1. These data advance our understanding of the deleterious effects of circulating MPs observed in disorders with diabetic complications. PMID- 26235827 TI - Persistent Dialkylsilanone Generated by Dehydrobromination of Dialkylbromosilanol. AB - A persistent dialkylsilanone was synthesized by the dehydrobromination of a dialkylbromosilanol with tris(trimethylsilyl)silyl potassium in solution at -80 degrees C: It was characterized by NMR and IR spectroscopy, and was tested in several reactions. In (29) Si NMR spectrum in [D8 ]toluene, the signal due to the unsaturated silicon nuclei was observed at 128.7 ppm. Reactions of the dialkylsilanone with water and mesitonitrile oxide gave a silanediol and a [2+3] cycloadduct, respectively. The silanone remains intact in [D8 ]toluene below -80 degrees C for at least two days, while it undergoes unprecedented isomerization to give a siloxysilene by means of 1,3-silyl migration at higher temperatures. PMID- 26235828 TI - Radiographic, computed tomographic and surgical anatomy of the equine sphenopalatine sinus in normal and diseased horses. AB - REASONS FOR PERFORMING STUDY: Knowledge of imaging anatomy, surgical anatomy and disorders affecting the sphenopalatine sinus are currently lacking. OBJECTIVES: To describe the computed tomographic (CT) and surgical anatomy of the sphenopalatine sinus and diagnosis, treatment and outcome in clinical cases with sphenopalatine sinus disease. STUDY DESIGN: Cadaver observational study and retrospective case series. METHODS: The sphenopalatine sinuses of 10 normal cadaver heads were examined with digital radiography, CT and sinoscopic examination prior to anatomical sectioning. Sphenopalatine sinus anatomy was described and compared between cadaver specimens across the imaging modalities. Medical records (January 2004-2014) of cases diagnosed with sphenopalatine sinus disease were reviewed. RESULTS: The anatomy of the sphenopalatine sinus was variable. The borders of the sphenopalatine sinus were not identifiable on plain radiographs, whereas CT provided useful anatomical information. The palatine portion of the sphenopalatine sinus was consistently accessible sinoscopically and the sphenoidal portion was accessible in 6/10 cadaver heads. Fourteen cases of sphenopalatine sinus disease were identified, presenting with one or more clinical signs of exophthalmos, blindness, unilateral epistaxis or unilateral nasal discharge. Diagnoses included neoplasia (7), progressive ethmoidal haematoma (4), sinus cyst (2) and empyema (1). Computed tomography provided diagnostic information but could not differentiate the nature of soft tissue masses. Standing sinoscopic access to the palatine portion of the sphenopalatine sinus was possible for evaluation, biopsy and resection of abnormal soft tissues. Surgical access to the sphenoidal portion was limited. Eight horses were alive at 1 year after diagnosis, with a worse outcome associated with CT evidence of bone loss and a diagnosis of neoplasia. CONCLUSIONS: Sphenopalatine sinus disease should be considered a rare cause of the clinical signs described. Knowledge of the anatomical variation of the sphenopalatine sinus is vital for interpreting CT images. A combination of CT and sinoscopy provides the most comprehensive approach for diagnosis and treatment of sphenopalatine sinus disease. PMID- 26235829 TI - Hospitalizations and deaths due to pertussis in children from 1996 to 2013. AB - OBJECTIVES: To assess temporal trends of hospitalizations and deaths from pertussis in Brazilian children in the period of 1996-2013. METHODS: This was a descriptive ecological study of temporal trends, based on the DATASUS database. The number of hospitalizations and deaths from pertussis in children up to 19 years of age from January 1996 to December 2013 was obtained. Descriptive statistics were applied for data analysis. RESULTS: During the study period, a total of 19,047 hospital admissions from pertussis were recorded, of which 88.2% occurred in infants younger than 1 year. In the period 1996-2010, the mean annual number of admissions was 755, ranging from a maximum of 1179 in 2004 to a minimum of 400 in 2010. There was an increase of admissions in the last three consecutive years (2011, 2012, and 2013) with 1177, 2954 and 3589 hospitalizations, respectively. There were 498 deaths from pertussis throughout the study period, of which 96.8% occurred in children younger than one year. There was an increase in the number of deaths from pertussis in children in the years 2011, 2012, and 2013, with 40, 93, and 87 recorded deaths, respectively. The increase in hospitalizations and deaths from pertussis in children occurred in all regions of the country, with the highest increase observed in the Southeast, North and Northeast regions. CONCLUSIONS: There was a substantial increase in hospitalizations and deaths from pertussis in children for three consecutive years (2011, 2012, and 2013) in all Brazilian regions. The most affected age group was that of children younger than one year. PMID- 26235830 TI - Feeding patients with preoperative symptoms of gastric outlet obstruction after pancreatoduodenectomy: Early oral or routine nasojejunal tube feeding? AB - BACKGROUND: Early oral feeding is currently considered the optimal routine feeding strategy after pancreatoduodenectomy (PD). Some have suggested that patients with preoperative symptoms of gastric outlet obstruction (GOO) who undergo PD have such a high risk of developing delayed gastric emptying that these patients should rather receive routine postoperative tube feeding. The aim of this study was to determine whether clinical outcomes after PD in these patients differ between postoperative early oral feeding and routine tube feeding. METHODS: We analyzed a consecutive multicenter cohort of patients with preoperative symptoms of GOO undergoing PD (2010-2013). Patients were categorized into two groups based on the applied postoperative feeding strategy (dependent on their center's routine strategy): early oral feeding or routine nasojejunal tube feeding. RESULTS: Of 497 patients undergoing PD, 83 (17%) suffered from preoperative symptoms of GOO. 49 patients received early oral feeding and 29 patients received routine tube feeding. Time to resumption of adequate oral intake (primary outcome; 14 vs. 12 days, p = 0.61) did not differ between these two feeding strategies. Furthermore, overall complications and length of stay were similar in both groups. Of the patients receiving early oral feeding, 24 (49%) ultimately required postoperative tube feeding. In patients with an uncomplicated postoperative course, early oral feeding was associated with shorter time to adequate oral intake (8 vs. 12 days, p = 0.008) and shorter hospital stay (9 vs. 13 days, p < 0.001). CONCLUSION: Also in patients with preoperative symptoms of GOO, early oral feeding can be considered the routine feeding strategy after PD. PMID- 26235831 TI - Continuous synthesis of methanol: heterogeneous hydrogenation of ethylene carbonate over Cu/HMS catalysts in a fixed bed reactor system. AB - Continuous fixed-bed catalytic hydrogenation of ethylene carbonate (EC) to methanol and ethylene glycol (EG), an emerging synthetic process of methanol via indirect conversion of CO2, was successfully performed over Cu/HMS catalysts prepared by the ammonia evaporation (AE) method. The catalysts possessed superb performance with a conversion of 100% and a selectivity to methanol of 74%. PMID- 26235832 TI - Assessing biofiltration repeatability: statistical comparison of two identical toluene removal systems. AB - Biofiltration of volatile organic compounds is still considered an emerging technology. Its reliability remains questionable as no data is available regarding process intrinsic repeatability. Herein, two identically operated toluene biofiltration systems are comprehensively compared, during long-term operation (129 days). Globally, reactors responded very similarly, even during transient conditions, with, for example, strong biological activities from the first days of operation, and comparable periods of lower removal efficiency (81.2%) after exposure to high inlet loads (140 g m(-3) h(-1)). Regarding steady states, very similar maximum elimination capacities up to 99 g m(-3) h(-1) were attained. Estimation of the process repeatability, with the paired samples Student's t-test, indicated no statistically significant difference between elimination capacities. Repeatability was also established for several descriptors of the process such as the carbon dioxide and biomass production, the pH and organic content of the leachates, and the moisture content of the packing material. While some parameters, such as the pH, presented a remarkably low divergence between biofilters (coefficient of variability of 1.4%), others, such as the organic content of the leachates, presented higher variability (30.6%) due to an uneven biomass lixiviation associated with stochastic hydrodynamics and biomass repartitions. Regarding process efficiency, it was established that less than 10% of fluctuation is to be expected between the elimination capacities of identical biofilter set-ups. A further statistical comparison between the first halves of the biofilter columns indicated very similar coefficients of variability, confirming the repeatability of the process, for different biofilter lengths. PMID- 26235833 TI - Learning to fly with broken wings - forcing a reappraisal of time and space. AB - BACKGROUND: When living with a chronic disease, the whole human being is affected and his/her experience of health challenged. AIM: This study had a dual aim: to obtain a new understanding of experiences of the body among persons suffering from the chronic neurological disease multiple sclerosis (MS) and how they come to terms with such experiences. METHOD: A total of ten interviews were re analysed using a hermeneutic approach. RESULTS: The experiences of the body were revealed as 'Learning to fly with broken wings', comprising two themes: 'Getting to know the foreign body' and 'Building a new living space', both requiring reappraisal of time and space. CONCLUSION: Living with a chronic disease such as MS means learning to fly with broken wings, which involves subordination to the body leading to a higher level of integration in the process of becoming towards health and well-being. PMID- 26235837 TI - Long-acting muscarinic antagonist + long-acting beta agonist versus long-acting beta agonist + inhaled corticosteroid for COPD: A systematic review and meta analysis. AB - Some trials have been conducted to compare long-acting muscarinic antagonist (LAMA) + long-acting beta agonist (LABA) versus LABA + inhaled corticosteroids (ICS) for chronic obstructive pulmonary disease (COPD), but no meta-analysis were reported. Two investigators independently searched for eligible articles using the PubMed, Web of Science and Cochrane databases. Articles in authors' reference files were also regarded as candidates. The eligibility criteria for the current meta-analysis were original trials written in English comparing the impact of LAMA + LABA and LABA + ICS for COPD patients. A pooled value for the continuous value was calculated using the genetic inverse variance method for mean difference. Incidence of events was evaluated using the odds ratio (OR). Minimal clinically important difference were 50 mL for forced expiratory volume in 1 s (FEV1 ), four points for St George Respiratory Questionnaire (SGRQ) and one point for transition dyspnoea index (TDI). We included seven randomized controlled trials and one cross-over trial with follow-up period of 6-26 weeks. Compared with LABA + ICS, LAMA + LABA led to significantly greater improvements of trough FEV1 by 71 (95% CI: 48-95) mL, TDI by 0.38 points (95% CI: 0.17-0.58), less exacerbations with an OR of 0.77 (95% CI: 0.62-0.96) and less pneumonia with an OR of 0.28 (95% CI: 0.12-0.68). Frequencies of any adverse event, serious adverse event, adverse event leading to discontinuation, all-cause death and change of total score of SGRQ were not different in both arms. LAMA + LABA might be a better option for treating COPD than LABA + ICS. PMID- 26235838 TI - Modulating light propagation in ZnO-Cu2O-inverse opal solar cells for enhanced photocurrents. AB - The advantages of employing an interconnected periodic ZnO morphology, i.e. an inverse opal structure, in electrodeposited ZnO/Cu2O devices are presented. The solar cells are fabricated using low cost solution based methods such as spin coating and electrodeposition. The impact of inverse opal geometry, mainly the diameter and thickness, is scrutinized. By employing 3 layers of an inverse opal structure with a 300 nm pore diameter, higher short circuit photocurrents (~84% improvement) are observed; however the open circuit voltages decrease with increasing interfacial area. Optical simulation using a finite difference time domain method shows that the inverse opal structure modulates light propagation within the devices such that more photons are absorbed close to the ZnO/Cu2O junction. This increases the collection probability resulting in improved short circuit currents. PMID- 26235842 TI - Electro-capillary effects in capillary filling dynamics of electrorheological fluids. AB - The flow of electrorheological fluids is characterized by an apparent increase in viscosity manifested by the yield stress property of the fluid, which is a function of the applied electric field and the concentration of the suspended solute phase within the dielectric medium. This property of electrorheological fluids generally hinders flow through a capillary if the imposed shear stress is lower than the induced yield stress. This results in a plug-like zone in the flow profile, thus giving the fluid Bingham plastic properties. In the present work, we study such influences of the yield stress on the capillary filling dynamics of an electrorheological fluid by employing a rheologically consistent reduced order formalism. One important feature of the theoretical formalism is its ability to address the intricate interplay between the surface tension and viscous forces, both of which depend sensitively on the electric field. Our analysis reveals that the progress of the capillary front is hindered at an intermediate temporal regime, which is attributable to the increase of the span of the plug-zone across the channel width with time. With a preliminary understanding on the cessation of the capillary front advancement due to the yield stress property of the electrorheological fluids, we further strive to achieve a basic comparison with an experimental study made earlier. Reasonable agreements with the reported data support our theoretical framework. Comprehensive scaling analysis brings further insight to our reported observations over various temporal regimes. PMID- 26235840 TI - Synthesis of Silaphenalenes by Ruthenium-Catalyzed Annulation between 1 Naphthylsilanes and Internal Alkynes through C-H Bond Cleavage. AB - Ruthenium-catalyzed annulation of 1-naphthylsilanes with internal alkynes afforded silaphenalenes through cleavage of the C-H bond at the 8-position of the naphthalene. [RuH2 (CO){P(p-FC6 H4 )3 }3 ] efficiently catalyzed the reaction. The use of 1-naphthyldiphenylsilane as a substrate resulted in a better yield of the annulation product compared to the use of silanes with alkyl groups on the silicon atom. Internal alkynes with both aryl and alkyl groups were tolerated in this reaction. PMID- 26235843 TI - Do Anti-Bredt Natural Products Exist? Olefin Strain Energy as a Predictor of Isolability. AB - Bredt's rule holds a special place in the realm of physical organic chemistry, but its application to natural products chemistry-the field in which the rule was originally formulated-is not well defined. Herein, the use of olefin strain (OS) energy as a readily calculated predictor of the stability of natural products containing a bridgehead alkene is introduced. Schleyer first used OS energies to classify parent bridgehead alkenes into "isolable", "observable", and "unstable" classes. OS calculations on natural products, using contemporary forcefield methods, unequivocally predict all structurally verified bridgehead alkene natural products to be "isolable". Thus, when one assigns the structure of a putative bridgehead alkene natural product, an OS in the "observable" or "unstable" ranges is a red flag for error. PMID- 26235839 TI - Developmental expression of the neuroligins and neurexins in fragile X mice. AB - Neuroligins and neurexins are transsynaptic proteins involved in the maturation of glutamatergic and GABAergic synapses. Research has identified synaptic proteins and function as primary contributors to the development of fragile X syndrome. Fragile X mental retardation protein (FMRP), the protein that is lacking in fragile X syndrome, binds neuroligin-1 and -3 mRNA. Using in situ hybridization, we examined temporal and spatial expression patterns of neuroligin (NLGN) and neurexin (NRXN) mRNAs in the somatosensory (S1) cortex and hippocampus in wild-type (WT) and fragile X knockout (FMR1-KO) mice during the first 5 weeks of postnatal life. Genotype-based differences in expression included increased NLGN1 mRNA in CA1 and S1 cortex, decreased NLGN2 mRNA in CA1 and dentate gyrus (DG) regions of the hippocampus, and increased NRXN3 mRNA in CA1, DG, and S1 cortex between female WT and FMR1-KO mice. In male mice, decreased expression of NRXN3 mRNA was observed in CA1 and DG regions of FMR1-KO mice. Sex differences in hippocampal expression of NLGN2, NRXN1, NRXN2, and NRXN3 mRNAs and in S1 cortex expression of NRXN3 mRNAs were observed WT mice, whereas sex differences in NLGN3, NRXN1, NRXN2, and NRXN3 mRNA expression in the hippocampus and in NLGN1, NRXN2 and NRXN3 mRNA expression in S1 cortex were detected in FMR1-KO mice. These results provide a neuroanatomical map of NLGN and NRXN expression patterns over postnatal development in WT and FMR1-KO mice. The differences in developmental trajectory of these synaptic proteins could contribute to long-term differences in CNS wiring and synaptic function. PMID- 26235841 TI - Scope and Mechanistic Analysis for Chemoselective Hydrogenolysis of Carbonyl Compounds Catalyzed by a Cationic Ruthenium Hydride Complex with a Tunable Phenol Ligand. AB - A cationic ruthenium hydride complex, [(C6H6)(PCy3)(CO)RuH](+)BF4(-) (1), with a phenol ligand was found to exhibit high catalytic activity for the hydrogenolysis of carbonyl compounds to yield the corresponding aliphatic products. The catalytic method showed exceptionally high chemoselectivity toward the carbonyl reduction over alkene hydrogenation. Kinetic and spectroscopic studies revealed a strong electronic influence of the phenol ligand on the catalyst activity. The Hammett plot of the hydrogenolysis of 4-methoxyacetophenone displayed two opposite linear slopes for the catalytic system 1/p-X-C6H4OH (rho = -3.3 for X = OMe, t-Bu, Et, and Me; rho = +1.5 for X = F, Cl, and CF3). A normal deuterium isotope effect was observed for the hydrogenolysis reaction catalyzed by 1/p-X C6H4OH with an electron-releasing group (kH/kD = 1.7-2.5; X = OMe, Et), whereas an inverse isotope effect was measured for 1/p-X-C6H4OH with an electron withdrawing group (kH/kD = 0.6-0.7; X = Cl, CF3). The empirical rate law was determined from the hydrogenolysis of 4-methoxyacetophenone: rate = kobsd[Ru][ketone][H2](-1) for the reaction catalyzed by 1/p-OMe-C6H4OH, and rate = kobsd[Ru][ketone][H2](0) for the reaction catalyzed by 1/p-CF3-C6H4OH. Catalytically relevant dinuclear ruthenium hydride and hydroxo complexes were synthesized, and their structures were established by X-ray crystallography. Two distinct mechanistic pathways are presented for the hydrogenolysis reaction on the basis of these kinetic and spectroscopic data. PMID- 26235844 TI - Insect-specific flaviviruses, a worldwide widespread group of viruses only detected in insects. AB - Several flaviviruses are important pathogens for humans and animals (Dengue viruses, Japanese encephalitis virus, Yellow-fever virus, Tick-borne encephalitis virus, West Nile virus). In recent years, numerous novel and related flaviviruses without known pathogenic capacity have been isolated worldwide in the natural mosquito population. However, phylogenetic studies have shown that genomic sequences of these viruses diverge from other flaviviruses. Moreover, these viruses seem to be exclusive of insects (they do not seem to grow on vertebrate cell lines), and were already defined as mosquito-only flaviviruses or insect specific flaviviruses. At least eleven of these viruses were isolated worldwide, and sequences ascribable to other eleven putative viruses were detected in several mosquito species. A large part of the cycle of these viruses is not well known, and their persistence in the environment is poorly understood. These viruses are detected in a wide variety of distinct mosquito species and also in sandflies and chironomids worldwide; a single virus, or the genetic material ascribable to a virus, was detected in several mosquito species in different countries, often in different continents. Furthermore, some of these viruses are carried by invasive mosquitoes, and do not seem to have a depressive action on their fitness. The global distribution and the continuous detection of new viruses in this group point out the likely underestimation of their number, and raise interesting issues about their possible interactions with the pathogenic flaviviruses, and their influence on the bionomics of arthropod hosts. Some enigmatic features, as their integration in the mosquito genome, the recognition of their genetic material in DNA forms in field-collected mosquitoes, or the detection of the same virus in both mosquitoes and sandflies, indicate that the cycle of these viruses has unknown characteristics that could be of use to reach a deeper understanding of the cycle of related pathogenic flaviviruses. PMID- 26235845 TI - Discovery and Characterization of New Hydroxamate Siderophores, Baumannoferrin A and B, produced by Acinetobacter baumannii. AB - Acinetobacter baumannii AYE does not produce acinetobactin but grows under iron limitation. Accordingly, analyses of AYE iron-restricted culture supernatants resulted in the isolation of two fractions, which contained only hydroxamates and showed siderophore activity. Structural analyses identified baumannoferrin A and baumannoferrin B, which differ only by a double bond. These siderophores are composed of citrate, 1,3-diaminopropane, 2,4-diaminobutyrate, decenoic acid, and alpha-ketoglutarate. Analysis of the AYE genome showed the presence of a 12-gene cluster coding for proteins similar to those involved in the production and utilization of the hydroxamate siderophores acinetoferrin and achromobactin. As A. baumannii AYE does not produce acinetobactin and harbors only one gene cluster encoding the production and utilization of a siderophore, this strain's growth under iron limitation depends on baumannoferrin, a novel hydroxamate that could play a role in its virulence. PMID- 26235846 TI - 5p deletions: Current knowledge and future directions. AB - Disorders resulting from 5p deletions (5p-) were first recognized by Lejeune et al. in 1963 [Lejeune et al. (1963); C R Hebd Seances Acad Sci 257:3098-3102]. 5p- is caused by partial or total deletion of the short arm of chromosome 5. The most recognizable phenotype is characterized by a high-pitched cry, dysmorphic features, poor growth, and developmental delay. This report reviews 5p- disorders and their molecular basis. Hemizygosity for genes located within this region have been implicated in contributing to the phenotype. A review of the genes on 5p which may be dosage sensitive is summarized. Because of the growing knowledge of these specific genes, future directions to explore potential targeted therapies for individuals with 5p- are discussed. (c) 2015 Wiley Periodicals, Inc. PMID- 26235850 TI - Conservative Treatment for Benign Prostatic Hyperplasia in Patients With Bladder Stones. AB - OBJECTIVE: To determine whether conservative management of benign prostatic hyperplasia (BPH) is an appropriate option for patients with bladder stones. METHODS: The study cohort comprised 34 men who underwent endoscopic bladder stone removal with subsequent conservative management of BPH, including watchful waiting and medical therapy (alpha-blocker +/- dutasteride), between April 2006 and January 2014. We recorded BPH-related complications after stone removal and compared International Prostate Symptom Scores, quality of life scores, and postvoid residual urine volume before and after treatment. Cumulative BPH-related complication-free survival and the preoperative parameters associated with the occurrence of BPH-related complications were also analyzed. RESULTS: Twenty-six patients (76.5%) treated with conservative management had no BPH-related complications, during a mean follow-up of 52.6 +/- 30.9 months. Mean International Prostate Symptom Scores fell from 13.5 +/- 7.1 before treatment to 9.7 +/- 6.3 after treatment (P = .025). One of the 34 patients (2.9%) experienced recurrent urinary infections, 2 (5.9%) had urinary retention, and 6 (17.6%) developed recurrent bladder stones. The cumulative BPH-related complication-free survival was 97.0% at 1 year, 81.8% at 3 years, and 70.5% at 5 years. Six of the men (17.6%) underwent invasive intervention for BPH after occurrence of these complications. Prostate volume was the only preoperative parameter associated with the occurrence of complications after stone removal (P = .035). CONCLUSION: Conservative management of BPH can be an appropriate treatment option in men with bladder stones and concurrent mild-to-moderate lower urinary tract symptoms. PMID- 26235847 TI - High ratio of programmed cell death protein 1 (PD-1)(+)/CD8(+) tumor-infiltrating lymphocytes identifies a poor prognostic subset of extrahepatic bile duct cancer undergoing surgery plus adjuvant chemoradiotherapy. AB - BACKGROUND AND PURPOSE: This study investigated the prognostic role of PD-L1 expression, PD-1(+) tumor-infiltrating lymphocytes (TILs), and the ratio of PD 1(+)/CD8(+) TILs in extrahepatic bile duct (EHBD) cancer. MATERIALS AND METHODS: We analyzed 83 patients with EHBD cancer who underwent curative surgery plus fluoropyrimidine-based chemoradiotherapy (CRT). Expressions of PD-L1, PD-1, and CD8 were assessed by immunohistochemistry. RESULTS: Fifty-six (68%) patients were PD-L1-positive, and its lower expression level was associated with hilar tumor location (P=0.044). A higher ratio of PD-1(+)/CD8(+) TILs was associated with poorer overall survival (OS) (P=0.032), relapse-free survival (RFS) (P=0.024), and distant metastasis-free survival (DMFS) (P=0.039) in Kaplan-Meier analyses, but survival differences were not observed according to the PD-L1 expression level. With Cox proportional hazards models, the ratio of PD-1(+)/CD8(+) TILs was the independent prognostic factor in OS (HR 2.47, 95% CI 1.04-5.86), RFS (HR 2.41, 95% CI 1.08-5.41), and DMFS (HR 2.67, 95% CI 1.00-7.11) after adjusting for other significant clinicopathologic variables. CONCLUSION: A strong survival impact of the ratio of PD-1(+)/CD8(+) TILs was observed in EHBD cancer. In the poor prognostic subgroup, the blockade of the immune checkpoint in combination with conventional multimodality treatment needs to be considered. PMID- 26235848 TI - Radiosensitivity index predicts for survival with adjuvant radiation in resectable pancreatic cancer. AB - BACKGROUND AND PURPOSE: Adjuvant radiation therapy for resectable pancreatic cancer remains controversial. Sub-populations of radiosensitive tumors might exist given the genetic heterogeneity of pancreatic cancers. We evaluated whether RSI is predictive of survival in pancreatic cancer treated with radiation. MATERIALS AND METHODS: We identified 73 genomically-profiled pancreas cancer patients treated with upfront surgery between 2000 and 2011 (48 radiation, 25 no radiation). Briefly, RSI score is derived from the expression of 10 specific genes and a linear regression algorithm modeled on SF2 of 48 cancer cells. The primary endpoint was to assess the association of RSI with overall survival. RESULTS: Median follow-up was 67months for surviving patients. On multivariate analysis, patients with radioresistant tumors had a trend toward worse survival (Hazard ratio [HR] 2.1 [95% CI 1.0-4.3], p=0.054). Among high-risk, irradiated patients (positive margins, positive lymph nodes, or a post-operative CA19-9 >90; n=31), radiosensitive patients had significantly improved survival compared with radioresistant patients (median 31.2 vs. 13.2months; HR 0.42 [0.19, 0.94], p=0.04). Among irradiated patients (n=48), low-risk patients lived longer than both high-risk patients with radiosensitive tumors and radioresistant tumors (HR 2.7 [1.0, 7.2], p=0.04 and HR 6.3 [2.3, 17.0], p<0.001, respectively). CONCLUSIONS: Integrating RSI with standard high-risk variables has the potential to refine the classification of high-risk resected pancreatic cancer patients treated with radiation therapy. PMID- 26235849 TI - Costs of epilepsy and cost-driving factors in children, adolescents, and their caregivers in Germany. AB - OBJECTIVE: To provide first data on the cost of epilepsy and cost-driving factors in children, adolescents, and their caregivers in Germany. METHODS: A population based, cross-sectional sample of consecutive children and adolescents with epilepsy was evaluated in the states of Hessen and Schleswig-Holstein (total of 8.796 million inhabitants) in all health care sectors in 2011. Data on socioeconomic status, course of epilepsy, and direct and indirect costs were recorded using patient questionnaires. RESULTS: We collected data from 489 children and adolescents (mean age +/- SD 10.4 +/- 4.2 years, range 0.5-17.8 years; 264 [54.0%] male) who were treated by neuropediatricians (n = 253; 51.7%), at centers for social pediatrics ("Sozialpaediatrische Zentren," n = 110, 22.5%) and epilepsy centers (n = 126; 25.8%). Total direct costs summed up to ?1,619 +/- ?4,375 per participant and 3-month period. Direct medical costs were due mainly to hospitalization (47.8%, ?774 +/- ?3,595 per 3 months), anticonvulsants (13.2%, ?213 +/- ?363), and ancillary treatment (9.1%, ?147 +/- ?344). The total indirect costs amounted to ?1,231 +/- ?2,830 in mothers and to ?83 +/- ?593 in fathers; 17.4% (n = 85) of mothers and 0.6% (n = 3) of fathers reduced their working hours or quit work because of their child's epilepsy. Independent cost-driving factors were younger age, symptomatic cause, and polytherapy with anticonvulsants. Older age, active epilepsy, symptomatic cause, and polytherapy were independent predictors of higher antiepileptic drug (AED) costs, whereas younger age, longer epilepsy duration, symptomatic cause, disability, and parental depression were independent predictors for higher indirect costs. SIGNIFICANCE: Treatment of children and adolescents with epilepsy is associated with high direct costs due to frequent inpatient admissions and high indirect costs due to productivity losses in mothers. Direct costs are age-dependent and higher in patients with symptomatic epilepsy and polytherapy. Indirect costs are higher in the presence of a child's disability and parental depression. PMID- 26235852 TI - Does autogenous bone graft work? A logistic regression analysis of data from 159 papers in the foot and ankle literature. AB - BACKGROUND: While autogenous cancellous iliac crest bone graft is the gold standard for foot and ankle surgery, it lacks Level I evidence. Although one third of all graft cases performed in the United States today rely on allograft, some surgeons believe no graft is necessary. We hypothesized that a systematic review of the foot and ankle literature would reveal that (1) autogenous bone graft during foot and ankle arthrodesis would demonstrate healing rates that were superior to the use of either using allograft or no bone graft at all, and (2) these differences would be even more dramatic in patients having risk factors that impair bone healing. To our knowledge, neither of these assessments to date has ever been performed with this body of literature. The goal of this study was to review the use and union rates of bone graft during foot and ankle arthrodesis and determine if autogenous bone graft was superior. METHODS: A literature search was performed to include articles between 1959 and 2012 using autograft, allograft, and/or no bone graft for foot and/or ankle arthrodesis. Case reports involving fewer than four patients, investigations failing to incorporate outcome data, those involving orthobiologic augmentation, and those including vascularized graft, xenograft, or pediatric patients were excluded. Recorded search results included patient demographics, comorbidities, pre-operative diagnosis, surgical procedure, bone graft type and indication, union rate, method of fixation, patient satisfaction, all outcome scores, definition of healing/success, and any listed complications including revision. Final data were stratified based upon the type of graft material. RESULTS: This search generated 953 related articles, of which 159 studies (5327 patients) met inclusion criteria. The majority (153/159) were retrospective case series. Systematic review demonstrated a trend toward higher union rates for cancellous autograft (OR 1.39, p=0.11), structural autograft (OR 1.52, p=0.09), and cancellous allograft (OR 1.31, p=0.52) relative to no graft material, but none reached statistical significance. Compared to no graft, structural allograft trended toward worse performance (OR 0.62, p=0.17). The overall probability of union was 93.7% for cancellous autograft, 94.2% for structural autograft, 93.3% for cancellous allograft, 91.4% for no graft, and 86.9% for structural allograft. When only comparing the 19 papers that included a no graft arm (91.9% union rate), data revealed the highest union using cancellous autograft (95.1%, OR 1.73, p=0.09) and structural autograft (96.3%, OR 2.33, p=0.06) while only 76% for structural allograft. No significant statistical association existed between union rates and other recorded variables. CONCLUSION: Systematic analysis of bone graft use in foot and ankle fusions favors the use of autograft and cancellous allograft for optimized healing rates, although no differences were statistically significant. If we assume that graft material been chosen for more complex procedures having lower anticipated union rates, then these data lend further support to the use of autograft and cancellous allograft. LEVEL OF EVIDENCE: Level IV. PMID- 26235855 TI - Isolated talonavicular joint arthrodesis through minimal incision surgery. AB - BACKGROUND: The purpose of this study was to analyze bony fusion and functional outcomes after talonavicular arthrodesis (TNA) using an original minimally invasive surgery (MIS). METHODS: There was a total of 11 feet in 11 patients who underwent TNA and were followed up for 47 months (range 40.8-53.1). Functional outcomes were measured by AOFAS and quality of life by eight sections of SF-36. RESULTS: Radiographic and clinical consolidation was achieved in 10 of 11 cases. In the AOFAS score, physical function improved a mean of 34.4 points (95% CI: 23.2-45.6; p<.0001) and pain improved a mean of 23.6 points (95% CI: 17.4-29.8; p<.0001). One osteoporotic and rheumatic patient had a non-union. No cases of early complications, such as wound infections, neurovascular damage or delayed wound healing, occurred. CONCLUSION: Isolated TNA by MIS could be an option for the treatment of TN arthritis, especially for patients at greater risk of wound healing complications. LEVEL OF EVIDENCE: Level IV, case series. PMID- 26235854 TI - Periprosthetic osteolysis after AES total ankle replacement: Conventional radiography versus CT-scan. AB - BACKGROUND: The aim of this study was to compare conventional X-rays and CT-scan in detecting peri-prosthetic osteolytic lesions, a major concern after total ankle replacement (TAR). METHODS: We prospectively assessed 50 patients (mean age 56 years), consecutively operated on by the same senior surgeon, between 2003 and 2006 and with a mean follow-up period of 4 years (range, 2-6.2). The component used was AES total ankle replacement. The etiologies for total ankle arthroplasty were: posttraumatic in 50%, osteoarthritis secondary to instability in 36%. Plain radiographs were analyzed by 4 independent observers, using a 10-zone protocol (location) and 5 size categories. RESULTS: At 4-year follow-up, all patients had been CT-scan assessed with the same protocol by 2 independent observers. Plain radiographs showed dramatic progression of severe periprosthetic lyses (>10mm): from 14% to 36% of interface cysts for the tibial component respectively at 2 and 4-year follow-up and from 4% to 30% for the talar implant. The talar component was more accurately assessed by CT-scan (mean frontal and sagittal talar lesion: from 270 mm2 to 288 mm2 for CT-scan versus 133 mm2 to 174 mm2 for X-rays). For tibial cysts, axial views showed larger lesions (313 mm2 than frontal (194 mm2) or sagittal (213.5 mm2) views. At 4-year follow-up, 24% of patients had revision with curetage or arthrodesis, and at 7 years follow-up 38% were revised. CONCLUSION: These results are similar to recent AES series, justifying withdrawal of this device. CT-scan was more accurate than X-rays for detecting and quantifying periprosthetic osteolysis. We recommend a yearly radiological control and CT-scan in case of lesion on X-rays. PMID- 26235853 TI - Patient satisfaction and function after bilateral ankle arthrodeses. AB - BACKGROUND: The optimum way to manage patients with bilateral ankle arthritis (AA) is unclear. METHODS: This review was performed to report the midterm satisfaction and functional outcome of a series of patients who have undergone bilateral staged ankle arthrodesis. RESULTS: Eight patients, median age 68.5 yrs (range 59-80) were followed-up for a median of 58.5 months (range 24-100). All fusions united in a median time of 12.8 weeks (range 10-19) Their median AOFAS hindfoot score was 79.5 (range 71-90). Six patients (75%) were very satisfied, one was satisfied, and the other neither satisfied nor dissatisfied. Two patients developed symptomatic subtalar arthritis requiring subtalar fusion. CONCLUSIONS: This is the first study to report the outcome of bilateral AA independent to that of unilateral AA. Bilateral AA appears to give patients a good functional result with high patient reported satisfaction into the medium term. PMID- 26235858 TI - Evaluation of first metatarsal head declination through a modified distal osteotomy in hallux rigidus surgery. A cadaveric model. AB - BACKGROUND: First metatarsal osteotomies have been described for treatment of hallux rigidus. Most of these techniques result in declination of the first metatarsal head through shortening of the metatarsal and transfer metatarsalgia may result. Our objective was to evaluate the declination effect of a distal metatarsal osteotomy when different angulations and lateral translations are applied. MATERIALS AND METHODS: A cadaveric study was conducted performing a modified distal oblique osteotomy, which produces head declination while limiting shortening. Several transverse inclination angles (0-10-20-30-40 degrees ) were used. Thereafter, plantar translation of the metatarsal head was registered at different lateral displacements (1, 3, 5mm). RESULTS: Twenty-two specimens were included. Three feet were operated on with a 0 degrees of angulation in the transverse plane, 6 with 10 degrees , 5 with 20 degrees , 5 with 30 degrees , and 3 with 40 degrees . Head declination significantly increased with higher angulation and with greater lateral translations (p<0.001), but the interrelationship between these two variables did not achieve statistical significance (p=0.597). In regards to angulation, significant differences in head declination were found between 0 degrees (0.1-0.7 mm), 10 degrees -20 degrees (0.5-1.2mm) and 30 degrees -40 degrees (1.3-2.4mm). The metatarsal sesamoid joint was compromised when the osteotomy was performed at a 40 degrees inclination angle. CONCLUSIONS: Metatarsal head declination is determined by the inclination angle of the oblique limb of the osteotomy and lateral displacement of the metatarsal head. Our results suggest that the effect of lateral displacement is an independent factor from angulation. The latter may impact surgery planning and may improve clinical outcome by selecting a safer inclination angle when lateral displacement of the metatarsal head is being considered. LEVEL OF EVIDENCE: Level II-A, systematic review with homogeneity of cohort studies. PMID- 26235857 TI - Open surgical management of high energy ipsilateral fractures of the fibula and calcaneus. AB - BACKGROUND: Simultaneous ipsilateral fractures of the calcaneus and fibula are the result of high-energy injuries. Open surgical treatment of both fractures can be performed with incisions based on the described blood supply of the lower extremity. METHODS: A retrospective review for all patients with ipsilateral fractures of the calcaneus and fibula was performed over an eight-year period. Thirty-eight patients were identified. Eleven patients (28.9%) were treated with open reduction and internal fixation through two separate incisions. Average follow-up was 48.8 weeks. RESULTS: Two patients (18.1%) required a secondary procedure. Three patients (27.2%) developed incisional cellulitis that resolved with oral antibiotics and one patient required local wound care. All fractures united. CONCLUSIONS: Ipsilateral fractures of the calcaneus and fibula require open reduction and internal fixation when closed or percutaneous treatment is not appropriate. We describe an operative approach based on the angiosomes of the lower extremity that allows for treatment of these complex injuries and report the associated complications. PMID- 26235859 TI - Histological evaluation of calcaneal tuberosity cartilage--A proposed donor site for osteochondral autologous transplant for talar dome osteochondral lesions. AB - BACKGROUND: Osteochondral Autologous Transplant (OATs) as a treatment option for Osteochondral lesions (OCLs) of the talar dome frequently uses the distal femur as the donor site which is associated with donor site morbidity in up to 50%. Some studies have described the presence of hyaline cartilage in the posterior superior calcaneal tuberosity. The aim of this study was to evaluate the posterior superior calcaneal tuberosity to determine if it can be a suitable donor site for OATs of the talus METHODS: In this cadaveric study, we histologically evaluated 12 osteochondral plugs taken from the posterior superior calcaneal tuberosity and compared them to 12 osteochondral plugs taken from the talar dome. RESULTS: In the talar dome group, all samples had evidence of hyaline cartilage with varying degrees of GAG staining. The average hyaline cartilage thickness in the samples was 1.33 mm. There was no evidence of fibrocartilage, fibrous tissue or fatty tissue in this group. In contrast, the Calcaneal tuberosity samples had no evidence of hyaline cartilage. Fibrocartilage was noted in 3 samples only. CONCLUSIONS: We believe that the structural differences between the talus and calcanium grafts render the posterior superior clancaneal tuberosity an unsuitable donor site for OATs in the treatment of OCL of the talus. PMID- 26235860 TI - Immediate fullweightbearing after tarsometatarsal arthrodesis for hallux valgus correction--Does it increase the complication rate? AB - BACKGROUND: The arthrodesis of the first tarsometatarsal joint has a high correction potential in the treatment of hallux valgus deformity. Compared to distal correction procedures, a pseudarthrosis rate of 12-20% is quoted, however. In a prospective study the results of two different treatment procedures after correction arthrodesis were compared. METHODS: In 17 cases the patients were mobilised with a short arthrodeses shoe with floor contact (NWB group) and in 17 cases in a short arthrodeses shoe with immediate fullweightbearing (FWB group). Clinical and radiological evaluation was done preoperatively, six weeks and one year postoperatively, including visual analogue pain scale and AOFAS score pre- and one year postoperatively. RESULTS: There was no increased complication rate in the group with FWB group. The patients in the FWB group were significantly earlier fit for work. CONCLUSION: Immediate fullweightbearing after TMT I arthrodesis using a plantar plate should be established as a standard posttreatment. PMID- 26235856 TI - Long-term beneficial effects of platelet-rich plasma for non-insertional Achilles tendinopathy. AB - BACKGROUND: The aim of this retrospective study is evaluating the long-term clinical outcome in patients affected by mid-portion Chronic Recalcitrant Achilles Tendinopathies (CRAT) treated with administration of single platelet rich plasma (PRP). METHODS: A total of 83 tendons (73 patients, 59 males and 14 females; age 43+/-17.5 years) affected by non-insertional CRAT were treated with single PRP injection. These were evaluated with the Victorian Institute of Sport Assessment - Achilles (VISA-A) questionnaire, Blazina score and satisfaction index at baseline at intervals of 3 weeks, 3 months, 6 months. Final follow-up was carried out at a mean of 50.1 months (range, 24-96). RESULTS: Baseline VISA-A was 45+/-15. Results relative to the final follow-up improved significantly to a mean of 88+/-8 (p<00.1). Blazina was used for patients practicing sports (54 tendons out of 46 different patients): 37 tendons were grade IIIa, 11 II, and 6 IIIbis. Final follow-up Blazina scores improved for 45 grade 0, 5 I, 4 II (p<00.5). Seventy-six tendons (91.6%) were rated as satisfactory and patients would repeat the treatment. Seven tendons (8.4%) were classified as unsatisfactory at the 6 months follow-up and underwent a second PRP injection. In addition to this, patients reported no Achilles tendon rupture. CONCLUSIONS: The study shows beneficial effects and low complication rate following of single PRP injections on a large cohort of patients with mid-long-term follow-up. No cases reported Achilles tendon rupture, in contrast to literature, which described CRAT as one of the most common risk factors. The use of a single PRP injection can therefore be a safe and attractive alternative in the treatment of non insertional CRATs. PMID- 26235862 TI - Articular congruency of the Salto Talaris total ankle prosthesis. AB - BACKGROUND: The Salto-Talaris polyethylene articulating surface was designed to allow, but limit accessory motion. This investigation examines surface characteristics between the polyethylene bearing and anatomic talar component in various positions of function. METHODS: A Salto Talaris talar prosthesis and matching polyethylene bearing were scanned to create digital solid body models and manipulated to assess surface contact during simulated gait. With computer micromanipulation of the component positions, the surface intersections were recorded for 15 different alignments. RESULTS: The Salto Talaris has limited contact congruity with four points of contact in dorsiflexion, neutral, and plantarflexion. Lateral and medial translations showed only 2-point contact. The radii of curvatures between the talar component and polyethylene surfaces do not match. There was no sulcus contact yet component separation distance was small, suggesting increased loads. CONCLUSION: Surface incongruency was measured based on computer model analysis which raises a concern of increased contact pressures. PMID- 26235861 TI - Tibiotalocalcaneal arthrodesis with a compressive retrograde nail: A retrospective study of 59 nails. AB - BACKGROUND: Tibiotalocalcaneal arthrodesis is an important salvage method for patients with complex hindfoot problems. This study reports the elective results of combined subtalar and ankle arthrodesis using one design of retrograde intramedullary compression nail. METHODS: Retrospective review identified 58 patients undergoing 59 tibiotalocalcaneal arthrodesis procedures. Mean follow up was 9.15 (3-36) months with average age 60.7 (22-89) years. A function and subjective patient satisfaction questionnaire was achieved in 89%. RESULTS: 53 patients (93%) achieved union at a mean time of 4.17 months. Four patients (8%) subjectively thought the procedure was of no benefit while 42 (84%) had an excellent or good result. The mean visual analogue scale (VAS) score for preoperative functional pain was 7.46 compared to 1.98 post-operatively (p<0.001). CONCLUSIONS: This device and technique offers an effective treatment of hindfoot pathology giving reliable compression and subsequent fusion with excellent patient satisfaction and pain relief. LEVEL OF EVIDENCE: IV case series. PMID- 26235863 TI - Metal allergy after first metatarsophalangeal total joint replacement--Case report. AB - A 62-year-old female patient presented with a symptomatic metal allergy six weeks after first metatarsophalangeal total joint replacement using ROTOGLIDE implant. Preoperatively, there was no history of hypersensitivity. The symptomatic dermatitis was evaluated using dermal patch testing. The implant had to be removed. The possible agents for the allergic reaction are discussed. PMID- 26235866 TI - Re: "Isolated osteochondral fracture of the metatarsal head of lesser toes" [Foot Ankle Surg (http://dx.doi.org/10.1016/j.fas.2015.01.011)]. PMID- 26235864 TI - Technical tips for the removal of TightRope ankle syndesmosis fixation. PMID- 26235867 TI - Response to "Re: Isolated osteochondral fracture of the metatarsal head of lesser toes" [Foot Ankle Surg]. PMID- 26235865 TI - Modified arthroscopic Brostrom procedure. AB - The open modified Brostrom anatomic repair technique is widely accepted as the reference standard for lateral ankle stabilization. However, there is high incidence of intra-articular pathologies associated with chronic lateral ankle instability which may not be addressed by an isolated open Brostrom procedure. Arthroscopic Brostrom procedure with suture anchor has been described for anatomic repair of chronic lateral ankle instability and management of intra articular lesions. However, the complication rates seemed to be higher than open Brostrom procedure. Modification of the arthroscopic Brostrom procedure with the use of bone tunnel may reduce the risk of certain complications. PMID- 26235868 TI - Comment on "Comparison of postoperative costs of two surgical techniques for hallux valgus (Kramer vs. scarf)". PMID- 26235869 TI - Response to letter to the editor on "Comparison of postoperative costs of two surgical techniques for hallux valgus (Kramer vs. scarf)". PMID- 26235872 TI - Posterior talus osteochondroma a rare location, treated by posterior ankle arthroscopy. AB - The common cause of posterior ankle impingement syndrome is impingement of the Os trigonum or the posterior talar process. We report a case of a 46-year-old lady having osteochondroma of the posterior talar process, a rare occurrence at this site. This patient was treated with posterior ankle arthroscopic excision through the 2-portal posterior ankle arthroscopy technique in the prone position. 6 months post-operatively, her ankle pain disappeared and ankle range of movement improved significantly and there is no recurrence of the tumour. PMID- 26235870 TI - Letter to the editor on "Gastrocnemius recession for foot and ankle conditions in adults: Evidence-based recommendations". PMID- 26235871 TI - Response to letter to the editor on "Gastrocnemius recession for foot and ankle conditions in adults: Evidence-based recommendations". PMID- 26235873 TI - Inactivated Sendai virus induces apoptosis and autophagy via the PI3K/Akt/mTOR/p70S6K pathway in human non-small cell lung cancer cells. AB - Inactivated Sendai virus (HVJ-E) has shown potential anticancer efficacy in various cancer cells. However, the ability of HVJ-E to regulate cancer cell survival and death remains largely unknown. In the present study we first found that HVJ-E exhibited cytotoxic effects in the non-small cell lung cancer cell (NSCLC) line A549 and cisplatin-resistant A549 cells (A549/DDP). The suppression of cell viability was due to both the activation of caspases and the JNK and p38 MAPK signaling pathways in A549 and A549/DDP human lung cancer cells. In addition, we demonstrated that HVJ-E could induce autophagy in NSCLC cells via the PI3K/Akt/mTOR/p70S6K signaling pathway for the first time. Inhibiting autophagy in A549/DDP cells and inducing autophagy in A549 cells enhanced HVJ-E induced apoptosis. These findings provide a molecular basis of HVJ-E-mediated cell death and support the notion that combination treatment with autophagy modulators is an effective strategy to augment the cytotoxic effects of HVJ-E in NSCLC cells. PMID- 26235877 TI - Functional analyses of carnivorous plant-specific amino acid residues in S-like ribonucleases. AB - Unlike plants with no carnivory, carnivorous plants seem to use S-like ribonucleases (RNases) as an enzyme for carnivory. Carnivorous plant-specific conserved amino acid residues are present at four positions around the conserved active site (CAS). The roles of these conserved amino acid residues in the enzymatic function were explored in the current study by preparing five recombinant variants of DA-I, the S-like RNase of Drosera adelae. The kcat and kcat/Km values of the enzymes revealed that among the four variants with a single mutation, the serine to glycine mutation at position 111 most negatively influenced the enzymatic activity. The change in the bulkiness of the amino acid residue side-chain seemed to be the major cause of the above effect. Modeling of the three dimensional (3D) structures strongly suggested that the S to G mutation at 111 greatly altered the overall enzyme conformation. The conserved four amino acid residues are likely to function in keeping the two histidine residues, which are essential for the cleavage of RNA strands, and the CAS in the most functional enzymatic conformation. PMID- 26235875 TI - Arginine 112 is involved in HCV translation modulation by NS5A domain I. AB - HCV NS5A has three domains, which have multiple roles in the viral life cycle. We previously found that NS5A is able to down-regulate HCV RNA translation through a mechanism requiring the polyU/UC region within the viral 3'UTR to which NS5A binds. In this study, we further investigated the role of domain I in modulating viral translation. Using a series of deletion and substitution mutants, we identified a number of positively charged residues that played a role in this modulatory effect, most prominently R112. The R112A mutation negated the ability of domain I and full-length NS5A to modulate viral translation. Additionally, the R112A mutation impeded domain I binding to the polyU/UC RNA, suggesting a mechanism for this down-regulatory effect. Finally, the R112A mutation rendered HCV replication deficient. These results collectively point to a crucial role for the R112 residue of NS5A in the modulation of HCV life cycle by NS5A. PMID- 26235874 TI - MiR-135a inhibits migration and invasion and regulates EMT-related marker genes by targeting KLF8 in lung cancer cells. AB - Epithelial-mesenchymal transition (EMT) has been shown to be related to the pathogenesis of various diseases. Recently, microRNAs (miRNA) have been recognized as a new class of genes involved in human tumorigenesis. In this study, we found that the expression levels of miR-135a were dramatically decreased in NSCLC cell lines and clinical NSCLC tissue samples. Then, we demonstrated that miR-135a significantly suppressed the migration and invasion of lung cancer cells in vitro, suggesting that miR-135a may be a novel tumor suppressor. Further studies revealed that the transcription factor KLF8 was a target gene of miR-135a in NSCLC cells, as miR-135a bound directly to the 3' untranslated region (3'-UTR) of KLF8, thus reducing both the expression of KLF8 at the mRNA and protein levels. In addition, the EMT marker E-cadherin or vimentin was also down-regulated or up-regulated on miR-135a treatment. Moreover, silencing KLF8 was able to inhibit the migration and invasion of lung cancer cells. In conclusion, these findings indicate that miR-135a suppresses the migration and invasion of NSCLC cells through targeting KLF8, which is involved in the EMT process. This finding provides new insight into the mechanism of NSCLC progression. PMID- 26235876 TI - Biochemical characterization of a novel bifunctional glycosyl-1-phosphate transferase involved in the exopolysaccharide biosynthesis. AB - Ebosin produced by Streptomyces sp. 139 is a novel exopolysaccharide with anti rheumatic arthritis activity in vivo and its biosynthesis gene cluster (ste) has been previously identified. In our previous research, ste5 gene has been identified as priming glycosyltransferase involved in Ebosin biosynthesis. However, it remains unclear how ste5 initiated Ebosin biosynthesis in molecular level. Here we show that Ebosin derivative produced by ste5 mutant lost the antagonist activities for IL-1R and Overexpression of ste5 in mutant dramatically enhanced the antagonist activities for IL-1R. For biochemical characterization of Ste5, the ste5 gene was cloned and expressed in Escherichia coli BL21. We identified that the recombinant Ste5 can transfer galactose-1-Phosphate (Gal-1-P) or glucose-1-Phosphate (Glc-1-P) from UDP-galactose and UDP-glucose to the lipid carrier located in the cytoplasmic membrane of Streptomyces sp. 139 (ste5(-)) with a continuous coupled spectrophotometric assay. 12.6 MUM of Km was for UDP galactose and 23.9 MUM for UDP-glucose respectively. Our results indicate that Ste5 is bifunctional Gal-1-P and Glc-1-P transferase to initiate Ebosin biosynthesis and may be further applied in remoulding carbohydrate compounds. PMID- 26235882 TI - Coexistent ganglioglioma, focal cortical dysplasia, and hippocampal sclerosis (triple pathology) in chronic epilepsy. AB - The most commonly identified pathologies in patients with medically intractable epilepsy include focal cortical dysplasia, hippocampal sclerosis, tumors, and remote ischemic damage. Surgery has proven to be an effective therapeutic modality in most of such patients. The coexistence of multiple pathologies in resected tissues is well documented, particularly ganglioglioma and focal cortical dysplasia. Cases of triple pathology are, however, extraordinarily unusual. We report 2 cases of triple pathology including hippocampal sclerosis, ganglioglioma, and focal cortical dysplasia. Cases of pathologically confirmed hippocampal sclerosis diagnosed between January 2000 to December 2012 (n= 349) were reviewed, and only 2 cases (0.6%) with triple pathology were identified. The histopathologic and clinical features of these 2 cases are reviewed. The patients included a 6-year-old girl and 10-year-old boy. The former patient presented with a 4-year history of epilepsy and oppositional defiant disorder. Imaging identified a lesion in the left parahippocampal gyrus and posterior hippocampus. The latter patient presented with an 8-year history of epilepsy, attention deficient hyperactivity disease, and a pervasive developmental disorder. Imaging identified a lesion in the left posterior temporal and occipital region. Resected tissues in both patients showed a ganglioglioma (World Health Organization grade I) with accompanying focal cortical dysplasia and hippocampal sclerosis. Both patients were seizure free on antiepileptic medication at last follow-up at 20 and 38 months, respectively. The prevalence of triple pathology including hippocampal sclerosis is low (<1% in the current study). Surgical intervention for triple pathology cases anecdotally appears effective in achieving seizure control. PMID- 26235878 TI - The role of endoplasmic reticulum stress and insulin resistance in the occurrence of goose fatty liver. AB - In mammals, insulin resistance (IR) is required for the occurrence of non alcoholic fatty liver disease, and endoplasmic reticulum stress (ERS) contributes to IR. As geese have physiological and metabolic characteristics different from mammals, it is unclear whether these mechanisms also underlie the occurrence of goose fatty liver. To address this, 70-day-old geese were treated with an ERS inducer or overfed, and variables associated with ERS or IR were subsequently determined. The data indicated that the group of geese treated with the ERS inducer for 20d appeared to be more intolerant to blood glucose than the control group, and their livers showed features of hepatic steatosis, suggesting ERS can induce IR and hepatic steatosis in geese. In contrast, overfeeding did not induce ERS, probably due to the upregulated expression of fatty acid desaturases, but induced higher fasting/postprandial blood glucose as well as glucose intolerance in geese, which was accompanied by a dramatic increase of liver weight. Taken together, these findings delineated the role of ERS and IR in the occurrence of goose fatty liver. PMID- 26235884 TI - Dynamics of polyhydroxyalkanoate accumulation in aerobic granules during the growth-disintegration cycle. AB - The polyhydroxyalkanoate (PHA) accumulation dynamics in aerobic granules that undergo the growth-disintegration cycle were investigated. Four sequencing batch reactors (SBR) were inoculated with aerobic granules at different stages of development (different sizes). Different sizes of aerobic granules showed varying PHA contents. Thus, further study was conducted to investigate the diffusion of substrate and oxygen on PHA accumulation using various organic loading rates (OLR) and aeration rates (AR). An increase in OLR from 0.91 to 3.64kg COD/m(3)day increased the PHA content from 0.66 to 0.87g PHA/g CDW. Meanwhile, an AR increase from 1 to 4L/min only accelerated the maximum PHA accumulation without affecting the PHA content. However, the PHA composition only changes with AR, while the hydroxyvalerate (HV) content increased at a higher AR. PMID- 26235886 TI - Evidence for the existence of Li2S2 clusters in lithium-sulfur batteries: ab initio Raman spectroscopy simulation. AB - Using density functional theory calculations and ab initio molecular dynamics simulations we have studied the structures and the Raman spectra of Li2S4 clusters, which are believed to be the last polysulfide intermediates before the formation of Li2S2/Li2S during the discharge process in Li-S batteries. Raman spectra have been obtained using a new technique to estimate polarizabilities using Wannier functions. We have observed clear evidence of Li2S4-> Li2S2 transition by studying systematic changes in the simulated Raman spectra of (Li2S4)n, n = 1, 4, and 8 towards that of (Li2S2)8. Furthermore, we have shown that the dominant Raman peak of the Li2S2 cluster at ~440 cm(-1) arises from sulfur-sulfur stretching mode. This peak has been experimentally observed in the discharged state of Li-S batteries and has also been attributed to the formation of Li2S2. We have also demonstrated that the transition is mainly due to the strong electrostatic interactions between Li2S4 monomers, which results in energy lowering by arranging the local Li(+delta)-S(-delta) dipole moments in an anti parallel fashion. PMID- 26235881 TI - The anti-esophageal cancer cell activity by a novel tyrosine/phosphoinositide kinase inhibitor PP121. AB - Here we explored the potential effect of PP121, a novel dual inhibitor of tyrosine and phosphoinositide kinases, against human esophageal cancer cells. We showed that PP121 exerted potent cytotoxic effect in primary (patient-derived) and established (Eca-109, TE-1 and TE-3 lines) esophageal cancer cells, possibly through activating caspase-3-dependnent apoptosis. PP121 was, however, non cytotoxic to the normal human esophageal epithelial cells (EECs). At the molecular level, we showed that PP121 blocked Akt-mTOR (mammalian target of rapamycin) activation in esophageal cancer cells, which was restored by introducing a constitutively-active Akt (CA-Akt). Yet, CA-Akt only partly inhibited cytotoxicity by PP121 in Eca-109 cells. Importantly, we showed that PP121 inhibited nuclear factor kappa B (NFkappaB) signaling activation in esophageal cancer cells, which appeared independent of Akt-mTOR blockage. In vivo, oral administration of PP121 remarkably inhibited Eca-109 xenograft growth in nude mice, and significantly improved mice survival. Further, the immunohistochemistry (IHC) and Western blot assays analyzing xenografted tumors showed that PP121 inhibited Akt-mTOR and NFkappaB activations in vivo. Together, we demonstrate that PP121 potently inhibits esophageal cancer cells in vitro and in vivo, possibly through concurrently inhibiting Akt-mTOR and NFkappaB signalings. PMID- 26235880 TI - Involvement of transcription repressor Snail in the regulation of human telomerase reverse transcriptase (hTERT) by transforming growth factor-beta. AB - Human telomerase reverse transcriptase (hTERT), a catalytic subunit of telomerase, is the primary determinant for telomerase enzyme activity, which has been associated with cellular immortality. Expression of the hTERT gene is regulated by various extracellular (external) stimuli and is aberrantly up regulated in more than 90% of cancers. Here we show that hTERT gene expression was repressed in response to transforming growth factor-beta (TGF-beta) by a mechanism dependent on transcription factors Snail and c-Myc. TGF-beta activated Snail and down-regulated c-Myc gene expression. In addition, ectopic expression of Snail strongly inhibited hTERT promoter activity, although co-expression of c Myc abrogated this effect. Chromatin immunoprecipitation (ChIP) analysis revealed that TGF-beta decreased c-Myc occupancy and dramatically increased recruitment of Snail to the E-box motifs of the hTERT promoter, thereby repressing hTERT expression. Our findings suggest a dynamic alteration in hTERT promoter occupancy by Snail and c-Myc is the mechanistic basis for TGF-beta-mediated regulation of hTERT. PMID- 26235879 TI - Shikonin causes apoptosis by up-regulating p73 and down-regulating ICBP90 in human cancer cells. AB - Shikonin, a natural naphthoquinone isolated from the Chinese traditional medicine Zi Cao (purple gromwell), is known to suppress the growth of several cancer cell types. In this study, we evaluated the pro-apoptotic effects of shikonin on MCF-7 and HeLa cells, and investigated the underlying mechanism. Shikonin-induced apoptosis was associated with activation of caspase-3, poly(ADP-ribose) polymerase (PARP) cleavage, up-regulation of p73, and down-regulation of BCL-2. Shikonin also induced up-regulation of the tumor suppressor gene, p16(INK4A). Increasing transcriptional activity of p16(INK4A) by shikonin treatment, we observed in luciferase promoter assay, reflects reduced promoter binding by down regulation of ICBP90 (inverted CCAAT box binding protein, 90 kDa), which are involved in down-regulation of its partner, DNMT1 (DNA methyltransferase 1). On the basis of these results, we conclude that shikonin causes apoptosis via a p73 related, caspase-3-dependent pathway. PMID- 26235883 TI - Urothelial Carcinoma with shadow cell, lipid cell and sebaceous (skin adnexal) differentiation: Clinicopathological and immunohistochemical study of 10 cases. AB - We discuss the histological and immunohistochemical features of 6 cases of urothelial carcinomas of lipid cell variant and 4 cases with shadow cell differentiation, one of which showed additionally sebaceous differentiation, one of which shows additional sebaceous differentiation, from our archive cases from the last 15 years. Conventional urothelial carcinoma (UC) was seen in all lipid cell variant cases, and micropapillary carcinoma was seen in 3. The ratio of the lipid cell component was between 10% and 40% in these 6 cases. Typical histologic features of the lipid cell variant include lipoblast-like cells with a notched nuclear appearance, abundant vacuoles, an eccentric nucleus, and pagetoid spread in some areas. GATA3 and pancytokeratin AE1/AE3 immunohistochemical staining were positive in all cases. Adipophilin was positive in various degrees in 5 of the 6 lipid cell variant cases but was also positive in the case with sebaceous differentiation. alpha-methylacyl-CoA racemase was positive in the lipid cell areas and negative or focal weakly positive in the conventional UC areas in 4 of the 6 cases. Vimentin, S-100 protein, and PAX8 were negative in the lipid cell component. Follow-up information was available for all cases with follow-up ranging from 6 to 84 months (mean, 34 months). Four patients died of the disease. One pT4 patient who had been followed up for 6 months lives with the disease, whereas another is disease free. In conclusion, the lipid cell variant is a rare UC variant that usually presents at an advanced stage, and tumor cells are histologically similar to lipoblasts, resemble sebaceous differentiation, and show positive immunohistochemical staining with adipophilin. PMID- 26235887 TI - Grain-size dependence of mechanical properties in polycrystalline boron-nitride: a computational study. AB - The field of research in polycrystalline hexagonal boron nitride (PBN) has been enjoying extraordinary growth recently, in no small part due to the rise of graphene and the technical advancement of mass production in polycrystalline 2D materials. However, as the grain size in 2D materials can strongly affect their materials properties and the performance of their relevant devices, it is highly desirable to investigate this effect in PBN and leverage the service capability of PBN-based devices. Here we employ molecular dynamics simulations to explore the effects of grain size in PBN on its mechanical properties such as Young's modulus, yield strength, toughness, and energy release rate as well as its failure mechanism. By visualizing and comparing the tensile failure of PBN with and without a predefined crack we have shown that the grain size of PBN is positively correlated with its elastic modulus, yield strength and toughness. Through inclusion of a crack with varying length in the PBN samples, the energy release rate is determined for each grain size of PBN and it is concluded that the energy release rate increases with an increase in the average grain size of PBN. These findings offer useful insights into utilizing PBN for mechanical design in composite materials, abrasion resistance, and electronic devices etc. PMID- 26235885 TI - Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex. AB - Cerebral cavernous malformations 2 (CCM2) loss is associated with the familial form of CCM disease. The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis in mice and interacts physically with CCM2, but how this interaction is mediated and its relevance to cerebral vasculature are unknown. Here we report that Mekk3 plays an intrinsic role in embryonic vascular development. Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain blood vessels leakage. We discover direct interaction between CCM2 harmonin homology domain (HHD) and the N terminus of MEKK3, and determine a 2.35 A cocrystal structure. We find Mekk3 deficiency impairs neurovascular integrity, which is partially dependent on Rho-ROCK signalling, and that disruption of MEKK3:CCM2 interaction leads to similar neurovascular leakage. We conclude that CCM2:MEKK3-mediated regulation of Rho signalling is required for maintenance of neurovascular integrity, unravelling a mechanism by which CCM2 loss leads to disease. PMID- 26235888 TI - Efficacy and safety of high-dose daptomycin (>6 mg/kg) for complicated bone and joint infections and implant-associated infections caused by Gram-positive bacteria. PMID- 26235889 TI - Severe combined immunodeficiency--an update. AB - Severe combined immunodeficiencies (SCIDs) are a group of inherited disorders responsible for severe dysfunctions of the immune system. These diseases are life threatening when the diagnosis is made too late; they are the most severe forms of primary immunodeficiency. SCID patients often die during the first two years of life if appropriate treatments to reconstitute their immune system are not undertaken. Conventionally, SCIDs are classified according either to the main pathway affected by the molecular defect or on the basis of the specific immunologic phenotype that reflects the stage where the blockage occurs during the differentiation process. However, during the last few years many new causative gene alterations have been associated with unusual clinical and immunological phenotypes. Many of these novel forms of SCID also show extra hematopoietic alterations, leading to complex phenotypes characterized by a functional impairment of several organs, which may lead to a considerable delay in the diagnosis. Here we review the biological and clinical features of SCIDs paying particular attention to the most recently identified forms and to their unusual or extra-immunological clinical features. PMID- 26235890 TI - Role of linoleic acid in arsenical palmar keratosis. AB - BACKGROUND: Chronic arsenic exposure can lead to palmoplantar keratosis. In the stratum corneum of skin, linoleic acid is of the utmost importance to the inflammation, keratinization, and regeneration processes. OBJECTIVES: The aims of this study were: (i) to present quantitative information on the linoleic acid fraction of intercorneocyte lipids, and (ii) to elucidate the role of linoleic acid in the pathophysiology of arsenical keratosis. METHODS: Lipid extracts were collected from keratotic lesions in seven patients, seven arsenic-exposed subjects, and seven non-exposed control subjects. Linoleic acid levels of the specimens were estimated by reverse-phase high-performance liquid chromatography (RP-HPLC). RESULTS: There was a significant (P < 0.001) increase in mean +/- standard error (SE) linoleic acid levels in arsenical keratosis patients (palm: 25.66 +/- 4.95 MUg/cm(2); dorsum: 28.25 +/- 6.20 MUg/cm(2)) compared with arsenic exposed (palm: 2.75 +/- 0.85 MUg/cm(2); dorsum: 1.96 +/- 0.64 MUg/cm(2)) and non exposed (palm: 1.52 +/- 0.61 MUg/cm(2); dorsum: 1.28 +/- 0.39 MUg/cm(2)) control subjects. There was no significant difference (P = 0.556) in linoleic acid concentration in the non-affected skin of the dorsum of the hand (28.25 +/- 6.20 MUg/cm(2)) compared with that in the palmar sites (25.66 +/- 4.95 MUg/cm(2)) in the patient group. The change in linoleic acid levels in the arsenic-exposed control group did not differ from that in non-exposed controls (P = 1.000). CONCLUSIONS: Linoleic acid concentration is elevated in arsenical keratosis; this finding warrants further investigation to ascertain whether linoleic acid plays a direct role in the pathophysiology of arsenical keratosis. PMID- 26235891 TI - Alpha-Synuclein Expression in the Oligodendrocyte Lineage: an In Vitro and In Vivo Study Using Rodent and Human Models. AB - In this study, we sought evidence for alpha-synuclein (ASYN) expression in oligodendrocytes, as a possible endogenous source of ASYN to explain its presence in glial inclusions found in multiple system atrophy (MSA) and Parkinson's disease (PD). We identified ASYN in oligodendrocyte lineage progenitors isolated from the rodent brain, in oligodendrocytes generated from embryonic stem cells, and in induced pluripotent stem cells produced from fibroblasts of a healthy individual and patients diagnosed with MSA or PD, in cultures in vitro. Notably, we observed a significant decrease in AlphaSYN during oligodendrocyte maturation. Additionally, we show the presence of transcripts in PDGFRAlpha/CD140a(+) cells and SOX10(+) oligodendrocyte lineage nuclei isolated by FACS from rodent and human healthy and diseased brains, respectively. Our work identifies ASYN in oligodendrocyte lineage cells, and it offers additional in vitro cellular models that should provide significant insights of the functional implication of ASYN during oligodendrocyte development and disease. PMID- 26235894 TI - Activating Endogenous Neural Precursor Cells Using Metformin Leads to Neural Repair and Functional Recovery in a Model of Childhood Brain Injury. AB - The development of cell replacement strategies to repair the injured brain has gained considerable attention, with a particular interest in mobilizing endogenous neural stem and progenitor cells (known as neural precursor cells [NPCs]) to promote brain repair. Recent work demonstrated metformin, a drug used to manage type II diabetes, promotes neurogenesis. We sought to determine its role in neural repair following brain injury. We find that metformin administration activates endogenous NPCs, expanding the size of the NPC pool and promoting NPC migration and differentiation in the injured neonatal brain in a hypoxia-ischemia (H/I) injury model. Importantly, metformin treatment following H/I restores sensory-motor function. Lineage tracking reveals that metformin treatment following H/I causes an increase in the absolute number of subependyma derived NPCs relative to untreated H/I controls in areas associated with sensory motor function. Hence, activation of endogenous NPCs is a promising target for therapeutic intervention in childhood brain injury models. PMID- 26235898 TI - Probing the range of applicability of structure- and energy-adjusted QM/MM link bonds. AB - The hydrogen-capping method is one of the most popular and widely used coupling schemes for quantum mechanics/molecular mechanics (QM/MM)-molecular dynamics simulations of macromolecular systems. This is mostly due to the fact that it is fairly convenient to implement and parametrize, thus providing an excellent compromise between accuracy and computational effort. In this work, a viable and straight-forward approach to optimize the placing of the link atom on a suitable distance ratio between the frontier atoms is discussed. To further increase the accuracy, instead of global parameters for all amino acids, different parameter sets for each type of amino acid are derived. The dependency of the link bond parameters on the chemical environment and the used QM-method is probed to assess the range of applicability of the parametrization. Suitable sets of parameters for RI-MP2, B3LYP, (RI)-B3LYP-D3, and RI-BLYP-D3 at triple-zeta level for all relevant proteinogenic amino acids are presented. Furthermore, the scope and range of the perturbation, stemming from the introduction of link bonds is evaluated through application of the presented QM/MM scheme in calculations of the active site of 15S-lipoxygenase. PMID- 26235897 TI - Combined effects of photodynamic therapy and irrigants in disinfection of root canals. AB - In this study, the combined effects of photodynamic therapy and irrigants in eradicating common endodontic pathogens are evaluated. Roots of 80 extracted single rooted teeth are divided into 2 groups (1) mechanical flushing; (2) antibacterial irrigation. After cleaning and shaping, they are inoculated with either (A) Streptococcus mutans or (B) Enterococcus faecalis and incubated. They are again subdivided and either only irrigated or irrigated and lased. Dentin shavings are taken from root canal walls and cultured. Statistical analysis using One-Way ANOVA and Post-hoc tests are done. The combination eradicated both bacteria. Antibacterial irrigants controlled S. mutans better than PDT (p = 0.041). The combination of PDT and antibacterial irrigation proposed in this study can be used in all primary cases for thorough and reliable disinfection of root canals but may be highly effective in resistant cases like endodontic failures, as E. faecalis is prevalent in such cases. PMID- 26235895 TI - Podocyte Regeneration Driven by Renal Progenitors Determines Glomerular Disease Remission and Can Be Pharmacologically Enhanced. AB - Podocyte loss is a general mechanism of glomerular dysfunction that initiates and drives the progression of chronic kidney disease, which affects 10% of the world population. Here, we evaluate whether the regenerative response to podocyte injury influences chronic kidney disease outcome. In models of focal segmental glomerulosclerosis performed in inducible transgenic mice where podocytes are tagged, remission or progression of disease was determined by the amount of regenerated podocytes. When the same model was established in inducible transgenic mice where renal progenitors are tagged, the disease remitted if renal progenitors successfully differentiated into podocytes, while it persisted if differentiation was ineffective, resulting in glomerulosclerosis. Treatment with BIO, a GSK3s inhibitor, significantly increased disease remission by enhancing renal progenitor sensitivity to the differentiation effect of endogenous retinoic acid. These results establish renal progenitors as critical determinants of glomerular disease outcome and a pharmacological enhancement of their differentiation as a possible therapeutic strategy. PMID- 26235899 TI - Anesthesia, surgical stress, and "long-term" outcomes. AB - An increasing body of evidence shows that the choice of anesthetic can strongly influence more than simply the quality of anesthesia. Regional and general anesthesia have often been compared to ascertain whether one provides benefits through dampening the stress response or harms by accelerating cancer progression. Regional anesthesia offers considerable advantages, by suppressing cortisol and catecholamine levels and reducing muscle breakdown postoperatively. It also has less immunosuppressive effect and potentially reduces the proinflammatory cytokine response. As such, vital organ functions (e.g., brain and kidney) may be better preserved with regional anesthetics, however, further study is needed. Volatile general anesthetics appear to promote cancer malignancy in comparison to regional and intravenous general anesthetics, and reduce the body's ability to act against cancer cells by suppression of natural killer cell activity. There is not sufficient evidence to support an alteration of current clinical practice, however, further research into this area is warranted due to the potential implications elicited by current studies. PMID- 26235893 TI - alpha-5 Laminin Synthesized by Human Pluripotent Stem Cells Promotes Self Renewal. AB - Substrate composition significantly impacts human pluripotent stem cell (hPSC) self-renewal and differentiation, but relatively little is known about the role of endogenously produced extracellular matrix (ECM) components in regulating hPSC fates. Here we identify alpha-5 laminin as a signature ECM component endogenously synthesized by undifferentiated hPSCs cultured on defined substrates. Inducible shRNA knockdown and Cas9-mediated disruption of the LAMA5 gene dramatically reduced hPSC self-renewal and increased apoptosis without affecting the expression of pluripotency markers. Increased self-renewal and survival was restored to wild-type levels by culturing the LAMA5-deficient cells on exogenous laminin-521. Furthermore, treatment of LAMA5-deficient cells with blebbistatin or a ROCK inhibitor partially restored self-renewal and diminished apoptosis. These results demonstrate that endogenous alpha-5 laminin promotes hPSC self-renewal in an autocrine and paracrine manner. This finding has implications for understanding how stem cells dynamically regulate their microenvironment to promote self-renewal and provides guidance for efforts to design substrates for stem cell bioprocessing. PMID- 26235892 TI - C/EBPalpha Activates Pre-existing and De Novo Macrophage Enhancers during Induced Pre-B Cell Transdifferentiation and Myelopoiesis. AB - Transcription-factor-induced somatic cell conversions are highly relevant for both basic and clinical research yet their mechanism is not fully understood and it is unclear whether they reflect normal differentiation processes. Here we show that during pre-B-cell-to-macrophage transdifferentiation, C/EBPalpha binds to two types of myeloid enhancers in B cells: pre-existing enhancers that are bound by PU.1, providing a platform for incoming C/EBPalpha; and de novo enhancers that are targeted by C/EBPalpha, acting as a pioneer factor for subsequent binding by PU.1. The order of factor binding dictates the upregulation kinetics of nearby genes. Pre-existing enhancers are broadly active throughout the hematopoietic lineage tree, including B cells. In contrast, de novo enhancers are silent in most cell types except in myeloid cells where they become activated by C/EBP factors. Our data suggest that C/EBPalpha recapitulates physiological developmental processes by short-circuiting two macrophage enhancer pathways in pre-B cells. PMID- 26235896 TI - Transcriptional Profiling of Hypoxic Neural Stem Cells Identifies Calcineurin NFATc4 Signaling as a Major Regulator of Neural Stem Cell Biology. AB - Neural stem cells (NSCs) reside in a hypoxic microenvironment within the brain. However, the crucial transcription factors (TFs) that regulate NSC biology under physiologic hypoxia are poorly understood. Here we have performed gene set enrichment analysis (GSEA) of microarray datasets from hypoxic versus normoxic NSCs with the aim of identifying pathways and TFs that are activated under oxygen concentrations mimicking normal brain tissue microenvironment. Integration of TF target (TFT) and pathway enrichment analysis identified the calcium-regulated TF NFATc4 as a major candidate to regulate hypoxic NSC functions. Nfatc4 expression was coordinately upregulated by top hypoxia-activated TFs, while NFATc4 target genes were enriched in hypoxic NSCs. Loss-of-function analyses further revealed that the calcineurin-NFATc4 signaling axis acts as a major regulator of NSC self renewal and proliferation in vitro and in vivo by promoting the expression of TFs, including Id2, that contribute to the maintenance of the NSC state. PMID- 26235901 TI - Failure to attain stretched penile length after intracavernosal injection of a vasodilator agent is predictive of veno-occlusive dysfunction on penile duplex Doppler ultrasonography. AB - Penile duplex Doppler ultrasound (PDDU) assesses the etiology of erectile dysfunction. Peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) are common PDDU parameters. We assessed whether stretched penile length (SPL) in the flaccid state and measured penile length at peak erection after intracavernosal injection (ICI) of a vasodilator during PDDU correlated with the etiology of erectile dysfunction. We performed a retrospective review of 93 patients who underwent PDDU for erectile dysfunction. Normal and stretched penile length were measured, both at a flaccid state prior to ICI and at peak erection during PDDU. Collected data included patient demographics, vascular, and anatomic parameters. The mean age was 52 years. SPL was equivalent to peak penile length after ICI in 60 patients (65%, group 1) and did not match in 33 (35%, group 2). There were no significant differences between the two groups in terms of flaccid, stretched, and post-ICI erect penile lengths, IIEF score, PSV, percent rigidity or tumescence, and vasodilator dose used. Patients in group 2 had less of a change in penile length from flaccid to erect state (36% vs. 44%, p = 0.02), higher EDV (12.0 vs. 8.5, p = 0.041), lower RI (0.6 vs. 1.0, p = 0.046), and more veno-occlusive dysfunction (82% vs. 53%, p = 0.001). On multivariate analysis, failure to reach maximum SPL at peak ICI erection (OR 2.255, CI 1.191-4.271, p = 0.0126), EDV (OR 1.281, CI 1.115-1.471, p < 0.001) and RI (OR 0.694, CI 0.573-0.723, p = 0.009) predicted veno-occlusive dysfunction. Failure to reach maximal SPL during PDDU using ICI with a vasodilator agent predicted veno-occlusive dysfunction, which is independent of both penile rigidity and tumescence. This measurement could serve as another diagnostic tool for predicting veno-occlusive dysfunction when PDDU is not readily available. Limitations include the subjective nature of penile measurements and different PGE1 doses used. PMID- 26235902 TI - A misleading tumor. Benign metastatic leiomyoma. PMID- 26235900 TI - YIP1 family member 4 (YIPF4) is a novel cellular binding partner of the papillomavirus E5 proteins. AB - E5 proteins are amongst the least understood of the Human Papillomavirus (HPV) encoded gene products. They are small, membrane-integrated proteins known to modulate a number of critical host pathways associated with pathogenesis including growth factor receptor signaling and immune evasion. Their role in the virus life cycle is less clear, indicating a role in the productive stages of the life cycle. However, a mechanism for this is currently lacking. Here we describe the identification of a novel binding partner of E5, YIPF4 using yeast two-hybrid analysis. YIPF4 is also a poorly characterized membrane spanning protein. Mutagenesis studies implicated the transmembrane regions of each protein as important for their interaction. Binding to YIPF4 was found for all E5 proteins tested suggesting that this interaction may mediate a conserved E5 function. In normal human keratinocytes YIPF4 expression was down-regulated upon differentiation and this reduction was partially rescued in cells harbouring HPV. Despite the conserved nature of the interaction with E5, siRNA mediated depletion of YIPF4 failed to impede two well-characterized functions of E5, namely EGFR trafficking or HLA class I presentation. Continued studies of YIPF4 are warranted to determine its role in the PV life cycle. PMID- 26235903 TI - Reversed Halo Sign: What Lies Beneath? PMID- 26235904 TI - Characterization of Spaghetti Prepared Under Different Drying Conditions. AB - Spaghetti dried at low (max. 50 degrees C), high (max. 70 degrees C), and very high (max. 85 degrees C) temperatures were characterized by their color, surface structure, rupture strength, texture analysis, and sauce retention capacity. The texture and sauce retention capacity were estimated for cooked spaghetti. The color of the spaghetti's methanol extracts, as evaluated through absorbance at 440 and 466 nm, did not depend on the drying temperature. A trend was observed in the surface texture of spaghetti, as estimated by atomic force microscopy and mercury intrusion porosimetry, where the surface was rougher when dried at higher temperatures than at low temperatures. Furthermore, the rupture strength was also higher for the spaghetti dried at higher temperatures. This result can be ascribed to the formation of stronger gluten networks, promoted by denaturation of gluten at the higher temperatures. However, the hardness of cooked spaghetti was not affected by the drying temperature, a result attributable to the action of water sorption to offset any differences in hardness among the spaghettis dried at the 3 different temperatures. The sauce retention capacity of cooked spaghetti was evaluated using a dextran solution as a simulated sauce, and by this method, the capacity of the spaghetti dried at a low temperature was shown to be significantly lower than that of the spaghetti dried at higher temperatures. This can be ascribed to the smoother surface of cooked spaghetti dried at the lower temperature and also to the leakage of amylose onto the surface during cooking. PMID- 26235905 TI - Anti-inflammatory and anti-bacterial effects of iron chelation in experimental sepsis. AB - BACKGROUND: Sepsis is the systemic inflammatory response to an infection. Generation of reactive oxygen species represents an important part of the inflammatory cascade in sepsis. Dysregulation of iron homeostasis can further promote the generation of radicals and amplify the damage caused by systemic immune activation. This can potentially be suppressed or prevented by iron chelation. Therefore, this study was designed to examine the effects of a novel iron chelator (DIBI) with or without standard antibiotic treatment in colon ascendens stent peritonitis (CASP)-induced experimental sepsis. METHODS: Six groups of animals (n = 7-10) were included in the study: sham surgery; untreated CASP animals; CASP and subcutaneous (sc) or intraperitoneal DIBI administration, respectively; CASP and imipenem sc; and combination of DIBI and imipenem sc. RESULTS: We observed a 55% reduction in leukocyte adhesion in V1 venules after sc administration of DIBI and a 40% reduction after imipenem treatment, when compared to untreated CASP animals (P < 0.05). A further reduction in the number of adherent leukocytes in V1 venules has been observed after combined treatment with DIBI and imipenem (66%). A significant decrease in bacterial count was observed from 2200 (150-64,000) to 100 (1-420) colony forming units per milliliter in blood in the sc DIBI and imipenem combination group (P = 0.0065). The bacterial count in the peritoneal lavage fluid was also significantly reduced in the sc imipenem group and the sc DIBI and imipenem combination group (P = 0.0021 and P = 0.0001, respectively) when compared to untreated CASP animals. CONCLUSIONS: These findings suggest a potential role of iron chelators in the treatment of sepsis. PMID- 26235906 TI - Animal models in surgical lymphedema research--a systematic review. AB - BACKGROUND: Chronic secondary lymphedema is a well-known complication in oncologic surgery. Autologous lymph node transplantation, lymphovenous anastomosis, and other lymphatic surgeries have been developed in the last decades with rising clinical application. Animal models to explore the pathophysiology of lymphedema and microsurgical interventions have reached great popularity, although the induction of stable lymphedema in animals is still challenging. The aim of this review was to systematically assess lymphedema animal models and their potential use to study surgical interventions. MATERIALS AND METHODS: A systematic review according to the PRISMA guidelines was performed without time or language restriction. Studies describing new or partially new models were included in chronological order. Models for primary and secondary lymphedema were assessed, and their potential for surgical procedures was evaluated. RESULTS: The systematic search yielded 8590 discrete articles. Of 180 articles included on basis of title, 84 were excluded after abstract review. Ninety-six were included in the final analysis with 24 key articles. CONCLUSIONS: No animal model is perfect, and many models show spontaneous lymphedema resolution. The rodent limb appears to be the most eligible animal model for experimental reconstruction of the lymphatic function as it is well accessible for vascularized tissue transfer. There is a need for standardized parameters in experimental lymphedema quantification. Also, more permanent models to study the effect of free vascularized lymph node transfer are needed. PMID- 26235907 TI - Use of botulinum toxin for genitourinary conditions: What is the evidence? AB - Botulinum toxin A is licensed for the treatment of urinary incontinence due to neurogenic detrusor overactivity (NDO) and overactive bladder (OAB). Only onabotulinumtoxinA has at this moment such approval, in NDO at a dose of 200 U and in OAB at a dose of 100 U. Regulatory phase 3 trials have been carried out in both conditions. In NDO it was shown to decrease urinary incontinence, to improve urodynamic parameters and to increase quality of life in multiple sclerosis and spinal cord injured patients. Adverse events included urinary tract infections and necessity of de novo clean intermittent catheterization, which occurred mainly in patients with multiple sclerosis. In OAB patients with urge incontinence, onabotulinumtoxinA decreased urinary incontinence and micturition frequency while improving quality of life. Again, main adverse events were urinary tract infections and transient urinary retentions. Long-term studies in both NDO and OAB demonstrate the efficacy and safety of the treatment. Available phase 3 trials of onabotulinumtoxinA in benign prostatic hyperplasia did not show any relevant efficacy in improving lower urinary tract symptoms. PMID- 26235908 TI - Beneficial effects of vitamin E supplementation against the oxidative stress on Cylindrospermopsin-exposed tilapia (Oreochromis niloticus). AB - Cylindrospermopsin (CYN) is known to produce changes in some oxidative stress biomarkers in fish acutely and subchronically exposed to the toxin. The present study investigated the effects of vitamin E supplementation against the oxidative stress induced by pure CYN in tilapia (Oreochromis niloticus). Fish were pretreated with 700 mg vitamin E/kg fish body weight (bw)/day for 7 days by oral route, and on day seven, they received a single oral dose of 400 MUg pure CYN/kg fish bw, and were killed after 24 h. The biomarkers evaluated included lipid peroxidation (LPO), protein and DNA oxidation, glutathione-S-transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) and gamma-glutamyl-cysteine synthetase (gamma-GCS) activities, and ratio of reduced glutathione-oxidized glutathione (GSH/GSSG). This is the first study showing that vitamin E supplementation is effective at reducing the toxicity induced by CYN, recovering the biomarkers assayed to basal levels. Therefore, vitamin E can be considered a useful chemoprotectant that reduces hepatic and renal oxidative stress and can be used in the prophylaxis and treatment of CYN-related intoxication in fish. PMID- 26235909 TI - Achieving significantly enhanced visible-light photocatalytic efficiency using a polyelectrolyte: the composites of exfoliated titania nanosheets, graphene, and poly(diallyl-dimethyl-ammonium chloride). AB - A high-performance visible-light-active photocatalyst is prepared using the polyelectrolyte/exfoliated titania nanosheet/graphene oxide (GO) precursor by flocculation followed by calcination. The polyelectrolyte poly(diallyl-dimethyl ammonium chloride) serves not only as an effective binder to precipitate GO and titania nanosheets, but also boosts the overall performance of the catalyst significantly. Unlike most titania nanosheet-based catalysts reported in the literature, the composite absorbs light in the UV-Vis-NIR range. Its decomposition rate of methylene blue is 98% under visible light. This novel strategy of using a polymer to enhance the catalytic performance of titania nanosheet-based catalysts affords immense potential in designing and fabricating next-generation photocatalysts with high efficiency. PMID- 26235910 TI - Charge carrier mobility in hybrid halide perovskites. AB - The charge transport properties of hybrid halide perovskites are investigated with a combination of density functional theory including van der Waals interaction and the Boltzmann theory for diffusive transport in the relaxation time approximation. We find the mobility of electrons to be in the range 5-10 cm(2)V(-1)s(-1) and that for holes within 1-5 cm(2)V(-1)s(-1), where the variations depend on the crystal structure investigated and the level of doping. Such results, in good agreement with recent experiments, set the relaxation time to about 1 ps, which is the time-scale for the molecular rotation at room temperature. For the room temperature tetragonal phase we explore two possible orientations of the organic cations and find that the mobility has a significant asymmetry depending on the direction of the current with respect to the molecular axis. This is due mostly to the way the PbI3 octahedral symmetry is broken. Interestingly we find that substituting I with Cl has minor effects on the mobilities. Our analysis suggests that the carrier mobility is probably not a key factor in determining the high solar-harvesting efficiency of this class of materials. PMID- 26235911 TI - Violent death in a rare peroxisomal disease--Zellweger syndrome. AB - Peroxisomal diseases are rare (1:50,000), genetically determined disorders (autosomal recessive), systemic, multiorgan illnesses with prominent involvement of the nervous system, caused either by the failure to form or to maintain the peroxisome, or by a defect in the function of a single or multiple peroxisomal enzymes. Peroxisomes contain approximately 50 enzymes which are responsible for many metabolic reactions, and play an important role in the oxidation of saturated very-long-chain fatty acids (VLCFA). The authors present the case of a Romanian boy, who died at the age of 1.6 of one of the peroxisomal diseases Zellweger syndrome. Newborn infants with Zellweger syndrome have a typical dysmorphic facies, neonatal seizures, profound hypotonia, and eye abnormalities. Major abnormalities are present in the liver (fibrotic), kidney (cortical cysts), and brain (lipid-laden macrophages and histiocytes in cortical and periventricular areas, demyelination, centrosylvian polymicrogyria and pachygyria)-cerebro-hepato-renal syndrome (CHRS) (Zellweger). Infants with Zellweger syndrome rarely live more than a few months, but in this case the survival was longer, and the cause of death was not directly the peroxisomal disease but a violent cause of death-mechanical asphyxia with tracheo-bronchial food aspiration. The authors present the results of investigations carried out during the child's life, but also data collected at the autopsy and hystopathological postnecroptic investigations. By presenting this case, the authors wish to bring to your attention a rare pathology in forensic practice by the paradox of finding a common violent cause of death, asphyxia with food aspiration, in a rare metabolic-genetic disease, which is usually fatal by itself. PMID- 26235912 TI - Molecular architecture of silk fibroin of Indian golden silkmoth, Antheraea assama. AB - The golden silk spun by Indian golden silkmoth Antheraea assama, is regarded for its shimmering golden luster, tenacity and value as biomaterial. This report describes the gene coding for golden silk H-fibroin (AaFhc), its expression, full length sequence and structurally important motifs discerning the underlying genetic and biochemical factors responsible for its much sought-after properties. The coding region, with biased isocodons, encodes highly repetitious crystalline core, flanked by a pair of 5' and 3' non-repetitious ends. AaFhc mRNA expression is strictly territorial, confined to the posterior silk gland, encoding a protein of size 230 kDa, which makes homodimers making the elementary structural units of the fibrous core of the golden silk. Characteristic polyalanine repeats that make tight beta-sheet crystals alternate with non-polyalanine repeats that make less orderly antiparallel beta-sheets, beta-turns and partial alpha-helices. Phylogenetic analysis of the conserved N-terminal amorphous motif and the comparative analysis of the crystalline region with other saturniid H-fibroins reveal that AaFhc has longer, numerous and relatively uniform repeat motifs with lower serine content that assume tighter beta-crystals and denser packing, which are speculated to be responsible for its acclaimed properties of higher tensile strength and higher refractive index responsible for golden luster. PMID- 26235914 TI - Endocrinological correlates of male bimaturism in wild Bornean orangutans. AB - Among primates, orangutans are unique in having pronounced male bimaturism leading to two fully adult morphs that differ in both physical appearance and behavior. While unflanged males have a female-like appearance, flanged males have the full suite of secondary sexual characteristics, including cheek flanges and a large throat sac. So far, hormonal correlates of arrested development in unflanged males and the expression of secondary sexual characteristics in flanged males have only been studied in zoo-housed individuals. In this study, we investigated fecal androgen and glucocorticoid metabolites as hormonal correlates of male bimaturism in 17 wild adult Bornean orangutans (Pongo pygmaeus) in Central Kalimantan, Indonesia. We predicted and found higher androgen levels in flanged males compared to unflanged males, probably due to ongoing strong competition among flanged males who meet too infrequently to establish a clear linear dominance hierarchy. Furthermore, we found no difference in fecal glucocorticoid metabolite concentrations between flanged and unflanged males, indicating that social stress is unlikely to explain arrested development in unflanged wild orangutans. The only actively developing male in our study showed significantly higher androgen levels during the period of development than later as a fully flanged male. This supports earlier findings from zoo studies that elevated androgen levels are associated with the development of secondary sexual characteristics. PMID- 26235913 TI - Transcriptome Dynamics of Developing Photoreceptors in Three-Dimensional Retina Cultures Recapitulates Temporal Sequence of Human Cone and Rod Differentiation Revealing Cell Surface Markers and Gene Networks. AB - The derivation of three-dimensional (3D) stratified neural retina from pluripotent stem cells has permitted investigations of human photoreceptors. We have generated a H9 human embryonic stem cell subclone that carries a green fluorescent protein (GFP) reporter under the control of the promoter of cone-rod homeobox (CRX), an established marker of postmitotic photoreceptor precursors. The CRXp-GFP reporter replicates endogenous CRX expression in vitro when the H9 subclone is induced to form self-organizing 3D retina-like tissue. At day 37, CRX+ photoreceptors appear in the basal or middle part of neural retina and migrate to apical side by day 67. Temporal and spatial patterns of retinal cell type markers recapitulate the predicted sequence of development. Cone gene expression is concomitant with CRX, whereas rod differentiation factor neural retina leucine zipper protein (NRL) is first observed at day 67. At day 90, robust expression of NRL and its target nuclear receptor NR2E3 is evident in many CRX+ cells, while minimal S-opsin and no rhodopsin or L/M-opsin is present. The transcriptome profile, by RNA-seq, of developing human photoreceptors is remarkably concordant with mRNA and immunohistochemistry data available for human fetal retina although many targets of CRX, including phototransduction genes, exhibit a significant delay in expression. We report on temporal changes in gene signatures, including expression of cell surface markers and transcription factors; these expression changes should assist in isolation of photoreceptors at distinct stages of differentiation and in delineating coexpression networks. Our studies establish the first global expression database of developing human photoreceptors, providing a reference map for functional studies in retinal cultures. PMID- 26235915 TI - Multimeric xanthates as carbonic anhydrase inhibitors. AB - The field of multivalent inhibition of enzymes is growing exponentially from the first reported multivalent effect on a glycosidase enzyme. However, the investigations have generally remained restricted to carbohydrate-processing enzymes. Carbonic anhydrases are ubiquitous metallo-enzymes involved in many key biological processes, that catalyze the reversible hydration/dehydration of [Formula: see text]. This study reports the first synthesis of multimeric xanthates addressing the selectivity and potency of CA multivalent inhibition. Six multivalent compounds containing three, four, and six xanthate moieties were prepared and assayed against four relevant CA isoforms together with their monovalent analogues. Some of the multimers were stronger inhibitors than the monomeric species. For hCA I, the two best molecules 18 and 20 showed an improvement of the ligand affinity of 4.8 and 2.3 per xanthate units (valence corrected values), respectively, which corresponds to a clear multivalent effect. Moreover, the biochemical assays demonstrated that the multimeric presentation of xanthates, also affected the selectivity of the relative inhibition among the four CAs assayed. PMID- 26235916 TI - X-ray crystal structure and activity of fluorenyl-based compounds as transthyretin fibrillogenesis inhibitors. AB - Transthyretin (TTR) is a 54 kDa homotetrameric protein that transports thyroxine (T4) and retinol (vitamin A), through its association with retinol binding protein (RBP). Under unknown conditions, it aggregates to form fibrils associated with TTR amyloidosis. Ligands able to inhibit fibril formation have been studied by X-ray crystallography. The use of polyethylene glycol (PEG) instead of ammonium sulphate or citrate has been evaluated as an alternative to obtain new TTR complexes with (R)-3-(9-fluoren-9-ylideneaminooxy)-2-methyl-N (methylsulfonyl) propionamide (48R(1)) and 2-(9H-fluoren-9-ylideneaminooxy) acetic acid (ES8(2)). The previously described fluorenyl based inhibitors (S)-3 ((9H-fluoren-9-ylideneamino)oxy)-2-methylpropanoic acid (6BD) and 3-((9H-fluoren 9-ylideneamino)oxy)propanoic acid (7BD) have been re-evaluated with the changed crystallization method. The new TTR complexes with compounds of the same family show that the 9-fluorenyl motif can occupy alternative hydrophobic binding sites. This augments the potential use of this scaffold to yield a large variety of differently substituted mono-aryl compounds able to inhibit TTR fibril formation. PMID- 26235917 TI - Bisphosphonic acids as effective inhibitors of Mycobacterium tuberculosis glutamine synthetase. AB - Inhibition of glutamine synthetase (GS) is one of the most promising strategies for the discovery of novel drugs against tuberculosis. Forty-three bisphosphonic and bis-H-phosphinic acids of various scaffolds, bearing aromatic substituents, were screened against recombinant GS from Mycobacterium tuberculosis. Most of the studied compounds exhibited activities in micromolar range, with N-(3,5 dichlorophenyl)-2-aminoethylidenebisphoshonic acid, N-(3,5-difluorophenyl)-2 aminoethylidene-bisphoshonic acid and N-(3,4-dichlorophenyl)-1-hydroxy-1,1 ethanebisphosphonic acid showing the highest potency with kinetic parameters similar to the reference compound - L-methionine-S-sulfoximine. Moreover, these inhibitors were found to be much more effective against pathogen enzyme than against the human ortholog. Thus, with the bone-targeting properties of the bisphosphonate compounds in mind, this activity/selectivity profile makes these compounds attractive agents for the treatment of bone tuberculosis. PMID- 26235918 TI - Hot melt extruded and injection moulded disulfiram-loaded PLGA millirods for the treatment of glioblastoma multiforme via stereotactic injection. AB - Glioblastoma multiforme (GBM) has a poor prognosis and is one of the most common primary malignant brain tumours in adults. Stereotactic injections have been used to deliver chemotherapeutic drugs directly into brain tumours. This paper describes the development of disulfiram (DSF)-loaded biodegradable millirods manufactured using hot melt extrusion (HME) and injection moulding (IM). The paper demonstrates that the stability of the DSF within the millirods is dependent on the manufacturing technique used as well as the drug loading. The physical state of the DSF within the millirods was dependent on the fabrication process, with the DSF in the HME millirods being either completely amorphous within the PLGA, while the DSF within the IM millirods retained between 54 and 66% of its crystallinity. Release of DSF from the millirods was dependent on the degradation rate of the PLGA, the manufacturing technique used as well as the DSF loading. DSF in the 10% (w/w) DSF loaded HME millirods and the 20% (w/w) DSF loaded HME and IM millirods had a similar cytotoxicity against a GBM cell line compared to the unprocessed DSF control. However, the 10% (w/w) DSF-loaded IM millirods had a significantly lower cytotoxicity when compared to the unprocessed control. PMID- 26235919 TI - Investigation into process-induced de-aggregation of cohesive micronised API particles. AB - The aim of this study was to assess the impact of unit processes on the de aggregation of a cohesive micronised API within a pharmaceutical formulation using near-infrared chemical imaging. The impact on the primary API particles was also investigated using an image-based particle characterization system with integrated Raman analysis. The blended material was shown to contain large, API rich domains which were distributed in-homogeneously across the sample, suggesting that the blending process was not aggressive enough to disperse aggregates of micronised drug particles. Cone milling, routinely used to improve the homogeneity of such cohesive formulations, was observed to substantially reduce the number and size of API rich domains; however, several smaller API domains survived the milling process. Conveyance of the cone milled formulation through the Alexanderwerk WP120 powder feed system completely dispersed all remaining aggregates. Importantly, powder feed transmission of the un-milled formulation was observed to produce an equally homogeneous API distribution. The size of the micronised primary drug particles remained unchanged during powder feed transmission. These findings provide further evidence that this powder feed system does induce shear, and is in fact better able to disperse aggregates of a cohesive micronised API within a blend than the blend-mill-blend step. PMID- 26235920 TI - Preparation and characterisation of hexamidine salts. AB - Hexamidine diisethionate (HEX D) has been used in the personal care industry and in a number of over-the-counter (OTC) drug products as an antimicrobial agent since the 1950's. Recently, the compound has also been investigated for its beneficial effects on skin health. Surprisingly, there is only limited information describing the physicochemical properties of this compound in the literature. The objective of this work was therefore to conduct a comprehensive programme of characterisation of HEX D as well as its dihydrochloride salt (HEX H). HEX H was prepared from HEX D by a simple acid addition reaction. Both salts were characterised using Nuclear Magnetic Resonance (NMR), Differential scanning calorimetry (DSC), and Thermogravimetric analysis (TGA). A new high performance liquid chromatographic method was developed and validated for both compounds. The pH in aqueous solution as well as respective distribution coefficients between octanol and pH 7.4 buffer were also determined. Finally, solubility and short term stability studies were conducted in a range of solvents. NMR analysis confirmed the preparation of HEX H from HEX D. Thermal analysis indicated the melting points of HEX D and HEX H were 225 degrees C and 266 degrees C respectively. HPLC analysis confirmed the purity of both salts. LogD values at pH 7.4 were -0.74 for HEX D and -0.70 for HEX H respectively. The physicochemical properties of two HEX salts have been established using a range of analytical approaches. Detailed solubility and stability data have also been collated. This information will be useful in the design of novel formulations for targeted delivery of these compounds to the skin. PMID- 26235921 TI - 3D printing of tablets containing multiple drugs with defined release profiles. AB - We have employed three-dimensional (3D) extrusion-based printing as a medicine manufacturing technique for the production of multi-active tablets with well defined and separate controlled release profiles for three different drugs. This 'polypill' made by a 3D additive manufacture technique demonstrates that complex medication regimes can be combined in a single tablet and that it is viable to formulate and 'dial up' this single tablet for the particular needs of an individual. The tablets used to illustrate this concept incorporate an osmotic pump with the drug captopril and sustained release compartments with the drugs nifedipine and glipizide. This combination of medicines could potentially be used to treat diabetics suffering from hypertension. The room temperature extrusion process used to print the formulations used excipients commonly employed in the pharmaceutical industry. Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) and X-ray powder diffraction (XRPD) were used to assess drug-excipient interaction. The printed formulations were evaluated for drug release using USP dissolution testing. We found that the captopril portion showed the intended zero order drug release of an osmotic pump and noted that the nifedipine and glipizide portions showed either first order release or Korsmeyer Peppas release kinetics dependent upon the active/excipient ratio used. PMID- 26235922 TI - The parameters influencing the morphology of poly(E-caprolactone) microspheres and the resulting release of encapsulated drugs. AB - Polymer microparticles used for drug encapsulation and delivery have various surface morphologies depending on the type of formulation ingredients and parameters of the manufacture process. This works aims at investigating the critical parameters governing the morphology of microparticles and to underline the influence of their surface state on the drug release. The classical fabrication process by the "emulsion-solvent evaporation" is addressed using poly(E-caprolactone) as the polymer and methylene chloride as the volatile organic solvent. The typical surfactants poly(vinyl alcohol) and polysorbate 80 have been considered. Scanning electron microscopy observations showed the various surface morphologies mainly depending on the stirring rate, the viscosity of the oil phase and by the presence of inappropriate surfactants. Because of arrested coalescence during solvent evaporation, the evaporation of the organic solvent causing particles hardening is the most important parameter that controls the morphology. Indeed, slow evaporation allows partial coalescence of the soft particles swollen by the organic solvent, whereas the particles morphology is frozen rapidly upon fast evaporation, thus preventing damaged surface states. Moreover, an effective stabilizing system for the primary emulsion is also a determining factor to control the final morphology. The morphology of the particles has a definite influence on the drug delivery of cholecalciferol. The surface morphology should be taken into consideration in the design of polymer microparticles because it allows a control over the drug release kinetics. PMID- 26235923 TI - Exploring the 'aggregation-prone' core of human Cystatin C: A structural study. AB - Amyloidogenic proteins like human Cystatin C (hCC) have been shown to form dimers and oligomers by exchange of subdomains of the monomeric proteins. Normally, the hCC monomer, a low molecular type 2 Cystatin, consists of 120 amino acid residues and functions as an inhibitor of cysteine proteases. The oligomerization of hCC is involved in the pathophysiology of a rare form of amyloidosis namely Icelandic hereditary cerebral amyloid angiopathy, in which an L68Q mutant is deposited as amyloid in brain arteries of young adults. In order to find the shortest stretch responsible to drive the fibril formation of hCC, we have previously demonstrated that the LQVVR peptide forms amyloid fibrils, in vitro (Tsiolaki et al., 2015). Predictions by AMYLPRED, an amyloidogenic determinant prediction algorithm developed in our lab, led us to synthesize and experimentally study two additional predicted peptides derived from hCC. Along with our previous findings, in this work, we reveal that these peptides self-assemble, in a similar way, into amyloid-like fibrils in vitro, as electron microscopy, X-ray fiber diffraction, ATR FT-IR spectroscopy and Congo red staining studies have shown. Further to our experimental results, all three peptides seem to have a fundamental contribution in forming the "aggregation-prone" core of human Cystatin C. PMID- 26235925 TI - Differential associations between obesity and behavioral measures of impulsivity. AB - A growing literature indicates that impulsivity is a fundamental behavioral process that underlies obesity. However, impulsivity is a multidimensional construct, which comprises independent patterns of decision-making that could be uniquely associated with obesity. No research to date has clarified whether obesity is differentially associated with specific behavioral aspects of impulsivity. This study examined whether obesity was differentially associated with patterns of decision-making associated with impulsivity-delay discounting, probability discounting, and response inhibition. Young adults (n = 296; 44.3% male) age 18-30 were recruited from the community with media advertisements. Participants completed a series of standard self-report measures of health outcomes and behavioral measures of delay discounting, probability discounting, and response inhibition individually in a laboratory. Associations between body mass index (BMI) and behavioral outcomes in the whole sample indicated that BMI was associated with age, delay discounting, and probability discounting, but not response inhibition. A logistic regression that included age, sex, and substance use as covariates found that delay discounting, but neither probability discounting nor response inhibition, was associated with obesity status. Sensitivity to delay, rather than response inhibition and sensitivity to uncertainty, may be the best correlate of obesity status in adults. These findings are relevant to our understanding of the fundamental behavioral processes associated with obesity. PMID- 26235926 TI - The novel atypical retinoid ST5589 down-regulates Aurora Kinase A and has anti tumour activity in lymphoma pre-clinical models. AB - Despite the marked improvements in the treatment of lymphomas, there is still a need for new therapeutic agents. Synthetic retinoids represent a class of compounds with anti-cancer activity. Here, we report the preclinical activity of a new member of this class, the ST1926-derivative ST5589, in lymphomas. ST5589 presented a dose-dependent anti-proliferative activity in almost all of the 25 lymphoma cell lines analysed, with a median 50% inhibitory concentration of 433 nM. Apoptosis was observed in 8/11 cell lines. ST5589 induced changes in the gene expression profiles of the cell lines, including the down-regulation of Aurora Kinase A (AURKA). Specific gene expression signatures were associated with a higher sensitivity to the compound and combination of ST5589 with carfilzomib revealed the importance of proteasome activity in mediating the anti-tumour activity of ST5589. In conclusion, we have identified a new mechanism of action of atypical retinoids as anti-cancer compounds, and the encouraging results obtained with the new ST1926-derivative ST5589 provide the basis for further developments of the compound. PMID- 26235924 TI - Current and emerging modalities for detection of cardiotoxicity in cardio oncology. AB - Advancements in diagnostic tools and curative-intent therapies have improved cancer-specific survival. With prolonged survival, patients are now subject to increased aging and development of cardiovascular risk factors such that further improvements in cancer-specific mortality are at risk of being offset by increased cardiovascular mortality. Moreover, established and novel adjuvant therapies used in cancer treatment are associated with unique and varying degrees of direct as well as indirect myocardial and cardiovascular injury (i.e., cardiotoxicity). Current approaches for evaluating anticancer therapy-induced injury have limitations, particularly lack of sensitivity for early detection of subclinical cardiac and cardiovascular dysfunction. With emerging evidence suggesting early prevention and treatment can mitigate the degree of cardiotoxicity and limit interruption of life-saving cancer therapy, the importance of early detection is increasingly paramount. Newer imaging modalities, functional capacity testing and blood biomarkers have the potential to improve early detection of cardiotoxicity and reduce cardiovascular morbidity and mortality. PMID- 26235927 TI - Comparison of Outcomes of Transcatheter Aortic Valve Implantation in Patients >=90 Years Versus <90 Years. AB - Transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS) is increasingly performed in nonagenarians. There is scarce evidence on the feasibility and safety of balloon-expandable TAVI in this patient population. A total of 734 patients who underwent balloon-expandable TAVI at our institute were included in the study. We compared 136 patients who were aged at least 90 years at the time of TAVI (mean age 92.4 +/- 2.4 years) with the remaining 598 younger patients (mean age 79.7 +/- 7.8 years). Valve Academic Research Consortium 2 end points were compared between the 2 groups. Diabetes mellitus, coronary artery disease (CAD), peripheral artery disease (PAD), and chronic lung disease were significantly less prevalent in patients aged >=90 years. In contrast, the prevalence of frailty, chronic renal failure, and atrial fibrillation was significantly higher in these patients. Device success was 96% in both groups. All-cause mortality at 30 days and 1 year was 2.9% and 12.5% versus 2.8% and 12.3% in patients aged >=90 and <90, respectively (p = 0.95 for both). All major complication rates were similar between groups. Nonagenarians had higher rates of minor vascular complications (13.2% vs 7.7%; p = 0.04). In conclusion, performing balloon-expandable TAVI in carefully selected group of nonagenarians is feasible and offers clinical benefit comparable to patients aged <90 years. Advanced age, in the absence of significant co-morbidities, should not deter clinicians from evaluating patients for TAVI for severe AS. PMID- 26235928 TI - Comparison of Risk of Re-hospitalization, All-Cause Mortality, and Medical Care Resource Utilization in Patients With Heart Failure and Preserved Versus Reduced Ejection Fraction. AB - Because heart failure (HF) with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) are different clinical entities with differing demographic characteristics, common HF outcomes may occur at different rates. Comparative outcome studies have been equivocal, and studies comparing resource utilization are scant. We used an observational cohort design to study 6,513 patients hospitalized for HF who had an EF measured during the hospitalization and were discharged alive within 30 days. We excluded 677 patients with borderline EF values (41% to 49%) and categorized the remaining as HFrEF (EF <=40%, n = 2,205) and HFpEF (EF >50%, n = 3,631). Patients were followed for up to 1 year for all-cause re-hospitalization and mortality and annualized medical resource utilization. Patients with HFrEF and HFpEF experienced similar adjusted incidence rates of re-hospitalization, but those with HFrEF had a 39% increased risk of mortality at 30 days (rate ratio 1.39, 95% confidence interval 1.10 to 1.76) and 25% greater risk at 1 year (rate ratio1.25, 95% confidence interval 1.12 to 1.41). After adjustment for covariates, patients with HFpEF incurred significantly more annualized outpatient visits (21.5 vs 20.1, p = 0.002) and emergency room visits (3.24 vs 2.94, p = 0.002) than those with HFrEF, but absolute differences were small. High inpatient and pharmacy utilization did not differ. Our study suggests that whether a patient has HFrEF or HFpEF has little bearing on risk of re-hospitalization or inpatient resource utilization in the year after an HF hospitalization. Both groups experienced high mortality, but those with HFrEF had greater risk. In conclusion, from the standpoint of resource use, HF can be considered a single entity. PMID- 26235929 TI - Effect of Pericardial Effusion Complicating ST-Elevation Myocardial Infarction as Predictor of Extensive Myocardial Damage and Prognosis. AB - Pericardial effusion (PE) is a common complication following ST-elevation myocardial infarction (STEMI). However, the frequency and prognostic relevance of PE complicating STEMI are unknown. Aim of this study was to investigate the exact incidence, infarct characteristics, and the prognostic impact of moderate-to large PEs detected by cardiac magnetic resonance (CMR) in patients with acute reperfused STEMI. In total, 780 patients with STEMI reperfused by angioplasty (<12 hours after symptom onset) were enrolled in this CMR study at 8 centers. CMR was completed in median 3 days after infarction using a standardized protocol. Central core laboratory-masked analysis for the presence of moderate-to-large PE was performed. The primary clinical end point was the occurrence of major adverse cardiac events (MACE) defined as composite of all-cause death, reinfarction, and new congestive heart failure within 12 months after the index event. A moderate to-large PE was detected in 183 patients (24%). Patients with moderate-to-large PEs had significantly larger infarcts, less myocardial salvage, a larger extent of microvascular obstruction, higher incidence of intramyocardial hemorrhage, and more pronounced left ventricular dysfunction (p <0.001 for all). Significant predictors of a moderate-to-large PE were age, Thrombolysis in Myocardial Infarction flow before percutaneous coronary intervention, and infarct size. MACE rates were significantly higher in the PE group (p = 0.003) and a moderate-to large PE was identified as a significant independent predictor for MACE (hazard ratio 3.12, 95% confidence interval 1.49 to 6.81; p = 0.003) together with Thrombolysis in Myocardial Infarction risk score and left ventricular ejection fraction. In conclusion, a moderate-to-large PE complicating STEMI is a common finding (almost 25%) and related to more severe infarcts with subsequent significantly increased MACE rates during 1-year follow-up. Consequently, a moderate-to-large PE is a marker of poor outcome in patients with STEMI. PMID- 26235930 TI - Management of a delayed post-pancreatoduodenectomy haemorrhage using endovascular techniques. AB - BACKGROUND: A delayed post-pancreatoduodenectomy haemorrhage is associated with a significant increase in peri-operative mortality. Endovascular techniques are frequently used for a delayed haemorrhage. However, limited data exists on the short- and long-term outcomes of this approach. A retrospective review over a 10 year period at a quaternary-referral pancreatic centre was performed. METHODS: Between 2002-2012, 1430 pancreatoduodenectomies were performed, and 32 patients had a delayed haemorrhage (occurring >24 h post-operatively) managed by endovascular techniques. The clinicopathological variables related to a haemorrhage were investigated. RESULTS: A total of 42 endovascular procedures were performed at a median of 25 days, with the majority of delayed haemorrhages occurring after 7 days. There were four deaths (13%) with three occurring in patients with a grade C haemorrhage. Seven patients (22%) experienced rebleeding, and two patients developed hepatic abscesses. CONCLUSION: A delayed haemorrhage post-pancreaticoduodenectomy can be managed by endovascular techniques with acceptable morbidity and mortality. Rebleeding and hepatic abscesses may occur and can be managed non-operatively in most cases. The association of a delayed haemorrhage with a pancreatic fistula makes this a challenging clinical problem. PMID- 26235931 TI - Site-Dependent Reference Point Microindentation Complements Clinical Measures for Improved Fracture Risk Assessment at the Human Femoral Neck. AB - In contrast to traditional approaches to fracture risk assessment using clinical risk factors and bone mineral density (BMD), a new technique, reference point microindentation (RPI), permits direct assessment of bone quality; in vivo tibial RPI measurements appear to discriminate patients with a fragility fracture from controls. However, it is unclear how this relates to the site of the most clinically devastating fracture, the femoral neck, and whether RPI provides information complementary to that from existing assessments. Femoral neck samples were collected at surgery after low-trauma hip fracture (n = 46; 17 male; aged 83 [interquartile range 77-87] years) and compared, using RPI (Biodent Hfc), with 16 cadaveric control samples, free from bone disease (7 male; aged 65 [IQR 61-74] years). A subset of fracture patients returned for dual-energy X-ray absorptiometry (DXA) assessment (Hologic Discovery) and, for the controls, a micro-computed tomography setup (HMX, Nikon) was used to replicate DXA scans. The indentation depth was greater in femoral neck samples from osteoporotic fracture patients than controls (p < 0.001), which persisted with adjustment for age, sex, body mass index (BMI), and height (p < 0.001) but was site-dependent, being less pronounced in the inferomedial region. RPI demonstrated good discrimination between fracture and controls using receiver-operating characteristic (ROC) analyses (area under the curve [AUC] = 0.79 to 0.89), and a model combining RPI to clinical risk factors or BMD performed better than the individual components (AUC = 0.88 to 0.99). In conclusion, RPI at the femoral neck discriminated fracture cases from controls independent of BMD and traditional risk factors but dependent on location. The clinical RPI device may, therefore, supplement risk assessment and requires testing in prospective cohorts and comparison between the clinically accessible tibia and the femoral neck. (c) 2015 American Society for Bone and Mineral Research. PMID- 26235933 TI - Trimethylamine N-Oxide From Gut Microbiota in Chronic Kidney Disease Patients: Focus on Diet. AB - Low-protein diet is the recommended nutritional intervention for nondialysis chronic kidney disease (CKD) patients because excess protein intake can damage kidney function and produce uremic toxins. Some of these toxins are generated from amino acids breakdown by gut microbiota as p-cresyl sulfate and indoxyl sulfate that have been clearly associated with cardiovascular mortality in CKD patients. Another uremic toxin, trimethylamine N-oxide (TMAO), a degradation product of choline and L-carnitine (which come mainly from animal protein such as red meat and eggs) is now considered as a proatherogenic metabolite. In the present review, we will highlight the relationship between TMAO, diet and cardiovascular aspects, and the potential concerns about TMAO in nondialysis CKD patients. PMID- 26235934 TI - Hydrothermal synthesis of organometal halide perovskites for Li-ion batteries. AB - A facile hydrothermal method was developed to prepare CH3NH3PbBr3 and CH3NH3PbI3. The as-prepared products were utilized in lithium batteries as anode materials with good performance. Considering the structural diversity, more hybrid perovskites can be targets for further optimization, indicating their promising potential in Li-ion battery applications. PMID- 26235932 TI - Dietary Intake of Proteins and Calories Is Inversely Associated With The Oxidation State of Plasma Thiols in End-Stage Renal Disease Patients. AB - OBJECTIVES: Oxidative stress contributes to the pathogenesis of protein-energy wasting in maintenance hemodialysis (MHD) patients, but knowledge of specific effectors and mechanisms remains fragmented. Aim of the study was to define whether and how food intake is involved in the causal relationship between oxidative stress and protein-energy wasting. METHODS: Seventy-one adult MHD patients and 24 healthy subjects (control) were studied cross-sectionally with analyses of diet record and of oxidative stress, as measured by a battery of plasma thiols including the protein sulfhydryl (-SH) group (PSH) levels (a marker of total protein-SH reducing capacity), the protein thiolation index (PTI, the ratio between disulfide, i.e., oxidized and reduced -SH groups in proteins), low molecular mass (LMM) thiols, LMM disulfides, and mixed LMM-protein disulfides. In addition, interleukin-6 (IL-6), albumin, C-reactive protein, and neutrophil gelatinase-associated lipocalin (NGAL) were measured as markers of inflammation. RESULTS: The patients showed low energy (22.0 +/- 8.4 kcal/kg/day) and adequate protein (1.0 +/- 0.4 g/kg/day) intakes, high levels of cystine (CySS; patients vs. CONTROL: 113.5 [90.9-132.8] vs. 68.2 [56.2-75.7] MUM), cysteinylated proteins (CySSP; 216.0 [182.8-254.0] vs. 163.5 [150.0-195.5] MUM), and high PTI (0.76 [0.61-0.88] vs. 0.43 [0.40-0.54]; P < .001 in all comparisons). In patients, variation of CySSP was explained by a standard regression model (R = 0.775; P = .00001) that included significant contributions of protein intake (beta = 0.361), NGAL (beta = 0.387), age (beta = 0.295), and albumin (beta = 0.457). In the same model, variation of PTI (R = 0.624; P = .01) was explained by protein intake (beta = -0.384) and age (beta = 0.326) and NGAL (beta = 0.311). However, when PSH was entered as dependent variable (R = 0.730; P = .0001), only serum albumin (beta = 0.495) and age (beta = -0.280), but not dietary intake or NGAL, contributed to the model. CONCLUSIONS: In MHD, markers of thiol oxidation including CySSP and PTI show independent association with dietary intake and NGAL, whereas PSH, a marker of thiol-reducing capacity, did not associate with these same variables. The mechanism(s) responsible for inverse association between oxidative stress and food intake in MHD remain undefined. PMID- 26235936 TI - Motor organization of positive and negative emotional vocalization in the cat midbrain periaqueductal gray. AB - Neurochemical microstimulation in different parts of the midbrain periaqueductal gray (PAG) in the cat generates four different types of vocalization, mews, howls, cries, and hisses. Mews signify positive vocal expression, whereas howls, hisses, and cries signify negative vocal communications. Mews were generated in the lateral column of the intermediate PAG and howls and hisses in the ventrolateral column of the intermediate PAG. Cries were generated in two regions, the lateral column of the rostral PAG and the ventrolateral column of the caudal PAG. To define the specific motor patterns belonging to mews, howls, and cries, the following muscles were recorded during these vocalizations: larynx (cricothyroid, thyroarytenoid, and posterior cricoarytenoid), tongue (genioglossus), jaw (digastric), and respiration (diaphragm, internal intercostal, external abdominal oblique, and internal abdominal oblique) muscles. Furthermore, the frequency, intensity, activation cascades, and turns and amplitude analyses of the electromyograms (EMGs) during these vocalizations were analyzed. The results show that each type of vocalization consists of a specific, circumscribed motor coordination. The nucleus retroambiguus (NRA) in the caudal medulla serves as the final premotor interneuronal output system for vocalization. NRA neurochemical microstimulation also generated vocalizations (guttural sounds). Analysis of the EMGs demonstrated that these vocalizations consist of only small parts of the emotional voalizations generated by neurochemical stimulation in the PAG. These results demonstrate that motor organization of positive and negative emotional vocal expressions are segregated in the PAG and that the PAG uses the NRA as a tool to gain access to the motoneurons generating vocalization. PMID- 26235935 TI - Human leukocyte antigen class II DRB1*1302 allele protects against cervical cancer: At which step of multistage carcinogenesis? AB - We investigated the role of human leukocyte antigen (HLA) class II alleles in multistage cervical carcinogenesis. Cross-sectional analysis for HLA association with cervical cancer included 1253 Japanese women: normal cytology (NL, n = 341), cervical intraepithelial neoplasia grade 1 (CIN1, n = 505), CIN grade 2 or 3 (CIN2/3, n = 96), or invasive cervical cancer (ICC, n = 311). The HLA class II allele frequencies were compared by Fisher's exact test or the chi(2) -test. The Bonferroni adjustment corrected for multiple comparisons. Among the study subjects, 454 women with low-grade squamous intraepithelial lesion cytology were prospectively monitored by cytology and colposcopy every 3-4 months to analyze cumulative risk of CIN3 within the next 10 years in relation to HLA class II alleles. HLA class II DRB1*1302 allele frequency was similar between women with NL (11.7%) and CIN1 (11.9%), but significantly decreased to 5.2% for CIN2/3 and 5.8% for ICC (P = 0.0003). Correction for multiple testing did not change this finding. In women with low-grade squamous intraepithelial lesion cytology, the cumulative risk of CIN3 diagnosed within 10 years was significantly reduced among DRB1*1302-positive women (3.2% vs. 23.7%, P = 0.03). In conclusion, the two different types of analysis in this single study showed the protective effect of the DRB1*1302 allele against progression from CIN1 to CIN2/3. PMID- 26235937 TI - In Vitro Activity of Tea Tree Oil Vaginal Suppositories against Candida spp. and Probiotic Vaginal Microbiota. AB - The aim of this work is to evaluate the in vitro microbicidal activity of vaginal suppositories (VS) containing tea tree oil (TTO-VS) towards Candida spp. and vaginal probiotics. A total of 20 Candida spp. strains, taken from patients with vaginitis and from an established type collection, including reference strains, were analysed by using the CLSI microdilution method. To study the action of VS towards the beneficial vaginal microbiota, the sensitivity of Bifidobacterium animalis subsp. lactis (DSM 10140) and Lactobacillus spp. (Lactobacillus casei R 215 and Lactobacillus acidophilus R-52) was tested. Both TTO-VS and TTO showed fungicidal activity against all strains of Candida spp. whereas placebo-VS or the Aloe gel used as controls were ineffective. The study of fractional fungicidal concentrations (FFC) showed synergistic interaction with the association between Amphotericin B and TTO (0.25 to 0.08 ug/ml, respectively) against Candida albicans. Instead, the probiotics were only affected by TTO concentration >= 4% v/v, while, at concentrations < 2% v/v, they remained viable. TTO-VS exhibits, in vitro, a selective fungicidal action, slightly affecting only the Bifidobacteriun animalis strain growth belonging to the vaginal microbiota. In vivo studies are needed to confirm the efficacy to prevent acute or recurrent vaginal candidiasis. PMID- 26235938 TI - Interaction potentials from arbitrary multi-particle trajectory data. AB - Understanding the complex physics of particle-based systems at the nanoscale and mesoscale increasingly relies on simulation methods, empowered by exponential advances in computing speed. A major impediment to progress lies in reliably obtaining the interaction potential functions that control system behavior - which are key inputs for any simulation approach - and which are often difficult or impossible to obtain directly using traditional experimental methods. Here, we present a straightforward methodology for generating pair potential functions from large multi-particle trajectory datasets, with no operational constraints regarding their state of equilibration, degree of damping or presence of hydrodynamic interactions. Using simulated datasets, we demonstrate that the method is highly robust against trajectory perturbations from Brownian motion and common errors introduced by particle tracking algorithms. Given the recent rapid pace of advancement in high-speed and three-dimensional microscopy and associated particle tracking algorithms, we anticipate a near future experimental regime where easily collected high-dimensional trajectory sets can be rapidly converted to the detailed interaction and hydrodynamic force fields required to replicate the system's physics in simulation. PMID- 26235939 TI - Glutathione metabolism links FOXRED1 to NADH:ubiquinone oxidoreductase (complex I) deficiency: A hypothesis. AB - FOXRED1 mutations result in complex I (NADH:ubiquinone oxidoreductase) deficiencies and Leigh syndrome (subacute necrotizing encephalomyelopathy). FOXRED1 is a mitochondrial flavoprotein related to N-methyl amino acid dehydrogenases. How is FOXRED1 required for the biogenesis of complex I? I present a hypothesis that suggests FOXRED1 catalytic activity as a sarcosine oxidase protects the developing fetus from oxidative stress during pregnancy. Loss of FOXRED1, coupled with protein, choline and/or folate-deficient diets results in the depletion of glutathione, the dysregulation of nitric oxide metabolism and the peroxynitrite-mediated inactivation of complex I. PMID- 26235940 TI - Consequences of chromsome18q deletions. AB - Providing clinically relevant prognoses and treatment information for people with a chromsome18q deletion is particularly challenging because every unrelated person has a unique region of hemizygosity. The hemizygous region can involve almost any region of 18q including between 1 and 101 genes (30 Mb of DNA). Most individuals have terminal deletions, but in our cohort of over 350 individuals 23% have interstitial deletions. Because of this heterogeneity, we take a gene by gene approach to understanding the clinical consequences. There are 196 genes on 18q. We classified 133 of them as dosage insensitive, 15 (8%) as dosage sensitive leading to haploinsufficiency while another 10 (5%) have effects that are conditionally haploinsufficient and are dependent on another factor, genetic or environmental in order to cause an abnormal phenotype. Thirty-seven genes (19%) have insufficient information to classify their dosage effect. Phenotypes attributed to single genes include: congenital heart disease, minor bone morphology changes, central nervous system dysmyelination, expressive speech delay, vesicouretreral reflux, polyposis, Pitt-Hopkins syndrome, intellectual disability, executive function impairment, male infertility, aural atresia, and high frequency sensorineural hearing loss. Additionally, identified critical regions for other phenotypes include: adolescent idiopathic scoliosis and pectus excavatum, Virchow-Robin perivascular spaces, small corpus callosum, strabismus, atopic disorders, mood disorder, IgA deficiency, nystagmus, congenital heart disease, kidney malformation, vertical talus, CNS dysmyelination growth hormone deficiency and cleft palate. Together these findings make it increasingly feasible to compile an individualized syndrome description based on each person's individuated genotype. Future work will focus on understanding molecular mechanisms leading to treatment. PMID- 26235941 TI - Enhanced Ca(2+) response and stimulation of prostaglandin release by the bradykinin B2 receptor in human retinal pigment epithelial cells primed with proinflammatory cytokines. AB - Kallikrein, kininogen and kinin receptors are present in human ocular tissues including the retinal pigment epithelium (RPE), suggesting a possible role of bradykinin (BK) in physiological and/or pathological conditions. To test this hypothesis, kinin receptors expression and function was investigated for the first time in human fetal RPE cells, a model close to native RPE, in both control conditions and after treatment with proinflammatory cytokines. Results showed that BK evoked intracellular Ca(2+) transients in human RPE cells by activating the kinin B2 receptor. Pretreatment of the cells with TNF-alpha and/or IL-1beta enhanced Ca(2+) response in a time- and concentration-dependent additive manner, whereas the potency of BK and that of the selective B2 receptor antagonist, fasitibant chloride, both in the nanomolar range, remained unaffected. Cytokines have no significant effect on cell number and viability and on the activity of other GPCRs such as the kinin B1, acetylcholine, ATP and thrombin receptors. Immunoblot analysis and immunofluorescence studies revealed that cytokines treatment was associated with an increase in both kinin B2 receptor and COX-2 expression and with the secretion of prostaglandin E1 and E2 into the extracellular medium. BK, through activation of the kinin B2 receptor, potentiated the COX-2 mediated prostaglandin release in cytokines-primed RPE cells while new protein synthesis and prostaglandin production contribute to the potentiating effect of cytokines on BK-induced Ca(2+) response. In conclusion, overall data revealed a cross-talk between the kinin B2 receptor and cytokines in human RPE in promoting inflammation, a key feature in retinal pathologies including diabetic retinopathy and macular edema. PMID- 26235942 TI - Pharmacological Activities and Hydrolysis by Peptidases of [Phospho-Ser(6)] Bradykinin (pS(6)-BK). AB - Phosphorylated kininogen and some of its fragments containing serine phosphorylated bradykinin ([pS(6)]-Bk) were identified in human serum and plasma by a phosphoproteomic approach. We report the kininogenase ability of human tissue and plasma kallikreins and tryptase to generate [pS(6)]-Bk or Lys-[pS(6)] Bk having as substrate the synthetic human kininogen fluorescent fragment Abz MISLMKRPPGF[pS(386)]PFRSSRI-NH2. The pharmacological assays of [pS(6)]-Bk showed it as a full B2 bradykinin receptor agonist in smooth muscle, it produces a portal liver hypertensive response in rat and mouse paw edema that lasts longer than Bk. The rat hypotensive response to infusions of Bk is greater than that of [pS(6)]Bk, both if injected through femoral vein or aorta. [pS(6)]-Bk was more resistant than Bk to kininase digestion performed with angiotensin converting enzyme, neprilysin, thimet oligopeptidase, aminopeptidase P and carboxypeptidase M. (1)H-NMR experiments indicated that [pS(6)]-Bk has lower flexibility, with the pS(6)-P(7) bond restricted to the trans conformation, and can explain [pS(6)]-Bk resistance to hydrolysis. In conclusion, [pS(6)]-Bk presenting lower activity than Bk, with longer lasting effects and being slowly released by kininogenases from synthetic Abz-MISLMKRPPGF[pS(386)]PFRSSRI-NH2, suggests that phosphorylation of the kininogens can be an efficient kallikrein-kinin system regulator. PMID- 26235944 TI - Detection of entanglement in asymmetric quantum networks and multipartite quantum steering. AB - The future of quantum communication relies on quantum networks composed by observers sharing multipartite quantum states. The certification of multipartite entanglement will be crucial to the usefulness of these networks. In many real situations it is natural to assume that some observers are more trusted than others in the sense that they have more knowledge of their measurement apparatuses. Here we propose a general method to certify all kinds of multipartite entanglement in this asymmetric scenario and experimentally demonstrate it in an optical experiment. Our results, which can be seen as a definition of genuine multipartite quantum steering, give a method to detect entanglement in a scenario in between the standard entanglement and fully device independent scenarios, and provide a basis for semi-device-independent cryptographic applications in quantum networks. PMID- 26235943 TI - Volleyball and Basketball Enhanced Bone Mass in Prepubescent Boys. AB - The aim of this study was to examine the effect of volleyball and basketball practice on bone acquisition and to determine which of these 2 high-impact sports is more osteogenic in prepubertal period. We investigated 170 boys (aged 10-12 yr, Tanner stage I): 50 volleyball players (VB), 50 basketball players (BB), and 70 controls. Bone mineral content (BMC, g) and bone area (BA, cm(2)) were measured by dual-energy X-ray absorptiometry at different sites. We found that, both VB and BB have a higher BMC at whole body and most weight-bearing and nonweight-bearing sites than controls, except the BMC in head which was lower in VB and BB than controls. Moreover, only VB exhibited greater BMC in right and left ultra-distal radius than controls. No significant differences were observed between the 3 groups in lumbar spine, femoral neck, and left third D radius BMC. Athletes also exhibited a higher BA in whole body, limbs, lumbar spine, and femoral region than controls. In addition, they have a similar BA in head and left third D radius with controls. The VB exhibited a greater BA in most radius region than controls and a greater femoral neck BA than BB. A significant positive correlation was reported between total lean mass and both BMC and BA in whole body, lumbar spine, total hip, and right whole radius among VB and BB. In summary, we suggest that volleyball and basketball have an osteogenic effect BMC and BA in loaded sites in prepubescent boys. The increased bone mass induced by both volleyball and basketball training in the stressed sites was associated to a decreased skull BMC. Moreover, volleyball practice produces a more sensitive mechanical stress in loaded bones than basketball. This effect seems translated by femoral neck expansion. PMID- 26235946 TI - Antimicrobial activity of doubly-stapled alanine/lysine-based peptides. AB - In this study, we examined the potential of Verdine's double-stapling system for the de novo design of amphipathic helical antimicrobial peptides. We designed, synthesized, and tested a prototypical doubly-stapled helix of an alanine/lysine based model sequence, which showed reasonable antimicrobial activities and highly increased proteolytic stability. We then show that its hemolytic activity as well as antimicrobial activities can be further manipulated through the systematic modifications. Overall, the preliminary results obtained from this study imply that the doubly-stapled helices of short peptides can serve as a highly promising scaffold for the rational design of potent, selective, and metabolically stable antimicrobial peptides that can combat against the growing problems of antibiotic resistance. PMID- 26235945 TI - Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing bicyclic aminobenzazepines for anaplastic lymphoma kinase (ALK) inhibitor. AB - A series of novel 2,4-diaminopyrimidine compounds bearing bicyclic aminobenzazepine were synthesized and evaluated for their anti-ALK activities. The activities of these compounds were confirmed in both enzyme- and cell-based ALK assays. Amongst compounds synthesized, KRCA-0445 showed very promising results in pharmacokinetic study and in vivo efficacy study with H3122 xenograft mouse model. PMID- 26235947 TI - Design, synthesis, and in vivo activity of novel inhibitors of delta-5 desaturase for the treatment of metabolic syndrome. AB - The synthesis, SAR, and in vivo activity of inhibitors of delta-5 desaturase are described. Ring-constraint of the initial series provided access to a variety of in vitro active chemotypes, from which the indazole was selected. Examples from the indazole series displayed in vivo activity in reducing the enzymatic activity of liver delta-5 desaturase. PMID- 26235948 TI - Discovery of highly potent, lung-localized epithelial sodium channel inhibitors. AB - The design, synthesis and biological evaluation of novel dimeric pyrazinoylguanidines for the treatment of cystic fibrosis (CF) are reported herein. When administered directly to the lung in a guinea pig tracheal potential difference (TPD) model, the dimeric compounds were found to have superior potency, longer duration of action in the lung, and significantly reduced extra pulmonary exposure in comparison to the corresponding monomeric ENaC blockers, which have been evaluated in the clinic but shown to have dose-limiting kidney toxicity. PMID- 26235949 TI - Interfacial inhibitors. AB - Targeting macromolecular interface is a general mechanism by which natural products inactivate macromolecular complexes by stabilizing normally transient intermediates. Demonstrating interfacial inhibition mechanism ultimately relies on the resolution of drug-macromolecule structures. This review focuses on medicinal drugs that trap protein-DNA complexes by binding at protein-DNA interfaces. It provides proof-of-concept and detailed structural and mechanistic examples for topoisomerase inhibitors and HIV integrase inhibitors. Additional examples of recent interfacial inhibitors for protein-DNA interfaces are provided, as well as prospects for targeting previously 'undruggable' targets including transcription, replication and chromatin remodeling complexes. References and discussion are included for interfacial inhibitors of protein protein interfaces. PMID- 26235950 TI - Identification of orally-bioavailable antagonists of the TRPV4 ion-channel. AB - Antagonists of the TRPV4 receptor were identified using a focused screen, followed by a limited optimization program. The leading compounds obtained from this exercise, RN-1665 23 and RN-9893 26, showed moderate oral bioavailability when dosed to rats. The lead molecule, RN-9893 26, inhibited human, rat and murine variants of TRPV4, and showed excellent selectivity over related TRP receptors, such as TRPV1, TRPV3 and TRPM8. The overall profile for RN-9893 may permit its use as a proof-of-concept probe for in vivo applications. PMID- 26235951 TI - Synthesis and biological evaluation of novel 3,9-substituted beta-carboline derivatives as anticancer agents. AB - In our previous studies on 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole (YC-1) analogs, we synthesised numerous substituted carbazole and alpha-carboline derivatives, which exhibited anticancer activity. In this study, we designed and synthesised a series of 3,9-substituted beta-carbolines, by replacing the tricyclic rings of carbazole and alpha-carboline derivatives with isosteric beta carboline, and evaluated anticancer activity. We observed that 9-(2 methoxybenzyl)-beta-carboline-3-carboxylic acid (11a) inhibited the growth of HL 60 cells by inducing apoptosis, with a half maximal inhibitory concentration of 4.0 MUM. Our findings indicate that beta-carboline derivatives can be used as lead compounds for developing novel antitumor agents. PMID- 26235952 TI - Efficient synthesis of the intermediate of abacavir and carbovir using a novel (+)-gamma-lactamase as a catalyst. AB - The enantiomers of 2-azabicyclo[2.2.1]hept-5-en-3-one (gamma-lactam) are key chiral synthons in the synthesis of antiviral drugs such as carbovir and abacavir. (+)-gamma-Lactamase can be used as a catalyst in the enzymatic preparation of optically pure (-)-gamma-lactam. Here, a (+)-gamma-lactamase discovered from Bradyrhizobium japonicum USDA 6 by sequence-structure guided genome mining was cloned, purified and characterized. The enzyme possesses a significant catalytic activity towards gamma-lactam. The active site of the (+) gamma-lactamase was studied by homologous modeling and molecular docking, and the accuracy of the prediction was confirmed by site-specific mutagenesis. The (+) gamma-lactamase reveals the great practical potential as an enzymatic method for the efficient production of carbocyclic nucleosides of pharmaceutical interest. PMID- 26235953 TI - Synthesis and inhibitory activity of substrate-analog fructosyl peptide oxidase inhibitors. AB - Fructosyl peptide oxidases (FPOXs) play a crucial role in the diagnosis of diabetes. Their main function is to cleave fructosyl amino acids or fructosyl peptides into glucosone and the corresponding amino acids/dipeptides. In this study, the substrate-analog FPOX inhibitors 1a-c were successfully designed and synthesized. These inhibitors mimic N(alpha)-fructosyl-L-valine (Fru-Val), [N(alpha)-fructosyl-L-valyl]-L-histidine (Fru-ValHis), and N(epsilon)-fructosyl-L lysine (epsilonFru-Lys), respectively. The secondary nitrogen atom in the natural substrates, linking fructose and amino acid or dipeptide moieties, was substituted in 1a-c with a sulfur atom to avoid enzymatic cleavage. Kinetic studies revealed that 1a-c act as competitive inhibitors against an FPOX obtained from Coniochaeta sp., and Ki values of 11.1, 66.8, and 782 MUM were obtained for 1a-c, respectively. PMID- 26235954 TI - Development of an experimental model of maternal allergic asthma during pregnancy. AB - Maternal asthma during pregnancy adversely affects pregnancy outcomes but identification of the cause/s, and the ability to evaluate interventions, is limited by the lack of an appropriate animal model. We therefore aimed to characterise maternal lung and cardiovascular responses and fetal-placental growth and lung surfactant levels in a sheep model of allergic asthma. Immune and airway functions were studied in singleton-bearing ewes, either sensitised before pregnancy to house dust mite (HDM, allergic, n = 7) or non-allergic (control, n = 5), and subjected to repeated airway challenges with HDM (allergic group) or saline (control group) throughout gestation. Maternal lung, fetal and placental phenotypes were characterised at 140 +/- 1 days gestational age (term, ~147 days). The eosinophil influx into lungs was greater after HDM challenge in allergic ewes than after saline challenge in control ewes before mating and in late gestation. Airway resistance increased throughout pregnancy in allergic but not control ewes, consistent with increased airway smooth muscle in allergic ewes. Maternal allergic asthma decreased relative fetal weight (-12%) and altered placental phenotype to a more mature form. Expression of surfactant protein B mRNA was 48% lower in fetuses from allergic ewes than controls, with a similar trend for surfactant protein D. Thus, allergic asthma in pregnant sheep modifies placental phenotype, and inhibits fetal growth and lung development consistent with observations from human pregnancies. Preconceptional allergen sensitisation and repeated airway challenges in pregnant sheep therefore provides an animal model to identify mechanisms of altered fetal development and adverse pregnancy outcomes caused by maternal asthma in pregnancy. PMID- 26235955 TI - Neuropeptide S receptor gene variation modulates anterior cingulate cortex Glx levels during CCK-4 induced panic. AB - An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S (NPS) system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans. Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene (NPSR1) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment. CCK-4 injection was followed by a strong panic response. A significant time*genotype interaction was detected (p=.008), with significantly lower ACC Glx/Cr levels in T allele carriers as compared to AA homozygotes 5min after injection (p=.003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned. The present pilot data suggests NPSR1 gene variation to modulate Glx levels in the ACC during acute states of stress and anxiety, with blunted, i.e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers. Our results underline the notion of a genetically driven rapid and dynamic response mechanism in the neural regulation of human anxiety and further strengthen the emerging role of the NPS system in anxiety. PMID- 26235957 TI - Striatal NOS1 has dimorphic expression and activity under stress and nicotine sensitization. AB - Nicotine exerts its addictive influence through the meso-cortico-limbic reward system, where the striatum is essential. Nicotine addiction involves different neurotransmitters, nitric oxide (NO) being especially important, since it triggers the release of the others by positive feedback. In the nervous system, NO is mainly produced by nitric oxide synthase 1 (NOS1). However, other subtypes of synthases can also synthesize NO, and little is known about the specific role of each isoform in the process of addiction. In parallel, NOS activity and nicotine addiction are also affected by stress and sexual dimorphism. To determine the specific role of this enzyme, we analyzed both NOS expression and NO synthesis in the striatum of wild-type and NOS1-knocked out (KO) mice of both sexes in situations of nicotine sensitization and stress. Our results demonstrated differences between the caudate-putamen (CP) and nucleus accumbens (NA). With respect to NOS1 expression, the CP is a dimorphic region (27.5% lower cell density in males), but with a stable production of NO, exclusively due to this isoform. Thus, the nitrergic system of CP may not be involved in stress or nicotine addiction. Conversely, the NA is much more variable and strongly involved in both situations: its NO synthesis displays dimorphic variations at both basal (68.5% reduction in females) and stress levels (65.9% reduction in males), which disappear when nicotine is infused. Thus, the KO animals showed an increase in NO production (21.7%) in the NA, probably by NOS3, in an attempt to compensate the lack of NOS1. PMID- 26235956 TI - Glutamatergic synapse protein composition of wild-type mice is sensitive to in utero MTHFR genotype and the timing of neonatal vigabatrin exposure. AB - The enzyme methylenetetrahydrofolate-reductase (MTHFR) is part of the homocysteine and folate metabolic pathways. In utero, Mthfr-deficient environment has been reported as a risk factor for neurodevelopmental disorders such as autism and neural tube defects. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between Mthfr deficiency and neonatal exposure to the GABA-potentiating drug vigabatrin (GVG) in mice alters anxiety, memory, and social behavior in a gender-dependent manner. In addition, a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the cerebral cortex was shown. Here we show that in utero MTHFR deficiency is sufficient to alter the levels of glutamate receptor subunits GluR1, GluR2, and NR2B in the cerebral cortex and hippocampus of adult offspring with a WT genotype. In addition, FMRP1, CAMKII alpha and gamma, and NLG1 levels in WT offspring were vulnerable to the in utero genotype. These effects depend on brain region and the cellular compartment tested. The effect of in utero MTHFR deficiency varies with the age of neonatal GVG exposure to modify GluR1, NR2A, reelin, CAMKII alpha, and NLG1 levels. These changes in molecular composition of the glutamatergic synapse were associated with increased anxiety-like behavior. Complex, multifactorial disorders of the nervous system show significant association with several genetic and environmental factors. Our data exemplify the contribution of an in utero MTHFR-deficient environment and early exposure to an antiepileptic drug to the basal composition of the glutamatergic synapses. The robust effect is expected to alter synapse function and plasticity and the cortico-hippocampal circuitry. PMID- 26235958 TI - Kidneys do not like excess body fat. PMID- 26235959 TI - Association of age and BMI with kidney function and mortality: a cohort study. AB - BACKGROUND: Compared with normal weight, obesity might be associated with worse clinical outcomes, including chronic kidney disease. Whether this association is modified by age is not known. We investigated the association of BMI with progressive loss of kidney function and all-cause mortality in US veterans. METHODS: In a national cohort of 3,376,187 US veterans with an estimated glomerular filtration rate (eGFR) of more than 60 mL/min per 1.73 m(2), we assessed the association of BMI in patients of different ages (<40 years, 40 years to <50 years, 50 years to <60 years, 60 years to <70 years, 70 years to <80 years, and >=80 years) with loss of kidney function and with all-cause mortality in logistic regression models and Cox proportional hazards models adjusted for ethnic origin, sex, comorbidities, medications, and baseline eGFR. FINDINGS: 274,764 (8.1%) of 3,376,187 veterans had a rapid decline in kidney function (decrease in slope of >5 mL/min per 1.73 m(2)). The lowest risk for loss of kidney function was noted in patients with BMI of at least 25 kg/m(2) but less than 30 kg/m(2). A generally consistent U-shaped association was noted between BMI and rapid loss of kidney function that was more prominent with increasing age, except in the patients younger than 40 years, in whom BMI did not seem to be predictive of renal function impairment. 672,341 veterans died (28.7 per 1000 patient-years, 95% CI 28.6-28.7) over a median follow-up of 6.8 years (IQR 6.5 7.7). BMI also showed a U-shaped association with mortality, which was similar in all age groups. INTERPRETATION: A BMI of 30 kg/m(2) or more is associated with rapid loss of kidney function in patients with eGFR of at least 60 mL/min per 1.73 m(2), and this association is accentuated in older patients. A BMI of 35 kg/m(2) or more is also associated with high mortality. A BMI of at least 25 kg/m(2) but less than 30 kg/m(2) is associated with the best clinical outcomes. FUNDING: National Institute of Health, Memphis VA Medical Center, Long Beach VA Healthcare System, Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development, and VA Information Resource Center. PMID- 26235960 TI - Computer-assisted surgical planning and intraoperative guidance in fetal surgery: a systematic review. AB - Fetal surgery has become a clinical reality, with interventions for twin-to-twin transfusion syndrome (TTTS) and spina bifida demonstrated to improve outcome. Fetal imaging is evolving, with the use of 3D ultrasound and fetal MRI becoming more common in clinical practise. Medical imaging analysis is also changing, with technology being developed to assist surgeons by creating 3D virtual models that improve understanding of complex anatomy, and prove powerful tools in surgical planning and intraoperative guidance. We introduce the concept of computer assisted surgical planning, and present the results of a systematic review of image reconstruction for fetal surgical planning that identified six articles using such technology. Indications from other specialities suggest a benefit of surgical planning and guidance to improve outcomes. There is therefore an urgent need to develop fetal-specific technology in order to improve fetal surgical outcome. PMID- 26235961 TI - The prevention of Cronobacter infections in hospital neonatal intensive care units. PMID- 26235962 TI - Superconductivity Series in Transition Metal Dichalcogenides by Ionic Gating. AB - Functionalities of two-dimensional (2D) crystals based on semiconducting transition metal dichalcogenides (TMDs) have now stemmed from simple field effect transistors (FETs) to a variety of electronic and opto-valleytronic devices, and even to superconductivity. Among them, superconductivity is the least studied property in TMDs due to methodological difficulty accessing it in different TMD species. Here, we report the systematic study of superconductivity in MoSe2, MoTe2 and WS2 by ionic gating in different regimes. Electrostatic gating using ionic liquid was able to induce superconductivity in MoSe2 but not in MoTe2 because of inefficient electron accumulation limited by electronic band alignment. Alternative gating using KClO4/polyethylene glycol enabled a crossover from surface doping to bulk doping, which induced superconductivities in MoTe2 and WS2 electrochemically. These new varieties greatly enriched the TMD superconductor families and unveiled critical methodology to expand the capability of ionic gating to other materials. PMID- 26235963 TI - Small-scale drivers: the importance of nutrient availability and snowmelt timing on performance of the alpine shrub Salix herbacea. AB - Alpine plant communities are predicted to face range shifts and possibly extinctions with climate change. Fine-scale environmental variation such as nutrient availability or snowmelt timing may contribute to the ability of plant species to persist locally; however, variation in nutrient availability in alpine landscapes is largely unmeasured. On three mountains around Davos, Switzerland, we deployed Plant Root Simulator probes around 58 Salix herbacea plants along an elevational and microhabitat gradient to measure nutrient availability during the first 5 weeks of the summer growing season, and used in situ temperature loggers and observational data to determine date of spring snowmelt. We also visited the plants weekly to assess performance, as measured by stem number, fruiting, and herbivory damage. We found a wide snowmelt gradient which determined growing season length, as well as variations of an order of magnitude or more in the accumulation of 12 nutrients between different microhabitats. Higher nutrient availability had negative effects on most shrub performance metrics, for instance decreasing stem number and the proportion of stems producing fruits. High nutrient availability was associated with increased herbivory damage in early melting microhabitats, but among late-emerging plants this pattern was reversed. We demonstrate that nutrient availability is highly variable in alpine settings, and that it strongly influences performance in an alpine dwarf shrub, sometimes modifying the response of shrubs to snowmelt timing. As the climate warms and human-induced nitrogen deposition continues in the Alps, these factors may contribute to patterns of local plants persistence. PMID- 26235964 TI - Mechanisms driving diversity-productivity relationships differ between exotic and native communities and are affected by gastropod herbivory. AB - Biodiversity experiments have shown that productivity usually increases with plant species richness. However, most of those studies disregarded the importance of trophic interactions to the diversity-productivity relationship, and focused on the loss of native species while ignoring invasions by exotic species. Yet, as functional complementarity and the impact of plant antagonists are likely to differ between native and exotic communities, the diversity-productivity relationship may change when native communities are invaded by exotic species. We conducted a mesocosm experiment to test how diversity effects, evenness, and productivity differed between exotic and native assemblages of grassland plants, and how these communities were influenced by slug herbivory. In line with other experiments, we found higher productivity in exotic than in native communities. However, different mechanisms (complementarity vs. selection effect) contributed to the positive diversity-productivity relationships in exotic vs. native communities. Against expectations, native communities showed much lower evenness and a greater selection effect, suggesting that competitive dominance among native species may be even stronger than among exotic species. Slug herbivory decreased productivity independently of species origin and species diversity. However, exotic communities showed a threefold higher complementarity effect than native communities in the absence of slugs, which was mainly driven by differences in the responses of native and exotic legumes and nonleguminous herbs. Our results imply that underlying mechanisms for the positive diversity productivity relationship differ between native and exotic communities in the early stages of community development, and that differential responses of plant functional groups to generalist herbivory can contribute to this pattern. PMID- 26235965 TI - Fast gap-free enumeration of conformations and sequences for protein design. AB - Despite significant successes in structure-based computational protein design in recent years, protein design algorithms must be improved to increase the biological accuracy of new designs. Protein design algorithms search through an exponential number of protein conformations, protein ensembles, and amino acid sequences in an attempt to find globally optimal structures with a desired biological function. To improve the biological accuracy of protein designs, it is necessary to increase both the amount of protein flexibility allowed during the search and the overall size of the design, while guaranteeing that the lowest energy structures and sequences are found. DEE/A*-based algorithms are the most prevalent provable algorithms in the field of protein design and can provably enumerate a gap-free list of low-energy protein conformations, which is necessary for ensemble-based algorithms that predict protein binding. We present two classes of algorithmic improvements to the A* algorithm that greatly increase the efficiency of A*. First, we analyze the effect of ordering the expansion of mutable residue positions within the A* tree and present a dynamic residue ordering that reduces the number of A* nodes that must be visited during the search. Second, we propose new methods to improve the conformational bounds used to estimate the energies of partial conformations during the A* search. The residue ordering techniques and improved bounds can be combined for additional increases in A* efficiency. Our enhancements enable all A*-based methods to more fully search protein conformation space, which will ultimately improve the accuracy of complex biomedically relevant designs. PMID- 26235966 TI - Early Diagnosis of Migraine Necessary in Children: 10-Year Follow-Up. AB - BACKGROUND: The prevalence of migraine in individuals younger than 20 years old is 8%, with a mean age at onset of younger than 8 years. However, the long-term prognosis of migraine attacks has not been clearly established. OBJECTIVE: Our main objective was to evaluate disease course 10 years after migraine diagnosis in a cohort of children and adolescents. METHODS: Migraine was diagnosed in 1999 in a pediatric headache reference center using International Headache Society criteria. In 2009, all patients were interviewed by telephone on the persistence and characteristics of any headaches. The main end point was prevalence of persistent migraine attacks in 2009. Variables associated with persistent attacks were analyzed. RESULTS: Overall, 142 children were diagnosed with migraine in 1999. Of these, 84 were interviewed by telephone in 2009. In 1999, the mean age was 11.6 +/- 3.1 years, 54% were male, and 50% had migraine without aura. Migraine attacks were common (1-3 attacks/week in 38%). Mean age at onset was 7 years and 4 months (+/-3 years). In 2009, migraine prevalence was 39/84 (46% [95% confidence interval 36-56]), 12 patients (14%) were headache-free, and 62 patients (74%) had tension-type headaches that were isolated headaches in 33 (39%) patients. The rate of patients with at least one migraine attack per week fell from 37% to 8% (P = 0.001) over the 10-year period. Age at the first visit to the center was significantly higher in 2009 migraine sufferers than nonsufferers (12.5 +/- 3.0 versus 10.9 +/- 3.1 years (P = 0.02)). In multivariate analysis, age >=12 years at the time of first presentation was the only significant factor associated with long-term chronic migraine (odds ratio = 3.0 [1.1-8.0]). CONCLUSIONS: Ten years after first presentation, 46% of patients had migraine but the frequency of attacks had diminished. The only factor associated with chronic migraine was age >=12 years at first presentation. PMID- 26235967 TI - Prevalence of masked uncontrolled hypertension according to the number of office blood pressure measurements. AB - INTRODUCTION AND OBJECTIVES: The reported prevalence of masked uncontrolled hypertension (MUCH) varies because many studies are not comparable as they use different measurement methodologies. To evaluate the influence of the number of office blood pressure readings on the prevalence of MUCH we conducted a cross sectional, multicenter study in treated hypertensive patients. PATIENTS AND METHODS: We carried out an observational, cross-sectional, multicenter study in 33 Spanish hospital-based hypertension units, involving 35 investigators and 12 Autonomous Communities. Six blood pressure readings and a 24-h ambulatory blood pressure monitoring were performed in treated hypertensive patients. The means of the first 3 readings (P123), the 2nd, 3rd and 4th readings (P234), the 3rd, 4th and 5th readings (P345) and the last 3 readings (P456) were compared with mean 24 h blood pressure. MUCH was defined as office blood pressure <140/90mmHg and 24-h blood pressure >=130/80mmHg, considering the first 3 readings (MUCH123), the 2nd, 3rd and 4th readings (MUCH234), the 3rd, 4th and 5th readings (MUCH345) and the last 3 readings (MUCH456). RESULTS: We included 498 hypertensive patients. Mean (standard deviation) office blood pressure measurements were: (P123) 141(18)/82(11); (P234) 139(17)/81(11); (P345) 138(17)/81(11) and (P456) 137(16)/80(10) mmHg. Mean 24-h blood pressure was 127(13.8)/75(9.5) mmHg. The correlation coefficients between ambulatory and office systolic/diastolic blood pressure were (P123):0.48/0.50; (P234):0.50/0.52; (P345):0.50/0.54; and (P456):0.50/0.55 (p<0.001, all). The prevalences of MUCH123, MUCH234, MUCH345 and MUCH456 were 14.5%, 18.9%, 19.5% and 21.1%, respectively. CONCLUSIONS: The prevalence of MUCH diagnosis depends on the serial office blood pressure readings, being much higher for the last three blood pressure readings. Discarding the first and second office blood pressure measures seems to be the most accurate method for diagnosing MUCH. PMID- 26235968 TI - Combination of vitamin E and clomiphene citrate in treating patients with idiopathic oligoasthenozoospermia: A prospective, randomized trial. AB - The most common cause of male infertility is idiopathic oligoasthenozoospermia. Empirical medical treatment for idiopathic male infertility is still a controversial issue. The aim of this study was to evaluate any possible effects of combining vitamin E as antioxidant and clomiphene citrate as antiestrogen on spermatozoa concentration and motility in comparison to give either of medications alone in patients with idiopathic oligoasthenozoospermia. This is a comparative prospective randomized study. Ninety patients with idiopathic oligoasthenozoospermia were randomized into equally three groups: Group A: received vitamin E (400 mg/day) for 6 months. Group B: received clomiphene citrate (25 mg daily) for 6 months. Group C: received combination of both drugs in the same doses for 6 months. All patients were subjected to the following: history taking, general and genital examination, semen analysis, serum FSH, total testosterone, and scrotal duplex. Semen examination was performed according to the guidelines of (WHO, 2010), at the start of treatment and was repeated after 3 months and after 6 months of treatment. Regarding vitamin E group, there was insignificant increase in mean sperm concentration after 6 months of treatment in comparison to baseline. On the other hand, there was a significant improvement of mean sperm concentration in the other two groups after 6 months of treatment, with more significance in combination therapy group (p = 0.001). The mean total sperm motility has improved in all patients groups, in comparison to baseline, with more significance in combination therapy group. In vitamin E group, it was 28.07 +/- 9.65% (p = 0.000). For those in clomiphene citrate group, was 33.33 +/- 14.10% (p = 0.003) and 40.50 +/- 17.54% (p = 0.000) in combination therapy group. Combining antioxidant and anti-estrogen therapy is a valid option for the treatment of a selected group of men with unexplained isolated oligoasthenozoospermia. PMID- 26235969 TI - Neuregulin-1 protects against acute optic nerve injury in rat model. AB - OBJECTIVES: In this study, we employed a rat model and examined the expression pattern of neuregulin-1 (NRG-1) in optic nerve and retinal ganglion cells (RGCs) in response to optic nerve injury to understand the role of NRG-1 in conferring protection against acute optic nerve injury. METHOD: Forty-eight male rats were randomly divided into two groups, the sham-operation group (n=24) and optic nerve injury group (n=24). Flash visual evoked potentials (FVEP) and fundography images were acquired at different time points following optic nerve injury (2h, 1d, 2d, 7d, 14d and 28d). Semi-quantitative analysis of NGR-1 expression pattern was performed by immunohistochemistry (IHC) staining. In a related experiment, 100 male rats were randomly divided into NGR-1 treatment group (n=60) (treated with increasing dose of NGR-1 at 0.5MUg, 1MUg and 3MUg), normal saline (NS) group (n=20) and negative control group (n=20). Optic nerve injury was induced in all the animals and in situ cell death was measured by detecting the apoptosis rates using TUNEL assay. RESULTS: Fundus photography results revealed no detectable differences between the sham-operation group and optic nerve injury group at 2h, 1d, 2d and 7d. However at 2weeks, the optic discs turned pale in all animals in the optic nerve injury group. NRG-1 expression increased significantly at all time points in the optic nerve injury group (P<0.05), compared to the sham operation group, with NRG-1 expression peaking at 14d and gradually declining by 28d. Statistically significant differences in amplitude and latency of P100 wave were also detected between the optic nerve injury and sham-operation group (P<0.05). In related experiment, compared to NS group, treatment with 1MUg and 3MUg of recombinant human NRG-1 resulted in statistically significant FVEP-P100 amplitude values (all P<0.05). Further, compared to the NS group, ganglion cell apoptosis was dramatically reduced in the NRG-1 group at all time points and the reduction was statistically significant in 3MUg NRG-1 treatment group at 7d, 14d and 28d (all P<0.05). CONCLUSION: Our results strongly suggest that NRG-1 is highly effective in preserving normal optic nerve function and is essential for tissue repair following optic nerve injury. Thus, NRG-1 expression confers protection against acute optic nerve injury in a dose-dependent manner. PMID- 26235970 TI - Nonlinear dynamics in the perceptual grouping of connected surfaces. AB - Evidence obtained using the dynamic grouping method has shown that the grouping of an object's connected surfaces has properties characteristic of a nonlinear dynamical system. When a surface's luminance changes, one of its boundaries is perceived moving across the surface. The direction of this dynamic grouping (DG) motion indicates which of two flanking surfaces has been grouped with the changing surface. A quantitative measure of overall grouping strength (affinity) for adjacent surfaces is provided by the frequency of DG motion perception in directions promoted by the grouping variables. It was found that: (1) variables affecting surface grouping for three-surface objects evolve over time, settling at stable levels within a single fixation, (2) how often DG motion is perceived when a surface's luminance is perturbed (changed) depends on the pre-perturbation affinity state of the surface grouping, (3) grouping variables promoting the same surface grouping combine cooperatively and nonlinearly (super-additively) in determining the surface grouping's affinity, (4) different DG motion directions during different trials indicate that surface grouping can be bistable, which implies that inhibitory interactions have stabilized one of two alternative surface groupings, and (5) when alternative surface groupings have identical affinity, stochastic fluctuations can break the symmetry and inhibitory interactions can then stabilize one of the surface groupings, providing affinity levels are not too high (which results in bidirectional DG motion). A surface grouping network is proposed within which boundaries vary in salience. Low salience or suppressed boundaries instantiate surface grouping, and DG motion results from changes in boundary salience. PMID- 26235971 TI - Substituted Phthalic Anhydrides from Biobased Furanics: A New Approach to Renewable Aromatics. AB - A novel route for the production of renewable aromatic chemicals, particularly substituted phthalic acid anhydrides, is presented. The classical two-step approach to furanics-derived aromatics via Diels-Alder (DA) aromatization has been modified into a three-step procedure to address the general issue of the reversible nature of the intermediate DA addition step. The new sequence involves DA addition, followed by a mild hydrogenation step to obtain a stable oxanorbornane intermediate in high yield and purity. Subsequent one-pot, liquid phase dehydration and dehydrogenation of the hydrogenated adduct using a physical mixture of acidic zeolites or resins in combination with metal on a carbon support then allows aromatization with yields as high as 84 % of total aromatics under relatively mild conditions. The mechanism of the final aromatization reaction step unexpectedly involves a lactone as primary intermediate. PMID- 26235972 TI - Pathogenicity of Bovine Neonatal Pancytopenia-associated vaccine-induced alloantibodies correlates with Major Histocompatibility Complex class I expression. AB - Bovine Neonatal Pancytopenia (BNP), a fatal bleeding syndrome of neonatal calves, is caused by maternal alloantibodies absorbed from colostrum and is characterized by lymphocytopenia, thrombocytopenia and bone marrow hypoplasia. An inactivated viral vaccine is the likely source of alloantigens inducing BNP-associated alloantibodies in the dam. In this study the specificity of BNP alloantibodies was assessed and was linked to the pathology of BNP. We demonstrated that Major Histocompatibility Complex class I (MHC I) and Very Late Antigen-3, an integrin alpha3/beta1 heterodimer, were the major targets of BNP alloantibodies. However, alloantibody binding to various bovine cell types correlated with MHC I expression, rather than integrin beta1 or alpha3 expression. Likewise, alloantibody-dependent complement-mediated cell lysis correlated strongly with MHC I expression. Examination of several tissues of third trimester bovine foetuses revealed that cells, shown to be affected in calves with BNP, were characterized by high MHC class I expression and high levels of alloantibody binding. We conclude that in spite of the heterogeneous specificity of BNP associated maternal alloantibodies, MHC I-specific antibodies mediate the pathogenicity of BNP in the calf and that cells with high MHC I expression were preferentially affected in BNP. PMID- 26235973 TI - Respiratory and autonomic dysfunction in children with autism spectrum disorders. AB - INTRODUCTION: Cardiac parasympathetic hypofunction has been reported in autism spectrum disorders (ASD). This usually is linked to respiratory dysrhythmia which has been documented in some children with ASD. OBJECTIVES: This study evaluated the cardiorespiratory functions in ASD to elucidate the physiologic basis of behaviors. METHODS: Nineteen children with ASD and 18 age matched controls underwent autonomic function monitoring at a defined resting state using the NeuroScope. The non-invasive real time beat-to-beat blood pressure was measured by Portapres and fed into the NeuroScope where heart rate, cardiac vagal tone and cardiac sensitivity to baroreceptor were derived from the EKG and blood pressure waveforms using the Vagosoft software; and respiratory rate and rhythm were measured simultaneously by plethysmograph. Respiration was analyzed breath by breath using our prior published methods. RESULTS: Various respiratory dysrhythmias, particularly Biot's and Cheyne-Stokes respiration, were detected in children with ASD, who also exhibited greater variability in respiratory rhythm and amplitudes than controls. The respiratory dysrhythmia in children with ASD was associated with a lower cardiac vagal activity. CONCLUSION: The Biot's breathing and Cheyne-Stokes respiration coupled with cardiac vagal hypofunction in ASD suggest a brainstem dysfunction consistent with our previous findings. The low parasympathetic activity could explain in part the chronic sensory hyperarousal state in children with ASD. PMID- 26235975 TI - Invasive assessment of coronary microvascular dysfunction in hypertrophic cardiomyopathy: the index of microvascular resistance. AB - We present a review of microvascular dysfunction in hypertrophic cardiomyopathy (HCM) and an interesting case of a symptomatic familial HCM patient with inducible ischemia by single photon emission computed tomography. Coronary angiography revealed normal epicardial arteries. Pressure wire measurements of fractional flow reserve (FFR), coronary flow reserve (CFR) and index of microvascular resistance (IMR) demonstrated a significant microcirculatory dysfunction. This is the first such case that documents this abnormality invasively using the IMR. The measurement of IMR, a novel marker of microcirculatory dysfunction, provides novel insights into the pathophysiology of this condition. PMID- 26235974 TI - Protease recognition sites in Bet v 1a are cryptic, explaining its slow processing relevant to its allergenicity. AB - Despite a high similarity with homologous protein families, only few proteins trigger an allergic immune response with characteristic TH2 polarization. This puzzling observation is illustrated by the major birch pollen allergen Bet v 1a and its hypoallergenic protein isoforms, e.g., Bet v 1d. Given the key role of proteolytic processing in antigen presentation and T cell polarization, we investigated the recognition of Bet v 1 isoforms by the relevant protease cathepsin S. We found that at moderately acidic pH values Bet v 1a bound to cathepsin S with significantly lower affinity and was more slowly cleaved than its hypoallergenic isoform Bet v 1d. Only at pH values <= 4.5 the known proteolytic cleavage sites in Bet v 1a became accessible, resulting in a strong increase in affinity towards cathepsin S. Antigen processing and class II MHC loading occurs at moderately acidic compartments where processing of Bet v 1a and Bet v 1d differs distinctly. This difference translates into low and high density class II MHC loading and subsequently in TH2 and TH1 polarization, respectively. PMID- 26235977 TI - The impact of precise robotic lesion length measurement on stent length selection: ramifications for stent savings. AB - BACKGROUND/PURPOSE: Coronary stent deployment outcomes can be negatively impacted by inaccurate lesion measurement and inappropriate stent length selection (SLS). We compared visual estimate of these parameters to those provided by the CorPath 200(r) Robotic PCI System. METHODS: Sixty consecutive patients who underwent coronary stent placement utilizing the CorPath System were evaluated. The treating physician assessed orthogonal images and provided visual estimates of lesion length and SLS. The robotic system was then used for the same measures. SLS was considered to be accurate when visual estimate and robotic measures were in agreement. Visual estimate SLSs were considered to be "short" or "long" if they were below or above the robotic-selected stents, respectively. RESULTS: Only 35% (21/60) of visually estimated lesions resulted in accurate SLS, whereas 33% (20/60) and 32% (19/60) of the visually estimated SLSs were long and short, respectively. In 5 cases (8.3%), 1 less stent was placed based on the robotic lesion measurement being shorter than the visual estimate. CONCLUSIONS: Visual estimate assessment of lesion length and SLS is highly variable with 65% of the cases being inaccurately measured when compared to objective measures obtained from the robotic system. The 32% of the cases where lesions were visually estimated to be short represents cases that often require the use of extra stents after the full lesion is not covered by 1 stent [longitudinal geographic miss (LGM)]. Further, these data showed that the use of the robotic system prevented the use of extra stents in 8.3% of the cases. Measurement of lesions with robotic PCI may reduce measurement errors, need for extra stents, and LGM. PMID- 26235976 TI - Operator radiation exposure during right or left transradial coronary angiography: A phantom study. AB - BACKGROUND: Previous studies showed a possible lower radiation dose absorbed by operators comparing LRA and RRA for percutaneous coronary procedures. The reasons of this lower radiation dose are not well known. The aim of this study was to evaluate the radiation dose absorbed by operators comparing left with right radial access (LRA and RRA respectively) during a simulated diagnostic coronary angiography using a phantom. METHODS: A coronary angiography examination was simulated on a phantom by 5 operators using eight projections with 5 seconds fluoroscopy each. Each operator was equipped with 4 electronic dosimeters placed at thorax, at left wrist, at left head and at hip level. Radiation doses were expressed in picosievert and normalized by dose area product. RESULTS: LRA compared to RRA was associated with a significant lower operator dose at wrist (36pSv/cGYcm(2) [IQR 18-59pSv/cGYcm(2)] and 48pSv/cGYcm(2) [IQR 22 148pSv/cGYcm(2)] respectively, p=0.01) and thorax (3pSv/cGYcm(2) [IQR 2 5pSv/cGYcm(2)] and 10pSv/cGYcm(2) [6-23pSv/cGYcm(2)] respectively, p<0.001) but with a significant higher radiation dose at hip level (102pSv/cGYcm(2) [IQR 44 199pSv/cGYcm(2)] and 67pSv/cGYcm(2) [IQR 39-132pSv/cGYcm(2)] respectively, p=0.02). Conversely the radiation dose at left side of the head did not show significant differences between the two approaches. CONCLUSIONS: In this phantom study simulating a diagnostic coronarography the use of LRA compared to RRA was associated with a significant lower radiation dose at wrist and thorax but with an increased dose at hip level. SUMMARY: To evaluate the radiation dose absorbed by operators comparing left with right radial access (LRA and RRA respectively) we simulated a diagnostic coronary angiography using a dedicated phantom. Operators were equipped with dedicated electronic dosimeters at wrist, hip, head and thorax level. LRA compared to RRA was associated with a significant lower operator dose at wrist and thorax but with a significant higher radiation dose at hip level whereas the radiation dose at left side of the head did not show significant differences between the two approaches. PMID- 26235978 TI - Eosinophilia and Fever with Levetiracetam: A Case Report. AB - Levetiracetam is considered by many clinicians to be one of the most benign antiepileptic medications available. We report the case of a 24-year-old man presenting with seizures for which he was started on levetiracetam. Despite an extensive work-up and treatment of possible infectious and noninfectious issues, the patient remained intermittently febrile. When a marked peripheral eosinophilia was noted, the patient's levetiracetam was discontinued and phenytoin prescribed. The fever resolved within 24 hours, and the patient's eosinophilia count returned to normal limits following discharge back to his long term care facility. We estimate the probability of this reaction related to levetiracetam as probable based on a score of 7 on the Naranjo scale. Clinicians should be aware of the possibility that levetiracetam may be an offending agent in a patient with unexplained fever and eosinophilia. These may be early signs of the progression to a more serious drug hypersensitivity reaction, such as drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome. PMID- 26235980 TI - The paracrine effect of mesenchymal human stem cells restored hearing in beta tubulin induced autoimmune sensorineural hearing loss. AB - The aim of this study was to examine the activities of hASCs (Human Adipose tissue Derived Stem Cells) on experimental autoimmune hearing loss (EAHL) and how human stem cells regenerated mouse cochlea cells. We have restored hearing in 19 years old white female with autoimmune hearing loss with autologous adipose tissue derived stem cells and we wish to understand the mechanism of restoration of hearing in animal model. BALB/c mice underwent to develop EAHL; mice with EAHL were given hASCs intraperitoneally once a week for 6 consecutive weeks. ABR were examined over time. The helper type 1 autoreactive responses and T-reg cells were examined. H&E staining or immunostaining with APC conjugated anti-HLA-ABC antibody were conducted. The organ of Corti, stria vascularis, spira ligament and spiral ganglion in stem cell group are normal. In control group, without receiving stem cells, the organ of Corti is replaced by a single layer of cells, atrophy of stria vascularis. Systemic infusion of hASCs significantly improved hearing function and protected hair cells in established EAHL. The hASCs decreased the proliferation of antigen specific Th1/Th17 cells and induced the production of anti-inflammatory cytokine interleukin10 in splenocytes. They also induced the generation of antigen specific CD4(+)CD25(+)Foxp3(+)T-reg cells. The experiment showed the restoration is due to the paracrine activities of human stem cells, since there are newly regenerated mice spiral ganglion cells, not human mesenchymal stem cells derived tissue given by intraperitoneally. PMID- 26235979 TI - Age-regulated function of autophagy in the mouse inner ear. AB - Autophagy is a highly conserved catabolic process essential for embryonic development and adult homeostasis. The autophagic machinery supplies energy by recycling intracellular components and facilitates the removal of apoptotic cells. In the inner ear, autophagy has been reported to play roles during early development in the chicken embryo and in the response to otic injury in the adult mouse. However, there are no studies on the expression of the autophagy machinery in the postnatal and adult inner ear. Insulin-like growth factor 1 (IGF-1) is one of the factors that regulate both otic development and cochlear postnatal maturation and function. Here, we hypothesised that autophagy could be one of the processes involved in the cochlear development and functional maturation. We report that autophagy-related genes (ATG) Becn1, Atg4g and Atg5 are expressed in the mouse cochlea, vestibular system and brainstem cochlear nuclei from late developmental stages to adulthood. Atg9 was studied in the mouse cochlea and showed a similar pattern. The presence of autophagic flux was confirmed by decreased sequestosome 1 (SQSTM1/p62) and increased relative levels of microtubule-associated protein light chain 3-II (LC3-II). Inner ear autophagy flux is developmentally regulated and is lower at perinatal stages than in the adult mouse, where an expression plateau is reached at the age of two-months, coinciding with the age at which full functional activity is reached. Expression is maintained in adult mice and declines after the age of twelve months. LC3B labelling showed that autophagy was primarily associated with spiral ganglion neurons. Over time, Igf1 wild type mice showed lower expression of genes coding for IGF-1 high affinity receptor and the family factor IGF-2 than null mice. Parallel analysis of autophagy machinery gene expression showed no significant differences between the genotypes over the lifespan of the null mice. Taken together, these results show that the autophagy machinery expression in the inner ear is regulated with age but is not compromised by the chronic absence of IGF-1. Our data also strongly support that the up-regulation of autophagy machinery genes is concomitant with the functional maturation of the inner ear. PMID- 26235981 TI - Effect of pH and temperature on antioxidant responses of the thick shell mussel Mytilus coruscus. AB - This study evaluated the combined effects of seawater pH decrease and temperature increase on the activity of antioxidant enzymes in the thick shell mussel Mytilus coruscus, an ecological and economic bivalve species widely distributed along the East China Sea. Mussels were exposed to three pH levels (8.1, 7.7 and 7.3) and two temperatures (25 degrees C and 30 degrees C) for 14 days. Activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione (GSH), acid phosphatase (ACP), alkaline phosphatase (AKP) and glutamic-pyruvic transaminase (GPT) were measured in gills and digestive glands after 1, 3, 7 and 14 days of exposure. All enzymatic activities were significantly impacted by pH, temperature. Enzymatic activities at the high temperature were significantly higher than those at the low temperature, and the mussels exposed to pH 7.3 showed significantly higher activities than those under higher pH condition for all enzymes except ACP. There was no interaction between temperature and pH in two third of the measured activities suggesting similar mode of action for both drivers. Interaction was only consistently significant for GPX. PCA revealed positive relationships between the measured biochemical indicators in both gills and digestive glands. Overall, our results suggest that decreased pH and increased temperature induce a similar anti-oxidative response in the thick shell mussel. PMID- 26235982 TI - Characterization of interleukin-1beta as a proinflammatory cytokine in grass carp (Ctenopharyngodon idella). AB - Interleukin-1beta (IL-1beta) is a well-characterized cytokine that plays key roles in cellular responses to infection, inflammation, and immunological challenges in mammals. In this study, we identified and analyzed a grass carp (Ctenopharyngodon idella) ortholog of IL-1beta (gcIL-1beta), examined its expression patterns in various tissues in both healthy and lipopolysaccharide (LPS)-stimulated specimens, and evaluated its proinflammatory activities. The gcIL-1beta gene consists of seven exons and six introns. The full-length cDNA sequence contains an open reading frame of 813 nucleotides. The deduced amino acid sequence exhibits a characteristic IL-1 signature but lacks the typical IL 1beta converting enzyme cleavage site that is conserved in mammals. In the phylogenetic tree, IL-1betas from grass carp and other members of the Cyprinidae family clustered into a single group. Expression pattern analysis revealed that gcIL-1beta is constitutively expressed in all 11 tissues examined, and LPS stimulation leads to significant up-regulation in muscle, liver, intestine, skin, trunk kidney, head kidney, and gill. Recombinant grass carp IL-1beta (rgcIL 1beta) was generated prokaryotically as a fusion protein of Trx-rgcIL-1beta. An anti-rgcIL-1beta polyclonal antibody (rgcIL-1beta pAb) was raised in mice against the purified Trx-rgcIL-1beta. Western blot analysis confirmed that rgcIL-1beta pAb reacted specifically with gcIL-1beta in C. idella kidney (CIK) cells. Quantitative real-time PCR data indicated that intestinal mRNA expression levels of endogenous IL-1beta, IL-1R2, and TNF-alpha were significantly up-regulated following Trx-rgcIL-1beta exposure. The inhibitory activities of rgcIL-1beta pAb against the inflammatory response were confirmed in a model of Aeromonas hydrophila-induced intestinal inflammation. Our immunohistochemical study revealed that the degree and intensity of inflammatory cell infiltration are fully consistent with the observed mRNA expression patterns of these key inflammatory genes. Taken together, these data suggest that gcIL-1beta plays a critical role in the proinflammatory response in the grass carp intestine. PMID- 26235983 TI - Novel application of brain-targeting polyphenol compounds in sleep deprivation induced cognitive dysfunction. AB - Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), comprised of grape seed polyphenol extract, Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment. We found that BDPP significantly improves sleep deprivation-induced contextual memory deficits, possibly through the activation of CREB and mTOR signaling pathways. We also identified brain-available polyphenol metabolites from BDPP, among which quercetin-3-O-glucuronide activates CREB signaling and malvidin-3-O-glucoside activates mTOR signaling. In combination, quercetin and malvidin-glucoside significantly attenuated sleep deprivation-induced cognitive impairment in -a mouse model of acute sleep deprivation. Our data suggests the feasibility of using select brain-targeting polyphenol compounds derived from BDPP as potential therapeutic agents in promoting resilience against sleep deprivation-induced cognitive dysfunction. PMID- 26235984 TI - Correcting for Sample Contamination in Genotype Calling of DNA Sequence Data. AB - DNA sample contamination is a frequent problem in DNA sequencing studies and can result in genotyping errors and reduced power for association testing. We recently described methods to identify within-species DNA sample contamination based on sequencing read data, showed that our methods can reliably detect and estimate contamination levels as low as 1%, and suggested strategies to identify and remove contaminated samples from sequencing studies. Here we propose methods to model contamination during genotype calling as an alternative to removal of contaminated samples from further analyses. We compare our contamination-adjusted calls to calls that ignore contamination and to calls based on uncontaminated data. We demonstrate that, for moderate contamination levels (5%-20%), contamination-adjusted calls eliminate 48%-77% of the genotyping errors. For lower levels of contamination, our contamination correction methods produce genotypes nearly as accurate as those based on uncontaminated data. Our contamination correction methods are useful generally, but are particularly helpful for sample contamination levels from 2% to 20%. PMID- 26235986 TI - Incorporating Functional Information in Tests of Excess De Novo Mutational Load. AB - A number of recent studies have investigated the role of de novo mutations in various neurodevelopmental and neuropsychiatric disorders. These studies attempt to implicate causal genes by looking for an excess load of de novo mutations within those genes. Current statistical methods for assessing this excess are based on the implicit assumption that all qualifying mutations in a gene contribute equally to disease. However, it is well established that different mutations can have radically different effects on the ultimate protein product and, as a result, on disease risk. Here, we propose a method, fitDNM, that incorporates functional information in a test of excess de novo mutational load. Specifically, we derive score statistics from a retrospective likelihood that incorporates the probability of a mutation being damaging to gene function. We show that, under the null, the resulting test statistic is distributed as a weighted sum of Poisson random variables and we implement a saddlepoint approximation of this distribution to obtain accurate p values. Using simulation, we have shown that our method outperforms current methods in terms of statistical power while maintaining validity. We have applied this approach to four de novo mutation datasets of neurodevelopmental and neuropsychiatric disorders: autism spectrum disorder, epileptic encephalopathy, schizophrenia, and severe intellectual disability. Our approach also implicates genes that have been implicated by existing methods. Furthermore, our approach provides strong statistical evidence supporting two potentially causal genes: SUV420H1 in autism spectrum disorder and TRIO in a combined analysis of the four neurodevelopmental and neuropsychiatric disorders investigated here. PMID- 26235985 TI - Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling. AB - Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations. PMID- 26235988 TI - FGF23 Regulates Bone Mineralization in a 1,25(OH)2 D3 and Klotho-Independent Manner. AB - Fibroblast growth factor-23 (Fgf23) is a bone-derived hormone, suppressing phosphate reabsorption and vitamin D hormone (1,25(OH)2 D3 ) production in the kidney. It has long been an enigma why lack of Fgf23 or of Klotho, the coreceptor for Fgf23, leads to severe impairment in bone mineralization despite the presence of hypercalcemia and hyperphosphatemia. Using Fgf23(-/-) or Klotho(-/-) mice together with compound mutant mice lacking both Fgf23 or Klotho and a functioning vitamin D receptor, we show that in Klotho(-/-) mice the mineralization defect is solely driven by 1,25(OH)2 D3 -induced upregulation of the mineralization inhibiting molecules osteopontin and pyrophosphate in bone. In Fgf23(-/-) mice, the mineralization defect has two components, a 1,25(OH)2 D3 -driven component similar to Klotho(-/-) mice and a component driven by lack of Fgf23, causing additional accumulation of osteopontin. We found that FGF23 regulates osteopontin secretion indirectly by suppressing alkaline phosphatase transcription and phosphate production in osteoblastic cells, acting through FGF receptor-3 in a Klotho-independent manner. Hence, FGF23 secreted from osteocytes may form an autocrine/paracrine feedback loop for the local fine-tuning of bone mineralization. PMID- 26235989 TI - Perception of available space during chimpanzee introductions: Number of accessible areas is more important than enclosure size. AB - Restricting animals to different areas of their enclosure, for both brief and extended durations, is a key element of animal management practices. With such restrictions, available space decreases and the choices the animals can make are more limited, particularly in relation to social dynamics. When unfamiliar individuals are introduced to each other, group dynamics can be unpredictable and understanding space usage is important to facilitate successful introductions. We studied the behavioral, welfare-related responses of two groups of zoo-housed chimpanzees (n = 22) as they were introduced to each other and experienced a variety of enclosure restrictions and group composition changes. Our analysis of available space while controlling for chimpanzee density, found that arousal related scratching and yawning decreased as the number of enclosure areas (separate rooms) available increased, whereas only yawning decreased as the amount of available space (m(2)) increased. Allogrooming, rubbing, and regurgitation/reingestion rates remained constant as both the number of enclosure areas and amount of space changed. Enclosure space is important to zoo-housed chimpanzees, but during introductions, a decrease in arousal-related scratching indicates that the number of accessible areas is more important than the total amount of space available, suggesting that it is important to provide modular enclosures that provide choice and flexible usage, to minimize the welfare impact of short- and long-term husbandry needs. PMID- 26235987 TI - Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development. AB - Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life. Identification of single-gene mutations that cause CAKUT permits the first insights into related disease mechanisms. However, for most cases the underlying defect remains elusive. We identified a kindred with an autosomal-dominant form of CAKUT with predominant ureteropelvic junction obstruction. By whole exome sequencing, we identified a heterozygous truncating mutation (c.1010delG) of T Box transcription factor 18 (TBX18) in seven affected members of the large kindred. A screen of additional families with CAKUT identified three families harboring two heterozygous TBX18 mutations (c.1570C>T and c.487A>G). TBX18 is essential for developmental specification of the ureteric mesenchyme and ureteric smooth muscle cells. We found that all three TBX18 altered proteins still dimerized with the wild-type protein but had prolonged protein half life and exhibited reduced transcriptional repression activity compared to wild-type TBX18. The p.Lys163Glu substitution altered an amino acid residue critical for TBX18-DNA interaction, resulting in impaired TBX18-DNA binding. These data indicate that dominant-negative TBX18 mutations cause human CAKUT by interference with TBX18 transcriptional repression, thus implicating ureter smooth muscle cell development in the pathogenesis of human CAKUT. PMID- 26235990 TI - Accurate Reporting of Door-to-Balloon Times. PMID- 26235991 TI - Robot-assisted Hybrid Coronary Revascularisation: Systematic Review. AB - BACKGROUND: Hybrid coronary revascularisation (HCR) for multi-vessel coronary artery disease combines surgical bypass grafting for the left anterior descending (LAD) coronary artery and percutaneous coronary intervention (PCI) for non-LAD coronary arteries. The present systematic review was conducted to assess the available evidence on robotic-assisted HCR and explore the potential advantages and disadvantages it proposes. METHODS: A comprehensive search from six electronic databases was performed for studies reporting outcomes for robotic assisted hybrid coronary revascularisation. Eight studies were identified from six electronic databases amenable for qualitative assessment and pooled quantitative analysis. RESULTS: There were no in-hospital deaths reported. Pooled myocardial infarction rates was 1.2% (range 0-3.7%), pooled strokes was 0.8% (range: 0-1.7%), freedom from reintervention was 92.5% (range 70.4-100%), and freedom from angina was 92.9% (range 74.3-100%). LITA patency ranged from 89 100%, while hospital stay ranged from 4-8.1 days. CONCLUSIONS: The current data suggests potentially acceptable mortality and complication rates, when patients are carefully selected and operated on by expert cardiovascular teams. However, due to the heterogeneous nature of the evidence and lack of long-term outcomes, this promising technique warrants future comparative and randomised studies before becoming a part of mainstay coronary interventions. PMID- 26235992 TI - Prevention of Sternal Wound Infections by use of a Surgical Incision Management System: First Reported Australian Case Series. AB - BACKGROUND: Sternal wound infections are considered a costly and potentially devastating consequence of the median sternotomy in cardiothoracic surgery. Surgical incision management employs the technique of applying a closed, negative pressure vacuum dressing to a closed wound. Several studies have demonstrated a reduction in sternal wound infections using this system. METHODS: A retrospective audit of cases receiving surgical incision management demonstrated a statistically significant reduction in sternal wound infections against a predicted rate. RESULTS: Of the 62 patients identified, only one was complicated by a sternal wound infection with the greatest reduction seen in the high-risk infection group. CONCLUSIONS: Although smaller in size, the results compared well to trials conducted in larger European and US centres. Although not advocating surgical incision management for routine use, it should be considered on patients considered high-risk for sternal wound infection, such as diabetics, the elderly and the obese. PMID- 26235993 TI - What is the Yield of Testing for Coronary Artery Disease after an Emergency Department Attendance with Chest Pain? AB - BACKGROUND: Guidelines recommend testing for coronary artery disease (CAD) for emergency department (ED) patients with a negative workup for acute coronary syndrome (ACS). The rationale is that, although myocardial infarction has been ruled out, the presentation could still indicate cardiac ischaemia. Evidence supporting this recommendation is weak. METHODS: Planned sub-study of prospective cohort study of ED chest pain patients with a negative ACS workup who were discharged. Primary outcome of interest was occurrence of major adverse cardiac events (MACE) within 30 days. Secondary outcomes were rate of combined MACE or revascularisation and rates and outcome of referral for CAD testing. Analyses were descriptive. RESULTS: 742 patients were included; median age 56, 52% male. There were two MACE within 30 days (0.3%; 95% CI 0.07-1%). Two patients had revascularisation without ACS - combined MACE or revascularisation rate 0.5% (95% CI 0.2-1.4%). Seventy-five per cent of patients with adverse events had previously known CAD. There was no statistically significant difference in outcome between those referred for testing and those who were not. Age, TIMI score 0-1 and absence of known CAD performed well as potential discriminators for selective testing. CONCLUSIONS: In our study the rate of MACE within 30 days was very low, coronary intervention was rare and most patients with MACE or revascularisation had previously known CAD. For young patients, those without known CAD and those with a low TIMI score, the risk of clinically significant CAD appears to be very low. It adds to the case for abandoning routine testing for CAD. PMID- 26235994 TI - Designing Molecular Printboards: A Photolithographic Platform for Recodable Surfaces. AB - A light induced strategy for the design of beta-cyclodextrin (CD) based supramolecular devices is introduced, presenting a novel tool to fabricate multifunctional biointerfaces. Precision photolithography of a modified beta-CD was established on a light sensitive tetrazole surface immobilized on a bioinspired polydopamine (PDA) anchor layer via various shadow masks, as well as via direct laser writing (DLW), in order to craft any desired printboard design. Interfacial molecular recognition provided by light generated cavitate domains was demonstrated via spatially resolved encoding, erasing, and recoding of distinct supramolecular guest patterns. Thus, the light directed shaping of receptor monolayers introduces a powerful path to control supramolecular assemblies on various surfaces. PMID- 26235995 TI - The clinical relevance of sexual dysfunction in systemic sclerosis. AB - Systemic sclerosis is a chronic multi-organ autoimmune disease, leading to important clinical and psychological implications. Among organ complications, sexual dysfunction is a major issue for both male and female gender, with high prevalence and great impact on quality of life, although frequently not addressed by both clinicians and patients. While erectile dysfunction is the most common cause of sexual problems in males, genital tract and general physical changes are major contributors to sexual impairment in females. This review presents current state of the art on this topic, discussing published data on presentation, evaluation and therapeutic options. PMID- 26235996 TI - Brazilian group of flow cytometry (GBCFLUX) panels for acute leukemia: Some insights. PMID- 26235997 TI - Editorial Comment. PMID- 26235999 TI - Editorial Comment. PMID- 26236000 TI - Study of the Recovery Patterns of Elderly Subacute Stroke Patients in an Interdisciplinary Neurorehabilitation Unit. AB - BACKGROUND: This study seeks to establish the facts of the improvement over time in elderly poststroke patients. METHODS: A retrospective study was performed with regard to 106 subacute stroke patients aged older than 65 years, who were treated in an interdisciplinary neurorehabilitation unit. Three assessment points were established (on admission, 6 months post-onset, and 12 months post-onset), with the scores relative to 10 assessment scales having been collected at each point. RESULTS: By means of a principal component analysis, a first component was obtained, which is taken to represent a combined index of the 10 scales and to express the overall health status of the patient. An analysis of variance of this first component enabled a clear improvement trend to be identified, with this being more marked during the first 6-month period (72.7%) than the second 6-month period (27.3%). CONCLUSIONS: The elderly stroke patients underwent an interdisciplinary rehabilitation program lasting 1 year, experimented an initial period of rapid recovery during the first 6 months followed by a less marked period of improvement. However, no stabilization period in the patients' progress was found. PMID- 26236001 TI - Cognitive Decline in Patients with Leukoaraiosis Within 5 Years after Initial Stroke. AB - BACKGROUND: Leukoaraiosis (LA) is closely associated with cognitive deficits. The association between LA and cognitive disorders, such as mild cognitive impairment (MCI) and dementia, after initial stroke has not been systematically studied. In this study, we sought to identify whether LA contributes to the occurrence of certain type of cognitive disorders after initial stroke. METHODS: Data from our Stroke Registry were examined, and 5-year follow-up data for LA and cognitive disorders were analyzed. We performed Kaplan-Meier analysis and log-rank test to assess the predictive value of LA for risk of cognitive decline and the Cox proportional hazards model to test the risk factors studied as independent determinants of cognitive impairment. RESULTS: The frequency of patients with normal cognitive function decreased significantly at 5 years compared with initial stroke (78% vs 70%; odds ratio, 1.51; 95% confidence interval, 1.41 1.62). Of 8784 patients, 1659 (19%) had dementia and 964 (11%) had MCI at the final analysis. After 5 years of follow-up, survival analysis showed that all patients with LA had an increased probability of MCI compared with those without LA (P < .0001). Patients with LA had an increased chance of dementia compared with those without LA (P < .0001) at the end of follow-up. Cognitive decline probability was significantly higher in patients with severe LA compared with those with mild/moderate LA (P < .0001). Cox regression analyses showed that recurrence of stroke (hazard ratio [HR], 3.92 [95% CI, 3.26-4.72]), hypertension (HR, 1.11 [95% CI, 1.0-1.22]), LA (HR, 1.15 [95% CI, 1.05-1.25]), age (HR, 1.05 [95% CI, 1.04-1.06]), hypercholesterolemia (HR, .86 [95% CI, .77-.95]), higher LDL cholesterol (HR, 1.21 [95% CI, 1.11-1.32]), lower HDL cholesterol (HR, .90 [95% CI, .83-.98]), coronary heart disease (HR, .85 [95% CI, .77-.94]), and National Institutes of Health Stroke Scale score at admission (HR, .77 [95% CI, .72-.82]) were also significantly associated with cognitive impairments. CONCLUSIONS: Our findings suggest that patients with LA may be at risk of developing new cognitive impairments at long-term period after initial stroke. The evaluation of the concomitant risk factors, besides providing insights about the possible mechanisms behind the cognitive dysfunction present in LA, may be of help for the prevention of cognitive impairments. PMID- 26236002 TI - Elevated Troponin Levels in Acute Stroke Patients Predict Long-term Mortality. AB - BACKGROUND: Elevated plasma levels of troponin in acute stroke patients are common and have in several studies been shown to predict in-hospital and short term mortality. Little is, however, known about the long-term prognosis of these patients. The aim of this study was to determine patient characteristics and 5 year mortality in patients with acute stroke and troponin elevation on admission. METHODS: A retrospective cohort study of all consecutive patients with acute stroke and a plasma troponin I (TnI) analyzed on admission to Danderyd Hospital between January 1, 2005, and January 1, 2006 (n = 247). Patient characteristics were obtained from the Swedish National Stroke Register, Riksstroke, as well as hospital records. Mortality data were obtained from the Swedish Cause of Death Register. RESULTS: There were 133 patients (54%) with TnI less than .03 MUg/L (normal), 74 patients (30%) with TnI .03-.11 MUg/L (low elevation), and 40 patients (16%) with TnI greater than .11 MUg/L (high elevation). TnI elevations were associated with a higher age, prior ischemic stroke, chronic heart failure, renal insufficiency, stroke severity, and ST segment elevation or depression on admission. The rate of hyperlipidemia decreased with increasing TnI. Adjusted for age and comorbidity, elevated TnI values on admission had a significantly and sustained increased mortality over the 5-year follow-up, with a hazard ratio of 1.90 (95% confidence interval, 1.33-2.70). CONCLUSIONS: Troponin elevation in patients with acute stroke, even when adjusted for several possible confounders, is associated with an almost 2-fold increased risk of 5-year mortality. PMID- 26236003 TI - The Impact of Diagnosing Branch Atheromatous Disease for Predicting Prognosis. AB - BACKGROUND: We had reported that, in the acute phase of the brain penetrating artery infarction, patients with branch atheromatous disease (BAD) tended to be worsened compared with the lacunar infarction (LI). Because no prospective study has been reported, we composed a multicenter study (Japan Branch Atheromatous Disease [J-BAD] Registry) in which patients of penetrating artery infarction were prospectively enrolled for exploring the clinical features of BAD. METHODS: From the associated 9 hospitals, acute ischemic stroke patients were asked to be enrolled in the J-BAD Registry and classified into the lenticulostriate arterial (LSA) infarction (n = 124) and the pontine penetrating arterial (PPA) infarction (n = 42) groups. The clinical courses and the repeated magnetic resonance imaging findings were investigated. RESULTS: Neurologic worsening was observed at a significantly higher rate in BAD compared with the LI patients in both the LSA and PPA groups (P < .01, 45.1% versus 22.6% and 46.7% versus 0%, respectively). In the LSA group, the enlargement of the ischemic lesion was significantly more frequent in BAD compared with the LI patients (P < .01, 66.2% and 34.0%, respectively). There was a significant relation between the enlargement of the lesion and the worsening of neurologic deficits (P < .001). Moreover, the clinical features, which predict the lesion enlargement, were BAD and older age. CONCLUSIONS: LSA infarction of BAD diagnosis or older age patients might show an increase of lesion size and a tendency of neurologic worsening. It could be important to discriminate BAD from other ischemic stroke subtypes, in regard to the prediction of prognosis. PMID- 26236004 TI - Reversing hard won victories in the name of human rights: a critique of the General Comment on Article 12 of the UN Convention on the Rights of Persons with Disabilities. AB - The UN Convention on the Rights of Persons with Disabilities (CRPD) is a major milestone in safeguarding the rights of persons with disabilities. However, the General Comment on Article 12 of the CRPD threatens to undermine critical rights for persons with mental disabilities, including the enjoyment of the highest attainable standard of health, access to justice, the right to liberty, and the right to life. Stigma and discrimination might also increase. Much hinges on the Committee on the Rights of Persons with Disabilities' view that all persons have legal capacity at all times irrespective of mental status, and hence involuntary admission and treatment, substitute decision-making, and diversion from the criminal justice system are deemed indefensible. The General Comment requires urgent consideration with the full participation of practitioners and a broad range of user and family groups. PMID- 26236005 TI - Psychiatric morbidity after a major yet transient disaster. PMID- 26236006 TI - Psychiatric disorders and suicide attempts in Swedish survivors of the 2004 southeast Asia tsunami: a 5 year matched cohort study. AB - BACKGROUND: Survivors of natural disasters are thought to be at an increased risk of psychiatric disorders, however the extent of this risk, and whether it is linked to pre-existing psychopathology, is not known. We aimed to establish whether Swedish survivors of tsunamis from the 2004 Sumatra-Andaman earthquake had increased risks of psychiatric disorders and suicide attempts 5 years after repatriation. METHODS: We identified Swedish survivors repatriated from southeast Asia (8762 adults and 3742 children) and 864 088 unexposed adults and 320 828 unexposed children matched for sex, age, and socioeconomic status. We retrieved psychiatric diagnoses and suicide attempts from the Swedish patient register for the 5 years after the tsunami (from Dec 26, 2004, to Jan 31, 2010) and estimated hazard ratios (HRs), then adjusted for pre-tsunami psychiatric disorders, and, for children, for parental pre-tsunami disorders. FINDINGS: Exposed adults were more likely than unexposed adults to receive any psychiatric diagnosis (547 [6.2%] vs 47 734 [5.5%]; adjusted HR 1.21, 95% CI 1.11-1.32), particularly stress related disorders (187 [2.1%] vs 8831 [1.0%]; 2.27, 1.96-2.62) and suicide attempts (38 [0.43%] vs 2752 [0.32%]; 1.54, 1.11-2.13), but not mood or anxiety disorders. Risk of psychiatric diagnoses did not differ between exposed and unexposed children and adolescents (248 [6.6] vs 22 081 [6.9%]; 0.98, 0.86-1.11), although exposed children and adolescents had a higher risk for suicide attempts with uncertain intent (1.43; 1.01-2.02) and stress-related disorders (1.79; 1.30 2.46), mainly during the first 3 months after the tsunami. INTERPRETATION: The 2004 tsunami was, independently of previous psychiatric morbidity, associated with an increased risk of severe psychopathology, mainly stress-related disorders and suicide attempts, in children and adults. Survivors of natural disasters should be targeted with early interventions and active long-term follow-up to prevent, detect, and alleviate psychiatric disorders that might follow. FUNDING: The Swedish Council for Working Life and Social Research, Swedish Board of Health and Welfare, Polish Ministry of Science and Higher Education, Swedish Society for Medical Research. PMID- 26236007 TI - Smoking as a causal risk factor for schizophrenia. PMID- 26236008 TI - Weighing Up Fish and Omega-3 PUFA Advice with Accurate, Balanced Scales: Stringent Controls and Measures Required for Clinical Trials. PMID- 26236009 TI - Clinically relevant copy number variations detected in cerebral palsy. AB - Cerebral palsy (CP) represents a group of non-progressive clinically heterogeneous disorders that are characterized by motor impairment and early age of onset, frequently accompanied by co-morbidities. The cause of CP has historically been attributed to environmental stressors resulting in brain damage. While genetic risk factors are also implicated, guidelines for diagnostic assessment of CP do not recommend for routine genetic testing. Given numerous reports of aetiologic copy number variations (CNVs) in other neurodevelopmental disorders, we used microarrays to genotype a population-based prospective cohort of children with CP and their parents. Here we identify de novo CNVs in 8/115 (7.0%) CP patients (~1% rate in controls). In four children, large chromosomal abnormalities deemed likely pathogenic were found, and they were significantly more likely to have severe neuromotor impairments than those CP subjects without such alterations. Overall, the CNV data would have impacted our diagnosis or classification of CP in 11/115 (9.6%) families. PMID- 26236010 TI - Mechanistic Evidence of Viscum schimperi (Viscaceae) Antihyperglycemic Activity: From a Bioactivity-guided Approach to Comprehensive Metabolite Profiling. AB - Diabetes mellitus is possibly the world's largest growing metabolic disorder. Effective treatment of diabetes is increasingly dependent on active constituents of medicinal plants capable of controlling hyperglycemia as well as its secondary complications. Viscum schimperi Engl. is a plant growing in Saudi Arabia and known for its antidiabetic activity. The potential antidiabetic activity of its methanol extract as well as its chloroform, n-butanol, and the remaining water fractions was evaluated in streptozotocin-induced diabetic rats at two dose levels. The antidiabetic activity was assessed through the determination of fasting blood glucose level, insulin levels, area under the curve (AUC) in oral glucose tolerance test, glucose absorption in isolated rat gut assay, and glucose uptake by psoas muscle. Moreover, large-scale untargeted metabolite profiling of methanol extract was performed via UPLC-PDA and qTOF-MS (ultra-performance liquid chromatography photodiode array detection and quadrupole time-of-flight mass spectrometry) respectively, to explore its chemical composition and standardization of its extract. Multivariate statistical analysis including principal component analysis and orthogonal projection to latent structures discriminant analysis was used to determine bioactives in its fractions. In conclusion, oleanane triterpenes and O-caffeoyl quinic acid conjugates were the major compounds that might account for antihyperglycemic effect of the plant. PMID- 26236011 TI - Towards a heterarchical approach to biology and cognition. AB - In this article we challenge the pervasive notion of hierarchy in biological and cognitive systems and delineate the basis for a complementary heterarchical approach starting from the seminal ideas of Warren McCullock and Gregory Bateson. We intend these considerations as a contribution to the different scientific disciplines working towards a multilevel integrative perspective of biological and cognitive processes, such as systems and integrative biology and neuroscience, social and cultural neuroscience, social signal transduction and psychoneuroimmunology, for instance. We argue that structures and substrates are by necessity organized hierarchically, while communication processes - and their embeddedness - are rather organized heterarchically. Before getting into the implications of the heterarchical approach and its congeniality with the semiotic perspective to biology and cognition, we introduce a set of notions and concepts in order to advance a framework that considers the heterarchical embeddedness of different layers of physiological, behavioral, affective, cognitive, technological and socio-cultural levels implicit in networks of interacting minds, considering the dynamic complementarity of bottom-up and top-down causal links. This should contribute to account for the integration, interpretation and response to complex aggregates of information at different levels of organization in a developmental context. We illustrate the dialectical nature of embedded heterarchical processes by addressing the simultaneity and circularity of cognition and volition, and how such dialectics can be present in primitive instances of proto-cognition and proto-volition, giving rise to our claim that subjectivity and semiotic freedom are scalar properties. We collate the framework with recent empirical systemic approaches to biology and integrative neuroscience, and conclude with a reflection on its implications to the understanding of the emergence of pathological conditions in multi-level semiotic systems. PMID- 26236012 TI - Discovery, Annotation, and Functional Analysis of Long Noncoding RNAs Controlling Cell-Cycle Gene Expression and Proliferation in Breast Cancer Cells. AB - We describe a computational approach that integrates GRO-seq and RNA-seq data to annotate long noncoding RNAs (lncRNAs), with increased sensitivity for low abundance lncRNAs. We used this approach to characterize the lncRNA transcriptome in MCF-7 human breast cancer cells, including >700 previously unannotated lncRNAs. We then used information about the (1) transcription of lncRNA genes from GRO-seq, (2) steady-state levels of lncRNA transcripts in cell lines and patient samples from RNA-seq, and (3) histone modifications and factor binding at lncRNA gene promoters from ChIP-seq to explore lncRNA gene structure and regulation, as well as lncRNA transcript stability, regulation, and function. Functional analysis of selected lncRNAs with altered expression in breast cancers revealed roles in cell proliferation, regulation of an E2F-dependent cell-cycle gene expression program, and estrogen-dependent mitogenic growth. Collectively, our studies demonstrate the use of an integrated genomic and molecular approach to identify and characterize growth-regulating lncRNAs in cancers. PMID- 26236014 TI - Interactions of Melanoma Cells with Distal Keratinocytes Trigger Metastasis via Notch Signaling Inhibition of MITF. AB - The most critical stage in initiation of melanoma metastasis is the radial to vertical growth transition, yet the triggers of this transition remain elusive. We suggest that the microenvironment drives melanoma metastasis independently of mutation acquisition. Here we examined the changes in microenvironment that occur during melanoma radial growth. We show that direct contact of melanoma cells with the remote epidermal layer triggers vertical invasion via Notch signaling activation, the latter serving to inhibit MITF function. Briefly, within the native Notch ligand-free microenvironment, MITF, the melanocyte lineage master regulator, binds and represses miR-222/221 promoter in an RBPJK-dependent manner. However, when radial growth brings melanoma cells into contact with distal differentiated keratinocytes that express Notch ligands, the activated Notch intracellular domain impairs MITF binding to miR-222/221 promoter. This de repression of miR-222/221 expression triggers initiation of invasion. Our findings may direct melanoma prevention opportunities via targeting specific microenvironments. PMID- 26236013 TI - Pin1-Induced Proline Isomerization in Cytosolic p53 Mediates BAX Activation and Apoptosis. AB - The cytosolic fraction of the tumor suppressor p53 activates the apoptotic effector protein BAX to trigger apoptosis. Here we report that p53 activates BAX through a mechanism different from that associated with activation by BH3 only proteins (BIM and BID). We observed that cis-trans isomerization of proline 47 (Pro47) within p53, an inherently rare molecular event, was required for BAX activation. The prolyl isomerase Pin1 enhanced p53-dependent BAX activation by catalyzing cis-trans interconversion of p53 Pro47. Our results reveal a signaling mechanism whereby proline cis-trans isomerization in one protein triggers conformational and functional changes in a downstream signaling partner. Activation of BAX through the concerted action of cytosolic p53 and Pin1 may integrate cell stress signals to induce a direct apoptotic response. PMID- 26236015 TI - Circadian Oscillation of Sulfiredoxin in the Mitochondria. AB - Hydrogen peroxide (H2O2) released from mitochondria regulates various cell signaling pathways. Given that H2O2-eliminating enzymes such as peroxiredoxin III (PrxIII) are abundant in mitochondria, however, it has remained unknown how such release can occur. Active PrxIII-SH undergoes reversible inactivation via hyperoxidation to PrxIII-SO2, which is then reduced by sulfiredoxin. We now show that the amounts of PrxIII-SO2 and sulfiredoxin undergo antiphasic circadian oscillation in the mitochondria of specific tissues of mice maintained under normal conditions. Cytosolic sulfiredoxin was found to be imported into the mitochondria via a mechanism that requires formation of a disulfide-linked complex with heat shock protein 90, which is promoted by H2O2 released from mitochondria. The imported sulfiredoxin is degraded by Lon in a manner dependent on PrxIII hyperoxidation state. The coordinated import and degradation of sulfiredoxin provide the basis for sulfiredoxin oscillation and consequent PrxIII SO2 oscillation in mitochondria and likely result in an oscillatory H2O2 release. PMID- 26236016 TI - Epididymal Binder of SPerm genes and proteins: what do we know a decade later? AB - Binder of SPerm (BSP) proteins from ungulates (more specifically bull, bison, buffalo, stallion, boar, goat, and ram) have been extensively studied in the past 30 years. These proteins secreted by seminal vesicles constitute between 1 and 60% of total seminal plasma proteins depending on the species. In addition to sharing many biochemical characteristics such as the ability to bind to gelatin, glycosaminoglycans, choline phospholipids, and lipoproteins, they also share a main function: promoting sperm capacitation. Over the last 10 years, new members of the BSP superfamily have been discovered. These proteins found in bulls, humans, mice, and rabbits are expressed in the epididymides rather than in seminal vesicles and constitute only a minute percentage of the seminal plasma proteins. However, they share many characteristics with BSPs expressed by accessory glands including their structure, their ability to bind to the aforementioned BSP ligands, as well as their ability to promote sperm capacitation. More investigations need to be done on epididymal BSP proteins, but studies described in this review constitute a solid foundation toward deciphering the significance of epididymal BSP proteins in male fertility. PMID- 26236017 TI - Finely Tuned Polymer Interlayers Enhance Solar Cell Efficiency. AB - Three conjugated polymer zwitterions (CPZs), containing thiophene-, diketopyrrolopyrrole- (DPP), and naphthalene diimide (NDI) backbones, were synthesized with pendant zwitterions, specifically sulfobetaine groups. Diboronate-ester-functionalized bithiophene and benzothiadiazole monomers were copolymerized with zwitterion-substituted dibromothiophene, DPP, and NDI monomers by A2 + B2 Suzuki polymerization. The CPZs were incorporated into polymer solar cells (PSCs) as interlayers between the photoactive layer and Ag cathode. The thiophene-based CPZs gave power conversion efficiencies (PCEs) of about 5%, while the narrow-energy-gap DPP- and NDI-based CPZs performed exceptionally well, giving PCEs of 9.49% and 10.19%, respectively. The interlayer thickness had only a minor impact on the device performance for the DPP- and NDI-CPZs, a finding attributed to their electron-transport properties. Ultraviolet photoelectron and reflectance spectroscopies, combined with external quantum efficiency measurements, provided structure-property relationships that lend insight into the function of CPZ interlayers in PSCs. NDI-based CPZ interlayers provide some of the best performing organic solar cells reported to date, and prove useful in conjunction with high-performing polymer-active layers and stable, high-work function, metal cathodes. PMID- 26236018 TI - Mephentermine dependence syndrome - A new emerging trend of substance use. PMID- 26236019 TI - Soft matter perspective on protein crystal assembly. AB - Crystallography may be the gold standard of protein structure determination, but obtaining the necessary high-quality crystals is also in some ways akin to prospecting for the precious metal. The tools and models developed in soft matter physics to understand colloidal assembly offer some insights into the problem of crystallizing proteins. This topical review describes the various analogies that have been made between proteins and colloids in that context. We highlight the explanatory power of patchy particle models, but also the challenges of providing guidance for crystallizing specific proteins. We conclude with a presentation of possible future research directions. This review is intended for soft matter scientists interested in protein crystallization as a self-assembly problem, and as an introduction to the pertinent physics literature for protein scientists more generally. PMID- 26236021 TI - How do bilinguals identify the language of the words they read? AB - How do bilinguals detect the language of the words they read? Recent electrophysiological research using the masked priming paradigm combining primes and targets from different languages has shown that bilingual readers identify the language of the words within approximately 200 ms. Recent evidence shows that language-detection mechanisms vary as a function of the orthographic markedness of the words (i.e., whether or not a given word contains graphemic combinations that are not legal in the other language). The present study examined how the sub lexical orthographic regularities of words are used as predictive cues. Spanish Basque bilinguals and Spanish monolinguals (control group) were tested in an Event-Related Potential (ERP) experiment, using the masked priming paradigm. During the experiment, Spanish targets were briefly preceded by unrelated Spanish or Basque words. Unrelated Basque words could contain bigram combinations that are either plausible or implausible in the target language (Spanish). Results show a language switch effect in the N250 and N400 components for marked Basque primes in both groups, whereas, in the case of unmarked Basque primes, language switch effects were found in bilinguals but not monolinguals. These data demonstrate that statistical orthographic regularities of words play an important role in bilingual language detection, and provide new evidence supporting the assumptions of the BIA+ extended model. PMID- 26236020 TI - Epigenetics and therapeutic targets mediating neuroprotection. AB - The rapidly evolving science of epigenetics is transforming our understanding of the nervous system in health and disease and holds great promise for the development of novel diagnostic and therapeutic approaches targeting neurological diseases. Increasing evidence suggests that epigenetic factors and mechanisms serve as important mediators of the pathogenic processes that lead to irrevocable neural injury and of countervailing homeostatic and regenerative responses. Epigenetics is, therefore, of considerable translational significance to the field of neuroprotection. In this brief review, we provide an overview of epigenetic mechanisms and highlight the emerging roles played by epigenetic processes in neural cell dysfunction and death and in resultant neuroprotective responses. This article is part of a Special Issue entitled SI: Neuroprotection. PMID- 26236022 TI - Effects of non-invasive brain stimulation on associative memory. AB - Associative memory refers to remembering the association between two items, such as a face and a name. It is a crucial part of daily life, but it is also one of the first aspects of memory performance that is impacted by aging and by Alzheimer's disease. Evidence suggests that transcranial direct current stimulation (tDCS) can improve memory performance, but few tDCS studies have investigated its impact on associative memory. In addition, no prior study of the effects of tDCS on memory performance has systematically evaluated the impact of tDCS on different types of memory assessments, such as recognition and recall tests. In this study, we measured the effects of tDCS on associative memory performance in healthy adults, using both recognition and recall tests. Participants studied face-name pairs while receiving either active (30 min, 2 mA) or sham (30 min, 0.1 mA) stimulation with the anode placed at F9 and the cathode placed on the contralateral upper arm. Participants in the active stimulation group performed significantly better on the recall test than participants in the sham group, recalling 50% more names, on average, and making fewer recall errors. However, the two groups did not differ significantly in terms of their performance on the recognition memory test. This investigation provides evidence that stimulation at the time of study improves associative memory encoding, but that this memory benefit is evident only under certain retrieval conditions. PMID- 26236023 TI - ERP effects and perceived exclusion in the Cyberball paradigm: Correlates of expectancy violation? AB - A virtual ball-tossing game called Cyberball has allowed the identification of neural structures involved in the processing of social exclusion by using neurocognitive methods. However, there is still an ongoing debate if structures involved are either pain- or exclusion-specific or part of a broader network. In electrophysiological Cyberball studies we have shown that the P3b component is sensitive to exclusion manipulations, possibly modulated by the probability of ball possession of the participant (event "self") or the presumed co-players (event "other"). Since it is known from oddball studies that the P3b is not only modulated by the objective probability of an event, but also by subjective expectancy, we independently manipulated the probability of the events "self" and "other" and the expectancy for these events. Questionnaire data indicate that social need threat is only induced when the expectancy for involvement in the ball-tossing game is violated. Similarly, the P3b amplitude of both "self" and "other" events was a correlate of expectancy violation. We conclude that both the subjective report of exclusion and the P3b effect induced in the Cyberball paradigm are primarily based on a cognitive process sensitive to expectancy violations, and that the P3b is not related to the activation of an exclusion specific neural alarm system. PMID- 26236025 TI - NMDA receptor binding is reduced within mesocorticolimbic regions following chronic inhalation of toluene in adolescent rats. AB - The purposeful inhalation of volatile solvents, such as toluene, to induce self intoxication is prevalent, particularly within adolescent populations. Chronic misuse results in cognitive and neurobiological impairments, as well as an increased risk for addictive behaviours in adulthood. Toluene-induced neuroadaptations within mesocorticolimbic circuitry are thought, in part, to mediate some of the adverse outcomes of toluene misuse, however our understanding of the neuroadaptive processes remains equivocal. An understanding of these processes is particularly important relative to exposure that occurs during adolescence and at concentrations that reflect various patterns of use. Therefore, we exposed male adolescent Wistar rats (postnatal day [PN] 27) to either air or low or high concentrations of inhaled toluene in a chronic and intermittent fashion (CIT, 3,000 or 10,000ppm) for 1 h/day, 3-5 times per week for 4 weeks to model different patterns of human inhalant abuse. Brains were subsequently analysed using autoradiography, qPCR and immunohistochemistry 3 days following the exposure period to investigate toluene-induced neuroadaptations within mesocorticolimbic circuitry. In CIT-exposed rats binding to N-methyl-D aspartate (NMDA) receptors containing the GluN2B subunit, as determined using [(3)H]-ifenprodil, was decreased in a concentration-related manner in the caudal cingulate cortex, dorsal striatum and accumbens; however, this was not associated with changes in GluN2B protein expression. There were no differences in [(3)H] epibatidine binding to heteromeric neuronal nicotinic acetylcholine (nACh) receptors. Relative expression of mRNA transcripts encoding NMDA, nACh, gamma aminobutyric acid type-A (GABAA) and dopamine receptor subunits was unchanged in all regions assessed following CIT. Our data suggest that adolescent CIT exposure impacts NMDA receptors within regions of corticostriatal circuitry, possibly via post-translational mechanisms. Dysfunctional glutamatergic signalling within corticostriatal regions may contribute to the adverse outcomes observed following adolescent toluene abuse. PMID- 26236026 TI - Perceptual and cognitive neural correlates of the useful field of view test in older adults. AB - The Useful Field of View Test (UFOV) is often used as a behavioral assessment of age-related decline in visual perception and cognition. Poor performance may reflect slowed processing speed, difficulty dividing attention, and difficulty ignoring irrelevant information. However, the underlying neural correlates of UFOV performance have not been identified. The relationship between older adults' UFOV performance and event-related potential (ERP) components reflecting visual processing was examined. P1 amplitude increased with better UFOV performance involving object identification (subtest 1), suggesting that this task is associated with stimulus processing at an early perceptual level. Better performance in all UFOV subtests was associated with faster speed of processing, as reflected by decreases in P3b latency. Current evidence supports the hypothesis that the UFOV recruits both early perceptual and later cognitive processing involved in attentional control. The implications of these results are discussed. PMID- 26236024 TI - Galectin-1 suppresses methamphetamine induced neuroinflammation in human brain microvascular endothelial cells: Neuroprotective role in maintaining blood brain barrier integrity. AB - Methamphetamine (Meth) abuse can lead to the breakdown of the blood-brain barrier (BBB) integrity leading to compromised CNS function. The role of Galectins in the angiogenesis process in tumor-associated endothelial cells (EC) is well established; however no data are available on the expression of Galectins in normal human brain microvascular endothelial cells and their potential role in maintaining BBB integrity. We evaluated the basal gene/protein expression levels of Galectin-1, -3 and -9 in normal primary human brain microvascular endothelial cells (BMVEC) that constitute the BBB and examined whether Meth altered Galectin expression in these cells, and if Galectin-1 treatment impacted the integrity of an in-vitro BBB. Our results showed that BMVEC expressed significantly higher levels of Galectin-1 as compared to Galectin-3 and -9. Meth treatment increased Galectin-1 expression in BMVEC. Meth induced decrease in TJ proteins ZO-1, Claudin-3 and adhesion molecule ICAM-1 was reversed by Galectin-1. Our data suggests that Galectin-1 is involved in BBB remodeling and can increase levels of TJ proteins ZO-1 and Claudin-3 and adhesion molecule ICAM-1 which helps maintain BBB tightness thus playing a neuroprotective role. Galectin-1 is thus an important regulator of immune balance from neurodegeneration to neuroprotection, which makes it an important therapeutic agent/target in the treatment of drug addiction and other neurological conditions. PMID- 26236027 TI - Incomplete inhibition of central postural commands during manual motor imagery. AB - Imagined movements exhibit many of the behavioral and neurophysiological characteristics of executed actions. As a result, they are considered simulations of physical actions with an inhibition mechanism that suppresses overt movement. This inhibition is incomplete, as it does not block autonomic preparation, and it also does not effectively suppress postural adjustments planned in support of imagined movements. It has been suggested that a central inhibition command may fail to suppress postural adjustments because it may not have access to afference based elaborations of the postural response that occur downstream of central motor planning. Here, we measured changes in the postural response associated with imagining manual reaching movements under varying levels of imagined loading of the arm. We also manipulated stance stability, and found that postural sway reduced with increased (imagined) arm loading when imagining reaching movements from the less stable stance. As there were no afferent signals associated with the loading constraint, these results suggest that postural adjustments can leak during motor imagery because the postural component of the central motor plan is itself not inhibited effectively. PMID- 26236028 TI - Functional brain network changes associated with clinical and biochemical measures of the severity of hepatic encephalopathy. AB - Functional properties of the brain may be associated with changes in complex brain networks. However, little is known about how properties of large-scale functional brain networks may be altered stepwise in patients with disturbance of consciousness, e.g., an encephalopathy. We used resting-state fMRI data on patients suffering from various degrees of hepatic encephalopathy (HE) to explore how topological and spatial network properties of functional brain networks changed at different cognitive and consciousness states. Severity of HE was measured clinically and by neuropsychological tests. Fifty-eight non-alcoholic liver cirrhosis patients and 62 normal controls were studied. Patients were subdivided into liver cirrhosis with no outstanding HE (NoHE, n=23), minimal HE with cognitive impairment only detectable by neuropsychological tests (MHE, n=28), and clinically overt HE (OHE, n=7). From the earliest stage, the NoHE, functional brain networks were progressively more random, less clustered, and less modular. Since the intermediate stage (MHE), increased ammonia level was accompanied by concomitant exponential decay of mean connectivity strength, especially in the primary cortical areas and midline brain structures. Finally, at the OHE stage, there were radical reorganization of the topological centrality i.e., the relative importance-of the hubs and reorientation of functional connections between nodes. In summary, this study illustrated progressively greater abnormalities in functional brain network organization in patients with clinical and biochemical evidence of more severe hepatic encephalopathy. The early-than-expected brain network dysfunction in cirrhotic patients suggests that brain functional connectivity and network analysis may provide useful and complementary biomarkers for more aggressive and earlier intervention of hepatic encephalopathy. Moreover, the stepwise deterioration of functional brain networks in HE patients may suggest that hierarchical network properties are necessary for normal brain function. PMID- 26236029 TI - Interaction envelope: Local spatial representations of objects at all scales in scene-selective regions. AB - While several cortical regions have been highlighted for their category selectivity (e.g., scene-selective regions like the parahippocampal place area, object selective regions like the lateral occipital complex), a growing trend in cognitive neuroscience has been to investigate what particular perceptual properties these regions calculate. Classical scene-selective regions have been particularly targeted in recent work as being sensitive to object size or other related properties. Here we test to which extent these regions are sensitive to spatial information of stimuli at any size. We introduce the spatial object property of "interaction envelope," defined as the space through which a user transverses to interact with an object. In two functional magnetic resonance imaging experiments, we examined activity in a comprehensive set of perceptual regions of interest for when human participants viewed object images varying along the dimensions of interaction envelope and physical size. Importantly, we controlled for confounding perceptual and semantic object properties. We find that scene-selective regions are in fact sensitive to object interaction envelope for small, manipulable objects regardless of real-world size and task. Meanwhile, small-scale entity regions maintain selectivity to stimulus physical size. These results indicate that regions traditionally associated with scene processing may not be solely sensitive to larger object and scene information, but instead are calculating local spatial information of objects and scenes of all sizes. PMID- 26236030 TI - Non-parametric representation and prediction of single- and multi-shell diffusion weighted MRI data using Gaussian processes. AB - Diffusion MRI offers great potential in studying the human brain microstructure and connectivity. However, diffusion images are marred by technical problems, such as image distortions and spurious signal loss. Correcting for these problems is non-trivial and relies on having a mechanism that predicts what to expect. In this paper we describe a novel way to represent and make predictions about diffusion MRI data. It is based on a Gaussian process on one or several spheres similar to the Geostatistical method of "Kriging". We present a choice of covariance function that allows us to accurately predict the signal even from voxels with complex fibre patterns. For multi-shell data (multiple non-zero b values) the covariance function extends across the shells which means that data from one shell is used when making predictions for another shell. PMID- 26236032 TI - Supportive care needs and distress in patients with non-melanoma skin cancer: Nothing to worry about? AB - PURPOSE: There is a paucity of psychosocial research on non-melanoma skin cancer (NMSC) despite the fact that these malignancies mainly develop on the head and neck, frequently recur, and are associated with an increased risk for other cancers. The current study aims to respond to this gap in the scholarship by determining the prevalence of supportive care needs and examining the relationship between patients' needs and distress. METHOD: A cross-sectional research protocol included a consecutive sample of 60 patients with squamous and/or basal cell carcinomas who completed a survey comprised of the Skin Cancer Index (SCI), the Hospital Anxiety and Depression Scale (HADS), the Supportive Care Needs (SCNS) Survey, an inquiry about informational needs regarding skin cancer prevention, and a socio-demographic questionnaire. RESULTS: More than half of the patients indicated unmet needs, most frequently endorsing moderate and high needs for help with: the prevention of future skin cancers, the health system and informational matters. Psychological needs were strongly associated with skin cancer-specific and general distress. Higher levels of anxious and depressive symptoms were related to greater patient needs across all domains. CONCLUSIONS: Despite NMSC not being life threatening in most cases, there is a significant proportion of patients, who have unmet supportive care needs and experience heightened distress levels. This study raises awareness for health care professionals to be vigilant about the supportive care needs and the psychological health of patients with non-melanoma skin cancer. PMID- 26236031 TI - Abnormalities in brain structure and biochemistry associated with mdx mice measured by in vivo MRI and high resolution localized (1)H MRS. AB - Duchenne muscular dystrophy (DMD), an X-linked disorder caused by the lack of dystrophin, is characterized by the progressive wasting of skeletal muscles. To date, what is known about dystrophin function is derived from studies of dystrophin-deficient animals, with the most common model being the mdx mouse. Most studies on patients with DMD and in mdx mice have focused on skeletal muscle and the development of therapies to reverse, or at least slow, the severe muscle wasting and progressive degeneration. However, dystrophin is also expressed in the CNS. Both mdx mice and patients with DMD can have cognitive and behavioral changes, but studies in the dystrophic brain are limited. We examined the brain structure and metabolites of mature wild type (WT) and mdx mice using magnetic resonance imaging and spectroscopy (MRI/MRS). Both structural and metabolic alterations were observed in the mdx brain. Enlarged lateral ventricles were detected in mdx mice when compared to WT. Diffusion tensor imaging (DTI) revealed elevations in diffusion diffusivities in the prefrontal cortex and a reduction of fractional anisotropy in the hippocampus. Metabolic changes included elevations in phosphocholine and glutathione, and a reduction in gamma-aminobutyric acid in the hippocampus. In addition, an elevation in taurine was observed in the prefrontal cortex. Such findings indicate a regional structural change, altered cellular antioxidant defenses, a dysfunction of GABAergic neurotransmission, and a perturbed osmoregulation in the brain lacking dystrophin. PMID- 26236033 TI - Variability and repeatability analysis of plantar pressure during gait in older people. AB - INTRODUCTION: Repeatability and variability of the plantar pressure during walking are important components in the clinical assessment of the elderly. However, there is a lack of information on the uniformity of plantar pressure patterns in the elderly. OBJECTIVE: To analyze the repeatability and variability in plantar pressure considering mean, peak and asymmetries during aged gait. METHODS: Plantar pressure was monitored in four different days for ten elderly subjects (5 female), with mean+/-standard-deviation age of 73+/-6 years, walking barefoot at preferred speed. Data were compared between steps for each day and between different days. RESULTS: Mean and peak plantar pressure values were similar between the different days of evaluation. Asymmetry indexes were similar between the different days evaluated. CONCLUSION: Plantar pressure presented a consistent pattern in the elderly. However, the asymmetry indexes observed suggest that the elderly are exposed to repetitive asymmetric loading during locomotion. Such result requires further investigation, especially concerning the role of these asymmetries for development of articular injuries. PMID- 26236034 TI - Cerium(IV) Hexanuclear Clusters from Cerium(III) Precursors: Molecular Models for Oxidative Growth of Ceria Nanoparticles. AB - Reactions of cerium(III) nitrate, Ce(NO3 )3 ?6 H2 O, with different carboxylic acids, such as pivalic acid, benzoic acid, and 4-methoxybenzoic acid, in the presence of a tridentate N,N,N-donor ligand, diethylenetriamine (L(1) ), under aerobic conditions yielded the corresponding cerium hexamers Ce6 O8 (O2 CtBu)8 (L(1) )4 (1), Ce6 O8 (O2 CC6 H5 )8 (L(1) )4 (2), and Ce6 O8 (O2 CC6 H4 -4-OCH3 )8 (L(1) )4 (3). Hexamers 1, 2, and 3 contain the same octahedral Ce(IV) 6 O8 core, in which all interstitial oxygen atoms are connected by MU3 -oxo bridging ligands. In contrast, treatment of the Ce(IV) precursor (NH4 )2 Ce(NO3 )6 (CAN) with pivalic acid and the ligand L(1) under the same conditions afforded Ce6 O4 (OH)4 (O2 CtBu)12 (L(1) )2 (4), exhibiting a deformed octahedral Ce(IV) 6 O4 (OH)4 core containing MU3 -oxo and MU3 -hydroxo moieties in defined positions. In contrast to the formation of 1-3, the use of N-methyldiethanolamine (L) in the reaction with Ce(NO3 )3 ?6 H2 O and pivalic acid afforded a previously reported Ce(III) dinuclear cluster, Ce2 (O2 CtBu)6 L2 , even in the presence of dioxygen. ESI-MS analysis of the reaction mixture clearly indicated the importance of the ligand L(1) in promoting oxidation of the Ce(III) aggregates, [Cen (O2 CtBu)3n (L(1) )2 ], which is necessary for the formation of Ce(IV) hexamers. PMID- 26236036 TI - Liposomal Bupivacaine for Total Knee Arthroplasty. PMID- 26236035 TI - Mathematical modelling of local calcium and regulated exocytosis during inhibition and stimulation of glucagon secretion from pancreatic alpha-cells. AB - Glucagon secretion from pancreatic alpha-cells is dysregulated in diabetes. Despite decades of investigations of the control of glucagon release by glucose and hormones, the underlying mechanisms are still debated. Recently, mathematical models have been applied to investigate the modification of electrical activity in alpha-cells as a result of glucose application. However, recent studies have shown that paracrine effects such as inhibition of glucagon secretion by glucagon like peptide 1 (GLP-1) or stimulation of release by adrenaline involve cAMP mediated effects downstream of electrical activity. In particular, depending of the intracellular cAMP concentration, specific types of Ca(2+) channels are inhibited or activated, which interacts with mobilization of secretory granules. To investigate these aspects of alpha-cell function theoretically, we carefully developed a mathematical model of Ca(2+) levels near open or closed Ca(2+) channels of various types, which was linked to a description of Ca(2+) below the plasma membrane, in the bulk cytosol and in the endoplasmic reticulum. We investigated how the various subcellular Ca(2+) compartments contribute to control of glucagon-exocytosis in response to glucose, GLP-1 or adrenaline. Our studies refine previous modelling studies of alpha-cell function, and provide deeper insight into the control of glucagon secretion. PMID- 26236037 TI - Catalytic C-C Bond Formation and the Hendricksonian Ideal: Atom- and Redox Economy, Stereo- and Site-Selectivity. PMID- 26236038 TI - Tradeoffs from Integrating Diagnosis and Treatment in Markets for Health Care. PMID- 26236039 TI - Wireless Communication of Intraoral Devices and Its Optimal Frequency Selection. AB - This paper explores communication methods and frequencies for wireless intraoral electronic devices, by using an intraoral tongue drive system (iTDS) as a practical example. Because intraoral devices do not meet the operating conditions of the body channel communication, we chose radio frequency communication. We evaluated and compared three frequencies in industrial, scientific, and medical bands (27 MHz, 433.9 MHz, and 2.48 GHz) in terms of their data link performance based on path loss and radiation patterns over horizontal and vertical planes. To do so, we dynamically minimize the impedance mismatch caused by the varying oral environment by applying the adaptive impedance matching technique to 433.9 MHz and 2.48 GHz bands. Experimental results showed that 27 MHz has the smallest path loss in the near-field up to 39 cm separation between transmitter and receiver antennas. However, 433.9 MHz shows the best performance beyond 39 cm and offers a maximum operating distance of 123 cm with 0 dBm transmitter output power. These distances were obtained by a bit error rate test and verified by a link budget analysis and full functionality test of the iTDS with computer access. PMID- 26236040 TI - Simulating Silicon Photomultiplier Response to Scintillation Light. AB - The response of a Silicon Photomultiplier (SiPM) to optical signals is affected by many factors including photon-detection efficiency, recovery time, gain, optical crosstalk, afterpulsing, dark count, and detector dead time. Many of these parameters vary with overvoltage and temperature. When used to detect scintillation light, there is a complicated non-linear relationship between the incident light and the response of the SiPM. In this paper, we propose a combined discrete-time discrete-event Monte Carlo (MC) model to simulate SiPM response to scintillation light pulses. Our MC model accounts for all relevant aspects of the SiPM response, some of which were not accounted for in the previous models. We also derive and validate analytic expressions for the single-photoelectron response of the SiPM and the voltage drop across the quenching resistance in the SiPM microcell. These analytic expressions consider the effect of all the circuit elements in the SiPM and accurately simulate the time-variation in overvoltage across the microcells of the SiPM. Consequently, our MC model is able to incorporate the variation of the different SiPM parameters with varying overvoltage. The MC model is compared with measurements on SiPM-based scintillation detectors and with some cases for which the response is known a priori. The model is also used to study the variation in SiPM behavior with SiPM circuit parameter variations and to predict the response of a SiPM-based detector to various scintillators. PMID- 26236041 TI - A System Calibration and Fast Iterative Reconstruction Method for Next-Generation SPECT Imagers. AB - Recently, high-resolution gamma cameras have been developed with detectors containing > 105-106 elements. Single-photon emission computed tomography (SPECT) imagers based on these detectors usually also have a large number of voxel bins and therefore face memory storage issues for the system matrix when performing fast tomographic reconstructions using iterative algorithms. To address these issues, we have developed a method that parameterizes the detector response to a point source and generates the system matrix on the fly during MLEM or OSEM on graphics hardware. The calibration method, interpolation of coefficient data, and reconstruction results are presented in the context of a recently commissioned small-animal SPECT imager, called FastSPECT III. PMID- 26236042 TI - Effect of breed and pasture type on methane emissions from weaned lambs offered fresh forage. AB - To investigate the extent to which enteric methane (CH4) emissions from growing lambs are explained by simple body weight and diet characteristics, a 2 * 2 Latin square changeover design experiment was carried out using two sheep breeds and two fresh pasture types. Weaned lambs of two contrasting breed types were used: Welsh Mountain (WM, a small, hardy hill breed) and Welsh Mule * Texel (TexX, prime lamb) (n = 8 per breed). The lambs were zero-grazed on material cut from recently reseeded perennial ryegrass and extensively managed permanent pasture. In each experimental period, individual ad libitum dry matter intake (DMI) was determined indoors following an adaptation period of 2 weeks, and CH4 emissions were measured individually in open-circuit respiration chambers over a period of 3 days. Although total daily CH4 emissions were lower for the WM lambs than for the TexX lambs (13.3 v. 15.7 g/day, respectively) when offered fresh forage, the yield of CH4 per unit DMI was similar for the two breed types (16.4 v. 17.7 g CH4/kg DMI). Total output of CH4 per day was higher when lambs were offered ryegrass compared with permanent pasture (16.1 v. 12.9 g/day, respectively), which was probably driven by differences in DMI (986 v. 732 g/day). Methane emissions per unit DMI (16.4 v. 17.7 g CH4/kg DMI) and proportion of gross energy intake excreted as CH4 (0.052 v. 0.056 MJ/MJ) were both higher on the permanent pasture. No forage * breed type interactions were identified. The results indicate that forage type had a greater impact than breed type on CH4 emissions from growing weaned lambs. It can be concluded that when calculating CH4 emissions for inventory purposes, it is more important to know what forages growing lambs are consuming than to know what breeds they are. PMID- 26236043 TI - Alcohol Consumption, Dating Relationships, and Preliminary Sexual Outcomes in Collegiate Natural Drinking Groups. AB - This study tested the effects of committed relationships and presence of dates on alcohol consumption and preliminary sexual outcomes in natural drinking groups (NDGs). Undergraduate drinkers (N = 302) answered an online questionnaire on their most recent participation in a NDG. The interaction between relationship commitment and presence of a date on alcohol consumption was significant. Among students not in committed relationships, those dating within their NDG reported heavier drinking than those not dating. Students in committed relationships drank less than those who were not committed only when their partners were present. The positive correlation between drinking and sexual contact was significant only for those who were not in committed relationships. Implications for future research and interventions are discussed. PMID- 26236044 TI - Effects of MERV 16 filters and routine work practices on enclosed cabs for reducing respirable dust and DPM exposures in an underground limestone mine. AB - An effective technique to minimize miners' respirable dust and diesel exposure on mobile mining equipment is to place mine operators in enclosed cabs with designed filtration and pressurization systems. Many factors affect the performance of these enclosed cab systems, and one of the most significant factors is the effectiveness of the filtration system. High-efficiency particulate air (HEPA) type filters are typically used because they are highly efficient at capturing all types and sizes of particles, including those in the submicron range such as diesel particulate matter (DPM). However, in laboratory tests, minimum efficiency reporting value (MERV) 16 filters have proven to be highly efficient for capturing DPM and respirable dust. Also, MERV 16 filters can be less restrictive to cab airflow and less expensive than HEPA filters. To verify their effectiveness in the field, MERV 16 filters were used in the enclosed cab filtration system on a face drill and roof bolting mining machine and tested at an underground limestone mine. Test results showed that DPM and respirable dust concentrations were reduced by more than 90% when the cabs were properly sealed. However, when the cab door was opened periodically throughout the shift, the reduction efficiency of the MERV 16 filters was reduced to 80% on average. PMID- 26236045 TI - Connecting Youth and Young Adults with Autism Spectrum Disorders to Community Life. AB - Equipping youth with autism spectrum disorders (ASD) to flourish during and after high school is central to the purpose and practice of special education. However, many students with ASD are leaving high school without the preparation and connections needed to engage meaningfully in their communities. This article reviews research-based approaches for connecting adolescents with ASD to life beyond the classroom by describing promising practices for fostering inclusion in postsecondary education and community activities. Recognizing that relationships are at the core of community life, emphasis is placed on fostering social connections as an essential aspect of helping young people with ASD thrive in these settings. We conclude with suggestions for school staff to support the successful transitions of young people with ASD. PMID- 26236046 TI - Sociological Ambivalence and Funeral Consumption. AB - This article builds on Hillcoat-Nalletamby and Phillips' (2011) conceptualization of sociological ambivalence within the relational framework to examine a particular consumption practice, the funeral. We develop understanding of social, cultural and relational issues that arise from the experience associated with funeral-arranging. This is not a voluntary behaviour but one engaged with through force of circumstance and which involves commercial and relational decisions. Drawing on data from 10 interviews from a larger UK study, we focus on ambivalence surrounding choice and its impact on relations, showing how sentiments including love, obligation, regret and revenge evolve and transform past and future relationships. PMID- 26236047 TI - Suicide in the City: Do Characteristics of Place Really Influence Risk? AB - OBJECTIVE: This article investigates the role of social context on individual suicide mortality with attention paid to the possibility that contextual effects are simply the sum of individual characteristics associated with suicide. METHODS: We use restricted data from the 1986-2006 National Health Interview Survey-Linked Mortality Files, which include nearly one million records and 1,300 suicides, to examine the role of familial and socioeconomic context on adult suicide. RESULTS: Results show that adults living in cities with more socioeconomic disadvantage and fewer families living together have higher odds of suicidal death than adults living in less disadvantaged cities and cities with more families living together, respectively, after controlling for individual level socioeconomic status, marital status, and family size. CONCLUSION: The findings support classic sociological arguments that the risk of suicide is indeed influenced by the social milieu and cannot simply be explained by the aggregation of individual characteristics. PMID- 26236048 TI - Metal Catalyzed Allylic Alkylation: Its Development in the Trost Laboratories. PMID- 26236049 TI - 4-Acetoxy-2,2-dimethylbutanoate: a useful carbohydrate protecting group for the selective formation of beta-(1->3)-d-glucans. AB - The use of 4-acetoxy-2,2-dimethylbutanoyl protecting group for the C2-hydroxyl allows the selective formation of beta-glycosides without producing alpha glycosides. This very bulky protecting group can be removed under mild conditions. PMID- 26236050 TI - Synthesis of anti-inflammatory alpha-and beta-linked acetamidopyranosides as inhibitors of toll-like receptor 4 (TLR4). AB - The low-molecular weight isopropyl 2-acetamido-alpha-glucoside 16 (C34) inhibits toll-like receptor 4 (TLR4) in enterocytes and macrophages in vitro, and reduces systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. We used a copper(II)-mediated solvolysis of anomeric oxazolines and an acid-mediated conversion of beta-glucosamine and beta-galactosamine pentaacetates to generate analogs of 16 at the anomeric carbon and at C-4 of the pyranose ring. These compounds were evaluated for their influence on TLR4 mediated inflammatory signaling in cultured enterocytes and monocytes. Their efficacy was confirmed using a NF-kB-luciferase reporter mouse, thus establishing the first structure-activity relationship (SAR) study in this series and identifying the more efficacious isopropyl 2-acetamido-alpha-galactoside 17. PMID- 26236051 TI - Total Synthesis of Clavosolide A via Tandem Allylic Oxidation/Oxa-Conjugate Addition Reaction. AB - The tandem allylic oxidation/oxa-conjugate addition reaction promoted by the gem disubstituent effect in conjunction with the NHC-mediated oxidative esterification was explored for the facile synthesis of clavosolide A. PMID- 26236053 TI - Trapping Hemiacetals with Phosphono Substituted Palladium pi-Allyl Complexes for the Synthesis of Substituted Cyclic Ethers. AB - Oxidation of hydroxy substituted phosphono allylic carbonates gave the aldehyde substituted phosphonates in good yield. Stereospecific palladium (0)-catalyzed cyclization in the presence of methanol or water gave acetal tetrahydrofuran and tetrahydropyran vinyl phosphonate products derived from hemiacetal trapping. The tetrahydrofuran acetals undergo Lewis acid catalyzed addition of nucleophiles to give diastereoisomeric mixtures of substituted tetrahydrofurans. PMID- 26236052 TI - Development of 6H-Chromeno[3,4-c]pyrido[3',2':4,5]thieno[2,3-e]pyridazin-6-ones as Par-4 Secretagogues. AB - Nitrosation and cyclization of 4-(3-aminothieno[2,3-b]pyridine-2-yl)-2H-chromen-2 ones 1 afforded substituted 6H-chromeno[3,4-c]pyrido[3',2':4,5]thieno[2,3 e]pyridazin-6-ones 2 that inhibited the intermediary filament protein, vimentin, at low micromolar concentrations. This inhibition promoted the secretion of Prostate Apoptosis Response-4 protein (Par-4), which selectively triggered apoptosis in prostate cancer cells such as CWR22Rv1, LNCaP-derivative C4-2B, PC-3 and its aggressive analog, PC-3 MM2. PMID- 26236054 TI - Formation of Fused Aromatic Architectures via an Oxidative Dearomatization - Radical Cyclization Rearomatization Approach. AB - A new mild C-C bond forming cyclization approach of catechol derivatives is reported. This approach relies on an initial dearomatization step using lead (IV) acetate followed by a carefully controlled radical cyclization step, which under the reaction conditions also facilitates rearomatization. Triethylborane is the key to the success of this reaction as it enables the reaction to proceed at low temperatures and is also believed to aid rearomatization. The amount and ratio of triethylborane and reducing agent (tributyltinhydride) that is employed as well as the concentration the reaction is run at are all essential to the success of this new approach. PMID- 26236055 TI - Studies on a biomimetic oxidative dimerization approach to the hibarimicins. AB - Nature utilizes dimerization as a method of producing structurally complex metabolites. The microbial metabolites known collectively as the hibarimicins are one example of complex natural products produced biosynthetically by dimerization of a phenolic aromatic polyketide. Described in this communication are model studies aimed at demonstrating regiocontrolled oxidative dimerization of phenolic ring systems related to the biosynthetic precursor of the hibarimicin family of natural products. PMID- 26236056 TI - Bullying May Be Fueled by the Desperate Need to Belong. AB - Human beings have a fundamental need to belong, for ongoing positive interactions with others who provide companionship and caring (Baumeister & Leary, 1995). Children may hit, exclude, or harass others electronically because when their own needs for belongingness are threatened, or when they want to enhance their own status, they lash out and hurt others in the way they think will be most painful, by engaging in behaviors that undermine the target's sense of belongingness. For reasons discussed below, children and adolescents might be especially vulnerable to desperate needs for belongingness. Viewing bullying as motivated by the need to belong has profound implications for prevention and intervention programs to reduce bullying. PMID- 26236057 TI - Glutamate modulators in the treatment of obsessive-compulsive disorder. AB - Established treatments for obsessive-compulsive disorder (OCD) are of benefit in approximately 3 of every 4 patients, but refractory disease remains distressingly common, and many treatment responders continue to experience considerable morbidity. This motivates a search for new insights into pathophysiology that may inform novel treatment strategies. Much recent work has focused on the neurotransmitter glutamate. Several lines of neurochemical and genetic evidence suggests that glutamate dysregulation may contribute to OCD, although much remains unclear. The off-label use of a number of pharmacological agents approved for other indications has been investigated in refractory OCD. We summarize investigations of memantine, riluzole, ketamine, D-cycloserine, glycine, N acetylserine, topiramate, and lamotrigine. Evidence exists for benefit from each of these in some patients; though none has been proven effective with sufficient clarity to be considered part of standard care, these agents are options in individuals whose symptoms are refractory to better-established therapeutic strategies. PMID- 26236059 TI - Perceived Emotion Control Moderates the Relationship between Neuroticism and Generalized Anxiety Disorder. AB - The relationships between neuroticism, perceived emotion control, and generalized anxiety disorder (GAD) severity were examined in 293 individuals diagnosed with GAD at a specialty anxiety disorders clinic. Hierarchical regression analyses performed within a structural equation modeling framework revealed that (1) neuroticism and perceived emotion control both predicted a latent variable of GAD in the expected direction, and (2) perceived emotion control moderated the relationship between neuroticism and GAD severity, such that lower levels of perceived emotion control were associated with a stronger relationship between neuroticism and GAD severity. The other dimensions of perceived control (i.e., stress and threat control) did not moderate the effect of neuroticism on GAD severity. The findings are discussed with regard to their implications to conceptual models of the psychopathology of GAD, and theory-based differential relationships between dimensions of vulnerability, perceived control, and anxiety disorders. PMID- 26236060 TI - A Flexible Bayesian Approach to Monotone Missing Data in Longitudinal Studies with Nonignorable Missingness with Application to an Acute Schizophrenia Clinical Trial. AB - We develop a Bayesian nonparametric model for a longitudinal response in the presence of nonignorable missing data. Our general approach is to first specify a working model that flexibly models the missingness and full outcome processes jointly. We specify a Dirichlet process mixture of missing at random (MAR) models as a prior on the joint distribution of the working model. This aspect of the model governs the fit of the observed data by modeling the observed data distribution as the marginalization over the missing data in the working model. We then separately specify the conditional distribution of the missing data given the observed data and dropout. This approach allows us to identify the distribution of the missing data using identifying restrictions as a starting point. We propose a framework for introducing sensitivity parameters, allowing us to vary the untestable assumptions about the missing data mechanism smoothly. Informative priors on the space of missing data assumptions can be specified to combine inferences under many different assumptions into a final inference and accurately characterize uncertainty. These methods are motivated by, and applied to, data from a clinical trial assessing the efficacy of a new treatment for acute Schizophrenia. PMID- 26236058 TI - Fluid Mechanics of Blood Clot Formation. AB - Intravascular blood clots form in an environment in which hydrodynamic forces dominate and in which fluid-mediated transport is the primary means of moving material. The clotting system has evolved to exploit fluid dynamic mechanisms and to overcome fluid dynamic challenges to ensure that clots that preserve vascular integrity can form over the wide range of flow conditions found in the circulation. Fluid-mediated interactions between the many large deformable red blood cells and the few small rigid platelets lead to high platelet concentrations near vessel walls where platelets contribute to clotting. Receptor ligand pairs with diverse kinetic and mechanical characteristics work synergistically to arrest rapidly flowing cells on an injured vessel. Variations in hydrodynamic stresses switch on and off the function of key clotting polymers. Protein transport to, from, and within a developing clot determines whether and how fast it grows. We review ongoing experimental and modeling research to understand these and related phenomena. PMID- 26236061 TI - Risk Classification with an Adaptive Naive Bayes Kernel Machine Model. AB - Genetic studies of complex traits have uncovered only a small number of risk markers explaining a small fraction of heritability and adding little improvement to disease risk prediction. Standard single marker methods may lack power in selecting informative markers or estimating effects. Most existing methods also typically do not account for non-linearity. Identifying markers with weak signals and estimating their joint effects among many non-informative markers remains challenging. One potential approach is to group markers based on biological knowledge such as gene structure. If markers in a group tend to have similar effects, proper usage of the group structure could improve power and efficiency in estimation. We propose a two-stage method relating markers to disease risk by taking advantage of known gene-set structures. Imposing a naive bayes kernel machine (KM) model, we estimate gene-set specific risk models that relate each gene-set to the outcome in stage I. The KM framework efficiently models potentially non-linear effects of predictors without requiring explicit specification of functional forms. In stage II, we aggregate information across gene-sets via a regularization procedure. Estimation and computational efficiency is further improved with kernel principle component analysis. Asymptotic results for model estimation and gene set selection are derived and numerical studies suggest that the proposed procedure could outperform existing procedures for constructing genetic risk models. PMID- 26236062 TI - New Statistical Learning Methods for Estimating Optimal Dynamic Treatment Regimes. AB - Dynamic treatment regimes (DTRs) are sequential decision rules for individual patients that can adapt over time to an evolving illness. The goal is to accommodate heterogeneity among patients and find the DTR which will produce the best long term outcome if implemented. We introduce two new statistical learning methods for estimating the optimal DTR, termed backward outcome weighted learning (BOWL), and simultaneous outcome weighted learning (SOWL). These approaches convert individualized treatment selection into an either sequential or simultaneous classification problem, and can thus be applied by modifying existing machine learning techniques. The proposed methods are based on directly maximizing over all DTRs a nonparametric estimator of the expected long-term outcome; this is fundamentally different than regression-based methods, for example Q-learning, which indirectly attempt such maximization and rely heavily on the correctness of postulated regression models. We prove that the resulting rules are consistent, and provide finite sample bounds for the errors using the estimated rules. Simulation results suggest the proposed methods produce superior DTRs compared with Q-learning especially in small samples. We illustrate the methods using data from a clinical trial for smoking cessation. PMID- 26236063 TI - Social and Emotional Learning Services and Child Outcomes in Third Grade: Evidence from a Cohort of Head Start Participants. AB - A variety of universal school-based social and emotional learning (SEL) programs have been designed in the past decades to help children improve social-emotional and academic skills. Evidence on the effectiveness of SEL programs has been mixed in the literature. Using data from a longitudinal follow-up study of children (n = 414) originally enrolled in a clustered randomized controlled trial (RCT) when they were in Head Start, we examined whether universal SEL services in third grade were associated with the development of children from disadvantaged families. We took advantage of pairwise matching in the RCT design to compare children who had similar family background and preschool experiences but received different doses of SEL services in third grade. The results showed that the frequent (i.e., weekly to daily) exposure to SEL opportunities was associated with favorable social-emotional and academic development in third grade, including increased social skills, student-teacher relationship, and academic skills, as well as reduced impulsiveness. PMID- 26236064 TI - Accuracy of continuum electrostatic calculations based on three common dielectric boundary definitions. AB - We investigate the influence of three common definitions of the solute/solvent dielectric boundary (DB) on the accuracy of the electrostatic solvation energy DeltaGel computed within the Poisson Boltzmann and the generalized Born models of implicit solvation. The test structures include small molecules, peptides and small proteins; explicit solvent DeltaGel are used as accuracy reference. For common atomic radii sets BONDI, PARSE (and ZAP9 for small molecules) the use of van der Waals (vdW) DB results, on average, in considerably larger errors in DeltaGel than the molecular surface (MS) DB. The optimal probe radius rhow for which the MS DB yields the most accurate DeltaGel varies considerably between structure types. The solvent accessible surface (SAS) DB becomes optimal at rhow ~ 0.2 A (exact value is sensitive to the structure and atomic radii), at which point the average accuracy of DeltaGel is comparable to that of the MS-based boundary. The geometric equivalence of SAS to vdW surface based on the same atomic radii uniformly increased by rhow gives the corresponding optimal vdW DB. For small molecules, the optimal vdW DB based on BONDI + 0.2 A radii can yield DeltaGel estimates at least as accurate as those based on the optimal MS DB. Also, in small molecules, pairwise charge-charge interactions computed with the optimal vdW DB are virtually equal to those computed with the MS DB, suggesting that in this case the two boundaries are practically equivalent by the electrostatic energy criteria. In structures other than small molecules, the optimal vdW and MS dielectric boundaries are not equivalent: the respective pairwise electrostatic interactions in the presence of solvent can differ by up to 5 kcal/mol for individual atomic pairs in small proteins, even when the total DeltaGel are equal. For small proteins, the average decrease in pairwise electrostatic interactions resulting from the switch from optimal MS to optimal vdW DB definition can be mimicked within the MS DB definition by doubling of the solute dielectric constant. However, the use of the higher interior dielectric does not eliminate the large individual deviations between pairwise interactions computed within the two DB definitions. It is argued that while the MS based definition of the dielectric boundary is more physically correct in some types of practical calculations, the choice is not so clear in some other common scenarios. PMID- 26236065 TI - Methods for Collection of Participant-aided Sociograms for the Study of Social, Sexual and Substance-using Networks Among Young Men Who Have Sex with Men. AB - In this study, we adapted and tested a participant-aided sociogram approach for the study of the social, sexual, and substance use networks of young men who have sex with men (YMSM); a population of increasing and disproportionate risk of HIV infection. We used a combination of two interviewer-administered procedures: completion of a pre-numbered list form to enumerate alters and to capture alter attributes; and a participant-aided sociogram to capture respondent report of interactions between alters on an erasable whiteboard. We followed the collection of alter interactions via the sociogram with a traditional matrix-based tie elicitation approach for a sub-sample of respondents for comparison purposes. Digital photographs of each network drawn on the whiteboard serve as the raw data for entry into a database in which group interactions are stored. Visual feedback of the network was created at the point of data entry, using NetDraw network visualization software for comparison to the network structure elicited via the sociogram. In a sample of 175 YMSM, we found this approach to be feasible and reliable, with high rates of participation among those eligible for the study and substantial agreement between the participant-aided sociogram in comparison to a traditional matrix-based approach. We believe that key strengths of this approach are the engagement and maintenance of participant attention and reduction of participant burden for alter tie elicitation. A key weakness is the challenge of entry of interview-based list form and sociogram data into the database. Our experience suggests that this approach to data collection is feasible and particularly appropriate for an adolescent and young adult population. This builds on and advances visualization-based approaches to social network data collection. PMID- 26236066 TI - Peers' Perceptions of Gender Nonconformity: Associations with Overt and Relational Peer Victimization and Aggression in Early Adolescence. AB - The current study used reports from 318 early adolescents to examine the associations of peer-reported gender nonconformity with peer- and self-reported overt and relational victimization and aggression and possible sex differences in these associations. Multiple-group structural equation modeling revealed that higher levels of peer-reported gender nonconformity were associated with higher self- and peer-reports of overt and relational victimization and aggression among males and females. The association between peer-reported gender nonconformity and peer-reported overt aggression was moderated by participant sex, such that the association was stronger for females compared to males. Results suggest that perceived gender nonconformity is associated with problematic peer relations, especially among females, in early adolescence and implications of these associations are discussed. PMID- 26236067 TI - Joint reconstruction of activity and attenuation map using LM SPECT emission data. AB - Attenuation and scatter correction in single photon emission computed tomography (SPECT) imaging often requires a computed tomography (CT) scan to compute the attenuation map of the patient. This results in increased radiation dose for the patient, and also has other disadvantages such as increased costs and hardware complexity. Attenuation in SPECT is a direct consequence of Compton scattering, and therefore, if the scattered photon data can give information about the attenuation map, then the CT scan may not be required. In this paper, we investigate the possibility of joint reconstruction of the activity and attenuation map using list-mode (LM) SPECT emission data, including the scattered photon data. We propose a path-based formalism to process scattered-photon data. Following this, we derive analytic expressions to compute the Cramer-Rao bound (CRB) of the activity and attenuation map estimates, using which, we can explore the fundamental limit of information-retrieval capacity from LM SPECT emission data. We then suggest a maximum-likelihood (ML) scheme that uses the LM emission data to jointly reconstruct the activity and attenuation map. We also propose an expectation-maximization (EM) algorithm to compute the ML solution. PMID- 26236068 TI - SmartCAM: An adaptive clinical SPECT camera. AB - An adaptive pinhole aperture that fits a GE MaxiCam Single-Photon-Emission Computed Tomography (SPECT) system has been designed, built, and is undergoing testing. The purpose of an adaptive aperture is to allow the imaging system to make adjustments to the aperture while imaging data are being acquired. Our adaptive pinhole aperture can alter several imaging parameters, including field of view, resolution, sensitivity, and magnification. The dynamic nature of such an aperture allows for imaging of specific regions of interest based on initial measurements of the patient. Ideally, this mode of data collection will improve the understanding of a patient's condition, and will facilitate better diagnosis and treatment. The aperture was constructed using aluminum and a low melting point, high-stopping-power metal alloy called Cerrobend. The aperture utilizes a rotating disk for the selection of a pinhole configuration; as the aluminum disk rotates, different pinholes move into view of the camera face and allow the passage of gamma rays through that particular pinhole. By controlling the angular position of the disk, the optical characteristics of the aperture can be modified, allowing the system to acquire data from controlled regions of interest. First testing was performed with a small radioactive source to prove the functionality of the aperture. PMID- 26236069 TI - Molecular Imaging in the College of Optical Sciences - An Overview of Two Decades of Instrumentation Development. AB - During the past two decades, researchers at the University of Arizona's Center for Gamma-Ray Imaging (CGRI) have explored a variety of approaches to gamma-ray detection, including scintillation cameras, solid-state detectors, and hybrids such as the intensified Quantum Imaging Device (iQID) configuration where a scintillator is followed by optical gain and a fast CCD or CMOS camera. We have combined these detectors with a variety of collimation schemes, including single and multiple pinholes, parallel-hole collimators, synthetic apertures, and anamorphic crossed slits, to build a large number of preclinical molecular imaging systems that perform Single-Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), and X-Ray Computed Tomography (CT). In this paper, we discuss the themes and methods we have developed over the years to record and fully use the information content carried by every detected gamma-ray photon. PMID- 26236070 TI - Imaging properties of pixellated scintillators with deep pixels. AB - We have investigated the light-transport properties of scintillator arrays with long, thin pixels (deep pixels) for use in high-energy gamma-ray imaging. We compared 10*10 pixel arrays of YSO:Ce, LYSO:Ce and BGO (1mm * 1mm * 20 mm pixels) made by Proteus, Inc. with similar 10*10 arrays of LSO:Ce and BGO (1mm * 1mm * 15mm pixels) loaned to us by Saint-Gobain. The imaging and spectroscopic behaviors of these scintillator arrays are strongly affected by the choice of a reflector used as an inter-pixel spacer (3M ESR in the case of the Proteus arrays and white, diffuse-reflector for the Saint-Gobain arrays). We have constructed a 3700-pixel LYSO:Ce Prototype NIF Gamma-Ray Imager for use in diagnosing target compression in inertial confinement fusion. This system was tested at the OMEGA Laser and exhibited significant optical, inter-pixel cross-talk that was traced to the use of a single-layer of ESR film as an inter-pixel spacer. We show how the optical cross-talk can be mapped, and discuss correction procedures. We demonstrate a 10*10 YSO:Ce array as part of an iQID (formerly BazookaSPECT) imager and discuss issues related to the internal activity of 176Lu in LSO:Ce and LYSO:Ce detectors. PMID- 26236071 TI - Detector, collimator and real-time reconstructor for a new scanning-beam digital x-ray (SBDX) prototype. AB - Scanning-beam digital x-ray (SBDX) is an inverse geometry fluoroscopy system for low dose cardiac imaging. The use of a narrow scanned x-ray beam in SBDX reduces detected x-ray scatter and improves dose efficiency, however the tight beam collimation also limits the maximum achievable x-ray fluence. To increase the fluence available for imaging, we have constructed a new SBDX prototype with a wider x-ray beam, larger-area detector, and new real-time image reconstructor. Imaging is performed with a scanning source that generates 40,328 narrow overlapping projections from 71 * 71 focal spot positions for every 1/15 s scan period. A high speed 2-mm thick CdTe photon counting detector was constructed with 320*160 elements and 10.6 cm * 5.3 cm area (full readout every 1.28 MUs), providing an 86% increase in area over the previous SBDX prototype. A matching multihole collimator was fabricated from layers of tungsten, brass, and lead, and a multi-GPU reconstructor was assembled to reconstruct the stream of captured detector images into full field-of-view images in real time. Thirty-two tomosynthetic planes spaced by 5 mm plus a multiplane composite image are produced for each scan frame. Noise equivalent quanta on the new SBDX prototype measured 63%-71% higher than the previous prototype. X-ray scatter fraction was 3.9-7.8% when imaging 23.3-32.6 cm acrylic phantoms, versus 2.3-4.2% with the previous prototype. Coronary angiographic imaging at 15 frame/s was successfully performed on the new SBDX prototype, with live display of either a multiplane composite or single plane image. PMID- 26236072 TI - Feasibility of CT-based 3D anatomic mapping with a scanning-beam digital x-ray (SBDX) system. AB - This study investigates the feasibility of obtaining CT-derived 3D surfaces from data provided by the scanning-beam digital x-ray (SBDX) system. Simulated SBDX short-scan acquisitions of a Shepp-Logan and a thorax phantom containing a high contrast spherical volume were generated. 3D reconstructions were performed using a penalized weighted least squares method with total variation regularization (PWLS-TV), as well as a more efficient variant employing gridding of projection data to parallel rays (gPWLS-TV). Voxel noise, edge blurring, and surface accuracy were compared to gridded filtered back projection (gFBP). PWLS reconstruction of a noise-free reduced-size Shepp-Logan phantom had 1.4% rRMSE. In noisy gPWLS-TV reconstructions of a reduced-size thorax phantom, 99% of points on the segmented sphere perimeter were within 0.33, 0.47, and 0.70 mm of the ground truth, respectively, for fluences comparable to imaging through 18.0, 27.2, and 34.6 cm acrylic. Surface accuracies of gFBP and gPWLS-TV were similar at high fluences, while gPWLS-TV offered improvement at the lowest fluence. The gPWLS-TV voxel noise was reduced by 60% relative to gFBP, on average. High contrast linespread functions measured 1.25 mm and 0.96 mm (FWHM) for gPWLS-TV and gFBP. In a simulation of gated and truncated projection data from a full sized thorax, gPWLS-TV reconstruction yielded segmented surface points which were within 1.41 mm of ground truth. Results support the feasibility of 3D surface segmentation with SBDX. Further investigation of artifacts caused by data truncation and patient motion is warranted. PMID- 26236073 TI - Validation of Osteoarthritis synthetic defect database via non-rigid registration. AB - Temporomandibular joint (TMJ) disorders are a group of conditions that cause pain and dysfunction in the jaw joint and the muscles controlling jaw movement. However, diagnosis and treatment of these conditions remain controversial. To date, there is no single sign, symptom, or test that can clearly diagnose early stages of osteoarthritis (OA). Instead, the diagnosis is based on a consideration of several factors, including radiological evaluation. The current radiological diagnosis scores of TMJ pathology are subject to misdiagnosis. We believe these scores are limited by the acquisition procedures, such as oblique cuts of the CT and head positioning errors, and can lead to incorrect diagnoses of flattening of the head of the condyle, formation of osteophytes, or condylar pitting. This study consists of creating and validating a methodological framework to simulate defects in CBCT scans of known location and size, in order to create synthetic TMJ OA database. User-generated defects were created using a non-rigid deformation protocol in CBCT. All segmentation evaluation, surface distances and linear distances from the user-generated to the simulated defects showed our methodological framework to be very precise and within a voxel (0.5 mm) of magnitude. A TMJ OA synthetic database will be created next, and evaluated by expert radiologists, and this will serve to evaluate how sensitive the current radiological diagnosis tools are. PMID- 26236075 TI - A proof of Bell's inequality in quantum mechanics using causal interactions. AB - We give a simple proof of Bell's inequality in quantum mechanics using theory from causal interaction, which, in conjunction with experiments, demonstrates that the local hidden variables assumption is false. The proof sheds light on relationships between the notion of causal interaction and interference between treatments. PMID- 26236074 TI - Evaluating Changes in the Prevalence of the Autism Spectrum Disorders (ASDs). AB - Autism spectrum disorders (ASDs) are estimated to occur among about one percent of children in the United States. This estimate is in line with estimates from other industrialized countries. However, the identified prevalence of ASDs has increased significantly in a short time period based on data from multiple studies including the U.S. Centers for Disease Control and Prevention's (CDC) Autism and Developmental Disabilities Monitoring (ADDM) Network. Whether increases in ASD prevalence are partly attributable to a true increase in the risk of developing ASD or solely to changes in community awareness and identification patterns is not known. It is clear that more children are identified with an ASD now than in the past and the impact on individuals, families, and communities is significant. However, disentangling the many potential reasons for ASD prevalence increases has been challenging. Understanding the relative contribution of multiple factors such as variation in study methods, changes in diagnostic and community identification, and potential changes in risk factors is an important priority for the ADDM Network and for CDC. This article summarizes the discussion from a workshop that was co-sponsored by CDC and Autism Speaks as a forum for sharing knowledge and opinions of a diverse range of stakeholders about changes in ASD prevalence. Panelists discussed recommendations for building on existing infrastructure and developing new initiatives to better understand ASD trends. The information, research, and opinions shared during this workshop add to the knowledge base about ASD prevalence in an effort to stimulate further work to understand the multiple reasons behind increasing ASD prevalence. PMID- 26236076 TI - Correlation of Parathormone and the Serum Values of Acidum Uricum with Calcium Nephrolithiasis Examined by Three Different Methods of Diagnostics. AB - INTRODUCTION: Urolithiasis is a multifactorial disease. Changes in social and economic living conditions have generated changes in chemical composition of urolith too. Although calcium is a predominant crystalline constituent of kidney stones in 80% of cases, metabolic disorders are not the main reason for their formation. Hyperparathyroidism may be a cause of occurrence of calcium lithiasis, however, the biggest number of its occurrence is not a consequence of elevated values of parathormone. Acid uric has a pervasive presence in all body fluids. The serum level of acid uric is determined by its rate of synthesis, rate of excretion by kidney and gastrointestinal tract, and metabolism. GOAL: The goal of our study is to determine a correlation of calcium lithiasis of the upper part of the urinary tract with the parathormone values and the concomitant values of acidum uricum. MATERIAL AND METHODS: The study was prospective and included 120 patients with calcium lithiasis of the upper part of urinary tract, divided in three age categories, 20-40 years, 40-60 years and older than 60 years. The diagnosis of calcium lithiasis of the upper part of the urinary tract was made on the basis of urinary tract ultrasonography, and kidney-ureter-bladder radiography (KUB) /intravenous urography (IVU), urine culture and chemical analysis of stone with patients who had a spontaneous emission of stone or following some of the methods for active removal of stone; with some patients non-contrast (NCCT) was carried out too. All patients were subjected to the laboratory analysis of the serum level of acidum uricum and parathormone. RESULTS: With observed 120 patients suffering from calcium urolithiasis, who belonged to adult population, no patient had an elevated value of parathormone, while three patients (2.5%) had the values of acidum uricum higher than the reference values. The average value (for both parameters) was the lowest with the youngest patients and vice versa, and only in the group of 40 to 60 years of age there were patients whose values of the acidum uricum parameter was outside the interval of reference values; the other age groups did not have such values. Based on the analysis of the variance, as a statistical method, it was determined that the average values of acidum uricum in different age groups were statistically significantly different, which is not the case for the parameter parathormone. (p>0,05). CONCLUSION: The biggest number of nephrolithiasis is not a consequence of elevated values of parathormone. Hyperuricosemia may be present with calcium urolithiasis, without participation in forming kidney stones, most probably as an indirect sign of the existence of the initial insulin resistance and metabolic disease. PMID- 26236077 TI - Evaluation of Biocompatibility of Root Canal Sealers on L929 Fibroblasts with Multiscan EX Spectrophotometer. AB - INTRODUCTION: The purpose of the current study was to estimate the biocompatibility of endodontic sealers with different bases on L929 mouse fibroblasts permanent cell line using Multiscan EX Spectrophotometer. MATERIALS AND METHODS: Endodontics sealers used in this study were GuttaFlow (Roeko) silicone based sealer, AH plus (De Tray-DENTSPLY) epoxy resin based, Apexit (Vivadent) calcium hydroxide based and Endorez (Ultradent) methacrylate based sealer. Sealer were tested trough time, freshly mixed 24 h, 48h and 7 days after setting. Biocompatibility was determinate on permanent cell lines L929 mouse fibroblasts trough cytotoxicity using MTT assay. Level of absorption was measured with multi scan EX spectrophotometer on length 420-600 nm. RESULTS: Sealer based on calcium hydroxide Apexit Plus, GuttaFlow silicone based sealer and AH plus epoxy resin based sealer, have shown a low cytotoxicity through the all periods of time on culture of L292 mouse fibroblasts. Methacrylate based sealer, Endorez showed moderate cytotoxicity when freshly mixed and after 7 days. After 24 hours the visibility of the cells was 74,0% and after 48 hours 65,1%. which is slightly cytotoxic. CONCLUSIONS: According to results of this study there is a statistically significant difference among the groups p<0,05 for all the tested sealers. Apexit Plus, GuttaFlow and AH plus can be considered as biocompatibile. EndoREZ sealer which is based on methacrylate, after 7 days shows 50,1% of visible live cells which is considered as moderate cytotoxicity. PMID- 26236079 TI - Relationship Between Psychological Empowerment and Productivity of Medical Librarians. AB - INTRODUCTION: Psychological empowerment is really important and has remarkable effect on different organizational variables such as job satisfaction, organizational commitment, productivity, etc. So the aim of this study was to investigate the relationship between psychological empowerment and productivity of Librarians in Isfahan Medical University. METHODS: This was correlational research. Data were collected through two questionnaires. Psychological empowerment questionnaire and the manpower productivity questionnaire of Gold. Smith Hersey which their content validity was confirmed by experts and their reliability was obtained by using Cronbach's Alpha coefficient, 0.89 and 0.9 respectively. Due to limited statistical population, did not used sampling and review was taken via census. So 76 number of librarians were evaluated. Information were reported on both descriptive and inferential statistics (correlation coefficient tests Pearson, Spearman, T-test, ANOVA), and analyzed by using the SPSS19 software. FINDINGS: In our study, the trust between partners and efficacy with productivity had the highest correlation. Also there was a direct relationship between psychological empowerment and the productivity of labor (r =0.204). In other words, with rising of mean score of psychological empowerment, the mean score of efficiency increase too. CONCLUSIONS: The results showed that if development programs of librarian's psychological empowerment increase in order to their productivity, librarians carry out their duties with better sense. Also with using the capabilities of librarians, the development of creativity with happen and organizational productivity will increase. PMID- 26236078 TI - Development of a Fuzzy Decision Support System to Determine the Severity of Obstructive Pulmonary in Chemical Injured Victims. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is the most common known complication of exposure to mustard gas. Thus, all clinical guidelines have provided some recommendation for diagnosis, clinical management and treatment of this disease. Decision support systems are used to increase the acceptance of clinical guidelines. The purpose of this research is to develop a CDSS to determine the severity of COPD in chemical injured victims. OBJECTIVES: Development of a decision support system to determine the severity of COPD. PATIENTS AND METHODS: First, the variables influencing to determining the severity of the disease was classified through studying the clinical guidelines. Then, the fuzzy model was implemented. To testing the system, the data from 50 patients were used. RESULTS: the overall accuracy in determining the severity of the injury is equal to 92%, these indicators reflect the proper functioning of the system to assist the physician regarding the diagnosis of chronic obstructive pulmonary disease and determining its severity. CONCLUSIONS: The CDSS has efficient results and satisfactory performance. Although, the medical expert systems cannot be expected to provide 100 percent correct responses, however, they can be useful in the areas of patient management, diagnosis and treatment planning. PMID- 26236080 TI - The Influence of Aortic Valve Replacement on Functional Moderate - To-Severe Mitral Regurgitation in Patients with Aortic Valve Stenosis. AB - GOAL: The aim of this study was to show whether the concomitant functional mitral regurgitation in patients undergoing aortic valve replacement improves after this surgical procedure and to identify preoperative echocardiographic parameters that may influence the lack of improvement in mitral regurgitation (MR) after aortic valve replacement (AVR). MATERIAL AND METHODS: The study included 45 patients with severe aortic stenosis and concomitant moderate to severe (+2/+3)mitral regurgitation. RESULTS: The results of our study indicated an improvement in the degree of mitral regurgitation in 24 patients. The most prominent parameters responsible for the lack of improvement of mitral regurgitation in our study were LVIDd, ERO, RVol, pulmonary artery systolic pressure and left atrial diameter. Identification of echocardiographic predictors may assist in selection of patients for whom more aggressive surgical treatment is advised. CONCLUSION: Concomitant moderate to severe functional MR indicates that MV should be repaired or replaced at the time of aortic valve surgery where at least two of indicated predicted preoperative echocardiographic parameters are present. PMID- 26236081 TI - Real Time Recognition of Heart Attack in a Smart Phone. AB - BACKGROUND: In many countries, including our own, cardiovascular disease is the most common cause of mortality and morbidity. Myocardial infarction (heart attack) is of particular importance in heart disease as well as time and type of reaction to acute myocardial infarction and these can be a determining factor in patients' outcome. METHODS: In order to reduce physician attendance time and keep patients informed about their condition, the smart phone as a common communication device has been used to process data and determine patients' ECG signals. For ECG signal analysis, we used time domain methods for extracting the ST-segment as the most important feature of the signal to detect myocardial infarction and the thresholding methods and linear classifiers by LabVIEW Mobile Module were used to determine signal risk. RESULTS: The sensitivity and specificity as criteria to evaluate the algorithm were 98% and 93.3% respectively in real time. CONCLUSIONS: This algorithm, because of the low computational load and high speed, makes it possible to run in a smart phone. Using Bluetooth to send the data from a portable monitoring system to a smart phone facilitates the real time applications. By using this program on the patient's mobile, timely detection of infarction so to inform patients is possible and mobile services such as SMS and calling for a physician's consultation can be done. PMID- 26236082 TI - Barriers to Research Activities from the Perspective of the Students of Isfahan University of Medical Sciences. AB - INTRODUCTION: Necessity to establish a coherent and targeted research context in order to development of any country is increasingly important. But the basic step in creating an effective research context would be enrichment motivation of researchers especially students and resolve barriers of research. Therefore, the purpose of this study was to determine barriers of research activities from the perspective of students of Isfahan University of Medical Sciences. METHODS: This is research. Data was collected with author made questionnaire. The study sample consisted of students from Isfahan medical university and sample size based on Krejcie and Morgan table was 357. Sampling was Stratified Random. The validity of questionnaire confirmed by Library and information professionals and reliability based on Cronbach's Alpha was 0.933, respectively. The type of descriptive statistics was (percentage, frequency and mean) and inferential statistics (T test, ANOVA, one-Sample Statistics) and SPSS software was used. FINDINGS: Results showed that the mean of barriers to research activities among students of Isfahan University of Medical Sciences was 3.89 +/- 0. 483. The highest mean was related to density of students' curriculum (4.22+/- 0.968) and lowest mean related to lack of access to appropriate library resources. Also, the mean of research activities 's barriers, according to aspects showed that the mean in individual barriers level (4.06+/-0.635) was more than other aspects: social and cultural aspects (4.01+/- 0.661), economical aspect (4.04+/- 0.787) and organizational barriers (3.78+/-0.503). The lowest mean was related to organizational barriers. Also there is no difference between mean of research activities' barriers of student of Isfahan University of Medical Sciences with regarded of gender, level of education and college. CONCLUSION: According to results of this research, although, the main barriers between students was individual barriers such as: lack of sufficient familiarity with research methods, insufficient experience in research and lack of familiarity with the terms of the articles in publication, but other aspects like economic, cultural, social and organizational was in bad condition too. Therefore it is suggested that workshops related to research methodologies is executed, like proposal writing, writing articles in university especially for students and administrators support student's research activities, effectively. PMID- 26236083 TI - Diabetes Research in Iran: a Scientometric Analysis of Publications Output. AB - INTRODUCTION: In the developing countries, diabetes mellitus as a chronic diseases, have replaced infectious diseases as the main causes of morbidity and mortality. International Diabetes Federation (IDF) recently estimates 382 million people have diabetes globally and more than 34.6 million people in the Middle East Region and this number will increase to 67.9 million by 2035. The aim of this study was to analyze Iran's research performance on diabetes in national and international context. METHODS: This Scientometric analysis is based on the Iranian publication data in diabetes research retrieved from the Scopus citation database till the end of 2014. The string used to retrieve the data was developed using "diabetes" keyword in title, abstract and keywords, and finally Iran in the affiliation field was our main string. RESULTS: Iran's cumulative publication output in diabetes research consisted of 4425 papers from 1968 to 2014, with an average number of 96.2 papers per year and an annual average growth rate of 25.5%. Iran ranked 25th place with 4425 papers among top 25 countries with a global share of 0.72 %. Average of Iran's publication output was 6.19 citations per paper. The average citation per paper for Iranian publications in diabetes research increased from 1.63 during 1968-1999 to 10.42 for 2014. CONCLUSIONS: Although diabetic population of Iran is increasing, number of diabetes research is not remarkable. International Diabetes Federation suggested increased funding for research in diabetes in Iran for cost-effective diabetes prevention and treatment. In addition to universal and comprehensive services for diabetes care and treatment provided by Iranian health care system, Iranian policy makers should invest more on diabetes research. PMID- 26236084 TI - Data Standards in Tele-radiology. AB - Data standards play an important role to provide interoperability among different system. As other applications of telemedicine, the tele-radiology needs these standards to work properly. In this article, we conducted a review to introduce some data standards about tele-radiology. By searching PUBMED and Google Scholar database, we find more relevant articles about data standards in tele-radiology. Three categories of standards identified, including data interchange, document and terminology standards. Data interchange standards, including those which facilitate the understanding of the format of a massage between systems, such as DICOM and HL7. Document standards, including those which facilitate the contents of a massage, such as DICOM SR and HL7 CDA. And terminology standards, including those which facilitate the understanding of concepts of the domain. Since, the harmonization between different standards are important to meet interoperability, so the more effort is needed to conduct harmonization between tele-radiology standards and other domain. PMID- 26236085 TI - Education and Training for Major Incidents Through Medical Response to Major Incidents-MRMI course. AB - Incidence of major incidents nowadays is in constant growth, especially in last decade. Main goal of all health systems is to minimize and prevent tragic outcomes of major incidents, thus reducing morbidity and mortality and psychological and physical suffering. Lessons learned from Major Incidents throughout the World point out that tragical outcomes could be avoided through adequate preparation and planning. Necessity to plan and to educate to response to Major incident is greater than ever. Finally it is legal obligation that every hospital has plan in case of Major Incident. Effective planning must incorporate: identification of risks, methods of prevention, identification of all recourses, anticipation of errors and detailed protocol of response for each participant. Knowledge and skills needed for Major incident situations must be adopted through interactive training and practical exercise ("learning by doing"). That can be achieved by field exercises and by simulation model. Simulation model has many advantages and enables simultaneous education and training of all participants; scene, transport, hospitals, communication and command which than can be evaluated through objective outcomes. The goal is to train medical staff in real time, on position they are assigned to, with available resources in conditions of Major incident. PMID- 26236087 TI - Successful Implantation of Bipolar Epicardial Leads and Dual Chamber Pacemaker in Infant After Postoperative Atrioventricular Heart Block. AB - Total atrioventricular (AV) block is inconvenient and serious complication of open heart surgery. Permanent total AV block requires the implantation of permanent pacemaker in order to allow normal hemodynamics and patient's survival. In infancy additional challenge is the surgical approach, the selection of electrodes and PM, as well as place of implantation. We are publishing case report of successful double-chamber DDD pacemaker implantation at an infant born with Fallot tetralogy and with low birth weight due to complete AV block after primary surgical correction of these congenital defects. PMID- 26236086 TI - Information Retrieval in Telemedicine: a Comparative Study on Bibliographic Databases. AB - BACKGROUND AND AIMS: The first step in each systematic review is selection of the most valid database that can provide the highest number of relevant references. This study was carried out to determine the most suitable database for information retrieval in telemedicine field. METHODS: Cinhal, PubMed, Web of Science and Scopus databases were searched for telemedicine matched with Education, cost benefit and patient satisfaction. After analysis of the obtained results, the accuracy coefficient, sensitivity, uniqueness and overlap of databases were calculated. RESULTS: The studied databases differed in the number of retrieved articles. PubMed was identified as the most suitable database for retrieving information on the selected topics with the accuracy and sensitivity ratios of 50.7% and 61.4% respectively. The uniqueness percent of retrieved articles ranged from 38% for Pubmed to 3.0% for Cinhal. The highest overlap rate (18.6%) was found between PubMed and Web of Science. Less than 1% of articles have been indexed in all searched databases. CONCLUSION: PubMed is suggested as the most suitable database for starting search in telemedicine and after PubMed, Scopus and Web of Science can retrieve about 90% of the relevant articles. PMID- 26236088 TI - Dermatoglyphics and Reproductive Risk in a Family with Robertsonian Translocation 14q;21q. AB - AIM: The present study is carried out to evaluate the risk of giving birth to children with Down syndrome in a family with Robertsonian translocation 14q;21q, and to find the dermatoglyphic changes present in carriers of this translocation. METHODS: Cytogenetics diagnosis has been made according to Moorhead and Seabright method, while the analysis of prints (dermatoglyphics analysis) was made with the Cummins and Midlo method. RESULTS: Cytogenetic diagnosis has been made in a couple who suffered the spontaneous miscarriages and children with Down syndrome. Robertsonian translocation between chromosomes 14 and 21 (45, XX, der (14; 21) (q10; q10)) was found in a female partner who had four pregnancies, in two of which was found fetus karyotype with trisomy in chromosome 21 and pregnancies were terminated. The outcome of fourth pregnancy was twin birth, one of them with normal karyotype and another with Down syndrome due to Robertsonian translocation inherited by mother side. Specific dermatoglyphics traits are found in the child carrying Down syndrome, whereas several traits of dermatoglyphics characteristic of Down syndrome have been displayed among the silent carriers of Robertsonian translocation 14q;21q. CONCLUSION: Robertsonian translocation found in female partner was the cause of spontaneous miscarriages, of giving birth to a child with Down syndrome, and of trisomy of chromosome 21 due to translocation in two pregnancies. PMID- 26236089 TI - The Most Influential Scientists in the Development of Medical Informatics (6): Heinz Zemanek. PMID- 26236090 TI - Air exchange rates from atmospheric CO2 daily cycle. AB - We propose a new approach for measuring ventilation air exchange rates (AERs). The method belongs to the class of tracer gas techniques, but is formulated in the light of systems theory and signal processing. Unlike conventional CO2 based methods that assume the outdoor ambient CO2 concentration is constant, the proposed method recognizes that photosynthesis and respiration cycle of plants and processes associated with fuel combustion produce daily, quasi-periodic, variations in the ambient CO2 concentrations. These daily variations, which are within the detection range of existing monitoring equipment, are utilized for estimating ventilation rates without the need of a source of CO2 in the building. Using a naturally-ventilated residential apartment, AERs obtained using the new method compared favorably (within 10%) to those obtained using the conventional CO2 decay fitting technique. The new method has the advantages that no tracer gas injection is needed, and high time resolution results are obtained. PMID- 26236091 TI - Episodic Memory Does Not Add Up: Verbatim-Gist Superposition Predicts Violations of the Additive Law of Probability. AB - Fuzzy-trace theory's assumptions about memory representation are cognitive examples of the familiar superposition property of physical quantum systems. When those assumptions are implemented in a formal quantum model (QEMc), they predict that episodic memory will violate the additive law of probability: If memory is tested for a partition of an item's possible episodic states, the individual probabilities of remembering the item as belonging to each state must sum to more than 1. We detected this phenomenon using two standard designs, item false memory and source false memory. The quantum implementation of fuzzy-trace theory also predicts that violations of the additive law will vary in strength as a function of reliance on gist memory. That prediction, too, was confirmed via a series of manipulations (e.g., semantic relatedness, testing delay) that are thought to increase gist reliance. Surprisingly, an analysis of the underlying structure of violations of the additive law revealed that as a general rule, increases in remembering correct episodic states do not produce commensurate reductions in remembering incorrect states. PMID- 26236092 TI - 'Put Your Money Where Your Mouth Is!': Effects of Streaks on Confidence and Betting in a Binary Choice Task. AB - Human choice under uncertainty is influenced by erroneous beliefs about randomness. In simple binary choice tasks, such as red/black predictions in roulette, long outcome runs (e.g. red, red, red) typically increase the tendency to predict the other outcome (i.e. black), an effect labeled the "gambler's fallacy." In these settings, participants may also attend to streaks in their predictive performance. Winning and losing streaks are thought to affect decision confidence, although prior work indicates conflicting directions. Over three laboratory experiments involving red/black predictions in a sequential roulette task, we sought to identify the effects of outcome runs and winning/losing streaks upon color predictions, decision confidence and betting behavior. Experiments 1 (n = 40) and 3 (n = 40) obtained trial-by-trial confidence ratings, with a win/no win payoff and a no loss/loss payoff, respectively. Experiment 2 (n = 39) obtained a trial-by-trial bet amount on an equivalent scale. In each experiment, the gambler's fallacy was observed on choice behavior after color runs and, in experiment 2, on betting behavior after color runs. Feedback streaks exerted no reliable influence on confidence ratings, in either payoff condition. Betting behavior, on the other hand, increased as a function of losing streaks. The increase in betting on losing streaks is interpreted as a manifestation of loss chasing; these data help clarify the psychological mechanisms underlying loss chasing and caution against the use of betting measures ("post-decision wagering") as a straightforward index of decision confidence. (c) 2014 The Authors. Journal of Behavioral Decision Making published by John Wiley & Sons Ltd. PMID- 26236093 TI - Distraction during Deployment: Marital Relationship Associations with Spillover for Deployed Army Soldiers. AB - Military spouses often have concerns regarding the impact of their communication on soldiers during deployment. However, literature is mixed regarding how communication between soldiers and spouses may impact soldiers' self-reported work functioning during deployment, suggesting the need to evaluate moderating factors. In the current study, three relationship factors (marital satisfaction, conflictual communication, and proportion of conversation focused on problems) were tested as moderators of communication frequency and negative marriage-to work spillover for soldiers. Whereas the three relationship factors were independently related to negative spillover, none significantly moderated the relationship between communication frequency and spillover. The overall pattern of results suggests that (a) lower marital satisfaction, a focus on problems during communication, and conflictual communication are each strongly linked to spillover for deployed soldiers, and (b) military couples may be self-restricting deployment communication frequency when experiencing less marital satisfaction and higher rates of negative communication. Implications for communication during deployment are discussed. PMID- 26236095 TI - Manganese superoxide dismutase promotes interaction of actin, S100A4 and Talin, and enhances rat gastric tumor cell invasion. AB - It has been demonstrated that cancer cells are under high levels of oxidative stress and express high levels of Manganese superoxide dismutase (MnSOD) to protect themselves and support the anabolic metabolism needed for growth and cell motility. The aim of this study was to identify proteins that may have a correlation with invasion and redox regulation by mitochondrial reactive oxygen species (ROS). MnSOD scavenges superoxide anions generated from mitochondria and is an important regulator of cellular redox status. Oxidative posttranslational modification of cysteine residues is a key mechanism that regulates protein structure and function. We hypothesized that MnSOD regulates intracellular reduced thiol status and promotes cancer invasion. A proteomic thiol-labeling approach with 5-iodoacetamidofluorescein was used to identify changes in intracellular reduced thiol-containing proteins. Our results demonstrate that overexpression of MnSOD maintained the major structural protein, actin, in a reduced state, and enhanced the invasion ability in gastric mucosal cancer cells, RGK1. We also found that the expression of Talin and S100A4 were increased in MnSOD-overexpressed RGK1 cells. Moreover, Talin bound not only with actin but also with S100A4, suggesting that the interaction of these proteins may, in part, contribute to the invasive ability of rat gastric cancer. PMID- 26236094 TI - Advanced glycation end-products: modifiable environmental factors profoundly mediate insulin resistance. AB - Advanced glycation end-products are toxic by-products of metabolism and are also acquired from high-temperature processed foods. They promote oxidative damage to proteins, lipids and nucleotides. Aging and chronic diseases are strongly associated with markers for oxidative stress, especially advanced glycation end products, and resistance to peripheral insulin-mediated glucose uptake. Modifiable environmental factors including high levels of refined and simple carbohydrate diets, hypercaloric diets and sedentary lifestyles drive endogenous formation of advanced glycation end-products via accumulation of highly reactive glycolysis intermediates and activation of the polyol/aldose reductase pathway producing high intracellular fructose. High advanced glycation end-products overwhelm innate defenses of enzymes and receptor-mediated endocytosis and promote cell damage via the pro-inflammatory and pro-oxidant receptor for advanced glycation end-products. Oxidative stress disturbs cell signal transduction, especially insulin-mediated metabolic responses. Here we review emerging evidence that restriction of dietary advanced glycation end-products significantly reduces total systemic load and insulin resistance in animals and humans in diabetes, polycystic ovary syndrome, healthy populations and dementia. Of clinical importance, this insulin sensitizing effect is independent of physical activity, caloric intake and adiposity level. PMID- 26236096 TI - Coenzyme Q10 and alpha-lipoic acid: antioxidant and pro-oxidant effects in plasma and peripheral blood lymphocytes of supplemented subjects. AB - Reactive oxygen species not only cause damage but also have a physiological role in the protection against pathogens and in cell signalling. Mitochondrial nutrients, such as coenzyme Q10 and alpha-lipoic acid, beside their acknowledged antioxidant activities, show interesting features in relation to their redox state and consequent biological activity. In this study, we tested whether oral supplementation with 200 mg/day of coenzyme Q10 alone or in association with 200 mg/die of alpha-lipoic acid for 15 days on 16 healthy subjects was able to modulate the oxidative status into different compartments (plasma and cells), in basal condition and following an oxidative insult in peripheral blood lymphocytes exposed in vitro to H2O2. Data have shown that tested compounds produced antioxidant and bioenergetic effects improving oxidative status of the lipid compartment and mitochondrial functionality in peripheral blood lymphocytes. Simultaneously, an increased intracellular reactive oxygen species level was observed, although they did not lead to enhanced DNA oxidative damage. Coenzyme Q10 and alpha-lipoic acid produced beneficial effects also steering intracellular redox poise toward a pro-oxidant environment. In contrast with other antioxidant molecules, pro-oxidant activities of tested mitochondrial nutrients and consequent oxidant mediated signalling, could have important implications in promoting adaptive response to oxidative stress. PMID- 26236097 TI - Mangosteen pericarp extract inhibits the formation of pentosidine and ameliorates skin elasticity. AB - The inhibition of advanced glycation end-products (AGEs) by daily meals is believed to become an effective prevention for lifestyle-related diseases. In the present study, the inhibitory effect of hot water extracts of mangosteen (Garcinia mangostana L.) pericarp (WEM) on the formation of pentosidine, one of AGEs, in vitro and in vivo and the remedial effect on skin conditions were measured. WEM significantly inhibited pentosidine formation during gelatin incubation with ribose. Several compounds purified from WEM, such as garcimangosone D and rhodanthenone B, were identified as inhibitors of pentosidine formation. Oral administration of WEM at 100 mg/day to volunteer subjects for 3 months reduced the serum pentosidine contents. Because obtaining skin biopsies from healthy volunteers is ethically difficult, AGE accumulation in the skin was estimated by a fluorescence detector. The oral administration of WEM significantly reduced the skin autofluorescence intensity, demonstrating that WEM also reduced AGE accumulation in the skin. Furthermore, the elasticity and moisture content of the skin was also improved by WEM. These results demonstrate that intakes of WEM reduces the glycation stress and results in the improvement of skin conditions. PMID- 26236098 TI - Biochemical effects, hypolipidemic and anti-inflammatory activities of Artemisia vulgaris extract in hypercholesterolemic rats. AB - The purpose of the present study was to investigate hypolipidemic and anti inflammatory effects of Artemisia vulgaris extract in hypercholesterolemic rats. Hypercholesterolemia was induced by feeding of rats with high fat diet containing 3% cholesterol in olein oil, for 8 weeks. Feeding of rats with high fat diet for 8 weeks, leading to a significant increase in serum triglycerides, total cholesterol, low density lipoprotein cholesterol, malondialdehyde and nitric oxide, tumor necrosis factor-alpha levels and a significant decrease in serum high density lipoprotein cholesterol level, liver hydroxymethylglutaryl-CoA reductase activity and paraoxonase-1 activities as compared to the normal control group. Treatment of high fat diet rats with Artemisia vulgaris extract for 4 weeks at a dose of 100 mg/kg per day, resulted in normalized serum lipid profile, a significant increase in paraoxonase-1 activity and decrease in serum malondialdehyde, nitric oxide and tumor necrosis factor-alpha level as compared to high fat diet-treated animals. Also the extract caused a significant decrease in hydroxymethylglutaryl-CoA reductase activity as compared with both high fat diet-treated animals and control ones. In conclusion, Artemisia vulgaris extract has hypolipidemic, anti-inflammatory, antioxidant properties; it may serve as a source for the prevention of atherosclerosis and cardiovascular diseases. PMID- 26236099 TI - Suppression of intestinal carcinogenesis in Apc-mutant mice by limonin. AB - Limonoids in citrus fruits are known to possess multiple biological functions, such as anti-proliferative functions in human cancer cell lines. Therefore, we aimed to investigate the suppressive effect of limonin on intestinal polyp development in Apc-mutant Min mice. Five-week-old female Min mice were fed a basal diet or a diet containing 250 or 500 ppm limonin for 8 weeks. The total number of polyps in mice treated with 500 ppm limonin decreased to 74% of the untreated control value. Neoplastic cell proliferation in the polyp parts was assessed by counting PCNA positive cells, and a tendency of reduction was obtained by limonin treatment. Moreover, expression levels of c-Myc and MCP-1 mRNA in the polyp part were reduced by administration of limonin. We finally confirmed the effects of limonin on beta-catenin signaling, and found limonin significantly inhibited T-cell factor/lymphocyte enhancer factor-dependent transcriptional activity in a dose-dependent manner in the Caco-2 human colon cancer cell line. Our results suggest that limonin might be a candidate chemopreventive agent against intestinal carcinogenesis. PMID- 26236100 TI - The effects of moderate exercise on secretory IgA production in mice depends on dietary carbohydrate intake. AB - Secretory immunoglobulin A (sIgA) is produced from intestinal mucosa and is essential in preventing infection. We analyzed the influence of moderate exercise on intestinal sIgA production and antioxidative function under different carbohydrate nutritional conditions. Thirty-six mice were fed an experimental diet for 10 weeks-a high-carbohydrate (HC) diet, a low-carbohydrate (LC) diet, or a control (C) diet. After 1 week on the experimental diets, mice were divided into sedentary and exercise groups (n = 6/group), where the exercise consisted of treadmill running for 30 min/day at 11 m/min for 6 days/week in 9 consecutive weeks. Intestinal sIgA levels in the exercise groups fed C or LC diets were significantly lower compared with the parallel sedentary groups, or exercise group mice fed HC diet. Expression of the polymeric immunoglobulin receptor (pIgR) in the small intestine was significantly higher in the exercise group fed a HC diet. Superoxide dismutase activity in the small intestine was higher in the exercise group than in the sedentary group, with no effects resulting from intake carbohydrate levels. Our results indicated that moderate exercise reduced the levels of intestinal sIgA depending on decreasing of carbohydrate intake, which is connected with the expression of pIgR. PMID- 26236102 TI - Effect of long-term proton pump inhibitor therapy and healing effect of irsogladine on nonsteroidal anti-inflammatory drug-induced small-intestinal lesions in healthy volunteers. AB - This study assessed time-course changes of the small intestinal lesions during long-term treatment with diclofenac sodium plus omeprazole and the effects of irsogladine on such lesions. Thirty two healthy volunteers were treated with diclofenac sodium (75 mg/day) plus omeprazole (10 mg/day) for 6 weeks, with irsogladine (4 mg/day) added from weeks 6 to 10 (Group A) or with diclofenac sodium plus irsogladine for 6 weeks (Group B). Five volunteers received diclofenac sodium plus omeprazole for 10 weeks (Group C). Subjects underwent capsule endoscopy at each time. In Group A, the number of lesions remarkably increased at week 2, but the worse was not found at week 6 compared with week 2, whereas no exacerbation of lesions was observed in Group B. Additional treatment with irsogladine from weeks 6 to 10 in Group A significantly decreased the number of lesions at weeks 10 compared with Group C. In Group C, no significant change in lesions was observed since weeks 2. In conclusions, a PPI did not prevent the occurrence of small intestinal damage. However such lesions were not aggravated since weeks 2. These suggested mucosal adaptation may occur in the small intestine. Irsogladine was effective in both preventing and healing such lesions. PMID- 26236101 TI - Metabolomics changes in a rat model of obstructive jaundice: mapping to metabolism of amino acids, carbohydrates and lipids as well as oxidative stress. AB - The study examined the global metabolic and some biochemical changes in rats with cholestasis induced by bile duct ligation (BDL). Serum samples were collected in male Wistar rats with BDL (n = 8) and sham surgery (n = 8) at day 3 after surgery for metabolomics analysis using a combination of reversed phase chromatography and hydrophilic interaction chromatography (HILIC) and quadrupole-time-of-flight mass spectrometry (Q-TOF MS). The serum levels of malondialdehyde (MDA), total antioxidative capacity (T-AOC), glutathione (GSH) and glutathione disulfide (GSSG), the activities of superoxide dismutase (SOD) and glutathion peroxidase (GSH-Px) were measured to estimate the oxidative stress state. Key changes after BDL included increased levels of l-phenylalanine, l-glutamate, l-tyrosine, kynurenine, l-lactic acid, LysoPC(c) (14:0), glycine and succinic acid and decreased levels of l-valine, PC(b) (19:0/0:0), taurine, palmitic acid, l isoleucine and citric acid metabolism products. And treatment with BDL significantly decreased the levels of GSH, T-AOC as well as SOD, GSH-Px activities, and upregulated MDA levels. The changes could be mapped to metabolism of amino acids and lipids, Krebs cycle and glycolysis, as well as increased oxidative stress and decreased antioxidant capability. Our study indicated that BDL induces major changes in the metabolism of all 3 major energy substances, as well as oxidative stress. PMID- 26236103 TI - Effect of a barley-vegetable soup on plasma carotenoids and biomarkers of cardiovascular disease. AB - Functional foods that provide benefits beyond their traditional nutritional value have attracted much interest. Aim of the study was to evaluate the nutritional and the functional properties of a frozen ready-to-eat soup containing barley and pigmented vegetables. Both glycaemic index and the glyceamic load of ready-to-eat soup were evaluated in vivo. Moreover the bioavailability of carotenoids (lutein and beta-carotene) and the effect on lipid profile and lipid peroxidation were studied in 38 volunteers whose diet was supplemented for two weeks with a daily portion (250 g) of the ready-to-eat soup. Plasma levels of carotenoids (lutein and beta-carotene) and plasma total antioxidant capacity significantly increased after 2 weeks of treatment. Furthermore, we observed a decrease in the levels of lipids (total cholesterol and low density lipoprotein-cholesterol) and of markers of lipid peroxidation (oxidized low density lipoprotein and lipid hydroperoxides) in plasma of all subjects. The glyceamic index of the product was 36, therefore it could be considered a low glyceamic index food. An accurate selection of vegetable foods results in a palatable and healthy product that provides benefits on plasma lipids and lipid peroxidation (Protocol number 211525). PMID- 26236104 TI - Is the serum l-arginine level during early pregnancy a predictor of pregnancy induced hypertension? AB - The objective of this study was to determine the concentration of serum l arginine in healthy pregnant women and infant cord blood and to compare them with those in patients with pregnancy-induced hypertension (PIH). The serum concentration of l-arginine in normal pregnant women at early gestation (n = 186) was determined and analyzed based on maternal factors such as the age, pre pregnancy body mass index (BMI), smoking and alcohol habits before pregnancy. Similarly, the concentration of cord blood of the newborns (n = 142) was also analyzed. These values were compared with those in the PIH group (n = 21). The potential risk factors for PIH were also estimated. The serum concentration of l arginine at early gestation in normal pregnant women (88.65 +/- 19.96 uM) was not affected by the maternal age and BMI before pregnancy. A lower l-arginine concentration at early gestation (<70 uM) significantly elevated PIH risk [adjusted odds ratio (OR) = 4.26, 95% CI 1.29-14.50]. In addition, either women with large body mass before pregnancy (BMI>25 kg/m(2)) or primipara women also showed a significant association with PIH risk [adjusted OR = 10.55 (2.95-40.68); 5.25 (1.72-19.15), respectively]. In conclusion, a lower l-arginine concentration at early gestation, overweight before pregnancy (BMI>25 kg/m(2)) and primipara could predict to the development of PIH. PMID- 26236105 TI - The relationship between metabolic syndrome and increase of metabolic syndrome score and serum vitamin D levels in Korean adults: 2012 Korean National Health and Nutrition Examination Survey. AB - The present study was conducted to assess the relationship between metabolic syndrome and metabolic syndrome score (MSS) and serum vitamin D levels in adults aged 20 or older (n = 5,483) using 2012 Korean National Health and Nutrition Examination Survey data, which represents national data in Korea. Key study results were as follows: First, serum 25-hydroxyvitamin D [25(OH)D] levels decreased significantly with an increase in MSS (p = 0.004), shown by serum 25(OH)D levels after adjusting the variables (age, gender, BMI, TC, HDL-C, FBS, SBP, and DBP, etc.). These were 17.30 +/- 0.16 ng/ml for MSS 0, 17.13 +/- 0.15 ng/ml for MSS 1, 17.02 +/- 0.16 ng/ml for MSS 2, 16.60 +/- 0.20 ng/ml for MSS 3, 16.55 +/- 0.28 ng/ml for MSS 4, and 15.52 +/- 0.50 ng/ml for MSS 5. Second, after adjusting the related variables, serum 25(OH)D levels were significantly lower (p = 0.004) in the metabolic syndrome group (16.49 +/- 0.19 ng/ml) than the non metabolic syndrome group (17.16 +/- 0.09 ng/ml). In conclusion, metabolic syndrome and the increased levels of its components are inversely associated with the serum vitamin D concentration in Korean adults. PMID- 26236106 TI - Erratum. AB - [This corrects the article DOI: 10.3164/jcbn.14-81.]. PMID- 26236108 TI - Prosocial Behavior: Long-Term Trajectories and Psychosocial Outcomes. AB - This study investigated developmental trajectories for prosocial behavior for a sample followed from age 10 - 18 and examined possible adjustment outcomes associated with membership in different trajectory groups. Participants were 136 boys and 148 girls, their teachers, and their parents (19.4% African American, 2.4% Asian, 51.9% Caucasian, 19.5% Hispanic, and 5.8% other). Teachers rated children's prosocial behavior yearly in grades 4 - 12. At the end of the 12th grade year, teachers, parents, and participants reported externalizing behaviors and participants reported internalizing symptoms, narcissism, and features of borderline personality disorder. Results suggested that prosocial behavior remained stable from middle childhood through late adolescence. Group-based mixture modeling revealed three prosocial trajectory groups: low (18.7%), medium (52.8%), and high (29.6%). Membership in the high prosocial trajectory group predicted lower levels of externalizing behavior as compared to the low prosocial trajectory group, and for girls, lower levels of internalizing symptoms. Membership in the medium prosocial trajectory group also predicted being lower on externalizing behaviors. Membership in the high prosocial trajectory group predicted lower levels of borderline personality features for girls only. PMID- 26236107 TI - Psychological Benefits of Nonpharmacological Methods Aimed for Improving Balance in Parkinson's Disease: A Systematic Review. AB - Parkinson's disease (PD) is a serious condition with a major negative impact on patient's physical and mental health. Postural instability is one of the cardinal difficulties reported by patients to deal with. Neuroanatomical, animal, and clinical studies on nonparkinsonian and parkinsonian subjects suggest an important correlation between the presence of balance dysfunction and multiple mood disorders, such as anxiety, depression, and apathy. Considering that balance dysfunction is a very common symptom in PD, we can presume that by its management we could positively influence patient's state of mind too. This review is an analysis of nonpharmacological methods shown to be effective and successful for improving balance in patients suffering from PD. Strategies such as general exercise, robotic assisted training, Tai Chi, Qi Gong, Yoga, dance (such as tango or ballet), box, virtual reality-based, or neurofeedback-based techniques and so forth can significantly improve the stability in these patients. Beside this physical outcome, many methods have also shown effect on quality of life, depression level, enjoyment, and motivation to continue in practicing the method independently. The purpose of this review is to provide information about practical and creative methods designed to improve balance in PD and highlight their positive impact on patient's psychology. PMID- 26236109 TI - Pegylated Interferon-alpha Modulates Liver Concentrations of Activin-A and Its Related Proteins in Normal Wistar Rat. AB - AIMS: To measure the expression of activin betaA-subunit, activin IIA and IIB receptors, Smad4, Smad7, and follistatin in the liver and the liver and serum concentrations of mature activin-A and follistatin in normal rat following treatment with pegylated interferon-alpha (Peg-INF-alpha) and ribavirin (RBV). MATERIALS AND METHODS: 40 male Wistar rats were divided equally into 4 groups: "control," "Peg-only" receiving 4 injections of Peg-INF-alpha (6 ug/rat/week), "RBV-only" receiving ribavirin (4 mg/rat/day) orally, and "Peg & RBV" group receiving both drugs. The expression of candidate molecules in liver was measured by immunohistochemistry and quantitative PCR. The concentrations of mature proteins in serum and liver homogenate samples were measured using ELISA. RESULTS: Peg-INF-alpha +/- RBV altered the expression of all candidate molecules in the liver at the gene and protein levels (P < 0.05) and decreased activin-A and increased follistatin in serum and liver homogenates compared with the other groups (P < 0.05). There were also significant correlations between serum and liver activin-A and follistatin. CONCLUSION: Peg-INF-alpha modulates the hepatic production of activin-A and follistatin, which can be detected in serum. Further studies are needed to explore the role of Peg-INF-alpha on the production of activins and follistatin by the liver and immune cells. PMID- 26236110 TI - Relationship between Prolactin Plasma Levels and White Matter Volume in Women with Multiple Sclerosis. AB - BACKGROUND: The role of prolactin (PRL) on tissue injury and repair mechanisms in multiple sclerosis (MS) remains unclear. The aim of this work was to investigate the relationship between PRL plasma levels and brain damage as measured by magnetic resonance imaging (MRI). METHODS: We employed a chemiluminescence immunoassay for measuring plasma levels of PRL. We used a 1.5 T scanner to acquire images and Jim 4.0 and SIENAX software to analyse them. RESULTS: We included 106 women with relapsing remitting (RR) MS and stable disease in the last two months. There was no difference in PRL plasma levels between patients with and without gadolinium enhancement on MRI. PRL plasma levels correlated with white matter volume (WMV) (rho = 0.284, p = 0.014) but not with grey matter volume (GMV). Moreover, PRL levels predicted changes in WMV (Beta: 984, p = 0.034). CONCLUSIONS: Our data of a positive association between PRL serum levels and WMV support the role of PRL in promoting myelin repair as documented in animal models of demyelination. The lack of an increase of PRL in the presence of gadolinium enhancement, contrasts with the view considering this hormone as an immune-stimulating and detrimental factor in the inflammatory process associated with MS. PMID- 26236111 TI - ATP-Binding Pocket-Targeted Suppression of Src and Syk by Luteolin Contributes to Its Anti-Inflammatory Action. AB - Luteolin is a flavonoid identified as a major anti-inflammatory component of Artemisia asiatica. Numerous reports have demonstrated the ability of luteolin to suppress inflammation in a variety of inflammatory conditions. However, its exact anti-inflammatory mechanism has not been fully elucidated. In the present study, the anti-inflammatory mode of action in activated macrophages of luteolin from Artemisia asiatica was examined by employing immunoblotting analysis, a luciferase reporter gene assay, enzyme assays, and an overexpression strategy. Luteolin dose-dependently inhibited the secretion of nitric oxide (NO) and prostaglandin E2 (PGE2) and diminished the levels of mRNA transcripts of inducible NO synthase (iNOS), tumor necrosis factor- (TNF-) alpha, and cyclooxygenase-2 (COX-2) in lipopolysaccharide- (LPS-) and pam3CSK-treated macrophage-like RAW264.7 cells without displaying cytotoxicity. Luteolin displayed potent NO-inhibitory activity and also suppressed the nuclear translocation of NF-kappaB (p65 and p50) via blockade of Src and Syk, but not other mitogen-activated kinases. Overexpression of wild type Src and point mutants thereof, and molecular modelling studies, suggest that the ATP-binding pocket may be the luteolin-binding site in Src. These results strongly suggest that luteolin may exert its anti-inflammatory action by suppressing the NF-kappaB signaling cascade via blockade of ATP binding in Src and Syk. PMID- 26236112 TI - PSP toxin levels and plankton community composition and abundance in size fractionated vertical profiles during spring/summer blooms of the toxic dinoflagellate Alexandrium fundyense in the Gulf of Maine and on Georges Bank, 2007, 2008, and 2010: 2. Plankton community composition and abundance. AB - As part of the Gulf of Maine Toxicity (GOMTOX) project, we determined Alexandrium fundyense abundance, paralytic shellfish poisoning (PSP) toxin levels in various plankton size fractions, and the community composition of potential grazers of A. fundyense in plankton size fractions during blooms of this toxic dinoflagellate in the coastal Gulf of Maine and on Georges Bank in spring and summer of 2007, 2008, and 2010. PSP toxins and A. fundyense cells were found throughout the sampled water column (down to 50 m) in the 20-64 MUm size fractions. While PSP toxins were widespread throughout all size classes of the zooplankton grazing community, the majority of the toxin was measured in the 20-64 MUm size fraction. A. fundyense cellular toxin content estimated from field samples was significantly higher in the coastal Gulf of Maine than on Georges Bank. Most samples containing PSP toxins in the present study had diverse assemblages of grazers. However, some samples clearly suggested PSP toxin accumulation in several different grazer taxa including tintinnids, heterotrophic dinoflagellates of the genus Protoperidinium, barnacle nauplii, the harpacticoid copepod Microsetella norvegica, the calanoid copepods Calanus finmarchicus and Pseudocalanus spp., the marine cladoceran Evadne nordmanni, and hydroids of the genus Clytia. Thus, a diverse assemblage of zooplankton grazers accumulated PSP toxins through food-web interactions. This raises the question of whether PSP toxins pose a potential human health risk not only from nearshore bivalve shellfish, but also potentially from fish and other upper-level consumers in zooplankton-based pelagic food webs. PMID- 26236113 TI - Lumbar spinal canal stenosis-special features. PMID- 26236114 TI - Outcomes are favorable in Asian patients undergoing deltoid-on open rotator cuff repair without acromioplasty. AB - BACKGROUND: To evaluate if rotator cuff repair without acromioplasty would result in improvement in outcomes without the risks associated with acromioplasty in Asian patients. METHODS: 38 primary repairs of tears of the rotator cuff were performed through a deltoid-on approach. The Simple Shoulder Test (SST) and UCLA shoulder rating scale were measured preoperatively and at 2 years post operatively. RESULTS: There was a significant improvement in the SST 2 years post operatively (p < 0.001). UCLA scores for pain control and function (p < 0.001) also significantly improved 2 years post-operatively. CONCLUSION: Outcomes are favorable in Asians following deltoid-on open rotator cuff repair without acromioplasty. LEVEL OF EVIDENCE: III. PMID- 26236115 TI - Mechanical testing of patellofemoral instability after induced failure of the patellofemoral ligament reconstruction using four differents cadavers grafts. AB - PURPOSE: To ascertain whether differences exist in joint instability after experimentally induced failure of medial patellofemoral ligament (MPFL) reconstruction in the cadaver knee with the four graft types most widely used for this procedure, and whether any of these grafts are associated with decreased risk in the event of failure. METHODS: Between March 2011 and March 2012, eight cadavers obtained from the local medical examiner's office were randomly allocated into four groups (four knees each). In each group, a different graft technique was used for MPFL reconstruction. The forces required to induce lateral dislocation of the patella before reconstruction and after experimental failure of surgical reconstruction were recorded. The tested graft techniques were then compared to assess which was associated with the least instability after failed reconstruction. RESULTS: When we compared the groups I (semitendinosus) and II (patellar tendon), the mean differences of the force required to produce a dislocation of the patella before and after the failure were 0.5 N and 12.5 N, respectively (p = 0.028). In comparison between groups I and III (medial third of the quadriceps tendon) the mean differences of the force required to produce dislocation before and after the failure caused were 0.5 N and 22 N, respectively (p < 0.001). In comparison between groups I and IV (Medial third of the quadriceps tendon) we found the mean differences of the force required to produce dislocation before and after the failure caused were 0.5 N and 5 N, respectively (p > 0.999). CONCLUSIONS: There were differences in residual instability after simulated MPFL reconstruction failure depending on graft type. Use of the free semitendinosus graft technique was associated with the least risk of residual instability in case of reconstruction failure. PMID- 26236116 TI - Clinical and haematological predictors of acute hematogenous Methicillin Resistant Staphylococcus aureus (MRSA) osteomyelitis & septic arthritis. AB - INTRODUCTION: In the present study, we observed differences in the clinical and haematological parameters in patients of MRSA and non MRSA acute osteoarticular infection. METHODOLOGY: For the patients of acute haematogenous osteomyelitis/septic arthritis, clinical features, haematological parameters and blood & aspirate cultures were recorded. RESULTS: Of 81 patients enrolled in the study, 61 were culture positive (22% MRSA). Statistically significant difference was found only in CRP (P < 0.001). ROC curve analysis shows that CRP levels of >13.9 mg/L, MRSA bone and joint infection could be predicted with 92.9% sensitivity and 79.1% specificity (AUC = 89.1). CONCLUSION: Estimation of serum CRP levels at the time of presentation can aid in distinguishing MRSA osteomyelitis from non MRSA one. PMID- 26236117 TI - Efficacy of early surgery and causes of surgical delay in patients with hip fracture. AB - BACKGROUND: Whether early surgery for hip fractures is effective remains controversial. The current Japanese medical system poses some constraints on conducting early surgery. We examined the usefulness of early surgery and factors that delay surgery in patients with hip fractures treated at our hospital. METHODS: Among 314 patients aged >=60 years treated for hip fractures since January 2006, 270 patients (55 men, 215 women; mean age 84.1 years; femoral neck fracture in 111, trochanteric fracture in 159) who underwent surgery were studied. They were divided into an early surgery group (surgery up to 1 day after admission) and a delayed surgery group (later than 1 day). Clinical parameters analyzed included age, gender, pre-injury residence, pre-injury ambulatory ability, admission during public holiday, fracture site, fracture type, blood tests and urinalysis at admission, chest radiography, electrocardiography, number of systemic chronic diseases, dementia, surgical modality, blood transfusion, length of hospital stay, ambulatory ability at discharge, and hospital death. After performing univariate analysis between two groups, the parameters that were identified as significant were further tested by multivariate analysis. RESULTS: Among 270 patients treated for hip fracture, 112 patients (41.5%) received early surgery. Multivariate analysis identified admission during public holiday, electrocardiographic abnormalities, femoral head replacement, and length of hospital stay as significant independent factors. CONCLUSION: The causes of surgical delay were admission during public holiday, electrocardiographic abnormalities, and femoral head replacement. Although length of hospital stay was shorter in patients with early surgery, there was no difference in outcome. PMID- 26236118 TI - The effect of peri-operative blood loss on postoperative pain following total knee arthroplasty. AB - AIM: This study aimed to investigate a possible link between peri-operative blood loss and post-operative pain following primary total knee arthroplasty (TKA). METHOD: A retrospective study was carried out using data from two RCTs (403 patients). Blood loss was estimated using Gross et al's formula. Blood transfusions were factored into calculations. Pain scores were obtained using a visual analogue score. RESULTS: Multiple regression analysis showed no relationship (0.09) and analysis of variance showed no significant difference (p = 0.597). Null hypothesis accepted. CONCLUSION: Minimising blood-loss remains an important goal during surgery. On-going efforts should be made to improve patient satisfaction following TKA. PMID- 26236120 TI - Outpatient minimally invasive spine surgery using endoscopy for the treatment of lumbar spinal stenosis among obese patients. AB - INTRODUCTION: The safety and effectiveness of outpatient endoscopic minimally invasive spinal surgery (MISS) for the treatment of lumbar spinal stenosis among obese patients is not well documented. METHODS: Pain, disability, and surgical variables were examined on 41 adult obese patients that underwent lumbar laminotomy and foraminotomy surgeries. RESULTS: A significant decrease in pain and disability scores between preoperative and postoperative were found (p value's < 0.001). DISCUSSION: MISS using endoscopy can achieve sufficient decompression that results in a significant reduction in the level of pain and disability among obese patients with minimal blood loss and no complications. PMID- 26236119 TI - Severe vascular complications and intervention following elective total hip and knee replacement: A 16-year retrospective analysis. AB - INTRODUCTION: Iatrogenic vascular injuries associated with elective orthopaedic joint procedures are relatively rare, however when they do occur they carry a risk of significant morbidity and mortality. The aim of this study was to investigate the incidence of vascular complications and resultant need for specialist intervention following elective total hip replacement (THR) and total knee replacement(TKR). METHODS: This was a retrospective analysis of prospectively collected data. The primary outcome measure was vascular complication requiring an interventional radiology procedures or vascular surgery. As a secondary outcome measure postoperative Modified Knee Society Scores and Harris Hip Scores were analysed to assess long term clinical outcome. RESULTS: Six cases of vascular injury requiring specialist intervention were identified. From 2073 total TKRs there were one cases of popliteal artery injury, one case of venous injury and two case of lateral geniculate artery injury (0.19%). From 1601 THRs there were two cases (0.12%) of arterial injury. All patients were treated successfully by a vascular surgeon or an interventional radiologist. Patient outcome varied considerably with the poorest results seen in the THR group. CONCLUSIONS: Iatrogenic vascular complications following elective THR and TKR carry a risk of significant morbidity and mortality. It is important that surgeons and trainees performing these procedures are conscious of these risks and able to identify vascular injuries promptly when they occur. Detailed preoperative assessment, an awareness of anatomical variants and close liaison with a vascular surgeon may all help to reduce the number and severity of adverse outcomes. PMID- 26236121 TI - Fracture of the polyethylene tibial post in a posterior stabilized knee prosthesis: A case report and review of literature. AB - We report a case of fracture of tibial polyethylene post fracture from base in a 56 year old lady 10 years from posterior stabilized total knee arthroplasty following trivial trauma. There have been signs of wear at the base especially anteriorly. After revision of tibial polyethylene component patient developed complete relief of symptom. PMID- 26236123 TI - Oral conditions in renal disorders and treatment considerations - A review for pediatric dentist. AB - This article reviews the current understanding of the oral and dental aspects of chronic renal disease (CRD). A PubMed literature search was performed and all relevant studies were assessed. As the number of people suffering from CRD increases worldwide, dentists are expected to encounter more patients with CRD who need oral care. In children, CRD can elicit a wide spectrum of oral manifestations in the hard and soft tissues. Bleeding, altered drug metabolism, impaired immune function, and an increased risk of dentally induced bacterial endocarditis are some important features that require attention. Dental management of patients with CRD requires that clinicians appreciate that multiple systems can be affected by the disease. Dentists should consult with nephrologists regarding the specific precautions required for each patient. Medical treatments in these patients may need to be postponed due to an unfavorable oral health status or potential risk of life-threatening infection after surgery. Improving oral hygiene and performing necessary dental and oral treatment before hemodialysis or transplantation may prevent endocarditis and septicemia in these patients. Hence, treatment plans should be formulated to restore the patient's dentition and protect them from potentially severe infections of dental origin. PMID- 26236124 TI - The effect of orthodontic bands or tubes upon periodontal status during the initial phase of orthodontic treatment. AB - INTRODUCTION: Orthodontic bands cause periodontal inflammation. In theory, the use of a buccal tube (bond) instead of a band should prevent or minimize periodontal changes because the bonds are positioned away from the gingival margins. OBJECTIVE: The primary aim of this study was to investigate the periodontal status of orthodontic bands compared with bonds in the first three months of orthodontic treatment. MATERIALS AND METHODS: Twenty-four orthodontic patients (mean age = 12.6 years) were enrolled in this Randomized Controlled Trial (RCT). Using the cross-mouth technique, bands and bonds were used in opposite quadrants. Periodontal parameters including the presence or absence of Bleeding On Probing (BOP) and Probing Depths (PDs) were taken at the start and three months into treatment. RESULTS: Bands caused a statistically significant change in the Bleeding On Probing (BOP) (P = 0.001 and 0.021) and bonds displayed a statistically insignificant change in the Bleeding On Probing (BOP) (P = 0.125 and 1.00) for the upper and lower arch. The difference in Probing Depths (PDs) between bands and bonds was also statistically significant (P = 0.001). CONCLUSION: Molar bands are associated with greater periodontal inflammation compared with molar bonds in the first three months of fixed orthodontic treatment. PMID- 26236125 TI - Prevalence and severity of temporomandibular disorders among university students in Riyadh. AB - OBJECTIVE: The aim of this study was to evaluate the prevalence and severity of temporomandibular disorders (TMDs) among male university students in Riyadh, Saudi Arabia. The role of relevant medical and dental histories in the assessment of TMD in this Arab population was also addressed. METHODS: Required information was collected via a questionnaire. The first part of the questionnaire was used to obtain the medical and dental histories of participants. The second part included 10 questions regarding common TMD symptoms. Fonseca's anamnestic index (FAI) was used to classify TMD severity as "no dysfunction", "light dysfunction", "moderate dysfunction", or "severe dysfunction". RESULTS: Of the 600 distributed questionnaires, 400 questionnaires were completed (response rate: 66.6%). Mean age of eligible participants was 21.90 +/- 1.79 years. Psychological stress (30.5%) and direct restorations (77%) were the most commonly reported items on the medical and dental histories respectively for the total number of participants. According to the FAI, 53.2% of participants were classified as having no dysfunction, followed by light (36.1%), moderate (9.6%), and severe dysfunction (1.1%). CONCLUSIONS: Based on the FAI, mild to moderate prevalence of TMD appears to exist among male university students in Riyadh. Histories of psychological stress and dental treatment were evident among these students. Information obtained from the FAI may be helpful in assessing the prevalence of TMD and has important implications for the early diagnosis of TMD and the prevention of future TMD-related complications. PMID- 26236126 TI - Dental age assessment of Western Saudi children and adolescents. AB - AIM: The aim of this study was to evaluate the use of the London Atlas of Human Tooth Development and Eruption for age estimation in Saudi Arabian children and adolescents (aged 2-20 years), for forensic odontology application. MATERIALS AND METHODS: This cross-sectional survey analyzed orthopantomograms (OPGs) of the complete dentition (including root development) to estimate the deviation from chronological age. Each OPG was de-identified and analyzed individually and classified into age-groups by the lead author, using the methods of the Atlas of Tooth Development. RESULTS: OPGs from a total of 252 patients [110 (44%) males, 142 (56%) females] aged 2-20 years (24-240 months) were examined in this study. The average estimated and chronological ages of subjects differed significantly p < 0.001 (143 +/- 55.4 vs. 145 +/- 57.9 months). Most (65.5%) estimates were within 12 months of subjects' chronological ages; 19% overestimated and 15.5% underestimated age by >12 months. CONCLUSION: This study, conducted in a sub population of different origin than the UK sample used for the development of the London Atlas, identified variation in age estimates that may have significant impacts on results. The establishment of a composite international repository of atlas-based data for diverse ethnic sub-populations would be of great value to clinicians across the globe. PMID- 26236127 TI - The efficacy of Salvadora persica extracts in preserving the viability of human foreskin fibroblasts. AB - OBJECTIVE: To evaluate the efficacy of Salvadora persica hexane and ethanol extracts in preserving the viability of human foreskin fibroblasts. MATERIALS AND METHODS: Normal human foreskin cells were cultivated in Dulbecco modified Minimum Essential Medium (D-MEM) supplemented with 10% fetal bovine serum and 2 mM of l glutamine. Cell pellets were suspended in the following test solutions: (1) Hank's Balanced Salt Solution (HBSS); (2) homogenized milk; (3) hexane extract of S. persica; or (4) ethanol extract of S. persica. D-MEM with no serum was used as a positive control. For each condition, cell count was adjusted to 8 * 10(5) cells/ml, and the cells were incubated in the solutions for either 30, 60, or 120 min. Subsequently, the nonviable cells were separated from the viable cells using the trypan blue dye stain. The ratio of viable to nonviable cells was recorded using a cell counter. Statistical analysis of the data was accomplished by one way analysis of variance using SPSS Version 16. The level of significance was 5% (p < .05). RESULTS: We did not detect a significant difference when comparing the percentage of viable cells in test solutions at the three incubation periods (30 min, p = 0.478; 60 min, p = 0.606; 120 min, p = 0.091). Homogenized milk preserved the viability of foreskin fibroblasts better than all other tested solutions. Incubation of cells in S. persica hexane and ethanol extracts resulted in a similar percentage of viable cells to incubation of cells in HBSS for each incubation period. CONCLUSIONS: S. persica hexane and ethanol extracts should be considered an alternative storage medium to HBSS. PMID- 26236128 TI - A needs assessment survey of dental public health graduate education in Saudi Arabia. AB - OBJECTIVES: The Faculty of Dentistry at King Abdulaziz University (KAU) is planning to develop a master's program in dental public health (DPH). To develop a curriculum for this program, a needs assessment was conducted in order to identify the level of DPH expertise that currently exists in Saudi Arabia, to identify gaps in knowledge, and to explore current perceptions regarding this type of program. METHODS: A competency-based survey instrument was administered to private and government affiliated dental practitioners in Jeddah, Saudi Arabia. Participants' knowledge, attitudes, and competencies in DPH were assessed. In addition, questions were submitted that addressed preferred strategies of teaching, curriculum delivery methods, course content, and prerequisites for DPH. These data were combined with data previously collected from dentists holding academic positions at KAU (n = 146) and were analyzed using Statistical Analysis System version 9.3 software. Mean values and frequencies were calculated for the study variables. Proportional odds ratios and 95% confidence intervals were estimated to assess differences in educational preferences and DPH competencies according to age, gender, and qualification. RESULTS: Most of the participants (95%) reported a need for a DPH graduate program. The respondents had a basic knowledge of DPH and moderate experience in DPH competencies. A variety of preferred educational strategies and methods were identified and differences in educational preferences according to age, gender, and qualification of the respondents were identified. The responses obtained also acknowledged skills and competencies that the participants considered most important for a DPH practice and that would be important for students accepted into a DPH graduate program. CONCLUSIONS: This needs assessment survey represents a preliminary step in establishing a DPH graduate program that addresses current gaps in knowledge and in the practice of public health dentistry. This survey also provided valuable feedback regarding the development of course content for a graduate education program in DPH. PMID- 26236129 TI - Fit accuracy of metal partial removable dental prosthesis frameworks fabricated by traditional or light curing modeling material technique: An in vitro study. AB - OBJECTIVE: The aim of this study was to compare the fit accuracies of metal partial removable dental prosthesis (PRDP) frameworks fabricated by the traditional technique (TT) or the light-curing modeling material technique (LCMT). MATERIALS AND METHODS: A metal model of a Kennedy class III modification 1 mandibular dental arch with two edentulous spaces of different spans, short and long, was used for the study. Thirty identical working casts were used to produce 15 PRDP frameworks each by TT and by LCMT. Every framework was transferred to a metal master cast to measure the gap between the metal base of the framework and the crest of the alveolar ridge of the cast. Gaps were measured at three points on each side by a USB digital intraoral camera at *16.5 magnification. Images were transferred to a graphics editing program. A single examiner performed all measurements. The two-tailed t-test was performed at the 5% significance level. RESULTS: The mean gap value was significantly smaller in the LCMT group compared to the TT group. The mean value of the short edentulous span was significantly smaller than that of the long edentulous span in the LCMT group, whereas the opposite result was obtained in the TT group. CONCLUSION: Within the limitations of this study, it can be concluded that the fit of the LCMT-fabricated frameworks was better than the fit of the TT-fabricated frameworks. The framework fit can differ according to the span of the edentate ridge and the fabrication technique for the metal framework. PMID- 26236130 TI - Combination of bone allograft, barrier membrane and doxycycline in the treatment of infrabony periodontal defects: A comparative trial. AB - AIM: The purpose of the present study was to compare the regenerative potential of noncontained periodontal infrabony defects treated with decalcified freeze dried bone allograft (DFDBA) and barrier membrane with or without local doxycycline. METHODS: This study included 48 one- or two-wall infrabony defects from 24 patients (age: 30-65 years) seeking treatment for chronic periodontitis. Defects were randomly divided into two groups and were treated with a combination of DFDBA and barrier membrane, either alone (combined treatment group) or with local doxycycline (combined treatment + doxycycline group). At baseline (before surgery) and 3 and 6 months after surgery, the pocket probing depth (PPD), clinical attachment level (CAL), radiological bone fill (RBF), and alveolar height reduction (AHR) were recorded. Analysis of variance and the Newman-Keuls post hoc test were used for statistical analysis. A two-tailed p-value of less than 0.05 was considered to be statistically significant. RESULTS: In the combined treatment group, the PPD reduction was 2.00 +/- 0.38 mm (32%), CAL gain was 1.25 +/- 0.31 mm (17.9%), and RBF was 0.75 +/- 0.31 mm (20.7%) after 6 months. In the combined treatment + doxycycline group, these values were 2.75 +/- 0.37 mm (44%), 1.5 +/- 0.27 mm (21.1%), and 1.13 +/- 0.23 mm (28.1%), respectively. AHR values for the groups without and with doxycycline were 12.5% and 9.4%, respectively. CONCLUSION: There was no significant difference in the regeneration of noncontained periodontal infrabony defects between groups treated with DFDBA and barrier membrane with or without doxycycline. PMID- 26236131 TI - Changes in quality of life after orthognathic surgery in Saudi patients. AB - AIM: This study was conducted to measure the impact of orthognathic surgery on quality of life in Saudi patients. MATERIALS AND METHODS: Patients with a discrepancy of 5 mm or more who underwent orthognathic surgery either single jaw or bimaxillary at the Department of Oral and Maxillofacial Surgery, College of Dentistry, King Saud University, between September 2007 and June 2013 were included in the study. They were asked to complete the Arabic version of the 22 item Orthognathic Quality of Life Questionnaire (OQLQ) preoperatively and postoperatively. Responses at these two timepoints were compared using paired t tests, with the significance level set to P < 0.05. RESULTS: Seventeen patients participated in the study. Total OQLQ scores and those in the instrument's four domains (oral function, facial aesthetics, awareness of dentofacial aesthetics, and social aspects) indicated that quality of life was significantly improved by orthognathic surgery (all P < 0.001). The social aspect domain was shown to be more important for patients than were facial aesthetics and oral function. CONCLUSION: The present study revealed highly significant improvement in Saudi patients' quality of life following orthognathic surgery. This improvement was evident in all four OQLQ domains. PMID- 26236133 TI - A Compelling Call to Action to Establish a Culture of Respect. AB - A culture of respect is vital to providing health care safely. PMID- 26236134 TI - Medicaid Plan Skirts Key Drug-Access Issues: Changes to Medical Loss Ratio, Network Adequacy Disputed. AB - CMS Medicaid plan ignores major drug-access issues. PMID- 26236132 TI - Dental management of a patient fitted with subcutaneous Implantable Cardioverter Defibrillator device and concomitant warfarin treatment. AB - Automated Implantable Cardioverter Defibrillators (AICD), simply known as an Implantable Cardioverter Defibrillator (ICD), has been used in patients for more than 30 years. An Implantable Cardioverter Defibrillator (ICD) is a small battery powered electrical impulse generator that is implanted in patients who are at a risk of sudden cardiac death due to ventricular fibrillation, ventricular tachycardia or any such related event. Typically, patients with these types of occurrences are on anticoagulant therapy. The desired International Normalized Ratio (INR) for these patients is in the range of 2-3 to prevent any subsequent cardiac event. These patients possess a challenge to the dentist in many ways, especially during oral surgical procedures, and these challenges include risk of sudden death, control of post-operative bleeding and pain. This article presents the dental management of a 60 year-old person with an ICD and concomitant anticoagulant therapy. The patient was on multiple medications and was treated for a grossly neglected mouth with multiple carious root stumps. This case report outlines the important issues in managing patients fitted with an ICD device and at a risk of sudden cardiac death. PMID- 26236136 TI - Pharmaceutical Approval Update. AB - Eluxadoline (Viberzi) for irritable bowel syndrome with diarrhea; tiotropium bromide/olodaterol inhalation spray (Stiolto Respimat) for chronic obstructive pulmonary disease; and sirolimus (Rapamune) for lymphangioleiomyomatosis. PMID- 26236137 TI - Apremilast (Otezla): A New Oral Treatment for Adults With Psoriasis and Psoriatic Arthritis. AB - Apremilast (Otezla): A new oral treatment for adults with psoriasis and psoriatic arthritis. PMID- 26236138 TI - Brand and Generics Companies Unite to Pressure FDA: They Want the Agency to Drop Its Safety-Label Plan and Adopt Their Alternative. AB - Fear of lawsuits and customer confusion have greeted a Food and Drug Administration plan to let generic drug companies change labels quickly, without prior agency approval, when they learn of adverse effects once the generic reaches the market. PMID- 26236140 TI - First-in-Class CDK4/6 Inhibitor Palbociclib Could Usher in a New Wave of Combination Therapies for HR+, HER2- Breast Cancer. AB - Women with hormone receptor-positive, human epidermal growth factor receptor 2- negative breast cancer-the most common subtype-have new options as palbociclib and similar drugs debut. This article outlines the rationale and evidence for their use. PMID- 26236141 TI - Ebola: Working Toward Treatments and Vaccines. AB - After killing more than 11,000 people in West Africa, the largest known outbreak of the deadly Ebola virus has largely subsided-but development of effective antiviral countermeasures remains a concern. Several experimental products show promise. PMID- 26236139 TI - Parkinson's Disease and Its Management: Part 1: Disease Entity, Risk Factors, Pathophysiology, Clinical Presentation, and Diagnosis. AB - This article-the first of a five-part series-discusses possible causes, symptoms, diagnosis, and goals for treatment of Parkinson's disease. Identifying diseases that have similar presentations is an important component of the diagnostic process. PMID- 26236143 TI - Exciting Therapies Ahead in Prostate Cancer. AB - Robust drug-development programs targeting the second most common male cancer (after skin cancer) will help increase U.S. market sales to $3.7 billion by 2023. PMID- 26236142 TI - American Society of Clinical Oncology. AB - We review key research findings on renal cell carcinoma, prostate cancer, melanoma, myelofibrosis, multiple myeloma, and chronic lymphocytic leukemia. PMID- 26236144 TI - Guided by Theory, Informed by Practice: Training and Support for the Good Behavior Game, a Classroom-based Behavior Management Strategy. AB - Moving evidence-based practices for classroom behavior management into real-world settings is a high priority for education and public health. This paper describes the development and use of a model of training and support for the Good Behavior Game (GBG), one of the few preventive interventions shown to have positive outcomes for elementary school children lasting through to young adulthood, ages 19-21, including reductions in the use of drugs and alcohol, school-based mental health services, and suicide ideation and attempts. We first describe the conceptual framework guiding the development of the model of training and support. Data on implementation of the model, from an ongoing trial of GBG being conducted in partnership with the Houston Independent School District, are then presented. We end with a discussion of the lessons learned and the implications for the next stage of research and practice. PMID- 26236145 TI - REDUCING AMBIGUITY IN THE FUNCTIONAL ASSESSMENT OF PROBLEM BEHAVIOR. AB - Severe problem behavior (e.g., self-injury and aggression) remains among the most serious challenges for the habilitation of persons with intellectual disabilities and is a significant obstacle to community integration. The current standard of behavior analytic treatment for problem behavior in this population consists of a functional assessment and treatment model. Within that model, the first step is to assess the behavior-environment relations that give rise to and maintain problem behavior, a functional behavioral assessment. Conventional methods of assessing behavioral function include indirect, descriptive, and experimental assessments of problem behavior. Clinical investigators have produced a rich literature demonstrating the relative effectiveness for each method, but in clinical practice, each can produce ambiguous or difficult-to-interpret outcomes that may impede treatment development. This paper outlines potential sources of variability in assessment outcomes and then reviews the evidence on strategies for avoiding ambiguous outcomes and/or clarifying initially ambiguous results. The end result for each assessment method is a set of best practice guidelines, given the available evidence, for conducting the initial assessment. PMID- 26236146 TI - Comparison of cap lamp and laser illumination for detecting visual escape cues in smoke. AB - The Illuminating Engineering Society of North America reports that an underground mine is the most difficult environment to illuminate (Rea, 2000). Researchers at the U.S. National Institute for Occupational Safety and Health (NIOSH) Office of Mine Safety and Health Research (OMSHR) are conducting ongoing studies designed to explore different lighting technologies for improving mine safety. Underground miners use different visual cues to escape from a smoke-filled environment. Primary and secondary escapeways are marked with reflective ceiling tags of various colors. Miners also look for mine rail tracks. The main objective of this paper is to compare different lighting types and ceiling tag colors to differentiate what works best in a smoke-filled environment. Various cap lamps (LED and incandescent) and lasers (red, blue, green) were compared to see which options resulted in the longest detection distances for red, green and blue reflective markers and a section of mine rail track. All targets advanced toward the human subject inside of a smoke-filled room to simulate the subject walking in a mine environment. Detection distances were recorded and analyzed to find the best cap lamp, laser color and target color in a smoke environment. Results show that cap lamp, laser color and target color do make a difference in detection distances and are perceived differently based on subject age. Cap lamps were superior to lasers in all circumstances of ceiling tag detection, with the exception of the green laser. The incandescent cap lamp worked best in the simulated smoke compared to the LED cap lamps. The green laser was the best color for detecting the tags and track compared to the red and blue lasers. The green tags were the easiest color to detect on the ceiling. On average, the track was easier for the subjects to detect than the ceiling tags. PMID- 26236147 TI - Longitudinal Imaging of Heart Development With Optical Coherence Tomography. AB - Optical coherence tomography (OCT) has great potential for deciphering the role of mechanics in normal and abnormal heart development. OCT images tissue microstructure and blood flow deep into the tissue (1-2mm) at high spatiotemporal resolutions allowing unprecedented images of the developing heart. Here, we review the advancement of OCT technology to image heart development and report some of our recent findings utilizing OCT imaging under environmental control for longitudinal imaging. Precise control of the environment is absolutely required in longitudinal studies that follow the growth of the embryo or studies comparing normal versus perturbed heart development to obtain meaningful in vivo results. These types of studies are essential to tease out the influence of cardiac dynamics on molecular expression and their role in the progression of congenital heart defects. PMID- 26236148 TI - Tensor scale: An analytic approach with efficient computation and applications. AB - Scale is a widely used notion in computer vision and image understanding that evolved in the form of scale-space theory where the key idea is to represent and analyze an image at various resolutions. Recently, we introduced a notion of local morphometric scale referred to as "tensor scale" using an ellipsoidal model that yields a unified representation of structure size, orientation and anisotropy. In the previous work, tensor scale was described using a 2-D algorithmic approach and a precise analytic definition was missing. Also, the application of tensor scale in 3-D using the previous framework is not practical due to high computational complexity. In this paper, an analytic definition of tensor scale is formulated for n-dimensional (n-D) images that captures local structure size, orientation and anisotropy. Also, an efficient computational solution in 2- and 3-D using several novel differential geometric approaches is presented and the accuracy of results is experimentally examined. Also, a matrix representation of tensor scale is derived facilitating several operations including tensor field smoothing to capture larger contextual knowledge. Finally, the applications of tensor scale in image filtering and n-linear interpolation are presented and the performance of their results is examined in comparison with respective state-of-art methods. Specifically, the performance of tensor scale based image filtering is compared with gradient and Weickert's structure tensor based diffusive filtering algorithms. Also, the performance of tensor scale based n-linear interpolation is evaluated in comparison with standard n-linear and windowed-sinc interpolation methods. PMID- 26236149 TI - Anterior-Posterior Connectivity within the Default Mode Network Increases During Maturation. AB - The default mode network (DMN) supports self-referential thought processes important for successful socialization including: theory-of-mind, episodic memory, and prospection. Connectivity between DMN's nodes, which are distributed between the frontal, temporal, and parietal lobes, change with age and may continue changing into adulthood. We have previously explored the maturation of functional connections in the DMN as they relate to autism spectrum disorder (ASD) in children 6 to 18 years of age. In this chapter, we refine our earlier study of DMN functional maturation by focusing on the development of inter-nodal connectivity in a larger pool of typically developing people 6 to 25 years of age (mean = 13.22 years +/- 5.36 s.d.; N = 36; 42% female). Correlations in BOLD activity (Fisher's Z) between ROIs revealed varying strengths of functional connectivity between regions, the strongest of which was between the left and right inferior parietal lobules or IPLs (Z = 0.62 +/- 0.25 s.d.) and the weakest of which was between the posterior cingulate cortex (PCC) and right middle temporal gyrus or MTG (Z = 0.06 +/- 0.22 s.d.). Further, connectivity between two pairs of DMN nodes significantly increased as a quadratic function of age (p < 0.05), specifically the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and PCC nodes and the left IPL and right MTG nodes. The correlation between ACC/mPFC <-> PCC connectivity and age was more significant than the correlation between left IPL <-> right MTG connectivity and age by more than an order of magnitude. We suggest that these changes in functional connectivity in part underlie the introspective mental changes known to commonly occur between the preadolescent and adult years. A range of neurological and psychological conditions that hamper social interactions, from ASD to psychopathy, may be marked by deviations from this maturational trajectory. PMID- 26236151 TI - Digital Three-dimensional Reconstruction Based On Integral Imaging. AB - This paper presents a digital three dimensional reconstruction method based on a set of small-baseline elemental images captured with a micro-lens array and a CCD sensor. In this paper, we adopt the ASIFT (Affine Scale-invariant feature transform) operator as the image registration method. Among the set of captured elemental images, the elemental image located in the middle of the overall image field is used as the reference and corresponding matching points in each elemental image around the reference elemental are calculated, which enables to accurately compute the depth value of object points relatively to the reference image frame. Using optimization algorithm with redundant matching points can achieve 3D reconstruction finally. Our experimental results are presented to demonstrate excellent performance in accuracy and speed of the proposed algorithm. PMID- 26236150 TI - Astrocytes in the optic nerve head express putative mechanosensitive channels. AB - PURPOSE: To establish whether optic nerve head astrocytes express candidate molecules to sense tissue stretch. METHODS: We used conventional PCR, quantitative PCR, and single-cell reverse transcription PCR (RT-PCR) to assess the expression of various members of the transient receptor potential (TRP) channel family and of the recently characterized mechanosensitive channels Piezo1 and 2 in optic nerve head tissue and in single, isolated astrocytes. RESULTS: Most TRP subfamilies (TRPC, TRPM, TRPV, TRPA, and TRPP) and Piezo1 and 2 were expressed in the optic nerve head of the mouse. Quantitative real-time PCR analysis showed that TRPC1, TRPM7, TRPV2, TRPP2, and Piezo1 are the dominant isoforms in each subfamily. Single-cell RT-PCR revealed that many TRP isoforms, TRPC1-2, TRPC6, TRPV2, TRPV4, TRPM2, TRPM4, TRPM6-7, TRPP1-2, and Piezo1-2, are expressed in astrocytes of the optic nerve head, and that most astrocytes express TRPC1 and TRPP1-2. Comparisons of the TRPP and Piezo expression levels between different tissue regions showed that Piezo2 expression was higher in the optic nerve head and the optic nerve proper than in the brain and the corpus callosum. TRPP2 also showed higher expression in the optic nerve head. CONCLUSIONS: Astrocytes in the optic nerve head express multiple putative mechanosensitive channels, in particular the recently identified channels Piezo1 and 2. The expression of putative mechanosensitive channels in these cells may contribute to their responsiveness to traumatic or glaucomatous injury. PMID- 26236152 TI - Degradation of trichloroethene by siderite-catalyzed hydrogen peroxide and persulfate: Investigation of reaction mechanisms and degradation products. AB - A binary catalytic system, siderite-catalyzed hydrogen peroxide (H2O2) coupled with persulfate (S2O82-), was investigated for the remediation of trichloroethene (TCE) contamination. Batch experiments were conducted to investigate reaction mechanisms, oxidant decomposition rates, and degradation products. By using high performance liquid chromatography (HPLC) coupled with electron paramagnetic resonance (EPR), we identified four radicals (hydroxyl (HO.), sulfate (SO4-.), hydroperoxyl (HO2.), and superoxide (O2-.)) in the siderite-catalyzed H2O2-S2O82- system. In the absence of S2O82- (i.e., siderite-catalyzed H2O2), a majority of H2O2 was decomposed in the first hour of the experiment, resulting in the waste of HO.. The addition of S2O82- moderated the H2O2 decomposition rate, producing a more sustainable release of hydroxyl radicals that improved the treatment efficiency. Furthermore, the heat released by H2O2 decomposition accelerated the activation of S2O82-, and the resultant SO4-. was the primary oxidative agent during the first two hours of the reaction. Dichloroacetic acid was firstly detected by ion chromatography (IC). The results of this study indicate a new insight to the reaction mechanism for the catalytic binary H2O2-S2O82- oxidant system, and the delineation of radicals and the discovery of the chlorinated byproduct provide useful information for efficient treatment of chlorinated solvent contamination in groundwater. PMID- 26236153 TI - Alkyl Sulfinates: Formal Nucleophiles for Synthesizing TosMIC Analogs. AB - Alkyl sulfinates function as formal nucleophiles in Mannich-type reactions to give sulfonyl formamides, which are readily dehydrated to the corresponding sulfonylmethyl isonitriles. The efficient, two-step synthesis provides a general route to sulfonylmethyl isonitriles from readily available methyl sulfinates or thiols. Mechanistic analysis reveals that the unusual nucleophlicity of the alkyl sulfinates arises from the in situ release of sulfinic acids. PMID- 26236154 TI - A pilot study to assess the utility and perceived effectiveness of a tool for diagnosing feeding difficulties in children. AB - BACKGROUND: Food dislikes in children may result in avoiding particular food/s with major sources of essential nutrients leading to increased risk of impaired growth or cognitive development and compromised immune function. It is necessary to identify conditions contributing to feeding difficulty and associated complications. An instrument was designed to assist diagnosis and management of children with feeding difficulties. The study was conducted to test utility of the "Identification and Management of Feeding Difficulties (IMFeD)" tool in Indian children. METHODS: A prospective, cross-sectional study was conducted in Indian children between 2 and 10 years identified to have picky eating behaviour. After completion of both pro forma sections (parent and physician) of the IMFeD tool, the child's specific feeding difficulty was diagnosed and appropriate nutritional and/or behavioural counselling was provided. The subjects were followed at 30 and 60 days post-intervention. RESULTS: According to 66% of paediatricians the IMFeD tool was very easy to use. Approximately 85% of paediatricians required <=20 min to administer the tool, diagnose the feeding difficulty(ies) and provide specific counselling or behavioural management. More than 70% of parents were satisfied and willing to accept the use of the IMFeD tool. After 60 days, 65% of the parents were either less worried or not worried at all about the feeding behaviour of the child using recommendations made on the basis of the IMFeD tool. The toolkit helped parents to know what to do if their child had a feeding problem. A total of 90% of the parents expressed that the tool is useful for assessing feeding difficulties in children. CONCLUSION: The IMFeD tool can be effectively used to identify feeding difficulties in Indian children. This toolkit also helps to offer nutritional and behavioural guidance as a part of the management. PMID- 26236155 TI - Perceptions of preceptorship in clinical practice after completion of a continuous professional development course- a qualitative study Part II. AB - BACKGROUND: For health care professionals, clinical practice is a vital part of education, and in several countries, teaching is a regulated part of the role of nurses and health care staff. The added responsibility of taking on the teaching of students during clinical practice; thus, balancing clinical and educational demands, might lead to feelings of stress and burnout. Being a skilled and experienced professional is not automatically linked to being a skilled educator as teaching of a subject is a completely different story. Preceptors who participate in educational initiatives are better prepared to address challenges and are more satisfied with the preceptor role. The aim of the current study was to evaluate preceptors' experiences of preceptorship in clinical practice after completion of a credit bearing continuous professional development course on advanced level. METHODS: This was a small-scale interpretative qualitative study drawing data from focus group interviews and written accounts from reflective journals. Data were analysed through the process of naturalistic inquiry. RESULTS: Our findings show that the participants, who took part in and completed the CPD course, had developed skills and competences they believed to be necessary to drive pedagogical development at their respective workplaces. This is illustrated by the main category Leading educational development and explained by four sub-categories: 1/ increased ability to give collegial support; 2/ increased trust in one's abilities; 3/ increased emphasis on reflection; and 4/ increased professional status. CONCLUSIONS: A well-structured program based on the needs of preceptors and developed in partnership between educational and clinical settings seems to be successful in terms of preceptors' perceived increase of their competence, abilities and professional status. What seems to be missing, not only from the current study but also from previous research, is to what extent properly prepared preceptors impact on student learning and this needs to be further investigated. PMID- 26236156 TI - Antisense oligonucleotides against microRNA-21 reduced the proliferation and migration of human colon carcinoma cells. AB - BACKGROUND: Colon carcinoma is one of the commonly tumors that threaten human beings as its highly morbidity and mortality. Recent evidences suggested that microRNA-21 (miR-21) played an important role in the development of colon carcinoma and might be a potential biological marker for the diagnosis and prognosis of colon carcinoma. However, the potential effect of miR-21 based therapeutic studies in colon carcinoma remains to be fully elucidated. METHODS: In present study, we constructed an eukaryotic expression vector encoding antisense oligonucleotides against miR-21 (termed as p-miR-21-ASO) and the expression of miRNA-21 in human colon cancer was detected by Real-time PCR. To assess its possible effect on the proliferation and migration capacity of human colon carcinoma cells in vitro, CCK-8 assay, colony formation assay and cell invasion, as well as migration assay, were performed respectively. Moreover, PTEN, one of target molecules of miRNA-21, was analyzed by Western blot and Fluorescence activated cell sorter assay. Finally, the transduction of AKT and ERK pathways in human colon carcinoma cells was determined by Western blot. RESULTS: We found that transiently transfection of p-miR-21-ASO could efficiently decrease the relative expression of miR-21 in human colon carcinoma HCT116 cells, accompanied by impaired proliferation and clone formation. Furthermore, we found that down-regulation of miR-21 also could significantly abrogate the invasion and migration capacity in vitro, as well as the expression of vascular endothelial growth factor which is critical for the metastatic capacity of colon carcinoma cells. Mechanistic evidence showed that down-regulation of miR-21 increased the expression of its target molecule PTEN in HCT116 cells. Finally, we revealed that the expression level of both phosphor-ERK1/2 and phosphor-AKT also were altered. CONCLUSIONS: Therefore, our data suggested miR-21 ASO against miR-21 might be a useful strategy to alter the expression of miR-21 in colon carcinoma cells, which was helpful for the development of miR-21-based therapeutic strategies against clinical colon carcinoma. PMID- 26236157 TI - Quantifying demographic and socioeconomic transitions for computational epidemiology: an open-source modeling approach applied to India. AB - BACKGROUND: Demographic and socioeconomic changes such as increasing urbanization, migration, and female education shape population health in many low and middle-income countries. These changes are rarely reflected in computational epidemiological models, which are commonly used to understand population health trends and evaluate policy interventions. Our goal was to create a "backbone" simulation modeling approach to allow computational epidemiologists to explicitly reflect changing demographic and socioeconomic conditions in population health models. METHODS: We developed, evaluated, and "open-sourced" a generalized approach to incorporate longitudinal, commonly available demographic and socioeconomic data into epidemiological simulations, illustrating the feasibility and utility of our approach with data from India. We constructed a series of nested microsimulations of increasing complexity, calibrating each model to longitudinal sociodemographic and vital registration data. We then selected the model that was most consistent with the data (i.e., greater accuracy) while containing the fewest parameters (i.e., greater parsimony). We validated the selected model against additional data sources not used for calibration. RESULTS: We found that standard computational epidemiology models that do not incorporate demographic and socioeconomic trends quickly diverged from past mortality and population size estimates, while our approach remained consistent with observed data over decadal time courses. Our approach additionally enabled the examination of complex relations between demographic, socioeconomic and health parameters, such as the relationship between changes in educational attainment or urbanization and changes in fertility, mortality, and migration rates. CONCLUSIONS: Incorporating demographic and socioeconomic trends in computational epidemiology is feasible through the "open source" approach, and could critically alter population health projections and model-based evaluations of health policy interventions in unintuitive ways. PMID- 26236158 TI - The Relation of Erythropoietin Towards Hemoglobin and Hematocrit in Varying Degrees of Renal Insufficiency. AB - INTRODUCTION: Hypoxia is a basic stimulant in production of erythropoietin (EPO). The primary function of erythrocytes is the transport of oxygen to tissues. Erythropoietin stimulates erythropoiesis which leads to increased production of erythrocytes- their total mass. This increases the capacity of the blood to carry oxygen, reduces the hypoxic stimulus and provides a negative feedback of stopping EPO production. The aim of this study was to establish a quantitative relationship between the concentration of erythropoietin, hemoglobin and hematocrit in different values of renal insufficiency. MATERIAL AND METHODS: The survey was conducted on 562 subjects divided into two groups: with and without renal insufficiency. EPO, hemoglobin, hematocrit, serum creatinine and additional parameters iron, vitamin B12, and folic acid were determined by using immunochemical and spectrophotometric methods and glomerular filtration rate (GFR) was calculated as well. RESULTS: EPO values (median) grow to the first degree of renal insufficiency, as compared to EPO values of healthy subjects, this increase is statistically significant, p=0.002. With further deterioration of renal function the values of EPO between all pathological groups are decreasing, and this decrease is statistically significant between first and second degree of renal insufficiency (RI) p<0.001. In the group of healthy subjects EPO is correlated rho = -0.532, p <0.0005 with hematocrit. The correlations are negative and strong and can be predicted by regression line (EP0 = 41.375- Hct * .649; EPO = 61.41-Hb * 0.355). In the group of subjects with the first degree of renal insufficiency EPO is in correlation with hematocrit rho= 0.574, p<0, 0005. It is also correlated with hemoglobin rho=-0.580, p< 0.0005. The correlation is negative (EP0= 42.168- Hct * 0.678). In the group of subjects with the third degree of renal insufficiency EPO is in correlation with hemoglobin rho=0.257, p=0.028. The correlation is medium strong and positive. In the group of subjects with third and fourth degree of renal insufficiency EPO is not in correlation with hemoglobin and hematocrit p>0.05. CONCLUSION: Renal dysfunction, depending on the level of RI effects differently on the biosynthesis of EPO in a diseased kidney, and consequently it also has a different effect on biosynthesis of HB in bone marrow and its content in the blood. PMID- 26236159 TI - Epidemiological Features of Bronchiolitis in the Pediatric Clinic of Clinical center of Sarajevo University. AB - OBJECTIVE: To present the epidemiological features of bronchiolitis in a one-year period in patients of Pediatric Clinic, Clinical Centre of Sarajevo University. INTRODUCTION: Bronchiolitis is the most common respiratory infection of early infant age. The disease is one the most common reason for hospitalization of children under the age of six months. The disease is characterized by occurrences in the winter season November-March. For daily diagnosing of severe forms of bronchiolitis as a clinical syndrome, often sufficient are the knowledge of the epidemiological data, age of the patient, clinical examination and insight into the risk factors. PATIENTS AND METHODS: The history of the disease in 155 infant patients, who were clinically treated because of bronchiolitis in the period from February 2013 to February 2014 in the Department of Pediatric Pulmonary Clinic in Sarajevo was retrospectively analyzed. RESULTS: The majority of patients were aged less than 6 months (87.7%). The monthly distribution of bronchiolitis had a peak in January and February. Almost 50% of patients had a risk factors for the development of severe forms of bronchiolitis out of which the most common were artificial diet (53.5%), low birth weight below 2500g (17%), prematurity (16.1%), congenital heart anomalies (14.2%), bronchopulmonary dysplasia (1.9%). 46,5% of patients were on natural nutrition. 46 patients (29.6%) were serologically or by respi-strip test in nasopharyngeal lavage positive on respiratory syncytial virus (RSV). There were no patients who required mechanical ventilation. CONCLUSION: During the one-year period, bronchiolitis was the most common diagnose in the early infantile period up to 6 months, with a peak incidence in January and February. Risk factors such as prematurity, low birth weight, congenital heart anomalies and bronchopulmonary dysplasia have been less present in the studied period compared to the period before the introduction of RSV chemoprophylaxis. The epidemiological data obtained have facilitated the diagnosis, and accordingly the timely and appropriate treatment of bronchiolitis. PMID- 26236160 TI - The 10-year Absolute Risk of Cardiovascular (CV) Events in Northern Iran: a Population Based Study. AB - BACKGROUND: The present study was conducted to estimate 10-year cardiovascular disease events (CVD) risk using three instruments in northern Iran. MATERIAL AND METHODS: Baseline data of 3201 participants 40-79 of a population based cohort which was conducted in Northern Iran were analyzed. Framingham risk score (FRS), World Health Organization (WHO) risk prediction charts and American college of cardiovascular / American heart association (ACC/AHA) tool were applied to assess 10-year CVD events risk. The agreement values between the risk assessment instruments were determined using the kappa statistics. RESULTS: Our study estimated 53.5%of male population aged 40-79 had a 10 -year risk of CVD events>=10% based on ACC/AHA approach, 48.9% based on FRS and 11.8% based on WHO risk charts. A 10 -year risk>=10% was estimated among 20.1% of women using the ACC/AHA approach, 11.9%using FRS and 5.7%using WHO tool. ACC/AHA and Framingham tools had closest agreement in the estimation of 10-year risk>=10% (kappa=0.7757) in meanwhile ACC/AHA and WHO approaches displayed highest agreement (kappa=0.6123) in women. CONCLUSION: Different estimations of 10-year risk of CVD event were provided by ACC/AHA, FRS and WHO approaches. PMID- 26236161 TI - Demographic and Socioeconomic Characteristics Among Primary Health Care Users Diagnosed with Osteoarthritis in Albania. AB - AIM: The aim of this study was to describe the distribution of demographic factors and socioeconomic characteristics among primary health care users diagnosed with osteoarthritis in Albania, a transitional country in the Western Balkans. METHODS: This study included all individuals diagnosed with osteoarthritis during January 2013 - December 2014 in selected primary health care centers in Tirana, the capital city of Albania. Overall, 1179 adult individuals were diagnosed with osteoarthritis (521 men and 658 women) during this time period. The overall mean age of study participants was 59.0+/-10.1 years (60.1+/-10.6 years in men and 58.1+/-9.6 years in women). The diagnosis of osteoarthritis was based on the history of the disease, physical examination, laboratory findings and radiological findings. Binary logistic regression was used to assess the sex-differences regarding demographic factors and socioeconomic characteristics among participants diagnosed with osteoarthritis. RESULTS: In multivariable-adjusted logistic regression models, female gender was inversely associated with the age-group (OR=0.67, 95%CI=0.47-0.95) and educational level (OR=0.39, 95%CI=0.25-0.61), but positively related to rural birthplace (OR=1.47, 95%CI=1.14-1.89) and unemployment (OR=1.40, 95%CI=1.02-1.92) of the patients diagnosed with osteoarthritis. CONCLUSION: Our findings provide novel evidence about the distribution of demographic factors and socioeconomic characteristics among adult individuals diagnosed with osteoarthritis in primary health care services in Albania. Future studies should assess the distribution of the major risk factors for osteoarthritis among adult men and women in transitional Albania. PMID- 26236162 TI - Prevalence of Side Effects Treatment with Carbamazepine and Other Antiepileptics in Patients with Epilepsy. AB - OBJECTIVE: This paper reveals the studies of carbamazepine monitoring in the manifestation of side effects during clinical use. It is important to realize that these ranges are derived statistically, with most patients who have high levels suffering side effects and some with poor control having low levels. Broadly, the newer agents have advantages of lower risk of side effects and less drug interaction. At the presence they are more expensive than the, than "older" agents. Current recommendations and practice are to use newer agents as second line drugs, although in some countries there are gaining favour as potential first line agents. METHODS: In the study 91 patients with epilepsy were involved from which 53 or 58.2% were female and 38 or 41.8% were male with no great significant difference between two genders (X(2)=2.47, P=0.116). However, according to the study results female patients had slightly greater prevalence of epilepsy than man. Average age of epileptic patients was 23.2 years (SD +/- 16.4 years), in the range 1-66 years. Patient distribution was present within all age groups, but 59.4% of all patients were up to 20 years old. The highest prevalence of epilepsy was in the group age 6-15 years old: 33.0%. There were also children 1 - 5 years old with 7 or 7.7% of the patients, and the patients older than 60 years with 4 or 4.4% of the patients. Patient distribution according to the age and gender results with no female patient over 60 year old and more female patients in the age group 1-5 years. However statistically this did not produce a highly significant difference (T-test= 0.72, P=0.437) between average age according to the gender. The average age of the female gender was 22.1 year (SD +/- 14.2 years), with the range 2-55 years, while the average age of the male patients was 24.6 year (SD +/-19.2 years), with the range 1-66 years. CONCLUSION: Unwanted side effects of antiepileptic drugs analyzed in the study are frequent, but not so severe as to be life threatening. Treatment of epilepsy with these three drugs (carbamazepine, ac.valproic and phenobarbitone) would be the first choice of treatment, with the best safety and efficacy. Application of this therapy is rarely compromised because of the appearance of unwanted side effects. Replacement or termination of therapy may be applied if actual therapy is not adequate for the management of epileptic attacks. PMID- 26236163 TI - Epidemiology of Rheumatoid Arthritis in Southern Albania. AB - OBJECTIVES: The aim of this study was to assess the prevalence, incidence and the burden of rheumatoid arthritis (RA) in the Southern Albania. MATERIAL AND METHODS: This is an epidemiologic observational study with cross-sectional analyses of all patients with RA who lived in Southern Albania during the 1995 2011 years. The RA prevalence, incidence and disability-adjusted life years (DALY) were assessed. RESULTS: During the 1995-2011 years, 194 patients (154 females and 40 males) with RA living in Southern Albania were identified. The prevalence of RA in 2011 was 0.25% in general population and 0.34% in adult (>14 years) population. The incidence of RA in 2011 was 0.012% (12 new cases per 100000 inhabitants) and 0.016% (16 new cases per 100000 adults). The prevalence increased (from 0.036% in 1996 to 0.25% in 2011) and the incidence did not change over the study period. The mortality was 3.2% (n=7 deaths). The DALY due to RA was 823 years per 100000 inhabitants during 1995-2011 years. CONCLUSION: RA in Southern Albania has a prevalence of 0.25 % and an annual incidence of 0.012% in the general population in 2011. RA was responsible for a considerable burden on the health of population during the 1995-2011 years. PMID- 26236164 TI - Tobacco Smoking Habits Among First Year Medical Students, University of Prishtina, Kosovo: Cross-sectional Study. AB - INTRODUCTION: Tobacco smoking remains the leading causes of preventable morbidity and mortality in the world, requiring intensified national and international public health response. World Health Organization (WHO) has urged health professional organizations to encourage and support their members to be models for not using tobacco products and promote tobacco-free culture. Healthcare students are the future authority of the health society, they are in a position to play a vital role and have impact on social norms related to smoking. AIM: To determine the prevalence of tobacco smoking among healthcare students of Medical Faculty, University of Prishtina in Kosovo, so that recommendations can be made for its cessation among healthcare providers and thereafter the community. MATERIALS AND METHODS: Descriptive cross-sectional study was conducted using self administrated questionnaire prepared for this purpose. A total of 284 first year healthcare students of Medical Faculty, University of Prishtina in Kosovo were enrolled in the study. The data were analyzed using SPSS 22. RESULTS: All respondents completed the questionnaire, giving a response rate of 100% (general medicine=180, dentistry = 104). The prevalence of students who have ever smoked was 53.2%. However, only 8.9% (9.1% M vs. 8.7% F) of the general medicine students and 5.8% (4.8% M vs. 6.5% F) of dentistry students declared that smoke tobacco every day. Overall, the research shows that the prevalence of occasional smokers among medical students in Kosova is quite high. PMID- 26236165 TI - Antimicrobial Susceptibility/Resistance of Streptococcus Pneumoniae. AB - INTRODUCTION: Pneumococcal infections are a major cause of morbidity and mortality worldwide, whose treatment is threatened with an increase in the number of strains resistant to antibiotic therapy. GOAL: The main goal of this research was to investigate the presence of antimicrobial susceptibility/resistance of S. pneumoniae. MATERIAL AND METHODS: Taken are swabs of the nose and nasopharynx, eye and ear. In vitro tests that were made in order to study the antimicrobial resistance of pneumococci are: disk diffusion method and E-test. RESULTS: The resistance to inhibitors of cell wall synthesis was recorded at 39.17%, protein synthesis inhibitors 19.67%, folate antagonists 47.78% and quinolone in 1.11%. S. pneumoniae has shown drug resistance to erythromycin in 45%, clindamycin in 45%, chloramphenicol-0.56%, rifampicin-6.11%, tetracycline-4.67%, penicillin-G in 4.44%, oxacillin in 73.89%, ciprofloxacin in 1.11% and trimethoprim sulfamethoxazole in 5.34% of cases. CONCLUSION: The highest resistance pneumococcus showed to erythromycin, clindamycin and trimethoprim sulfamethoxazole and these should be avoided in the treatment. The least resistance pneumococcus showed to tetracycline, rifampicin, chloramphenicol, penicillin-G and ciprofloxacin. PMID- 26236166 TI - Drug Addiction as Risk for Suicide Attempts. AB - INTRODUCTION: Suicide is closely linked to the substances use. Therefore it is very important to confirm the factors that affect the possibility of suicidal behavior. METHODOLOGY: The survey included 200 respondents; 100 heroin addicts on the substitution program that attempted suicide and 100 opiate addicts who have not attempted suicide. The evaluation included a questionnaire with socio demographic, hereditary and addiction data, legal problems and then the Minnesota Multiphasic Personality Inventory-MMPI-2. RESULTS: The results showed a statistically significant difference compared to the personality structure, especially pronounced in hypersensitive structures, in relation to the duration of addictive experience and duration of heroin by intravenous route, as well as in relation to the presence of psychotic disorders, drug abuse and suicidal behavior in the family. CONCLUSION: As risk factors among opiate addicts are indentified interfered biological and psychological factors and the effects of the substances themselves. PMID- 26236167 TI - E-referral Solutions: Successful Experiences, Key Features and Challenges- a Systematic Review. AB - BACKGROUND: around the world health systems constantly face increasing pressures which arise from many factors, such as an ageing population, patients and providers demands for equipment's and services. In order to respond these challenges and reduction of health system's transactional costs, referral solutions are considered as a key factor. This study was carried out to identify referral solutions that have had successes. METHODS: relevant studies identified using keywords of referrals, consultation, referral system, referral model, referral project, electronic referral, electronic booking, health system, healthcare, health service and medical care. These searches were conducted using PubMed, ProQuest, Google Scholar, Scopus, Emerald, Web of Knowledge, Springer, Science direct, Mosby's index, SID, Medlib and Iran Doc data bases. 4306 initial articles were obtained and refined step by step. Finally, 27 articles met the inclusion criteria. RESULTS: we identified seventeen e-referral systems developed in UK, Norway, Finland, Netherlands, Denmark, Scotland, New Zealand, Canada, Australia, and U.S. Implemented solutions had variant degrees of successes such as improved access to specialist care, reduced wait times, timeliness and quality of referral communication, accurate health information transfer and integration of health centers and services. CONCLUSION: each one of referral solutions has both positive and changeable aspects that should be addressed according to sociotechnical conditions. These solutions are mainly formed in a small and localized manner. PMID- 26236168 TI - A Review of the Effects of Anxiety During Pregnancy on Children's Health. AB - BACKGROUND: Although pregnancy is often portrayed as a time of great joy, that's not the reality for all women. The adverse, long-term, stable, and sometimes, irreparable effects of anxiety during pregnancy can change pregnancy into an agonizing and unpleasant event of women's life span. AIM: The aim of this study was to explore the adverse effects of anxiety in pregnancy on children's health in order to promote child health. METHODS: In this narrative review the researchers searched in public databases like Google Scholar general search engine, and then more specific: Science Direct, Scientific Information Database, Magiran, Irandoc, Pubmed, Scopus, Cochrane library, and Psych info using Medical Subject Headings (MeSH) keywords: anxiety, maternal anxiety, pregnancy, pregnancy outcome, control and prevention restricted to English / Persian language, during the 20 years ago. Then those articles written by renowned experts were selected. At first, a list of 60 papers generated from the initial search. Then reviewers studied titles and abstracts and finally, quality assessment of full text studies was performed by two independent reviewers. Researchers reviewed summary of all articles sought, ultimately used data from 25 full articles to compile this review paper. RESULTS: The findings were classified into four groups Biological, Mental, Behavioral, and Medical effects of anxiety during pregnancy. CONCLUSIONS: The effects of anxiety during pregnancy on offspring's health are serious and thought-provoking to which the need for identifying and screening of anxiety disorders in prenatal care is necessary. PMID- 26236169 TI - The Viewpoints of Students and Evaluation Experts About Performance Processes of Faculty Member Evaluation at Mazandaran University of Medical Sciences, 2014. AB - BACKGROUND AND PURPOSE: One of the most common ways used in most of the countries and Iran to determine the status of teacher training is the evaluation by students. The most common method of evaluation is the survey questionnaire, the content of a number of questions about educational activities provided to the students. The researchers plan to evaluate the students' and experts' performances at Mazandaran University of Medical Sciences on the process of evaluating the performance of teachers, they examined in 2014. MATERIALS AND METHODS: This study surveys the students and experts in the evaluation of faculty members' performance process. The study subjects were 3904 students and 37 evaluation expert of Mazandaran University of Medical Sciences. Using Cochran sampling formula of 350 students through proportional stratified random sampling were selected. The experts' viewpoint, method was used. Data collection tools consisted of 14 questions with answers Yes, or, I don't know. Descriptive Statistical analysis of the data and chi-square test was performed. RESULTS: From total of 350 students, 346 and the entire 37 evaluations expert participated in this study. Most of the students, 80 (23.12%) and the largest number of experts, 8 (21.62%) were from Sari Allied Medical Sciences Faculty. Most of the demographic information about gender were, 255 female students (74.56%) and 29 female experts (78.37%). In most age groups of students, 188 (55.62 percent) were in the category of 18 to 20 years, and the experts, 19 (51.35%) were in the category of 22 and 31 years. Most students, 232 of them (70.95%) were in semester 2 and 4. Most experts, 20 (54.05 percent) were under 10 years of work experience. The comparison between the views of students and experts in the evaluation process between the schools of Mazandaran University of Medical Sciences, Sari School of Nursing and Midwifery, there was difference between the opinions of experts and students (p-value=0.01. It showed 86.7% student and 33.3% of experts is satisfied with the evaluation process. CONCLUSION: on comparison of students and experts viewpoints on the implementation of the evaluation process, it is noteworthy that among students of different opinions on how the evaluation process. It worth to mention that there is insignificant difference between their viewpoints and majority of students and evaluation experts with the evaluation the process. In addition, the experts evaluated at different schools, most of them are satisfied the process. PMID- 26236170 TI - Depiction of Trends in Administrative Healthcare Data from Hospital Information System. AB - BACKGROUND: administrative healthcare data are among main components of hospital information system. Such data can be analyzed and deployed for a variety of purposes. The principal aim of this research was to depict trends of administrative healthcare data from HIS in a general hospital from March 2011 to March 2014. METHODS: data set used for this research was extracted from the SQL database of the hospital information system in Razi general hospital located in Marand. The data were saved as CSV (Comma Separated Values) in order to facilitate data cleaning and analysis. The variables of data set included patient's age, gender, final diagnosis, final diagnosis code based on ICD-10 classification system, date of hospitalization, date of discharge, LOS(Length of Stay), ward, and survival status of the patient. Data were analyzed and visualized after applying appropriate cleansing and preparing techniques. RESULTS: morbidity showed a constant trend over three years. Pregnancy, childbirth and the puerperium were the leading category of final diagnosis (about 32.8 %). The diseases of the circulatory system were the second class accounting for 13 percent of the hospitalization cases. The diseases of the digestive system had the third rank (10%). Patients aged between 14 and 44 constituted a higher proportion of total cases. Diseases of the circulatory system was the most common class of diseases among elderly patients (age>=65). The highest rate of mortality was observed among patients with final diagnosis of the circulatory system diseases followed by those with diseases of the respiratory system, and neoplasms. Mortality rate for the ICU and the CCU patients were 62% and 33% respectively. The longest average of LOS (7.3 days) was observed among patients hospitalized in the ICU while patients in the Obstetrics and Gynecology ward had the shortest average of LOS (2.4 days). Multiple regression analysis revealed that LOS was correlated with variables of surgery, gender, and type of payment, ward, the class of final diagnosis and age. CONCLUSION: this study presents trends in administrative health care data residing in hospital information system of a general public hospital. Patterns in morbidity, mortality and length of stay can inform decision making in health care management. Mining trends in administrative healthcare data can add value to the health care management. PMID- 26236171 TI - Epidemiology and Clinical Research Design, Part 2: Principles. AB - This is the third article covering core knowledge in scholarly activities for neonatal physicians. In this article, we discuss various principles of epidemiology and clinical research design. A basic knowledge of these principles is necessary for conducting clinical research and for proper interpretation of studies. This article reviews bias and confounding, causation, incidence and prevalence, decision analysis, cost-effectiveness, sensitivity analysis, and measurement. PMID- 26236172 TI - Case 1: Lactic Acidosis and Respiratory Distress in a 10-Day-Old Infant. PMID- 26236173 TI - Intensive Motivational Interviewing for Women with Alcohol Problems. AB - Motivational interviewing (MI) for the treatment of alcohol and drug problems is typically conducted over 1 to 3 sessions. This paper reports on an evaluation of an intensive 9-session version of MI (IMI) compared to a standard single MI session (SMI). Although no differences between IMI and SMI were found for methamphetamine use, there was an unexpected finding that women but not men with co-occurring alcohol problems in the IMI condition reduced the severity of their alcohol problems significantly more than those in the SMI condition at 4- and 6 month follow-up. Stronger perceived alliance with the therapist was associated with better outcome. Findings indicate that alcohol outcomes for women might be improved with the addition of more MI sessions. A current study is assessing the impact of IMI for women with more serious alcohol problems. Qualitative interviews are being conducted with women to better understand how IMI is helpful and why it appears to add benefit for women but not men. PMID- 26236174 TI - Connecting free energy surfaces in implicit and explicit solvent: an efficient method to compute conformational and solvation free energies. AB - The ability to accurately model solvent effects on free energy surfaces is important for understanding many biophysical processes including protein folding and misfolding, allosteric transitions, and protein-ligand binding. Although all atom simulations in explicit solvent can provide an accurate model for biomolecules in solution, explicit solvent simulations are hampered by the slow equilibration on rugged landscapes containing multiple basins separated by barriers. In many cases, implicit solvent models can be used to significantly speed up the conformational sampling; however, implicit solvent simulations do not fully capture the effects of a molecular solvent, and this can lead to loss of accuracy in the estimated free energies. Here we introduce a new approach to compute free energy changes in which the molecular details of explicit solvent simulations are retained while also taking advantage of the speed of the implicit solvent simulations. In this approach, the slow equilibration in explicit solvent, due to the long waiting times before barrier crossing, is avoided by using a thermodynamic cycle which connects the free energy basins in implicit solvent and explicit solvent using a localized decoupling scheme. We test this method by computing conformational free energy differences and solvation free energies of the model system alanine dipeptide in water. The free energy changes between basins in explicit solvent calculated using fully explicit solvent paths agree with the corresponding free energy differences obtained using the implicit/explicit thermodynamic cycle to within 0.3 kcal/mol out of ~3 kcal/mol at only ~8% of the computational cost. We note that WHAM methods can be used to further improve the efficiency and accuracy of the implicit/explicit thermodynamic cycle. PMID- 26236175 TI - Blood-sampling collection prior to surgery may have a significant influence upon biomarker concentrations measured. AB - BACKGROUND: Biomarkers can be subtle tools to aid the diagnosis, prognosis and monitoring of therapy and disease progression. The validation of biomarkers is a cumbersome process involving many steps. Serum samples from lung cancer patients were collected in the framework of a larger study for evaluation of biomarkers for early detection of lung cancer. The analysis of biomarker levels measured revealed a noticeable difference in certain biomarker values that exhibited a dependence of the time point and setting of the sampling. Biomarker concentrations differed significantly if taken before or after the induction of anesthesia and if sampled via venipuncture or arterial catheter. METHODS: To investigate this observation, blood samples from 13 patients were drawn 1-2 days prior to surgery (T1), on the same day by venipuncture (T2) and after induction of anesthesia via arterial catheter (T3). The biomarkers Squamous Cell Carcinoma antigen (CanAG SCC EIA, Fujirebio Diagnostics, Malvern, USA), Carcinoembrionic Antigen (CEA), and CYFRA 21-1 (Roche Diagnostics GmbH, Mannheim, Germany) were analyzed. RESULTS: SCC showed a very strong effect in relation to the sampling time and procedure. While the first two points in time (T1; T2) were highly comparable (median fold-change: 0.84; p = 0.7354; correlation rho = 0.883), patients showed a significant increase (median fold-change: 4.96; p = 0.0017; correlation rho = -0.036) in concentration when comparing T1 with the sample time subsequent to anesthesia induction (T3). A much weaker increase was found for CYFRA 21-1 at T3 (median fold-change: 1.40; p = 0.0479). The concentration of CEA showed a very small, but systematic decrease (median fold-change: 0.72; p = 0.0039). CONCLUSIONS: In this study we show the unexpectedly marked influence of blood withdrawal timing (before vs. after anesthesia) and procedure (venous versus arterial vessel puncture) has on the concentration of the protein biomarker SCC and to a less extent upon CYFRA21-1. The potential causes for these effects remain to be elucidated in subsequent studies, however these findings highlight the importance of a standardized, controlled blood collection protocol for biomarker detection. PMID- 26236176 TI - Tolerance of Chemoorganotrophic Bioleaching Microorganisms to Heavy Metal and Alkaline Stresses. AB - The bioleaching potential of the bacterium Bacillus mucilaginosus and the fungus Aspergillus niger towards industrial residues was investigated by assessing their response towards various heavy metals (including arsenic, cadmium, cobalt, chromium, nickel, lead, and zinc) and elevated pH. The plate diffusion method was performed for each metal to determine the toxicity effect. Liquid batch cultures were set up for more quantitative evaluation as well as for studying the influence of basicity. Growth curves were prepared using bacterial/fungal growth counting techniques such as plate counting, optical density measurement, and dry biomass determination. Cadmium, nickel, and arsenite had a negative influence on the growth of B. mucilaginosus, whereas A. niger was sensitive to cadmium and arsenate. However, it was shown that growth recovered when microorganisms cultured in the presence of these metals were inoculated onto metal-free medium. Based on the findings of the bacteriostatic/fungistatic effect of the metals and the adaptability of the microorganisms to fairly elevated pH values, it is concluded that both strains have potential applicability for further research concerning bioleaching of alkaline waste materials. PMID- 26236177 TI - Diffusion Tensor MRI Assessment of Skeletal Muscle Architecture. AB - Diffusion-tensor magnetic resonance imaging (DTI) offers great potential for understanding structure-function relationships in skeletal muscle. The basis for these studies is that water diffuses more readily along the long axes of muscle fibers than along their transverse axes. This diffusion anisotropy can be characterized using a tensor, with the orientation of the principal eigenvalue corresponding to the long axis of the muscle fiber. These local, voxel-based directions can be combined by a fiber tracking algorithm to reconstruct the whole muscle architecture. The fiber tracking data can be used to characterize important muscle architectural parameters, such as pennation angle, fiber length, and physiological cross-sectional area. The second and third eigenvalues convey information about muscle structural properties along the fibers' transverse axes. A comprehensive description of the sources of transverse diffusion restriction in muscle and how their relative importance may vary with the image acquisition conditions does not yet exist, but may ultimately make DTI a useful tool in studies of skeletal muscle microstructure as well. Ultimately, DTI-based longitudinal studies of changes in muscle architecture may provide insight into the relationships between structure and function in muscle, the time frames of muscle wasting, and in studying adaptations that maintain muscle functionality. PMID- 26236178 TI - Perceived benefits and health risks of cigarette smoking among young adults: insights from a cross-sectional study. AB - BACKGROUND: Perceptions of smoking-related health risks and benefits among young adults (18-24 years) and their smoking behaviour have not been adequately studied in low-income countries like Nepal. This study has examined the perceived risks and the benefits of smoking among young adults who smoke vs. don't smoke. METHODS: A cross-sectional study was carried out from August to September 2013 among 315 young adults (18-24) from four conveniently selected private colleges of different faculties in Kathmandu Metropolis. The anonymous, self-administrated and semi structured questionnaire contained the information on individual information; smoking behaviour; and perceptions on smoking-related risks and benefits. Kaplan-Meier analysis was used to identify the mean age of smoking initiation. Cox proportion hazard regression was used to assess the relationship between current smoking behaviours and the perceived risks and the benefits of smoking. RESULTS: Overall, the prevalence of current smoking was 16.2 % (Male =28.4 % and female =5.38 %). The mean age of smoking initiation was 16.6 and 17.7 years for male and female respectively. The risk of becoming a current smoking being a management student was higher (HR = 4.72, 95 % CI: 2.19; 10.20) than being a medical student. The risk of current smoking behaviour significantly increased with those who believed that smoking was enjoyable (HR = 4.74, 2.58; 8.72); would help to deal with problems or stress (3.19, 1.76; 5.79); would feel comfortable with friends (4.29, 2.33; 7.92); would be relaxing (6.95, 3.60; 13.43); and something to do when feel bored (3.42, 1.91; 6.13). The young adults who believed that smoking would make yellow teeth (0.53, 0.30; 0.94) and yellow nail (0.53, 0.29; 0.95); and would be bad to their health (0.45, 0.21; 0.98) were significantly at lower risk of becoming a current smoking. CONCLUSION: Positive perceptions related to smoking are common among young adults. To discourage smoking, future intervention programs should focus communicating not only health risks but also counteract perception of benefits related to smoking. PMID- 26236180 TI - A framework to analyze cerebral mean diffusivity using surface guided diffusion mapping in diffusion tensor imaging. AB - The mean diffusivity (MD) value has been used to describe microstructural properties in Diffusion Tensor Imaging (DTI) in cortical gray matter (GM). Recently, researchers have applied a cortical surface generated from the T1 weighted volume. When the DTI data are analyzed using the cortical surface, it is important to assign an accurate MD value from the volume space to the vertex of the cortical surface, considering the anatomical correspondence between the DTI and the T1-weighted image. Previous studies usually sampled the MD value using the nearest-neighbor (NN) method or Linear method, even though there are geometric distortions in diffusion-weighted volumes. Here we introduce a Surface Guided Diffusion Mapping (SGDM) method to compensate for such geometric distortions. We compared our SGDM method with results using NN and Linear methods by investigating differences in the sampled MD value. We also projected the tissue classification results of non-diffusion-weighted volumes to the cortical midsurface. The CSF probability values provided by the SGDM method were lower than those produced by the NN and Linear methods. The MD values provided by the NN and Linear methods were significantly greater than those of the SGDM method in regions suffering from geometric distortion. These results indicate that the NN and Linear methods assigned the MD value in the CSF region to the cortical midsurface (GM region). Our results suggest that the SGDM method is an effective way to correct such mapping errors. PMID- 26236179 TI - AMPK: a master energy regulator for gonadal function. AB - From C. elegans to mammals (including humans), nutrition and energy metabolism significantly influence reproduction. At the cellular level, some detectors of energy status indicate whether energy reserves are abundant (obesity), or poor (diet restriction). One of these detectors is AMPK (5' AMP-activated protein kinase), a protein kinase activated by ATP deficiency but also by several natural substances such as polyphenols or synthetic molecules like metformin, used in the treatment of insulin resistance. AMPK is expressed in muscle and liver, but also in the ovary and testis. This review focuses on the main effects of AMPK identified in gonadal cells. We describe the role of AMPK in gonadal steroidogenesis, in proliferation and survival of somatic gonadal cells and in the maturation of oocytes or spermatozoa. We discuss also the role of AMPK in germ and somatic cell interactions within the cumulus-oocyte complex and in the blood testis barrier. Finally, the interface in the gonad between AMPK and modification of metabolism is reported and discussion about the role of AMPK on fertility, in regards to the treatment of infertility associated with insulin resistance (male obesity, polycystic ovary syndrome). PMID- 26236181 TI - Interactive effects of culture and sex hormones on the sex role self-concept. AB - Sex role orientation, i.e., a person's masculinity or femininity, influences cognitive and emotional performance, like biological sex. While it is now widely accepted that sex differences are modulated by the hormonal status of female participants (menstrual cycle, hormonal contraceptive use), the question, whether hormonal status and sex hormones also modulate participants sex role orientation has hardly been addressed previously. The present study assessed sex role orientation and hormonal status as well as sex hormone levels in three samples of participants from two different cultures (Northern American, Middle European). Menstrual cycle phase did not affect participant's masculinity or femininity, but had a significant impact on reference group. While women in their follicular phase (low levels of female sex hormones) determined their masculinity and femininity in reference to men, women in their luteal phase (high levels of female sex hormones) determined their masculinity and femininity in reference to women. Hormonal contraceptive users rated themselves as significantly more feminine and less masculine than naturally cycling women. Furthermore, the impact of biological sex on the factorial structure of sex role orientation as well as the relationship of estrogen to masculinity/femininity was modulated by culture. We conclude that culture and sex hormones interactively affect sex role orientation and hormonal status of participants should be controlled for when assessing masculinity and/or femininity. PMID- 26236182 TI - Preliminary analysis using multi-atlas labeling algorithms for tracing longitudinal change. AB - Multicenter longitudinal neuroimaging has great potential to provide efficient and consistent biomarkers for research of neurodegenerative diseases and aging. In rare disease studies it is of primary importance to have a reliable tool that performs consistently for data from many different collection sites to increase study power. A multi-atlas labeling algorithm is a powerful brain image segmentation approach that is becoming increasingly popular in image processing. The present study examined the performance of multi-atlas labeling tools for subcortical identification using two types of in-vivo image database: Traveling Human Phantom (THP) and PREDICT-HD. We compared the accuracy (Dice Similarity Coefficient; DSC and intraclass correlation; ICC), multicenter reliability (Coefficient of Variance; CV), and longitudinal reliability (volume trajectory smoothness and Akaike Information Criterion; AIC) of three automated segmentation approaches: two multi-atlas labeling tools, MABMIS and MALF, and a machine learning-based tool, BRAINSCut. In general, MALF showed the best performance (higher DSC, ICC, lower CV, AIC, and smoother trajectory) with a couple of exceptions. First, the results of accumben, where BRAINSCut showed higher reliability, were still premature to discuss their reliability levels since their validity is still in doubt (DSC < 0.7, ICC < 0.7). For caudate, BRAINSCut presented slightly better accuracy while MALF showed significantly smoother longitudinal trajectory. We discuss advantages and limitations of these performance variations and conclude that improved segmentation quality can be achieved using multi-atlas labeling methods. While multi-atlas labeling methods are likely to help improve overall segmentation quality, caution has to be taken when one chooses an approach, as our results suggest that segmentation outcome can vary depending on research interest. PMID- 26236183 TI - Tuning properties and dynamic range of type 1 vomeronasal receptors. AB - The mouse vomeronasal organ (VNO) expresses chemosensory receptors that detect intra-species as well as inter-species cues. The vomeronasal neurons are thought to be highly selective in their responses. The tuning properties of individual receptors remain difficult to characterize due to the lack of a robust heterologous expression system. Here, we take a transgenic approach to ectopically express two type 1 vomeronasal receptors in the mouse VNO and characterize their responses to steroid compounds. We find that V1rj2 and V1rj3 are sensitive to two sulfated estrogens (SEs) and can be activated by a broad variety of sulfated and glucuronidated steroids at high concentrations. Individual neurons exhibit narrow range of concentration-dependent activation. Collectively, a neuronal population expressing the same receptor covers a wide dynamic range in their responses to SEs. These properties recapitulate the response profiles of endogenous neurons to SEs. PMID- 26236184 TI - Stem cell models of polyglutamine diseases and their use in cell-based therapies. AB - Polyglutamine diseases are fatal neurological disorders that affect the central nervous system. They are caused by mutations in disease genes that contain CAG trinucleotide expansions in their coding regions. These mutations are translated into expanded glutamine chains in pathological proteins. Mutant proteins induce cytotoxicity, form intranuclear aggregates and cause neuronal cell death in specific brain regions. At the moment there is no cure for these diseases and only symptomatic treatments are available. Here, we discuss novel therapeutic approaches that aim in neuronal cell replacement using induced pluripotent or adult stem cells. Additionally, we present the beneficial effect of genetically engineered mesenchymal stem cells and their use as disease models or RNAi/gene delivery vehicles. In combination with their paracrine and cell-trophic properties, such cells may prove useful for the development of novel therapies against polyglutamine diseases. PMID- 26236186 TI - Shiga toxin type-2 (Stx2) induces glutamate release via phosphoinositide 3-kinase (PI3K) pathway in murine neurons. AB - Shiga toxin-producing Escherichia coli (STEC) can cause central nervous system (CNS) damage resulting in paralysis, seizures, and coma. The key STEC virulence factors associated with systemic illness resulting in CNS impairment are Shiga toxins (Stx). While neurons express the Stx receptor globotriaosylceramide (Gb3) in vivo, direct toxicity to neurons by Stx has not been studied. We used murine neonatal neuron cultures to study the interaction of Shiga toxin type 2 (Stx2) with cell surface expressed Gb3. Single molecule imaging three dimensional STochastic Optical Reconstruction Microscopy-Total Internal Reflection Fluorescence (3D STORM-TIRF) allowed visualization and quantification of Stx2-Gb3 interactions. Furthermore, we demonstrate that Stx2 increases neuronal cytosolic Ca(2+), and NMDA-receptor inhibition blocks Stx2-induced Ca(2+) influx, suggesting that Stx2-mediates glutamate release. Phosphoinositide 3-kinase (PI3K) specific inhibition by Wortmannin reduces Stx2-induced intracellular Ca(2+) indicating that the PI3K signaling pathway may be involved in Stx2-associated glutamate release, and that these pathways may contribute to CNS impairment associated with STEC infection. PMID- 26236185 TI - Neuronal and microglial regulators of cortical wiring: usual and novel guideposts. AB - Neocortex functioning relies on the formation of complex networks that begin to be assembled during embryogenesis by highly stereotyped processes of cell migration and axonal navigation. The guidance of cells and axons is driven by extracellular cues, released along by final targets or intermediate targets located along specific pathways. In particular, guidepost cells, originally described in the grasshopper, are considered discrete, specialized cell populations located at crucial decision points along axonal trajectories that regulate tract formation. These cells are usually early-born, transient and act at short-range or via cell-cell contact. The vast majority of guidepost cells initially identified were glial cells, which play a role in the formation of important axonal tracts in the forebrain, such as the corpus callosum, anterior, and post-optic commissures as well as optic chiasm. In the last decades, tangential migrating neurons have also been found to participate in the guidance of principal axonal tracts in the forebrain. This is the case for several examples such as guideposts for the lateral olfactory tract (LOT), corridor cells, which open an internal path for thalamo-cortical axons and Cajal-Retzius cells that have been involved in the formation of the entorhino-hippocampal connections. More recently, microglia, the resident macrophages of the brain, were specifically observed at the crossroads of important neuronal migratory routes and axonal tract pathways during forebrain development. We furthermore found that microglia participate to the shaping of prenatal forebrain circuits, thereby opening novel perspectives on forebrain development and wiring. Here we will review the last findings on already known guidepost cell populations and will discuss the role of microglia as a potentially new class of atypical guidepost cells. PMID- 26236187 TI - Mechanisms and regulation of iron trafficking across the capillary endothelial cells of the blood-brain barrier. AB - The transcellular trafficking of iron from the blood into the brain interstitium depends on iron uptake proteins in the apical membrane of brain microvascular capillary endothelial cells and efflux proteins at the basolateral, abluminal membrane. In this review, we discuss the three mechanisms by which these cells take-up iron from the blood and the sole mechanism by which they efflux this iron into the abluminal space. We then focus on the regulation of this efflux pathway by exocrine factors that are released from neighboring astrocytes. Also discussed are the cytokines secreted by capillary cells that regulate the expression of these glial cell signals. Among the interstitial factors that regulate iron efflux into the brain is the Amyloid precursor protein (APP). The role of this amyliodogenic species in brain iron metabolism is discussed. Last, we speculate on the potential relationship between iron transport at the blood-brain barrier and neurological disorders associated with iron mismanagement. PMID- 26236188 TI - Gene therapy and peripheral nerve repair: a perspective. AB - Clinical phase I/II studies have demonstrated the safety of gene therapy for a variety of central nervous system disorders, including Canavan's, Parkinson's (PD) and Alzheimer's disease (AD), retinal diseases and pain. The majority of gene therapy studies in the CNS have used adeno-associated viral vectors (AAV) and the first AAV-based therapeutic, a vector encoding lipoprotein lipase, is now marketed in Europe under the name Glybera. These remarkable advances may become relevant to translational research on gene therapy to promote peripheral nervous system (PNS) repair. This short review first summarizes the results of gene therapy in animal models for peripheral nerve repair. Secondly, we identify key areas of future research in the domain of PNS-gene therapy. Finally, a perspective is provided on the path to clinical translation of PNS-gene therapy for traumatic nerve injuries. In the latter section we discuss the route and mode of delivery of the vector to human patients, the efficacy and safety of the vector, and the choice of the patient population for a first possible proof-of concept clinical study. PMID- 26236190 TI - The choroid plexus is modulated by various peripheral stimuli: implications to diseases of the central nervous system. AB - The blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB) form the barriers of the brain. These barriers are essential not only for the protection of the brain, but also in regulating the exchange of cells and molecules in and out of the brain. The choroid plexus (CP) epithelial cells and the arachnoid membrane form the BCSFB. The CP is structurally divided into two independent compartments: one formed by a unique and continuous line of epithelial cells that rest upon a basal lamina; and, a second consisting of a central core formed by connective and highly vascularized tissue populated by diverse cell types (fibroblasts, macrophages and dendritic cells). Here, we review how the CP transcriptome and secretome vary depending on the nature and duration of the stimuli to which the CP is exposed. Specifically, when the peripheral stimulation is acute the CP response is rapid, strong and transient, whereas if the stimulation is sustained in time the CP response persists but it is weaker. Furthermore, not all of the epithelium responds at the same time to peripheral stimulation, suggesting the existence of a synchrony system between individual CP epithelial cells. PMID- 26236189 TI - Flipping the transcriptional switch from myelin inhibition to axon growth in the CNS. AB - Poor regeneration of severed axons in the central nervous system (CNS) limits functional recovery. Regeneration failure involves interplay of inhibitory environmental elements and the growth state of the neuron. To find internal changes in gene expression that might overcome inhibitory environmental cues, we compared several paradigms that allow growth in the inhibitory environment. Conditions that allow axon growth by axotomized and cultured dorsal root ganglion (DRG) neurons on CNS myelin include immaturity (the first few postnatal days), high levels of cyclic adenosine mono phosphate (cAMP), and conditioning with a peripheral nerve lesion before explant. This shift from inhibition to growth depends on transcription. Seeking to understand the transcriptome changes that allow axon growth in the CNS, we collaborated with the Marie Filbin laboratory to identify several mRNAs that are functionally relevant, as determined by gain- and loss-of-function studies. In this Perspective, we review evidence from these experiments and discuss the merits of comparing multiple regenerative paradigms to identify a core transcriptional program for CNS axon regeneration. PMID- 26236191 TI - The deafness gene DFNA5 induces programmed cell death through mitochondria and MAPK-related pathways. AB - Cell death exists in many different forms. Some are accidental, but most of them have some kind of regulation and are called programmed cell death. Programmed cell death (PCD) is a very diverse and complex mechanism and must be tightly regulated. This study investigated PCD induced by DFNA5, a gene responsible for autosomal dominant hearing loss (HL) and a tumor suppressor gene (TSG) involved in frequent forms of cancer. Mutations in DFNA5 lead to exon 8 skipping and result in HL in several families. Expression of mutant DFNA5, a cDNA construct where exon 8 is deleted, was linked to PCD both in human cell lines and in Saccharomyces cerevisiae. To further investigate the cell death mechanism induced by mutant DFNA5, we performed a microarray study in both models. We used wild type DFNA5, which does not induce cell death, as a reference. Our data showed that the yeast pathways related to mitochondrial ATP-coupled electron transport chain, oxidative phosphorylation and energy metabolism were up-regulated, while in human cell lines, MAP kinase-related activity was up-regulated. Inhibition of this pathway was able to partially attenuate the resulting cell death induced by mutant DFNA5 in human cell lines. In yeast, the association with mitochondria was demonstrated by up-regulation of several cytochrome c oxidase (COX) genes involved in the cellular oxidative stress production. Both models show a down regulation of protein sorting- and folding-related mechanisms suggesting an additional role for the endoplasmic reticulum (ER). The exact relationship between ER and mitochondria in DFNA5-induced cell death remains unknown at this moment, but these results suggest a potential link between the two. PMID- 26236193 TI - An ultrastructural analysis of the effects of ethanol self-administration on the hypothalamic paraventricular nucleus in rhesus macaques. AB - A bidirectional relationship between stress and ethanol exists whereby stressful events are comorbid with problematic ethanol use and prolonged ethanol exposure results in adaptations of the physiological stress response. Endocrine response to stress is initiated in the hypothalamic paraventricular nucleus (PVN) with the synthesis and release of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). Alterations in CRH and AVP following long-term ethanol exposure in rodents is well demonstrated, however little is known about the response to ethanol in primates or the mechanisms of adaptation. We hypothesized that long-term ethanol self-administration in nonhuman primates would lead to ultrastructural changes in the PVN underlying adaptation to chronic ethanol. Double-label immunogold electron microscopy (EM) was used to measure presynaptic gamma-aminobutyric acid (GABA) and glutamate density within synaptic terminals contacting CRH- and AVP-immunoreactive dendrites. Additionally, pituitary-adrenal hormones (ACTH, cortisol, DHEA-s and aldosterone) under two conditions (low and mild stress) were compared before and after self-administration. All hormones were elevated in response to the mild stressor independent of ethanol consumption. The presynaptic glutamate density in recurrent (i.e., intra hypothalamic) CRH terminals was highly related to ethanol intake, and may be a permissive factor in increased drinking due to stress. Conversely, glutamate density within recurrent AVP terminals showed a trend-level increase following ethanol, but was not related to average daily consumption. Glutamate density in non-recurrent AVP terminals was related to aldosterone under the low stress condition while GABAergic density in this terminal population was related to water consumption. The results reveal distinct populations of presynaptic terminals whose glutamatergic or GABAergic density were uniquely related to water and ethanol consumption and circulating hormones. PMID- 26236194 TI - The Utility of Next-Generation Sequencing in Gene Discovery for Mutation-Negative Patients with Rett Syndrome. AB - Rett syndrome (RTT) is a rare, severe disorder of neuronal plasticity that predominantly affects girls. Girls with RTT usually appear asymptomatic in the first 6-18 months of life, but gradually develop severe motor, cognitive, and behavioral abnormalities that persist for life. A predominance of neuronal and synaptic dysfunction, with altered excitatory-inhibitory neuronal synaptic transmission and synaptic plasticity, are overarching features of RTT in children and in mouse models. Over 90% of patients with classical RTT have mutations in the X-linked methyl-CpG-binding (MECP2) gene, while other genes, including cyclin dependent kinase-like 5 (CDKL5), Forkhead box protein G1 (FOXG1), myocyte specific enhancer factor 2C (MEF2C), and transcription factor 4 (TCF4), have been associated with phenotypes overlapping with RTT. However, there remain a proportion of patients who carry a clinical diagnosis of RTT, but who are mutation negative. In recent years, next-generation sequencing technologies have revolutionized approaches to genetic studies, making whole-exome and even whole genome sequencing possible strategies for the detection of rare and de novo mutations, aiding the discovery of novel disease genes. Here, we review the recent progress that is emerging in identifying pathogenic variations, specifically from exome sequencing in RTT patients, and emphasize the need for the use of this technology to identify known and new disease genes in RTT patients. PMID- 26236195 TI - An electromechanical model of neuronal dynamics using Hamilton's principle. AB - Damage of the brain may be caused by mechanical loads such as penetration, blunt force, shock loading from blast, and by chemical imbalances due to neurological diseases and aging that trigger not only neuronal degeneration but also changes in the mechanical properties of brain tissue. An understanding of the interconnected nature of the electro-chemo-mechanical processes that result in brain damage and ultimately loss of functionality is currently lacking. While modern mathematical models that focus on how to link brain mechanics to its biochemistry are essential in enhancing our understanding of brain science, the lack of experimental data required by these models as well as the complexity of the corresponding computations render these models hard to use in clinical applications. In this paper we propose a unified variational framework for the modeling of neuronal electromechanics. We introduce a constrained Lagrangian formulation that takes into account Newton's law of motion of a linear viscoelastic Kelvin-Voigt solid-state neuron as well as the classic Hodgkin Huxley equations of the electronic neuron. The system of differential equations describing neuronal electromechanics is obtained by applying Hamilton's principle. Numerical simulations of possible damage dynamics in neurons will be presented. PMID- 26236192 TI - Molecular pathophysiology and pharmacology of the voltage-sensing module of neuronal ion channels. AB - Voltage-gated ion channels (VGICs) are membrane proteins that switch from a closed to open state in response to changes in membrane potential, thus enabling ion fluxes across the cell membranes. The mechanism that regulate the structural rearrangements occurring in VGICs in response to changes in membrane potential still remains one of the most challenging topic of modern biophysics. Na(+), Ca(2+) and K(+) voltage-gated channels are structurally formed by the assembly of four similar domains, each comprising six transmembrane segments. Each domain can be divided into two main regions: the Pore Module (PM) and the Voltage-Sensing Module (VSM). The PM (helices S5 and S6 and intervening linker) is responsible for gate opening and ion selectivity; by contrast, the VSM, comprising the first four transmembrane helices (S1-S4), undergoes the first conformational changes in response to membrane voltage variations. In particular, the S4 segment of each domain, which contains several positively charged residues interspersed with hydrophobic amino acids, is located within the membrane electric field and plays an essential role in voltage sensing. In neurons, specific gating properties of each channel subtype underlie a variety of biological events, ranging from the generation and propagation of electrical impulses, to the secretion of neurotransmitters and to the regulation of gene expression. Given the important functional role played by the VSM in neuronal VGICs, it is not surprising that various VSM mutations affecting the gating process of these channels are responsible for human diseases, and that compounds acting on the VSM have emerged as important investigational tools with great therapeutic potential. In the present review we will briefly describe the most recent discoveries concerning how the VSM exerts its function, how genetically inherited diseases caused by mutations occurring in the VSM affects gating in VGICs, and how several classes of drugs and toxins selectively target the VSM. PMID- 26236196 TI - Interaction of electrically evoked activity with intrinsic dynamics of cultured cortical networks with and without functional fast GABAergic synaptic transmission. AB - The modulation of neuronal activity by means of electrical stimulation is a successful therapeutic approach for patients suffering from a variety of central nervous system disorders. Prototypic networks formed by cultured cortical neurons represent an important model system to gain general insights in the input-output relationships of neuronal tissue. These networks undergo a multitude of developmental changes during their maturation, such as the excitatory-inhibitory shift of the neurotransmitter GABA. Very few studies have addressed how the output properties to a given stimulus change with ongoing development. Here, we investigate input-output relationships of cultured cortical networks by probing cultures with and without functional GABAAergic synaptic transmission with a set of stimulation paradigms at various stages of maturation. On the cellular level, low stimulation rates (<15 Hz) led to reliable neuronal responses; higher rates were increasingly ineffective. Similarly, on the network level, lowest stimulation rates (<0.1 Hz) lead to maximal output rates at all ages, indicating a network wide refractory period after each stimulus. In cultures aged 3 weeks and older, a gradual recovery of the network excitability within tens of milliseconds was in contrast to an abrupt recovery after about 5 s in cultures with absent GABAAergic synaptic transmission. In these GABA deficient cultures evoked responses were prolonged and had multiple discharges. Furthermore, the network excitability changed periodically, with a very slow spontaneous change of the overall network activity in the minute range, which was not observed in cultures with absent GABAAergic synaptic transmission. The electrically evoked activity of cultured cortical networks, therefore, is governed by at least two potentially interacting mechanisms: A refractory period in the order of a few seconds and a very slow GABA dependent oscillation of the network excitability. PMID- 26236197 TI - An excitatory GABA loop operating in vivo. AB - While it has been proposed that the conventional inhibitory neurotransmitter GABA can be excitatory in the mammalian brain, much remains to be learned concerning the circumstances and the cellular mechanisms governing potential excitatory GABA action. Using a combination of optogenetics and two-photon calcium imaging in vivo, we find that activation of chloride-permeable GABAA receptors in parallel fibers (PFs) of the cerebellar molecular layer of adult mice causes parallel fiber excitation. Stimulation of PFs at submaximal stimulus intensities leads to GABA release from molecular layer interneurons (MLIs), thus creating a positive feedback loop that enhances excitation near the center of an activated PF bundle. Our results imply that elevated chloride concentration can occur in specific intracellular compartments of mature mammalian neurons and suggest an excitatory role for GABAA receptors in the cerebellar cortex of adult mice. PMID- 26236198 TI - An in vitro method to manipulate the direction and functional strength between neural populations. AB - We report the design and application of a Micro Electro Mechanical Systems (MEMs) device that permits investigators to create arbitrary network topologies. With this device investigators can manipulate the degree of functional connectivity among distinct neural populations by systematically altering their geometric connectivity in vitro. Each polydimethylsilxane (PDMS) device was cast from molds and consisted of two wells each containing a small neural population of dissociated rat cortical neurons. Wells were separated by a series of parallel micrometer scale tunnels that permitted passage of axonal processes but not somata; with the device placed over an 8 * 8 microelectrode array, action potentials from somata in wells and axons in microtunnels can be recorded and stimulated. In our earlier report we showed that a one week delay in plating of neurons from one well to the other led to a filling and blocking of the microtunnels by axons from the older well resulting in strong directionality (older to younger) of both axon action potentials in tunnels and longer duration and more slowly propagating bursts of action potentials between wells. Here we show that changing the number of tunnels, and hence the number of axons, connecting the two wells leads to changes in connectivity and propagation of bursting activity. More specifically, the greater the number of tunnels the stronger the connectivity, the greater the probability of bursting propagating between wells, and shorter peak-to-peak delays between bursts and time to first spike measured in the opposing well. We estimate that a minimum of 100 axons are needed to reliably initiate a burst in the opposing well. This device provides a tool for researchers interested in understanding network dynamics who will profit from having the ability to design both the degree and directionality connectivity among multiple small neural populations. PMID- 26236199 TI - State-of-art neuroanatomical target analysis of high-definition and conventional tDCS montages used for migraine and pain control. AB - Although transcranial direct current stimulation (tDCS) studies promise to modulate cortical regions associated with pain, the electric current produced usually spreads beyond the area of the electrodes' placement. Using a forward model analysis, this study compared the neuroanatomic location and strength of the predicted electric current peaks, at cortical and subcortical levels, induced by conventional and High-Definition-tDCS (HD-tDCS) montages developed for migraine and other chronic pain disorders. The electrodes were positioned in accordance with the 10-20 or 10-10 electroencephalogram (EEG) landmarks: motor cortex-supraorbital (M1-SO, anode and cathode over C3 and Fp2, respectively), dorsolateral prefrontal cortex (PFC) bilateral (DLPFC, anode over F3, cathode over F4), vertex-occipital cortex (anode over Cz and cathode over Oz), HD-tDCS 4 * 1 (one anode on C3, and four cathodes over Cz, F3, T7, and P3) and HD-tDCS 2 * 2 (two anodes over C3/C5 and two cathodes over FC3/FC5). M1-SO produced a large current flow in the PFC. Peaks of current flow also occurred in deeper brain structures, such as the cingulate cortex, insula, thalamus and brainstem. The same structures received significant amount of current with Cz-Oz and DLPFC tDCS. However, there were differences in the current flow to outer cortical regions. The visual cortex, cingulate and thalamus received the majority of the current flow with the Cz-Oz, while the anterior parts of the superior and middle frontal gyri displayed an intense amount of current with DLPFC montage. HD-tDCS montages enhanced the focality, producing peaks of current in subcortical areas at negligible levels. This study provides novel information regarding the neuroanatomical distribution and strength of the electric current using several tDCS montages applied for migraine and pain control. Such information may help clinicians and researchers in deciding the most appropriate tDCS montage to treat each pain disorder. PMID- 26236200 TI - Distribution of vasotocin- and vasoactive intestinal peptide-like immunoreactivity in the brain of blue tit (Cyanistes coeruleus). AB - Blue tits (Cyanistes coeruleus) are songbirds, used as model animals in numerous studies covering a wide field of research. Nevertheless, the distribution of neuropeptides in the brain of this avian species remains largely unknown. Here we present some of the first results on distribution of Vasotocine (AVT) and Vasoactive intestinal peptide (VIP) in the brain of males and females of this songbird species, using immunohistochemistry mapping. The bulk of AVT-like cells are found in the hypothalamic supraoptic, paraventricular and suprachiasmatic nuclei, bed nucleus of the stria terminalis, and along the lateral forebrain bundle. Most AVT-like fibers course toward the median eminence, some reaching the arcopallium, and lateral septum. Further terminal fields occur in the dorsal thalamus, ventral tegmental area and pretectal area. Most VIP-like cells are in the lateral septal organ and arcuate nucleus. VIP-like fibers are distributed extensively in the hypothalamus, preoptic area, lateral septum, diagonal band of Broca. They are also found in the bed nucleus of the stria terminalis, amygdaloid nucleus of taenia, robust nucleus of the arcopallium, caudo-ventral hyperpallium, nucleus accumbens and the brainstem. Taken together, these results suggest that both AVT and VIP immunoreactive structures show similar distribution to other avian species, emphasizing evolutionary conservatism in the history of vertebrates. The current study may enable future investigation into the localization of AVT and VIP, in relation to behavioral and ecological traits in the brain of tit species. PMID- 26236201 TI - Central melanopsin projections in the diurnal rodent, Arvicanthis niloticus. AB - The direct effects of photic stimuli on behavior are very different in diurnal and nocturnal species, as light stimulates an increase in activity in the former and a decrease in the latter. Studies of nocturnal mice have implicated a select population of retinal ganglion cells that are intrinsically photosensitive (ipRGCs) in mediation of these acute responses to light. ipRGCs are photosensitive due to the expression of the photopigment melanopsin; these cells use glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP) as neurotransmitters. PACAP is useful for the study of central ipRGC projections because, in the retina, it is found exclusively within melanopsin cells. Little is known about the central projections of ipRGCs in diurnal species. Here, we first characterized these cells in the retina of the diurnal Nile grass rat using immunohistochemistry (IHC). The same basic subtypes of melanopsin cells that have been described in other mammals were present, but nearly 25% of them were displaced, primarily in its superior region. PACAP was present in 87.7% of all melanopsin cells, while 97.4% of PACAP cells contained melanopsin. We then investigated central projections of ipRGCs by examining the distribution of immunoreactive PACAP fibers in intact and enucleated animals. This revealed evidence that these cells project to the suprachiasmatic nucleus, lateral geniculate nucleus (LGN), pretectum, and superior colliculus. This distribution was confirmed with injections of cholera toxin subunit beta coupled with Alexa Fluor 488 in one eye and Alexa Fluor 594 in the other, combined with IHC staining of PACAP. These studies also revealed that the ventral and dorsal LGN and the caudal olivary pretectal nucleus receive less innervation from ipRGCs than that reported in nocturnal rodents. Overall, these data suggest that although ipRGCs and their projections are very similar in diurnal and nocturnal rodents, they may not be identical. PMID- 26236202 TI - Central projections of antennular chemosensory and mechanosensory afferents in the brain of the terrestrial hermit crab (Coenobita clypeatus; Coenobitidae, Anomura). AB - The Coenobitidae (Decapoda, Anomura, Paguroidea) is a taxon of hermit crabs that includes two genera with a fully terrestrial life style as adults. Previous studies have shown that Coenobitidae have evolved a sense of spatial odor localization that is behaviorally highly relevant. Here, we examined the central olfactory pathway of these animals by analyzing central projections of the antennular nerve of Coenobita clypeatus, combining backfilling of the nerve with dextran-coupled dye, Golgi impregnations and three-dimensional reconstruction of the primary olfactory center, the antennular lobe. The principal pattern of putative olfactory sensory afferents in C. clypeatus is in many aspects similar to what have been established for aquatic decapod crustaceans, such as the spiny lobster Panulirus argus. However, there are also obvious differences that may, or may not represent adaptations related to a terrestrial lifestyle. In C. clypeatus, the antennular lobe dominates the deutocerebrum, having more than one thousand allantoid-shaped subunits. We observed two distinct patterns of sensory neuron innervation: putative olfactory afferents from the aesthetascs either supply the cap/subcap region of the subunits or they extend through its full depth. Our data also demonstrate that any one sensory axon can supply input to several subunits. Putative chemosensory (non-aesthetasc) and mechanosensory axons represent a different pathway and innervate the lateral and median antennular neuropils. Hence, we suggest that the chemosensory input in C. clypeatus might be represented via a dual pathway: aesthetascs target the antennular lobe, and bimodal sensilla target the lateral antennular neuropil and median antennular neuropil. The present data is compared to related findings in other decapod crustaceans. PMID- 26236204 TI - Editorial: The Claustrum: charting a way forward for the brain's most mysterious nucleus. PMID- 26236203 TI - Age-related changes in dentate gyrus cell numbers, neurogenesis, and associations with cognitive impairments in the rhesus monkey. AB - The generation of new neurons in the adult mammalian brain is well-established for the hippocampal dentate gyrus (DG). However, the role of neurogenesis in hippocampal function and cognition, how it changes in aging, and the mechanisms underlying this are yet to be elucidated in the monkey brain. To address this, we investigated adult neurogenesis in the DG of 42 rhesus monkeys (39 cognitively tested) ranging in age from young adult to the elderly. We report here that there is an age-related decline in proliferation and a delayed development of adult neuronal phenotype. Additionally, we show that many of the new neurons survive throughout the lifetime of the animal and may contribute to a modest increase in total neuron number in the granule cell layer of the DG over the adult life span. Lastly, we find that measures of decreased adult neurogenesis are only modestly predictive of age-related cognitive impairment. PMID- 26236205 TI - Information maintenance in working memory: an integrated presentation of cognitive and neural concepts. AB - Working memory (WM) maintains information in a state that it is available for processing. A host of various concepts exist which define this core function at different levels of abstraction. The present article intended to bring together existing cognitive and neural explanatory approaches about the architecture and neural mechanisms of information maintenance in WM. For this, we highlight how existing WM concepts define information retention and present different methodological approaches which led to the assumption that information can exist in various components and states. This view is broadened by neural concepts focussing on various forms of phase synchronization and molecular biological mechanisms relevant for retaining information in an active state. An integrated presentation of different concepts and methodological approaches can deepen our understanding of this central WM function. PMID- 26236206 TI - Impaired spatial memory and enhanced long-term potentiation in mice with forebrain-specific ablation of the Stim genes. AB - Recent findings point to a central role of the endoplasmic reticulum-resident STIM (Stromal Interaction Molecule) proteins in shaping the structure and function of excitatory synapses in the mammalian brain. The impact of the Stim genes on cognitive functions remains, however, poorly understood. To explore the function of the Stim genes in learning and memory, we generated three mouse strains with conditional deletion (cKO) of Stim1 and/or Stim2 in the forebrain. Stim1, Stim2, and double Stim1/Stim2 cKO mice show no obvious brain structural defects or locomotor impairment. Analysis of spatial reference memory in the Morris water maze revealed a mild learning delay in Stim1 cKO mice, while learning and memory in Stim2 cKO mice was indistinguishable from their control littermates. Deletion of both Stim genes in the forebrain resulted, however, in a pronounced impairment in spatial learning and memory reflecting a synergistic effect of the Stim genes on the underlying neural circuits. Notably, long-term potentiation (LTP) at CA3-CA1 hippocampal synapses was markedly enhanced in Stim1/Stim2 cKO mice and was associated with increased phosphorylation of the AMPA receptor subunit GluA1, the transcriptional regulator CREB and the L-type Voltage-dependent Ca(2+) channel Cav1.2 on protein kinase A (PKA) sites. We conclude that STIM1 and STIM2 are key regulators of PKA signaling and synaptic plasticity in neural circuits encoding spatial memory. Our findings also reveal an inverse correlation between LTP and spatial learning/memory and suggest that abnormal enhancement of cAMP/PKA signaling and synaptic efficacy disrupts the formation of new memories. PMID- 26236207 TI - Self-regulation of circumscribed brain activity modulates spatially selective and frequency specific connectivity of distributed resting state networks. AB - The mechanisms of learning involved in brain self-regulation have still to be unveiled to exploit the full potential of this methodology for therapeutic interventions. This skill of volitionally changing brain activity presumably resembles motor skill learning which in turn is accompanied by plastic changes modulating resting state networks. Along these lines, we hypothesized that brain regulation and neurofeedback would similarly modify intrinsic networks at rest while presenting a distinct spatio-temporal pattern. High-resolution electroencephalography preceded and followed a single neurofeedback training intervention of modulating circumscribed sensorimotor low beta-activity by kinesthetic motor imagery in eleven healthy participants. The participants were kept in the deliberative phase of skill acquisition with high demands for learning self-regulation through stepwise increases of task difficulty. By applying the corrected imaginary part of the coherency function, we observed increased functional connectivity of both the primary motor and the primary somatosensory cortex with their respective contralateral homologous cortices in the low beta-frequency band which was self-regulated during feedback. At the same time, the primary motor cortex-but none of the surrounding cortical areas-showed connectivity to contralateral supplementary motor and dorsal premotor areas in the high beta-band. Simultaneously, the neurofeedback target displayed a specific increase of functional connectivity with an ipsilateral fronto-parietal network in the alpha-band while presenting a de-coupling with contralateral primary and secondary sensorimotor areas in the very same frequency band. Brain self regulation modifies resting state connections spatially selective to the neurofeedback target of the dominant hemisphere. These are anatomically distinct with regard to the cortico-cortical connectivity pattern and are functionally specific with regard to the time domain of coherent activity consistent with a Hebbian-like sharpening concept. PMID- 26236208 TI - Overexpression of mineralocorticoid receptors does not affect memory and anxiety like behavior in female mice. AB - Mineralocorticoid receptors (MRs) have been implicated in behavioral adaptation and learning and memory. Since-at least in humans-MR function seems to be sex dependent, we examined the behavioral relevance of MR in female mice exhibiting transgenic MR overexpression in the forebrain. Transgenic MR overexpression did not affect contextual fear memory or cued fear learning and memory. Moreover, MR overexpressing and control mice discriminated equally well between fear responses in a combined cue and context fear conditioning paradigm. Also context-memory in an object recognition task was unaffected in MR overexpressing mice. We conclude that MR overexpression in female animals does not affect fear conditioned responses and object recognition memory. PMID- 26236209 TI - Persistent active avoidance correlates with activity in prelimbic cortex and ventral striatum. AB - Persistent avoidance is a prominent symptom of anxiety disorders and is often resistant to extinction-based therapies. Little is known about the circuitry mediating persistent avoidance. Using a recently described platform-mediated active avoidance task, we assessed activity in several structures with c-Fos immuno-labeling. In Task 1, rats were conditioned to avoid a tone-signaled shock by moving to a safe platform, and then were extinguished over two days. One day later, failure to retrieve extinction correlated with increased activity in the prelimbic prefrontal cortex (PL), ventral striatum (VS), and basal amygdala (BA), and decreased activity in infralimbic prefrontal cortex (IL), consistent with pharmacological inactivation studies. In Task 2, the platform was removed during extinction training and fear (suppression of bar pressing) was extinguished to criterion over 3-5 days. The platform was then returned in a post-extinction test. Under these conditions, avoidance levels were equivalent to Experiment 1 and correlated with increased activity in PL and VS, but there was no correlation with activity in IL or BA. Thus, persistent avoidance can occur independently of deficits in fear extinction and its associated structures. PMID- 26236210 TI - Deafferented controllers: a fundamental failure mechanism in cortical neuroprosthetic systems. AB - Brain-machine interface (BMI) research assumes that patients with disconnected neural pathways could naturally control a prosthetic device by volitionally modulating sensorimotor cortical activity usually responsible for movement coordination. However, computational approaches to motor control challenge this view. This article examines the predictions of optimal feedback control (OFC) theory on the effects that loss of motor output and sensory feedback have on the normal generation of motor commands. Example simulations of unimpaired, totally disconnected, and deafferented controllers illustrate that by neglecting the dynamic interplay between motor commands, state estimation, feedback and behavior, current BMI systems face translational challenges rooted in a debatable assumption and experimental models of limited validity. PMID- 26236211 TI - Neural Connectivity in Epilepsy as Measured by Granger Causality. AB - Epilepsy is a chronic neurological disorder characterized by repeated seizures or excessive electrical discharges in a group of brain cells. Prevalence rates include about 50 million people worldwide and 10% of all people have at least one seizure at one time in their lives. Connectivity models of epilepsy serve to provide a deeper understanding of the processes that control and regulate seizure activity. These models have received initial support and have included measures of EEG, MEG, and MRI connectivity. Preliminary findings have shown regions of increased connectivity in the immediate regions surrounding the seizure foci and associated low connectivity in nearby regions and pathways. There is also early evidence to suggest that these patterns change during ictal events and that these changes may even by related to the occurrence or triggering of seizure events. We present data showing how Granger causality can be used with EEG data to measure connectivity across brain regions involved in ictal events and their resolution. We have provided two case examples as a demonstration of how to obtain and interpret such data. EEG data of ictal events are processed, converted to independent components and their dipole localizations, and these are used to measure causality and connectivity between these locations. Both examples have shown hypercoupling near the seizure foci and low causality across nearby and associated neuronal pathways. This technique also allows us to track how these measures change over time and during the ictal and post-ictal periods. Areas for further research into this technique, its application to epilepsy, and the formation of more effective therapeutic interventions are recommended. PMID- 26236212 TI - The man who mistook his neuropsychologist for a popstar: when configural processing fails in acquired prosopagnosia. AB - We report the case of an individual with acquired prosopagnosia who experiences extreme difficulties in recognizing familiar faces in everyday life despite excellent object recognition skills. Formal testing indicates that he is also severely impaired at remembering pre-experimentally unfamiliar faces and that he takes an extremely long time to identify famous faces and to match unfamiliar faces. Nevertheless, he performs as accurately and quickly as controls at identifying inverted familiar and unfamiliar faces and can recognize famous faces from their external features. He also performs as accurately as controls at recognizing famous faces when fracturing conceals the configural information in the face. He shows evidence of impaired global processing but normal local processing of Navon figures. This case appears to reflect the clearest example yet of an acquired prosopagnosic patient whose familiar face recognition deficit is caused by a severe configural processing deficit in the absence of any problems in featural processing. These preserved featural skills together with apparently intact visual imagery for faces allow him to identify a surprisingly large number of famous faces when unlimited time is available. The theoretical implications of this pattern of performance for understanding the nature of acquired prosopagnosia are discussed. PMID- 26236213 TI - Dual pathways to prospective remembering. AB - According to the multiprocess framework (McDaniel and Einstein, 2000), the cognitive system can support prospective memory (PM) retrieval through two general pathways. One pathway depends on top-down attentional control processes that maintain activation of the intention and/or monitor the environment for the triggering or target cues that indicate that the intention should be executed. A second pathway depends on (bottom-up) spontaneous retrieval processes, processes that are often triggered by a PM target cue; critically, spontaneous retrieval is assumed not to require monitoring or active maintenance of the intention. Given demand characteristics associated with experimental settings, however, participants are often inclined to monitor, thereby potentially masking discovery of bottom-up spontaneous retrieval processes. In this article, we discuss parameters of laboratory PM paradigms to discourage monitoring and review recent behavioral evidence from such paradigms that implicate spontaneous retrieval in PM. We then re-examine the neuro-imaging evidence from the lens of the multiprocess framework and suggest some critical modifications to existing neuro cognitive interpretations of the neuro-imaging results. These modifications illuminate possible directions and refinements for further neuro-imaging investigations of PM. PMID- 26236214 TI - Promoting the translation of intentions into action by implementation intentions: behavioral effects and physiological correlates. AB - The present review addresses the physiological correlates of planning effects on behavior. Although intentions to act qualify as predictors of behavior, accumulated evidence indicates that there is a substantial gap between even strong intentions and subsequent action. One effective strategy to reduce this intention-behavior gap is the formation of implementation intentions that specify when, where, and how to act on a given goal in an if-then format ("If I encounter situation Y, then I will initiate action Z!"). It has been proposed that implementation intentions render the mental representation of the situation highly accessible and establish a strong associative link between the mental representations of the situation and the action. These process assumptions have been examined in behavioral research, and in physiological research, a field that has begun to investigate the temporal dynamics of and brain areas involved in implementation intention effects. In the present review, we first summarize studies on the cognitive processes that are central to the strategic automation of action control by implementation intentions. We then examine studies involving critical samples with impaired self-regulation. Lastly, we review studies that have applied physiological measures such as heart rate, cortisol level, and eye movement, as well as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) studies on the neural correlates of implementation intention effects. In support of the assumed processes, implementation intentions increased goal attainment in studies on cognitive processes and in critical samples, modulated brain waves related to perceptual and decision processes, and generated less activity in brain areas associated with effortful action control. In our discussion, we reflect on the status quo of physiological research on implementation intentions, methodological and conceptual issues, related research, and propose future directions. PMID- 26236216 TI - The mean-variance relationship reveals two possible strategies for dynamic brain connectivity analysis in fMRI. AB - When studying brain connectivity using fMRI, signal intensity time-series are typically correlated with each other in time to compute estimates of the degree of interaction between different brain regions and/or networks. In the static connectivity case, the problem of defining which connections that should be considered significant in the analysis can be addressed in a rather straightforward manner by a statistical thresholding that is based on the magnitude of the correlation coefficients. More recently, interest has come to focus on the dynamical aspects of brain connectivity and the problem of deciding which brain connections that are to be considered relevant in the context of dynamical changes in connectivity provides further options. Since we, in the dynamical case, are interested in changes in connectivity over time, the variance of the correlation time-series becomes a relevant parameter. In this study, we discuss the relationship between the mean and variance of brain connectivity time series and show that by studying the relation between them, two conceptually different strategies to analyze dynamic functional brain connectivity become available. Using resting-state fMRI data from a cohort of 46 subjects, we show that the mean of fMRI connectivity time-series scales negatively with its variance. This finding leads to the suggestion that magnitude- versus variance based thresholding strategies will induce different results in studies of dynamic functional brain connectivity. Our assertion is exemplified by showing that the magnitude-based strategy is more sensitive to within-resting-state network (RSN) connectivity compared to between-RSN connectivity whereas the opposite holds true for a variance-based analysis strategy. The implications of our findings for dynamical functional brain connectivity studies are discussed. PMID- 26236215 TI - Exploring associations between gaze patterns and putative human mirror neuron system activity. AB - The human mirror neuron system (MNS) is hypothesized to be crucial to social cognition. Given that key MNS-input regions such as the superior temporal sulcus are involved in biological motion processing, and mirror neuron activity in monkeys has been shown to vary with visual attention, aberrant MNS function may be partly attributable to atypical visual input. To examine the relationship between gaze pattern and interpersonal motor resonance (IMR; an index of putative MNS activity), healthy right-handed participants aged 18-40 (n = 26) viewed videos of transitive grasping actions or static hands, whilst the left primary motor cortex received transcranial magnetic stimulation. Motor-evoked potentials recorded in contralateral hand muscles were used to determine IMR. Participants also underwent eyetracking analysis to assess gaze patterns whilst viewing the same videos. No relationship was observed between predictive gaze and IMR. However, IMR was positively associated with fixation counts in areas of biological motion in the videos, and negatively associated with object areas. These findings are discussed with reference to visual influences on the MNS, and the possibility that MNS atypicalities might be influenced by visual processes such as aberrant gaze pattern. PMID- 26236217 TI - Combining self-organizing mapping and supervised affinity propagation clustering approach to investigate functional brain networks involved in motor imagery and execution with fMRI measurements. AB - Clustering analysis methods have been widely applied to identifying the functional brain networks of a multitask paradigm. However, the previously used clustering analysis techniques are computationally expensive and thus impractical for clinical applications. In this study a novel method, called SOM-SAPC that combines self-organizing mapping (SOM) and supervised affinity propagation clustering (SAPC), is proposed and implemented to identify the motor execution (ME) and motor imagery (MI) networks. In SOM-SAPC, SOM was first performed to process fMRI data and SAPC is further utilized for clustering the patterns of functional networks. As a result, SOM-SAPC is able to significantly reduce the computational cost for brain network analysis. Simulation and clinical tests involving ME and MI were conducted based on SOM-SAPC, and the analysis results indicated that functional brain networks were clearly identified with different response patterns and reduced computational cost. In particular, three activation clusters were clearly revealed, which include parts of the visual, ME and MI functional networks. These findings validated that SOM-SAPC is an effective and robust method to analyze the fMRI data with multitasks. PMID- 26236218 TI - Prognostic value of cerebrospinal fluid free fatty acid levels in patients with acute ischemic stroke. AB - In this study, prognostic value of cerebrospinal fluid (CSF) free fatty acid (FFA) levels in patients confirmed with acute ischemic stroke (AIS) was evaluated in a Chinese population. A prospective cohort designed study was conducted at our hospital of the Emergency department from November, 2012 to September, 2014. The National Institutes of Health Stroke Scale (NIHSS) score on admission was applied to assess CSF levels of FFA and specific severity degree of stroke. Evaluation of the prognostic outcomes of those stroke patients used the modified Rankin scale scores at 90-days. Logistic regression analysis analyzed the prognostic value of FFA. NIHSS score results suggested a positive relationship between levels of CSF FFA levels and severity of stroke. There was an obviously higher trend of CSF FFA levels in patients with CE stroke than those of the non-CE stroke patients, with statistically difference (P < 0.05). Further, CSF FFA levels were evidently lower in those 73 patients with favorable outcome when compared to those with unfavorable outcomes [0.21(IQR, 0.11-0.28) mmol/L vs. 0.36 (IQR, 0.27-0.50) mmol/L, P < 0.0001, P < 0.0001]. Multivariate analysis results after possible confounders adjustment indicated that there was an increased risk of unfavorable outcome associated with CSF FFA levels >=0.29 mmol/L (OR 5.12, 95%CI: 2.35-10.28; P < 0.0001). Collectively, CSF level of FFA at admission was suggested to be a useful, independent short-term prognostic marker in Chinese patient with AIS. PMID- 26236219 TI - The combined effects of neurostimulation and priming on creative thinking. A preliminary tDCS study on dorsolateral prefrontal cortex. AB - The role of prefrontal cortex (PFC) in influencing creative thinking has been investigated by many researchers who, while succeeding in proving an effective involvement of PFC, reported suggestive but sometimes conflicting results. In order to better understand the relationships between creative thinking and brain activation in a more specific area of the PFC, we explored the role of dorsolateral PFC (DLPFC). We devised an experimental protocol using transcranial direct-current stimulation (tDCS). The study was based on a 3 (kind of stimulation: anodal vs. cathodal vs. sham) * 2 (priming: divergent vs. convergent) design. Forty-five healthy adults were randomly assigned to one stimulation condition. Participants' creativity skills were assessed using the Product Improvement subtest from the Torrance Tests of Creative Thinking (TTCT). After 20 min of tDCS stimulation, participants were presented with visual images of common objects. Half of the participants were instructed to visualize themselves using the object in an unusual way (divergent priming), whereas the other half were asked to visualize themselves while using the object in a common way (convergent priming). Priming was aimed at inducing participants to adopt different attitudes toward the creative task. Afterwards, participants were asked to describe all of the possible uses of the objects that were presented. Participants' physiological activation was recorded using a biofeedback equipment. Results showed a significant effect of anodal stimulation that enhanced creative performance, but only after divergent priming. Participants showed lower skin temperature values after cathodal stimulation, a finding which is coherent with studies reporting that, when a task is not creative or creative thinking is not prompted, people show lower levels of arousal. Differences in individual levels of creativity as assessed by the Product Improvement test were not influential. The involvement of DLPFC in creativity has been supported, presumably in association to shift of attention modulated by priming. PMID- 26236220 TI - Modulation of sensorimotor cortex by repetitive peripheral magnetic stimulation. AB - This study examines with transcranial magnetic stimulation (TMS) and with functional magnetic resonance imaging (fMRI) whether 20 min of repetitive peripheral magnetic stimulation (rPMS) has a facilitating effect on associated motor controlling regions. Trains of rPMS with a stimulus intensity of 150% of the motor threshold (MT) were applied over right hand flexor muscles of healthy volunteers. First, with TMS, 10 vs. 25 Hz rPMS was examined and compared to a control group. Single and paired pulse motor evoked potentials (MEPs) from flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles were recorded at baseline (T0), post rPMS (T1), 30 min post (T2), 1 h post (T3) and 2 h post rPMS (T4). Then, with fMRI, 25 Hz rPMS was compared to sham stimulation by utilizing a finger tapping activation paradigm. Changes in bloodoxygen level dependent (BOLD) contrast were examined at baseline (PRE), post rPMS (POST1) and 1 h post rPMS (POST2). With TMS facilitation was observed in the target muscle (FCR) following 25 Hz rPMS: MEP recruitment curves (RCs) were increased at T1, T2 and T3, and intracortical facilitation (ICF) was increased at T1 and T2. No effects were observed following 10 Hz rPMS. With fMRI the BOLD contrast at the left sensorimotor area was increased at POST1. Compared to inductions protocols based on transcutaneous electrical stimulation and mechanical stimulation, the rPMS induced effects appeared shorter lasting. PMID- 26236221 TI - Depressive symptoms related to low fractional anisotropy of white matter underlying the right ventral anterior cingulate in older adults with atherosclerotic vascular disease. AB - We sought to characterize the relationship between integrity of the white matter underlying the ventral anterior cingulate (vAC) and depressive symptoms in older adults with atherosclerotic vascular disease (AVD), a condition associated with preferential degeneration of the white matter. The vAC was defined as including white matter underlying ventral Brodmann Area 24 and Brodmann Area 25, corresponding with the "subcallosal" and "subgenual" cingulate respectively. This region of interest was chosen based on the preponderance of evidence that the white matter in the region plays a critical role in the manifestation of depressive symptoms. Participants had current unequivocal diagnoses of AVD and were between 55 and 90 years-old. Fractional anisotropy (FA) was used as an index of white matter integrity and organization. Whole-brain mean diffusivity (MD) was used as an index of global white matter lesion burden. Depressive symptoms were measured using the Symptom Checklist-90-Revised (SCL-90-R) Depression Scale. Depressive symptoms were significantly related to low FA in the right vAC (r = 0.356, df = 30, p = 0.045) but not the left vAC (r = 0.024, df = 30, p = 0.896) after controlling for total brain MD (a statistical control for global white matter lesion burden). Further, depressive symptoms were significantly related to low FA in the right vAC (r = -0.361, df = 31, p = 0.039), but not the left vAC (r = 0.259, df = 31, p = 0.145) when controlled for the contralateral vAC FA. The correlation coefficients for this follow-up analysis were found to be significantly different between left and right vAC (Z = 2.310, p = 0.021). Poor white matter health in the vAC may be a biological mechanism for depressive symptoms in older adults with vascular disease. Further studies may corroborate that the right vAC plays a unique role in depressive symptom manifestation in cases where the white matter is preferentially affected, as is the case in AVD. This could lead to future targeting of the region for somatic antidepressant treatment, as well as the development of a precise approach for patients with white matter damage, which could produce significant improvement in quality of life, medical morbidity, and mortality. PMID- 26236222 TI - Decoding illusory self-location from activity in the human hippocampus. AB - Decades of research have demonstrated a role for the hippocampus in spatial navigation and episodic and spatial memory. However, empirical evidence linking hippocampal activity to the perceptual experience of being physically located at a particular place in the environment is lacking. In this study, we used a multisensory out-of-body illusion to perceptually 'teleport' six healthy participants between two different locations in the scanner room during high resolution functional magnetic resonance imaging (fMRI). The participants were fitted with MRI-compatible head-mounted displays that changed their first-person visual perspective to that of a pair of cameras placed in one of two corners of the scanner room. To elicit the illusion of being physically located in this position, we delivered synchronous visuo-tactile stimulation in the form of an object moving toward the cameras coupled with touches applied to the participant's chest. Asynchronous visuo-tactile stimulation did not induce the illusion and served as a control condition. We found that illusory self-location could be successfully decoded from patterns of activity in the hippocampus in all of the participants in the synchronous (P < 0.05) but not in the asynchronous condition (P > 0.05). At the group-level, the decoding accuracy was significantly higher in the synchronous than in the asynchronous condition (P = 0.012). These findings associate hippocampal activity with the perceived location of the bodily self in space, which suggests that the human hippocampus is involved not only in spatial navigation and memory but also in the construction of our sense of bodily self-location. PMID- 26236223 TI - Lateralized frontal activity for Japanese phonological processing during child development. AB - Phonological awareness is essential for reading, and is common to all language systems, including alphabetic languages and Japanese. This cognitive factor develops during childhood, and is thought to be associated with shifts in brain activity. However, the nature of this neurobiological developmental shift is unclear for speakers of Japanese, which is not an alphabetical language. The present study aimed to reveal a shift in brain functions for processing phonological information in native-born Japanese children. We conducted a phonological awareness task and examined hemodynamic activity in 103 children aged 7-12 years. While younger children made mistakes and needed more time to sort phonological information in reverse order, older children completed the task quickly and accurately. Additionally, younger children exhibited increased activity in the bilateral dorsolateral prefrontal cortex (DLPFC), which may be evidence of immature phonological processing skills. Older children exhibited dominant activity in the left compared with the right DLPFC, suggesting that they had already acquired phonological processing skills. We also found significant effects of age and lateralized activity on behavioral performance. During earlier stages of development, the degree of left lateralization appears to have a smaller effect on behavioral performance. Conversely, in later stages of development, the degree of left lateralization appears to have a stronger influence on behavioral performance. These initial findings regarding a neurobiological developmental shift in Japanese speakers suggest that common brain regions play a critical role in the development of phonological processing skills among different languages systems, such as Japanese and alphabetical languages. PMID- 26236224 TI - Predicting individual brain maturity using dynamic functional connectivity. AB - Neuroimaging-based functional connectivity (FC) analyses have revealed significant developmental trends in specific intrinsic connectivity networks linked to cognitive and behavioral maturation. However, knowledge of how brain functional maturation is associated with FC dynamics at rest is limited. Here, we examined age-related differences in the temporal variability of FC dynamics with data publicly released by the Nathan Kline Institute (NKI; n = 183, ages 7-30) and showed that dynamic inter-region interactions can be used to accurately predict individual brain maturity across development. Furthermore, we identified a significant age-dependent trend underlying dynamic inter-network FC, including increasing variability of the connections between the visual network, default mode network (DMN) and cerebellum as well as within the cerebellum and DMN and decreasing variability within the cerebellum and between the cerebellum and DMN as well as the cingulo-opercular network. Overall, the results suggested significant developmental changes in dynamic inter-network interaction, which may shed new light on the functional organization of typical developmental brains. PMID- 26236226 TI - A new paradigm and computational framework to estimate stop-signal reaction time distributions from the inhibition of complex motor sequences. AB - Inhibitory control is an important component of executive function that allows organisms to abort emerging behavioral plans or ongoing actions on the fly as new sensory information becomes available. Current models treat inhibitory control as a race between a Go- and a Stop process that may be mediated by partially distinct neural substrates, i.e., the direct and the hyper-direct pathway of the basal ganglia. The fact that finishing times of the Stop process (Stop-Signal Reaction Time, SSRT) cannot be observed directly has precluded a precise comparison of the functional properties that govern the initiation (GoRT) and inhibition (SSRT) of a motor response. To solve this problem, we modified an existing inhibitory paradigm and developed a non-parametric framework to measure the trial-by-trial variability of SSRT. A series of simulations verified that the non-parametric approach is on par with a parametric approach and yields accurate estimates of the entire SSRT distribution from as few as ~750 trials. Our results show that in identical settings, the distribution of SSRT is very similar to the distribution of GoRT albeit somewhat shorter, wider and significantly less right skewed. The ability to measure the precise shapes of SSRT distributions opens new avenues for research into the functional properties of the hyper-direct pathway that is believed to mediate inhibitory control. PMID- 26236225 TI - Velocity neurons improve performance more than goal or position neurons do in a simulated closed-loop BCI arm-reaching task. AB - Brain-Computer Interfaces (BCIs) that convert brain-recorded neural signals into intended movement commands could eventually be combined with Functional Electrical Stimulation to allow individuals with Spinal Cord Injury to regain effective and intuitive control of their paralyzed limbs. To accelerate the development of such an approach, we developed a model of closed-loop BCI control of arm movements that (1) generates realistic arm movements (based on experimentally measured, visually-guided movements with real-time error correction), (2) simulates cortical neurons with firing properties consistent with literature reports, and (3) decodes intended movements from the noisy neural ensemble. With this model we explored (1) the relative utility of neurons tuned for different movement parameters (position, velocity, and goal) and (2) the utility of recording from larger numbers of neurons-critical issues for technology development and for determining appropriate brain areas for recording. We simulated arm movements that could be practically restored to individuals with severe paralysis, i.e., movements from an armrest to a volume in front of the person. Performance was evaluated by calculating the smallest movement endpoint target radius within which the decoded cursor position could dwell for 1 s. Our results show that goal, position, and velocity neurons all contribute to improve performance. However, velocity neurons enabled smaller targets to be reached in shorter amounts of time than goal or position neurons. Increasing the number of neurons also improved performance, although performance saturated at 30-50 neurons for most neuron types. Overall, our work presents a closed-loop BCI simulator that models error corrections and the firing properties of various movement-related neurons that can be easily modified to incorporate different neural properties. We anticipate that this kind of tool will be important for development of future BCIs. PMID- 26236227 TI - Motor planning under temporal uncertainty is suboptimal when the gain function is asymmetric. AB - For optimal action planning, the gain/loss associated with actions and the variability in motor output should both be considered. A number of studies make conflicting claims about the optimality of human action planning but cannot be reconciled due to their use of different movements and gain/loss functions. The disagreement is possibly because of differences in the experimental design and differences in the energetic cost of participant motor effort. We used a coincident timing task, which requires decision making with constant energetic cost, to test the optimality of participant's timing strategies under four configurations of the gain function. We compared participant strategies to an optimal timing strategy calculated from a Bayesian model that maximizes the expected gain. We found suboptimal timing strategies under two configurations of the gain function characterized by asymmetry, in which higher gain is associated with higher risk of zero gain. Participants showed a risk-seeking strategy by responding closer than optimal to the time of onset/offset of zero gain. Meanwhile, there was good agreement of the model with actual performance under two configurations of the gain function characterized by symmetry. Our findings show that human ability to make decisions that must reflect uncertainty in one's own motor output has limits that depend on the configuration of the gain function. PMID- 26236228 TI - Pattern activation/recognition theory of mind. AB - In his 2012 book How to Create a Mind, Ray Kurzweil defines a "Pattern Recognition Theory of Mind" that states that the brain uses millions of pattern recognizers, plus modules to check, organize, and augment them. In this article, I further the theory to go beyond pattern recognition and include also pattern activation, thus encompassing both sensory and motor functions. In addition, I treat checking, organizing, and augmentation as patterns of patterns instead of separate modules, therefore handling them the same as patterns in general. Henceforth I put forward a unified theory I call "Pattern Activation/Recognition Theory of Mind." While the original theory was based on hierarchical hidden Markov models, this evolution is based on their precursor: stochastic grammars. I demonstrate that a class of self-describing stochastic grammars allows for unifying pattern activation, recognition, organization, consistency checking, metaphor, and learning, into a single theory that expresses patterns throughout. I have implemented the model as a probabilistic programming language specialized in activation/recognition grammatical and neural operations. I use this prototype to compute and present diagrams for each stochastic grammar and corresponding neural circuit. I then discuss the theory as it relates to artificial network developments, common coding, neural reuse, and unity of mind, concluding by proposing potential paths to validation. PMID- 26236229 TI - Subject-specific computational modeling of DBS in the PPTg area. AB - Deep brain stimulation (DBS) in the pedunculopontine tegmental nucleus (PPTg) has been proposed to alleviate medically intractable gait difficulties associated with Parkinson's disease. Clinical trials have shown somewhat variable outcomes, stemming in part from surgical targeting variability, modulating fiber pathways implicated in side effects, and a general lack of mechanistic understanding of DBS in this brain region. Subject-specific computational models of DBS are a promising tool to investigate the underlying therapy and side effects. In this study, a parkinsonian rhesus macaque was implanted unilaterally with an 8-contact DBS lead in the PPTg region. Fiber tracts adjacent to PPTg, including the oculomotor nerve, central tegmental tract, and superior cerebellar peduncle, were reconstructed from a combination of pre-implant 7T MRI, post-implant CT, and post mortem histology. These structures were populated with axon models and coupled with a finite element model simulating the voltage distribution in the surrounding neural tissue during stimulation. This study introduces two empirical approaches to evaluate model parameters. First, incremental monopolar cathodic stimulation (20 Hz, 90 MUs pulse width) was evaluated for each electrode, during which a right eyelid flutter was observed at the proximal four contacts (-1.0 to 1.4 mA). These current amplitudes followed closely with model predicted activation of the oculomotor nerve when assuming an anisotropic conduction medium. Second, PET imaging was collected OFF-DBS and twice during DBS (two different contacts), which supported the model predicted activation of the central tegmental tract and superior cerebellar peduncle. Together, subject specific models provide a framework to more precisely predict pathways modulated by DBS. PMID- 26236230 TI - A three-dimensional mathematical model for the signal propagation on a neuron's membrane. AB - In order to be able to examine the extracellular potential's influence on network activity and to better understand dipole properties of the extracellular potential, we present and analyze a three-dimensional formulation of the cable equation which facilitates numeric simulations. When the neuron's intra- and extracellular space is assumed to be purely resistive (i.e., no free charges), the balance law of electric fluxes leads to the Laplace equation for the distribution of the intra- and extracellular potential. Moreover, the flux across the neuron's membrane is continuous. This observation already delivers the three dimensional cable equation. The coupling of the intra- and extracellular potential over the membrane is not trivial. Here, we present a continuous extension of the extracellular potential to the intracellular space and combine the resulting equation with the intracellular problem. This approach makes the system numerically accessible. On the basis of the assumed pure resistive intra- and extracellular spaces, we conclude that a cell's out-flux balances out completely. As a consequence neurons do not own any current monopoles. We present a rigorous analysis with spherical harmonics for the extracellular potential by approximating the neuron's geometry to a sphere. Furthermore, we show with first numeric simulations on idealized circumstances that the extracellular potential can have a decisive effect on network activity through ephaptic interactions. PMID- 26236231 TI - Protective effects of ginseng on neurological disorders. AB - Ginseng (Order: Apiales, Family: Araliaceae, Genus: Panax) has been used as a traditional herbal medicine for over 2000 years, and is recorded to have antianxiety, antidepressant and cognition enhancing properties. The protective effects of ginseng on neurological disorders are discussed in this review. Ginseng species and ginsenosides, and their intestinal metabolism and bioavailability are briefly introduced. This is followed by molecular mechanisms of effects of ginseng on the brain, including glutamatergic transmission, monoamine transmission, estrogen signaling, nitric oxide (NO) production, the Keap1/Nrf2 adaptive cellular stress pathway, neuronal survival, apoptosis, neural stem cells and neuroregeneration, microglia, astrocytes, oligodendrocytes and cerebral microvessels. The molecular mechanisms of the neuroprotective effects of ginseng in Alzheimer's disease (AD) including beta-amyloid (Abeta) formation, tau hyperphosphorylation and oxidative stress, major depression, stroke, Parkinson's disease and multiple sclerosis are presented. It is hoped that this discussion will stimulate more studies on the use of ginseng in neurological disorders. PMID- 26236234 TI - Editorial: Aging, neurogenesis and neuroinflammation in hearing loss and protection. PMID- 26236232 TI - Fractality of sensations and the brain health: the theory linking neurodegenerative disorder with distortion of spatial and temporal scale invariance and fractal complexity of the visible world. AB - The theory that ties normal functioning and pathology of the brain and visual system with the spatial-temporal structure of the visual and other sensory stimuli is described for the first time in the present study. The deficit of fractal complexity of environmental influences can lead to the distortion of fractal complexity in the visual pathways of the brain and abnormalities of development or aging. The use of fractal light stimuli and fractal stimuli of other modalities can help to restore the functions of the brain, particularly in the elderly and in patients with neurodegenerative disorders or amblyopia. Non linear dynamics of these physiological processes have a strong base of evidence, which is seen in the impaired fractal regulation of rhythmic activity in aged and diseased brains. From birth to old age, we live in a non-linear world, in which objects and processes with the properties of fractality and non-linearity surround us. Against this background, the evolution of man took place and all periods of life unfolded. Works of art created by man may also have fractal properties. The positive influence of music on cognitive functions is well-known. Insufficiency of sensory experience is believed to play a crucial role in the pathogenesis of amblyopia and age-dependent diseases. The brain is very plastic in its early development, and the plasticity decreases throughout life. However, several studies showed the possibility to reactivate the adult's neuroplasticity in a variety of ways. We propose that a non-linear structure of sensory information on many spatial and temporal scales is crucial to the brain health and fractal regulation of physiological rhythms. Theoretical substantiation of the author's theory is presented. Possible applications and the future research that can experimentally confirm or refute the theoretical concept are considered. PMID- 26236235 TI - Redox regulation of cGMP-dependent protein kinase Ialpha in the cardiovascular system. AB - Elevated levels of oxidants in biological systems have been historically referred to as "oxidative stress," a choice of words that perhaps conveys an imbalanced view of reactive oxygen species in cells and tissues. The term stress suggests a harmful role, whereas a contemporary view is that oxidants are also crucial for the maintenance of homeostasis or adaptive signaling that can actually limit injury. This regulatory role for oxidants is achieved in part by them inducing oxidative post-translational modifications of proteins which may alter their function or interactions. Such mechanisms allow changes in cell oxidant levels to be coupled to regulated alterations in enzymatic function (i.e., signal transduction), which enables "redox signaling." In this review we focus on the role of cGMP-dependent protein kinase (PKG) Ia disulfide dimerisation, an oxidative modification that is induced by oxidants that directly activates the enzyme, discussing how this impacts on the cardiovascular system. Additionally, how this oxidative activation of PKG may coordinate with or differ from classical activation of this kinase by cGMP is also considered. PMID- 26236236 TI - Frog intestinal perfusion to evaluate drug permeability: application to p-gp and cyp3a4 substrates. AB - To evaluate the reliability of using in situ frog intestinal perfusion technique for permeability assessment of carrier transported drugs which are also substrates for CYP enzymes. Single Pass Intestinal Perfusion (SPIP) studies were performed in frogs of the species Rana tigrina using established method for rats with some modifications after inducing anesthesia. Effective permeability coefficient (P eff) of losartan and midazolam was calculated in the presence and absence of inhibitors using the parallel-tube model. Peff of losartan when perfused alone was found to be 0.427 +/- 0.27 * 10(-4)cm/s and when it was co perfused with inhibitors, significant change in P eff was observed. Peff of midazolam when perfused alone was found to be 2.03 +/- 0.07 * 10(-4)cm/s and when it was co-perfused with inhibitors, no significant change in P eff was observed. Comparison of P eff calculated in frog with that of other available models and also humans suggested that the P eff-values are comparable and reflected well with human intestinal permeability. It is possible to determine the P eff-value for compounds which are dual substrates of P-glycoprotein and CYP3A4 using in situ frog intestinal perfusion technique. The calculated P eff-values correlated well with reported P eff-values of probe drugs. comparison of the P eff-value of losartan obtained with that of reported human's P eff and Caco 2 cell data, and comparison of the P eff-value of midazolam with that of reported rat's P eff, we could conclude that SPIP from model can be reliably used in preclinical studies for permeability estimation. This model may represent a valuable alternative to the low speed and high cost of conventional animal models (typically rodents) for the assessment of intestinal permeability. PMID- 26236233 TI - Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer's disease: the role, regulation and restoration of LRP1. AB - Amyloid beta (Abeta) homeostasis in the brain is governed by its production and clearance mechanisms. An imbalance in this homeostasis results in pathological accumulations of cerebral Abeta, a characteristic of Alzheimer's disease (AD). While Abeta may be cleared by several physiological mechanisms, a major route of Abeta clearance is the vascular-mediated removal of Abeta from the brain across the blood-brain barrier (BBB). Here, we discuss the role of the predominant Abeta clearance protein-low-density lipoprotein receptor-related protein 1 (LRP1)-in the efflux of Abeta from the brain. We also outline the multiple factors that influence the function of LRP1-mediated Abeta clearance, such as its expression, shedding, structural modification and transcriptional regulation by other genes. Finally, we summarize approaches aimed at restoring LRP1-mediated Abeta clearance from the brain. PMID- 26236237 TI - Cholesteryl ester transfer protein: ace of spades, queen of hearts, or the joker? PMID- 26236238 TI - Editorial: Monitoring endogenous GPCRs: lessons for drug design. PMID- 26236239 TI - Studying GPCR/cAMP pharmacology from the perspective of cellular structure. AB - Signal transduction via G-protein coupled receptors (GPCRs) relies upon the production of cAMP and other signaling cascades. A given receptor and agonist pair, produce multiple effects upon cellular physiology which can be opposite in different cell types. The production of variable cellular effects via the signaling of the same GPCR in different cell types is a result of signal organization in space and time (compartmentation). This organization is usually based upon the physical and chemical properties of the membranes in which the GPCRs reside and the repertoire of downstream effectors and co-factors that are available at that location. In this review we explore mechanisms of GPCR signal compartmentation and broadly review the state-of-the-art methodologies which can be utilized to study them. We provide a clear rationale for a "localized" approach to the study of the pharmacology and physiology of GPCRs and particularly the secondary messenger cAMP. PMID- 26236240 TI - Modifications of myofilament protein phosphorylation and function in response to cardiac arrest induced in a swine model. AB - Cardiac arrest is a prevalent condition with a poor prognosis, attributable in part to persistent myocardial dysfunction following resuscitation. The molecular basis of this dysfunction remains unclear. We induced cardiac arrest in a porcine model of acute sudden death and assessed the impact of ischemia and reperfusion on the molecular function of isolated cardiac contractile proteins. Cardiac arrest was electrically induced, left untreated for 12 min, and followed by a resuscitation protocol. With successful resuscitations, the heart was reperfused for 2 h (IR2) and the muscle harvested. In failed resuscitations, tissue samples were taken following the failed efforts (IDNR). Actin filament velocity, using myosin isolated from IR2 or IDNR cardiac tissue, was nearly identical to myosin from the control tissue in a motility assay. However, both maximal velocity (25% faster than control) and calcium sensitivity (pCa50 6.57 +/- 0.04 IDNR vs. 6.34 +/- 0.07 control) were significantly (p < 0.05) enhanced using native thin filaments (actin+troponin+tropomyosin) from IDNR samples, suggesting that the enhanced velocity is mediated through an alteration in muscle regulatory proteins (troponin+tropomyosin). Mass spectrometry analysis showed that only samples from the IR2 had an increase in total phosphorylation levels of troponin (Tn) and tropomyosin (Tm), but both IR2 and IDNR samples demonstrated a significant shift from mono-phosphorylated to bis-phosphorylated forms of the inhibitory subunit of Tn (TnI) compared to control. This suggests that the shift to bis-phosphorylation of TnI is associated with the enhanced function in IDNR, but this effect may be attenuated when phosphorylation of Tm is increased in tandem, as observed for IR2. There are likely many other molecular changes induced following cardiac arrest, but to our knowledge, these data provide the first evidence that this form cardiac arrest can alter the in vitro function of the cardiac contractile proteins. PMID- 26236241 TI - Chronographic Imprint of Age-Induced Alterations in Heart Rate Dynamical Organization. AB - Beat-to-beat changes in the heart period are transformed into a network of increments between subsequent RR-intervals, which enables graphical descriptions of short-term heart period variability. Three types of such descriptions are considered: (1) network graphs arising from a set of vertices and directed edges, (2) contour plots of adjacency matrices A, representing the networks and transition matrices T, resulting from A, and (3) vector plots of gradients of the matrices A and T. Two indices are considered which summarize properties of A and T: the approximate deceleration capacity and the entropy rate. The method, applied to time series of nocturnal RR-intervals recorded from healthy subjects of different ages, reveals important aspect of changes in the autonomic activity caused by biological aging. Independent of the subject's age, following accelerations, a pendulum-like dynamics appears. With decelerations, this dynamics develops in line with the subject's age. This aging transition can be graphically visualized by vectors connecting the maxima of the transition probabilities of T, which, metaphorically, resemble a chronometer or the hands of a clock. PMID- 26236242 TI - Quality of Smartphone Apps Related to Panic Disorder. AB - Quality of smartphone apps related to panic: smartphone apps have a growing role in health care. This study assessed the quality of English-language apps for panic disorder (PD) and compared paid and free apps. Keywords related to PD were entered into the Google Play Store search engine. Apps were assessed using the following quality indicators: accountability, interactivity, self-help score (the potential of smartphone apps to help users in daily life), and evidence-based content quality. The Brief DISCERN score and the criteria of the "Health on the Net" label were also used as content quality indicators as well as the number of downloads. Of 247 apps identified, 52 met all inclusion criteria. The content quality and self-help scores of these PD apps were poor. None of the assessed indicators were associated with payment status or number of downloads. Multiple linear regressions showed that the Brief DISCERN score significantly predicted the content quality and self-help scores. Poor content quality and self-help scores of PD smartphone apps highlight the gap between their technological potential and the overall quality of available products. PMID- 26236244 TI - Intrusive Mental Imagery in Psychological Disorders: Is the Self the Key to Understanding Maintenance? PMID- 26236245 TI - Grid cells on steeply sloping terrain: evidence for planar rather than volumetric encoding. AB - Neural encoding of navigable space involves a network of structures centered on the hippocampus, whose neurons -place cells - encode current location. Input to the place cells includes afferents from the entorhinal cortex, which contains grid cells. These are neurons expressing spatially localized activity patches, or firing fields, that are evenly spaced across the floor in a hexagonal close packed array called a grid. It is thought that grids function to enable the calculation of distances. The question arises as to whether this odometry process operates in three dimensions, and so we queried whether grids permeate three dimensional (3D) space - that is, form a lattice - or whether they simply follow the environment surface. If grids form a 3D lattice then this lattice would ordinarily be aligned horizontally (to explain the usual hexagonal pattern observed). A tilted floor would transect several layers of this putative lattice, resulting in interruption of the hexagonal pattern. We model this prediction with simulated grid lattices, and show that the firing of a grid cell on a 40 degrees tilted surface should cover proportionally less of the surface, with smaller field size, fewer fields, and reduced hexagonal symmetry. However, recording of real grid cells as animals foraged on a 40 degrees -tilted surface found that firing of grid cells was almost indistinguishable, in pattern or rate, from that on the horizontal surface, with if anything increased coverage and field number, and preserved field size. It thus appears unlikely that the sloping surface transected a lattice. However, grid cells on the slope displayed slightly degraded firing patterns, with reduced coherence and slightly reduced symmetry. These findings collectively suggest that the grid cell component of the metric representation of space is not fixed in absolute 3D space but is influenced both by the surface the animal is on and by the relationship of this surface to the horizontal, supporting the hypothesis that the neural map of space is "multi planar" rather than fully volumetric. PMID- 26236243 TI - Disturbed Amino Acid Metabolism in HIV: Association with Neuropsychiatric Symptoms. AB - Blood levels of the amino acid phenylalanine, as well as of the tryptophan breakdown product kynurenine, are found to be elevated in human immunodeficiency virus type 1 (HIV-1)-infected patients. Both essential amino acids, tryptophan and phenylalanine, are important precursor molecules for neurotransmitter biosynthesis. Thus, dysregulated amino acid metabolism may be related to disease associated neuropsychiatric symptoms, such as development of depression, fatigue, and cognitive impairment. Increased phenylalanine/tyrosine and kynurenine/tryptophan ratios are associated with immune activation in patients with HIV-1 infection and decrease upon effective antiretroviral therapy. Recent large-scale metabolic studies have confirmed the crucial involvement of tryptophan and phenylalanine metabolism in HIV-associated disease. Herein, we summarize the current status of the role of tryptophan and phenylalanine metabolism in HIV disease and discuss how inflammatory stress-associated dysregulation of amino acid metabolism may be part of the pathophysiology of common HIV-associated neuropsychiatric conditions. PMID- 26236246 TI - Neural encoding of large-scale three-dimensional space-properties and constraints. AB - How the brain represents represent large-scale, navigable space has been the topic of intensive investigation for several decades, resulting in the discovery that neurons in a complex network of cortical and subcortical brain regions co operatively encode distance, direction, place, movement etc. using a variety of different sensory inputs. However, such studies have mainly been conducted in simple laboratory settings in which animals explore small, two-dimensional (i.e., flat) arenas. The real world, by contrast, is complex and three dimensional with hills, valleys, tunnels, branches, and-for species that can swim or fly-large volumetric spaces. Adding an additional dimension to space adds coding challenges, a primary reason for which is that several basic geometric properties are different in three dimensions. This article will explore the consequences of these challenges for the establishment of a functional three-dimensional metric map of space, one of which is that the brains of some species might have evolved to reduce the dimensionality of the representational space and thus sidestep some of these problems. PMID- 26236248 TI - Improving care quality and preventing maltreatment in institutional care - a feasibility study with caregivers. AB - Institutionalized children in low-income countries often face maltreatment and inadequate caregiving. In addition to prior traumatization and other childhood adversities in the family of origin, abuse and neglect in institutional care are linked to various mental health problems. By providing a manualized training workshop for caregivers, we aimed at improving care quality and preventing maltreatment in institutional care. In Study 1, 29 participating caregivers rated feasibility and efficacy of the training immediately before, directly after, and 3 months following the training workshop. The results showed high demand, good feasibility, high motivation, and acceptance of caregivers. They reported improvements in caregiver-child relationships, as well as in the children's behavior. Study 2 assessed exposure to maltreatment and the mental health of 28 orphans living in one institution in which all caregivers had been trained. The children were interviewed 20 months before, 1 month before, and 3 months after the training. Children reported a decrease in physical maltreatment and assessments showed a decrease in mental health problems. Our approach seems feasible under challenging circumstances and provides first hints for its efficacy. These promising findings call for further studies testing the efficacy and sustainability of this maltreatment prevention approach. PMID- 26236247 TI - Visual aids improve diagnostic inferences and metacognitive judgment calibration. AB - Visual aids can improve comprehension of risks associated with medical treatments, screenings, and lifestyles. Do visual aids also help decision makers accurately assess their risk comprehension? That is, do visual aids help them become well calibrated? To address these questions, we investigated the benefits of visual aids displaying numerical information and measured accuracy of self assessment of diagnostic inferences (i.e., metacognitive judgment calibration) controlling for individual differences in numeracy. Participants included 108 patients who made diagnostic inferences about three medical tests on the basis of information about the sensitivity and false-positive rate of the tests and disease prevalence. Half of the patients received the information in numbers without a visual aid, while the other half received numbers along with a grid representing the numerical information. In the numerical condition, many patients especially those with low numeracy-misinterpreted the predictive value of the tests and profoundly overestimated the accuracy of their inferences. Metacognitive judgment calibration mediated the relationship between numeracy and accuracy of diagnostic inferences. In contrast, in the visual aid condition, patients at all levels of numeracy showed high-levels of inferential accuracy and metacognitive judgment calibration. Results indicate that accurate metacognitive assessment may explain the beneficial effects of visual aids and numeracy-a result that accords with theory suggesting that metacognition is an essential part of risk literacy. We conclude that well-designed risk communications can inform patients about healthrelevant numerical information while helping them assess the quality of their own risk comprehension. PMID- 26236249 TI - The mental representation of the human gait in young and older adults. AB - The link between mental representation (MREP) structures and motor performance has been evidenced for a great variety of movement skills, but not for the human gait. Therefore the present study sought to investigate the cognitive memory structures underlying the human gait in young and older adults. In a first experiment, gait parameters at comfortable gait speed (OptoGait) were compared with gait-specific MREPs (structural dimensional analysis of MREP; SDA-M) in 36 young adults. Participants were divided into a slow- and fast-walking group. The proven relationship between gait speed and executive functions such as working memory led to the hypothesis that gait pattern and MREP differ between slow- and fast-walking adults. In a second experiment, gait performance and MREPs were compared between 24 young (27.9 years) and 24 elderly (60.1 years) participants. As age-related declines in gait performance occur from the seventh decade of life onward, we hypothesized that gait parameters would not be affected until the age of 60 years accompanied by unchanged MREP. Data of experiment one revealed that gait parameters and MREPs differed significantly between slow and fast walkers. Notably, eleven previously incurred musculoskeletal injuries were documented for the slow walkers but only two injuries and one disorder for fast walkers. Experiment two revealed no age-related differences in gait parameters or MREPs between healthy young and older adults. In conclusion, the differences in gait parameters associated with lower comfortable gait speeds are reflected by differences in MREPs, whereby SDA-M data indicate that the single limb support phase may serve as a critical functional period. These differences probably resulted from previously incurred musculoskeletal injuries. Our data further indicate that the human gait and its MREP are stable until the age of 60. SDA-M may be considered as a valuable clinical tool for diagnosis of gait abnormalities and monitoring of therapeutic effectiveness. PMID- 26236250 TI - On the limits of the relation of disgust to judgments of immorality. AB - Two correlational studies (ns = 400; 90) examined the association of judgments of immorality and disgust (hypothesized in much current research and theory). Across 40 scenarios in Study 1, immorality was positively correlated with negative emotions, especially anger. With anger partialed, disgust was significantly, but weakly, correlated with immorality, r(38) = 0.22, p < 0.05. Study 2 asked whether the immorality-disgust correlation is due to a confound: immoral events often include elements implicitly or explicitly implying pathogens, such as blood or semen. Across 22 scenarios, those implying pathogens were associated with disgust, but those without pathogens, whether moral or immoral, rarely were. We propose that the relation between disgust and immorality is largely coincidental, resulting from (a) using the word disgust to express anger with or even dislike of immoral acts and (b) the presence of incidental elements capable of eliciting disgust. PMID- 26236252 TI - The influence of spatial ability and experience on performance during spaceship rendezvous and docking. AB - Manual rendezvous and docking (manual RVD) is a challenging space task for astronauts. Previous research showed a correlation between spatial ability and manual RVD skills among participants at early stages of training, but paid less attention to experts. Therefore, this study tried to explore the role of spatial ability in manual RVD skills in two groups of trainees, one relatively inexperienced and the other experienced operators. Additionally, mental rotation has been proven essential in RVD and was tested in this study among 27 male participants, 15 novices, and 12 experts. The participants performed manual RVD tasks in a high fidelity simulator. Results showed that experience moderated the relation between mental rotation ability and manual RVD performance. On one hand, novices with high mental rotation ability tended to perform that RVD task more successfully; on the other hand, experts with high mental rotation ability showed not only no performance advantage in the final stage of the RVD task, but had certain disadvantages in their earlier processes. Both theoretical and practical implications were discussed. PMID- 26236251 TI - Mental health problems in adolescents with cochlear implants: peer problems persist after controlling for additional handicaps. AB - The aims of the present multi-center study were to investigate the extent of mental health problems in adolescents with a hearing loss and cochlear implants (CIs) in comparison to normal hearing (NH) peers and to investigate possible relations between the extent of mental health problems of young CI users and hearing variables, such as age at implantation, or functional gain of CI. The survey included 140 adolescents with CI (mean age = 14.7, SD = 1.5 years) and 140 NH adolescents (mean age = 14.8, SD = 1.4 years), their parents and teachers. Participants were matched by age, gender and social background. Within the CI group, 35 adolescents were identified as "risk cases" due to possible and manifest additional handicaps, and 11 adolescents were non-classifiable. Mental health problems were assessed with the Strengths and Difficulties Questionnaire (SDQ) in the versions "Self," "Parent," and "Teacher." The CI group showed significantly more "Peer Problems" than the NH group. When the CI group was split into a "risk-group" (35 "risk cases" and 11 non-classifiable persons) and a "non risk group" (n = 94), increased peer problems were perceived in both CI subgroups by adolescents themselves. However, no further differences between the CI non risk group and the NH group were observed in any rater. The CI risk-group showed significantly more hyperactivity compared to the NH group and more hyperactivity and conduct problems compared to the CI non-risk group. Cluster analyses confirmed that there were significantly more adolescents with high problems in the CI risk-group compared to the CI non-risk group and the NH group. Adolescents with CI, who were able to understand speech in noise had significantly less difficulties compared to constricted CI users. Parents, teachers, and clinicians should be aware that CI users with additionally special needs may have mental health problems. However, peer problems were also experienced by CI adolescents without additional handicaps. PMID- 26236253 TI - Visual stability-what is the problem? PMID- 26236254 TI - Authentic leadership: application to women leaders. AB - The purpose of this perspective article is to present the argument that authentic leadership is a gendered representation of leadership. We first provide a brief history of leadership theories and definitions of authentic leadership. We then critique authentic leadership and offer arguments to support the premise that authentic leadership is not gender-neutral and is especially challenging for women. PMID- 26236255 TI - The relationship between obesity and quality of life in Brazilian adults. AB - The incidence of obesity has reached epidemic proportions, affecting 30% of the adult population globally. During the last decade, the rising rates of obesity in developing countries has been particularly striking. One potential consequence of obesity is a decline in quality of life (QoL). Thus, the objective of the present study was to investigate the possible relationship between obesity, defined by body mass index (BMI), and QoL, evaluated using the short version of the World Health Organization Quality of Life (WHOQOL) scale in a Brazilian population. The sample consisted of 30 men and 30 women, divided into three groups according to BMI: normal weight, obese, and morbidly obese. All of the subjects responded to the WHOQOL inventories. The results indicated that the groups with lower BMIs had better QoL than the groups with higher BMIs. Being overweight interfered with QoL equally in both sexes, with no difference found between men and women. The results indicate the necessity of multidisciplinary care of obese individuals. PMID- 26236256 TI - Neural systems and hormones mediating attraction to infant and child faces. AB - We find infant faces highly attractive as a result of specific features which Konrad Lorenz termed "Kindchenschema" or "baby schema," and this is considered to be an important adaptive trait for promoting protective and caregiving behaviors in adults, thereby increasing the chances of infant survival. This review first examines the behavioral support for this effect and physical and behavioral factors which can influence it. It then provides details of the increasing number of neuroimaging and electrophysiological studies investigating the neural circuitry underlying this baby schema effect in parents and non-parents of both sexes. Next it considers potential hormonal contributions to the baby schema effect in both sexes and the neural effects associated with reduced responses to infant cues in post-partum depression, anxiety and drug taking. Overall the findings reviewed reveal a very extensive neural circuitry involved in our perception of cuteness in infant faces, with enhanced activation compared to adult faces being found in brain regions involved in face perception, attention, emotion, empathy, memory, reward and attachment, theory of mind and also control of motor responses. Both mothers and fathers also show evidence for enhanced responses in these same neural systems when viewing their own as opposed to another child. Furthermore, responses to infant cues in many of these neural systems are reduced in mothers with post-partum depression or anxiety or have taken addictive drugs throughout pregnancy. In general reproductively active women tend to rate infant faces as cuter than men, which may reflect both heightened attention to relevant cues and a stronger activation in their brain reward circuitry. Perception of infant cuteness may also be influenced by reproductive hormones with the hypothalamic neuropeptide oxytocin being most strongly associated to date with increased attention and attraction to infant cues in both sexes. PMID- 26236257 TI - The linguistics of schizophrenia: thought disturbance as language pathology across positive symptoms. AB - We hypothesize that linguistic (dis-)organization in the schizophrenic brain plays a more central role in the pathogenesis of this disease than commonly supposed. Against the standard view, that schizophrenia is a disturbance of thought or selfhood, we argue that the origins of the relevant forms of thought and selfhood at least partially depend on language. The view that they do not is premised by a theoretical conception of language that we here identify as 'Cartesian' and contrast with a recent 'un-Cartesian' model. This linguistic model empirically argues for both (i) a one-to-one correlation between human specific thought or meaning and forms of grammatical organization, and (ii) an integrative and co-dependent view of linguistic cognition and its sensory-motor dimensions. Core dimensions of meaning mediated by grammar on this model specifically concern forms of referential and propositional meaning. A breakdown of these is virtually definitional of core symptoms. Within this model the three main positive symptoms of schizophrenia fall into place as failures in language mediated forms of meaning, manifest either as a disorder of speech perception (Auditory Verbal Hallucinations), abnormal speech production running without feedback control (Formal Thought Disorder), or production of abnormal linguistic content (Delusions). Our hypothesis makes testable predictions for the language profile of schizophrenia across symptoms; it simplifies the cognitive neuropsychology of schizophrenia while not being inconsistent with a pattern of neurocognitive deficits and their correlations with symptoms; and it predicts persistent findings on disturbances of language-related circuitry in the schizophrenic brain. PMID- 26236259 TI - Can you hear my age? Influences of speech rate and speech spontaneity on estimation of speaker age. AB - Cognitive hearing science is mainly about the study of how cognitive factors contribute to speech comprehension, but cognitive factors also partake in speech processing to infer non-linguistic information from speech signals, such as the intentions of the talker and the speaker's age. Here, we report two experiments on age estimation by "naive" listeners. The aim was to study how speech rate influences estimation of speaker age by comparing the speakers' natural speech rate with increased or decreased speech rate. In Experiment 1, listeners were presented with audio samples of read speech from three different speaker age groups (young, middle aged, and old adults). They estimated the speakers as younger when speech rate was faster than normal and as older when speech rate was slower than normal. This speech rate effect was slightly greater in magnitude for older (60-65 years) speakers in comparison with younger (20-25 years) speakers, suggesting that speech rate may gain greater importance as a perceptual age cue with increased speaker age. This pattern was more pronounced in Experiment 2, in which listeners estimated age from spontaneous speech. Faster speech rate was associated with lower age estimates, but only for older and middle aged (40-45 years) speakers. Taken together, speakers of all age groups were estimated as older when speech rate decreased, except for the youngest speakers in Experiment 2. The absence of a linear speech rate effect in estimates of younger speakers, for spontaneous speech, implies that listeners use different age estimation strategies or cues (possibly vocabulary) depending on the age of the speaker and the spontaneity of the speech. Potential implications for forensic investigations and other applied domains are discussed. PMID- 26236258 TI - Grasping actions and social interaction: neural bases and anatomical circuitry in the monkey. AB - The study of the neural mechanisms underlying grasping actions showed that cognitive functions are deeply embedded in motor organization. In the first part of this review, we describe the anatomical structure of the motor cortex in the monkey and the cortical and sub-cortical connections of the different motor areas. In the second part, we review the neurophysiological literature showing that motor neurons are not only involved in movement execution, but also in the transformation of object physical features into motor programs appropriate to grasp them (through visuo-motor transformations). We also discuss evidence indicating that motor neurons can encode the goal of motor acts and the intention behind action execution. Then, we describe one of the mechanisms-the mirror mechanism-considered to be at the basis of action understanding and intention reading, and describe the anatomo-functional pathways through which information about the social context can reach the areas containing mirror neurons. Finally, we briefly show that a clear similarity exists between monkey and human in the organization of the motor and mirror systems. Based on monkey and human literature, we conclude that the mirror mechanism relies on a more extended network than previously thought, and possibly subserves basic social functions. We propose that this mechanism is also involved in preparing appropriate complementary response to observed actions, allowing two individuals to become attuned and cooperate in joint actions. PMID- 26236260 TI - Arousal, valence, and the uncanny valley: psychophysiological and self-report findings. AB - The main prediction of the Uncanny Valley Hypothesis (UVH) is that observation of humanlike characters that are difficult to distinguish from the human counterpart will evoke a state of negative affect. Well-established electrophysiological [late positive potential (LPP) and facial electromyography (EMG)] and self-report [Self-Assessment Manikin (SAM)] indices of valence and arousal, i.e., the primary orthogonal dimensions of affective experience, were used to test this prediction by examining affective experience in response to categorically ambiguous compared with unambiguous avatar and human faces (N = 30). LPP and EMG provided direct psychophysiological indices of affective state during passive observation and the SAM provided self-reported indices of affective state during explicit cognitive evaluation of static facial stimuli. The faces were drawn from well-controlled morph continua representing the UVH' dimension of human likeness (DHL). The results provide no support for the notion that category ambiguity along the DHL is specifically associated with enhanced experience of negative affect. On the contrary, the LPP and SAM-based measures of arousal and valence indicated a general increase in negative affective state (i.e., enhanced arousal and negative valence) with greater morph distance from the human end of the DHL. A second sample (N = 30) produced the same finding, using an ad hoc self-rating scale of feelings of familiarity, i.e., an oft-used measure of affective experience along the UVH' familiarity dimension. In conclusion, this multi-method approach using well-validated psychophysiological and self-rating indices of arousal and valence rejects - for passive observation and for explicit affective evaluation of static faces - the main prediction of the UVH. PMID- 26236261 TI - Can an intervention based on a serious videogame prior to cognitive behavioral therapy be helpful in bulimia nervosa? A clinical case study. AB - BACKGROUND: Several studies have highlighted the implications of impulsivity and novelty seeking for both the maintenance and the process of recovery from bulimia nervosa (BN). Cognitive behavioral therapy (CBT) is the treatment of choice for BN, but for some cases, this treatment alone might not be sufficient for reducing the high levels of impulsivity. The paper presents a case report of a patient with BN, examining the effectiveness of using a videogame (VG; Playmancer) as an additional intervention designed to address impulsivity. DESIGN: Psychometric and neuropsychological measures were collected at baseline. After this assessment, Playmancer was applied prior to CBT, following an "A-B-A-C-A" single case experimental design. Impulsivity levels were assessed with the Conner's Continuous Performance Test II (CPT-II). After the Playmancer treatment, the patient started CBT, and the levels of impulsivity were recorded again. Finally, psychometric and neuropsychological measures were collected after treatment. Weekly frequency of binges and vomiting were also recorded during the entire procedure. RESULTS: After the VG intervention, psychometric measures such as anxiety levels, impulsivity and novelty seeking decreased. Regarding the neuropsychological measures, impulsivity levels (measured with the CPT-II) progressively decreased throughout the intervention, and an improvement in decision making capacities was observed. Furthermore, the frequency of binges also decreased during and after the VG intervention. DISCUSSION: This case report suggests that using the Playmancer VG to reduce impulsivity prior to CBT may enhance the final results of the treatment for BN. PMID- 26236262 TI - The role of rotational hand movements and general motor ability in children's mental rotation performance. AB - Mental rotation of visual images of body parts and abstract shapes can be influenced by simultaneous motor activity. Children in particular have a strong coupling between motor and cognitive processes. We investigated the influence of a rotational hand movement performed by rotating a knob on mental rotation performance in primary school-age children (N = 83; age range: 7.0-8.3 and 9.0 10.11 years). In addition, we assessed the role of motor ability in this relationship. Boys in the 7- to 8-year-old group were faster when mentally and manually rotating in the same direction than in the opposite direction. For girls and older children this effect was not found. A positive relationship was found between motor ability and accuracy on the mental rotation task: stronger motor ability related to improved mental rotation performance. In both age groups, children with more advanced motor abilities were more likely to adopt motor processes to solve mental rotation tasks if the mental rotation task was primed by a motor task. Our evidence supports the idea that an overlap between motor and visual cognitive processes in children is influenced by motor ability. PMID- 26236263 TI - Editorial: The impact of learning to read on visual processing. PMID- 26236264 TI - Developmental changes in face visual scanning in autism spectrum disorder as assessed by data-based analysis. AB - Individuals with autism spectrum disorder (ASD) present reduced visual attention to faces. However, contradictory conclusions have been drawn about the strategies involved in visual face scanning due to the various methodologies implemented in the study of facial screening. Here, we used a data-driven approach to compare children and adults with ASD subjected to the same free viewing task and to address developmental aspects of face scanning, including its temporal patterning, in healthy children, and adults. Four groups (54 subjects) were included in the study: typical adults, typically developing children, and adults and children with ASD. Eye tracking was performed on subjects viewing unfamiliar faces. Fixations were analyzed using a data-driven approach that employed spatial statistics to provide an objective, unbiased definition of the areas of interest. Typical adults expressed a spatial and temporal strategy for visual scanning that differed from the three other groups, involving a sequential fixation of the right eye (RE), left eye (LE), and mouth. Typically developing children, adults and children with autism exhibited similar fixation patterns and they always started by looking at the RE. Children (typical or with ASD) subsequently looked at the LE or the mouth. Based on the present results, the patterns of fixation for static faces that mature from childhood to adulthood in typical subjects are not found in adults with ASD. The atypical patterns found after developmental progression and experience in ASD groups appear to remain blocked in an immature state that cannot be differentiated from typical developmental child patterns of fixation. PMID- 26236265 TI - Preferences for different insomnia treatment options in people with schizophrenia and related psychoses: a qualitative study. AB - Symptoms of psychosis such as hallucinations and delusions can be intrusive and unwanted and often remain treatment-resistant. Due to recent progress in basic and clinical sciences, novel approaches such as sleep-based interventions are increasingly becoming offered to address the physical and mental health issues of people with severe mental illness. While the primary outcome is to improve sleep, studies have demonstrated that interventions that target symptoms of insomnia can also produce improvements in the severity of psychotic symptoms, quality of life, and functional outcomes. This study presents qualitative data on the attitudes and preferences of people with schizophrenia and schizo-affective disorders to three different types of therapies for insomnia (standard pharmacological, melatonin-based, and cognitive and/or behavior therapy). Interviews included discussions regarding the perceived advantages and limitations of different therapies, enablers to taking up the preferred option, as well as personal strategies that have helped respondents with sleep problems in the past. Results showed that, when given the choice, these individuals prefer psychological and behavioral-type therapy to other sleep interventions because of its potential to support and empower them in taking responsibility for their own recovery. Pharmacological therapies, by contrast, are viewed as useful in managing acute sleep problems, but only as a short-term solution. Overall, the findings underscore the need for patients' active engagement when making decisions about treatment options. PMID- 26236266 TI - Dissociable functions of reward inference in the lateral prefrontal cortex and the striatum. AB - In a complex and uncertain world, how do we select appropriate behavior? One possibility is that we choose actions that are highly reinforced by their probabilistic consequences (model-free processing). However, we may instead plan actions prior to their actual execution by predicting their consequences (model based processing). It has been suggested that the brain contains multiple yet distinct systems involved in reward prediction. Several studies have tried to allocate model-free and model-based systems to the striatum and the lateral prefrontal cortex (LPFC), respectively. Although there is much support for this hypothesis, recent research has revealed discrepancies. To understand the nature of the reward prediction systems in the LPFC and the striatum, a series of single unit recording experiments were conducted. LPFC neurons were found to infer the reward associated with the stimuli even when the monkeys had not yet learned the stimulus-reward (SR) associations directly. Striatal neurons seemed to predict the reward for each stimulus only after directly experiencing the SR contingency. However, the one exception was "Exclusive Or" situations in which striatal neurons could predict the reward without direct experience. Previous single-unit studies in monkeys have reported that neurons in the LPFC encode category information, and represent reward information specific to a group of stimuli. Here, as an extension of these, we review recent evidence that a group of LPFC neurons can predict reward specific to a category of visual stimuli defined by relevant behavioral responses. We suggest that the functional difference in reward prediction between the LPFC and the striatum is that while LPFC neurons can utilize abstract code, striatal neurons can code individual associations between stimuli and reward but cannot utilize abstract code. PMID- 26236267 TI - The path of ambivalence: tracing the pull of opposing evaluations using mouse trajectories. AB - Ambivalence refers to a psychological conflict between opposing evaluations, often experienced as being torn between alternatives. This dynamic aspect of ambivalence is hard to capture with outcome-focused measures, such as response times or self-report. To gain more insight into ambivalence as it unfolds, the current work uses an embodied measure of pull, drawing on research in dynamic systems. In three studies, using different materials, we tracked people's mouse movements as they chose between negative and positive evaluations of attitude objects. When participants evaluated ambivalent attitude objects, their mouse trajectories showed more pull of the non-chosen evaluative option than when they evaluated univalent attitude objects, revealing that participants were literally torn between the two opposing evaluations. We address the relationship of this dynamic measure to response time and self-reports of ambivalence and discuss implications and avenues for future research. PMID- 26236268 TI - Oral communication in individuals with hearing impairment-considerations regarding attentional, cognitive and social resources. AB - Traditionally, audiology research has focused primarily on hearing and related disorders. In recent years, however, growing interest and insight has developed into the interaction of hearing and cognition. This applies to a person's listening and speech comprehension ability and the neural realization thereof. The present perspective extends this view to oral communication, when two or more people interact in social context. Specifically, the impact of hearing impairment and cognitive changes with age is discussed. In focus are executive functions, a group of top-down processes that guide attention, thought and action according to goals and intentions. The strategic allocation of the limited cognitive processing capacity among concurrent tasks is often effortful, especially under adverse communication conditions and in old age. Working memory, a sub-function extensively discussed in cognitive hearing science, is here put into the context of other executive and cognitive functions required for oral communication and speech comprehension. Finally, taking an ecological view on hearing impairment, activity limitations and participation restrictions are discussed regarding their psycho-social impact and third-party disability. PMID- 26236270 TI - Possible relation between psychosis and the unconscious: a review of "The Unconscious," by Freud. AB - This review intends to present some elements of the Freudian thinking on psychosis, focusing on the relations between psychosis and the unconscious. The unconscious phenomena which episodically cross the neurotic individual are massively and continuously shown on psychosis. The psychotic individual appears to be constantly invaded by the other, like a strange person, which bursts inside of him/her and presents itself as a threat to the process of construction of this person's identity. But what is the relation between the unconscious and psychosis in the Freudian text? It could be hypothesized that the psychotic individual may be invaded by a pulsating unconscious which demands a symbolic mediation. This reveals the importance of associating verbal construction to medication in cases of psychosis. PMID- 26236269 TI - Aging and the number sense: preserved basic non-symbolic numerical processing and enhanced basic symbolic processing. AB - Aging often leads to general cognitive decline in domains such as memory and attention. The effect of aging on numerical cognition, particularly on foundational numerical skills known as the number sense, is not well-known. Early research focused on the effect of aging on arithmetic. Recent studies have begun to investigate the impact of healthy aging on basic numerical skills, but focused on non-symbolic quantity discrimination alone. Moreover, contradictory findings have emerged. The current study aimed to further investigate the impact of aging on basic non-symbolic and symbolic numerical skills. A group of 25 younger (18 25) and 25 older adults (60-77) participated in non-symbolic and symbolic numerical comparison tasks. Mathematical and spelling abilities were also measured. Results showed that aging had no effect on foundational non-symbolic numerical skills, as both groups performed similarly [RTs, accuracy and Weber fractions (w)]. All participants showed decreased non-symbolic acuity (accuracy and w) in trials requiring inhibition. However, aging appears to be associated with a greater decline in discrimination speed in such trials. Furthermore, aging seems to have a positive impact on mathematical ability and basic symbolic numerical processing, as older participants attained significantly higher mathematical achievement scores, and performed significantly better on the symbolic comparison task than younger participants. The findings suggest that aging and its lifetime exposure to numbers may lead to better mathematical achievement and stronger basic symbolic numerical skills. Our results further support the observation that basic non-symbolic numerical skills are resilient to aging, but that aging may exacerbate poorer performance on trials requiring inhibitory processes. These findings lend further support to the notion that preserved basic numerical skills in aging may reflect the preservation of an innate, primitive, and embedded number sense. PMID- 26236271 TI - Corollary discharges and fatigue-related symptoms: the role of attentional focus. PMID- 26236272 TI - Editorial: Learning a non-native language in a naturalistic environment: insights from behavioral and neuroimaging research. PMID- 26236273 TI - Tryptophan supplementation and the response to unfairness in healthy volunteers. AB - Experimental manipulation of serotonin (5-HT) availability has been shown to modulate social behavior. For instance, serotonin depletion increased the rejection rates of unfair offers in the ultimatum game (UG), whereas a single dose of the serotonin reuptake inhibitor (citalopram) decreased rejection rates. These effects were observed immediately after the manipulation. The aim of this study was to investigate the effect of prolonged tryptophan (TRP) supplementation on UG performance in healthy individuals. A randomized double-blind placebo (PLC) controlled design was used. Healthy volunteers (N = 47) completed the UG before and after a 6-day intervention of TRP (2.8 g/day) or PLC. Impulsivity was measured with a Go-Stop task. The overall analyses showed that TRP supplementation had no significant effect on UG scores, but the direction of the effect was opposite from expectations. Because repeated performance of the UG may lead to unwanted learning effects or strategical changes, additional analyses were conducted in which participants (N = 7) who accepted all offers on the second measurement were excluded. These analyses revealed that the TRP-group rejected very unfair offers more often than the PLC group. The groups did not differ on impulsivity. Increasing serotonin through TRP supplements increased the rejection of very unfair offers. The direction of our findings is inconsistent with earlier studies that showed that increasing 5-HT availability results in less rejection of unfair offers. The current findings thus importantly suggest that effects of acute vs. prolonged enhancement of 5-HT availability may differ. Also, the outcomes show that the UG is a complex task and participants' decisions may depend on context, e.g., prior experience with the task. PMID- 26236275 TI - Olfactory asymmetric dysfunction in early Parkinson patients affected by unilateral disorder. AB - INTRODUCTION: Parkinson's disease (PD) often first presents with asymmetric motor symptoms. A number of studies have now established that sensory deficits can also be similarly asymmetric. It is well established that PD is associated with marked olfactory dysfunction, but whether this too present asymmetrically is a currently contentious question. METHODS: To address this, we recruited 12 early stage Parkinson patients with right-sided motor symptoms and compared them to 12 healthy age-matched controls on tests of olfactory identification and recognition, administered separately to each nostril. RESULTS: Data analyses indicated that Parkinson patients performed worse with the left nostril on both tasks, while no nostril-related differences were observed for the healthy age matched control group on the same comparisons. CONCLUSION: These findings support the idea that asymmetric deficits do extend into olfactory performance in PD-as they do into other sensory domains-and we examine the possibility that they might be a particular feature of right-sided motor symptom presentation. PMID- 26236274 TI - Do gender differences in audio-visual benefit and visual influence in audio visual speech perception emerge with age? AB - Gender and age have been found to affect adults' audio-visual (AV) speech perception. However, research on adult aging focuses on adults over 60 years, who have an increasing likelihood for cognitive and sensory decline, which may confound positive effects of age-related AV-experience and its interaction with gender. Observed age and gender differences in AV speech perception may also depend on measurement sensitivity and AV task difficulty. Consequently both AV benefit and visual influence were used to measure visual contribution for gender balanced groups of young (20-30 years) and middle-aged adults (50-60 years) with task difficulty varied using AV syllables from different talkers in alternative auditory backgrounds. Females had better speech-reading performance than males. Whereas no gender differences in AV benefit or visual influence were observed for young adults, visually influenced responses were significantly greater for middle aged females than middle-aged males. That speech-reading performance did not influence AV benefit may be explained by visual speech extraction and AV integration constituting independent abilities. Contrastingly, the gender difference in visually influenced responses in middle adulthood may reflect an experience-related shift in females' general AV perceptual strategy. Although young females' speech-reading proficiency may not readily contribute to greater visual influence, between young and middle-adulthood recurrent confirmation of the contribution of visual cues induced by speech-reading proficiency may gradually shift females AV perceptual strategy toward more visually dominated responses. PMID- 26236276 TI - Biopsy Proven Tumefactive Multiple Sclerosis with Concomitant Glioma: Case Report and Review of the Literature. AB - We report a case of pathologically confirmed tumefactive multiple sclerosis (MS) followed shortly thereafter by the diagnosis of an oligoastrocytoma. The complexity of diagnosis and management of concomitant presence of tumefactive MS and glial cell tumors is discussed. PMID- 26236277 TI - Abnormal Auditory Gain in Hyperacusis: Investigation with a Computational Model. AB - Hyperacusis is a frequent auditory disorder that is characterized by abnormal loudness perception where sounds of relatively normal volume are perceived as too loud or even painfully loud. As hyperacusis patients show decreased loudness discomfort levels (LDLs) and steeper loudness growth functions, it has been hypothesized that hyperacusis might be caused by an increase in neuronal response gain in the auditory system. Moreover, since about 85% of hyperacusis patients also experience tinnitus, the conditions might be caused by a common mechanism. However, the mechanisms that give rise to hyperacusis have remained unclear. Here, we have used a computational model of the auditory system to investigate candidate mechanisms for hyperacusis. Assuming that perceived loudness is proportional to the summed activity of all auditory nerve (AN) fibers, the model was tuned to reproduce normal loudness perception. We then evaluated a variety of potential hyperacusis gain mechanisms by determining their effects on model equal loudness contours and comparing the results to the LDLs of hyperacusis patients with normal hearing thresholds. Hyperacusis was best accounted for by an increase in non-linear gain in the central auditory system. Good fits to the average patient LDLs were obtained for a general increase in gain that affected all frequency channels to the same degree, and also for a frequency-specific gain increase in the high-frequency range. Moreover, the gain needed to be applied after subtraction of spontaneous activity of the AN, which is in contrast to current theories of tinnitus generation based on amplification of spontaneous activity. Hyperacusis and tinnitus might therefore be caused by different changes in neuronal processing in the central auditory system. PMID- 26236278 TI - Enhancement of Cortical Network Activity in vitro and Promotion of GABAergic Neurogenesis by Stimulation with an Electromagnetic Field with a 150 MHz Carrier Wave Pulsed with an Alternating 10 and 16 Hz Modulation. AB - In recent years, various stimuli were identified capable of enhancing neurogenesis, a process which is dysfunctional in the senescent brain and in neurodegenerative and certain neuropsychiatric diseases. Applications of electromagnetic fields to brain tissue have been shown to affect cellular properties and their importance for therapies in medicine is recognized. In this study, differentiating murine cortical networks on multiwell microelectrode arrays were repeatedly exposed to an extremely low-electromagnetic field (ELEMF) with alternating 10 and 16 Hz frequencies piggy backed onto a 150 MHz carrier frequency. The ELEMF exposure stimulated the electrical network activity and intensified the structure of bursts. Further, the exposure to electromagnetic fields within the first 28 days in vitro of the differentiation of the network activity induced also reorganization within the burst structure. This effect was already most pronounced at 14 days in vitro after 10 days of exposure. Overall, the development of cortical activity under these conditions was accelerated. These functional electrophysiological changes were accompanied by morphological ones. The percentage of neurons in the neuron glia co-culture was increased without affecting the total number of cells, indicating an enhancement of neurogenesis. The ELEMF exposure selectively promoted the proliferation of a particular population of neurons, evidenced by the increased proportion of GABAergic neurons. The results support the initial hypothesis that this kind of ELEMF stimulation could be a treatment option for specific indications with promising potential for CNS applications, especially for degenerative diseases, such as Alzheimer's disease and other dementias. PMID- 26236279 TI - Corrigendum: A Theoretical Study on Seasonality. AB - [This corrects the article on p. 94 in vol. 6, PMID: 25999912.]. PMID- 26236280 TI - CD8(+) T Cell-Mediated Neuronal Dysfunction and Degeneration in Limbic Encephalitis. AB - Autoimmune inflammation of the limbic gray matter structures of the human brain has recently been identified as major cause of mesial temporal lobe epilepsy with interictal temporal epileptiform activity and slowing of the electroencephalogram, progressive memory disturbances, as well as a variety of other behavioral, emotional, and cognitive changes. Magnetic resonance imaging exhibits volume and signal changes of the amygdala and hippocampus, and specific anti-neuronal antibodies binding to either intracellular or plasma membrane neuronal antigens can be detected in serum and cerebrospinal fluid. While effects of plasma cell-derived antibodies on neuronal function and integrity are increasingly becoming characterized, potentially contributing effects of T cell mediated immune mechanisms remain poorly understood. CD8(+) T cells are known to directly interact with major histocompatibility complex class I-expressing neurons in an antigen-specific manner. Here, we summarize current knowledge on how such direct CD8(+) T cell-neuron interactions may impact neuronal excitability, plasticity, and integrity on a single cell and network level and provide an overview on methods to further corroborate the in vivo relevance of these mechanisms mainly obtained from in vitro studies. PMID- 26236281 TI - Editorial: Natriuretic Hormones. PMID- 26236282 TI - Age-Associated Weight Gain, Leptin, and SIRT1: A Possible Role for Hypothalamic SIRT1 in the Prevention of Weight Gain and Aging through Modulation of Leptin Sensitivity. AB - The hypothalamus is the principal regulator of body weight and energy balance. It modulates both energy intake and energy expenditure by sensing the energy status of the body through neural inputs from the periphery as well as direct humoral inputs. Leptin, an adipokine, is one of the humoral factors responsible for alerting the hypothalamus that enough energy is stored in the periphery. Plasma leptin levels are positively linked to adiposity; leptin suppress energy intake and stimulates energy expenditure. However, prolonged increases in plasma leptin levels due to obesity cause leptin resistance, affecting both leptin access to hypothalamic neurons and leptin signal transduction within hypothalamic neurons. Decreased sensing of peripheral energy status through leptin may lead to a positive energy balance and gradual gains in weight and adiposity, further worsening leptin resistance. Leptin resistance, increased adiposity, and weight gain are all associated with aging in both humans and animals. Central insulin resistance is associated with similar observations. Therefore, improving the action of humoral factors in the hypothalamus may prevent gradual weight gain, especially during middle age. SIRT1 is a NAD(+)-dependent protein deacetylase with numerous substrates, including histones, transcription factors, co-factors, and various enzymes. SIRT1 improves both leptin sensitivity and insulin sensitivity by decreasing the levels of several molecules that impair leptin and insulin signal transduction. SIRT1 and NAD(+) levels decrease with age in the hypothalamus; increased hypothalamic SIRT1 levels prevent age-associated weight gain and improve leptin sensitivity in mice. Therefore, preventing the age dependent loss of SIRT1 function in the hypothalamus could improve the action of humoral factors in the hypothalamus as well as central regulation of energy balance. PMID- 26236283 TI - Role of the Extracellular and Intracellular Loops of Follicle-Stimulating Hormone Receptor in Its Function. AB - Follicle-stimulating hormone receptor (FSHR) is a leucine-rich repeat containing class A G-protein coupled receptor belonging to the subfamily of glycoprotein hormone receptors (GPHRs), which includes luteinizing hormone/choriogonadotropin receptor (LH/CGR) and thyroid-stimulating hormone receptor. Its cognate ligand, follicle-stimulating hormone binds to, and activates FSHR expressed on the surface of granulosa cells of the ovary, in females, and Sertoli cells of the testis, in males, to bring about folliculogenesis and spermatogenesis, respectively. FSHR contains a large extracellular domain (ECD) consisting of leucine-rich repeats at the N-terminal end and a hinge region at the C-terminus that connects the ECD to the membrane spanning transmembrane domain (TMD). The TMD consists of seven alpha-helices that are connected to each other by means of three extracellular loops (ELs) and three intracellular loops (ILs) and ends in a short-cytoplasmic tail. It is well established that the ECD is the primary hormone binding domain, whereas the TMD is the signal transducing domain. However, several studies on the ELs and ILs employing site directed mutagenesis, generation of chimeric receptors and in vitro characterization of naturally occurring mutations have proven their indispensable role in FSHR function. Their role in every phase of the life cycle of the receptor like post translational modifications, cell surface trafficking, hormone binding, activation of downstream signaling, receptor phosphorylation, hormone-receptor internalization, and recycling of hormone-receptor complex have been documented. Mutations in the loops causing dysregulation of these processes lead to pathophysiological conditions. In other GPHRs as well, the loops have been convincingly shown to contribute to various aspects of receptor function. This review article attempts to summarize the extensive contributions of FSHR loops and C-terminal tail to its function. PMID- 26236284 TI - Metatranscriptome analysis reveals host-microbiome interactions in traps of carnivorous Genlisea species. AB - In the carnivorous plant genus Genlisea a unique lobster pot trapping mechanism supplements nutrition in nutrient-poor habitats. A wide spectrum of microbes frequently occurs in Genlisea's leaf-derived traps without clear relevance for Genlisea carnivory. We sequenced the metatranscriptomes of subterrestrial traps vs. the aerial chlorophyll-containing leaves of G. nigrocaulis and of G. hispidula. Ribosomal RNA assignment revealed soil-borne microbial diversity in Genlisea traps, with 92 genera of 19 phyla present in more than one sample. Microbes from 16 of these phyla including proteobacteria, green algae, amoebozoa, fungi, ciliates and metazoans, contributed additionally short-lived mRNA to the metatranscriptome. Furthermore, transcripts of 438 members of hydrolases (e.g., proteases, phosphatases, lipases), mainly resembling those of metazoans, ciliates and green algae, were found. Compared to aerial leaves, Genlisea traps displayed a transcriptional up-regulation of endogenous NADH oxidases generating reactive oxygen species as well as of acid phosphatases for prey digestion. A leaf-vs. trap transcriptome comparison reflects that carnivory provides inorganic P- and different forms of N-compounds (ammonium, nitrate, amino acid, oligopeptides) and implies the need to protect trap cells against oxidative stress. The analysis elucidates a complex food web inside the Genlisea traps, and suggests ecological relationships between this plant genus and its entrapped microbiome. PMID- 26236285 TI - Mechanistic lessons learned from studies of planktonic bacteria with metallic nanomaterials: implications for interactions between nanomaterials and biofilm bacteria. AB - Metal and metal-oxide nanoparticles (NPs) are used in numerous applications and have high likelihood of entering engineered and natural environmental systems. Careful assessment of the interaction of these NPs with bacteria, particularly biofilm bacteria, is necessary. This perspective discusses mechanisms of NP interaction with bacteria and identifies challenges in understanding NP-biofilm interaction, considering fundamental material attributes and inherent complexities of biofilm structure. The current literature is reviewed, both for planktonic bacteria and biofilms; future challenges and complexities are identified, both in light of the literature and a dataset on the toxicity of silver NPs toward planktonic and biofilm bacteria. This perspective aims to highlight the complexities in such studies and emphasizes the need for systematic evaluation of NP-biofilm interaction. PMID- 26236286 TI - Cross-cultural science: ten lessons. AB - Concerns of infectious disease outbreaks have recently reached the forefront of global security issues and resulted in new engagements among foreign science advisors, host country scientists, and officials. There are lessons to be learned from the numerous organizations working in global regions of endemic disease who are building capacity to survey pathogens and prevent and contain epidemics. Working with foreign scientists, health professionals, and administrators can be challenging; building partnerships based on respect and mutual trust is key to achieve effective change. Engendering ownership, working toward mutual success, paying close attention to cultural norms and the local regulatory climate, close collaboration with other stakeholders, and imaginative problem solving all contribute to mission success. PMID- 26236288 TI - Recreational drug use among individuals living with HIV in Europe: review of the prevalence, comparison with the general population and HIV guidelines recommendations. AB - BACKGROUND: Adherence problems, interactions and higher rate of risk activities have been observed in HIV individuals using recreational drugs. Our aim was to describe recreational drug use in both HIV individuals and general population in Europe, and to assess at what extent HIV guidelines address this issue. METHODS: Data on recreational drug use across Europe were obtained from the European Monitoring Centre for Drugs and Drug Addiction for the general population, and through Pubmed search. for HIV patients. We assessed the incorporation of recreational drug issues in HIV treatment guidelines for the following topics: (a) recreational drugs; (b) adherence to antiretrovirals; (c) interactions; (d) transmission risk. Guidelines included: World Health Organization; European Aids Clinical Society; U.S. Department of Health and Human Services; International Antiviral Society-USA; and seven European national guidelines. RESULTS: 29 countries reported recreational drug use in general population. The highest prevalences were observed for Cannabis (i.e., 8-10% in Spain, France, and Czech Republic) followed by cocaine, amphetamines and ecstasy. The 13 studies selected in the systematic review showed a great variability in recreational drug use on the HIV population. Apart from classical recreational drugs, we found a relevant use of new drugs including sexual experience enhancers. Polydrug consumption was about 50% in some studies. Most guidelines included general information about recreational drugs, showing great variability on the inclusion of the evaluated topics. We found more specific, evidence-based recommendations on interactions, followed by medication adherence and transmission risk. CONCLUSIONS: Available data on the people living with HIV suggest a higher use of recreational drugs than in the general population, which is already relevant. However, recreational drug issues should be included or addressed more thoroughly in most guidelines. PMID- 26236287 TI - Probiotic-based strategies for therapeutic and prophylactic use against multiple gastrointestinal diseases. AB - Probiotic bacteria offer a number of potential health benefits when administered in sufficient amounts that in part include reducing the number of harmful organisms in the intestine, producing antimicrobial substances and stimulating the body's immune response. However, precisely elucidating the probiotic effect of a specific bacterium has been challenging due to the complexity of the gut's microbial ecosystem and a lack of definitive means for its characterization. This review provides an overview of widely used and recently described probiotics, their impact on the human's gut microflora as a preventative treatment of disease, human/animal models being used to help show efficacy, and discusses the potential use of probiotics in gastrointestinal diseases associated with antibiotic administration. PMID- 26236289 TI - The effect of carbon subsidies on marine planktonic niche partitioning and recruitment during biofilm assembly. AB - The influence of resource availability on planktonic and biofilm microbial community membership is poorly understood. Heterotrophic bacteria derive some to all of their organic carbon (C) from photoautotrophs while simultaneously competing with photoautotrophs for inorganic nutrients such as phosphorus (P) or nitrogen (N). Therefore, C inputs have the potential to shift the competitive balance of aquatic microbial communities by increasing the resource space available to heterotrophs (more C) while decreasing the resource space available to photoautotrophs (less mineral nutrients due to increased competition from heterotrophs). To test how resource dynamics affect membership of planktonic communities and assembly of biofilm communities we amended a series of flow through mesocosms with C to alter the availability of C among treatments. Each mesocosm was fed with unfiltered seawater and incubated with sterilized microscope slides as surfaces for biofilm formation. The highest C treatment had the highest planktonic heterotroph abundance, lowest planktonic photoautotroph abundance, and highest biofilm biomass. We surveyed bacterial 16S rRNA genes and plastid 23S rRNA genes to characterize biofilm and planktonic community membership and structure. Regardless of resource additions, biofilm communities had higher alpha diversity than planktonic communities in all mesocosms. Heterotrophic plankton communities were distinct from heterotrophic biofilm communities in all but the highest C treatment where heterotrophic plankton and biofilm communities resembled each other after 17 days. Unlike the heterotrophs, photoautotrophic plankton communities were different than photoautotrophic biofilm communities in composition in all treatments including the highest C treatment. Our results suggest that although resource amendments affect community membership and structure, microbial lifestyle (biofilm vs. planktonic) has a stronger influence on community composition. PMID- 26236290 TI - Food-bacteria interplay: pathometabolism of emetic Bacillus cereus. AB - Bacillus cereus is a Gram-positive endospore forming bacterium known for its wide spectrum of phenotypic traits, enabling it to occupy diverse ecological niches. Although the population structure of B. cereus is highly dynamic and rather panmictic, production of the emetic B. cereus toxin cereulide is restricted to strains with specific genotypic traits, associated with distinct environmental habitats. Cereulide is an ionophoric dodecadepsipeptide that is produced non ribosomally by an enzyme complex with an unusual modular structure, named cereulide synthetase (Ces non-ribosomal peptide synthetase). The ces gene locus is encoded on a mega virulence plasmid related to the B. anthracis toxin plasmid pXO1. Cereulide, a highly thermo- and pH- resistant molecule, is preformed in food, evokes vomiting a few hours after ingestion, and was shown to be the direct cause of gastroenteritis symptoms; occasionally it is implicated in severe clinical manifestations including acute liver failures. Control of toxin gene expression in emetic B. cereus involves central transcriptional regulators, such as CodY and AbrB, thereby inextricably linking toxin gene expression to life cycle phases and specific conditions, such as the nutrient supply encountered in food matrices. While in recent years considerable progress has been made in the molecular and biochemical characterization of cereulide toxin synthesis, far less is known about the embedment of toxin synthesis in the life cycle of B. cereus. Information about signals acting on toxin production in the food environment is lacking. We summarize the data available on the complex regulatory network controlling cereulide toxin synthesis, discuss the role of intrinsic and extrinsic factors acting on toxin biosynthesis in emetic B. cereus and stress how unraveling these processes can lead to the development of novel effective strategies to prevent toxin synthesis in the food production and processing chain. PMID- 26236292 TI - The impact of absorbed photons on antimicrobial photodynamic efficacy. AB - Due to increasing resistance of pathogens toward standard antimicrobial procedures, alternative approaches that are capable of inactivating pathogens are necessary in support of regular modalities. In this instance, the photodynamic inactivation of bacteria (PIB) may be a promising alternative. For clinical application of PIB it is essential to ensure appropriate comparison of given photosensitizer (PS)-light source systems, which is complicated by distinct absorption and emission characteristics of given PS and their corresponding light sources, respectively. Consequently, in the present study two strategies for adjustment of irradiation parameters were evaluated: (i) matching energy doses applied by respective light sources (common practice) and (ii) by development and application of a formula for adjusting the numbers of photons absorbed by PS upon irradiation by their corresponding light sources. Since according to the photodynamic principle one PS molecule is excited by the absorption of one photon, this formula allows comparison of photodynamic efficacy of distinct PS per excited molecule. In light of this, the antimicrobial photodynamic efficacy of recently developed PS SAPYR was compared to that of clinical standard PS Methylene Blue (MB) regarding inactivation of monospecies biofilms formed by Enterococcus faecalis and Actinomyces naeslundii whereby evaluating both adjustment strategies. PIB with SAPYR exhibited CFU-reductions of 5.1 log10 and 6.5 log10 against E. faecalis and A. naeslundii, respectively, which is declared as a disinfectant efficacy. In contrast, the effect of PIB with MB was smaller when the applied energy dose was adjusted compared to SAPYR (CFU-reductions of 3.4 log10 and 4.2 log10 against E. faecalis and A. naeslundii), or there was even no effect at all when the number of absorbed photons was adjusted compared to SAPYR. Since adjusting the numbers of absorbed photons is the more precise and adequate method from a photophysical point of view, this strategy should be considered in further studies when antimicrobial efficacy rates of distinct PS light source systems are compared. PMID- 26236291 TI - Pathogens protection against the action of disinfectants in multispecies biofilms. AB - Biofilms constitute the prevalent way of life for microorganisms in both natural and man-made environments. Biofilm-dwelling cells display greater tolerance to antimicrobial agents than those that are free-living, and the mechanisms by which this occurs have been investigated extensively using single-strain axenic models. However, there is growing evidence that interspecies interactions may profoundly alter the response of the community to such toxic exposure. In this paper, we propose an overview of the studies dealing with multispecies biofilms resistance to biocides, with particular reference to the protection of pathogenic species by resident surface flora when subjected to disinfectants treatments. The mechanisms involved in such protection include interspecies signaling, interference between biocides molecules and public goods in the matrix, or the physiology and genetic plasticity associated with a structural spatial arrangement. After describing these different mechanisms, we will discuss the experimental methods available for their analysis in the context of complex multispecies biofilms. PMID- 26236293 TI - Comparative secretomics reveals novel virulence-associated factors of Vibrio parahaemolyticus. AB - Vibrio parahaemolyticus is a causative agent of serious human seafood-borne gastroenteritis disease and even death. In this study, for the first time, we obtained the secretomic profiles of seven V. parahaemolyticus strains of clinical and food origins. The strains exhibited various toxic genotypes and phenotypes of antimicrobial susceptibility and heavy metal resistance, five of which were isolated from aquatic products in Shanghai, China. Fourteen common extracellular proteins were identified from the distinct secretomic profiles using the two dimensional gel electrophoresis (2-DE) and liquid chromatography tandem mass spectrometry (LC-MS/MS) techniques. Of these, half were involved in protein synthesis and sugar transport of V. parahaemolyticus. Strikingly, six identified proteins were virulence-associated factors involved in the pathogenicity of some other pathogenic bacteria, including the translation elongation factor EF-Tu, pyridoxine 5'-phosphate synthase, sigma(54) modulation protein, dihydrolipoyl dehydrogenase, transaldolase and phosphoglycerate kinase. In addition, comparative secretomics also revealed several extracellular proteins that have not been described in any bacteria, such as the ribosome-recycling factor, translation elongation factor EF-Ts, phosphocarrier protein HPr and maltose binding protein MalE. The results in this study will facilitate the better understanding of the pathogenesis of V. parahaemolyticus and provide data in support of novel vaccine candidates against the leading seafood-borne pathogen worldwide. PMID- 26236294 TI - Highly diverse recombining populations of Vibrio cholerae and Vibrio parahaemolyticus in French Mediterranean coastal lagoons. AB - Vibrio parahaemolyticus and Vibrio cholerae are ubiquitous to estuarine and marine environments. These two species found in Mediterranean coastal systems can induce infections in humans. Environmental isolates of V. cholerae (n = 109) and V. parahaemolyticus (n = 89) sampled at different dates, stations and water salinities were investigated for virulence genes and by a multilocus sequence based analysis (MLSA). V. cholerae isolates were all ctxA negative and only one isolate of V. parahaemolyticus displayed trh2 gene. Most Sequence Types (ST) corresponded to unique ST isolated at one date or one station. Frequent recombination events were detected among different pathogenic species, V. parahaemolyticus, V. cholerae, Vibrio mimicus, and Vibrio metoecus. Recombination had a major impact on the diversification of lineages. The genetic diversity assessed by the number of ST/strain was higher in low salinity condition for V. parahaemolyticus and V. cholerae whereas the frequency of recombination events in V. cholerae was lower in low salinity condition. Mediterranean coastal lagoon systems housed V. cholerae and V. parahaemolyticus with genetic diversities equivalent to the worldwide diversity described so far. The presence of STs found in human infections as well as the frequency of recombination events in environmental vibrios populations could predict a potential epidemiological risk. PMID- 26236295 TI - Commentary: The absence of protein Y4yS affects negatively the abundance of T3SS Mesorhizobium loti secretin, RhcC2, in bacterial membranes. PMID- 26236296 TI - Ultra high pressure homogenization (UHPH) inactivation of Bacillus amyloliquefaciens spores in phosphate buffered saline (PBS) and milk. AB - Ultra high pressure homogenization (UHPH) opens up new areas for dynamic high pressure assisted thermal sterilization of liquids. Bacillus amyloliquefaciens spores are resistant to high isostatic pressure and temperature and were suggested as potential surrogate for high pressure thermal sterilization validation. B. amyloliquefaciens spores suspended in PBS buffer (0.01 M, pH 7.0), low fat milk (1.5%, pH 6.7), and whole milk (3.5%, pH 6.7) at initial concentration of ~10(6) CFU/mL were subjected to UHPH treatments at 200, 300, and 350 MPa with an inlet temperature at ~80 degrees C. Thermal inactivation kinetics of B. amyloliquefaciens spores in PBS and milk were assessed with thin wall glass capillaries and modeled using first-order and Weibull models. The residence time during UHPH treatments was estimated to determine the contribution of temperature to spore inactivation by UHPH. No sublethal injury was detected after UHPH treatments using sodium chloride as selective component in the nutrient agar medium. The inactivation profiles of spores in PBS buffer and milk were compared and fat provided no clear protective effect for spores against treatments. Treatment at 200 MPa with valve temperatures lower than 125 degrees C caused no reduction of spores. A reduction of 3.5 log10CFU/mL of B. amyloliquefaciens spores was achieved by treatment at 350 MPa with a valve temperature higher than 150 degrees C. The modeled thermal inactivation and observed inactivation during UHPH treatments suggest that temperature could be the main lethal effect driving inactivation. PMID- 26236297 TI - The requirements for rumen-degradable protein per unit of fermentable organic matter differ between fibrous feed sources. AB - Ruminant feed evaluation systems use constant minimum requirements of rumen degradable protein (RDP) and often relate this to apparently degradable organic matter (OM). However, studies with tropical forages indicate that RDP: apparently degraded OM might not be constant across high-fiber diets. This was tested with semi-continuous ruminal cultures (Rusitec) using dried contrasting low-protein fiber sources: brachiaria hay (high in fiber, medium lignified), apple pomace (medium in fiber, highly lignified), and sugar beet pulp (medium in fiber and lignification). Each feed was incubated at 14 g dry matter day(-1) with 0, 0.85, 1.7, 3.4, 6.8, 13.6, or 27.2 mg g(-1) urea. The amount of urea needed to reach a similar basal concentration of ammonia in the incubation fluid was tested for each feed in advance. Apparent fiber and OM degradability were determined after 48 h of incubation. Data was evaluated by regressions and analysis of variance. The response curve of incubation fluid ammonia to urea supplementation was similar in slope in all feeds. Plateaus in apparent OM degradability in relation to ammonia concentration were determined. The ammonia concentration where apparent OM and fiber degradability reached 95% of maximum was approached in the order of pomace < pulp < hay. With regard to fiber degradability, a plateau was reached at >= 80 g kg(-1) crude protein only with hay and pomace, whilst a linear relationship existed between RDP and OM degradation for pulp. In hay the ratio RDP: OM degraded was equal to 1.6 but was only 1.0 in the other feeds. There was no obvious lack of branched short-chain fatty acids at low RDP. Thus, the hypothesis was confirmed but the demand for RDP seems even higher in tropical forage compared to food industrial byproducts. The efficiency of urea to promote apparent OM and fiber degradation was also variable. Thus, it seems that minimum thresholds of either RDP or ruminal ammonia concentration may not be reflected appropriately by constants. PMID- 26236298 TI - H2O2 production rate in Lactobacillus johnsonii is modulated via the interplay of a heterodimeric flavin oxidoreductase with a soluble 28 Kd PAS domain containing protein. AB - Host and commensals crosstalk, mediated by reactive oxygen species (ROS), has triggered a growing scientific interest to understand the mechanisms governing such interaction. However, the majority of the scientific studies published do not evaluate the ROS production by commensals bacteria. In this context we recently showed that Lactobacillus johnsonii N6.2, a strain of probiotic value, modulates the activity of the critical enzymes 2,3-indoleamine dioxygenase via H2O2 production. L. johnsonii N6.2 by decreasing IDO activity, is able to modify the tryptophan/kynurenine ratio in the host blood with further systemic consequences. Understanding the mechanisms of H2O2 production is critical to predict the probiotic value of these strains and to optimize bacterial biomass production in industrial processes. We performed a transcriptome analysis to identify genes differentially expressed in L. johnsonii N6.2 cells collected from cultures grown under different aeration conditions. Herein we described the biochemical characteristics of a heterodimeric FMN reductase (FRedA/B) whose in vitro activity is controlled by LjPAS protein with a typical Per-Arnst-Sim (PAS) sensor domain. Interestingly, LjPAS is fused to the FMN reductase domains in other lactobacillaceae. In L. johnsonii, LjPAS is encoded by an independent gene which expression is repressed under anaerobic conditions (>3 fold). Purified LjPAS was able to slow down the FRedA/B initial activity rate when the holoenzyme precursors (FredA, FredB, and FMN) were mixed in vitro. Altogether the results obtained suggest that LjPAS module regulates the H2O2 production helping the cells to minimize oxidative stress in response to environmental conditions. PMID- 26236299 TI - Power limits for microbial life. AB - To better understand the origin, evolution, and extent of life, we seek to determine the minimum flux of energy needed for organisms to remain viable. Despite the difficulties associated with direct measurement of the power limits for life, it is possible to use existing data and models to constrain the minimum flux of energy required to sustain microorganisms. Here, a we apply a bioenergetic model to a well characterized marine sedimentary environment in order to quantify the amount of power organisms use in an ultralow-energy setting. In particular, we show a direct link between power consumption in this environment and the amount of biomass (cells cm(-3)) found in it. The power supply resulting from the aerobic degradation of particular organic carbon (POC) at IODP Site U1370 in the South Pacific Gyre is between ~10(-12) and 10(-16) W cm(-3). The rates of POC degradation are calculated using a continuum model while Gibbs energies have been computed using geochemical data describing the sediment as a function of depth. Although laboratory-determined values of maintenance power do a poor job of representing the amount of biomass in U1370 sediments, the number of cells per cm(-3) can be well-captured using a maintenance power, 190 zW cell(-1), two orders of magnitude lower than the lowest value reported in the literature. In addition, we have combined cell counts and calculated power supplies to determine that, on average, the microorganisms at Site U1370 require 50-3500 zW cell(-1), with most values under ~300 zW cell(-1). Furthermore, we carried out an analysis of the absolute minimum power requirement for a single cell to remain viable to be on the order of 1 zW cell(-1). PMID- 26236300 TI - Marinobacter subterrani, a genetically tractable neutrophilic Fe(II)-oxidizing strain isolated from the Soudan Iron Mine. AB - We report the isolation, characterization, and development of a robust genetic system for a halophilic, Fe(II)-oxidizing bacterium isolated from a vertical borehole originating 714 m below the surface located in the Soudan Iron Mine in northern Minnesota, USA. Sequence analysis of the 16S rRNA gene places the isolate in the genus Marinobacter of the Gammaproteobacteria. The genome of the isolate was sequenced using a combination of short- and long-read technologies resulting in two contigs representing a 4.4 Mbp genome. Using genomic information, we used a suicide vector for targeted deletion of specific flagellin genes, resulting in a motility-deficient mutant. The motility mutant was successfully complemented by expression of the deleted genes in trans. Random mutagenesis using a transposon was also achieved. Capable of heterotrophic growth, this isolate represents a microaerophilic Fe(II)-oxidizing species for which a system for both directed and random mutagenesis has been established. Analysis of 16S rDNA suggests Marinobacter represents a major taxon in the mine, and genetic interrogation of this genus may offer insight into the structure of deep subsurface communities as well as an additional tool for analyzing nutrient and element cycling in the subsurface ecosystem. PMID- 26236301 TI - Plant hairy root cultures as plasmodium modulators of the slime mold emergent computing substrate Physarum polycephalum. AB - Roots of the medicinal plant Valeriana officinalis are well-studied for their various biological activities. We applied genetically transformed V. officinalis root biomass to exert control of Physarum polycephalum, an amoeba-based emergent computing substrate. The plasmodial stage of the P. polycephalum life cycle constitutes a single, multinucleate cell visible by unaided eye. The plasmodium modifies its network of oscillating protoplasm in response to spatial configurations of attractants and repellents, a behavior that is interpreted as biological computation. To program the computing behavior of P. polycephalum, a diverse and sustainable library of plasmodium modulators is required. Hairy roots produced by genetic transformation with Agrobacterium rhizogenes are a metabolically stable source of bioactive compounds. Adventitious roots were induced on in vitro V. officinalis plants following infection with A. rhizogenes. A single hairy root clone was selected for massive propagation and the biomass was characterized in P. polycephalum chemotaxis, maze-solving, and electrical activity assays. The Agrobacterium-derived roots of V. officinalis elicited a positive chemotactic response and augmented maze-solving behavior. In a simple plasmodium circuit, introduction of hairy root biomass stimulated the oscillation patterns of slime mold's surface electrical activity. We propose that manipulation of P. polycephalum with the plant root culture platform can be applied to the development of slime mold microfluidic devices as well as future models for engineering the plant rhizosphere. PMID- 26236302 TI - In vitro interaction of Stenotrophomonas maltophilia with human monocyte-derived dendritic cells. AB - Stenotrophomonas maltophilia is increasingly identified as an opportunistic pathogen in immunocompromised, cancer and cystic fibrosis (CF) patients. Knowledge on innate immune responses to S. maltophilia and its potential modulation is poor. The present work investigated the ability of 12 clinical S. maltophilia strains (five from CF patients, seven from non-CF patients) and one environmental strain to survive inside human monocyte-derived dendritic cells (DCs). The effects of the bacteria on maturation of and cytokine secretion by DCs were also measured. S. maltophilia strains presented a high degree of heterogeneity in internalization and intracellular replication efficiencies as well as in the ability of S. maltophilia to interfere with normal DCs maturation. By contrast, all S. maltophilia strains were able to activate DCs, as measured by increase in the expression of surface maturation markers and proinflammatory cytokines secretion. PMID- 26236304 TI - Commentary: Toward a new focus in antibiotic and drug discovery from the Streptomyces arsenal. PMID- 26236303 TI - The origin, source, and cycling of methane in deep crystalline rock biosphere. AB - The emerging interest in using stable bedrock formations for industrial purposes, e.g., nuclear waste disposal, has increased the need for understanding microbiological and geochemical processes in deep crystalline rock environments, including the carbon cycle. Considering the origin and evolution of life on Earth, these environments may also serve as windows to the past. Various geological, chemical, and biological processes can influence the deep carbon cycle. Conditions of CH4 formation, available substrates and time scales can be drastically different from surface environments. This paper reviews the origin, source, and cycling of methane in deep terrestrial crystalline bedrock with an emphasis on microbiology. In addition to potential formation pathways of CH4, microbial consumption of CH4 is also discussed. Recent studies on the origin of CH4 in continental bedrock environments have shown that the traditional separation of biotic and abiotic CH4 by the isotopic composition can be misleading in substrate-limited environments, such as the deep crystalline bedrock. Despite of similarities between Precambrian continental sites in Fennoscandia, South Africa and North America, where deep methane cycling has been studied, common physicochemical properties which could explain the variation in the amount of CH4 and presence or absence of CH4 cycling microbes were not found. However, based on their preferred carbon metabolism, methanogenic microbes appeared to have similar spatial distribution among the different sites. PMID- 26236305 TI - A flexible and economical barcoding approach for highly multiplexed amplicon sequencing of diverse target genes. AB - High throughput sequencing of phylogenetic and functional gene amplicons provides tremendous insight into the structure and functional potential of complex microbial communities. Here, we introduce a highly adaptable and economical PCR approach to barcoding and pooling libraries of numerous target genes. In this approach, we replace gene- and sequencing platform-specific fusion primers with general, interchangeable barcoding primers, enabling nearly limitless customized barcode-primer combinations. Compared to barcoding with long fusion primers, our multiple-target gene approach is more economical because it overall requires lower number of primers and is based on short primers with generally lower synthesis and purification costs. To highlight our approach, we pooled over 900 different small-subunit rRNA and functional gene amplicon libraries obtained from various environmental or host-associated microbial community samples into a single, paired-end Illumina MiSeq run. Although the amplicon regions ranged in size from approximately 290 to 720 bp, we found no significant systematic sequencing bias related to amplicon length or gene target. Our results indicate that this flexible multiplexing approach produces large, diverse, and high quality sets of amplicon sequence data for modern studies in microbial ecology. PMID- 26236306 TI - Eradication of high viable loads of Listeria monocytogenes contaminating food contact surfaces. AB - This study demonstrates the efficacy of cold gaseous ozone treatments at low concentrations in the eradication of high Listeria monocytogenes viable cell loads from glass, polypropylene, stainless steel, and expanded polystyrene food contact surfaces. Using a step by step approach, involving the selection of the most resistant strain-surface combinations, 11 Listeria sp. strains resulted inactivated by a continuous ozone flow at 1.07 mg m(-3) after 24 or 48 h of cold incubation, depending on both strain and surface evaluated. Increasing the inoculum level to 9 log CFU coupon(-1), the best inactivation rate was obtained after 48 h of treatment at 3.21 mg m(-3) ozone concentration when cells were deposited onto stainless steel and expanded polystyrene coupons, resulted the most resistant food-contact surfaces in the previous assays. The addition of naturally contaminated meat extract to a high load of L. monocytogenes LMG 23775 cells, the most resistant strain out of the 11 assayed Listeria sp. strains, led to its complete inactivation after 4 days of treatment. To the best of our knowledge, this is the first report describing the survival of L. monocytogenes and the effect of ozone treatment under cold storage conditions on expanded polystyrene, a commonly used material in food packaging. The results of this study could be useful for reducing pathogen cross-contamination phenomena during cold food storage. PMID- 26236307 TI - Characterization of pH dependent Mn(II) oxidation strategies and formation of a bixbyite-like phase by Mesorhizobium australicum T-G1. AB - Despite the ubiquity of Mn oxides in natural environments, there are only a few observations of biological Mn(II) oxidation at pH < 6. The lack of low pH Mn oxidizing bacteria (MOB) isolates limits our understanding of how pH influences biological Mn(II) oxidation in extreme environments. Here, we report that a novel MOB isolate, Mesorhizobium australicum strain T-G1, isolated from an acidic and metalliferous uranium mining area, can oxidize Mn(II) at both acidic and neutral pH using different enzymatic pathways. X-ray diffraction, Raman spectroscopy, and scanning electron microscopy with energy dispersive X-ray spectroscopy revealed that T-G1 initiated bixbyite-like Mn oxide formation at pH 5.5 which coincided with multi-copper oxidase expression from early exponential phase to late stationary phase. In contrast, reactive oxygen species (ROS), particularly superoxide, appeared to be more important for T-G1 mediated Mn(II) oxidation at neutral pH. ROS was produced in parallel with the occurrence of Mn(II) oxidation at pH 7.2 from early stationary phase. Solid phase Mn oxides did not precipitate, which is consistent with the presence of a high amount of H2O2 and lower activity of catalase in the liquid culture at pH 7.2. Our results show that M. australicum T-G1, an acid tolerant MOB, can initiate Mn(II) oxidation by varying its oxidation mechanisms depending on the pH and may play an important role in low pH manganese biogeochemical cycling. PMID- 26236308 TI - NagC represses N-acetyl-glucosamine utilization genes in Vibrio fischeri within the light organ of Euprymna scolopes. AB - Bacteria often use transcription factors to regulate the expression of metabolic genes in accordance to available nutrients. NagC is a repressor conserved among gamma-proteobacteria that regulates expression of enzymes involved in the metabolism of N-acetyl-glucosamine (GlcNAc). The polymeric form of GlcNAc, known as chitin, has been shown to play roles in chemotactic signaling and nutrition within the light organ symbiosis established between the marine bacterium Vibrio fischeri and the Hawaiian squid Euprymna scolopes. Here, we investigate the impact of NagC regulation on the physiology of V. fischeri. We find that NagC repression contributes to the fitness of V. fischeri in the absence of GlcNAc. In addition, the inability to de-repress expression of NagC-regulated genes reduces the fitness of V. fischeri in the presence of GlcNAc. We find that chemotaxis toward GlcNAc or chitobiose, a dimeric form of GlcNAc, is independent of NagC regulation. Finally, we show that NagC represses gene expression during the early stages of symbiosis. Our data suggest that the ability to regulate gene expression with NagC contributes to the overall fitness of V. fischeri in environments that vary in levels of GlcNAc. Furthermore, our finding that NagC represses gene expression within the squid light organ during an early stage of symbiosis supports the notion that the ability of the squid to provide a source of GlcNAc emerges later in host development. PMID- 26236309 TI - Commentary: "There's been a Flaw in Our Thinking". PMID- 26236310 TI - The Thymic Orchestration Involving Aire, miRNAs, and Cell-Cell Interactions during the Induction of Central Tolerance. AB - Developing thymocytes interact sequentially with two distinct structures within the thymus: the cortex and medulla. Surviving single-positive and double-positive thymocytes from the cortex migrate into the medulla, where they interact with medullary thymic epithelial cells (mTECs). These cells ectopically express a vast set of peripheral tissue antigens (PTAs), a property termed promiscuous gene expression that is associated with the presentation of PTAs by mTECs to thymocytes. Thymocyte clones that have a high affinity for PTAs are eliminated by apoptosis in a process termed negative selection, which is essential for tolerance induction. The Aire gene is an important factor that controls the expression of a large set of PTAs. In addition to PTAs, Aire also controls the expression of miRNAs in mTECs. These miRNAs are important in the organization of the thymic architecture and act as posttranscriptional controllers of PTAs. Herein, we discuss recent discoveries and highlight open questions regarding the migration and interaction of developing thymocytes with thymic stroma, the ectopic expression of PTAs by mTECs, the association between Aire and miRNAs and its effects on central tolerance. PMID- 26236312 TI - Imaging of NKT Cell Recirculation and Tissue Migration during Antimicrobial Immunity. PMID- 26236311 TI - Mucosal Immunity and B Cells in Teleosts: Effect of Vaccination and Stress. AB - Fish are subjected to several insults from the environment, which may endanger animal survival. Mucosal surfaces are the first line of defense against these threats, acting as a physical barrier to protect the animal but also functioning as an active immune tissue. Thus, four mucosal-associated lymphoid tissues (MALTs), which lead the immune responses in gut, skin, gills, and nose, have been described in fish. Humoral and cellular immunity, as well as their regulation and the factors that influence the response in these mucosal lymphoid tissues, are still not well known in most fish species. Mucosal B-lymphocytes and immunoglobulins (Igs) are key players in the immune response that takes place in those MALTs. The existence of IgT as a mucosal specialized Ig gives us the opportunity of measuring specific responses after infection or vaccination, a fact that was not possible until recently in most fish species. The vaccination process is influenced by several factors, being stress one of the main stimuli determining the success of the vaccine. Thus, one of the major goals in a vaccination process is to avoid possible situations of stress, which might interfere with fish immune performance. However, interaction between immune and neuroendocrine systems at mucosal tissues is still unknown. In this review, we will summarize the latest findings about B-lymphocytes and Igs in mucosal immunity and the effect of stress and vaccination on B-cell response at mucosal sites. It is important to point out that a limited number of studies have been published regarding stress in mucosa and very few about the influence of stress over mucosal B-lymphocytes. PMID- 26236314 TI - Editorial: Structural and Computational Glycobiology - Immunity and Infection. PMID- 26236313 TI - Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities. AB - Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and cell survival via activating NF-kappaB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of psychedelics, such as serotonin and sigma-1 receptors, have also been shown to play crucial roles in numerous immunological processes. This emerging field also offers promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the scarcity of available review literature renders the topic unclear and obscure, mostly posing psychedelics as illicit drugs of abuse and not as physiologically relevant molecules or as possible agents of future pharmacotherapies. In this paper, the immunomodulatory potential of classical serotonergic psychedelics, including N,N dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-iodoamphetamine, and 3,4-methylenedioxy methamphetamine will be discussed from a perspective of molecular immunology and pharmacology. Special attention will be given to the functional interaction of serotonin and sigma-1 receptors and their cross-talk with toll-like and RIG-I like pattern-recognition receptor-mediated signaling. Furthermore, novel approaches will be suggested feasible for the treatment of diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer's disease. PMID- 26236317 TI - Respiratory processes in non-photosynthetic plastids. AB - Chlororespiration is a respiratory process located in chloroplast thylakoids which consists in an electron transport chain from NAD(P)H to oxygen. This respiratory chain involves the NAD(P)H dehydrogenase complex, the plastoquinone pool and the plastid terminal oxidase (PTOX), and it probably acts as a safety valve to prevent the over-reduction of the photosynthetic machinery in stress conditions. The existence of a similar respiratory activity in non-photosynthetic plastids has been less studied. Recently, it has been reported that tomato fruit chromoplasts present an oxygen consumption activity linked to ATP synthesis. Etioplasts and amyloplasts contain several electron carriers and some subunits of the ATP synthase, so they could harbor a similar respiratory process. This review provides an update on the study about respiratory processes in chromoplasts, identifying the major gaps that need to be addressed in future research. It also reviews the proteomic data of etioplasts and amyloplasts, which suggest the presence of a respiratory electron transport chain in these plastids. PMID- 26236315 TI - Cross-Presentation of Cell-Associated Antigens by MHC Class I in Dendritic Cell Subsets. AB - Dendritic cells (DCs) have the unique ability to pick up dead cells carrying antigens in tissue and migrate to the lymph nodes where they can cross-present cell-associated antigens by MHC class I to CD8(+) T cells. There is strong in vivo evidence that the mouse XCR1(+) DCs subset acts as a key player in this process. The intracellular processes underlying cross-presentation remain controversial and several pathways have been proposed. Indeed, a wide number of studies have addressed the cellular process of cross-presentation in vitro using a variety of sources of antigen and antigen-presenting cells. Here, we review the in vivo and in vitro evidence supporting the current mechanistic models and disscuss their physiological relevance to the cross-presentation of cell associated antigens by DCs subsets. PMID- 26236316 TI - Co-operative intermolecular kinetics of 2-oxoglutarate dependent dioxygenases may be essential for system-level regulation of plant cell physiology. AB - Can the stimulus-driven synergistic association of 2-oxoglutarate dependent dioxygenases be influenced by the kinetic parameters of binding and catalysis?In this manuscript, I posit that these indices are necessary and specific for a particular stimulus, and are key determinants of a dynamic clustering that may function to mitigate the effects of this trigger. The protein(s)/sequence(s) that comprise this group are representative of all major kingdoms of life, and catalyze a generic hydroxylation, which is, in most cases accompanied by a specialized conversion of the substrate molecule. Iron is an essential co-factor for this transformation and the response to waning levels is systemic, and mandates the simultaneous participation of molecular sensors, transporters, and signal transducers. Here, I present a proof-of-concept model, that an evolving molecular network of 2OG-dependent enzymes can maintain iron homeostasis in the cytosol of root hair cells of members of the family Gramineae by actuating a non reductive compensatory chelation by the phytosiderophores. Regression models of empirically available kinetic data (iron and alpha-ketoglutarate) were formulated, analyzed, and compared. The results, when viewed in context of the superfamily responding as a unit, suggest that members can indeed, work together to accomplish system-level function. This is achieved by the establishment of transient metabolic conduits, wherein the flux is dictated by kinetic compatibility of the participating enzymes. The approach adopted, i.e., predictive mathematical modeling, is integral to the hypothesis-driven acquisition of experimental data points and, in association with suitable visualization aids may be utilized for exploring complex plant biochemical systems. PMID- 26236318 TI - Identification of novel drought-responsive microRNAs and trans-acting siRNAs from Sorghum bicolor (L.) Moench by high-throughput sequencing analysis. AB - Small non-coding RNAs (sRNAs) namely microRNAs (miRNAs) and trans-acting small interfering RNAs (tasi-RNAs) play a crucial role in post-transcriptional regulation of gene expression and thus the control plant development and stress responses. In order to identify drought-responsive miRNAs and tasi-RNAs in sorghum, we constructed small RNA libraries from a drought tolerant (M35-1) and susceptible (C43) sorghum genotypes grown under control and drought stress conditions, and sequenced by Illumina Genome Analyzer IIx. Ninety seven conserved and 526 novel miRNAs representing 472 unique miRNA families were identified from sorghum. Ninety-six unique miRNAs were found to be regulated by drought stress, of which 32 were up- and 49 were down-regulated (fold change >= 2 or <= -2) at least in one genotype, while the remaining 15 miRNAs showed contrasting drought regulated expression pattern between genotypes. A maximum of 17 and 18 miRNAs was differentially regulated under drought stress condition in the sensitive and tolerant genotypes, respectively. These results suggest that genotype dependent stress responsive regulation of miRNAs may contribute, at least in part, to the differential drought tolerance of sorghum genotypes. We also identified two miR390-directed TAS3 gene homologs and the auxin response factors as tasi-RNA targets. We predicted more than 1300 unique target genes for the novel and conserved miRNAs. These target genes were predicted to be involved in different cellular, metabolic, response to stimulus, biological regulation, and developmental processes. Genome-wide identification of stress-responsive miRNAs, tasi-RNAs and their targets identified in this study will be useful in unraveling the molecular mechanisms underlying drought stress responses and genetic improvement of biomass production and stress tolerance in sorghum. PMID- 26236319 TI - Harnessing phytomicrobiome signaling for rhizosphere microbiome engineering. AB - The goal of microbiome engineering is to manipulate the microbiome toward a certain type of community that will optimize plant functions of interest. For instance, in crop production the goal is to reduce disease susceptibility, increase nutrient availability increase abiotic stress tolerance and increase crop yields. Various approaches can be devised to engineer the plant-microbiome, but one particularly promising approach is to take advantage of naturally evolved plant-microbiome communication channels. This is, however, very challenging as the understanding of the plant-microbiome communication is still mostly rudimentary and plant-microbiome interactions varies between crops species (and even cultivars), between individual members of the microbiome and with environmental conditions. In each individual case, many aspects of the plant microorganisms relationship should be thoroughly scrutinized. In this article we summarize some of the existing plant-microbiome engineering studies and point out potential avenues for further research. PMID- 26236320 TI - Identification of heat-responsive genes in carnation (Dianthus caryophyllus L.) by RNA-seq. AB - Carnation (Dianthus caryophyllus L.) is an important flower crop, having substantial commercial value as a cut-flower due to the long vase-life and wide array of flower colors and forms. Standard carnation varieties perform well under cool climates but are very susceptible to high temperatures which adversely affect the yield and the quality of the cut-flowers. Despite several studies of carnation contributing to the number of expressed sequence tags (ESTs), transcriptomic information of this species remains very limited, particularly regarding abiotic stress-related genes. Here, transcriptome analysis was performed to generate expression profiles of heat stress (HS)-responsive genes in carnation. We sequenced a cDNA library constructed with mixed RNA from carnation leaves subjected to 42 degrees C HS (0, 0.5, 1, and 2 h) and 46 degrees C HS (0.5, 1, and 2 h), and obtained 45,604,882 high quality paired-end reads. After de novo assembly and quantitative assessment 99,255 contigs were generated with an average length of 1053 bp. We then obtained functional annotations by aligning contigs with public protein databases including NR, SwissProt, KEGG, and COG. Using the above carnation transcriptome as the reference, we compared the effects of high temperature treatments (42 degrees C: duration 0.5, 2, or 12 h) delivered to aseptic carnation seedlings, relative to untreated controls, using the FPKM metric. Overall, 11,471 genes were identified which showed a significant response to one or more of the three HS treatment times. In addition, based on GO and metabolic pathway enrichment analyses, a series of candidate genes involved in thermo-tolerance responses were selected and characterized. This study represents the first expression profiling analysis of D. caryophyllus under heat stress treatments. Numerous genes were found to be induced in response to HS, the study of which may advance our understanding of heat response of carnation. PMID- 26236321 TI - How to let go: pectin and plant cell adhesion. AB - Plant cells do not, in general, migrate. They maintain a fixed position relative to their neighbors, intimately linked through growth and differentiation. The mediator of this connection, the pectin-rich middle lamella, is deposited during cell division and maintained throughout the cell's life to protect tissue integrity. The maintenance of adhesion requires cell wall modification and is dependent on the actin cytoskeleton. There are developmental processes that require cell separation, such as organ abscission, dehiscence, and ripening. In these instances, the pectin-rich middle lamella must be actively altered to allow cell separation, a process which also requires cell wall modification. In this review, we will focus on the role of pectin and its modification in cell adhesion and separation. Recent insights gained in pectin gel mechanics will be discussed in relation to existing knowledge of pectin chemistry as it relates to cell adhesion. As a whole, we hope to begin defining the physical mechanisms behind a cells' ability to hang on, and how it lets go. PMID- 26236322 TI - The impact of the absence of aliphatic glucosinolates on water transport under salt stress in Arabidopsis thaliana. AB - Members of the Brassicaceae are known for their contents of nutrients and health promoting phytochemicals, including glucosinolates. Exposure to salinity increases the levels of several of these compounds, but their role in abiotic stress response is unclear. The effect of aliphatic glucosinolates on plant water balance and growth under salt stress, involving aquaporins, was investigated by means of Arabidopsis thaliana mutants impaired in aliphatic glucosinolate biosynthesis, which is controlled by two transcription factors: Myb28 and Myb29. The double mutant myb28myb29, completely lacking aliphatic glucosinolates, was compared to wild type Col-0 (WT) and the single mutant myb28. A greater reduction in the hydraulic conductivity of myb28myb29 was observed under salt stress, when compared to the WT and myb28; this correlated with the abundance of both PIP1 and PIP2 aquaporin subfamilies. Also, changes in root architecture in response to salinity were genotype dependent. Treatment with NaCl altered glucosinolates biosynthesis in a similar way in WT and the single mutant and differently in the double mutant. The results indicate that short-chain aliphatic glucosinolates may contribute to water saving under salt stress. PMID- 26236323 TI - Hexokinase 1 is required for glucose-induced repression of bZIP63, At5g22920, and BT2 in Arabidopsis. AB - Simple sugars, like glucose (Glc) and sucrose (Suc), act as signals to modulate the expression of hundreds of genes in plants. Frequently, however, it remains unclear whether this regulation is induced by the sugars themselves or by their derivatives generated in the course of carbohydrate (CH) metabolism. In the present study, we tested the relevance of different CH metabolism and allocation pathways affecting expression patterns of five selected sugar-responsive genes (bZIP63, At5g22920, BT2, MGD2, and TPS9) in Arabidopsis thaliana. In general, the expression followed diurnal changes in the overall sugar availability. However, under steady growth conditions, this response was hardly impaired in the mutants for CH metabolizing/ transporting proteins (adg1, sex1, sus1-4, sus5/6, and tpt2), including also hexokinase1 (HXK1) loss- and gain-of-function plants-gin2.1 and oe3.2, respectively. In addition, transgenic plants carrying pbZIP63::GUS showed no changes in reporter-gene-expression when grown on sugar under steady state conditions. In contrast, short-term treatments of agar-grown seedlings with 1% Glc or Suc induced pbZIP63::GUS repression, which became even more apparent in seedlings grown in liquid media. Subsequent analyses of liquid-grown gin2.1 and oe3.2 seedlings revealed that Glc -dependent regulation of the five selected genes was not affected in gin2.1, whereas it was enhanced in oe3.2 plants for bZIP63, At5g22920, and BT2. The sugar treatments had no effect on ATP/ADP ratio, suggesting that changes in gene expression were not linked to cellular energy status. Overall, the data suggest that HXK1 does not act as Glc sensor controlling bZIP63, At5g22920, and BT2 expression, but it is nevertheless required for the production of a downstream metabolic signal regulating their expression. PMID- 26236324 TI - Comparative physiology of allopatric Populus species: geographic clines in photosynthesis, height growth, and carbon isotope discrimination in common gardens. AB - Populus species with wide geographic ranges display strong adaptation to local environments. We studied the clinal patterns in phenology and ecophysiology in allopatric Populus species adapted to similar environments on different continents under common garden settings. As a result of climatic adaptation, both Populus tremula L. and Populus balsamifera L. display latitudinal clines in photosynthetic rates (A), whereby high-latitude trees of P. tremula had higher A compared to low-latitude trees and nearly so in P. balsamifera (p = 0.06). Stomatal conductance (g s) and chlorophyll content index (CCI) follow similar latitudinal trends. However, foliar nitrogen was positively correlated with latitude in P. balsamifera and negatively correlated in P. tremula. No significant trends in carbon isotope composition of the leaf tissue (delta(13)C) were observed for both species; but, intrinsic water-use efficiency (WUEi) was negatively correlated with the latitude of origin in P. balsamifera. In spite of intrinsically higher A, high-latitude trees in both common gardens accomplished less height gain as a result of early bud set. Thus, shoot biomass was determined by height elongation duration (HED), which was well approximated by the number of days available for free growth between bud flush and bud set. We highlight the shortcoming of unreplicated outdoor common gardens for tree improvement and the crucial role of photoperiod in limiting height growth, further complicating interpretation of other secondary effects. PMID- 26236325 TI - Allelopathic effects of glucosinolate breakdown products in Hanza [Boscia senegalensis (Pers.) Lam.] processing waste water. AB - Boscia senegalensis is a drought resistant shrub whose seeds are used in West Africa as food. However, the seeds, or hanza, taste bitter which can be cured by soaking them in water for 4-7 days. The waste water resulting from the processing takes up the bitter taste, which makes it unsuitable for consumption. When used for irrigation, allelopathic effects were observed. Glucosinolates and their breakdown products are the potential causes for both the bitter taste and the allelopathic effects. The objectives of this study are to identify and quantify the glucosinolates present in processed and unprocessed hanza as well as different organs of B. senegalensis, to analyze the chemical composition of the processing water, and to pinpoint the causal agent for the allelopathic properties of the waste water. Hanza (seeds without testa), leaves, branches, unripe, and ripe fruits were collected in three populations and subjected to glucosinolate analyses. Methylglucosinolates (MeGSL) were identified in all plant parts and populations, with the highest concentrations being found in the hanza. The levels of MeGSLs in the hanza reduced significantly during the soaking process. Waste water was collected for 6 days and contained large amounts of macro- and micronutrients, MeGSL as well as methylisothiocyanate (MeITC), resulting from the conversion of glucosinolates. Waste water from days 1-3 (High) and 4-6 (Low) was pooled and used to water seeds from 11 different crops to weeds. The High treatment significantly delayed or reduced germination of all the plant species tested. Using similar levels of MeITC as detected in the waste water, we found that germination of a subset of the plant species was inhibited equally to the waste water treatments. This confirmed that the levels of methylisiothiocyanate in the waste water were sufficient to cause the allelopathic effect. This leads to the possibility of using hanza waste water in weed control programs. PMID- 26236326 TI - MorTAL Kombat: the story of defense against TAL effectors through loss-of susceptibility. AB - Many plant-pathogenic xanthomonads rely on Transcription Activator-Like (TAL) effectors to colonize their host. This particular family of type III effectors functions as specific plant transcription factors via a programmable DNA-binding domain. Upon binding to the promoters of plant disease susceptibility genes in a sequence-specific manner, the expression of these host genes is induced. However, plants have evolved specific strategies to counter the action of TAL effectors and confer resistance. One mechanism is to avoid the binding of TAL effectors by mutations of their DNA binding sites, resulting in resistance by loss-of susceptibility. This article reviews our current knowledge of the susceptibility hubs targeted by Xanthomonas TAL effectors, possible evolutionary scenarios for plants to combat the pathogen with loss-of-function alleles, and how this knowledge can be used overall to develop new pathogen-informed breeding strategies and improve crop resistance. PMID- 26236328 TI - Erratum: Current insights into hormonal regulation of microspore embryogenesis. AB - [This corrects the article on p. 424 in vol. 6, PMID: 26113852.]. PMID- 26236327 TI - Phenylalanine and tyrosine levels are rate-limiting factors in production of health promoting metabolites in Vitis vinifera cv. Gamay Red cell suspension. AB - Environmental stresses such as high light intensity and temperature cause induction of the shikimate pathway, aromatic amino acids (AAA) pathways, and of pathways downstream from AAAs. The induction leads to production of specialized metabolites that protect the cells from oxidative damage. The regulation of the diverse AAA derived pathways is still not well understood. To gain insight on that regulation, we increased AAA production in red grape Vitis vinifera cv. Gamay Red cell suspension, without inducing external stress on the cells, and characterized the metabolic effect of this induction. Increased AAA production was achieved by expressing a feedback-insensitive bacterial form of 3-deoxy- D arabino-heptulosonate 7-phosphate synthase enzyme (AroG (*)) of the shikimate pathway under a constitutive promoter. The presence of AroG(*) protein led to elevated levels of primary metabolites in the shikimate and AAA pathways including phenylalanine and tyrosine, and to a dramatic increase in phenylpropanoids. The AroG (*) transformed lines accumulated up to 20 and 150 fold higher levels of resveratrol and dihydroquercetin, respectively. Quercetin, formed from dihydroquercetin, and resveratrol, are health promoting metabolites that are induced due to environmental stresses. Testing the expression level of key genes along the stilbenoids, benzenoids, and phenylpropanoid pathways showed that transcription was not affected by AroG (*). This suggests that concentrations of AAAs, and of phenylalanine in particular, are rate-limiting in production of these metabolites. In contrast, increased phenylalanine production did not lead to elevated concentrations of anthocyanins, even though they are also phenylpropanoid metabolites. This suggests a control mechanism of this pathway that is independent of AAA concentration. Interestingly, total anthocyanin concentrations were slightly lower in AroG(*) cells, and the relative frequencies of the different anthocyanins changed as well. PMID- 26236329 TI - Restoration of epigenetically silenced SULF1 expression by 5-aza-2-deoxycytidine sensitizes hepatocellular carcinoma cells to chemotherapy-induced apoptosis. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the second most frequent cause of cancer death worldwide. Sulfatase 1 (SULF1) functions as a tumor suppressor in HCC cell lines in vitro, but also has an oncogenic effect in some HCCs in vivo. AIM: To examine the mechanisms regulating SULF1 and its function in HCC. METHODS: First, SULF1 mRNA and protein expression were examined. Second, we examined SULF1 gene copy number in HCC cells. Third, we assessed whether DNA methylation or methylation and/or acetylation of histone marks on the promoter regulate SULF1 expression. Finally, we examined the effect of 5-Aza-dC on sulfatase activity and drug-induced apoptosis. RESULTS: SULF1 mRNA was down-regulated in 9/11 HCC cell lines but only 6/10 primary tumors. SULF1 mRNA correlated with protein expression. Gene copy number assessment by fluorescence in situ hybridization showed intact SULF1 alleles in low SULF1 expressing cell lines. CpG island methylation in the SULF1 promoter and two downstream CpG islands did not show an inverse correlation between DNA methylation and SULF1 expression. However, chromatin immunoprecipitation showed that the SULF1 promoter acquires a silenced chromatin state in low SULF1-expressing cells through an increase in di/trimethyl K9H3 and trimethyl-K27H3 and a concomitant loss of activating acetyl K9, K14H3 marks. 5-Aza-dC restored SULF1 mRNA expression in SULF1-negative cell lines, with an associated increase in sulfatase activity and sensitization of HCC cells to cisplatin-induced apoptosis. CONCLUSION: SULF1 gene silencing in HCC occurs through histone modifications on the SULF1 promoter. Restoration of SULF1 mRNA expression by 5-Aza-dC sensitized HCC cells to drug-induced apoptosis. PMID- 26236330 TI - Should we treat aging as a disease? The consequences and dangers of miscategorisation. AB - The aging of the population represents one of the largest healthcare challenges facing the world today. The available scientific evidence shows that interventions are available now that can target fundamental "aging" processes or pathways. Sufficient economic evidence is available to argue convincingly that this approach will also save enormous sums of money which could then be deployed to solve other urgent global problems. However, as yet this scenario has barely entered the public consciousness and, far from being a point of vigorous debate, seems to be ignored by policy makers. Understanding why this lethargy exists is important given the urgent need to deal with the challenge represented by population aging. In this paper I hypothesize that one major cause of inaction is a widely held, but flawed, conceptual framework concerning the relationship between aging and disease that categorizes the former as "natural" and the latter as "abnormal." This perspective is sufficient in itself to act as a disincentive to intervention by rendering those who hold it prone to the "naturalistic fallacy" but can give rise to active hostility to biogerontology if coupled with loose and/or blurred understanding of the goals and potential of the field. PMID- 26236331 TI - Regulation of IL-17 in autoimmune diseases by transcriptional factors and microRNAs. AB - In recent years, IL-17A (IL-17), a pro-inflammatory cytokine, has received intense attention of researchers and clinicians alike with documented effects in inflammation and autoimmune diseases. IL-17 mobilizes, recruits and activates different cells to increase inflammation. Although protective in infections, overproduction of IL-17 promotes inflammation in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, among others. Regulating IL 17 levels or action by using IL-17-blocking antibodies or IL-17R antagonist has shown to attenuate experimental autoimmune diseases. It is now known that in addition to IL-17-specific transcription factor, RORgammat, several other transcription factors and select microRNAs (miRNA) regulate IL-17. Given that miRNAs are dysregulated in autoimmune diseases, a better understanding of transcriptional factors and miRNA regulation of IL-17 expression and function will be essential for devising potential new therapies. In this review, we will overview IL-17 induction and function in relation to autoimmune diseases. In addition, current findings on transcriptional regulation of IL-17 induction and plausible interplay between IL-17 and miRNA in autoimmune diseases are highlighted. PMID- 26236332 TI - Quantitative affinity purification mass spectrometry: a versatile technology to study protein-protein interactions. AB - While the genomic revolution has dramatically accelerated the discovery of disease-associated genes, the functional characterization of the corresponding proteins lags behind. Most proteins fulfill their tasks in complexes with other proteins, and analysis of protein-protein interactions (PPIs) can therefore provide insights into protein function. Several methods can be used to generate large-scale protein interaction networks. However, most of these approaches are not quantitative and therefore cannot reveal how perturbations affect the network. Here, we illustrate how a clever combination of quantitative mass spectrometry with different biochemical methods provides a rich toolkit to study different aspects of PPIs including topology, subunit stoichiometry, and dynamic behavior. PMID- 26236333 TI - MicroRNAs as clinical biomarkers? PMID- 26236334 TI - Evaluation of GWAS candidate susceptibility loci for uterine leiomyoma in the multi-ethnic NIEHS uterine fibroid study. AB - We evaluated the association of 56 candidate SNPs identified in two published genome-wide association studies (GWAS) of uterine leiomyoma (UL), or fibroids, with the risk and tumor size in the multi-ethnic uterine fibroid study (NIEHS UFS). The selected SNPs were genotyped in 916 premenopausal women of African American (AA) and European American (EA) descents and their association with the outcomes was evaluated in race-stratified models and in meta-analysis of risk in NIEHS-UFS and discovery and replication GWAS in the Japanese population. We report moderate associations of variant rs4954368 in THSD7B (thrombospondin, type I, domain containing 7B) with tumor size in pooled analysis of AA and EA samples (P = 0.004), and at TNRC6B (trinucleotide repeat containing 6B) variants rs138039 and rs139909 in EA (P = 0.001 and 0.008, respectively). The most significant associations with risk in meta-analysis were observed at TNRC6B variants rs739182 (P = 3.7 * 10(-10)) and rs2072858 (P = 1.1 * 10(-9)) and were stronger than those reported in the discovery GWAS (P = 2.01 * 10(-8) and 2.58 * 10(-8), respectively). The present study failed to replicate the associations reported for CCDC57 and FASN in a discovery GWAS in populations of European descent. Consistent with previous replication studies in the Right From the Start Study (RFTS) and the BioVU DNA repository, we provide independent evidence for association of TNRC6B with both risk and size of UL. The present study is the first to report a replicated association of THSD7B with UL, albeit with tumor size and not with risk. PMID- 26236335 TI - High-throughput technologies for gene expression analyses: what we have learned for noise-induced cochlear degeneration? AB - Noise-induced hearing loss is a common cause of acquired hearing loss in the adult population. Acoustic overstimulation causes cochlear damage through mechanical stress to the tissue. Consequently, complex molecular changes are initiated, and these changes lead to morphological and biological alterations in the cochlea, which in turn compromise the cochlear function and cause hearing loss. In the past 10 years, there have been significant advances in our understanding of the molecular mechanisms of noise-induced hearing loss. These advances are attributed, in part, to the development of high-throughput technologies for the global analyses of molecular changes. In this review, we briefly describe the newly developed methods for investigating the molecular responses of the cochlea to acoustic trauma and the knowledge generated from these studies. We also discuss the strengths and limitations of each technique and the major challenges to investigate cochlear degeneration following acoustic injury. PMID- 26236336 TI - Role of the Aspartate Transaminase and Platelet Ratio Index in Assessing Hepatic Fibrosis and Liver Inflammation in Adolescent Patients with HBeAg-Positive Chronic Hepatitis B. AB - This study described an index of aspartate aminotransferase-to-platelet ratio index (APRI) to assess hepatic fibrosis with limited expense and widespread availability compared to the liver biopsy in adolescent patients with CHB. PMID- 26236337 TI - Development and Validation of a GC-MS Method for the Detection and Quantification of Clotiapine in Blood and Urine Specimens and Application to a Postmortem Case. AB - Introduction. Clotiapine is an atypical antipsychotic of the dibenzothiazepine class introduced in a few European countries since 1970, efficient in treatment resistant schizophrenic patients. There is little published data on the therapeutic and toxic concentrations of this drug. Aims. The aim of the present study is the development and validation of a method that allows the detection and quantification of clotiapine in blood and urine specimens by gas chromatography mass spectrometry (GC-MS). Methods. Validation was performed working on spiked postmortem blood and urine samples. Samples were extracted with liquid-liquid extraction (LLE) technique at pH 8.5 with n-hexane/dichloromethane (85/15 v/v) and analysis was followed by GC-MS. Methadone-d9 was used as internal standard. Results. The limit of detection (LOD) was 1.2 and 1.3 ng/mL for urine and blood, respectively, while the lower limit of quantification (LLOQ) was 3.9 and 4.3 ng/mL, respectively. Linearity, precision, selectivity, accuracy, and recovery were also determined. The method was applied to a postmortem case. The blood and urine clotiapine concentrations were 1.32 and 0.49 MUg/mL, respectively. Conclusions. A reliable GC-MS method for the detection and quantification of clotiapine in blood and urine samples has been developed and fully validated and then applied to a postmortem case. PMID- 26236338 TI - Shynthesis and Characterizations of Calcium Hydroxyapatite Derived from Crabs Shells (Portunus pelagicus) and Its Potency in Safeguard against to Dental Demineralizations. AB - Crab's shells of Portunus pelagicus species were used as raw materials for synthesis of hydroxyapatite were used for protection against demineralization of teeth. Calcination was conducted to crab's shells of Portunus pelagicus at temperature of 1000 degrees C for 5 hours. The results of calcination was reacted with (NH4)2HPO4, then dried at 110 degrees C for 5 hours. Sintering was conducted to results of precipitated dried with temperature variations 400-1000 degrees C for a hour each variation of temperature then characterized by X-ray diffractometer and FTIR in order to obtain the optimum formation temperature of hydroxyapatite is 800 degrees C. The hydroxyapatite is then tested its effectiveness in protection against tooth demineralization using acetate buffer pH 5.0 with 1 M acetic acid concentration with the addition of hydroxyapatite and time variation of immersion. The results showed that the rate of tooth demineralization in acetate buffer decreased significantly with the provision of hydroxyapatite into a solution where the addition of the magnitude of hydroxyapatite is greater decrease in the rate of tooth demineralization. PMID- 26236339 TI - An Insight into Methods and Practices in Hip Arthroplasty in Patients with Rheumatoid Arthritis. AB - Total hip arthroplasty (THA) has improved the quality of life of patients with hip arthritis. Orthopedic community is striving for excellence to improve surgical techniques and postoperative care. Despite these efforts, patients continue facing postoperative complications. In particular, patients with rheumatoid arthritis display a higher risk of certain complications such as dislocation, periprosthetic infection, and shorter prosthesis durability. In this review we present the current knowledge of hip arthroplasty in patients with rheumatoid arthritis with more insight into common practices and interventions directed at enhancing recovery of these patients and current shortfalls. PMID- 26236340 TI - Total Hip Arthroplasty in Systemic Lupus Erythematosus: A Systematic Review. AB - The prognosis of systemic lupus erythematosus (SLE) has greatly improved in recent years, resulting in an increased number of patients reporting musculoskeletal complications such as osteonecrosis of the femoral head. Total hip arthroplasty (THA) can be utilised to alleviate the pain associated with this; however postoperative outcomes in patients with SLE are uncertain. A systematic review of the literature was conducted to identify articles presenting results of THA in SLE, and nine suitable papers were found. All papers were level IV evidence. Pooling the results, a total of 162 patients underwent 214 total hip arthroplasties. Mean follow-up was 72.5 months. The mean Harris Hip Score improved from 45.5 preoperatively to 88.6 and last follow-up. Seventeen percent of patients experienced at least one complication. Superficial wound infection occurred in 3.3%. Revision was required in 2.8% of cases. The mortality rate was 18.5% however no deaths were attributable to undergoing THA. Given the paucity of data present in the literature, more studies are required to adequately assess the postoperative outcomes of THA in patients with SLE, particularly complication rates. PMID- 26236341 TI - Current Concepts in the Management of Rheumatoid Hand. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease caused by a T cell driven autoimmune process, which majorly involves the diarthrodial joints. It affects 1% of the US population, and approximately 70% of patients with RA develop pathologies of the hand, especially of the metacarpophalangeal joints (MCP). Furthermore, also the extensor and flexor tendons of the fingers are frequently involved. The first line of treatment should be conservative. Three general classes of drugs are currently available for RA: nonsteroidal anti inflammatory agents (NSAIDs), corticosteroids, and disease modifying antirheumatic drugs (DMARDs). Encouraging results have been obtained using DMARDs. However, when severe deformities occur or when patients are unresponsive to medical management and injections therapy, surgical intervention should be performed to relieve pain and restore function. Several surgical options have been described for the management of MCP joint deformities, including soft tissue procedures, arthrodesis, and prosthetic replacement. Tendons ruptures are generally managed with tendon transfer surgery, while different surgical procedures are available to treat fingers deformities. The aim of the present review is to report the current knowledge in the management of MCP joint deformities, as well as tendons damage and fingers deformities, in patients with RA. PMID- 26236342 TI - Unruptured Aneurysm of Sinus of Valsalva Coexisting with the Large Ventricular Septal Defect and Severe Aortic Regurgitation in a Young Man. AB - Introduction. Unruptured sinus of valsalva aneurysm (SVA) is a rare congenital anomaly, particularly, when it coexists with a ventricular septal defect (VSD) and aortic regurgitation due to the prolapse of the elongated aortic cusp into the VSD. In this report, we present the case of a 19-year-old young man with VSD challenging in spite of dyspnea and lower limb edema. Presentation of Case. Its diagnosis was made on the basis of transthoracic echocardiography results. Surgical management consisted of replacing the SVA with mechanical valve prosthesis. A Gore-Tex patch repaired the VSD. Discussion. In the follow-up periods, clinical and echocardiographic tests showed that the patient was in excellent status. Conclusion. SVA requires a surgical procedure due to its high risk of mortality in unoperated patients and a good safety of surgery. PMID- 26236343 TI - Collapsing Focal Segmental Glomerulosclerosis in a Patient with Acute Malaria. AB - Introduction. Collapsing focal segmental glomerulosclerosis (FSGS) is most commonly seen in association with HIV infection. Rare data is available about the association between collapsing FSGS and malaria. Case Description. A 72-year-old African male patient presented to the hospital for generalized body aches, fatigue, fever, and night sweats for three days. He had history of recent travel to Ghana. Patient looked in acute distress and was shivering. Laboratory tests showed elevated serum creatinine (Cr) of 2.09 mg/dL (baseline was 1.5 mg/dL in 2012). Hospital course was significant for rapid elevation of Cr to 9.5 mg/dL and proteinuria of 7.9 grams. Autoimmune studies resulted negative. Blood smear resulted positive for Plasmodium falciparum and patient was treated with Artemether/Lumefantrine. Patient's fever and pain improved, but kidney function continued to deteriorate and he became oliguric. On day seven, he was started on Hemodialysis. Tests for different causes of glomerular pathology were also negative. He underwent left kidney biopsy which resulted in findings consistent with severe collapsing glomerulopathy. Discussion. This case illustrates a biopsy proven collapsing FSGS likely secondary to malarial infection requiring renal replacement therapy. Literature review revealed only few case reports that suggested the possible association of malaria with secondary form of FSGS. PMID- 26236344 TI - Intramucosal Signet Ring Cell Gastric Cancer Diagnosed 15 Months after the Initial Endoscopic Examination. AB - The size and shape of intramucosal signet ring gastric cancer in this case remained endoscopically unchanged for 15 months. Laparoscopy-assisted distal gastrectomy was performed, and immunohistochemical analysis revealed Ki-67 and p53 mutations to be negative in this case. Signet ring gastric cancer has long been thought to confer a worse prognosis than other forms of gastric cancer; however, our case did not progress to advanced gastric cancer for 15 months. PMID- 26236345 TI - Unusual Extramedullary Plasmacytoma: A Rare but Possible Cause of Lymphadenopathy in Chronic Lymphocytic Leukemia. AB - Cervical bilateral lymphadenopathy is a frequent event during chronic lymphocytic leukemia (CLL) natural history. However, lymph node biopsy is generally not required as long as transformation into an aggressive lymphoma (Richter syndrome) is not suspected. We present here a rare case of CLL patient who developed progressive bilateral cervical lymph node and bilateral tonsillar hypertrophy. CLL front-line therapy was ineffective leading to adenectomy and diagnosis of concomitant extramedullary plasmacytoma. Radiotherapy did not result in the disappearance of lymphadenopathy. Adenectomy should be performed in CLL cases to avoid misdiagnosis. PMID- 26236347 TI - Safety of Allogeneic Umbilical Cord Blood Stem Cells Therapy in Patients with Severe Cerebral Palsy: A Retrospective Study. AB - This retrospective study aimed to assess the safety of patients with severe cerebral palsy (CP), who received allogeneic umbilical cord blood stem cells (UCBSCs) treatment from August 2009 to December 2012 in Guangdong Provincial Hospital of Chinese Medicine. A total of 47 patients with average age of 5.85 +/- 6.12 years were evaluated in this study. There was no significant association with allogeneic UCBSCs treatments found in the data of the laboratory index . No casualties occurred. Some adverse events during treatments were found in 26 (55.3%) patients, including fever (42.6%) and vomiting (21.2%). Intrathecal infusion and the ages at the initiation of treatment (<=10 years old) were risk factors for the occurrence of adverse events by logistic regression analysis. However, all adverse events disappeared after symptomatic treatment. No treatment related serious adverse events were found in follow-up visits within 6 months. In conclusion, allogeneic UCBSCs treatment was relatively safe for severe CP patients. PMID- 26236346 TI - Stem Cell Hierarchy and Clonal Evolution in Acute Lymphoblastic Leukemia. AB - Cancer is characterized by a remarkable intertumoral, intratumoral, and cellular heterogeneity that might be explained by the cancer stem cell (CSC) and/or the clonal evolution models. CSCs have the ability to generate all different cells of a tumor and to reinitiate the disease after remission. In the clonal evolution model, a consecutive accumulation of mutations starting in a single cell results in competitive growth of subclones with divergent fitness in either a linear or a branching succession. Acute lymphoblastic leukemia (ALL) is a highly malignant cancer of the lymphoid system in the bone marrow with a dismal prognosis after relapse. However, stabile phenotypes and functional data of CSCs in ALL, the so called leukemia-initiating cells (LICs), are highly controversial and the question remains whether there is evidence for their existence. This review discusses the concepts of CSCs and clonal evolution in respect to LICs mainly in B-ALL and sheds light onto the technical controversies in LIC isolation and evaluation. These aspects are important for the development of strategies to eradicate cells with LIC capacity. Common properties of LICs within different subclones need to be defined for future ALL diagnostics, treatment, and disease monitoring to improve the patients' outcome in ALL. PMID- 26236349 TI - The dollars and sense of chronic hepatitis C infection management. PMID- 26236348 TI - Characterization of Nestin, a Selective Marker for Bone Marrow Derived Mesenchymal Stem Cells. AB - Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into multiple cell lineages and contributing to tissue repair and regeneration. Characterization of the physiological function of MSCs has been largely hampered by lack of unique markers. Nestin, originally found in neuroepithelial stem cells, is an intermediate filament protein expressed in the early stages of development. Increasing studies have shown a particular association between Nestin and MSCs. Nestin could characterize a subset of bone marrow perivascular MSCs which contributed to bone development and closely contacted with hematopoietic stem cells (HSCs). Nestin expressing (Nes(+)) MSCs also play a role in the progression of various diseases. However, Nes(+) cells were reported to participate in angiogenesis as MSCs or endothelial progenitor cells (EPCs) in several tissues and be a heterogeneous population comprising mesenchymal cells and endothelial cells in the developing bone marrow. In this review article, we will summarize the progress of the research on Nestin, particularly the function of Nes(+) cells in bone marrow, and discuss the feasibility of using Nestin as a specific marker for MSCs. PMID- 26236350 TI - Preventing ophthalmia neonatorum. AB - The use of silver nitrate as prophylaxis for neonatal ophthalmia was instituted in the late 1800s to prevent the devastating effects of neonatal ocular infection with Neisseria gonorrhoeae. At that time - during the preantibiotic era - many countries made such prophylaxis mandatory by law. Today, neonatal gonococcal ophthalmia is rare in Canada, but ocular prophylaxis for this condition remains mandatory in some provinces/ territories. Silver nitrate drops are no longer available and erythromycin, the only ophthalmic antibiotic eye ointment currently available for use in newborns, is of questionable efficacy. Ocular prophylaxis is not effective in preventing chlamydial conjunctivitis. Applying medication to the eyes of newborns may result in mild eye irritation and has been perceived by some parents as interfering with mother-infant bonding. Physicians caring for newborns should advocate for rescinding mandatory ocular prophylaxis laws. More effective means of preventing ophthalmia neonatorum include screening all pregnant women for gonorrhea and chlamydia infection, and treatment and follow-up of those found to be infected. Mothers who were not screened should be tested at delivery. Infants of mothers with untreated gonococcal infection at delivery should receive ceftriaxone. Infants exposed to chlamydia at delivery should be followed closely for signs of infection. PMID- 26236351 TI - Canada's National Advisory Committee on Immunization: Celebrating 50 years. AB - Vaccines have saved more lives than any other innovation in modern medicine. National immunization committees play a vital role in the development of evidence based recommendations for the use of vaccines. The present article describes the evolution and work of the National Advisory Committee on Immunization in Canada as the group marks its 50th anniversary. The article also provides insight into the future challenges that the committee is likely to face. PMID- 26236352 TI - 2015 Dr Lindsay E Nicolle Award. PMID- 26236353 TI - Improving health care efficiency through the integration of a physician assistant into an infectious diseases consult service at a large urban community hospital. AB - BACKGROUND: Physician assistants (PAs) have recently been introduced into the Canadian health care system in some provinces; however, there are little data demonstrating their impact. METHODS: A retrospective case-control study was conducted between January 2010 and December 2013. Length of stay (LOS) and mortality were examined in the infectious diseases consult service (IDCS) compared with hospital-wide controls. The two-year period before the introduction of the PA to the IDCS of a large urban community hospital in Canada (2010 to 2011) was compared with the two-year period following the introduction of the PA (2012 to 2013). RESULTS: Following the introduction of a PA to the IDCS, there was a decrease in time to consultation from 21.4 h to 14.3 h (P<0.0001). LOS was significantly decreased among IDCS patients by 3.6 days more than that seen in matched hospital-wide controls (P=0.0001). Mortality did not significantly change after PA introduction in either cases or controls. DISCUSSION/CONCLUSION: PAs can improve health efficiencies in the Canadian health care setting, leading to reduction in LOS. PMID- 26236354 TI - Urinary tract infection diagnosis and response to therapy in long-term care: A prospective observational study. AB - BACKGROUND: The prevalence of asymptomatic bacteriuria among residents of long term care (LTC) facilities is high, and is a source of inappropriate antibiotic prescription. OBJECTIVE: To establish symptoms and signs associated with a positive urine culture, and to determine whether antibiotic therapy is associated with functional improvement. METHODS: A total of 101 LTC patients were prospectively observed after submission of urine for culture. RESULTS: The culture positivity rate was consistent with the expected asymptomatic bacteriuria rate. Change in mental status and male sex were associated with culture positivity. Treatment decisions were not consistent with culture results. Treatment did not lead to improvement in activities of daily living scores at two days or seven days. DISCUSSION: Significant growth cannot be well predicted based on clinical variables; thus, the decision to submit urine is somewhat arbitrary. Because urine culture testing and treatment does not lead to functional improvement, restricting access to the test may be reasonable. CONCLUSION: Urine culture testing in LTC facilities does not lead to functional improvement. PMID- 26236355 TI - Antimicrobial susceptibility of Canadian isolates of Helicobacter pylori in Northeastern Ontario. AB - BACKGROUND: Helicobacter pylori plays a significant role in gastritis and ulcers. It is a carcinogen as defined by the WHO, and infection can result in adenocarcinomas and mucosa-associated lymphoid tissue lymphomas. In Canada, rates of antimicrobial resistance are relatively unknown, with very few studies conducted in the past 15 years. OBJECTIVE: To examine rates of resistance in Sudbury, Ontario, compare antimicrobial susceptibility methods and attempt to determine the molecular basis of antibiotic resistance. METHODS: Patients attending scheduled visits at Health Sciences North (Sudbury, Ontario) provided gastric biopsy samples on a volunteer basis. In total, 20 H pylori isolates were collected, and antimicrobial susceptibility testing (on amoxicillin, tetracycline, metronidazole, ciprofloxacin, levofloxacin and clarithromycin) was conducted using disk diffusion and E-test methods. Subsequently, genomic DNA from these isolates was sequenced to detect mutations associated with antimicrobial resistance. RESULTS: Sixty-five percent of the isolates were found to be resistant to at least one of the listed antibiotics according to E-test. Three isolates were found to be resistant to >=3 of the above-mentioned antibiotics. Notably, 25% of the isolates were found to be resistant to both metronidazole and clarithromycin, two antibiotics that are normally prescribed as part of first line regimens in the treatment of H pylori infections in Canada and most of the world. Among the resistant strains, the sequences of 23S ribosomal RNA and gyrA, which are linked to clarithromycin and ciprofloxacin/levofloxacin resistance, respectively, revealed the presence of known point mutations associated with antimicrobial resistance. CONCLUSIONS: In general, resistance to metronidazole, ciprofloxacin/levofloxacin and clarithromycin has increased since the studies in the early 2000s. These results suggest that surveillance programs of H pylori antibiotic resistance may need to be revisited or improved to prevent antimicrobial therapy failure. PMID- 26236356 TI - A case series of third-trimester raltegravir initiation: Impact on maternal HIV-1 viral load and obstetrical outcomes. AB - OBJECTIVE: To describe the impact of initiating raltegravir (RAL)-containing combination antiretroviral therapy (cART) regimens on HIV viral load (VL) in pregnant women who have high or suboptimal VL suppression late in pregnancy. METHODS: HIV-infected pregnant women who started RAL-containing cART after 28 weeks' gestation from 2007 to 2013 were identified in two university hospital centres. RESULTS AND DISCUSSION: Eleven HIV-infected women started RAL at a median gestational age of 35.7 weeks (range 31.1 to 38.0 weeks). Indications for RAL initiation were late presentation in pregnancy (n=4) and suboptimal VL suppression secondary to poor adherence or viral resistance (n=7). Mean VL at the time of RAL initiation was 73,959 copies/mL (range <40 to 523,975 copies/mL). Patients received RAL for a median of 20 days (range one to 71 days). The mean decline in VL from the time of RAL initiation to delivery was 1.93 log, excluding one patient who received only one RAL dose and one patient with undetectable VL at the time of RAL initiation. After eight days on RAL, 50% of the women achieved a VL <1000 copies/mL (the threshold for recommended Caesarean section to reduce the risk for perinatal transmission). There were no cases of perinatal HIV transmission. CONCLUSION: The present study provides preliminary data to support the use of RAL-containing cART to expedite HIV-1 VL reduction in women who have a high VL or suboptimal VL suppression late in pregnancy, and to decrease the risk of HIV perinatal transmission while avoiding Caesarean section. Further assessment of RAL safety during pregnancy is warranted. PMID- 26236357 TI - Lyme disease: Knowledge and practices of family practitioners in southern Quebec. AB - BACKGROUND: Public health authorities in Quebec have responded to the progressive emergence of Lyme disease (LD) with surveillance activities and education for family physicians (FPs) who are key actors in both vigilance and case management. OBJECTIVES: To describe FPs' clinical experience with LD, their degree of knowledge, and their practices in two areas, one with known infected tick populations (Monteregie) and one without (regions nearby Monteregie). METHODS: In the present descriptive cross-sectional study, FPs were recruited during educational sessions. They were asked to complete a questionnaire assessing their clinical experience with Lyme disease, their knowledge of signs and symptoms of LD, and their familiarity with accepted guidelines for diagnosing and treating LD in two clinical scenarios (tick bite and erythema migrans). RESULTS: A total of 201 FPs participated, mostly from Monteregie (n=151). Overall, results revealed a moderate lack of knowledge and suboptimal practices rather than systematically insufficient knowledge or inadequate practices. A majority of participants agreed to more education on LD. As expected, FPs from Monteregie had a higher clinical experience with tick bites (57% versus 25%), better knowledge of LD endemic areas in Canada and erythema migrans characteristics, and better management of erythema migrans (72% versus 50%). CONCLUSION: The present study documented the inappropriate intention to order serology tests for tick bites and the unjustified intention to use tick analysis for diagnostic purposes. Such practices should be discouraged because they are unnecessary and overuse collective laboratory and medical resources. In addition, public health authorities must pursue their education efforts regarding FPs to optimize case management. PMID- 26236358 TI - A family cluster of Chagas disease detected through selective screening of blood donors: A case report and brief review. AB - Chagas disease (CD) is a protozoan infection caused by Trypanosoma cruzi, which is transmitted by triatomine insect vectors in parts of Latin America. In a nonendemic country, such as Canada, spread can still occur via vertical transmission, and infected blood or organ donations. The Canadian Blood Services and Hema-Quebec have both implemented selective screening of blood donors for CD based on risk factors. In 2011, Hema-Quebec identified two seropositive 'at-risk' Chilean siblings who had donated blood in Montreal, Quebec. They were referred to the JD MacLean Centre for Tropical Diseases (Montreal, Quebec) for confirmatory testing (T cruzi excreted-secreted antigen ELISA, polymerase chain reaction and/or radioimmunoprecipitation assay) and follow-up. Screening of the rest of the family revealed two other seropositive family members (the mother and sister). While their geographical history in Chile suggests vectorial transmission, this family cluster of CD raises the possibility of vertical transmission. Congenital infection should always be considered among CD-positive mothers and pregnant women. With blood donor screening, Canadian physicians will increasingly see patients with CD and should know how to manage them appropriately. In addition to the case presentation, the authors review the transmission, screening and clinical management of CD in a nonendemic context. PMID- 26236359 TI - Parents' and adolescents' willingness to be vaccinated against serogroup B meningococcal disease during a mass vaccination in Saguenay-Lac-St-Jean (Quebec). AB - A mass vaccination campaign with the 4CMenB vaccine (Bexsero(r); Novartis Pharmaceutical Canada Inc) was launched in a serogroup B endemic area in Quebec. A telephone survey was conducted to assess parental and adolescent opinions about the acceptability of the vaccine. Intent to receive the vaccine or vaccine receipt was reported by the majority of parents (93%) and adolescents (75%). Meningitis was perceived as being a dangerous disease by the majority of parents and adolescents. The majority of respondents also considered the 4CMenB vaccine to be safe and effective. The main reason for positive vaccination intention or behaviour was self-protection, while a negative attitude toward vaccination in general was the main reason mentioned by parents who did not intend to have their child vaccinated. Adolescents mainly reported lack of interest, time or information, and low perceived susceptibility and disease severity as the main reasons for not intending to be vaccinated or not being vaccinated. PMID- 26236360 TI - An unusual case of meningitis. AB - Pasteurella multocida is a rare cause of bacterial meningitis. A 56-year-old man with several pets developed a profoundly decreased level of consciousness following left tympanomastoidectomy. Lumbar puncture produced cerebrospinal fluid with the typical findings of meningitis (low glucose, high protein, high leukocytes). Cultures from the cerebrospinal fluid and a swab of the left ear revealed Gram-negative coccobacillus identified as P multocida. The organism was sensitive to ceftriaxone, ampicillin and penicillin, and a 14-day course of intravenous penicillin was used as definitive treatment, resulting in full recovery. Although rare, P multocida should be considered as a potential cause of meningitis in patients with animal exposure, particularly in the setting of recent cranial surgery. PMID- 26236361 TI - Primitive hepatic venous plexus in a child with scimitar syndrome and pulmonary sequestration. AB - We report a case of scimitar syndrome with pulmonary sequestration, persistent primitive hepatic venous plexus and stenosis of the inferior vena cava in a child presenting with failure to thrive. Such associations are rare but may have implications when planning interventions for patients with complex congenital heart disease. PMID- 26236362 TI - Dysphagia in an Adult Tetralogy of Fallot with Double aortic arch. AB - Double aortic arch (DAA) is a common vascular ring. It may occur in isolation or coexist with various types of congenital heart disease. The anomaly usually presents in early infancy. This reports a 23yr old male presenting with dysphagia, who was found to have a double aortic arch and tetralogy of Fallot. Both lesions were successfully corrected surgically. PMID- 26236363 TI - Three dimensional echocardiographic assessment of multiple rhabdomyoma in newborn. AB - BACKGROUND: Cardiac rhabdomyomas represent the most common primary cardiac tumour in children and are strongly associated with tuberous sclerosis complex. RESULTS: We reported a newborn for whom three-dimensional echocardiogram, with multiplane mode, real-time imaging, full volume and i-slice view, allowed detailed visualisation of multiple highly echogenic and well-circumscribed cardiac rhabdomyoma. CONCLUSIONS: Three-dimensional imaging allowed a better definition of the tumour characteristics and provided a better delineation of the spatial relationship of the mass with a tomographic perspective. Three dimensional imaging may facilitate a possible operative planning and should be included in cardiac mass evaluation and follow-up. PMID- 26236364 TI - Accuracy of pulse oximetry screening for detecting critical congenital heart disease in the newborns in rural hospital of Central India. AB - BACKGROUND: Congenital cardiovascular malformations are the most common category of birth defects and responsible for mortality in the first twelve months of life. Critical congenital heart disease (CCHD) will be present in approximately one quarter of these children, which requires catheter or surgery intervention in the first year of life. AIM: To determine the accuracy of pulse oximetry for detecting clinically unrecognized CCHD in the newborns. METHODS: Pulse oximetry was performed on clinically normal newborns within first 4 hours of life. If screening oxygen saturation (SpO2) was below 90%, echocardiography was then performed. INCLUSION CRITERIA: All newborns who were admitted in postnatal ward & NICU. EXCLUSION CRITERIA: Out born babies and babies with a prenatal diagnosis of duct dependent circulation. RESULTS: Pulse-oximetric screening was performed on 2110 clinically normal newborns. Low SpO2 (<90%) was found in eight babies seven of them had CCHD, including three neonates with TGA, two with tricuspid atresia, one with tetralogy of fallot and one with transposition of great vessels. A pulse oximetry cut-off value of below 90% for detecting CCHD showed 100% sensitivity, 99.95% specificity, 87.50% positive predictive value, 100% negative predictive value. CONCLUSIONS: Pulse oximetry is safe, feasible and noninvasive, can be used as screening tool for detecting CCHD in clinically normal newborn. If SpO2 is below 90% in clinically normal newborns within 4 hours of birth, urgent echocardiography is suggested to rule out CCHD. PMID- 26236365 TI - Classical Supravalvar Aortic Stenosis and Peripheral Pulmonary Stenosis. AB - Supravalvar aortic stenosis as well as peripheral pulmonary stenosis are rare forms of congenital heart disease, which occur, however, relatively frequently in association. Here we report and discuss the classical findings of SVAS and PPS upon clinical examination and imaging in a six-year-old girl that presented with repeated respiratory tract infections and failure to thrive. PMID- 26236366 TI - Prenatal diagnosis of isolated atrioventricular discordance using fetal echocardiography. PMID- 26236367 TI - The value of multimodality imaging for detection, characterisation and management of a wall adhering structure in the right atrium. AB - The case presents a wall adherent structure in the right atrium in a young patient with peripheral t-cell lymphoma followed by successful prolonged lysis therapy resulting in the resolution of the thrombus is presented. This case highlights the utility of multimodality imaging in an accurate assessment of the right atrium thrombus and the effectiveness of prolonged lysis therapy. PMID- 26236368 TI - The chest x-ray in delayed presentation of coarctation of the aorta. PMID- 26236369 TI - Brief Images: Massive pericardial effusion. AB - Significant pericardial effusions are an uncommon but very important disorder in childhood. In our patient, cross-sectional imaging demonstrated a massive pericardial effusion. The underlying etiology here was connective tissue disease causing recurrent pericardial effusion. An associated left-sided pleural effusion was noted. Clinicians must be aware of this disorder in the pediatric age group, performing a thorough evaluation in all children with large pericardial effusions, and managing appropriately. PMID- 26236370 TI - The chest x-ray in congenital heart disease 6. PMID- 26236371 TI - Ectopia cordis. A report of two cases in Cameroon. AB - We report two cases of ectopia cordis in two children aged one day and twenty months respectively. A one day old newborn had complete thoracic ectopia cordis associated with an internal cardiac defect and severe thoracic and abdominal wall malformations. Our centre does not have the facilities to manage complex congenital defects and prior to being transferred to a cardiac centre, the neonate died on the second day of admission. A 20-month old baby had partial ectopia of the heart and a defect in the abdominal wall. He had no major congenital cardiac defect and has remained clinically stable with no life threatening symptoms. PMID- 26236372 TI - Severe reversible dilated cardiomyopathy associated with a large left ventricular thrombus in a young child with middle aortic syndrome. AB - We report a case of a seven-year girl who presented with severe dilated cardiomyopathy (DCM) associated with a large thrombus in the left ventricle (LV). She had a long segment stenosis of the lower thoracic descending aorta, possibly due to non-specific aortitis and underwent successful stent angioplasty. The LV thrombus resolved after heparin without sequelae. PMID- 26236373 TI - Giant coronary sinus aneurysm and multiple coronary artery aneurysms in a pediatric patient. PMID- 26236374 TI - RCC prolapse causing Aortic regurgitation in a restrictive VSD. PMID- 26236375 TI - Tetralogy of Fallot with absent pulmonary valve syndrome; an imaging challenge. PMID- 26236376 TI - An asymptomatic 11 year child with ruptured sinus of Valsalva. PMID- 26236377 TI - Maslinic Acid, a Triterpene from Olive, Affects the Antioxidant and Mitochondrial Status of B16F10 Melanoma Cells Grown under Stressful Conditions. AB - Maslinic acid (MA) is a natural compound whose structure corresponds to a pentacyclic triterpene. It is abundant in the cuticular lipid layer of olives. MA has many biological and therapeutic properties related to health, including antitumor, anti-inflammatory, antimicrobial, antiparasitic, antihypertensive, and antioxidant activities. However, no studies have been performed to understand the molecular mechanism induced by this compound in melanoma cancer. The objective of this study was to examine the effect of MA in melanoma (B16F10) cells grown in the presence or absence of fetal bovine serum (FBS). We performed cell proliferation measurements, and the reactive oxygen species (ROS) measurements using dihydrorhodamine 123 (DHR 123) and activities of catalase, glucose 6 phosphate dehydrogenase, glutathione S-transferase, and superoxide dismutase. These changes were corroborated by expression assays. FBS absence reduced cell viability decreasing IC50 values of MA. The DHR 123 data showed an increase in the ROS level in the absence of FBS. Furthermore, MA had an antioxidant effect at lower assayed levels measured as DHR and antioxidant defense. However, at higher dosages MA induced cellular damage by apoptosis as seen in the results obtained. PMID- 26236378 TI - Auricular Acupressure Can Modulate Pain Threshold. AB - The objective of our study was to investigate if auriculotherapy (AT) can modulate pain threshold. In our experiments, AT consisted of placing Vaccaria seeds over the "fingers point" of one ear. Two groups of healthy volunteers were enrolled for the study. Each subject was asked to perform an autoalgometric test developed by our group on three occasions: before, 1 hour after, AT and 24 hours after AT. Participants of the first group received a 2-minute long session of AT, while participants of the second group received a 2-minute long session of sham treatment, consisting of a puncture/massage above the skin of the neck. The autoalgometric test consisted of applying an increasing pressure with the finger tips and finger-backs of four fingers by the subjects themselves (i.e., eight sites were evaluated) against a round-shaped needle for two times: until a minimum pain sensation (first time, minimal test) or a maximally tolerable pain sensation (second time, maximal test). Our results showed a significant higher pain threshold in the maximal test at 24 hours after AT compared to sham treatment. This result indicates for the first time that AT can increase pain tolerability, rather than affecting the minimal pain threshold. PMID- 26236379 TI - Interaction of Glucagon G-Protein Coupled Receptor with Known Natural Antidiabetic Compounds: Multiscoring In Silico Approach. AB - Glucagon receptor (GCGR) is a secretin-like (class B) family of G-protein coupled receptors (GPCRs) in humans that plays an important role in elevating the glucose concentration in blood and has thus become one of the promising therapeutic targets for treatment of type 2 diabetes mellitus. GCGR based inhibitors for the treatment of type 2 diabetes are either glucagon neutralizers or small molecular antagonists. Management of diabetes without any side effects is still a challenge to the medical system, and the search for a new and effective natural GCGR antagonist is an important area for the treatment of type 2 diabetes. In the present study, a number of natural compounds containing antidiabetic properties were selected from the literature and their binding potential against GCGR was determined using molecular docking and other in silico approaches. Among all selected natural compounds, curcumin was found to be the most effective compound against GCGR followed by amorfrutin 1 and 4-hydroxyderricin. These compounds were rescored to confirm the accuracy of binding using another scoring function (x score). The final conclusions were drawn based on the results obtained from the GOLD and x-score. Further experiments were conducted to identify the atomic level interactions of selected compounds with GCGR. PMID- 26236381 TI - Sympathetic Arousal during a Touch-Based Healing Ritual Predicts Increased Well Being. AB - Objective. There is mounting evidence that more elaborate treatment rituals trigger larger nonspecific effects. The reasons for this remain unclear. In a pilot field study, we investigated the role of psychophysiological changes during a touch-based healing ritual for improvements in subjective well-being. Methods. Heart rate, respiratory rate, and skin conductance levels (SCL) were continuously assessed in 22 subjects before, during, and after a touch-based healing ritual. Participants rated their expectations and subjective well-being was assessed before and after the ritual by the "Short Questionnaire on Current Disposition". Results. Subjective well-being increased significantly from before to after the ritual. The analysis of psychophysiological changes revealed a significant increase in respiratory rate from baseline to ritual, while skin conductance, heart rate, and heart rate variability did not change. Increases in SCL as well as decreases in respiratory rate from baseline to ritual were significantly associated with improvements in subjective well-being. Regression analyses showed increases in SCL to be the only significant predictor of improvements in well being. Conclusion. Higher sympathetic arousal during a touch-based healing ritual predicted improvements in subjective well-being. Results suggest the occurrence of an anticipatory stress response, that is, a state of enhanced sympathetic activity that is known to precede relaxation. PMID- 26236380 TI - Effect of Imperatorin on the Spontaneous Motor Activity of Rat Isolated Jejunum Strips. AB - Imperatorin, a psoralen-type furanocoumarin, is a potent myorelaxant agent acting as a calcium antagonist on vascular smooth muscle. Its effects on other types of smooth muscle remain unknown. Therefore, the aim of this study was to investigate the hypothesized myorelaxant effect of imperatorin on gut motor activity and, possibly, to define the underlying mechanism of action. Imperatorin was made available for pharmacological studies from the fruits of the widely available Angelica officinalis through the application of high-performance countercurrent chromatography (HPCCC). Imperatorin generated reversible relaxation of jejunum strips dose-dependently (1-100 MUM). At 25 and 50 MUM, imperatorin caused relaxation comparable to the strength of the reaction induced by isoproterenol (Isop) at 0.1 MUM. The observed response resulted neither from the activation of soluble guanylate cyclase, nor from beta-adrenoreceptor involvement, nor from Ca(2+)-activated potassium channels. Imperatorin relaxed intestine strips precontracted with high potassium concentration, attenuated the force and duration of K(+)-induced contractions, and modulated the response of jejunum strips to acetylcholine. The results suggest that imperatorin probably interacts with various Ca(2+) influx pathways in intestine smooth muscle. The types of some calcium channels involved in the activity of imperatorin will be examined in a subsequent study. PMID- 26236382 TI - Apoptosis-Inducing Activity of Marine Sponge Haliclona sp. Extracts Collected from Kosrae in Nonsmall Cell Lung Cancer A549 Cells. AB - Although various anticancer drugs have been developed for the treatment of nonsmall cell lung cancer, chemotherapeutic efficacy is still limited. Natural products such as phytochemicals have been screened as novel alternative materials, but alternative funds such as marine bioresources remain largely untapped. Of these resources, marine sponges have undergone the most scrutiny for their biological activities, including antiinflammatory, antiviral, and anticancer properties. However, the biological mechanisms of the activities of these marine sponges are still unclear. We investigated the anticancer activity of marine sponges collected from Kosrae in Micronesia and examined their mechanisms of action using nonsmall cell lung cancer A549 cells as a model system. Of 20 specimens, the Haliclona sp. (KO1304-328) showed both dose- and time-dependent cytotoxicity. Further, methanol extracts of Haliclona sp. significantly inhibited cell proliferation and cell viability. A549 cells treated with Haliclona sp. demonstrated induced expression of c-Jun N-terminal kinase (JNK), p53, p21, caspase-8, and caspase-3. The percentage of apoptotic cells significantly increased in A549 cultures treated with Haliclona sp. These results indicate that Haliclona sp. induces apoptosis via the JNK-p53 pathway and caspase 8, suggesting that this marine sponge is a good resource for the development of drugs for treatment of nonsmall cell lung cancer. PMID- 26236383 TI - Bioceramic Resonance Effect on Meridian Channels: A Pilot Study. AB - Bioceramic is a kind of material which emits nonionizing radiation and luminescence, induced by visible light. Bioceramic also facilitates the breakup of large clusters of water molecules by weakening hydrogen bonds. Hydrogen bond weakening, which allows water molecules to act in diverse ways under different conditions, is one of the key mechanisms underlying the effects of Bioceramic on biophysical and physical-chemical processes. Herein, we used sound to amplify the effect of Bioceramic and further developed an experimental device for use in humans. Thirteen patients who suffered from various chronic and acute illnesses that severely affected their sleep patterns and life quality were enrolled in a trial of Bioceramic resonance (i.e., rhythmic 100-dB sound waves with frequency set at 10 Hz) applied to the skin surface of the anterior chest. According to preliminary data, a "Propagated Sensation along Meridians" (PSM) was experienced in all Bioceramic resonance-treated patients but not in any of the nine control patients. The device was believed to enhance microcirculation through a series of biomolecular and physiological processes and to subject the specific meridian channels of Traditional Chinese Medicine (TCM) to coherent vibration. This noninvasive technique may offer an alternative to needle acupuncture and other traditional medical practices with clinical benefits. PMID- 26236384 TI - Antioxidant and Anti-Inflammatory Activities of Kenyan Leafy Green Vegetables, Wild Fruits, and Medicinal Plants with Potential Relevance for Kwashiorkor. AB - Background. Inflammation, together with related oxidative stress, is linked with the etiology of kwashiorkor, a form of severe acute malnutrition in children. A diet rich in anti-inflammatory and antioxidant phytochemicals may offer potential for the prevention and treatment of kwashiorkor. We selected and assayed five leafy green vegetables, two wild fruits, and six medicinal plants from Kenya for their antioxidant and anti-inflammatory properties. Consensus regarding medicinal plant use was established from ethnobotanical data. Methods. Antioxidant activity and phenolic content were determined using the oxygen radical absorbance capacity (ORAC) assay and Folin-Ciocalteu procedure, respectively. Anti-inflammatory activity was assessed in vitro targeting the inflammatory mediator tumour necrosis factor-alpha (TNF-alpha). Results. Mangifera indica (leaves used medicinally) showed the greatest antioxidant activity (5940 +/- 632 uM TE/ug) and total phenolic content (337 +/- 3 mg GAE/g) but Amaranthus dubius (leafy vegetable) showed the greatest inhibition of TNF-alpha (IC50 = 9 +/- 1 MUg/mL), followed by Ocimum americanum (medicinal plant) (IC50 = 16 +/- 1 MUg/mL). Informant consensus was significantly correlated with anti-inflammatory effects among active medicinal plants (r (2) = 0.7639, P = 0.0228). Conclusions. Several plant species commonly consumed by Kenyan children possess activity profiles relevant to the prevention and treatment of kwashiorkor and warrant further investigation. PMID- 26236385 TI - Induction of Thioredoxin Reductase 1 by Korean Red Ginseng Water Extract Regulates Cytoprotective Effects on Human Endothelial Cells. AB - Korean Red Ginseng is a popular herbal medicine and is widely used in many food products. KRG has biological benefits related to vascular diseases including diabetes, hypertension, atherosclerosis, and other cardiac diseases and KRG has antioxidant and anti-hyperlipidemic actions. KRG decreases the level of oxidative stress and suppresses proinflammatory cytokines and cell adhesion molecules, thus protecting endothelial dysfunction. Mammalian Thioredoxin reductase 1 is an NADPH dependent selenoprotein, essential for antioxidant defense and DNA synthesis and repair, that regulates the redox system by modulating redox-sensitive transcription factors and thiol-containing proteins. Here, we show that KRG water extract increases the expression of TrxR1 in human umbilical vein endothelial cells via the p38 and PKC-delta signaling pathways. The induction of TrxR1 expression by KRG was confirmed by Western blot analysis and reverse transcription polymerase chain reaction. However, the increase in TrxR1 expression was abolished by specific silencing of the p38 and PKC-delta genes. In addition, we demonstrated that auranofin, a TrxR1 inhibitor, weakens the protective effect of KRG against H2O2-induced cell death as measured by the terminal transferase dUTP nick end labeling assay. These results suggest that KRG may have protective effects in vascular diseases by upregulating TrxR1 in endothelial cells, thereby inhibiting the generation of reactive oxygen species and cell death. PMID- 26236386 TI - Intestinal obstruction in a mentally retarded patient due to pica. AB - A 40-year-old mentally retarded Japanese man was admitted at rehabilitation facility for handicapped persons and found dead in his bed. His neonatal period was complicated by seizures, and he had a medical history of schizophrenia. A postmortem computed tomography scan suggested an intestinal obstruction, but the cause was unknown. To clarify the cause of death, a medicolegal autopsy was carried out. The gastrointestinal tract was found to contain copious amounts of cloth pieces. A diagnosis of intestinal obstruction secondary to pica of clothes was made. Despite still being an essentially neglect condition; mental retardation is cause to significant burden to the patient, his relatives and caregivers and the whole society. Moreover, people with mental retardation may be at increased risk for potentially self-injury due to ingestion of non-eating substance or incongruent intake of eating substances, which may on turn lead to severe or even life-threatening medical and surgical complications as herein reported. Specific attention also to pica in mentally-retarded patients with sudden, severe, gastrointestinal events, should therefore be placed in order to prevent potential death or otherwise severe chronic consequences, ideally aiming at enhancing the early recognition and multi-disciplinary management of those psychological stressors or triggers potentially responsible for pica too. PMID- 26236387 TI - A case of methyl ethyl ketone peroxide poisoning and a review of complications and their management. AB - Methyl Ethyl Ketone Peroxide (MEKP) is a highly toxic clear liquid used as a solvent. It is a strong oxidizing agent and a corrosive. Acute and chronic toxicity can occur as an occupational hazard. Ingestion is associated with corrosive burns leading to stricture formation, inhalational pneumonitis, acidosis, liver failure and renal failure. In this paper we present a case of a young patient who intentionally ingested MEKP. The patient developed multiple complications including proximal intestinal obstruction, acidosis and acute kidney injury. He was managed conservatively and recovered after a prolonged hospital stay. He had multiple inflammatory strictures on esophageal endoscopy, which improved over 3-6 moths. PMID- 26236388 TI - Comet assay based DNA evaluation of fuel filling stations and automobile workshops workers from Khyber Pakhtunkhwa province, Pakistan. AB - BACKGROUND: Fuel filling stations workers and automobile workshops mechanics are consistently exposed to gasoline hydrocarbons during their occupation, this may cause DNA damage. Objective of this study was to evaluate the level of DNA damage in subjects occupationally exposed to these hydrocarbons. METHODS: Comet assay was performed on blood lymphocytes of exposed subjects to assess the probable DNA damage. 100 cells per individual were scored and graded by comet tail length. Exposed group consisted of 98 subjects (age 25.4 +/- 7.2 years), of which 68 were CNG/Petrol filling men and 30 were automobile workshop workers, selected randomly from different service stations and automobile workshops of populated and adjacent cities of Peshawar, Mardan and Nowshera of Khyber Pakhtunkhwa province, while control group included 92 subjects (age 26.7 +/- 11.8 years) were also from the same areas. RESULTS: Significantly high level of DNA damage was found in the subjects exposed to gasoline hydrocarbons as compared to control subjects (173.2 +/- 50.1 and 61.0 +/- 25.0, P = 0.001, respectively). Period of exposure and use of tobacco also showed considerable effects (P < 0.05) on DNA damage, while effect of age and daily working hours on total comet score (TCS) were non significant (P > 0.05). CONCLUSIONS: The results of our study concluded that petroleum hydrocarbons have the potential to cause DNA damage in the exposed subjects. The study also suggested that protective strategies should be implemented by the concerned authorities to minimize exposure to fuel hydrocarbons. PMID- 26236389 TI - Do overweight workers profit by workplace health promotion, more than their normal-weight peers? Evaluation of a worksite intervention. AB - BACKGROUND: Worksite health promotion programs have been identified as strongly effective in decreasing body weight and increasing awareness and change in health behavior. Aim of this study is to determine the effects of a multi-component intervention in workplace health promotion. METHODS: In a controlled study trail, 1,573 workers of a logistics company had the chance to participate in a one year worksite health promotion program. Main elements of the multi-component intervention were physical activity training in combination with nutrition counseling. Employees completed a questionnaire at baseline and then again after twelve month. Main outcome variables were changes in body weight and health behaviors. Secondary outcomes were subjective health indicators. RESULTS: Our results showed preliminary improvements in physical activity and eating behavior among normal weight and overweight/obesity weight groups. No significant weight reduction could be found, only a minimal reduction of BMI. The reduction was larger in the overweight group. Workers considered overweight or obese showed significantly greater body weight loss and changes in eating behavior than workers with a normal weight status. Workers with obesity/overweight scored their general health status significantly lower than their colleagues with normal weight status. No significant improvements were found for overall perception of health status between baseline and follow-up in the BMI-groups. CONCLUSION: This 12-month intervention-control study suggests that a well-implemented multi component workplace health promotion program may support substantial change in health behavior (e.g. nutrition and physical activity). It is indicated that overweight employees may especially profit from such worksite health promotion. An investigation of long-term effects of this multi-component intervention is strongly recommended. PMID- 26236390 TI - Automated Delineation of Vessel Wall and Thrombus Boundaries of Abdominal Aortic Aneurysms Using Multispectral MR Images. AB - A correct patient-specific identification of the abdominal aortic aneurysm is useful for both diagnosis and treatment stages, as it locates the disease and represents its geometry. The actual thickness and shape of the arterial wall and the intraluminal thrombus are of great importance when predicting the rupture of the abdominal aortic aneurysms. The authors describe a novel method for delineating both the internal and external contours of the aortic wall, which allows distinguishing between vessel wall and intraluminal thrombus. The method is based on active shape model and texture statistical information. The method was validated with eight MR patient studies. There was high correspondence between automatic and manual measurements for the vessel wall area. Resulting segmented images presented a mean Dice coefficient with respect to manual segmentations of 0.88 and a mean modified Hausdorff distance of 1.14 mm for the internal face and 0.86 and 1.33 mm for the external face of the arterial wall. Preliminary results of the segmentation show high correspondence between automatic and manual measurements for the vessel wall and thrombus areas. However, since the dataset is small the conclusions cannot be generalized. PMID- 26236392 TI - NLRP1 and NLRP3 polymorphisms in mesothelioma patients and asbestos exposed individuals a population-based autopsy study from North East Italy. AB - NRLP1 (rs12150220, rs9889625, rs9900356, rs6502867, rs2670660) and NLRP3 (rs35829419, rs10754558) polymorphisms have been analyzed in 69 subjects with documented asbestos exposure and death for malignant pleural mesothelioma and 59 patients with documented asbestos exposure but death for other causes, all from a North East Italy. No association was found between NLRP1 and NLRP3 polymorphisms and susceptibility to develop mesothelioma using the general, dominant or recessive models. Also haplotype analysis did not reveal any significant association with mesothelioma. Our findings, being controversial with respect to another study on Italian patients, do suggest the need of further studies to unravel the contribution of NLRP1 and NLRP3 in susceptibility to mesothelioma. PMID- 26236391 TI - Surgical management of AAST grades III-V hepatic trauma by Damage control surgery with perihepatic packing and Definitive hepatic repair-single centre experience. AB - BACKGROUND: Severe liver injury in trauma patients still accounts for significant morbidity and mortality. Operative techniques in liver trauma are some of the most challenging. They include the broad and complex area, from damage control to liver resection. MATERIAL AND METHOD: This is a retrospective study of 121 trauma patients with hepatic trauma American Association for Surgery of Trauma (AAST) grade III-V who have undergone surgery. Indications for surgery include refractory hypotension not responding to resuscitation due to uncontrolled hemorrhage from liver trauma; massive hemoperitonem on Focused assessment by ultrasound for trauma (FAST) and/or Diagnostic peritoneal lavage (DPL) as well as Multislice Computed Tomography (MSCT) findings of the severe liver injury and major vascular injuries with active bleeding. RESULTS: Non-survivors have significantly higher AAST grade of liver injury and higher Injury Severity Score (ISS) (p = 0.000; p = 0.0001). Non-survivors have significant hypotension on arrival and lower Glasgow Coma Scale (GCS) on admission (p = 0.000; p = 0.0001). Definitive hepatic repair was performed in 62(51.2 %) patient. Damage Control, liver packing and planned re-laparotomy after 48 h were used in 59(48.8 %). There was no statistically significant difference in terms of the surgical approach. There was significant difference in the amount of red blood cells (RBC) transfusion in the first 24 h between survivors and non-survivors (p = 0.001). Overall mortality rate was 33.1 %. Regarding complications non-survivors had significantly prolonged bleeding and higher rate of Acute respiratory distress syndrome (ARDS) (p = 0.0001; p = 0.0001), while survivors had significantly higher rate of pleural effusion (p = 0.0001). CONCLUSION: All efforts in the treatment of severe liver injuries should be directed to the rapid and effective control of bleeding, because uncontrollable hemorrhage is the cause of early death and it requires massive blood transfusion, all of which contributes to the late fatal complication. PMID- 26236393 TI - The Mechanics of Human Achievement. AB - Countless studies have addressed why some individuals achieve more than others. Nevertheless, the psychology of achievement lacks a unifying conceptual framework for synthesizing these empirical insights. We propose organizing achievement related traits by two possible mechanisms of action: Traits that determine the rate at which an individual learns a skill are talent variables and can be distinguished conceptually from traits that determine the effort an individual puts forth. This approach takes inspiration from Newtonian mechanics: achievement is akin to distance traveled, effort to time, skill to speed, and talent to acceleration. A novel prediction from this model is that individual differences in effort (but not talent) influence achievement (but not skill) more substantially over longer (rather than shorter) time intervals. Conceptualizing skill as the multiplicative product of talent and effort, and achievement as the multiplicative product of skill and effort, advances similar, but less formal, propositions by several important earlier thinkers. PMID- 26236394 TI - Predictors of self-injury cessation and subsequent psychological growth: results of a probability sample survey of students in eight universities and colleges. AB - BACKGROUND: Factors affecting non-suicidal self-injury cessation are poorly understood. The aim of this study was to identify differences between individuals with current and past non-suicidal self-injury (NSSI) in a large probability sample of university students using quantitative and qualitative methods. Predictors of psychological growth related following NSSI cessation were also examined. METHOD: The sample included 836 students who participated in a larger online study of well-being at eight U.S. colleges and who reported current or past history of repeated NSSI. The average age of respondents used in analysis was 21.3 years. They were 78.3 % female and 21.7 % male and were 70.7 % Caucasian, 1.4 % African American/Black, 5.5 % Hispanic, 7.8 % Asian/Asian American and 14.7 % other. Analyses tested differences in demographics, NSSI characteristics (e.g. lifetime frequency, number of NSSI functions, NSSI disclosure), formal help-seeking, psychosocial factors, and mental health and trauma histories. RESULTS: Individuals with current NSSI status were more likely to be female and slightly younger, to report higher NSSI lifetime frequency, more NSSI forms and functions, thinking of themselves as a "self-injurer", and current psychological distress. Individuals with current NSSI status were less likely to report that self-injury interfered with life, that therapy was useful in stopping, perceiving social support, having a sense of meaning in life, access to more emotion regulation strategies, and life satisfaction. Qualitative data suggested that cessation may be attributable to changes in ability to regulate emotion (62.6 %), self-awareness (38.7 %), and important relationships to others (36.0 %). Psychological growth after stopping NSSI was predicted by more severe NSSI (form and perceived NSSI dependence), having talked about NSSI with others and higher numbers of confidantes, perceived life satisfaction, and a history of suicide action. CONCLUSIONS: These findings add to the still nascent body of literature examining processes related to NSSI cessation. Our results point to the importance of help-seeking and social support, as well as psychosocial processes in stopping NSSI. PMID- 26236395 TI - Alleviation of carbon catabolite repression in Enterobacter aerogenes for efficient utilization of sugarcane molasses for 2,3-butanediol production. AB - BACKGROUND: Due to its cost-effectiveness and rich sugar composition, sugarcane molasses is considered to be a promising carbon source for biorefinery. However, the sugar mixture in sugarcane molasses is not consumed as efficiently as glucose in microbial fermentation due to complex interactions among their utilizing pathways, such as carbon catabolite repression (CCR). In this study, 2,3 butanediol-producing Enterobacter aerogenes was engineered to alleviate CCR and improve sugar utilization by modulating its carbon preference. RESULTS: The gene encoding catabolite repressor/activator (Cra) was deleted in the genome of E. aerogenes to increase the fructose consumption rate. However, the deletion mutation repressed sucrose utilization, resulting in the accumulation of sucrose in the fermentation medium. Cra regulation on expression of the scrAB operon involved in sucrose catabolism was verified by reverse transcription and real time PCR, and the efficiency of sucrose utilization was restored by disrupting the scrR gene and overexpressing the scrAB operon. In addition, overexpression of the ptsG gene involved in glucose utilization enhanced the glucose preference among mixed sugars, which relieved glucose accumulation in fed-batch fermentation. In fed-batch fermentation using sugarcane molasses, the maximum titer of 2,3-butanediol production by the mutant reached 140.0 g/L at 54 h, which was by far the highest titer of 2,3-butanediol with E. aerogenes achieved through genetic engineering. CONCLUSIONS: We have developed genetically engineered E. aerogenes as a 2,3-butanediol producer that efficiently utilizes sugarcane molasses. The fermentation efficiency was dramatically improved by the alleviation of CCR and modulation of carbon preference. These results offer a metabolic engineering approach for achieving highly efficient utilization of mixed sugars for the biorefinery industry. PMID- 26236397 TI - Model-driven intracellular redox status modulation for increasing isobutanol production in Escherichia coli. AB - BACKGROUND: Few strains have been found to produce isobutanol naturally. For building a high performance isobutanol-producing strain, rebalancing redox status of the cell was very crucial through systematic investigation of redox cofactors metabolism. Then, the metabolic model provided a powerful tool for the rational modulation of the redox status. RESULTS: Firstly, a starting isobutanol-producing E. coli strain LA02 was engineered with only 2.7 g/L isobutanol produced. Then, the genome-scale metabolic modeling was specially carried out for the redox cofactor metabolism of the strain LA02 by combining flux balance analysis and minimization of metabolic adjustment, and the GAPD reaction catalyzed by the glyceraldehyde-3-phosphate dehydrogenase was predicted as the key target for redox status improvement. Under guidance of the metabolic model prediction, a gapN-encoding NADP(+) dependent glyceraldehyde-3-phosphate dehydrogenase pathway was constructed and then fine-tuned using five constitutive promoters. The best strain LA09 was obtained with the strongest promoter BBa_J23100. The NADPH/NADP + ratios of strain LA09 reached 0.67 at exponential phase and 0.64 at stationary phase. The redox modulations resulted in the decrease production of ethanol and lactate by 17.5 and 51.7% to 1.32 and 6.08 g/L, respectively. Therefore, the isobutanol titer was increased by 221% to 8.68 g/L. CONCLUSIONS: This research has achieved rational redox status improvement of isobutanol-producing strain under guidance of the prediction and modeling of the genome-scale metabolic model of isobutanol-producing E. coli strain with the aid of synthetic promoters. Therefore, the production of isobutanol was dramatically increased by 2.21-fold from 2.7 to 8.68 g/L. Moreover, the developed model-driven method special for redox cofactor metabolism was of very helpful to the redox status modulation of other bio-products. PMID- 26236396 TI - Closely related fungi employ diverse enzymatic strategies to degrade plant biomass. AB - BACKGROUND: Plant biomass is the major substrate for the production of biofuels and biochemicals, as well as food, textiles and other products. It is also the major carbon source for many fungi and enzymes of these fungi are essential for the depolymerization of plant polysaccharides in industrial processes. This is a highly complex process that involves a large number of extracellular enzymes as well as non-hydrolytic proteins, whose production in fungi is controlled by a set of transcriptional regulators. Aspergillus species form one of the best studied fungal genera in this field, and several species are used for the production of commercial enzyme cocktails. RESULTS: It is often assumed that related fungi use similar enzymatic approaches to degrade plant polysaccharides. In this study we have compared the genomic content and the enzymes produced by eight Aspergilli for the degradation of plant biomass. All tested Aspergilli have a similar genomic potential to degrade plant biomass, with the exception of A. clavatus that has a strongly reduced pectinolytic ability. Despite this similar genomic potential their approaches to degrade plant biomass differ markedly in the overall activities as well as the specific enzymes they employ. While many of the genes have orthologs in (nearly) all tested species, only very few of the corresponding enzymes are produced by all species during growth on wheat bran or sugar beet pulp. In addition, significant differences were observed between the enzyme sets produced on these feedstocks, largely correlating with their polysaccharide composition. CONCLUSIONS: These data demonstrate that Aspergillus species and possibly also other related fungi employ significantly different approaches to degrade plant biomass. This makes sense from an ecological perspective where mixed populations of fungi together degrade plant biomass. The results of this study indicate that combining the approaches from different species could result in improved enzyme mixtures for industrial applications, in particular saccharification of plant biomass for biofuel production. Such an approach may result in a much better improvement of saccharification efficiency than adding specific enzymes to the mixture of a single fungus, which is currently the most common approach used in biotechnology. PMID- 26236399 TI - Cytogenetic and molecular characterization of a recombinant X chromosome in a family with a severe neurologic phenotype and macular degeneration. AB - BACKGROUND: Duplications of MECP2 gene in males cause a syndrome characterized by distinctive clinical features, including severe to profound mental retardation, infantile hypotonia, mild dysmorphic features, poor speech development, autistic features, seizures, progressive spasticity and recurrent infections. Patients with complex chromosome rearrangements, leading to Xq28 duplication, share most of the clinical features of individuals with tandem duplications, in particular neurologic problems, suggesting a major pathogenetic role of MECP2 overexpression. RESULTS: We performed cytogenetic and molecular cytogenetic studies in a previously described family with affected males showing congenital ataxia, late-onset progressive myoclonic encephalopathy and selective macular degeneration. Microsatellite, FISH and array-CGH analyses identified a recombinant X chromosome with a deletion of the PAR1 region, encompassing SHOX, replaced by a duplicated segment of the Xq28 terminal portion, including MECP2. CONCLUSIONS: Our report describes the identification of the actual genetic cause underlying a severe syndrome that previous preliminary analyses erroneously associated to a terminal Xp22.33 region. In the present family as well as in previously reported patients with similar rearrangements, the observed neurologic phenotype is ascribable to MECP2 duplication, with an undefined contribution of the other involved genes. Maculopathy, presented by affected males reported here, could be a novel clinical feature associated to Xq28 disomy due to recombinant X chromosomes, but at present the underlying pathogenetic mechanism is unknown and this potential clinical correlation should be confirmed through the collection of additional patients. PMID- 26236398 TI - A recurrent deletion on chromosome 2q13 is associated with developmental delay and mild facial dysmorphisms. AB - We report two unrelated patients with overlapping chromosome 2q13 deletions (patient 1 in chr2:111415137-113194067 bp and patient 2 in chr2:110980342 113007823 bp, hg 19). Patient 1 presents with developmental delay, microcephaly and mild dysmorphic facial features, and patient 2 with autism spectrum disorder, borderline cognitive abilities, deficits in attention and executive functions and mild dysmorphic facial features. The mother and maternal grandmother of patient 1 were healthy carriers of the deletion. Previously, 2q13 deletions were reported in 27 patients, and the interpretation of its clinical significance varied. Our findings support that the 2q13 deletion is associated with a developmental delay syndrome manifesting with variable expressivity and reduced penetrance which poses a challenge for genetic counselling as well as the clinical recognition of 2q13 deletion patients. PMID- 26236400 TI - The BisPCR(2) method for targeted bisulfite sequencing. AB - BACKGROUND: DNA methylation has emerged as an important regulator of development and disease, necessitating the design of more efficient and cost-effective methods for detecting and quantifying this epigenetic modification. Next generation sequencing (NGS) techniques offer single base resolution of CpG methylation levels with high statistical significance, but are also high cost if performed genome-wide. Here, we describe a simplified targeted bisulfite sequencing approach in which DNA sequencing libraries are prepared following sodium bisulfite conversion and two rounds of PCR for target enrichment and sample barcoding, termed BisPCR(2). RESULTS: We have applied the BisPCR(2) technique to validate differential methylation at several type 2 diabetes risk loci identified in genome-wide studies of human islets. We confirmed some previous findings while not others, in addition to identifying novel differentially methylated CpGs at these genes of interest, due to the much higher depth of sequencing coverage in BisPCR(2) compared to prior array-based approaches. CONCLUSION: This study presents a robust, efficient, and cost effective technique for targeted bisulfite NGS, and illustrates its utility by reanalysis of prior findings from genome-wide studies. PMID- 26236401 TI - Immunotherapy treatments for small-cell lung cancer: past, present and future. AB - Small-cell lung cancer remains a considerable cause of morbidity and mortality. To this day, first-line therapy continues to be a platinum agent with etoposide, combined with radiation therapy in cases of limited stage disease. Numerous, largely unsuccessful, attempts at controlling the disease have included different chemotherapy strategies, the utilization of antiangiogenic agents, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors and other treatment modalities. Immunotherapy, including vaccines, immune response modifiers, inhibitors of check point blockades and immunologic-targeted toxins may well be the future of treatment, not only to enhance the proven chemotherapy effects, but to improve the control of minimal residual disease and the response with salvage chemotherapy. This article reviews the current advances in immunotherapeutic strategies against small-cell lung cancer. PMID- 26236402 TI - Synergy Maps: exploring compound combinations using network-based visualization. AB - BACKGROUND: The phenomenon of super-additivity of biological response to compounds applied jointly, termed synergy, has the potential to provide many therapeutic benefits. Therefore, high throughput screening of compound combinations has recently received a great deal of attention. Large compound libraries and the feasibility of all-pairs screening can easily generate large, information-rich datasets. Previously, these datasets have been visualized using either a heat-map or a network approach-however these visualizations only partially represent the information encoded in the dataset. RESULTS: A new visualization technique for pairwise combination screening data, termed "Synergy Maps", is presented. In a Synergy Map, information about the synergistic interactions of compounds is integrated with information about their properties (chemical structure, physicochemical properties, bioactivity profiles) to produce a single visualization. As a result the relationships between compound and combination properties may be investigated simultaneously, and thus may afford insight into the synergy observed in the screen. An interactive web app implementation, available at http://richlewis42.github.io/synergy-maps, has been developed for public use, which may find use in navigating and filtering larger scale combination datasets. This tool is applied to a recent all-pairs dataset of anti-malarials, tested against Plasmodium falciparum, and a preliminary analysis is given as an example, illustrating the disproportionate synergism of histone deacetylase inhibitors previously described in literature, as well as suggesting new hypotheses for future investigation. CONCLUSIONS: Synergy Maps improve the state of the art in compound combination visualization, by simultaneously representing individual compound properties and their interactions. The web-based tool allows straightforward exploration of combination data, and easier identification of correlations between compound properties and interactions. PMID- 26236403 TI - Solid Phase Extraction of Trace Elements in Waterand Tissue Samples on a Mini Column with Diphenylcarbazone Impregnated Nano-TiO2 and Their Determination by Inductively Coupled Plasma Optical Emission Spectrometry. AB - This study presents a simple, robust and environmentally friendly solid phase preconcentration procedure for multielement determination by inductively coupled plasma optical emission spectrometry (ICP-OES) using diphenylcarbazone (DPC) impregnated TiO2 nanopowder (n-TiO2). DPC was successfully impregnated onto n TiO2 in colloidal solution. A number of elements, including Co(II), Cr(III), Cu(II), Fe(III), Mn(II) and Zn(II) were quantitatively preconcentrated from aqueous solutions between pH 8 and 8.5 at a flow rate of 2 mL min-1, and then eluted with 2 mL of 5% (v/v) HNO3. A mini-column packed with 0.12 g DPC impregnated n-TiO2 retained all elements quantitatively from up to 250 mL multielement solution (2.5 MUg per analyte) affording an enrichment factor of 125. The limits of detection (LOD) for preconcentration of 50 mL blank solutions (n = 12) were 0.28, 0.15, 0.25, 0.22, 0.12, and 0.10 MUg L-1 for Co, Cr, Cu, Fe, Mn, and Zn, respectively. The relative standard deviation (RSD) for five replicate determinations was 0.8, 3.4, 2.6, 2.2, 1.2 and 3.3% for Co, Cr, Cu, Fe, Mn and Zn, respectively, at 5 MUg L-1 level. The method was validated with analysis of Freshwater (SRM 1643e) and Lobster hepatopancreas (TORT-2) certified reference materials, and then applied to the determination of the elements from tap water and lake water samples by ICP-OES. PMID- 26236405 TI - Some (dis)assembly required: partial unfolding in the Par-6 allosteric switch. AB - Allostery is commonly described as a functional connection between two distant sites in a protein, where a binding event at one site alters affinity at the other. Here we review the conformational dynamics that encode an allosteric switch in the PDZ domain of Par-6. Par-6 is a scaffold protein that organizes other proteins into a complex required to initiate and maintain cell polarity. NMR measurements revealed that the PDZ domain samples an evolutionarily conserved unfolding intermediate allowing rearrangement of two adjacent loop residues that control ligand binding affinity. Cdc42 binding to Par-6 creates a novel interface between the PDZ domain and the adjoining CRIB motif that stabilizes the high affinity PDZ conformation. Thermodynamic and kinetic studies suggest that partial PDZ unfolding is an integral part of the Par-6 switching mechanism. The Par-6 CRIB-PDZ module illustrates two important structural aspects of protein evolution: the interface between adjacent domains in the same protein can give rise to allosteric regulation, and thermodynamic stability may be sacrificed to increase the sampling frequency of an unfolding intermediate required for conformational switching. PMID- 26236404 TI - Structural and functional connectivity in the default mode network in 22q11.2 deletion syndrome. AB - BACKGROUND: The neural endophenotype associated with 22q11.2 deletion syndrome (22q11DS) includes deviant cortical development and alterations in brain connectivity. Resting-state functional magnetic resonance imaging (fMRI) findings also reported disconnectivity within the default mode network (DMN). In this study, we explored the relationship between functional and structural DMN connectivity and their changes with age in patients with 22q11DS in comparison to control participants. Given previous evidence of an association between DMN disconnectivity and the manifestation of psychotic symptoms, we further investigated this relationship in our group of patients with 22q11DS. METHODS: T1 weighted, diffusion, and resting-state fMRI scans were acquired from 41 patients with 22q11DS and 43 control participants aged 6 to 28 years. A data-driven approach based on independent component analysis (ICA) was used to identify the DMN and to define regions of interest for the structural and functional connectivity analysis. Prodromal psychotic symptoms were assessed in adolescents and adults using the positive symptom scores of the Structured Interview of Prodromal Syndromes (SIPS). Connectivity measures were compared between groups and correlated with age. Repeating the between-group analysis in three different age bins further assessed the presence of age-related alterations in DMN connectivity. Structural and functional connectivity measures were then correlated with the SIPS scores. RESULTS: A simultaneous reduction of functional and structural connectivity between core medial nodes of the DMN was observed. Furthermore, structural connectivity measures significantly increased with age in the control group but not in patients with 22q11DS, suggesting the presence of an age-related alteration of the DMN structural connections. No correlations were found between the DMN disconnectivity and expression of prodromal symptoms in 22q11DS. CONCLUSIONS: These findings indicate the presence of functional and structural DMN disconnectivity in 22q11DS and that patients with 22q11DS fail to develop normal structural connections between medial DMN nodes. This suggests the presence of altered neurodevelopmental trajectories in 22q11DS. PMID- 26236406 TI - Hydrofluorination of Alkynes Catalysed by Gold Bifluorides. AB - We report the synthesis of nine new N-heterocyclic carbene gold bifluoride complexes starting from the corresponding N-heterocyclic carbene gold hydroxides. A new methodology to access N,N'-bis(2,6-diisopropylphenyl)imidazol-2-ylidene gold(I) fluoride starting from N,N'-bis(2,6-diisopropylphenyl)imidazol-2-ylidene gold(I) hydroxide and readily available potassium bifluoride is also reported. These gold bifluorides were shown to be efficient catalysts in the hydrofluorination of symmetrical and unsymmetrical alkynes, thus affording fluorinated stilbene analogues and fluorovinyl thioethers in good to excellent yields with high stereo- and regioselectivity. The method is exploited further to access a fluorinated combretastatin analogue selectively in two steps starting from commercially available reagents. PMID- 26236407 TI - DNA methylation levels are highly correlated between pooled samples and averaged values when analysed using the Infinium HumanMethylation450 BeadChip array. AB - BACKGROUND: DNA methylation is a heritable and stable epigenetic mark implicated in complex human traits. Epigenome-wide association studies (EWAS) using array based technology are becoming widely used to identify differentially methylated sites associated with complex diseases. EWAS studies require large sample sizes to detect small effects, which increases project costs. In the present study we propose to pool DNA samples in methylation array studies as an affordable and accurate alternative to individual samples studies, in order to reduce economic costs or when low amounts of DNA are available. For this study, 20 individual DNA samples and 4 pooled DNA samples were analysed using the Illumina Infinium HumanMethylation450 BeadChip array to evaluate the efficiency of the pooling approach in EWAS studies. Statistical power calculations were also performed to discover the minimum sample size needed for the pooling strategy in EWAS. RESULTS: A total of 485,577 CpG sites across the whole genome were assessed. Comparison of methylation levels of all CpG sites between individual samples and their related pooled samples revealed highly significant correlations (rho > 0.99, p-val < 10(-16)). These results remained similar when assessing the 101 most differentially methylated CpG sites (rho > 0.98, p-val < 10(-16)). Also, it was calculated that n = 43 is the minimum sample size required to achieve a 95 % statistical power and a 10(-06) significance level in EWAS, when using a DNA pool strategy. CONCLUSIONS: DNA pooling strategies seems to accurately provide estimations of averaged DNA methylation state using array based EWAS studies. This type of approach can be applied to the assessment of disease phenotypes, reducing the amount of DNA required and the cost of large-scale epigenetic analyses. PMID- 26236408 TI - The role of BRCA1 and BRCA2 mutations in prostate, pancreatic and stomach cancers. AB - The association of germline mutations in the breast cancer susceptibility gene 1 (BRCA1) and the breast cancer susceptibility gene 2 (BRCA2) with the development of breast and ovarian cancers have been widely researched and recognised. It is known that these genes function at multiple sites in the body. Research has subsequently evolved into the connection of BRCA1/2 with cancers at other sites within the body. This review examines the association of BRCA1/2 germline gene mutations with prostate, pancreatic and stomach cancers. An extensive literature search revealed conflicting findings regarding the association of BRCA1/2 gene mutations with these cancers. Most studies suggest that there is an association between BRCA1/2 mutations and carcinoma of the prostate, pancreas and stomach, but some reports propose that such a correlation may be due to factors other than possessing a mutated BRCA1/2 gene, and other associations may be revealed as further epidemiological information becomes available. The review concludes that as more knowledge arises about the mechanisms of BRCA1/2 gene mutations, it should pave the way for future screening programmes to be applied effectively. PMID- 26236409 TI - How to treat actinic keratosis? An update. AB - Actinic keratosis (AKs) is one of the most common skin lesions leading to an increased risk of developing squamous cell carcinoma and other skin malignancies. The lesions principally arise as a result of excessive ultraviolet (UV) exposure. AKs may regress spontaneously, remain stable or evolve to invasive squamous cell carcinoma. The risk of squamous cell carcinoma is significantly increased patients with more than 5 AKs. The main mechanisms involved in the formation of AK are inflammation, mutagenesis, oxidative stress, impaired apoptosis, immunosuppression, disregulation of cell growth and proliferation, and tissue remodeling. Human papilloma virus has also been correlated with the formation of some AKs. As an individual ages, his skin is exposed to increasing cumulative amounts of UV light and other environmental insults. This is especially true for the head, neck and forearms. These insults do not target only the skin where individual lesions develop, but also the surrounding area. In this area undetectable preclinical AK lesions or dysplastic cells may be present. The whole affected area is known as the 'field'. Therefore, management is divided into lesion-directed and field-directed therapies. Currently, the therapies in use are lesion-directed cryotherapy and/or excision, and field-directed topical agents: 5 fluorouracil, diclofenac, photodynamic therapy, imiquimod, and ingenol mebutate. Combining lesion- and field-directed therapies showed good results and several novel therapies are under investigation. Treatment is variable and personalized, what makes a gold standard management algorithm difficult to design. This review aims to describe the rationale behind the available treatment options for AKs based on current understanding of pathophysiology and epidemiology. PMID- 26236410 TI - Temporary henna tattoos and hypertrichosis: a case report and review of the literature. AB - BACKGROUND: Temporary black henna tattooing is highly popular among children and young adults in some regions. The unmonitored addition of different products to darken the color of pure henna has been the cause of many tattoo-associated dermatoses. OBSERVATION: Hypertrichosis secondary to henna pseudotattoo is a rare, newly recognized cutaneous manifestation. Only 4 case reports of henna tattooing causing localized hypertrichosis have been reported in the literature. We report a case of hypertrichosis and eczematous reaction to temporary henna tattoo. CONCLUSION: Hypertrichosis secondary to black henna is independent of the presence of contact dermatitis. The mechanism by which black henna induces hair growth remains unclear. PMID- 26236411 TI - Hemosiderotic dermatofibroma: clinical and dermoscopic presentation mimicking melanoma. AB - BACKGROUND: Dermatofibromas are common benign skin neoplasms. MAIN OBSERVATIONS: The authors report the clinical, dermoscopic and histopathological features of a hemosiderotic dermatofibroma mimicking melanoma in an 85-year-old woman. CONCLUSIONS: Atypical dermoscopic patterns may prove difficult to differentiate from melanocytic lesions, and because of its polymorphic, melanoma-like presentation, definite diagnosis of hemosiderotic dermatofibroma can be reached by histopathological examination. PMID- 26236412 TI - Pigmented colloid milium associated with exogenous ochronosis in a farmer with long-term exposure to fertilizers. AB - BACKGROUND: Colloid milium is a rare cutaneous deposition disorder characterized by translucent papules developing on sun-exposed regions such as the face, neck and dorsal aspects of the hands and back. Exogenous ochronosis is caused by the accumulation of homogentisic acid resulting from long-term application of certain topical agents. Histology is characterized by yellow-brown pigment deposits in the papillary dermis. Prolonged use of hydroquinone may result in the development of the pigmented form of colloid milium, sometimes in association with ochronosis. CASE REPORT: A 53-year-old man presented with a 3-year history of multiple slow spreading pigmented papules on the dorsa of his hands, nose and ears. The patient had a long history of exposure to sun and fertilizers with no history of using hydroquinone bleaching creams. A later biopsy revealed the diagnosis of pigmented colloid milium associated with exogenous ochronosis. CONCLUSION: UV light damage and long contact with fertilizers may have a role in the development of pigmented colloid milium associated with exogenous ochronosis. PMID- 26236413 TI - Erlotinib induced ectropion following papulopustular rash. AB - BACKGROUND: Erlotinib is a targeted anti-cancer drug which acts through the inhibition of epidermal growth factor receptor (EGFR). MAIN OBSERVATIONS: A 79 year-old developed bilateral ectropion after he received erlotinib treatment for lung adenocarcinoma. The ectropion completely resolved with symptomatic treatment without any modification in erlotinib therapy. CONCLUSIONS: EGFR inhibitors are frequently associated with a variety of mucocutaneous adverse events. Ocular toxicity associated with these agents has been reported rarely. We present this case to underline the importance of recognition of newly reported cutaneous and ocular adverse events of targeted therapies. PMID- 26236414 TI - Photoletter to the editor: Lamellar ichthyosis and arthrogryposis in a premature neonate. AB - Lamellar ichthyosis is a rare congenital disorder characterized by collodion membrane at birth and facial anomalies (eclabium and ectropion). The major underlying genetic defect is in TGM1, with mutations of this gene found in 50% of patients. An early diagnosis is fundamental in view of establishing a specific treatment due to the severity of the disease. We report a case of severe lamellar ichthyosis and arthrogryposis, without the typical facial presentation, negative for TGM1 mutations. The clinical improvement was achieved only after treatment with oral retinoids, highlighting the importance of early diagnosis and prompt administration of a specific therapy. PMID- 26236415 TI - Photoletter to the editor: Pigmented dermatofibrosarcoma protuberans in a 4-year old girl and ultrasonographic findings. AB - Dermatofibrosarcoma protuberans (DFSP) in children is often clinically misdiagnosed as hemangioma or vascular malformation. Ultrasonography and color Doppler imaging are useful noninvasive tools for the diagnosis of skin tumors and may help distinguish DFSP from other vascular skin lesions in children. PMID- 26236416 TI - Photoletter to the editor: An eczema-like, pruritic, nonbullous form of bullous pemphigoid. AB - We report a case with an unusual manifestation of bullous pemphigoid (BP) in a 57 year-old woman. She presented with a one-month history of pruritus and multiple annular patches with central regression on her trunk and extremities and there were no signs of corresponding internal malignancy. Eosinophilic spongiosis was observed in histopathologic examination and direct immunofluorescence studies revealed a strong linear staining pattern of the basement membrane zone with C3 and IgG. This unusual case indicates that a lack of blisters does not necessarily exclude a diagnosis of BP, and supports previous reports suggesting gyrate erythema can be an initial manifestation of bullous disease. PMID- 26236417 TI - Endovascular Stent-Graft Treatment of Giant Celiac Artery Pseudoaneurysm. AB - BACKGROUND: Visceral artery aneurysms (VAAs) comprise an uncommon but life threatening vascular disease. When rupture is the first clinical presentation, mortality rate reaches 70%. Increased use of cross-sectional imaging has led to a greater rate of diagnosis (40-80%) of asymptomatic VAAs. In the past, surgery was the treatment of choice for VAAs carrying high risk of mortality and morbidity. CASE REPORT: A 22-year-old man, who had undergone gastric, pancreatic and aortic surgery 2.5 years earlier, presented with progressive abdominal pain. Multidetector computed tomography scan revealed an 8-cm celiac pseudoaneurysm. We report a giant celiac pseudoaneurysm treated with stent-graft implantation. CONCLUSIONS: Endovascular treatment of VAA is a safe and effective method alternative to surgery. PMID- 26236418 TI - A Rare Complication of the Thyroid Malignancies: Jugular Vein Invasion. AB - BACKGROUND: Unilateral invasion of the internal jugular vein (IJV) after subtotal thyroidectomy caused by local recurrence of papillary thyroid carcinoma is extremely rare. We report a case of papillary thyroid carcinoma which invades IJV with hypervascular tumor thrombus. CASE REPORT: We report a case of a 52-year-old woman with a history of previous thyroid operation who presented with a 2-month history of a painless, growing, hard, solitary mass on the left side of the neck. Clinical examination revealed also ipsilateral cervical lymphadenopathy. Radiological examination showed a necrotic and cystic mass arising from the operated area extending and invading the left jugular vein wall with hypervascular tumor thrombus. Cytological examination of the mass confirmed a papillary thyroid carcinoma (PTC) and enlarged metastatic lymph nodes. Therefore, total thyroidectomy with left neck dissection and segmental resection of the left internal jugular vein were performed, and the tumor thrombus was cleared successfully. CONCLUSIONS: Invasion of IJV with hypervascular tumor thrombosis is an extremely rare condition in papillary thyroid carcinoma. Thrombosis of IJV is probably underdiagnosed. Early-stage diagnosis is important for long-term survival rates. PMID- 26236419 TI - Parental Monitoring and Risky Behavior in Bahamian Youth. AB - Adolescent involvement in risk behaviors is a concern that crosses geographical and cultural boundaries. Research has identified a number of factors which influence child behavior outcomes. This study explored the role of perceived neighborhood problems, parent-child relationships and parental monitoring, as they relate to engagement in risk behaviors among a sample of 497 Bahamian early adolescents. Contrary to the hypothesized direction, results of the latent growth model showed an increase in perceived parental monitoring over the four year period. Consistent with our hypotheses, adolescents who reported greater monitoring reported less involvement in sexual activity, less involvement in physical fights and less alcohol consumption. Positive interactions between parent and child also significantly predicted the initial status and rate of change of parental monitoring. PMID- 26236420 TI - MODELLING COUNTY LEVEL BREAST CANCER SURVIVAL DATA USING A COVARIATE-ADJUSTED FRAILTY PROPORTIONAL HAZARDS MODEL. AB - Understanding the factors that explain differences in survival times is an important issue for establishing policies to improve national health systems. Motivated by breast cancer data arising from the Surveillance Epidemiology and End Results program, we propose a covariate-adjusted proportional hazards frailty model for the analysis of clustered right-censored data. Rather than incorporating exchangeable frailties in the linear predictor of commonly-used survival models, we allow the frailty distribution to flexibly change with both continuous and categorical cluster-level covariates and model them using a dependent Bayesian nonparametric model. The resulting process is flexible and easy to fit using an existing R package. The application of the model to our motivating example showed that, contrary to intuition, those diagnosed during a period of time in the 1990s in more rural and less affluent Iowan counties survived breast cancer better. Additional analyses showed the opposite trend for earlier time windows. We conjecture that this anomaly has to be due to increased hormone replacement therapy treatments prescribed to more urban and affluent subpopulations. PMID- 26236421 TI - Perceptual mapping of chemesthetic stimuli in naive assessors. AB - Chemesthetic compounds, responsible for sensations such as burning, cooling, and astringency, are difficult stimuli to work with, especially when the evaluation task requires retasting. Here, we developed a protocol by which chemesthetic compounds can be assessed using sorting. We compared the performance of two cohorts of untrained assessors on this task, one with nose clips and the other without. Similarity matrices were analyzed using multidimensional scaling (MDS) to produce perceptual maps for the two cohorts. Overall, the groupings from the nose open cohort tended to follow a biological basis, consistent with previous findings that suggest compounds that activate a common receptor will elicit similar sensations. The nose-open and nose-pinched cohorts generated significantly different maps. The nose-pinched cohort had a higher variance in the MDS solution than the nose-open group. While the nose-open cohort generated seven clusters, the nose-pinched cohort generated only two clusters, seemingly based on the ready identification of chemesthetic sensations or not. There was less consensus regarding the attributes used to describe the samples in the nose pinched cohort than in the nose-open cohort as well, as this cohort collectively generated more attributes but fewer were significant in regression. PMID- 26236422 TI - BMI but Not Race Contributes to Vitamin D-Parathyroid Hormone Axis in Peripubertal Girls. AB - Currently, there is widespread interest in establishing 25-hydroxy vitamin D (25OHD) level preventing a secondary elevation in parathyroid hormone (PTH). The aim of this study was to identify the 25OHD nadir resulting in a rise of PTH and to determine if this inflection point is weight- or race-specific during growth and development in peripubertal girls. A total of 104 normal (n = 61) and overweight (n = 43) African American (AA) and European American (EA) girls, 5 to 14 years of age, were included. Though AAs had lower 25OHD levels, there was no difference in PTH compared with EAs. A 25OHD concentration of 27.2 ng/mL (P < .01) was indicated to increase PTH in normal-weight girls, although a statistically significant level was not established in overweight girls. No race difference in inflection point was observed. These data suggest a potential influence of weight status on the 25OHD-PTH inflection point in peripubertal girls. Accordingly, on determination of 25OHD level reflecting optimal health, consideration of weight status appears to be important during this critical period of growth and development. PMID- 26236423 TI - Neuroprotection by Cocktails of Dietary Antioxidants under Conditions of Nerve Growth Factor Deprivation. AB - Dietary antioxidants may be useful in counteracting the chronic inflammatory status in neurodegenerative diseases by reducing oxidative stress due to accumulation of reactive oxygen species (ROS). In this study, we newly described the efficacy of a number of dietary antioxidants (polyphenols, carotenoids, thiolic compounds, and oligoelements) on viability of neuronal PC12 cells following Nerve Growth Factor (NGF) deprivation, a model of age-related decrease of neurotrophic support that triggers neuronal loss. Neuroprotection by antioxidants during NGF deprivation for 24 h was largely dependent on their concentrations: all dietary antioxidants were able to efficiently support cell viability by reducing ROS levels and restoring mitochondrial function, while preserving the neuronal morphology. Moreover, ROS reduction and neuroprotection during NGF withdrawal were also achieved with defined cocktails of 3-6 different antioxidants at concentrations 5-60 times lower than those used in single treatments, suggesting that their antioxidant activity was preserved also at very low concentrations. Overall, these data indicate the beneficial effects of antioxidants against oxidative stress induced by decreased NGF availability and suggest that defined cocktails of dietary factors at low concentrations might be a suitable strategy to reduce oxidative damage in neurodegenerative diseases, while limiting possible side effects. PMID- 26236424 TI - Cytokine Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, and omega-3 PUFAs. AB - An involvement of the immune system has been suggested in Rett syndrome (RTT), a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2) or, more rarely, cyclin-dependent kinase-like 5 (CDKL5). To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg) response, as well as chemokines, were investigated in MECP2- (MECP2-RTT) (n = 16) and CDKL5 Rett syndrome (CDKL5-RTT) (n = 8), before and after omega-3 polyunsaturated fatty acids (PUFAs) supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. In MECP2-RTT, a Th2-shifted balance was evidenced, whereas in CDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4) were upregulated. In MECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced in CDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system. PMID- 26236427 TI - Dietary Antioxidant and Flavonoid Intakes Are Reduced in the Elderly. AB - The objective of this study was to determine sources and patterns of antioxidant and flavonoid intakes in the elderly (61-74 yrs) in comparison with young (20-40 yrs) and middle age (41-60 yrs) groups in a cross-sectional study. More than 6000 subjects of both genders, aged 20-74 years, participants of the National Multicenter Health Survey (WOBASZ) took part in this study. Daily food consumption was estimated by the single 24-hour dietary recall. Dietary total antioxidant capacity (TAC) and flavonoid content (FC) were calculated according to the amount of food consumed by the participants combined with antioxidant capacity and flavonoid contents in foods. Food consumption, dietary TAC, and FC were significantly lower in the elderly, especially elderly women in comparison to the young and middle age groups. The consumption of tea, coffee, and apples was associated with the largest contribution to dietary TAC and FC in all participants. Despite high nutrient density of the energy-adjusted diet of ageing people, the elderly consumed the lowest amounts of antioxidants and flavonoids due to the lowest food intake. PMID- 26236425 TI - The Effect of Etoricoxib on Hepatic Ischemia-Reperfusion Injury in Rats. AB - Ischemia-reperfusion (I/R) damage is known to be a pathological process which continues with the increase of oxidants and expands with the inflammatory response. There is not any study about protective effect of etoricoxib on the liver I/R damage in literature. OBJECTIVE: This study investigates the effect of etoricoxib on oxidative stress induced by I/R of the rat liver. MATERIAL AND METHODS: Experimental animals were divided into four groups as liver I/R control (LIRC), 50 mg/kg etoricoxib + liver I/R (ETO-50), 100 mg/kg etoricoxib + liver I/R (ETO-100), and healthy group (HG). ETO-50 and ETO-100 groups were administered etoricoxib, while LIRC and HG groups were orally given distilled water by gavage. Hepatic artery was clamped for one hour to provide ischemia, and then reperfusion was provided for 6 hours. Oxidant, antioxidant, and COX-2 gene expressions were studied in the liver tissues. ALT and AST were measured. RESULTS: Etoricoxib in 50 and 100 mg/kg doses changed the levels of oxidant/antioxidant parameters such as MDA, MPO, tGSH, GSHRd, GST, SOD, NO, and 8 OH/Gua in favour of antioxidants. Furthermore, etoricoxib prevented increase of COX-2 gene expression and ALT and AST levels. This important protective effect of etoricoxib on the rat liver I/R can be tested in the clinical setting. PMID- 26236428 TI - Topology Synthesis of a 1-Translational and 3-Rotational Parallel Manipulator With an Articulated Traveling Plate. AB - Driven by the increasing demands of the aircraft assemblage for the pose adjustment equipment in the large-scale component docking, this paper carries out the topology synthesis of a 1-translational and 3-rotational (1T3R) four degrees of freedom (DoF) parallel manipulator with an articulated traveling plate. First, the articulated traveling plate is defined as that includes more than one rigid body articulated by one or more kinematic joints. Then, the relationship among the DoFs of the parallel manipulator and the articulated traveling plate and the number of the in-parts are proposed. According to the agreement of the arrangement way between the open-loop limbs and the in-parts, the topology synthesis procedure of the 1T3R 4-DoF parallel manipulator with an articulated traveling plate is proposed. Finally, their topology structures are obtained by discussing those of four types in terms of 1D-H, 1D-V type with opposite layout and 1D-H, 1D-V type with adjacent layout, in which the topology structures exist only for 1D-H and 1D-V type with opposite layout. PMID- 26236426 TI - Carqueja (Baccharis trimera) Protects against Oxidative Stress and beta-Amyloid Induced Toxicity in Caenorhabditis elegans. AB - Carqueja (Baccharis trimera) is a native plant found throughout South America. Several studies have shown that Carqueja has antioxidant activity in vitro, as well as anti-inflammatory, antidiabetic, analgesic, antihepatotoxic, and antimutagenic properties. However, studies regarding its antioxidant potential in vivo are limited. In this study, we used Caenorhabditis elegans as a model to examine the antioxidant effects of a Carqueja hydroalcoholic extract (CHE) on stress resistance and lifespan and to investigate whether CHE has a protective effect in a C. elegans model for Alzheimer's disease. Here, we show for the first time, using in vivo assays, that CHE treatment improved oxidative stress resistance by increasing survival rate and by reducing ROS levels under oxidative stress conditions independently of the stress-related signaling pathways (p38, JNK, and ERK) and transcription factors (SKN-1/Nrf and DAF-16/Foxo) tested here. CHE treatment also increased the defenses against beta-amyloid toxicity in C. elegans, in part by increasing proteasome activity and the expression of two heat shock protein genes. Our findings suggest a potential neuroprotective use for Carqueja, supporting the idea that dietary antioxidants are a promising approach to boost the defensive systems against stress and neurodegeneration. PMID- 26236429 TI - Comparison of Oral and Intranasal Midazolam/Ketamine Sedation in 3-6-year-old Uncooperative Dental Patients. AB - Background and aims. There are several known sedative drugs, with midazolam and ketamine being the most commonly used drugs in children. The aim of this study was to compare the effect of intranasal and oral midazolam plus ketamine in children with high levels of dental anxiety. Materials and methods. A crossover double-blind clinical trial was conducted on 23 uncooperative children aged 3-6 (negative or definitely negative by Frankel scale), who required at least two similar dental treatment visits. Cases were randomly given ketamine (10 mg/kg) and midazolam (0.5 mg/kg) through oral or intranasal routes in each visit. The sedative efficacy of the agents was assessed by an overall success rate judged by two independent pediatric dentists based on Houpt's scale for sedation. Data analysis was carried out using Wilcoxon test and paired t-test. Results. Intranasal administration was more effective in reduction of crying and movement during dental procedures compared to oral sedation (P<0.05). Overall behavior control was scored higher in nasal compared to oral routes at the time of LA injection and after 15 minutes (P<0.05). The difference was found to be statistically significant at the start and during treatment. However, the difference was no longer significant after 30 minutes, with the vital signs remaining within physiological limits. Recovery time was longer in the intranasal group (P<0.001) with a more sleepy face (P=0.004). Conclusion. . Intranasal midazolam/ketamine combination was more satisfactory and effective than the oral route when sedating uncooperative children. PMID- 26236430 TI - Locating Mandibular Foramen in Children with Mandibular Retrognathism in Mixed Dentition. AB - Background and aims. One of the most common reasons forthe inferior alveolar nerve block anesthesia failure is the variation in mandibular foramen location. The aim of this study was to assess the location of mandibular foramen in children with mandibular retrognathism in comparison to children with normal skeletal occlusion in the mixed dentition. Materials and methods. One hundred and twenty panoramic radiographs of patients in mixed dentition period, undergoing orthodontic treatment, were selected based on inclusion criteria, skeletal occlusion and stage of dental development. The radiographs were divided into two groups: I: 60 panoramic radiographs of patients with normal skeletal occlusion (15 in each of the Hellman dental age stages); II: 60 panoramic radiographs of patients with mandibular retrognathism (15 in each of the Hellman dental age stages). The radiographs were traced and the linear distance from the mandibular foramen to the borders of the mandibular ramus and its angular position were identified. The measurements were compared between the two groups and among the four dental age groups by t-test, ANOVA and post hoc tests. Results. No statistically significant differences werefound between the patients with normal skeletal occlusion and patients with mandibular retrognathism (P>0.05). Statistical tests showed significant differences in the vertical location of mandibular foramen and gonial angle between the four dental age groups (P<0.05). Conclusion. Mandibular retrognathism does not have a significant impact on the location of the mandibular foramen in the mixed dentition period. The child's dental age would be considered in the localization of the mandibular foramen. PMID- 26236431 TI - A Comparison of the Accuracy of Four Age Estimation Methods Based on Panoramic Radiography of Developing Teeth. AB - Background and aims. Tooth development is widely used in determining age and state of maturity. Dental age is of high importance in forensic and pediatric dentistry and also orthodontic treatment planning .The aim of this study was to compare the accuracy of four radiographic age estimation methods. Materials and methods. Orthopantomographic images of 537 healthy children (age: 3.9-14.5 years old) were evaluated. Dental age of the subjects was determined through Demirjian's, Willem's, Cameriere's, and Smith's methods. Differences and correlations between chronological and dental ages were assessed by paired t tests and Pearson's correlation analysis, respectively. Results. The mean chronological age of the subjects was 8.93 +/- 2.04 years. Overestimations of age were observed following the use of Demirjian's method (0.87 +/- 1.00 years), Willem's method (0.36 +/- 0.87 years), and Smith's method (0.06 +/- 0.63 years). However, Cameriere's method underestimated age by 0.19 +/- 0.86 years. While paired t-tests revealed significant differences between the mean chronological age and ages determined by Demirjian's, Willem's, and Cameriere's methods (P < 0.001), such a significant difference was absent between chronological age and dental age based on Smith's method (P = 0.079). Pearson's correlation analysis suggested linear correlations between chronological age and dental age determined by all four methods. Conclusion. Our findings indicated Smith's method to have the highest accuracy among the four assessed methods. How-ever, all four methods can be used with acceptable accuracy. PMID- 26236432 TI - Does Timing of Eruption in First Primary Tooth Correlate with that of First Permanent Tooth? A 9-years Cohort Study. AB - Background and aims. Predicting the teeth eruption time is a valuable tool in pediatric dentistry since it can affects scheduling dental and orthodontic treatments. This study investigated the relationship between the eruption time of first primary and permanent teeth and the variation in the eruption time considering socioeconomic status (SES) in a 9-year population- based cohort study. Materials and methods . 307 subjects were examined at bimonthly intervals during the first and second years of life and then at six-month intervals until the eruption of first permanent tooth. Eruption times of primary and permanent tooth were recorded for each child. A modified form of Kuppuswamy's scale was used to assess the SES. Results. Among 267 subjects completed all follow-ups, the eruption time for first primary and permanent teeth indicated a direct strong correlation; in that one month delayed or early eruption of firstprimary tooth resulted in 4.21 months delayed or early eruption of first appearing permanent tooth (r = 0.91, n = 267, P <0.001). No significant correlation was observed between the eruption time of first primary and first permanent teeth and SES (P = 0.67, P = 0.75, respectively). Conclusion. The eruption timing for the first primary tooth had a correlation with the first permanent tooth eruption tim-ing, while SES did not have any influence on eruption times. PMID- 26236433 TI - Comparison of Primary Molar Crown Dimensions with Stainless Steel Crowns in a Sample of Iranian Children. AB - Background and aims. Due to anatomic variation in tooth anatomy between populations, this study compared the buccolingual (BL) and mesiodistal (MD) dimensions of primary molars with those of stainless steel crowns (SSCs) in anIranian population. Materials and methods. Impressions were taken from both dental arches of children, and casts were poured. Teeth with caries, restoration, hypoplasia or other dental anomalies were excluded. 216 primary molars were selected and divided into 4 groups of 54 each (maxillary and mandibular first and second primary molars). MD/BL dimensions were measured using a digital caliper with 0.01 mm precision on casts and SCCs (3M brand). Data were assessed using paired t-test, post hoc test and ANOVA. P < 0.05 was considered statistically significant. Results. The MD dimension of the lower first molar SSC and the BL dimension of the lower second molar SSC had the least difference with the corresponding values of the respective teeth. The MD dimension of the upper second molar SSC and the BL dimension of the upper first molar SSC had the greatest difference with the corresponding values in the respective teeth. Comparison of the two different brands of SSCs for the upper first molar revealed that both types had significant differences with the teeth in terms of both MD (P = 0.0) and BL (P = 0.0) dimensions. Conclusion. In the studied population, best adaptation was seen in second lower molars and the least adaptationswere seen in first and second upper molars. PMID- 26236434 TI - Clinical Success Rate of Compomer and Amalgam Class II Restorations in First Primary Molars: A Two-year Study. AB - Background and aims. The majority of failures in Class II amalgam restorations occur in the first primary molar teeth; in addition, use of compomer instead of amalgam for primary molar teeth restorations is a matter of concern. The aim ofthe present study was to compare the success rate of Class II compomer and amalgam restorations in the first primary molars. Materials and methods. A total of 17 amalgams and 17 compomer restorations were placed in 17 children based on a split-mouth design. Restorations were assessed at 12- and 24-month intervals for marginal integrity, the anatomic form and recurrent caries. Data were analyzed with SPSS 11. Chi-squared test was applied for the analysis. Statistical significance was set at P<0.05. Results. A total 34 restorations of 28 restorations (14 pairs) of the total restorations still survived after 24 months. Compomerrestorations showed significantly better results in marginal integrity. Recurrent caries was significantly lower incompomer restorations compared to amalgam restorations. Cumulative success rate at 24-month interval was significantlyhigher in compomer restorations compared to amalgam restorations. There was no statistically significant difference inanatomic form between the two materials. Conclusion. Compomer appears to be a suitable alternative to amalgam for Class II restorations in the first primary mo-lars. PMID- 26236435 TI - Prevalence of Head and Neck Tumors in Children under 12 Years of Age Referred to the Pathology Department of Children's Hospital in Tabriz during a 10-year Period. AB - Background and aims. Head and neck tumors are the most common complaints of people referring to different medical sections, especially in children. The aim of this study was to evaluate the prevalence of these tumors in children less than 12 years of age to provide a better perspective for future studies. Materials and methods. All the files in Department of Pathology at Tabriz Pediatric Hospital from 2001 to 2011 were screened for head and neck tumors in children under 12 years of age. Data including age and gender as well as the type, the location, and benign/malignant characteristic of the tumor were recorded. Data were analyzed by SPSS 15 statistical software, using descriptive statistics and chi-square test. Results. A total of 160 cases were identified. Most of the tumors were benign (68%) and most of the tumors occurred in the neck region (41%). The most frequent benign and malignant tumors were lymphangioma and non-Hodgkin lymphoma, respectively. The majority of benign tumors were found in children younger than 2 years old (P=0.007), but there was no age predilection for malignant tumors. Conclusion. According to our results, benign tumors were more prevalent than malignant ones. Although a low rate of benign tumors in males shows that more attention should be paid to the early diagnosis of head and neck tumors. PMID- 26236436 TI - Incidence Assessment of MTHFR C677T and A1298C Polymorphisms in Iranian Non syndromic Cleft Lip and/or Palate Patients. AB - Background and aims. The aim of the present study is to determine the incidence of MTHFR C677 T and A1298C muta-tions in Iranian patients with cleft lip and/or cleft palate. Materials and methods. We screened 61 Iranian patients with cleft lip and/or cleft palate for mutations in the two alleles of MTHFR gene associated with cleft lip and/or palate: A1298C and C677T, using Polymerase Chain Reaction following by RFLP. Results. The 677T and 1298C homozygote genotypes showed a frequency of 36.1% and 11.4%, respectively. Combined genotype frequencies in newborns having oral clefts showed that the highest genotype was 677TT/1298AA (22.9%) and 677TT/1298CC genotypes were not observed. Conclusion. The results showed that 65.6% of all patients had at least one T mutant allele in C677T and 58.9% C mutant allele for A1298C. According to the frequencies of homozygosity of mutant alleles, it could be said that MTHFR genotype of 677TT shows a greater role in having oral clefts. PMID- 26236437 TI - Evaluation of Salivary Streptococcus mutans and Dental Caries in Children with Heart Diseases. AB - Background and aims . In the presence of certain systemic diseases, oral microflora may aggravate the condition of the disease. Microbial population in the oral cavity especially with heart disease can increase the risk of bacterial endocarditis. The aim of this study was to evaluate the rate of oral Streptococcus mutansand the rate of caries in children suffering from heart disease. Materials and methods. In this cross-sectional research, 66 children with congenital or acquired heart disease and 50 healthy children were selected. Children were orally examined and decayed, missing, and filled teeth (DMFT) index was recorded for each subject. Saliva samples were taken from all subjects, and cultured on a special laboratory media and another specific media for S. mutans (sorbitoll +manitol). Bacterial counts were recorded, and for statistical analysis, chi square, Pearson's, and Exact Fisher tests were performed using SPSS 16 software. Results. The rate of S. mutans in children with congenital heart disease was significantly higher than the rates in childrenwith acquired heart disease and healthy control subjects. The mean DMFT in children with acquired heart disease who tookpenicillin as prophylaxis monthly was significantly lower than the other groups. Conclusion . The results revealed lower oral bacteria counts and comparatively lower caries rates in children with heart diseases, probably because of an effect of the regular prophylactic antibiotic regimen. PMID- 26236438 TI - Relationship of Salivary Lactoferrin and Lysozyme Concentrations with Early Childhood Caries. AB - Background and aims. Lysozyme and lactoferrin are salivary proteins which play an important role in innate defense mechanisms against bacteria. This study investigated the association of salivary lysozyme and lactoferrin concentrations with early childhood caries (ECC). Materials and methods. This study was carried out on 42 healthy children (age range, 36 to 71 months), of whom 21 were caries free (CF) and 21 had ECC. Disposable needle-less syringes were used to collect unstimulated saliva from buccal and labial vestibules. Fifteen children who had ECC were treated completely and their saliva was collected in the same way for the second time, three months after treatment. Lysozyme and lactoferrin concentrations were measured and recorded by the ELISA method. The intergroup comparisons were carried out using chi-square, Student's t-test and Wilcoxon signed ranked test. A P-value less than 0.05 was considered as statistically significant. Results. The mean concentration of lysozyme was significantly higher in CF group compared with that of ECC group (P = 0.04). Although the mean concentration of lactoferrin in ECC group was higher in comparison with ECC group, the difference was not statistically significant (P = 0.06). After dental treatment, the mean concentrations of lysozyme and lactoferrin did not change in comparison with their concentrations before treatment. Conclusion. ECC may have a relationship with lower concentrations of unstimulated salivary lactoferrin and lysozyme and reduced amounts of these two salivary proteins may be a risk factor for dental caries in children. PMID- 26236439 TI - Social and Behavioral Determinants for Early Childhood Caries among Preschool Children in India. AB - Background and aims. Early Childhood Caries (ECC) is a public health problem with biological, social and behavioural determinants and the notion that the principal etiology is inappropriate feeding modalities is no longer tenable. Hence this study was undertaken to assess the relationship between ECC and socio-demographic factors, dietary habits, oral hygiene habits and parental characteristics. Materials and methods. The study involved a dental examination of 1400 children aged 0-71 months, recording caries using Gruebbel's deft index and a structured questionnaire to interview parents or caretakers. The tabulated data was statistically analyzed using t-test and ANOVA at 5% level of significance. Results. The variables significantly associated with ECC were age (P<0.001), geographical location (P<0.05), duration of breast/bottle feeding (P<0.001), use of sweetened pacifiers (P<0.001), frequency of snacking (P<0.05), frequency of tooth brushing (P<0.001), the person responsible for child's oral health care (P<0.05) and education level of parents (P<0.05). However, other variables like child's gender, number of siblings, types of snack the child preferred and age at which tooth brushing was instituted did not have statistically significant relationship with ECC (P>0.05). Conclusion. ECC is preventable and manageable with proper information and skills. It is important for healthcare professionals, family physicians and parents to be cognizant of the involved risk factors as their preventive efforts represent the first line of defense. PMID- 26236440 TI - Knowledge of Emergency Management of Traumatized Teeth among Schoolteachers in Mashhad, Iran. AB - Background and aims. Dental trauma is an important oral health problem in children that requires immediate and appropriate management for long term success. The aim of this study was to evaluate the knowledge of elementary school teachers about emergency management of traumatic dental injuries in children. Materials and methods. A total of 163 teachers from 21 elementary schools from Mashhad, Iran participated in this study. Data were collected using a two-part questionnaire comprised of questions regarding demographic data and participants' knowledge about dental trauma. Results. The level of the teachers' knowledge was moderate (53.3%). Of the 163 participants, 104 (63.8%) were females and 59 (36.2%) were males. Among several predictors that were surveyed in this study, only the age of respondents signifi-cantly impacted the teachers' knowledge (P = 0.004). Conclusion. The results of this study showed the moderate level of knowledge of teachers regarding emergency manage-ment of traumatized teeth. Adding dental trauma management courses in the teacher training curriculum and requiring teachers to be updated in regards to this issue can improve their knowledge and thus led to better management of traumatic dental injuries in children. PMID- 26236442 TI - Knowledge, Awareness and Practice Regarding Needle Stick Injuries in Dental Profession in India. PMID- 26236441 TI - Social Determinants of Tooth Loss among a Group of Iranian Female Heads of Household. AB - Background and aims. Tooth loss may lead to mastication disability, which in turn has important impact on individual's quality of life. Social and psychological factors have been shown to be associated with tooth loss. This study aimed to investigate the social determinants and prevalence of tooth loss, and presence of functional dentition among female heads of household under support of Welfare Organization in Mashhad, Iran. Materials and methods. In current study 556 participants aged 16-76 years were recruited. Sociodemographic characteristics (age, level of education, family size, and monthly income) were collected using interviewer-led questionnaire. Data about number of teeth and functional dentition were obtained by oral examination. The data were analyzed using Chi square, Kruskal-Wallis, T-test and binary logistic regression analysis. Results. Four percent of participants were edentulous. Tooth loss was significantly associated with level of education, age and family size (P < 0.001). There was no significant association between level of income and tooth loss (P = 0.88). Only 37.5% of dentate subjects had functional dentition (anterior and premolar teeth). Women older than 40 years were 0.63 times less likely to have functional dentition than those younger than 40 years. Females with at least a high-school diploma were six times more likely to have functional dentition than their illiterate counterparts. Conclusion. Social determinants of functional dentition should be taken into account when planning oral health promoting programs for female heads of household. For reducing oral health inequalities access to dental services should be facilitated. PMID- 26236443 TI - Cancer Screening: Should Cancer Screening be Essential Component of Primary Health Care in Developing Countries? AB - BACKGROUND: Cancer is a fatal disease and is on the rise across the globe. In India, breast, cervix and the oral cavity are the leading cancer sites, but, unfortunately, in-spite of availability of screening tools, there is no organized cancer screening program in India. The main objective of this study was to review the performance of various cancer screening modalities in a resource poor setting. METHODS: MEDLINE and web of science electronic database was searched from January 1990 to December 2013, using keywords such as "breast cancer, cervical cancer, oral cancer and their corresponding mesh terms were also used in combination with Boolean operators OR, AND." Two authors independently selected studies published in English and conducted in India. A total of 16 studies was found relevant and eligible for the review. The data on sensitivity and specificity of various screening tool was extracted and analyzed. RESULTS: Most of the reported screening trails in India are on cervical cancer and few on breast and oral cancer screening. The pooled estimates of sensitivity and specificity of cervical cancer screening test such as visual inspection with acetic acid, magnified visual inspection with acetic acid, visual inspection with Lugol's iodine, cytology (Papanicolaou smear) and human papillomavirus deoxyribonucleic acid was found to be 68.76% and 84.02%, 63.27% and 85.43%, 81.86% and 87.03%, 63.25% and 93.17% and 75.04% and 91.66%, respectively. Sensitivity and specificity of clinical breast examination was found to be 94.30% and 94.30%, respectively. Oral cancer screening through visual inspection by trained health care worker was found to have 87.90% sensitivity and 92.05% specificity. CONCLUSIONS: Our study highlights the availability and success of visual screening tools in early detection and mortality reduction of major neoplasia in resource-poor health care settings and recommends implementation of oral and cervical cancer screening as part of assured primary health care package in developing countries. PMID- 26236444 TI - Health Information System in Primary Health Care: The Challenges and Barriers from Local Providers' Perspective of an Area in Iran. AB - BACKGROUND: Health information system (HIS) has been utilized for collecting, processing, storing, and transferring the required information for planning and decision-making at different levels of health sector to provide quality services. In this study, in order to provide high-quality HIS, primary health care (PHC) providers' perspective on current challenges and barriers were investigated. METHODS: This study was carried out with a qualitative approach using semi structured audiotaped focus group discussions (FGDs). One FGD was conducted with 13 Behvarz and health technicians as front-line workers and the other with 16 personnel including physicians, statisticians, and health professionals working in health centers of the PHC network in KUMS. The discussions were transcribed and then analyzed using the framework analysis method. RESULTS: The identified organizational challenges were categorized into two groups: HIS structure and the current model of PHC in urban areas. Furthermore, the structural challenges were classified into HIS management structure (information systems resources, including human, supplies, and organizational rules) and information process. CONCLUSIONS: The HIS works effectively and efficiently when there are a consistency and integrity between the human, supplies, and process aspects. Hence, multifaceted interventions including strengthening the organizational culture to use the information in decisions, eliminating infrastructural obstacles, appointing qualified staff and more investment for service delivery at urban areas are the most fundamental requirements of high-quality HIS in PHC. PMID- 26236445 TI - Two Episodes of Cutaneous Non-Tuberculous Mycobacterial Infection in a Patient with Psoriasis. AB - Non-tuberculous mycobacteria (NTM) are a group of environmental pathogens, which cause a broad spectrum of disease. The incidence of NTM infection is increasing, especially in immunocompromized patients. The past three decades also saw a rapid increase in the incidence of NTM infection involving otherwise healthy subjects. We report a case of cutaneous NTM infection in a 79-year-old Chinese woman, who was receiving methotrexate for psoriasis. Mycobacterial culture grew Mycobacterium abscessus, and the lesions cleared with a combination of oral clarithromycin, ciprofloxacin and doxycycline. Interestingly, she then developed a second episode of cutaneous NTM infection with Mycobacterium haemophilum over the same body region, five years after stoppage of methotrexate. Both episodes were separated in time and involved different species, indicating that they were independent from each other. We further discuss the risk factors for cutaneous NTM infection, treatment, and highlight the need for diagnostic vigilance. PMID- 26236446 TI - Treatment Modalities of Necrobiosis Lipoidica: A Concise Systematic Review. AB - Necrobiosis lipoidica (NL) is a rare inflammatory granulomatous skin disorder closely associated with diabetes mellitus. The aim of this paper is to review and discuss all the treatment modalities proposed and tested for this disease. A systematic review of the existing literature was conducted to investigate all the available data and summarize all the clinical trials, case reports and original articles on NL. Two major databases (PubMed and Google Scholar) were used. We have examined about 70 articles. Numerous treatment modalities have been currently investigated to compare recalcitrant NL. Being rare, most of the studies regarding this disease are case reports or small-scale clinical trials. We have found that, in spite of plentiful investigations carried out during the years, there is no treatment modality that has proved to be utterly satisfactory in treating NL. PMID- 26236447 TI - The Use of Chemotherapeutics for the Treatment of Keloid Scars. AB - Keloid scars are pathological scars, which develop as a result of exaggerated dermal tissue proliferation following cutaneous injury and often cause physical, psychological and cosmetic problems. Various theories regarding keloidogenesis exist, however the precise pathophysiological events remain unclear. Many different treatment modalities have been implicated in their management, but currently there is no entirely satisfactory method for treating all keloid lesions. We review a number of different chemotherapeutic agents which have been proposed for the treatment of keloid and hypertrophic scars while giving insight into some of the novel chemotherapeutic drugs which are currently being investigated. Non-randomized trials evaluating the influence of different chemotherapeutic agents, such as 5-fluorouracil (5-FU); mitomycin C; bleomycin and steroid injection, either alone or in combination with other chemotherapeutic agents or alternative treatment modalities, for the treatment of keloids were identified using a predefined PubMed search strategy. Twenty seven papers were identified. Scar improvement >=50% was found in the majority of cases treated with 5-FU, with similar results found for mitomycin C, bleomycin and steroid injection. Combined intralesional 5-FU and steroid injection produced statistically significant improvements when compared to monotherapy. Monotherapy recurrence rates ranged from 0-47% for 5-FU, 0-15% for bleomycin and 0-50% for steroid injection. However, combined therapy in the form of surgical excision and adjuvant 5-FU or steroid injections demonstrated lower recurrence rates; 19% and 6% respectively. Currently, most of the literature supports the use of combination therapy (usually surgery and adjuvant chemotherapy) as the mainstay treatment of keloids, however further investigation is necessary to determine success rates over longer time frames. Furthermore, there is the potential for novel therapies, but further investigation is required to elucidate their true efficacy. PMID- 26236448 TI - An Epidemiological Study of 97 Cases of Primary Cicatricial Alopecia in Iran. AB - Cicatricial alopecia can produce major psychosocial disturbance. This study aimed to evaluate epidemiological features of primary cicatricial alopecia (PCA). Epidemiological and histological types of scarring alopecia were determined. The chi-squared test and t-test were performed to examine the relationship between different variables using SPSS 16. A total of 97 cases, 35 (36.1%) men and 62 (63.9%) women, with an average age of 37 (SD=12.7), were included in this study. The female/male (F/M) ratio was 1.7:1 for total cases, 1.92:1 for the lymphocytic type, and 1:1.5 for the neutrophilic type. No relationship was found between type of job (indoor or outdoor), clinical findings and histological types. Discoid lupus erythematous (DLE) was the most common histological type (63.9%). PCA was found to mainly affect middle-aged individuals. The high percentage of DLE in the present study is in agreement with some similar studies. PMID- 26236449 TI - Paraspinal Arterio-Venous Fistula in Children: Two More Cases of an Exceptional Malformation. AB - We report on the case of two toddlers who presented in the last 2 years with heart and vascular murmur, respectively, and in whom the diagnosis of paraspinal arterio-venous fistula was made. Paraspinal arterio-venous fistulae in children are extremely rare congenital or post-traumatic vascular malformations. In the rare case of connection with the spinal venous system, they might affect spinal vascularization due to potential venous congestion. Interventional embolization rather than surgery is the treatment of choice for such lesions. Up to now, there is no consensus about the indication of prophylactic closure of asymptomatic fistulae. However, close clinical follow-up with repeated spinal magnetic resonance imaging to exclude venous congestion is mandatory for young asymptomatic patients until treatment. PMID- 26236450 TI - Ovarian Cancer During Pregnancy: A Case Report and Literature Review. AB - Ovarian cancer during pregnancy is a rare event. Little is known about the treatment of this condition due to lack of prospective randomized trials and cohort studies. In this paper the authors reported a rare case of small cells ovarian cancer, diagnosed at 16 weeks of gestation, treated with conservative surgery at 18 weeks and chemotherapy. At week 38, the patient underwent caesarean section and delivered a healthy baby girl. Staging surgery was then carried out followed by adjuvant chemotherapy. Thus the findings from this case concluded that prognosis and quality of the patient's life should be a priority, chemotherapy during the second trimester seems to be safe however, potential risks of this interventions still has to be considered. PMID- 26236451 TI - Treatment of Costal Osteochondroma Causing Spinal Cord Compression by Costotransversectomy: Case Report and Review of the Literature. AB - In laminectomies for costal osteochondroma causing spinal cord compression, visualization of the extraforaminal part of the tumor is limited. The authors describe using a costotransversectomy to resolve spinal cord compression by a costal osteochondroma invading through the neural foramen. A 21-year-old woman with hereditary multiple exostoses presented with hand numbness and progressive neck and upper back pain. Plain radiographs identified a large lesion of the T2 and T3 pedicles, with encroachment on the T2-3 neural foramen causing ~50% spinal canal stenosis. Costotransversectomy was performed to resect the cartilaginous portions of the osteochondroma, debulk the mass, and decompress the spinal canal. A mass of mature bone was left, but no appreciable cartilaginous tumor. At five year follow-up, the patient had improvement of neck pain, no new neurological deficits. a stable residual mass, and no new osteochondromas, indicating that appropriate surgical management can yield good results and no evidence of recurrence. PMID- 26236452 TI - Septic Arthritis of the Temporomandibular Joint in an Infant. AB - Infantile temporomandibular joint septic arthritis is an uncommon paediatric infection, but one which carries the potential for severe morbidity and mortality. Early diagnosis and aggressive medical and possibly surgical management is indicated for the best outcomes. The presenting clinical features are non-specific in a neonate and an infant; as such a high degree of clinical suspicion is required. We present the case of an eleven-month-old boy who has made a full recovery from an acute temporomandibular joint septic arthritis and review the relevant literature. PMID- 26236453 TI - Surgical Removal of an Unrecognized Tapestry Needle from the Urethra. AB - The variety of intraurethral foreign bodies has been reported in literature. Most of them tend to be self-inserted because of sexual or erotic reasons. We report a 23-year old male patient who had tapestry needle into his urethra, which was not self-inserted. The patient was referred to our institution with dysuria and hematuria. There was microscopic hematuria in urine analysis and no pathologic sign in sonography. The needle was detected in proximal urethra in pelvic X-ray and endoscopic visualization revealed that it was trapped in mucosa. The needle was successfully removed by open surgery. Main treatment for the removal of urethral foreign bodies is usually endoscopic but open surgery may be required in some cases especially cutting foreign bodies. PMID- 26236454 TI - Computed Tomography-Guided Cryoablation of Local Recurrence after Primary Resection of Pancreatic Adenocarcinoma. AB - The optimal management of local recurrences after primary resection of pancreatic cancer still remains to be clarified. A 58-year-old woman developed an isolated recurrence of pancreatic cancer six year after distal pancreatectomy. Re resection was attempted but the lesion was deemed unresectable at surgery. Then chemotherapy was administrated without obtaining a reduction of the tumor size nor an improvement of the patient's symptoms. Thus the patient underwent percutaneous cryoablation under computed tomography (CT)-guidance obtaining tumor necrosis and a significant improvement in the quality of life. A CT scan one month later showed a stable lesion with no contrast enhancement. While the use of percutaneous cryoblation has widened its applications in patients with unresectable pancreatic cancer, it has never been described for the treatment of local pancreatic cancer recurrence after primary resection. Percutaneous cryoablation deserves further studies in the multimodality treatment of local recurrence after primary pancreatic surgery. PMID- 26236455 TI - Recurrent Thymoma in the Retroperitoneal Space: A Rare Case Report. AB - Thymoma is an epithelial neoplasm of the thymus, which commonly lies in the anterior mediastinum and recurrences of thymoma generally are locally, and retroperitoneal recurrence is considered to be rare. A 46-year old Asian woman with invasive thymoma had undergone thymectomy 10 years ago. Computed tomography demonstrated a well-circumscribed mass in the left retroperitoneal space. The patient had not any symptom including myasthenia gravis. Because on the anterior mediastinum area shows no sign of tumor recurrence and the mass adjacent to the vertebral body, neurogenic tumor was suspected. Surgical resection was performed using a retroperitoneal approach, which revealed the tumor adhering neighboring diaphragm. The tumor was histologically diagnosed to be type B1 thymoma according to the World Health Organization classification. The retroperitoneal mass was an unusual local recurrence after thymectomy. The patients whose had under invasive thymectomy should be evaluated carefully when finding retroperitoneal mass during follow-up. PMID- 26236456 TI - Vertebrobasilar Dolichoectasia Induced Hydrocephalus: the Water-Hammer Effect. AB - Vertebrobasilar dolichoectasia is a clinical entity associated rarely with obstructive hydrocephalus. We present a 48-year old male with a profound dilatation of the ventricular system due to a dolichoectatic basilar artery, as appeared in imaging studies. The patient suffered from longstanding hydrocephalus and presenile dementia. The underlying mechanism for obstructive hydrocephalus due to vertebrobasilar dolichoectasia is considered to be both a water-hammer effect and a direct compression of adjacent structures. We suggest prompt surgical intervention upon diagnosis as a first choice treatment in order to avoid further complications. PMID- 26236457 TI - Anterior Sacral Meningocele Masquerading as an Ovarian Cyst: A Rare Clinical Presentation Associated with Marfan Syndrome. AB - Anterior sacral meningocele is a very rare clinical entity characterized by herniation of a meningeal sac through a sacrococcygeal defect. We report a case of a 20-year old female with Marfan syndrome who presented with abdominal distention that was misdiagnosed as an ovarian cyst on pelvic ultrasound. Pelvic magnetic resonance (MR) imaging showed large, well-defined multiloculated intrasacral and presacral cysts communicating via two separate broad necks and extending through defects in anterior aspect of sacral vertebrae. This case emphasizes that anterior sacral meningocele should be considered in the differential diagnosis of cases with pelvic cysts particularly in patients with underlying connective tissue disorders. Because severe neurologic complications or even death may occur without proper preoperative planning in such cases, MR imaging should always be performed for evaluation and characterization of pelvis cystic lesions. PMID- 26236458 TI - Rare Presentation of Gall Bladder Tuberculosis in a Non Immuno-Compromised Patient. AB - The gall bladder is least common intra-abdominal organ to be involved by tuberculosis. It is either part of systemic miliary tuberculosis or abdominal tuberculosis. Isolated gall bladder tuberculosis is even rarer, can presents either as calculus or acalculus cholecystitis. Gall bladder tuberculosis presenting as a localized perforation with a sinus formation into anterior abdominal wall is unreported complication in a non immuno-compromised person. A 48-year old female presented with a gradually increasing swelling in right hypochondrium. Abdominal ultrasound showed superficial collection over right hypochondrium with intraperitoneal extension. Computed tomography showed localized gall bladder perforation with extension to the abdominal wall. Patient underwent emergency exploration and cholecystectomy with excision of sinus tract and drainage of abdominal wall abscess. Histopathological examination showed granulomatous cholecystitis suggestive of tuberculosis of gall bladder with extension into the sinus tract. She had an uneventful recovery and was treated with 6-month antitubercular therapy after surgery. PMID- 26236459 TI - Use of Recombinant Factor VIIa in Symptomatic Intracerebral Hemorrhage Following Intravenous Thrombolysis. AB - Symptomatic intracerebral hemorrhage (sICH) occurs in up to 7% of stroke patients treated with thrombolytic therapy. There are limited data on the effectiveness of the reversal agents used for intravenous tissue plasminogen activator related intracranial bleeds. We report a patient with sICH following intravenous thrombolysis whose intracerebral hemorrhage continued to expand despite treatment with platelets and cryoprecipitate, needing recombinant factor VIIa use for stabilization before surgical evacuation. Factor VIIa along with routine reversal agents following intravenous thrombolysis related sICH may further enhance clot stability and reduce the risk of hematoma expansion. It could be a bridge to definitive surgical management in those patients. PMID- 26236460 TI - Structure-Based Design, Synthesis by Click Chemistry and in Vivo Activity of Highly Selective A3 Adenosine Receptor Agonists. AB - 2-Arylethynyl derivatives of (N)-methanocarba adenosine 5'-uronamides are selective A3AR (adenosine receptor) agonists. Here we substitute a 1,2,3-triazol 1-yl linker in place of the rigid, linear ethynyl group to eliminate its potential metabolic liability. Docking of nucleosides containing possible short linker moieties at the adenine C2 position using a hybrid molecular model of the A3AR (based on the A2AAR agonist-bound structure) correctly predicted that a triazole would maintain the A3AR selectivity, due to its ability to fit a narrow cleft in the receptor. The analogues with various N6 and C2-aryltriazolyl substitution were synthesized and characterized in binding (Ki at hA3AR 0.3 - 12 nM) and in vivo to demonstrate efficacy in controlling chronic neuropathic pain (chronic constriction injury). Among N6-methyl derivatives, a terminal pyrimidin 2-yl group in 9 (MRS7116) increased duration of action (36% pain protection at 3 h) in vivo. N6-Ethyl 5-chlorothien-2-yl analogue 15 (MRS7126) preserved in vivo efficacy (85% protection at 1 h) with short duration. Larger N6 groups, e.g. 17 (MRS7138, >90% protection at 1 and 3 h), greatly enhanced in vivo activity. Thus, we have combined structure-based methods and phenotypic screening to identify nucleoside derivatives having translational potential. PMID- 26236461 TI - Amine alpha-heteroarylation via photoredox catalysis: a homolytic aromatic substitution pathway. AB - The direct alpha-heteroarylation of tertiary amines has been accomplished via photoredox catalysis to generate valuable benzylic amine pharmacophores. A variety of five-and six-membered chloroheteroarenes are shown to function as viable coupling partners for the alpha-arylation of a diverse range of cyclic and acyclic amines. Evidence is provided for a homolytic aromatic substitution mechanism, in which a catalyticallygenerated alpha-amino radical undergoes direct addition to an electrophilic chloroarene. PMID- 26236462 TI - Rescuing the Cochlea: the challenges. PMID- 26236464 TI - Anterior and posterior subareas of the dorsolateral frontal cortex in socially relevant decisions based on masked affect expressions. AB - Socially-relevant decisions are based on clearly recognizable but also not consciously accessible affective stimuli. We studied the role of the dorsolateral frontal cortex (DLFC) in decision-making on masked affect expressions using functional magnetic resonance imaging. Our paradigm permitted us to capture brain activity during a pre-decision phase when the subjects viewed emotional expressions below the threshold of subjective awareness, and during the decision phase, which was based on verbal descriptions as the choice criterion. Using meta analytic connectivity modeling, we found that the preparatory phase of the decision was associated with activity in a right-posterior portion of the DLFC featuring co-activations in the left-inferior frontal cortex. During the subsequent decision a right-anterior and more dorsal portion of the DLFC became activated, exhibiting a different co-activation pattern. These results provide evidence for partially independent sub-regions within the DLFC, supporting the notion of dual associative processes in intuitive judgments. PMID- 26236463 TI - Clinical Utilisation of High-frequency DPOAEs. AB - The value of assessing auditory function at frequencies above 8kHz to detect age related changes and ototoxic damage in the cochlea is well established but not commonplace. Physiological changes in the auditory periphery due to age and ototoxicity are initially evident, and most prominent, at frequencies above 8kHz [1]. The most well investigated use of hearing thresholds and otoacoustic emissions above 8kHz is in monitoring auditory function in patients undergoing chemotherapy [2]. Ototoxic changes in hearing thresholds at frequencies between 10-14kHz prior to the manifestation of any changes at lower frequencies have been consistently documented in these patients. Age-related changes in hearing also appear at frequencies above 8kHz prior to any observable changes at regular audiometric frequencies [3]. The value of using hearing thresholds at frequencies above 8kHz to detect noise-induced hearing loss is debated in the literature with some reports of hearing thresholds at frequencies above 8kHz demonstrating more sensitivity to noise-induced damage than others [4]. PMID- 26236465 TI - ViennaNGS: A toolbox for building efficient next- generation sequencing analysis pipelines. AB - Recent achievements in next-generation sequencing (NGS) technologies lead to a high demand for reuseable software components to easily compile customized analysis workflows for big genomics data. We present ViennaNGS, an integrated collection of Perl modules focused on building efficient pipelines for NGS data processing. It comes with functionality for extracting and converting features from common NGS file formats, computation and evaluation of read mapping statistics, as well as normalization of RNA abundance. Moreover, ViennaNGS provides software components for identification and characterization of splice junctions from RNA-seq data, parsing and condensing sequence motif data, automated construction of Assembly and Track Hubs for the UCSC genome browser, as well as wrapper routines for a set of commonly used NGS command line tools. PMID- 26236466 TI - A reanalysis of mouse ENCODE comparative gene expression data. AB - Recently, the Mouse ENCODE Consortium reported that comparative gene expression data from human and mouse tend to cluster more by species rather than by tissue. This observation was surprising, as it contradicted much of the comparative gene regulatory data collected previously, as well as the common notion that major developmental pathways are highly conserved across a wide range of species, in particular across mammals. Here we show that the Mouse ENCODE gene expression data were collected using a flawed study design, which confounded sequencing batch (namely, the assignment of samples to sequencing flowcells and lanes) with species. When we account for the batch effect, the corrected comparative gene expression data from human and mouse tend to cluster by tissue, not by species. PMID- 26236467 TI - Psoriasis is characterized by deficient negative immune regulation compared to transient delayed-type hypersensitivity reactions. AB - Diphencyprone (DPCP) is a hapten that causes delayed-type hypersensitivity (DTH) reactions in human skin, and is used as a topical therapeutic for alopecia areata, warts, and cutaneous melanoma metastases. We examined peak DTH reactions induced by DPCP (3 days post-challenge) by comprehensive gene expression and histological analysis. To better understand how these DTH reactions naturally resolve, we compared our DPCP biopsies to those from patients with psoriasis vulgaris, a chronic inflammatory disease that does not resolve. By both microarray and qRT-PCR, we found that psoriasis lesional skin has significantly lower expression of many negative immune regulators compared to peak DPCP reactions. These regulators include: interleukin-10, cytotoxic T lymphocyte associated 4 (CTLA4), programmed cell death 1 (PD1), programmed cell death 1 ligand 1 (PDL1), programmed cell death 1 ligand 2 (PDL2), and indoleamine 2,3 dioxygenase (IDO1). Their decreased expression was confirmed at the protein level by immunohistochemistry. To more completely determine the balance of positive vs. negative immune regulators in both DPCP reactions and psoriasis, we developed one comprehensive gene list for positive regulatory (inflammatory) genes, and another for negative regulatory (immunosuppressive) genes, through Gene Ontology terms and literature review. With this approach, we found that DPCP reactions have a higher ratio of negative to positive regulatory genes (both in terms of quantity and expression levels) than psoriasis lesional skin. These data suggest that the disease chronicity that distinguishes psoriasis from transient DTH reactions may be related to absence of negative immune regulatory pathways, and induction of these is therefore of therapeutic interest. Further study of these negative regulatory mechanisms that are present in DPCP reactions, but not in psoriasis, could reveal novel players in the pathogenesis of chronic inflammation. The DPCP system used here thus provides a tractable model for primary discovery of pathways potentially involved in immune regulation in peripheral tissues. PMID- 26236469 TI - Magnetic Resonance Imaging in Neuropsychiatric Lupus. AB - Neuropsychiatric lupus is a major diagnostic challenge, and a main cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Magnetic resonance imaging (MRI) is, by far, the main tool for assessing the brain in this disease. Conventional and advanced MRI techniques are used to help establishing the diagnosis, to rule out alternative diagnoses, and recently, to monitor the evolution of the disease. This review explores the neuroimaging findings in SLE, including the recent advances in new MRI methods. PMID- 26236468 TI - Echocardiography in the evaluation of athletes. AB - Echocardiography is currently a widely available imaging technique that can provide useful data in the field of sports cardiology particularly in two areas: pre-participation screening and analysis of the cardiac adaptation induced by exercise. The application of pre-participation screening and especially, the type and number of used diagnostic tests remains controversial. Echocardiography has shown though, higher sensitivity and specificity as compared to the ECG, following a protocol adapted to athletes focused on ruling out the causes of sudden death and the most common disorders in this population. It is still a subject of controversy the actual cost of adding it, but depending on the type of sport, echocardiography might be cost-effective if added in the first line of examination. Regarding the evaluation of cardiac adaptation to training in athletes, echocardiography has proved to be useful in the differential diagnosis of diseases that can cause sudden death, analysing both the left ventricle (hypertrophy cardiomyopathy, dilated cardiomyopathy, left ventricle non compaction) and the right ventricle (arrhythmogenic right ventricular cardiomyopathy). The aim of this paper is to review the current knowledge and the clinical practical implications of it on the field of echocardiography when applied in sport cardiology areas. PMID- 26236470 TI - Problematizing Digital Research Evaluation using DOIs in Practice-Based Arts, Humanities and Social Science Research. AB - This paper explores emerging practices in research data management in the arts, humanities and social sciences (AHSS). It will do so vis-a-vis current citation conventions and impact measurement for research in AHSS. Case study findings on research data inventoried at Goldsmiths', University of London will be presented. Goldsmiths is a UK research-intensive higher education institution which specialises in arts, humanities and social science research. The paper's aim is to raise awareness of the subject-specific needs of AHSS scholars to help inform the design of future digital tools for impact analysis in AHSS. Firstly, I shall explore the definition of research data and how it is currently understood by AHSS researchers. I will show why many researchers choose not to engage with digital dissemination techniques and ORCID. This discussion must necessarily include the idea that practice-based and applied AHSS research are processes which are not easily captured in numerical 'sets' and cannot be labelled electronically without giving careful consideration to what a group or data item 'represents' as part of the academic enquiry, and therefore how it should be cited and analysed as part of any impact assessment. Then, the paper will explore: the role of the monograph and arts catalogue in AHSS scholarship; how citation practices and digital impact measurement in AHSS currently operate in relation to authorship and how digital identifiers may hypothetically impact on metrics, intellectual property (IP), copyright and research integrity issues in AHSS. I will also show that, if we are to be truly interdisciplinary, as research funders and strategic thinkers say we should, it is necessary to revise the way we think about digital research dissemination. This will involve breaking down the boundaries between AHSS and other types of research. PMID- 26236471 TI - Case Report: melanoma and melanocytic nevus differentiation with reflectance confocal microscopy. AB - Historically, melanoma has been typically diagnosed by naked-eye examination and confirmed with invasive biopsy. However, recently the use of reflectance confocal microscopy enables non-invasive bedside diagnosis of clinically equivocal lesions. We present a case in which reflectance confocal microscopy was used to evaluate two skin lesions in the same patient confirming the diagnosis of a melanoma and potentially avoiding invasive biopsy in the second benign melanocytic lesion. Clinicians should be aware of the availability of new non invasive technologies that can aid in early diagnosis of malignant skin tumors and potentially reduce the number of benign lesion excisions. PMID- 26236473 TI - Thermal Decomposition Based Synthesis of Ag-In-S/ZnS Quantum Dots and Their Chlorotoxin-Modified Micelles for Brain Tumor Cell Targeting. AB - Cadmium-free silver-indium-sulfide (Ag-In-S or AIS) chalcopyrite quantum dots (QDs) as well as their core-shell structures (AIS/ZnS QDs) are being paid significant attention in biomedical applications because of their low toxicity and excellent optical properties. Here we report a simple and safe synthetic system to prepare high quality AIS and AIS/ZnS QDs using thermal decomposition. The synthetic system simply involves heating a mixture of silver acetate, indium acetate, and oleic acid in dodecanethiol at 170 degrees C to produce AIS QDs with a 13% quantum yield (QY). After ZnS shell growth, the produced AIS/ZnS QDs achieve a 41% QY. To facilitate phase transfer and bioconjugation of AIS/ZnS QDs for cellular imaging, these QDs were loaded into the core of PLGA-PEG (5k:5k) based micelles to form AIS/ZnS QD-micelles. Cellular imaging studies showed that chlorotoxin-conjugated QD-micelles can be specifically internalized into U-87 brain tumor cells. This work discloses that the scalable synthesis of AIS/ZnS QDs and the facile surface/interface chemistry for phase transfer and bioconjugation of these QDs may open an avenue for the produced QD-micelles to be applied to the detection of endogenous targets expressed on brain tumor cells, or more broadly to cell- or tissue-based diagnosis and therapy. PMID- 26236472 TI - Recent scientific advances in leiomyoma (uterine fibroids) research facilitates better understanding and management. AB - Uterine leiomyomas (fibroids) are the most prevalent medical problem of the female reproductive tract, but there are few non-surgical treatment options. Although many advances in the understanding of the molecular components of these tumors have occurred over the past five years, an effective pharmaceutical approach remains elusive. Further, there is currently no clinical method to distinguish a benign uterine leiomyoma from a malignant leiomyosarcoma prior to treatment, a pressing need given concerns about the use of the power morcellator for minimally invasive surgery. This paper reviews current studies regarding the molecular biology of uterine fibroids, discusses non-surgical approaches and suggests new cutting-edge therapeutic and diagnostic approaches. PMID- 26236474 TI - Standardizing metadata and taxonomic identification in metabarcoding studies. AB - High-throughput sequencing-based metabarcoding studies produce vast amounts of ecological data, but a lack of consensus on standardization of metadata and how to refer to the species recovered severely hampers reanalysis and comparisons among studies. Here we propose an automated workflow covering data submission, compression, storage and public access to allow easy data retrieval and inter study communication. Such standardized and readily accessible datasets facilitate data management, taxonomic comparisons and compilation of global metastudies. PMID- 26236475 TI - Use of hand hygiene agents as a surrogate marker of compliance in Hungarian long term care facilities: first nationwide survey. AB - BACKGROUND: Hand hygiene practice is an important measure for preventing infections in long-term care facilities (LTCFs). However, low compliance with hand hygiene has been reported in a number of studies. The purpose of this study was to provide an overview of the first reference data collected on alcohol-based handrub (ABHR) and antiseptic soap consumption, as surrogate markers for hand hygiene compliance by healthcare workers (HCWs) in Hungarian LTCFs. The objective was to inform stakeholders on the need of hand hygiene improvement in these settings. METHODS: Between 5 May and 30 September 2014, we conducted a nationwide, cross-sectional survey using a standardized self-administered questionnaire; all Hungarian LTCFs were eligible. The Statistical Package for Social Sciences (SPSS) version 20.0 was used for data analysis. RESULTS: The questionnaire was completed by 354 LTCFs, representing 24 % of all Hungarian LTCFs. In total, the median consumption of ABHR and antimicrobial soap was 15.5 L (IQR, 0-800 L) and 60 L (IQR, 0-1,680 L) per LTCFs, and 2.2 mL (IQR, 0.4-9.1 mL) and 12.1 mL (IQR, 0.7-32.8 mL) per HCWs in 2013, respectively. The estimated number of hand hygiene actions was 0.6 hygienic handrub/HCW per day (IQR, 0 12.8/HCWs) and 2.4 hygienic handwashing/HCW per day (IQR, 0-21.9/HCWs; P = .001), respectively. CONCLUSIONS: This study suggests that non-compliance with hand hygiene is a significant problem in Hungarian LTCFs. Based on our results, there is an urgent need for a nationwide multimodal hand hygiene promotion strategy including education and performance monitoring and feedback in all LTCFs. Furthermore, monitoring of ABHR consumption constitute an additional component of the existing National Nosocomial Surveillance system. PMID- 26236476 TI - Co-existence of acute appendicitis and inflammatory myofibroblastic tumor of the small intestine: A case report. AB - INTRODUCTION: Inflammatory myofibroblastic tumor as a rare neoplastic lesion is seen most commonly in the pulmonary system. Beside the presence of limited number of inflammatory myofibroblastic tumors of the gastrointestinal tract in the literature, co-existence with acute appendicitis has not been reported before. PRESENTATION OF CASE: A 27-year-old woman admitted to emergency department with acute abdominal pain at the right lower quadrant. The initial diagnosis was as acute appendicitis. Intraoperatively, a mass with a diameter of almost 5 cm originated from the distal ileal segments neighboring the appendix was seen. The patient was managed by segmental resection of the small intestine including the mass with appendectomy. Histologically, there were bundles of spindle cells accompanied by lymphoplasmocytic infiltration. The immunohistochemical studies showed that tumor cells were positive for smooth muscle actin, vimentin, perinuclear activity for anaplastic lymphoma kinase and CD 68. The final pathologic diagnosis was inflammatory myofibroblastic tumor. DISCUSSION: Concomitant resection of tumoral lesions detected in the neighbor intestinal segments during appendectomy should be considered to diagnose and treat. For the diagnosis of inflammatory myofibroblastic tumor, immunohistochemistry pattern including positivity for actin, vimentin, CD 68 and anaplastic lymphoma kinase plays a crucial role. Therefore, detailed immunohistochemistry analysis should be performed in suspicious cases. CONCLUSION: Coexistence of inflammatory myofibroblastic tumor located in the gastrointestinal system with acute appendicitis is a rare event. Complete surgical excision should be regarded as the mainstay of the treatment. Long-term follow up with serial imaging techniques is recommended. PMID- 26236477 TI - Severe and enduring anorexia nervosa (SE-AN): in search of a new paradigm. PMID- 26236478 TI - Full-wave acoustic and thermal modeling of transcranial ultrasound propagation and investigation of skull-induced aberration correction techniques: a feasibility study. AB - BACKGROUND: Transcranial focused ultrasound (tcFUS) is an attractive noninvasive modality for neurosurgical interventions. The presence of the skull, however, compromises the efficiency of tcFUS therapy, as its heterogeneous nature and acoustic characteristics induce significant distortion of the acoustic energy deposition, focal shifts, and thermal gain decrease. Phased-array transducers allow for partial compensation of skull-induced aberrations by application of precalculated phase and amplitude corrections. METHODS: An integrated numerical framework allowing for 3D full-wave, nonlinear acoustic and thermal simulations has been developed and applied to tcFUS. Simulations were performed to investigate the impact of skull aberrations, the possibility of extending the treatment envelope, and adverse secondary effects. The simulated setup comprised an idealized model of the ExAblate Neuro and a detailed MR-based anatomical head model. Four different approaches were employed to calculate aberration corrections (analytical calculation of the aberration corrections disregarding tissue heterogeneities; a semi-analytical ray-tracing approach compensating for the presence of the skull; two simulation-based time-reversal approaches with and without pressure amplitude corrections which account for the entire anatomy). These impact of these approaches on the pressure and temperature distributions were evaluated for 22 brain-targets. RESULTS: While (semi-)analytical approaches failed to induced high pressure or ablative temperatures in any but the targets in the close vicinity of the geometric focus, simulation-based approaches indicate the possibility of considerably extending the treatment envelope (including targets below the transducer level and locations several centimeters off the geometric focus), generation of sharper foci, and increased targeting accuracy. While the prediction of achievable aberration correction appears to be unaffected by the detailed bone-structure, proper consideration of inhomogeneity is required to predict the pressure distribution for given steering parameters. CONCLUSIONS: Simulation-based approaches to calculate aberration corrections may aid in the extension of the tcFUS treatment envelope as well as predict and avoid secondary effects (standing waves, skull heating). Due to their superior performance, simulationbased techniques may prove invaluable in the amelioration of skull-induced aberration effects in tcFUS therapy. The next steps are to investigate shear-wave-induced effects in order to reliably exclude secondary hot spots, and to develop comprehensive uncertainty assessment and validation procedures. PMID- 26236479 TI - Breeding short-tailed shearwaters buffer local environmental variability in south eastern Australia by foraging in Antarctic waters. AB - BACKGROUND: Establishing patterns of movements of free-ranging animals in marine ecosystems is crucial for a better understanding of their feeding ecology, life history traits and conservation. As central place foragers, the habitat use of nesting seabirds is heavily influenced by the resources available within their foraging range. We tested the prediction that during years with lower resource availability, short-tailed shearwaters (Puffinus tenuirostris) provisioning chicks should increase their foraging effort, by extending their foraging range and/or duration, both when foraging in neritic (short trips) and distant oceanic waters (long trips). Using both GPS and geolocation data-loggers, at-sea movements and habitat use were investigated over three breeding seasons (2012-14) at two colonies in southeastern Australia. RESULTS: Most individuals performed daily short foraging trips over the study period and inter-annual variations observed in foraging parameters where mainly due to few individuals from Griffith Island, performing 2-day trips in 2014. When performing long foraging trips, this study showed that individuals from both colonies exploited similar zones in the Southern Ocean. The results of this study suggest that individuals could increase their foraging range while exploiting distant feeding zones, which could indicate that short-tailed shearwaters forage in Antarctic waters not only to maintain their body condition but may also do so to buffer against local environmental stochasticity. Lower breeding performances were associated with longer foraging trips to distant oceanic waters in 2013 and 2014 indicating they could mediate reductions in food availability around the breeding colonies by extending their foraging range in the Southern Ocean. CONCLUSIONS: This study highlights the importance of foraging flexibility as a fundamental aspect of life history in coastal/pelagic marine central place foragers living in highly variable environments and how these foraging strategies are use to buffer this variability. PMID- 26236480 TI - Sperm DNA fragmentation after radioiodine treatment for differentiated thyroid cancer. AB - BACKGROUND: Treatment of differentiated thyroid cancer usually consists of a total thyroidectomy followed by one or several courses of radioiodine ((131)I). (131)I is known to have deleterious effects on radiation sensitive tissues and irradiation to the testes has been shown after its administration. We investigated effects of such treatment on sperm DNA in a patient with differentiated thyroid carcinoma. METHODS: The patient, a 32-year-old male with differentiated thyroid carcinoma treated by total thyroidectomy and radioiodine therapy, performed 6 semen samples in total, 3 for sperm banking and 3 for semen exploration, that were analysed for classic semen parameters. DNA integrity was analysed by flow cytometry: sperm DNA fragmentation index (DFI) and high DNA stainability (HDS) were analyzed by sperm chromatin structure assay, DNA fragmentation was analyzed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. RESULTS: Moderate oligozoospermia was observed as early as 3 months after a first dose of (131)I and became severe at 5 months. Total sperm count was reduced up to 12 months after the second dose of (131)I. Sperm DFI was increased 3.25 months after the first dose of (131)I. All parameters returned to normal values 28 months after the second (131)I dose. CONCLUSIONS: Treatment with (131)I induces alterations in sperm chromatin as well as in sperm parameters a short time (3 months) after a first dose of (131)I with persistence of sperm alterations until 12 months after a second dose. Sperm banking should be recommended before treatment. PMID- 26236481 TI - NOSH-aspirin (NBS-1120), a dual nitric oxide and hydrogen sulfide-releasing hybrid, reduces inflammatory pain. AB - The development of nitric oxide (NO)- and hydrogen sulfide (H2S)-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) has generated more potent anti inflammatory drugs with increased safety profiles. A new hybrid molecule incorporating both NO and H2S donors into aspirin (NOSH-aspirin) was recently developed. In the present study, the antinociceptive activity of this novel molecule was compared with aspirin in different models of inflammatory pain. It was found that NOSH-aspirin inhibits acetic acid-induced writhing response and carrageenan (Cg)-induced inflammatory hyperalgesia in a dose-dependent (5-150 MUmol/kg, v.o.) manner, which was superior to the effect of the same doses of aspirin. NOSH-aspirin's antinociceptive effect was also greater and longer compared to aspirin upon complete Freund's adjuvant (CFA)-induced inflammatory hyperalgesia. Mechanistically, NOSH-aspirin, but not aspirin, was able to reduce the production/release of interleukin-1 beta (IL-1beta) during Cg-induced paw inflammation. Furthermore, NOSH-aspirin, but not aspirin, reduced prostaglandin E2-induced hyperalgesia, which was prevented by treatment with a ATP-sensitive potassium channel (KATP) blocker (glibenclamide; glib.). Noteworthy, the antinociceptive effect of NOSH-aspirin was not associated with motor impairment. The present results indicate that NOSH-aspirin seems to present greater potency than aspirin to reduce inflammatory pain in several models. The enhanced effects of NOSH-aspirin seems to be due to its ability to reduce the production of pronociceptive cytokines such as IL-1 beta and directly block hyperalgesia caused by a directly acting hyperalgesic mediator in a mechanism dependent on modulation of KATP channels. In conclusion, we would like to suggest that NOSH-aspirin represents a prototype of a new class of analgesic drugs with more potent effects than the traditional NSAID, aspirin. PMID- 26236482 TI - The discovery of a selective and potent A2a agonist with extended lung retention. AB - Although the anti-inflammatory role of the A2a receptor is well established, controversy remains with regard to the therapeutic value for A2a agonists in treatment of inflammatory lung diseases, also as a result of unwanted A2a mediated cardiovascular effects. In this paper, we describe the discovery and characterization of a new, potent and selective A2a agonist (compound 2) with prolonged lung retention and limited systemic exposure following local administration. To support the lead optimization chemistry program with compound selection and profiling, multiple in vitro and in vivo assays were used, characterizing compound properties, pharmacodynamics (PD), and drug concentrations. Particularly, pharmacokinetic-PD modeling was applied to quantify the effects on the cardiovascular system, and an investigative toxicology study in rats was performed to explore potential myocardial toxicities. Compound 2, in comparison to a reference A2a agonist, UK-432,097, demonstrated higher solubility, lower lipophilicity, lower plasma protein binding, high rat lung retention (28% remaining after 24 h), and was efficacious in a lung inflammatory rat model following intratracheal dosing. Despite these properties, compound 2 did not provide a sufficient therapeutic index, that is, separation of local anti inflammatory efficacy in the lung from systemic side effects in the cardiovascular system. The plasma concentration that resulted in induction of hypotension (half maximal effective concentration; EC50 0.5 nmol/L) correlated to the in vitro A2a potency (rIC50 0.6 nmol/L). Histopathological lesions in the heart were observed at a dose level which is threefold above the efficacious dose level in the inflammatory rat lung model. In conclusion, compound 2 is a highly potent and selective A2a agonist with significant lung retention after intratracheal administration. Despite its local anti-inflammatory efficacy in rat lung, small margins to the cardiovascular effects suggested limited therapeutic value of this compound for treatment of inflammatory lung disease by the inhaled route. PMID- 26236483 TI - Novel aspects of cholinergic regulation of colonic ion transport. AB - Nicotinic receptors are not only expressed by excitable tissues, but have been identified in various epithelia. One aim of this study was to investigate the expression of nicotinic receptors and their involvement in the regulation of ion transport across colonic epithelium. Ussing chamber experiments with putative nicotinic agonists and antagonists were performed at rat colon combined with reverse transcription polymerase chain reaction (RT-PCR) detection of nicotinic receptor subunits within the epithelium. Dimethylphenylpiperazinium (DMPP) and nicotine induced a tetrodotoxin-resistant anion secretion leading to an increase in short-circuit current (I sc) across colonic mucosa. The response was suppressed by the nicotinic receptor antagonist hexamethonium. RT-PCR experiments revealed the expression of alpha2, alpha4, alpha5, alpha6, alpha7, alpha10, and beta4 nicotinic receptor subunits in colonic epithelium. Choline, the product of acetylcholine hydrolysis, is known for its affinity to several nicotinic receptor subtypes. As a strong acetylcholinesterase activity was found in colonic epithelium, the effect of choline on I sc was examined. Choline induced a concentration-dependent, tetrodotoxin-resistant chloride secretion which was, however, resistant against hexamethonium, but was inhibited by atropine. Experiments with inhibitors of muscarinic M1 and M3 receptors revealed that choline-evoked secretion was mainly due to a stimulation of epithelial M3 receptors. Although choline proved to be only a partial agonist, it concentration dependently desensitized the response to acetylcholine, suggesting that it might act as a modulator of cholinergically induced anion secretion. Thus the cholinergic regulation of colonic ion transport - up to now solely explained by cholinergic submucosal neurons stimulating epithelial muscarinic receptors - is more complex than previously assumed. PMID- 26236484 TI - Pharmacological properties of acid N-thiazolylamide FFA2 agonists. AB - FFA2 is a receptor for short-chain fatty acids. Propionate (C3) and 4-chloro alpha-(1-methylethyl)-N-2-thiazolyl-benzeneacetamide (4-CMTB), the prototypical synthetic FFA2 agonist, evoke calcium mobilization in neutrophils and inhibit lipolysis in adipocytes via this G-protein-coupled receptor. 4-CMTB contains an N thiazolylamide motif but no acid group, and 4-CMTB and C3 bind to different sites on FFA2 and show allosteric cooperativity. Recently, FFA2 agonists have been described that contain both N-thiazolylamide and carboxylate groups, reminiscent of bitopic ligands. These are thought to engage the carboxylate-binding site on FFA2, but preliminary evidence suggests they do not bind to the same site as 4 CMTB even though both contain N-thiazolylamide. Here, we describe the characterization of four FFA2 ligands containing both N-thiazolylamide and carboxylate. (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4 oxobutanoic acid (compound 14) exhibits allosteric agonism with 4-CMTB but not C3. Three other compounds agonize FFA2 in [(35)S]GTPgammaS-incorporation or cAMP assays but behave as inverse agonists in yeast-based gene-reporter assays, showing orthosteric antagonism of C3 responses but allosteric antagonism of 4 CMTB responses. Thus, the bitopic-like FFA2 ligands engage the orthosteric site but do not compete at the site of 4-CMTB binding on an FFA2 receptor molecule. Compound 14 activates FFA2 on human neutrophils and mouse adipocytes, but appears not to inhibit lipolysis upon treatment of human primary adipocytes in spite of the presence of a functional FFA2 receptor in these cells. Hence, these new ligands may reveal differences in coupling of FFA2 between human and rodent adipose tissues. PMID- 26236485 TI - Pharmacological profiling of the hemodynamic effects of cannabinoid ligands: a combined in vitro and in vivo approach. AB - The receptors mediating the hemodynamic responses to cannabinoids are not clearly defined due to the multifarious pharmacology of many commonly used cannabinoid ligands. While both CB1 and TRPV1 receptors are implicated, G protein-coupled receptor 55 (GPR55) may also mediate some of the hemodynamic effects of several atypical cannabinoid ligands. The present studies attempted to unravel the pharmacology underlying the in vivo hemodynamic responses to ACEA (CB1 agonist), O-1602 (GPR55 agonist), AM251 (CB1 antagonist), and cannabidiol (CBD; GPR55 antagonist). Agonist and antagonist profiles of each ligand were determined by ligand-induced GTPgammaS binding in membrane preparations expressing rat and mouse CB1 and GPR55 receptors. Blood pressure responses to ACEA and O-1602 were recorded in anesthetized and conscious mice (wild type, CB1 (-/-) and GPR55(-/-)) and rats in the absence and presence of AM251 and CBD. ACEA demonstrated GTPgammaS activation at both receptors, while O-1602 only activated GPR55. AM251 exhibited antagonist activity at CB1 and agonist activity at GPR55, while CBD demonstrated selective antagonist activity at GPR55. The depressor response to ACEA was blocked by AM251 and attenuated by CBD, while O-1602 did not induce a depressor response. AM251 caused a depressor response that was absent in GPR55(-/ ) mice but enhanced by CBD, while CBD caused a small vasodepressor response that persisted in GPR55(-/-) mice. Our findings show that assessment of the pharmacological profile of receptor activation by cannabinoid ligands in in vitro studies alongside in vivo functional studies is essential to understand the role of cannabinoids in hemodynamic control. PMID- 26236486 TI - TRO40303, a mitochondrial-targeted cytoprotective compound, provides protection in hepatitis models. AB - TRO40303 is cytoprotective compound that was shown to reduce infarct size in preclinical models of myocardial infarction. It targets mitochondria, delays mitochondrial permeability transition pore (mPTP) opening and reduces oxidative stress in cardiomyocytes submitted to ischemia/reperfusion in vitro. Because the involvement of the mitochondria and the mPTP has been demonstrated in chronic as well as acute hepatitis, we investigated the potential of TRO40303 to prevent hepatocyte injury. A first set of in vitro studies showed that TRO40303 (from 0.3 to 3 MUmol/L) protected HepG2 cells and primary mouse embryonic hepatocytes (PMEH) from palmitate intoxication, a model mimicking steatohepatitis. In PMEH, TRO40303 provided similar protection against cell death due to Jo2 anti-Fas antibody intoxication. Further studies were then preformed in a mouse model of Fas-induced fulminant hepatitis induced by injecting Jo2 anti-Fas antibody. When mice received a sublethal dose of Jo2 at 125 MUg/kg, TRO40303 pretreatment prevented liver enzyme elevation in plasma in parallel with a decrease in cytochrome C release from mitochondria and caspase 3 and 7 activation in hepatic tissue. When higher, lethal doses of Jo2 were administered, TRO40303 (10 and 30 mg/kg) significantly reduced mortality by 65-90% when administered intraperitoneally (i.p.) 1 h before Jo2 injection, a time when TRO40303 plasma concentrations reached their peak. TRO40303 (30 mg/kg, i.p.) was also able to reduce mortality by 30-50% when administered 1 h postlethal Jo2 intoxication. These results suggest that TRO40303 could be a promising new therapy for the treatment or prevention of hepatitis. PMID- 26236488 TI - Helping to drive the robustness of preclinical research - the assay capability tool. AB - Numerous articles in Nature, Science, Pharmacology Research and Perspectives, and other biomedical research journals over the past decade have highlighted that research is plagued by findings that are not reliable and cannot be reproduced. Poor experiments can occur, in part, as a consequence of inadequate statistical thinking in the experimental design, conduct and analysis. As it is not feasible for statisticians to be involved in every preclinical experiment many of the same journals have published guidelines on good statistical practice. Here, we outline a tool that addresses the root causes of irreproducibility in preclinical research in the pharmaceutical industry. The Assay Capability Tool uses 13 questions to guide scientists and statisticians during the development of in vitro and in vivo assays. It promotes the absolutely essential experimental design and analysis strategies and documents the strengths, weaknesses, and precision of an assay. However, what differentiates it from other proposed solutions is the emphasis on how the resulting data will be used. An assay can be assigned a low, medium, or high rating to indicate the level of confidence that can be afforded when making important decisions using data from that assay. This provides transparency on the appropriate interpretation of the assay's results in the light of its current capability. We suggest that following a well-defined process during assay development and use such as that laid out within the Assay Capability Tool means that whatever the results, positive or negative, a researcher can have confidence to make decisions upon and publish their findings. PMID- 26236487 TI - Dimeric human sulfotransferase 1B1 displays cofactor-dependent subunit communication. AB - The cytosolic sulfotransferases (SULTs) are dimeric enzymes that catalyze the transformation of hydrophobic drugs and hormones into hydrophilic sulfate esters thereby providing the body with an important pathway for regulating small molecule activity and excretion. While SULT dimerization is highly conserved, the necessity for the interaction has not been established. To perform its function, a SULT must efficiently bind the universal sulfate donor, 3'-phosphoadenosine-5' phosphosulfate (PAPS), and release the byproduct, 3', 5'-diphosphoadenosine (PAP), following catalysis. We hypothesize this efficient binding and release of PAPS/PAP may be connected to SULT dimerization. To allow for the visualization of dynamic protein interactions critical for addressing this hypothesis and to generate kinetically testable hypotheses, molecular dynamic simulations (MDS) of hSULT1B1 were performed with PAPS and PAP bound to each dimer subunit in various combinations. The results suggest the dimer subunits may possess the capability of communicating with one another in a manner dependent on the presence of the cofactor. PAP or PAPS binding to a single side of the dimer results in decreased backbone flexibility of both the bound and unbound subunits, implying the dimer subunits may not act independently. Further, binding of PAP to one subunit of the dimer and PAPS to the other caused increased flexibility in the subunit bound to the inactive cofactor (PAP). These results suggest SULT dimerization may be important in maintaining cofactor binding/release properties of SULTs and provide hypothetical explanations for SULT half-site reactivity and substrate inhibition, which can be analyzed in vitro. PMID- 26236489 TI - Key role of publication of clinical data for target validation. AB - Drug discovery productivity has failed to improve markedly in recent years and a key issue is high attrition due to efficacy failures in initial proof-of concept clinical studies. This reflects the fact that preclinical "target validation" studies do not always translate into man, where ultimate target validation must reside. Given these facts, it is easy to see the importance of results from those first clinical validation studies for overall target validation. There are various initiatives to promote the publication of clinical data, but many clinical results, particularly negative results, remain unpublished, are published in obscure places or are published after a considerable delay. This gives rise to the potential that vast sums of money could be spent on compounds for which the molecular target has essentially been invalidated, but the data are not publicly available. Pharmacology, Research and Perspectives has indicated that it will welcome publication of all data pertinent to target validation, particularly negative data (clinical and preclinical), and it will do so in a form that should be relatively rapid and easy to achieve. PMID- 26236490 TI - Replication - why we need to publish our findings. AB - The pharmacology research sector is changing to accommodate a need for greater transparency and better standards. The themed articles contained herein explain how Pharmacology Research and Perspectives (PR&P) has responded to this agenda. This issue of PR&P contains three articles that consider the reliability of pharmacological research publications, and approaches to their improvement in this regard. This first article explains the importance of publishing findings that confirm or repudiate published findings (so called "replication" studies). It also emphasizes that PR&P actively encourages submission of such articles, and seeks to oppose the publication bias that favors publication of "positive" findings. The second paper explores some initiatives to publish "negative" clinical findings, including a PR&P initiative. The final paper elaborates a toolkit that can be applied to drug discovery research to facilitate the reliability of findings. PMID- 26236491 TI - Erratum. AB - [This corrects the article on p. e00115 in vol. 3, PMID: 25729582.]. PMID- 26236492 TI - Sphingobacterium multivorum: case report and literature review. AB - We describe the case of a 67-year-old African American woman with multiple medical problems who presented with septic shock resulting from Sphingobacterium multivorum bacteraemia. S. multivorum, a Gram-negative bacillus, is ubiquitous in nature and is rarely involved in human infections. However, it is intrinsically resistant to many commonly administered antibiotics and can be a life-threatening microorganism. PMID- 26236493 TI - International Mycoplasma pneumoniae typing study: interpretation of M. pneumoniae multilocus variable-number tandem-repeat analysis. AB - Typing of Mycoplasma pneumoniae by multiple-locus variable-number tandem repeat analysis (MLVA) is increasingly in use. However, no specific internationally agreed guidance is available. Thirty M. pneumoniae DNA samples including serial dilutions of a type strain were sent to six international laboratories to perform MLVA and results were compared. Good correlation was observed, indicating that this methodology can be robustly performed in multiple sites. However, differences due to interpretation of fragment size, repeat sequence identification and repeat numbering led to inconsistency in the final profiles assigned by laboratories. We propose guidelines for interpreting M. pneumoniae MLVA typing and assigning the number of repeats. PMID- 26236494 TI - High prevalence of bla OXA-23 in Acinetobacter spp. and detection of bla NDM-1 in A. soli in Cuba: report from National Surveillance Program (2010-2012). AB - As a first national surveillance of Acinetobacter in Cuba, a total of 500 Acinetobacter spp. isolates recovered from 30 hospitals between 2010 and 2012 were studied. Acinetobacter baumannii-calcoaceticus complex accounted for 96.4% of all the Acinetobacter isolates, while other species were detected at low frequency (A. junii 1.6%, A. lwoffii 1%, A. haemolyticus 0.8%, A. soli 0.2%). Resistance rates of isolates were 34-61% to third-generation cephalosporins, 49 50% to beta-lactams/inhibitor combinations, 42-47% to aminoglycosides, 42-44% to carbapenems and 55% to ciprofloxacin. However, resistance rates to colistin, doxycycline, tetracycline and rifampin were less than 5%. Among carbapenem resistant isolates, 75% harboured different bla OXA genes (OXA-23, 73%; OXA-24, 18%; OXA-58, 3%). The bla NDM-1 gene was identified in an A. soli strain, of which the species was confirmed by sequence analysis of 16S rRNA gene, rpoB, rpoB rpoC and rpoL-rpoB intergenic spacer regions and gyrB. The sequences of bla NDM-1 and its surrounding genes were identical to those reported for plasmids of A. baumannii and A. lwoffi strains. This is the first report of bla NDM-1 in A. soli, together with a high prevalence of OXA-23 carbapenemase for carbapenem resistance in Acinetobacter spp. in Cuba. PMID- 26236495 TI - THE IPUMS COLLABORATION: INTEGRATING AND DISSEMINATING THE WORLD'S POPULATION MICRODATA. AB - The Integrated Public Use Microdata Series (IPUMS) International partnership is a project of the Minnesota Population Center and national statistical agencies, dedicated to collecting and distributing census data from around the world. IPUMS is currently disseminating data on over a half-billion persons enumerated in more than 250 census samples from 79 countries. The data series includes information on a broad range of population characteristics, including fertility, nuptiality, life-course transitions, migration, labor-force participation, occupational structure, education, ethnicity, and household composition. This paper describes sample characteristics and data structure; the data integration process including the creation of constructed family interrelationship variables; the flexible dissemination system that enables researchers to build customized extracts of pooled census samples across time and place; and some of the most significant findings that have emerged from the database. PMID- 26236497 TI - Untethering the TIR1 auxin receptor from the SCF complex increases its stability and inhibits auxin response. AB - Plant genomes encode large numbers of F-box proteins (FBPs), the substrate recognition subunit of SKP1-CULLIN-F-box (SCF) ubiquitin ligases. There are ~700 FBPs in Arabidopsis, most of which are uncharacterized. TIR1 is among the best studied plant FBPs and functions as a receptor for the plant hormone auxin. Here we use a yeast two-hybrid system to identify novel TIR1 mutants with altered properties. The analysis of these mutants reveals that TIR1 associates with the CULLIN1 (CUL1) subunit of the SCF through the N-terminal H1 helix of the F-box domain. Mutations that untether TIR1 from CUL1 stabilize the FBP and cause auxin resistance and associated growth defects, probably by protecting TIR1 substrates from degradation. Based on these results we propose that TIR1 is subject to autocatalytic degradation when assembled into an SCF. Further, our results suggest a general method for determining the physiological function of uncharacterized FBPs. Finally, we show that a key amino acid variation in the F box domain of auxin signalling F-box (AFB1), a closely related FBP, reduces its ability to form an SCF, resulting in an increase in AFB1 levels. PMID- 26236498 TI - Optical Coherence Tomography Reveals New Insights into the Accommodation Mechanism. AB - Purpose. To evaluate the movement of the anterior and posterior lens poles during naturally stimulated accommodation in children using anterior segment optical coherence tomography (OCT). Methods. This is a prospective, observational, noncomparative case series including 18 eyes of nine children. Analysis of the anterior segment in the accommodated and unaccommodated state (with cycloplegia) was done using anterior segment OCT. The main outcome measures were the position of the anterior and posterior lens poles (in relation to the cornea) and lens thickness (LT). Results. A Statistically significant forward movement of the anterior lens pole and backward movement of the posterior lens pole with an increase in LT were found during accommodation (P < 0.001). There was no significant difference between the degree of movement of the anterior lens pole and the posterior lens pole during accommodation (P = 0.944). Conclusions. Anterior segment OCT provides a rapid noncontact method for studying accommodation in children. The backward movement of the posterior lens pole during accommodation nearly equals the forward movement of its anterior pole. These data minimize the theoretical hydraulic effect of the vitreous during accommodation, adding more support to the capsular theory of Helmholtz. PMID- 26236496 TI - The impact and treatment of obesity in kidney transplant candidates and recipients. AB - The prevalence of obesity in patients with chronic kidney failure and renal transplant candidates has paralleled the epidemic in the general population. The associated risks of surgical complications and long-term cardiovascular death are significant: most transplant centers consider obesity a relative contra indication for transplant. Few studies have focused on conservative weight loss strategies in transplant patients. Studies using administrative databases have found that only a minority of wait-listed patients lose weight and with no apparent benefit to transplant outcomes. The only clinical trial in this area found that an intensive weight-loss program had significantly better success (to listing) than self-directed weight loss. However, only a minority that succeeded with the help of a program (36 %), while the "diet and exercise" group had negligible results. Laparoscopy has radically shortened the recovery time and decreased the complications associated with bariatric surgery. Reports in transplant patients, who were previously deemed too medically complex, have demonstrated a dramatic and rapid weight loss. The only randomized clinical trial in patients with CKD, which compared sleeve gastrectomy to best medical care clearly favoured the surgical arm for weight loss, but was too small to assess other outcomes. The emerging experience is small but quite promising. Surgical complications and the effect on immunosuppression remain the chief concerns regarding the use of bariatric surgery in transplant patients. Rigorous prospective studies will be essential to properly evaluate the expected weight loss and the effect on pharmacokinetics of immunosuppressive medications. A routine role for bariatric surgery in transplantation would require evidence of improvements in patient-important outcomes and evidence of safety. PMID- 26236499 TI - Pathophysiological Relationship between Infections and Systemic Vasculitis. AB - The development of autoimmune disorders requires a combination of genetic, immunological, and environmental factors. Infectious agents, such as viruses and bacteria, can trigger autoimmunity through different mechanisms, and for systemic vasculitis in particular, microbial agents have been suggested to be involved in its pathogenesis. Although the exact mechanisms have not been fully elucidated, different theories have been postulated. This review considers the role of infections in the etiology of primary vasculitis, emphasizing their related immunological events. PMID- 26236501 TI - Analysis of Complications in Postbariatric Abdominoplasty: Our Experience. AB - Abdominoplasty is one of the most popular body-contouring procedures. It is associated with a significant number of complications: the most common ones are seroma, hematoma, infection, wound-healing problems, and skin flap necrosis. From January 2012 to December 2014, 25 patients (18 women and 7 men) (mean age: 51 years) underwent abdominoplastic surgery at the Plastic Surgery Section, Department of Surgical Sciences, University of Parma, Italy. All patients reported a weight loss between 15 kg and 47 kg. All of the of 25 patients were included in the study; minor and major complications were seen in 17 (68%) and 8 (32%) patients, respectively. The percentage of complications in our patients was as follows: 9 patients with seroma (36%); 4 patients with wound dehiscence with delayed wound healing (16%); 3 cases with hematoma (12%); 2 patients with postoperative bleeding (8%); 1 patient (4%) with an umbilical necrosis; 1 patient (4%) with a deep vein thrombosis; 3 patients with infected seroma (12%); and 2 patients with wound infection (8%). There were no cases of postoperative mortality. The aim of this study is to analyze our complications in postbariatric abdominoplasty. PMID- 26236500 TI - Efficacy and Safety of Intravenous Ferric Carboxymaltose in Geriatric Inpatients at a German Tertiary University Teaching Hospital: A Retrospective Observational Cohort Study of Clinical Practice. AB - Current iron supplementation practice in geriatric patients is erratic and lacks evidence-based recommendations. Despite potential benefits in this population, intravenous iron supplementation is often withheld due to concerns regarding pharmacy expense, perceived safety issues, and doubts regarding efficacy in elderly patients. This retrospective, observational cohort study aimed to evaluate the safety and efficacy of intravenous ferric carboxymaltose (FCM, Ferinject) in patients aged >75 years with iron deficiency anaemia (IDA). Within a twelve-month data extraction period, the charts of 405 hospitalised patients aged 65-101 years were retrospectively analysed for IDA, defined according to WHO criteria for anaemia (haemoglobin: <13.0 g/dL (m)/<12.0 g/dL (f)) in conjunction with transferrin saturation <20%. Of 128 IDA patients screened, 51 (39.8%) received intravenous iron. 38 patient charts were analysed. Mean cumulative dose of intravenous FCM was 784.4 +/- 271.7 mg iron (1-3 infusions). 18 patients (47%) fulfilled treatment response criteria (>=1.0 g/dL increase in haemoglobin between baseline and hospital discharge). AEs were mild/moderate, most commonly transient increases of liver enzymes (n = 5/13.2%). AE incidence was comparable with that observed in patients <75 years. No serious AEs were observed. Ferric carboxymaltose was well tolerated and effective for correction of Hb levels and iron stores in this cohort of IDA patients aged over 75 years. PMID- 26236502 TI - One-Stop Clinic Utilization in Plastic Surgery: Our Local Experience and the Results of a UK-Wide National Survey. AB - Introduction. "See and treat" one-stop clinics (OSCs) are an advocated NHS initiative to modernise care, reducing cancer treatment waiting times. Little studied in plastic surgery, the existing evidence suggests that though they improve care, they are rarely implemented. We present our experience setting up a plastic surgery OSC for minor skin surgery and survey their use across the UK. Methods. The OSC was evaluated by 18-week wait target compliance, measures of departmental capacity, and patient satisfaction. Data was obtained from 32 of the 47 UK plastic surgery departments to investigate the prevalence of OSCs for minor skin cancer surgery. Results. The OSC improved 18-week waiting times, from a noncompliant mean of 80% to a compliant 95% average. Department capacity increased 15%. 95% of patients were highly satisfied with and preferred the OSC to a conventional service. Only 25% of UK plastic surgery units run OSCs, offering varying reasons for not doing so, 42% having not considered their use. Conclusions. OSCs are underutilised within UK plastic surgery, where a significant proportion of units have not even considered their benefit. This is despite associated improvements in waiting times, department capacity, and levels of high patient satisfaction. We offer our considerations and local experience instituting an OSC service. PMID- 26236503 TI - Evaluation of TB Case Finding through Systematic Contact Investigation, Chhattisgarh, India. AB - Rationale. Contact investigation is an established tool for early case detection of tuberculosis (TB). In India, contact investigation is not often conducted, despite national policy, and the yield of contact investigation is not well described. Objective. To determine the yield of evaluating household contacts of sputum smear-positive TB cases in Rajnandgaon district, Chhattisgarh, India. Methods. Among 14 public health care facilities with sputum smear microscopy services, home visits were conducted to identify household contacts of all registered sputum smear-positive TB cases. We used a standardized protocol to screen for clinical symptoms suggestive of active TB with additional referral for chest radiograph and sputa collection. Results. From December 2010 to May 2011, 1,556 household contacts of 312 sputum smear-positive TB cases were identified, of which 148 (9.5%) were symptomatic. Among these, 109 (73.6%) were evaluated by sputum examination resulting in 11 cases (10.1%) of sputum smear-positive TB and 4 cases (3.6%) of smear-negative TB. Household visits contributed additional 63% TB cases compared to passive case detection alone. Conclusion. A standard procedure for conducting household contact investigation identified additional TB cases in the community and offered an opportunity to initiate isoniazid chemoprophylaxis among children. PMID- 26236504 TI - Hypobaric Hypoxia Imbalances Mitochondrial Dynamics in Rat Brain Hippocampus. AB - Brain is predominantly susceptible to oxidative stress and mitochondrial dysfunction during hypobaric hypoxia, and therefore undergoes neurodegeneration due to energy crisis. Evidences illustrate a high degree of association for mitochondrial fusion/fission imbalance and mitochondrial dysfunction. Mitochondrial fusion/fission is a recently reported dynamic mechanism which frequently occurs among cellular mitochondrial network. Hence, the study investigated the temporal alteration and involvement of abnormal mitochondrial dynamics (fusion/fission) along with disturbed mitochondrial functionality during chronic exposure to hypobaric hypoxia (HH). The Sprague-Dawley rats were exposed to simulated high altitude equivalent to 25000 ft for 3, 7, 14, 21, and 28 days. Mitochondrial morphology, distribution within neurons, enzyme activity of respiratory complexes, Deltapsi m , ADP: ATP, and expression of fission/fusion key proteins were determined. Results demonstrated HH induced alteration in mitochondrial morphology by damaged, small mitochondria observed in neurons with disturbance of mitochondrial functionality and reduced mitochondrial density in neuronal processes manifested by excessive mitochondrial fragmentation (fission) and decreased mitochondrial fusion as compared to unexposed rat brain hippocampus. The study suggested that imbalance in mitochondrial dynamics is one of the noteworthy mechanisms occurring in hippocampal neurons during HH insult. PMID- 26236505 TI - Management of Overweight during Childhood: A Focus Group Study on Health Professionals' Experiences in General Practice. AB - Background. Because of the increasing prevalence of overweight and obesity in childhood in the Western world, focus on the management in general practice has also increased. Objective. To explore the experiences of general practitioners (GPs) and practice nurses participating in a randomised controlled trial (RCT) comparing two management programmes in general practice for children who are overweight or obese. Methods. Three focus groups with GPs and nurses participating in the RCT. Transcribed data were analysed using systematic text condensation followed by thematic analysis. Results. Health professionals considered it their responsibility to offer a management programme to overweight children. They recognised that management of overweight during childhood was a complex task that required an evidence-based strategy with the possibility of supervision. Health professionals experienced a barrier to addressing overweight in children. However, increasing awareness of obesity in childhood and its consequences in society was considered helpful to reach an understanding of the articulations concerning how best to address the issue. Conclusions. Health professionals in general practice recognised that they have a special obligation, capacity, and role in the management of obesity in childhood. Implementation of future management programmes must address existing barriers beyond an evidence based standardised strategy. PMID- 26236506 TI - EDSS Change Relates to Physical HRQoL While Relapse Occurrence Relates to Overall HRQoL in Patients with Multiple Sclerosis Receiving Subcutaneous Interferon beta 1a. AB - Objective. To compare patterns of associations of changes in mental and physical health dimensions of health-related quality of life (HRQoL) over time with relapse occurrence and changes in Expanded Disability Status Scale (EDSS) scores in patients with relapsing multiple sclerosis (RMS). Methods. This 24-month, phase IV, observational study enrolled 334 patients with RMS who received interferon beta-1a 44 MUg or 22 MUg subcutaneously three times weekly. At each 6 month visit, patients completed the Multiple Sclerosis Quality of Life-54 (MSQOL 54) and site investigators assessed EDSS and recorded relapse occurrence. A generalized linear model procedure was used for multivariable analyses (per protocol) that explored unique associations of EDSS score change and relapse occurrence with MSQOL-54 physical health composite score (PCS) and mental health composite score (MCS). Results. HRQoL improved over 2 years among those who completed the study. Occurrence of >=1 relapse was significantly associated with lower MSQOL-54 PCS and MCS. Changes in EDSS score were significantly associated with MSQOL-54 PCS, but not MCS. Conclusions. HRQoL assessments, particularly those that examine mental health, may provide information on the general health status of patients with RMS that would not be recognized using traditional clinician-assessed measures of disease severity and activity. This trial is registered with ClinicalTrials.gov; identifier: NCT01141751. PMID- 26236507 TI - Pyramidal Lobe of the Thyroid Gland: Surgical Anatomy in Patients Undergoing Total Thyroidectomy. AB - Background. Anatomic variations, the presence of the pyramidal lobe (PL), may impact completeness of thyroidectomy and effect of surgical treatment. Method. This study included 166 patients who underwent total thyroidectomy. The anterior cervical region between the thyroid isthmus and the hyoid bone was dissected during thyroid surgery. The incidence, size, and anatomical features of the PL were established in these patients. Results. The incidence of PL was 65.7%. No gender difference was found for PL incidence. The base of the PL was located at the isthmus in 52.3%, the left lobe in 29.4%, and the right lobe in 18.3% of patients. The mean length of the PL was 22.7 (range, 5-59) mm. The PL was longer than 30 mm in 23% of patients. One-third of the patients with short PL were men whereas women accounted for 80% of patients with long PL. Conclusions. The high incidence indicates that the PL is a common part of the thyroid. The PL generally originates from the isthmus near midline and is of variable length, extending from the isthmus up to the hyoid bone. Considering that the PL is a common structure, the prelaryngeal region should be dissected to achieve the completeness of thyroidectomy. PMID- 26236508 TI - Subjective Experiences of Speech and Language Therapy in Patients with Parkinson's Disease: A Pilot Study. AB - Purpose. Parkinson's disease can produce a range of speech-language pathologies, which may require intervention. While evaluations of speech-language therapy have been undertaken, no work has been undertaken to capture patients' experiences of therapy. This was the aim of the present study. Methods. Semistructured interviews, using themes derived from the literature, were conducted with nine Parkinson's disease patients, all of whom had undergone speech-language therapy. Participants' responses were analysed in accordance with Thematic Network Analysis. Results. Four themes emerged: emotional reactions (frustration, embarrassment, lack of confidence, disappointment, and anxiety); physical impact (fatigue, breathing and swallowing, and word production); practical aspects (cost of treatment, waiting times, and the actual clinical experience); and expectations about treatment (met versus unmet). Conclusions. While many benefits of speech-language therapy were reported, several negative issues emerged which could impact adversely on rehabilitation. Parkinson's disease is associated with a range of psychological and physical sequelae, such as fatigue and depression; recognising any individual experiences which could exacerbate the existing condition and incorporating these into treatment planning may improve rehabilitation outcomes. PMID- 26236510 TI - Gingival Cyst of the Adult as Early Sequela of Connective Tissue Grafting. AB - The subepithelial connective tissue graft (SCTG) is a highly predictable procedure with low complication rate. The reported early complications consist of typical postsurgical sequelae, such as pain and swelling. This case report describes the development and management of a gingival cyst following SCTG to obtain root coverage. Three weeks after SCTG procedure, a slightly raised, indurated, ~5 mm diameter asymptomatic lesion was evident. Excisional biopsy was performed and the histopathological evaluation confirmed the gingival cyst diagnosis. At the 1-year follow-up, the site had complete root coverage and normal tissue appearance and the patient remained asymptomatic. PMID- 26236509 TI - Neurophysiological Correlates of Central Fatigue in Healthy Subjects and Multiple Sclerosis Patients before and after Treatment with Amantadine. AB - In ten healthy subjects and in ten patients suffering from Multiple Sclerosis (MS), we investigated the cortical functional changes induced by a standard fatiguing repetitive tapping task. The Cortical Silent Period (CSP), an intracortical, mainly GABAB-mediated inhibitory phenomenon, was recorded by two different hand muscles, one acting as prime mover of the fatiguing index-thumb tapping task (First Dorsal Interosseous, FDI) and the other one not involved in the task but sharing largely overlapping central, spinal, and peripheral innervation (Abductor Digiti Minimi, ADM). At baseline, the CSP was shorter in patients than in controls. As fatigue developed, CSP changes involved both the "fatigued" FDI and the "unfatigued" ADM muscles, suggesting a cortical spread of central fatigue mechanisms. Chronic therapy with amantadine annulled differences in CSP duration between controls and patients, possibly through restoration of more physiological levels of intracortical inhibition in the motor cortex. These inhibitory changes correlated with the improvement of fatigue scales. The CSP may represent a suitable marker of neurophysiological mechanisms accounting for central fatigue generation either in controls or in MS patients, involving corticospinal neural pools supplying not only the fatigued muscle but also adjacent muscles sharing an overlapping cortical representation. PMID- 26236511 TI - Subcutaneous Emphysema, Pneumomediastinum, and Pneumorrhachis after Cocaine Inhalation. AB - Introduction. The most prominent complications of cocaine use are adverse effects in the cardiovascular and central nervous systems. Free air in the mediastinum and subcutaneous tissue may be observed less frequently, whereas free air in the spinal canal (pneumorrhachis) is a very rare complication of cocaine abuse. In this report we present a case of pneumorrhachis that developed after cocaine use. Case. A 28-year-old male patient was admitted to the emergency department with shortness of breath, chest pain, and swelling in the neck and face which started four hours after he had sniffed cocaine. On physical examination, subcutaneous crepitations were felt with palpation of the jaw, neck, and upper chest area. Diffuse subcutaneous emphysema, pneumomediastinum, and pneumorrhachis were detected in the computed tomography imaging. The patient was treated conservatively and discharged uneventfully. Discussion. Complications such as pneumothorax, pneumomediastinum, and pneumoperitoneum that are associated with cocaine use may be seen due to increased intrathoracic pressure. The air then may flow into the spinal canal resulting in pneumorrhachis. Emergency physicians should know the possible complications of cocaine use and be prepared for rare complications such as pneumorrhachis. PMID- 26236512 TI - Unexpected Bone Metastases from Thyroid Cancer. AB - Objective. To present a complicated case of differentiated thyroid carcinoma (DTC) with metastases to the skull that was evident on I-131 whole body scan (WBS) but negative on other imaging modalities in a low risk patient. Methods. We will discuss clinical course, imaging, pathological findings, and treatment of the patient with skull metastasis from DTC. Pertinent literature on imaging and pathology findings as well as radioactive iodine (RAI) treatment impact on quality of life and survival in patients with bone metastases from DTC will be reviewed. Results. The patient is a 37-year-old woman with a diagnosis of DTC who had focal areas of increased uptake in the head on WBS with no correlative findings on CT and MRI. Initially, false positive findings were suspected since patient had a low risk for developing metastases. However, the persistent findings on post-RAI treatment WBS, following two courses of treatment, were highly concerning for metastatic bone disease. WBC performed 6 months following the second RAI treatment revealed resolution of the findings. Conclusions. False positive findings in WBS are frequent and may be due to contamination, perspiration, or folliculitis of the scalp as well as benign lesions such as meningioma, hematoma, cavernous angioma, and metallic sutures. However, metastatic disease should always be considered even if the patient has low risk of distant metastatic disease and correlative images do not support the diagnosis. RAI therapy appears to improve the survival rates and quality of life of thyroid cancer patients with bone metastases based on retrospective studies. PMID- 26236513 TI - Paraganglioma Presenting as Postpartum Fever of Unknown Origin. AB - A young healthy postpartum mother presented with intermittent high fevers and tachycardia. Appropriate testing was done to rule out infectious causes including pan cultures but no identifiable infectious source was found. A CT of the abdomen showed a retroperitoneal mass with two small pulmonary nodules and a bony metastatic lesion. She was found to have stage 4 extra-adrenal paraganglioma with metastases to the lungs and spine. She underwent resection of the mass and is currently undergoing palliative radiation to the spine for pain control. Subsequent genetic testing identified a likely pathogenic variant in SDHB, confirming a diagnosis of Hereditary Paraganglioma-Pheochromocytoma syndrome. PMID- 26236514 TI - Transient Global Amnesia as the First Clinical Symptom for Malignant B-Cell Lymphoma with Central Nervous System Involvement. AB - We present the case of an elderly male who was diagnosed with transient global amnesia (TGA), only to be diagnosed with B-cell lymphoma with central nervous system involvement a few weeks later. This is the first ever case reported in literature with lymphoma presenting as TGA. Literature review and pertinent points regarding high-yield imaging protocol for presumed TGA patients are discussed. PMID- 26236515 TI - Uterine Intravenous Leiomyomatosis with Cardiac Extension: Radiologic Assessment with Surgical and Pathologic Correlation. AB - We present the computed tomography (CT) and magnetic resonance (MR) imaging findings of a 71-year-old woman with a cardiac extension of intravenous leiomyoma (IVL) that arose from the uterus, extended to the inferior vena cava (IVC), and reached the right ventricle through the right ovarian vein. Radiologic-pathologic correlation showed that the intravascular cord-like mass originating from the IVC and extending to the right ventricle was composed of degenerated smooth muscle cells with a number of large vessels that were regarded as arteries; moreover, the arteries within the cord-like mass appeared to be looping internally. Given the disappearance of the right ovarian venous wall around the IVL pathologically, extracting the tumor from the ovarian vein during an operation is considered to be impossible retrospectively. Also it was difficult to identify even the intravenous extension of the uterine leiomyoma histopathologically. Therefore, contrast-enhanced CT, in particular arterial phase imaging, provided important information that revealed the mass, range, and path of the lesion, ensuring that an appropriate operative plan could be drawn up and the tumor completely excised. PMID- 26236516 TI - Secretory Carcinoma of the Breast: Report of Two Cases and Review of the Literature. AB - Secretory carcinoma of the breast is an extremely rare subtype of breast cancer characterized by intracellular or extracellular secretion and granular eosinophilic cytoplasm of the neoplastic cells. The disease which was considered to be predominant in younger age group has been recognized in adult population too and tends to show slow growth and indolent behavior. The disease occurs preferentially in females and only 27 cases have been reported amongst males. An optimal treatment for the disease subtype has been debated because of the paucity of data. We report two cases (one female and one male) of this rare disease that underwent treatment at our institution. PMID- 26236517 TI - Lung Metastasis Mimicking Fingertip Infection. AB - Metastasis fingers (acral metastasis) are finding a poor prognosis. Past medical history should be questioned and metastasis from primary tumor should be kept in mind in patients with pain, swelling, and hyperemia in fingers. Successful surgical treatment on acral metastasis does not extend the life expectancy; however, it reduces the patient's pain during his terminal period, saves the functions of the limb, and increases life comfort. PMID- 26236518 TI - Two Cases of Contact Anterior Cruciate Ligament Rupture Combined with a Posterolateral Tibial Plateau Fracture. AB - Background. The combined occurrence of ACL rupture with a posterolateral tibial plateau fracture has not yet been reported. Two cases of such injuries have been treated in our department for the past three years. Findings. The two patients both suffered injuries from traffic accidents. The radiological examinations showed a ruptured ACL with fracture of the posterolateral tibial plateau. Reconstruction of the ACL was performed via a standard anatomical single bundle ACL reconstruction technique with autologous tendon by arthroscopy. A posterolateral tibia plateau approach was used to reduce and fix the fractured area with the aid of lag screws. After a one-year follow-up, the two patients recovered well and physical examinations showed full knee range of motion with no evidence of ACL instability. Conclusions. The cause of this type injury of ACL rupture with a posterolateral tibial plateau fracture was thought to be by a violent internal tibial rotation/anterior tibial translation without any valgus or varus knee force mechanism during the accident. Satisfactory clinical results were achieved with a standard anatomical single bundle ACL reconstruction by arthroscopy and ORIF for the posterolateral plateau fracture. Both patients reported excellent knee function and fracture healing. PMID- 26236519 TI - A Dual Biomechanical Failure: Exeter Stem and Pubic Rami Insufficiency Fracture, following Hybrid Total Hip Arthroplasty. AB - Introduction. Incidence of Exeter stem fracture is extremely uncommon. Pubic rami insufficiency fractures following arthroplasty are also rare. To our knowledge no cases of spontaneous stem failure with previous insufficiency fractures have yet been reported. Case Presentation. This report describes a case of spontaneous fracture through a cemented Exeter stem in a 66-year-old patient who had previously undergone a hybrid total hip replacement and was found to have bifocal pubic rami insufficiency fractures. The patient presented 18-year postprimary surgery with spontaneous fracture of the middle third of the cemented femoral stem and adjacent proximal femur. Conclusion. This report demonstrates a unique case of Exeter stem fracture with previous pelvic insufficiency fractures. The case adds to the rare occurrences of Exeter stem failure in the literature and highlights the risk of potential insufficiency fractures in patients undergoing total hip replacement. PMID- 26236520 TI - Neoprene Orthopaedic Supports: An Underrecognised Cause of Allergic Contact Dermatitis. AB - Thioureas, often contained within neoprene to provide water resistance, are an important cause of allergic contact dermatitis (ACD) in those who use neoprene products. We wish to present three cases of thiourea-induced ACD from three different orthopaedic supports containing neoprene. The first case was a 67-year old woman who developed an itchy rash on her heel three weeks after using a neoprene insole for plantar fasciitis. The second case was a 47-year-old man who developed an itchy rash on his wrist after wearing neoprene wrist splints for psoriatic arthropathy. The third case was a 77-year-old woman who experienced a severe erythematous rash with blistering from a neoprene elbow brace she received following a humeral fracture. All patients were patch tested to the British Society of Cutaneous Allergy Standard and rubber series and a cut piece from all the relevant supports. At 96 hours, all patients had a + reaction to mixed dialkylthiourea, diethylthiourea, and the supports' material. No other positive patch test reactions were identified. As neoprene is fast becoming one of the most popular materials used for orthopaedic supports, awareness of this reaction and close liaison between dermatologists and orthopaedic surgeons are therefore essential to allow for early recognition of this complication. PMID- 26236521 TI - Recurrent Postoperative Spinal Epidural Hematoma in a Patient with Protein S Deficiency. AB - A 71-year-old man underwent cervical laminectomy and developed two symptomatic epidural hematomas during the acute postoperative period. On both occasions, drain obstruction was the predominant cause. Congenital Protein S deficiency was diagnosed postoperatively. Protein S is a vitamin K-dependent natural anticoagulant and is essential for inhibiting thrombosis in microcirculation. We assume that Protein S deficiency followed by perioperative bed-rest and surgical invasiveness led to severe hypercoagulability and subsequent drain obstruction. The present findings suggest that both bleeding disorders and hypercoagulability are risk factors for postoperative symptomatic epidural hematoma. PMID- 26236522 TI - Diabetic Muscle Infarction of the Tibialis Anterior and Extensor Hallucis Longus Muscles Mimicking the Malignant Soft-Tissue Tumor. AB - One of the most common causes of skeletal muscle infarction is diabetic muscle infarction (DMI), a rare complication associated with poorly controlled diabetes. We report an atypical case of DMI localized in the tibialis anterior (TA) and extensor hallucis longus (EHL) muscles of an elderly individual. A 64-year-old man with type 2 diabetes mellitus presented with a 6-month history of a palpable mass in his lower left leg. Magnetic resonance imaging (MRI) revealed that the mass exhibited heterogeneous signals on T1- and T2-weighted images and slight heterogeneous enhancement within the muscles on fat suppressed T1-weighted images. Because histopathological analysis revealed mostly necrotic muscle tissues but no neoplastic cells, we resected the affected muscles. A typical symptom of DMI is severe abrupt-onset pain in the region of the affected muscles, but the patient did not complain of pain. Therefore, the diagnosis and treatment for DMI were delayed, and widespread irreversible muscle necrosis developed. MRI findings of DMI can be similar to that of a malignant soft-tissue tumor. So, it is necessary to consider the malignant soft-tissue tumor as one of the differential diagnoses of DMI. PMID- 26236523 TI - Treatment of Bifocal Cyst Hydatid Involvement in Right Femur with Teicoplanin Added Bone Cement and Albendazole. AB - Although bone involvement associated with cyst hydatid is rarely seen, it can cause unintended results such as high recurrence rate, infection, sepsis, or amputation of relevant extremity. Because of this reason, its treatment is difficult and disputed. In the case of bifocal bone cyst hydatid in right femur, along with albendazole treatment, result of resecting cyst surgically and its treatment with teicoplanin with added bone cement is given. In conclusion, since the offered treatment method both supports bone in terms of mechanical aspect and also can prevent secondary infection, the method is thought to be a good and safe treatment approach. PMID- 26236524 TI - Partial Recurrent Laryngeal Nerve Paralysis or Paresis? In Search for the Accurate Diagnosis. AB - "Partial paralysis" of the larynx is a term often used to describe a hypomobile vocal fold as is the term "paresis." We present a case of a dysphonic patient with a mobility disorder of the vocal fold, for whom idiopathic "partial paralysis" was the diagnosis made after laryngeal electromyography, and discuss a proposition for a different implementation of the term. PMID- 26236525 TI - Solitary Laryngeal Metastasis from Transitional Cell Carcinoma of the Kidney: Clinical Case and Review of the Literature. AB - The urogenital tract is a rare origin of laryngeal metastasis; transitional cell carcinoma with laryngeal metastases had never been reported previously. In this paper, we describe the clinical and pathological characteristics, evolution, and treatment of the first reported case of a laryngeal metastasis of a TCC followed by a brief review of the literature. PMID- 26236526 TI - Solitary Fibrous Tumour of the Parotid Gland: A Case Report and Review of the Literature. AB - Introduction. Solitary fibrous tumours (SFT) of the parotid gland are a very rare group of spindle-cell tumours with only 28 cases reported in the literature. This review aims to report an additional case of parotid SFT and provide a review of all reported cases of this rare condition. Case Presentation. A 26-year-old male presented a 3 cm well-demarcated, slowly enlarging mass which was completely excised, revealing histological and immunohistochemical features of SFT. Discussion. Reviews of all reported cases suggest that histology and immunohistochemistry are paramount in the diagnosis of SFT. These features, along with clinical presentation and management of this rare condition, will be discussed. PMID- 26236527 TI - Eccrine Spiradenoma Arising from the Breast Skin. AB - Eccrine spiradenomas are uncommon, benign lesions, which are thought to originate from the eccrine sweat glands. They are common in young adults and are without a sex predilection. Here we report a case of eccrine spiradenoma of the breast skin in a 39-year-old woman who presented with a breast nodule for 10 years. It is crucial to take eccrine spiradenoma into consideration in superficial, well circumscribed, breast skin/subcutaneous lesions. It is useful to recognize the two-cell populations constituting this tumor: small, dark, basaloid cells with hyperchromatic nuclei, which are immunoreactive for P63 and calponin, and larger cells with a pale nucleus, often near the center of the cluster (inner cells), which are immunoreactive for CK7 and CD117 (C-kit). PMID- 26236528 TI - Giant Ovarian Cyst Masquerading as Massive Ascites in an 11-Year-Old. AB - We are presenting a unique case of an 11-year-old girl admitted for investigation of progressive abdominal distention of more than one-year duration. Due to the complete cystic nature of the mass and its enormous size, it was not visualized by the ultrasound and was reported as massive ascites. MRI and postoperative histopathology confirmed a diagnosis of giant serous cystadenoma of the right ovary. She underwent a right ovarian cystectomy with complete preservation of both ovaries and fallopian tubes and is doing well on outpatient follow-up. PMID- 26236529 TI - Congenital Pulmonary Airway Malformation in an Adult Male: A Case Report with Literature Review. AB - Congenital pulmonary airway malformation (CPAM) is a rare cystic lung lesion formed as a result of anomalous development of airways in fetal life. Majority of the cases are recognized in neonates and infants with respiratory distress with very few presenting later in adult life. A 24-year-old male with history of three separate episodes of pneumonia in the last 6 months presented with left sided pleuritic chest pain for 4 days. He was tachycardic and tachypneic at presentation. White blood count was 14 * 10(9)/L. Chest X-ray showed left lower lobe opacity. CT angiogram of thorax showed a well-defined area of low attenuation in the left lower lobe with dedicated pulmonary arterial and venous drainage and resolving infection, suggesting CPAM. He underwent left lower lobe lobectomy. Histopathology confirmed type 2 CPAM. CPAM is a rare congenital anatomic abnormality that can present with recurrent infections in adults. As a number of cases remain asymptomatic and symptomatic cases are often missed, prevalence of CPAM might be higher than currently reported. PMID- 26236530 TI - Combined Intrathoracic and Subcutaneous Splenosis Discovered 51 Years after Abdominal Trauma. AB - Splenosis is a rare condition that results from the autotransplantation of splenic parenchyma into unexpected locations such as the abdomen or subcutaneous tissue. In the presence of coexisting injury to the diaphragm intrathoracic transplantation can occur emerging as single or multiple pleural-based masses. This occurs after traumatic rupture of the spleen and is usually asymptomatic, only to be discovered incidentally on routine thoracic or abdominal imaging. To our knowledge this is the third documented case of combined intrathoracic and subcutaneous splenosis found in English literature. This occurred in a 71-year old male involved in a motor vehicle accident at age 19 requiring urgent splenectomy. He has a significant cigarette smoking history and was referred to our hospital for further evaluation of an abnormality seen on shoulder X-ray. PMID- 26236531 TI - Undiagnosed Systemic Lupus Erythematosus Presenting as Hemophagocytic Lymphohistiocytosis. AB - Hemophagocytic Lymphohistiocytosis (HLH) is rarely diagnosed in adults. Incidence is reported as one case per million persons per year. It can be triggered by conditions that affect immune homeostasis as infections, malignancies, and rheumatologic disorders. The following case demonstrates a rare instance in which undiagnosed systemic lupus erythematosus (SLE) presented as HLH. A 28-year-old male presented with progressive weakness and recurrent fevers for 2 months. Vital signs were within normal limits except for temperature of 100.3 degrees F. His exam was unremarkable except for a left cervical scar and malar rash. His labs showed pancytopenia with neutropenia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. Hemophagocytosis was present on bone marrow biopsy. All workup for a source of infection was negative. A tentative diagnosis of HLH was made based on clinical presentation and laboratory data. The patient was treated with an HLH protocol. Later, it was determined that his HLH was actually secondary to a primary diagnosis of SLE. The patient was treated for SLE with an immunosuppressive regimen of cyclosporine and dexamethasone, and he improved dramatically. HLH rarely presents due to a rheumatologic condition such as SLE. Physicians should consider testing for SLE in patients diagnosed with HLH. PMID- 26236532 TI - Developmentally Delayed Male with Mincer Blade Obstructing the Oesophagus for a Period of Time Suspected to Be 6 Months. AB - Introduction. Sharp, retained foreign bodies in the oesophagus are associated with severe complications. Developmentally delayed patients are especially subject to foreign objects. We describe a 37-year-old, developmentally delayed male with a mincer blade obstructing the oesophagus. Six months prior to surgical intervention, the patient was hospitalized in a condition of sepsis and pneumonia where the thoracic X-ray reveals a foreign body in the proximal oesophagus. When rehospitalized 6 months later, a mincer blade of the type used in immersion blenders was surgically removed. During these 6 months the patient's main symptoms were dysphagia, weight loss, and diarrhoea. When developmentally delayed patients present with dysphagia, we strongly encourage the awareness of the possible presence of foreign bodies. To our knowledge this is the first reported case of a mincer blade in the oesophagus. PMID- 26236533 TI - Extraskeletal Ewing's Sarcoma Arising from the Sciatic Nerve: A Diagnostic Challenge. AB - Ewing's sarcoma is a common bone tumour of childhood but is a rare occurrence in individuals over 20 years of age. Few cases are reported as originating from peripheral nerves. We present an unusual case of extraosseous Ewing's sarcoma originating from the sciatic nerve in a 66-year-old patient which had the clinical hallmarks of a benign nerve sheath tumour. Following discussion at a multidisciplinary meeting, excision biopsy of the suspected benign nerve sheath tumour was planned. At operation, the mass had malignant features. Histology confirmed the presence of Ewing's sarcoma. Due to the morbidity of nerve resection, radiotherapy and chemotherapy were commenced. Ewing's sarcoma is known to mimic benign pathologies. In this case there were subtle signs of a malignant process in the form of unremitting pain. It is vital to keep in mind the less common tumours that can affect the peripheral nervous system in such cases. PMID- 26236534 TI - Small Bowel Perforation as a Postoperative Complication from a Laminectomy. AB - Chronic low back pain is one of the leading chief complaints affecting adults in the United States. As a result, this increases the percentage of patients that will eventually undergo surgical intervention to alleviate debilitating, chronic symptoms. A 37-year-old woman presented ten hours postoperatively after a lumbar laminectomy with an acute abdomen due to the extraordinarily rare complication of small bowel injury secondary to deep surgical penetration. PMID- 26236535 TI - Use of Methyl Tert-Butyl Ether for the Treatment of Refractory Intrahepatic Biliary Strictures and Bile Casts: A Modern Perspective. AB - Cholelithiasis is a prevalent problem in the United States with 14% or more adults affected. Definitive treatment of cholelithiasis is cholecystectomy. When cholecystectomy yields minimal resolution treatment options include expectant management of asymptomatic gallstones or endoscopic retrograde cholangiopancreatogram. We present a case of intrahepatic biliary casts where surgical option was not possible, interventional radiology was unsuccessful, and methyl tert-butyl ether was used to dissolve the biliary obstruction. Dissolution therapy of gallstones was first reported in 1722 when Vollisnieri used turpentine in vitro. While diethyl ether has excellent solubilizing capacity, its low boiling point limited its use surgically as it vaporizes immediately. Diethyl ether can expand 120-fold during warming to body temperature after injection into the biliary system making it impractical for routine use. The use of dissolution is out of favor due to the success of laparoscopic cholecystectomy. Epidemiological studies have shown the general population should have minimal concerns from passive exposure. Dissolution using MTBE remains a viable option if surgical or endoscopic options are not available. However, because of risks involved to both the patient and the staff, careful multidisciplinary team approach must be undertaken to minimize the risks and provide the best possible care to the patient. PMID- 26236536 TI - Locally Advanced, Unresectable Squamous Cell Carcinoma of the Gallbladder. AB - Primary squamous cell carcinoma (SCC) of the gallbladder is a rare malignancy of the gallbladder, accounting for less than 5% of gallbladder pathology. Initial presentation is often similar to adenocarcinoma of the gallbladder. SCC tends to be more locally aggressive, however, and possesses a worse prognosis than adenocarcinoma. We report a case of locally advanced SCC of the gallbladder. PMID- 26236537 TI - Extradigital Glomus Tumor of Thigh. AB - Glomus tumors are benign neoplasms that arise from neuromyoarterial glomus bodies. They represent around 1-5% of all soft-tissue tumors. High temperature, sensitivity, and pain and localized tenderness are the classical triad of symptoms. Most glomus tumors represent in the subungual area of digits. Extradigital glomus tumors are a very rare entity. There are rare cases of these tumors reported to be in shoulder, elbow, knee, wrist, even stomach, colon, and larynx. We are reporting a case of a glomus tumor on thigh and discuss the histological and immunohistochemical features. PMID- 26236538 TI - Optimization of a CUPRAC-Based HPLC Postcolumn Assay and Its Applications for Ginkgo biloba L. Extracts. AB - The aim of the present work was to improve and validate the HPLC-CUPRAC postcolumn method for the evaluation of active antioxidant markers from the acetonic extracts of Ginkgo biloba leaves. Improvement of the HPLC online assay was performed by evaluating the suitable loop temperature, the reaction loop length, and the impact of flow rate. Separation of the analytes was performed by the HPLC method on an ACE C18 analytical column using a gradient elution program. The separated antioxidant markers in the extracts reacted with copper(II) neocuproine (Cu(II)-Nc) reagent in the postcolumn reaction coil. The reagent was reduced by antioxidants to the copper(I)-neocuproine (Cu(I)-Nc) chelate with a maximum absorption at 450 nm. Validation experiments confirmed sufficient precision, sensitivity, and effectiveness of the corresponding method, which could be used for further evaluations of active antioxidant compounds in similar plant materials. PMID- 26236539 TI - Recent Developments in the Speciation and Determination of Mercury Using Various Analytical Techniques. AB - This paper reviews the speciation and determination of mercury by various analytical techniques such as atomic absorption spectrometry, voltammetry, inductively coupled plasma techniques, spectrophotometry, spectrofluorometry, high performance liquid chromatography, and gas chromatography. Approximately 126 research papers on the speciation and determination of mercury by various analytical techniques published in international journals since 2013 are reviewed. PMID- 26236540 TI - Comparison of Mineral Element Content in a Functional Food Maca (Lepidium meyenii Walp.) from Asia and South America. AB - Contents of eight mineral elements in maca (Lepidium meyenii Walp.) from China and Peru were determined by inductively coupled plasma optical emission spectroscopy. Cu contents in maca samples from China (2.5-31 mg kg(-1) dry weight, dw) were higher than the samples from Peru (<2.1 mg kg(-1) dw). Na in two samples from China was found to be significantly of high content (2400 and 2600 mg kg(-1) dw). The contents (mg kg(-1) dw) of B, Co, Cr, Li, Ni, and Zn were, respectively, 8.1-21, <0.023, <1.1~3.5, 0.020-0.17, 0.085-4.5, and 10-39 for the samples from China, while being 6.6-12, <0.023, <1.1~2.3, 0.035-0.063, 0.68-1.7, and 27-39 for the samples from Peru. PMID- 26236541 TI - Depression, Alcohol Dependence and Abuse, and Drinking and Driving Behavior. AB - BACKGROUND: Alcohol dependence/abuse and depression are positively related. Prior studies focused on relationships between drinking and driving and alcohol dependence/abuse, drinking and driving and problem drinking, or drinking and driving and depression separately. No study has addressed how depression is linked to drinking and driving through various underlying channels in the same study. METHODS: This study investigated relationships between depression, alcohol dependence/abuse, and the number of self-reported drinking and driving episodes. We also explored underlying behavioral channels between depression and alcohol dependence/abuse and binge drinking, reducing drinking amounts when planning to drive, and use of designated drivers. Data on 1,634 drinkers came from a survey fielded in eight U.S. cities. We employed ordinary least squares regression (OLS) and path analysis to assess drinking and driving and underlying channels. RESULTS: With OLS, being depressed increased the number of drinking and driving episodes during the past year by 0.572. This increase decreased to 0.411 episodes/year increase after adding socio-demographic characteristics and household income and lost statistical significance after controlling for alcohol dependence/abuse. The path analysis showed that depression is positively associated with drinking and driving, indirectly operating through not using a designated driver, but is not directly associated with drinking and driving. Alcohol dependence/abuse is directly associated with drinking and driving, and indirectly with drinking and driving through binge drinking. CONCLUSION: Our results suggest that treatment should focus on helping individuals with depression to obtain assistance from others, such as obtaining a designated driver. Since self-control of drinking in anticipation of driving did not significantly reduce drinking and driving episodes, this study finds no empirical support for emphasizing improved self-control when the treatment objective is reducing drinking and driving frequency. While binge drinking is associated with drinking and driving, the more appropriate way to influence binge drinking is treating alcohol dependence/abuse rather than depression per se. PMID- 26236542 TI - Perceptions of Personalized Medicine in an Academic Health System: Educational Findings. AB - OBJECTIVE: Prior reports demonstrate that personalized medicine implementation in clinical care is lacking. Given the program focus at Duke University on personalized medicine, we assessed health care providers' perspectives on their preparation and educational needs to effectively integrate personalized medicine tools and applications into their clinical practices. METHODS: Data from 78 health care providers who participated in a larger study of personalized and precision medicine at Duke University were analyzed using Qualtrics (descriptive statistics). Individuals age 18 years and older were recruited for the larger study through broad email contacts across the university and health system. All participants completed an online 35-question survey that was developed, pilot tested, and administered by a team of interdisciplinary researchers and clinicians at the Center for Applied Genomics and Precision Medicine. RESULTS: Overall, providers reported being ill-equipped to implement personalized medicine in clinical practice. Many respondents identified educational resources as critical for strengthening personalized medicine implementation in both research and clinical practice. Responses did not differ significantly between specialists and primary providers or by years since completion of the medical degree. CONCLUSIONS: Survey findings support prior calls for provider and patient education in personalized medicine. Respondents identified focus areas in training, education, and research for improving personalized medicine uptake. Given respondents' emphasis on educational needs, now may be an ideal time to address these needs in clinical training and public education programs. PMID- 26236543 TI - Risk Factors for Physical Violence against Partners in the U.S. AB - OBJECTIVE: To examine unique and relative predictive values of demographic, social learning, developmental, psychopathology, and dyadic variables as risk factors for perpetration of intimate partner physical aggression in a national sample of married or cohabitating individuals. METHOD: Men (n=798) and women (n=770) were selected from the public use data file of the 2003 National Comorbidity Survey Replication (NCS-R) which used a multi-stage cluster sampling design. RESULTS: Eight percent of women and 5% of men reported perpetrating physical aggression in the past year. Based on multivariable regression analyses, among men, the unique risk factors for perpetrating physical aggression were parental violence, dating before age 14, dating aggression, Intermittent Explosive Disorder (IED) before and after age 20, and being victimized by partner. Among women, significant risk factors were younger age, dating aggression, IED before age 20, cohabiting, victimization by partner, and marital/relationship strain. CONCLUSIONS: A number of social learning, developmental, adult psychopathology, and dyadic factors were significant. Two dyadic variables, victimization and marital strain, had by far the strongest associations with perpetration of partner aggression. Given that dating aggression and early IED were risk factors for male and female IPV much later in life suggests early interventions for those at risk. PMID- 26236544 TI - Increasing Proliferation of Intrinsic Tubular Cells after Renal Ischemia reperfusion Injury in Adult Rat. AB - The kidney is capable of regeneration following injury. However, whether renal stem/progenitor cells contribute to the repair process after injury, as well as the origin of the cells that repair and replace damaged renal tubule cells remains debated. Therefore, better understanding of the repair process will be critical to developing new strategies for the treatment of acute renal failure. Using an ischemia-reperfusion injury mode and an immunocytochemistry method, we counted the number of BrdU-positive cells in damged regions at different durations of reperfusion. We found that BrdU, a cell proliferative marker, was mainly incorporated in the tubular cells of both medulla and cortex 1 day after reperfusion. The number of BrdU-positive cells reached a peak at 3 days and lasted for two months after injury. BrdU-positive cells were barely found in the renal glomerulus and the parietal layer of Bowman's capsule after injury, and only a few were found in the intersititium. PAX2, an embryonic renal marker, was also increased in renal tubule cells. Confocal images show that BrdU-positive cells co-expressed PAX2, but not the activated form of caspase-3, a cell death marker. Our data suggest that renal stem-like cells or dedifferentiation of surviving renal tubular cells in both the medulla and cortex may predominantly contribute to the repair process after renal ischemia-reperfusion injury in rat. PMID- 26236545 TI - Clinical Characteristics for the Relationship between Type-2 Diabetes Mellitus and Cognitive Impairment: A Cross-Sectional Study. AB - We explored the potential differences in cognitive status, lipid and glucose metabolism, ApoEepsilon4 alleles and imaging between diabetic and non-diabetic subjects. 83 subjects with normal cognitive function and 114 mild cognitive impaired patients were divided into four groups by history of diabetes. General demographics was collected from all participants followed by MRI scan, biochemical examinations and a series of neuropsychological tests. Student's t test, multiple regressions and one-way ANOVA were applied to investigate the differences between groups. Comparing diabetic patients with non-diabetic subjects in the mild cognitive impaired group, we found several decreased items in recall of three words in MMSE (p=0.020), AVLT and SCWT (p<0.050). The multiple linear regression revealed that two-hour glucose level (B= -0.255, p<0.001) and fasting C-peptide (B= -0.466, p=0.001) had negative effects on the score of MMSE. In addition, diabetic patients treated with insulin and other diabetes medication performed better in part of the AVLT (p<0.050) compared to patients with insulin treatment or oral antidiabetic medication only. Patients with metformin medication had a better memory outcome compared to patients with sulphonylurea medication in the AVLT long delay free recall (p =0.010). These findings show that patients of mild cognitive impairment with diabetes mellitus have a worse outcome in attention, information processing speed and memory compared to non diabetic patients. Higher two-hour glucose level and C-peptide level may be risk factors for severe cognitive impairment in type-2 diabetes mellitus patients. The results of this study also suggest that medication may have effects on cognitive function. PMID- 26236546 TI - Herbal Formula Danggui-Shaoyao-San Promotes Neurogenesis and Angiogenesis in Rat Following Middle Cerebral Artery Occlusion. AB - Current studies demonstrated that traditional Chinese herbal formula Danggui Shaoyao-San (DSS) is not only used for the treatment of menstrual disorder, but has also found its use in neurological diseases. However, the neuroprotective role of DSS on ischemia-induced brain injury is still unclear. The aim of the present study is to explore the effect of DSS in ischemic brain injury. Total 30 adult female Sprague-Dawley rats underwent 90 min transient middle cerebral artery occlusion (MCAO). DSS (600 mg/kg) was administered through the intragastric route at the time of reperfusion and then performed every day thereafter until sacrifice. Results showed that DSS treatment significantly improved neurobehavioral outcomes (N=10 per group, P<0.05). Immunohistochemical staining showed that microvessel density in the perifocal region of DSS-treated rats was significantly increased compared to the saline-treated group (N=4 per group, P<0.01). Similarly, the numbers of BrdU(+)/DCX(+) cells in the subventricular zone were increased in DSS-treated rats compared to the saline treated group (P<0.05). Furthermore, we demonstrated that DSS treatment activated vascular endothelial growth factor (N=4 per group, P<0.05) and promoted eNOS phosphorylation (N=4 per group, P<0.05). Thus, we concluded that DSS promoted focal angiogenesis and neurogenesis, and attenuated ischemia-induced brain injury in rats after MCAO, suggesting that DSS is a potential drug for ischemic stroke therapy. PMID- 26236547 TI - Activity-Based Restorative Therapies after Spinal Cord Injury: Inter institutional conceptions and perceptions. AB - This manuscript is a review of the theoretical and clinical concepts provided during an inter-institutional training program on Activity-Based Restorative Therapies (ABRT) and the perceptions of those in attendance. ABRT is a relatively recent high volume and intensity approach toward the restoration of neurological deficits and decreasing the risk of secondary conditions associated with paralysis after spinal cord injury (SCI). ABRT is guided by the principle of neuroplasticity and the belief that even those with chronic SCI can benefit from repeated activation of the spinal cord pathways located both above and below the level of injury. ABRT can be defined as repetitive-task specific training using weight-bearing and external facilitation of neuromuscular activation. The five key components of ABRT are weight-bearing activities, functional electrical stimulation, task-specific practice, massed practice and locomotor training which includes body weight supported treadmill walking and water treadmill training. The various components of ABRT have been shown to improve functional mobility, and reverse negative body composition changes after SCI leading to the reduction of cardiovascular and other metabolic disease risk factors. The consensus of those who received the ABRT training was that ABRT has much potential for enhancement of recovery of those with SCI. Although various institutions have their own strengths and challenges, each institution was able to initiate a modified ABRT program. PMID- 26236548 TI - Low HbA1c and Increased Mortality Risk-is Frailty a Confounding Factor? AB - Diabetes mellitus is increasingly becoming an older person disease due to the increased survival and aging of the population. Previous studies which showed benefits of tight glycemic control and a linear relationship between HbA1c and mortality have largely included younger patients newly diagnosed with diabetes and with less comorbidities. Recent studies, which included older population with diabetes, have shown a U-shaped relationship of increased mortality associated with low HbA1c. The mechanism of such relationship is unclear. There was no direct causal link between low HbA1c and mortality. It appears that malnutrition, inflammation and functional decline are characteristics shared by the populations that showed increased mortality and low HbA1c. In these studies functional status, disability or frailty was not routinely measured. Therefore, although adjustment for comorbidities was made there may be a residual confounding by unmeasured factors such as frailty. Thus, frailty or decline in functional reserve may be the main confounding factor explaining the relationship between increased mortality risk and low HbA1c. PMID- 26236549 TI - Does Upper Extremity Training Influence Body Composition after Spinal Cord Injury? AB - Spinal cord injury (SCI) leads to serious body composition adaptations characterized by increasing whole body fat mass and decreased soft tissue lean mass (LM). These adaptations in body composition may lead to several cardio metabolic disorders that reduce the quality of life, increase patients' and caregivers' burden and eventually leads to mortality. Exercise, an appropriate dietary regimen, and an active lifestyle may alleviate several of the negative effects on body composition after a SCI. Today however, there is no established consensus on the recommended dose, frequency or type of exercise to ameliorate several of the body composition sequelae after an acute SCI. Resistance training has been previously recommended as an effective strategy to restore soft tissue LM and decrease fat mass (FM). The strategy can be simply implemented as a routine home-based training program using free weights or resistance bands after a SCI. Additionally, upper extremity (UE) circuit resistance training has been previously used to improve cardiovascular and metabolic parameters after a SCI; however compared to the vast knowledge regarding the able-bodied (AB) population, the effects of UE circuit resistance training on body composition after a SCI is not well established. In summary, the available evidence does not support the rationale that UE circuit resistance training can lead to positive adaptations in body composition after a SCI. Further studies are suggested to examine the effects of UE circuit resistance training on body composition. PMID- 26236551 TI - Trigeminal neuralgia associated with Chiari 1 malformation: symptom resolution following craniocervical decompression and duroplasty: Case report and review of the literature. AB - BACKGROUND: Trigeminal neuralgia (TN) may rarely be the presenting or only symptom of Chiari 1 malformation (CM). Isolated case reports have described resolution of TN following craniocervical decompression where TN is present in association with CM. CASE REPORT: This report discusses an unusual case of pure TN associated with CM that was successfully treated with craniocervical decompression and duroplasty and reviews the limited literature on the subject. CONCLUSION: TN may be the sole presenting symptom of CM and can be successfully managed with craniocervical decompression. Clinicians should be aware of the association of TN with CM and consider surgical management. PMID- 26236552 TI - CSF hydrothorax without intrathoracic catheter migration in children with ventriculoperitoneal shunt. AB - BACKGROUND: Thoracic complications of ventriculoperitoneal (VP) shunts have been extensively reported in the literature. Cerebrospinal fluid (CSF) hydrothorax without catheter migration, however, has been rarely described and poorly understood. CASE DESCRIPTION: We describe development of pleural effusion and respiratory distress in a 3-year-old boy with no evidence of VP shunt catheter displacement on plain radiograph and stable ventricle size on rapid sequence magnetic resonance imaging (MRI) brain. Chest X-ray revealed complete opacity of right hemithorax. Pleural effusion was consistent with transudate. Beta-2 transferrin returned positive. The patient underwent externalization of VP shunt, and upon resolution of effusion, re-internalization with new distal shunt catheter. A literature review of CSF hydrothorax in children without intrathoracic shunt migration was performed. Eleven cases were identified in the English literature. Age at VP shunt placement ranged from birth to 8 years of age. Interval from VP shunt placement to CSF hydrothorax ranged from 1.5 months to 5 years. History of shunt revision was reported in two cases. Presenting symptoms also included ascites and inguinal hernia or hydrocele. Reported diagnostic studies consist of CSF culture, radionuclide shuntogram, beta-2 transferrin, and beta-trace protein. Laterality of the VP shunt and development of pleural effusion were predominantly right sided. Definitive surgical treatment included VA shunt, repositioning of the peritoneal catheter, and endoscopic choroid plexus coagulation. CONCLUSION: CSF hydrothorax is a rare thoracic complication of VP shunt placement with no radiographic evidence of shunt migration or malfunction. Postulated mechanisms include limited peritoneal capacity to resorb CSF in children and microscopic communications present in congenital diaphragmatic hiatuses. PMID- 26236553 TI - "Countersinking" of reservoir in an irradiated patients can decrease tension on scalp closure. AB - BACKGROUND: Subcutaneous reservoirs are used to provide therapy by establishing access to cerebrospinal fluid. However, it is associated with complications such as hemorrhage, infection, malfunction, and malpositioning. In an irradiated field with thin skin, use of reservoir can result in wound dehiscence, wound infection, and device extrusion. CASE DESCRIPTION: We introduced a "countersinking" technique for the reservoir placement which involves the creation of bony recess in the skull to effectively accommodate the reservoir and decrease the protrusion. "Countersinking" of the reservoir can result in tension-free closure of the scalp and allow durable coverage of the reservoir. In the representative case, the incisional wound healed completely without any concern for wound dehiscence and the countersink technique may have contributed to effective healing of the radiated scalp. CONCLUSION: Countersinking of the reservoir can be a strategy to prevent complications such as wound dehiscence, and device extrusion in any patient, but in irradiated patients with very thin skin it also enables tension-free closure of the wound. PMID- 26236550 TI - Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment. AB - Alzheimer's disease (AD), the major cause of dementia among the elderly world wide, manifests in familial and sporadic forms, and the latter variety accounts for the majority of the patients affected by this disease. The etiopathogenesis of sporadic AD is complex and uncertain. The autopsy studies of AD brain have provided limited understanding of the antemortem pathogenesis of the disease. Experimental AD research with transgenic animal or various cell based models has so far failed to explain the complex and varied spectrum of AD dementia. The review, therefore, emphasizes the importance of AD related risk factors, especially those with metabolic implications, identified from various epidemiological studies, in providing clues to the pathogenesis of this complex disorder. Several metabolic risk factors of AD like hypercholesterolemia, hyperhomocysteinemia and type 2 diabetes have been studied extensively both in epidemiology and experimental research, while much less is known about the role of adipokines, pro-inflammatory cytokines and vitamin D in this context. Moreover, the results from many of these studies have shown a degree of variability which has hindered our understanding of the role of AD related risk factors in the disease progression. The review also encompasses the recent recommendations regarding clinical and neuropathological diagnosis of AD and brings out the inherent uncertainty and ambiguity in this area which may have a distinct impact on the outcome of various population-based studies on AD-related risk factors. PMID- 26236554 TI - How I Do It: Management of spina bifida in a hospital in The People's Republic of China. AB - We present our personal experience on patients with Spina Bifida. It is the result of having treated 1600 children for 12 years at Shanghai Children's Medical Center. We classify the cases on Spina Bifida Manifesta (myelomeningocele, myelocele, lypomyelomeningocele) or Spina Bifida Oculta (lipoma, dermal sinus and thickened filum terminale). For the former, we recommend surgery within 24-48 h after birth. For the latter we recommend preventive surgery months after birth. We acknowledge that the diameter of the spinal canal is a problem for large remnant lesions. In cases of myelomeningocele, we prefer to place the shunt and close the defect in the same procedure, it reduces the risks inherent to exposure to anesthesia, reduces hospital stay, and related costs. If there is a suspicious of infection, we do not place the shunt on the same procedure. The personal description of the preferred techniques for closure of the different defects is described. PMID- 26236555 TI - Management of hydrocephalus in children with posterior fossa tumors. PMID- 26236556 TI - Huge familial colloid cyst of the third ventricle: An extraordinary presentation. AB - BACKGROUND: Since the use of computed tomography and magnetic resonance imaging, colloid cysts (CCs) are discovered more frequently and subsequently their true incidence exceeds the numbers previously estimated. In 1986, the first familial case was reported in two identical twin brothers. To date, a total of 17 of these cases have been reported, all differing in the pattern of affected family members. CASE DESCRIPTION: Here, we describe a unique presentation of a familial case and review the relevant literature on CCs and their natural history to improve our understanding of these cases. CONCLUSION: Familial CC can present in various patterns, sizes, and forms. A genetic factor is likely to be responsible in these cases, and further research is warranted to clarify this phenomenon. PMID- 26236558 TI - Intrahepatic Cholestasis of Pregnancy and Serum Bile Acids in HIV-Infected Pregnant Women. AB - OBJECTIVES: Intra-hepatic cholestasis of pregnancy (ICP) is uncommon, but has severe effects on pregnancy outcomes. ICP is characterized by elevated serum bile acids and liver enzymes and preferentially affects women with liver disorders. We compared bile acids and pregnancy outcomes of HIV-infected pregnant women, who commonly have elevated live enzymes, with uninfected controls. METHODS: Twenty four HIV-infected, including 2 co-infected with hepatitis C virus (HCV), and 25 uninfected women were tested during early and late pregnancy and postpartum. RESULTS: After exclusion of the HCV-infected women, serum bile acids were similar in HIV-infected and uninfected participants. -glutamyl transpeptidase was elevated in HIV-infected compared with uninfected women during pregnancy and postpartum. Bilirubin and aspartate transaminase were higher in uninfected compared with HIV-infected women in early pregnancy, but subsequently similar. Bile acids in late pregnancy correlated with bile acids in the baby at birth. An HIV- and HCV-co-infected pregnant woman with active hepatitis developed ICP complicated by fetal distress. Another co-infected participant without active hepatitis had an uneventful pregnancy and delivery. CONCLUSION: In the absence of HCV co-infection, bile acid metabolism appeared to be similar in HIV-infected and uninfected pregnant women. Both HIV-infected and uninfected pregnant women had mild liver enzyme elevations. PMID- 26236557 TI - HIV Associated Chronic Obstructive Pulmonary Disease in Nigeria. AB - OBJECTIVE: To determine the prevalence and risk factors for chronic obstructive pulmonary disease (COPD) among HIV-infected adults in Nigeria. DESIGN: Cross sectional study. METHODS: HIV-infected adults aged >= 30 years with no acute ailments accessing care at the antiretroviral therapy clinic of Jos University Teaching Hospital were enrolled consecutively. Participants were interviewed to obtain pertinent demographic and clinical information, including exposure to risk factors for COPD. Post-bronchodilator spirometry was carried out. HIV related information was retrieved from the clinic medical records. COPD case-definition was based on the Global Initiative for Obstructive Lung Disease (GOLD) criteria using post-bronchodilator FEV1/FVC <0.7. COPD prevalence was also calculated using the lower limit of normal for FEV1/FVC criteria (LLN) from the European Respiratory Society normative equation. Factors associated with COPD were determined using logistic regression models. RESULTS: Study population comprised 356 HIV infected adults with mean age of 44.5 (standard deviation, 7.1) years and 59% were female. The mean time elapsed since HIV diagnosis was 7.0 (SD, 2.6) years and 97.5% of the respondents were on stable ART with virologic suppression present in 67.2%. Prevalence of COPD were 15.4% (95% confidence interval [CI] 11.7-19.2), 12.07% (95% CI 8.67-15.48), 22.19% (95% CI 18.16-26.83) using GOLD, ERS LLN and GLI LLN diagnostic criteria respectively. In multivariate analyses adjusting for gender, exposure to cigarette smoke or biomass, history of pulmonary tuberculosis, use of antiretroviral therapy, current CD4 T-cell count and HIV RNA, only age > 50 years was independently associated with COPD with OR 3.4; 95% CI 1.42-8.17 when compared to ages 30-40 years. CONCLUSION: HIV associated COPD is common in our population of HIV patients. PMID- 26236559 TI - In vivo mouse fluorescence imaging for folate-targeted delivery and release kinetics. AB - Many cancer cells over-express folate receptors, and this provides an opportunity for both folate-targeted fluorescence imaging and the development of targeted anti-cancer drugs. We present an optical imaging modality that allows for the monitoring and evaluation of drug delivery and release through disulfide bond reduction inside a tumor in vivo for the first time. A near-infrared folate targeting fluorophore pair was synthesized and used to image a xenograft tumor grown from KB cells in a live mouse. The in vivo results are shown to be in agreement with previous in vitro studies, confirming the validity and feasibility of our method as an effective tool for preclinical studies in drug development. PMID- 26236560 TI - Life after Genocide: Mental Health, Education, and Social Support of Orphaned Survivors. AB - Thousands of orphaned survivors of the 1994 Rwandan Genocide against the Tutsi were not only exposed to extraordinarily severe forms of violence, but also many of these children took on the responsibility of caring and providing for other child survivors. This study describes the poverty, educational attainment, social support and mental health of orphaned heads of household (OHH) fourteen years after the genocide, and analyzes how violence exposure during the genocide and post-genocide stressors contributed to symptoms of posttraumatic stress disorder (PTSD) and distress. Participants were 61 members of an OHH community organization who were interviewed in 2002 about their genocide experiences and who provided a follow-up assessment of post-genocide risk factors and PTSD and distress symptoms in 2008. Almost all of the OHH in this study reported low social support, high levels of poverty, and high rates of PTSD and distress symptoms. Lower educational attainment predicted PTSD symptoms and partially mediated the association between exposure to genocide violence and PTSD. Distress was predicted by lack of social support and witnessing family members harmed during the genocide. Results suggest that public health and community efforts to improve educational outcomes and to strengthen and expand social support networks may improve mental health outcomes of OHH. PMID- 26236562 TI - Post Disaster Governance, Complexity and Network Theory: Evidence from Aceh, Indonesia After the Indian Ocean Tsunami 2004. AB - This research aims to understand the organizational network typology of large- scale disaster intervention in developing countries and to understand the complexity of post--disaster intervention, through the use of network theory based on empirical data from post--tsunami reconstruction in Aceh, Indonesia, during 2005/-2007. The findings suggest that the ' degrees of separation' (or network diameter) between any two organizations in the field is 5, thus reflecting 'small- world' realities and therefore making no significant difference with the real human networks, as found in previous experiments. There are also significant loops in the network reflecting the fact that some actors tend to not cooperate, which challenges post- disaster coordination. The findings show the landscape of humanitarian actors is not randomly distributed. Many actors were connected to each other through certain hubs, while hundreds of actors make 'scattered' single 'principal--client' links. The paper concludes that by understanding the distribution of degree, centrality, 'degrees of separation' and visualization of the network, authorities can improve their understanding of the realities of coordination, from macro to micro scales. PMID- 26236561 TI - Virtual Disaster Simulation: Lesson Learned from an International Collaboration That Can Be Leveraged for Disaster Education in Iran. AB - Disaster education needs innovative educational methods to be more effective compared to traditional approaches. This can be done by using virtual simulation method. This article presents an experience about using virtual simulation methods to teach health professional on disaster medicine in Iran. The workshop on the "Application of New Technologies in Disaster Management Simulation" was held in Tehran in January 2015. It was co-organized by the Disaster and Emergency Health Academy of Tehran University of Medical Sciences and Emergency and the Research Center in Disaster Medicine and Computer Science applied to Medicine (CRIMEDIM), Universita del Piemonte Orientale. Different simulators were used by the participants, who were from the health system and other relevant fields, both inside and outside Iran. As a result of the workshop, all the concerned stakeholders are called on to support this new initiative of incorporating virtual training and exercise simulation in the field of disaster medicine, so that its professionals are endowed with field-based and practical skills in Iran and elsewhere. Virtual simulation technology is recommended to be used in education of disaster management. This requires capacity building of instructors, and provision of technologies. International collaboration can facilitate this process. PMID- 26236564 TI - Lipopolysaccharide Attenuates CD40 Ligand-Induced Regulatory B10 Cell Expansion and IL-10 Production in Mouse Splenocytes. AB - Toll-like receptors (TLRs) play a key role in B cell-mediated innate and adaptive immunity. It has been shown that interleukin 10 (IL-10)-producing regulatory B cells (B10 cells) can negatively regulate cellular immune responses and inflammation in autoimmune diseases. In this study, we determined the effect of TLR4 signaling on the CD40-activated B10 cell competency. The results demonstrated that LPS and CD40L synergistically stimulated proliferation of mouse splenocytes. The percentage of B10 cells in cultured splenocytes was significantly increased after CD40L stimulation but such increase was diminished by the addition of LPS. Such effects by LPS were only observed in cells from WT but not TLR4-/- mice. IL-10 mRNA expression and protein production in B10 cells from cultured splenocytes were significantly up-regulated by CD40L stimulation but were inhibited after the addition of LPS in a TLR4-dependent manner. This study suggests that LPS-induced TLR4 signaling attenuate CD40L-activated regulatory B10 cell competency. PMID- 26236563 TI - The effects of obesity on venous thromboembolism: A review. AB - Obesity has emerged as a global health issue that is associated with wide spectrum of disorders, including coronary artery disease, diabetes mellitus, hypertension, stroke, and venous thromboembolism (VTE). VTE is one of the most common vascular disorders in the United States and Europe and is associated with significant mortality. Although the association between obesity and VTE appears to be moderate, obesity can interact with other environmental or genetic factors and pose a significantly greater risk of VTE among individuals who are obese and who are exposed simultaneously to several other risk factors for VTE. Therefore, identification of potential interactions between obesity and certain VTE risk factors might offer some critical points for VTE interventions and thus minimize VTE morbidity and mortality among patients who are obese. However, current obesity measurements have limitations and can introduce contradictory results in the outcome of obesity. To overcome these limitations, this review proposes several future directions and suggests some avenues for prevention of VTE associated with obesity as well. PMID- 26236565 TI - B Cells with Regulatory Function in Animal Models of Autoimmune and Non Autoimmune Diseases. AB - Although the identification of B cell subsets with negative regulatory functions and the definition of their mechanisms of action are recent events, the important negative regulatory roles of B cells in immune responses are now broadly recognized. There is an emerging appreciation for the pivotal role played by B cells in several areas of human diseases including autoimmune diseases and non autoimmune diseases such as parasite infections and cancer. The recent research advancement of regulatory B cells in human disease coincides with the vastly accelerated pace of research on the bridging of innate and adaptive immune system. Current study and our continued research may provide better understanding of the mechanisms that promote regulatory B10 cell function to counteract exaggerated immune activation in autoimmune as well as non-autoimmune conditions. This review is focused on the current knowledge of BREG functions studied in animal models of autoimmune and non-autoimmune diseases. PMID- 26236566 TI - Xenopus as a Model for GI/Pancreas Disease. AB - Diseases affecting endodermal organs like the pancreas, lung and gastrointestinal (GI) tract have a substantial impact on human welfare. Since many of these are congenital defects that arise as a result of defects during development broad efforts are focused on understanding the development of these organs so as to better identify risk factors, disease mechanisms and therapeutic targets. Studies implementing model systems, like the amphibian Xenopus, have contributed immensely to our understanding of signaling (e.g. Wnt, FGF, BMP, RA) pathways and gene regulation (e.g. hhex, ptf1a, ngn3) that underlie normal development as well as disease progression. Recent advances in genome engineering further enhance the capabilities of the Xenopus model system for pursuing biomedical research, and will undoubtedly result in a boom of new information underlying disease mechanisms ultimately leading to advancements in diagnosis and therapy. PMID- 26236567 TI - Infection, Inflammation and Healing in Zebrafish: Intestinal Inflammation. AB - Inflammatory bowel diseases (IBD), which include Crohn's disease and ulcerative colitis, contribute to significant morbidity and mortality globally. Despite an increase in incidence, IBD onset is still poorly understood. Mouse models of IBD recapitulate several aspects of human disease, but limited accessibility for live imaging and the lack of forward genetics highlight the need for new model systems for disease onset characterization. Zebrafish represent a powerful platform to model IBD using forward and reverse genetics, live imaging of transgenic lines and physiological assays. In this review, we address current models of IBD in zebrafish and newly developed reagents available for future studies. PMID- 26236568 TI - Recent Developments in Understanding the Role of Aqueous Humor Outflow in Normal and Primary Open Angle Glaucoma. AB - Primary open angle glaucoma (POAG) is the second leading cause of blindness in the world's rapidly aging population. POAG is characterized by progressive degeneration of neural structures in the posterior segment, often associated with a concomitant elevation of intraocular pressure. Changes in IOP are believed to be caused by a disruption in the normal outflow of aqueous humor. This article reviews recent research associated with normal and POAG aqueous humor outflow. Novel findings elucidating biochemical and pathological changes in the ocular tissues affected in POAG are presented. Stem cell research, identification of lymphatic markers, and increased use of mouse models give researchers exciting new tools to understand aqueous humor outflow, changes associated with POAG and identify underlying causes of the disease. PMID- 26236569 TI - New Drugs You Are Going to Read About: Serelaxin, Ularitide, TRV027. AB - Nitrovasodilators have long been used as first-line treatment for hypertensive acute heart failure (AHF). Although effective for BP control and symptom alleviation, this class of agents has never been shown to improve mortality or prevent hospital readmissions. Consequently, there has been tremendous interest in development of newer vasodilators with more beneficial therapeutic profiles. In this review, we focus on three of the most promising agents currently being studied: serelaxin, ularitide, and TRV027. While regulatory approval has yet to be obtained, should they prove beneficial in on-going trials, we are looking at a new era of drug therapy that could supplant more conventional treatments and broaden the horizon for management of patients with AHF. PMID- 26236570 TI - Growth and Change for the Global Spine Journal. PMID- 26236571 TI - Targeted Learning of the Mean Outcome under an Optimal Dynamic Treatment Rule. AB - We consider estimation of and inference for the mean outcome under the optimal dynamic two time-point treatment rule defined as the rule that maximizes the mean outcome under the dynamic treatment, where the candidate rules are restricted to depend only on a user-supplied subset of the baseline and intermediate covariates. This estimation problem is addressed in a statistical model for the data distribution that is nonparametric beyond possible knowledge about the treatment and censoring mechanism. This contrasts from the current literature that relies on parametric assumptions. We establish that the mean of the counterfactual outcome under the optimal dynamic treatment is a pathwise differentiable parameter under conditions, and develop a targeted minimum loss based estimator (TMLE) of this target parameter. We establish asymptotic linearity and statistical inference for this estimator under specified conditions. In a sequentially randomized trial the statistical inference relies upon a second-order difference between the estimator of the optimal dynamic treatment and the optimal dynamic treatment to be asymptotically negligible, which may be a problematic condition when the rule is based on multivariate time dependent covariates. To avoid this condition, we also develop TMLEs and statistical inference for data adaptive target parameters that are defined in terms of the mean outcome under the estimate of the optimal dynamic treatment. In particular, we develop a novel cross-validated TMLE approach that provides asymptotic inference under minimal conditions, avoiding the need for any empirical process conditions. We offer simulation results to support our theoretical findings. PMID- 26236572 TI - ACTIVITY IN CORTICAL MIDLINE STRUCTURES IS MODULATED BY SELF-CONSTRUAL CHANGES DURING ACCULTURATION. AB - Recent immigrants to another culture generally experience a period of acculturation during which they show self-construal changes. Here, we examine how this acculturation period alters brain activity associated with self-referential cognition. Twenty-seven native Chinese-speaking recent immigrants completed a trait-judgment task in which they judged whether a series of psychological traits applied to themselves and, separately, whether these traits applied to their mothers. Participants were scanned at two intervals: within the first two months of their arrival in the United States (Time 1), and also six months after the initial scan (Time 2). Results already revealed a significant self-vs.-mother differentiation at Time 1 in the medial prefrontal cortex (MPFC) and posterior cingulate cortex (PCC). However, at time 2, this pattern diverged depending on whether immigrants became more or less like their original culture. That is to say, for immigrants who became less like Easterners, the self vs. mother difference remained, whereas for participants who became even more like Easterners, the self vs. mother difference in cortical midline structures disappeared. These findings support the notion that self-construal changes during the process of acculturation are reflected in the relative engagement of brain structures implicated in self-referential processing (i.e., MPFC and PCC) when judging traits with reference to oneself or a close other. PMID- 26236573 TI - SOCR data dashboard: an integrated big data archive mashing medicare, labor, census and econometric information. AB - INTRODUCTION: Intuitive formulation of informative and computationally-efficient queries on big and complex datasets present a number of challenges. As data collection is increasingly streamlined and ubiquitous, data exploration, discovery and analytics get considerably harder. Exploratory querying of heterogeneous and multi-source information is both difficult and necessary to advance our knowledge about the world around us. RESEARCH DESIGN: We developed a mechanism to integrate dispersed multi-source data and service the mashed information via human and machine interfaces in a secure, scalable manner. This process facilitates the exploration of subtle associations between variables, population strata, or clusters of data elements, which may be opaque to standard independent inspection of the individual sources. This a new platform includes a device agnostic tool (Dashboard webapp, http://socr.umich.edu/HTML5/Dashboard/) for graphical querying, navigating and exploring the multivariate associations in complex heterogeneous datasets. RESULTS: The paper illustrates this core functionality and serviceoriented infrastructure using healthcare data (e.g., US data from the 2010 Census, Demographic and Economic surveys, Bureau of Labor Statistics, and Center for Medicare Services) as well as Parkinson's Disease neuroimaging data. Both the back-end data archive and the front-end dashboard interfaces are continuously expanded to include additional data elements and new ways to customize the human and machine interactions. CONCLUSIONS: A client-side data import utility allows for easy and intuitive integration of user-supplied datasets. This completely open-science framework may be used for exploratory analytics, confirmatory analyses, meta-analyses, and education and training purposes in a wide variety of fields. PMID- 26236574 TI - Endophenotypes for Alcohol Use Disorder: An Update on the Field. AB - The endophenotype concept was first proposed as a strategy to use (purportedly) genetically simpler phenotypes in gene identification studies for psychiatric disorders, and is distinct from the closely related concept of intermediate phenotypes. In the area of alcohol use disorder (AUD) research, two candidate endophenotypes have produced replicable genetic associations: level of response to alcohol and neurophysiology markers (e.g., event-related oscillations and event-related potentials). Additional candidate endophenotypes from the cognitive, sensory, and neuroimaging literatures show promise, although more evidence is needed to fully evaluate their potential utility. Translational approaches to AUD endophenotypes have helped characterize the underlying neurobiology and genetics of AUD endophenotypes and identified relevant pharmacological interventions. Future research that capitalizes on the polygenic nature of endophenotypes and emphasizes endophenotypes that may change across development will enhance the usefulness of this concept to understand the genetically-influenced pathways toward AUD. PMID- 26236576 TI - Translating Developmental Neuroscience to Substance Use Prevention. AB - Several preventive interventions have demonstrated efficacy in reducing substance use. However, opportunities exist to further improve prevention approaches. The application of recent advances in developmental neuroscience can inform the design, implementation, and evaluation of substance use prevention programs. This paper first briefly describes the developmental integration of the prefrontal cortex with emotion and motivation centers of the brain, and the implications of this process for substance use vulnerability. Discussed next are specific examples of how developmental neuroscience can inform prevention timing, development, and evaluation. Contextual considerations are then suggested including a critical role for schools in substance misuse prevention. Finally, current theoretical and methodological challenges to the translation of developmental neuroscience to substance use prevention are discussed. PMID- 26236575 TI - Neuroimaging Risk Markers for Substance Abuse: Recent Findings on Inhibitory Control and Reward System Functioning. AB - Rates of alcohol and other drug use rise sharply throughout adolescence and peak in the early 20s. Likewise, prevalence of first-time substance use disorder (SUD) and past-year SUD both peak between ages 18-23. SUD is associated with a host of negative outcomes and is a serious health concern. Understanding the mechanisms that precede the onset and escalation of substance use is crucial in order to develop more effective prevention and intervention strategies for children and adolescents at risk for SUD. In this review, we discuss recent findings from functional neuroimaging studies in children, adolescents, and emerging adults that focus on uncovering the neural underpinnings of SUD risk. The focus is on inhibitory control and reward circuitry due to their involvement in risk-taking behaviors, which are heightened in adolescence and may facilitate substance use. We discuss convergences in the literature and highlight findings suggesting that the association between SUD risk and neurofunctioning may be moderated by age, gender, and history of substance use. Recommendations for future directions are also discussed. PMID- 26236577 TI - Challenges in Studying Modifiable Risk Factors for Birth Defects. AB - Conducting research to identify modifiable risk factors for birth defects is difficult for a variety of reasons. While some challenges are familiar to researchers across many disciplines, the confluence of issues affecting birth defects research may not be well understood by those outside of the field. This article describes several methodological challenges to the study of birth defects and ways these challenges might be addressed: (1) ascertainment, definition and classification of birth defects; (2) exposure assessment on modifiable risk factors; (3) analytical challenges related to small numbers and multiple statistical tests; (4) the role of genetics, including the collection of specimens and analysis of genetic data; and (5) challenges in translating research and demonstrating public health impact. Understanding these issues is important for researchers planning studies, reviewers evaluating the scientific merit of results from these studies, and consumers of the research, including fellow researchers, policy makers, health care providers, and families. PMID- 26236578 TI - The Cost of Transplant Immunosuppressant Therapy: Is This Sustainable? AB - A solid organ transplant is life-saving therapy that engenders the use of immunosuppressive medications for the lifetime of the transplanted organ and its recipient. Conventional therapy includes both induction therapy (a biologic that is infused peri-operatively) followed by maintenance therapy. The cost of these medications is a constant concern and the advent of generics has brought this cost down modestly. For those lacking long term insurance coverage, this may be a significant out of pocket expense that is not affordable. Moreover, transplant Centers are managing higher risk transplant recipients that require more complex induction regimens and longer term use of such biologic agents in the context of desensitization or abrogation of de novo antibody mediated injury. While in kidney transplantation, Medicare part B covers three years of medication, there is frequent non-adherence due to cost after that time-point. The impact of the Affordable Care Act remains uncertain at this time. Finally the pipeline of new therapies is limited due to the cost of development of a drug, the inherent cost of clinical studies, and lack of defined endpoints for newer therapies in high risk patients. These new therapies are of high value to the community but will contribute additional burden to current drug costs. PMID- 26236579 TI - Diphenyl ditelluride intoxication triggers histological changes in liver, kidney, and lung of mice. AB - Tellurium compounds may be cytotoxic to different cells types. Thus, this work evaluated the effect of diphenyl ditelluride ((PhTe)2), an organotellurium commonly used in organic synthesis, on the morphology of liver, kidney, and lung. Adult mice were acutely (a subcutaneous single dose: 250 MUmol/kg) or subchronically (one daily subcutaneous dose: 10 or 50 MUmol/kg for 7 and 14 days) exposed to (PhTe)2. Afterwards, the histological analyses of liver, kidney, and lungs were performed. Liver histology revealed that the hepatocytes of mice subchronically exposed to (PhTe)2 presented cytoplasmic vacuolization, hydropic degeneration, and hyperchromatic nuclei. Subchronic exposure to 50 MUmol/kg (PhTe)2 also caused hepatic necrosis. Microvesicular and macrovesicular steatosis were identified in liver of mice acutely exposed to (PhTe)2. Acute and subchronic intoxication with (PhTe)2 induced changes on epithelial cells of renal tubules, namely, loss of brush border and cytoplasmatic vacuolization. Atrophy and hypertrophy, cast proteinaceous formation, and acute tubular necrosis were also identified in renal tissue. Mice subchronically exposed to 50 MUmol/kg (PhTe)2 developed intra-alveolar edema and alveolar wall congestion in some areas of lungs. Acute exposure to (PhTe)2 did not cause histological changes in lungs. Our data show that (PhTe)2 may be considered a histotoxic agent for liver, kidney, and lung. PMID- 26236580 TI - Sirtuin 1 and aging theory for chronic obstructive pulmonary disease. AB - Chronic Obstructive Pulmonary disease (COPD) is an inflammatory syndrome that represents an increasing health problem, especially in the elderly population. Drug therapies are symptomatic and inadequate to contrast disease progression and mortality. Thus, there is an urgent need to clarify the molecular mechanisms responsible for this condition in order to identify new biomarkers and therapeutic targets. Processes including oxidant/antioxidant, protease/antiprotease, and proliferative/antiproliferative balance and control of inflammatory response become dysfunctional during aging as well as in COPD. Recently it was suggested that Sirtuin 1 (SIRT1), an antiaging molecule involved in the response to oxidative stress and chronic inflammation, is implicated in both development and progression of COPD. The present review focuses on the involvement of SIRT1 in the regulation of redox state, inflammation, and premature senescence, all crucial characteristics of COPD phenotypes. Recent evidence corroborating the statement of the "aging theory for COPD" was also discussed. PMID- 26236581 TI - Temporal trends in prevalence of Plasmodium falciparum molecular markers selected for by artemether-lumefantrine treatment in pre-ACT and post-ACT parasites in western Kenya. AB - Artemether-lumefantrine (AL) became the first-line treatment for uncomplicated malaria in Kenya in 2006. Studies have shown AL selects for SNPs in pfcrt and pfmdr1 genes in recurring parasites compared to the baseline infections. The genotypes associated with AL selection are K76 in pfcrt and N86, 184F and D1246 in pfmdr1. To assess the temporal change of these genotypes in western Kenya, 47 parasite isolates collected before (pre-ACT; 1995-2003) and 745 after (post-ACT; 2008-2014) introduction of AL were analyzed. In addition, the associations of parasite haplotype against the IC50 of artemether and lumefantrine, and clearance rates were determined. Parasite genomic DNA collected between 1995 and 2014 was analyzed by sequencing or PCR-based single-base extension on Sequenom MassARRAY. IC50s were determined for a subset of the samples. One hundred eighteen samples from 2013 to 2014 were from an efficacy trial of which 68 had clearance half lives. Data revealed there were significant differences between pre-ACT and post ACT genotypes at the four codons (chi-square analysis; p < 0.0001). The prevalence of pfcrt K76 and N86 increased from 6.4% in 1995-1996 to 93.2% in 2014 and 0.0% in 2002-2003 to 92.4% in 2014 respectively. Analysis of parasites carrying pure alleles of K + NFD or T + YYY haplotypes revealed that 100.0% of the pre-ACT parasites carried T + YYY and 99.3% of post-ACT parasites carried K + NFD. There was significant correlation (p = 0.04) between lumefantrine IC50 and polymorphism at pfmdr1 codon 184. There was no difference in parasite clearance half-lives based on genetic haplotype profiles. This study shows there is a significant change in parasite genotype, with key molecular determinants of AL selection almost reaching saturation. The implications of these findings are not clear since AL remains highly efficacious. However, there is need to closely monitor parasite genotypic, phenotypic and clinical dynamics in response to continued use of AL in western Kenya. PMID- 26236583 TI - Higher daily physical activity is associated with higher osteocalcin levels in adolescents. AB - BACKGROUND: Exercise stimulates bone remodeling and improves insulin sensitivity (Si), even without associated weight loss. Osteocalcin (OCN), a bone-derived protein, is associated with improved Si. PURPOSE: We examined how daily physical activity is associated with OCN and Si. METHODS: Physical activity was measured through questionnaires completed in Minneapolis from 2010-2012. A physical activity score (PAQsum) was calculated to quantify physical activity (range 1-5). OCN and bone specific alkaline phosphatase (BAP) were measured by ELISA. Si was measured by the insulin modified frequently sampled IV glucose tolerance test. RESULTS: The mean PAQsum value was 2.4+/-0.8 in 47 participants (12-17.9 years old). PAQsum was positively associated with OCN (p= 0.006). Participants with PAQsum<2 had significantly lower OCN levels compared to participants with PAQsum>2 (p<0.02). Obesity did not modify the association between PAQsum and OCN. There was no statistically significant association between PAQsum and Si or between OCN and Si, even after adjustment for percent body fat. CONCLUSIONS: OCN is higher in more physically active individuals. More research is needed to clarify the relationship between OCN, physical activity and Si. PMID- 26236582 TI - An in vitro iron superoxide dismutase inhibitor decreases the parasitemia levels of Trypanosoma cruzi in BALB/c mouse model during acute phase. AB - In order to identify new compounds to treat Chagas disease during the acute phase with higher activity and lower toxicity than the reference drug benznidazole (Bz), two hydroxyphthalazine derivative compounds were prepared and their trypanocidal effects against Trypanosoma cruzi were evaluated by light microscopy through the determination of IC50 values. Cytotoxicity was determined by flow cytometry assays against Vero cells. In vivo assays were performed in BALB/c mice, in which the parasitemia levels were quantified by fresh blood examination; the assignment of a cure was determined by reactivation of blood parasitemia levels after immunosuppression. The mechanism of action was elucidated at metabolic and ultra-structural levels, by (1)H NMR and TEM studies. Finally, as these compounds are potentially capable of causing oxidative damage in the parasites, the study was completed, by assessing their activity as potential iron superoxide dismutase (Fe-SOD) inhibitors. High-selectivity indices observed in vitro were the basis of promoting one of the tested compounds to in vivo assays. The tests on the murine model for the acute phase of Chagas disease showed better parasitemia inhibition values than those found for Bz. Compound 2 induced a remarkable decrease in the reactivation of parasitemia after immunosuppression. Compound 2 turned out to be a great inhibitor of Fe-SOD. The high antiparasitic activity and low toxicity together with the modest costs for the starting materials render this compound an appropriate molecule for the development of an affordable anti-Chagas agent. PMID- 26236584 TI - Inhibition of ASCT2 is essential in all-trans retinoic acid-induced reduction of adipogenesis in 3T3-L1 cells. AB - Vitamin A has preventive effects on obesity. All-trans retinoic acid (ATRA), the active form of vitamin A, inhibits lipid accumulation in 3T3-L1 cells in an experimental adipogenesis model. We found that ATRA suppressed up-regulation of the amino acid transporter, Asct2, in adipogenerating 3T3-L1 cells. We observed that Asct2 was up-regulated at 1 day after adipogenesis stimuli. The Asct2 inhibitor l-gamma-glutamyl-p-nitroanilide (GPNA) decreased lipid accumulation. Glutamine-free conditions also suppressed adipogenesis. Suppression of adipogenesis by ATRA may be through Asct2 reduction. These results indicate that Asct2 could be a target for obesity prevention and treatment. PMID- 26236585 TI - Co-infection of long-standing extensively drug-resistant Mycobacterium tuberculosis (XDR-TB) and non-tuberculosis mycobacteria: A case report. AB - We report a 69-years-old Iranian HIV negative male patient, with long-standing pulmonary tuberculosis (eleven years) co-infected with non-tuberculosis mycobacteria. Despite of initiation of first line anti-tuberculosis therapy after diagnosis the patient poorly respond because of low compliance with anti-TB treatment. After several incomplete treatments the smear was still positive and thus drug susceptibility tests were performed on isolated organism which revealed that the organisms was resistant not only against isoniazid and rifampin but also against Ofloxacin (OFX), Capreomycin (CAP), p-aminosalicylic acid (PAS), ethionamide (ETH), Kanamycin (KAN), ciprofloxacin (Cip), amikacin (AMK) and cycloserine (CYC). Persistence and resistance of infection had led us to do more investigation using molecular methods, which revealed co-infection with Non tuberculosis mycobacteria (NTM). The patient is still alive with cough and shortness of breath. PMID- 26236586 TI - Emphysema mimicking interstitial lung disease: Two case reports. AB - Honeycombing in general is a sign of severe end-stage fibrosis. Here we present two cases, where the combination of emphysema, acute inflammation and pulmonary embolism gave an appearance of honeycombing seen in pulmonary fibrosis. HRCT interpretation in the evaluation of acutely ill patients with pulmonary infection is a challenge. Our case reports emphasize the importance of a multidisciplinary approach, when it comes to patients with suspected complicated pulmonary diseases. At the same time they give very realistic examples of the challenges found in diagnosing patients with simultaneous acute and chronic pulmonary diseases. PMID- 26236587 TI - Flow-volume loop abnormality detecting a previously unrecognized right upper lobe tracheal bronchus. AB - Tracheal bronchus is a rare anatomic variant in which a bronchus originates from the trachea. Patients may be asymptomatic or present with a variety of respiratory symptoms. We present a case of a patient who presented with a history of poorly controlled asthma and a persistent abnormality of the flow-volume loop. Bronchoscopy revealed a tracheal bronchus with narrowed right-sided bronchial orifices. An unrecognized tracheal bronchus may result in serious complications during elective or emergent endotracheal intubation. Spirometry testing may reveal abnormalities of the flow-volume loop associated with altered airflow. Relying on spirometric values without assessing the shape of the flow-volume loop may lead to misdiagnosis and inappropriate management of lung pathology. PMID- 26236588 TI - A case of spontaneous regression of pulmonary mucosa-associated lymphoid tissue (MALT) type lymphoma with Sjogren's syndrome treated with methotrexate for rheumatoid arthritis. AB - A 72-year-old man who had suffered from rheumatoid arthritis (RA) and Sjogren's syndrome (Sjs) since he was 66 years of age had been treated with methotrexate (MTX) for six years. He presented with a cough, sputum and dyspnea on exertion, and computed tomography findings showed multiple ground-glass opacities in both of his lungs. A biopsy of the lungs revealed low-grade mucosa-associated lymphoid tissue (MALT) type B-cell non-Hodgkin's lymphoma. Spontaneous complete remission of the lymphoma was achieved six months after withdrawing immune suppression with MTX. To our knowledge, no previous cases of spontaneous regression of pulmonary MALT-type lymphoma with Sjs treated with MTX for RA have been reported. Patients on MTX who are being treated for RA should be carefully monitored, especially when they have been diagnosed with coexistent Sjs. PMID- 26236589 TI - Liquid fluorocarbon lavage to clear thrombus from the distal airways after severe pulmonary hemorrhage requiring extracorporeal life support (ECLS). AB - Massive pulmonary hemorrhage can pose a significant therapeutic challenge. Traditional methods of airway clearance using saline lavage and direct thrombus removal via bronchoscopy have limited ability to retrieve thrombi from deep airways. We report a patient on extracorporeal life support with massive pulmonary hemorrhage resulting in extensive alveolar and airway thrombus extending well beyond the proximal airways and the novel use of perfluorodecalin lavage to facilitate airway clearance and lung recruitment. CLINICAL TRIAL REGISTRATION: None. PMID- 26236590 TI - Systemic-to-pulmonary venous shunt in a patient with non-Hodgkin lymphoma: A case report and review of the literature. AB - We describe a case of a systemic-to-pulmonary venous shunt secondary to superior vena cava obstruction in a patient with newly diagnosed non-Hodgkin lymphoma. This rare condition manifested with symptoms of dyspnea and hypoxemia that were out of proportion to the pleural effusion diagnosed on chest imaging. Standard treatment of such rare collateral plexuses is observation. However, it is important for clinicians to be cognizant that in rare cases such plexuses can lead to right-to-left shunt complications such as embolism. PMID- 26236591 TI - Tracheobronchopathia osteochondroplastica: Case report and literature review. AB - Tracheobronchopathia osteochondroplastica (TPO) is a rare disorder characterized as multiple osseous or cartilaginous nodules in the submucosa of trachea and main bronchi. TPO remains an under recognized entity due to lack of awareness. Four cases of TPO are reported in this review as well as various facets of TPO description. PMID- 26236592 TI - Foreign body aspiration - Sometimes a tough nut to crack. AB - Foreign body aspiration (FBA) is a dangerous and potentially life-threatening event. We report the case of a 24-month old boy, who was initially presented with an episode of obstructive bronchitis to the family pediatrician. Then, while being treated with empiric antibiotics, he aspirated a peanut. Although resulting in a coughing episode, the mother did initially not ascribe any relevancy to it. Since the diagnosis of obstructive bronchitis had already been established, only an in-depth history taking session with the mother could help figure out, why the boy's symptoms got worse instead of better. This article underlines the importance of accurate history taking and clinical examination. PMID- 26236593 TI - Diaphragm pacing failure secondary to deteriorated chest wall mechanics: When a good diaphragm does not suffice to take a good breath in. AB - Diaphragm pacing allows certain quadriplegic patients to be weaned from mechanical ventilation. Pacing failure can result from device dysfunction, neurotransmission failure, or degraded lung mechanics (such as atelectasis). We report two cases where progressive pacing failure was attributed to deteriorated chest wall mechanics. The first patient suffered from cervical spinal cord injury at age 45, was implanted with a phrenic stimulator (intrathoracic), successfully weaned from ventilation, and permanently paced for 7 years. Pacing effectiveness then slowly declined, finally attributed to rib cage stiffening due to ankylosing spondylitis. The second patient became quadriplegic after meningitis at age 15, was implanted with a phrenic stimulator (intradiaphragmatic) and weaned. After a year hypoventilation developed without obvious cause. In relationship with complex endocrine disorders, the patient had gained 31 kg. Pacing failure was attributed to excessive mechanical inspiratory load. Rib cage mechanics abnormalities should be listed among causes of diaphragm pacing failure and it should be kept in mind that a "good diaphragm" is not sufficient to produce a "good inspiration". PMID- 26236594 TI - Hereditary mucoepithelial dysplasia and severe respiratory distress. AB - Hereditary mucoepithelial dysplasia (HMD) is a rare autosomal dominant disorder characterized by mucoepithelial disruption of the skin, hair and mucous membranes. It results from defective gap junction formation and leads to non scarring alopecia, mucosal erythema, perineal erythematous intertrigo, involvement of the conjunctival mucosa, and pulmonary disease. We present a case of severe respiratory distress in an initially healthy full term infant born to a mother with HMD. This infant later developed signs and symptoms of HMD. A high index of suspicion for pulmonary infection with atypical organism is essential in infants with a family history of HMD who present with respiratory distress. PMID- 26236595 TI - Timolol-induced interstitial lung disease. AB - Timolol maleate is a non-selective beta-adrenergic receptor blocking agent with demonstrated efficacy in the treatment of open-angle glaucoma. A 76 year old female who presented with productive cough, progressive dyspnea and hypoxia after starting timolol maleate opthalamic drops following glaucoma surgery. The patient was diagnosed with interstitial lung disease secondary to timolol treatment and after cessation of the offending agent along with corticosteroid treatment, symptoms improved drastically. Elimination of other possible causes of disease along with evolution of radiological and functional signs left us with a diagnosis of timolol-induced interstitial lung disease. To our knowledge, this is the second reported case of timolol-induced interstitial lung disease. PMID- 26236596 TI - Syndrome of iron pill inhalation in four patients with accidental tablet aspiration: Severe airway complications are described. AB - Iron pill inhalation represents a uncommon cause of syntomatic endobronchial foreign bodies. Unlike foreign body, the direct contact of iron tablet onto the bronchial mucosa results in severe bronchial damage in addition to obstruction and local irritation. Four patients with Iron Pill Inhalation Syndrome are described. All but one patient developed irreversible bronchial stenosis as late post inflammatory complication. Bronchoscopic features and clinical evolution are described in order to reduce the risk of severe side-effects in patients highly suspected for iron pill aspiration. PMID- 26236597 TI - Delayed post-lobectomy pulmonary artery stump thrombosis. AB - We present a 67 year old male patient who underwent VATS right upper lobectomy with en bloc chest wall resection and right lower lobe superior segmentectomy for atypical Ewing Sarcoma. Serial chest CT scan done more than two years after the initial resection showed a new filling defect in the right upper pulmonary artery stump. A repeat chest CT scan after three months of oral anticoagulation showed complete resolution of the filling defect. PMID- 26236598 TI - Chronic mould exposure as a risk factor for severe community acquired pneumonia in a patient requiring extra corporeal membrane oxygenation. AB - A previously fit and well man developed acute respiratory failure due to environmental mould exposure from living in damp rental accommodation. Despite aggressive intensive care management he rapidly deteriorated and required respiratory and cardiac Extracorporeal Membrane Oxygenation. We hypothesize that poor domiciliary conditions may make an underestimated contribution to community respiratory disease. These conditions may present as acute and severe illness with non-typical pathogens identified. PMID- 26236599 TI - Pneumothorax triggered by the combination of gefitinib and amrubicin and treated with endobronchial silicone spigots. AB - Pneumothorax is a rare complication in cancer chemotherapy. We report a case in which a male patient with advanced non-small cell lung cancer (NSCLC) developed repetitive pneumothorax after receiving a combination of the chemotherapeutic drugs gefitinib and amrubicin (GEF + AMR). Both episodes of pneumothorax occurred on the 3rd day of GEF + AMR administration. Tube thoracostomy was performed, but pulmonary air leaks persisted in the second pneumothorax. Whereas surgical intervention was not applicable because of poor respiratory reserve, the chest tube was successfully removed by endoscopic occlusion of bronchopleural fistula with endobronchial Watanabe spigots (EWSs), a type of silicone bronchial blocker. PMID- 26236600 TI - Bronchopulmonary Kaposi's sarcoma. AB - Kaposi's sarcoma (KS) is a highly vascular tumour, which was first described by the Hungarian dermatologist Moritz Kaposi Kohn before the discovery of the human immunodeficiency virus (HIV). Historically, KS has been linked to immunosuppression or to elderly male patients, especially in relation to diffuse cutaneous KS. We describe a case of Bronchopulmonary Kaposi's sarcoma in a patient with AIDS who was successfully treated with HAART and Liposomal Doxorubicin chemotherapy. PMID- 26236601 TI - Successful treatment with carboplatin and nanoparticle albumin-bound paclitaxel in a patient with pulmonary spindle cell carcinoma. AB - INTRODUCTION: Pulmonary spindle cell carcinoma (SpCC) is a rare subtype of non small-cell lung cancer (NSCLC) and, in general, is chemoresistance. CASE: A sixty five year-old male patient with metastatic pulmonary SpCC was initially treated with cisplatin and docetaxel, but his disease progressed. Then, he received a combination chemotherapy with carboplatin and nab-PTX followed by maintenanced chemotherapy with nab-PTX. Fluorodeoxyglucose (FDG) positron-emission CT revealed a substantial decrease of FDG accumulation in the primary tumor, and the response continued for more than 7 months. DISCUSSION: Preclinical models suggested that nab-PTX may reach the tumor microenvironment more efficiently than solvent-based paclitaxel (sb-PTX) and be preferentially taken up by cancer cells. Considering that there is no effective treatment for patients with pulmonary SpCC, nab-PTX may merit further investigation in patients with pulmonary SpCC. PMID- 26236602 TI - Spontaneous chylothorax complicating small cell lung cancer - Review of aetiology and diagnosis. AB - We report the first case of spontaneous chylothorax complicating small cell lung cancer. A 52 year old female presented with exertional dyspnoea, left-sided chest and neck pain, and dysphagia. The chest X-ray on admission revealed a large left sided pleural effusion. A subsequent CT chest showed a large anterior mediastinal mass with a left brachiocephalic and jugular vein thrombosis. The patient underwent medical thoracoscopy with chest drain insertion, which drained pleural fluid high in triglycerides, consistent with a chylothorax. Due to its uncommon nature, the management of chylothorax is not well defined. Alongside the case report, we provide a review of aetiology, mechanism and diagnosis with a brief summary of treatment options. PMID- 26236603 TI - Pneumonia and disseminated bacteremia with Pasteurella multocida in the immune competent host: A case report and a review of the literature. AB - Pasteurella multocida is primarily an opportunistic infection, most commonly of skin and soft tissue following animal bites particularly in the elderly and immunocompromised. While invasive disease with P. multocida has been documented in patients at high risk, such as those with organ transplants, malignancy, and cirrhosis, infections other than cellulitis associated with this pathogen are exceedingly rare in the immunocompetent population. We report a 70 year old Caucasian female with occurrence of a P. multocida pneumonia and resultant bacteremia in an immunocompetent host. Similar to prior case studies, the patient presented with a history of having significant exposure to animals at her residence. We undertook a review of the literature for reports of disseminated P. multocida in immunocompotent hosts in the absence of the typical presentation of cellulitis. Literature has suggested the possibility of nasal and oropharyngeal colonization of patients with frequent interactions with domestic animals, in whom periods of suppressed immune function may lead to activation of infection. P. multocida is commonly susceptible to most beta-lactams, including those utilized for the treatment of community acquired pneumonia. The utilization of macrolides should be avoided in these patients as susceptibilities are unpredictable, however fluoroquinolones maintain activity and may be an alternative therapy. PMID- 26236604 TI - Iatrogenic "buffalo chest" bilateral pneumothoraces following unilateral transbronchial lung biopsies in a bilateral lung transplant recipient. AB - We present a 54 year old male patient who had a bilateral lung transplant sixteen years ago for Alpha-1 Antitrypsin Deficiency-related emphysema. He was referred for flexible bronchoscopy with transbronchial biopsies to evaluate new mild exertional dyspnea and worsening of his FEV1. Eight transbronchial biopsies were done from the right middle lobe and the right lower lobe. Post procedure he developed bilateral pneumothoces that required emergent bilateral pleural 'pigtail' catheters. To our knowledge, this is the first reported case of bilateral pneumothoraces that developed after a unilateral procedure in a bilateral lung transplant recipient relatively late after the transplant. PMID- 26236605 TI - Diffuse alveolar hemorrhage caused by exposure to organic dust. AB - Diffuse alveolar hemorrhage, a life-threatening disease, can complicate various conditions. We herein describe, for the first time, a patient with diffuse alveolar hemorrhage caused by exposure to organic dust. A 49-year-old woman who worked as a cantaloupe farmer in a greenhouse was referred to our hospital for sudden onset of dyspnea 3 h after exposure to organic dust. A chest X-ray and computed tomography scan performed on admission showed diffuse ground-glass opacities in both lung fields. Suspecting hypersensitivity pneumonitis, fiberoptic bronchoscopy was performed. Mucopurulent sputum was present in the trachea and both bronchi, and bronchoalveolar lavage revealed a progressively bloody return, typical of diffuse alveolar hemorrhage. Based on the history and bronchoscopy findings, she was diagnosed with diffuse alveolar hemorrhage following exposure to organic dust and was treated with antibiotics and corticosteroids. Diffuse alveolar hemorrhage should be considered in the differential diagnosis of diffuse ground-glass opacities observed on radiographs in farmers following exposure to organic dust. PMID- 26236606 TI - Successful treatment of chronic lower respiratory tract infection by macrolide administration in a patient with intralobar pulmonary sequestration and primary ciliary dyskinesia. AB - Primary ciliary dyskinesia (PCD) is a genetic disease associated with abnormalities in ciliary structure and function. Although recurrent respiratory infection associated with ciliary dysfunction is a common clinical feature, there is no standardized treatment or management of respiratory infection in PCD patients. Here, we report that respiratory infection with PCD and intralobar sequestration (ILS) were treated successfully with clarithromycin before the surgical resection of ILS. A 15-year-old non-smoking Japanese woman was admitted for productive cough and dyspnea on exertion. Chest CT scan on admission showed complex cystic LESIONS with air-fluid level in the right lower lobe, and diffuse nodular shadows in the whole lobe of the lung. On flexible bronchoscopy examination, sputum and bronchiolar fluid cultures revealed Staphylococcus aureus (S. aureus). An electron microscopic examination of the cilia showed inner dynein arm deficiency. Administration of clarithromycin improved the lower respiratory tract infection associated with S. aureus. CT angiography after clarithromycin treatment demonstrated an aberrant systemic artery arising from the celiac trunk and supplying the cystic mass lesions that were incorporated into the normal pulmonary parenchyma without their own pleural covering. Based on these results, the patient was diagnosed with PCD and ILS. Because of the clarithromycin treatment, resection of the ILS was performed safely without any complications. Although further observation of clarithromycin treatment is needed, we believe that clarithromycin may be considered one of the agents for treating PCD. PMID- 26236607 TI - Fatal pulmonary hemorrhage after taking anticoagulation medication. AB - We describe a 64-year-old man with extensive diffuse acute lung hemorrhage, presumably as a result of anticoagulation therapy. We evaluated reports in the literature concerning acute exacerbation (acute lung injury of unknown cause) in UIP and other forms of fibrotic interstitial pneumonias. We also evaluated autopsy tissue in this case in order to determine the cause of death in this 64 year-old man, who was initially thought to have an asbestos-related disease. Based on the autopsy findings, this man died as a result of anticoagulation therapy; specifically, the use of Xarelto((r)) (rivaroxaban). PMID- 26236608 TI - A case of pulmonary lymphangioleiomyomatosis complicated with uterine and retroperitoneal tumors. AB - A 39-year-old female experienced dyspnea on exertion for eight months. Chest CT demonstrated findings of Lymphangioleiomyomatosis (LAM), including diffuse thin walled cystic lesions. A surgical lung biopsy revealed human melanoma black-45 positive cell infiltration and aggregation, resulting in a diagnosis of sporadic LAM without tuberous sclerosis complex. Pelvic MRI showed two large tumors, one of which was in the myometrium and the other was in the retroperitoneal space. Because we were not able to exclude the presence of malignant tumors using MR imaging, the tumors were surgically resected. The histopathology demonstrated the resected tumors to be composed of LAM cells. The patient's symptoms worsened, and sirolimus was administered, which improved the dyspnea and pulmonary function. The adverse effect was mild liver damage. Following the initiation of treatment with sirolimus, transient elevation of the serum KL-6 level was detected without interstitial pneumonia. This LAM case complicated with large uterine and retroperitoneal tumors was successfully treated with surgical resection and sirolimus. PMID- 26236609 TI - Scrotal wall metastasis from a primary lung adenocarcinoma. AB - This a case of a 77 years old male heavy smoker, known to have Combined Pulmonary Fibrosis and Emphysema complicated by a primary invasive adenocarcinoma of the lung with bone metastasis, who presented with a two weeks history of right inguino-scrotal pain and swelling. Imaging studies revealed a right paratesticular formation that appeared to involve the epididymis and the scrotal wall. A biopsy of the mass showed morphological and Immunophenotypic features in favor of metastasis of an adenocarcinoma of the lung. Based on our literature review, there are only few published cases about scrotal wall metastasis of a lung primary. PMID- 26236610 TI - Fusobacterium necrophorum presenting as isolated lung nodules. AB - Fusobacterium necrophorum causes Lemierre's syndrome - a dramatic and distinct condition beginning with pharyngitis before proceeding to internal jugular vein septic thrombophlebitis and respiratory tract infection in otherwise healthy individuals. It is rare, but by far the most common pathway to parenchymal lung disease with this organism. Here we describe we a 34 year old healthy lady who was nontoxic without any antecedent illness who presented with lung nodules due to fusobacterium necrophorum as the sole manifestation of disease. Leading diagnostic consideration prior to culture data was pulmonary vasculitis. Identifying her disease process was a somewhat chance occurrence, and it began to resolve prior to antibiotic therapy. Though it would be difficult to recommend keen awareness of this organism given its rarity, it is important to consider that its scope may be broader than traditionally considered. PMID- 26236611 TI - Unilateral pulmonary vein atresia: A rare case of hemoptysis. AB - We present a rare case of hemoptysis secondary to isolated unilateral pulmonary vein atresia. Isolated pulmonary vein atresia is a rare condition in which patients typically acquire a diagnosis in infancy and early childhood [Mataciunas et al.; Pourmoghadam et al.]. Our patient presented during puberty with several previous episodes of hemoptysis prior to her admission and diagnosis. The initial diagnosis was suspected in our patient from chest computerized tomography (CT), and confirmed with cardiac catheterization and pulmonary angiography. Treatment aim is to preserve lung function and minimize irreversible pulmonary remodeling [Pourmoghadam et al.; Harrison et al.]. Conservative monitoring can be considered with milder or asymptomatic cases, while others may require preoperative collateral artery banding, surgical anastomosis between the pulmonary vein (PV) & left atrium (LA) and even pneumonectomy [Pourmoghadam et al.]. PMID- 26236612 TI - Inflammatory bowel disease of the lung: The role of infliximab? AB - Pulmonary extra-intestinal manifestations (EIM) of inflammatory bowel disease are well described with a variable incidence. We present a case of Crohn's disease with pulmonary EIM including chronic bronchitis with non-resolving bilateral cavitary pulmonary nodules and mediastinal lymphadenopathy successfully treated with infliximab. Additionally, we present a case summary from a literature review on pulmonary EIM successfully treated with infliximab. Current treatment recommendations include an inhaled and/or systemic corticosteroid regimen which is largely based on case reports and expert opinion. We offer infliximab as an adjunctive therapy or alternative to corticosteroids for treatment of inflammatory bowel disease related pulmonary EIM. PMID- 26236613 TI - Postcardiac injury syndrome following vascular interventional radiofrequency ablation for paroxysmal atrial fibrillation. AB - Postcardiac injury syndrome (PCIS) occurs following a pericardial or myocardial injury. On the other hand, PCIS following cardiac catheter intervention is rare and can be difficult to diagnose because of its delayed onset. A 24-year-old man underwent radiofrequency ablation (RFA) for paroxysmal atrial fibrillation and suffered from general fatigue and left-sided pleural effusion three months after the procedure. His symptoms and effusion were effectively treated within a month by administrating nonsteroidal anti-inflammatory drugs. However, seven months later, he developed left-sided chest pain and low-grade fever. Computed tomography showed a thickening of the parietal pleura and reccurence of the pleural effusion. Pleural biopsy by video-assisted thoracoscopy demonstrated chronic pleuritis with a non-necrotizing granulomatous reaction. Given the previous RFA, and in the absence of infection or malignant disease, he was diagnosed with PCIS and treated with colchicine. PMID- 26236614 TI - Glutaric aciduria type 2 presenting with acute respiratory failure in an adult. AB - Glutaric aciduria (GTA) type II can be seen as late onset form with myopathic phenotype. We present a case of a 19-year old female with progressive muscle weakness was admitted in intensive care unit (ICU) with respiratory failure and acute renal failure. Patient was unconscious. Pupils were anisocoric and light reflex was absent. She had hepatomegaly. The laboratory results showed a glucose level of 70 mg/dl and the liver enzymes were high. The patient also had hyponatremia (117 mEq/L) and lactate level of 3.9 mmol/L. Tandem MS and organic acid analysis were compatible with GTA type II. Carnitine 1gr, riboflavin 100 mg and co-enzymeQ10 100 mg was arranged. After four months from beginning of treatment tandem MS results are improved. Respiratory failure, acute renal failure due to profound proximal myopathy can be due to glutaric aciduria type II that responded rapidly to appropriate therapy. PMID- 26236615 TI - Rash, disseminated intravascular coagulation and legionella: Episode 10 and a rewind into the past. AB - Legionella pneumophila is the most common cause of legionellosis and is one of the organisms causing atypical pneumonia. We report the presentation of disseminated intravascular coagulation (DIC) and skin rash in a single case of severe Legionella pneumonia. The unique clinical presentation of a diffuse rash diagnosed as purpura fulminans and the unpredictable variations encountered during the diagnostic work-up of the case make this write-up crucial. This article synthesizes all reported cases of L. pneumonia associated with cutaneous manifestations as well as cases presenting with DIC. Furthermore, this manuscript illustrates the correlation between cutaneous and coagulopathic manifestations, and morbidity and mortality from L. pneumonia. PMID- 26236616 TI - A case of Trousseau syndrome caused by pulmonary adenocarcinoma that was controlled for one year and 10 months with thrombosis treatment using an EGFR tyrosine kinase inhibitor and chemotherapy. AB - A 47-year-old female with no history of previous illnesses developed cerebral infarction and was diagnosed with lung cancer, specifically EGFR mutation positive adenocarcinoma, and Trousseau syndrome. The patient's response to anticoagulant therapy with non-fractionated heparin was very poor; however we were able to control the thrombosis with chemotherapy. She survived for one year and 10 months following treatment with gefitinib, CBDCA + PEM and erlotinib, without recurrence of thrombosis. Trousseau syndrome carries a poor prognosis and controlling thrombosis is difficult. In this case, the administration of anticancer therapy allowed use to control the patient's thrombosis. Therefore, this case highlights the importance of treating cancer in patients with Trousseau syndrome. In addition, the FDP and D-dimer levels changed in parallel with changes in the CEA level, which suggests that the activity of cancer is related to an internal thrombotic tendency. Hence, changes in the FDP and D-dimer values are associated with the efficacy of treatment with EGFR tyrosine kinase inhibitors and chemotherapy and may function as markers of recurrence. PMID- 26236617 TI - Microscopic polyangiitis associated with pleuropericarditis, pulmonary embolism and pulmonary hemorrhage as a complication of silicosis. AB - Silica (silicon dioxide) occupational exposure has been linked to both pulmonary and extra-pulmonary toxicity. Silicosis is the major pulmonary toxicity, which has also been associated with the development of collagen-vascular disease and with anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis, especially perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA). The most common pulmonary manifestations of microscopic polyangitis (MPA) are interstitial fibrosis and alveolar hemorrhage. We describe a patient who had unusual presentation of microscopic polyangitis, characterized by lung hemorrhage, rapidly progressive glomerulonephritis, pleuropericarditis and pulmonary embolism that was associated with a history of silica exposure and radiologic evidence for silicosis. PMID- 26236618 TI - Minocycline-induced acute eosinophilic pneumonia: A case report and review of the literature. AB - Acute eosinophilic pneumonia (AEP) can be a challenging diagnosis and is often initially misdiagnosed as one of the more common pneumonia syndromes such as acute respiratory distress syndrome. Early bronchoalveolar lavage (BAL) is critical in distinguishing the diagnosis to initiate proper management. The etiology of AEP is unknown, though many drugs have been implicated, including minocycline. Minocycline is commonly used for pneumonia, acute bronchitis, urinary tract infections, and acne and is likely the cause of AEP in our patient. There are 26 case reports of minocycline-induced AEP. In most cases, outcomes were favorable and symptoms rapidly resolved upon discontinuation of minocycline, with 11 cases employing steroids, one case twelve hours of CPAP and another 5 days of intubation. None resulted in mortality. Although it is difficult to evaluate without further studies, steroids should be recommended for minocycline induced AEP, especially for those with severe or persistent symptoms. PMID- 26236619 TI - Multifocal primary amyloidosis of the airways: Case report and review of the literature. AB - Primary localized amyloidosis of the airways is an uncommon disorder characterized by amyloid deposits in the airway mucosa. In contrast to systemic amyloidosis other organs are not involved. Among the entities of airway amyloidosis, tracheobronchial amyloidosis is comparatively the most common subtype in the lower respiratory tract and laryngeal amyloidosis in the upper respiratory tract. The pathophysiology of localized airway amyloidosis is poorly understood. The clinical presentation is variable and often non-specific. No general consensus exists with regard to optimal treatment resulting in a variety of modalities used in clinical practice to manage this disorder. We report the case of a 50 year old woman with multifocal localized amyloidosis of the tracheobronchial tree and the upper airways. Tracheobronchial amyloidosis was treated with endoscopic debulking and external beam radiation, sinunasal amyloid deposits were surgically excised and are currently under surveillance. The importance of this extremely rare case lies in the multifocal presentation of an uncommon disorder requiring a multidisciplinary approach to offer optimal treatment including external beam radiation. PMID- 26236620 TI - Dark sputum: An atypical presentation of primary pulmonary malignant melanoma. AB - Primary melanoma of the lung is an extremely rare clinical entity. We found only 32 cases reported in literature, and in two of these multiple brain metastases were present. We describe a case of primary lung melanoma with brain and skin metastases that presented with an initial clinical diagnosis of pneumonia. A 55 year-old white man presented with cough productive of dark sputum and fever. A chest x-ray showed a right lung infiltration. After failure to respond to usual treatment for pneumonia, bronchoscopy examination and CT scan revealed a right pulmonary mass. The CT-guided biopsy confirmed a diagnosis of malignant melanoma. The primary lung origin of the tumor was demonstrated by the characteristic junctional pattern of melanoma cells. Further evaluation revealed metastases in the brain and in skin. Primary lung melanoma is an uncommon neoplasm that may be confused with more conventional types of lung cancer. Careful interpretation of histopathological information in correlation with all other clinical, laboratory and imaging studies may be needed to establish a diagnosis. Evaluation for metastases should include looking at the eyes, brain, skin. Due to the small number of cases reported in literature, there is no experience on the management and the prognosis of the disease. PMID- 26236621 TI - Palliative embolisation for intrapulmonary shunting in lepidic predominant adenocarcinoma of the lung. AB - Lepidic predominant adenocarcinoma (LPA) (formerly known as bronchioalveolar carcinoma) has rarely been reported to cause refractory hypoxia with intrapulmonary shunting [1-7]. We describe a case who underwent the palliative strategy of intravascular right lower pulmonary artery embolisation with an 18 mm Amplatzer II vascular plug to reduce intrapulmonary shunting. This is the first report we are aware of using this minimally invasive procedure to treat this condition. PMID- 26236622 TI - Diffuse vascular hamartoma with malignant behavior. AB - Pulmonary hamartomas are benign lesions, usually asymptomatic and incidentally discovered on a routine chest radiograph; occasionally, however, this benign lesion may cause life threatening symptoms due to it's location and diffuse vascular involvement. We report the case of a 27 year-old male, non-smoker, who presented with dyspnea, cough, hemoptysis and weight loss. He was found to have a mass in the right hilar region which also involved the right main bronchus, pulmonary artery and esophagus. Surgical biopsy of the lesion led to the diagnosis of diffuse vascular hamartoma. Although it was a benign lesion, due to the size and location, surgical removal was not possible and patient died 10 years after being diagnosed with the condition. PMID- 26236624 TI - An aggressive, solitary non-healing ulcer: Not always cancerous. PMID- 26236623 TI - Microscopic polyangiitis preceded by combined pulmonary fibrosis and emphysema. AB - A 73-year-old male metalworker was admitted to our hospital with a 3-year history of progressive dry cough. Chest high-resolution computed tomography revealed emphysematous changes and reticular lesions, which is referred to as combined pulmonary fibrosis and emphysema (CPFE). Surgical lung biopsy specimens revealed unclassified interstitial pneumonia, including a nonspecific interstitial pneumonia pattern and usual interstitial pneumonia pattern. Two years after his first admission he developed rapid progressive renal dysfunction with an elevated level of myeloperoxidase-antineutrophil cytoplasmic antibody (428 EU). A renal biopsy specimen revealed interstitial nephritis and glomerulonephritis. Consequently, microscopic polyangiitis preceded by CPFE was diagnosed. Despite transient exacerbation of renal involvement, his general condition remained mostly stable during a 2-year period of corticosteroid treatment. He ultimately died from severe pneumococcal pneumonia associated with acute lung injury. PMID- 26236625 TI - Hypersensitivity pneumonitis caused by the broom grass (Calluna vulgaris). AB - Hypersensitivity pneumonitis (HP), is an inflammatory disease that represents one possible response of the interstitial and parenchymal tissue to the intensive and repeated inhalation of organic dusts or reactive chemicals substances. In this case report, for the first time in the literature as we know, acute hypersensitivity pneumonitis in a patient who working in broom grass manufacturing were presented. Broom manufacturer employee 35 years old female patient was admitted with dyspnea, fever and cough, beginning the three months before. Physical examination, there were bilateral basal crackles. On Thorax CT bilateral diffuse ground-glass opacity and mosaic perfusion were observed. Patient was hospitalized, IV prednisolone therapy was started. Almost complete clinical improvement was achieved. We would like to emphasize that detailed occupational history should be questioned; because; diagnosis of acute HP, due to the mixing with the viral infection or atypical pneumonia, easily skipped. PMID- 26236626 TI - Connectivity and tissue microstructural alterations in right and left temporal lobe epilepsy revealed by diffusion spectrum imaging. AB - Focal epilepsy is increasingly recognized as the result of an altered brain network, both on the structural and functional levels and the characterization of these widespread brain alterations is crucial for our understanding of the clinical manifestation of seizure and cognitive deficits as well as for the management of candidates to epilepsy surgery. Tractography based on Diffusion Tensor Imaging allows non-invasive mapping of white matter tracts in vivo. Recently, diffusion spectrum imaging (DSI), based on an increased number of diffusion directions and intensities, has improved the sensitivity of tractography, notably with respect to the problem of fiber crossing and recent developments allow acquisition times compatible with clinical application. We used DSI and parcellation of the gray matter in regions of interest to build whole-brain connectivity matrices describing the mutual connections between cortical and subcortical regions in patients with focal epilepsy and healthy controls. In addition, the high angular and radial resolution of DSI allowed us to evaluate also some of the biophysical compartment models, to better understand the cause of the changes in diffusion anisotropy. Global connectivity, hub architecture and regional connectivity patterns were altered in TLE patients and showed different characteristics in RTLE vs LTLE with stronger abnormalities in RTLE. The microstructural analysis suggested that disturbed axonal density contributed more than fiber orientation to the connectivity changes affecting the temporal lobes whereas fiber orientation changes were more involved in extratemporal lobe changes. Our study provides further structural evidence that RTLE and LTLE are not symmetrical entities and DSI-based imaging could help investigate the microstructural correlate of these imaging abnormalities. PMID- 26236627 TI - Brain effective connectivity during motor-imagery and execution following stroke and rehabilitation. AB - Brain areas within the motor system interact directly or indirectly during motor imagery and motor-execution tasks. These interactions and their functionality can change following stroke and recovery. How brain network interactions reorganize and recover their functionality during recovery and treatment following stroke are not well understood. To contribute to answering these questions, we recorded blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) signals from 10 stroke survivors and evaluated dynamical causal modeling (DCM)-based effective connectivity among three motor areas: primary motor cortex (M1), pre-motor cortex (PMC) and supplementary motor area (SMA), during motor imagery and motor-execution tasks. We compared the connectivity between affected and unaffected hemispheres before and after mental practice and combined mental practice and physical therapy as treatments. The treatment (intervention) period varied in length between 14 to 51 days but all patients received the same dose of 60 h of treatment. Using Bayesian model selection (BMS) approach in the DCM approach, we found that, after intervention, the same network dominated during motor-imagery and motor-execution tasks but modulatory parameters suggested a suppressive influence of SM A on M1 during the motor-imagery task whereas the influence of SM A on M1 was unrestricted during the motor-execution task. We found that the intervention caused a reorganization of the network during both tasks for unaffected as well as for the affected hemisphere. Using Bayesian model averaging (BMA) approach, we found that the intervention improved the regional connectivity among the motor areas during both the tasks. The connectivity between PMC and M1 was stronger in motor-imagery tasks whereas the connectivity from PMC to M1, SM A to M1 dominated in motor-execution tasks. There was significant behavioral improvement (p = 0.001) in sensation and motor movements because of the intervention as reflected by behavioral Fugl-Meyer (FMA) measures, which were significantly correlated (p = 0.05) with a subset of connectivity. These findings suggest that PMC and M1 play a crucial role during motor-imagery as well as during motor-execution task. In addition, M1 causes more exchange of causal information among motor areas during a motor-execution task than during a motor-imagery task due to its interaction with SM A. This study expands our understanding of motor network involved during two different tasks, which are commonly used during rehabilitation following stroke. A clear understanding of the effective connectivity networks leads to a better treatment in helping stroke survivors regain motor ability. PMID- 26236628 TI - A multi-contrast MRI study of microstructural brain damage in patients with mild cognitive impairment. AB - OBJECTIVES: The aim of this study was to investigate pathological mechanisms underlying brain tissue alterations in mild cognitive impairment (MCI) using multi-contrast 3 T magnetic resonance imaging (MRI). METHODS: Forty-two MCI patients and 77 healthy controls (HC) underwent T1/T2* relaxometry as well as Magnetization Transfer (MT) MRI. Between-groups comparisons in MRI metrics were performed using permutation-based tests. Using MRI data, a generalized linear model (GLM) was computed to predict clinical performance and a support-vector machine (SVM) classification was used to classify MCI and HC subjects. RESULTS: Multi-parametric MRI data showed microstructural brain alterations in MCI patients vs HC that might be interpreted as: (i) a broad loss of myelin/cellular proteins and tissue microstructure in the hippocampus (p <= 0.01) and global white matter (p < 0.05); and (ii) iron accumulation in the pallidus nucleus (p <= 0.05). MRI metrics accurately predicted memory and executive performances in patients (p <= 0.005). SVM classification reached an accuracy of 75% to separate MCI and HC, and performed best using both volumes and T1/T2*/MT metrics. CONCLUSION: Multi-contrast MRI appears to be a promising approach to infer pathophysiological mechanisms leading to brain tissue alterations in MCI. Likewise, parametric MRI data provide powerful correlates of cognitive deficits and improve automatic disease classification based on morphometric features. PMID- 26236630 TI - Helpful invaders: Can cane toads reduce the parasite burdens of native frogs? AB - Many invading species have brought devastating parasites and diseases to their new homes, thereby imperiling native taxa. Potentially, though, invaders might have the opposite effect. If they take up parasites that otherwise would infect native taxa, but those parasites fail to develop in the invader, the introduced species might reduce parasite burdens of the native fauna. Similarly, earlier exposure to the other taxon's parasites might 'prime' an anuran's immune system such that it is then able to reject subsequent infection by its own parasite species. Field surveys suggest that lungworm counts in native Australian frogs decrease after the arrival of invasive cane toads (Rhinella marina), and laboratory studies confirm that native lungworm larvae enter, but do not survive in, the toads. In laboratory trials, we confirmed that the presence of anurans (either frogs or toads) in an experimental arena reduced uptake rates of lungworm larvae by anurans that were later added to the same arena. However, experimental exposure to lungworms from native frogs did not enhance a toad's ability to reject subsequent infection by its own lungworm species. PMID- 26236629 TI - White matter tract signatures of impaired social cognition in frontotemporal lobar degeneration. AB - Impairments of social cognition are often leading features in frontotemporal lobar degeneration (FTLD) and likely to reflect large-scale brain network disintegration. However, the neuroanatomical basis of impaired social cognition in FTLD and the role of white matter connections have not been defined. Here we assessed social cognition in a cohort of patients representing two core syndromes of FTLD, behavioural variant frontotemporal dementia (bvFTD; n = 29) and semantic variant primary progressive aphasia (svPPA; n = 15), relative to healthy older individuals (n = 37) using two components of the Awareness of Social Inference Test, canonical emotion identification and sarcasm identification. Diffusion tensor imaging (DTI) was used to derive white matter tract correlates of social cognition performance and compared with the distribution of grey matter atrophy on voxel-based morphometry. The bvFTD and svPPA groups showed comparably severe deficits for identification of canonical emotions and sarcasm, and these deficits were correlated with distributed and overlapping white matter tract alterations particularly affecting frontotemporal connections in the right cerebral hemisphere. The most robust DTI associations were identified in white matter tracts linking cognitive and evaluative processing with emotional responses: anterior thalamic radiation, fornix (emotion identification) and uncinate fasciculus (sarcasm identification). DTI associations of impaired social cognition were more consistent than corresponding grey matter associations. These findings delineate a brain network substrate for the social impairment that characterises FTLD syndromes. The findings further suggest that DTI can generate sensitive and functionally relevant indexes of white matter damage in FTLD, with potential to transcend conventional syndrome boundaries. PMID- 26236631 TI - Patterns of ectoparasitism in North American red squirrels (Tamiasciurus hudsonicus): Sex-biases, seasonality, age, and effects on male body condition. AB - Within many species, males are often more heavily parasitised than females. Several hypotheses have been proposed to explain this phenomenon, including immunocompetence handicaps, sexual size dimorphism and behavioural differences. Here we set out to test the latter two hypotheses and make inferences about the former by assessing patterns of ectoparasitism across various life-history stages in a population of North American red squirrels (Tamiasciurus hudsonicus). We also conducted an ectoparasite removal experiment to investigate the effects of ectoparasites on male body condition. We found that males were more intensely parasitized than females, but only during the mating period. There was no difference in ectoparasite intensity between male and female juveniles at birth or at emergence, suggesting that ectoparasites do not exploit male red squirrels for longer-range natal dispersal. Male red squirrels in our population were slightly heavier than females, however we did not find any evidence that this dimorphism drives male-biased ectoparasitism. Finally, we could not detect an effect of ectoparasite removal on male body mass. Our results lend support to the hypothesis that ectoparasites exploit their male hosts for transmission and that male red squirrels are important for the transmission dynamics of ectoparasites in this population; however, the mechanisms (i.e., immunocompetence, testosterone) are not known. PMID- 26236632 TI - A standardised faecal collection protocol for intestinal helminth egg counts in Asian elephants, Elephas maximus. AB - The quantitative assessment of parasite infection is necessary to measure, manage and reduce infection risk in both wild and captive animal populations. Traditional faecal flotation methods which aim to quantify parasite burden, such as the McMaster egg counting technique, are widely used in veterinary medicine, agricultural management and wildlife parasitology. Although many modifications to the McMaster method exist, few account for systematic variation in parasite egg output which may lead to inaccurate estimations of infection intensity through faecal egg counts (FEC). To adapt the McMaster method for use in sampling Asian elephants (Elephas maximus), we tested a number of possible sources of error regarding faecal sampling, focussing on helminth eggs and using a population of over 120 semi-captive elephants distributed across northern Myanmar. These included time of day of defecation, effects of storage in 10% formalin and 10% formol saline and variation in egg distribution between and within faecal boluses. We found no significant difference in the distribution of helminth eggs within faecal matter or for different defecation times, however, storage in formol saline and formalin significantly decreased egg recovery. This is the first study to analyse several collection and storage aspects of a widely-used traditional parasitology method for helminth parasites of E. maximus using known host individuals. We suggest that for the modified McMaster technique, a minimum of one fresh sample per elephant collected from any freshly produced bolus in the total faecal matter and at any point within a 7.5 h time period (7.30am-2.55 pm) will consistently represent parasite load. This study defines a protocol which may be used to test pre-analytic factors and effectively determine infection load in species which produce large quantities of vegetative faeces, such as non ruminant megaherbivores. PMID- 26236633 TI - A survey of Angiostrongylus species in definitive hosts in Queensland. AB - Despite the recent sporadic reports of angiostrongyliasis in humans, dogs and wildlife in eastern Australia there has been no systematic study to explore the epidemiology of Angiostrongylus spp. in definitive and intermediate hosts in the region. Little is known about the epidemiology of Angiostrongylus species in the definitive host in southeast Queensland, since the only survey conducted in this region was performed in the late 1960s. In this study, free-living populations of Rattus spp. were sampled and examined for the presence of adult and larval Angiostrongylus in the lungs, and of larvae in faeces. The prevalence of infection with Angiostrongylus spp. was 16.5% in Rattus spp. trapped in urban Brisbane and surrounds. This prevalence is much higher than estimates of earlier studies. This highlights the possible risk of zoonotic infection in children, dogs and wildlife in this region and indicates the necessity for public awareness as well as more detailed epidemiological studies on this parasite in eastern Australia. PMID- 26236634 TI - Severe myoclonic epilepsy of infancy: Seizure reduction during adjunctive eslicarbazepine in two cases. PMID- 26236635 TI - Letter from the Editor. PMID- 26236636 TI - Venous Ulcers. AB - Venous leg ulcers are the most frequent form of wounds seen in patients. This article presents an overview on some practical aspects concerning diagnosis, differential diagnosis and treatment. Duplex ultrasound investigations are essential to ascertain the diagnosis of the underlying venous pathology and to treat venous refluxes. Differential diagnosis includes mainly other vascular lesions (arterial, microcirculatory causes), hematologic and metabolic diseases, trauma, infection, malignancies. Patients with superficial venous incompetence may benefit from endovenous or surgical reflux abolition diagnosed by Duplex ultrasound. The most important basic component of the management is compression therapy, for which we prefer materials with low elasticity applied with high initial pressure (short-stretch bandages and Velcro-strap devices). Local treatment should be simple, absorbing and not sticky dressings keeping adequate moisture balance after debridement of necrotic tissue and biofilms are preferred. After the ulcer is healed compression therapy should be continued in order to prevent recurrence. PMID- 26236637 TI - The History of Negative Pressure Wound Therapy (NPWT): From "Lip Service" to the Modern Vacuum System. AB - Negative pressure wound therapy (NPWT) is a commonly used modality to facilitate tissue granulation and thus hasten the healing process. While the modern vacuum systems are quite sophisticated, their historic origins can be traced to ancient times. This is a historic review of the precursors to the current negative pressure wound therapy. PMID- 26236638 TI - Wet-to-Dry Dressings Do Not Provide Moist Wound Healing. AB - The purpose of this study was to determine if using advanced wound care dressings leads to improved outcomes as compared to wet-to-dry dressings. Based on a review of literature published in the last eight years, with the exception of one landmark article published in 2001, strong support was found that advanced wound care dressings improved outcomes when compared to wet-to-dry dressings. Some of the outcomes compared were healing time, pain, infection rates, and costs; several articles took it a step further stating that the use of wet-to-dry dressings is considered sub-standard practice. The articles provided evidence based support for the use of moist wound healing. PMID- 26236639 TI - Case Report on Calciphylaxis: An Early Diagnosis and Treatment May Improve Outcome. AB - This is a case report of a patient who presented to the wound care center with LE ulcerations that were subsequently diagnosed with calciphylaxis. She was an insulin dependent diabetic with renal disease, but unaware of her critical kidney status. She was treated with local wound care, a partial parathyroidectomy, and started on dialysis. She is currently healed with no recurrence of ulcerations. Her ulcerations were controlled with conservative wound care and no surgical debridement. PMID- 26236640 TI - Photoacoustic imaging driven by an interstitial irradiation source. AB - Photoacoustic (PA) imaging has shown tremendous promise in providing valuable diagnostic and therapy-monitoring information in select clinical procedures. Many of these pursued applications, however, have been relatively superficial due to difficulties with delivering light deep into tissue. To address this limitation, this work investigates generating a PA image using an interstitial irradiation source with a clinical ultrasound (US) system, which was shown to yield improved PA signal quality at distances beyond 13 mm and to provide improved spectral fidelity. Additionally, interstitially driven multi-wavelength PA imaging was able to provide accurate spectra of gold nanoshells and deoxyhemoglobin in excised prostate and liver tissue, respectively, and allowed for clear visualization of a wire at 7 cm in excised liver. This work demonstrates the potential of using a local irradiation source to extend the depth capabilities of future PA imaging techniques for minimally invasive interventional radiology procedures. PMID- 26236642 TI - Photoacoustic transients generated by laser irradiation of thin films. AB - Irradiation of an optically thin layer immersed in a transparent fluid with pulsed laser radiation can generate photoacoustic waves through two mechanisms. The first of these is the conventional optical heating of the layer followed by thermal expansion, in which the mechanical motion of the expansion launches a pair of oppositely directed sound waves. A second, recently reported mechanism, is operative when heat is conducted to the transparent medium raising its temperature, while at the same time reducing the temperature in the absorbing body. The latter mechanism has been shown to result in compressive transients at the leading edges of the photoacoustic waveforms. Here the photoacoustic effect produced by irradiating thin metal films which undergo negligible thermal expansion under optical irradiation, but which generate sound solely by the heat transfer mechanism is investigated. Solution to the wave equation for the photoacoustic effect from the heat transfer mechanism is given and compared with the results of experiments using nanosecond laser pulses to irradiate thin metal films. PMID- 26236641 TI - Multispectral photoacoustic microscopy based on an optical-acoustic objective. AB - We have developed reflection-mode multispectral photoacoustic microscopy (PAM) based on a novel optical-acoustic objective that integrates a customized ultrasonic transducer and a commercial reflective microscope objective into one solid piece. This technical innovation provides zero chromatic aberration and convenient confocal alignment of the optical excitation and acoustic detection. With a wavelength-tunable optical-parametric-oscillator laser, we have demonstrated multispectral PAM over an ultrabroad spectral range of 270-1300 nm. A near-constant lateral resolution of ~2.8 MUm is achieved experimentally. Capitalizing on the consistent performance over the ultraviolet, visible, and near-infrared range, multispectral PAM enables label-free concurrent imaging of cell nucleus (DNA/RNA contrast at 270 nm), blood vessel (hemoglobin contrast at 532 nm), and sebaceous gland (lipid contrast at 1260 nm) at the same spatial scale in a living mouse ear. PMID- 26236643 TI - Determination of thermoelastic material properties by differential heterodyne detection of impulsive stimulated thermal scattering. AB - The underlying working principle of detecting impulsive stimulated scattering signals in a differential configuration of heterodyne diffraction detection is unraveled by involving optical scattering theory. The feasibility of the method for the thermoelastic characterization of coating-substrate systems is demonstrated on the basis of simulated data containing typical levels of noise. Besides the classical analysis of the photoacoustic part of the signals, which involves fitting surface acoustic wave dispersion curves, the photothermal part of the signals is analyzed by introducing thermal wave dispersion curves to represent and interpret their grating wavelength dependence. The intrinsic possibilities and limitations of both inverse problems are quantified by making use of least and most squares analysis. PMID- 26236645 TI - Androgen receptor gene polymorphism in zebra species. AB - Androgen receptor genes (AR) have been found to have associations with reproductive development, behavioral traits, and disorders in humans. However, the influence of similar genetic effects on the behavior of other animals is scarce. We examined the loci AR glutamine repeat (ARQ) in 44 Grevy's zebras, 23 plains zebras, and three mountain zebras, and compared them with those of domesticated horses. We observed polymorphism among zebra species and between zebra and horse. As androgens such as testosterone influence aggressiveness, AR polymorphism among equid species may be associated with differences in levels of aggression and tameness. Our findings indicate that it would be useful to conduct further studies focusing on the potential association between AR and personality traits, and to understand domestication of equid species. PMID- 26236646 TI - Genotyping and meta-analysis of KIF6 Trp719Arg polymorphism in South Indian Coronary Artery Disease patients: A case-control study. AB - The KIF6 719Arg allele is an interesting genomic variant widely screened in various populations and is reported to be associated with the risk of Coronary Artery Disease (CAD) and statin treatment outcome. Recent population based clinical studies and large-scale meta-analyses pondered over the role of 719Arg variant in CAD risk and treatment response. We screened the KIF6 Trp719Arg polymorphism (rs20455) in south Indian CAD patients in a case-control approach. A total of 1042 samples (510 CAD patients and 532 controls) were screened for the KIF6 Trp719Arg SNP by TaqMan SNP genotyping assay, followed by meta-analysis of the genotype data of non-Europeans reports. The 719Arg risk genotype (GG) was observed in 29.6% of CAD cases and in 30.1% of controls with an odds ratio (OR) of 1.07 (95% CI: 0.76-1.50), p value = 0.709. No significant difference in the genotype frequency was observed between CAD and controls in both dominant model (AG + GG vs AA) and allelic model (719Arg vs 719Trp) with an OR of 1.11 (p = 0.491) and 1.03 (p = 0.767), respectively. The covariate analysis indicated that smoking & alcohol consumption increased the risk for MI among CAD patients. Meta analysis showed that the KIF6 719Arg allele is not associated with CAD risk in both fixed effect (p = 0.515, OR = 1.023, 95% CI = 0.956-1.094) and random effect (p = 0.547, OR = 1.022, 95% CI = 0.953-1.096). The symmetrical shape of the Egger's funnel plots revealed that there is no publication bias. These results suggest that there is no association of KIF6 719Arg allele with CAD risk in South Indian population and the meta-analysis confirms the same among non-European population. PMID- 26236644 TI - Localization of Transcranial Targets for Photoacoustic-Guided Endonasal Surgeries. AB - Neurosurgeries to remove pituitary tumors using the endonasal, transsphenoidal approach often incur the risk of patient death caused by injury to the carotid arteries hidden by surrounding sphenoid bone. To avoid this risk, we propose intraoperative photoacoustic vessel visualization with an optical fiber attached to the surgical tool and an external ultrasound transducer placed on the temple. Vessel detection accuracy is limited by acoustic propagation properties, which were investigated with k-Wave simulations. In a two-layer model of temporal bone (3200 m/s sound speed, 1-4 mm thickness) and surrounding tissues, the localization error was <=2 mm in the tranducer's axial dimension, while temporal bone curvature further degraded target localization. Phantom experiments revealed that multiple image targets (e.g. sphenoid bone and vessels) can be visualized, particularly with coherence-based beamforming, to determine tool-to-vessel proximity despite expected localization errors. In addition, the potential flexibility of the fiber position relative to the transducer and vessel was elucidated. PMID- 26236647 TI - Comprehensive assessment of expression of insulin signaling pathway components in subcutaneous adipose tissue of women with and without polycystic ovary syndrome. AB - OBJECTIVE: Insulin resistance is a common feature of polycystic ovary syndrome (PCOS). The insulin signaling pathway consists of two major pathways, the metabolic and the mitogenic cascades. The many components of these pathways have not been comprehensively analyzed for differential expression in insulin responsive tissues in PCOS. The goal of this study was to determine whether the core elements of the insulin signal transduction cascade were differentially expressed in subcutaneous adipose tissue (SAT) between PCOS and controls. MATERIALS/METHODS: Quantitative real-time PCR for 36 insulin signaling pathway genes was performed subcutaneous adipose tissue from 22 white PCOS and 13 healthy controls. RESULTS: Genes in the insulin signaling pathway were not differentially expressed in subcutaneous adipose tissue between PCOS and controls (P>0.05 for all). Components mainly of the mitogenic pathway were correlated with both androgens and metabolic phenotypes. Expression levels of five genes (MKNK1, HRAS, NRAS, KRAS, and GSK3A) were positively correlated with total testosterone level (rho>0, P<0.05). Inverse correlation was found between expression of six genes (HRAS, MAP2K2, NRAS, MAPK3, GRB2, and SHC1) and metabolic traits (body mass index, fasting glucose, fasting insulin, and HOMA-IR) (rho<0, P<0.05). CONCLUSIONS: Differential expression of core insulin signaling pathway components in subcutaneous adipose tissue is not a major contributor to the pathogenesis of PCOS. Correlation between clinical phenotypes and expression of several genes in the mitogenic limb of the insulin signaling pathway suggests mitogenic signaling by insulin may regulate steroidogenesis and glucose homeostasis. PMID- 26236648 TI - Depression and violence: a Swedish population study. AB - BACKGROUND: Depression increases the risk of a range of adverse outcomes including suicide, premature mortality, and self-harm, but associations with violent crime remain uncertain. We aimed to determine the risks of violent crime in patients with depression and to investigate the association between depressive symptoms and violent crime in a cohort of twins. METHODS: We conducted two studies. The first was a total population study in Sweden of patients with outpatient diagnoses of depressive disorders (n=47,158) between 2001 and 2009 and no lifetime inpatient episodes. Patients were age and sex matched to general population controls (n=898,454) and risk of violent crime was calculated. Additionally, we compared the odds of violent crime in unaffected half-siblings (n=15,534) and full siblings (n=33,516) of patients with the general population controls. In sensitivity analyses, we examined the contribution of substance abuse, sociodemographic factors, and previous criminality. In the second study, we studied a general population sample of twins (n=23,020) with continuous measures of depressive symptoms for risk of violent crime. FINDINGS: During a mean follow-up period of 3.2 years, 641 (3.7%) of the depressed men and 152 (0.5%) of the depressed women violently offended after diagnosis. After adjustment for sociodemographic confounders, the odds ratio of violent crime was 3.0 (95% CI 2.8-3.3) compared with the general population controls. The odds of violent crime in half-siblings (adjusted odds ratio 1.2 [95% CI 1.1-1.4]) and full siblings (1.5, 95% CI 1.3-1.6) were significantly increased, showing some familial confounding of the association between depression and violence. However, the odds increase remained significant in individuals with depression after adjustment for familial confounding, and in those without substance abuse comorbidity or a previous violent conviction (all p<0.0001). In the twin study, during the mean follow-up time of 5.4 years, 88 violent crimes were recorded. Depressive symptoms were associated with increased risk of violent crime and a sensitivity analysis identified little difference in risk estimate when all crimes (violent and non-violent) was the outcome. INTERPRETATION: Risk of violent crime was increased in individuals with depression after adjustment for familial, sociodemographic and individual factors in two longitudinal studies. Clinical guidelines should consider recommending violence risk assessment in certain subgroups with depression. FUNDING: Wellcome Trust and the Swedish Research Council. PMID- 26236649 TI - Outlining the limits of partial nephrectomy. AB - Amongst nephron-sparing modalities, partial nephrectomy (PN) is the standard of care in the treatment of renal cell carcinoma (RCC). Despite the increasing utilization of PN, particularly propagated by robot-assisted, minimally invasive approaches for small renal masses (SRMs), the limits of PN appear to be also evolving. In this review, we sought to address the tumour stage beyond which PN may be oncologically perilous. While the evidence supports PN in the treatment of tumours < pT2a, PN may have a role in advanced or metastatic RCC. Other scenarios wherein PN has limited utility are also explored, including anatomical or surgical factors that dictate the difficulty of the case, such as prior renal surgery. Lastly, we discuss the emerging role of molecular biomarkers, specifically epigenetics, to aid in the risk stratification of SRMs and to select tumours optimally suited for PN. PMID- 26236650 TI - Predicting Adverse Health Outcomes in Long-Term Survivors of a Childhood Cancer. AB - More than 80% of children and young adults diagnosed with invasive cancer will survive five or more years beyond their cancer diagnosis. This population has an increased risk for serious illness- and treatment-related morbidity and premature mortality. A number of these adverse health outcomes, such as cardiovascular disease and some second primary neoplasms, either have modifiable risk factors or can be successfully treated if detected early. Absolute risk models that project a personalized risk of developing a health outcome can be useful in patient counseling, in designing intervention studies, in forming prevention strategies, and in deciding upon surveillance programs. Here, we review existing absolute risk prediction models that are directly applicable to survivors of a childhood cancer, discuss the concepts and interpretation of absolute risk models, and examine ways in which these models can be used applied in clinical practice and public health. PMID- 26236652 TI - Solid Lipid Nanoparticles as Efficient Drug and Gene Delivery Systems: Recent Breakthroughs. AB - In recent years, nanomaterials have been widely applied as advanced drug and gene delivery nanosystems. Among them, solid lipid nanoparticles (SLNs) have attracted great attention as colloidal drug delivery systems for incorporating hydrophilic or lipophilic drugs and various macromolecules as well as proteins and nucleic acids. Therefore, SLNs offer great promise for controlled and site specific drug and gene delivery. This article includes general information about SLN structures and properties, production procedures, characterization. In addition, recent progress on development of drug and gene delivery systems using SLNs was reviewed. PMID- 26236651 TI - The Effect of Hypoxia on Mesenchymal Stem Cell Biology. AB - Although physiological and pathological role of hypoxia have been appreciated in mammalians for decades however the cellular biology of hypoxia more clarified in the past 20 years. Discovery of the transcription factor hypoxia-inducible factor (HIF)-1, in the 1990s opened a new window to investigate the mechanisms behind hypoxia. In different cellular contexts HIF-1 activation show variable results by impacting various aspects of cell biology such as cell cycle, apoptosis, differentiation and etc. Mesenchymal stem cells (MSC) are unique cells which take important role in tissue regeneration. They are characterized by self-renewal capacity, multilineage potential, and immunosuppressive property. Like so many kind of cells, hypoxia induces different responses in MSCs by HIF- 1 activation. The activation of this molecule changes the growth, multiplication, differentiation and gene expression profile of MSCs in their niche by a complex of signals. This article briefly discusses the most important effects of hypoxia in growth kinetics, signalling pathways, cytokine secretion profile and expression of chemokine receptors in different conditions. PMID- 26236653 TI - The Relation Between Thermodynamic and Structural Properties and Cellular Uptake of Peptides Containing Tryptophan and Arginine. AB - PURPOSE: Cell-penetrating peptides (CPPs) are used for delivering drugs and other macromolecular cargo into living cells. In this paper, we investigated the relationship between the structural/physicochemical properties of four new synthetic peptides containing arginine-tryptophan in terms of their cell membrane penetration efficiency. METHODS: The peptides were prepared using solid phase synthesis procedure using FMOC protected amino acids. Fluorescence-activated cell sorting and fluorescence imaging were used to evaluate uptake efficiency. Prediction of the peptide secondary structure and estimation of physicochemical properties was performed using the GOR V method and MPEx 3.2 software (Wimley White scale, helical wheel projection and total hydrophobic moment). RESULTS: Our data showed that the uptake efficiency of peptides with two tryptophans at the C- and N-terminus were significantly higher (about 4-fold) than that of peptides containing three tryptophans at both ends. The distribution of arginine at both ends also increased the uptake efficiency 2.52- and 7.18-fold, compared with arginine distribution at the middle of peptides. CONCLUSION: According to the obtained results the value of transfer free energies of peptides from the aqueous phase to membrane bilayer could be a good predictor for the cellular uptake efficiency of CPPs. PMID- 26236654 TI - Nano and Microparticulate Chitosan Based System for Formulation of Carvedilol Rapid Melt Tablet. AB - PURPOSE: In the present study rapid melt tablets (RMT's) of carvedilol were prepared by using ionotropic-gelated chitosan nanoparticles using a spray-drying method. Carvedilol is beta-adrenergic antagonist and its oral bioavailability is about 25-35% because of first pass metabolism. METHODS: The spray-dried microparticles were formulated into RMT's using a wet granulation process. The Formulation and optimization of carvedilol loaded RMTs using nano and microparticulate chitosan based system (NMCS) was done by using 32 factorial designs. RESULTS: Drug entrapment efficiency of about 64.9 % (w/w) and loading capacity of 14.44% (w/w) were achieved for the microparticles, which were ranged from 1 MUm to 4 MUm in diameter. RESULTS of disintegration tests showed that the formulated RMTs could be completely dissolved within 40 seconds. Dissolution studies suggested that Carvedilol is released more slowly from tablets made using the microencapsulation process compared with tablets containing Carvedilol that is free or in the form of nanoparticles. CONCLUSION: RESULTS shown that the development of new RMTs designed with crosslinked microparticle might be a rational way to overcome the unwanted taste of conventional RMTs and the side effects related to Carvedilol intrinsic characteristics. The development of Carvedilol NMCS using ludiflash as RMTs could be used as a promising approach for improving the solubility and oral bioavailability of water insoluble drug. PMID- 26236655 TI - Study of the Efficacy of Real Time-PCR Method for Amikacin Determination Using Microbial Assay. AB - PURPOSE: Microbial assay is used to determine the potency of antibiotics and vitamins. In spite of its advantages like simplicity and easiness, and to reveal the slight changes in the molecules, the microbial assay suffers from significant limitations; these methods are of lower specificity, accuracy and sensitivity. The objective of the present study is to evaluate the efficacy of real time-PCR technique in comparison with turbidimetric method for microbial assay of amikacin. METHODS: Microbial determination of amikacin by turbidimetric method was performed according to USP. Also amikacin concentrations were determined by microbial assay using taq-man quantitative PCR method. Standard curves in different concentration for both methods were plotted and method validation parameters of linearity, precision and accuracy were calculated using statistical procedures. RESULTS: The RT-PCR method was linear in the wider concentration range (5.12 - 38.08 for RT-PCR versus 8.00 - 30.47 for turbidimetric method) with a better correlation coefficient (0.976 for RT-PCR versus 0.958 for turbidimetric method). RT-PCR method with LOQ of 5.12 ng/ml was more sensitive than turbidimetric method with LOQ of 8.00 ng/ml and the former could detect and quantify low concentrations of amikacin. The results of accuracy and precision evaluation showed that the RT-PCR method was accurate and precise in all of the tested concentration. CONCLUSION: The RT-PCR method described here provided an accurate and precise technique for measurement of amikacin potency and it can be a candidate for microbial determination of the antibiotics with the same test organism. PMID- 26236656 TI - Comparative Study on the Effects of Ceftriaxone and Monocytes on Recovery after Spinal Cord Injury in Rat. AB - PURPOSE: Comparison between the efficacy of ceftriaxone and monocytes on improvement of neuron protection and functional recovery after spinal cord injury (SCI) in rat. METHODS: Rats were randomly divided into three groups of ten. Spinal cord injury was performed on rats under general anesthesia using the weight dropping method. Ceftriaxone was injected intraperitoneally 200 mg/kg/day for seven days after SCI. Monocytes were injected 2 * 105 cells 4 days after SCI. Hind limb motor function was assessed using the Basso, Beattie and Bresnahan (BBB) scale. Corticospinal tract (CST) axons were traced by injection of biotin dextran amine (BDA) into the sensorimotor cortex. RESULTS: There were statistically significant differences in BBB scores in ceftriaxone in comparison to both monocytes receiving and control groups. On the other hand there were statistically significant differences in axon counting in both ceftriaxone and monocytes receiving groups in comparison to control group. CONCLUSION: Our findings suggest that ceftriaxone improves functional recovery more effective than monocytes in rats after SCI. These results are from an experimental model and validation is required for further investigation. PMID- 26236657 TI - Ghrelin Administration Increases the Bax/Bcl-2 Gene Expression Ratio in the Heart of Chronic Hypoxic Rats. AB - PURPOSE: Programmed cell death or apoptosis, is a biochemical procedure that initiates due to some conditions, including hypoxia. Bax and Bcl-2 are among the agents that regulate apoptosis. The amplification of the first one triggers the initiation of apoptosis, and the second one prevents it. Ghrelin is an endogenous peptide that antiapoptosis is its new effect. The aim of this study is to examine the effect of ghrelin on the Bax/Bcl-2 ratio. METHODS: Twenty four wistar rats were divided randomly in three groups; control, hypoxic + saline and hypoxic + ghrelin. Hypoxic animals lived in O2 11% for 2 weeks and received either saline or ghrelin subcutaneously daily. The bax and Bcl-2 gene expression were measured by Real-Time RT-PCR. RESULTS: Chronic hypoxia increased the Bax gene expression significantly compared with normal animals (P = 0.008), but the Bcl-2 was not affected by hypoxia. The Bax/Bcl-2 ratio also amplified significantly (P=0.005). Ghrelin administration significantly increased the Bax/Bcl-2 ratio in the hypoxic animals compared to the hypoxic + saline and normal groups (p=0.042 and P= 0.001, respectively). CONCLUSION: In the present study, animals' treatment with ghrelin leads to an increment of Bax/Bcl-2 ratio, which indicates a controversy related to cardioprotection of ghrelin. PMID- 26236658 TI - Adenovirus-Mediated Over-Expression of Nrf2 Within Mesenchymal Stem Cells (MSCs) Protected Rats Against Acute Kidney Injury. AB - PURPOSE: Recent developments in the field of cell therapy have led to a renewed interest in treatment of acute kidney injury (AKI). However, the early death of transplanted mesenchymal stem cells (MSCs) in stressful microenvironment of a recipient tissue is a major problem with this kind of treatment. The objective of this study was to determine whether overexpression of a cytoprotective factor, nuclear factor erythroid-2 related factor 2 (Nrf2), in MSCs could protect rats against AKI. METHODS: The Nrf2 was overexpressed in MSCs by recombinant adenoviruses, and the MSCs were implanted to rats suffering from cisplatin induced AKI. RESULTS: The obtained results showed that transplantation with the engineered MSCs ameliorates cisplatin-induced AKI. Morphologic features of the investigated kidneys showed that transplantation with the MSCs in which Nrf2 had been overexpressed significantly improved the complications of AKI. CONCLUSION: These findings suggested that the engineered MSCs might be a good candidate to be further evaluated in clinical trials. However, detailed studies must be performed to investigate the possible carcinogenic effect of Nrf2 overexpression. PMID- 26236659 TI - Therapeutic Efficacy of Orally Delivered Doxorubicin Nanoparticles in Rat Tongue Cancer Induced by 4-Nitroquinoline 1-Oxide. AB - PURPOSE: Oral cancer is one of the most significant cancers in the world, and squamous cell carcinoma makes up about 94% of oral malignancies. The aim of the present study was to compare the efficacy of doxorubicin plus methotrexate - loaded nanoparticles on tongue squamous cell carcinoma induced by 4NQO and compare it with the commercial doxorubicin and methotrexate delivered orally on seventy SD male rats. METHODS: 70 rats were divided into five groups. During the study, the animals were weighed by a digital scale once a week. Number of mortalities was recorded in the data collection forms. At the end of the treatment, biopsy samples were taken from rat tongues in order to evaluate the severity of dysplasia and the extent of cell proliferation. The results were analyzed using ANOVA, descriptive statistics and chi-square test. RESULTS: No statistically significant difference was found in the mean weight of five groups (p>0.05). No significant relationship was found between groups and mortality rate (P = 0. 39). In addition, there was a significant relationship between groups and the degree of dysplasia (P <0.001). The statistical analysis showed a significant relationship between groups and the rate of cell proliferation (p <0.001). CONCLUSION: The results of the present study showed that the use of doxorubicin plus methotrexate - loaded nanoparticles orally had more therapeutic effects than commercial doxorubicin plus methotrexate. PMID- 26236660 TI - Evaluating the Anti-nociceptive and Anti-inflammatory Effects of Ketotifen and Fexofenadine in Rats. AB - PURPOSE: As H1 and H3 receptors' roles has been defined in peripheral pains in some papers and because histamine is known for its role in inflammatory responses; this study investigated the possible analgesic and anti-inflammatory effects of ketotifen and fexofenadine as relatively safe long acting anti histamines in both chronic chemical pain and acute inflammation in rats. METHODS: In this study, male Sprague-Dawley rats weighing 225-250 grams were used. In order to evaluate the chemical chronic pain, sub-plantar injection of formalin applied and the pain scores were recorded every 15 seconds during 60 minutes. Carrageenan injection to the right hind paw was used for induction of acute inflammation and the paw edema was measured every 60 minutes for 4 hours. RESULTS: Based on the results, both ketotifen and fexofenadine were able to significantly diminish chemical acute and chronic pain as well as inflammation in comparison with the control group and the effects were acceptable according to the standard treatment. Both effects for fexofenadine started later than those of ketotifen. CONCLUSION: According to the outcomes of the study, ketotifen and fexofenadine demonstrated significant analgesic and anti-inflammatory characteristics in both models of chemical pain and acute inflammation in laboratory animals. PMID- 26236661 TI - Study of the Electrophoretic Behavior of Cephalosporins by Capillary Zone Electrophoresis. AB - PURPOSE: The aim of the study was the characterization of the electrophoretic behavior of cephalosporins from different generation having different structural characteristics in order to develop a rapid, simple and efficient capillary electrophoretic method for their identification and simultaneous separation from complex mixtures. METHODS: Ten cephalosporin derivatives (cefaclor, cefadroxil, cefalexin, cefazolin, cefoxitin, cefuroxime, cefoperazone, cefotaxime, ceftazidime, ceftriaxone) were analyzed by capillary zone electrophoresis using different background electrolyte solutions at different pH values. Electrophoretic mobilities of the analytes were calculated, the influence of the electrophoretic parameteres on the separation was established and the analytical conditions were optimized. RESULTS: Taking into consideration their structural and chemical properties cephalosporins can be detected over a pH range between 6 and 10. The best results were obtained using a buffer solution containing 25 mM disodium hydrogenophosphate - 25 mM sodium dihydrogenophosphate, at a pH - 7.00, + 25 kV voltage at a temperature of 25 degrees C, UV detection at 210 nm. Using the optimized analytical conditions we achieved the simultaneous baseline separation for seven cephalosporins in less then 10 minutes. CONCLUSION: Using the described optimized electrophoretic procedures, capillary electrophoresis can be used for the identification and determination of cephalosporins in formulated pharmaceutical products and for their separation from complex mixtures. PMID- 26236662 TI - Voluntary Exercise Protects Heart from Oxidative Stress in Diabetic Rats. AB - PURPOSE: Oxidative stress plays a key role in the onset and development of diabetes complications. In this study, we evaluated whether voluntary exercise could alleviate oxidative stress in the heart and blood of streptozotocin - induced diabetic rats. METHODS: 28 male Wistar rats were randomly divided into four groups (n=7): control, exercise, diabetes and exercise + diabetes. Diabetes was induced by injection of streptozotocin in male rats. Rats in the trained groups were subjected to voluntary running wheel exercise for 6 weeks. At the end of six weeks blood and heart tissue samples were collected and used for determination of antioxidant enzymes (including SOD, GPX and CAT activities) and MDA level. RESULTS: Exercise significantly reduced MDA levels both in the heart tissue (p<0.01) and blood samples (p<0.05). In addition, exercise significantly increased SOD (p<0.05), GPX (p<0.001) and CAT (p<0.05) in the heart tissue. Voluntary exercise also significantly increased SOD (p<0.01), GPX (p<0.05) and CAT (p<0.001) in the blood. CONCLUSION: Voluntary exercise diminishes the MDA level in blood and heart tissue of diabetic rats. It also accentuates activities of SOD, GPX and CAT. Therefore, it may be considered a useful tool for the reduction of oxidative stress in diabetes. PMID- 26236663 TI - Experimental Design to Predict Process Variables in the Microcrystals of Celecoxib for Dissolution Rate Enhancement Using Response Surface Methodology. AB - PURPOSE: The purpose of the present investigation was to increase the solubility and dissolution rate of celecoxib (CLX) by preparing microcrystals of drug by solvent change precipitation. METHODS: This procedure was optimized in order to obtain stable and homogeneous particles with a small particle size, high yield and fast dissolution rate. CLX agglomerates were prepared with brij35 (stabilizer agent) using acetone as solvent, water as non-solvent, respectively. The agglomerates were characterized by DSC, XRD, FTIR studies. A full-factorial design was employed to study the effect of independent variables, the amounts of stirring rate (X1), volume of organic solvent (X2), volume of aqueous solvent (X3), time of stirring (X4), concentration of Brij (X5), concentration of Tween 80 (X6), concentration of HPMC (X7) on dependent variables, particle size (PS), drug content (DC), drug released after 15 min (Q15), crystal yield (CY), Gibbs free energy change (DeltaG degrees tr), antalpy change (DeltaH) and saturated solubility (Ss). RESULTS: The DSC and FTIR results indicated the absence of any interactions between drug and stabilizers. These studies showed a decrease in crystalinity in agglomerates. The crystals exhibited significantly improved micromeritic properties compared to pure drug. The drug content and crystal yield were in the range of 32.84-48.22% and 64.55-83.33% with all formulations, respectively. The solubility and drug release rates increased with an increase in concentration of stabilizer. CONCLUSION: The results show that microcrystals of the drug in stabilizer considerably enhanced the dissolution rate. PMID- 26236664 TI - Cloning and Stable Expression of cDNA Coding For Platelet Endothelial Cell Adhesion Molecule -1 (PECAM-1, CD31) in NIH-3T3 Cell Line. AB - PURPOSE: PECAM-1 (CD31) is a glycoprotein expressed on endothelial and bone marrow precursor cells. It plays important roles in angiogenesis, maintenance and integration of the cytoskeleton and direction of leukocytes to the site of inflammation. We aimed to clone the cDNA coding for human CD31 from KG1a for further subcloning and expression in NIH-3T3 mouse cell line. METHODS: CD31 cDNA was cloned from KG1a cell line after total RNA extraction and cDNA synthesis. Pfu DNA polymerase-amplified specific band was ligated to pGEMT-easy vector and sub cloned in pCMV6-Neo expression vector. After transfection of NIH-3T3 cells using 3 MUg of recombinant construct and 6 MUl of JetPEI transfection reagent, stable expression was obtained by selection of cells by G418 antibiotic and confirmed by surface flow cytometry. RESULTS: 2235 bp specific band was aligned completely to human CD31 reference sequence in NCBI database. Transient and stable expression of human CD31 on transfected NIH-3T3 mouse fibroblast cells was achieved (23% and 96%, respectively) as shown by flow cytometry. CONCLUSION: Due to murine origin of NIH-3T3 cell line, CD31-expressing NIH-3T3 cells could be useful as immunogen in production of diagnostic monoclonal antibodies against human CD31, with no need for purification of recombinant proteins. PMID- 26236665 TI - Overexpression of Metastatic Related MicroRNAs, Mir-335 and Mir-10b, by Staphylococcal Enterotoxin B in the Metastatic Breast Cancer Cell Line. AB - PURPOSE: One of the advanced cancer therapy strategies is immune-stimulating compound based immunotherapy Staphylococcal enterotoxin B (SEB) is one of the potent superantigens, which can efficiently activate antitumor immune response to eradicate tumor growth and inhibit metastasis. Herein, we evaluated the effect of SEB on the expression of two master microRNAs, mir-335 and mir-10b, involved in metastasis. METHODS: A metastatic breast cancer cell line MDA-MB231was treated with four different concentrations of SEB, including 10, 10(2), 10(3) and 10(4) ng/ml, for 24 and 48 hours. To identify the cytotoxic effect of SEB, treated cells were examined by MTT assay. The stem loop RT-PCR (TaqMan) was used to analyze the mir-335 and mir-10b expression. RESULTS: RESULTS showed that SEB significantly increased the expression of mir-335 both after 24 and 48 hours (pv < 0.001 and pv < 0.05, respectively). No significant differences were found in the mir-10b expression. CONCLUSION: Moreover, our findings demonstrated no cytotoxic effect of SEB on the treated cells. Our results suggest that SEB probably induces its anti-metastatic effect via the expression regulation of the main genes which contributes to metastasis. PMID- 26236666 TI - Increased P-35, EBI3 Transcripts and Other Treg Markers in Peripheral Blood Mononuclear Cells of Breast Cancer Patients with Different clinical Stages. AB - PURPOSE: Currently, cancer as a major problem around the world threatens human health and has a high incidence in developing countries. Many reports have indicated that patients suffering from cancer demonstrate decreased antitumor immune responses as well as a high prevalence of T regulatory population. It has been reported that Foxp3(+)Tregs exert suppression by cell contact-dependent mechanisms which are mediated by soluble factors such as immunosuppressive cytokines like IL-10, TGF-beta and IL-35. Consequently there is a great need to identify prognostic and diagnostic biomarkers of regulatory T cells for vaccine and drug development. METHODS: In this study IL-10, TGF-beta, IL-35 and Foxp3 mRNA gene expression has been measured in peripheral blood of 40 breast cancer patients and 40 normal age-matched women using quantitative real-time PCR (qRT PCR) method with Master Mix reaction containing SYBER Green. GAPDH gene was used as housekeeping gene. RESULTS: Our data demonstrated a significant up-regulation of IL-10, TGF-beta, P35, EBI3 and Foxp3 gene expression in patients' peripheral blood compared to normal healthy controls (p<0.05). CONCLUSION: The data suggests that the immune system is suppressed in breast cancer patients, which may be due to elevated Treg cells population. These results may be useful for diagnostic or therapeutic purposes. However it may require more investigations. PMID- 26236667 TI - Preparation of Poly Acrylic Acid-Poly Acrylamide Composite Nanogels by Radiation Technique. AB - PURPOSE: Nanogel, a nanoparticle prepared from a cross-linked hydrophilic polymer network, has many biomedical applications. A radiation technique has recently been introduced as one of the appropriate methods for the preparation of polymeric nanogels due to its additive-free initiation and easy control procedure. METHODS: We have investigated the formation of nano-sized polymeric gels, based on the radiation-induced inter- and intra-molecular cross-linking of the inter-polymer complex (IPC) of polyacrylamide (PAAm) and polyacrylic acide (PAAc). RESULTS: The results indicated that the prepared polymeric complex composed of PAAm and PAAc was converted into nanogel by irradiation under different doses (1, 3, 5 and 7 kGy). This was due to inter- and intra-molecular cross-linking at the range of 446-930 nm as characterized by the photon correlation spectroscopy method. Increasing the irradiation dose reduced the size of nanoparticles to 3 kGy; however, the higher doses increased the size and size distribution. Scanning electron microscopy images indicated the nanogel formation in the reported size by particle size and showed the microcapsule structure of the prepared nanogels. Biocompatibility of nanogels were assessed and proved by MTT assay. CONCLUSION: It was concluded that low dose irradiation can be successfully applied for nanometre-ranged hydrogel. PMID- 26236668 TI - Triamcinolone Acetonide Oromucoadhesive Paste for Treatment of Aphthous Stomatitis. AB - PURPOSE: The aim of this study was to prepare the optimized oral paste formulation of Triamcinolone acetonide intended to be used in aphtous stomatitis. METHODS: Plastibases were prepared using mineral oil and polyethylene (95:5). Oral paste formulations were prepared with different mixtures of three hydrocolloids solids, including gelatin, pectin and sodium carboxymethylcellulose, with different ratios, as well as Plastibase. Long-term and short-term stability of prepared formulations were studied in the case of color and consistency of pastes. Franz diffusion cell and dialysis membrane were employed for release study. Release data were fitted in the kinetic models to find out the mechanism of drug release. RESULTS: Formulation containing 60% plastibase, 3.3% pectin, 6.6% gelatin and 30% carboxymethylcellulose showed desired durability of adhesion, spreadability and rheology property in healthy volunteers and was compared with reference formulation (Adcortyl((r))) in the case of release profile. Although, optimized formulation and Adcortyl followed the Higuchi and first order release kinetics respectively, optimized formulation showed similar release profile to reference formulation. CONCLUSION: Optimized oral paste formulation of Triamcinolone Acetonide showed similar characteristics with reference formulation and could be used as an effective drug delivery system for the treatment of recurrent aphthous stomatitis. PMID- 26236669 TI - Ghrelin Improves Antioxidant Defense in Blood and Brain in Normobaric Hypoxia in Adult Male Rats. AB - PURPOSE: Hypoxia is one of the important factors in formation of reactive oxygen species (ROS). Ghrelin is a peptide hormone that reduces oxidative stress. However, antioxidant effect of ghrelin on blood and brain in normobaric hypoxia condition has not yet been investigated. METHODS: thirty-two animals were randomly divided into four (n=8) experimental groups: Control (C), ghrelin (Gh), hypoxia (H), hypoxic animals that received ghrelin (H+Gh). Normobaric systemic hypoxia (11% O2) was induced in rats for 48 hours. Effect of ghrelin (80 MUg/kg, i.p) on serum TAC and MDA and brain SOD, CAT, GPx and MDA were assessed. RESULTS: Hypoxia significantly (p<0.001) increased both blood and brain MDA Levels. Ghrelin treatment significantly (p<0.001) decreased blood MDA levels both in control and hypoxia, and brain MDA levels in hypoxia conditions. Brain SOD, CAT and GPx variations were not significant in two days of hypoxia. Ghrelin treatment also could not significantly increase activity of SOD, CAT and GPx in brain. Total antioxidant capacity of serum increased in ghrelin treatment both in control and hypoxic conditions, although it was only significant (p<0.01) in control conditions. CONCLUSION: Our findings showed that administration of ghrelin may be useful in reducing blood and brain oxidative stress in normobaric hypoxia condition. PMID- 26236670 TI - Host-guest Inclusion Complexes between Mitiglinide and the Naturally Occurring Cyclodextrins alpha, beta, and gamma: A Theoretical Approach. AB - PURPOSE: The present study is aimed to study the host-guest inclusion complexation of the naturally occurring cyclodextrins (CDs), namely; (alpha CD,beta-CD, and gamma-CD) with mitiglinide (MIT). METHODS: Host-guest inclusion complexation was simulated using semi-empirical PM3 method. RESULTS: The obtained results clearly indicate that the complexes formed are energetically favored in the presence of gamma-CD (Ecomp = -17.884 kcal/mol) of the optimal configurations of (1:1) MIT/gamma-CD inclusion complexes. Moreover, the results obtained reveal that the formation of more stable MIT/gamma-CD complex compared to MIT/alpha-CD or MIT/beta-CD complexes is primarily due to differences in intermolecular hydrogen bonding. CONCLUSION: The present theoretical results may be informative to scientists who are devoting themselves to developing effective methods for enhancing the drug solubility. PMID- 26236671 TI - Plasma fibrinogen degradation products in oral submucous fibrosis. AB - CONTEXT: Plasma fibrinogen degradation products (FDPs) and oral submucous fibrosis (OSMF). BACKGROUND: OSMF is a chronic, progressive, scarring disease of multifactorial etiology. Areca nut is found to be the main cause of this disease. But it has been found in the routine clinical practice that some individuals with the habit of areca nut chewing may not show any clinical evidence of OSMF, while some individuals without the habit of areca nut chewing are found to have OSMF. So, there must be some other factors associated with OSMF. Recently, plasma FDPs have been identified as an early indicator of disease in OSMF patients. A systematic review of their role would help to elucidate whether there is an association of these FDPs in the pathogenesis of OSMF or not. OBJECTIVE: To review studies reported in the literature elucidating the role of these plasma FDPs in OSMF. MATERIALS AND METHODS: Articles were searched in PubMed; MEDLINE using appropriate key words like "plasma fibrinogen degradation products" and "oral submucous fibrosis." Hand search of journals was also performed. Articles were reviewed and analyzed. RESULTS: The search strategy revealed nine relevant articles which studied the role of these plasma FDPs in the etiopathogenesis of OSMF and further progression of this disease with the increased clinical grades and the risk of carcinoma, but the exact role of these factors is still obscure. CONCLUSION: The data validate the role of plasma FDPs in the etiopathogenesis of OSMF. Studies with a large sample size are still required to evaluate the definite association between these FDPs and OSMF. It has the advantage of being a noninvasive method to evaluate the stage of OSMF patients, instead of using the invasive techniques like biopsy. PMID- 26236673 TI - Efficacy of various combinations of irrigants and medicaments on Candida albican: An in vitro study. AB - OBJECTIVE: To evaluate the efficacy of 3% sodium hypochlorite (NaOCl), 17% ethylenediaminetetraacetic acid (EDTA), calcium hydroxide [Ca (OH)2], and 2% chlorhexidine in various combinations on Candida albicans in root canals for 48 h and 10 days. MATERIALS AND METHODS: In this in vitro study, 95 extracted teeth were instrumented. MTCC 183 strain of C. albicans was introduced into the root canals and after 7 days, the average value of colony forming units (CFUs)/ml was determined in all the roots. Then the teeth were randomly divided into three groups: Group I (n = 15) was the control group and only saline was added to it. In group II (n = 40), 3% NaOCl was used as the irrigant and in group III (n = 40), 3% NaOCl and 17% EDTA were used as irrigants. Groups II and III were further divided into two subgroups (A and B) having 20 teeth each. After irrigation, Ca (OH)2 was placed in subgroup A and 2% chlorhexidine digluconate (CHX) solution in subgroup B of both groups as intracanal medicament. After 48 h, the CFUs/ml was determined in 45 teeth (5 from the control group and 10 from each subgroup). After 10 days, the CFUs/ml was determined in the remaining 50 teeth (10 from the control group and 10 from each subgroup). For statistical analysis, Statistical Package for Social Sciences (SPSS version 15, Chicago IL, USA) was used. RESULTS: A decrease in CFUs/ml of C. albicans was noted in all subgroups at 48 h, but the combination of NaOCl, EDTA, and CHX (group IIIB) was the most effective showing value of 0.095 * 10(5) CFUs/ml. On the 10(th) day, the CFUs/ml of C. albicans was further decreased in all subgroups; but again, subgroup IIIB was the most effective showing a value of 0.025 * 10(5) CFUs/ml. There was statistically significant difference in CFUs/ml of C. albicans at 48 h and on 10(th) day in all study groups. CONCLUSION: The antimicrobial activity of irrigant and intracanal medicament has a positive role in controlling the growth of C. albicans. PMID- 26236672 TI - Zirconia in dental implantology: A review. AB - BACKGROUND: Titanium has been the most popular material of choice for dental implantology over the past few decades. Its properties have been found to be most suitable for the success of implant treatment. But recently, zirconia is slowly emerging as one of the materials which might replace the gold standard of dental implant, i.e., titanium. MATERIALS AND METHODS: Literature was searched to retrieve information about zirconia dental implant and studies were critically analyzed. PubMed database was searched for information about zirconia dental implant regarding mechanical properties, osseointegration, surface roughness, biocompatibility, and soft tissue health around it. The literature search was limited to English language articles published from 1975 to 2015. RESULTS: A total of 45 papers met the inclusion criteria for this review, among the relevant search in the database. CONCLUSION: Literature search showed that some of the properties of zirconia seem to be suitable for making it an ideal dental implant, such as biocompatibility, osseointegration, favourable soft tissue response and aesthetics due to light transmission and its color. At the same time, some studies also point out its drawbacks. It was also found that most of the studies on zirconia dental implants are short-term studies and there is a need for more long-term clinical trials to prove that zirconia is worth enough to replace titanium as a biomaterial in dental implantology. PMID- 26236674 TI - Assessment of the awareness level of dental students toward Middle East Respiratory Syndrome-coronavirus. AB - BACKGROUND: Infection prevention and control measures are critical to prevent the possible spread of Middle East Respiratory Syndrome-coronavirus (MERS-CoV) in healthcare facilities. Therefore, healthcare workers should be aware of all procedures concerning prevention of and protection from MERS-CoV. OBJECTIVE: The aim of this study is to improve the knowledge of the dental students and evaluate their awareness about MERS-CoV. MATERIALS AND METHODS: A questionnaire was made according to MOH information and 200 dental students (Al-Farabi Colleges, Jeddah) were interviewed to evaluate their knowledge about MERS-CoV. RESULTS: More than half of the dental students (54%) interviewed had good knowledge about the etiology, symptoms, and treatment of MERS-CoV. Measurements for infection control and protection were also known (79%). The sources of information for the students were: college (27%), MOH (25%), media (24%), and social community (23%), while 17% of the students interviewed had no idea about it. CONCLUSION: Dental students had good knowledge about MERS-CoV. However, more information still must be provided by MOH and college for the medical staff. PMID- 26236675 TI - Prevalence and characteristics of non-syndromic hypodontia among Turkish orthodontic patient population. AB - BACKGROUND: Hypodontia is often used as a collective term for congenital absence of primary or secondary teeth, although specifically it describes the absence of one to six teeth excluding third molars. The prevalence of hypodontia varies from 0.03 to 10.1% in various populations. MATERIALS AND METHODS: In this retrospective study, we reviewed the records of Turkish orthodontic patients treated between 1994 and 2003. A total of 1236 orthodontic patients (507 girls, 729 boys) were included in this study. The age of the patients ranged from 11 to 20 years. Data were collected and entered into the SPSS 20 program for statistical analysis. The Chi-square test was used to analyze differences in the distribution of hypodontia, sex, and malocclusion type. RESULTS: In the total sample of 1236 patients who were orthodontically treated, hypodontia was found in 82 children, including 45 girls and 37 boys. The prevalence of hypodontia was 7%. Patients with more severe hypodontia showed a tendency to exhibit a class II relationship. The mandibular second premolar were the most commonly missing teeth in 48 girls and 26 boys. CONCLUSION: Hypodontia may lead to some clinical problems including malocclusions, esthetic and functional complaints, and also psychological problems. All cases should be evaluated by an interdisciplinary approach for appropriate treatment choice. Our data emphasize the importance of detailed and careful radiographic examination. This helps in long-term and effective treatment planning according to a child's individual requirements. PMID- 26236676 TI - Effectiveness of supervised oral health maintenance in hearing impaired and mute children- A parallel randomized controlled trial. AB - CONTEXT: Individuals with special needs may have great limitations in oral hygiene performance due to their potential motor, sensory, and intellectual disabilities. Thus, oral health care utilization is low among the disabled people. Hearing disorders affect the general behavior and impair the level of social functioning. OBJECTIVES: The present study was conducted to assess the dental health outcomes following supervised tooth brushing among institutionalized hearing impaired and mute children in Jaipur, Rajasthan. MATERIALS AND METHODS: The study followed a single-blind, parallel, and randomized controlled design. A total of 315 students were divided into three groups of 105 children each. Group A included resident students, who underwent supervised tooth brushing under the supervision of their parents. The non resident students were further divided into two groups: Group B and Group C. Group B children were under the supervision of a caregiver and Group C children were under the supervision of both investigator and caregiver. RESULTS: There was an average reduction in plaque score during the subsequent second follow-up conducted 3 weeks after the start of the study and in the final follow-up conducted at 6 weeks. There was also a marked reduction in the gingival index scores in all the three groups. CONCLUSION: The program of teacher and parent supervised toothbrushing with fluoride toothpaste can be safely targeted to socially deprived communities and can enable a significant reduction in plaque and gingival scores. Thus, an important principle of oral health education is the active involvement of parents and caregivers. PMID- 26236677 TI - Efficacy of antimicrobial property of two commercially available chemomechanical caries removal agents (Carisolv and Papacarie): An ex vivo study. AB - PURPOSE: The purpose of the study is to evaluate the antimicrobial efficacy of Carisolv and Papacarie. There are only a few studies comparing the primary teeth. The objective of this study is to assess the effects of Carisolv and Papacarie on cariogenic flora and to compare them. MATERIALS AND METHODS: Fifteen children aged 4-8 years who had at least two primary molars with broad occlusal cavitated lesions showing brown and softened dentin samples were selected. The selected 30 teeth were randomly divided into two groups of 15 teeth each for Carisolv and Papacarie. Dentin samples of both groups were taken prior to and following caries removal. The total viable count and lactobacilli count were determined and expressed as colony forming units per milliliter. The two methods of caries removal were then compared and the data were statistically analyzed. RESULTS: The data of both agents (groups) were analyzed by Wilcoxon signed-rank test before and after application and showed statistical significance. Inter-comparison of data of both groups was analyzed by Mann-Whitney U test for total viable count and total Lactobacillus count which showed no statistical significance. CONCLUSION: Carisolv and Papacarie have similar antibacterial efficacy against cariogenic flora as chemomechanical caries removal agents. PMID- 26236678 TI - Clinical and radiographic evaluation of periodontal intrabony defects by open flap surgery alone or in combination with Biocollagen((r)) membrane: A randomized clinical trial. AB - BACKGROUND: Guided tissue regeneration (GTR) is often incorporated in regenerative periodontal surgical procedures. However, the actual benefits of adding GTR to such a procedure remain undocumented. The purpose of this randomized controlled trial was to investigate the contribution of GTR to the outcomes of open flap debridement (OFD) in the treatment of intrabony defects. MATERIALS AND METHODS: A total of 16 patients of both sexes satisfying the criteria of chronic periodontitis and each of whom displayed one intrabony defect were randomly assigned to two groups, i.e. either treated with open flap surgery and GTR (group 1) or with open flap surgery alone (group 2), in this parallel-arm study. The soft tissue and hard tissue measurements, including probing pocket depth (PD), clinical attachment level (CAL), and bone mineral density were recorded at baseline and 3,6 and 12 months after surgery. The differences with a P < 0.05 were considered significant. RESULTS: Results showed that the membrane group showed significant difference when compared with open flap surgery alone, in relation to the degree of periodontal pocket, clinical attachment loss, and bone density. CONCLUSION: The findings of this study suggest that biocollagen membrane could be considered as an option in the treatment of intrabony defects. Biocollagen membrane alone gives favorable clinical results in the treatment of intrabony defects. Open flap debridement resulted in acceptable clinical results in the treatment of intrabony defects. PMID- 26236679 TI - Role of yoga and physical activity in work-related musculoskeletal disorders among dentists. AB - BACKGROUND: Work-related musculoskeletal pain is one of the occupational hazards in dentists. AIMS: To find the prevalence and severity of musculoskeletal pain in dentists, to compare musculoskeletal pain among dentists practicing yoga, those practicing physical activities, and those without any physical activity, and also to know the effects of sex, age, and workload on musculoskeletal pain. MATERIALS AND METHODS: A self-reporting work-related questionnaire and the Nordic questionnaire for analysis of musculoskeletal disorders were given to graduated dentists attending Indian dental conference in Mumbai, to know the musculoskeletal pain experienced in the last 12 months and feedback was obtained from 220 dentists. RESULTS: The prevalence of musculoskeletal pain in dentists was 34.5%. Prevalence of musculoskeletal pain was 10.5%, 21.7%, and 45.6% in dentists with regular yoga practice, other physical activity, and no physical activity, respectively. There was statistically significant difference in the prevalence of musculoskeletal pain among dentists who were practicing yoga when compared with those in no regular activity group. CONCLUSION: Within the limitations of the study, there was significant role of physical activity on the quality and quantity of work-related musculoskeletal disorders experienced by dentists. Yoga was found to be more effective than other modes of physical activities. More research is needed on musculoskeletal problems in dentists, with an emphasis on larger sample sizes and correlating other factors like age and sex of the dentists, duration of practice, years of practicing yoga, and working hours per week. PMID- 26236680 TI - Caries experience in the primary dentition and presence of plaque in 7-year-old Chinese children: A 4-year time-lag study. AB - OBJECTIVES: The aim of the present study was to test the hypothesis that dental caries prevalence and caries experience in primary dentitions has increased over 4 years and to compare the presence of plaque on permanent teeth in child cohorts over 4 years. MATERIALS AND METHODS: A time-lag study design was used comprising two cohorts of children aged 7 years from the same five primary schools in Wuhan examined in 2007 and 2011. Two calibrated examiners visually assessed plaque accumulation according to the Greene and Vermillion Index and the dentitions according to the Atraumatic Restorative Treatment (ART) caries criteria. Analysis of variance (ANOVA), logistic regression, and Chi-square test were used to test for differences between dependent and independent variables. RESULTS: The 2007 sample consisted of 817 children and the 2011 sample consisted of 1010 children. The prevalence of dental caries (d3mft) was 68.2% in 2007 and 67.7% in 2011, while that of d2mft was 78.5% in 2007 and 71.4% in 2011 (P < 0.0006). The mean d3mft score was 2.8 in 2007 and 3.1 in 2011 (P = 0.046), while the mean d3mfs score was 4.9 in 2007 and 7.3 in 2011 (P < 0.0001). The d3-component of the d3mft index was 73% in 2007 and 69% in 2011, while the f-component was 22% in 2007 and 26% in 2011. The hypothesis was not accepted. The proportion of children with plaque code 3 (extensive coverage) was higher in 2011 (21.8%) than in age mates in 2007 (5.7%). CONCLUSIONS: There were no obvious signs that dental caries prevalence had been increased in primary dentitions of this child population between 2007 and 2011. But as the mean caries experience scores at the surface level were higher in 2011 than in 2007, monitoring caries prevalence remains essential, but should start at an earlier age than that covered by this study. Health and educational authorities should collaborate in setting up programs aimed at ensuring good oral health for school children. PMID- 26236681 TI - Periodontal health awareness among gynecologists in Riyadh, Saudi Arabia. AB - OBJECTIVE: To determine the knowledge of periodontal disease and pregnancy outcomes among the gynecologists practicing in Riyadh, Saudi Arabia. MATERIALS AND METHODS: A cross-sectional survey of 200 randomly chosen gynecologists from Riyadh was carried out by using a structured, self-administered, closed-ended questionnaire. Knowledge of periodontal disease and possible ways of prevention; knowledge of periodontal disease and pregnancy outcomes; and oral self-care attitudes among gynecologists were assessed. RESULTS: One-quarter of the gynecologists knew the meaning of dental plaque. Almost 57.5% believed that the frequency of toothbrushing should be increased during pregnancy. Eighty percent of gynecologists were aware of the serious effects of smoking on the pregnant woman and her child. Less than half (44.5%) believed that there is a relationship between gum disease and premature labor. Gynecologists working in the government sector were significantly more aware about the causes of inflamed gum in pregnancy, gum disease and its prevention, and negative effects of smoking on pregnancy. A significantly higher percentage of male and senior gynecologists aged between 50 and 54 years answered that gum disease would lead to the delivery of a preterm or low-birth-weight infant. CONCLUSION: Gynecologists considered in the present study showed an acceptable level of knowledge and awareness toward periodontal health and the association between periodontal disease and adverse pregnancy outcomes. PMID- 26236682 TI - Comparing the antiplaque efficacy of 0.5% Camellia sinensis extract, 0.05% sodium fluoride, and 0.2% chlorhexidine gluconate mouthwash in children. AB - BACKGROUND: Dental caries is a multifactorial disease which requires a susceptible host, a cariogenic microflora, and a suitable substrate that must be present for a sufficient length of time. Tea is prepared by the infusion of dried leaves of the tea plant, Camellia sinensis, which contains bioactive compounds like polyphenols, flavonoids, and catechins that are thought to be responsible for the health benefits that have traditionally been attributed to tea. These compounds have multidimensional effects such as antibacterial action, inhibitory action on the bacterial and salivary amylase, and inhibition of acid production. AIMS: The aim of this study is to compare the antiplaque efficacy of 0.5% C. sinensis extract, 0.05% sodium fluoride, and 0.2% chlorhexidine gluconate mouthwash in children. MATERIALS AND METHODS: A randomized blinded controlled trial with 60 healthy children of age group 9-14 years was carried out. The subjects were randomly assigned to three groups, i.e. group A - 0.2% chlorhexidine gluconate, group B - 0.05% sodium fluoride, and group C - 0.5% C. sinensis extract, with 20 subjects per group. Plaque accumulation and gingival condition were recorded using plaque index and gingival index. Oral hygiene was assessed by simplified oral hygiene index (OHIS). Salivary pH was assessed using indikrom pH strips. Plaque, gingival, and simplified OHI scores as well as salivary pH were recorded at baseline, immediately after first rinse, after 1 week, and in the 2(nd) week. STATISTICAL ANALYSIS USED: The data were analyzed using a computer software program (SPSS version 17). Analysis of variance (ANOVA) tests were used to identify significant differences between the means of the study groups. Finally, paired t-tests were used to assess the significance of changes within each group between time periods. Critical P values of significance were set at 0.05 and the confidence level set at 95%. RESULTS: Mean plaque and gingival scores were reduced over the 2-week trial period in the experimental groups. Antiplaque effectiveness was observed in all groups, the highest being in group C (P < 0.05). Chlorhexidine gluconate and tea showed comparative effectiveness on gingiva better than sodium fluoride (P < 0.05). The salivary pH increase was sustained and significant in groups B and C compared to group A. Oral hygiene improvement was better appreciated in groups A and C. CONCLUSIONS: The effectiveness of 0.5% C. sinensis extract was more compared to 0.05% sodium fluoride and 0.2% chlorhexidine gluconate mouth rinses. It should be explored as a cost-effective and safe long-term adjunct to oral self-care of patients as it has prophylactic benefits with minimum side effects. PMID- 26236683 TI - Predictors of dental rehabilitation in children aged 3-12 years. AB - OBJECTIVES: The aim of this study was to evaluate the proportion of completed treatments and to study the factors affecting the full mouth dental rehabilitation in pediatric patients treated by undergraduate students at the College of Dental Medicine Teaching Clinics, University of Sharjah. MATERIALS AND METHODS: A retrospective study was conducted on 270 children aged less than 12 years (mean age 7.6, SD 2.04). Comprehensive dental rehabilitation reports of child patients that were completed by final year dental undergraduate students from the year 2009 to 2011 were reviewed. Data on complete history, oral examination, dental charting, and treatment plan were collected from pediatric dentistry case sheet. Dental caries was charted using WHO 1997 criteria. Dental treatment needs and completion of dental care delivered to children involved in this study were assessed using DMFT/deft scores. RESULTS: Percentages of treatment provided included completed restorations (94%) and space management (84%) in primary dentition, whereas 98% of restoration and 94% of required sealants were completed in permanent dentition. The percentage of completed dental treatment including sealant placement was 61%. Age of the child and the number of decayed teeth present before the start of the treatment significantly correlated with the children in the incomplete treatment category (P < 0.05). CONCLUSIONS: Therefore, a worthy dental care was provided in a holistic approach to the children attending College of Dental Medicine training clinics. Age of the child and the number of decayed teeth were the factors affecting dental rehabilitation in children aged 3-12 years. PMID- 26236684 TI - Pathological evaluation for sterilization of routinely used prosthodontic and endodontic instruments. AB - BACKGROUND: In daily practice of dentistry, we use same instruments on many patients. Before use, all instruments must be cleaned, disinfected, and sterilized to prevent any contamination. Pre-cleaning and sterilization of some devices can be difficult because of their small size and complex architecture. Dental burs and endodontic files are such instruments. Dental burs come in a variety of shapes and sizes, all with highly complex and detailed surface features. AIM: To determine the effectiveness of various disinfectants and sterilization techniques for disinfection and resterilization of dental burs and endodontic files. MATERIALS AND METHODS: The materials used for the study were dental burs and endodontic files. Disinfectants used were Quitanet plus, glutaraldehyde, glass-bead sterilizer, and autoclave. The sterility of used dental burs and endodontic files was analyzed. Burs and files that had been used were pre-cleaned, resterilized, and then tested for various pathogens. Each item was transferred by sterile technique into Todd-Hewitt broth, incubated at 37 degrees C for 72 h, and observed for bacterial growth. RESULTS: The present study shows that the endodontic files and burs sterilized by autoclaving and glutaraldehyde showed complete sterilization. Burs and files immersed in glutaraldehyde (2.4%) for 12 h showed complete sterilization, whereas Quitanet plus solution and glass-bead sterilizer showed incomplete sterilization. CONCLUSION: The present study results indicate that autoclaving and glutaraldehyde (2.4%) showed complete sterilization. Other methods cannot be relied upon for sterilization. PMID- 26236685 TI - Prevalence of undiagnosed HIV infection among dental patients in a Nigerian secondary healthcare facility. AB - OBJECTIVE: To determine the prevalence of undiagnosed HIV infection among patients attending the Dental Clinic of General Hospital Minna, Niger State, Nigeria. MATERIALS AND METHODS: The study was a prospective study of 1080 dental patients of General Hospital Minna. RESULTS: Out of the 1080 patients counseled, only 200 gave consent to participate in the study. Of the 200 participants, 8 tested positive for HIV, giving a prevalence of 4.0%. Females and participants in the sixth and fifth decades of life were found to have higher prevalence of undiagnosed HIV. Corpers and traders had higher prevalence of undiagnosed HIV. Participants with periodontal complaints (bleeding gums and shaking teeth) also had higher prevalence of undiagnosed HIV. The proportion of participants that reported having knowledge about the actual existence, risk factors, and prevention of HIV/AIDS was high. The proportion of participants who expressed willingness to receive more information on HIV-related issues was high. CONCLUSION: One out of 25 patients attending this secondary healthcare setting for dental services had undiagnosed HIV infection. This highlights the need for the establishment of voluntary counseling and testing (VCT) unit in the dental clinics and also re-emphasizes the strict compliance of standard precaution in dental practices. PMID- 26236686 TI - The effect of three polishing systems on surface roughness of flowable, microhybrid, and packable resin composites. AB - OBJECTIVES: The aim of this study was to evaluate the effects of three different polishing systems on the surface roughness of three types of resin composite materials. MATERIALS AND METHODS: Three types of resin composites (Heliomolar flow, TPH spectrum, and Tetric Ceram HB) and three polishing systems (Astropol, Enhance, and Soflex) were used. A total number of 40 samples were prepared from each one of the restorative materials and divided randomly into four groups (n = 10) according to the polishing procedure. The first group underwent no treatment and was used as a control group. Each one of the remaining groups was polished with one of the tested polishing systems. After completion of sample preparation, the mean surface roughness (Ra) value was measured using a surface profilometer. Data were analyzed using one-way analysis of variance (ANOVA). RESULTS: The control group of each material recorded the lowest Ra value. Among the tested polishing systems, the groups finished with Soflex system exhibited the lowest Ra value. Among the resin composites, Heliomolar flow exhibited the lowest Ra value, regardless of the polishing system used. CONCLUSIONS: The smoothest surface of all types of resin composite was achieved under Mylar strip. PMID- 26236687 TI - Evaluation of premalignant and malignant lesions by fluorescent light (VELscope). AB - AIM: The purpose of this study was the early detection of premalignant and malignant oral soft lesions by fluorescent light (VELscope). MATERIALS AND METHODS: A total of 748 patients were evaluated through clinical and fluorescent light analysis of the entire oral cavity. Any lesion that was detected underwent a surgical excision biopsy as the golden standard for the detection of the lesion's histology; then a comparison was made between the results to assure the efficacy of the fluorescent light analysis outcome. RESULTS: About 9.4% of the lesions detected were abnormal lesions and 83.09% had loss of fluorescent light effect. Based on the use of surgical biopsy, the machine had a sensitivity of 74.1% and a specificity of 96.3%. According to the statistical analysis, the P value was much lower than 0.05, so we can conclude that at 95% confidence level, there was significant agreement between VELscope results and biopsy results. Kappa coefficient value was approximately 0.5, which means that the strength of the agreement was medium. CONCLUSION: VELscope can be used as a clinical diagnostic aid in the detection of premalignant and malignant lesions of the oral cavity. In addition, it helps in the detection of the borders in both surgical biopsy and surgical excision. PMID- 26236688 TI - Spontaneous Transformation of Murine Oviductal Epithelial Cells: A Model System to Investigate the Onset of Fallopian-Derived Tumors. AB - High-grade serous carcinoma (HGSC) is the most lethal ovarian cancer histotype. The fallopian tube secretory epithelial cells (FTSECs) are a proposed progenitor cell type. Genetically altered FTSECs form tumors in mice; however, a spontaneous HGSC model has not been described. Apart from a subpopulation of genetically predisposed women, most women develop ovarian cancer spontaneously, which is associated with aging and lifetime ovulations. A murine oviductal cell line (MOE(LOW)) was developed and continuously passaged in culture to mimic cellular aging (MOE(HIGH)). The MOE(HIGH) cellular model exhibited a loss of acetylated tubulin consistent with an outgrowth of secretory epithelial cells in culture. MOE(HIGH) cells proliferated significantly faster than MOE(LOW), and the MOE(HIGH) cells produced more 2D foci and 3D soft agar colonies as compared to MOE(LOW) MOE(HIGH) were xenografted into athymic female nude mice both in the subcutaneous and the intraperitoneal compartments. Only the subcutaneous grafts formed tumors that were negative for cytokeratin, but positive for oviductal markers, such as oviductal glycoprotein 1 and Pax8. These tumors were considered to be poorly differentiated carcinoma. The differential molecular profiles between MOE(HIGH) and MOE(LOW) were determined using RNA-Seq and confirmed by protein expression to uncover pathways important in transformation, like the p53 pathway, the FOXM1 pathway, WNT signaling, and splicing. MOE(HIGH) had enhanced protein expression of c-myc, Cyclin E, p53, and FOXM1 with reduced expression of p21. MOE(HIGH) were also less sensitive to cisplatin and DMBA, which induce lesions typically repaired by base-excision repair. A model of spontaneous tumorogenesis was generated starting with normal oviductal cells. Their transition to cancer involved alterations in pathways associated with high-grade serous cancer in humans. PMID- 26236689 TI - In vivo Effects in Melanoma of ROCK Inhibition-Induced FasL Overexpression. AB - Ectopic Fas-ligand (FasL) expression in tumor cells is responsible for both tumor escape through tumor counterattack of Fas-positive infiltrating lymphocytes and tumor rejection though inflammatory and immune responses. We have previously shown that RhoA GTPase and its effector ROCK negatively control FasL membrane expression in murine melanoma B16F10 cells. In this study, we found that B16F10 treatment with the ROCK inhibitor H1152 reduced melanoma development in vivo through FasL membrane overexpression. Although H1152 treatment did not reduce tumor growth in vitro, pretreatment of tumor cells with this inhibitor delayed tumor appearance, and slowed tumor growth in C57BL/6 immunocompetent mice. Thanks to the use of mice-bearing mutated Fas receptors (B6/lpr), we found that reduced tumor growth, observed in immunocompetent mice, was linked to FasL overexpression induced by H1152 treatment. Tumor growth analysis in immunosuppressed NUDE and IFN-gamma-KO mice highlighted major roles for T lymphocytes and IFN-gamma in the H1152-induced tumor growth reduction. Histological analyses of subcutaneous tumors, obtained from untreated versus H1152-treated B16F10 cells, showed that H1152 pretreatment induced a strong intratumoral infiltration of leukocytes. Cytofluorometric analysis showed that among these leukocytes, the number of activated CD8 lymphocytes was increased. Moreover, their antibody-induced depletion highlighted their main responsibility in tumor growth reduction. Subcutaneous tumor growth was also reduced by repeated intravenous injections of a clinical ROCK inhibitor, Fasudil. Finally, H1152-induced ROCK inhibition also reduced pulmonary metastasis implantation independently of T cell-mediated immune response. Altogether, our data suggest that ROCK inhibitors could become interesting pharmacological molecules for melanoma immunotherapy. PMID- 26236691 TI - Combination Therapies to Inhibit the RAF/MEK/ERK Pathway in Melanoma: We are not Done Yet. PMID- 26236690 TI - Cross-Talk between Adiponectin and IGF-IR in Breast Cancer. AB - Obesity is a chronic and multifactorial disorder that is reaching epidemic proportions. It is characterized by an enlarged mass of adipose tissue caused by a combination of size increase of preexisting adipocytes (hypertrophy) and de novo adipocyte differentiation (hyperplasia). Obesity is related to many metabolic disorders like hypertension, type 2 diabetes, metabolic syndrome, and cardiovascular disease, and it is associated with an increased risk of cancer development in different tissues including breast. Adipose tissue is now regarded as not just a storage reservoir for excess energy, but rather as an endocrine organ, secreting a large number of bioactive molecules called adipokines. Among these, adiponectin represents the most abundant adipose tissue-excreted protein, which exhibits insulin sensitizing, anti-inflammatory, and antiatherogenic properties. The serum concentrations of adiponectin are inversely correlated with body mass index. Recently, low levels of plasma adiponectin have been associated with an increased risk for obesity-related cancers and development of more aggressive phenotype, concomitantly with alterations in the bioavailability of insulin-like growth factor-I (IGF-I) and IGF-I receptor (IGF-IR) signaling pathways. In this review, we discuss the cross-talk between adiponectin/AdipoR1 and IGF-I/IGF-IR in breast cancer. PMID- 26236693 TI - Clinical significance of single-port laparoscopic splenectomy: comparison of single-port and multiport laparoscopic procedure. AB - PURPOSE: Single-port laparoscopic splenectomy has been performed sporadically. The aim of this study is to assess our experience with single-port laparoscopic splenectomy compared to conventional multiport laparoscopic surgery for the usual treatment modality for various kinds of splenic disease. METHODS: Between October 2008 to February 2014, 29 patients underwent single-port laparoscopic splenectomy and 32 patients received multiport laparoscopic splenectomy. We retrospectively analyzed the clinical outcomes of single-port group and multiport group. RESULTS: The body mass index and disease profiles of the both groups were similar. The operative times of single-port and multiport group were 113.6 +/- 39.9 and 95.9 +/- 38.9 minutes, respectively (P = 0.946). The operative blood loss of the two groups were 295.8 +/- 301.3 and 322.5 +/- 254.5 mL (P = 0.582). Postoperative retrieved splenic weight of the single-port and multiport groups were 283.9 +/- 300.7 and 362.3 +/- 471.8 g, respectively (P = 0.261). One single-port partial splenectomy and 6 multiport partial splenectomies were performed in this study. There was one intraoperative gastric wall injury. It occurred in single-port group, which was successfully managed during the operation. Each case was converted to laparotomy in both groups due to bleeding. There was one mortality case in the multiport laparoscopic splenectomy group, which was not related to the splenectomy. Mean hospital stay of the single-port and multiport group was 5.8 +/- 2.5 and 7.3 +/- 5.2 days respectively (P = 0.140). CONCLUSION: Single port laparoscopic splenectomy seems to be a feasible approach for various kinds of splenic disease compared to multiport laparoscopic surgery. PMID- 26236692 TI - Production of poly(3-hydroxybutyrate) by Halomonas boliviensis in an air-lift reactor. AB - BACKGROUND: Microbial polyesters, also known as polyhydroxyalkanoates (PHAs), closely resemble physical and mechanical features of petroleum derived plastics. Recombinant Escherichia coli strains are being used in industrial production of PHAs in Stirred Tank Bioreactors (STRs). However, use of Air-Lift Reactors (ALRs) has been known to offer numerous technical operating options over STRs, and as such has been successfully implemented in many bioprocesses. Halomonas boliviensis is a halophilic bacterium that is known to assimilate various carbohydrates and convert them into a particular type of PHA known as poly(3 hydroxybutyrate) (PHB). Owing to this capability, it has been used to synthesize the polyester using hydrolysates of starch or wheat bran in stirred tank bioreactors. RESULTS: This research article firstly describes the production of PHB in shake flasks by H. boliviensis using different combinations of carbohydrates and partially hydrolyzed starch as carbon sources. The highest PHB yields, between 56 and 61 % (wt.), were achieved when either starch hydrolysate or a mixture of glucose and xylose were used as carbon sources. The starch hydrolysate obtained in this study was then used as carbon source in an ALR. The largest amount of PHB, 41 % (wt.), was attained after 24 hrs of cultivation during which maltose in the hydrolysate was assimilated more rapidly than glucose during active cell growth; however, the rate of assimilation of both the carbohydrates was found to be similar during synthesis of PHB. An incomplete pentose phosphate pathway, which lacks 6-phosphogluconate dehydrogenase, was deduced from the genome sequence of this bacterium and may result in the characteristic assimilation of glucose and maltose by the cells. CONCLUSIONS: This study showed that the production of PHB by H. boliviensis using cheap substrates such as starch hydrolysate in a simple production system involving an ALR is feasible. Both maltose and glucose in the hydrolysate induce cell growth and PHB synthesis; most likely the cells balance adequately CoA and NAD(P)H during the assimilation of these carbohydrates. The combination of cheap substrates, simple production systems and the use of non-strict sterile conditions by the halophile H. boliviensis are desirable traits for large scale production of PHB, and should lead to a competitive bioprocess. PMID- 26236694 TI - The effects of the end-to-side inverted mattress pancreaticojejunostomy on postoperative pancreatic fistula: a single surgeon's experience. AB - PURPOSE: Various pancreaticojejunostomy (PJ) techniques have been devised to minimize the rate of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD). This study describes a modification of the mattress suture PJ technique, which we call "inverted mattress PJ (IM)". The results of an IM group and a historical consecutive control group were compared to determine how the IM technique affected POPF. METHODS: From 2003 to 2010, 186 consecutive patients underwent PD. A former group of 52 consecutive patients who underwent conventional duct-to-mucosa PJ (DM) was used as a historical control group. The IM technique was utilized for the IM group (134 patients). The clinicopathological features and surgical outcomes of the 2 groups were compared, with a particular focus on postoperative POPFs. RESULTS: The average surgery duration was shorter in the IM group (580.3 minutes vs. 471 minutes, P < 0.001). Grades B and C POPFs occurred less frequently in the IM group, but the difference was not statistically significant (17.3% vs. 9.7%, P = 0.200). However, no grade C POPF occurred in the IM group compared with 5.8% of grade C POPFs (3/52) in the DM group (P = 0.020). Three patients died (1 in the DM group and 2 in the IM group). The causes of death were arrhythmia in 2 cases and Candida sepsis in 1 case. POPF was not causally related to the 3 deaths. CONCLUSION: IM end-to-side PJ shortened operation time and increased safety with no incidence of grade C POPF. PMID- 26236695 TI - The safety and efficacy of percutaneous transhepatic gallbladder drainage in elderly patients with acute cholecystitis before laparoscopic cholecystectomy. AB - PURPOSE: Laparoscopic cholecystectomy (LC) is the standard management for acute cholecystitis. Percutaneous transhepatic gallbladder drainage (PTGBD) may be an alternative interim strategy before surgery in elderly patients with comorbidities. This study was designed to evaluate the safety and efficacy of PTGBD for elderly patients (>60 years) with acute cholecystitis. METHODS: We reviewed consecutive patients diagnosed with acute cholecystitis between January 2009 and December 2013. Group I included patients who underwent PTGBD, and patients of group II did not undergo PTGBD before LC. RESULTS: All 116 patients (72.7 +/- 7.1 years) were analyzed. The preoperative details of group I (n = 39) and group II (n = 77) were not significantly different. There was no significant difference in operative time (P = 0.057) and intraoperative estimated blood loss (P = 0.291). The rate of conversion to open operation of group I was significantly lower than that of group II (12.8% vs. 32.5%, P < 0.050). No significant difference of postoperative morbidity was found between the two groups (25.6% vs. 26.0%, P = 0.969). In addition, perioperative mortality was not significantly different. Preoperative hospital stay of group I was significantly longer than that of group II (10.3 +/- 5.7 days vs. 4.4 +/- 2.8 days, P < 0.050). However, two groups were not significantly different in total hospital stay (16.3 +/- 9.0 days vs. 13.4 +/- 6.5 days, P = 0.074). CONCLUSION: PTGBD is a proper preoperative management before LC for elderly patients with acute cholecystitis. PMID- 26236696 TI - Association between genetic polymorphisms in cortactin and susceptibility to gastric cancer. AB - PURPOSE: Overexpression of cortactin (CTTN) in human tumors has been proposed to result in increased cell migration and metastatic potential. Here, we determined the frequencies of CTTN g.-9101C>T, g.-8748C>T, and g.72C>T polymorphisms in apparently healthy subjects and gastric cancer patients, respectively, and the influence of the CTTN polymorphisms on gastric cancer susceptibility. METHODS: Blood samples were collected from 267 patients and 533 controls. CTTN g.-8748C>T and g.-9101C>T polymorphisms were determined using polymerase chain reaction restriction fragment length polymorphism; the g.72C>T polymorphism was determined using the TaqMan method. RESULTS: Genotype frequencies of the CTTN g.-9101C>T polymorphism were 97.5% (TT), 2.5% (TC), and 0% (CC) in the patient group, and 98.6% (TT), 1.4% (TC), and 0% (CC) in the control group. Genotype frequencies of the CTTN g.-8748C>T polymorphism were 93.3% (TT), 6.8% (TC), and 0% (CC) in the patient group, and 94.2% (TT), 5.8% (TC), and 0% (CC) in the control group. Genotype frequencies of the CTTN g.72C>T polymorphism were 82.4% (CC), 17.2% (CT), and 0.4% (TT) in the patient group, and 78.0% (CC), 20.1% (CT), and 1.9% (TT) in the control group. Genotype and allele frequencies of the CTTN g.-9101C>T polymorphism differed significantly between the advanced gastric cancer and control groups. Patients with advanced gastric cancer, possessing the TC genotype, had a significantly poorer prognosis than the group with the TT genotype. CONCLUSION: The CTTN g.-9101C>T polymorphism might influence advanced gastric cancer susceptibility. However, the role of the CTTN g.-9101C>T, g. 8748C>T, and g.72C>T polymorphisms requires careful interpretation and confirmation through larger studies. PMID- 26236697 TI - Preoperative neutrophil-to-lymphocyte ratio is a prognostic factor for overall survival in patients with gastric cancer. AB - PURPOSE: Preoperative neutrophil-to-lymphocyte ratio (NLR) reflects patients' inflammation status, clinical stage, and survival in various malignancies. However, only a limited amount of information on the clinical importance and prognostic significance of NLR in gastric cancer has been reported. The objective of this study is to assess the prognostic values of preoperative NLR in patients with gastric cancer. METHODS: During the period between August 1, 2005 and December 31, 2011, we collected data from 601 patients among those who had undergone surgery for gastric cancer at the Department of Surgery, Konkuk University Medical Center. We classified the subjects into high NLR (NLR >= 1.7) group and low NLR (NLR < 1.7) group. RESULTS: The gender, age, and American Society of Anesthesiologists (ASA) score did not differ in the two NLR groups. The pathologic features (tumor size, histology, number of examined lymph node, T stage, N stage, and TNM stage) did not differ either, except for tumor location (P = 0.006). Multivariate analysis identified TNM stage, NLR, and age as significant prognostic factors. Gender, tumor size, location, and histology did not show their prognostic significance when we applied the Cox proportional hazard model. CONCLUSION: Our study verified that advanced stage, high preoperative NLR (NLR >= 1.7), and old age (>= 70 years) are significant, independent prognostic factor for overall survival in patients with gastric cancer. PMID- 26236698 TI - The repair of umbilical hernia in cirrhotic patients: 18 consecutive case series in a single institute. AB - PURPOSE: Traditionally, the surgical repair of umbilical hernia in cirrhotic patients with ascites is avoided because of a significant recurrence rate and perioperative morbidity/mortality. However, recent reports recommend early elective surgery in these patients because surgery-related complications can be reduced with minimally invasive surgery and development of perioperative patient care. The current study was conducted to analyze safety and feasibility of umbilical hernia repairs performed in a single institute. METHODS: A single center retrospective analysis of patients' data was conducted. Eighteen patients with umbilical hernia accompanied by liver cirrhosis underwent hernia repair in the period between 2005 and 2012. The charts of these patients were reviewed and demographic data, postoperative complications, and recurrence were recorded. RESULTS: Eleven males and seven females with a mean age of 62.9 years were analyzed. Two of the patients were classified as Child's class A, 11 as Child's class B, and five as Child's class C. Four patients underwent emergency surgery because of perforations in the hernia sac in two cases and incarcerated hernias in the other two cases. Of the 18 patients who underwent surgery, four (22%) experienced a recurrence, three (17%) developed edema at the surgical sites, one (5%) experienced hepatic coma, and one (5%) showed postoperative variceal hemorrhage. All of these events occurred after emergency surgery. CONCLUSION: In contrast to traditional concepts, early and elective repair of umbilical hernia can be performed easily and safely in cirrhotic patients. PMID- 26236699 TI - YouTube as a potential training method for laparoscopic cholecystectomy. AB - PURPOSE: The purpose of this study was to analyze the educational quality of laparoscopic cholecystectomy (LC) videos accessible on YouTube, one of the most important sources of internet-based medical information. METHODS: The keyword 'laparoscopic cholecystectomy' was used to search on YouTube and the first 100 videos were analyzed. Among them, 27 videos were excluded and 73 videos were included in the study. An arbitrary score system for video quality, devised from existing LC guidelines, were used to evaluate the quality of the videos. Video demographics were analyzed by the quality and source of the video. Correlation analysis was performed. RESULTS: When analyzed by video quality, 11 (15.1%) were evaluated as 'good', 40 (54.8%) were 'moderate', and 22 (30.1%) were 'poor', and there were no differences in length, views per day, or number of likes, dislikes, and comments. When analyzed by source, 27 (37.0%) were uploaded by primary centers, 20 (27.4%) by secondary centers, 15 (20.5%) by tertiary centers, 5 (6.8%) by academic institutions, and 6 (8.2%) by commercial institutions. The mean score of the tertiary center group (6.0 +/- 2.0) was significantly higher than the secondary center group (3.9 +/- 1.4, P = 0.001). The video score had no correlation with views per day or number of likes. CONCLUSION: Many LC videos are accessible on YouTube with varying quality. Videos uploaded by tertiary centers showed the highest educational value. This discrepancy in video quality was not recognized by viewers. More videos with higher quality need to be uploaded, and an active filtering process is necessary. PMID- 26236700 TI - Primary hepatic tuberculosis mimicking intrahepatic cholangiocarcinoma: report of two cases. AB - Hepatic tuberculosis (TB) is usually associated with pulmonary or miliary TB, but primary hepatic TB is very uncommon even in countries with high prevalence of TB. The clinical manifestation of primary hepatic TB is atypical and imaging modalities are unhelpful for differential diagnosis of the liver mass. Image guided needle biopsy is the best diagnostic method for primary hepatic TB. In the cases presented here, we did not perform liver biopsy because we believed the liver masses were cholangiocarcinoma, but primary hepatic TB was ultimately confirmed by postoperative pathology. Here we report two cases of patients who were diagnosed with primary hepatic TB mimicking mass-forming intrahepatic cholangiocarcinoma. PMID- 26236701 TI - Necrotizing fasciitis of the breast in a pregnant woman successfully treated using negative-pressure wound therapy. AB - Necrotizing fasciitis (NF) is a rare and rapidly progressive disease involving the skin, subcutaneous tissue, and deep soft tissue. Although NF can occur any part of the body, the breast is an uncommon primary site for NF, and its occurrence in the breast during pregnancy has never previously been reported. Here, we report the case of a healthy 31-year-old pregnant woman who presented with NF of the left breast that was successfully treated with breast-conserving debridement and secondary wound closure using negative-pressure wound therapy. PMID- 26236702 TI - Endovascular aortic aneurysm repair using a bifurcated stent graft in a patient with femoro-femoral bypass. AB - A challenging iliac anatomy remains a major obstacle to successful endovascular aortic aneurysm repair. The authors experienced an abdominal aortic aneurysm with bilateral common iliac artery aneurysms in a patient that had undergone femoro femoral bypass due to left external iliac artery (EIA) occlusion. To treat this patient in a totally endovascular manner, a bifurcated stent graft was used. One iliac limb was deployed in the right internal iliac artery (IIA) and the other in the right EIA; the left IIA was embolized with coils. Here, the authors describe the procedure used and provide technical tips. PMID- 26236703 TI - Quantitative Evaluation of the Community Research Fellows Training Program. AB - CONTEXT: The community research fellows training (CRFT) program is a community based participatory research (CBPR) initiative for the St. Louis area. This 15 week program, based on a Master in Public Health curriculum, was implemented by the Division of Public Health Sciences at Washington University School of Medicine and the Siteman Cancer Center. OBJECTIVES: We measure the knowledge gained by participants and evaluate participant and faculty satisfaction of the CRFT program both in terms of meeting learning objectives and actively engaging the community in the research process. PARTICIPANTS: We conducted analyses on 44 community members who participated in the CRFT program and completed the baseline and follow-up knowledge assessments. MAIN OUTCOME MEASURES: Knowledge gain is measured by a baseline and follow-up assessment given at the first and final session. Additionally, pre- and post-tests are given after the first 12 sessions. To measure satisfaction, program evaluations are completed by both the participants and faculty after each topic. Mid-way through the program, a mid term evaluation was administered to assess the program's community engagement. We analyzed the results from the assessments, pre- and post-tests, and evaluations. RESULTS: The CRFT participants' knowledge increased at follow-up as compared with baseline on average by a 16.5 point difference (p < 0.0001). Post-test scores were higher than pre-test scores for 11 of the 12 sessions. Both participants and faculty enjoyed the training and rated all session well. CONCLUSION: The CRFT program was successful in increasing community knowledge, participant satisfaction, and faculty satisfaction. This success has enhanced the infrastructure for CBPR as well as led to CBPR pilot projects that address health disparities in the St. Louis Greater Metropolitan Area. PMID- 26236704 TI - Prevalence and Correlates for Psychosocial Distress Among In-School Adolescents in Zambia. AB - There is scanty information on correlates for psychosocial distress in Zambia. Secondary analysis was conducted using the data collected in 2004 in Zambia during the global school-based health survey to determine the prevalence and correlates for psychosocial distress. Logistic regression analyses were used to estimate magnitudes of associations between exposure factors and the outcome, while the Yates' corrected Chi-squared test was used to compare proportions at the 5% significance level. A total of 2257 students participated in the survey of which 54.2% were males. Males were generally older than females (p < 0.001). Significantly, more females than males were bullied (p = 0.036), involved in a fight (p = 0.019), and consumed alcohol (p = 0.012). Psychosocial distress was detected in 15.7% of the participants (14.4% of males and 16.8% of females). Age <14 years, male gender, parental support for males, and having close friends were protective factors against psychosocial distress. Risk factors for psychosocial distress were being bullied, involvement in a fight, alcohol consumption, being physically active, and parental support. The prevalence of psychosocial distress among adolescents in Zambia appears to be common. There is a need to validate the psychosocial distress indicators that were used in the current study. PMID- 26236705 TI - Does the Implementation of Official User Charges Help to Eradicate Informal Payments - Lessons to be Learnt from the Hungarian Experience. PMID- 26236707 TI - The Feasibility of Using Acoustic Markers of Speech for Optimizing Patient Outcomes during Randomized Amplitude Variation in Deep Brain Stimulation: A Proof of Principle Methods Study. AB - BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for reducing symptoms of tremor. A common and typically subjectively determined adverse effect of DBS is dysarthria. Current assessment protocols are driven by the qualitative judgments of treating clinicians and lack the sensitivity and objectivity required to optimize patient outcomes where multiple stimulation parameters are trialed. OBJECTIVE: To examine the effect of DBS on speech in patients receiving stimulation to the posterior sub-thalamic area (PSA) via randomized manipulation of amplitude parameters. METHODS: Six patients diagnosed with tremor receiving treatment via DBS of the PSA were assessed in a double-blinded, within-subjects experimental protocol. Amplitude (i.e., voltage or current) was randomly adjusted across 10 settings, while speech samples (e.g., sustained vowel, counting to 10) were recorded to identify the patient-specific settings required for optimal therapeutic benefit (reduced tremor) with minimal adverse effects (altered speech). Speech production between stimulation parameters was quantified using acoustic analysis. RESULTS: Speech changed as a response to DBS but those changes were not uniform across patients nor were they generally in line with changes in amplitude with the exception of reduced vocal control and increased mean silence length in two patients. Speech outcomes did not correlate with changes in tremor. CONCLUSION: Intra-individual changes in speech were detected as a response to modified amplitude; however, no clear pattern was observed across patients as a group. The use of objective acoustic measures allows for quantification of speech changes during DBS optimization protocols, even when those changes are subtle and potentially difficult to detect perceptually. PMID- 26236706 TI - Understanding DNA under oxidative stress and sensitization: the role of molecular modeling. AB - DNA is constantly exposed to damaging threats coming from oxidative stress, i.e., from the presence of free radicals and reactive oxygen species. Sensitization from exogenous and endogenous compounds that strongly enhance the frequency of light-induced lesions also plays an important role. The experimental determination of DNA lesions, though a difficult subject, is somehow well established and allows to elucidate even extremely rare DNA lesions. In parallel, molecular modeling has become fundamental to clearly understand the fine mechanisms related to DNA defects induction. Indeed, it offers an unprecedented possibility to get access to an atomistic or even electronic resolution. Ab initio molecular dynamics may also describe the time-evolution of the molecular system and its reactivity. Yet the modeling of DNA (photo-)reactions does necessitate elaborate multi-scale methodologies to tackle a damage induction reactivity that takes place in a complex environment. The double-stranded DNA environment is first characterized by a very high flexibility, but also a strongly inhomogeneous electrostatic embedding. Additionally, one aims at capturing more subtle effects, such as the sequence selectivity which is of critical important for DNA damage. The structure and dynamics of the DNA/sensitizers complexes, as well as the photo-induced electron- and energy transfer phenomena taking place upon sensitization, should be carefully modeled. Finally the factors inducing different repair ratios for different lesions should also be rationalized. In this review we will critically analyze the different computational strategies used to model DNA lesions. A clear picture of the complex interplay between reactivity and structural factors will be sketched. The use of proper multi-scale modeling leads to the in-depth comprehension of DNA lesions mechanisms and also to the rational design of new chemo-therapeutic agents. PMID- 26236709 TI - Ovarian Drilling in PCOS: Is it Really Useful? AB - Polycystic ovary syndrome (PCOS) is a frequent disorder, affecting approximately 5-10% of infertile women. It can represent more than 80% of cases of infertility due to anovulation. The main goal of treatment is the induction of mono-ovulatory cycles. A pragmatic management of infertility in PCOS will allow most patients to conceive. Weight loss and clomiphene citrate (CC) are the first-line components of patients treatment before gonadotrophins are used. However, during gonadotrophin administration, there is a high risk of ovarian hyper-stimulation and multiple pregnancies. So, surgery with laparoscopic ovarian drilling is often used before gonadotrophins in order to obtain normal ovulatory cycles. PMID- 26236708 TI - Depot-Based Delivery Systems for Pro-Angiogenic Peptides: A Review. AB - Insufficient vascularization currently limits the size and complexity for all tissue engineering approaches. Additionally, increasing or re-initiating blood flow is the first step toward restoration of ischemic tissue homeostasis. However, no FDA-approved pro-angiogenic treatments exist, despite the many pre clinical approaches that have been developed. The relatively small size of peptides gives advantages over protein-based treatments, specifically with respect to synthesis and stability. While many pro-angiogenic peptides have been identified and shown promising results in vitro and in vivo, the majority of biomaterials developed for pro-angiogenic drug delivery focus on protein delivery. This narrow focus limits pro-angiogenic therapeutics as peptides, similar to proteins, suffer from poor pharmacokinetics in vivo, necessitating the development of controlled release systems. This review discusses pro-angiogenic peptides and the biomaterials delivery systems that have been developed, or that could easily be adapted for peptide delivery, with a particular focus on depot based delivery systems. PMID- 26236710 TI - Cellular Mechanisms of Drosophila Heart Morphogenesis. AB - Many of the major discoveries in the fields of genetics and developmental biology have been made using the fruit fly, Drosophila melanogaster. With regard to heart development, the conserved network of core cardiac transcription factors that underlies cardiogenesis has been studied in great detail in the fly, and the importance of several signaling pathways that regulate heart morphogenesis, such as Slit/Robo, was first shown in the fly model. Recent technological advances have led to a large increase in the genomic data available from patients with congenital heart disease (CHD). This has highlighted a number of candidate genes and gene networks that are potentially involved in CHD. To validate genes and genetic interactions among candidate CHD-causing alleles and to better understand heart formation in general are major tasks. The specific limitations of the various cardiac model systems currently employed (mammalian and fish models) provide a niche for the fly model, despite its evolutionary distance to vertebrates and humans. Here, we review recent advances made using the Drosophila embryo that identify factors relevant for heart formation. These underline how this model organism still is invaluable for a better understanding of CHD. PMID- 26236711 TI - Comparative Genomics Revealed Genetic Diversity and Species/Strain-Level Differences in Carbohydrate Metabolism of Three Probiotic Bifidobacterial Species. AB - Strains of Bifidobacterium longum, Bifidobacterium breve, and Bifidobacterium animalis are widely used as probiotics in the food industry. Although numerous studies have revealed the properties and functionality of these strains, it is uncertain whether these characteristics are species common or strain specific. To address this issue, we performed a comparative genomic analysis of 49 strains belonging to these three bifidobacterial species to describe their genetic diversity and to evaluate species-level differences. There were 166 common clusters between strains of B. breve and B. longum, whereas there were nine common clusters between strains of B. animalis and B. longum and four common clusters between strains of B. animalis and B. breve. Further analysis focused on carbohydrate metabolism revealed the existence of certain strain-dependent genes, such as those encoding enzymes for host glycan utilisation or certain membrane transporters, and many genes commonly distributed at the species level, as was previously reported in studies with limited strains. As B. longum and B. breve are human-residential bifidobacteria (HRB), whereas B. animalis is a non-HRB species, several of the differences in these species' gene distributions might be the result of their adaptations to the nutrient environment. This information may aid both in selecting probiotic candidates and in understanding their potential function as probiotics. PMID- 26236712 TI - Regadenoson-Stress Dynamic Myocardial Perfusion Improves Diagnostic Performance of CT Angiography in Assessment of Intermediate Coronary Artery Stenosis in Asymptomatic Patients. AB - The prospective study included 54 asymptomatic high-risk patients who underwent coronary CT angiography (CTA) and regadenoson-induced stress CT perfusion (rsCTP). Diagnostic accuracy of significant stenosis (>=50%) determination was evaluated for CTA alone and CTA + rsCTP in 27 patients referred to ICA due to the positive rsCTP findings. Combined evaluation of CTA + rsCTP had higher diagnostic accuracy over CTA alone (per-segment: specificity 96 versus 68%, p = 0.002; per vessel: specificity 95 versus 75%, p = 0.012) and high overruling rate of rsCTP was proved in intermediate stenosis (40-70%). Results demonstrate a significant additional value of rsCTP in the assessment of intermediate coronary artery stenosis found with CTA. PMID- 26236713 TI - Environmental Enrichment Attenuated Sevoflurane-Induced Neurotoxicity through the PPAR-gamma Signaling Pathway. AB - Sevoflurane is the most widely used inhaled anesthetic. Environmental enrichment (EE) can reverse sevoflurane-induced learning and memory impairment in young mice. However, the mechanism by which EE elicits this effect is unclear. The peroxisome proliferator-activated receptor (PPAR) regulatory pathway plays a critical role in the regulation of inflammation in central nervous system diseases. In this study, we investigated whether EE attenuates sevoflurane induced learning and memory disability via the PPAR signaling pathway. Six-day old mice were treated with 3% sevoflurane for 2 hours daily from postnatal day 6 (P6) to P8. Then, the mice were treated with EE. The effects of sevoflurane on learning and memory function, PPAR-gamma expression in the brain, and the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and 5-bromodeoxyuridine-positive cells in the hippocampus were determined. Sevoflurane induced neuronal apoptosis and neurogenesis inhibition, which may impair learning and memory in young mice. Furthermore, sevoflurane downregulated PPAR-gamma expression. Both EE and the PPAR-gamma agonist, rosiglitazone, attenuated sevoflurane-induced neuronal apoptosis, neurogenesis inhibition, and learning and memory impairment. Our findings suggest that EE ameliorated sevoflurane-induced neurotoxicity and learning and memory impairment through the PPAR-gamma signaling pathway. PPAR-gamma may be a potential therapeutic target for preventing or treating sevoflurane-induced neurotoxicity. PMID- 26236714 TI - Highly Flexible Silicone Coated Neural Array for Intracochlear Electrical Stimulation. AB - We present an effective method for tailoring the flexibility of a commercial thin film polymer electrode array for intracochlear electrical stimulation. Using a pneumatically driven dispensing system, an average 232 +/- 64 MUm (mean +/- SD) thickness layer of silicone adhesive coating was applied to stiffen the underside of polyimide multisite arrays. Additional silicone was applied to the tip to protect neural tissue during insertion and along the array to improve surgical handling. Each array supported 20 platinum sites (180 MUm dia., 250 MUm pitch), spanning nearly 28 mm in length and 400 MUm in width. We report an average intracochlear stimulating current threshold of 170 +/- 93 MUA to evoke an auditory brainstem response in 7 acutely deafened felines. A total of 10 arrays were each inserted through a round window approach into the cochlea's basal turn of eight felines with one delamination occurring upon insertion (preliminary results of the in vivo data presented at the 48th Annual Meeting American Neurotology Society, Orlando, FL, April 2013, and reported in Van Beek-King 2014). Using microcomputed tomography imaging (50 MUm resolution), distances ranging from 100 to 565 MUm from the cochlea's central modiolus were measured. Our method combines the utility of readily available commercial devices with a straightforward postprocessing step on the order of 24 hours. PMID- 26236715 TI - Generation of a Fibrin Based Three-Layered Skin Substitute. AB - A variety of skin substitutes that restore epidermal and dermal structures are currently available on the market. However, the main focus in research and clinical application lies on dermal and epidermal substitutes whereas the development of a subcutaneous replacement (hypodermis) is often disregarded. In this study we used fibrin sealant as hydrogel scaffold to generate a three layered skin substitute. For the hypodermal layer adipose-derived stem cells (ASCs) and mature adipocytes were embedded in the fibrin hydrogel and were combined with another fibrin clot with fibroblasts for the construction of the dermal layer. Keratinocytes were added on top of the two-layered construct to form the epidermal layer. The three-layered construct was cultivated for up to 3 weeks. Our results show that ASCs and fibroblasts were viable, proliferated normally, and showed physiological morphology in the skin substitute. ASCs were able to differentiate into mature adipocytes during the course of four weeks and showed morphological resemblance to native adipose tissue. On the surface keratinocytes formed an epithelial-like layer. For the first time we were able to generate a three-layered skin substitute based on a fibrin hydrogel not only serving as a dermal and epidermal substitute but also including the hypodermis. PMID- 26236716 TI - Left Atrial Appendage: Physiology, Pathology, and Role as a Therapeutic Target. AB - Atrial fibrillation (AF) is the most common clinically relevant cardiac arrhythmia. AF poses patients at increased risk of thromboembolism, in particular ischemic stroke. The CHADS2 and CHA2DS2-VASc scores are useful in the assessment of thromboembolic risk in nonvalvular AF and are utilized in decision-making about treatment with oral anticoagulation (OAC). However, OAC is underutilized due to poor patient compliance and contraindications, especially major bleedings. The Virchow triad synthesizes the pathogenesis of thrombogenesis in AF: endocardial dysfunction, abnormal blood stasis, and altered hemostasis. This is especially prominent in the left atrial appendage (LAA), where the low flow reaches its minimum. The LAA is the remnant of the embryonic left atrium, with a complex and variable morphology predisposing to stasis, especially during AF. In patients with nonvalvular AF, 90% of thrombi are located in the LAA. So, left atrial appendage occlusion could be an interesting and effective procedure in thromboembolism prevention in AF. After exclusion of LAA as an embolic source, the remaining risk of thromboembolism does not longer justify the use of oral anticoagulants. Various surgical and catheter-based methods have been developed to exclude the LAA. This paper reviews the physiological and pathophysiological role of the LAA and catheter-based methods of LAA exclusion. PMID- 26236717 TI - Animal Models and "Omics" Technologies for Identification of Novel Biomarkers and Drug Targets to Prevent Heart Failure. AB - It is now accepted that heart failure (HF) is a complex multifunctional disease rather than simply a hemodynamic dysfunction. Despite its complexity, stressed cardiomyocytes often follow conserved patterns of structural remodelling in order to adapt, survive, and regenerate. When cardiac adaptations cannot cope with mechanical, ischemic, and metabolic loads efficiently or become chronically activated, as, for example, after infection, then the ongoing structural remodelling and dedifferentiation often lead to compromised pump function and patient death. It is, therefore, of major importance to understand key events in the progression from a compensatory left ventricular (LV) systolic dysfunction to a decompensatory LV systolic dysfunction and HF. To achieve this, various animal models in combination with an "omics" toolbox can be used. These approaches will ultimately lead to the identification of an arsenal of biomarkers and therapeutic targets which have the potential to shape the medicine of the future. PMID- 26236718 TI - A Fast Cluster Motif Finding Algorithm for ChIP-Seq Data Sets. AB - New high-throughput technique ChIP-seq, coupling chromatin immunoprecipitation experiment with high-throughput sequencing technologies, has extended the identification of binding locations of a transcription factor to the genome-wide regions. However, the most existing motif discovery algorithms are time-consuming and limited to identify binding motifs in ChIP-seq data which normally has the significant characteristics of large scale data. In order to improve the efficiency, we propose a fast cluster motif finding algorithm, named as FCmotif, to identify the (l, d) motifs in large scale ChIP-seq data set. It is inspired by the emerging substrings mining strategy to find the enriched substrings and then searching the neighborhood instances to construct PWM and cluster motifs in different length. FCmotif is not following the OOPS model constraint and can find long motifs. The effectiveness of proposed algorithm has been proved by experiments on the ChIP-seq data sets from mouse ES cells. The whole detection of the real binding motifs and processing of the full size data of several megabytes finished in a few minutes. The experimental results show that FCmotif has advantageous to deal with the (l, d) motif finding in the ChIP-seq data; meanwhile it also demonstrates better performance than other current widely-used algorithms such as MEME, Weeder, ChIPMunk, and DREME. PMID- 26236719 TI - Evaluation of Intracochlear Trauma Caused by Insertion of Cochlear Implant Electrode Arrays through Different Quadrants of the Round Window. AB - HYPOTHESIS: This study aimed to evaluate whether there is a difference in the degree of intracochlear trauma when the cochlear implant electrode arrays is inserted through different quadrants of the round window membrane. BACKGROUND: The benefits of residual hearing preservation in cochlear implant recipients have promoted the development of atraumatic surgeries. Minimal trauma during electrode insertion is crucial for residual hearing preservation. METHODS: In total, 25 fresh human temporal bones were subjected to mastoidectomy and posterior tympanotomy. The cochlear implant electrode array was inserted through the anterosuperior quadrant of the round window membrane in 50% of the bones and through the anteroinferior quadrant in the remaining 50%. The temporal bones were dehydrated, embedded in epoxy, serially polished, stained, viewed through a stereomicroscope, and photographed with the electrode arrays in situ. The resulting images were analyzed for signs of intracochlear trauma. RESULTS: Histological examinations revealed varying degrees of damage to the intracochlear structures, although the incidence and severity of intracochlear trauma were not influenced by the quadrant of insertion. CONCLUSIONS: The incidence and severity of intracochlear trauma were similar in all samples, irrespective of electrode array insertion through the anterosuperior or anteroinferior quadrant of the round window membrane. PMID- 26236720 TI - Animal Models of Peritoneal Dialysis: Thirty Years of Our Own Experience. AB - Experimental animal models improve our understanding of technical problems in peritoneal dialysis PD, and such studies contribute to solving crucial clinical problems. We established an acute and chronic PD model in nonuremic and uremic rats. We observed that kinetics of PD in rats change as the animals are aging, and this effect is due not only to an increasing peritoneal surface area, but also to changes in the permeability of the peritoneum. Changes of the peritoneal permeability seen during chronic PD in rats are comparable to results obtained in humans treated with PD. Effluent dialysate can be drained repeatedly to measure concentration of various bioactive molecules and to correlate the results with the peritoneal permeability. Additionally we can study in in vitro conditions properties of the effluent dialysate on cultured peritoneal mesothelial cells or fibroblasts. We can evaluate acute and chronic effect of various additives to the dialysis fluid on function and permeability of the peritoneum. Results from such study are even more relevant to the clinical scenario when experiments are performed in uremic rats. Our experimental animal PD model not only helps to understand the pathophysiology of PD but also can be used for testing biocompatibility of new PD fluids. PMID- 26236722 TI - Written Language Ability in Mandarin-Speaking Children with Cochlear Implants. AB - Objectives. To examine narrative writing in cochlear implant (CI) children and understand the factors associated with unfavorable outcomes. Materials and Methods. Forty-five CI children in grades 2-6 participated in this study. They received CIs at 4.1 +/- 2.1 years of age and had used them for 6.5 +/- 2.7 years. A story-writing test was conducted and scored on 4 subscales: Total Number of Words, Words per Sentence, Morphosyntax, and Semantics. Scores more than 1.5 SD lower than the mean of the normal-hearing normative sample were considered problematic. Language and speech skills were examined. Results. Significantly more implanted students were problematic on "Total Number of Words" (p < 0.001), "Words per Sentence" (p = 0.049), and "Semantics" (p < 0.001). Poorer receptive language and auditory performance were independently associated with problematic "Total Number of Words" (R (2) = 0.489) and "Semantics" (R (2) = 0.213), respectively. "Semantics" problem was more common in lower graders (grades 2-4) than in higher graders (grades 5-6; p = 0.016). Conclusion. Implanted children tend to write stories that are shorter, worse-organized, and without a plot, while formulating morphosyntactically correct sentences. Special attention is required on their auditory and language performances, which could lead to written language problems. PMID- 26236721 TI - Functional and Structural Consequences of Damaging Single Nucleotide Polymorphisms in Human Prostate Cancer Predisposition Gene RNASEL. AB - A commonly diagnosed cancer, prostate cancer (PrCa), is being regulated by the gene RNASEL previously known as PRCA1 codes for ribonuclease L which is an integral part of interferon regulated system that mediates antiviral and antiproliferative role of the interferons. Both somatic and germline mutations have been implicated to cause prostate cancer. With an array of available Single Nucleotide Polymorphism data on dbSNP this study is designed to sort out functional SNPs in RNASEL by implementing different authentic computational tools such as SIFT, PolyPhen, SNPs&GO, Fathmm, ConSurf, UTRScan, PDBsum, Tm-Align, I Mutant, and Project HOPE for functional and structural assessment, solvent accessibility, molecular dynamics, and energy minimization study. Among 794 RNASEL SNP entries 124 SNPs were found nonsynonymous from which SIFT predicted 13 nsSNPs as nontolerable whereas PolyPhen-2 predicted 28. SNPs found on the 3' and 5' UTR were also assessed. By analyzing six tools having different perspectives an aggregate result was produced where nine nsSNPs were found to be most likely to exert deleterious effect. 3D models of mutated proteins were generated to determine the functional and structural effect of the mutations on ribonuclease L. The initial findings were reinforced by the results from I-Mutant and Project HOPE as these tools predicted significant structural and functional instability of the mutated proteins. Expasy-ProSit tool defined the mutations to be situated in the functional domains of the protein. Considering previous analysis this study revealed a conclusive result deducing the available SNP data on the database by identifying the most damaging three nsSNP rs151296858 (G59S), rs145415894 (A276V), and rs35896902 (R592H). As such studies involving polymorphisms of RNASEL were none to be found, the results of the current study would certainly be helpful in future prospects concerning prostate cancer in males. PMID- 26236723 TI - The Relation between Nonverbal IQ and Postoperative CI Outcomes in Cochlear Implant Users: Preliminary Result. AB - Objectives. This study assessed the correlation between performance intelligence and the postoperative cochlear implant (CI) outcome in Korean-speaking children. In addition, the relationship between the performance intelligence subscales and the post-CI speech outcome was evaluated. Materials and Methods. Thirteen pediatric CI users (five males, eight females; median age at implantation 6.2 (range 1.3-14.2) years; median age at intelligence test 9.3 (range 5-16) years) who were tested using the Korean Educational Development Institute-Wechsler Intelligence Scale for children were studied. The correlations between the intelligence scores and 1-2 years postoperative Categories of Auditory Performance (CAP) scores and between subscales of performance and 1-2 years postoperative CAP scores were analyzed. Results. There was no correlation between the categories of verbal intelligence quotient (IQ) and performance IQ for "mentally retarded" and "average," respectively (Spearman's rho = 0.42, P = 0.15). There was a strong correlation between performance IQ and the postoperative CAP scale (Spearman's rho = 0.8977, P = 0.0008). "Picture arrangement" and "picture completion," reflecting social cognition, were strongly correlated with the postoperative CAP scales. Conclusion. Performance intelligence, especially social cognition, was strongly related to the postoperative CI outcome of cochlear implant users. Therefore, auditory rehabilitation, including social rehabilitation, should maximize the postoperative CI outcomes. PMID- 26236724 TI - Hypoxia Induces a Metabolic Shift and Enhances the Stemness and Expansion of Cochlear Spiral Ganglion Stem/Progenitor Cells. AB - Previously, we demonstrated that hypoxia (1% O2) enhances stemness markers and expands the cell numbers of cochlear stem/progenitor cells (SPCs). In this study, we further investigated the long-term effect of hypoxia on stemness and the bioenergetic status of cochlear spiral ganglion SPCs cultured at low oxygen tensions. Spiral ganglion SPCs were obtained from postnatal day 1 CBA/CaJ mouse pups. The measurement of oxygen consumption rate, extracellular acidification rate (ECAR), and intracellular adenosine triphosphate levels corresponding to 20% and 5% oxygen concentrations was determined using a Seahorse XF extracellular flux analyzer. After low oxygen tension cultivation for 21 days, the mean size of the hypoxia-expanded neurospheres was significantly increased at 5% O2; this correlated with high-level expression of hypoxia-inducible factor-1 alpha (Hif 1alpha), proliferating cell nuclear antigen (PCNA), cyclin D1, Abcg2, nestin, and Nanog proteins but downregulated expression of p27 compared to that in a normoxic condition. Low oxygen tension cultivation tended to increase the side population fraction, with a significant difference found at 5% O2 compared to that at 20% O2. In addition, hypoxia induced a metabolic energy shift of SPCs toward higher basal ECARs and higher maximum mitochondrial respiratory capacity but lower proton leak than under normoxia, where the SPC metabolism was switched toward glycolysis in long-term hypoxic cultivation. PMID- 26236725 TI - Modeling of Auditory Neuron Response Thresholds with Cochlear Implants. AB - The quality of the prosthetic-neural interface is a critical point for cochlear implant efficiency. It depends not only on technical and anatomical factors such as electrode position into the cochlea (depth and scalar placement), electrode impedance, and distance between the electrode and the stimulated auditory neurons, but also on the number of functional auditory neurons. The efficiency of electrical stimulation can be assessed by the measurement of e-CAP in cochlear implant users. In the present study, we modeled the activation of auditory neurons in cochlear implant recipients (nucleus device). The electrical response, measured using auto-NRT (neural responses telemetry) algorithm, has been analyzed using multivariate regression with cubic splines in order to take into account the variations of insertion depth of electrodes amongst subjects as well as the other technical and anatomical factors listed above. NRT thresholds depend on the electrode squared impedance (beta = -0.11 +/- 0.02, P < 0.01), the scalar placement of the electrodes (beta = -8.50 +/- 1.97, P < 0.01), and the depth of insertion calculated as the characteristic frequency of auditory neurons (CNF). Distribution of NRT residues according to CNF could provide a proxy of auditory neurons functioning in implanted cochleas. PMID- 26236727 TI - An Improved Opposition-Based Learning Particle Swarm Optimization for the Detection of SNP-SNP Interactions. AB - SNP-SNP interactions have been receiving increasing attention in understanding the mechanism underlying susceptibility to complex diseases. Though many works have been done for the detection of SNP-SNP interactions, the algorithmic development is still ongoing. In this study, an improved opposition-based learning particle swarm optimization (IOBLPSO) is proposed for the detection of SNP-SNP interactions. Highlights of IOBLPSO are the introduction of three strategies, namely, opposition-based learning, dynamic inertia weight, and a postprocedure. Opposition-based learning not only enhances the global explorative ability, but also avoids premature convergence. Dynamic inertia weight allows particles to cover a wider search space when the considered SNP is likely to be a random one and converges on promising regions of the search space while capturing a highly suspected SNP. The postprocedure is used to carry out a deep search in highly suspected SNP sets. Experiments of IOBLPSO are performed on both simulation data sets and a real data set of age-related macular degeneration, results of which demonstrate that IOBLPSO is promising in detecting SNP-SNP interactions. IOBLPSO might be an alternative to existing methods for detecting SNP-SNP interactions. PMID- 26236726 TI - Diversity and Global Distribution of IncL/M Plasmids Enabling Horizontal Dissemination of beta-Lactam Resistance Genes among the Enterobacteriaceae. AB - Antibiotic resistance determinants are frequently associated with plasmids and other mobile genetic elements, which simplifies their horizontal transmission. Several groups of plasmids (including replicons of the IncL/M incompatibility group) were found to play an important role in the dissemination of resistance genes encoding beta-lactamases. The IncL/M plasmids are large, broad host range, and self-transmissible replicons. We have identified and characterized two novel members of this group: pARM26 (isolated from bacteria inhabiting activated sludge from a wastewater treatment plant) and pIGT15 (originating from a clinical strain of Escherichia coli). This instigated a detailed comparative analysis of all available sequences of IncL/M plasmids encoding beta-lactamases. The core genome of these plasmids is comprised of 20 genes with conserved synteny. Phylogenetic analyses of these core genes allowed clustering of the plasmids into four separate groups, which reflect their antibiotic resistance profiles. Examination of the biogeography of the IncL/M plasmids revealed that they are most frequently found in bacteria of the family Enterobacteriaceae originating from the Mediterranean region and Western Europe and that they are able to persist in various ecological niches even in the absence of direct antibiotic selection pressure. PMID- 26236728 TI - Diverse Roles of Heparan Sulfate and Heparin in Wound Repair. AB - Heparan sulfate (HS) and heparin (Hp) are linear polysaccharide chains composed of repeating (1->4) linked pyrosulfuric acid and 2-amino-2-deoxy glucopyranose (glucosamine) residue. Mentioned glycosaminoglycans chains are covalently O linked to serine residues within the core proteins creating heparan sulfate/heparin proteoglycans (HSPG). The latter ones participate in many physiological and pathological phenomena impacting both the plethora of ligands such as cytokines, growth factors, and adhesion molecules and the variety of the ECM constituents. Moreover, HS/Hp determine the effective wound healing process. Initial growth of HS and Hp amount is pivotal during the early phase of tissue repair; however heparan sulfate and heparin also participate in further stages of tissue regeneration. PMID- 26236729 TI - Sequence and Structure Analysis of Biological Molecules Based on Computational Methods. PMID- 26236730 TI - GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration. AB - GHK (glycyl-L-histidyl-L-lysine) is present in human plasma, saliva, and urine but declines with age. It is proposed that GHK functions as a complex with copper 2+ which accelerates wound healing and skin repair. GHK stimulates both synthesis and breakdown of collagen and glycosaminoglycans and modulates the activity of both metalloproteinases and their inhibitors. It stimulates collagen, dermatan sulfate, chondroitin sulfate, and the small proteoglycan, decorin. It also restores replicative vitality to fibroblasts after radiation therapy. The molecule attracts immune and endothelial cells to the site of an injury. It accelerates wound-healing of the skin, hair follicles, gastrointestinal tract, boney tissue, and foot pads of dogs. It also induces systemic wound healing in rats, mice, and pigs. In cosmetic products, it has been found to tighten loose skin and improve elasticity, skin density, and firmness, reduce fine lines and wrinkles, reduce photodamage, and hyperpigmentation, and increase keratinocyte proliferation. GHK has been proposed as a therapeutic agent for skin inflammation, chronic obstructive pulmonary disease, and metastatic colon cancer. It is capable of up- and downregulating at least 4,000 human genes, essentially resetting DNA to a healthier state. The present review revisits GHK's role in skin regeneration in the light of recent discoveries. PMID- 26236731 TI - The Use of Stem Cells in Burn Wound Healing: A Review. AB - Burn wound healing involves a series of complex processes which are subject to intensive investigations to improve the outcomes, in particular, the healing time and the quality of the scar. Burn injuries, especially severe ones, are proving to have devastating effects on the affected patients. Stem cells have been recently applied in the field to promote superior healing of the wounds. Not only have stem cells been shown to promote better and faster healing of the burn wounds, but also they have decreased the inflammation levels with less scar progression and fibrosis. This review aims to highlight the beneficial therapeutic effect of stem cells in burn wound healing and to discuss the involved pathways and signaling molecules. The review covers various types of burn wound healing like skin and corneal burns, along with the alternative recent therapies being studied in the field of burn wound healing. The current reflection of the attitudes of people regarding the use of stem cells in burn wound healing is also stated. PMID- 26236733 TI - The Utility of 3D Left Atrial Volume and Mitral Flow Velocities as Guides for Acute Volume Resuscitation. AB - Left ventricular end-diastolic pressure (LVEDP) is the foundation of cardiac function assessment. Because of difficulties and risks associated with its direct measurement, correlates of LVEDP derived by pulmonary artery (PA) catheterization or transesophageal echocardiography (TEE) are commonly adopted. TEE has the advantage of being less invasive; however TEE-based estimation of LVEDP using correlates such as left ventricular end-diastolic volume (LVEDV) has technical difficulties that limit its clinical usefulness. Using intraoperative acute normovolemic hemodilution (ANH) as a controlled hemorrhagic model, we examined various mitral flow parameters and three-dimensional reconstructions of left atrial volume as surrogates of LVEDP. Our results demonstrate that peak E wave velocity and left atrial end-diastolic volume (LAEDV) correlated with known changes in intravascular volume associated with ANH. Although left atrial volumetric analysis was done offline in our study, recent advances in echocardiographic software may allow for continuous display and real-time calculation of LAEDV. Along with the ease and reproducibility of acquiring Doppler images of flow across the mitral valve, these two correlates of LVEDP may justify a more widespread use of TEE to optimize intraoperative fluid management. The clinical applicability of peak E wave velocity and LAEDV still needs to be validated during uncontrolled resuscitation. PMID- 26236732 TI - Cochlear Implant Outcomes and Genetic Mutations in Children with Ear and Brain Anomalies. AB - BACKGROUND: Specific clinical conditions could compromise cochlear implantation outcomes and drastically reduce the chance of an acceptable development of perceptual and linguistic capabilities. These conditions should certainly include the presence of inner ear malformations or brain abnormalities. The aims of this work were to study the diagnostic value of high resolution computed tomography (HRCT) and magnetic resonance imaging (MRI) in children with sensorineural hearing loss who were candidates for cochlear implants and to analyse the anatomic abnormalities of the ear and brain in patients who underwent cochlear implantation. We also analysed the effects of ear malformations and brain anomalies on the CI outcomes, speculating on their potential role in the management of language developmental disorders. METHODS: The present study is a retrospective observational review of cochlear implant outcomes among hearing impaired children who presented ear and/or brain anomalies at neuroimaging investigations with MRI and HRCT. Furthermore, genetic results from molecular genetic investigations (GJB2/GJB6 and, additionally, in selected cases, SLC26A4 or mitochondrial-DNA mutations) on this study group were herein described. Longitudinal and cross-sectional analysis was conducted using statistical tests. RESULTS: Between January 1, 1996 and April 1, 2012, at the ENT-Audiology Department of the University Hospital of Ferrara, 620 cochlear implantations were performed. There were 426 implanted children at the time of the present study (who were <18 years). Among these, 143 patients (64 females and 79 males) presented ear and/or brain anomalies/lesions/malformations at neuroimaging investigations with MRI and HRCT. The age of the main study group (143 implanted children) ranged from 9 months and 16 years (average = 4.4; median = 3.0). CONCLUSIONS: Good outcomes with cochlear implants are possible in patients who present with inner ear or brain abnormalities, even if central nervous system anomalies represent a negative prognostic factor that is made worse by the concomitant presence of cochlear malformations. Common cavity and stenosis of the internal auditory canal (less than 2 mm) are negative prognostic factors even if brain lesions are absent. PMID- 26236734 TI - Freestyle Local Perforator Flaps for Facial Reconstruction. AB - For the successful reconstruction of facial defects, various perforator flaps have been used in single-stage surgery, where tissues are moved to adjacent defect sites. Our group successfully performed perforator flap surgery on 17 patients with small to moderate facial defects that affected the functional and aesthetic features of their faces. Of four complicated cases, three developed venous congestion, which resolved in the subacute postoperative period, and one patient with partial necrosis underwent minor revision. We reviewed the literature on freestyle perforator flaps for facial defect reconstruction and focused on English articles published in the last five years. With the advance of knowledge regarding the vascular anatomy of pedicled perforator flaps in the face, we found that some perforator flaps can improve functional and aesthetic reconstruction for the facial defects. We suggest that freestyle facial perforator flaps can serve as alternative, safe, and versatile treatment modalities for covering small to moderate facial defects. PMID- 26236736 TI - Type of Renal Replacement Therapy (Hemodialysis versus Peritoneal Dialysis) Does Not Affect Cytokine Gene Expression or Clinical Parameters of Renal Transplant Candidates. AB - Patients with renal failure suffer from immune disturbances, caused by uremic toxins and influenced by dialysis treatment. The aim of the present study was to reveal whether type of dialysis modality (hemodialysis, HD, versus peritoneal dialysis, PD) differentially affects the immunocompetence, particularly the expression of genes involved in the immune response. MATERIAL: 87 renal transplant candidates (66 HD, 21 PD) were included in the study. METHODS: The peripheral blood RNA samples were obtained with the PAXgene Blood system just before transplantation. The gene expression of CASP3, FAS, TP53, FOXP3, IFNG, IL2, IL6, IL8, IL10, IL17, IL18, LCN2, TGFB1, and TNF was assessed with real-time PCR on custom-designed low density arrays (TaqMan). Gene expression data were analyzed in relation to pretransplant clinical parameters. RESULTS: The mean expression of examined genes showed no significant differences between PD and HD with the exception of FAS, expression of which was 30% higher in PD patients compared to the HD group. There was nonsignificantly higher expression of proinflammatory cytokines in the PD group. The clinical inflammatory parameters (CRP, albumin, cholesterol, and hemoglobin levels) did not differ between the groups. CONCLUSION: Type of renal replacement therapy exerts no differential effect on cytokine gene expression or inflammatory clinical parameters. PMID- 26236735 TI - Echocardiographic Evaluation of Left Atrial Mechanics: Function, History, Novel Techniques, Advantages, and Pitfalls. AB - Left atrial (LA) functional analysis has an established role in assessing left ventricular diastolic function. The current standard echocardiographic parameters used to study left ventricular diastolic function include pulsed-wave Doppler mitral inflow analysis, tissue Doppler imaging measurements, and LA dimension estimation. However, the above-mentioned parameters do not directly quantify LA performance. Deformation studies using strain and strain-rate imaging to assess LA function were validated in previous research, but this technique is not currently used in routine clinical practice. This review discusses the history, importance, and pitfalls of strain technology for the analysis of LA mechanics. PMID- 26236737 TI - Synthesis and Properties of Flexible Polyurethane Using Ferric Catalyst for Hypopharyngeal Tissue Engineering. AB - Biodegradable polyurethane is an ideal candidate material to fabricate tissue engineered hypopharynx from its good mechanical properties and biodegradability. We thus synthesized a hydrophilic polyurethane via reactions among polyethylene glycol (PEG), e-caprolactone (e-CL) and hexamethylene diisocyanate (HDI), and thrihydroxymethyl propane (TMP). The product possessed a fast degradability due to its good wettability and good mechanical parameters with the elongations at break (137 +/- 10%) and tensile strength (4.73 +/- 0.46 MPa), which will make it a good matrix material for soft tissue like hypopharynx. Its biological properties were evaluated via in vitro and in vivo tests. The results showed that this hydrophilic polyurethane material can support hypopharyngeal fibroblast growth and owned good degradability and low inflammatory reaction in subcutaneous implantation. It will be proposed as the scaffold for hypopharyngeal tissue engineering research in our future study. PMID- 26236738 TI - Low versus High Fluence Parameters in the Treatment of Facial Laceration Scars with a 1,550 nm Fractional Erbium-Glass Laser. AB - Purpose. Early postoperative fractional laser treatment has been used to reduce scarring in many institutions, but the most effective energy parameters have not yet been established. This study sought to determine effective parameters in the treatment of facial laceration scars. Methods. From September 2012 to September 2013, 57 patients were enrolled according to the study. To compare the low and high fluence parameters of 1,550 nm fractional erbium-glass laser treatment, we virtually divided the scar of each individual patient in half, and each half was treated with a high and low fluence setting, respectively. A total of four treatment sessions were performed at one-month intervals and clinical photographs were taken at every visit. Results. Results were assessed using the Vancouver Scar Scale (VSS) and global assessment of the two portions of each individual scar. Final evaluation revealed that the portions treated with high fluence parameter showed greater difference compared to pretreatment VSS scores and global assessment values, indicating favorable cosmetic results. Conclusion. We compared the effects of high fluence and low fluence 1,550 nm fractional erbium glass laser treatment for facial scarring in the early postoperative period and revealed that the high fluence parameter was more effective for scar management. PMID- 26236739 TI - Improved Salinity Tolerance in Carrizo Citrange Rootstock through Overexpression of Glyoxalase System Genes. AB - Citrus plants are widely cultivated around the world and, however, are one of the most salt stress sensitive crops. To improve salinity tolerance, transgenic Carrizo citrange rootstocks that overexpress glyoxalase I and glyoxalase II genes were obtained and their salt stress tolerance was evaluated. Molecular analysis showed high expression for both glyoxalase genes (BjGlyI and PgGlyII) in 5H03 and 5H04 lines. Under control conditions, transgenic and wild type plants presented normal morphology. In salinity treatments, the transgenic plants showed less yellowing, marginal burn in lower leaves and showed less than 40% of leaf damage compared with wild type plants. The transgenic plants showed a significant increase in the dry weight of shoot but there are no differences in the root and complete plant dry weight. In addition, a higher accumulation of chlorine is observed in the roots in transgenic line 5H03 but in shoot it was lower. Also, the wild type plant accumulated around 20% more chlorine in the shoot compared to roots. These results suggest that heterologous expression of glyoxalase system genes could enhance salt stress tolerance in Carrizo citrange rootstock and could be a good biotechnological approach to improve the abiotic stress tolerance in woody plant species. PMID- 26236740 TI - The Effect of Bone Marrow-Derived Mesenchymal Stem Cells and Their Conditioned Media Topically Delivered in Fibrin Glue on Chronic Wound Healing in Rats. AB - Bone marrow-derived mesenchymal stem cells (BM-MSCs) represent a modern approach for management of chronic skin injuries. In this work, we describe BM-MSCs application versus their conditioned media (CM) when delivered topically admixed with fibrin glue to enhance the healing of chronic excisional wounds in rats. Fifty-two adult male rats were classified into four groups after induction of large-sized full-thickness skin wound: control group (CG), fibrin only group (FG), fibrin + MSCs group (FG + SCs), and fibrin + CM group (FG + CM). Healing wounds were evaluated functionally and microscopically. Eight days after injury, number of CD68+ macrophages infiltrating granulation tissue was considerably higher in the latter two groups. Although--later--none of the groups depicted a substantially different healing rate, the quality of regenerated skin was significantly boosted by the application of either BM-MSCs or their CM both (1) structurally as demonstrated by the obviously increased mean area percent of collagen fibers in Masson's trichrome-stained skin biopsies and (2) functionally as supported by the interestingly improved epidermal barrier as well as dermal tensile strength. Thus, we conclude that topically applied BM-MSCs and their CM via fibrin vehicle--could effectively improve the quality of healed skin in chronic excisional wounds in rats, albeit without true acceleration of wound closure. PMID- 26236741 TI - Stability Testing of a Wide Bone-Anchored Device after Surgery without Skin Thinning. AB - OBJECTIVE: To longitudinally follow the osseointegration using Resonance Frequency Analysis (RFA) for different lengths of abutment on a new wide bone anchored implant, introduced with the non-skin thinning surgical technique. STUDY DESIGN: A single-center, prospective 1 year study following adults with bone anchored hearing implants. MATERIALS AND METHODS: Implantation was performed and followed for a minimum of 1 year. All patients were operated on according to the tissue preserving technique. A 4.5 mm wide fixture (Oticon Medical) with varying abutments (9 to 12 mm) was used and RFA was tested 1 week, 7 weeks, 6 months, and 12 months later. Implant Stability Quotient (ISQ), was measured from 1 to 100. Stability was compared to a group of patients (N = 7) implanted with another brand (Cochlear BI400) of 4.5 mm fixtures. RESULTS: All 10 adults concluded the study. None of the participants lost their implant during the test period indicating a good anchoring of abutments to the wide fixture tested. Stability testing was shown to vary depending on abutment length and time after surgery and with higher values for shorter abutments and increasing values over the first period of time. One patient changed the abutment from 12 to 9 mm and another from a 9 to a 12 during the year. No severe skin problems, numbness around the implant, or cosmetic problems arose. CONCLUSION: After 1 year of follow-up, combination of a wide fixture implant and the non-skin thinning surgical technique indicates a safe procedure with good stability and no abutment losses. PMID- 26236742 TI - Preparative Purification of Liriodendrin from Sargentodoxa cuneata by Macroporous Resin. AB - The preparative purification of liriodendrin from Sargentodoxa cuneata using macroporous resin combined with crystallization process was evaluated. The properties of adsorption/desorption of liriodendrin on eight macroporous resins were investigated systematically. X-5 resin was selected as the most suitable medium for liriodendrin purification. The adsorption of liriodendrin on X-5 resin fitted well with the pseudo-second-order kinetic model and Langmuir isotherm model. Dynamic adsorption/desorption tests were performed using a glass column packed with X-5 resin to optimize the separation process of liriodendrin. After one treatment with X-5 resin, the content of liriodendrin in the product was increased 48.73-fold, from 0.85% to 41.42%, with a recovery yield of 88.9%. 97.48% liriodendrin was obtained by further crystallization and determined by HPLC. The purified product possessed strong antioxidant activity. In conclusion, purification of liriodendrin might expend its further pharmacological researches and further applications in pharmacy. PMID- 26236743 TI - Immunohistochemical Expression of Collagens in the Skin of Horses Treated with Leukocyte-Poor Platelet-Rich Plasma. AB - This study evaluated the immunohistochemical expression of type I (COL I) and III (COL III) collagens during the healing process of skin treated with leukocyte poor platelet-rich plasma (LP-PRP). Seven healthy gelding crossbred horses aged 16 to 17 years were used. Two rectangle-shaped wounds were created surgically in the right and left gluteal regions. Twelve hours after wound induction, 0.5 mL of the LP-PRP was administered in each edge of the wounds of one of the gluteal regions. The contralateral region was used as control (CG). Three samples were obtained: after wound induction (T0), 14 days (T1) of healing process, and after complete closure of the skin (T2). The normal skin (T0) showed strong staining for type III and I collagen in papillary and reticular dermis, respectively. In the scar of the treated group, COL III showed important (p < 0.05) increase in immunoreaction in T2 compared with T1. The administration of a single dose of LP PRP 12 h after induction of wound in horses does not influence formation of collagens I and III. However, the intense labeling for COL III suggests that the tissue was still weak during the macroscopic closure of the wound, demonstrating that healing was not completely finished. PMID- 26236744 TI - Bearing-Foreign Material Deposition on Retrieved Co-Cr Femoral Heads: Composition and Morphology. AB - Bearing-foreign material deposition onto a femoral head can occur from contact with an acetabular shell due to dislocation, reduction, or subluxation. The purpose of this study was to comprehensively characterize deposit regions on retrieved cobalt-chrome femoral heads from metal-on-polyethylene total hip arthroplasties that had experienced such adverse events. The morphology, topography, and composition of deposition regions were characterized using macrophotography, optical profilometry, scanning electron microscopy, energy dispersive spectroscopy, and X-ray photoelectron spectroscopy. The deposit areas were relatively large, they were much rougher than the surrounding undamaged clean areas, and they displayed several distinct morphologies. Titanium alloy elements were the predominant constituents. Calcium and phosphorous were also detected within the deposit areas, in a composition that could nucleate abrasive hydroxyapatite. In addition, tungsten-rich particles, likely present as tungsten carbide, were observed on top of the titanium deposits. The increased roughness associated with these deposition features would be expected to accelerate damage and wear of the opposing liner and hence accelerate the development of osteolysis. PMID- 26236745 TI - Corrigendum to "Evaluating the Importance of the Carotid Chemoreceptors in Controlling Breathing during Exercise in Man". PMID- 26236746 TI - Delta Cell Hyperplasia in Adult Goto-Kakizaki (GK/MolTac) Diabetic Rats. AB - Reduced beta cell mass in pancreatic islets (PI) of Goto-Kakizaki (GK) rats is frequently observed in this diabetic model, but knowledge on delta cells is scarce. Aiming to compare delta cell physiology/pathology of GK to Wistar rats, we found that delta cell number increased over time as did somatostatin mRNA and delta cells distribution in PI is different in GK rats. Subtle changes in 6-week old GK rats were found. With maturation and aging of GK rats, disturbed cytoarchitecture occurred with irregular beta cells accompanied by delta cell hyperplasia and loss of pancreatic polypeptide (PPY) positivity. Unlike the constant glucose-stimulation index for insulin PI release in Wistar rats, this index declined with GK age, whereas for somatostatin it increased with age. A decrease of GK rat PPY serum levels was found. GK rat body weight decreased with increasing hyperglycemia. Somatostatin analog octreotide completely blocked insulin secretion, impaired proliferation at low autocrine insulin, and decreased PPY secretion and mitochondrial DNA in INS-1E cells. In conclusion, in GK rats PI, significant local delta cell hyperplasia and suspected paracrine effect of somatostatin diminish beta cell viability and contribute to the deterioration of beta cell mass. Altered PPY-secreting cells distribution amends another component of GK PI's pathophysiology. PMID- 26236747 TI - Effect of Global ATGL Knockout on Murine Fasting Glucose Kinetics. AB - Mice deficient in adipose triglyceride lipase (ATGL(-/-)) present elevated ectopic lipid levels but are paradoxically glucose-tolerant. Measurement of endogenous glucose production (EGP) and Cori cycle activity provide insights into the maintenance of glycemic control in these animals. These parameters were determined in 7 wild-type (ATGL(+/-)) and 6 ATGL(-/-) mice by a primed-infusion of [U-(13)C6]glucose followed by LC-MS/MS targeted mass-isotopomer analysis of blood glucose. EGP was quantified by isotope dilution of [U-(13)C6]glucose while Cori cycling was estimated by analysis of glucose triose (13)C-isotopomers. Fasting plasma free fatty-acids were significantly lower in ATGL(-/-) versus control mice (0.43 +/- 0.05 mM versus 0.73 +/- 0.11 mM, P < 0.05). Six-hour fasting EGP rates were identical for both ATGL(-/-) and control mice (79 +/- 11 versus 71 +/- 7 MUmol/kg/min, resp.). Peripheral glucose metabolism was dominated by Cori cycling (80 +/- 2% and 82 +/- 7% of glucose disposal for ATGL(-/-) and control mice, resp.) indicating that peripheral glucose oxidation was not significantly upregulated in ATGL(-/-) mice under these conditions. The glucose (13)C-isotopomer distributions in both ATGL(-/-) and control mice were consistent with extensive hepatic pyruvate recycling. This suggests that gluconeogenic outflow from the Krebs cycle was also well compensated in ATGL(-/-) mice. PMID- 26236748 TI - Current Smoking Dose-Dependently Associated with Decreased beta-Cell Function in Chinese Men without Diabetes. AB - The aim of this study was to evaluate the associations between chronic smoking and insulin resistance and beta-cell function in Chinese men without diabetes. A total of 1,568 participants were recruited by multistage sampling. Using homeostatic model assessment (HOMA), geometric means of insulin resistance (HOMA IR) and beta-cell function (HOMA-beta) with 95% confidence interval (CI) were calculated by general linear model. Odds ratios (ORs) with 95% CI were estimated to evaluate the associations between smoking status and insulin resistance and beta-cell deficiency under a logistic regression model. Current smokers had higher levels of 2 h glucose (6.66 versus 6.48 mmol/L) for oral glucose tolerance test and lower levels of fasting insulin (5.68 versus 6.03 mU/L) than never smokers. The adjusted means for HOMA-beta (%) were 54.86 in current smokers and 58.81 in never smokers (P = 0.0257). Current smoking was associated with beta cell deficiency (OR 1.29, 95% CI 1.01-1.64) compared to never smoking. The beta cell function gradually decreased with increasing smoking intensity (P trend = 0.0026), and the differences were statistically significant when the pack-year of smoking was 20 or above. No association was observed between smoking status and HOMA-IR. Our study suggested that chronic smoking may dose-dependently suppress insulin secretion in Chinese men. PMID- 26236749 TI - Illness Perception and Depressive Symptoms among Persons with Type 2 Diabetes Mellitus: An Analytical Cross-Sectional Study in Clinical Settings in Nepal. AB - Background. This study aimed to assess the relationship between illness perception and depressive symptoms among persons with diabetes. Method. This was an analytical cross-sectional study conducted among 379 type 2 diabetic patients from three major clinical settings of Kathmandu, Nepal. Results. The prevalence of depressive symptoms was 44.1% (95% CI: 39.1, 49.1). Females (p < 0.01), homemakers (p < 0.01), 61-70 age group (p = 0.01), those without formal education (p < 0.01), and people with lower social status (p < 0.01) had significantly higher proportion of depressive symptoms than the others. Multivariable analysis identified age (beta = 0.036, p = 0.016), mode of treatment (beta = 0.9, p = 0.047), no formal educational level (beta = 1.959, p = 0.01), emotional representation (beta = 0.214, p < 0.001), identity (beta = 0.196, p < 0.001), illness coherence (beta = -0.109, p = 0.007), and consequences (beta = 0.093, p = 0.049) as significant predictors of depressive symptoms. Conclusion. Our study demonstrated a strong relationship between illness perception and depressive symptoms among diabetic patients. Study finding indicated that persons living with diabetes in Nepal need comprehensive diabetes education program for changing poor illness perception, which ultimately helps to prevent development of depressive symptoms. PMID- 26236751 TI - Corrigendum to "The Story of CD4 (+) CD28(-) T Cells Revisited: Solved or Still Ongoing?". PMID- 26236750 TI - Immunotherapy of Ovarian Cancer: The Role of Checkpoint Inhibitors. AB - Ovarian cancer is the most important cause of gynecological cancer-related mortality, with the majority of women presenting with advanced disease. Although surgery and chemotherapy can improve survival rates, it is necessary to integrate alternative strategies to improve the outcomes. Advances in understanding the role of immune system in the pathogenesis of cancer have led to the rapid evolvement of immunotherapy, which might establish a sustained immune system response against recurring cancer cells. Recently, it has emerged that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called "immune checkpoints," which turn off the immune system. Similarly, cancer cells are able to use these checkpoints to avoid immune control and rejection. Inhibition of these inhibitory pathways represents a potent strategy in the fight against cancer and is currently under investigation with encouraging results in some cancers, such as melanoma. In ovarian cancer researches are still in an early phase, but with promising results. In this review we will explore the rationale of immunotherapy in ovarian cancer with a special focus on these emerging molecules. PMID- 26236752 TI - NKG2D Signaling Leads to NK Cell Mediated Lysis of Childhood AML. AB - Natural killer cells have been shown to be relevant in the recognition and lysis of acute myeloid leukemia. In childhood acute lymphoblastic leukemia, it was shown that HLA I expression and KIR receptor-ligand mismatch significantly impact ALL cytolysis. We characterized 14 different primary childhood AML blasts by flow cytometry including NKG2D ligands. Further HLA I typing of blasts was performed and HLA I on the AML blasts was quantified. In two healthy volunteer NK cell donors HLA I typing and KIR genotyping were done. Blasts with high NKG2D ligand expression had significantly higher lysis by isolated NK cells. Grouping the blasts by NKG2D ligand expression led to a significant inverse correlation of HLA I expression and cytolysis in NKG2D low blasts. Furthermore, a significant positive correlation of NKG2D ligand expression and blast cytolysis was shown. No impact of KIR ligand-ligand mismatch was found but a significantly increased lysis of homozygous C2 blasts by KIR2DL1 negative NK cells (donor B) was revealed. In conclusion, NKG2D signaling leads to NK cell mediated lysis of childhood AML despite high HLA I expression. PMID- 26236753 TI - IgG4-Related Disease Presenting as Recurrent Mastoiditis With Central Nervous System Involvement. AB - We report a case of a 43-year-old female who presented with right ear fullness and otorrhea. She was initially diagnosed with mastoiditis that was not responsive to multiple courses of antibiotics and steroids. She was then diagnosed with refractory inflammatory pseudotumor, and subsequent treatments included several mastoidectomies, further steroids, and radiation therapy. The patient went on to develop mastoiditis on the contralateral side as well as central nervous system involvement with headaches and right-sided facial paresthesias. Reexamination of the mastoid tissue revealed a significantly increased number of IgG4-positive cells, suggesting a diagnosis of IgG4-related disease. The patient improved clinically and radiographically with rituximab and was able to taper off azathioprine and prednisone. IgG4-related disease should be considered in patients with otologic symptoms and be on the differential diagnosis in patients with inflammatory pseudotumor. Staining for IgG and IgG4 is essential to ensure a prompt diagnosis and treatment. PMID- 26236754 TI - Individual Differences and Fitting Methods for the Two-Choice Diffusion Model of Decision Making. AB - Methods of fitting the diffusion model were examined with a focus on what the model can tell us about individual differences. Diffusion model parameters were obtained from the fits to data from two experiments and consistency of parameter values, individual differences, and practice effects were examined using different numbers of observations from each subject. Two issues were examined, first, what sizes of differences between groups can be obtained to distinguish between groups and second, what sizes of differences would be needed to find individual subjects that had a deficit relative to a control group. The parameter values from the experiments provided ranges that were used in a simulation study to examine recovery of individual differences. This study used several diffusion model fitting programs, fitting methods, and published packages. In a second simulation study, 64 sets of simulated data from each of 48 sets of parameter values (spanning the range of typical values obtained from fits to data) were fit with the different methods and biases and standard deviations in recovered model parameters were compared across methods. Finally, in a third simulation study, a comparison between a standard chi-square method and a hierarchical Bayesian method was performed. The results from these studies can be used as a starting point for selecting fitting methods and as a basis for understanding the strengths and weaknesses of using diffusion model analyses to examine individual differences in clinical, neuropsychological, and educational testing. PMID- 26236755 TI - Tobacco Taxes in the Southeastern US States: Views from Former Legislators. AB - OBJECTIVES: We examine influences on southeastern state legislators' actions related to tobacco tax increases. METHODS: In 2014, we interviewed 26 former state legislators in southeastern states via phone. RESULTS: Themes regarding factors impeding increasing tobacco taxes included: tobacco's legacy in the South, protecting vulnerable populations from increased cigarette costs, concern about economic impact, opposing "sin" taxes, concern about impact on reelection, and perceptions that constituents oppose all taxes. The major theme in support of increasing tobacco taxes was health concern. Prior attempts at passing legislation resulted in political leveraging, deal-making, or compromising. CONCLUSIONS: Legislators' misperceptions of constituent opposition and impact on economy, among other impediments to increased tobacco taxes, must be addressed. PMID- 26236756 TI - Methodology to study the three-dimensional spatial distribution of prostate cancer and their dependence on clinical parameters. AB - A methodology to study the relationship between clinical variables [e.g., prostate specific antigen (PSA) or Gleason score] and cancer spatial distribution is described. Three-dimensional (3-D) models of 216 glands are reconstructed from digital images of whole mount histopathological slices. The models are deformed into one prostate model selected as an atlas using a combination of rigid, affine, and B-spline deformable registration techniques. Spatial cancer distribution is assessed by counting the number of tumor occurrences among all glands in a given position of the 3-D registered atlas. Finally, a difference between proportions is used to compare different spatial distributions. As a proof of concept, we compare spatial distributions from patients with PSA greater and less than [Formula: see text] and from patients older and younger than 60 years. Results suggest that prostate cancer has a significant difference in the right zone of the prostate between populations with PSA greater and less than [Formula: see text]. Age does not have any impact in the spatial distribution of the disease. The proposed methodology can help to comprehend prostate cancer by understanding its spatial distribution and how it changes according to clinical parameters. Finally, this methodology can be easily adapted to other organs and pathologies. PMID- 26236757 TI - Characteristics and health service utilization in two samples of young injection drug users recruited using direct and referral methods in San Francisco, California. PMID- 26236758 TI - Mouse Models of Uncomplicated and Fatal Malaria. AB - Mouse models have demonstrated utility in delineating the mechanisms underlying many aspects of malaria immunology and physiology. The most common mouse models of malaria employ the rodent-specific parasite species Plasmodium berghei, P. yoelii, and P. chabaudi, which elicit distinct pathologies and immune responses and are used to model different manifestations of human disease. In vitro culture methods are not well developed for rodent Plasmodium parasites, which thus require in vivo maintenance. Moreover, physiologically relevant immunological processes are best studied in vivo. Here, we detail the processes of infecting mice with Plasmodium, maintaining the parasite in vivo, and monitoring parasite levels and health parameters throughout infection. PMID- 26236759 TI - Earlier treatment of NMDAR antibody encephalitis in children results in a better outcome. PMID- 26236761 TI - Acute optic neuritis: Unmet clinical needs and model for new therapies. AB - Idiopathic demyelinating optic neuritis (ON) most commonly presents as acute unilateral vision loss and eye pain and is frequently associated with multiple sclerosis. Although emphasis is often placed on the good recovery of high contrast visual acuity, persistent deficits are frequently observed in other aspects of vision, including contrast sensitivity, visual field testing, color vision, motion perception, and vision-related quality of life. Persistent and profound structural and functional changes are often revealed by imaging and electrophysiologic techniques, including optical coherence tomography, visual evoked potentials, and nonconventional MRI. These abnormalities can impair patients' abilities to perform daily activities (e.g., driving, working) so they have important implications for patients' quality of life. In this article, we review the sequelae from ON, including clinical, structural, and functional changes and their interrelationships. The unmet needs in each of these areas are considered and the progress made toward meeting those needs is examined. Finally, we provide an overview of past and present investigational approaches for disease modification in ON. PMID- 26236760 TI - Update on biomarkers in neuromyelitis optica. AB - Neuromyelitis optica (NMO) (and NMO spectrum disorder) is an autoimmune inflammatory disease of the CNS primarily affecting spinal cord and optic nerves. Reliable and sensitive biomarkers for onset, relapse, and progression in NMO are urgently needed because of the heterogeneous clinical presentation, severity of neurologic disability following relapses, and variability of therapeutic response. Detecting aquaporin-4 (AQP4) antibodies (AQP4-IgG or NMO-IgG) in serum supports the diagnosis of seropositive NMO. However, whether AQP4-IgG levels correlate with disease activity, severity, response to therapy, or long-term outcomes is unclear. Moreover, biomarkers for patients with seronegative NMO have yet to be defined and validated. Collaborative international studies hold great promise for establishing and validating biomarkers that are useful in therapeutic trials and clinical management. In this review, we discuss known and potential biomarkers for NMO. PMID- 26236762 TI - Sleep disorder, chorea, and dementia associated with IgLON5 antibodies. PMID- 26236763 TI - Content Analysis of Trends in Print Magazine Tobacco Advertisements. AB - OBJECTIVES: To provide a descriptive and comparative content analysis of tobacco print magazine ads, with a focus on rhetorical and persuasive themes. METHODS: Print tobacco ads for cigarettes, cigars, e-cigarettes, moist snuff, and snus (N = 171) were content analyzed for the physical composition/ad format (e.g., size of ad, image, setting, branding, warning label) and the content of the ad (e.g., rhetorical themes, persuasive themes). RESULTS: The theme of pathos (that elicits an emotional response) was most frequently utilized for cigarette (61%), cigar (50%), and moist snuff (50%) ads, and the theme of logos (use of logic or facts to support position) was most frequently used for e-cigarette (85%) ads. Additionally, comparative claims were most frequently used for snus (e.g., "spit free," "smoke-free") and e-cigarette ads (e.g., "no tobacco smoke, only vapor," "no odor, no ash"). Comparative claims were also used in cigarette ads, primarily to highlight availability in different flavors (e.g., "bold," "menthol"). CONCLUSIONS: This study has implications for tobacco product marketing regulation, particularly around limiting tobacco advertising in publications with a large youth readership and prohibiting false or misleading labels, labeling, and advertising for tobacco products, such as modified risk (unless approved by the FDA) or therapeutic claims. PMID- 26236764 TI - Validation of a Respiratory Symptom Questionnaire in Adolescent Smokers. AB - OBJECTIVES: Adolescent smokers experience respiratory symptoms as a consequence of smoking, which may be impacted by harm-reduction products. We sought to validate the American Thoracic Society Questionnaire (ATSQ), a measure of respiratory symptoms, in adolescent smokers. METHODS: Data were drawn from 2 studies of adolescents (ages 14 to 19). Study 1 (N = 118) comprised daily smokers. Study 2 (N = 216) comprised 118 smokers and 98 nonsmokers; a subset of the total sample comprised 70 matched pairs of smokers and non-smokers. RESULTS: The ATSQ showed high internal consistency. In Study 1, ATSQ scores were positively correlated with dependence. In Study 2, scores were positively correlated with CO, cotinine, and cigarettes per day; and scores were significantly greater for smokers than non-smokers. CONCLUSIONS: The ATSQ offers a psychometrically valid method for measuring respiratory symptoms in adolescent smokers. PMID- 26236766 TI - Smartphone applications to support weight loss: current perspectives. AB - Lower cost alternatives are needed for the traditional in-person behavioral weight loss programs to overcome challenges of lowering the worldwide prevalence of overweight and obesity. Smartphones have become ubiquitous and provide a unique platform to aid in the delivery of a behavioral weight loss program. The technological capabilities of a smartphone may address certain limitations of a traditional weight loss program, while also reducing the cost and burden on participants, interventionists, and health care providers. Awareness of the advantages smartphones offer for weight loss has led to the rapid development and proliferation of weight loss applications (apps). The built-in features and the mechanisms by which they work vary across apps. Although there are an extraordinary number of a weight loss apps available, most lack the same magnitude of evidence-based behavior change strategies typically used in traditional programs. As features develop and new capabilities are identified, we propose a conceptual model as a framework to guide the inclusion of features that can facilitate behavior change and lead to reductions in weight. Whereas the conventional wisdom about behavior change asserts that more is better (with respect to the number of behavior change techniques involved), this model suggests that less may be more because extra techniques may add burden and adversely impact engagement. Current evidence is promising and continues to emerge on the potential of smartphone use within weight loss programs; yet research is unable to keep up with the rapidly improving smartphone technology. Future studies are needed to refine the conceptual model's utility in the use of technology for weight loss, determine the effectiveness of intervention components utilizing smartphone technology, and identify novel and faster ways to evaluate the ever-changing technology. PMID- 26236765 TI - Predicted Impact of Nicotine Reduction on Smokers with Affective Disorders. AB - OBJECTIVES: In 2009 the FDA acquired the authority to reduce the nicotine content in cigarettes if appropriate for public health, prompting research to evaluate the implications of this policy scientifically. Studies in non-psychiatric populations show that reducing the nicotine content of cigarettes to non addictive levels reduces smoking rates and nicotine dependence. However, few studies have examined this hypothesis in vulnerable populations. METHODS: In this narrative review we examined the extant literature on the effects of nicotine reduction or cessation on symptoms of withdrawal, as well as psychiatric symptoms, among those with affective disorders. RESULTS: Following initial withdrawal from nicotine, smokers with affective disorders experience more severe mood disruption than smokers without these disorders. Use of very low nicotine content (VLNC) cigarettes during abstinence may help mitigate the mood-disrupting effects of initial abstinence. Once the initial effects of nicotine withdrawal on mood have passed, longer-term abstinence is associated with psychiatric improvement rather than worsening. CONCLUSIONS: These findings suggest that if a national nicotine reduction policy were to be implemented, smokers with affective disorders would need additional support to overcome initial withdrawal but that long-term outcomes would likely be positive. PMID- 26236767 TI - The HOPE social media intervention for global HIV prevention in Peru: a cluster randomised controlled trial. AB - BACKGROUND: Social media technologies offer new approaches to HIV prevention and promotion of testing. We examined the efficacy of the Harnessing Online Peer Education (HOPE) social media intervention to increase HIV testing among men who have sex with men (MSM) in Peru. METHODS: In this cluster randomised controlled trial, Peruvian MSM from Greater Lima (including Callao) who had sex with a man in the past 12 months, were 18 years of age or older, were HIV negative or serostatus unknown, and had a Facebook account or were willing to create one (N=556) were randomly assigned (1:1) by concealed allocation to join intervention or control groups on Facebook for 12 weeks. For the intervention, Peruvian MSM were trained and assigned to be HIV prevention mentors (peer-leaders) to participants in Facebook groups. The interventions period lasted 12 weeks. Participants in control groups received an enhanced standard of care, including standard offline HIV prevention available in Peru and participation in Facebook groups (without peer leaders) that provided study updates and HIV testing information. After accepting a request to join the groups, continued participation was voluntary. Participants also completed questionnaires on HIV risk behaviours and social media use at baseline and 12 week follow-up. The primary outcome was the number of participants who received a free HIV test at a local community clinic. The facebook groups were analysed as clusters to account for intracluster correlations. This trial is registered with ClinicalTrials.gov, number NCT01701206. FINDINGS: Of 49 peer-leaders recruited, 34 completed training and were assigned at random to the intervention Facebook groups. Between March 19, 2012, and June 11, 2012, and Sept 26, 2012, and Dec 19, 2012, 556 participants were randomly assigned to intervention groups (N=278) or control groups (N=278); we analyse data for 252 and 246. 43 participants (17%) in the intervention group and 16 (7%) in the control groups got tested for HIV (adjusted odds ratio 2.61, 95% CI 1.55-4.38). No adverse events were reported. INTERPRETATION: Development of peer-mentored social media communities seemed to be an efficacious method to increase HIV testing among high-risk populations in Peru. Results suggest that the HOPE social media intervention could improve HIV testing rates among MSM in Peru. FUNDING: National Institute of Mental Health. PMID- 26236768 TI - Decomposition and Mineralization of Dimethyl Phthalate in an Aqueous Solution by Wet Oxidation. AB - Dimethyl phthalate (DMP) was treated via wet oxygen oxidation process (WOP). The decomposition efficiency eta DMP of DMP and mineralization efficiency eta TOC of total organic carbons were measured to evaluate the effects of operation parameters on the performance of WOP. The results revealed that reaction temperature T is the most affecting factor, with a higher T offering higher eta DMP and eta TOC as expected. The eta DMP increases as rotating speed increases from 300 to 500 rpm with stirring enhancement of gas liquid mass transfer. However, it exhibits reduction effect at 700 rpm due to purging of dissolved oxygen by overstirring. Regarding the effects of pressure P T, a higher P T provides more oxygen for the forward reaction with DMP, while overhigh P T increases the absorption of gaseous products such as CO2 and decomposes short chain hydrocarbon fragments back into the solution thus hindering the forward reaction. For the tested P T of 2.41 to 3.45 MPa, the results indicated that 2.41 MPa is appropriate. A longer reaction time of course gives better performance. At 500 rpm, 483 K, 2.41 MPa, and 180 min, the eta DMP and eta TOC are 93 and 36%, respectively. PMID- 26236769 TI - Conventional, Hybrid, or Electric Vehicles: Which Technology for an Urban Distribution Centre? AB - Freight transport has an important impact on urban welfare. It is estimated to be responsible for 25% of CO2 emissions and up to 50% of particles matters generated by the transport sector in cities. Facing that problem, the European Commission set the objective of reaching free CO2 city logistics by 2030 in major urban areas. In order to achieve this goal, electric vehicles could be an important part of the solution. However, this technology still faces a number of barriers, in particular high purchase costs and limited driving range. This paper explores the possible integration of electric vehicles in urban logistics operations. In order to answer this research question, the authors have developed a fleet size and mix vehicle routing problem with time windows for electric vehicles. In particular, an energy consumption model is integrated in order to consider variable range of electric vehicles. Based on generated instances, the authors analyse different sets of vehicles in terms of vehicle class (quadricycles, small vans, large vans, and trucks) and vehicle technology (petrol, hybrid, diesel, and electric vehicles). Results show that a fleet with different technologies has the opportunity of reducing costs of the last mile. PMID- 26236770 TI - Charging Guidance of Electric Taxis Based on Adaptive Particle Swarm Optimization. AB - Electric taxis are playing an important role in the application of electric vehicles. The actual operational data of electric taxis in Shenzhen, China, is analyzed, and, in allusion to the unbalanced time availability of the charging station equipment, the electric taxis charging guidance system is proposed basing on the charging station information and vehicle information. An electric taxis charging guidance model is established and guides the charging based on the positions of taxis and charging stations with adaptive mutation particle swarm optimization. The simulation is based on the actual data of Shenzhen charging stations, and the results show that electric taxis can be evenly distributed to the appropriate charging stations according to the charging pile numbers in charging stations after the charging guidance. The even distribution among the charging stations in the area will be achieved and the utilization of charging equipment will be improved, so the proposed charging guidance method is verified to be feasible. The improved utilization of charging equipment can save public charging infrastructure resources greatly. PMID- 26236771 TI - A Novel Range-Extended Strategy for Fuel Cell/Battery Electric Vehicles. AB - The range-extended electric vehicle is proposed to improve the range anxiety drivers have of electric vehicles. Conventionally, a gasoline/diesel generator increases the range of an electric vehicle. Due to the zero-CO2 emission stipulations, utilizing fuel cells as generators raises concerns in society. This paper presents a novel charging strategy for fuel cell/battery electric vehicles. In comparison to the conventional switch control, a fuzzy control approach is employed to enhance the battery's state of charge (SOC). This approach improves the quick loss problem of the system's SOC and thus can achieve an extended driving range. Smooth steering experience and range extension are the main indexes for development of fuzzy rules, which are mainly based on the energy management in the urban driving model. Evaluation of the entire control system is performed by simulation, which demonstrates its effectiveness and feasibility. PMID- 26236772 TI - Hierarchical Control Strategy for the Cooperative Braking System of Electric Vehicle. AB - This paper provides a hierarchical control strategy for cooperative braking system of an electric vehicle with separated driven axles. Two layers are defined: the top layer is used to optimize the braking stability based on two sliding mode control strategies, namely, the interaxle control mode and signal axle control strategies; the interaxle control strategy generates the ideal braking force distribution in general braking condition, and the single-axle control strategy can ensure braking safety in emergency braking condition; the bottom layer is used to maximize the regenerative braking energy recovery efficiency with a reallocated braking torque strategy; the reallocated braking torque strategy can recovery braking energy as much as possible in the premise of meeting battery charging power. The simulation results show that the proposed hierarchical control strategy is reasonable and can adapt to different typical road surfaces and load cases; the vehicle braking stability and safety can be guaranteed; furthermore, the regenerative braking energy recovery efficiency can be improved. PMID- 26236773 TI - Detecting and Preventing Sybil Attacks in Wireless Sensor Networks Using Message Authentication and Passing Method. AB - Wireless sensor networks are highly indispensable for securing network protection. Highly critical attacks of various kinds have been documented in wireless sensor network till now by many researchers. The Sybil attack is a massive destructive attack against the sensor network where numerous genuine identities with forged identities are used for getting an illegal entry into a network. Discerning the Sybil attack, sinkhole, and wormhole attack while multicasting is a tremendous job in wireless sensor network. Basically a Sybil attack means a node which pretends its identity to other nodes. Communication to an illegal node results in data loss and becomes dangerous in the network. The existing method Random Password Comparison has only a scheme which just verifies the node identities by analyzing the neighbors. A survey was done on a Sybil attack with the objective of resolving this problem. The survey has proposed a combined CAM-PVM (compare and match-position verification method) with MAP (message authentication and passing) for detecting, eliminating, and eventually preventing the entry of Sybil nodes in the network. We propose a scheme of assuring security for wireless sensor network, to deal with attacks of these kinds in unicasting and multicasting. PMID- 26236774 TI - On Intuitionistic Fuzzy beta-Almost Compactness and beta-Nearly Compactness. AB - The concept of intuitionistic fuzzy beta-almost compactness and intuitionistic fuzzy beta-nearly compactness in intuitionistic fuzzy topological spaces is introduced and studied. Besides giving characterizations of these spaces, we study some of their properties. Also, we investigate the behavior of intuitionistic fuzzy beta-compactness, intuitionistic fuzzy beta-almost compactness, and intuitionistic fuzzy beta-nearly compactness under several types of intuitionistic fuzzy continuous mappings. PMID- 26236775 TI - Analysis of Ageing Effect on Li-Polymer Batteries. AB - Lithium-ion batteries are a key technology for current and future energy storage in mobile and stationary application. In particular, they play an important role in the electrification of mobility and therefore the battery lifetime prediction is a fundamental aspect for successful market introduction. Numerous studies developed ageing models capable of predicting battery life span. Most of the previous works compared the effect of the ageing factors to a battery's cycle life. These cycles are identical, which is not the case for electric vehicles applications. Indeed, most of the available information is based on results from laboratory testing, under very controlled environments, and using ageing protocols, which may not correctly reflect the actual utilization. For this reason, it is important to link the effect of duty cycles with the ageing of the batteries. This paper proposes a simple method to investigate the effect of the duty cycle on the batteries lifetime through tests performed on different cells for different kinds of cycle. In this way, a generic complex cycle can be seen as a composition of elemental cycles by means of Rainflow procedures. Consequently, the ageing due to any cycle can be estimated starting from the knowledge of simpler cycles. PMID- 26236776 TI - Identifying Patients with Undiagnosed COPD in Primary Care Settings: Insight from Screening Tools and Epidemiologic Studies. AB - OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, yet research suggests this disease is greatly underdiagnosed. This literature review sought to summarize the most common and significant variables associated with case-finding or missed cases of COPD to inform more effective and efficient detection of high-risk COPD patients in primary care. METHODS: PubMed and EMBASE were searched for articles describing case-finding and epidemiologic research to detect or characterize new cases of COPD. International studies in primary and non-primary care settings, published in English from 2002-2014, were eligible for inclusion. Studies related to risk factors for development of COPD were excluded. RESULTS: Of the 33 studies identified and reviewed, 21 were case-finding or screening and 12 were epidemiological, including cross-sectional, longitudinal, and retrospective designs. A range of variables were identified within and across studies. Variables common to both screening and epidemiological studies included age, smoking status, and respiratory symptoms. Seven significant predictors from epidemiologic studies did not appear in screening tools. No studies targeted discovery of higher risk patients such as those with reduced lung function or risks for exacerbations. CONCLUSION: Variables used to identify new cases of COPD or differentiate COPD cases and non-cases are wide- ranging, (from sociodemographic to self-reported health or health history variables), providing insight into important factors for case identification. Further research is underway to develop and test the best, smallest variable set that can be used as a screening tool to identify people with undiagnosed, high-risk COPD in primary care. PMID- 26236778 TI - Stuttering Lacunes: An Acute Role for Clopidogrel? AB - INTRODUCTION: Intravenous tissue plasminogen activator (IV tPA) has revolutionized the treatment of acute ischemic stroke. However, there remain situations when administration is relatively contraindicated (eg. , arrival outside the accepted treatment window, mild or rapidly improving symptoms). Optimal treatment in these situations is less clear. CASE SERIES: We describe a small case series of 7 patients presenting with fluctuating symptoms concerning for a capsular warning syndrome (acute isolated motor and/or sensory deficits without cortical signs, usually attributed to small vessel pathology), often referred to as a "stuttering lacune", who were orally loaded with 300mg of clopidogrel. Four of the 7 patients had complete resolution of their symptoms following the load. The others experienced stabilization of their deficits, but were discharged with mild persistent symptoms. Four patients had evidence of diffusion bright lesions on MRI, while the others had no evidence of infarction. None of the patients experienced hemorrhagic conversion of their infarct or other bleeding complications. CONCLUSION: Our experience suggests that acutely loading with clopidogrel may be both effective and well tolerated in the treatment of stuttering lacunes. PMID- 26236777 TI - The AXL Receptor is a Sensor of Ligand Spatial Heterogeneity. AB - The AXL receptor is a TAM (Tyro3, AXL, MerTK) receptor tyrosine kinase (RTK) important in physiological inflammatory processes such as blood clotting, viral infection, and innate immune-mediated cell clearance. Overexpression of the receptor in a number of solid tumors is increasingly appreciated as a key drug resistance and tumor dissemination mechanism. Although the ligand-receptor (Gas6 AXL) complex structure is known, literature reports on ligand-mediated signaling have provided conflicting conclusions regarding the influence of other factors such as phosphatidylserine binding, and a detailed, mechanistic picture of AXL activation has not emerged. Integrating quantitative experiments with mathematical modeling, we show here that AXL operates to sense local spatial heterogeneity in ligand concentration, a feature consistent with its physiological role in inflammatory cell responses. This effect arises as a result of an intricate reaction-diffusion interaction. Our results demonstrate that AXL functions distinctly from other RTK families, a vital insight for envisioned design of AXL-targeted therapeutic intervention. PMID- 26236779 TI - Feasibility of Single-Input Tracer Kinetic Modeling with Continuous-Time Formalism in Liver 4-Phase Dynamic Contrast-Enhanced CT. AB - The modeling of tracer kinetics with use of low-temporal-resolution data is of central importance for patient dose reduction in dynamic contrast-enhanced CT (DCE-CT) study. Tracer kinetic models of the liver vary according to the physiologic assumptions imposed on the model, and they can substantially differ in the ways how the input for blood supply and tissue compartments are modeled. In this study, single-input flow-limited (FL), Tofts-Kety (TK), extended TK (ETK), Hayton-Brady (HB), two compartment exchange (2CX), and adiabatic approximation to the tissue homogeneity (AATH) models were applied to the analysis of liver 4-phase DCE-CT data with fully continuous-time parameter formulation, including the bolus arrival time. The bolus arrival time for the 2CX and AATH models was described by modifying the vascular transport operator theory. Initial results indicate that single-input tracer kinetic modeling is feasible for distinguishing between hepatocellular carcinoma and normal liver parenchyma. PMID- 26236780 TI - Information-Preserving Pseudo-Enhancement Correction for Non-Cathartic Low-Dose Dual-Energy CT Colonography. AB - In CT colonography (CTC), orally administered positive-contrast fecal-tagging agents can cause artificial elevation of the observed radiodensity of adjacent soft tissue. Such pseudo-enhancement makes it challenging to differentiate polyps and folds reliably from tagged materials, and it is also present in dual-energy CTC (DE-CTC). We developed a method that corrects for pseudo-enhancement on DE CTC images without distorting the dual-energy information contained in the data. A pilot study was performed to evaluate the effect of the method visually and quantitatively by use of clinical non-cathartic low-dose DE-CTC data from 10 patients including 13 polyps covered partially or completely by iodine-based fecal tagging. The results indicate that the proposed method can be used to reduce the pseudo-enhancement distortion of DE-CTC images without losing material specific dual-energy information. The method has potential application in improving the accuracy of automated image-processing applications, such as computer-aided detection and virtual bowel cleansing in CTC. PMID- 26236781 TI - Application of Pseudo-enhancement Correction to Virtual Monochromatic CT Colonography. AB - In CT colonography, orally administered positive-contrast fecal-tagging agents are used for differentiating residual fluid and feces from true lesions. However, the presence of high-density tagging agent in the colon can introduce erroneous artifacts, such as local pseudo-enhancement and beam-hardening, on the reconstructed CT images, thereby complicating reliable detection of soft-tissue lesions. In dual-energy CT colonography, such image artifacts can be reduced by the calculation of virtual monochromatic CT images, which provide more accurate quantitative attenuation measurements than conventional single-energy CT colonography. In practice, however, virtual monochromatic images may still contain some pseudo-enhancement artifacts, and efforts to minimize radiation dose may enhance such artifacts. In this study, we evaluated the effect of image-based pseudo-enhancement post-correction on virtual monochromatic images in standard dose and low-dose dual-energy CT colonography. The mean CT values of the virtual monochromatic standard-dose CT images of 51 polyps and those of the virtual monochromatic low-dose CT images of 20 polyps were measured without and with the pseudo-enhancement correction. Statistically significant differences were observed between uncorrected and pseudo-enhancement-corrected images of polyps covered by fecal tagging in standard-dose CT (p < 0.001) and in low-dose CT (p < 0.05). The results indicate that image-based pseudo-enhancement post-correction can be useful for optimizing the performance of image-processing applications in virtual monochromatic CT colonography. PMID- 26236783 TI - Inspired and stabilized by nature: ribosomal synthesis of the human voltage gated ion channel (VDAC) into 2D-protein-tethered lipid interfaces. AB - We present an elegant synthesis and reconstitution approach for functional studies of voltage responsive membrane proteins. For such studies, we propose a planar architecture of an S-layer-supported lipid membrane as a suitable matrix for presenting unmodified membrane protein species, and here we focus on the voltage-dependent anion channel (VDAC) from human mitochondria. The presented cell-free strategy, in which VDAC proteins are synthesized in bacterial cell lysate, into a membrane structure, offers a great advantage in the study of such subtle membrane proteins over the conventional, cell-based synthesis approach in terms of reproducibility. The material-assay combination is superior over cell culture related synthesis and purification approaches as here we bypass by a one step synthesis procedure the complex cell culture, and expression and purification endeavours, and, moreover, the protein of interest never has to be detergent solubilized and had been synthesized de novo. We provide here a detailed description from the all over procedure and our first results, describing in detail the cell-free synthesis and robustness of such a material assay combination: functional VDAC protein species embedded in a planar membrane architecture and ready for electrochemical characterization. PMID- 26236782 TI - Application of mid-infrared (MIR) microscopy imaging for discrimination between follicular hyperplasia and follicular lymphoma in transgenic mice. AB - Mid-infrared (MIR) microscopy imaging is a vibrational spectroscopic technique that uses infrared radiation to image molecules of interest in thin tissue sections. A major advantage of this technology is the acquisition of local molecular expression profiles, while maintaining the topographic integrity of the tissue. Therefore, this technology has become an essential tool for the detection and characterization of the molecular components of many biological processes. Using this method, it is possible to investigate the spatial distribution of proteins and small molecules within biological systems by in situ analysis. In this study, we have evaluated the potential of mid-infrared microscopy imaging to study biochemical changes which distinguish between reactive lymphadenopathy and cancer in genetically modified mice with different phenotypes. We were able to demonstrate that MIR microscopy imaging and multivariate image analyses of different mouse genotypes correlated well with the morphological tissue features derived from HE staining. Using principal component analyses, we were also able to distinguish spectral clusters from different phenotype samples, particularly from reactive lymphadenopathy (follicular hyperplasia) and cancer (follicular lymphoma). PMID- 26236785 TI - Are metal-free pristine carbon nanotubes electrocatalytically active? AB - Metal-free (i.e., residual metallic impurities-blocked) carbon nanotubes (CNTs) do show electrocatalytic activity for H2 evolution, O2 evolution and O2 reduction reactions (HER, OER & ORR) in alkaline solutions, but their activities strongly depend on the number of walls or inner tubes with a maximum for CNTs with 2-3 walls. PMID- 26236784 TI - A combination of tri-modal cancer imaging and in vivo drug delivery by metal organic framework based composite nanoparticles. AB - Multifunctional Fe3O4@polyacrylic acid/Au nanoclusters/zeolitic imidazolate framework-8 nanoparticles (Fe3O4@PAA/AuNCs/ZIF-8 NPs) integrating tri-modal cancer imaging (magnetic resonance, computed X-ray tomography and fluorescence imaging) and chemotherapy into a single system were fabricated by using a facile, mild and reproducible strategy. The obtained NPs possess many merits including ultrahigh doxorubicin (DOX) loading capability (1.54 mg DOX per mg NPs), dual pH responsive controlled drug release, tri-modal cancer imaging ability, facile magnetic separation and good biocompatibility. Importantly, the NPs exhibit low systematic toxicity and high antitumor therapy efficacy in vivo through tail vein injection. Furthermore, the achievement of in vitro tri-modal cancer cell imaging reveals the potential of Fe3O4@PAA/AuNCs/ZIF-8 NPs for cancer diagnosis and visualized-synergistic therapy. Taken together, Fe3O4@PAA/AuNCs/ZIF-8 NPs can be developed as a promising theranostic agent that combines multiple capabilities for cancer treatment. PMID- 26236786 TI - Non-covalent phosphorylcholine coating reduces protein adsorption and phagocytic uptake of microparticles. AB - Phosphorylcholine co-polymer was assembled on model polystyrene microparticles through a simple, widely-applicable ethanol coating process. The coating rendered particles resistant to protein adsorption and phagocytosis by macrophages, making it useful for a range of biological applications. PMID- 26236787 TI - Corannulene derivatives with low LUMO levels and dense convex-concave packing for n-channel organic field-effect transistors. AB - Electron-deficient corannulene derivatives incorporating cyano and imide groups into the corannulene core were synthesized, which showed low LUMO (lowest unoccupied molecular orbital) levels and dense convex-concave packing structures in single crystals. These two features help to realize the first n-channel organic field-effect transistors (OFETs) in air based on corannulene derivatives. PMID- 26236788 TI - Distinct reactivities on segmented selenium nanorods. AB - We demonstrate a new approach to synthesize several unique nanostructures by tuning the selective reactivities on individual symmetry-breaking segmented selenium nanorods (SBS-SeNRs). The segment-selective reactions from thiolated silane endowed the formation of float-like SBS-SeNR@SiO2 with a silica coating on the t-Se segment. Several other unique nanostructures were further synthesized by applying other selective reactions, such as Se chemical removal and nanogold deposition. Such a segmented nanomaterial of SBS-SeNRs acts as a new chemical template for preparing various segmented nanocomposites. PMID- 26236789 TI - Production of ultra-deep sulfur-free diesels using a sustainable catalytic system based on UiO-66(Zr). AB - The porous metal-organic framework UiO-66(Zr) obtained via non modulated synthesis, has revealed to be a notable heterogeneous catalyst, enabling extremely fast and very efficient desulfurization of a multicomponent model diesel and also a real diesel fuel. PMID- 26236791 TI - High capacity and exceptional cycling stability of ternary metal sulfide nanorods as Li ion battery anodes. AB - Ternary spinel NiCo2S4 nanorods are tested for the first time as anode electrodes for Li ion batteries. When the electrode is fabricated using the carboxymethyl cellulose-polyacryl amide composite binder, it is found to restrict or suppress the formation of a polymeric gel passivation layer. As a result, the electrode not only delivers excellent specific capacity, but also an outstanding rate and cyclic stability with almost no decay up to 100 charge-discharge cycles. PMID- 26236790 TI - Pulsed EPR spectroscopy distance measurements of DNA internally labelled with Gd(3+)-DOTA. AB - Gd(3+) is increasingly used in EPR spectroscopy due to its increased intracellular stability and signal-to-noise ratios. Here we present the incorporation of Gd(3+)-DOTA into internal positions in DNA. Distance measurements via pulsed Electron Paramagnetic Resonance (EPR) spectroscopy in vitro and in cellula proved enhanced stability and efficiency compared to nitroxide labels. PMID- 26236792 TI - Acute management of shoulder dislocations. PMID- 26236793 TI - Obesity, orthopaedics, and outcomes. PMID- 26236794 TI - Japanese Neurosurgeons and Microsurgical Anatomy: A Historical Review. AB - Research in microneurosurgical anatomy has contributed to great advances in neurosurgery in the last 40 years. Many Japanese neurosurgeons have traveled abroad to study microsurgical anatomy and played major roles in advancing and spreading the knowledge of anatomy, overcoming their disadvantage that the cadaver study has been strictly limited inside Japan. In Japan, they initiated an educational system for surgical anatomy that has contributed to the development and standardization of Japanese neurosurgery. For example, the Japanese Society for Microsurgical Anatomy started an annual educational meeting in the middle of 1980s and published its proceedings in Japanese every year for approximately 20 years. These are some of the achievements that bring worldwide credit to Japanese neurosurgeons. Not only should Japanese neurosurgeons improve their educational system but they should also contribute to the international education in this field, particularly in Asia. PMID- 26236795 TI - Stem Cell Transplantation Enhances Endogenous Brain Repair after Experimental Stroke. AB - Stem cell transplantation for stroke treatment has been a promising therapy in small and large animal models, and many clinical trials are ongoing to establish this strategy in a clinical setting. However, the mechanism underlying functional recovery after stem cell transplantation has not been fully established and there is still a need to determine the ideal subset of stem cells for such therapy. We herein reviewed the recent evidences showing the underlying mechanism of functional recovery after cell transplantation, focusing on endogenous brain repair. First, angiogenesis/neovascularization is promoted by trophic factors including vascular endothelial growth factor secreted from stem cells, and stem cells migrated to the lesion along with the vessels. Second, axonal sprouting, dendritic branching, and synaptogenesis were enhanced altogether in the both ipsilateral and contralateral hemisphere remapping the pyramidal tract across the board. Finally, endogenous neurogenesis was also enhanced although little is known how much these neurogenesis contribute to the functional recovery. Taken together, it is clear that stem cell transplantation provides functional recovery via endogenous repair enhancement from multiple ways. This is important to maximize the effect of stem cell therapy after stroke, although it is still undetermined which repair mechanism is mostly contributed. PMID- 26236796 TI - Regenerative Medicine for Parkinson's Disease. AB - Regenerative medicine for Parkinson's disease (PD) is expected to develop dramatically with the advancement of biotechnology as represented by induced pluripotent stem cells. Existing therapeutic strategy for PD consists of medication using L-DOPA, surgery such as deep brain stimulation and rehabilitation. Current treatment cannot stop the progression of the disease, although there is definite therapeutic effect. True neurorestoration is strongly desired by regenerative medicine. This review article describes the historical development of regenerative medicine for PD, with a focus on fetal nigral cell transplantation and glial cell line-derived neurotrophic factor infusion. Subsequently, the current status of regenerative medicine for PD in terms of cell therapy and gene therapy are reviewed. In the end, the future direction to realize regenerative medicine for PD is discussed. PMID- 26236797 TI - Trends and Outcomes in the Treatment of Gliomas Based on Data during 2001-2004 from the Brain Tumor Registry of Japan. AB - The committee of Brain Tumor Registry of Japan (BTRJ) was founded in 1973 and conducts surveys and analyses of incidence, therapeutic methods, and treatment outcomes of primary and metastatic brain tumors with the cooperation of the Japan Neurosurgical Society members. Newly diagnosed 3,000-4,000 primary brain tumors and 600-1,000 brain metastases patients were enrolled in each year. This report describes the trends and treatment outcomes of gliomas from BTRJ volume 13, including 13,431 patients with primary brain tumors who newly started treatment from 2001 to 2004. Data from 382 diffuse astrocytomas (DAs), 121 oligodendrogliomas (OLs), 90 oligoastrocytomas (OAs), 513 anaplastic astrocytomas (AAs), 126 anaplastic oligodendrogliomas (AOs), 106 anaplastic oligoastrocytomas (AOAs), and 1,489 glioblastomas (GBMs) were analyzed for overall survival (OS) and progression free survival (PFS) depending on age, symptoms, Karnofsky performance status, location of the tumor, extent of resection (EOR), initial radiotherapy and chemotherapy. The 5-year PFS rates of the patients with DA, OL+OA, AA, AO+AOA, and GBM were 57.0%, 74.6%, 28.7%, 54.0%, and 9.2%, and the 5 year OS rates were 75.0%, 90.0%, 41.1%, 68.2%, and 10.1%, respectively. Higher EOR>=75% in DA and OL+OA and that >=50% in AA, AO+AOA, and GBM significantly prolonged OS. Complications and cause of death were also reported. BTRJ had been edited for all the patients, researchers, and especially for clinicians at bedside to give useful information about brain tumors and to contribute to the advances in brain tumor treatment. This report revealed various clinical problematic issues pertaining to the diagnosis and treatment of gliomas. PMID- 26236798 TI - Intraoperative Functional Mapping and Monitoring during Glioma Surgery. AB - Glioma surgery represents a significant advance with respect to improving resection rates using new surgical techniques, including intraoperative functional mapping, monitoring, and imaging. Functional mapping under awake craniotomy can be used to detect individual eloquent tissues of speech and/or motor functions in order to prevent unexpected deficits and promote extensive resection. In addition, monitoring the patient's neurological findings during resection is also very useful for maximizing the removal rate and minimizing deficits by alarming that the touched area is close to eloquent regions and fibers. Assessing several types of evoked potentials, including motor evoked potentials (MEPs), sensory evoked potentials (SEPs) and visual evoked potentials (VEPs), is also helpful for performing surgical monitoring in patients under general anesthesia (GA). We herein review the utility of intraoperative mapping and monitoring the assessment of neurological findings, with a particular focus on speech and the motor function, in patients undergoing glioma surgery. PMID- 26236799 TI - Pathology and Molecular Genetics of Meningioma: Recent Advances. AB - Meningiomas are the most common intracranial primary neoplasm in adults. Although the spectrum of clinical and molecular genetic issues regarding meningiomas remains undefined, novel genetic alterations that are associated with tumor morphology, malignancy, or location have recently been discovered. This review focuses on recent advances in understanding of the heterogenous pathology of meningiomas, particularly on associations between the clinical, histological, etiological, epidemiological, and molecular genetical aspects of the neoplasm. PMID- 26236800 TI - Pathology and Genetics of Diffuse Gliomas in Adults. AB - The current World Health Organization (WHO) classification of tumors of the central nervous system (CNS) is essentially a lineage-oriented classification based on a presumable developmental tree of CNS. A four-tiered WHO grading scheme has been successfully applied to a spectrum of diffusely infiltrative astrocytomas, but it is not fully applicable to other gliomas, including oligodendrogliomas and ependymomas. Recent genetic studies have revealed that the major categories of gliomas, such as circumscribe astrocytomas, infiltrating astrocytomas/oligodendrogliomas, and glioblastoma, roughly correspond to major genetic alterations, including isocitrate dehydrogenases (IDHs) 1/2 mutations, TP53 mutations, co-deletion of chromosome arms 1p/19q, and BRAF mutation/fusion. These genetic alterations are clinically significant in terms of the response to treatment(s) and/or the prognosis. It is, thus, rational that future classification of gliomas should be based on genotypes, rather than phenotypes, although the genetic features of each tumor are not sufficiently understood at present to draw a complete map of the gliomas, and genetic testing is not yet available worldwide, particularly in Asian and African countries. This review summarizes the current concepts of the WHO classification, as well as the current understanding of the major genetic alterations in glioma and the potential use of these alterations as diagnostic criteria. PMID- 26236801 TI - Dose-dense Temozolomide: Is It Still Promising? AB - Glioblastoma (GBM) has proven to be incurable despite recent progress on its standard of care using temozolomide (TMZ) as the main trunk of initial therapy for newly diagnosed GBM. One of the main reasons accounting for the dismal prognosis is attributed to lack of active therapeutic regimens at recurrence. Since TMZ is the most active cytotoxic agent against GBM, and the standard dosing of TMZ has shown favorable safety profile in clinical trials, re-challenge with TMZ in increased dose density schedules for recurrent tumors that have evaded from prior standard TMZ therapy appears to be a rational approach and has been intensively exploited. A number of phase II clinical trials using different alternating scheduling of dose-dense TMZ (ddTMZ) have shown superior efficacy over the standard TMZ or historical controls with other alkylating agents including nitrosoureas and procarbazine. One ddTMZ schedule, consisting of a 21 days on/7-days off regimen was applied to newly-diagnosed GBM as the adjuvant monotherapy after completion of combined radiation and TMZ and failed to demonstrate survival benefit in a large phase III trial (RTOG 0525). Thus its role in TMZ-pretreated, recurrent GBM should be carefully pursuit in randomized trials, e.g., planned JCOG 1308 trial comparing a 7-days on/7-days off ddTMZ regimen used upfront at the first relapse followed by bevacizumab on progression versus bevacizumab alone, investigating whether insertion of ddTMZ prior to bevacizumab could bestow better outcome in the recurrent setting. In this article, mode of action, past trials, and future directions of ddTMZ therapy are discussed. PMID- 26236802 TI - Pathophysiology, Diagnosis, and Treatment of Radiation Necrosis in the Brain. AB - New radiation modalities have made it possible to prolong the survival of individuals with malignant brain tumors, but symptomatic radiation necrosis becomes a serious problem that can negatively affect a patient's quality of life through severe and lifelong effects. Here we review the relevant literature and introduce our original concept of the pathophysiology of brain radiation necrosis following the treatment of brain, head, and neck tumors. Regarding the pathophysiology of radiation necrosis, we introduce two major hypotheses: glial cell damage or vascular damage. For the differential diagnosis of radiation necrosis and tumor recurrence, we focus on the role of positron emission tomography. Finally, in accord with our hypothesis regarding the pathophysiology, we describe the promising effects of the anti-vascular endothelial growth factor antibody bevacizumab on symptomatic radiation necrosis in the brain. PMID- 26236803 TI - Adult growth hormone deficiency: current concepts. AB - The clinical syndrome of adult growth hormone deficiency (AGHD) was widely recognized in the 1980s. In this review, we first describe the clinical features and diagnosis of AGHD and then state the effects of growth hormone (GH) therapy for these patients. The main characteristics of AGHD are abnormal body composition, dyslipidemia, insulin resistance, and an impaired quality of life (QoL) due to decreased psychological well-being. For diagnosing AGHD, the international consensus guidelines have suggested that an insulin tolerance test (ITT) is the gold standard, but in Japan, the growth hormone releasing peptide-2 (GHRP-2) test is available and is recommended as a convenient and safe GH stimulating test. The cut-off for diagnosing severe AGHD is a peak GH concentration of 9 g/L during the GHRP-2 test. Since 2006, GH therapy has been approved for Japanese patients with severe AGHD. For adults, GH replacement therapy should be initiated at a low dose (3 g/kg body weight/day), followed by individualized dose titration while monitoring patients' clinical status and serum insulin-like growth factor-I (IGF-I) concentrations. A variety of favorable effects of GH replacement have been indicated; however, it has not yet been established fully whether there is a direct effect of GH treatment on reducing mortality. PMID- 26236804 TI - Medical management of functioning pituitary adenoma: an update. AB - The treatment of functioning pituitary adenoma (FPA) must achieve endocrinological remission as well as tumor size reduction. The first-line treatment of FPA except prolactinoma is transsphenoidal surgery (TSS). Medical treatments and/or radiation will be applied as adjuvant therapies succeeding to TSS. In patients with prolactinoma, dopamine agonists, especially cabergoline, are quite efficient. Dopamine agonists decrease plasma prolactin levels and induce shrinkage in most patients and can be ceased in some of them. In patients with acromegaly, dopamine agonists, somatostatin analogues, and growth hormone receptor antagonist have been used as a monotherapy or the combination, and the high remission rate can be achieved. Pasireotide having high affinity to type 5 somatostatin receptors will be available for the patients presenting resistance against type 2 receptor agonists, such as octreotide and lanreotide. The preceding treatment with somatostatin analogues is beneficial for improving the success rate of TSS. The chimera compounds of somatostatin analogues and dopamine agonists have been investigated. The medical treatments of Cushing's disease are challenging, if TSS is not successful. To suppress ACTH secretion, dopamine agonists and somatostatin analogues have been examined, but neither came to show a sufficient effect. Pasireotide reduces urinary cortisol excretion with a high remission rate. Adrenal enzyme inhibitors (AEIs), such as metyrapone, can inhibit cortisol synthesis form adrenal glands promptly and sufficiently in most of patients. LCI699, a newly developed AEI, is more potent than metyrapone and will be available. We should use available medical treatments for improving the prognosis and quality of life. PMID- 26236805 TI - Indication and limitations of endoscopic extended transsphenoidal surgery for craniopharyngioma. AB - The transsphenoidal approach has been utilized in intrasellar craniopharyngioma surgeries. However, the advent of endoscopic extended transsphenoidal approach (EETSA) has expanded its indication to suprasellar craniopharyngiomas. We compared the indication and limitations of EETSA to those of unilateral basal interhemispheric approach (UBIHA), which presents similar indications for surgery. We analyzed 30 patients with tumors located below the foramen of Monro and the lateral boundary extending slightly beyond the internal carotid artery (UBIHA: N=18; EETSA: N=12). Postoperative magnetic resonance imaging (MRI) revealed gross total resection in 10 patients in the EETSA group (83.3%) and 12 in the UBIHA group (66.7%). Postoperative MRI in the EETSA group revealed residual tumor at the cavernous sinus in one patient, at the prepontine in one; in the UBIHA group, residual tumors were located in the retrochiasmatic area in two patients, infundibulum-hypothalamus in one, on the stalk in one, and in the intrasellar region in two. No intergroup differences were observed in the preservation of pituitary function and postoperative improvement of visual function. The extent of resection was better with EETSA than with UBIHA. EETSA is considered the first-line therapy because the distance between the optic chiasm and the superior border of the pituitary is large; the lateral extension does not go beyond the internal carotid artery; and the tumor does not extend inferiorly beyond the posterior clinoid process. However, in patients showing poorly developed sphenoid sinuses or pituitary stalks anterior to the tumor, surgery is difficult regardless of the selection criteria. PMID- 26236806 TI - Endoscopic endonasal skull base surgery: advantages, limitations, and our techniques to overcome cerebrospinal fluid leakage: technical note. AB - In recent years, resections of midline skull base tumors have been conducted using endoscopic endonasal skull base (EESB) approaches. Nevertheless, many surgeons reported that cerebrospinal fluid (CSF) leakage is still a major complication of these approaches. Here, we report the results of our 42 EESB surgeries and discuss the advantages and limits of this approach for resecting various types of tumors, and also report our technique to overcome CSF leakage. All 42 cases involved midline skull base tumors resected using the EESB technique. Dural incisions were closed using nasoseptal flaps and fascia patch inlay sutures. Total removal of the tumor was accomplished in seven pituitary adenomas (33.3%), five craniopharyngiomas (62.5%), five tuberculum sellae meningiomas (83.3%), three clival chordomas (100%), and one suprasellar ependymoma. Residual regions included the cavernous sinus, the outside of the intracranial part of the internal carotid artery, the lower lateral part of the posterior clivus, and the posterior pituitary stalk. Overall incidence of CSF leakage was 7.1%. Even though the versatility of the approach is limited, EESB surgery has many advantages compared to the transcranial approach for managing mid-line skull base lesions. To avoid CSF leakage, surgeons should have skills and techniques for complete closure, including use of the nasoseptal flap and fascia patch inlay techniques. PMID- 26236807 TI - Usefulness of intraoperative monitoring of visual evoked potentials in transsphenoidal surgery. AB - Postoperative visual outcome is a major concern in transsphenoidal surgery (TSS). Intraoperative visual evoked potential (VEP) monitoring has been reported to have little usefulness in predicting postoperative visual outcome. To re-evaluate its usefulness, we adapted a high-power light-stimulating device with electroretinography (ERG) to ascertain retinal light stimulation. Intraoperative VEP monitoring was conducted in TSSs in 33 consecutive patients with sellar and parasellar tumors under total venous anesthesia. The detectability rates of N75, P100, and N135 were 94.0%, 85.0%, and 79.0%, respectively. The mean latencies and amplitudes of N75, P100, and N135 were 76.8+/-6.4 msec and 4.6+/-1.8 MUV, 98.0+/ 8.6 msec and 5.0+/-3.4 MUV, and 122.1+/-16.3 msec and 5.7+/-2.8 MUV, respectively. The amplitude was defined as the voltage difference from N75 to P100 or P100 to N135. The criterion for amplitude changes was defined as a >50% increase or 50% decrease in amplitude compared to the control level. The surgeon was immediately alerted when the VEP changed beyond these thresholds, and the surgical manipulations were stopped until the VEP recovered. Among the 28 cases with evaluable VEP recordings, the VEP amplitudes were stable in 23 cases and transiently decreased in 4 cases. In these 4 cases, no postoperative vision deterioration was observed. One patient, whose VEP amplitude decreased without subsequent recovery, developed vision deterioration. Intraoperative VEP monitoring with ERG to ascertain retinal light stimulation by the new stimulus device was reliable and feasible in preserving visual function in patients undergoing TSS. PMID- 26236808 TI - Transoral vs. endoscopic endonasal approach for clival/upper cervical chordoma. AB - The surgical results of 18 cases of clival/upper cervical chordoma treated in the last decade via the endoscopic endonasal approach (EEA, 9 cases) and the transoral-transpalatal approach (TO-TPA, 9 cases) were compared. Each group showed the same incidence of subdural invasion, with 5 cases each. The superior (frontal base) and lateral surgical fields were wider by EEA, but the inferior view lower than the cranio-vertebral junction (CVJ) was wider by TO-TPA. Gross total removal was achieved in 3 cases in the EEA group, but in only 1 case in the TO-TPA group. Differences in radicality might be due to the extent of the lateral and subdural overview. However for large tumors extending below the CVJ, TO-TPA was the only viable approach for surgical removal. Surgical complications were higher in the EEA (4 cases) than the TO-TPA group (1 case), and were mainly caused by aggressive management of subdural invasion in the EEA group. Post operative oral intake was earlier and the operative time was shorter in the EEA group. The surgical results were more radical and less invasive in the EEA group than the TO-TPA group. However in tumors extending below the CVJ, the surgical field in EEA was limited, indicating the need to use the transoral route or a combination of routes. A higher complication rate following subdural management was a negative factor that requires improvement in the EEA group and two-staged EEA followed by a transcranial approach may be considered for the cases with subdural invasion. PMID- 26236809 TI - Endoscopic endonasal surgical approach to the oculomotor trigone from the cavernous sinus. AB - Knowledge of anatomy visualized endoscopically is necessary to perform endoscopic surgical procedures safely. The cavernous sinuses are complicated structures with major blood vessels and nerves seated deeply in the center of the skull base. Anatomical orientation during surgery is essential for deep and narrow skull base surgery. While performing surgery involving the cavernous sinuses, understanding of the structures identifiable via a transsphenoidal view can allow comprehension of the relationship between a lesion and the surrounding structures, thus preventing intraoperative complications. The objective of this study was to dissect the neurovascular structures in the cavernous sinus deeply inside the oculomotor trigone through a transsphenoidal view, and to determine the relationships among anatomical landmarks in the path of surgery. Ten fresh silicone-injected cadaveric heads were evaluated. Four millimeter-diameter rigid endoscopes with 0 degrees and 30 degrees rod-lenses were utilized to perform an endonasal transsphenoidal approach. The detailed position and course of the major components in each cavernous sinus were assessed under panoramic view. We also validated the utility of this approach by successfully excising a huge pituitary adenoma. PMID- 26236810 TI - Endoscopic endonasal approach to the middle cranial fossa through the cavernous sinus triangles: anatomical considerations. AB - The lateral limit of endoscopic endonasal surgery has yet to be defined. The aim of this study was to investigate the lateral limit of endoscopic endonasal surgery at the level of the sphenoid sinus. Access from the sphenoid sinus to the middle cranial fossa through the cavernous sinus triangles was evaluated by cadaver dissection. Anatomical analysis demonstrated that the medial temporal dura mater was exposed through the anterior area of the clinoidal triangle, anteromedial triangle, and superior area of the anterolateral triangle, indicating potential corridors to the middle cranial fossa. This study suggests that the cavernous sinus triangles are applicable in selected cases to manage middle cranial fossa lesions by endoscopic endonasal surgery. PMID- 26236811 TI - Analysis of the bacterial flora in the nasal cavity and the sphenoid sinus mucosa in patients operated on with an endoscopic endonasal transsphenoidal approach. AB - The aim of this study was to analyze the bacterial flora in the nasal cavity and sphenoid sinus and evaluate the sensitivity of these bacteria to antibiotics that can be used to prevent postoperative meningitis. Bacteria of the preoperative nasal cavity and intraoperative sphenoid sinus mucosa were cultured and analyzed in 40 patients (20 men and 20 women; mean age, 52.2 years) who underwent endoscopic transsphenoidal surgery. The sensitivity of these bacteria to cephalosporin, a representative prophylactic antibiotic, was examined. Staphylococcus epidermidis was the most frequently detected species in both spaces; 24 (38.7%) of 62 isolates in the nasal cavity and 26 (37.1%) of 70 isolates in the sphenoid sinus. In contrast, Corynebacterium species were found mainly in the nasal cavity, and anaerobic bacteria were found only in the sphenoid sinus. Bacteria that were resistant to cephalosporin were found in the nasal cavity in 3.2% of patients and in the sphenoid sinus in 20% of patients. In conclusion, the composition of bacterial flora, including bacteria that are resistant to prophylactic antibiotics, differs between the nasal cavity and the sphenoid sinus. PMID- 26236812 TI - Current perioperative management of anticoagulant and antiplatelet use in neuroendovascular therapy: analysis of JR-NET1 and 2. AB - To evaluate current perioperative antithrombotic management in neuroendovascular therapy in Japan, we analyzed perioperative anticoagulant and antiplatelet use in various procedures and examined their relationships with periprocedural adverse events. Patient's data from nationwide surveys administered by the Japanese Registry of Neuroendovascular Therapy (JR-NET) between January 2005 and December 2007 (JR-NET1) and January 2008 and December 2009 (JR-NET2) were retrospectively analyzed. Compared to JR-NET1, the frequency of perioperative antiplatelet therapy and dual or triple therapy were increased for either aneurysm coiling and percutaneous transluminal angioplasty or stenting in JR-NET2. Although ischemic complications were significantly decreased (4.2% vs. 2.1%, p<0.001), hemorrhagic complications (2.1% vs. 5.3%, p<0.001), severe adverse events (1.5% vs. 2.1%, p<0.001), and total perioperative complications (8.3% vs. 10.3%, p<0.001) were significantly increased in JR-NET2. The rate of hemorrhagic complications was significantly higher in patients with triple or more perioperative antiplatelet therapy (preoperative: 5.3% vs. 9.2%, p<0.0001, postoperative: 5.7% vs. 12.7%, p<0.0001). Perioperative antithrombotic therapy was performed more frequently and intensively in neuroendovascular therapy in Japan. While ischemic complications were decreased, hemorrhagic complications and severe adverse events were increased. These results suggest that intensive antithrombotic therapy has a potential risk of hemorrhagic complications for Japanese patients. PMID- 26236813 TI - Detailed Analysis of Puncture Site Vascular Complications in Japanese Registry of Neuroendovascular Therapy (JR-NET) and JR-NET2. AB - A subgroup analysis of access site complications in the Japanese Registry of Neuroendovascular Therapy (JR-NET) and JR-NET2, which were retrospective registry studies, was performed. Puncture site vascular complications occurred in 195 (0.63%, mean age: 69.2) of all 31,836 patients. Most of these complications resulted from surgery in main hospitals (186 patients, 0.67%, P<0.001) and scheduled surgery (167 patients, 0.73%, P<0.001). Carotid artery stenting (81 patients, 1.04%, p<0.001), extracranial percutaneous transluminal angioplasty (PTA) (15 patients, 1.02%, p<0.001), and intracranial PTA (10 patients, 0.81%, p<0.05) were associated with significantly higher incidence of complications. The incidence of puncture site vascular complications was correlated with the number of antiplatelet drugs (p<0.001) and intraoperative heparinization (p<0.05). PMID- 26236815 TI - Japanese Registry of Neuroendovascular Therapy: Extracranial Steno-occlusive Diseases except for Internal Carotid Artery Stenosis. AB - Although utilization of endovascular treatment of extracranial steno-occlusive lesions except for internal carotid artery stenosis continues to increase, there is no consensus regarding the natural course and standard treatment of these lesions. The aim of this study was to characterize the utility of endovascular treatment for extracranial steno-occlusive lesions except for internal carotid artery stenosis. A total of 1249 procedures for extracranial steno-occlusive lesions were identified from the Japanese Registry of Neuroendovascular Therapy (JR-NET) and JR-NET2. Excluding the cases of carotid lesions (290 cases), endovascular procedures were performed for 471 (37.7%) subclavian artery stenoses, 404 (32.3%) extracranial vertebral artery stenoses, and 38 (3.0%) innominate artery stenoses with a technical success rate of 97.2%. A stent was placed for 783 lesions and percutaneous transluminal angioplasty was performed for 183 lesions. Forty complications were reported in this cohort. Among these, ischemic complications were the most frequent (12 cases). Comparison between JR NET1 and JR-NET2 demonstrated a marked increase in the number of procedures, a change in the utilization of antiplatelet therapy, and an increased rate of favorable outcome. We conclude that the endovascular treatment for extracranial steno-occlusive lesions is relatively safe. Continuous efforts should be made to reduce the complication rate, and further trials are needed to validate the beneficial effect of this procedure. PMID- 26236814 TI - Endovascular Treatment of Acute Stroke with Major Vessel Occlusion before Approval of Mechanical Thrombectomy Devices in Japan: Japanese Registry of Neuroendovascular Therapy (JR-NET) and JR-NET 2. AB - The aim of this study was to clarify the general status and historical transition of endovascular therapy (EVT) of acute stroke with major vessel occlusion before approval of mechanical thrombectomy devices in Japan from January 2005 to December 2009. We extracted 1,409 acute ischemic stroke patients receiving EVT (513 women, 69.8+/-11.8 years) from two nationwide registry studies, the Japanese Registry of Neuroendovascular Therapy (JR-NET) and JR-NET 2. The median baseline National Institutes of Health Stroke Scale (NIHSS) score was 18, and 81.3% of the patients received EVT within 6 hours after symptom onset. The culprit occluded arteries were the internal carotid artery (ICA) in 21.2%, middle cerebral artery (MCA) in 53.0%, and basilar artery (BA) in 20.6%. Intravenous thrombolysis was administered to 6.7% of the patients, and EVT mainly consisted of intra-arterial thrombolysis and percutaneous balloon angioplasty/balloon clot disruption. The final recanalization rate was 82.5%, and the clinical outcome was favorable in 35.8% and fatal in 11.6% at 30 days after onset or at discharge. There was no significant change in neurological severity at baseline throughout the study period, but the onset-to-treatment time became longer and the proportion of ICA or BA occlusion increased annually. Although the final recanalization rate was similar throughout the study period, the incidence of a favorable outcome tended to decreased annually from 41.0% to 29.0%. These results could be considered as baseline data that can be used to validate the beneficial effects of novel EVT devices in Japan. PMID- 26236816 TI - Angioplasty and Stenting for Intracranial Stenosis. AB - Of the patients enrolled in the Japanese Registry of Neuroendovascular Therapy (JR-NET), a surveillance study in Japanese, 1133 patients who underwent intracranial percutaneous transluminal angioplasty (PTA)/stenting for intracranial stenosis during the period from 2005 to 2009 were investigated. A technical success was achieved in 98.3% of the patients, and 70.5% and 7.5% had a residual stenosis of <30% and >=50%, respectively. The incidence of ischemic complications and hemorrhagic complications was as low as 7.7% and 2.5%, respectively, but tended to increase in patients who underwent stenting. While a significant correlation with ischemic complications was observed in previously untreated patients and patients who underwent stenting followed by post dilatation, a significant correlation with hemorrhagic complications was observed in patients who received emergency treatment and those treated between 24 hours and 14 days of the onset. Flexible intracranial stents are expected to contribute to improvement in the treatment outcome. PMID- 26236817 TI - Epidemiology of Dural Arteriovenous Fistula in Japan: Analysis of Japanese Registry of Neuroendovascular Therapy (JR-NET2). AB - We developed the Japanese Registry of Neuroendovascular Therapy 2 (JR-NET2) database and used the information for a retrospective, nation-wide multicenter, observational study to clarify the clinical characteristics, current status of procedures, and outcome of patients treated by neuroendovascular therapy in Japan. In this report, we analyzed the clinical characteristics of dural arteriovenous fistulas (dAVFs) in the JR-NET2 database. All patients with dAVFs treated with endovascular therapy in 150 Japanese hospitals were included. Patient characteristics, clinical presentations, and imaging characteristics were analyzed. A total of 1,075 patients with dAVFs underwent 1,520 endovascular procedures. Of 1,075 patients, 45% were men and 55% were women. The mean age was 65+/-13 years. The most frequent location of dAVFs was the cavernous sinus (43.6%), followed by the transverse-sigmoid sinus (TSS) (33.4%). Twelve percent of the patients had intracranial hemorrhage, 9% had venous infarction, and 3% had convulsion. The statistically significant independent risk factors of intracranial hemorrhage were TSS, superior sagittal sinus (SSS), tentorium, anterior cranial fossa, cranio-cervical junction, cortical venous reflux (CVR), and varix. Risk factors of venous infarction were age older than 60 years, male sex, TSS, SSS, and CVR. Risk factors of convulsion were male sex, SSS, and CVR. This is the largest nationwide report, to date, of the clinical characteristics of dAVFs treated by neuroendovascular therapy. CVR was a major risk factor of aggressive symptoms. PMID- 26236818 TI - Endovascular Treatment of Spinal Vascular Lesion in Japan: Japanese Registry of Neuroendovascular Therapy (JR-NET) and JR-NET2. AB - A subgroup analysis of spinal vascular lesions in the Japanese Registry of Neuroendovascular Therapy (JR-NET) and JR-NET2, retrospective registry studies conducted in 2005-2009, was performed to understand the current status of treatment in Japan. Of 201 spinal lesions enrolled, 98 analyzable cases of spinal dural arteriovenous fistula (SDAVF), 43 of spinal perimedullary arteriovenous fistula (SPAVF), and 23 of spinal intramedullary arteriovenous malformation (SIAVM) were assessed. Treatment was radical in the majority (83.6%) of SDAVF, palliative in the majority (70.6%) of SIAVM, and radical and palliative in a similar number of cases of SPAVF. Total occlusion was achieved in 26 (54.2%) SDAVF cases, 9 (29.0%) SPAVF, and 4 (23.5%) SIAVM. Treatment-related complications occurred in 3 (3.1%) SDAVF cases, 7 (16.3%) SPAVF, and 1 (4.3%) SIAVM. Post-treatment neurological improvement was achieved in 49 (50.0%) of SDAVF cases, 15 (34.9%) SPAVF, and 5 (21.7%) SIAVM. The modified Rankin Scale (mRS) of 0, 1, or 2 on postoperative day 30, the primary endpoint, was achieved in 62 (63.3%) SDAVF cases, 26 (60.5%) SPAVF, and 12 (52.2%) SIAVM. The mRS of 0-2 on postoperative day 30 was correlated with presymptomatic mRS of 0-2 [P<0.0001, odds ratio (OR): 42.88, 95% confidence interval (CI): 14.83-123.97] and postoperative neurological improvement (P=0.046, OR: 2.57, 95% CI: 1.02-6.48). In Japan, endovascular treatment of spinal vascular lesions was administered safely. Good mRS on postoperative day 30 was highly correlated with good pre-symptomatic mRS, suggesting necessity of early diagnosis and treatment. PMID- 26236819 TI - Endovascular Treatment of Aneurysmal Subarachnoid Hemorrhage in Japanese Registry of Neuroendovascular Therapy (JR-NET) 1 and 2. AB - To distinguish the characteristics of ruptured cerebral aneurysm that are suitable for endovascular treatment from those that are not, we evaluated factors that influenced the results of aneurysm embolization in patients with ruptured cerebral aneurysm, based on data from the Japanese Registry of Neuroendovascular Therapy (JR-NET) 1 and 2. The multivariate analysis revealed that young patients, patients with low modified Rankin Scale (mRS) scores before onset, and patients with low World Federation of Neurosurgical Societies (WFNS) grades had good outcome. Compared to proximal internal carotid artery (ICA) aneurysms, the odds ratio of middle cerebral artery (MCA) aneurysms was 1.67, indicating poorer outcome for MCA aneurysms, and patients with small, wide-neck cerebral aneurysms had poor outcome. Patients treated after 15 days had better outcome than during other periods. The timing of treatment, however, did not influence the outcome in patients treated within 14 days. The outcome was poorer when the responsible doctor for the treatment was a specialist or a non-specialist than a supervisory doctor. The outcome of patients treated with bare platinum coils, and three dimensional (3D) rotational angiography was better, and the outcome of patients who completed treatment with body filling was poorer than in patients with complete occlusion. Perioperative hemorrhagic complications, all ischemic complications, and rebleeding occurred in 4.5%, 6.4%, and 1.4% of patients, respectively. All these complications had poor outcome factors on day 30, with odds ratios of 2.72, 2.96, and 25.49, respectively. We must be fully aware of these risk factors and determine indications for the treatment when endovascular treatment is performed as the treatment of choice for ruptured cerebral aneurysm. PMID- 26236820 TI - Parent Artery Occlusion for Unruptured Cerebral Aneurysms: The Japanese Registry of Neuroendovascular Therapy (JR-NET) 1 and 2. AB - Parent artery occlusion (PAO) is an alternative to surgical clipping or endovascular endosaccular coil embolization for the management of cerebral aneurysms. Most giant and fusiform aneurysms are not amenable to endosaccular coil embolization due to anatomical considerations, such as a broad-neck. However, majority of reports regarding the safety of PAO are based on case series involving a relatively small number of patients. In the present study, a total of 381 consecutive patients with unruptured cerebral aneurysms who were treated with PAO were extracted from the Japanese Registry of Neuroendovascular Therapy (JR NET) 1 and JR-NET2 database, which are nationwide surveys conducted by the Japanese Society of Neuroendovascular Therapy. The mean age of the 381 patients was 58.1 years, and 59.3% were female. The aneurysmal location included the vertebral artery (42%) and the cavernous portion of internal carotid artery (32%). The aneurysm size and shape consisted of fusiform (45%), giant (25%), and large (22%). Symptomatic lesions were present in 59.8% of the population. Technical success was achieved in 98.4%. The 30-day morbidity and mortality rates were 3.1% and 1.0%, respectively. The most frequent procedure-related complication was ischemic stroke, which occurred in 12.9% (distal embolism, 6.0%; branch occlusion, 3.9%). The 30-day morbidity and mortality rates related to ischemic strokes were 2.1% and 0.3%, respectively. PAO for unruptured aneurysms is feasible with a high technical success rate. Peri-procedural management of ischemic stroke is the key to enhance the safety of this treatment option. PMID- 26236821 TI - Endovascular Treatment for Ruptured Vertebral Artery Dissecting Aneurysms: Results from Japanese Registry of Neuroendovascular Therapy (JR-NET) 1 and 2. AB - In treating ruptured vertebral artery dissecting aneurysms (VADAs), neuroendovascular therapy (NET) represented by coil obliteration is considered to be a reliable intervention. However, there has been no multi-center based study in this setting so far. In this article, results of NET for ruptured VADA obtained from Japanese Registry of Neuroendovascular Therapy (JR-NET) 1 and 2 were assessed to elucidate the factors associated with favorable outcome. A total of 213 in JR-NET1 and 381 patients in JR-NET2 with ruptured VADA were included, and they were separately analyzed because several important datasets such as vasospasm and site of dissecting aneurysms in relation to the posterior inferior cerebellar artery (PICA) were collected only in JR-NET1. The ratio of poor World Federation of Neurosurgical Societies (WFNS) grade (4 and 5) was 48.8% and 53.9%, and the ratio of favorable outcome (modified Rankin scale, mRS 0 to 2) at 30 days after onset was 61.1 % and 49.1% in JR-NET1 and 2, respectively. In both studies, poor WFNS grade and procedural complication were independently correlated as negative factors for favorable outcome. In JR-NET1, PICA-involved lesion was also designated as a negative factor while elderly age and absence of postprocedural antithrombotic therapy was detected as other negative factors in JR-NET2. The ratios of favorable outcome in poor grade patients were 25.4% in JR-NET1 and 31.3% in JR-NET2, which seemed compatible with the previous studies. These results may provide a baseline data for the NET in this disease and could be useful for validating the benefits of novel devices. PMID- 26236822 TI - Current Status of Endovascular Treatment for Vasospasm following Subarachnoid Hemorrhage: Analysis of JR-NET2. AB - Endovascular treatments are employed for cerebral vasospasm following subarachnoid hemorrhage, which is not responded to the medical treatments. However, the effect or complication of the treatments is not known well. Here, we analyzed the data of Japanese Registry of Neuroendovascular Therapy 2 (JR-NET2) and revealed current status of the endovascular treatment for the cerebral vasospasm. JR-NET2 is conducted from January 1, 2007 to December 31, 2009. Information on the clinical status, imaging studies, treatment methods, the results of treatment, and status 30 days later were recorded. Totally 645 treatments for 480 patients (mean age, 59.4 years; 72.7% woman) were included. Factors related to the neurological improvement and treatment related complications were statistically analyzed. Treatments for ruptured cerebral aneurysm were direct surgery for 366 cases and endovascular treatment for 253 cases. The timing of the endovascular treatment for the cerebral vasospasm was within 3 hours in 209 cases, 3-6 hours in 158 cases, and more than 6 hours in 158 cases. Intra-arterial vasodilator was employed for the 495 cases and percutaneous transluminal angioplasty for 140 cases. Neurological improvement was observed in 372 cases and radiological improvement was seen in 623 cases. The treatment related complication occurred in 20 cases (3.1%), including 6 cases of intracranial hemorrhage, 5 cases of cerebral ischemia, a case of puncture site trouble, and 8 cases of others. Statistical analysis showed early treatment was related to the neurological improvement. Current status of endovascular treatment for cerebral vasospasm was revealed. Endovascular treatment was effective for vasospasm especially was performed early. PMID- 26236823 TI - Real-world Experience of Carotid Artery Stentingin Japan: Analysis of 7,134 Cases from JR-NET1 and 2Nationwide Retrospective Multi-center Registries. AB - The present study aimed to demonstrate the "real-world" experiences of carotid artery stenting (CAS) in Japan using Japanese Registry of Neuroendovascular Therapy (JR-NET) 1 and 2, retrospective nationwide multi-center surveillances. JR NET1 and 2 registries are retrospective surveillances conducted between January 2005 and December 2007 and January 2008 and December 2009, respectively, in Japan regarding neuroendovascular therapy. A total of 7,134 procedures (1,943 for JR NET1 and 5,191 for JR-NET2) were included in this study and retrieved data were analyzed retrospectively. Treatment results of two surveillance periods were similar. In JR-NET2 registry, total of 5,191 lesions were treated by CAS and 5,008 of 5,191 procedures (96.5%) were performed by the board-certified surgeons of Japanese Society of Neuroendovascular Therapy. The rate of technical success was extremely high (99.99%), and the rate of clinically significant complication was low (3.2%). These results were comparable to a previous large study in Japan. Multivariate logistic analysis revealed that age [odds ratio (OR), 1.04 per year; 95% confidence interval (CI), 1.02-1.07; p=0.0004), symptomatic lesion (OR, 1.87; 95% CI; p=0.0004), and the use of closed-cell type stent (OR, 0.58; 95% CT, 0.32 1.00; p=0.05) were independently associated with clinically significant complications. It was revealed that good clinical results were achieved in patients who underwent CAS in Japan. It is expected that the evolution of devices and increasing experiences of surgeons would lead to further improvement of the clinical results, and further investigation would be required to clarify the optimal treatment strategy and therapeutic efficacy of CAS, especially in symptomatic lesions. PMID- 26236824 TI - A dimensionless ordered pull-through model of the mammalian lens epithelium evidences scaling across species and explains the age-dependent changes in cell density in the human lens. AB - We present a mathematical (ordered pull-through; OPT) model of the cell-density profile for the mammalian lens epithelium together with new experimental data. The model is based upon dimensionless parameters, an important criterion for inter-species comparisons where lens sizes can vary greatly (e.g. bovine (approx. 18 mm); mouse (approx. 2 mm)) and confirms that mammalian lenses scale with size. The validated model includes two parameters: beta/alpha, which is the ratio of the proliferation rate in the peripheral and in the central region of the lens; and gamma(GZ), a dimensionless pull-through parameter that accounts for the cell transition and exit from the epithelium into the lens body. Best-fit values were determined for mouse, rat, rabbit, bovine and human lens epithelia. The OPT model accounts for the peak in cell density at the periphery of the lens epithelium, a region where cell proliferation is concentrated and reaches a maximum coincident with the germinative zone. The beta/alpha ratio correlates with the measured FGF 2 gradient, a morphogen critical to lens cell survival, proliferation and differentiation. As proliferation declines with age, the OPT model predicted age dependent changes in cell-density profiles, which we observed in mouse and human lenses. PMID- 26236825 TI - Emergence of collective changes in travel direction of starling flocks from individual birds' fluctuations. AB - One of the most impressive features of moving animal groups is their ability to perform sudden coherent changes in travel direction. While this collective decision can be a response to an external alarm cue, directional switching can also emerge from the intrinsic fluctuations in individual behaviour. However, the cause and the mechanism by which such collective changes of direction occur are not fully understood yet. Here, we present an experimental study of spontaneous collective turns in natural flocks of starlings. We employ a recently developed tracking algorithm to reconstruct three-dimensional trajectories of each individual bird in the flock for the whole duration of a turning event. Our approach enables us to analyse changes in the individual behaviour of every group member and reveal the emergent dynamics of turning. We show that spontaneous turns start from individuals located at the elongated tips of the flocks, and then propagate through the group. We find that birds on the tips deviate from the mean direction of motion much more frequently than other individuals, indicating that persistent localized fluctuations are the crucial ingredient for triggering a collective directional change. Finally, we quantitatively verify that birds follow equal-radius paths during turning, the effects of which are a change of the flock's orientation and a redistribution of individual locations in the group. PMID- 26236826 TI - Walking dynamics are symmetric (enough). AB - Many biological phenomena such as locomotion, circadian cycles and breathing are rhythmic in nature and can be modelled as rhythmic dynamical systems. Dynamical systems modelling often involves neglecting certain characteristics of a physical system as a modelling convenience. For example, human locomotion is frequently treated as symmetric about the sagittal plane. In this work, we test this assumption by examining human walking dynamics around the steady state (limit cycle). Here, we adapt statistical cross-validation in order to examine whether there are statistically significant asymmetries and, even if so, test the consequences of assuming bilateral symmetry anyway. Indeed, we identify significant asymmetries in the dynamics of human walking, but nevertheless show that ignoring these asymmetries results in a more consistent and predictive model. In general, neglecting evident characteristics of a system can be more than a modelling convenience--it can produce a better model. PMID- 26236828 TI - Large suprasellar mass: question. PMID- 26236829 TI - Mammary Stem Cells. Preface. PMID- 26236827 TI - Which games are growing bacterial populations playing? AB - Microbial communities display complex population dynamics, both in frequency and absolute density. Evolutionary game theory provides a natural approach to analyse and model this complexity by studying the detailed interactions among players, including competition and conflict, cooperation and coexistence. Classic evolutionary game theory models typically assume constant population size, which often does not hold for microbial populations. Here, we explicitly take into account population growth with frequency-dependent growth parameters, as observed in our experimental system. We study the in vitro population dynamics of the two commensal bacteria (Curvibacter sp. (AEP1.3) and Duganella sp. (C1.2)) that synergistically protect the metazoan host Hydra vulgaris (AEP) from fungal infection. The frequency-dependent, nonlinear growth rates observed in our experiments indicate that the interactions among bacteria in co-culture are beyond the simple case of direct competition or, equivalently, pairwise games. This is in agreement with the synergistic effect of anti-fungal activity observed in vivo. Our analysis provides new insight into the minimal degree of complexity needed to appropriately understand and predict coexistence or extinction events in this kind of microbial community dynamics. Our approach extends the understanding of microbial communities and points to novel experiments. PMID- 26236830 TI - Demographic heterogeneity and the dynamics of open populations. AB - Individuals vary in their phenotype and propensity for growth and survival, but the demographic consequences of this remain poorly understood. We extend previous theoretical work on benthic marine populations and formulate a new model to evaluate how demographic heterogeneity among newly settled reef fish affects population stability. We simulated settlement, growth, and mortality of a small reef fish, the common triplefin (Forsterygion lapillurn) in an open "subpopulation" using a delay-differential equation model framework. We modeled demographic heterogeneity with a discrete number of "quality" types, motivated by our previous empirical observations: individuals were either "high quality" (immigrants from nearby subpopulations) or "low quality" (immigrants from distant subpopulations); in our model, quality influences how quickly individuals develop at a given competitor density. Our results demonstrate how demographic heterogeneity and juvenile competition interact to qualitatively alter the effects of settlement on population stability. Specifically, our model suggests that a mixture of quality types can stabilize the equilibrium even when equal settlement of either type alone would result in an unstable equilibrium. These results highlight the importance of among-individual variation in a metapopulation context, and suggest that in systems where dispersal influences individual quality, connectivity may serve to stabilize local populations. PMID- 26236831 TI - Tainted resurrection: metal pollution is linked with reduced hatching and high juvenile mortality in Daphnia egg banks. AB - Many taxa, from plants to zooplankton, produce long-lasting dormant propagules capable of temporal dispersal. In some cases, propagules can persist for decades or even centuries before emerging from seed and egg banks. Despite impressive longevity, relatively little is known about how the chemical environment experienced before or during dormancy affects the fate and performance of individuals. This study examines the hatching rate and developmental success of Daphnia hatched from diapausing eggs isolated from sediments from four lakes that experienced varying levels of metal contamination. Two hundred seventy-three animals were hatched from lake sediments deposited over the past century. Hatching rate was negatively influenced by metal contamination and sediment age. There was a robust positive relationship between sediment metal concentrations and juvenile mortality in Daphnia hatching from those sediments. The negative effect of metals on Daphnia hatching and juvenile survival may stem from metal bioaccumulation, genetic effects, or reduced maternal investment in diapausing embryos. Regardless of the specific mechanism driving this trend, exposure to metals may impose strong selection on Daphnia diapausing egg banks. PMID- 26236832 TI - Spatial convergent cross mapping to detect causal relationships from short time series. AB - Recent developments in complex systems analysis have led to new techniques for detecting causal relationships using relatively short time series, on the order of 30 sequential observations. Although many ecological observation series are even shorter, perhaps fewer than ten sequential observations, these shorter time series are often highly replicated in space (i.e., plot replication). Here, we combine the existing techniques of convergent cross mapping (CCM) and dewdrop regression to build a novel test of causal relations that leverages spatial replication, which we call multispatial CCM. Using examples from simulated and real-world ecological data, we test the ability of multispatial CCM to detect causal relationships between processes. We find that multispatial CCM successfully detects causal relationships with as few as five sequential observations, even in the presence of process noise and observation error. Our results suggest that this technique may constitute a useful test for causality in systems where experiments are difficult to perform and long time series are not available. This new technique is available in the multispatialCCM package for the R programming language. PMID- 26236833 TI - Rigorous home range estimation with movement data: a new autocorrelated kernel density estimator. AB - Quantifying animals' home ranges is a key problem in ecology and has important conservation and wildlife management applications. Kernel density estimation (KDE) is a workhorse technique for range delineation problems that is both statistically efficient and nonparametric. KDE assumes that the data are independent and identically distributed (IID). However, animal tracking data, which are routinely used as inputs to KDEs, are inherently autocorrelated and violate this key assumption. As we demonstrate, using realistically autocorrelated data in conventional KDEs results in grossly underestimated home ranges. We further show that the performance of conventional KDEs actually degrades as data quality improves, because autocorrelation strength increases as movement paths become more finely resolved. To remedy these flaws with the traditional KDE method, we derive an autocorrelated KDE (AKDE) from first principles to use autocorrelated data, making it perfectly suited for movement data sets. We illustrate the vastly improved performance of AKDE using analytical arguments, relocation data from Mongolian gazelles, and simulations based upon the gazelle's observed movement process. By yielding better minimum area estimates for threatened wildlife populations, we believe that future widespread use of AKDE will have significant impact on ecology and conservation biology. PMID- 26236834 TI - Unveiling the species-rank abundance distribution by generalizing the Good-Turing sample coverage theory. AB - Based on a sample of individuals, we focus on inferring the vector of species relative abundance of an entire assemblage and propose a novel estimator of the complete species-rank abundance distribution (RAD). Nearly all previous estimators of the RAD use the conventional "plug-in" estimator Pi (sample relative abundance) of the true relative abundance pi of species i. Because most biodiversity samples are incomplete, the plug-in estimators are applied only to the subset of species that are detected in the sample. Using the concept of sample coverage and its generalization, we propose a new statistical framework to estimate the complete RAD by separately adjusting the sample relative abundances for the set of species detected in the sample and estimating the relative abundances for the set of species undetected in the sample but inferred to be present in the assemblage. We first show that P, is a positively biased estimator of pi for species detected in the sample, and that the degree of bias increases with increasing relative rarity of each species. We next derive a method to adjust the sample relative abundance to reduce the positive bias inherent in j. The adjustment method provides a nonparametric resolution to the longstanding challenge of characterizing the relationship between the true relative abundance in the entire assemblage and the observed relative abundance in a sample. Finally, we propose a method to estimate the true relative abundances of the undetected species based on a lower bound of the number of undetected species. We then combine the adjusted RAD for the detected species and the estimated RAD for the undetected species to obtain the complete RAD estimator. Simulation results show that the proposed RAD curve can unveil the true RAD and is more accurate than the empirical RAD. We also extend our method to incidence data. Our formulas and estimators are illustrated using empirical data sets from surveys of forest spiders (for abundance data) and soil ciliates (for incidence data). The proposed RAD estimator is also applicable to estimating various diversity measures and should be widely useful to analyses of biodiversity and community structure. PMID- 26236835 TI - The importance of spatial models for estimating the strength of density dependence. AB - Identifying the existence and magnitude of density dependence is one of the oldest concerns in ecology. Ecologists have aimed to estimate density dependence in population and community data by fitting a simple autoregressive (Gompertz) model for density dependence to time series of abundance for an entire population. However, it is increasingly recognized that spatial heterogeneity in population densities has implications for population and community dynamics. We therefore adapt the Gompertz model to approximate, local densities over continuous space instead of population-wide abundance, and allow productivity to vary spatially using Gaussian random fields. We then show that the conventional (nonspatial) Gompertz model can result in biased estimates of density dependence (e.g., identifying oscillatory dynamics when not present) if densities vary spatially. By contrast, the spatial Gompertz model provides accurate and precise estimates of density dependence for a variety of simulation scenarios and data availabilities. These results are corroborated when comparing spatial and nonspatial models for data from 10 years and -100 sampling stations for three long-lived rockfishes (Sebastes spp.) off the California, USA coast. In this case, the nonspatial model estimates implausible oscillatory dynamics on an annual time scale, while the spatial model estimates strong autocorrelation and is supported by model selection tools. We conclude by discussing the importance of improved data archiving techniques, so that spatial models can be used to reexamine classic questions regarding the existence and magnitude of density. dependence in wild populations. PMID- 26236836 TI - Stream invertebrate productivity linked to forest subsidies: 37 stream-years of reference and experimental data. AB - Riparian habitats provide detrital subsidies of varying quantities and qualities to recipient ecosystems. We used long-term data from three reference streams (covering 24 stream-years) and 13-year whole-stream organic matter manipulations to investigate the influence of terrestrial detrital quantity and quality on benthic invertebrate community structure, abundance, biomass, and secondary production in rockface (RF) and mixed substrates (MS) of forested headwater streams. Using a mesh canopy covering the entire treatment stream, we examined effects of litter ex'clusion, small- and large-wood removal, and addition of artificial wood (PVC) and leaves of varying quality on organic matter standing crops and invertebrate community structure and function. We assessed differences in functional feeding group distribution between substrate types as influenced by organic matter manipulations and long-term patterns of predator and prey production in manipulated vs. reference years. Particulate organic matter standing crops in MS of the treatment stream declined drastically with each successive year of litter exclusion, approaching zero after three years. Monthly invertebrate biomass and annual secondary production was positively related to benthic organic matter in the MS habitats. Rockface habitats exhibited fewer changes than MS habitats across all organic matter manipulations. With leaf addition, the patterns of functional group distribution among MS and RF habitats returned to patterns seen in reference streams. Secondary production per unit organic matter standing crop was greatest for the leaf addition period, followed by the reference streams, and significantly less for the litter exclusion and wood removal periods. These data indicate that the limited organic matter remaining in the stream following litter exclusion and wood removal was more refractory than that in the reference streams, whereas the added leaf material was more labile and readily converted into invertebrate production. Predator production and total production were tightly coupled in reference and treatment streams, indicating strong relationships between predators and their prey. Results from the artificial wood addition demonstrate that physical structure alone will not restore invertebrate productivity without detrital resources from the riparian forest. Our long-term studies conducted over three decades at the ecosystem scale unequivocally show the necessity of maintaining and restoring aquatic-terrestrial linkages in forested headwater streams. PMID- 26236837 TI - Organic forms dominate hydrologic nitrogen export from a lowland tropical watershed. AB - Observations of high dissolved inorganic nitrogen (DIN) concentrations in stream water have reinforced the notion that primary tropical rain forests cycle nitrogen (N) in relative excess compared to phosphorus. Here we test this notion by evaluating hydrologic N export from a small watershed on the Osa Peninsula, Costa Rica, where prior research has shown multiple indicators of conservative N cycling throughout the ecosystem. We repeatedly measured a host of factors known to influence N export for one year, including stream water chemistry and upslope litterfall, soil N availability and net N processing rates, and soil solution chemistry at the surface, 15- and 50-cm depths. Contrary to prevailing assumptions about the lowland N cycle, we find that dissolved organic nitrogen (DON) averaged 85% of dissolved N export for 48 of 52 consecutive weeks. For most of the year stream water nitrate (NO3-) export was very low, which reflected minimal net N processing and DIN leaching from upslope soils. Yet, for one month in the dry season, NO3- was the major component of N export due to a combination of low flows and upslope nitrification that concentrated NO3- in stream water. Particulate organic N (PON) export was much larger than dissolved forms at 14.6 kg N x ha(-1) x yr(-1), driven by soil erosion during storms. At this rate, PON export was slightly greater than estimated inputs from free-living N fixation and atmospheric N deposition, which suggests that erosion-driven PON export could constrain ecosystem level N stocks over longer timescales. This phenomenon is complimentary to the "DON leak" hypothesis, which postulates that the long-term accumulation of ecosystem N in unpolluted ecosystems is constrained by the export of organic N independently of biological N demand. Using an established global sediment generation model, we illustrate that PON erosion may be an important vector for N loss in tropical landscapes that are geomorphically active. This study supports an emerging view that landscape geomorphology influences nutrient biogeochemistry and limitation, though more research is needed to understand the mechanisms and spatial significance of erosional N loss from terrestrial ecosystems. PMID- 26236838 TI - Biomass is the main driver of changes in ecosystem process rates during tropical forest succession. AB - Over half of the world's forests are disturbed, and the rate at which ecosystem processes recover after disturbance is important for the services these forests can provide. We analyze the drivers' underlying changes in rates of key ecosystem processes (biomass productivity, litter productivity, actual litter decomposition, and potential litter decomposition) during secondary succession after shifting cultivation in wet tropical forest of Mexico. We test the importance of three alternative drivers of ecosystem processes: vegetation biomass (vegetation quantity hypothesis), community-weighted trait mean (mass ratio hypothesis), and functional diversity (niche complementarity hypothesis) using structural equation modeling. This allows us to infer the relative importance of different mechanisms underlying ecosystem process recovery. Ecosystem process rates changed during succession, and the strongest driver was aboveground biomass for each of the processes. Productivity of aboveground stem biomass and leaf litter as well as actual litter decomposition increased with initial standing vegetation biomass, whereas potential litter decomposition decreased with standing biomass. Additionally, biomass productivity was positively affected by community-weighted mean of specific leaf area, and potential decomposition was positively affected by functional divergence, and negatively by community-weighted mean of leaf dry matter content. Our empirical results show that functional diversity and community-weighted means are of secondary importance for explaining changes in ecosystem process rates during tropical forest succession. Instead, simply, the amount of vegetation in a site is the major driver of changes, perhaps because there is a steep biomass buildup during succession that overrides more subtle effects of community functional properties on ecosystem processes. We recommend future studies in the field of biodiversity and ecosystem functioning to separate the effects of vegetation quality (community-weighted mean trait values and functional diversity) from those of vegetation quantity (biomass) on ecosystem processes and services. PMID- 26236839 TI - An empirical investigation of why species-area relationships overestimate species losses. AB - It is generally assumed that, when natural habitat is converted to human dominated land cover, such habitat is lost to its native species. Most literature assumes that species richness should vary as a function of remaining natural area, following the well-known species-area relationship (i.e., classic SAR). However, classic SARs have consistently overestimated species losses resulting from conversion of natural forested land cover to human-dominated landscapes. Moreover, richness is sometimes a peaked function of remaining natural habitat. Recent studies propose modified SAR models based on species' utilization of multiple habitat types, yet none fully explain a peaked species-area relationship. Here, we evaluate the responses of total avian richness, forest bird richness, and open-habitat bird richness to remaining natural land cover within 991 quadrats, each 100 km2, across southern Ontario, Canada. Total bird species richness peaks at roughly 50% natural land cover. Richness of forest birds varies as a classic power function of forested area. In contrast, richness of birds that prefer open habitats does not increase monotonically with either natural- or human-dominated land cover. Richness of open-habitat species can be predicted when we partition human-dominated land cover into an "available human dominated" component and "lost" habitat. Disiinguishing three land-cover types (natural, available human-dominated, and lost) can thus permit accurate predictions of species richness in landscapes with differing levels of natural habitat conversion. PMID- 26236840 TI - Predicting competitive shifts and responses to climate change based on latitudinal distributions of species assemblages. AB - Many terrestrial plant and marine benthic communities involve intense competition for space as a means to survive and reproduce. Superior competitors can dominate other species numerically with high reproductive rates, indirectly with high growth rates that facilitate space acquisition, or directly with competitive overgrowth. To assess how climate change could affect competitive interactions, we examined latitudinal patterns in growth rates and overgrowth competition via field surveys and experiments with marine epibenthic communities. Epibenthic fouling communities are dominated by invasive tunicates, bryozoans, and other species that grow on docks, boats, and other artificial structures. Fouling communities are space limited, so growth rate and overgrowth competition play an important role in shaping abundance patterns. We experimentally assessed temperature-dependent growth rates of several tunicates and bryozoans in eight regions spanning the U.S. east and west coasts. Several species displayed positive growth responses to warmer temperature in the northern portions of their latitudinal ranges, and vice versa. We used photo surveys of floating docks in at least 16 harbors in each region to compare communities and overgrowth competition. There was a strong correlation across species and regions between growth rate and competitive ability, indicating that growth plays an important role in competitive outcomes. Because growth rates are typically temperature dependent for organisms that compete for space, including terrestrial plants, fungi, algae, bacteria, and sessile benthic organisms, global warming could affect competitive outcomes. Our results suggest that these competitive shifts can be predicted by species' relative growth rates and latitudinal ranges. PMID- 26236841 TI - Fire alters ecosystem carbon and nutrients but not plant nutrient stoichiometry or composition in tropical savanna. AB - Fire and nutrients interact to influence the global distribution and dynamics of the savanna biome, but the results of these interactions are both complex and poorly known. A critical but unresolved question is whether short-term losses of carbon and nutrients caused by fire can trigger long-term and potentially compensatory responses in the nutrient stoichiometry of plants, or in the abundance of dinitrogen-fixing trees. There is disagreement in the literature about the potential role of fire on savanna nutrients, and, in turn, on plant stoichiometry and composition. A major limitation has been the lack of fire manipulations over time scales sufficiently long for these interactions to emerge. We use a 58-year, replicated, large-scale, fire manipulation experiment in Kruger National Park (South Africa) in savanna to quantify the effect of fire on (1) distributions of carbon, nitrogen, and phosphorus at the ecosystem scale; (2) carbon: nitrogen: phosphorus stoichiometry of above- and belowground tissues of plant species; and (3) abundance of plant functional groups including nitrogen fixers. Our results show dramatic effects of fire on the relative distribution of nutrients in soils, but that individual plant stoichiometry and plant community composition remained unexpectedly resilient. Moreover, measures of nutrients and carbon stable isotopes allowed us to discount the role of tree cover change in favor of the turnover of herbaceous biomass as the primary mechanism that mediates a transition from low to high 'soil carbon and nutrients in the absence of fire. We conclude that, in contrast to extra-tropical grasslands or closed canopy forests, vegetation in the savanna biome may be uniquely adapted to nutrient losses caused by recurring fire. PMID- 26236842 TI - Recruitment limitation of long-lived conifers: implications for climate change responses. AB - Seed availability and suitable microsites for germination are likely to severely constrain the responses of plant species to climate change, especially at and beyond range edges. For example, range shifts may be slow if seed availability is low at range edges due to low parent-tree abundance or reduced fecundity. Even when seeds are available, climatic and biotic factors may further limit the availability of suitable microsites for recruitment. Unfortunately, the importance of seed and microsite limitation during range shifts remains unknown, since few studies have examined both factors simultaneously, particularly across species' ranges. To address this issue, we assessed seed availability and the factors influencing germination for six conifer species across a large environmental gradient encompassing their elevational ranges. Specifically, we assessed (1) how parent-tree abundance influences annual seed availability; (2) how seed limitation varies across species' ranges; (3) how climatic and biotic factors affect germination; and (4) how seed and suitable microsite availability covary annually within and among species. We found that seed availability declined toward species' upper range edges for most species, primarily due to low parent-tree abundance rather than declining fecundity. Range expansions are thus likely to be lagged with respect to climate change, as long generation times preclude rapid increases in tree density. Negative impacts of canopy cover on germination rates suggest range shifts will further be slowed by competition with existing vegetation. Moreover, years of high seed production were generally correlated among species, but not correlated with the availability of suitable microsites, implying that seedling competition and the interaction between seed and microsite limitation will further constrain recruitment. However, the nature of microsite limitation varied strongly between treeline and low-elevation species due to differing responses to snowpack duration and. competition, suggesting that treeline species may be quicker to shift their ranges in response to warming than low-elevation species. In all, our results demonstrate that seed and microsite limitation will likely result in lagged responses to climate change but with differences among species leading to complex range shift dynamics. PMID- 26236843 TI - Separating the role of biotic interactions and climate in determining adaptive response of plants to climate change. AB - Altered rainfall regimes will greatly affect the response of plant species to climate change. However, little is known about how direct effects of changing precipitation on plant performance may depend on other abiotic factors and biotic interactions. We used reciprocal transplants between climatically very different sites with simultaneous manipulation of soil, plant population origin, and neighbor conditions to evaluate local adaptation and possible adaptive response of four Eastern Mediterranean annual plant species to climate change. The effect of site on plant performance was negligible, but soil origin had a strong effect on fecundity, most likely due to differential water retaining ability. Competition by neighbors strongly reduced fitness. We separated the effects of the abiotic and biotic soil properties on plant performance by repeating the field experiment in a greenhouse under homogenous environmental conditions and including a soil biota manipulation treatment. As in the field, plant performance differed among soil origins and neighbor treatments. Moreover, we found plant species-specific responses to soil biota that may be best explained by the differential sensitivity to negative and positive soil biota effects. Overall, under the conditions of our experiment with two contrasting sites, biotic interactions had a strong effect on plant fitness that interacted with and eventually overrode climate. Because climate and biotic interactions covary, reciprocal transplants and climate gradient studies should consider soil biotic interactions and abiotic conditions when evaluating climate change effects on plant performance. PMID- 26236844 TI - Gender inequality in predispersal seed predation contributes to female seed set advantage in a gynodioecious species. AB - Most flowering plants are hermaphrodites. However, in gynodioecious species, some members of the population are male-sterile and reproduce only by setting seed, while others gain fitness through both male and female function. How females compensate for the loss of male function remains unresolved for most gynodioecious species. Here, as with many plants, fitness differences may be influenced by interactions with multiple species. However, whether multiple species interactions result in gender-specific fitness differences remains unknown. Using observational data from 2009-2010, we quantified seed set of the two sex morphs of Polemonium foliosissimu and asked how it is affected by pollination, and seed predation from a dipteran predispersal seed predator (Anthomyiidae: Hylemya sp.). We assessed seed production and losses to predation in 27 populations for one year and in six populations for a second year. Females set significantly more seed than did hermaphrodites in both years. Of the fitness components we assessed, including the number of flowers per plant, fruit set, seeds/fruit, and proportion of fruits destroyed by Hylemya, only fruit destruction differed significantly between the sexes. In one year, seeds/fruit and predation had a stronger effect on seed set for hermaphrodites than for females. Because predispersal seed predators do not pollinate flowers, their effects may depend on successful pollination of flowers on which they oviposit. To examine if genders differed in pollen limitation and seed predation and/or their interactive effects, in 2011 we hand-pollinated flowers and removed seed predator eggs in a fully factorial design. Both sexes were pollen limited, but their degree of pollen limitation did not differ. However, predation reduced.seed set more for hermaphrodites than for females. We found no significant interaction between hand pollen and seed predation, and no interaction between hand pollination and gender. Our results suggest that while interactions with both pollinators and seed predators affect reproductive success, floral enemies can cause inequality in seed set between genders. The next step is to understand how the seed set advantage affects long-term fitness and persistence of females in gynodioecious populations. PMID- 26236845 TI - Herbivory drives zonation of stress-tolerant marsh plants. AB - Ecological studies of plant distributions along environmental gradients, such as plant zonation in salt marshes, have primarily focused on abiotic stress and plant interactions (competition and facilitation). A decades-old paradigm is that the stressful and benign boundaries of salt marsh plants are determined by abiotic stress and competition, respectively. Although consumers have long been recognized as mediating algal and sessile animal zonation in the rocky intertidal, their role in generating plant zonation in salt marshes remains largely unexplored. We examined the zonation of two annual succulents, Salicornia europaea and Suaeda salsa, along an elevation gradient in a northern Chinese salt marsh, with and without manipulating the common herbivorous crab Helice tientsinensis. Salicornia occupies waterlogged, low-salinity habitats, whereas Suaeda dominates non-waterlogged, hypersaline habitats at higher elevations. We first conducted a pot experiment crossing salinity, waterlogging, and competition, followed by a field experiment with removal of competitors, and found that neither waterlogging nor salinity stress explained the absence of either species from the other's zone, while Suaeda competitively excluded Salicornia from the upper non-waterlogged zone. We then conducted field and lab herbivory experiments, which showed that Helice preferentially grazed Suaeda at waterlogged low elevations and that Helice grazing on Suaeda increased with waterlogging. These results reveal that while competition plays a role in the zonation by excluding Salicornia from the upper Suaeda zone, crab grazing limits the success of Suaeda in the lower Salicornia zone. These findings challenge the idea that plant interactions and abiotic stress are sufficient to explain marsh zonation in all cases, and highlight an overlooked role of consumers, a role potentially general across diverse intertidal ecosystems. Future models of plant distributions should consider how consumer pressure interacts with plant interactions and abiotic stress across environmental gradients. PMID- 26236846 TI - Meta-analysis: abundance, behavior, and hydraulic energy shape biotic effects on sediment transport in streams. AB - An increasing number of studies have emphasized the need to bridge the disciplines of ecology and geomorphology. A large number of case studies show that organisms can affect erosion, but a comprehensive understanding of biological impacts on sediment transport conditions is still lacking. We use meta analysis to synthesize published data to quantify the effects of the abundance, body size, and behavior of organisms on erosion in streams. We also explore the influence of current velocity, discharge, and sediment grain size on the strength of biotic effects on erosion. We found that species that both increase erosion (destabilizers) and decrease erosion (stabilizers) can alter incipient sediment motion, sediment suspension, and sediment deposition above control conditions in which the organisms were not present. When abundance was directly manipulated, these biotic effects were consistently stronger in the higher abundance treatment, increasing effect sizes by 66%. Per capita effect size and per capita biomass were also consistently positively correlated. Fish and crustaceans were the most studied organisms, but aquatic insects increased the effect size by 550 x compared to other types of organisms after accounting for biomass. In streams with lower discharge and smaller grain sizes, we consistently found stronger biotic effects. Taken collectively, these findings provide synthetic evidence that biology can affect physical processes in streams, and these effects can be mediated by hydraulic energy. We suggest that future studies focus on understudied organisms, such as biofilms, conducting experiments under realistic field conditions, and developing hypotheses for the effect of biology on erosion and velocity currents in the context of restoration to better understand the forces that mediate physical disturbances in stream ecosystems. PMID- 26236847 TI - Experimental evidence for strong stabilizing forces at high functional diversity of aquatic microbial communities. AB - Unveiling the mechanisms that promote coexistence in biological communities is a fundamental problem in ecology. Stable coexistence of many species is commonly observed in natural communities. Most of these natural communities, however, are composed of species from multiple trophic and functional groups, while theory and experiments on coexistence have been focusing on functionally similar species. Here, we investigated how functional diversity affects the stability of species coexistence and productivity in multispecies communities by characterizing experimentally all pairwise species interactions in a pool of 11 species of eukaryotes (10 protists and one rotifer) belonging to three different functional groups. Species within the same functional group showed stronger competitive interactions compared to among-functional group interactions. This often led to competitive exclusion between species that had higher functional relatedness, but only at low levels of species richness. Communities with higher functional diversity resulted in increased species coexistence and community biomass production. Our experimental findings and the results of a stochastic model tailored to the experimental interaction matrix suggest the emergence of strong stabilizing forces when species from different functional groups interact in a homogeneous environment. By combining theoretical analysis with experiments we could also disentangle the relationship between species richness and functional diversity, showing that functional diversity per se is a crucial driver of productivity and stability in multispecies community. PMID- 26236848 TI - Annual dynamics of wild bee densities: attractiveness and productivity effects of oilseed rape. AB - Mass-flowering crops may affect long-term population dynamics, but effects on pollinators have never been studied across several years. We monitored wild bees in oilseed rape fields in 16 landscapes in Germany in two consecutive years. Effects on bee densities of landscape oilseed rape cover in the years of monitoring and in the previous years were evaluated with landscape data from three consecutive years. We fit empirical data to a mechanistic model to provide estimates for oilseed rape attractiveness and its effect on bee productivity in comparison to the rest of the landscape, and we evaluated consequences for pollinator densities in consecutive years. Our results show that high oilseed rape cover in the previous year enhances current densities of wild bees (except for bumble bees). Moreover, we show a strong attractiveness of and dilution on (i.e., decreasing bee densities with increasing landscape oilseed rape cover) oilseed rape for bees during flowering in the current year, modifying the effect of the previous year's oilseed rape cover in the case of wild bees (excluding Bombus). As long as other factors such as nesting sites or natural enemies do not limit bee reproduction, our findings suggest long-term positive effects of mass flowering crops on bee populations, at least for non-Bombus generalists, which possibly help to maintain crop pollination services even when crop area increases. Similar effects are conceivable for other organisms providing ecosystem services in annual crops and should be considered in future studies. PMID- 26236849 TI - Host manipulation of bumble bee queens by Sphaerularia nematodes indirectly affects foraging of non-host workers. AB - Sphaerularia bombi Dufour is a major parasite of bumble bee queens that manipulates its host's behavior: parasitized queens do not breed and found nests but continue to fly into the early summer months. We examined the indirect consequences of this host manipulation on non-host workers in central Hokkaido Island, Japan. In this area, parasitism of Bombus terrestris by S. bombi is common but does not affect every queen; therefore, as summer begins, B. terrestris queens continue to dominate some flower patches and disappear from others. At sites dominated by parasitized queens, we found that the nectar standing crop of red clover was smaller, B. terrestris workers carried out fewer legitimate visits to red clover and more nectar robberies, and the workers were smaller than at other sites. Removing queens from a site increased the nectar standing crop of red clover, the frequency of worker visits to red clover, and the size of the workers. These results suggest that host manipulation by S. bombi increased competition for flower resources among host queens and non-host workers and altered the interaction between plants and non-host flower visitors. PMID- 26236850 TI - Ecological strategies predict associations between aquatic and genetic connectivity for dryland amphibians. AB - The study of how population genetic structure is shaped by attributes of the environment is a central scientific pursuit in ecology and conservation. But limited resources may prohibit landscape genetics studies for many threatened species, particularly given the pace of current environmental change. Understanding the extent to which species' ecological strategies--their life histories, biology, and behavior-predict patterns and drivers of population connectivity is a critical step in evaluating the potential of multi-taxa inference in landscape genetics. We present results of a landscape genetic study of three dryland amphibians: the canyon treefrog (Hyla arenicolor), red-spotted toad (Anaxyrus punctatus), and Mexican spadefoot (Spea multiplicata). These species characterize a range of ecological strategies, driven primarily by different water dependencies, enabling amphibian survival in arid and semiarid environments. We examined a suite of hypothesized relationships between genetic connectivity and landscape connectivity across species. We found a positive relationship between population differentiation and water dependency, e.g., longer larval development periods and site fidelity for reliable water sources. We also found that aquatic connectivity is important for all species, particularly when considered with topography (slope). The effect of spatial scale varied by species, with canyon treefrogs and Mexican spadefoots characterized by relatively consistent results at different scales in contrast to the stark differences in results for red-spotted toads at different scales. Using ecological information to predict relationships between genetic and landscape connectivity is a promising approach for multi-taxa inference and may help inform conservation efforts where single-species genetic studies are not possible. PMID- 26236851 TI - Productivity and fishing pressure drive variability in fish parasite assemblages of the Line Islands, equatorial Pacific. AB - Variability in primary productivity and fishing pressure can shape the abundance, species composition, and diversity of marine life. Though parasites comprise nearly half of marine species, their responses to these important forces remain little explored. We quantified parasite assemblages at two spatial scales, across a gradient in productivity and fishing pressure that spans six coral islands of the Line Islands archipelago and within the largest Line Island, Kiritimati, which experiences a west-to-east gradient in fishing pressure and upwelling driven productivity. In the across-islands data set, we found that increasing productivity was correlated with increased parasite abundance overall, but that the effects of productivity differed among parasite groups. Trophically transmitted parasites increased in abundance with increasing productivity, but directly transmitted parasites did not exhibit significant changes. This probably arises because productivity has stronger effects on the abundance of the planktonic crustaceans and herbivorous snails that serve as the intermediate hosts of trophically transmitted parasites than on the higher-trophic level fishes that are the sole hosts of directly transmitted parasites. We also found that specialist parasites increased in response to increasing productivity, while generalists did not, possibly because specialist parasites tend to be more strongly limited by host availability than are generalist parasites. After the effect of productivity was controlled for, fishing was correlated with decreases in the abundance of trophically transmitted parasites, while directly transmitted parasites appeared to track host density; we observed increases in the abundance of parasites using hosts that experienced fishing-driven compensatory increases in abundance. The within-island data set confirmed these patterns for the combined effects of productivity and fishing on parasite abundance, suggesting that our conclusions are robust across a span of spatial scales. Overall, these results indicate that there are strong and variable effects of anthropogenic and natural drivers on parasite abundance and taxonomic richness. These effects are likely to be mediated by parasite traits, particularly by parasite transmission strategies. PMID- 26236852 TI - Delivery of marine larvae to shore requires multiple sequential transport mechanisms. AB - Most sedentary marine animals disperse from their place of origin during their initial life stages as larvae. The delivery of planktonic larvae back to coastal adult habitats after weeks or months of offshore development is commonly thought to be stochastic, resulting in large recruitment fluctuations and making predictive understanding of population dynamics difficult. Time series of invertebrate settlement on intertidal shores have been used to infer how various oceanographic processes deliver planktonic larvae ashore. However, the possibility that successful settlement may involve a series of different transport mechanisms, which are sequentially utilized by late-stage larvae, has received little attention. To address this, we monitored both the delivery of mussel and barnacle larvae to inner-shelf moorings positioned 200-1400 m from the shore, and larval settlement in the intertidal adult habitat, at two contrasting sites: a headland forming an upwelling center and a downstream bay. Model selection was employed to determine the most likely scenario(s) of larval onshore transport from four a priori transport mechanisms individually and in combination: (1) upwelling or relaxation/downwelling, (2) tidal motions, (3) diurnal sea breezes, and (4) surface waves. Mussel larvae were delivered to the inner shelf during upwelling in the bay, but during downwelling at the headland, and were further transported to the shore by surface waves at both locales. In contrast, the delivery of barnacle larvae to the inner shelf occurred during relaxation/downwelling events at both sites, and intertidal settlement coincided with spring tides, suggesting a role for internal tides in their onshore transport. Thus, sequential mechanisms appear to be utilized by larvae to get to the shore, involving interactions of regional-scale upwelling/downwelling processes and local-scale tidal and surface-wave processes, which differ among taxa and among sites with different topography. A bottleneck for larval delivery across the surf zone may be a result of out-of-phase steps in sequential transport mechanisms leaving larvae lost "in transit." PMID- 26236853 TI - Dynamic regulation of partner abundance mediates response of reef coral symbioses to environmental change. AB - Regulating partner abunclance may allow symmotic organisms to mediate interaction outcomes, facilitating adaptive responses to environmental change. To explore the capacity for-adaptive regulation in an ecologically important endosymbiosis, we studied the population dynamics of symbiotic algae in reef-building corals under different abiotic contexts. We found high natural variability in symbiont abundance in corals across reefs, but this variability converged to different symbiont-specific abundances when colonies were maintained under constant conditions. When conditions changed seasonally, symbiont abundance readjusted to new equilibria. We explain these patterns using an a priori model of symbiotic costs and benefits to the coral host, which shows that the observed changes in symbiont abundance are consistent with the maximization of interaction benefit under different environmental conditions. These results indicate that, while regulating symbiont abundance helps hosts sustain maximum benefit in a dynamic environment, spatiotemporal variation in abiotic factors creates a broad range of symbiont abundances (and interaction outcomes) among corals that may account for observed natural variability in performance (e.g., growth rate) and stress tolerance (e.g., bleaching susceptibility). This cost or benefit framework provides a new perspective on the dynamic regulation of reef coral symbioses and illustrates that the dependence of interaction outcomes on biotic and abiotic contexts may be important in understanding how diverse mutualisms respond to environmental change. PMID- 26236854 TI - Parasite and nutrient enrichment effects on Daphnia interspecific competition. AB - Increased productivity due to nutrient enrichment is hypothesized to affect density-dependent processes, such as transmission success of horizontally transmitting parasites. Changes in nutrient availability can also modify the stoichiometry and condition of individual hosts, which may affect their susceptibility for parasites as well as the growth conditions for parasites within the host. Consequently, if not balanced by increased host immuno competence or life history responses, changes in the magnitude of parasite effects with increasing nutrient availability are expected. If these parasite effects are host-species specific, this may lead to shifts in the host community structure. We here used the Daphnia- parasite model system to study the effect of nutrient enrichment on parasite-mediated competition in experimental mesocosms. In the absence of parasites, D. magna was competitively dominant to D. pulex at both low and high nutrient levels. Introduction of parasites resulted in infections of D. magna, but not of D. pulex and, as such, reversed the competitive hierarchy between these two species. Nutrient addition resulted in an increased prevalence and infection intensity of some of the parasites on D. magna. However, there was no evidence that high nutrient levels enhanced negative effects of parasites on the hosts. Costs associated with parasite infections may have been compensated by better growth conditions for D. magna in the presence of high nutrient levels. PMID- 26236855 TI - Plant neighborhood effects on herbivory: damage is both density and frequency dependent. AB - Neighboring plants can affect the likelihood that a focal plant is attacked by herbivores. Both the density of conspecific neighbors (resource concentration or dilution effects) and the relative density of heterospecific neighbors (associational effects or effects of neighbor frequency) within the local neighborhood can affect herbivore load and plant damage. Understanding how these neighborhood effects influence processes such as plant competition or natural selection on plant resistance traits will require knowing how both plant density and frequency affect damage, but previous studies have generally confounded density and frequency effects. In this study, we independently manipulated the absolute density and frequency (i.e., relative density) of two plant species (Solanum carolinense and Solidago altissima) to characterize neighborhood composition effects on S. carolinense damage by herbivores, providing the first picture of how both density and frequency of neighbors influence damage in a single system. We found both a positive effect of S. carolinense density on S. carolinense damage (a resource concentration effect) and a nonlinear effect of S. altissima frequency on S. carolinense damage (associational susceptibility). If these types of patterns are common in nature, future studies seeking to understand neighborhood effects on damage need to incorporate both density and frequency effects and capture any nonlinear effects by selecting a range of values rather than focusing on only a pair of densities or frequencies. This type of data on neighborhood effects will allow us to understand the contribution of neighborhood effects to population-level processes such as competition, the evolution of plant resistance to herbivores, and yield gains in agricultural crop mixtures. PMID- 26236856 TI - A single ectomycorrhizal fungal species can enable a Pinus invasion. AB - Like all obligately ectomycorrhizal plants, pines require ectomycorrhizal fungal symbionts to complete their life cycle. Pines introduced into regions far from their native range are typically incompatible with local ectomycorrhizal fungi, and, when they invade, coinvade with fungi from their native range. While the identities and distributions of coinvasive fungal symbionts of pine invasions are poorly known, communities that have been studied are notably depauperate. However, it is not yet clear whether any number of fungal coinvaders is able to support a Pinaceae invasion, or whether very depauperate communities are unable to invade. Here, we ask whether there is evidence for a minimum species richness of fungal symbionts necessary to support a pine/ectomycorrhizal fungus coinvasion. We sampled a Pinus contorta invasion front near Coyhaique, Chile, using molecular barcoding to identify ectomycorrhizal fungi. We report that the site has a total richness of four species, and that many invasive trees appear to be supported by only a single ectomycorrhizal fungus, Suillus luteus. We conclude that a single ectomycorrhizal (ECM) fungus can suffice to enable a pine invasion. PMID- 26236857 TI - Does N2 fixation amplify the temperature dependence of ecosystem metabolism? AB - Variation in resource supply can cause variation in temperature dependences of metabolic processes (e.g., photosynthesis and respiration). Understanding such divergence is particularly important when using metabolic theory to predict ecosystem responses to climate warming. Few studies, however, have assessed the effect of temperature-resource interactions on metabolic processes, particularly in cases where the supply of limiting resources exhibits temperature dependence. We investigated the responses of biomass accrual, gross primary production (GPP), community respiration (CR), and N2 fixation to warming during biofilm development in a streamside channel experiment. Areal rates of GPP, CR, biomass accrual, and N2 fixation scaled positively with temperature, showing a 32- to 71-fold range across the temperature gradient (approximately 7 degrees-24 degrees C). Areal N2 fixation rates exhibited apparent activation energies (1.5-2.0 eV; 1 eV = approximately 1.6 x 10(-19) J) approximating the activation energy of the nitrogenase reaction. In contrast, mean apparent activation energies for areal rates of GPP (2.1-2.2 eV) and CR (1.6-1.9 eV) were 6.5- and 2.7-fold higher than estimates based on metabolic theory predictions (i.e., 0.32 and 0.65 eV, respectively) and did not significantly differ from the apparent activation energy observed for N2 fixation. Mass-specific activation energies for N2 fixation (1.4-1.6 eV), GPP (0.3-0.5 eV), and CR (no observed temperature relationship) were near or lower than theoretical predictions. We attribute the divergence of areal activation energies from those predicted by metabolic theory to increases in N2 fixation with temperature, leading to amplified temperature dependences of biomass accrual and areal rates of GPP and R. Such interactions between temperature dependences must be incorporated into metabolic models to improve predictions of ecosystem responses to climate change. PMID- 26236858 TI - Predator nonconsumptive effects on prey recruitment weaken with recruit density. AB - We investigated the nonconsumptive effects (NCEs) of predatory dogwhelks (Nucella lapillus) on intertidal barnacle (Semibalanus balanoides) recruitment through field experiments on the Gulf of St. Lawrence coast and the Atlantic coast of Nova Scotia, Canada. We studied the recruitment seasons (May-June) of 2011 and 2013. In 2011, the Gulf coast had five times more nearshore phytoplankton (food for barnacle larvae and recruits) during the recruitment season and yielded a 58% higher barnacle recruit density than the Atlantic coast at the end of the recruitment season. In 2013, phytoplankton levels and barnacle recruit density were similar on both coasts and also lower than for the Gulf coast in 2011. Using the comparative-experimental method, the manipulation of dogwhelk presence (without allowing physical contact with prey) revealed that dogwhelk cues limited barnacle recruitment under moderate recruit densities (Atlantic 2011/2013 and Gulf 2013) but had no effect under a high recruit density (Gulf 2011). Barnacle recruits attract settling larvae through chemical cues. Thus, the highest recruit density appears to have neutralized dogwhelk effects. This study suggests that the predation risk perceived by settling larvae may decrease with increasing recruit density and that prey food supply may indirectly influence predator NCEs on prey recruitment. PMID- 26236859 TI - The raison d'etre of chemical ecology. AB - Chemical ecology is a mechanistic approach to understanding the causes and consequences of species interactions, distribution, abundance, and diversity. The promise of chemical ecology stems from its potential to provide causal mechanisms that further our understanding of ecological interactions and allow us to more effectively manipulate managed systems. Founded on the notion that all organisms use endogenous hormones and chemical compounds that mediate interactions, chemical ecology has flourished over the past 50 years since its origin. In this essay we highlight the breadth of chemical ecology, from its historical focus on pheromonal communication, plant-insect interactions, and coevolution to frontier themes including community and ecosystem effects of chemically mediated species interactions. Emerging approaches including the -omics, phylogenetic ecology, the form and function of microbiomes, and network analysis, as well as emerging challenges (e.g., sustainable agriculture and public health) are guiding current growth of this field. Nonetheless, the directions and approaches we advocate for the future are grounded in classic ecological theories and hypotheses that continue to motivate our broader discipline. PMID- 26236860 TI - Sex-based differences in the adaptive value of social behavior contrasted against morphology and environment. AB - The adaptive nature of sociality has long been a central question in ecology and evolution. However, the relative importance of social behavior for fitness, compared to morphology and environment, remains largely unknown. We assessed the importance of sociality for fitness (lamb production and survival) in a population of mark6d bighorn sheep (Ovis canadensis) over 16 years (n = 1022 sheep-years). We constructed social networks from observations (n = 38,350) of group membership (n = 3150 groups). We then tested whether consistent individual differences in social behavior (centrality) exist and evaluated their relative importance compared to factors known to affect fitness: mass, age, parental effects, and population density. Sheep exhibited consistent individual differences in social centrality. Controlling for maternal carryover effects and age, the positive effect of centrality in a social network on adult female lamb production and survival was equal or greater than the effect of body mass or population density. Social centrality had less effect on male survival and no effect on adult male lamb production or lamb survival. Through its effect on lamb production and survival, sociality in fission-fusion animal societies may ultimately influence population dynamics equally or more than morphological or environmental effects. PMID- 26236861 TI - A late-Quaternary perspective, on atmospheric pCO2, climate, and fire as drivers of C4-grass abundance. AB - Various environmental factors, including atmospheric CO2 (pCO2), regional climate, and fire, have been invoked as primary drivers of long-term variation in C4 grass abundance. Evaluating these hypotheses has been difficult because available paleorecords often lack information on past C4 grass abundance or potential environmental drivers. We analyzed carbon isotope ratios (delta13C) of individual grains of grass pollen in the sediments of two East African lakes to infer changes in the relative abundance of C3 vs. C4 grasses during the past 25 000 years. Results were compared with concurrent changes in pCO2, temperature, moisture balance, and fire activity. Our grass-pollen delta13C analysis reveals a dynamic history of grass-dominated vegetation in equatorial East Africa: C4 grasses have not consistently dominated lowland areas, and high-elevation grasses have not always been predominantly C3. On millennial timescales, C4 grass abundance does not correlate with charcoal influx at either site, suggesting that fire was not a major proximate control of the competitive balance between C3 and C4 grasses. Above the present-day treeline on Mt. Kenya, C4 grass abundance declined from an average of approximately 90% during the glacial period to less than approximately 60% throughout the Holocene, coincident with increases in pCO2 and temperature, and shifts in moisture balance. In the lowland savanna southeast of Mt. Kilimanjaro, C4 grass abundance showed no such directional trend, but fluctuated markedly in association with variation in rainfall amount and seasonal drought severity. These results underscore spatiotemporal variability in the relative influence of pCO2 and climate on the interplay of C3 and C4 grasses and shed light on an emerging conceptual model regarding the expansion of C4 dominated grasslands in Earth's history. They also suggest that future changes in the C3/C4 composition of grass-dominated ecosystems will likely exhibit striking spatiotemporal variability as a result of varying combinations of environmental controls. PMID- 26236862 TI - Disruption of a protective ant-plant mutualism by an invasive ant increases elephant damage to savanna trees. AB - Invasive species can indirectly affect ecosystem processes via the disruption of mutualisms. The mutualism between the whistling thorn acacia (Acacia drepanolobium) and four species of symbiotic ants is an ecologically important one; ants strongly defend trees against elephants, which can otherwise have dramatic impacts on tree cover. In Laikipia, Kenya, the invasive big-headed ant (Pheidole megacephala) has established itself at numerous locations within the last 10-15 years. In invaded areas on five properties, we found that three species of symbiotic Crematogaster ants were virtually extirpated, whereas Tetraponera penzigi co-occurred with P. megacephala. T. penzigi appears to persist because of its nonaggressive behavior; in a whole-tree translocation experiment, Crematogaster defended host trees against P. megacephala, but were extirpated from trees within hours. In contrast, T. penzigi retreated into domatia and withstood invading ants for >30 days. In the field, the loss of defensive Crematogaster ants in invaded areas led to a five- to sevenfold increase in the number of trees catastrophically damaged by elephants compared to uninvaded areas. In savannas, tree cover drives many ecosystem processes and provides essential forage for many large mammal species; thus, the invasion of big-headed ants may strongly alter the dynamics and diversity of East Africa's whistling thorn savannas by disrupting this system's keystone acaciaant mutualism. PMID- 26236863 TI - Experimental evidence for an intraspecific Janzen-Connell effect mediated by soil biota. AB - The negative effect of soil pathogens on seedling survival varies considerably among conspecific individuals, but the underlying mechanisms are largely unknown. For variation between heterospecifics, a common explanation is the Janzen-Connell effect: negative density dependence in survival due to specialized pathogens aggregating on common hosts. We test whether an intraspecific Janzen-Connell effect exists, i.e., whether the survival chances of one population's seedlings surrounded by a different conspecific population increase with genetic difference, spatial distance, and trait dissimilarity between them. In a shade house experiment, we grew seedlings of five populations of each of two subtropical tree species (Castanopsis fissa and Canarium album) for which we measured genetic distance using intersimple sequence repeat (ISSR) analysis and eight common traits/characters, and we treated them with soil material or soil biota filtrate collected from different populations. We found that the relative survival rate increased with increasing dissimilarity measured by spatial distance, genetic distance, and trait differences between the seedling and the population around which the soil was collected. This effect disappeared after soil sterilization. Our results provide evidence that genetic variation, trait similarity, and spatial distance can explain intraspecific variation in plant soil biotic interactions and suggest that limiting similarity also occurs at the intraspecific level. PMID- 26236864 TI - Multi-stressor impacts on fungal diversity and ecosystem functions in streams: natural vs. anthropogenic stress. AB - Biological assemblages are often subjected to multiple stressors emerging from both anthropogenic activities and naturally stressful conditions, and species' responses to simultaneous stressors may differ from those predicted based on the individual effects of each stressor alone. We studied the influence of land-use disturbance (forest drainage) on fungal decomposer assemblages and leaf decomposition rates in naturally harsh (low pH caused by black-shale dominated geology) vs. circumneutral streams. We used pyrosequencing to determine fungal richness and assemblage structure. Decomposition rates did not differ between circumneutral and naturally acidic reference sites. However, the effect of forest drainage on microbial decomposition was more pronounced in the naturally acidic streams than in circumneutral streams. Single-effect responses of fungal assemblages were mainly related to geology. Community similarity was significantly higher in the naturally acidic disturbed sites than in corresponding reference sites, suggesting that land-use disturbance simplifies fungal assemblages in naturally stressful conditions. Naturally acidic streams supported distinct fungal assemblages with many OTUs (operational taxonomic unit) unique to these streams. Our results indicate that fungal assemblages in streams are sensitive to both structural and functional impairment in response to multiple stressors. Anthropogenic degradation of naturally acidic streams may decrease regional fungal diversity and impair ecosystem functions, and these globally occurring environments therefore deserve special attention in conservation planning. PMID- 26236865 TI - Does flood rhythm drive ecosystem responses in tropical riverscapes? AB - Biotic communities are shaped by adaptations from generations of exposure to selective pressures by recurrent and often infrequent events. In large rivers, floods can act as significant agents of change, causing considerable physical and biotic disturbance while often enhancing productivity and diversity. We show that the relative balance between these seemingly divergent outcomes can be explained by the rhythmicity, or predictability of the timing and magnitude, of flood events. By analyzing biological data for large rivers that span a gradient of rhythmicity in the Neotropics and tropical Australia, we find that systems with rhythmic annual floods have higher-fish species richness, more stable avian populations, and elevated rates of riparian forest production compared with those with arrhythmic flood pulses. Intensification of the hydrological cycle driven by climate change, coupled with reductions in runoff due to water extractions for human use and altered discharge from impoundments, is expected to alter the hydrologic rhythmicity of floodplain rivers with significant consequences for both biodiversity and productivity. PMID- 26236866 TI - Terrestrial orchids in a tropical forest: best sites for abundance differ from those for reproduction. AB - Suitable habitat for a species is often modeled by linking its distribution patterns with landscape characteristics. However, modeling the relationship between fitness and landscape characteristics is less common. In this study we take a novel approach towards species distribution modeling (SDM) by investigating factors important not only for species occurrence, but also abundance and physical size, as well as fitness measures. We used the Neotropical terrestrial orchid Prescottia stachyodes as our focal species, and compiled geospatial information on habitat and neighboring plants for use in a two-part conditional SDM that accounted for zero inflation and reduced spatial autocorrelation bias. First, we modeled orchid occurrence, and then within suitable sites we contrasted habitat characteristics important for orchid abundance as compared to plant size. We then tested possible fitness implications, informed by analyses of allometric scaling of reproductive effort and lamina area, as well as size-density relationships in areas of P. stachyodes co-occurrence. We determined that orchid presence was based on a combination of biotic and abiotic factors (indicator species, diffuse solar radiation). Within these sites, P. stachyodes abundance was higher on flat terrain, with fine, moderately well-drained soil, and areas without other native orchids, whereas plant size was greater in less rocky areas. In turn, plant size determined reproductive effort, with floral display height proportionate to lamina area (more photosynthates); however, allometric scaling of flower quantity suggests a higher energy cost for production, or maintenance, of flowers. Overall, habitat factors most important for abundance differed from those for size (and thus reproductive effort), suggesting that sites optimal for either recruitment or survival may not be the primary source of seeds. For plots with multiple P. stachyodes plants, size-density relationships differed depending on the size class examined, which may reflect context-dependent population dynamics. Thus, ecological resolution provided by SDM can be enhanced by incorporating abundance and fitness measures. PMID- 26236867 TI - Species associations structured by environment and land-use history promote beta diversity in a temperate forest. AB - Patterns of diversity and community composition in forests are controlled by a combination of environmental factors, historical events, and stochastic or neutral mechanisms. Each of these processes has been linked to forest community assembly, but their combined contributions to alpha and beta-diversity in forests has not been well explored. Here we use variance partitioning to analyze approximately 40,000 individual trees of 49 species, collected within 137 ha of sampling area spread across a 900-ha temperate deciduous forest reserve in Pennsylvania to ask (1) To what extent is site-to-site variation in species richness and community composition of a temperate forest explained by measured environmental gradients and by spatial descriptors (used here to estimate dispersal-assembly or unmeasured, spatially structured processes)? (2) How does the incorporation of land-use history information increase the importance attributed to deterministic community assembly? and (3) How do the distributions and abundances of individual species within the community correlate with these factors? Environmental variables (i.e., topography, soils, and distance to stream), spatial descriptors (i.e., spatial eigenvectors derived from Cartesian coordinates), and land-use history variables (i.e., land-use type and intensity, forest age, and distance to road), explained about half of the variation in both species richness and community composition. Spatial descriptors explained the most variation, followed by measured environmental variables and then by land- use history. Individual species revealed variable responses to each of these sets of predictor variables. Several species were associated with stream habitats, and others were strictly delimited across opposing north- and south-facing slopes. Several species were also associated with areas that experienced recent (i.e., <100 years) human land-use impacts. These results indicate that deterministic factors, including environmental and land-use history variables, are important drivers of community response. The large amount of "unexplained" variation seen here (about 50%) is commonly observed in other such studies attempting to explain distribution and abundance patterns of plant communities. Determining whether such large fractions of unaccounted for variation are caused by a lack of sufficient data, or are an indication of stochastic features of forest communities globally, will remain an important challenge for ecologists in the future. PMID- 26236868 TI - Evidence of soil nutrient availability as the proximate constraint on growth of treeline trees in northwest Alaska. AB - The position of the Arctic treeline, which is a key regulator of surface energy exchange and carbon cycling, is widely thought to be controlled by temperature. Here, we present evidence that soil nutrient availability, rather than temperature, may be the proximate control on growth of treeline trees at our study site in northwest Alaska. We examined constraints on growth and allocation of white spruce in three contrasting habitats. The habitats had similar aboveground climates, but soil temperature declined from the riverside terrace to the forest to the treeline. We identified six lines of evidence that conflict with the hypothesis of direct temperature control and/or point to the importance of soil nutrient availability. First, the magnitude of aboveground growth declined from the terrace to the forest to the treeline, along gradients of diminishing soil nitrogen (N) availability and needle N concentration. Second, peak rates of branch extension, main stem radial and fine-root growth were generally not coincident with seasonal air and soil temperature maxima. At the treeline, in particular, rates of aboveground and fine-root growth declined well before air and soil temperatures reached their seasonal peaks. Third, in contrast with the hypothesis of temperature-limited growth, growing season average net photosynthesis was positively related to the sum of normalized branch extension, main stem radial and fine-root growth across trees and sites. Fourth, needle nonstructural carbohydrate concentration was significantly higher on the terrace, where growth was greatest. Fifth, annual branch extension growth was positively related to snow depth, consistent with the hypothesis that deeper snow promotes microbial activity and greater soil nutrient availability. Finally, the tree ring record revealed a large growth increase during late 20th-century climate warming on the terrace, where soil N availability is relatively high. Meanwhile, trees in the forest and at the treeline showed progressively smaller growth increases. Our results suggest temperature effects on tree growth at our study sites may be mediated by soil nutrient availability, making responses to climate change more complex and our ability to interpret the tree ring record more challenging than previously thought. PMID- 26236869 TI - Intermediate disturbance in experimental landscapes improves persistence of beetle metapopulations. AB - Human-dominated landscapes often feature patches that fluctuate in suitability through space and time, but there is little experimental evidence relating the consequences of dynamic patches for species persistence. We used a spatially and temporally dynamic metapopulation model to assess and compare metapopulation capacity and persistence for red flour beetles (Tribolium castaneum) in experimental landscapes differentiated by resource structure, patch dynamics (destruction and restoration), and connectivity. High connectivity increased the colonization rate of beetles, but this effect was less pronounced in heterogeneous relative to homogeneous landscapes. Higher connectivity and faster patch dynamics increased extinction rates in landscapes. Lower connectivity promoted density-dependent emigration. Heterogeneous landscapes containing patches of different carrying capacity enhanced landscape-level occupancy probability. The highest metapopulation capacity and persistence was observed in landscapes with heterogeneous patches, low connectivity, and slow patch dynamics. Control landscapes with no patch dynamics exhibited rapid declines in abundance and approached extinction due to increased adult mortality in the matrix, higher pupal cannibalism by adults, and extremely low rates of exchange between remaining habitable patches. Our results highlight the role of intermediate patch dynamics, intermediate connectivity, and the nature of density dependence of emigration for persistence of species in heterogeneous landscapes. Our results also demonstrate the importance of incorporating local dynamics into the estimation of metapopulation capacity for conservation planning. PMID- 26236870 TI - Modeling spatiotemporal dynamics of outbreaking species: influence of environment and migration in a locust. AB - Many pest species exhibit huge fluctuations in population abundance. Understanding their large-scale and long-term dynamics is necessary to develop effective control and management strategies. Occupancy models represent a promising approach to unravel interactions between environmental factors and spatiotemporal dynamics of outbreaking populations. Here, we investigated population dynamics of the Australian plague locust, Chortoicetes terminifera, using density data collected between 1988 and 2010 by the Australian Plague Locust Commission over more than 3 million km2 in eastern Australia. We applied multistate and autologistic multi-season occupancy models to test competing hypotheses about environmental and demographic processes affecting the large scale dynamics of the Australian plague locust. We found that rainfall and land cover predictors best explained the spatial variability in outbreak probability across eastern Australia. Outbreaks are more likely to occur in temperate than tropical regions, with a faster and more continuous response to rainfall in desert than in agricultural areas. Our results also support the hypothesis that migration tends to propagate outbreaks only locally (over distances lower than 400 km) rather than across climatic regions. Our study suggests that locust outbreak forecasting and management systems could be improved by implementing key environmental factors and migration in hierarchical spatial models. Finally, our modeling framework can be seen as a step towards bridging the gap between mechanistic and more phenomenological models in the spatial analysis of fluctuating populations. PMID- 26236871 TI - Response of N cycling to nutrient inputs in forest soils across a 1000-3000 m elevation gradient in the Ecuadorian Andes. AB - Large areas in the tropics receive elevated atmospheric nutrient inputs. Presently, little is known on how nitrogen (N) cycling in tropical montane forest soils will respond to such increased nutrient inputs. We assessed how gross rates of mineral N production (N mineralization and nitrification) and microbial N retention (NH4+ and NO3- immobilization and dissimilatory NO3- reduction to NH4+ [DNRA]) change with elevated N and phosphorus (P) inputs in montane forest soils at 1000-, 2000-, and 3000-m elevations in south Ecuador. At each elevation, four replicate plots (20 x 20 m each) of control, N (added at 50 kg N x ha(-1) x yr( 1)), P (added at 10 kg P x ha(-1) x yr(-1)), and combined N+P additions have been established since 2008. We measured gross N cycling rates in 2010 and 2011, using 15N pool dilution techniques with in situ incubation of intact soil cores taken from the top 5 cm of soil. In control plots, gross soil-N cycling rates decreased.with increase in elevation, and microbial N retention was tightly coupled with mineral N production. At 1000 m and 2000 m, four-year N and combined N + P additions increased gross mineral N production but decreased NH4+ and NO3- immobilization and DNRA compared to the control. At 3000 m, four-year N and combined N + P additions increased gross N mineralization rates and decreased DNRA compared to the control; although NH4+ and NO3- immobilization in the N and N + P plots were not different' from the control, these were lower than their respective mineral N production. At all elevations, decreased microbial N retention was accompanied by decreased microbial biomass C and C:N ratio. P addition did not affect any of the soil-N cycling processes. Our results signified that four years of N addition, at a rate expected to occur at these sites, uncoupled the soil-N cycling processes, as indicated by decreased microbial N retention. This fast response of soil-N cycling processes across elevations implies that greater attention should be paid to the biological implications on montane forests of such uncoupled soil-N cycling. PMID- 26236872 TI - Naturalization of central European plants in North America: species traits, habitats, propagule pressure, residence time. AB - The factors that promote invasive behavior in introduced plant species occur across many scales of biological and ecological organization. Factors that act at relatively small scales, for example, the evolution of biological traits associated with invasiveness, scale up to shape species distributions among different climates and habitats, as well as other characteristics linked to invasion, such as attractiveness for cultivation (and by extension propagule pressure). To identify drivers of invasion it is therefore necessary to disentangle the contribution of multiple factors that are interdependent. To this end, we formulated a conceptual model describing the process of invasion of central European species into North America based on a sequence of "drivers." We then used confirmatory path analysis to test whether the conceptual model is supported by a statistical model inferred from a comprehensive database containing 466 species. The path analysis revealed that naturalization of central European plants in North America, in terms of the number of North American regions invaded, most strongly depends on residence time in the invaded range and the number of habitats occupied by species in their native range. In addition to the confirmatory path analysis, we identified the effects of various biological traits on several important drivers of the conceptualized invasion process. The data supported a model that included indirect effects of biological traits on invasion via their effect on the number of native range habitats occupied and cultivation in the native range. For example, persistent seed banks and longer flowering periods are positively correlated with number of native habitats, while a stress-tolerant life strategy is negatively correlated with native range cultivation. However, the importance of the biological traits is nearly an order of magnitude less than that of the larger scale drivers and highly dependent on the invasion stage (traits were associated only with native range drivers). This suggests that future research should explicitly link biological traits to the different stages of invasion, and that a failure to consider residence time or characteristics of the native range may seriously overestimate the role of biological traits, which, in turn, may result in spurious predictions of plant invasiveness. PMID- 26236873 TI - Phenological mismatch with abiotic conditions implications for flowering in Arctic plants. AB - Although many studies have examined the phenological mismatches between interacting organisms, few have addressed the potential for mismatches between phenology and seasonal weather conditions. In the Arctic, rapid phenological changes in many taxa are occurring in association with earlier snowmelt. The timing of snowmelt is jointly affected by the size of the late winter snowpack and the temperature during the spring thaw. Increased winter snowpack results in delayed snowmelt, whereas higher air temperatures and faster snowmelt advance the timing of snowmelt. Where interannual variation in snowpack is substantial, changes in the timing of snowmelt can be largely uncoupled from changes in air temperature. Using detailed, long-term data on the flowering phenology of four arctic plant species from Zackenberg, Greenland, we investigate whether there is a phenological component to the temperature conditions experienced prior to and during flowering. In particular, we assess the role of timing of flowering in determining pre-flowering exposure to freezing temperatures and to the temperatures-experienced prior to flowering. We then examine the implications of flowering phenology for flower abundance. Earlier snowmelt resulted in greater exposure to freezing conditions, suggesting an increased potential for a mismatch between the timing of flowering and seasonal weather conditions and an increased potential for negative consequences, such as freezing 'damage. We also found a parabolic relationship between the timing of flowering and the temperature experienced during flowering after taking interannual temperature effects into account. If timing of flowering advances to a cooler period of the growing season, this may moderate the effects of a general warming trend across years. Flower abundance was quadratically associated with the timing of flowering, such that both early and late flowering led to lower flower abundance than did intermediate flowering. Our results indicate that shifting the timing of flowering affects the temperature experienced during flower development and flowering beyond that imposed by interannual variations in climate. We also found that phenological timing may affect flower abundance, and hence, fitness. These findings suggest that plant population responses to future climate change will be shaped not only by extrinsic climate forcing, but also by species' phenological responses. PMID- 26236874 TI - Using plant traits to explain plant-microbe relationships involved in nitrogen acquisition. AB - It has long been recognized that plant species and soil microorganisms. are tightly linked, but understanding how different species vary in their effects on soil is currently limited. In this study, we identified those. plant characteristics (identity, specific functional traits, or resource acquisition strategy) that were the best predictors of nitrification and denitrification processes. Ten plant populations representing eight species collected from three European grassland sites were chosen for their contrasting plant trait values and resource acquisition strategies. For each individual plant, leaf and root traits and the associated potential microbial activities (i.e., potential denitrification rate [DEA], maximal nitrification rate [NEA], and NH4+ affinity of the microbial community [NHScom]) were measured at two fertilization levels under controlled growth conditions. Plant traits were powerful predictors of plant-microbe interactions, but relevant plant traits differed in relation to the microbial function studied. Whereas denitrification was linked to the relative growth rate of plants, nitrification was strongly correlated to root trait characteristics (specific root length, root nitrogen concentration, and plant affinity for NH4+) linked to plant N cycling. The leaf economics spectrum (LES) that commonly serves as an indicator of resource acquisition strategies was not correlated to microbial activity. These results suggest that the LES alone is not a good predictor of microbial activity, whereas root traits appeared critical in understanding plant-microbe interactions. PMID- 26236875 TI - Variation in the local population dynamics of the short-lived Opuntia macrorhiza (Cactaceae). AB - Spatiotemporal variation in demographic rates can have profound effects for population persistence, especially for dispersal-limited species living in fragmented landscapes. Long-term studies of plants in such habitats help with understanding the impacts of fragmentation on population persistence but such studies are rare. In this work, we reanalyzed demographic data from seven years of the short-lived cactus Opuntia macrorhiza var. macrorhiza at five plots in Boulder, Colorado. Previous work combining data from all years and all plots predicted a stable population (deterministic log lamda approximately 0). This approach assumed that all five plots were part of a single population. Since the plots were located in a suburban-agricultural interface separated by highways, grazing lands, and other barriers, and O. macrorhiza is likely dispersal limited, we analyzed the dynamics of each plot separately using stochastic matrix models assuming each plot represented a separate population. We found that the stochastic population growth rate log lamdaS varied widely between populations (log lamdaS = 0.1497, 0.0774, -0.0230, -0.2576, -0.4989). The three populations with the highest growth rates were located close together in space, while the two most isolated populations had the lowest growth rates suggesting that dispersal between populations is critical for the population viability of O. macrorhiza. With one exception, both our prospective (stochastic elasticity) and retrospective (stochastic life table response experiments) analysis suggested that means of stasis and growth, especially of smaller plants, were most important for population growth rate. This is surprising because recruitment is typically the most important vital rate in a short-lived species such as O. macrorhiza. We found that elasticity to the variance was mostly negligible, suggesting that O. macrorhiza populations are buffered against large temporal variation. Finally, single-year elasticities to means of transitions to the smallest stage (mostly due to reproduction) and growth differed considerably from their long-term elasticities. It is important to be aware of this difference when using models to predict the effect of manipulating plant vital rates within the time frame of typical plant demographic studies. PMID- 26236876 TI - Comparing seed dispersal effectiveness by frugivores at the community level. AB - Seed dispersal effectiveness (SDE) is the contribution of dispersers to plant recruitment and is estimated as the product of the number of seeds dispersed (quantity) and the probability of recruitment of each dispersed seed (quality). Although SDE is a key concept in seed dispersal ecology, few studies estimate SDE and none has a community approach. Oceanic islands, with simple communities, are ideal for this purpose. In this study, we compared the SDE of the main types of dispersers (lizards and passerine birds) at the community level in a given habitat. We estimated SDE using a stochastic simulation model parameterized with empirical data on quantity and quality components measured throughout the recruitment process. Although lizards are highly frugivorous and their density was approximately 20 times higher than that of birds, lizards and birds dispersed a similar quantity of seeds. This may be due to lower intake of seeds by lizards due to their slower metabolism (approximately 20 times lower than birds). This low metabolic rate limits the importance of lizards as seed dispersers, but it is compensated by extraordinarily high lizard densities in the study area (approximately 9600 individuals/km2). High densities of lizards are typical of islands, and this helps to explain why dispersal by lizards seems mainly an island phenomenon. Birds and lizards showed functional complementarity, especially regarding seed dispersal distribution patterns. In fact, lizards dispersed more seeds in shrublands and open sites, and birds in woodlands and beneath canopies, with their joint contribution helping to maximize recruitment. Lizards provided higher SDE than birds for 7 out of 11 plant species. The disperser with a higher quantity for a given plant generally had the higher quality, and plants could be classified as bird- or lizard-dependent for dispersal. This dependence increased when considering SDE instead of dispersal quantity only. Moreover, quality was a better predictor of SDE than quantity, which should be considered when parameterizing interaction networks, as this might affect inferences about their architecture. PMID- 26236877 TI - Limiting resources in sessile systems: food enhances diversity and growth of suspension feeders despite available space. AB - Much of our understanding of competition comes trom onservations in sessue systems, such as rainforests and marine invertebrate communities. In terrestrial systems, sessile species often compete for multiple limiting resources (i.e., space, light, and nutrients), but in marine systems, space is viewed as the primary or sole limiting resource. Competition theory, on the other hand, suggests that competition for a single limiting resource is unlikely to maintain high species diversity, but manipulative tests of competition for other resources in marine benthic systems are exceedingly rare. Here, we manipulate the availability of food for a classic system, marine sessile invertebrate communities, and investigate the effects on species diversity, abundance, and composition during early succession as well as on the growth of bryozoan populations in the field. We found the number of species to be greater, available space to be lower, and the community composition to be different in assemblages subjected to increased food availability compared to controls. Similarly, laboratory-settled bryozoans deployed into the field grew more in the presence of enhanced food. Our results suggest that food can act as a limiting resource, affecting both diversity and abundance, even when bare space is still available in hard-substratum communities. Consequently, broadening the view of resource limitation beyond solely space may increase our understanding and predictability of marine sessile systems. PMID- 26236878 TI - Water flow and fin shape polymorphism in coral reef fishes. AB - Water flow gradients have been linked to phenotypic differences and swimming performance across a variety of fish assemblages. However, the extent to which water motion shapes patterns of phenotypic divergence within species remains unknown. We tested the generality of the functional relationship between swimming morphology and water flow by exploring the extent of fin and body shape polymorphism in 12 widespread species from three families (Acanthuridae, Labridae, Pomacentridae) of pectoral-fin swimming (labriform) fishes living across localized wave exposure gradients. The pectoral fin shape of Labridae and Acanthuridae species was strongly related to wave exposure: individuals with more tapered, higher aspect ratio (AR) fins were found on windward reef crests, whereas individuals with rounder, lower AR fins were found on leeward, sheltered reefs. Three of seven Pomacentridae species showed similar trends, and pectoral fin shape was also strongly related to wave exposure in pomacentrids when fin aspect ratios of three species were compared across flow habitats at very small spatial scales (<100 m) along a reef profile (reef slope, crest, and back lagoon). Unlike fin shape, there were no intraspecific differences in fish body fineless ratio across habitats or depths. Contrary to our predictions, there was no pattern relating species' abundances to polymorphism across habitats (i.e., abundance was not higher at sites where morphology is better adapted to the environment). This suggests that there are behavioral and/or physiological mechanisms enabling some species to persist across flow habitats in the absence of morphological differences. We suggest that functional relationships between swimming morphology and water flow not only structure species assemblages, but are yet another important variable contributing to phenotypic differences within species. The close links between fin shape polymorphism and local water flow conditions appear to be important for understanding species' distributions as well as patterns of diversification across environmental gradients. PMID- 26236879 TI - Groundwater controls ecological zonation of salt marsh macrophytes. AB - Ecological zonation of salt marsh macrophytes is strongly influenced by hydrologic factors, but these factors are poorly understood. We examined groundwater flow patterns through surficial sediments in two saltmarshes in the southeastern United States to quantify hydrologic differences between distinct ecological zones. Both sites included tall- or medium-form Spartina alterniflora near the creek bank; short-form Spartina alterniflora in the mid-marsh; salt flats and Salicornia virginica in the high marsh; and Juncus roemarianus in brackish-to-fresh areas adjacent to uplands. Both sites had relatively small, sandy uplands and similar stratigraphy consisting of marsh muds overlying a deeper sand layer. We found significant hydrologic differences between the four ecological zones. In the zones colonized by S. alterniflora, the vertical flow direction oscillated with semi-diurnal tides. Net flow (14-day average) through the tall S. alterniflora zones was downward, whereas the short S. alterniflora zones included significant periods of net upward groundwater flow. An examination of tidal efficiency at these sites suggested that the net flow patterns rather than tidal damping controlled the width of the tall S. alterniflora zone. In contrast to the S. alterniflora zones, hypersaline zones populated by S. virginica were characterized by sustained periods (days) of continuous upward flow of saline water during neap tides. The fresher zone populated by J. roemarianus showed physical flow patterns that were similar to the hypersaline zones, but the upwelling porewaters were fresh rather than saline. These flow patterns were influenced by the hydrogeologic framework of the marshes, particularly differences in hydraulic head between the upland water table and the tidal creeks. We observed increases in hydraulic head of approximately 40 cm from the creek to the upland in the sand layers below both marshes, which is consistent with previous observations that sandy aquifers below fine-grained marsh soils act as conduits for flow from uplands to tidal creeks. This hydrologic framework supports relatively good drainage near the creek, increased waterlogging in the mid-marsh, and the development of hypersalinity adjacent to the freshwater upland. These hydrologic differences in turn support distinct ecological zones. PMID- 26236880 TI - Phenological decoupling of mortality from wave forcing in kelp beds. AB - Kelps often live in a harsh hydrodynamic environment where wave-driven dislodgement of individuals can alter the biodiversity and functioning of reef systems, and increase production in coastal ecosystems adjacent to reefs. The current paradigm is that winter storms tear kelps from reefs once hydrodynamic forces exceed attachment or tissue strength--a threshold response that implies a pulsed relationship between wave forces and dislodgement. Here, we challenge this understanding by showing how kelp phenology can decouple susceptibility to dislodgement from seasonal patterns in wave forces. We measured kelp dislodgement rates and hydrodynamic forces at nine subtidal reefs over two years (n = 4320 kelps tagged and monitored). Contrary to expectation, we found relatively low and constant dislodgement rates for all reefs (13% +/- 6% [mean per season +/- SD]) in spite of a strong temporal pattern in wave action and extreme water velocities (winter peaks up to 3-4 m/s). A biomechanical model, based on the balance between kelp attachment strength and hydrodynamic drag, demonstrated that severe reduction in individual kelp size toward winter (>50% decrease in biomass for all sites) minimized drag and made the kelps less susceptible to high water velocities, allowing individuals to survive storm velocities over 3-4 m/s. We conclude that the timing of reduced susceptibility to disturbance, through the seasonal reduction of individual kelp biomass that coincides with times of highest water velocities is critical to the dynamics of kelp dislodgement and survival. We propose that phenological processes maintain many kelp beds in a higher degree of population stability and equilibrium with hydrodynamic forces than previously believed. PMID- 26236881 TI - Kelp forest size alters microbial community structure and function on Vancouver Island, Canada. AB - Bacteria are ubiquitous and important components of marine ecosystems, yet the interaction between bacteria and higher trophic levels remain poorly understood. The trophic cascade involving sea otters, urchins, and kelp in the North Pacific is a classic case of altered ecosystem states; however, its impacts on microbial communities are unknown. We investigated the response of microbial communities to variation in kelp abundance between regions with and without sea otter populations along the west coast of Vancouver Island, British Columbia, Canada. We compared bacterial community structure and function between regions with large and small kelp forests, including an subset of the bacterial community that produces alginate lyase, which allows direct utilization of kelp carbon. The abundance and activity of alginate-lyase-producing bacteria were 3.2 and 1.4 times higher, respectively, in the region with large kelp forests, and declined rapidly with increasing distance from kelp. Total bacterial abundance was 2.7 times greater, and bacteria grew faster and experienced more zooplankton grazing and viral-mediated mortality in the presence of large kelp forests. These patterns suggest that larger kelp forests produce more detritus and dissolved organic matter, which stimulate microbial activity. Our results indicate that variation in kelp forest size alters the community structure and productivity of microbes and contributes to the growing evidence that top predators interact with microbes and ecosystem processes through a cascade of indirect effects. PMID- 26236882 TI - Long-term declines in nutritional quality of tropical leaves. AB - Global change is affecting plant and animal populations and many of the changes are likely subtle and difficult to detect. Based on greenhouse experiments, changes in temperature and rainfall, along with elevated CO2, are expected to impact the nutritional quality of leaves. Here, we show a decline in the quality of tree leaves 15 and 30 years after two previous studies in an undisturbed area of tropical forest in Kibale National Park, Uganda. After 30 years in a sample of multiple individuals of ten tree species, the mature leaves of all but one species increased in fiber concentrations, with a mean increase of 10%; tagged individuals of one species increased 13% in fiber. After 15 years, in eight tree species the fiber of young leaves increased 15%, and protein decreased 6%. Like many folivores, Kibale colobus monkeys select leaves with a high protein-to-fiber ratio, so for these folivores declining leaf quality could have a major impact. Comparisons among African and Asian forests show a strong correlation between colobine biomass and the protein-to-fiber ratio of the mature leaves from common tree species. Although this model, predicts a 31% decline in monkey abundance for Kibale, we have not yet seen these declines. PMID- 26236883 TI - More than 1470 manuscripts have been submitted to Ecology in 2014, up about 6% from 2013. PMID- 26236884 TI - Ocean acidification through the lens of ecological theory. AB - Ocean acidification, chemical changes to the carbonate system of seawater, is emerging as a key environmental challenge accompanying global warming and other human-induced perturbations. Considerable research seeks to define the scope and character of potential outcomes from this phenomenon, but a crucial impediment persists. Ecological theory, despite its power and utility, has been only peripherally applied to the problem. Here we sketch in broad strokes several areas where fundamental principles of ecology have the capacity to generate insight into ocean acidification's consequences. We focus on conceptual models that, when considered in the context of acidification, yield explicit predictions regarding a spectrum of population- and community-level effects, from narrowing of species ranges and shifts in patterns of demographic connectivity, to modified consumer-resource relationships, to ascendance of weedy taxa and loss of species diversity. Although our coverage represents only a small fraction of the breadth of possible insights achievable from the application of theory, our hope is that this initial foray will spur expanded efforts to blend experiments with theoretical approaches. The result promises to be a deeper and more nuanced understanding of ocean acidification'and the ecological changes it portends. PMID- 26236885 TI - To predict the niche, model colonization and extinction. AB - Ecologists frequently try to predict the future geographic distributions of species. Most studies assume that the current distribution of a species reflects its environmental requirements (i.e., the species' niche). However, the current distributions of many species are unlikely to be at equilibrium with the current distribution of environmental conditions, both because of ongoing invasions and because the distribution of suitable environmental conditions is always changing. This mismatch between the equilibrium assumptions inherent in many analyses and the disequilibrium conditions in the real world leads to inaccurate predictions of species' geographic distributions and suggests the need for theory and analytical tools that avoid equilibrium assumptions. Here, we develop a general theory of environmental associations during periods of transient dynamics. We show that time-invariant relationships between environmental conditions and rates of local colonization and extinction can produce substantial temporal variation in occupancy-environment relationships. We then estimate occupancy-environment relationships during three avian invasions. Changes in occupancy-environment relationships over time differ among species but are predicted by dynamic occupancy models. Since estimates of the occupancy-environment relationships themselves are frequently poor predictors of future occupancy patterns, research should increasingly focus on characterizing how rates of local colonization and extinction vary with environmental conditions. PMID- 26236886 TI - Assessing the impacts of nonrandom seed dispersal by multiple frugivore partners on plant recruitment. AB - Directed dispersal is defined as enhanced dispersal of seeds into suitable microhabitats, resulting in higher recruitment than if seeds were dispersed randomly. While this constitutes one of the main explanations for the adaptive value of frugivore-mediated seed dispersal, the generality of this advantage has received little study, particularly when multiple dispersers are involved. We used probability recruitment models of a long-lived rainforest tree in Madagascar to compare recruitment success under dispersal by multiple frugivores, no dispersal, and random dispersal. Models were parameterized using a three-year recruitment experiment and observational data of dispersal events by three frugivorous lemur species that commonly disperse its seeds. Frugivore-mediated seed dispersal was nonrandom with respect to canopy cover and increased modeled per-seed sapling recruitment fourfold compared to no dispersal. Seeds dispersed by one frugivore, Eulemur rubriventer, had higher modeled recruitment probability than seeds dispersed randomly. However, as a group, our models suggest that seeds dispersed by lemurs would have lower recruitment than if dispersal were random. Results demonstrate the importance of evaluating the contribution of multiple frugivores to plant recruitment for understanding plant population dynamics and the ecological and evolutionary significance of seed dispersal. PMID- 26236887 TI - Erosion rates as a potential bottom-up control of forest structural characteristics in the Sierra Nevada Mountains. AB - The physical characteristics of landscapes place fundamental constraints on vegetation growth and ecosystem function. In actively eroding landscapes, many of these characteristics are controlled by long-term erosion rates: increased erosion rates generate steeper topography and reduce the depth and extent of weathering, limiting moisture storage capacity and impacting nutrient availability. Despite the potentially important bottom-up control that erosion rates place on substrate characteristics, the relationship between the two is largely unexplored. We investigate spatial variations in aboveground biomass (AGB) across a structurally diverse mixed coniferous/deciduous forest with an order of magnitude erosion-rate gradient in the Northern Californian Sierra Nevada, USA, using high resolution LiDAR data and field plots. Mean basin slope, a proxy for erosion rate, accounts for 32% of variance in AGB within our field area (P < 0.001), considerably outweighing the effects of mean annual precipitation, temperature, and bedrock lithology. This highlights erosion rate as a potentially important, but hitherto unappreciated, control on AGB and forest structure. PMID- 26236888 TI - Liana competition with tropical trees varies seasonally but not with tree species identity. AB - Lianas in tropical forests compete intensely with trees for above- and belowground resources and limit tree growth and regeneration. Liana competition with adult canopy trees may be particularly strong, and, if lianas compete more intensely with some tree species than others, they may influence tree species composition. We performed the first systematic, large-scale liana removal experiment to assess the competitive effects of lianas on multiple tropical tree species by measuring sap velocity and growth in a lowland tropical forest in Panama. Tree sap velocity increased 60% soon after liana removal compared to control trees, and tree diameter growth increased 25% after one year. Although tree species varied in their response to lianas, this variation was not significant, suggesting that lianas competed similarly with all tree species examined. The effect of lianas on tree sap velocity was particularly strong during the dry season, when soil moisture was low, suggesting that lianas compete intensely with trees for water. Under the predicted global change scenario of increased temperature and drought intensity, competition from lianas may become more prevalent in seasonal tropical forests, which, according to our data, should have a negative effect on most tropical tree species. PMID- 26236889 TI - How do animals optimize the size-number trade-off when aging? Insights from reproductive senescence patterns in marmots. AB - We investigated the influence of female age on five reproductive traits and on the offspring size-number trade-off from an extensive data set spanning 20 years of study on free-ranging Alpine marmots. Offspring mass increased with female age, whereas litter size and reproductive allocation remained constant in females up to 10 years of age and declined thereafter. Although reproductive allocation declined, post-weaning juvenile survival and the size-number trade-off did not change markedly throughout a female's lifetime. Senescence of annual reproductive success (i.e., the number of offspring surviving their first hibernation within a given litter) only resulted from senescence of litter size. The data were insufficient to determine whether the decrease in litter size with age was caused by declining litter size at birth, offspring pre-weaning survival, or both. Regardless, our findings demonstrate that marmot females display a size-number trade-off invariant with age, and that their reproductive tactic involves increasing offspring size at the cost of decreasing litter size with increasing age. As a result, reproductive performance remains constant throughout a female's lifetime, despite the deleterious effects of senescence in litter size. PMID- 26236890 TI - Everybody loses: intraspecific competition induces tragedy of the commons in Allenby's gerbils. AB - Interference competition may lead to a tragedy of the commons in which individuals driven by self-interest reduce the fitness of the entire group. We investigated this hypothesis in Allenby's gerbils, Gerbillus andersoni allenbyi, by comparing foraging behaviors of single vs. pairs of gerbils. We recorded strong interference competition within the foraging pairs. Competition reduced the amount of time the gerbils spent foraging, as well as foraging efficiency since part of the foragers' attention was directed toward detecting competitors (apparent predation risk). Single gerbils harvested significantly more food than the combined efforts of two gerbils foraging together. Competition reduced the success of both individuals within a pair by more than 50%, making this a case of the tragedy of the commons where each individual's investment in competition reduces the success of all individuals within the group, including its own. Despite their great costs, competitive behaviors will be selected for as long as one individual achieves higher fitness than the other. In nature, interspecific interactions, such as predation risk, may act to reduce and regulate the deleterious effects of intraspecific competition. PMID- 26236891 TI - Interannual variability: a crucial component of space use at the territory level. AB - Interannual variability in space use and how that variation is influenced by density-dependent and density-independent factors are important processes in population ecology. Nevertheless, interannual variability has been neglected by the majority of space use studies. We assessed that variation for wolves living in 15 different packs within Yellowstone National Park during a 13-year period (1996-2008). We estimated utilization distributions to quantify the intensity of space use within each pack's territory each year in summer and winter. Then, we used the volume of intersection index (VI) to quantify the extent to which space use varied from year to year. This index accounts for both the area of overlap and differences in the intensity of use throughout a territory and ranges between 0 and 1. The mean VI index was 0.49, and varied considerably, with approximately 20% of observations (n = 230) being <0.3 or >0.7. In summer, 42% of the variation was attributable to differences between packs. These differences can be attributable to learned behaviors and had never been thought to have such an influence on space use. In winter, 34% of the variation in overlap between years was attributable to interannual differences in precipitation and pack size. This result reveals the strong influence of climate on predator space use and underlies the importance of understanding how climatic factors are going to affect predator populations in the occurrence of climate change. We did not find any significant association between overlap and variables representing density dependent processes (elk and wolf densities) or intraspecific competition (ratio of wolves to elk). This last result poses a challenge to the classic view of predator-prey systems. On a small spatial scale, predator space use may be driven by factors other than prey distribution. PMID- 26236892 TI - Contrasting between- and within-individual trait effects on mortality risk in a long-lived seabird. AB - Individual life span is the most important determinant of lifetime reproductive success and fitness across taxa. Identifying the relationships between life history traits and survival therefore is fundamental to understanding the evolution of a species' traits. Especially important in this respect is to separate the contributions of between- and within-individual trait effects, because only such an approach can identify markers of individual quality and expose within-individual processes such as aging or the occurrence of costs of reproduction. Here we report a rigorous cross-trait comparison in which we quantify effects of between- and within- individual variation in phenology, body mass, and reproductive performance on mortality risk in a long-lived seabird, the Common Tern Sterna hirundo. Between individuals, earlier arrival at the breeding colony, earlier egg-laying, greater body mass, and more successful reproduction are associated with a lower mortality risk, and are markers of individual quality. The standardized between-individual effects of arrival and laying date especially stand out, suggesting that phenology represents the best proxy for life span. In contrast, within individuals, earlier phenology, greater body mass, and more successful reproduction are associated with a higher mortality risk, as is a reduced probability of breeding. After correcting for changes in traits with age, within-individual effects of phenology, breeding probability, clutch size, and egg volume remain significantly associated with mortality risk, which reveals survival costs of early arrival and initial investment in reproduction, but suggests terminal effects in breeding probability. Overall, our study illustrates the usefulness of separating between- and within-individual trait effects on fitness measures to identify markers of individual quality and life-history trade offs in natural populations. PMID- 26236893 TI - Predation and associational refuge drive ontogenetic niche shifts in an arctiid caterpillar. AB - Despite the ubiquity of ontogenetic niche shifts, their drivers and consequences are poorly understood. Different nutritional requirements and stage-specific physiological limitations have often been offered as explanations for these life history features, but emerging work has demonstrated that top-down factors may also be important. We studied the roles of predation and associational refuge in ontogenetic niche shifts for a holometabolous insect (Platyprepia virginalis), which shifts habitats and host plants to pupate. We examined the effect of pupation site selection across habitats and host plants by late-instar caterpillars on the rate of predation during the relatively vulnerable pupal stage. Studying the ontogenetic transition from mobile caterpillar to non feeding, sessile pupa allows isolation of top-down effects from bottom-up, nutritional effects. An observational study supported previous findings that feeding caterpillars preferred marsh habitats, but pupating caterpillars preferred prairie habitats. Experiments demonstrated that caterpillars preferred to pupate within a physically defended plant species. Pupation within this defended plant species resulted in reduced predation (an associational refuge), and removal of the physical defense structures negated the reduced-predation effect. This experiment shows that ontogenetic niche shifts can be driven by predation and can involve facilitation by a host plant that provides a refuge to predation. The co-option of plant chemical defenses by animals is widely established. However, finding a clear example in which an animal exploits a plant's physical defense is rare, especially in the context of ontogenetic niche shifts. This work shows that facilitation mediated by refuge from predation provided by host plants and life-stage-dependent predation risk can interact to shape species' distributions. PMID- 26236894 TI - Species traits outweigh nested structure in driving the effects of realistic biodiversity loss on productivity. AB - While most studies of the relationship between biodiversity and ecosystem functioning have examined randomized diversity losses, several recent experiments have employed nested, realistic designs and found that realistic species losses had larger consequences than random losses for ecosystem functioning. Progressive, realistic, biodiversity losses are generally strongly nested, but this nestedness is a potentially confounding effect. Here, we address whether nonrandom trait loss or degree of nestedness drives the relationship between diversity and productivity in a realistic biodiversity-loss experiment. We isolated the effect of nestedness through post hoc analyses of data from an experimental biodiversity manipulation in a California serpentine grassland. We found that the order in which plant traits are lost as diversity declines influences the diversity-productivity relationship more than the degree of nestedness does. Understanding the relationship between the expected order of species loss and functional traits is becoming increasingly important in the face of ongoing biodiversity loss worldwide. Our findings illustrate the importance of species composition and the order of species loss, rather than nestedness per se, for understanding the mechanisms underlying the effects of realistic species losses on ecosystem functioning. PMID- 26236895 TI - Plant diversity effects on soil microbial functions and enzymes are stronger than warming in a grassland experiment. AB - Anthropogenic changes in biodiversity and atmospheric temperature significantly influence ecosystem processes. However, little is known about potential interactive effects of plant diversity and warming on essential ecosystem properties, such as soil microbial functions and element cycling. We studied the effects of orthogonal manipulations of plant diversity (one, four, and 16 species) and warming (ambient, +1.5 degrees C, and +3 degrees C) on soil microbial biomass, respiration, growth after nutrient additions, and activities of extracellular enzymes in 2011 and 2012 in the BAC (biodiversity and climate) perennial grassland experiment site at Cedar Creek, Minnesota, USA. Focal enzymes are involved in essential biogeochemical processes of the carbon, nitrogen, and phosphorus cycles. Soil microbial biomass and some enzyme activities involved in the C and N cycle increased significantly with increasing plant diversity in both years. In addition, 16-species mixtures buffered warming induced reductions in topsoil water content. We found no interactive effects of plant diversity and warming on soil microbial biomass and growth rates. However, the activity of several enzymes (1,4-beta-glucosidase, 1,4-beta-N-acetylglucosaminidase, phosphatase, peroxidase) depended on interactions between plant diversity and warming with elevated activities of enzymes involved in the C, N, and P cycles at both high plant diversity and high warming levels. Increasing plant diversity consistently decreased microbial biomass-specific enzyme activities and altered soil microbial growth responses to nutrient additions, indicating that plant diversity changed nutrient limitations and/or microbial community composition. In contrast to our expectations, higher plant diversity only buffered temperature effects on soil water content, but not on microbial functions. Temperature effects on some soil enzymes were greatest at high plant diversity. In total, our results suggest that the fundamental temperature ranges of soil microbial communities may be sufficiently broad to buffer their functioning against changes in temperature and that plant diversity may be a dominant control of soil microbial processes in a changing world. PMID- 26236896 TI - Vegetation exerts a greater control on litter decomposition than climate warming in peatlands. AB - Historically, slow decomposition rates have resulted in the accumulation of large amounts of carbon in northern peatlands. Both climate warming and vegetation change can alter rates of decomposition, and hence affect rates of atmospheric CO2 exchange, with consequences for climate change feedbacks. Although warming and vegetation change are happening concurrently, little is known about their relative and interactive effects on decomposition processes. To test the effects of warming and vegetation change on decomposition rates, we placed litter of three dominant species (Calluna vulgaris, Eriophorum vaginatum, Hypnum jutlandicum) into a peatland field experiment that combined warming.with plant functional group removals, and measured mass loss over two years. To identify potential mechanisms behind effects, we also measured nutrient cycling and soil biota. We found that plant functional group removals exerted a stronger control over short-term litter decomposition than did approximately 1 degrees C warming, and that the plant removal effect depended on litter species identity. Specifically, rates of litter decomposition were faster when shrubs were removed from the plant community, and these effects were strongest for graminoid and bryophyte litter. Plant functional group removals also had strong effects on soil biota and nutrient cycling associated with decomposition, whereby shrub removal had cascading effects on soil fungal community composition, increased enchytraeid abundance, and increased rates of N mineralization. Our findings demonstrate that, in addition to litter quality, changes in vegetation composition play a significant role in regulating short-term litter decomposition and belowground communities in peatland, and that these impacts can be greater than moderate warming effects. Our findings, albeit from a relatively short-term study, highlight the need to consider both vegetation change and its impacts below ground alongside climatic effects when predicting future decomposition rates and carbon storage in peatlands. PMID- 26236897 TI - Neglected role of fungal community composition in explaining variation in wood decay rates. AB - Decomposition of wood is an important component of global carbon cycling. Most wood decomposition models are based on tree characteristics and environmental conditions; however, they do not include community dynamics of fungi that are the major wood decomposers. We examined the factors explaining variation in sapwood decay in oak tree stumps two and five years after cutting. Wood moisture content was significantly correlated with sapwood decay in younger stumps, whereas ITS based composition and species richness of the fungal community were the best predictors for mass loss in the older stumps. Co-occurrence analysis showed that, in freshly cut trees and in younger stumps, fungal communities were nonrandomly structured, whereas fungal communities in old stumps could not be separated from a randomly assembled community. These results indicate that the most important factors explaining variation in wood decay rates can change over time and that the strength of competitive interactions between fungi in decaying tree stumps may level off with increased wood decay. Our field analysis further suggests that ascomycetes may have a prominent role in wood decay, but their wood-degrading abilities need to be further tested under controlled conditions. The next challenging step will be to integrate fungal community assembly processes in wood decay models to improve carbon sequestration estimates of forests. PMID- 26236898 TI - Plant community richness and microbial interactions structure bacterial communities in soil. AB - Plant species, plant community diversity and microbial interactions can significantly impact soil microbial communities, yet there are few data on the interactive effects of plant species and plant community diversity on soil bacterial communities. We hypothesized that plant species and plant community diversity affect soil bacterial communities by setting the context in which bacterial interactions occur. Specifically, we examined soil bacterial community composition and diversity in relation to plant "host" species, plant community richness, bacterial antagonists, and soil edaphic characteristics. Soil bacterial communities associated with four different prairie plant species (Andropogon gerardii, Schizachyrium scoparium, Lespedeza capitata, and' Lupinus perennis) grown in plant communities of increasing species richness (1, 4, 8, and 16 species) were sequenced. Additionally, soils were evaluated for populations of antagonistic bacteria and edaphic characteristics. Plant species effects on soil bacterial community composition were small and depended on plant community richness. In contrast, increasing plant community richness significantly altered soil bacterial community composition and was negatively correlated with bacterial diversity. Concentrations of soil carbon, organic matter, nitrogen, phosphorus, and potassium were similarly negatively correlated with bacterial diversity, whereas the proportion of antagonistic bacteria was positively correlated with soil bacterial diversity. Results suggest that plant species influences on soil bacterial communities depend on plant community diversity and are mediated through the effects of plant-derived resources on antagonistic soil microbes. PMID- 26236900 TI - Microbial composition alters the response of litter decomposition to environmental change. AB - Kecent studies cemonstrate that microorganisms are sensitive to environmental change, and that their community composition influences ecosystem functioning. However, it is unknown whether microbial composition interacts with the environment to affect the response of ecosystem processes to changing abiotic conditions. To investigate the potential for such interactive effects on leaf litter decomposition, we manipulated microbial composition and three environmental factors predicted to change in the future (moisture, nitrogen availability, and temperature). We isolated fungal and bacterial taxa from leaf litter and used them to construct unique communities. Communities were inoculated into microcosms containing sterile leaf litter and exposed to four environmental treatments (control conditions, increased temperature, decreased moisture, and elevated nitrogen availability). Respiration was tracked over 60 days, and communities were pyrosequenced to assess compositional changes. As hypothesized, composition and environmental treatment interacted to influence respiration rates. In particular, microbial composition interacted more strongly with changing nitrogen availability and less so with changing moisture or temperature. Further, the magnitude of a community's response to a particular environmental change was partly. explained by changes in composition over the course of the experiment; microcosms that showed a large change in respiration rate included more taxa whose relative abundance changed as well. Together, these results suggest that information about microbial composition may be more useful for predicting functional responses to some types of environmental changes than others. PMID- 26236899 TI - Effects of species' similarity and dominance on the functional and phylogenetic structure of a plant meta-community. AB - Different assembly processes drive the spatial structure of meta-communities (beta-diversity). Recently, functional and phylogenetic diversities have been suggested as indicators of these assembly processes. Assuming that diversity is a good proxy for niche overlap, high beta-diversity along environmental gradients should be the result of environmental filtering while low beta-diversity should stem from competitive interactions. So far, studies trying to disentangle the relative importance of these assembly processes have provided mixed results. One reason for this may be that these studies often rely on a single measure of diversity and thus implicitly make a choice on how they account for species relative abundances and how species similarities are captured by functional traits or phylogeny. Here, we tested the effect of gradually scaling the importance of dominance (the weight given to dominant vs. rare species) and species similarity (the weight given to small vs. large similarities) on resulting beta-diversity patterns of an alpine plant meta-community. To this end, we combined recent extensions of the Hill numbers framework with Pagel's phylogenetic tree transformation approach. We included functional (based on the leaf-height-seed spectrum) and phylogenetic facets of beta-diversity in our analysis and explicitly accounted for effects of environmental and spatial covariates. We found that functional beta-diversity, was high when the same weight was given to dominant vs. rare species and to large vs. small species' similarities. In contrast, phylogenetic beta-diversity was low when greater weight was given to dominant species and small species' similarities. Those results suggested that different environments along the gradients filtered different species according to their functional traits, while, the same competitive lineages dominated communities across the gradients. Our results highlight that functional vs. phylogenetic facets, presence-absence vs. abundance structure and different weights of species' dissimilarity provide complementary and important information on the drivers of meta-community structure. By utilizing the full extent of information provided by the flexible frameworks of Hill numbers and Pagel's tree transformation, we propose a new approach to disentangle the patterns resulting from different assembly processes. PMID- 26236901 TI - Disentangling above- and belowground neighbor effects on the growth, chemistry, and arthropod community on a focal plant. AB - Neighboring plants can influence arthropods on a focal plant, and this can result in associational resistance or associational susceptibility. These effects can be mediated by above- and belowground interactions between the neighbor and focal plant, but determining the relative contribution of the above- and belowground effects remains an open challenge. We performed a common garden experiment with a design that enabled us to disentangle the above- and belowground effects of five different plant species on the growth and chemistry of the focal plant ragwort (Jacobaea vulgaris), and the arthropod community associated with this plant. Aboveground effects of different neighboring plant species were more important for the growth and quality of J. vulgaris and for the arthropod abundance on this plant than belowground effects of neighbors. This remained true when only indirect neighbor effects (via affecting the biomass or quality of the focal plant) were considered. The aboveground neighbor effects on arthropod abundance on the focal plant were strongly negative. However, the magnitude of the effect depended on the identity of the neighboring species, and herbivore abundance on the focal plant was higher when surrounded by conspecific than when surrounded by heterospecific plants. We also observed interactions between above- and belowground neighbor effects, indicating that these effects may be nonadditive. We conclude that above- and belowground associational effects are not equally strong, and that neighbor effects on plant-arthropod interactions occur predominantly aboveground. PMID- 26236902 TI - Explaining maximum variation in productivity requires phylogenetic diversity and single functional traits. AB - Many community experiments have shown a positive relationship between plant biodiversity and community productivity, with biodiversity measured in multiple ways based on taxonomy, function, and phylogeny. Whether these different measures of biodiversity and their interactions explain variation in productivity in natural assemblages has rarely been tested. In a removal experiment using natural alpine assemblages in the Tibetan Plateau, we manipulated species richness and functional diversity to examine how different measures of biodiversity predict aboveground biomass production. We combined different biodiversity measures (functional, phylogenetic, richness, evenness) in generalized linear models to determine which combinations provided the most parsimonious explanations of variation in biomass production. Although multivariate functional diversity indices alone consistently explained more variation in productivity than other single measures, phylogenetic diversity and plant height represented the most parsimonious combination. In natural assemblages, single metrics alone cannot fully explain ecosystem function. Instead, a combination of phylogenetic diversity and traits with weak or no phylogenetic signal is required to explain the effects of biodiversity loss on ecosystem function. PMID- 26236903 TI - What drives masting? The phenological synchrony hypothesis. AB - Annually variable and synchronous seed production, or masting behavior, is a widespread phenomenon with dramatic effects on wildlife populations and their associated communities. Proximally, masting is often correlated with environmental factors and most likely involves differential pollination success and resource allocation, but little is known about how these factors interact or how they influence seed production. We studied masting in the valley oak (Quercus lobata Nee), a California endemic tree, and report evidence that phenological synchrony in flowering driven by microclimatic variability determines the size of the acorn crop through its effects on pollen availability and fertilization success. These findings integrate two of the major factors believed to influence seed production in wind-pollinated species-environmental conditions and pollen limitation-by means of a coherent mechanistic hypothesis for how highly variable and synchronized annual seed production is accomplished. We illustrate how, by means of a simulation based on the mechanism proposed here, climate change may influence masting patterns through its effects on environmental variability. PMID- 26236904 TI - Community-level net spillover of natural enemies from managed to natural forest. AB - Edge effects in fragmented natural habitats may De exaceroateci by intensive land use in the surrounding landscape. Given that most managed systems have higher primary productivity than adjacent natural systems, theory suggests that bottom up subsidized consumers are likely to spill over from managed to natural habitats. Furthermore, the magnitude of spillover is likely to differ between generalist and specialist consumers, because of differences in their ability to use the full spectrum of resources. However, it is unknown whether there is indeed asymmetrical spillover of consumers between managed and natural habitats, and whether this is related to resource abundance or the trophic specialization of the consumer. We used flight intercept traps to measure spillover of generalist predators (Vespula wasps, Vespidae) and more specialist predators (106 species of parasitoids, Ichneumonidae and Braconidae) across habitat edges between native New Zealand forest and exotic plantation forest over a summer season. We found net spillover of both generalist and specialist predators from plantation to native forest, and that this was greater for generalists. To test whether natural enemy spillover from managed habitats was related to prey (caterpillar) abundance (i.e., whether it was bottom-up productivity driven, due to increased primary productivity), we conducted a large-scale herbivore reduction experiment at half of our plantation sites, by helicopter spraying caterpillar-specific insecticide over 2.5 ha per site. We monitored bidirectional natural enemy spillover and found that herbivore reduction reduced generalist but not specialist predator spillover. Trophic generalists may benefit disproportionately from high resource productivity in a habitat, and their cross habitat spillover effects on natural food webs may be an important source of consumer pressure in mosaic landscapes. PMID- 26236905 TI - Understanding uncertainty in temperature effects on vector-borne disease: a Bayesian approach. AB - Extrinsic environmental factors influence the distribution and population dynamics of many organisms, including insects that are of concern for human health and agriculture. This is particularly true for vector-borne infectious diseases like malaria, which is a major source of morbidity and mortality in humans. Understanding the mechanistic links between environment and population processes for these diseases is key to predicting the consequences of climate change on transmission and for developing effective interventions. An important measure of the intensity of disease transmission is the reproductive number R0. However, understanding the mechanisms linking R0 and temperature, an environmental factor driving disease risk, can be challenging because the data available for parameterization are often poor. To address this, we show how a Bayesian approach can help identify critical uncertainties in components of R0 and how this uncertainty is propagated into the estimate of R0. Most notably, we find that different parameters dominate the uncertainty at different temperature regimes: bite rate from 15 degrees C to 25 degrees C; fecundity across all temperatures, but especially approximately 25-32 degrees C; mortality from 20 degrees C to 30 degrees C; parasite development rate at degrees 15-16 degrees C and again at approximately 33-35 degrees C. Focusing empirical studies on these parameters and corresponding temperature ranges would be the most efficient way to improve estimates of R0. While we focus on malaria, our methods apply to improving process-based models more generally, including epidemiological, physiological niche, and species distribution models. PMID- 26236906 TI - Additive effects of pollinators and herbivores result in both conflicting and reinforcing selection on floral traits. AB - Mutualists and antagonists are known to respond to similar floral cues, and may thus cause opposing selection on floral traits. However, we lack a quantitative understanding of their independent and interactive effects. In a population of the orchid Gymnadenia conopsea, we manipulated the intensity of pollination and herbivory in a factorial design to examine whether both interactions influence selection on flowering phenology, floral display, and morphology. Supplemental hand-pollination increased female fitness by 31% and one-quarter of all plants were damaged by herbivores. Both interactions contributed to selection. Pollinators mediated selection for later flowering and herbivores for earlier flowering, while both selected for longer spurs. The strength of selection was similar for both agents, and their effects were additive. As a consequence, there was no. net selection on phenology, whereas selection on spur length was strong. The experimental results demonstrate that both pollinators and herbivores can markedly influence the strength of selection on flowering phenology and floral morphology, and cause both conflicting and reinforcing selection. They also indicate that the direction of selection on phenology will vary with the relative intensity of the mutualistic and antagonistic interaction, potentially resulting in both temporal and among-population variation in optimal flowering time. PMID- 26236907 TI - Floral visitation by the Argentine ant reduces bee visitation and plant seed set. AB - Ants often visit flowers, but have only seldom been documented to provide effective pollination services. Floral visitation by ants can also compromise plant reproduction in situations where ants interfere with more effective pollinators. Introduced ants may be especially likely to reduce plant reproductive success through floral visitation, but existing experimental studies have found little support for this hypothesis. Here, we combine experimental and observational approaches to examine the importance of floral visitation by the nonnative Argentine ant (Linepithema humile) on plant species native to Santa Cruz Island, California, USA. First, we determine how L. humile affects floral visitor diversity, bee visitation rates, and levels of pollen limitation for the common, focal plant species island morning glory (Calystegia macrostegia ssp. macrostegia). Second, we assess the broader ecological consequences of floral visitation by L. humile by comparing floral visitation networks between invaded and uninvaded sites. The Argentine ant and native ants both visited island morning glory flowers, but L. humile was much more likely to behave aggressively towards other floral visitors and to be the sole floral occupant. The presence of L. humile in morning glory flowers reduced floral visitor diversity, decreased rates of bee visitation, and increased levels of pollen limitation. Network comparisons between invaded and uninvaded. sites revealed differences in both network structure and species-level attributes. In. invaded sites, floral visitors were observed on fewer plant species, ants had a higher per-plant interaction strength relative to that of other visitors, and interaction strengths between bees and plants were weaker. These results illustrate that introduced ants can negatively affect plant reproduction and potentially disrupt pollination services at an ecosystem scale. PMID- 26236908 TI - Extrafloral nectaries have a limited effect on the structure of arboreal ant communities in a Neotropical savanna. AB - How environmental contexts shape the strength of species interactions, and their influence on community structure, remains a key focus for the field of community ecology. In particular, the extent to which local competitive interactions impact community structure, and whether this differs across contexts, persists as a general issue that is unresolved across a broad range of animal systems. Studies of arboreal ants have shown that competitive interactions over carbon-rich exudates from extrafloral nectaries (EFNs) and homopteran aggregations can have positive and negative effects on the local abundances of individual species. Nevertheless, it is still unclear the extent to which these local effects scale to community-level effects. Here we address the role of food from extrafloral nectaries on the structure of arboreal ant communities in a savanna of central Brazil. We did this with a combination of a diversity survey across tree species with and without EFNs, a repeated survey at times of peak EFN activity, and testing of our survey findings with two experimental manipulations of nectar availability that also provided supplementary nesting cavities. Species richness, but not composition, differed significantly between trees with and without EFNs. However, trees with EFNs had, on average, only 9% more species than those without EFNs. Furthermore, ant species richness did not differ significantly between periods of high and low EFN activity. Although nectar supplementation significantly affected nest occupation rates, this difference was seen solely in. the experiment with a massive supply of nectar and there was no effect on total ant richness or identity of the focal assemblages. Our findings suggest that the effects of extrafloral nectar on the abundances of arboreal ants at local scales do not scale to a strong structuring force at the community level. We suggest that this is most likely due to a lack of specificity of community members for EFN tree species, and the diffuse temporal and spatial nature of the availability of active EFNs. These properties mean that observable short-lived activity and competition over particular EFNs does not ultimately drive lasting changes in the associated assemblage of species, and therefore, the community as a whole. PMID- 26236909 TI - Kelp canopy facilitates understory algal assemblage via competitive release during early stages of secondary succession. AB - Kelps are conspicuous foundation species in marine ecosystems that alter the composition of understory algal assemblages. While this may be due to changes in the competitive interactions between algal species, how kelp canopies mediate propagule supply and establishment success of understory algae is not well known. In Southern California, USA, Eisenia arborea forms dense kelp canopies in shallow subtidal environments and is associated with an understory dominated by red algal species. In canopy-free areas, however, the algal assemblage is comprised of mostly brown algal species. We used a combination of mensurative and manipulative experiments to test whether Eisenia facilitates the understory assemblage by reducing competition between these different types of algae by changes in biotic interactions and/or recruitment. Our results show Eisenia facilitates a red algal assemblage via inhibition of brown algal settlement into the canopy zone, allowing recruitment to occur by vegetative means rather than establishment of new individuals. In the canopy-free zone, however, high settlement and recruitment rates suggest competitive interactions shape the community there. These results demonstrate that foundation species alter the distribution and abundance of associated organisms by affecting not only interspecific interactions but also propagule supply and recruitment limitation. PMID- 26236910 TI - Recovering aspen follow changing elk dynamics in Yellowstone: evidence of a trophic cascade? AB - To investigate the extent and causes of recent quaking aspen (Populus tremuloides) recruitment in northern Yellowstone National Park, we measured browsing intensity and height of young aspen in 87 randomly selected aspen stands in 2012, and compared our results to similar data collected in 1997-1998. We also examined the relationship between aspen recovery and the distribution of Rocky Mountain elk (Cervus elaphus) and bison (Bison bison) on the Yellowstone northern ungulate winter range, using ungulate fecal pile densities and annual elk count data. In 1998, 90% of young aspen were browsed and none were taller-than 200 cm, the height at which aspen begin to escape from elk browsing. In 2012, only 37% in the east and 63% in the west portions of the winter range were browsed, and 65% of stands in the east had young aspen taller than 200 cm. Heights of young aspen were inversely related to browsing intensity, with the least browsing and greatest heights in the eastern portion of the range, corresponding with recent changes in elk density and distribution. In contrast with historical elk distribution (1930s-1990s), the greatest densities of elk recently (2006-2012) have been north of the park boundary (approximately 5 elk/km2), and in the western part of the range (2-4 elk/km2), with relatively few elk in the eastern portion of the range (<2 elk/km2), even in mild winters. This redistribution of elk and decrease in density inside the park, and overall reduction in elk numbers, explain why many aspen stands have begun to recover. Increased predation pressure following the reintroduction of gray wolves (Canis lupius) in 1995-1996 played a role in these changing elk population dynamics, interacting with other influences including increased predation by bears (Ursus spp.), competition with an expanding bison population, and shifting patterns of human land use and hunting outside the park. The resulting new aspen recruitment is evidence of a landscape-scale trophic cascade in which a resurgent large carnivore community, combined with other ecological changes, has benefited aspen through effects on ungulate prey. PMID- 26236911 TI - Nonrandom community assembly and high temporal turnover promote regional coexistence in tropics but not temperate zone. AB - A persistent challenge for ecologists is understanding the ecological mechanisms that maintain global patterns of biodiversity, particularly the latitudinal diversity gradient of peak species richness in the tropics. Spatial and temporal variation in community composition contribute to these patterns of biodiversity, but how this variation and its underlying processes change across latitude remains unresolved. Using a model system of sessile marine invertebrates across 25 degrees of latitude, from the temperate zone to the tropics, we tested the prediction that spatial and temporal patterns of taxonomic richness and composition, and the community assembly processes underlying these patterns, will differ across latitude. Specifically, we predicted that high beta diversity (spatial variation in composition) and high temporal turnover contribute to the high species richness of the tropics. Using a standardized experimental approach that controls for several confounding factors that hinder interpretation of prior studies, we present results that support our predictions. In the temperate zone, communities were more similar across spatial scales from centimeters to tens of kilometers and temporal scales up to one year than at lower latitudes. Since the patterns at northern latitudes were congruent with a null model, stochastic assembly processes are implicated. In contrast, the communities in the tropics were a dynamic spatial and temporal mosaic, with low similarity even across small spatial scales and high temporal turnover at both local and regional scales. Unlike the temperate zone, deterministic community assembly processes such as predation likely contributed to the high beta diversity in the tropics. Our results suggest that community assembly processes and temporal dynamics vary across latitude and help structure and maintain latitudinal patterns of diversity. PMID- 26236912 TI - Spatial complexity reduces interaction strengths in the meta-food web of a river floodplain mosaic. AB - Theory states that both the spatial complexity of landscapes and the strength of interactions between consumers and their resources are important for maintaining biodiversity and the balance of nature. Spatial complexity is hypothesized to promote biodiversity by reducing the potential for competitive exclusion; whereas, models show that weak trophic interactions can enhance stability and maintain biodiversity by dampening destabilizing oscillations associated with strong interactions. Here, we show that spatial complexity can reduce the strength of consumer-resource interactions in natural food webs. By sequentially aggregating food webs of individual aquatic habitat patches across a floodplain mosaic, we found that increasing spatial complexity resulted in decreases in the strength of interactions between predators and prey, owing to a greater proportion of weak interactions and a reduced proportion of strong interactions in the meta-food web. The main mechanism behind this pattern was that some patches provided predation refugia for species that were often strongly preyed upon in other patches. If weak trophic interactions do indeed promote stability, then our findings may signal an additional mechanism by which complexity and stability are linked in nature. In turn, this may have implications for how the values of landscape complexity, and the costs of biophysical homogenization, are assessed. PMID- 26236913 TI - Dispersal, environmental forcing, and parasites combine to affect metapopulation synehrony and stability. AB - Dispersal can have positive and negative effects on metapopulation stability and persistence. One prediction is that high levels of dispersal synchronize density fluctuations between subpopulations. However, little is still known about how biotic and abiotic factors combine to modify the effects of dispersal rate on synchrony and metapopulation dynamics. In a fully factorial experimental design, we investigated the combined effects of (1) dispersal, (2) parasite infection, and (3) synchrony in temperature fluctuations on subpopulation synchrony, metapopulation instability, and minimum population size, in laboratory metapopulations of the ciliate Paramecium caudatum. Metapopulations, comprising two subpopulations linked by high or low levels of dispersal, were exposed to daily fluctuations in temperature between permissive (23 degrees C) and restrictive (5 degrees C) conditions. Infected metapopulations started the experiment with one subpopulation uninfected, while the other was infected at a prevalence of 5% with the bacterial parasite Holospora undulata. The temperature synchrony treatment involved subpopulations within a metapopulation following the same (synchronous temperatures) or different (asynchronous temperatures) temporal sequences. Population size was tracked over the 56-day experiment. We found that subpopulation density fluctuations were synchronized by high dispersal in infected metapopulations, and by synchronous temperatures in all metapopulations. Subpopulation synchrony was positively correlated with metapopulation instability and minimum metapopulation size, highlighting the multiple consequences of our treatments for metapopulation dynamics. Our results illustrate how parasites can generate dispersal-driven synchrony in non-cycling, declining populations. This "biotic forcing" via a natural enemy added to the temperature-dependent environmental forcing. We therefore conclude that predictions of metapopulation persistence in natural populations require simultaneous investigation of multiple ecological and epidemiological factors. PMID- 26236914 TI - Network structure beyond food webs: mapping non-trophic and trophic interactions on Chilean rocky shores. AB - How multiple types of non-trophic interactions map onto trophic networks in real communities remains largely unknown. We present the first effort, to our knowledge, describing a comprehensive ecological network that includes all known trophic and diverse non-trophic links among >100 coexisting species for the marine rocky intertidal community of the central Chilean coast. Our results suggest that non-trophic interactions exhibit highly nonrandom structures both alone and with respect to food web structure. The occurrence of different types of interactions, relative to all possible links, was well predicted by trophic structure and simple traits of the source and target species. In this community, competition for space and positive interactions related to habitat/refuge provisioning by sessile and/or basal species were by far the most abundant non trophic interactions. If these patterns are orroborated in other ecosystems, they may suggest potentially important dynamic constraints on the combined architecture of trophic and non-trophic interactions. The nonrandom patterning of non-trophic interactions suggests a path forward for developing a more comprehensive ecological network theory to predict the functioning and resilience of ecological communities. PMID- 26236915 TI - Inorganic-Organic Thiol-ene Coated Mesh for Oil/Water Separation. AB - A highly efficient mesh for oil/water separation was fabricated by using a superhydrophobic and superoleophilic coating of thiol-ene hybrid, consisting of pentaerythritol tetra(3-mercaptopropionate) (PETMP), 2,4,6,8-tetramethyl-2,4,6,8 tetravinylcyclotetrasiloxane (TMTVSi), and hydrophobic fumed silica nanoparticles, via a simple two-step fabrication process. Spray deposition and UV curing photopolymerization were sequentially performed, during which solvent evaporation provides microscale roughness while nanoparticle aggregation forms nanoscale roughness. The hierarchical morphologies were stabilized after UV curing photopolymerization. High contact angle (>150 degrees ) and low roll-off angle (<5 degrees ) were achieved due to the multiscale roughness structure of the hierarchical morphologies. These coatings also have excellent chemical resistance, as well as temperature and pH stability, after curing. PMID- 26236916 TI - Crystallization Dynamics of Organolead Halide Perovskite by Real-Time X-ray Diffraction. AB - We analyzed the crystallization process of the CH3NH3PbI3 perovskite by observing real-time X-ray diffraction immediately after combining a PbI2 thin film with a CH3NH3I solution. A detailed analysis of the transformation kinetics demonstrated the fractal diffusion of the CH3NH3I solution into the PbI2 film. Moreover, the perovskite crystal was found to be initially oriented based on the PbI2 crystal orientation but to gradually transition to a random orientation. The fluctuating characteristics of the crystallization process of perovskites, such as fractal penetration and orientational transformation, should be controlled to allow the fabrication of high-quality perovskite crystals. The characteristic reaction dynamics observed in this study should assist in establishing reproducible fabrication processes for perovskite solar cells. PMID- 26236917 TI - Development of structural marker peptides for cystic fibrosis transmembrane conductance regulator in cell plasma membrane by reversed-footprinting mass spectrometry. AB - A targeted mass spectrometry-based method is presented that adopts the fast photochemical oxidation of proteins (FPOP) for footprinting of cystic fibrosis transmembrane conductance regulator (CFTR) membrane transporter at its original plasma membrane location. Two analytical imperatives were sought: (1) overall simplification in data acquisition and analysis and (2) lower quantitation limits, which enabled direct analysis of intrinsically low-abundance transmembrane proteins. These goals were achieved by using a reversed footprinting technique that monitored the unoxidized peptides remaining after the FPOP treatment. In searching for structurally informative peptides, a workflow was designed for accurate and precise quantitation of CFTR peptides produced from proteolytically digesting the plasma membrane subproteome of cells. This sample preparation strategy mitigated the need for challenging purification of large quantities of structurally intact CFTR. On the basis of the interrogated peptides, it was proposed a concept of the structural marker peptide that could report CFTR structure and function in cells. The reversed-footprinting mass spectrometry extends the FPOP technology to study conformation and interaction changes of low-abundance proteins directly in their endogenous cellular locations. PMID- 26236918 TI - Development of Inhibitors of Salicylic Acid Signaling. AB - Salicylic acid (SA) plays important roles in the induction of systemic acquired resistance (SAR) in plants. Determining the mechanism of SAR will extend our understanding of plant defenses against pathogens. We recently reported that PAMD is an inhibitor of SA signaling, which suppresses the expression of the pathogenesis-related PR genes and is expected to facilitate the understanding of SA signaling. However, PAMD strongly inhibits plant growth. To minimize the side effects of PAMD, we synthesized a number of PAMD derivatives, and identified compound 4 that strongly suppresses the expression of the PR genes with fewer adverse effects on plant growth than PAMD. We further showed that the adverse effects on plant growth were partially caused the stabilization of DELLA, which is also related to the pathogen responses. These results indicate that compound 4 would facilitate our understanding of SA signaling and its cross talk with other plant hormones. PMID- 26236919 TI - Longitudinal Course of Physical Function in People With Symptomatic Knee Osteoarthritis: Data From the Multicenter Osteoarthritis Study and the Osteoarthritis Initiative. AB - OBJECTIVE: Pain and functional decline are hallmarks of knee osteoarthritis (OA). Nevertheless, longitudinal studies unexpectedly reveal stable or improved physical function. The aim of this study was to impute missing and pre-total knee replacement (TKR) values to describe physical function over time among people with symptomatic knee OA. METHODS: We included participants from the Multicenter Osteoarthritis Study (MOST) and the Osteoarthritis Initiative (OAI) with incident symptomatic knee OA, observed during the first 30 months in MOST and 36 months in OAI. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function (WOMAC-PF), the 5-times sit-to-stand test, and the 20-meter walk test were assessed at 4 and 5 years in MOST and at 6 years in OAI. We used a multiple imputation method for missing visits, and estimated pre-TKR values close to the time of TKR, using a fitted local regression smoothing curve. In mixed effect models, we investigated the physical function change over time, using data before and after imputation and calculation of pre-TKR values. RESULTS: In MOST, 225 (8%) had incident knee OA, with corresponding 577 (12.7%) in OAI. After adjusting for pre-TKR values and imputing missing values, we found that WOMAC-PF values remained stable or slightly declined over time, and the 20-meter-walk test results changed from stable in nonimputed analyses to worsening using imputed data. CONCLUSION: Data from MOST and OAI showed stable to worsening physical function over time in people with incident symptomatic knee OA after imputing missing values and adjusting pre-TKR values. PMID- 26236920 TI - Inhibition of polo like kinase 1 in sarcomas induces apoptosis that is dependent on Mcl-1 suppression. AB - Sarcomas are rare cancers and the current treatments in inoperable or metastatic disease have not been shown to prolong survival. In order to develop novel targeted therapies, we tested the efficacy of polo-like kinase 1 (PLK-1) inhibitor (TAK-960) in sarcoma. All the sarcoma cell lines were sensitive to TAK 960 with IC50s in the low nanomolar range. We chose MPNST, CHP100 and LS141 for our studies and of which MPNST cells exclusively underwent polyploidy after a delay in mitosis for about 18 hours; CHP100 cells, after a 24h mitotic delay, died of apoptosis; LS141, after a delay in mitosis stayed at 4N with mild apoptosis. Apoptosis induced by TAK-960 in CHP100 was associated with down regulation of Mcl-1 and the effect was recapitulated by down-regulating PLK1 by siRNA, confirming that the effect of TAK-960 on Mcl-1 expression is target specific. With suppression of Mcl-1 by siRNA, TAK-960 induced apoptosis in MPNST cells as well. These effects were confirmed in vivo, such that TAK-960 more effectively inhibited CHP100 than MPNST xenografts. In the setting of PLK-1 inhibition, Mcl-1 down regulation is shown to be an important determinant of apoptosis. Collectively, the net effect of this is to drive cells to apoptosis, resulting in a greater anti-tumor effect in vivo. Therefore, targeting PLK-1 should have a greater impact in treating sarcomas provided there is concomitant suppression of Mcl-1. These results further indicate that Mcl-1 could be an important biomarker to predict sensitivity to the induction of apoptosis by PLK-1 targeted therapy in sarcoma. PMID- 26236921 TI - Mechanisms of CO2 Capture into Monoethanolamine Solution with Different CO2 Loading during the Absorption/Desorption Processes. AB - Though the mechanism of MEA-CO2 system has been widely studied, there is few literature on the detailed mechanism of CO2 capture into MEA solution with different CO2 loading during absorption/desorption processes. To get a clear picture of the process mechanism, (13)C nuclear magnetic resonance (NMR) was used to analyze the reaction intermediates under different CO2 loadings and detailed mechanism on CO2 absorption and desorption in MEA was evaluated in this work. The results demonstrated that the CO2 absorption in MEA started with the formation of carbamate according to the zwitterion mechanism, followed by the hydration of CO2 to form HCO3(-)/CO3(2-), and accompanied by the hydrolysis of carbamate. It is interesting to find that the existence of carbamate will be influenced by CO2 loading and that it is rather unstable at high CO2 loading. At low CO2 loading, carbamate is formed fast by the reaction between CO2 and MEA. At high CO2 loading, it is formed by the reaction of CO3(-)/CO3(2-) with MEA, and the formed carbamate can be easily hydrolyzed by H(+). Moreover, CO2 desorption from the CO2 saturated MEA solution was proved to be a reverse process of absorption. Initially, some HCO3(-) were heated to release CO2 and other HCO3(-) were reacted with carbamic acid (MEAH(+)) to form carbamate, and the carbamate was then decomposed to MEA and CO2. PMID- 26236922 TI - Discrimination of human semen specimens by NMR data, sperm parameters, and statistical analysis. AB - Human seminal fluid is a complex mixture of secretions originated from epididymis and the male accessory sex glands. It contains a variety of both inorganic and organic components, among which proteins are a major part of the high molecular mass substances. In this study, 83 human seminal plasma samples were analyzed using a combined Nuclear Magnetic Resonance (NMR) Spectroscopy and Principal Component Analysis (PCA) approach to discriminate patients in relation to semen characteristics and/or conditions affecting the fertility status. Results showed a discrimination between patients with leukocytospermia and with the concomitant presence of varicocele/ex varicocele and leukocytospermia. Patients with testicular cancer, necrozoospermia, and azoospermia were separated from the other patient clusters. In addition, a differentiation of semen quality was also possible. This study represents to first use of sperm parameters together with NMR data as variables in the PCA analysis. Furthermore, this methodology allows the identification of the metabolites which play the most important role in identifying differences among human seminal plasma samples. PMID- 26236923 TI - Diverse states and properties of polymer nanoparticles and gel formed by polyethyleneimine and aldehydes and analytical applications. AB - Multicolor polymer nanoparticles (or dots) were prepared via the reaction between hyperbranched polyethyleneimine (PEI) and aldehydes, and when the concentration of aldehydes was lower, the final mixture displayed gelation behavior. This phenomenon can be applied to visual detection of aldehydes. Moreover, the colors of the polymer dots and gel are varied by using different kinds of aldehydes, which can be utilized for visual discrimination of aldehydes. For simplicity, we focus our attention on the interaction between PEI and formaldehyde. The nanoparticles show an average diameter of 42 nm, emit bright cyan fluorescence with high quantum yield, and exhibit high water dispersibility and excellent photostability. Due to the advantages, our polymer nanoparticles (PNPs) are utilized as a fluorescent probe for imaging in living SK-N-SH cells. Furthermore, valuable explorations have been carried out on the fundamental properties of PNPs, such as concentration-dependent fluorescence, pH-dependent fluorescence, and solvent effect. PMID- 26236924 TI - [Influence of monotherapy with telbivudine or entecavir on renal function in patients with chronic hepatitis B]. AB - OBJECTIVE: To compare renal function in chronic hepatitis B (CHB) patients before and after antiviral treatment with either telbivudine or entecavir administered as monotherapy,as well as to assess the impact of these antivirals on renal function in patients with mild renal impairment and to provide evidence for optimizing each as an antiviral treatment of CHB. METHODS: A total of 120 patients with CHB were enrolled for study and treated with either telbivudine (600 mg/d) or entecavir (0.5 mg/d). The normalization rate of alanine aminotransferase (ALT), the undetectable rate of HBV DNA, the level of serum creatinine (CR) and the estimated glomerular filtration rate (eGFR) were compared from the baseline period to post-treatment week 52 weeks and to post-treatment week 104. The chi-square test and t-test were used for statistical analyses. RESULTS: After 104 weeks of telbivudine monotherapy, the patients showed significant improvement in renal function (vs. baseline), with improved creatinine level (t=2.917, P=0.005) and eGFR (t=-2.736, P =0.008). Treatment with entecavir monotherapy did not provide significant improvement in renal function (at week 104, creatinine and eGFR: t=-2.727, P =0.007 and t=2.218, P=0.028). However, subgroup analysis of the mean change in eGFR indicated that both telbivudinetreated patients and entecavir-treated patients who entered the study with the poorest eGFR (at baseline, less than 90 mL/min/1.73 m-2) had better eGFR improvement after treatment (25.93 +/- 2.21, n=11 vs. 8.17 +/- 10.14, n=7), and there was a significant difference between the telbivudine group than the entecavir group (t=4.323, P =0.001). Virological breakthrough was more frequent in the telbivudine group than in the entecavir group (at week 104, 15.0% vs. 1.7%, P=0.017). CONCLUSION: Compared with entecavir monotherapy, telbivudine monotherapy provides a renoprotective effect in patients with CHB. While these results may suggest a benefit of telbivudine monotherapy for CHB patients with high risk for renal impairment, they do not support the application of telbivudine as a first-line therapy for nucleos(t)ide-na(i)ve HBV patients because of the related high rate of virological resistance. PMID- 26236925 TI - [High sustained virological response to optimized therapy for refractory chronic hepatitis C treatment-na(i)ve patients: a multicenter randomized study]. AB - OBJECTIVE: To perform a prospective,multicenter,open,randomized study to determine a treatment regimen for treatment-naive patients with refractory chronic hepatitis C (RHC) using the predictive value (PV) of early virological response (EVR). METHODS: A total of 438 patients from 18 hospitals were recruited between December 2008 and December 2010 and administered peg-interferon/ribavirin treatment for 12 weeks. Patients who achieved complete EVR (cEVR) were assigned to group A for a 48-week course of treatment, while patients without cEVR were randomly allocated to either group B 1 for a 72-week course of treatment or to group B2 for a 96-week course of treatment. Serum hepatitis C virus RNA levels at baseline,treatment weeks 4, 12 and 24, end of treatment, and post-treatment week 24 were measured and used to evaluate the efficiency of therapy. RESULTS: The overall sustained virological response (SVR) rate was 85.1%. In all, 91.0% of patients achieved cEVR and were assigned to group A, which had an SVR rate of 90.8%. There was no statistically significant difference in the SVR rates of groups B1 and B2 (29.4% vs. 25.0%, P more than 0.05). The positive PV of rapid virological response (RVR), cEVR and delayed virological response (DVR) for SVR was 93.4%, 90.8% and 77.8% respectively, and the negative PV of RVR, EVR and DVR for SVR was 28.0%, 93.3% and 100% respectively. Overall, 66.9% of the patients experienced adverse events (AEs), but only 1.9% of patients experienced sevcre AEs. CONCLUSION: The majority of Chinese RHC treatmentna(i)ve patients (91.0%) can achieve cEVR and a high SVR rate with a low rate of severe AEs using the cEVR guided personal treatment regimen. PMID- 26236926 TI - [Intrahepatic hepatitis B virus covalently closed circular DNA correlation with serum HBV DNA, serum HBsAg, alanine aminotransferase and age]. AB - OBJECTIVE: To investigate the correlation between intrahepatic eovalently closed circular (ccc)DNA of hepatitis B virus (HBV) and pathogen-and patient-related parameters. METHODS: Ultrasound-guided liver biopsies were obtained from 60 patients with chronic HBV infection. Levels of intrahepatic HBV cccDNA and serum HBV DNA were measured by quantitative fluorescence PCR. Level of serum hepatitis B surface antigen (HBsAg) was measured by chemiluminescence immunoassay. Clinical parameters, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (AKP), albumin, globulin (GLO), white blood cell, platelet, prothrombin-international normalized ratio, were measured by standard assay. Demographic information was recorded.The correlation between intrahepatic HBV cccDNA and pathogen-and patient-related parameters was assessed. RESULTS: Intrahepatic HBV cccDNA level was negatively correlated with age, GLO, ALT and grade of necroinflammation. Patients with age of 30 years or more showed significantly higher level of HBV cccDNA level than patients under 30 years-old (7.44+/-0.58 and 5.66+/-1.35; t=7.157, P less than 0.001). Intrahepatic HBV cccDNA level was positively correlated with serum HBV DNA level (r=0.916, P less than 0.001) and serum HBsAg level (r=0.727, P less than 0.001). The median ratio of HBV cccDNA to HBV DNA was 1.18, and of HBV cccDNA to HBsAg was 1.67. CONCLUSION: Intrahepatic HBV cccDNA levels decrease with age, level of ALT, level of GLO and grade of liver necroinflammation, but increase with level of serum HBV DNA and level of serum HBsAg. To a certain extent, serum HBV DNA and serum HBsAg levels may be a sufficient marker of intrahepatic HBV cccDNA levels. PMID- 26236927 TI - [Quality evaluation and clinical applicability of pyrosequencing assay kit for detecting hepatitis B virus resistance]. AB - OBJECTIVE: To evaluate the quality and clinical applicability of pyrosequencing assay kit for detecting hepatitis B virus resistance (HBV DRT). METHODS: Serial dilutions of the International Standard for HBV DNA were used to test the detection limit of the PCR for HBV DRT. Plasmids containing the either a wild type (WT) copy or one of 10 mutant (MT) copies of the HBV RT gene were used to prepare a series of samples with various mutation ratios. To construct the linear relationship between the true mutation rate and the detected mutation rate, each sample was repeated at least 10 times. A total of 102 clinical samples were analyzed by Sanger sequencing and retested by the PCR for HBV DRT to determine the concordance of these two methods. RESULTS: The lower detection limit of the PCR for HBV DRT was 50 IU/ml. Except for the RT236 MT, the correlation between the true mutation rate and the detected mutation rate for the other nine resistance-related mutation sites were excellent, with R2 more than 0.98 (P less than 0.001). Among the 102 clinical samples, four were not amplified successfully by PCR. The results were significantly different between the PCR for HBV DRT method and the Sanger sequencing method (x2 = 71.2, P less than 0.001), and concordance was observed for 897/969 (92.6%) amino acid positions in 98 samples. Concordant results were achieved in 46/98 (46.9%) samples at all 10 mutation sites. For detection of a single mutation site, concordance rates ranged from 71.5% to 100% at the 10 mutation sites, respectively. Analysis of discordant samples showed that in 87.5% (63/72), Sanger sequencing detected WT and the PCR for HBV DRT detected WT/MT. In 5.6% (4/72) of samples, Sanger sequencing detected WT/MT and the PCR for HBV DRT detected WT. In the remaining 6.9% (5/72) of samples, Sanger sequencing detected WT but PCR for HBV DRT detected MT. CONCLUSION: The PCR for HBV DRT showed high sensitivity and accuracy in detecting antiviral drug-resistant mutations. The method is superior to Sanger sequencing for detecting minor mutations and can be used for early detection of a resistance mutation. PMID- 26236928 TI - [Serum procalcitonin in cirrhotic patients with sepsis]. AB - OBJECTIVE: To assess the clinical value ofprocalcitonin in cirrhotic patients with severe infection by comparing the serum procalcitonin levels in those patients with and without liver cirrhosis when suffering from sepsis. METHODS: A total of 225 septic patients were included in the study,including 91 patients without hepatopathy, 80 patients with cirrhosis, and 54 patients with chronic liver disease. The serum procalcitonin level was measured in all patients and statistically assessed for correlation with relevant clinical biochemistry indicators. The t-test, ANOVA test, Mann-Whitney U test, chi-square test and Spearman's correlation analysis were used for statistical analyses. RESULTS: The patients with cirrhosis showed significantly lower serum procalcitonin levels (0.84 (0.32-3.44) ng/ml) than the patients with no hepatopathy (2.17 (0.70-9.18) ng/ml) or the patients with chronic liver disease (2.12 (0.33-13.61) ng/ml) (both P less than 0.05); the patients in the no hepatopathy group and the chronic liver disease group showed statistically similar levels of serum procalcitonin (P=0.616). The patients with cirrhosis of Child-Pugh grade C showed significantly higher level of serum procalcitonin (1.25 (0.54-4.61) ng/ml) than those patients with Child-Pugh grade B (0.33 (0.14-1.31) ng/ml; P=0.026), suggesting that patients with Child-Pugh C stage cirrhosis may be more susceptible to gram negative bacterial infection. In the cirrhosis group,serum procalcitonin level was positively correlated with white blood cell (WBC) count (r=0.312) and percentage of neutrophils (N%) (r=0.228) (both P less than 0.05). Correlation analysis of the no hepatopathy group and the chronic liver disease group showed no correlation between serum procalcitonin level and either WBC or N%. CONCLUSION: Under the sepsis condition, cirrhotic patients have lower serum procalcitonin level than patients without cirrhosis, and the serum procalcitonin level is positively correlated with WBC count and N%. PMID- 26236929 TI - [Efficacy of splenic artery trunk embolization with detachable balloon for portal hypertension and hypersplenism]. AB - OBJECTIVE: To investigate the efficacy of detachable balloon for splenic artery trunk embolization in patients with cirrhotic portal hypertension and hypersplenism. METHODS: Eight patients with cirrhotic portal hypertension received splenic artery trunk disconnection using detachable balloons under the guidance of digital subtraction angiography. The diameter and blood flow of the portal vein, the superior mesenteric vein, the splenic vein and the hepatic artery were measured by color Doppler ultrasound. Markers of liver function and blood coagulation, and routine blood parameters were assessed. Gastroscopy was used to evaluate to the degree of gastroesophageal varices. All complications experienced during the perioperative period were recorded. RESULTS: The portal vein diameter decreased from 1.55+/-0.38 cm to 1.55+/-0.38 cm, and the splenic artery diameter decreased from 1.45+/-0.10 cm to 1.41+/-0.09 cm (P < 0.05). The portal vein blood flow was reduced from 971.52+/-174.77 ml/min to 785.86+/-100.17 ml/min, and the splenic vein blood flow decreased from 938.01+/-208.86 ml/min to 644.02+/-188.15 ml/min, while the hepatic artery blood flow increased from 261.25+/-65.47 ml/min to 449.32+/-84.05 ml/min (P < 0.05). The symptoms of splenism were improved effectively, with platelet counts rising from 37.75+/ 10.61*109/L to 138.63+/-28.22*109/L after the procedure (P < 0.05). There were no episodes of severe complications or death in the perioperative period, and all patients showed remarkable improvement in markers of liver function and coagulation function, and improvement of esophagogastric varices. CONCLUSIONS: The interventional disconnection technique of the splenic artery trunk using detachable balloon for the treatment of portal hypertension and hypersplenism is safe and effective. PMID- 26236930 TI - [Effect of aquaporin 9 on proliferation, apoptosis, invasiveness and migration of HepG2 cells]. AB - OBJECTIVE: To investigate the impact of aquaporin 9 (AQP9) on the proliferation,apoptosis,invasiveness and migration of hepatocellular carcinoma cells using the HepG2 cell line. METHODS: A lentiviral vector targeting the coding region of human AQP9 was constructed. The recombinant lentiviral vector was harvested from the 293T cell line and transfected into the HepG2 cell line; resistant cell clones were selected with puromycin. Three groups of cells were established, including the CC group (control without lentiviral vector), the PWPI group (control with empty carrier virus), and the AQP9 overexpression group (experimental with the AQP9 recombinant virus). Transfection efficiency was validated by laser confocal microscopy.Expression of AQP9 was detected in the transfected HepG2 cells by westem blotting (protein) and real-time qPCR (mRNA). AQP9 effects on proliferation, migration, invasion and apoptosis of the HepG2 cell line were assessed by plate colony formation assay, woumd healing assay, transwell assay and flow cytometry. RESULTS: The green fluorescent protein of the recombinant lentiviral vector was appropriately distributed in the cell membrane. The AQP9 overexpression group showed significantly higher AQP9 mRNA and protein levels than the PWPI group and the CC group (both P < 0.01). Cells with AQP9 overexpression showed a lower colony formation rate (16.93+/-3.19% vs. CC group: 23.53+/-2.10% and PWPI group: 23.00+/-2.02%; F=6.46, P=0.032) and a lower overall apoptosis rate (44.96+/-3.53% vs. CC group:19.7+/-2.49% and PWPI group: 24.37+/ 2.38%; F=66.88, P < 0.01). The AQP9 overexpression group also showed significantly higher number of cells in the G1 stage and significantly lower number of cells in the S stage (G1: 66.58+/-0.99% and S:15.25+/-1.81%), significantly smaller cell migration distance (P=0.01 < 0.05), and significantly suppressed invasiveness (17+/-8 vs. CC group:109+/-9 and PWPI group: 95+/-11; P=0.01 < 0.05). CONCLUSION: In HepG2 cells, AQP9 significantly reduces the migrative and invasive capabilities, induces cell apoptosis, and inhibits cell proliferation via cell cycle arrest at the G1/S phases. PMID- 26236931 TI - [Pathology of hepatic iron deposition in hemochromatosis]. AB - OBJECTIVE: To identify the type of iron deposition and describe its amount, distribution and associated lesions, in order to support an etiologic diagnosis for hemochromatosis. METHODS: Hematoxylineosin (HE) stain, reticular fiber stain, Masson's stain and Perl's iron stain were used to assess liver biopsies from 31 patients with hemochromatosis. The Ishak scoring system and Deugnier scoring system were used to assess the histological change in liver and to semi-quantify the excess of hepatic iron. Genetic testing results were received from a portion of the patients and used in analysis. RESULTS: One patient had hereditary (-HFE) hemochromatosis complicated with Gilbert's syndrome, for which the pattern of iron deposition was similar to that of the four patients with Gilbert's syndrome. Iron accumulation appeared as fine granules predominating at the biliary pole of cells and was distributed throughout the lobule with a decreasing gradient spanning from the periportal to centrolobular areas. Mild chronic inflammation was found to be commonly associated with low stage fibrosis.One patient had HFE hemochromatosis complicated with hepatitis B virus infection, and the pattern of iron deposition resembled that in the eight patients with viral hepatitis, wherein the deposition was mainly in the sinusoidal cells and/or portal macrophages. Histological grading and fibrosis staging differed among patients. The five patients with blood disordered showed iron accumulation mainly in the periportal hepatocytes, but mesenchymal iron deposits were also present. The grade of inflammation, as well as of fibrosis,was mild. The five patients with alcoholic disease and the five patients with drug-induced hepatitis showed hepatic iron deposition in swollen or ballooned hepatocytes. The two patients with excessive iron supply showed iron deposition localized within the parenchymal and mesenchymal cells. CONCLUSION: Etiologic diagnosis of hemochromatosis relies on both the type of iron deposition and the nature of associated lesions. Liver biopsy is necessary for both diagnosis and prognosis. PMID- 26236932 TI - [Effect of neutrophil gelatinase-associated lipocalin on prognosis of patients with type 2 hepatorenal syndrome]. AB - OBJECTIVE: To investigate the effect of neutrophil gelatinase-associated lipocalin (NGAL) on prognosis of patients with type 2 hepatorenal syndrome (HRS). METHODS: A total of 54 patients with type 2 HRS were included in the study, and stratified for analysis according to survival status at 6-month followup:survival group, n=25; death group, n=29. Single factor analysis was used to compare the betweengroup differences for levels of plasma NGAL, urine NGAL, renin, aldosterone, and blood biochemical indicators. The Cox proportional hazard regression model was used to assess the prognosis of patients with type 2 HRS. The F-test, t-test, chi-square test, Pearson's correlation analysis, and Cox regression model were used for the statistical analyses. RESULTS: The HRS patients with liver cirrhosis showed significantly lower levels of hemoglobin, platelets and albumin (all P < 0.05), but significantly higher international normalized ratio and levels of aspartate aminotransferase, alanine arninotransferase, total bilirubin, direct bilirubin, serum creatinine, plasma NGAL, urine NGAL, renin and aldosterone (all P < 0.05). Plasma NGAL and urine NGAL were positively correlated with renin, aldosterone, blood creatinine, MELD score, Child-Pugh score and ascites (P < 0.05). The patients in the 6-month survival group showed significantly lower levels of albumin, serum sodium, serum creatinine, plasma NGAL, urine NGAL, renin, and aldosterone than those in the death group (P < 0.05), but significantly higher glomerular filtration rate (vs. death group, P < 0.05). The Cox proportional hazard regression model showed that MELD, plasma NGAL, total bilirubin and creatinine were influencing factors of 6 month prognosis for patients with type 2 HRS (relative risk: 1.214, 1.157, 1.098 and 1.016 respectively). CONCLUSION: Plasma NGAL is high in patients with type 2 FHRS, and is associated with risk of death. PMID- 26236933 TI - [Etiologies of non-hemolytic jaundice in infants: a retrospective analysis of 3113 cases]. AB - OBJECTIVE: To investigate the causes of non-hemolytic jaundice among infants in Chongqing, China from the period of 1982 to 2011 and to determine whether the etiologies have changed over the past 30 years. METHODS: The medical records of 3 113 infants,aged 1 month to 1 year,admitted to our hospital with non-hemolytic jaundice were collected and stratified according to decade-long time periods: group A (1982-1991), n=537; group B (1992-2001), n=786; group C (2002-2011), n=1 790. Data on sex, age, etiology and bilirubin level were retrospectively assessed using the chi-square test. RESULTS: In the three groups, boys consistently accounted for the majority of cases (group A:74.3%, group B:66.7%, group C:62.6%). In group A, 52% of the patients were 1-2 months of age; the peak age of patients in both group B and C was 2-3 months (group B:67.8%, group C:61.0%). Group A showed the highest level of patients with mildly elevated total bilirubin level (80.3%); however, moderately elevated total bilirubin level was most frequent in group B (53.4%) and group C (49.7%). The main etiologic diagnoses of the patients in group A were cytomegalovirus (CMV) infection (31.7%), sepsis (18.2%), hepatitis B virus (HBV) (1.3%), and biliary tract anomalies (1.3%); 46.6% of the cases had unclear cause. The main etiologic diagnoses of the cases in group B were CMV infection (36.0%), sepsis (21.5%), breast milk jaundice (2.0%), and HBV (1.9%); 37.9% of the cases had unclear cause. The main etiologic diagnoses of the cases in group C were CMV infection (42.6%), sepsis (7.5%), breast milk jaundice (17.7%), and biliary tract anomalies (2.46%); 29.1% of the cases had unclear cause. CONCLUSION: In Chongqing, infective factors, especially CMV, remain the main cause of nonhemolytic jaundice in infants, but bacterial etiologies have declined over the past 30 years.Non-infective factors, such as biliary tract anomalies and inherited metabolic diseases, have trended upwards. Although there has been great progress in the clinical management of non hemolytic jaundice in infants, etiological diagnosis remains a challenge and further study is needed to eliminate this condition. PMID- 26236934 TI - [Molecular mechanism of tumor necrosis factor-alpha monoclonal antibody in hepatopulmonary syndrome in rats]. AB - OBJECTIVE: To investigate the molecular mechanism of tumor necrosis factor-alpha (TNF-a) monoclonal antibody (McAb) in hepatopulmonary syndrome using a rat model. METHODS: Sixty adult male Sprague-Dawley rats, weighing 250 +/- 25 g, were randomized to a sham operation group, a common bile duct ligation (CBDL) group, or a CBDL+TNF-alphat McAb treatment group. The CBDL operation group was further divided into five subgroups, and the CBDL+TNF-alpha McAb treatment group was further divided into four subgroups. After the experimental period, all rats were sacrificed for excision of lung and liver tissues. Hematoxylin-eosin (HE) and Masson staining were performed to observe the extent of liver fibrosis,and HE staining was used to histopathologically assess changes in the lung tissue. Immunohistochemistry and western blotting were used to investigate the changes in expression levels of FAK, p-FAK and PTEN in lung. RESULTS: The extent of inflammatory responses and fibrosis in the liver was significantly lower in the CBDL+TNF-alpha McAb treatment group as compared to those in the CBDL group. The inflammatory responses in the lung were also significantly lower in the CBDL+TNF alpha McAb treatment group as compared to that in the CBDL group. The CBDL+TNF alpha McAb treatment group also showed less extensive distribution of FAK and p FAK protein in lung tissues,but more extensive distribution of PTEN protein. CONCLUSION: FAK and PTEN are associated with hepatopulmonary syndrome in rats. The therapeutic effect of TNF-alpha McAb may involve modulation of the expression of FAK and PTEN. PMID- 26236935 TI - Ubiquitination pathway as a target to develop abiotic stress tolerance in rice. AB - Abiotic stresses may result in significant losses in rice grain productivity. Protein regulation by the ubiquitin/proteasome system has been studied as a target mechanism to optimize adaptation and survival strategies of plants to different environmental stresses. This article aimed at highlighting recent discoveries about the roles ubiquitination may play in the exposure of rice plants to different abiotic stresses, enabling the development of modified plants tolerant to stress. Responses provided by the ubiquitination process include the regulation of the stomatal opening, phytohormones levels, protein stabilization, cell membrane integrity, meristematic cell maintenance, as well as the regulation of reactive oxygen species and heavy metals levels. It is noticeable that ubiquitination is a potential means for developing abiotic stress tolerant plants, being an excellent alternative to rice (and other cultures) improvement programs. PMID- 26236936 TI - Metabolic and evolutionary origin of actin-binding polyketides from diverse organisms. AB - Actin-targeting macrolides comprise a large, structurally diverse group of cytotoxins isolated from remarkably dissimilar micro- and macroorganisms. In spite of their disparate origins and structures, many of these compounds bind actin at the same site and exhibit structural relationships reminiscent of modular, combinatorial drug libraries. Here we investigate biosynthesis and evolution of three compound groups: misakinolides, scytophycin-type compounds and luminaolides. For misakinolides from the sponge Theonella swinhoei WA, our data suggest production by an uncultivated 'Entotheonella' symbiont, further supporting the relevance of these bacteria as sources of bioactive polyketides and peptides in sponges. Insights into misakinolide biosynthesis permitted targeted genome mining for other members, providing a cyanobacterial luminaolide producer as the first cultivated source for this dimeric compound family. The data indicate that this polyketide family is bacteria-derived and that the unusual macrolide diversity is the result of combinatorial pathway modularity for some compounds and of convergent evolution for others. PMID- 26236938 TI - Effect of Keratocyte Supernatant on Epithelial Cell Migration and Proliferation After Corneal Crosslinking (CXL). AB - PURPOSE: To evaluate the effect of keratocyte supernatant (harvesting time, riboflavin concentration and UV-A-light illumination) on migration and proliferation of human corneal epithelial cells (HCECs) by CXL, in vitro. METHODS: Primary human keratocytes isolated from 8 normal and 6 keratoconus corneas were cultured. Thereafter, keratocytes in 0%, 0.05% or 1% riboflavin solution were split into samples without and with 370 nm UVA-light-illumination. After removal of the riboflavin solution, keratocytes were incubated in the mentioned keratocyte culture medium at 37 degrees C and keratocyte supernatant was harvested after 5 and 24 hours. Keratocyte supernatant without riboflavin and UVA treatment, was used as control. HCECs were cultured until reaching confluence, the HCEC culture medium was replaced by the keratocyte supernatant and HCEC migration was analyzed using the wound-healing assay. HCEC proliferation was determined by the cell proliferation ELISA BrdU (colorimetric) kit. Statistical analysis was performed using a linear mixed model in the framework of a Generalized Estimating Equations (GEE) approach to analyze the effect of harvesting time, riboflavin concentration and UV-A-light illumination using IBM SPSS version 22. RESULTS: Riboflavin concentration, UVA-light illumination and harvesting time of normal or keratoconus keratocyte supernatant had no significant impact on HCEC proliferation (p > 0.10). Riboflavin concentration did not show significant impact on HCEC migration using normal or keratoconus keratocyte supernatant (p > 0.10), however, longer harvesting time of normal or keratoconus keratocyte supernatant significantly increased (p = 0.01 for both) and UVA-light illumination of keratoconus keratocyte supernatant (p < 0.001) significantly decreased HCEC migration. CONCLUSION: Harvesting time, riboflavin concentration and UV-A-light illumination of normal and keratoconus keratocyte cultures has no impact on proliferation of HCECs, in the short term. However, 24 hours harvesting time (both for normal and keratoconus keratocytes) increases and UVA-light-illumination of keratoconus keratocyte cultures decreases HCEC migration. PMID- 26236937 TI - Analysis of 51 cyclodipeptide synthases reveals the basis for substrate specificity. AB - Cyclodipeptide synthases (CDPSs) constitute a family of peptide bond-forming enzymes that use aminoacyl-tRNAs for the synthesis of cyclodipeptides. Here, we describe the activity of 41 new CDPSs. We also show that CDPSs can be classified into two main phylogenetically distinct subfamilies characterized by specific functional subsequence signatures, named NYH and XYP. All 11 previously characterized CDPSs belong to the NYH subfamily, suggesting that further special features may be yet to be discovered in the other subfamily. CDPSs synthesize a large diversity of cyclodipeptides made up of 17 proteinogenic amino acids. The identification of several CDPSs having the same specificity led us to determine specificity sequence motifs that, in combination with the phylogenetic distribution of CDPSs, provide a first step toward being able to predict the cyclodipeptides synthesized by newly discovered CDPSs. The determination of the activity of ten more CDPSs with predicted functions constitutes a first experimental validation of this predictive approach. PMID- 26236939 TI - Long-Term Amorphous Drug Stability Predictions Using Easily Calculated, Predicted, and Measured Parameters. AB - The purpose of this study was to develop a predictive model of the amorphous stability of drugs with particular relevance for poorly water-soluble compounds. Twenty-five representative neutral poorly soluble compounds with a diverse range of physicochemical properties and chemical structures were systematically selected from an extensive library of marketed drug products. The physical stability of the amorphous form, measured over a 6 month period by the onset of crystallization of amorphous films prepared by melting and quench-cooling, was assessed using polarized light microscopy. The data were used as a response variable in a statistical model with calculated/predicted or measured molecular, thermodynamic, and kinetic parameters as explanatory variables. Several multiple linear regression models were derived, with varying balance between calculated/predicted and measured parameters. It was shown that inclusion of measured parameters significantly improves the predictive ability of the model. The best model demonstrated a prediction accuracy of 82% and included the following as parameters: melting and glass transition temperatures, enthalpy of fusion, configurational free energy, relaxation time, number of hydrogen bond donors, lipophilicity, and the ratio of carbon to heteroatoms. Good predictions were also obtained with a simpler model, which was comprised of easily acquired quantities: molecular weight and enthalpy of fusion. Statistical models are proposed to predict long-term amorphous drug stability. The models include readily accessible parameters, which are potentially the key factors influencing amorphous stability. The derived models can support faster decision making in drug formulation development. PMID- 26236940 TI - Meta-analysis on efficacy and safety of new oral anticoagulants for venous thromboembolism prophylaxis in overweight and obese postarthroplasty patients. AB - Obesity is an independent risk factor for venous thromboembolism (VTE), and the risk rises further in the postarthroplasty period. Although medication doses often require adjustment for the altered pharmacokinetic profile in obese patients, the efficacy and safety of a fixed-dose regimen of new oral anticoagulants (NOACs) in overweight and obese patients remain unclear. Relevant studies were identified through searches of major databases. Phase III randomized controlled trials that compared NOACs against low-molecular-weight heparin (LMWH) in the prevention of VTE in postarthroplasty patients were included. Efficacy and safety outcomes with NOACs in overweight (BMI 25-29 kg/m) and obese (BMI >= 30 kg/m) patients were assessed. In five trials involving 16 674 patients, NOACs were found similar to LMWH in preventing VTE and VTE-related deaths after arthroplasty in both overweight and obese patients [odds ratio (OR) 0.64, P = 0.19 and OR 0.76, P = 0.43, respectively]. Similarly, the risk of major or clinically relevant bleeding was similar to LMWH in overweight patient with a trend toward lower bleeding in obese patients (OR 0.83, P = 0.54 and OR 0.44, P = 0.07 respectively). Apixaban was found to be more effective than LMWH in obese patients (OR 0.54, P = 0.01) with the lower dose of dabigatran (150 mg) being less effective (OR 1.81, P = 0.02). Our study suggests that a fixed-dose regimen of dabigatran might be ineffective in severe obesity. However, apixaban at the currently recommended dose seems to be superior to LMWH in obese patients with noninferior bleeding risk. PMID- 26236941 TI - Safety and efficacy of the use of institutional unfractionated heparin protocols for therapeutic anticoagulation in obese patients: a retrospective chart review. AB - Obesity is an independent risk factor for venous thromboembolism and ischemic heart disease. Optimal dosing strategies for heparin in obese patients are limited, as this population is mostly underrepresented in clinical trials. We evaluated the therapeutic efficacy and safety of unfractionated heparin dosing protocols when used in obese patients. A retrospective review of treatment effects was performed to analyse patient specific data regarding the use of therapeutic heparin in patients divided into four weight groups (<100, 100 to <125, 125 to <150 and >=150 kg). Patients received heparin via the dosing protocols approved by the institution's Pharmacy and Therapeutics (P&T) committee. Demographics, heparin protocol used, heparin dosage, therapy duration, laboratory values and indicators for bleeding complications were reviewed for adult patients receiving heparin for more than 48 h. Two hundred and forty patients were analysed, including 60 patients in each weight group. A significant difference was found across the groups in time to therapeutic activated partial thromboplastin time (aPTT) (P = 0.002) and mean heparin dosage at first therapeutic aPTT based on total body weight (units/kg per h) (P < 0.001). The mean first therapeutic heparin dose was approximately 16.0 units/kg per h in the less than 100 kg group and 11.3-13.0 units/kg per h in larger weight groups. The incidence rates of haemorrhagic complications appeared similar across the groups. Total body weight is the best predictor of a patient's requirement of heparin, but heparin infusion rates should be reduced in obese patients. Our study results showed that patients with at least 150 kg of body weight required 11.3 +/- 2.7 units/kg per h on average to achieve a therapeutic aPTT. PMID- 26236942 TI - Successful intracavitary tissue plasminogen activator treatment of gastrocnemius intramuscular hematoma in a patient following anticoagulant therapy with warfarin: case report. AB - Warfarin is an anticoagulant used in a variety of clinical indications and may rarely cause severe bleeding that can be life-threatening. Although intramuscular bleeding frequently occurs, secondary to trauma, it can be induced in cases with bleeding tendency. Hematoma is often treated with conventional methods. However, surgical decompression can also be applied. In this article, we report a case of gastrocnemius intramuscular hematoma, which was successfully treated with intracavitary tissue plasminogen activator that was recently used in the treatment of abdominal and pelvic abscess. PMID- 26236944 TI - Is intraplatelet cGMP jeopardized to inhibit platelet activation in severe preeclampsia? PMID- 26236945 TI - Unpredictable coupling: thrombophilia in a patient with Marfan syndrome. PMID- 26236946 TI - Many confounding factors can affect mean platelet volume in euthyroid Hashimoto's thyroiditis patients. PMID- 26236943 TI - The impact of disseminated intravascular coagulation on the outcome of cancer patients with venous thromboembolism. PMID- 26236948 TI - Rupture of the muscle-tendon complex in tensile test. Comparison between experimentations and discrete element modeling. PMID- 26236947 TI - AMPK inhibits MTDH expression via GSK3beta and SIRT1 activation: potential role in triple negative breast cancer cell proliferation. AB - Recent studies have highlighted the involvement of metadherin (MTDH), an oncogenic protein, in promoting cancer progression, metastasis and chemoresistance in many cancers including mammary carcinomas. However, the molecular regulation of MTDH is still not completely understood. In this study we document that AMP activated protein kinase (AMPK) activation-induced anti proliferative effects are, in part, mediated by inhibiting MTDH expression in MDA MB-231 and BT-549 triple negative breast cancer (TNBC) cells. 5-Aminoimidazole-4 carboxamide ribonucleotide (AICAR), an AMPK activator, caused growth arrest, inhibition of migration and invasion of TNBC cells. Intriguingly, AICAR or metformin treatment resulted in significant downregulation of MTDH expression via inhibiting c-Myc expression. In contrast, treatment of cells with compound C, an inhibitor of AMPK, increased both c-Myc and MTDH expressions in TNBC cells. Also, AMPK activation caused increased glycogen synthase kinase 3beta (GSK3beta) activity by inhibiting the inactive phosphorylation at Ser9, on the one hand, and activation of sirtuin1 (SIRT1) by inhibiting Ser47 phosphorylation, as evidenced by deacetylation of p53, on the other hand. Moreover, AMPK-induced GSK3beta and SIRT1 activities were found to be responsible for inhibiting c-Myc-mediated upregulation of MTDH, as LiCl (an inhibitor of GSK3beta) and EX-527 (an inhibitor of SIRT1) reversed AICAR-mediated downregulation of c-Myc and MTDH expressions. Similar results were observed with siSIRT1 treatment. Furthermore, AICAR and EX 527 treatments caused increased cell death under MTDH-depleted conditions. Finally, we uncovered a novel regulation of MTDH expression and showed that AMPK activation by inducing GSK3beta and SIRT1 downregulates MTDH expression via inhibiting c-Myc in TNBC cells. PMID- 26236949 TI - Blue-Green Color Tunable Solution Processable Organolead Chloride-Bromide Mixed Halide Perovskites for Optoelectronic Applications. AB - Solution-processed organo-lead halide perovskites are produced with sharp, color pure electroluminescence that can be tuned from blue to green region of visible spectrum (425-570 nm). This was accomplished by controlling the halide composition of CH3NH3Pb(BrxCl1-x)3 [0 <= x <= 1] perovskites. The bandgap and lattice parameters change monotonically with composition. The films possess remarkably sharp band edges and a clean bandgap, with a single optically active phase. These chloride-bromide perovskites can potentially be used in optoelectronic devices like solar cells and light emitting diodes (LEDs). Here we demonstrate high color-purity, tunable LEDs with narrow emission full width at half maxima (FWHM) and low turn on voltages using thin-films of these perovskite materials, including a blue CH3NH3PbCl3 perovskite LED with a narrow emission FWHM of 5 nm. PMID- 26236950 TI - Description and Identification of the Peripheral Immune Response Trajectories Over Time in First-Time and Recurrent Stroke/Transient Ischemic Attack. AB - A unique extant database to explain heterogeneity in peripheral immune response (PIR) over time in response to stroke/transient ischemic attack (TIA) was used to compare changes in PIR between first-time and recurrent stroke/TIA and to identify distinct and common trajectories of change in the PIR in stroke/TIA. Associations between risk factors for stroke (hypertension, smoking, diabetes, hypercholesterolemia, infection) and PIR trajectory were quantified using multivariate random effects modeling. With comparable admission values, patients with recurrent stroke/TIA had a persistent elevation in lymphocyte percentage as opposed to the significant decline in lymphocyte percentages over time observed in those with first-time stroke/TIA. Two naturally occurring trajectories of the PIR to stroke/TIA were observed, one indicative of a primed PIR and one indicative of an unprimed PIR. A large proportion of the sample, 80%, was classified as having persistently higher lymphocyte percentages and lower neutrophil percentages over time compared with the remainder of the sample. When controlling for risk factors for stroke, adults admitted with recurrent stroke/TIA without infection were more than three times as likely to have a primed PIR (i.e., the high lymphocyte-low neutrophil trajectory) than those with first-time stroke with infection. Interventions for reduction of neurological deficits require tight implementation windows early after stroke occurs. The outlined classification of cases in these primed and unprimed trajectories of the PIR adds to the knowledge of optimal clinical timing for de novo immune-based interventions. PMID- 26236951 TI - Stent Retrieval Devices and Time Prove Beneficial in Large Vessel Occlusions: A Synopsis of Four Recent Studies for Mechanical Retrieval and Revascularization. PMID- 26236953 TI - Molecular Dynamics Simulations and Structural Network Analysis of c-Abl and c-Src Kinase Core Proteins: Capturing Allosteric Mechanisms and Communication Pathways from Residue Centrality. AB - The Abl and Src tyrosine kinases play a fundamental regulatory role in orchestrating functional processes in cellular networks and represent an important class of therapeutic targets. Crystallographic studies of these kinases have revealed a similar structural organization of multidomain complexes that confers salient features of their regulatory mechanisms. Molecular characterization of the interaction networks and regulatory residues by which the SH3 and SH2 domains act cooperatively with the catalytic domain to suppress or promote kinase activation presents an active area of structural, biochemical, and computational investigations. In this work, we combine biophysical simulations with computational modeling of the residue interaction networks to characterize allosteric mechanisms of kinase regulation and gain insight into differential sensitivity of c-Abl and c-Src kinases to specific drug binding. Using these approaches, we examine dynamics of cooperative rearrangements in the residue interaction networks and elucidate the structural role of regulatory residues responsible for modulation of kinase activity. We have found that global network parameters such as residue centrality can unambiguously distinguish functional sites that are responsible for mediating allosteric interactions in the regulatory assemblies. This study has revealed mechanistic aspects of allosteric mechanisms and communication pathways by which the SH3 and SH2 domains may exert their regulatory influence on the catalytic domain and kinase activity. We have also found that high centrality residues can be linked to each other to form efficient and robust routes that transmit allosteric signals between spatially separated regulatory regions. The presented results have demonstrated that global features of the residue interaction networks may serve as transparent and robust indicators of kinase regulatory mechanisms and accurately pinpoint key functional residues. PMID- 26236952 TI - High School Diet and Risk of Crohn's Disease and Ulcerative Colitis. AB - BACKGROUND: Diet may play an important role in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC); yet, there are few prospective studies of dietary factors. None have examined the association between adolescent diet and risk of inflammatory bowel diseases (CD and UC). METHODS: This study included women enrolled in Nurses' Health Study II who completed a validated high school dietary questionnaire in 1998. We examined the effect of dietary patterns (prudent or Western diet) and individual components of each patterns. We documented incident cases of CD and UC through 2011 based on physician review of medical records and used Cox proportional hazards models adjusting for confounders to estimate hazard ratios and confidence intervals for CD and UC. RESULTS: Over 763,229 person-years of follow-up, we identified 70 incident cases of CD and 103 cases of UC. Compared with women in the lowest quartile of a prudent diet score (characterized by greater intake of fruits, vegetables, and fish), women in the highest quartile had a 53% lower risk of CD (hazard ratio, 0.47; 95% confidence interval, 0.23-0.98; P trend = 0.04). Specifically, greater intake of fish (P trend = 0.01) and fiber (P trend = 0.06) were associated with lower risk of CD. In contrast, Western diet score was not associated with risk of CD. Neither dietary patterns nor individual food or nutrient groups was associated with UC. CONCLUSIONS: Adolescent diet is associated with risk of CD, but not UC, offering insights into disease pathogenesis. PMID- 26236954 TI - The mammalian autophagy initiator complex contains 2 HORMA domain proteins. AB - ATG101 is an essential component of the ULK complex responsible for initiating cellular autophagy in mammalian cells; its 3-dimensional structure and molecular function, however, are currently unclear. Here we present the X-ray structure of human ATG101. The protein displays an open HORMA domain fold. Both structural properties and biophysical evidence indicate that ATG101 is locked in this conformation, in contrast to the prototypical HORMA domain protein MAD2. Moreover, we discuss a potential mode of dimerization with ATG13 as a fundamental aspect of ATG101 function. PMID- 26236955 TI - The supportive spouse at work: Does being work-linked help? AB - Using a sample of 639 dual-career couples, we examined the role of work-related spousal support on work-family balance and subsequent outcomes for both the job incumbent as well as his or her spouse. We further investigated whether the resource of work-related spousal support contributed to greater balance for those couples who were work-linked (work in same organization, same occupation, or both) and those who were not. We found work-related spousal support contributed to work-family balance and subsequent improved family satisfaction and job satisfaction of the job incumbent. Furthermore, support crossed over to the spouse through increased work-family balance to decrease stress transmission to enhance family satisfaction and reduce relationship tension of the spouse. Implications for researchers and organizational leaders are discussed. PMID- 26236956 TI - Extended work availability and its relation with start-of-day mood and cortisol. AB - The opportunity to work at any time and place, which is facilitated by mobile communication technologies, reinforces employer expectations that employees are available for work beyond regular work hours. This study investigates the relation of daily extended work availability with psychological and physiological well-being and the mediating role of recovery experiences. We hypothesized that recovery is limited under conditions of extended work availability, which may impair well-being. A sample of 132 individuals from 13 organizations provided daily survey measures over a period of 4 days during which they were required to be available during nonworking hours and 4 days during which they were not required to be available. A subsample of 51 persons provided morning cortisol levels in addition to the survey data. The analysis of within-person processes using multilevel structural equation modeling revealed significant effects of extended work availability on the daily start-of-day mood and cortisol awakening response. Mediation analysis revealed that the recovery experience of control over off-job activities mediated the observed relationship with start-of-day mood but not the relationship with the cortisol awakening response. The results demonstrate that nonwork hours during which employees are required to remain available for work cannot be considered leisure time because employees' control over their activities is constrained and their recovery from work is restricted. PMID- 26236957 TI - Maternal history of parentification and warm responsiveness: The mediating role of knowledge of infant development. AB - Maternal history of parentification in the family of origin poses subsequent risk to parenting quality during the transition to parenthood. The present study builds on prior work by evaluating whether the association between maternal parentification history and warm responsiveness is mediated by maternal knowledge of infant development in first time mothers. Using data from a prospective longitudinal study on the transition to motherhood, maternal knowledge of infant development and observational codings of warm responsiveness were examined across the first 18 months of parenthood for 374 mothers who also provided retrospective reports of their childhood parentification experiences. Results indicated that maternal retrospective reports of higher engagement in parentified roles in family of origin were associated with poorer knowledge of infant development across the first 18 months of parenthood and, in turn, less warm responsiveness with 18-month-old children. However, maternal parentification history did not significantly influence changes in maternal warm responsiveness across the transition to parenthood. These findings suggest that preventive interventions targeting maternal knowledge of infant development as early as the prenatal period may be useful for preventing poor warm responsiveness. PMID- 26236958 TI - The association of punitive parenting practices and adolescent achievement. AB - This article uses a nationally representative dataset to investigate the extent to which academic-related parenting practices and the home environment during middle childhood (ages 11-13) predict achievement in late adolescence (N = 486; age range: 16-18 years). Results from path analyses indicated that parental endorsement of punitive strategies (e.g., lecture, punish, restrict activities) in response to academic underperformance during middle school predict lower literacy and math achievement 5 years later. In contrast, more cognitively stimulating homes predict higher literacy and math achievement 5 years later. Parenting practices and the home environment indicators, however, did not predict changes in achievement. Socioeconomic and race and ethnicity differences in parenting were also found. PMID- 26236959 TI - Relationship education and marital satisfaction in newlywed couples: A propensity score analysis. AB - The purpose of this study was to investigate whether premarital relationship education and characteristics of relationship education in a community sample of newlywed couples predicted marital trajectories over 27 months. Newlywed couples (N = 191) completed measures of marital satisfaction 9 times over 27 months, and prior to marriage they provided information about relationship education and demographic, personal, and relationship risk factors for marital distress. Propensity scores (i.e., the probability of receiving relationship education) were estimated using the marital distress risk factors, and used to derive a matched sample of 72 couples who participated in relationship education and 86 couples who did not. Multilevel analyses of the propensity score matched sample (n = 158) indicated that wives who participated in relationship education had declines in marital satisfaction while wives who did not receive relationship education maintained satisfaction over time. Furthermore, the more hours of relationship education the couple participated in, the less steeply their marital satisfaction declined. Findings indicate that participation in community-based relationship education may not prevent declines in marital satisfaction for newlywed couples. A possible explanation is that the quality of relationship education available to couples is generally poor and could be greatly improved by inclusion of empirically based relationship information and skills training that are known to lead to stronger marriages. PMID- 26236961 TI - Three dimensional functional analysis of the human mandibular movements. PMID- 26236960 TI - Ethylene acts as a negative regulator of glucose induced lateral root emergence in Arabidopsis. AB - Plants, being sessile organisms, are more exposed to the hazards of constantly changing environmental conditions globally. During the lifetime of a plant, the root system encounters various challenges such as obstacles, pathogens, high salinity, water logging, nutrient scarcity etc. The developmental plasticity of the root system provides brilliant adaptability to plants to counter the changes exerted by both external as well as internal cues and achieve an optimized growth status. Phytohormones are one of the major intrinsic factors regulating all aspects of plant growth and development both independently as well as through complex signal integrations at multiple levels. We have previously shown that glucose (Glc) and brassinosteroid (BR) signalings interact extensively to regulate lateral root (LR) development in Arabidopsis. (1) Auxin efflux as well as influx and downstream signaling components are also involved in Glc-BR regulation of LR emergence. Here, we provide evidence for involvement of ethylene signaling machinery downstream to Glc and BR in regulation of LR emergence. PMID- 26236962 TI - Constructing Failure: Leonard Hayflick, Biomedicine, and the Problems with Tissue Culture. AB - By examining the use of tissue culture in post-war American biomedicine, this paper investigates how scientists experience and manage failure. I study how Leonard Hayflick forged his new definition of failure and ways of managing it by refuting Alexis Carrel's definition of failure alongside his theory of the immortality of cultured cells. Unlike Carrel, Hayflick claimed that every vertebrate somatic cell should eventually die, unless it transformed into a tumour cell. This claim defined cell death, which had been a problem leading to a laboratory failure, as a normal phenomenon. On the other hand, permanent life, which had been considered a normal cellular characteristic, became a major factor causing scientific failure, since it implied malignant transformation that scientists hoped to control. Hayflick then asserted that his cell strains and method would partly enable scientists to manage this factor-especially that occurred through viral infection-alongside other causes of failure in routine tasks, including bacterial contamination. I argue that the growing biomedical enterprise fostered this work of Hayflick's, which had repercussions in both his career and the uses of cells in diverse investigations. His redefinition of failure in the age of biomedicine resulted in the broad dissemination of his cells, medium, and method as well as his long struggle with the National Institutes of Health (NIH), which caused his temporarily failed career. PMID- 26236963 TI - The effect of region of interest strategies on apparent diffusion coefficient assessment in patients treated with palliative radiation therapy to brain metastases. AB - BACKGROUND: Although diffusion-weighted magnetic resonance imaging (DW-MRI) is widely used in radiation therapy (RT) response studies, no standard of delineating the region of interest (ROI) exists. In this retrospective study, we evaluate the effect of four ROI strategies on the apparent diffusion coefficients (ADC) in patients receiving palliative RT to brain metastases. MATERIAL AND METHODS: Twenty-two metastases from nine patients, treated with whole-brain irradiation (30 Gy in 10 fractions) were analyzed. Patients were scanned with a 1T MR system to acquire DW- (eight b-values), T2*W-, T2W- and T1W scans, before start of RT (pre-RT) and at the 9th/10th fraction (end-RT). The following ROI strategies were applied. ROIb800 and ROIb0: Entire tumor volume visible on DW(b = 800 s/mm(2)) and DW(b = 0 s/mm(2)) images, respectively. ROIb800vi: Viable tumor volume based on DW(b = 800 s/mm(2)). ROIb800rep: ROIb800 from pre-RT scan replicated to end-RT scan. Delineations were aided by co-registered T1W, T2W and T2*W images. ADC was estimated with two mono-exponential fits and one bi exponential fit. RESULTS: Differences in absolute ADC values were non-significant across ROI strategy independent of fitting method, while significantly different between fitting methods. Evaluation of individual metastases showed that ROI strategies disagreed on the relative ADC change (from pre-RT to end-RT) in 13 of the 22 metastases when all fitting methods were added up. CONCLUSION: The ROI strategies have an effect on the relative ADC change, which may be important for the assessment of individual patient's response to RT and the interpretation of the current literature. PMID- 26236964 TI - Time-Resolved Investigation of Cobalt Oxidation by Mn(III)-Rich delta-MnO2 Using Quick X-ray Absorption Spectroscopy. AB - Manganese oxides are important environmental oxidants that control the fate of many organic and inorganic species including cobalt. We applied ex situ quick X ray absorption spectroscopy (QXAS) to determine the time evolution of Co(II) and Co(III) surface loadings and their respective average surface speciation in Mn(III)-rich delta-MnO2 samples at pH 6.5 and loadings of 0.01-0.20 mol Co mol( 1) Mn. In this Mn oxide, which contained few unoccupied vacancies but abundant Mn(III) at edge and interlayer sites, Co(II) sorption and oxidation started at the particle edges. We found no evidence for Co(II) oxidation by interlayer Mn(III) or Mn(III, IV) adjacent to vacancy sites at <10 min. After 10 min, basal surface sites were implicated due to slow Co oxidation by interlayer Mn(III) and reactive sites formed upon removal of interlayer Mn(III), such that 50-60% of the sorbed Co was incorporated into the MnO2 sheets or adsorbed at vacancy sites by 12 h. Our findings indicate that the redox reactivity of surface sites depends on Mn valence and crystallographic location, with Mn(III) at the edges being the most effective oxidant at short reaction times and Mn(III,IV) in the MnO2 sheet contributing at longer reaction times. PMID- 26236965 TI - Simulation of orthotic treatment in adolescent idiopathic scoliosis using a subject-specific finite element model. PMID- 26236969 TI - Nonneurologists and the Dopamine Transporter Scan. PMID- 26236970 TI - Changes in Hospitalizations, Treatment Patterns, and Outcomes During Major Cardiovascular Meetings. PMID- 26236971 TI - Changes in Hospitalizations, Treatment Patterns, and Outcomes During Major Cardiovascular Meetings. PMID- 26236972 TI - Changes in Hospitalizations, Treatment Patterns, and Outcomes During Major Cardiovascular Meetings. PMID- 26236973 TI - Changes in Hospitalizations, Treatment Patterns, and Outcomes During Major Cardiovascular Meetings--Reply. PMID- 26236974 TI - Outcomes After Out-of-Hospital Cardiac Arrest Treated by Basic vs Advanced Life Support. PMID- 26236975 TI - Outcomes After Out-of-Hospital Cardiac Arrest Treated by Basic vs Advanced Life Support. PMID- 26236976 TI - Outcomes After Out-of-Hospital Cardiac Arrest Treated by Basic vs Advanced Life Support. PMID- 26236977 TI - American Board of Internal Medicine and Maintenance of Certification Standards. PMID- 26236978 TI - Basic vs Advanced Life Support for Out-of-Hospital Cardiac Arrest--Reply. PMID- 26236979 TI - American Board of Internal Medicine and Maintenance of Certification Standards. PMID- 26236980 TI - American Board of Internal Medicine and Maintenance of Certification Standards. PMID- 26236982 TI - Incorrect Role of Funder/Sponsor Statement. PMID- 26236981 TI - American Board of Internal Medicine and Maintenance of Certification Standards- Reply. PMID- 26236983 TI - Errors in Figure Labels. PMID- 26236984 TI - Error in Figure and Text. PMID- 26236985 TI - The Treatment of Verrucae Pedis Using Falknor's Needling Method: A Review of 46 Cases. AB - Human Papilloma Virus (HPV) related verrucae pedis persist, seemingly evading host immune surveillance, yet sometimes disappear with inflammation. The absence, or reduction, of a cellular immune response may explain why verrucae treatments are not uniformly successful and treatment can be difficult even in immune competent individuals. Little investigation has been undertaken into the potential benefit and efficacy of needling verrucae, a treatment modality causing HPV infected keratinocyte destruction in addition to inducing an assumed enhanced immune response. A review of clinical practice is presented, reporting the treatment method and results of data collected from a retrospective review of 45 patients. Thirty-one (69%) cases demonstrated complete resolution of verrucae following needling treatment. Three patients demonstrated reduction in size and pain whilst 11 showed no improvement. No adverse events were noted. Needling may have a place in the management of verrucae pedis in an adult population but a large scale study utilising objective measures and a control intervention would provide more detailed efficacy data along with a greater understanding of the effects of this treatment on long term immunity. PMID- 26236986 TI - Factors Affecting Ankle Support Device Usage in Young Basketball Players. AB - This cross-sectional study explores factors affecting the decision of basketball players to wear ankle support devices (ASDs). A questionnaire regarding attitudes towards ASD usage was developed based on the Health Belief Model (HBM). The questionnaire assessed HBM perceptions (susceptibility, severity, benefits, and barriers) and modifying factors (demographic, personal history of ankle injury, influence of coach to preventive action) that may affect an athlete's decision to wear ASDs. One hundred forty basketball players competing at the recreational, high school, or university levels completed the questionnaire, with the questionnaires being completed at the basketball gymnasium or at home. It was found that athletes whose coaches enforced ASD use were significantly more likely to wear them (OR: 35.71; 95% CI: 10.01, 127.36), as were athletes who perceived ankle injuries to be severe (OR: 2.77; 95% CI: 1.04, 7.37). Previous injury did not significantly increase the odds of using an ASD. The combined influence of coach enforcement and previous injury had the greatest effect on increasing ASD use. The largest barrier to ASD use was a lack of aesthetic appeal. Strategies aimed at increasing players' willingness to wear ankle protection should be emphasized among coaches and parents as this may increase use of ASDs. PMID- 26236987 TI - Risk Factors for Antenatal Depression and Associations with Infant Birth Outcomes: Results From a South African Birth Cohort Study. AB - BACKGROUND: Maternal antenatal depression may be particularly prevalent in low- and middle-income countries, but there is a paucity of data on its effect on birth outcomes in such settings. We investigated risk factors for antenatal depression and the associations between depression and infant birth outcomes in the Drakenstein Child Health Study (DCHS), a birth cohort study in the Western Cape, South Africa. METHODS: The prevalence of depression in pregnant women enrolled in the DCHS from primary care antenatal clinics was measured using the Beck Depression Inventory (BDI-II). Predictors of antenatal depression were investigated using logistic regression, and the associations between depression and infant birth outcomes were examined in linear regression models. RESULTS: Among 726 pregnant women (median age: 26 years), 156 (21%) had BDI-II scores suggesting depression. Independent predictors of depression included single marital status, low socioeconomic status (SES), recent stressful life events, unplanned pregnancy, childhood trauma, and past-year intimate partner violence. No association was observed between antenatal depression and preterm birth. Strong associations were observed between antenatal depression and decreased infant weight-for-age (WAZ) and head circumference-for-age (HCAZ) z-scores at birth. In multivariable analysis, the association between depression and decreased HCAZ remained significant, when adjusted for clinic, SES, and recent stressful life events. CONCLUSIONS: Antenatal depression and associated risk factors are highly prevalent in this setting and are associated with adverse fetal growth. Maternal mental health may be an important predictor of infant growth in utero. PMID- 26236988 TI - Prediction of fracture risk in patients with osteoporosis: a brief review. AB - Osteoporosis, a well-defined and growing public health problem, is a disease characterized by increased bone turnover and decreased bone mass with associated skeletal fragility, resulting in an increased risk of fracture. It is often unrecognized until the late stages when fragility fractures have occurred. In adults, early recognition of the disease prior to the occurrence of fractures followed by timely and efficient initiation of appropriate treatment can reduce fracture risk. In this article, we review clinical modalities available to effectively predict fracture risk in patients with osteoporosis. Bone mineral density and presence of clinical risk factors may be combined to provide a more comprehensive osteoporotic fracture risk assessment. Use of FRAX may serve as a general guideline for clinical management and deciding a threshold for cost effective pharmacological intervention. Elevated bone turnover markers are predictive of high fracture risk and can provide additional clinical information as well. PMID- 26236989 TI - Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. AB - Progressive kidney fibrosis contributes greatly to end-stage renal failure, and no specific treatment is available to preserve organ function. During renal fibrosis, myofibroblasts accumulate in the interstitium of the kidney, leading to massive deposition of extracellular matrix and organ dysfunction. The origin of myofibroblasts is manifold, but the contribution of an epithelial-to-mesenchymal transition (EMT) undergone by renal epithelial cells during kidney fibrosis is still debated. We show that the reactivation of Snai1 (encoding snail family zinc finger 1, known as Snail1) in mouse renal epithelial cells is required for the development of fibrosis in the kidney. Damage-mediated Snail1 reactivation induces a partial EMT in tubular epithelial cells that, without directly contributing to the myofibroblast population, relays signals to the interstitium to promote myofibroblast differentiation and fibrogenesis and to sustain inflammation. We also show that Snail1-induced fibrosis can be reversed in vivo and that obstructive nephropathy can be therapeutically ameliorated in mice by targeting Snail1 expression. These results reconcile conflicting data on the role of the EMT in renal fibrosis and provide avenues for the design of novel anti fibrotic therapies. PMID- 26236990 TI - Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections. AB - Endogenous mechanisms leading to host protection and resolution of infections without immunosuppression are of wide interest. Here we elucidate the structures of four new host-protective molecules produced in neutrophil-endothelial cocultures and present in human and mouse tissues after sterile inflammation or infection. The bioactive molecules contain conjugated triene and diene double bonds, carry an alcohol at C13 and are derived from n-3 docosapentaenoic acid (DPA, C22:5). These compounds, termed 13-series resolvins (RvTs), demonstrated potent protective actions increasing mice survival during Escherichia coli infections. RvTs also regulated human and mouse phagocyte responses stimulating bacterial phagocytosis and regulating inflammasome components. Their biosynthesis during neutrophil-endothelial cell interactions was initiated by endothelial cyclooxygenase-2 (COX-2), increased by atorvastatin via S-nitrosylation of COX-2 and reduced by COX-2 inhibitors. The actions of atorvastatin and RvTs were additive in E. coli infections in mice, where they accelerated resolution of inflammation and increased survival >60%. Taken together, these results document host-protective molecules in bacterial infections, namely RvTs, derived from n-3 DPA via transcellular biosynthesis and increased by atorvastatin. These molecules regulate key innate protective responses in the resolution of infectious inflammation. PMID- 26236993 TI - Characteristic lipid profiles of canine non-Hodgkin's lymphoma from surgical biopsy tissue sections and fine needle aspirate smears by desorption electrospray ionization--mass spectrometry. AB - Canine non-Hodgkin's lymphoma (NHL) is a heterogeneous group of cancers representing approximately 15% of all canine cancers. Further, canine NHL mimics human disease in regards to histopathology and clinical behavior and could function as a comparative model. Diagnosis is currently performed by histopathological evaluation of surgical biopsy specimens and fine needle aspirate (FNA) cytology, an alternative and less invasive method for diagnosis. Desorption electrospray ionization - mass spectrometry (DESI-MS) imaging was performed on tissue sections of surgical biopsies and FNA smears. Mass spectra acquired from normal lymph nodes and NHL tumors were explored using multivariate statistics (e.g. principal component analysis). Tissue sections yielded a predicted sensitivity of 100% for normal and 93.1% for tumor. Further, preliminary results suggest B-cell and T-cell lymphoma can be discriminated (CV sensitivity of 95.5% and 85.7%, respectively). Normal and B-cell NHL FNA samples analyzed by DESI produced spectra that were similar to spectra obtained from surgical biopsies. FNA samples were evaluated using a PCA-LDA classification system built using tissue section data, exploring if the chemical information obtained from the different sample types is similar and whether DESI-MS performed on FNA samples is of diagnostic value. FNA prediction rate for normal (85.7%) and B-cell NHL (89.3%) indicated that DESI-MS analysis of FNA, not previously explored, could provide rapid preliminary diagnosis. Certainly, MS provides complementary molecular information to be used in conjunction with histopathology/cytology, potentially improving diagnostic confidence. The methodology outlined here is applicable to canine NHL, further supports canine models of human NHL, and translation to humans is envisioned. PMID- 26236991 TI - Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. AB - Kidney fibrosis is marked by an epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs). Here we find that, during renal fibrosis, TECs acquire a partial EMT program during which they remain associated with their basement membrane and express markers of both epithelial and mesenchymal cells. The functional consequence of the EMT program during fibrotic injury is an arrest in the G2 phase of the cell cycle and lower expression of several solute and solvent transporters in TECs. We also found that transgenic expression of either Twist1 (encoding twist family bHLH transcription factor 1, known as Twist) or Snai1 (encoding snail family zinc finger 1, known as Snail) expression is sufficient to promote prolonged TGF-beta1-induced G2 arrest of TECs, limiting the cells' potential for repair and regeneration. In mouse models of experimentally induced renal fibrosis, conditional deletion of Twist1 or Snai1 in proximal TECs resulted in inhibition of the EMT program and the maintenance of TEC integrity, while also restoring cell proliferation, dedifferentiation-associated repair and regeneration of the kidney parenchyma and attenuating interstitial fibrosis. Thus, inhibition of the EMT program in TECs during chronic renal injury represents a potential anti-fibrosis therapy. PMID- 26236992 TI - Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice. AB - Myostatin (also known as growth and differentiation factor 8) is a secreted member of the transforming growth factor-beta (TGF-beta) family that is mainly expressed in skeletal muscle, which is also its primary target tissue. Deletion of the myostatin gene (Mstn) in mice leads to muscle hypertrophy, and animal studies support the concept that myostatin is a negative regulator of muscle growth and regeneration. However, myostatin deficiency also increases bone formation, mainly through loading-associated effects on bone. Here we report a previously unknown direct role for myostatin in osteoclastogenesis and in the progressive loss of articular bone in rheumatoid arthritis (RA). We demonstrate that myostatin is highly expressed in the synovial tissues of RA subjects and of human tumor necrosis factor (TNF)-alpha transgenic (hTNFtg) mice, a model for human RA. Myostatin strongly accelerates receptor activator of nuclear factor kappaB ligand (RANKL)-mediated osteoclast formation in vitro through transcription factor SMAD2-dependent regulation of nuclear factor of activated T cells (NFATC1). Myostatin deficiency or antibody-mediated inhibition leads to an amelioration of arthritis severity in hTNFtg mice, chiefly reflected by less bone destruction. Consistent with these effects in hTNFtg mice, the lack of myostatin leads to increased grip strength and less bone erosion in the K/BxN serum-induced arthritis model in mice. The results strongly suggest that myostatin is a potent therapeutic target for interfering with osteoclast formation and joint destruction in RA. PMID- 26236994 TI - Trends in breastfeeding initiation, continuation, and exclusivity by maternal prepregnancy weight: 2004-2011. AB - OBJECTIVE: To examine trends in breastfeeding initiation, continuation, and exclusivity by prepregnancy weight from 2004 to 2011 and the associations between these outcomes and prepregnancy weight. METHODS: Data from the 2004 to 2011 Pregnancy Risk Assessment Monitoring System, a survey of women with a recent live birth from 34 states and New York City, were used. Trends in breastfeeding initiation, continuation, and exclusivity at 12 weeks postpartum were evaluated by prepregnancy BMI. Logistic regression was used to identify the association between prepregnancy BMI and the breastfeeding outcomes. RESULTS: Among 244,196 women, with increasing BMI, a decreasing number of women initiated, continued, and breastfed exclusively. From 2004 to 2011, the rates of breastfeeding initiation increased significantly for women of all weight classes (P < 0.01), and the disparity between normal-weight women and women with obesity class III narrowed. Among all women, breastfeeding continuation increased significantly for women of almost all weight classes (P < 0.01), although the disparity between normal-weight women and women with obesity class III worsened. From 2009 to 2011, among all women, exclusive breastfeeding increased significantly among women with normal and overweight BMI (P < 0.01) but decreased among obese class III; the disparity between women with normal and obese class III BMI worsened. CONCLUSIONS: Our results highlight the need for more concentrated efforts on breastfeeding continuation and exclusivity, particularly for women with obesity. PMID- 26236995 TI - Automatic cell detection in bright-field microscopy for microbeam irradiation studies. AB - Automatic cell detection in bright-field illumination microscopy is challenging due to cells' inherent optical properties. Applications including individual cell microbeam irradiation demand minimisation of additional cell stressing factors, so contrast-enhancing fluorescence microscopy should be avoided. Additionally, the use of optically non-homogeneous substrates amplifies the problem. This research focuses on the design of a method for automatic cell detection on polypropylene substrate, suitable for microbeam irradiation. In order to fulfil the relative requirements, the Harris corner detector was employed to detect apparent cellular features. These features-corners were clustered based on a dual clustering technique according to the density of their distribution across the image. Weighted centroids were extracted from the clusters of corners and constituted the targets for irradiation. The proposed method identified more than 88% of the 1,738 V79 Chinese hamster cells examined. Moreover, a processing time of 2.6 s per image fulfilled the requirements for a near real-time cell detection irradiation system. PMID- 26236996 TI - Corrigendum: Diosgenin-induced cognitive enhancement in normal mice is mediated by 1,25D3-MARRS. PMID- 26236998 TI - Percutaneous Balloon Compression for Trigeminal Neuralgia: Imaging and Technical Aspects. AB - Trigeminal neuralgia attacks are among the most painful conditions known. Trigeminal neuralgias are hypothesized to be caused by neurovascular conflict at the trigeminal root entry zone in the prepontine cistern. A range of therapeutic options is available including open surgical microvascular decompression and several percutaneous ablative techniques (eg, radiofrequency rhizotomy and glycerol gangliolysis). Percutaneous balloon compression of the Gasserian retroganglionic rootlets has been reported to have results comparable to those of other minimally invasive techniques. This operative approach has proven popular with neurosurgeons as it is considered to be technically easier to perform than other methods. Nevertheless, pain physicians might regard this technique as challenging, relatively risky, and requiring special expertise. Accordingly, in this imaging article, we describe our percutaneous balloon compression procedure, paying particular attention to the technical and radiological details. PMID- 26236997 TI - Early sustained unresponsiveness after short-course egg oral immunotherapy: a randomized controlled study in egg-allergic children. AB - BACKGROUND: No studies have evaluated the potential of egg oral immunotherapy (egg-OIT) to induce sustained unresponsiveness after discontinuing therapy following short-term treatments. OBJECTIVE: We assessed the efficacy of short course egg-OIT to induce sustained unresponsiveness. METHODS: Sixty-one egg allergic children, 5 to 17 years old, with positive double-blind placebo controlled food challenge (DBPCFC) to dehydrated egg white (EW) were randomized to receive egg-OIT (OITG) for 3 months (maintenance dose one undercooked egg every 48 hours) or to continue egg avoidance diet (control group, CG) for 4 months. Children who completed egg-OIT avoided egg for 1 month. At 4 months, both groups underwent a DBPCFC. OITG participants who passed this challenge were instructed to add egg to their diet ad libitum. Immune markers were studied at different time points. RESULTS: Ninety-three percent (28/30) of OITG children were desensitized in a median of 32.5 days (IQR, 14 days). At 4 months, 1/31 (3%) in CG passed DBPCFC and 11/30 (37%) of OITG (95% CI, 14 to 51%; P = 0.003), all of them were consuming egg at 36 months. A decrease in EW, OVA and OVM skin test results and OVA-specific IgE (sIgE) levels was observed on OITG at 4 months (P = 0.001). EW-, OVA- and OVM-sIgE levels prior to the start of egg avoidance diet were lower in OITG children who passed DBPCFC at 4 months than in those who did not pass it. EW- and OVM-sIgE showed the best diagnostic performance in predicting DBPCFC result at 4 months. Levels above optimal EW-sIgE cut-off of 7.1 kU/L indicated 90% probability of failing DBPCFC. CONCLUSION: This is the first demonstration of sustained unresponsiveness with a three-month egg-OIT protocol. Almost all treated subjects were desensitized and 37% achieved sustained unresponsiveness. EW-sIgE levels at the end of treatment predicted sustained unresponsiveness. This protocol shows a new approach to OIT for egg-allergic children. PMID- 26236999 TI - Characterization of Specific Roles of Sodium Channel Subtypes in Regional Anesthesia. AB - BACKGROUND AND OBJECTIVES: Commonly used local anesthetics (eg, lidocaine) are nonselective in blocking sodium channel subtypes, potentially resulting in adverse events, such as prolonged muscle paralysis and unstable hemodynamics. Subtype-selective sodium channel block might avoid these unwanted adverse effects while preserving desirable anesthetic effects. The contributions of sodium channel subtypes in different components of regional anesthesia are unclear and this study assumed that selective sodium channel subtype block might produce selective nerve block. METHODS: Sciatic nerve block was performed in mice with lidocaine (nonselective sodium channel blocker), tetrodotoxin (TTX, TTX-sensitive sodium channel blocker), and A-803467 (selective Nav1.8 subtype blocker). Tactile sensory, pinprick, and thermal sensory block as well as motor block were evaluated after injection of study drugs. Median effective concentration (EC50) of lidocaine, TTX, and A-803467 as well as their blocking durations were determined. RESULTS: Lidocaine produced regional anesthetic effects including tactile, pinprick, and thermal sensory block as well as motor block, with EC50 [mean, 95% confidence intervals (CIs)] of 4.4 (3.7-5.2), 9.4 (8.0-10.9), 5.2 (4.3 6.2), and 3.7 (3.3-4.2) mmol/L, respectively. Tetrodotoxin produced tactile sensory block and motor block with EC50 (mean, 95% CIs) of 7.7 (6.0-11.0) and 8.3 (7.4-9.8) MUmol/L, respectively; whereas A-803467 produced tactile sensory block only, with EC50 (mean, 95% CIs) of 12.6 (11.7-15.6) MUmol/L. CONCLUSIONS: Sodium channel subtype selective blockers could induce selective nerve blocks. Tetrodotoxin-sensitive sodium channel subtypes contribute to low-threshold sensory block (eg, tactile) and motor block. Unexpectedly, selective Nav1.8 subtype block induced low-threshold sensory block rather than nociceptive or motor block. PMID- 26237000 TI - Risk Factors for and Prediction of a Difficult Neuraxial Block: A Cohort Study of 73,579 Patients from the Danish Anaesthesia Database. AB - BACKGROUND: A difficult neuraxial block (DNB) may be associated with complications. The aims of this study were to estimate the prevalence of DNB, assess patient-related and organizational factors associated with DNB, and evaluate the diagnostic accuracy of an accumulated risk score for predicting DNB. METHODS: A consecutive cohort of 73,579 patients was retrieved. A predefined DNB score and information on patient-related and organizational factors were included in the analyses. Logistic regression analysis was performed. We evaluated the diagnostic accuracy of an accumulated weighted point score of the patient-related risk factors of DNB. RESULTS: The prevalence of DNB and abandoned neuraxial block was 3.9 (95% confidence interval [95% CI], 3.7-4.0) and 0.2 (95% CI, 0.16-0.22), respectively. Body mass index of 35 or higher and previous DNB were associated with DNB, with 3.23 (95% CI, 2.87-3.65) and 2.00 (95% CI, 1.33-3.00), respectively. However, the remaining patient-related covariates were associated with DNB with substantial lower odds ratios. The diagnostic accuracy of an accumulated sum score demonstrated an area under the curve of 0.62 (95% CI, 0.61 0.64), a positive predictive value of 5%, and a positive likelihood ratio of 1.4. CONCLUSIONS: Despite of strong statistical association between DNB and the tested risk factors, the low odds ratios and estimates of the diagnostic test indicate that the clinical impact using an accumulated risk sum score is limited. PMID- 26237002 TI - Spinal Anesthesia in a Patient With a History of Systemic Capillary Leak Syndrome (Clarkson Disease). AB - OBJECTIVE: The aim of this study was to review the relative risks, benefits, and anesthetic considerations of neuraxial, regional, and general anesthesia in a patient with known systemic capillary leak syndrome (SCLS) who presents for elective total knee replacement. CASE REPORT: Systemic capillary leak syndrome (or Clarkson disease) is a rare disorder involving endothelial dysfunction of uncertain pathogenesis characterized by the development of hypotension, hemoconcentration, and hypoalbuminemia in the absence of secondary causes of shock. Literature regarding the anesthetic management of such patients is extremely sparse. To date, all published cases involved those who experienced exacerbations preoperatively, intraoperatively, or postoperatively. There are no reports pertaining to the anesthetic management of patients with a history of the disease who are under remission. We present a case report of a patient with a history of SCLS who underwent elective unilateral total knee arthroplasty under spinal anesthesia. The patient tolerated the procedure well without any evidence of perioperative capillary leak exacerbation. CONCLUSIONS: Spinal anesthesia constitutes a viable option for a patient with a history of SCLS in sustained remission. It remains unclear whether general or neuraxial anesthesia confers the best risk-to-benefit ratio for such patients. PMID- 26237001 TI - Adductor Canal Block With 10 mL Versus 30 mL Local Anesthetics and Quadriceps Strength: A Paired, Blinded, Randomized Study in Healthy Volunteers. AB - BACKGROUND AND OBJECTIVES: Adductor canal block (ACB) is predominantly a sensory nerve block, but excess volume may spread to the femoral triangle and reduce quadriceps strength. We hypothesized that reducing the local anesthetic volume from 30 to 10 mL may lead to fewer subjects with quadriceps weakness. METHODS: We performed a paired, blinded, randomized trial including healthy men. All subjects received bilateral ACBs with ropivacaine 0.1%; 10 mL in 1 leg and 30 mL in the other leg. The primary outcome was the difference in number of subjects with quadriceps strength reduced by more than 25% from baseline in 2 consecutive assessments. Secondary outcomes were quadriceps strength as a percentage of baseline at predefined time points, functional outcome assessed by the 30-Second Chair Stand Test (1 leg at a time), and sensory block. Clinicaltrials.gov Identifier: NCT01981746. RESULTS: We included and analyzed 26 subjects. For either volume, 2 subjects had a reduction in quadriceps strength by more than 25% from baseline (difference, 0%; 95% confidence interval, -13 to 13; P > 0.999). Similarly, we found no significant differences between volumes in quadriceps strength at any of the predefined time points or in sensory block. The only statistically significant difference between volumes was found in the 30-Second Chair Stand Test at 2 hours (P = 0.02), but this difference had disappeared at 4 hours (P = 0.06). CONCLUSIONS: Varying the volume of ropivacaine 0.1% used for ACB between 10 and 30 mL did not have a statistically significant or clinically relevant impact on quadriceps strength. PMID- 26237003 TI - Handling missing data in matched case-control studies using multiple imputation. AB - Analysis of matched case-control studies is often complicated by missing data on covariates. Analysis can be restricted to individuals with complete data, but this is inefficient and may be biased. Multiple imputation (MI) is an efficient and flexible alternative. We describe two MI approaches. The first uses a model for the data on an individual and includes matching variables; the second uses a model for the data on a whole matched set and avoids the need to model the matching variables. Within each approach, we consider three methods: full conditional specification (FCS), joint model MI using a normal model, and joint model MI using a latent normal model. We show that FCS MI is asymptotically equivalent to joint model MI using a restricted general location model that is compatible with the conditional logistic regression analysis model. The normal and latent normal imputation models are not compatible with this analysis model. All methods allow for multiple partially-observed covariates, non-monotone missingness, and multiple controls per case. They can be easily applied in standard statistical software and valid variance estimates obtained using Rubin's Rules. We compare the methods in a simulation study. The approach of including the matching variables is most efficient. Within each approach, the FCS MI method generally yields the least-biased odds ratio estimates, but normal or latent normal joint model MI is sometimes more efficient. All methods have good confidence interval coverage. Data on colorectal cancer and fibre intake from the EPIC-Norfolk study are used to illustrate the methods, in particular showing how efficiency is gained relative to just using individuals with complete data. PMID- 26237004 TI - Dysfunctional mitochondria regulate the size of root apical meristem and leaf development in Arabidopsis. AB - Mitochondria play an important role in maintaining metabolic and energy homeostasis in the plant cell. Thus, perturbation of mitochondrial structure and function will affect plant growth and development. Arabidopsis slow growth3 (slo3) is defective in At3g61360 that encodes a pentatricopeptide repeat (PPR) protein. Analysis of slo3 mitochondrial RNA metabolism revealed that the splicing of nad7 intron 2 is impaired, which leads to a dramatic reduction in complex I activity. So the SLO3 PPR protein is a splicing factor that is required for the removal of nad7 intron 2 in Arabidopsis. The slo3 mutant plants have obvious phenotypes with severe growth retardation and delayed development. The size of root apical meristem (RAM) is reduced and the production of meristem cells is decreased in slo3. Furthermore, the rosette leaves of slo3 are curled or crinkled, which may be derived from uneven growth of the leaf surface. The underlying mechanisms by which dysfunctional mitochondria affect these growth and developmental phenotypes have yet to be established. Nonetheless, plant hormone auxin is known to play an important role in orchestrating the development of RAM and leaf shape. It is possible that dysfunctional mitochondria may interact with auxin signaling pathways to regulate the boundary of RAM and the cell division arrest front during leaf growth in Arabidopsis. PMID- 26237005 TI - Pressure ulcer risk of patient handling sling use. AB - Patient handling slings and lifts reduce the risk of musculoskeletal injuries for healthcare providers. However, no published evidence exists of their safety with respect to pressure ulceration for vulnerable populations, specifically persons with spinal cord injury, nor do any studies compare slings for pressure distribution. High-resolution interface pressure mapping was used to describe and quantify risks associated with pressure ulceration due to normal forces and identify at-risk anatomical locations. We evaluated 23 patient handling slings with 4 nondisabled adults. Sling-participant interface pressures were recorded while participants lay supine on a hospital bed and while suspended during typical patient transfers. Sling-participant interface pressures were greatest while suspended for all seated and supine slings and exceeded 200 mm Hg for all seated slings. Interface pressures were greatest along the sling seams (edges), regardless of position or sling type. The anatomical areas most at risk while participants were suspended in seated slings were the posterior upper and lower thighs. For supine slings, the perisacral area, ischial tuberosities, and greater trochanters were most at risk. The duration of time spent in slings, especially while suspended, should be limited. PMID- 26237006 TI - How Much Vitamin D Is Enough? PMID- 26237007 TI - Student Perception of Improvement in Communication and Value in 2 Interprofessional Education Delivery Formats. AB - A preferred format to deliver interprofessional education (IPE) has not been described. The aim of this study was to compare students' (N = 150) perceived value and improvement in communication between an IPE activity delivered using a comprehensive versus an abbreviated format. Although both formats were perceived by students to improve their communication skills and add value to their education, students indicated the abbreviated format was more effective than the comprehensive format. PMID- 26237008 TI - A Systematic Review of the Literature on Health Literacy in Nursing Education. AB - Health literacy has an impact on patient health outcomes and should be included in prelicensure nursing curricula to prepare the next generation of nurses to provide care for patients with limited health literacy. Nursing curricula should go beyond inclusion of patient teaching strategies. This article provides a systematic review of the current literature related to health literacy in nursing education and identifies implications for nursing curricula. PMID- 26237010 TI - Enzyme-Linked Immunosorbent Assays. AB - This unit describes six different ELISA systems for the detection of specific antibodies, soluble antigens, or cell-surface antigens. In all six systems, soluble reactants are removed from solution after specifically binding to solid phase reactants. In the first four protocols, solid-phase reactants are prepared by adsorbing an antigen or antibody onto plastic microtiter plates; in the next two protocols, the solid-phase reactants are cell-associated molecules. In all protocols, the solid-phase reagents are incubated with secondary or tertiary reactants covalently coupled to an enzyme. Unbound conjugates are washed out and a chromogenic or fluorogenic substrate is added. As the substrate is hydrolyzed by the bound enzyme conjugate, a colored or fluorescent product is generated. Finally, the product is detected visually or with a microtiter plate reader. The amount of product generated is proportional to the amount of analysate in the test mixture. One of the support protocols can be used to optimize the different ELISAs. A second support protocol presents a method for preparing alkaline phosphatase conjugates. PMID- 26237009 TI - Models to Study NK Cell Biology and Possible Clinical Application. AB - Natural killer (NK) cells are large granular lymphocytes of the innate immune system, responsible for direct targeting and killing of both virally infected and transformed cells. NK cells rapidly recognize and respond to abnormal cells in the absence of prior sensitization due to their wide array of germline-encoded inhibitory and activating receptors, which differs from the receptor diversity found in B and T lymphocytes that is due to the use of recombination-activation gene (RAG) enzymes. Although NK cells have traditionally been described as natural killers that provide a first line of defense prior to the induction of adaptive immunity, a more complex view of NK cells is beginning to emerge, indicating they may also function in various immunoregulatory roles and have the capacity to shape adaptive immune responses. With the growing appreciation for the diverse functions of NK cells, and recent technological advancements that allow for a more in-depth understanding of NK cell biology, we can now begin to explore new ways to manipulate NK cells to increase their clinical utility. In this overview unit, we introduce the reader to various aspects of NK cell biology by reviewing topics ranging from NK cell diversity and function, mouse models, and the roles of NK cells in health and disease, to potential clinical applications. (c) 2015 by John Wiley & Sons, Inc. PMID- 26237011 TI - Isolation of Mouse Neutrophils. AB - Neutrophils represent the first line of defense against bacterial and fungal pathogens. Indeed, patients with inherited and acquired qualitative and quantitative neutrophil defects are at high risk for developing bacterial and fungal infections and suffering adverse outcomes from these infections. Therefore, research aiming at defining the molecular factors that modulate neutrophil effector function under homeostatic conditions and during infection is essential for devising strategies to augment neutrophil function and improve the outcome of infected individuals. This unit describes a reproducible density gradient centrifugation-based protocol that can be applied in any laboratory to harvest large numbers of highly enriched and highly viable neutrophils from the bone marrow of mice both at the steady state and following infection with Candida albicans as described in UNIT. In another protocol, we also present a method that combines gentle enzymatic tissue digestion with a positive immunomagnetic selection technique or Fluorescence-activated cell sorting (FACS) to harvest highly pure and highly viable preparations of neutrophils directly from mouse tissues such as the kidney, the liver or the spleen. Finally, methods for isolating neutrophils from mouse peritoneal fluid and peripheral blood are included. Mouse neutrophils isolated by these protocols can be used for examining several aspects of cellular function ex vivo including pathogen binding, phagocytosis and killing, neutrophil chemotaxis, oxidative burst, degranulation and cytokine production, and for performing neutrophil adoptive transfer experiments. PMID- 26237012 TI - Detection of Intracellular Cytokines by Flow Cytometry. AB - Intracellular cytokine staining (ICCS), employing fluorescently labeled MAbs detected by flow cytometry, has emerged as the premier technique for studying cytokine expression at the single-cell level. Advances in polychromatic flow cytometry have dramatically enhanced the sophistication of ICCS investigations. ICCS can simultaneously measure multiple cytokines within a single cell, allowing the detection of complex cytokine phenotypes. Additionally, cytokines can be measured with a variety of other analytes, including transcription factors, proliferation dilution dyes, activation markers, and viability dyes. This capability, combined with the high throughput inherent in the instrumentation, gives ICCS an enormous advantage over other single-cell techniques such as ELISPOT, limiting dilution, and T cell cloning. The unit describes intracellular staining of cells that have already been stimulated in vitro and fixed. Methods for in vitro activation by PMA and ionomycin or antigens, fixation of cell suspensions, and cell surface staining are also described. PMID- 26237013 TI - Development of HPLC Chiral Stationary Phases Based on (+)-(18-Crown-6)-2,3,11,12 tetracarboxylic Acid and Their Applications. AB - Crown ether-based chiral stationary phases (CSPs) have been known to be useful for the resolution of racemic primary amino compounds. In particular, CSPs based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid have been reported to be useful for the resolution of secondary amino compounds as well as primary amino compounds. In this article, the process of developing various CSPs based on (+) (18-crown-6)-2,3,11,12-tetracarboxylic acid to improve the chiral recognition efficiency and/or the stability of the CSPs and their applications to the resolution of various primary and nonprimary amino compounds are reviewed. PMID- 26237014 TI - Porous frameworks constructed by non-covalent linking of substitution-inert metal complexes. AB - The incorporation of active sites into metal-organic frameworks (MOFs) or porous coordination polymers (PCPs) is an attractive way to functionalise these materials. However, the methodology to organise substitution-inert metal-based secondary building units (SBUs) with active sites into MOFs or PCPs via coordination driven self-assembly is severely limited. In this study, we successfully assembled substitution-inert paddle-wheel Rh(II) dimers to afford three novel porous frameworks, Rh2(ppeb)4(THF)2 (1-THF), Rh2(ppeb)4(3-pentanone)2 (1-PN) and Rh2(ppeb)4(1-adamantylamine)2 (1-AD) (ppeb = 4 [(perfluorophenyl)ethynyl]benzoate), by using non-covalent interactions. Multipoint arene-perfluoroarene (Ar-Ar(F)) interactions, which allow the unidirectional face-to-face interaction mode of aromatic rings, were used to assemble the substitution-inert paddle-wheel Rh(II) dimers. The obtained frameworks were structurally characterisation by single crystal X-ray diffraction, and it is found that all structures exhibited a one-dimensional channel with active axial sites exposed to the pores. The porous properties of the obtained frameworks were also investigated by thermogravimetric analysis, gas adsorption and powder X-ray diffraction measurements. Moreover, the ligand substitution reaction at the active axial sites was examined at the crystalline state and the flexible structural transformation with the change of channel shapes and sizes was observed. PMID- 26237015 TI - Clinical Results of Hypomethylating Agents in AML Treatment. AB - Epigenetic changes play an important role in the development of acute myeloid leukemia (AML). Unlike gene mutations, epigenetic changes are potentially reversible, which makes them attractive for therapeutic intervention. Agents that affect epigenetics are the DNA methyltransferase inhibitors, azacitidine and decitabine. Because of their relatively mild side effects, azacitidine and decitabine are particularly feasible for the treatment of older patients and patients with co-morbidities. Both drugs have remarkable activity against AML blasts with unfavorable cytogenetic characteristics. Recent phase 3 trials have shown the superiority of azacitidine and decitabine compared with conventional care for older AML patients (not eligible for intensive treatment). Results of treatment with modifications of the standard azacitidine (seven days 75 mg/m(2) SC; every four weeks) and decitabine (five days 20 mg/m(2) IV; every four weeks) schedules have been reported. Particularly, the results of the 10-day decitabine schedule are promising, revealing complete remission (CR) rates around 45% (CR + CRi (i.e., CR with incomplete blood count recovery) around 64%) almost comparable with intensive chemotherapy. Application of hypomethylating agents to control AML at the cost of minimal toxicity is a very promising strategy to "bridge" older patients with co-morbidities to the potential curative treatment of allogeneic hematopoietic cell transplantation. In this article, we discuss the role of DNA methyltransferase inhibitors in AML. PMID- 26237016 TI - Hyponatremia and the Thyroid: Causality or Association? AB - Thyroid disorders, particularly hypothyroidism, have historically been implicated in the development of serum hyponatremia. However, in more recent years, this paradigm has been challenged, and it has been suggested that the link between hypothyroidism and hyponatremia may merely be an association. This review will focus on the thyroid and its link with serum hyponatremia, and review the available literature on the topic. PMID- 26237018 TI - Implications of Hyponatremia in Liver Transplantation. AB - Although there are a limited number of quality studies, appropriate peri operative management of serum electrolytes seems to reduce adverse outcomes in liver transplantation. Hyponatremia is defined as the presence of serum concentration of sodium equal <=130 mmol/L and it is detected in approximately 20% of patients with end stage liver disease waiting for a liver transplant (LT). This paper will focus on the pathogenesis of dilutional hyponatremia and its significance in terms of both candidacy for LT and post-operative outcomes. PMID- 26237017 TI - The Potential for iPS-Derived Stem Cells as a Therapeutic Strategy for Spinal Cord Injury: Opportunities and Challenges. AB - Spinal cord injury (SCI) is a devastating trauma causing long-lasting disability. Although advances have occurred in the last decade in the medical, surgical and rehabilitative treatments of SCI, the therapeutic approaches are still not ideal. The use of cell transplantation as a therapeutic strategy for the treatment of SCI is promising, particularly since it can target cell replacement, neuroprotection and regeneration. Cell therapies for treating SCI are limited due to several translational roadblocks, including ethical and practical concerns regarding cell sources. The use of iPSCs has been particularly attractive, since they avoid the ethical and moral concerns that surround other stem cells. Furthermore, various cell types with potential for application in the treatment of SCI can be created from autologous sources using iPSCs. For applications in SCI, the iPSCs can be differentiated into neural precursor cells, neurons, oligodendrocytes, astrocytes, neural crest cells and mesenchymal stromal cells that can act by replacing lost cells or providing environmental support. Some methods, such as direct reprogramming, are being investigated to reduce tumorigenicity and improve reprogramming efficiencies, which have been some of the issues surrounding the use of iPSCs clinically to date. Recently, iPSCs have entered clinical trials for use in age-related macular degeneration, further supporting their promise for translation in other conditions, including SCI. PMID- 26237019 TI - Malignant Cardiac Tamponade from Non-Small Cell Lung Cancer: Case Series from the Era of Molecular Targeted Therapy. AB - Cardiac tamponade complicating malignant pericardial effusion from non-small cell lung cancer (NSCLC) is generally associated with extremely poor prognosis. With improved systemic chemotherapy and molecular targeted therapy for NSCLC in recent years, the prognosis of such patients and the value of invasive cardiothoracic surgery in this setting have not been adequately examined. We report outcomes from a contemporary case series of eight patients who presented with malignant cardiac tamponade due to NSCLC to an Australian academic medical institution over an 18 months period. Two cases of cardiac tamponade were de novo presentations of NSCLC and six cases were presentations following previous therapy for NSCLC. The median survival was 4.5 months with a range between 9 days to alive beyond 17 months. The two longest survivors are still receiving active therapy at 17 and 15 months after invasive surgical pericardial window respectively. One survivor had a histological subtype of large cell neuroendocrine carcinoma and the other received targeted therapy for epidermal growth factor receptor mutation. These results support the consideration of active surgical palliation to treating this oncological emergency complicating NSCLC, including the use of urgent drainage, surgical creation of pericardial window followed by appropriate systemic therapy in suitably fit patients. PMID- 26237020 TI - Hyponatremia in Patients with Cirrhosis of the Liver. AB - Hyponatremia is common in cirrhosis. It mostly occurs in an advanced stage of the disease and is associated with complications and increased mortality. Either hypovolemic or, more commonly, hypervolemic hyponatremia can be seen in cirrhosis. Impaired renal sodium handling due to renal hypoperfusion and increased arginine-vasopressin secretion secondary to reduced effective volemia due to peripheral arterial vasodilation represent the main mechanisms leading to dilutional hyponatremia in this setting. Patients with cirrhosis usually develop slowly progressing hyponatremia. In different clinical contexts, it is associated with neurological manifestations due to increased brain water content, where the intensity is often magnified by concomitant hyperammonemia leading to hepatic encephalopathy. Severe hyponatremia requiring hypertonic saline infusion is rare in cirrhosis. The management of asymptomatic or mildly symptomatic hyponatremia mainly rely on the identification and treatment of precipitating factors. However, sustained resolution of hyponatremia is often difficult to achieve. V2 receptor blockade by Vaptans is certainly effective, but their long-term safety, especially when associated to diuretics given to control ascites, has not been established as yet. As in other conditions, a rapid correction of long-standing hyponatremia can lead to irreversible brain damage. The liver transplant setting represents a condition at high risk for the occurrence of such complications. PMID- 26237021 TI - Scalable Electrophysiological Investigation of iPS Cell-Derived Cardiomyocytes Obtained by a Lentiviral Purification Strategy. AB - Disease-specific induced pluripotent stem (iPS) cells can be generated from patients and differentiated into functional cardiomyocytes for characterization of the disease and for drug screening. In order to obtain pure cardiomyocytes for automated electrophysiological investigation, we here report a novel non-clonal purification strategy by using lentiviral gene transfer of a puromycin resistance gene under the control of a cardiac-specific promoter. We have applied this method to our previous reported wild-type and long QT syndrome 3 (LQTS 3) specific mouse iPS cells and obtained a pure cardiomyocyte population. These cells were investigated by action potential analysis with manual and automatic planar patch clamp technologies, as well as by recording extracellular field potentials using a microelectrode array system. Action potentials and field potentials showed the characteristic prolongation at low heart rates in LQTS 3 specific, but not in wild-type iPS cell-derived cardiomyocytes. Hence, LQTS 3 specific cardiomyocytes can be purified from iPS cells with a lentiviral strategy, maintain the hallmarks of the LQTS 3 disease and can be used for automated electrophysiological characterization and drug screening. PMID- 26237024 TI - Three Adult Cases of Orbital Hidrocystoma Presenting with Blepharoptosis. AB - PURPOSE: To report adult cases of superior orbital apocrine hidrocystoma. METHODS: Retrospective case series of three patients with superior orbital apocrine hidrocystoma and blepharoptosis with review of the clinical aspects of each of the cases. RESULTS: All three cases presented with blepharoptosis. Two of the cases had occult hidrocystoma, and one was visibly subcutaneous at presentation. CONCLUSIONS: Although rare and more common along the eyelid margin, apocrine hidrocystomas may occur in the orbit leading to secondary blepharoptosis and should be included within the differential diagnosis of orbital cysts. Physicians should therefore be aware of this possibility. PMID- 26237025 TI - Design of a Tumorigenicity Test for Induced Pluripotent Stem Cell (iPSC)-Derived Cell Products. AB - Human Pluripotent Stem Cell (PSC)-derived cell therapy holds enormous promise because of the cells' "unlimited" proliferative capacity and the potential to differentiate into any type of cell. However, these features of PSC-derived cell products are associated with concerns regarding the generation of iatrogenic teratomas or tumors from residual immature or non-terminally differentiated cells in the final cell product. This concern has become a major hurdle to the introduction of this therapy into the clinic. Tumorigenicity testing is therefore a key preclinical safety test in PSC-derived cell therapy. Tumorigenicity testing becomes particularly important when autologous human induced Pluripotent Stem Cell (iPSC)-derived cell products with no immuno-barrier are considered for transplantation. There has been, however, no internationally recognized guideline for tumorigenicity testing of PSC-derived cell products for cell therapy. In this review, we outline the points to be considered in the design and execution of tumorigenicity tests, referring to the tests and laboratory work that we have conducted for an iPSC-derived retinal pigment epithelium (RPE) cell product prior to its clinical use. PMID- 26237023 TI - Pediatric AML: From Biology to Clinical Management. AB - Pediatric acute myeloid leukemia (AML) represents 15%-20% of all pediatric acute leukemias. Survival rates have increased over the past few decades to ~70%, due to improved supportive care, optimized risk stratification and intensified chemotherapy. In most children, AML presents as a de novo entity, but in a minority, it is a secondary malignancy. The diagnostic classification of pediatric AML includes a combination of morphology, cytochemistry, immunophenotyping and molecular genetics. Outcome is mainly dependent on the initial response to treatment and molecular and cytogenetic aberrations. Treatment consists of a combination of intensive anthracycline- and cytarabine containing chemotherapy and stem cell transplantation in selected genetic high risk cases or slow responders. In general, ~30% of all pediatric AML patients will suffer from relapse, whereas 5%-10% of the patients will die due to disease complications or the side-effects of the treatment. Targeted therapy may enhance anti-leukemic efficacy and minimize treatment-related morbidity and mortality, but requires detailed knowledge of the genetic abnormalities and aberrant pathways involved in leukemogenesis. These efforts towards future personalized therapy in a rare disease, such as pediatric AML, require intensive international collaboration in order to enhance the survival rates of pediatric AML, while aiming to reduce long-term toxicity. PMID- 26237029 TI - Lower limb reaction force asymmetry in rowers with and without a history of back injury. AB - Back injury is common in rowers. Asymmetrical lower limb reaction force on the foot stretchers during rowing may compromise trunk biomechanics and lead to back injury. However, such a mechanism remains putative. Therefore, this study examined lower limb reaction force in experienced rowers with and without a history of back injury. Six rowers who suffered from back injury for more than one week in the past year and another 19 rowers who were never injured performed maximal exertion rowing on a fixed-head rowing machine for 30 strokes. Peak force, average and peak loading rate of the lower limb reaction force during the middle 10-stroke were recorded using strain-gauge transducers placed at the foot stretchers. Asymmetries and intra-limb variability were quantified as asymmetry indices and coefficients of variation, respectively. No significant asymmetry was observed in all selected kinetic parameters between the injured and healthy rowers (p = 0.448-0.722, Hedges' g = 0.162-0.310). Subgroup analyses also did not reveal any significant kinetic differences between injured and healthy scullers or sweepers (p = 0.194-0.855, Hedges' g = 0.203-0.518). Rowers with a history of back injury, regardless of the rowing types, did not demonstrate greater lower limb reaction force asymmetry when compared with healthy rowers. PMID- 26237027 TI - The State of Play with iPSCs and Spinal Cord Injury Models. AB - The application of induced pluripotent stem cell (iPSC) technologies in cell based strategies, for the repair of the central nervous system (with particular focus on the spinal cord), is moving towards the potential use of clinical grade donor cells. The ability of iPSCs to generate donor neuronal, glial and astrocytic phenotypes for transplantation is highlighted here, and we review recent research using iPSCs in attempts to treat spinal cord injury in various animal models. Also discussed are issues relating to the production of clinical grade iPSCs, recent advances in transdifferentiation protocols for iPSC-derived donor cell populations, concerns about tumourogenicity, and whether iPSC technologies offer any advantages over previous donor cell candidates or tissues already in use as therapeutic tools in experimental spinal cord injury studies. PMID- 26237026 TI - NLRP3 Inflammasome and Pathobiology in AMD. AB - Age-related macular degeneration (AMD) is the leading cause of central vision loss and blindness in the elderly. It is characterized by a progressive loss of photoreceptors in the macula due to damage to the retinal pigment epithelium (RPE). Clinically, it is manifested by drusen deposition between the RPE and underlying choroid and accumulation of lipofuscin in the RPE. End-stage disease is characterized by geographic atrophy (dry AMD) or choroidal neovascularization (wet AMD). The NLRP3 inflammasome has recently been implicated in the disease pathology. Here we review the current knowledge on the involvement of this multiprotein complex and its effector cytokines interleukin-1beta (IL-1beta) and IL-18 in AMD progression. We also describe cell death mechanisms that have been proposed to underlie RPE degeneration in AMD and discuss the role of autophagy in the regulation of disease progression. PMID- 26237030 TI - Time-Resolved Light Scattering Study on the Kinetics of the Liquid-Liquid Transition in Triphenyl Phosphite. AB - There is experimental evidence suggesting the existence of a liquid-liquid transition (LLT) in a single-component liquid. However, none of this evidence is free from controversy, including the case of a molecular liquid, triphenyl phosphite, which we study here. Furthermore, the kinetics of LLT has been largely unexplored. Here we study the phase-transition dynamics of triphenyl phosphite in a supercooled liquid state by means of time-resolved polarized and depolarized small-angle light scattering to clarify whether the transition is a liquid-liquid transition (LLT) or merely nanocrystal formation. A part of this study was recently reported in another of our papers [Shimizu, R.; Kobayashi, M.; Tanaka, H. Phys. Rev. Lett. 2014, 112, 125702]. A detailed analysis of our experimental results of light scattering and the comparison with heat evolution during LLT have revealed the following facts. The polarized scattering from domains has a finite (nonzero) intensity in the low-wavenumber limit, and the time evolution of its average intensity is almost proportional to the square of the heat-releasing rate. The depolarized scattering intensity monotonically increases in the process of LLT during isothermal annealing above the spinodal temperature TSD but exhibits a peak below TSD. On the basis of these results, we suggest that the primary process is LLT, whose order parameter is of a nonconserved nature, but accompanies nanocrystal formation. In the NG-type LLT, the sharp interface between liquid II droplets and the liquid I matrix promotes nanocrystal formation there, whereas much less nanocrystal formation is induced in the SD-type LLT due to the lack of such sharp interfaces. PMID- 26237031 TI - Corrigendum: Simultaneous submicrometric 3D imaging of the micro-vascular network and the neuronal system in a mouse spinal cord. PMID- 26237032 TI - Rate of multilingual phonological acquisition: Evidence from a cross-sectional study of English-Mandarin-Malay. AB - Early child multilingual acquisition is under-explored. Using a cross-sectional study approach, the present research investigates the rate of multilingual phonological acquisition of English-Mandarin-Malay by 64 ethnic Chinese children aged 2;06-4;05 in Malaysia--a multiracial-multilingual country of Asia. The aims of the study are to provide clinical norms for speech development in the multilingual children and to compare multilingual acquisition with monolingual and bilingual acquisition. An innovative multilingual phonological test which adopts well-defined scoring criteria drawing upon local accents of English, Mandarin and Malay is proposed and described in this article. This procedure has been neglected in the few existing Chinese bilingual phonological acquisition studies resulting in peculiar findings. The multilingual children show comparable phonological acquisition milestones to that of monolingual and bilingual peers acquiring the same languages. The implications of the present results are discussed. The present findings contribute to the development of models and theories of child multilingual acquisition. PMID- 26237033 TI - Biofluid Biomarkers of Mild Traumatic Brain Injury: Whither Plasma Tau. PMID- 26237034 TI - Fluorinated Oligomers and Polymers in Photopolymerization. PMID- 26237035 TI - D-Glucose-Derived 1,2,4-Trioxepanes: Synthesis, Conformational Study, and Antimalarial Activity. AB - New enantiomerically pure 1,2,4-trioxepanes 10a,b/11a,b were synthesized from D glucose. Their conformational behavior was studied by low-temperature NMR and substantiated by DFT calculations. On evaluation of in vitro antimalarial activity, the adamantyl derivative 11b showed IC50 values in the low micromolar range, particularly against the W2 chloroquine-resistant Plasmodium falciparum strain (IC50 = 0.15 +/- 0.12 MUM). PMID- 26237036 TI - Prescribing Generic Medication in Chronic Musculoskeletal Pain Patients: An Issue of Representations, Trust, and Experience in a Swiss Cohort. AB - OBJECTIVE: Parallel to an ever stronger advocacy for the use of generics, various sources of information report concerns regarding substitution. The literature indicates that information regarding substitution is not univocal. The aim of this qualitative study was to explore patients' representations regarding generics in patients suffering from non-specific disabling chronic musculoskeletal pain, as these patients are confronted with the issue of the prescription and/or substitution of original formulations with generics. METHODS: Qualitative methods were selected because the aim was to access the range of patients' representations and to consider their conceptions. Standardized face-to face semi-structured interviews were used, and transcripts were submitted to content analysis. RESULTS: Patients' representations suggest that they might be confident in taking a generic medication: when he/she has an understanding of generics as resulting from a development process that has become part of the public domain; the generic medication is prescribed by the physician; each prescription is discussed, i.e., the patient is prescribed the generic version of a given medication and not a generic medication. DISCUSSION: Economic arguments are not sufficient to justify substitution, and may even raise issues calling upon cognitive dissonance. Even in non-life-threatening diseases, negative cues require attention and need be de-emphasized - in particular lower price as an indication of lower quality, and generic status as contradictory with advocating individualization of medication. PMID- 26237037 TI - Vasopressors for the Treatment of Septic Shock: Systematic Review and Meta Analysis. AB - OBJECTIVE: International guidelines recommend dopamine or norepinephrine as first line vasopressor agents in septic shock. Phenylephrine, epinephrine, vasopressin and terlipressin are considered second-line agents. Our objective was to assess the evidence for the efficiency and safety of all vasopressors in septic shock. METHODS: Systematic review and meta-analysis. We searched electronic database of MEDLINE, CENTRAL, LILACS and conference proceedings up to June 2014. We included randomized controlled trials comparing different vasopressors for the treatment of adult patients with septic shock. Primary outcome was all-cause mortality. Other clinical and hemodynamic measurements were extracted as secondary outcomes. Risk ratios (RR) and mean differences with 95% confidence intervals (CI) were pooled. RESULTS: Thirty-two trials (3,544 patients) were included. Compared to dopamine (866 patients, 450 events), norepinephrine (832 patients, 376 events) was associated with decreased all-cause mortality, RR 0.89 (95% CI 0.81-0.98), corresponding to an absolute risk reduction of 11% and number needed to treat of 9. Norepinephrine was associated with lower risk for major adverse events and cardiac arrhythmias compared to dopamine. No other mortality benefit was demonstrated for the comparisons of norepinephrine to epinephrine, phenylephrine and vasopressin / terlipressin. Hemodynamic data were similar between the different vasopressors, with some advantage for norepinephrine in central venous pressure, urinary output and blood lactate levels. CONCLUSIONS: Evidence suggests a survival benefit, better hemodynamic profile and reduced adverse events rate for norepinephrine over dopamine. Norepinephrine should be regarded as the first line vasopressor in the treatment of septic shock. PMID- 26237038 TI - Impact of Zeolite Aging in Hot Liquid Water on Activity for Acid-Catalyzed Dehydration of Alcohols. AB - The location and stability of Bronsted acid sites catalytically active in zeolites during aqueous phase dehydration of alcohols were studied on the example of cyclohexanol. The catalytically active hydronium ions originate from Bronsted acid sites (BAS) of the zeolite that are formed by framework tetrahedral Si atom substitution by Al. Al K-edge extended X-ray absorption fine structure (EXAFS) and (27)Al magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopies in combination with density functional theory (DFT) calculations are used to determine the distribution of tetrahedral Al sites (Al T-sites) both qualitatively and quantitatively for both parent and HBEA catalysts aged in water prior to catalytic testing. The aging procedure leads to partial degradation of the zeolite framework evidenced from the decrease of material crystallinity (XRD) as well as sorption capacity (BET). With the exception of one commercial zeolite sample, which had the highest concentration of framework silanol-defects, there is no evidence of Al coordination modification after aging in water. The catalyst weight-normalized dehydration rate correlated best with the sum of strong and weak Bronsted acidic protons both able to generate the hydrated hydronium ions. All hydronium ions were equally active for the acid-catalyzed reactions in water. Zeolite aging in hot water prior to catalysis decreased the weight normalized dehydration reaction rate compared to that of the parent HBEA, which is attributed to the reduced concentration of accessible Bronsted acid sites. Sites are hypothesized to be blocked due to reprecipitation of silica dissolved during framework hydrolysis in the aging procedure. PMID- 26237039 TI - Inspiring the next generation of physician-scientists. AB - As academic physician-scientists, one of the most important things we do is mentor young trainee-scientists. There obviously is no one right way to mentor or a set of rules one can follow; it's a very personal matter, and very much depends on one's personality. For much of my career, I gave very little thought as to how I mentored my trainees or to whether I was any good at it. Like many investigators, perhaps, I was just too busy with the daily activities of research to consider how I was guiding my students. Here, I take a look back and reflect on my experiences as a mentor and the factors that I believe contribute to the success of trainees as independent scientists. PMID- 26237040 TI - A conversation with Stuart Kornfeld. PMID- 26237042 TI - Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma. PMID- 26237043 TI - Retraction. Targeted expression of a human pituitary tumor-derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis. PMID- 26237041 TI - MECP2 disorders: from the clinic to mice and back. AB - Two severe, progressive neurological disorders characterized by intellectual disability, autism, and developmental regression, Rett syndrome and MECP2 duplication syndrome, result from loss and gain of function, respectively, of the same critical gene, methyl-CpG-binding protein 2 (MECP2). Neurons acutely require the appropriate dose of MECP2 to function properly but do not die in its absence or overexpression. Instead, neuronal dysfunction can be reversed in a Rett syndrome mouse model if MeCP2 function is restored. Thus, MECP2 disorders provide a unique window into the delicate balance of neuronal health, the power of mouse models, and the importance of chromatin regulation in mature neurons. In this Review, we will discuss the clinical profiles of MECP2 disorders, the knowledge acquired from mouse models of the syndromes, and how that knowledge is informing current and future clinical studies. PMID- 26237044 TI - mRNA deadenylation and telomere disease. PMID- 26237045 TI - FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3. PMID- 26237046 TI - Kidney growth and hypertrophy: the role of mTOR and vesicle trafficking. PMID- 26237047 TI - MicroRNA-486 as a Biomarker for Early Diagnosis and Recurrence of Non-Small Cell Lung Cancer. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) is a leading cause of cancer death worldwide. Early diagnosis is essential for improvements of prognosis and survival of the patients. Currently, there is no effective biomarker available in clinical settings for early detection of lung cancer. Altered expressions in many cancer types including NSCLC and stable existence in plasma make microRNAs (miRNAs) a group of potentially useful biomarkers for clinical assessments of patients with NSCLC. OBJECTIVES: To evaluate the potential values of miRNAs as blood-based biomarkers for early diagnosis and prognosis in NSCLC patients. METHODS: Peripheral blood samples from healthy volunteers and early-staged NSCLC patients before and after surgery were collected, and plasma was separated. Expression of ten miRNAs in the plasma and tumor sections of the patients was detected by quantitative real-time polymerase chain reaction. RESULTS: MiRNA (miR)-486 and miR-150 were found to significantly distinguish lung cancer patients from healthy volunteers. Area under curve of miR-486 and miR-150 were 0.926 (sensitivity, 0.909; specificity, 0.818) and 0.752 (sensitivity, 0.818; specificity, 0.818), respectively. In response to therapy, patients with down regulated miR-486 expression showed prolonged recurrence-free survival than those with un-reduced miR-486 expression (median, unreached vs. 19 months; hazard ratio, 0.1053; 95% confidence interval, 0.01045 to 1.060; P=0.056). CONCLUSIONS: The results suggest that miR-486 and miR-150 could be potential blood-based biomarkers for early diagnosis of NSCLC. Monitoring change of miR-486 expression in plasma might be an effective and non-invasive method for recurrence prediction of early-staged NSCLC patients. PMID- 26237049 TI - Unplanned Excision of Extremity Soft Tissue Sarcoma in Korea: A Nationwide Study Based on a Claims Registry. AB - Unplanned excision of extremity soft tissue sarcoma (STS) is common and has detrimental effects not only on patients' oncologic outcomes but also on functional and economic issues. However, no study has analyzed a nationwide population-based database. To estimate the incidence and treatment pattern of unplanned excision in extremity STS in the Korean population, a nationwide epidemiologic study was performed using the Korean Health Insurance Review and Assessment Service database, a centralized nationwide healthcare claims registry of Korea that covers the entire Korean population. Among 1,517 patients with extremity STS in the 4-year study period, 553 (36.5%) underwent unplanned excision (unplanned group). About 80% of unplanned excisions were performed in tertiary or general hospitals. Of the unplanned group, 240 (43.4%) underwent re excision with or without radiation therapy and/or chemotherapy, and 51 (9.2%) did not undergo re-excision but were treated with radiation therapy and/or chemotherapy; whereas, 262 (47.4%) did not undergo any further treatment following unplanned excision. This study is the first nationwide population-based study on the unplanned excision of extremity STS. The results may have implications in establishing preventive or therapeutic measures to reduce the burden of unplanned excision of extremity STS. PMID- 26237051 TI - Allergy And Anaphylaxis: Principles Of Acute Emergency Management. AB - Allergic reactions and anaphylaxis are potentially life-threatening processes that present with a variety of clinical symptoms. Emergency clinicians must be able to recognize these presentations and make prompt clinical decisions regarding management of a patient's airway, treatment options, and disposition of a patient who improves after initial presentation. Furthermore, emergency clinicians may be faced with patients who have atypical presentations or require special consideration, such as high-risk patients with comorbid conditions and patients who do not respond to first-line treatments. An increasing number of patients in the United States carry allergy diagnoses, and it is expected that this subset of the population will continue to seek care in the emergency department. This review assesses the research and evidence on the diagnosis, etiology, and treatment of anaphylaxis, as well as the utilization of epinephrine, both in and out of the hospital setting. PMID- 26237048 TI - Biochemical Characterization of a Mycobacteriophage Derived DnaB Ortholog Reveals New Insight into the Evolutionary Origin of DnaB Helicases. AB - The bacterial replicative helicases known as DnaB are considered to be members of the RecA superfamily. All members of this superfamily, including DnaB, have a conserved C- terminal domain, known as the RecA core. We unearthed a series of mycobacteriophage encoded proteins in which the RecA core domain alone was present. These proteins were phylogenetically related to each other and formed a distinct clade within the RecA superfamily. A mycobacteriophage encoded protein, Wildcat Gp80 that roots deep in the DnaB family, was found to possess a core domain having significant sequence homology (Expect value < 10-5) with members of this novel cluster. This indicated that Wildcat Gp80, and by extrapolation, other members of the DnaB helicase family, may have evolved from a single domain RecA core polypeptide belonging to this novel group. Biochemical investigations confirmed that Wildcat Gp80 was a helicase. Surprisingly, our investigations also revealed that a thioredoxin tagged truncated version of the protein in which the N-terminal sequences were removed was fully capable of supporting helicase activity, although its ATP dependence properties were different. DnaB helicase activity is thus, primarily a function of the RecA core although additional N terminal sequences may be necessary for fine tuning its activity and stability. Based on sequence comparison and biochemical studies we propose that DnaB helicases may have evolved from single domain RecA core proteins having helicase activities of their own, through the incorporation of additional N-terminal sequences. PMID- 26237050 TI - Early Signaling in Primary T Cells Activated by Antigen Presenting Cells Is Associated with a Deep and Transient Lamellal Actin Network. AB - Cellular signaling transduction critically depends on molecular interactions that are in turn governed by dynamic subcellular distributions of the signaling system components. Comprehensive insight into signal transduction requires an understanding of such distributions and cellular structures driving them. To investigate the activation of primary murine T cells by antigen presenting cells (APC) we have imaged more than 60 signaling intermediates during T cell stimulation with microscopy across resolution limits. A substantial number of signaling intermediates associated with a transient, wide, and actin-associated lamellum extending from an interdigitated T cell:APC interface several micrometers into the T cell, as characterized in detail here. By mapping the more than 60 signaling intermediates onto the spatiotemporal features of cell biological structures, the lamellum and other ones previously described, we also define distinct spatial and temporal characteristics of T cell signal initiation, amplification, and core signaling in the activation of primary T cells by APCs. These characteristics differ substantially from ones seen when T cells are activated using common reductionist approaches. PMID- 26237052 TI - Layered Double Hydroxide Assemblies with Controllable Drug Loading Capacity and Release Behavior as well as Stabilized Layer-by-Layer Polymer Multilayers. AB - A stable drug release system with magnetic targeting is essential in a drug delivery system. In the present work, layered double hydroxide assemblies stabilized by layer-by-layer polymer multilayers were prepared by alternative deposition of poly(allylamine hydrochloride) and poly(acrylic acid) species on composite particles of Fe3O4 and ZnAl-LDH and then covalent cross-linkage of the polymer multilayers by photosensitive cross-linker. The successful fabrication was recorded by Zeta potential and Fourier transform infrared spectrum measurements. The formed assemblies were stable in high pH solutions (pH > 7). The drug loading capacity and release behavior of the assemblies could be controlled by treatment with appropriate acidic solution, and were confirmed by loading and release of a simulated drug, methylene blue. The formed assemblies possessed enough saturated magnetic strength and were sensitive to external magnetic field which was essential for targeting drug delivery. The formed assemblies were multifunctional assemblies with great potential as drug delivery system. PMID- 26237053 TI - Emotional closeness to parents and grandparents: A moderated mediation model predicting adolescent adjustment. AB - Warm and emotionally close relationships with parents and grandparents have been found in previous studies to be linked with better adolescent adjustment. The present study, informed by Family Systems Theory and Intergenerational Solidarity Theory, uses a moderated mediation model analyzing the contribution of the dynamics of these intergenerational relationships to adolescent adjustment. Specifically, it examines the mediating role of emotional closeness to the closest grandparent in the relationship between emotional closeness to a parent (the offspring of the closest grandparent) and adolescent adjustment difficulties. The model also examines the moderating role of emotional closeness to parents in the relationship between emotional closeness to grandparents and adjustment difficulties. The study was based on a sample of 1,405 Jewish Israeli secondary school students (ages 12-18) who completed a structured questionnaire. It was found that emotional closeness to the closest grandparent was more strongly associated with reduced adjustment difficulties among adolescents with higher levels of emotional closeness to their parents. In addition, adolescent adjustment and emotional closeness to parents was partially mediated by emotional closeness to grandparents. Examining the family conditions under which adolescents' relationships with grandparents is stronger and more beneficial for them can help elucidate variations in grandparent-grandchild ties and expand our understanding of the mechanisms that shape child outcomes. PMID- 26237054 TI - Mothers' use of blogs while engaged in family-based treatment for a child's eating disorder. AB - INTRODUCTION: We explore parents' use of blogs while engaged in family-based treatment (FBT), a form of treatment in which parents engage as the primary givers of care for a child's eating disorder. We sought to bring together emergent literature on the value of blogging for social support with a body of literature on caregiving for a child with an eating disorder and to understand how parents use blogs while engaged in FBT. METHOD: We conducted a thematic analysis of 138 blog entries written by 5 mothers. RESULTS: Two main themes emerged: the importance of support and shifts in parenting. Blogs detailed how parents actively seek to meet their needs during a difficult time using online interactions to bolster sources of support that exist offline. This intensive form of treatment also provoked shifts in parenting, which parents described on their blogs. Parents' blogs were rich with descriptions of their use of mutually reinforcing on- and offline support. DISCUSSION: The unique context of the blogs allowed for access to data that were not generated for the purpose of research. Results add to the growing body of literature about parents' caregiving experiences and use of blogs for social support, and they offer implications for using online spaces as adjunct support for families. (PsycINFO Database Record PMID- 26237055 TI - Use of a resiliency framework to examine pregnancy and birth outcomes among adolescents: A qualitative study. AB - INTRODUCTION: Adolescent childbearing has been viewed as a social, political, and public health priority since the 1970s. Research has primarily focused on the negative consequences of teen pregnancy; less research has explored factors associated with healthy pregnancy and birth experiences in this population. METHOD: Using open-ended and qualitative techniques, researchers performed individual interviews with 15 adolescent mothers (15 to 19 years of age) recruited from a Women's and Children's Clinic in Southern Louisiana, who had experienced a healthy pregnancy and bore a full-term, normal birth weight infant. We used a resiliency framework to identify factors that may have supported positive health outcomes despite risks associated with low-income and/or marginalized minority status. RESULTS: A total of 15 mothers of multiple racial/ethnic identities were included in the analysis. Mothers discussed potential protective factors that we classified as either assets (internal factors) or resources (external factors). Mothers demonstrated strong assets including self-efficacy and self-acceptance and important resources including familial support and partner support during pregnancy which may have contributed to their resiliency. DISCUSSION: Ensuring access to social and structural supports as well as supporting adolescent-friendly health and social policies may be key to promoting healthy maternal and infant outcomes among young women who become pregnant. (PsycINFO Database Record PMID- 26237057 TI - Comparative Biochemical and Proteomic Analyses of Soybean Seed Cultivars Differing in Protein and Oil Content. AB - This study develops differential protein profiles of soybean (Glycine max) seeds (cv. Saedanbaek and Daewon) varying in protein (47.9 and 39.2%) and oil (16.3 and 19.7%) content using protamine sulfate (PS) precipitation method coupled with a 2D gel electrophoresis (2DGE) approach. Of 71 detected differential spots between Daewon and Saedanbaek, 48 were successfully identified by MALDI-TOF/TOF. Gene ontology analysis revealed that up-regulated proteins in Saedanbaek were largely associated with nutrient reservoir activity (42.6%), which included mainly seed storage proteins (SSPs; subunits of glycinin and beta-conglycinin). Similar results were also obtained in two cultivars of wild soybean (G. soja cv. WS22 and WS15) differing in protein content. Western blots confirmed higher accumulation of SSPs in protein-rich Saedanbaek. Findings presented and discussed in this study highlight a possible involvement of the urea cycle for increased accumulation of SSPs and hence the higher protein content in soybean seeds. PMID- 26237056 TI - Triple-Emitting Dumbbell Fluorescent Nanoprobe for Multicolor Detection and Imaging Applications. AB - The combination of different fluorescent species into one nanostructure to develop fluorescent nanoparticles with multiple emission signatures by a single wavelength excitation has become a very popular research area in the field of multiplex bioanalysis, diagnostics, and multicolor imaging. However, these novel hybrids must be elaborately designed to ensure that the unique properties of each component are conveyed, i.e., fluorescent species and nanoparticles, and are maximized without serious interactions with each other. Herein, a first triple fluorescence dumbbell nanoprobe with large Stokes shift based on incorporating fluorescein isothiocyanate (FITC) and lanthanide complexes onto Au-Fe3O4 NPs was synthesized. This hybrid displays well-resolved triple fluorescence emission, with FITC at 515 nm, Tb(III) complex at 545 nm, and Eu(III) complex at 616 nm under a single-excitation wavelength and is used for highly selective and sensitive colorimetric detection of Cu(2+) with a detection limit of 30 nM. Under different Cu(2+) concentrations, this hybrid exhibited distinguishable multiple colors under UV light, and the color could change in the presence of different concentrations of Cu(2+). This sensor for ratio/multianalyte microscopic imaging of Cu(2+) in HeLa cells and BHK cells was also demonstrated. Target molecules, such as folic acid, can be covalently attached to the fluorescent nanoparticle surface to serve as an effective probe for simultaneous multicolor imaging folate receptor-overexpressing HeLa cell lines in vitro. PMID- 26237058 TI - Online 2D-LC-MS/MS assay to quantify therapeutic protein in human serum in the presence of pre-existing antidrug antibodies. AB - The formation of antidrug antibodies (ADA) can interfere with the accurate quantitation of therapeutic proteins, leading to significantly underestimated drug concentrations and confounded pharmacokinetic (PK) data interpretation. Although highly desirable, development of ADA-tolerant bioanalytical methods enabling unbiased measurement of both free and ADA-bound drug presents a considerable challenge. We report herein the development and validation of a robust LC-MS assay capable of quantifying therapeutic protein immunoglobulin A1 protease (IgAP) in human serum in the presence of pre-existing anti-IgAP antibodies. The procedure included sodium dodecyl sulfate (SDS) denaturation and chemical reduction of serum proteins to dissociate ADA-drug bindings, followed by tryptic digestion of protein pellets and subsequent LC-MS analysis of the surrogate IgAP peptide using stable isotope labeled peptide internal standard. Substantial enhancements in the sensitivity and selectivity were achieved by the combination of online two-dimensional reversed-phase LC (2D-LC) operated in high and low pH buffers, respectively, for efficient enrichment and quantitation of the surrogate peptide by multiple-reaction monitoring (MRM) mass spectrometry. Unlike ligand-binding assay, our method is not prone to interferences from ADA, allowing accurate and precise measurement of the IgAP in the range of 0.05 to 10 MUg/mL in 25 MUL of human serum with a wide range of anti-IgAP antibody levels. The intra- and inter-run precision (coefficient of variation (CV%)) was within 11.5% and 10.5%, respectively, and the bias was within +/-7.1% for all quality control (QC) concentrations. With little modification, the described method can readily be applicable to the quantitation of other biotherapeutic proteins in the ADA-positive clinical matrices. PMID- 26237059 TI - Multivalency at Interfaces: Supramolecular Carbohydrate-Functionalized Graphene Derivatives for Bacterial Capture, Release, and Disinfection. AB - A supramolecular carbohydrate-functionalized two-dimensional (2D) surface was designed and synthesized by decorating thermally reduced graphene sheets with multivalent sugar ligands. The formation of host-guest inclusions on the carbon surface provides a versatile strategy, not only to increase the intrinsic water solubility of graphene-based materials, but more importantly to let the desired biofunctional binding groups bind to the surface. Combining the vital recognition role of carbohydrates and the unique 2D large flexible surface area of the graphene sheets, the addition of multivalent sugar ligands makes the resulting carbon material an excellent platform for selectively wrapping and agglutinating Escherichia coli (E. coli). By taking advantage of the responsive property of supramolecular interactions, the captured bacteria can then be partially released by adding a competitive guest. Compared to previously reported scaffolds, the unique thermal IR-absorption properties of graphene derivatives provide a facile method to kill the captured bacteria by IR-laser irradiation of the captured graphene-sugar-E. coli complex. PMID- 26237060 TI - Analysis of Various Subsets of Circulating Mononuclear Cells in Asymptomatic Coronary Artery Disease. AB - The objective of this study was to evaluate the correlation between multiple cardiovascular risk factors (MCRFs) and circulating mononuclear cells (CMCs) in asymptomatic coronary artery disease patients. DESIGN AND METHODS: 126 subjects (54 male), aged 48 to 62 years, with asymptomatic coronary artery disease (CAD) documented previously with angiography, and 25 healthy volunteers were enrolled in the study. The flow cytometric technique was used for predictably distinguishing cell subsets that depend on the expression of CD14, CD34, Tie-2, CD45, and CD309 (VEGFR2). RESULTS: The analysis of the outcome obtained shows a trend of an increase in circulating CD45(-)CD34(+) CMCs and a reduction in CMC population defined as CD14(+)CD309(+) and CD14(+)CD309(+)Tie(2+) in known asymptomatic CAD patients in comparison with healthy volunteers. Substantial correlations between CD45(-)CD34(+) and conventional cardiovascular risk factors (hs-CRP, T2DM, serum uric acid and hypertension) were found in the patient cohort. The concentrations of CD14(+)CD309(+) and CD14(+)CD309(+)Tie(2+) CMCs had effect on such factors as T2DM (RR = 1.21; 95% CI = 1.10-1.40; p = 0.008), hs-CRP > 2.54 mg/L (RR = 1.29; 95% CI = 1.12-1.58; p = 0.006), Agatston score index (RR = 1.20; 95% CI = 1.15-1.27; p = 0.034), and occurrence of three and more cardiovascular risk factors (RR = 1.31; 95% CI = 1.12-1.49; p = 0.008). CONCLUSION: It is postulated that the reduction in circulating CD14(+)CD309(+) and CD14(+)CD309(+)Tei(2+) CMCs is related to a number of cardiovascular risk factors in asymptomatic patients with known CAD. PMID- 26237061 TI - Recurrent Fever of Unknown Origin (FUO) Due to Periodic Fever, Aphthous Stomatititis, Pharyngitis and Adenitis (FAPA) Syndrome in an Adult. AB - FAPA syndrome (periodic fever, aphthous stomatititis, pharyngitis and adenitis) is a relatively new entity described in pediatric patients. In adults, reports of FAPA are limited to rare case reports. The differential diagnosis of FAPA in adults includes Behcet's syndrome, familial Mediterranean fever (FMF), Hyper IgD syndrome and juvenile rheumatoid arthritis (JRA), i.e., adult Still's disease. With FAPA syndrome, between episodes patients are completely asymptomatic and serologic inflammatory markers such as erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and white blood cell (WBC) count are normal. The etiology of FAFA is unknown, but lack of secondary cases or clustering in close contacts, lack of seasonality, and the lack of progression for years argue against an infectious etiology. We describe an extremely rare case of an adult with a recurrent FUO with profuse night sweats and prominent chills due to FAPA syndrome. PMID- 26237062 TI - Short Term Culture of Human Mesenchymal Stem Cells with Commercial Osteoconductive Carriers Provides Unique Insights into Biocompatibility. AB - For spinal fusions and the treatment of non-union fractures, biological substrates, scaffolds, or carriers often are applied as a graft to support regeneration of bone. The selection of an appropriate material critically influences cellular function and, ultimately, patient outcomes. Human bone marrow mesenchymal stem cells (BMSCs) are regarded as a critical component of bone healing. However, the interactions of BMSCs and commercial bone matrices are poorly reported. BMSCs were cultured with several commercially available bone substrates (allograft, demineralized bone matrix (DBM), collagen, and various forms of calcium phosphates) for 48 h to understand their response to graft materials during surgical preparation and the first days following implantation (cell retention, gene expression, pH). At 30 and 60 min, bone chips and inorganic substrates supported significantly more cell retention than other materials, while collagen-containing materials became soluble and lost their structure. At 48 h, cells bound to beta-tricalcium phosphate-hydroxyapatite (betaTCP-HA) and porous hydroxyapatite (HA) granules exhibited osteogenic gene expression statistically similar to bone chips. Through 24 h, the DBM strip and betaTCP collagen became mildly acidic (pH 7.1-7.3), while the DBM poloxamer-putties demonstrated acidity (pH < 5) and the bioglass-containing carrier became basic (pH > 10). The dissolution of DBM and collagen led to a loss of cells, while excessive pH changes potentially diminish cell viability and metabolism. Extracts from DBM-poloxamers induced osteogenic gene expression at 48 h. This study highlights the role that biochemical and structural properties of biomaterials play in cellular function, potentially enhancing or diminishing the efficacy of the overall therapy. PMID- 26237063 TI - Bone-Targeted Agents for the Management of Breast Cancer Patients with Bone Metastases. AB - Despite advances in adjuvant therapy for breast cancer, bone remains the most common site of recurrence. The goal of therapy for these patients is palliative and focused on maximizing the duration and quality of their life, while concurrently minimizing any disease or treatment-related complications. Bone metastases predispose patients to reduced survival, pain, impaired quality of life and the development of skeletal-related events. With an increased understanding of the pathophysiology of bone metastasis, effective treatments for their management have evolved and are now in widespread clinical use. This article will discuss the pathogenesis of bone metastases and review the key clinical evidence for the efficacy and safety of currently available systemic bone-targeted therapies in breast cancer patients with an emphasis on bisphosphonates and the receptor activator of nuclear factor kappa B ligand (RANKL) inhibitors. We will also discuss novel strategies and therapies currently in development. PMID- 26237064 TI - Where Do Bone-Targeted Agents RANK in Breast Cancer Treatment? AB - Breast cancer cells preferentially metastasise to the skeleton, owing, in part, to the fertile environment provided by bone. Increased bone turnover releases growth factors that promote tumour cell growth. In turn, tumour cells release factors that stimulate further bone turnover, resulting in a vicious cycle of metastasis growth and bone destruction. The RANK-RANK ligand (RANKL) pathway plays a key role in this cycle, and inhibition of RANKL using the fully-human monoclonal antibody denosumab, has demonstrated efficacy in delaying skeletal complications associated with bone metastases in three phase 3 trials. Preclinical studies suggest that the RANKL pathway also plays a role in breast cancer tumourigenesis and migration to bone. In a subgroup analysis of the negative Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, the bisphosphonate zoledronic acid showed potential for improving survival in patients who were postmenopausal; however, a prospective study in this patient population is required to validate this observation. Ongoing trials are examining whether adjuvant blockade of the RANKL pathway using denosumab can prevent disease recurrence in patients with high-risk breast cancer. These are building on analogous studies that have shown that denosumab improves bone metastasis-free survival in prostate cancer and suggested that it confers an overall survival benefit in non-small-cell lung cancer. PMID- 26237065 TI - Aging Impairs the Proliferative Capacity of Cardiospheres, Cardiac Progenitor Cells and Cardiac Fibroblasts: Implications for Cell Therapy. AB - INTRODUCTION: Cardiospheres (CS) are self-assembling clusters of cells that can be grown from cardiac tissue. They contain a heterogeneous cell population that includes cardiac progenitor cells (CPCs) and cardiac fibroblasts. CS and CPCs have been shown to improve cardiac function after myocardial infarction (MI) in experimental models and are now being studied in clinical trials. The effects of aging on the proliferative capacity of CS and CPCs, and the paracrine signaling between cell types, remain incompletely understood. METHODS AND RESULTS: We compared the growth of CS from young and aging murine hearts at baseline and following MI. The number of CS from young and aging hearts was similar at baseline. However, after MI, young hearts had a dramatic increase in the number of CS that grew, but this proliferative response to MI was virtually abolished in the aging heart. Further, the proportion of cells within the CS that were CPCs (defined as Sca-1(stem cell antigen-1)(+)/CD45(-)) was significantly lower in aging hearts than young hearts. Thus the number of available CPCs after culture from aging hearts was substantially lower than from young hearts. Cardiac fibroblasts from aging hearts proliferated more slowly in culture than those from young hearts. We then investigated the interaction between aging cardiac fibroblasts and CPCs. We found no significant paracrine effects on proliferation between these cell types, suggesting the impaired proliferation is a cell autonomous problem. CONCLUSIONS: Aging hearts generate fewer CPCs, and aging CPCs have significantly reduced proliferative potential following MI. Aging cardiac fibroblasts also have reduced proliferative capacity, but these appear to be cell autonomous problems, not caused by paracrine signaling between cell types. PMID- 26237066 TI - Engraftment Outcomes after HPC Co-Culture with Mesenchymal Stromal Cells and Osteoblasts. AB - Haematopoietic stem cell (HSC) transplantation is an established cell-based therapy for a number of haematological diseases. To enhance this therapy, there is considerable interest in expanding HSCs in artificial niches prior to transplantation. This study compared murine HSC expansion supported through co culture on monolayers of either undifferentiated mesenchymal stromal cells (MSCs) or osteoblasts. Sorted Lineage(-) Sca-1(+) c-kit(+) (LSK) haematopoietic stem/progenitor cells (HPC) demonstrated proliferative capacity on both stromal monolayers with the greatest expansion of LSK shown in cultures supported by osteoblast monolayers. After transplantation, both types of bulk-expanded cultures were capable of engrafting and repopulating lethally irradiated primary and secondary murine recipients. LSKs co-cultured on MSCs showed comparable, but not superior, reconstitution ability to that of freshly isolated LSKs. Surprisingly, however, osteoblast co-cultured LSKs showed significantly poorer haematopoietic reconstitution compared to LSKs co-cultured on MSCs, likely due to a delay in short-term reconstitution. We demonstrated that stromal monolayers can be used to maintain, but not expand, functional HSCs without a need for additional haematopoietic growth factors. We also demonstrated that despite apparently superior in vitro performance, co-injection of bulk cultures of osteoblasts and LSKs in vivo was detrimental to recipient survival and should be avoided in translation to clinical practice. PMID- 26237067 TI - Mechanisms of Metastatic Tumor Dormancy. AB - Tumor metastasis can occur years after an apparent cure due to a phenomenon known as metastatic tumor dormancy; in which tumor masses or individual tumor cells are growth restricted for extended periods of time. This period of dormancy is induced and maintained by several mechanisms, including: (1) Tumor microenvironment factors such as cytokine expression, immunosurveillance and angiogenesis; (2) Metastasis suppressor gene activity; and (3) Cancer therapeutics. Disseminated tumor cells (DTC) are the key cells that result in dormant tumors. However, many challenges exist towards isolating DTCs for mechanistic studies. The main DTC that may represent the dormant cell is the cancer stem cells (CSC) as they have a slow proliferation rate. In addition to limited knowledge regarding induction of tumor dormancy, there are large gaps in knowledge regarding how tumors escape from dormancy. Emerging research into cancer stem cells, immunotherapy, and metastasis suppressor genes, may lead to new approaches for targeted anti-metastatic therapy to prevent dormancy escape. Overall, an enhanced understanding of tumor dormancy is critical for better targeting and treatment of patients to prevent cancer recurrence. PMID- 26237069 TI - In Silico Exploration for New Antimalarials: Arylsulfonyloxy Acetimidamides as Prospective Agents. AB - A strategy is described to identify new antimalarial agents to overcome the drug resistance and/or failure issues through in silico screening of multiple biological targets. As a part of this, three enzymes namely CTPS, CK, and GST were selected, from among 56 drug targets of P. falciparum, and used them in virtual screening of ZINC database entries which led to the design and synthesis of arylsulfonyloxy acetimidamides as their consensus inhibitors. From these, two compounds showed good activity against sensitive (3D7; IC50, 1.10 and 1.45 MUM) and resistant (K1; IC50, 2.10 and 2.13 MUM) strains of the parasite, and they were further investigated through docking and molecular dynamics simulations. The findings of this study collectively paved the way for arylsulfonyloxy acetimidamides as a new class of antimalarial agents. PMID- 26237068 TI - Prevention and Treatment of Bone Metastases in Breast Cancer. AB - In breast cancer patients, bone is the most common site of metastases. Medical therapies are the basic therapy to prevent distant metastases and recurrence and to cure them. Radiotherapy has a primary role in pain relief, recalcification and stabilization of the bone, as well as the reduction of the risk of complications (e.g., bone fractures, spinal cord compression). Bisphosphonates, as potent inhibitors of osteoclastic-mediated bone resorption are a well-established, standard-of-care treatment option to reduce the frequency, severity and time of onset of the skeletal related events in breast cancer patients with bone metastases. Moreover bisphosphonates prevent cancer treatment-induced bone loss. Recent data shows the anti-tumor activity of bisphosphonates, in particular, in postmenopausal women and in older premenopausal women with hormone-sensitive disease treated with ovarian suppression. Pain is the most frequent symptom reported in patients with bone metastases, and its prevention and treatment must be considered at any stage of the disease. The prevention and treatment of bone metastases in breast cancer must consider an integrated multidisciplinary approach. PMID- 26237070 TI - Liquid-Liquid Phase Separation in a Dual Variable Domain Immunoglobulin Protein Solution: Effect of Formulation Factors and Protein-Protein Interactions. AB - Dual variable domain immunoglobulin proteins (DVD-Ig proteins) are large molecules (MW ~ 200 kDa) with increased asymmetry because of their extended Y like shape, which results in increased formulation challenges. Liquid-liquid phase separation (LLPS) of protein solutions into protein-rich and protein-poor phases reduces solution stability at intermediate concentrations and lower temperatures, and is a serious concern in formulation development as therapeutic proteins are generally stored at refrigerated conditions. In the current work, LLPS was studied for a DVD-Ig protein molecule as a function of solution conditions by measuring solution opalescence. LLPS of the protein was confirmed by equilibrium studies and by visually observing under microscope. The protein does not undergo any structural change after phase separation. Protein-protein interactions were measured by light scattering (kD) and Tcloud (temperature that marks the onset of phase separation). There is a good agreement between kD measured in dilute solution with Tcloud measured in the critical concentration range. Results indicate that the increased complexity of the molecule (with respect to size, shape, and charge distribution on the molecule) increases contribution of specific and nonspecific interactions in solution, which are affected by formulation factors, resulting in LLPS for DVD-Ig protein. PMID- 26237071 TI - Where Does the Transformation of Precipitated Ceria Nanoparticles in Hydroponic Plants Take Place? AB - Cerium oxide nanoparticles (CeO2 NPs) have been found to be partly biotransformed from Ce(IV) to Ce(III) in plants, yet the transformation process and mechanism are not fully understood. Here, we try to clarify the specific site and necessary conditions for the transformation of precipitated CeO2 NPs in hydroponic cucumber plants. Three different treatment modes were adopted according to whether the NPs were incubated with roots all the time or not. Results showed that exposure modes significantly affect the translocation and transformation of CeO2 NPs. In the normal exposure mode, Ce was present as a Ce(IV) and Ce(III) mixture in the roots and shoots, and the proportion of Ce(III) in the shoots was enhanced obviously with the increase of exposure time. The results of short-time incubation and petiole exposure modes suggested that CeO2 NPs could not be reduced within a short incubation time (3 h) or be further reduced inside the plant tissues. It was deduced that root surfaces are the sites, and the physicochemical interaction between the NPs and root exudates at the nanobio interface is the necessary condition for the transformation of CeO2 NPs in plant systems. These results will contribute to understanding the transformation mechanism of CeO2 and other metal based NPs and properly evaluate their ecological effects. PMID- 26237072 TI - pi-Radical to sigma-Radical Tautomerization in One-Electron-Oxidized 1 Methylcytosine and Its Analogs. AB - In this work, iminyl sigma-radical formation in several one-electron-oxidized cytosine analogs, including 1-MeC, cidofovir, 2'-deoxycytidine (dCyd), and 2' deoxycytidine 5'-monophosphate (5'-dCMP), were investigated in homogeneous, aqueous (D2O or H2O) glassy solutions at low temperatures by employing electron spin resonance (ESR) spectroscopy. Upon employing density functional theory (DFT) (DFT/B3LYP/6-31G* method), the calculated hyperfine coupling constant (HFCC) values of iminyl sigma-radical agree quite well with the experimentally observed ones, thus confirming its assignment. ESR and DFT studies show that the cytosine iminyl sigma-radical is a tautomer of the deprotonated cytosine pi-cation radical [cytosine pi-aminyl radical, C(N4-H)(*)]. Employing 1-MeC samples at various pHs ranging from ca. 8 to 11, ESR studies show that the tautomeric equilibrium between C(N4-H)(*) and the iminyl sigma-radical at low temperature is too slow to be established without added base. ESR and DFT studies agree that, in the iminyl sigma-radical, the unpaired spin is localized on the exocyclic nitrogen (N4) in an in-plane pure p-orbital. This gives rise to an anisotropic nitrogen hyperfine coupling (Azz = 40 G) from N4 and a near isotropic beta-nitrogen coupling of 9.7 G from the cytosine ring nitrogen at N3. Iminyl sigma-radical should exist in its N3-protonated form, as the N3-protonated iminyl sigma-radical is stabilized in solution by over 30 kcal/mol (DeltaG = -32 kcal/mol) over its conjugate base, the N3-deprotonated form. This is the first observation of an isotropic beta hyperfine ring nitrogen coupling in an N-centered DNA radical. Our theoretical calculations predict that the cytosine iminyl sigma-radical can be formed in double-stranded DNA by a radiation-induced ionization-deprotonation process that is only 10 kcal/mol above the lowest energy path. PMID- 26237073 TI - Efficacy of simple integrated group rehabilitation program for patients with knee osteoarthritis: Single-blind randomized controlled trial. AB - We investigated the role of an evidence-based integrated group rehabilitation program on the treatment of patients with knee osteoarthritis (KOA). This was a two-group, randomized controlled, 8 wk trial with 41 patients with moderate to very severe KOA. Patients were assigned to an intervention group (IG) or control group (CG). After both groups had received a self-management education program, IG participants underwent a rehabilitation program, including educational aspects about KOA followed by exercises. CG participants received only general health orientation about KOA during this period. The outcome measures were the Lequesne algofunctional index; 36-Item Short Form Health Survey (SF-36); and chair-stand, sit-and-reach, timed up-and-go, and 6-minute walk tests. Analysis of covariance revealed significant postintervention improvements of IG participants compared with CG participants (p < 0.05) on Lequesne total score and pain and function subdomains; SF-36 physical function, role physical, bodily pain, general health, vitality, and role emotional subdomains; and performance assessed by chair-stand, timed up-and-go, and 6-minute walk tests. Focusing on the primary outcome (Lequesne total score), the mean +/- standard deviation after 8 wk was 5.50 +/- 2.98 for the IG and 7.87 +/- 3.48 for the CG (p = 0.009). The corresponding effect size (partial eta squared with 90% confidence interval) was 0.23 (0.04 0.42), indicating a large effect. The presented rehabilitation program reduced pain and improved quality of life and function in patients with KOA. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; Progressive Collective-exercise Program on the Knee Osteoarthritis; NCT01850862; https://clinicaltrials.gov/ct2/show/NCT01850862?term=NCT01850862&rank=1. PMID- 26237074 TI - Hybrid simplified spherical harmonics with diffusion equation for light propagation in tissues. AB - Aiming at the limitations of the simplified spherical harmonics approximation (SPN) and diffusion equation (DE) in describing the light propagation in tissues, a hybrid simplified spherical harmonics with diffusion equation (HSDE) based diffuse light transport model is proposed. In the HSDE model, the living body is first segmented into several major organs, and then the organs are divided into high scattering tissues and other tissues. DE and SPN are employed to describe the light propagation in these two kinds of tissues respectively, which are finally coupled using the established boundary coupling condition. The HSDE model makes full use of the advantages of SPN and DE, and abandons their disadvantages, so that it can provide a perfect balance between accuracy and computation time. Using the finite element method, the HSDE is solved for light flux density map on body surface. The accuracy and efficiency of the HSDE are validated with both regular geometries and digital mouse model based simulations. Corresponding results reveal that a comparable accuracy and much less computation time are achieved compared with the SPN model as well as a much better accuracy compared with the DE one. PMID- 26237075 TI - Epigenetic landscape correlates with genetic subtype but does not predict outcome in childhood acute lymphoblastic leukemia. AB - Although children with acute lymphoblastic leukemia (ALL) generally have a good outcome, some patients do relapse and survival following relapse is poor. Altered DNA methylation is highly prevalent in ALL and raises the possibility that DNA methylation-based biomarkers could predict patient outcome. In this study, genome wide methylation analysis, using the Illumina Infinium HumanMethylation450 BeadChip platform, was carried out on 52 diagnostic patient samples from 4 genetic subtypes [ETV6-RUNX1, high hyperdiploidy (HeH), TCF3-PBX1 and dic(9;20)(p11-13;q11)] in a 1:1 case-control design with patients who went on to relapse (as cases) and patients achieving long-term remission (as controls). Pyrosequencing assays for selected loci were used to confirm the array-generated data. Non-negative matrix factorization consensus clustering readily clustered samples according to genetic subgroups and gene enrichment pathway analysis suggested that this is in part driven by epigenetic disruption of subtype specific signaling pathways. Multiple bioinformatics approaches (including bump hunting and individual locus analysis) were used to identify CpG sites or regions associated with outcome. However, no associations with relapse were identified. Our data revealed that ETV6-RUNX1 and dic(9;20) subtypes were mostly associated with hypermethylation; conversely, TCF3-PBX1 and HeH were associated with hypomethylation. We observed significant enrichment of the neuroactive ligand receptor interaction pathway in TCF3-PBX1 as well as an enrichment of genes involved in immunity and infection pathways in ETV6-RUNX1 subtype. Taken together, our results suggest that altered DNA methylation may have differential impacts in distinct ALL genetic subtypes. PMID- 26237077 TI - Corrigendum. PMID- 26237076 TI - Environmentally induced epigenetic transgenerational inheritance of sperm epimutations promote genetic mutations. AB - A variety of environmental factors have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. This involves the germline transmission of epigenetic information between generations. Exposure specific transgenerational sperm epimutations have been previously observed. The current study was designed to investigate the potential role genetic mutations have in the process, using copy number variations (CNV). In the first (F1) generation following exposure, negligible CNV were identified; however, in the transgenerational F3 generation, a significant increase in CNV was observed in the sperm. The genome-wide locations of differential DNA methylation regions (epimutations) and genetic mutations (CNV) were investigated. Observations suggest the environmental induction of the epigenetic transgenerational inheritance of sperm epimutations promote genome instability, such that genetic CNV mutations are acquired in later generations. A combination of epigenetics and genetics is suggested to be involved in the transgenerational phenotypes. The ability of environmental factors to promote epigenetic inheritance that subsequently promotes genetic mutations is a significant advance in our understanding of how the environment impacts disease and evolution. PMID- 26237078 TI - Quantitative large scale gene expression profiling from human stem cell culture micro samples using multiplex pre-amplification. AB - Transcriptional profiling is a powerful tool to study biological mechanisms during stem cell differentiation and reprogramming. Genome-wide methods like microarrays or next generation sequencing are expensive, time consuming, and require special equipment and bioinformatics expertise. Quantitative RT-PCR remains one of today's most widely accepted and used methods for analyzing gene expression in biological samples. However, limitations in the amount of starting materials often hinder the quantity and quality of information that could be obtained from a given sample. Here, we present a fast 4-step workflow allowing direct, column-free RNA isolation from limited human pluripotent stem cell (hPSC) cultures that is directly compatible with subsequent reverse transcription, target specific multiplex pre-amplification, and standard SYBR-Green quantitative PCR (qPCR) analysis. The workflow delivers excellent correlations in normalized gene-expression data obtained from different samples of hPSCs over a wide range of cell numbers (500-50,000 cells). We demonstrate accurate and unbiased target gene quantification in limiting stem cell cultures which allows for monitoring embryoid body differentiation and induced pluripotent stem cell (iPSC) reprogramming. This method highlights a rapid and cost effective screening process, allowing reduction of culture formats and increase of processing throughputs for various stem cell applications. PMID- 26237079 TI - Pancreatic Gastrointestinal Stromal Tumor after Upper Gastrointestinal Hemorrhage and Performance of Whipple Procedure: A Case Report and Literature Review. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal system. These types of tumors originate from any part of the tract as well as from the intestine, colon, omentum, mesentery or retroperitoneum. GIST is a rare tumor compared to other types of tumors, accounting for less than 1% of all gastrointestinal tumors. CASE REPORT: A 56-year-old male patient was hospitalized due to an upper gastrointestinal hemorrhage and the start of abdominal pain on the same day. In the upper gastrointestinal endoscopy that was performed, a solitary mass was found in the second section of the duodenum and a blood vessel (Forrest type 2a) was seen. The extent and location of the mass was detected by abdominal tomography. After hemodynamic recovery, a Whipple procedure was performed without any complications. A subsequent histopathological examination detected a c-kit positive (CD117) pancreatic GIST with high mitotic index. CONCLUSIONS: The most effective treatment method for GISTs is surgical resection. In patients with a head of pancreatic GIST, the Whipple procedure can be used more safely and effectively. PMID- 26237080 TI - Molecular Mechanisms of Alzheimer's Biomarker FDDNP Binding to Abeta Amyloid Fibril. AB - Using isobaric-isothermal replica exchange molecular dynamics and the all-atom explicit water model, we examined the binding of FDDNP biomarkers to the Abeta amyloid fibril fragment. Our results can be summarized as follows. First, FDDNP ligands bind with high affinity to the Abeta fibril, and the hydrophobic effect together with pi-stacking interactions are the dominant factors governing FDDNP binding. In comparison, electrostatic interactions and hydrogen bonding play a minor role. Second, our simulations reveal a strong tendency of bound FDDNP molecules for self-aggregation. Accordingly, about two-thirds of all bound ligands form aggregated clusters of various sizes, and ligand-ligand interactions make considerable contribution to FDDNP binding. Third, FDDNP ligands bind to two distinct sites on the Abeta fibril. Primary binding sites (NT) are located at the N-terminals of Abeta10-40 peptides, whereas secondary ones (CE) occur on the concave fibril edge near fibril channels. The NT sites are characterized by strong hydrophobic and pi-stacking interactions, favorable binding entropy resulting from multiple FDDNP binding orientations and propensity for self aggregation but relatively weak van der Waals interactions. In contrast, the CE sites offer stronger van der Waals binding interactions but weaker hydrophobic and aromatic interactions and less favorable binding entropy. By comparing our data with previous studies, we suggest that the primary binding locations identified by us are likely to occur in other Abeta fibril polymorphic structures. We also show that FDDNP binds via distinct mechanisms to Abeta fibrils and monomers. We argue that FDDNP binds with stronger affinity to benign Abeta monomers than to the fibrils, raising questions about the ability of FDDNP to selectively label amyloid deposits. PMID- 26237081 TI - Tudor Staphylococcal Nuclease plays two antagonistic roles in RNA metabolism under stress. AB - Adaptation to stress entails a repertoire of molecular pathways that remodel the proteome, thereby promoting selective translation of pro-survival proteins. Yet, translation of other proteins, especially those which are harmful for stress adaptation is, on the contrary, transiently suppressed through mRNA decay or storage. Proteome remodeling under stress is intimately associated with the cytoplasmic ribonucleoprotein (RNP) complexes called stress granules (SGs) and processing bodies (PBs). The molecular composition and regulation of SGs and PBs in plants remain largely unknown. Recently, we identified the Arabidopsis Tudor Staphylococcal Nuclease (TSN, Tudor-SN or SND1) as a SG- and PB-associated protein required for mRNA decapping under stress conditions. Here we show that SGs localize in close proximity to PBs within plant cells that enable the exchange of molecular components. Furthermore, we provide a meta-analysis of mRNA degradome of TSN-deficient plants suggesting that TSN might inhibit the degradation of mRNAs which are involved in stress adaptation. Our results establish TSN as a versatile mRNA regulator during stress. PMID- 26237082 TI - Aqueous Flare as an Indicator of Response to Dexamethasone Treatment in Retinal Vein Occlusions: A Pilot Study. AB - PURPOSE: To investigate aqueous flare change patterns in retinal vein occlusions (RVO) following intravitreal application of dexamethasone implant. To evaluate the correlations between central macular thickness (CMT), best corrected visual acuity (BCVA) and aqueous flare values. METHODS: This prospective, interventional pilot study included 40 eyes of 40 patients with macular edema associated with RVO. All patients received intravitreal injection of dexamethasone implant at baseline visit. Full ophthalmologic examination, CMT and aqueous flare measurements were performed prior to injection and repeated at months 1, 3, and 5. Aqueous flare, BCVA and CMT changes between visits were assessed. Further statistical analysis was performed to investigate correlations between these three parameters. RESULTS: The patients consist of 23 (57.5%) men and 17 (42.5%) women with a mean age of 65.7 +/- 6.2 years. Of the 40 eyes, 24 (60%) had branch retinal vein occlusion and 16 (40%) had central retinal vein occlusion. BCVA (log MAR) was significantly correlated with aqueous flare at each visit (r = 0.436, p = 0.005; r = 0.349, p = 0.027; r = 0.357, p = 0.024; r = 0.551, p = 0.000, respectively). Flare values were also correlated with CMT measurements in 3rd and 5th months (r = 0.324, p = 0.042; r = 0.556, p = 0.000, respectively). Comparing the percentage change in CMT and flare values over time, the change in CMT from baseline to 3rd and 5th months (r = 0.441, p = 0.004, r = 0.448, p = 0.004), from 1st month to 3rd and 5th months (r = 0.441, p = 0.004; r = 0.461, p = 0.003) and from 3rd month to 5th month were directly correlated with aqueous flare changes (r = 0.584, p = 0.000). Twenty-two eyes (55%) required second dexamethasone implant application at 5th month. CONCLUSION: Considering the inflammatory base of RVO, dexamethasone implants effectively decreased the flare values in the anterior chamber. The CMT change was directly correlated with aqueous flare values. PMID- 26237083 TI - Predicting postoperative knee flexion during gait of cerebral palsy children. PMID- 26237085 TI - Synthesis and Development of Graphene-Inorganic Semiconductor Nanocomposites. PMID- 26237084 TI - Autophagy of cytoplasmic bulk cargo does not require LC3. AB - To investigate the role of LC3 in bulk autophagy we compared its autophagic lysosomal processing (using an improved quantitative immunoblotting method) with autophagic-lysosomal bulk cargo flux (measured by our established LDH [lactate dehydrogenase] sequestration assay) in amino acid-starved rat hepatocytes treated with cycloheximide to prevent new LC3 influx. Block-release experiments with the reversible autophagy inhibitors 3-methyladenine (3MA) and thapsigargin (TG) showed that while only 3MA suppressed phagophoric LC3 attachment (lipidation), both inhibitors prevented phagophore closure (cargo sequestration). Upon release from closure blockade, some autophagic-lysosomal LC3 flux was resumed even in the presence of 3MA, i.e., without an accompanying bulk cargo flux. Conversely, whereas the autophagic-lysosomal flux of LC3 halted within ~100 min of cycloheximide treatment, the bulk cargo flux continued at a high rate. siRNA mediated knockdown of LC3 family proteins in LNCaP prostate carcinoma cells confirmed that autophagy of cytoplasmic bulk cargo was completely LC3 independent also in these cells, and in the absence of cycloheximide. However, a strong requirement for GABARAP family proteins was evident. Since bulk autophagy of cytoplasm (macroautophagy) and autophagic-lysosomal LC3 processing may apparently be mutually independent, LC3 would seem to be unsuitable as a general indicator of autophagy. PMID- 26237086 TI - The impacts of community social capital on the life satisfaction of older adults in Hong Kong: the moderator role of intergenerational family capital. AB - OBJECTIVE: This study examined the moderator role of intergenerational family capital on the relationship between community social capital and life satisfaction of older Chinese adults. METHOD: The data were derived from a quota sampling of 372 older adults aged 60 and above, who were interviewed at four districts in Hong Kong in 2011. Multiple group analysis was employed to examine the proposed model. RESULTS: For the low family capital group, community social capital was found to be a significant predictor of life satisfaction, even when the well-known covariates were controlled. However, the association between community social capital and life satisfaction was statistically non-significant among the high family capital group. DISCUSSION: The findings highlighted the interplay between community social capital and intergenerational family capital, which supported community social capital replacement theory in understanding the mechanism linking social capital to life satisfaction in older age in a Chinese context. Community social capital can play a compensatory role in maintaining the mental health of older people. It is particularly important for older adults who lack family support and/or suffer from social isolation and loneliness in local communities. PMID- 26237088 TI - What is the recommended size of a Volume of Interest for cancellous bone? A skeleton-based study. PMID- 26237087 TI - Preprophase band formation and cortical division zone establishment: RanGAP behaves differently from microtubules during their band formation. AB - Correct positioning of the division plane is a prerequisite for plant morphogenesis. The preprophase band (PPB) is a key intracellular structure of division site determination. PPB forms in G2 phase as a broad band of microtubules (MTs) that narrows in prophase and specializes few-micrometer-wide cortical belt region, named the cortical division zone (CDZ), in late prophase. The PPB comprises several molecules, some of which act as MT band organization and others remain in the CDZ marking the correct insertion of the cell plate in telophase. Ran GTPase-activating protein (RanGAP) is accumulated in the CDZ and forms a RanGAP band in prophase. However, little is known about when and how RanGAPs gather in the CDZ, and especially with regard to their relationships to MT band formation. Here, we examined the spatial and temporal distribution of RanGAPs and MTs in the preprophase of onion root tip cells using confocal laser scanning microscopy and showed that the RanGAP band appeared in mid-prophase as the width of MT band was reduced to nearly 7 um. Treatments with cytoskeletal inhibitors for 15 min caused thinning or broadening of the MT band but had little effects on RanGAP band in mid-prophase and most of late prophase cells. Detailed image analyses of the spatial distribution of RanGAP band and MT band showed that the RanGAP band positioned slightly beneath the MT band in mid-prophase. These results raise a possibility that RanGAP behaves differently from MTs during their band formation. PMID- 26237089 TI - Copper-Catalyzed Formal [4 + 1] Cycloaddition of Benzamides and Isonitriles via Directed C-H Cleavage. AB - A copper-catalyzed formal [4 + 1] cycloaddition of benzamides and isonitriles via 8-aminoquinoline-directed C-H cleavage has been developed. The reaction proceeds well even in the presence of a base metal catalyst, CuBr.SMe2, alone to deliver the corresponding 3-iminoisoindolinones in good yields. Moreover, the unique acceleration effects of diphenyl sulfide are also disclosed. PMID- 26237090 TI - Wobble<->Watson-Crick tautomeric transitions in the homo-purine DNA mismatches: a key to the intimate mechanisms of the spontaneous transversions. AB - The intrinsic capability of the homo-purine DNA base mispairs to perform wobble< >Watson-Crick/Topal-Fresco tautomeric transitions via the sequential intrapair double proton transfer was discovered for the first time using QM (MP2/DFT) and QTAIM methodologies that are crucial for understanding the microstructural mechanisms of the spontaneous transversions. PMID- 26237091 TI - Redox Control of the Binding Modes of an Organic Receptor. AB - The modulation of noncovalent bonding interactions by redox processes is a central theme in the fundamental understanding of biological systems as well as being ripe for exploitation in supramolecular science. In the context of host guest systems, we demonstrate in this article how the formation of inclusion complexes can be controlled by manipulating the redox potential of a cyclophane. The four-electron reduction of cyclobis(paraquat-p-phenylene) to its neutral form results in altering its binding properties while heralding a significant change in its stereoelectronic behavior. Quantum mechanics calculations provide the energetics for the formation of the inclusion complexes between the cyclophane in its various redox states with a variety of guest molecules, ranging from electron poor to electron-rich. The electron-donating properties displayed by the cyclophane were investigated by probing the interaction of this host with electron-poor guests, and the formation of inclusion complexes was confirmed by single-crystal X-ray diffraction analysis. The dramatic change in the binding mode depending on the redox state of the cyclophane leads to (i) aromatic donor acceptor interactions in its fully oxidized form and (ii) van der Waals interactions when the cyclophane is fully reduced. These findings lay the foundation for the potential use of this class of cyclophane in various arenas, all the way from molecular electronics to catalysis, by virtue of its electronic properties. The extension of the concept presented herein into the realm of mechanically interlocked molecules will lead to the investigation of novel structures with redox control being expressed over the relative geometries of their components. PMID- 26237092 TI - AAID Acknowledges Jack A. Hahn, DDS: A Leader, Educator, and Innovator. PMID- 26237093 TI - Does Abutment Collar Length Affect Abutment Screw Loosening After Cyclic Loading? AB - A significant vertical space that is corrected with vertical ridge augmentation may necessitate selection of longer abutments, which would lead to an increased vertical cantilever. This study investigated the influence of different abutment collar heights on single-unit dental implant screw-loosening after cyclic loading. Fifteen implant-abutment assemblies each consisted of an internal hexagonal implant were randomly assigned to 3 groups: Group1, consisting of 5 abutments with 1.5 mm gingival height (GH); Group2, 5 abutments with 3.5 mm GH; and Group3, 5 abutments with 5.5 mm GH. Each specimen was mounted in transparent auto-polymerizing acrylic resin block, and the abutment screw was tightened to 35 Ncm with an electric torque wrench. After 5 minutes, initial torque loss (ITL) was recorded for all specimens. Metal crowns were fabricated with 45 degrees occlusal surface and were placed on the abutments. A cyclic load of 75 N and frequency of 1 Hz were applied perpendicular to the long axis of each specimen. After 500 000 cycles, secondary torque loss (STL) was recorded. One-way ANOVA analysis was used to evaluate the effects of abutment collar height before and after cyclic loading. One-way ANOVA showed that ITL among the groups was not significantly different (P = .52), while STL was significantly different among the groups (P = .008). Post-hoc Tukey HSD tests showed that STL values were significantly different between the abutments with 1.5 mm GH (Group1) and with 5.5 mm GH (Group3) (P = .007). A paired comparison t-test showed that cyclic loading significantly influenced the STL in comparison with the ITL in each group. Within the limitations of this study, it can be concluded that increase in height of the abutment collar could adversely affect the torque loss of the abutment screw. PMID- 26237094 TI - Body stance influences the visual vertical perception in patients with vestibular disorders. PMID- 26237095 TI - Community Health Needs Assessments: A Framework for America's Hospitals. PMID- 26237096 TI - A case description of speech disturbance and treatment following corrective surgery for stress velopharyngeal incompetence. AB - The purpose of this study was to determine the effectiveness of a motor learning guided (MLG) approach to speech treatment in a unique case of speech disturbance following surgery for stress velopharyngeal incompetence (SVPI). The patient was a 20-year-old female college student. Treatment took place over 6 sessions and focused on eliciting productions through a hierarchy of clinician support, with an emphasis on self-evaluation and -correction. Acoustic measurements and ratings from the treating clinician and unfamiliar listeners revealed a speech disturbance following surgery that was corrected following speech treatment. The patient's main difficulty appeared to be in producing the vocalic/postvocalic approximant, /r/, although vowel distortions were also noted. These difficulties may be explained by the structural alteration and formation of scar tissue as a result of surgery. The results provide initial support for an MLG approach to treating an acquired speech disturbance following SVPI surgery; however, additional research is warranted. PMID- 26237097 TI - The 'timing hypothesis' for estrogen therapy in menopausal symptom management. PMID- 26237098 TI - Analysis of inflammasomes and antiviral sensing components reveals decreased expression of NLRX1 in HIV-positive patients assuming efficient antiretroviral therapy. AB - OBJECTIVE: Few studies have investigated the importance of different components of the inflammasome system and of innate mitochondrial sensing (IMS) pathways in HIV infection and its treatment. We analysed the expression of several components of the inflammasome and of the IMS in HIV-positive patients taking successful combination antiretroviral therapy (cART). METHODS: We enrolled 20 HIV-positive patients under cART, who achieved viral suppression since at least 10 months and 20 age and sex-matched healthy donors. By RT-PCR, using peripheral blood mononuclear cells (PBMCs), we quantified the mRNA expression of 16 genes involved in inflammasome activation and regulation (AIM2, NAIP, PYCARD, CASP1, CASP5, NLRP6, NLRP1, NLRP3, TXNIP, BCL2, NLRC4, PANX1, P2RX7, IL-18, IL-1beta, SUGT1) and eight genes involved in IMS (MFN2, MFN1, cGAS, RIG-I, MAVS, NLRX1, RAB32, STING). RESULTS: Compared with controls, HIV-positive patients showed significantly lower mRNA levels of the mitochondrial protein NLRX1, which plays a key role in regulating apoptotic cell death; main PBMC subpopulations behave in a similar manner. No differences were observed in the expression of inflammasome components, which however showed complex correlations. CONCLUSION: The decreased level of NLRX1 in HIV infection could suggest that the virus is able to downregulate mechanisms linked to triggering of cell death in several immune cell types. The fact that HIV-positive patients did not show altered expression of inflammasome components, nor of most genes involved in IMS, suggests that the infection and/or the chronic immune activation does not influence the transcriptional machinery of innate mechanisms able to trigger inflammation at different levels. PMID- 26237100 TI - Atypical symptoms of acute retroviral syndrome seen in one-third of patients with primary HIV infection. PMID- 26237099 TI - A 15-year study of the impact of community antiretroviral therapy coverage on HIV incidence in Kenyan female sex workers. AB - OBJECTIVE: To test the hypothesis that increasing community antiretroviral therapy (ART) coverage would be associated with lower HIV incidence in female sex workers (FSWs) in Mombasa District, Kenya. DESIGN: Prospective cohort study. METHODS: From 1998 to 2012, HIV-negative FSWs were asked to return monthly for an interview regarding risk behavior and testing for sexually transmitted infections including HIV. We evaluated the association between community ART coverage and FSW's risk of becoming HIV infected using Cox proportional hazards models adjusted for potential confounding factors. RESULTS: One thousand, four hundred and four FSWs contributed 4335 woman-years of follow-up, with 145 acquiring HIV infection (incidence 3.35/100 woman-years). The ART rollout began in 2003. By 2012, an estimated 52% of HIV-positive individuals were receiving treatment. Community ART coverage was inversely associated with HIV incidence (adjusted hazard ratio 0.77; 95% confidence interval 0.61-0.98; P = 0.03), suggesting that each 10% increase in coverage was associated with a 23% reduction in FSWs' risk of HIV acquisition. Community ART coverage had no impact on herpes simplex virus type-2 incidence (adjusted hazard ratio 0.97; 95% confidence interval 0.79-1.20; P = 0.8). CONCLUSION: Increasing general population ART coverage was associated with lower HIV incidence in FSWs. The association with HIV incidence, but not herpes simplex virus type-2 incidence, suggests that the effect of community ART coverage may be specific to HIV. Interventions such as preexposure prophylaxis and antiretroviral-containing microbicides have produced disappointing results in HIV prevention trials with FSWs. These results suggest that FSWs' risk of acquiring HIV infection might be reduced through the indirect approach of increasing ART coverage in the community. PMID- 26237101 TI - Population-based analysis of HIV-1 antibodies reveals structural constraints that may inform vaccine design. PMID- 26237102 TI - CD8+ T-memory stem cells maintain the capacity for a cellular immune response against HIV-1 in patients on suppressive antiretroviral therapy. PMID- 26237103 TI - Heterotrimeric G protein subunits differentially respond to endoplasmic reticulum stress in Arabidopsis. AB - Canonical heterotrimeric G proteins in eukaryotes are major components that localize at plasma membrane and transmit extracellular stimuli into the cell. Genome of a seed plant Arabidopsis thaliana encodes at least one Galpha (GPA1), one Gbeta (AGB1), and 3 Ggamma (AGG1, AGG2 and AGG3) subunits. The loss-of function mutations of G protein subunit(s) cause multiple defects in development as well as biotic and abiotic stress responses. However, it remains elusive how these subunits differentially express these defects. Here, we report that Arabidopsis heterotrimeric G protein subunits differentially respond to the endoplasmic reticulum (ER) stress. An isolated homozygous mutant of AGB1, agb1-3, was more sensitive to the tunicamycin-induced ER stress compared to the wild type and the other loss-of-function mutants of G protein subunits. Moreover, ER stress responsive genes were highly expressed in the agb1-3 plant. Our results indicate that AGB1 positively contributes to ER stress tolerance in Arabidopsis. PMID- 26237104 TI - Three-dimensional appearance of apophyseal joint ankylosis. PMID- 26237106 TI - Mouse Polyomavirus: Propagation, Purification, Quantification, and Storage. AB - Mouse polyomavirus (MPyV) is a member of the Polyomaviridae family, which comprises non-enveloped tumorigenic viruses infecting various vertebrates including humans and causing different pathogenic responses in the infected organisms. Despite the variations in host tropism and pathogenicity, the structure of the virions of these viruses is similar. The capsid, with icosahedral symmetry (o, 45 nm, T = 7d), is composed of a shell of 72 capsomeres of structural proteins, arranged around the nucleocore containing approximately 5 kbp-long circular dsDNA in complex with cellular histones. MPyV has been one of the most studied polyomaviruses and serves as a model virus for studies of the mechanisms of cell transformation and virus trafficking, and for use in nanotechnology. It can be propagated in primary mouse cells (e.g., in whole mouse embryo cells) or in mouse epithelial or fibroblast cell lines. In this unit, propagation, purification, quantification, and storage of MPyV virions are presented. PMID- 26237107 TI - In Vitro Replication Assay for Merkel Cell Polyomavirus (MCPyV). AB - Merkel cell polyomavirus (MCPyV) genomes are clonally integrated in tumor cells of ~95% of all Merkel cell carcinoma (MCC) cases. The virus is highly prevalent; however, where the virus persists and which cell types are permissive for MCPyV replication is still unknown. As a consequence, very little information is available about the life cycle and no fully permissive in vitro replication system has been established. Recently, semi-permissive replication systems based on wild-type MCPyV genomes recovered from the skin of healthy donors or synthetic MCPyV genomes constructed from consensus sequences have been established. The transfection of this intramolecular re-circularized MCPyV DNA into some human cell lines recapitulates efficient DNA replication of the viral genome, viral gene expression as well as moderate levels of virus particle formation. However, serial transmission of infectious virus is still restricted in these cells. PMID- 26237105 TI - Production of Furin-Cleaved Papillomavirus Pseudovirions and Their Use for In Vitro Neutralization Assays of L1- or L2-Specific Antibodies. AB - Immunization with Human Papillomavirus (HPV) L1 virus-like particles or L2 capsid protein elicits neutralizing antibodies that mediate protection. A high throughput and sensitive in vitro neutralization assay is therefore valuable for prophylactic HPV vaccine studies. Over several hours during infection of the genital tract, virions take on a distinct intermediate conformation, including a required furin cleavage of L2 at its N-terminus. This intermediate is an important target for neutralization by L2-specific antibody, but it is very transiently exposed during in vitro infection of most cell lines resulting in insensitive measurement for L2, but not L1-specific neutralizing antibodies. To model this intermediate, we describe a protocol to generate furin-cleaved HPV pseudovirions (fc-PsV), which deliver an encapsidated reporter plasmid to facilitate infectivity measurements. We also describe a protocol for use of fc PsV in a high-throughput in vitro neutralization assay for the sensitive measurement of both L1 and L2-specific neutralizing antibodies. PMID- 26237108 TI - Detection and Isolation of Epichloe Species, Fungal Endophytes of Grasses. AB - Epichloe species (including former Neotyphodium species) are endophytic fungi that significantly affect fitness of cool-season grass hosts, potentially by increasing nutrient uptake and resistance to drought, parasitism and herbivory. Epichloe species are obligately biotrophic, living in the intercellular spaces of their plant hosts, and spreading systemically throughout host aerial tissues. The reproduction of Epichloe species is versatile; some strains have both sexual and asexual modes of reproduction, but others are restricted to one or the other mode. The reproduction mode determines the dissemination mechanism, and the asexual species most important to agriculture are strictly seed-borne, cause no signs or symptoms, and are undetectable except by specialized microscopic, molecular or antigenic procedures. These procedures can be used to identify endophytes in a variety of plant tissues. Similar protocols can be modified to detect less common symbionts, such as the penicillate "p-endophytes," when they occur by themselves or together with Epichloe species. PMID- 26237109 TI - Infant Rabbit Model for Diarrheal Diseases. AB - Vibrio cholerae is the agent of cholera, a potentially lethal diarrheal disease that remains a significant threat to populations in developing nations. The infant rabbit model of cholera is the only non-surgical small animal model system that closely mimics human cholera. Following orogastric inoculation, V. cholerae colonizes the intestines of infant rabbits, and the animals develop severe cholera-like diarrhea. In this unit, we provide a detailed description of the preparation of the V. cholerae inoculum, the inoculation process and the collection and processing of tissue samples. This infection model is useful for studies of V. cholerae factors and mechanisms that promote its intestinal colonization and enterotoxicity, as well as the host response to infection. The infant rabbit model of cholera enables investigations that will further our understanding of the pathophysiology of cholera and provides a platform for testing new therapeutics. PMID- 26237111 TI - Assistive technologies for self-managed pressure ulcer prevention in spinal cord injury: a scoping review. AB - Pressure ulcers (PUs) in individuals with spinal cord injury (SCI) present a persistent and costly problem. Continuing effort in developing new technologies that support self-managed care is an important prevention strategy. Specifically, the aims of this scoping review are to review the key concepts and factors related to self-managed prevention of PUs in individuals with SCI and appraise the technologies available to assist patients in self-management of PU prevention practices. There is broad consensus that sustaining long-term adherence to prevention regimens is a major concern. Recent literature highlights the interactions between behavioral and physiological risk factors. We identify four technology categories that support self-management: computer-based educational technologies demonstrated improved short-term gains in knowledge (2 studies), interface pressure mapping technologies demonstrated improved adherence to pressure-relief schedules up to 3 mo (5 studies), electrical stimulation confirmed improvements in tissue tolerance after 8 wk of training (3 studies), and telemedicine programs demonstrated improvements in independence and reduced hospital visits over 6 mo (2 studies). Overall, self-management technologies demonstrated low-to-moderate effectiveness in addressing a subset of risk factors. However, the effectiveness of technologies in preventing PUs is limited due to a lack of incidence reporting. In light of the key findings, we recommend developing integrated technologies that address multiple risk factors. PMID- 26237110 TI - Selections that isolate recombinant mitochondrial genomes in animals. AB - Homologous recombination is widespread and catalyzes evolution. Nonetheless, its existence in animal mitochondrial DNA is questioned. We designed selections for recombination between co-resident mitochondrial genomes in various heteroplasmic Drosophila lines. In four experimental settings, recombinant genomes became the sole or dominant genome in the progeny. Thus, selection uncovers occurrence of homologous recombination in Drosophila mtDNA and documents its functional benefit. Double-strand breaks enhanced recombination in the germline and revealed somatic recombination. When the recombination partner was a diverged Drosophila melanogaster genome or a genome from a different species such as Drosophila yakuba, sequencing revealed long continuous stretches of exchange. In addition, the distribution of sequence polymorphisms in recombinants allowed us to map a selected trait to a particular region in the Drosophila mitochondrial genome. Thus, recombination can be harnessed to dissect function and evolution of mitochondrial genome. PMID- 26237112 TI - Weight loss outcomes in patients with pain. AB - OBJECTIVE: To determine whether the presence or severity of pain is predictive of suboptimal weight loss outcomes in behavioral weight management programs. METHODS: This is a secondary data analysis comparing weight loss among participants with overweight/obesity who participated in a 12-month randomized controlled trial. Of the 481 participants randomized, 394 (81.9%) had available pain data and were categorized by Pain Type (back pain, arthritis pain, both, or neither) and Pain Severity (no pain, moderate pain, or severe pain). Dietary and physical activity outcomes were also explored. RESULTS: High rates of moderate and severe (80.2%), and back and arthritis (72.6%), pain were observed. Linear mixed models showed significant differences in % weight loss among Pain Severity, but not Pain Type, groups. Patients with severe pain lost significantly less weight (-0.1 kg, 95% CI = -1.5, -1.2) compared to those with either moderate or no pain (-1.9 kg, 95% CI = -2.5, -1.3; -2.1 kg, 95% CI = -3.3, -1.0, respectively). Patients with arthritis pain lost a significant amount of weight despite only minor improvements in walking distance. CONCLUSIONS: Pain severity, but not pain type, is predictive of suboptimal weight loss outcomes. PMID- 26237113 TI - Liquid chromatography enantioseparations of halogenated compounds on polysaccharide-based chiral stationary phases: role of halogen substituents in molecular recognition. AB - Halogenated chiral molecules have become important in several fields of science, industry, and society as drugs, natural compounds, agrochemicals, environmental pollutants, synthetic products, and chiral supports. Meanwhile, the perception of the halogen moiety in organic compounds and its role in recognition processes changed. Indeed, the recognition of the halogen bond as an intermolecular interaction occurring when the halogen acts as a Lewis acid had a strong impact, particularly in crystal engineering and medicinal chemistry. Due to this renewed interest in the potentialities of chiral organohalogens, here we focus on selected recent applications dealing with enantioseparations of halogenated compounds on polysaccharide-based chiral stationary phases (CSPs), widely used in liquid chromatography (LC). In particular, recently the first case of halogen bonding-driven high-performance LC (HPLC) enantioseparation was reported on a cellulose-based CSP. Along with enantioseparations performed under conventional HPLC, representative applications using supercritical fluid chromatography (SFC) are reported. PMID- 26237114 TI - Emergence of Metallic Properties at LiFePO4 Surfaces and LiFePO4/Li2S Interfaces: An Ab Initio Study. AB - The atomic and electronic structures of the LiFePO4 (LFP) surface, both bare and reconstructed upon possible oxygenation, are theoretically studied by ab initio methods. On the basis of total energy calculations, the atomic structure of the oxygenated surface is proposed, and the effect of surface reconstruction on the electronic properties of the surface is clarified. While bare LFP(010) surface is insulating, adsorption of oxygen leads to the emergence of semimetallic behavior by inducing the conducting states in the band gap of the system. The physical origin of these conducting states is investigated. We further demonstrate that deposition of Li2S layers on top of oxygenated LFP(010) surface leads to the formation of additional conducting hole states in the first layer of Li2S surface because of the charge transfer from sulfur p-states to the gap states of LFP surface. This demonstrates that oxygenated LFP surface not only provides conducting layers itself, but also induces conducting channels in the top layer of Li2S. These results help to achieve further understanding of potential role of LFP particles in improving the performance of Li-S batteries through emergent interface conductivity. PMID- 26237115 TI - Formation of C(sp(2))-boronate esters by borylative cyclization of alkynes using BCl3. AB - BCl3 is an inexpensive electrophile which induces the borylative cyclization of a wide range of substituted alkynes to regioselectively form polycycles containing synthetically versatile C(sp(2) )?boronate esters. It proceeds rapidly, with good yields and is compatible with a range of functional groups and substitution patterns. Intermolecular 1,2-carboboration of alkynes is also achieved using BCl3 to generate trisubstituted vinyl boronate esters. PMID- 26237116 TI - External locus of control contributes to racial disparities in memory and reasoning training gains in ACTIVE. AB - Racial disparities in cognitive outcomes may be partly explained by differences in locus of control. African Americans report more external locus of control than non-Hispanic Whites, and external locus of control is associated with poorer health and cognition. The aims of this study were to compare cognitive training gains between African American and non-Hispanic White participants in the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study and determine whether racial differences in training gains are mediated by locus of control. The sample comprised 2,062 (26% African American) adults aged 65 and older who participated in memory, reasoning, or speed training. Latent growth curve models evaluated predictors of 10-year cognitive trajectories separately by training group. Multiple group modeling examined associations between training gains and locus of control across racial groups. Compared to non-Hispanic Whites, African Americans evidenced less improvement in memory and reasoning performance after training. These effects were partially mediated by locus of control, controlling for age, sex, education, health, depression, testing site, and initial cognitive ability. African Americans reported more external locus of control, which was associated with smaller training gains. External locus of control also had a stronger negative association with reasoning training gain for African Americans than for Whites. No racial difference in training gain was identified for speed training. Future intervention research with African Americans should test whether explicitly targeting external locus of control leads to greater cognitive improvement following cognitive training. PMID- 26237117 TI - Comparison of secondhand smoke exposure in minority and nonminority children with asthma. AB - OBJECTIVE: This study determined if secondhand smoke (SHS) exposure is related to asthma-related functional morbidity by examining racial/ethnic differences in non Latino White (NLW), African American, and Latino families and whether racial/ethnic SHS exposure differences across families persist when accounting for smoking factors. METHODS: Participants were 305 caregiver smokers of children with asthma. Two passive dosimeters measured secondhand smoke: one in the home and one worn by the child. RESULTS: Higher SHS exposure was related to greater asthma-related functional morbidity. African Americans had higher levels of home SHS exposure than did Latinos (p = .003) or NLWs (p = .021). SHS exposure as assessed by the child-worn dosimeter did not differ across race/ethnicity. African American families were less likely to report a household smoking ban (46.4%) compared to Latinos (79.2%) and NLWs (67.9%; p < .05). African Americans were less likely to report having two or more smokers in the home (37.2%) compared to NLWs (53.6%; p < .05). NLWs reported the highest number of cigarettes smoked daily (Mdn = 15.00) compared to Latinos (Mdn = 10.00; p = .001) and African Americans (Mdn = 10.00; p < .001). SHS home exposure levels were regressed on race/ethnicity and relevant covariates. Household smoking ban (p < .001) and only one smoker in the home (p = .005) were associated with lower levels of SHS in the home; race/ethnicity was not significant. CONCLUSIONS: Differences in SHS exposure across race/ethnicity exist among children with asthma, possibly due to differential presence of a household smoking ban and number of smokers in the home. PMID- 26237118 TI - Kinetic and Structural Characterization of the Interaction of 6-Methylidene Penem 2 with the beta-Lactamase from Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis is intrinsically resistant to most beta-lactam antibiotics because of the constitutive expression of the blaC-encoded beta lactamase. This enzyme has extremely high activity against penicillins and cephalosporins, but weaker activity against carbapenems. The enzyme can be inhibited by clavulanate, avibactam, and boronic acids. In this study, we investigated the ability of 6-methylidene beta-lactams to inhibit BlaC. One such compound, penem 2, inhibited BlaC more than 70 times more efficiently than clavulanate. The compound forms a covalent complex with BlaC as shown by mass spectrometry. Crystallization of the complex revealed that the bound inhibitor was covalently attached via the Ser70 active site residue and that the covalently, acylated form of the inhibitor had undergone additional chemistry yielding a 4,7-thiazepine ring in place of the beta-lactam and a thiazapyroline ring generated as a result of beta-lactam ring opening. The stereochemistry of the product of the 7-endo-trig cyclization was the opposite of that observed previously for class A and D beta-lactamases. Addition of penem 2 greatly synergized the antibacterial properties of both ampicillin and meropenem against a growing culture of M. tuberculosis. Strikingly, penem 2 alone showed significant growth inhibition, suggesting that in addition to its capability of efficiently inhibiting BlaC, it also inhibited the peptidoglycan cross-linking transpeptidases. PMID- 26237119 TI - De novo protein design as a methodology for synthetic bioinorganic chemistry. AB - The major advances in molecular and structural biology and automated peptide and DNA synthesis of the 1970s and 1980s generated fertile conditions in the 1990s for the exploration of designed proteins as a new approach for inorganic chemists to generate biomolecular mimics of metalloproteins. This Account follows the development of the TRI peptide family of three-stranded coiled coils (3SCC) and alpha3D family of three-helix bundles (3HB) as scaffolds for the preparation of metal binding sites within de novo designed constructs. The 3SCC were developed using the concept of a heptad repeat (abcdefg) putting hydrophobes in the a and d positions. The TRI peptides contain four heptads with capping glycines. Via substitution of leucine hydrophobes, metal ligands can be introduced into the a or d sites in order to bind metals. First, the ability to use cysteine substituted 3SCC aggregates to impose higher or lower coordination numbers on Hg(II) and Cd(II) or matching the coordination preferences of As(III) and Pb(II) is discussed. Then, methods to develop dual site peptides capable of discriminating metals based on their type (e.g., Cd(II) vs Pb(II)), their preference for a vs d sites, and then their coordination number is described. Once these principles of metal site differentiation are described, we shift to building dual site peptides using both cysteine and histidine metal binding sites. This approach provides a construct with both a Hg(II) structural and a Zn(II) hydrolytic center, the latter of which is capable of hydrating CO2. With these Zn(II) proteins, we consider the relative importance of the location of the catalytic center along the primary sequence of the peptide and show that only minor perturbations in catalytic efficiencies are observed based on metal location. We then assess the feasibility of preparing enzymes competent to reduce nitrite with copper centers in a histidine-rich environment. As part of this discussion, we examine the influence of surface residues on catalyst reduction potentials and catalytic efficiencies. We end describing approaches to prepare asymmetric proteins that can incorporate acid-base catalysts or water channels. In this respect, we highlight modifications of a helix-turn-helix-turn-helix motif called alpha3D and show how this 3HB can be modified to bind heavy metals or to make Zn(II) centers, which are active hydrolytic catalysts. A comparison is made to the comparable parallel 3SCC. PMID- 26237120 TI - Independent Control of Optical and Explosive Properties: Pyrazole-Tetrazine Complexes of First Row Transition Metals. AB - Complexes of 3-amino-6-(3,5-dimethylpyrazole)tetrazine) (NH2TzDMP, 1) and 3-(3,3' dinitroazetidine)-6-(3,5-dimethylpyrazole)tetrazine) (DNAZTzDMP, 2) with first row transition metal centers were synthesized. Reactions of Fe(II)(H2O)6(BF4)2 and Fe(NO3)3.9H2O with 1 and 2 both led to complexes of the form [(RTzDMP)3Fe]X2 (X = BF4, R = NH2 (3), DNAZ (4); X = NO3, R = NH2 (5), DNAZ (6)), which showed intense MLCT bands in the visible region of the spectrum. Ligands 1 and 2 also reacted with Cu(II)(NO3)2.5/2H2O to form [(RTzDMP)2Cu(NO3)][NO3] (R = NH2 (7), DNAZ (8)) in addition to reacting with Cu(I)(CH3CN)4(PF6) to form [(RTzDMP)2Cu][PF6] (R = NH2 (9), DNAZ (10)). Lastly reactions of 1 and 2 with Co(NO3)2.6H2O and Ni(NO3)2.6H2O led to [(NH2TzDMP)2Co(H2O) (NO3)][NO3] (11), [(DNAZTzDMP)2Co(H2O)2][NO3]2 (12), [(NH2TzDMP)3Ni][NO3]2 (13), and [(DNAZTzDMP)2Ni(H2O)2][NO3]2 (14). The complexes display rich electrochemical and photophysical properties that are unaffected by derivation with explosive groups. PMID- 26237121 TI - Food Byproducts as a New and Cheap Source of Bioactive Compounds: Lignans with Antioxidant and Anti-inflammatory Properties from Crataegus pinnatifida Seeds. AB - During the process of manufacturing hawthorn (Crataegus pinnatifida) juice and jam, a significant quantity of byproducts (leaves, seeds) is generated. The antioxidant and anti-inflammatory bioassay-guided fractionation of the extract of hawthorn seeds has led to the isolation of eight new lignans, hawthornnins A-H (1 8), and seven known analogues (9-15). Their structures were elucidated by spectroscopic techniques, including 1D and 2D NMR and CD spectra. The radical scavenging effects of all isolated compounds were investigated. 1-6 and 8 showed moderate activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH), whereas 1-6 and 14 displayed good 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) free radical-scavenging activities that were even more potent than that of trolox. In addition, all isolates were evaluated for their anti-inflammatory activities by detecting the nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) production by the LPS-induced murine macrophage cell line RAW264.7, and compounds 1-7, 13, and 14 exhibited potent inhibition of NO and TNF-alpha production. The structure-activity relationships of isolated lignans were also examined, and the results obtained show that C. pinnatifida seeds can be regarded as a potential new and cheap source of antioxidants and inflammation inhibitors. PMID- 26237122 TI - Dual signaling molecule sensor for rapid detection of hydrogen sulfide based on modified tetraphenylethylene. AB - A dual signaling molecule sensor has received increasing attention owing to its ability to read out target analytes with more than one transduction channel and thus make the results more convincing. Here we have developed a dual signaling molecule sensor that is well suited for monitoring hydrogen sulfide (H2S) levels through fluorescence, UV-visible adsorption, and visual mode. Results showed the selective and instantaneous responses of sensor toward intracellular H2S. Moreover, the sensor was successfully applied to imaging of H2S levels in Caenorhabditis elegans (C. elegans) and observed the changes of H2S under starvation of C. elegans. Altogether, the sensor was proved to be a useful tool for tracking H2S levels in cells and in vivo. The merits of two kinds of independent signaling molecules allow us to select different output modes according to the different samples. PMID- 26237123 TI - Retraction: An actin-dependent spindle position checkpoint ensures the asymmetric division in mouse oocytes. PMID- 26237124 TI - Corrigendum: Epidermal growth factor receptor subunit locations determined in hydrated cells with environmental scanning electron microscopy. PMID- 26237125 TI - Fast and long-range triplet exciton diffusion in metal-organic frameworks for photon upconversion at ultralow excitation power. AB - The conversion of low-energy light into photons of higher energy based on sensitized triplet-triplet annihilation upconversion (TTA-UC) has emerged as a promising wavelength-shifting methodology because it permits UC at excitation powers as low as the solar irradiance. However, its application has been significantly hampered by the slow diffusion of excited molecules in solid matrices. Here, we introduce metal-organic frameworks (MOFs) that promote TTA-UC by taking advantage of triplet exciton migration among fluorophores that are regularly aligned with spatially controlled chromophore orientations. We synthesized anthracene-containing MOFs with different molecular orientations, and the analysis of TTA-UC emission kinetics unveiled a high triplet diffusion rate with a micrometre-scale diffusion length. Surface modification of MOF nanocrystals with donor molecules and their encapsulation in glassy poly(methyl methacrylate) (PMMA) allowed the construction of molecular-diffusion-free solid state upconverters, which lead to an unprecedented maximization of overall UC quantum yield at excitation powers comparable to or well below the solar irradiance. PMID- 26237126 TI - Metal-organic frameworks: Framing upconversion materials. PMID- 26237127 TI - Epitaxial growth of two-dimensional stanene. AB - Following the first experimental realization of graphene, other ultrathin materials with unprecedented electronic properties have been explored, with particular attention given to the heavy group-IV elements Si, Ge and Sn. Two dimensional buckled Si-based silicene has been recently realized by molecular beam epitaxy growth, whereas Ge-based germanene was obtained by molecular beam epitaxy and mechanical exfoliation. However, the synthesis of Sn-based stanene has proved challenging so far. Here, we report the successful fabrication of 2D stanene by molecular beam epitaxy, confirmed by atomic and electronic characterization using scanning tunnelling microscopy and angle-resolved photoemission spectroscopy, in combination with first-principles calculations. The synthesis of stanene and its derivatives will stimulate further experimental investigation of their theoretically predicted properties, such as a 2D topological insulating behaviour with a very large bandgap, and the capability to support enhanced thermoelectric performance, topological superconductivity and the near-room-temperature quantum anomalous Hall effect. PMID- 26237128 TI - Nanocapillarity-mediated magnetic assembly of nanoparticles into ultraflexible filaments and reconfigurable networks. AB - The fabrication of multifunctional materials with tunable structure and properties requires programmed binding of their building blocks. For example, particles organized in long-ranged structures by external fields can be bound permanently into stiff chains through electrostatic or van der Waals attraction, or into flexible chains through soft molecular linkers such as surface-grafted DNA or polymers. Here, we show that capillarity-mediated binding between magnetic nanoparticles coated with a liquid lipid shell can be used for the assembly of ultraflexible microfilaments and network structures. These filaments can be magnetically regenerated on mechanical damage, owing to the fluidity of the capillary bridges between nanoparticles and their reversible binding on contact. Nanocapillary forces offer opportunities for assembling dynamically reconfigurable multifunctional materials that could find applications as micromanipulators, microbots with ultrasoft joints, or magnetically self repairing gels. PMID- 26237130 TI - Erratum: A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer. PMID- 26237131 TI - One-Pot Synthesis of Carbon Nanofibers from CO2. AB - Carbon nanofibers, CNFs, due to their superior strength, conductivity, flexibility, and durability have great potential as a material resource but still have limited use due to the cost intensive complexities of their synthesis. Herein, we report the high-yield and scalable electrolytic conversion of atmospheric CO2 dissolved in molten carbonates into CNFs. It is demonstrated that the conversion of CO2 -> CCNF + O2 can be driven by efficient solar, as well as conventional, energy at inexpensive steel or nickel electrodes. The structure is tuned by controlling the electrolysis conditions, such as the addition of trace transition metals to act as CNF nucleation sites, the addition of zinc as an initiator and the control of current density. A less expensive source of CNFs will facilitate its adoption as a societal resource, and using carbon dioxide as a reactant to generate a value added product such as CNFs provides impetus to consume this greenhouse gas to mitigate climate change. PMID- 26237129 TI - Unjamming and cell shape in the asthmatic airway epithelium. AB - From coffee beans flowing in a chute to cells remodelling in a living tissue, a wide variety of close-packed collective systems-both inert and living-have the potential to jam. The collective can sometimes flow like a fluid or jam and rigidify like a solid. The unjammed-to-jammed transition remains poorly understood, however, and structural properties characterizing these phases remain unknown. Using primary human bronchial epithelial cells, we show that the jamming transition in asthma is linked to cell shape, thus establishing in that system a structural criterion for cell jamming. Surprisingly, the collapse of critical scaling predicts a counter-intuitive relationship between jamming, cell shape and cell-cell adhesive stresses that is borne out by direct experimental observations. Cell shape thus provides a rigorous structural signature for classification and investigation of bronchial epithelial layer jamming in asthma, and potentially in any process in disease or development in which epithelial dynamics play a prominent role. PMID- 26237132 TI - Pharmacokinetic and Other Considerations for Drug Therapy During Targeted Temperature Management. AB - OBJECTIVE: To synthesize an emerging body of literature describing pharmacokinetic alterations and related pharmacodynamic implications affecting drugs commonly used in patients receiving targeted temperature management following cardiac arrest. DATA SOURCES: Peer-reviewed articles indexed in PubMed. STUDY SELECTION: A systematic search of the PubMed database for relevant preclinical studies and clinical and observational trials of physiologic changes and drug pharmacokinetic and pharmacodynamic alterations, especially during targeted temperature management/therapeutic hypothermia, but also from cardiac surgery and acute stroke hypothermia models. DATA EXTRACTION: Detailed review of information contained in published scientific work. DATA SYNTHESIS: Physiologic changes during targeted temperature management significantly alter both the pharmacokinetic and the pharmacodynamic parameters of medications. Current literature describes these alterations and provides practical considerations for management of medications. Medication selection should center on the pharmacokinetics and pharmacodynamics of agents in an attempt to ameliorate potential adverse effects. CONCLUSIONS: This review provides an overview of physiologic changes associated with targeted temperature management and practical considerations for the management of medications. Clinicians should understand and anticipate potential drug-therapy interactions of targeted temperature management and mitigate adverse outcomes by appropriate medication selection, dosing, and monitoring. We discuss complications of hypothermia including shivering, electrolyte abnormalities, hemodynamic changes, arrhythmias, and seizures. We review management of these complications as well as considerations for sedation, analgesia, anticoagulation, and prognostication. Approach to interpretation of the clinical significance of drug interactions during targeted temperature management therapy is also addressed. PMID- 26237133 TI - Prevalence and Risk Factors of Stress Cardiomyopathy After Convulsive Status Epilepticus in ICU Patients. AB - OBJECTIVE: Although stress cardiomyopathy has been described in association with epilepsy, its frequency in patients with convulsive status epilepticus remains unknown. Accordingly, we sought to determine the prevalence and risk factors of stress cardiomyopathy in patients admitted to the ICU for convulsive status epilepticus. DESIGN: Prospective, descriptive, single-center study. SETTING: Medical-surgical ICU of a teaching hospital. PATIENTS: Thirty-two consecutive ventilated patients (21 men; age, 50 +/- 18 yr; Simplified Acute Physiology Score II, 53 +/- 15; Sequential Organ Failure Assessment, 6 +/- 2) hospitalized in the ICU for convulsive status epilepticus. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hemodynamic parameters, transthoracic echocardiography, biological data, and electrocardiogram were obtained serially on ICU admission (H0), and after 6, 12, 24, and 48 hours of hospitalization (H6, H12, H24, and H48). Stress cardiomyopathy was defined as a 20% decrease in left ventricular ejection fraction between H0 or H6 and H48. Stress cardiomyopathy was diagnosed in 18 patients (56%; 95% CI, 38-74%). Mean left ventricular ejection fraction, left ventricular stroke index and cardiac index were initially (at H0 or H6 according to lowest individual values) significantly reduced in stress cardiomyopathy patients (45 +/- 14% vs 61 +/- 6%, p < 0.001; 24 +/- 8 vs 28 +/- 8 mL/m(2), p < 0.05; 2.3 +/- 0.7 vs 3.0 +/- 0.8 L/min/m(2), p < 0.05, respectively) and increased secondarily to reach similar mean values than those observed in patients without transient left ventricular dysfunction at H24. Dobutamine was more frequently used in patients with stress cardiomyopathy. Mean lactate level was increased and significantly higher in stress cardiomyopathy patients at H0 and H6, whereas mean central venous oxygen saturation was preserved but significantly lower in this group. Only three patients with stress cardiomyopathy had left ventricular regional wall motion abnormalities but normal coronary angiography. Risk factors of stress cardiomyopathy were age and Simplified Acute Physiology Score II. CONCLUSIONS: These results suggest that stress cardiomyopathy is common in patients admitted to the ICU for convulsive status epilepticus. Accordingly, these patients should be screened for stress cardiomyopathy and monitored if they present with hemodynamic compromise. PMID- 26237135 TI - Correspondence. PMID- 26237136 TI - RESOLUTION OF A GIANT PIGMENT EPITHELIAL DETACHMENT WITH HALF-DOSE AFLIBERCEPT. AB - PURPOSE: To describe the use of half-dose anti-vascular endothelial growth factor therapy in a patient with giant pigment epithelial detachments. METHODS: Observational case report. A 76-year-old woman with neovascular age-related macular degeneration presented with massive bilateral pigment epithelial detachments measuring over 1000 MUm in height. Her right eye was treated with standard-dose aflibercept, which led to two large retinal pigment epithelium tears. Treatment of the left eye with half-dose aflibercept led to complete resolution of the detachment without tear formation. RESULTS: Half-dose anti vascular endothelial growth factor therapy resulted in resolution of a giant pigment epithelial detachment ~1500 MUm in maximal height and 10 mm in diameter. CONCLUSION: Reduced-dose anti-vascular endothelial growth factor therapy may be considered as a treatment option for very large pigment epithelial detachments at high risk for retinal pigment epithelium tear formation. PMID- 26237134 TI - Mental Health and Exposure to the United States: Key Correlates from the Hispanic Community Health Study of Latinos. AB - We examined the association between exposure to the U.S. and symptoms of poor mental health among adult Hispanic/Latinos (N = 15,004) overall and by Hispanic/Latino background. Using data from the Hispanic Community Health Study of Latinos (HCHS/SOL), we estimated logistic regressions to model the risk of moderate to severe symptoms of psychological distress, depression, and anxiety as a function of years in the U.S. and six key psychosocial risk and protective factors. In unadjusted models, increased time in the U.S. was associated with higher risk of poor mental health. After adjustment for just three key factors- perceived discrimination, perceived U.S. social standing, and the size of close social networks--differences in the odds of poor mental health by years in the U.S became insignificant for Hispanics/Latinos overall. However, analyses by Hispanic/Latino background revealed different patterns of association with exposure to the U.S. that could not be fully explained. PMID- 26237137 TI - MULTIMODAL IMAGING OF SYPHILITIC MULTIFOCAL RETINITIS. AB - PURPOSE: To describe multimodal imaging of syphilitic multifocal retinitis. METHODS: Observational case series. RESULTS: Two patients developed multifocal retinitis after treatment of unrecognized syphilitic uveitis with systemic corticosteroids in the absence of appropriate antibiotic therapy. Multimodal imaging localized the foci of retinitis within the retina in contrast to superficial retinal precipitates that accumulate on the surface of the retina in eyes with untreated syphilitic uveitis. Although the retinitis resolved after treatment with systemic penicillin in both cases, vision remained poor in the patient with multifocal retinitis involving the macula. CONCLUSION: Treatment of unrecognized syphilitic uveitis with corticosteroids in the absence of antitreponemal treatment can lead to the development of multifocal retinitis. Multimodal imaging, and optical coherence tomography in particular, can be used to distinguish multifocal retinitis from superficial retinal precipitates or accumulations. PMID- 26237138 TI - A Novel Covalent mTOR Inhibitor, DHM25, Shows in Vivo Antitumor Activity against Triple-Negative Breast Cancer Cells. AB - Constitutive activation of the PI3K/mTOR signaling pathway contributes to carcinogenesis and metastasis in most, if not all, breast cancers. From a chromene backbone reported to inhibit class I PI3K catalytic subunits, several rounds of chemical syntheses led to the generation of a new collection of chromologues that showed enhanced ability to kill PI3K-addicted cancer cells and to inhibit Akt phosphorylation at serine 473, a hallmark of PI3K/mTOR activation. This initial screen uncovered a chromene designated DHM25 that exerted potent antitumor activity against breast tumor cell lines. Strikingly, DHM25 was shown to be a selective and covalent inhibitor of mTOR using biochemical and cellular analyses, modeling, and a large panel of kinase activity assays spanning the human kinome (243 kinases). Finally, in vivo, this novel drug was an efficient inhibitor of growth and metastasis of triple-negative breast cancer cells, paving the way for its clinical application in oncology. PMID- 26237139 TI - Most common problems across health conditions as described by the International Classification of Functioning, Disability, and Health. AB - Health conditions are associated with a variety of functional outcomes. Even though functional outcomes are diverse for different health conditions, they can have important commonalities. The aim of this study was to identify the most common problems in functioning across the wide range of health conditions using the International Classification of Functioning (ICF). Existing databases created for the 21 ICF Core Sets studies were descriptively analyzed. These included data collected in 44 countries on 9978 patients with one of 21 health conditions as the main diagnosis. A frequency cutoff of 50% was used to identify the most common problems in functioning when looking at single health conditions and across them. No category was identified as common to all health conditions included in the study. Fifteen most frequent categories were common in 10 to 13 health conditions out of 21. Eleven categories correspond to the list of activities and participation, and four to the list of body functions. These are related to mobility, daily routine, mental functions, intimate relations, employment, and leisure. Some health conditions have more commonalities between each other. The most common problems across health conditions are therefore related to mental functions, mobility, daily life, intimate relations, employment, and leisure. The results contribute toward the identification of the universal set of ICF categories that can be used in clinical practice for the general assessment of functioning. PMID- 26237140 TI - Drug Distribution in Microspheres Enhances Their Anti-Inflammatory Properties in the Gottingen Minipig. AB - The foreign body reaction (FBR), one of the body's defense mechanisms against foreign materials, results in loss of implant biocompatibility. A popular strategy to prevent FBR is the constant release of dexamethasone in the tissue surrounding the implant. However, FBR prevention has not been sufficiently studied in large animal models, which offer a better representation of the human subcutaneous tissue physiology. Accordingly, a long-term strategy to prevent FBR to subcutaneous implants in a large animal model is necessary to translate the existing research for clinical applications. Here, a poly(lactic-co-glycolic) (PLGA) microsphere/poly(vinyl alcohol) (PVA) hydrogel composite coating for one month prevention of FBR in Gottingen minipigs was developed. A modified PLGA microsphere formulation process is presented, that utilizes coprecipitation of dexamethasone and PLGA. Traditional methods result in heterogeneous distribution of large drug crystals in the microsphere matrix, which in turn results in low drug loading since the drug crystal size is close to that of the microspheres. The modified microsphere preparation method showed homogeneous distribution of dexamethasone, which in turn gave rise to increased drug loading, low burst release, and minimal lag phase. Elimination of the lag phase was dictated from previous work that compared FBR between rats and minipigs. The ability of the coatings to improve implant biocompatibility was successfully tested in vivo via histological examination of explanted tissue from the area surrounding the implants. The biocompatible coatings presented here are suitable for miniaturized implantable devices, such as biosensors, that require constant communication with the local microenvironment. PMID- 26237141 TI - Contribution of Brown Carbon to Direct Radiative Forcing over the Indo-Gangetic Plain. AB - The Indo-Gangetic Plain is a region of known high aerosol loading with substantial amounts of carbonaceous aerosols from a variety of sources, often dominated by biomass burning. Although black carbon has been shown to play an important role in the absorption of solar energy and hence direct radiative forcing (DRF), little is known regarding the influence of light absorbing brown carbon (BrC) on the radiative balance in the region. With this in mind, a study was conducted for a one month period during the winter-spring season of 2013 in Kanpur, India that measured aerosol chemical and physical properties that were used to estimate the sources of carbonaceous aerosols, as well as parameters necessary to estimate direct forcing by aerosols and the contribution of BrC absorption to the atmospheric energy balance. Positive matrix factorization analyses, based on aerosol mass spectrometer measurements, resolved organic carbon into four factors including low-volatile oxygenated organic aerosols, semivolatile oxygenated organic aerosols, biomass burning, and hydrocarbon like organic aerosols. Three-wavelength absorption and scattering coefficient measurements from a Photo Acoustic Soot Spectrometer were used to estimate aerosol optical properties and estimate the relative contribution of BrC to atmospheric absorption. Mean +/- standard deviation values of short-wave cloud free clear sky DRF exerted by total aerosols at the top of atmosphere, surface and within the atmospheric column are -6.1 +/- 3.2, -31.6 +/- 11, and 25.5 +/- 10.2 W/m(2), respectively. During days dominated by biomass burning the absorption of solar energy by aerosols within the atmosphere increased by ~35%, accompanied by a 25% increase in negative surface DRF. DRF at the top of atmosphere during biomass burning days decreased in negative magnitude by several W/m(2) due to enhanced atmospheric absorption by biomass aerosols, including BrC. The contribution of BrC to atmospheric absorption is estimated to range from on average 2.6 W/m(2) for typical ambient conditions to 3.6 W/m(2) during biomass burning days. This suggests that BrC accounts for 10-15% of the total aerosol absorption in the atmosphere, indicating that BrC likely plays an important role in surface and boundary temperature as well as climate. PMID- 26237142 TI - Bone Targeted Therapies for Bone Metastasis in Breast Cancer. AB - Cancer metastasis to the bone develops commonly in patients with various malignancies, and is a major cause of morbidity and diminished quality of life in many affected patients. Emerging treatments for metastatic bone disease have arisen from advances in our understanding of the unique cellular and molecular mechanisms that contribute to the bone metastasis. The tendency of cancer cells to metastasize to bone is probably the end result of many factors including vascular pathways, the highly vascular nature of the bone marrow (which increases the probability that cancer cells will be deposited in bone marrow capillaries), and molecular characteristics of the cancer cells that allow them to adapt to the bone marrow microenvironment. The goals of treating osseous metastases are manifold. Proper treatment can lead to significant improvements in pain control and function, and maintain skeletal integrity. The treatment plan requires a multidisciplinary approach. Widespread metastatic disease necessitates systemic therapy, while a localized problem is best managed with surgery, external beam radiotherapy, or both. Patients with bone metastasis can have prolonged survival, and proper management can have a significant impact on their quality of life. We will review the factors in this article that are promising molecular bone targeted therapies or will be likely targets for future therapeutic intervention to restore bone remodeling and suppress tumor growth. PMID- 26237143 TI - Can Zoledronic Acid be Beneficial for Promoting Tumor Response in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy? AB - The antitumor effect of bisphosphonates (BPs) is under increasing scrutiny. Preclinical and clinical evidence has shown that BPs might sensitize breast tumors to chemotherapy. Here, we present a review of current preclinical and clinical evidence for antitumor effects of BPs, and evaluate how BPs might play a role in neoadjuvant treatment of women with breast cancer. PMID- 26237144 TI - Mesenchymal Stromal Cells: Updates and Therapeutic Outlook in Rheumatic Diseases. AB - Multipotent mesenchymal stromal cells or mesenchymal stem cells (MSCs) are adult stem cells exhibiting functional properties that have opened the way for cell based clinical therapies. MSCs have been reported to exhibit immunosuppressive as well as healing properties, improving angiogenesis and preventing apoptosis or fibrosis through the secretion of paracrine mediators. This review summarizes recent progress on the clinical application of stem cells therapy in some inflammatory and degenerative rheumatic diseases. To date, most of the available data have been obtained in preclinical models and clinical efficacy needs to be evaluated through controlled randomized double-blind trials. PMID- 26237145 TI - Laparoscopic Surgery for Ovarian Pregnancy using Diathermy Hook with Conservation of Ovary: A Case Report and Literature Review. AB - A 31-year-old woman presented with a 7-week history of irregular vaginal bleeding without abdominal pain. She had been using the intrauterine contraceptive device (IUD) for the last 3 years. A pregnancy test was positive and subsequent serum beta human chorionic gonadotropin (beta-HCG) was 4992 mIU/mL. A transvaginal ultrasound scan demonstrated an empty uterus with an associated adnexal mass but no free fluid. A right primary ovarian ectopic pregnancy was diagnosed a laparoscopy. This was managed laparoscopically using monopolar diathermy hook with conservation of the ovary and minimal blood loss. Ovarian pregnancy is rare, especially in women without the classical risk factors for tubal pregnancy, and efforts should be made to exclude ectopic pregnancy in the absence of abdominal pain in a woman of reproductive age presenting with prolonged and irregular vaginal bleeding. Methods to conserve the ovary are also encouraged in cases of ovarian pregnancy. PMID- 26237146 TI - How do Midwives and Physicians Discuss Childhood Vaccination with Parents? AB - Even if vaccination is often described as one of the great achievements of public health, results of recent studies have shown that parental acceptance of vaccination is eroding. Health providers' knowledge and attitudes about vaccines are important determinants of their own vaccine uptake, their intention to recommend vaccines to patients and the vaccine uptake of their patients. The purpose of this article is to compare how midwives and physicians address vaccination with parents during pregnancy and in postpartum visits. Thirty semi structured interviews were conducted with midwives and physicians practicing in the province of Quebec, Canada. Results of our analysis have shown that physicians adopt an "education-information" stance when discussing vaccination with parents in the attempt to "convince" parents to vaccinate. In contrast, midwives adopted a neutral stance and gave information on the pros and cons of vaccination to parents while leaving the final decision up to them. Findings of this study highlight the fact that physicians and midwives have different views regarding their role and responsibilities concerning vaccination. It may be that neither of these approaches is optimal in promoting vaccination uptake. PMID- 26237147 TI - Cutaneous Cryptococcoma in a Patient on TNF-alpha Inhibition. AB - An 87-year old Caucasian male with past medical history of rheumatoid arthritis (RA) and chronic kidney disease presents with left hand erythema, pain, tenderness, induration and edema. Clinically, these hand findings began proximal to the metacarpo-phalangeal joints and extended to the distal wrist. He was noted to have ipsilateral axillary lymph node enlargement but denied any constitutional signs or symptoms. Laboratory markers of inflammation were poor prognostic indicators due to relatively active RA, the use of chronic daily glucocorticoids and weekly adalimumab use. Oral antibiotics were administered with limited success leading to a skin biopsy which reported a hematogenously disseminated fungal panniculitis; cultures grew Cryptococcus neoformans, however, serum cryptococcal antigen was negative. With initial fluconazole treatment, skin findings and lymphadenopathy improved gradually over the next six months. However, the patient's improvement stagnated and his condition reverted back to the state of initial presentation. PMID- 26237148 TI - The Roles of Epithelial-to-Mesenchymal Transition (EMT) and Mesenchymal-to Epithelial Transition (MET) in Breast Cancer Bone Metastasis: Potential Targets for Prevention and Treatment. AB - Many studies have revealed molecular connections between breast and bone. Genes, important in the control of bone remodeling, such as receptor activator of nuclear kappa (RANK), receptor activator of nuclear kappa ligand (RANKL), vitamin D, bone sialoprotein (BSP), osteopontin (OPN), and calcitonin, are expressed in breast cancer and lactating breast. Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) effectors play critical roles during embryonic development, postnatal growth, and epithelial homeostasis, but also are involved in a number of pathological conditions, including wound repair, fibrosis, inflammation, as well as cancer progression and bone metastasis. Transforming growth factor beta (TGFbeta), insulin-like growth factor I & II (IGF I & II), platelet-derived growth factor (PDGF), parathyroid hormone-related protein (PTH(rP)), vascular endothelial growth factor (VEGF), epithelial growth factors II/I (ErbB/EGF), interleukin 6 (IL-6), IL-8, IL-11, IL-1, integrin alphavbeta3, matrix metalloproteinases (MMPs), catepsin K, hypoxia, notch, Wnt, bone morphogenetic proteins (BMP), and hedgehog signaling pathways are important EMT and MET effectors identified in the bone microenviroment facilitating bone metastasis formation. Recently, Runx2, an essential transcription factor in the regulation of mesenchymal cell differentiation into the osteoblast lineage and proper bone development, is also well-recognized for its expression in breast cancer cells promoting osteolytic bone metastasis. Understanding the precise mechanisms of EMT and MET in the pathogenesis of breast cancer bone metastasis can inform the direction of therapeutic intervention and possibly prevention. PMID- 26237149 TI - Bone Health in Patients with Breast Cancer: Recommendations from an Evidence Based Canadian Guideline. AB - Bone loss is common in patients with breast cancer. Bone modifying agents (BMAs), such as bisphosphonates and denosumab, have been shown to reverse or stabilize bone loss and may be useful in the primary and metastatic settings. The purpose of this review is to provide clear evidence-based strategies for the management of bone loss and its symptoms in breast cancer. A systematic review of clinical trials and meta-analyses published between 1996 and 2012 was conducted of MEDLINE and EMBASE. Reference lists were hand-searched for additional publications. Recommendations were developed based on the best available evidence. Zoledronate, pamidronate, clodronate, and denosumab are recommended for metastatic breast cancer patients; however, no one agent can be recommended over another. Zoledronate or any oral bisphosphonate and denosumab should be considered in primary breast cancer patients who are postmenopausal on aromatase inhibitor therapy and have a high risk of fracture and/or a low bone mineral density and in premenopausal primary breast cancer patients who become amenorrheic after therapy. No one agent can be recommended over another. BMAs are not currently recommended as adjuvant therapy in primary breast cancer for the purpose of improving survival, although a major Early Breast Cancer Cooperative Trialists' Group meta-analysis is underway which may impact future practice. Adverse events can be managed with appropriate supportive care. PMID- 26237151 TI - Repeat Lumbar Puncture: CSF Lactic Acid Levels are Predictive of Cure with Acute Bacterial Meningitis. AB - A common clinical problem concerns the utility of repeat lumbar puncture (LP) in adults with acute bacterial meningitis (ABM), e.g., pneumococcal meningitis [1]. An LP is initially done for diagnostic purposes in patients with suspected ABM, i.e., diagnostic lumbar puncture (DLP). A repeat LP (RLP) may be done 1-3 days after the initial DLP, if the patient shows no improvement. If a patient with ABM is not doing well after three days, adequacy of antimicrobial therapy is the main concern. Other reasons for RLP is to detect possible intracranial complications of ABM unrelated to adequacy of therapy [1-2]. PMID- 26237150 TI - The Regenerative Role of the Fetal and Adult Stem Cell Secretome. AB - For a long time, the stem cell regenerative paradigm has been based on the assumption that progenitor cells play a critical role in tissue repair by means of their plasticity and differentiation potential. However, recent works suggest that the mechanism underlying the benefits of stem cell transplantation might relate to a paracrine modulatory effect rather than the replacement of affected cells at the site of injury. Therefore, mounting evidence that stem cells may act as a reservoir of trophic signals released to modulate the surrounding tissue has led to a paradigm shift in regenerative medicine. Attention has been shifted from analysis of the stem cell genome to understanding the stem cell "secretome", which is represented by the growth factors, cytokines and chemokines produced through paracrine secretion. Insights into paracrine-mediated repair support a new approach in regenerative medicine and the isolation and administration of specific stem cell-derived paracrine factors may represent an extremely promising strategy, introducing paracrine-based therapy as a novel and feasible clinical application. In this review, we will discuss the regenerative potential of fetal and adult stem cells, with particular attention to their secretome. PMID- 26237152 TI - New Insights on the Biophysical Interaction of Resveratrol with Biomembrane Models: Relevance for Its Biological Effects. AB - Resveratrol has been widely studied because of its pleiotropic effects in cancer therapy, neuroprotection, and cardioprotection. It is believed that the interaction of resveratrol with biological membranes may play a key role in its therapeutic activity. The capacity of resveratrol to partition into lipid bilayers, its possible location within the membrane, and the influence of this compound on the membrane fluidity were investigated using membrane mimetic systems composed of egg l-alpha-phosphatidylcholine (EPC), cholesterol (CHOL), and sphingomyelin (SM). The results showed that resveratrol has greater affinity for the EPC bilayers than for EPC:CHOL [4:1] and EPC:CHOL:SM [1:1:1] membrane models. The increased difficulty in penetrating tight packed membranes is also demonstrated by fluorescence quenching of probes and by fluorescence anisotropy measurements. Resveratrol may be involved in the regulation of cell membrane fluidity, thereby contributing for cell homeostasis. PMID- 26237153 TI - Effects of repetitive low-level blast exposure on visual system and ocular structures. AB - The purpose of this study was to determine whether repetitive exposure to low level blasts during military breacher training produces acute and cumulative damage to the ocular tissues or visual system. The effects of low-level blast exposure on high-contrast visual acuity, contrast sensitivity, oculomotor function, color vision, visual field (VF), pupillary light reflex, corneal endothelial cell density (ECD), macular thickness, retinal nerve fiber layer thickness, and cup-to-disc ratio were assessed using a battery of standard clinical ophthalmic tests administered 10 times over a 2-year period. Data from nine breacher instructors (Cadre) were compared with data from four breacher engineers (CONTROL). The Cadre group showed higher vertical deviation at near than the CONTROL group over time. The VF mean deviation on the left eye that tended to be worse in the Cadre group was worse throughout the study, suggesting a decrease in VF sensitivity (Cadre: -0.20 +/- 0.15 dB; CONTROL: 1.05 +/- 0.15 dB; p = 0.03). The Cadre group had a reduced ECD (right eye: Cadre 2,502 cells/mm(2) vs CONTROL 2,808 cells/mm(2), p = 0.05; left eye: Cadre 2,558 cells/mm(2) vs CONTROL 2,892 cells/mm(2), p = 0.04). These results suggest that even low-level primary blast has the potential to produce occult eye injury. PMID- 26237154 TI - A scatter correction method for contrast-enhanced dual-energy digital breast tomosynthesis. AB - Contrast-enhanced dual energy digital breast tomosynthesis (CE-DE-DBT) is designed to image iodinated masses while suppressing breast anatomical background. Scatter is a problem, especially for high energy acquisition, in that it causes severe cupping artifact and iodine quantitation errors. We propose a patient specific scatter correction (SC) algorithm for CE-DE-DBT. The empirical algorithm works by interpolating scatter data outside the breast shadow into an estimate within the breast shadow. The interpolated estimate is further improved by operations that use an easily obtainable (from phantoms) table of scatter-to primary-ratios (SPR)--a single SPR value for each breast thickness and acquisition angle. We validated our SC algorithm for two breast emulating phantoms by comparing SPR from our SC algorithm to that measured using a beam passing pinhole array plate. The error in our SC computed SPR, averaged over acquisition angle and image location, was about 5%, with slightly worse errors for thicker phantoms. The SC projection data, reconstructed using OS-SART, showed a large degree of decupping. We also observed that SC removed the dependence of iodine quantitation on phantom thickness. We applied the SC algorithm to a CE-DE mammographic patient image with a biopsy confirmed tumor at the breast periphery. In the image without SC, the contrast enhanced tumor was masked by the cupping artifact. With our SC, the tumor was easily visible. An interpolation-based SC was proposed by (Siewerdsen et al 2006 Med. Phys. 33 187-97) for cone-beam CT (CBCT), but our algorithm and application differ in several respects. Other relevant SC techniques include Monte-Carlo and convolution-based methods for CBCT, storage of a precomputed library of scatter maps for DBT, and patient acquisition with a beam-passing pinhole array for breast CT. Our SC algorithm can be accomplished in clinically acceptable times, requires no additional imaging hardware or extra patient dose and is easily transportable between sites. PMID- 26237155 TI - Electrophoretic Transport of Single DNA Nucleotides through Nanoslits: A Molecular Dynamics Simulation Study. AB - There is potential for flight time based DNA sequencing involving disassembly into individual nucleotides which would pass through a nanochannel with two or more detectors. We performed molecular dynamics simulations of electrophoretic motion of single DNA nucleotides through 3 nm wide hydrophobic slits with both smooth and rough walls. The electric field (E) varied from 0.0 to 0.6 V/nm. The nucleotides adsorb and desorb from walls multiple times during their transit through the slit. The nucleotide-wall interactions differed due to nucleotide hydrophobicities and wall roughness which determined duration and frequency of nucleotide adsorptions and their velocities while adsorbed. Transient association of nucleotides with one, two, or three sodium ions occurred, but the mean association numbers (ANs) were weak functions of nucleotide type. Nucleotide-wall interactions contributed more to separation of nucleotide flight time distributions than ion association and thus indicate that nucleotide-wall interactions play a defining role in successfully discriminating between nucleotides on the basis of their flight times through nanochannels/slits. With smooth walls, smaller nucleotides moved faster, but with rough walls larger nucleotides moved faster due to fewer favorable wall adsorption sites. This indicates that roughness, or surface patterning, might be exploited to achieve better time-of-flight based discrimination between nucleotides. PMID- 26237156 TI - Low vaccine coverage among children born to HIV infected women in Niamey, Niger. AB - BACKGROUND: The effect of mother's HIV-status on child vaccination is an important public health issue in countries with high HIV prevalence. We conducted a study in a primary healthcare center located in Niamey, the capital of Niger, which offers free of charge services to HIV positive and/or underprivileged mothers, with the aim of assessing: 1) vaccination coverage for children 0-36 months old, born to HIV-infected mothers, and 2) the impact of maternal HIV status on child vaccination. METHODS: Mothers of children less than 36 months old attending the center were interviewed, to collect information on vaccines administered to their child, and family's socio-demographic characteristics. RESULTS: Overall, 502 children were investigated. Children of HIV-seropositive mothers were less likely to receive follow up vaccinations for Diphtheria-Tetanus Pertussis (DTP) than those of HIV-seronegative mothers, with a prevalence ratio (PR) of 2.03 (95%CI: 1.58-2.61). Children born to HIV-seropositive mothers were less likely to miss vaccination for MMR than those born to HIV negative mothers, with a RR of 0.46 (95%CI: 0.30-0.72). CONCLUSIONS: Vaccine coverage among children born to HIV infected mothers was rather low. It is important to favor access to vaccination programs in this population. PMID- 26237157 TI - NOX4 in Mitochondria: Yeast Two-Hybrid-Based Interaction with Complex I Without Relevance for Basal Reactive Oxygen Species? AB - NADPH oxidases (NOXs) represent the only known dedicated source of reactive oxygen species (ROS) and thus a prime therapeutic target. Type 4 NOX is unique as it produces H2O2, is constitutively active, and has been suggested to localize to cardiac mitochondria, thus possibly linking mitochondrial and NOX-derived ROS formation. The aim of this study was to identify NOX4-binding proteins and examine the possible physiological localization of NOX4 to mitochondria and its impact on mitochondrial ROS formation. We here provide evidence that NOX4 can, in principle, enter protein-protein interactions with mitochondrial complex I NADH dehydrogenase subunits, 1 and 4L. However, under physiological conditions, NOX4 protein was neither detectable in the kidney nor in cardiomyocyte mitochondria. The NOX inhibitor, GKT136901, slightly reduced ROS formation in cardiomyocyte mitochondria, but this effect was observed in both wild-type and Nox4(-/-) mice. NOX4 may thus associate with mitochondrial complex I proteins, but in cardiac and renal mitochondria under basal conditions, expression is beyond our detection limits and does not contribute to ROS formation. PMID- 26237158 TI - Pentanuclear lanthanide pyramids based on thiacalix[4]arene ligand exhibiting slow magnetic relaxation. AB - A series of pentanuclear Ln(III) clusters, [Ln5(MU4-OH)(MU3-OH)4(L1)(acac)6] (H4L1 = p-tert-butylthiacalix[4]arene; acac = acetylacetonate; Ln = Dy, Ho, Er) and [Ln5(MU5-OH)(MU3-OH)4(L1)(L2)2(acac)2(CH3OH)2] (H3L2 = 5,11,17,23 tetrakis(1,1-dimethylethyl)-25,26,27-trihydroxy-28-methoxy thiacalix[4]arene; Ln = Dy, Ho, Er), have been synthesized based on the thiacalix[4]arene ligand. All of these complexes feature a square-based pyramid with four triangular Ln3 structural motifs. One MU4-OH group bridges four Ln(III) ions in the basal plane of , while the OH group in complexes adopts the MU5-coordination mode. Our results illuminate the coordination modes of the versatile thiacalix[4]arene ligands and their application to new cluster compounds. The structural and magnetic studies confirm that the molecular symmetries and coordination geometries for lanthanide metal cores have a significant effect on some parameters as single-molecule magnets. Among them, two Dy5 pyramids exhibit distinct slow magnetic relaxation. PMID- 26237162 TI - Comparative genomics of pectinacetylesterases: Insight on function and biology. AB - Pectin acetylation influences the gelling ability of this important plant polysaccharide for the food industry. Plant apoplastic pectinacetylesterases (PAEs) play a key role in regulating the degree of pectin acetylation and modifying their expression thus represents one way to engineer plant polysaccharides for food applications. Identifying the major active enzymes within the PAE gene family will aid in our understanding of this biological phenomena as well as provide the tools for direct trait manipulation. Using comparative genomics we propose that there is a minimal set of 4 distinct PAEs in plants. Possible functional diversification of the PAE family in the grasses is also explored with the identification of 3 groups of PAE genes specific to grasses. PMID- 26237163 TI - Microscope Integrated Intraoperative Spectral Domain Optical Coherence Tomography for Cataract Surgery: Uses and Applications. AB - AIM: To demonstrate the uses and applications of a microscope integrated intraoperative Optical Coherence Tomography in Micro Incision Cataract Surgery (MICS) and Femtosecond Laser Assisted Cataract Surgery (FLACS). METHODS: Intraoperative real time imaging using the RESCANTM 700 (Carl Zeiss Meditec, Oberkochen, Germany) was done for patients undergoing MICS as well as FLACS. The OCT videos were reviewed at each step of the procedure and the findings were noted and analyzed. RESULTS: Microscope Integrated Intraoperative Optical Coherence Tomography was found to be beneficial during all the critical steps of cataract surgery. We were able to qualitatively assess wound morphology in clear corneal incisions, in terms of subclinical Descemet's detachments, tears in the inner or outer wound lips, wound gaping at the end of surgery and in identifying the adequacy of stromal hydration, for both FLACS as well as MICS. It also enabled us to segregate true posterior polar cataracts from suspected cases intraoperatively. Deciding the adequate depth of trenching was made simpler with direct visualization. The final position of the intraocular lens in the capsular bag and the lack of bioadhesivity of hydrophobic acrylic lenses were also observed. CONCLUSIONS: Even though Microscope Integrated Intraoperative Optical Coherence Tomography is in its early stages for its application in cataract surgery, this initial assessment does show a very promising role for this technology in the future for cataract surgery both in intraoperative decision making as well as for training purposes. PMID- 26237164 TI - A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma. AB - Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated pretransplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995 and 2010. The probabilities of PFS at 1, 5 and 10 years were 66% (95% confidence interval (CI): 62-70), 52% (95% CI: 48-57) and 47% (95% CI: 42-51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score ?90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low-, intermediate- and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64-80), 53% (95% CI: 47-59) and 23% (95% CI: 9-36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk of progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT. PMID- 26237165 TI - Effect of conditioning regimens on graft failure in myelofibrosis: a retrospective analysis. AB - In myelofibrosis, the introduction of reduced-intensity conditioning (RIC) preceding allogeneic stem cell transplantation (SCT) resulted in lower transplant related mortality rates compared with myeloablative conditioning. However, lowering the intensity of conditioning may increase the risk of graft failure in myelofibrosis, although hitherto this has not been indisputably proven. We here report the outcome of 53 patients who underwent allogeneic SCT with different conditioning regimens (RIC and non-myeloablative (NMA)) in three transplantation centers in the Netherlands. The cumulative incidence of graft failure within 60 days after SCT was high (28%), and this was primarily associated with the intensity of the conditioning regimen. Cumulative neutrophil engraftment at 60 days was lower in patients who received NMA conditioning compared with those who received RIC (56% vs 84%, P=0.03). Furthermore, of six patients who received a second transplantation after graft failure, the three patients with RIC regimens subsequently engrafted, whereas the three patients who received a second NMA regimen did not. This study indicates that in myelofibrosis, NMA regimens result in high engraftment failure rates. We propose the use of more intensive conditioning regimens, incorporating busulfan or melphalan. PMID- 26237167 TI - Reply to 'allogeneic hematopoietic cell transplantation for concurrent multiple myeloma and myelodysplastic syndrome'. PMID- 26237166 TI - Fludarabine and treosulfan compared with other reduced-intensity conditioning regimens for allogeneic stem cell transplantation in patients with lymphoid malignancies. AB - Allogeneic stem-cell transplantation (SCT) is a potentially curative therapy for lymphoid malignancies. Myeloablative conditioning is associated with high non relapse mortality (NRM). Reduced-intensity condition (RIC) reduces NRM but relapse rate is increased. Novel regimens with intensive anti-malignancy activity but limited toxicity are of benefit. We evaluated outcomes of 144 lymphoma patients given allogeneic SCT with RIC consisting of fludarabine and treosulfan (FT, n=50), intravenous-busulfan (FB2, n=38) or melphalan (FM, n=56). Sixty-nine patients (48%) had chemo-sensitive disease and 75 (52%) had chemo-refractory disease at SCT. The median follow-up is 39 months (4-149). Three-year survival was 67, 74 and 48% after FT, FB2 and FM, in chemo-sensitive disease (P=0.14) and 34, 11 and 17% in chemo-refractory disease, respectively (P=0.08). Three-year NRM was 24, 24 and 54% (P=0.002), whereas relapse mortality was 22, 34 and 18%, respectively (P=0.13). Multivariate analysis identified a high comorbidity-score, chemo-refractory disease and FM as associated with shortened survival. In conclusion, FB2 is associated with low NRM and good results in chemo-sensitive disease, but with higher relapse mortality rates. FM controls disease better, but with high NRM. FT probably balances these outcomes more optimally. It is as safe as FB2 and as cytoreductive as FM, resulting in improved outcome, mostly in advanced disease. PMID- 26237168 TI - Prevalence of menstrual cycles and outcome of 50 pregnancies after high-dose chemotherapy and auto-SCT in non-Hodgkin and Hodgkin lymphoma patients younger than 40 years. AB - Data are limited regarding the prevalence of menstrual cycles and pregnancies after high-dose chemotherapy (HDC) and auto-stem cell transplantation (SCT). Female patients who underwent HDC auto-SCT for non-Hodgkin and Hodgkin lymphoma (1997-2012) were reviewed. The selection criteria were as follows: (1) alive without disease 12 and 24 months after auto-SCT for menstrual cycles and pregnancy, respectively, (2) age <40 years at auto-SCT, and (3) no primary infertility. One-hundred and seventy-six females underwent single auto-SCT. Eighty-nine were eligible for menstrual cycles and pregnancy analysis. Median age at auto-SCT was 25 years (14-40 years), at pregnancy 27 years (20-37 years), median follow-up 65 months (range 24-190). Regular menstrual-cycles resumed in 56/89 patients (63%). Increasing age (P=0.02) and number of prior chemotherapy cycles (P=0.02) are associated with higher risk of amenorrhea. Forty patients tried to get pregnant, 26 (65%) became pregnant 50 times: 43 (86%) live birth, 7 (14%) miscarriage and 2/50 had birth defects. Twenty-four patients practiced breastfeeding (median duration 4 months (1-24 months)). Enough breast milk production was reported 62.5% vs 100% in those patients who did or did not receive above the diaphragm radiation therapy, respectively, (P=0.066). Our data highlights significantly higher than perceived incidence of menstrual cycle resumption, successful pregnancies and breastfeeding after HDC auto-SCT. PMID- 26237169 TI - Re-invigorating rather than re-inventing the wheel: augmenting the impact of salvage autologous stem cell transplantation for multiple myeloma in the era of novel agents. PMID- 26237170 TI - Supramolecular Glycosylation Accelerates Proteolytic Degradation of Peptide Nanofibrils. AB - Despite the recent consensus that the oligomers of amyloid peptides or aberrant proteins are cytotoxic species, there is still a need for an effective way to eliminate the oligomers. Based on the fact that normal proteins are more glycosylated than pathogenic proteins, we show that a conjugate of nucleobase, peptide, and saccharide binds to peptides from molecular nanofibrils and accelerates the proteolytic degradation of the molecular nanofibrils. As the first example of the use of supramolecular glycosylation to dissociate molecular nanofibrils and to accelerate the degradation of peptide aggregates, this work illustrates a new method that ultimately may lead to an effective approach for degrading cytotoxic oligomers of peptides or aberrant proteins. PMID- 26237171 TI - Thoracic aortic aneurysm: 4D flow MRI and computational fluid dynamics model. PMID- 26237172 TI - Trapping cells in senescence with a lamin cage. PMID- 26237173 TI - Turnip vein clearing virus movement protein nuclear activity: Do Tobamovirus movement proteins play a role in immune response suppression? AB - Plant viruses' cell-to-cell movement requires the function of virally encoded movement proteins (MPs). The Tobamovirus, Tobacco mosaic virus (TMV) has served as the model virus to study the activities of single MPs. However, since TMV does not infect the model plant Arabidopsis thaliana I have used a related Tobamovirus, Turnip vein-clearing virus (TVCV). I recently showed that, despite belonging to the same genus, the behavior of the 2 viruses MPs differ significantly during infection. Most notably, MP(TVCV), but not MP(TMV), targets the nucleus and induces the formation of F actin-containing filaments that associate with chromatin. Mutational analyses showed that nuclear localization of MP(TVCV) was necessary for TVCV local and systemic infection in both Nicotiana benthamiana and Arabidopsis. In this addendum, I propose possible targets for the MP(TVCV) nuclear activity, and suggest viewing MPs as viral effector-like proteins, playing a role in the inhibition of plant defense. PMID- 26237174 TI - Bone water at the nanoscale: a molecular dynamics study. PMID- 26237176 TI - Doctors' perceptions of the cost of consumable items used in neonatal intensive care. PMID- 26237177 TI - A probabilistic study of the ultrasonic reflection coefficient from cortical bones. PMID- 26237175 TI - Psychological and social resources relate to biomarkers of allostasis in newly admitted nursing home residents. AB - OBJECTIVES: This paper presents preliminary baseline data from a prospective study of nursing home adaptation that attempts to capture the complexity of residents' adaptive resources by examining psychological, social, and biological variables from a longitudinal conceptual framework. Our emphasis was on validating an index of allostasis. METHOD: In a sample of 26 long-term care patients, we measured 6 hormone and protein biomarkers to capture the concept of allostasis as an index of physiological resilience, related to other baseline resources, including frailty, hope and optimism, social support, and mental health history, collected via interview with the resident and collaterals. We also examined the performance of self-report measures reflecting psychosocial and well-being constructs, given the prevalence of cognitive impairment in nursing homes. RESULTS: Our results supported both the psychometric stability of our self report measures, and the preliminary validity of our index of allostasis. Each biomarker was associated with at least one other resilience resource, suggesting that our choice of biomarkers was appropriate. As a group, the biomarkers showed good correspondence with the majority of other resource variables, and our standardized summation score was also associated with physical, social, and psychological resilience resources, including those reflecting physical and mental health vulnerability as well as positive resources of social support, optimism, and hope. CONCLUSION: Although these results are based on a small sample, the effect sizes were large enough to confer some confidence in the value of pursuing further research relating biomarkers of allostasis to psychological and physical resources and well-being. PMID- 26237178 TI - Enantioselective Oxidation of Alkenes with Potassium Permanganate Catalyzed by Chiral Dicationic Bisguanidinium. AB - Chiral anion-controlled ion-pairing catalysis was demonstrated to be a wide ranging strategy that can utilize a variety of cationic metal species. In a similar manner, we envision a complementary strategy using chiral cation in partnership with inorganic anionic metal salts. Herein, we report a chiral dicationic bisguanidinium-catalyzed asymmetric oxidation reaction of alkenes with potassium permanganate. Chiral induction is attributed to ion-pairing interaction between chiral cation and enolate anion. The success of the current permanganate oxidation reaction together with mechanistic insights should provide inspiration for expansion to other anionic metal salts and would open up new paradigms for asymmetric transition metal catalysis, phase-transfer catalysis, and ion-pairing catalysis. PMID- 26237179 TI - Repeated evolution of exaggerated dewlaps and other throat morphology in lizards. AB - The existence of elaborate ornamental structures in males is often assumed to reflect the outcome of female mate choice for showy males. However, female mate choice appears weak in many iguanian lizards, but males still exhibit an array of ornament-like structures around the throat. We performed a phylogenetic comparative study to assess whether these structures have originated in response to male-male competition or the need for improved signal efficiency in visually difficult environments. We found little evidence for the influence of male-male competition. Instead, forest species were more likely to exhibit colourful throat appendages than species living in open habitats, suggesting selection for signal efficiency. On at least three independent occasions, throat ornamentation has become further elaborated into a large, conspicuously coloured moving dewlap. Although the function of the dewlap is convergent, the underlying hyoid apparatus has evolved very differently, revealing the same adaptive outcome has been achieved through multiple evolutionary trajectories. More generally, our findings highlight that extravagant, ornament-like morphology can evolve in males without the direct influence of female mate choice and that failure to consider alternative hypotheses for the evolution of these structures can obscure the true origins of signal diversity among closely related taxa. PMID- 26237180 TI - Evading inhibitory constraints--destabilizing p110alpha/p85alpha interactions. PMID- 26237181 TI - Control of FoxO4 Activity and Cell Survival by TRIM22 Directs TLR3-Stimulated Cells Toward IFN Type I Gene Induction or Apoptosis. AB - Activation of innate immune response, induced after the recognition of double stranded RNA (dsRNA), formed during replication of most viruses, results in intracellular signaling cascades ultimately culminating in the expression of type I interferon (IFN). In this study, we provide the first evidence that FoxO4 triggers the activation of the innate immune signaling pathway in coupling stimulation of TLR3 and RIG-like receptors by the synthetic dsRNA analog, poly(I:C), to IFN-beta and IFN-induced gene induction, whereas knockdown of FoxO4 had opposite effects. Similar effects of FoxO4 were observed during paramyxovirus mediated IFN-beta transcriptional induction. We further found that knockdown of FoxO4 did not affect IRF3 and NF-kappaB activation by poly(I:C), suggesting that FoxO4 would act downstream in the signaling pathway. In addition, we show that the IFN-induced TRIM22 ubiquitin ligase targets FoxO4 and antagonizes its activity through an unrelated ubiquitin/autophagosomic-lysosomal pathway. Unexpectedly, TRIM22 knockdown strongly sensitizes cells to dsRNA-induced caspase dependent apoptosis, as early as 2 h after poly(I:C) stimulation, concomitantly to the inhibition of the expression of the antiapoptotic protein, Bcl-2, indicating that TRIM22 might be a key factor for controlling the cell survival after TLR3 stimulation. Taken together, our data demonstrate that the regulation of FoxO4 protein expression and cell survival by TRIM22 controls TLR3-mediated IFN type I gene induction, preventing excessive antiviral response through dsRNA induced apoptosis. PMID- 26237182 TI - Deductive derivation and turing-computerization of semiparametric efficient estimation. AB - Researchers often seek robust inference for a parameter through semiparametric estimation. Efficient semiparametric estimation currently requires theoretical derivation of the efficient influence function (EIF), which can be a challenging and time-consuming task. If this task can be computerized, it can save dramatic human effort, which can be transferred, for example, to the design of new studies. Although the EIF is, in principle, a derivative, simple numerical differentiation to calculate the EIF by a computer masks the EIF's functional dependence on the parameter of interest. For this reason, the standard approach to obtaining the EIF relies on the theoretical construction of the space of scores under all possible parametric submodels. This process currently depends on the correctness of conjectures about these spaces, and the correct verification of such conjectures. The correct guessing of such conjectures, though successful in some problems, is a nondeductive process, i.e., is not guaranteed to succeed (e.g., is not computerizable), and the verification of conjectures is generally susceptible to mistakes. We propose a method that can deductively produce semiparametric locally efficient estimators. The proposed method is computerizable, meaning that it does not need either conjecturing, or otherwise theoretically deriving the functional form of the EIF, and is guaranteed to produce the desired estimates even for complex parameters. The method is demonstrated through an example. PMID- 26237183 TI - Visual context processing dysfunctions in youth at high risk for psychosis: Resistance to the Ebbinghaus illusion and its symptom and social and role functioning correlates. AB - Impaired visual context processing is closely linked with expression of symptoms in people with psychosis. However, to date, there have been no investigations of this phenomenon in the critical ultra high-risk (UHR) period immediately preceding the onset of psychosis. In total, 73 participants (33 UHR, 40 control) were evaluated with clinical and global functioning interviews and with a computerized task that required comparing the size of 2 target circles. Targets could appear by themselves (no-context condition), or within a context that made size judgment easier (helpful condition) or more difficult (misleading condition). Susceptibility to illusion was measured as the accuracy differences between the no-context and the helpful (i.e., helpful-index) and the misleading (i.e., misleading-index) conditions. Both groups exhibited approximately the same percentage of accurate responses to the no-context condition. However, the UHR subjects exhibited significantly less susceptibility to the illusion, performing superior to controls on the misleading index. The UHR group also showed less susceptibility on the helpful index, but this was not significant. Lower susceptibility on the misleading index was associated with increased negative symptoms and role functioning at a trend level. Lower susceptibility on the helpful index was significantly associated with increased negative symptoms and both poor role and social functioning. These results indicate that visual context processing is impaired during the UHR period, and is related to core illness features, suggesting that this task may be a useful biomarker in studies of UHR participants. PMID- 26237184 TI - Genetic variants in 6-mercaptopurine pathway as potential factors of hematological toxicity in acute lymphoblastic leukemia patients. AB - AIM: We investigated the associations between variants in genes coding for enzymes and transporters related to the 6-mercaptopurine pathway and clinical outcomes in pediatric patients with acute lymphoblastic leukemia. MATERIALS & METHODS: Statistical association between gender, age and genotypes of selected SNPs, and the risks of hematological toxicity and relapse were investigated using a Cox proportional hazard model in 70 acute lymphoblastic leukemia patients from upper Egypt. RESULTS: We found significant associations between ITPA, IMPDH1, SLC29A1, SLC28A2, SLC28A3 and ABCC4 SNPs and one or more of the hematological toxicity manifestations (neutropenia, agranulocytosis and leukopenia); age was significantly related to relapse. CONCLUSION: Genetic polymorphisms in enzymes and transporters involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity. PMID- 26237186 TI - Asymmetric Anterior Distraction for Transversely Distorted Maxilla and Midfacial Anteroposterior Deficiency in a Patient With Cleft Lip/Palate: Two-Stage Surgical Approach. AB - The present report describes a male patient with a unilateral cleft lip and palate who presented with midfacial anteroposterior and transverse deficiency. Correction involved a two-stage surgical-orthodontic approach: asymmetric anterior distraction of the segmented maxilla followed by two-jaw surgery (LeFort I and bilateral sagittal splitting ramus osteotomies). The present case demonstrates that the asymmetric elongation of the maxilla with anterior distraction is an effective way to correct a transversely distorted alveolar form and midfacial anteroposterior deficiency. Furthermore, successful tooth movement was demonstrated in the new bone created by distraction. PMID- 26237185 TI - Gene expression profile of zeitlupe/lov kelch protein1 T-DNA insertion mutants in Arabidopsis thaliana: Downregulation of auxin-inducible genes in hypocotyls. AB - Elongation of hypocotyl cells has been studied as a model for elucidating the contribution of cellular expansion to plant organ growth. ZEITLUPE (ZTL) or LOV KELCH PROTEIN1 (LKP1) is a positive regulator of warmth-induced hypocotyl elongation under white light in Arabidopsis, although the molecular mechanisms by which it promotes hypocotyl cell elongation remain unknown. Microarray analysis showed that 134 genes were upregulated and 204 genes including 15 auxin-inducible genes were downregulated in the seedlings of 2 ztl T-DNA insertion mutants grown under warm conditions with continuous white light. Application of a polar auxin transport inhibitor, an auxin antagonist or an auxin biosynthesis inhibitor inhibited hypocotyl elongation of control seedlings to the level observed with the ztl mutant. Our data suggest the involvement of auxin and auxin-inducible genes in ZTL-mediated hypocotyl elongation. PMID- 26237187 TI - The Deepithelialized Dorsal Tongue Flap for Reconstruction of Anterior Palatal Fistulae: Literature Review and Presentation of Our Experience in Egypt. AB - OBJECTIVE: The purpose of this study was to present our experience with the closure of challenging palatal fistulae using the deepithelialized dorsal anterior tongue flap. We highlight the efficacy of suturing the tip of the tongue flap to the nasal septum for prevention of flap detachment. DESIGN: Prospective analysis of cleft patients with anterior palatal fistulae repaired by deepithelialized dorsal anterior tongue flap. SETTING: Institutional center. PATIENTS/PARTICIPANTS: A total of 30 patients with anterior palatal fistulae in the setting of previous cleft palate or fistula repair. INTERVENTIONS: Deepithelialized dorsal anterior tongue flap for treatment of anterior palatal fistulae. OUTCOME MEASURES: Patients had repair using deepithelialized dorsal anterior tongue flap between 2011 and 2014. Patients' photographs and clinical records were collected. The technique of flap harvesting and method of securing it in its position are described in this study. RESULTS: Patients were followed up over a mean period of 13.8 months to check flap viability, competent repair, and donor site function and aesthetics. All patients showed uneventful healing without complications. CONCLUSIONS: This technique offered a secure method of palatal fistulae reconstruction. Further research is needed to show this technique's advantages and drawbacks. PMID- 26237188 TI - Orthodontic Treatment and Long-Term Management of a Patient With Marfan Syndrome. AB - Marfan syndrome (MFS) is caused by abnormal systemic connective tissue. The main clinical manifestations include long limbs, long slender fingers, lens subluxation, abnormal cardiac valves, and aortic aneurysm. We report the case of an 11-year-old patient with MFS who underwent orthodontic treatment and was followed up until the age of 25 years. We found no significant differences in tooth movement between the patient with MFS and healthy subjects. However, because patients with MFS show characteristic facial growth and an increased risk of developing systemic comorbidities, their dental status requires careful observation over time. PMID- 26237189 TI - Fabrication of a Feeding Obturator for Infants. AB - Large clefts in the lip and palate are common congenital anomalies. If the cleft palate is large enough, conventional feeding techniques may not provide proper nutrition for the infant. Feeding obturators will aid in the ability of the infant to attain suction and help the infant to feed adequately. It is necessary for the infant to have sustained weight gain prior to surgery to correct the cleft lip and/or palate. Fabrication of an infant feeding obturator is a simple technique using materials found in every dental office. An impression is made using modeling plastic impression compound. This impression is relined using irreversible hydrocolloid, and the resulting cast is used to enable a vacuum formed obturator to be fabricated. The vacuum-formed obturator is smoothed and adjusted in the infant's mouth to ensure closure of the palate but allows pace posteriorly to allow normal breathing. The resulting obturator is well retained in the infant's mouth, allowing feeding. PMID- 26237190 TI - The Buccinator Mucomuscular Flap: An In-Depth Analysis and Evaluation of Its Role in the Management of Velopharyngeal Dysfunction. AB - BACKGROUND: A significant proportion of patients with cleft palate experience persisting velopharyngeal dysfunction (VPD) after primary surgery. Pharyngoplasty is the most common procedure to correct inadequate velopharyngeal closure. Although it is often effective, it poses a risk for postoperative airway obstruction. The mucomuscular buccinator flap is a more recent alternative: In the largest case series to date, we outline its use and evaluate its effectiveness in managing persistent VPD. METHODS: Over 9 years, 103 buccinator flap procedures were performed by the Cambridge group to improve velar function. Clinical records were retrospectively assessed: 60 patients were analyzed by two expert speech and language therapists external to the group using the Cleft Audit Protocol for Speech-Augmented. In a subset of patients, the buccinator flap was interpolated between the limbs of a large mucosal Z-plasty. Consensus listening was undertaken, and interrater reliability was calculated for 24.17% of the cohort. The remaining samples were assessed by a single listener following calibrated consensus listening. RESULTS: There was a significant reduction in VPD (P < .001). Preoperatively, 68.5% of patients demonstrated marked VPD, falling to 24.1% postoperatively. The buccinator procedure demonstrated significant improvement for three of four individual speech parameters: hypernasality, passive cleft speech characteristics, and audible nasal emission. Overall, 13.5% of patients required further corrective speech surgery. CONCLUSIONS: The buccinator mucomuscular flap reliably and effectively improves velar function in the management of VPD and has low complication rates. We therefore recommend the use of the buccinator flap in primary surgical management of persisting VPD. PMID- 26237191 TI - Individualized Prophylaxis in Patients with Esophageal Replacement Because of Cancer. AB - BACKGROUND: Presented are the findings from an analysis of respiratory inflammatory complications in patients undergoing esophageal replacement because of cancer. Respiratory complications are manifested most frequently within five post-operative days, thus, they are likely to be caused by potentially pathogenic micro-organisms originating from the primary or secondary microflora. METHODS: Sputum samples were collected 1-2 wks pre-operatively. In cases of positive microbiologic finding of some potential pathogens, individualized antibiotic prophylaxis was designed. RESULTS: Patients with individualized prophylaxis had fewer respiratory complications (10%) than patients with general antibiotic prophylaxis (41%). CONCLUSIONS: The approach to pre-operative sputum tests should be changed. If culture results are positive for bacteria with high resistance to antimicrobial agents or yeasts, the so-called individualized prophylaxis based on these particular results should be used. PMID- 26237192 TI - Wrong to be Right: Margin Laterality is an Independent Predictor of Biochemical Failure After Radical Prostatectomy. AB - OBJECTIVES: To examine the impact of positive surgical margin (PSM) laterality on failure after radical prostatectomy (RP). A PSM can influence local recurrence and outcomes after salvage radiation. Unlike intrinsic risk factors, a PSM is caused by intervention and thus iatrogenic failures may be elucidated by analyzing margin laterality as surgical approach is itself lateralized. PATIENTS AND METHODS: We reviewed 226 RP patients between 1991 and 2013 with PSM. Data includes operation type, pre/postoperative PSA, surgical pathology, and margin type (location, focality, laterality). The median follow-up was 47 months. Biochemical recurrence after RP was defined as PSA>=0.1 ng/mL or 2 consecutive rises above nadir. Ninety-two patients received salvage radiation therapy (SRT). Failure after SRT was defined as any PSA>=0.2 ng/mL or greater than presalvage. Kaplan-Meier and Cox multivariate analyses compared relapse rates. RESULTS: The majority of PSM were iatrogenic (58%). Laterality was associated with differences in median relapse: right 20 versus left 51 versus bilateral 14 months (P<0.01). Preoperative PSA, T-stage, Gleason grade, and laterality were associated with biochemical progression on univariate and multivariate analyses. Right-sided margins were more likely to progress than left (hazard ratio, 1.67; P=0.04). More right-sided margins were referred for SRT (55% right vs. 23% left vs. 22% bilateral), but were equally salvaged. Only T-stage and pre-SRT PSA independently influenced SRT success. CONCLUSIONS: Most PSM are iatrogenic, with right-sided more likely to progress (and sooner) than left sided. Margin laterality is a heretofore unrecognized independent predictor of biochemical relapse and hints at the need to modify the traditional unilateral surgical technique. PMID- 26237193 TI - Chemoradiation for High-grade Neuroendocrine Carcinoma of the Rectum and Anal Canal. AB - OBJECTIVES: We evaluated outcomes in patients with high-grade neuroendocrine (HGNE) carcinoma of the anorectum treated with pelvic chemoradiation. MATERIALS AND METHODS: Between January 1, 2000 and February 17, 2013, 10 patients were confirmed to have HGNE carcinoma of the rectum or anal canal and treated with pelvic chemoradiation (radiation dose >=45 Gy). Overall survival (OS), locoregional control (LRC), progression-free survival (PFS), and patterns of failure were evaluated. RESULTS: Eight had pure HGNE carcinoma and 2 had HGNE carcinoma with minor component of adenocarcinoma. Median age was 62 years. Median follow-up was 15 months (range, 3 to 128 mo). Tumor stages included TxN0M0 (1), II (1), III (4), and IV (4) including 2 with only inguinal involvement. Median tumor size was 5.5 cm (range, 3 to 7 cm). Patients received postoperative chemoradiation (1), preoperative chemoradiation (2), and chemoradiation without surgery (7). Median dose was 50.4 Gy (range, 45 to 60 Gy). All patients received chemotherapy before or after chemoradiation. Seven had pelvic LRC; 2 had possible and 1 had confirmed local progression. Both patients who had preoperative chemoradiation only had microscopic focus of residual carcinoma at surgery. Seven had disease progression; of which all developed distant progression, with distant progression occurring as the first event in 6 (liver, lung, bone, and abdominal nodes). Actuarial 2-year PFS and OS were 30% and 46%, respectively. One patient received prophylactic cranial irradiation; only one of the other 9 patient developed brain metastasis. CONCLUSIONS: Pelvic chemoradiation provided LRC for the majority of the patients' lifetime. Most patients had distant failure, but patterns of distant failure do not support routine prophylactic cranial irradiation. PMID- 26237194 TI - Survival Outcomes Improved in Contemporary Cohort of Patients With Pelvic or Abdominal Recurrence After Treatment for Stage I/II Endometrial Carcinoma. AB - OBJECTIVES: Pelvic and abdominal recurrences in stage I/II endometrial carcinoma are associated with poor outcomes, yet prognostic factors for survival after recurrence are not well described. Herein, we identify patients with pelvic or abdominal recurrence after surgery for stage I/II endometrial carcinoma and describe symptoms at presentation, prognostic factors, and salvage treatment toxicity. MATERIALS AND METHODS: This is a retrospective cohort of 20 consecutively treated patients with recurrence after treatment for stage I/II endometrial carcinoma followed by our Institution's Radiation Oncology Department from 1998 to 2015. RESULTS: The median time to pelvic or abdominal recurrence was 18.1 months (range, 4.2 to 59.6 mo), with 50% of recurrences at extranodal locations. Two-year progression-free survival (PFS) was 44% and 2-year overall survival (OS) was 82%. Salvage treatments varied widely, including chemotherapy and radiotherapy (RT) (7), surgery and RT (3), and surgery, chemotherapy, and RT (3). On univariate analysis of PFS, symptoms at recurrence (P=0.04) and extranodal recurrences (P<0.01) were found to be statistically significant negative prognosticators for PFS. On univariate analysis of OS, increasing age at recurrence and presence of symptoms were found to have a trend toward statistically significant association with negative OS outcomes (P=0.08 and P=0.10, respectively). CONCLUSIONS: Our study demonstrates that long-term survival for pelvic or abdominal recurrences is possible with curative salvage therapy. The presence of symptoms is a negative prognostic factor in treatment outcome, and imaging may be effective for diagnosis in symptomatic and asymptomatic patients. Larger studies need to be performed to confirm these findings. PMID- 26237195 TI - Influence of noncircular chainring on male physiological parameters in hand cycling. AB - The purpose of this study was to examine the influence of a noncircular chainring (NCC) compared with a conventional circular chainring (CC) on hand cycling performance. Eleven nondisabled male participants with no hand cycling experience initially completed an incremental exercise test. Afterward, the participants completed two 20 s sprint tests, followed by a 20 min endurance test and then another two 20 s sprint tests. An NCC and a CC were used in random order on two separate occasions. To compare the effects of the NCC and CC on power data of the sprint tests and metabolic response during the endurance test, a two-way analysis of variance for repeated measures was used. Average power values of the sprint tests showed no significant difference between NCC and CC, but over time, values of the first and third sprint tests were higher than those of the second and fourth sprint tests for both chainrings. Values of energy expenditure (kilojoules), gross efficiency (percentage), and net efficiency (percentage) after 10 and 20 min during the endurance test using NCC and CC showed no significant differences (p > 0.05) either between tests or over time. Under the current test conditions and focusing on physiological parameters, a performance optimization using an NCC in hand cycling could not be proven. PMID- 26237196 TI - Baseline Predictors for Good Versus Poor Visual Outcomes in the Treatment of Neovascular Age-Related Macular Degeneration With Intravitreal Anti-VEGF Therapy. AB - PURPOSE: To examine the baseline factors associated with good (20/60 or better) versus poor (20/200 or worse) visual outcomes in eyes with treatment-naive neovascular age-related macular degeneration (AMD) receiving intravitreal antivascular endothelial growth factor (VEGF) on a treat-and-extend regimen (TER). METHODS: An observational, retrospective series of patients managed with a TER, identified as having either good or poor visual outcomes, was examined. A multivariate regression analysis of baseline characteristics identified factors associated with good and poor vision at 2, 3, and 4 years. Neovascular subtypes were identified using fluorescein angiography (FA) alone and the anatomic classification system with FA and optical coherence tomography (OCT). RESULTS: One hundred thirty-eight patients (154 eyes) fit the inclusion criteria at 2 years, 106 patients (113 eyes) at 3 years, and 72 patients (74 eyes) at 4 years. In the multivariate analysis, type 1 lesions, according to anatomic classification, had better vision at 24 months (95% CI: [3.1, 82.7], P = 0.01), 36 months (95% CI: [1.97, 24.17], P = 0.003), and 48 months (95% CI: [2.01, 65.47], P = 0.006). Clopidogrel use was associated with poor vision at 24 months (95% CI: [0.03, 0.68], P = 0.013). Vision at 3 months was the best predictor of vision at year 4 (beta = -4.277, P = 0.002). CONCLUSIONS: Eyes with neovascular AMD managed with a TER of anti-VEGF therapy having type 1 neovascularization at baseline were more likely to maintain good vision over 4 years, whereas clopidogrel use predicted poor vision at 2 years. Vision at 3 months was the best predictor for favorable long-term vision. PMID- 26237197 TI - Quantitative Noninvasive Angiography of the Fovea Centralis Using Speckle Variance Optical Coherence Tomography. AB - PURPOSE: To demonstrate the utility of speckle variance optical coherence tomography (svOCT), a noninvasive angiographic technique, for evaluating the foveal vasculature. METHODS: Twelve normal human eyes were imaged with svOCT (1060-nm, 100-kHz custom-built system) and fluorescein angiography (FA; Topcon TRC-50DX with 5.0 megapixel resolution camera). Manual tracing techniques were used to quantify the foveal vasculature, including foveal avascular zone (FAZ) metrics (area, perimeter, greatest diameter, and lowest diameter). Reproducibility of these measurements was determined. The FAZ was imaged in 25 normal eyes using svOCT and 15 donor eyes using confocal scanning laser microscopy. Retinal capillary plexuses in donor eyes were perfusion-labeled with phalloidin conjugated to Alexa Fluor 546. RESULTS: Speckle variance OCT is able to stratify the foveal circulation into inner and deep capillary plexuses as well as reliably quantify and assess the morphometric dimensions of the human FAZ. Capillary density measurements were significantly greater in svOCT than FA (31.2 +/- 1.6% vs. 19.3 +/- 1.9% of total tissue area; P < 0.001). Measurements were highly reproducible (all P > 0.366). All FAZ metrics were significantly lower in histology than svOCT (all P < 0.001). CONCLUSIONS: Speckle variance OCT permits precise, reproducible, and noninvasive visualization of the human foveal vasculature. Speckle variance OCT may become an important adjunct in evaluating patients with retinal vascular diseases. PMID- 26237199 TI - Endovascular Therapy for Acute Ischemic Stroke: Dawn of a New Era. PMID- 26237198 TI - Accurate Imputation-Based Screening of Gln368Ter Myocilin Variant in Primary Open Angle Glaucoma. AB - PURPOSE: Myocilin (MYOC) is a well-established primary open-angle glaucoma (POAG) risk gene, with rare variants known to have high penetrance. The most common clinically relevant risk variant, Gln368Ter, has an allele frequency of 0.1% to 0.3% in populations of European ancestry. Detection of rare MYOC variants has traditionally been conducted using Sanger sequencing. Here we report the use of genotyping arrays and imputation to assess whether rare variants including Gln368Ter can be reliably detected. METHODS: A total of 1155 cases with advanced POAG and 1992 unscreened controls genotyped on common variant arrays participated in this study. Accuracy of imputation of Gln368Ter variants was compared with direct sequencing. A genome-wide association study was performed using additive model adjusted for sex and the first six principal components. RESULTS: We found that although the arrays we used were designed to tag common variants, we could reliably impute the Gln368Ter variant (rs74315329). When tested in 1155 POAG cases and 1992 controls, rs74315329 was strongly associated with risk (odds ratio = 15.53, P = 1.07 * 10-9). All POAG samples underwent full sequencing of the MYOC gene, and we found a sensitivity of 100%, specificity of 99.91%, positive predictive value of 95.65%, and negative predictive value of 100% between imputation and sequencing. Gln368Ter was also accurately imputed in a further set of 1801 individuals without POAG. Among the total set of 3793 (1992 + 1801) individuals without POAG, six were predicted (probability > 95%) to carry the risk variant. CONCLUSIONS: We demonstrate that some clinically important rare variants can be reliably detected using arrays and imputation. These results have important implications for the detection of clinically relevant incidental findings in ongoing and future studies using arrays. PMID- 26237200 TI - Use of an Online Patient Portal and Glucose Control in Primary Care Patients with Diabetes. AB - The objective was to assess the effect of online use of a patient portal on improvement of glycohemoglobin (HbA1c) in patients with type 2 diabetes presenting to primary care clinics. This retrospective cohort design used data from a primary care patient data registry that captured all ambulatory visits to the academic medical center's primary care clinics. A total of 1510 patients with diabetes were included because they had at least 1 visit with a documented HbA1c value between January 1, 2010, and June 30, 2013. Degree of patient portal use was defined as no use, read only, and read and write. Linear regression models were computed to measure the association between degree of patient portal use and HbA1c control before and after adjusting for demographics, comorbidity, and volume of health care use. Patients who were nonusers of the patient portal's e mail function had consistently higher average HbA1c values than patients who read and wrote e-mails. After adjusting for demographics, health services utilization, and comorbid conditions, patients who read and wrote e-mails still had significantly (P<0.001) lower average HbA1c values compared to nonusers (beta= 0.455; 95% confidence interval [CI]:-.632-.277). In adjusted analysis, patients who only read e-mail also had significantly (P<0.05) lower mean HbA1c values compared to nonusers (beta=-0.311, 95%CI:-.61--0.012). Patients with more active e-mail communication via a patient portal appeared to have the greatest likelihood of HbA1c control. Patients should be encouraged to use this resource as a means of communication with providers and not merely a passive source of information. (Population Health Management 2016;19:125-131). PMID- 26237201 TI - Closing the Treatment Gap for Cardiac Rehabilitation. PMID- 26237202 TI - Circulating persistent organic pollutants and body fat distribution: Evidence from NHANES 1999-2004. AB - OBJECTIVE: To evaluate and compare the correlations of various circulating persistent organic pollutants (POPs) with fat mass percentages (FM%) of trunk, leg, and whole body measured by dual-energy X-ray absorptiometry. METHODS: This study included 2358 adults (>=20 years) in the National Health and Nutrition Examination Survey 1999-2004. Partial Pearson correlation coefficients were calculated, after adjusting for major confounders, including age, smoking status, and history of lactation and parity. Wolfe's method was used to compare correlation coefficients derived from the same participants. RESULTS: Twelve POPs showed significantly different correlations with fat depots in trunk and leg regions. beta-hexachlorocyclohexane, heptachlorodibenzo-p-dioxin, octachlorodibenzo-p-dioxin, and polychlorinated biphenyl (PCB)-126 showed stronger positive correlations with trunk FM% than with leg FM%, whereas PCBs with >=6 chlorines were more inversely correlated with trunk FM% than leg FM%. Age-stratified analysis showed stronger inverse correlations between POPs and trunk FM% mainly in participants <40 years, whereas stronger positive correlations between POPs and trunk FM% were observed in older participants. CONCLUSIONS: Stronger associations between POPs and trunk fat as compared to leg fat possibly indicated a more important role of trunk fat in the pharmacokinetics of POPs, or a stronger effect of POPs, as endocrine disruptors, on trunk fat metabolism. PMID- 26237208 TI - Predicting recidivism with the Psychological Inventory of Criminal Thinking Styles (PICTS) in community-supervised male and female federal offenders. AB - Higher order scores derived from the Psychological Inventory of Criminal Thinking Styles (PICTS; Walters, 1995) have been found to predict recidivism in released prison inmates with effect sizes in the low-moderate to medium range. The current study sought to determine whether the PICTS is capable of predicting general recidivism in a sample of 81,881 male and 14,519 female offenders on federal probation or supervised release. Results indicated that the PICTS General Criminal Thinking, Proactive, and Reactive scores and 6 of the 7 thinking style scales predicted recidivism in follow-ups of 6 or more months, 12 or more months, and 24 or more months with effect sizes in the low-moderate to medium range. The effect sizes were reduced to small and low-moderate, respectively, when age and prior arrests were controlled for in a series of partial correlations. It was also noted that the PICTS General Criminal Thinking score contributed significant diagnostic information to recidivism prediction in both males and females above and beyond the information provided by a comprehensive risk assessment procedure. These results indicate that the PICTS may be a useful adjunct to other risk assessment procedures in providing comprehensive risk prediction and management services to offenders under community supervision. (PsycINFO Database Record PMID- 26237203 TI - Terminal PEGylated DNA-Gold Nanoparticle Conjugates Offering High Resistance to Nuclease Degradation and Efficient Intracellular Delivery of DNA Binding Agents. AB - Over the past 10 years, polyvalent DNA-gold nanoparticle (DNA-GNP) conjugate has been demonstrated as an efficient, universal nanocarrier for drug and gene delivery with high uptake by over 50 different types of primary and cancer cell lines. A barrier limiting its in vivo effectiveness is limited resistance to nuclease degradation and nonspecific interaction with blood serum contents. Herein we show that terminal PEGylation of the complementary DNA strand hybridized to a polyvalent DNA-GNP conjugate can eliminate nonspecific adsorption of serum proteins and greatly increases its resistance against DNase I-based degradation. The PEGylated DNA-GNP conjugate still retains a high cell uptake property, making it an attractive intracellular delivery nanocarrier for DNA binding reagents. We show that it can be used for successful intracellular delivery of doxorubicin, a widely used clinical cancer chemotherapeutic drug. Moreover, it can be used for efficient delivery of some cell-membrane-impermeable reagents such as propidium iodide (a DNA intercalating fluorescent dye currently limited to the use of staining dead cells only) and a diruthenium complex (a DNA groove binder), for successful staining of live cells. PMID- 26237204 TI - Sex-based biomedical research policy needs an implementation plan. PMID- 26237209 TI - Reliability, factor structure, and measurement invariance of the Dominic Interactive across European countries: Cross-country utility of a child mental health self-report. AB - Large-scale international surveys are important to globally evaluate, monitor, and promote children's mental health. However, use of young children's self reports in these studies is still controversial. The Dominic Interactive, a computerized DSM-IV-based child mental health self-report questionnaire, has unique characteristics that may make it preeminently appropriate for usage in cross-country comparisons. This study aimed to determine scale score reliabilities (omega) of the Dominic Interactive in a sample of 8,135 primary school children, ages 6-11 years old, in 7 European countries, to confirm the proposed 7-scale factor structure, and to test for measurement invariance of scale and item scores across countries. Omega reliability values for scale scores were good to high in every country, and the factor structure was confirmed for all countries. A thorough examination of measurement invariance provided evidence for cross-country test score comparability of 5 of the 7 scales and partial scale score invariance of 2 anxiety scales. Possible explanations for this partial invariance include cross-country differences in conceptualizing items and defining what is socially and culturally acceptable anxiety. The convincing evidence for validity of score interpretation makes the Dominic Interactive an indispensable tool for cross-country screening purposes. (PsycINFO Database Record PMID- 26237210 TI - Assessing the triarchic model of psychopathy in adolescence: Reliability and validity of the Triarchic Psychopathy Measure (TriPM) in three samples of Italian community-dwelling adolescents. AB - To assess the psychometric properties and construct validity of the Italian translation of the Triarchic Psychopathy Measure (TriPM) in adolescents, we administered the inventory to 3 independent samples of Italian high school students (Ns = 609, 618, and 1,142). Cronbach's alpha values greater than .80 were observed for the TriPM scale scores in all samples. In Sample 1, overall scores on the Youth Psychopathic Traits Inventory correlated substantially with TriPM total scores, r = .77, p < .001. Data from Study 1 also demonstrated adequate 3-month test-retest reliabilities for the 3 TriPM subscales. In Study 2, TriPM scores significantly predicted scores on a self-report measure of delinquent behaviors, Radjusted2 = .25, p < .001. In Study 3, five-factor domain scores showed significant relations with TriPM scale scores consistent with results reported for adults. Consistent with a hypothesized role of fearlessness in psychopathy, adolescents at high psychopathy risk (i.e., >97th percentile on the TriPM) reported lower fear in response to emotion-eliciting movie clips than low-psychopathy participants. In addition, scores on a measure of hedonistic moral tendencies discriminated between adolescents at high as opposed to low psychopathy. Similarly, scores on the Reflective Function Questionnaire for Youths were negatively correlated with TriPM scores. As a whole, our findings provide further support for the reliability and validity of the TriPM and its cross-cultural utility, and provide initial evidence of its effectiveness with community-dwelling adolescents. PMID- 26237211 TI - Organic-Catholyte-Containing Flexible Rechargeable Lithium Batteries. AB - Organic-catholyte-containing flexible rechargeable lithium batteries are developed using fused cyclic quinone derivatives. The structural dependence of the quinone isomers in the liquid catholyte is studied using a combined experimental and theoretical approach. Stable electrochemical performance even under severe bending/stretching deformations is successfully demonstrated by prototype batteries containing liquid catholytes. PMID- 26237212 TI - Directed Self-Assembly of Micron-Sized Gold Nanoplatelets into Oriented Flexible Stacks with Tunable Interplate Distance. AB - A growing demand for control over the interparticle spacing and the orientation of anisotropic metallic particles into self-assembled structures is fuelled by their use in potential applications such as in plasmonics, catalysis, sensing, and optoelectronics. Here, we present an improved high yield synthesis method to fabricate micron- and submicron-sized gold nanoplatelets with a thickness less than 20 nm using silver nanoplatelets as seeds. By tuning the depth of the secondary minimum in the DLVO interaction potential between these particles, we are able to assemble the platelets into dynamic and flexible stacks containing thousands of platelets arranged face-to-face with well-defined spacing. Moreover, we demonstrate that the length of the stacks, and the interplate distance can be controlled between tens and hundreds of nm with the ionic strength. We use a high frequency external electric field to control the orientation of the stacks and direct the stacks into highly organized 2D and 3D assemblies that strongly polarize light. PMID- 26237213 TI - Key Residues Regulating the Reductase Activity of the Human Mitochondrial Apoptosis Inducing Factor. AB - The human Apoptosis Inducing Factor (hAIF) is a bifunctional NAD(P)H-dependent flavoreductase involved in both mitochondrial energy metabolism and caspase independent cell death. Even though several studies indicate that both functions are redox controlled by NADH binding, the exact role of hAIF as a reductase in healthy mitochondria remains unknown. Upon reduction by NADH, hAIF dimerizes and produces very stable flavin/nicotinamide charge transfer complexes (CTC), by stacking of the oxidized nicotinamide moiety of the NAD(+) coenzyme against the re-face of the reduced flavin ring of its FAD cofactor. Such complexes are critical to restrict the hAIF efficiency as a reductase. The molecular basis of the hAIF reductase activity is here investigated by analyzing the role played by residues contributing to the interaction of the FAD isoalloxazine ring and of the nicotinamide moiety of NADH at the active site. Mutations at K177 and E314 produced drastic effects on the hAIF ability to retain the FAD cofactor, indicating that these residues are important to set up the holo-enzyme active site conformation. Characterization of P173G hAIF indicates that the stacking of P173 against the isoalloxazine ring is relevant to determine the flavin environment and to modulate the enzyme affinity for NADH. Finally, the properties of the F310G and H454S hAIF mutants indicate that these two positions contribute to form a compact active site essential for NADH binding, CTC stabilization, and NAD(+) affinity for the reduced state of hAIF. These features are key determinants of the particular behavior of hAIF as a NADH-dependent oxidoreductase. PMID- 26237214 TI - "Assuming the privilege" of bridging divides: Abigail Fowler-Chumos, practical phrenology, and America's Gilded Age. AB - Nineteenth-century phrenology is often presented as a failed or pseudoscience. Based on erroneous anatomical assumptions and indirect observation, phrenology as such offers historians of psychology an object lesson in what scientists ought not do (e.g., Boring, 1929). As a practical profession, however, phrenology presents a more complicated narrative. This is particularly true in the United States where in the hands of practitioners including and influenced by the Fowler family, phrenology maintained a cultural presence long after being rejected by the scientific and medical mainstream (Janik, 2014). The prevalence of women practitioners, whose work and lives have yet to be adequately explored, represents another complication. Abigail Ayers Doe Fowler-Chumos, third wife of America's "great gun of phrenology" Orson Squire Fowler, is one practitioner worthy of closer examination (Davies, 1955, p. 46). Using the separate spheres concept (Kerber, 1988) and newspaper announcements, articles, and advertisements spanning the 1870s to 1920s, this article explores Abigail Ayers Doe Fowler Chumos' development as a practical phrenologist. Her story suggests much about the unrecognized capacity of practical phrenology to create concepts and practices of selfhood capable of moving women beyond the private and domestic, while also preparing all Americans for modern psychology. PMID- 26237215 TI - Diverse ways of perturbing the human arachidonic acid metabolic network to control inflammation. AB - Inflammation and other common disorders including diabetes, cardiovascular disease, and cancer are often the result of several molecular abnormalities and are not likely to be resolved by a traditional single-target drug discovery approach. Though inflammation is a normal bodily reaction, uncontrolled and misdirected inflammation can cause inflammatory diseases such as rheumatoid arthritis and asthma. Nonsteroidal anti-inflammatory drugs including aspirin, ibuprofen, naproxen, or celecoxib are commonly used to relieve aches and pains, but often these drugs have undesirable and sometimes even fatal side effects. To facilitate safer and more effective anti-inflammatory drug discovery, a balanced treatment strategy should be developed at the biological network level. In this Account, we focus on our recent progress in modeling the inflammation-related arachidonic acid (AA) metabolic network and subsequent multiple drug design. We first constructed a mathematical model of inflammation based on experimental data and then applied the model to simulate the effects of commonly used anti inflammatory drugs. Our results indicated that the model correctly reproduced the established bleeding and cardiovascular side effects. Multitarget optimal intervention (MTOI), a Monte Carlo simulated annealing based computational scheme, was then developed to identify key targets and optimal solutions for controlling inflammation. A number of optimal multitarget strategies were discovered that were both effective and safe and had minimal associated side effects. Experimental studies were performed to evaluate these multitarget control solutions further using different combinations of inhibitors to perturb the network. Consequently, simultaneous control of cyclooxygenase-1 and -2 and leukotriene A4 hydrolase, as well as 5-lipoxygenase and prostaglandin E2 synthase were found to be among the best solutions. A single compound that can bind multiple targets presents advantages including low risk of drug-drug interactions and robustness regarding concentration fluctuations. Thus, we developed strategies for multiple-target drug design and successfully discovered several series of multiple-target inhibitors. Optimal solutions for a disease network often involve mild but simultaneous interventions of multiple targets, which is in accord with the philosophy of traditional Chinese medicine (TCM). To this end, our AA network model can aptly explain TCM anti-inflammatory herbs and formulas at the molecular level. We also aimed to identify activators for several enzymes that appeared to have increased activity based on MTOI outcomes. Strategies were then developed to predict potential allosteric sites and to discover enzyme activators based on our hypothesis that combined treatment with the projected activators and inhibitors could balance different AA network pathways, control inflammation, and reduce associated adverse effects. Our work demonstrates that the integration of network modeling and drug discovery can provide novel solutions for disease control, which also calls for new developments in drug design concepts and methodologies. With the rapid accumulation of quantitative data and knowledge of the molecular networks of disease, we can expect an increase in the development and use of quantitative disease models to facilitate efficient and safe drug discovery. PMID- 26237216 TI - Synthesis of Copper-Antimony-Sulfide Nanocrystals for Solution-Processed Solar Cells. AB - The p-type nanocrystals (NCs) of copper-based chalcogenides, such as CuInSe2 and Cu2ZnSnS4, have attracted increasing attention in photovoltaic applications due to their potential to produce cheap solution-processed solar cells. Herein, we report the synthesis of copper-antimony-sulfide (CAS) NCs with different crystal phases including CuSbS2, Cu3SbS4, and Cu12Sb4S13. In addition, their morphology, crystal phase, and optical properties were characterized using transmission electron microscopy, X-ray diffractometry, UV-vis-near-IR spectroscopy, and photoemission yield spectroscopy. The morphology, crystal phase, and electronic structure were significantly dependent on the chemical composition in the CAS system. Devices were fabricated using particulate films consisting of CAS NCs prepared by spin coating without a high-temperature treatment. The CAS NC-based devices exhibited a diode-like current-voltage characteristic when coupled with an n-type CdS layer. In particular, the CuSbS2 NC devices exhibited photovoltaic responses under simulated sunlight, demonstrating its applicability for use in solution-processed solar cells. PMID- 26237217 TI - Knowledge, Attitudes, Practices and Beliefs about Medical Male Circumcision (MMC) among a Sample of Health Care Providers in Haiti. AB - BACKGROUND: Haiti has the highest number of people living with HIV infection in the Caribbean/Latin America region. Medical male circumcision (MMC) has been recommended to help prevent the spread of HIV. We sought to assess knowledge, attitudes, practices and beliefs about MMC among a sample of health care providers in Haiti. METHODS: A convenience sample of 153 health care providers at the GHESKIO Centers in Haiti responded to an exploratory survey that collected information on several topics relevant to health providers about MMC. Descriptive statistics were calculated for the responses and multivariable logistic regression was conducted to determine opinions of health care providers about the best age to perform MMC on males. Bayesian network analysis and sensitivity analysis were done to identify the minimum level of change required to increase the acceptability of performing MMC at age less than 1 year. RESULTS: The sample consisted of medical doctors (31.0%), nurses (49.0%), and other health care professionals (20.0%). Approximately 76% showed willingness to offer MMC services if they received training. Seventy-six percent believed that their male patients would accept circumcision, and 59% believed infancy was the best age for MMC. More than 90% of participants said that MMC would reduce STIs. Physicians and nurses who were willing to offer MMC if provided with adequate training were 2.5 (1.15-5.71) times as likely to choose the best age to perform MMC as less than one year. Finally, if the joint probability of choosing "the best age to perform MMC" as one year or older and having the mistaken belief that "MMC prevents HIV entirely" is reduced by 63% then the probability of finding that performing MMC at less than one year acceptable to health care providers is increased by 35%. CONCLUSION: Participants demonstrated high levels of knowledge and positive attitudes towards MMC. Although this study suggests that circumcision is acceptable among certain health providers in Haiti, studies with larger and more representative samples are needed to confirm this finding. PMID- 26237218 TI - Investigation of Parallel Radiofrequency Transmission for the Reduction of Heating in Long Conductive Leads in 3 Tesla Magnetic Resonance Imaging. AB - Deep Brain Stimulation (DBS) is increasingly used to treat a variety of brain diseases by sending electrical impulses to deep brain nuclei through long, electrically conductive leads. Magnetic resonance imaging (MRI) of patients pre- and post-implantation is desirable to target and position the implant, to evaluate possible side-effects and to examine DBS patients who have other health conditions. Although MRI is the preferred modality for pre-operative planning, MRI post-implantation is limited due to the risk of high local power deposition, and therefore tissue heating, at the tip of the lead. The localized power deposition arises from currents induced in the leads caused by coupling with the radiofrequency (RF) transmission field during imaging. In the present work, parallel RF transmission (pTx) is used to tailor the RF electric field to suppress coupling effects. Electromagnetic simulations were performed for three pTx coil configurations with 2, 4, and 8-elements, respectively. Optimal input voltages to minimize coupling, while maintaining RF magnetic field homogeneity, were determined for all configurations using a Nelder-Mead optimization algorithm. Resulting electric and magnetic fields were compared to that of a 16 rung birdcage coil. Experimental validation was performed with a custom-built 4 element pTx coil. In simulation, 95-99% reduction of the electric field at the tip of the lead was observed between the various pTx coil configurations and the birdcage coil. Maximal reduction in E-field was obtained with the 8-element pTx coil. Magnetic field homogeneity was comparable to the birdcage coil for the 4- and 8-element pTx configurations. In experiment, a temperature increase of 2+/ 0.15 degrees C was observed at the tip of the wire using the birdcage coil, whereas negligible increase (0.2+/-0.15 degrees C) was observed with the optimized pTx system. Although further research is required, these initial results suggest that the concept of optimizing pTx to reduce DBS heating effects holds considerable promise. PMID- 26237220 TI - Ecosystem Evapotranspiration as a Response to Climate and Vegetation Coverage Changes in Northwest Yunnan, China. AB - Climate and human-driven changes play an important role in regional droughts. Northwest Yunnan Province is a key region for biodiversity conservation in China, and it has experienced severe droughts since the beginning of this century; however, the extent of the contributions from climate and human-driven changes remains unclear. We calculated the ecosystem evapotranspiration (ET) and water yield (WY) of northwest Yunnan Province, China from 2001 to 2013 using meteorological and remote sensing observation data and a Surface Energy Balance System (SEBS) model. Multivariate regression analyses were used to differentiate the contribution of climate and vegetation coverage to ET. The results showed that the annual average vegetation coverage significantly increased over time with a mean of 0.69 in spite of the precipitation fluctuation. Afforestation/reforestation and other management efforts attributed to vegetation coverage increase in NW Yunnan. Both ET and WY considerably fluctuated with the climate factors, which ranged from 623.29 mm to 893.8 mm and -51.88 mm to 384.40 mm over the time period. Spatially, ET in the southeast of NW Yunnan (mainly in Lijiang) increased significantly, which was in line with the spatial trend of vegetation coverage. Multivariate linear regression analysis indicated that climatic factors accounted for 85.18% of the ET variation, while vegetation coverage explained 14.82%. On the other hand, precipitation accounted for 67.5% of the WY. We conclude that the continuous droughts in northwest Yunnan were primarily climatically driven; however, man-made land cover and vegetation changes also increased the vulnerability of local populations to drought. Because of the high proportion of the water yield consumed for subsistence and poor infrastructure for water management, local populations have been highly vulnerable to climate drought conditions. We suggest that conservation of native vegetation and development of water-conserving agricultural practices should be implemented as adaptive strategies to mitigate climate change. PMID- 26237219 TI - Dexmedetomidine Reduces Shivering during Mild Hypothermia in Waking Subjects. AB - BACKGROUND AND PURPOSE: Reducing body temperature can prolong tolerance to ischemic injury such as stroke or myocardial infarction, but is difficult and uncomfortable in awake patients because of shivering. We tested the efficacy and safety of the alpha-2-adrenergic agonist dexmedetomidine for suppressing shivering induced by a rapid infusion of cold intravenous fluids. METHODS: Ten subjects received a rapid intravenous infusion of two liters of cold (4 degrees C) isotonic saline on two separate test days, and we measured their core body temperature, shivering, hemodynamics and sedation for two hours. On one test day, fluid infusion was preceded by placebo infusion. On the other test day, fluid infusion was preceded by 1.0 MUg/kg bolus of dexmedetomidine over 10 minutes. RESULTS: All ten subjects experienced shivering on placebo days, with shivering beginning at a mean (SD) temperature of 36.6 (0.3) degrees C. The mean lowest temperature after placebo was 36.0 (0.3) degrees C (range 35.7-36.5 degrees C). Only 3/10 subjects shivered on dexmedetomidine days, and the mean lowest temperature was 35.7 (0.4) degrees C (range 35.0-36.3 degrees C). Temperature remained below 36 degrees C for the full two hours in 6/10 subjects. After dexmedetomidine, subjects had moderate sedation and a mean 26 (13) mmHg reduction in blood pressure that resolved within 90 minutes. Heart rate declined a mean 23 (11) bpm after both placebo and dexmedetomidine. Dexmedetomidine produced no respiratory depression. CONCLUSION: Dexmedetomidine decreases shivering in normal volunteers. This effect is associated with decreased systolic blood pressure and sedation, but no respiratory depression. PMID- 26237221 TI - Knapsack--TOPSIS Technique for Vertical Handover in Heterogeneous Wireless Network. AB - In a heterogeneous wireless network, handover techniques are designed to facilitate anywhere/anytime service continuity for mobile users. Consistent best possible access to a network with widely varying network characteristics requires seamless mobility management techniques. Hence, the vertical handover process imposes important technical challenges. Handover decisions are triggered for continuous connectivity of mobile terminals. However, bad network selection and overload conditions in the chosen network can cause fallout in the form of handover failure. In order to maintain the required Quality of Service during the handover process, decision algorithms should incorporate intelligent techniques. In this paper, a new and efficient vertical handover mechanism is implemented using a dynamic programming method from the operation research discipline. This dynamic programming approach, which is integrated with the Technique to Order Preference by Similarity to Ideal Solution (TOPSIS) method, provides the mobile user with the best handover decisions. Moreover, in this proposed handover algorithm a deterministic approach which divides the network into zones is incorporated into the network server in order to derive an optimal solution. The study revealed that this method is found to achieve better performance and QoS support to users and greatly reduce the handover failures when compared to the traditional TOPSIS method. The decision arrived at the zone gateway using this operational research analytical method (known as the dynamic programming knapsack approach together with Technique to Order Preference by Similarity to Ideal Solution) yields remarkably better results in terms of the network performance measures such as throughput and delay. PMID- 26237222 TI - Potentially Modifiable Factors Associated with Death of Infants and Children with Severe Pneumonia Routinely Managed in District Hospitals in Malawi. AB - OBJECTIVE: To investigate recognised co-morbidities and clinical management associated with inpatient pneumonia mortality in Malawian district hospitals. METHODS: Prospective cohort study, of patient records, carried out in Malawi between 1st October 2000 and 30th June 2003. The study included all children aged 0-59 months admitted to the paediatric wards in sixteen district hospitals throughout Malawi with severe and very severe pneumonia. We compared individual factors between those that survived (n = 14 076) and those that died (n = 1 633). RESULTS: From logistic regression analysis, predictors of death in hospital, adjusted for age, sex and severity grade included comorbid conditions of meningitis (OR =2.49, 95% CI 1.50-4.15), malnutrition (OR =2.37, 95% CI 1.94 2.88) and severe anaemia (OR =1.41, 95% CI 1.03-1.92). Requiring supplementary oxygen (OR =2.16, 95% CI 1.85-2.51) and intravenous fluids (OR =3.02, 95% CI 2.13 4.28) were associated with death while blood transfusion was no longer significant (OR =1.10, 95% CI 0.77-1.57) when the model included severe anaemia. CONCLUSIONS: This study identified a number of challenges to improve outcome for Malawian infants and children hospitalised with pneumonia. These included improved assessment of co-morbidities and more rigorous application of standard case management. PMID- 26237223 TI - Online analysis of single cyanobacteria and algae cells under nitrogen-limited conditions using aerosol time-of-flight mass spectrometry. AB - Metabolomics studies typically perform measurements on populations of whole cells which provide the average representation of a collection of many cells. However, key mechanistic information can be lost using this approach. Investigating chemistry at the single cell level yields a more accurate representation of the diversity of populations within a cell sample; however, this approach has many analytical challenges. In this study, an aerosol time-of-flight mass spectrometer (ATOFMS) was used for rapid analysis of single algae and cyanobacteria cells with diameters ranging from 1 to 8 MUm. Cells were aerosolized by nebulization and directly transmitted into the ATOFMS. Whole cells were determined to remain intact inside the instrument through a combination of particle sizing and imaging measurements. Differences in cell populations were observed after perturbing Chlamydomonas reinhardtii cells via nitrogen deprivation. Thousands of single cells were measured over a period of 4 days for nitrogen-replete and nitrogen limited conditions. A comparison of the single cell mass spectra of the cells sampled under the two conditions revealed an increase in the dipalmitic acid sulfolipid sulfoquinovosyldiacylglycerol (SQDG), a chloroplast membrane lipid, under nitrogen-limited conditions. Single cell peak intensity distributions demonstrate the ability of the ATOFMS to measure metabolic differences of single cells. The ATOFMS provides an unprecedented maximum throughput of 50 Hz, enabling the rapid online measurement of thousands of single cell mass spectra. PMID- 26237224 TI - Proteomic Analysis of Isolated Plasma Membrane Fractions from the Mammary Gland in Lactating Cows. AB - The mammary gland of dairy cows is a formidable lipid-synthesizing machine for lactation. This unique function depends on the activities of plasma membrane (PM) proteins in mammary cells. Little information is known about the expression profiles of PM proteins and their functions during the lactating process. This study investigated the proteome map of PM fractions of mammary gland in lactating cows using 1D-Gel-LC-MS/MS and identified 872 nonredundant proteins with 141 unknown proteins, wherein 215 were PM-associated proteins. Most of the PM associated proteins were binding, transport, and catalytic proteins such as annexin proteins, heat shock proteins, integrins, RAS oncogene family members, and S100 calcium binding proteins. The PM-associated pathways such as caveolae mediated endocytosis, leukocyte extravasation, aldosterone signaling in epithelial cells, and remodeling of epithelial adherens junctions were also significantly over-represented. Proteomic analysis revealed the characteristics and predicted functions of PM proteins isolated from the lactating bovine mammary gland. These results further provide experimental evidence for the presence of many proteins predicted in the annotated bovine genome. The data generated here also provide a reference for the PM-related functional research in the mammary gland of lactating cows. PMID- 26237225 TI - ARM-seq: AlkB-facilitated RNA methylation sequencing reveals a complex landscape of modified tRNA fragments. AB - High-throughput RNA sequencing has accelerated discovery of the complex regulatory roles of small RNAs, but RNAs containing modified nucleosides may escape detection when those modifications interfere with reverse transcription during RNA-seq library preparation. Here we describe AlkB-facilitated RNA methylation sequencing (ARM-seq), which uses pretreatment with Escherichia coli AlkB to demethylate N(1)-methyladenosine (m(1)A), N(3)-methylcytidine (m(3)C) and N(1)-methylguanosine (m(1)G), all commonly found in tRNAs. Comparative methylation analysis using ARM-seq provides the first detailed, transcriptome scale map of these modifications and reveals an abundance of previously undetected, methylated small RNAs derived from tRNAs. ARM-seq demonstrates that tRNA fragments accurately recapitulate the m(1)A modification state for well characterized yeast tRNAs and generates new predictions for a large number of human tRNAs, including tRNA precursors and mitochondrial tRNAs. Thus, ARM-seq provides broad utility for identifying previously overlooked methyl-modified RNAs, can efficiently monitor methylation state and may reveal new roles for tRNA fragments as biomarkers or signaling molecules. PMID- 26237226 TI - Automated, high-throughput derivation, characterization and differentiation of induced pluripotent stem cells. AB - Induced pluripotent stem cells (iPSCs) are an essential tool for modeling how causal genetic variants impact cellular function in disease, as well as an emerging source of tissue for regenerative medicine. The preparation of somatic cells, their reprogramming and the subsequent verification of iPSC pluripotency are laborious, manual processes limiting the scale and reproducibility of this technology. Here we describe a modular, robotic platform for iPSC reprogramming enabling automated, high-throughput conversion of skin biopsies into iPSCs and differentiated cells with minimal manual intervention. We demonstrate that automated reprogramming and the pooled selection of polyclonal pluripotent cells results in high-quality, stable iPSCs. These lines display less line-to-line variation than either manually produced lines or lines produced through automation followed by single-colony subcloning. The robotic platform we describe will enable the application of iPSCs to population-scale biomedical problems including the study of complex genetic diseases and the development of personalized medicines. PMID- 26237227 TI - ProteoPlex: stability optimization of macromolecular complexes by sparse-matrix screening of chemical space. AB - Molecular machines or macromolecular complexes are supramolecular assemblies of biomolecules with a variety of functions. Structure determination of these complexes in a purified state is often tedious owing to their compositional complexity and the associated relative structural instability. To improve the stability of macromolecular complexes in vitro, we present a generic method that optimizes the stability, homogeneity and solubility of macromolecular complexes by sparse-matrix screening of their thermal unfolding behavior in the presence of various buffers and small molecules. The method includes the automated analysis of thermal unfolding curves based on a biophysical unfolding model for complexes. We found that under stabilizing conditions, even large multicomponent complexes reveal an almost ideal two-state unfolding behavior. We envisage an improved biochemical understanding of purified macromolecules as well as a substantial boost in successful macromolecular complex structure determination by both X-ray crystallography and cryo-electron microscopy. PMID- 26237228 TI - EEG and functional ultrasound imaging in mobile rats. AB - We developed an integrated experimental framework that extends the brain exploration capabilities of functional ultrasound imaging to awake and mobile rats. In addition to acquiring hemodynamic data, this method further allows parallel access to electroencephalography (EEG) recordings of neuronal activity. We illustrate this approach with two proofs of concept: a behavioral study on theta rhythm activation in a maze running task and a disease-related study on spontaneous epileptic seizures. PMID- 26237230 TI - Interstellar Anions: The Role of Quantum Chemistry. AB - Six anions have been conclusively detected in the interstellar medium (ISM). They all arrived within a five-year window ending five years ago. Why have no new anions been detected? It is likely a lack of laboratory data for novel anions. This work reviews the role that valence and dipole-bound excited states may play in the formation, detection, and lifetime of anions that may yet be observed in the ISM and how quantum chemistry enhances this understanding. The list of interstellar anions has certainly not been exhausted by any means, but electronic, spectroscopic, and structural data must be provided to aid in any future detections. Quantum chemistry has the flexibility and completeness to provide a full picture of these systems and has shown exceptional accuracies of late. The work reviewed herein gives an overview of what quantum chemical computations have produced and will continue to provide related to anions and how this will enhance both laboratory experiment and astronomical observation. PMID- 26237229 TI - Mutational interference mapping experiment (MIME) for studying RNA structure and function. AB - RNA regulates many biological processes; however, identifying functional RNA sequences and structures is complex and time-consuming. We introduce a method, mutational interference mapping experiment (MIME), to identify, at single nucleotide resolution, the primary sequence and secondary structures of an RNA molecule that are crucial for its function. MIME is based on random mutagenesis of the RNA target followed by functional selection and next-generation sequencing. Our analytical approach allows the recovery of quantitative binding parameters and permits the identification of base-pairing partners directly from the sequencing data. We used this method to map the binding site of the human immunodeficiency virus-1 (HIV-1) Pr55(Gag) protein on the viral genomic RNA in vitro, and showed that, by analyzing permitted base-pairing patterns, we could model RNA structure motifs that are crucial for protein binding. PMID- 26237231 TI - Erratum: The reduction of surface plasmon losses in quasi-suspended graphene. PMID- 26237232 TI - Corrigendum: DW-F5: A novel formulation against malignant melanoma from Wrightia tinctoria. PMID- 26237233 TI - Polysulfide-Blocking Microporous Polymer Membrane Tailored for Hybrid Li-Sulfur Flow Batteries. AB - Redox flow batteries (RFBs) present unique opportunities for multi-hour electrochemical energy storage (EES) at low cost. Too often, the barrier for implementing them in large-scale EES is the unfettered migration of redox active species across the membrane, which shortens battery life and reduces Coulombic efficiency. To advance RFBs for reliable EES, a new paradigm for controlling membrane transport selectivity is needed. We show here that size- and ion selective transport can be achieved using membranes fabricated from polymers of intrinsic microporosity (PIMs). As a proof-of-concept demonstration, a first generation PIM membrane dramatically reduced polysulfide crossover (and shuttling at the anode) in lithium-sulfur batteries, even when sulfur cathodes were prepared as flowable energy-dense fluids. The design of our membrane platform was informed by molecular dynamics simulations of the solvated structures of lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) vs lithiated polysulfides (Li2Sx, where x = 8, 6, and 4) in glyme-based electrolytes of different oligomer length. These simulations suggested polymer films with pore dimensions less than 1.2-1.7 nm might incur the desired ion-selectivity. Indeed, the polysulfide blocking ability of the PIM-1 membrane (~0.8 nm pores) was improved 500-fold over mesoporous Celgard separators (~17 nm pores). As a result, significantly improved battery performance was demonstrated, even in the absence of LiNO3 anode protecting additives. PMID- 26237234 TI - Bacterially Antiadhesive, Optically Transparent Surfaces Inspired from Rice Leaves. AB - Because of the growing prevalence of antimicrobial resistance strains, there is an increasing need to develop material surfaces that prevent bacterial attachment and contamination in the absence of antibiotic agents. Herein, we present bacterial antiadhesive materials inspired from rice leaves. "Rice leaf-like surfaces" (RLLS) were fabricated by a templateless, self-masking reactive-ion etching approach. Bacterial attachment on RLLS was characterized under both static and dynamic conditions using Gram-negative Escherichia coli O157:H7 and Gram-positive Staphylococcus aureus. RLLS surfaces showed exceptional bacterial antiadhesion properties with a >99.9% adhesion inhibition efficiency. Furthermore, the optical properties of RLLS were investigated using UV-vis-NIR spectrophotometry. In contrast to most other bacterial antiadhesive surfaces, RLLS demonstrated optical-grade transparency (i.e., >=92% transmission). We anticipate that the combination of bacterial antiadhesion efficiency, optical grade transparency, and the convenient single-step method of preparation makes RLLS a very attractive candidate for the surfaces of biosensors; endoscopes; and microfluidic, bio-optical, lab-on-a-chip, and touchscreen devices. PMID- 26237235 TI - Acute pain assessment tools: let us move beyond simple pain ratings. AB - PURPOSE OF REVIEW: This review highlights challenges and current trends in tools used to assess acute pain across the lifespan. RECENT FINDINGS: A plethora of similar assessment tools exist for acute pain, most focused on self-report of pain intensity. Attempts to improve the frequency and visibility of pain assessment by prompting pain as 'the fifth vital sign' resulted in unintended consequences, creating a pressing need for a conceptual shift to multidimensional assessment of acute pain. SUMMARY: Valid and pragmatic assessment of pain is essential for effective pain management. Unidimensional scales that capture self reported pain intensity ratings undervalue to the complexity of the pain experience. Pain is a biopsychosocial experience and assessment is a complex social transaction and an exchange of the meaning of pain that demands a more comprehensive approach. PMID- 26237236 TI - New oral anticoagulants and neuraxial regional anesthesia. AB - PURPOSE OF REVIEW: As the increased use of new oral anticoagulants may put patients at particular risk of bleeding, experts suggested strategies to perform neuraxial anesthesia as well tolerated as possible. This review summarizes different approaches. RECENT FINDINGS: Data from licensing studies, drug pharmacology, registries, authorities and expert opinions are available and covered by the article. Spinal epidural hematoma formation associated with neuraxial blocks is rare. There has been no epidural hematoma described in the scientific literature with the concurrent use of new oral anticoagulants and neuroaxial anesthesia yet. SUMMARY: A simplified approach covering recent recommendations is given which may aid well tolerated use of neuraxial blocks in patients taking new oral anticoagulants. PMID- 26237237 TI - Nucleation and Growth of Lithium Peroxide in the Li-O2 Battery. AB - We study the relationship between Li2O2 morphology and the electrochemical performance of the Li-O2 battery using a combination of experiment and theory. Experimental Li-O2 battery discharge curves are accurately captured by a theoretical model in which electrode performance is limited by the nucleation and growth of discrete Li2O2 nanostructures in the cathode. We further show that the characteristic sharp voltage drop widely reported at the end of discharge results from the decrease in electrochemical surface area as Li2O2 covers the cathode surface. Preventing surface nucleation is highlighted as a core strategy for increasing Li-O2 battery capacity. PMID- 26237238 TI - Bibliometric Analysis of Medication Errors and Adverse Drug Events Studies. AB - OBJECTIVES: Medication errors and adverse drug events are a key concern of the health-care industry. The objectives of this study were to map the intellectual structure of the studies of medication errors and adverse drug events and to investigate the developing path of this literature and interrelationships among the main topics. METHODS: The Web of Science database was searched for documentation of medication errors and adverse drug events from 1961 to 2013. The most cited articles and references were profiled and analyzed using HistCite software to draw a historiograph and Ucinet software to draw a sociogram. RESULTS: The database search revealed 3343 medication errors and 3342 adverse drug event documents. The most cited articles on medication errors focused on 3 key themes from 1961 to 2013, namely, medication errors in adult inpatients, computerized physician order entry in medication error studies, and medication errors in pediatric inpatients. The developing path for the most cited articles about adverse drug events from 1987 to 2013 was as follows: detection, analysis, effect, and prevention from adult inpatient to pediatric inpatient settings and from hospitalized care to ambulatory care. In addition, social network analysis based on the most cited references revealed a close relationship between medication errors and adverse drug events. CONCLUSIONS: The mapping results provide a valuable tool for researchers to access the literature in this field and can be used to help identify the direction of medication errors and adverse drug events research. PMID- 26237239 TI - Impact and Culture Change After the Implementation of a Preprocedural Checklist in an Interventional Radiology Department. AB - OBJECTIVE: It has been accepted that the implementation of the a preprocedural surgical checklist can reduce perioperative morbidity and mortality in the operating suite. From this success, there has been focus on applying this intervention to other clinical areas. The objective of this study was to evaluate the acceptance and culture change after the implementation of a preprocedural checklist in the interventional radiology suite. METHODS: A preimplementation audit was performed to identify the need for a checklist in the department. A checklist was then developed, based on the surgical model. At 1 and 12 months after implementation, a survey was distributed to the staff at 3 separate teaching centers. RESULTS: Results showed that opinion of the checklist was generally positive, with staff agreement that it served as an important communication tool was in the patient's best interest, and presented a good opportunity for the team to identify important issues. CONCLUSIONS: The checklist was regarded as having little effect on delay between cases. In our setting, the checklist has become a useful and consistent safety measure to ensure that relevant patient data are brought to the forefront before intervention. As a secondary benefit, it also serves as an important communication tool and improves collaboration among team members. PMID- 26237240 TI - VITREOMACULAR TRACTION AFFECTS ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT OUTCOMES FOR EXUDATIVE AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To evaluate the effect of vitreomacular traction (VMT) on visual acuity outcomes and central retinal thickness (CRT) measurements after intravitreal anti vascular endothelial growth factor (anti-VEGF) therapy for treatment of exudative age-related macular degeneration (AMD). METHODS: In this retrospective series, the authors evaluate the clinical records and optical coherence tomography of 34 eyes of 32 patients, with VMT confirmed on optical coherence tomography at baseline, to assess the effects of VMT on anti-VEGF therapy for newly diagnosed exudative wet AMD. Best-corrected visual acuity at baseline, 1, 3, 6, 9, and 12 months and CRT at baseline, 3, 6, and 12 months were assessed. Comparison was made with a control group of 29 eyes of 28 patients with wet AMD and no VMT on optical coherence tomography and with key variable-dosing studies for anti-VEGF in exudative AMD (CATT, HARBOR, PrONTO, SUSTAIN, and Gupta et al). RESULTS: Best corrected visual acuity results showed a visual acuity improvement that peaked at 3 months with 2.47 letters, well below other variable-dosing studies for anti VEGF therapy in exudative AMD. This was then followed by a steady decline with mean best-corrected visual acuity at 12 months ending below the baseline level ( 1.00 letters) compared with a gain of 9.39 letters in the control group at 12 months. Comparison of the mean CRT in the VMT group between baseline and 12 months showed no significant difference (P = 0.67), whereas the PrONTO study and control groups showed a highly significant difference at 12 months compared with baseline (P < 0.001). Mean CRT values at 6 months and 12 months were essentially at baseline levels (0.26 MUm, -0.62 MUm, respectively). CONCLUSION: Vitreomacular traction at baseline, existing concurrently with newly diagnosed exudative AMD treated with intravitreal anti-VEGF therapy on a variable-dosing regime, was associated with poorer visual outcomes and a decreased response to reduction in CRT, compared with a control group of wet AMD without VMT and compared with major variable-dosing studies for intravitreal anti-VEGF in exudative AMD. PMID- 26237241 TI - 2-Phenoxy-1,4-naphthoquinones: From a Multitarget Antitrypanosomal to a Potential Antitumor Profile. AB - A small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives was initially developed to optimize the antitrypanosomatid profile of the multitarget hit compound B6 (1). The whole series was evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and two compounds (14 and 21) showed good activity, despite a concomitant mammalian cytotoxicity. Furthermore, a subset also inhibited the glycolytic TbGAPDH enzyme in vitro. In light of these results and aware of the antitumor properties of quinones, the anticancer potential of some selected derivatives was investigated. Intriguingly, the tested compounds displayed antitumor activity, while being less toxic against noncancerous cells. The observed cytotoxic potency was ascribed to a multitarget mechanism of action accounting for hGAPDH inhibition and mitochondrial toxicity. Overall, the development of further derivatives, able to finely modulate multiple pathways of cancer or parasite cell metabolism, might lead to more effective treatments against these devastating diseases. PMID- 26237242 TI - Negative emissions physically needed to keep global warming below 2 degrees C. AB - To limit global warming to <2 degrees C we must reduce the net amount of CO2 we release into the atmosphere, either by producing less CO2 (conventional mitigation) or by capturing more CO2 (negative emissions). Here, using state-of the-art carbon-climate models, we quantify the trade-off between these two options in RCP2.6: an Intergovernmental Panel on Climate Change scenario likely to limit global warming below 2 degrees C. In our best-case illustrative assumption of conventional mitigation, negative emissions of 0.5-3 Gt C (gigatonnes of carbon) per year and storage capacity of 50-250 Gt C are required. In our worst case, those requirements are 7-11 Gt C per year and 1,000-1,600 Gt C, respectively. Because these figures have not been shown to be feasible, we conclude that development of negative emission technologies should be accelerated, but also that conventional mitigation must remain a substantial part of any climate policy aiming at the 2- degrees C target. PMID- 26237243 TI - Central action of ELABELA reduces food intake and activates arginine vasopressin and corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. AB - ELABELA (ELA) is a novel hormone consisting of 32 amino acid peptides found in humans as well as other vertebrates and is considered to play an important role in the circulatory system through the apelin receptor (APJ). However, whether ELA also acts in the central nervous system remains unknown. Here, we show that ELA functions as an anorexigenic hormone in adult mouse brain. An intracerebroventricular injection of ELA reduces food intake and activates arginine vasopressin (AVP) and corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN), a hypothalamic region that regulates food intake. Cytosolic calcium ([Ca]i) measurement shows that ELA dose dependently increases [Ca]i in single AVP and CRH-immunoreactive neurons isolated from the PVN. Our data suggest that ELA functions as an anorexigenic hormone through activation of AVP and CRH neurons in the PVN. PMID- 26237244 TI - Hybrid model of price pair comparisons: evidence from an event-related potential study. AB - It remains unclear whether number and unit are represented holistically (i.e. number and unit were processed as a whole) or compositionally (number and unit were processed separately) in the brain. The current study asked participants to compare price pairs with different monetary units that were presented serially. The close and far distances were defined in terms of the overall magnitude between two prices. Electrophysiological results showed that the distance effects were observed on the N2 component at the frontal regions, with far distances eliciting more negativity than close distances. This result suggests that participants compute the holistic price magnitudes before comparing them. Furthermore, a congruence effect was observed in the parietal regions. Incongruent prices elicited more negative amplitude than congruent prices on the N2 component, which implied that numbers and monetary units were processed separately over the same time course. Taken together, these findings suggest that numbers and monetary units are represented holistically and compositionally, which supports the hybrid model. PMID- 26237245 TI - Tempol alleviates intracerebral hemorrhage-induced brain injury possibly by attenuating nitrative stress. AB - Intracerebral hemorrhage (ICH)-induced brain injury leads to irreversible disruption of the blood-brain barrier (BBB) and fatality brain edema with massive cell death. Although secondary damage could, in principle, be preventable, no effective treatment approaches currently exist for patients with ICH. Tempol, a catalytic scavenger of peroxynitrite (ONOO)-derived free radicals, has been proven to ameliorate brain injury in several types of brain insults. This study aims to investigate the potential neuroprotective effect of tempol after ICH and to explore the underlying mechanisms. Collagenase-induced ICH was performed in rats. Tempol was administered immediately after ICH. The effects of tempol on ICH were evaluated by assessing neurological deficits, BBB permeability, brain edema, and apoptotic cell death. The mechanisms of action of tempol, with its clear ability on the derivative of ONOO [3-nitrotyrosine (3-NT), ONOO, and its derivative-mediated nitration marker] and expression of tight junction protein [zonula occludens-1 (ZO-1)], were also investigated. Perihematomal 3-NT increased significantly following ICH and expressed around vessels accompanied by reduced and discontinuous expression of ZO-1. Tempol treatment significantly suppressed 3 NT formation and preserved ZO-1 levels, and led to improvement in neurological outcomes and reduction of BBB leakiness, brain edema, and apoptosis. In conclusion, tempol has neuroprotective potential in experimental ICH and may help combat ICH-induced brain injury in patients. PMID- 26237247 TI - Taming Cell Penetrating Peptides: Never Too Old To Teach Old Dogs New Tricks. AB - Cell penetrating peptides (CPPs) have received substantial attention due to their intrinsic property to cross plasma membranes or even as helpers to facilitate the cellular entry of drug molecules, macromolecules, and nanoparticles. Although CPPs and CPP-like peptides provided versatile platforms for drug delivery, their nonselectivity or lack of delivery efficiency is stirring up debates as to the tactics for the optimizing the CPPs themselves. The good news is that, as spurred by the recent progress in the understanding of tumor microenvironment as well as biochemistry and material sciences, we have made attempts in working on perfecting or even "taming" CPPs and CPP-functionalized drug vectors for tumor delivery, and some of them afforded gratifying results. Due to the fact that these peptides are mainly short peptides made up of amino acids (5-30 amino acids), the addition, modification, or replacement of amino acids might lead to surprisingly improved performance. Several novel environment-responsive CPPs or CPP-like peptides have also been discovered. In this review we will discuss the measures taken to harness the power of CPPs and the discovery of environment responsive peptides with CPP properties. PMID- 26237246 TI - Atmospheric Feedback of Urban Boundary Layer with Implications for Climate Adaptation. AB - Atmospheric structure changes in response to the urban form, land use, and the type of land cover (LULC). This interaction controls thermal and air pollutant transport and distribution. The interrelationships among LULC, ambient temperature, and air quality were analyzed and found to be significant in a case study in Cincinnati, Ohio, U.S.A. Within the urban canopy layer (UCL), traffic origin PM2.5 and black carbon followed Gaussian dispersion in the near road area in the daytime, while higher concentrations, over 1 order of magnitude, were correlated to the lapse rate under nocturnal inversions. In the overlying urban boundary layer (UBL), ambient temperature and PM2.5 variations were correlated among urban-wide locations indicating effective thermal and mass communications. Beyond the spatial correlation, LULC-related local urban heat island effects are noteworthy. The high-density urbanized zone along a narrow highway-following corridor is marked by higher nighttime temperature by ~1.6 degrees C with a long term increase by 2.0 degrees C/decade, and by a higher PM2.5 concentration, than in the low-density residential LULC. These results indicate that the urban LULC may have contributed to the nocturnal thermal inversion affecting urban air circulation and air quality in UCL and UBL. Such relationships point to the potentials of climate adaptation through urban planning. PMID- 26237248 TI - Pressure-Induced Transition of Bilayers in a Nonionic Surfactant Solution. AB - Pressure effects on the bilayers of polyoxyethylene type nonionic surfactant in water have been investigated by means of small- and wide-angle X-ray scattering. It has been found that the Krafft transition from the micellar phase to the lamellar gel phase (Lbeta) is induced by pressure. By further pressurizing, the lamellar structural parameters, such as the repeat distance d and Caille parameter eta, discontinuously decrease after taking a maximum. All the SAXS and WAXS results revealed that the Lbeta phase is transformed into the higher-ordered lamellar crystal phase (Lc). On the basis of these observations, we have made the T-C and T-P phase diagrams. PMID- 26237249 TI - Treatment and Prevention of Bone Metastases from Breast Cancer: A Comprehensive Review of Evidence for Clinical Practice. AB - Bone is the most common site of metastasis from breast cancer. Bone metastases from breast cancer are associated with skeletal-related events (SREs) including pathological fractures, spinal cord compression, surgery and radiotherapy to bone, as well as bone pain and hypercalcemia, leading to impaired mobility and reduced quality of life. Greater understanding of the pathophysiology of bone metastases has led to the discovery and clinical utility of bone-targeted agents such as bisphosphonates and the receptor activator of nuclear factor kappa-B ligand (RANK-L) antibody, denosumab. Both are now a routine part of the treatment of breast cancer bone metastases to reduce SREs. With regards to prevention, there is no evidence that oral bisphosphonates can prevent bone metastases in advanced breast cancer without skeletal involvement. Several phase III clinical trials have evaluated bisphosphonates as adjuvant therapy in early breast cancer to prevent bone metastases. The current published data do not support the routine use of bisphosphonates in unselected patients with early breast cancer for metastasis prevention. However, significant benefit of adjuvant bisphosphonates has been consistently observed in the postmenopausal or ovarian suppression subgroup across multiple clinical trials, which raises the hypothesis that its greatest anti-tumor effect is in a low estrogen microenvironment. An individual patient data meta-analysis will be required to confirm survival benefit in this setting. This review summarizes the key evidence for current clinical practice and future directions. PMID- 26237250 TI - Economical Analysis of Different Clinical Approaches in Pre-Viability Amniorrhexis-A Case Series. AB - Prolonged oligohydramnios following extreme preterm prelabour rupture of membranes (EPPROM) is traditionally associated with a high morbidity and mortality to both the mother and the baby. The clinical maternal evaluation and fetal ultrasound assessment may provide important prognostic information for the clinicians and should be taken into account when counselling the patients so as to provide them with enough information to make decision of continuing or interrupting the pregnancy. Current financial constraints on the National Healthcare Service (NHS) resources make it imperative for clinical decision makers and budgetary planners to make the right decision of continuing or terminating a second trimester pre-viability amniorrhexis for desperate parents. To assess the economic consequences following EPPROM, the risk of infection to both baby and mother, psychological impact on the parents and associated complications and further disability after delivery on this fragile group of patients to the NHS resources. We review the clinical course, outcome, and the challenges to parents and health care professionals on three pregnancies complicated by EPPROM, occurring before 24 weeks' gestation with a membrane rupture to delivery interval (latent period) of 14 days or more. The anticipated birth of an extremely premature infant poses many challenges for parents and health care professionals. As parents are faced with difficult decisions that can have a long-term impact on the infant, family and country's resources, it is critical to provide the type of information and support that is needed by them. Taking all these into consideration with the period of ventilation and respiratory assistance in Neonatal Intensive Care Unit (NICU) is essential to provide maximum chances for survival, minimizing the risk for long term sequelae of the neonate and provides the parents enough time to decide on making the right decision with the associated guidance of the healthcare provider. PMID- 26237252 TI - Clinical Guidelines on Long-Term Pharmacotherapy for Bipolar Disorder in Children and Adolescents. AB - Bipolar disorder is a severe affective disorder which can present in adolescence, or sometimes earlier, and often requires a pharmacotherapeutic approach. The phenomenology of bipolar disorder in children and adolescents appears to differ from that of adult patients, prompting the need for specific pharmacotherapy guidelines for long-term management in this patient population. Current treatment guidelines were mainly developed based on evidence from studies in adult patients, highlighting the requirement for further research into the pharmacotherapy of children and adolescents with bipolar disorder. This review compares and critically analyzes the available guidelines, discussing the recommended medication classes, their mechanisms of action, side effect profiles and evidence base. PMID- 26237253 TI - Women's Attitudes Regarding Prenatal Testing for a Range of Congenital Disorders of Varying Severity. AB - Little is known about women's comparative attitudes towards prenatal testing for different categories of genetic disorders. We interviewed women who delivered healthy infants within the past year and assessed attitudes towards prenatal screening and diagnostic testing, as well as pregnancy termination, for Down syndrome (DS), fragile X (FraX), cystic fibrosis (CF), spinal muscular atrophy (SMA), phenylketonuria (PKU) and congenital heart defects (CHD). Ninety-five women aged 21 to 48 years participated, of whom 60% were Caucasian, 23% Asian, 10% Latina and 7% African American; 82% were college graduates. Ninety-five to ninety-eight percent indicated that they would have screening for each condition, and the majority would have amniocentesis (64% for PKU to 72% for SMA). Inclinations regarding pregnancy termination varied by condition: Whereas only 10% reported they would probably or definitely terminate a pregnancy for CHD, 41% indicated they would do so for DS and 62% for SMA. Most women in this cohort reported that they would undergo screening for all six conditions presented, the majority without the intent to terminate an affected pregnancy. These women were least inclined to terminate treatable disorders (PKU, CHD) versus those associated with intellectual disability (DS, FraX) and were most likely to terminate for SMA, typically lethal in childhood. PMID- 26237254 TI - Associations between U.S. Adult Obesity and State and County Economic Conditions in the Recession. AB - This study examines the association between state and county unemployment rates and individuals' body weight status during the latest recession in the U.S. We used the U.S. Behavioral Risk Factor Surveillance System (BRFSS) data in 2007, 2009 and 2011, which were collected from 722,692 American adults aged 18 or older. Overweight and obesity were defined as body mass index (BMI) >=25, and >=30, respectively. Multivariate linear and logistic regressions were applied to assess the association between BMI, risks of overweight and obesity, and state and county unemployment rates. State unemployment rates were negatively associated with individual BMI across years, while county unemployment rates were significantly positively associated with BMI and obesity rates in all years (p < 0.05). However, the scale of the positive relationship was reduced in 2009 and 2011. Stratified analyses were conducted among adults with employment and without employment. The unemployed group's body weight status was not related to state- and county-level economic conditions in most times. In the pooled analyses with all three years' data, the relationship between unemployment rates and body weight status were consistently reduced after the recession of 2008-2009. Our results indicated that macroeconomic conditions at different levels can have different associations with individuals' obesity risk across time. PMID- 26237251 TI - Stem Cells on Biomaterials for Synthetic Grafts to Promote Vascular Healing. AB - This review is divided into two interconnected parts, namely a biological and a chemical one. The focus of the first part is on the biological background for constructing tissue-engineered vascular grafts to promote vascular healing. Various cell types, such as embryonic, mesenchymal and induced pluripotent stem cells, progenitor cells and endothelial- and smooth muscle cells will be discussed with respect to their specific markers. The in vitro and in vivo models and their potential to treat vascular diseases are also introduced. The chemical part focuses on strategies using either artificial or natural polymers for scaffold fabrication, including decellularized cardiovascular tissue. An overview will be given on scaffold fabrication including conventional methods and nanotechnologies. Special attention is given to 3D network formation via different chemical and physical cross-linking methods. In particular, electron beam treatment is introduced as a method to combine 3D network formation and surface modification. The review includes recently published scientific data and patents which have been registered within the last decade. PMID- 26237255 TI - Maternal Germinal Trisomy 21 in Down Syndrome. AB - It has now been over 50 years since it was discovered that Down syndrome is caused by an extra chromosome 21, i.e., trisomy 21. In the interim, it has become clear that in the majority of cases, the extra chromosome is inherited from the mother, and there is, in this respect, a strong maternal age effect. Numerous investigations have been devoted to clarifying the underlying mechanism, most recently suggesting that this situation is exceedingly complex, involving both biological and environmental factors. On the other hand, it has also been proposed that germinal trisomy 21 mosaicism, arising during the very early stages of maternal oogenesis with accumulation of trisomy 21 germ cells during subsequent development, may be the main predisposing factor. We present data here on the incidence of trisomy 21 mosaicism in a cohort of normal fetal ovarian samples, indicating that an accumulation of trisomy 21 germ cells does indeed take place during fetal oogenesis, i.e., from the first to the second trimester of pregnancy. We presume that this accumulation of trisomy 21 (T21) cells is caused by their delay in maturation and lagging behind the normal cells. We further presume that this trend continues during the third trimester of pregnancy and postnatally, up until ovulation, thereby explaining the maternal age effect in Down syndrome. PMID- 26237256 TI - Preferences for Prenatal Tests for Cystic Fibrosis: A Discrete Choice Experiment to Compare the Views of Adult Patients, Carriers of Cystic Fibrosis and Health Professionals. AB - As new technologies enable the development of non-invasive prenatal diagnosis (NIPD) for cystic fibrosis (CF), research examining stakeholder views is essential for the preparation of implementation strategies. Here, we compare the views of potential service users with those of health professionals who provide counselling for prenatal tests. A questionnaire incorporating a discrete choice experiment examined preferences for key attributes of NIPD and explored views on NIPD for CF. Adult patients (n = 92) and carriers of CF (n = 50) were recruited from one children's and one adult NHS specialist CF centre. Health professionals (n = 70) were recruited via an e-mail invitation to relevant professional bodies. The key attribute affecting service user testing preferences was no miscarriage risk, while for health professionals, accuracy and early testing were important. The uptake of NIPD by service users was predicted to be high and includes couples that would currently decline invasive testing. Many service users (47%) and health professionals (55.2%) thought the availability of NIPD for CF would increase the pressure to undergo prenatal testing. Most service users (68.5%) thought NIPD for CF should be offered to all pregnant women, whereas more health professionals (68.2%) thought NIPD should be reserved for known carrier couples. The implications for clinical practice are discussed. PMID- 26237257 TI - Post-Laminectomy Wound Infections: Colonized Seromas Mimicking Wound Infections. AB - OBJECTIVE: Post-operative laminectomy wounds are frequently accompanied by seromas. Post-operative wound drainage may be colonized or infected. The differentiation of wound colonization from infection is difficult for non infectious disease physicians. METHODS: External chart reviewers classified 31/1531 laminectomies (over three years) as post-operative wound infections. We re-evaluated these cases using infectious disease criteria, i.e., while pathogens may be cultured from both colonized and infected wounds, only wound infections have a purulent discharge with abundant white blood cells (WBCs) on Gram stain. Colonized wounds have positive wound cultures but no/few WBCs on Gram stain. RESULTS: We found only 11/31 actual wound infections, the remainder were not bona fide wound infections, but were colonized seromas. CONCLUSION: Post-laminectomy colonized seromas that are culture positive for one or more organisms often mimic wound infections. In the era of public reporting of nosocomial infections, it is important that external reviewers differentiate colonization from infection to provide regulatory agencies with accurate data. PMID- 26237258 TI - Towards a Treatment of Stress Urinary Incontinence: Application of Mesenchymal Stromal Cells for Regeneration of the Sphincter Muscle. AB - Stress urinary incontinence is a significant social, medical, and economic problem. It is caused, at least in part, by degeneration of the sphincter muscle controlling the tightness of the urinary bladder. This muscular degeneration is characterized by a loss of muscle cells and a surplus of a fibrous connective tissue. In Western countries approximately 15% of all females and 10% of males are affected. The incidence is significantly higher among senior citizens, and more than 25% of the elderly suffer from incontinence. When other therapies, such as physical exercise, pharmacological intervention, or electrophysiological stimulation of the sphincter fail to improve the patient's conditions, a cell based therapy may improve the function of the sphincter muscle. Here, we briefly summarize current knowledge on stem cells suitable for therapy of urinary incontinence: mesenchymal stromal cells, urine-derived stem cells, and muscle derived satellite cells. In addition, we report on ways to improve techniques for surgical navigation, injection of cells in the sphincter muscle, sensors for evaluation of post-treatment therapeutic outcome, and perspectives derived from recent pre-clinical studies. PMID- 26237259 TI - Frontotemporal White Matter in Adolescents with, and at-Risk for, Bipolar Disorder. AB - Frontotemporal neural systems are highly implicated in the emotional dysregulation characteristic of bipolar disorder (BD). Convergent genetic, postmortem, behavioral and neuroimaging evidence suggests abnormalities in the development of frontotemporal white matter (WM) in the pathophysiology of BD. This review discusses evidence for the involvement of abnormal WM development in BD during adolescence, with a focus on frontotemporal WM. Findings from diffusion tensor imaging (DTI) studies in adults and adolescents are reviewed to explore possible progressive WM abnormalities in the disorder. Intra- and interhemispheric frontotemporal abnormalities were reported in adults with BD. Although evidence in children and adolescents with BD to date has been limited, similar intrahemispheric and interhemispheric findings have also been reported. The findings in youths suggest that these abnormalities may represent a trait marker present early in the course of BD. Functional connectivity studies, demonstrating a relationship between WM abnormalities and frontotemporal dysfunction in BD, and DTI studies of vulnerability in first-degree relatives of individuals with BD, are discussed. Together, findings suggest the involvement of abnormal frontotemporal WM development in the pathophysiology of BD and that these abnormalities may be early trait markers of vulnerability; however, more studies are critically needed. PMID- 26237260 TI - Circadian Phase Preference in Pediatric Bipolar Disorder. AB - Pediatric bipolar disorder (BD) rates have notably increased over the past three decades. Given the significant morbidity and mortality associated with BD, efforts are needed to identify factors useful in earlier detection to help address this serious public health concern. Sleep is particularly important to consider given the sequelae of disrupted sleep on normative functioning and that sleep is included in diagnostic criteria for both Major Depressive and Manic Episodes. Here, we examine one component of sleep-i.e., circadian phase preference with the behavioral construct of morningness/eveningness (M/E). In comparing 30 BD and 45 typically developing control (TDC) participants, ages 7-17 years, on the Morningness-Eveningness Scale for Children (MESC), no between-group differences emerged. Similar results were found when comparing three groups (BD ADHD; BD+ADHD; TDC). Consistent with data available on circadian phase preference in adults with BD, however, we found that BD adolescents, ages 13 years and older, endorsed significantly greater eveningness compared to their TDC peers. While the current findings are limited by reliance on subjective report and the high-rate of comorbid ADHD among the BD group, this finding that BD teens demonstrate an exaggerated shift towards eveningness than would be developmentally expected is important. Future studies should compare the circadian rhythms across the lifespan for individuals diagnosed with BD, as well as identify the point at which BD youth part ways with their healthy peers in terms of phase preference. In addition, given our BD sample was overall euthymic, it may be that M/E is more state vs. trait specific in latency age youth. Further work would benefit from assessing circadian functioning using a combination of rating forms and laboratory-based measures. Improved understanding of sleep in BD may identify behavioral targets for inclusion in prevention and intervention protocols. PMID- 26237261 TI - Effectiveness of Proadrenomedullin Enhanced CURB65 Score Algorithm in Patients with Community-Acquired Pneumonia in "Real Life", an Observational Quality Control Survey. AB - BACKGROUND: An intervention trial found a trend for shorter length of stay (LOS) in patients with community-acquired pneumonia (CAP) when the CURB65 score was combined with the prognostic biomarker proadrenomedullin (ProADM) (CURB65-A). However, the efficacy and safety of CURB65-A in real life situations remains unclear. METHODS: From September, 2011, until April, 2012, we performed a post study prospective observational quality control survey at the cantonal Hospital of Aarau, Switzerland of consecutive adults with CAP. The primary endpoint was length of stay (LOS) during the index hospitalization and within 30 days. We compared the results with two well-defined historic cohorts of CAP patients hospitalized in the same hospital with the use of multivariate regression, namely 83 patients in the observation study without ProADM (OPTIMA I) and the 169 patients in the intervention study (OPTIMA II RCT). RESULTS: A total of 89 patients with confirmed CAP were included. As compared to patients with CURB65 only observed in the OPTIMA I study, adjusted regression analysis showed a significant shorter initial LOS (7.5 vs. 10.4 days; -2.32; 95% CI, -4.51 to 0.13; p = 0.04) when CURB65-A was used in clinical routine. No significant differences were found for LOS within 30 days. There were no significant differences in safety outcomes in regard to mortality and ICU admission between the cohorts. CONCLUSION: This post-study survey provides evidence that the use of ProADM in combination with CURB65 (CURB65-A) in "real life" situations reduces initial LOS compared to the CURB65 score alone without apparent negative effects on patient safety. PMID- 26237262 TI - Preimplantation Genetic Diagnosis: Prenatal Testing for Embryos Finally Achieving Its Potential. AB - Preimplantation genetic diagnosis was developed nearly a quarter-century ago as an alternative form of prenatal diagnosis that is carried out on embryos. Initially offered for diagnosis in couples at-risk for single gene genetic disorders, such as cystic fibrosis, spinal muscular atrophy and Huntington disease, preimplantation genetic diagnosis (PGD) has most frequently been employed in assisted reproduction for detection of chromosome aneuploidy from advancing maternal age or structural chromosome rearrangements. Major improvements have been seen in PGD analysis with movement away from older, less effective technologies, such as fluorescence in situ hybridization (FISH), to newer molecular tools, such as DNA microarrays and next generation sequencing. Improved results have also started to be seen with decreasing use of Day 3 blastomere biopsy in favor of polar body or Day 5 trophectoderm biopsy. Discussions regarding the scientific, ethical, legal and social issues surrounding the use of sequence data from embryo biopsy have begun and must continue to avoid concern regarding eugenic or inappropriate use of this technology. PMID- 26237263 TI - Pediatric Bipolar Disorder: Subtype Trend and Impact of Behavioral Comorbidities. AB - The diagnosis of pediatric bipolar disorder (PBD) has increased dramatically in community-treated youth in the past 20 years. No previous study has assessed the trend in PBD subtype diagnoses or the impact of clinician-reported behavioral comorbidities (BC) on psychotropic medication prescribing patterns. This study aims: (1) to characterize national trends in PBD visits in relation to PBD subtypes; and (2) to assess differences in socio-demographic PBD subtype diagnostic patterns and psychotropic medications prescribed in PBD visits with and without behavioral comorbidities (w/w/o BC). PBD visits for 1999-2010 from the National Ambulatory Medical Care Survey (NAMCS) data were assessed using population-weighted chi-square and logistic regression analyses. While PBD visit rates were stable across 12 years, the proportional shift of subtype diagnosis from Bipolar I (89.0%) in 1999-2002 to Bipolar Not Otherwise Specified (NOS) (74.1%) in 2007-2010 was notable. Compared with PBD without behavioral comorbidities (w/o BC), PBD visits w/BC had greater proportions of the bipolar NOS subtype, more males, 2-14-year-olds, and more publicly-insured visits. The prescription of antipsychotics (60% vs. 61%) was common in PBD visits regardless of the presence of behavioral comorbidities. Stimulants were the predominant class prescribed for PBD visits with BC (67.8% vs. 9.4%). Antidepressants were significantly greater in PBD visits without BC (41.6% vs. 21.0%). Overall one third of PBD youth visits were prescribed antipsychotics concomitant with other psychotropic classes. Behavioral conditions accompanying PBD visits were prominent, suggesting the need for monitoring and evaluating the outcomes of complex medication regimens in community populations. PMID- 26237264 TI - The Impacts of Obesity and Metabolic Abnormality on Carotid Intima-Media Thickness and Non-Alcoholic Fatty Liver Disease in Children from an Inland Chinese City. AB - The Chinese inland, where low child obesity and overweight rates were reported in earlier studies, has recently experienced rapid economy changes. This may impact children's health. In the present study, we investigated the obesity rate, metabolic health status, and their impacts on carotid intima-media thickness (IMT) and non-alcoholic fatty liver disease (NAFLD) among children from Yueyang, an inland city of China. We found that the obesity rate was about 5% for both 7- and 11-year olds. Overweightness rates were 9.5% and 11.5% for the 7- and 11-year olds, respectively. Clinical and laboratory examinations revealed significant differences among different weight groups in the 11-year old volunteers, which were absent in the 7-year olds. Further statistical analysis showed that: age, BMI, blood pressure, triglyceride level, and metabolic abnormality were positively correlated to carotid IMT; triglyceride level, obesity, male, and the number of metabolic abnormalities were independent risk factors for NAFLD in these children. Our study suggests that: childhood overweightness and obesity are now epidemic in Yueyang, which have contributed to increased carotid IMT and may also increased NAFLD incidents; and serum triglyceride level is a critical factor in the development of childhood NAFLD. Thus, childhood metabolic health warrants further vigorous research in the inland of China. PMID- 26237265 TI - Volumetric x-ray coherent scatter imaging of cancer in resected breast tissue: a Monte Carlo study using virtual anthropomorphic phantoms. AB - Breast cancer patients undergoing surgery often choose to have a breast conserving surgery (BCS) instead of mastectomy for removal of only the breast tumor. If post-surgical analysis such as histological assessment of the resected tumor reveals insufficient healthy tissue margins around the cancerous tumor, the patient must undergo another surgery to remove the missed tumor tissue. Such re excisions are reported to occur in 20%-70% of BCS patients. A real-time surgical margin assessment technique that is fast and consistently accurate could greatly reduce the number of re-excisions performed in BCS. We describe here a tumor margin assessment method based on x-ray coherent scatter computed tomography (CSCT) imaging and demonstrate its utility in surgical margin assessment using Monte Carlo simulations. A CSCT system was simulated in GEANT4 and used to simulate two virtual anthropomorphic CSCT scans of phantoms resembling surgically resected tissue. The resulting images were volume-rendered and found to distinguish cancerous tumors embedded in complex distributions of adipose and fibroglandular breast tissue (as is expected in the breast). The images exhibited sufficient spatial and spectral (i.e. momentum transfer) resolution to classify the tissue in any given voxel as healthy or cancerous. ROC analysis of the classification accuracy revealed an area under the curve of up to 0.97. These results indicate that coherent scatter imaging is promising as a possible fast and accurate surgical margin assessment technique. PMID- 26237266 TI - Auditory difficulties in blast-exposed Veterans with clinically normal hearing. AB - Vast numbers of blast-injured Operation Iraqi Freedom/Operation Enduring Freedom/Operation New Dawn personnel report postconcussive symptoms that include headache, dizziness, poor memory, and difficulty concentrating. In addition, many report hearing problems, such as difficulty understanding speech in noise, yet have no measureable peripheral auditory deficits. In this article, self-report and performance-based measures were used to assess 99 blast-exposed Veterans. All participants reported auditory problems in difficult listening situations but had clinically normal hearing. Participants' scores on self-report questionnaires of auditory difficulties were more similar to scores of older individuals with hearing impairment than to those of younger individuals with normal hearing. Participants showed deficits relative to published normative data on a number of performance-based tests that have demonstrated sensitivity to auditory processing deficits. There were several measures on which more than the expected number of participants (15.9%) performed one or more standard deviations below the mean. These were assessments of speech understanding in noise, binaural processing, temporal resolution, and speech segregation. Performance was not universally poor, with approximately 53% of participants performing abnormally on between 3 and 6 of the 10 measures. We concluded that participants exhibited task-specific deficits that add to the evidence suggesting that blast injury results in damage to the central auditory system. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov; Approaches to Auditory Rehabilitation for Mild Traumatic Brain Injury (mTBI); NCT00930774; https://clinicaltrials.gov/ct2/show/NCT00930774?term=NCT00930774&rank=1. PMID- 26237267 TI - Diazoalkane complexes of ruthenium with tris(pyrazolyl)borate and bis(pyrazolyl)acetate ligands. AB - Diazoalkane complexes [Ru(Tp)(N2CAr1Ar2)(PPh3)L]BPh4 ( and ) [Tp = tris(pyrazolyl)borate; L = P(OMe)3, P(OEt)3; Ar1 = Ar2 = Ph; Ar1 = Ph, Ar2 = p tolyl; Ar1Ar2 = C12H8] were prepared by allowing chloro-compounds RuCl(Tp)(PPh3)L to react with diazoalkane in the presence of NaBPh4. Acrylonitrile CH2[double bond, length as m-dash]C(H)CN reacts with diazoalkane complexes to give 3H pyrazole derivatives [Ru(Tp){N[double bond, length as m dash]NC(Ar1Ar2)CH(CN)CH2}(PPh3){P(OMe)3}]BPh4 and [Ru(Tp){N[double bond, length as m-dash]NC(Ar1Ar2)CH2C(H)CN}(PPh3){P(OMe)3}]BPh4 (). Diazoalkane complexes [Ru(bpza)(N2CAr1Ar2)(PPh3)2]BPh4 () [bpza = bis(pyrazolyl)acetate] were also prepared. All complexes were characterised by IR and NMR spectroscopy and X-ray crystal structure determination of [Ru(Tp){N2C(Ph)(p-tolyl)}(PPh3){P(OMe)3}]BPh4 (). The differences exhibited by [Ru(Tp){N2C(Ph)(p-tolyl)}(PPh3){P(OMe)3}](+) and [Ru(Cp){N2C(Ph)(p-tolyl)}(PPh3){P(OMe)3}](+), as regards coordination of the diazoalkane ligand and reactivity towards alkenes, were explained on the basis of a comparative DFT study. PMID- 26237268 TI - Functional characterization of PCRK1, a putative protein kinase with a role in immunity. AB - In Arabidopsis, defense signaling is triggered by the perception of conserved molecular patterns by pattern recognition receptors (PRRs). Signal transduction from the PRRs requires members of a family of Receptor-Like Cytoplasmic Kinases (RLCKs). Previously, we described one such RLCK, PTI Compromised Receptor-Like Cytoplasmic Kinase 1 (PCRK1) that is important for immunity induced by Microbe Associated Molecular Patterns (MAMPs) as well as Damage Associated Molecular Patterns (DAMPs). In this study, we measured the growth of Pma ES4326 in double mutants carrying pcrk1 together with the salicylic acid (SA) biosynthesis mutation sid2-2 or the jasmonic acid (JA) receptor mutation coi1-1, showing that the function of PCRK1 is SA independent but may be partially dependent on JA. Mutation of phosphorylated serine residues S232, S233 and S237 compromised the immune signaling function of PCRK1. PMID- 26237270 TI - Investigation of the potential of Raman spectroscopy for oral cancer detection in surgical margins. AB - The poor prognosis of oral cavity squamous cell carcinoma (OCSCC) patients is associated with residual tumor after surgery. Raman spectroscopy has the potential to provide an objective intra-operative evaluation of the surgical margins. Our aim was to understand the discriminatory basis of Raman spectroscopy at a histological level. In total, 127 pseudo-color Raman images were generated from unstained thin tissue sections of 25 samples (11 OCSCC and 14 healthy) of 10 patients. These images were clearly linked to the histopathological evaluation of the same sections after hematoxylin and eosin-staining. In this way, Raman spectra were annotated as OCSCC or as a surrounding healthy tissue structure (i.e., squamous epithelium, connective tissue (CT), adipose tissue, muscle, gland, or nerve). These annotated spectra were used as input for linear discriminant analysis (LDA) models to discriminate between OCSCC spectra and healthy tissue spectra. A database was acquired with 88 spectra of OCSCC and 632 spectra of healthy tissue. The LDA models could distinguish OCSCC spectra from the spectra of adipose tissue, nerve, muscle, gland, CT, and squamous epithelium in 100%, 100%, 97%, 94%, 93%, and 75% of the cases, respectively. More specifically, the structures that were most often confused with OCSCC were dysplastic epithelium, basal layers of epithelium, inflammation- and capillary rich CT, and connective and glandular tissue close to OCSCC. Our study shows how well Raman spectroscopy enables discrimination between OCSCC and surrounding healthy tissue structures. This knowledge supports the development of robust and reliable classification algorithms for future implementation of Raman spectroscopy in clinical practice. PMID- 26237271 TI - Klotho: a tumor suppressor and modulator of the Wnt/beta-catenin pathway in human hepatocellular carcinoma. AB - Klotho, an anti-aging gene, has recently been shown to contribute to human hepatic tumorigenesis. In addition, it is known that Wnt signaling is antagonized by the protein klotho. Because augmented Wnt signaling has an important role in tumorigenesis of human hepatocellular carcinoma (HCC), we studied the relationship of klotho expression and activity to the Wnt pathway in this malignancy. Immunohistochemical analysis performed on tissue arrays revealed that klotho expression levels were significantly lower in HCC than in adjacent noncancerous tissues, while klotho staining was inversely correlated with clinical stage and histologic grade. Patients with klotho-expressing tumors had longer survival periods than did those with klotho-negative tumors. Overexpression of klotho as well as treatment with soluble klotho protein reduced hepatoma cell growth in vitro and in vivo, whereas klotho silencing enhanced cellular proliferation. Moreover, forced expression of klotho inhibited Wnt/beta catenin signaling, as confirmed by reduced expression of beta-catenin, inhibition of translocation of beta-catenin from the cytoplasm to the nucleus, and reduced expression of c-myc and cyclin D1, two known target genes of the Wnt/beta-catenin pathway. In contrast, activation of the Wnt/beta-catenin pathway was enhanced when klotho was silenced by inhibitory RNAs. Furthermore, serum levels of soluble klotho in patients with malignant tumors were studied, and results suggested a significant increase in these levels in HCC patients. These data suggest that klotho acts as a tumor suppressor and an inhibitor of the Wnt/beta-catenin pathway in HCC, and moreover, that soluble klotho is a potential serum biomarker for HCC. PMID- 26237272 TI - Whole slide image cytometry: a novel method to detect abnormal DNA content in Barrett's esophagus. AB - Barrett's esophagus (BE) is a precursor of esophageal adenocarcinoma (EAC). Both low-grade dysplasia (LGD) and high-grade dysplasia (HGD) are associated with an increased risk of progression to EAC. However, histological interpretation and grading of dysplasia (particularly LGD) is subjective and poorly reproducible. This study has combined whole slide imaging with DNA image cytometry to provide a novel method for the detection of abnormal DNA content through image analysis of tissue sections. A total of 20 cases were evaluated, including 8 negative for dysplasia (NFD), 6 LGD, and 6 HGD. Feulgen-stained esophageal sections were scanned in their entirety. Barrett's mucosa was interactively chosen for automatic nuclei segmentation where irrelevant cell types were ignored. The combined DNA content histogram for all nuclei within selected image regions was then obtained. In addition, three histogram measurements were computed, including xER-5C, 2cDI, and DNA-MG. Visual evaluation suggested the shape of DNA content histograms from NFD, LGD, and HGD cases exhibiting identifiable differences. The histogram measurements, xER-5C, 2cDI, and DNA-MG, were shown to be effective in differentiating metaplastic from dysplastic cases with statistical significance. Moreover, they also successfully separated NFD, LGD, and HGD patients with statistical significance. Whole slide image cytometry is a novel and effective method for the detection of abnormal DNA content in BE. Compared with histological review, it is more objective. Compared with flow cytometry and cytology-preparation image cytometry, it is low cost, simple to use, only requires a single 1 MUm section, and facilitates selection of tissue and topographical correlation. Whole slide image cytometry can detect differences in DNA content between NFD, LGD, and HGD patients in this cross-sectional study. Abnormal DNA content detection by whole slide image cytometry is a promising biomarker of progression that could affect future diagnostics in BE. PMID- 26237273 TI - Tissue-type plasminogen activator suppresses activated stellate cells through low density lipoprotein receptor-related protein 1. AB - Hepatic stellate cell (HSC) activation and trans-differentiation into myofibroblast (MFB)-like cells is key for fibrogenesis after liver injury and a potential therapeutic target. Recent studies demonstrated that low-density lipoprotein receptor-related protein 1 (LRP1)-dependent signaling by tissue-type plasminogen activator (t-PA) is a pro-fibrotic regulator of the MFB phenotype in kidney. This study investigated whether LRP1 signaling by t-PA is also relevant to HSC activation following injury. Primary and immortalized rat HSCs were treated with t-PA and assayed by western blot, MTT, and TUNEL. In vitro results were then verified using an in vivo, acute carbon tetrachloride (CCl4) injury model that examined the phenotype and recovery kinetics of MFBs from wild-type animals vs mice with a global (t-PA) or HSC-targeted (LRP1) deletion. In vitro, in contrast to kidney MFBs, exogenous, proteolytically inactive t-PA suppressed, rather than induced, activation markers in HSCs following phosphorylation of LRP1. This process was mediated by LRP1 as inhibition of t-PA binding to LRP1 blocked the effects of t-PA. In vivo, following acute injury, phosphorylation of LRP1 on activated HSCs occurred immediately prior to their disappearance. Mice lacking t-PA or LRP1 retained higher densities of activated HSCs for a longer time period compared with control mice after injury cessation. Hence, t-PA, an FDA-approved drug, contributes to the suppression of activated HSCs following injury repair via signaling through LRP1. This renders t-PA a potential target for exploitation in treating patients with fibrosis. PMID- 26237275 TI - Beyond the Butterfly: Sc2C2@C(2v)(9)-C86, an Endohedral Fullerene Containing a Planar, Twisted Sc2C2 Unit with Remarkable Crystalline Order in an Unprecedented Carbon Cage. AB - The synthesis, isolation, and characterization of a new endohedral fullerene, Sc2C88, is reported. Characterization by single crystal X-ray diffraction revealed that it is the carbide Sc2C2@C(2v)(9)-C86 with a planar, twisted Sc2C2 unit inside a previously unseen C(2v)(9)-C86 fullerene cage. PMID- 26237274 TI - Inhibition of dipeptidyl peptidase IV protects tacrolimus-induced kidney injury. AB - Accumulating evidence shows that a gut-released hormone, the glucagon-like peptide-1 (GLP-1), has not only a glucose-lowering effect but also a renoprotective effect against kidney injury. In this study, we investigated whether a dipeptidyl peptidase (DPP) IV inhibitor has a protective effect against tacrolimus-induced renal injury. Rats were treated with tacrolimus (1.5 mg/kg, subcutaneously) and the DPP IV inhibitor MK0626 (10 or 20 mg/kg, oral gavage) for 4 weeks. MK0626 treatment attenuated tacrolimus-induced renal dysfunction, tubulointerstitial fibrosis, and arteriolopathy. Moreover, these improvements were accompanied by a reduction in oxidative stress and apoptosis. MK0626 treatment increased the blood level of GLP-1 and the level of its receptor in tissue sections but did not alter the levels of other DPP IV substrates, such as neuropeptide Y and the stromal cell-derived factor-1. These data suggest that DPP IV inhibition has an important role in the renoprotection against tacrolimus induced nephrotoxicity via antioxidative and antiapoptotic effects and preservation of the GLP-1 system. PMID- 26237276 TI - Efficacy, Safety and Acceptability of Orthokeratology on Slowing Axial Elongation in Myopic Children by Meta-Analysis. AB - PURPOSE: To compare the efficacy, safety and acceptability of a treatment group (Orthokeratology) to a control group (single vision Spectacles) on slowing axial elongation in children. METHODS: We searched studies in MEDLINE, EMBASE and the Cochrane Library up to January 2015 for randomized controlled trials (RCTs) and observational studies. We pooled the mean differences between the Orthokeratology and Control groups for axial elongation and the OR for rates of adverse events and dropout. RESULTS: Three RCTs and six cohort studies with 667 children aged 6 16 years old were included. Two years' mean differences in axial elongation were 0.27 mm (95% confidence intervals [CI], -0.32 to -0.23) in all studies, -0.28 mm (95% CI, -0.35 to -0.20) in RCTs and -0.27 mm (95% CI, -0.32 to -0.22) in cohort studies (p < 0.01). At 6 months, 1 year, 1.5 years and 2 years, mean differences in axial elongation were -0.13 mm, -0.19 mm, -0.23 mm, and -0.27 mm (p < 0.01), respectively. The effect was greater in Asian children than Caucasian (-0.28 mm versus -0.22 mm) and in children with moderate to high myopia when compared to children with low myopia (-0.35 mm versus -0.25 mm). Orthokeratology had more non significant adverse events (odd ratio [OR], 8.87; 95% CI, 3.79-20.74; p < 0.01) but comparable dropout rates (OR = 0.84, 95% CI, 0.40-1.74, p = 0.64) than control. CONCLUSION: Orthokeratology has significantly greater efficacy in controlling axial elongation in children compared to Spectacle correction. The safety and acceptability results are good, and there appears to be a greater myopia control effect in Chinese children compared to Caucasians, and in those with higher initial myopia. PMID- 26237277 TI - Significance of Increasing n-3 PUFA Content in Pork on Human Health. AB - Evidence for the health-promoting effects of food rich in n-3 polyunsaturated fatty acids (n-3 PUFA) is reviewed. Pork is an important meat source for humans. According to a report by the US Department of Agriculture ( http://www.ers.usda.gov/topics ), the pork consumption worldwide in 2011 was about 79.3 million tons, much higher than that of beef (48.2 million tons). Pork also contains high levels of unsaturated fatty acids relative to ruminant meats (Enser, M., Hallett, K., Hewett, B., Fursey, G. A. J. and Wood, J. D. (1996) . Fatty acid content and composition of English beef, lamb, and pork at retail. Meat Sci. 44:443-458). The available literature indicates that the levels of eicosatetraenoic and docosahexaenoic in pork may be increased by fish-derived or linseed products, the extent of which being dependent on the nature of the supplementation. Transgenic pigs and plants show promise with high content of n-3 PUFA and low ratio of n-6/n-3 fatty acids in their tissues. The approaches mentioned for decreasing n-6/n-3 ratios have both advantages and disadvantages. Selected articles are critically reviewed and summarized. PMID- 26237278 TI - Direction of illumination controls gametophyte orientation in seedless plants and related algae. AB - The environmental influences that determine dorsiventral or axial gametophyte orientation are unknown for most modern seedless plants. To fill this gap, an experimental laboratory system was employed to evaluate the relative effects of light direction and gravity on body orientation of the dorsiventral green alga Coleochaete orbicularis, and gametophytes of liverworts Blasia pusilla and Marchantia polymorpha, early-diverging moss Sphagnum compactum, and fern Ceratopteris richardii, the latter functioning as experimental control. Replicate clonal cultures were experimentally illuminated only from above, only from below, or from multiple directions, with the same near-saturation PAR level for periods brief enough to minimize nutrient limitation effects, and orientation of new growth was evaluated. For all species tested, direction of illumination exerted stronger control over gametophyte body orientation than gravity. When illuminated only from below: 1) axial Sphagnum gametophores that had initially grown into an overlying air space inverted growth by 180 degrees , burrowing into the substrate; 2) new growth of dorsiventral Blasia, Marchantia, and Ceratopteris gametophytes-whose ventral rhizoids initially penetrated agar substrate and dorsal surfaces initially faced overlying airspace-twisted 180 degrees so that ventral surfaces bearing rhizoids faced overlying air space and rhizoids extended into the air; and 3) Coleochaete lost typical dorsiventral organization and diagnostic dorsal hairs. Direction of illumination also exerted stronger control over orientation of liverwort new growth than surface contact did. These results indicate that early land plants likely inherited light-directed gametophyte body orientation from ancestral streptophyte algae and suggest a mechanism for reorientation of gametophyte-dominant land plants after spatial disturbance. PMID- 26237279 TI - The effects of plaque morphology and material properties on peak cap stress in human coronary arteries. AB - Heart attacks are often caused by rupture of caps of atherosclerotic plaques in coronary arteries. Cap rupture occurs when cap stress exceeds cap strength. We investigated the effects of plaque morphology and material properties on cap stress. Histological data from 77 coronary lesions were obtained and segmented. In these patient-specific cross sections, peak cap stresses were computed by using finite element analyses. The finite element analyses were 2D, assumed isotropic material behavior, and ignored residual stresses. To represent the wide spread in material properties, we applied soft and stiff material models for the intima. Measures of geometric plaque features for all lesions were determined and their relations to peak cap stress were examined using regression analyses. Patient-specific geometrical plaque features greatly influence peak cap stresses. Especially, local irregularities in lumen and necrotic core shape as well as a thin intima layer near the shoulder of the plaque induce local stress maxima. For stiff models, cap stress increased with decreasing cap thickness and increasing lumen radius (R = 0.79). For soft models, this relationship changed: increasing lumen radius and increasing lumen curvature were associated with increased cap stress (R = 0.66). The results of this study imply that not only accurate assessment of plaque geometry, but also of intima properties is essential for cap stress analyses in atherosclerotic plaques in human coronary arteries. PMID- 26237281 TI - Estimation of hip joint center from the external body shape: a preliminary study. PMID- 26237282 TI - Catalyst-Directed Diastereoselective Isomerization of Allylic Alcohols for the Stereoselective Construction of C(20) in Steroid Side Chains: Scope and Topological Diversification. AB - The stereoselective construction of C20 in steroidal derivatives by a highly diastereoselective Ir-catalyzed isomerization of primary allylic alcohols is reported. A key aspect of this strategy is a straightforward access to geometrically pure steroidal enol tosylate and enol triflate intermediates for subsequent high yielding stereoretentive Negishi cross-coupling reactions to allow structural diversity to be introduced. A range of allylic alcohols participates in the diastereoselective isomerization under the optimized reaction conditions. Electron-rich and electron-poor aryl or heteroaryl substituents are particularly well-tolerated, and the stereospecific nature of the reaction provides indifferently access to the natural C20-(R) and unnatural C20-(S) configurations. Alkyl containing substrates are more challenging as they affect regioselectivity of iridium-hydride insertion. A rationale for the high diastereoselectivities observed is proposed for aryl containing precursors. The scope of our method is further highlighted through topological diversification in the side chain and within the polycyclic domain of advanced and complex steroidal architectures. These findings have the potential to greatly simplify access to epimeric structural analogues of important steroid scaffolds for applications in biological, pharmaceutical, and medical sciences. PMID- 26237280 TI - Regulation of Ace2-dependent genes requires components of the PBF complex in Schizosaccharomyces pombe. AB - The division cycle of unicellular yeasts is completed with the activation of a cell separation program that results in the dissolution of the septum assembled during cytokinesis between the 2 daughter cells, allowing them to become independent entities. Expression of the eng1(+) and agn1(+) genes, encoding the hydrolytic enzymes responsible for septum degradation, is activated at the end of each cell cycle by the transcription factor Ace2. Periodic ace2(+) expression is regulated by the transcriptional complex PBF (PCB Binding Factor), composed of the forkhead-like proteins Sep1 and Fkh2 and the MADS box-like protein Mbx1. In this report, we show that Ace2-dependent genes contain several combinations of motifs for Ace2 and PBF binding in their promoters. Thus, Ace2, Fkh2 and Sep1 were found to bind in vivo to the eng1(+) promoter. Ace2 binding was coincident with maximum level of eng1(+) expression, whereas Fkh2 binding was maximal when mRNA levels were low, supporting the notion that they play opposing roles. In addition, we found that the expression of eng1(+) and agn1(+) was differentially affected by mutations in PBF components. Interestingly, agn1(+) was a major target of Mbx1, since its ectopic expression resulted in the suppression of Mbx1 deletion phenotypes. Our results reveal a complex regulation system through which the transcription factors Ace2, Fkh2, Sep1 and Mbx1 in combination control the expression of the genes involved in separation at the end of the cell division cycle. PMID- 26237283 TI - Males on demand: the environmental-neuro-endocrine control of male sex determination in daphnids. AB - Branchiopod crustaceans (e.g., Daphnia sp.) and some other taxa utilize both asexual and sexual reproduction to maximize population sustainability. The decision to switch from asexual to sexual reproduction is triggered by environmental cues that foretell a potentially detrimental change in environmental conditions. This review describes the cascade of events beginning with environmental cues and ending with changes in gene expression that dictate male sex determination in daphnids, the initial event in the switch to sexual reproduction. Several environmental cues have been identified which, either in isolation or in combination, stimulate male sex determination. These cues are typically associated with change of season, exhaustion of resources or loss of habitat. Maternal daphnids receive and respond to these cues, we propose, through the secretion of neuropeptides, which suppress (hyperglycemic hormone-like neuropeptides, allatostatin) or stimulate (allatotropin) the male sex differentiation program. In response, maternal daphnids produce the male sex determining hormone, methyl farnesoate. Methyl farnesoate binds to a protein MET that dimerizes with the protein SRC forming an active transcription factor. This complex then regulates the expression of genes, primarily doublesex (dsx), involved in programming the single-celled embryo to develop into a male. In the absence of methyl farnesoate programming, the embryo develops into a female. Epigenetic modifications of the genome as a possible mode of methyl farnesoate action and the utility of this model to decipher the role of epigenetics in sex differentiation in other species are discussed. PMID- 26237284 TI - Less severe cerebral palsy outcomes in infants treated with therapeutic hypothermia. AB - AIM: To describe the incidence, type and severity of cerebral palsy at 24 months in a regional cohort of infants treated with whole-body therapeutic hypothermia for neonatal encephalopathy. METHODS: Data were collected prospectively in a regional centre providing TH. Antenatal and perinatal clinical variables and severity of encephalopathy were collected. Infants were assessed at 18 months using the Bayley Scales of Infant and Toddler Development-III, and the presence and severity of CP was investigated at 24 months. RESULTS: A total of 125 of 132 infants fulfilled entry criteria for TH trials and completed 72 h of TH. Sixteen (13%) of the 125 infants died, and eight (6%) were not available for follow-up. Eighteen infants (14%; 18% of those assessed) developed CP. Of these, 12 (67%) were classified using the Gross Motor Function Classification System, at level 1, six (33%) at level 5 and none at levels 2, 3 or 4. CONCLUSION: Our regional clinical cohort had lower mortality and comparable rates of CP compared with historical outcomes in TH trials. In contrast to historical cohorts, only one third of the 18 children with CP were severely affected and 12 were mildly affected, all of whom were independently ambulant by 24 months. PMID- 26237285 TI - Assessing Air Pollutant-Induced, Health-Related External Costs in the Context of Nonmarginal System Changes: A Review. AB - Marginal analysis is the usual approach to environmental economic assessment, for instance, of health-related external costs due to energy-associated air pollutant emissions. However, nonlinearity exists in all steps of their assessment, i.e., atmospheric dispersion, impact assessment, and monetary valuation. Dedicated assessments thus appear necessary when evaluating large systems or their changes such as in green accounting or the implications of economy-wide energy transitions. Corresponding approaches are reviewed. Tools already exist that allow assessing a marginal change (e.g., one power plant's emissions) for different background emission scenarios that merely need to be defined and implemented. When assessing nonmarginal changes, the top-down approach is considered obsolete, and four variants of the bottom-up approach with different application domains were identified. Variants 1 and 2 use precalculated external cost factors with different levels of sophistication, suitable for energy systems modeling, optimizing for social (i.e., private and external) costs. Providing more reliable results due to more detailed modeling, emission sources are assessed individually or jointly in variants 3 and 4, respectively. Aiming at considering nonlinearity more fully and simultaneously following marginal analysis principles, I propose a variant 3-based approach, subdividing an aggregate (i.e., a nonmarginal change) into several smaller changes. Its strengths and drawbacks, notably the associated effort, are discussed. PMID- 26237287 TI - Is motivational interviewing effective at reducing alcohol misuse in young adults? A critical review of Foxcroft et al. (2014). AB - Foxcroft, Coombes, Wood, Allen, and Almeida Santimano (2014) recently conducted a meta-analysis evaluating the effectiveness of motivational interviewing (MI) in reducing alcohol misuse for youth up to Age 25. They concluded that the overall effect sizes of MI in this population were too small to be clinically meaningful. The present article critically reviews the Foxcroft et al. meta-analysis, highlighting weaknesses such as problems with search strategies, flawed screening and reviews of full-text articles, incorrect data abstraction and coding, and, accordingly, improper effect size estimation. In addition, between-study heterogeneity and complex data structures were not thoughtfully considered or handled using best practices for meta-analysis. These limitations undermine the reported estimates and broad conclusion made by Foxcroft et al. about the lack of MI effectiveness for youth. We call for new evidence on this question from better executed studies by independent researchers. Meta-analysis has many important utilities for translational research. When implemented well, the overall effectiveness, as well as different effectiveness for different populations, can be examined via meta-analysis. Emerging methods utilizing individual participant level data, such as integrative data analysis, may be particularly helpful for identifying the sources of clinical and methodological heterogeneity that matter. The need to better understand the mechanisms of alcohol interventions has never been louder in the addiction field. Through more concerted efforts throughout all phases of generating evidence, we may achieve large-scale evidence that is efficient and robust and provides critical answers for the field. PMID- 26237286 TI - Chronic adolescent marijuana use as a risk factor for physical and mental health problems in young adult men. AB - Some evidence suggests that youth who use marijuana heavily during adolescence may be particularly prone to health problems in later adulthood (e.g., respiratory illnesses, psychotic symptoms). However, relatively few longitudinal studies have prospectively examined the long-term physical and mental health consequences associated with chronic adolescent marijuana use. The present study used data from a longitudinal sample of Black and White young men to determine whether different developmental patterns of marijuana use, assessed annually from early adolescence to the mid-20s, were associated with adverse physical (e.g., asthma, high blood pressure) and mental (e.g., psychosis, anxiety disorders) health outcomes in the mid-30s. Analyses also examined whether chronic marijuana use was more strongly associated with later health problems in Black men relative to White men. Findings from latent class growth curve analysis identified 4 distinct subgroups of marijuana users: early onset chronic users, late increasing users, adolescence-limited users, and low/nonusers. Results indicated that the 4 marijuana use trajectory groups were not significantly different in terms of their physical and mental health problems assessed in the mid-30s. The associations between marijuana group membership and later health problems did not vary significantly by race. Findings are discussed in the context of a larger body of work investigating the potential long-term health consequences of early onset chronic marijuana use, as well as the complications inherent in studying the possible link between marijuana use and health effects. PMID- 26237289 TI - Quantile regression analysis of censored longitudinal data with irregular outcome dependent follow-up. AB - In many observational longitudinal studies, the outcome of interest presents a skewed distribution, is subject to censoring due to detection limit or other reasons, and is observed at irregular times that may follow a outcome-dependent pattern. In this work, we consider quantile regression modeling of such longitudinal data, because quantile regression is generally robust in handling skewed and censored outcomes and is flexible to accommodate dynamic covariate outcome relationships. Specifically, we study a longitudinal quantile regression model that specifies covariate effects on the marginal quantiles of the longitudinal outcome. Such a model is easy to interpret and can accommodate dynamic outcome profile changes over time. We propose estimation and inference procedures that can appropriately account for censoring and irregular outcome dependent follow-up. Our proposals can be readily implemented based on existing software for quantile regression. We establish the asymptotic properties of the proposed estimator, including uniform consistency and weak convergence. Extensive simulations suggest good finite-sample performance of the new method. We also present an analysis of data from a long-term study of a population exposed to polybrominated biphenyls (PBB), which uncovers an inhomogeneous PBB elimination pattern that would not be detected by traditional longitudinal data analysis. PMID- 26237288 TI - The academic consequences of marijuana use during college. AB - Although several studies have shown that marijuana use can adversely affect academic achievement among adolescents, less research has focused on its impact on postsecondary educational outcomes. This study utilized data from a large longitudinal cohort study of college students to test the direct and indirect effects of marijuana use on college grade point average (GPA) and time to graduation, with skipping class as a mediator of these outcomes. A structural equation model was evaluated taking into account a variety of baseline risk and protective factors (i.e., demographics, college engagement, psychological functioning, alcohol and other drug use) thought to contribute to college academic outcomes. The results showed a significant path from baseline marijuana use frequency to skipping more classes at baseline to lower first-semester GPA to longer time to graduation. Baseline measures of other drug use and alcohol quantity exhibited similar indirect effects on GPA and graduation time. Over time, the rate of change in marijuana use was negatively associated with rate of change in GPA, but did not account for any additional variance in graduation time. Percentage of classes skipped was negatively associated with GPA at baseline and over time. Thus, even accounting for demographics and other factors, marijuana use adversely affected college academic outcomes, both directly and indirectly through poorer class attendance. Results extend prior research by showing that marijuana use during college can be a barrier to academic achievement. Prevention and early intervention might be important components of a comprehensive strategy for promoting postsecondary academic achievement. PMID- 26237290 TI - Shear wear elastography of the human Achilles tendon: a cadaveric study of factors influencing the repeatability. PMID- 26237291 TI - A Retrospective 30 Years After Discovery of the Enhanced Permeability and Retention Effect of Solid Tumors: Next-Generation Chemotherapeutics and Photodynamic Therapy--Problems, Solutions, and Prospects. AB - Solid tumor has unique vascular architecture, excessive production of vascular mediators, and extravasation of macromolecules from blood vessels into the tumor tissue interstitium. These features comprise the phenomenon named the EPR effect of solid tumors, described in 1986. Our investigations on the EPR revealed that many mediators, such as bradykinin, NO, and prostaglandins, are involved in the EPR effect, which is now believed to be the most important element for cancer selective drug delivery. However, tumors in vivo manifest great diversity, and some demonstrate a poor EPR effect, for example, because of impaired vascular flow involving thrombosis, with poor drug delivery and therapeutic failure. Another important element of this effect is that it operates in metastatic cancers. Because few drugs are currently effective against metastases, the EPR effect offers a great advantage in nanomedicine therapy. The EPR effect can also be augmented two to three times via nitroglycerin, ACE inhibitors, and angiotensin II-induced hypertension. The delivery of nanomedicines to tumors can thereby be enhanced. In traditional PDT, most PSs had low MW and little tumor selective accumulation. Our hydroxypropylmetacrylamide-polymer-conjugated-PS, zinc protoporphyrin (apparent MW >50 kDa) showed tumor-selective accumulation, as revealed by fluorescent imaging of autochthonous cancers. After one i.v. injection of polymeric PS followed by two or three xenon light irradiation/treatments, most tumors regressed. Thus, nanoprobes with the EPR effect seem to have remarkable effects. Enhancing the EPR effect by using vascular modulators will aid innovations in PDT for greater tumor-targeted drug delivery. PMID- 26237292 TI - Molecular biomarkers in colorectal carcinoma. AB - Colorectal cancer is a tumor with increasing incidence which represents one of the first leading causes of death worldwide. Gene alterations described for colorectal cancer include genome instability (microsatellite and chromosomal instability), CpG islands methylator phenotype, microRNA, histone modification, protein biomarkers, gene mutations (RAS, BRAF, PI3K, TP53, PTEN) and polymorphisms (APC, CTNNB1, DCC). In this article, biomarkers with prognostic value commonly found in colorectal cancer will be reviewed. PMID- 26237294 TI - Death without Prolonging Dying. PMID- 26237293 TI - Some fundamental aspects of modeling auxin patterning in the context of auxin ethylene-cytokinin crosstalk. AB - The activities of hormones in the Arabidopsis root depend on cellular context and exhibit either synergistic or antagonistic interactions. Patterning in Arabidopsis root development is coordinated via a localized auxin concentration maximum in the root tip, mediating transcription of key regulatory genes. Auxin concentration and response are each regulated by diverse interacting hormones and gene expression and therefore cannot change independently of those hormones and genes. For example, experimental data accumulated over many years have shown that both ethylene and cytokinin regulate auxin concentration and response. Using the crosstalk of auxin-ethylene-cytokinin as a paradigm, we discuss the links between experimental data, reaction kinetics and spatiotemporal modeling to dissect hormonal crosstalk. In particular, we discuss how kinetic equations for modeling auxin concentration are formulated based on experimental data and also the underlying assumptions for deriving those kinetic equations. Furthermore, we show that, by integrating kinetic equations with spatial root structure, modeling of spatiotemporal hormonal crosstalk is a powerful tool for analyzing and predicting the roles of multiple hormone interactions in auxin patterning. Finally, we summarize important considerations in developing a spatiotemporal hormonal crosstalk model for plant root development. PMID- 26237295 TI - Manual wheelchair satisfaction among long-term users and caregivers: a French study. AB - Wheelchair mobility is a prerequisite to being able to carry out important activities and to participate in social life. Level of satisfaction with the wheelchair and overall quality of life were found to be positively associated. The aim of this study was to determine the level of satisfaction of French manual wheelchair (MW) users and caregivers with MW characteristics. A total of 132 users and 76 caregivers completed a questionnaire about their level of satisfaction with their MW characteristics. Satisfaction scores were independent of age, sex, reason for MW use, and time of use. As a whole, MW users are satisfied. However, a few parameters such as MW weight and difficulties propelling outdoors demonstrate a low level of satisfaction among users. MW weight, brakes, and height of pushing handles are the less satisfying elements among caregivers. In conclusion, the majority of French MW users are satisfied, but some characteristics, such as weight, must be optimized. Considering caregiver needs is paramount when aiming to improve MW parameters such as brakes or pushing handles. Improvement in some wheelchair parameters seems to be important in achieving improved level of satisfaction and increased participation and active lifestyle among MW users and caregivers. PMID- 26237296 TI - Can RNAi Target Salmonid Whirling Disease In Vivo? PMID- 26237297 TI - Winter is coming: How humans forage in a temporally structured environment. AB - Much is known about visual search for single targets, but relatively little about how participants "forage" for multiple targets. One important question is how long participants will search before moving to a new display. Evidence suggests that participants should leave when intake drops below the average rate ("optimal foraging," Charnov, 1976). However, the real world has temporal structure (e.g., seasons) that could influence behavior. Does it matter if winter is coming and the next display will be worse than the last? We gave participants a series of search displays and asked them to collect targets as fast as possible. Target density was structured-rising and falling systematically across trials. We measured the duration for which participants foraged in each display (trials were terminated by participants). Foraging behavior was affected by temporal structure counter to a simple optimal foraging account, observers searched displays longer when quality was falling compared to rising (Experiments 1 and 2). Additionally, we found that temporal structure altered explicit predictions about display quality (Experiment 2). These results demonstrate that foraging theories need to consider richer models of observers' representations of the world. PMID- 26237298 TI - Optimizing the rapid measurement of detection thresholds in infants. AB - Accurate measures of perceptual threshold are difficult to obtain in infants. In a clinical context, the challenges are particularly acute because the methods must yield meaningful results quickly and within a single individual. The present work considers how best to maximize speed, accuracy, and reliability when testing infants behaviorally and suggests some simple principles for improving test efficiency. Monte Carlo simulations, together with empirical (visual acuity) data from 65 infants, are used to demonstrate how psychophysical methods developed with adults can produce misleading results when applied to infants. The statistical properties of an effective clinical infant test are characterized, and based on these, it is shown that (a) a reduced (false-positive) guessing rate can greatly increase test efficiency, (b) the ideal threshold to target is often below 50% correct, and (c) simply taking the max correct response can often provide the best measure of an infant's perceptual sensitivity. PMID- 26237299 TI - Locating the cortical bottleneck for slow reading in peripheral vision. AB - Yu, Legge, Park, Gage, and Chung (2010) suggested that the neural bottleneck for slow peripheral reading is located in nonretinotopic areas. We investigated the potential rate-limiting neural site for peripheral reading using fMRI, and contrasted peripheral reading with recognition of peripherally presented line drawings of common objects. We measured the BOLD responses to both text (three letter words/nonwords) and line-drawing objects presented either in foveal or peripheral vision (10 degrees lower right visual field) at three presentation rates (2, 4, and 8/second). The statistically significant interaction effect of visual field * presentation rate on the BOLD response for text but not for line drawings provides evidence for distinctive processing of peripheral text. This pattern of results was obtained in all five regions of interest (ROIs). At the early retinotopic cortical areas, the BOLD signal slightly increased with increasing presentation rate for foveal text, and remained fairly constant for peripheral text. In the Occipital Word-Responsive Area (OWRA), Visual Word Form Area (VWFA), and object sensitive areas (LO and PHA), the BOLD responses to text decreased with increasing presentation rate for peripheral but not foveal presentation. In contrast, there was no rate-dependent reduction in BOLD response for line-drawing objects in all the ROIs for either foveal or peripheral presentation. Only peripherally presented text showed a distinctive rate dependence pattern. Although it is possible that the differentiation starts to emerge at the early retinotopic cortical representation, the neural bottleneck for slower reading of peripherally presented text may be a special property of peripheral text processing in object category selective cortex. PMID- 26237300 TI - Impact of astigmatism and high-order aberrations on subjective best focus. AB - We studied the role of native astigmatism and ocular aberrations on best-focus setting and its shift upon induction of astigmatism in 42 subjects (emmetropes, myopes, hyperopes, with-the-rule [WTR] and against-the-rule [ATR] myopic astigmats). Stimuli were presented in a custom-developed adaptive optics simulator, allowing correction for native aberrations and astigmatism induction (+1 D; 6-mm pupil). Best-focus search consisted on randomized-step interleaved staircase method. Each subject searched best focus for four different images, and four different conditions (with/without aberration correction, with/without astigmatism induction). The presence of aberrations induced a significant shift in subjective best focus (0.4 D; p < 0.01), significantly correlated (p = 0.005) with the best-focus shift predicted from optical simulations. The induction of astigmatism produced a statistically significant shift of the best-focus setting in all groups under natural aberrations (p = 0.001), and in emmetropes and in WTR astigmats under corrected aberrations (p < 0.0001). Best-focus shift upon induced astigmatism was significantly different across groups, both for natural aberrations and AO-correction (p < 0.0001). Best focus shifted in opposite directions in WTR and ATR astigmats upon induction of astigmatism, symmetrically with respect to the best-focus shift in nonastigmatic myopes. The shifts are consistent with a bias towards vertical and horizontal retinal blur in WTR and ATR astigmats, respectively, indicating adaptation to native astigmatism. PMID- 26237301 TI - Desmosine and Isodesmosine as a Novel Biomarker for Pulmonary Arterial Hypertension: A Pilot Study. AB - Delayed diagnosis is common in patients with pulmonary arterial hypertension (PAH). Right-sided heart catheterization, the gold standard for diagnosis, is invasive and cannot be applied for routine screening. Some biomarkers have been looked into; however, due to the lack of a clear pathological mechanism linking the marker to PAH, the search for an ideal one is still ongoing. Elastin is a significant structural constituent of blood vessels. Its synthesis involves cross linking of monomers by 2 amino acids, desmosine and isodesmosine (D&I). Being extremely stable, elastin undergoes little metabolic turnover in healthy individuals resulting in very low levels of D&I amino acids in the human plasma, urine, or sputum. We hypothesized that in PAH patients, the elastin turnover is high; which in turn should result in elevated levels of D&I in plasma and urine. Using mass spectrometry, plasma and urine levels of D&I were measured in 20 consecutive patients with PAH confirmed by cardiac catheterization. The levels were compared with 13 healthy controls. The mean level of total plasma D&I in patients with PAH was 0.47 ng/mL and in controls was 0.19 ng/mL (P = 0.001). The mean levels of total D&I in the urine of PAH patients was 20.55 mg/g creatinine and in controls was 12.78 mg/g creatinine (P = 0.005). The mean level of free D&I in the urine of PAH patients was 10.34 mg/g creatinine and in controls was 2.52 mg/g creatinine (P < 0.001). This is the first study highlighting that the serum and urine D&I has a potential to be a novel screening biomarker for patients with PAH. It paves the way for larger studies to analyze its role in assessing for disease severity and response to treatment. PMID- 26237302 TI - Abdominoperineal Resection, Pelvic Exenteration, and Additional Organ Resection Increase the Risk of Surgical Site Infection after Elective Colorectal Surgery: An American College of Surgeons National Surgical Quality Improvement Program Analysis. AB - BACKGROUND: Determining predictors of surgical site infection (SSI) in a large cohort is important for the design of accurate SSI surveillance programs. We hypothesized that additional organ resection and pelvic exenterative procedures are associated independently with a higher risk of SSI. METHODS: Patients in the American College of Surgeons National Surgical Quality Improvement Program(r) (ACS NSQIP(r); American College of Surgeons, Chicago, IL) database (2005-2012) were identified (n=112,282). Surgical site infection (superficial or deep SSI) at 30 d was the primary outcome. Using primary and secondary CPT(r) codes (American Medical Association, Chicago, IL) pelvic exenteration was defined and additional organ resection was defined as: bladder resection/repair, hysterectomy, partial vaginectomy, additional segmental colectomy, small bowel, gastric, or diaphragm resection. Univariable analysis of patient and procedure factors identified significant (p<0.05) predictors, which were modeled using stepwise logistic regression. RESULTS: The rate of SSI was 9.2%. After adjusting for operative duration, predictors of SSI were body mass index (BMI) 25-29.9 (odds ratio [OR]: 1.3), BMI 30-34.9 (OR: 1.59), BMI 35-39.9 (OR: 2.11), BMI>40 (OR: 2.51), pulmonary comorbidities (OR: 1.22), smoking (OR: 1.24), bowel obstruction (OR: 1.40), wound classification 3 or 4 (OR: 1.18), and abdominoperineal resection (OR: 1.58). Laparoscopic or laparoscopically assisted procedures offered a protective effect against incision infection (OR: 0.55). Additional organ resection (OR: 1.08) was also associated independently with SSI, but the magnitude of the effect was decreased after accounting for operative duration. In the analysis that excludes operative duration, pelvic exenteration is associated with SSI (OR: 1.38), but incorporating operative duration into the model results in this variable becoming non-significant. CONCLUSIONS: In addition to other factors, obesity, surgery for bowel obstruction, abdominoperineal resection, and additional organ resection are independently associated with a higher risk of SSI. Surgical site infection risk in pelvic exenteration and multiple organ resection cases appears to be mediated by prolonged operative duration. In these established high-risk sub-groups of patients, aggressive interventions to prevent SSI should be implemented. PMID- 26237303 TI - A Telephone Support Program to Reduce Costs and Hospital Admissions for Patients at Risk of Readmissions: Lessons from an Evaluation of a Complex Health Intervention. AB - This study aimed to evaluate the effectiveness of a telephone health coaching and support service provided to members of an Australian private health insurance fund-Telephonic Complex Care Program (TCCP)-on hospital use and associated costs. A case-control pre-post study design was employed using propensity score matching. Private health insurance members (n=273) who participated in TCCP between April and December 2012 (cases) were matched (1:1) to members who had not previously been enrolled in the program or any other disease management programs offered by the insurer (n=232). Eligible members were community dwelling, aged >=65 years, and had 2 or more hospital admissions in the 12 months prior to program enrollment. Preprogram variables that estimated the propensity score included: participant demographics, diagnoses, and hospital use in the 12 months prior to program enrollment. TCCP participants received one-to-one telephone support, personalized care plan, and referral to community-based services. Control participants continued to access usual health care services. Primary outcomes were number of hospital admission claims and total benefits paid for all health care utilizations in the 12 months following program enrollment. Secondary outcomes included change in total benefits paid, hospital benefits paid, ancillary benefits paid, and total hospital bed days over the 12 months post enrollment. Compared with matched controls, TCCP did not appear to reduce health care utilization or benefits paid in the 12 months following program enrollment. However, program characteristics and implementation may have impacted its effectiveness. In addition, challenges related to evaluating complex health interventions such as TCCP are discussed. (Population Health Management 2016;19:187-195). PMID- 26237304 TI - Peripheral Total Tau in Military Personnel Who Sustain Traumatic Brain Injuries During Deployment. AB - IMPORTANCE: Approximately one-third of military personnel who deploy for combat operations sustain 1 or more traumatic brain injuries (TBIs), which increases the risk for chronic symptoms of postconcussive disorder, posttraumatic stress disorder, and depression and for the development of chronic traumatic encephalopathy. Elevated concentrations of tau are observed in blood shortly following a TBI, but, to our knowledge, the role of tau elevations in blood in the onset and maintenance of chronic symptoms after TBI has not been investigated. OBJECTIVES: To assess peripheral tau levels in military personnel exposed to TBI and to examine the relationship between chronic neurological symptoms and tau elevations. DESIGN, SETTING, AND PARTICIPANTS: Observational assessment from September 2012 to August 2014 of US military personnel at the Madigan Army Medical Center who had been deployed within the previous 18 months. Plasma total tau concentrations were measured using a novel ultrasensitive single molecule enzyme-linked immunosorbent assay. Classification of participants with and without self-reported TBI was made using the Warrior Administered Retrospective Casualty Assessment Tool. Self-reported symptoms of postconcussive disorder, posttraumatic stress disorder, and depression were determined by the Neurobehavioral Symptom Inventory, the Posttraumatic Stress Disorder Checklist Military Version, and the Quick Inventory of Depressive Symptomatology, respectively. Group differences in tau concentrations were determined through analysis of variance models, and area under the receiver operating characteristic curve determined the sensitivity and specificity of tau concentrations in predicting TBI and chronic symptoms. Seventy participants with self-reported TBI on the Warrior Administered Retrospective Casualty Assessment Tool and 28 control participants with no TBI exposure were included. MAIN OUTCOMES AND MEASURES: Concentration of total tau in peripheral blood. RESULTS: Concentrations of plasma tau were significantly elevated in the 70 participants with self-reported TBI compared with the 28 controls (mean [SD], 1.13 [0.78] vs 0.63 [0.48] pg/mL, respectively; F1,97 = 4.97; P = .03). Within the self-reported TBI cases, plasma total tau concentrations were significantly associated with having a medical record of TBI compared with self-reported TBI only (mean [SD], 1.57 [0.92] vs 0.85 [0.52] pg/mL, respectively; F1,69 = 6.15; P = .02) as well as reporting the occurrence of 3 of more TBIs during deployment compared with fewer than 3 TBIs (mean [SD], 1.52 [0.82] vs 0.82 [0.60] pg/mL, respectively; F1,69 = 8.57; P = .008). The severity of total postconcussive symptoms correlated with total tau concentrations in the self-reported TBI group (r = 0.37; P = .003). CONCLUSIONS AND RELEVANCE: Military personnel who report multiple TBIs have long-term elevations in total tau concentration. The total tau concentration relates to symptoms of postconcussive disorder. PMID- 26237305 TI - Efficacy of water preloading before main meals as a strategy for weight loss in primary care patients with obesity: RCT. AB - OBJECTIVE: To investigate the efficacy of water preloading before meals as a weight loss strategy for adults with obesity. METHODS: A two-group randomized controlled trial was conducted in Birmingham, England. Eighty-four adults with obesity were recruited from general practices. All participants were given a face to-face weight management consultation at baseline (30 min) and a follow-up telephone consultation at 2 weeks (10 min). At baseline, participants were randomized to either drinking 500 ml of water 30 min before their main meals or an attention control group where participants were asked to imagine their stomach was full before meals. The primary outcome was weight change at 12-week follow up. Several measures of adherence were also used, including 24 h total urine collections. RESULTS: 41 participants were randomized to the intervention group and 43 to the comparator group. The water preloading group lost -1.3 kg (95% CI 2.4 to -0.1, P = 0.028) more than comparators at follow up. Adjusting for ethnicity, deprivation, age, and gender resulted in the intervention group losing -1.2 kg (95% CI -2.4 to 0.07, P = 0.063) more than the comparator. CONCLUSIONS: There is preliminary evidence that water preloading before main meals leads to a moderate weight loss at follow up. ISRCTN33238158. PMID- 26237306 TI - Downloading Diabetes Device Information. PMID- 26237307 TI - Upcoming Devices for Diabetes Management: The Artificial Pancreas as the Hallmark Device. PMID- 26237308 TI - Hypoglycemia Reduction and Changes in Hemoglobin A1c in the ASPIRE In-Home Study. AB - BACKGROUND: ASPIRE In-Home randomized 247 subjects with type 1 diabetes to sensor augmented pump therapy with or without the Threshold Suspend (TS) feature, which interrupts insulin delivery at a preset sensor glucose value. We studied the effects of TS on nocturnal hypoglycemia (NH) in relation to baseline hemoglobin A1c (A1C) and change in A1C during the study. MATERIALS AND METHODS: NH event rates and mean area under curve (AUC) of NH events were evaluated at different levels of baseline A1C (<7%, 7-8%, and >8%) and at different levels of changes in A1C (less than -0.3% [decreased], -0.3% to 0.3% [stable], and >0.3% [increased]), in the TS Group compared with the Control Group (sensor-augmented pump only). RESULTS: In the TS Group, 27.9% of the NH events were accompanied by a confirmatory blood glucose value, compared with 39.3% in the Control Group. Among subjects with baseline A1C levels of <7% or 7-8%, those in the TS Group had significantly lower NH event rates than those in the Control Group (P=0.001 and P=0.004, respectively). Among subjects with decreased or stable A1C levels, those in the TS Group had significantly lower NH event rates, and the events had lower AUCs (P<=0.001 for each). Among subjects with increased A1C levels, those in the TS Group had NH events with significantly lower AUCs (P<0.001). CONCLUSIONS: Use of the TS feature was associated with decreases in the rate and severity (as measured by AUC) of NH events in many subjects, including those with low baseline A1C levels and those whose A1C values decreased during the study period. Use of the TS feature can help protect against hypoglycemia in those wishing to intensify diabetes management to achieve target glucose levels. PMID- 26237309 TI - Participation in Cardiac Rehabilitation Programs Among Older Patients After Acute Myocardial Infarction. PMID- 26237310 TI - In Vitro Comparison of Raypex 6 and Endopilot Using a Novel, Computer-Aided Measurement System, for Determining the Working Length. AB - INTRODUCTION: Experimental evaluation of endometric devices usually relies on visual, subjective detection of the apical constriction to determine the accuracy of measurements. The aim of the present study was to analyze the accuracy of measurements of Raypex 6 and EndoPilot using a novel, objective image-analysis system. METHODS: Onehundred and twenty teeth were randomized and allocated to three groups: After coronal flaring, either Raypex 6 or EndoPilot were used to determine the endodontic working length during instrumentation using manual files (RPM and EPM group respectively). In addition, EndoPilot was used for continuous, automatic measurement during rotating instrumentation (EPA group). If the working length had been reached according to endometric results, the files were fixed in place. Tooth and file were then embedded and prepared for analysis. Subsequently, the distance between the tip of the file and the apical constriction (DAC) or the apical foramen (DAF) was calculated using trigonometric analysis and the position of the file relative to AC and AF was analyzed. RESULTS: Both inter- and intra examiner-reliability of the trigonometric analysis were nearly perfect (ICC = 0.999, p<0.001). DAC was not significantly different between groups (p>0.05, t test). DAF was significantly decreased when EPA had been used compared to EPM (p<0.05, Exact-test). EPA resulted in files being positioned beyond AF significantly more often than the other two methods (p<0.01). CONCLUSIONS: All methods allowed reliable detection of AC. However, EPA significantly increased the risk of overpreparation. Objective, digital assessment based on image analysis was suitable to compare the accuracy of different endometric devices. PMID- 26237311 TI - Cone-Beam Computed Tomography Assessment of Lower Facial Asymmetry in Unilateral Cleft Lip and Palate and Non-Cleft Patients with Class III Skeletal Relationship. AB - INTRODUCTION: To evaluate, using cone-beam computed tomography (CBCT), both the condylar-fossa relationships and the mandibular and condylar asymmetries between unilateral cleft lip and palate (UCLP) patients and non-cleft patients with class III skeletal relationship, and to investigate the factors of asymmetry contributing to chin deviation. METHODS: The UCLP and non-cleft groups consisted of 30 and 40 subjects, respectively, in mixed dentition with class III skeletal relationships. Condylar-fossa relationships and the dimensional and positional asymmetries of the condyles and mandibles were examined using CBCT. Intra-group differences were compared between two sides in both groups using a paired t-test. Furthermore, correlations between each measurement and chin deviation were assessed. RESULTS: It was observed that 90% of UCLP and 67.5% of non-cleft subjects had both condyles centered, and no significant asymmetry was found. The axial angle and the condylar center distances to the midsagittal plane were significantly greater on the cleft side than on the non-cleft side (P=0.001 and P=0.028, respectively) and were positively correlated with chin deviation in the UCLP group. Except for a larger gonial angle on the cleft side, the two groups presented with consistent asymmetries showing shorter mandibular bodies and total mandibular lengths on the cleft (deviated) side. The average chin deviation was 1.63 mm to the cleft side, and the average absolute chin deviation was significantly greater in the UCLP group than in the non-cleft group (P=0.037). CONCLUSION: Compared with non-cleft subjects with similar class III skeletal relationships, the subjects with UCLP showed more severe lower facial asymmetry. The subjects with UCLP presented with more asymmetrical positions and rotations of the condyles on axial slices, which were positively correlated with chin deviation. PMID- 26237312 TI - Cytoskeletal Reorganization Drives Mesenchymal Condensation and Regulates Downstream Molecular Signaling. AB - Skeletal condensation occurs when specified mesenchyme cells self-organize over several days to form a distinctive cartilage template. Here, we determine how and when specified mesenchyme cells integrate mechanical and molecular information from their environment, forming cartilage condensations in the pharyngeal arches of chick embryos. By disrupting cytoskeletal reorganization, we demonstrate that dynamic cell shape changes drive condensation and modulate the response of the condensing cells to Fibroblast Growth Factor (FGF), Bone Morphogenetic Protein (BMP) and Transforming Growth Factor beta (TGF-beta) signaling pathways. Rho Kinase (ROCK)-driven actomyosin contractions and Myosin II-generated differential cell cortex tension regulate these cell shape changes. Disruption of the condensation process inhibits the differentiation of the mesenchyme cells into chondrocytes, demonstrating that condensation regulates the fate of the mesenchyme cells. We also find that dorsal and ventral condensations undergo distinct cell shape changes. BMP signaling is instructive for dorsal condensation specific cell shape changes. Moreover, condensations exhibit ventral characteristics in the absence of BMP signaling, suggesting that in the pharyngeal arches ventral morphology is the ground pattern. Overall, this study characterizes the interplay between cytoskeletal dynamics and molecular signaling in a self-organizing system during tissue morphogenesis. PMID- 26237313 TI - Serum Cardiac Troponin-I is Superior to Troponin-T as a Marker for Left Ventricular Dysfunction in Clinically Stable Patients with End-Stage Renal Disease. AB - BACKGROUND: Serum troponin assays, widely used to detect acute cardiac ischemia, might be useful biomarkers to detect chronic cardiovascular disease (CVD). Cardiac-specific troponin-I (cTnI) and troponin-T (cTnT) generally detect myocardial necrosis equally well. In dialysis patients however, serum cTnT levels are often elevated, unlike cTnI levels. The present study aims to elucidate the associations of cTnI and cTnT with CVD in clinically stable dialysis patients. METHODS: Troponin levels were measured using 5th generation hs-cTnT assays (Roche) and STAT hs-cTnI assays (Abbott) in a cohort of dialysis patients. Serum troponin levels were divided into tertiles with the lowest tertile as a reference value. Serum troponins were associated with indicators of CVD such as left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF) and the presence of coronary artery disease (CAD). Associations were explored using regression analysis. RESULTS: We included 154 consecutive patients, 68+/-7 years old, 77% male, 70% hemodialysis. Median serum cTnT was 51ng/L (exceeding the 99th percentile of the healthy population in 98%) and median serum cTnI was 13ng/L (elevated in 20%). A high cTnI (T3) was significantly associated with a higher LVMI (Beta 31.60; p=0.001) and LVEF (Beta -4.78; p=0.005) after adjusting for confounders whereas a high serum cTnT was not. CAD was significantly associated with a high cTnT (OR 4.70 p=0.02) but not with a high cTnI. Unlike cTnI, cTnT was associated with residual renal function (Beta:-0.09; p=0.006). CONCLUSION: In the present cohort, serum cTnI levels showed a stronger association with LVMI and LVEF than cTnT. However, cTnT was significantly associated with CAD and residual renal function, unlike cTnI. Therefore, cTnI seems to be superior to cTnT as a marker of left ventricular dysfunction in asymptomatic dialysis patients, while cTnT might be better suited to detect CAD in these patients. PMID- 26237314 TI - Alcohol and Exercise Affect Declining Kidney Function in Healthy Males Regardless of Obesity: A Prospective Cohort Study. AB - BACKGROUND: Although lifestyle is associated with metabolic syndrome and cardiovascular diseases, there has been no sufficient evidence of lifestyles on incident chronic kidney disease (CKD). The purpose of this prospective cohort study is to investigate the effects of lifestyles on kidney function in healthy people. METHODS: A total of 7473 healthy people were enrolled in this Saitama Cardiometabolic Disease and Organ Impairment Study, Japan. Data on alcohol consumption, exercise frequency, and sleep duration were collected. The outcome event was incident CKD or decrease in estimated glomerular filtration rate (eGFR) by >25% in 3 years. RESULTS: Subjects were classified into four groups according to body mass index and gender. Mean +/- standard deviation of age was 38.8+/-10.5 years; eGFR, 78.1+/-15.2 ml/min/1.73 m2. In the male groups, multivariate logistic regression models showed that the outcome events were associated with a small amount of alcohol consumed (20 to 140 g of alcohol/week) (ref. more than 140 g of alcohol/week); non-obese male, adjusted odds ratio 1.366 (95% confidence interval, 1.086, 1.718); obese male (body mass index >=25), 1.634 (1.160, 2.302); and with frequent exercise (twice a week or more) (ref. no exercise); non-obese male, 1.417 (1.144, 1.754); obese male, 1.842 (1.317, 2.577). Sleep duration was not associated with the outcome events. CONCLUSION: These findings suggest that, regardless of obesity, a small amount of alcohol consumed and high exercise frequency were associated with the increased risk of loss of kidney function in the male groups. PMID- 26237315 TI - 4D offline PET-based treatment verification in scanned ion beam therapy: a phantom study. AB - At the Heidelberg Ion-Beam Therapy Center, patient irradiation with scanned proton and carbon ion beams is verified by offline positron emission tomography (PET) imaging: the beta+-activity measured within the patient is compared to a prediction calculated on the basis of the treatment planning data in order to identify potential delivery errors. Currently, this monitoring technique is limited to the treatment of static target structures. However, intra-fractional organ motion imposes considerable additional challenges to scanned ion beam radiotherapy. In this work, the feasibility and potential of time-resolved (4D) offline PET-based treatment verification with a commercial full-ring PET/CT (x ray computed tomography) device are investigated for the first time, based on an experimental campaign with moving phantoms. Motion was monitored during the gated beam delivery as well as the subsequent PET acquisition and was taken into account in the corresponding 4D Monte-Carlo simulations and data evaluation. Under the given experimental conditions, millimeter agreement between the prediction and measurement was found. Dosimetric consequences due to the phantom motion could be reliably identified. The agreement between PET measurement and prediction in the presence of motion was found to be similar as in static reference measurements, thus demonstrating the potential of 4D PET-based treatment verification for future clinical applications. PMID- 26237316 TI - Sex differences in drug abuse: Etiology, prevention, and treatment. AB - This special issue exemplifies one of the major goals of the current editor of Experimental and Clinical Psychopharmacology (Dr. Suzette Evans): to increase the number of manuscripts that emphasize females and address sex differences. Taken together, these articles represent a broad range of drug classes and approaches spanning preclinical research to treatment to better understand the role of sex differences in drug abuse. While not all studies found sex differences, we want to emphasize that finding no sex difference is just as important as confirming one, and should be reported in peer-reviewed journals. It is our intention and hope that this special issue will further advance scientific awareness about the importance of accounting for sex differences in the study of substance abuse. Participant sex is an essential variable to consider in developing a more comprehensive understanding of substance abuse. Rather than viewing investigating sex differences as burdensome, investigators should seize this opportune area ripe for innovative research that is long overdue. PMID- 26237317 TI - Sex differences in monoamines following amphetamine and social reward in adolescent rats. AB - Interaction with social peers may increase rates of drug self-administration, but a recent study from our laboratory showed that social interaction may serve as a type of alternative reward that competes with drug taking in adolescent male rats. Based on those previous results, the current study examined sex differences in preference for social interaction compared with amphetamine (AMPH) in adolescent rats using the conditioned place preference (CPP) paradigm. Similar to previous results with males, females showed AMPH CPP regardless of whether they were individual- or pair-housed. In contrast to males, however, females failed to show social CPP, and they did not prefer a peer-associated compartment over an AMPH-associated compartment in a free-choice test. In separate experiments, dopamine (DA) and serotonin (5-HT) metabolite levels were measured in adolescent males and females that were exposed acutely to peer interaction, no peer interaction, AMPH, or saline. In amygdala, levels of the DA metabolite dihydroxyphenylacetic acid (DOPAC) were altered more in response to peer interaction in males than females; in contrast, there was a greater amygdala DOPAC response to AMPH in females. Furthermore, there were greater changes in the 5-HT metabolite hydroxyindoleacetic acid (5-HIAA) in females than in males following social interaction. These results indicate that the ability of peer interactions to reduce drug reward is greater in adolescent males than females, perhaps due to a greater ability of social cues to activate limbic reward mechanisms in males or a greater ability of AMPH cues to activate limbic reward mechanisms in females. PMID- 26237318 TI - The impact of gonadal hormones on cannabinoid dependence. AB - Cannabis is the most widely used illicit substance in the United States. Women report greater positive subjective effects of cannabis, and greater cannabis withdrawal compared to men. Female rodents are more sensitive than males to some acute effects of Delta9-tetrahydrocannabinol (THC), and females also develop greater tolerance to THC in some assays. The purpose of this study was to determine whether gonadal hormones modulate THC dependence in rats. Adult rats were gonadectomized (GDX) or sham-GDX, and hormone was replaced in half of the GDX rats of each sex (testosterone in males; estradiol and/or progesterone in females). THC (30 mg/kg) or vehicle was administered twice daily for 6.5 days, followed on the seventh day by vehicle or rimonabant challenge and assessment for withdrawal-related behaviors. Sham-GDX females developed greater tolerance than males to THC-induced hypothermia, and GDX females given progesterone showed greater tolerance to THC-induced locomotor suppression. Rimonabant precipitated withdrawal, as evidenced by increased somatic signs (forepaw tremors, licking) and increased startle amplitude. Testosterone in GDX males decreased withdrawal induced licking. Estradiol and progesterone in GDX females increased withdrawal induced chewing, and progesterone increased withdrawal-induced sniffing. These results suggest that estradiol and progesterone may promote the development of dependence, whereas testosterone may protect against dependence. While the present study indicates that testosterone and estradiol produce opposite effects on THC-induced behavior, estradiol appears to play a broader role than testosterone in modulating THC's behavioral effects. PMID- 26237319 TI - Discriminative stimulus effects of morphine and oxycodone in the absence and presence of acetic acid in male and female C57Bl/6 mice. AB - The use of prescription opioids for clinical management of pain remains problematic because of concerns about addiction associated with opioid use. Another difficulty in pain management is the increasing evidence for sex differences in pain behavior and opioid-induced behavioral effects. However, few studies have documented the abuse potential of prescription opioids as a function of pain in rodents, with significant gaps in the literature pertaining to sex differences in the interaction between pain and opioid effects. The present study evaluated the effects of an experimentally induced acute pain state (acetic acid injections) on the potency of morphine and oxycodone to produce discriminative stimulus effects in male and female C57Bl/6 mice trained to discriminate 3.2 mg/kg morphine from saline. Acetic acid injections attenuated the stimulus potency of morphine by 2.2-fold but not the stimulus potency of oxycodone in male mice. Acetic acid injections did not alter the discriminative stimulus effects of either morphine or oxycodone in female mice. The antinociceptive effects of the 2 opioids were evaluated using the acetic acid-induced stretching test. For antinociceptive effects, morphine was 2.0-fold less potent relative to oxycodone in male mice, whereas morphine and oxycodone were equipotent in female mice. Taken together, these results indicate that acetic acid-induced acute pain differentially modulates the discriminative stimulus effects of morphine in male and female mice and that this change may be related to the variable antinociceptive effectiveness of these opioids across sexes. PMID- 26237320 TI - Effects of consuming a diet high in fat and/or sugar on the locomotor effects of acute and repeated cocaine in male and female C57BL/6J mice. AB - Drug abuse and obesity are serious public health problems. Dopamine plays a central role in mediating the reinforcing effects of drugs and food. Prolonged use of drugs is known to alter the function and/or sensitivity of many neurotransmitter systems, including dopamine; however, the impact of consuming foods high in fat and/or sugar is less clear. These studies characterized the locomotor effects of acute and repeated cocaine in male and female C57BL/6J mice consuming 1 of 4 diets: (a) standard chow + water; (b) standard chow + 10% sucrose solution; (c) high-fat chow + water; or (d) high-fat chow + 10% sucrose solution. The acute locomotor effects of cocaine (3.2-32.0 mg/kg) were evaluated 4 weeks after initiating dietary conditions; the effects of repeated cocaine administration were evaluated after 5, 6, 7, and 12 weeks. During acute tests, mice consuming a diet high in fat and/or sucrose exhibited greater locomotor responses to cocaine than mice consuming standard chow and water, regardless of sex. Although diet-induced enhancements persisted across repeated cocaine testing, locomotor sensitization developed more rapidly in females drinking sucrose (and consuming either standard or high-fat chow) than in females consuming standard chow and water. In addition to providing evidence that consuming a diet high in fat and/or sugar enhances abuse-related effects of cocaine in ways that might increase vulnerability to abuse cocaine, these studies identified a potentially important sex-related difference in the interaction between nutrition and cocaine effects, with the impacts of sucrose consumption being greater in females than in males. PMID- 26237321 TI - Sex differences in associations between cannabis craving and neural responses to cannabis cues: Implications for treatment. AB - Preclinical and clinical research indicates that there are sex differences in how men and women initiate, progress, respond to, and withdraw from cannabis use; however, neurophysiological differences, such as neural responses to cannabis cues, are not well understood. Using functional MRI and an event-related blood oxygen level-dependent backward-masking task, we compared neural responses to backward-masked cannabis cues to neutral cues in treatment-seeking, cannabis dependent adults (N = 44; 27 males) and examined whether sex differences exist. In addition, functional MRI findings were correlated with cannabis craving. Backward-masked cannabis cues elicited greater neural responses than neutral cues in reward-related brain regions, including the striatum, hippocampus/amygdala, insula, anterior cingulate cortex, and lateral orbitofrontal cortex, p < .01, k > 121 voxels. Although no significant sex differences in neural responses to cannabis cues emerged, women showed a positive correlation between neural responses to cannabis cues in the bilateral insula and cannabis craving and an inverse correlation between neural responses to cannabis cues in the left lateral orbitofrontal cortex and cannabis craving. Men, however, showed a positive correlation between neural responses to cannabis cues in the striatum and cannabis craving. Given that cues and craving are important triggers and the focus on many behavioral treatment approaches, these findings suggest that treatment-seeking, cannabis-dependent men and women may benefit from sex-specific and tailored cannabis use disorder treatments. PMID- 26237322 TI - Sex differences in resting state brain function of cigarette smokers and links to nicotine dependence. AB - Sex--a marker of biological and social individual differences--matters for drug use, particularly for cigarette smoking, which is the leading cause of preventable death in the United States. More men than women smoke, but women are less likely than men to quit. Resting state brain function, or intrinsic brain activity that occurs in the absence of a goal-directed task, is important for understanding cigarette smoking, as it has been shown to differentiate between smokers and nonsmokers. But, it is unclear whether and how sex influences the link between resting state brain function and smoking behavior. In this study, the authors demonstrate that sex is indeed associated with resting state connectivity in cigarette smokers, and that sex moderates the link between resting state connectivity and self-reported nicotine dependence. Using functional MRI and behavioral data from 50 adult daily smokers (23 women), the authors found that women had greater connectivity than men within the default mode network, and that increased connectivity within the reward network was related to increased nicotine tolerance in women but to decreased nicotine tolerance in men. Findings highlight the importance of sex-related individual differences reflected in resting state connectivity for understanding the etiology and treatment of substance use problems. PMID- 26237323 TI - Speech volume indexes sex differences in the social-emotional effects of alcohol. AB - Men and women differ dramatically in their rates of alcohol use disorder (AUD), and researchers have long been interested in identifying mechanisms underlying male vulnerability to problem drinking. Surveys suggest that social processes underlie sex differences in drinking patterns, with men reporting greater social enhancement from alcohol than women, and all-male social drinking contexts being associated with particularly high rates of hazardous drinking. But experimental evidence for sex differences in social-emotional response to alcohol has heretofore been lacking. Research using larger sample sizes, a social context, and more sensitive measures of alcohol's rewarding effects may be necessary to better understand sex differences in the etiology of AUD. This study explored the acute effects of alcohol during social exchange on speech volume--an objective measure of social-emotional experience that was reliably captured at the group level. Social drinkers (360 male; 360 female) consumed alcohol (.82 g/kg males; .74 g/kg females), placebo, or a no-alcohol control beverage in groups of 3 over 36-min. Within each of the 3 beverage conditions, equal numbers of groups consisted of all males, all females, 2 females and 1 male, and 1 female and 2 males. Speech volume was monitored continuously throughout the drink period, and group volume emerged as a robust correlate of self-report and facial indexes of social reward. Notably, alcohol-related increases in group volume were observed selectively in all-male groups but not in groups containing any females. Results point to social enhancement as a promising direction for research exploring factors underlying sex differences in problem drinking. PMID- 26237324 TI - Sex differences in self-report and behavioral measures of disinhibition predicting marijuana use across adolescence. AB - Disinhibition has been consistently linked to substance use across development. Recent research suggests, however, that these relations may be influenced by both sex and measurement approach. The current study examined the moderating effect of sex on the association between behavioral and self-report measures of disinhibition and marijuana use across adolescence. Participants were 115 boys and 89 girls initially evaluated at Grade 8 using a laboratory behavioral assessment and self-report questionnaires of disinhibitory variables. Marijuana use was measured annually from Grades 9 through 12. Results suggest that boys and girls did not differ on either self-reported or behaviorally assessed levels of disinhibition, and that disinhibition measured using both approaches was associated with increases in marijuana use over time. There was a significant interaction between sex and disinhibition, suggesting that boys (but not girls) who self-reported elevations in disinhibition evidenced greater increases in marijuana use. The current findings add to a growing literature supporting the importance of using multiple methods to assess disinhibition and highlight the critical role of biological sex in understanding these relations. PMID- 26237325 TI - Effects of sex composition on group processes in alcohol prevention groups for teens. AB - Although most alcohol and other drug prevention programs for adolescents are offered in group settings, little is known about the possible effects of sex composition on group processes and mechanisms of change. Using the Group Actor Partner Interdependence Model framework, we examined how the sex constellation of adolescent prevention group members influenced youth satisfaction, engagement, and endorsement of healthy behavior during group. Participants in Project Options (N = 379; 61.8% girls; Mage = 16.1; SD = 1.4), a voluntary school-based alcohol prevention program, completed measures of satisfaction at each prevention session and observers rated engagement and change talk for each group. When analyses were oriented toward girls, their personal satisfaction, group-rated satisfaction, and group-level engagement were positively related to having more girls in the group. Similarly, in boys, personal satisfaction, satisfaction of the group as a whole, and engagement in groups improved when groups were composed of more girls. Statements supportive of healthy alcohol/drug-related decision making were unrelated to group composition. The findings suggest that the composition of girls and boys in groups has differential effects on some group processes. This avenue of research has merit for understanding the mechanisms associated with satisfaction and engagement in adolescent substance use prevention programs. PMID- 26237328 TI - Transient Particle Energies in Shortcuts to Adiabatic Expansions of Harmonic Traps. AB - The expansion of a harmonic potential that holds a quantum particle may be realized without any final particle excitation but much faster than adiabatically via "shortcuts to adiabaticity" (STA). While ideally the process time can be reduced to zero, practical limitations and constraints impose minimal finite times for the externally controlled time-dependent frequency protocols. We examine the role of different time-averaged energies (total, kinetic, potential, nonadiabatic) and of the instantaneous power in characterizing or selecting different protocols. Specifically, we prove a virial theorem for STA processes, set minimal energies (or times) for given times (or energies), and discuss their realizability by means of Dirac impulses or otherwise. PMID- 26237326 TI - Sex effects in cocaine-using methadone patients randomized to contingency management interventions. AB - Contingency management (CM) is an effective treatment for promoting cocaine abstinence in patients receiving methadone maintenance. However, few studies have examined the effect of sex on treatment outcomes in this population. This study evaluated the impact of sex on longest duration of abstinence (LDA) and percent negative urine samples in 323 cocaine-using methadone patients from 4 randomized clinical trials comparing CM to standard methadone care. Overall, women had better treatment outcomes compared with men, demonstrated by an increase in both LDA and percentages of negative samples. Patients receiving CM also had significantly higher LDA and percentages of negative samples compared to patients receiving standard care, but sex by treatment condition effects were not significant. These data suggest that cocaine-using methadone patients who are women have better substance use outcomes than men in interventions that regularly monitor cocaine use, and CM is equally efficacious regardless of sex. PMID- 26237327 TI - Sex differences in the latent class structure of alcohol use disorder: Does (dis)aggregation of indicators matter? AB - Many researchers have argued for a differential presentation of alcohol use disorder (AUD) between men and women. Latent class analysis is the most commonly used analytic technique for modeling AUD subcategories, and latent class analyses have supported a variety of class structures of AUD. This article examines whether these differential results are, in part, an artifact of whether researchers have (a) analyzed men and women in the same analysis and (b) aggregated item-level symptoms into AUD diagnostic criteria prior to analysis. These related methodological issues are examined using Wave 2 data from the National Epidemiologic Survey of Alcohol and Related Conditions (N = 22,177). Direct comparison of results when the sexes are modeled separately or together shows that women are classified differently depending on whether men are included in the analysis. A comparison of disaggregated item-level symptoms and aggregated AUD criteria suggests that aggregating data remove a subgroup, individuals who exhibit tolerance but are normative on all other AUD symptoms, which is of theoretical and clinical interest. Consequently, basic methodological issues that are rarely systematically studied appear to be important determinants of studies seeking to determine whether male and female alcoholism are structurally isomorphic. PMID- 26237330 TI - Catalytic Kinetic Resolution of Biaryl Compounds. AB - Biaryl compounds with axial chirality are very common in synthetic chemistry, especially in catalysis. Axially chiral biaryls are important due to their biological activities and extensive applications in asymmetric catalysis. Thus the development of efficient enantioselective methods for their synthesis has attracted considerable attention. This Minireview discusses the progress made in catalytic kinetic resolution of biaryl compounds and chronicles significant advances made recently in catalytic kinetic resolution of biaryl scaffolds. PMID- 26237329 TI - Analysis of the Human Prostate-Specific Proteome Defined by Transcriptomics and Antibody-Based Profiling Identifies TMEM79 and ACOXL as Two Putative, Diagnostic Markers in Prostate Cancer. AB - To better understand prostate function and disease, it is important to define and explore the molecular constituents that signify the prostate gland. The aim of this study was to define the prostate specific transcriptome and proteome, in comparison to 26 other human tissues. Deep sequencing of mRNA (RNA-seq) and immunohistochemistry-based protein profiling were combined to identify prostate specific gene expression patterns and to explore tissue biomarkers for potential clinical use in prostate cancer diagnostics. We identified 203 genes with elevated expression in the prostate, 22 of which showed more than five-fold higher expression levels compared to all other tissue types. In addition to previously well-known proteins we identified two poorly characterized proteins, TMEM79 and ACOXL, with potential to differentiate between benign and cancerous prostatic glands in tissue biopsies. In conclusion, we have applied a genome-wide analysis to identify the prostate specific proteome using transcriptomics and antibody-based protein profiling to identify genes with elevated expression in the prostate. Our data provides a starting point for further functional studies to explore the molecular repertoire of normal and diseased prostate including potential prostate cancer markers such as TMEM79 and ACOXL. PMID- 26237331 TI - Osmium Bisterpyridine Complexes with Redox-Active Amine Substituents: A Comparison Study with Ruthenium Analogues. AB - Five osmium complexes with redox-active amine substituents, [Os(ttpy)(Ntpy)](PF6)2 (1(PF6)2), [Os(Ntpy)2](PF6)2 (2(PF6)2), [Os(ttpy)(NPhtpy)](PF6)2 (3(PF6)2), [Os(Ntpy)(NPhtpy)](PF6)2 (4(PF6)2), and [Os(NPhtpy)2](PF6)2 (5(PF6)2), have been prepared, where ttpy is 4'-tolyl 2,2':6',2"-terpyridine, Ntpy is 4'-(di-p-anisylamino)-2,2':6',2"-terpyridine, and NPhtpy is 4'-(di-p-anisylaminophen-4-yl)-2,2':6',2"-terpyridine. X-ray crystallographic data of 2(PF6)2 and 4(PF6)2 are presented. These complexes show rich visible absorptions attributed to the singlet metal-to-ligand charge transfer ((1)MLCT), triplet MLCT, and intraligand charge-transfer transitions. Complexes 3(PF6)2 and 5(PF6)2 show weak emissions around 720 nm at room temperature. All complexes show stepwise oxidations of the osmium ion and the amine segment. However, the redox potentials and the order of the Os(III/II) and N(*+/0) processes vary significantly, depending on the electronic nature of the amine substituents. In the singly oxidized state, either Os(II) -> N(*+) MLCT or N -> Os(III) ligand-to-metal charge-transfer transitions in the near-infrared region have been observed. For complexes 2(PF6)2, 4(PF6)2, and 5(PF6)2 with two amine substituents, no evidence has been observed for the presence of osmium mediated amine-amine electronic coupling. Density functional theory (DFT) and time-dependent DFT calculations have been performed to complement these experimental results. The one-electron-oxidized forms 3(3+) and 5(3+) show distinct electron paramagnetic resonance (EPR) signals in CH3CN at room temperature. However, complexes 1(3+), 2(3+), and 4(3+) are EPR silent under similar conditions. In addition, a comparison study has been made between these osmium complexes and the previously reported ruthenium analogues. PMID- 26237332 TI - Light-Dark Adaptation of Channelrhodopsin Involves Photoconversion between the all-trans and 13-cis Retinal Isomers. AB - Channelrhodopsins (ChR) are light-gated ion channels of green algae that are widely used to probe the function of neuronal cells with light. Most ChRs show a substantial reduction in photocurrents during illumination, a process named "light adaptation". The main objective of this spectroscopic study was to elucidate the molecular processes associated with light-dark adaptation. Here we show by liquid and solid-state nuclear magnetic resonance spectroscopy that the retinal chromophore of fully dark-adapted ChR is exclusively in an all-trans configuration. Resonance Raman (RR) spectroscopy, however, revealed that already low light intensities establish a photostationary equilibrium between all trans,15-anti and 13-cis,15-syn configurations at a ratio of 3:1. The underlying photoreactions involve simultaneous isomerization of the C(13)?C(14) and C(15)?N bonds. Both isomers of this DAapp state may run through photoinduced reaction cycles initiated by photoisomerization of only the C(13)?C(14) bond. RR spectroscopic experiments further demonstrated that photoinduced conversion of the apparent dark-adapted (DAapp) state to the photocycle intermediates P500 and P390 is distinctly more efficient for the all-trans isomer than for the 13-cis isomer, possibly because of different chromophore-water interactions. Our data demonstrating two complementary photocycles of the DAapp isomers are fully consistent with the existence of two conducting states that vary in quantitative relation during light-dark adaptation, as suggested previously by electrical measurements. PMID- 26237333 TI - The effects of question repetition on responses when prosecutors and defense attorneys question children alleging sexual abuse in court. AB - This study examined the effects of repeated questions (n = 12,169) on 6- to 12 year-olds' testimony in child sexual abuse cases. We examined transcripts of direct- and cross-examinations of 120 children, categorizing how attorneys asked repeated questions in-court and how children responded. Defense attorneys repeated more questions (33.6% of total questions asked) than prosecutors (17.8%) and repeated questions using more suggestive prompts (38% of their repeated questions) than prosecutors (15%). In response, children typically repeated or elaborated on their answers and seldom contradicted themselves. Self contradictions were most often elicited by suggestive and option-posing prompts posed by either type of attorney. Child age did not affect the numbers of questions repeated, the types of prompts used by attorneys to repeat questions, or how children responded to repetition. Most (61.5%) repeated questions were repeated more than once and, as repetition frequency increased, so did the number of self-contradictions. "Asked-and-answered" objections were rarely raised (n = 45) and were more likely to be overruled than sustained by judges. Findings suggest that attorneys frequently ask children "risky" repeated questions. Both attorneys and the judiciary need more training in identifying and restricting the unnecessary repetition of questions. PMID- 26237334 TI - The impact of frequency of behavior and type of contact on judgments involving a criminal stalking case. AB - We investigated mock juror perceptions of the frequency of behavior and type of contact in an ex-intimate stalking case. We used a mock-juror methodology, in which 204 community members (129 women) read a stalking trial summary, rendered a verdict, and evaluated the intent of the defendant to cause the victim fear and distress, as well as the victim's experience with these emotions. The trial varied as to whether there were 5 or 30 stalking incidents and whether the stalking involved personal contact or stalking via text message. Results showed that females were more likely to render a guilty verdict when the victim had been stalked 30 times rather than 5 times while males were equally likely to render a guilty verdict regardless of the frequency. Mock jurors were significantly more likely to render guilty verdicts in the personal contact condition than in the text message condition. Females' perceptions of the victim's fear and distress mediated the frequency of incidents x gender interaction. The victim's fear and the defendant's intentions mediated the main effect of type of contact on verdict. Cognitive network analyses showed that victim fear and the defendant's intent to cause fear were central to participant verdict decision making. We discuss these results in terms of the implications, specifically that victim fear should be a primary focus in stalking legislation. PMID- 26237335 TI - "Thermal Charging" Phenomenon in Electrical Double Layer Capacitors. AB - Electrical double layer capacitors (EDLCs) are usually charged by applying a potential difference across the positive and negative electrodes. In this paper, we demonstrated that EDLCs can be charged by heating. An open circuit voltage of 80-300 mV has been observed by heating the supercapacitor to 65 degrees C. The charge generated at high temperature can be stored in the device after its returning to the room temperature, thus allowing the lighting up of LEDs by connecting the "thermally charged" supercapacitors in a series. The underlying mechanism is related to a thermo-electrochemical process that enhances the kinetics of Faradaic process at the electrode surface (e.g., surface redox reaction of functional group, or chemical adsorption/desorption of electrolyte ions) at higher temperature. Effects of "thermal charging" times, activation voltage, rate, and times on "thermally charged" voltage are studied and possible mechanisms are discussed. PMID- 26237336 TI - Porous Carbon Nanosheets Codoped with Nitrogen and Sulfur for Oxygen Reduction Reaction in Microbial Fuel Cells. AB - In this work, a simple synthesis strategy has been developed for the preparation of nitrogen- and sulfur-codoped porous carbon nanosheets (N/S-CNS) as a cathode catalyst for microbial fuel cells (MFCs). The as-prepared N/S-CNS showed favorable features for electrochemical energy conversion such as high surface area (1004 m(2) g(-1)), defect structure, and abundant exposure of active sites that arose primarily from porous nanosheet morphology. Benefiting from the unique nanostructure, the resulting nanosheets exhibited effective electrocatalytic activity toward oxygen reduction reaction (ORR). The onset potential of the N/S CNS in linear-sweep voltammetry was approximately -0.05 V vs Ag/AgCl in neutral phosphate buffer saline. Electrochemical impedance spectroscopy showed that the ohmic and charge-transfer resistance of the codoped catalyst were 1.5 and 14.8 Omega, respectively, both of which were lower than that of platinum/carbon (Pt/C). Furthermore, the electron-transfer number of the N/S-CNS was calculated to be ~3.5, suggesting that ORR on the catalyst proceeds predominantly through the favorable four-electron pathway. The MFC with N/S-CNS as a cathode catalyst generated current density (6.6 A m(-2)) comparable to that with Pt/C (7.3 A m( 2)). The high durability and low price indicate that N/S-CNS can be a competitive catalyst for applications of MFCs. PMID- 26237337 TI - Agarose-Based Substrate Modification Technique for Chemical and Physical Guiding of Neurons In Vitro. AB - A new low cost and highly reproducible technique is presented that provides patterned cell culture substrates. These allow for selective positioning of cells and a chemically and mechanically directed guiding of their extensions. The patterned substrates consist of structured agarose hydrogels molded from reusable silicon micro templates. These templates consist of pins arranged equidistantly in squares, connected by bars, which mold corresponding wells and channels in the nonadhesive agarose hydrogel. Subsequent slice production with a standard vibratome, comprising the described template pattern, completes substrate production. Invertebrate neurons of locusts and pond snails are used for this application as they offer the advantage over vertebrate cells as being very large and suitable for cultivation in low cell density. Their neurons adhere to and grow only on the adhesive areas not covered by the agarose. Agarose slices of 50 MUm thickness placed on glass, polystyrene, or MEA surfaces position and immobilize the neurons in the wells, and the channels guide their neurite outgrowth toward neighboring wells. In addition to the application with invertebrate neurons, the technique may also provide the potential for the application of a wide range of cell types. Long-term objective is the achievement of isolated low-density neuronal networks on MEAs or different culture substrates for various network analysis applications. PMID- 26237338 TI - Molecular Hemocompatibility of Graphene Oxide and Its Implication for Antithrombotic Applications. AB - Surface-induced blood clotting is one of the major problems associated with the long-term use of blood-contacting biomedical devices. Central to this obstructive blood clotting is the adsorption of plasma proteins following the interactions between blood and material surface. Of all proteins circulating in the blood plasma, albumin and fibrinogen are the two important proteins regulating the blood-material interaction. As such, the adsorption of plasma proteins has been used as an indicator for the assessment of the blood compatibility of the biomedical devices. Numerous nanomaterials have been developed for antithrombotic surface coating applications, including the 2D graphene and its derivatives. Here, the antithrombotic property of albumin-functionalized graphene oxide (albumin-GO) and its potential for antithrombotic coating application under flow are investigated. The loading capacities, conformational changes, and adsorptions of albumin and fibrinogen on GO are probed. It is observed that GO possesses a high loading capacity for both proteins and simultaneously, it does not disrupt the overall secondary structure and conformational stability of albumin. Both albumin and fibrinogen adsorb well on the surface of GO. Subsequently, it is demonstrated that the albumin-functionalized GO possesses enhanced antithrombotic effect and may potentially be used as an antithrombotic coating material of blood contacting devices under dynamic flow. PMID- 26237339 TI - Plant seed species identification from chemical fingerprints: a high-throughput application of direct analysis in real time mass spectrometry. AB - Plant species identification based on the morphological features of plant parts is a well-established science in botany. However, species identification from seeds has largely been unexplored, despite the fact that the seeds contain all of the genetic information that distinguishes one plant from another. Using seeds of genus Datura plants, we show here that the mass spectrum-derived chemical fingerprints for seeds of the same species are similar. On the other hand, seeds from different species within the same genus display distinct chemical signatures, even though they may contain similar characteristic biomarkers. The intraspecies chemical signature similarities on the one hand, and interspecies fingerprint differences on the other, can be processed by multivariate statistical analysis methods to enable rapid species-level identification and differentiation. The chemical fingerprints can be acquired rapidly and in a high throughput manner by direct analysis in real time mass spectrometry (DART-MS) analysis of the seeds in their native form, without use of a solvent extract. Importantly, knowledge of the identity of the detected molecules is not required for species level identification. However, confirmation of the presence within the seeds of various characteristic tropane and other alkaloids, including atropine, scopolamine, scopoline, tropine, tropinone, and tyramine, was accomplished by comparison of the in-source collision-induced dissociation (CID) fragmentation patterns of authentic standards, to the fragmentation patterns observed in the seeds when analyzed under similar in-source CID conditions. The advantages, applications, and implications of the chemometric processing of DART MS derived seed chemical signatures for species level identification and differentiation are discussed. PMID- 26237341 TI - Atlanto-occipital Instability Following Endoscopic Endonasal Approach for Lower Clival Lesions: Experience With 212 Cases. AB - BACKGROUND: The endoscopic endonasal approach (EEA) for craniocervical lesions involving the lower clivus and occipital condyles carries an unclear risk of atlanto-occipital (AO) instability requiring arthrodesis. OBJECTIVE: Elucidate risk factors for AO instability following EEA for clival lesions. METHODS: We reviewed patients with clival tumors who underwent EEA at our institution between 2002 and 2012. Resection of the lower clivus, foramen magnum, AO joint, and occipital condyles were evaluated on fine-cut postoperative computed tomography. RESULTS: Two hundred twelve patients (mean age 47.9 years, 57.1% male) underwent transclival EEA for lower clival lesions. In addition to the lower clivus, resection involved the condyle in 14.2% of patients, the foramen magnum in 16.5%, and the AO joint in 1.4%. Quantification of condyle resection revealed complete resection in 3 cases, 75% resection in 8 cases, 50% resection in 6 cases, and 25% resection in 13 cases. Seven of these patients had EEA combined with an open, far lateral approach. In total, 7 patients required arthrodesis following EEA (3.3%), 4 of them after a combined approach. All patients who underwent arthrodesis had primary bone tumors such as chordoma, chondrosarcoma, or osteosarcoma (P = .022). Degree of condyle resection was a significant factor predisposing to occipitocervical instability (P = .001 and P < .001 for 75% and 100% condyle resection, respectively). Use of a combined approach was significantly associated with arthrodesis (P < .001). CONCLUSION: EEA resection of the occipital condyles that results in greater than 75% condyle resection or EEA in combination with an open approach significantly increases the risk of AO instability and likely necessitates AO fixation. ABBREVIATIONS: AO, atlanto-occipitalEEA, endoscopic endonasal approachOC, occipitocervical. PMID- 26237342 TI - Intracranial Interdigitating Dendritic Cell Sarcoma: First Case Report. AB - BACKGROUND AND IMPORTANCE: This is the first report of a primarily intracranial interdigitating dendritic cell sarcoma (IDCS). CLINICAL PRESENTATION: A 39-year old patient with right hemiparesis underwent complete resection of a large parafalcine tumor with subsequent complete recovery of neurological symptoms. Histologically, the tumor was diagnosed as IDCS. Extensive staging did not reveal any extracranial manifestation of this disease. After 1.5 years, the patient remains recurrence free and is being observed closely. CONCLUSION: IDCS are exceedingly rare tumors and so far have not been found intracranially. On the basis of the limited experience with extracranial occurrence, this tumor is best managed by complete resection and careful oncological observation. ABBREVIATIONS: FDCS, follicular dendritic cell sarcomaIDCS, interdigitating dendritic cell sarcomaRTU, ready-to-use kit. PMID- 26237344 TI - Molecular valves for controlling gas phase transport made from discrete angstrom sized pores in graphene. AB - An ability to precisely regulate the quantity and location of molecular flux is of value in applications such as nanoscale three-dimensional printing, catalysis and sensor design. Barrier materials containing pores with molecular dimensions have previously been used to manipulate molecular compositions in the gas phase, but have so far been unable to offer controlled gas transport through individual pores. Here, we show that gas flux through discrete angstrom-sized pores in monolayer graphene can be detected and then controlled using nanometre-sized gold clusters, which are formed on the surface of the graphene and can migrate and partially block a pore. In samples without gold clusters, we observe stochastic switching of the magnitude of the gas permeance, which we attribute to molecular rearrangements of the pore. Our molecular valves could be used, for example, to develop unique approaches to molecular synthesis that are based on the controllable switching of a molecular gas flux, reminiscent of ion channels in biological cell membranes and solid-state nanopores. PMID- 26237345 TI - Anomalous ultrafast dynamics of hot plasmonic electrons in nanostructures with hot spots. AB - The interaction of light and matter in metallic nanosystems is mediated by the collective oscillation of surface electrons, called plasmons. After excitation, plasmons are absorbed by the metal electrons through inter- and intraband transitions, creating a highly non-thermal distribution of electrons. The electron population then decays through electron-electron interactions, creating a hot electron distribution within a few hundred femtoseconds, followed by a further relaxation via electron-phonon scattering on the timescale of a few picoseconds. In the spectral domain, hot plasmonic electrons induce changes to the plasmonic resonance of the nanostructure by modifying the dielectric constant of the metal. Here, we report on the observation of anomalously strong changes to the ultrafast temporal and spectral responses of these excited hot plasmonic electrons in hybrid metal/oxide nanostructures as a result of varying the geometry and composition of the nanostructure and the excitation wavelength. In particular, we show a large ultrafast, pulsewidth-limited contribution to the excited electron decay signal in hybrid nanostructures containing hot spots. The intensity of this contribution correlates with the efficiency of the generation of highly excited surface electrons. Using theoretical models, we attribute this effect to the generation of hot plasmonic electrons from hot spots. We then develop general principles to enhance the generation of energetic electrons through specifically designed plasmonic nanostructures that could be used in applications where hot electron generation is beneficial, such as in solar photocatalysis, photodetectors and nonlinear devices. PMID- 26237346 TI - Real-time imaging of microparticles and living cells with CMOS nanocapacitor arrays. AB - Platforms that offer massively parallel, label-free biosensing can, in principle, be created by combining all-electrical detection with low-cost integrated circuits. Examples include field-effect transistor arrays, which are used for mapping neuronal signals and sequencing DNA. Despite these successes, however, bioelectronics has so far failed to deliver a broadly applicable biosensing platform. This is due, in part, to the fact that d.c. or low-frequency signals cannot be used to probe beyond the electrical double layer formed by screening salt ions, which means that under physiological conditions the sensing of a target analyte located even a short distance from the sensor (~1 nm) is severely hampered. Here, we show that high-frequency impedance spectroscopy can be used to detect and image microparticles and living cells under physiological salt conditions. Our assay employs a large-scale, high-density array of nanoelectrodes integrated with CMOS electronics on a single chip and the sensor response depends on the electrical properties of the analyte, allowing impedance-based fingerprinting. With our platform, we image the dynamic attachment and micromotion of BEAS, THP1 and MCF7 cancer cell lines in real time at submicrometre resolution in growth medium, demonstrating the potential of the platform for label/tracer-free high-throughput screening of anti-tumour drug candidates. PMID- 26237347 TI - High-frequency nano-optomechanical disk resonators in liquids. AB - Nano- and micromechanical resonators are the subject of research that aims to develop ultrasensitive mass sensors for spectrometry, chemical analysis and biomedical diagnosis. Unfortunately, their merits generally diminish in liquids because of an increased dissipation. The development of faster and lighter miniaturized devices would enable improved performances, provided the dissipation was controlled and novel techniques were available to drive and readout their minute displacement. Here we report a nano-optomechanical approach to this problem using miniature semiconductor disks. These devices combine a mechanical motion at high frequencies (gigahertz and above) with an ultralow mass (picograms) and a moderate dissipation in liquids. We show that high-sensitivity optical measurements allow their Brownian vibrations to be resolved directly, even in the most-dissipative liquids. We investigate their interaction with liquids of arbitrary properties, and analyse measurements in light of new models. Nano-optomechanical disks emerge as probes of rheological information of unprecedented sensitivity and speed, which opens up applications in sensing and fundamental science. PMID- 26237348 TI - Corrigendum: A method for human teratogen detection by geometrically confined cell differentiation and migration. PMID- 26237349 TI - Nanoscale Single-Element Color Filters. AB - Visible-light filters constructed from nanostructured materials typically consist of a metallic grating and rely on the excitation of surface plasmon polaritons (SPPs). In order to operate at full efficiency, the number of grating elements needs to be maximized such that light can couple more efficiently to the SPPs through improved diffraction. Such conditions impose a limitation on the compactness of the filter since a larger number of grating elements represents a larger effective size. For emerging applications involving nanoscale transmitters or receivers, a device that can filter localized excitations is highly anticipated but is challenging to realize through grating-type filters. In this work, we present the design of an optical filter operating with a single element, marking a departure from diffractive plasmonic coupling. Our device consists of a ZnO nanorod enclosed by two layers of Ag film. For diffraction-limited light focused on the nanorod, narrow passbands can be realized and tuned via variation of the nanorod diameter across the visible spectrum. The spectral and spatial filtering originates from scattering cancellation localized at the nanorod due to the cavity and nanorod exhibiting opposite effective dipole moments. This ability to realize high-performance optical filtering at the ultimate size introduces intriguing possibilities for nanoscale near-field communication or ultrahigh resolution imaging pixels. PMID- 26237350 TI - Corrigendum: Direct Identification of On-Bead Peptides Using Surface-Enhanced Raman Spectroscopic Barcoding System for High-Throughput Bioanalysis. PMID- 26237351 TI - Assessment and management of connective tissue disease-associated interstitial lung disease. AB - The intersection of the connective tissue diseases (CTD) and the interstitial lung diseases (ILD) is complex. Although often considered as a single entity, "CTD-ILD" actually reflects a heterogeneous spectrum of diverse CTDs and a variety of patterns of interstitial pneumonia. The evaluation of patients with CTD that develop ILD, or the assessment for underlying CTD in those presenting with presumed "idiopathic" ILD can be challenging and these evaluations can be optimized by effective multidisciplinary collaboration. When a diagnosis of CTD ILD is confirmed, careful and thorough assessments to determine extra- versus intra-thoracic disease activity, and degrees of impairment are needed. Pharmacologic intervention with immunosuppression is the mainstay of therapy for all forms of CTD-ILD, but should be reserved only for those that demonstrate clinically significant and/or progressive disease. The management of CTD-ILD is not yet evidence based and there is a desperate need for controlled trials across the spectrum of CTD-ILD. Non-pharmacologic management strategies and addressing comorbidities or aggravating factors should be part of a comprehensive treatment plan for individuals with CTD-ILD. PMID- 26237352 TI - Beneficial Impact of bFGF Antisense Therapy in a Rat Model of Pulmonary Fibrosis. AB - OBJECTIVES: This study aims to explore basic fibroblast growth factor (bFGF)'s role in the development of pulmonary fibrosis through applying bFGF antisense oligonucleotide therapy in a rat model of pulmonary fibrosis. METHODS: Thirty rats were randomly divided into five groups: bFGF sense-transfected, bFGF antisense-transfected, null vector-transfected, pulmonary fibrosis (PF), and control groups. Sense, antisense, null, and PF groups were administered bleomycin to induce pulmonary fibrosis. Sense, antisense, and null vectors were intratracheally injected into the lungs of their respective groups followed by sacrifice after 28 days post-injection. Lung coefficients, H&E and Masson trichome staining, and serum and bronchoalveolar lavage fluid bFGF expression were comparatively assessed in addition to lung homogenate mRNA expressions of several select proteins and hydroxyproline content. RESULTS: The antisense and sense groups had significantly decreased and increased lung coefficients and pulmonary fibrosis than the PF and null groups, respectively, with the pulmonary fibrosis stage positively correlated with treatment. Antisense, PF, and null groups showed significantly reduced collagen fiber levels compared to the sense group. The antisense group displayed significantly lower serum and lavage fluid bFGF expression in addition to significantly lower bFGF, alpha-smooth muscle actin, Smad3, transforming growth factor-beta1, connective tissue growth factor, collagen I (and significantly higher Smad7) mRNA expression relative to the PF and null groups. The antisense and sense groups showed significantly higher hydroxyproline content relative to the PF and null groups. CONCLUSIONS: bFGF appears to promote collagen I synthesis and upregulates TGF-beta1/Smad signaling to promote lung fibroblast proliferation and differentiation in pulmonary fibrosis. bFGF antisense oligonucleotide therapy shows promise in preventing the development of pulmonary fibrosis, likely though a TGF-beta1/Smad-based signaling mechanism. PMID- 26237353 TI - Structured multidisciplinary discussion of HRCT scans for IPF/UIP diagnosis may result in indefinite outcomes. AB - Recent ATS/ERS/JRS/ALAT guidelines for the diagnosis and management of Idiopathic Pulmonary Fibrosis (IPF) have defined key features and specific high-resolution computerized tomography (HRCT) patterns for the diagnosis of UIP. The aim is the sorting of patients with suspected IPF into three subgroups, confident, possible or inconsistent with UIP patterns, after a multidisciplinary discussion (MDD). Specialists in respiratory diseases, radiologists and pathologists should reach IPF diagnosis based on either patients' clinical, radiological and laboratory data, either submitting patients to surgical biopsy. After ATS/ERS/JRS/ALAT recommendations have been applied, it has been identified a subgroup of patients showing uniform apical-basal distribution of honeycombing and reticular abnormalities that could not be categorized as confident, or possible nor inconsistent with UIP. These patients were subsequently diagnosed with IPF after MDD and lung biopsy. Inclusion of this pattern in the recommendation for IPF diagnosis would be worth considering. PMID- 26237354 TI - Inhaled Interferon and Diffusion Capacity in Idiopathic Pulmonary Fibrosis (IPF). AB - BACKGROUND: Using data from a previously reported phase 2 safety trial, testing inhaled interferon gamma (IFN-gamma) for IPF, we analyzed effects on full pulmonary function tests (PFTs) for efficacy before and after therapy and designed a randomized controlled trial of inhaled IFN-gamma to treat IPF. METHODS: Ten patients with IPF had received inhaled IFN-gamma (Actimmune, InterMune) for 80 weeks. Full PFTs were available 20-50 weeks before Rx and monthly during Rx. Eighty-nine observations were used in the analysis. Linear mixed models for modeling longitudinal data were used to test if the PFT change over time was significantly different before and after IFN-gamma. Autoregressive dependence structure with order one was consistently selected as the best one to model the intra-patient correlation over time. Normality assumption was confirmed. Significance level was set at 0.05. Using published literature and our data we performed a sample size calculation based on simulated data. RESULTS: The change over time in DLCO was significantly different before and after IFN-gamma treatment. DLCO decreased over time before treatment but increased after treatment (p-value=0.03). Changes in TLC, FRC, RV and FVC were not statistically significant. With a sample size of 60, a placebo controlled, randomized trial has about 90% power to detect a significant difference in the change rate of DLCO in the groups of patients treated with IFN-gamma vs placebo. CONCLUSIONS: DLCO was significantly improved following inhaled (IFN-gamma) as treatment for IPF. Our data suggest that previous studies utilizing parenteral IFN-gamma may have failed because of the mode of delivery. Future randomized, controlled, phase 3 trials, comparing the difference in PFT behavior (specifically DLCO) longitudinally may be more sensitive to drug effect and serve as a valuable clinical endpoint. PMID- 26237355 TI - Benefits of physical training in patients with idiopathic or end-stage sarcoidosis-related pulmonary fibrosis: a pilot study. AB - BACKGROUND: The natural history of disease in patients with stage IV (fibrotic) sarcoidosis may mirror that of patients with idiopathic pulmonary fibrosis (IPF). Both are bothered by progressive dyspnea, exercise limitation and fatigue. OBJECTIVE: To establish whether patients suffering from pulmonary fibrosis might benefit from a physical training program. STUDY DESIGN: Twenty-four eligible patients referred to the out-patient clinic of the ild care expertise team of Hospital Gelderse Vallei, Ede, The Netherlands between November 2012 and November 2013 were included in this observational pilot study of a 12-week physical training program. Outcomes, including exercise capacity, skeletal muscle strength, lung function and fatigue were assessed at two time points: 1) baseline; and 2) after completion of a 12-week physical training program. RESULTS: At baseline, the percentage predicted DLCO, FVC, FEV1 and exercise capacity (assessed by six-minute walking distance (6MWD) or maximal oxygen uptake) was reduced in both groups. After program completion, exercise capacity improved (>10% improvement 6MWD) in 13 subjects (54.2%): 7 with IPF and 6 with sarcoidosis subjects. Other secondary endpoints, including pulmonary function tests and patient-reported outcome measures improved in some subjects. CONCLUSION: A 12-week physical training program improved or maintained exercise capacity in patients with IPF (despite disease progression) or fibrotic sarcoidosis. The results from this pilot study could be used to design prospective studies aimed at answering lingering questions about exercise training in patients with these progressive, incurable conditions. PMID- 26237356 TI - Does physical training reduce fatigue in sarcoidosis? AB - BACKGROUND: Sarcoidosis patients frequently experience fatigue, exercise intolerance and muscle weakness, resulting in reduced quality of life (QOL). Scientific studies on the benefits of physical training in sarcoidosis have been scarce, so the aim of this pilot study was to examine the impact of a 13-week physical training program on fatigue, physical functions and QOL in fatigued sarcoidosis patients and/or patients with exercise intolerance. METHODS: 18 sarcoidosis patients participated in a 13-week physical training program. The Fatigue Assessment Scale (FAS), World Health Organization Quality of Life-BREF assessment instrument (WHOQOL-BREF),Medical Research Council (MRC) dyspnea scale, Visual Analogue Scale (VAS), six-minute walk test (6MWT), submaximal bicycle test and muscle strength of the quadriceps and elbow flexors were assessed at baseline and after the program. RESULTS: FAS scores had decreased (mean difference -2.7 points, 95% CI -4.4 to -1.1) after completion of the training program, along with improvements in WHOQOLBREF psychological health domain (mean difference 0.9 points, 95% CI 0.2 to 1.7) and MRC dyspnea score (mean difference -0.4 points, 95% CI -0.8 to -0.1). 6MWD improved by 34.6 m (95% CI 20.3 to 49.0) and mean heart rate on the bicycle test improved (mean difference 8.4 beats/minute, 95% CI -13.8 to -3.0), as did quadriceps strength (mean difference 10.7 kg, 95% CI 5.5 to 15.9). CONCLUSION: Fatigue reduced after a period of physical training in sarcoidosis patients. Moreover, psychological health and physical functions improved. Future studies are warranted to assess the benefits of physical training in sarcoidosis. PMID- 26237357 TI - Glucocorticoids and Sarcoidosis: A Longitudinal Study on the Effects on Cortical and Trabecular Bone. AB - BACKGROUND: Glucocorticoid induced osteoporosis is a well-known side effect of glucocorticoid treatment. In sarcoidosis the impact on bone by glucocorticoid treatment is complex due to hormonal disturbances of calcium and vitamin-D, which by itself may cause bone loss. In this study we aimed to investigate the longitudinal impact of glucocorticoids on cortical and trabecular bone in patients with mild, recently diagnosed sarcoidosis. METHODS: Ten patients (8 females; mean age 44 (+/-13)) were studied during one year of glucocorticoid treatment. The assessment of mainly cortical to purely trabecular bone was made by dual X-ray absorptiometry (DXA) of the spine and hip, quantitative ultrasound of the calcaneus, and magnetic resonance relaxometry of the spine and calcaneus. Bone and hormonal measurements were performed at baseline, after 3, 6, and 12 months, and baseline, 3 weeks and 3 months, respectively. RESULTS: DXA of the spine, decreased from baseline at 6 months (P=0.01). R2' of the calcaneus decreased with time (B: -3.6;P=0.03). In the females (n=8) there was a significant decrease in DXA of the spine when comparing 3 months and 6 months (P=0.03), and 3 months and 12 months (P=0.02) and a decrease in R2'of the calcaneus from baseline to 12 months (P=0.01). There was no change in hormonal levels. CONCLUSION: Treatment of initial mild sarcoidosis with dose tapered glucocorticoid therapy only mildly affects the final trabecular and cortical bone and hormone levels. Dose tapering is an important part in glucocorticoid therapy, likely contributing to the mild effects on bone observed in this study. PMID- 26237358 TI - Outcome of cardiac sarcoidosis after radiofrequency ablation and placement of AICD- A propensity matched analysis. AB - BACKGROUND: Cardiac Sarcoidosis (CS) can lead to life-threatening ventricular dysrhythmias and sudden death. Immunosuppressive medications, radiofrequency ablation (RFA), and implantable cardioverter defibrillators (ICD) have been utilized to manage ventricular dysrhythmias but their benefits remain poorly defined. OBJECTIVE: The aim of this study is to assess the durability of RFA in CS population and to determine outcome predictors after RFA. METHODS: We compared the CS patients who had RFA+/-ICD against those with only ICD placement and contemporaneous patients with arrhythmogenic right ventricular dysplasia (ARVD) who had RFA. We analyzed time to a composite first event of appropriate ICD therapy, subsequent RFA, cardiac transplantation or death. We also evaluated variables predicting recurrence of ventricular dysrhythmias, including LVEF, cardiac involvement on PET scan, percent of ventricular ectopic beats, number of inducible VT foci and success of the RFA procedure. We used propensity matching and multivariable regression to adjust for baseline differences between the groups to identify outcome predictors. RESULTS: Thirty ablations for VT were performed in 20 CS patients (13 had concomitant ICD placement); 12 ablations were done in eight ARVD patients and 33 CS patients with only ICD placements were included in this cohort. The median follow-up period was 48 (9-173) months. Fourteen (70%) patients reached composite end points after RFA compared to 13 (63%) following ICD placement and five (87%) in the ARVD cohort. There was a significant time difference to reach composite end points (p=0.02) in favor of ICD only cohort. The median number of ICD therapies were higher in the CS-RFA group (p=0.01). The requirement for ICD therapy increased over time following RFA, especially after 12 months. Variables predicting earlier time-to-event were EF <40% (OR=13.2) and unsuccessful RFA procedure (OR=7.9). The presence of more than one inducible VT morphology was associated with higher likelihood of unsuccessful RFA (p=0.03). CONCLUSION: RFA can be an effective modality for the short-term treatment of ventricular dysrhythmias in cardiac sarcoidosis; however, after more than 12 months, the number of appropriate therapies escalates. Accordingly, ICD placement is recommended for all patients who undergo RFA for VT associated with CS, whether it is successful or not. Low LVEF and unsuccessful ablation were strong predictors of future events. PMID- 26237359 TI - Primary dural lymphoma: Complete remission after treatment with radiation therapy. AB - Central nervous system (CNS) involvement in sarcoidosis is rare and typically occurs in 5-10% of patients. Neurological symptoms in a patient with known sarcoidosis can be attributed to neurosarcoidosis without thorough evaluation. Primary Dural Lymphoma (PDL) is an extremely rare form of non-Hodgkin lymphoma. Although PDL is technically a subtype of primary CNS lymphoma, the two entities vary markedly in their histological grade, clinical course, prognosis and treatment. The most common dural- based lesion found on CNS imaging is meningioma. It shares many imaging, clinical and epidemiologic features of PDL which often leads to misdiagnosis of PDL as meningioma. We present a case where a PDL was diagnosed after CNS symptoms failed to resolve after steroid therapy for presumed neurosarcoidosis. PMID- 26237360 TI - Autologous cytokine-induced killer (CIK) immunotherapy in a case of disseminated tuberculosis. AB - A 23-year-old woman had dry cough, fever and chest tightness for 1 months. Through thoracic CT scan and serological examination, the patient was clinically diagnosed as disseminated tuberculosis. she was given anti-tuberculosis therapy combined with autologous cytokine-induced killer (CIK) immunotherapy. Through the close follow-ups we found that after immunotherapy Her condition would have a swift improvement and she do not appear liver damage after a large doses of antibiotic therapy. In conclusion, adjuvant autologous CIK immunotherapy is an effective approach for disseminated tuberculosis. PMID- 26237362 TI - Cellular evidence for efference copy in Drosophila visuomotor processing. AB - Each time a locomoting fly turns, the visual image sweeps over the retina and generates a motion stimulus. Classic behavioral experiments suggested that flies use active neural-circuit mechanisms to suppress the perception of self-generated visual motion during intended turns. Direct electrophysiological evidence, however, has been lacking. We found that visual neurons in Drosophila receive motor-related inputs during rapid flight turns. These inputs arrived with a sign and latency appropriate for suppressing each targeted cell's visual response to the turn. Precise measurements of behavioral and neuronal response latencies supported the idea that motor-related inputs to optic flow-processing cells represent internal predictions of the expected visual drive induced by voluntary turns. Motor-related inputs to small object-selective visual neurons could reflect either proprioceptive feedback from the turn or internally generated signals. Our results in Drosophila echo the suppression of visual perception during rapid eye movements in primates, demonstrating common functional principles of sensorimotor processing across phyla. PMID- 26237363 TI - Instrumental learning of traits versus rewards: dissociable neural correlates and effects on choice. AB - Humans learn about people and objects through positive and negative experiences, yet they can also look beyond the immediate reward of an interaction to encode trait-level attributes. We found that perceivers encoded both reward and trait level information through feedback in an instrumental learning task, but relied more heavily on trait representations in cross-context decisions. Both learning types implicated ventral striatum, but trait learning also recruited a network associated with social impression formation. PMID- 26237364 TI - Naturalistic stimulation drives opposing heterosynaptic plasticity at two inputs to songbird cortex. AB - Songbirds learn precisely sequenced motor skills (songs) subserved by distinct brain areas, including the premotor cortical analog HVC, which is essential for producing learned song, and a 'cortical'-basal ganglia loop required for song plasticity. Inputs from these nuclei converge in RA (robust nucleus of the arcopallium), making it a likely locus for song learning. However, activity dependent synaptic plasticity has never been described in either input. Using a slice preparation, we found that stimulation patterns based on singing-related activity were able to drive opposing changes in the strength of RA's inputs: when one input was potentiated, the other was depressed, with the direction and magnitude of changes depending on the relative timing of stimulation of the inputs. Moreover, pharmacological manipulations that blocked synaptic plasticity in vitro also prevented reinforcement-driven changes to song in vivo. Together, these findings highlight the importance of precise timing in the basal ganglia motor cortical interactions subserving adaptive motor skills. PMID- 26237365 TI - Dynamic rewiring of neural circuits in the motor cortex in mouse models of Parkinson's disease. AB - Dynamic adaptations in synaptic plasticity are critical for learning new motor skills and maintaining memory throughout life, which rapidly decline with Parkinson's disease (PD). Plasticity in the motor cortex is important for acquisition and maintenance of motor skills, but how the loss of dopamine in PD leads to disrupted structural and functional plasticity in the motor cortex is not well understood. Here we used mouse models of PD and two-photon imaging to show that dopamine depletion resulted in structural changes in the motor cortex. We further discovered that dopamine D1 and D2 receptor signaling selectively and distinctly regulated these aberrant changes in structural and functional plasticity. Our findings suggest that both D1 and D2 receptor signaling regulate motor cortex plasticity, and loss of dopamine results in atypical synaptic adaptations that may contribute to the impairment of motor performance and motor memory observed in PD. PMID- 26237366 TI - Learning to expect the unexpected: rapid updating in primate cerebellum during voluntary self-motion. AB - There is considerable evidence that the cerebellum has a vital role in motor learning by constructing an estimate of the sensory consequences of movement. Theory suggests that this estimate is compared with the actual feedback to compute the sensory prediction error. However, direct proof for the existence of this comparison is lacking. We carried out a trial-by-trial analysis of cerebellar neurons during the execution and adaptation of voluntary head movements and found that neuronal sensitivities dynamically tracked the comparison of predictive and feedback signals. When the relationship between the motor command and resultant movement was altered, neurons robustly responded to sensory input as if the movement was externally generated. Neuronal sensitivities then declined with the same time course as the concurrent behavioral learning. These findings demonstrate the output of an elegant computation in which rapid updating of an internal model enables the motor system to learn to expect unexpected sensory inputs. PMID- 26237368 TI - Spatial Variation of Aerosol Chemical Composition and Organic Components Identified by Positive Matrix Factorization in the Barcelona Region. AB - The spatial distribution of PM1 components in the Barcelona metropolitan area was investigated using on-road mobile measurements of atmospheric particle- and gas phase compounds during the DAURE campaign in March 2009. Positive matrix factorization (PMF) applied to organic aerosol (OA) data yielded 5 factors: hydrocarbon-like OA (HOA), cooking OA (COA), biomass burning OA (BBOA), and low volatility and semivolatile oxygenated OA (LV-OOA and SV-OOA). The area under investigation (~500 km(2)) was divided into six zones (city center, harbor, industrial area, precoastal depression, 2 mountain ranges) for measurements and data analysis. Mean zonal OA concentrations are 4.9-9.5 MUg m(-3). The area is heavily impacted by local primary emissions (HOA 14-38%, COA 10-18%, BBOA 10-12% of OA); concentrations of traffic-related components, especially black carbon, are biased high due to the on-road nature of the measurements. The formation of secondary OA adds more than half of the OA burden outside the city center (SV-OOA 14-40%, LV-OOA 17-42% of OA). A case study of one measurement drive from the shore to the precoastal mountain range furthest downwind of the city center indicates the importance of nonfossil over anthropogenic secondary OA based on OA/CO. PMID- 26237369 TI - Evaluation of Water Sanitation Health Education Programme: Working with the Knowledge of the Basic Sanitation Services in a Developing Community in Rural Haiti after the 2010 Earthquake. AB - OBJECTIVE: The aim of this study is to measure the knowledge regarding the new sanitation water system being implemented in Dessources, a rural community in the municipality of Croix-des-Bouquets in Haiti after a two-year intervention programme. DESIGN AND METHODS: A cross-sectional epidemiologic design was used to measure the knowledge of the people in the community using a semi-structured questionnaire. Data collection followed a face-to-face interview process in all houses of the community. The instrument content validity was performed by a panel of experts followed by Cronbach's alpha test to establish the reliability of knowledge scale. In addition, association measures were done using Stata 11.0 statistical package. RESULTS: Content validity test were performed with minimum changes and an alpha of 0.74 was obtained for the scale. Response rate was 65.57% (41/60 houses); non-participants were only those who did not meet the inclusion criteria. Most of the participants (77.5%) were 21-49 years old and 85% had been living in the community for more than 20 years. Bivariate analysis showed that the people of Dessources had adequate knowledge. Significant differences, however, were found among the zones that are not in use of the new sanitary systems and among families with more than seven members per house. CONCLUSIONS: Differences found can be explained based on the Rogers theoretical diffusion of innovation model. The evaluation shows that people of Dessources in Haiti have a high knowledge regarding the new water sanitation system and provided evidence of an adequate health education programme intervention. PMID- 26237370 TI - Absolute Configuration and Conformational Study of Psammaplysins A and B from the Balinese Marine Sponge Aplysinella strongylata. AB - The absolute configuration of psammaplysin A (1) has been assigned as (6R,7R) using experimental and calculated electronic circular dichroism (ECD) data and NMR analysis of MPA esters prepared from the acetamide derivative of 1. Detailed conformational analyses of a truncated model compound of 1 with an in vacuo method and with the PCM solvent model for MeOH have identified the major conformers and factors governing the ECD spectrum of 1. The correlation of the ECD data with the stereochemistry of 1 allows configurational assignment of related psammaplysin analogues on the basis of their ECD spectra. PMID- 26237367 TI - Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome. AB - Hippocampal pathology is likely to contribute to cognitive disability in Down syndrome, yet the neural network basis of this pathology and its contributions to different facets of cognitive impairment remain unclear. Here we report dysfunctional connectivity between dentate gyrus and CA3 networks in the transchromosomic Tc1 mouse model of Down syndrome, demonstrating that ultrastructural abnormalities and impaired short-term plasticity at dentate gyrus CA3 excitatory synapses culminate in impaired coding of new spatial information in CA3 and CA1 and disrupted behavior in vivo. These results highlight the vulnerability of dentate gyrus-CA3 networks to aberrant human chromosome 21 gene expression and delineate hippocampal circuit abnormalities likely to contribute to distinct cognitive phenotypes in Down syndrome. PMID- 26237371 TI - Influence of Intrapartum Antibiotic Prophylaxis for Group B Streptococcus on Gut Microbiota in the First Month of Life. AB - OBJECTIVES: The effect of intrapartum antibiotic prophylaxis (IAP) for group B Streptococcus (GBS) on bacterial colonization of the infant's gut has not been investigated extensively. We aimed to evaluate the effect of IAP on gut microbiota in healthy term infants, also exploring the influence of type of feeding. METHODS: Healthy term infants, whose mothers had been screened for GBS in late gestation, were divided into 2 groups: infants born to GBS-positive mothers who had received IAP versus controls. Neonatal fecal samples were collected at 7 and 30 days of life; DNA was extracted, and quantification of selected microbial groups (Lactobacillus spp, Bifidobacterium spp, and Bacteroides fragilis group) was performed by real-time PCR. RESULTS: A total of 84 infant-mother pairs were recruited. Bifidobacteria count was significantly lower in the IAP group at 7 days of life (median [interquartile range] 6.01 Log colony-forming unit per gram [5.51-6.98] vs 7.80 [6.61-8.26], P = 0.000). No differences in Bifidobacteria count at 30 days or in Lactobacilli and B fragilis counts at any time point were documented. Furthermore, at 7 days of life, infants who had not received IAP and were exclusively human milk-fed had higher counts of Bifidobacteria. Regardless of IAP treatment, infants fed exclusively human milk had higher Lactobacillus spp counts both at 7 and 30 days of life. CONCLUSIONS: IAP alters gut microflora by reducing the count of Bifidobacteria, which is further affected in infants receiving formula feeding. Whether these alterations could have long-term consequences on health and disease requires further investigation. PMID- 26237372 TI - Nutritional/Growth Status in a Large Cohort of Medically Fragile Children Receiving Long-Term Enteral Nutrition Support. AB - OBJECTIVE: The aim of the present study was to assess the nutritional status and growth of medically fragile children receiving long-term enteral nutritional support (ENS). METHODS: A retrospective cross-sectional survey was conducted at a tertiary-level pediatric hospital. Growth features and nutritional intake of children (n = 287) receiving ENS were evaluated. During a period of 5 years (2009 2013), study patients in the age group of 1 to 36 months had been referred for the explicit reason of tube weaning. Data were documented with the help of ARCHIMED (version 46.2) and analyzed using SPSS for Windows version 21. Nutritional/growth status was determined by using World Health Organization growth standard tables. RESULTS: Anthropometric parameters of children were compared with World Health Organization standards, and the prevalence of underweight, wasting, and stunting was very high despite being exclusively or predominantly on ENS. Results revealed that the age of a child, inadequate amount of caloric supply/day, the diagnosis of small-for-gestational age, and the type of tube (nasogastric tube) were significantly associated with growth/nutritional status (P < 0.05). Duration of ENS in the percentage of the cohort's lifetime and the main diagnosis were not associated with nutritional/growth outcomes. CONCLUSIONS: In medically fragile children, ENS does not ensure adequate growth per se. ENS requires highly specialized and individually tailored management and in many cases regular adjustments. Long-term tube feeding plans often seem unable to ensure the required amount of nutritional support, which surely compromise the individual efficacy of ENS. PMID- 26237373 TI - A Nursing Survey on Nutritional Care Practices in French-Speaking Pediatric Intensive Care Units: NutriRea-Ped 2014. AB - OBJECTIVES: Malnutrition in critically ill children contributes to morbidity and mortality. The French-speaking pediatric intensive care nutrition group (NutriSIP) aims to promote optimal nutrition through education and research. METHODS: The NutriSIP-designed NutriRea-Ped study included a cross-sectional survey. This 62-item survey was sent to the nursing teams of all of the French speaking pediatric intensive care units (PICUs) to evaluate nurses' nutrition knowledge and practices. One nurse per PICU was asked to answer and describe the practices of their team. RESULTS: Of 44 PICUs, 40 responded in Algeria, Belgium, Canada, France, Lebanon, Luxemburg, and Switzerland. The majority considered nutrition as a priority care but only 12 of the 40 (30%) had a nutrition support team, 26 of the 40 (65%) had written nutrition protocols, and 19 of 39 (49%) nursing teams felt confident with the nutrition goals. Nursing staff generally did not know how to determine nutritional requirements or to interpret malnutrition indices. They were also unaware of reduced preoperative fasting times and fast-track concepts. In 17 of 35 (49%) PICUs, the target start time for enteral feeding was within the first 24 hours; however, frequent interruptions occurred because of neuromuscular blockade, fasting for extubation or surgery, and high gastric residual volumes. Combined pediatric neonatal intensive care units were less likely to perform systematic nutritional assessment and to start enteral nutrition rapidly. CONCLUSIONS: We found a large variation in nursing practices around nutrition, exacerbated by the lack of nutritional guidelines but also because of the inadequate nursing knowledge around nutritional factors. These findings encourage the NutriSIP to improve nutrition through focused education programs and research. PMID- 26237374 TI - Development and Validation of a Multiplexed Protein Quantitation Assay for the Determination of Three Recombinant Proteins in Soybean Tissues by Liquid Chromatography with Tandem Mass Spectrometry. AB - Currently, traditional immunochemistry technologies such as enzyme-linked immunosorbent assays (ELISA) are the predominant analytical tool used to measure levels of recombinant proteins expressed in genetically engineered (GE) plants. Recent advances in agricultural biotechnology have created a need to develop methods capable of selectively detecting and quantifying multiple proteins in complex matrices because of increasing numbers of transgenic proteins being coexpressed or "stacked" to achieve tolerance to multiple herbicides or to provide multiple modes of action for insect control. A multiplexing analytical method utilizing liquid chromatography with tandem mass spectrometry (LC-MS/MS) has been developed and validated to quantify three herbicide-tolerant proteins in soybean tissues: aryloxyalkanoate dioxygenase (AAD-12), 5-enol-pyruvylshikimate-3 phosphate synthase (2mEPSPS), and phosphinothricin acetyltransferase (PAT). Results from the validation showed high recovery and precision over multiple analysts and laboratories. Results from this method were comparable to those obtained with ELISA with respect to protein quantitation, and the described method was demonstrated to be suitable for multiplex quantitation of transgenic proteins in GE crops. PMID- 26237375 TI - Real-Time Drug Release Analysis of Enzyme and pH Responsive Polysaccharide Nanovesicles. AB - The accurate estimation of drug release kinetics of polymeric vehicles is an indispensable prerequisite for the developments of successful drug carriers for cancer therapy. The present investigation reports the development of time resolved fluorescence spectroscopic approach for the real-time release kinetics of fluorophore loaded polysaccharide vesicles that are potential vectors in cancer treatment. The polysaccharide vesicles were custom designed with appropriate enzyme and pH responsiveness and loaded with water-soluble biocompatible fluorophore Rhodamine B (Rh-B). The semipermeable membrane dialysis method along with steady state absorbance spectroscopic technique was found to be inaccurate for the estimation of drug release. Time correlated single photon counting (TCSPC) technique was found to exhibit significant difference in excited state decay profiles and fluorescent lifetime of Rh-B in the free and polymer bound states. This enabled the establishment of real-time drug release protocols by TCSPC method for polysaccharide vesicles that are responsible to pH and enzyme with respect to intracellular compartments. Real-time analysis predicted the release kinetics 20-25% higher accuracy when compared to the dialysis method under in vitro conditions. Moreover, the ability of enzyme to cleave the polysaccharide vesicles was further validated by docking studies. The positioning of the molecules in active site of enzyme and the binding energy data were generated using AUTODOCK program to study the rupture of polysaccharide vesicles. This new TCSPC technique could be very useful for studying the drug release pattern of synthetic polymer vesicles loaded with Rh-B fluorophore. PMID- 26237376 TI - The Arabidopsis ortholog of the DEAH-box ATPase Prp16 influences auxin-mediated development. AB - In animals and yeasts, the DEAH-box RNA-dependent ATPase Prp16 facilitates pre mRNA splicing. However, in Chlamydomonas reinhardtii and Caenorhabditis elegans, Prp16 orthologs are not important for general pre-mRNA splicing, but are required for gene silencing and sex determination, respectively. The CLUMSY VEIN (CUV) gene, which encodes a unique Prp16 ortholog in Arabidopsis thaliana, influences auxin-mediated development. A loss-of-function cuv-1 mutation tells us that CUV does not facilitate splicing of pre-mRNA substrates indiscriminately, but differentially effects splicing and expression of genes. Here we show that CUV influences root-meristem maintenance and planar polarity of root-hair positioning, both of which are processes regulated by auxin. We propose that Arabidopsis PRP16/CUV differentially facilitates the expression of genes, including genes involved in auxin biosynthesis, transport, perception and signaling, and that in this way it influences auxin-mediated development. PMID- 26237377 TI - Biologism in Psychiatry: A Young Man's Experience of Being Diagnosed with "Pediatric Bipolar Disorder". AB - Pediatric bipolar disorder is a diagnosis that arose in the mid 1990s in the USA and has mostly remained confined to that nation. In this article a young American man (under a pseudonym) describes his experience of having the diagnosis throughout his adolescent years. His story was conveyed via correspondence and a meeting with the author, an Australian child psychiatrist. The young American's story reveals several issues that afflict contemporary psychiatry, particularly in the USA, where social and economic factors have contributed to the rise of a dominant biomedical paradigm-or "biologism". This focus on the "bio" to the relative exclusion of the "psychosocial" in both diagnosis and treatment can have serious consequences as this young man's story attests. The author explores aspects of his tale to analyze how the pediatric bipolar disorder "epidemic" arose and became emblematic of a dominant biologism. This narrative points to the need, depending on the service and country, to return to or retain/improve a balanced biopsychosocial perspective in child and adolescent mental health. Child psychiatry needs to advocate for health systems that support deeper listening to our patients. Then we can explore with them the full range of contextual factors that contribute to symptoms of individual and family distress. PMID- 26237378 TI - Can Characteristics of Reciprocal Translocations Predict the Chance of Transferable Embryos in PGD Cycles? AB - Translocation carriers have an increased risk of miscarriage or the birth of a child with congenital anomalies. Preimplantation genetic diagnosis (PGD) is performed in translocation carriers to select for balanced embryos and, thus, increase the chance of an ongoing pregnancy. However, a common experience is that reciprocal translocation carriers produce a high percentage of unbalanced embryos, which cannot be transferred. Therefore, the pregnancy rates in PGD in this patient group are low. In a cohort of 85 reciprocal translocation carriers undergoing PGD we have searched for cytogenetic characteristics of the translocations that can predict the percentage of balanced embryos. Using shape algorithms, the most likely segregation mode per translocation was determined. Shape algorithm, breakpoint location, and relative chromosome segment sizes proved not to be independent predictors of the percentage of balanced embryos. The ratio of the relative sizes of the translocated segments of both translocation chromosomes can give some insight into the chance of transferable embryos: Very asymmetrical translocations have a higher risk of unbalanced products (p = 0.048). Counseling of the couples on the pros and cons of all their reproductive options remains very important. PMID- 26237379 TI - Hyponatremia: A Risk Factor for Early Overt Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt Creation. AB - Hepatic encephalopathy (HE) is a frequent complication in cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS). Hyponatremia (HN) is a known contributing risk factor for the development of HE. Predictive factors, especially the effect of HN, for the development of overt HE within one week of TIPS placement were assessed. A single-center, retrospective chart review of 71 patients with cirrhosis who underwent TIPS creation from 2006-2011 for non variceal bleeding indications was conducted. Baseline clinical and laboratory characteristics were collected. Factors associated with overt HE within one week were identified, and a multivariate model was constructed. Seventy one patients who underwent 81 TIPS procedures were evaluated. Fifteen patients developed overt HE within one week. Factors predictive of overt HE within one week included pre TIPS Na, total bilirubin and Model for End-stage Liver Disease (MELD)-Na. The odds ratio for developing HE with pre-TIPS Na <135 mEq/L was 8.6. Among patients with pre-TIPS Na <125 mEq/L, 125-129.9 mEq/L, 130-134.9 mEq/L and >=135 mEq/L, the incidence of HE within one week was 37.5%, 25%, 25% and 3.4%, respectively. Lower pre-TIPS Na, higher total bilirubin and higher MELD-Na values were associated with the development of overt HE post-TIPS within one week. TIPS in hyponatremic patients should be undertaken with caution. PMID- 26237380 TI - The Power and the Promise of Cell Reprogramming: Personalized Autologous Body Organ and Cell Transplantation. AB - Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) or direct reprogramming to desired cell types are powerful and new in vitro methods for the study of human disease, cell replacement therapy, and drug development. Both methods to reprogram cells are unconstrained by the ethical and social questions raised by embryonic stem cells. iPSC technology promises to enable personalized autologous cell therapy and has the potential to revolutionize cell replacement therapy and regenerative medicine. Potential applications of iPSC technology are rapidly increasing in ambition from discrete cell replacement applications to the iPSC assisted bioengineering of body organs for personalized autologous body organ transplant. Recent work has demonstrated that the generation of organs from iPSCs is a future possibility. The development of embryonic-like organ structures bioengineered from iPSCs has been achieved, such as an early brain structure (cerebral organoids), bone, optic vesicle-like structures (eye), cardiac muscle tissue (heart), primitive pancreas islet cells, a tooth-like structure (teeth), and functional liver buds (liver). Thus, iPSC technology offers, in the future, the powerful and unique possibility to make body organs for transplantation removing the need for organ donation and immune suppressing drugs. Whilst it is clear that iPSCs are rapidly becoming the lead cell type for research into cell replacement therapy and body organ transplantation strategies in humans, it is not known whether (1) such transplants will stimulate host immune responses; and (2) whether this technology will be capable of the bioengineering of a complete and fully functional human organ. This review will not focus on reprogramming to iPSCs, of which a plethora of reviews can be found, but instead focus on the latest developments in direct reprogramming of cells, the bioengineering of body organs from iPSCs, and an analysis of the immune response induced by iPSC-derived cells and tissues. PMID- 26237381 TI - Beyond Trisomy 21: Additional Chromosomal Anomalies Detected through Routine Aneuploidy Screening. AB - Prenatal screening is often misconstrued by patients as screening for trisomy 21 alone; however, other chromosomal anomalies are often detected. This study aimed to systematically review the literature and use diagnostic meta-analysis to derive pooled detection and false positive rates for aneuploidies other than trisomy 21 with different prenatal screening tests. Non-invasive prenatal testing had the highest detection (DR) and lowest false positive (FPR) rates for trisomy 13 (DR: 90.3%; FPR: 0.2%), trisomy 18 (DR: 98.1%; FPR: 0.2%), and 45,X (DR: 92.2%; FPR: 0.1%); however, most estimates came from high-risk samples. The first trimester combined test also had high DRs for all conditions studied (trisomy 13 DR: 83.1%; FPR: 4.4%; trisomy 18 DR: 91.9%; FPR: 3.5%; 45,X DR: 70.1%; FPR: 5.4%; triploidy DR: 100%; FPR: 6.3%). Second trimester triple screening had the lowest DRs and highest FPRs for all conditions (trisomy 13 DR: 43.9%; FPR: 8.1%; trisomy 18 DR: 70.5%; FPR: 3.3%; 45,X DR: 77.2%; FPR: 9.3%). Prenatal screening tests differ in their ability to accurately detect chromosomal anomalies. Patients should be counseled about the ability of prenatal screening to detect anomalies other than trisomy 21 prior to undergoing screening. PMID- 26237383 TI - Prenatal Isolated Ventricular Septal Defect May Not Be Associated with Trisomy 21. AB - The aim of this study was to examine if isolated fetal ventricular septal defect (VSD) is associated with trisomy 21. One hundred twenty six cases with prenatal VSD diagnosed by a pediatric cardiologist were reviewed. Cases with known risk factors for congenital heart disease, the presence of other major anomalies, soft signs for trisomy 21 or a positive screen test for trisomy 21 were excluded. Ninety two cases formed the study group. None of the cases in the study group had trisomy 21. The upper limit of prevalence for trisomy 21 in isolated VSD is 3%. When prenatal VSD is not associated with other major anomalies, soft markers for trisomy 21 or a positive nuchal translucency or biochemical screen, a decision whether to perform genetic amniocentesis should be individualized. The currently unknown association between isolated VSD and microdeletions and microduplications should be considered when discussing this option. PMID- 26237382 TI - Cortical Volume Alterations in Conduct Disordered Adolescents with and without Bipolar Disorder. AB - BACKGROUND: There is increasing evidence that bipolar disorder (BD) and conduct disorder (CD) are co-occurring disorders. Magnetic resonance imaging has revealed differences in the structure and function of the frontal cortex in these disorders when studied separately; however, the impact of BD comorbidity on brain structure in adolescents with CD has not yet been examined. METHOD: We conducted an optimized voxel based morphometry (VBM) study of juvenile offenders with the following diagnoses: conduct disorder with comorbid bipolar disorder (CD-BD; n = 24), conduct disorder without bipolar disorder (CD; n = 24) and healthy controls (HC, n = 24). Participants were 13-17 years of age, in a residential treatment facility for repeat offenders. The three groups in this study were similar in age, gender, socioeconomic status and ethnicity. RESULTS: We found CD-BD subjects had decreased volume relative to controls at the voxel level in the right medial prefrontal cortex (PFC). Using a Threshold-Free Cluster Enhancement (TFCE) technique, the CD-BD subjects had significantly decreased volumes of the right medial prefrontal cortex and portions of the superior and inferior frontal gyrus, anterior cingulate and temporal gyrus. The CD subjects did not have differences in brain volume compared to control subjects or CD-BD subjects. CONCLUSIONS: Our findings suggest the comorbidity between CD and BD is associated with neurobiological impact namely volumetric differences from healthy controls. Furthermore subjects with this comorbidity had poorer lifetime functioning, more mood and attentional dysfunction, and more medication exposure than subjects with CD who were not BD. PMID- 26237384 TI - The Role of RNAs and microRNAs in Non-Invasive Prenatal Diagnosis. AB - In this paper, all possible clinical applications of circulating mRNA and miRNA for non-invasive prenatal diagnosis appearing in the medical literature so far are described. Data from the literature have also been reported and commented on along with some possible future applications. PMID- 26237386 TI - First Trimester Aneuploidy Screening Markers in Women with Pre-Gestational Diabetes Mellitus. AB - OBJECTIVE: To investigate whether maternal serum pregnancy associated plasma protein-A (PAPP-A), total beta human chorionic gonadotropin (hCG) levels and nuchal translucency (NT) measurements differ in women with pre-gestational diabetes mellitus (PGDM) compared to non-diabetic controls and to assess whether correction factors are needed for diabetic women in calculation of aneuploidy risks. STUDY DESIGN: We performed a retrospective study of all women who underwent first trimester aneuploidy screening (11 + 0 to 13 + 6 weeks) from 2005 to 2011. The primary study outcome was the difference in PAPP-A, beta-hCG and NT multiples of median between women with PGDM and non-diabetic women. RESULTS: Of 6741 eligible patients, 103 patients with PGDM were using insulin and 4 patients were using oral hypoglycemic agents; the latter were excluded due to small number. There was 12% reduction of median PAPP-A (p = 0.001) and 18% reduction of median hCG (p = 0.006) in women with PGDM receiving insulin. There was no difference in NT. CONCLUSIONS: In women with PGDM receiving insulin, PAPP-A and beta-hCG levels are significantly lower compared to non-diabetic women. This suggests that when calculating risks for aneuploidy, correction factors should be considered to adjust PAPP-A and beta-hCG concentrations to those seen in non diabetic women. PMID- 26237385 TI - The Roles of Vitamin A in the Regulation of Carbohydrate, Lipid, and Protein Metabolism. AB - Currently, two-thirds of American adults are overweight or obese. This high prevalence of overweight/obesity negatively affects the health of the population, as obese individuals tend to develop several chronic diseases, such as type 2 diabetes and cardiovascular diseases. Due to obesity's impact on health, medical costs, and longevity, the rise in the number of obese people has become a public health concern. Both genetic and environmental/dietary factors play a role in the development of metabolic diseases. Intuitively, it seems to be obvious to link over-nutrition to the development of obesity and other metabolic diseases. However, the underlying mechanisms are still unclear. Dietary nutrients not only provide energy derived from macronutrients, but also factors such as micronutrients with regulatory roles. How micronutrients, such as vitamin A (VA; retinol), regulate macronutrient homeostasis is still an ongoing research topic. As an essential micronutrient, VA plays a key role in the general health of an individual. This review summarizes recent research progress regarding VA's role in carbohydrate, lipid, and protein metabolism. Due to the large amount of information regarding VA functions, this review focusses on metabolism in metabolic active organs and tissues. Additionally, some perspectives for future studies will be provided. PMID- 26237387 TI - Genetic Testing in the Diagnosis of Primary Ciliary Dyskinesia: State-of-the-Art and Future Perspectives. AB - Primary ciliary dyskinesia (PCD) is a heterogeneous autosomal recessive condition affecting around 1:15,000. In people with PCD, microscopic motile cilia do not move normally resulting in impaired clearance of mucus and debris leading to repeated sinopulmonary infection. If diagnosis is delayed, permanent bronchiectasis and deterioration of lung function occurs. Other complications associated with PCD include congenital heart disease, hearing impairment and infertility. A small number of longitudinal studies suggest that lung function deteriorates before diagnosis of PCD but may stabilise following diagnosis with subsequent specialist management. Early diagnosis is therefore essential, but for a number of reasons referral for diagnostic testing is often delayed until older childhood or even adulthood. Functional diagnostic tests for PCD are expensive, time consuming and require specialist equipment and scientists. In the last few years, there have been considerable developments to identify genes associated with PCD, currently enabling 65% of patients to be identified by bi-allelic mutations. The rapid identification of new genes continues. This review will consider the evidence that early diagnosis of PCD is beneficial. It will review the recent advances in identification of PCD-associated genes and will discuss the role of genetic testing in PCD. It will then consider whether screening for PCD antenatally or in the new born is likely to become a feasible and acceptable for this rare disease. PMID- 26237388 TI - Prenatal Screening Using Maternal Markers. AB - Maternal markers are widely used to screen for fetal neural tube defects (NTDs), chromosomal abnormalities and cardiac defects. Some are beginning to broaden prenatal screening to include pregnancy complications such as pre-eclampsia. The methods initially developed for NTDs using a single marker have since been built upon to develop high performance multi-maker tests for chromosomal abnormalities. Although cell-free DNA testing is still too expensive to be considered for routine application in public health settings, it can be cost-effective when used in combination with existing multi-maker marker tests. The established screening methods can be readily applied in the first trimester to identify pregnancies at high risk of pre-eclampsia and offer prevention though aspirin treatment. Prenatal screening for fragile X syndrome might be adopted more widely if the test was to be framed as a form of maternal marker screening. PMID- 26237389 TI - Prevention of Bone Metastases in Breast Cancer Patients. Therapeutic Perspectives. AB - One in four breast cancer patients is at risk of developing bone metastases in her life time. The early prevention of bone metastases is a crucial challenge. It has been suggested that the use of zoledronic acid (ZOL) in the adjuvant setting may reduce the persistence of disseminated tumor cells and thereby might improve outcome, specifically in a population of patients with a low estrogen microenvironment. More recently, the results of a large meta-analysis from 41 randomized trials comparing a bisphosphonate (BP) to placebo or to an open control have been presented at the 2013 San Antonio Breast Cancer Meeting. Data on 17,016 patients confirm that adjuvant BPs, irrespective of the type of treatment or the treatment schedule and formulation (oral or intra-venously (IV)), significantly reduced bone recurrences and improved breast cancer survival in postmenopausal women. No advantage was seen in premenopausal women. BPs are soon likely to become integrated into standard practice. Published data on the mechanisms involved in tumor cell seeding from the primary site, in homing to bone tissues and in the reactivation of dormant tumor cells will be reviewed; these might offer new ideas for innovative combination strategies. PMID- 26237390 TI - Non-Invasive Prenatal Testing Using Cell Free DNA in Maternal Plasma: Recent Developments and Future Prospects. AB - Recent advances in molecular genetic technologies have facilitated non-invasive prenatal testing (NIPT) through the analysis of cell-free fetal DNA in maternal plasma. NIPT can be used to identify monogenic disorders including the identification of autosomal recessive disorders where the maternally inherited mutation needs to be identified in the presence of an excess of maternal DNA that contains the same mutation. In the future, simultaneous screening for multiple monogenic disorders is anticipated. Several NIPT methods have been developed to screen for trisomy. These have been shown to be effective for fetal trisomy 21, 18 and 13. Although the testing has been extended to sex chromosome aneuploidy, robust estimates of the efficacy are not yet available and maternal mosaicism for gain or loss of an X-chromosome needs to be considered. Using methods based on the analysis of single nucleotide polymorphisms, diandric triploidy can be identified. NIPT is being developed to identify a number of microdeletion syndromes including alpha-globin gene deletion. NIPT is a profoundly important development in prenatal care that is substantially advancing the individual patient and public health benefits achieved through conventional prenatal screening and diagnosis. PMID- 26237392 TI - Optimal Pharmacologic Treatment Strategies in Obesity and Type 2 Diabetes. AB - The prevalence of obesity has increased to pandemic levels worldwide and is related to increased risk of morbidity and mortality. Metabolic comorbidities are commonly associated with obesity and include metabolic syndrome, pre-diabetes, and type 2 diabetes. Even if the prevalence of obesity remains stable until 2030, the anticipated numbers of people with diabetes will more than double as a consequence of population aging and urbanization. Weight reduction is integral in the prevention of diabetes among obese adults with pre-diabetes. Lifestyle intervention and weight reduction are also key in the management of type 2 diabetes. Weight loss is challenging for most obese patients, but for those with diabetes, it can pose an even greater challenge due to the weight gain associated with many treatment regimens. This article will review optimal treatment strategies for patients with comorbid obesity and type 2 diabetes. The role of anti-obesity agents in diabetes will also be reviewed. This literature review will provide readers with current strategies for the pharmacologic treatment of obesity and diabetes with a focus on the weight outcomes related to diabetes treatments. PMID- 26237393 TI - It's More Than a Blood Test: Patients' Perspectives on Noninvasive Prenatal Testing. AB - Noninvasive prenatal testing (NIPT) offers pregnant women a new risk assessment tool for fetal aneuploidy that is superior to conventional screening tests. We conducted focus groups with women who were currently pregnant or had recently delivered in the past year to characterize their perspectives about NIPT and to explore factors they would consider during decision making about its use. Women identified accuracy, early timing, testing ease, and determination of fetal sex as advantages of NIPT over other screens, and the noninvasive method of NIPT as an advantage over diagnostic tests. False positive and false negative results, anxiety, cost and insurance coverage were seen as disadvantages of NIPT. Women who do not want fetal aneuploidy information most likely will not undergo NIPT, despite its advantages over other screening tests. However, given its advantages, the decision to have NIPT is straightforward for women who want genetic information about the fetus. Women emphasized the need to make autonomous, private, and informed choices about NIPT, as they would with any prenatal genetic testing option. These perspectives may guide clinicians to conduct effective and clinically relevant counseling with pregnant women who consider utilizing this new genetic technology. PMID- 26237391 TI - Molecular Mechanisms of Retinoid Receptors in Diabetes-Induced Cardiac Remodeling. AB - Diabetic cardiomyopathy (DCM), a significant contributor to morbidity and mortality in diabetic patients, is characterized by ventricular dysfunction, in the absence of coronary atherosclerosis and hypertension. There is no specific therapeutic strategy to effectively treat patients with DCM, due to a lack of a mechanistic understanding of the disease process. Retinoic acid, the active metabolite of vitamin A, is involved in a wide range of biological processes, through binding and activation of nuclear receptors: retinoic acid receptors (RAR) and retinoid X receptors (RXR). RAR/RXR-mediated signaling has been implicated in the regulation of glucose and lipid metabolism. Recently, it has been reported that activation of RAR/RXR has an important role in preventing the development of diabetic cardiomyopathy, through improving cardiac insulin resistance, inhibition of intracellular oxidative stress, NF-kappaB-mediated inflammatory responses and the renin-angiotensin system. Moreover, downregulated RAR/RXR signaling has been demonstrated in diabetic myocardium, suggesting that impaired RAR/RXR signaling may be a trigger to accelerate diabetes-induced development of DCM. Understanding the molecular mechanisms of retinoid receptors in the regulation of cardiac metabolism and remodeling under diabetic conditions is important in providing the impetus for generating novel therapeutic approaches for the prevention and treatment of diabetes-induced cardiac complications and heart failure. PMID- 26237394 TI - Knowledge and Educational Needs about Pre-Implantation Genetic Diagnosis (PGD) among Oncology Nurses. AB - Preimplantation genetic diagnosis (PGD), a form of assisted reproductive technology, is a new technology with limited awareness among health care professionals and hereditary cancer families. Nurses play a key role in the care of patients and are often in an ideal position to discuss and refer patients on sensitive quality of life issues, such as PGD. Two hundred and one nurses at Moffitt Cancer Center (MCC) responded to an online survey assessing knowledge and educational needs regarding PGD and families with hereditary cancer. The majority of respondents were female (n = 188), white (n = 175), had an RN/BSN degree (n = 83), and provided outpatient care at the cancer center (n = 102). More than half of respondents (78%) were unfamiliar with PGD prior to the survey and respondents who had heard of PGD had limited knowledge. More than half of the participants reported PGD was an acceptable option for families with hereditary cancer syndromes and thought individuals with a strong family or personal history should be provided with information about PGD. This study indicates that oncology nurses may benefit from and desire education about PGD. With advances in reproductive technology and options, further PGD education is needed among healthcare professionals. An examination of current oncology nursing curriculum and competencies regarding genetic education may identify need for future revisions and updates. PMID- 26237395 TI - Roles of Sphingolipid Metabolism in Pancreatic beta Cell Dysfunction Induced by Lipotoxicity. AB - Pancreatic beta cells secrete insulin in order to maintain glucose homeostasis. However, various environmental stresses such as obesity have been shown to induce loss of secretory responsiveness in pancreatic beta cells and pancreatic beta cell apoptosis which can favor the development of type 2 diabetes (T2D). Indeed, elevated levels of free fatty acids (FFAs) have been shown to induce beta cell apoptosis. Importantly, the chronic adverse effects of FFAs on beta cell function and viability are potentiated in the presence of hyperglycaemia, a phenomenon that has been termed gluco-lipotoxicity. The molecular mechanisms underlying the pathogenesis of gluco-lipotoxicity in pancreatic beta cells are not completely understood. Recent studies have shown that sphingolipid metabolism plays a key role in gluco-lipotoxicity induced apoptosis and loss of function of pancreatic beta cells. The present review focuses on how the two main sphingolipid mediators, ceramides and sphingoid base-1-phosphates, regulate the deleterious effects of gluco-lipotoxicity on pancreatic beta cells. The review highlights the role of a sphingolipid biostat on the dysregulation of beta cell fate and function induced by gluco-lipotoxicity, offering the possibility of new therapeutic targets to prevent the onset of T2D. PMID- 26237396 TI - Microarray Technology for the Diagnosis of Fetal Chromosomal Aberrations: Which Platform Should We Use? AB - The advantage of microarray (array) over conventional karyotype for the diagnosis of fetal pathogenic chromosomal anomalies has prompted the use of microarrays in prenatal diagnostics. In this review we compare the performance of different array platforms (BAC, oligonucleotide CGH, SNP) and designs (targeted, whole genome, whole genome, and targeted, custom) and discuss their advantages and disadvantages in relation to prenatal testing. We also discuss the factors to consider when implementing a microarray testing service for the diagnosis of fetal chromosomal aberrations. PMID- 26237397 TI - Health properties of oca (Oxalis tuberosa) and yacon (Smallanthus sonchifolius). AB - Andean roots and tubers are underexploited crops; many contain compounds beneficial to health, so a greater knowledge of their properties is important for encouraging their consumption. The aim of this work was to study the content of bioactive compounds of yacon and oca and their effect on intestinal health using as a model rats of the Wistar strain. Two varieties of ocas (Overa and Rosada) and yacon, which contain significant amounts of fructooligosaccharides and phenolic compounds, were chosen. Rats of the Wistar strain were fed for two months with diets containing these foods in amounts sufficient to provide 8% of fiber. A significant decrease in pH values and an increment in lactobacilli and bifidobacteria counts in the cecum of rats fed with inulin, oca Rosada and Overa were observed; there was no significant decrease in enterobacteriaceae and enterococci counts. The cecum antioxidant activity was incremented in rats fed with the experimental foods with respect to the control diets. The components of dietary fiber and phenolic compound contents in yacon and oca produce effects that contribute to the intestinal health of the experimental animals. PMID- 26237398 TI - A New Strategy for Smoking Cessation: Characterization of a Bacterial Enzyme for the Degradation of Nicotine. AB - Smoking is the leading cause of preventable diseases; thus, effective smoking cessation aids are crucial for reducing the prevalence of cigarette smoking and smoking-related illnesses. In our current campaign we offer a nicotine-degrading enzyme from Pseudomonas putida, NicA2, a flavin-containing protein. To explore its potential, a kinetic evaluation of the enzyme was conducted, which included determination of K(m), k(cat), buffer/serum half-life, and thermostability. Additionally, the catabolism profile of NicA2 was elucidated to assess the potential toxicity of the nicotine-derived products. In characterizing the enzyme, a favorable biochemical profile of the enzyme was discovered, making NicA2 a prospective therapeutic candidate. This approach provides a new avenue for the field of nicotine addiction therapy. PMID- 26237399 TI - Willingness to Consult a Veterinarian on Physician's Advice for Zoonotic Diseases: A Formal Role for Veterinarians in Medicine? AB - Physicians appear to find zoonotic diseases a challenge and consider that this topic belongs more to the veterinary profession. However, veterinarians have no formal role in clinical medicine. Data were collected as part of the Queensland Social Survey 2014 to determine the willingness of the public, if diagnosed with a zoonotic disease, to consult a veterinarian on the advice of a physician. Self reported willingness to consult with a veterinarian at the respondent's own expense was 79.8% (95% CI: 81.96%-77.46%) (976/1223). If the cost was funded by Medicare, the Australian public health insurance scheme, 90.7% (95% CI: 92.18% 88.92%) (1109/1223) would be willing to consult a veterinarian. Therefore, a large majority of Australian residents would be willing to consult with a veterinarian on the advice of their physician if they had a zoonotic disease. Does this indicate a possible new role for veterinarians under Clinical One Health? PMID- 26237400 TI - Fluorescent Protein Based FRET Pairs with Improved Dynamic Range for Fluorescence Lifetime Measurements. AB - Fluorescence Resonance Energy Transfer (FRET) using fluorescent protein variants is widely used to study biochemical processes in living cells. FRET detection by fluorescence lifetime measurements is the most direct and robust method to measure FRET. The traditional cyan-yellow fluorescent protein based FRET pairs are getting replaced by green-red fluorescent protein variants. The green-red pair enables excitation at a longer wavelength which reduces cellular autofluorescence and phototoxicity while monitoring FRET. Despite the advances in FRET based sensors, the low FRET efficiency and dynamic range still complicates their use in cell biology and high throughput screening. In this paper, we utilized the higher lifetime of NowGFP and screened red fluorescent protein variants to develop FRET pairs with high dynamic range and FRET efficiency. The FRET variations were analyzed by proteolytic activity and detected by steady state and time-resolved measurements. Based on the results, NowGFP-tdTomato and NowGFP-mRuby2 have shown high potentials as FRET pairs with large fluorescence lifetime dynamic range. The in vitro measurements revealed that the NowGFP tdTomato has the highest Forster radius for any fluorescent protein based FRET pairs yet used in biological studies. The developed FRET pairs will be useful for designing FRET based sensors and studies employing Fluorescence Lifetime Imaging Microscopy (FLIM). PMID- 26237401 TI - Agitation Rate and Time for Complete Dissolution in BCS Biowaivers Based on Investigation of a BCS Biowaiver for Dexketoprofen Tablets. AB - The objective of the present work is to investigate the validity of the existing requirements for BCS biowaivers of immediate release products containing a class I drug in relation to the agitation rate (50 or 75 rpm in the paddle apparatus) and the time limit for complete dissolution (30 min) in the current biowaivers in vitro dissolution tests. Further, the possibility of extensions will be examined since it has been proposed that the time limit for complete dissolution should be revised to 60 min, and also, if cone formation occurs with apparatus 2 at 50 rpm, then a higher agitation rate is acceptable to eliminate it. The development of four generic dexketoprofen immediate release tablets is described. Dexketoprofen is the eutomer of ketoprofen. According to the BCS, dexketoprofen is a class I drug. Three out of the four products failed to show bioequivalence for Cmax in the initial bioequivalence study conducted with the product despite similar but nonrapid dissolution profiles at 50 rpm in the paddle apparatus, or similar and very rapid dissolution profiles at 75 rpm. In conclusion, these data indicate that BCS biowaivers for class I drugs should be granted only when dissolution with the paddle apparatus is complete in 30 min at 50 rpm. The time limit for complete dissolution should not be extended to 60 min. Furthermore, the agitation rate should not be increased to 75 rpm, even in the case of a coning effect. PMID- 26237404 TI - Weed Dynamics during Transition to Conservation Agriculture in Western Kenya Maize Production. AB - Weed competition is a significant problem in maize (Zea mays, L.) production in Sub-Saharan Africa. Better understanding of weed management and costs in maize intercropped with beans (Phaseolus vulgaris, L.) during transition to conservation agricultural systems is needed. Changes in weed population and maize growth were assessed for a period of three years at Bungoma where crops are grown twice per year and at Trans-Nzoia where crops are grown once per year. Treatments included three tillage practices: minimum (MT), no-till (NT) and conventional (CT) applied to three cropping systems: continuous maize/bean intercropping (TYPICAL), maize/bean intercropping with relayed mucuna after bean harvest (RELAY) and maize, bean and mucuna planted in a strip intercropping arrangement (STRIP). Herbicides were used in NT, shallow hand hoeing and herbicides were used in MT and deep hoeing with no herbicides were used in CT. Weed and maize performance in the maize phase of each cropping system were assessed at both locations and costs of weed control were estimated at Manor House only. Weed density of grass and forb species declined significantly under MT and NT at Manor House and of grass species only at Mabanga. The greatest declines of more than 50% were observed as early as within one year of the transition to MT and NT in STRIP and TYPICAL cropping systems at Manor House. Transitioning to conservation based systems resulted in a decline of four out of five most dominant weed species. At the same time, no negative impact of MT or NT on maize growth was observed. Corresponding costs of weed management were reduced by $148.40 ha(-1) in MT and $149.60 ha(-1) in NT compared with CT. In conclusion, farmers can benefit from effective and less expensive weed management alternatives early in the process of transitioning to reduced tillage operations. PMID- 26237402 TI - Serious Adverse Events in the Canadian Registry of Children Receiving Palivizumab (CARESS) for Respiratory Syncytial Virus Prevention. AB - OBJECTIVES: To evaluate the safety and tolerability of palivizumab for RSV prophylaxis in high-risk children in everyday practice. METHODS: High-risk children prophylaxed against RSV infection were recruited into a prospective, observational, Canadian RSV Evaluation Study of Palivizumab (CARESS) registry with active, serious adverse event (SAE) monitoring from 2008 to 2013. SAE reports were systematically collected and assessed for severity and relationship to palivizumab. Data were analyzed by Chi-square or Fisher Exact Tests to examine group differences in proportions. RESULTS: 13025 infants received 57392 injections. Hospitalizations for respiratory-related illness (RIH) were reported in 915 patients, and SAEs other than RIH were reported in 52 patients. Of these, 6 (0.05%) patients had a total of 14 hypersensitivity reactions that were deemed possibly or probably related to palivizumab (incidence: 2.8 per 10,000 patient months). The SAEs of 42 patients were assessed as not related to palivizumab. SAEs in the remaining 4 patients were not classifiable as their records were incomplete. There were no significant demographic predictors of SAE occurrence. CONCLUSIONS: Under active surveillance, a small proportion of infants in the CARESS registry experienced SAEs that had a potential relationship with palivizumab and these appeared to be unpredictable in terms of onset. Palivizumab appears to be a safe and well-tolerated antibody for RSV prophylaxis in high-risk children in routine practice. PMID- 26237405 TI - A Regional Categorization for "New-Type Urbanization" in China. AB - Regional differences in the character of urbanization in China are substantial. The promotion of what has been termed "new-type urbanization" cannot, as a result of these regional differences, be expected to follow a universal approach- rather, such a development must objectively adhere to locational and category specific principles and adopt differentiated urbanization development models. Regional categorization is often used in geography, but is rarely deployed in research addressing human and social problems relating to urbanization. In March 2014, China published the National New-type Urbanization Plan (2014-2020), which calls for the scientific and reasonable planning of "new-type urbanization," and appropriate regional categorizations are urgently needed in order to guide this reform. Responding to this challenge, this research engaged in the design of a "dominantly quantitative analysis, qualitatively supplemented" method in order to divide China into 5 main regions and 47 sub-regions in terms of new-type urbanization. The paper discusses the features and key problems of each region. This study introduces a new method for regional categorization, thereby remedying the lack of regional categorization in relation to "new-type urbanization" in China, and ultimately promoting the development of regional categorization in the humanities as a valuable reference for healthy and sustainable Chinese urbanization. PMID- 26237406 TI - Severe Acute Pancreatitis: Gut Barrier Failure, Systemic Inflammatory Response, Acute Lung Injury, and the Role of the Mesenteric Lymph. AB - BACKGROUND: Severe acute pancreatitis (AP) often leads to distant organ dysfunction with a high morbidity and mortality rate. The most common and earliest organ to fail is the lungs, but the exact pathophysiological mechanisms underlying the disease are still unclear. No successful targeted therapy exists, and treatment is limited to organ supportive care. It is believed that the gut is involved in the development of distant organ failure, as severe AP is associated with changes in the microcirculation, gut permeability/motility, bacterial translocation, and activation of the gut-associated lymphoid tissue (GALT). Experimental evidence implicates the mesenteric lymph as a primary route for these toxic factors to gain access to the systemic circulation. This literature overview was made to survey these mechanisms and the potential of surgical interventions on the thoracic duct as a means of therapy. METHODS: Review of the pertinent English-language literature. RESULTS: In experimental studies, interruption of mesenteric lymphatic flow has preventive qualities for acute lung injury (ALI) in the setting of critical illness with various etiologies. Experimentally, diversion of mesenteric lymph is able to prevent ALI if done before its development, whereas a later intervention partially reduces the lung damage. Few studies have investigated surgical approaches to the thoracic duct in human beings under these circumstances, and the ones that have been performed are of low quality and have conflicting results. It seems likely that the intervention would need to be performed prior to the development of ALI to obtain maximum benefits, which complicates its application clinically, because prediction of ALI cannot today be done with high precision. CONCLUSION: Studies are ongoing to identify the factors carried in mesenteric lymph that may cause end-organ failure (e.g., ALI) and, once recognized, might allow the development of novel targeted agents that would modify the disease course. PMID- 26237403 TI - Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques. AB - HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses. PMID- 26237407 TI - Factors affecting ultraviolet-A photon emission from beta-irradiated human keratinocyte cells. AB - The luminescence intensity of 340+/-5 nm photons emitted from HaCaT (human keratinocyte) cells was investigated using a single-photon-counting system during cellular exposure to (90)Y beta-particles. Multiple factors were assessed to determine their influence upon the quantity and pattern of photon emission from beta-irradiated cells. Exposure of 1 x 10(4) cells/5 mL to 703 MUCi resulted in maximum UVA photoemission at 44.8 x 10(3)+/-2.5 x 10(3) counts per second (cps) from live HaCaT cells (background: 1-5 cps); a 16-fold increase above cell-free controls. Significant biophoton emission was achieved only upon stimulation and was also dependent upon presence of cells. UVA luminescence was measured for (90)Y activities 14 to 703 MUCi where a positive relationship between photoemission and (90)Y activity was observed. Irradiation of live HaCaT cells plated at various densities produced a distinct pattern of emission whereby luminescence increased up to a maximum at 1 x 10(4) cells/5 mL and thereafter decreased. However, this result was not observed in the dead cell population. Both live and dead HaCaT cells were irradiated and were found to demonstrate different rates of photon emission at low beta activities (?400 MUCi). Dead cells exhibited greater photon emission rates than live cells which may be attributable to metabolic processes taking place to modulate the photoemissive effect. The results indicate that photon emission from HaCaT cells is perturbed by external stimulation, is dependent upon the activity of radiation delivered, the density of irradiated cells, and cell viability. It is postulated that biophoton emission may be modulated by a biological or metabolic process. PMID- 26237408 TI - Reconstructing the reproductive mode of an Ediacaran macro-organism. AB - Enigmatic macrofossils of late Ediacaran age (580-541 million years ago) provide the oldest known record of diverse complex organisms on Earth, lying between the microbially dominated ecosystems of the Proterozoic and the Cambrian emergence of the modern biosphere. Among the oldest and most enigmatic of these macrofossils are the Rangeomorpha, a group characterized by modular, self-similar branching and a sessile benthic habit. Localized occurrences of large in situ fossilized rangeomorph populations allow fundamental aspects of their biology to be resolved using spatial point process techniques. Here we use such techniques to identify recurrent clustering patterns in the rangeomorph Fractofusus, revealing a complex life history of multigenerational, stolon-like asexual reproduction, interspersed with dispersal by waterborne propagules. Ecologically, such a habit would have allowed both for the rapid colonization of a localized area and for transport to new, previously uncolonized areas. The capacity of Fractofusus to derive adult morphology by two distinct reproductive modes documents the sophistication of its underlying developmental biology. PMID- 26237409 TI - Ascorbate protects neurons against oxidative stress: a Raman microspectroscopic study. AB - Oxidative stress due to excessive accumulation of reactive oxygen or nitrogen species in the brain as seen in certain neurodegenerative diseases can have deleterious effects on neurons. Hydrogen peroxide, endogenously generated in neurons under normal physiological conditions, can produce an excess of hydroxyl radical via a Fenton mediated mechanism. This may induce acute oxidative injury if not scavenged or removed effectively by antioxidants. There are several biochemical assay methods to estimate oxidative injury in cells; however, they do not provide information on the biochemical changes as the cells get damaged progressively under oxidative stress. Raman microspectroscopy offers the possibility of real time monitoring of the chemical composition of live cells undergoing oxidative stress under physiological conditions. In the present study, a hippocampal neuron coculture was used to observe the acute impact of hydroxyl radicals generated by hydrogen peroxide in the presence of Fe(2+) (Fenton reaction). Raman peaks related to nucleic acids (725, 782, 1092, 1320, 1340, 1420, and 1576 cm(-1)) showed time-dependent changes over the experimental period (60 min), indicating the breakdown of the phosphodiester backbone as well as nuclear bases. Interestingly, ascorbic acid (a potent antioxidant) when cotreated with Fenton reactants showed protection of cells as inferred from the Raman spectra, presumably by scavenging hydroxyl radicals. Little or no change in the Raman spectra was observed for untreated control cells and for cells exposed to Fe(2+) only, H2O2 only, and ascorbate only. A live-dead assay study also supported the current observations. Hence, Raman microspectroscopy has the potential to be an excellent noninvasive tool for early detection of oxidative stress that is seen in neurodegenerative diseases. PMID- 26237410 TI - Spots, not stripes, from just holding on. PMID- 26237411 TI - Maternal Mortality in Taiwan: A Nationwide Data Linkage Study. AB - BACKGROUND: To examine the changes in the maternal mortality ratio (MMR) and causes of maternal death in Taiwan based on nationwide linked data sets. METHODS: We linked four population-based data sets (birth registration, birth notification, National Health Insurance inpatient claims, and cause of death mortality data) to identify maternal deaths for 2004-2011. Subsequently, we calculated the MMR (deaths per 100,000 live births) and the proportion of direct and indirect causes of maternal death by maternal age and year. FINDINGS: Based on the linked data sets, we identified 236 maternal death cases, of which only 102 were reported in officially published mortality data, with an underreporting rate of 57% [(236-102) * 100 / 236]. The age-adjusted MMR was 18.4 in 2004-2005 and decreased to 12.5 in 2008-2009; however, the MMR leveled off at 12.6 in 2010 2011. The MMR increased from 5.2 in 2008-2009 to 7.1 in 2010-2011 for patients aged 15-29 years. Women aged 15-29 years had relatively lower proportion in dying from direct causes (amniotic fluid embolism and obstetric hemorrhage) compared with their counterpart older women. CONCLUSIONS: Approximately two-thirds of maternal deaths were not reported in officially published mortality data. Routine surveillance of maternal mortality by using enhanced methods is necessary to monitor the health status of reproductive-age women. Furthermore, a comprehensive maternal death review is necessary to explore the preventability of these maternal deaths. PMID- 26237412 TI - In vitro Effects of Prostaglandin Analogs on Cultured Astrocytes Obtained from the Lamina Cribrosa. AB - PURPOSE: To evaluate the effects of prostaglandin analogs (PGAs) on cell viability and apoptosis in cultured astrocytes obtained from the lamina cribrosa (LC) of the human optic nerve head (ONH). METHODS: Astrocytes were cultured from LC samples obtained from human donor ONH and treated with three kinds of acid form of PGAs: latanoprost (LAT-A), tafluprost (TAF-A), and bimatoprost (BIM-A) (0.1, 1, 10, 50 and 100 ug/mL). Cell viability was assessed using the WST-1 assay. Cell apoptosis was measured using the deoxynucleotidyl transferase (TdT) mediated dUTP nick end-labeling (TUNEL) assay. Apoptotic protein expression was evaluated using western blot analysis. RESULTS: ONH astrocytes expressed FP receptor in western blot analysis. In the presence of 0.1 ug/mL of LAT-A, BIM-A, and TAF-A, the cell viability was 85%, 85% and 82%, respectively. WST-1 assay revealed about 50% of cell viability following treatment with 50 ug/mL of all PGAs. After exposing astrocytes to 10 ug/mL of each PGA for 24 hours, apoptotic cells were stained in TUNEL assay. Western blot analysis revealed that the PGAs up-regulated Bax (pro-apoptotic protein) and down-regulated Bcl-xL (anti apoptotic protein) in the astrocytes. CONCLUSIONS: PGAs affected cell viability in cultured astrocytes obtained from human ONH LC. PGA treatment may induce apoptosis in ONH astrocytes. PMID- 26237413 TI - Molecular Cytogenetic Identification of a New Wheat-Rye 6R Chromosome Disomic Addition Line with Powdery Mildew Resistance. AB - Rye (Secale cereale L.) possesses many valuable genes that can be used for improving disease resistance, yield and environment adaptation of wheat (Triticum aestivum L.). However, the documented resistance stocks derived from rye is faced severe challenge due to the variation of virulent isolates in the pathogen populations. Therefore, it is necessary to develop desirable germplasm and search for novel resistance gene sources against constantly accumulated variation of the virulent isolates. In the present study, a new wheat-rye line designated as WR49 1 was produced through distant hybridization and chromosome engineering protocols between common wheat cultivar Xiaoyan 6 and rye cultivar German White. Using sequential GISH (genomic in situ hybridization), mc-FISH (multicolor fluorescence in situ hybridization), mc-GISH (multicolor GISH) and EST (expressed sequence tag)-based marker analysis, WR49-1 was proved to be a new wheat-rye 6R disomic addition line. As expected, WR49-1 showed high levels of resistance to wheat powdery mildew (Blumeria graminis f. sp. tritici, Bgt) pathogens prevalent in China at the adult growth stage and 19 of 23 Bgt isolates tested at the seedling stage. According to its reaction pattern to different Bgt isolates, WR49-1 may possess new resistance gene(s) for powdery mildew, which differed from the documented powdery mildew gene, including Pm20 on chromosome arm 6RL of rye. Additionally, WR49-1 was cytologically stable, had improved agronomic characteristics and therefore could serve as an important bridge for wheat breeding and chromosome engineering. PMID- 26237414 TI - Differential mRNA Accumulation upon Early Arabidopsis thaliana Infection with ORMV and TMV-Cg Is Associated with Distinct Endogenous Small RNAs Level. AB - Small RNAs (sRNAs) play important roles in plant development and host-pathogen interactions. Several studies have highlighted the relationship between viral infections, endogenous sRNA accumulation and transcriptional changes associated with symptoms. However, few studies have described a global analysis of endogenous sRNAs by comparing related viruses at early stages of infection, especially before viral accumulation reaches systemic tissues. An sRNA high throughput sequencing of Arabidopsis thaliana leaf samples infected either with Oilseed rape mosaic virus (ORMV) or crucifer-infecting Tobacco mosaic virus (TMV Cg) with slightly different symptomatology at two early stages of infection (2 and 4 dpi) was performed. At early stages, both viral infections strongly alter the patterns of several types of endogenous sRNA species in distal tissues with no virus accumulation suggesting a systemic signaling process foregoing to virus spread. A correlation between sRNAs derived from protein coding genes and the associated mRNA transcripts was also detected, indicating that an unknown recursive mechanism is involved in a regulatory circuit encompassing this sRNA/mRNA equilibrium. This work represents the initial step in uncovering how differential accumulation of endogenous sRNAs contributes to explain the massive alteration of the transcriptome associated with plant-virus interactions. PMID- 26237415 TI - Generation of Functional Cardiomyocytes from Efficiently Generated Human iPSCs and a Novel Method of Measuring Contractility. AB - Human induced pluripotent stem cells (iPSCs) derived cardiomyocytes (iCMCs) would provide an unlimited cell source for regenerative medicine and drug discoveries. The objective of our study is to generate functional cardiomyocytes from human iPSCs and to develop a novel method of measuring contractility of CMCs. In a series of experiments, adult human skin fibroblasts (HSF) and human umbilical vein endothelial cells (HUVECs) were treated with a combination of pluripotent gene DNA and mRNA under specific conditions. The iPSC colonies were identified and differentiated into various cell lineages, including CMCs. The contractile activity of CMCs was measured by a novel method of frame-by-frame cross correlation (particle image velocimetry-PIV) analysis. Our treatment regimen transformed 4% of HSFs into iPSC colonies at passage 0, a significantly improved efficiency compared with use of either DNA or mRNA alone. The iPSCs were capable of differentiating both in vitro and in vivo into endodermal, ectodermal and mesodermal cells, including CMCs with >88% of cells being positive for troponin T (CTT) and Gata4 by flow cytometry. We report a highly efficient combination of DNA and mRNA to generate iPSCs and functional iCMCs from adult human cells. We also report a novel approach to measure contractility of iCMCs. PMID- 26237417 TI - Anaerobic physical evaluation of young national rowers. PMID- 26237416 TI - Tumor-Targeting Salmonella typhimurium A1-R Arrests a Chemo-Resistant Patient Soft-Tissue Sarcoma in Nude Mice. AB - A patient-derived nude-mouse model of soft-tissue sarcoma has been established and treated in the following groups: (1) untreated controls; (2) gemcitabine (GEM) (80 mg/kg, ip, weekly, 3 weeks); (3) Pazopanib (100 mg/kg, orally, daily, 3 weeks) and (4) Salmonella typhimurium A1-R (5 * 10(7) CFU/body, ip, weekly, 3 weeks). The sarcoma was resistant to GEM (p = 0.879). Pazopanib tended to reduce the tumor volume compared to the untreated mice, but there was no significant difference (p = 0.115). S. typhimurium A1-R significantly inhibited tumor growth compared to the untreated mice (p = 0.001). S. typhimurium A1-R was the only effective treatment for the soft-tissue sarcoma nude mouse model among all treatments including a newly approved multiple tyrosine kinase inhibitor; Pazopanib. These results suggest tumor-targeting S. typhimurium A1-R is a promising treatment for chemo-resistant soft-tissue sarcoma. PMID- 26237418 TI - 3D cancer cell migration in collagen matrices. PMID- 26237420 TI - The varieties of momentum-like experience. AB - Cognition and behavior exhibit biases consistent with future expectations, and some of these biases result in momentum-like effects and have been linked with the idea of momentum. These momentum-like effects include representational momentum, operational momentum, attentional momentum, behavioral momentum, and psychological momentum. Effects of numerous variables involving characteristics of the target, display, context, or observer on each momentum-like effect are considered, and similarities of different momentum-like effects are considered. It is suggested that representational momentum, operational momentum, and attentional momentum reflect similar or overlapping mechanisms based on a perceptual time-scale and extrapolation primarily across space, and that behavioral momentum and psychological momentum reflect similar or overlapping mechanisms based on a longer time-scale and extrapolation primarily across time. It is further suggested that all 5 forms of momentum-like effect could reflect a more general extrapolation mechanism that anticipates the future action, behavior, or outcome of a given target, person, or process. A list of properties characterizing momentum-like effects is proposed, and constraints and issues relevant to future models of momentum-like effects are discussed. (PsycINFO Database Record PMID- 26237419 TI - Concerted Evolution of Duplicate Control Regions in the Mitochondria of Species of the Flatfish Family Bothidae (Teleostei: Pleuronectiformes). AB - Mitogenomes of flatfishes (Pleuronectiformes) exhibit the greatest diversity of gene rear-rangements in teleostean fishes. Duplicate control regions (CRs) have been found in the mito-genomes of two flatfishes, Samariscus latus (Samaridae) and Laeops lanceolata (Bothidae), which is rare in teleosts. It has been reported that duplicate CRs have evolved in a concerted fashion in fishes and other animals, however, whether concerted evo-lution exists in flatfishes remains unknown. In this study, based on five newly sequenced and six previously reported mitogenomes of lefteye flounders in the Bothidae, we explored whether duplicate CRs and concerted evolution exist in these species. Results based on the present study and previous reports show that four out of eleven bothid species examined have duplicate CRs of their mitogenomes. The core regions of the duplicate CRs of mitogenomes in the same species have identical, or nearly identical, sequences when compared to each other. This pattern fits the typical characteristics of concerted evolution. Additionally, phylogenetic and ancestral state reconstruction analysis also provided evidence to support the hypothesis that duplicate CRs evolved concertedly. The core region of concerted evolution is situated at the conserved domains of the CR of the mitogenome from the termination associated sequences (TASs) to the conserved sequence blocks (CSBs). Commonly, this region is con-sidered to regulate mitochondrial replication and transcription. Thus, we hypothesize that the cause of concerted evolution of the duplicate CRs in the mtDNAs of these four bothids may be related to some function of the conserved sequences of the CRs during mitochondrial rep-lication and transcription. We hope our results will provide fresh insight into the molecular mechanisms related to replication and evolution of mitogenomes. PMID- 26237421 TI - Pentoxifylline for Anemia in Chronic Kidney Disease: A Systematic Review and Meta Analysis. AB - BACKGROUND: Pentoxifylline (PTX) is a promising therapeutic approach for reducing inflammation and improving anemia associated to various systemic disorders. However, whether this agent may be helpful for anemia management also in CKD patients is still object of debate. STUDY DESIGN: Systematic review and meta analysis. POPULATION: Adults with CKD (any KDOQI stage, including ESKD patients on regular dialysis) and anemia (Hb<13 g/dL in men or < 12 g/dL in women). SEARCH STRATEGY AND SOURCES: Cochrane CENTRAL, EMBASE, Ovid-MEDLINE and PubMed were searched for studies providing data on the effects of PTX on anemia parameters in CKD patients without design or follow-up restriction. INTERVENTION: PTX derivatives at any dose regimen. OUTCOMES: Hemoglobin, hematocrit, ESAs dosage and resistance (ERI), iron indexes (ferritin, serum iron, TIBC, transferrin and serum hepcidin) and adverse events. RESULTS: We retrieved 11 studies (377 patients) including seven randomized controlled trials (all comparing PTX to placebo or standard therapy) one retrospective case-control study and three prospective uncontrolled studies. Overall, PTX increased hemoglobin in three uncontrolled studies but such improvement was not confirmed in a meta-analysis of seven studies (299 patients) (MD 0.12 g/dL, 95% CI -0.22 to 0.47). Similarly, there were no conclusive effects of PTX on hematocrit, ESAs dose, ferritin and TSAT in pooled analyses. Data on serum iron, ERI, TIBC and hepcidin were based on single studies. No evidence of increased rate of adverse events was also noticed. LIMITATIONS: Small sample size and limited number of studies. High heterogeneity among studies with respect to CKD and anemia severity, duration of intervention and responsiveness/current therapy with iron or ESAs. CONCLUSIONS: There is currently no conclusive evidence supporting the utility of pentoxifylline for improving anemia control in CKD patients. Future trials designed on hard, patient centered outcomes with larger sample size and longer follow-up are advocated. PMID- 26237422 TI - Urinary Tract Infections in Kidney Transplant Patients Due to Escherichia coli and Klebsiella pneumoniae-Producing Extended-Spectrum beta-Lactamases: Risk Factors and Molecular Epidemiology. AB - Urinary tract infection (UTI) is a common complication after kidney transplantation, often associated to graft loss and increased healthcare costs. Kidney transplant patients (KTPs) are particularly susceptible to infection by Enterobacteriaceae-producing extended-spectrum beta-lactamases (ESBLs). A retrospective case-control study was conducted to identify independent risk factors for ESBL-producing Escherichia coli and Klebsiella pneumoniae in non hospitalized KTPs with UTI. Forty-nine patients suffering from UTI by ESBL producing bacteria (ESBL-P) as case group and the same number of patients with UTI by ESBL negative (ESBL-N) as control-group were compared. Clinical data, renal function parameters during UTI episodes, UTI recurrence and relapsing rate, as well as risk factors for recurrence, molecular characterization of isolates and the respective antimicrobial susceptibility profile were evaluated. Diabetes mellitus (p <0.007), previous antibiotic prophylaxis (p=0.017) or therapy (p<0.001), previous UTI (p=0.01), relapsing infection (p=0.019) and patients with delayed graft function after transplant (p=0.001) represented risk factors for infection by ESBL positive Enterobacteriaceae in KTPs. Interestingly, the period of time between data of transplantation and data of UTI was shorter in case of ESBL-P case-group (28.8 months) compared with ESBL-N control-group (50.9 months). ESBL-producing bacteria exhibited higher resistance to fluoroquinolones (p=0.002), trimethoprim-sulfamethoxazole (p<0.001) and gentamicin (p<0.001). Molecular analysis showed that blaCTX-M was the most common ESBL encoding gene (65.3%), although in 55.1% of the cases more than one ESBL gene was found. In 29.4% of K. pneumoniae isolates, three bla-genes (blaCTX-M-blaTEM-blaSHV) were simultaneously detected. Low estimated glomerular filtration rate (p=0.009) was found to be risk factor for UTI recurrence. Over 60% of recurrent UTI episodes were caused by genetically similar strains. UTI by ESBL-producing Enterobacteriaceae in KTPs represent an important clinical challenge regarding not only hospitalized patients but also concerning outpatients. PMID- 26237424 TI - Does patient-prosthesis mismatch after aortic valve replacement affect survival and quality of life in elderly patients? AB - BACKGROUND: To evaluate the impact of patient-prosthesis mismatch (PPM) on survival, functional status, and quality of life (QoL) after aortic valve replacement (AVR) with small prosthesis size in elderly patients. METHODS: Between January 2005 and December 2013, 152 patients with pure aortic stenosis, aged at least 75 years, underwent AVR, with a 19 or 21 mm prosthetic heart valve. PPM was defined as an indexed effective orifice area less than 0.85 cm/m. Median age was 82 years (range 75-93 years). Mean follow-up was 56 months (range 1-82 months) and was 98% complete. Late survival rate, New York Heart Association functional class, and QoL (RAND SF-36) were assessed. RESULTS: Overall, PPM was found in 78 patients (53.8%). Among them, 42 patients (29%) had an indexed effective orifice area less than 0.75 cm/m and 17 less than 0.65 cm/m (11.7%). Overall survival at 5 years was 78 +/- 4.5% and was not influenced by PPM (P = NS). The mean New York Heart Association class for long-term survivors with PPM improved from 3.0 to 1.7 (P < 0.001). QoL (physical functioning 45.18 +/- 11.35, energy/fatigue 49.36 +/- 8.64, emotional well being 58.84 +/- 15.44, social functioning 61.29 +/- 6.15) was similar to that of no-PPM patients (P = NS). CONCLUSION: PPM after AVR does not affect survival, functional status, and QoL in patients aged at least 75 years. Surgical procedures, often time-consuming, contemplated to prevent PPM, may therefore be not justified in this patient subgroup. PMID- 26237423 TI - Relationship between Auditory and Cognitive Abilities in Older Adults. AB - OBJECTIVE: The objective was to evaluate the association of peripheral and central hearing abilities with cognitive function in older adults. METHODS: Recruited from epidemiological studies of aging and cognition at the Rush Alzheimer's Disease Center, participants were a community-dwelling cohort of older adults (range 63-98 years) without diagnosis of dementia. The cohort contained roughly equal numbers of Black (n=61) and White (n=63) subjects with groups similar in terms of age, gender, and years of education. Auditory abilities were measured with pure-tone audiometry, speech-in-noise perception, and discrimination thresholds for both static and dynamic spectral patterns. Cognitive performance was evaluated with a 12-test battery assessing episodic, semantic, and working memory, perceptual speed, and visuospatial abilities. RESULTS: Among the auditory measures, only the static and dynamic spectral pattern discrimination thresholds were associated with cognitive performance in a regression model that included the demographic covariates race, age, gender, and years of education. Subsequent analysis indicated substantial shared variance among the covariates race and both measures of spectral-pattern discrimination in accounting for cognitive performance. Among cognitive measures, working memory and visuospatial abilities showed the strongest interrelationship to spectral pattern discrimination performance. CONCLUSIONS: For a cohort of older adults without diagnosis of dementia, neither hearing thresholds nor speech-in-noise ability showed significant association with a summary measure of global cognition. In contrast, the two auditory metrics of spectral-pattern discrimination ability significantly contributed to a regression model prediction of cognitive performance, demonstrating association of central auditory ability to cognitive status using auditory metrics that avoided the confounding effect of speech materials. PMID- 26237425 TI - Long-term events following atrial fibrillation rate control or transcatheter ablation: a multicenter observational study. AB - BACKGROUND: Atrial fibrillation increases thromboembolic risk. Oral anticoagulation with antivitamin K (AVK) reduces thromboembolic event rate, but increases hemorrhagic risk. OBJECTIVE: The aim of the present study was to describe long-term cerebral thromboembolic/hemorrhagic event rates in atrial fibrillation patients managed by rhythm control, pursued by atrial fibrillation transcatheter ablation (AFTCA), and rate control strategy. METHODS AND RESULTS: One thousand and five hundred consecutive patients referring to three medical care centers for atrial fibrillation were retrospectively divided into three groups: AFTCA maintaining AVK (group A); AFTCA discontinuing AVK (group B); and rate control strategy and AVK (group C). Thromboembolic and hemorrhagic events were recorded in 60 +/- 28 months of follow-up. Thromboembolic events did not differ between the groups (5/500, 1% group A; 7/500, 1.4% group B; 11/500, 2.2% group C; P = 0.45), and hemorrhagic events were greater in group A (9/500, 1.8%) and C (12/500, 2.4%) than in group B (no events; P = 0.003). Among patients with CHA2DS2 VASc score 2 or less, thromboembolic events did not differ in the group discontinuing AVK (group B, 4/388, 1%) or not (group A, 1/319, 0.3%; P = 0.38), whereas hemorrhagic events were more common in patients on AVK (5/319, 1.5% group A and 3/175, 1.7% group C; P = 0.02) compared with those discontinuing AVK (0/388, group B). Following AFTCA (groups A and B), 299/1000 experienced atrial fibrillation relapses; all thromboembolic events (12/299, 4%) occurred within these patients (P < 0.001). CONCLUSION: Considering this multicenter design study, AVK continuation following AFTCA, especially within patients with low-to intermediate thromboembolic risk, confers a hemorrhagic risk greater to the thromboembolic protective effect. All thromboembolic events following AFTCA occur within patients experiencing atrial fibrillation relapses; therefore, in patients with high thromboembolic risk routine rhythm monitoring is essential after AVK discontinuation. PMID- 26237426 TI - Ideal Bioorthogonal Reactions Using A Site-Specifically Encoded Tetrazine Amino Acid. AB - Bioorthogonal reactions for labeling biomolecules in live cells have been limited by slow reaction rates or low component selectivity and stability. Ideal bioorthogonal reactions with high reaction rates, high selectivity, and high stability would allow for stoichiometric labeling of biomolecules in minutes and eliminate the need to wash out excess labeling reagent. Currently, no general method exists for controlled stoichiometric or substoichiometric labeling of proteins in live cells. To overcome this limitation, we developed a significantly improved tetrazine-containing amino acid (Tet-v2.0) and genetically encoded Tet v2.0 with an evolved aminoacyl-tRNA synthetase/tRNA(CUA) pair. We demonstrated in cellulo that protein containing Tet-v2.0 reacts selectively with cyclopropane fused trans-cyclooctene (sTCO) with a bimolecular rate constant of 72,500 +/- 1660 M(-1) s(-1) without reacting with other cellular components. This bioorthogonal ligation of Tet-v2.0-protein reacts in cellulo with substoichiometric amounts of sTCO-label fast enough to remove the labeling reagent from media in minutes, thereby eliminating the need to wash out label. This ideal bioorthogonal reaction will enable the monitoring of a larger window of cellular processes in real time. PMID- 26237427 TI - Memristors: Memory elements in potato tubers. AB - A memristor is a nonlinear element because its current-voltage characteristic is similar to that of a Lissajous pattern for nonlinear systems. This element was postulated recently and researchers are looking for it in different biosystems. We investigated electrical circuitry of red Irish potato tubers (Solanum tuberosum L.). The goal was to discover if potato tubers might have a new electrical component - a resistor with memory. The analysis was based on a cyclic current-voltage characteristic where the resistor with memory should manifest itself. We found that the electrostimulation by bipolar sinusoidal or triangle periodic waves induces electrical responses in the potato tubers with fingerprints of memristors. Tetraethylammonium chloride, an inhibitor of voltage gated K(+) channels, transforms a memristor to a resistor in potato tubers. Our results demonstrate that a voltage gated K(+) channel in the excitable tissue of potato tubers has properties of a memristor. Uncoupler carbonylcyanide-4 trifluoromethoxy-phenyl hydrazone decreases the amplitude of electrical responses at low and high frequencies of bipolar periodic sinusoidal or triangle electrostimulating waves. The discovery of memristors in plants creates a new direction in the understanding of electrical phenomena in plants. PMID- 26237431 TI - The Effect of Interfacial Geometry on Charge-Transfer States in the Phthalocyanine/Fullerene Organic Photovoltaic System. AB - The dependence of charge-transfer states on interfacial geometry at the phthalocyanine/fullerene organic photovoltaic system is investigated. The effect of deviations from the equilibrium geometry of the donor-donor-acceptor trimer on the energies of and electronic coupling between different types of interfacial electronic excited states is calculated from first-principles. Deviations from the equilibrium geometry are found to destabilize the donor-to-donor charge transfer states and to weaken their coupling to the photoexcited donor-localized states, thereby reducing their ability to serve as charge traps. At the same time, we find that the energies of donor-to-acceptor charge transfer states and their coupling to the donor-localized photoexcited states are either less sensitive to the interfacial geometry or become more favorable due to modifications relative to the equilibrium geometry, thereby enhancing their ability to serve as gateway states for charge separation. Through these findings, we eludicate how interfacial geometry modifications can play a key role in achieving charge separation in this widely studied organic photovoltaic system. PMID- 26237430 TI - The transcriptomic landscape and directed chemical interrogation of MLL rearranged acute myeloid leukemias. AB - Using next-generation sequencing of primary acute myeloid leukemia (AML) specimens, we identified to our knowledge the first unifying genetic network common to the two subgroups of KMT2A (MLL)-rearranged leukemia, namely having MLL fusions or partial tandem duplications. Within this network, we experimentally confirmed upregulation of the gene with the most subtype-specific increase in expression, LOC100289656, and identified cryptic MLL fusions, including a new MLL ENAH fusion. We also identified a subset of MLL fusion specimens carrying mutations in SPI1 accompanied by inactivation of its transcriptional network, as well as frequent RAS pathway mutations, which sensitized the leukemias to synthetic lethal interactions between MEK and receptor tyrosine kinase inhibitors. This transcriptomics-based characterization and chemical interrogation of human MLL-rearranged AML was a valuable approach for identifying complementary features that define this disease. PMID- 26237432 TI - Rapid human-induced divergence of life-history strategies in Bahamian livebearing fishes (family Poeciliidae). AB - Human-induced rapid environmental change (HIREC) can have dramatic impacts on ecosystems, leading to rapid trait changes in some organisms and extinction in others. Such changes in traits signify that human actions can lead to cases of increased phenotypic diversity and consequently can strongly impact population-, community- and ecosystem-level dynamics. Here, we examine whether the ecological consequences of habitat fragmentation have led to changes in the life histories of three native species of mosquitofish (Gambusia spp.) inhabiting tidal creeks on six different Bahamian islands. We address two important questions: (i) How predictable and parallel are life-history changes in response to HIREC across islands and species, and (ii) what is the relative importance of shared (i.e. parallel) responses to fragmentation, differences between species or islands and species- or island-specific responses to fragmentation? Phenotypic differences between fragmentation regimes were as great or greater than differences between species or islands. While some adult life histories (lean weight and fat content) showed strong, shared responses to fragmentation, offspring-related life histories (embryo fat and fecundity) exhibited idiosyncratic, island-specific responses. While shared responses to fragmentation appeared largely driven by a reduction in piscivorous fish density, increased conspecific density and changes in salinity, we found some evidence that among-population variation in male reproductive investment and embryo fat content may have arisen via variation in conspecific density. Our results suggest that phenotypic responses to HIREC can be complex, with the predictability of response varying across traits. We therefore emphasize the need for more theoretical and empirical work to better understand the predictability of phenotypic responses to human-induced disturbances. PMID- 26237428 TI - Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma. AB - Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2 stage meta-analysis of CMM genome-wide association studies (GWAS). This meta analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 * 10( 8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology. PMID- 26237429 TI - A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. AB - Anthracyclines are used in over 50% of childhood cancer treatment protocols, but their clinical usefulness is limited by anthracycline-induced cardiotoxicity (ACT) manifesting as asymptomatic cardiac dysfunction and congestive heart failure in up to 57% and 16% of patients, respectively. Candidate gene studies have reported genetic associations with ACT, but these studies have in general lacked robust patient numbers, independent replication or functional validation. Thus, the individual variability in ACT susceptibility remains largely unexplained. We performed a genome-wide association study in 280 patients of European ancestry treated for childhood cancer, with independent replication in similarly treated cohorts of 96 European and 80 non-European patients. We identified a nonsynonymous variant (rs2229774, p.Ser427Leu) in RARG highly associated with ACT (P = 5.9 * 10(-8), odds ratio (95% confidence interval) = 4.7 (2.7-8.3)). This variant alters RARG function, leading to derepression of the key ACT genetic determinant Top2b, and provides new insight into the pathophysiology of this severe adverse drug reaction. PMID- 26237433 TI - First test of the prompt gamma ray timing method with heterogeneous targets at a clinical proton therapy facility. AB - Ion beam therapy promises enhanced tumour coverage compared to conventional radiotherapy, but particle range uncertainties significantly blunt the achievable precision. Experimental tools for range verification in real-time are not yet available in clinical routine. The prompt gamma ray timing method has been recently proposed as an alternative to collimated imaging systems. The detection times of prompt gamma rays encode essential information about the depth-dose profile thanks to the measurable transit time of ions through matter. In a collaboration between OncoRay, Helmholtz-Zentrum Dresden-Rossendorf and IBA, the first test at a clinical proton accelerator (Westdeutsches Protonentherapiezentrum Essen, Germany) with several detectors and phantoms is performed. The robustness of the method against background and stability of the beam bunch time profile is explored, and the bunch time spread is characterized for different proton energies. For a beam spot with a hundred million protons and a single detector, range differences of 5 mm in defined heterogeneous targets are identified by numerical comparison of the spectrum shape. For higher statistics, range shifts down to 2 mm are detectable. A proton bunch monitor, higher detector throughput and quantitative range retrieval are the upcoming steps towards a clinically applicable prototype. In conclusion, the experimental results highlight the prospects of this straightforward verification method at a clinical pencil beam and settle this novel approach as a promising alternative in the field of in vivo dosimetry. PMID- 26237435 TI - Regioselective Synthesis of V-Shaped Bistriazinyl-phenanthrolines. AB - A new, regioselective synthesis of V-shaped 2,9-bis(6-(4-halophenyl)-1,2,4 triazin-3-yl)-1,10-phenanthrolines (4XPhBTPhen) ligands was developed, creating access to a simple and reliable synthesis of precursors for future supramolecular actinide complexing systems. Described is a reactant-directed regioselective synthetic method, which was found to be high yielding and reliable and yields exclusively 6,6'-phenyl BTPhen derivatives (including 4-chloro and 4-bromo) in five simple steps. Molecular and crystal structures of PhBTP and PhBTPhen products are fully determined and both were found to be in space group C2/c. Additionally, molecular and crystal structures of Z and E isomers of 2-hydrazono 2-phenylacetaldehyde oxime, a reagent in the synthetic route, reveal existence of strong intramolecular N-H...O hydrogen bonding in the Z isomer explaining its lower solubility in water. PMID- 26237436 TI - Challenges in the classification of fibrotic ILD. AB - According to current international guidelines the idiopathic interstitial pneumonias (IIPs) are grouped into three categories; major, rare, and unclassifiable. Idiopathic pulmonary fibrosis (IPF) is one of the major IIPs and has been recognised as a distinct clinical entity since 2001. This has led to significant advances in our understanding and treatment of the disease and to the identification of new therapeutic targets. While multidisciplinary team assessment yields a definite diagnosis in many cases of interstitial lung disease (ILD), 15-25% of patients remain unclassifiable. This can be due to inadequate clinical, pathological, or radiological data (e.g., where a biopsy is not performed) or because results of investigations show major discrepancies, overlapping features, or mixed patterns. Patients with unclassifiable disease tend to be of similar age to those with IPF and older than those with connective tissue disorders. Survival of patients with unclassifiable disease is intermediate between IPF and non-IPF ILD. There is no single recommended treatment for patients with unclassifiable disease. However, the ILD-GAP index has recently been validated in this group and can risk-stratify patients based on four easily measurable variables. "Disease behaviour classification" (DBC) is an alternative, pragmatic approach to managing patients with unclassifiable disease. The ILD-GAP index has been shown to provide strong prognostic information in these hard-to-treat patients. In the future, new diagnostic tools such as protein biomarkers may become available to help guide therapeutic decisions. PMID- 26237434 TI - Distinct Regulation of Transmitter Release at the Drosophila NMJ by Different Isoforms of nemy. AB - Synaptic transmission is highly plastic and subject to regulation by a wide variety of neuromodulators and neuropeptides. In the present study, we have examined the role of isoforms of the cytochrome b561 homologue called no extended memory (nemy) in regulation of synaptic strength and plasticity at the neuromuscular junction (NMJ) of third instar larvae in Drosophila. Specifically, we generated two independent excisions of nemy that differentially affect the expression of nemy isoforms. We show that the nemy45 excision, which specifically reduces the expression of the longest splice form of nemy, leads to an increase in stimulus evoked transmitter release and altered synaptic plasticity at the NMJ. Conversely, the nemy26.2 excision, which appears to reduce the expression of all splice forms except the longest splice isoform, shows a reduction in stimulus evoked transmitter release, and enhanced synaptic plasticity. We further show that nemy45 mutants have reduced levels of amidated peptides similar to that observed in peptidyl-glycine hydryoxylating mono-oxygenase (PHM) mutants. In contrast, nemy26.2 mutants show no defects in peptide amidation but rather display a decrease in Tyramine beta hydroxylase activity (TbetaH). Taken together, these results show non-redundant roles for the different nemy isoforms and shed light on the complex regulation of neuromodulators. PMID- 26237437 TI - Challenges in the classification of fibrotic ILD: Patient case 1. AB - PATIENT PRESENTATION AND CLINICAL HISTORY: The patient is a 43-year-old male non smoker who works as a farmer and cheese-maker. He complained of a dry cough for 6 12 months without fever or other clinical signs. His medical history was unremarkable with no use of drugs or alcohol and no signs of Raynaud's syndrome. In his family history he had two first-degree relatives with pulmonary fibrosis, one of whom also had rheumatoid arthritis. PMID- 26237438 TI - Challenges in the classification of fibrotic ILD: Patient case 2. AB - PATIENT PRESENTATION AND DIAGNOSTIC WORK-UP: The patient is a 72-year-old man presenting with dyspnoea on exertion. He is a former heavy smoker (40 pack-years) and his father, now deceased, had rheumatoid arthritis (RA). On physical examination he had mild bi-basilar crackles but no finger clubbing. Autoimmune serology was positive for rheumatoid factor (RF: 25 IU/ml). Lung function tests showed normal FVC, a FEV1/FVC ratio of 72% and a TLCO of 49% predicted. Lung CT showed centrilobular and paraseptal emphysema, subpleural fine reticulation and traction bronchiolectasis, with no clear basal predominance (Figure 1). BAL cytology showed 83% alveolar macrophages, 12% lymphocytes, 3% neutrophils, and 2% eosinophils. PMID- 26237439 TI - IPF, comorbidities and management implications. AB - Idiopathic pulmonary fibrosis (IPF) is a complex disease that is associated with various respiratory and non-respiratory comorbidities. The most common comorbidity is cardiovascular disease (CVD), which increases in incidence with increasing duration of IPF and is associated with a higher risk of mortality. The direction of causality between CVD and IPF is unclear. There is evidence that IPF is associated with a prothrombotic state; however, warfarin is not beneficial in IPF patients. Lung cancer is another common comorbidity, being present in more than 50% of IPF patients at 10 years after diagnosis. IPF and lung cancer share several risk factors and pathogenic pathways and also show a similar anatomic distribution; this can make radiological diagnosis difficult. As with CVD, lung cancer in IPF patients is associated with a significantly worse prognosis and treatment options are limited. Surgery, chemotherapy, and radiotherapy have all been associated with an increased risk of morbidity and mortality. However, treatment may be considered in selected patients with less advanced cancer and less advanced IPF. Emphysema may occur in patients with IPF and is believed to represent a distinct clinical syndrome, known as the combined pulmonary fibrosis and emphysema (CPFE) syndrome. CPFE has a strong male predominance, is strongly linked with smoking, and has distinct radiographic features. CPFE is also associated with a very high frequency of pulmonary hypertension, which is associated with a poor prognosis. There are no specific treatments for CPFE and evaluation of IPF therapies in CPFE patients is urgently needed. PMID- 26237440 TI - IPF, comorbidities and management implications: Patient case 1. AB - PATIENT PRESENTATION AND FOLLOW-UP: The patient was a 54-year-old man who presented with mild dyspnoea, a persistent cough and "velcro" crackles. He worked as a carpenter and smoked (10 pack-years) until 14 years ago. He had arterial hypertension and suffered a deep vein thrombosis 2 years ago. His lung function was impaired with an FVC of 70% and DLCO of 43%. PMID- 26237441 TI - IPF, comorbidities and management implications: Patient case 2. AB - PATIENT PRESENTATION AND DIAGNOSIS: The patient is a 50-year-old woman who was referred to a tertiary centre with an HRCT showing definite UIP and a 6-minute walking distance of 145 metres. She was severely ill at presentation with a diffusion capacity of just 20%.The patient had a history of peripheral arterial disease and had undergone both aortofemoral and femoro-femoral bypass due to arteriosclerosis and gluteal ischaemia. She also was suffering from renal impairment and had recently quit smoking. PMID- 26237442 TI - Challenges in IPF diagnosis, current management and future perspectives. AB - Recent developments have clarified our understanding of IPF and improved outcomes with two viable new therapeutic options, pirfenidone and nintedanib. In spite of these advances, questions and challenges concerning IPF still remain. Here we will focus on some of these unresolved areas: the diagnosis of IPF is hindered by limitations in current practice guidelines, surgical lung biopsy is contraindicated in many patients, the accuracy of prognostic evaluation needs to be increased and tolerability factors can jeopardise adherence to treatment. We will also identify new developments shaping the future of IPF management such as cryobiopsy, increased understanding of genetic factors and new treatment paradigms, which may help to fulfil currently unmet needs. PMID- 26237443 TI - Challenges in IPF diagnosis, current management and future perspectives: Patient case 1. AB - PATIENT PRESENTATION AND DIAGNOSIS: A 78-year-old female was referred to our department in April 2011 with shortness of breath. Clinical examination revealed bilateral limited crackles but no signs of finger clubbing. Lung function evaluation showed a percent predicted FVC of 78 and DLco of 67. The patient underwent HRCT imaging which showed cardinal features of a UIP pattern enabling a rapid diagnosis of IPF without the need for surgical lung biopsy. PMID- 26237444 TI - Challenges in IPF diagnosis, current management and future perspectives: Patient case 2. AB - PATIENT PRESENTATION AND DIAGNOSIS: The patient is a 73-year-old male retired house painter and ex-smoker who was admitted to the respiratory medicine department of a district hospital in Greece due to the presence of streaks of blood in his sputum. His past medical history included coronary artery disease, arterial hypertension and supraventricular tachycardia (SVT). A high resolution computed tomography (HRCT) was performed which showed enlarged mediastinal lymph nodes with evidence of fibrosis. PMID- 26237445 TI - AIR 2014 - The Year in IPF. PMID- 26237446 TI - Tackling Cell Transplantation Anoikis: An Injectable, Shape Memory Cryogel Microcarrier Platform Material for Stem Cell and Neuronal Cell Growth. AB - Highly macroporous semisynthetic cryogel microcarriers can be synthesized for culturing stem cells and neuronal type cells. Growth factors loaded to heparin containing microcarriers show near zero-order release kinetics and cell-loaded microcarriers can be injected through a fine gauge cannula without negative effect on the cells. These carriers can be applied for cell transplantation applications. PMID- 26237447 TI - Comparing multistep immobilized metal affinity chromatography and multistep TiO2 methods for phosphopeptide enrichment. AB - Phosphopeptide enrichment from complicated peptide mixtures is an essential step for mass spectrometry-based phosphoproteomic studies to reduce sample complexity and ionization suppression effects. Typical methods for enriching phosphopeptides include immobilized metal affinity chromatography (IMAC) or titanium dioxide (TiO2) beads, which have selective affinity and can interact with phosphopeptides. In this study, the IMAC enrichment method was compared with the TiO2 enrichment method, using a multistep enrichment strategy from whole cell lysate, to evaluate their abilities to enrich for different types of phosphopeptides. The peptide-to-beads ratios were optimized for both IMAC and TiO2 beads. Both IMAC and TiO2 enrichments were performed for three rounds to enable the maximum extraction of phosphopeptides from the whole cell lysates. The phosphopeptides that are unique to IMAC enrichment, unique to TiO2 enrichment, and identified with both IMAC and TiO2 enrichment were analyzed for their characteristics. Both IMAC and TiO2 enriched similar amounts of phosphopeptides with comparable enrichment efficiency. However, phosphopeptides that are unique to IMAC enrichment showed a higher percentage of multiphosphopeptides as well as a higher percentage of longer, basic, and hydrophilic phosphopeptides. Also, the IMAC and TiO2 procedures clearly enriched phosphopeptides with different motifs. Finally, further enriching with two rounds of TiO2 from the supernatant after IMAC enrichment or further enriching with two rounds of IMAC from the supernatant TiO2 enrichment does not fully recover the phosphopeptides that are not identified with the corresponding multistep enrichment. PMID- 26237448 TI - Five Xanthomonas type III effectors suppress cell death induced by components of immunity-associated MAP kinase cascades. AB - Mitogen-activated protein kinase (MAPK) cascades play a fundamental role in signaling of plant immunity and mediate elicitation of cell death. Xanthomonas spp. manipulate plant signaling by using a type III secretion system to deliver effector proteins into host cells. We examined the ability of 33 Xanthomonas effectors to inhibit cell death induced by overexpression of components of MAPK cascades in Nicotiana benthamiana plants. Five effectors inhibited cell death induced by overexpression of MAPKKKalpha and MEK2, but not of MAP3Kepsilon. In addition, expression of AvrBs1 in yeast suppressed activation of the high osmolarity glycerol MAPK pathway, suggesting that the target of this effector is conserved in eukaryotic organisms. These results indicate that Xanthomonas employs several type III effectors to suppress immunity-associated cell death mediated by MAPK cascades. PMID- 26237449 TI - CSN6 positively regulates c-Jun in a MEKK1-dependent manner. AB - c-Jun is a proto-oncoprotein that is commonly overexpressed in many types of cancer and is believed to regulate cell proliferation, the cell cycle, and apoptosis by controlling AP-1 activity. Understanding the c-Jun regulation is important to develop treatment strategy for cancer. The COP9 signalosome subunit 6 (CSN6) plays a critical role in ubiquitin-mediated protein degradation. MEKK1 is a serine/threonine kinase and E3 ligase containing PHD/RING domain involved in c-Jun ubiquitination. Here, we show that CSN6 associates with MEKK1 and reduces MEKK1 expression level by facilitating the ubiquitin-mediated degradation of MEKK1. Also we show that CSN6 overexpression diminishes MEKK1-mediated c-Jun ubiquitination, which is manifested in mitigating osmotic stress-mediated c-Jun downregulation. Thus, CSN6 is involved in positively regulating the stability of c-Jun. Overexpression of CSN6 correlates with the upregulation of c-Jun target gene expression in cancer. These findings provide new insight into CSN6-MEKK1-c Jun axis in tumorigenesis. PMID- 26237450 TI - Compost Grown Agaricus bisporus Lacks the Ability to Degrade and Consume Highly Substituted Xylan Fragments. AB - The fungus Agaricus bisporus is commercially grown for the production of edible mushrooms. This cultivation occurs on compost, but not all of this substrate is consumed by the fungus. To determine why certain fractions remain unused, carbohydrate degrading enzymes, water-extracted from mushroom-grown compost at different stages of mycelium growth and fruiting body formation, were analyzed for their ability to degrade a range of polysaccharides. Mainly endo-xylanase, endo-glucanase, beta-xylosidase and beta-glucanase activities were determined in the compost extracts obtained during mushroom growth. Interestingly, arabinofuranosidase activity able to remove arabinosyl residues from doubly substituted xylose residues and alpha-glucuronidase activity were not detected in the compost enzyme extracts. This correlates with the observed accumulation of arabinosyl and glucuronic acid substituents on the xylan backbone in the compost towards the end of the cultivation. Hence, it was concluded that compost grown A. bisporus lacks the ability to degrade and consume highly substituted xylan fragments. PMID- 26237451 TI - Identification of novel putative-binding proteins for cellular prion protein and a specific interaction with the STIP1 homology and U-Box-containing protein 1. AB - Prion diseases involve the conversion of the endogenous cellular prion protein, PrP(C), into a misfolded infectious isoform, PrP(Sc). Several functions have been attributed to PrP(C), and its role has also been investigated in the olfactory system. PrP(C) is expressed in both the olfactory bulb (OB) and olfactory epithelium (OE) and the nasal cavity is an important route of transmission of diseases caused by prions. Moreover, Prnp(-/-) mice showed impaired behavior in olfactory tests. Given the high PrP(C) expression in OE and its putative role in olfaction, we screened a mouse OE cDNA library to identify novel PrP(C)-binding partners. Ten different putative PrP(C) ligands were identified, which were involved in functions such as cellular proliferation and apoptosis, cytoskeleton and vesicle transport, ubiquitination of proteins, stress response, and other physiological processes. In vitro binding assays confirmed the interaction of PrP(C) with STIP1 homology and U-Box containing protein 1 (Stub1) and are reported here for the first time. Stub1 is a co-chaperone with ubiquitin E3 ligase activity, which is associated with neurodegenerative diseases characterized by protein misfolding and aggregation. Physiological and pathological implications of PrP(C)-Stub1 interaction are under investigation. The PrP(C)-binding proteins identified here are not exclusive to the OE, suggesting that these interactions may occur in other tissues and play general biological roles. These data corroborate the proposal that PrP(C) is part of a multiprotein complex that modulates several cellular functions and provide a platform for further studies on the physiological and pathological roles of prion protein. PMID- 26237453 TI - Efficacy of Combined Photoablative-Photodynamic Diode Laser Therapy Adjunctive to Scaling and Root Planing in Periodontitis: Randomized Split-Mouth Trial with 4 Year Follow-Up. AB - OBJECTIVE: We previously showed that photoablative laser therapy followed by multiple photodynamic cycles (PAPD) after scaling/root planing (SRP) improved healing of periodontitis patients as compared with conventional SRP after 1-year follow-up. This study reports the favorable results of PAPD plus SRP in patients with chronic periodontitis at a 4-year follow-up. MATERIALS AND METHODS: Twenty four patients were studied. Maxillary left or right quadrants were randomly assigned to PAPD laser treatment or sham-treatment and SRP. PAPD consisted of: (1) photoablative intra/extrapocket de-epithelization with diode laser (lambda 810 nm, 1 W), and (2) photodynamic treatments (4-10 weekly) with diode laser (lambda 635 nm, 100 mW) and 0.3% methylene blue as photoactive antiseptic, performed after SRP. Sham treatment was performed with switched- off laser. Probing depth (PD), clinical attachment level (CAL), and bleeding-on-probing (BOP) were evaluated. Additional disease markers, namely polymorphonuclear leukocytes (PMN), erythrocytes (RBC), damaged epithelial cells (DEC), and bacteria were assayed by cytofluorescence on gingival exfoliative samples. RESULTS: At 4-year follow-up, PAPD plus SRP significantly improved PD, CAL, and BOP, as well as bacterial contamination and PMN-RBC shedding in the exfoliative samples, compared with sham treatment plus SRP. This effect was greater than that observed at 1-year follow-up. CONCLUSIONS: PAPD plus SRP provided significant, durable improvement of chronic periodontitis over sham treatment plus SRP alone. PMID- 26237452 TI - Adipose-Derived Mesenchymal Stem Cells Ameliorate Ulcerative Colitis Through miR 1236 Negatively Regulating the Expression of Retinoid-Related Orphan Receptor Gamma. AB - Mesenchymal stem cells (MSCs) were reported to accelerate the curing of ulcerative colitis (UC). Altered expression of microRNAs (miRNAs) has recently revealed association with UC. However, the effect of adipose-derived MSCs (ASCs) on UC and the mechanism of how miRNAs regulate UC remain unclear. We investigated the effect of ASCs on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced UC in rat colon tissues. qRT-PCR and immunofluorescence analyses were performed to monitor the expression of miR-1236 and its target molecule, retinoid-related orphan receptor gamma (RORgamma). Regulation of the expression of RORgamma by miR-1236 was assessed using luciferase reporter construct assays and miR-1236 mimic transfection. The relationship between miR-1236 and RORgamma was further investigated in HT29 cells induced by TNF-alpha. ASCs highly ameliorated UC and decreased the inflammation markers in rats with TNBS-induced UC. In addition, ASCs upregulated the expression of miR-1236 and decreased the expression of RORgamma in the TNBS-induced rat model of UC. The luciferase reporter assay and bioinformatic analysis demonstrated that the expression of RORgamma was directly targeted and regulated by miR-1236. Specifically, the expression of RORgamma was suppressed by miR-1236 mimic and enhanced by miR-1236 inhibitor. Furthermore, we demonstrated that exogenous miR-1236 mimic could inhibit the expression of RORgamma in HT29 cell induced by TNF-alpha. ASCs effectively alleviated UC in rats with the expression of miR-1236 alteration, and miR-1236 may play important roles in UC by downregulating the expression of RORgamma. PMID- 26237456 TI - Infant With a Unilateral Parotid Mass, Recurrent Otitis Media, and Macrocephaly. Plexiform neurofibroma. PMID- 26237457 TI - The Broad Approach of a Structural Intervention Study and the Lack of Effect Detection: Target Population and Sampling Issues. PMID- 26237459 TI - Errors in Abstract and Text. PMID- 26237458 TI - The Broad Approach of a Structural Intervention Study and the Lack of Effect Detection--Reply. PMID- 26237460 TI - Error in Text. PMID- 26237461 TI - Error in SD Value in Table. PMID- 26237463 TI - Incorrect and Misleading Data. PMID- 26237462 TI - Errors and Misleading Data in Table. PMID- 26237464 TI - Speech and Language Delays in Young Children. PMID- 26237465 TI - Lung Ultrasonography Score to Evaluate Oxygenation and Surfactant Need in Neonates Treated With Continuous Positive Airway Pressure. AB - IMPORTANCE: Lung ultrasonography (LUS) is a bedside technique useful to diagnose neonatal respiratory problems, but, to our knowledge, no data are available about its use for monitoring lung function or eventually guiding surfactant therapy. OBJECTIVE: To determine the diagnostic accuracy of a neonatal-adapted LUS score to evaluate oxygenation and predict need for surfactant administration. DESIGN, SETTING, AND PARTICIPANTS: Prospective diagnostic accuracy study following STARD (Standards for the Reporting of Diagnostic Accuracy Studies) guidelines at a tertiary level academic neonatal intensive care unit in 2014. All neonates admitted to the neonatal intensive care unit with signs of respiratory distress were eligible, and 130 neonates were enrolled. The LUS score was calculated in the first hours of life under continuous positive airway pressure. The transcutaneous partial pressure of oxygen (Ptco2) to fraction of inspired oxygen (Fio2) ratio, alveolar-arterial gradient, oxygenation index, and arterial to alveolar ratio were calculated within 30 minutes from LUS, using transcutaneous blood gas monitoring. Surfactant was administered according to 2013 European guidelines. MAIN OUTCOMES AND MEASURES: Correlation between LUS score and indices of oxygenation and prediction of surfactant administration. RESULTS: Among the 130 neonates in this study, the LUS score was significantly correlated with all indices of oxygenation, independent from gestational age (GA) (Ptco2 to Fio2 ratio: GA >= 34 weeks: rho = -0.57; GA <34 weeks: rho = -0.62; P < .001; alveolar arterial gradient: GA >= 34 weeks: rho = 0.62; GA <34 weeks: rho = 0.59; P < .001; oxygenation index: GA >= 34 weeks: rho = 0.63; GA <34 weeks: rho = 0.69; P < .001; and arterial to alveolar ratio: GA >= 34 weeks: rho = -0.60; GA <34 weeks: rho = -0.56; P < .001). The LUS score predicted the need for surfactant better in preterm babies with a GA less than 34 weeks (area under the curve = 0.93; 95% CI, 0.86-0.99; P < .001) than in term and late-preterm neonates with a GA of 34 weeks or greater (area under the curve = 0.71; 95% CI, 0.54-0.90; P = .02); the areas under the curve for these 2 GA subgroups are significantly different (P = .02). In babies with a GA less than 34 weeks, a LUS score cutoff of 4 predicted surfactant administration with 100% sensitivity and 61% specificity, yielding a posttest probability of 72%. CONCLUSIONS AND RELEVANCE: The LUS score is well correlated with oxygenation status in both term and preterm neonates, and it shows good reliability to predict surfactant administration in preterm babies with a GA less than 34 weeks under continuous positive airway pressure. PMID- 26237466 TI - Effects of a Birth Hospital's Neonatal Intensive Care Unit Level and Annual Volume of Very Low-Birth-Weight Infant Deliveries on Morbidity and Mortality. AB - IMPORTANCE: The annual volume of deliveries of very low-birth-weight (VLBW) infants has a greater effect on mortality risk than does neonatal intensive care unit (NICU) level. The differential effect of these hospital factors on morbidity among VLBW infants is uncertain. OBJECTIVE: To assess the independent effects of a birth hospital's annual volume of VLBW infant deliveries and NICU level on the risk of several neonatal morbidities and morbidity-mortality composite outcomes that are predictive of future neurocognitive development. DESIGN, SETTING, AND PARTICIPANTS: Retrospective, population-based cohort study (performed in 2014) of all VLBW infants without severe congenital anomalies delivered in all hospitals in California, Missouri, and Pennsylvania between January 1, 1999, and December 31, 2009 (N = 72,431). Risk-adjusted odds ratios and risk-adjusted probabilities were determined by logistic regression. MAIN OUTCOMES AND MEASURES: The primary study outcomes were the individual composites of death or bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity, and severe intraventricular hemorrhage. RESULTS: Among the 72,431 VLBW infants in the present study, birth at a hospital with 10 or less deliveries of VLBW infants per year was associated with the highest risk-adjusted probability of death (15.3% [95% CI, 14.4%-16.3%]), death or severe intraventricular hemorrhage (17.5% [95% CI, 16.5%-18.6%]), and death or necrotizing enterocolitis (19.3% [95% CI, 18.1% 20.4%]). These complications were also more common among infants born at hospitals with a level I or II NICU compared with infants delivered at hospitals with a level IIIB/C NICU. The risk-adjusted probability of death or retinopathy of prematurity was highest among infants born at hospitals with a level IIIB/C NICU and lowest among infants born at hospitals with a level IIIA NICU. When the effects of NICU level and annual volume of VLBW infant deliveries were evaluated simultaneously, the annual volume of deliveries was the stronger contributor to the risk of death, death or severe intraventricular hemorrhage, and death or necrotizing enterocolitis. CONCLUSIONS AND RELEVANCE: The risk of death or severe intraventricular hemorrhage and death or necrotizing enterocolitis was lowest among infants born in hospitals that had both a high volume of VLBW infant deliveries and a high-level NICU. Antenatal transfer of high-risk pregnancies to these hospitals may reduce mortality and improve outcomes. PMID- 26237467 TI - Conformational Heterogeneity Determined by Folding and Oligomer Assembly Routes of the Interferon Response Inhibitor NS1 Protein, Unique to Human Respiratory Syncytial Virus. AB - The nonstructural NS1 protein is an essential virulence factor of the human respiratory syncytial virus, with a predominant role in the inhibition of the host antiviral innate immune response. This inhibition is mediated by multiple protein-protein interactions and involves the formation of large oligomeric complexes. There is neither a structure nor sequence or functional homologues of this protein, which points to a distinctive mechanism for blocking the interferon response among viruses. The NS1 native monomer follows a simple unfolding kinetics via a nativelike transition state ensemble, with a half-life of 45 min, in agreement with a highly stable core structure at equilibrium. Refolding is a complex process that involves several slowly interconverting species compatible with proline isomerization. However, an ultrafast folding event with a half-life of 0.2 ms is indicative of a highly folding compatible species within the unfolded state ensemble. On the other hand, the oligomeric assembly route from the native monomer, which does not involve unfolding, shows a monodisperse and irreversible end-point species triggered by a mild temperature change, with half lives of 160 and 26 min at 37 and 47 degrees C, respectively, and at a low protein concentration (10 MUM). A large secondary structure change into beta sheet structure and the formation of a dimeric nucleus precede polymerization by the sequential addition of monomers at the surprisingly low rate of one monomer every 34 s. The polymerization phase is followed by the binding to thioflavin-T indicative of amyloid-like, albeit soluble, repetitive beta-sheet quaternary structure. The overall process is reversible only up until ~8 min, a time window in which most of the secondary structure change takes place. NS1's multiple binding activities must be accommodated in a few binding interfaces at most, something to be considered remarkable given its small size (15 kDa). Thus, conformational heterogeneity, and in particular oligomer formation, may provide a means of expand its binding repertoire. These equilibria will be determined by variables such as macromolecular crowding, protein-protein interactions, expression levels, turnover, or specific subcellular localization. The irreversible and quasi-spontaneous nature of the oligomer assembly, together with the fact that NS1 is the most abundant viral protein in infected cells, makes its accumulation highly conceivable under conditions compatible with the cellular milieu. The implications of NS1 oligomers in the viral life cycle and the inhibition of host innate immune response remain to be determined. PMID- 26237468 TI - An Adjusted Likelihood Ratio Approach Analysing Distribution of Food Products to Assist the Investigation of Foodborne Outbreaks. AB - In order to facilitate foodborne outbreak investigations there is a need to improve the methods for identifying the food products that should be sampled for laboratory analysis. The aim of this study was to examine the applicability of a likelihood ratio approach previously developed on simulated data, to real outbreak data. We used human case and food product distribution data from the Norwegian enterohaemorrhagic Escherichia coli outbreak in 2006. The approach was adjusted to include time, space smoothing and to handle missing or misclassified information. The performance of the adjusted likelihood ratio approach on the data originating from the HUS outbreak and control data indicates that the adjusted approach is promising and indicates that the adjusted approach could be a useful tool to assist and facilitate the investigation of food borne outbreaks in the future if good traceability are available and implemented in the distribution chain. However, the approach needs to be further validated on other outbreak data and also including other food products than meat products in order to make a more general conclusion of the applicability of the developed approach. PMID- 26237469 TI - Same-Hospital Readmission Rates as a Measure of Pediatric Quality of Care. AB - IMPORTANCE: Health care systems, payers, and hospitals use hospital readmission rates as a measure of quality. Although hospitals can track readmissions back to themselves (hospital A to hospital A), they lack information when their patients are readmitted to different hospitals (hospital A to hospital B). Because hospitals lack different-hospital readmission (DHR) data, they may underestimate all-hospital readmission (AHR) rates (hospital A to hospital A or B). OBJECTIVES: To determine the prevalence of 30-day pediatric DHRs; to assess the effect of DHR on readmission performance; and to identify patient and hospital characteristics associated with DHR. DESIGN, SETTING, AND PARTICIPANTS: We analyzed all-payer inpatient claims for 701,263 pediatric discharges (patients aged 0-17 years) from 177 acute care hospitals in New York State from January 1, 2005, through November 30, 2009, to identify 30-day same-hospital readmissions (SHRs), DHRs, and AHRs. Data analysis was performed from March 12, 2013, through April 6, 2015. We compared excess readmission ratios (calculated per the Medicare formula) using SHRs and AHRs to determine what might happen if the federal formula were applied to a specific state and to evaluate how often hospitals might accurately anticipate-using data available to them--whether they would incur penalties (excess readmission ratio >1) for readmissions. Using multivariate logistic regression, we identified patient- and hospital-level predictors of DHR vs SHR. MAIN OUTCOMES AND MEASURES: The proportion of DHRs vs SHRs, AHR and SHR rates, and excess readmissions. RESULTS: Different-hospital readmissions constituted 13.9% of 31,325 AHRs. At the individual hospital level, the median (interquartile range) percentage of DHRs was 21.6% (12.8%-39.1%). The median (interquartile range) adjusted AHR rate was 3.4% (3.0%-4.1%), 38.9% higher than the median adjusted SHR rate of 2.5% (2.0%-3.4%) (P < .001). Excess readmission ratios using SHRs inaccurately anticipated penalties (changed from >1 to <= 1 or vice versa) for 20 of the 177 hospitals (11.3%); all were nonchildren's hospitals and 18 of 20 (90.0%) were nonteaching hospitals. Characteristics associated with higher odds ratios (ORs) (reported with 95% CIs) of DHR in multivariate analyses included being younger (compared with age <1 year, ORs [95% CIs] for the other age categories ranged from 0.76 [0.66-0.88] to 0.85 [0.73-0.99]); being white (ORs [95% CIs] for nonwhite race/ethnicity ranged from 0.74 [0.65-0.84] to 0.88 [0.79-0.99]); having private insurance (1.14 [1.04-1.24]); having a chronic condition indicator for a mental disorder (1.33 [1.13-1.56]) or a disease of the nervous system (1.37 [1.20-1.57]) or circulatory system (1.20 [1.00-1.43]); and admission to a nonchildren's (1.62 [1.01-2.60]), urban (ORs for nonurban hospitals ranged from 0.35 [0.24-0.52] to 0.36 [0.21-0.64]), or lower-volume (0.73 [0.64-0.84]) hospital (P < .05 for each). CONCLUSIONS AND RELEVANCE: Different-hospital readmissions differentially affect hospitals' pediatric readmission rates and anticipated performance, making SHRs an incomplete surrogate for AHRs-particularly for certain hospital types. Failing to incorporate DHRs into readmission measurement may impede quality assessment, anticipation of penalties, and quality improvement. PMID- 26237470 TI - Magnetic-Nanoflocculant-Assisted Water-Nonpolar Solvent Interface Sieve for Microalgae Harvesting. AB - Exploitation of magnetic flocculants is regarded as a very promising energy saving approach to microalgae harvesting. However, its practical applicability remains limited, mainly because of the problem of the postharvest separation of magnetic flocculants from microalgal flocs, which is crucial both for magnetic flocculant recycling and high-purity microalgal biomasses, but which is also a very challenging and energy-consuming step. In the present study, we designed magnetic nanoflocculants dually functionalizable by two different organosilane compounds, (3-aminopropyl)triethoxysilane (APTES) and octyltriethoxysilane (OTES), which flocculate negatively charged microalgae and are readily detachable at the water-nonpolar organic solvent (NOS) interface only by application of an external magnetic field. APTES functionalization imparts a positive zeta potential charge (29.6 mV) to magnetic nanoflocculants, thereby enabling microalgae flocculation with 98.5% harvesting efficiency (with a dosage of 1.6 g of dMNF/g of cells). OTES functionalization imparts lipophilicity to magnetic nanoflocculants to make them compatible with NOS, thus effecting efficient separation of magnetic flocculants passing through the water-NOS interface sieve from hydrophilic microalgae. Our new energy-saving approach to microalgae harvesting concentrates microalgal cultures (~1.5 g/L) up to 60 g/L, which can be directly connected to the following process of NOS-assisted wet lipid extraction or biodiesel production, and therefore provides, by simplifying multiple downstream processes, a great potential cost reduction in microalgae-based biorefinement. PMID- 26237471 TI - Fetal Aneuploidy Detection by Cell-Free DNA Sequencing for Multiple Pregnancies and Quality Issues with Vanishing Twins. AB - Non-invasive prenatal testing (NIPT) by random massively parallel sequencing of maternal plasma DNA for multiple pregnancies is a promising new option for prenatal care since conventional non-invasive screening for fetal trisomies 21, 18 and 13 has limitations and invasive diagnostic methods bear a higher risk for procedure related fetal losses in the case of multiple gestations compared to singletons. In this study, in a retrospective blinded analysis of stored twin samples, all 16 samples have been determined correctly, with four trisomy 21 positive and 12 trisomy negative samples. In the prospective part of the study, 40 blood samples from women with multiple pregnancies have been analyzed (two triplets and 38 twins), with two correctly identified trisomy 21 cases, confirmed by karyotyping. The remaining 38 samples, including the two triplet pregnancies, had trisomy negative results. However, NIPT is also prone to quality issues in case of multiple gestations: the minimum total amount of cell-free fetal DNA must be higher to reach a comparable sensitivity and vanishing twins may cause results that do not represent the genetics of the living sibling, as described in two case reports. PMID- 26237472 TI - Maternal Serum Screening Markers and Adverse Outcome: A New Perspective. AB - There have been a number of studies evaluating the association of aneuploidy serum markers with adverse pregnancy outcome. More recently, the development of potential treatments for these adverse outcomes as well as the introduction of cell-free fetal DNA (cffDNA) screening for aneuploidy necessitates a re evaluation of the benefit of serum markers in the identification of adverse outcomes. Analysis of the literature indicates that the serum markers tend to perform better in identifying pregnancies at risk for the more severe but less frequent form of individual pregnancy complications rather than the more frequent but milder forms of the condition. As a result, studies which evaluate the association of biomarkers with a broad definition of a given condition may underestimate the ability of such markers to identify pregnancies that are destined to develop the more severe form of the condition. Consideration of general population screening using cffDNA solely must be weighed against the fact that traditional screening using serum markers enables detection of severe pregnancy complications, not detectable with cffDNA, of which many may be amenable to treatment options. PMID- 26237473 TI - The Psychological Challenges of Replacing Conventional Karyotyping with Genomic SNP Array Analysis in Prenatal Testing. AB - Pregnant couples tend to prefer a maximum of information about the health of their fetus. Therefore, we implemented whole genome microarray instead of conventional karyotyping (CK) for all indications for prenatal diagnosis (PND). The array detects more clinically relevant anomalies, including early onset disorders, not related to the indication and more genetic anomalies of yet unquantifiable risk, so-called susceptibility loci (SL) for mainly neurodevelopmental disorders. This manuscript highlights the psychological challenges in prenatal genetic counselling when using the array and provides counselling suggestions. First, we suggest that pre-test decision counselling should emphasize deliberation about what pregnant couples wish to learn about the future health of their fetus more than information about possible outcomes. Second, pregnant couples need support in dealing with SL. Therefore, in order to consider the SL in a proportionate perspective, the presence of phenotypes associated with SL in the family, the incidence of a particular SL in control populations and in postnatally ascertained patients needs highlighting during post-test genetic counselling. Finally, the decision that couples need to make about the course of their pregnancy is more complicated when the expected phenotype is variable and not quantifiable. Therefore, during post-test psychological counseling, couples should concretize the options of continuing and ending their pregnancy; all underlying feelings and thoughts should be made explicit, as well as the couple's resources, in order to attain adequate decision making. As such, pre- and post-test counselling aids pregnant couples in handling the uncertainties that may accompany offering a broader scope of genetic PND using the array. PMID- 26237474 TI - Hepatic Atypical Protein Kinase C: An Inherited Survival-Longevity Gene that Now Fuels Insulin-Resistant Syndromes of Obesity, the Metabolic Syndrome and Type 2 Diabetes Mellitus. AB - This review focuses on how insulin signals to metabolic processes in health, why this signaling is frequently deranged in Western/Westernized societies, how these derangements lead to, or abet development of, insulin-resistant states of obesity, the metabolic syndrome and type 2 diabetes mellitus, and what our options are for restoring insulin signaling, and glucose/lipid homeostasis. A central theme in this review is that excessive hepatic activity of an archetypal protein kinase enzyme, "atypical" protein kinase C (aPKC), plays a critically important role in the development of impaired glucose metabolism, systemic insulin resistance, and excessive hepatic production of glucose, lipids and proinflammatory factors that underlie clinical problems of glucose intolerance, obesity, hepatosteatosis, hyperlipidemia, and, ultimately, type 2 diabetes. The review suggests that normally inherited genes, in particular, the aPKC isoforms, that were important for survival and longevity in times of food scarcity are now liabilities in times of over-nutrition. Fortunately, new knowledge of insulin signaling mechanisms and how an aberration of excessive hepatic aPKC activation is induced by over-nutrition puts us in a position to target this aberration by diet and/or by specific inhibitors of hepatic aPKC. PMID- 26237475 TI - Pregnancy Loss Following Amniocentesis or CVS Sampling-Time for a Reassessment of Risk. AB - Risk of procedure-related pregnancy loss is currently widely quoted in the UK as 1% for amniocentesis and 1.5% for chorionic villus sampling. Published data suggest that these risk figures are out of date and inaccurate, and that new guidelines are required for pre-test counseling. It is our opinion that accurate and evidence-based information concerning miscarriage risk is vital when counseling women, as exaggeration of this risk may deter women from testing, or cause unjustified remorse if a miscarriage ensues. It is also essential that health-care economists are aware of the up-to-date evidence on "procedure-related risk" when applying risk-benefit analysis to assess new technology for non invasive screening. PMID- 26237476 TI - Exome Sequencing in Fetuses with Structural Malformations. AB - Prenatal diagnostic testing is a rapidly advancing field. An accurate diagnosis of structural anomalies and additional abnormalities in fetuses with structural anomalies is important to allow "triage" and designation of prognosis. This will allow parents to make an informed decision relating to the pregnancy. This review outlines the current tests used in prenatal diagnosis, focusing particularly on "new technologies" such as exome sequencing. We demonstrate the utility of exome sequencing above that of conventional karyotyping and Chromosomal Microarray (CMA) alone by outlining a recent proof of concept study investigating 30 parent fetus trios where the fetus is known to have a structural anomaly. This may allow the identification of pathological gene anomalies and consequently improved prognostic profiling, as well as excluding anomalies and distinguishing between de novo and inherited mutations, in order to estimate the recurrence risk in future pregnancies. The potential ethical dilemmas surrounding exome sequencing are also considered, and the future of prenatal genetic diagnosis is discussed. PMID- 26237478 TI - Limitations of Aneuploidy and Anomaly Detection in the Obese Patient. AB - Obesity is a worldwide epidemic and can have a profound effect on pregnancy risks. Obese patients tend to be older and are at increased risk for structural fetal anomalies and aneuploidy, making screening options critically important for these women. Failure rates for first-trimester nuchal translucency (NT) screening increase with obesity, while the ability to detect soft-markers declines, limiting ultrasound-based screening options. Obesity also decreases the chances of completing the anatomy survey and increases the residual risk of undetected anomalies. Additionally, non-invasive prenatal testing (NIPT) is less likely to provide an informative result in obese patients. Understanding the limitations and diagnostic accuracy of aneuploidy and anomaly screening in obese patients can help guide clinicians in counseling patients on the screening options. PMID- 26237477 TI - Gut-Brain Endocrine Axes in Weight Regulation and Obesity Pharmacotherapy. AB - In recent years, the obesity epidemic has developed into a major health crisis both in the United States as well as throughout the developed world. With current treatments limited to expensive, high-risk surgery and minimally efficacious pharmacotherapy, new therapeutic options are urgently needed to combat this alarming trend. This review focuses on the endogenous gut-brain signaling axes that regulate appetite under physiological conditions, and discusses their clinical relevance by summarizing the clinical and preclinical studies that have investigated manipulation of these pathways to treat obesity. PMID- 26237480 TI - A 26-Year Experience in Chorionic Villus Sampling Prenatal Genetic Diagnosis. AB - This report describes the trends of chorionic villus sampling (CVS) referred for prenatal genetic diagnosis in the past two and a half decades in a Portuguese Center. Our cohort of 491 CVS was mostly performed by the transcervical method at the 12th gestational week. Data collected within the framework of this study relate to the following: sampling method, referral reason versus abnormality and incidence of procedure-related pregnancy loss, that declined to about 0.5% over the last 15 years. The year 2000 represented a change in referral reasons for chorionic tissue collection, shifting from almost exclusively for cytogenetic testing to an increasing number of molecular tests for monogenic disorders. Herein, success rates as well as cytogenetic and/or molecular DNA results are presented. These latter include not only tests for several monogenic disorders, but also aneuploidy and maternal cell contamination screening. This retrospective analysis reiterates that CVS is a safe and reliable first trimester technique for prenatal diagnosis in high genetic risk pregnancies. PMID- 26237479 TI - Chromosomal Mosaicism in Human Feto-Placental Development: Implications for Prenatal Diagnosis. AB - Chromosomal mosaicism is one of the primary interpretative issues in prenatal diagnosis. In this review, the mechanisms underlying feto-placental chromosomal mosaicism are presented. Based on the substantial retrospective diagnostic experience with chorionic villi samples (CVS) of a prenatal diagnosis laboratory the following items are discussed: (i) The frequency of the different types of mosaicism (confined placental, CPM, and true fetal mosaicisms, TFM); (ii) The risk of fetal confirmation after the detection of a mosaic in CVS stratified by chromosome abnormality and placental tissue involvement; (iii) The frequency of uniparental disomy for imprinted chromosomes associated with CPM; (iv) The incidence of false-positive and false-negative results in CVS samples analyzed by only (semi-)direct preparation or long term culture; and (v) The implications of the presence of a feto-placental mosaicism for microarray analysis of CVS and non invasive prenatal screening (NIPS). PMID- 26237481 TI - Impact of Cell-Free Fetal DNA Screening on Patients' Choice of Invasive Procedures after a Positive California Prenatal Screen Result. AB - Until recently, maternal serum analyte levels paired with sonographic fetal nuchal translucency measurement was the most accurate prenatal screen available for Trisomies 18 and 21, (91% and 94% detection and false positive rates of 0.31% and 4.5% respectively). Women with positive California Prenatal Screening Program (CPSP) results have the option of diagnostic testing to determine definitively if the fetus has a chromosomal abnormality. Cell-free fetal (cff-) DNA screening for Trisomies 13, 18, and 21 was first offered in 2012, allowing women with positive screens to choose additional screening before diagnostic testing. Cff-DNA sensitivity rates are as high as 99.9% and 99.1%, with false positive rates of 0.4% and 0.1%, for Trisomies 18 and 21, respectively. A retrospective chart review was performed in 2012 on 500 CPSP referrals at the University of California, San Diego Thornton Hospital. Data were collected prior to and after the introduction of cff-DNA. There was a significant increase in the number of participants who chose to pursue additional testing and a decrease in the number of invasive procedures performed after cff-DNA screening was available. We conclude that as fetal aneuploidy screening improves, the number of invasive procedures will continue to decrease. PMID- 26237482 TI - Screening and Invasive Testing in Twins. AB - Prenatal screening and testing for trisomy 21 in twin pregnancies poses a number of challenges: the exact estimate of the a priori risk of trisomy 21, the choice of prenatal screening test and/or invasive techniques to employ for the diagnosis and the impact of the result on the options of treatment in case of discordant results within a twin pair or among multiples. These different aspects are discussed below while recognizing that many issues remain unresolved. PMID- 26237483 TI - Health Resource Utilization Associated with Skeletal-Related Events in Patients with Advanced Prostate Cancer: A European Subgroup Analysis from an Observational, Multinational Study. AB - This study aimed to increase the understanding of health resource utilization (HRU) associated with skeletal-related events (SREs) occurring in patients with bone metastases secondary to advanced prostate cancer. A total of 120 patients from Germany, Italy, Spain and the United Kingdom were enrolled in this observational study. They had bone metastases secondary to prostate cancer and had experienced at least one SRE in the 97 days before giving informed consent. HRU data were collected retrospectively for 97 days before enrolment and prospectively for up to 18-21 months. HRU, including the number and duration of inpatient hospitalizations, number of outpatient and emergency department visits and procedures, was independently attributed by investigators to an SRE. Of the 222 SREs included in this analysis, 26% were associated with inpatient stays and the mean duration per SRE was 21.4 days (standard deviation (SD) 17.8 days). Overall, 174 SREs (78%) required an outpatient visit and the mean number of visits per SRE was 4.6 (SD 4.6). All SREs are associated with substantial HRU. Preventing SREs in patients with advanced prostate cancer and bone metastases may help to reduce the burden to both patients and European healthcare systems. PMID- 26237484 TI - Consequences of Abdominal Adiposity within the Metabolic Syndrome Paradigm in Black People of African Ancestry. AB - The metabolic syndrome (MetS) is a constellation of risk factors that are associated with increased risks for coronary heart disease and type 2 diabetes. Although the cause is unknown, abdominal adiposity is considered the underpinning of these metabolic alterations. Hence, increased abdominal adiposity contributes to dyslipidemia, hyperglycemia, beta cell dysfunction, insulin resistance, hypertension and inflammation. The role of abdominal adiposity in the causation of metabolic alterations that lead to the clinical expression of the MetS has become a focus of active research. In addition, there are ethnic/racial differences in the manifestation of the MetS. Therefore, the focus of this current review is to: (1) explore the consequences of abdominal obesity within the MetS paradigm; and (2) discuss the impact of ethnicity/race on MetS in Black People of African Ancestry (PAA). PMID- 26237485 TI - Non-Invasive Prenatal Diagnosis in the Management of Preimplantation Genetic Diagnosis Pregnancies. AB - Prenatal diagnosis (PD) is recommended in pregnancies after a Preimplantation Genetic Diagnosis (PGD). However, conventional PD entails a risk of fetal loss which makes PGD patients reluctant to undergo obstetric invasive procedures. The presence of circulating fetal DNA in maternal blood allows performing a non invasive prenatal diagnosis (NIPD) without risk for the pregnancy outcome. This work shows the introduction of NIPD for confirmation of PGD results in eight pregnancies. In those pregnancies referred to PGD for an X-linked disorder (six out of eight), fetal sex determination in maternal blood was performed to confirm fetal sex. One pregnancy referred to PGD for Marfan syndrome and one referred for Huntington disease (HD) were also analyzed. In seven out of eight cases, PGD results were confirmed by NIPD in maternal blood. No results were obtained in the HD pregnancy. NIPD in PGD pregnancies can be a reliable alternative for couples that after a long process feel reluctant to undergo PD due to the risk of pregnancy loss. PMID- 26237487 TI - Hyponatremia: Special Considerations in Older Patients. AB - Hyponatremia is especially common in older people. Recent evidence highlights that even mild, chronic hyponatremia can lead to cognitive impairment, falls and fractures, the latter being in part due to bone demineralization and reduced bone quality. Hyponatremia is therefore of special significance in frail older people. Management of hyponatremia in elderly individuals is particularly challenging. The underlying cause is often multi-factorial, a clear history may be difficult to obtain and clinical examination is unreliable. Established treatment modalities are often ineffective and carry considerable risks, especially if the diagnosis of underlying causes is incorrect. Nevertheless, there is some evidence that correction of hyponatremia can improve cognitive performance and postural balance, potentially minimizing the risk of falls and fractures. Oral vasopressin receptor antagonists (vaptans) are a promising innovation, but evidence of their safety and effect on important clinical outcomes in frail elderly individuals is limited. PMID- 26237486 TI - Importance of Beta Cell Function for the Treatment of Type 2 Diabetes. AB - Type 2 diabetes (T2DM) is characterized by insulin resistance and beta cell dysfunction. Recent evidence has emerged that beta cell dysfunction is a common pathogenetic feature of both type 1 and type 2 diabetes, and T2DM never develops without beta cell dysfunction. Therefore, treatment of T2DM should aim to restore beta cell function. Although the treatment of T2DM has greatly improved over the past few decades, remaining issues in the current treatment of T2DM include (1) hypoglycemia; (2) body weight gain; (3) peripheral hyperinsulinemia and (4) postprandial hyperglycemia, which are all associated with inappropriate insulin supplementation, again underpinning the important role of endogenous and physiological insulin secretion in the management of T2DM. This review summarizes the current knowledge on beta cell function in T2DM and discusses the treatment strategy for T2DM in relation to beta cell dysfunction. PMID- 26237488 TI - Fetal Cell Based Prenatal Diagnosis: Perspectives on the Present and Future. AB - The ability to capture and analyze fetal cells from maternal circulation or other sources during pregnancy has been a goal of prenatal diagnostics for over thirty years. The vision of replacing invasive prenatal diagnostic procedures with the prospect of having the entire fetal genome in hand non-invasively for chromosomal and molecular studies for both clinical and research use has brought many investigators and innovations into the effort. While the object of this desire, however, has remained elusive, the aspiration for this approach to non-invasive prenatal diagnosis remains and the inquiry has continued. With the advent of screening by cell-free DNA analysis, the standards for fetal cell based prenatal diagnostics have been sharpened. Relevant aspects of the history and the current status of investigations to meet the goal of having an accessible and reliable strategy for capturing and analyzing fetal cells during pregnancy are reviewed. PMID- 26237489 TI - First Trimester Ultrasound in Prenatal Diagnosis-Part of the Turning Pyramid of Prenatal Care. AB - First-trimester sonographic assessment of the risk of chromosomal abnormalities is routinely performed throughout the world, primarily by measuring fetal nuchal translucency thickness between 11-13 weeks' gestation, combined with assessment of serum markers. The development of high-frequency transvaginal transducers has led to improved ultrasound resolution and better visualization of fetal anatomy during the first-trimester. Continuous improvement in ultrasound technology allows a thorough detailed assessment of fetal anatomy at the time of the nuchal translucency study. Using transabdominal or transvaginal sonography, or a combination of both approaches, it is now possible to diagnose a wide range of fetal anomalies during the first trimester. Multiple studies reported early diagnosis of major fetal anomalies after demonstrating the association of increased nuchal translucency thickness with structural defect in chromosomally normal and abnormal fetuses. Normal sonographic findings provide reassurance for women at high risk while detection of fetal malformation during the first trimester enables discussion and decisions about possible treatments and interventions, including termination of pregnancy, during an early stage of pregnancy. PMID- 26237490 TI - Potential and Challenges of Induced Pluripotent Stem Cells in Liver Diseases Treatment. AB - Tens of millions of patients are affected by liver disease worldwide. Many of these patients can benefit from cell therapy involving living metabolically active cells, either by treatment of their liver disease, or by prevention of their disease phenotype. Cell therapies, including hepatocyte transplantation and bioartificial liver (BAL) devices, have been proposed as therapeutic alternatives to the shortage of transplantable livers. Both BAL and hepatocyte transplantation are cellular therapies that avoid use of a whole liver. Hepatocytes are also widely used in drug screening and liver disease modelling. However, the demand for human hepatocytes, heavily outweighs their availability by conventional means. Induced pluripotent stem cells (iPSCs) technology brings together the potential benefits of embryonic stem cells (ESCs) (i.e., self-renewal, pluripotency) and addresses the major ethical and scientific concerns of ESCs: embryo destruction and immune-incompatibility. It has been shown that hepatocyte like cells (HLCs) can be generated from iPSCs. Furthermore, human iPSCs (hiPSCs) can provide an unlimited source of human hepatocytes and hold great promise for applications in regenerative medicine, drug screening and liver diseases modelling. Despite steady progress, there are still several major obstacles that need to be overcome before iPSCs will reach the bedside. This review will focus on the current state of efforts to derive hiPSCs for potential use in modelling and treatment of liver disease. PMID- 26237491 TI - Counseling Challenges with Variants of Uncertain Significance and Incidental Findings in Prenatal Genetic Screening and Diagnosis. AB - Prenatal genetic screening and testing provides prospective parents information about the health of their fetus. It is offered to find or address an increased risk for chromosomal abnormalities or other genetic conditions in the fetus or to identify the cause of fetal structural abnormalities detected by prenatal imaging. Genome-wide tests, such as the already widely-used chromosomal microarray analysis and emerging diagnostic whole exome and whole genome sequencing, have improved the ability to detect clinically significant findings, but have also increased the chance of detecting incidental findings and variants of uncertain significance. There is an extensive ongoing discussion about optimal strategies for diagnostic laboratories to report such findings and for providers to communicate them with patients. While consensus opinions and guidelines are beginning to appear, they often exclude the prenatal setting, due to its unique set of challenging considerations. These include more limited knowledge of the impact of genetic variants when prospectively detected in an ongoing pregnancy, the absence or limitations of detecting clinically recognizable phenotypes at the time of testing and the different decision-making processes that will ensue from testing. In this review, we examine these challenges within the medical ethical framework unique to prenatal care. PMID- 26237492 TI - Actual Therapeutic Indication of an Old Drug: Urea for Treatment of Severely Symptomatic and Mild Chronic Hyponatremia Related to SIADH. AB - Oral urea has been used in the past to treat various diseases like gastric ulcers, liver metastases, sickle cell disease, heart failure, brain oedema, glaucoma, Meniere disease, etc. We have demonstrated for years, the efficacy of urea to treat euvolemic (SIADH) or hypervolemic hyponatremia. We briefly describe the indications of urea use in symptomatic and paucisymptomatic hyponatremic patients. Urea is a non-toxic, cheap product, and protects against osmotic demyelinating syndrome (ODS) in experimental studies. Prospective studies showing the benefit to treat mild chronic hyponatremia due to SIADH and comparing water restriction, urea, high ceiling diuretics, and antivasopressin antagonist antagonist should be done. PMID- 26237494 TI - Effect of Arbuscular Mycorrhizal Fungi On Yield and Phytoremediation Performance of Pot Marigold (Calendula officinalis L.) Under Heavy Metals Stress. AB - In order to study the effect of mycorrhizal fungi (inoculated and non-inoculated) and heavy metals stress [0, Pb (150 and 300 mg/kg) and Cd (40 and 80 mg/kg)] on pot marigold (Calendula officinalis L.), a factorial experiment was conducted based on a randomized complete block design with 4 replications in Research Greenhouse of Department of Horticultural Sciences, University of Tehran, Iran, during 2012-2013. Plant height, herbal and flower fresh and dry weight, root fresh and dry weight and root volume, colonization percentage, total petal extract, total petal flavonoids, root and shoot P and K uptakes, and Pb and Cd accumulations in root and shoot were measured. Results indicated that with increasing soil Pb and Cd concentration, growth and yield of pot marigold was reduced significantly; Cd had greater negative impacts than Pb. However, mycorrhizal fungi alleviated these impacts by improving plant growth and yield. Pot marigold concentrated high amounts of Pb and especially Cd in its roots and shoots; mycorrhizal plants had a greater accumulation of these metals, so that those under 80 mg/kg Cd soil(-1) accumulated 833.3 and 1585.8 mg Cd in their shoots and roots, respectively. In conclusion, mycorrhizal fungi can improve not only growth and yield of pot marigold in heavy metal stressed condition, but also phytoremediation performance by increasing heavy metals accumulation in the plant organs. PMID- 26237493 TI - Real-Space Observation of Short-Period Cubic Lattice of Skyrmions in MnGe. AB - Three-dimensional forms of skyrmion aggregate, such as a cubic lattice of skyrmions, are anticipated to exist, yet their direct observations remain elusive. Here, we report real-space observations of spin configurations of the skyrmion-antiskyrmion cubic-lattice in MnGe with a very short period (~3 nm) and hence endowed with the largest skyrmion number density. The skyrmion lattices parallel to the {100} atomic lattices are directly observed using high-resolution Lorentz transmission electron microscopes, simultaneously with underlying atomic lattice fringes. PMID- 26237495 TI - Self-Rated Health Among Patients with Coronary Artery Disease Enrolled in a Cardiovascular Risk Reduction Service. AB - Little is known about the use of the single self-rated health (SRH) status item measuring health-related quality of life among people with coronary artery disease (CAD). The objective of this study was to assess relationships between SRH and recurrent coronary events, mortality, health care utilization, and intermediate clinical outcomes and to assess predictors of fair/poor SRH. A total of 5573 patients enrolled in a comprehensive cardiac risk reduction service managed by clinical pharmacy specialists were evaluated over a 2-year period. Regression modeling explored relationships among variables, modeling SRH separately as an independent and a dependent variable. The 1374 (24.7%) respondents reporting fair/poor SRH differed statistically from 4199 (75.3%) respondents reporting good/very good/excellent SRH in terms of age, sex, ethnicity, number of comorbid conditions, DxCG scores, lifestyle behaviors, blood pressure control, and inpatient and emergency department (ED) utilization. Respondents reporting fair/poor health were more likely to have recurrent major coronary events (MCE), including death. Fair/poor SRH was consistently statistically significant when it was included as a predictor in regression modeling for poor blood pressure control, health care utilization, MCE, and all cause mortality. Variables associated with fair/poor SRH in regression modeling included females, Hispanic ethnicity, >=1 baseline ED visit, and DxCG score. Exercising <30 minutes per week was strongly associated with fair/poor SRH. Single-item SRH status may help identify patients with CAD at higher risk of poor blood pressure control, recurrent MCE, and death and those who may benefit from interventions to increase physical activity. PMID- 26237496 TI - Identifying contextual influences of community reintegration among injured servicemembers. AB - Research suggests that community reintegration (CR) after injury and rehabilitation is difficult for many injured servicemembers. However, little is known about the influence of the contextual factors, both personal and environmental, that influence CR. Framed within the International Classification of Functioning, Disability and Health and Social Cognitive Theory, the quantitative portion of a larger mixed-methods study of 51 injured, community dwelling servicemembers compared the relative contribution of contextual factors between groups of servicemembers with different levels of CR. Cluster analysis indicated three groups of servicemembers showing low, moderate, and high levels of CR. Statistical analyses identified contextual factors (e.g., personal and environmental factors) that significantly discriminated between CR clusters. Multivariate analysis of variance and discriminant analysis indicated significant contributions of general self-efficacy, services and assistance barriers, physical and structural barriers, attitudes and support barriers, perceived level of disability and/or handicap, work and school barriers, and policy barriers on CR scores. Overall, analyses indicated that injured servicemembers with lower CR scores had lower general self-efficacy scores, reported more difficulty with environmental barriers, and reported their injuries as more disabling. PMID- 26237497 TI - Correlates of VA mental health treatment utilization among OEF/OIF/OND veterans: Resilience, stigma, social support, personality, and beliefs about treatment. AB - Veterans of Operations Iraqi Freedom/Enduring Freedom/New Dawn (OEF/OIF/OND) tend not to engage in mental health care. Identifying modifiable factors related to mental health service utilization could facilitate development of interventions to increase utilization. The current study examined the relationship between mental health care utilization and measures of PTSD symptoms, resilience, stigma, beliefs about mental health care, perceived barriers to mental health care, posttraumatic growth and meaning, social support, and personality factors in a sample of 100 OEF/OIF/OND veterans with PTSD symptoms referred to VA mental health care. Participants who received psychotherapy and pharmacotherapy (PP) scored higher on measures of PTSD symptoms, stigma, and adaptive beliefs about mental health treatment, and lower on measures of resilience, postdeployment social support, emotional stability, and conscientiousness, than participants who received no treatment (NT). Participants who received psychotherapy only (PT) scored higher on a measure of PTSD symptoms than NT participants. PT participants scored higher on an emotional stability measure and lower on measures of PTSD symptoms and stigma than PP participants. Multinomial logistic regression including all variables significantly related to treatment utilization indicated that PTSD symptoms and adaptive beliefs about psychotherapy and pharmacotherapy were higher in the PT and PP groups than in the NT group, and concerns about discrimination were higher in the PP group than the NT group. Interventions targeting beliefs about mental health care could increase mental health treatment utilization among OEF/OIF/OND veterans. Concerns about stigma may affect the utilization process differently at different decision points. (PsycINFO Database Record PMID- 26237498 TI - Dose intensity and toxicity associated with Taxotere formulation: a retrospective study in a population of breast cancer patients treated with docetaxel as an adjuvant or neoadjuvant chemotherapy. AB - Docetaxel is an antineoplastic drug from the taxane family that inhibits tubulin polymerization. Its brand name is Taxotere. In mid-2010, the formulation of Taxotere changed from a two-vial preparation needing a predilution (T2V) to a one vial ready-to-use preparation (T1V). The aim of this study was to compare the toxicity profile of these two formulations. This retrospective observational and monocentric study included all patients who received Taxotere-based chemotherapy (100 mg/m) as an adjuvant or a neoadjuvant treatment for localized breast cancer, following initial treatment with anthracycline-based chemotherapy. Patients received either T2V or T1V Taxotere depending on the period of treatment. The main endpoint was the ratio of the dose of Taxotere received to that scheduled (R=docetaxel dose received/docetaxel dose scheduled). The secondary endpoint was tolerance. A total of 97 patients were included: 39 in the T2V group and 58 in the T1V group. The ratio of docetaxel received/docetaxel scheduled was significantly lower in the T1V than in the T2V group (0.83 vs. 0.95, respectively; P=0.028). A higher proportion of patients did not receive the totality of the scheduled dose in the T1V than in the T2V group (28 vs. 8%, respectively; P=0.03). Furthermore, the proportion of patients experiencing cutaneous toxicity was significantly higher in the T1V than in the T2V group (50 vs. 15%, respectively; P<0.001) as well as for neurological toxicity (31 vs. 15%, respectively; P=0.03). The frequency of grade 3 toxicities was higher in the T1V than in the T2V group (50 vs. 8%, P=0.016). The frequency of idiosyncratic toxicities was not affected by the change of formulation (4.7 vs. 5.4%, P=0.98). This study shows that patients treated with the T1V formulation received a significantly smaller dose of Taxotere than patients treated with T2V. In this small retrospective study, no conclusions can be drawn as to why a change in formulation would be associated with differences in dose tolerance. However, it does encourage caution and need for clinical data analysis when adopting even minor changes in the formulation of well-known anticancer drugs. PMID- 26237499 TI - A significant response to sorafenib in a woman with advanced lung adenocarcinoma and a BRAF non-V600 mutation. AB - Lung adenocarcinoma includes recurrent activating oncogenic mutations (EGFR, EML4 ALK, ROS1) that have been associated with response to EGFR and ALK inhibitors. Platinum-based chemotherapy is the standard therapy for non-oncodrivers population. Sorafenib is a small molecule that blocks the activation of C-RAF, B RAF, c-KIT, FLT-3, RET, VEGFR-2, VEGFR-3 and PDGFR approved for advanced renal cell and hepatocellular carcinoma (b, c). Many studies have evaluated sorafenib in advanced non-small-cell lung cancer (NSCLC), with different results. We present a case report of a patient with NSCLC and the BRAF G469R mutation who showed a dramatic response to sorafenib. PMID- 26237500 TI - Bortezomib and fenretinide induce synergistic cytotoxicity in mantle cell lymphoma through apoptosis, cell-cycle dysregulation, and IkappaBalpha kinase downregulation. AB - Mantle cell lymphoma (MCL) remains incurable for most patients, and proteasome inhibitors like bortezomib induce responses in a minority of patients with relapsed disease. Fenretinide is a retinoid that has shown preclinical activity in B-cell lymphomas. We hypothesized that these agents could yield augmented antitumor activity. MCL lines (Granta-519, Jeko-1, and Rec-1) were treated with escalating concentrations of bortezomib and fenretinide singly and in combination. Cytotoxicity was assessed using the MTT assay. Flow cytometric methods were used to assess apoptosis and necrosis, with annexin V-FITC/propidium iodide staining, and G1 and G2 cell-cycle changes were assessed by DAPI staining. Changes in cyclin D1, cyclin B, IkappaBalpha, and IKKalpha expressions were quantified by western blotting. Cytotoxicity was mediated through apoptosis; both agents showed observed versus expected cytotoxicities of 92.2 versus 55.1% in Granta-519, of 87.6 versus 36.3% in Jeko-1, and of 63.2 versus 29.8% in Rec-1. Isobolographic analysis confirmed synergy in Jeko-1 and Rec-1 cell lines. Bortezomib induced G2-phase arrest, with a 1.7-fold increase compared with control, and fenretinide resulted in G1-phase arrest, with an increase of 1.3 fold compared with control. In the combination, G2-phase arrest predominated, with a 1.4-fold increase compared with control, and there was reduced expression of cyclin D1 to 24%, cyclin B to 52 and 64%, cyclin D3 to 25 and 43%, IkappaBalpha to 23 and 46%, and IkappaBalpha kinase to 34 and 44%. Bortezomib and fenretinide exhibit synergistic cytotoxicity against MCL cell lines. This activity is mediated by IkappaBalpha kinase modulation, decreased cyclin expression, cell cycle dysregulation, and apoptotic cell death. PMID- 26237501 TI - Cumulative meta-analysis of epidermal growth factor receptor-tyrosine kinase inhibitors as first-line therapy in metastatic non-small-cell lung cancer. AB - We carried out a meta-analysis to evaluate the benefit of epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) over the standard first-line platinum-based chemotherapy for metastatic non-small-cell lung cancer (NSCLC). Studies that were considered eligible included controlled prospective randomized phase III studies in patients with NSCLC stages IIIB or IV. These patients received standard first line platinum-based chemotherapy or EGFR-TKI; overall survival and progression free survival (PFS) with adequate data were available to calculate and estimate the hazard ratio (HR) with a confidence interval (CI) of 95%. Eight studies were identified that compared EGFR-TKI versus standard first-line platinum-based chemotherapy to treat NSCLC in 2962 patients. Patients receiving EGFR-TKI showed significantly longer PFS [HR=0.266 (95% CI=0.20-0.35), P<0.0001]. No significant difference in overall survival [HR=0.946 (95% CI=0.35-2.53), P=0.912] was observed between the groups. The cumulative meta-analysis of the studies showed that, since 2011 (OPTIMAL study), the PFS benefit in the EGFR-TKI arm was statistically significantly longer. Toxicity values greater than or equal to 3 in the most prevalent EGFR-TKI group included skin rash, diarrhea, and increased aminotransferase. EGFR-TKI treatment significantly extends PFS, with acceptable toxicities than platinum-based chemotherapy. Thus, they should be considered as the first choice in the first-line treatment for patients with NSCLC and with the EGFR mutation. PMID- 26237502 TI - Pseudomonas aeruginosa Infection after Pancreatoduodenectomy: Risk Factors and Clinic Impacts. AB - BACKGROUND: Pseudomonas aeruginosa (P. aeruginosa) is a leading cause of nosocomial infections, which is difficult to treat because of limited susceptibility to antimicrobial agents. In China, isolation rates of P. aeruginosa were observed to increase by year. The incidence of infectious complications after pancreatoduodenectomy (PD) were high. However, there was no data available regarding P. aeruginosa infection in patients undergoing PD. This study evaluated the risk factors and clinical impacts of P. aeruginosa infection on patient after PD. METHODS: 119 patients who underwent PD with post-operative infectious complications were monitored for P. aeruginosa infection. The patients were grouped as P. aeruginosa infection and non-P. aeruginosa infection. Univariable and multivariable analyses were used to identify risk factors for P. aeruginosa infection. RESULTS: 42 (35.3%) of the119 patients were P. aeruginosa positive after PD. The sites of P. aeruginosa infection included (1) abdominal drain fluid (76%); (2) sputum (7%); (3) central line catheter tip cultures (2%); and (4) combination of sites (14%). Pseudomonas aeruginosa isolates were susceptible to Polymyxin B, Amikacin and Gentamicin, resistant to Aztreonam Piperacillin-tazobactam, Imipenem and Ceftazidime. History of diabetes mellitus (OR=2.981, P=0.023), pancreatic fistula (OR=4.699, P=0.001), use of carbapenems (OR=3.236, P=0.013), and fluoroquinolones (OR=2.940, P=0.044), antibiotics, and length of ICU stay (OR=2.133, P=0.022) independently predicted post-operative P. aeruginosa infection. Pseudomonas aeruginosa infection was related to severe post operative complications, including delayed gastric emptying and post pancreatectomy hemorrhage, but was not related to not 30-d mortality or a longer post-operative stay. CONCLUSIONS: This analytic study highlights the prevalence and high drug resistance of P. aeruginosa after PD. Pseudomonas aeruginosa infection was related to severe post-operative complications but not 30-d mortality. Measures to combat P. aeruginosa infection would likely decrease the accidence of P. aeruginosa infection and benefit patients' outcomes. PMID- 26237503 TI - Bilayers at High pH in the Fatty Acid Soap Systems and the Applications for the Formation of Foams and Emulsions. AB - In our previous work, we reported bilayers at high pH in the stearic acid/CsOH/H2O system, which was against the traditional viewpoint that fatty acid (FA) bilayers must be formed at the pKa of the fatty acid. Herein, the microstructures at high pH of several fatty acid soap systems were investigated systematically. We found that palmitic acid/KOH/H2O, palmitic acid/CsOH/H2O, stearic acid/KOH/H2O, and stearic acid/CsOH/H2O systems can form bilayers at high pH. The bilayer structure was demonstrated by cryogenic transmission electron microscopy (cryo-TEM) and deuterium nuclear magnetic resonance ((2)H NMR), and molecular dynamics simulation was used to confirm the formation of bilayers. The influence of fatty acids with different chain lengths (n = 10, 12, 14, 16, and 18) and different counterions including Li(+), Na(+), K(+), Cs(+), (CH3)4N(+), (C2H5)4N(+), (C3H7)4N(+), and (C4H9)4N(+) on the formation of bilayers was discussed. The stability of foam and emulsification properties were compared between bilayers and micelles, drawing the conclusion that bilayer structures possess a much stronger ability to foam and stronger emulsification properties than micelles do. PMID- 26237504 TI - An introduction and integration of cross-classified, multiple membership, and dynamic group random-effects models. AB - In longitudinal studies, time-varying group membership and group effects are important issues that need to be addressed. In this article we describe use of cross-classified and multiple membership random-effects models to address time varying group membership, and dynamic group random-effects models to address time varying group effects. We propose new models that integrate features of existing models, evaluate these models through simulation, provide guidance on how to fit these models, and apply the models in 2 real data examples. The discussion focuses on challenges in the application of these models. PMID- 26237505 TI - Testing nonnested structural equation models. AB - In this article, we apply Vuong's (1989) likelihood ratio tests of nonnested models to the comparison of nonnested structural equation models (SEMs). Similar tests have been previously applied in SEM contexts (especially to mixture models), though the nonstandard output required to conduct the tests has limited their use and study. We review the theory underlying the tests and show how they can be used to construct interval estimates for differences in nonnested information criteria. Through both simulation and application, we then study the tests' performance in nonmixture SEMs and describe their general implementation via free R packages. The tests offer researchers a useful tool for nonnested SEM comparison, with barriers to test implementation now removed. (PsycINFO Database Record PMID- 26237506 TI - Residual tests in the analysis of planned contrasts: Problems and solutions. AB - It is current practice that researchers testing specific, theory-driven predictions do not only use a planned contrast to model and test their hypotheses, but also test the residual variance (the C+R approach). This analysis strategy relies on work by Abelson and Prentice (1997), who suggested that the result of a planned contrast needs to be interpreted in light of the variance that is left after the variance explained by the contrast has been subtracted from the variance explained by the factors of the statistical model. Unfortunately, the C + R approach leads to 6 fundamental problems. In particular, the C + R approach (a) relies on the interpretation of a nonsignificant result as evidence for no effect, (b) neglects the impact of sample size, (c) creates problems for a priori power analyses, (d) may lead to significant effects that lack a meaningful interpretation, (e) may give rise to misinterpretations, and (f) is inconsistent with the interpretation of other statistical analyses. Given these flaws, researchers should refrain from testing the residual variance when conducting planned contrasts. Single contrasts, Bayes factors, and likelihood ratios provide reasonable alternatives that are less problematic. PMID- 26237507 TI - Right-sizing statistical models for longitudinal data. AB - Arguments are proposed that researchers using longitudinal data should consider more and less complex statistical model alternatives to their initially chosen techniques in an effort to "right-size" the model to the data at hand. Such model comparisons may alert researchers who use poorly fitting, overly parsimonious models to more complex, better-fitting alternatives and, alternatively, may identify more parsimonious alternatives to overly complex (and perhaps empirically underidentified and/or less powerful) statistical models. A general framework is proposed for considering (often nested) relationships between a variety of psychometric and growth curve models. A 3-step approach is proposed in which models are evaluated based on the number and patterning of variance components prior to selection of better-fitting growth models that explain both mean and variation-covariation patterns. The orthogonal free curve slope intercept (FCSI) growth model is considered a general model that includes, as special cases, many models, including the factor mean (FM) model (McArdle & Epstein, 1987), McDonald's (1967) linearly constrained factor model, hierarchical linear models (HLMs), repeated-measures multivariate analysis of variance (MANOVA), and the linear slope intercept (linearSI) growth model. The FCSI model, in turn, is nested within the Tuckerized factor model. The approach is illustrated by comparing alternative models in a longitudinal study of children's vocabulary and by comparing several candidate parametric growth and chronometric models in a Monte Carlo study. PMID- 26237508 TI - Validation of a method for dispatching discrete sensors on an insole for plantar pressure analysis. PMID- 26237509 TI - The active site of O-GlcNAc transferase imposes constraints on substrate sequence. AB - O-GlcNAc transferase (OGT) glycosylates a diverse range of intracellular proteins with O-linked N-acetylglucosamine (O-GlcNAc), an essential and dynamic post translational modification in metazoans. Although this enzyme modifies hundreds of proteins with O-GlcNAc, it is not understood how OGT achieves substrate specificity. In this study, we describe the application of a high-throughput OGT assay to a library of peptides. We mapped sites of O-GlcNAc modification by electron transfer dissociation MS and found that they correlate with previously detected O-GlcNAc sites. Crystal structures of four acceptor peptides in complex with Homo sapiens OGT suggest that a combination of size and conformational restriction defines sequence specificity in the -3 to +2 subsites. This work reveals that although the N-terminal TPR repeats of OGT may have roles in substrate recognition, the sequence restriction imposed by the peptide-binding site makes a substantial contribution to O-GlcNAc site specificity. PMID- 26237511 TI - The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD. AB - Mycobacterium tuberculosis (Mtb) induces necrosis of infected cells to evade immune responses. Recently, we found that Mtb uses the protein CpnT to kill human macrophages by secreting its C-terminal domain, named tuberculosis necrotizing toxin (TNT), which induces necrosis by an unknown mechanism. Here we show that TNT gains access to the cytosol of Mtb-infected macrophages, where it hydrolyzes the essential coenzyme NAD(+). Expression or injection of a noncatalytic TNT mutant showed no cytotoxicity in macrophages or in zebrafish zygotes, respectively, thus demonstrating that the NAD(+) glycohydrolase activity is required for TNT-induced cell death. To prevent self-poisoning, Mtb produces an immunity factor for TNT (IFT) that binds TNT and inhibits its activity. The crystal structure of the TNT-IFT complex revealed a new NAD(+) glycohydrolase fold of TNT, the founding member of a toxin family widespread in pathogenic microorganisms. PMID- 26237512 TI - Early embryonic-like cells are induced by downregulating replication-dependent chromatin assembly. AB - Cellular plasticity is essential for early embryonic cells. Unlike pluripotent cells, which form embryonic tissues, totipotent cells can generate a complete organism including embryonic and extraembryonic tissues. Cells resembling 2-cell stage embryos (2C-like cells) arise at very low frequency in embryonic stem (ES) cell cultures. Although induced reprogramming to pluripotency is well established, totipotent cells remain poorly characterized, and whether reprogramming to totipotency is possible is unknown. We show that mouse 2C-like cells can be induced in vitro through downregulation of the chromatin-assembly activity of CAF-1. Endogenous retroviruses and genes specific to 2-cell embryos are the highest-upregulated genes upon CAF-1 knockdown. Emerging 2C-like cells exhibit molecular characteristics of 2-cell embryos and higher reprogrammability than ES cells upon nuclear transfer. Our results suggest that early embryonic like cells can be induced by modulating chromatin assembly and that atypical histone deposition may trigger the emergence of totipotent cells. PMID- 26237510 TI - Structure and mechanism of the Rubisco-assembly chaperone Raf1. AB - Biogenesis of the photosynthetic enzyme Rubisco, a complex of eight large (RbcL) and eight small (RbcS) subunits, requires assembly chaperones. Here we analyzed the role of Rubisco accumulation factor1 (Raf1), a dimer of ~40-kDa subunits. We find that Raf1 from Synechococcus elongatus acts downstream of chaperonin assisted RbcL folding by stabilizing RbcL antiparallel dimers for assembly into RbcL8 complexes with four Raf1 dimers bound. Raf1 displacement by RbcS results in holoenzyme formation. Crystal structures show that Raf1 from Arabidopsis thaliana consists of a beta-sheet dimerization domain and a flexibly linked alpha-helical domain. Chemical cross-linking and EM reconstruction indicate that the beta domains bind along the equator of each RbcL2 unit, and the alpha-helical domains embrace the top and bottom edges of RbcL2. Raf1 fulfills a role similar to that of the assembly chaperone RbcX, thus suggesting that functionally redundant factors ensure efficient Rubisco biogenesis. PMID- 26237513 TI - Soluble CD40 Ligand in Aspirin-Treated Patients Undergoing Cardiac Catheterization. AB - Plasma soluble CD40 ligand (sCD40L) is mainly generated by cleavage of CD40L from the surface of activated platelets, and therefore considered a platelet activation marker. Although the predictive value of sCD40L for ischemic events has been demonstrated in patients with acute coronary syndromes (ACS), studies on the association of sCD40L with cardiovascular outcomes in lower risk populations yielded heterogeneous results. We therefore sought to investigate factors influencing sCD40L levels, and the predictive value of sCD40L for long-term ischemic events in unselected, aspirin-treated patients undergoing cardiac catheterization. sCD40L was determined by a commercially available enzyme-linked immunosorbent assay in 682 consecutive patients undergoing cardiac catheterization. Two-year follow-up data were obtained from 562 patients. Dual antiplatelet therapy with aspirin and clopidogrel was associated with significantly lower levels of sCD40L and lower platelet surface expressions of P selectin and activated GPIIb/IIIa compared to aspirin monotherapy (all p<=0.01). Hypertension was linked to lower plasma concentrations of sCD40L, whereas female sex, increasing high-sensitivity C-reactive protein, and hematocrit were associated with higher sCD40L concentrations (all p<0.05). sCD40L levels were similar in patients without and with the primary endpoint in the overall study population (p = 0.4). Likewise, sCD40L levels did not differ significantly between patients without and with the secondary endpoints (both p>=0.4). Similar results were obtained when only patients with angiographically-proven coronary artery disease (n = 459), stent implantation (n = 205) or ACS (n = 125) were analyzed. The adjustment for differences in patient characteristics by multivariate regression analyses did not change the results. ROC curve analyses did not reveal cut-off values for sCD40L for the prediction of the primary or secondary endpoints. In conclusion, plasma sCD40L levels are reduced by antiplatelet therapy with clopidogrel, but not associated with long-term ischemic outcomes in unselected consecutive aspirin-treated patients undergoing cardiac catheterization. PMID- 26237514 TI - Genome-Wide Analysis of C2H2 Zinc-Finger Family Transcription Factors and Their Responses to Abiotic Stresses in Poplar (Populus trichocarpa). AB - BACKGROUND: C2H2 zinc-finger (C2H2-ZF) proteins are a large gene family in plants that participate in various aspects of normal plant growth and development, as well as in biotic and abiotic stress responses. To date, no overall analysis incorporating evolutionary history and expression profiling of the C2H2-ZF gene family in model tree species poplar (Populus trichocarpa) has been reported. PRINCIPAL FINDINGS: Here, we identified 109 full-length C2H2-ZF genes in P. trichocarpa, and classified them into four groups, based on phylogenetic analysis. The 109 C2H2-ZF genes were distributed unequally on 19 P. trichocarpa linkage groups (LGs), with 39 segmental duplication events, indicating that segmental duplication has been important in the expansion of the C2H2-ZF gene family. Promoter cis-element analysis indicated that most of the C2H2-ZF genes contain phytohormone or abiotic stress-related cis-elements. The expression patterns of C2H2-ZF genes, based on heatmap analysis, suggested that C2H2-ZF genes are involved in tissue and organ development, especially root and floral development. Expression analysis based on quantitative real-time reverse transcription polymerase chain reaction indicated that C2H2-ZF genes are significantly involved in drought, heat and salt response, possibly via different mechanisms. CONCLUSIONS: This study provides a thorough overview of the P. trichocarpa C2H2-ZF gene family and presents a new perspective on the evolution of this gene family. In particular, some C2H2-ZF genes may be involved in environmental stress tolerance regulation. PtrZFP2, 19 and 95 showed high expression levels in leaves and/or roots under environmental stresses. Additionally, this study provided a solid foundation for studying the biological roles of C2H2-ZF genes in Populus growth and development. These results form the basis for further investigation of the roles of these candidate genes and for future genetic engineering and gene functional studies in Populus. PMID- 26237515 TI - Mammalian synthetic circuits with RNA binding proteins for RNA-only delivery. AB - Synthetic regulatory circuits encoded in RNA rather than DNA could provide a means to control cell behavior while avoiding potentially harmful genomic integration in therapeutic applications. We create post-transcriptional circuits using RNA-binding proteins, which can be wired in a plug-and-play fashion to create networks of higher complexity. We show that the circuits function in mammalian cells when encoded in modified mRNA or self-replicating RNA. PMID- 26237516 TI - High-throughput determination of RNA structure by proximity ligation. AB - We present an unbiased method to globally resolve RNA structures through pairwise contact measurements between interacting regions. RNA proximity ligation (RPL) uses proximity ligation of native RNA followed by deep sequencing to yield chimeric reads with ligation junctions in the vicinity of structurally proximate bases. We apply RPL in both baker's yeast (Saccharomyces cerevisiae) and human cells and generate contact probability maps for ribosomal and other abundant RNAs, including yeast snoRNAs, the RNA subunit of the signal recognition particle and the yeast U2 spliceosomal RNA homolog. RPL measurements correlate with established secondary structures for these RNA molecules, including stem-loop structures and long-range pseudoknots. We anticipate that RPL will complement the current repertoire of computational and experimental approaches in enabling the high-throughput determination of secondary and tertiary RNA structures. PMID- 26237518 TI - Six-electron reduction of nitrite to ammonia by cytochrome c nitrite reductase: insights from density functional theory studies. AB - In this Forum Article, an extensive discussion of the mechanism of six-electron, seven-proton nitrite reduction by the cytochrome c nitrite reductase enzyme is presented. On the basis of previous studies, the entire mechanism is summarized and a unified picture of the most plausible sequence of elementary steps is presented. According to this scheme, the mechanism can be divided into five functional stages. The first phase of the reaction consists of substrate binding and N-O bond cleavage. Here His277 plays a crucial role as a proton donor. In this step, the N-O bond is cleaved heterolytically through double protonation of the substrate. The second phase of the mechanism consists of two proton-coupled electron-transfer events, leading to an HNO intermediate. The third phase involves the formation of hydroxylamine, where Arg114 provides the necessary proton for the reaction. The second N-O bond is cleaved in the fourth phase of the mechanism, again triggered by proton transfer from His277. The Tyr218 side chain governs the fifth and last phase of the mechanism. It consists of radical transfer and ammonia formation. Thus, this mechanism implies that all conserved active-site side chains work in a concerted way in order to achieve this complex chemical transformation from nitrite to ammonia. The Forum Article also provides a detailed discussion of the density functional theory based cluster model approach to bioinorganic reactivity. A variety of questions are considered: the resting state of enzyme and substrate binding modes, interaction with the metal site and with active-site side chains, electron- and proton-transfer events, substrate dissociation, etc. PMID- 26237517 TI - Differentiation of pluripotent stem cells to muscle fiber to model Duchenne muscular dystrophy. AB - During embryonic development, skeletal muscles arise from somites, which derive from the presomitic mesoderm (PSM). Using PSM development as a guide, we establish conditions for the differentiation of monolayer cultures of mouse embryonic stem (ES) cells into PSM-like cells without the introduction of transgenes or cell sorting. We show that primary and secondary skeletal myogenesis can be recapitulated in vitro from the PSM-like cells, providing an efficient, serum-free protocol for the generation of striated, contractile fibers from mouse and human pluripotent cells. The mouse ES cells also differentiate into Pax7(+) cells with satellite cell characteristics, including the ability to form dystrophin(+) fibers when grafted into muscles of dystrophin-deficient mdx mice, a model of Duchenne muscular dystrophy (DMD). Fibers derived from ES cells of mdx mice exhibit an abnormal branched phenotype resembling that described in vivo, thus providing an attractive model to study the origin of the pathological defects associated with DMD. PMID- 26237519 TI - A Thermally Conductive Separator for Stable Li Metal Anodes. AB - Li metal anodes have attracted considerable research interest due to their low redox potential (-3.04 V vs standard hydrogen electrode) and high theoretical gravimetric capacity of 3861 mAh/g. Battery technologies using Li metal anodes have shown much higher energy density than current Li-ion batteries (LIBs) such as Li-O2 and Li-S systems. However, issues related to dendritic Li formation and low Coulombic efficiency have prevented the use of Li metal anode technology in many practical applications. In this paper, a thermally conductive separator coated with boron-nitride (BN) nanosheets has been developed to improve the stability of the Li metal anodes. It is found that using the BN-coated separator in a conventional organic carbonate-based electrolyte results in the Coulombic efficiency stabilizing at 92% over 100 cycles at a current rate of 0.5 mA/cm(2) and 88% at 1.0 mA/cm(2). The improved Coulombic efficiency and reliability of the Li metal anodes is due to the more homogeneous thermal distribution resulting from the thermally conductive BN coating and to the smaller surface area of initial Li deposition. PMID- 26237522 TI - Wetting-Dewetting and Dispersion-Aggregation Transitions Are Distinct for Polymer Grafted Nanoparticles in Chemically Dissimilar Polymer Matrix. AB - Simulations and experiments are conducted on mixtures containing polymer grafted nanoparticles in a chemically distinct polymer matrix, where the graft and matrix polymers exhibit attractive enthalpic interactions at low temperatures that become progressively repulsive as temperature is increased. Both coarse-grained molecular dynamics simulations, and X-ray scattering and neutron scattering experiments with deuterated polystyrene (dPS) grafted silica and poly(vinyl methyl ether) PVME matrix show that the sharp phase transition from (mixed) dispersed to (demixed) aggregated morphologies due to the increasingly repulsive effective interactions between the blend components is distinct from the continuous wetting-dewetting transition. Strikingly, this is unlike the extensively studied chemically identical graft-matrix composites, where the two transitions have been considered to be synonymous, and is also unlike the free (ungrafted) blends of the same graft and matrix homopolymers, where the wetting dewetting is a sharp transition coinciding with the macrophase separation. PMID- 26237520 TI - Treatment of Vitamin D Insufficiency in Postmenopausal Women: A Randomized Clinical Trial. AB - IMPORTANCE: Experts debate optimal 25-hydroxyvitamin D (25[OH]D) levels for musculoskeletal health. OBJECTIVE: To compare the effects of placebo, low-dose cholecalciferol, and high-dose cholecalciferol on 1-year changes in total fractional calcium absorption, bone mineral density, Timed Up and Go and five sit to-stand tests, and muscle mass in postmenopausal women with vitamin D insufficiency. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, placebo-controlled clinical trial was conducted at a single center in Madison, Wisconsin, from May 1, 2010, through July 31, 2013, and the final visit was completed on August 8, 2014. A total of 230 postmenopausal women 75 years or younger with baseline 25(OH)D levels of 14 through 27 ng/mL and no osteoporosis were studied. INTERVENTIONS: Three arms included daily white and twice monthly yellow placebo (n=76), daily 800 IU vitamin D3 and twice monthly yellow placebo (n=75), and daily white placebo and twice monthly 50,000 IU vitamin D3 (n=79). The high-dose vitamin D regimen achieved and maintained 25(OH)D levels>=30 ng/mL. MAIN OUTCOMES AND MEASURES: Outcome measures were 1-year change in total fractional calcium absorption using 2 stable isotopes, bone mineral density and muscle mass using dual energy x-ray absorptiometry, Timed Up and Go and five sit to-stand tests, functional status (Health Assessment Questionnaire), and physical activity (Physical Activity Scale for the Elderly), with Benjamini-Hochberg correction of P values to control for the false discovery rate. RESULTS: After baseline absorption was controlled for, calcium absorption increased 1% (10 mg/d) in the high-dose arm but decreased 2% in the low-dose arm (P = .005 vs high-dose arm) and 1.3% in the placebo arm (P = .03 vs high-dose arm). We found no between arm changes in spine, mean total-hip, mean femoral neck, or total-body bone mineral density, trabecular bone score, muscle mass, and Timed Up and Go or five sit-to-stand test scores. Likewise, we found no between-arm differences for numbers of falls, number of fallers, physical activity, or functional status. CONCLUSIONS AND RELEVANCE: High-dose cholecalciferol therapy increased calcium absorption, but the effect was small and did not translate into beneficial effects on bone mineral density, muscle function, muscle mass, or falls. We found no data to support experts' recommendations to maintain serum 25(OH)D levels of 30 ng/mL or higher in postmenopausal women. Instead, we found that low- and high dose cholecalciferol were equivalent to placebo in their effects on bone and muscle outcomes in this cohort of postmenopausal women with 25(OH)D levels less than 30 ng/mL. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00933244. PMID- 26237523 TI - 3D printed microfluidics for biological applications. AB - The term "Lab-on-a-Chip," is synonymous with describing microfluidic devices with biomedical applications. Even though microfluidics have been developing rapidly over the past decade, the uptake rate in biological research has been slow. This could be due to the tedious process of fabricating a chip and the absence of a "killer application" that would outperform existing traditional methods. In recent years, three dimensional (3D) printing has been drawing much interest from the research community. It has the ability to make complex structures with high resolution. Moreover, the fast building time and ease of learning has simplified the fabrication process of microfluidic devices to a single step. This could possibly aid the field of microfluidics in finding its "killer application" that will lead to its acceptance by researchers, especially in the biomedical field. In this paper, a review is carried out of how 3D printing helps to improve the fabrication of microfluidic devices, the 3D printing technologies currently used for fabrication and the future of 3D printing in the field of microfluidics. PMID- 26237524 TI - Analysis of chemical equilibrium of silicon-substituted fluorescein and its application to develop a scaffold for red fluorescent probes. AB - Fluorescein is a representative green fluorophore that has been widely used as a scaffold of practically useful green fluorescent probes. Here, we report synthesis and characterization of a silicon-substituted fluorescein, i.e., 2-COOH TokyoMagenta (2-COOH TM), which is a fluorescein analogue in which the O atom at the 10' position of the xanthene moiety of fluorescein is replaced with a Si atom. This fluorescein analogue forms a spirolactone ring via intramolecular nucleophilic attack of the carboxylic group in a pH-dependent manner. Consequently, 2-COOH TM exhibits characteristic large pH-dependent absorption and fluorescence spectral changes: (1) 2-COOH TM is colorless at acidic pH, whereas fluorescein retains observable absorption and fluorescence even at acidic pH, and the absorption maximum is also shifted; (2) the absorption spectral change occurs above pH 7.0 for 2-COOH TM and below pH 7.0 for fluorescein; (3) 2-COOH TM shows a much sharper pH response than fluorescein because of its pKa inversion, i.e., pKa1 > pKa2. These features are also different from those of a compound without the carboxylic group, 2-Me TokyoMagenta (2-Me TM). Analysis of the chemical equilibrium between pH 3.0 and 11.0 disclosed that 2-COOH TM favors the colorless and nonfluorescent lactone form, compared with fluorescein. Substitution of Cl atoms at the 4' and 5' positions of the xanthene moiety of 2-COOH TM to obtain 2 COOH DCTM shifted the equilibrium so that the new derivative exists predominantly in the strongly fluorescent open form at physiological pH (pH 7.4). To demonstrate the practical utility of 2-COOH DCTM as a novel scaffold for red fluorescent probes, we employed it to develop a probe for beta-galactosidase. PMID- 26237525 TI - Erratum to: Skeletal Relapse After Mandibular Setback in Bi Max Surgery: Intraoral Vertical Ramus versus Bilateral Sagittal Split Osteotomies. AB - [This corrects the article DOI: 10.1007/s12663-013-0555-y.]. PMID- 26237528 TI - Erratum: Parity effect of bipolar quantum Hall edge transport around graphene antidots. PMID- 26237526 TI - White matter integrity, hippocampal volume, and cognitive performance of a world famous nonagenarian track-and-field athlete. AB - Physical activity (PA) and cardiorespiratory fitness (CRF) are associated with successful brain and cognitive aging. However, little is known about the effects of PA, CRF, and exercise on the brain in the oldest-old. Here we examined white matter (WM) integrity, measured as fractional anisotropy (FA) and WM hyperintensity (WMH) burden, and hippocampal (HIPP) volume of Olga Kotelko (1919 2014). Olga began training for competitions at age of 77 and as of June 2014 held over 30 world records in her age category in track-and-field. We found that Olga's WMH burden was larger and the HIPP was smaller than in the reference sample (58 healthy low-active women 60-78 years old), and her FA was consistently lower in the regions overlapping with WMH. Olga's FA in many normal-appearing WM regions, however, did not differ or was greater than in the reference sample. In particular, FA in her genu corpus callosum was higher than any FA value observed in the reference sample. We speculate that her relatively high FA may be related to both successful aging and the beneficial effects of exercise in old age. In addition, Olga had lower scores on memory, reasoning and speed tasks than the younger reference sample, but outperformed typical adults of age 90-95 on speed and memory. Together, our findings open the possibility of old-age benefits of increasing PA on WM microstructure and cognition despite age-related increase in WMH burden and HIPP shrinkage, and add to the still scarce neuroimaging data of the healthy oldest-old (>90 years) adults. PMID- 26237529 TI - Predicting the Surgical Margin of Resection in Periocular Cutaneous Neoplasms and the Significance of Reconstruction Following Mohs Micrographic Surgery. AB - PURPOSE: To evaluate the features of periocular cutaneous malignancies that may contribute to larger surgical defects or require more complex reconstructive procedures. METHODS: A retrospective review of 181 patients with biopsy proven periocular cutaneous malignancies seen between April 2005 and September 2010, and undergoing Mohs micrographic surgery was performed. The longest horizontal and vertical diameters of the tumor and the post-Mohs surgical defect were measured in each patient. These measurements were used to calculate the relative margin of resection (MOR) required for tumor eradication as well as the size of the surgical defect. The date of surgery, histologic diagnosis and location of the tumor, type of reconstruction, and the presence of recurrence were also recorded. RESULTS: The average MOR for all tumor subtypes taken together was 3.4 mm horizontally and 2.6 mm vertically for basal cell carcinomas (BCCA). The post Mohs defect area was 3.2 times greater than the preoperative tumor area for all BCCA subtypes, and 3.9 times greater for morphea type (p = 0.8083). The average MOR for squamous cell carcinomas (SCCA) was 5.1 mm horizontally and 3.7 mm vertically. The post-Mohs defect area was 3.8 times greater than the preoperative tumor area for SCCAs. When comparing the preoperative horizontal tumor diameter to the horizontal MOR of BCCAs and SCCAs, the correlation was 0.23 (p < 0.0001) and 0.31 (p < 0.0001), respectively. While the average MOR was within standard limits, a significant number of tumors required a greater MOR. On review of the data, 30.6% of patients with BCCA required a MOR greater than 3 mm, 17.3% of patients with BCCA required a MOR greater than 4 mm, and 29.1% of patients with SCCA required a MOR of greater than 5 mm. Tumors located at the lateral canthus required the largest MOR (p < 0.01), while those on the lower eyelid were associated with the smallest MOR in BCCAs. As expected from anatomical considerations, tumors at the medial canthus required significantly more complex reconstruction procedures (p < 0.01). An ordered logistic regression model demonstrated that BCCA preoperative clinical tumor surface area was a significant indicator for the degree of reconstruction required (p < 0.01). CONCLUSIONS: Standard 3 mm to 4 mm MOR for BCCAs, and 5 mm MOR for SCCAs could result in an unacceptable risk of tumor recurrence if the surgical margins are not examined histologically. With increasing preoperative tumor size, there is an increase in the MOR required for BCCA and SCCA, supporting that large tumors require a greater MOR. PMID- 26237530 TI - Prostaglandin Eyedrops Are Associated With Decreased Thicknesses of Eyelid Dermis and Orbicularis Oculi Muscle: Ultrasonographic Findings. AB - PURPOSE: To investigate the effect of prostaglandin analog eyedrops on the periorbital soft tissue using high-resolution ultrasonography. METHODS: In this cross-sectional study, the authors included patients with bilateral glaucoma on unilateral prostaglandin therapy for the past 12 or more contiguous months. High resolution ultrasonography was performed bilaterally on the upper and lower eyelids of each subject to measure thicknesses of dermis, orbicularis oculi muscle, and skin to arcus marginalis distance. Comparisons were made between eyes on prostaglandin eyedrops versus those not on prostaglandin analogs. RESULTS: Twenty patients (16 females, 4 males) with a mean age of 67.2 +/- 6.4 years were recruited. The mean duration of prostaglandin analog therapy was 5.4 +/- 3.9 years. The authors found that eyes on prostaglandin analog therapy had statistically significantly reduced thicknesses of dermis, orbicularis oculi muscle, and skin to arcus marginalis distance in the upper and lower eyelids compared with the fellow eyes (p < 0.05 for all). In univariate regression analysis, the amount of changes in thicknesses of dermis, orbicularis oculi muscle, and skin to arcus marginalis distance among eyes on prostaglandin analog therapy and the fellow eyes was not statistically significantly associated with different variables including age, gender, years of being on prostaglandin analog therapy, type of prostaglandin analog, history of glaucoma and/or cataract surgeries, intraocular pressure, and number of glaucoma medications. CONCLUSIONS: The findings indicate that eyes on prostaglandin analog therapy have reduced thicknesses of dermis, orbicularis oculi muscle, and skin to arcus marginalis distance compared with the fellow eyes. PMID- 26237531 TI - Histopathologic Clues in Diagnosing Oral Mucosal Grafts to the Conjunctiva. AB - Excised redundant, forniceal "conjunctival" tissue from a 67-year-old man who experienced a chemical injury to his OS 25 years earlier was evaluated histopathologically with the hematoxylin-eosin, periodic acid Schiff (PAS) with and without diastase, mucicarmine, and Alcian blue methods. Additional immunoperoxidase testing for gross cystic disease fluid protein-15 (GCDFP-15) was undertaken. Non-keratinizing squamous epithelium composed of 8 to 10 layers of swollen keratinocytes without goblet cells surmounted a variably dense and well vascularized collagenized lamina propria deep to which, in submucosal fibroadipose tissue, was embedded an accessory gland. The acini of the gland were composed of both GCDFP-15-positive serous cells and mucicarmine-positive goblet cells, indicating they were seromucinous rather than entirely serous, as is characteristic of normal lacrimal glandular tissue. Different features of the surface epithelium, the lamina propria, and the submucosa can separate the conjunctival and oral mucous membranes. A close analysis of the cytologic composition of associated accessory glands can reinforce the correct diagnosis of an oral mucous membrane graft when the past surgical history is unclear, because only serous cells but not mucocytes comprise the lacrimal glandular units. PMID- 26237532 TI - A Review of Eyelid Margin Malpositions: A Unique Spectrum in a South-East Asian Tertiary Hospital. AB - PURPOSE: Due to the anatomical differences between the Asian and non-Asian eyelid, the authors hypothesize a different spectrum of eyelid margin malposition conditions seen in Singapore as compared with a predominant Caucasian population. The purpose of the study is to describe the spectrum of eyelid margin malpositions that were operated in a South-East Asian Tertiary Hospital. METHODS: Retrospective study involving all patients who required surgery for eyelid margin malpositions over a 2-year period. The etiology and ethnic spread of patients were analyzed for each eyelid margin malposition. RESULTS: A total of 249 eyelids (144 patients) were analyzed. There were 127 Chinese (88.2%), 8 Malays (5.6%), 6 Indians (4.2%), 2 Indonesians (1.4%), and 1 Korean (0.7%). Epiblepharon (53.4%) was the commonest surgery performed, followed by entropion (25.7%) and ectropion (20.9%). Among patients with epiblepharon and entropion, Chinese patients formed the overwhelming majority (>95%). There were no Eurasians or Indians who presented with epiblepharon or entropion. Among patients with ectropion, there was a higher representation of Indian patients (16.7%). CONCLUSIONS: This study shows that the spectrum of eyelid margin malpositions in Singapore is unique and that developmental epiblepharon remains the commonest eyelid margin malposition requiring surgery. In terms of involutional eyelid margin malpositions, entropion is more common than ectropion, especially among the Chinese. The similarity in terms of eyelid involvement and ethnic distribution of both epiblepharon and involutional entropion suggests that there is a common factor in both these conditions, which the authors infer is due to the unique anatomy of the Asian eyelid. PMID- 26237533 TI - AtTCTP2 mRNA and protein movement correlates with formation of adventitious roots in tobacco. AB - The Translationally Controlled Tumor Proteins, or TCTP, is a superfamily of exclusively eukaryotic proteins essential in the regulation of proliferation and general growth. However, it is clear that these are multifunctional proteins given (1) the pleiotropic effects of its mutations, and (2), the multiple processes in which this protein is involved. TCTP function in general is conserved, since Arabidopsis AtTCTP1 can rescue a Drosophila mutant, and vice versa. It has become clear, however, that these proteins may have "taxon specific" functions. In the case of plants, mRNA and/or proteins have been found in the phloem translocation stream of different species, suggesting a role in long-distance signaling. We have found that a second Arabidopsis TCTP gene, AtTCTP2, codes for a protein that moves long-distance through a graft union in tobacco. Interestingly, the mRNA is also transported long-distance. Both mRNA and protein move long-distance; interestingly, the movement, while more efficient from source to sink tissues, also occurs in the opposite direction. The protein reaches the nuclei of parenchyma cells and adventitious roots. Furthermore, it is clear that the long-distance delivery of AtTCTP2 protein and mRNA is required for the induction of adventitious roots. A model is presented that accounts for these observations. PMID- 26237534 TI - Matching Nanoantenna Field Confinement to FRET Distances Enhances Forster Energy Transfer Rates. AB - Forster resonance energy transfer (FRET) is widely applied in chemistry, biology, and nanosciences to assess distances on sub-10 nm scale. Extending the range and applicability of FRET requires enhancement of the fluorescence energy transfer at a spatial scale comparable to the donor-acceptor distances. Plasmonic nanoantennas are ideal to concentrate optical fields at a nanoscale fully matching the FRET distance range. Here, we present a resonant aluminum nanogap antenna tailored to enhance single molecule FRET. A 20 nm gap confines light into a nanoscale volume, providing a field gradient on the scale of the donor-acceptor distance, a large 10-fold increase in the local density of optical states, and strong intensity enhancement. With our dedicated design, we obtain 20-fold enhancement on the fluorescence emission of donor and acceptor dyes, and most importantly up to 5-fold enhancement of the FRET rate for donor-acceptor separations of 10 nm. We also provide a thorough framework of the fluorescence photophysics occurring in the nanoscale gap volume. The presented enhancement of energy transfer flow at the nanoscale opens a yet unexplored facet of the various advantages of optical nanoantennas and provides a new strategy toward biological applications of single molecule FRET at micromolar concentrations. PMID- 26237535 TI - Compromised responses to dietary methionine restriction in adipose tissue but not liver of ob/ob mice. AB - OBJECTIVE: Dietary methionine restriction (MR) reduces adiposity and hepatic lipids and increases overall insulin sensitivity in part by reducing lipogenic gene expression in liver, inducing browning of white adipose tissue (WAT), and enhancing the lipogenic and oxidative capacity of the remodeled WAT. METHODS: Ob/ob mice have compromised beta-adrenergic receptor expression in adipose tissue and were used to test whether MR could ameliorate obesity, insulin resistance, and disordered lipid metabolism. RESULTS: In contrast to responses in wild-type mice, MR failed to slow accumulation of adiposity, increase lipogenic and thermogenic gene expression in adipose tissue, reduce serum insulin, or increase serum adiponectin in ob/ob mice. However, MR produced comparable reductions in hepatic lipids and lipogenic gene expression in both genotypes. In addition, MR was fully effective in increasing insulin sensitivity in adiponectin(-/-) mice. CONCLUSIONS: These findings show that diet-induced changes in hepatic lipid metabolism are independent of weight loss and remodeling of WAT and are not required for insulin sensitization. In contrast, the failure of ob/ob mice to mount a normal thermogenic response to MR suggests that the compromised responsiveness of adipose tissue to SNS input is an important component of the inability of the diet to correct their obesity and insulin resistance. PMID- 26237536 TI - The "Speedy" Synthesis of Atom-Specific (15)N Imino/Amido-Labeled RNA. AB - Although numerous reports on the synthesis of atom-specific (15)N-labeled nucleosides exist, fast and facile access to the corresponding phosphoramidites for RNA solid-phase synthesis is still lacking. This situation represents a severe bottleneck for NMR spectroscopic investigations on functional RNAs. Here, we present optimized procedures to speed up the synthesis of (15)N(1) adenosine and (15)N(1) guanosine amidites, which are the much needed counterparts of the more straightforward-to-achieve (15)N(3) uridine and (15)N(3) cytidine amidites in order to tap full potential of (1)H/(15)N/(15)N-COSY experiments for directly monitoring individual Watson-Crick base pairs in RNA. Demonstrated for two preQ1 riboswitch systems, we exemplify a versatile concept for individual base-pair labeling in the analysis of conformationally flexible RNAs when competing structures and conformational dynamics are encountered. PMID- 26237537 TI - Cinnamon extract improves the body composition and attenuates lipogenic processes in the liver and adipose tissue of rats. AB - In models of metabolic disorders, cinnamon improves glucose and lipid metabolism. This study explores the effect of chronic supplementation with aqueous cinnamon extract (CE) on the lipid metabolism of rats. Male adult Wistar rats were separated into a control group (CTR) receiving water and a CE Group receiving aqueous cinnamon extract (400 mg of cinnamon per kg body mass per day) by gavage for 25 consecutive days. Cinnamon supplementation did not change the food intake or the serum lipid profile but promoted the following changes: lower body mass gain (P = 0.008), lower relative mass of white adipose tissue (WAT) compartments (P = 0.045) and higher protein content (percentage of the carcass) (P = 0.049). The CE group showed lower leptin mRNA expression in the WAT (P = 0.0017) and an important tendency for reduced serum leptin levels (P = 0.059). Cinnamon supplementation induced lower mRNA expression of SREBP1c (sterol regulatory element-binding protein 1c) in the WAT (P = 0.001) and liver (P = 0.013) and lower mRNA expression of SREBP2 (P = 0.002), HMGCoA reductase (3-hydroxy-3 methylglutaryl-CoA reductase) (P = 0.0003), ACAT1 (acetyl-CoA acetyltransferase 1) (P = 0.032) and DGAT2 (diacylglycerol O-acyltransferase 2) (P = 0.03) in the liver. These changes could be associated with the reduced esterified cholesterol and triacylglycerol content detected in this tissue. Our results suggest that chronic ingestion of aqueous cinnamon extract attenuates lipogenic processes, regulating the expression of key enzymes and transcriptional factors and their target genes, which are directly involved in lipogenesis. These molecular changes possibly promote adaptations that would prevent an increase in circulating cholesterol and triacylglycerol levels and prevent lipid accumulation in tissues, such as liver and WAT. Therefore, we speculate that cinnamon may also be useful for preventing or retarding the development of lipid disorders. PMID- 26237538 TI - The Effect of Compression Ratio, Fuel Octane Rating, and Ethanol Content on Spark Ignition Engine Efficiency. AB - Light-duty vehicles (LDVs) in the United States and elsewhere are required to meet increasingly challenging regulations on fuel economy and greenhouse gas (GHG) emissions as well as criteria pollutant emissions. New vehicle trends to improve efficiency include higher compression ratio, downsizing, turbocharging, downspeeding, and hybridization, each involving greater operation of spark ignited (SI) engines under higher-load, knock-limited conditions. Higher octane ratings for regular-grade gasoline (with greater knock resistance) are an enabler for these technologies. This literature review discusses both fuel and engine factors affecting knock resistance and their contribution to higher engine efficiency and lower tailpipe CO2 emissions. Increasing compression ratios for future SI engines would be the primary response to a significant increase in fuel octane ratings. Existing LDVs would see more advanced spark timing and more efficient combustion phasing. Higher ethanol content is one available option for increasing the octane ratings of gasoline and would provide additional engine efficiency benefits for part and full load operation. An empirical calculation method is provided that allows estimation of expected vehicle efficiency, volumetric fuel economy, and CO2 emission benefits for future LDVs through higher compression ratios for different assumptions on fuel properties and engine types. Accurate "tank-to-wheel" estimates of this type are necessary for "well-to-wheel" analyses of increased gasoline octane ratings in the context of light duty vehicle transportation. PMID- 26237539 TI - Julian Martin. Abstracting the shape. PMID- 26237541 TI - Effect of Temperature on the Shear-Thickening Behavior of Fumed Silica Suspensions. AB - Shear-thickening fluids (STFs) can be subjected to a significant temperature variation in many applications. Polymeric or oligomeric fluids are commonly used as suspending media for STFs. Because the viscosities of polymeric fluids are strongly temperature-dependent, large temperature changes can profoundly affect the shear-thickening responses. Here, the effect of temperature on the shear thickening behavior of four low-molecular-weight polymeric glycols/fumed silica suspensions is reported. The dispersed-phase volume fraction, its surface chemistry, and the chemical compositions of the suspending media were varied. These factors influence the viscosity and the interactions between the suspended particles and the suspending media. Fumed silica particles with two different silanol-group surface densities were suspended in the polymeric glycols, where these silanol surface groups formed hydrogen bonds with the suspending media's glycols and internal oxygen atoms. Steady-shear experiments were performed over a temperature range spanning approximately 100 degrees C. The critical shear rate for the onset of shear thickening decreased with decreasing temperature. The critical shear rates were inversely proportional to the viscosity of the pure suspending media over these same temperature ranges. The response of STFs to varying both the temperature and shear rate investigated here will help to design application-specific STFs. Mitigation of a hypervelocity (6.81 km/s) impact on an aluminum facesheet sandwich composite filled with one of these STFs was demonstrated. PMID- 26237542 TI - Parental experiences of racial discrimination and youth racial socialization in two-parent African American families. AB - OBJECTIVES: Parents experiencing racial discrimination are likely to transmit racial socialization messages to their children to protect them from future injustices. This study was conducted to better understand the role of parents' racial discrimination in their racial socialization practices for 2-parent African American families. METHOD: Using a sample from the Promoting Strong African American Families (N = 322 couples) program, we examined the effects of experienced discrimination on one's own and one's partner's racial socialization practices with male (n = 154) and female (n = 168) offspring. RESULTS: Multiple group actor-partner interdependence models showed that racial discrimination was associated with racial socialization practices. In addition, maternal experiences of discrimination had stronger relations to socialization messages relayed to daughters and greater paternal experiences of discrimination had stronger relations to socialization messages given to sons. CONCLUSIONS: This study demonstrates variability in how male and female children in African American families are socialized as a result of their parents' experiences with racial discrimination. PMID- 26237540 TI - Unsaturated fatty acids as high-affinity ligands of the C-terminal Per-ARNT-Sim domain from the Hypoxia-inducible factor 3alpha. AB - Hypoxia-inducible transcription factors (HIF) form heterodimeric complexes that mediate cell responses to hypoxia. The oxygen-dependent stability and activity of the HIF-alpha subunits is traditionally associated to post-translational modifications such as hydroxylation, acetylation, ubiquitination, and phosphorylation. Here we report novel evidence showing that unsaturated fatty acids are naturally occurring, non-covalent structural ligands of HIF-3alpha, thus providing the initial framework for exploring its exceptional role as a lipid sensor under hypoxia. PMID- 26237543 TI - Father involvement in Mexican-origin families: Preliminary development of a culturally informed measure. AB - OBJECTIVES: An increasing body of research has documented the significant influence of father involvement on children's development and overall well-being. However, extant research has predominately focused on middle-class Caucasian samples with little examination of fathering in ethnic minority and low-income families, particularly during the infancy period. The present study evaluated measures of early father involvement (paternal engagement, accessibility, and responsibility) that were adapted to capture important cultural values relevant to the paternal role in Mexican-origin families. METHODS: A sample of 180 Mexican origin mothers (M age = 28.3) and 83 Mexican-origin fathers (M age = 31.5) were interviewed during the perinatal period. RESULTS: Descriptive analyses indicated that Mexican-origin fathers are involved in meaningful levels of direct interaction with their infant. A 2-factor model of paternal responsibility was supported by factor analyses, consisting of a behavioral responsibility factor aligned with previous literature and culturally derived positive machismo factor. Qualities of the romantic relationship, cultural orientation, and maternal employment status were related to indices of father involvement. CONCLUSIONS: These preliminary results contribute to understanding of the transition to fatherhood among low-income Mexican-origin men and bring attention to the demographic, social, and cultural contexts in which varying levels of father involvement may emerge. PMID- 26237544 TI - Finding the door: Critical incidents facilitating gang exit among indigenous men. AB - OBJECTIVE: Our aim was to generate a categorical scheme to describe how participants exited from gang life. METHOD: We utilized the CIT (Butterfield, Borgen, Amundson, & Maglio, 2005; Flanagan, 1954; Woolsey, 1986) and explored gang exit processes among 10 Indigenous men living in Manitoba and Saskatchewan, Canada. Participants responded to the question: What facilitated gang exit for you? RESULTS: They provided 136 critical incidents that were organized into 13 categories of behaviors and experiences that facilitated their exit from gang life: (a) working in the legal workforce, (b) accepting support from family or girlfriend, (c) helping others stay out of gang life, (d) not wanting to go back to jail, (e) accepting responsibility for family, (f) accepting guidance and protection, (g) participating in ceremony, (h) avoiding alcohol, (i) publically expressing that you were out of the gang, (j) wanting legit relationships outside gangs, (k) experiencing a native brotherhood, (l) stopping self from reacting like a gangster, and (m) acknowledging the drawbacks of gang violence. CONCLUSION: The categorical scheme is presented, described with use of extensive quotes from this research, theoretical and clinical implications are discussed, and suggestions for future research are offered. (PsycINFO Database Record PMID- 26237545 TI - A systems biology approach for diagnostic and vaccine antigen discovery in tropical infectious diseases. AB - PURPOSE OF REVIEW: There is a need for improved diagnosis and for more rapidly assessing the presence, prevalence, and spread of newly emerging or reemerging infectious diseases. An approach to the pathogen-detection strategy is based on analyzing host immune response to the infection. This review focuses on a protein microarray approach for this purpose. RECENT FINDINGS: Here we take a protein microarray approach to profile the humoral immune response to numerous infectious agents, and to identify the complete antibody repertoire associated with each disease. The results of these studies lead to the identification of diagnostic markers and potential subunit vaccine candidates. These results from over 30 different organisms can also provide information about common trends in the humoral immune response. SUMMARY: This review describes the implications of the findings for clinical practice or research. A systems biology approach to identify the antibody repertoire associated with infectious diseases challenge using protein microarray has become a powerful method in identifying diagnostic markers and potential subunit vaccine candidates, and moreover, in providing information on proteomic feature (functional and physically properties) of seroreactive and serodiagnostic antigens. Combining the detection of the pathogen with a comprehensive assessment of the host immune response will provide a new understanding of the correlations between specific causative agents, the host response, and the clinical manifestations of the disease. PMID- 26237547 TI - The intestinal microbiome and health. AB - PURPOSE OF REVIEW: A diverse array of microbes colonizes the human intestine. In this review, we seek to outline the current state of knowledge on what characterizes a 'healthy' or 'normal' intestinal microbiome, what factors modify the intestinal microbiome in the healthy state and how the intestinal microbiome affects normal host physiology. RECENT FINDINGS: What constitutes a 'normal' or 'healthy' intestinal microbiome is an area of active research, but key characteristics may include diversity, richness and a microbial community's resilience and ability to resist change. A number of factors, including age, the host immune system, host genetics, diet and antibiotic use, appear to modify the intestinal microbiome in the normal state. New research shows that the microbiome likely plays a critical role in the healthy human immune system and metabolism. SUMMARY: It is clear that there is a complicated bidirectional relationship between the intestinal microbiota and host which is vital to health. An enhanced understanding of this relationship will be critical not only to maximize and maintain human health but also to shape our understanding of disease and to foster new therapeutic approaches. PMID- 26237546 TI - Tropical and travel-associated norovirus: current concepts. AB - PURPOSE OF REVIEW: We highlight recent advances relevant to understanding norovirus infections in the tropics, both in populations living in developing settings and travelers to these regions. RECENT FINDINGS: Because of the decrease in diarrheal disease associated with the global rollout of vaccines against rotavirus, norovirus is emerging as the predominant cause of diarrhea morbidity among children in the tropics, and evidence suggests that it contributes to adult disease in endemic populations and travelers. In addition to identifying potential target populations for preventive measures, we provide an update on norovirus vaccine development and concepts related to their implementation in low income and middle-income countries. SUMMARY: These current concepts related to norovirus-attributable disease burden, clinical significance, and economic impact can potentially be applied to tailoring efforts to prevent and mitigate the effects of this important enteropathogen. PMID- 26237548 TI - Antibiotics, microbiota and health: are there dangers hiding in plain sight? PMID- 26237549 TI - Understanding artemisinin-resistant malaria: what a difference a year makes. AB - PURPOSE OF REVIEW: The emergence of artemisinin resistance in Southeast Asia (SEA), where artemisinin combination therapies (ACTs) are beginning to fail, threatens global endeavors to control and eliminate Plasmodium falciparum malaria. Future efforts to prevent the spread of this calamity to Africa will benefit from last year's tremendous progress in understanding artemisinin resistance. RECENT FINDINGS: Multiple international collaborations have established that artemisinin resistance is associated with slow parasite clearance in patients, increased survival of early-ring-stage parasites in vitro, single-nucleotide polymorphisms (SNPs) in the parasite's kelch protein gene (K13), parasite 'founder' populations sharing a genetic background of four additional SNPs, parasite transcriptional profiles reflecting an 'unfolded protein response' and decelerated parasite development, and elevated parasite phosphatidylinositol-3-kinase activity. In Western Cambodia, where the K13 C580Y mutation is approaching fixation, the frontline ACT is failing to cure nearly half of patients, likely due to partner drug resistance. In Africa, where dozens of K13 mutations have been detected at low frequency, there is no evidence yet of artemisinin resistance. SUMMARY: In SEA, clinical and epidemiological investigations are urgently needed to stop the further spread of artemisinin resistance, monitor the efficacy of ACTs where K13 mutations are prevalent, identify currently-available drug regimens that cure ACT failures, and rapidly advance new antimalarial compounds through preclinical studies and clinical trials. PMID- 26237550 TI - Aire controls gene expression in the thymic epithelium with ordered stochasticity. AB - The transcription factor Aire controls immunological tolerance by inducing the ectopic thymic expression of many tissue-specific genes, acting broadly by removing stops on the transcriptional machinery. To better understand Aire's specificity, we performed single-cell RNA-seq and DNA-methylation analysis of Aire-sufficient and Aire-deficient medullary epithelial cells (mTECs). Each of Aire's target genes was induced in only a minority of mTECs, independently of DNA methylation patterns, as small inter-chromosomal gene clusters activated in concert in a proportion of mTECs. These microclusters differed between individual mice. Thus, our results suggest an organization of the DNA or of the epigenome that results from stochastic determinism but is 'bookmarked' and stable through mTEC divisions, which ensures more effective presentation of self antigens and favors diversity of self-tolerance between individuals. PMID- 26237551 TI - Commensal bacteria direct selective cargo sorting to promote symbiosis. AB - Mucosal immunity protects a host from intestinal inflammation and infection and is profoundly influenced by symbiotic bacteria. Here we report that in mice symbiotic bacteria directed selective cargo sorting in Paneth cells to promote symbiosis through Nod2, a cytosolic bacterial sensor, and the multifunctional protein kinase LRRK2, both encoded by inflammatory bowel disease (IBD)-associated genes. Commensals recruited Nod2 onto lysozyme-containing dense core vesicles (DCVs), which was required for DCV localization of LRRK2 and a small GTPase, Rab2a. Deficiency of Nod2, LRRK2 or Rab2a or depletion of commensals resulted in lysosomal degradation of lysozyme. Thus, commensal bacteria and host factors orchestrate the lysozyme-sorting process to protect the host from enteric infection, implicating Paneth cell dysfunction in IBD pathogenesis. PMID- 26237552 TI - T cell receptor dwell times control the kinase activity of Zap70. AB - Kinase recruitment to membrane receptors is essential for signal transduction. However, the underlying regulatory mechanisms are poorly understood. We investigated how conformational changes control T cell receptor (TCR) association and activity of the kinase Zap70. Structural analysis showed that TCR binding or phosphorylation of Zap70 triggers a transition from a closed, autoinhibited conformation to an open conformation. Using Zap70 mutants with defined conformations, we found that TCR dwell times controlled Zap70 activity. The closed conformation minimized TCR dwell times and thereby prevented activation by membrane-associated kinases. Parallel recruitment of coreceptor-associated Lck kinase to the TCR ensured Zap70 phosphorylation and stabilized Zap70 TCR binding. Our study suggests that the dynamics of cytosolic enzyme recruitment to the plasma membrane regulate the activity and function of receptors lacking intrinsic catalytic activity. PMID- 26237554 TI - Antihypertensive drug use and risk of cognitive decline in the very old: an observational study - the Newcastle 85+ Study. AB - OBJECTIVES: Older adults are a fast growing group in society and are at high risk of hypertension, cognitive decline and dementia. Antihypertensive drugs, particularly calcium channel blockers (CCB), have been associated with a decreased risk of cognitive decline and dementia. We used observational data to examine the association between antihypertensive drug class and change in cognitive function. METHODS: The Newcastle 85+ Study is a population-based cohort study recruiting individuals aged 85 (born in 1921) via general/family practices in Newcastle/North Tyneside, United Kingdom. Data, including blood pressure, antihypertensive drug use and cognitive function [assessed using the Standardized Mini-Mental State Exam (SMMSE)], were collected at baseline and 3-year follow-up. RESULTS: The study population comprised 238 participants with a diagnosis of hypertension, prescribed antihypertensive drug treatment and with baseline and follow-up SMMSE assessment. There was an association between CCB use and less cognitive decline over 3 years (rate of decline was lower by 1.29 SMMSE points (95% confidence interval 0.16-2.42; P = 0.03) compared with those taking other antihypertensive classes after adjustment for age, sex, years of education, baseline SMMSE score, smoking, BMI, baseline blood pressure, and incident cerebrovascular event. This finding was even stronger in the cognitively intact (SMMSE >24), wherein rate of cognitive decline was lower by 1.33 SMMSE points (95% confidence interval 0.30-2.37; P = 0.01), but was not seen for other antihypertensive classes. CONCLUSION: Findings provide support for an association between CCB use and a lower rate of cognitive decline in very old adults with hypertension. PMID- 26237553 TI - Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells. AB - Expression of tissue-restricted self antigens (TRAs) in medullary thymic epithelial cells (mTECs) is essential for the induction of self-tolerance and prevents autoimmunity, with each TRA being expressed in only a few mTECs. How this process is regulated in single mTECs and is coordinated at the population level, such that the varied single-cell patterns add up to faithfully represent TRAs, is poorly understood. Here we used single-cell RNA sequencing and obtained evidence of numerous recurring TRA-co-expression patterns, each present in only a subset of mTECs. Co-expressed genes clustered in the genome and showed enhanced chromatin accessibility. Our findings characterize TRA expression in mTECs as a coordinated process that might involve local remodeling of chromatin and thus ensures a comprehensive representation of the immunological self. PMID- 26237555 TI - Plasma proteomics classifiers improve risk prediction for renal disease in patients with hypertension or type 2 diabetes. AB - OBJECTIVE: Micro and macroalbuminuria are strong risk factors for progression of nephropathy in patients with hypertension or type 2 diabetes. Early detection of progression to micro and macroalbuminuria may facilitate prevention and treatment of renal diseases. We aimed to develop plasma proteomics classifiers to predict the development of micro or macroalbuminuria in hypertension or type 2 diabetes. METHODS: Patients with hypertension (n = 125) and type 2 diabetes (n = 82) were selected for this case-control study from the Prevention of REnal and Vascular ENd-stage Disease cohort and the Steno Diabetes Center. Cases transitioned from normo to microalbuminuria, or from micro to macroalbuminuria. Controls, matched for age, sex, and baseline albuminuria stage, did not transition. Follow-up was 3.0 +/- 0.9 years. Plasma proteomics profiles were measured by liquid chromatography-electrospray-trap mass-spectrometry. Classifiers were developed and cross-validated for prediction of transition in albuminuria stage. Improvement in risk prediction was tested on top of a reference model of baseline albuminuria, estimated glomerular filtration rate, and renin-angiotensin aldosterone system intervention. RESULTS: In hypertensive patients, the classifier improved risk prediction for transition in albuminuria stage on top of the reference model (C-index from 0.69 to 0.78; P < 0.01). In type 2 diabetes, the classifier improved risk prediction for transition from micro to macroalbuminuria (C-index from 0.73 to 0.80; P = 0.04). In both diseases, the identified peptides were linked to pathways recognized to contribute to nephropathy, including fibrosis, inflammation, angiogenesis, and mineral metabolism. CONCLUSIONS: Plasma proteomics predict the transition in albuminuria stage beyond established renal risk markers in hypertension or type 2 diabetes. External validation is needed to assess reproducibility. PMID- 26237556 TI - Blood pressure variability and the development of early neurological deterioration following acute ischemic stroke. AB - OBJECTIVES: Early neurological deterioration (END) is a common condition associated with poor outcome after acute ischemic stroke. We studied association between blood pressure (BP) variability and development of END. METHODS: In this retrospective observational study, we studied a consecutive series of patients hospitalized for acute ischemic stroke within 24 h of onset. The primary outcome of interest was the development of END according to predefined criteria within the first 72 h of stroke onset. During this period, the mean, maximum (max), and minimum (min) values for the SBP and DBP were measured. The following parameters of BP variability were calculated for the SBP and DBP: the difference between the maximum and minimum (max-min), the SD, and the coefficient of variation. RESULTS: Of the 1161 patients enrolled in the study (mean age, 67.5 +/- 13.3 years; 59.6% men), 210 (18.1%) developed END. All of the BP variability parameters were linearly associated with END independent of mean BP and potential clinical variables (P values < 0.05 on likelihood ratio tests for trend), except for SBPmax-min. Among the other BP parameters, SBPmean, SBPmax, DBPmax, and DBPmin were independently associated with END. After adjustments for potential confounders, the odds for END increased 14-21% with each increase of one standard deviation in the BP variability parameter. CONCLUSION: BP variability is independently and linearly associated with the development of neurologic deterioration in acute stage of ischemic stroke. PMID- 26237557 TI - Reflected rather than forward wave pressures account for brachial pressure independent relations between aortic pressure and end-organ changes in an African community. AB - AIMS: To determine whether brachial blood pressure (BP)-independent relations between aortic pressure and cardiovascular damage are better explained by reflected (backward) (Pb) or forward (Pf) wave pressure effects. METHODS: In 1174 participants from a community of African ancestry, we assessed central aortic pulse pressure (PPc), Pb, and Pf (radial applanation tonometry, SphygmoCor) as well as left ventricular mass index (LVMI) (n = 786), aortic pulse wave velocity (PWV) (n = 1019), carotid intima-media thickness (IMT) (n = 578), transmitral early-to-late left ventricular diastolic velocity (E/A) (n = 779) and estimated glomerular filtration rate (eGFR) (n = 1174). RESULTS: Independent of mean arterial pressure and confounders, PPc, and both Pb and Pf were associated with end-organ measures or damage (P < 0.05 to P < 0.0001). With adjustments for brachial PP and confounders, Pb remained directly associated with LVMI (partial r = 0.09, P < 0.01), PWV (partial r = 0.28, P < 0.0001), and IMT (partial r = 0.28, P < 0.0001), and inversely associated with E/A (partial r = -0.31, P < 0.0001) and eGFR (partial r = -0.14, P < 0.0001). Similar relations were noted with the presence of end-organ damage (P < 0.05 to P < 0.0001). In contrast, with adjustments for brachial PP and confounders, Pf no longer retained direct relations with LVMI, PWV, and IMT or inverse relations with E/A and eGFR. Adjustments for Pb, but not Pf, diminished brachial PP-independent relationships between PPc and end-organ measures. Independent relations between Pb, but not Pf and end-organ measures, were largely attributed to Pb accounting for most of the variation in brachial-to-aortic PP amplification. CONCLUSIONS: In communities of African ancestry, brachial BP-independent relations between aortic pressure and end-organ changes are largely attributed to an impact of reflected rather than forward wave pressures. PMID- 26237558 TI - Carotid flow velocity/diameter ratio is a predictor of cardiovascular events in hypertensive patients. AB - OBJECTIVE: The aim of this study was to evaluate the performance of common carotid artery diameter, flow velocity and flow velocity/artery diameter ratio as predictors of major adverse cardiovascular events (MACEs) in a sample of hypertensive patients. METHODS: A cohort of 403 hypertensive patients was followed up for a median of 1260 (714) days, and 27 suffered MACEs. At baseline, participants were evaluated by clinical, laboratory, echocardiographic and carotid ultrasound analysis. RESULTS: Patients with peak-systolic flow velocity (sFV) less than the median value and systolic artery diameter (sAD) greater than the median value presented the worst clinical outcome compared to those with isolated sFV less than the median value or sAD greater than the median value, suggesting an additive effect of these two variables. Further, Kaplan-Meier analysis demonstrated worse outcome for individuals with sFV/sAD ratio less than 85.7/s (optimal cut-off point obtained by receiver-operating characteristic analysis) compared to those with higher sFV/sAD values (log-rank test: P < 0.0001). In stepwise multivariable Cox-regression analyses, sFV/sAD was significantly associated with MACEs (P < 0.001), whereas carotid intima-media thickness and clinically defined high cardiovascular risk did not. Furthermore, area under the receiver-operating characteristic curve for sFV/sAD was higher than that for Framingham risk score (0.77 versus 0.64; P = 0.045), whereas adding sFV/sAD to the Framingham risk factors resulted in increased net reclassification improvement (P = 0.041) and integrated discrimination improvement (P < 0.001). CONCLUSIONS: Lower carotid sFV/sAD was associated with MACEs in hypertensive patients independent of cardiovascular prediction models and carotid intima-media thickness. These findings suggest that this index may be a promising approach to identify hypertensive subjects at increased risk for future cardiovascular events. PMID- 26237559 TI - Prevalence and factors related to inappropriately high left ventricular mass in patients with rheumatoid arthritis without overt cardiac disease. AB - OBJECTIVES: Due to the chronic inflammatory status, specific neuro-hormones and progression of arterial stiffness, patients with rheumatoid arthritis (RA) are exposed to the development of excessive left ventricular mass disproportionate to the need to compensate left ventricular load. This condition, named inappropriately high left ventricular mass (iLVM), is associated with unfavorable prognosis in patients with hypertension, aortic stenosis or diabetes. In this study, we assessed prevalence and factors associated with iLVM in a large cohort of patients with RA and tested the hypothesis that RA per se is a condition related to iLVM. METHODS: We prospectively analyzed 235 RA patients without overt cardiac disease recruited between January and December 2014, who were compared with 235 controls matched for age, sex, BMI, prevalence of hypertension and diabetes. iLVM was defined as measured/predicted LVM ratio above 123%. LVM was predicted in each individual by using a simple equation considering height, sex and left ventricular work. RESULTS: iLVM was detected in 150 RA patients (64%) and in 30 controls (15%; P < 0.001). In patients with RA, the variables independently associated with iLVM emerged by multivariate logistic regression analysis were left ventricular systolic dysfunction measured as mid-wall shortening and concentric left ventricular geometry. Considering both groups of patients with RA and matched controls, RA was the strongest variable related to iLVM (odds ratio 3.37, 95% confidence interval 1.37-8.31, P = 0.008). CONCLUSIONS: Two-thirds of patients with RA without overt cardiac disease have iLVM, which is associated with left ventricular systolic dysfunction and concentric geometry. RA per se is a condition closely related to iLVM. PMID- 26237560 TI - Real-world evidence of suboptimal blood pressure control in patients with type 2 diabetes. AB - AIMS: In order to eventually improve blood pressure (BP) management, the aim of this study was to identify subgroups of type 2 diabetes mellitus (T2DM) patients with distinct trajectories of SBP levels. Identifying subgroups with distinct SBP trajectories helps to better understand the course of SBP levels in T2DM patients and its associated consequences. Subgroup characteristics were determined and the prevalence of complications and mortality rates over time in the different subgroups was investigated. METHODS: Five thousand, seven hundred and eleven T2DM patients with at least two SBP follow-up measurements were selected from a prospective T2DM cohort of 9849 T2DM patients. The mean follow-up period was 5.7 years (range 2-9 years). Latent Class Growth Modeling, as currently the most flexible cluster analysis available, was performed to identify subgroups of patients with distinct SBP trajectories. Subgroup characteristics were determined by multinomial logistic regression analyses. RESULTS: Four subgroups with distinct SBP trajectories were identified. The largest subgroup (85.6%) showed adequate SBP control (at or around 140 mmHg) over time. The second subgroup (5.6%) were hypertensive in the first years, responded slowly to BP management and eventually reached SBP control. The third subgroup (3.4%) showed deteriorating hypertension during the first 4 years, then showed insufficient response to BP management. The fourth subgroup (5.4%) showed deteriorating hypertension over time. Patients within subgroups 2-4 were significantly older, comprised more women, used more antihypertensive medication and had a higher prevalence of retinopathy, microalbuminuria and cardiovascular disease (CVD) mortality. CONCLUSION: More than 85% reached and maintained adequate SBP control. Subgroups with a more unfavourable course of SBP control also showed higher rates of microvascular complications and CVD mortality over time. This study identified important subgroups to target in order to improve BP management in T2DM patients. PMID- 26237561 TI - Angiotensin receptor blockers are not associated with reduced inflammatory markers in the general population. AB - OBJECTIVE: Angiotensin receptor blockers (ARBs) have been suggested to reduce inflammation in randomized controlled trials. We assessed the association between ARBs and inflammatory markers in a general population setting. METHODS: This is a population-based prospective study conducted in Lausanne, Switzerland. Baseline data from 933 participants on antihypertensive drugs (424 on ARBs) was collected in 2003-2006. Follow-up data from 1120 participants (572 on ARBs) was collected in 2009-2012. C-reactive protein (CRP), interleukins 1beta and 6 and tumor necrosis factor alpha (TNF-alpha) were assessed and categorized in quartiles. RESULTS: At baseline, no differences were found between participants taking or not taking ARBs for all inflammatory markers studied, and this association persisted after multivariate adjustment: odds ratios (ORs) and (95% confidence interval) for being in the highest quartile of interleukin-1beta, interleukin-6, TNF-alpha and CRP for participants on ARB compared to participants not on ARB were 1.23 (0.89-1.70), 1.26 (0.93-1.70), 1.14 (0.85-1.53) and 1.27 (0.96-1.69) respectively (P > 0.05). These findings were further replicated in the follow-up study: OR and (95% CI) of 1.10 (0.78-1.55), 0.87 (0.64-1.19), 0.83 (0.61-1.14) and 0.91 (0.68-1.22) for interleukin-1beta, interleukin-6, TNF-alpha and CRP respectively (P > 0.05). Finally, no effect of ARBs was found when comparing participants who received ARBs throughout the 5.4-year follow-up with participants on other antihypertensive drugs: OR and (95% CI) of 0.93 (0.61 1.42), 0.80 (0.54-1.17), 0.86 (0.59-1.25) and 0.95 (0.67-1.35) for interleukin 1beta, interleukin-6, TNF-alpha and CRP respectively (P > 0.05). CONCLUSION: ARBs are not associated with reduced levels of inflammatory markers in the general population. PMID- 26237562 TI - Long-term intake of animal flesh and risk of developing hypertension in three prospective cohort studies. AB - OBJECTIVE: Prospective data are scarce on the relation of red meat, seafood, and poultry consumption with hypertension risk. Although red and processed meats are generally considered to have adverse cardiovascular consequences, seafood is believed to be protective and poultry's effect is controversial. METHODS: We prospectively examined the independent association of long-term intake of animal flesh with incident hypertension in three longitudinal cohort studies of nonhypertensive individuals: Nurses' Health Study (NHS, n = 62 273 women), Nurses' Health Study II (NHS II, n = 88 831 women), and Health Professionals Follow-Up Study (HPFS, n = 37 414 men). We used multivariable Cox proportional hazards regression to study the associations of different types of animal flesh with the risk of developing hypertension while controlling for other hypertension risk factors. We then used fixed-effects meta-analysis to derive pooled estimates of effect. RESULTS: Compared with participants whose consumption was less than 1 serving/month, the pooled hazard ratios among those whose intake was at least 1 serving/day were 1.30 (95% confidence interval 1.23-1.39) for total meat (a combination of processed and unprocessed red meat), 1.22 (1.12-1.34) for poultry, and 1.05 (0.98-1.13) for seafood. Seafood was associated with an increased risk of hypertension in HPFS and NHS II, but not NHS. Consumption of any animal flesh at least 1 serving/day was associated with an increased hypertension risk [pooled hazard ratio = 1.30 (1.16-1.47)]. CONCLUSION: Long-term intake of meat and poultry were associated with increased risk of hypertension. In contrast to our hypothesis, we found a weak but significant trend toward an increased risk of hypertension with increasing seafood consumption. PMID- 26237563 TI - Hypertension and chronic kidney disease: respective contribution of mean and pulse pressure and arterial stiffness. AB - Hypertension (HTN) in chronic kidney disease (CKD) is influenced by blood pressure (BP) and the progression of CKD, including hemodialysis and renal transplantation. To date, the efficacy of antihypertensive drug strategies has chiefly been assessed by measuring steady-state systolic, diastolic and mean arterial pressures (MAP). However, recently elucidated features of the BP curve have highlighted other important goals, that is, the specific roles of pulse pressure (PP), arterial stiffness, pulse wave velocity (PWV) and wave reflections as potentially deleterious factors affecting the progression of HTN and CKD. Pharmacological strategies to date have included progressive withdrawal of alpha blocking agents; efficacy of beta-blockers for coronary prevention; use of angiotensin blockade in HTN with glomerular injury, using angiotensin-converting enzyme inhibition or receptor blockade, as mono but never double-blockade, to avoid major complications; development of combination therapies with diuretics and/or calcium channel blockers. Nowadays, most clinical trials show that SBP, DBP and MAP-lowering is an effective strategy, although results no longer show preference for any specific drug class.Studies of arterial stiffness in CKD have become crucial. In older individuals, PWV is considerably elevated. The 'stiffness gradient' disappears or is inverted (normally, aortic PWV is lower than brachial PWV). Despite BP-lowering, PP is insufficiently dampened, thus promoting microcirculatory damage, progression of arterial calcifications and disturbed wave reflections, which all increase the risk of mortality. In the absence of effective hemodialysis or graft, increased arterial stiffness is therefore a major cardiovascular risk factor in CKD. PMID- 26237564 TI - RNA-protein interactions in plant disease: hackers at the dinner table. AB - Plants are the source of most of our food, whether directly or as feed for the animals we eat. Our dinner table is a trophic level we share with the microbes that also feed on the primary photosynthetic producers. Microbes that enter into close interactions with plants need to evade or suppress detection and host immunity to access nutrients. They do this by deploying molecular tools - effectors - which target host processes. The mode of action of effector proteins in these events is varied and complex. Recent data from diverse systems indicate that RNA-interacting proteins and RNA itself are delivered by eukaryotic microbes, such as fungi and oomycetes, to host plants and contribute to the establishment of successful interactions. This is evidence that pathogenic microbes can interfere with the host software. We are beginning to see that pathogenic microbes are capable of hacking into the plants' immunity programs. PMID- 26237565 TI - Distribution of gap and micromotion during compressive loading around a cementless femoral stem. PMID- 26237566 TI - Resolution enhancement in MR spectroscopy of red bone marrow fat via intermolecular double-quantum coherences. AB - High-resolution (1)H magnetic resonance spectroscopy (MRS) is generally inaccessible in red bone marrow (RBM) tissues using conventional MRS techniques. This is because signal from these tissues suffers from severe inhomogeneity in the main static B0 field originated from the intrinsic honeycomb structures in trabecular bone. One way to reduce effects of B0 field inhomogeneity is by using the intermolecular double quantum coherence (iDQC) technique, which has been shown in other systems to obtain signals insensitive to B0 field inhomogeneity. In the present study, we employed an iDQC approach to enhance the spectral resolution of RBM. The feasibility and performance of this method for achieving high resolution MRS was verified by experiments on phantoms and pig vertebral bone samples. Unsaturated fatty acid peaks which overlap in the conventional MRS were well resolved and identified in the iDQC spectrum. Quantitative comparison of fractions of three types of fatty acids was performed between iDQC spectra on the in situ RMB and conventional MRS on the extracted fat from the same RBM. Observations of unsaturated fatty acids with iDQC MRS may provide valuable information and may hold potential in diagnosis of diseases such as obesity, diabetes, and leukemia. PMID- 26237567 TI - Hemobilia Secondary to Transjugular Intrahepatic Portosystemic Shunt Procedure: A Case Report. AB - A 59 year-old woman with liver cirrhosis due to hepatitis C, complicated by refractory hepatic hydrothorax was treated with a TIPS (transjugular intrahepatic portosystemic shunt) procedure. The procedure was complicated by substantial gastrointestinal hemorrhage. EGD (esophagogastroduodenoscopy) was performed and revealed hemobilia. A hepatic angiogram was then performed revealing a fistulous tract between a branch of the hepatic artery and biliary tree. Bleeding was successfully stopped by embolization of the bleeding branch of the right hepatic artery. Hemobilia is a rare cause of upper gastrointestinal bleeding with an increasing incidence due to the widespread use of invasive hepatobiliary procedures. Hemobilia is an especially uncommon complication of TIPS procedures. We recommend that in cases of hemobilia after TIPS placement, a physician should immediately evaluate the bleeding to exclude an arterio-biliary fistula. PMID- 26237568 TI - Isolation of Undifferentiated Female Germline Cells from Adult Drosophila Ovaries. AB - This unit describes a method for isolating undifferentiated, stem cell-like germline cells from adult Drosophila ovaries. Here, we demonstrate that this population of cells can be effectively purified from hand-dissected ovaries in considerably large quantities. Tumor ovaries with expanded populations of undifferentiated germline cells are first removed from fly abdomens and dissociated into a cell suspension with the aid of protease treatment. The target cells, which express Vasa-green fluorescent protein (GFP) fusion protein under the control of the germline-specific vasa promoter, are specifically selected from the suspension via fluorescence-activated cell sorting (FACS). These protocols can be adapted to isolate other cell types from fly ovaries, such as somatic follicle cells or escort cells, by driving GFP expression in the respective target cells. PMID- 26237569 TI - In Situ Hybridization to Identify Gut Stem Cells. AB - In recent years, considerable effort has been directed toward identifying the repertoire of genes specifically expressed in adult stem cells. In this unit, we describe an in situ hybridization protocol adapted for the analysis of gene expression in the intestinal mucosa. This methodology allows researchers to quickly visualize the expression profile of putative stem cell markers with a high degree of sensitivity and resolution. PMID- 26237570 TI - Regional Cell Specific RNA Expression Profiling of FACS Isolated Drosophila Intestinal Cell Populations. AB - The adult Drosophila midgut is built of five distinct cell types, including stem cells, enteroblasts, enterocytes, enteroendocrine cells, and visceral muscles, and is divided into five major regions (R1 to R5), which are morphologically and functionally distinct from each other. This unit describes a protocol for the isolation of Drosophila intestinal cell populations for the purpose of cell type specific transcriptome profiling from the five different regions. A method to select a cell type of interest labeled with green or yellow fluorescent protein (GFP, YFP) by making use of the GAL4-UAS bipartite system and fluorescent activated cell sorting (FACS) is presented. Total RNA is isolated from the sorted cells of each region, and linear RNA amplification is used to obtain sufficient amounts of high-quality RNA for analysis by microarray, RT-PCR, or RNA sequencing. This method will be useful for quantitative transcriptome comparison across intestinal cell types in the different regions under normal and various experimental conditions. PMID- 26237571 TI - Culture and Isolation of Brain Tumor Initiating Cells. AB - Brain tumors are typically composed of heterogeneous cells that exhibit distinct phenotypic characteristics and proliferative potentials. Only a relatively small fraction of cells in the tumor with stem cell properties, termed brain tumor initiating cells (BTICs), possess an ability to differentiate along multiple lineages, self-renew, and initiate tumors in vivo. This unit describes protocols for the culture and isolation BTICs. We applied culture conditions and assays originally used for normal neural stem cells (NSCs) in vitro to a variety of brain tumors. Using fluorescence-activated cell sorting for the neural precursor cell surface marker CD133/CD15, BTICs can be isolated and studied prospectively. Isolation of BTICs from GBM bulk tumor will enable examination of dissimilar morphologies, self-renewal capacities, tumorigenicity, and therapeutic sensitivities. As cancer is also considered a disease of unregulated self-renewal and differentiation, an understanding of BTICs is fundamental to understanding tumor growth. Ultimately, it will lead to novel drug discovery approaches that strategically target the functionally relevant BTIC population. PMID- 26237572 TI - TALEN- and CRISPR/Cas9-Mediated Gene Editing in Human Pluripotent Stem Cells Using Lipid-Based Transfection. AB - Using custom-engineered nuclease-mediated genome editing, such as Transcription Activator-Like Effector Nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) RNA-guided Cas9 nucleases, human pluripotent stem cell (hPSC) lines with knockout or mutant alleles can be generated and differentiated into various cell types. This strategy of genome engineering in hPSCs will prove invaluable for studying human biology and disease. Here, we provide a detailed protocol for design and construction of TALEN and CRISPR vectors, testing of their nuclease activity, and delivery of TALEN or CRISPR vectors into hPSCs. In addition, we describe the use of single-stranded oligodeoxynucleotides (ssODNs) to introduce or repair point mutations. Next, we describe the identification of edited hPSC clones without antibiotic selection, including their clonal selection, genotyping, and expansion for downstream applications. PMID- 26237574 TI - Evolution of structural and functional diversification among plant Argonautes. AB - Argonautes (AGOs) are the effector proteins of the RNA-induced silencing (RISC) complex, formed during the phenomena of small-RNA mediated post-transcriptional gene silencing. AGOs are a large family of proteins; their number varies from a few (4 in Chlamydomonas reinhardtii) to many (18 in Oryza sativa) in plants. Genetics-guided analysis have demonstrated the roles of some of the AGOs during growth and development of plants. Biochemical studies have further revealed differences in functional specificities among AGOs. How the AGO family expanded in different plant species during the course of evolution is starting to emerge. We hypothesized that 4 classes of AGOs evolved after divergence of unicellular green algae when an ancestral AGO underwent duplication events. Evolution of multicellularity may have coincided with the diversification of AGOs. A comparative sequence and structure analysis of the plant AGOs, including those from the mosses and the unicellular algae, show not only conformational differences between those from lower and higher plants, but also functional divergence of important sites. PMID- 26237575 TI - Gas-Phase Reactivity of Cesium-Containing Species by Quantum Chemistry. AB - Thermodynamics and kinetics of cesium species reactions have been studied by using high-level quantum chemical tools. A systematic theoretical study has been done to find suitable methodology for calculation of reliable thermodynamic properties, allowing us to determine bimolecular rate constants with appropriate kinetic theories of gas-phase reactions. Four different reactions have been studied in this work: CsO + H2 = CsOH + H (R1), Cs + HI = CsI + H (R2), CsI + H2O = CsOH + HI (R3), and CsI + OH = CsOH + I (R4). All reactions involve steam, hydrogen, and iodine in addition of cesium. Most of the reactions are fast and (R3) and (R4) proceed even without energetic barrier. In terms of chemical reactivity in the reactor coolant system (RCS) in the case of severe accident, it can be expected that there will be no kinetic limitations for main cesium species (CsOH and CsI) transported along the RCS. Cs chemical speciation inside the RCS should be governed by the thermodynamics. PMID- 26237573 TI - A Photostable Silicon Rhodamine Platform for Optical Voltage Sensing. AB - This paper describes the design and synthesis of a photostable, far-red to near infrared (NIR) platform for optical voltage sensing. We developed a new, sulfonated silicon rhodamine fluorophore and integrated it with a phenylenevinylene molecular wire to create a Berkeley Red Sensor of Transmembrane potential, or BeRST 1 ("burst"). BeRST 1 is the first member of a class of far red to NIR voltage sensitive dyes that make use of a photoinduced electron transfer (PeT) trigger for optical interrogation of membrane voltage. We show that BeRST 1 displays bright, membrane-localized fluorescence in living cells, high photostability, and excellent voltage sensitivity in neurons. Depolarization of the plasma membrane results in rapid fluorescence increases (24% DeltaF/F per 100 mV). BeRST 1 can be used in conjunction with fluorescent stains for organelles, Ca(2+) indicators, and voltage-sensitive fluorescent proteins. In addition, the red-shifted spectral profile of BeRST 1, relative to commonly employed optogenetic actuators like ChannelRhodopsin2 (ChR2), which require blue light, enables optical electrophysiology in neurons. The high speed, sensitivity, photostability and long-wavelength fluorescence profiles of BeRST 1 make it a useful platform for the noninvasive, optical dissection of neuronal activity. PMID- 26237576 TI - Long non-coding RNA Linc00152 is involved in cell cycle arrest, apoptosis, epithelial to mesenchymal transition, cell migration and invasion in gastric cancer. AB - Gastric cancer remains a serious threat to public health with high incidence and mortality worldwide. Accumulating evidence demonstrates that long non-coding RNAs (lncRNAs) play important roles in regulating gene expression and are involved in various pathological processes, including gastric cancer. To investigate the possible role of dysregulated lncRNAs in gastric cancer development, we performed lncRNA microarray and identified 3141 significantly differentially expressed lncRNAs in gastric cancer tissues. Next, some of deregulated lncRNAs were validated among about 60 paired gastric cancer specimens such as Linc00261, DKFZP434K028, RPL34-AS1, H19, HOTAIR and Linc00152. Our results found that the decline of DKFZP434K028 and RPL34-AS1, and the increased expression of Linc00152 positively correlated with larger tumor size. The high expression levels of HOTAIR were associated with lymphatic metastasis and poor differentiation. Since the biological roles of Linc00152 are largely unknown in gastric cancer pathogenesis, we assessed its functions by silencing its up-regulation in gastric cancer cells. We found that Linc00152 knockdown could inhibit cell proliferation and colony formation, promote cell cycle arrest at G1 phase, trigger late apoptosis, reduce the epithelial to mesenchymal transition (EMT) program, and suppress cell migration and invasion. Taken together, we delineate the gastric cancer lncRNA signature and demonstrate the oncogenic functions of Linc00152. These findings may have implications for developing lncRNA-based biomarkers for diagnosis and therapeutics for gastric cancer. PMID- 26237578 TI - Chirality Control in Enzyme-Catalyzed Dynamic Kinetic Resolution of 1,3 Oxathiolanes. AB - The origin of enantioenrichment in enzyme-catalyzed dynamic kinetic resolution of 1,3-oxathiolane derivatives, key intermediates for asymmetric lamivudine synthesis, was elucidated. The chirality control could be determined by chiral HPLC and NOE NMR spectroscopy using a modified 1,3-oxathiolane compound obtained through enzyme-catalyzed selective hydrolysis. Solvent-dependent stereoselectivity was observed under biphasic conditions using different organic solvents with phosphate buffer. PMID- 26237577 TI - Real-time sample analysis using a sampling probe and miniature mass spectrometer. AB - A miniature mass spectrometry system with a sampling probe has been developed for real-time analysis of chemicals from sample surfaces. The sampling probe is 1.5 m in length and is comprised of one channel for introducing the spray and the other channel for transferring the charged species back to the Mini MS. This system provides a solution to the problem of real-time mass spectrometry analysis of a three-dimensional object in the field and is successful with compounds including those in inks, agrochemicals, explosives, and animal tissues. This system can be implemented in the form of a backpack MS with a sampling probe for forensic analysis or in the form of a compact MS with an intrasurgical probe for tissue analysis. PMID- 26237579 TI - Differences in the Toxicological Potential of 2D versus Aggregated Molybdenum Disulfide in the Lung. AB - 2D molybdenum disulfide (MoS2 ) has distinct optical and electronic properties compared to aggregated MoS2 , enabling wide use of these materials for electronic and biomedical applications. However, the hazard potential of MoS2 has not been studied extensively. Here, a comprehensive analysis of the pulmonary hazard potential of three aqueous suspended forms of MoS2 -aggregated MoS2 (Agg-MoS2 ), MoS2 exfoliated by lithiation (Lit-MoS2 ), and MoS2 dispersed by Pluronic F87 (PF87-MoS2 )-is presented. No cytotoxicity is detected in THP-1 and BEAS-2B cell lines. However, Agg-MoS2 induces strong proinflammatory and profibrogenic responses in vitro. In contrast, Lit- and PF87-MoS2 have little or no effect. In an acute toxicity study in mice, Agg-MoS2 induces acute lung inflammation, while Lit-MoS2 and PF87-MoS2 have little or no effect. In a subchronic study, there is no evidence of pulmonary fibrosis in response to all forms of MoS2 . These data suggest that exfoliation attenuates the toxicity of Agg-MoS2 , which is an important consideration toward the safety evaluation and use of nanoscale MoS2 materials for industrial and biological applications. PMID- 26237580 TI - Dielectric property measurement of ocular tissues up to 110 GHz using 1 mm coaxial sensor. AB - Measurement of the dielectric properties of ocular tissues up to 110 GHz was performed by the coaxial probe method. A coaxial sensor was fabricated to allow the measurement of small amounts of biological tissues. Four-standard calibration was applied in the dielectric property measurement to obtain more accurate data than that obtained with conventional three-standard calibration, especially at high frequencies. Novel data of the dielectric properties of several ocular tissues are presented and compared with data from the de facto database. PMID- 26237581 TI - hUTP24 is essential for processing of the human rRNA precursor at site A1, but not at site A0. AB - Production of ribosomes relies on more than 200 accessory factors to ensure the proper sequence of steps and faultless assembly of ribonucleoprotein machinery. Among trans-acting factors are numerous enzymes, including ribonucleases responsible for processing the large rRNA precursor synthesized by RNA polymerase I that encompasses sequences corresponding to mature 18S, 5.8S, and 25/28S rRNA. In humans, the identity of most enzymes responsible for individual processing steps, including endoribonucleases that cleave pre-rRNA at specific sites within regions flanking and separating mature rRNA, remains largely unknown. Here, we investigated the role of hUTP24 in rRNA maturation in human cells. hUTP24 is a human homolog of the Saccharomyces cerevisiae putative PIN domain-containing endoribonuclease Utp24 (yUtp24), which was suggested to participate in the U3 snoRNA-dependent processing of yeast pre-rRNA at sites A0, A1, and A2. We demonstrate that hUTP24 interacts to some extent with proteins homologous to the components of the yeast small subunit (SSU) processome. Moreover, mutation in the putative catalytic site of hUTP24 results in slowed growth of cells and reduced metabolic activity. These effects are associated with a defect in biogenesis of the 40S ribosomal subunit, which results from decreased amounts of 18S rRNA as a consequence of inaccurate pre-rRNA processing at the 5'-end of the 18S rRNA segment (site A1). Interestingly, and in contrast to yeast, site A0 located upstream of A1 is efficiently processed upon UTP24 dysfunction. Finally, hUTP24 inactivation leads to aberrant processing of 18S rRNA 2 nucleotides downstream of the normal A1 cleavage site. PMID- 26237582 TI - Binding of GID1 to DELLAs promotes dissociation of GAF1 from DELLA in GA dependent manner. AB - Gibberellins (GAs) are important phytohormones for plant growth and development. DELLAs are members of the plant-specific GRAS protein family and act as repressors of GA signaling. DELLAs are rapidly degraded in the presence of GAs. GA-GID1-DELLA complexes are recognized and ubiquitinated by the SCF(SLY) complex. The sleepy1 (sly1) F-box mutant exhibits dwarfism and low-germination phenotypes due to high accumulation of DELLAs. Overexpression of GID1 in the sly1 mutant partially rescues these phenotypes without degradation of DELLAs suggesting that proteolysis independent regulation of DELLAs exists in GA signaling. But the molecular mechanisms of non-proteolytic regulation of DELLA are largely unknown. Recently we identified a DELLA binding transcription factor, GAI-ASSOCIATED FACTOR1 (GAF1). GAF1 also interacts with co-repressor TOPLESS RELATED (TPR) in nuclei. DELLAs and TPR act as coactivator and corepressor of GAF1, respectively. GAs converts the GAF1 complex from transcriptional activator to repressor via degradation of DELLAs. The overexpression of DeltaPAM, lacking of DELLAs binding region of GAF1, partially rescue dwarf phenotypes of GA deficient or GA insensitive mutant. In this study, we investigate the relationship between non proteolytic regulation of DELLAs and GA signaling via DELLA-GAF1 complex using modified yeast two-hybrid system. PMID- 26237583 TI - Thermogelling and Chemoselectively Cross-Linked Hydrogels with Controlled Mechanical Properties and Degradation Behavior. AB - Chemoselectively cross-linked hydrogels have recently gained increasing attention for the development of novel, injectable biomaterials given their limited side reactions. In this study, we compared the properties of hydrogels obtained by native chemical ligation (NCL) and its recently described variation termed oxo ester-mediated native chemical ligation (OMNCL) in combination with temperature induced physical gelation. Triblock copolymers consisting of cysteine functionalities, thermoresponsive N-isopropylacrylamide (NIPAAm) units and degradable moieties were mixed with functionalized poly(ethylene glycol) (PEG) cross-linkers. Thioester or N-hydroxysuccinimide (NHS) functionalities attached to PEG reacted with cysteine residues of the triblock copolymers via either an NCL or OMNCL pathway. The combined physical and chemical cross-linking resulted in rapid network formation and mechanically strong hydrogels. Stiffness of the hydrogels was highest for thermogels that were covalently linked via OMNCL. Specifically, the storage modulus after 4 h reached a value of 26 kPa, which was over a 100 times higher than hydrogels formed by solely thermal physical interactions. Endothelial cells showed high cell viability of 98 +/- 2% in the presence of OMNCL cross-linked hydrogels after 16 h of incubation, in contrast to a low cell viability (13 +/- 7%) for hydrogels obtained by NCL cross-linking. Lysozyme was loaded in the gels and after 2 days more than 90% was released, indicating that the cross-linking reaction was indeed chemoselective as the protein was not covalently grafted to the hydrogel network. Moreover, the degradation rates of these hydrogels under physiological conditions could be tailored from 12 days up to 6 months by incorporation of a monomer containing a hydrolyzable lactone ring in the thermosensitive triblock copolymer. These results demonstrate a high tunability of mechanical properties and degradation rates of these in situ forming hydrogels that could be used for a variety of biomedical applications. PMID- 26237584 TI - Evaluating the Role of Birth Weight and Gestational Age on Acute Lymphoblastic Leukemia Risk Among Those of Hispanic Ethnicity. AB - High birth weight is an established risk factor for childhood acute lymphoblastic leukemia (ALL), especially in children younger than 5 years of age at diagnosis. The goal of this study was to explore the association between being born large for gestational age and the risk for ALL by race/ethnicity to determine if the role of this risk factor differed by these characteristics. The authors compared birth certificate data of 575 children diagnosed with ALL who were younger than 5 years and included in the Texas Cancer Registry, Texas Department of Health, between the years 1995 and 2003 with 11,379 controls matched by birth year. Stratified odds ratios were calculated for risk of ALL by birth weight for gestational age, categorized in 3 groups, small, appropriate, and large for gestational age (SGA, AGA, and LGA, respectively), for each race/ethnicity group. The risk of developing ALL was higher among Hispanics who were LGA (odds ratio [OR] = 1.90, 95% confidence interval [CI]: 1.34-2.68) compared with LGA non Hispanic whites (OR = 1.27, 95% CI: 0.87-1.86) after adjusting for infant gender, year of birth, maternal age, birth order, and presence of Down syndrome. However, the difference was not statistically significant. These results suggest that there may be differences in the association between higher growth in utero and risk of childhood ALL among Hispanics versus non-Hispanic whites. PMID- 26237585 TI - Pediatric Survivors of Retinoblastoma Are at Risk for Altered Bone Metabolism After Chemotherapy Treatment Early in Life. AB - Survivors of childhood cancer frequently suffer from endocrine late effects, which are, at least partly, attributed to toxic effects of chemotherapy. Treatment of retinoblastoma typically involves chemotherapy at a very young age. The authors conducted a cross-sectional study to assess bone health in a pediatric cohort of 33 survivors of retinoblastoma (mean age: 4.4 years) who had undergone chemotherapy treatment at an especially young age (mean age: 0.76 years). Of these patients, 14 had unilateral and 19 bilateral retinoblastoma. Polychemotherapy consisted of treatment with cyclophosphamide, etoposide, vincristine, and carboplatin. Ten patients had undergone external beam radiotherapy. Clinical and biochemical parameters of growth, pubertal development, and bone health were obtained. A vitamin D deficiency was found in 51.7% of the patients, and 13.7% of patients displayed severe vitamin D deficiency. Secondary hyperparathyroidism and altered readings for bone formation or resorption markers were present in 15%. Nine percent reported bone pain or experienced fractures of the long bones after primary diagnosis. No difference between children with bilateral and unilateral disease or irradiated versus nonirradiated children was observed. The parameters of thyroid function, growth, and pubertal development were within age-appropriate norms in almost all children. In conclusion, altered parameters of bone health can be present in survivors of retinoblastoma at a young age and warrant regular follow-up in these children. The endocrine hypothalamic-pituitary axes, however, were not impaired at this early age in this group of survivors of retinoblastoma. PMID- 26237586 TI - Secondary Solid Malignancies After High-Grade Glioma Treatment in Pediatric Patients. AB - Due to the poor survival in high-grade glioma (HGG), secondary solid malignancies (SSM) following pediatric HGG are scarce. The authors present the experience from the HIT-HGG database in Germany, Austria, and Switzerland. Five out of 1228 pediatric HGG patients developed a SSM following a latency of 29-122 months from primary HGG diagnosis. In 4 patients, the SSM may be attributed to previous radiotherapy or a tumor predisposition syndrome, reflected by a markedly increased cumulative incidence rate of SSM in patients with tumor predisposition. Survival was devastating, since none of the patients survived beyond 18 months from SSM diagnosis. PMID- 26237587 TI - Anthropometric and Biochemical Assessment of Nutritional Status in Pediatric Cancer Patients. AB - Children are at greater risk for malnutrition due to increased needs of nutrients to obtain appropriate growth, and they exhibit elevated substrate needs due to cancer and its treatment. This study aimed to report anthropometric and biochemical evaluation of nutritional status in children with cancer at initial presentation and during treatment. A prospective, controlled study was performed in the pediatric oncology department of a tertiary care center. Control group consisted of the siblings of patients. Weight, height, body mass index, triceps skinfold thickness, and serum levels of total protein, albumin, prealbumin, serum lipids, trace minerals, C-reactive protein (CRP), and vitamins were compared in patients and controls at initial presentation and at 6th month after the onset of treatment. According to weight for height, the frequency of malnutrition was 16% at initial presentation and 22% at 6th month. Triceps skinfold thickness was significantly thinner in patients than controls at both measurements. Patients had lower levels of prealbumin, albumin, iron, folate, zinc, and vitamin C and higher levels of ferritin, vitamin B12, and copper. Serum CRP levels were significantly higher in cancer patients at initial presentation and seemed to be correlated with copper levels. Compared with other patients, malnourished patients had significantly higher levels of vitamin B12 at 6th month. Results of the current study demonstrate that trace minerals, vitamins, and anthropometric measures may yield important clues for nutritional status and disease activity in pediatric oncology patients. However, validation and updating these potential markers warrant further trials on larger series. PMID- 26237590 TI - Bifunctional Modification of Graphitic Carbon Nitride with MgFe2O4 for Enhanced Photocatalytic Hydrogen Generation. AB - To gain high photocatalytic activity for hydrogen evolution, both charge separation efficiency and surface reaction kinetics must be improved, and together would be even better. In this study, the visible light photocatalytic hydrogen production activity of graphitic carbon nitride (g-C3N4) was greatly enhanced with MgFe2O4 modification. It was demonstrated that MgFe2O4 could not only extract photoinduced holes from g-C3N4, leading to efficient charge carrier separation at the g-C3N4/MgFe2O4 interface, but also act as an oxidative catalyst accelerating the oxidation reaction kinetics at g-C3N4 surface. This dual function of MgFe2O4 thus contributed to the great improvement (up to three-fold) in photocatalytic activity for hydrogen generation over g-C3N4/MgFe2O4 as compared to pristine g-C3N4, after loading Pt by photoreduction method. It was revealed that in the Pt/g-C3N4/MgFe2O4 system, the photoinduced electrons and holes were entrapped by Pt and MgFe2O4, respectively, giving rise to the promoted charge separation; moreover, as evidenced by electrochemical analysis, the electrocatalysis effect of MgFe2O4 benefited the oxidation reaction at g-C3N4 surface. PMID- 26237589 TI - Influenza A Virus Infection, Innate Immunity, and Childhood. AB - Infection with influenza A virus is responsible for considerable morbidity and mortality in children worldwide. While it is apparent that adequate activation of the innate immune system is essential for pathogen clearance and host survival, an excessive inflammatory response to infection is detrimental to the young host. A review of the literature indicates that innate immune responses change throughout childhood. Whether these changes are genetically programmed or triggered by environmental cues is unknown. The objectives of this review are to summarize the role of innate immunity in influenza A virus infection in the young child and to highlight possible differences between children and adults that may make children more susceptible to severe influenza A infection. A better understanding of age-related differences in innate immune signaling will be essential to improve care for this high-risk population. PMID- 26237588 TI - Modest Interference with Actin Dynamics in Primary T Cell Activation by Antigen Presenting Cells Preferentially Affects Lamellal Signaling. AB - Dynamic subcellular distributions of signaling system components are critical regulators of cellular signal transduction through their control of molecular interactions. Understanding how signaling activity depends on such distributions and the cellular structures driving them is required for comprehensive insight into signal transduction. In the activation of primary murine T cells by antigen presenting cells (APC) signaling intermediates associate with various subcellular structures, prominently a transient, wide, and actin-associated lamellum extending from an interdigitated T cell:APC interface several micrometers into the T cell. While actin dynamics are well established as general regulators of cellular organization, their role in controlling signaling organization in primary T cell:APC couples and the specific cellular structures driving it is unresolved. Using modest interference with actin dynamics with a low concentration of Jasplakinolide as corroborated by costimulation blockade we show that T cell actin preferentially controls lamellal signaling localization and activity leading downstream to calcium signaling. Lamellal localization repeatedly related to efficient T cell function. This suggests that the transient lamellal actin matrix regulates T cell signaling associations that facilitate T cell activation. PMID- 26237591 TI - Proton MR Spectroscopy for Diagnosis and Evaluation of Treatment Efficacy in Parkinson Disease. AB - PURPOSE: To assess the neurochemical profile in the putamen of patients with parkinsonian syndromes undergoing L-3,4-dihydroxyphenylalanine (L-DOPA) treatment (drug-on) or after withdrawal of L-DOPA medication (drug-off) compared with healthy volunteers to identify dopaminergic therapy-sensitive biomarkers of Parkinson disease. MATERIALS AND METHODS: The local institutional review board approved the study, and all participants gave informed consent. A short echo-time (29 msec) single-voxel (1-cm(3)) proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopic approach was used at 3 T to explore the metabolic profile in the putamen of patients with Parkinson disease. Spectra obtained from 20 healthy volunteers were blindly compared with spectra obtained from 20 patients with parkinsonian syndromes in drug-on and drug-off conditions in a randomized permuted block study to assess the accuracy of diagnostic biomarkers for Parkinson disease and efficacy of L-DOPA therapy. The statistical tests were two sided, with a type-I error set at alpha of .05. Random-effects models were used to compare healthy subjects and patients with parkinsonian syndromes in drug-on or drug-off conditions. RESULTS: Measured concentrations of putaminal total N acetylaspartate (tNAA) (8.1 +/- 0.2 vs 9.4 +/- 0.4; P < .01), total creatine (tCr) (7.5 +/- 0.2 vs 8.3 +/- 0.3; P < .01), and myo-inositol (m-Ins) (3.8 +/- 0.3 vs 5.6 +/- 0.4; P < .001) were significantly lower in patients with parkinsonian syndromes in drug-off condition than in healthy volunteers. Moreover, L-DOPA therapy restored tNAA (9.1 +/- 0.4 vs 8.1 +/- 0.2; P < .01) and tCr (8.1 +/- 0.3 vs 7.5 +/- 0.2; P < .01) levels, whereas m-Ins levels remained unchanged. The combined glutamate and glutamine and choline showed no changes in drug-off or drug-on condition compared with those in control subjects. CONCLUSION: tNAA, tCr, and m-Ins were identified as putative biomarkers of Parkinson disease in the putamen of patients. tNAA and tCr levels are responsive to L-DOPA therapy. PMID- 26237592 TI - Human iPS Cell-Derived Germ Cells: Current Status and Clinical Potential. AB - Recently, fertile spermatozoa and oocytes were generated from mouse induced pluripotent (iPS) cells using a combined in vitro and in vivo induction system. With regard to germ cell induction from human iPS cells, progress has been made particularly in the male germline, demonstrating in vitro generation of haploid, round spermatids. Although iPS-derived germ cells are expected to be developed to yield a form of assisted reproductive technology (ART) that can address unmet reproductive needs, genetic and/or epigenetic instabilities abound in iPS cell generation and germ cell induction. In addition, there is still room to improve the induction protocol in the female germline. However, rapid advances in stem cell research are likely to make such obstacles surmountable, potentially translating induced germ cells into the clinical setting in the immediate future. This review examines the current status of the induction of germ cells from human iPS cells and discusses the clinical potential, as well as future directions. PMID- 26237593 TI - Neurosurgical Hyponatremia. AB - Hyponatremia is a frequent electrolyte imbalance in hospital inpatients. Acute onset hyponatremia is particularly common in patients who have undergone any type of brain insult, including traumatic brain injury, subarachnoid hemorrhage and brain tumors, and is a frequent complication of intracranial procedures. Acute hyponatremia is more clinically dangerous than chronic hyponatremia, as it creates an osmotic gradient between the brain and the plasma, which promotes the movement of water from the plasma into brain cells, causing cerebral edema and neurological compromise. Unless acute hyponatremia is corrected promptly and effectively, cerebral edema may manifest through impaired consciousness level, seizures, elevated intracranial pressure, and, potentially, death due to cerebral herniation. The pathophysiology of hyponatremia in neurotrauma is multifactorial, but most cases appear to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Classical treatment of SIADH with fluid restriction is frequently ineffective, and in some circumstances, such as following subarachnoid hemorrhage, contraindicated. However, the recently developed vasopressin receptor antagonist class of drugs provides a very useful tool in the management of neurosurgical SIADH. In this review, we summarize the existing literature on the clinical features, causes, and management of hyponatremia in the neurosurgical patient. PMID- 26237594 TI - Clinical Potentials of Cardiomyocytes Derived from Patient-Specific Induced Pluripotent Stem Cells. AB - The lack of appropriate human cardiomyocyte-based experimental platform has largely hindered the study of cardiac diseases and the development of therapeutic strategies. To date, somatic cells isolated from human subjects can be reprogramed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into functional cardiomyocytes. This powerful reprogramming technology provides a novel in vitro human cell-based platform for the study of human hereditary cardiac disorders. The clinical potential of using iPSCs derived from patients with inherited cardiac disorders for therapeutic studies have been increasingly highlighted. In this review, the standard procedures for generating patient-specific iPSCs and the latest commonly used cardiac differentiation protocols will be outlined. Furthermore, the progress and limitations of current applications of iPSCs and iPSCs-derived cardiomyocytes in cell replacement therapy, disease modeling, drug-testing and toxicology studies will be discussed in detail. PMID- 26237595 TI - iPSC-Based Models to Unravel Key Pathogenetic Processes Underlying Motor Neuron Disease Development. AB - Motor neuron diseases (MNDs) are neuromuscular disorders affecting rather exclusively upper motor neurons (UMNs) and/or lower motor neurons (LMNs). The clinical phenotype is characterized by muscular weakness and atrophy leading to paralysis and almost invariably death due to respiratory failure. Adult MNDs include sporadic and familial amyotrophic lateral sclerosis (sALS-fALS), while the most common infantile MND is represented by spinal muscular atrophy (SMA). No effective treatment is ccurrently available for MNDs, as for the vast majority of neurodegenerative disorders, and cures are limited to supportive care and symptom relief. The lack of a deep understanding of MND pathogenesis accounts for the difficulties in finding a cure, together with the scarcity of reliable in vitro models. Recent progresses in stem cell field, in particular in the generation of induced Pluripotent Stem Cells (iPSCs) has made possible for the first time obtaining substantial amounts of human cells to recapitulate in vitro some of the key pathogenetic processes underlying MNDs. In the present review, recently published studies involving the use of iPSCs to unravel aspects of ALS and SMA pathogenesis are discussed with an overview of their implications in the process of finding a cure for these still orphan disorders. PMID- 26237596 TI - Comparing ESC and iPSC-Based Models for Human Genetic Disorders. AB - Traditionally, human disorders were studied using animal models or somatic cells taken from patients. Such studies enabled the analysis of the molecular mechanisms of numerous disorders, and led to the discovery of new treatments. Yet, these systems are limited or even irrelevant in modeling multiple genetic diseases. The isolation of human embryonic stem cells (ESCs) from diseased blastocysts, the derivation of induced pluripotent stem cells (iPSCs) from patients' somatic cells, and the new technologies for genome editing of pluripotent stem cells have opened a new window of opportunities in the field of disease modeling, and enabled studying diseases that couldn't be modeled in the past. Importantly, despite the high similarity between ESCs and iPSCs, there are several fundamental differences between these cells, which have important implications regarding disease modeling. In this review we compare ESC-based models to iPSC-based models, and highlight the advantages and disadvantages of each system. We further suggest a roadmap for how to choose the optimal strategy to model each specific disorder. PMID- 26237597 TI - Effects of Hyponatremia on the Brain. AB - Hyponatremia is a very common electrolyte disorder, especially in the elderly, and is associated with significant morbidity, mortality and disability. In particular, the consequences of acute hyponatremia on the brain may be severe, including permanent disability and death. Also chronic hyponatremia can affect the health status, causing attention deficit, gait instability, increased risk of falls and fractures, and osteoporosis. Furthermore, an overly rapid correction of hyponatremia can be associated with irreversible brain damage, which may be the result of the osmotic demyelination syndrome. This review analyzes the detrimental consequences of acute and chronic hyponatremia and its inappropriate correction on the brain and the underlying physiopathological mechanisms, with a particular attention to the less known in vivo and in vitro effects of chronic hyponatremia. PMID- 26237598 TI - Obesity as an Early Symptom of the AMIS Syndrome. AB - We review evidence that the AMIS (Absence of Meal-induced Insulin Sensitization) syndrome describes a paradigm fundamental to development of obesity. The hypoglycemic response to a pulse of insulin is doubled after a meal as a result of Hepatic Insulin Sensitizing Substance (HISS), released from the liver to act selectively on muscle, heart and kidney. In the absence of HISS action, the hypoglycemic response to insulin is the same as in the fasted state, and only half of what it should be. Postprandial hyperglycemia ensues, with compensatory hyperinsulinemia, resultant hyperlipidemia and elevated free radical stress. Storage of nutrient energy shifts from glycogen in muscle to fat. Chronic AMIS results in adiposity, occurs with age, is accelerated with sucrose supplement, and prevented by a synergistic antioxidant. Exercise reverses AMIS, as do pharmaceuticals that mimic the "feeding signals". The AMIS syndrome develops as a sequence of pathologies based on the consequences of absence of HISS action, including adiposity as the earliest symptom. Cardiac dysfunction, hypertension, hypercholesterolemia, and fatty liver are related to lack of HISS action. The AMIS syndrome hypothesis is mechanistic-based and accounts for the major pathologies associated with prediabetes, obesity, diabetes and metabolic syndrome. AMIS can be diagnosed, prevented and treated. PMID- 26237599 TI - Incidence, Etiology and Outcomes of Hyponatremia after Transsphenoidal Surgery: Experience with 344 Consecutive Patients at a Single Tertiary Center. AB - Hyponatremia is often seen after transsphenoidal surgery and is a source of considerable economic burden and patient-related morbidity and mortality. We performed a retrospective review of 344 patients who underwent transsphenoidal surgery at our institution between 2006 and 2012. Postoperative hyponatremia was seen in 18.0% of patients at a mean of 3.9 days postoperatively. Hyponatremia was most commonly mild (51.6%) and clinically asymptomatic (93.8%). SIADH was the primary cause of hyponatremia in the majority of cases (n = 44, 71.0%), followed by cerebral salt wasting (n = 15, 24.2%) and desmopressin over-administration (n = 3, 4.8%). The incidence of postoperative hyponatremia was significantly higher in patients with cardiac, renal and/or thyroid disease (p = 0.0034, Objective Risk (OR) = 2.60) and in female patients (p = 0.011, OR = 2.18) or patients undergoing post-operative cerebrospinal fluid drainage (p = 0.0006). Treatment with hypertonic saline (OR = -2.4, p = 0.10) and sodium chloride tablets (OR = 1.57, p = 0.45) was associated with a non-significant trend toward faster resolution of hyponatremia. The use of fluid restriction and diuretics should be de-emphasized in the treatment of post-transsphenoidal hyponatremia, as they have not been shown to significantly alter the time-course to the restoration of sodium balance. PMID- 26237600 TI - Hyponatraemia in Emergency Medical Admissions-Outcomes and Costs. AB - Healthcare systems in the developed world are struggling with the demand of emergency room presentations; the study of the factors driving such demand is of fundamental importance. From a database of all emergency medical admissions (66,933 episodes in 36,271 patients) to St James' Hospital, Dublin, Ireland, over 12 years (2002 to 2013) we have explored the impact of hyponatraemia on outcomes (30 days in-hospital mortality, length of stay (LOS) and costs). Identified variables, including Acute Illness Severity, Charlson Co-Morbidity and Chronic Disabling Disease that proved predictive univariately were entered into a multivariable logistic regression model to predict the bivariate of 30 days in hospital survival. A zero truncated Poisson regression model assessed LOS and episode costs and the incidence rate ratios were calculated. Hyponatraemia was present in 22.7% of episodes and 20.3% of patients. The 30 days in-hospital mortality rate for hyponatraemic patients was higher (15.9% vs. 6.9% p < 0.001) and the LOS longer (6.3 (95% CI 2.9, 12.2) vs. 4.0 (95% CI 1.5, 8.2) p < 0.001). Both parameters worsened with the severity of the initial sodium level. Hospital costs increased non-linearly with the severity of initial hyponatraemia. Hyponatraemia remained an independent predictor of 30 days in-hospital mortality, length of stay and costs in the multi-variable model. PMID- 26237601 TI - Age-Related Macular Degeneration: A Disease of Systemic or Local Complement Dysregulation? AB - Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries. The role of complement in the development of AMD is now well-established. While some studies show evidence of complement dysregulation within the eye, others have demonstrated elevated systemic complement activation in association with AMD. It is unclear which one is the primary driver of disease. This has important implications for designing novel complement-based AMD therapies. We present a summary of the current literature and suggest that intraocular rather than systemic modulation of complement may prove more effective. PMID- 26237603 TI - Review of Tolvaptan's Pharmacokinetic and Pharmacodynamic Properties and Drug Interactions. AB - Tolvaptan is an arginine vasopressin (AVP) antagonist that acts to increase excretion of free water (aquaresis) in patients without introducing electrolyte abnormalities or worsening renal function. It works via blockade of vasopressin-2 receptors at the renal collecting duct. Since the approval of tolvaptan for the treatment of hypervolemic and euvolemic hyponatremia in 2009, new studies have been reported to better characterize its pharmacokinetic and pharmacodynamic profile of tolvaptan. This paper is a review of both these clinical studies, as well as previous literature, in order to help guide appropriate clinical use of tolvaptan in patients. With appropriate monitoring of serum sodium, tolvaptan may be safely dose escalated from 15 mg once daily to a maximum effective dose of 60 mg once daily for multiple days, to achieve optimal aqauretic effects. In terms of drug interactions, co-administration of moderate to potent CYP3A4 inhibitors and inducers should be avoided. Tolvaptan should also be co-administered with caution and proper monitoring in the presence of P-glycoprotein substrate and strong inhibitors. Co-administration of tolvaptan with diuretic therapy did not appear to alter the aquaretic effect of tolvaptan; and was shown to be safe and well tolerated. PMID- 26237602 TI - Physiopathological, Epidemiological, Clinical and Therapeutic Aspects of Exercise Associated Hyponatremia. AB - Exercise-associated hyponatremia (EAH) is dilutional hyponatremia, a variant of inappropriate antidiuretic hormone secretion (SIADH), characterized by a plasma concentration of sodium lower than 135 mEq/L. The prevalence of EAH is common in endurance (<6 hours) and ultra-endurance events (>6 hours in duration), in which both athletes and medical providers need to be aware of risk factors, symptom presentation, and management. The development of EAH is a combination of excessive water intake, inadequate suppression of the secretion of the antidiuretic hormone (ADH) (due to non osmotic stimuli), long race duration, and very high or very low ambient temperatures. Additional risk factors include female gender, slower race times, and use of nonsteroidal anti-inflammatory drugs. Signs and symptoms of EAH include nausea, vomiting, confusion, headache and seizures; it may result in severe clinical conditions associated with pulmonary and cerebral edema, respiratory failure and death. A rapid diagnosis and appropriate treatment with a hypertonic saline solution is essential in the severe form to ensure a positive outcome. PMID- 26237604 TI - The Future of Prenatal Diagnosis and Screening. AB - The future of prenatal diagnosis and screening lies in developing clinical approaches and laboratory technologies applicable to genetic analyses and therapeutic interventions during embryonic development. PMID- 26237605 TI - Hyponatremia in Patients with Spontaneous Intracerebral Hemorrhage. AB - Hyponatremia is the most frequently encountered electrolyte abnormality in critically ill patients. Hyponatremia on admission has been identified as an independent predictor of in-hospital mortality in patients with spontaneous intracerebral hemorrhage (sICH). However, the incidence and etiology of hyponatremia (HN) during hospitalization in a neurointensive care unit following spontaneous intracerebral hemorrhage (sICH) remains unknown. This was a retrospective analysis of consecutive patients admitted to Detroit Receiving Hospital for sICH between January 2006 and July 2009. All serum Na levels were recorded for patients during the ICU stay. HN was defined as Na <135 mmol/L. A total of 99 patients were analyzed with HN developing in 24% of sICH patients. Patients with HN had an average sodium nadir of 130 +/- 3 mmol/L and an average time from admission to sodium <135 mmol/L of 3.9 +/- 5.7 days. The most common cause of hyponatremia was syndrome of inappropriate antidiuretic hormone (90% of HN patients). Patients with HN were more likely to have fever (50% vs. 23%; p = 0.01), infection (58% vs. 28%; p = 0.007) as well as a longer hospital length of stay (14 (8-25) vs. 6 (3-9) days; p < 0.001). Of the patients who developed HN, fifteen (62.5%) patients developed HN in the first week following sICH. This shows HN has a fairly high incidence following sICH. The presence of HN is associated with longer hospital length of stays and higher rates of patient complications, which may result in worse patient outcomes. Further study is necessary to characterize the clinical relevance and treatment of HN in this population. PMID- 26237608 TI - High Prevalence of Asymptomatic Sexually Transmitted Infections among Men Who Have Sex with Men. AB - BACKGROUND: Men who have sex with men (MSM) are disproportionately affected by sexually transmitted infection. The aim of this cross-sectional study is to prospectively detect the prevalence of chlamydia trachomatis (CT), neisseria gonorrhoeae (NG), mycoplasma genitalium (MG), and high risk human papillomavirus (HR-HPV), and syphilis in a population of asymptomatic sexually active MSM. METHODS: Rectal, pharyngeal, and urine samples for CT, NG, MG, and HR-HPV were analyzed in 116 MSM patients attending the clinic for their routine follow-up during the period the study was conducted: 99 patients were issued from the clinic routine follow-up for their HIV infection, and 17 attended the clinic because they were sexual partners of an HIV infected male. RESULTS: An STI was found in 16% of the patients (19/116), with at least one bacterial strain (CT, NG, or MG) found in one site (the pharynx, rectum, or urine). CONCLUSIONS: In this study, 16% of the MSM reporting recent RAI were asymptomatic carriers of rectal CT, NG, or MG. According to the high prevalence of asymptomatic STIs found in our MSM population and in other studies, prevention efforts in the form of counseling about the risk of STI need to be done in the population of MSM. PMID- 26237606 TI - Opportunities and Limitations of Modelling Alzheimer's Disease with Induced Pluripotent Stem Cells. AB - Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) has opened the way for patient-specific disease modelling. Following their differentiation into neuronal cell types, iPSC have enabled the investigation of human neurodegenerative diseases, such as Alzheimer's disease (AD). While human iPSCs certainly provide great opportunities to repeatedly interrogate specific human brain cell types of individuals with familial and sporadic forms of the disease, the complex aetiology and timescale over which AD develops in humans poses particular challenges to iPSC-based AD models. Here, we discuss the current state-of-play in the context of these and other iPSC model-related challenges and elaborate on likely future developments in this field of research. PMID- 26237607 TI - Differentiating SIADH from Cerebral/Renal Salt Wasting: Failure of the Volume Approach and Need for a New Approach to Hyponatremia. AB - Hyponatremia is the most common electrolyte abnormality. Its diagnostic and therapeutic approaches are in a state of flux. It is evident that hyponatremic patients are symptomatic with a potential for serious consequences at sodium levels that were once considered trivial. The recommendation to treat virtually all hyponatremics exposes the need to resolve the diagnostic and therapeutic dilemma of deciding whether to water restrict a patient with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or administer salt and water to a renal salt waster. In this review, we briefly discuss the pathophysiology of SIADH and renal salt wasting (RSW), and the difficulty in differentiating SIADH from RSW, and review the origin of the perceived rarity of RSW, as well as the value of determining fractional excretion of urate (FEurate) in differentiating both syndromes, the high prevalence of RSW which highlights the inadequacy of the volume approach to hyponatremia, the importance of changing cerebral salt wasting to RSW, and the proposal to eliminate reset osmostat as a subtype of SIADH, and finally propose a new algorithm to replace the outmoded volume approach by highlighting FEurate. This algorithm eliminates the need to assess the volume status with less reliance on determining urine sodium concentration, plasma renin, aldosterone and atrial/brain natriuretic peptide or the BUN to creatinine ratio. PMID- 26237609 TI - Herpes Simplex Virus (HSV-1) Encephalitis Mimicking Glioblastoma: Case Report and Review of the Literature. AB - Glioblastoma multiforme (GBM) often presents as a brain mass with encephalitis. In a patient with GBM, subsequent presentation with new onset encephalitis may be due to another GBM or Herpes simplex virus 1 (HSV-1) encephalitis. We present a case of HSV-1 encephalitis mimicking GBM in a patient with previous GBM. PMID- 26237611 TI - The Legal Past, Present and Future of Prenatal Genetic Testing: Professional Liability and Other Legal Challenges Affecting Patient Access to Services. AB - This chapter is an overview of the current status of the law in the United States regarding prenatal genetic testing with an emphasis on issues related to professional liability and other challenges affecting patient access to prenatal genetic testing. The chapter discusses the roles that federal regulations, promulgated by the Centers for Medicare and Medicaid Services (CMS), the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC), play in the regulation of prenatal genetic tests. The chapter discusses tort litigation based on allegations of malpractice in the provision of prenatal genetic testing and how courts have analyzed issues related to causation, damages and mitigation of damages. The chapter provides reference information regarding how individual states address causes of action under the tort theories of wrongful birth and wrongful life. The chapter concludes with a discussion of future legal issues that may affect clinical prenatal genetic testing services arising from the continued expansion of prenatal genetic testing, legal restrictions on access to abortion and the potential development of embryonic treatments. PMID- 26237610 TI - Induced Pluripotent Stem Cells Derived from Alzheimer's Disease Patients: The Promise, the Hope and the Path Ahead. AB - The future hope of generated induced pluripotent stem cells (iPS cells) from Alzheimer's disease patients is multifold. Firstly, they may help to uncover novel mechanisms of the disease, which could lead to the development of new and unprecedented drugs for patients and secondly, they could also be directly used for screening and testing of potential new compounds for drug discovery. In addition, in the case of familial known mutations, these cells could be targeted by use of advanced gene-editing techniques to correct the mutation and be used for future cell transplantation therapies. This review summarizes the work so far in regards to production and characterization of iPS cell lines from both sporadic and familial Alzheimer's patients and from other iPS cell lines that may help to model the disease. It provides a detailed comparison between published reports and states the present hurdles we face with this new technology. The promise of new gene-editing techniques and accelerated aging models also aim to move this field further by providing better control cell lines for comparisons and potentially better phenotypes, respectively. PMID- 26237612 TI - Targeted Therapy of FLT3 in Treatment of AML-Current Status and Future Directions. AB - Internal tandem duplications (ITDs) of the gene encoding the Fms-Like Tyrosine kinase-3 (FLT3) receptor are present in approximately 25% of patients with acute myeloid leukemia (AML). The mutation is associated with poor prognosis, and the aberrant protein product has been hypothesized as an attractive therapeutic target. Various tyrosine kinase inhibitors (TKIs) have been developed targeting FLT3, but in spite of initial optimism the first generation TKIs tested in clinical studies generally induce only partial and transient hematological responses. The limited treatment efficacy generally observed may be explained by numerous factors; extensively pretreated and high risk cohorts, suboptimal pharmacodynamic and pharmacokinetic properties of the compounds, acquired TKI resistance, or the possible fact that inhibition of mutated FLT3 alone is not sufficient to avoid disease progression. The second-generation agent quizartinb is showing promising outcomes and seems better tolerated and with less toxic effects than traditional chemotherapeutic agents. Therefore, new generations of TKIs might be feasible for use in combination therapy or in a salvage setting in selected patients. Here, we sum up experiences so far, and we discuss the future outlook of targeting dysregulated FLT3 signaling in the treatment of AML. PMID- 26237613 TI - iPS Cells for Modelling and Treatment of Retinal Diseases. AB - For many decades, we have relied on immortalised retinal cell lines, histology of enucleated human eyes, animal models, clinical observation, genetic studies and human clinical trials to learn more about the pathogenesis of retinal diseases and explore treatment options. The recent availability of patient-specific induced pluripotent stem cells (iPSC) for deriving retinal lineages has added a powerful alternative tool for discovering new disease-causing mutations, studying genotype-phenotype relationships, performing therapeutics-toxicity screening and developing personalised cell therapy. This review article provides a clinical perspective on the current and potential benefits of iPSC for managing the most common blinding diseases of the eye: inherited retinal diseases and age-related macular degeneration. PMID- 26237615 TI - Co-thought and co-speech gestures are generated by the same action generation process. AB - People spontaneously gesture when they speak (co-speech gestures) and when they solve problems silently (co-thought gestures). In this study, we first explored the relationship between these 2 types of gestures and found that individuals who produced co-thought gestures more frequently also produced co-speech gestures more frequently (Experiments 1 and 2). This suggests that the 2 types of gestures are generated from the same process. We then investigated whether both types of gestures can be generated from the representational use of the action generation process that also generates purposeful actions that have a direct physical impact on the world, such as manipulating an object or locomotion (the action generation hypothesis). To this end, we examined the effect of object affordances on the production of both types of gestures (Experiments 3 and 4). We found that individuals produced co-thought and co-speech gestures more often when the stimulus objects afforded action (objects with a smooth surface) than when they did not (objects with a spiky surface). These results support the action generation hypothesis for representational gestures. However, our findings are incompatible with the hypothesis that co-speech representational gestures are solely generated from the speech production process (the speech production hypothesis). PMID- 26237614 TI - The Insulin-Like Growth Factor System in Obesity, Insulin Resistance and Type 2 Diabetes Mellitus. AB - The insulin-like growth factor (IGF) system, acting in concert with other hormone axes, is important in normal metabolism. In obesity, the hyperinsulinaemia that accompanies peripheral insulin resistance leads to reduced growth hormone (GH) secretion, while total IGF-I levels are relatively unchanged due to increased hepatic GH sensitivity. IGF-binding protein (IGFBP)-1 levels are suppressed in relation to the increase in insulin levels in obesity and low levels predict the development of type 2 diabetes several years later. Visceral adiposity and hepatic steatosis, along with a chronic inflammation, contribute to the IGF system phenotype in individuals with metabolic syndrome and type 2 diabetes mellitus, including changes in the normal inverse relationship between IGFBP-1 and insulin, with IGFBP-1 concentrations that are inappropriately normal or elevated. The IGF system is implicated in the vascular and other complications of these disorders and is therefore a potential therapeutic target. PMID- 26237617 TI - The curious case of orthographic distinctiveness: Disruption of categorical processing. AB - How does orthographic distinctiveness affect recall of structured (categorized) word lists? On one theory, enhanced item-specific information (e.g., more distinct encoding) in concert with robust relational information (e.g., categorical information) optimally supports free recall. This predicts that for categorically structured lists, orthographically distinct (OD) word lists should be recalled better than orthographically common (OC) word lists. Another possibility is that OD items produce a far-reaching impairment in relational processing, including that of categorical information. This view anticipates an advantage in recall for OC items relative to OD lists. In Experiment 1 categorically structured OC lists produced better recall performance and higher clustering than did categorically structured OD lists. When words were presented in capital letters, thereby minimizing orthographic distinctiveness, OC and OD lists showed equivalent recall and category clustering (Experiment 2). When recall was cued with category labels, OC items were still better recalled than OD items (Experiment 3). These patterns, along with category access and items-per category recalled, are consistent with the interpretation that orthographic distinctiveness creates a disruption in encoding of inter-item associations within a category. This interpretation expands previous work indicating that orthographic distinctiveness disrupts encoding of serial order information, another kind of inter-item association. (PsycINFO Database Record PMID- 26237616 TI - Two are not better than one: Combining unitization and relational encoding strategies. AB - In recognition memory, recollection is defined as retrieval of the context associated with an event, whereas familiarity is defined as retrieval based on item strength alone. Recent studies have shown that conventional recollection based tasks, in which context details are manipulated for source memory assessment at test, can also rely on familiarity when context information is "unitized" with the relevant item information at encoding. Unlike naturalistic episodic memories that include many context details encoded in different ways simultaneously, previous studies have focused on unitization and its effect on the recognition of a single context detail. To further understand how various encoding strategies operate on item and context representations, we independently assigned unitization and relational association to 2 context details (size and color) of each item and tested the contribution of recollection and familiarity to source recognition of each detail. The influence of familiarity on retrieval of each context detail was compared as a function of the encoding strategy used for each detail. Receiver operating characteristic curves suggested that the unitization effect was not additive and that similar levels of familiarity occurred for 1 or multiple details when unitization was the only strategy applied during encoding. On the other hand, a detrimental effect was found when relational encoding and unitization were simultaneously applied to 1 item such that a salient nonunitized context detail interfered with the effortful processing required to unitize an accompanying context detail. However, this detrimental effect was not reciprocal and possibly dependent on the nature of individual context details. (PsycINFO Database Record PMID- 26237618 TI - Re-encountering individuals who previously engaged in joint gaze modulates subsequent gaze cueing. AB - We assessed the extent to which previous experience of joint gaze with people (i.e., looking toward the same object) modulates later gaze cueing of attention elicited by those individuals. Participants in Experiments 1 and 2a/b first completed a saccade/antisaccade task while a to-be-ignored face either looked at, or away from, the participants' eye movement target. Two faces always engaged in joint gaze with the participant, whereas 2 other faces never engaged in joint gaze. Then, we assessed standard gaze cueing in response to these faces to ascertain the effect of these prior interactions on subsequent social attention episodes. In Experiment 1, the face's eyes moved before the participant's target appeared, meaning that the participant always gaze-followed 2 faces and never gaze-followed 2 other faces. We found that this prior experience modulated the timecourse of subsequent gaze cueing. In Experiments 2a/b, the participant looked at the target first, then was either followed (i.e., the participant initiated joint gaze), or was not followed. These participants then showed an overall decrement of gaze cueing with individuals who had previously followed participants' eyes (Experiment 2a), an effect that was associated with autism spectrum quotient scores and modulated perceived trustworthiness of the faces (Experiment 2b). Experiment 3 demonstrated that these modulations are unlikely to be because of the association of different levels of task difficulty with particular faces. These findings suggest that establishing joint gaze with others influences subsequent social attention processes that are generally thought to be relatively insensitive to learning from prior episodes. PMID- 26237619 TI - How sequential changes in reward magnitude modulate cognitive flexibility: Evidence from voluntary task switching. AB - There is much evidence that the prospect of reward modulates cognitive control in terms of more stable behavior. Increases in expected reward magnitude, however, have been suggested to increase flexible behavior as evidenced by reduced switch costs. In a series of experiments, the authors provide evidence that this increased cognitive flexibility following increases in reward magnitude also promotes deliberate task switching. A modified task switching paradigm with forced- and free-choice trials and varying reward prospects was used. In Experiments 1-3 the prospect of a reward increase as compared to unchanged high reward increased voluntary switching rate (VSR). Experiment 4 showed that the prospect of a reward decrease did not alter VSR as compared to unchanged low reward. Experiment 5 used a standard voluntary task switching procedure and confirmed VSR effects found in Experiments 1-4. These findings are strong evidence for a mechanism that biases the cognitive system either toward stability or flexibility depending on changing reward expectation. Results are discussed within the framework of the adaptive gain theory. PMID- 26237620 TI - [Not Available]. PMID- 26237621 TI - Comparison of muscle activation pattern between alpine skiing and snowboarding. PMID- 26237623 TI - Preparing Parents to Be Present for Their Child's Anesthesia Induction: A Randomized Controlled Trial. AB - BACKGROUND: The purpose of this study is to compare the effectiveness of a brief preparation intervention for parental presence during induction of anesthesia (PPIA preparation) with a PPIA with standard preparation (PPIA standard). METHODS: Ninety-three children, aged 2 to 10 years, undergoing elective surgery at a children's hospital participated together with their parents. Parents were randomly assigned to receive either PPIA preparation or PPIA standard before their children's induction of anesthesia. Children of parents assigned to each group were compared on measures of preoperative anxiety, cooperation at induction, emergence delirium, and postoperative pain. Parents were compared on measures of state anxiety and self-efficacy about their role in the operating room (OR). RESULTS: The effectiveness of parental presence in reducing children's preoperative anxiety was not improved by the intervention at the holding stage (P =0.15, Wilcoxon Mann-Whitney odds [WMWodds; 95% confidence interval {CI}] = 1.41 [0.75-3.10]), the point at which the family left the holding area (P = 0.39, WMWodds [95% CI] = 1.18 [0.60-2.45]), the point that they entered the OR (P =0.28, WMWodds [95% CI] = 1.23 [0.65-2.67]), or the point at which the anesthesia mask was introduced (P = 1.3, WMWodds [95% CI] = 1.23 [0.64-2.63]). However, parents who received PPIA preparation trended toward greater self-efficacy about their role in the OR than those who received PPIA standard (P = 0.03, WMWodds [95% CI] = 1.69 [1.07-2.87]). CONCLUSIONS: A brief, video-based intervention aimed at preparing parents to be present for their child's anesthesia induction was not successful in reducing the children's preoperative anxiety. However, it is unclear whether parents included in this study actually performed as instructed in the intervention to reduce their children's anxiety. Future research should monitor parent behavior and support parental performance to reduce their children's preoperative anxiety. PMID- 26237624 TI - Solvation Thermodynamic Properties of Hydrogen Sulfide in [C4mim][PF6], [C4mim][BF4], and [C4mim][Cl] Ionic Liquids, Determined by Molecular Simulations. AB - Removal of hydrogen sulfide (H2S) and acid gases from natural gas is accomplished by absorption processes using a solvent. The gas solubility in a liquid can be used to measure the degree of removal of the gas and is quantified by the Henry's constant, the free energy of solvation at infinite dilution, or the excess chemical potential. In this work, Henry's constants and thermodynamic properties of solvation of H2S were calculated in three ionic liquids: [C4mim][PF6], [C4mim][BF4], and [C4mim][Cl] ([C4mim], 1-butyl-3-methyl imidazolium). The first step in this work was the evaluation of the force fields for the gas and condensed phases in order to obtain accurate values for the excess chemical potential for H2S on each ionic liquid using free energy perturbation techniques. In the H2S-[C4mim][PF6] and H2S-[C4mim][BF4] systems, the results obtained by molecular simulation agree with the experimental values reported in the literature. However, the solvation free energy calculated for the H2S-[C4mim][Cl] system can be considered predictive because of the lack of experimental data at the simulated conditions. Based on these results, the best solvent for removing H2S is [C4mim][Cl] because it has the highest affinity for this species (lowest value of the Henry's constant). Also, solvation thermodynamic properties such as enthalpy and entropy were calculated in order to evaluate their contribution to the free energy of solvation. PMID- 26237622 TI - Intraoperative Magnesium Administration Does Not Reduce Postoperative Atrial Fibrillation After Cardiac Surgery. AB - BACKGROUND: Hypomagnesemia has been associated with an increased risk of postoperative atrial fibrillation (POAF). Although previous studies have suggested a beneficial effect of magnesium (Mg) therapy, almost all of these are limited by small sample size and relatively low Mg dose. We hypothesized that high-dose Mg decreases the occurrence of new-onset POAF, and we tested this hypothesis by using data from a prospective trial that assessed the effect of Mg on cognitive outcomes in patients undergoing cardiac surgery. METHODS: A total of 389 patients undergoing cardiac surgery were enrolled in this double-blind, placebo-controlled trial. Subjects were randomized to receive Mg as a 50-mg/kg bolus immediately after induction of anesthesia followed by another 50 mg/kg as an infusion given over 3 hours (total dose, 100 mg/kg) or placebo. We tested the effect of Mg therapy on POAF with logistic regression, adjusting for the risk of atrial fibrillation (AF) by using the Multicenter Study of Perioperative Ischemia risk index for Atrial Fibrillation after Cardiac Surgery. RESULTS: Among the 363 patients analyzed, after we excluded patients with chronic or acute preoperative AF (placebo: n = 177; Mg: n = 186), the incidence of new-onset POAF was 42.5% (95% confidence interval [CI], 35%-50%) in the Mg group compared with 37.9% (95% CI, 31%-45%) in the placebo group (P = 0.40). The 95% CI for this absolute risk difference of 4.6% is -5.5% to 14.7%. The time to onset of POAF also was identical between the groups, and no significant effect of Mg was found in logistic regression analysis after we adjusted for AF risk (odds ratio, 1.09; 95% CI, 0.69-1.72; P = 0.73). CONCLUSIONS: High-dose intraoperative Mg therapy did not decrease the incidence of new-onset POAF after cardiac surgery. PMID- 26237625 TI - Invasive Infection of Post-Surgical Esophagocutaneous Fistula Due to Providencia stuartii. PMID- 26237626 TI - Can impaired working memory functioning be improved by training? A meta-analysis with a special focus on brain injured patients. AB - OBJECTIVE: Deficits in working memory (WM) are commonly observed after brain injuries and cause severe impairments in patients' everyday life. It is still under debate if training can enhance or rehabilitate WM in case of malfunction. The current meta-analysis investigates this issue from a clinical point of view. It addresses under which conditions and for which target group WM training may be justifiable. METHOD: Relevant WM training studies were identified by searching electronic literature databases with a comprehensive search term. In total, 103 studies, which added up to 112 independent group comparisons (N = 6,113 participants), were included in the analysis. RESULTS: Overall, WM training caused a moderate and long-lasting improvement in untrained WM tasks. Moreover, improvement of WM functioning led to sustainable better evaluation of everyday life functioning, however, effect sizes were small. Concerning transfer effects on other cognitive domains, long-lasting improvements with small effect sizes were observed in cognitive control and reasoning/intelligence. In contrast, small immediate, but no long-term effects were found for attention and long-term memory. Studies with brain injured patients demonstrated long-lasting improvements in WM functions with moderate to large effect sizes. A main moderator variable of intervention efficacy is the number of training sessions applied. CONCLUSION: WM training produces long-lasting beneficial effects which are strongly pronounced in patients with acquired brain injuries. This finding supports the application of WM training in clinical settings. To determine optimal training conditions, future studies must systematically investigate the characteristics of interventions as they are at present inevitably confounded. PMID- 26237628 TI - Neural correlates of prospective memory impairments in schizophrenia. AB - OBJECTIVE: Prospective memory (PM) refers to the ability to remember to carry out intended actions after a delay. PM impairments are common in schizophrenia patients and are thought to be related to their prefrontal cortex dysfunction; however, this has not yet been examined directly in the research literature. The current study aimed to examine abnormalities in brain activation during PM task performance in schizophrenia patients. METHOD: Twenty-two schizophrenia patients and 25 matched healthy controls were scanned in a 3-T MRI machine while performing a PM task. RESULTS: The results showed that compared to the healthy controls, schizophrenia patients performed significantly worse on the PM task. Furthermore, they exhibited decreased brain activation in frontal cortex including the right superior frontal gyri (Brodmann area 10), and other related brain areas like the anterior cingulate gyrus, parietal and temporal cortex, including precuneus, and some subcortext, including parahippocampal gyrus and putamen. CONCLUSIONS: These findings confirm the involvement and importance of the prefrontal cortex in PM and show evidence of hypofrontality in schizophrenia patients while performing a PM task. PMID- 26237627 TI - Late-life depression is not associated with dementia-related pathology. AB - OBJECTIVE: To test the hypothesis that late-life depression is associated with dementia-related pathology. METHOD: Older participants (n = 1,965) in 3 longitudinal clinical-pathologic cohort studies who had no cognitive impairment at baseline underwent annual clinical evaluations for a mean of 8.0 years (SD = 5.0). The authors defined depression diagnostically, as major depression during the study period, and psychometrically, as elevated depressive symptoms during the study period, and established their relation to cognitive outcomes (incident dementia, rate of cognitive decline). A total of 657 participants died and underwent a uniform neuropathologic examination. The authors estimated the association of depression with 6 dementia-related markers (tau tangles, beta amyloid plaques, Lewy bodies, hippocampal sclerosis, gross and microscopic infarcts) in logistic regression models. RESULTS: In the full cohort, 9.4% were diagnosed with major depression and 8.6% had chronically elevated depressive symptoms, both of which were related to adverse cognitive outcomes. In the 657 persons who died and had a neuropathologic examination, higher beta-amyloid plaque burden was associated with higher likelihood of major depression (present in 11.0%; OR = 1.392, 95% CI = 1.088, 1.780) but not with elevated depressive symptoms (present in 11.3%; OR = 0.919, 95% CI = 0.726, 1.165). None of the other pathologic markers was related to either of the depression measures. Neither dementia nor antidepressant medication modified the relation of pathology to depression. CONCLUSION: The results do not support the hypothesis that major depression is associated with dementia-related pathology. PMID- 26237630 TI - 3D location deduced by inertial measurement units: a challenging problem. PMID- 26237629 TI - Novel data-mining approach identifies biomarkers for diagnosis of Kawasaki disease. AB - BACKGROUND: As Kawasaki disease (KD) shares many clinical features with other more common febrile illnesses and misdiagnosis, leading to a delay in treatment, increases the risk of coronary artery damage, a diagnostic test for KD is urgently needed. We sought to develop a panel of biomarkers that could distinguish between acute KD patients and febrile controls (FC) with sufficient accuracy to be clinically useful. METHODS: Plasma samples were collected from three independent cohorts of FC and acute KD patients who met the American Heart Association definition for KD and presented within the first 10 d of fever. The levels of 88 biomarkers associated with inflammation were assessed by Luminex bead technology. Unsupervised clustering followed by supervised clustering using a Random Forest model was used to find a panel of candidate biomarkers. RESULTS: A panel of biomarkers commonly available in the hospital laboratory (absolute neutrophil count, erythrocyte sedimentation rate, alanine aminotransferase, gamma glutamyl transferase, concentrations of alpha-1-antitrypsin, C-reactive protein, and fibrinogen, and platelet count) accurately diagnosed 81-96% of KD patients in a series of three independent cohorts. CONCLUSION: After prospective validation, this eight-biomarker panel may improve the recognition of KD. PMID- 26237631 TI - Two-Step Growth of Two-Dimensional WSe2/MoSe2 Heterostructures. AB - Two dimensional (2D) materials have attracted great attention due to their unique properties and atomic thickness. Although various 2D materials have been successfully synthesized with different optical and electrical properties, a strategy for fabricating 2D heterostructures must be developed in order to construct more complicated devices for practical applications. Here we demonstrate for the first time a two-step chemical vapor deposition (CVD) method for growing transition-metal dichalcogenide (TMD) heterostructures, where MoSe2 was synthesized first and followed by an epitaxial growth of WSe2 on the edge and on the top surface of MoSe2. Compared to previously reported one-step growth methods, this two-step growth has the capability of spatial and size control of each 2D component, leading to much larger (up to 169 MUm) heterostructure size, and cross-contamination can be effectively minimized. Furthermore, this two-step growth produces well-defined 2H and 3R stacking in the WSe2/MoSe2 bilayer regions and much sharper in-plane interfaces than the previously reported MoSe2/WSe2 heterojunctions obtained from one-step growth methods. The resultant heterostructures with WSe2/MoSe2 bilayer and the exposed MoSe2 monolayer display rectification characteristics of a p-n junction, as revealed by optoelectronic tests, and an internal quantum efficiency of 91% when functioning as a photodetector. A photovoltaic effect without any external gates was observed, showing incident photon to converted electron (IPCE) efficiencies of approximately 0.12%, providing application potential in electronics and energy harvesting. PMID- 26237632 TI - The value of magnetic resonance imaging and ultrasonography (MRI/US)-fusion biopsy platforms in prostate cancer detection: a systematic review. AB - Despite limitations considering the presence, staging and aggressiveness of prostate cancer, ultrasonography (US)-guided systematic biopsies (SBs) are still the 'gold standard' for the diagnosis of prostate cancer. Recently, promising results have been published for targeted prostate biopsies (TBs) using magnetic resonance imaging (MRI) and ultrasonography (MRI/US)-fusion platforms. Different platforms are USA Food and Drug Administration registered and have, mostly subjective, strengths and weaknesses. To our knowledge, no systematic review exists that objectively compares prostate cancer detection rates between the different platforms available. To assess the value of the different MRI/US-fusion platforms in prostate cancer detection, we compared platform-guided TB with SB, and other ways of MRI TB (cognitive fusion or in-bore MR fusion). We performed a systematic review of well-designed prospective randomised and non-randomised trials in the English language published between 1 January 2004 and 17 February 2015, using PubMed, Embase and Cochrane Library databases. Search terms included: 'prostate cancer', 'MR/ultrasound(US) fusion' and 'targeted biopsies'. Extraction of articles was performed by two authors (M.G. and A.A.) and were evaluated by the other authors. Randomised and non-randomised prospective clinical trials comparing TB using MRI/US-fusion platforms and SB, or other ways of TB (cognitive fusion or MR in-bore fusion) were included. In all, 11 of 1865 studies met the inclusion criteria, involving seven different fusion platforms and 2626 patients: 1119 biopsy naive, 1433 with prior negative biopsy, 50 not mentioned (either biopsy naive or with prior negative biopsy) and 24 on active surveillance (who were disregarded). The Quality Assessment of Diagnostic Accuracy Studies (QUADAS 2) tool was used to assess the quality of included articles. No clear advantage of MRI/US fusion-guided TBs was seen for cancer detection rates (CDRs) of all prostate cancers. However, MRI/US fusion-guided TBs tended to give higher CDRs for clinically significant prostate cancers in our analysis. Important limitations of the present systematic review include: the limited number of included studies, lack of a general definition of 'clinically significant' prostate cancer, the heterogeneous study population, and a reference test with low sensitivity and specificity. Today, a limited number of prospective studies have reported the CDRs of fusion platforms. Although MRI/US-fusion TB has proved its value in men with prior negative biopsies, general use of this technique in diagnosing prostate cancer should only be performed after critical consideration. Before bringing MRI/US fusion-guided TB in to general practice, there is a need for more prospective studies on prostate cancer diagnosis. PMID- 26237634 TI - Universal strategy to engineer catalytic DNA hairpin assemblies for protein analysis. AB - Nucleic acids can be programmed into enzyme-free catalytic DNA circuits (CDCs) to carry out various functions ranging from DNA computing to signal amplifications for biosensing. Catalytic hairpin assembly (CHA), the accelerated hybridization between two DNA hairpins catalyzed by a DNA input, is one of the most widely studied and used CDCs for amplified detection of nucleic acids and small molecules. So far, it is still challenging to expand CHAs to proteins largely due to the lack of a universal strategy to construct protein-responsive CHAs. To address this challenge, we demonstrate that a rationally designed protein-DNA binding complex can be used as an effective catalyst to accelerate CHA reactions. On the basis of this principle, we developed specific CHAs for a number of important protein biomarkers, including human alpha-thrombin, human prostate specific antigen, and human epidermal growth factor receptor 2. Upon establishing this panel of protein-responsive CHAs, we further explore their potential applications to the detection of specific protein biomarkers from human serum samples and cancer cells. PMID- 26237635 TI - Retraction. Milestone in the NTB phase investigation and beyond: direct insight into molecular self-assembly. PMID- 26237636 TI - Microleakage of Class I and II Composite Resin Restorations Using a Sonic-resin Placement System. AB - OBJECTIVES: To determine microleakage of posterior Class I and II restorations using the SonicFill composite resin system. METHODS AND MATERIALS: Eighty previously extracted third molars were randomly assigned to four preparation/restoration groups (n=20): Group A: Class I preparations restored with SonicFill system/bulk fill; Group B: Class II preparations restored with SonicFill system/bulk fill; Group C: Class I preparations restored with Herculite Ultra composite resin/incremental technique; and Group D: Class II preparations restored with Herculite Ultra composite resin/incremental technique. Class I preparations were approximately 3.0 mm in width buccolingually and 3.0 mm in depth. Class II preparations were approximately 3.0 mm in width buccolingually, 1.5 mm in axial depth, and 4.0 mm in gingival depth. In all groups, the enamel and dentin surfaces were conditioned with Kerr 37.5% phosphoric acid, followed by application of Optibond Solo Plus adhesive system. Following restoration, the specimens were thermocycled, immersed in methylene blue dye, and embedded in acrylic resin. Specimen blocks were sectioned in the mesiodistal direction, with marginal dye penetration (microleakage) examined using a 20* binocular microscope. Class I and II restoration microleakage was scored separately using a 0-3 ordinal ranking system. Statistical analyses were conducted using nonparametric testing at the p < 0.05 level of significance. RESULTS: Significantly less microleakage was associated with both Class I restorative groups (A and C), SonicFill bulk fill and Herculite Ultra incremental fill, compared to the Class II restorative groups (B and D), SonicFill/bulk fill and Herculite Ultra/incremental fill. CONCLUSIONS: According to the results of this study, the materials (SonicFill vs Herculite Ultra), C-factors, and insertion techniques (bulk vs incremental) did not appear to be significant influences with regard to marginal microleakage; however, the type of preparation cavity (Class I vs Class II) and the subsequent bonding surface (enamel vs dentin [cementum]) proved to be significant factors. PMID- 26237637 TI - Detection of Caries Around Amalgam Restorations on Approximal Surfaces. AB - To evaluate the in vitro performance of the International Caries Detection and Assessment System (ICDAS) visual examination, bitewing radiography (BW), and the DIAGNOdent 2190, a pen-type laser fluorescence device (LFpen), in detecting caries around amalgam restorations on approximal surfaces. Approximal surfaces (N=136) of permanent posterior teeth (N=110) with Class II amalgam restorations were assessed twice by two experienced examiners using ICDAS, BW, and LFpen. The occurrence of proximal overhangs was also evaluated. The teeth were histologically prepared and assessed for caries extension. Different cutoff limits for the LFpen were used. Intraexaminer and interexaminer reproducibility showed moderate to good agreement for all the methods (weighted kappa/intraclass correlation coefficient=0.40 to 0.87). The specificities at D1 (all visible lesions affecting enamel) and D3 (lesions extended into dentin) were, respectively, 0.41 and 0.82 for ICDAS, 0.70 and 0.82 for BW, and 0.77-0.89 and 0.88-0.94 for LFpen. The sensitivities were 0.80 and 0.52 for ICDAS, 0.56 and 0.51 for BW, and 0.04-0.23 and 0.01-0.02 for LFpen at D1 and D3, respectively. At the D1/D3 thresholds, the accuracy and the area under the receiver operating characteristic curve (Az) values were similar and statistically higher for ICDAS (0.65/0.68 and 0.633/0.688) and BW (0.64/0.68 and 0.655/0.719), respectively; whereas, LFpen presented lower accuracy (0.37-0.44/0.49-0.52) and Az (0.390 0.454/0.345-0.395) values. The occurrence of overhangs (26.8%) was shown to be irrelevant in determining the presence of secondary caries. The ICDAS and BW methods presented the best performance in detecting caries lesions affecting enamel and dentin on approximal surfaces of amalgam restorations. PMID- 26237638 TI - Effect of High Irradiance on Depth of Cure of a Conventional and a Bulk Fill Resin-based Composite. AB - OBJECTIVES: This study evaluated the effect of using three commercial light curing units (LCUs) delivering a range of irradiance values, but delivering similar radiant exposures on the depth of cure of two different resin-based composites (RBCs). METHODS: A conventional hybrid RBC (Z100 shade A2, 3M ESPE) or a bulk fill RBC (Tetric EvoCeram Bulk Fill shade IVA, Ivoclar Vivadent) was packed into a 10-mm deep semicircular metal mold with a 2-mm internal radius. The RBC was exposed to light from a plasma-arc-curing (PAC) light (Sapphire Plus, DenMat) for five seconds, a quartz-tungsten-halogen (QTH) light (Optilux 501, Kerr) for 40 seconds, or a light-emitting-diode (LED) light (S10, 3M ESPE) for 20 seconds and 40 seconds (control). The Knoop microhardness was then measured as soon as possible at the top surface and at three points every 0.5 mm down from the surface. For each RBC, a repeated measures analysis of variance (ANOVA) model was used to predict the Knoop hardness in a manner analogous to a standard regression model. This predicted value was used to determine at what depth the RBC reached 80% of the mean hardness achieved at the top surface with any light. RESULTS: The PAC light delivered an irradiance and radiant exposure of 7328 mW/cm(2) and 36.6 J/cm(2), respectively, to the RBCs; the QTH light delivered 936 mW/cm(2) and 37.4 J/cm(2) and in 20 seconds the LED light delivered 1825 mW/cm(2) and 36.5 J/cm(2). In 40 seconds, the control LED light delivered a radiant exposure of 73.0 J/cm(2). For Z100, using 80% of the maximum hardness at the top surface as the criteria for adequate curing, all light exposure conditions achieved the 2.0-mm depth of cure claimed by the manufacturer. The LED light used for 40 seconds achieved the greatest depth of cure (5.0 mm), and the PAC light used for five seconds, the least (2.5 mm). Tetric EvoCeram Bulk Fill achieved a 3.5-mm depth of cure when the broad-spectrum QTH light was used for 40 seconds delivering 37.4 J/cm(2). It required a 40-second exposure time with the narrow spectrum LED, delivering approximately 73 J/cm(2) to reach a depth of cure of 4 mm. CONCLUSIONS: When delivering a similar radiant exposure of 37 J/cm(2), the QTH (40 seconds) and LED (20 seconds) units achieved a greater depth of cure than the PAC (five seconds) light. For both resins, the greatest depth of cure was achieved when the LED light was used for 40 seconds delivering 73 J/cm(2) (p<0.05). PMID- 26237639 TI - Effect of Photoactivation Timing on the Mechanical Properties of Resin Cements and Bond Strength of Fiberglass Post to Root Dentin. AB - OBJECTIVES: This study tested the hypothesis that photoactivation timing and resin cement affect mechanical properties and bond strength of fiberglass posts to root dentin at different depths. METHODS: Fiberglass posts (Exacto, Angelus) were luted with RelyX Unicem (3M ESPE), Panavia F 2.0 (Kuraray), or RelyX ARC (3M ESPE) using three photoactivation timings: light curing immediately, after three minutes, or after five minutes. Push-out bonding strength, PBS (n=10) was measured on each root region (coronal, middle, apical). The elastic modulus (E) and Vickers hardness (VHN) of the cement layer along the root canal were determined using dynamic indentation (n=5). A strain-gauge test was used to measure post-gel shrinkage of each cement (n=10). Residual shrinkage stress was assessed with finite element analysis. Data were analyzed with two-way analysis of variance in a split-plot arrangement and a Tukey test (alpha=0.05). Multiple linear regression analysis was used to determine the influence of study factors. RESULTS: The five-minute delay photoactivation timing significantly increased the PBS for all resin cements evaluated. The PBS decreased significantly from coronal to apical root canal regions. The mean values for E and VHN increased significantly with the delayed photoactivation for RelyX Unicem and decreased from coronal to apical root regions for all resin cements with the immediate curing timing. CONCLUSIONS: The PBS of fiber posts to root dentin, E, and VHN values were affected by the root canal region, photoactivation timing, and resin cement type. Shrinkage stress values decreased gradually with delayed photoactivation for all the cements. PMID- 26237640 TI - In Vitro Biocompatibility of Contemporary Bulk-fill Composites. AB - This study evaluated the biocompatibility of contemporary bulk-fill resin-based composites (RBCs) including PRG (pre-reacted glass ionomer) materials based on the International Organization for Standardization 10993. In addition, the effect of composite thickness on cytotoxicity was also assessed. Two standard composites, two bulk-fill PRG RBCs, and three bulk-fill non-PRG RBCs were investigated. Block-shaped specimens of 2-mm and 4-mm thickness were cured with an irradiance of 700 mW/cm(2) for 20 seconds with a light-emitting diode curing light and eluted with culture medium at 37 degrees C for 24 hours. L929 mouse fibroblasts were exposed to extracts at varying dilutions (1:1, 1:2, and 1:10) for 24 hours. Analyses were performed to assess cytotoxicity, phase contrast microscopy, and quantitative cell viability. Among the bulk-fill RBCs, extracts of PRG materials resulted in the lowest cell viability. At 4-mm thickness, undiluted extracts of bulk-fill non-PRG RBCs had significantly higher cell viability than the standard composites. Chemical composition, specimen thickness, and testing concentrations of extracts had significant effects on cell viability and morphology. Cytotoxic effects of composites on cell viability were parallel with cell morphologic changes. Not all bulk-fill RBCs demonstrated high cell viability (>70%) at 4-mm thickness despite manufacturers' recommendations of bulk placement and curing. PMID- 26237641 TI - Effectiveness of Fluorescence-based Methods in Monitoring Progression of Noncavitated Caries-like Lesions on Smooth Surfaces. AB - Although there has been a significant decrease in caries prevalence in developed countries, the slower progression of dental caries requires methods capable of detecting and quantifying lesions at an early stage. The aim of this study was to evaluate the effectiveness of fluorescence-based methods (DIAGNOdent 2095 laser fluorescence device [LF], DIAGNOdent 2190 pen [LFpen], and VistaProof fluorescence camera [FC]) in monitoring the progression of noncavitated caries like lesions on smooth surfaces. Caries-like lesions were developed in 60 blocks of bovine enamel using a bacterial model of Streptococcus mutans and Lactobacillus acidophilus . Enamel blocks were evaluated by two independent examiners at baseline (phase I), after the first cariogenic challenge (eight days) (phase II), and after the second cariogenic challenge (a further eight days) (phase III) by two independent examiners using the LF, LFpen, and FC. Blocks were submitted to surface microhardness (SMH) and cross-sectional microhardness analyses. The intraclass correlation coefficient for intra- and interexaminer reproducibility ranged from 0.49 (FC) to 0.94 (LF/LFpen). SMH values decreased and fluorescence values increased significantly among the three phases. Higher values for sensitivity, specificity, and area under the receiver operating characteristic curve were observed for FC (phase II) and LFpen (phase III). A significant correlation was found between fluorescence values and SMH in all phases and integrated loss of surface hardness (DeltaKHN) in phase III. In conclusion, fluorescence-based methods were effective in monitoring noncavitated caries-like lesions on smooth surfaces, with moderate correlation with SMH, allowing differentiation between sound and demineralized enamel. PMID- 26237642 TI - Evaluation of the Radiopacities of Bulk-fill Restoratives Using Two Digital Radiography Systems. AB - This study investigated the radiopacity values of bulk-fill restoratives by using two digital radiography systems. Nine bulk-fill restoratives and a conventional composite were used in the study. Six disc-shaped specimens were prepared from each of these materials, three each at thicknesses of 1 mm and 2 mm, and tooth slices with these same thicknesses were obtained. As a control, an aluminum step wedge varying in thickness from 0.5 to 10 mm in was used. Three specimens of each of the materials, together with the tooth slice and the aluminum step wedge, were placed over a complementary metal oxide semiconductor (CMOS) sensor and a storage photostimulable phosphor (PPS) plate system and exposed using a dental x-ray unit. The images were analyzed using a software program to measure the mean gray values (MGVs). Five measurements were obtained from each of the restorative materials, the enamel, the dentin, and the stepwedge. The MGVs were converted to the equivalent aluminum thicknesses. Three-way analysis of variance (ANOVA) was used to determine the significance of the differences among the groups. A Tukey test was applied for pairwise comparisons (p<0.05). All composite-based restoratives were found to have greater radiopacities than enamel or dentin. Equia Fil had the lowest radiopacity value. Radiopacity increased as the thicknesses of the restorative material increased. The CMOS system showed significantly higher radiopacity values than the PSP system. In conclusion, all investigated bulk-fill restoratives passed the International Organization for Standardization and American National Standard Institute/American Dental Association requirements for radiopacity values when evaluated with the two digital radiography systems. PMID- 26237643 TI - Two-year Randomized, Controlled Clinical Trial of a Flowable and Conventional Composite in Class I Restorations. AB - OBJECTIVES: This study evaluated the two-year clinical performance and volumetric wear of a flowable resin composite compared to a conventional highly filled composite resin in Class I restorations. METHODS AND MATERIALS: In this single center, single-blinded, comparator-controlled clinical study (Institutional Review Board approved), 120 carious teeth distributed in 60 patients were randomly assigned to four calibrated practitioners who placed occlusal restorations (n=60 flowable and n=60 conventional composite). Direct and indirect assessment at baseline, six months, one year, and two years occurred during which the modified Cvar and Ryge criteria were evaluated. Volumetric wear was determined by superimposition of profilometer scans of baseline and two-year casts. RESULTS: At two years, there was no significant difference in anatomic form (p=0.80), color match (p=0.08), marginal adaptation (p=0.89), marginal discoloration (p=0.79), surface integrity (p=0.18), secondary caries (p=0.66), cold sensitivity (p=0.522), occlusal sensitivity (p=0.818), or volumetric wear (p=0.661) between materials. Both materials showed a decrease in all criteria except secondary caries (p=0.95) over time. Two-year mean volumetric wear was 3.16 +/- 2.38 mm(3) for the flowable composite and 3.43 +/- 2.50 mm(3) for the conventional composite. CONCLUSIONS: The flowable and conventional composites used in this study have similar clinical efficacy after two years of service when placed as Class I occlusal restorations having isthmus widths less than one-half the intercuspal distance. PMID- 26237644 TI - Effect of Restorative Protocol on Cuspal Strain and Residual Stress in Endodontically Treated Molars. AB - OBJECTIVES: To evaluate the effect of the restorative protocol on cuspal strain, fracture resistance, residual stress, and mechanical properties of restorative materials in endodontically treated molars. METHODS: Forty-five molars received mesio-occlusal-distal (MOD) Class II preparations and endodontic treatment followed by direct restorations using three restorative protocols: composite resin (CR) only (Filtek Supreme, 3M-ESPE), resin modified glass ionomer cement in combination with CR (Vitremer, 3M-ESPE in pulp chamber and Filtek Supreme in MOD cavity), conventional glass ionomer cement in combination with composite resin (CGI-CR) (Ketac Fil, 3M-ESPE in pulp chamber and Filtek Supreme in MOD cavity). Cuspal strain was measured using strain gauges, and fracture resistance was tested with an occlusal load. Elastic modulus (EM) and Vickers hardness (VH) of the restorative materials were determined at different depths using dynamic microhardness indentation. Curing shrinkage was measured using the strain gauge technique. The restorative protocols were also simulated in finite element analysis (FEA). The shrinkage strain, cuspal strain, EM, VH, and fracture resistance data were statistically analyzed using split-plot analysis of variance and Tukey test (p=0.05). Residual shrinkage stresses were expressed in modified von Mises equivalent stresses. RESULTS: Shrinkage strain values (in volume %) were Ketac Fil (0.08+/-0.01) < Vitremer (0.18+/-0.01) < Filtek Supreme (0.54+/ 0.03). Cuspal strain was higher and fracture resistance was lower when using CR only compared with the techniques that used glass ionomer. The EM and VH of the materials in the pulp chamber were significantly lower for glass ionomer. The FEA showed that using CR only resulted in higher residual stresses in enamel and root dentin close to the pulp chamber than the combinations with glass ionomers (RMGI CR and CGI-CR). CONCLUSIONS: The choice of restorative protocol significantly affected the biomechanical behavior of endodontically treated molars. Using glass ionomer to fill the pulp chamber is recommended when endodontically treated molars receive direct composite restorations because it reduces cuspal strain and increases fracture resistance. PMID- 26237645 TI - Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. AB - Histone methylation regulates DNA repair. However, the mechanisms that underlie the regulation of histone methylation during this repair remain to be further defined. Here, we show that exposure to ionizing radiation induces DNA-PK dependent phosphorylation of nuclear fumarase at Thr 236, which leads to an interaction between fumarase and the histone variant H2A.Z at DNA double-strand break (DSB) regions. Locally generated fumarate inhibits KDM2B histone demethylase activity, resulting in enhanced dimethylation of histone H3 Lys 36; in turn, this increases the accumulation of the Ku70-containing DNA-PK at DSB regions for non-homologous end-joining DNA repair and cell survival. These findings reveal a feedback mechanism that underlies DNA-PK regulation by chromatin-associated fumarase and an instrumental function of fumarase in regulating histone H3 methylation and DNA repair. PMID- 26237646 TI - Niche appropriation by Drosophila intestinal stem cell tumours. AB - Mutations that inhibit differentiation in stem cell lineages are a common early step in cancer development, but precisely how a loss of differentiation initiates tumorigenesis is unclear. We investigated Drosophila intestinal stem cell (ISC) tumours generated by suppressing Notch (N) signalling, which blocks differentiation. Notch-defective ISCs require stress-induced divisions for tumour initiation and an autocrine EGFR ligand, Spitz, during early tumour growth. On achieving a critical mass these tumours displace surrounding enterocytes, competing with them for basement membrane space and causing their detachment, extrusion and apoptosis. This loss of epithelial integrity induces JNK and Yki/YAP activity in enterocytes and, consequently, their expression of stress dependent cytokines (Upd2, Upd3). These paracrine signals, normally used within the stem cell niche to trigger regeneration, propel tumour growth without the need for secondary mutations in growth signalling pathways. The appropriation of niche signalling by differentiation-defective stem cells may be a common mechanism of early tumorigenesis. PMID- 26237647 TI - CapZ regulates autophagosomal membrane shaping by promoting actin assembly inside the isolation membrane. AB - A fundamental question regarding autophagosome formation is how the shape of the double-membrane autophagosomal vesicle is generated. Here we show that in mammalian cells assembly of an actin scaffold inside the isolation membrane (the autophagosomal precursor) is essential for autophagosomal membrane shaping. Actin filaments are depolymerized shortly after starvation and actin is assembled into a network within the isolation membrane. When formation of actin puncta is disrupted by an actin polymerization inhibitor or by knocking down the actin capping protein CapZbeta, isolation membranes and omegasomes collapse into mixed membrane bundles. Formation of actin puncta is PtdIns(3)P dependent, and inhibition of PtdIns(3)P formation by treating cells with the PI(3)K inhibitor 3 MA, or by knocking down Beclin-1, abolishes the formation of actin puncta. Binding of CapZ to PtdIns(3)P, which is enriched in omegasomes, stimulates actin polymerization. Our findings illuminate the mechanism underlying autophagosomal membrane shaping and provide key insights into how autophagosomes are formed. PMID- 26237648 TI - Optimizing the Safe Use of Direct Oral Anticoagulants in Older Patients: A Teachable Moment. PMID- 26237649 TI - Perspectives on Knowledge Discovery Algorithms Recently Introduced in Chemoinformatics: Rough Set Theory, Association Rule Mining, Emerging Patterns, and Formal Concept Analysis. AB - Knowledge Discovery in Databases (KDD) refers to the use of methodologies from machine learning, pattern recognition, statistics, and other fields to extract knowledge from large collections of data, where the knowledge is not explicitly available as part of the database structure. In this paper, we describe four modern data mining techniques, Rough Set Theory (RST), Association Rule Mining (ARM), Emerging Pattern Mining (EP), and Formal Concept Analysis (FCA), and we have attempted to give an exhaustive list of their chemoinformatics applications. One of the main strengths of these methods is their descriptive ability. When used to derive rules, for example, in structure-activity relationships, the rules have clear physical meaning. This review has shown that there are close relationships between the methods. Often apparent differences lie in the way in which the problem under investigation has been formulated which can lead to the natural adoption of one or other method. For example, the idea of a structural alert, as a structure which is present in toxic and absent in nontoxic compounds, leads to the natural formulation of an Emerging Pattern search. Despite the similarities between the methods, each has its strengths. RST is useful for dealing with uncertain and noisy data. Its main chemoinformatics applications so far have been in feature extraction and feature reduction, the latter often as input to another data mining method, such as an Support Vector Machine (SVM). ARM has mostly been used for frequent subgraph mining. EP and FCA have both been used to mine both structural and nonstructural patterns for classification of both active and inactive molecules. Since their introduction in the 1980s and 1990s, RST, ARM, EP, and FCA have found wide-ranging applications, with many thousands of citations in Web of Science, but their adoption by the chemoinformatics community has been relatively slow. Advances, both in computer power and in algorithm development, mean that there is the potential to apply these techniques to larger data sets and thus to different problems in the future. PMID- 26237650 TI - Prebiotic effect of Agave fourcroydes fructans: an animal model. AB - The use of prebiotics such as fructans has increased in human and animal nutrition because of their productive performance and health benefits. Agave fourcroydes has shown high concentrations of fructans in their stems; however, there is no information on new products derived from this plant that might enhance its added value. Therefore, we evaluated the prebiotic effect of Agave fourcroydes fructans in an animal model. Male mice (C57BL/6J) were fed on parallel form with a standard diet or diets supplemented with 10% of fructans from Cichorium intybus (Raftilose P95) and Agave fourcroydes from Cuba for 35 days. The body weight, food intake, blood glucose, triglycerides and cholesterol, gastrointestinal organ weights, fermentation indicators in cecal and colon contents and mineral content in femurs were determined. The body weight and food intake of mice were not significantly modified by any treatment. However, serum glucose, cholesterol and triglycerides decreased (P < 0.01) in the fructans groups with respect to the standard diet group; this decrement was higher in the A. fourcroydes group with respect to the Raftilose P95 group. Mice groups supplemented with fructans exhibited increased (P < 0.01) total and wall cecal and colon weights. The fermentation indicators, short-chain fatty acids (SCFAs) and pH decreased (P < 0.001) in the groups that consumed fructans in their diets with respect to the standard diet. The diets supplemented with fructans also increased the mineral concentrations of calcium (P < 0.01) and magnesium (P < 0.05) in the right femurs. In conclusion, the inclusion of fructans from Agave fourcroydes in the mice diet induced a prebiotic response, similar to or greater than the commercial product (Raftilose P95) and this constitutes a promising alternative with potential use not only in animal but also in human diets. PMID- 26237651 TI - Erratum: Effects of time delay and space on herbivore dynamics: linking inducible defenses of plants to herbivore outbreak. PMID- 26237652 TI - Limited acquisition and generalisation of rhotics with ultrasound visual feedback in childhood apraxia. AB - Ultrasound visual feedback of the tongue is one treatment option for individuals with persisting speech sound errors. This study evaluated children's performance during acquisition and generalisation of American English rhotics using ultrasound feedback. Three children aged 10-13 with persisting speech sound errors associated with childhood apraxia of speech (CAS) were treated for 14 one hour sessions. Two of the participants increased the accuracy of their rhotic production during practise trials within treatment sessions, but none demonstrated generalisation to untreated words. Lack of generalisation may be due to a failure to acquire the target with sufficient accuracy during treatment, or to co-existing linguistic weaknesses that are not addressed in a motor-based treatment. Results suggest a need to refine the intervention procedures for CAS and/or a need to identify appropriate candidates for intervention to optimise learning. PMID- 26237653 TI - High-resolution mass spectrometry for detecting Acetylcholine in Arabidopsis. AB - Acetylcholine (ACh) was first identified a century ago, and has long been known as a neurotransmitter in animals. However, it has been shown recently that the occurrence of ACh is widespread among various non-animal species including higher plants. Although previous reports suggest that various plant species are capable of responding to exogenously applied ACh, the molecular basis for ACh biosynthesis and regulatory mechanisms mediated by endogenous ACh are largely unclear. This is partly because of the lack of conclusive data on the occurrence and the tissue specificity of ACh in plants. To this end, we performed various analyses including liquid chromatography electro-chemical detection (LC-ECD), liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. The results, together with electrospray ionization-orbitrap Fourier transform mass spectrometry (ESI-orbitrap FT-MS) analysis provide strong evidence that ACh exists in Arabidopsis thaliana tissues. The results also showed that the level of ACh is highest in seed, followed by root and cotyledon. Moreover, exogenously applied ACh inhibited the elongation of Arabidopsis root hairs. These results collectively indicate that ACh exists primarily in seed and root in Arabidopsis seedlings, and plays a pivotal role during the initial stages of seedling development by controlling root hair elongation in Arabidopsis. PMID- 26237654 TI - Continuous Veno-Venous Hemodiafiltration and Plasma Exchange in Infantile Acute Liver Failure. AB - OBJECTIVES: The purpose of the current study was to assess our multidisciplinary approach consisting of early application of neurology-oriented intensive care, aggressive artificial liver support and liver transplantation at the appropriate time for infants with acute liver failure. DESIGN: Retrospective cohort study. SETTING: A tertiary pediatric medical center in Japan. PATIENTS: Seventeen infants younger than 12 months with acute liver failure who subsequently underwent liver transplantation between February 2006 and June 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The patients varied from 1 to 11 months, with a median of 6 months. The median body weight was 8.0 kg (range, 2.7-10 kg). With respect to the encephalopathy grading before liver transplantation, four cases were categorized as grade II, seven cases were categorized as grade III, and five cases were categorized as grade IV. Continuous veno-venous hemodiafiltration and plasma exchange were applied to all the infants until liver transplantation. Bilirubin, ammonia, prothrombin time/international normalized ratio and creatinine decreased significantly after continuous veno venous hemodiafiltration + plasma exchange (p < 0.001). The median value of catecholamine index changed from 10 to 0 (range, 0-20.6). Notably, among the 16 infants who underwent electroencephalography assessment, five did not show slow waves throughout their stay, and one who did so before treatment ceased to show any after treatment. The all patients underwent living-donor liver transplantation and were subsequently discharged from the PICU. The overall survival rate was 88% (15/17) with a median follow-up period of 28 months (range, 2-64 mo). Regarding the neurological outcomes of the survivors, 73% (11/15) had no neurological morbidities and 20% (3/15) had mild disabilities. CONCLUSIONS: Our multidisciplinary approach for infants with acute liver failure achieved favorable outcomes. Further investigations are needed to examine the efficacy of the artificial liver support. PMID- 26237655 TI - Changes to Workflow and Process Measures in the PICU During Transition From Semi to Full Electronic Health Record. AB - OBJECTIVES: Studies showing the changes in workflow during transition from semi to full electronic medical records are lacking. This objective study is to identify the changes in workflow in the PICU during transition from semi to full electronic health record. DESIGN: Prospective observational study. Children's Hospital of Wisconsin Institutional Review Board waived the need for approval so this study was institutional review board exempt. This study measured clinical workflow variables at a 72-bed PICU during different phases of transition to a full electronic health record, which occurred on November 4, 2012. Phases of electronic health record transition were defined as follows: pre-electronic health record (baseline data prior to transition to full electronic health record), transition phase (3 wk after electronic health record), and stabilization (6 mo after electronic health record). Data were analyzed for the three phases using Mann-Whitney U test with a two-sided p value of less than 0.05 considered significant. SETTING: Seventy-two bed PICU. PATIENTS: All patients in the PICU were included during the study periods. MEASUREMENTS AND MAIN RESULTS: Five hundred and sixty-four patients with 2,355 patient days were evaluated in the three phases. Duration of rounds decreased from a median of 9 minutes per patient pre--electronic health record to 7 minutes per patient post electronic health record. Time to final note decreased from 2.06 days pre--electronic health record to 0.5 days post electronic health record. Time to first medication administration after admission also decreased from 33 minutes pre--electronic health record and 7 minutes post electronic health record. Time to Time to medication reconciliation was significantly higher pre-electronic health record than post electronic health record and percent of medication reconciliation completion was significantly lower pre--electronic health record than post electronic health record and percent of medication reconciliation completion was significantly higher pre--electronic health record than. There was no significant change in time between placement of discharge order and physical transfer from the unit [corrected].changes clinical workflow in a PICU with decreased duration of rounds, time to final note, time to medication administration, and time to medication reconciliation completion. There was no change in the duration from medical to physical transfer. PMID- 26237656 TI - Pediatric Organ Donation Potential at a Children's Hospital. AB - OBJECTIVES: To estimate the organ donation potential of patients dying at a children's hospital. DESIGN: Retrospective cohort study. SETTING: A free standing, 271-bed, tertiary Children's Hospital with a pediatric trauma center. PATIENTS: Patients dying in any ICU during 2011-2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 224 deaths, 23 (10%) met neurologic criteria for death: 18 donated organs (conversion rate 78%), 47 (19%) died without prior limitation of life-sustaining therapies, and the remaining 69% had withdrawal of life-sustaining therapies. Among those dying after withdrawal of life-sustaining therapies (n = 154), the organ procurement organization was not notified prior to death in 24%, and older patients were more likely to be referred compared to those less than 1 year old. Infection, cancer, and organ dysfunction were the most frequent conditions that disqualified dying patients from suitability for donation. Just over half of children more than 1 year old were suitable for donation after withdrawal of life-sustaining therapies compared to a fifth of infants (19%). Of 45 suitable for donation, 37 (82%) died within 1 hour. None of 7 infants younger than 1 month old died within 20 minutes, compared with 46% of infants between 1 month and 1 year (n = 6) and 72% of older children. Thirty three families (73%) did not permit donation after circulatory criteria for death whereas 12 (27%) gave permission for donation, and all 12 were actual donors (conversion rate 12/37 [32%]). CONCLUSIONS: The number of pediatric potential candidates for donation after circulatory determination of death was significantly larger than potential candidates for donation after neurologic determination of death at our hospital, but the actual donation rate was significantly lower. Increasing acceptance of donation after circulatory determination of death could increase organ donation. Among all children having withdrawal of life-sustaining therapies, donation after circulatory determination of death potential is less for infants. PMID- 26237657 TI - Risk Factors for Extubation Failure Following Neonatal Cardiac Surgery. AB - OBJECTIVE: Extubation failure after neonatal cardiac surgery has been associated with considerable postoperative morbidity, although data identifying risk factors for its occurrence are sparse. We aimed to determine risk factors for extubation failure in our neonatal cardiac surgical population. DESIGN: Retrospective chart review. SETTING: Urban tertiary care free-standing children's hospital. PATIENTS: Neonates (0-30 d) who underwent cardiac surgery at our institution between January 2009 and December 2012 was performed. INTERVENTIONS: Extubation failure was defined as reintubation within 72 hours after extubation from mechanical ventilation. Multivariate logistic regression analysis was performed to determine independent risk factors for extubation failure. MEASUREMENTS AND MAIN RESULTS: We included 120 neonates, of whom 21 (17.5%) experienced extubation failure. On univariate analysis, patients who failed extubation were more likely to have genetic abnormalities (24% vs 6%; p = 0.023), hypoplastic left heart (43% vs 17%; p = 0.009), delayed sternal closure (38% vs 12%; p = 0.004), postoperative infection prior to extubation (38% vs 11%; p = 0.002), and longer duration of mechanical ventilation (median, 142 vs 58 hr; p = 0.009]. On multivariate analysis, genetic abnormalities, hypoplastic left heart, and postoperative infection remained independently associated with extubation failure. Furthermore, patients with infection who failed extubation tended to receive fewer days of antibiotics prior to their first extubation attempt when compared with patients with infection who did not fail extubation (4.9 +/- 2.6 vs 7.3 +/- 3; p = 0.073). CONCLUSIONS: Neonates with underlying genetic abnormalities, hypoplastic left heart, or postoperative infection were at increased risk for extubation failure. A more conservative approach in these patients, including longer pre-extubation duration of antibiotic therapy for postoperative infections, may be warranted. PMID- 26237658 TI - Risk Factors for Delayed Enteral Nutrition in Critically Ill Children. AB - OBJECTIVE: Delayed enteral nutrition, defined as enteral nutrition started 48 hours or more after admission to the PICU, is associated with an inability to achieve full enteral nutrition and worse outcomes in critically ill children. We reviewed nutritional practices in six medical-surgical PICUs and determined risk factors associated with delayed enteral nutrition in critically ill children. DESIGN: Retrospective cross-sectional study using medical records as source of data. SETTING: Six medical-surgical PICUs in northeastern United States. PATIENTS: Children less than 21 years old admitted to the PICU for 72 hours or more excluding those awaiting or recovering from abdominal surgery. MEASUREMENTS AND MAIN RESULTS: A total of 444 children with a median age of 4.0 years were included in the study. Enteral nutrition was started at a median time of 20 hours after admission to the PICU. There was no significant difference in time to start enteral nutrition among the PICUs. Of those included, 88 children (19.8%) had delayed enteral nutrition. Risk factors associated with delayed enteral nutrition were noninvasive (odds ratio, 3.37; 95% CI, 1.69-6.72) and invasive positive pressure ventilation (odds ratio, 2.06; 95% CI, 1.15-3.69), severity of illness (odds ratio for every 0.1 increase in pediatric index of mortality 2 score, 1.39; 95% CI, 1.14-1.71), procedures (odds ratio, 3.33; 95% CI, 1.67-6.64), and gastrointestinal disturbances (odds ratio, 2.05; 95% CI, 1.14-3.68) within 48 hours after admission to the PICU. Delayed enteral nutrition was associated with failure to reach full enteral nutrition while in the PICU (odds ratio, 4.09; 95% CI, 1.97-8.53). Nutrition consults were obtained in less than half of the cases, and none of the PICUs used tools to assure the adequacy of energy and protein nutrition. CONCLUSIONS: Institutions in this study initiated enteral nutrition for a high percentage of patients by 48 hours of admission. Noninvasive positive pressure ventilation was most strongly associated with delay enteral nutrition. A better understanding of these risk factors and assessments of nutritional requirements should be explored in future prospective studies. PMID- 26237659 TI - Strong Coupling between ZnO Excitons and Localized Surface Plasmons of Silver Nanoparticles Studied by STEM-EELS. AB - We investigated the strong coupling between the excitons of ZnO nanowires (NWs) and the localized surface plasmons (LSPs) of individual Ag nanoparticles (NPs) by monochromated electron energy loss spectroscopy (EELS) in an aberration-corrected scanning transmission electron microscopy (STEM) instrument. The EELS results confirmed that the hybridization of the ZnO exciton with the LSPs of the Ag NP created two plexcitons: the lower branch plexcitons (LPs) with a symmetrical dipole distribution and the upper branch plexcitons (UPs) with an antisymmetrical dipole distribution. The spatial maps of the LP and UP excitations reveal the nature of the LSP-exciton interactions. With decreasing size of the Ag NP the peak energies of the LPs and UPs showed a blue-shift and an anticrossing behavior at the ZnO exciton energy was observed. The coupled oscillator model explains the dispersion curve of the plexcitons and a Rabi splitting energy of ~170 meV was deduced. The high spatial and energy resolution STEM-EELS approach demonstrated in this work is general and can be extended to study the various coupling interactions of a plethora of metal-semiconductor nanocomposite systems. PMID- 26237660 TI - EDTA-Cross-Linked beta-Cyclodextrin: An Environmentally Friendly Bifunctional Adsorbent for Simultaneous Adsorption of Metals and Cationic Dyes. AB - The discharge of metals and dyes poses a serious threat to public health and the environment. What is worse, these two hazardous pollutants are often found to coexist in industrial wastewaters, making the treatment more challenging. Herein, we report an EDTA-cross-linked beta-cyclodextrin (EDTA-beta-CD) bifunctional adsorbent, which was fabricated by an easy and green approach through the polycondensation reaction of beta-cyclodextrin with EDTA as a cross-linker, for simultaneous adsorption of metals and dyes. In this setting, cyclodextrin cavities are expected to capture dye molecules through the formation of inclusion complexes and EDTA units as the adsorption sites for metals. The adsorbent was characterized by FT-IR, elemental analysis, SEM, EDX, zeta-potential, and TGA. In a monocomponent system, the adsorption behaviors showed a monolayer adsorption capacity of 1.241 and 1.106 mmol g(-1) for Cu(II) and Cd(II), respectively, and a heterogeneous adsorption capacity of 0.262, 0.169, and 0.280 mmol g(-1) for Methylene Blue, Safranin O, and Crystal Violet, respectively. Interestingly, the Cu(II)-dye binary experiments showed adsorption enhancement of Cu(II), but no significant effect on dyes. The simultaneous adsorption mechanism was further confirmed by FT-IR, thermodynamic study, and elemental mapping. Overall, its facile and green fabrication, efficient sorption performance, and excellent reusability indicate that EDTA-beta-CD has potential for practical applications in integrative and efficient treatment of coexistenting toxic pollutants. PMID- 26237661 TI - Acute forearm compartment syndrome in a newborn caused by reperfusion after spontaneous axillary artery thrombosis. AB - Acute compartment syndrome of the forearm in newborns is often misdiagnosed and can be disastrous if left untreated. Here, we report a full-term infant of a diabetic mother with underlying heterozygosity for MTHFR C677T and A1298C alleles. A spontaneous thrombosis occurred in the left axillary artery immediately after birth. The patient responded well to anticoagulant (heparin) and thrombolytic (tissue plasminogen activator) agents. After reperfusion of the extremity, acute compartment syndrome developed. Emergent fasciotomy was performed. In this case, effective collaboration between pediatricians and orthopedic surgeons resulted in salvage of the extremity, with good clinical and functional results. PMID- 26237662 TI - Scarf-Akin osteotomy for hallux valgus in juvenile and adolescent patients. AB - Hallux valgus (HV) has been reported to affect 22-36% of adolescents, with a recurrence rate of around 30-40%. Operative treatment may be indicated in symptomatic deformities where conservative management has failed to halt progression of the deformity. There remains genuine concern with respect to high complication rates including recurrence and stiffness of the metatarsophalangeal joint following operative treatment in adolescents. We report the clinical, functional and radiological outcomes of the Scarf-Akin procedure in the treatment of juvenile and adolescent HV. A review of single surgeon series was carried out of all children who underwent Scarf and Akin osteotomies as a combined procedure for HV between February 2001 and 2010. The preoperative and postoperative intermetatarsal angle (IMA1-2), hallux valgus angle, distal metatarsal articular angle and ratio of the length of first metatarsal to that of the second metatarsal were determined. The American Orthopaedic Foot and Ankle Score was used for functional assessment. Twenty-nine patients (47 feet) underwent Scarf Akin osteotomies for moderate to severe HV. The average age of the patients at surgery was 11.7 years. The 6-week postoperative radiographs confirmed a significant improvement in the IMA, hallux valgus angle and distal metatarsal articular angle, in all the 47 feet, but 10 patients (14 feet, 29.8%) reported recurrence of hallux valgus at subsequent reviews. The radiological recurrence rate in our series was 29.8%, with 21.3% of patients symptomatic enough to require a revision operation. We report a high recurrence rate in hallux valgus operation in children and hence recommend postponement of correction until skeletal maturity. PMID- 26237663 TI - Ambulance patients with nondocumented sepsis have a high mortality risk: a retrospective study. AB - OBJECTIVE: Sepsis is a serious disease leading to high mortality. Early recognition is important because treatment is most effective when started quickly.The primary aim of this retrospective cohort study was to assess how many sepsis patients are documented as septic by ambulance staff. The secondary aims were to investigate how many sepsis patients are transported by ambulance, to compare them with patients transported otherwise, to investigate which factors influence documentation of sepsis and to assess whether documentation influences mortality. METHODS: We retrieved all data from ambulance and emergency department charts of patients who visited the internist in the emergency department from March 2011 to July 2012. RESULTS: In total, 47.4% (n=363) sepsis patients were transported by ambulance. These patients were older (71.5 vs. 55.7 years, P<0.0001), admitted more frequently (97.2 vs. 85.4%, P<0.001), significantly more frequently had severe sepsis (47.4 vs. 25.8%, P<0.0001) or septic shock (12.4 vs. 4.0%, P<0.0001), and died more frequently within 28 days (17.9 vs. 7.2%, P<0.0001) than those who were transported otherwise.In 41.9% of ambulance patients, sepsis was not documented by ambulance staff. Measurement of temperature was important for documentation of sepsis (odds ratio 11.2, 95% confidence interval 5.2-24.4). In 32.1% of ambulance patients, sepsis could have been identified by assessing vital signs. Mortality in these nondocumented patients was higher than that in documented patients (25.7 vs. 12.9%, P=0.003). CONCLUSION: Ambulance patients are seriously ill, but sepsis is often not documented by ambulance staff. Nondocumentation is associated with high mortality and could be resolved by assessing vital signs, particularly the temperature. PMID- 26237664 TI - Mechanical cardiopulmonary resuscitation in in-hospital cardiac arrest: a systematic review. AB - With increasing rates of in-hospital cardiac arrest, improving resuscitation outcomes is essential. Mechanical chest compressors seem to be related to improved outcome in out-of hospital cardiac arrest; however, the literature on its use in in-hospital cardiac arrest is scarce. We used the Medline public database to systematically review patient outcomes considering mechanical cardiopulmonary resuscitation in in-hospital cardiac arrest. Fourteen studies were found, most cases (n=17), three cohort studies, a clinical pilot study and a registry study. The reported survival rate was high (35 out of 89 patients, 39%) and full neurological recovery was described in 91% of the survivors. Two studies did not report survival rates. Especially in patients with in-hospital cardiac arrest because of treatable causes, early start of mechanical chest compressions could improve future patient outcomes because of better (coronary and brain) perfusion during mechanical chest compressions compared with manual chest compressions. However, the current literature is probably influenced by publication bias and more high-quality research is needed. PMID- 26237665 TI - Hydrogel Ring for Topical Drug Delivery to the Ocular Posterior Segment. AB - PURPOSE: To investigate the efficacy of a topical hydrogel ring for drug delivery to the posterior segment of the rabbit eye. MATERIALS AND METHODS: Novel hydrogel corneal lenses (CL), scleral/corneal lenses (S/CL), and rings were prepared using poly(hydroxyethyl methacrylate). The devices were immersed in 0.3% ofloxacin ophthalmic solution (OOS) to homogeneously distribute the drug throughout the hydrogel. The medicated CL, S/CL, Ring 1 (standard ring), or Ring 2 (shape optimized ring) was applied to the surface of the cornea, cornea/bulbar conjunctiva, or bulbar conjunctiva of albino rabbits, respectively. Medicated rings did not touch the corneal surface. In another group, one OOS drop was administered to the eye. After 0.25-8 hours, the hydrogel devices were removed and ocular tissues were harvested. High-performance liquid chromatography (HPLC) was used to measure the ofloxacin concentration in the devices and tissues. The drug concentrations in the posterior segment tissues were compared among ofloxacin delivery methods. RESULTS: One hour after placement, eyes treated with Ring 1 or S/CL had markedly higher ofloxacin levels in the posterior segment tissues (conjunctiva, sclera, and retina/choroid) than eyes treated with topical OOS or a CL. Lower levels of ofloxacin were found in anterior segment tissues (cornea and aqueous humor) in eyes treated with Ring 1 compared to those treated with S/CL. Ring 2 most effectively delivered ofloxacin to the retina/choroid. The tissue ofloxacin concentration in the fellow eye was markedly lower than the eye treated with Ring 2. CONCLUSIONS: Our results suggest that hydrogel rings are effective in delivering topical ophthalmic drugs to the posterior segment. The drugs are most likely delivered via the transconjunctival/scleral route by lateral diffusion across the bulbar conjunctiva and through the sclera. Systemic drug delivery to the posterior segment is minimal. PMID- 26237666 TI - One-Pot Synthesis of Three-Dimensional Graphene/Carbon Nanotube/SnO2 Hybrid Architectures with Enhanced Lithium Storage Properties. AB - Three-dimensional (3D) graphene/carbon nanotube (CNT)/SnO2 (GCS) hybrid architectures were constructed by a facile and cost-effective self-assembly method through hydrothermal treatment of a mixture of Sn(2+), CNTs, and graphene oxide (GO). The resultant GCS displayed a 3D hierarchically porous structure with large surface area and excellent electrical conductivity, which could effectively prevent the aggregation and volume variation of SnO2 and accelerate the transport of ions and electrons through 3D pathways. Benefiting from the unique structure and the synergistic effect of different components in the hybrid architectures, the GCS exhibited a remarkably improved reversible capacity of 842 mAh g(-1) after 100 cycles at 0.2 A g(-1) and excellent rate performance for lithium storage compared with that of graphene/SnO2 (GS) hybrid architectures. Hence, the impressive results presented here could provide a universal platform for fabricating graphene/CNT-based hybrid architectures with promising applications in various fields. PMID- 26237668 TI - Anesthetic Management of an Unusual Case of Coats' Disease Complex: Use of Dexmedetomidine. PMID- 26237669 TI - Link between Peripheral Artery Disease and Heart Rate Variability in Hemodialysis Patients. AB - Peripheral artery disease (PAD) and low heart rate variability (HRV) are highly prevalent in hemodialysis patients, and both are associated with increased cardiovascular morbidity and mortality. This study aims to examine the suggested relationship between PAD and HRV, and the relationship of parameters before and after hemodialysis. This study enrolled 161 maintenance hemodialysis patients. PAD was defined as ABI < 0.9 in either leg. HRV was performed to assess changes before and after hemodialysis. The change in HRV (?HRV) was defined as post hemodialysis HRV minus pre-hemodialysis HRV. Patients' clinical parameters were collected from the dialysis records. All HRV parameters except high frequency (HF) % were lower in patients with PAD than patients without PAD, though not achieving significant level. In patients without PAD, HF (P = 0.013), low frequency (LF) % (P = 0.028) and LF/HF (P = 0.034) were significantly elevated after hemodialysis, whereas no significant HRV parameters change was noted in patients with PAD. Serum intact parathyroid hormone was independently associated with ?HF (beta = -0.970, P = 0.032) and ?LF% (beta = -12.609, P = 0.049). Uric acid level (beta = -0.154, P = 0.027) was negatively associated with ?LF/HF in patients without PAD. Our results demonstrated that some of the HRV parameters were significantly increased after hemodialysis in patients without PAD, but not in patients with PAD, reflecting a state of impaired sympatho-vagal equilibrium. Severity of secondary hyperparathyroidism and hyperuricemia contributed to lesser HRV parameters increase after hemodialysis in patients without PAD. PMID- 26237670 TI - Anaerobic 5-Hydroxybenzimidazole Formation from Aminoimidazole Ribotide: An Unanticipated Intersection of Thiamin and Vitamin B12 Biosynthesis. AB - Comparative genomics of the bacterial thiamin pyrimidine synthase (thiC) revealed a paralogue of thiC (bzaF) clustered with anaerobic vitamin B12 biosynthetic genes. Here we demonstrate that BzaF is a radical S-adenosylmethionine enzyme that catalyzes the remarkable conversion of aminoimidazole ribotide (AIR) to 5 hydroxybenzimidazole (5-HBI). We identify the origin of key product atoms and propose a reaction mechanism. These studies represent the first step in solving a long-standing problem in anaerobic vitamin B12 assembly and reveal an unanticipated intersection of thiamin and vitamin B12 biosynthesis. PMID- 26237671 TI - Performance characterization of compressed sensing positron emission tomography detectors and data acquisition system. AB - In the field of information theory, compressed sensing (CS) had been developed to recover signals at a lower sampling rate than suggested by the Nyquist-Shannon theorem, provided the signals have a sparse representation with respect to some base. CS has recently emerged as a method to multiplex PET detector readouts thanks to the sparse nature of 511 keV photon interactions in a typical PET study. We have shown in our previous numerical studies that, at the same multiplexing ratio, CS achieves higher signal-to-noise ratio (SNR) compared to Anger and cross-strip multiplexing. In addition, unlike Anger logic, multiplexing by CS preserves the capability to resolve multi-hit events, in which multiple pixels are triggered within the resolving time of the detector. In this work, we characterized the time, energy and intrinsic spatial resolution of two CS detectors and a data acquisition system we have developed for a PET insert system for simultaneous PET/MRI. The CS detector comprises a 2 x 4 mosaic of 4 x 4 arrays of 3.2 x 3.2 x 20 mm(3) lutetium-yttrium orthosilicate crystals coupled one-to-one to eight 4 x 4 silicon photomultiplier arrays. The total number of 128 pixels is multiplexed down to 16 readout channels by CS. The energy, coincidence time and intrinsic spatial resolution achieved by two CS detectors were 15.4+/ 0.1% FWHM at 511 keV, 4.5 ns FWHM and 2.3 mm FWHM, respectively. A series of experiments were conducted to measure the sources of time jitter that limit the time resolution of the current system, which provides guidance for potential system design improvements. These findings demonstrate the feasibility of compressed sensing as a promising multiplexing method for PET detectors. PMID- 26237672 TI - Overview of Probing Protein-Ligand Interactions Using NMR. AB - Nuclear magnetic resonance (NMR) is a powerful technique for the study and characterization of protein-ligand interactions. In this unit we review both experiments where the NMR spectrum of the protein is observed (protein-observed NMR experiments) and those where the NMR spectra of the ligand is observed (ligand-observed NMR experiments) for the identification of binding partners, the measurement of protein-ligand affinity, the design of molecules that are active against biological targets such as proteins, and the assessment of the binding modes of the ligands. Ligand-observed methods discussed in this unit are Nuclear Overhauser Effect (NOE)-based approaches, with well-known experiments such as the Saturation Transfer Difference, Water-Ligand Observed via Gradient Spectroscopy (WaterLOGSY), and transferred-Nuclear Overhauser Effect Spectroscopy (tr-NOESY) experiments, and also the INPHARMA experiment. Regarding protein-observed experiments, this unit focuses on the use of chemical shift perturbations observed in protein-NMR spectra upon ligand binding. Also discussed is how these chemical shift perturbations can be used for the analysis of protein-ligand complexes, including fast structure determination when combined with docking. PMID- 26237673 TI - Using Single Lectins to Enrich Glycoproteins in Conditioned Media. AB - Lectins are sugar-binding proteins that can recognize and bind to carbohydrates conjugated to proteins and lipids. Coupled with mass spectrometry technologies, lectin affinity chromatography is becoming a popular approach for identification and quantification of glycoproteins in complex samples such as blood, tumor tissues, and cell lines. Given the commercial availability of a large number of lectins that recognize diverse sugar structures, it is now possible to isolate and study glycoproteins for biological and medical research. This unit provides a general guide to single-lectin-based enrichment of glycoproteins from serum-free conditioned media. Due to the unique carbohydrate specificity of most lectins and the complexity of the samples, optimization steps may be required to evaluate different elution buffers and methods as well as binding conditions, for each lectin, for optimal recovery of bound glycoproteins. PMID- 26237674 TI - Detergent Analysis in Protein Samples Using Mid-Infrared (MIR) Spectroscopy. AB - Quantitating relative levels of detergent present in protein preparations or samples derived from biological material, such as tissue or body fluids, is important because the presence of detergent may affect downstream analyses as well as protein structure/function. Especially because sample volumes, analysts' available time, and other resources may be limited, a method that consumes little sample and that is rapid and simple is needed for detergent analysis. It would also be preferable to have a method that is generally applicable across many aliphatic chain-containing molecules with many different physical properties. In this unit, methods are described for analyzing detergents and proteins in detergent-protein mixtures using mid-infrared (MIR) spectroscopy. A protocol is also included for efficient removal of unbound detergents from a protein sample accompanied by MIR-based monitoring of both detergent and protein content. This rapid monitoring of sample preparation during the workflow enables users to make timely decisions about sample preparation strategies that maximize both analyte purity and yield. PMID- 26237676 TI - Cell-Free Expression of G Protein-Coupled Receptors. AB - The large-scale production of recombinant G protein-coupled receptors (GPCRs) is one of the major bottlenecks that hamper functional and structural studies of this important class of integral membrane proteins. Heterologous overexpression of GPCRs often results in low yields of active protein, usually due to a combination of several factors, such as low expression levels, protein insolubility, host cell toxicity, and the need to use harsh and often denaturing detergents (e.g., SDS, LDAO, OG, and DDM, among others) to extract the recombinant receptor from the host cell membrane. Many of these problematic issues are inherently linked to cell-based expression systems and can therefore be circumvented by the use of cell-free systems. In this unit, we provide a range of protocols for the production of GPCRs in a cell-free expression system. Using this system, we typically obtain GPCR expression levels of ~1 mg per ml of reaction mixture in the continuous-exchange configuration. Although the protocols in this unit have been optimized for the cell-free expression of GPCRs, they should provide a good starting point for the production of other classes of membrane proteins, such as ion channels, aquaporins, carrier proteins, membrane bound enzymes, and even large molecular complexes. PMID- 26237675 TI - Applications of Lipid Nanodiscs for the Study of Membrane Proteins by Surface Plasmon Resonance. AB - Methods for the initial steps of surface plasmon resonance analysis of membrane proteins incorporated in lipid nanodiscs are described. Several types of Biacore sensor chips are available and require distinct strategies to immobilize proteonanodiscs on the chip surface. The procedures for immobilization on three of these chips (NTA, antibody coupled CM5, and L1) are described in this unit and results are demonstrated for a model system with cytochrome P4503A4 (CYP3A4) in nanodiscs binding to a polyclonal anti-CYP3A4 antibody. Advantages and disadvantages of each chip type are considered. PMID- 26237677 TI - Novel insights into the function of LHCSR3 in Chlamydomonas reinhardtii. AB - Light is essential for photosynthesis but excess light is hazardous as it may lead to the formation of reactive oxygen species. Photosynthetic organisms struggle to optimize light utilization and photosynthesis while minimizing photo oxidative damage. Hereby light to heat dissipation via specialized proteins is a potent mechanism to acclimate toward excess light. In the green alga Chlamydomonas reinhardtii the expression of an ancient light-harvesting protein LHCSR3 enables cells to dissipate harmful excess energy. Herein we summarize newest insights into the function of LHCSR3 from C. reinhardtii. PMID- 26237678 TI - Manual Physical Therapy for Non-Surgical Treatment of Adhesion-Related Small Bowel Obstructions: Two Case Reports. AB - BACKGROUND: Adhesion formation is a widely acknowledged risk following abdominal or pelvic surgery. Adhesions in the abdomen or pelvis can cause or contribute to partial or total small bowel obstruction (SBO). These adhesions deter or prevent the passage of nutrients through the digestive tract, and may bind the bowel to the peritoneum, or other organs. Small bowel obstructions can quickly become life threatening, requiring immediate surgery to resect the bowel, or lyse any adhesions the surgeon can safely access. Bowel repair is an invasive surgery, with risks including bowel rupture, infection, and peritonitis. An additional risk includes the formation of new adhesions during the healing process, creating the potential for subsequent adhesiolysis or SBO surgeries. OBJECTIVE: Report the use of manual soft tissue physical therapy for the reversal of adhesion-related partial SBOs, and create an initial inquiry into the possibility of nonsurgical lysis of adhesions. CASE REPORTS: Two patients presenting with SBO symptoms due to abdominal adhesions secondary to abdominal and pelvic surgery were treated with manual soft tissue physical therapy focused on decreasing adhesions. CONCLUSIONS: Successful treatment with resolution of symptom presentation of partial SBO and sustained results were observed in both patients treated. PMID- 26237680 TI - MgZnO Nanocrystals: Mechanism for Dopant-Stimulated Self-Assembly. AB - Understanding the growth behavior of nanocrystals (NCs), especially when heteroatoms are introduced, is very important for the optimization of doping (or alloying) and optoelectronic performances. Here, it is reported on the observation of alloying-facilitated self-assembly of MgZnO NCs and the underlying mechanism of alloying concentration-dependent surface grafting. Using the developed one-pot thermolysis of Zn and Mg organic salts with the help of oleylamine (OAm) and oleic acid (OA), the Mg ions can be introduced into the ZnO lattice without phase separation with concentrations as high as 20%. Interestingly, with the increase of Mg alloying concentration, the morphologies of the products transform from monodispersed NCs to nanoflowers, and then nanobouquet superstructures, which have quasi-monocrystal features and obey the oriented attachment rules. According to the analyses of surface functional groups, a mechanism involving concentration-dependent surface grafting is proposed for such alloying-facilitated self-assembly. PMID- 26237682 TI - Sludge Reduction by H2O2 Oxidation with Fe/MgO Catalyst. AB - This study aimed to determine whether catalytic pretreatment can be used as a method to reduce the amount of wastewater sludge. In this study, H2O2 oxidation in the presence of a heterogeneous Fe/MgO catalyst was added to the pretreatment step. Initially a laboratory-scale test showed a TCOD (total chemical oxygen demand) was reduced 27.4% during catalytic oxidation compared to 2.1% in a catalyst-free option. Catalytic pretreatment was then evaluated in a bench-scale flow-loop test. Two bench systems were composed of identical serial processes that included anaerobic digestion, aerobic digestion, and coagulating sedimentation. The only difference between the two processes was whether catalytic pretreatment of sediment sludge was used or not. Results showed that catalyst-free oxidation TCOD gradually increased from 4200 to 7800 mg/L while catalytic oxidation maintained TCOD values at 4200 +/- 200 mg/L. In addition, catalytic pretreatment reduced total nitrogen from 46.9 to 41.0 mg/L and phosphate from 3.1 to 2.3 mg/L. PMID- 26237681 TI - Temsirolimus inhibits cell growth in combination with inhibitors of the B-cell receptor pathway. AB - Lately, mTOR inhibitors have gained clinical relevance in malignant lymphoma. Still, rapamycin derivatives may activate a pro-survival feedback loop through PI3K-Akt. In this current study, temsirolimus effectively reduced cell growth in GCB and ABC diffuse large cell B-cell lymphoma (GCB=30-66%, ABC=45-57%). Combination treatment with the PI3K-delta inhibitor idelalisib additively effected ABC and GCB lymphoma (GCB=16-38%, ABC=25-50%). Since Bruton's Tyrosine Kinase (BTK) plays a significant role for the survival of ABC lymphoma, this study also combined the BTK inhibitor ibrutinib with temsirolimus, which resulted in additive cell growth reduction (ibrutinib 50%, temsirolimus 44%, combination 25%) in ABC lymphoma. In contrast, bortezomib, which has been shown previously to be efficient in ABC lymphoma, revealed an antagonistic effect with temsirolimus in some GCB lymphoma (temsirolimus 53%, temsirolimus+bortezomib 63%). Western blot analysis identified the increase of phosphorylated pro-survival kinases Akt and PDK as a possible underlying mechanism of this interaction. PMID- 26237683 TI - Production of Biohydrogen from Wastewater by Klebsiella oxytoca ATCC 13182. AB - Production of biohydrogen from distillery effluent was carried out by using Klebsiella oxytoca ATCC 13182. The work focuses on optimization of pH, temperature, and state of bacteria, which are the various affecting factors for fermentative biohydrogen production. Results indicates that at 35 degrees C for suspended cultures, the production was at its maximum (i.e., 91.33 +/- 0.88 mL) when compared with other temperatures. At 35 degrees C and at pH 5 and 6, maximum productions of 117.67 +/- 1.45 and 111.67 +/- 2.72 mL were observed with no significant difference. When immobilized, Klebsiella oxytoca ATCC 13182 was used for biohydrogen production at optimized conditions, production was 186.33 +/ 3.17 mL. Hence, immobilized cells were found to be more advantageous for biological hydrogen production over suspended form. Physicochemical analysis of the effluent was conducted before and after fermentation and the values suggested that the fermentative process is an efficient method for biological treatment of wastewater. PMID- 26237679 TI - Cdk5 promotes DNA replication stress checkpoint activation through RPA-32 phosphorylation, and impacts on metastasis free survival in breast cancer patients. AB - Cyclin dependent kinase 5 (Cdk5) is a determinant of PARP inhibitor and ionizing radiation (IR) sensitivity. Here we show that Cdk5-depleted (Cdk5-shRNA) HeLa cells show higher sensitivity to S-phase irradiation, chronic hydroxyurea exposure, and 5-fluorouracil and 6-thioguanine treatment, with hydroxyurea and IR sensitivity also seen in Cdk5-depleted U2OS cells. As Cdk5 is not directly implicated in DNA strand break repair we investigated in detail its proposed role in the intra-S checkpoint activation. While Cdk5-shRNA HeLa cells showed altered basal S-phase dynamics with slower replication velocity and fewer active origins per DNA megabase, checkpoint activation was impaired after a hydroxyurea block. Cdk5 depletion was associated with reduced priming phosphorylations of RPA32 serines 29 and 33 and SMC1-Serine 966 phosphorylation, lower levels of RPA serine 4 and 8 phosphorylation and DNA damage measured using the alkaline Comet assay, gamma-H2AX signal intensity, RPA and Rad51 foci, and sister chromatid exchanges resulting in impaired intra-S checkpoint activation and subsequently higher numbers of chromatin bridges. In vitro kinase assays coupled with mass spectrometry demonstrated that Cdk5 can carry out the RPA32 priming phosphorylations on serines 23, 29, and 33 necessary for this checkpoint activation. In addition we found an association between lower Cdk5 levels and longer metastasis free survival in breast cancer patients and survival in Cdk5 depleted breast tumor cells after treatment with IR and a PARP inhibitor. Taken together, these results show that Cdk5 is necessary for basal replication and replication stress checkpoint activation and highlight clinical opportunities to enhance tumor cell killing. PMID- 26237684 TI - Mechanisms for Reduced Excess Sludge Production in the Cannibal Process. AB - Reducing excess sludge production is increasingly attractive as a result of rising costs and constraints with respect to sludge treatment and disposal. A technology in which the mechanisms remain not well understood is the Cannibal process, for which very low sludge yields have been reported. The objective of this work was to use modeling as a means to characterize excess sludge production at a full-scale Cannibal facility by providing a long sludge retention time and removing trash and grit by physical processes. The facility was characterized by using its historical data, from discussion with the staff and by conducting a sampling campaign to prepare a solids inventory and an overall mass balance. At the evaluated sludge retention time of 400 days, the sum of the daily loss of suspended solids to the effluent and of the waste activated sludge solids contributed approximately equally to the sum of solids that are wasted daily as trash and grit from the solids separation module. The overall sludge production was estimated to be 0.14 g total suspended solids produced/g chemical oxygen demand removed. The essential functions of the Cannibal process for the reduction of sludge production appear to be to remove trash and grit from the sludge by physical processes of microscreening and hydrocycloning, respectively, and to provide a long sludge retention time, which allows the slow degradation of the "unbiodegradable" influent particulate organics (XU,Inf) and the endogenous residue (XE). The high energy demand of 1.6 kWh/m3 of treated wastewater at the studied facility limits the niche of the Cannibal process to small- to medium sized facilities in which sludge disposal costs are high but electricity costs are low. PMID- 26237685 TI - Influencing Factors for Organic Spill Recovery Performance with a Novel Polypropylene-Methacrylate Sorbent. AB - Insoluble organic matter released to the water body through accidental spillage imposes serious damage on the environment. Polypropylene (PP) fiber and methacrylate resin, however, end up in certain morphology or low sorption capacity after a single use. In this study, a novel sorbent was prepared by radiation-induced graft polymerization of butyl methacrylate (BMA) onto PP fiber matrix to retain the advantages of both PP fibers and methacrylate resins to overcome the shortcomings of each used alone. The different parameters including irradiation power, irradiation time and monomer concentration that effect the grafting degree of grafted fiber were studied. The resulting grafted fibers (PP-g BMA) were evaluated in this study in terms of sorption capacity, retention behaviors and reusability properties. The investigation revealed that the homopolymerization rate, organic matter temperature and pH values of organic-over water aqueous solution are the most important factors in the sorption performance of polypropylene grafted fiber sorbent. PMID- 26237686 TI - Assessing the Nonbiodegradable Fraction of the Thickened Waste Activated Sludge. AB - In this study, the feasibility of using three methods to estimate the nonbiodegradable fraction of five thickened waste activated sludge (TWAS) samples was evaluated using long-term biochemical methane potential tests at four substrate to biomass ratios. The nonbiodegradable fraction was calculated based on the remaining volatile suspended solids (VSS), remaining total chemical oxygen demand (TCOD), and remaining total organic carbon (TOC). It was evident that the nonbiodegradable fraction of TWAS ranged from 12 to 27%. The average nonbiodegradable fractions of TWAS were 21, 18, and 23% based on remaining VSS, TCOD, and TOC, respectively. The proposed method can be potentially used to characterize biosolids for design and modeling anaerobic treatment processes. PMID- 26237687 TI - Variations in Depth and Chemical Composition of Groundwater During an Interval in Intermittent Water Delivery. AB - Based on monitoring data collected from 2006 to 2009 at the lower reaches of the Tarim River, tempo-spatial variations in groundwater depth and chemistry during an approximately 3-year interval of intermittent water delivery were studied. Results indicate that as the groundwater depth increased at the upper sector of the river's lower reaches from March 2007 to September 2009, so too did the main chemical composition of groundwater. Groundwater depth at the intermediate sector also increased, but major ions in groundwater declined. The groundwater depth at the lower sector started to decrease in August 2008, and the concentrations of main ions in the groundwater generally rose and fell along with the variations in groundwater depth. The groundwater depth and chemistry in the monitoring wells located at a distance from the aqueduct expressed complex changes at different sections. For instance, at the section near the Daxihaizi Reservoir Section B, groundwater depth increased gradually, but chemical composition changed little. In contrast, the groundwater depth of monitoring wells far from the Daxihaizi Reservoir (Section I) decreased and salt content in the groundwater increased. In sectors at a moderate distance from the reservoir, groundwater depth decreased and concentrations of main ions significantly increased. PMID- 26237688 TI - Oxygen Demand of Fresh and Stored Sulfide Solutions and Sulfide-Rich Constructed Wetland Effluent. AB - This study investigated the contribution of hydrogen sulfide to biological oxygen demand (BOD5) and chemical oxygen demand (COD) in wastewater effluents, and documented the effect of storage times and conditions on the BOD5 and COD of pH adjusted sodium sulfide solutions as well as graywater wetland effluent. Initial COD measurements of sulfide solutions were 84-89% of the theoretical oxygen demand (ThOD), 1.996 mg O2/mg S, whereas unseeded BOD5 measurements were 55-77%. For sulfide solutions, all storage conditions led to declines of >15% (COD, BOD5), and >31% (sulfide). For wetland effluent, storage without headspace was effective in reducing COD losses (3.7%), compared to storage with headspace (17%), and affected changes in turbidity, UVA-254 and pH. The results suggest that storage times and conditions should be controlled and reported when reporting BOD5 and COD of sulfide-rich samples. Wetland models representing sulfate reduction as a method of COD removal may need to be reconsidered. PMID- 26237689 TI - Decolourization of Methylene Blue in Water Using Bentonite Impregnated with Ti and Ag as Photocatalyst. AB - This article used bentonite impregnated with titanium and silver, respectively, as photocatalyst, to degrade methylene blue (MB) under conditions of MB solutions exposed to sodium lamp and sunlight. Due to the semi-conducting properties of synthesized bentonite catalysts, when exposed to sodium lamp and sunlight, catalyst particles are excited for photocatalysis to achieve decolourization. After an FT-IR analysis, this study finds that smectite catalysts have significant and complicated wave crests between the fingerprint area with wave numbers 415~600 cm-1 and 750~1170 cm-1. The bentonite impregnated with Ti(4+) (Sm Ti) and with Ag+ (Sm-Ag) removes MB through the mechanisms of adsorption and degradation, while the commercial product of titanium dioxide (TiO2) only exhibits the capability of MB degradation. At present, a heterogeneous photocatalytic system has been fully applied for use in daily life, with its efficiency determined by the free radical action of electrons and holes, the generation efficiency of .OH. PMID- 26237690 TI - Sensitivity-Based Calibration of the Soil and Water Assessment Tool for Hydrologic Cycle Simulation in the Cong Watershed, Vietnam. AB - For better water resources management in quality and quantity, an accurate model is needed for simulating the hydrologic cycle and water quality dynamics at a watershed scale. In this study, a semi-distributed hydrologic model, the Soil and Water Assessment Tool (SWAT), was applied for hydrologic cycle assessment in the Cong Watershed, Vietnam. After model-output and accuracy-based sensitivity analyses were conducted without and with observation data, respectively, model parameters were calibrated and validated using meteorological and runoff data observed between 1961 and 1975. Model performance in annual, monthly, and daily flow simulations was assessed using the Nash-Sutcliffe Efficiency coefficient and the coefficient of determination (R2). As a result, the accuracy-based sensitivity analysis better identified the key parameters, as compared to the model output-based sensitivity analysis, resulting in better flow simulations in the Cong River. The calibrated model performed well in hydrologic cycle simulations in the Cong Watershed, suggesting the applicability of the SWAT model. PMID- 26237691 TI - Reducing SCADA System Nuisance Alarms in the Water Industry in Northern Ireland. AB - The advancement of telemetry control for the water industry has increased the difficulty of managing large volumes of nuisance alarms (i.e., alarms that do not require a response). The aim of this study was to identify and reduce the number of nuisance alarms that occur for Northern Ireland (NI) Water by carrying out alarm duration analysis to determine the appropriate length of persistence (an advanced alarm management tool) that could be applied. All data were extracted from TelemWeb (NI Water's telemetry monitoring system) and analyzed in Excel. Over a 6-week period, an average of 40 000 alarms occurred per week. The alarm duration analysis, which has never been implemented before by NI Water, found that an average of 57% of NI Water alarms had a duration of <5 minutes. Applying 5-minute persistence, therefore, could prevent an average 26 816 nuisance alarms per week. Most of these alarms were from wastewater assets. PMID- 26237692 TI - In-stream Physical Heterogeneity, Rainfall Aided Flushing, and Discharge on Stream Water Quality. AB - Implications of instream physical heterogeneity, rainfall-aided flushing, and stream discharge on water quality control have been investigated in a headwater stream of a climatic region that has contrasting dry and wet seasons. Dry (low flow) season's physical heterogeneity showed a positive correlation with good water quality. However, in the wet season, physical heterogeneity showed minor or no significance on water quality variations. Furthermore, physical heterogeneity appeared to be more complementary with good water quality subsequent to rainfall events. In many cases stream discharge was a reason for poor water quality. For the dry season, graywater inputs to the stream could be held responsible. In the wet season, it was probably the result of catchment level disturbances (e.g., regulation of ephemeral freshwater paths). Overall, this study revealed the importance of catchment-based approaches on water quality improvement in tandem with in-stream approaches framed on a temporal scale. PMID- 26237693 TI - Epigenetic variation contributes to environmental adaptation of Arabidopsis thaliana. AB - Epigenetic variation is frequently observed in plants and direct relationships between differences in DNA methylation and phenotypic responses to changing environments have often been described. The identification of contributing genetic loci, however, was until recently hampered by the lack of suitable genome wide mapping resources that specifically segregate for epigenetic marks. The development of epi-RIL populations in the model species Arabidopsis thaliana has alleviated this obstacle, enabling the accurate genetic analysis of epigenetic variation. Comprehensive morphological phenotyping of a ddm1 derived epi-RIL population in different environments and subsequent epi-QTL mapping revealed a high number of epi-QTLs and pleiotropic effects of several DMRs on numerous traits. For a number of these epi-QTLs epistatic interactions could be observed, further adding to the complexity of epigenetic regulation. Moreover, linkage to epigenetic marks indicated a specific role for DNA-methylation variation, rather than TE transposition, in plastic responses to changing environments. These findings provide supportive evidence for a role of epigenetic regulation in evolutionary and adaptive processes. PMID- 26237694 TI - How to use the elasticity of a badminton racket to increase its speed by 80%? PMID- 26237695 TI - Moral Distress in Pediatric Intensive Care. PMID- 26237696 TI - Microscopic Aspects of Silicon-Mediated Rice Resistance to Leaf Scald. AB - This study investigated the effect of silicon (Si) on the potentiation of rice resistance against leaf scald at the microscopic level. Rice plants ('Primavera') were grown in a nutrient solution containing 0 (-Si) or 2 mM (+Si) Si. The foliar Si concentration of the +Si plants (3.6 dag/kg) increased in comparison with the Si plants (0.3 dag/kg). An X-ray microanalysis revealed that the leaf tissue of +Si plants infected with Microdochium oryzae had higher peaks and deposition of insoluble Si than that of -Si plants. The high foliar Si concentration for the +Si plants reduced the expansion of leaf scald lesions. Scanning electron microscopy revealed that fungal hyphae and appressorium-like structures of M. oryzae were more abundant in the leaf surface of -Si plants relative to +Si plants. At both histopathological and ultrastructural levels, fungal hyphae grew abundantly into the leaf tissue of -Si plants. By contrast, rice cell walls were rarely degraded and fungal hyphae were often surrounded by amorphous granular material in the leaf tissue of +Si plants. Conidiophores emerged from stomata 36 h after fungal penetration, and conidia were noticed inside the leaf tissue of the -Si plants in great abundance. The collective results of the present study showed a high concentration and deposition of Si and a considerable deposition of phenolic-like compounds in the leaf tissue of +Si plants. These results indicate that the potentiation of the phenylpropanoid pathway in these plants supplied with Si was favorable for the increase in rice resistance to leaf scald. PMID- 26237697 TI - Cell Therapy Regulatory Toolkit: an online regulatory resource. PMID- 26237698 TI - Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from nonacademic institutions 1 February-31 March 2015. PMID- 26237699 TI - Bone regeneration using mesenchymal stem cells: challenges and future perspectives in regenerative surgery. PMID- 26237700 TI - Adipose-derived stem cell transplantation for therapeutic lymphangiogenesis in a mouse secondary lymphedema model. AB - AIM: Secondary lymphedema is observed in common after postmalignancy treatment of the breast and the gynecologic organs but effective therapies are not established. Adipose-derived stem cells (ADSCs), which are pluripotent, regenerative in local injection, are tested for murine hindlimb secondary lymphedema by regenerative method. METHODS & RESULTS: Mice were divided into four groups: no ADSCs, 1 * 10(6) ADSCs, 1 * 10(5) ADSCs and 1 * 10(4) ADSCs (each group, n = 20) in a stringent surgical resection and irradiation. Circumferential measurement, lymphatic flow assessment and quantification of lymphatic vessels were performed. RESULTS: The numbers of lymphatic vessels by LYVE-1 immunohistochemistry, and VEGF-C- or VEGFR3-expressing cells were significantly increased in transplanted groups (p < 0.05). CONCLUSION: ADSCs can restore the lymphatic vascular network in secondary lymphedema with increased collecting vessels. PMID- 26237701 TI - Systemic human CD34(+) cells populate the brain and activate host mechanisms to counteract nigrostriatal degeneration. AB - AIM: Here we investigated the neuroprotective potential of systemic CD34(+) human cord blood cells (hCBCs) in a 6-hydroxydopamine rat model of Parkinson's disease. METHODS: Purified CD34(+) hCBCs were intravenously administered to rats subjected to 6-hydroxydopamine 24 h earlier, and behavioral and immunohistological analysis performed. RESULTS: CD34(+) hCBC administration significantly prevented host nigrostriatal degeneration inducing behavioral recovery in treated rats. Although donor hCBCs did not differentiate into neural phenotypes, they stimulated the production of new neuroblasts and angiogenesis, and reduced gliosis in recipient animals. Importantly, surviving donor hCBCs were identified, and their tissue distribution pattern correlated with the observed therapeutic effects. CONCLUSION: Peripherally applied CD34(+) hCBCs can migrate into brain tissues and elicit host-based protective mechanisms to support the survival of midbrain dopamine neurons. PMID- 26237702 TI - Proliferation and osteogenic differentiation of mesenchymal stromal cells in a novel porous hydroxyapatite scaffold. AB - AIM: To compare the effect of bovine bone derived porous hydroxyapatite (BDHA) scaffold on proliferation and osteogenic differentiation of human bone marrow derived mesenchymal stromal cells (hMSCs) compared with commercial hydroxyapatite (CHA) scaffold. MATERIALS AND METHODS: The porosity and pore size were analyzed using micro-CT. The biocompatibility was demonstrated by alamar blue assay, and cell attachment through SEM and Hoechst staining. The osteogenic differentiation was demonstrated using biochemical assay and osteogenic gene expression. RESULTS: BDHA and CHA scaffolds showed porosity of 76.6 +/- 0.6 and 64.3 +/- 0.3% and pore size diameter of 0.04-0.25 and 0.1-2.6 mm, respectively. hMSCs proliferation, ALP activity, osteocalcin secretion and osteogenic gene expression are comparable in both the scaffolds. CONCLUSION: These results demonstrated that BDHA is biocompatible, supports cell adhesion and promotes proliferation and osteogenic differentiation. PMID- 26237703 TI - Allogeneic cell therapy bioprocess economics and optimization: downstream processing decisions. AB - AIM: To develop a decisional tool to identify the most cost effective process flowsheets for allogeneic cell therapies across a range of production scales. MATERIALS & METHODS: A bioprocess economics and optimization tool was built to assess competing cell expansion and downstream processing (DSP) technologies. RESULTS: Tangential flow filtration was generally more cost-effective for the lower cells/lot achieved in planar technologies and fluidized bed centrifugation became the only feasible option for handling large bioreactor outputs. DSP bottlenecks were observed at large commercial lot sizes requiring multiple large bioreactors. The DSP contribution to the cost of goods/dose ranged between 20 55%, and 50-80% for planar and bioreactor flowsheets, respectively. CONCLUSION: This analysis can facilitate early decision-making during process development. PMID- 26237704 TI - The use of urinary bladder matrix in the treatment of trauma and combat casualty wound care. AB - Treatment of combat injuries and resulting wounds can be difficult to treat due to compromised and evolving tissue necrosis, environmental contaminants, multidrug resistant microbacterial and/or fungal infections, coupled with microvascular damage and/or hypovascularized exposed vital structures. Our group has developed surgical care algorithms with identifiable salvage techniques to achieve stable, definitive wound coverage often with the aid of certain regenerative medicine biologic scaffold materials and advanced wound care to facilitate tissue coverage and healing. This case series reports on the role of urinary bladder matrix scaffolds in the wound care and reconstruction of traumatic and combat wounds. Urinary bladder matrix was found to facilitate definitive soft tissue reconstruction by establishing a neovascularized soft tissue base acceptable for second stage wound and skin coverage options within traumatic and combat-related wounds. PMID- 26237705 TI - Developing stem cell therapies for juvenile and adult-onset Huntington's disease. AB - Stem cell therapies have been explored as a new avenue for the treatment of neurologic disease and damage within the CNS in part due to their native ability to mimic repair mechanisms in the brain. Mesenchymal stem cells have been of particular clinical interest due to their ability to release beneficial neurotrophic factors and their ability to foster a neuroprotective microenviroment. While early stem cell transplantation therapies have been fraught with technical and political concerns as well as limited clinical benefits, mesenchymal stem cell therapies have been shown to be clinically beneficial and derivable from nonembryonic, adult sources. The focus of this review will be on emerging and extant stem cell therapies for juvenile and adult onset Huntington's disease. PMID- 26237707 TI - Erratum. PMID- 26237706 TI - Current practices and reform proposals for the regulation of advanced medicinal products in Canada. AB - We describe the Canadian regulatory framework for evaluating advanced medicinal products based on current policies, guidance documents and regulations and analyze proposed reforms. Our analysis is based on a documentary review supplemented by discussions with Health Canada officials. We present an overview of the Canadian regulatory framework for cell and gene therapy, medical devices and manufacturing facilities. We use the approval of ProchymalTM to highlight Canada's conditional marketing approval system. Finally, we discuss proposed changes to the regulatory framework in response to identified gaps, stakeholder consultations and international harmonization initiatives. Based on our analyses, we suggest that Canadian regulators have taken a reasonable approach in applying their regulatory framework without compromising on product safety. PMID- 26237708 TI - Corrigendum. PMID- 26237709 TI - Do mechanical properties of Achilles tendon influence torque steadiness? PMID- 26237710 TI - Age-related changes in the antidepressant-like effect of desipramine and fluoxetine in the rat forced-swim test. AB - Some reports suggest that older patients are less responsive to antidepressants than young adults, but this idea has not been fully supported. Here, we investigated the role of aging in the behavioral effects of the antidepressants, desipramine (DMI) (5, 10, and 20 mg/kg) and fluoxetine (FLX) (5, 10, and 20 mg/kg) in young adults (3-5 months), middle-aged (MA, 12-15 months), and senescent (SE, 23-25 months) male rats in the forced-swim test. In addition, locomotor activity and motor coordination were assessed as side-effects. DMI and fluoxetine produced an antidepressant-like effect in YA and MA animals, although in the latter group, a shift to the right in the dose-response curve was found for DMI. Importantly, neither drug was effective in SE animals. Motor side effects were produced mainly by DMI in MA and SE rats. Therefore, a decrease in the antidepressant-like effect is associated strongly with senescence as well as an increased vulnerability to motor side-effects, particularly of tricyclics. This study is significant because SE animals are scarcely studied in pharmacological screening tests, and our findings might be useful for improving antidepressant treatments for the increasing aged population. PMID- 26237711 TI - Corrigendum: 3D-Printed Microfluidic Device for the Detection of Pathogenic Bacteria Using Size-based Separation in Helical Channel with Trapezoid Cross Section. PMID- 26237712 TI - Are clinical parameters sufficient to model gait patterns in patients with cerebral palsy using a multilinear approach? AB - The aim of this study was to evaluate whether clinical parameters are sufficient using, a multilinear regression model, to reproduce the sagittal plane joint angles (hip, knee, and ankle) in cerebral palsy gait. A total of 154 patients were included. The two legs were considered (308 observations). Thirty-six clinical parameters were used as regressors (range of motion, muscle strength, and spasticity of the lower). From the clinical gait analysis, the joint angles of the sagittal plane were selected. Results showed that clinical parameter does not provide sufficient information to recover joint angles and/or that the multilinear regression model is not an appropriate solution. PMID- 26237713 TI - 7(th) International Symposium: Safety and Health in Agricultural and Rural Populations - Global Perspectives. PMID- 26237714 TI - Cage Versus Noncage Laying-Hen Housings: Respiratory Exposures. AB - The objective of this study was to compare the personal respiratory exposures of poultry workers in three different types of layer housing under commercial production conditions. Workers were randomly assigned to each of conventional cage, enriched cage, and aviary barns in a crossover repeated-measures design for three observation periods over the hens' lifetime. Inhalable and fine particulate matter (PM) and endotoxin in both size fractions were assessed by personal and area samplers over the work shift. Concentrations of inhalable PM, PM2.5 (PM with an aerodynamic diameter <2.5 MUm), and endotoxin in both size fractions were higher in aviary than either the conventional or enriched barns. Geometric means (95% confidence intervals [CIs]) of inhalable PM and endotoxin for the aviary, conventional, and enriched barns were 8.9 (6.8-11.5) mg/m(3) and 7517.9 (5403.2 10,460.2) EU/m(3), 3.7 (2.8-4.8) mg/m(3) and 1655.7 (1144.6-2395.2) EU/m(3), 2.4 (1.8-3.3) mg/m(3) and 1404.8 (983.3-2007.0) EU/m(3), respectively. Area samplers recorded a lower mean inhalable PM concentration and higher PM2.5 concentration than personal samplers. Ammonia concentrations were low throughout three monitoring seasons. These findings show that the aviary barns pose higher respiratory exposures to poultry workers than either conventional or enriched barns. PMID- 26237715 TI - Cage Versus Noncage Laying-Hen Housings: Worker Respiratory Health. AB - The objective of this study was to compare respiratory health of poultry workers in conventional cage, enriched cage and aviary layer housing on a single commercial facility, motivated by changing requirements for humane housing of hens. Three workers were randomly assigned daily, one to each of conventional cage, enriched cage, and aviary housing in a crossover repeated-measures design for three observation periods (for a total of 123 worker-days, eight different workers). Workers' exposure to particles were assessed (Arteaga et al. J Agromedicine. 2015;20:this issue) and spirometry, exhaled nitric oxide, respiratory symptoms, and questionnaires were conducted pre- and post-shift. Personal exposures to particles and endotoxin were significantly higher in the aviary than the other housings (Arteaga et al., 2015). The use of respiratory protection was high; the median usage was 70% of the shift. Mixed-effects multivariate regression models of respiratory cross-shift changes were marginally significant, but the aviary system consistently posted the highest decrements for forced expiratory volume in 1 and 6 seconds (FEV1 and FEV6) compared with the enriched or conventional housing. The adjusted mean difference in FEV1 aviary - enriched cage housing was -47 mL/s, 95% confidence interval (CI): (-99 to 4.9), P = .07. Similarly, for FEV6, aviary - conventional housing adjusted mean difference was -52.9 mL/6 s, 95% CI: (-108 to 2.4), P = .06. Workers adopting greater than median use of respiratory protection were less likely to exhibit negative cross-shift pulmonary function changes. Although aviary housing exposed workers to significantly higher respiratory exposures, cross-shift pulmonary function changes did not differ significantly between houses. Higher levels of mask use were protective; poultry workers should wear respiratory protection as appropriate to avoid health decrements. PMID- 26237716 TI - Where Do Agricultural Producers Get Safety and Health Information? AB - There is little empirical guidance regarding communication sources and channels used and trusted by agricultural producers. The goal of this study was to characterize frequency of use and levels of trust in agricultural safety and health information sources and channels accessed by agricultural producers. A sample of 195 agricultural producers was surveyed at county fairs in Iowa. Information was collected about the frequency of use and level of trust in 14 information sources and channels. Associations between age, gender, and education level and use and trust of each information source or channel were estimated using logistic regression. The sample consisted of 72% men with a mean age of 50.1 (SD = 15.6) years. Newspaper and magazine articles were the most commonly used agricultural safety and health information source or channel; 77% (n = 140) of respondents reporting using them at least monthly. Among those reporting monthly or more frequent use, 75% reported trusting mostly or completely, compared with 58% using and 49% trusting the Internet. High levels of use and trust of newspaper and magazine articles did not vary significantly by age, gender, or education level. Age in the highest tertile (57-83 years) was marginally associated with lower odds of using, as well as using and trusting, all the information sources and channels studied except for medical clinics (use only: odds ratio [OR], 3.51, 95% confidence interval [CI], 0.79-15.64; use and trust: OR, 5.90, 95% CI, 0.91-38.42). These findings suggest that traditional media may be more effective than digital media for delivering agricultural safety and health information to agricultural producers. Medical clinics may be an untapped venue for communicating with older agricultural producers. PMID- 26237717 TI - Equity in Whom Gets Studied: A Systematic Review Examining Geographical Region, Gender, Commodity, and Employment Context in Research of Low Back Disorders in Farmers. AB - Farmers are at high risk of having low back disorders (LBDs). Agriculture employs half the global workforce, but it is unclear whether all farming populations are represented equitably in the LBD literature. This systematic review quantifies the number and quality of research studies by geographical region, agricultural commodity, and farmer characteristics. MEDLINE, Web of Science, CINAHL, Scopus, and Embase databases were searched using conceptual groups of search terms: "farming" and "LBD." Screening and extraction were performed by two researchers in parallel, then reconciled through discussion. Extracted study characteristics included location of study; commodity produced; worker sex, ethnicity, and migration status; type of employment; and study quality. These were compared with agricultural employment statistics from the International Labour Organization and World Bank. From 125 articles, roughly half (67) did not specify the employment context of the participants in terms of migration status or subsistence versus commercial farming. Although in many regions worldwide women make up the bulk of the workforce, only a minority of low back disorder studies focus on women. Despite the predominance of the agricultural workforce in developing nations, 91% of included studies were conducted in developed nations. There was no significant difference in study quality by geographic region. The nature of the world's agricultural workforce is poorly represented by the literature when it comes to LBD research. If developing nations, female sex, and migrant work are related to increased vulnerability, then these groups need more representation to achieve equitable occupational health study. PMID- 26237718 TI - Characteristics and Costs of Disability Pensions in Finnish Agriculture Based on 5-Year Insurance Records. AB - The characteristics and costs of disability pensions in Finnish farmers were investigated. The data included a total of 4,088 permanent or temporary disability pensions of the self-employed Finnish farming population over a 5-year period (2008-2012), an annual rate of 1.04 new cases per 100 person-years (males 0.94/100 and females 1.24/100). These cases resulted in the loss of almost 6,800 person-years and 60.2 million Euros in pension costs in the 5-year period. Almost half of the outcomes (44.6%) were primarily related to diseases of the musculoskeletal system (MSDs). Other common outcomes were mental and behavioral disorders (17.5%), injuries (9.8%), diseases of the circulatory system (7.8%), and diseases of the nervous system (6.6%). Relative proportions of these outcomes and their costs were similar with few exceptions. Although farmers have high risk of acute traumatic injuries, they also have a high risk of chronic conditions that affect their work ability. Particularly MSDs were common primary reasons for disability pension among farmers in general and among female farmers in particular. In addition to healthy lifestyle choices, improvements in the working environment and methods to reduce heavy or repetitive manual labor should be emphasized in vocational and extension education of farmers. Modern working conditions with meaningful and varied work tasks could enhance both physical and mental well-being of farmers and thus reinforce and extend their careers. PMID- 26237719 TI - Prevalence of Musculoskeletal Disorders Among Saskatchewan Farmers. AB - The extent of the musculoskeletal disorder (MSD) problem is not well understood among Canadian farmers, and little too is known about their epidemiology. The purpose of this study was therefore to (1) determine the prevalence of MSDs among farmers in one Canadian province; and (2) describe the types and severities of these disorders and patterns in their occurrence. This cross-sectional analysis was conducted using baseline survey data from the Saskatchewan Farm Injury Cohort Study. Reports of MSDs, demographic and health-related variables, reports of farm related injuries, and economic conditions of individual farms were available for 2595 adult participants from 1212 farms in Saskatchewan, Canada. Relationships between MSDs and time spent doing farm work were investigated using tests of association. The participation rate was 48.8%. Most (85.6%) of participants reported having musculoskeletal pain in at least one body part over the past year. The lower back was most frequently affected (57.7%), followed by shoulders (44.0%), and neck (39.6%). More serious pain prevented 27.9% of respondents from performing regular work activities. MSD prevalence did not vary by sex, commodity type, or by total hours of farm work completed; prevalence was significantly (P < .05) related to time spent performing biomechanically demanding tasks such as heavy lifting and working with arms overhead. The most common MSD site in farmers was the low back, followed by the upper and then lower extremities. Although this study aimed to identify high-risk groups, lack of differences between demographic groups suggests that the majority of farmers are at risk for MSDs. PMID- 26237720 TI - Farm Exposure and Atopy in Men and Women: The Saskatchewan Rural Health Study. AB - Associations between farming exposures and atopy can vary by timing of exposure and sex. We examined associations between adult atopy, sex, and farm living in a rural Canadian population. In 2010, we conducted a baseline survey of 11,982 households located in four agricultural regions of Saskatchewan, Canada. Of the 7225 adults aged 18-75, 1658 underwent clinical assessments including skin testing. Of these, 1599 participants underwent skin prick testing to four common allergens. We defined atopy as >3 mm reaction to any of four allergens compared with saline control. Farming exposures were farm living in the first year of life and current farm living. All analyses were stratified by sex. The prevalence of atopy was 17.8% and was higher in men than women (P < .001). The most common allergy was to grasses (8.8%) followed by house dust mite (HDM) mixed (8.1%). Atopy was lower in those subjects with an early farm exposure (P = .08) and who were female (P = .03). After adjusting for education, age, and smoking status, both current and early farm exposures were associated with decreased sensitization to cat atopy in women that was stronger with current exposure (P < .05). Men had significantly decreased atopic sensitization to Alternaria with an early farm exposure and increased atopic sensitization to HDM with a current farm exposure. In this rural population, the protective effect of an early farm exposure for any atopy was weak overall. The impact of farming exposures on atopy was allergen dependent and varied by sex. PMID- 26237721 TI - Prevalence and Risk Factors of Respiratory Symptoms in Rural Population. AB - Research has shown that respiratory symptoms, including chronic cough, chronic phlegm, shortness of breath, and wheeze, are important markers that contribute to hospitalization, lung function decline, and other respiratory illness. This report aims to estimate the prevalence of respiratory symptoms and associated environmental risk factors in farming and nonfarming rural-dwelling people. A baseline mail-out questionnaire to assess respiratory health outcomes as well as individual and contextual determinants in farm and small town cohorts was sent to 11,004 households within four geographical regions of Saskatchewan, Canada, in 2010. Completed questionnaires were received from 4624 households (8261 individuals). Outcome variables examined for this report were chronic cough, chronic phlegm, shortness of breath, and ever wheeze. Clustering effect within households was adjusted using generalized estimating equations. The prevalence of respiratory symptoms was chronic cough, 9.2% (farm vs. nonfarm: 8.1% vs. 10.0%); chronic phlegm, 8.2% (farm vs. nonfarm: 6.7% vs. 9.3%); shortness of breath, 29.1% (farm vs. nonfarm: 25.5% vs. 31.6%); and ever wheeze, 40.6% (farm vs. nonfarm: 38.1% vs. 42.5%). There was a significantly higher prevalence of each respiratory symptomin the nonfarming population compared with the farming population (P < .01). Respiratory symptoms were positively associated with smoking, allergic reaction to inhaled allergens, and other environmental factors for farming and nonfarming populations. The prevalence of respiratory symptoms was higher in the nonfarming rural population compared with the farming rural population. Environmental exposures such as work-related or home environment play an important role in the increased prevalence of respiratory symptoms in farming and nonfarming populations. PMID- 26237722 TI - Farm Activities and Agricultural Injuries in Youth and Young Adult Workers. AB - Youth and young adults who work in the agricultural sector experience high rates of injury. This study aimed to investigate relations between high-risk farm activities and the occurrence of agricultural injuries in these vulnerable groups. A cross-sectional analysis was conducted using written questionnaire data from 1135 youth and young adults from the Saskatchewan Farm Injury Cohort. The prevalence of agricultural injury was estimated at 4.9%/year (95% confidence interval [CI]: 3.7, 6.2). After adjustment for important covariates, duration of farm work was strongly associated with the occurrence of injury (risk ratio [RR] = 8.0 [95% CI: 1.7, 36.7] for 10-34 vs. <10 hours/week; RR = 10.3 [95% CI: 2.2, 47.5] for those working 35+ hours/week). Tractor maintenance, tractor operation, chores with large animals, herd maintenance activities, and veterinary activities were identified as risk factors for agricultural injury. Risks for agricultural injury among youth and young adults on farms relate directly to the amounts and types of farm work exposures that young people engage in. PMID- 26237723 TI - The Association of Sleep Loss and Balance Stability in Farmers. AB - Sleep deprivation has been linked to injuries, illnesses, and reduced performance measures. Yet, it is unclear how sleep loss contributes to the high rates of injuries and falls in agriculture. In this study, the authors evaluated sleep loss and quantified its association with balance in five farmers, who wore an ActiWatch to record their sleeping patterns in six repeated weekly observation periods. Acute sleep loss was computed as the net sleep (sleeping hours the night before balance testing - average sleep hours during the week). All farmers performed four balance tests on either one foot or both feet and with eyes open or closed. Balance was measured using a pressure mat to monitor the change in center of pressure (CoP) of the feet in anteroposterior (AP) and mediolateral (ML) directions. Spearman's rank correlation coefficient indicated balance outcomes were strongly and negatively correlated with the net sleep (P < .05). As the net sleep decreased, farmers became less stable, particularly indicated by an increase in the area, total displacement, and deviations of CoP in both AP and ML directions while standing on both feet with eyes open. Fisher's exact test showed an association between the CoP in AP direction and the net sleep (P = .020, odds ratio [OR] = 7.37). Thus, the odds of having reduced balance stability were 7.4 times higher when farmers slept less than their average hours during the night prior to the balance test. These results suggest that acute sleep loss impacts balance stability that may lead to falls. Understanding the association of sleep loss and balance stability is important in prevention of agricultural injuries. PMID- 26237724 TI - Rural Dwelling and Temporal Trends in Relation to Childhood Asthma and Related Conditions in Belarus: A Repeated Cross-sectional Survey. AB - There is a lack of asthma research in Belarus, with no investigation of temporal trends. The purpose of the study was to determine the prevalence of asthma and related conditions comparing urban and rural children while investigating temporal changes in the region of Grodno, Belarus. A repeated cross-sectional survey design was used. Parents completed surveys on behalf of the child. Data collection was based on the International Study of Asthma and Allergies in Children (ISAAC) survey and included 5020 urban and rural children aged 7-15 years in 2009-2010 and 4953 children in 2014 from the Grodno Region. Asthma prevalence in 2009 was 1.4% compared with 1.8% in 2014, whereas spastic bronchitis prevalence was higher (2009: 6.8%; 2014: 8.5%). After adjustment for confounders, rural dwelling showed a statistically significant inverse association with each of the allergic conditions or symptoms. However, asthma (odds ratio [OR] = 1.01, 95% confidence interval [CI] = 0.69-1.50) was not associated with rural dwelling. A diagnosis of asthma was more likely in 2014 compared with 2009 (OR = 1.57, 95% CI = 1.05-2.33), as was spastic bronchitis (OR = 1.26, 95% CI = 1.06-1.51). Maternal smoking was associated with the presence of respiratory symptoms. The data showed that the prevalence of diagnosed asthma was comparable between urban and rural areas but lower than other regions, there was generally an increase in the prevalence of asthma and related conditions, and that temporal changes did not vary by urban-rural status. The prevalence of spastic bronchitis was over 3 times higher than that of asthma. These findings also suggest that the presence of undiagnosed asthma in children is occurring in the Grodno Region. PMID- 26237725 TI - Latino Farmworkers in Saskatchewan: Language Barriers and Health and Safety. AB - As part of a study focused on the experiences of Latino migrant farmworkers in Saskatchewan, Canada, we have attempted to understand how language barriers (LBs) broadly understood may affect farmworkers and their employers, workplace communications, and occupational health and safety (OHS). Drawing on critical ethnography and intercultural communication theory, qualitative interviews were conducted with 39 Latino migrant farmworkers, 11 farmer-employers, two OHS civil servants, and two former Canadian farmworkers. Our findings suggest that LBs interfere with the establishment of effective communications between Latino farmworkers, other farm enterprise personnel, civil servants, and health services providers. LBs impede establishment of the kinds of sustained two-way communications needed for maintaining safe and healthy working environments. All of the stakeholders involved were found to contribute in some manner to the propagation of LBs. The risks for the physical and psychological well-being of migrant farmworkers are substantial, but despite the fact that LBs are generally recognized as a challenge and as a source of risk, they are not widely seen as warranting any systematic response. It is critical that Latino migrant workers learn more English and that their Canadian employers and supervisors learn more Spanish. Beyond that, there is an urgent need for a multistakeholder coalition that moves to address LBs by training certified interpreters and liaison personnel who can facilitate better communications between migrant workers, their employers, and other stakeholders. PMID- 26237726 TI - Risk Factors for Heat-Related Illness in Washington Crop Workers. AB - Crop workers are at high risk of heat-related illness (HRI) from internal heat generated by heavy physical work, particularly when laboring in hot and humid conditions. The aim of this study was to identify risk factors for HRI symptoms in Washington crop workers using an audio computer-assisted self-interview (A CASI) instrument that has undergone reliability and validity evaluation. A cross sectional A-CASI survey of 97 crop workers in Washington State was conducted during the summer of 2013. Potential HRI risk factors in demographic, training, work, hydration, clothing, health, and environmental domains were selected a priori for evaluation. Mixed-effects logistic regression was used to identify risk factors for self-reported symptoms associated with heat strain and HRI (dizziness/light-headedness or heavy sweating) experienced at work in hot conditions. An increase in age was associated with a lower odds of HRI symptoms (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.87-0.98). Piece rate compared with hourly payment (OR = 6.20; 95% CI = 1.11-34.54) and needing to walk for more than 3 minutes to get to the toilet, compared with less than 3 minutes (OR = 4.86; 95% CI = 1.18-20.06), were associated with a higher odds of HRI symptoms. In this descriptive study of risk factors for HRI symptoms in Washington crop workers, decreased age (and less work experience), piece rate pay, and longer distance to the toilet were associated with self-reported HRI symptoms. Modifiable workplace factors should be considered in HRI prevention efforts that are evaluated using objective measures in representative working populations. PMID- 26237727 TI - The Hierarchy of Control in the Epidemic of Farm Injury. AB - The application of the hierarchy of control (HOC) is a well-established approach to hazard reduction in industrial workplaces. However, it has not been generally applied in farm workplaces. The objective was to determine current practices of farmers in the context of a modified HOC, and the effect of these practices on farm injury outcomes. A self-reported mail survey of 1196 Saskatchewan farm operations was conducted in 2013. Selected survey questions were used as proxy measures of the farm owner-operator's practices relevant to each of the six steps of increasing importance in a modified HOC: (1) hazard identification; (2) risk assessment; (3) personal protection; (4) administrative controls; (5) engineering controls; and (6) elimination of the hazard. Analysis used basic descriptive statistics and logistic regression to examine associations of interest. When four of the six HOC steps were adhered to, there was a significant protective effect: odds ratio (OR) = 0.32 (95% confidence interval [CI]: 0.14-0.74) for any injury and OR = 0.27 (95% CI: 0.07-0.99) for serious injury in the overall study population. For farm owner-operators utilizing four of the six steps in the modified HOC, there was a significant protective effect for any injury (OR = 0.30, 95% CI: 0.11-0.83). Although there is a considerable absence of use of elements of the HOC among farm operators, for farmers who adhere to these steps, there is a significant reduction in their risk for injury. Prevention strategies that embrace the practice of these principles may be effective in the control of farm workplace injury. PMID- 26237728 TI - Factors to be Considered in Developing Occupational Regulations for Quad Bikes in Australia. AB - Quad bikes are popular vehicles in agricultural occupational settings. Quad bike rollovers are a leading cause of deaths in the Australian agricultural industry; current regulations appear to have had limited impact on quad bike deaths. The objectives of this study were (1) to explore whether regulation is perceived by regulators, users, retailers, and health professionals as an effective approach to quad bike safety in North West Outback Queensland, Australia; and (2) to consider the ways that perceptions of quad bike safety and use in North West Outback Queensland could inform the development of regulatory guidelines for the occupational use of quad bikes in agricultural industries. Focus group sessions and interviews were conducted November 2011 to May 2012 with farmers, health care providers, regulators, and retailers. Participants displayed a variety of opinions about perceived impacts of current regulatory changes to enhance quad bike safety, including changes to local induction processes and use of personal protective equipment on local enterprises. Many users perceived that policing the use of quad bikes would be difficult and regulators acknowledged the challenges to development of regulatory requirements and their ability to monitor and regulate use. Regulators also discussed the challenges of differentiating between work-related incidents and recreational incidents on farms. If regulation is going to be effective in improving the safety of quad bikes, there are some key moments times where this could occur, including at production, point of sale, within business policies, and everyday use by farm workers. The results highlight mixed reactions to regulatory change as a safety approach for occupational quad bike use. The interactions between regulators and the agricultural community are key in the development of sound policies that meet the standard required by regulation, monitoring, and implementation of safety policies into practice on farms. PMID- 26237729 TI - Staying Fit for Farming-A Health Booklet Designed for Irish Farmers. AB - The objectives of this study were to design a health booklet specifically targeted to farmers with clear and understandable messages through the use of simple terminologies, pictures, agricultural references, and farmer-related case studies; and to maximize the profile and reach of the booklet to empower farmers to take increased control of their own health. Seven focus groups were carried out with farmers and professionals from the agricultural sector to explore the health needs of farmers and their attitudes and behaviors in relation to their health. Findings from these focus groups informed the content and design of the booklet "Staying Fit for Farming-A Health Booklet for Farmers." This booklet was launched on 25 September 2013 and received widespread publicity in both print and broadcast media. A high-quality print resolution of the booklet was made available nationally (approximately 70,500 print circulation sales) through the Irish Farmers Journal on 25 January 2014. The journal included a feature on the booklet, encouraging farmers to see the booklet as an important resource for their health and as a long-term source of health information. The booklet has been adopted by the Irish Heart Foundation as a resource for its "Farmers Have Hearts-Heart Health Checks" program. The booklet has helped push farmers' health into the forefront identifying health as a key driver of "staying fit for farming." The approach taken to consult with farmers and farm organizations helped ensure maximum buy-in from the target group to hopefully motivate farmers to take increased responsibility for their own health. PMID- 26237730 TI - Supporting Healthy Eating Among Rural Early Years Children: A Pulse Crop Pilot Intervention Study. AB - Dietary patterns are closely linked to healthy child development, which in turn is a powerful determinant of lifelong health and well-being. As many early years children spend a large part of their day in childcare centers, educators can have a large influence on their healthy eating behaviors. In Saskatchewan, a number of childcare centers are located in rural communities and research suggests that rural educators are influenced by unique factors when providing healthy eating opportunities for children. In order to diversify and improve the diets of rural early years children, a pulse crop intervention was piloted tested in one rural childcare center. A pre and post 28-week intervention design was used to evaluate the pulse crop intervention on increasing educators' knowledge and awareness about pulse crops and supporting educators in incorporating pulse crops into centers' menus. Overall, the intervention was effective in increasing rural educators' knowledge and use of pulse crops. Additionally, educators were able to diversify and increase the number of healthy meals offered in the childcare center. The lessons learned can be used to improve and expand the intervention to other childcare centers in Saskatchewan and beyond, in turn supporting the healthy development of early years children. PMID- 26237734 TI - Corrigendum. PMID- 26237735 TI - Preoperative JJ stent placement in ureteric and renal stone treatment: results from the Clinical Research Office of Endourological Society (CROES) ureteroscopy (URS) Global Study. AB - OBJECTIVE: To compare outcomes of ureteric and renal stone treatment with ureteroscopy (URS) in patients with or without the placement of a preoperative JJ stent. PATIENTS AND METHODS: The Clinical Research Office of the Endourological Society (CROES) URS Global Study collected prospective data for 1 year on consecutive patients with ureteric or renal stones treated with URS at 114 centres around the world. Patients that had had preoperative JJ stent placement were compared with those that did not. Inverse-probability-weighted regression adjustment (IPWRA) was used to examine the effect of preoperative JJ stent placement on the stone-free rate (SFR), length of hospital stay (LOHS), operative duration, and complications (rate and severity). RESULTS: Of 8 189 patients with ureteric stones, there were 978 (11.9%) and 7 133 patients with and without a preoperative JJ stent, respectively. Of the 1 622 patients with renal stones, 590 (36.4%) had preoperative stenting and 1 002 did not. For renal stone treatment, preoperative stent placement increased the SFR and operative time, and there was a borderline significant decrease in intraoperative complications. For ureteric stone treatment, preoperative stent placement was associated with longer operative duration and decreased LOHS, but there was no difference in the SFR and complications. One major limitation of the study was that the reason for JJ stent placement was not identified preoperatively. CONCLUSIONS: The placement of a preoperative JJ stent increases SFRs and decreases complications in patients with renal stones but not in those with ureteric stones. PMID- 26237737 TI - Blood-Borne Revitalization of the Aged Brain. AB - In the modern medical era, more diverse and effective treatment options have translated to increased life expectancy. With this increased life span comes increased age-associated disease and the dire need to understand underlying causes so that therapies can be designed to mitigate the burden to health and the economy. Aging exacts a seemingly inevitable multisystem deterioration of function that acts as a risk factor for a variety of age-related disorders, including those that devastate organs of limited regenerative potential, such as the brain. Rather than studying the brain and mechanisms that govern its aging in isolation from other organ systems, an emerging approach is to understand the relatively unappreciated communication that exists between the brain and systemic environment. Revisiting classical methods of experimental physiology in animal models has uncovered surprising regenerative activity in young blood with translational implications for the aging liver, muscle, brain, and other organs. Soluble factors present in young or aged blood are sufficient to improve or impair cognitive function, respectively, suggesting an aging continuum of brain relevant systemic factors. The age-associated plasma chemokine CCL11 has been shown to impair young brain function while GDF11 has been reported to increase the generation of neurons in aged mice. However, the identities of specific factors mediating memory-enhancing effects of young blood and their mechanisms of action are enigmatic. Here we review brain rejuvenation studies in the broader context of systemic rejuvenation research. We discuss putative mechanisms for blood-borne brain rejuvenation and suggest promising avenues for future research and development of therapies. PMID- 26237738 TI - Deciding about (neo-)adjuvant rectal and breast cancer treatment: Missed opportunities for shared decision making. AB - BACKGROUND: The first step in shared decision making (SDM) is creating choice awareness. This is particularly relevant in consultations concerning preference sensitive treatment decisions, e.g. those addressing (neo-)adjuvant therapy. Awareness can be achieved by explicitly stating, as the 'reason for encounter', that a treatment decision needs to be made. It is unknown whether oncologists express such reason for encounter. This study aims to establish: 1) if 'making a treatment decision' is stated as a reason for the encounter and if not, what other reason for encounter is provided; and 2) whether mentioning that a treatment decision needs to be made is associated with enhanced patient involvement in decision making. MATERIAL AND METHODS: Consecutive first consultations with: 1) radiation oncologists and rectal cancer patients; or 2) medical oncologists and breast cancer patients, facing a preference-sensitive treatment decision, were audiotaped. The tapes were transcribed and coded using an instrument developed for the study. Oncologists' involvement of patients in decision making was coded using the OPTION-scale. RESULTS: Oncologists (N = 33) gave a reason for encounter in 70/100 consultations, usually (N = 52/70, 74%) at the start of the consultation. The reason for encounter stated was 'making a treatment decision' in 3/100 consultations, and 'explaining treatment details' in 44/100 consultations. The option of foregoing adjuvant treatment was not explicitly presented in any consultation. Oncologist' involvement of patients in decision making was below baseline (Md OPTION-score = 10). Given the small number of consultations in which the need to make a treatment decision was stated, we could not investigate the impact thereof on patient involvement. CONCLUSION: This study suggests that oncologists rarely express that a treatment decision needs to be made in consultations concerning preference-sensitive treatment decisions. Therefore, patients might not realize that foregoing (neo-)adjuvant treatment is a viable choice. Oncologists miss a crucial opportunity to facilitate SDM. PMID- 26237739 TI - Specialty Society Clinical Practice Guidelines: Time for Evolution or Revolution? PMID- 26237736 TI - The marine n-3 PUFA DHA evokes cytoprotection against oxidative stress and protein misfolding by inducing autophagy and NFE2L2 in human retinal pigment epithelial cells. AB - Accumulation and aggregation of misfolded proteins is a hallmark of several diseases collectively known as proteinopathies. Autophagy has a cytoprotective role in diseases associated with protein aggregates. Age-related macular degeneration (AMD) is the most common neurodegenerative eye disease that evokes blindness in elderly. AMD is characterized by degeneration of retinal pigment epithelial (RPE) cells and leads to loss of photoreceptor cells and central vision. The initial phase associates with accumulation of intracellular lipofuscin and extracellular deposits called drusen. Epidemiological studies have suggested an inverse correlation between dietary intake of marine n-3 polyunsaturated fatty acids (PUFAs) and the risk of developing neurodegenerative diseases, including AMD. However, the disease-preventive mechanism(s) mobilized by n-3 PUFAs is not completely understood. In human retinal pigment epithelial cells we find that physiologically relevant doses of the n-3 PUFA docosahexaenoic acid (DHA) induce a transient increase in cellular reactive oxygen species (ROS) levels that activates the oxidative stress response regulator NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2). Simultaneously, there is a transient increase in intracellular protein aggregates containing SQSTM1/p62 (sequestosome 1) and an increase in autophagy. Pretreatment with DHA rescues the cells from cell cycle arrest induced by misfolded proteins or oxidative stress. Cells with a downregulated oxidative stress response, or autophagy, respond with reduced cell growth and survival after DHA supplementation. These results suggest that DHA both induces endogenous antioxidants and mobilizes selective autophagy of misfolded proteins. Both mechanisms could be relevant to reduce the risk of developing aggregate-associate diseases such as AMD. PMID- 26237740 TI - Erratum: Identification of the gene defect responsible for severe hypercholesterolaemia using whole-exome sequencing. PMID- 26237741 TI - Screening to prevent anal cancer: Current thinking and future directions. PMID- 26237742 TI - Five-year Antibody Persistence and Booster Response to a Single Dose of Meningococcal A, C, W and Y Tetanus Toxoid Conjugate Vaccine in Adolescents and Young Adults: An Open, Randomized Trial. AB - BACKGROUND: We evaluated antibody persistence after 1 dose of meningococcal serogroups ACWY tetanus toxoid (MenACWY-TT) or diphtheria toxoid (MenACWY-DT) conjugate vaccines and subsequent booster responses to MenACWY-TT. METHODS: In the initial phase II, open, multicenter study (NCT00454909), 872 participants aged 10-25 years received 1 MenACWY-TT or MenACWY-DT dose. In this study (NCT00715910), antibody persistence was evaluated at years 1, 3 and 5 by serum bactericidal activity assays using human complement (hSBA). At year 5, all participants received a MenACWY-TT booster dose. Immune responses at 1-month postbooster were compared with a control group including 101 participants aged 15 30 years who received a primary MenACWY-TT dose. Solicited and unsolicited adverse events were recorded for 4 and 31 days, respectively, followed by a 6 month extended safety follow-up. RESULTS: At year 5, >=79.5% of MenACWY-TT-primed (n = 170) and MenACWY-DT-primed (n = 45) participants had hSBA titers >=1:8 for MenC, MenW and MenY, and >=37.5% for MenA. For all serogroups, >=85.7% and >=67.1% of MenACWY-TT booster and primary dose recipients exhibited vaccine responses 1-month postmvaccination, respectively. Geometric mean titers were potentially higher in primed versus naive participants, with no potential difference between MenACWY-TT-primed and MenACWY-DT-primed participants (exploratory analyses). MenACWY-TT had a clinically acceptable safety profile. CONCLUSIONS: Before the booster dose administration at year 5, hSBA-MenC, -MenW and -MenY antibody persistence was observed in most participants. However, only >=37.5% of MenACWY-TT and 44.4% of MenACWY-DT recipients retained hSBA-MenA titers >=1:8. MenACWY-TT booster doses elicited robust anamnestic responses, irrespective of the priming vaccine, and were well tolerated. PMID- 26237743 TI - Host and Microbial Predictors of Childhood Extrathoracic Tuberculosis and Tuberculosis Meningitis. AB - BACKGROUND: Childhood tuberculosis (TB) is a major infectious disease causing morbidity and mortality in children and yet has been largely ignored until recently. This study is the first study to characterize childhood TB in China incorporating both Mycobacterium tuberculosis genetic characteristics and patient data. METHODS: We analyzed a total of 331 culture-confirmed childhood TB cases and 158 M. tuberculosis isolates from a subset of the study sample. Univariate and multivariate logistic regression analyses were performed to identify host and microbial predictors for having extrathoracic TB alone, concurrent thoracic and extrathoracic TB and TB meningitis (TBM), respectively. RESULTS: Fifty-eight percent (192/331) of the study subjects had extrathoracic TB, and 139 (42.0%) cases had TBM. Both age of less than 5 years [adjusted odds ratio (OR): 4.52; 95% confidence interval (CI): 1.27-16.16] and female sex (adjusted OR: 2.72; 95% CI: 1.03-7.18) were significantly associated with extrathoracic TB alone, whereas living in rural area (adjusted OR: 2.35; 95% CI: 1.06-5.18) was significantly associated with thoracic-extrathoracic TB. Age of less than 5 years was also strongly associated with TBM (adjusted OR: 3.63; 95% CI: 1.64-8.05). Sixty-four percent (101/158) of the study isolates were Beijing lineage strains. Infection with Beijing lineage strains was significantly associated with thoracic extrathoracic TB (adjusted OR: 2.39; 95% CI: 1.11-5.15) and TBM (adjusted OR: 2.25; 95% CI: 1.10-4.60). CONCLUSIONS: Both microbial and host factors can affect the outcome of M. tuberculosis infection in children. Future studies incorporating host and pathogen data from different populations are warranted to develop new strategies for childhood TB control. PMID- 26237744 TI - To Treat or to Prevent?: Reducing the Population Burden of Violence-related Post traumatic Stress Disorder. AB - BACKGROUND: Violence-related post-traumatic stress disorder (PTSD) remains a prevalent and disabling psychiatric disorder in urban areas. However, the most effective allocation of resources into prevention and treatment to reduce this problem is unknown. We contrasted the impact of two interventions on violence related PTSD: (1) a population-level intervention intended to prevent violence (i.e., hot-spot policing), and (2) an individual-level intervention intended to shorten PTSD duration (i.e., cognitive-behavioral therapy-CBT). METHODS: We used agent-based modeling to simulate violence and PTSD in New York City under four scenarios: (1) no intervention, (2) targeted policing to hot spots of violence, (3) increased access to CBT for people who suffered from violence-related PTSD, and (4) a combination of the two interventions. RESULTS: Combined prevention and treatment produced the largest decrease in violence-related PTSD prevalence: hot spot policing plus a 50% increase in CBT for 5 years reduced the annual prevalence of violence-related PTSD from 3.6% (95% confidence interval = 3.5%, 3.6%) to 3.4% (3.3%, 3.5%). It would have been necessary to implement hot-spot policing or to increase CBT by 200% for 10 years for either intervention to achieve the same reduction in isolation. CONCLUSIONS: This study provides an empirically informed demonstration that investment in combined strategies that target social determinants of mental illness and provide evidence-based treatment to those affected by psychiatric disorders can produce larger reductions in the population burden from violence-related PTSD than either preventive or treatment interventions alone. However, neither hot-spot policing nor CBT, alone or combined, will produce large shifts in the population prevalence of violence related PTSD. PMID- 26237745 TI - Ambient Fine Particulate Matter, Nitrogen Dioxide, and Hypertensive Disorders of Pregnancy in New York City. AB - BACKGROUND: Previous studies suggested a possible association between fine particulate matter air pollution (PM2.5) and nitrogen dioxide (NO2) and the development of hypertensive disorders of pregnancy, but effect sizes have been small and methodologic weaknesses preclude firm conclusions. METHODS: We linked birth certificates in New York City in 2008-2010 to hospital discharge diagnoses and estimated air pollution exposure based on maternal address. The New York City Community Air Survey provided refined estimates of PM2.5 and NO2 at the maternal residence. We estimated the association between exposures to PM2.5 and NO2 in the first and second trimester and risk of gestational hypertension, mild preeclampsia, and severe preeclampsia among 268,601 births. RESULTS: In unadjusted analyses, we found evidence of a positive association between both pollutants and gestational hypertension. However, after adjustment for individual covariates, socioeconomic deprivation, and delivery hospital, we did not find evidence of an association between PM2.5 or NO2 in the first or second trimester and any of the outcomes. CONCLUSIONS: Our data did not provide clear evidence of an effect of ambient air pollution on hypertensive disorders of pregnancy. Results need to be interpreted with caution considering the quality of the available exposure and health outcome measures and the uncertain impact of adjusting for hospital. Relative to previous studies, which have tended to identify positive associations with PM2.5 and NO2, our large study size, refined air pollution exposure estimates, hospital-based disease ascertainment, and little risk of confounding by socioeconomic deprivation, does not provide evidence for an association. PMID- 26237746 TI - Surface Chemical Gradient Affects the Differentiation of Human Adipose-Derived Stem Cells via ERK1/2 Signaling Pathway. AB - To understand the role of surface chemistry on cell behavior and the associated molecular mechanisms, we developed and utilized a surface chemical gradient of amine functional groups by carefully adjusting the gas composition of 1,7 octadiene (OD) and allylamine (AA) of the plasma phase above a moving substrate. The chemical gradient surface used in the present work shows an increasing N/C ratio and wettability from the OD side toward the AA side with no change in surface topography. Under standard culture conditions (with serum), human adipose derived stem cells (hASCs) adhesion and spreading area increased toward the AA side of the gradient. However, there were no differences in cell behavior in the absence of serum. These results, supported by the trends in proteins adsorption on the gradient surface, demonstrated that surface chemistry affects the response of hASCs through cell-adhesive serum proteins, rather than interacting directly with the cells. The expression of p-ERK and the osteogenic differentiation increased toward the AA side of the gradient, while adipogenic differentiation decreased in the same direction; however, when the activation of ERK1/2 was blocked by PD98059, the levels of osteogenic or adipogenic differentiation on different regions of the chemical gradient were the same. This indicates that ERK1/2 may be an important downstream signaling pathway of surface chemistry directed stem cell fate. PMID- 26237749 TI - Transcriptome Analysis Reveals that Red and Blue Light Regulate Growth and Phytohormone Metabolism in Norway Spruce [Picea abies (L.) Karst]. AB - The mechanisms by which different light spectra regulate plant shoot elongation vary, and phytohormones respond differently to such spectrum-associated regulatory effects. Light supplementation can effectively control seedling growth in Norway spruce. However, knowledge of the effective spectrum for promoting growth and phytohormone metabolism in this species is lacking. In this study, 3 year-old Norway spruce clones were illuminated for 12 h after sunset under blue or red light-emitting diode (LED) light for 90 d, and stem increments and other growth traits were determined. Endogenous hormone levels and transcriptome differences in the current needles were assessed to identify genes related to the red and blue light regulatory responses. The results showed that the stem increment and gibberellin (GA) levels of the seedlings illuminated by red light were 8.6% and 29.0% higher, respectively, than those of the seedlings illuminated by blue light. The indoleacetic acid (IAA) level of the seedlings illuminated by red light was 54.6% lower than that of the seedlings illuminated by blue light, and there were no significant differences in abscisic acid (ABA) or zeatin riboside [ZR] between the two groups of seedlings. The transcriptome results revealed 58,736,166 and 60,555,192 clean reads for the blue-light- and red-light illuminated samples, respectively. Illumina sequencing revealed 21,923 unigenes, and 2744 (approximately 93.8%) out of 2926 differentially expressed genes (DEGs) were found to be upregulated under blue light. The main KEGG classifications of the DEGs were metabolic pathway (29%), biosynthesis of secondary metabolites (20.49%) and hormone signal transduction (8.39%). With regard to hormone signal transduction, AUXIN-RESISTANT1 (AUX1), AUX/IAA genes, auxin-inducible genes, and early auxin-responsive genes [(auxin response factor (ARF) and small auxin-up RNA (SAUR)] were all upregulated under blue light compared with red light, which might have yielded the higher IAA level. DELLA and phytochrome-interacting factor 3 (PIF3), involved in negative GA signaling, were also upregulated under blue light, which may be related to the lower GA level. Light quality also affects endogenous hormones by influencing secondary metabolism. Blue light promoted phenylpropanoid biosynthesis, phenylalanine metabolism, flavonoid biosynthesis and flavone and flavonol biosynthesis, accompanied by upregulation of most of the genes in their pathways. In conclusion, red light may promote stem growth by regulating biosynthesis of GAs, and blue light may promote flavonoid, lignin, phenylpropanoid and some hormones (such as jasmonic acid) which were related to plant defense in Norway spruce, which might reduce the primary metabolites available for plant growth. PMID- 26237750 TI - A Case of P-Wave Mimicry: Cherchez le P. PMID- 26237751 TI - Asymmetric functional interaction between chaperonin and its plastidic cofactors. AB - The specific cochaperonin, chloroplast chaperonin (Cpn)20, consisting of two tandem GroES-like domains, is present abundantly in plant and algal chloroplasts, in addition to Cpn10, which is similar in size to GroES. How Cpn20 oligomers, containing six or eight 10-kDa domains, cooperate with the heptameric ring of chaperonin at the same time as encountering symmetry mismatch is unclear. In the present study, we characterized the functional cooperation of cochaperonins, including two plastidic Cpn20 homo-oligomers from Arabidopsis (AtCpn20) and Chlamydomonas (CrCPN20), and one algal CrCPNs hetero-oligomer, consisting of three cochaperonins, CrCPN11, CrCPN20 and CrCPN23, with two chaperonins, Escherichia coli GroEL and Chlamydomonas CrCPN60. AtCpn20 and CrCPNs were functional for assisting both chaperonins in folding model substrates ribulose bisphosphate carboxylase oxygenase from Rhodospirillum rubrum (RrRubisco) in vitro and complementing GroES function in E. coli. CrCPN20 cooperated only with CrCPN60 (and not GroEL) to refold RrRubisco in vitro and showed differential complementation with the two chaperonins in E. coli. Cochaperonin concatamers, consisting of six to eight covalently linked 10-kDa domains, were functionally similar to their respective native forms. Our results indicate that symmetrical match between chaperonin and cochaperonin is not an absolute requisite for functional cooperation. PMID- 26237753 TI - Celebrating the ACP Centennial: From the Annals Archive-Diagnosing Chest Pain. PMID- 26237752 TI - Electronic Interventions for Alcohol Misuse and Alcohol Use Disorders: A Systematic Review. AB - BACKGROUND: The use of electronic interventions (e-interventions) may improve treatment of alcohol misuse. PURPOSE: To characterize treatment intensity and systematically review the evidence for efficacy of e-interventions, relative to controls, for reducing alcohol consumption and alcohol-related impairment in adults and college students. DATA SOURCES: MEDLINE (via PubMed) from January 2000 to March 2015 and the Cochrane Library, EMBASE, and PsycINFO from January 2000 to August 2014. STUDY SELECTION: English-language, randomized, controlled trials that involved at least 50 adults who misused alcohol; compared an e-intervention group with a control group; and reported outcomes at 6 months or longer. DATA EXTRACTION: Two reviewers abstracted data and independently rated trial quality and strength of evidence. DATA SYNTHESIS: In 28 unique trials, the modal e intervention was brief feedback on alcohol consumption. Available data suggested a small reduction in consumption (approximately 1 drink per week) in adults and college students at 6 months but not at 12 months. There was no statistically significant effect on meeting drinking limit guidelines in adults or on binge drinking episodes or social consequences of alcohol in college students. LIMITATIONS: E-interventions that ranged in intensity were combined in analyses. Quantitative results do not apply to short-term outcomes or alcohol use disorders. CONCLUSION: Evidence suggests that low-intensity e-inter ventions produce small reductions in alcohol consumption at 6 months, but there is little evidence for longer-term, clinically significant effects, such as meeting drinking limits. Future e-interventions could provide more intensive treatment and possibly human support to assist persons in meeting recommended drinking limits. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs. PMID- 26237754 TI - First Code. PMID- 26237755 TI - State of Research Funding From the National Institutes of Health for Criminal Justice Health Research. PMID- 26237756 TI - State of Research Funding From the National Institutes of Health for Criminal Justice Health Research. PMID- 26237757 TI - Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia. PMID- 26237758 TI - Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia. PMID- 26237759 TI - Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia. PMID- 26237760 TI - Anticoagulation? Antiplatelet? What's the Score? PMID- 26237761 TI - Anticoagulation? Antiplatelet? What's the Score? PMID- 26237762 TI - Association Among Hypoxemia, Patent Foramen Ovale, and Mediastinal Germ Cell Tumor: A Case Report. PMID- 26237763 TI - In The Clinic: Hyponatremia. PMID- 26237764 TI - Web Exclusives. Annals Graphic Medicine: Mom's Flock. PMID- 26237765 TI - Prognostic significance of L-type amino acid transporter 1 (LAT1) expression in cutaneous melanoma. AB - Amino acid transporters play a crucial role in the development and invasiveness of cancer cells. However, it remains unclear whether or not the expression of L type amino acid transporter 1 (LAT1) has prognostic significance in patients with cutaneous melanoma. A total of 128 patients with cutaneous melanoma were evaluated. Tumor sections were stained by immunohistochemistry for LAT1, CD98, Ki 67, and microvessel density determined by CD34 and p53. We also analyzed 30 specimens of patients with melanocytic nevi as negative controls. LAT1 and CD98 were highly expressed in 58% (75/128) and 75% (97/128), respectively. The rates of positivity for LAT1 in the melanocytic nevi were 0% (0/30). The expression of LAT1 was associated significantly with tumor thickness, T factor, CD98 expression, cell proliferation (Ki-67), and microvessel density (CD34). By Spearman's rank test, LAT1 expression was correlated with CD98, Ki-67, and CD34. By univariate analysis, tumor thickness, ulceration, disease staging, LAT1, and CD34 showed a significant relationship with overall survival and disease-free survival. Furthermore, a multivariate analysis confirmed that LAT1 was an independent prognostic factor for predicting a poor prognosis. This study had a small sample size. LAT1 can serve as a significant prognostic factor to predict a poor outcome and it may therefore play an important role in the aggressiveness of cutaneous melanoma. PMID- 26237766 TI - Association between tumor size and Breslow's thickness in malignant melanoma: a cross-sectional, multicenter study. AB - The aim of this study was to assess the potential role of tumor diameter in explaining variations in tumoral invasion and in the initial prognosis for patients with malignant melanoma (MM). This was a multicenter, cross-sectional study that recruited between 2000 and 2009 patients with primary in-situ MM (Tis) and invasive cutaneous MM. Tis and MMs with a Breslow's thickness less than 1 mm (T1) were grouped (Tis-T1) and tumors with a Breslow's thickness 1 mm or more were also analyzed in combination (T2-T4). The tumor size was measured after routine formalin tissue fixation. Primary outcomes were the correlation between Breslow's thickness and tumor size, and the role of tumor size in explaining variations in Breslow's thickness, as assessed by the Pearson correlation test and logistic binary regression with calculation of the odds ratios. A total of 1610 MM patients were included and analyzed. The Pearson correlation between tumor size and Breslow's thickness was 0.42, with a determination coefficient of R2=0.18 (P>0.01). Correlations between tumor size and thickness were stronger in patients aged 30-60 years (r=0.42, R2=0.1764, P<0.001) and in tumors arising on the upper limbs (r=0.55, R2=0.3025). The odds ratio of identifying a T2-T4 stage MM in patients with tumors larger than 1 cm in size was 2.76 (95% confidence interval 2.25-3.39, P<0.001). Even though a direct, positive, and strong association between tumoral size and Breslow's thickness might be expected in melanoma cases, the strength of this association has been moderate. Tumor size explains a low burden of the variation observed in the Breslow's thickness. PMID- 26237767 TI - Fitness Tracker to Assess Sleep: Beyond the Market. PMID- 26237768 TI - Short- and Long-Term Sleep Stability in Insomniacs and Healthy Controls. AB - STUDY OBJECTIVES: Assess the short- and long-term stability of sleep duration in patients with insomnia and normal-sleeping controls. DESIGN: Observational short term and prospective studies. SETTING: Sleep laboratory. PARTICIPANTS: Patients with insomnia (n = 150) and controls (n = 151) were recruited from the local community or sleep disorders clinic. A subsample of 95 men from the Penn State Adult Cohort (PSAC) were followed up 2.6 y after their initial visit. MEASUREMENTS: Participants underwent a physical examination and 8-h polysomnography (PSG) recording for 3 consecutive nights (controls and insomniacs), or 2 single nights separated by several years (PSAC). Intraclass correlation coefficients (ICCs) assessed the stability of the variables total sleep time (TST), sleep onset latency (SOL), and wake after sleep onset (WASO). We also examined persistence of the first-night classification of "short" versus "normal" sleep duration on subsequent nights. RESULTS: Stability of TST, SOL, and WASO based on 1 night were slight to moderate in both patients with insomnia (ICC = 0.37-0.57) and controls (ICC = 0.39-0.59), and became substantial to almost perfect when based on the average of 3 nights (ICC = 0.64-0.81). We observed similar degrees of stability for TST and WASO in the longitudinal sample, with moderate stability based on a single night and substantial stability based on both nights. In examining the persistence of "short" and "normal" sleep duration, 71.4% (controls), 74.7% (patients with insomnia), and 72.6% (longitudinal sample) of participants retained their first-night classifications over subsequent nights. CONCLUSIONS: Sleep duration variables, particularly total sleep time based on 3 consecutive nights in both patients with insomnia and controls or two single-night recordings separated by several years, are stable and reflect a person's habitual sleep. Furthermore, a single night in the laboratory may be useful for reliably classifying one's sleep duration. PMID- 26237769 TI - Associations between Cardioembolic Stroke and Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: To assess etiology of ischemic stroke in patients with obstructive sleep apnea (OSA) compared with controls. This information may aid in determining how OSA increases stroke risk and facilitate recurrent stroke prevention in patients with OSA. DESIGN: Retrospective, case-control study. SETTING: Academic tertiary referral center. PATIENTS: Consecutive patients who underwent polysomnography and had an ischemic stroke within 1 year were identified. Stroke subtype was determined using two validated algorithms. Polysomnographic results were used to separate patients into OSA cases and controls. Information regarding cardiovascular risks, neuroimaging, and echocardiographic data were collected. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: In 53 subjects, cardioembolic (CE) strokes were more common among OSA cases than controls (72% versus 33%, P = 0.01). The majority of CE strokes occurred in those with moderate to severe OSA. Atrial fibrillation (AF) was more frequent in OSA cases (59% versus 24%, P = 0.01). The association between OSA and CE stroke remained significant after controlling for AF (P = 0.03, odds ratio 4.5). CONCLUSIONS: There appears to be a strong association between obstructive sleep apnea (OSA) and cardioembolic (CE) stroke. In patients with OSA presenting with cryptogenic stroke, high clinical suspicion for CE is warranted. This may lead to consideration of diagnostic studies to identify CE risk factors such as paroxysmal atrial fibrillation (AF). CE strokes are more common in patients with OSA even after adjusting for AF. This finding may reflect a high rate of occult paroxysmal AF in this population; alternatively, OSA may lead to CE strokes through mechanisms independent of AF. PMID- 26237770 TI - Sleep Patterns in Adults with a Diagnosis of High-Functioning Autism Spectrum Disorder. AB - STUDY OBJECTIVES: To examine sleep patterns and sleep problems and their relationship with daytime functioning in adults with a diagnosis of an autism spectrum disorder and no comorbid intellectual disability (high-functioning autism spectrum disorder [HFASD]) compared to neurotypical (NT) adults. DESIGN: Cross-sectional. SETTING: Home-based study. PARTICIPANTS: 36 adults with HFASD and 36 age-, intelligence quotient- and sex-matched NT adults. MEASUREMENTS: Participants completed an online questionnaire battery including the Pittsburgh Sleep Quality Index (PSQI), a 14-d sleep wake diary and 14-d actigraphy data collection. RESULTS: Adults with HFASD had significantly more general sleep disturbances and higher scores on the PSQI, longer sleep onset latencies (actigraphy), and poorer sleep efficiency (diary) and these results remained significant after accounting for the False Discovery Rate. Those adults with HFASD who did not have a comorbid diagnosis of anxiety/depression had significantly shorter total sleep time (diary and actigraphy) compared to NT adults. Compared to NT adults, the HFASD group self-reported significantly poorer refreshment scores upon waking in the morning and higher scores on the daytime dysfunction due to sleepiness subscale of the PSQI. CONCLUSIONS: These findings support the notion that problems related to sleep, in particular insomnia, continue into adulthood in individuals with high-functioning autism spectrum disorder. PMID- 26237771 TI - Optic Nerve Dysfunction in Obstructive Sleep Apnea: An Electrophysiological Study. AB - STUDY OBJECTIVES: The aim of this study was to evaluate the integrity of the visual system in patients affected by obstructive sleep apnea (OSA) by means of electroretinogram (ERG) and visual evoked potential (VEP). METHODS: We performed electrophysiological study of the visual system in a population of severe OSA (apnea-hypopnea events/time in bed >= 30/h) patients without medical comorbidities compared to a group of healthy controls similar for age, sex, and body mass index. Patients and controls did not have visual impairment or systemic disorders with known influence on the visual system. ERG and VEP were elicited by a reversal pattern generated on a television monitor at low (55') and high (15') spatial frequencies stimulation. Daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS) in both patients and controls. RESULTS: In comparison with healthy controls (n = 27), patients with OSA (n = 27) showed a significant latency delay coupled with a significant amplitude reduction of P100 wave of VEP at all spatial frequencies in both eyes. No significant differences between groups were detected as concerning ERG components. No correlations were found between polygraphic parameters, ESS scores, or VEP and ERG components in OSA patients. CONCLUSIONS: This study documented that patients with OSA, without medical comorbidities, present VEP alteration as documented by lower amplitude and longer latency of the P100 component than healthy controls. These altered electrophysiological findings may be the expression of optic nerve dysfunction provoked by hypoxia, acidosis, hypercarbia and airway obstruction, frequently observed in patients with OSA. Hence, we hypothesize that OSA per se may impair optic nerve function. PMID- 26237772 TI - Sleep Deprivation and Recovery Sleep Prior to a Noxious Inflammatory Insult Influence Characteristics and Duration of Pain. AB - STUDY OBJECTIVES: Insufficient sleep and chronic pain are public health epidemics. Sleep loss worsens pain and predicts the development of chronic pain. Whether previous, acute sleep loss and recovery sleep determine pain levels and duration remains poorly understood. This study tested whether acute sleep deprivation and recovery sleep prior to formalin injection alter post-injection pain levels and duration. METHODS: Male Sprague-Dawley rats (n = 48) underwent sleep deprivation or ad libitum sleep for 9 hours. Thereafter, rats received a subcutaneous injection of formalin or saline into a hind paw. In the recovery sleep group, rats were allowed 24 h between sleep deprivation and the injection of formalin. Mechanical and thermal nociception were assessed using the von Frey test and Hargreaves' method. Nociceptive measures were performed at 1, 3, 7, 10, 14, 17 and 21 days post-injection. RESULTS: Formalin caused bilateral mechanical hypersensitivity (allodynia) that persisted for up to 21 days post-injection. Sleep deprivation significantly enhanced bilateral allodynia. There was a synergistic interaction when sleep deprivation preceded a formalin injection. Rats allowed a recovery sleep period prior to formalin injection developed allodynia only in the injected limb, with higher mechanical thresholds (less allodynia) and a shorter recovery period. There were no persistent changes in thermal nociception. CONCLUSION: The data suggest that acute sleep loss preceding an inflammatory insult enhances pain and can contribute to chronic pain. The results encourage studies in a model of surgical pain to test whether enhancing sleep reduces pain levels and duration. PMID- 26237773 TI - Increased Muscle Sympathetic Nerve Activity and Impaired Executive Performance Capacity in Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: To investigate muscle sympathetic nerve activity (MSNA) response and executive performance during mental stress in obstructive sleep apnea (OSA). METHODS: Individuals with no other comorbidities (age = 52 +/- 1 y, body mass index = 29 +/- 0.4, kg/m2) were divided into two groups: (1) control (n = 15) and (2) untreated OSA (n = 20) defined by polysomnography. Mini-Mental State of Examination (MMSE) and Inteligence quocient (IQ) were assessed. Heart rate (HR), blood pressure (BP), and MSNA (microneurography) were measured at baseline and during 3 min of the Stroop Color Word Test (SCWT). Sustained attention and inhibitory control were assessed by the number of correct answers and errors during SCWT. RESULTS: Control and OSA groups (apnea-hypopnea index, AHI = 8 +/- 1 and 47 +/- 1 events/h, respectively) were similar in age, MMSE, and IQ. Baseline HR and BP were similar and increased similarly during SCWT in control and OSA groups. In contrast, baseline MSNA was higher in OSA compared to controls. Moreover, MSNA significantly increased in the third minute of SCWT in OSA, but remained unchanged in controls (P < 0.05). The number of correct answers was lower and the number of errors was significantly higher during the second and third minutes of SCWT in the OSA group (P < 0.05). There was a significant correlation (P < 0.01) between the number of errors in the third minute of SCWT with AHI (r = 0.59), arousal index (r = 0.55), and minimum O2 saturation (r = 0.57). CONCLUSIONS: As compared to controls, MSNA is increased in patients with OSA at rest, and further significant MSNA increments and worse executive performance are seen during mental stress. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov, registration number: NCT002289625. PMID- 26237775 TI - Contribution of Inflammation, Oxidative Stress, and Antioxidants to the Relationship between Sleep Duration and Cardiometabolic Health. AB - OBJECTIVES: To explore the interrelationship and mediating effect of factors that are beneficial (i.e., antioxidants) and harmful (i.e., inflammation and oxidative stress) to the relationship between sleep and cardiometabolic health. DESIGN: Cross-sectional data from the 2005-2006 National Health and Nutrition Examination Survey. SETTING: Nationally representative population sample from the US. PARTICIPANTS: Age >= 20 y with sleep data; final analytical sample of n = 2,079. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Metabolic syndrome was classified according to the Joint Interim Statement, and sleep duration was categorized as very short, short, adequate, and long sleepers (<= 4, 5-6, 7-8, and >= 9 h per night, respectively). The indirect mediation effect was quantified as large (>= 0.25), moderate (>= 0.09), modest (>= 0.01), and weak (< 0.01). In general, inflammation was above the current clinical reference range across all sleep duration categories, whereas oxidative stress was elevated among short and very short sleepers. Select sleep duration- cardiometabolic health relationships were mediated by C-reactive protein (CRP), gamma-glutamyl transferase (GGT), carotenoids, uric acid, and vitamins C and D, and were moderated by sex. Specifically, moderate-to-large indirect mediation by GGT, carotenoids, uric acid, and vitamin D were found for sleep duration-waist circumference and systolic blood pressure relationships, whereas vitamin C was a moderate mediator of the sleep duration-diastolic blood pressure relationship. CONCLUSIONS: Several factors related to inflammation, oxidative stress, and antioxidant status were found to lie on the casual pathway of the sleep duration-cardiometabolic health relationship. Further longitudinal studies are needed to confirm our results. PMID- 26237774 TI - Predictors for Development of Excessive Daytime Sleepiness in Women: A Population Based 10-Year Follow-Up. AB - STUDY OBJECTIVES: To analyze predictors of excessive daytime sleepiness (EDS) and to analyze how changes within risk factors over time predict incident EDS in women. DESIGN: Population-based prospective study. SETTING: General population of the City of Uppsala, Sweden. PARTICIPANTS: From a random, general population sample of 7,051 women from the Sleep and HEalth in women ("SHE") cohort, 4,322 women without EDS at baseline were followed up after 10 y. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: At baseline and follow-up, women answered a questionnaire on sleeping habits, somatic disease, obesity, insomnia, anxiety and depression, lifestyle, and social factors. The risk of incident EDS was analyzed from changes over time in risk factors using logistic regression modeling. Of the women, EDS developed in 7.9%. Incident: insomnia (adjusted odds ratio = 5.01; 95% confidence interval 3.63-6.92), anxiety and/or depression (3.34; 2.22-5.02), somatic disease (1.73; 1.17-2.55), obesity (1.91; 1.14-2.57), snoring (1.91; 1.17 3.10) and smoking (4.31; 1.95-9.54) were all independent risk factors for the development of EDS. In addition, persistent: insomnia (4.44; 2.97-6.65) and anxiety and/or depression (4.91; 3.17-7.62) increased the risk of developing EDS. Apart from incident: snoring and obesity, similar results were obtained when only including women without somatic disease in the analyses. CONCLUSION: Insomnia, anxiety and/or depression, and smoking were the most important factors for predicting incident excessive daytime sleepiness (EDS) and, in addition, somatic disease, obesity, and snoring predicted EDS. It is important not only to treat these conditions but also to inform women of the importance of a healthy lifestyle in order to prevent and reduce EDS in women. PMID- 26237776 TI - Region-Specific Dissociation between Cortical Noradrenaline Levels and the Sleep/Wake Cycle. AB - STUDY OBJECTIVES: The activity of the noradrenergic system of the locus coeruleus (LC) is high in wake and low in sleep. LC promotes arousal and EEG activation, as well as attention, working memory, and cognitive flexibility. These functions rely on prefrontal cortex and are impaired by sleep deprivation, but the extent to which LC activity changes during wake remains unclear. Moreover, it is unknown whether noradrenergic neurons can sustain elevated firing during extended wake. Recent studies show that relative to LC neurons targeting primary motor cortex (M1), those projecting to medial prefrontal cortex (mPFC) have higher spontaneous firing rates and are more excitable. These results suggest that noradrenaline (NA) levels should be higher in mPFC than M1, and that during prolonged wake LC cells targeting mPFC may fatigue more, but direct evidence is lacking. METHODS: We performed in vivo microdialysis experiments in adult (9-10 weeks old) C57BL/6 mice implanted for chronic electroencephalographic recordings. Cortical NA levels were measured during spontaneous sleep and wake (n = 8 mice), and in the course of sleep deprivation (n = 6). RESULTS: We found that absolute NA levels are higher in mPFC than in M1. Moreover, in both areas they decline during sleep and increase during wake, but these changes are faster in M1 than mPFC. Finally, by the end of sleep deprivation NA levels decline only in mPFC. CONCLUSIONS: Locus coeruleus (LC) neurons targeting prefrontal cortex may fatigue more markedly, or earlier, than other LC cells, suggesting one of the mechanisms underlying the cognitive impairment and the increased sleep presure associated with sleep deprivation. COMMENTARY: A commentary on this article appears in this issue on page 11. PMID- 26237777 TI - A Daytime Nap Facilitates Generalization of Word Meanings in Young Toddlers. AB - STUDY OBJECTIVES: One of the key processes in language development is generalization--the selection and extension of relevant features and information to similar objects and concepts. Little is known about how sleep influences generalization, and studies on the topic are inconclusive. Our aim was to investigate how a nap affects generalization in 16-mo-olds. We hypothesized that a nap is necessary for successful generalization of word meanings. METHODS: Twenty-eight 16-mo-old, typically developing toddlers were randomly assigned to nap and wake groups. We trained toddlers with two novel object-word pairs and tested their initial ability to generalize. Toddlers took part in an intermodal preferential looking task, in which they were shown different colored versions of the original objects and heard one of the trained labels. If toddlers understand the label, they are expected to increase their looking time to the target. Looking behavior was measured with an automated eye tracker. Afterward, the nap group went to sleep, while the wake group stayed awake for approximately 2 h. We then repeated the test of their performance on the generalization task. RESULTS: A significant interaction of group and session was found in preferential looking. The performance of the nap group increased after the nap, whereas that of the wake group did not change. CONCLUSIONS: Our results suggest that napping improves generalization in toddlers. PMID- 26237778 TI - Cardiovascular Consequences in Children with Obstructive Sleep Apnea: Is It Possible to Predict Them? PMID- 26237779 TI - Prevalence of Sleep Disordered Breathing Symptoms and Risk Factors for Chronic Diseases: Are There Differences in Countries of High and Low Income? PMID- 26237781 TI - Aggravating factors associated with the severity of aortic regurgitation and clinical characteristics of patients with quadricuspid aortic valve. AB - BACKGROUND AND AIM OF THE STUDY: Quadricuspid aortic valve (QAV) is a rare congenital anomaly. Aortic regurgitation (AR) has been suggested to be the major functional abnormality of QAV. The study aim was to define the clinical characteristics of patients with QAV through echocardiography, thereby identifying factors related to the severity of AR. METHODS: Patients diagnosed with QAV by echocardiography were enrolled from electronic medical records obtained between November 1994 and May 2012. RESULTS: Twenty-six patients diagnosed with QAV were identified. AR was present in 20 of these patients (77%), among which 12 (46%) exhibited significant AR. Aortic stenosis was rare (n = 1; 4%). Patient age and severity of AR were weakly correlated. The most frequent valve morphology type was three equally sized cusps and one smaller cusp (n = 12; 46%), followed by two larger, equally sized cusps and two smaller, equally sized cusps (n = 6; 23%). The latter morphology type was accompanied by a high prevalence of significant AR (5/6; 83%). The initial clinical symptoms of the patients included dyspnea and chest pain (n = 14; 54%), other congenital abnormalities (n = 4; 15%), and arrhythmias (n = 4; 15%). Among the patients with significant AR, 10 were symptomatic. CONCLUSION: Approximately half of the patients with QAV had significant AR at the time of initial diagnosis by echocardiography. The severity of AR appeared to be correlated with patient age and valve morphology. These factors should be considered during echocardiographic assessment and follow up treatment for QAV. PMID- 26237783 TI - Harvard researchers headline conference on gene editing. PMID- 26237782 TI - Healthy lifestyle protects women against heart disease. PMID- 26237784 TI - Pay attention to signs of depression. PMID- 26237785 TI - The dollars and sense of long-term care. Why you should plan now for care you may need later. PMID- 26237786 TI - Ask the doctor. The other night I work up at about 2 a.m., and my heart was pumping hard and my lower jaw ached. It lasted about an hour, even though I took an aspirin. Then I fell asleep. In the morning everything was fine. Was that a heart attack? PMID- 26237787 TI - Ask the doctor. Why do people over 60 lose height? I've lost a few inches over the years. Can this be prevented? PMID- 26237788 TI - 8 pill-free ways to lower your blood pressure. Try losing weight, changing your diet, and exercising. PMID- 26237789 TI - Don't just sit there. Easy ways to increase activity and cut down on sedentary time. PMID- 26237790 TI - New concerns about diet sodas. They're linked to calorie absorption, high blood pressure, and heart trouble. PMID- 26237791 TI - Should you take probiotics? The "good bacteria" may healp healthy people but aren't formally recommended. PMID- 26237792 TI - Review finds no sign of memory loss from statins. PMID- 26237793 TI - One in 10 men may be taking aspirin unnecessarily. PMID- 26237794 TI - Acetaminophen: minimal relief for knee arthritis pain. PMID- 26237795 TI - Atrial fibrillation: living with a common heart condition. Preventing stroke is the top priority if your heart is beating irregularly. A variety of options can control symptoms. PMID- 26237796 TI - Doing more with the same resources. PMID- 26237797 TI - [COMPUTER-ASSISTED SURGERY FOR RENAL TUMORS]. AB - The main objective of this article is to show the role of modern computer technology in performing virtual and real surgical procedures for renal tumors. At the present time, 3D based modeling makes it possible to preoperatively identify individual strategy and tactics of treatment of a patient. PMID- 26237798 TI - [EFFECTIVENESS OF EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY IN PATIENTS WITH UROLITHIASIS OF A SOLITARY KIDNEY]. AB - The article presents results of extracorporeal shock wave lithotripsy (ESWL) in 62 patients with urolithiasis of a solitary kidney. In 50 (80.6%) patients calculi were located in the kidney and in 12 (19.4%) patients in the ureter. Effectiveness of ESWL at 3 month follow-up was 85.5%, which is somewhat lower than in patients with two healthy kidneys due to the choice of sparing low-energy modes of lithotripsy. The effectiveness of ESWL depended on the size of the original calculi (p<0.0001), and the baseline urodynamics of the upper urinary tract (p<0.0001). The rates of complications (32.3%) and auxiliary procedures (16.1%) were relatively low, due to the usage of pre-drainage of the kidney before a session of ESWL in patients with large and multiple calculi. There was no correlation between the occurrence of complications during treatment and the clinical form of a solitary kidney (p>0.05). In patients with stones larger than 1 cm and a moderate baseline abnormalities of the upper urinary tract urodynamics ESWL was less effective (p<0.0001), they had increased time of lithotripsy (p=0.013), more sessions (p<0.0001), complications (19.4%, p=0.043) and auxiliary manipulation (9.7%). Nevertheless, the duration of stay in hospital in the postoperative period did not correlate with the size of calculus (p=0.504). Extracorporeal shock wave lithotripsy is a highly effective and safe treatment of stones of a solitary kidney. Rational choice of indications and contraindications for the use of ESWL in a specific clinical situation is of great importance. PMID- 26237799 TI - [INCIDENCE OF NOSOCOMIAL UROPATHOGENS AND DYNAMICS OF THEIR SENSITIVITY]. AB - In order to determine the basic spectrum of urinary tract infections and their sensitivity to modern antimicrobials, the 5-year (2009-2013) study of 2621 isolates ofuropathogens from inpatients of two centers of Novosibirsk and Barnaul was carried out. Instability of proportion of the isolated microorganisms both in time and in two compared neighboring regions was found. The role of E. coli was insignificant: in Barnaul the maximum share E. coli among all uropathogens was 56.1% in 2009 (with a five-fold drop in the next year to 10.5%), Novosibirsk share of E. coli increased from 28,1% in 2009 to 49.4% in 2013, with an unaccountable fall to 33.5% in 2011. In evaluating the resistance of E. coli, many groups have shown a steady growth in antibiotic resistance. Resistance of microflora to 2nd generation cephalosporins increased by 3 times, to ciprofloxacin - by 2 times and to amoxicillin - by 7 times. However, there were virtually no strains resistant to carbapenems. Zero resistance to fosfomycin was found - all strains were susceptible to this antibiotic within 5 years. Range of UTI pathogen species in two adjacent regions was subject to significant fluctuations, no patterns were identified. In contrast, the level of microflora resistance increased. Within 5 years, it increased to basic antibiotics by 7 times, while maintaining a low resistance to nitrofurantoin, gentamicin and imipenem, and zero resistance to fosfomycin. The results of this study are consistent with international data on the partial loss of E. coli role as the leading uropathogen. Gram-positive cocci are becoming increasingly important, which is worth considering when choosing a drug for empiric therapy. Optimal antibiotics and uroseptics for treatment of patients with acute uncomplicated cystitis remain fosfomycin and nitrofurantoin, as was shown earlier. PMID- 26237800 TI - [SURGICAL TREATMENT OF STRICTURES OR OBLITERATIONS OF URETHRA]. AB - The article introduces the clinical and statistical analysis of 113 patients treated for urethral strictures (US) in the urological clinic of the Rostov State Medical University in 2011. 58% of patients experienced a recurrent course of the disease. Radical curative surgery was possible in 93 (82.3%) patients. In other cases, non-invasive strategy was indicated (13.3%) or surgery for urethral stricture was impossible due to comorbidities (4.4%). Resection with urethral end to-end anastomosis, which is the most effective approach to the treatment of patients with US, was possible in only half of the patients (51.8%). In the rest of the patients, one-, two- or more stage urethroplasty substitution was carried out. By the end of 2013, treatment of 84 (90.3%) patients was completed with a total of 110 operations. 9 (9.7%) patients were scheduled for operation in 2014. PMID- 26237801 TI - [THE ROLE OF MAGNETIC RESONANCE IMAGING IN THE DIAGNOSIS OF STRICTURE DISEASE OF THE MALE URETHRA]. AB - The article presents a comprehensive study of 121 patients with stricture disease of the male urethra. Diagnosis and staging of the disease were made on the basis of medical imaging, namely retrograde urethrography, voiding cystourethrography and magnetic resonance imaging with complex pulse sequences developed by the authors. The results were compared with surgical findings and morphological study of surgical specimens. Detailed semiotics of magnetic resonance imaging of stricture disease, differences in the visualization of traumatic and inflammatory strictures of various locations, as well as features of primary and recurrent lesions are described. Detailed analysis of the data shows significant advantages of MRI in identifying stricture disease of the male urethra over traditional methods of endoscopic visualization. It makes possible to increase the diagnostic accuracy for detection of the disease and better surgical planning strategy. PMID- 26237802 TI - [INJECTION OF BOTULINUM TOXIN TYPE A IN THE BLADDER DETRUSOR AND SUBMUCOSA IN PATIENTS WITH OVERACTIVE BLADDER WITHOUT DETRUSOR OVERACTIVITY]. AB - The objective of the study was to compare the efficacy and safety of injections of botulinum toxin type A in the submucosal layer of the bladder and in detrusor in patients who were refractory to anticholinergic therapy of overactive bladder without detrusor overactivity. 100 U botulinum toxin type A was diluted in 10 ml of 0.9% saline and injected with 0.5 ml (5 units) of this solution in 20 points of the bladder (the back and side walls except Letto triangle). In twenty-two patients (the first group) botulinum toxin was injected into the submucosal layer of the bladder, while in 34 patients (second group) - into the detrusor. In the first group after 1 and 3 months 3 (14%) patients and after 6 months 2 (9%) patients had positive treatment outcomes (improvement of symptoms in more than 50%). In 22 (65%) of the 34 patients of the second group positive results were observed at 1 and 3 months and in 17 (50%) - at 6 months. After 9 months, all patients had a relapse of urgent and frequent urination. Difficulties in emptying the bladder were observed in three (9%) of the second group patients who had to resort to periodic self-catheterization for 2-20 weeks. The obtained results allow us to state that the injections of 100 U of botulinum toxin type A in the submucosal layer of the bladder are ineffective in patients with overactive bladder without detrusor overactivity, whereas injections in the detrusor lead to a statistically significant improvement in symptoms of urgent and frequent urination for 6 months. PMID- 26237803 TI - [THE QUANTIFICATION OF SULPHATED GLYCOSAMINOGLYCANS IN RAT URINE IN EXPERIMENTAL HEMORRHAGIC CYSTITIS]. AB - The paper presents the study of the excretion of sulfated glycosaminoglycans (GAG) in the urine of rats in experimental hemorrhagic cystitis induced by cyclophosphamide and treated with glycosaminoglycan replacement therapy. Rats were given intraperitoneal injections of cyclophosphamide at a dose of 100 mg per 1 kg body weight and subsequently treated with intragastric administration of the combined preparation of glycosaminoglycans containing glucosamine hydrochloride and chondroitin sulfate at a dose of 10 and 100 mg per 1 kg of body weight. Within 24 or 72 hours after cystitis induction there was a statistically significant increase in urinary GAG excretion. The study also found a decrease (from 1.34 to 1.22 mg/dL) in urinary GAG within 0 to 72 hours following induction of acute cystitis without glycosaminoglycan therapy. In the subchronic model of inflammation in the bladder, upon repeated administration of low doses of cyclophosphamide (50 mg/kg), decrease in urinary GAG within 0 to 72 hours (1,32+/ 0,13 mg/dL) as well as increased excretion after 96 hours at a concentration of 2,29+/-0,13 mg/L after initiation cystitis were found. PMID- 26237804 TI - [EFFECTIVENESS OF COMBINED TREATMENT OF HPV INFECTION]. AB - This study evaluates the effectiveness of immunomodulating drug isoprinosine in a comprehensive treatment of genital warts in men. Most of the patients were aged 20-30 years. The combination therapy was found to have long term effectiveness. In the group of patients undergoing only destructive methods of treatment relapse after 8 month follow-up was diagnosed in 32% and in patients of the combination therapy group (destruction plus isoprinosine) - in 7% of patients. The pharmacological action of the drug (immunostimulating, antiviral) and the effectiveness of its combination with destructive therapies justify the use of inosine pranobex (isoprinosine) both in the complex therapy of genital warts and for the prevention of the disease recurrence. PMID- 26237805 TI - [APPLICATION OF DIFERELIN AND ITS PERSPECTIVES]. AB - The article presents a brief overview of luteinizing hormone-releasing hormone analogs in the treatment of prostate cancer. The authors report their experience with this drug class by an example of Diferelin. The experience with abiraterone in treatment of patients with hormonal resistance is described. PMID- 26237806 TI - [USE OF PHYTO- AND PELOIDOTHERAPY IN TREATMENT AND PREVENTION OF CHRONIC CYSTITIS IN WOMEN]. AB - The article presents the findings of herbal- and peloidotherapy as a combination treatment inpatientswith chronic cystitis. The effectiveness of treatment was evaluated by the dynamics of clinical findings, results of laboratory and instrumental studies (increase functional bladder capacity, improvement / normalization of urinalysis, elimination of bacteriuria, improvement of microcirculation). The results showed high efficiency of phytoplankton and pelotherapy in normalization of urodynamics and microcirculation of the bladder mucosa. Upgraded combination scheme for the treatment of chronic cystitis significantly improved patient outcomes. PMID- 26237807 TI - [FEATURES OF PERCUTANEOUS NEPHROLITHOTRIPSY IN PATIENTS WITH UROLITHIASIS OF SOLITARY KIDNEY]. AB - The article describes the results of percutaneous nephrolithotomy (PCNL) in 49 urolithiasis patients with a solitary kidney. In 44 (89.8%) patients the calculi were located in the kidney, in 5 (10.2%) patients - in the upper third of the ureter. The calculi were single (18; 36.7%), multiple (14; 28.6%) or stag-horn (17; 34.7%). Efficiency of PCNL estimated immediately after surgery and at the end of the third month of observation was 75.5 and 93.9%, respectively. Stone size (p=0.594), the baseline state of urodynamics of the upper urinary tract (p=0.205) did not affect the renal clearance at PCNL. Enlargement of initial calculus size positively correlated with the number of required treatment sessions (p=0.013), duration of surgery (p<0.0001), and the length of postoperative hospital stay (p<0.0001). Complications were common (44.9%), but the auxiliary manipulations were performed infrequently (26.5%). No associations were found between the size of calculus, the number of complications and secondary manipulations (p=0.361). No correlations were found between the clinical form of a solitary kidneywith urolithiasis and the occurrence of complications during the treatment course (p=0.121), as well as between the presence of complications and the cause of the "loss" of the contralateral kidney (p> 0.05). Thus, percutaneous nephrolithotripsy is a highly effective method modality of treatment of solitary kidney urolithiasis. Appropriate selection of indications and contraindications for PCNL, preoperative preparation, surgical technique, postoperative patient management are of great importance. PMID- 26237809 TI - [SUPERSELECTIVE PROSTATIC ARTERY EMBOLIZATION AS A PREPARATORY STEP BEFORE TURP IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA IN PATIENTS WITH LARGE PROSTATES]. AB - The study included 59 patients with benign prostatic hyperplasia (BPH) and high risk of anesthesia who underwent superselective embolization of prostatic arteries. The examination included a survey on the International Prostate Symptom Score (IPSS), assessment of quality of life (QoL), estimation of prostate and node size with transrectal ultrasound, determination of prostate-specific antigen level; in doubtful cases a needle prostate biopsy was performed. To analyze the quality of urination uroflowmetry was conducted. The effectiveness of the treatment was evaluated after 6, 12 and 24 months follow-up. By the 6th month of observation I-PSS score significantly decreased, while the maximum urine flow rate increased. This trend kept up during the subsequent six-month follow-up. The results of 24 months follow-up after embolization showed stable effect. Prostate and node volumes and reduced on average by 53% and 47%, respectively; the maximal reduction of prostate volume was 82%. 17 (28.8%) patients with prostate size reduction to less than 80 cm3 underwent transurethral resection of the prostate. In conclusion, prostatic artery embolization may be considered as a method of preoperative treatment of BPH patients with large prostates and multiple comorbidities, providing them with the possibility of endoscopic treatment. Further study will allow working out the methodology of embolization, to accurately determine the indications and contraindications for this treatment modality and to introduce it to clinical practice. PMID- 26237808 TI - [TRANSURETHRAL CONTACT URETERAL LITHOTRIPSY IN A GASEOUS (CO2) MEDIUM]. AB - The paper describes for the first time the method of contact ureteral lithotripsy in gaseous (CO2) medium. It presents the results of a comparative study of urolithiasis patients treated with this treatment modality (study group, n=30) and with traditional contact ureteral lithotripsy in liquid medium (control group, n=30). The incidence of retrograde migration of calculus in the kidney in the study group was 0%, while it was 16.6% in the control group. Acute or exacerbation of chronic pyelonephritis was diagnosed in only 3 (10%) patients in the control group. The suggested method of contact ureteral lithotripsy is safe and provides several advantages over traditional contact ureteral lithotripsy in a fluid medium, such as: physiologic validity, absence of calculus hypermobility (increased mobility), improved visualization during surgery and high cost effectiveness. PMID- 26237810 TI - [INTRAOPERATIVE CONTROL OF THE EFFECTIVENESS OF TRANSURETHRAL RESECTION OF NON MUSCLE-INVASIVE BLADDER CANCER]. AB - This paper presents results of 82 patients treated for non-muscle-invasive bladder cancer. 28 patients underwent transurethral resection of bladder cancer (TURB) as a monotherapy, 28 - TURB with photodynamic control, 26 - TURB with dynamic transurethral sonography. Analysis of the 5-year recurrence rate, pattern and timing of recurrence depending on the modality of intraoperative control of TURB effectiveness was performed. The overall recurrence rate in the first group was 60.71%, of them local recurrence in the resection area occurred in 21.43% of cases, outside of the region of resection - in 28.57% of cases, and progression - in 10.71%. In the second group the overall recurrence rate was 25%, recurrence in the resection area was diagnosed in 7.14% of patients, outside of the region of resection - in 14.29% and progression - in 3.57%. In the third group of patients over a 5-year period local recurrence in the resection area was identified in 3.84% of cases, outside of the region of resection - in 23.07% of cases and no cases of disease progression were observed. The results showed that TURB without additional intraoperative imaging of surgery effectiveness was not a radical treatment for non-muscle-invasive bladder cancer. Photodynamic control increases the surgery effectiveness by preventing recurrences outside the resection region. It allows identifying microscopic modified urothelium clones, but does not affect the rate of disease progression. Intraoperative transurethral ultrasound guidance increases TURB effectiveness by preventing both relapse in the area of resection and disease progression. PMID- 26237811 TI - [CORRECTION OF BLOOD CIRCULATION IN THE PROSTATE IN PATIENTS WITH CHRONIC PROSTATITIS ASSOCIATED WITH UROGENITAL INFECTIONS]. AB - The aim of the study was to assess the effect of a combined preparation of Vitaprost on blood supply and microcirculation in the prostate gland in 35 patients with chronic infectious urethral prostatitis. The effectiveness of treatment was estimated by a combination of clinical, bacteriological and instrumental diagnostic methods. Transrectal ultrasonography with color Doppler and laser Doppler flowmetry were used to estimate all components of blood circulation in the prostate. Examination results obtained before and after treatment showed better clinical outcomes and improved parameters of blood flow and microcirculation in the prostate in patients receiving Vitapost. These results indicate that combination therapy including Vitaprost is effective in correcting blood flow and microcirculatory disorders of the prostate and can be utilized in the treatment of chronic infectious urethral prostatitis. PMID- 26237812 TI - [INCIDENCE OF ACUTE URINARY RETENTION IN PATIENTS WITH PROSTATIC ADENOMA AND 8 YEAR LONG TAMSULOSIN THERAPY]. AB - This report introduces results of an 8-year study estimating the risk of acute urinary retention in patients with stage I prostatic adenoma. Patients were randomly assigned into two groups. The first group consisted of 331 men was regularly taking Omnic (tamsulosin) 0.4 mg 1 time daily for 8 years as a means of medical therapy. The second group consisted of 334 patients treated with herbal preparations (Gentos, Tadenan or Speman). In the case of acute urinary retention patients were taken to the urological department to release urine from the urinary bladder by catheterization or by the surgical procedure. The incidence of acute urinary retention in group 1 ranged from 0.3 to 1.2% per year and, for a total of 8 years of follow-up was 6.45%. In the second group, it ranged from 1.8 to 7.3% per year, making a total of 36.2%. Therefore, the risk of acute urinary retention in patients receiving Omnic (tamsulosin) was reduced by 5.6 times in comparison with the group of patients treated with herbal medications. Thus, the need for surgery decreased from 27.8 to 6.3%. According to the results of an 8 year long tamsulosin was found as a safe and highly effective means to reduce the risk of acute urinary retention. PMID- 26237813 TI - [STRUCTURAL ABNORMALITIES OF THE OBSTRUCTED URETEROVESICAL JUNCTION]. AB - The article presents a morphological study of UVJ removed during surgery in 110 children with stage III hydronephrosis. Morphological changes in resected UVJs indicate a predominance of sclerotic transformation accompanied by different types of dysplasia. PMID- 26237814 TI - [VESICOURETERAL REFLUX INTO SMALL KIDNEY DIAGNOSTIC AND THERAPEUTIC PARADIGM]. AB - The causes of renal size reductionin children by 20 percent or more from the age norm include abnormalities of urodynamics of upper (UUT) and lower (LUT) urinary tract, combined with vesicoureteral reflux (VUR) and infra-vesical obstruction (IVO). Several issues regarding diagnosis and choice of treatment in children with small kidneys depending on the severity of functional abnormalities and the presence of comorbidities still remain controversial. 101 children with small kidneys accounting for 3.1% of the entire number of urologic patients admitted to the clinic were followed for 25 years. 78 (77.2%) patients were simultaneously diagnosed as having ipsilateral vesicoureteral reflux (VUR) (2.4% of the total number of hospitalized children). Moreover, contralateral VUR was found in 63% of patients. In 5.1% of children, anomalies of the contralateral kidney were identified: lumbar dystopia (3.8%), duplication of the renal pelvis and ureter (1.3%). Combination with IVO was found in 25.5% of cases. 75 (96%) children with vesicoureteral reflux into the small kidney were operated on. Reconstructive plastic surgery was made in 72 (92%) those patients. Indications for conservative management were identified in patients with intermittent VUR of I-II degree into small kidney or both kidneys. In case of detection of IVO, initial surgery was carried out to eliminate the obstruction. Conservative therapy was aimed at getting rid of the inflammatory process, restoring the function of kidney and bladder, and at the treatment of concomitant vulvovaginitis. In the absence of positive results of 6-8 months of conservative treatment or in case of the negative clinical course, the operation was considered justified. Indications for antireflux surgery were the failure of conservative therapy for intermittent VUR into small kidney or both kidneys, the presence of VUR of III-V degree into one or both kidneys. In cases of bilateral VUR antireflux surgery was performed simultaneously. Indications for nephrureterectomy were complete loss of kidney function, a combination of several unfavorable prognostic signs, namely a significant reduction of the renalsize (renal area less than 30% of the age norm); severely impaired kidney function (reduced contribution to the total accumulation of up to 10% or less); the presence of ultrasonic and radiographic evidence of secondary shrinkage; pronounced abnormalities of UUT urodynamics; failure of treatment of frequent and severe pyelonephritis exacerbations. It is shown that VUR is often combined with a decreased renal size, creating difficulties in selecting treatment tactics and determining the prognosis of the disease further. The proper strategy is to prevent disease progression and reduce the need for organ-removal surgery in children. PMID- 26237815 TI - [AN EVIDENCE BASED UPDATE ON THE INVESTIGATION AND MANAGEMENT OF MALE LOWER URINARY TRACT SYMPTOMS]. AB - In this review, we aim to summarise the evidence regarding the diagnosis and management of male Lower urinary tract symptoms (LUTS). It is inevitable that with an ageing population the prevalence of male LUTS is likely to increase. Thus symptom prevention and preservation of quality oflife (QoL) feature as high priorities for clinicians and patients alike. There are now a number of different pharmacological options available to men with LUTS which lead to significant improvements in symptom scores, flow rate and QoL. Meta-analyses have shown the benefits for 5-alpha reductase inhibitors, antimuscarinics, alpha blockers and more recently the phosphodiesterase-5 inhibitors. High level evidence also exists for combinations of all of the above agents with alpha blockers except phosphodiesterase-5 inhibitors and so men with concomitant storage symptoms, prostate volume >30ml/ PSA>1.4 or erectile dysfunction may be considered for combination treatment. The last few years have seen an increase in the data regarding less invasive methods of cystometry. Although these do not provide the same information as cystometry, they may have a role in answering specific questions and counselling men with BPH/LUTS. The key to incorporating these newer techniques in the assessment of men will lie with standardisation and use for specific indications. In an era of personalised medicine, appropriate patient selection is likely to provide the key to the most effective clinical investigative and management strategy. PMID- 26237816 TI - [COLLAGEN BIOMATRIX IN RECONSTRUCTIVE UROLOGY]. AB - The paper presents leading problems faced by surgeons performing reconstructive plastic replacement of the bladder, types of biomatrix used in urology, their application and the perspectives for their further use. PMID- 26237817 TI - [VARICOCELECTOMY IN ADOLESCENTS: WHO AND WHEN TO OPERATE]. AB - In studying the problem of varicocele in children and adolescents, there was a consistency of objectives chosen by researchers both today and half a century ago. Nearly all researchers start with phrases about the absence of reliable evidence of a direct negative impact of varicocele on male reproductive function, but yet they express confidence in the need for prophylactic varicocelectomy in children and adolescents in some cases. This demonstrates the necessity of prognostic indicators that could be used for selection of adolescents requiring surgery in circumstances of the limited feasibility of investigating the reproductive function. PMID- 26237818 TI - [SEXUAL FUNCTION OF PATIENTS UNDERGOING RADICAL PROSTATECTOMY: A MODERN VIEW OF THE PROBLEM]. AB - Radical prostatectomy (RP) is deemed to be the most effective standard treatment option for men with prostate cancer (PC). However, RP is accompanied by a number of complications leading to a substantial decline in the quality of sexual life of operated patients. Major complications of RP include: decreased sex drive, deterioration of erectile function, deformation of the penis, abnormal ejaculation and orgasmic dysfunction. Based on the current literature, the article deals with the issue of prevention and rehabilitation of patients after radical prostatectomy, describes the methods of conservative and surgical correction of complications, associated with surgical treatment of PC. PMID- 26237819 TI - [USE OF SILDENAFIL CITRATE FOR TREATMENT OF ERECTILE DYSFUNCTION OF VARIOUS ETIOLOGY]. AB - Erectile dysfunction is closely linked to the general state of both physical and psychological wellness. Among the major risk factors are heart disease, arterial hypertension, diabetes, hyperlipidemia, as well as sedentary lifestyle, smoking and alcohol abuse. Also, the disease is more frequently found in men undergoing radiation therapy or surgery for prostate cancer. Psychological correlates include anxiety, depression and irritability. Despite a higher prevalence among older men, erectile dysfunction is not considered an inevitable part of aging. Due to polyetiology of the disease, sildenafil is regarded as the gold standard of treatment, and new high quality generic drugs are marketed. The article covers the use of sildenafil in patients with diseases of the cardiovascular system, diabetes, hypogonadism. Effectiveness of sildenafil in patients on chronic hemodialysis as well as in patients undergoing radical prostatectomy is discussed. The issue of addiction to sildenafil is outlined. PMID- 26237820 TI - [RADICAL LAPAROSCOPIC NEPHRECTOMY WITH INFERIOR VENA CAVA THROMBECTOMY]. AB - Laparoscopic radical nephrectomy has proven itself as the "gold standard" treatment of renal cell carcinoma. Inferior vena cava (IVC) tumor thrombus is a complicating factor that occurs in 5% to 10% of patients with renal cell carcinoma. In world literature, there are only anecdotal reports on using laparoscopic approach for IVC thrombectomy in patients with renal cell carcinoma. Herein we report our experience of laparoscopic radical nephrectomy and thrombectomy of the level II tumor thrombus in the IVC. Two patients (79-year-old female and 48-year-old male) underwent radical nephrectomy with thrombectomy from IVC for renal cell carcinoma T3bNxM0 complicated by the formation of a tumor thrombus in the IVC. To do this, IVC was isolated, the right gonadal and lumbar veins were ligated and transected. The IVC and the left renal vein blood flow were controlled with a plastic clip and Satinski clamp. After thrombectomy and resection of the IVC, the wall the defect was sutured with continuous Prolene suture. Laparoscopic radical nephrectomy with thrombectomy without conversion to open surgery was successfully carried out in both patients. During 6-18 months follow-up no local recurrence or distant metastasis were observed. Laparoscopic radical nephrectomy with thrombectomy for renal cell carcinoma complicated with tumor thrombus level II is a safe and reproducible method, which can be applied to a specific population of patients. PMID- 26237821 TI - [BILATERAL NEPHROURETERECTOMY WITH CYSTOPROSTATECTOMY AD BLOC AND LYMPHADENECTOMY IN A PATIENT WITH END-STAGE RENAL FAILURE AND CANCER OF THE URINARY BLADDER T2BN0M0]. AB - The article introduces a clinical example of a patient who was first diagnosed with bladder cancer, which contributed to the development of end-stage renal failure. Initially, given the significant upper urinary tract retention and post renal acute renal failure, the patient underwent bilateral percutaneous nephrostomy. Taking into account periodic gross hematuria, cystoscopy and transurethral electrocoagulation and biopsy of bladder tumor were performed and bladder cancer was identified. Despite adequate functioning of nephrostome drainage and daily urine output up to 3000 ml, kidney failure was not resolved. After creation of an arteriovenous fistula, a hemodialysis program was launched. The patient continued to experience persistent gross hematuria, he had a hectic fever, which was estimated as a symptom of acute pyelonephritis. The patient was scheduled for bilateral nephroureterectomy, cystoprostatectomy as the only option to remove the source of bleeding and infection. The operation was carried out without complications. The patient is currently maintained on chronic hemodialysis and followed by an oncologist at the place of residence; there are no data of bladder PMID- 26237822 TI - [FLEXIBLE NEPHSCOPY AND NEPHROLITOEXTRACTION IN A GASEOUS MEDIUM (CO2) IN A PATIENT WITH RESIDUAL CALCULI OF THE RIGHT KIDNEY]. AB - Flexible endoscopy is an integral part of modern endourology. However, the use of flexible endoscopes in a liquid medium predispose to some difficulties and disadvantages of this technique. This article presents a clinical observation of use of a flexible nephroscope for extraction of residual calculi in a gaseous medium (CO2) in a patient with residual calculi of the right kidney. PMID- 26237823 TI - [Farkhad Ataullaevich Akilov (on the 60th anniversary)]. PMID- 26237824 TI - [Shalekenov Bulat Uahitovich (on the 60th anniversary)]. PMID- 26237825 TI - [In memory of Oleg Leonidovich Tiktinskij (1928-2015)]. PMID- 26237826 TI - Modified dachengqi tang improves decreased gastrointestinal motility in postoperative esophageal cancer patients. AB - OBJECTIVE: To investigate the clinical effects of modified dachengqi tang (DCQT) on promoting gastrointestinal motility in post-operative esophageal cancer patients. METHODS: Sixty postoperative esophageal cancer patients were enrolled and randomly assigned to the modified treatment group or the control group (30 patients in each group). Patients in the treatment group were given DCQT made from decocted herbs and administered via nasojejunal tube at a dosage of 150 mL. Gastrointestinal motility was assessed by recording time for recovery of bowel sounds, flatus, defecation, and the total amount of gastric drainage during the first three postoperative days. Plasma motilin (MTL) and vasoactive intestinal peptide (VIP) were measured one hour before and three days after surgery. RESULTS: Compared with the control group, the times to first bowel sound, flatus, and defecation were significantly shorter and there was less gastric drainage in the treatment group (P < 0.01, P < 0.01, P < 0.01, and P < 0.05, respectively). In the treatment group, postoperative plasma MTL was significantly higher (P < 0.01) and VIP was significantly lower than those in the control group (P < 0.05). There was no difference found in either MTL or VIP from before to after operation in the treatment group (P > 0.05). MTL was significantly lower and VIP was higher postoperatively in the control group, compared to before surgery (P < 0.01). CONCLUSION: Modified DCQT effectively improved decreased gastrointestinal motility in postoperative esophageal cancer patients by increasing MTL and reducing VIP. PMID- 26237827 TI - Alzheimer's disease treated with combined therapy based on nourishing marrow and reinforcing Qi. AB - OBJECTIVE: To study the efficacy and safety of combined Traditional Chinese Medicine (TCM) therapy based on nourishing marrow to improve intellect and reinforcing Qi to activate bloodon mild to moderate Alzheimer's disease (AD). METHODS: Sixty-six patients with AD, whose Mini-Mental State Examination (MMSE) score were from 10-24, were randomized equally into an intervention group and a control group. The control group was given Aricept (5 mg, once daily). The intervention group was further divided into Yang-Qi deficiency (n = 18) and of Yin-Qi deficiency (n = 15) subgroups. Patients in the Yang-Qi deficiency group were intravenously administered shenfu injection, 60 mL, and deproteinized calf blood injection (DCBI), 1.2 g, once daily. The Yin-Qi deficiency group was given shenmai injection, 60 mL, and DCBI, 1.2 g, once daily. Each course lasted 21 days. RESULTS: Compared with the control group and with pre-treatment in the same group, MMSE, clinical dementia rating, and activities of daily living scale scores in the intervention group were significantly improved (all P < 0.05). These metrics mildly improved in the control group compared with before treatment (P > 0.05). No adverse effects were observed in any group during treatment. CONCLUSION: We found that combined TCM therapy is effective and safe for managing mild to moderate AD. PMID- 26237828 TI - Effects on type 2 diabetes complicated with pulmonary tuberculosis: regiment of insulin, isoniazid, rifampicin, pyrazinamide and ethambutol versus the regiment plus Qi-boosting and Yin-nourishing decoction of Traditional Chinese Medicine. AB - OBJECTIVE: To observe the clinical effect on type 2 diabetes mellitus (T2DM) complicated with pulmonary tuberculosis (TB) of insulin, isoniazid, rifampicin, pyrazinamide and ethambutol (conventional medication) administered together with Qi-boosting and Yin-nourishing decoction derived from Traditional Chinese Medicine (TCM). METHODS: A total of 60 patients with T2DM complicated with pulmonary TB were randomly and equally divided into positive control group and treatment group. The control group was treated with Western conventional regiment (WCR): insulin, isoniazid, rifampicin, pyrazinamide, and ethambutol, whereas the treatment group was given both WCR and Qi-boosting and Yin-nourishing decoction prepared from TCM. RESULTS: After the treatment, 20 (66.7%) and 11 (36.7%) cases showed sputum bacteria negative conversion in the WCR plus TCM group and WCM group respectively (P < 0.05). A total of 25 (83.3%) and 18 (60%) cases showed improvement in lung lesion in the WCR plus TCM group and WCM group respectively (P < 0.05). Compared with WCR group, fasting plasma glucose and 2-hour postprandial blood glucose levels in the WCR plus TCM group significantly decreased (P < 0.05 and P < 0.01, respectively). CONCLUSION: Qi-boosting and Yin nourishing decoction combined with the Western medication showed better curative effect in treating T2DM complicated with pulmonary TB compared with the group using the conventional Western Medicine alone. PMID- 26237829 TI - Influences of AMY1 gene copy number and protein expression on salivary alpha amylase activity before and after citric acid stimulation in splenic asthenia children. AB - OBJECTIVE: To compare the correlations between salivary alpha-amylase (sAA) activity and amylase, alpha 1 (salivary) gene (AMYl) copy number or its gene expression between splenic asthenia and healthy children, and investigate the reasons of attenuated sAA activity ratio before and after citric acid stimulation in splenic asthenia children. METHODS: Saliva samples from 20 splenic asthenia children and 29 healthy children were collected before and after citric acid stimulation. AMYl copy number, sAA activity, and total sAA and glycosylated sAA contents were determined, and their correlations were analyzed. RESULTS: Although splenic asthenia and healthy children had no differences in AMY1 copy number, splenic asthenia children had positive correlations between AMY1 copy number and sAA activity before or after citric acid stimulation. Splenic asthenia children had a higher sAA glycosylated proportion ratio and glycosylated sAA content ratio, while their total sAA content ratio and sAA activity ratio were lower compared with healthy children. The glycosylated sAA content ratio was higher than the total sAA content ratio in both groups. Splenic asthenia and healthy children had positive correlations between total sAA or glycosylated sAA content and sAA activity. However, the role played by glycosylated sAA content in sAA activity in healthy children increased after citric acid stimulation, while it decreased in splenic asthenia children. CONCLUSION: Genetic factors like AMY1 copy number variations, and more importantly, sAA glycosylation abnormalities leading to attenuated sAA activity after citric acid stimulation, which were the main reasons of the attenuated sAA activity ratio in splenic asthenia children compared with healthy children. PMID- 26237830 TI - Effect of sanhuangwuji powder, anti-rheumatic drugs, and ginger-partitioned acupoint stimulation on the treatment of rheumatoid arthritis with peptic ulcer: a randomized controlled study. AB - OBJECTIVE: To observe the efficacy and safety of oral sanhuangwuji powder, anti rheumatic drugs (ARDs), and ginger-partitioned acupoint stimulation at zusanli (ST 36) on the treatment of rheumatoid arthritis (RA) complicated by peptic ulcer. METHODS: This prospective randomized controlled study included 180 eligible inpatients and outpatients randomly assigned to an ARD treatment (n.= 60), ginger-partitioned stimulation (n = 60), or combination treatment (n = 60). Patients assigned to the ARD group were given oral celecoxib, methotrexate, and esomeprazole. Patients assigned to the ginger-partitioned stimulation group were given ginger-partitioned acupoint stimulation at zusanli (ST 36) in addition to the ARDs. Patients in the combination treatment group were given oral sanhuangwuji powder, ginger-partitioned acupoint stimulation at susanli (ST 36), and ARDs. All patients were followed up for 2 months to evaluate clinical effects and safety. The study was registered in the World Health Organization database at the General Hospital of Chengdu Military Area Command Chinese People's Liberation Army (ChiCTR-TCC12002824). RESULTS: The combination treatment group had significantly greater improvements in RA symptoms, laboratory outcomes, and gastrointestinal symptom scores, compared with the other groups (P < 0.05). The peptic ulcer healing rate in the combination treatment group was significantly greater than that in the ARD treatment group (chi2= 16.875, P < 0.05) and the ginger-partitioned stimulation group (chi2= 6.171, P < 0.05). CONCLUSION: Combination treatment with ginger-partitioned acupoint stimulation at zusanli (ST 36), oral sanhuangwuji powder, and ARDs had a better clinical effect for RA with complicated peptic ulcer, compared with ARD treatmentalone or in combination with ginger-partitioned acupoint stimulation. PMID- 26237831 TI - Effect of auricular pressing treatment on myopia in children. AB - OBJECTIVE: To observe the effect of pressing auricular points on myopia in children. METHODS: Myopic children aged 8-9 years were divided into two groups. The Chinese herb Semen Vaccariae was used to stimulate the auricular points of CO10, LO5, TF4, CO15, CO12, and CO13 for three treatment courses for the experimental group (n = 39), while the same therapy was not given to the control group (n = 33). Binocular naked vision of the experimental group and the control group before and after the intervention was measured using a standard E visual.acuity chart. RESULTS: There was no difference in the binocular naked vision between the experimental group and the control group before the intervention. In contrast, there was significant improvement in binocular naked vision in the experimental group after the intervention compared with the control group (P < 0.05). CONCLUSION: When combined with external medical application, non-invasive auricular therapy could improve the function of myopia in children. Auricular pressing was well received by the children. PMID- 26237832 TI - Effect of electro-acupuncture on gene expression in heart of rats with stress induced pre-hypertension based on gene chip technology. AB - OBJECTIVE: To explore electro-acupuncture's (EA's) effect on gene expression in heart of rats with stress-induced pre-hypertension and try to reveal its biological mechanism based on gene chip technology. METHODS: Twenty-seven Wistar male rats were randomly divided into 3 groups. The stress-induced hypertensive rat model was prepared by electric foot-shocks combined with generated noise. Molding cycle lasted for 14 days and EA intervene was applied,on rats in model + EA group during model preparation. Rat Gene 2.0 Sense Target Array technology was used for the determination of gene expression profiles and the screened key genes were verified by real-time quantitative polymerase chain reaction (RT-PCR) method. RESULTS: Compared with blank control group, 390 genes were changed in model group; compared with model control group, 330 genes were changed in model+EA group. Significance analysis of gene function showed that the differentially expressed genes are those involved in biological process, molecular function and cellular components. RT-PCR result of the screened key genes is consistent with that of gene chip test. CONCLUTION: EA could significantly lower blood pressure of stress-induced pre-hypertension rats and affect its gene expression profile in heart. Genes that related to the contraction of vascular smooth muscle may be involved in EA's anti-hypertensive mechanism. PMID- 26237833 TI - Tetrahydroxy stilbene glucoside improved the behavioral disorders of APP695V717I transgenic mice by inhibiting the expression of Beclin-1 and LC3-II. AB - OBJECTIVE: To observe the effect of tetrahydroxy stilbene glucoside (TSG) on the behavior of APP695V717I transgenic mouse models and the expression of autophagy associated proteins Beclin-1 and LC3-II. METHODS: Forty 3-month-old APP695V717I transgenic mice were randomized equally into either a TSG group (n = 20) or a model group (n = 20). A normal control group consisted of C57BL/6J mice of the same age and background (n = 20). The TSG group received TSG intragastric administration for 1 month. Behavior was measured using the Morris water maze and the Y-maze tests. Changes in pro- tein expression and mRNA of autophagy associated Beclin-1 and LC3-II in mice hippocampus were detected by western blot and Reverse Transcription-Polymerase Chain Reaction (RT-PCR) analyses. RESULTS: The number of electric-stimulus escapes significantly increased and the Morris water maze test showed prolonged escape latency, greater swimming distance, less time taken to cross the exact former platform location in the model group, and increased mRNA and protein expressions of Beclin-1 and LC3-II compared with the control group (P < 0.05). The TSG group showed a decrease in the number of electric-stimulus escapes, shorter escape latency and swimming distance, greater time taken to cross the exact former platform location, and decreased mRNA and protein expressions of Beclin-1 and LC3-II compared with the model group (P < 0.05). CONCLUSION: these results indicate that tetrahydroxy stilbene glucoside can decrease expressions of Beclin-1 and LC3-II in the autophagy pathway. It can attenuate injury to endoplasmic reticulum functions caused by Ab neurotoxicity, improving learning, memorizing, and spatial orientation behavior in mice. PMID- 26237834 TI - Effect of acupuncture at Fengchi (GB 20) on the activity of myosin light chain kinase in the middle meningeal artery of migraine modeled rats. AB - OBJECTIVE: To study the effect of acupuncture at Fengchi (GB 20) on the activation of myosin light chain kinase (MLCK) in the middle meningeal artery of migraine modeled rats. METHODS: Forty-four clean grade healthy female Sprague Dawley (SD) rats were randomly divided into four groups: the control group, blank control group, Fengchi (GB 20) acupuncture group, and Fengchi (GB 20) prevention group. Neurogenic inflammation of these rats was induced by electrical stimulation. The gamma-32P infiltration method was then used to detect MLCK activation in the middle meningeal artery, and immunocytochemistry was applied to detect the structural protein expression of MLCK. RESULTS: The miaraine model was successfully established in the rats. Compared with the control group, MLCK activation was significantly decreased in the blank control group (P < 0.01). CONCLUSION: The activation of MLCK in the middle meningeal artery was increased by acupuncture at Fengchi (GB 20), indicating its effectiveness in preventing and curing on acute migraine attacks. PMID- 26237835 TI - Danshen (Radix Salviae Miltiorrhizae) reverses renal injury induced by myocardial infarction. AB - OBJECTIVE: To evaluate the protection of danshen (Radix Salviae Miltiorrhizae) (SM) injection in myocardial infarction (MI) induced renal damage. METHODS: Forty male C57 mice were divided into control group, MI group and SM group. In MI group, the left coronary artery was occluded for 8 weeks; the same procedure was used for the SM group, with the additional step of SM (0.2 mL) administered intraperitoneally for 56 days. Before surgery and 8 weeks later, transthoracic echocardiography was performed and urine protein and albumin was measured. At the end of the time, all mice were killed and kidneys removed for reactive oxygen species (ROS) and fibrosis analysis, plasma was collected for blood urea nitrogen and serum creatinine determination. RESULTS: MI slightly decreased renal function and increased production of ROS, accompanied with renal fibrosis. Administration of SM reduced production of ROS and increased renal function, it also reduced renal fibrosis. CONCLUSION: MI plays a causal role in renal injury and SM exerts renal-protective effects, probably by its antioxidant activities. PMID- 26237836 TI - Effect of jiaweiwumel decoction on regulatory T cells and interleukin-10 in a rat model of ulcerative colitis. AB - OBJECTIVE: To investigate the effect of a decoction made from the Traditional Chinese Medicine wumei pill, on regulatory T cells and interleukin-10 (IL-10) in a rat model of ulcerative colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). METHODS: Rat ulcerative colitis was induced with TNBS. All modeled rats were randomly divided into six groups: normal control group; model group; sulfasalazine suppositories treatment group; and high, moderate, and low dosage of jiaweiwumei decoction groups (12 rats each). Colon injury index was evaluated after 14 days. After peripheral blood lymphocyte separation, CD4+ T cells and CD4+/CD25+ T cell percentage was detected by flow cytometry. The content of IL-10 in serum and intestinal mucosa tissue was detected by sandwich enzyme-linked immunosorbent assay. RESULTS: Colon injury indices in the decoction groups were effectively reduced, compared with the model group (P < 0.05). Compared with that of the control group, the CD4+/CD25+ to CD4+ T lymphocyte ratio of the model group was significantly lower, while the decoction treatment improved the CD4 +/CD25 + to CD4 + T lymphocyte ratio (P < 0.05). The serum and mucosal IL-10 content of the model group was significantly lower (P < 0.05) than that in the control group, while the decoction group had significantly higher serum and intestinal mucosal IL-10 content than that in the model group (P < 0.05). The regulatory T cell content was negatively correlated with the colonic injury index (r = 0.68, P < 0.05), and positively correlated with the content of serum IL-10 (r= 0.87, P < 0.05) and intestinal mucosal IL-10 (r= 0.79, P < 0.05). CONCLUSION: Jiaweiwumei decoction had significant effects on regulatory T cells and IL-10 in rats with TNBS-induced ulcerative colitis. PMID- 26237837 TI - Evaluation of antileishmanial, antibacterial and brine shrimp cytotoxic potential of crude methanolic extract of Herb Ocimum basilicum (Lamiacea). AB - OBJECTIVE: To collect and screen for ethnopharmacological properties (antileishmanial, antibacterial and brine lethality assays) of medicinal plan Ocimum basilicum from Peshawar region (34.008 latitude and 71.57 altitudes). METHODS: In the present study a general antileishmanial activity against Leishmania tropica strair was carried out. The antibacterial potential of the plant was performed against 06 gram positiv and 06 gram negative bacteria. Brine shrimp cyto- toxicity assay at different concentrations were investigated. RESULTS: The anti-promastigotes profile of the plant showed good antileishmanial activity exhibited LC50 value 21.67 ug/mL. The result for gram positive antibacterial activity revealed that the O. basilicum leaves extract possesses significant inhibitory activity at highest two concentrations ranging from 20.66 +/- 0.31 to 31.86 +/- 0.80 for Clostridium perfringens type C and Bacillus subtitilis, respectively, as compared to the gentamycin (27.36 +/- 0.55 and 21.80 +/- 0.72, respectively). For gram negative bacteria good activity was observed. A highest zone of inhibition was recorded for Pseudomonas aeroginosa (28.83 +/- 0.28) at the highest concentration (10 mg/ mL). The LC50 value obtained for brine shrimp lethality assay was 91.56 ug/mL. CONCLUSION: The herb basil possesses effective cidal activities which make this plant a good candidate for the isolation of antiprotozoal and antibacterial compounds which may lead to the development of novel drug. PMID- 26237838 TI - Heat induces adenosine triphosphate release from mast cells in vitro: a putative mechanism for moxibustion. AB - OBJECTIVE: To investigate the role of adenosine tri-phosphate (ATP) purinergic signaling in mast cells (MCs) modulated by heat to further understand the molecular mechanisms of moxibustion. METHODS: Skin temperatures induced by monkshood cake moxibustion were evaluated by measuring the Neiguan acupoint (PC 6) from 31 participants with a digital thermocouple thermometer. Temperatures of 43 degrees C and 52 degrees C were applied to cultured human leukemia mast cell line HMC-1 in vitro. Calcium fluorescence was applied to detect intracellular Ca2+ ([Ca2+]). Extracellular ATP contents were measured by luciferin-luciferase assay. RESULTS: Maximum skin temperatures mostly ranged from 40-45 degrees C , but some reached up to 50 degrees C. Both 43 degrees C and 52 degrees C induced MC degranulation, which was accompanied by an increase in [Ca2+] and ATP release. Complexing extracellular Ca2+ with 5 mM ethylene glycol-bis (beta aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) inhibited the noxious, heat induced elevation of [Ca2+]i and prevented the enhanced ATP secretion by those. cells at 52 degrees C, but not 43 degrees C. CONCLUSION: Monkshood cake moxibustion can generate heat sufficient to trigger cellular events of MCs, including degranulation, [Ca2+]i elevation, and ATP release, suggesting that purinergic signals originating from MCs are possibly the initiating response of acupoints to moxibustion. PMID- 26237839 TI - Topography of spinal column and kidney receptors as illustrated by microsystem of the foot. AB - OBJECTIVE: To test the accuracy of the distribution of reflective zones on the feet as proposed by William Fitzgerald using the spine and kidney receptors as reference points. METHODS: Spine and feet lengths were measured first along straight lines and then again, taking into consideration the anatomical curves. The spinal column was further measured with regard to its individual regions (cervical, thoracic, lumbar, sacrum-coccyx). Straight-line measurements were taken with the help of an anthropometer. Measurements that took into account all of the curves were performed with the opisometer (also known as a "map measurer"). All the measurements were accurate to within 1 mm. The study subjects were a healthy, physically fit 16-year-old female student and a 53-year-old male office employee exposed to an average dose of physical exercise. RESULTS: The kidney receptor in the foot did not reflect onto the predetermined lumbar section of the spinal column as measured along the straight line or with regard to curves. Instead, in both subjects the kidney receptor reflected onto the thoracic spine. CONCLUSION: Te particular level of the spinal cord that innervates the given organ controls the distribution of receptors of individual organs in the foot. PMID- 26237840 TI - Key elements required to publish a good article: consensus among executive editors of Traditional Chinese Medicine and integrative medicine journals - a Delphi study. AB - OBJECTIVE: To explore consensus among Traditional Chinese Medicine (TCM)/integrative medicine (IM) journal executive editors in China regarding: (a) Their perceptions about the differences between papers published in Chinese/English journals; (b) the key elements required for publishing a good quality paper; (c) how editors manage and decide on the manuscripts submitted to their journals. METHODS: A three classic round Delphi was conducted with a purposive sample of TCM/M Chinese journal executive editors. The key themes and items generated from six open ended questions in the first round were redistributed to the editors in two subsequent questionnaire rounds and scored on a five-point Likert scale. Consensus, reliability and stability of responses were assessed between the editors in the same round and between rounds. RESULTS: All ten editors initially agreeing to participate completed the three rounds, provided 60 comments in the first round, relating to 6 themes on: elements of publishing good quality article; differences between Chinese and English published articles; reasons for low quality of Chinese studies; maintaining the journal's good reputation; initiatives and strategies; and differences between Chinese and English versions of the same journal. High levels of consensus were reached for 97% items. Intra-class correlation (ICC) coefficient for agreement among editors was high in both second and third round and there was a good stability between the two rounds. CONCLUSION: High inter/intra-editor agreement was identified in the differences between TCM/IM research papers published in English and Chinese. Publishing standards and probity are keys in elevating the reputation of research. Editors' perspectives in maintaining and improving quality journal can be viewed as fundamental for editors and researchers in publishing any articles. PMID- 26237842 TI - Protein kinase-based neural signaling pathways for ginsenosides: a retrospective review. AB - Ginsenosides are the main active components of ginseng, which have been reported to target brain tissues and produce multiple neuroprotective effects. Ginsenosides have been shown to improve learning ability and memory in normal aged animals, and in an animal model of memory impairment. However, its underlying pharmacological mechanisms are very complicated, especially with regard to its effects on the activation of protein kinases in neurons. Previous reports have shown that some protein kinases may be affected by ginsenosides, including protein kinase C, calcium/calmodulin-dependent protein kinase II, c-Jun N terminal kinase, and protein tyrosine kinase. In this paper, protein kinases that may underlie the mechanisms of ginsenosides will be discussed. PMID- 26237841 TI - Common parameters of acupuncture for the treatment of hypertension used in animal models. AB - Hypertension is associated with at least 7.6 million annual deaths worldwide. While pharmacotherapy may provide good control for blood pressure, it sometimes induces adverse effects. Meanwhile, acupuncture has been used for the treatment of cardiovascular diseases, such as hypertension, coronary artery disease, and stroke, but its mechanisms of actions remain poorly understood. The efficacy of acupuncture depends on multiple constituent elements including acupoints, manipulation skills, and implementation programs, which are termed as acupuncture prescription. This review summarized the previous information of experimental use of acupuncture on animals including species, hypertension models, acupoints selection, acupoint location, stimulation protocols, and evaluation of effectiveness to provide useful guidance for researchers when performing acupuncture in animal experiments. PMID- 26237843 TI - Review of the powder and decoction formulae in Traditional Chinese Medicine based on pharmacologically active substances and clinical evidence. AB - Powder formulae are an indispensable part of prescription in Traditional Chinese Medicine. Powder formulae are. characterized by good therapeutic efficacy and low dose used for their preparation. Analysis of the therapeutic application and material basis of pharmacological active substance in power formulae can enable the development of new powder formulae. This in turn can contribute to reduction of wastage of drug material, relief of shortage of herbal medicinal resources and sustainable development of Traditional Chinese Medicine. PMID- 26237844 TI - New drug pricing: does it make any sense? PMID- 26237845 TI - A HEALTHY NEW YEAR! PMID- 26237846 TI - PUSHING POPULATION HEALTH MANAGEMENT. PMID- 26237847 TI - EMPOWERING PHYSICIANS TO IMPROVE VALUE. PMID- 26237848 TI - CHIEF MEDICAL OFFICER: CHANGING ROLES AND SKILL SETS. PMID- 26237849 TI - POLITICS AND A BROKEN PROMISE: WHY PEOPLE ARE LOSING THEIR PHYSICIANS IN POST-ACA AMERICA. PMID- 26237850 TI - MANAGING CUSTOMER RELATIONSHIPS - A HEALTH CARE IMPERATIVE. PMID- 26237852 TI - APPLYING THE RISK DISCERNMENT PROCESS. PMID- 26237851 TI - AT YOUR SERVICE LINE. PMID- 26237853 TI - BUILDING A DASHBOARD FOR A CARDIOVASCULAR CENTER OF EXCELLENCE. PMID- 26237854 TI - DOES STRUCTURE DRIVE STRATEGY FOR COMMUNITY HEALTH SYSTEMS? PMID- 26237855 TI - ARE YOU A NARCISSIST? PMID- 26237856 TI - LOSING AND WINNING UNDER THE ACA IN 2015. PMID- 26237857 TI - HOSPITAL BOARDS - WHY QUALITY AND SAFETY MATTER. PMID- 26237858 TI - THE ONLY CONSTANT IS CHANGE. PMID- 26237859 TI - EPISODE PAYMENTS MAKING PROGRESS. PMID- 26237860 TI - MEASUREMENT: ACCOUNTING FOR RELIABILITY IN PERFORMANCE ESTIMATES. AB - When evaluating physician performance measures, physician leaders are faced with the quandary of determining whether departures from expected physician performance measurements represent a true signal or random error. This uncertainty impedes the physician leader's ability and confidence to take appropriate performance improvement actions based on physician performance measurements. Incorporating reliability adjustment into physician performance measurement is a valuable way of reducing the impact of random error in the measurements, such as those caused by small sample sizes. Consequently, the physician executive has more confidence that the results represent true performance and is positioned to make better physician performance improvement decisions. Applying reliability adjustment to physician-level performance data is relatively new. As others have noted previously, it's important to keep in mind that reliability adjustment adds significant complexity to the production, interpretation and utilization of results. Furthermore, the methods explored in this case study only scratch the surface of the range of available Bayesian methods that can be used for reliability adjustment; further study is needed to test and compare these methods in practice and to examine important extensions for handling specialty-specific concerns (e.g., average case volumes, which have been shown to be important in cardiac surgery outcomes). Moreover, it's important to note that the provider group average as a basis for shrinkage is one of several possible choices that could be employed in practice and deserves further exploration in future research. With these caveats, our results demonstrate that incorporating reliability adjustment into physician performance measurements is feasible and can notably reduce the incidence of "real" signals relative to what one would expect to see using more traditional approaches. A physician leader who is interested in catalyzing performance improvement through focused, effective physician performance improvement is well advised to consider the value of incorporating reliability adjustments into their performance measurement system. PMID- 26237861 TI - RE-ENGINEERING AMERICA'S PHYSICIAN WORK FORCE. PMID- 26237862 TI - THE FIVE P'S TO INFLUENCE PHYSICIANS. PMID- 26237864 TI - WHY I CANNOT HEAR 'NO' - CONFESSIONS OF A SURGEON. PMID- 26237863 TI - ASSESSMENT OF A PHYSICIAN'S WORKPLACE BEHAVIOR. PMID- 26237865 TI - AN INTERVIEW TOOL TO PREDICT DISRUPTIVE PHYSICIAN BEHAVIOR. PMID- 26237866 TI - INTELLECTUAL BOX CANYONS. PMID- 26237867 TI - KEYS TO DEVELOPING A COMMUNITY-BASED CONCUSSION CLINIC. PMID- 26237868 TI - POLITICS AND A BROKEN PROMISE: THE ACA FACES ANOTHER ELECTION CYCLE. PMID- 26237869 TI - INTEGRATING PREVENTION - HOW THE NEW BIOMEDICAL PREVENTION METHOD FOR HIV WILL AFFECT YOUR HEALTH CARE ORGANIZATION. PMID- 26237870 TI - ICD-10, ELECTRONIC DOCUMENTATION AND CMS SET TO COLLIDE. PMID- 26237871 TI - EXECUTIVE COACHING IN ACADEMIC MEDICINE - THE NET UNDER THE TIGHTROPE. PMID- 26237872 TI - [The effect of abused drugs on the developing brain during childhood and adolescence]. AB - Exposure to drugs of abuse during adolescence may lead to developmental disturbances, which may have functional consequences as well. Especially detrimental to the brain is substantial binge drinking, which may in the worst case lead to loss of the brain's gray matter gray substance and reduced integrity of the white matter. These changes are reflected in many cognitive functions. Also cannabis interferes with brain maturation and causes impairment of cognitive functioning. Although the structural changes induced by drugs are likely to largely return to normal after cessation of use, their overall effect on the functional capacity of the young may be significant. PMID- 26237873 TI - [When will a patient with pulmonary embolism be fit to go home?]. AB - Most of the patients with pulmonary embolism have in Finland been treated in inpatient wards, there is much to be learned about the identification of patients with low risk of death. The assessment is based on clinical factors. Circulation should furthermore be stable without any signs of increased workload of the right side of the heart. Appropriate patient education and case-specific follow-up must be taken care of. Direct oral anticoagulants are a good alternative to low molecular weight heparin and warfarin therapy. PMID- 26237874 TI - [Progressive multifocal encephalopathy in a LED patient]. AB - Progressive multifocal encephalopathy (PML) is a rare demyelinating disease of the central nervous system, caused by the reactivation of the JC virus in the body during immunosuppression. The use of monoclonal antibodies predisposes to PML, and the epidemiology of the disease has changed. We describe the first PML published from Finland and associated with rituximab treatment in a LED patient. PMID- 26237875 TI - [Transluminal coronary angioplasty during resuscitation--an option not to be ignored]. AB - We describe a prolonged and successful in-hospital resuscitation, during which the cause of cardiac arrest was treated by transluminal coronary angioplasty. A closed cardiac massage device was used in the resuscitation of the patient, and the treatment required close collaboration between the cardiologist and the resuscitation team. In spite of the difficult initial situation and several disturbances of vital functions the patient was discharged in good condition. PMID- 26237876 TI - [Update on Current Care Guidelines. Current Care Guideline: Stable Coronary Artery Disease]. AB - This guideline covers coronary heart disease symptoms, diagnosis and treatment. Stable coronary heart disease refers to a disease in, which patients have stable symptoms and evidence of ischemia or significant stenosis of coronary artery. Diagnosis is based on medical history and exercise test, which is the primary diagnostic test. Coronary angiography is in selected cases necessary to confirm the diagnosis and assess invasive treatment. Pharmacotherapy aims to improve the survival of the patient, relieve symptoms and improve quality of life. The guideline also deals with invasive treatment either with PCI or CABG. PMID- 26237877 TI - [Duties of child protection in suspected child abuse]. AB - Child protection is taking part in the elucidation of the child's situation and providing help in cases of suspected child abuse. The child is always the client of child protection. Additional persons to be worked with include the parents and other partners. When abuse is suspected, the child's immediate need for help will be assessed and the situation of the whole family is discussed in child protection. The child's overall situation is evaluated in collaboration with the police and healthcare. It is essential to recognize the violence and to combine the various supportive measures into an entity to the best interest of the child. PMID- 26237878 TI - [Criminal investigation in violent and sex crimes against children]. AB - The investigation of violent and sex crimes against children differs from that of the crimes of violence against adults. This is why every attempt is made to concentrate the investigation of these cases to police officers having received specialized training. The most significant difference in the investigation of violent crimes against children and adults is related to the hearing of children as complainants. A child under the age of 15 will not be heard in the court, and thus the hearing of a child in the stage of preliminary investigation forms part of the trial. The different status of a child must also be taken into account in other investigational procedures. A person under 18 must be treated in accordance with her/his age and developmental status. PMID- 26237879 TI - [When suspicion of child sexual abuse is raised--what to do?]. AB - Upon a raised suspicion of child sexual abuse, time must be taken to control and calm down tne situation. It is important for those working with children to take actions without causing problems to the course of the possible criminal process. Advance issue with treatment guidelines is a good way to confirm adequate basic information about the phenomenon. Hearing the child and detailed documentation of the information are essential. Excessive questioning may have a negative impact on the criminal process. The urgency of somatic investigations is determined by the last possible time of occurrence of the suspected abuse. PMID- 26237880 TI - [Suspected physical child abuse--recognition and actions in health care]. AB - Every physician meeting with children should be aware of the most common types of injury and situations causing concern associated with child abuse. When encountering a child who has been or suspected to have been abused, even the physician may get anxious and uncertain about what he/she should be able to do. It is worth remembering that at the beginning the best way a doctor can help the child is to take care of the basic aspects of her/his work: careful clinical examination, appropriate medical record entries and prompt reports to the authorities. PMID- 26237881 TI - [Radiological examinations in suspected physical abuse of a child]. AB - Injuries associated with child abuse involve typical imaging findings that should be recognized by every radiologist, because a radiologist may be the first person to raise doubts about abuse. Subdural and subarachnoid hemorrhages in the vicinity of the longitudinal cerebral fissure are characteristic of a brain injury resulting from shaking. Magnetic resonance imaging is the most recommendable method of imaging. At the acute stage, computed tomography is sufficient for the detection of conditions requiring immediate neurosurgical treatment, if magnetic resonance imaging is not possible. Ultrasonography is not sensitive enough for this purpose. Fractures in a child under the age of one year are always suspicious, especially rib fractures. Injuries of the liver, pancreas and intestine are often found in the abdominal region. Contrast-enhanced CT scan is the best investigation in injuries of the lungs and the abdominal region. If a suspicion of physical abuse is raised upon imaging studies, it is important to bring this to the notice of the attending physician and note the issue also in the report. PMID- 26237882 TI - [Life after cardiac infarction]. AB - Many of those having had cardiac infarction suffer only a minor myocardial injury and are discharged after balloon angioplasty with open coronary arteries and well pumping cardiac muscle. Returning to normal life may, however, be tough. On the other hand, after a few days of hospital care the discharged person does not always even note having fallen ill. At and between both extremes the affected person needs guidance, support, encouraging and appropriate medication. Living habits have an essential effect on both short-term and long-term prognosis, and sensible living also results in a better well-being. PMID- 26237883 TI - [Pseudotumors caused by hip prostheses]. AB - More than 100000 hip replacements have been performed in Finland. In the hip replacement operations performed due to osteoarthritis, the artificial joint surfaces are made of metal, plastic or ceramics. Pseudotumors associated with metal-on-metal (MoM) sliding surfaces have received worldwide attention. Soft issue lesions, not always symptomatic, may develop around the joint replacements. These may even require joint revision surgery. PMID- 26237884 TI - [Tobacco withdrawal in individuals suffering from mental disorders]. AB - Smoking is very common in individuals with mental illnesses, but smoking cessation help is inadequately offered to them. Some 54% of Finnish psychiatrists often advise their patients to quit smoking, yet 34% often recommend nicotine replacement therapy, and only 12% of them often prescribe tobacco withdrawal medication. Factors that affect advisement in smoking cessation include the psychiatrists' own attitudes and personal smoking history, barriers within the work settings, and the patient's diagnosis. Because smoking poses detrimental effects on the treatment of psychiatric illnesses, as well as on the health of the patient, tailored and more intensive smoking cessation counseling should be offered to individuals with mental illnesses. PMID- 26237885 TI - [Diagnosis and treatment of actinic keratosis]. AB - Actinic keratoses are premalignant skin lesions with the risk of converting into squamous cell carcinoma, and therefore they should be treated. Treatment modalities include cryotherapy, photodynamic therapy, carbon dioxide laser and also topical treatments such as imiquimode, ingenol mebutate, 5-fluorouracil and diclophenac. In the future, the treatment of actinic keratosis can be more often done in primary health care. The most favorable treatment modality depends on patient age, general health, and the thickness, size and localization of the lesion. PMID- 26237886 TI - [Hereditary macrothrombocytopenia and hearing loss]. AB - We describe an autosomal dominant hereditary thrombocytopenia syndrome caused by a defect in the MYH9 gene. Of our three patients, all have thrombocytopenia from birth, and their thrombocytes are large in size. The hemorrhagic tendency caused by thrombocytopenia is often mild. Approximately 60% of the patients develop sensorineural hearing loss and approx. 30% develop renal insufficiency that frequently progresses to require hemodialysis. It is of particular importance to recognize the thrombocytopenia as being hereditary and permanent in order to save the patients from useless and harmful therapeutic efforts. PMID- 26237887 TI - [Update on Current Care Guideline: Diabetic retinopathy]. AB - Good treatment of diabetes decreases the risk of diabetic retinopathy. The goals of the treatment are adequate glucose balance, blood pressure and prevention of metabolic syndrome. Every patient with diabetes should regularly be screened for diabetic retinopathy. Timely and efficient treatment of retinopathy significantly decreases the risk of visual impairment. PMID- 26237888 TI - [Health effects of living habits]. AB - Single healthy living habits such as non-smoking and regular physical activity decrease the risk of common non-communicable diseases, unsuccessful aging and premature death to a small to moderate degree. Their cumulative effects are, however, large. Only a small minority of people adhere well to all healthy living habits or even the healthiest ones. Consequently, the population attributable fractions of major public health problems due to unhealthy lifestyles are large. Substantial improvement of public health calls for policies and programs to influence the root causes of the lifestyles in the multiple environments and systems where they are developed, maintained, and changed. PMID- 26237889 TI - [Magnetic resonance imaging of patients with cardiac pacemakers--a safe mode of operation]. AB - Owing to potential serious safety risks, magnetic resonance imagings of patients having cardiac pacemakers have long been forbidden. Due to the increased demand, modes of operation have, however, been developed for safe imaging, taking the benefit-risk aspects into account. The mode of operation devised in collaboration between the HUCH Cardiology Outpatient Clinic and the radiology unit of the HUS Medical Imaging and Physiology makes safe magnetic resonance imagings possible without body area restrictions for all kinds of cardiac pacemaker patients. By using the developed mode of operation, imaging of 268 patients with cardiac pacemakers have already been carried out safely by the end of October 2014. We describe the content of the mode of operation and the current status of the investigations, with a brief look into the future. PMID- 26237890 TI - [Outcome of eating disorder patients treated in tertiary care]. AB - BACKGROUND: We assessed the outcome of eating disorder patients treated in a specialized treatment setting. MATERIAL AND METHODS: Register-based follow-up study of adults (n = 2 450, 95% women, age range 18-62 years). For each patient four background-matched controls were selected. RESULTS: The hazard ratio for all cause mortality was 6.51 in anorexia, 2.97 in bulimia and 1.77 in BED. Autoimmune diseases were more common in patients than in controls. Bulimia and BED were associated with increased type 2 diabetes risk. Pregnancy and childbirth rates were lower among patients than among controls. CONCLUSIONS: Eating disorders are associated with multiple health problems and increased mortality risk. PMID- 26237891 TI - [Diaphragmatic rupture: case report of a rare complication of labor]. AB - A diaphragmatic rupture associated with labor is a rare complication of pregnancy with high fetal and maternal mortality. Due to non-specific symptoms and rareness of the disease the diagnosis can be challenging. We present a case of a healthy 26-year old woman with one previous childbirth who presented upper abdominal pain, tachycardia and dyspnea during labor. Immediately after labor, a left-sided diaphragmatic rupture complicated with ventricle perforation was diagnosed. After prompt diagnosis and immediate surgical care, including thoracotomy and laparotomy, both patient and child experienced a full recovery. PMID- 26237892 TI - [Diagnosis of soft tissue tumors--multidisciplinary collaboration]. AB - The number of soft tissue sarcomas found in Finland yearly is around 200 cases. Benign soft tissue tumors are common. The patients having a tumor with a deep location in the tissue or a large superficial tumor should be readily referred for imaging studies and consultations with the sarcoma teams of university hospitals. The diagnosis of sarcoma is based on medical history, clinical examination, imaging, examination of a biopsy, and frequently also on molecular genetic analyses. In imaging, the best resolution is provided by MRI. Targeting of the biopsy is an essential part of imaging. Gradus is the most important histology-based factor affecting the prognosis and treatment of the tumor. PMID- 26237893 TI - [Surgical treatment of soft tissue sarcomas]. AB - Surgical excision of the tumor with a tumor-free margin is always the most important form of treatment of soft tissue sarcoma. Although a local management of the tumor would in many cases be achieved by amputation, the functional and psychological consequences would often be significant. Better knowledge of the biology of different subtypes along with the progress in the forms of treatment has improved the prognosis. Modern surgical treatment aims at functional resection with tumor-free margins and preservation of the limb, whenever possible. If necessary, the operation will be complemented with postoperative radiotherapy. Adjuvant chemotherapy or chemoradiotherapy are given in some cases. PMID- 26237894 TI - [Oncologic therapy of soft tissue sarcoma]. AB - Surgery with a margin of resection is the only curative form of treatment of soft tissue sarcoma. The combination of surgery and radiotherapy can, however, be used to lower the risk of local recurrence, if wide margins are not achieved e.g. in order to preserve the function of a limb. By using combination chemotherapy, disease recurrence can in the highest-risk patients be decreased to some extent. Radiotherapy provides palliative relief from a number of the patient's symptoms. The diagnosis and treatment of soft tissue sarcoma require an early participation of a multidisciplinary team familiarized with these rare tumors. PMID- 26237895 TI - [New vaccines against group B meningococcal diseases]. AB - There has been no efficient general vaccine against serogroup B meningococcus (MenB), since its polysialic acid capsule is of low immunogenicity and could potentially induce autoimmunity. Reverse vaccinology has revealed new promising protein candidates for vaccine development. One of them is factor H-binding protein (fHbp), which has the potential to curb the alternative pathway of human complement. As fHbp can elicit antibodies that promote complement-mediated lysis, a vaccine partly based on it has been introduced against MenB infections. FHbp has been the milestone protein for structural vaccinology to create optimal chimeric antigens for vaccine use. PMID- 26237896 TI - [Autoimmune enteropathy]. AB - Autoimmune enteropathy (AIE) is characterized by protracted diarrhea, malabsorption, immunomediated damage to the intestinal mucosa, and unresponsiveness to changes in diet. The disease is mainly manifested in the small intestine. Lymphocyte deposits are present on the mucous membrane, and anti enterocyte or anti-goblet cell antibodies have been described in the majority of affected persons. AIE occurs primarily in infants. Immunosuppressive drugs have been used with varying success. The prognosis of AlE is dependent on the degree of severity of the damage to the intestinal mucosa and extraintestinal symptoms and diseases associated therewith. PMID- 26237897 TI - [Severe atopy and allergy--rare hyper-IgE syndrome caused by the DOCK8 mutation as underlying condition]. AB - The DOCK8 hyperimmunoglobulin E syndrome is an autosomal recessive primary combined immunological deficiency. Severe atopic eczema having its onset in infancy, food allergies, chronic viral infections of the skin, and recurrent pneumonias are central symptoms. Serum IgE level is high and eosinophilia is found in the blood. In addition, abnormalities in the number and function of lymphocytes can be detected. The disease may be difficult to distinguish from severe allergic eczema and asthma. The diagnosis is made through a gene test. We describe a 13-year-old boy, whose disease was cured with allogenic stem cell transplantation. PMID- 26237898 TI - [Update on Current Care Guidelines: Post-traumatic Stress Disorder]. AB - The updated Current Care Guidelines for ASD and PTSD recommend psychosocial support and careful monitoring for acute stress reaction (ASR) and acute stress disorder (ASD). If symptoms require, short focused cognitive-behavioral psychotherapy can be used for ASD. Medication is rarely necessary. Trauma-focused psychotherapeutic interventions are the first-line treatment for post-traumatic stress disorder (PTSD). Antidepressant medication is an effective second-line treatment. Psychotherapeutic interventions and medication should often be combined. Specific groups, such as children, the elderly, and military and peacekeeping personnel need tailored interventions. PMID- 26237899 TI - [Psychiatry at the maternal clinic]. AB - Various mental disorders are encountered at the maternal clinic. Pregnancy predisposes to some mental disorders, most commonly depressive and anxiety disorders. The recognition of substance use disorders during pregnancy is very important, but difficult owing to the associated disgrace. An eating disorder with an onset preceding the pregnancy may cause problems for growth and development of the fetus and should thus be identified early enough. The rare but severe postpartum psychosis may often break out only after discharge from the maternity hospital. Drug therapy during pregnancy requires careful consideration and clear-cut reasoning. PMID- 26237900 TI - [Somatic health of a mental patient]. AB - The most common somatic problems in mental patients are physical inactivity, an unhealthy diet, overweight and cardiometabolic disorders. Neurologic problems associated with medication, disturbances in sexual functions and adverse effects associated with smoking may also be significant. Patients suffering from psychiatric disturbances require regular monitoring based on a therapeutic plan perceiving the individual needs, in which the problems caused by the symptoms in seeking medical care and implementation of the treatments must be taken into account. Somatic health status and the need for psychosocial support are worth considering in the individual treatment plan. PMID- 26237901 TI - [Diagnosis and drug therapy of anxiety disorders in primary health care]. AB - Generalized anxiety disorder, panic disorder and social phobia are common in primary health care patients. They may, however, be difficult to identify, since the patients seek medical attention primarily because of somatic symptoms. Anxiety disorders cause suffering, impair functional capability and are frequently accompanied by excessive use of healthcare services. These disorders are often accompanied by comorbid depression, which must be taken into consideration in the therapy. They are treated with psychotherapy, drug treatment or combination thereof. SSRI and SNRI drugs are the first-line choice of medication. PMID- 26237902 TI - [Recognition of mood disorders]. AB - A mood disorder involves lowering or elevation or mood and usually also somatic symptoms associated with anxiety, substance abuse problems or a personality disorder. In addition to diagnoses, the stage and degree of severity of the disorder and the patients' own motivation influence the treatability of the patients. The expectations and hopes of the patients are associated with their life and medical history, social situations and increasingly heterogenous cultural backgrounds. A good and continuous therapeutic relationship can contribute to the treatment motivation and result. PMID- 26237903 TI - [Cognitive symptoms in an elderly patient--maintaining the functional capacity is always important]. AB - In primary health care, elderly patients having problems in their ability to deal with information are increasingly encountered as a result of lessened institutional care and altered population structure. The most common causes of cognitive problems in the elderly include delusional disorder, various progressive memory diseases and delirium. Treatment of cognitive problems is multidisciplinary collaboration, and maintaining the functional capacity is important at all stages of the disease. Memory disorder medications clearly increase the time of functional capacity, provided that their use is started early enough. Pharmacologic therapy of behavioral symptoms requires expertise, and easily emerging drawbacks frequently exceed the benefits of the medications. PMID- 26237904 TI - [Circulating cell-free DNA as biomarker for cancer *header*]. AB - The rapid accumulation of mutations in cancers and the resulting clonal heterogeneity frequently lead to generation of drug-resistant populations of cancer cells. Examinations requiring a tissue biopsy are invasive, making real time monitoring of the disease difficult. One alternative to support tissue-based testing is fluid biopsy. Malignant cells release to the patient's circulation DNA, which contains somatic mutations and epigenetic changes characteristic of each cancer. Sufficiently sensitive methods of investigation enable the detection of tumor DNA in the blood sample, whereby it can be utilized e.g. in the monitoring of disease progression. PMID- 26237905 TI - [Cardiac effects of radiation therapy]. AB - Because of increased life-expentancy cancer patients having undergone radiation therapy nowadays live longer, and late-appearing adverse effects are therefore playing a more significant role. Radiation therapy given to the chest is known to approximately double the risk of heart disease, the cumulative total radiation dose being the most important risk-increasing factor. The most significant adverse effects appear only years after the treatment. The mortality from late manifestations reduces the total benefit of radiation therapy. Patients with radiation therapy due to a cancer of the left breast or Hodgkin's lymphoma are particularly susceptible to cardiac effects. A safe radiation dose is not known. PMID- 26237906 TI - [Adverse cardiac effects associated with anticancer drugs]. AB - With the development of new protein kinases, antibodies, immunomodulators and hormonal treatments, significant progress has taken place in the last few years in the pharmacological treatment of cancers. At the same time, old cytotoxic drugs still remain in use. In regard to the heart, anthracyclines are the most problematic cytotoxic drugs, as they may cause cardiac insufficiency that is manifested only years after the treatment. Also trastuzumab and kinase inhibitors may cause cardiac insufficiency. Fluoropyrimidines cause myocardial ischemia for some patients. Treatments targeting VEGF inhibition are frequently associated with significant elevation of blood pressure. PMID- 26237907 TI - [Radiologic side effects of cancer therapy]. AB - Cancer therapy agents can cause a vast spectrum of side effects which can be detected with various imaging techniques. These side effects can affect all organs and vary from non-symptomatic to fatal. The rapid evolution of cancer therapy brings constantly new agents into clinical practice. Some side effects may be detected only after the marketing approval of the therapy. The radiological findings usually lead into a suspicion of a drug side effect especially if there are no other imminent causes for the findings. Collaboration between the radiologist and the treating physician is essential in the diagnostic work-up. PMID- 26237908 TI - [Children's limb fractures]. AB - Children's limb fractures are commonly seen in general practice and emergency departments. Diagnostics relies on relevant clinical examination and good quality radiographs and will be supplemented with CT scanning, when necessary. The treatment of fracture must not interfere with the child's normal bone growth. Conservative treatment with reduction under anesthesia is the treatment of choice. With operative treatment, rigid fixation of the fracture is not necessary; K-wires and elastic intramedullary nails are widely used. Although the aim of the treatment is exact positioning of the fracture, growing bone has a great capacity of remodeling, which may correct malposition. PMID- 26237910 TI - [Adults with mild mental retardation and intelligence tests]. AB - One of the criteria for mild mental retardation is a total level of less than 70 IQ points measured by an intelligence test. The results of intelligence tests are approximate. There are differences in the norms of test versions, and measurement error must be taken into account in individual testing. A total level of 80 measured by adult tests utilized in Finland does not exclude the possibility of mild mental retardation, and a total level of 60 does not confirm it. The test performance should be compared with other measures, such as school and work history, practical functional capacity and previous test results. PMID- 26237909 TI - [Phenotype and incidence of Creutzfeldt-Jakob disease in Finland in 1997-2013]. AB - INTRODUCTION: The incidence of Creutzfeldt-Jakob disease (CJD) in Finland in 1974 1989 was reported to be 0.6/1 000 000. Our aim was to compare the current incidence of CJD in Finland with the earlier incidence and also study the diagnostics of the disease. METHODS: Register study of the Finnish CJD cases from 1997 to 2012 and the clinical data of CJD patients within the Hospital District of Southwest Finland from 2007 to 2013. RESULTS: There were 119 cases. The average yearly incidence was 1.36-1.44/1 000 000. CONCLUSIONS: Compared with the previous study, the incidence in Finland appears to have increased. The change is propably due to increased awareness and improved diagnostic methods. PMID- 26237911 TI - [Insidious duodenal injury in a child]. AB - Duodenal injuries in children are rare. However, we should keep in mind the possibility of duodenal injury in blunt abdominal trauma. Findings on imaging can be normal in spite of duodenal perforation and symptoms may become manifest later after trauma. Duodenal perforation diagnosed within 24 hours can be treated with primary closure and drainage. The safest operative treatment is pyloric exclusion or duodenal diverticularization and gastrojejunostomy or pancreaticoduodenectomy in most serious injuries. Delay in diagnosis is associated with increased complication rate, hospitalization and mortality. PMID- 26237912 TI - [Update on current care guidelines. Current care guideline: Acute lower respiratory tract infection in adults]. AB - Pneumonia is recognised in patients suffering from acute cough or deteriorated general condition. Patients with acute cough without pneumonia-related symptoms or clinical findings do not benefit from antimicrobial treatment. Those with suspected or confirmed pneumonia are treated with antibiotics, amoxicillin being the first choice. Most patients with pneumonia can be treated at home. Those with severe symptoms are referred to hospital. Patients are always encouraged to contact his/her physician if the symptoms worsen or do not ameliorate within 2-3 days. Patients aged 50 years or older and smokers are controlled by thoracic radiography in 6-8 weeks. PMID- 26237913 TI - [Update on Current Care Guideline: Multiple sclerosis]. AB - Treatment for relapsing-remitting multiple sclerosis (RRMS) is initiated upon fulfillment of new McDonald 2010 criteria for RRMS. In addition, lumbar puncture is an essential diagnostic method. Interferon-beta, dimethyl fumarate, glatiramer acetate and teriflunomide are the first-line immunomodulating drugs (IMD) for RRMS. If the disease is active according to clinical or MRI evaluation during the first-line IMD treatment, alemtuzumab, fingolimod or natalizumab may be considered as second-line therapies. IMD treatment is discontinued upon the transition of RRMS to secondary progressive phase. Rehabilitation should be considered at every phase of the disease. PMID- 26237914 TI - [Amyotrophic lateral sclerosis and respiratory insufficiency]. AB - Amyotrophic lateral sclerosis (ALS) is a disease causing degeneration of motor neurons, without any curative treatment. The most common cause of death is respiratory arrest due to atrophy of the respiratory musculature. ALS-associated respiratory insufficiency differs in mechanism from the more common causes of dyspnea, such as diseases of pulmonary or cardiac origin. Recognizing the respiratory insufficiency can be challenging for a clinician. It should be possible to predict the development of respiratory insufficiency in order to avoid leaving the treatment decisions concerning respiratory insufficiency to emergency services. Noninvasive ventilatory support can be used to alleviate the patient's dyspnea. It is actually recommended as the first-line treatment of ALS associated respiratory insufficiency. PMID- 26237915 TI - [Premature ovarian insufficiency--a threat to a woman's health?]. AB - Premature ovarian insufficiency (POI) is characterized by cessation of menstruation and elevated follicle stimulating hormone levels before the age of 40. Patients may have hypoestrogenic symptoms such as hot flushes. Most cases are idiopathic but the underlying mechanisms can be genetic, autoimmune-based or iatrogenic. Long-term deprivation of estrogen has serious implications for cardiovascular health and bone density. Early impaired fertility and infertility may be the main concerns for the patients. Hormone replacement therapy until the normal age of menopause is recommended, even though the scientific evidence is inadequate. The only proven method of achieving pregnancy in these patients is by ovum donation. PMID- 26237916 TI - [Maternal-fetal attachment during pregnancy--possibility and challenge for anterpartal care]. AB - Mother's substance abuse, depression, very young or old age, poor social support, private negative experiences of personal relationships in childhood, and fear of childbirth may impair the normal development of attachment during pregnancy. The recognition of potential risk factors of attachment of the pregnant mother and future early interaction is possible in anterpartal care. Systematic development and study of effectiveness of interventions strengthening the attachment are essential. Ultrasound consultation appears to be one of the promising tools in strengthening the attachment. PMID- 26237917 TI - [How does sleeping restore our brain?]. AB - The central function of sleep is to keep our brain functional, but what is the restoration that sleep provides? Sleep after learning improves learning outcomes. According to the theory of synaptic homeostasis the total strength of synapses, having increased during the day, is restored during sleep, making room for the next day's experiences. According to the theory of active synaptic consolidation, repetition during sleep strengthens the synapses, and these strengthened synapses form a permanent engram. According to a recent study, removal of waste products from the brain may also be one of the functions of sleep. PMID- 26237918 TI - [Laryngitis in childhood]. AB - The most common causative agents of laryngitis are parainfluenza viruses. The diagnosis of laryngitis in children is a clinical one, typical symptoms including dry, often barking cough and inspiratory difficulty and wheezing. Typical age of occurrence is 0.5 to 3 years. In children under one year of age the structural and functional anomalies causing symptoms resembling laryngitis in connection with an infection should not be disregarded. Most patients can be nursed at home. An orally administered glucocorticoid and inhaled racemic adrenalin are effective drugs in emergency service. PMID- 26237919 TI - [The Finnish first year junior high school students gambling behaviour is associated with substance use and low academic performance]. AB - BACKGROUND: The study investigated Finnish 7th grade school children's gambling behaviour and gambling prevalence. METHOD: Participants (N = 988) in this study were from eleven schools in Finland.Chi2X-tests, mean comparisons and correlations were used to analyse the data. The retention rate was 9.,6%. RESULTS: Nearly one-third of the participants had gambled once or twice. .,0% of the participants were problem gamblers and .,8% gambled at-risk level. Significant others' gambling was associated with participants 'problem gambling. CONCLUSIONS: Adolescent problem gambling prevalence and at-risk level of gambling were higher compared to the adult population. Replication of this study with the larger sample is needed in order to confirm the results. PMID- 26237920 TI - [Acute angle-closure glaucoma triggered by epidemic nephropathy]. AB - Epidemic nephropathy, i.e. nephropatia epidemica is a febrile illness caused by the Puumala virus and involving a transient impairment in kidney function. Additional commonly experienced symptoms include headache, backache and limb pain, as well as drowsiness or restlessness and nausea. Visual disturbances appear in approx. one third of those affected with the disease. Blurring of vision is the most common problem. We describe a patient case in which a previously healthy woman contracted epidemic nephropathy causing ocular symptoms that were strong. PMID- 26237921 TI - [Update on current care guidelines. The tendon disorders of the shoulder]. AB - Degenerative rotator cuff tendon disease (tendinopathy) is the most common disorder of the shoulder. A full-thickness tear of the rotator cuff may be caused by degeneration, or it may develop due to an acute trauma. The typical symptoms include pain and functional deficiencies. Diagnostics is based on clinical findings. The primary radiologic imaging is x-ray. Degenerative tendon diseases are primarily treated conservatively in primary health care, the most important treatment modality is physiotherapy-guided therapeutic rehabilitation. Surgical treatment is considered in full-thickness rotator cuff tears, especially after traumatic onset. PMID- 26237922 TI - [Chronic liver disease and thrombosis risk]. AB - The coagulopathy of chronic liver disease involves elevated risks for thrombosis in the portal vein and extra-splanchic sites. Hypercoagulability may moreover accelerate liver fibrosis progression. Cirrhosis-related portal vein thrombosis is associated with decompensation events and inferior prognosis; anticoagulation therapy achieves complete recanalization in -40% of recent thromboses and prevents thrombosis progression in chronic cases. Standard thrombosis prophylaxis seems appropriate for hospitalized cirrhotic patients. This review provides practical guidance to tailoring anticoagulation therapy in cirrhosis according to individual bleeding risk. We also propose an algorithm for using anticoagulation and transjugular intrahepatic portosystemic shunts in the treatment of cirrhotic portal vein thrombosis. PMID- 26237923 TI - [Laryngeal cancer in Finland]. AB - The risk of developing laryngeal cancer increases after 50 years of age. Of the risk factors, smoking has decreased significantly, but alcohol consumption has increased. The significance of HPV infection is lower compared with oropharyngeal cancer. Early laryngeal cancer can be successfully treated with surgery or radiation therapy. For cancers that have spread further (T3 and T4), a combination of surgery and radiotherapy or a combination of radiotherapy and cytostatic chemotherapy are used. By using a voice prosthesis, most patients are able to achieve a fairly good speech quality after laryngectomy. PMID- 26237924 TI - [Finnish language proficiency of immigrant physicians in medical licensure examinations]. AB - BACKGROUND: Physicians immigrating to Finland from countries outside the EU/EEA must pass a language test and three medical licensure examinations (MLE) in Finnish. Failing rates are high and remarkably variable. MATERIAL AND METHODS: MLE examination papers were analyzed with linguistic criteria: writing skills and word frequency. Results of the linguistic analyses were compared with the MLE scores. RESULTS: Better results in writing skills analysis correlate with higher scores in MLE. Also a higher portion of rare words correlates with higher scores in MLE. CONCLUSIONS: The mandatory language test does not serve as a valid measurement tool for immigrant physicians. PMID- 26237925 TI - [Sepsis after thermoablation and sterilization]. AB - Endometrial ablation is a commonly used procedure in the treatment of heavy menstrual bleeding. The procedure is considered quite safe, but may also involve severe complications. We present a patient who developed life-threatening sepsis after the procedure. PMID- 26237926 TI - [Diagnosing gender identity]. AB - Transsexualism and other variations of gender identity are based on a stable sense of identity. The aetiology of this phenomenon is not fully known. Suffering caused by gender dysphoria is alleviated with sex reassignment. The psychiatric assessment of both adolescents and adults has been centralized in Finland to two university hospitals, the Helsinki University Hospital and Tampere University Hospital. In both hospitals, multidisciplinary teams aim at differential diagnosis by using well-known psychiatric and psychological instruments. Wishes for sex reassignment that are caused by a mental health disorder are excluded. Assessment in adolescence is challenging because the identity in youth is still forming. PMID- 26237927 TI - [Hormonal treatment of transsexual persons]. AB - The primary investigations and starting the hormonal treatment of transsexual persons takes place in Helsinki and Tampere University hospitals as part of the real life period. The hormones used are estrogen and anti-androgen for MtoF and testosterone for FtoM persons. The medication suppresses the endogenous sex hormone production and brings about the desired features of the other sex. While the recommended doses result in physiological hormone levels, higher doses do not hasten or increase the desired changes and are a health risk. After the transition period, the follow up is referred to the person's home district. The physical and psychological status and laboratory values are evaluated at the yearly follow-up doctor visits. Although the hormone doses are lowered and percutaneous administration route is favored upon aging, stopping the medication is not recommended. PMID- 26237928 TI - [Effect of sex reassignment on mental well-being and quality of life]. AB - Transgender people find their natal sex and the corresponding gender role unpleasant and alien, and wish to be able to live in the gender role and body of the other sex. Gender dysphoria is effectively alleviated by sex reassignment treatments. Quality of life is improved among the majority of patients, and regrets are rare. Psychiatric symptoms at the initiation of the transition process, discrimination, negative attitudes, losses in relationships, and complications in somatic treatments may deteriorate the social integration and quality of life of the transgender people. Health-care professionals can ease the transition process by organizing support for transgender individuals according to the same principles as they do for other people. PMID- 26237929 TI - [Surgery of the breast on transgender persons]. AB - For a female-to-male transgender person, mastectomy is the most important procedure making the social interaction easier. Along with the size of the breasts, the quantity and quality of skin will influence the selection of surgical technique. Although complications are rare, corrective surgery is performed for as many as 40% of the patients. Of male-to-female transsexual persons, 60 to 70% opt for breast enlargement. Breast enlargement can be carried out by using either silicone implants or fat transplantation. Since the surgical procedures on breasts are irreversible, their implementation requires confirmation of the diagnosis of transsexualism by a multidisciplinary team. PMID- 26237930 TI - [Genital surgery for transgender people]. AB - Genital surgery is performed at the final stage of the gender reassignment process and is in Finland by statutory regulation of 2003 concentrated to be carried out by the HUCH multiprofessional team. Statutory recommendations from the psychiatry units at both HUCH and Tays Central Hospital are required for this. Sex reassignment surgery will be undertaken on the basis of a steadfast wish of an adult patient on the condition that he/she understands the risks associated with surgery and is mentally and physically fit for the operation. PMID- 26237931 TI - [Care of voice among transgender people]. AB - In some cases transgender people spontaneously find vocal expression that is acceptable. The testosterone medication usually lowers the female voice (F to M) enough. Feminization of the male voice (M to F) needs more often care. Speech and voice therapy is usually the primary treatment. In some cases pitch-elevating surgery is needed. This will raise the pitch or at least eliminate spontaneous male voicing (cough, laughter). If cosmetically unacceptable, a prominent Adam's apple will be removed. PMID- 26237932 TI - [Reduction of hairiness of a transsexual person]. AB - Reduction of male pattern hairiness--especially facial hairiness--is important for the identity of a transsexual female. Methods of treatment include epilation, waxing, chemical depilation, planing, electrolysis, eflornitine cream and methods based on optical light. Also the hormonal therapies utilized in the treatment process reduce the degree of hairiness and make the hairs thinner. Instead of hair removal, one should rather speak of reducing hairiness, since life-long hairlessness is usually not achieved even by the most effective methods of hair reduction. Aspects affecting the choice of treatment include skin type, quality of hair, tolerability and availability of treatment, among other things. PMID- 26237933 TI - CAT OF THE MONTH. Critically Appraised Topics. Preventive Dental Programs Initiated During Pregnancy Are Effective in Reducing the Incidence of Severe Early Childhood Caries (UT CAT # 2680). PMID- 26237934 TI - Oral and Maxillofacial Pathology. Case of Month. Cherubism. PMID- 26237935 TI - Methods dentists use to diagnose primary caries lesions prior to restorative treatment: Findings from The Dental PBRN. AB - OBJECTIVE: To (1) quantify the diagnostic techniques used by Dental Practice Based Research Network (DPBRN) dentists before they decide to treat primary caries lesions surgically and (2) examine whether certain dentist, practice, and patient characteristics are associated with their use. METHODS: A total of 228 DPBRN dentists recorded information on 5,676 consecutive restorations inserted due to primary caries lesions on 3,751 patients. Practitioner-investigators placed a mean of 24.9 (SD = 12.4) restorations. Lesions were categorized as posterior proximal, anterior proximal, posterior occiusal, posterior smooth, or anterior smooth. Techniques used to diagnose the lesion were categorized as clinical assessment, radiographs, and/or optical. Statistical analysis utilized generalized mixed-model ANOVA to account for the hierarchical structure of the data. RESULTS: By lesion category, the diagnostic technique combinations used most frequently were clinical assessment plus radiographs for posterior proximal (47%), clinical assessment for anterior proximal (51%), clinical assessment for posterior occlusal (46%), clinical assessment for posterior smooth (77%), and clinical assessment for anterior smooth (80%). Diagnostic technique was significantly associated with lesion category after adjusting for clustering in dentists (p < 0.0001). CONCLUSION: These results--obtained during actual clinical procedures rather than from questionnaire-based hypothetical scenarios- quantified the diagnostic techniques most commonly used during the actual delivery of routine restorative care. Diagnostic technique varied by lesion category and with certain practice and patient characteristics. PMID- 26237936 TI - Randomized controlled trial of a TiO2 Semiconductor toothbrush on mild-to moderate periodontitis.. AB - The Soladey toothbrush (Shiken Corp., Osaka, Japan) is based on the principle that electrical induction will cause a wetted titanium dioxide semiconductor to emit electrons. The manufacturer claims that in addition to the established mechanical benefits of brushing, the flow of electrons from the brush head may disrupt ionic bonding of plaque, neutralize bacterial organic acids, and thus confer an advantage over a conventional toothbrush. AIM: Determine whether a TiO2 semiconductor-containing toothbrush confers an advantage over a conventional toothbrush in adult patients with mild-to-moderate gingivitis/periodontitis. MATERIALS and METHODS: Seventy-one patients with mild-to-moderate gingivitis/periodontitis were enrolled in this randomized, double-blind, placebo controlled modified crossover trial that compared the Soladey-3 titanium dioxide semiconductor toothbrush (Shiken Corp., Osaka, Japan) to an otherwise identical toothbrush containing an inert resin core in place of the semiconductor. Changes in indices of gingivitis and periodontitis were the primary outcomes. RESULTS: Sixty-six patients completed the study. Relative to baseline, an almost two-fold increased gingival crevice fluid flow followed both active and control treatments was statistically significant. Relative to the inactive control device, the active Soladey-3 toothbrush had no clinically meaningful effects on selected markers of gingivitis/periodontitis. CONCLUSIONS: The active Soladey-3 toothbrush did not substantially impact selected markers of gingivitis/periodontitis by the end of a two-week treatment period in adult patients with mild-to-moderate disease. Both inactive (control) and active (TiO2 semi-conductor) versions of the Soladey toothbrushes significantly increased crevice fluid flow. PMID- 26237937 TI - The Trusting Face of Early Twentieth Century Dentistry. PMID- 26237938 TI - Treating Patients with Anxiety or Special Needs: There's Always a Way. PMID- 26237939 TI - Filling Gaps in the Affordable Care Act's Coverage Using Health Savings Accounts and Supplemental Coverage. PMID- 26237940 TI - Five-star: Where do we go from here? PMID- 26237941 TI - The importance of humor in medicine. PMID- 26237942 TI - Trends in prevalence of patient case-mix adjusters used in the Medicare dialysis payment system. AB - OBJECTIVES: The Medicare End-Stage Renal Disease Prospective Payment System (PPS) used data from 2006-08 to set weights for each case-mix adjuster that is part of the bundled payment formula. The details of the population case-mix were not made public, and little is known about consistency of case-mix over time. This study estimated the prevalence of case-mix adjusters during 2006-2008 and analyzed changes in case-mix prevalence from 2000-2008. METHODS: Cross-sectional cohort study using United States Renal Data System data for Medicare dialysis patients. Three 3-year cohorts (2000-02, 2003-05, 2006-08) were analyzed for changes over time in case-mix prevalence. RESULTS: Double-digit trends were observed in many case-mix categories between 2000-02 and 2006-08. Large declines were observed in prevalence of patients with low BMI, pericarditis, new to dialysis, and ages 18 44. Large increases were observed in chronic co-morbidities, pneumonia and age cohort 80+. CONCLUSIONS: Substantial changes in case-mix adjuster prevalence suggest the PPS payment formula should be regularly updated. PMID- 26237943 TI - Improving outcomes with better CKD care. PMID- 26237944 TI - [The Mechanisms of Orientation Sensitivity of Human Vision System. Part II: Neural Patterns of Early Processing of Information about Line Orientation]. AB - The high density EEG was registered in 41 healthy subjects (20 males, 21 females) in the cardinal (horizontal and vertical) and oblique (45 and 135 deg) line orientation identification task. The analysis of the adaptive amplitude maximum (4 ms averaging) of P1 and N1 evoked potentials in the symmetrical occipital, parietal and inferior temporal areas and dipole source modelling showed the anisotropy of cortical responses in the 80-150 ms interval. The amplitude is higher on the oblique orientations as comparison with cardinal ones. The temporal and regional features of cortical answers were discovered. The earlier selective response (~90 ms latency) is registered.in the parietal areas, while the later (~145 ms latency) is found in the occipital ones. We discovered a number of sex related differences in the early stages of line orientation detection. In males, the amplitude of components is higher; they have broader area of localisation of their dipole sources: in addition to the occipital and parietal regions, cortex of the temporal regions is involved. Theobtained data are discussed in the context of the idea of effective neural coding (Barlow, 1959) and the features of spatial information processing in the visual system of males and females. PMID- 26237945 TI - [Unconscious Acoustical Stimuli Effects on Event-related Potentials in Humans]. AB - Unconscious perception essentially affects human behavior. The main results in this area obtained in experiments with visual stimuli. However, the acoustical stimuli play not less important role in behavior. The main idea of this paper is the electroencephalographic investigation of unconscious acoustical stimulation effects on electro-physiological activity of the brain. For this purpose, the event-related potentials were acquired under unconscious stimulus priming paradigm. The one syllable, three letter length, Russian words and pseudo-words with single letter substitution were used as primes and targets. As a result, we find out that repetition and alternative priming similarly affects the event related potential's component with 200 ms latency after target application in frontal parietal and temporal areas. Under alternative priming the direction of potential amplitude modification nearby 400 ms was altered for word and semi-word targets. Alternative priming reliably increase ERP's amplitude in 400 ms locality with pseudo-word targets and decrease it under word targets. Taking into account, that all participants were unable to distinguish the applied prime stimuli, we can assume that the event-related potential changes evoked by unconscious perception of acoustical stimuli. The ERP amplitude dynamics revealed in current investigation demonstrate the opportunity of subliminal acoustical stimuli to modulate the electrical activity evoked by verbal acoustical stimulation. PMID- 26237946 TI - [The Spatial-Frequency Characteristics of the Visual System in Schizophrenia]. AB - In order to determine the spatial-frequancy characteristics of the visual system of healthy subjects and patients with schizophrenia, we used the contrast comparison of two Gabor gratings with sinusoidal distribution of brightness. The Gabor gratings have low, medium or high spatial frequencies; the neurons of magnocellular and parvocellular channels are sensitive to these frequencies to different extents. We found an increase in sensitivity to the contrast when comparing the gratings with low frequencies (to which magnocellular channels are most sensitive) in the patients with first-episode schizophrenia who had not receive long-term antipsychotic treatment, as compared with the control group. On the contrary, the sensitivity to the gratings with medium and high spatial frequencies in this group of patients was lower, as well as in patients with first-episode schizophrenia who had received long-term treatment. The patients with chronic schizophrenia showed a decrease in contrast sensitivity in all tested ranges of frequencies. We obtained supplementary evidence of the enhancement of internal noise in the visual system of the patients with schizophrenia. The results help us to explain the clinical data on the development of visual perceptual diorders at different stages of schizophrenia. PMID- 26237947 TI - [The Analysis of Changes in EEG Patterns in Response to Transmittent Photic Stimulation in Different Disorders of Central Nervous System]. AB - In this study, for the first time, the photic driving reaction in patients with different disorders of the functional state of central nervous system caused by cerebrovascular conditions of different severity was examined by wavelet analysis of electroencephalographic (EEG) fragments. The background fragments of EEG in the group of patients with vegetative-vascular dystonia, are characterized by lower values of the wavelet spectrum energy in the alpha range than the fragments in the control group. In patients from the groups of vertebrobasilar insufficiency and atherosclerotic damage of cerebral blood vessels, the values of energy in delta range is even lower. The wavelet analysis of reactive patterns has demonstrated the different photic driving of beta, theta and alpha ranges in the patients of various groups. The study demonstrates the possibility of quantitative estimation of the human brain lability of light stimulus perception by the wavelet analysis. The results can be used for the adequate choice of treatment for a patient with cerebrovascular disorder. PMID- 26237948 TI - [Changes in the Spectral Characteristics of EEG during Neurofeedback Training]. AB - We used the ratio of spectral characteristics of the EEG alpha and beta frequencies recorded in 10 apparently healthy subjects (university students) to control a computer cursor in the graphic interface in three scenarios with the use of neurofeedback. Our results showed that the scenario which uses the power of alpha- and beta-2-frequencies provided the highest accuracy and the best speed control. The parameters of beta-1-frequency were found to be less effective since an increase or a decrease of their power could result from an increase or a decrease of the power of alpha- and beta-2-frequencies. However, the subjects got the skill of cursor control with efficiency of 81%, gradually growing during learning, after a relatively short period of time (5 trainings per 2 weeks). PMID- 26237949 TI - [Typical Patterns of Neuronal Activity in Relay and Nonspecific Thalamic Nuclei in Patients with Spasmodic Torticollis]. AB - Neuronal activity of 50 neurons in nonspecific (Rt, MD) and relay (Voi, Voa) thalamic nuclei was analyzed. Data were obtained by microelectrode technique during 14 stereotactic operations in patients with spasmodic torticollis. Application of Poincare maps and Gap-statistics allowed to reveal 3 main patterns of neuronal activity: irregular single spikes, low-threshold Ca(2+)-dependent rhythmic (3-5 Hz) bursts and combination of bursts and single spikes. In some cases, grouping (in Voi and Rt nuclei) and long burst (in Voa nucleus) patterns were observed. Grouping pattern consist of low-density groups of spikes with tendency to periodicity in range 1-1.5 Hz. Long burst pattern consist of long dense groups of spikes with random length and invariant interburst intervals. Main numerical estimations of 3 most spread patterns of neuronal activity were obtained by parametric analysis. In results, investigated thalamic nuclei significantly distinguished from each other by characteristics of burst activity but average firing rate of these nuclei hadn't significant differences. These data may be useful for functional identification of thalamic nuclei during stereotactic neurosurgery operation in patients with movement disorders. PMID- 26237950 TI - [Blood Flow and Regional Blood Flow Rate in the Middle Cerebral Artery during Surgical Leg Lengthening in Patients with Congenital and Acquired Limb Shortening]. AB - This is a comparative study of changes in blood flow rate in the popliteal artery, the arteries of bone regenerate and cerebral arteries in 45 patients with congenital and acquired diseases of the limbs at different stages of surgical lengthening of 3-15 cm shortened shin by Ilizarov method. We observed an increase in regional blood flow rate in all patients during the periods of distraction and fixation. A 25% increase in blood flow rate in the middle cerebral artery on the contralateral side was found only in patients of the first adult age with acquired limb shortening. Basing on the analysis of the reaction of cerebral arteries during a functional test with additional muscle work, we suggested that the absence of reaction in congenital diseases is caused by relative excess of somatic afferentation which results from morphological and functional immaturity of brain regulatory systems. PMID- 26237951 TI - [The Effect of Single Aerobic Training on the Regulation of Mitochondrial Biogenesis in Skeletal Muscles of Trained Men: a Time-Course Study]. AB - Adaptation of skeletal muscles to physical training depends on intensity and duration of exercise sessions. The purpose of this study was to investigate the effect of the duration of moderately intensive single aerobic exercise session (60% V(O2max)) on the activation of signalling kinases which regulate PGC-1alpha gene expression and on the expression of regulatory genes of mitochondrial biogenesis and muscle catabolism. Nine athletes (V(O2max)) 59 mL/min/kg) performed 30-, 60-, and 90-min cycling sessions. An exercise-induced increase in PGC-1alpha gene expression was proved to occur without activation of AM PK, p38 MAPK and CAMKII. It was found that 60- and 90-min sessions result in comparable increases of PGC-lalpha gene expression, while VEGFA gene expression increased only after 90-min session. Even 90-min exercise did not induce the activation of FOXO1-E3 ubiquitin ligase pathway and did not result in an increase of expression of exercise-induced catabolic genes. PMID- 26237952 TI - [The Specific Effects of Magnetic Stimulation Depending on the Specialization of Sportsmen]. AB - The article presents data on the effect of magnetic stimulation of quadriceps muscle in the professional sportsmen: cyclists and long jumpers (Magstim Rapid 2 magnetic stimulator was used). In the experiments involving 3 cyclists and 4 long jumpers, both male and female, we observed an increase in the effect of FR muscle fibers (Burke classification) on the process of muscle tension during magnetic stimulation in the frequency range of the activity of motor units. We found some differences between these two types of sportsmen, which result from the characteristics of muscle tension during typical muscle activity. PMID- 26237953 TI - [Comparison of the Results of Satellite Studies of "Mars-500" Experiment Participans in Syktyvkar and Almaty]. AB - Participants of "Mars-500" experiment living in Syktyvkar (northerners) and Almaty (southerners) were studied throughout the year in various seasons. Latitude-caused differences of vegetative index values (RMSSD and pNN50) between groups were found in summer. Northerners were found to have significant seasonal shifts in thermoregulation parameters and RMSSD and pNN50 values. Southerners showed no seasonal changes in abovementioned indices. Participants from both groups were shown to have deviations of several physiological parameters from moderate latitude norms. Many participants from both groups demonstrated stress in adaptation mechanisms. Orthostatic tests performed in both groups revealed deficiencies in regulation of blood circulation. PMID- 26237954 TI - [Vasomotor Endothelial Function in Healthy Individuals: Contact Types of Character]. AB - We studied the vascular endothelial vasomotor function in healthy young individuals, depending on the type of character accentuation, levels of neuroticism, depression and anxiety. It is shown that the types of character accentuation effect on endothelial vasomotor function in healthy men and women. Personality characteristics of a person can be a significant risk factor for disease, the pathogenesis of which is the starting element of endothelial vasomotor dysfunction. PMID- 26237955 TI - [Agonists of u- and delta-Opioid Receptors in the Regulation of IL-2, IL-4 and IFN-gamma Production by Peripheral Blood Cells in vitro]. AB - It was found that beta-endorphin stimulates the PHA (phytohemagglutinin)-induced production of interleukin-4 and has no affect on the production of interferon gamma in unfractionated leukocytic suspension. In the culture of purified CD4+ T cells, beta-endorphin does not affect the concentration of IL-2, IL-4, and IFN gamma, but stimulates the production of IL-4 and inhibits the production of IFN gamma when adding monocytes to the culture. Selective delta-agonist DADLE enhances the PHA-induced production of IL-4 in unfractionated leukocytic suspension and in CD4+ lymphocytes+monocytes system. The synthesis of IFN-gamma by purified CD4+ lymphocytes is not afected by the presence of DADLE, DAGO ad Deltorphin II; but when adding monocytes to the culture, the synthesis rate decreases. beta-endorphin and selective MU-agonist DAGO enhance the production of IFN-gamma by stimulated neutrophils. The production of IFN-gamma in CD8+ lymphocytes is not affected by beta-endorphin. Thus, opioid peptides have a predominantly Th2 polarizing effect, which is monocyte-mediated, hindering the development of cell response by inhibiting IFN-gamma, and stimulating the production of I L-4 by activating delta-receptor. On the other hand, neutrophils can enhance the production of IFN-gamma by stimulating MU-receptor. PMID- 26237956 TI - [Endotoxin Is a Companent in Pathogenesis of Chronic Viral Diseases]. AB - The level of endotoxin and indicators of activity of antiendotoxin immunity (antibody concentration to glycolipid Re-chemotype and general antigen of enterobacteria) were estimated in serum of 174 patients with persistent viral infections (viruses: herpes simplex, hepatitis C, human immunodeficiency). The presence of markers of systemic inflammatory response syndrome (interleukin IL 1beta) and acquired immunodeficiency (CD4+) in HIV-infected patients were also determined. Persistent viral infections are accompanied by endotoxin aggression intestinal origin (caused by them), which is able to induce the development of systemic inflammatory response syndrome. In HIV-infected patients with this syndrome is cyclical, when the phase of hyperactivity replaced immunodeficiency. Schematically, this process can be represented as the following sequence of events: HIV-mediated damage to the intestinal barrier--the development of endotoxin aggression--induction ofsystemic inflammatory response syndrome--the depletion of the immune system, which is transient and is related to the duration of activity of the virus replication cycle, i.e., with damage to enterocytes. Using antiendotoxin component (means of reducing levels of endotoxin in the blood) in the scheme of treatment of persistent viral infections can serve as an element of a successful prevention of complications. PMID- 26237957 TI - [Approximate Estimation of Human Bronchial Resistance during Forced Exhalation]. AB - In this article, we present biomechanical, acoustic biomechanical and acoustic anthropometric surrogate measures of bronchial resistance during forced exhalation. It was shown that the biomechanical surrogate measure provides a rather accurate estimate of bronchial resistance in the middle and in the end of the forced expiratory maneuver in healthy subjects. Statistical prediction of the limits of normal bronchial resistance during forced exhalation in healthy individuals was proved to be possible on the basis of acoustic biomechanical and acoustic anthropometric surrogate measurements. We suggest that the ratio of increments of biomechanical and acoustic surrogate measures of bronchial resistance may be useful for estimating the extent of bronchial obstruction and detecting the affected levels of the bronchial tree of patients with obstructive lung diseases. PMID- 26237959 TI - Cost data comparisons help sway surgeons to standardize supplies. PMID- 26237958 TI - [The DC-Potential of the Brain in Older Women Circumpolar Region]. AB - DC-potential of the brain was performed in 97 women 55-74 years old living in the circumpolar region. Study and analysis of the distribution level DC-potential brain mapping was carried out by the measured values of monopolar constant potentials. The resulting distribution characteristics DC-potential compared with the average values for the corresponding normative age period. The features of the distribution of the level of DC-potential in women of circumpolar region at the age of 55-74 years, such as smoothing hemispheric asymmetry and increase total cerebral energy compared with reference values in most parts of the brain. PMID- 26237960 TI - Hospital accreditation options expand beyond Joint Commission. PMID- 26237961 TI - Using more robust data leads to better outcomes. PMID- 26237962 TI - Structured OR educational programs shorten orientation period. PMID- 26237963 TI - SCOREing patient safety with a proactive approach. PMID- 26237964 TI - Checklists help staff keep cool in the heat of an OR crisis. PMID- 26237965 TI - AAAHC issues guidelines for obese patients. PMID- 26237966 TI - [Electroacupuncture Intervention Enhances Splenic Natural Killer Cell Activity via Inhibiting Phosphorylation of ERK 5 in the Hypothalamus of Surgically Traumatized Rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) on cytotoxic activity of splenic natural killer (NK) cells after surgical trauma via extracellular signal-regulated kinase (ERK) 5 pathway in the rats' hypothalamus, so as to explore its mechanism underlying improving immune disorders after surgery. METHODS: Sprague-Dawley rats were randomly divided into the following 6 groups: control, trauma model, EA, sham EA, 4 nmol-BIX 02188 (an inhibitor for ERK 5 catalytic activity) and 20 nmol-BIX 02188 (n = 6 rats per group). The surgical trauma model was established by making a longitudinal incision (6 cm in length) along the median line of the back to expose the spinal column and another longitudinal incision along the abdominal median line. EA (2 Hz/15 Hz, 1 - 2 mA) was applied to bilateral "Zusanli" (ST 36) for 30 min immediately after surgery. For rats of the BIX groups, intra-lateral ventricular microinjection of BIX 02188 (10 uL, 4 nmol or 20 nmol, or saline for control rats) was conducted 30 min before the surgery. The expression level and protein of phosphorylated ERK 5 (p ERK 5) and corticotropin-releasing factor (CRF) protein were measured by immunohistochemistry and Western blot, respectively. The cytotoxicity of splenic NK cells and the expression of splenic Perforin and Granzyme-B genes were measured by lactate dehydrogenase (LDH) release assay and real-time PCR, respectively. RESULTS: In comparison with the control group, hypothalamic p-ERK 5 immunoactivity, p-ERK 5 protein and CRF protein expression levels were significantly up-regulated in the model group (P<0. 01, P<0. 05), while splenic NK cell cytotoxicity and Perforin mRNA and Granzyme-B mRNA expression levels were notably down-regulated in the model group (P <0. 05, P < 0. 01). Following EA and administration of ERK 5 antagonist, the increased expression levels of p-ERK 5 immunoactivity in the EA group, and p-ERK 5 and CRF proteins in both EA and 20 nmol-BIX 02188 groups were obviously down-regulated (P<0. 05, P<0. 01), without changes in the sham EA and 4 nmol-BIX 02188 groups (P>0. 05) except the increased p-ERK 5 protein in the 4 nmol-BIX 02188 group. In addition, the down-regulated NK cell activity, Perforin mRNA and Granzyme-B mRNA expression levels were significantly reversed in the EA and 20 nmol-BIX 02188 groups (P<0. 05, P<0. 01). No significant differences were found between the EA group and 20 nmol-BIX 02188 group in down-regulating hypothalamic p-ERK 5 and CRF protein expression and up regulating splenic NK cytotoxicity and Perforin and Granzyme-B gene expression (P>0. 05). CONCLUSION: EA can promote the cytotoxicity of splenic NK cells in surgical trauma rats, which may be closely associated with its functions in down regulating trauma-induced activation of ERK 5 pathway and production of CRF in the hypothalamus. PMID- 26237967 TI - [Electrophysiological Characteristics of Sensitized Acupoints after Acute Intestinal Mucosal Injury in Rats]. AB - OBJECTIVE: To observe the dynamic distribution of the extravasated Evans Blue (EB) dye points at the skin after acute colorectal mucosal injury (AIMI) so as to reveal characteristics of acupoint sensitization. METHODS: Forty adult male SD rats were randomly divided into control (n= 10), AIMI (n=20) and AIMI-recovery (n= 10) groups. According to the reaction state (EB-dye extravasation), each group was further divided into resting state (control), sensitized state (appearance of extravasated EB points), recovery state (disappearance of the extravasated EB points), non-sensitization (NS, no extravasated EB points) state and NS recovery state. The AIMI model was induced by perfusion of 2. 5% mustard oil into the colorectum via a thin tube. Evans blue dye was injected into the caudal vein 4 h after AIMI modeling. The distribution of plasma extravasated EB dye points at the skin of the lower limbs was observed. The C-fiber discharge of the separated ipsilateral sciatic nerve was induced by electrical stimulation of the EB-extravasated acupoints and non-acupoint at the threshold and double-fold threshold using an electric stimulator and recorded using a bicelectric amplifier computer system. RESULTS: In AIMI rats, the extravasated EB-dye points were found to overlap the "Xiqian" and "Zusanli" (ST 36)-"Shangjuxu"(ST 37) regions. Moreover, the thresholds of C-fiber discharges induced by electrical stimulation of "Xiqian" and "Zusanli" (ST 36)-"Shangluxu"(ST 37) regions were significantly lower than those of the regions without extravasated EB dye acupoint and non acupoint(P<0. 01, P<0. 05). The numbers of C-fiber discharges evoked by 2-fold threshold electro-stimulation at the "Xiqian" and "Zusanli" (ST 36)-"Shangjuxu" (ST 37) regions were obviously more than those of stimulation of non-acupoint which were experiencing sensitized state(P<0. 01, P<0. 05). CONCLUSION: In rats with acute colorectal mucosal injury, electrical stimulation of the acupoints where the extravasated EB-dye points appear may produce an obvious increase of C fiber discharges under lower electro-stimulation threshold, suggesting a larger action of the sensitized acupoint. PMID- 26237968 TI - [Effect of Electroacupuncture on Expression of Cortical srGAP 1 and Cdc 42 in Rats with Focal Cerebral Infarction]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) intervention on the neurological function and the expression change of Slit-Robo GTPase-activating protein-1 (srGAP 1) and cell division-cycle 42 (Cdc 42) in the cortex of rats with cerebral ischemic injury (CIRI) , so as to explore the mechanism of EA in the management of cerebral infarction. METHODS: A total of 48 male Sprague Dawley (SD) rats were randomly and equally divided into control, model, non-acupoint EA and EA groups (n = 12/group). The CIRI model was established based on the modified Zea Longa method. EA intervention was applied for 30 min, once a day for 14 days. Modified neurologic severity scores (mNSS) were assessed on day 1,3,7 and 14 after mode- ling. Immunofluorescence assay was used to detect the immunoactivity and distribution of srGAP 1 and Cdc 42 in the cortical ischemic region. Western blot was employed to detect the expression of srGAP 1 and Cdc 42 in the affected cortex. RESULTS: The mNSS displayed that the neurological score in the EA group was significantly lower than that in the model group and non acupoint EA group at the 7th d and 14th d (P<0. 01). Immunofluorescence results showed that cerebral srGAP 1 and Cdc 42 were ex- pressed mainly in the cytoplasm. The fluorescence intensity of srGAP 1 of the EA group was significantly lower than that of the model group and non-acupoint EA group(P<0. 01). Meanwhile the fluorescence intensity of Cdc 42 of the EA group was markedly higher than that in the model group and non-acupoint EA group(P<0. 01). Western blot assay indicated that the expression level of srGAP 1 in the model group was significantly higher than that of the control group( P<0. 01) ,and that of the EA group was much lower than those of the model group and non-acupoint EA group(P<0. 01). There was no significant difference of srGAP 1 expression levels between the non-acupoint EA group and the model group(P>0. 05). Additionally, the protein expression of Cdc 42 in the model group was slightly higher than that of the control group(P>0. 05), and that of the EA group was significantly higher than those of the model group and non-acupoint EA group(P<0. 01). There was no significant difference of Cdc 42 expression levels between the non-acupoint EA group and the model group(P>0. 05). CONCLUSION: Cerebral infarction induced increase of cerebral srGAP 1 and decrease of Cdc 42 can be reversed by acupoint EA intervention in CIRI rats, which may be responsible for its effect in improving impaired neurological function after cerebral infarction. PMID- 26237969 TI - [Effect of Electroacupuncture on Ultrastructure of Oligodendrocytes and Expression of the Related Marker Proteins in the Marginal Zone of Cerebral Ischemia Locus in Rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) on changes of ultrastructure of oligodendrocytes in the marginal zone of the cerebral ischemia (CI) locus in rats with cerebral infarction so as to reveal its mechanism underlying improving ischemic cerebral diseases. METHODS: Ninety male SD rats were randomized into sham operation, model and electroacupuncture (EA) groups which were further divided into five subgroups: 1 h, 1 d, 3 d, 7 d, and 21 d after CI (n = 6 in each subgroup). The CI model was established by occlusion of the middle cerebral artery. EA (1 - 3 mA) was applied to "Baihui" (GV 20) and "Dazhui" (GV 14) for 30 min, once a day for 1 h, 1 d, 3 d, 7 d and 21 d, respectively. The ultrastructural changes of oligodendrocytes in the marginal zone of the ischemic cerebral tissue were observed by transmission electron microscope. The immunoactivity levels of A2B5, O4 and 2',3'-cyclic-nucleotide 3' phosphodiesterase (CNPase) for labeling the oligodendrocyte precursor cells, immature oligodendrocytes, and mature oligodendrocytes respectively were detected by immunohistochemistry. RESULTS: The oligodendrocytes were swelling in structure and increased in number after cerebral ischemia. Compared with the model group, the degree of swelling of oligodendrocytes was obviously decreased and new oligodendrocyte proliferation was found in the EA group. In comparison with the sham group, the immunoactivity levels of cerebral A2B5 and CNPase proteins on day 3 and 7 were significantly higher in the model group (P<0. 05), while those of O4 on day 1, 3, 7 and 21 were obviously lower in the model group (P<0. 01). Following EA intervention, the immunoactivity levels of cerebral A2B5, O4 and CNPase proteins were significantly up-regulated in the EA group in comparison with the model group (P<0. 0 1 , P<0. 05). CONCLUSION: EA intervention may reduce the structural damage of oligodendrocytes in CI rats, which may be associated with its effects in promoting the expression of cerebral A2B5, O4 and CNPase proteins, suggesting an involvement of glial cells in the protective effect of EA. PMID- 26237970 TI - [Influence of Moxibustion on TLR 4-MyD 88-NF-KB Signal Transduction Pathway of Synovial Tissue in Rheumatoid Arthritis Rats]. AB - OBJECTIVE: To observe the effect of moxibustion intervention on the expression of toll-like receptor-4 (TLR 4), myeloid differentiation factor 88(MyD 88), and nuclear factor kappa B p 65 (NF-kappaB p 65) genes of knee-joint synovial cells in rheumatoid arthritis (RA) rats, so as to explore its molecular mechanism underlying improving RA. METHODS: Forty SD rats were randomly divided into normal control, RA model, moxibustion and medication groups (n = 10). The RA model was duplicated by raising the rats in a windy, cold and wet environment, followed by injecting Freund's complete adjuvant (0. 15 mL) into the rat's foot. Moxibustion was applied to "Shenshu" (BL 23) and "Zusanli" (ST 36) for 20 min, once daily for 15 days. Rats of the medication group were treated by intragastric administration of tripterygium wilfordii (8. 75 mL/kg), once daily for 15 days. Pathological changes of the synovial tissues were detected by H. E. stain, the contents of serum TNF-alpha and IL-1 detected by radioimmunoassay, and the expression levels of TLR 4 mRNA, MyD 88 mRNA and TRAF-6 mRNA of synovial tissue were analyzed by real time-PCR, and the NF-kappaB p 65 immunoactivity was assayed by immunohistochemistry. RESULTS: In comparison with the normal control group, the synovial tissue of the knee-joint was impaired remarkably and infiltrated by numerous inflammatory cells, and the synovial surface got thickening because of hyperplasia in the model group. Following moxibustion and medication, these situations such as synovial infiltration of inflammatory, synovial cell proliferation were alleviated. The serum TNF-alpha and IL-1 contents and synovial TLR 4 mRNA, MyD 88 mRNA, TRAF-6 mRNA and NF-kappaB p 65 expression levels were remarkably higher in the model group than in the control group(P<0. 01). After moxibustion and medication, the contents of serum TNF-alpha and IL-1, the expression levels of TLR 4 mRNA, MyD 88 mRNA, TRAF-6 mRNA and NF-kappaB p 65 were significantly down-regulated(P<0. 01, P<0. 05). CONCLUSION: Moxibustion intervention can improve pathological changes of the knee-joint synovial membrane tissue in RA rats, which may be related with its effect in inhibiting abnormal activation of TLR 4-MyD 88-NF-kappaB pathway in synovial tissue. PMID- 26237971 TI - [Effects of Moxibustion on Expression of STAT 1, SOCS mRNA in Synovium of Rats with Rheumatoid Arthritis]. AB - OBJECTIVE: To observe the effect of moxibustion on mRNA expression of signal transducers and activators of transcription 1 (STAT 1), suppressors of cytokine signaling (SOCS) in synovium of rheumatoid arthritis (RA) rats, and to investigate its mechanism for relieving RA. METHODS: 40 Wistar rats were equally and randomly divided into control, model, moxibustion, acupuncture and infrared groups (n = 8 in each group). RA model was developed by putting rats in windy, cold and damp room and injection of Freund's complete adjuvant. Bilateral "Shenshu" (BL 23) were stimulated by the respective means for 20 min in duration, once every other day, ten times in total. The swelling degree of voix pedis (perimeter) of rats was measured. The contents of serum interleukin-1 (IL-1) and interleukin-2(IL-2) were detected by radioimmunoassay, and expression of STAT 1, SOCS mRNA in synovium were assessed by RT-PCR. RESULTS: Rats in model group had acute and severe swelling of voix pedis, together with the increase of serum IL-1 content and decrease of IL-2 content, and down-regulation of mRNA expression of both STAT 1 and SOCS in synovium(all P<0. 01). All three modalities of treatment alleviated the swelling and reversed the relevant changes(P<0. 05, P<0. 01) , however, moxibustion produced greater effects than acupuncture or infrared in elevating IL-2 content and up-regulating mRNA expression of both STAT 1 and SOCS. CONCLUSION: Moxibustion achieves the effects of anti-inflammation and joint swelling reduction of RA via decrease of IL-1, increase of IL-2 in serum and up regulation of STAT 1, SOCS mRNA expression in synovium. PMID- 26237972 TI - [Effect of Electroacupuncture Intervention on Expression of NR 2 B Subunit of NMDA Receptor in Amygdala during Morphine Withdrawal in Rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) on the spatial learning-memory ability and the expression of NR 2 B subunit of NMDA receptor in the amygdala (AMG) in rats with morphine withdrawal. METHODS: A total of 40. SD rats were randomized into control, model, manual acupuncture and EA groups (n = 10 in each group). The morphine withdrawal model was established by subcutaneous injection of morphine hydrochloride injection at doses of 20, 30, 40, 50 and 50 mg . kg-1 . d-1 continuously for 5 days, followed by injection of naloxone (i. p., 3 mg/kg) for rapid induction of withdrawal syndrome. Manual acupuncture or EA stimulation was applied to bilateral "Shenshu"(BL 23) and "Zusanli" (ST 36), once daily for 6 days. Morris water maze swimming test was conducted for detecting the rats' spatial learning-memory ability. The expression levels of NR 2 B protein and mRNA in AMG was measured by Western blot and Real time-PCR, respectively. RESULTS: Compared to the control group, the escape latency on day 5 of swimming tests was obviously prolonged in the model group (P<0. 01), while in comparison with the model group, the escape latencies in both manual acupuncture and EA groups were obviously shortened (P<0. 01), suggesting an improvement of the rats' learning-memory ability. In addition, the expression levels of NR 2 B protein in both manual acupuncture and EA groups and that of NR 2 B mRNA in the EA group were significantly higher than those of the model group (P<0. 01, P<0. 05). CONCLUSION: Both manual acupuncture and EA interventions can improve the learning memory ability in morphine withdrawal rats, which is probably partially related to their effects in up-regulating the expression of NR 2 B in the AMG. PMID- 26237973 TI - [Effects of Acupuncture Stimulation on Dynamic Changes of Cerebral TNF-alpha and C-reaction Protein Levels in Cerebral Ischemia-reperfusion Rats]. AB - OBJECTIVE: To observe the influence of "Tong Du Tiao Shen" (Governor-Vessel Dredging and Mental Activity Regulating) acupuncture method on dynamic changes of cerebral TNF-alpha and C-reaction protein (CRP) levels in focal cerebral ischemia reperfusion (CI/R) rats, so as to master the optimal time point of acupuncture therapy for cerebral infarction. Methods A total of 72 adult male Wistar rats were randomly divided into blank control, sham-operation, model and acupuncture groups which were further divided into 6 h, 24 h and 48 h subgroups (n 6 in each subgroup) . The CI/R model was established by occlusion of the middle cerebral artery. Acupuncture stimulation of "Baihui" (GV 20), "Fengfu" (GV 16) and "Dazhui" (GV 14) was conducted for 30 min. Neurological deficit symptoms were assessed with the Zea-Longa neurological deficit score and TNF-alpha and CRP contents in the brain tissue were detected using double sandwich ABC-ELISA method. RESULTS: In comparison with the model group, the Zea-Longa neurological deficit score was significantly decreased in the acupuncture group (P<0. 01). Cerebral TNF-alpha and CRP levels at time-points of 6 h, 24 h and 48 h after CI/R were significantly increased in the model group than in both control and sham groups (P<0. 01). In the acupuncture group, cerebral TNF-alpha and CRP levels were obviously lower than those of the model group (P<0. 01). CONCLUSION: Manual acupuncture stimulation of GV 20, GV 16 and GV 14 can relieve neurological deficit function in CI/R rats, which may be related to its function in suppressing TNF-alpha and CRP levels. PMID- 26237974 TI - [Effect of Electroacupuncture at "Shuigou" (GV 26) on Immunoactivity and Content of Protein Kinase C in the Middle Cerebral Artery in Acute Cerebral Infarction Rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) intervention on expression and content of protein kinase C (PKC) in the middle cerebral artery in acute cerebral infarction (ACI) rats so as to explore its mechanism underlying improvement of ACI. METHODS: Wistar rats were randomly divided into normal control (n = 6), sham operation (n = 30), ACI model (n = 30), and EA (n = 30) groups, and the latter three groups were further divided into 0. 5 h, 1 h, 3 h, 6 h and 12 h subgroups (n = 6 in each subgroup). The ACI model was established by occlusion of the middle cerebral artery (MCAO). EA (15 Hz, 1 mA) was applied to "Shuigou" (GV 26) for 20 min. The PKC expression levels and activity in the vascular smooth muscle of the middle cerebral artery were detected using immunohistochemistry and ELISA, respectively. RESULTS: In comparison with the control group, the immunoactivity and activities of PKC in the middle cerebral artery tissue at 0. 5 h, 1 h, 3 h, 6 h and 12 h were significantly increased in the model group (P<0. 05). After EA intervention, the expression levels and activities of PKC at the 5 time-points were markedly down-regulated in comparison with the model group at the same corresponding time-point (P<0. 05). No significant changes of PKC expression and activity were found in the sham operation group (P>0. 05). CONCLUSION: EA intervention can up-regulate the immunoactivity and activity of PKC in the vascular smooth muscle of the middle cerebral artery in ACI rats, which may contribute to its effect in improving ACI by relieving arterial spasm. PMID- 26237975 TI - [Protective Effect of Preventative Moxibustion on Myocardial Cells in Mice Experiencing Moderate-intensity and Exhausted Exercise]. AB - OBJECTIVE: To observe the effect of preventative moxibustion on cardiomyocytes in mice experiencing different intensities of exercise. METHODS: Kunming mice were randomly divided into blank control (n = 10) , blank-moxibustion (n = 10), moderate-intensity exercise (MIE) model (n = 8), MIE-moxibustion (n = 9), exhausted-exercise model (n = 8), and exhausted-exercise moxibustion (n = 8) groups. Preventative moxibustion was applied to "Zusanli" (ST 36) and "Guanyuan" (CV 4) for 5 min, once daily (except Saturdays or Sundays) for 3 weeks. The apoptotic cardiomyocytes were detected by light microscope after terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL staining), and the ultrastructure of cardiomyocytes was observed by using transmission electron microscope. RESULTS: Compared with the blank control group, the rates of the apoptotic cardiomyocytes were considerably increased in both MIE and exhausted-exercise model groups (P<0. 05). Comparison between the MIE model and MIE-moxibustion groups and between the exhausted-exercise model and exhausted exercise, moxibustion groups showed that the apoptotic rates of cardiomyocytes were significantly lower in the two moxibustion groups than in the two model groups (P<0. 05). In mice experiencing preventative moxibustion, the injured state of the cardiomyocytes including dissolved myofilaments of myocardial fibers, disorder of arrangement and increased interspace of myofilaments, and decreased number of partial myocardial bundles, and the increase of matrix electron density was relatively milder in comparison with their individual exercise model groups. CONCLUSION: Preventative moxibustion may reduce MIE and exhausted exercise induced apoptosis of cardiomyocytes in mice and lessen myocardial injury. PMID- 26237976 TI - [Effect of Warm-needle Moxibustion on Expression of Transfer Growth Factor-beta1 and Insulin- like Growth Factor I in Knee Cartilage of Rabbits with Knee Osteoarthritis]. AB - OBJECTIVE: To observe the effect of warm-needle moxibustion on transfer growth factor-beta1 (TGF-beta1) and insulin-like growth factor I (IGF-I) expression in knee cartilage of knee osteoarthritis (KOA) rabbits so as to explore its underlying mechanism in improving osteoarthritis. METHODS: Thirty Japanese white rabbits were randomly and equally divided into control, model and warm-needle moxibustion(treatment) groups (n = 10 in each group). The KOA model was made by immobilization of the rabbit knee. Warm-needle moxibustion was applied to internal and external Dubi (ST 35), Yanglingquan (GB 34) and Xuehai (SP 10) on the affected side for 30 min in each session and for consecutive 4 weeks. The expression levels of TGF-P 1 and IGF-I in the knee cartilage tissue were assessed by means of radioimmunoassay. HE staining was carried out to examine the morphological changes of knee cartilage. RESULTS: In comparison with the control group, the expression levels of both TGF-beta1 and IGF-I were up-regulated in the model group(P<0. 05) and then down-regulated after the warm-needle moxibustion treatment(P<0. 05). In addition, after the treatment the surface of the knee cartilage of rabbits became smoother and less cell proliferations and clusters were found in the cartilage in the warm-needle moxibustion group compared to those of the model group. CONCLUSION: Warm-needle moxibustion therapy can inhibit the overexpression of TGF-beta1 and IGF-I in the knee cartilage of rabbits with KOA, which may be responsible for its effect in improving pathological changes of the cartilage. PMID- 26237977 TI - [Effect of Electroacupuncture at "Yanglingquan" (GB 34) Acupoint on White Blood Cell Count and Gallbladder Wall Thickness in Rabbits with Acute Cholecystitis]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) at "Yanglingquan"(GB 34) acupoint on white blood cell (WBC) count and gallbladder wall thickness in rabbits with acute cholecystitis, so as to explore the inherent correlation between the gallbladder and GB 34 acupoint according to the theory of Chinese medicine. METHODS: Thirty-two male rabbits were randomly and equally divided into control group, model group, EA "Yanglingquan"(GB 34) group (EA-GB 34) and EA "Yinlingquan"(SP 9) group (EA-SP 9). The acute cholecystitis model was induced by intra-gallbladder injection of escherichia coli liquid. EA stimulation was delivered once per day for consecutive 7 days. WBC count and gallbladder wall thickness were measured to assess the effects of EA treatment. HE staining was carried out to examine the pathological changes of the gallbladder tissue. RESULTS: Compared with the control group,WBC count and gallbladder wall thickness of the model group were significantly increased (P<0. 05), and those changes were reversed by EA intervention at either GB 34 or SP 9 acupoints (P<0. 05). As to WBC count, there was no significant difference between EA-GB 34 and EA-SP 9 groups (P>0. 05), whereas for reducing gallbladder wall thickness, EA stimulation at GB 34 acupoint resulted in a better effect than that of EA at SP 9 acupoint (P<0. 05). CONCLUSION: EA produces positive therapeutic benefits on acute cholecystitis in rabbits. It seems that stimulation at "Yan - glingquan" acupoint gives rise to a better effect than that of "Yinlingquan" acupoint in particular for the reduction of gallbladder wall thickhess. PMID- 26237978 TI - [Observation on Therapeutic Effects of Acupuncture Combined with Cutaneous Electrical Stimulation for Dysphagia in Patients with Cerebral 1nfarction]. AB - OBJECTIVE: To observe the clinical effect of acupuncture combined with neck-skin electrical stimulation (NSES) on dysphagia in patients with cerebral infarction (CI). METHODS: A total of 120 CI patients with dysphagia were randomly divided into acupuncture group, NSES group and acupuncture + NSES group (combined treatment group, n = 40 in each group). Acupuncture stimulation of Fengchi (GB20), Yifeng (TE 17), etc., and blood-letting of Jinjin (EX-HN 12) and Yuye (EX HN 13) were administrated. NSES was applied to the bilateral sites of the neck median line. The treatment was given once daily for two weeks. The swallow function and swallow dysfunction degree of the dysphasia patients were evaluated by water swallow test and food-intake scale, respectively. RESULTS: After one week's and two weeks' treatment, the water swallow score and swallow dysfunction score were significantly improved in the acupuncture, NSES and combined treatment groups (P<0. 01), and the difference values between pre- and post-treatment of the water swallow score and swallow ability score in the combined treatment group were obviously higher than those of the acupuncture and NSES groups (P<0. 01, P<0. 05). No significant differences were found between the acupuncture and NSES groups in both the water swallow score and swallow ability score after one and two weeks' treatment (P>0. 05). Of the three 40 cases in the acupuncture, NSES and combined treatment groups, 16, 18 and 27 were basically cured, 2, 3 and 5 experienced marked improvement, 15, 13 and 7 were improved, and 7, 6 and 1 failed in the treatment, with the effective rates being 82.5%, 85.0% and 97. 5%, respectively. The therapeutic effect of the combined treatment group was apparently superior to that of the simple acupuncture and simple NSES groups (P<0. 01). CONCLUSION: Acupuncture and NSES intervention is effective in improving dysphasia in CI patients and the effect of combined treatment of acupuncture and NSES is obviously better than that of the simple acupuncture and simple NSES. PMID- 26237979 TI - [Clinical Trials of Slow-rapid Reinforcing-reducing Needling Manipulation at Jiaji (EX-B 2) Acupoint for Lumbar Intervertebral Disc Protrusion]. AB - OBJECTIVE: To observe the clinical effect of slow-rapid reinforcing-reducing needling manipulation at Jiaji (EX-B 2) acupoint for lumbar intervertebral disc protrusion. METHODS: Sixty subjects met the inclusion criteria of disc herniation were randomly divided into treatment group (n = 30) and control group (n = 30). In the treatment group, the stimulation mode (slow or fast, reinforcement or reduction) of Jiaji acupoints (EX-B 2) was based on the status of the patients by an overall analysis of symptoms and signs. Other acupoints such as Huantiao (GB 30), Weizhong (BL 40), etc. were stimulated with uniform reinforcing-reducing manipulation. In the control group, all the acupoints were stimulated in uniform reinforcing-reducing mode. The treatment was conducted once a day, continuously for 18 days with 1 day's break between every 6 days. The clinical efficacy appraisal, visual analogue scale (VAS) and Japanese orthopaedic association (JOA) scores and traditional Chinese medicine (TCM) syndrome scores were used for outcome assessment. RESULTS: In comparison with pretreatment, the VAS scores and TCM syndrome scores were significantly decreased in both control and treatment groups (P<0. 05), and the JOA scores were markedly increased after the treatment (P<0. 05). The therapeutic effects of the treatment group were obviously superior to those of the control group in down-regulating the VAS score and TCM syndome score and up-regulating JOA score (P<0. 05). CONCLUSION: Slow-fast reinforcing reducing needling manipulation is superior to the routine acupuncture in the management of lumbar intervertebral disc protrusion. PMID- 26237980 TI - [Randomized Controlled Clinical Trials for Treatment of Child Amblyopia with Otopoint Pellet-pressure Combined with Chinese Medical Herbs]. AB - OBJECTIVE: To observe the clinical effedt of auricular pressure combined with Chinese herbal medicine for amblyopia. METHODS: A total of 66 child patients with amblyopia were randomly divided into Chinese herbal medicine (control) and herbal medicine+ auricular pressure (treatment) groups, with 33 patients in each group. The patients in the control group were treated with Chinese medical herbs as Danggui (Radix Angelicae Sinensis), Gouqizi (Fructus Lycii), Baijuhua (Flos Chrysanthemi), Baizhu (Rhizoma Atractylodis Macrocephalae), Shudi (Radix Rehmanniae Proeparata), Baishao (Radix Paeoniae Alba) , etc. according to syndrome differentiation, while the patients in the treatment group were treated by auricular pressure of otopoints Yan (Eye), Gan (Liver), Shen (Kidney), Xin (Heart), Mu 1 (Eye-1), Mu 2(Eye-2), and Pi (Spleen) and herbal medicines (being the same to the control group). The treatment was conducted for 6 months. After the treatment, the clinical effect, improvement degree of vision, onset time of improvement, and recurrence rate in the 3 and 6 months' follow-up visit were analyzed. RESULTS: Of the 45 and 47 eyes in the treatment and control groups, 22 and 15 were basically cured, 12 and 5 had marked improvement, 9 and 20 were improved, 2 and 7 failed in the treatment, with the effective rates being 75. 56% and 42.55%, respectively. In comparison with pre-treatment, the visual acuity in both control group and treatment group were improved (P<0. 05). The numbers of children who had improvement of visual acuity after 2 weeks, one month in the control group and treatment group were 26 and 31 eyes, 10 and 11 eyes, respectively. The recurrence rate 6 months after the treatment was 50. 00 % in the control group and 16. 28% in the treatment group. The effective rate of the treatment group was significantly superior to that of the control group (P<0. 05). CONCLUSION: Auricular pressure combined with Chinese medical herb treatment is effective in improving visual acuity, and had a higher efficacy, faster action, and lower recurrence rate in amblyopia children in comparison with simple herbal medicine treatment. PMID- 26237981 TI - [Analysis of Therapeutic Regularities and Characteristics of Blood-letting Therapy for Acne Patients Based on Data Mining]. AB - OBJECTIVE: To analyze the therapeutic regularities and characteristics of blood letting therapy for acne in the past clinical practice by using data mining. METHODS: Original papers about acne treated by pricking blood therapy were searched and screened from common databases as Chinese National Knowledge Infrastructure Database (CNKI), WanFang Data, SinoMed, Ovid, ScienceDirect, Socolar, SciFinder, Foreign Medical Journal Full-Text Service (FMJS) and PubMed using keywords of acne+bleeding therapy, acne+blood-letting, acne+ pricking blood, followed by establishing a data plateform to conduct a data mining using Online Analytical Processing (OLAP). RESULTS: A total of 230 original journal articles about acne treated by pricking blood therapy were collected. The included acne cases with wind-heat pattern were predoment, being 56 in frequency times and acounting for 24. 78 %. In the treatment of acne, the therapeutic tool, three-edged needle was often used, being 168 in frequency and acounting for 71.79%. The frequently employed acupoints were those of the Governor Vessel and Bladder Meridian, such as Dazhui (GV 14) and back-shu points. When auricular points used for blood-letting, Erjian (EX-HN 6) and the Vena of the auricular back were most frequently selected. In addition to blood-letting, other therapies such as Chinese herbal medicines, filiform needles, and otopoint-pellet pressure were also used in combination, being 166 in items and constituting 72. 17%. Generally, blood-letting treatment was conducted once every three days (twice a week) or once every two days (three times a week) for about 20 sessions for each acne patient. CONCLUSION: Blood-letting therapy is effective in the treatment of acne. But if used in combination with other therapies, the therapeutic effect would be better. PMID- 26237982 TI - Medical Advice from Lawyers: A Content Analysis of Advertising for Drug Injury Lawsuits. AB - This study examined the medical information contained in a sample of television ads soliciting consumers for lawsuits against drug and medical device manufactures. Almost all such ads involved drugs or devices that have not been recalled and remain on the market. These ads raise important public health questions because they may influence the prospective medical decisions of viewers. The ads contained extensive descriptions of serious adverse events associated with the drugs or devices but almost uniformly failed to disclose information relating to the likelihood of such events. They also failed to effectively advise viewers to consult a doctor. Results also identified a subset of ads that mimicked public service announcements, claiming to be. a "medical alert" "consumer alert" or "FDA warning" at the start of the ad. Most such ads did not disclose the attorney source of the advertising until the final few seconds. PMID- 26237983 TI - The Legal and Regulatory Status of Biosimilars: How Product Naming and State Substitution Laws May Impact the United States Healthcare System. AB - Alongside the constitutional controversy ultimately addressed by the Supreme Court, the colossal Patient Protection and Affordable Care Act (ACA) ushered in a new paradigm for regulation of biologics by the Food and Drug Administration (FDA). Nestled within the expansive ACA, the Biologics Price Competition and Innovation Act (BPCIA) set forth an abbreviated pathway to market for "biosimilar" and "interchangeable" biological products. While the current BPCIA implementation debate focuses chiefly on the scope of scientific and technical assessments by the FDA and the effect on the emergent biosimilar industry, two issues will prove essential for determinations of access to and costs of the resulting products: how the biosimilar and interchangeable biosimilar biologics are to be named, and whether pharmacist substitution is appropriate for products the FDA deems interchangeable. This article examines the current debate surrounding the use of nonproprietary names for biosimilar biologics, as well as state efforts to reconcile automatic substitution laws for the eventual products. In particular, the article addresses the implications for patients and the United States health care system, highlighting the potential negative effect on anticipated cost-savings, hindrances for effective tracking and reporting of adverse events, and a general lack of consistency in state laws. PMID- 26237984 TI - Medical Evidence and Expertise in Abortion Jurisprudence. AB - For another thing, the division of medical opinion about the matter at most means uncertainty, a factor that signals the presence of risk, not its absence. That division here involves highly qualified knowledgeable experts on both sides of the issue.--Stenberg v. Carhart, 2000. While we find no reliable data to measure the phenomenon, it seems unexceptionable to conclude some women come to regret their choice to abort the infant life they once created and sustained.--Gonzales v. Carhart, 2007. PMID- 26237985 TI - Priority Setting, Cost-Effectiveness, and the Affordable Care Act. AB - The Affordable Care Act (ACA) may be the most important health law statute in American history, yet much of the most prominent legal scholarship examining it has focused on the merits of the court challenges it has faced rather than delving into the details of its priority-setting provisions. In addition to providing an overview of the ACA's provisions concerning priority setting and their developing interpretations, this Article attempts to defend three substantive propositions. First, I argue that the ACA is neither uniformly hostile nor uniformly friendly to efforts to set priorities in ways that promote cost and quality. Second, I argue that the ACA does not take a single, unified approach to priority setting; rather, its guidance varies depending on the aspect of the healthcare system at issue (Patient Centered Outcomes Research Institute, Medicare, essential health benefits) and the factors being excluded from priority setting (age, disability, life expectancy). Third, I argue that cost effectiveness can be achieved within the ACA's constraints, but that doing so will require adopting new approaches to cost-effectiveness and priority setting. By limiting the use of standard cost-effectiveness analysis, the ACA makes the need for workable rivals to cost-effectiveness analysis a pressing practical concern rather than a mere theoretical worry. PMID- 26237986 TI - Do You Own Your 3D Bioprinted Body? Analyzing Property Issues at the Intersection of Digital Information and Biology. PMID- 26237987 TI - The Medical Marijuana Catch-22: How the Federal Monopoly on Marijuana Research Unfairly Handicaps the Rescheduling Movement. PMID- 26237988 TI - APPROVED: Revisions to Requirements for Organizations Providing Diagnostic Imaging Services. PMID- 26237989 TI - Dental Clinic Surveys: Clarification Regarding Infection Control and Environment of Care. PMID- 26237990 TI - APPROVED: Acute Stroke-Ready Hospital Advanced Certification Program. PMID- 26237991 TI - Clarifications and Expectations. EC Dashboard Keeps Compliance Front and Center. Step-by-Step Tips for Creating and Using Valuable Dashboard. PMID- 26237992 TI - Thromboelastography--does it impact blood component transfusion in pediatric heart surgery? AB - BACKGROUND: The administration of blood products during pediatric cardiac surgery is common. We sought to determine if thromboelastography (TEG) is a cost effective tool to reduce blood product transfusion in open pediatric cardiac surgery. MATERIALS AND METHODS: A retrospective case-control study was undertaken for 150 pediatric cardiac patients requiring cardiopulmonary bypass from January 2010-May 2012, in a University-affiliated pediatric hospital. Fifty sequential patients operated on when TEG was used were compared with 100 control patients before TEG availability. Groups were matched 2:1 for age and risk adjustment for congenital heart surgery score. Blood product utilization was compared between groups, as were outcomes metrics such as postoperative complications, length of stay, and hospital costs of transfusions. RESULTS: Demographic variables, risk adjustment for congenital heart surgery score classifications, and cardiopulmonary bypass times were similar between groups. Red cell and plasma transfusion were comparable between groups. TEG patients saw a substantial reduction in the administration of platelet (1 versus 2.2 U; P < 0.0001) and cryoprecipitate (0.7 versus 1.7 U; P < 0.0001) transfusions. A greater than 50% reductions in hospital costs of platelet ($595 versus $1309) and cryoprecipitate ($39 versus $94) transfusions were observed in the TEG group. Mortality, length of stay, ventilator requirements, postoperative bleeding, and thrombotic events were equivalent. CONCLUSIONS: Intraoperative TEG use reduced platelet and cryoprecipitate transfusions without an increase in postoperative complications. TEG is a cost-effective method to direct blood product replacement. PMID- 26237993 TI - Contralateral adrenal abnormalities in Conn's syndrome. AB - BACKGROUND: During the course of evaluation for primary hyperaldosteronism, cross sectional imaging is obtained in efforts to identify patients with an aldosterone producing adenoma (APA). A subset of these patients will have a synchronous, contralateral adrenal abnormality. Adrenal vein sampling (AVS) further guides clinical decision making by identifying unilateral (APA) versus bilateral hypersecretion. In the subset of patients with contralateral adrenal abnormalities, it is unclear how this affects the durability of an adrenalectomy for APA. This study characterizes this group of patients to assess the efficacy of surgical intervention. METHODS: A retrospective review of patients undergoing adrenalectomy for APA based on AVS at a university practice. Preoperative and postoperative patient characteristics, laboratory evaluations, imaging results, and final pathology were noted. RESULTS: From 2000 to 2011, 103 patients with APA underwent unilateral adrenalectomy. Eighteen patients (17%) had discordant results between AVS and imaging. Most of these patients were male (78%), and the mean age was 57 +/- 13 y. Median duration of follow-up was 3.5 y [1 y, 6 y]. All patients with initial hypokalemia were rendered normokalemic after the operation. Four patients increased their antihypertensive regimen during the follow-up period. These patients all had nodular hyperplasia on final pathology. CONCLUSIONS: In patients with bilateral adrenal abnormalities who have undergone unilateral adrenalectomy for primary hyperaldosteronism, patients with clear APAs on final pathology appear to have durable outcomes after resection. Conversely, nodular hyperplasia on final pathology may be a risk factor for ongoing aldosterone hypersecretion. An algorithm for biochemical surveillance in this subset of patients should be considered. PMID- 26237995 TI - USP46: a new piece of the memory puzzle? AB - Long-term potentiation (LTP) and long-term depression (LTD) are crucial for synaptic plasticity, and are driven by AMPA receptor (AMPAR) trafficking. Recent findings indicate that the ubiquitin-proteasome system, the main protein degradation machinery of the cell, plays a significant role in memory formation by regulating the induction and maintenance of LTP. Although previously suggested as a possibility, deubiquitination of mammalian AMPARs had not been demonstrated, and the search for an enzyme that mediates the processes continued. This Editorial Highlight discusses the relevance of a study published in the current issue of Journal of Neurochemistry, in which the authors Huo and collaborators now identified ubiquitin-specific peptidase 46 (USP46) as a specific AMPAR deubiquitinase. PMID- 26237994 TI - People with insomnia: experiences with sedative hypnotics and risk perception. AB - BACKGROUND: Sedative hypnotics form an important part of managing insomnia and are recommended for short-term use. It is standard practice for clinicians to inform the patient to use medications only 'when required', but the use of these medications is often chronic. Little is known about the impact of standard labelling/instructions on promoting appropriate medication use for managing insomnia. OBJECTIVE: To explore patient medication-taking beliefs, experiences and behavioural practices relating to the use of pharmacological/complementary sleep aids for insomnia. SETTING AND PARTICIPANTS: Specialist sleep/psychology clinics and the general community in Sydney, Australia. METHOD: Semi-structured interviews were conducted with 51 people with insomnia using a schedule of questions to gauge their experiences, beliefs and current practices relating to insomnia medication use. Interviews were audio-recorded, transcribed verbatim and subjected to Framework Analysis to identify emergent themes. RESULTS: Participants held distinctive views about the safety and efficacy of complementary and pharmacological agents but do not intuitively turn to medications to resolve their sleep complaint. Medication use was affirmed through tangible medication-taking cues due to the ambivalence in current instructions and labelling. Practices such as dosage modification, medication substitution and delaying medication use might be important drivers for psychological dependence. CONCLUSION: Current labelling and instructions do not necessarily promote the quality use of sedative hypnotics due to the variability in patient interpretations. Clarifying the timing, quantity and frequency of medication administration as well as insomnia symptom recognition would play a significant role in optimizing the role of pharmacotherapy in the management of insomnia. PMID- 26237996 TI - Novel Approach to Three-Dimensional Echocardiographic Quantification of Right Ventricular Volumes and Function from Focused Views. AB - BACKGROUND: Echocardiographic assessment of the right ventricle is difficult because of its complex shape. Three-dimensional echocardiographic (3DE) imaging allows more accurate and reproducible analysis of the right ventricle than two dimensional methodology. However, three-dimensional volumetric analysis has been hampered by difficulties obtaining consistently high-quality coronal views, required by the existing software packages. The aim of this study was to test a new approach for volumetric analysis without coronal views by using instead right ventricle-focused three-dimensional acquisition with multiple short-axis views extracted from the same data set. METHODS: Transthoracic 3DE and cardiovascular magnetic resonance (CMR) images were prospectively obtained on the same day in 147 patients with wide ranges of right ventricular (RV) size and function. RV volumes and ejection fraction were measured from 3DE images using the new software and compared with CMR reference values. Comparisons included linear regression and Bland-Altman analyses. Repeated measurements were performed to assess measurement variability. RESULTS: Sixteen patients were excluded because of suboptimal image quality (89% feasibility). RV volumes and ejection fraction obtained with the new 3DE technique were in good agreement with CMR (end diastolic volume, r = 0.95; end-systolic volume, r = 0.96; ejection fraction, r = 0.83). Biases were, respectively, -6 +/- 11%, 0 +/- 15%, and -7 +/- 17% of the mean measured values. In a subset of patients with suboptimal 3DE images, the new analysis resulted in significantly improved accuracy against CMR and reproducibility, compared with previously used coronal view-based techniques. The time required for the 3DE analysis was approximately 4 min. CONCLUSIONS: The new software is fast, reproducible, and accurate compared with CMR over a wide range of RV size and function. Because right ventricle-focused 3DE acquisition is feasible in most patients, this approach may be applicable to a broader population of patients who can benefit from RV volumetric assessment. PMID- 26237997 TI - Comment on: Technical factors associated with anastomotic leak after Roux-en-Y gastric bypass. PMID- 26237998 TI - Ab Initio Molecular Dynamics Study on the Interactions between Carboxylate Ions and Metal Ions in Water. AB - The interaction between a carboxylate anion (deprotonated propanoic acid) and the divalent Mg(2+), Ca(2+), Sr(2+), Ba(2+) metal ions is studied via ab initio molecular dynamics. The main focus of the study is the selectivity of the carboxylate-metal ion interaction in aqueous solution. The interaction is modeled by explicitly accounting for the solvent molecules on a DFT level. The hydration energies of the metal ions along with their diffusion and mobility coefficients are determined and a trend correlated with their ionic radius is found. Subsequently, a series of 16 constrained molecular dynamics simulations for every ion is performed, and the interaction free energy is obtained from thermodynamic integration of the forces between the metal ion and the carboxylate ion. The results indicate that the magnesium ion interacts most strongly with the carboxylate, followed by calcium, strontium, and barium. Because the interaction free energy is not enough to explain the selectivity of the reaction observed experimentally, more detailed analysis is performed on the simulation trajectories to understand the steric changes in the reaction complex during dissociation. The solvent dynamics appear to play an important role during the dissociation of the complex and also in the observed selectivity behavior of the divalent ions. PMID- 26237999 TI - The potential of aerobic exercise training in mitigating cardiovascular side effects of cancer therapy. PMID- 26238000 TI - Self-efficacy and relevance of bioscience for nursing, midwifery and healthcare students. AB - AIMS AND OBJECTIVES: To examine nursing, midwifery and allied healthcare students' self-efficacy for science, perceived relevance of bioscience to their studies and expectations for academic success and the changes that occur after completing first-year introductory bioscience subjects. BACKGROUND: Bioscience is a foundation subject that underpins nursing, midwifery and other allied health courses. Bioscience subjects continue to be source of anxiety for students in those courses. Raising students' self-efficacy and perceptions of the importance and utility of bioscience to practice may be a way of ameliorating students' expectations and confidence in this subject area. DESIGN: A prospective correlational survey design. METHODS: Students were surveyed in the first semester of first year and the commencement of the second year. Students were drawn from nursing, midwifery, public health and allied health courses. The surveys contained scales for self-efficacy for science, perceived relevance of bioscience to their course and personal expectations for success in their bioscience subject. RESULTS: Ninety-seven and 82 students completed survey 1 and 2 respectively. Twenty-six surveys could be matched. Self-efficacy increased from survey 1 to survey 2, but expectations for academic success and task value, a measure for relevance, were lower. This was statistically significant for the matched pair sample. Using a mean split, students with high self-efficacy valued science more and had higher expectations for success in their bioscience courses than those with low self-efficacy. CONCLUSION: Academic success in bioscience, confidence undertaking science tasks and perceiving bioscience as relevant to their course are interwoven concepts that are important for nursing, midwifery and applied healthcare students and ultimately for their professional practice. RELEVANCE TO CLINICAL PRACTICE: Literature indicates practitioners may not feel confident in their bioscience knowledge. Assisting undergraduate students to develop confidence in and perceive the relevance of bioscience to their discipline may ultimately impact on clinical practice. PMID- 26238001 TI - Incorrect diagnosis of Clostridium difficile infection in a university hospital in Japan. AB - Physicians often fail to suspect Clostridium difficile infection (CDI) and many microbiology laboratories use suboptimal diagnostic techniques. To estimate the extent of and reasons for incorrect diagnosis of CDI in Japan, we investigated toxigenic C. difficile isolated from all stool culture samples and clinical course. Over a 12-month period in 2010, all stool culture samples (n = 975) submitted from inpatients in a university hospital in Japan were cultured for C. difficile and routine microbiological testing was conducted. In total, 177 C. difficile isolates were recovered, and 127 isolates were toxigenic. Among the toxin-A-positive/toxin-B-positive isolates, 12 were also positive for the binary toxin gene. However, clinically important ribotypes, such as 027 and 078, were not identified. A total of 58 (45.7%) cases with toxigenic C. difficile had unformed stool, and the incidence CDI was 1.6 cases per 10,000 patient-days. Of these 58 cases, 40 were not diagnosed in routine testing due to a lack of clinical suspicion (24.1%, 14/58) or a negative C. difficile toxin assay result (44.8%, 26/58). A stool toxin assay was performed in 54 patients (78.2%, 54/69) who did not have unformed stool. The present study demonstrated that a significant number of CDI cases in Japan might be overlooked or misdiagnosed in clinical practice due to a lack of clinical suspicion and limitations of microbiological testing for CDI in Japan. Providing education to promote awareness of CDI among physicians is important to improve the accuracy of diagnosis in Japan. PMID- 26238002 TI - Shallow Groundwater Conveyance of Geologically Derived Contaminants to Urban Creeks in Southern California. AB - In California alone, there are currently over 200 instances on the EPA's list of impaired water bodies with unknown sources of excessive salinity or trace contaminants. This investigation focuses on Orange County, CA, a region that has undergone extensive hydrological modification, relies heavily on imported water for municipal supply, and has come under regulatory scrutiny for elevated TDS, sulfate, Cd, Ni, and Se. A survey of shallow groundwater weeps and springs, discharging directly to urban creeks, reveals high concentrations of TDS, sulfate, Cd, Ni, Zn, Cu, and Se that are often far in excess of water quality standards. Isotopic (delta(34)S and delta(18)O) and geochemical evidence indicate that the source of sulfate and TDS is weathering of sulfide minerals in the Capistrano Formation marine mudstone and dissolution of secondary minerals formed during past periods of sulfide oxidation, rather than anthropogenic inputs. The relative availability of carbonate minerals along the flow path appears to control pH, which then influences trace metal mobility to surface waters. Stable isotopes of H2O indicate that despite widespread use of imported water, meteoric recharge dominates shallow groundwater inputs with municipal sources contributing only 13-29% of discharge. These findings highlight the importance of understanding the hydrogeological setting to properly apportion contaminant sources and conveyances. PMID- 26238003 TI - Mechanical tradeoffs associated with glenosphere lateralization in reverse shoulder arthroplasty. AB - BACKGROUND: Scapular notching in reverse shoulder arthroplasty occurs in up to 97% of patients. Notching is associated with decreased strength and reduced motion and may lead to long-term failure due to polyethylene wear. Many implant systems lateralize the glenosphere to address scapular notching, but the mechanical tradeoffs of lateralization have not been rigorously evaluated. We hypothesized that lateralization would decrease bony impingement but also decrease the mechanical advantage of the deltoid. METHODS: Finite element models were created using the same implants with different amounts of glenoid lateralization: 5 mm of medialization to replicate glenoid erosion, as well as 2.5, 5, 7.5, and 10 mm of lateralization. Tests were performed with static and dynamic scapulae for motion in either the coronal or scapular plane. The angle of impingement between the scapula and the humeral polyethylene was recorded, as was the deltoid force required to elevate the arm. RESULTS: Increasing lateralization decreased impingement while increasing the deltoid force required to elevate the arm. Differences were found between the static and dynamic scapulae, with the dynamic scapula model having increased humeral adduction before impinging. The impingement angle was also substantially affected by the bony prominences on the inferior scapula, showing how individual bony anatomy can affect impingement. CONCLUSION: Lateralization is effective in increasing impingement-free range of motion but also increases the deltoid force required to perform identical tasks. In addition, impingement is determined by scapular motion, which should be included in all shoulder models. PMID- 26238004 TI - The ulnar greater sigmoid notch "coverage angle": bone and cartilage contribution. Magnetic resonance imaging anatomic study on 78 elbows. AB - BACKGROUND: To study the degree of coverage provided by the greater sigmoid notch (GSN) to the humeral trochlea, as well as the contribution of the olecranon and coronoid process cartilage tips to this angle, and its variations. METHODS: We recruited 39 healthy volunteers, comprising 19 women and 20 men, with a mean age of 28 years (range, 21-32 years). High-definition magnetic resonance images were obtained for the right and left elbows. Four angles were measured on the sagittal plane passing through the coronoid and olecranon tips: angle A, identified by 2 lines from the trochlea center to the olecranon bone-cartilage junction and olecranon cartilage tip; angle B, identified by 2 lines from the trochlea center to the olecranon and coronoid bone-cartilage junction; angle C, identified by 2 lines from the trochlea center to the coronoid bone-cartilage junction and coronoid cartilage tip; and GSN coverage angle (GSN-ca), defined as the sum of angles A, B, and C. Pearson correlation tests, t tests, and intraclass correlation coefficients were used for statistical analyses. RESULTS: The mean angle A, angle B, and angle C values were 6 degrees (range, 2 degrees -12 degrees ), 182 degrees (range, 153 degrees -204 degrees ), and 9 degrees (range, 2 degrees -16 degrees ), respectively. No correlations were found between these 3 angles. The mean GSN-ca was 198 degrees (range, 167 degrees -222 degrees ), and the GSN-ca was less than 180 degrees in 8% of the cases. No significant differences emerged for side or gender or for total length of the ulna. CONCLUSION: The GSN showed significantly different shapes on the sagittal plane that we defined as closed type when the GSN-ca was greater than 180 degrees (92%) and as open type when the GSA-ca was less than 180 degrees (8%). The cartilage tip contribution varied and was not correlated with that of bone. PMID- 26238006 TI - [Angiosome-directed revascularization of critical limb ischaemia]. AB - Critical limb ischaemia is the major cause of amputation in the developed world. When performing revascularization of the lower limb, guidelines recommend grafting of the "least diseased distal artery with the best continuous run-off to the ankle/foot... regardless of location" often implying indirect perfusion of the ischaemic area through collaterals. An alter-native strategy, called the "angiosome model", advocates a strategy which provides blood supply directly to the ischaemic area. This paper reviews the current evidence of indirect versus angiosome-directed revascularization of the lower limb. PMID- 26238007 TI - [Cutaneous lupus erythematosus]. AB - Cutaneous lupus erythematosus (LE) is an autoimmune disease. The most common clinical forms are acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE) and discoid LE (DLE). Cutaneous LE, mainly ACLE, can be the first sign of systemic LE (SLE). DLE and SCLE are less associated with development of SLE, however, up to 85% of patients with SLE have cutaneous manifestations. The aetiology is multifactorial. Drugs such as proton pump inhibitors can induce SCLE, while UV light and smoking can worsen the lesions. Treatment includes preventive strategies in addition to topical steroids and systemic hydroxychloroquine. PMID- 26238005 TI - Assessment of glenoid chondral healing: comparison of microfracture to autologous matrix-induced chondrogenesis in a novel rabbit shoulder model. AB - BACKGROUND: Management of glenohumeral arthrosis in young patients is a considerable challenge, with a growing need for non-arthroplasty alternatives. The objectives of this study were to develop an animal model to study glenoid cartilage repair and to compare surgical repair strategies to promote glenoid chondral healing. METHODS: Forty-five rabbits underwent unilateral removal of the entire glenoid articular surface and were divided into 3 groups--untreated defect (UD), microfracture (MFx), and MFx plus type I/III collagen scaffold (autologous matrix-induced chondrogenesis [AMIC])--for the evaluation of healing at 8 weeks (12 rabbits) and 32 weeks (33 rabbits) after injury. Contralateral shoulders served as unoperated controls. Tissue assessments included 11.7-T magnetic resonance imaging (long-term healing group only), equilibrium partitioning of an ionic contrast agent via micro-computed tomography (EPIC-MUCT), and histologic investigation (grades on International Cartilage Repair Society II scoring system). RESULTS: At 8 weeks, x-ray attenuation, thickness, and volume did not differ by treatment group. At 32 weeks, the T2 index (ratio of T2 values of healing to intact glenoids) was significantly lower for the MFx group relative to the AMIC group (P = .01) whereas the T1rho index was significantly lower for AMIC relative to MFx (P = .01). The micro-computed tomography-derived repair tissue volume was significantly higher for MFx than for UD. Histologic investigation generally suggested inferior healing in the AMIC and UD groups relative to the MFx group, which exhibited improvements in both integration of repair tissue with subchondral bone and tidemark formation over time. DISCUSSION: Improvements conferred by AMIC were limited to magnetic resonance imaging outcomes, whereas MFx appeared to promote increased fibrous tissue deposition via micro-computed tomography and more hyaline-like repair histologically. The findings from this novel model suggest that MFx promotes biologic resurfacing of full-thickness glenoid articular injury. PMID- 26238008 TI - [Diagnostic imaging techniques for hepatic metastases from colorectal cancer]. AB - Hepatic metastases (HM) are amongst the most important prognostic factors in patient survival from colorectal cancer. The diagnostic imaging techniques for accurate detection and characterization of colorectal metastases are therefore vital. In a review of the literature, MRI showed the highest sensitivity for detection of HM lesions < 1 cm, but the amount of MR scanners is insufficient. Contrast-enhanced ultrasound and computed tomography have similar sensitivity for detection of HM, but each method also have limitation such as operator dependency or enhanced risk of cancer due to ionizing radiation. PMID- 26238009 TI - [Pragmatic trials are important to medical research]. AB - High-quality scientific evidence may be inadequate to support real world decision making. Assessment of applicability and generalizability of medical scientific evidence is needed for the practitioner. Often, large differences between trial participants and actual end-users of interventions exist. We present the difference between efficacy and effectiveness in connection with trial design and encourage critical evaluation of external validity. Pragmatic design of trials can be considered a preferred choice to limit the prevailing gap between current evidence and practice. PMID- 26238010 TI - PET-based dose painting in non-small cell lung cancer: Comparing uniform dose escalation with boosting hypoxic and metabolically active sub-volumes. AB - BACKGROUND AND PURPOSE: We compared two imaging biomarkers for dose-escalation in patients with advanced non-small cell lung cancer (NSCLC). Treatment plans boosting metabolically active sub-volumes defined by FDG-PET or hypoxic sub volumes defined by HX4-PET were compared with boosting the entire tumour. MATERIALS AND METHODS: Ten NSCLC patients underwent FDG- and HX4-PET/CT scans prior to radiotherapy. Three isotoxic dose-escalation plans were compared per patient: plan A, boosting the primary tumour (PTVprim); plan B, boosting sub volume with FDG >50% SUVmax (PTVFDG); plan C, boosting hypoxic volume with HX4 tumour-to-background >1.4 (PTVHX4). RESULTS: Average boost volumes were 507 +/- 466 cm(3) for PTVprim, 173 +/- 127 cm(3) for PTVFDG and 114 +/- 73 cm(3) for PTVHX4. The smaller PTVHX4 overlapped on average 87 +/- 16% with PTVFDG. Prescribed dose was escalated to 87 +/- 10 Gy for PTVprim, 107 +/- 20 Gy for PTVFDG, and 117 +/- 15 Gy for PTVHX4, with comparable doses to the relevant organs-at-risk (OAR). Treatment plans are available online (https://www.cancerdata.org/10.1016/j.radonc.2015.07.013). CONCLUSIONS: Dose escalation based on metabolic sub-volumes, hypoxic sub-volumes and the entire tumour is feasible. Highest dose was achieved for hypoxia plans, without increasing dose to OAR. For most patients, boosting the metabolic sub-volume also resulted in boosting the hypoxic volume, although to a lower dose, but not vice versa. PMID- 26238011 TI - The descriptive epidemiology of daily sitting time as a sedentary behavior in multiple sclerosis. AB - BACKGROUND: Sedentary behavior is pervasive among the general population, but little is known about the epidemiology of this behavior in multiple sclerosis (MS). OBJECTIVE: We compared self-reported sitting time (ST), as a measure of sedentary behavior, between persons with MS and healthy controls, and examined ST across demographic and clinical characteristics of those with MS. METHODS: 1081 persons with MS and 150 healthy controls self-reported ST based on the International Physical Activity Questionnaire (IPAQ), and completed the Godin Leisure-Time Exercise Questionnaire (GLTEQ) and a demographic/clinical scale. Data were analyzed using analysis of variance, bivariate correlations, and stepwise regression analysis. RESULTS: There was not a significant difference in ST between persons with MS and controls (F = 0.01, p = 0.95), and persons with MS reported 450.9 +/- 220.6 min of ST per day. ST was weakly associated with GLTEQ scores in MS (r = -0.21, p < 0.001), but not controls. ST significantly differed as functions of marital status, physical activity level, employment status, education, and degree of ambulatory impairment among those with MS. CONCLUSIONS: ST does not differ between persons with MS and healthy controls, but those with MS report a large amount of this sedentary behavior that is potentially an independent correlate of health and disease outcomes. PMID- 26238012 TI - The enigma of the clandestine association between chloroquine and HIV-1 infection. AB - OBJECTIVES: The antimalarial drug chloroquine (CQ) dampens the immune system and is used in the treatment of autoimmune disorders. CQ also shows antiviral activity against nonenveloped and enveloped viruses, including HIV-1. Persistent immune activation in chronic HIV-1infection leads to CD4 T-cell depletion. CQ is envisioned to attenuate immune activation and virus activity in HIV-1-infected patients. The role of CQ in immune activation and virus activity is discussed here. METHODS: To elucidate the effect of CQ on immune activation, a retrospective review of published clinical trials, in vivo experimental studies in animals, and the most relevant in vitro observations in HIV-1-infected cells, together with observations from our own laboratory studies, was carried out and the findings discussed. RESULTS: In a few clinical studies and animal experiments, CQ was ineffective in decreasing immune activation and HIV-1 infection. In vitro, CQ markedly increased HIV-1 infection in astrocytes and other non-CD4 cells. CONCLUSIONS: The use of CQ in HIV-1-infected patients is questionable. The evidence for a dampening of immune activation by CQ is inconclusive. PMID- 26238013 TI - Association of factor V Leiden, Janus kinase 2, prothrombin, and MTHFR mutations with primary Budd-Chiari syndrome in Egyptian patients. AB - BACKGROUND AND AIM: Budd-Chiari syndrome (BCS) is defined as obstruction of hepatic venous outflow anywhere from the small hepatic veins to the suprahepatic inferior vena cava. The pathogenesis of BCS is still not fully understood. This study aimed to evaluate the association of factor V Leiden (FVL), Janus kinase 2 (JAK2), prothrombin, and methylene tetrahydrofolate reductase (MTHFR) mutations with primary BCS. METHODS: The study was carried out on 35 patients with primary BCS and 15 age and gender matched healthy individuals as a control group. Genotyping of FVL, prothrombin, and MTHFR mutations was determined by GENEQUALITY AB-THROMBO TYPE kit based on the reverse hybridization principle. JAK2 mutation was determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: There was a statistically significant difference between patients and controls regarding FVL, MTHFR C677T, and MTHFR A1298C mutations with odds ratio of 1.83, 2.0, and 1.79, respectively. Hetero MTHFR C677T, hetero FVL, and hetero MTHFR A1298C were the most common etiological factors being responsible for 57.1, 42.9, and 42.9% of primary BCS cases, respectively. CONCLUSION: It could be concluded that BCS is a multifactorial disease; in the current study, MTHFR C677T mutation was the most common cause of disease. Identification of one cause of BCS should not eliminate investigations for detection of other etiological factors. PMID- 26238014 TI - Non-invasive Assessment and Symptomatic Improvement of the Obstructed Nose (NASION): a physiology-based patient-centred approach to treatment selection and outcomes assessment in nasal obstruction. AB - OBJECTIVES: To evaluate the impact of selecting treatment for nasal obstruction on the basis of a structured physiology-based assessment protocol on patient outcomes. DESIGN: Prospective longitudinal study. SETTING: District general hospital. PARTICIPANTS: A population of 71 patients with a mean age of 33 years, containing 36 males, presented with nasal obstruction for consideration of nasal surgery. All patients underwent a structured clinical assessment, skin prick allergy testing and oral-nasal flow-volume loop examination. Fifty-one patients completed the follow-up, and mean follow-up was 11 months. MAIN OUTCOME MEASURES: NOSE, SNOT-22 and NASION scales. RESULTS: Of the 51 patients who completed follow up, six had conservative treatment, 28 had septal/turbinate surgery, and 17 underwent nasal valve surgery. Mean NOSE score fell from 68 +/- 18 to 39 +/- 31 following the treatment. Mean SNOT-22 score fell from 47 +/- 20 to 29 +/- 26 following the treatment. The difference between pre-treatment and post-treatment NOSE and SNOT-22 scores were statistically significant. Success rate of septal/turbinate surgery in patients without nasal allergy was 88%, and this fell to 42% in patients undergoing septal/turbinate surgery who also had nasal allergy. Presence of nasal allergy was the only independent predictor of treatment failure. Patients with nasal valve surgery reported significantly greater symptomatic improvement following surgery. The newly formed NASION scale demonstrated internal consistency with a Cronbach alpha of 0.9 and excellent change-responsiveness and convergent validity with correlation coefficients of 0.64 and 0.77 against treatment-related changes in SNOT-22 and NOSE scales, respectively. CONCLUSIONS: Successful surgical outcomes can be achieved with the use of a structured history, clinical evaluation and physiological testing. Flow volume loops can help elucidate the cause of nasal obstruction. The newly formed NASION scale is a validated retrospective single time-point patient outcome measure. PMID- 26238015 TI - Sphingosine-1-phosphate receptor 1 (S1PR1) expression in non-muscle invasive urothelial carcinoma: Association with poor clinical outcome and potential therapeutic target. AB - AIM: Sphingosine-1-phosphate receptor 1 (S1PR1) promotes tumour cell survival, invasion, anti-apoptosis, metastasis and radio/chemo-resistance in various cancers. However, the expression pattern and prognostic implications of S1PR1 in urothelial carcinoma remain unclear and thus were addressed here. METHODS: Tissue microarrays composed of 395 initially diagnosed and transurethral resected urothelial carcinomas of the urinary bladder were immunostained for S1PR1 and phosphor-signal transducer and activator of transcription 3 (pSTAT3). S1PR1 expression was analysed according to clinicopathological features, expression of several anti-apoptosis/proliferation-related markers and patient's survival. RESULTS: S1PR1 positivity was observed in 45.3% of urothelial carcinomas. Among patients with non-muscle invasive urothelial carcinoma (NMIC), S1PR1 positivity was associated with higher grade (P<0.001), higher subepithelial invasive component (P=0.006), lower papillary component (P=0.002), presence of metastasis (P=0.042) and high cancer-specific death (P<0.001). S1PR1 expression was correlated with pSTAT3 (P<0.001), survivin (P=0.008) and Ki-67 (P<0.001) expression. S1PR1 positivity predicted a shorter cancer-specific survival (CSS) in NMICs (P<0.001) and stage T1/high grade (T1HG) tumours (P=0.002). The Cox multivariate model was composed of S1PR1, survivin, lymphovascular invasion and age, and C-index was 0.781. S1PR1 positivity was correlated with shorter CSS in p53-positive T1HG carcinoma (P=0.003) in contrast to p53-negative T1HG carcinoma (P=0.205). In p53-overexpressing NMIC, S1PR1 was the only variable of the survival model and the C-index was 0.719. CONCLUSIONS: S1PR1 expression was associated with unfavourable clinicopathological features and the expression of several anti-apoptosis/proliferation-related markers in urothelial carcinoma. S1PR1 serves as an independent predictor of cancer-specific death in NMIC. The model including S1PR1 showed highly accurate prediction for CSS in NMIC patients regardless of the modality of adjuvant therapy. PMID- 26238016 TI - Molecular effects of the phosphatidylinositol-3-kinase inhibitor NVP-BKM120 on T and B-cell acute lymphoblastic leukaemia. AB - BACKGROUND: Constitutive activation of the PI3K pathway in T cell acute lymphoblastic leukaemia (T-ALL) has been reported and in a mouse model, PI3K activation, together with MYC, cooperates in Burkitt lymphoma (BL) pathogenesis. We investigated the effects of NVP-BKM120, a potent pan-class I PI3K inhibitor, in lymphoblastic leukaemia cell lines. METHODS: Effects of NVP-BKM120 on cell viability, clonogenicity, apoptosis, cell cycle, cell signalling and autophagy were assessed in vitro on T-ALL (Jurkat and MOLT-4) and BL (Daudi and NAMALWA) cell lines. RESULTS: NVP-BKM120 treatment decreased cell viability and clonogenic growth in all tested cells. Moreover, the drug arrested cell cycling in association with a decrease in Cyclin B1 protein levels, and increased apoptosis. Immunoblotting analysis of cells treated with the drug revealed decreased phosphorylation, in a dose-dependent manner, of AKT, mTOR, P70S6K and 4EBP1, with stable total protein levels. Additionally, we observed a dose-dependent decrease in BAD phosphorylation, in association with augmented BAX:BCL2 ratio. Quantification of autophagy showed a dose-dependent increase in acidic vesicular organelles in all cells tested. CONCLUSION: In summary, our present study establishes that NVP-BKM120 presents an effective antitumour activity against T ALL and BL cell lines. PMID- 26238018 TI - The role and function of acceptance and commitment therapy and behavioral flexibility in pain management. PMID- 26238017 TI - Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma. AB - BACKGROUND: We compared survival outcomes and risk of venous thromboembolism (VTE) among patients with advanced and early-stage ovarian clear cell carcinoma (OCCC) and serous ovarian carcinoma (SOC), as well as potential links with interleukin-6 (IL-6) levels. METHODS: A multicenter case-control study was conducted in 370 patients with OCCC and 938 with SOC. In a subset of 200 cases, pretreatment plasma IL-6 levels were examined. FINDINGS: Patients with advanced OCCC had the highest 2-year cumulative VTE rates (advanced OCCC 43.1%, advanced SOC 16.2%, early-stage OCCC 11.9% and early-stage SOC 6.4%, P<0.0001) and the highest median levels of IL-6 (advanced OCCC 17.8 pg/mL, advanced SOC 9.0 pg/mL, early-stage OCCC 4.2 pg/mL and early-stage SOC 5.0 pg/mL, P=0.006). Advanced OCCC (hazard ratio [HR] 3.38, P<0.0001), thrombocytosis (HR 1.42, P=0.032) and elevated IL-6 (HR 8.90, P=0.046) were independent predictors of VTE. In multivariate analysis, patients with advanced OCCC had significantly poorer 5 year progression-free and overall survival rates than those with advanced SOC (P<0.01), and thrombocytosis was an independent predictor of decreased survival outcomes (P<0.01). Elevated IL-6 levels led to poorer 2-year progression-free survival rates in patients with OCCC (50% versus 87.5%, HR 4.89, P=0.016) than in those with SOC (24.9% versus 40.8%, HR 1.40, P=0.07). INTERPRETATION: Advanced OCCC is associated with an increased incidence of VTE and decreased survival outcomes, which has major implications for clinical management of OCCC. PMID- 26238019 TI - A survey of conservation of sea spider and Drosophila Hox protein activities. AB - Hox proteins have well-established functions in development and evolution, controlling the final morphology of bilaterian animals. The common phylogenetic origin of Hox proteins and the associated evolutionary diversification of protein sequences provide a unique framework to explore the relationship between changes in protein sequence and function. In this study, we aimed at questioning how sequence variation within arthropod Hox proteins influences function. This was achieved by exploring the functional impact of sequence conservation/divergence of the Hox genes, labial, Sex comb reduced, Deformed, Ultrabithorax and abdominalA from two distant arthropods, the sea spider and the well-studied Drosophila. Results highlight a correlation between sequence conservation within the homeodomain and the degree of functional conservation, and identify a novel functional domain in the Labial protein. PMID- 26238021 TI - MicroRNA-128a, BMI1 polycomb ring finger oncogene, and reactive oxygen species inhibit the growth of U-87 MG glioblastoma cells following exposure to X-ray radiation. AB - Radiotherapy is an important therapeutic strategy for the treatment of numerous types of malignant tumors, including glioma. However, radioresistance and anti apoptotic mechanisms decrease the efficacy of radiotherapy in many patients with glioma. BMI1 polycomb ring finger oncogene (Bmi-1) is an oncogene associated with radioresistance in tumor cells. MicroRNA (miRNA)-128a is a brain-specific miRNA, which suppresses Bmi-1 expression. The present study investigated the effects of various radiation intensities on U-87 MG glioma cells, as well as the role of reactive oxygen species (ROS), Bmi-1, and miRNA-128a in the cellular response to radiotherapy. The response of U-87 MG cells following exposure to X-ray radiation was assessed using a cell growth curve and inhibition ratio. Cell cycle distribution and the levels of intracellular ROS were evaluated by flow cytometry. The mRNA expression levels of Bmi-1 and those of miRNA-128a in U-87 MG cells exposed to X-ray radiation were evaluated by reverse transcription quantitative polymerase chain reaction. X-ray radiation did not decrease the number of U-87 MG cells; however, it did inhibit cellular growth in a dose dependent manner. Following exposure to X-ray radiation for 24 h, cell cycle distribution was altered, with an increase in the number of cells in G0/G1 phase. The mRNA expression levels of Bmi-1 were downregulated in the 1 and 2 Gy groups, and upregulated in the 6 and 8 Gy groups. The expression levels of miRNA-128a were upregulated in the 1 and 2 Gy groups, and downregulated in the 8 Gy group. The levels of ROS were increased following exposure to >=2 Gy, and treatment with N-acetyl cysteine was able to induce radioresistance. These results suggested that U-87 MG cells exhibited radioresistance. High doses of X-ray radiation increased the expression levels of Bmi-1, which may be associated with the evasion of cellular senescence. miRNA-128a and its downstream target gene Bmi-1 may have an important role in the radioresistance of U-87 MG glioma cells. In addition, ROS may be involved in the mechanisms underlying the inhibitory effects of X-ray radiation in U-87 MG cells, and the downregulation of ROS may induce radioresistance. PMID- 26238020 TI - Tetrapod axial evolution and developmental constraints; Empirical underpinning by a mouse model. AB - The tetrapod vertebral column has become increasingly complex during evolution as an adaptation to a terrestrial life. At the same time, the evolution of the vertebral formula became subject to developmental constraints acting on the size of the cervical and thoraco-lumbar regions. In the course of our studies concerning the evolution of Hox gene regulation, we produced a transgenic mouse model expressing fish Hox genes, which displayed a reduced number of thoraco lumbar vertebrae and concurrent sacral homeotic transformations. Here, we analyze this mutant stock and conclude that the ancestral, pre-tetrapodial Hox code already possessed the capacity to induce vertebrae with sacral characteristics. This suggests that alterations in the interpretation of the Hox code may have participated to the evolution of this region in tetrapods, along with potential modifications of the HOX proteins themselves. With its reduced vertebral number, this mouse stock violates a previously described developmental constraint, which applies to the thoraco-lumbar region. The resulting offset between motor neuron morphology, vertebral patterning and the relative positioning of hind limbs illustrates that the precise orchestration of the Hox-clock in parallel with other ontogenetic pathways places constraints on the evolvability of the body plan. PMID- 26238022 TI - Impact of reduced levels of APE1 transcripts on the survival of patients with urothelial carcinoma of the bladder. AB - Molecular evidence indicates that alterations in genes involved in the maintenance of genome stability may be related to susceptibility to bladder carcinoma. Our goal was to evaluate the prognostic role of base excision repair (BER) genes in a cohort of patients diagnosed with primary urothelial carcinoma of the bladder (UCB). The levels of all APE1, XRCC1 and POLB transcripts were detected by quantitative real-time PCR (qPCR) technique in tumor samples from 52 patients undergoing transurethral resection (TUR) for primary UCB at the Department of Urology, Brazilian National Cancer Institute, Rio de Janeiro. Increased levels of APE1, XRCC1 and POLB transcripts were significantly associated with high-grade tumors when compared to these levels in low-grade tumors (p<0.01) and could be attributed to different mechanisms of transcriptional regulation as a response to tumorigenesis and oxidative stress. By analyzing the collected data in the present study, regardless of pathological grade or stage, univariate analysis revealed that the reduced levels of APE1 transcripts were significantly associated with cancer-specific mortality (p=0.032). Furthermore, the variant genotype (TG/GG) of the APE1 T1349G polymorphism was observed in 75% of a subset of patients who concomitantly experienced reduced levels of the APE1 transcript and death and/or recurrence events. Taken together, our data reinforce the idea that human DNA repair mechanisms must be finely regulated in order to avoid instability leading to tumorigenesis and poor clinical outcomes in UCB patients. PMID- 26238027 TI - The effects of acupuncture and traditional Chinese medicines on apoptosis of brain tissue in a rat intracerebral hemorrhage model. AB - OBJECTIVE: This study aimed to evaluate the effects of Chinese herbs and acupuncture on the neuronal apoptosis and the expression of apoptosis-related genes in the brain tissue of rats following intracerebral hemorrhage (ICH). METHODS: Collagenase VII was injected into the caudate nucleus of Sprague-Dawley rats to induce ICH. Chinese herbs (musk, borneol and tetrandrine) were intragastrically administered, and acupuncture was performed using Dazhui, Fengfu and Shuigou acupoints. Each group was further subdivided into 4 subgroups based on treatment duration (6-hour, 24-hour, 72-hour, and 1-week). Neurological impairment score, TUNEL assay and apoptotic markers, BCL-2, BAX, and caspase-3 were used to evaluate the apoptosis status after ICH and subsequent treatment. RESULTS: Chinese herbal therapy and acupuncture improved neurological impairment compared with no therapy and sham-operated animals. Significant differences in TUNEL positive cells were found between treatment groups (p < 0.001) and over time (p < 0.001). Differential expression of BCL-2, BAX, and caspase-3 was observed between treatment groups (p = 0.014 for BAX and < 0.05 for BCL-2 and caspase-3) and treatment duration groups (p = 0.006 for BAX and < 0.05 BCL-2 and caspase-3). CONCLUSIONS: Results indicate that Chinese herbs and acupuncture may improve neural impairment and reduce apoptosis, although there was no difference between therapies in a rat model of ICH. Additional experiments are needed to further clarify the role of these therapies following ICH. PMID- 26238028 TI - Paediatrics: Urinary flow rate after TIP urethroplasty for hypospadias. PMID- 26238029 TI - Urinary incontinence: TRPM8 influences bladder filling. PMID- 26238030 TI - Prostate cancer: Avoiding excess confirmatory biopsies. PMID- 26238031 TI - Kidney cancer: AXL RTK--a therapeutic target in RCC? PMID- 26238032 TI - Measuring human locomotor control using EMG and EEG: Current knowledge, limitations and future considerations. AB - Electrical signals encoding different forms of information can be observed at multiple levels of the human nervous system. Typically, these signals have been recorded in a rather isolated fashion with little overlap between the static recordings of electroencephalography (EEG) commonly used in neuroscience and the typical surface electromyography (EMG) recordings used in biomechanics. However, within the last decade, there has been an emerging need to link the electrical activation patterns of brain areas during movement to the behavior of the musculoskeletal system. This review discusses some of the most recent studies using the EEG and/or EMG to study the neural control of movement and human locomotion as well as studies quantifying the connectivity between brain and muscles. The focus is on rhythmic locomotor-type activities; however, results are discussed within the framework of initial work that has been done in upper and lower limbs during static and dynamic contractions. Limitations and current challenges as well as the possibility and functional interpretation of studying the connectivity between the cortex and skeletal muscles using a measure of coherence are discussed. The manuscript is geared toward scientists interested in the application of EEG in the field of locomotion, sports and exercise. PMID- 26238033 TI - Hypothyroidism minimizes the effects of acute hepatic failure caused by endoplasmic reticulum stress and redox environment alterations in rats. AB - The aim of this study was to investigate if a protective effect from hypothyroidism in acute liver failure resulted from reduced endoplasmic reticulum stress and changes to the redox environment. Twenty male Sprague-Dawley rats were divided in four groups: (1) euthyroid (sham surgery), (2) hypothyroid, (3) euthyroid (sham surgery)+thioacetamide and (4) hypothyroid+thioacetamide. Hypothyroidism was confirmed two weeks after thyroidectomy, and thioacetamide (TAA) (400mg/kg, ip) was administrated to the appropriate groups for three days with supportive therapy. Grades of encephalopathy in all animals were determined using behavioral tests. Animals were decapitated and their blood was obtained to assess liver function. The liver was dissected: the left lobe was used for histology and the right lobe was frozen for biochemical assays. Body weight, rectal temperature and T4 concentration were lower in hypothyroid groups. When measurements of oxidative stress markers, redox environment, gamma glutamylcysteine synthetase and glutathione-S-transferase were determined, we observed that hypothyroid animals with TAA compensated better with oxidative damage than euthyroid animals treated with TAA. Furthermore, we measured reduced expressions of GADD34, caspase-12 and GRP78 and subsequently less hypothyroidism induced cellular damage in hypothyroid animals. We conclude that hypothyroidism protects against hepatic damage caused by TAA because it reduces endoplasmic reticulum stress and changes to the redox environment. PMID- 26238034 TI - A comparative study of ZnAl2O4 nanoparticles synthesized from different aluminum salts for use as fluorescence materials. AB - Three ZnAl2O4 samples were prepared via a modified polyacrylamide gel method using a citric acid solution with different aluminum salt starting materials, including AlCl3 ? 6H2O, Al2(SO4)3 ? 18H2O, and Al(NO3)3 ? 9H2O under identical conditions. The influence of different aluminum salts on the morphologies, phase purity, and optical and fluorescence properties of the as-prepared ZnAl2O4 nanoparticles were studied. The experimental results demonstrate that the phase purity, particle size, morphology, and optical and fluorescence properties of ZnAl2O4 nanoparticles can be manipulated by the use of different aluminum salts as starting materials. The energy bandgap (Eg) values of ZnAl2O4 nanoparticles increase with a decrease in particle size. The fluorescence spectra show that a major blue emission band around 400 nm and two weaker side bands located at 410 and 445 nm are observed when the excitation wavelength is 325 nm. The ZnAl2O4 nanoparticles prepared from Al(NO3)3 ? 9H2O exhibit the largest emission intensity among the three ZnAl2O4 samples, followed in turn by the ZnAl2O4 nanoparticles prepared from Al2(SO4)3 ? 18H2O and AlCl3?6H2O. These differences are attributed to combinational changes in Eg and the defect types of the ZnAl2O4 nanoparticles. PMID- 26238035 TI - High Burden of HIV Infection and Risk Behaviors Among Female Sex Workers in Three Main Urban Areas of Mozambique. AB - This is the first integrated biological and behavioral survey among female sex workers (FSW) in Mozambique. Using respondent-driven sampling, 400, 411 and 429 FSW were enrolled respectively in Maputo, Beira and Nampula in 2011-2012. Estimates were produced using RDSAT 7.1. HIV prevalence was 31.2, 23.6, and 17.8 % in each location respectively. Among HIV-positive FSW, 48.1, 79.8 and 89.6 % in each city, were unaware of their serostatus. Condom use at last sex with a client was 85.8, 73.4 and 62.8 % among FSW, respectively. HIV was associated with current age, age of first sex for money, low educational level, and having had a genital ulcer in the last 6 months. Results suggest the urgent need to increase behavioral and structural interventions in this key population. PMID- 26238036 TI - Alcohol Use and HIV Testing in a National Sample of Women. AB - The HIV/AIDS epidemic continues to disproportionately affect racial and ethnic minority groups and women in the United States. Prevention research suggests that reduced alcohol use and increased HIV testing are associated with lower incidence of HIV transmission among high-risk populations. Multivariable logistic regression analyses of the 2009 National Health Interview Survey data were performed for a national sample of 15,470 adult women to examine the relationship between alcohol use and likelihood of HIV testing. There is a significant association between level of alcohol use and HIV testing. Women who identified as heavy drinkers and moderate drinkers were significantly less likely to report ever testing for HIV. Findings add to the limited literature on the association between alcohol use and HIV testing behaviors among women. Given the incidence of HIV among women, this study highlights the importance of HIV testing, especially for alcohol-using women. PMID- 26238038 TI - Iteratively Developing an mHealth HIV Prevention Program for Sexual Minority Adolescent Men. AB - Five activities were implemented between November 2012 and June 2014 to develop an mHealth HIV prevention program for adolescent gay, bisexual, and queer men (AGBM): (1) focus groups to gather acceptability of the program components; (2) ongoing development of content; (3) Content Advisory Teams to confirm the tone, flow, and understandability of program content; (4) an internal team test to alpha test software functionality; and (5) a beta test to test the protocol and intervention messages. Findings suggest that AGBM preferred positive and friendly content that at the same time, did not try to sound like a peer. They deemed the number of daily text messages (i.e., 8-15 per day) to be acceptable. The Text Buddy component was well received but youth needed concrete direction about appropriate discussion topics. AGBM determined the self-safety assessment also was acceptable. Its feasible implementation in the beta test suggests that AGBM can actively self-determine their potential danger when participating in sexual health programs. Partnering with the target population in intervention development is critical to ensure that a salient final product and feasible protocol are created. PMID- 26238039 TI - Reducing Risky Sex Among College Students: Prospects for Context-Specific Interventions. AB - Better understanding the contribution of specific drinking contexts to alcohol use and risky sexual behaviors can help target effective prevention programs to specific locations and types of drinkers. We used a sample of college students to investigate whether more frequent and heavier drinking in specific drinking contexts was associated with unplanned sex, unprotected sex, and number of sexual contacts. Greater frequencies of drinking in almost all contexts (Greek parties, off-campus parties, campus events, dorms, and bars) were associated with greater numbers of sexual partners, unplanned sex and unprotected sex; heavier drinking at bars increased risks related to all outcomes. Risks related to frequencies of use of contexts were similar for men and women, but heavier drinking at bars was associated with more unprotected sex among males only. We discuss these observations in light of their implications for developing context-specific interventions to reduce community viral load in high-risk populations. PMID- 26238037 TI - Optimization of Multicomponent Behavioral and Biobehavioral Interventions for the Prevention and Treatment of HIV/AIDS. AB - To move society toward an AIDS-free generation, behavioral interventions for prevention and treatment of HIV/AIDS must be not only effective, but also cost effective, efficient, and readily scalable. The purpose of this article is to introduce to the HIV/AIDS research community the multiphase optimization strategy (MOST), a new methodological framework inspired by engineering principles and designed to develop behavioral interventions that have these important characteristics. Many behavioral interventions comprise multiple components. In MOST, randomized experimentation is conducted to assess the individual performance of each intervention component, and whether its presence/absence/setting has an impact on the performance of other components. This information is used to engineer an intervention that meets a specific optimization criterion, defined a priori in terms of effectiveness, cost, cost effectiveness, and/or scalability. MOST will enable intervention science to develop a coherent knowledge base about what works and does not work. Ultimately this will improve behavioral interventions systematically and incrementally. PMID- 26238041 TI - Investigating the Evidence of the Real-Life Impact of Acute Hyperglycaemia. AB - Poorly controlled diabetes mellitus (DM) is associated with the development of long-term micro- and macro-vascular complications. The predominant focus of anti diabetic therapy has been on lowering glycosylated haemoglobin levels, with a strong emphasis on fasting plasma glucose (particularly in Type 2 DM). There is considerable evidence indicating that post-meal hyperglycaemic levels are independently associated with higher risks of macro-vascular disease. Although some have identified mechanisms which may account for these observations, interventions which have specifically targeted postprandial glucose rises showed little or no effect in reducing cardiovascular risk. Clinical experience and some recent studies suggest acute hyperglycaemia affects cognition and other indicators of performance, equivalent to impairment seen during hypoglycaemia. In this brief report, we evaluated the published studies and argue that acute hyperglycaemia is worth investigating in relation to the real-life implications. In summary, evidence exists suggesting that acute hyperglycaemia may lead to impaired cognitive performance and productivity, but the relationship between these effects and daily activities remains poorly understood. Further research is required to enhance our understanding of acute hyperglycaemia in daily life. A better appreciation of clinically relevant effects of acute hyperglycaemia will allow us to determine whether it needs to be addressed by specific treatment. FUNDING: Novo Nordisk A/S Soborg, Denmark. PMID- 26238040 TI - Functional analysis of the nasopharyngeal carcinoma primary tumor-associated gene interaction network. AB - The aim of the present study was to investigate the molecular mechanism of nasopharyngeal carcinoma (NPC) primary tumor development through the identification of key genes using bioinformatics approaches. Using the GSE53819 microarray dataset, acquired from the Gene Expression Omnibus database, differentially expressed genes (DEGs) were screened out between NPC primary tumor and control samples, followed by hierarchical clustering analysis. The Search Tool for the Retrieval of Interacting Genes database was utilized to build a protein-protein interaction network to identify key node proteins. In total, 1,067 DEGs, including 326 upregulated genes and 741 downregulated genes, were identified between the NPC and control samples. The results of the hierarchical clustering analysis demonstrated that 95% of the DEGs were sample-specific. Furthermore, PDZ binding kinase (PBK), centromere protein F (CENPF), actin binding protein anillin (ANLN), exonuclease 1 (EXO1) and chromosome 15 open reading frame 42 (C15ORF42) were included in the obtained network module, which was closely associated with the cell cycle and nucleic acid metabolic process GO functions. The results of the present study revealed that EXO1, CENPF, ANLN, PBK and C15ORF42 may be involved in the mechanism of NPC via modulating the cell cycle and nucleic acid metabolic processes, and may serve as molecular biomarkers for the diagnosis of this disease. PMID- 26238042 TI - Nanoscale switch for vortex polarization mediated by Bloch core formation in magnetic hybrid systems. AB - Vortices are fundamental magnetic topological structures characterized by a curling magnetization around a highly stable nanometric core. The control of the polarization of this core and its gyration is key to the utilization of vortices in technological applications. So far polarization control has been achieved in single-material structures using magnetic fields, spin-polarized currents or spin waves. Here we demonstrate local control of the vortex core orientation in hybrid structures where the vortex in an in-plane Permalloy film coexists with out-of plane maze domains in a Co/Pd multilayer. The vortex core reverses its polarization on crossing a maze domain boundary. This reversal is mediated by a pair of magnetic singularities, known as Bloch points, and leads to the transient formation of a three-dimensional magnetization structure: a Bloch core. The interaction between vortex and domain wall thus acts as a nanoscale switch for the vortex core polarization. PMID- 26238044 TI - Study on the protective effect of the KIR3DL1 gene in ankylosing spondylitis. AB - OBJECTIVE: Ankylosing spondylitis (AS) is an autoimmune disease that mainly affects the sacroiliac joints and the spine of the lower back. The disease is strongly associated with HLA-B27. Additional genes, single-nucleotide polymorphisms, and molecular components have been identified to be associated with AS, but the exact mechanism that drives disease development remains poorly understood. The killer cell immunoglobulin-like receptors (KIRs) are regulators of cytotoxicity of natural killer cells and T cell subsets and may be relevant in binding to HLA-B27 and the development of AS. We undertook this study to identify possible associations of KIR genotype with susceptibility to AS and disease characteristics including the presence of the HLA-B27 allele, disease severity, and uveitis. METHODS: We performed complete genotyping of the KIR locus in 303 Caucasian AS patients, 119 randomly selected healthy Caucasian controls, and 50 HLA-B27-positive healthy Caucasian controls by multiplex ligation-dependent probe amplification assay for detection of gene presence and copy number. RESULTS: We did not observe a significant association of any specific KIR gene or haplotype with susceptibility to AS or any other clinical manifestation. Disease severity, as measured by fulfilling the criteria for treatment with tumor necrosis factor blocking therapy, was linked to a lower number of genes for the functional variant of KIR3DL1 (P = 0.007). CONCLUSION: Our exploratory study indicates that KIR genes are not a major risk factor for susceptibility to AS. However, the data do suggest a role for KIRs in progression of the disease, whereby KIR3DL1 has a protective effect against the more severe manifestations of AS. PMID- 26238045 TI - Synthesis and antimicrobial potential of nitrofuran-triazole congeners. AB - A series of 5-nitrofuran-triazole congeners were designed and synthesized by carrying out suitable structural modifications of the previously reported counterparts and were evaluated for their antimicrobial potential against both Gram-positive and Gram-negative bacterial strains. The compounds exhibited promising inhibition towards different Gram-positive pathogenic strains, while mild inhibitory effects were observed towards Gram-negative bacterial strains. Some of the compounds 9f, 9g, 9l and 9m were most active among the series, exhibiting a MIC value of 1.9 MUg mL(-1) against different bacterial strains. The bactericidal activity was found to be in coherence with the bacterial growth inhibition data. The compounds were tested against fourteen different fungal strains and were found to possess excellent antifungal activities. Interestingly, all the compounds were equipotent to miconazole against one or more of the tested fungal strains and showed good activity against the other counterparts. A similar trend was observed in the case of their minimum fungicidal concentration values. Moreover, compound 9f exhibited two fold superior antifungal activity (MIC = 3.9 MUg mL(-1)) than the standard miconazole (MIC = 7.8 MUg mL(-1)) against C. albicans and C. parapsilosis. These compounds also effectively inhibited biofilm formation and compound 9f exhibited excellent anti-biofilm activity demonstrating a biofilm inhibitory concentration (BIC) as low as 0.8 MUg mL(-1). A brief mechanistic study carried out on the most effective conjugate 9f indicated that it inhibits the ergosterol biosynthesis, thereby exhibiting antifungal effects. Molecular modelling studies carried out to study the binding modes of 9f correlates well with the antifungal activity and supported by ergosterol biosynthesis inhibition assay data. Most of these compounds exhibited ten times lower cytotoxicity toward the normal cells compared to the antimicrobial activity. PMID- 26238047 TI - Historical Overview and General Methods of Membrane Potential Imaging. AB - Voltage imaging was first conceived in the late 1960s and efforts to find better organic voltage sensitive dyes began in the 1970s and continue until today. At the beginning it was difficult to measure an action potential signal from a squid giant axon in a single trial. Now it is possible to measure the action potential in an individual spine. Other chapters will discuss advances in voltage imaging technology and applications in a variety of biological preparations. The development of genetically encoded voltage sensors has started. A genetically encoded sensor could provide cell type specific expression and voltage recording (see Chap. 20). Optimizing the signal-to-noise ratio of an optical recording requires attention to several aspects of the recording apparatus. These include the light source, the optics and the recording device. All three have improved substantially in recent years. Arc lamp, LED, and laser sources are now stable, more powerful, and less expensive. Cameras for recording activity have frames rates above 1 kHz and quantum efficiencies near 1.0 although they remain expensive. The sources of noise in optical recordings are well understood. Both the apparatus and the noise sources are discussed in this chapter. PMID- 26238048 TI - Design and Use of Organic Voltage Sensitive Dyes. AB - The chemistry and the physics of voltage sensitive dyes (VSDs) should be understood and appreciated as a prerequisite for their optimal application to problems in neuroscience cardiology. This chapter provides a basic understanding of the properties of the large variety of available organic VSDs. The mechanisms by which the dyes respond to voltage guides the best set up of the optics for recording or imaging electrophysiological activity. The physical and chemical properties of the dyes can be tuned to optimize delivery to and staining of the cells in different experimental preparations. The aim of this chapter is to arm the experimentalists who use the dyes with enough information and data to be able to intelligently choose the best dye for their specific requirements. PMID- 26238046 TI - Biological Effects of Simvastatin Formulated as pMDI on Pulmonary Epithelial Cells. AB - PURPOSE: The aim of this study is to evaluate the biological effects of Calu-3 epithelial cells in response to the delivery of simvastatin (SV) via solution pressurized metered dose inhaler (pMDI). METHODS: SV pMDI was aerosolised onto Calu-3 air-interface epithelial cells using a modified glass twin stage impinger. The transport of SV across Calu-3 cells, mucus production, inflammatory cytokines production i.e., interleukin (IL) 6, 8 and tumour necrosis factor alpha (TNF- alpha) and oxidative stress from Calu-3 cells following treatment with SV pMDI was investigated and compared to untreated cells. RESULTS: It was found that SV had the ability to penetrate into the respiratory epithelium and convert into its active SV hydroxy acid (SVA) metabolite. Furthermore, the amount of mucus produced was significantly reduced when SV was deposited on Calu-3 compared to untreated cells. Additionally, SV delivered by pMDI reduces production of IL-6, 8 and TNF-alpha from Calu-3 following stimulation with lipopolysaccharide (LPS). SV also showed equivalent antioxidant property to vitamin E. CONCLUSIONS: Treatment with SV solution pMDI formulation on Calu-3 cells reduces mucus production, inflammatory cytokines and oxidative stress. This formulation could potentially be used clinically as muco-inhibitory and anti-inflammatory therapy for treatment of chronic lung diseases. PMID- 26238049 TI - Imaging Submillisecond Membrane Potential Changes from Individual Regions of Single Axons, Dendrites and Spines. AB - A central question in neuronal network analysis is how the interaction between individual neurons produces behavior and behavioral modifications. This task depends critically on how exactly signals are integrated by individual nerve cells functioning as complex operational units. Regional electrical properties of branching neuronal processes which determine the input-output function of any neuron are extraordinarily complex, dynamic, and, in the general case, impossible to predict in the absence of detailed measurements. To obtain such a measurement one would, ideally, like to be able to monitor, at multiple sites, subthreshold events as they travel from the sites of origin (synaptic contacts on distal dendrites) and summate at particular locations to influence action potential initiation. It became possible recently to carry out this type of measurement using high-resolution multisite recording of membrane potential changes with intracellular voltage-sensitive dyes. This chapter reviews the development and foundation of the method of voltage-sensitive dye recording from individual neurons. Presently, this approach allows monitoring membrane potential transients from all parts of the dendritic tree as well as from axon collaterals and individual dendritic spines. PMID- 26238050 TI - Combining Membrane Potential Imaging with Other Optical Techniques. AB - Membrane potential imaging using voltage-sensitive dyes can be combined with other optical techniques for a variety of applications. Combining voltage imaging with Ca2+ imaging allows correlating membrane potential changes with intracellular Ca2+ signals or with Ca2+ currents. Combining voltage imaging with uncaging techniques allows analyzing electrical signals elicited by photorelease of a particular molecule. This approach is also a useful tool to calibrate the change in fluorescence intensity in terms of membrane potential changes from different sites permitting spatial mapping of electrical activity. Finally, combining voltage imaging with optogenetics, in particular with channelrhodopsin stimulation, opens the gate to novel investigations of brain circuitries by allowing measurements of synaptic signals mediated by specific sets of neurons. Here we describe in detail the methods of membrane potential imaging in combination with other optical techniques and discus some important applications. PMID- 26238052 TI - Monitoring Integrated Activity of Individual Neurons Using FRET-Based Voltage Sensitive Dyes. AB - Pairs of membrane-associated molecules exhibiting fluorescence resonance energy transfer (FRET) provide a sensitive technique to measure changes in a cell's membrane potential. One of the FRET pair binds to one surface of the membrane and the other is a mobile ion that dissolves in the lipid bilayer. The voltage related signal can be measured as a change in the fluorescence of either the donor or acceptor molecules, but measuring their ratio provides the largest and most noise-free signal. This technology has been used in a variety of ways; three are documented in this chapter: (1) high throughput drug screening, (2) monitoring the activity of many neurons simultaneously during a behavior, and (3) finding synaptic targets of a stimulated neuron. In addition, we provide protocols for using the dyes on both cultured neurons and leech ganglia. We also give an updated description of the mathematical basis for measuring the coherence between electrical and optical signals. Future improvements of this technique include faster and more sensitive dyes that bleach more slowly, and the expression of one of the FRET pair genetically. PMID- 26238051 TI - Monitoring Spiking Activity of Many Individual Neurons in Invertebrate Ganglia. AB - Optical recording with fast voltage sensitive dyes makes it possible, in suitable preparations, to simultaneously monitor the action potentials of large numbers of individual neurons. Here we describe methods for doing this, including considerations of different dyes and imaging systems, methods for correlating the optical signals with their source neurons, procedures for getting good signals, and the use of Independent Component Analysis for spike-sorting raw optical data into single neuron traces. These combined tools represent a powerful approach for large-scale recording of neural networks with high temporal and spatial resolution. PMID- 26238053 TI - Monitoring Population Membrane Potential Signals from Neocortex. AB - Voltage-sensitive dyes (VSDs) and optical imaging are useful tools for studying spatiotemporal patterns of population neuronal activity in cortex. Because fast VSDs respond to membrane potential changes with microsecond temporal resolution, these are better suited than calcium indicators for recording rapid neural signals. Here we describe methods for using a 464 element photodiode array and fast VSDs to record signals ranging from large scale network activity in brain slices and in vivo mammalian preparations with sensitivity comparable to local field potential (LFP) recordings. With careful control of dye bleaching and phototoxicity, long recording times can be achieved. Absorption dyes have less photo-toxicity than fluorescent dyes. In brain slices, the total recording time in each slice can be 1,000-2,000 s, which can be divided into hundreds of short recording trials over several hours. In intact brains when fluorescent dyes are used, reduced light intensity can also increase recording time. In this chapter, we will discuss technical details for the methods to achieve reliable VSD imaging with high sensitivity and long recording time. PMID- 26238054 TI - Voltage Imaging in the Study of Hippocampal Circuit Function and Plasticity. AB - Synaptic plasticity has the capacity to alter the function of neural circuits, and long-term potentiation (LTP) of synaptic transmission induced by high frequency electrical activity has the capacity to store information in neural circuits. The cellular and molecular mechanisms of LTP have been studied intensively for many years and much progress has been made on this front. By contrast, how synaptic plasticity alters circuit function has received much less attention and remains poorly understood. Voltage imaging provides a powerful general technique for the study of neural circuitry, and studies of synaptic plasticity with voltage imaging are beginning to reveal important aspects of how the function of a neural circuit can change when the strength of its synapses has been modified. The hippocampus has an important role in learning and memory and the plasticity of its synapses has received much attention. Voltage imaging with voltage sensitive dye in the CA1 region of a hippocampal slice has shown that spatial patterns of enhancement following LTP induction can diverge from the spatial patterns elicited by electrical stimulation, suggesting that LTP exhibits a distinct organizational structure. LTP can alter the throughput of electrical activity in the dentate gyrus of a hippocampal slice, to gate transmission on to the CA3 region. The spatial patterns evoked by complex electrical stimulation can be stored within the CA3 region in a hippocampal slice, allowing patterns to be reconstructed with simpler electrical stimulation. Thus, voltage imaging has demonstrated that the CA3 circuit has the capacity for pattern completion. These studies with voltage sensitive dye illustrate a range of interesting and novel questions that can be addressed at the population level. It is hoped that future imaging experiments with single-cell resolution using genetically-encoded voltage sensors will provide a more detailed picture of how synaptic plasticity modifies the information processing capabilities of neural circuits. PMID- 26238055 TI - Monitoring Population Membrane Potential Signals During Development of the Vertebrate Nervous System. AB - The functional organization of the vertebrate central nervous system (CNS) during the early phase of development has long been unclear, because conventional electrophysiological means have several technical limitations. First, early embryonic neurons are small and fragile, and the application of microelectrodes is often difficult. Second, the simultaneous recording of electrical activity from multiple sites is limited, and as a consequence, response patterns of neural networks cannot be assessed. Optical recording techniques with voltage-sensitive dyes have overcome these obstacles and provided a new approach to the analysis of the functional development/organization of the CNS. In this review, we provide detailed information concerning the recording of optical signals in the embryonic nervous system. After outlining methodological considerations, we present examples of recent progress in optical studies on the embryonic nervous system with special emphasis on two topics. The first is the study of how synapse networks form in specific neuronal circuits. The second is the study of non specific correlated wave activity, which is considered to play a fundamental role in neural development. These studies clearly demonstrate the utility of fast voltage-sensitive dye imaging as a powerful tool for elucidating the functional organization of the vertebrate embryonic CNS. PMID- 26238056 TI - Imaging the Dynamics of Mammalian Neocortical Population Activity In-Vivo. AB - Neural computations underlying sensory perception, cognition and motor control are performed by populations of neurons at different anatomical and temporal scales. Few techniques are currently available for exploring dynamics of local and large range populations. Voltage-sensitive dye imaging (VSDI) reveals neural population activity in areas ranging from a few tens of microns to a couple of centimeters, or two areas up to ~10 cm apart. VSDI provides a sub-millisecond temporal resolution, and a spatial resolution of about 50 MUm. The dye signal emphasizes subthreshold synaptic potentials. VSDI has been applied in the mouse, rat, gerbil, ferret, tree shrew, cat and monkey cortices, in order to explore lateral spread of retinotopic or somatotopic activation, the dynamic spatiotemporal pattern resulting from sensory activation, including the somatosensory, olfactory, auditory, and visual modalities, as well as motor preparation and the properties of spontaneously-occurring population activity. In this chapter we focus on VSDI in-vivo and review results obtained mostly in the visual system in our laboratory. PMID- 26238057 TI - Imaging the Dynamics of Neocortical Population Activity in Behaving and Freely Moving Mammals. AB - The development of functional imaging techniques applicable to neuroscience and covering a wide range of spatial and temporal scales has greatly facilitated the exploration of the relationships between cognition, behaviour and electrical brain activity. For mammals, the neocortex plays a particularly profound role in generating sensory perception, controlling voluntary movement, higher cognitive functions and planning goal-directed behaviours. Since these remarkable functions of the neocortex cannot be explored in simple model preparations or in anesthetised animals, the neural basis of behaviour must be explored in awake behaving subjects. Because neocortical function is highly distributed across many rapidly interacting regions, it is essential to measure spatiotemporal dynamics of cortical activity in real-time. Extensive work in anesthetised mammals has shown that in vivo Voltage-Sensitive Dye Imaging (VSDI) reveals the neocortical population membrane potential dynamics at millisecond temporal resolution and subcolumnar spatial resolution. Here, we describe recent advances indicating that VSDI is also already well-developed for exploring cortical function in behaving monkeys and mice. The first animal model, the non-human primate, is well-suited for fundamental exploration of higher-level cognitive function and behavior. The second animal model, the mouse, benefits from a rich arsenal of molecular and genetic technologies. In the monkey, imaging from the same patch of cortex, repeatedly, is feasible for a long period of time, up to a year. In the rodent, VSDI is applicable to freely moving and awake head-restrained mice. Interactions between different cortical areas and different cortical columns can therefore now be dynamically mapped through VSDI and related to the corresponding behaviour. Thus by applying VSDI to mice and monkeys one can begin to explore how behaviour emerges from neuronal activity in neuronal networks residing in different cortical areas. PMID- 26238058 TI - Optical Imaging of Cardiac Action Potential. AB - This chapter reviews the major milestones and scientific achievements facilitated by optical imaging of the action potential in the heart over more than four decades since its introduction. We discuss the limitations of this technique, which sometimes are not fully recognized; the unresolved issues, such as motion artifacts, and the newest developments and future directions. PMID- 26238059 TI - Optical Mapping of Ventricular Fibrillation Dynamics. AB - There is very limited information regarding the dynamic patterns of the electrical activity during ventricular fibrillation (VF) in humans. Most of the data used to generate and test hypotheses regarding the mechanisms of VF come from animal models and computer simulations and the quantification of VF patterns is non-trivial. Many of the experimental recordings of the dynamic spatial patterns of VF have been obtained from mammals using "optical mapping" or "video imaging" technology in which "phase maps" are derived from high-resolution transmembrane recordings from the heart surface. The surface manifestation of the unstable reentrant waves sustaining VF can be identified as "phase singularities" and their number and location provide one measure of VF complexity. After providing a brief history of optical mapping of VF, we compare and contrast a quantitative analysis of VF patterns from the heart surface for four different animal models, hence providing physiological insight into the variety of VF dynamics among species. We found that in all four animal models the action potential duration restitution slope was actually negative during VF and that the spatial dispersion of electrophysiological parameters were not different during the first second of VF compared to pacing immediately before VF initiation. Surprisingly, our results suggest that APD restitution and spatial dispersion may not be essential causes of VF dynamics. Analyses of electrophysiological quantities in the four animal models are consistent with the idea that VF is essentially a two-dimensional phenomenon in small rabbit hearts whose size are near the boundary of the "critical mass" required to sustain VF, while VF in large pig hearts is three-dimensional and exhibits the maximal theoretical phase singularity density, and thus will not terminate spontaneously. PMID- 26238061 TI - Biophotonic Modelling of Cardiac Optical Imaging. AB - Computational models have been recently applied to simulate and better understand the nature of fluorescent photon scattering and optical signal distortion during cardiac optical imaging. The goal of such models is both to provide a useful post processing tool to facilitate a more accurate and faithful comparison between computational simulations of electrical activity and experiments, as well as providing essential insight into the mechanisms underlying this distortion, suggesting ways in which it may be controlled or indeed utilised to maximise the information derived from the recorded fluorescent signal. Here, we present different modelling methodologies developed and used in the field to simulate both the explicit processes involved in optical signal synthesis and the resulting consequences of the effects of photon scattering within the myocardium upon the optically-detected signal. We focus our attentions to two main types of modelling approaches used to simulate light transport in cardiac tissue, specifically continuous (reaction-diffusion) and discrete stochastic (Monte Carlo) methods. For each method, we provide both a summary of the necessary methodological details of such models, in addition to brief reviews of relevant application studies which have sought to apply these methods to elucidate important information regarding experimentally-recorded optical signals under different circumstances. PMID- 26238062 TI - Towards Depth-Resolved Optical Imaging of Cardiac Electrical Activity. AB - The spatiotemporal dynamics of arrhythmias are likely to be complex three dimensional phenomena. Yet, the lack of high-resolution three-dimensional imaging techniques, both in the clinic and the experimental lab, limits our ability to better understand the mechanisms of such arrhythmias. Optical mapping using voltage-sensitive dyes is a widely used tool in experimental electrophysiology. It has been known for decades that even in its most basic application, epi fluorescence, the optical signal contains information from within a certain intramural volume. Understanding of this fundamental property of optical signals has paved the way towards novel three-dimensional optical imaging techniques. Here, we review our current understanding of the three-dimensional nature of optical signals; how penetration depths of cardiac optical imaging can be improved by using novel imaging modalities and finally, we highlight new techniques inspired from optical tomography and aiming at full depth-resolved optical mapping of cardiac electrical activity. PMID- 26238060 TI - Imaging of Ventricular Fibrillation and Defibrillation: The Virtual Electrode Hypothesis. AB - Ventricular fibrillation is the major underlying cause of sudden cardiac death. Understanding the complex activation patterns that give rise to ventricular fibrillation requires high resolution mapping of localized activation. The use of multi-electrode mapping unraveled re-entrant activation patterns that underlie ventricular fibrillation. However, optical mapping contributed critically to understanding the mechanism of defibrillation, where multi-electrode recordings could not measure activation patterns during and immediately after a shock. In addition, optical mapping visualizes the virtual electrodes that are generated during stimulation and defibrillation pulses, which contributed to the formulation of the virtual electrode hypothesis. The generation of virtual electrode induced phase singularities during defibrillation is arrhythmogenic and may lead to the induction of fibrillation subsequent to defibrillation. Defibrillating with low energy may circumvent this problem. Therefore, the current challenge is to use the knowledge provided by optical mapping to develop a low energy approach of defibrillation, which may lead to more successful defibrillation. PMID- 26238063 TI - Two-Photon Excitation of Fluorescent Voltage-Sensitive Dyes: Monitoring Membrane Potential in the Infrared. AB - Functional imaging microscopy based on voltage-sensitive dyes (VSDs) has proven effective for revealing spatio-temporal patterns of activity in vivo and in vitro. Microscopy based on two-photon excitation of fluorescent VSDs offers the possibility of recording sub-millisecond membrane potential changes on micron length scales in cells that lie upwards of one millimeter below the brain's surface. Here we describe progress in monitoring membrane voltage using two photon excitation (TPE) of VSD fluorescence, and detail an application of this emerging technology in which action potentials were recorded in single trials from individual mammalian nerve terminals in situ. Prospects for, and limitations of this method are reviewed. PMID- 26238064 TI - Random-Access Multiphoton Microscopy for Fast Three-Dimensional Imaging. AB - Studies in several important areas of neuroscience, including analysis of single neurons as well as neural networks, continue to be limited by currently available experimental tools. By combining molecular probes of cellular function, such as voltage-sensitive or calcium-sensitive dyes, with advanced microscopy techniques such as multiphoton microscopy, experimental neurophysiologists have been able to partially reduce this limitation. These approaches usually provide the needed spatial resolution along with convenient optical sectioning capabilities for isolating regions of interest. However, they often fall short in providing the necessary temporal resolution, primarily due to their restrained laser scanning mechanisms. In this regard, we review a method of laser scanning for multiphoton microscopy that overcomes the temporal limitations of pervious approaches and allows for what is known as 3D Random Access Multiphoton (3D RAMP) microscopy, an imaging technique that supports full three dimensional recording of many sites of interest on physiologically relevant time scales. PMID- 26238065 TI - Second Harmonic Imaging of Membrane Potential. AB - The non-linear optical effect known as second harmonic generation (SHG) has been recognized since the earliest days of the laser. But it has only been in the last 20 years that it has begun to emerge as a viable microscope imaging contrast mechanism for visualization of cell and tissue structure and function. This is because only small modifications are required to equip a standard laser scanning 2-photon microscope for second harmonic imaging microscopy (SHIM). SHG signals from certain membrane-bound dyes are highly sensitive to membrane potential, indicating that SHIM may become a valuable probe of cell physiology. However, for the current generation of dyes and microscopes, the small signal size limits the number of photons that can be collected during the course of a fast action potential. Better dyes and optimized microscope optics could ultimately lead to the ability to image neuronal electrical activity with SHIM. PMID- 26238066 TI - Genetically Encoded Protein Sensors of Membrane Potential. AB - Organic voltage-sensitive dyes offer very high spatial and temporal resolution for imaging neuronal function. However these dyes suffer from the drawbacks of non-specificity of cell staining and low accessibility of the dye to some cell types. Further progress in imaging activity is expected from the development of genetically encoded fluorescent sensors of membrane potential. Cell type specificity of expression of these fluorescent protein (FP) voltage sensors can be obtained via several different mechanisms. One is cell type specificity of infection by individual virus subtypes. A second mechanism is specificity of promoter expression in individual cell types. A third, depends on the offspring of transgenic animals with cell type specific expression of cre recombinase mated with an animal that has the DNA for the FP voltage sensor in all of its cells but its expression is dependent on the recombinase activity. Challenges remain. First, the response time constants of many of the new FP voltage sensors are slower (2-10 ms) than those of organic dyes. This results in a relatively small fractional fluorescence change, DeltaF/F, for action potentials. Second, the largest signal presently available is only ~40% for a 100 mV depolarization and many of the new probes have signals that are substantially smaller. Large signals are especially important when attempting to detect fast events because the shorter measurement interval results in a relatively small number of detected photons and therefore a relatively large shot noise (see Chap. 1). Another kind of challenge has occurred when attempts were made to transition from one species to another or from one cell type to another or from cell culture to in vivo measurements.Several laboratories have recently described a number of novel FP voltage sensors. Here we attempt to critically review the current status of these developments in terms of signal size, time course, and in vivo function. PMID- 26238067 TI - Computerized histomorphometric study of the splenic collagen polymorphism: A control-tissue for polarization microscopy. AB - Previous articles have pointed out the presence of type III collagen within the extracellular structure of the parenchymatous organs. This study aimed to quantitatively characterize the collagen polymorphism at the capsule and parenchymal trabeculae of the largest lymphoid organ of the body i.e., the spleen, in mouse, rat, and rabbit models. Following a Picrosirius Red Polarization procedure and computer assisted image analysis of paraffin sections, the results showed (1) a predominant and significantly higher amount of type III collagen in the trabeculae area compared to the capsule area in the three species, (2) no statistical difference among the three species concerning the parenchymal collagen polymorphism or the type I/type III collagen ratio, (3) a heterogeneous type I/type III collagen ratio varying from 0.86 (mouse) to 6.62 (rabbit) in the fibromuscular capsule region. A qualitative analysis corroborated these histomorphometric results. In conclusion, the spleen may be used as (1) a control tissue to qualitatively visualize type I and III collagen under polarization microscopy and to validate the quality of PSR staining (2) an aid to accurately calibrate the angle of polarization before quantitative measurements of type I and type III collagen. Among the studied species, the rabbit spleen appeared to be the most appropriate control tissue as it showed the highest amount of type I collagen in the capsule and a similarly high amount of type III collagen in the parenchymal trabeculae. PMID- 26238068 TI - Clinical Comparison of Non-Myeloablative Conditioning with Anti-Thymocyte Globulin and Fludarabine for Patients with Hematologic Malignancies. AB - BACKGROUND: The influence of different non-myeloablative conditioning regimens on clinical outcome remains undefined. MATERIAL AND METHODS: We retrospectively analyzed the hematopoietic reconstitution, graft-versus-host disease (GVHD), and quality of life (QOL) in 56 patients with hematologic malignancies who underwent non-myeloablative stem cell transplantation (NST) with a conditioning regimen based on anti-thymocyte globulin (ATG), followed by donor lymphocyte infusion (n=24), or Fludarabine (FLU) (n=32). Hematopoietic stem cells were derived from low-resolution HLA-matched identical sibling donors. RESULTS: The blood type transformation and platelet reconstitution presented significantly earlier in the FLU group than the ATG group (P<0.05). Within 100 days post-transplantation, the incidence of grade I-IV acute GVHD was significantly lower in the ATG group than the FLU group (P<0.05). After 100 days post-transplant, extensive chronic GVHD (cGVHD) was more prevalent in the ATG group than the FLU group (P<0.05). There were lower cumulative risk of relapse and higher non-relapse-related mortality in the ATG group, but better QOL in the FLU group within 24 months, and no difference in 3-year disease-free survival (DFS) or overall survival (OS) between the 2 groups (P>0.05). CONCLUSIONS: The FLU-based conditioning regimen improved hematopoietic reconstitution and decreased extensive cGVHD, but there was no difference in 3-year DFS or OS between the 2 groups. PMID- 26238069 TI - TP53 mutations are associated with higher rates of pathologic complete response to anthracycline/cyclophosphamide-based neoadjuvant chemotherapy in operable primary breast cancer. AB - The role of TP53 mutations in predicting response to neoadjuvant chemotherapy in breast cancer remains controversial. The aims of this study were to investigate whether TP53 mutations were associated with response and survival in breast cancer patients who received neoadjuvant chemotherapy. Therefore, we identified TP53 mutations in the core-needle biopsy tumor samples obtained before the neoadjuvant chemotherapy from 351 operable primary breast cancer patients who either received anthracycline/cyclophosphamide-based (n = 252) or paclitaxel (n = 99) neoadjuvant chemotherapy. We found that 41.0% (144 of 351) of patients harbored TP53 mutations, and 14.8% of patients achieved a pCR (pathologic complete response) after neoadjuvant chemotherapy. Among patients treated with anthracycline/cyclophosphamide (n = 252), patients with TP53 mutations had a significantly higher pCR rate than those with wild-type (28.6 vs.7.1%; p < 0.001), and TP53 mutation was an independent favorable predictor of pCR [odds ratio (OR) = 3.41; 95% confidence interval (CI) 1.50-7.77; p = 0.003] in this group; moreover, patients with TP53 mutation had a better distant recurrence-free survival (DRFS) than those with wild-type [unadjusted hazard ratio (HR) = 0.43; 95% CI 0.20-0.94; p = 0.030] in this group. Among patients treated with paclitaxel (n = 99), no significant difference in pCR rates was observed between patients with or without TP53 mutations (15.2 vs. 11.3%; p = 0.57). Our results suggested that patients with TP53 mutations are more likely to respond to anthracycline/ cyclophosphamide-based neoadjuvant chemotherapy and have a favorable survival. PMID- 26238070 TI - HAUSP-nucleolin interaction is regulated by p53-Mdm2 complex in response to DNA damage response. AB - HAUSP (herpes virus-associated ubiquitin specific protease, known as ubiquitin specific protease 7), one of DUBs, regulates the dynamics of the p53 and Mdm2 network in response to DNA damage by deubiquitinating both p53 and its E3 ubiquitin ligase, Mdm2. Its concerted action increases the level of functional p53 by preventing proteasome-dependent degradation of p53. However, the protein substrates that are targeted by HAUSP to mediate DNA damage responses in the context of the HAUSP-p53-Mdm2 complex are not fully identified. Here, we identified nucleolin as a new substrate for HAUSP by proteomic analysis. Nucleolin has two HAUSP binding sites in its N- and C-terminal regions, and the mutation of HAUSP interacting peptides on nucleolin disrupts their interaction and it leads to the increased level of nucleolin ubiquitination. In addition, HAUSP regulates the stability of nucleolin by removing ubiquitin from nucleolin. Nucleolin exists as a component of the HAUSP-p53-Mdm2 complex, and both Mdm2 and p53 are required for the interaction between HAUSP and nucleolin. Importantly, the irradiation increases the HAUSP-nucleolin interaction, leading to nucleolin stabilization significantly. Taken together, this study reveals a new component of the HAUSP-p53-Mdm2 complex that governs dynamic cellular responses to DNA damage. PMID- 26238072 TI - [Retraction] Interleukin-11 induces the expression of matrix metalloproteinase 13 in gastric cancer SCH cells partly via the PI3K-AKT and JAK-STAT3 pathways. PMID- 26238071 TI - Emodin inhibits angiogenesis in pancreatic cancer by regulating the transforming growth factor-beta/drosophila mothers against decapentaplegic pathway and angiogenesis-associated microRNAs. AB - Emodin is a traditional Chinese medicine, which has been demonstrated to inhibit the growth of pancreatic cancer cells. However, the underlying molecular mechanisms remain to be elucidated. The present study investigated whether emodin suppresses angiogenesis in pancreatic cancer. A nude mouse pancreatic cancer xenograft model was established using SW1990 human pancreatic cancer cells by surgical orthotopic implantation. Different doses of emodin were injected into the abdominal cavities of the tumor-bearing mouse models and controls three times each week for 2 weeks. The tumors were measured and weighed, the expression of cluster of differentiation 34 was detected using immunochemistry, and microvessel densities were calculated. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were performed to determine the mRNA and protein expression levels of transforming growth factor (TGF)-beta and drosophila mothers against decapentaplegic (Smad) homologs. The angiogenesis-associated microRNAs (miR), miR-20, miR-155 and miR-210 were assessed by RT-qPCR. A negative dose-dependent association was revealed between treatment with emodin and the volume and weight of tumors and microvessel density. Emodin was associated with lower mRNA and protein expression levels of TGF-beta1 and its downstream target, angiopoietin-like 4, and higher mRNA and protein expression levels of TGF-beta receptor (TbetaR)I, TbetaRII and Smad4. Notably, treatment with emodin was associated with lower expression levels of miR-155 and miR-210 and higher expression levels of miR-20b. The present study suggested that treatment with emodin may repress angiogenesis in pancreatic cancer by altering the activities of the TGF-beta/Smad pathway and angiogenesis-associated miR-20b, miR-155, and miR-210. PMID- 26238073 TI - Identification of a non-coding KLF4 transcript generated from intron retention and downregulated in human hepatocellular carcinoma. AB - The Kruppel-like factor 4 (KLF4) gene is related to various biological processes including stem cell reprogramming and tumorigenesis. In this study, we identified and characterized a non-coding transcript of KLF4, which was designated KLF4-003, in human liver tissue samples. KLF4-003 was identified in a number of cell lines by reverse transcription PCR and DNA sequencing. Its expression levels were determined in 54 pairs of human hepatocellular carcinoma (HCC) tissues and a number of HCC cell lines by real-time PCR (RT-PCR). Methylation status of KLF4 003 CpG islands was determined by bisulfite sequencing. The regulatory effect of KLF4-003 CpG islands hypermethylation in Hep3B cells was then validated by the 5 aza-dC demethylation treatment, followed by RT-PCR analysis. Receiver operating characteristic (ROC) curve was created to evaluate the diagnostic value for differentiating between HCC cancer and benign diseases. The association study between KLF4-003 expression level and clinical traits of HCC patients was performed with SPSS. We found that KLF4-003 was downregulated in 46 out of 54 HCC samples compared with their adjunct normal tissues. The reduced KLF4-003 expression was significantly associated with HCC recurrence (P=0.045) in the follow-up of 31 HCC patients. Significant differences were detected between the methylation status of HCC specimens and their adjacent normal controls. Demethylation treatment significantly rescued the expression of KLF4-003 in Hep3B cells. Such observation indicated that the CpG island hypermethylation was at least partially responsible for the downregulation of KLF4-003 in HCC. The area under ROC curve for the prediction of HCC reached 0.803 (95% CI=0.719-0.886, P<0.001). Our results suggested that the expression of KLF4-003 was epigenetically regulated by methylation status of a KLF4-003 CpG island in HCC. The differential expression of KLF4-003 might play an important role in HCC development and might serve as a potential biomarker for the diagnosis of HCC. PMID- 26238074 TI - Attrition from surgical residency training: perspectives from those who left. AB - BACKGROUND: High rates of attrition from general surgery residency may threaten the surgical workforce. We sought to gain further insight regarding resident motivations for leaving general surgery residency. METHODS: We conducted in-depth interviews to generate rich narrative data that explored individual experiences. An interdisciplinary team used the constant comparative method to analyze the data. RESULTS: Four themes characterized experiences of our 19 interviewees who left their residency program. Participants (1) felt an informal contract was breached when clinical duties were prioritized over education, (2) characterized a culture in which there was no safe space to share personal and programmatic concerns, (3) expressed a scarcity of role models who demonstrated better work life balance, and (4) reported negative interactions with authority resulting in a profound loss of commitment. CONCLUSIONS: As general surgery graduate education continues to evolve, our findings may inform interventions and policies regarding programmatic changes to boost retention in surgical residency. PMID- 26238075 TI - Intraoperative radiotherapy for early breast cancer and age: clinical characteristics and outcomes. AB - BACKGROUND: Eligibility criteria for intraoperative radiation therapy (IORT) for breast cancer are being established. Impact of age, one criterion, on short-term complications/outcomes was evaluated. METHODS: Institutional Review Board approved retrospective review of early-stage breast cancer patients undergoing breast conserving surgery and IORT from January 2011 to June 2013 were reviewed. Data collected were demographics, comorbidities, histopathology, intraoperative data, adjuvant treatment, and outcomes. Local recurrence (LR), re-excision rates, and complications were evaluated by age group using descriptive statistics. RESULTS: The total number of patients was 100 (43 patients <70, 57 patients >=70). No significant differences existed between groups in tumor size, operative time, estrogen receptor status, nodal status, tumor grade, or margin excision. Wound infection rates were low for both groups (P = .21). Two LR occurred (both patients >=70). Median follow-up time was 24 months. CONCLUSION: IORT with its low rate of LR and wound complications may be a reasonable alternative to whole breast irradiation for early-stage breast cancer, regardless of age. PMID- 26238076 TI - ROS-induced nanotherapeutic approach for ovarian cancer treatment based on the combinatorial effect of photodynamic therapy and DJ-1 gene suppression. AB - This study represents a novel approach for intraoperative ovarian cancer treatment based on the combinatorial effect of a targeted photodynamic therapy (PDT) associated with suppression of the DJ-1 protein, one of the key players in the ROS defense of cancer cells. To assess the potential of the developed therapy, dendrimer-based nanoplatforms for cancer-targeted delivery of near infrared photosensitizer, phthalocyanine, and DJ-1 siRNA have been constructed. In vitro studies revealed that therapeutic efficacy of the combinatorial approach was enhanced when compared to PDT alone and this enhancement was more pronounced in ovarian carcinoma cells, which are characterized by higher basal levels of DJ 1 protein. Moreover, the ovarian cancer tumors exposed to a single dose of combinatorial therapy were completely eradicated from the mice and the treated animals showed no evidence of cancer recurrence. Thus, the developed therapeutic approach can be potentially employed intraoperatively to eradicate unresactable cancer cells. FROM THE CLINICAL EDITOR: The complete clearance of microscopic residual tumor cells during excision surgery is important to improve survival of the patient. In this interesting paper, the authors developed a novel approach using targeted photodynamic therapy (PDT), combining a photosensitizer, phthalocyanine, and DJ-1 siRNA for the treatment of ovarian cancer. The data showed that this approach increased cancer cell killing and may pave way for future clinical studies. PMID- 26238077 TI - Biodistribution, excretion, and toxicity of mesoporous silica nanoparticles after oral administration depend on their shape. AB - Mesoporous silica nanoparticles (MSNs) have been proven to be effective drug carriers for oral delivery. However, little attention has been paid to their in vivo biodistribution and toxicity after oral administration. The effect of particle shape on their in vivo behavior is also unknown. In this study, we systematically studied the acute toxicity and biodistribution of three types of MSNs with aspect ratios (ARs) of 1, 1.75 and 5 after oral administration. The effect of particle shape as a key physicochemical parameter of MSNs was discussed. With the increase of AR, MSNs showed decreased in vivo biodegradation, systematic absorption and excretion, especially decreased liver distribution and urinal excretion. During the period of urinal excretion, MSNs induced a shape dependent renal damage including hemorrhage, vascular congestion and renal tubular necrosis. These findings will enrich the knowledge to rationally engineer bionanomaterials, and bring new insights into nanotoxicity. FROM THE CLINICAL EDITOR: Advances in nanotechnology have resulted in improvement in drug delivery, of which mesoporous silica nanoparticles have been used as carriers for oral drugs. Nonetheless, studies on their absorption, distribution, metabolism, excretion (ADME) and toxicity still need to be performed. In this article, authors evaluated the effects of particle size and shape on in vivo behavior. The findings would shine light on future design of future drug delivery systems. PMID- 26238078 TI - Development of anti-HER2 fragment antibody conjugated to iron oxide nanoparticles for in vivo HER2-targeted photoacoustic tumor imaging. AB - Photoacoustic (PA) imaging is a promising imaging modality that provides biomedical information with high sensitivity and resolution. Iron oxide nanoparticles (IONPs) have been regarded as remarkable PA contrast agents because of their low toxicity and biodegradable properties. However, IONP delivery is restricted by its modest leakage and retention in tumors. In this study, we designed IONPs (20nm, 50nm, and 100nm) conjugated with anti-HER2 moieties [whole IgG, single-chain fragment variable (scFv), and peptide] for HER2-targeted PA tumor imaging. The binding affinity, cellular uptake, and in vivo biodistribution were examined. We propose 20-nm anti-HER2 scFv-conjugated IONPs (SNP20) as a novel PA contrast agent. SNP20 demonstrated high affinity and specific binding to HER2-expressing cells; it selectively visualized HER2-positive tumors in PA imaging studies. These data indicate that SNP20 is a potential PA contrast agent for imaging of HER2-expressing tumors. FROM THE CLINICAL EDITOR: Iron oxide nanoparticles have been demonstrated to be good contrast agents for tumor imaging. They may also be useful in photoacoustic (PA) imaging, which can provide high sensitivity data and image resolution. The authors here coupled iron oxide nanoparticles with anti-HER2 antibody fragment and showed significant retention of these nanoparticles in tumors. This combination may provide another option for enhanced imaging of tumors. PMID- 26238079 TI - Fluorescent CSC models evidence that targeted nanomedicines improve treatment sensitivity of breast and colon cancer stem cells. AB - To be able to study the efficacy of targeted nanomedicines in marginal population of highly aggressive cancer stem cells (CSC), we have developed a novel in vitro fluorescent CSC model that allows us to visualize these cells in heterogeneous population and to monitor CSC biological performance after therapy. In this model tdTomato reporter gene is driven by CSC specific (ALDH1A1) promoter and contrary to other similar models, CSC differentiation and un-differentiation processes are not restrained and longitudinal studies are feasible. We used this model for preclinical validation of poly[(d,l-lactide-co-glycolide)-co-PEG] (PLGA-co-PEG) micelles loaded with paclitaxel. Further, active targeting against CD44 and EGFR receptors was validated in breast and colon cancer cell lines. Accordingly, specific active targeting toward surface receptors enhances the performance of nanomedicines and sensitizes CSC to paclitaxel based chemotherapy. FROM THE CLINICAL EDITOR: Many current cancer therapies fail because of the failure to target cancer stem cells. This surviving population soon proliferates and differentiates into more cancer cells. In this interesting article, the authors designed an in vitro cancer stem cell model to study the effects of active targeting using antibody-labeled micelles containing chemotherapeutic agent. This new model should allow future testing of various drug/carrier platforms before the clinical phase. PMID- 26238080 TI - Next generation covered stents made from nanocomposite materials: A complete assessment of uniformity, integrity and biomechanical properties. AB - Covered stents are stents wrapped with a thin polymeric membrane, and are typically used to treat vessel aneurysms and seal perforated arteries. Current covered stents suffer from restenosis due to limitations in material and fabrication methods which leaves metallic struts directly exposed to blood. We have developed a biocompatible and haemocompatible nanocomposite polymer, polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU). We devised a novel combination of ultrasonic spray atomisation system and dip coating process to produce small calibre covered stents with metal struts fully embedded within the membrane, which also yields greater coating uniformity. Stent polymer bonding was enhanced via silanisation and coating of reactive pre polymer. Platelet studies supported the non-thrombogenicity of POSS-PCU. Biomechanical performances including diametrical compliance, bending strength, radial strength and recoil were evaluated and optimised. This proof-of-principle manufacturing technique could lead to the development of next-generation small calibre adult and paediatric covered stents. These stents are currently undergoing preclinical trial. From the Clinical Editor: The use of stents to treat vascular diseases is now the standard of care in the clinical setting. Nonetheless, a major problem of the current stents is the risk of restenosis and thrombosis. The authors developed a nanocomposite material using polyhedral oligomeric silsesquioxane and poly(carbonate-urea) urethane (POSS-PCU) and incorporated into metallic stents. Preliminary data have already shown promising results. It is envisaged that this would further lead to better stent technology in the future. PMID- 26238081 TI - Combined effects of PLGA and vascular endothelial growth factor promote the healing of non-diabetic and diabetic wounds. AB - Growth factor therapies to induce angiogenesis and thereby enhance the blood perfusion, hold tremendous potential to address the shortcomings of current impaired wound care modalities. Vascular endothelial growth factor stimulates (VEGF) wound healing via multiple mechanisms. Poly(lactic-co-glycolic acid) (PLGA) supplies lactate that accelerates neovascularization and promotes wound healing. Hence, we hypothesized that the administration of VEGF encapsulated in PLGA nanoparticles (PLGA-VEGF NP) would promote fast healing due to the sustained and combined effects of VEGF and lactate. In a splinted mouse full thickness excision model, compared with untreated, VEGF and PLGA NP, PLGA-VEGF NP treated wounds showed significant granulation tissue formation with higher collagen content, re-epithelialization and angiogenesis. The cellular and molecular studies revealed that PLGA-VEGF NP enhanced the proliferation and migration of keratinocytes and upregulated the expression of VEGFR2 at mRNA level. We demonstrated the combined effects of lactate and VEGF for active healing of non diabetic and diabetic wounds. FROM THE CLINICAL EDITOR: The study of wound healing has been under a tremendous amount of research over recent years. In diabetic wounds, vasculopathy leading to localized ischemia would often result in delayed ?wound healing. In this article, the authors encapsulated vascular endothelial growth factor stimulates (VEGF) in PLGA nanoparticles and studies the potential pro-healing effects. It was found that the combination of these two components provided synergistic actions for healing. The encouraging results should provide a basis for combination therapy in the future. PMID- 26238082 TI - miR-219-5p plays a tumor suppressive role in colon cancer by targeting oncogene Sall4. AB - Sall4 is a novel oncogene found upregulated in several malignancies including colon cancer. However, its upstream regulatory miRNA is still undefined. miR-219 5p is regarded as a tumor-related miRNA in cancer research. Nevertheless, its actual role of whether inhibiting or promoting tumorigenesis is unclear in colon cancer. Potential interaction between Sall4 and miR-219-5p is predicted by TargetScan. CCK-8 test was used for evaluation of cell proliferation and cell survival rates. Western blot analysis and real-time PCR were applied for detection of target molecules. Luciferase assay was a direct confirmation of mutual interaction. Wound healing assay and transwell assay were conducted for cell migration and invasion tests. Flow cytometry was used for cell apoptosis analysis. Tissue specimens and cell lines were explored for miR-219-5p inhibition on colon cancer proliferation, migration, invasion, apoptosis and drug resistance by targeting Sall4. The results show that miR-219-5p inhibited carcinogenesis of colon cancer by targeting oncogene Sall4. PMID- 26238083 TI - Does the death knell toll for phlebotomy in NAFLD? PMID- 26238085 TI - Prognostic factors in surgical resection of sacral chordoma. AB - BACKGROUND AND OBJECTIVES: The best treatment of sacral chordoma is surgical resection, nowadays associated with optimized radiation therapy. We analysed 1) the oncologic outcome in a large series; 2) the effect of previous intralesional surgery, resection level, tumor volume and margins on survivorship to local recurrence (LR) and 3) the complication rate. METHODS: We reviewed 71 patients with sacral chordomas. Forty-eight resections were proximal to S3. Mean tumor volume was 535 cm3. Eleven received previous intralesional surgery elsewhere. Margins were wide in 44 resections, wide-contaminated in 11, marginal in 9 and intralesional in 7. RESULTS: Overall survival was 92%, 65% and 44% at 5, 10 and 15 years. At a mean of 9.5 years 37 were NED (54.4%), 23 died with disease (33.8%) and 8 were alive with disease (11.7%). Relapses included 15 LRs, 6 distant metastases, 17 both. LR rate was significantly higher in patients with previous surgery (p=0.0217), with inadequate margins (p= 0.0339) and large tumors(p<0.01), whereas resection level was not significant. Multivariate analysis confirmed the role of tumor volume. Complication rate was high (80.9%) with an infection rate of 41.2%. CONCLUSIONS: The most prominent adverse factor for LR was previous intralesional surgery. LR rate was related with inadequate margins and tumor volume. PMID- 26238084 TI - Role of PI4K and PI3K-AKT in ERK1/2 activation by GnRH in the pituitary gonadotropes. AB - The role of PI4K and PI3K-AKT in ERK1/2 activation by GnRH was examined. A relatively long preincubation (60 min) with wortmannin (10 nM and 10 MUM), and LY294002 (10 MUM and 100 MUM) (doses known to inhibit PI3K and PI4K, respectively), were required to inhibit GnRH-and PMA-stimulated ERK1/2 activity in alphaT3-1 and LbetaT2 gonadotrope cells. A similar preincubation protocol was required to demonstrate inhibition of IGF-1-stimulated AKT activation lending support for the need of prolonged incubation (60 min) with wortmannin in contrast to other cellular systems. To rule out that the inhibitors acted upon PI(4,5)P2 levels, we followed the [Ca(2+)]i response to GnRH and found that wortmannin has no significant effect on GnRH-induced [Ca(2+)]i responses. Surprisingly, GnRH and PMA reduced, while IGF-1 increased AKT phosphorylation. We suggest that PI3K inhibits GnRH-stimulated alphaGSU activity, has no effect upon GnRH-stimulated LHbeta activity and enhanced the GnRH-stimulated FSHbeta transcription. Hence, PI4K and PI3K-AKT play a role in GnRH to ERK1/2 signaling, while PI3K may regulate also GnRH-induced gonadotropin gene expression. PMID- 26238086 TI - Antiradical capacity of ommochromes. AB - Ommochromes are colored substances that apparently function as biological signals among arthropods and insects. These substances may prevent oxidative stress by scavenging free radicals. Two principal mechanisms exist for scavenging free radicals: the electron transfer and hydrogen atom transfer. In this investigation, a theoretical study of the antiradical capacity of five ommochromes was performed within the density functional theory framework. Vertical ionization energy and vertical electron affinity were used to study the electron transfer mechanism between ommochromes and four free radicals: CH3O*, NO2*, HO*, and HOO*. For the hydrogen transfer mechanism, dissociation energy (D0) and Gibbs free energy were calculated, taking into account hydrogen atoms at different positions in the ommochromes. Both mechanisms are thermodynamically possible. The best antiradical is ommatin D. The UV/VIS spectra for ommochromes were obtained with ommatin D registering as the ommochrome with the greatest lambdamax value. In summary, ommatin D is the best antiradical and also the redder molecule. These results are important and may help to elucidate the function of these molecules in the animal kingdom. Graphical abstract Ommochromes are red and yellow substances present in arthropods and insects. According with computational chemistry, these substances present the capacity of prevent oxidative stress since they scavenge free radicals. These results may help to elucidate the function of these molecules in the animal Kingdom. PMID- 26238088 TI - Systematic review of barriers and facilitators to accessing and engaging with mental health care among at-risk young people. AB - INTRODUCTION: This study aims to review the literature on barriers and facilitators to accessing and engaging with mental health care among young people from potentially disadvantaged groups, including young people identified as Aboriginal or Torres Strait Islander (ATSI); culturally and linguistically diverse (CALD); lesbian, gay, bisexual, transgender, queer, or intersex (LGBTQI); homeless; substance using; and youth residing in rural or remote areas. METHODS: Fourteen databases were searched to identify qualitative and quantitative researches that examined barriers and/or facilitators to mental health care among the six groups of potentially disadvantaged young people. RESULTS: Out of 62 studies identified, 3 were conducted with ATSI young people, 1 with CALD young people, 4 with LGBTQI young people, 14 with homeless young people, 24 with substance-using young people, and 16 with young people residing in rural or remote areas. Findings generally confirmed barriers already established for all young people, but indicated that some may be heightened for young people in the six identified groups. Findings also pointed to both similarities and differences between these groups, suggesting that ATSI, CALD, LGBTQI, homeless, substance using, and rural young people have some similar needs with respect to not only mental health care, but also other needs likely to reflect their individual circumstances. DISCUSSION: This systematic review highlights that young people from potentially disadvantaged groups have distinct needs that must be recognized to improve their experiences with mental health care. Future research of good methodological quality with young people is needed to increase accessibility of, and engagement with, mental health care. PMID- 26238087 TI - Factors associated with failure of enhanced recovery programs after laparoscopic colon cancer surgery: a single-center retrospective study. AB - BACKGROUND: Although enhanced recovery programs (ERPs) have been proven to be beneficial after laparoscopic colon surgery, they may result in adverse clinical outcomes following failure. This study analyzed risk factors associated with ERP failure after laparoscopic colon cancer surgery. METHODS: We analyzed the outcomes of 208 patients who underwent ERPs following laparoscopic colon cancer surgery between June 2007 and April 2013. The ERP included early oral feeding, early ambulation, and regular laxative administration. ERP failure was defined as postoperative hospital stay of more than 5 days related to postoperative complications, unplanned readmission within 30 days of surgery, or death. RESULTS: Surgical procedures included anterior resection (n = 101), right hemicolectomy (n = 90), and left hemicolectomy (n = 17). The mean postoperative hospital stay was 6.5 +/- 2.3 days (range 3-24 days). ERP failure occurred in 36 patients (17.3%), with no mortality; reasons included ileus (n = 14), wound infection (n = 4), chylous drainage (n = 3), anastomotic bleeding (n = 3), pneumonia (n = 1), or readmission (n = 11) owing to delayed complications. Univariable analysis showed that ERP failure was associated with proximal colon cancer, side-to-side anastomosis, longer operation time, increased blood loss, and longer resected specimen length. Multivariable analysis showed that side-to side anastomosis [odds ratio (OR) 4.534; 95% confidence interval (CI) 1.902 10.811; P = 0.001] and increased blood loss (OR 1.004; 95% CI 1.001-1.008; P = 0.041) were independent risk factors for ERP failure. CONCLUSIONS: We showed that increased blood loss and side-to-side anastomosis in comparison with end-to-end anastomosis were independent risk factors associated with ERP failure after laparoscopic colon cancer surgery. This suggests that intraoperative elements may be important determinants to obtain successful postoperative recovery in the era of ERP. PMID- 26238089 TI - Sensory recalibration integrates information from the immediate and the cumulative past. AB - Vision usually provides the most accurate and reliable information about the location of objects in our environment, and thus serves as a reference for recalibrating auditory spatial maps. Recent studies have shown that recalibration does not require accumulated evidence of cross-modal mismatch to be triggered, but occurs as soon as after one single exposure. Here we tested whether instantaneous recalibration and recalibration based on accumulated evidence represent the same underlying learning mechanism or involve distinct neural systems. Participants had to localize two sounds, a low- and a high-frequency tone, which were paired with opposite directions of audiovisual spatial mismatch (leftward vs. rightward). In accordance with the cumulative stimulus history, localization in unimodal auditory trials was shifted in opposite directions for the two sound frequencies. On a trial-by-trial basis, however, frequency-specific recalibration was reduced when preceded by an audiovisual stimulus with a different sound frequency and direction of spatial mismatch. Thus, the immediate past invoked an instantaneous frequency-invariant recalibration, while the cumulative past invoked changes in frequency-specific spatial maps. These findings suggest that distinct recalibration mechanisms operating at different timescales jointly determine sound localization behavior. PMID- 26238090 TI - Probiotics modify human intestinal mucosa-associated microbiota in patients with colorectal cancer. AB - Studies using animal models have demonstrated that probiotics may have a beneficial role in the prevention of colorectal cancer (CRC); however, the underlying mechanism of the beneficial effects of interventional probiotic treatment on gut microbiota has remained elusive. In the present study, pyrosequencing of the V3 region of the 16S rRNA genes was conducted in order to determine the extent to which probiotics alter the microbiota. The observations of the present study indicated that the microbial structure of cancerous tissue differed significantly from that of healthy individuals and that the CRC microbiota exhibited lower diversity. It was indicated that interventional treatment with probiotics increased the density and diversity of mucosal microbes, and altered the mucosa-associated microbiota. Pyrosequencing demonstrated that probiotics significantly reduced (5-fold) the abundance of a bacterial taxon assigned to the genus Fusobacterium, which had been previously suggested to be a contributing factor to increase tumorigenesis. Accordingly, interventional probiotic therapy is suggested to be able to improve the composition of the mucosal microbial flora and significantly reduce the abundance of mucosa-associated pathogens in patients with CRC. PMID- 26238091 TI - The Heuristic of Form: Mitochondrial Morphology and the Explanation of Oxidative Phosphorylation. AB - In the 1950s and 1960s, the search for the mechanism of oxidative phosphorylation by biochemists paralleled the description of mitochondrial form by George Palade and Fritiof Sjostrand using electron microscopy. This paper explores the extent to which biochemists studying oxidative phosphorylation took mitochondrial form into account in the formulation of hypotheses, design of experiments, and interpretation of results. By examining experimental approaches employed by the biochemists studying oxidative phosphorylation, and their interactions with Palade, I suggest that use of mitochondrial form as a guide to experimentation and interpretation varied considerably among investigators. Most notably, Peter Mitchell, whose chemiosmotic hypothesis was ultimately the basis of the correct mechanism of oxidative phosphorylation, incorporated crucial aspects of mitochondrial form into his model that others failed to recognize. I discuss these historical observations in terms of the background and training of the biochemists, as well as a proposed heuristic of form, whose use may increase the possibility that biologically meaningful molecular mechanisms will be discovered. PMID- 26238092 TI - On the Origins of the Quinarian System of Classification. AB - William Sharp Macleay developed the quinarian system of classification in his Horae Entomologicae, published in two parts in 1819 and 1821. For two decades, the quinarian system was widely discussed in Britain and influenced such naturalists as Charles Darwin, Richard Owen, and Thomas Huxley. This paper offers the first detailed account of Macleay's development of the quinarian system. Macleay developed his system under the shaping influence of two pressures: (1) the insistence by followers of Linnaeus on developing artificial systems at the expense of the natural system and (2) the apparent tension between the continuity of organic nature and the failure of linear classification schemes (which continuity seemed to require). Against what he perceived as dogmatic indolence on the part of the Linnaeans, Macleay developed a philosophy of science in which hypotheses that exceeded the available evidence should be proposed and subjected to severe tests. He also developed a novel comparative anatomical methodology, the method of variation, to aid in his search for the natural system. Using this method, he developed an intricate system that showed how organic nature could be continuous without being linear. A failure to appreciate these facets of Macleay's thought has led to several misunderstandings of him and his work, most notably that he was an idealist. These misunderstandings are here rebutted. PMID- 26238093 TI - Real-time sonoelastography findings of a hypermobile child: a new technique in the assessment of tendon laxity. PMID- 26238095 TI - Draft genome of Kocuria polaris CMS 76or(T) isolated from cyanobacterial mats, McMurdo Dry Valley, Antarctica: an insight into CspA family of proteins from Kocuria polaris CMS 76or(T). AB - Kocuria polaris strain CMS 76or(T) is a gram-positive, orange-pigmented bacterium isolated from a cyanobacterial mat sample from a pond located in McMurdo Dry Valley, Antarctica. It is psychrotolerant, orange pigmented, hydrolyses starch and Tween 80 and reduces nitrate. We report the 3.78-Mb genome of K. polaris strain CMS 76or(T), containing 3416 coding sequences, including one each for 5S rRNA, 23S rRNA, 16S rRNA and 47 tRNA genes, and the G+C content of DNA is 72.8%. An investigation of Csp family of proteins from K. polaris strain CMS 76or(T) indicated that it contains three different proteins of CspA (peg.319, peg.2255 and 2832) and the length varied from 67 to 69 amino acids. The three different proteins contain all the signature amino acids and two RNA binding regions that are characteristic of CspA proteins. Further, the CspA from K. polaris strain CMS 76or(T) was different from CspA of four other species of the genus Kocuria, Cryobacterium roopkundense and E. coli indirectly suggesting the role of CspA of K. polaris strain CMS 76or(T) in psychrotolerant growth of the bacterium. PMID- 26238094 TI - Factors associated with the intensification of treatment in rheumatoid arthritis in clinical practice. AB - The aim of the present study was to analyse the patterns of treatment adjustment in rheumatoid arthritis (RA) patients with active disease in routine clinical care. This was a cross-sectional study of consecutive patients with RA conducted in five hospitals. Activity scales (DAS28-ESR) and function (HAQ) were measured, as well as whether ultrasound was performed as part of the assessment. Treatment decision (no changes/reduction/intensification) and time to the next scheduled visit were the outcomes variables. Associated factors were analysed by multilevel regression models. A total of 343 patients were included (77 % women, mean age 57 years, mean RA duration 10 years), of whom 44 % were in remission by DAS28. Treatment was continued in 202 (59 %) patients, reduced in 57 (16 %), and intensified in 83 (24 %). In the 117 patients with active RA (DAS28 >= 3.2), treatment was intensified in 61 (52 %). Factors associated with treatment intensification were physician and patient VAS, and DAS28, but not the centre. In the multilevel regression analysis with intensification of treatment as dependent variable, the following factors were significantly associated: DAS28 [OR 3.67 (95 % CI 2.43-5.52)], patient VAS [OR 1.04 (95 % CI 1.01-1.08)], and have performed an ultrasound [OR 3.36 (95 % CI 1.47-7.68)]. Factors associated with time to the next scheduled visit (an average of 4.3 months) were patient and physician VAS, DAS28, and centre. In clinical practice, half of the patients with active RA maintain or reduce the treatment. The decision to intensify treatment in active RA as recommended by a treat-to-target strategy is complex in practice. PMID- 26238096 TI - Leak or Fistula After Sleeve Gastrectomy: Treatment with Pigtail Drain by the Rendezvous Technique. AB - After a sleeve gastrectomy, a leak or fistula is a serious complication. Laparoscopic drainage, drainage under US or CT scan control, or endoscopic insertion of a stent can be used, but a major re-operation is sometimes unavoidable. Endoscopic drainage with a pigtail catheter could give more success and fewer complications, but the insertion of the drain is not always possible nor does it always provide a perfect drainage. If a laparoscopic second look appears necessary, it is possible to insert a pigtail drain laparoscopically, but under endoscopic control, ensuring a correct positioning of the drain both in the peritoneal cavity and in the gastric tube. This simultaneous "rendezvous" technique could combine in this situation the advantages of purely surgical techniques and of purely endoscopic or image-guided techniques. PMID- 26238097 TI - Newly designed delta neutrophil index-to-serum albumin ratio prognosis of early mortality in severe sepsis. AB - PURPOSE: We evaluated the ratio of delta neutrophil index (DNI) to albumin (A) in patients receiving early goal-directed therapy (EGDT) to determine the prognostic significance of the DNI/A ratio as a marker of early mortality in critically ill patients with suspected sepsis. METHODS: We retrospectively analyzed records from a prospective EGDT registry in an emergency department (ED) and screened eligible adult patients who were admitted to the ED with severe sepsis and/or septic shock. The new DNI/A ratio was calculated as the DNI value on each hospital day divided by the initial albumin level on ED admission. The clinical outcome was mortality after 28 days. RESULTS: A total of 120 patients receiving EGDT were included in this study. Multivariate Cox proportional-hazard models revealed that higher DNI/A ratios on day 1 (hazard ratio [HR], 1.068; 95% confidence interval [CI], 1.01-1.13; P = .0209) and the peak day (HR, 1.057; 95% CI, 1.001-1.116; P = .0456) were independent risk factors for mortality at 28 days. Our study demonstrated that the increased trend toward 28-day mortality was associated with a DNI/A ratio greater than 8.4 on day 1 (HR, 2.513; 95% CI, 0.950-6.64; P = .0528) and a higher DNI/A ratio (>6.4) on the peak day (average, 4.2 days; HR, 2.953; 95% CI, 1.033-8.441; P < .001) in patients with severe sepsis receiving EGDT. CONCLUSION: The ratio of DNI to serum albumin on ED admission is a promising prognostic marker of 28-day mortality in patients with severe sepsis receiving EGDT. PMID- 26238098 TI - Drinking to near death--acute water intoxication leading to neurogenic stunned myocardium. AB - Neurogenic stunned myocardium is a rare disease entity that has been typically described as a consequence of subarachnoid hemorrhage and, less commonly, seizures. Here we describe a case of a healthy young woman who drank excessive free water causing acute hyponatremia complicated by cerebral edema and seizure, leading to cardiogenic shock from neurogenic stunned myocardium. Two days later, she had complete return of her normal cardiac function. PMID- 26238100 TI - Optimal compressive force accelerates osteoclastogenesis in RAW264.7 cells. AB - Mechanical stress produced by orthodontic forces is a factor in the remodeling of periodontal ligaments (PDLs) and alveolar bone. It has been reported that the expression of a number of cytokines associated with osteoclastogenesis is upregulated when compressive forces act on osteoblasts and PDL cells. The present study investigated the effects of compressive forces on the formation of osteoclasts from the macrophage cell line RAW264.7. Compressive forces on osteoclasts were exerted using layers of 3, 5, 7, 9 or 14 glass cover slips on the 4th day of culture for 24 h. The number of osteoclasts was determined by counting the number of cells positive for tartrate-resistant acid phosphatase staining. Osteoclastogenesis advanced rapidly on days four and five. The number of osteoclasts with >8 nuclei peaked when the force of 7 slips was applied, which was therefore regarded as the optimal compressive force. Alterations in the expression of osteoclast-associated genes are associated with changes in the differentiation and fusion of macrophages in response to compressive forces; therefore, osteoclast-associated genes were assessed by reverse transcription quantitative polymerase chain reaction in the present study. The mRNA expression of osteoclast-associated genes increased significantly after 3 h of optimal compression, whereas mRNA expression increased after 24 h in the control group. These findings suggested that osteoclastogenesis of macrophages was accelerated when an optimal compressive force was applied. PMID- 26238099 TI - Mechanical properties of lipid bilayers from molecular dynamics simulation. AB - Lipid areas (Al), bilayer area compressibilities (KA), bilayer bending constants (KC), and monolayer spontaneous curvatures (c0) from simulations using the CHARMM36 force field are reported for 12 representative homogenous lipid bilayers. Al (or their surrogate, the average deuterium order parameter in the "plateau region" of the chain) agree very well with experiment, as do the KA. Simulated KC are in near quantitative agreement with vesicle flicker experiments, but are somewhat larger than KC from X-ray, pipette aspiration, and neutron spin echo for saturated lipids. Spontaneous curvatures of bilayer leaflets from the simulations are approximately 30% smaller than experimental values of monolayers in the inverse hexagonal phase. PMID- 26238101 TI - Chronic rhinosinusitis (CRS). PMID- 26238102 TI - Erratum. PMID- 26238103 TI - Erratum. PMID- 26238104 TI - Erratum. PMID- 26238105 TI - A GWAS assessment of the contribution of genomic imprinting to the variation of body mass index in mice. AB - BACKGROUND: Genomic imprinting is an epigenetic mechanism that can lead to differential gene expression depending on the parent-of-origin of a received allele. While most studies on imprinting address its underlying molecular mechanisms or attempt at discovering genomic regions that might be subject to imprinting, few have focused on the amount of phenotypic variation contributed by such epigenetic process. In this report, we give a brief review of a one-locus imprinting model in a quantitative genetics framework, and provide a decomposition of the genetic variance according to this model. Analytical deductions from the proposed imprinting model indicated a non-negligible contribution of imprinting to genetic variation of complex traits. Also, we performed a whole-genome scan analysis on mouse body mass index (BMI) aiming at revealing potential consequences when existing imprinting effects are ignored in genetic analysis. RESULTS: 10,021 SNP markers were used to perform a whole-genome single marker regression on mouse BMI using an additive and an imprinting model. Markers significant for imprinting indicated that BMI is subject to imprinting. Marked variance changed from 1.218 *10(-4) to 1.842 *10(-4) when imprinting was considered in the analysis, implying that one third of marked variance would be lost if existing imprinting effects were not accounted for. When both marker and pedigree information were used, estimated heritability increased from 0.176 to 0.195 when imprinting was considered. CONCLUSIONS: When a complex trait is subject to imprinting, using an additive model that ignores this phenomenon may result in an underestimate of additive variability, potentially leading to wrong inferences about the underlying genetic architecture of that trait. This could be a possible factor explaining part of the missing heritability commonly observed in genome-wide association studies (GWAS). PMID- 26238107 TI - Actinoplanes tropicalis sp. nov. and Actinoplanes cibodasensis sp. nov., isolated from leaf litter. AB - Two actinomycete strains, designated LIPI11-2-Ac034T and LIPI11-2-Ac042T, were isolated from leaf litter collected from Cibodas Botanical Garden, West Java, Indonesia. Phylogenetic analysis based on 16S rRNA gene sequences suggested that both isolates belong to the genus Actinoplanes. These isolates were closely related to Actinoplanes ferrugineus and Actinoplanes durhamensis with similarity values of 98.2 % and 97.7 % respectively, for strain LIPI11-2-Ac034T, and 99.0 % and 97.4-97.7 % respectively for strain LIPI11-2-Ac042T. Both isolates grew well on ISP 7 medium with brown soluble pigment production. Spores were motile and sporangia were irregular. The isolates contained meso-diaminopimelic acid in cell wall hydrolysates, and mannose, glucose and galactose in whole-cell hydrolysates. The predominant menaquinone of strain LIPI11-2-Ac034T was MK-9(H4) while that of strain LIPI11-2-Ac042T was MK-9(H6). The major cellular fatty acids were iso-C16 : 0, iso-C15 : 0 and anteiso-C15 : 0 for strain LIPI11-2-Ac034T, and iso-C16 : 0, anteiso-C15 : 0, iso-C15 : 0 and anteiso-C17 : 0 for strain LIPI11-2-Ac042T. Phosphatidylethanolamine was detected as the diagnostic polar lipid. The DNA G+C contents of strains LIPI11-2-Ac034T and LIPI11-2-Ac042T were 71.5 and 70.7 mol%, respectively. Based on the differential phenotypic characteristics and the results of DNA-DNA hybridization and phylogenetic analysis, it is proposed that strains LIPI11-2-Ac034T and LIPI11-2-Ac042T represent two novel species of the genus Actinoplanes, for which the names Actinoplanes tropicalis sp. nov. (type strain LIPI11-2-Ac034T = InaCC A459T = NBRC 110973T) and Actinoplanes cibodasensis sp. nov. (type strain LIPI11-2-Ac042T = InaCC A458T = NBRC 110974T) are proposed. PMID- 26238106 TI - Fluctuation between Powerlessness and Sense of Meaning--A Qualitative Study of Health Care Professionals' Experiences of Providing Health Care to Older Adults with Long-Term Musculoskeletal Pain. AB - BACKGROUND: There is an increasing number of older adults living with long-term musculoskeletal pain and related disabilities. These problems are frequently unrecognized, underreported, and inadequately treated. Since many older adults desire to remain at home for as long as possible, it is important that individualized and holistically tailored care is provided in these settings. However, there is a complexity in providing care in this context. The aim of this study was to describe health care professionals' experiences of providing health care to older adults living with long-term musculoskeletal pain at home. METHODS: The phenomenon, "To provide health care to older adults living with long-term musculoskeletal pain at home", was studied using reflective lifeworld research (RLR) which is based on phenomenological epistemology. Ten health care providers (nurse, physiotherapists, and occupational therapists) were interviewed and data was analysed. RESULTS: The health care professional's emotions fluctuated between powerlessness and meaningfulness. Needs, opportunities, understanding and respect had to be balanced in the striving to do good in the provision of health care in differing situations. Caring for older adults with long-term pain required courage to remain in the encounter despite feelings of insecurity and uncertainty about the direction of the dialogue. The essence of caring for older adults with long-term pain consisted of the following constituents: Sense of powerlessness; striving to provide good health care; and understanding and respect. CONCLUSIONS: The findings indicated that the health care professionals strived to do good and to provide health care that was holistic and sensitive to the older adults' needs. A significant sense of powerlessness in the situation was experienced by the health care professionals. These findings address and support the need to develop methods that can be used to guide health care providers who support older adults in the context of their homes. PMID- 26238108 TI - Prokaryotic expression and mechanism of action of alpha-helical antimicrobial peptide A20L using fusion tags. AB - BACKGROUND: Antimicrobial peptides have become important candidates as new antibiotics against resistant bacterial strains. However, the major industrial manufacture of antimicrobial peptides is chemical synthesis with high costs and in relatively small scale. The Ub-tag and SUMO-tag are useful for increasing the yield of enzymes and other proteins in expression system. In this study, antimicrobial peptide A20L (KWKSFLKTFKSAKKTVLHTLLKAISS), a derivative of V13K in the previous study is used as a template to be expressed in different Ub-tag and human SUMO tag systems to compare the prokaryotic expression approaches of antimicrobial peptide. The antibacterial mechanism of action and membrane specificity of A20L was further studied. METHODS: We fused the Ub and SUMO1/2/3/4 with A20L to construct expression plasmids. Ub-A20L and SUMO1/2/34 gene sequences were inserted into the pHUE plasmids and pET-28b+ plasmids, respectively, to construct pHUE-A20L plasmids and pET-28b+-SUMO1/2/3/4-A20L plasmids. These plasmids were transformed into E. coli Rosetta (DE3) and induced with IPTG to express Ub-A20L and SUMO1/2/3/4 fusion proteins. The recombinant proteins were found in the soluble fraction after being over expressed in E. coli Rosetta (DE3). Antibacterial and hemolytic activities and membrane permeabilization ability of A20L were determined. Peptide structure was also studied by circular dichroism experiments. RESULTS: A20L (KWKSFLKTFKSAKKTVLHTLLKAISS) was successfully expressed by fusion with an ubiquitin tag (Ub-tag) and human SUMO tags (SUMO1/2/3/4-tags). A20L exhibited antimicrobial activity against various Gram-negative and Gram-positive bacteria. Based on the hemolytic activity against human red blood cells, A20L showed good specificity against bacteria. The circular dichroism experiments illustrated that A20L was transferred into an alpha-helical structure in the presence of hydrophobic environment. The antibacterial mechanism of action and membrane specificity of A20L was further studied using membrane permeabilization experiments and tryptophan fluorescence and quenching experiments in liposomes. CONCLUSIONS: The Ub-tag and human SUMO tags represent good alternatives to chemical synthesis for the industrial production of antimicrobial peptides with low costs and high yields. The antibacterial mechanism of action of A20L was proved as membrane disruption. A20L showed stronger specificity on liposomes mimicking bacterial membrane than those mimicking eukaryotic cell membrane, which is consistent with the biological activity studies. PMID- 26238109 TI - Asymptomatic Plasmodium falciparum infections may not be shortened by acquired immunity. AB - BACKGROUND: The duration of untreated Plasmodium falciparum infections is a defining characteristic of the parasite's biology. It is not clear whether naturally acquired immunity (NAI) can shorten infections, despite the potential implications for malaria control and elimination as well as for basic research. METHODS: Data on the presence of P. falciparum msp2 genotypes in six blood samples collected over one year was analysed, together with four samples collected over 1 week, from a cohort in Navrongo (Ghana). Mathematical models assuming either exponential, Weibull, gamma, or log-normal infection durations were estimated separately for six age-groups. The method allowed for varying clonal acquisition and detection rates. RESULTS: The best fitting (Weibull) mean durations were 124 days (children <5 years old), 179 days (5-9 years), and 70-90 days (>10 years). This non-monotonic age pattern is not suggestive of an infection-clearing effect of NAI since immunity increases with exposure, and thus, age. Age-related differences in innate immunity are a more plausible explanation. 21% of blood-stage infections terminated within 1 week, in stark contrast to months of persistence in infections induced in neuro-syphilis patients (malariatherapy data). Age independence in this percentage raises the possibility that this clearance may result from innate mechanisms or genetic incompatibility between hosts and parasites, rather than from NAI. CONCLUSION: In all ages of hosts a substantial proportion of infections are cleared in the first days or weeks of appearance in the blood, while others persist for many months. Although cumulative exposure and NAI increase with age, this does apparently not translate into an increased rate of termination of infections. PMID- 26238110 TI - Does Pharmaceutical Pricing Transparency Matter? Examining Brazil's Public Procurement System. AB - BACKGROUND: We review procurement and pricing transparency practices for pharmaceutical products. We specifically focus on Brazil and examine its approach to increasing pricing transparency, with the aim of determining the level of effectiveness in lower prices using a tool (Banco de Precos em Saude, BPS) that only reveals purchase prices as compared to other tools (in other countries) that establish a greater degree of price transparency. METHODS: A general report of Precos em Saude (BPS) and Sistema Integrado de Administracao de Servicos Gerais (SIASG) pricing data was created for 25 drugs that met specific criteria. To explore the linear time trend of each of the drugs, separate regression models were fitted for each drug, resulting in a total of 19 models. Each model controlled for the state variable and the interaction between state and time, in order to accommodate expected heterogeneity in the data. Additionally, the models controlled for procurement quantities and the effect they have on the unit price. Secondary analysis using mixed effects models was also carried out to account for the impact that institutions and suppliers may have upon the unit price. Adjusting for these predictor variables (procurement quantities, supplier, purchasing institution) was important to determine the sole effect that time has had on unit prices. A total of 2 x 19 = 38 models were estimated to explore the overall effect of time on changes in unit price. All statistical analyses were performed using the R statistical software, while the linear mixed effects models were fitted using the lme4 R package. RESULTS: The findings from our analysis suggest that there is no pattern of consistent price decreases within the two Brazilian states during the five-year period for which the prices were analyzed. CONCLUSIONS: While the BPS does allow for an increase in transparency and information on drug purchase prices in Brazil, it has not shown to lead to consistent reductions in drug purchase prices for some of the most widely used medicines. This is indicative of a limited model for addressing the challenges in pharmaceutical procurement and puts into question the value of tools used globally to improve transparency in pharmaceutical pricing. PMID- 26238111 TI - Effects of acupuncture on serum metabolic parameters in premenopausal obese women: study protocol for a randomized controlled trial. AB - BACKGROUND: Complex metabolic changes cause obesity, making weight loss difficult. For this reason, understanding metabolism is important, and considering the shortcomings of conventional treatment options for obesity, acupuncture is a possible option. However, evidence supporting its efficacy on metabolic parameters in obese patients is lacking. The aim of this study is to investigate the effects of acupuncture on serum metabolic parameters in premenopausal obese women. METHODS/DESIGN: This ongoing study is a randomized, patient-assessor blind, two-arm parallel non-penetrating sham-controlled clinical trial. Eligible participants, premenopausal adult women (19 years of age or older) with a clinical diagnosis of obesity (body mass index of 25 kg/m(2) or more) blinded to the treatment received, will be randomly allocated blindly into the real acupuncture treatment group (manual acupuncture plus electroacupuncture, n = 60) or the sham acupuncture control group (sham acupuncture plus placebo acupuncture without electrical stimulation, n = 60) and receive treatment two times a week for a total of 12 sessions over 6 weeks. The primary outcome measure is the serum cholesterol and triglyceride (TG) levels at baseline and endpoint. The secondary outcomes are body weight, body fat mass, muscle mass, waist and hip circumference, other serum metabolic profiles, International Physical Activity Questionnaire (IPAQ), Social Readjustment Rating Scale (SRRS), Stress Response Inventory (SRI), Fatigue Severity Scale (FSS), the Korean version of the Beck Depression Inventory (BDI), and urine metabolites. Adverse events will be assessed at every visit. DISCUSSION: The results of this trial (which will be available in 2015) will provide important clinical evidence for the effect of acupuncture on serum metabolites and demonstrate how acupuncture can be helpful for the treatment of obesity. TRIAL REGISTRATION: Trial registration registered via US National Institutes of Health Clinical Trials registry (ClinicalTrials.gov) on 11 November 2014, identifier: NCT02066090 . PMID- 26238112 TI - Ischemia-Modified Albumin and Atherosclerosis in Patients With Familial Mediterranean Fever. AB - The constriction of vessels due to atherosclerotic lesions causes hypoxia/ischemia and oxidative changes resulting in transformation of free albumin to ischemia-modified albumin (IMA) in the circulation and increased carotid intima-media thickness (cIMT). We investigated the reliability of IMA increase in evaluating atherosclerosis in patients with familial Mediterranean fever (FMF) compared with cIMT. Patients with FMF (n = 58) diagnosed by the Tel Hashomer criteria in attack-free period and 38 healthy people were included in the study. Patient demographics as well as the clinical and laboratory characteristics of the healthy controls and patients with FMF were noted. The IMA levels and cIMT in patients with FMF were 0.30 +/- 0.09 absorbance units (ABSUs) and 1.12 +/- 0.27 mm, respectively, and in the control group, IMA levels and cIMT were 0.25 +/- 0.07 ABSU and 0.74 +/- 0.26 mm, respectively. The IMA levels and cIMT were significantly higher in patients with FMF than in controls (P= .020 andP< .0001, respectively). The IMA values showed positive correlation with cIMT in patients with FMF(r= .302,P= .041). Our results reveal that IMA--an oxidative stress marker--may be an indicator of atherosclerosis in patients with FMF. This finding deserves further investigation. PMID- 26238113 TI - The effects of angiotensin II signaling blockade on platelet activity in subjects with hypertension. AB - BACKGROUND: To investigate the effects of Angiotensin II receptor blockade (ARB) and angiotensin converting enzyme (ACE) inhibition on platelet reactivity in patients with mild to moderate hypertension. PFA-100 evaluates platelet function (expressed in seconds as closure time, CT) in anti-coagulated whole blood in vitro at high shear rates. The test cartridge is impregnated with either collagen and epinephrine (Col/Epi) or collagen and ADP (Col/ADP). METHODS: 33 patients were randomized to perindopril 4mg (n = 9), valsartan 80mg/d (n = 9) and for lifestyle modification (n = 15) for 4 weeks. Platelet reactivity was measured at baseline and after 4 weeks by PFA-100. Normotensive controls (n = 11) were also tested at baseline to standardize PFA-100 CT. Haematocrit, platelet count and plasma vWF antigen levels were measured. RESULTS: There was no difference in baseline haematocrit, platelet count or vWF antigen level between the groups. The vWF antigen levels measured after 4 weeks showed no significant difference either. Significant blood pressure reduction was seen in the treated group (SBP P = 0.002 and DBP P = 0.005) when compared to the life style modification group (SBP P = 0.06 and DBP P = 0.04) after 4 weeks. There was no significant statistical difference in Col/ADP CT in treated and non-treated groups but increase in CT (P = 0.05) in treated group with Col/Epi seen after 4 weeks. CONCLUSION: In patients with mild to moderate hypertension, valsartan and perindopril compared to life style modification demonstrate a significant decrease in platelet reactivity. PMID- 26238115 TI - The PLCO Cancer Screening Trial: Background, Goals, Organization, Operations, Results. AB - The randomized PLCO trial was designed to answer four primary questions: does screening for these cancers using often promoted tests reduce cancer-specific mortality? Nearly 155,000 men and women were allocated to screening or usual care arms in a 1:1 ratio under a centralized, secure randomization algorithm at ten competitively selected screening centers nationwide. Screened men received PSA blood tests and digital rectal examinations. Screened women received CA125 blood tests and trans-vaginal ultrasound. Both men and women in the screened arm received anterolateral view chest x-ray and 60 cm flexible sigmoidoscopy. Blood specimens were collected at each screening visit and buccal cell DNA was collected once from the usual care participants. Histology slides were collected for cancer cases. Participants completed a baseline questionnaire covering health and risk factors and a dietary questionnaire. Data collected on standardized machine-readable forms were scanned remotely at screening and laboratory sites utilizing PLCO dedicated, NCI provided and configured computer systems for quality checks, archiving, and analysis. Comprehensive quality assurance was implemented over recruitment, consenting, randomization, screening, data management, records keeping, patient-specific screening results reporting, follow up, and data analysis. Performance and data quality were monitored on-site and remotely by data edits, site visits, and random record audits. Specially trained and certified professionals performed screening procedures and medical record abstracting. An independent committee of medical specialists reviewed and certified case-specific cause of death. Scientific leadership was provided by NCI Project Officers, PLCO principal investigators, external consultants, and an independent data and safety monitoring board. PMID- 26238114 TI - In vivo and in silico investigation of antidiabetic activity of fruit of withania coagulans Dunal. AB - This study evaluates the antidiabetic activities of methanolic extract of Withania coagulans Dunal (Ashutosh booti) fruit (WCFE) in poloxamer-407 induced type 2 diabetic Wistar rats. The electrochemical behaviour of WCFE with anodic peak of 1.19+/- 0.01V was found similar to standards used indicating that extract is antioxidant in nature. Unlike diabetic control rats, the WCFE treated diabetic rats presented significant amelioration of glycaemia, insulinamia and lipid dysmetabolism, remarkable reduction of oxidative markers and improved cecal and pancreatic characteristics. HYBRID and FRED docking were performed for 25 documented WCFE botanicals for putative action mechanism concerning three diabetic therapeutic proteins namely PTP-1B, PPAR-gamma and DPP-IV fully support the in vivo findings. Botanicals like nicandrenone10 and Acnistin F have shown considerable interaction potential with aforesaid proteins. Results provide pharmacological evidence of WCFE as antihyperglyceamic mediated by interaction of various botanicals with various targets operating in diabetes mellitus. PMID- 26238116 TI - Data Processing and Analytic Support in the PLCO Cancer Screening Trial. AB - The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was a large, randomized controlled trial of cancer screening that also evolved over time into a unique epidemiologic cohort. Vast quantities of data have been collected since the beginning of the trial in 1993. Screening data was obtained through 2006. Questionnaire-based risk factor data (collected at baseline and at other points in the trial), vital status, cancer diagnoses and treatment, biospecimen data and additional ancillary efforts continue to be collected. Accurate data collection and efficient management methods are required to ensure high-quality data and valid and consistent analyses of trial outcomes. Information Management Services (IMS) was and continues to be responsible for processing and converting the collected raw PLCO data into comprehensive and accessible datasets. IMS also continues to provide a wide spectrum of analytic support including support for trial monitoring, data sharing, and epidemiologic research. In this paper, we describe the data processing and management requirements from the analytic team perspective, highlighting the various data sources and their complexity. We also illustrate the construction of usable analytic data files and discuss the wide range of analytic support provided. Instructions for accessing PLCO data also are provided. PMID- 26238117 TI - The PLCO Biorepository: Creating, Maintaining, and Administering a Unique Biospecimen Resource. AB - Inclusion of biospecimens in population-based studies is an integral part of understanding disease etiology, identifying biomarkers and developing prevention and treatment strategies. The Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial collected, processed and stored biospecimens from participants to create a biorepository of specimens which serves as a useful resource for a broad research community. PLCO collected blood samples from consented screening arm participants at six screening rounds and a buccal sample from consented control arm participants. In addition, formalin-fixed paraffin embedded tumor tissue specimens were collected for participants in both arms for selected cancer sites. Collection of biospecimens at multiple timepoints (i.e. serial samples) and prior to cancer diagnosis, paired with rich epidemiologic and screening data, makes the PLCO collection of biospecimens a uniquely valuable resource. As such, access to the PLCO biorepository is granted to investigators by a rigorous scientific review process and guided by a steering committee which is responsible for developing and implementing the biospecimen use policies. Here, we describe the procedures for biospecimen collection, processing, storage, requisition, and distribution, as well as data management employed in PLCO. We also provide examples of how the biospecimens have been used to advance cancer research and describe relevant lessons learned to help inform cohorts wishing to add or modify biospecimen collection. PMID- 26238118 TI - Comprehensive Quality Management (CQM) in the PLCO Trial. AB - The NCI imbedded the notion of comprehensive quality control and assurance (CQA) in the design concept for the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. PLCO implemented a comprehensive, adaptable quality assurance and control program to span more than 20 years of data collection, coordinate multiple institutions and committees, and integrate a wide variety of complex protocols. CQA concepts, practices, and procedures traced through all aspects of trial management, governance, and operations of PLCO. The driving force behind CQA in PLCO was scientific and clinical credibility of trial data and findings. CQA as implemented in PLCO was operationally analogous to the concept of Total Quality Management (TQM) described in the management literature. This paper describes CQA actualization in PLCO. PMID- 26238119 TI - Changes in and Impact of the Death Review Process in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. AB - Death review was conducted for the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial to avoid the biases associated with causes of death entered on death certificates. An algorithm selected deaths for review. Records on diagnosis and terminal illness were perused in the coordinating center and by the chair of the death review committee (DRC). Identifying information and randomization arm was removed. Three reviewers independently determined the cause of death. Disagreement was resolved at a meeting of the DRC. This process was subsequently simplified. The cause of death was determined by one DRC member and compared to the death certificate. With agreement the case was finalized. When discordant, the records were sent to a second DRC member. If the reviewers agreed, the case was finalized. If not, a third member reviewed. If two of the three reviewers agreed, the case was sent back to the discordant reviewer. If the reviewer remained discordant the case was resolved by a conference call. Of the 4728 death reviews that were completed, the DRC confirmed the death certificate underlying cause for over 90%. Between 5% and 13% of the certified deaths were regarded as indirect causes of death, associated with the treatment of the ascertained cancer; differential for prostate cancer, 11% in the intervention arm and 6% in the control. Without review, between 1% and 6% of the deaths that occurred would not have been assigned to the relevant PLCO cancer. The DRC completed 76% of those requiring review before the process ceased. PMID- 26238120 TI - The Attentional Demand of Automobile Driving Revisited: Occlusion Distance as a Function of Task-Relevant Event Density in Realistic Driving Scenarios. AB - OBJECTIVE: We studied the utility of occlusion distance as a function of task relevant event density in realistic traffic scenarios with self-controlled speed. BACKGROUND: The visual occlusion technique is an established method for assessing visual demands of driving. However, occlusion time is not a highly informative measure of environmental task-relevant event density in self-paced driving scenarios because it partials out the effects of changes in driving speed. METHOD: Self-determined occlusion times and distances of 97 drivers with varying backgrounds were analyzed in driving scenarios simulating real Finnish suburban and highway traffic environments with self-determined vehicle speed. RESULTS: Occlusion distances varied systematically with the expected environmental demands of the manipulated driving scenarios whereas the distributions of occlusion times remained more static across the scenarios. Systematic individual differences in the preferred occlusion distances were observed. More experienced drivers achieved better lane-keeping accuracy than inexperienced drivers with similar occlusion distances; however, driving experience was unexpectedly not a major factor for the preferred occlusion distances. CONCLUSION: Occlusion distance seems to be an informative measure for assessing task-relevant event density in realistic traffic scenarios with self-controlled speed. Occlusion time measures the visual demand of driving as the task-relevant event rate in time intervals, whereas occlusion distance measures the experienced task-relevant event density in distance intervals. APPLICATION: The findings can be utilized in context-aware distraction mitigation systems, human-automated vehicle interaction, road speed prediction and design, as well as in the testing of visual in-vehicle tasks for inappropriate in-vehicle glancing behaviors in any dynamic traffic scenario for which appropriate individual occlusion distances can be defined. PMID- 26238122 TI - Racial and Ethnic Disparities in Patients' Experience With Skilled Home Health Care Services. AB - Racial and ethnic disparities are found in many health care settings; however, there is little prior research on such disparities among patients receiving home health care services. This study used 2012 Home Health Care CAHPS((r)) data to identify any overall patient-level disparities in self-reported experience of care and to decompose these disparities according to whether they result from within-agency versus between-agency differences. Although patient experience of care ratings were high across all groups, the study identified consistently lower ratings for all minority groups on two of three Home Health Care CAHPS measures, with Asians reporting the greatest disparities. Three quarters of disparities were found to be within-agency disparities, which were primarily related to care processes and provider/patient communications rather than to specific health care services received. Despite high ratings in general, home health agencies may need to focus on cultural competency initiatives to address racial and ethnic disparities within their agencies. PMID- 26238121 TI - Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. AB - BACKGROUND: Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis. This Phase 2a study tested efficacy (Hb response) and safety of roxadustat in anemic nondialysis-dependent chronic kidney disease (NDD-CKD) subjects. METHODS: NDD-CKD subjects with hemoglobin (Hb) <=11.0 g/dL were sequentially enrolled into four dose cohorts and randomized to roxadustat or placebo two times weekly (BIW) or three times weekly (TIW) for 4 weeks, in an approximate roxadustat:placebo ratio of 3:1. Efficacy was assessed by (i) mean Hb change (DeltaHb) from baseline (BL) and (ii) proportion of Hb responders (DeltaHb >= 1.0 g/dL). Pharmacodynamic evaluation was performed in a subset of subjects. Safety was evaluated by adverse event frequency/severity. RESULTS: Of 116 subjects receiving treatment, 104 completed 4 weeks of dosing and 96 were evaluable for efficacy. BL characteristics for roxadustat and placebo groups were comparable. In roxadustat-treated subjects, Hb levels increased from BL in a dose-related manner in the 0.7, 1.0, 1.5 and 2.0 mg/kg groups. Maximum DeltaHb within the first 6 weeks was significantly higher in the 1.5 and 2.0 mg/kg groups than in the placebo subjects. Hb responder rates were dose dependent and ranged from 30% in the 0.7 mg/kg BIW group to 100% in the 2.0 mg/kg BIW and TIW groups versus 13% in placebo. CONCLUSIONS: Roxadustat transiently and moderately increased endogenous erythropoietin and reduced hepcidin. Adverse events were similar in the roxadustat and placebo groups. Roxadustat produced dose-dependent increases in blood Hb among anemic NDD-CKD patients in a placebo-controlled trial. CLINICAL TRIALS REGISTRATION: Clintrials.gov #NCT00761657. PMID- 26238123 TI - "Complicating relationships"--the water that doctors breathe. PMID- 26238125 TI - [Rethinking the Prescription's Comprehension: an Example of Care Centers for Deaf People]. AB - CONTEXT: Since the realization of the difficulties for Deaf people to access care, specific assisting services in french sign language (FSL) and adapted prevention campaigns have developed in France. Illiteracy, a significant problem among Deaf people, makes the comprehension of prescription uncertain. AIM: Exploring and describing the adaptations implemented by professional signers to avoid confusion related to prescription's directions. METHOD: This qualitative study in participant observation listed the different sources of confusion and the adaptations applied on prescriptions on a daily basis by eight practitioners and three intermediators who worked in six care cent ers for Deaf people. Interviews with deaf patients aimed to ascertain the encountered difficulties. These adaptations were presented, for a three-way correlation, during a national meeting attended by professional workers in care centers for Deaf people. They were subjected to a review by all attendees in order to generate a more consensual report. RESULTS: The sources of the identified misunderstandings turned out to be connected with time representation, the use of unknown words or words with double meaning, and the issuing of several documents. To reduce the risk of error, professional signers would use charts, calendars, drawings, replace durations by dates. Some of them requested that the patient would rephrase the understood information. Pros and cons, as well as the pat ient's profile were detailed for each adaptation. CONCLUSION: Even if no method can suppress all risks of confusion, this work leads us to a reflection on alterity through the risk of medicinal errors, on prescription in general, may it be directed to a patient with no particular vulnerability or to a handicapped or illiterate one. PMID- 26238126 TI - [ECRIN Standard Requirements for Good Clinical Practices-compliant Data Management in Multinational Clinical Trials]. AB - CONTEXT: Clinical studies involve an increasing amount of data collection and management. However, there is no specific quality standard sufficiently practical, in free access, and open for data management and the underlying IT infrastructure in academic units. ECRIN (European Clinical Research Infrastructures Network) published Standard requirements for certified data management units. We present a French version of these standards. METHODS: A group of experts produced the standards, by consensus. The first version was revised after two pilot audits for data centre certification were performed. RESULTS: The revised version includes 21 lists of five to ten standards, in three groups: information technologies, data management (DM) and "general". CONCLUSIONS: These standards offer a clear description of DM and IT requirements for clinical studies. Initially created for ECRIN certification purposes, they offer a very useful reference for academic DM structures. PMID- 26238124 TI - CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability. AB - The CCR4-NOT deadenylase complex plays crucial roles in mRNA decay and translational repression induced by poly(A) tail shortening. Although the in vitro activities of each component of this complex have been well characterized, its in vivo role in immune cells remains unclear. Here we show that mice lacking the CNOT3 subunit of this complex, specifically in B cells, have a developmental block at the pro- to pre-B cell transition. CNOT3 regulated generation of germline transcripts in the VH region of the immunoglobulin heavy chain (Igh) locus, compaction of the locus, and subsequent Igh gene rearrangement and destabilized tumor suppressor p53 mRNA. The developmental defect in the absence of CNOT3 could be partially rescued by ablation of p53 or introduction of a pre rearranged Igh transgene. Thus, our data suggest that the CCR4-NOT complex regulates B cell differentiation by controlling Igh rearrangement and destabilizing p53 mRNA. PMID- 26238127 TI - [A Woman Experienced Severe Thrombocytopenia When Treated With Fluvastatin]. AB - A 62-year-old woman treated with fluvastatin experienced three separate thrombocytopenic illnesses, severe on two occasions associated with nadir platelet count of 57 000/uL and 75 000/uL. The hospital pharmacist replaced fluvastatin by pravastatin during three stays. Platelet count has increased some days after this substitution. These results suggest that fluvastatin could be involved in these thrombocytopenic episodes. PMID- 26238128 TI - [Severe Caffeine Intentional Intoxication and Delayed Elimination: a Case Report]. AB - We report a massive intoxication by caffeine (20 g) with positive clinical evolution despite potentially lethal plasma concentrations (244 ug/mL) and delayed elimination. PMID- 26238130 TI - Recent advances in preimplantation genetic diagnosis. PMID- 26238129 TI - DRESS Syndrome Following Levofloxacin Exposure With Positive Patch-test. AB - Drug rash with eosinophilia and systemic symptoms (DRESS syndrome) in a severe cutaneous drug reaction, which can be life threatening. Levofloxacin has not been reported in literature as a causative drug. We are presenting an exceptional case of levofloxacin-induced DRESS without eosinophilia and with positive patch-tests to levofloxacin. PMID- 26238132 TI - Prevention in primary care is better than cure: The Hong Kong Reference Framework for Preventive Care for Older Adults--translating evidence into practice. AB - An ageing population is posing a great challenge to Hong Kong. Maintaining health and functional independence among older adults is of utmost importance, and requires the collaborative efforts of multiple health care disciplines from both the private and public sectors. The Reference Framework for Preventive Care for Older Adults, developed by the Task Force on Conceptual Model and Preventive Protocols under the auspices of the Working Group on Primary Care, aims to enhance primary care for this population group. The reference framework emphasises a comprehensive, integrated, and collaborative approach that involves providers of primary care from multiple disciplines. In addition to internet based information, helpful tools in the form of summary charts and Cue Cards are also produced to facilitate incorporation of recommendations by primary care providers into their daily practice. It is anticipated that wide adoption of the reference framework will contribute to improving older adults' health in our community. PMID- 26238133 TI - Idiopathic hypertrophic pachymeningitis mimicking prolactinoma with recurrent vision loss. AB - Idiopathic hypertrophic pachymeningitis is a rare inflammatory condition with diffuse thickening of the dura mater, which may cause a compressive effect or vascular compromise. We report on a 28-year-old Chinese woman with a history of granulomatous mastitis 7 years previously and oligomenorrhoea, headache, blurred vision, and raised prolactin level 2 years previously, that was diagnosed as prolactinoma and treated conservatively with bromocriptine. However, she had recurrent bilateral vision loss when the bromocriptine was stopped. Her symptoms were resolved by high-dose steroid injection but remained steroid-dependent. Serial magnetic resonance imaging scan showed progressive diffuse thickening of the pachymeningitis with disappearance of pituitary apoplexy. Lumbar puncture showed lymphocytosis with no organisms. Open biopsy of the meninges was performed and histology showed features of inflammatory infiltrates and vasculitis. This is an unusual presentation of a rare condition in this age-group, with co-existing granulomatous mastitis and chronic otitis media, and is a diagnostic challenge mimicking pituitary macroadenoma and meningioma in initial magnetic resonance imaging scans. PMID- 26238134 TI - Emphysematous pyelonephritis (class IIIa) managed with antibiotics alone. AB - A 54-year-old male with long-standing diabetes presented with vague left flank pain for 5 days with uncontrolled blood glucose. The patient was commenced on insulin and injectable ceftriaxone empirically, for possibly acute pyelonephritis. Ultrasound examination revealed extensive emphysematous pyelonephritis of upper half of left kidney with involvement of perinephric space. Computed tomography of abdomen confirmed the diagnosis of emphysematous pyelonephritis which was categorised as class IIIa. The recommended treatment for class IIIa emphysematous pyelonephritis is nephrectomy but the patient refused to give consent for surgery or even percutaneous drainage. Thus, the patient was continued on medical management alone and surprisingly showed marked recovery over the next few days. There were no new complications, and the patient was discharged after 2 weeks of antibiotics with 2 more weeks of oral antibiotics. After 4 months, the ultrasound showed normal kidneys. We present this case because it adds to the little existing evidence that conservative management can successfully cure patients with class IIIa emphysematous pyelonephritis, although supplementation with percutaneous drainage would have been better in this case. PMID- 26238135 TI - Aplasia of the optic nerve. AB - Aplasia of the optic nerve is an extraordinarily rare congenital anomaly that affects one or both optic nerves and is associated with the absence of the central retinal vessel and retinal ganglion cells. We report a case of unilateral optic nerve aplasia in a 4-month-old infant who was found to have left microphthalmos on routine postnatal checkup. Family history, antenatal history, and systemic evaluation were unremarkable. Magnetic resonance imaging showed absent left optic nerve with left microphthalmos. The optic chiasm was present and slightly deviated towards the right side. The remaining cerebral and ocular structures were normal. PMID- 26238136 TI - Acquired localised hypertrichosis in a Chinese child after cast immobilisation. AB - Hypertrichosis refers to excessive hair growth that is independent of any androgen effect. Hypertrichosis could be congenital or acquired, localised or generalised. The phenomenon of acquired localised hypertrichosis following cast application for a fracture is well known to orthopaedic surgeons, but is rarely encountered by primary care physicians. We describe a 28-month-old Chinese boy who had fracture of right leg as a result of an injury. He had a cast applied by an orthopaedic surgeon as treatment. On removal of the cast 6 weeks later, he was noticed to have significant hair growth on his right leg compared with the left leg. The patient was reassessed 3 months after removal of the cast. The hypertrichosis resolved completely with time. This patient was one of the youngest among the reported cases of acquired localised hypertrichosis after cast application. We illustrate the significance of management of post-cast-acquired localised hypertrichosis in the primary care setting. PMID- 26238137 TI - Clozapine-induced acute interstitial nephritis. AB - Acute interstitial nephritis is a common cause of acute kidney injury. Acute interstitial nephritis is most commonly induced by drug although the cause may also be infective, autoimmune, or idiopathic. Although eosinophilia and eosinophiluria may help identify this disease entity, the gold standard for diagnosis remains renal biopsy. Prompt diagnosis is important because discontinuation of the culprit drugs can reduce further kidney injury. We present a patient with an underlying psychiatric disorder who was subsequently diagnosed with clozapine-induced acute interstitial nephritis. Monitoring of renal function during clozapine therapy is recommended for early recognition of this rare side effect. PMID- 26238138 TI - An important update on medical consent. PMID- 26238139 TI - Heat treatment of biochemical samples to inactivate Ebola virus: does it work in practice? PMID- 26238140 TI - Plasma heating for inactivating Ebola virus. PMID- 26238141 TI - Acute basilar artery occlusion: an easily missed uncommon but devastating emergency. PMID- 26238142 TI - Use of colposcopy in a patient with recurrent genital ulcers. PMID- 26238143 TI - Effect of Rab23 on the proliferation and apoptosis in breast cancer. AB - Rab23, as a negative regulatory molecule of the Hedgehog (Hh) signaling pathway, may be a new target for treating carcinoma. In the present study, we aimed to determine whether Rab23 is expressed in breast cancer cells and whether Rab23 affects the viability and proliferation of breast cancer cells. We evaluated Rab23 expression in several breast cancer cell lines including MDA-MB-231, Bcap37 and MCF-7 by reverse transcription-PCR (RT-PCR), western blotting and immunofluorescence in vitro. We assessed cell growth and proliferation by 3-(4,5 dimethylthiazol-2-y1)-3,5-diphenyltetrazolium bromide (MTT), colony formation and bromodeoxyuridine (BrdU) incorporation assays. The distribution of the cell cycle and the rate of apoptosis were assessed using flow cytometry (FCM). In addition, we determined the mechanisms by which Rab23 regulates the Hh pathway by detecting the level of Gli molecules by RT-PCR. We found that Rab23 mRNA and protein levels were expressed in breast cancer cells, and the expression of Rab23 in MDA-MB-231 cells was higher than that in the MCF-7 cells. Rab23 protein was primarily expressed and localized in the cytoplasm surrounding the nucleus. The MTT assay showed that the absorbance value at A(490 nm) of the Rab23-transfected group was reduced in comparison with the control group. The number of colonies formed in the breast cancer cells was significantly reduced and BrdU labeling was weakened in the group transfected with Rab23. The results of FCM showed that overexpression of Rab23 protein caused cell cycle arrest in the G1 phase and a decrease in the S phase population as well as induction of apoptosis. Furthermore, Rab23 decreased Gli1 and Gli2 mRNA levels when compared with the control group. Our results indicate that Rab23 is expressed in breast cancer cells, and ectopic expression of Rab23 inhibits the growth and proliferation as well as induces cell apoptosis in breast cancer cells. These effects may be due to the inhibition by Rab23 of Gli1 and Gli2 mRNA expression. These results suggest that Rab23 is a potential target for the treatment of breast cancer. PMID- 26238144 TI - Fusion of cancer stem cells and mesenchymal stem cells contributes to glioma neovascularization. AB - The ability of tumor cells to autonomously generate tumor vessels has received considerable attention in recent years. However, the degree of autonomy is relative. Meanwhile, the effect of bone marrow-derived mesenchymal stem cells (BMSCs) on tumor neovascularization has not been fully elucidated. The present study aimed to illuminate whether cell fusion between glioma stem cells and BMSC is involved in glioma neovascularization. BMSCs were isolated from transgenic nude mice, of which all nucleated cells express green fluorescent protein (GFP). The immunophenotype and multilineage differentiation potential of BMSC were confirmed. SU3 glioma stem/progenitor cells were transfected with red fluorescent protein (SU3-RFP cells). In a co-culture system of BMSC-GFP and SU3-RFP, RFP+/GFP+ cells were detected and isolated by dual colors using FACS. The angiogenic effect of RFP+/GFP+ cells was determined in vivo and in vitro. Flow cytometry analysis showed that BMSC expressed high levels of CD105, C44, and very low levels of CD45 and CD11b. When co-cultured with SU3-RFP, 73.8% of cells co expressing RFP and GFP were identified as fused cells in the 5th generation. The fused cells exhibited tube formation ability in vitro and could give rise to a solid tumor and form tumor blood vessels in vivo. In the dual-color orthotopic model of transplantable xenograft glioma, yellow vessel-like structures that expressed CD105, RFP and GFP were identified as de novo-formed vessels derived from the fused cells. The yellow vessels observed in the tumor-bearing mice directly arose from the fusion of BMSCs and SU3-RFP cells. Thus, cell fusion is one of the driving factors for tumor neovascularization. PMID- 26238145 TI - The effect of synovial tissue volume shrinking on pain relief for knee osteoarthritis was overestimated or not? PMID- 26238146 TI - Endometriosis and the risks of systemic lupus erythematosus and rheumatoid arthritis in the Nurses' Health Study II. AB - OBJECTIVES: The aetiologies of endometriosis, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are all characterised by immune dysfunction. SLE and RA occur more often in women, and reproductive and hormonal factors have been shown to be related to increased risk. However, only one previous study has evaluated the temporal association between endometriosis and SLE or RA. We sought to investigate the association between laparoscopically confirmed endometriosis and subsequently diagnosed SLE and RA. METHODS: We analysed data from the Nurses' Health Study II (n=114 453 women) over a 22-year follow-up period. Multivariable, time-varying Cox proportional hazards models were used to calculate HRs and 95% CIs for the association between laparoscopically confirmed endometriosis and confirmed incident SLE or RA. RESULTS: From 1989 to 2011, 103 incident cases of SLE and 390 cases of RA were confirmed. Laparoscopically confirmed endometriosis was significantly associated with subsequent SLE diagnosis (HR=2.03; CI 1.17 to 3.51) and RA diagnosis (HR=1.41; CI 1.05 to 1.89). These associations were robust to adjustment for SLE or RA risk factors and for potential confounders; however, adjustment for hysterectomy and oophorectomy attenuated both relations such that they were no longer significant. No significant differences by infertility status or age (<45 years) were observed. CONCLUSIONS: Our findings suggest an association between endometriosis and risk of SLE and RA. It remains to be understood whether and how endometriosis itself, or hysterectomy or other factors associated with endometriosis, is related to risk of SLE or RA. PMID- 26238147 TI - Long-term outcomes and risk factors for aortic regurgitation after discrete subvalvular aortic stenosis resection in children. AB - OBJECTIVES: To characterise long-term outcomes after discrete subaortic stenosis (DSS) resection and to identify risk factors for reoperation and aortic regurgitation (AR) requiring repair or replacement. METHODS: All patients who underwent DSS resection between 1984 and 2009 at our institution with at least 36 months' follow-up were included. Demographic, surgical and echocardiographic data were reviewed. Outcomes were reoperation for recurrent DSS, surgery for AR, death and morbidities, including heart transplant, endocarditis and complete heart block. RESULTS: Median length of postoperative follow-up was 10.9 years (3-27.2 years). Reoperation occurred in 32 patients (21%) and plateaued 10 years after initial resection. Survival at 10 years and 20 years was 98.6% and 86.3%, respectively. Aortic valve (AoV) repair or replacement for predominant AR occurred in 31 patients (20%) during or after DSS resection. By multivariable analysis, prior aortic stenosis (AS) intervention (HR 22.4, p<0.001) was strongly associated with AoV repair or replacement. Risk factors for reoperation by multivariable analysis included younger age at resection (HR 1.24, p=0.003), preoperative gradient >=60 mm Hg (HR 2.23, p=0.04), peeling of membrane off AoV or mitral valve (HR 2.52, p=0.01), distance of membrane to AoV <7.0 mm (HR 4.03, p=0.03) and AS (HR 2.58, p=0.01). CONCLUSIONS: In this cohort, the incidence of reoperations after initial DSS resection plateaued after 10 years. Despite a significant rate of reoperation, overall survival was good. Concomitant congenital AS and its associated interventions significantly increased the risk of AR requiring surgical intervention. PMID- 26238148 TI - Measuring heart failure quality: does perfection matter? PMID- 26238149 TI - Ascorbic acid inhibits TPA-induced HL-60 cell differentiation by decreasing cellular H2O2 and ERK phosphorylation. AB - Retinoic acid (RA), vitamin D and 12-O-tetradecanoyl phorbol-13-acetate (TPA) can induce HL-60 cells to differentiate into granulocytes, monocytes and macrophages, respectively. Similar to RA and vitamin D, ascorbic acid also belongs to the vitamin family. High-dose ascorbic acid (>100 uM) induces HL-60 cell apoptosis and induces a small fraction of HL-60 cells to express the granulocyte marker, CD66b. In addition, ascorbic acid exerts an anti-oxidative stress function. Oxidative stress is required for HL-60 cell differentiation following treatment with TPA, however, the effect of ascorbic acid on HL-60 cell differentiation in combination with TPA treatment remains to be fully elucidated. The aim of the present study was to investigate the cellular effects of ascorbic acid treatment on TPA-differentiated HL-60 cells. TPA-differentiated HL-60 cells were used for this investigation, this study and the levels of cellular hydrogen peroxide (H2O2), caspase activity and ERK phosphorylation were determined following combined treatment with TPA and ascorbic acid. The results demonstrated that low dose ascorbic acid (5 uM) reduced the cellular levels of H2O2 and inhibited the differentiation of HL-60 cells into macrophages following treatment with TPA. In addition, the results of the present study further demonstrated that low-dose ascorbic acid inactivates the ERK phosphorylation pathway, which inhibited HL-60 cell differentiation following treatment with TPA. PMID- 26238150 TI - Sleep, health and memory: comparing parents of typically developing children and parents of children with special health-care needs. AB - Parents of children with special healthcare needs (CSHCNs) report poorer sleep than parents of typically developing (TD) children, which has been associated with poorer mental health. The relations between sleep disturbances and general health and memory among this population are unknown. The current study aimed to replicate the findings that parents of CSHCNs report poorer sleep quality than parents of TD children, and further examine how sleep is related to general health and memory. Participants (75 parents of TD children; 97 parents of CSHCNs) completed an online questionnaire consisting of: demographics, the Pittsburgh Sleep Quality Index (PSQI), the Prospective Retrospective Memory Questionnaire (PRMQ) and the Healthy Days Measure. Parents of CSHCNs reported worse global sleep than parents of TD children. Parents of CSHCNs took longer to fall asleep at night, had shorter sleep duration and worse subjective sleep quality than parents of TD children. Parents of CSHCNs also had worse prospective memory and were more likely to report poor general health than parents of TD children. Poorer sleep quality was associated with worse memory and health among both parents of TD children and parents of CSHCNs. Results from this study highlight the importance of addressing the sleep of parents of CSHCNs and support the need for more research in this area. By recognizing factors associated with parent's health and functioning, service providers may be better able to implement support programs for parents of CSHCNs. PMID- 26238152 TI - Combination of EUS-FNA and elastography (strain ratio) to exclude malignant solid pancreatic lesions: A prospective single-blinded study. AB - BACKGROUND: Negative results of EUS-FNA for solid pancreatic lesions (SPL) can be false ones. Combination with strain ratio (SR) may ensure a correct benign diagnosis of SPL. AIMS: We prospectively evaluated the sensitivity rate of EUS FNA and EUS elastography using the strain ratio method for diagnosing SPL. METHODS: Thirty-eight patients with SPL identified by CT or MRI between January 2013 and November 2013 were included in our prospective study. EUS diagnoses were made using SR by an endosonographer who was blinded to all clinical information. In SPL with adequate cellularity, the results of EUS-FNA were combined with strain ratio to diagnose SPL and the diagnostic value was calculated. RESULTS: Benign SPL were diagnosed in nine patients with surgical or guided-biopsy pathology (n = 3) and benign cells from FNA with stable disease during the 12 month follow-up time (n = 6). Using the best cut-off strain ratio level at 3.17, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy rate of EUS elastography were 86.2%, 66.7%, 89.3%, 60%, and 81.6%, respectively. For the 28 patients who underwent EUS-FNA with results of adequate cellularity; EUS-FNA alone versus combination of results of cytology and SR provided sensitivity, specificity, PPV, NPV, and accuracy rate at 90% versus 95.2, 100% versus 71.4%, 100% versus 90.9%, 80% versus 83.3, and 92.9% versus 89.3%, respectively. CONCLUSIONS: In this prospective single-blinded study, the negative results of both EUS-FNA and SR were more reliable to exclude malignant SPL. The sensitivity of EUS elastography by SR was not superior to EUS FNA. (c) 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd. PMID- 26238154 TI - Effects of X-ray irradiation in combination with ascorbic acid on tumor control. AB - Our previous studies demonstrated that the combination of treatment with ascorbic acid (AsA) and X-ray irradiation results in increased apoptosis in HL60 cells. The present study was performed to investigate the effects of the combined use of AsA and X-ray irradiation on epithelial cancer and sarcoma cells, and its potential use in future clinical treatment. X-ray irradiation combined with AsA treatment resulted in increased suppression of cell growth of HT1080, SAS and A549 cells in vitro compared with X-ray irradiation alone. The combined treatment also suppressed tumor growth in implanted HT-1080 cells in vivo. Using annexin V/propidium iodide staining and the detection of activated caspase 3, it was found that X-ray irradiation increased the apoptotic rate of HT1080 cells and resulted in G2/M arrest. However, apoptosis in the HT1080 cells treated with 5 mM AsA remained unchanged, and no changes were observed in the G2/M fraction. By contrast, AsA treatment caused increased suppression of proliferation compared with X-ray irradiation. These results suggested that 5 mM AsA slowed the cell cycle and reduced tumor growth. Therefore, X-ray irradiation combined with AsA treatment may be effective against epithelial cancer and sarcoma cells. PMID- 26238153 TI - Activated farnesoid X receptor attenuates apoptosis and liver injury in autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease associated with interface hepatitis, the presence of autoantibodies, regulatory T-cell dysfunction and raised plasma liver enzyme levels. The present study assessed the hepatoprotective and antiapoptotic role of farnesoid X receptor (FXR) in AIH. a mouse model of AIH was induced by treatment with concanavalin A (ConA). The FXR agonist, chenodeoxycholic acid (CDCA), was administered to mice exhibiting ConA induced liver injury and a normal control. Blood samples were obtained to detect the levels of aminotransferases and inflammatory cytokines. Liver specimens were collected, and hematoxylin-eosin staining was used for histopathological examination and detection. Apoptosis was evaluated using the terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) method. The expression levels of apoptosis-associated genes and proteins were determined by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The results demonstrated that FXR was downregulated at the mRNA and protein level in the liver specimens of mice induced with ConA induced hepatitis. Increased levels of aminotransferases and inflammatory cytokines, including interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-4 and IL-2, were detected in ConA-treated mice. The mice pretreated with the FXR agonist, CDCA, were more resistant to ConA hepatitis, as indicated by reduced levels of alanine transaminase/aspartate aminotransferase and aminotransferases. The activation of FXR ameliorated hepatocyte apoptosis, as demonstrated by TUNEL analysis and downregulation of the Fas/Fas ligand, tumor necrosis factor-related apoptosis-inducing ligand and caspase-3. Taken together, FXR activation ameliorated liver injury and suppressed inflammatory cytokines in ConA-induced hepatitis. FXR, therefore, exerts a protective role against ConA-induced apoptosis. PMID- 26238151 TI - Outcome of neuropsychiatric symptoms related to an antiretroviral drug following its substitution by nevirapine: the RELAX study. AB - OBJECTIVES: The primary objective was to evaluate the improvement in neuropsychiatric symptoms attributed to an antiretroviral drug after that drug was substituted with nevirapine. The secondary objective was to evaluate the impact on patient adherence and quality of life. METHODS: A prospective, observational study was carried out that included patients with HIV-1 plasma suppression for whom an antiretroviral drug was substituted with nevirapine because of central nervous system (CNS) side effects, a Pittsburgh Sleep Quality Index (PSQI) score > 5 or a Hospital Anxiety and Depression Scale (HADS) score >= 10, and who had not initiated psychoactive drug treatment during the prior 6 weeks. Evaluations were carried out at baseline and 1 and 3 months after the switch using the PSQI, HADS, Epworth Sleepiness Scale, Medical Outcomes Study Short Form 30 items (MOS-SF-30) and Simplified Medication Adherence Questionnaire (SMAQ). RESULTS: A total of 129 patients were included in the study. The drug substituted was mainly efavirenz (89.9%), and reasons for the switch included sleep disturbances (75.2%), anxiety (65.1%), depression (38.7%), attention disturbances (31%), and other reasons (31%), with a mean of 2.4 neuropsychiatric disturbances per patient. A statistically significant improvement was observed in all the tests evaluating neuropsychiatric symptoms and adherence at 1 and 3 months. The CD4 lymphocyte count remained stable (P = 0.096). Three (2.3%) patients had a detectable plasma HIV-1 RNA at the end of the study. Nine patients (6.9%) withdrew because of nevirapine-related toxicity (rash in seven patients and hypertransaminasaemia in two patients, none of which were > grade 2). CONCLUSIONS: The switch to nevirapine from a drug causing neuropsychiatric disturbances (primarily efavirenz) in subjects with virological suppression was effective in resolving those disturbances, with an improvement in all the parameters studied. This led to better adherence to treatment and quality of life, with no detrimental effect on their immunological and virological control. PMID- 26238155 TI - Expression profile of parkin isoforms in human gliomas. AB - Mutations of parkin gene are not restricted to familial forms of Parkinsonism but they also occur in a wide variety of malignancies including gliomas. Parkin over expression reduces glioma cells proliferation and analysis of its expression is predictive for the survival outcome of patients with glioma. To date have been identified 21 parkin alternative splice variants. However, most of the studies have focused their attention exclusively on full-length protein. In the present study, the expression profile of parkin isoforms in different grades of astrocytomas was analyzed for the first time, in order to evaluate their involvement in this malignancy. Furthermore, to investigate their role in cellular processes, their expression in three glioblastoma cell lines was analyzed following treatment with the proteasome inhibitor MG132, or induction of mitophagy with CCCP, or after serum deprivation. Results suggested that H20, H1 and H5 isoforms are always expressed in tumors both in vivo and in vitro models. Therefore, these isoforms might be used as specific biomarkers to develop a prognostic tool for brain tumors. PMID- 26238156 TI - MG132 enhances the radiosensitivity of lung cancer cells in vitro and in vivo. AB - Radiotherapy is a common treatment modality for lung cancer, however, radioresistance remains a fundamental barrier to attaining the maximal efficacy. Cancer cells take advantage of the ubiquitin-proteasome system (UPS) for increased proliferation and decreased apoptotic cell death. MG132 (carbobenzoxyl leucinyl-leucinyl-leucinal-H), a specific and selective reversible inhibitor of the 26S proteasome, has shown anticancer effect in multiple types of cancers. Previously, we have reported that MG132 enhances the anti-growth and anti metastatic effects of irradiation in lung cancer cells. However, whether MG132 can enhance the radiosensitivity in lung cancer cells in vitro and in vivo is still unknown. In this study, we found that MG132 increased apoptosis and dicentric chromosome ratio of A549 and H1299 cells treated by irradiation. Radiation-induced NF-kappaB expression and IkappaBalpha phosphorylation was attenuated in MG132 plus irradiation-treated cells. The in vivo model of H1299 xenografts of nude mice showed that the tumor size of MG132 plus irradiation treated xenografts was smaller than that of irradiation, MG132 or the control group. Moreover, MG132 plus irradiation group showed significant reduced Ki67 expression. Taken together, these results demonstrate that MG132 enhances the radiosensitivity through multiple mechanisms in vitro and in vivo. PMID- 26238157 TI - Annual Fecal Occult Blood Testing can be Safely Suspended for up to 5 Years After a Negative Colonoscopy in Asymptomatic Average-Risk Patients. AB - OBJECTIVES: Annual fecal occult blood testing (FOBT) is often continued in patients who have had a recent negative colonoscopy, despite recommendations to the contrary. This prospective study aimed to determine the proportion of patients with a positive FOBT who had adenomas and cancers on colonoscopy stratified according to the duration of time since the last negative colonoscopy. METHODS: A total of 1,119 asymptomatic average-risk patients >=50 years of age referred for a positive FOBT were prospectively identified and stratified by the duration of time since the last colonoscopy (never, >10 years, 5-10 years, or <5 years). The proportion of patients in each category with adenomas of any size, adenomas >=10 mm, advanced neoplasms, and cancers was assessed. RESULTS: The mean age (68.9+/-9.6 years), sex (95.2% male), and race (48.1% white, 32.1% black, 15.6% Hispanic, and 4.2% other) did not differ between the four groups. Overall, adenomas of any size were detected in 42.8% of patients, adenomas >=10 mm in 14.7%, advanced neoplasms in 20.7%, and cancers in 7.3%. Advanced neoplasms were detected in 30.4% of patients who have never had a colonoscopy, 27% in those who have had one greater than 10 years prior, 10.0% in 5-10 years prior, and 1.1% in less than 5 years prior. CONCLUSIONS: In asymptomatic average-risk patients with a negative colonoscopy within the last 5 years, the prevalence of adenomas is low, and no patient was diagnosed with cancer. These findings support the CDC recommendations to suspend annual FOBT for up to 5 years after a negative colonoscopy. PMID- 26238158 TI - Contribution of Liquid/Gas Mass-Transfer Limitations to Dissolved Methane Oversaturation in Anaerobic Treatment of Dilute Wastewater. AB - The mechanisms controlling the accumulation of dissolved methane in anaerobic membrane bioreactors (AnMBRs) treating a synthetic dilute wastewater (a glucose medium) were assessed experimentally and theoretically. The AnMBR was maintained at a temperature of 24-26 degrees C as the organic loading rate increased from 0.39 to 1.1 kg COD/m(3)-d. The measured concentration of dissolved methane was consistently 2.2- to 2.5-fold larger than the concentration of dissolved methane at thermodynamic equilibrium with the measured CH4 partial pressure, and the fraction of dissolved methane was as high as 76% of the total methane produced. The low gas production rate in the AnMBR significantly slowed the mass transport of dissolved methane to the gas phase. Although the production rate of total methane increased linearly with the COD loading rate, the concentration of dissolved methane only slightly increased with an increasing organic loading rate, because the mass-transfer rate increased by almost 5-fold as the COD loading increased from 0.39 to 1.1 kg COD/m(3)-d. Thus, slow mass transport kinetics exacerbated the situation in which dissolved methane accounted for a substantial fraction of the total methane generated from the AnMBR. PMID- 26238159 TI - Building a cardio-oncology program in a small- to medium-sized, nonprimary cancer center, academic hospital in the USA: challenges and pitfalls. PMID- 26238160 TI - Similar results for face mask versus mouthpiece during incremental exercise to exhaustion. AB - Investigations in the 1990s evaluated the influence of breathing assemblies on respiratory variables at rest and during exercise; however, research on new models of breathing assemblies is lacking. This study compared metabolic gas analysis data from a mouthpiece with a noseclip (MOUTH) and a face mask (MASK). Volunteers (7 males, 7 females; 25.1 +/- 2.7 years) completed two maximal treadmill tests within 1 week, one MOUTH and one MASK, in random order. The difference in maximal oxygen consumption (VO2max) between MOUTH (52.7 +/- 11.3 ml . kg(-1) . min(-1)) and MASK (52.2 +/- 11.7 ml . kg(-1) . min(-1)) was not significant (P = 0.53). Likewise, the mean MOUTH-MASK differences in minute ventilation (VE), fraction of expired oxygen (FEO2) and carbon dioxide (FECO2), respiration rate (RR), tidal volume (Vt), heart rate (HR), and rating of perceived exertion (RPE) at maximal and submaximal intensities were not significant (P > 0.05). Furthermore, there was no systematic bias in the error scores (r = -0.13, P = 0.66), and 12 of the 14 participants had a VO2max difference of <=3 ml . kg(-1) . min(-1) between conditions. Finally, there was no clear participant preference for using the MOUTH or MASK. Selection of MOUTH or MASK will not affect the participant's gas exchange or breathing patterns. PMID- 26238161 TI - Zinc deficiency during in vitro maturation of porcine oocytes causes meiotic block and developmental failure. AB - The present study investigated the effects of zinc deficiency during in vitro maturation (IVM) of porcine oocytes. Zinc deficiency was induced by administering the membrane-permeable zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylendiamine (TPEN). First, the effects of zinc deficiency during IVM on a TPEN treated group and a TPEN+zinc-treated group compared with a control group were assessed. The oocyte maturation rates and subsequent embryonic developmental competence of the TPEN+zinc-treated oocytes were similar to those of the control oocytes (metaphase II [MII] rate, 93.0 and 92.7%, respectively, and blastocyst [BL] formation rate, 42.0 and 40.0%, respectively). These results were significantly different from those obtained for the TPEN-treated oocytes (MII rate, 0.61%; BL formation rate, 0%). Although the TPEN-treated oocytes were arrested at metaphase I (MI), the distribution of microtubules was normal. However, microfilament formation was abnormal in the TPEN-treated oocytes. Furthermore, the effect of a temporary zinc deficiency during IVM on oocyte maturation and subsequent embryonic development was assessed. TPEN (10 uM) was added to the IVM medium for 0, 7, 15 or 22 h. The 0 h-treated oocytes showed an 83.9% MII rate, while the 7 h-treated oocytes had a significantly lower MII rate (44.8%). Most of the 15- and 22 h-treated oocytes were arrested at MI (MI rate: 98.0 and 97.2%, respectively; MII rate, 0% in both groups). Reductions in the BL formation were dependent on the TPEN treatment duration (29.3, 9.2, 0, and 0% after 0, 7, 15 and 22 h, respectively). In conclusion, zinc is an essential element for successful oocyte maturation and embryonic development in pigs. Zinc deficiency caused a meiotic block and had lasting effects on early embryonic development. PMID- 26238162 TI - Real-time optical monitoring of the wastewater treatment process. AB - One activated sludge process line was optically monitored in situ by a novel image analysis equipment. The results of the image analysis were studied to find out dependencies to the process variables of the wastewater treatment plant (WWTP) and to the quality of the treated wastewater. The quality parameter of the treated wastewater, suspended solids, was modelled using the image analysis results. The model can be used for evaluating the performance of the WWTP and for the better control for stable effluent quality. It was shown that the results of the online optical monitoring reveal useful information from the process and can be used in forecasting the quality of biologically treated wastewater. The optical monitoring method together with process measurements has an important role in keeping the process in stable operating conditions and avoiding environmental risks. PMID- 26238163 TI - Proinflammatory effects of the hemagglutinin protein of the avian influenza A (H7N9) virus and microRNA-mediated homeostasis response in THP-1 cells. AB - The pathology and immunological responses to hemagglutinin (HA) from H7N9 avian influenza viruses in humans remain unclear. The present study aimed to investigate the proinflammatory activity of the HA protein obtained from H7N9 viruses and the mechanisms underlying the homeostasis of microRNAs (miRNAs) in response to inflammatory stimuli. The expression of proinflammatory factors and miRNAs was assayed in the THP-1 cells using reverse transcription-quantitative polymerase chain reaction. Results showed that HA significantly increased the expression of interleukin (IL)-1alpha, IL-1beta and IL-6 in the THP-1 cells. Furthermore, HA and lipopolysaccharide exhibited synergic effects on the expression of IL-1alpha, IL-1beta and IL-6 in the THP-1 cells. Let-7e can target IL-6 and inhibit its expression. Notably, HA significantly increased let-7e expression in THP-1 cells and decreased the let-7e levels in the medium. However, the knockdown of toll-like receptor 4 (TLR4) significantly attenuated the effects of HA. These results indicate that the HA can induce inflammatory stress and may trigger an miRNA-mediated homeostasis response to this stress. The effects of HA appeared to be mediated by the TLR4 pathway. PMID- 26238164 TI - Emotional processing in patients with mild cognitive impairment: the influence of the valence and intensity of emotional stimuli: the valence and intensity of emotional stimuli influence emotional processing in patients with mild cognitive impairment. AB - We studied the ability of individuals with mild cognitive impairment (MCI) to process emotional facial expressions (EFEs). To date, no systematic study has addressed how variation in intensity affects recognition of the different type of EFEs in such subjects. DESIGN: Two groups of 50 elderly subjects, 50 healthy individuals and 50 with MCI, completed a task that involved identifying 180 EFEs prepared using virtual models. Two features of the EFEs were contemplated, their valence (operationalized in six basic emotions) and five levels of intensity. RESULTS: At all levels of intensity, elderly individuals with MCI were significantly worse at identifying each EFE than healthy subjects. Some emotions were easier to identify than others, with happiness proving to be the easiest to identify and disgust the hardest, and intensity influenced the identification of the EFEs (the stronger the intensity, the greater the number of correct identifications). Overall, elderly individuals with MCI had a poorer capacity to process EFEs, suggesting that cognitive ability modulates the processing of emotions, where features of such stimuli also seem to play a prominent role (e.g., valence and intensity). Thus, the neurological substrates involved in emotional processing appear to be affected by MCI. PMID- 26238165 TI - Negative work events reported online precede job loss in multiple sclerosis. AB - PURPOSE: Determine if a recently validated online survey of negative work events can predict future job loss among multiple sclerosis (MS) patients. METHOD: Evaluated were 284 employed individuals (63 healthy controls, 221 MS patients), every three months, using an online vocational monitoring tool. Job loss rates in MS patients were compared with the healthy controls. Survey responses from MS patients suffering job loss (n=23) were then compared to those maintaining employment. Analyses focused on the frequency of negative work events. RESULTS: While 23 (10%) of MS patients lost their job after baseline, there was no job loss among the healthy controls. Compared to stably employed patients, those suffering job loss had been diagnosed with MS later in life, were more likely to report a progressive disease course, and had greater physical disability as measured by the Patient Derived Disease Steps (PDDS). Declining patients were also more likely to report negative work events within three months of job loss (e.g., verbal criticism for errors or removal of responsibilities). Stepwise logistic regression predicting MS job loss retained the PDDS, age at diagnosis, years working for employer and reporting a negative work event. CONCLUSIONS: The results show that physical disability and patient reported risk factors for job loss can be monitored using an online survey tool. The tool can trigger clinical assessments to help prevent unemployment and assist patients in procuring disability benefits. PMID- 26238166 TI - The natural history of brain volume loss among patients with multiple sclerosis: a systematic literature review and meta-analysis. AB - BACKGROUND: Multiple sclerosis has been associated with progressive brain volume loss. OBJECTIVE: We aimed to systematically summarize reported rates of brain volume loss in multiple sclerosis and explore associations between brain volume loss and markers of disease severity. METHODS: A systematic literature search (2003-2013) was conducted to identify studies with >=12months of follow-up, reported brain volume measurement algorithms, and changes in brain volume. Meta analysis random-effects models were applied. Associations between brain volume change, changes in lesion volume and disease duration were examined in pre specified meta-regression models. RESULTS: We identified 38 studies. For the meta analysis, 12 studies that reported annualized percentage brain volume change (PBVC), specified first-generation disease-modifying treatments (e.g., interferon beta or glatiramer acetate) and used Structural Image Evaluation of Normalized Atrophy algorithm were analyzed. The annualized PBVC ranged from -1.34% to -0.46% per year. The pooled PBVC was -0.69% (95% CI=-0.87% to -0.50%) in study arms receiving first-generation disease-modifying treatments (N=6 studies) and -0.71% (95% CI=-0.81% to -0.61%) in untreated study arms (N=6 studies). CONCLUSIONS: In this study, the average multiple sclerosis patient receiving first-generation disease-modifying treatment or no disease-modifying treatment lost approximately 0.7% of brain volume/year, well above rates associated with normal aging (0.1% 0.3% of brain volume/year). PMID- 26238167 TI - Mad Honey: Reflections on Sweetness, Death, and the Politics of Healthcare. PMID- 26238168 TI - Herbs for Low-Back Pain, Acupuncture for Psychological Distress, Osteopathic Manipulative Therapy for Chronic Migraine, Honey Dressings for Burns, Vegetarian Diet and Risk of Colorectal Cancer. PMID- 26238169 TI - Estimating allele dropout probabilities by logistic regression: Assessments using Applied Biosystems 3500xL and 3130xl Genetic Analyzers with various commercially available human identification kits. AB - Phenomena called allele dropouts are often observed in crime stain profiles. Allele dropouts are generated because one of a pair of heterozygous alleles is underrepresented by stochastic influences and is indicated by a low peak detection threshold. Therefore, it is important that such risks are statistically evaluated. In recent years, attempts to interpret allele dropout probabilities by logistic regression using the information on peak heights have been reported. However, these previous studies are limited to the use of a human identification kit and fragment analyzer. In the present study, we calculated allele dropout probabilities by logistic regression using contemporary capillary electrophoresis instruments, 3500xL Genetic Analyzer and 3130xl Genetic Analyzer with various commercially available human identification kits such as AmpFlSTR(r) Identifiler(r) Plus PCR Amplification Kit. Furthermore, the differences in logistic curves between peak detection thresholds using analytical threshold (AT) and values recommended by the manufacturer were compared. The standard logistic curves for calculating allele dropout probabilities from the peak height of sister alleles were characterized. The present study confirmed that ATs were lower than the values recommended by the manufacturer in human identification kits; therefore, it is possible to reduce allele dropout probabilities and obtain more information using AT as the peak detection threshold. PMID- 26238170 TI - Cry4Ba and Cyt1Aa proteins from Bacillus thuringiensis israelensis: Interactions and toxicity mechanism against Aedes aegypti. AB - Individual crystal proteins from Bacillus thuringiensis israelensis exhibit variable levels of insecticidal activities against mosquito larvae. In all cases, they are much less active compared to the whole crystal proteins due to described complex synergistic interactions among them. In the present study we investigated the effects of Cyt1A98 (a Cyt1Aa type protein) on Cry4BLB (a Cry4Ba type toxin) insecticidal activity toward the dengue vector Aedes aegypti. The bioassay analyses demonstrated the ability of Cyt1A98 protein to enhance Cry4BLB toxin larvicidal activity even at a low proportion in the mixture (1%). In vitro interaction assays showed that Cyt1A98 provides supplementary binding sites for Cry4BLB in A. aegypti BBMVs. Moreover, it enhances the formation of Cry4BLB oligomeric structure. These results support that Cyt1A98 protein could act as a membrane-bound receptor fixing Cry4BLB delta-endotoxins and promoting its oligomerization. PMID- 26238171 TI - Selecting key toxins for focused development of elapid snake antivenoms and inhibitors guided by a Toxicity Score. PMID- 26238172 TI - Identification of tetrodotoxin-producing bacteria from goby Yongeichthys criniger. AB - Toxic goby fish (Yongeichthys criniger) containing tetrodotoxin (TTX), from Zhanjiang, Guangdong province, China, were screened for TTX-producing bacteria. Two toxic bacterial strains were isolated from the liver of Y. criniger and respectively denoted XC3-3 and XL-1. TTX production by the strains was confirmed by mouse bioassay, enzyme-linked immunosorbent assay and high performance liquid chromatography coupled with mass spectrometry. Based on morphological, physiological and biochemical characteristics and 16S rDNA phylogenetic analysis, strain XC3-3 was identified as Enterobacter cloaca and XL-1 was closely related to Rahnella aquatilis. These findings show for the first time that TTX-producing bacteria are symbiotic bacteria in goby and suggest that bacterial strains are at least partially responsible for TTX accumulation in Y. criniger. PMID- 26238173 TI - [Setting of a breast autologous microsurgical reconstructive surgery evolution in 20 years and review of 1138 cases]. AB - The authors conducted a retrospective study of breast reconstruction with DIEP free flap between 1994 and 2014 by a single team. MATERIAL AND METHOD: A retrospective analysis of all operative charts and hospitalization was conducted for the period from 1994 to 2014. The number of cases per year, the complication rate of the donor site and recipient site, and surgery time were recorded. Sequence analysis was conducted to determine the elements that have enabled to implement this technique reliably and effects of the learning curve. The series was split into two periods (1994/2011 and 2012/2014) corresponding to two different hospitals with the same team. RESULTS: The total number of shreds of 1138 between November 1994 and December 2014 respectively with 477 and 661 the period 1994/2011 to 2012/2014 period. The failure rate increased from 8% to 2.2%. CONCLUSION: The establishment of units mainly dedicated to microsurgical reconstruction can offer the DIEP technique reliably and reproducibly. PMID- 26238174 TI - Spindle cell variant of ameloblastic carcinoma: a case report and literature review. AB - Spindle cell variant of ameloblastic carcinoma is an extremely rare tumor. Severe dedifferentiated spindle cell variants are diagnostically challenging, particularly in small biopsy specimens. Here, we report a case of spindle cell variant of ameloblastic carcinoma in the mandible of a 69-year-old male patient and review the available literature. The tumor was surgically resected under general anesthesia. Histopathologic diagnosis of spindle cell carcinoma was made on incisional biopsy, and the final diagnosis was confirmed as spindle cell variant of ameloblastic carcinoma. Immunohistochemistry using cytokeratin and CK19 is helpful in determining the origin of spindle cell variant of ameloblastic carcinoma, particularly CK19 indicated that sarcomatoid spindle cells are derived from odontogenic epithelium. A review demonstrated higher mean age of patients compared with that of other types of ameloblastic carcinoma. The rates of mortality and local recurrence were concurrently 30%. No recurrence or metastasis was seen in the 23-month follow-up period in the present case. PMID- 26238176 TI - Protein-ligand and membrane-ligand interactions in pharmacology: the case of the translocator protein (TSPO). AB - The targets of many small molecule drugs are membrane proteins, and traditionally the focus of pharmacology is on the interaction between such receptors and their small molecule drug ligands. However, the lipid membranes of cells and organelles are increasingly appreciated as diverse and dynamic structures that also specifically interact with small molecule drugs and peptides, causing profound changes in the properties of these membranes, and modulating the function of the membrane and the proteins within it. Drug-membrane interactions are likely to have a role in both the therapeutic and toxic activity of a variety of compounds, and their role in the overall pharmacological effect of a drug needs to be understood more clearly. This is the case for the 18 kDa translocator protein (TSPO) and its ligands, where functions that were established based on pharmacological studies are being called into question. Re-examining the putative functions of the TSPO and the effects of its ligands reveals a need to consider in more detail the interplay between protein-ligand and membrane-ligand interactions, and the modulatory relationship between TSPO and the lipid membrane. PMID- 26238175 TI - 3-Hydroxyflavone and structural analogues differentially activate pregnane X receptor: Implication for inflammatory bowel disease. AB - Pregnane X receptor (PXR; NR1I2) is a member of the superfamily of nuclear receptors that regulates the expression of genes involved in various biological processes, including drug transport and biotransformation. In the present study, we investigated the effect of 3-hydroxyflavone and its structurally-related analogues on PXR activity. 3-Hydroxyflavone, galangin, kaempferol, querceetin, isorhamnetin, and tamarixetin, but not but not datiscetin, morin, myricetin, or syringetin, activated mouse PXR, as assessed in a cell-based reporter gene assay. By comparison, 3-hydroxyflavone activated rat PXR, whereas 3-hydroxyflavone, galangin, quercetin, isorhamnetin, and tamarixetin activated human PXR (hPXR). A time-resolved fluorescence resonance energy transfer competitive ligand-binding assay showed binding to the ligand-binding domain of hPXR by 3-hydroxyflavone, galangin, quercetin, isorhamnetin, and tamarixetin. 3-Hydroxyflavone and galangin, but not quercetin, isorhamnetin, or tamarixetin, recruited steroid receptor coactivator (SRC)-1, SRC-2, and SRC-3 to hPXR. In LS180 human colon adenocarcinoma cells, 3-hydroxyflavone, quercetin, and tamarixetin increased CYP3A4, CYP3A5, and ABCB1 mRNA expression, whereas galangin and isorhamnetin increased CYP3A4 and ABCB1 but not CYP3A5 mRNA expression. Datiscetin, kaempferol, morin, myricetin, and syringetin did not attenuate the extent of hPXR activation by rifampicin, suggesting they are not hPXR antagonists. Overall, flavonols activate PXR in an analogue-specific and species-dependent manner. Substitution at the C2' or C5' position of 3-hydroxyflavone with a hydroxyl or methoxy group rendered it incapable of activating hPXR. Understanding the structure-activity relationship of flavonols in hPXR activation may facilitate nutraceutical development efforts in the treatment of PXR-associated intestinal diseases, such as inflammatory bowel disease. PMID- 26238177 TI - Novel synthetic pyridyl analogues of CDDO-Imidazolide are useful new tools in cancer prevention. AB - Two new analogues of CDDO-Imidazolide (CDDO-Im), namely 1-[2-Cyano-3,12 dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-2-yl)-1H-imidazole ("CDDO-2P-Im") and 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-3-yl)-1H-imidazole ("CDDO-3P-Im") have been synthesized and tested for their potential use as chemopreventive drugs. At nanomolar concentrations, they were equipotent to CDDO Im for inducing differentiation and apoptosis in U937 leukemia cells. As inflammation and oxidative stress contribute to carcinogenesis, we also assessed their cytoprotective potential. The new compounds suppressed inducible nitric oxide synthase (iNOS) expression in RAW264.7 macrophage-like cells and significantly elevated heme oxygenase-1 (HO-1) and quinone reductase (NQO1) mRNA and protein levels in various mouse tissues in vivo. Most importantly, pharmacokinetic studies performed in vitro in human plasma and in vivo showed that each new analogue was more stable than CDDO-Im. Much higher concentrations of the new derivatives were found in mouse liver, lung, pancreas and kidney after gavage in contrast to CDDO-Im. Because of their better bioavailability and their excellent anti-inflammatory profile in vitro, CDDO-2P-Im and CDDO-3P-Im were tested for prevention in a highly relevant mouse lung cancer model, in which A/J mice develop lung carcinomas after injection of vinyl carbamate, a potent carcinogen. CDDO-2P-Im and CDDO-3P-Im were as effective as CDDO-Im for reducing the size and the severity of the lung tumors. PMID- 26238179 TI - Introductory letter: Address from the President of the Chilean Society of Pharmacology. PMID- 26238178 TI - Evidence for the role of lipid rafts and sphingomyelin in Ca2+-gating of Transient Receptor Potential channels in trigeminal sensory neurons and peripheral nerve terminals. AB - Transient Receptor Potential (TRP) cation channels, such as TRP Vanilloid 1 and TRP Ankyrin repeat domain 1 (TRPV1 and TRPA1) are nocisensors playing important role to signal pain. Two "melastatin" TRP receptors, like TRPM8 and TRPM3 are also expressed in a subgroup of primary sensory neurons. These channels serve as thermosensors with unique thermal sensitivity ranges and are activated also by several exogenous and endogenous chemical ligands inducing conformational changes from various allosteric ("multisteric") sites. We analysed the role of plasma membrane microdomains of lipid rafts on isolated trigeminal (TRG) neurons and TRPV1-expressing CHO cell line by measuring agonist-induced Ca2+ transients with ratiometric technique. Stimulation-evoked calcitonin gene related peptide (CGRP) release from sensory nerve endings of the isolated rat trachea by radioimmunoassay was also measured. Lipid rafts were disrupted by cleaving sphingomyelin (SM) with sphingomyelinase (SMase), cholesterol depletion with methyl beta-cyclodextrin (MCD) and ganglioside breakdown with myriocin. It has been revealed that intracellular Ca2+ increase responses evoked by the TRPV1 agonist capsaicin, the TRPA1 agonsits allyl isothiocyanate (AITC) and formaldehyde as well as the TRPM8 activator icilin were inhibited after SMase, MCD and myriocin incubation but the response to the TRPM3 agonist pregnenolon sulphate was not altered. Extracellular SMase treatment did not influence the thapsigargin-evoked Ca2+-release from intracellular stores. Besides the cell bodies, SMase also inhibited capsaicin- or AITC-evoked CGRP release from peripheral sensory nerve terminals, this provides the first evidence for the importance of lipid raft integrity in TRPV1 and TRPA1 gating on capsaicin sensitive nerve terminals. SM metabolites, ceramide and sphingosine, did not influence TRPA1 and TRPV1 activation on TRG neurons, TRPV1-expressing CHO cell line, and nerve terminals. We suggest, that the hydrophobic interactions between TRP receptors and membrane lipid raft interfaces modulate the opening properties of these channels and therefore, targeting this interaction might be a promising tool for drug developmental purposes. PMID- 26238180 TI - Novel players in cardioprotection: Insulin like growth factor-1, angiotensin-(1 7) and angiotensin-(1-9). AB - Insulin-like growth factor-1, angiotensin-(1-7) and angiotensin-(1-9) have been proposed to be important mediators in cardioprotection. A large body of evidence indicates that insulin like growth factor-1 has pleotropic actions in the heart (i.e., contractility, metabolism, hypertrophy, autophagy, senescence and cell death) and, conversely, its deficiency is associated with impaired cardiac function. Recently, we reported that insulin like growth factor-1 receptor is also located in plasma membrane invaginations with perinuclear localization, highlighting the role of nuclear Ca(2+) signaling in the heart. In parallel, angiotensin-(1-7) and angiotensin (1-9) acting through Mas receptor and angiotensin type 2 receptor have emerged as a novel anti-hypertensive molecules promoting vasodilatation and preventing heart hypertrophy. In this review we discuss the scientific evidence available regarding insulin-like growth factor-1, angiotensin-(1-7) and angiotensin-(1-9) in cardioprotection and its potential application as novel therapeutic targets for treating cardiac diseases. PMID- 26238181 TI - Rationale and design of a comparative effectiveness trial of home- and clinic based self-management support coaching for older adults with asthma. AB - Older adults with asthma face numerous barriers to effective self-management and asthma control, and experience worse outcomes than younger asthmatics. Yet, there have been no controlled trials of interventions specifically designed to improve their care and outcomes. Through a multi-stakeholder collaboration (patients, academia, community-based organizations, a state department of health, and an advocacy organization) we developed a multi-component asthma self-management support intervention to address the myriad psychosocial, functional, health status, and cognitive barriers to effective asthma self-management in adults ages 60 and older. We are recruiting 425 New Yorkers in Manhattan and the Bronx for a pragmatic randomized controlled trial with 3 arms: the intervention delivered in primary care settings or in their home, or usual care. In the intervention, care coaches use a novel screening tool to identify the specific barriers to asthma control and self-management they experience. Once identified, the coach and patient choose from a menu of actions to address it. The intervention emphasizes efficiency, flexibility, shared decision making and goal setting, communication strategies appropriate for individuals with limited cognition and literacy skills, and ongoing reinforcement and support. Additionally, we introduced asthma specific enhancements to the electronic health records of all participating clinical practices, including an asthma severity assessment, clinical decision support, and a patient-tailored asthma action plan. Patients will be followed for 12months and interviewed at baseline, 3, 6, and 12months and data on emergency department visits and hospitalizations will be obtained through the New York State Statewide Planning and Research Cooperative System. PMID- 26238182 TI - Does Management of Diabetic Ketoacidosis with Subcutaneous Rapid-acting Insulin Reduce the Need for Intensive Care Unit Admission? AB - BACKGROUND: In the last 20 years, rapid-acting insulin analogs have emerged on the market, including aspart and lispro, which may be efficacious in the management of diabetic ketoacidosis (DKA) when administered by non-intravenous (i.v.) routes. CLINICAL QUESTION: In patients with mild-to-moderate DKA without another reason for intensive care unit (ICU) admission, is the administration of a subcutaneous (s.c.) rapid-acting insulin analog a safe and effective alternative to a continuous infusion of i.v. regular insulin, and would such a strategy eliminate the need for ICU admission? EVIDENCE REVIEW: Five randomized controlled trials were identified and critically appraised. RESULTS: The outcomes suggest that there is no difference in the duration of therapy required to resolve DKA with either strategy. CONCLUSION: Current evidence supports DKA management with s.c. rapid-acting insulin analogs in a non-ICU setting in carefully selected patients. PMID- 26238183 TI - Variation Between Physicians and Mid-level Providers in Opioid Treatment for Musculoskeletal Pain in the Emergency Department. AB - BACKGROUND: Effective, appropriate, and safe opioid analgesia administration in the Emergency Department (ED) is a complex issue, with risks of both over- and underutilization of medications. OBJECTIVE: To assess for possible association between practitioner status (physician [MD] vs. mid-level provider [MLP]) and use of opioids for in-ED treatment of musculoskeletal pain (MSP). METHODS: This was a secondary, hypothesis-generating analysis of a subset of subjects who had ED analgesia noted as part of entry into a prospective registry trial of outpatient analgesia. The study was conducted at 12 U.S. academic EDs, 10 of which utilized MLPs. Patients were enrolled as a convenience sample from September 2012 through February 2014. Study patients were adults (>17 years of age) with acute MSP and eligibility for both nonsteroidal antiinflammatory drugs and opioids at ED discharge. The intervention of interest was whether patients received opioid therapy in the ED prior to discharge. RESULTS: MDs were significantly more likely to order opioids than MLPs for ED patients with MSP. The association between MD/MLP status and likelihood of treatment with opioids was similar in both classical logistic regression (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.1-4.5, p = 0.019) and in propensity-adjusted modeling (OR 2.1, 95% CI 1.0-4.5, p = 0.049). CONCLUSIONS: In preliminary analysis, MD/MLP status was significantly associated with likelihood of provider treatment of MSP with opioids. A follow-up study is warranted to confirm the results of this hypothesis-testing analysis and to inform efforts toward consistency in opioid therapy in the ED. PMID- 26238184 TI - Classical and non-classical proangiogenic factors as a target of antiangiogenic therapy in tumor microenvironment. AB - Angiogenesis is sustained by classical and non-classical proangiogenic factors (PFs) acting in tumor microenvironment and these factors are also potential targets of antiangiogenic therapies. All PFs induce the overexpression of several signaling pathways that lead to migration and proliferation of endothelial cells contributing to tumor angiogenesis and survival of cancer cells. In this review, we have analyzed each PF with its specific receptor/s and we have summarized the available antiangiogenic drugs (e.g. monoclonal antibodies) targeting these PFs, some of these agents have already been approved, others are currently in development for the treatment of several human malignancies. PMID- 26238186 TI - The association between carbon and nitrogen stable isotope ratios of human hair and metabolic syndrome. AB - BACKGROUND: It has been reported that stable isotope ratios can be used as biomarkers for animal protein intake. Meat consumption and high protein intake could be risk factors for metabolic disorders. We investigated whether the stable isotope ratios of carbon and nitrogen are associated with metabolic syndrome. METHODS: We conducted a cross-sectional study of 399 subjects (233 men and 166 women). Hair samples from 399 subjects were measured for stable isotope ratios of carbon (delta(13)C) and nitrogen (delta(15)N). RESULTS: The delta(15)N values progressively increased with the number of components of the metabolic syndrome present in study subjects (P for trend 0.047). In multivariable models, delta(15)N values were positively associated with the presence of metabolic syndrome (odds ratio, 1.53; 95% confidence interval, 1.09-2.14), whereas delta(13)C values were not (odds ratio, 0.97; 95% confidence interval, 0.72 1.30). The odds ratio (95% confidence interval) for metabolic syndrome comparing the highest to the lowest quartiles of delta(15)N values was 2.64 (1.17-5.92). CONCLUSIONS: The nitrogen, but not carbon, stable isotopic ratio of hair is independently associated with the presence of metabolic syndrome. The hair delta(15)N value might be a surrogate marker for clustering of risk factors in metabolic syndrome. PMID- 26238185 TI - MiR-497 decreases cisplatin resistance in ovarian cancer cells by targeting mTOR/P70S6K1. AB - The mechanism of cisplatin resistance in ovarian cancer is not clearly understood. In the present investigation, we found that the expression levels of miR-497 were reduced in chemotherapy-resistant ovarian cancer cells and tumor tissues due to hypermethylation of miR-497 promoter. Low miR-497 expression levels were associated with chemo-resistant phonotype of ovarian cancer. By analyzing the expression levels of miR-497, mTOR and p70S6K1 in a clinical gene expression array dataset, we found that mTOR and p70S6K1, two proteins correlated to chemotherapy-resistance in multiple types of human cancers, were inversely correlated with miR-497 levels in ovarian cancer tissues. By using an orthotopic ovarian tumor model and a Tet-On inducible miR-497 expression system, our results demonstrated that overexpression of miR-497 sensitizes the resistant ovarian tumor to cisplatin treatment. Therefore, we suggest that miR-497 might be used as a therapeutic supplement to increase ovarian cancer treatment response to cisplatin. PMID- 26238187 TI - An update on laboratory diagnosis in myasthenia gravis. AB - This review describes the state of the art for the use of laboratory testing in myasthenia gravis. The review brings a detailed description of the different clinical forms of auto-immune myasthenia and of the Lambert Eaton Myasthenic Syndrome (LEMS). They stress the differences between the different forms of acquired (auto-immune) myasthenia. Then they present a summary of the different antibodies found in the disease. They insist on the advantage of the RIPA assay to measure antibodies to the acetylcholine receptor. They stress the different types of contribution of each of these antibodies to the clinical diagnosis. They also describe the methods to measure each of the specific antibodies that have recently permitted to split the diagnosis: Abs to omega-conotoxin receptor in Lambert Eaton Myasthenic Syndrome (LEMS), abs to the acetylcholine receptor (AchR) in MG, Abs to muscle specific tyrosine kinase (MuSK) in Ab negative MG, and Abs to low molecular weight receptor related low-density lipo protein-4 (LRP 4). They also broach over the striated antibodies, less frequent and clinically less useful such as anti-titin, -ryanodine, -agrin and -rapsyn. This represent a 360 degrees view of the field as presented in Toronto in October 2014. PMID- 26238188 TI - Decreased circulating Th22 and Th17 cells in patients with aplastic anemia. AB - BACKGROUND: Aplastic anemia (AA) is an immune-mediated disorder and mainly related to active destruction of hematopoietic cells by effector T lymphocytes. T helper (Th) 22 cells characterized as a novel subset of CD4+ T cells participate in the pathogenesis of autoimmune and hematological diseases. However, the role of Th22 subset in AA remains unknown. METHODS: 31 untreated AA patients and 30 healthy controls were included in this study. The percentages of Th22, Th17 and pure Th17 cells in peripheral blood were detected by flow cytometry. ELISA to measure interleukin (IL)-22 and IL-17A plasma levels and qRT-PCR for the mRNA levels of Th22 and Th17 related molecules were performed. RESULTS: The proportions of Th22, pure Th17, Th17 cells and plasma levels of IL-22 were significantly lower in untreated AA patients than those in normal controls. A positive correlation was found between Th22 and pure Th17 cells in AA. Moreover, percentages of Th22 cells correlated positively with reticulocyte counts and percentages. In addition, STAT3/STAT5 mRNA expression ratio was elevated in AA patients. CONCLUSION: Together, our results showed Th22 cells correlating with clinical characteristics of AA patients, indicating a possible role of Th22 immune response in the pathogenesis and therapeutic intervention of AA. PMID- 26238189 TI - House dust mite allergens mediate the activation of c-kit in dendritic cells via Toll-like receptor 2. AB - Several studies have demonstrated that the c-kit proto-oncogene and its ligand, stem cell factor, are important in the development of asthma. House dust mite (HDM; Dermatophagoides pteronyssinus) allergens are a major trigger in the development and exacerbation of asthma. HDM allergens can induce the activation of c-kit in dendritic cells (DCs), leading to the development of allergic asthma. Previous studies have demonstrated that activation of Toll-like receptor 2 (TLR2) evokes a T helper (Th)2 immune response and promotes experimental asthma. The aim of the present study was to assess whether HDM mediates the activation of c-kit in DCs via TLR2. Monocyte-derived DCs were generated from C57BL/6 mice, and cultured with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor. The DCs were then sensitized with HDM (10 ug/ml) for 72 h. TLR2-specific small interfering (si)RNA was used to silence and inhibit the expression of TLR2 in the DCs. The expression levels of c-kit and B7 (CD80/CD86) were measured, by analyzing the DC culture supernatant for the presence of IL-6 and IL-12. Inhibition of TLR2 using specific siRNA downregulated the expression of c-kit in the HDM-activated DCs. In addition, silencing of TLR2 inhibited the expression of CD80/CD86, decreased the production of IL-6, and increased the production of IL 12. These results indicated that TRL2 are important in the activation of c-kit by HDM in DCs. PMID- 26238190 TI - Promiscuous interactions and protein disaggregases determine the material state of stress-inducible RNP granules. AB - RNA-protein (RNP) granules have been proposed to assemble by forming solid RNA/protein aggregates or through phase separation into a liquid RNA/protein phase. Which model describes RNP granules in living cells is still unclear. In this study, we analyze P bodies in budding yeast and find that they have liquid like properties. Surprisingly, yeast stress granules adopt a different material state, which is reminiscent of solid protein aggregates and controlled by protein disaggregases. By using an assay to ectopically nucleate RNP granules, we further establish that RNP granule formation does not depend on amyloid-like aggregation but rather involves many promiscuous interactions. Finally, we show that stress granules have different properties in mammalian cells, where they show liquid like behavior. Thus, we propose that the material state of RNP granules is flexible and that the solid state of yeast stress granules is an adaptation to extreme environments, made possible by the presence of a powerful disaggregation machine. PMID- 26238192 TI - Targeted delivery of doxorubicin to breast cancer cells by aptamer functionalized DOTAP/DOPE liposomes. AB - Doxorubicin is used to treat numerous types of tumors including breast cancer, yet dose-associated toxicities limit its clinical application. Here, we demonstrated a novel strategy by which to deliver doxorubicin to breast cancer cells by conjugating cancer cell-specific single-strand DNA aptamers with doxorubicin-encapsulated DOTAP:DOPE nanoparticles (NPs). We utilizing a whole cell-SELEX strategy, and 4T1 cells with high invasive and metastatic potential were used as target cells, while non-invasive and non-metastatic 67NR cells were used as subtractive cells. Ten potential aptamers were generated after multi-pool selection. Studies on the selected aptamers revealed that SRZ1 had the highest and specific binding affinity to 4T1 cells. Then we developed SRZ1 aptamer carried DOTAP:DOPE-DOX NPs. In vitro uptake results which were conducted by FACS indicated that the aptamer significantly promoted the uptake efficiency of DOTAP:DOPE-DOX NPs by 4T1 cells. ATPlite assay was performed to test 4T1, 67NR and NMuMG cell viability after treatment with free doxorubicin, DOTAP:DOPE-DOX particles and aptamer-loaded DOTAP:DOPE-DOX particles. As expected, the aptamers effectively enhanced accumulation of doxorubicin in the 4T1 tumor tissues as determined by in vivo mouse body images and biodistribution analysis. Consistent with the in vitro findings, aptamer-conjugated doxorubicin-loaded DOTAP:DOPE particles markedly suppressed tumor growth and significantly increased the survival rate of 4T1 tumor-bearing mice. These studies demonstrated that aptamer SRZ1 could be a promising molecule for chemotherapeutic drug targeting deliver. PMID- 26238191 TI - Species-wide whole genome sequencing reveals historical global spread and recent local persistence in Shigella flexneri. AB - Shigella flexneri is the most common cause of bacterial dysentery in low-income countries. Despite this, S. flexneri remains largely unexplored from a genomic standpoint and is still described using a vocabulary based on serotyping reactions developed over half-a-century ago. Here we combine whole genome sequencing with geographical and temporal data to examine the natural history of the species. Our analysis subdivides S. flexneri into seven phylogenetic groups (PGs); each containing two-or-more serotypes and characterised by distinct virulence gene complement and geographic range. Within the S. flexneri PGs we identify geographically restricted sub-lineages that appear to have persistently colonised regions for many decades to over 100 years. Although we found abundant evidence of antimicrobial resistance (AMR) determinant acquisition, our dataset shows no evidence of subsequent intercontinental spread of antimicrobial resistant strains. The pattern of colonisation and AMR gene acquisition suggest that S. flexneri has a distinct life-cycle involving local persistence. PMID- 26238193 TI - NOV inhibits proliferation while promoting apoptosis and migration in osteosarcoma cell lines through p38/MAPK and JNK/MAPK pathways. AB - The nephroblastoma overexpressed (NOV) gene, a member of the CCN gene family that encodes secreted proteins involved in a variety of processes including tumorigenesis, is often altered in a variety of tumors, including osteosarcoma. Recent studies indicated that NOV promotes osteosarcoma metastasis, but its biological functions and molecular mechanisms on osteosarcoma proliferation have yet to be fully elucidated. The aim of the present study was to examine the role of NOV in osteosarcoma biology. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis were performed to characterize the endogenous expression of NOV in osteosarcoma cell lines. Recombinant adenovirus expressing NOV/siNOV (AdNOV/AdsiNOV) was used to infect osteosarcoma cell lines with a relatively low/high endogenous NOV expression to determine the functional relevance of NOV expression to osteosarcoma cell growth and migration in vitro, respectively. As a result, osteosarcoma cell proliferation was significantly reduced by NOV upregulation, indicated by 3-(4,5-dimethylthiazol-2-yl)-2, 5 diphenyltrazolium bromide (MTT), colony forming assay and cell cycle analysis. Cell apoptosis was markedly induced, as indicated by Hoechst 33258 staining assay and flow cytometry (FCM) detection. Despite the antiproliferative effect, NOV transfected osteosarcoma cells exhibited increased migration ability. The possible molecular mechanisms underlying the biological role of NOV were also investigated. The results demonstrated that NOV increased the phosphorylation of p38 and c-Jun N-terminal kinase (JNK) mitogen-actived protein kinases (MAPKs) in osteosarcoma cell lines. When the phosphorylation of p38 and JNK were inhibited by SB203580 (p38 inhibitor) or SP600125 (JNK inhibitor), respectively, the NOV induced proliferation inhibition and cell apoptosis were reversed. In conclusion, the results revealed that NOV regulates the tumor growth of osteosarcoma cells through activation of the MAPK signaling pathway and promotes osteosarcoma cell migration in vitro. PMID- 26238194 TI - Identification and selection of normalization controls for quantitative transcript analysis in Blumeria graminis. AB - The investigation of obligate biotrophic pathogens, for example Blumeria graminis, presents a number of challenges. The sensitivity of many assays is reduced because of the presence of host material. Furthermore, the fungal structures inside and outside of the plant possess very different characteristics. Normalization genes are used in quantitative real-time polymerase chain reaction (qPCR) to compensate for changes as a result of the quantity and quality of template material. Such genes are used as references against which genes of interest are compared, enabling true quantification. Here, we identified six potential B. graminis and five barley genes for qPCR normalization. The relative changes in abundance of the transcripts were assayed across an infection time course in barley epidermis, in B. graminis epiphytic structures and haustoria. The B. graminis glyceraldehyde-3-phosphate dehydrogenase (GAPDH), actin (ACT) and histone 3 (H3) genes and the barley GAPDH, ubiquitin (UBI) and alpha-tubulin 2B (TUBA2B) genes were optimal normalization controls for qPCR during the infection cycle. These genes were then used for normalization in the quantification of the members of a Candidate Secreted Effector Protein (CSEP) family 21, a conidia-specific gene and barley genes encoding putative interactors of CSEP0064. The analysis demonstrates the importance of identifying which reference genes are appropriate for each investigation. PMID- 26238195 TI - A comparative analysis of host responses to avian influenza infection in ducks and chickens highlights a role for the interferon-induced transmembrane proteins in viral resistance. AB - BACKGROUND: Chickens are susceptible to infection with a limited number of Influenza A viruses and are a potential source of a human influenza pandemic. In particular, H5 and H7 haemagglutinin subtypes can evolve from low to highly pathogenic strains in gallinaceous poultry. Ducks on the other hand are a natural reservoir for these viruses and are able to withstand most avian influenza strains. RESULTS: Transcriptomic sequencing of lung and ileum tissue samples from birds infected with high (H5N1) and low (H5N2) pathogenic influenza viruses has allowed us to compare the early host response to these infections in both these species. Chickens (but not ducks) lack the intracellular receptor for viral ssRNA, RIG-I and the gene for an important RIG-I binding protein, RNF135. These differences in gene content partly explain the differences in host responses to low pathogenic and highly pathogenic avian influenza virus in chicken and ducks. We reveal very different patterns of expression of members of the interferon induced transmembrane protein (IFITM) gene family in ducks and chickens. In ducks, IFITM1, 2 and 3 are strongly up regulated in response to highly pathogenic avian influenza, where little response is seen in chickens. Clustering of gene expression profiles suggests IFITM1 and 2 have an anti-viral response and IFITM3 may restrict avian influenza virus through cell membrane fusion. We also show, through molecular phylogenetic analyses, that avian IFITM1 and IFITM3 genes have been subject to both episodic and pervasive positive selection at specific codons. In particular, avian IFITM1 showed evidence of positive selection in the duck lineage at sites known to restrict influenza virus infection. CONCLUSIONS: Taken together these results support a model where the IFITM123 protein family and RIG-I all play a crucial role in the tolerance of ducks to highly pathogenic and low pathogenic strains of avian influenza viruses when compared to the chicken. PMID- 26238196 TI - Overexpression of methionine adenosyltransferase in Corynebacterium glutamicum for production of S-adenosyl-l-methionine. AB - Two genes encoding methionine adenosyltransferase, SAM2 from Saccharomyces cerevisiae and metK from Corynebacterium glutamicum, were individually cloned into pDXW-8, the shuttle vector between Escherichia coli and C. glutamicum, and overexpressed in E. coli DH5alpha and C. glutamicum ATCC13032. In DH5alpha, both genes were overexpressed and their protein products showed the activity of methionine adenosyltransferase. In ATCC13032, metK was overexpressed, its product MetK showed the enzyme activity and could convert l-methionine to S-adenosyl-l methionine (SAM). However, when SAM2 was overexpressed in ATCC13032, neither the enzyme activity nor the conversion of SAM from l-methionine was observed. Reverse transcription PCR analysis and SDS-PAGE showed that SAM2 was transcribed but not translated in C. glutamicum. Therefore, SAM2-C, a mutant SAM2, was constructed by codon optimization, and overexpressed in ATCC13032; it was well transcribed and translated, and could convert l-methionine to SAM. Finally, SAM2-C and metK were individually overexpressed in E. coli BL21(DE3), and their products SAM2-C and MetK were purified and characterized. The optimum activity for both enzymes was found at pH 8.5 and 35 degrees C; SAM2-C and MetK have similar Km for ATP, but quite different Km for l-methionine. These results suggest that SAM2-C and MetK can be useful for developing C. glutamicum to produce SAM. PMID- 26238197 TI - Extrinsic tooth staining potential of high dose and sustained release iron syrups on primary teeth. AB - BACKGROUND: Iron in the form of oral supplements is routinely prescribed to children to help fight anemia, however tooth staining is a commonly reported complication. This study tests in vitro, the staining potential of two different forms of iron syrup on primary teeth. METHODS: Forty caries free primary central incisors were divided into four groups of ten teeth each. The control group comprised of ten teeth immersed in artificial saliva, while the test solutions were comprised of different forms of iron mixed with vitamins such that the iron content of each solution was approximately 100 mg (from 100 to 101.1 mg). The test solutions used iron syrup (Ferrose(r), SPIMACO, Jeddah, Saudi Arabia) with iron in the form of ferric oxide polymaltose (FOP), slow release formula (Ferroglobin(r), Vitabiotics ltd., London, UK) containing ferrous fumarate (FF and a combination of the two (FOP + FF). All the teeth were then immersed for 72 h and subjected to a protocol developed by Lee et al. to test staining. Color changes were measured using a wave dispersion spectro-photometer (Color-Eye 7000A, X-Rite Gmbh, Regensdorf, Switzerland) on the exposed labial surface at 4, 8, 24, 48 and 72 h. Two-way ANOVA with Scheffe's post hoc test was used to determine significance of difference in shade, while the Kurskull-Wallis test used to determine the significance of difference in clinical staining (?E > 3). RESULTS: While all three iron groups showed some amount of staining, the combination of the two forms of iron (FOP+FF) showed significantly lower incidence of clinical staining than the other two groups at the end of 72 h. At the end of 72 h the (FOP) had significantly higher ?E than ferrous fumarate (FF ) while the combination (FOP+ FF) had a significantly lower ?E than either group. CONCLUSION: In an in vitro model, combining different forms of iron seems to elicit a lower intensity of staining than equivalent doses of a single form of iron. PMID- 26238198 TI - New relative intensity ambulatory accelerometer thresholds for elderly men and women: the Generation 100 study. AB - BACKGROUND: Public health initiatives world-wide recommend increasing physical activity (PA) to improve health. However, the dose and the intensity of PA producing the most benefit are still debated. Accurate assessment of PA is necessary in order to 1) investigate the dose-response relationship between PA and health, 2) shape the most beneficial public health initiatives and 3) test the effectiveness of such initiatives. Actigraph accelerometer is widely used to objectively assess PA, and the raw data is given in counts per unit time. Count thresholds for low, moderate and vigorous PA are mostly based on absolute intensity. This leads to largely inadequate PA intensity assessment in a large proportion of the elderly, who due to their declining maximal oxygen uptake (VO2max) cannot reach the moderate/vigorous intensity as defined in absolute terms. To resolve this issue, here we report relative Actigraph intensity thresholds for the elderly. METHODS: Submaximal-oxygen-uptake, VO2max and maximal heart rate (HRmax) were measured in 111 70-77 year olds, while wearing an Actigraph-GT3X+. Relationship between VO2max percentage (%), counts-per-minute (CPM) and gender (for both the vertical-axis (VA) and vector-magnitude (VM)) and VO2max% and HRmax% was established using a mixed-regression-model. VM-and VA models were tested against each other to see which model predicts intensity of PA better. RESULTS: VO2max and gender significantly affected number of CPM at different PA intensities (p < 0.05). Therefore, intensity-thresholds were created for both men and women of ranging VO2max values (low, medium, high). VM-model was found to be a better predictor of PA-intensity than VA-model (p < 0.05). Established thresholds for moderate intensity (46-63 % of VO2max) ranged from 669 3367 and 834-4048 CPM and vigorous intensity (64-90 % of VO2max) from 1625-4868 and 2012-5423CPM, for women and men, respectively. Lastly, we used this evidence to derive a formula that predicts customized relative intensity of PA (either VO2max% or HRmax%) using counts-per-minute values as input. CONCLUSION: Intensity thresholds depend on VO2max, gender and Actigraph-axis. PA intensity-thresholds that take all these factors into account allow for more accurate relative intensity PA assessment in the elderly and will be useful in future PA research. TRIAL REGISTRATION: (ClinicalTrials.gov Identifier: NCT02017847, registered 17. December 2013). PMID- 26238199 TI - Test-retest reliability of Kinect's measurements for the evaluation of upper body recovery of stroke patients. AB - BACKGROUND: Performance indices provide quantitative measures for the quality of motion, and therefore, assist in analyzing and monitoring patients' progress. Measurement of performance indices requires costly devices, such as motion capture systems. Recent developments of sensors for game controllers, such as Microsoft Kinect, have motivated many researchers to develop affordable systems for performance measurement applicable to home and clinical care. In this work, the capability of Kinect in finding motion performance indices was assessed by analyzing intra-session and inter-session test-retest reliability. METHOD: Eighteen stroke patients and twelve healthy subjects participated in this investigation. The intra-session and inter-session reliability of eight performance indices, namely mean velocity (MV), normalized mean speed (NMS), normalized speed peaks (NSP), logarithm of dimensionless jerk (LJ), curvature (C), spectral arc length (SAL), shoulder angle (SA), and elbow angle (EA), were assessed using intra-class correlation coefficient (ICC), standard error of measurement (SEM) and coefficient of variation (CV). RESULTS: The results showed that, among the performance indices, MV, LJ, C, SA and EA have more than 0.9 ICC together with an acceptable SEM and CV in both stroke patients and healthy subjects. Comparing the results of different therapy sessions showed that MV, LJ and C are more sensitive than other indices, and hence, more capable of reflecting the progress of a patient during the rehabilitation process. CONCLUSION: The results of this study shows acceptable reliability and sensitivity across the sessions for MV, LJ and C measured by Kinect for both healthy subjects and stroke patients. The results are promising for the development of home-based rehabilitation systems, which can analyze patient's movements using Kinect as an affordable motion capture sensor. PMID- 26238200 TI - Combination of serum RASSF1A methylation and AFP is a promising non-invasive biomarker for HCC patient with chronic HBV infection. AB - BACKGROUND: Hypermethylation of the promoter region of the RAS association domain family 1A gene (RASSF1A) occurs widely in hepatocellular carcinoma (HCC) tissues. While the diagnostic performance of the use of RASSF1A methylation as a serum or plasma marker in patients with HCC has varied largely in the literature,we confirmed the clinical application value of serum RASSF1A methylation for HBV related HCC in this study. METHODS: A total of 584 participants were recruited into this study, including 190 patients with HCC, 114 patients with liver cirrhosis (LC), 120 patients with chronic hepatitis B (CHB) and 160 healthy individuals. Serum RASSF1A methylation was determined by the MethyLight method. In addition, we followed up 43 HCC patients who were unable to undergo surgery for 24 months. RESULTS: Serum RASSF1A methylation occurred significantly more frequently in patients with HCC (122/190, 64.2%) than in patients with LC (20/114, 17.5%), patients with CHB (6/120, 5.0%) and in healthy individuals (0/160, 0) (P < 0.001); moreover, it allowed for the discrimination of patients with HCC from those with CHB with an areas under the ROC curves (AUC) of 0.796 (64.2% sensitivity and 89.8% specificity). Furthermore, the AUC for the combination of serum RASSF1A methylation and AFP level (>=20 ng/L) was 0.876 (80.9% sensitivity and 93.4% specificity). Serum RASSF1A methylation positive in patients with HCC was associated with more malignant clinical characteristics and a worse overall survival (OS) (P < 0.05). CONCLUSION: Serum RASSF1A methylation demonstrated a satisfactory value for in the diagnosis of HBV related HCC, and could predict clinical progression and prognosis. In addition, our findings suggested that the combination of serum RASSF1A methylation and AFP level may be a promising non-invasive biomarker for the discrimination of patients with HCC from those with CHB. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_DPAT-D-15 00090.1. PMID- 26238201 TI - Impact of habitat fragmentation on tsetse populations and trypanosomosis risk in Eastern Zambia. AB - BACKGROUND: Fragmentation of tsetse habitat in eastern Zambia is largely due to encroachments by subsistence farmers into new areas in search of new agricultural land. The impact of habitat fragmentation on tsetse populations is not clearly understood. This study was aimed at establishing the impact of habitat fragmentation on physiological and demographic parameters of tsetse flies in order to enhance the understanding of the relationship between fragmentation and African animal trypanosomosis (AAT) risk. METHODS: A longitudinal study was conducted to establish the age structure, abundance, proportion of females and trypanosome infection rate of Glossina morsitans morsitans Westwood (Diptera: Glossinidae) in areas of varying degrees of habitat fragmentation in Eastern Zambia. Black screen fly rounds were used to sample tsetse populations monthly for 1 year. Logistic regression was used to analyse age, proportion of females and infection rate data. RESULTS: Flies got significantly older as fragmentation increased (p < 0.004). The proportion of old flies, i.e. above ovarian category four, increased significantly (P < 0.001) from 25.9% (CI 21.4-31.1) at the least fragmented site (Lusandwa) to 74.2% (CI 56.8-86.3) at the highly fragmented site (Chisulo). In the most fragmented area (Kasamanda), tsetse flies had almost disappeared. In the highly fragmented area a significantly higher trypanosome infection rate in tsetse (P < 0.001) than in areas with lower fragmentation was observed. Consequently a comparatively high trypanosomosis incidence rate in livestock was observed there despite lower tsetse density (p < 0.001). The overall proportion of captured female flies increased significantly (P < 0.005) as fragmentation reduced. The proportion increased from 0.135 (CI 0.10-0.18) to 0.285 (CI 0.26-0.31) at the highly and least fragmented sites, respectively. CONCLUSIONS: Habitat fragmentation creates conditions to which tsetse populations respond physiologically and demographically thereby affecting tsetse-trypanosome interactions and hence influencing trypanosomosis risk. Temperature rise due to fragmentation coupled with dominance of old flies in populations increases infection rate in tsetse and hence creates high risk of trypanosomosis in fragmented areas. Possibilities of how correlations between biological characteristics of populations and the degree of fragmentation can be used to structure populations based on their well-being, using integrated GIS and remote sensing techniques are discussed. PMID- 26238202 TI - Involvement of an intracellular vesicular transport process in naked-sgRNA mediated TRUE gene silencing. AB - tRNase ZL-utilizing efficacious gene silencing (TRUE gene silencing) is an RNA mediated gene expression control technology with therapeutic potential. Recently, our group demonstrated that a heptamer, mh1 (Bcl-2), targeting human Bcl-2 mRNA, can be taken up by cells without the use of any transfection reagents and can induce the apoptosis of leukemia cells. However, little is known regarding the mechanism of naked small guide (sg)RNA uptake by cultured cells. Therefore, in the present study the effects of various inhibitors on the induction of apoptosis by naked sgRNA treatment were investigated in order to identify the uptake pathway required for sgRNA function in cultured cells. Addition of the endocytosis inhibitors chlorpromazine, nystatin or methyl-beta-cyclodextrin together with naked effective sgRNA was unable to diminish the apoptosis-inducing effects of naked sgRNA or the reduction in target mRNA, suggesting that functional uptake of sgRNA by cells is clathrin-, caveolae- and raft-independent. Next, chloroquine, an inhibitor of lysosome acidification, and brefeldin A, an inhibitor that blocks protein transport from the Golgi apparatus to the endoplasmic reticulum were administered. In the presence of these compounds, the apoptosis-inducing effects of naked sgRNA were reduced. These results suggest that a vesicular transport process is involved in sgRNA-mediated TRUE gene silencing. A greater understanding of how naked sgRNAs enter cells and how they reach their target RNAs may aid in the design of more specifically-targeted and potent sgRNA drugs. PMID- 26238203 TI - MicroRNA-506 participates in pancreatic cancer pathogenesis by targeting PIM3. AB - MicroRNA (miRNA) is a type of short non-coding RNA that suppresses the expression of protein coding genes by partial complementary binding to the 3'-untranslated regions (UTRs) of mRNAs. miRNA expression alterations are involved in the initiation, progression and metastasis of human cancer and it has been suggested that miRNAs function as tumor suppressors as well as oncogenes in cancer development. PIM-3 is a member of the proto-oncogene PIM family, the aberrant expression of which exists in human pancreatic cancer tissues. There are reports indicating that overexpression of PIM3 is associated with the promotion of pancreatic cancer cell proliferation. The aim of the present study was to identify micro (mi)RNAs that regulate the expression of the oncogene PIM3 in PC. It was confirmed that the expression of PIM3 was regulated by miRNAs through an AGO2 knockout experiment. Subsequently, a dual luciferase assay system was constructed and used to screen 13 selected miRNAs that may target the PIM3 3'UTR directly. The results indicated that miR-15a/b, miR-16, miR-33a/b, miR-124, miR 195 and miR-506 repressed the luciferase activity by targeting the PIM3 3'UTR. However, only the expression of miR-506 was negatively correlated with PIM3 expression in PC tissues (r=-0.38, P=0.017). Furthermore, a biological functional study indicated that miR-506 functioned as a tumor suppressor by repressing PC cell proliferation, which was partially reversed by PIM3 overexpression. To the best of our knowledge, the present study was the first to reveal the tumor suppressor function of miR-506 in PC, which has the potential to be employed in the diagnosis and treatment of PC. PMID- 26238204 TI - The flavonoid p-hydroxycinnamic acid mediates anticancer effects on MDA-MB-231 human breast cancer cells in vitro: Implications for suppression of bone metastases. AB - Tumor invasion into bone tissues is associated with osteoclast and osteoblast recruitment, resulting in the liberation of growth factors from the bone matrix, which can feed back to enhance tumor growth resulting in the vicious cycle of bone metastasis. Activated nuclear factor-kappaB (NF-kappaB) in breast cancer cells has been shown to play a crucial role in the osteolytic bone metastasis of breast cancer in stimulating osteoclastogenesis. The flavonoid p-hydroxycinnamic acid (HCA) mediates bone anabolic and anti-catabolic effects by stimulating osteoblastic bone formation and suppressing osteoclastic bone resorption. However, the capacity of HCA to ameliorate the negative effects of breast cancer on bone cells has not been investigated. The present study was undertaken to determine the anticancer effects of HCA on MDA-MB-231 human breast cancer bone metastatic cells in vitro models. Proliferation of MDA-MB-231 cells was suppressed by culture with HCA (10-1000 nM) due to G1 and G2/M phase cell cycle arrest. The suppressive effects of HCA were mediated through signaling pathways that are related to NF-kappaB, extracellular signal-regulated kinase (ERK), protein kinase C, calcium signaling, phosphatidylinositol 3-kinase (PI3K) and nuclear transcription activity. HCA was also found to induce death of confluent cancer cells. Furthermore, co-culture with MDA-MB-231 cells suppressed mineralization and stimulated osteoclastogenesis in bone marrow cells. These alterations were prevented by HCA (10-250 nM). The present study demonstrates that HCA possesses anticancer properties in MDA-MB-231 human breast cancer cells and alleviates the negative effects on osteoblastogenesis and osteoclastogenesis in vitro. HCA may have important applications in the treatment of breast cancer bone metastasis. PMID- 26238205 TI - Effect of DR4 promoter methylation on the TRAIL-induced apoptosis in lung squamous carcinoma cell. AB - The aim of the present study was to examine the relationship between DR4 methylation status and gene expression and to determine whether DR4 methylation status affects TRAIL-induced apoptosis in lung squamous carcinoma cells. MSP, RT PCR and western blot analysis were applied to detect the methylation status and gene expression. An MTT assay was used to detect the cell proliferation inhibition rate and flow cytometry was utilized to detect the apoptotic rate. The results showed that there was no association of the apoptotic rate with the clinicopathological characteristics for 80.6% of 36 lung squamous carcinoma patients in the methylation status (P>0.05). In the lung squamous carcinoma patients, the probability of DR4 low expression was approximately 58.3%, which may be associated with DR4 promoter methylation. The results also showed that a low expression of DR4 was correlated with the prognosis of patients. The in vitro experiments suggested DR4 genes of H226 and SK-MES-1 cells were in the methylation status and their mRNA and proteins had a low expression. Following intervention with 5-Aza-CdR, the DR4 genes of H226 and SK-MES-1 cells were in the unmethylation status and their mRNA and protein expression was significantly upregulated compared with the pre-interference ones, with differences being statistically significant (P<0.05). In addition, following interference with 5 Aza-CdR, H226 and SK-MES-1 cells became significantly sensitive to TRAIL (P<0.05). The results revealed 5-Aza-CdR was able to reverse DR4 methy-lation status to upregulate its expression, thereby increasing the TRAIL-induced apoptosis in lung squamous carcinoma cells. Therefore, combining 5-Aza-CdR and TRAIL is a new strategy for treating lung squamous carcinoma. PMID- 26238206 TI - Validation of Self-Report of Chest X-Ray Exam at a Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Center. AB - It is imperative to measure the degree of contamination throughout the course of randomized controlled trials, as contamination, the receipt of the intervention arm regimen by control arm participants, can affect trial power. In the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, contamination was estimated through use of the self-administered Health Status Questionnaire (HSQ) annually to a randomly-selected subset of control arm participants. We examined agreement of self-report of chest x-ray on the HSQ with clinic records at one of the 10 PLCO screening centers (Henry Ford Health System, or HFHS). We focus on HFHS participants covered by the Health Alliance Plan (HAP), a managed health care insurance plan owned and operated by HFHS, because claims for care received both at HFHS and other facilities are available in HFHS databases for HAP enrollees. We examined agreement for the six years prior to HSQ completion, with HFHS clinic records considered to be the gold standard. For those who had complete HAP coverage during the six years, percent agreement was 0.69, sensitivity was 0.84, and positive predictive value was 0.76. Specificity and negative predicted value were low, however (0.28 and 0.38, respectively), and Cohen's kappa was 0.13. For groups with incomplete or no HAP coverage, and when timing of exam was considered, performance measures typically became lower, in some instances below 0.20. These data suggest that self-report of chest x-ray screening may not be accurate, although high prevalence of chest x-ray may make performance measures less interpretable. PMID- 26238207 TI - Lessons in Medical Record Abstraction from the Prostate, Lung, Colorectal, and Ovarian (PLCO) National Screening Trial. AB - The most rigorous and accurate approach to evaluating clinical events in cancer screening studies is to use data obtained through medical record abstraction (MRA). Although MRA is complex, the particulars of the procedure-such as the specific training and quality assurance processes, challenges of implementation, and other factors that influence the quality of abstraction--are usually not described in reports of studies that employed the technique. In this paper, we present the details of MRA activities used in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, which used MRA to determine primary and secondary outcomes and collect data on other clinical events. We describe triggers of the MRA cycle and the specific tasks that were part of the abstraction process. We also discuss training and certification of abstracting staff, and technical methods and communication procedures used for data quality assurance. We include discussion of challenges faced and lessons learned. PMID- 26238208 TI - Building Successful Relationships in the PLCO Cancer Screening Trial. AB - Biomedical research cannot succeed without funding, knowledgeable staff, and appropriate infrastructure. There are however equally important but intangible factors that are rarely considered in planning large multidisciplinary endeavors or evaluating their success. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial required extensive collaborations between individuals from many fields, including clinicians, clinical trialists, and administrators; it also addressed questions across the spectrum of cancer prevention and control. In this manuscript, we examine the experiences and opinions of trial staff regarding the building of successful relationships in PLCO. We summarize, in narrative form, data collected using open-ended questionnaires that were administered to the National Cancer Institute project officers, coordinating center staff, screening center principal investigators, and screening center coordinators in 2015, about 3 years after publication of the final primary trial manuscript. Trust, respect, listening to others, and in-person interaction were frequently mentioned as crucial to building successful relationships. PMID- 26238210 TI - Genetic characterization of porcine kobuvirus variants identified from healthy piglets in China. AB - In this study, two porcine kobuvirus strains, JS-01-CHN and JS-02a-CHN were detected from piglets with diarrhea and asymptomatic, respectively. The sequences of the two strains were analyzed using a bioinformatics software package. The full-length genome of JS-02a-CHN, was detected in healthy piglets was 8121 nucleotides (nt) long excluding the poly(A) tail. There was a 30 amino acid deletion in the 2B-coding region of JS-02a-CHN. We are the first to report a 30 amino acid deletion in porcine kobuvirus from asymptomatic piglets, indicating that porcine kobuvirus may have evolved differently based on geography and host differences. Fecal samples were obtained from pigs with diarrhea (n=91) and healthy (n=126) pigs and analyzed using RT-PCR. Of these, 64.8% (59/91) of diarrheic piglets and 19.8% (25/126) of healthy piglets were positive for PKV using VP1 specific primers. Twenty-eight (28) virus positive samples were randomly selected and the VP1 gene was analyzed. Phylogenetic analysis indicated that the 15 strains isolated from pigs with diarrhea clustered into different branches, while the VP1 sequences from clinically healthy pigs clustered into a single large group. These results indicate that the VP1 gene is diverse in pigs with diarrhea but conserved in healthy pigs in the Jiangsu Province. PMID- 26238209 TI - Treatment of cholestatic fibrosis by altering gene expression of Cthrc1: Implications for autoimmune and non-autoimmune liver disease. AB - Collagen triple helix repeat containing-1 (Cthrc1) is a documented specific inhibitor of TGF-beta signaling. Based on this observation, we developed the hypothesis that knocking in/knocking out the Cthrc1 gene in murine models of cholestasis would alter the natural history of cholestatic fibrosis. To study this thesis, we studied two murine models of fibrosis, first, common bile duct ligation (CBDL) and second, feeding of 3, 5-diethoxy-carbonyl-1, 4 dihydrocollidine (DDC). In both models, we administered well-defined adenoviral vectors that expressed either Cthrc1 or, alternatively, a short hairpin RNA (shRNA)-targeting Cthrc1 either before or after establishment of fibrosis. Importantly, when Cthrc1 gene expression was enhanced, we noted a significant improvement of hepatic fibrosis, both microscopically and by analysis of fibrotic gene expression. In contrast, when Cthrc1 gene expression was deleted, there was a significant exacerbation of fibrosis. To identify the mechanism of action of these significant effects produced by knocking in/knocking out Cthrc gene expression, we thence studied the interaction of Cthrc1 gene expression using hepatic stellate cells (HSCs) and human LX-2 cells. Importantly, we demonstrate that Cthrc1 is induced by TGF-beta1 via phospho-Smad3 binding to the promoter with subsequent transcription activation. In addition, we demonstrate that Cthrc1 inhibits TGF-beta signaling by accelerating degradation of phospho-Smad3 through a proteosomal pathway. Importantly, the anti-fibrotic effects can be recapitulated with a truncated fragment of Cthrc1. In conclusion, our findings uncover a critical negative feedback regulatory loop in which TGF-beta1 induces Cthrc1, which can attenuate fibrosis by accelerating degradation of phospho Smad3. PMID- 26238211 TI - The genetic architecture of a complex trait: Resistance to multiple toxins produced by Bacillus thuringiensis israelensis in the dengue and yellow fever vector, the mosquito Aedes aegypti. AB - The bacterial insecticide Bacillus thuringiensis subsp. israelensis (Bti) is an increasingly popular alternative to chemical insecticides for controlling mosquito populations. Because Bti toxicity relies on the action of four main toxins, resistance to Bti is very likely a complex phenotype involving several genes simultaneously. Dissecting the underlying genetic basis thus requires associating a quantitative measure of resistance to genetic variation at many loci in a segregating population. Here, we undertake this task using the dengue and yellow fever vector, the mosquito Aedes aegypti, as a study model. We conducted QTL (Quantitative Trait Locus) and admixture mapping analyses on two controlled crosses and on an artificial admixed population, respectively, all obtained from resistant and susceptible lab strains. We detected 16 QTL regions, among which four QTLs were revealed by different analysis methods. These four robust QTLs explained altogether 29.2% and 62.2% of the total phenotypic variance in the two QTL crosses, respectively. They also all showed a dominant mode of action. In addition, we found six loci showing statistical association with Bti resistance in the admixed population. Five of the supercontigs highlighted in this study contained candidate genes as suggested by their function, or by prior evidence from expression and/or outlier analyses. These genomic regions are thus good starting points for fine mapping of resistance to Bti or functional analyses aiming at identifying the underlying genes and mutations. Moreover, for the purpose of this work, we built the first Ae. aegypti genetic map based on markers associated with genes expressed in larvae. This genetic map harbors 229 SNP markers mapped across the three chromosomes for a total length of 311.9cM. It brought to light several assembly discrepancies with the reference genome, suggesting a high level of genome plasticity in Ae. aegypti. PMID- 26238212 TI - Mitigation of Salinity Buildup and Recovery of Wasted Salts in a Hybrid Osmotic Membrane Bioreactor-Electrodialysis System. AB - The osmotic membrane bioreactor (OMBR) is an emerging technology that uses water osmosis to accomplish separation of biomass from the treated effluent; however, accumulation of salts in the wastewater due to water flux and loss of draw solute because of reverse salt flux seriously hinder OMBR development. In this study, a hybrid OMBR-electrodialysis (ED) system was proposed and investigated to alleviate the salinity buildup. The use of an ED (3 V applied) could maintain a relatively low conductivity of 8 mS cm(-1) in the feed solution, which allowed the OMBR to operate for 24 days, about 6 times longer than a conventional OMBR without a functional ED. It was found that the higher the voltage applied to the ED, the smaller area of ion-exchange membrane was needed for salt separation. The salts recovered by the ED were successfully reused as a draw solute in the OMBR. At an energy consumption of 1.88-4.01 kWh m(-3), the hybrid OMBR-ED system could achieve a stable water flux of about 6.23 L m(-2) h(-1) and an efficient waste salt recovery of 1.26 kg m(-3). The hybrid OMBR-ED system could be potentially more advantageous in terms of less waste saline water discharge and salt recovery compared with a combined OMBR and reverse osmosis system. It also offers potential advantages over the conventional OMBR+post ED treatment in higher water flux and less wastewater discharge. PMID- 26238213 TI - Development of a gelatin-based polyurethane vascular graft by spray, phase inversion technology. AB - The capacity of a composite vascular graft constituting polyurethane (PU) and gelatin to support cell growth was investigated using human mesenchymal stem cells (hMSCs). Gelatin-based polyurethane grafts were fabricated by co-spraying polyurethane and gelatin using a spray, phase-inversion technique. Graft microstructure was investigated by light and scanning electron microscopy. Uniaxial tensile tests were performed to assess the grafts' mechanical properties in longitudinal and circumferential directions. hMSCs obtained from bone marrow aspirate were seeded onto flat graft samples. After 24, 48, and 72 h of incubation, cell morphology was evaluated by Giemsa staining and cell viability was calculated by XTT assay. SEM analysis evidenced that PU samples display a microporous structure, whereas the gelatin-based PU samples show a fibrillar appearance. The presence of cross-linked gelatin produced a significant increase of ultimate tensile strength and ultimate elongation in circumferential directions compared to PU material. Qualitative analysis of hMSC adhesion onto the grafts revealed remarkable differences between gelatin-based PU and control graft. hMSCs grown onto gelatin-based PU graft form a monolayer that reached confluence at 72 h, whereas cells seeded onto the control graft were not able to undergo appropriate spreading. hMSCs grown onto gelatin-based PU graft showed significantly higher viability than cells seeded onto bare PU at all time points. In conclusion, a composite vascular graft was successfully manufactured by simultaneous co-spraying of a synthetic polymer and a protein to obtain a scaffold that combines the mechanical characteristics of polyurethanes with the favorable cell interaction features of gelatin. PMID- 26238214 TI - Particle emissions from microalgae biodiesel combustion and their relative oxidative potential. AB - Microalgae are considered to be one of the most viable biodiesel feedstocks for the future due to their potential for providing economical, sustainable and cleaner alternatives to petroleum diesel. This study investigated the particle emissions from a commercially cultured microalgae and higher plant biodiesels at different blending ratios. With a high amount of long carbon chain lengths fatty acid methyl esters (C20 to C22), the microalgal biodiesel used had a vastly different average carbon chain length and level of unsaturation to conventional biodiesel, which significantly influenced particle emissions. Smaller blend percentages showed a larger reduction in particle emission than blend percentages of over 20%. This was due to the formation of a significant nucleation mode for the higher blends. In addition measurements of reactive oxygen species (ROS), showed that the oxidative potential of particles emitted from the microalgal biodiesel combustion were lower than that of regular diesel. Biodiesel oxygen content was less effective in suppressing particle emissions for biodiesels containing a high amount of polyunsaturated C20-C22 fatty acid methyl esters and generated significantly increased nucleation mode particle emissions. The observed increase in nucleation mode particle emission is postulated to be caused by very low volatility, high boiling point and high density, viscosity and surface tension of the microalgal biodiesel tested here. Therefore, in order to achieve similar PM (particulate matter) emission benefits for microalgal biodiesel likewise to conventional biodiesel, fatty acid methyl esters (FAMEs) with high amounts of polyunsaturated long-chain fatty acids (>=C20) may not be desirable in microalgal biodiesel composition. PMID- 26238215 TI - Histopathology of melanosis coli and determination of its associated genes by comparative analysis of expression microarrays. AB - Melanosis coli (MC) refers to the condition characterized by abnormal brown or black pigmentation deposits on the colonic mucosa. However, the histopathological findings and genes associated with the pathogenesis of melanosis coli remain to be fully elucidated. The present study aimed to examine the histopathological features and differentially expressed genes of MC. This involved performing hematoxylin and eosin staining, specific staining and immunohistochemistry on tissues sections, which were isolated from patients diagnosed with MC. DNA expression microarray analysis, western blotting and immunofluorescence assays were performed to analyze the differentially expressed genes of melanosis coli. The results demonstrated that the pigment deposits in MC consisted of lipofuscin. A TUNEL assay revealed that a substantial number of apoptotic cells were present within the macrophages and superficial lamina propria of the colonic epithelium. Expression microarray analysis revealed that the significantly downregulated genes were CYP3A4, CYP3A7, UGT2B11 and UGT2B15 in melanosis coli. Western blotting and immunofluorescence assays indicated that the expression of CYP3A4 in the normal tissue was higher than in the MC tissue. The results of the present study provided a comprehensive description of the histopathological characteristics and pathogenesis of MC and for the first time, to the best of our knowledge, demonstrated that the cytochrome P450-associated genes were significantly downregulated in melanosis coli. This novel information can be used to assist in further investigations of melanosis coli. PMID- 26238216 TI - Surgical management of abnormal uterine bleeding in fertile age women. AB - Abnormal uterine bleeding is a common gynecological disease and represents one of the most frequent reasons for hospital admission to a specialist unit, often requiring further surgical treatment. Following the so-called PALM-COEIN system we will attempt to further clarify the surgical treatments available today. The first group (PALM) is characterized by structural lesions, which may be more appropriately treated by means of surgical management. Although hysterectomy remains the definitive and decisive choice, there are many alternative techniques available. These minimally invasive procedures offer the opportunity for a more conservative approach. Precise and accurate counseling facilitates better patient selection, based on the patient's desires, age and disease type, allowing treatment to be individually tailored to each woman. PMID- 26238217 TI - Helicobacter pylori cytotoxin-associated gene A activates tumor necrosis factor alpha and interleukin-6 in gastric epithelial cells through P300/CBP-associated factor-mediated nuclear factor-kappaB p65 acetylation. AB - Helicobacter pylori-initiated chronic gastritis is characterized by the cytotoxin associated gene (Cag) pathogenicity island-dependent upregulation of pro inflammatory cytokines in gastric epithelial cells, which is largely mediated by the activation of nuclear factor (NF)-kappaB as a transcription factor. However, the precise regulation of NF-kappaB activation, particularly post-translational modifications in the CagA-induced inflammatory response, has remained elusive. The present study showed that Helicobacter pylori CagA, an important virulence factor, induced the expression of P300/CBP-associated factor (PCAF) in gastric epithelial cells. Further study revealed that PCAF was able to physically associate with the NF-kappaB p65 sub-unit and enhance its acetylation. More importantly, PCAF-induced p65 acetylation was shown to contribute to p65 phosphorylation and further upregulation of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in gastric adenocarcinoma cells. In conclusion, the results of the present study indicated that Helicobacter pylori CagA enhanced TNF-alpha and IL-6 in gastric adenocarcinoma cells through PCAF-mediated NF-kappaB p65 sub-unit acetylation. PMID- 26238218 TI - Aqueous extract of Psoralea corylifolia L. inhibits lipopolysaccharide-induced endothelial-mesenchymal transition via downregulation of the NF-kappaB-SNAIL signaling pathway. AB - The epithelial-mesenchymal transition (EMT) is a pivotal event in the invasion and metastasis of cancer cells. Psoralea corylifolia L. (PC) inhibits the proliferation of various cancer cells. However, its possible role in EMT has not been identified. In the present study, we examined the effects of an aqueous extract of Psoralea corylifolia L. (PCAE), a typical medicinal decoction, on the EMT. Lipopolysaccharide (LPS) induced EMT-like phenotypic changes, enhancing cell migration and invasion. However, PCAE markedly reduced the expression of the LPS induced EMT markers, including N-cadherin and vimentin, and increased the expression of beta-catenin. PCAE also inhibited cell migration and invasion in vitro. The effects of PCAE on the LPS-induced EMT were mediated by the inactivation of the NF-kappaB-SNAIL signaling pathway. The results provide new evidence that PCAE suppresses cancer cell invasion and migration by inhibiting EMT. Therefore, PCAE is a potentially effective dietary chemopreventive agent for malignant tumors since it inhibits metastasis. PMID- 26238219 TI - Trajectories of psychological states of women elite fencers during the final stages of international matches. AB - This study examined the trajectories and within-person synergies of psychological processes during the final stages of matches. A process-oriented approach was used with nine women elite fencers during an international competition. Multiple assessments of perceived control, threat and challenge appraisals, problem- and emotion-focused coping, positive and negative affects were completed after each touches using video recall method. Multilevel growth curve analyses (MGCAs) indicated that winning and losing matches were each characterised by distinct psychological processes. Specifically, perceived control, challenge appraisal, problem- and emotion-focused coping, and positive affects increased linearly and threat appraisal decreased linearly for wining matches, whereas negative affects increased linearly for losing matches. Regarding the within-person synergies of psychological processes, MGCAs indicated that (1) perceived control and challenge appraisal were significantly associated with problem- and emotion-focused coping for losing matches, the strength of these associations remaining consistent across touches; (2) problem-focused coping was significantly associated with negative affects whereas emotion-focused coping was significantly associated with positive affects for winning matches, the strength of these associations remaining consistent across touches; and (3) problem- and emotion-focused coping were significantly associated with negative affects for losing matches, the linear trajectory of negative affects accelerating at times when athletes had higher levels of emotion-focused coping. Overall, this study provided insights into transactional processes during competition. PMID- 26238220 TI - Arrhythmic complications of tyrosine kinase inhibitors. PMID- 26238221 TI - Selective gas adsorption in microporous metal-organic frameworks incorporating urotropine basic sites: an experimental and theoretical study. AB - The sorption of CO, CO2 and C2H2 by two urotropine-containing porous metal organic framework materials [Zn4(dmf)(ur)2(ndc)4] (H2ndc = 2,6 naphthalenedicarboxylic acid; ur = urotropine; dmf = dimethylformamide) and [Zn11(H2O)2(ur)4(bpdc)11] (H4bpdc = 4,4'-biphenyldicarboxylic acid) incorporating free N-donors has been investigated. These materials show pronounced affinity for CO2 and C2H2, and these observations are supported by interaction energy and ab initio DFT calculations. PMID- 26238222 TI - An observational study of cutaneous adverse drug reactions in a teaching hospital. AB - BACKGROUND: Pharmacotherapy is often impeded by adverse drug reactions (ADRs). Among these ADRs cutaneous reactions are the major class being easily identified and reported. If not noted early it has potential to develop into serious lesions. OBJECTIVE: To evaluate the clinical patterns of various drug induced cutaneous reactions. Setting A Teaching hospital in India. Methods All suspected cutaneous reactions to systemic drugs which were submitted to the ADR monitoring centre during a 6-month period (March 2014-August 2014) were analysed. Causality relationship, severity assessment and preventability assessment was also done. RESULTS: Out of 134 cutaneous ADRs, 56 % occurred in females, majority of cases were found in the age group of 41-50 years. The most common type of ADR was maculopapular rash (46.3 %) and majorly implicated drug class was antibiotics (51.3 %). Most (72.3 %) were mild. Polypharmacy and multiple comorbid conditions were important predisposing factors. Over half of the cases (58 %) were not preventable. CONCLUSION: Cutaneous adverse reaction patterns and their causes vary as the result of changing use of drugs. In India, antibiotics are responsible for the majority of the cutaneous adverse drug reactions, and maculopapular rash is the side effect that is most reported. PMID- 26238223 TI - Flow-induced alignment of (100) fcc thin film colloidal crystals. AB - The realization of structural diversity in colloidal crystals obtained by self assembly techniques remains constrained by thermodynamic considerations and current limits on our ability to alter structure over large scales using imposed fields and confinement. In this work, a convective-based procedure to fabricate multi-layer colloidal crystal films with extensive square-like symmetry is enabled by periodic substrate motion imposed during the continuous assembly. The formation of film-spanning domains of (100) fcc symmetry as a result of added vibration is robust across a range of micron-scale monosized spherical colloidal suspensions (e.g., polystyrene, silica) as well as substrate surface chemistries (e.g., hydrophobic, hydrophilic). The generation of extensive single crystalline (100) fcc domains as large as 15 mm(2) and covering nearly 40% of the colloidal crystalline film is possible by simply tuning coating conditions and multi-layer film thickness. Preferential orientation of the square-packed domains with respect to the direction of deposition is attributed to domain generation based upon a shear-related mechanism. Visualization during assembly gives clues toward the mechanism of this flow-driven self-assembly method. PMID- 26238224 TI - Nanostructured Electron-Selective Interlayer for Efficient Inverted Organic Solar Cells. AB - We report a unique nanostructured electron-selective interlayer comprising of In doped ZnO (ZnO:In) and vertically aligned CdSe tetrapods (TPs) for inverted polymer:fullerene bulkheterojunction (BHJ) solar cells. With dimension-controlled CdSe TPs, the direct inorganic electron transport pathway is provided, resulting in the improvement of the short circuit current and fill factor of devices. We demonstrate that the enhancement is attributed to the roles of CdSe TPs that reduce the recombination losses between the active layer and buffer layer, improve the hole-blocking as well as electron-transporting properties, and simultaneously improve charge collection characteristics. As a result, the power conversion efficiency of PTB7:PC70BM based solar cell with nanostructured CdSe TPs increases to 7.55%. We expect this approach can be extended to a general platform for improving charge extraction in organic solar cells. PMID- 26238225 TI - Time to Response to Citalopram Treatment for Agitation in Alzheimer Disease. AB - OBJECTIVE: Agitation is a common and significant problem in Alzheimer disease (AD). In the recent Citalopram for Agitation in Alzheimer's Disease (CitAD) study, citalopram was efficacious for the treatment of AD agitation. Here we examined the time course and predictors of response to treatment. METHODS: Response in CitAD was defined as a modified Alzheimer Disease Cooperative Study Clinical Global Impression of Change (CGIC) score of 1 or 2 or a Neurobehavioral Rating Scale agitation subscale (NBRS-A) score reduction >= 50% from baseline. "Stable early response" was defined as meeting the aforementioned criteria at both weeks 3 and 9, "late response" was response at week 9 but not at week 3, and "unstable response" was response at week 3 but not at week 9. RESULTS: In the primary analyses, citalopram was superior to placebo on both the CGIC and the NBRS-A response measures. Little between-group differences were found in response rates in the first 3 weeks of the study (21% versus 19% on the CGIC). Citalopram patients were more likely than placebo patients to be a late responder (18% versus 8% on CGIC, Fisher's exact p = 0.09; 31% versus 15% on NBRS-A, Fisher's exact p = 0.02). Approximately half of citalopram responders (45%-56%) at end of study achieved response later in the study compared with 30%-44% of placebo responders. CONCLUSION: Treatment with citalopram for agitation in AD needs to be at least 9 weeks in duration to allow sufficient time for full response. Study duration is an important factor to consider in the design of clinical trials for agitation in AD. PMID- 26238226 TI - Effects of the Minnesota Adaptation of the NYU Caregiver Intervention on Depressive Symptoms and Quality of Life for Adult Child Caregivers of Persons with Dementia. AB - OBJECTIVES: This study determined whether the NYU Caregiver Intervention for Adult Children (the NYUCI-AC) significantly reduced depressive symptoms and improved quality of life for adult child caregivers of persons with dementia. METHODS: The NYUCI-AC was evaluated within a single-blinded randomized controlled trial. The sample included 107 adult child caregivers of persons with dementia (N = 54 assigned to the multi-component treatment group; N = 53 assigned to a contact control group). Participants completed comprehensive assessments every 4 months during the first year and every 6 months thereafter for at least 2 years and up to 3.79 years. RESULTS: Individual growth curve models found that caregivers in the NYUCI-AC treatment condition indicated statistically significant (p <0.05) curvilinear decreases in symptoms of depression indicating withdrawal, apathy, and lack of vigor and increases in perceptions of overall quality of life over a 3-year period in comparison to control caregivers. CONCLUSIONS: The NYUCI-AC offered adult child caregivers the capacity, via individual and family counseling as well as ongoing support, to enhance their quality of life and overcome their social withdrawal and apathy over time. These findings lend additional support to the NYUCI as an evidence-based approach to support family caregivers of persons with dementia. PMID- 26238227 TI - Predictors of Societal Costs in Dementia Patients and Their Informal Caregivers: A Two-Year Prospective Cohort Study. AB - OBJECTIVES: Dementia poses a substantial economic burden on society. Knowing which factors predict high costs in dementia may help to better target interventions and optimize resource allocation. This study aimed to identify predictors of the total societal costs in dementia patients and their informal caregivers. DESIGN: Prospective cohort study with 2-year follow up. SETTING AND PARTICIPANTS: 192 community-dwelling patients with dementia and their primary informal caregivers in the Netherlands. MEASUREMENTS: Data on health care resource utilization, informal carer time and caregivers' work absenteeism were collected by cost diaries and interviews. Predictors of total costs were identified for patient-caregiver dyads, and for patients and informal caregivers separately by performing univariate and multivariate generalized linear models. RESULTS: Societal costs of patient-caregiver dyads averaged ?75,084 (SEM: ?4,263) in the first year and ?99,369 (SEM: ?6,441) in the second year. Sixty percent was attributed to costs of informal care. Patient impairments in activities of daily living (ADLs) and instrumental activities of daily living (IADLs), disruptions during daily activities of the caregiver, and receiving case management were significantly associated with higher costs in dyads. The same predictors remained significant for patients' costs separately, and for informal caregivers, a poorer caregiver's quality of life and having more chronic diseases determined higher costs. CONCLUSIONS: The societal costs of dementia are substantial and mainly due to high costs of informal care. The burden for caregivers caused by a disrupted schedule and patients' ADL and IADL dependencies contributed most to the total costs. Interventions targeting these factors effectively might result in relevant economic benefits for society. PMID- 26238229 TI - A Tablet-PC-Based Cancellation Test Assessing Executive Functions in Older Adults. AB - OBJECTIVE: To examine older adults' performance on a newly developed tablet-PC based cancellation test (e-CT) and to study its psychometric properties. METHODS: 94 older adults with normal cognitive functioning were recruited. The effects of age, education, sex, and experience with computer-based devices on the e-CT were examined. Construct validity was tested by correlating the e-CT with established measures of executive functions (EF) and episodic memory. Correlation coefficients were used to assess short-term test-retest reliablity. RESULTS: The mean age of participants was 74.6 (SD: 7.3) years and 78% were women. Sixty-nine percent had higher education level (> high school) and 76% used computer-based devices daily. The correct cancellations (CC) on the e-CT ranged from 18 to 56, with a mean (SD) of 40.3 (5.7). The CC was inversely correlated with advancing age (rs = -0.59, N = 94, p <0.001) and positively associated with higher education level (U(94) = 646.5, p = 0.02). No relationship was observed between the e-CT and sex or computer-based device experience. In multivariate analysis, only age remained significantly associated with CC (beta = -0.46, SE = 0.07, t = 6.47, df = 93, p <0.001). The e-CT correlated significantly with most of measures of EF. Highest correlations were found between the e-CT and the K-T test, a paper and-pencil cancellation test (rs = 0.63, N = 90, p <0.001) and TMT-B (rs = -0.41, N = 85, p <0.001). The e-CT did not correlate with the RL-RI 16 episodic memory test. The correlation between the first and second e-CT indicated good reliability (rs = 0.89, N = 13, p <0.001). CONCLUSIONS: Results suggested that e CT has good psychometric properties and may be useful for assessing EF in older adults. PMID- 26238228 TI - Chronic Depressive Symptomatology in Mild Cognitive Impairment Is Associated with Frontal Atrophy Rate which Hastens Conversion to Alzheimer Dementia. AB - OBJECTIVE: Investigate the association of chronic depressive symptomatology (chrDS) with cortical atrophy rates and conversion to Alzheimer dementia (AD) over 3 years in mild cognitive impairment (MCI). METHODS: In a multicenter, clinic-based study, MCI elderly participants were selected from the Alzheimer's Disease Neuroimaging Initiative repository, based on availability of both serial structural magnetic resonance imaging and chrDS endorsed on three depression related items from the Neuropsychiatric Inventory Questionnaire (chrDS N = 32 or no depressive symptoms N = 62) throughout follow-up. Clinical and laboratory investigations were performed every 6 months during the first 2 years and yearly thereafter (median follow-up: 3 years; interquartile range: 1.5-4.0 years). Cortical atrophy rates in 16 predefined frontotemporoparietal regions affected in major depression and AD and the rate of incident AD at follow-up. RESULTS: ChrDS in a single domain amnestic MCI sample were associated with accelerated cortical atrophy in the frontal lobe and anterior cingulate but not with atrophy rates in temporomedial or other AD-affected regions. During follow-up, 38 participants (42.7%) developed AD. Participants with chrDS had 60% shorter conversion time to AD than those without depressive symptoms. This association remained significant in survival models adjusted for temporomedial atrophy rates and showed the same trend in models adjusted for frontal cortical atrophy rate, which all increased the risk of AD. CONCLUSION: Our results suggest that chrDS associated with progressive atrophy of frontal regions may represent an additional risk factor for conversion to dementia in MCI as opposite to representing typical prodromal AD symptomatology. PMID- 26238230 TI - Does Apolipoprotein E Genotype Increase Risk of Postoperative Delirium? AB - OBJECTIVE: To determine whether apolipoprotein E (ApoE) is associated with postoperative delirium incidence, severity, and duration in older patients free of dementia at baseline. METHODS: The authors examined 557 nondemented patients aged 70 years or older undergoing major noncardiac surgery enrolled in the Successful Aging after Elective Surgery Study. Three ApoE measures were considered: epsilon2, epsilon4 carriers versus noncarriers, and a three-category ApoE measure. Delirium was determined using the Confusion Assessment Method (CAM) and chart review. We used generalized linear models to estimate the association between ApoE and delirium incidence, severity (peak CAM Severity [CAM-S] score), and days. RESULTS: ApoE epsilon2 and epsilon4 was present in 15% and 19%, respectively, and postoperative delirium occurred in 24%. Among patients with delirium, the mean peak CAM-S score was 8.0 (standard deviation: 4), with most patients experiencing 1 or 2 delirium days (51% or 28%, respectively). After adjusting for age, sex, surgical procedure, and preoperative cognitive function, ApoE epsilon4 and epsilon2 carrier status were not associated with postoperative delirium: RR for epsilon4=1.0, 95% CI: 0.7-1.5 and RR for epsilon2=0.9, 95% CI: 0.6-1.4. No association between ApoE and delirium severity or number of delirium days was observed. CONCLUSION: In older surgery patients free of dementia, our findings do not support the hypothesis that the ApoE genotype does not confer either risk or protection in postoperative delirium incidence, severity, or duration. Thus, an important genetic risk factor for Alzheimer disease does not affect risk of delirium. PMID- 26238231 TI - Amyloid-Independent Amnestic Mild Cognitive Impairment and Serum Apolipoprotein A1 Levels. AB - OBJECTIVES: The present study investigated the characteristics of amnestic mild cognitive impairment (aMCI) in subjects with low brain amyloid-beta (Abeta) burden. Furthermore, the relationships between amyloid-independent cognitive decline and serum lipid profiles, particularly apolipoprotein A1 (APOA1), were evaluated. DESIGN: Cross-sectional and longitudinal follow-up study. SETTING: University hospital dementia clinic. PARTICIPANTS: 28 aMCI and 35 cognitive normal (CN) elderly. MEASUREMENTS: The study measures included baseline assessments of the subjects' clinical characteristics, lipid profiles, and magnetic resonance imaging and (11)C-labelled Pittsburgh Compound B (PiB) positron emission tomography scans. Based on PiB retention at baseline, the aMCI subjects were divided into low Abeta (aMCI-) and high Abeta (aMCI+) subgroups. All aMCI subjects were followed up over a 1-year period. RESULTS: The aMCI- group had a longer duration of illness than did the aMCI+ group. None of the aMCI- subjects were diagnosed with Alzheimer disease (AD) dementia during the 1-year follow-up period, whereas 26.7% of aMCI+ subjects developed AD dementia. The aMCI group also exhibited lower serum APOA1 levels compared with both the aMCI+ and CN groups. Additionally, lower serum APOA1 levels were associated with cognitive decline and brain atrophy independent of Abeta deposition and vascular burden. CONCLUSIONS: Patients with aMCI- likely exhibit different clinical and pathophysiological characteristics than patients with aMCI+. Additionally, APOA1 may be an important contributor underlying amyloid-independent neurodegeneration. PMID- 26238232 TI - Older Adults with Mental Disorders: What Factors Distinguish Those Who Present to Emergency Departments for Mental Health Reasons from Those Who Do Not? AB - OBJECTIVE: To identify among older adults with mental disorders factors associated with those who present to emergency departments (EDs) for mental health reasons versus those who do not. METHODS: The authors conducted a secondary, cross-sectional analysis of the Medical Expenditure Panel Survey (MEPS), which comprises a representative sample of the U.S. civilian noninstitutionalized population. Of the MEPS participants ages 66 and older on December 31 of the survey years 2000-2005, the analysis sample (2,757) included the 177 persons with at least one mental health ED visit and the 2,580 persons with mental disorders without such a visit. The three categories of the Andersen behavioral model for healthcare services utilization-predisposing, enabling, and need factors-were used as the theoretical framework for the independent variables. RESULTS: Logistic regression analysis indicated that four need factors (adjustment disorder [OR: 3.42], psychosis [OR: 2.68], fair perceived physical health status [OR: 2.24], and anxiety disorder [OR: 1.85]) and two predisposing characteristics (widowed and living alone [OR: 1.68] and female [OR: 1.56]) were significantly associated with older adults with mental disorders who present to an ED for mental health reasons. Good perceived mental health status (OR: 0.55) was protective against presenting to an ED. CONCLUSION: EDs that serve populations with higher proportions of older persons that are women, widowed and living alone, with adjustment disorder, psychosis, anxiety disorders, or fair perceived physical health should expect to have a greater likelihood of older persons visiting the ED for mental health reasons. PMID- 26238233 TI - The significance of circulating tumor cells in prostate cancer patients undergoing adjuvant or salvage radiation therapy. AB - BACKGROUND: Following radical prostatectomy, success of adjuvant and salvage radiation therapy (RT) is dependent on the absence of micrometastatic disease. However, reliable prognostic/predictive factors for determining this are lacking. Therefore, novel biomarkers are needed to assist with clinical decision-making in this setting. Enumeration of circulating tumor cells (CTCs) using the regulatory approved CellSearch System (CSS) is prognostic in metastatic prostate cancer. We hypothesize that CTCs may also be prognostic in the post-prostatectomy setting. METHODS: Patient blood samples (n=55) were processed on the CSS to enumerate CTCs at 0, 6, 12 and 24 months after completion of RT. CTC values were correlated with predictive/prognostic factors and progression-free survival. RESULTS: CTC status (presence/absence) correlated significantly with positive margins (increased likelihood of CTC(neg) disease; P=0.032), and trended toward significance with the presence of seminal vesicle invasion (CTC(pos); P=0.113) and extracapsular extension (CTC(neg); P=0.116). Although there was a trend toward a decreased time to biochemical failure (BCF) in baseline CTC-positive patients (n=9), this trend was not significant (hazard ratio (HR)=0.3505; P=0.166). However, CTC-positive status at any point (n=16) predicted for time to BCF (HR=0.2868; P=0.0437). CONCLUSIONS: One caveat of this study is the small sample size utilized (n=55) and the low number of patients with CTC-positive disease (n=16). However, our results suggest that CTCs may be indicative of disseminated disease and assessment of CTCs during RT may be helpful in clinical decision-making to determine, which patients may benefit from RT versus those who may benefit more from systemic treatments. PMID- 26238234 TI - Oral simvastatin administration delays castration-resistant progression and reduces intratumoral steroidogenesis of LNCaP prostate cancer xenografts. AB - BACKGROUND: Growing evidence supports the idea that de novo steroidogenesis has an important role in prostate cancer's progression to the castration-resistant state following androgen deprivation therapy. Therefore, reducing the availability of cholesterol for use as a precursor in androgen synthesis may reduce proliferation and disease progression. METHODS: LNCaP xenograft-bearing mice were castrated and administered simvastatin via diet, and tumor volume and PSA concentration were monitored for 8 weeks post castration. Levels of serum and intratumoral androgens along with serum simvastatin and common toxicity markers were measured at end point. RESULTS: Reduced post-castration tumor growth rate in simvastatin-treated mice correlated with delayed time to castration-resistant progression, determined by two serum PSA doublings from post-castration nadir, when compared with xenografts in mice on control diet. At 8 weeks post castration, serum simvastatin levels were comparable to clinically relevant human doses with no evidence of overt muscle or liver toxicity. This suppressed post castration tumor growth in the simvastatin diet group was correlated with reduced intratumoral testosterone and dihydrotestosterone levels. CONCLUSIONS: Reduced tumor growth and intratumoral androgen levels observed in simvastatin-treated, castrated mice harboring LNCaP xenograft suggests that suppressing de novo steroidogenesis can delay castration-resistant progression of this tumor model. PMID- 26238236 TI - Thyroid function and autoimmunity in children and adolescents with Type 1 Diabetes Mellitus. AB - We evaluated 233 children and adolescents with T1 Diabetes to analyze the prevalence and characteristics of Autoimmune Thyroid Disease. AITD was found in 23%, the majority being female and patients older than 5 years of age. Screening is mandatory, and the best approach could be guided by gender and age. PMID- 26238235 TI - Genetic variants in the TEP1 gene are associated with prostate cancer risk and recurrence. AB - BACKGROUND: Telomere-related genes play an important role in carcinogenesis and progression of prostate cancer (PCa). It is not fully understood whether genetic variations in telomere-related genes are associated with development and progression in PCa patients. METHODS: Six potentially functional single nucleotide polymorphisms (SNPs) of three key telomere-related genes were evaluated in 1015 PCa cases and 1052 cancer-free controls, to test their associations with risk of PCa. Among 426 PCa patients who underwent radical prostatectomy (RP), the prognostic significance of the studied SNPs on biochemical recurrence (BCR) was also assessed using the Kaplan-Meier analysis and Cox proportional hazards regression model. The relative telomere lengths (RTLs) were measured in peripheral blood leukocytes using real-time PCR in the RP patients. RESULTS: TEP1 rs1760904 AG/AA genotypes were significantly associated with a decreased risk of PCa (odds ratio (OR): 0.77, 95% confidence interval (CI): 0.64-0.93, P=0.005) compared with the GG genotype. By using median RTL as a cutoff level, RP patients with TEP1 rs1760904 AG/AA genotypes tended to have a longer RTL than those with the GG genotype (OR: 1.55, 95% CI: 1.04-2.30, P=0.031). A significant interaction between TEP1 rs1713418 and age in modifying PCa risk was observed (P=0.005). After adjustment for clinicopathologic risk factors, the presence of heterozygotes or rare homozygotes of TEP1 rs1760904 and TNKS2 rs1539042 were associated with BCR in the RP cohorts (hazard ratio: 0.53, 95% CI: 0.36-0.79, P=0.002 and hazard ratio: 1.67, 95% CI: 1.07-2.48, P=0.017, respectively). CONCLUSIONS: These data suggest that genetic variations in the TEP1 gene may be biomarkers for risk of PCa and BCR after RP. PMID- 26238237 TI - The potential of using low cost naturally available biogenic substrates for biological removal of chlorophenol. AB - This study details the application of naturally available biogenic substrates (NABS) in microbial degradation of 2-chlorophenol (CP). Jatropha deoiled cakes (JDC) and Karanja deoiled cakes (KDC) are used as NABS. The potential of NABS is compared with standard biogenic substrate, glucose. The study was carried out with both acclimatized mixed culture and pure culture, Pseudomonas putida. Microbial activity of the culture was monitored by measuring reduction in chlorophenol concentration, COD, toxicity and Cl(-) ions evolution. The study was carried out for a total of 42days. It was observed that culture having NABS has shown similar chlorophenol reduction but higher COD and toxicity reduction. Amongst NABS, Jatropha deoiled cake (JDC) has shown superior results of 71% COD reduction compared to glucose and KDC. This study is one of the first kind illustrating the potential of these substrates in removing toxic chemicals from wastewaters. PMID- 26238238 TI - Nonsynaptic junctions on myelinating glia promote preferential myelination of electrically active axons. AB - The myelin sheath on vertebrate axons is critical for neural impulse transmission, but whether electrically active axons are preferentially myelinated by glial cells, and if so, whether axo-glial synapses are involved, are long standing questions of significance to nervous system development, plasticity and disease. Here we show using an in vitro system that oligodendrocytes preferentially myelinate electrically active axons, but synapses from axons onto myelin-forming oligodendroglial cells are not required. Instead, vesicular release at nonsynaptic axo-glial junctions induces myelination. Axons releasing neurotransmitter from vesicles that accumulate in axon varicosities induces a local rise in cytoplasmic calcium in glial cell processes at these nonsynaptic functional junctions, and this signalling stimulates local translation of myelin basic protein to initiate myelination. PMID- 26238239 TI - PI3K signaling in arterial diseases: Non redundant functions of the PI3K isoforms. AB - Cardiovascular diseases are the most common cause of death around the world. This includes atherosclerosis and the adverse effects of its treatment, such as restenosis and thrombotic complications. The development of these arterial pathologies requires a series of highly-intertwined interactions between immune and arterial cells, leading to specific inflammatory and fibroproliferative cellular responses. In the last few years, the study of phosphoinositide 3-kinase (PI3K) functions has become an attractive area of investigation in the field of arterial diseases, especially since inhibitors of specific PI3K isoforms have been developed. The PI3K family includes 8 members divided into classes I, II or III depending on their substrate specificity. Although some of the different isoforms are responsible for the production of the same 3-phosphoinositides, they each have specific, non-redundant functions as a result of differences in expression levels in different cell types, activation mechanisms and specific subcellular locations. This review will focus on the functions of the different PI3K isoforms that are suspected as having protective or deleterious effects in both the various immune cells and types of cell found in the arterial wall. It will also discuss our current understanding in the context of which PI3K isoform(s) should be targeted for future therapeutic interventions to prevent or treat arterial diseases. PMID- 26238240 TI - "Half a Century of Evolution of Neonatology: A Witness's Story" : Dr. K. C. Chaudhuri Lifetime Achievement Award Oration Delivered at AIIMS, New Delhi on 7th September 2014. AB - Lifetime achievement awards are awarded to recognize contributions during the career of an individual, rather than for a single or multiple contributions of a person in his/her field of specialty. I am highly honored being the recipient of the Dr. K. C. Chaudhuri Lifetime Achiement Award Oration. The award for me is significant for several reasons: First being associated with legendary figure such as Dr. Chaudhuri, secondly being recognized by my fellow Indian colleagues. Finally, it also marks half a century of my experience in development of subspecialty of neonatology in US. Some fifty and odd years ago, as an young novice from India I joined the mainstream of this evolution, thanks to my professors and mentors in US and thanks to America, the land of opportunity. During this odyssey, I met many great men and women of science and intellect, saw great scientific discoveries, many innovations, combined with social changes that led to significant reduction of neonatal mortality rates in the industrialized Western countries. I also saw the "Globalization" of "Modern Neonatology" in which I participated with vigor; thus, improving the newborn care in four corners of the world. I am proud that I had the opportunity to contribute a little to growth of neonatology in US and outside the US. This is the story of my professional life. The message of my life story for the younger generation is : Dream big, never give up your dreams. Hardwork, maintaining your integrity, and honesty are the three precepts that will define your character and you will be rewarded in the long run. PMID- 26238241 TI - Recombination of chl-fus gene (Plastid Origin) downstream of hop: a locus of chromosomal instability. AB - BACKGROUND: The co-chaperone Hop [heat shock protein (HSP) organizing protein] has been shown to act as an adaptor for protein folding and maturation, in concert with Hsp70 and Hsp90. The hop gene is of eukaryotic origin. Likewise, the chloroplast elongation factor G (cEF-G) catalyzes the translocation step in chloroplast protein synthesis. The chl-fus gene, which encodes the cEF-G protein, is of plastid origin. Both proteins, Hop and cEF-G, derived from domain duplications. It was demonstrated that the nuclear chl-fus gene locates in opposite orientation to a hop gene in Glycine max. We explored 53 available plant genomes from Chlorophyta to higher plants, to determine whether the chl-fus gene was transferred directly downstream of the primordial hop in the proto-eukaryote host cell. Since both genes came from exon/module duplication events, we wanted to explore the involvement of introns in the early origin and the ensuing evolutionary changes in gene structure. RESULTS: We reconstructed the evolutionary history of the two convergent plant genes, on the basis of their gene structure, microsynteny and microcolinearity, from 53 plant nuclear genomes. Despite a high degree (72%) of microcolinearity among vascular plants, our results demonstrate that their adjacency was a product of chromosomal rearrangements. Based on predicted exon--intron structures, we inferred the molecular events giving rise to the current form of genes. Therefore, we propose a simple model of exon/module shuffling by intronic recombinations in which phase 0 introns were essential for domain duplication, and a phase-1 intron for transit peptide recruiting. Finally, we demonstrate a natural susceptibility of the intergenic region to recombine or delete, seriously threatening the integrity of the chl-fus gene for the future. CONCLUSIONS: Our results are consistent with the interpretation that the chl-fus gene was transferred from the chloroplast to a chromosome different from that of hop, in the primitive photosynthetic eukaryote, and much later before the appearance of angiosperms, it was recombined downstream of hop. Exon/module shuffling mediated by symmetric intron phases (i.e., phase-0 introns) was essential for gene evolution. The intergenic region is prone to recombine, risking the integrity of both genes. PMID- 26238242 TI - Intravitreal injection of lipoamino acid-modified connexin43 mimetic peptide enhances neuroprotection after retinal ischemia. AB - Optic neuropathy is associated with retinal ganglion cell (RGC) loss leading to optic nerve damage and visual impairment. Recent research has shown that transient block of connexin43 (Cx43) hemichannels by a Cx43 mimetic peptide (MP), Peptide5, delivered systemically or by intravitreal injection after retinal ischemia inhibits uncontrolled hemichannel opening to provide significantly reduced vessel leak and inflammation as well as significantly enhanced RGC survival. We have previously shown, in vitro, that a chemically modified C12-C12 Cx43 MP has a twofold greater half-life in bovine vitreous (ex vivo) than the native peptide. The present study investigated the ability of intravitreally injected, chemically modified C12-C12-Cx43 MP to further enhance RGC survival in a rat retinal ischemia-reperfusion model. Intravitreally injected native Cx43 MP or C12-C12-Cx43 MP both minimized vessel leak, reduced inflammation, and protected RGC after ischemic injury. However, the modified C12-C12-Cx43 MP, with its prolonged vitreous stability, showed significantly lower levels of Cx43 expression post-injury, with a trend towards a greater reduction in vessel leak and further RGC protection, suggesting that these molecules may be a clinically relevant neuroprotective tool in the treatment of optic neuropathy. PMID- 26238244 TI - Priorities for global research into children's palliative care: results of an International Delphi Study. AB - BACKGROUND: There is an urgent need to develop an evidence base for children's palliative care (CPC) globally, and in particular in resource-limited settings. Whilst the volume of CPC research has increased in the last decade, it has not been focused on countries where the burden of disease is highest. For example, a review of CPC literature in sub Saharan Africa (SSA) found only five peer reviewed papers on CPC. This lack of evidence is not confined to SSA, but can be seen globally in specific areas, such as an insufficient research and evidence base on the treatment of pain and other symptoms in children. This need for an evidence base for CPC has been recognised for some time, however without understanding the priorities for research in CPC organisations, many struggle with how to allocate scarce resources to research. METHOD: The International Children's Palliative Care Network (ICPCN) undertook a Delphi study between October 2012 and February 2013 in order to identify the global research priorities for CPC. Members of the ICPCN Scientific Committee formed a project working group and were asked to suggest areas of research that they considered to be important. The list of 70 areas for research was put through two rounds of the Delphi process via a web-based questionnaire. ICPCN members and affiliated stakeholders (n = 153 from round 1 and n = 95 from round 2) completed the survey. Participants from SSA were the second largest group of respondents (28.1 % round 1, 24.2 % round 2) followed by Europe. RESULTS: A list of 26 research areas reached consensus. The top five priorities were: Children's understanding of death and dying; Managing pain in children where there is no morphine; Funding; Training; and Assessment of the WHO two-step analgesic ladder for pain management in children. CONCLUSIONS: Information from this study is important for policy makers, educators, advocates, funding agencies, and governments. Priorities for research pertinent to CPC throughout the world have been identified. This provides a much needed starting place for the allocation of funds and building research infrastructure. Researchers working in CPC are in a unique position to collaborate and produce the evidence that is needed. PMID- 26238243 TI - Zinc involvement in opioid addiction and analgesia--should zinc supplementation be recommended for opioid-treated persons? AB - INTRODUCTION: Zinc chelators were shown to facilitate some opioid-withdrawal signs in animals. Zinc deficiency, which affects more than 15% the world's population, is also common among opioid consumers and opioid-treated animals exhibit misbalances of zinc distribution. AIM: The present study focuses on how zinc ions interfere with opioid dependence/addiction and analgesia, trying to preliminary discuss if zinc supplementation in opioid-users should be recommended in order to reduce the risk of addiction. METHODS: All relevant literature was searched up to April 2015. The search was performed using the term "zinc" plus combinations of following terms: "opioid receptors", "opioid" or representatives of this class, "addiction", "dependence", "analgesia", and "pain". Human, animal, in vitro studies and reviews were including. RESULTS: Both human and animal studies revealed decreased serum zinc under opioid-administration conditions, attributed mainly to increased urinary elimination (humans) or redistribution (animals). Moreover, animal studies revealed decreased brain zinc levels in morphine-treated animals, with increased zinc hepatic levels, but also an enhancement of endogenous opioid system activity and a possible reduction of morphine withdrawal by zinc. In vitro studies revealed reduction of opioid ligands binding to receptors by zinc. However, the very few in vivo animal studies on opioid analgesia revealed controversial results, as zinc demonstrated clear analgesic effect, but zinc associated to opioids doesn't result in a potentiation of the analgesic effect. CONCLUSION: Zinc dietary supplementation in patients treated with opioids for cancer-related chronic pain should be considered, due to the high incidence of zinc deficiency, also well-documented in opioid consumers. The low toxicity of orally-administered zinc also pleads for this idea. The main contra-argument to zinc administration in opioid-treated persons is related to the way zinc influences opioid-induced analgesia. PMID- 26238245 TI - Correlates of property crime in a cohort of recently released prisoners with a history of injecting drug use. AB - BACKGROUND: Injecting drug use (IDU) is a strong predictor of recidivism and re incarceration in ex-prisoners. Although the links between drug use and crime are well documented, studies examining post-release criminal activity and re incarceration risk among ex-prisoners with a history of IDU are limited. We aimed to explore factors associated with property crime among people with a history of IDU recently released from prison. METHOD: Individuals with a history of IDU released from prison within the past month were recruited via targeted and snowball sampling methods from street drug markets and services for people who inject drugs (PWID) into a 6-month cohort study. A multivariate logistic regression analysis of baseline data identified adjusted associations with self reported property crime soon after release. RESULTS: Interviews were conducted a median of 23 days post-release with 141 participants. Twenty-eight percent reported property crime in this period and 85% had injected drugs since release. Twenty-three percent reported injecting at least daily. Reporting daily injecting (adjusted odds ratio (aOR) 4.36; 95% confidence interval (CI) = 1.45-13.07), illicit benzodiazepine use (aOR = 2.59; 95% CI = 1.02-5.67), being arrested (aOR = 6.12; 95% CI = 1.83-20.45) and contact with mental health services (aOR = 4.27; 95% CI = 1.45-12.60) since release were associated with property crime. CONCLUSION: Criminal activity soon after release was common in this sample of PWID, underscoring the need for improved pre-release, transitional and post release drug use dependence and prevention programmes. Addressing co-occurring mental disorder and poly-pharmaceutical misuse among those with a history of IDU in prison, and during the transition to the community, may reduce property crime in this group. PMID- 26238246 TI - Development of advantus(imidacloprid) soft chewable tablets for the treatment of Ctenocephalides felis infestations on dogs. AB - BACKGROUND: Studies reported here were conducted to evaluate the safety and effectiveness of advantus (imidacloprid) soft chewable tablets for the treatment of flea (Ctenocephalides felis) infestations on dogs and puppies 10 weeks of age or older and weighing 4 pounds or greater. METHODS: A pharmacokinetic study was conducted to evaluate parameters of orally administered imidacloprid. A dose confirmation study was conducted to confirm the efficacy of 0.75 mg/kg at 8, 12 or 24 hours post-treatment. A knockdown and speed of kill study was conducted to confirm the efficacy of 0.75 mg/kg dose at 0.5, 1, 4 or 24 hours post-treatment. The safety of a daily dose administered for six months at approximately 1, 3, and 5 times the maximum exposure dose of 3.75 mg/kg was evaluated in puppies. A field study was conducted to evaluate the safety and efficacy of a daily oral dose of 0.75 mg/kg for 14 days in client-owned dogs. RESULTS: The pharmacokinetic parameters of the final imidacloprid oral formulation were; Tmax 1.31 hours, Cmax 690.0 ng/mL, AUC 2615.5 h*ng/mL and half-life was 2.2 hours. The efficacy of 0.75 mg/kg BW was 98.6%, 99.9% and 100% at 8, 12 and 24 hours post-treatment, respectively. The live flea counts were significantly different (p < 0.0001) and the treatment was well tolerated. The flea counts at 1 hour post-treatment were significantly lower in the treated group and the speed of kill efficacy was 96.6% at 4 hours post-treatment in the knockdown and speed of kill study. The target animal safety study showed that the advantus soft chewable tablets administered orally to 10-week-old puppies once daily for 6 months at approximately 1, 3 and 5 times the maximum dose of 3.75 mg/kg was well tolerated and did not produce clinically relevant findings in Beagles. In the field study, efficacy of the soft chewable tablets administered daily for 14 days to flea-infested dogs was 98.2%. CONCLUSION: Imidacloprid administered orally as a soft chewable tablet for the treatment of fleas on dogs was safe and highly effective with a rapid knockdown effect and rapid elimination. PMID- 26238247 TI - A statistical perspective to visual masking. AB - A stimulus (mask) reduces the visibility of another stimulus (target) when they are presented in close spatio-temporal vicinity of each other, a phenomenon called visual masking. Visual masking has been extensively studied to understand dynamics of information processing in the visual system. In this study, we adopted a statistical point of view, rather than a mechanistic one, to investigate how mask-related activities might influence target-related ones within the context of visual masking. We modeled the distribution of response errors of human observers in three different visual masking experiments, namely para-/meta-contrast masking, pattern masking by noise, and pattern masking by structure. We adopted statistical models, which have been used previously in studies of visual short-term memory, to capture response characteristics of observers under masking conditions. We tested the following scenarios: (i) mask activity may reduce a target's signal-to-noise ratio (SNR) without interfering with its encoding precision. (ii) Mask activity may "interfere" with the encoding of a target and cause decreased precision in observer's reports. (iii) Decreased performance due to masking may result from the confusion or "misbinding" of a mask's features with those of the target, when they are similar as in the case of pattern masking by structure. Our results show that in all three types of masking, the reduction of a target's SNR was the primary process whereby masking occurred. A significant decrease, correlated with masking strength, in the precision of the target's encoding was observed in para-/meta-contrast and pattern masking by structure, but not in pattern masking by noise. We interpret these findings as the mask reducing the target's SNR (i) by suppressing or interrupting the signal of the target in para-/meta-contrast, (ii) by increasing noise in pattern masking by noise, and (iii) a combination of the two in pattern masking by structure. PMID- 26238249 TI - TMEM165 Deficiency: Postnatal Changes in Glycosylation. AB - Congenital disorders of glycosylation form a rapidly growing group of inherited metabolic diseases. As glycosylation affects proteins all over the organism, a mutation in a single gene leads to a multisystemic disorder. We describe a patient with TMEM165-CDG with facial dysmorphism, nephrotic syndrome, cardiac defects, enlarged cerebral ventricles, feeding problems, and neurological involvement. Having confirmed the diagnosis via prenatal diagnostics, we were able to observe the glycosylation right from birth, finding a pathological pattern already on the first day of life. Within the next few weeks, hypoglycosylation progressed to less sialylated and then also to hypogalactosylated isoforms. On the whole, there has not been much published evidence concerning postnatal glycosylation and its adaptational process. This is the first paper reporting changes in glycosylation patterns over the first postnatal weeks in TMEM165-CDG. PMID- 26238248 TI - Antibiotic resistance patterns of bacteria causing urinary tract infections in the elderly living in nursing homes versus the elderly living at home: an observational study. AB - BACKGROUND: Antibiotic resistance is a problem in nursing homes. Presumed urinary tract infections (UTI) are the most common infection. This study examines urine culture results from elderly patients to see if specific guidelines based on gender or whether the patient resides in a nursing home (NH) are warranted. METHODS: This is a cross sectional observation study comparing urine cultures from NH patients with urine cultures from patients in the same age group living in the community. RESULTS: There were 232 positive urine cultures in the NH group and 3554 in the community group. Escherichia coli was isolated in 145 urines in the NH group (64%) and 2275 (64%) in the community group. There were no clinically significant differences in resistance. Combined, there were 3016 positive urine cultures from females and 770 from males. Escherichia coli was significantly more common in females 2120 (70%) than in males 303 (39%) (p < 0.05). Enterococcus faecalis was significantly less common in females 223 (7%) than males 137 (18%) (p < 0.05). For females, there were lower resistance rates to ciprofloxacin among Escherichia coli (7% vs 12%; p < 0.05) and to mecillinam among Proteus mirabilis (3% vs 12%; p < 0.05). CONCLUSIONS: Differences in resistance rates for patients in the nursing home do not warrant separate recommendations for empiric antibiotic therapy, but recommendations based on gender seem warranted. PMID- 26238250 TI - Pearson Syndrome: A Retrospective Cohort Study from the Marrow Failure Study Group of A.I.E.O.P. (Associazione Italiana Emato-Oncologia Pediatrica). AB - Pearson syndrome (PS) is a very rare and often fatal multisystemic mitochondrial disorder involving the liver, kidney, pancreas, and hematopoietic and central nervous system. It is characterized principally by a transfusion-dependent anemia that usually improves over time, a tendency to develop severe infections, and a high mortality rate. We describe a group of 11 PS patients diagnosed in Italy in the period 1993-2014. The analysis of this reasonably sized cohort of patients contributes to the clinical profile of the disease and highlights a rough incidence of 1 case/million newborns. Furthermore, it seems that some biochemical parameters like increased serum alanine and urinary fumaric acid can help to address an early diagnosis. PMID- 26238251 TI - Transaldolase Deficiency: A New Case Expands the Phenotypic Spectrum. AB - Transaldolase (TALDO) deficiency has various clinical manifestations including liver dysfunction, hepatosplenomegaly, anemia, thrombocytopenia, and dysmorphic features. We report a case presenting prenatally with hyperechogenic bowel and intrauterine growth restriction. The infant was born small for gestational age, with cutis laxa and hypertrichosis. Postnatally, meconium plug was identified, complicated with intestinal obstruction necessitating laparotomy, partial resection of the intestine, and ileostomy. Liver biopsy revealed cholangiolar proliferation and portal fibrosis. He also suffered from persistent congenital thrombocytopenia requiring platelet transfusions and severe hypothyroidism with normal anatomical and structural gland responding only to the combination of T3 and T4 treatment. Neurologically, severe hypotonia and anisocoria were noted at the age of 2 months. Brain MRI was normal. Shortly after the abdominal surgery, a rapid liver failure ensued, which eventually led to his death. Specific metabolic tests ruled out glycosylation disorders, yet urine analysis using 1H NMR showed accumulation of sedoheptulose which was previously described in patients with transaldolase deficiency. Sequencing of the gene-encoding transaldolase (TALDO1) revealed a homozygous stop mutation c.669C>G; p.Tyr223*. In conclusion, we present an infant with a novel homozygous mutation in TALDO1, causing TALDO deficiency, and extend the clinical characteristics of this rare syndrome. PMID- 26238252 TI - Periventricular Calcification, Abnormal Pterins and Dry Thickened Skin: Expanding the Clinical Spectrum of RMND1? AB - BACKGROUND: We report a consanguineous Sudanese family whose two affected sons presented with a lethal disorder characterised by severe neonatal lactic acidosis, hypertonia, microcephaly and intractable seizures. One child had additional unique features of periventricular calcification, abnormal pterins and dry thickened skin. METHODS: Exome enrichment was performed on pooled genomic libraries from the two affected children and sequenced on an Illumina HiSeq2000. After quality control and variant identification, rare homozygous variants were prioritised. Respiratory chain complex activities were measured and normalised to citrate synthase activity in cultured patient fibroblasts. RMND1 protein levels were analysed by standard Western blotting. RESULTS: Exome sequencing identified a previously reported homozygous missense variant in RMND1 (c.1250G>A; p.Arg417Gln), the gene associated with combined oxidation phosphorylation deficiency 11 (COXPD11), as the most likely cause of this disorder. This finding suggests the presence of a mutation hotspot at cDNA position 1250. Patient fibroblasts showed a severe decrease in mitochondrial respiratory chain complex I, III and IV activities and protein expression, albeit with normal RMND1 levels, supporting a generalised disorder of mitochondrial translation caused by loss of function. CONCLUSIONS: The current study implicates RMND1 in the development of calcification and dermatological abnormalities, likely due to defective ATP dependent processes in vascular smooth muscle cells and skin. Review of reported patients with RMND1 mutations shows intra-familial variability and evidence of an evolving phenotype, which may account for the clinical variability. We suggest that COXPD11 should be considered in the differential for patients with calcification and evidence of a mitochondrial disorder. PMID- 26238253 TI - Rac1 and ROCK are implicated in the cell surface delivery of GLUT4 under the control of the insulin signal mimetic diDCP-LA-PE. AB - The phosphatidylethanolamine derivative 1,2-O-bis-[8-{2-(2-pentyl cyclopropylmethyl)-cyclopropyl}-octanoyl]-sn-glycero-3-phosphatidylethanolamine (diDCP-LA-PE) promoted GLUT4 translocation to the cell surface in differentiated 3T3-L1-GLUT4myc adipocytes through a pathway along a phosphatidylinositol 3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis, that mimics insulin signaling. Moreover, diDCP-LA-PE-induced GLUT4 translocation was suppressed by inhibitors of the Rho GTPase Rac1 and Rho-associated coiled-coil containing protein kinase (ROCK) or knocking-down Rac1 and ROCK1. The results of the present study show that Rac1 and ROCK are critical for regulation of GLUT4 trafficking by diDCP-LA-PE as well as insulin. PMID- 26238254 TI - Cardio-ankle vascular index (CAVI) differentiates pharmacological properties of vasodilators nicardipine and nitroglycerin in anesthetized rabbits. AB - Cardio-ankle vascular index (CAVI) has been developed for measurement of vascular stiffness from the aorta to tibial artery, which is clinically utilized for assessing the progress of arteriosclerosis. In this study, we established measuring system of the CAVI in rabbits, and assessed whether the index could reflect different pharmacological actions of nitroglycerin and nicardipine on the systemic vasculature. Rabbits were anesthetized with halothane, and the CAVI was calculated from the well-established basic equations with variables obtained from brachial and tibial blood pressure and phonocardiogram. Nicardipine (1, 3 and 10 MUg/kg, i.v.) decreased the blood pressure, femoral vascular resistance, and heart-ankle pulse wave velocity (haPWV). Meanwhile, no significant change was detected in the CAVI at the low or middle dose, which reflects the defining feature of the CAVI that is independent of blood pressure. The index increased at the high dose. Nitroglycerin (2, 4 and 8 MUg/kg, i.v.) decreased the blood pressure, femoral vascular resistance, and haPWV. Meanwhile, the CAVI was decreased during the nitroglycerin infusion, which may reflect its well-known pharmacological action dilating conduit arteries. These results suggest that the CAVI differentiates the properties of these vasodilators in vivo. PMID- 26238255 TI - Protein-Based Three-Dimensional Whispering-Gallery-Mode Micro-Lasers with Stimulus-Responsiveness. AB - For the first time, proteins, a promising biocompatible and functionality designable biomacromolecule material, acted as the host material to construct three-dimensional (3D) whispering-gallery-mode (WGM) microlasers by multiphoton femtosecond laser direct writing (FsLDW). Protein/Rhodamine B (RhB) composite biopolymer was used as optical gain medium innovatively. By adopting high viscosity aqueous protein ink and optimized scanning mode, protein-based WGM microlasers were customized with exquisite true 3D geometry and smooth morphology. Comparable to previously reported artificial polymers, protein-based WGM microlasers here were endowed with valuable performances including steady operation in air and even in aqueous environments, and a higher quality value (Q) of several thousands (without annealing). Due to the "smart" feature of protein hydrogel, lasing spectrum was responsively adjusted by step of ~0.4 nm blueshift per 0.83-mmol/L Na2SO4 concentration change (0 ~ 5-mmol/L in total leading to ~2.59-nm blueshift). Importantly, other performances including Q, FWHM, FSR, peak intensities, exhibited good stability during adjustments. So, these protein-based 3D WGM microlasers might have potential in applications like optical biosensing and tunable "smart" biolasers, useful in novel photonic biosystems and bioengineering. PMID- 26238256 TI - N-myc is a key switch regulating the proliferation cycle of postnatal cerebellar granule cell progenitors. AB - N-myc plays an important role in early cerebellar development; however, the role of N-myc in postnatal cerebellar development is still unknown. In this study, inducible and reversible N-myc mouse models (Nmyc(TRE/TRE):tTS and Nmyc(EGFP/TRE):tTS) are used to regulate and track the expression of endogenous N myc in vivo. Loss of N-myc at the neonatal stage results in reduced proliferation of granule cell precursors (GCPs) and reduced cerebellar volume/mass. Restoration of N-myc expression no later than postnatal day 4 can rescue the cerebellar developmental defect caused by the absence of N-myc after birth. During cerebellar postnatal development, N-myc acts as a key switch, regulating the proliferation cycle of postnatal granule cell progenitors. Loss of N-myc significantly impairs the Sonic hedgehog signalling pathway, and disrupts the expression of cell cycle effectors with a significant reduction of Ccnd2. More importantly, N-myc negatively regulates the expression of microRNA-9 during postnatal cerebellar development. Our findings demonstrate that over-expression of miR-9 can inhibit the proliferation of GCPs. The regulation of these factors by N-myc is at least partly responsible for the switch role of N-myc in the proliferation cycle of GCPs. PMID- 26238257 TI - Breaking bad news: Effects of forecasting diagnosis and framing prognosis. AB - OBJECTIVE: Research to support guidelines for breaking bad news is lacking. This study used an experimental paradigm to test two communication strategies, forecasting bad news and framing prognosis, in the context of cancer. METHODS: In a 2*2 design, 128 participants received bad news in a hypothetical consultation. A videotaped physician presented diagnostic and prognostic information, varying warning (warning shot vs. no warning), and framing (positive vs. negative). Effects on psychological distress, recall accuracy, and subjective interpretations of the news were assessed. RESULTS: Warning was not associated with lower psychological distress or improved recall. Individuals who heard a positively-framed prognosis had significantly less psychological distress, rated their prognosis better, and were more hopeful than those who heard a negatively framed prognosis. However, they also showed a trend toward reduced accuracy in recalling prognostic statistics. CONCLUSIONS: Results contribute to a growing body of literature exploring optimal approaches for communicating bad news in health care. PRACTICE IMPLICATIONS: Although research in clinical settings is needed to bolster results, findings suggest that when providers use positive framing to reduce distress about prognosis, they should also consider ways to overcome potential reductions in recall accuracy, such as repeating statistical information or supplementing with written information. PMID- 26238258 TI - The effects of gonadectomy and binge-like ethanol exposure during adolescence on open field behaviour in adult male rats. AB - Binge drinking ethanol exposure during adolescence can lead to long-term neurobehavioural damage. It is not known whether the pubertal surge in testosterone that occurs during adolescence might impact the neurobehavioural effects of early ethanol exposure in adult animals. We examined this hypothesis by performing sham or gonadectomy surgeries on Sprague-Dawley rats around postnatal day (P) 23. From P28-65,the rats were administered 3.0g/kg ethanol using a binge-like model of exposure. Dependent measurements included tests of open field behaviour, blood ethanol concentrations, and testosterone levels. As adults, significant decreases in open field activity were observed in the GX rats. The open field behaviour of the GX rats was restored after testosterone administration. Binge-like ethanol exposure altered most of the parameters of the open field behaviour, suggestive of alcohol-induced anxiety, but rats treated with alcohol in combination with gonadectomy showed less motor behaviour and grooming behaviour and an increase in immobility, suggesting ethanol-induced depression. These results indicated that testosterone is required for ethanol induced behavioural changes and that testicular hormones are potent stimulators of ethanol-induced behaviours. PMID- 26238260 TI - Chemokines and transplant outcome. AB - Improving long-term management, life-quality and outcome of transplant recipients continues to be a challenge. The impact of highly chemoattractant proteins as chemokines on transplant outcome is undeniable. These immunoactive molecules are critical in a wide variety of physiological and pathological processes, such as immunosurveillance, inflammation, infection, cancer, and rejection or tolerance after organ transplantation. Chemokines, playing an essential role in immune cell recruitment and localization within the graft, mirror the complex processes occurring in host-graft dialogue. In particular, the system of inflammatory chemokines and their receptors is modulated throughout all stages of transplantation and its inhibition counteracts rejection processes. The increase in chemokine expression at gene or protein level is, indeed, associated to multiorgan rejection. Thus, chemokines could serve as markers for risk of organ dysfunction/rejection and outcome predictors. This review intends to summarize chemokine function in transplantation and particularly focuses onto proinflammatory molecules such as CXC chemokines, which mediate early graft rejection in different organs and warrant consideration as predictors of outcome. The potentiality of chemokines - CXCL10 in particular - as systemic, robust, non invasive, reliable and reproducible biomarkers for post-transplantation surveillance is addressed. Ideally, chemokines, as potential tools to predict and improve outcome, could give clinicians the opportunity to ameliorate patients' life-quality. PMID- 26238259 TI - Blockade of MK2 is protective in inflammation-associated colorectal cancer development. AB - Chronic inflammation is a risk factor for colorectal cancer. The MAPK-activated protein kinase 2 (MK2) pathway controls multiple cellular processes including p38 dependent inflammation. This is the first study to investigate the role of MK2 in development of colitis-associated colon cancer (CAC). Herein, we demonstrate that MK2(-/-) mice are highly resistant to neoplasm development when exposed to AOM/DSS, while wild type (WT) C57BL/6 develop multiple neoplasms with the same treatment. MK2-specific cytokines IL-1, IL-6 and TNF-alpha were substantially decreased in AOM/DSS treated MK2(-/-) mouse colon tissues compared with WT mice, which coincided with a marked decrease in macrophage influx. Restoring MK2 competent macrophages by injecting WT bone marrow derived macrophages into MK2(-/ ) mice led to partial restoration of inflammatory cytokine production with AOM/DSS treatment; however, macrophages were not sufficient to induce neoplasm development. These results indicate that MK2 functions as an inflammatory regulator to promote colonic neoplasm development and may be a potential target for CAC. PMID- 26238261 TI - Profiling unauthorized natural resource users for better targeting of conservation interventions. AB - Unauthorized use of natural resources is a key threat to many protected areas. Approaches to reducing this threat include law enforcement and integrated conservation and development (ICD) projects, but for such ICDs to be targeted effectively, it is important to understand who is illegally using which natural resources and why. The nature of unauthorized behavior makes it difficult to ascertain this information through direct questioning. Bwindi Impenetrable National Park, Uganda, has many ICD projects, including authorizing some local people to use certain nontimber forest resources from the park. However, despite over 25 years of ICD, unauthorized resource use continues. We used household surveys, indirect questioning (unmatched count technique), and focus group discussions to generate profiles of authorized and unauthorized resource users and to explore motivations for unauthorized activity. Overall, unauthorized resource use was most common among people from poor households who lived closest to the park boundary and farthest from roads and trading centers. Other motivations for unauthorized resource use included crop raiding by wild animals, inequity of revenue sharing, and lack of employment, factors that created resentment among the poorest communities. In some communities, benefits obtained from ICD were reported to be the greatest deterrents against unauthorized activity, although law enforcement ranked highest overall. Despite the sensitive nature of exploring unauthorized resource use, management-relevant insights into the profiles and motivations of unauthorized resource users can be gained from a combination of survey techniques, as adopted here. To reduce unauthorized activity at Bwindi, we suggest ICD benefit the poorest people living in remote areas and near the park boundary by providing affordable alternative sources of forest products and addressing crop raiding. To prevent resentment from driving further unauthorized activity, ICDs should be managed transparently and equitably. PMID- 26238263 TI - Pushing the annotation of cellular activities to a higher resolution: Predicting functions at the isoform level. AB - In past decades, the experimental determination of protein functions was expensive and time-consuming, so numerous computational methods were developed to speed up and guide the process. However, most of these methods predict protein functions at the gene level and do not consider the fact that protein isoforms (translated from alternatively spliced transcripts), not genes, are the actual function carriers. Now, high-throughput RNA-seq technology is providing unprecedented opportunities to unravel protein functions at the isoform level. In this article, we review recent progress in the high-resolution functional annotations of protein isoforms, focusing on two methods developed by the authors. Both methods can integrate multiple RNA-seq datasets for comprehensively characterizing functions of protein isoforms. PMID- 26238262 TI - Mouse Genome Informatics (MGI): reflecting on 25 years. AB - From its inception in 1989, the mission of the Mouse Genome Informatics (MGI) resource remains to integrate genetic, genomic, and biological data about the laboratory mouse to facilitate the study of human health and disease. This mission is ever more feasible as the revolution in genetics knowledge, the ability to sequence genomes, and the ability to specifically manipulate mammalian genomes are now at our fingertips. Through major paradigm shifts in biological research and computer technologies, MGI has adapted and evolved to become an integral part of the larger global bioinformatics infrastructure and honed its ability to provide authoritative reference datasets used and incorporated by many other established bioinformatics resources. Here, we review some of the major changes in research approaches over that last quarter century, how these changes are reflected in the MGI resource you use today, and what may be around the next corner. PMID- 26238264 TI - The changing role of health-oriented international organizations and nongovernmental organizations. AB - Apart from governments, there are many other actors active in the health policy arena, including a wide array of international organizations (IOs), public private partnerships and non-governmental organizations (NGOs) that state as their main mission to improve the health of (low-income) populations of low income countries. Despite the steady rise in numbers and prominence of NGOs, however, there is lack of empirical knowledge about their functioning in the international policy arena, and most studies focus on the larger organizations. This has also caused a somewhat narrow focus of theoretical studies. Some scholars applied the 'principal-agent' theory to study the origins of IOs, for example, other focus on changing power relations. Most of those studies implicitly assume that IOs, public-private partnerships and large NGOs act as unified and rational actors, ignoring internal fragmentation and external pressure to change directions. We assert that the classic analytical instruments for understanding the shaping and outcome of public policy: ideas, interests and institutions apply well to the study of IOs. As we will show, changing ideas about the proper role of state and non-state actors, changing positions and activities of major stakeholders in the (international) health policy arena, and shifts in political institutions that channel the voice of diverging interests resulted in (and reflected) the changing positions of the health-oriented organizations-and also affect their future outlook. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26238265 TI - Analysis of putative mucosal SHIV susceptibility factors during repeated DMPA treatments in pigtail macaques. AB - BACKGROUND: Depot-medroxyprogesterone acetate (DMPA) has been associated in some studies with increased HIV susceptibility in women. We used a pigtail macaque model to document the effects of repeated DMPA treatments and their potential contribution to increased SHIV susceptibility. METHODS: Nine pigtails were administered 2.5, 1.5, or 0.5 mg/kg DMPA in study weeks one and four. Menstrual cycling, vaginal epithelial thickness, and other SHIV susceptibility factors were monitored for a mean of 24 study weeks. RESULTS: All DMPA treatments suppressed menstrual cycling and increased vaginal pH. The vaginal epithelium thinned naturally during baseline menstrual cycles (from mean of 351 to 161 MUm in late luteal phase). Following DMPA, the non-nucleated layer was temporarily absent. Two weeks post-second DMPA injection, mean epithelial thickness was 53, 45, and 167 MUm for the descending doses, respectively. CONCLUSIONS: All animals showed temporal vaginal epithelial thinning with loss of the non-nucleated layer, and vaginal pH changes post-DMPA injections. PMID- 26238267 TI - Long non-coding RNA HOTAIR: A novel oncogene (Review). AB - Long non-coding RNAs (lncRNAs) have been found to be pervasively transcribed in the genome and are critical regulators of the epigenome. Increasing evidence suggests that lncRNAs are aberrantly expressed in several types of human cancer and that they are important in the initiation, development and metastasis of human cancer. Previous studies have revealed that HOX transcript antisense intergenic RNA (HOTAIR) was frequently upregulated in various types of cancer, including breast cancer, esophageal cancer, lung cancer and gastric cancer. In addition, patients with high expression levels of HOTAIR have a significantly poorer prognosis, compared with those with low levels of expression. HOTAIR is involved in the control of cell apoptosis, growth, metastasis, angiogenesis, DNA repair and tumor cells metabolism. The present review provides an overview of the current knowledge concerning the role of HOTAIR in tumor development and progression. PMID- 26238266 TI - Cost-effectiveness of medical, endovascular and surgical management of peripheral vascular disease. AB - Peripheral arterial disease (PAD) is responsible for 20% of all US hospital admissions. Management of PAD has evolved over time to include many medical and transcatheter interventions in addition to the traditional surgical approach. Non invasive interventions including supervised exercise programs and antiplatelets use are economically attractive therapies that should be considered in all patients at risk. While surgery offers so far a clinically and economically appropriate option, the improvement of percutaneous transluminal angioplasty (PTA) technique with the addition of drug-coated balloons offers a reasonably clinically and economically attractive alternative that will continue to evolve in the future. PMID- 26238268 TI - Enhanced therapeutic effects against murine colon carcinoma induced by a Colon 26/Ag85A-CD226 tumor cell vaccine. AB - Genetically modified tumor cells represent one of the most effective cancer vaccine strategies. In the present study, we describe our approach for inducing an immune response against a colon carcinoma in BALB/c mice, using a Colon 26 tumor cell line expressing Ag85A and CD226. We investigated whether CD226 plays a promotive role for Ag85A against Colon 26 colon carcinoma. The therapeutic efficacy was investigated. The cytotoxic T lymphocyte (CTL) and natural killer (NK) cell cytotoxicity were assessed. Dynamic changes in interferon (IFN)-gamma levels in the spleen and the number of IFN-gamma-producing CD4+ or CD8+ T cells in the spleen or mesenteric lymph nodes were detected by enzyme-linked immunoabsorbent assay or flow cytometry. Extended survival times, delayed appearances of tumors, and reduced tumor volumes were achieved by preventive vaccination with the Colon 26/Ag85A-CD226 tumor cell vaccine. NK cell or CTL cytotoxicity in the spleens of mice immunized with the Colon 26/Ag85A-CD226 tumor cell vaccine was significantly higher than that in the other treatment groups. The numbers of CD4+ IFN-gamma+ and CD8+ IFN-gamma+ T cells were both significantly increased in mice immunized with the Colon 26/Ag85A-CD226 tumor cell vaccine in both the spleen and mesenteric lymph nodes. Our results indicated that the tumor vaccine expressing Ag85A and CD226 induced more intensive antitumor immunity than tumor vaccine expressing Ag85A or CD226 only. Moreover, the results suggest that Ag85A and CD226 play a synergistic antitumor effect and CD226 could be used as a genetic adjuvant to enhance the effects of Ag85A vaccine against murine colon carcinoma. PMID- 26238269 TI - A combined analysis of worldwide studies demonstrates an association between bipolar disorder and tobacco smoking behaviors in adults. AB - OBJECTIVES: Worldwide studies were combined to examine two hypotheses: (i) bipolar disorder is associated with smoking behaviors, compared with the general population; and (ii) smoking behavior prevalences in bipolar disorder are intermediate between those in major depressive disorder and those in schizophrenia. METHODS: Combined analyses used 56 articles on adults obtained from a PubMed search or the senior author's article collection. Odds ratios (ORs) and their 95% confidence intervals (CIs) compared current smoking, heavy smoking among current smokers, smoking cessation in ever smokers, and ever smoking in bipolar disorder versus control groups. RESULTS: The combined OR was 3.5 (CI: 3.39-3.54) in 51 current smoking studies of bipolar disorder versus the general population from 16 countries. More limited data provided an OR = 0.34 (CI: 0.31 0.37) for smoking cessation and an OR = 3.6 (CI: 3.30-3.80) for ever smoking. The combined OR was 0.76 (CI: 0.74-0.79) for current smoking in bipolar disorder versus schizophrenia in 20 studies from ten countries. Ever smoking may be lower in bipolar disorder than in schizophrenia (OR = 0.83, CI: 0.75-0.91). The OR was 2.05 (CI: 2.00-2.10) for current smoking in bipolar disorder versus major depression in 18 studies from seven countries. Ever smoking may be higher (OR = 1.5, CI: 1.40-1.70) and smoking cessation lower (OR = 0.51, CI: 0.45-0.59) in bipolar disorder than in major depression. CONCLUSIONS: Increased current smoking in bipolar disorder versus the general population reflected increased ever smoking (initiation) and decreased smoking cessation. Smoking behavior frequencies in bipolar disorder may be between those in depressive disorder and schizophrenia, with schizophrenia showing the highest severity level. PMID- 26238270 TI - Enhanced Broadband Electromagnetic Absorption in Silicon Film with Photonic Crystal Surface and Random Gold Grooves Reflector. AB - We show a hybrid structure consisting of Si film with photonic crystal surface and random triangular gold grooves reflector at the bottom, which is capable of realizing efficient, broad-band, wide-angle optical absorption. It is numerically demonstrated that the enhanced absorption in a broad wavelength range (0.3-9.9 MUm) due to the scattering effect of both sides of the structure and the created resonance modes. Larger thickness and period are favored to enhance the absorption in broader wavelength range. Substantial electric field concentrates in the grooves of surface photonic crystal and in the Si film. Our structure is versatile for solar cells, broadband photodetection and stealth coating. PMID- 26238271 TI - MicroRNA-34a attenuates the proliferation, invasion and metastasis of gastric cancer cells via downregulation of MET. AB - Proliferation, invasion and metastasis are key features of gastric cancer, contributing to high mortality rates in patients with gastric cancer worldwide. As a direct target of p53, the functions of microRNA (miR)-34a are important, but controversial, in the progression of gastric cancer. In the present study, the clinical importance of miR-34a in GC specimens (n=40) were investigated and were confirmed in an independent cohort from The Cancer Genome Atlas (TCGA; n=352). The prognostic value of miR-34a was analyzed using a Kaplan-Meier survival curve in the TCGA cohort, in combination with complete follow-up data (n=157). The level of miR-34a was detected in the human gastric cancer cell line and normal gastric epithelial cell line. The effect of miR-34a on proliferation and invasion were evaluated using Cell Counting Kit 8, colony formation and cell invasion assays. The molecular basis of miR-34a was determined by bioinformatics prediction. The correlation between miR-34a and MET was assessed using reverse transcription-quantitative polymerase chain reaction and western blot analyses. The results indicated that miR-34a was downregulated in the gastric cancer tissues, compared with the normal gastric tissues (P<0.01). miR-34a was negatively correlated with the depth of invasion and lymph node metastasis of gastric cancer (P<0.01). In the TCGA cohort, the levels of miR-34a were lower in T3 and T4 tumor stages, compared with the level in the T1 stage, and low levels of miR-34a predicted significantly longer survival rates in patients with GC (P<0.05). miR-34a also attenuated the proliferation ability, and inhibited the colony formation and cell invasion abilities of the cells (P<0.01). A negative correlation was observed between miR-34a and MET in gastric cancer (P<0.01; r= 0.9526), and >60% of cases exhibited consistent expression of miR-34a and MET in gastric cancer (P<0.01). In conclusion, miR-34a was associated with the clinicopathological features of gastric cancer and was a valuable predictor of patient prognosis. miR-34a acted as a tumor suppressor to inhibit gastric cancer proliferation and invasion via the downregulation of MET. PMID- 26238272 TI - Reply: To PMID 25524401. PMID- 26238273 TI - Olfaction in the kidney: 'smelling' gut microbial metabolites. AB - NEW FINDINGS: What is the topic of this review? This review covers recent findings highlighting roles for renal and vascular sensory receptors that modify blood pressure control in response to changes in gut microbial metabolites. What advances does it highlight? This review highlights the novel roles that G-protein coupled receptor 41 and olfactory receptor 78 play in blood pressure regulation. The gut microbiota have recently been recognized as an important component of host physiology and pathophysiology. Our recent studies have shown that a subset of gut microbial metabolites, known as short-chain fatty acids, act as ligands for host G-protein-coupled receptors (G-protein-coupled receptor 41 and olfactory receptor 78). Short-chain fatty acid-mediated activation of G-protein-coupled receptor 41 and olfactory receptor 78 modulates blood pressure control, both by modulating renin secretion and by modulating vascular tone directly. Further studies are needed in order to gain a better understanding of the underlying mechanism by which microbiota and microbial metabolites modulate host physiology and their potential implications in health and disease. PMID- 26238274 TI - Acute pyelonephritis in children. AB - Acute pyelonephritis is one of the most serious bacterial illnesses during childhood. Escherichia coli is responsible in most cases, however other organisms including Klebsiella, Enterococcus, Enterobacter, Proteus, and Pseudomonas species are being more frequently isolated. In infants, who are at major risk of complications such as sepsis and meningitis, symptoms are ambiguous and fever is not always useful in identifying those at high risk. A diagnosis of acute pyelonephritis is initially made on the basis of urinalysis; dipstick tests for nitrites and/or leukocyte esterase are the most accurate indicators of infection. Collecting a viable urine sample for urine culture using clean voided methods is feasible, even in young children. No gold standard antibiotic treatment exists. In children appearing well, oral therapy and outpatient care is possible. New guidelines suggest less aggressive imaging strategies after a first infection, reducing radiation exposure and costs. The efficacy of antibiotic prophylaxis in preventing recurrence is still a matter of debate and the risk of antibiotic resistance is a warning against its widespread use. Well-performed randomized controlled trials are required in order to better define both the imaging strategies and medical options aimed at preserving long-term renal function. PMID- 26238275 TI - Novel marker for the detection of sickle cell nephropathy: soluble FMS-like tyrosine kinase-1 (sFLT-1). AB - BACKGROUND: Given the burden and poor outcome of end-stage renal disease in sickle cell disease (SCD), early markers of sickle cell nephropathy (SN) are desirable. Disordered angiogenesis underlies many complications of SCD. We aimed to determine the relationship between serum FMS-like tyrosine kinase-1 (sFLT-1) and other biomarkers of renal damage for the early diagnosis of SN. METHODS: Forty-seven SCD patients and 49 healthy controls were enrolled. Microalbuminuria was determined in patient urine samples. Blood samples were tested for sFLT-1, serum creatinine, and various hemolysis and inflammation markers. Peripheral blood monocyte expression of sFLT-1 was measured using real-time polymerase chain reaction (PCR). RESULTS: The serum level of sFLT-1 (pg/ml) in SCD patients was higher than controls (median/range/IQR = 142/ 60-1300/61 pg/ml vs. 125/ 110 187/52 pg/ml, respectively) (p = 0.006). Median (range) of sFLT-1 level was higher in SCD patients with microalbuminuria compared to SCD patients with normoalbuminuria, 185 (140-1300) vs. 125 (60-189) mg/g, respectively) (p = 0.004). There was a significant positive correlation between serum sFLT-1 and microalbuminuria, lactate dehydrogenase (LDH), and indirect bilirubin (r = 0.59, 0.39, 0.30, and p = <0.001, 0.007, 0.041, respectively). sFLT-1 sensitivity in early detection of renal affection in SCD was 93.6%, while specificity was 68.6%. Finally, peripheral blood monocytes (PBM) sFLT-1 expression was significantly higher in SCD patients compared to controls (p = 0.05). CONCLUSIONS: sFLT-1 may contribute to pathogenesis of albuminuria in SCD patients and constitute a novel renal biomarker of SN. PMID- 26238277 TI - Peripheral sensory coding through oscillatory synchrony in weakly electric fish. AB - Adaptations to an organism's environment often involve sensory system modifications. In this study, we address how evolutionary divergence in sensory perception relates to the physiological coding of stimuli. Mormyrid fishes that can detect subtle variations in electric communication signals encode signal waveform into spike-timing differences between sensory receptors. In contrast, the receptors of species insensitive to waveform variation produce spontaneously oscillating potentials. We found that oscillating receptors respond to electric pulses by resetting their phase, resulting in transient synchrony among receptors that encodes signal timing and location, but not waveform. These receptors were most sensitive to frequencies found only in the collective signals of groups of conspecifics, and this was correlated with increased behavioral responses to these frequencies. Thus, different perceptual capabilities correspond to different receptor physiologies. We hypothesize that these divergent mechanisms represent adaptations for different social environments. Our findings provide the first evidence for sensory coding through oscillatory synchrony. PMID- 26238276 TI - Long-term outcome of childhood IgA nephropathy with minimal proteinuria. AB - BACKGROUND: Some patients with childhood immunoglobulin A nephropathy (IgAN) progress to end-stage renal disease within 20 years, while others achieve spontaneous remission even without medication. Prognosis of IgAN with minimal proteinuria (MP-IgAN, <0.5 g/day/1.73 m(2)) at diagnosis seems to be generally good. However, the long-term outcome for patients with childhood MP-IgAN has not yet been determined. METHODS: We retrospectively analyzed 385 children newly diagnosed with biopsy-proven IgAN between June 1976 and July 2009 whose renal biopsy specimens could be evaluated by the Oxford classification criteria. Of these 385 children with IgAN, 106 (27.5%) were diagnosed with MP-IgAN. We compared clinical and pathological findings between the 106 patients with MP-IgAN and the remaining 279 patients to elucidate the characteristics of MP-IgAN in children. RESULTS: Patients with MP-IgAN were identified through a school screening program (73.6%) or upon presentation with gross hematuria (26.4%). Patients with MP-IgAN had significantly milder pathological symptoms than those with IgAN. The most frequently used therapeutic regimes were angiotensin converting enzyme inhibitors (30.2%) and no therapy (36.8%). None of the patients with MP-IgAN reached stage III chronic kidney disease within 15 years after onset. Four patients with MP-IgAN (3.8 %) received immunosuppressive therapy during the course of the disease. CONCLUSION: Our results indicate that the outcome of patients with a diagnosis of childhood MP-IgAN is good, but that careful long-term observation is required. PMID- 26238279 TI - Erratum to: Recruitment of Gr1(+)CD11b(+)F4/80(+)Population in the Bone Marrow and Spleen by Irradiation-Induced Pulmonary Damage. PMID- 26238278 TI - Longitudinal Impact of a Family Critical Time Intervention on Children in High Risk Families Experiencing Homelessness: A Randomized Trial. AB - A randomized trial compared effects of a Family Critical Time Intervention (FCTI) to usual care for children in 200 newly homeless families in which mothers had diagnosable mental illness or substance problems. Adapted from an evidence-based practice to prevent chronic homelessness for adults with mental illnesses, FCTI combines housing and structured, time-limited case management to connect families leaving shelter with community services. Families were followed at five time points over 24 months. Data on 311 children-99 ages 1.5-5 years, 113 ages 6-10 years, and 99 ages 11-16 years-included mother-, teacher-, and child-reports of mental health, school experiences, and psychosocial well-being. Analyses used hierarchical linear modeling to investigate intervention effects and changes in child functioning over time. Referral to FCTI reduced internalizing and externalizing problems in preschool-aged children and externalizing for adolescents 11-16. The intervention led to declines in self-reported school troubles for children 6-10 and 11-16. Both experimental and control children in all age groups showed reductions in symptoms over time. Although experimental results were scattered, they suggest that FCTI has the potential to improve mental health and school outcomes for children experiencing homelessness. PMID- 26238280 TI - Retraction Note to: Different Aspects of Sartan + Calcium Antagonist Association Compared to the Single Therapy on Inflammation and Metabolic Parameters in Hypertensive Patients. PMID- 26238281 TI - Combining bone morphogenetic proteins-2 and -6 has additive effects on osteoblastic differentiation in vitro and accelerates bone formation in vivo. AB - While only two members of the bone morphogenetic protein subfamily (BMP-2 and -7) are approved to be used in combination with collagen type I in orthopaedic surgery, other BMPs are known to also be highly osteoinductive. Although all the osteogenic BMPs signal through Smad-1/-5/-8 phosphorylation, they show different preferences for the available BMP receptors. In this work we studied the effect of combining two osteogenic BMPs (-2 and -6), which belong to different groups within the subfamily and have different affinities to the existing BMP receptors. Both the growth and in vitro differentiation of MC3T3-E1 mouse preosteoblasts and rat bone marrow-derived mesenchymal stem cells (MSCs) were studied, as well as in vivo ectopic bone formation when the BMPs were intramuscularly implanted in rats with collagen type I sponges as carriers. The results show that these two growth factors have additive effects on the osteoblastic differentiation of cells in vitro and that their combination might be helpful to accelerate in vivo osteogenesis while reducing the amount of each individual BMP used. PMID- 26238282 TI - Analysis of perioperative radiation therapy in the surgical treatment of primary and recurrent retroperitoneal sarcoma. AB - BACKGROUND: Radiation therapy (RT) is increasingly utilized in conjunction with surgery for the treatment of retroperitoneal soft tissue sarcomas (RPS). Despite multiple theoretical advantages of RT, its role in the surgical management of this disease remains ill defined. METHODS: Patients undergoing surgery for RPS from 1990 to 2011 were identified. Patients were classified as having primary or recurrent disease, and then further stratified by the use of perioperative RT. Primary outcomes, including overall survival (OS) and recurrence-free survival (RFS), were estimated using the Kaplan-Meier method with comparisons based on the log rank test. Cox-proportional hazards modeling was used to estimate the independent effect of RT on survival. RESULTS: Ninety-four patients met final inclusion criteria. After adjusting for confounding variables, perioperative RT remained independently associated with a reduced risk of recurrence (HR 0.34, P < 0.01) and death (HR 0.30, P = 0.02). CONCLUSIONS: In this retrospective series, perioperative RT is an independent predictor of improved OS and RFS. These results provide additional support for the use of RT in the multimodality treatment of retroperitoneal sarcoma. PMID- 26238283 TI - The role of NOD1/CARD4 and NOD2/CARD15 genetic variations in lung cancer risk. AB - BACKGROUND AND AIM: NOD1/CARD4 and NOD2/CARD15 are members of the Nod-like receptor (NLR) family, and they contain a caspase recruitment domain (CARD). NLRs are located in the cytosol where they bind bacterial and viral ligands and play a key role in the innate and adaptive immune response, apoptosis, autophagy, and reactive oxygen species generation. NLR gene polymorphisms may shift the balance between pro- and anti-inflammatory cytokines and modulate the risk of infection, chronic inflammation, and cancer. NOD1/CARD4 and NOD2/CARD15 gene polymorphisms may also be associated with altered risks for many cancer types. The aim of our study was to evaluate the potential associations between lung cancer and NOD1/CARD4 and NOD2/CARD15 polymorphisms. METHOD: The NOD1/CARD4 (rs5743336) and NOD2/CARD15 (rs2066847) SNPs were analyzed by PCR restriction fragment-length polymorphism analysis (PCR-RFLP) in 260 subjects (lung cancer patients: n = 160; healthy controls: n = 100) of Turkish origin. PCR products were digested with AvaI for rs5743336 and ApaI for rs2066847 and then visualized. RESULTS: Comparisons of the genotypes between control and lung cancer patients were performed by Chi-square tests. We found a significant difference in the genotypic distribution of the rs5743336 variant of NOD1/CARD4 between lung cancer patients and controls (p = 0.010, chi (2) = 9.220). However, we did not identify any statistically significant difference for the p.Leu1007fsX1008 (rs2066847) genotype of NOD2/CARD15 between groups (p > 0.05). CONCLUSION: According to our data, the rs5743336 variant of the NOD1/CARD4 gene may influence the diagnosis and treatment of lung cancer, whereas the rs2066847 variant of the NOD2/CARD15 gene is not associated with lung cancer risk in the Turkish population. PMID- 26238284 TI - Inhibition of NADPH oxidase 4 induces apoptosis in malignant mesothelioma: Role of reactive oxygen species. AB - Malignant pleural mesothelioma (MPM) is an aggressive tumor that is characterized by dysregulated growth and resistance to apoptosis. Reactive oxygen species (ROS) generating NADPH oxidase (Nox) family enzymes have been suggested to be involved in neoplastic proliferation. Both the antioxidant N-acetylcysteine (NAC) and the inhibitor of flavoprotein-dependent oxidase, diphenylene iodonium (DPI), inhibited the cell viability of MPM cells in a dose-dependent manner. To examine whether Nox-mediated ROS generation confers antiapoptotic activity and thus a growth advantage to MPM cells, we analyzed the mRNA expression of Nox family members using quantitative RT-PCR in 7 MPM cell lines and a normal mesothelial cell line. Nox4 mRNA was expressed in all of the examined MPM cell lines, whereas little or no Nox2, Nox3 and Nox5 mRNA expression was detected. In 2 MPM cell lines, Nox4 mRNA expression was significantly higher than that in a normal mesothelial cell line. siRNAs targeting Nox4 suppressed ROS generation and cell viability in the MPM cell lines. In addition, DPI treatment and knockdown of Nox4 attenuated phosphorylation of AKT and ERK. Taken together, our results indicate that Nox4-mediated ROS, at least in part, transmit cell survival signals and their depletion leads to apoptosis, thus highlighting the Nox4-ROS-AKT signaling pathway as a potential therapeutic target for MPM treatment. PMID- 26238286 TI - Discussion. PMID- 26238285 TI - Cross-reactivity between group-5 and -21 mite allergens from Dermatophagoides farinae, Tyrophagus putrescentiae and Blomia tropicalis. AB - Group-5 and group-21 allergens, produced by house dust mites and storage mites are 36.6-55.8% identical in their sequences and are recognized by at least 50% of immunoglobulin (Ig)E from the sera of individuals allergic to dust mites. In the present study, recombinant group-5 and -21 allergens from three mite species, Dermatophagoides farinae (rDer f 5 and 21), Tyrophagus putrescentiae (rTyr p 5 and 21), and Blomia tropicalis (rBlo t 5 and 21), were purified from Escherichia coli, and the IgE reactivities and cross-reactivities of these allergen variants were assessed. The IgE binding frequencies of rDer f 5, rDer f 21, rTyr p 5, rTyr p 21, rBlo t and rBlo t 21 proteins were 64.95, 65.98, 30.41, 41.24, 30.93 and 21.65%, respectively. The IgE reactivity of rDer f 5 correlated highly with that of rDer f 21 (r=0.733). rTyr p 5 exhibited the highest level of correlation with rTyr p 21 (r=0.950), while the correlation of rBlo t 5 with rBlo t 21 was the lowest observed (r=0.104). The binding of IgE to rDer f 5 and rDer f 21 was not inhibited by any allergens but themselves. While rDer f 5 inhibited only 60.3% of IgE binding to rBlo t 5, rDer f 21 exhibited a high inhibitory effect against rTyr p 5 (93.01%), rTyr p 21 (92.12%), rBlo t 5 (86.97%) and rBlo t 21 (70.30%), implying cross-reactivity among mite species. The results of the present study demonstrated that the majority of the IgE reactivity to group-5 and -21 storage mite allergens is due to cross-reaction. It is therefore imperative to develop an accurate, component-resolved diagnosis for dust mite allergies. PMID- 26238287 TI - Appropriate patient selection or health care rationing? Lessons from surgical aortic valve replacement in the Placement of Aortic Transcatheter Valves I trial. AB - OBJECTIVES: The study objectives were to (1) compare the safety of high-risk surgical aortic valve replacement in the Placement of Aortic Transcatheter Valves (PARTNER) I trial with Society of Thoracic Surgeons national benchmarks; (2) reference intermediate-term survival to that of the US population; and (3) identify subsets of patients for whom aortic valve replacement may be futile, with no survival benefit compared with therapy without aortic valve replacement. METHODS: From May 2007 to October 2009, 699 patients with high surgical risk, aged 84 +/- 6.3 years, were randomized in PARTNER-IA; 313 patients underwent surgical aortic valve replacement. Median follow-up was 2.8 years. Survival for therapy without aortic valve replacement used 181 PARTNER-IB patients. RESULTS: Operative mortality was 10.5% (expected 9.3%), stroke 2.6% (expected 3.5%), renal failure 5.8% (expected 12%), sternal wound infection 0.64% (expected 0.33%), and prolonged length of stay 26% (expected 18%). However, calibration of observed events in this relatively small sample was poor. Survival at 1, 2, 3, and 4 years was 75%, 68%, 57%, and 44%, respectively, lower than 90%, 81%, 73%, and 65%, respectively, in the US population, but higher than 53%, 32%, 21%, and 14%, respectively, in patients without aortic valve replacement. Risk factors for death included smaller body mass index, lower albumin, history of cancer, and prosthesis-patient mismatch. Within this high-risk aortic valve replacement group, only the 8% of patients with the poorest risk profiles had estimated 1 year survival less than that of similar patients treated without aortic valve replacement. CONCLUSIONS: PARTNER selection criteria for surgical aortic valve replacement, with a few caveats, may be more appropriate, realistic indications for surgery than those of the past, reflecting contemporary surgical management of severe aortic stenosis in high-risk patients at experienced sites. PMID- 26238288 TI - Ion channels gated by acetylcholine and serotonin: structures, biology, and drug discovery. AB - The nicotinic acetylcholine receptors (nAChRs) and the 5-HT3 receptors (5-HT3Rs) are cation-selective members of the pentameric ligand-gated ion channels (pLGICs), which are oligomeric protein assemblies that convert a chemical signal into an ion flux through postsynaptic membrane. They are critical components for synaptic transmission in the nervous system, and their dysfunction contributes to many neurological disorders. The diverse subunit compositions of pLGICs give rise to complex mechanisms of ligand recognition, channel gating, and ion-selective permeability, which have been demonstrated in numerous electrophysiological and molecular biological studies, and unraveled by progress in studying the structural biology of this protein family. In this review, we discuss recent insights into the structural and functional basis of two cation-selective pLGICs, the nAChR and the 5-HT3R, including their subunit compositions, ligand binding, and channel gating mechanisms. We also discuss their relevant pharmacology and drug discovery for treating various neurological disorders. Finally, we review a model of two alternative ion conducting pathways based on the latest 5-HT3A crystal structure. PMID- 26238289 TI - Involvement of adrenoceptors, dopamine receptors and AMPA receptors in antidepressant-like action of 7-O-ethylfangchinoline in mice. AB - AIM: 7-O-ethylfangchinoline (YH-200) is a bisbenzylisoquinoline derivative. The aim of this study was to investigate the antidepressant-like action and underlying mechanisms of YH-200 in mice. METHODS: Mice were treated with YH-200 (15, 30, and 60 mg/kg, ig) or tetrandrine (30 and 60 mg/kg, ig) before conducting forced swimming test (FST), tail suspension test (TST), or open field test (OFT). RESULTS: YH-200 (60 mg/kg) significantly decreased the immobility time in both FST and TST, and prolonged the latency to immobility in FST. YH-200 (60 mg/kg) was more potent than the natural bisbenzylisoquinoline alkaloid tetrandrine (60 mg/kg) in FST. Pretreatment with alpha1-adrenoceptor antagonist prazosin (1 mg/kg), beta-adrenoceptor antagonist propranolol (2 mg/kg), dopamine D1/D5 receptor antagonist SCH23390 (0.05 mg/kg), dopamine D2/D3 receptor antagonist haloperidol (0.2 mg/kg) or AMPA receptor antagonist NBQX (10 mg/kg) prevented the antidepressant-like action of YH-200 (60 mg/kg) in FST. In contrast, pretreatment with alpha2 adrenoceptor antagonist yohimbine (1 mg/kg) augmented the antidepressant-like action of YH-200 (30 mg/kg) in FST. Chronic administration of YH-200 (30 and 60 mg/kg for 14 d) did not produce drug tolerance; instead its antidepressant-like action was strengthened. Chronic administration of YH-200 did not affect the body weight of mice compared to control mice. CONCLUSION: YH-200 exerts its antidepressant-like action in mice via acting at multi-targets, including alpha1, alpha2 and beta-adrenoceptors, D1/D5 and D2 /D3 receptors, as well as AMPA receptors. PMID- 26238290 TI - Protease Omi facilitates neurite outgrowth in mouse neuroblastoma N2a cells by cleaving transcription factor E2F1. AB - AIM: Omi is an ATP-independent serine protease that is necessary for neuronal function and survival. The aim of this study was to investigate the role of protease Omi in regulating differentiation of mouse neuroblastoma cells and to identify the substrate of Omi involved in this process. METHODS: Mouse neuroblastoma N2a cells and Omi protease-deficient mnd2 mice were used in this study. To modulate Omi and E2F1 expression, N2a cells were transfected with expression plasmids, shRNA plasmids or siRNA. Protein levels were detected using immunoblot assays. The interaction between Omi and E2F1 was studied using immunoprecipitation, GST pulldown and in vitro cleavage assays. N2a cells were treated with 20 MUmol/L retinoic acid (RA) and 1% fetal bovine serum to induce neurite outgrowth, which was measured using Image J software. RESULTS: E2F1 was significantly increased in Omi knockdown cells and in brain lysates of mnd2 mice, and was decreased in cells overexpressing wild-type Omi, but not inactive Omi S276C. In brain lysates of mnd2 mice, endogenous E2F1 was co-immunoprecipitated with endogenous Omi. In vitro cleavage assay demonstrated that Omi directly cleaved E2F1. Treatment of N2a cells with RA induced marked differentiation and neurite outgrowth accompanied by significantly increased Omi and decreased E2F1 levels, which were suppressed by pretreatment with the specific Omi inhibitor UCF 101. Knockdown of Omi in N2a cells suppressed RA-induced neurite outgrowth, which was partially restored by knockdown of E2F1. CONCLUSION: Protease Omi facilitates neurite outgrowth by cleaving the transcription factor E2F1 in differentiated neuroblastoma cells; E2F1 is a substrate of Omi. PMID- 26238291 TI - New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. AB - Benzo(a)pyrene (BaP) is a ubiquitous carcinogen resulting from incomplete combustion of organic compounds and also present at high levels in cigarette smoke. A wide range of biological effects has been attributed to BaP and its genotoxic metabolite BPDE, but the contribution to BaP toxicity of intermediary metabolites generated along the detoxification path remains unknown. Here, we report for the first time how 3-OH-BaP, 9,10-diol and BPDE, three major BaP metabolites, temporally relate to BaP-induced transcriptomic alterations in HepG2 cells. Since BaP is also known to induce AhR activation, we additionally evaluated TCDD to source the expression of non-genotoxic AhR-mediated patterns. 9,10-Diol was shown to activate several transcription factor networks related to BaP metabolism (AhR), oxidative stress (Nrf2) and cell proliferation (HIF-1alpha, AP-1) in particular at early time points, while BPDE influenced expression of genes involved in cell energetics, DNA repair and apoptotic pathways. Also, in order to grasp the role of BaP and its metabolites in chemical hepatocarcinogenesis, we compared expression patterns from BaP(-metabolites) and TCDD to a signature set of approximately nine thousand gene expressions derived from hepatocellular carcinoma (HCC) patients. While transcriptome modulation by TCDD appeared not significantly related to HCC, BaP and BPDE were shown to deregulate metastatic markers via non-genotoxic and genotoxic mechanisms and activate inflammatory pathways (NF-kappabeta signaling, cytokine-cytokine receptor interaction). BaP also showed strong repression of genes involved in cholesterol and fatty acid biosynthesis. Altogether, this study provides new insights into BaP-induced toxicity and sheds new light onto its mechanism of action as a hepatocarcinogen. PMID- 26238294 TI - Impaired mitochondrial protein synthesis in head and neck squamous cell carcinoma. AB - Human head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type worldwide, possibly due to the significant role of alcohol and tobacco use in its development. Underlying most cancers are defects in mitochondrial functions such as energy metabolism and apoptosis. In fact, the mutations in mitochondrial DNA (mtDNA), which encode proteins for oxidative phosphorylation (OXPHOS), have been associated with human head and neck cancers. Here, we investigated the changes in the expression of OXPHOS complexes and the contribution of the defects in mitochondrial translation in the progression of HNSCC. Western blot analyses of the several stage IVA HNSCC primary tumors have shown reduction in the expression of COII and ATP5A of the OXPHOS complexes IV and V subunits, respectively. On the other hand, expression of the majority of the OXPHOS subunits, except complex II SDHB subunit, was impaired in a patient with a stage IV tumor with a regional lymph node. Interestingly, an overall reduction in one of the mitochondrial-encoded subunits of the complex IV, COII, accentuated a possible defect in mitochondrial translation machinery in two of the stage IVA tumors. Evidence provided in this study suggests for the first time that the mitochondrial translation defect(s) could be due to a decrease in the expression of one of the essential mitochondrial ribosomal proteins, MRPL11, in head and neck tumor biopsies. We also observed an acquired mitochondrial translation deficiency in the HN8 cell line derived from a lymph node metastasis but not in the HN22 cells derived from the primary tumor of the same patient. These seminal observations suggest that the mitochondrial translation machinery deserves further investigation for accurate molecular assessment and treatment of HNSCC. PMID- 26238292 TI - Dissecting the heterogeneity of skin gene expression patterns in systemic sclerosis. AB - OBJECTIVE: To examine the heterogeneity of global transcriptome patterns in systemic sclerosis (SSc) skin in a large sample of patients with SSc and control subjects. METHODS: Skin biopsy specimens obtained from 61 patients enrolled in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort and 36 unaffected control subjects with a similar demographic background were examined by Illumina HumanHT-12 bead arrays. Followup experiments using quantitative polymerase chain reaction and immunohistochemical analysis were also performed. RESULTS: We identified 2,754 differentially expressed transcripts in SSc patients compared with controls. Clustering analysis revealed 2 prominent transcriptomes in SSc patients: the keratin and fibroinflammatory signatures. Higher keratin transcript scores were associated with shorter disease duration and interstitial lung disease, while higher fibroinflammatory scores were associated with diffuse cutaneous involvement, a higher skin score at the biopsy site, and a higher modified Rodnan skin thickness score. A subgroup of patients with significantly longer disease duration had a normal-like transcript pattern. Analysis of cell type-specific signature scores revealed remarkable heterogeneity across patients. Significantly higher scores were calculated for fibroblasts (72% of patients), microvascular cells (61%), macrophages (54%), and dendritic cells (DCs) (49%). The majority of samples with significantly higher fibroblast scores (35 of 44 [80%]) had significantly increased macrophage and/or DC scores. Further analysis and immunohistochemical staining indicated that the keratin signature was not a general marker of keratinocyte activation but was in fact associated with an activation pattern in hair and adnexal structures. CONCLUSION: Prominent fibroinflammatory and keratin signatures are present in SSc skin. Expression profiles of SSc skin show significant heterogeneity, and this finding might be useful for stratifying patients for targeted therapies or predicting the response to immunosuppression. PMID- 26238293 TI - Membrane biofilm development improves COD removal in anaerobic membrane bioreactor wastewater treatment. AB - Membrane biofilm development was evaluated to improve psychrophilic (15 degrees C) anaerobic membrane bioreactor (AnMBR) treatment of domestic wastewater. An AnMBR containing three replicate submerged membrane housings with separate permeate collection was operated at three levels of membrane fouling by independently controlling biogas sparging for each membrane unit. High membrane fouling significantly improved permeate quality, but resulted in dissolved methane in the permeate at a concentration two to three times the equilibrium concentration predicted by Henry's law. Illumina sequencing of 16S rRNA targeting Bacteria and Archaea and reverse transcription-quantitative polymerase chain reaction targeting the methyl coenzyme-M reductase (mcrA) gene in methanogens indicated that the membrane biofilm was enriched in highly active methanogens and syntrophic bacteria. Restoring fouled membranes to a transmembrane pressure (TMP) near zero by increasing biogas sparging did not disrupt the biofilm's treatment performance, suggesting that microbes in the foulant layer were tightly adhered and did not significantly contribute to TMP. Dissolved methane oversaturation persisted without high TMP, implying that methanogenesis in the biofilm, rather than high TMP, was the primary driving force in methane oversaturation. The results describe an attractive operational strategy to improve treatment performance in low-temperature AnMBR by supporting syntrophy and methanogenesis in the membrane biofilm through controlled membrane fouling. PMID- 26238295 TI - Analysis of metallic traces from the biodegradation of endomedullary AZ31 alloy temporary implants in rat organs after long implantation times. AB - AZ31 alloy has been tested as a biodegradable material in the form of endomedullary implants in female Wistar rat femurs. In order to evaluate the accumulation of potentially toxic elements from the biodegradation of the implant, magnesium (Mg), aluminium (Al), zinc (Zn), manganese (Mn) and fluorine (F) levels have been measured in different organs such as kidneys, liver, lungs, spleen and brain. Several factors that may influence accumulation have been taken into account: how long the implant has been in place, whether or not the bone is fractured, and the presence of an MgF2 protective coating on the implant. The main conclusions and the clinical relevance of the study have been that AZ31 endomedullary implants have a degradation rate of about 60% after 13 months, which is fully compatible with fracture consolidation. Neither bone fracture nor an MgF2 coating seems to influence the accumulation of trace elements in the studied organs. Aluminium is the only alloying element in this study that requires special attention. The increase in Al recovered from the sampled organs represents 3.95% of the amount contained in the AZ31 implant. Al accumulates in a statistically significant way in all the organs except the brain. All of this suggests that in long-term tests AZ31 may be a suitable material for osteosynthesis. PMID- 26238296 TI - Impact of Helicobacter pylori on the growth of hepatic orthotopic graft tumors in mice. AB - Helicobacter pylori is a well-known causative organism of chronic gastric diseases and has been found in many hepatic carcinoma samples. To explore the expression of apoptosis-related proteins and carcinoma development in H. pylori infected livers, we utilized BALB/cAnSlac mice to establish an H. pylori-infected model by oral inoculation and orthotopic grafts of hepatic tumors by H22 cells, respectively. We found that H. pylori colonies could not be cultured from all liver and tumor samples. However, its 16S rRNA was detectable in 85.3% of livers and 66.7% of tumors in the infected mice. Inflammatory cells were observed and thinly distributed in the lobule portions of the liver, and H. pylori mainly existed in the infected hepatic sinusoids and the necrotic areas of the infected tumors. No significant difference was found in liver to body weight ratio between the infected and uninfected. Moreover, the pathological tumor difference was unremarkable between the two. The proliferating cell nuclear antigen (PCNA) and Bcl-2-associated X protein (Bax) expression in the infected tumors was significantly higher and lower, respectively, than those of the uninfected tumors. However, no significant difference in Bcl-2 (B-cell lymphoma 2) expression existed. The results indicate that H. pylori found in the livers which were infected by H. pylori oral inoculation could contribute to the infiltration of inflammatory cells in livers. Although H. pylori has no significant impact on the liver to body weight ratio or tumor Bcl-2 expression, it may upregulate PCNA expression and downregulate Bax expression, respectively. All our findings show that H. pylori may promote proliferation and inhibit apoptosis of tumor cells. PMID- 26238297 TI - Evaluation of exposure to organophosphate, carbamate, phenoxy acid, and chlorophenol pesticides in pregnant women from 10 Caribbean countries. AB - Pesticides are commonly used in tropical regions such as the Caribbean for both household and agricultural purposes. Of particular concern is exposure during pregnancy, as these compounds can cross the placental barrier and interfere with fetal development. The objective of this study was to evaluate exposure of pregnant women residing in 10 Caribbean countries to the following commonly used classes of pesticides in the Caribbean: organophosphates (OPs), carbamates, phenoxy acids, and chlorophenols. Out of 438 urine samples collected, 15 samples were randomly selected from each Caribbean country giving a total of 150 samples. Samples were analyzed for the following metabolites: six OP dialkylphosphate metabolites [dimethylphosphate (DMP), dimethylthiophosphate (DMTP), dimethyldithiophosphate (DMDTP), diethylphosphate (DEP), diethylthiophosphate (DETP) and diethyldithiophosphate (DEDTP)]; two carbamate metabolites [2 isopropoxyphenol (2-IPP) and carbofuranphenol]; one phenoxy acid 2,4 dichlorophenoxyacetic acid (2,4-D); and five chlorophenols [2,4-dichlorophenol (DCP), 2,5-dichlorophenol (2,5-DCP), 2,4,5-trichlorophenol (TCP), 2,4,6 trichlorophenol (2,4,6-TCP), and pentachlorophenol (PCP)]. OP metabolites were consistently detected in >=60% of the samples from Antigua and Barbuda, Bermuda, and Jamaica. Of the carbamate metabolites, 2-IPP was detected in seven of the 10 Caribbean countries with a detection frequency around 30%, whereas carbofuranphenol was detected in only one sample. The detection frequency for the phenoxy acid 2,4-D ranged from 20% in Grenada to a maximum of 67% in Belize. Evidence of exposure to chlorophenol pesticides was also established with 2,4-DCP by geometric means ranging from 0.52 MUg L(-1) in St Lucia to a maximum of 1.68 MUg L(-1) in Bermuda. Several extreme concentrations of 2,5-DCP were detected in four Caribbean countries-Belize (1100 MUg L(-1)), Bermuda (870 MUg L(-1)), Jamaica (1300 MUg L(-1)), and St Kitts and Nevis (1400 MUg L(-1)). 2,4,5-TCP, 2,4,6-TCP, and pentachlorophenol were rarely detected. This biomonitoring study underscores the need for Caribbean public health authorities to encourage their populations, and in particular pregnant women, to become more aware of the potential routes of exposure to pesticides and to utilize these chemicals more cautiously given the possible adverse effects such exposures can have on their unborn children and infants. PMID- 26238298 TI - Duloxetine in treating generalized anxiety disorder in adults: A meta-analysis of published randomized, double-blind, placebo-controlled trials. AB - INTRODUCTION: We carried out a meta-analysis of published randomized, double blind, placebo-controlled trails to assess the efficacy and tolerability of duloxetine in treating generalized anxiety disorder (GAD). METHODS: A literature search was conducted using PubMed, ISI Web of Science, Medline, Cochrane Central Register of Controlled Trials databases until October 2014. The search terms used were "anxiety or anxious or generalized anxiety disorder" and "duloxetine or Cymbalta." Meta-analysis was conducted using Revman 5.1. A fixed-effects model was carried out on the response rates, remission rates, and symptom improvement. Risk ratio (RR) and mean difference (MD) were calculated. The overall effect size was calculated with 95% confidence intervals (CIs). RESULTS: Seven studies (n = 2,674) were found eligible for inclusion in analysis. Six studies provided data on response, which showed a significant difference between duloxetine and placebo (n = 1,975, RR = 1.48, 95% CI, 1.34-1.63). Remission rates revealed significant superiority of duloxetine (n = 2,399, RR = 1.60, 95% CI, 1.43-1.80). Change from baseline scores on Hamilton Rating Scale for Anxiety showed a reduction in anxiety symptoms to be significantly efficient for duloxetine (n = 1,135, MD = 3.34, 95% CI, 2.37-4.32). Duloxetine increased statistically Sheehan Disability Scale total score (n = 1,652, MD = 2.84, 95% CI, 2.08-3.60). The discontinuation of the duloxetine was not significantly different from that of the placebo. CONCLUSION: Duloxetine is moderately effective in treating GAD with improvement in overall function and well tolerability. PMID- 26238299 TI - An ominous radiographic feature: cortical ribbon sign. PMID- 26238300 TI - Impact of satisfactions with psychological reward and pay on Chinese nurses' work attitudes. AB - PURPOSE: To examine the impact of satisfaction with psychological rewards (received from the head nurse and from physicians) and with pay on Chinese nurses' work attitudes. METHOD: We conducted a cross-sectional survey in China. A total of 413 nurses completed our survey. We examined the effect of satisfactions with psychological rewards and pay on work attitudes by performing a series of hierarchical regression analyses. FINDINGS: We found that both satisfaction with pay and satisfaction with psychological rewards from the head nurse significantly predicted work attitudes, whereas satisfaction with psychological rewards from physicians did not. CONCLUSIONS: Our results illustrate that when nurses feel satisfied with their pay and the psychological rewards received from the head nurse they exhibit more positive work attitudes. PMID- 26238301 TI - Infertility and miscarriage: common pathways in manifestation and management. AB - The relationship between miscarriage and fertility is complex. While most healthcare settings treat miscarriage as a problem of subfertility in assisted reproduction units, others believe that miscarriage occurs in super-fertile women. Infertile women undergoing assisted reproduction are at a greater risk of having a miscarriage especially at an advanced age compared with women conceiving naturally. Aberrant expression of immunological factors and chromosomal abnormalities underlie both infertility and miscarriage. Common risk factors include increased maternal age, obesity, smoking, alcohol, pre-existing medical conditions and anatomical abnormalities of the reproductive system. Management pathways of both conditions may be similar with pre-implantation genetic testing and assisted reproductive technology used in both conditions. This paper discusses the synergies and differences between the two conditions in terms of their epidemiology, etiopathogenesis, risk factors and management strategies. The two conditions are related as degrees of severity of reproductive failure with common pathways in manifestation and management. PMID- 26238302 TI - Effects of psychosocial variables in the similarity and interdependence of physical activity levels among adolescent best friend dyads. AB - Given that physical activity (PA) tends to decrease with age during adolescence, addressing factors that affect change is important. This study examined the similarity and interdependence of PA as influenced by psychosocial factors among adolescent best friend dyads. A total of 660 adolescents, representing 330 best friend dyads, completed questionnaires with regard to PA, sitting time, perceived exercise benefits and barriers, physical self-perception and social support for PA. Dyads were also identified as reciprocal and non-reciprocal best friends; reciprocal means that both considered each other best friends and non-reciprocal were those in which only one considered the other a best friend. Data were analysed using a hierarchical linear model framework. Results indicated significant similarities between reciprocal best friend dyads for PA and sitting time, and for sitting time in non-reciprocal best friends (P values <.01). Psychosocial variables were associated with PA in reciprocal best friend dyads and with sitting time in reciprocal and non-reciprocal best friend dyads. Best friend gender, regular sports practice of the person, perceived exercise barriers of the best friend and best friend social support were the best predictors for PA. PMID- 26238303 TI - Dendrimer-encapsulated Pt nanoparticles with peroxidase-mimetic activity as biocatalytic labels for sensitive colorimetric analyses. AB - We demonstrate the feasible use of Pt nanoparticles encapsulated inside amine terminated fourth-generation polyamidoamine dendrimers as peroxidase-mimetic labels for sensitive colorimetric assays. This was performed by utilizing intrinsic dual functionalities of the dendrimer-encapsulated Pt nanoparticles, i.e. peroxidase-like activity and multiple conjugation sites. PMID- 26238305 TI - Surgical management of pituitary metastases. AB - BACKGROUND: Pituitary metastases are rare and commonly described in case reports or small case series. Due to its rarity this entity is not subject to standardized treatment guidelines, there is debate about typical initial symptoms that may lead to finding the correct diagnosis and information about the clinical course is also sparse. METHODS: We have conducted a retrospective analysis of patients with pituitary metastases who were surgically treated via a transsphenoidal procedure at our institution between 2006 and 2014. Underlying primary disease, clinical and surgical course as well as adjuvant radiotherapy and follow-up data are presented. RESULTS: 14 patients met the inclusion criteria (8 female, 6 male). Mean age was 61.5 years. Most patients became symptomatic with visual symptoms--both visual deterioration and/or diplopia (n = 13)--and anterior lobe insufficiency (n = 8). Surprisingly diabetes insipidus was only seen in three patients. All patients underwent transsphenoidal surgery initially, four patients had to undergo surgery for residual tumor or recurrence, two of them via a transcranial route. Breast cancer was the most common entity (n = 6), followed by prostate cancer (n = 3), nsclc (n = 2) and melanoma, thyroid cancer and renal cancer in one case each. Postoperative MRI showed gross total resection in four cases and residual disease in eight cases (subtotal resection, partial resection and biopsy), two patients files were incomplete regarding MRI-results. All patients underwent adjuvant radiotherapy. Survival after the initial diagnosis of cancer was 36 and 16 months after diagnosis of pituitary metastases. CONCLUSION: Our results indicate that transsphenoidal surgery is a safe method to resect pituitary metastases and that the extend of resection does not have an influence on survival time. Our results also indicate that diabetes insipidus may not be the most common initial symptom of pituitary metastases and lack thereof should not lead to making a wrong diagnosis and delaying appropriate therapy. PMID- 26238306 TI - Cardiac toxicity in the radiation treatment of esophageal cancer: an emerging concern. PMID- 26238304 TI - Gene expression in prolactinomas: a systematic review. AB - INTRODUCTION: Prolactinomas are the most common functional pituitary adenomas. Current classification systems rely on phenotypic elements and have few molecular markers for complementary classification. Treatment protocols for prolactinomas are also devoid of molecular targets, leaving those refractory to standard treatments without many options. METHODS: A systematic literature review was performed utilizing the PRISMA guidelines. We aimed to summarize prior research exploring gene and protein expression in prolactinomas in order to highlight molecular variations associated with tumor development, growth, and prolactin secretion. A PubMed search of select MeSH terms was performed to identify all studies reporting gene and protein expression findings in prolactinomas from 1990 to 2014. RESULTS: 1392 abstracts were screened and 51 manuscripts were included in the analysis, yielding 54 upregulated and 95 downregulated genes measured by various direct and indirect analytical methods. Of the many genes identified, three upregulated (HMGA2, HST, SNAP25), and three downregulated (UGT2B7, Let7, miR-493) genes were selected for further analysis based on our subjective identification of strong potential targets. CONCLUSIONS: Many significant genes have been identified and validated in prolactinomas and most have not been fully analyzed for therapeutic and diagnostic potential. These genes could become candidate molecular targets for biomarker development and precision drug targeting as well as catalyze deeper research efforts utilizing next generation profiling/sequencing techniques, particularly genome scale expression and epigenomic analyses. PMID- 26238307 TI - Combination of L-gossypol and low-concentration doxorubicin induces apoptosis in human synovial sarcoma cells. AB - The current study aimed to investigate the function of L-gossypol and low concentration doxorubicin (LCD) in the apoptosis of SW982 human synovial sarcoma cells (HSSCs). Wright-Giemsa staining, Hoechst 33258 staining and transmission electron microscopy were used to identify cellular morphological alterations. In addition, an MTT assay was performed to measure the inhibitory rate of the drug, flow cytometry was used to detect alterations in apoptosis and the cell cycle, and western blot analysis was used to detect Bcl-2 and Bax protein expression levels. Furthermore, the activity levels of caspase-3 and -9 were measured in apoptotic cells. Following combination therapy, significant alterations in cellular morphology were observed, including condensation of the nucleus and formation of apoptotic bodies. Cell growth was demonstrated to be inhibited significantly in a dose- and time-dependent manner. Flow cytometry results indicated that L-gossypol administration resulted in G1 phase arrest, whereas doxorubicin led to S phase arrest. Combination therapy resulted in a significant increase in the number of S phase-arrested cells. Following treatment with the drugs, Bcl-2 protein levels were observed to be reduced whilst Bax levels increased, and significant caspase-3 and -9 activation was observed during combination therapy. Combination therapy with L-gossypol and LCD inhibited cell proliferation and induced apoptosis in SW982 HSSCs at a significantly greater level compared with either treatment alone. It was hypothesized that these effects are mediated via downregulation of the Bcl-2 protein and upregulation of Bax protein. PMID- 26238308 TI - Endovascular Versus Open Repair as Primary Strategy for Ruptured Abdominal Aortic Aneurysm: A National Population-based Study. AB - OBJECTIVE/BACKGROUND: In randomized trials, no peri-operative survival benefit has been shown for endovascular (EVAR) repair of ruptured abdominal aortic aneurysm (rAAA) when compared with open repair. The aim of this study was to investigate the effect of primary repair strategy on early and midterm survival in a non-selected population based study. METHODS: The Swedish Vascular Registry was consulted to identify all rAAA repairs performed in Sweden in the period 2008 12. Centers with a primary EVAR strategy (treating > 50% of rAAA with EVAR) were compared with centers with a primary open repair strategy. Peri-operative outcome, midterm survival, and incidence of rAAA repair/100,000 inhabitants aged > 50 years were assessed. RESULTS: In total, 1,304 patients were identified. Three primary EVAR centers (pEVARc) operated on 236 patients (74.6% EVAR). Twenty six primary open repair centers (pORc) operated 1,068 patients (15.6% EVAR). Patients treated at pEVARc were more often referrals (28.0% vs. 5.3%; p < .01), had a higher rate of respiratory comorbidity (36.5% vs. 21.9%; p < .01), and higher pre-operative systolic blood pressure (84.3 vs. 72.3 mmHg; p < .01). There was no difference in mortality based on primary treatment strategy at 30 days (pEVARc 28.0%, n = 66; pORc 27.4%, n = 296 [p = .87]), 1 year (pEVARc 39.9%, n = 93; pORc 34.7%, n = 366 [p = .19]), or 2 years (42.1%, n = 94; 38.3%, n = 394 [p = .28]), either overall or in subgroups based on age or referral status. Overall, patients treated with EVAR were older (mean age 76.4 vs. 74.0 years; p < .01), and had a lower 30 day mortality (EVAR 21.6%, n = 74; odds ratio 29.6%, n = 288 [p = < .01]). Incidence of rAAA repair was lower in pEVARc regions (6.07, 95% confidence interval [CI] 5.01-7.13) when compared with pORc regions (8.15, 95% CI 7.64-8.66). CONCLUSION: There was no difference in mortality after rAAA repair among centers with a primary EVAR approach when compared with a primary open repair strategy, either peri-operatively or in the midterm. The study supports the early findings of the randomized controlled trials in a national population based setting. PMID- 26238309 TI - The May-Husni Procedure: A Reappraisal. AB - OBJECTIVES: The May-Husni procedure is a rarely used saphenofemoral venous bypass because of the small number of patients with post-thrombotic segmental femoral vein obstruction alone and the lack of validated selection criteria. There are only a few institutional series reporting the use of this technique. The purpose of this report is to present the author's experience and critically review the literature. METHODS: Within a 13 year period 12 patients with venous claudication, skin pigmentation, and severe pain and swelling of their legs underwent the May-Husni procedure. Their median age was 57 years (41-69 years). Imaging showed segmental venous obstruction of the femoral vein in all patients and poor or no inflow from the deep femoral vein. Two patients were lost to follow up and the remaining 10 patients were reviewed with a median follow up of 60 months (26-72 months). RESULTS: The saphenopopliteal bypass remained patent in all patients at follow up. The development of reflux of the saphenous conduit in four patients did not affect the clinical improvement. Venous claudication resolved, hyper-pigmentation improved, and pain was relieved in all patients. Recanalization of the femoral vein 3 years following thrombosis was followed by recurrence of the post-thrombotic symptoms in two patients. CONCLUSIONS: These results indicate that a highly selected subgroup of patients with severe symptomatic post-thrombotic syndrome secondary to chronic segmental obstruction of the femoral vein do well after the May-Husni procedure. In order to refine the criteria for the selection of patients who may benefit from this operation, there is a need for more studies that use a combination of hemodynamic and validated scales that diagnose and grade the severity of post-thrombotic syndrome. PMID- 26238310 TI - Determination of ABO blood group genotypes using the real-time loop-mediated isothermal amplification method. AB - ABO genotyping is commonly used in several situations, including blood transfusion, personal identification and disease detection. The present study developed a novel method for ABO genotyping, using loop-mediated isothermal amplification (LAMP). This method allows the simultaneous determination of six ABO genotypes under 40 min at a constant temperature of 62C. The genotypes of 101 blood samples were determined to be AA (n=6), AO (n=38), BB (n=12), BO (n=29), AB (n=8) and OO (n=8) by the LAMP assay. The results were compared with the phenotypes determined by serological assay and the genotypes determined by direct sequencing, and no discrepancies were observed. This novel and rapid method, with good accuracy and reasonably cost effective, provides a supplement to routine serological ABO typing and may also be useful in other point-of-care testing. PMID- 26238311 TI - Revelation of the Technological Versatility of the Eu(TTA)3Phen Complex by Demonstrating Energy Harvesting, Ultraviolet Light Detection, Temperature Sensing, and Laser Applications. AB - We synthesized the Eu(TTA)3Phen complex and present herein a detailed study of its photophysics. The investigations encompass samples dispersed in poly(vinyl alcohol) and in ethanol in order to explore the versatile applicability of these lanthanide-based materials. Details upon the interaction between Eu, TTA, and the Phen ligands are revealed by Fourier transform infrared and UV-visible absorption, complemented by steady state and temporally resolved emission studies, which provide evidence of an efficient energy transfer from the organic ligands to the central Eu(3+) ion. The material produces efficient emission even under sunlight exposure, a feature pointing toward suitability for luminescent solar concentrators and UV light sensing, which is demonstrated for intensities as low as 200 nW/cm(2). The paper further promotes the complex's capability to be used as luminescence-based temperature sensor demonstrated by the considerable emission intensity changes of ~4.0% per K in the temperature range of 50-305 K and ~7% per K in the temeperature range 305-340 K. Finally, increasing the optical excitation causes both spontaneous emission amplification and emission peak narrowing in the Eu(TTA)3Phen complex dispersed in poly(vinyl alcohol) - features indicative of stimulated emission. These findings in conjunction with the fairly large stimulated emission cross-section of 4.29 * 10(-20) cm(2) demonstrate that the Eu(TTA)3Phen complex dispersed in poly(vinyl alcohol) could be a very promising material choice for lanthanide-polymer based laser architectures. PMID- 26238312 TI - The Perception of Threat from Emotions in Predicting Binge Eating Behaviours in People Who Are Obese and Seeking Treatment for Their Weight. AB - OBJECTIVE: The affect regulation theory suggests that people binge eat to regulate negative emotional states. In this study, we used a basic emotions perspective to consider the role of perceived threat of emotions, emotional suppression and reduced emotional expressiveness in predicting binge eating behaviours in people who are obese. METHOD: Treatment-seeking participants with obesity (N = 51, body mass index range from 30.8 to 60.2 kg m-2 ) completed measures of 'perception of threat from emotion' as well as 'emotional expressiveness' and binge eating. RESULTS: The results demonstrated that perceived threat of sadness predicted binge eating (beta = .55, p < .05). Additionally, a mediation analysis revealed that reduced emotional expressiveness mediated the relationship between perceived threat of fear and binge eating (beta = .25, 95%). DISCUSSION: These findings are contextualized within a theoretical perspective that suggests that individuals who binge eat are threatened by certain emotional states and they use binge eating to suppress certain, but not all, emotional states. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Considering basic emotions within binge eating should be a part of a psychological assessment and treatment. This should consider how emotions could often be perceived as being threatening and their expression is limited. It is possible that the emotions of fear and sadness appear to be particularly threatening within binge eating/obese populations. PMID- 26238313 TI - Nematic liquid crystals confined in microcapillaries for imaging phenomena at liquid-liquid interfaces. AB - Here, we report the development of an experimental system based on liquid crystals (LCs) confined in microcapillaries for imaging interfacial phenomena. The inner surfaces of the microcapillaries were modified with octadecyltrichlorosilane to promote an escaped-radial configuration of LCs. We checked the optical appearance of the capillary-confined LCs under a crossed polarizing microscope and determined their arrangement based on side and top views. We then placed the capillary-confined LCs in contact with non-surfactant and surfactant solutions, producing characteristic textures of two bright lines and a four-petal shape, respectively. We also evaluated the sensitivity, stability, and reusability of the system. Our imaging system was more sensitive than previously reported LC thin film systems. The textures formed in microcapillaries were stable for more than 120 h and the capillaries could be reused at least 10 times. Finally, we successfully applied our system to image the interactions of phospholipids and bivalent metal ions. In summary, we developed a simple, small, portable, sensitive, stable, and reusable experimental system that can be broadly applied to monitor liquid-liquid interfacial phenomena. These results provide valuable information for designs using confined LCs as chemoresponsive materials in optical sensors. PMID- 26238314 TI - Diagnostic transcranial magnetic stimulation as a prognostic tool in children with acute transverse myelitis. AB - STUDY DESIGN: We performed transcranial magnetic stimulation (TMS) in children with sequelae of acute transverse myelitis. Single-pulse TMS protocol was implemented. Twenty controls and 24 patients with myelitis were enrolled. TMS was performed on 12-24 day after the onset of the first symptoms, average on 16th day. OBJECTIVES: The objective of our study was to evaluate motor pathways in children with viral myelitis using the TMS technique. SETTING: All investigations were performed in Scientific Research Institute for Children's Infections, Russia. RESULTS: There were statistically significant differences between the groups on central motor conduction time and motor evoked potential (MEPs) amplitudes. MEP thresholds were elevated, and MEP shape was abnormal in 96% of patients with myelitis (n=23). Three neurophysiologic patterns were observed: the presence of both cortical and spinal MEP, the absence of cortical MEP with the spinal MEP present and the total absence of both cortical and spinal MEP. Last finding was associated with paraplegia, resistant to any sort of treatment. CONCLUSION: Thus, myelitis in 96% of the cases causes neurophysiologic changes, which may be detected by TMS; the method may be used as a predicting tool. PMID- 26238315 TI - Clinical characteristics and surgical outcome of thoracic myelopathy caused by ossification of the ligamentum flavum: a retrospective analysis of 85 cases. AB - STUDY DESIGN: A retrospective comparative study. OBJECTIVES: To describe the clinical features and radiological findings, to assess the safety and effectiveness of posterior decompressive laminectomy and resection of the ossification of the ligamentum flavum (OLF), and to determine which presurgical and surgical variables were most closely related to postsurgical prognosis of thoracic myelopathy (TM) caused by OLF in China. METHODS: Eighty-five patients with the diagnosis of TM caused by OLF received surgical treatment from July 1998 to May 2012. Clinical data were collected from medical and operative records. Correlations between the surgical outcome and various factors were also analyzed. RESULTS: All cases were followed up for a mean of 49.2 months (range, 24-190 months) postoperatively. The mean Japanese Orthopaedic Association score was 3.8 points preoperatively and 8.2 points at the final follow-up, yielding a mean recovery rate of 63.0%. Postoperative complications included transient neurological deficits (9 cases), persistent neurological deficits (4 cases), dural tears (17 cases), cerebrospinal fluid leakage (9 cases), wound dehiscence (2 cases) and wound infection (3 cases). The OLF level (middle thoracic), preoperative duration of symptoms, intramedullary signal change on T2WI and preoperative severity of myelopathy were important predictors of surgical outcome. CONCLUSIONS: Biomechanical and anatomical factors may have a key role in thoracic OLF progression. Posterior decompressive laminectomy and resection of the OLF can be considered an effective, reliable and safe alternative procedure. The OLF level, preoperative duration of symptoms, intramedullary signal change on T2WI and preoperative severity of myelopathy were confirmed and significantly correlated with the surgical outcome. PMID- 26238316 TI - Functional impact of multidisciplinary outpatient program on patients with chronic complete spinal cord injury. AB - STUDY DESIGN: Prospective study. OBJECTIVES: The objective of this study was to determine whether an integrated and an intensive outpatient program would result in functional improvement of spinal cord injury (SCI) patients with American Spinal Injury Association Impairment Scale (AIS) A injuries as measured by the Spinal Cord Independence Measure (SCIM III). SETTING: Patient recruitment and evaluations were conducted at the Brain and Spinal Injury Repair Research Centre (BASIR), Tehran, Iran. METHODS: Observed SCIM III scores and SCI Ability Realization Measurement Index changes were used to measure the change in 134 patients with complete SCI (AIS A), after participation in an outpatient rehabilitation program consisting of a bimonthly multidisciplinary education program, combined with a twice-weekly occupational therapy, physical therapy and home nursing as a rehabilitation package for a 6-month period. RESULTS: A significant increase in median total SCIM III scores following comparison of 'pre treatment' scores and final 'post-treatment' scores (9.5 score, P<0.001) was found. The increase in final SCIM III scores was highest in lower cervical (8.75 scores) and thoracic cases (13.5 scores). With the exception of high cervical patients, all subgroups had a significant SCIM III score improvement. CONCLUSION: Multidisciplinary, outpatient rehabilitation programs are recommended as a safe and an effective post-injury rehabilitation for AIS A SCI patients. Such programs may complement inpatient rehabilitation and promote functional recovery. Multidisciplinary outpatient programs are effective in achieving long-term independence in SCI patients and reducing the cost of care for developing countries. This study suggests that high cervical injuries benefit more from inpatient programs. PMID- 26238317 TI - Pelvic floor muscle training in spinal cord injury and its impact on neurogenic detrusor over-activity and incontinence. AB - STUDY DESIGN: Two case studies. OBJECTIVES: To determine whether 6 weeks of regular pelvic floor muscle training (PFMT) can improve the strength and endurance of voluntary contractions in incomplete spinal cord injury and reduce neurogenic detrusor over-activity (NDO) and incontinence. SETTING: The London Spinal Cord Injury Centre, Stanmore, London, UK. METHODS: A 6-week programme of PFMT was conducted in two male subjects with stable supra-sacral motor incomplete (AIS C and D) spinal cord injuries. Clinical evaluations before and after training comprised measures of strength and endurance of voluntary pelvic floor contractions both objectively by anal canal-pressure measurements and subjectively using the modified Oxford grading system. NDO was determined by standard urodynamic tests of bladder function and incontinence measured by the International Consultation on Incontinence Questionnaire-Urology. RESULTS: Both subjects improved the strength and endurance of their pelvic floor muscle contractions by over 100% at the end of training. After training, Subject 1 (AIS D) was able to reduce bladder pressure during over-activity almost completely by voluntarily contracting the pelvic floor muscles. Subject 2 (AIS C) achieved a lesser reduction overall after training. Continence improved only in subject 1. CONCLUSION: These case studies provide evidence that a 6-week programme of PFMT may have a beneficial effect on promoting voluntary control of NDO and reduce incontinence in selected cases with a motor incomplete spinal cord lesion. PMID- 26238319 TI - Eight new cycloartane triterpenoids from Beesia calthifolia with hepatoprotective effects against D-galactosamine induced L02 cell damage. AB - Fourteen 20,24-epoxy-cycloartane triterpenoids, including eight new ones (1-8), were isolated from 95% ethanol extract of the rhizomes of Beesia calthifolia. Their structures were determined by spectroscopic and chemical methods, especially 2D NMR and HRMS techniques. Among them, four new compounds (1-4) possess carbonyl groups at C-16, which were rarely found in cycloartane triterpenoids from this genus. Relative configuration at C-12 in beesioside III (9) and its aglycone (10) was revised to be 12alpha-OH rather than the reported 12beta-OH. Some of the compounds showed potential hepatoprotective activities against human hepatic L02 cell damage induced by d-galactosamine. PMID- 26238318 TI - Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2. AB - Deregulated redox metabolism in cancer leads to oxidative damage to cellular components including deoxyribonucleoside triphosphates (dNTPs). Targeting dNTP pool sanitizing enzymes, such as MTH1, is a highly promising anticancer strategy. The MTH2 protein, known as NUDT15, is described as the second human homologue of bacterial MutT with 8-oxo-dGTPase activity. We present the first NUDT15 crystal structure and demonstrate that NUDT15 prefers other nucleotide substrates over 8 oxo-dGTP. Key structural features are identified that explain different substrate preferences for NUDT15 and MTH1. We find that depletion of NUDT15 has no effect on incorporation of 8-oxo-dGTP into DNA and does not impact cancer cell survival in cell lines tested. NUDT17 and NUDT18 were also profiled and found to have far less activity than MTH1 against oxidized nucleotides. We show that NUDT15 is not a biologically relevant 8-oxo-dGTPase, and that MTH1 is the most prominent sanitizer of the cellular dNTP pool known to date. PMID- 26238320 TI - Chemical constituents of Miliusa balansae leaves and inhibition of nitric oxide production in lipopolysaccharide-induced RAW 264.7 cells. AB - Methanolic extract of Miliusa balansae Finet et Gagnep exerts an anti inflammatory effect via inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophage cells. Three new megastigmane glycosides, milbasides A-C (1-3), together with fifteen known compounds (4-18), were isolated from the active fraction. Their chemical structures were elucidated using extensive spectroscopic analyses, including 1D and 2D NMR, HR ESI MS, and CD analysis, as well as comparison with previously reported data. Compounds 1-3, 11 and 14 (20.0 MUM) showed potent inhibitory activities with inhibition values of 98.5 +/- 1.6%, 90.9 +/- 7.8%, 84.8 +/- 3.5%, 91.5 +/- 8.7%, and 91.8 +/- 2.7%, respectively. Our results suggest that megastigmane glycosides from M. balansae leaves may be used to treat inflammatory diseases. PMID- 26238321 TI - Identification of amino acid appended acridines as potential leads to anti-cancer drugs. AB - In order to develop the amino acid appended acridines as potential leads for anticancer drugs, they were subjected to preliminary investigations. Screening through MTT assay as well as the phase contrast micrographs and Confocal images of immunostained C6 Glioma cells for markers such as alpha-tubulin, GFAP, mortalin and HSP-70 cells indicated that the compounds possess significant antiproliferative activity. The compounds also arrested cells in G0/G1 phase of the cell cycle as indicated by flow cytometry results. Moreover, the upregulation of the senescence markers such as mortalin and HSP70 in the presence of compounds 8, 9 and 12 indicate their senescence inducing potential. PMID- 26238322 TI - Indolylpiperidine derivatives as potent and selective alpha1B adrenoceptor antagonists. AB - A series of novel indolylpiperidine derivatives were synthesized, and their pharmacological profiles were assessed at rat alpha1A and alpha1B adrenoceptors through in vitro binding studies. Compound 12 (2-(3-(4-(6-fluoro-1H-indol-3 yl)piperidin-1-yl)propyl)-1,2,3,4-tetrahydroisoquinoline) was a potent alpha1B adrenoceptor antagonist (Ki=0.61 nM) and was about 40-fold more selective for the alpha1B adrenoceptor than for the alpha1A adrenoceptor. In addition, useful structure-activity relationship information was acquired for further improving selectivity for the alpha1B adrenoceptor. PMID- 26238323 TI - Discovery and structure-guided optimization of tert-butyl 6-(phenoxymethyl)-3 (trifluoromethyl)benzoates as liver X receptor agonists. AB - To obtain potent liver X receptor (LXR) agonists, a structure-activity relationship study was performed on a series of tert-butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improved the pharmacokinetic profile in mice, respectively. The obtained compound 32b increased blood ABCA1 mRNA expression without plasma TG elevation in both mice and cynomolgus monkeys. PMID- 26238324 TI - Synthesis and biological evaluation of levofloxacin core-based derivatives with potent antibacterial activity against resistant Gram-positive pathogens. AB - A series of C10 non-basic building block-substituted, levofloxacin core-based derivatives were synthesized in 43-86% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. The quinolone (S)-9-fluoro-10-(4-hydroxypiperidin-1-yl)-3-methyl-7-oxo 3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid L-arginine tetrahydrate exhibited superior antibacterial activity against quinolone susceptible and resistant strains compared with the clinically used fluoroquinolones ciprofloxacin, levofloxacin, moxifloxacin, penicillin, and vancomycin, especially to the methicillin-resistant Staphylococcus aureus clinical isolates, penicillin-resistant Streptococcus pneumoniae clinical isolates, and Streptococcus pyogenes. PMID- 26238325 TI - Identification of Two Novel Modifications at Tryptophan Residues. AB - Protein post-translational modifications (PTMs) play important roles in cellular physiology. Mass spectrometry (MS) has been developed into a powerful tool to identify all possible protein modifications. Herein, we describe our efforts to deduce the structures of two unknown modifications at tryptophan (Trp) residues (W + 92 Da and W + 108 Da). The two modifications were further confirmed by aligning the MS/MS fragmentation of synthetic peptide with in-vivo peptide identified. Finally, the mimic experiment elucidated how two Trp modifications occur. This study, therefore, expands current knowledge of Trp modifications. PMID- 26238326 TI - Using SEQUEST with theoretically complete sequence databases. AB - SEQUEST has long been used to identify peptides/proteins from their tandem mass spectra and protein sequence databases. The algorithm has proven to be hugely successful for its sensitivity and specificity in identifying peptides/proteins, the sequences of which are present in the protein sequence databases. In this work, we report on work that attempts a new use for the algorithm by applying it to search a complete list of theoretically possible peptides, a de novo-like sequencing. We used freely available mass spectral data and determined a number of unique peptides as identified by SEQUEST. Using masses of these peptides and the mass accuracy of 0.001 Da, we have created a database of all theoretically possible peptide sequences corresponding to the precursor masses. We used our recently developed algorithm for determining all amino acid compositions corresponding to a mass interval, and used a lexicographic ordering to generate theoretical sequences from the compositions. The newly generated theoretical database was many-fold more complex than the original protein sequence database. We used SEQUEST to search and identify the best matches to the spectra from all theoretically possible peptide sequences. We found that SEQUEST cross-correlation score ranked the correct peptide match among the top sequence matches. The results testify to the high specificity of SEQUEST when combined with the high mass accuracy for intact peptides. Graphical Abstract ?. PMID- 26238327 TI - Nanomanipulation-Coupled Matrix-Assisted Laser Desorption/ Ionization-Direct Organelle Mass Spectrometry: A Technique for the Detailed Analysis of Single Organelles. AB - We describe a novel technique combining precise organelle microextraction with deposition and matrix-assisted laser desorption/ionization (MALDI) for a rapid, minimally invasive mass spectrometry (MS) analysis of single organelles from living cells. A dual-positioner nanomanipulator workstation was utilized for both extraction of organelle content and precise co-deposition of analyte and matrix solution for MALDI-direct organelle mass spectrometry (DOMS) analysis. Here, the triacylglycerol (TAG) profiles of single lipid droplets from 3T3-L1 adipocytes were acquired and results validated with nanoelectrospray ionization (NSI) MS. The results demonstrate the utility of the MALDI-DOMS technique as it enabled longer mass analysis time, higher ionization efficiency, MS imaging of the co deposited spot, and subsequent MS/MS capabilities of localized lipid content in comparison to NSI-DOMS. This method provides selective organellar resolution, which complements current biochemical analyses and prompts for subsequent subcellular studies to be performed where limited samples and analyte volume are of concern. Graphical Abstract ?. PMID- 26238328 TI - Current Status of Prostate Artery Embolization for Lower Urinary Tract Symptoms: Review of World Literature. AB - Prostate artery embolization has emerged as a promising treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia. However, although it has gained increasing attention in radiology literature, it remains under-reported from a urologic perspective. We aim at providing an up-to-date review of this minimally invasive technique. Evidence suggests it is a promising and effective option for patients with large prostate volumes, multiple comorbidities, and suboptimal results from pharmacotherapy. Larger, randomized studies with longer follow-up periods are needed for this technique to be formally established in the urology community. PMID- 26238329 TI - Standardized Six-Step Approach to the Performance of the Focused Basic Obstetric Ultrasound Examination. AB - OBJECTIVES: This study aims to validate the feasibility and accuracy of a new standardized six-step approach to the performance of the focused basic obstetric ultrasound examination, and compare the new approach to the regular approach performed in the scheduled obstetric ultrasound examination. STUDY DESIGN: A new standardized six-step approach to the performance of the focused basic obstetric ultrasound examination, to evaluate fetal presentation, fetal cardiac activity, presence of multiple pregnancy, placental localization, amniotic fluid volume evaluation, and biometric measurements, was prospectively performed on 100 pregnant women between 18(+0) and 27(+6) weeks of gestation and another 100 pregnant women between 28(+0) and 36(+6) weeks of gestation. The agreement of findings for each of the six steps of the standardized six-step approach was evaluated against the regular approach. RESULTS: In all ultrasound examinations performed, substantial to perfect agreement (Kappa value between 0.64 and 1.00) was observed between the new standardized six-step approach and the regular approach. CONCLUSION: The new standardized six-step approach to the focused basic obstetric ultrasound examination can be performed successfully and accurately between 18(+0) and 36(+6) weeks of gestation. This standardized approach can be of significant benefit to limited resource settings and in point of care obstetric ultrasound applications. PMID- 26238330 TI - Blue space geographies: Enabling health in place. AB - Drawing from research on therapeutic landscapes and relationships between environment, health and wellbeing, we propose the idea of 'healthy blue space' as an important new development Complementing research on healthy green space, blue space is defined as; 'health-enabling places and spaces, where water is at the centre of a range of environments with identifiable potential for the promotion of human wellbeing'. Using theoretical ideas from emotional and relational geographies and critical understandings of salutogenesis, the value of blue space to health and wellbeing is recognised and evaluated. Six individual papers from five different countries consider how health can be enabled in mixed blue space settings. Four sub-themes; embodiment, inter-subjectivity, activity and meaning, document multiple experiences within a range of healthy blue spaces. Finally, we suggest a considerable research agenda - theoretical, methodological and applied for future work within different forms of blue space. All are suggested as having public health policy relevance in social and public space. PMID- 26238332 TI - Treatment of iliac artery bifurcation aneurysms with the second-generation straight iliac bifurcated device. AB - BACKGROUND: There are few long term studies to show the safety and efficacy of iliac artery aneurysm exclusion, especially in regards to the straight iliac branched device. The objective of our study was to add our data with a mean follow-up of 32 months to the existing data available. METHODS: Patients undergoing iliac bifurcation procedure either as standalone or in combination with abdominal aortic aneurysm exclusion at two vascular centers had data prospectively gathered between 2004 and 2014. Collected data was analyzed for baseline characteristics, procedural events, and clinical follow-up; variables included endoleaks, reinterventions, and internal iliac artery (IIA) closure. RESULTS: A total of 45 iliac vessels in 41 patients (36 male) with a mean age of 70.4 years were treated with the iliac branched device. Procedural success was achieved in 85% (35/41) of patients and 87% (39/45) vessels with no intraoperative death. Of the six technical failures, three occurred due to failure to place the straight iliac branched device or stent properly. Two occurred because of endoleaks at the end of the procedure, and one occurred because the IIA side-branch occluded and could not be reopened. The mean patient follow-up was 32.0 +/- 27.3 months (range, 0-109 months). During this time period, the IIA patency rate on an intention-to-treat basis was 81%, and the freedom from endoleak rate on an intention-to-treat basis was 76% per patient. The freedom from reintervention per patient was 75%. No patient reported symptoms of pelvic ischemia and permanent buttock claudication. CONCLUSIONS: In this study with mean follow-up of 32 months, treatment with iliac bifurcated devices is a safe and durable option in a carefully selected population of patients with iliac artery bifurcation aneurysms. PMID- 26238331 TI - Lycorine suppresses RANKL-induced osteoclastogenesis in vitro and prevents ovariectomy-induced osteoporosis and titanium particle-induced osteolysis in vivo. AB - Osteoclasts play an important role in diseases involving bone loss. In this study, we assessed the effect of a plant-derived natural alkaloid (lycorine, or LY) on osteoclastogenesis in vitro and in vivo. Our in vitro study showed that receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis could be inhibited by LY; this effect was due to inhibition of mitogen-activated protein kinase (MAPK) signalling via MAP kinase kinases (MKKs). The MAPK agonist anisomycin could partially rescue the inhibitory effect of LY. Furthermore, LY also played a protective role in both a murine ovariectomy (OVX) induced osteoporosis model and a titanium particle-induced osteolysis model. These results confirmed that LY was effective in preventing osteoclast-related diseases in vivo. In conclusion, our results show that LY is effective in suppressing osteoclastogenesis and therefore could be used to treat OVX-induced osteoporosis and wear particle-induced osteolysis. PMID- 26238333 TI - MicroRNA deregulation in symptomatic carotid plaque. AB - OBJECTIVE: Embolization of carotid stenotic plaques is the direct cause of stroke in nearly 20% of cases. Genetic mechanisms and especially the roles played by microRNAs in the regulation of plaque destabilization and rupture are mostly unknown. The aim of this pilot study was to compare the expression of seven microRNAs allegedly involved in plaque growth and instability (miR-100, 125a, 127, 133a, 145, 155, and 221), between symptomatic and asymptomatic human carotid plaques. METHODS: Thirty patients undergoing carotid endarterectomy in our department were prospectively included. Carotid plaques were subdivided into symptomatic (n = 15) and asymptomatic (n = 15) according to the presence or absence of stroke. After isolation of total RNA from atherosclerotic plaques, microRNAs were quantified by real-time polymerase chain reaction. RESULTS: The two groups of patients were comparable in terms of age, gender, risk factors for cerebral ischemia, medication, and stenosis severity. All seven microRNAs were quantified in extracted carotid plaques. miR-100, miR-125a, miR-127, miR-133a, miR-145, and miR-221 were significantly overexpressed in symptomatic vs asymptomatic plaques. miR-125a expression was significantly inversely correlated with the circulating level of low-density lipoprotein cholesterol in the symptomatic group. CONCLUSIONS: This pilot study evaluated the expression of seven selected miRNAs in human carotid plaques from a small group of patients and suggested a potential regulatory role for these miRNAs in evolution of the plaque towards growth, instability and rupture. Studies based on larger sample sizes are required to determine the potential use of miR-100, miR-125a, miR-127, miR-133a, miR-145, and miR-221 as biomarkers or therapeutic targets for stroke. PMID- 26238334 TI - Comprehensive functional characterization of murine infantile Batten disease including Parkinson-like behavior and dopaminergic markers. AB - Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten disease) is a neurodegenerative lysosomal storage disease caused by a deficiency in palmitoyl protein thioesterase-1 (PPT1). The PPT1-deficient mouse (Cln1(-/-)) is a useful phenocopy of human INCL. Cln1(-/-) mice display retinal dysfunction, seizures, motor deficits, and die at ~8 months of age. However, little is known about the cognitive and behavioral functions of Cln1(-/-) mice during disease progression. In the present study, younger (~1-2 months of age) Cln1(-/-) mice showed minor deficits in motor/sensorimotor functions while older (~5-6 months of age) Cln1(-/ ) mice exhibited more severe impairments, including decreased locomotor activity, inferior cued water maze performance, decreased running wheel ability, and altered auditory cue conditioning. Unexpectedly, certain cognitive functions such as some learning and memory capabilities seemed intact in older Cln1(-/-) mice. Younger and older Cln1(-/-) mice presented with walking initiation defects, gait abnormalities, and slowed movements, which are analogous to some symptoms reported in INCL and parkinsonism. However, there was no evidence of alterations in dopaminergic markers in Cln1(-/-) mice. Results from this study demonstrate quantifiable changes in behavioral functions during progression of murine INCL and suggest that Parkinson-like motor/sensorimotor deficits in Cln1(-/-) mice are not mediated by dopamine deficiency. PMID- 26238335 TI - High-throughput and quantitative genome-wide messenger RNA sequencing for molecular phenotyping. AB - BACKGROUND: We present a genome-wide messenger RNA (mRNA) sequencing technique that converts small amounts of RNA from many samples into molecular phenotypes. It encompasses all steps from sample preparation to sequence analysis and is applicable to baseline profiling or perturbation measurements. RESULTS: Multiplex sequencing of transcript 3' ends identifies differential transcript abundance independent of gene annotation. We show that increasing biological replicate number while maintaining the total amount of sequencing identifies more differentially abundant transcripts. CONCLUSIONS: This method can be implemented on polyadenylated RNA from any organism with an annotated reference genome and in any laboratory with access to Illumina sequencing. PMID- 26238336 TI - Complications from first-trimester aspiration abortion: a systematic review of the literature. AB - OBJECTIVE: We conducted a systematic review to examine the prevalence of minor and major complications following first-trimester aspiration abortion requiring medical or surgical intervention. STUDY DESIGN: We searched PubMed, Cumulative Index to Nursing and Allied Health Literature, Scopus and the Cochrane Library for articles published between 1980 and April 2015 that reported on repeat aspiration, hemorrhage, infection, cervical/vaginal trauma, uterine perforation, abdominal surgery, hospitalization, anesthesia-related complications and death. We limited our review to studies that included >=100 abortions performed by physicians in North America, Western Europe, Scandinavia and Australia/New Zealand. We compared the prevalence of complications that required additional interventions for abortions performed in office-based clinics and surgical center or hospital clinic settings. RESULTS: From 11,369 articles retrieved, 57 studies met our inclusion criteria. Evidence from 36 studies suggests that <=3.0% of procedures performed in any setting necessitates repeat aspiration. Hemorrhage not requiring transfusion occurred in 0-4.7% of office-based procedures and 0 4.1% of hospital-based procedures but was <=1.0% in 23 studies. Major complications requiring intervention, including hemorrhage requiring transfusion and uterine perforation needing repair, occurred in <=0.1% of procedures, and hospitalization was necessary in <=0.5% of cases in most studies. Anesthesia related complications occurred in <=0.2% of procedures in six office-based studies and <=0.5% of procedures performed in surgical centers or hospital-based clinics. No abortion-related deaths were reported. CONCLUSIONS: The percentage of first-trimester aspiration abortions that required interventions for minor and major complications was very low. Overall, the prevalence of major complications was similar across clinic contexts, indicating that this procedure can be safely performed in an office setting. IMPLICATIONS: Laws requiring abortion providers to have hospital admitting privileges or facilities to meet ambulatory surgical center standards would be unlikely to improve the safety of first-trimester aspiration abortion in office settings. PMID- 26238337 TI - Arginine-containing peptides as potent inhibitors of VIM-2 metallo-beta lactamase. AB - BACKGROUND: Metallo-beta-lactamases (MBLs) play an important role in the emergence of microbial resistance to beta-lactam antibiotics, and are hence considered targets for the design of novel therapeutics. We here report on the inhibitory effect of peptides containing multiple arginine residues on VIM-2, a clinically important MBL from Pseudomonas aeruginosa. METHODS: Enzyme kinetic assays in combination with fluorescence spectroscopy and stopped-flow UV-Vis spectrophotometry were utilized to explore the structure-activity relationship of peptides as inhibitors of VIM-2. RESULTS: Our studies show that the inhibitory potency of the investigated peptides was mainly dependent on the number of arginine residues in the center of the peptide sequence, and on the composition of the N-terminus. The most potent inhibitors were found to curtail enzyme function in the mid-to-low nanomolar range. Salts generally reduced peptide mediated inhibition. Analysis of the mode of inhibition suggests the peptides to act as mixed-type inhibitors with a higher affinity for the enzyme-substrate complex. Stopped-flow UV-Vis and fluorescence studies revealed the peptides to induce rapid protein aggregation, a phenomenon strongly correlated to the peptides' inhibitory potency. Inhibition of IMP-1 (another subclass B1 MBL) by the peptides was found to be much weaker than that observed with VIM-2, a finding which might be related to subtle molecular differences in the protein surfaces. CONCLUSION: The reported data indicate that arginine-containing peptides can serve as potent, aggregation-inducing inhibitors of VIM-2, and potentially of other MBLs. GENERAL SIGNIFICANCE: Arginine-containing peptides can be considered as a novel type of potent MBL inhibitors. PMID- 26238338 TI - Developing clinical decision tools to implement chronic disease prevention and screening in primary care: the BETTER 2 program (building on existing tools to improve chronic disease prevention and screening in primary care). AB - BACKGROUND: The Building on Existing Tools to Improve Chronic Disease Prevention and Screening in Family Practice (BETTER) trial demonstrated the effectiveness of an approach to chronic disease prevention and screening (CDPS) through a new skilled role of a 'prevention practitioner'(PP). The PP has appointments with patients 40-65 years of age that focus on primary prevention activities and screening of cancer (breast, colorectal, cervical), diabetes and cardiovascular disease and associated lifestyle factors. There are numerous and occasionally conflicting evidence-based guidelines for CDPS, and the majority of these guidelines are focused on specific diseases or conditions; however, primary care providers often attend to patients with multiple conditions. To ensure that high level evidence guidelines were used, existing clinical practice guidelines and tools were reviewed and integrated into blended BETTER tool kits. Building on the results of the BETTER trial, the BETTER tools were updated for implementation of the BETTER 2 program into participating urban, rural and remote communities across Canada. METHODS: A clinical working group consisting of PPs, clinicians and researchers with support from the Centre for Effective Practice reviewed the literature to update, revise and adapt the integrated evidence algorithms and tool kits used in the BETTER trial. These resources are nuanced, based on individual patient risk, values and preferences and are designed to facilitate decision-making between providers across the target diseases and lifestyle factors included in the BETTER 2 program. Using the updated BETTER 2 toolkit, clinicians 1) determine which CDPS actions patients are eligible to receive and 2) develop individualized 'prevention prescriptions' with patients through shared decision-making and motivational interviewing. RESULTS: The tools identify the patients' risks and eligible primary CDPS activities: the patient survey captures the patient's health history; the prevention visit form and integrated CDPS care map identify eligible CDPS activities and facilitate decisions when certain conditions are met; and the 'bubble diagram' and 'prevention prescription' promote shared decision-making. CONCLUSION: The integrated clinical decision making tools of BETTER 2 provide resources for clinicians and policymakers that address patients' complex care needs beyond single disease approaches and can be adapted to facilitate CDPS in the urban, rural and remote clinical setting. TRIAL REGISTRATION: The registration number of the original RCT BETTER trial was ISRCTN07170460 . PMID- 26238340 TI - S100A6 expression in cutaneous smooth muscle neoplasms. AB - The S100A6 protein is expressed in a variety of tissues and distinct staining patterns in S100A6 immunohistochemistry may be useful in the differential diagnosis of difficult lesions. We evaluated the staining pattern of the S100A6 antibody in 22 cases each of pilar leiomyoma (LM), angioleiomyoma (ALM), and cutaneous leiomyosarcoma (LMS). S100A6 labeled both the nucleus and cytoplasm of myocytes in positive cases. About 64% of LM and 86% ALM had positive staining to the S100A6 antibody but predominantly in a weak staining pattern. In contrast, 95% of the LMS exhibited moderate to strong staining with the S100A6 antibody. The difference in the frequency of positive cases was statistically significant in the LM vs LMS comparison (p = 0.025), but we found intensity of staining to be of greatest practical utility. Analysis between the groups taking in to consideration differences in intensity of staining using the nonparametric rank sum (Mann-Whitney U test) demonstrated that there was a statistically significant difference between LM and LMS and between ALM and LMS. Weak or absent S100A6 staining supports a diagnosis of LM, whereas strong positive staining supports a diagnosis of LMS. PMID- 26238339 TI - Impact of CYP24A1 overexpression on growth of colorectal tumour xenografts in mice fed with vitamin D and soy. AB - Our previous studies showed that the 1,25-dihydroxyvitamin D (1,25-D3) catabolizing enzyme, 1,25-dihydoxyvitamin D 24 hydroxylase (CYP24A1) was overexpressed in colorectal tumours and its level correlated with increased proliferation. We hypothesised that cells overexpressing CYP24A1 have growth advantage and a diet rich in vitamin D and soy would restore sensitivity to the anti-tumourigenic effects of vitamin D. Soy contains genistein, a natural CYP24A1 inhibitor. To determine causality between CYP24A1 and tumour growth, we established xenografts in male SCID mice with HT29 cells stably overexpressing either GFP-tagged CYP24A1 or GFP. Mice were fed with either high (2500 IU D3/kg) or low vitamin D (100 IU D3/kg) diet in the presence or absence of soy (20% diet). In vitro, cells overexpressing CYP24A1 grew faster than controls. 1,25-D3, the active vitamin D metabolite, reduced cell number only in the presence of the CYP24A1 inhibitor VID400. Regardless of the amount of vitamin D in the diet, xenografts overexpressing CYP24A1 grew faster, were heavier and more aggressive. Soy reduced tumour volume only in the control xenografts, while the tumours overexpressing CYP24A1 were larger in the presence of dietary soy. In conclusion, we demonstrate that CYP24A1 overexpression results in increased aggressiveness and proliferative potential of colorectal tumours. Irrespective of the dietary vitamin D3, dietary soy is able to increase tumour volume when tumours overexpress CYP24A1, suggesting that combination of vitamin D3 and soy could have an anti-tumourigenic effect only if CYP24A1 levels are normal. PMID- 26238341 TI - The status of neonatal screening in China, 2013. AB - OBJECTIVES: To investigate the status of neonatal screening in China in 2013. METHOD: All Chinese neonatal screening laboratories were asked to submit information about the number of newborns screened and for which diseases, the rate of acceptable blood spots, and the time between sample collection and delivery to laboratories and reporting. RESULTS: Of the 202 laboratories, 194 (96%) submitted data. In 2013, 73.6% (142/193) of laboratories testing for phenylketonuria (PKU), 72.7% (141/194) for congenital hypothyroidism (CH), 58.9% (43/73) for glucose-6-phosphate dehydrogenase (G6PD) deficiency and 53.1% (34/64) for congenital adrenal hyperplasia (CAH) screened more than 30,000 newborns. The incidences of PKU, CH, G6PD deficiency, and CAH were 1:12189, 1:2281, 1:44 and 1:6084, respectively. The estimated coverage of screening for PKU, CH, G6PD deficiency, and CAH were 86.3 ~ 87.5%, 87.9 ~ 89.1%, 24.0 ~ 25.0% and 18.9% ~ 19.9%, respectively. The rates of acceptable blood spots were >=98% in 161 (87.0%) of 185 laboratories. More than half the laboratories could not achieve a time from collection to reporting of 5 days. CONCLUSION: Neonatal screening has developed rapidly in China but the biggest challenge is still to increase coverage and expand the screening disease panel across the entire country. More government support is needed to make neonatal screening more efficient. PMID- 26238342 TI - Experience of sexual self-esteem among men living with HIV. AB - Much of the focus on sexual health for people living with HIV has been on promoting safe sex behaviours. However, also important for sexual health is a positive sexual self-esteem. This article reports on an interpretative phenomenological analysis of interviews with seven men about the impact that having HIV has had on their sense of sexual self. Five overarching themes were identified: the 'destruction' of a sexual self; feeling sexually hazardous; sexual inhibition; reclaiming a sexual self and finding a place through sero sorting. With HIV now being a chronic illness, interventions are required to support people to lead sexually satisfying lives. PMID- 26238343 TI - Functional expression of a novel Kunitz type protease inhibitor from the human blood fluke Schistosoma mansoni. AB - BACKGROUND: Schistosomes are able to survive for prolonged periods in the blood system, despite continuous contact with coagulatory factors and mediators of the host immune system. Protease inhibitors likely play a critical role in host immune modulation thereby promoting parasite survival in this extremely hostile environment. Even though Kunitz type serine protease inhibitors have been shown to play important physiological functions in a range of organisms these proteins are less well characterised in parasitic helminths. METHODS: We have cloned one gene sequence from S. mansoni, Smp_147730 (SmKI-1) which is coded for single domain Kunitz type protease inhibitor, E. coli-expressed and purified. Immunolocalisation and western blotting was carried out using affinity purified polyclonal anti-SmKI-1 murine antibodies to determine SmKI-1 expression in the parasite. Protease inhibitor assays and coagulation assays were performed to evaluate the functional roles of SmKI-1. RESULTS: SmKI-1 is localised in the tegument of adult worms and the sub-shell region of eggs. Furthermore, this Kunitz protein is secreted into the host in the ES products of the adult worm. Recombinant SmKI-1 inhibited mammalian trypsin, chymotrypsin, neutrophil elastase, FXa and plasma kallikrein with IC50 values of 35 nM, 61 nM, 56 nM, 142 nM and 112 nM, respectively. However, no inhibition was detected for pancreatic elastase or cathepsin G. SmKI-1 (4 MUM) delayed blood clot formation, reflected in an approximately three fold increase in activated partial thromboplastin time and prothrombin time. CONCLUSIONS: We have functionally characterised the first Kunitz type protease inhibitor (SmKI-1) from S. mansoni and show that it has anti inflammatory and anti-coagulant properties. SmKI-1 is one of a number of putative Kunitz proteins in schistosomes that have presumably evolved as an adaptation to protect these parasites from the defence mechanisms of their mammalian hosts. As such they may represent novel vaccine candidates and/or drug targets for schistosomiasis control. PMID- 26238345 TI - The hazards of button battery ingestion. PMID- 26238344 TI - Efficacy of palliative radiotherapy for gastric bleeding in patients with unresectable advanced gastric cancer: a retrospective cohort study. AB - BACKGROUND: Bleeding negatively impacts quality of life in patients with unresectable advanced gastric cancer and has the potential to be lethal. When blood transfusion and endoscopic hemostasis are unsuccessful to stop bleeding, radiation to stomach is selected in patients with unsuitable condition for surgery. We performed a retrospective cohort study to clarify the utility of radiotherapy in treating gastric bleeding, particularly for patients with limited life expectancy. METHODS: We evaluated the efficacy and safety of palliative radiotherapy in patients with advanced gastric cancer between January 2007 and December 2012 in Aichi Cancer Center Hospital. All patients had gastric bleeding requiring blood transfusion. We defined hemostasis as an increase in hemoglobin level to more than 7.0 g/dL together with the cessation of melena or hematemesis for at least 1 week. RESULTS: During the study period, 313 advanced gastric cancer patients treated in our institution. Of these 17 patients received gastric radiotherapy to stop bleeding. Two patients were excluded from analysis due to combined treatment of intravascular embolization. Eleven out of 15 patients (73 %) had undergone two or more previous chemotherapy regimens. Ten patients (67 %) had an Eastern Cooperative Oncology Group performance status of 3 and 14 patients (93 %) were in palliative prognostic index group B or C. The median total planned radiation dose was 30 Gy in 10 fractions. At a median interval of 2 days after initiation of radiotherapy, 11 patients (73 %) achieved hemostasis; rebleeding was observed in four patients (36 %). The median hemoglobin level before radiotherapy was significantly increased from 6.0 to 9.0 g/dL (p < 0.0001). The median volume of red blood cell transfusion was significantly decreased from 1120 to 280 mL (p = 0.007). The median rebleeding-free survival interval was 27 days, with a median overall survival of 63 days. The cause of death was bleeding in 1 patient (7 %) and cancer progression without bleeding in 12 patients (80 %). There were no severe adverse events attributable to radiotherapy. CONCLUSIONS: Palliative radiotherapy for gastric bleeding achieves hemostasis within a short time frame. This appears to be a useful treatment option, especially for patients with end-stage, unresectable advanced gastric cancer. PMID- 26238346 TI - Micromonospora oryzae sp. nov., isolated from roots of upland rice. AB - An actinomycete strain, designated CP2R9-1T, was isolated from root internal tissues of upland rice (Oryza sativa). Based on a polyphasic approach, strain CP2R9-1T was characterized as a member of the genus Micromonospora. meso Diaminopimelic acid and 3-OH-diaminopimelic acid were present in the cell-wall peptidoglycan. The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannosides, two unidentified phospholipids and four unidentified polar lipids. Predominant menaquinones were MK-9(H4), MK-9(H6) and MK-10(H4). Whole-cell sugars consisted of ribose, xylose, arabinose and glucose. Phylogenetic analysis of the nearly complete 16S rRNA gene sequence suggested that strain CP2R9-1T was closely related to Micromonospora haikouensis 232617T (99.32 % similarity), Micromonospora carbonacea DSM 43168T (99.18 %) and Micromonospora krabiensis MA-2T (99.16 %). Strain CP2R9-1T was distinct from its closest relatives based on low levels of DNA-DNA relatedness (21.3 +/- 0.1-41.7 +/- 0.7 %) and phenotypic differences. The results presented in this study showed that strain CP2R9-1T represents a novel species of the genus Micromonospora, for which the name Micromonospora oryzae sp. nov. is proposed. The type strain is CP2R9-1T ( = BCC 67266T = NBRC 110007T). PMID- 26238347 TI - Efficacy and safety of body weight-adapted oral cholecalciferol substitution in dialysis patients with vitamin D deficiency. AB - BACKGROUND: Vitamin D deficiency is highly prevalent in dialysis patients. Whether substitution of native vitamin D in these patients is beneficial is a matter of ongoing discussion, as is the optimal dosing schedule. The purpose of this study was to investigate the efficacy and safety of a body-weight adapted oral dosing regimen of cholecalciferol in dialysis patients. METHODS: In a prospective single-center study 56 prevalent dialysis patients with a baseline 25OHD3 level <20 ng/mL received 100 IU of cholecalciferol per kg body weight once weekly orally for 26 weeks. 25OHD3 was measured at baseline and at study end, iPTH every three months, serum calcium and phosphorous monthly. Concurrent medication including phosphate binders, calcitriol and cinacalcet and dialysate calcium concentration remained unchanged throughout the study. RESULTS: Baseline 25OHD3 was 9.9 +/- 4.1 ng/mL and increased to 26.1 +/- 8.8 ng/mL (P = 0.01). Fourteen patients (27 %) achieved a level > 30 ng/mL and all others above 20 ng/mL. Cinacalcet therapy was positively associated with the increase in 25OHD3 (P = 0.024). The plasma iPTH level significantly decreased from median 362 pg/mL to 297 pg/mL (P = 0.01). This decline was more pronounced in patients with higher baseline iPTH levels (P < 0.01) and differed significantly dependent on concurrent calcitriol therapy. A significant iPTH decrease was observed in patients receiving calcitriol (P = 0.031). Serum calcium and phosphorous did not change significantly throughout the study period. Cholecalciferol substitution was well tolerated without adverse effects. CONCLUSION: The dosing regimen of oral cholecalciferol supplementation with 100 IU per kg body weight per week for 26 weeks in dialysis patients with vitamin D deficiency causes a significant increase in 25OHD3 close to the supposed target level of 30 ng/mL and a significant reduction in iPTH, without affecting serum calcium or phosphorous levels. PMID- 26238348 TI - Targeted transperineal biopsy of the prostate has limited additional benefit over background cores for larger MRI-identified tumors. AB - PURPOSE: To compare histological outcomes in patients undergoing MRI-transrectal ultrasound fusion transperineal (MTTP) prostate biopsy and determine the incremental benefit of targeted cores. METHODS: Seventy-six consecutive patients with 89 MRI-identified targets underwent MTTP biopsy. Separate targeted biopsies and background cores were obtained according to a standardized protocol. Target biopsies were considered of added diagnostic value if these cores showed a higher Gleason grade than non-targeted cores taken from the same sector (Group 1, n = 41). Conversely, where background cores demonstrated an equal or higher Gleason grade, target cores were considered to be non-beneficial (Group 2, n = 48). RESULTS: There was no significant difference in age, PSA, prostate volume, time to-biopsy, and number of cores obtained between the groups. A greater proportion of target cores were positive for cancer (158/228; 69.3 %) compared to background (344/1881; 18.38 %). The median target volume was 0.54 cm(3) for Group 1 (range 0.09-2.79 cm(3)) and 1.65 cm(3) for Group 2 (0.3-9.07 cm(3)), p < 0.001. The targets in Group 1 had statistically lower diameters for short and long axes, even after correction for gland size. The highest area under the receiver operating characteristic curve was demonstrated when a lesion cutoff value of 1.0 cm in short axis was applied, resulting in a sensitivity of 83.3 % and a specificity of 82.9 %. CONCLUSIONS: When a combined systematic and targeted transperineal prostate biopsy is performed, there is limited benefit in acquiring additional cores from larger-volume targets with a short axis diameter >1.0 cm. PMID- 26238349 TI - Three novel Toll genes (PtToll1-3) identified from a marine crab, Portunus trituberculatus: Different tissue expression and response to pathogens. AB - The Toll signaling pathway is one of the most important regulators of the immune response in both vertebrates and invertebrates. Herein, three novel Toll (PtToll1 3) cDNA sequences were cloned from the swimming crab, Portunus trituberculatus. PtToll1 has 1003 amino acid residues and consists of an extracellular domain containing 15 leucine-rich repeats (LRRs) and a cytoplasmic Toll/interleukin-1 receptor (TIR) domain of 139 residues. PtToll2 encodes 1196 peptides, with an extracellular domain containing 28 LRRs and a cytoplasmic TIR domain. PtToll3 is 1229 residues long and contains 26 LRRs and a cytoplasmic TIR domain. Based on sequence and phylogenetic analyses, PtToll1 distinctly clustered with almost all crustacean Tolls, except Litopenaeus vannamei Toll3. However, PtToll2 and PtToll3 were separated from most reported crustacean Tolls, which mostly clustered with Drosophila melanogaster (Dm) Toll8, L. vannamei Toll3, and DmToll6. Reverse transcription PCR and real-time quantitative PCR analyses showed that PtToll1 and PtToll3 were constitutively expressed in all tissues tested, but PtToll2 mRNA was only highly enriched in gills. Upon challenges with Vibrio alginolyticus, Candida lusitaniae, or white spot syndrome virus (WSSV), the three Tolls exhibited different responses: the PtToll1 transcript was up-regulated in response to C. lusitaniae or V. alginolyticus challenge, but did not respond to WSSV challenge; both PtToll2 and PtToll3 mRNAs were down-regulated 12 h after C. lusitaniae or V. alginolyticus infection. However, WSSV elicited the expression of PtToll2 at 6 h post-infection, but suppressed transcription of PtToll3 at 24 h post-infection. The study provides valuable data for understanding the role of Toll pathways in the host defense against microbial pathogens, which will facilitate future studies on host-pathogen interactions in crabs. PMID- 26238350 TI - The Term Breech Trial results are generalisable. PMID- 26238351 TI - Immunological characterization and verification of recombinant streptococcal protein G. AB - Streptococcal protein G (SPG), which is an antigen of the Streptococcus sp. cell wall, is important due to its high specificity to immunoglobulin (Ig), as compared with staphylococcal protein A. However, the cost of commercial recombinant (r)SPG has so far hindered further research into the application of rSPG. Efficient high cell density fermentation of genetically modified Escherichia coli and purification technology have previously been studied as a means to obtain rSPG. In the present study, the immunological characterization of purified rSPG was compared with commercial SPG via western blot analysis. The results of the present study demonstrated that the IgG-binding capacity of purified rSPG was markedly higher, as compared with commercial SPG. Furthermore, purified rSPG cross-linked with Q Sepharose(r) Fast Flow exhibited excellent affinity with IgG in murine serum. In order to obtain relatively pure and accurate rSPG, the purified rSPG was identified by Nanoflow Liquid Chromatography Mass Spectrometry (MS)/MS spectrum. The results indicated that the two peptide fragments of purified rSPG corresponded to the Streptococcus sp. GX7805 protein G as listed in the National Center for Biotechnology Information database. The method described in the present study offers a novel practical method for the verification of rSPG in relatively pure form, in order to purify IgG or carry out immunolabeling processes. PMID- 26238352 TI - Signaling networks that regulate cell migration. AB - SUMMARY: Stimuli that promote cell migration, such as chemokines, cytokines, and growth factors in metazoans and cyclic AMP in Dictyostelium, activate signaling pathways that control organization of the actin cytoskeleton and adhesion complexes. The Rho-family GTPases are a key convergence point of these pathways. Their effectors include actin regulators such as formins, members of the WASP/WAVE family and the Arp2/3 complex, and the myosin II motor protein. Pathways that link to the Rho GTPases include Ras GTPases, TorC2, and PI3K. Many of the molecules involved form gradients within cells, which define the front and rear of migrating cells, and are also established in related cellular behaviors such as neuronal growth cone extension and cytokinesis. The signaling molecules that regulate migration can be integrated to provide a model of network function. The network displays biochemical excitability seen as spontaneous waves of activation that propagate along the cell cortex. These events coordinate cell movement and can be biased by external cues to bring about directed migration. PMID- 26238354 TI - Viral and transgenic reporters and genetic analysis of adult neurogenesis. AB - Stem and progenitor cells of the developing and adult brain can be effectively identified and manipulated using reporter genes, introduced into transgenic reporter mouse lines or recombinant viruses. Such reporters rely on an ever increasing variety of fluorescent proteins and a continuously expanding list of regulatory elements and of mouse lines engineered for cell- or time-specific recombination. An important extension of stem-cell-based genetic strategies is an opportunity to explore the properties of newly generated neurons and their contribution to synaptic plasticity. Here, we review available strategies for marking and quantifying various classes of stem and progenitor cells in the adult brain, genetically tracing their progeny, and studying the properties of stem cells and new neurons. We compare various experimental approaches to labeling and investigating stem cells and their progeny and discuss caveats and limitations inherent to each approach. PMID- 26238353 TI - Regulation of recombination and genomic maintenance. AB - Recombination is a central process to stably maintain and transmit a genome through somatic cell divisions and to new generations. Hence, recombination needs to be coordinated with other events occurring on the DNA template, such as DNA replication, transcription, and the specialized chromosomal functions at centromeres and telomeres. Moreover, regulation with respect to the cell-cycle stage is required as much as spatiotemporal coordination within the nuclear volume. These regulatory mechanisms impinge on the DNA substrate through modifications of the chromatin and directly on recombination proteins through a myriad of posttranslational modifications (PTMs) and additional mechanisms. Although recombination is primarily appreciated to maintain genomic stability, the process also contributes to gross chromosomal arrangements and copy-number changes. Hence, the recombination process itself requires quality control to ensure high fidelity and avoid genomic instability. Evidently, recombination and its regulatory processes have significant impact on human disease, specifically cancer and, possibly, neurodegenerative diseases. PMID- 26238355 TI - Functional differentiation of adult-born neurons along the septotemporal axis of the dentate gyrus. AB - Over the past several decades, the proliferation and integration of adult-born neurons into existing hippocampal circuitry has been implicated in a wide range of behaviors, including novelty recognition, pattern separation, spatial learning, anxiety behaviors, and antidepressant response. In this review, we suggest that the diversity in behavioral requirements for new neurons may be partly caused by separate functional roles of individual neurogenic niches. Growing evidence shows that the hippocampal formation can be compartmentalized not only along the classic trisynaptic circuit, but also along a longitudinal septotemporal axis. We suggest that subpopulations of hippocampal adult-born neurons may be specialized for distinct mnemonic- or mood-related behavioral tasks. We will examine the literature supporting a functional and anatomical dissociation of the hippocampus along the longitudinal axis and discuss techniques to functionally dissect the roles of adult-born hippocampal neurons in these distinct subregions. PMID- 26238357 TI - Size control in plants--lessons from leaves and flowers. AB - To achieve optimal functionality, plant organs like leaves and petals have to grow to a certain size. Beginning with a limited number of undifferentiated cells, the final size of an organ is attained by a complex interplay of cell proliferation and subsequent cell expansion. Regulatory mechanisms that integrate intrinsic growth signals and environmental cues are required to enable optimal leaf and flower development. This review focuses on plant-specific principles of growth reaching from the cellular to the organ level. The currently known genetic pathways underlying these principles are summarized and network connections are highlighted. Putative non-cell autonomously acting mechanisms that might coordinate plant-cell growth are discussed. PMID- 26238356 TI - The opposing actions of target of rapamycin and AMP-activated protein kinase in cell growth control. AB - Cell growth is a highly regulated, plastic process. Its control involves balancing positive regulation of anabolic processes with negative regulation of catabolic processes. Although target of rapamycin (TOR) is a major promoter of growth in response to nutrients and growth factors, AMP-activated protein kinase (AMPK) suppresses anabolic processes in response to energy stress. Both TOR and AMPK are conserved throughout eukaryotic evolution. Here, we review the fundamentally important roles of these two kinases in the regulation of cell growth with particular emphasis on their mutually antagonistic signaling. PMID- 26238358 TI - RNAi and heterochromatin assembly. AB - SUMMARY: The involvement of RNA interference (RNAi) in heterochromatin formation has become clear largely through studies in the fission yeast Schizosaccharomyces pombe and plants like Arabidopsis thaliana. This article discusses how heterochromatic small interfering RNAs are produced and how the RNAi machinery participates in the formation and function of heterochromatin. PMID- 26238359 TI - The striatum: where skills and habits meet. AB - After more than a century of work concentrating on the motor functions of the basal ganglia, new ideas have emerged, suggesting that the basal ganglia also have major functions in relation to learning habits and acquiring motor skills. We review the evidence supporting the role of the striatum in optimizing behavior by refining action selection and in shaping habits and skills as a modulator of motor repertoires. These findings challenge the notion that striatal learning processes are limited to the motor domain. The learning mechanisms supported by striatal circuitry generalize to other domains, including cognitive skills and emotion-related patterns of action. PMID- 26238362 TI - A novel brain metastasis xenograft model for convection-enhanced delivery of targeted toxins via a micro-osmotic pump system enabled for real-time bioluminescence imaging. AB - Brain metastasis is a common cause of mortality in patients with cancer, and is associated with poor prognosis. There is a current requirement for the identification of relevant brain metastasis tumor models, which may be used to test novel therapeutic agents and delivery systems in pre-clinical studies. The present study aimed to investigate the development of a murine model of brain metastasis, and the application of bioluminescence imaging (BLI) for monitoring tumor growth and response to targeted toxins (TT). A luciferase-modified human brain metastasis cell line was implanted into the caudate-putamen of athymic mice using a stereotactic frame. Tumor growth was monitored by BLI, and tumor volume was calculated from three-dimensional measurements of serial histopathological sections. Histopathological analyses revealed the presence of tumor growth within the caudate-putamen of all of the mice, and BLI was shown to be correlated with tumor volume. To evaluate whether this model would allow the detection of a therapeutic response, mice bearing metastatic brain tumor cell xenografts were treated with TT delivered by convection-enhanced delivery (CED), via a micro osmotic pump system. The TT-treated groups were submitted to metastatic brain tumor cell experiments, the results of which suggested that TT treatment delayed tumor growth, as determined by BLI monitoring, and significantly extended the survival of the mice. The results of the present study demonstrated the efficacy of a brain metastasis model for CED of TT via a micro-osmotic pump system in athymic mice, in which tumor growth and response to therapy were accurately monitored by BLI. In conclusion, this model may be well-suited for pre-clinical testing of potential therapeutics for the treatment of patients with metastatic brain tumors. PMID- 26238361 TI - Significance of expression of glucagon-like peptide 1 receptor in pancreatic cancer. AB - Glucagon-like peptide 1 (GLP-1) induces insulin secretion and proliferation of pancreatic beta-cells, and inhibits their apoptosis through the GLP-1 receptor (GLP-1R), thus providing a foundation for using GLP-1-based therapies for the treatment of type 2 diabetes. However, doubts have emerged regarding the drug safety of these therapies. We investigated the potential role of GLP-1R in pancreatic ductal adenocarcinoma (PDAC). GLP-1R expression was semi quantitatively evaluated by immunohistochemistry in 48 PDAC samples, and its correlations with clinicopathological features were investigated. CFPAC-1 cells were used for GLP-1R knockdown to evaluate its effects on cell proliferation, migration and invasion. GLP-1R expression was positive in 23 tumors and negative in 25 tumors. No correlations were found between GLP-1R expression status and clinicopathological characteristics. Furthermore, GLP-1R expression status did not affect the patient prognosis (P=0.74). The majority of lymph node metastases (11 of 15 samples examined; 73%) were positive for GLP-1R expression. Immunoreactivity for GLP-1R was also noted in sites of perineural and lymphovascular invasion. GLP-1R knockdown significantly reduced the proliferation, migration and invasion of CFPAC-1 cells (P<0.05). In conclusion, although GLP-1R is not an independent prognostic factor in PDAC patients, it appears to have some implications for PDAC metastatic ability. PMID- 26238363 TI - Sensitivity of mRNA Translation. AB - Using the dynamic mean-field approximation of the totally asymmetric simple exclusion process (TASEP), we investigate the effect of small changes in the initiation, elongation, and termination rates along the mRNA strand on the steady state protein translation rate. We show that the sensitivity of mRNA translation is equal to the sensitivity of the maximal eigenvalue of a symmetric, nonnegative, tridiagonal, and irreducible matrix. This leads to new analytical results as well as efficient numerical schemes that are applicable for large scale models. Our results show that in the usual endogenous case, when initiation is more rate-limiting than elongation, the sensitivity of the translation rate to small mutations rapidly increases towards the 5' end of the ORF. When the initiation rate is high, as may be the case for highly expressed and/or heterologous optimized genes, the maximal sensitivity is with respect to the elongation rates at the middle of the mRNA strand. We also show that the maximal possible effect of a small increase/decrease in any of the rates along the mRNA is an increase/decrease of the same magnitude in the translation rate. These results are in agreement with previous molecular evolutionary and synthetic biology experimental studies. PMID- 26238364 TI - New QM/MM implementation of the DFTB3 method in the gromacs package. AB - The approximate density-functional tight-binding theory method DFTB3 has been implemented in the quantum mechanics/molecular mechanics (QM/MM) framework of the Gromacs molecular simulation package. We show that the efficient smooth particle mesh Ewald implementation of Gromacs extends to the calculation of QM/MM electrostatic interactions. Further, we make use of the various free-energy functionalities provided by Gromacs and the PLUMED plugin. We exploit the versatility and performance of the current framework in three typical applications of QM/MM methods to solve biophysical problems: (i) ultrafast proton transfer in malonaldehyde, (ii) conformation of the alanine dipeptide, and (iii) electron-induced repair of a DNA lesion. Also discussed is the further development of the framework, regarding mostly the options for parallelization. PMID- 26238360 TI - Memory consolidation. AB - Conscious memory for a new experience is initially dependent on information stored in both the hippocampus and neocortex. Systems consolidation is the process by which the hippocampus guides the reorganization of the information stored in the neocortex such that it eventually becomes independent of the hippocampus. Early evidence for systems consolidation was provided by studies of retrograde amnesia, which found that damage to the hippocampus-impaired memories formed in the recent past, but typically spared memories formed in the more remote past. Systems consolidation has been found to occur for both episodic and semantic memories and for both spatial and nonspatial memories, although empirical inconsistencies and theoretical disagreements remain about these issues. Recent work has begun to characterize the neural mechanisms that underlie the dialogue between the hippocampus and neocortex (e.g., "neural replay," which occurs during sharp wave ripple activity). New work has also identified variables, such as the amount of preexisting knowledge, that affect the rate of consolidation. The increasing use of molecular genetic tools (e.g., optogenetics) can be expected to further improve understanding of the neural mechanisms underlying consolidation. PMID- 26238365 TI - Sex investment ratios in eusocial Hymenoptera support inclusive fitness theory. AB - Inclusive fitness theory predicts that sex investment ratios in eusocial Hymenoptera are a function of the relatedness asymmetry (relative relatedness to females and males) of the individuals controlling sex allocation. In monogynous ants (with one queen per colony), assuming worker control, the theory therefore predicts female-biased sex investment ratios, as found in natural populations. Recently, E.O. Wilson and M.A. Nowak criticized this explanation and presented an alternative hypothesis. The Wilson-Nowak sex ratio hypothesis proposes that, in monogynous ants, there is selection for a 1 : 1 numerical sex ratio to avoid males remaining unmated, which, given queens exceed males in size, results in a female-biased sex investment ratio. The hypothesis also asserts that, contrary to inclusive fitness theory, queens not workers control sex allocation and queen worker conflict over sex allocation is absent. Here, I argue that the Wilson Nowak sex ratio hypothesis is flawed because it contradicts Fisher's sex ratio theory, which shows that selection on sex ratio does not maximize the number of mated offspring and that the sex ratio proposed by the hypothesis is not an equilibrium for the queen. In addition, the hypothesis is not supported by empirical evidence, as it fails to explain 'split' (bimodal) sex ratios or data showing queen and worker control and ongoing queen-worker conflict. By contrast, these phenomena match predictions of inclusive fitness theory. Hence, the Wilson Nowak sex ratio hypothesis fails both as an alternative hypothesis for sex investment ratios in eusocial Hymenoptera and as a critique of inclusive fitness theory. PMID- 26238366 TI - Assessment of Retinal Structural and Functional Characteristics in Eyes with Autoimmune Retinopathy. AB - PURPOSE: To evaluate the thicknesses of individual retinal layers, and the correlation between structural changes and functional loss using spectral domain optical coherence tomography (SD-OCT) scans and electroretinograms (ERG), in eyes with autoimmune retinopathy (AIR). METHODS: SD-OCT raster scans of 12 eyes from 6 patients serologically diagnosed with AIR were evaluated. Retinal layers were segmented along a 5 mm horizontal scan passing through the fovea. Retinal layers analyzed include full retinal thickness (FRT), retinal pigment epithelium and Bruch's membrane complex (RPE+BM complex), photoreceptor layer (PRL), inner nuclear layer (INL), combined ganglion cell and inner plexiform layers (GCL+), nerve fiber layer (NFL), and combined GCL+ and NFL layers (GCL+/NFL). Changes in the thicknesses of the layers were assessed in 0.5 mm increments along the B-scan in the central, nasal, and temporal regions. These recorded values were compared to corresponding values of 51 eyes from 51 subjects with no known ocular pathology. Full-field ERGs were obtained at corresponding visits and were interpreted by a grader masked to the diagnoses and OCT findings. RESULTS: The mean age of the patients was 59.5 years (range, 33-83), with 4 males (66.6%). Within the control population of 51 subjects, mean age was 51.5 years (range, 40 75), with 25 males (49%). Eyes with AIR showed a loss of retinal tissue compared to eyes with no known ocular pathology at the fovea. Specifically, the FRT, RPE+BM complex, and PRL exhibited thinning of statistically significance. ERG findings demonstrated a functional deficit which showed a good correlation with structural loss. Fifty (50) percent of eyes experienced central photoreceptor (rod and cone) dysfunction and 75% of eyes displayed peripheral photoreceptor (rod and cone) dysfunction. CONCLUSIONS: Eyes with AIR show a loss of retinal tissue compared to eyes with no known ocular pathology. The greatest loss appears to occur in the RPE and PRL. ERG findings correlate strongly with the loss of tissue seen in these layers. Thus, therapeutic options may be targeted to preserve these regions of the retina. PMID- 26238367 TI - Therapies in Development for Non-Infectious Uveitis. AB - Uveitis represents a spectrum of diseases characterized by ocular inflammation that leads to significant visual loss if left untreated. Adequate, long-term control of inflammation with minimal systemic and local adverse effects is the preferred strategy for treating patients with uveitis. Pharmacotherapy for uveitis consists mainly of corticosteroids in various formulations such as topical, local, intraocular and systemic. However, monotherapy with corticosteroids is often unacceptable due to serious adverse effects on various organ systems. There exist limitations with the use of steroid-sparing systemic immunosuppressive agents, as these medications may have significant adverse events and a narrow therapeutic window. Thus, newer molecular targets that act on various steps of the inflammatory pathway appear to be promising emerging strategies for treating uveitis. Specially designed monoclonal antibodies in development can potentially halt the inflammatory processes resulting in remission of the disease. In the index review, novel molecular agents and biological therapies that have shown promising efficacy and safety data in preclinical and clinical studies have been summarized. In addition, new drug delivery systems that may ensure high intraocular therapeutic levels of pharmacologic agents have been highlighted. PMID- 26238368 TI - The Role of alphaA-Crystallin in Experimental Autoimmune Uveitis. AB - Uveitis refers to a group of ocular inflammatory diseases that can lead to blindness. For years, researchers have been trying to decipher the underlying mechanisms and develop therapeutic strategies using the model of experimental autoimmune uveitis (EAU). Recently, alphaA-crystallin has been found to be upregulated in EAU and can even ameliorate its severity through different mechanisms, suggesting its use as a potent therapeutic factor against uveitis. Here we review the protective role of alphaA-crystallin and discuss its functional mechanisms in EAU. PMID- 26238369 TI - Mouse Models of Experimental Autoimmune Uveitis: Comparative Analysis of Adjuvant Induced vs Spontaneous Models of Uveitis. AB - Mouse models of experimental autoimmune uveitis (EAU) mimic unique features of human uveitis, and serve as a template for preclinical study. The "classical" EAU model is induced by active immunization of mice with the retinal protein IRBP in adjuvant, and has proved to be a useful tool to study basic mechanisms and novel therapy in human uveitis. Several spontaneous models of uveitis induced by autoreactive T cells targeting on IRBP have been recently developed in IRBP specific TCR transgenic mice (R161H) and in AIRE(-/-) mice. The "classical" immunization-induced EAU exhibits acute ocular inflammation with two distinct patterns: (i) severe monophasic form with extensive destruction of the retina and rapid loss of visual function, and (ii) lower grade form with an acute onset followed by a prolonged chronic phase of disease. The spontaneous models of uveitis in R161H and AIRE(-/-) mice have a gradual onset and develop chronic ocular inflammation that ultimately leads to retinal degeneration, along with a progressive decline of visual signal. The adjuvant-dependent model and adjuvant free spontaneous models represent distinct aspects and/or various forms of human uveitis. This review will discuss and compare clinical manifestations, pathology as well as visual function of the retina in the different models of uveitis, as measured by fundus imaging and histology, optical coherence tomography (OCT) and electroretinography (ERG). PMID- 26238370 TI - Cytokine Expression Profile in Aqueous Humor and Sera of Patients with Acute Anterior Uveitis. AB - PURPOSE: To evaluate cytokine expression profile in aqueous humor and sera in patients with HLAB27 associated acute anterior uveitis (AAU) and idiopathic AAU. METHODS: Twenty patients with AAU and 17 controls were recruited from August 2012 to March 2013. Study subjects with uveitis were divided into two groups: 9 patients with idiopathic AAU and 11 patients with HLA-B27 associated AAU. Complete ophthalmological examinations were performed and clinical features of each group were clearly documented. Aqueous humor and sera were collected and the concentration of 15 immune mediators (IL-1beta, IL-4, IL-6, IL-10, IL-17A, IL 17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, TNF-alpha, IFN-gamma, sCD40L) were measured in both aqueous humor and sera simultaneously by multiplex immunoassay. RESULTS: There were significantly higher levels of multiple cytokines in aqueous humor in patients with uveitis compared to controls, including IL-1beta, IL-6, IL 10, IL-17a, IL-17f, IL-21, IL-25, IL-31, IFN-gamma, TNF-alpha, and sCD40L. The levels of IL-17a in aqueous humor correlated significantly with disease activity in patients with idiopathic AAU, while the level of IFN-gamma in aqueous humor correlated significantly with disease activity in patients with HLA-B27 associated AAU. There was no significant difference in serum cytokine expression between uveitis patients and controls except IL-6, elevated in patients with both idiopathic and HLA-B27 associated AAU. CONCLUSION: Cytokine expression pattern in the aqueous humor, in contrast to that in serum, may reflect intraocular immune reactions during active inflammation in patients with AAU. Both Th1 and Th17 are involved in immunopathogenesis of HLA-B27 associated and idiopathic AAU, but a different cytokine pattern was identified in these two clinical entities. A predominant Th17-driven immune response may play an important role in the immunopathogenesis of idiopathic AAU, while Th1 dominant immune response may be responsible for the inflammation in HLA-B27 associated AAU. PMID- 26238371 TI - TLR3 and TLR4 But not TLR2 are Involved in Vogt-Koyanagi- Harada Disease by Triggering Proinflammatory Cytokines Production Through Promoting the Production of Mitochondrial Reactive Oxygen Species. AB - Vogt-Koyanagi-Harada (VKH) disease is considered to be an autoimmune disease possibly triggered by an abnormal response to infection. Activation of TLRs signaling pathways by microbial products can drive inflammatory responses and adaptive immunity. In the present study, we investigated the role of TLRs in the pathogenesis of VKH disease. We showed that the expression of TLR3 and TLR4, but not TLR2, was significantly increased in monocyte-derived macrophages (MDMs) from VKH patients with active uveitis compared to controls. VKH patients with active uveitis showed an elevated level of IL-1beta, IL-6, IL-8, TNF-alpha and reactive oxygen species (ROS) in MDMs. IL-1beta, IL-6, IL-8 and TNF-alpha production could be significantly upregulated and downregulated by a ROS activator or inhibitor, respectively. Downregulation of the NLRP3 inflammasome significantly inhibited the production of IL-1beta but not IL-6, IL-8 and TNF-alpha. The phosphorylation levels of p38 and ERK1/2 were significantly higher in MDMs from active VKH patients compared to controls. Inhibition of p38 or ERK1/2 significantly decreased IL-1beta, IL-6, IL-8 and TNF-alpha expression. These results suggest that the increased expression of TLR3/4 in MDMs may be involved in the pathogenesis of VKH disease by the induction of inflammatory cytokines which is mediated by enhanced production of ROS. PMID- 26238372 TI - Ocular Inflammatory Diseases: Molecular Pathogenesis and Immunotherapy. AB - Uveitis is a diverse group of potentially sight-threatening intraocular inflammatory diseases of infectious or autoimmune etiology and accounts for more than 10% of severe visual handicaps in the United States. Pathology derives from the presence of inflammatory cells in the optical axis and sustained production of cytotoxic cytokines and other immuneregulatory proteins in the eye. The main therapeutic goals are to down-regulate the immune response, preserve the integrity of the ocular architecture and eventually eliminate the inciting uveitogenic stimuli. Current therapy is based on topical or systemic corticosteroid with or without second line agents and serious adverse effects of these drugs are the impetus for development of less toxic and more specific therapies for uveitis. This review summarizes the pathophysiology of uveitis, molecular mechanisms that regulate the initiation and progression of uveitis and concludes with emerging strategies for the treatment of this group of potentially blinding diseases. PMID- 26238373 TI - Spontaneous Ocular Autoimmunity in Mice Expressing a Transgenic T Cell Receptor Specific to Retina: A Tool to Dissect Mechanisms of Uveitis. AB - The "classical" EAU model induced by immunization of mice with the retinal protein IRBP or its peptides has been very useful to study basic mechanisms of ocular inflammation, but is inadequate for some types of studies due to the need for active immunization in the context of strong bacterial adjuvants. We generated transgenic (Tg) mice on the B10.RIII background that express a T cell receptor (TCR) specific for IRBP161-180. Three strains of TCR Tg mice were established. Spontaneous uveitis developed in two of the three strains by 2-3 months of age. Susceptibility correlated with a higher copy number of the transgenic TCR and a higher proportion of TCR Tg T cells in the peripheral repertoire. Even in mice with uveitis, peripheral IRBP-specific CD4(+) T cells displayed mostly a naive phenotype. In contrast, T cells infiltrating uveitic eyes mostly showed an effector/memory phenotype, and included Th1, Th17 as well as T regulatory cells. These mice thus provide a new and distinct model of uveitis from the "classical" EAU, and may represent some types of uveitis more faithfully. Importantly, this new transgenic model of uveitis can serve as a template for therapeutic manipulations, and as a source of naive retina-specific T cells for a variety of basic and pre-clinical studies. Several examples of such studies will be discussed. PMID- 26238374 TI - [Diagnostics of pain in old age. Perspectives on a multidimensional phenomenon]. AB - Old people's experience of pain differs markedly from that of younger people. Old people not only suffer from pain more often but also the pain is predominantly chronic in nature. In many cases older patients experience pain from more than one cause at any time due to multimorbidity. Against this backdrop this article examines the question of how diagnostic procedures of pain have to be specific for older patients and how these requirements are currently met in clinical practice. Diagnostic procedures in older persons need to be rooted in a biopsychosocial understanding of pain that also takes into account that the pain experience is always made up of several pain dimensions. A comprehensive understanding of pain communication also has to be taken into account as well as age-specific influences. In older persons pain assessment needs to encompass motivational affective, sensory discriminative and cognitive evaluative aspects. If pain assessment is limited to pain severity or the observation of pain behavior only, important information is lacking and important biographical, health-related, phenomenological and care-specific information cannot be used for the benefit of the patient. Different dimensions of pain cannot be used variably but need to be regarded as complementing elements; however, this approach is currently not always possible to follow through in clinical practice especially with age-related illnesses, such as dementia. Currently, only the geriatric pain interview (Geriatrisches Schmerzinterview) is available as a multidimensional tool for the assessment of pain in older people. There is a clear need for more and extended research and development of tools and processes to comprehensively assess pain in older persons. PMID- 26238375 TI - [Activating physiotherapy for chronic pain in elderly patients. Recommendations, barriers and resources]. AB - Elderly patients with chronic pain are particularly at risk of functional limitations up to the loss of autonomy and social life. To facilitate autonomy, mobility and quality of life, physiotherapy plays an essential role in pain management. Nevertheless, programs that are specifically geared towards the needs of older patients are still uncommon. This article offers recommendations for structuring physiotherapy programs based on international guideline recommendations. First examples of pain management concepts for older adults demonstrate the positive results of activating therapy. Additionally, this article provides insights into barriers and resources of affected patients and all actors involved. However, physiotherapeutic treatment for aged chronic pain patients in Germany still shows considerable shortcomings but also offers an exciting challenge for the future. PMID- 26238376 TI - The prognostic value of hepatic venous pressure gradient in patients with cirrhosis is highly dependent on the accuracy of the technique. AB - Hepatic venous pressure gradient (HVPG), the difference between wedged (WHVP) and free hepatic vein pressure (FHVP), predicts survival in patients with cirrhosis. It has been suggested for the use of inferior vena cava (IVC) value instead of FHVP to calculate HVPG when the difference between proximal FHVP (obtained at 2 cm from the hepatic vein outlet) and IVC (measured at the level of the hepatic ostium) is >2 mm Hg. However, there are no data supporting this recommendation. The main aim of the study was to establish which gradient, WHVP-FHVP (HVPG-Free) or WHVP-IVC (HVPG-IVC), better correlates with orthotopic liver transplantation (OLT)-free survival. This work was a retrospective evaluation of hepatic hemodynamic studies of 380 consecutive patients with cirrhosis performed from January 2006 to December 2012 with follow-up until December 2013. Patients had a mean age of 56+/-10 years and 64.7% were men. Mean Child-Pugh was 7+/-2. HVPG Free (16+/-5 mm Hg) was significantly lower than HVPG-IVC (17+/-5.5 mm Hg; P<0.001). During a mean follow-up of 43 months, 40 patients were transplanted and 111 died. A total of 285 (75%) patients had an FHVP-IVC difference within +/-2 mm Hg (no discrepancy) and 95 (25%) patients<-2 mm Hg or >2 mm Hg (discrepancy). In patients without discrepancy, 16 mm Hg was the best cut-off value predicting survival, independently of being calculated as HVPG-Free or HVPG-IVC. However, in those patients with discrepancy, 16 mm Hg was still the best cut-off value for HVPG-Free, but not for HVPG-IVC, among which 25 patients (26%) were misclassified regarding their risk of OLT/death. CONCLUSIONS: Given that WHVP-FHVP was more accurate in assessing prognosis than WHVP-IVC, HVPG should be calculated as the gradient between WHVP and FHVP, but not with IVC, in order to optimize its prognostic value and in identifying different risk population. PMID- 26238377 TI - Postulating Traumatic Stress Disorders. PMID- 26238378 TI - Abnormal Fear Memory as a Model for Posttraumatic Stress Disorder. AB - For over a century, clinicians have consistently described the paradoxical co existence in posttraumatic stress disorder (PTSD) of sensory intrusive hypermnesia and declarative amnesia for the same traumatic event. Although this amnesia is considered as a critical etiological factor of the development and/or persistence of PTSD, most current animal models in basic neuroscience have focused exclusively on the hypermnesia, i.e., the persistence of a strong fear memory, neglecting the qualitative alteration of fear memory. The latest is characterized by an underrepresentation of the trauma in the context-based declarative memory system in favor of its overrepresentation in a cue-based sensory/emotional memory system. Combining psychological and neurobiological data as well as theoretical hypotheses, this review supports the idea that contextual amnesia is at the core of PTSD and its persistence and that altered hippocampal amygdalar interaction may contribute to such pathologic memory. In a first attempt to unveil the neurobiological alterations underlying PTSD-related hypermnesia/amnesia, we describe a recent animal model mimicking in mice some critical aspects of such abnormal fear memory. Finally, this line of argument emphasizes the pressing need for a systematic comparison between normal/adaptive versus abnormal/maladaptive fear memory to identify biomarkers of PTSD while distinguishing them from general stress-related, potentially adaptive, neurobiological alterations. PMID- 26238380 TI - When flanker meets the n-back: What EEG and pupil dilation data reveal about the interplay between the two central-executive working memory functions inhibition and updating. AB - We investigated the interplay between inhibition and updating, two executive working memory (WM) functions. We applied a novel task paradigm consisting of flanker stimuli presented within an n-back task and studied the interaction between inhibitory demands and load on WM updating using behavioral measures, EEG, and pupil dilation. In contrast to studies that examine the interaction between inhibitory demands and load on WM storage components, the current task paradigm allowed testing the interaction between the executive WM components updating and inhibition. We found a reduced flanker interference effect for the highest (2-back) updating load condition compared to lower updating load conditions on most measures. We interpret these findings as indicating that inhibitory control and WM updating are closely intertwined executive functions. Increased load on updating seemed to result in an overall more activated attentional network thus enhancing inhibitory control, such that task performance is less susceptible to distracting information. PMID- 26238381 TI - A heavy-metal tolerant novel bacterium, Alcaligenes pakistanensis sp. nov., isolated from industrial effluent in Pakistan. AB - Two strains, NCCP-650(T) and NCCP-667, were isolated from industrial effluent and their taxonomic positions were investigated using a polyphasic taxonomic approach. The strains were found to be Gram-stain negative, strictly aerobic, motile short rods, which are tolerant to heavy-metals (Cr(+2), As(+2), Pb(+2) and Cu(+2)). Cells were observed to grow at a temperature range of 10-37 degrees C (optimal 25-33 degrees C), pH range of 5.5-10.0 (optimal 6.5-7.5) and can tolerate 0-7 % NaCl (w/v) (optimum 0-1 %) in tryptic soya agar medium. Sequencing of the 16S rRNA gene and two housekeeping genes, gyrB and nirK, of the isolated strains revealed that both strains belong to the Betaproteobacteria showing highest sequence similarities with members of the genus Alcaligenes. The chemotaxonomic data [major quinones as Q-8; predominant cellular fatty acids as summed features 3 (C16 :1 omega7c/iso-C15 :0 2OH) and C16:0 followed by Summed features 2 (iso-C16 :1 I/C14 :0 3OH), C17:0 Cyclo and C18:1 omega7c; major polar lipids as diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and one unidentified aminolipid] also supported the affiliation of the isolated strains with the genus Alcaligenes. DNA-DNA hybridizations between the two strains and with closely related type strains of species of the genus Alcaligenes confirmed that both isolates belong to a single novel species within the genus Alcaligenes. On the basis of phylogenetic analyses, physiological, biochemical characteristics and DNA-DNA hybridization, the isolated strains can be differentiated from established Alcaligenes species and thus represent a novel species, for which the name Alcaligenes pakistanensis sp. nov. is proposed with the type strain NCCP-650(T) (=LMG 28368(T) = KCTC42083(T) = JCM 30216(T)). PMID- 26238382 TI - Genes related to antioxidant metabolism are involved in Methylobacterium mesophilicum-soybean interaction. AB - The genus Methylobacterium is composed of pink-pigmented methylotrophic bacterial species that are widespread in natural environments, such as soils, stream water and plants. When in association with plants, this genus colonizes the host plant epiphytically and/or endophytically. This association is known to promote plant growth, induce plant systemic resistance and inhibit plant infection by phytopathogens. In the present study, we focused on evaluating the colonization of soybean seedling-roots by Methylobacterium mesophilicum strain SR1.6/6. We focused on the identification of the key genes involved in the initial step of soybean colonization by methylotrophic bacteria, which includes the plant exudate recognition and adaptation by planktonic bacteria. Visualization by scanning electron microscopy revealed that M. mesophilicum SR1.6/6 colonizes soybean roots surface effectively at 48 h after inoculation, suggesting a mechanism for root recognition and adaptation before this period. The colonization proceeds by the development of a mature biofilm on roots at 96 h after inoculation. Transcriptomic analysis of the planktonic bacteria (with plant) revealed the expression of several genes involved in membrane transport, thus confirming an initial metabolic activation of bacterial responses when in the presence of plant root exudates. Moreover, antioxidant genes were mostly expressed during the interaction with the plant exudates. Further evaluation of stress- and methylotrophic-related genes expression by qPCR showed that glutathione peroxidase and glutathione synthetase genes were up-regulated during the Methylobacterium-soybean interaction. These findings support that glutathione (GSH) is potentially a key molecule involved in cellular detoxification during plant root colonization. In addition to methylotrophic metabolism, antioxidant genes, mainly glutathione-related genes, play a key role during soybean exudate recognition and adaptation, the first step in bacterial colonization. PMID- 26238383 TI - The lesson for us in a bipolar disorder patient comorbid with dissociative amnesia. PMID- 26238384 TI - Neural substrates of risky decision making in individuals with Internet addiction. AB - OBJECTIVE: With the wide and rapid expansion of computers and smartphones, Internet use has become an essential part of life and an important tool that serves various purposes. Despite the advantages of Internet use, psychological and behavioral problems, including Internet addiction, have been reported. In response to growing concern, researchers have focused on the characteristics of Internet addicts. However, relatively little is known about the behavioral and neural mechanisms that underlie Internet addiction, especially with respect to risky decision making, which is an important domain frequently reported in other types of addictions. METHOD: To examine the neural characteristics of decision making in Internet addicts, Internet addicts and healthy controls were scanned while they performed a financial decision-making task. RESULTS: Relative to healthy controls, Internet addicts showed (1) more frequent risky decision making; (2) greater activation in the dorsal anterior cingulate cortex and the left caudate nucleus, which are brain regions involved in conflict monitoring and reward, respectively; and (3) less activation in the ventrolateral prefrontal cortex, an area associated with cognitive control/regulation. CONCLUSION: These findings suggest that risky decision making may be an important behavioral characteristic of Internet addiction and that altered brain function in regions associated with conflict monitoring, reward and cognitive control/regulation might be critical biological risk factors for Internet addiction. PMID- 26238379 TI - An Overview of Translationally Informed Treatments for Posttraumatic Stress Disorder: Animal Models of Pavlovian Fear Conditioning to Human Clinical Trials. AB - Posttraumatic stress disorder manifests after exposure to a traumatic event and is characterized by avoidance/numbing, intrusive symptoms and flashbacks, mood and cognitive disruptions, and hyperarousal/reactivity symptoms. These symptoms reflect dysregulation of the fear system likely caused by poor fear inhibition/extinction, increased generalization, and/or enhanced consolidation or acquisition of fear. These phenotypes can be modeled in animal subjects using Pavlovian fear conditioning, allowing investigation of the underlying neurobiology of normative and pathological fear. Preclinical studies reveal a number of neurotransmitter systems and circuits critical for aversive learning and memory that have informed the development of therapies used in human clinical trials. In this review, we discuss the evidence for a number of established and emerging pharmacotherapies and device-based treatments for posttraumatic stress disorder that have been developed via a bench to bedside translational model. PMID- 26238385 TI - Air quality in the assisted reproduction laboratory: a mini-review. AB - Quality of air in the clinical embryology laboratory is considered critical for high in vitro fertilization (IVF) success rates, yet evidence for best practices is lacking. Predominantly anecdotal reports on relationships between air quality and IVF success rates have resulted in minimal authentic clinical laboratory guidelines or in recommendations that are based on industrial cleanroom particulate standards with little attention to chemical air filtration. As a result, a nascent industry of costly, specialized air handling equipment for IVF laboratories has emerged to provide air quality solutions that have not been clearly assessed or verified. Clinics are embracing such technology because their embryology laboratories have become epicenters of assisted reproductive technology as the practice of IVF has moved to blastocyst transfers and utilization of trophectoderm biopsy for preimplantation genetic testing (PGT). Thus, a laboratory's ability to culture, biopsy, and freeze blastocysts is a rate limiting step that depends on technical proficiency and a supportive and stable culture environment based on a foundation of high-quality ambient air. This review aims to describe how evidence for the importance of air quality, in particular the role of volatile organic compounds (VOC), has resulted in an evolution of clinical practice that has arguably contributed to improved outcomes. PMID- 26238386 TI - The beneficial effects of polyethylene glycol-superoxide dismutase on ovarian tissue culture and transplantation. AB - PURPOSE: Reducing the ischemic damage from free radicals that is inflicted on ovarian tissue is critical for successful ovarian tissue transplantation. Polyethylene glycol-superoxide dismutase (PEG-SOD) is mimetic of superoxide dismutase (SOD) and powerful free radical scavenger acts by reducing superoxide anions. The objective of study was to evaluate effects of PEG-SOD on mouse ovarian tissues in in vitro culture and in autotransplantation. METHODS: Ovaries were collected and randomly divided into four groups that received different doses of PEG-SOD. To assess effects of PEG-SOD on in vitro cultures, four different doses of PEG-SOD were applied to in vitro culture media during in vitro culturing following ovarian tissue vitrification and warming. To evaluate effects of PEG-SOD on ovarian tissue transplantation, four different doses of PEG-SOD were applied for 2, 7, and 21 days to mice following vitrified-warmed mouse ovarian tissue autotransplantation. RESULTS: The percentage of primordial follicles was maintained at the highest dose of PEG-SOD for 2 h in vitro, and there was a significant decrease in the percentage of apoptotic follicles at 2 h, but not at later time points. The highest dose of PEG-SOD also maintained primordial, primary, and secondary follicles 2 days post-transplantation, but only primordial follicles were maintained up to 21 days after transplantation. CONCLUSIONS: PEG-SOD is protective mainly toward primordial follicles only for a short interval in vitro, presumably via antioxidant effects. PEG-SOD may be a promising additive for preserving ovarian tissue integrity, at least for primordial follicles, up to 21 days post-transplantation. PMID- 26238387 TI - Antimullerian hormone levels are inversely associated with body mass index (BMI) in women with polycystic ovary syndrome. AB - PURPOSE: The purpose of this paper is to determine whether antimullerian hormone (AMH) levels were associated with BMI in patients with diagnosed infertility, and more specifically, in patients with polycystic ovarian syndrome (PCOS). METHODS: A retrospective cohort study reviewed all females who presented to the clinical investigators' practice between November 2011 and March 2013. The following data was retrieved from the medical record: (1) AMH level, (2) age, (3) BMI, (4) ethnicity, and (5) if infertile, etiology of infertility. RESULTS: AMH levels were available for 489 women. Of these, 104 were diagnosed with PCOS. Overall, there was no association between BMI and AMH (r -0.04, p > 0.05). On the other hand, in the women with PCOS, there was a significant association between BMI and AMH (r -0.31, p < 0.01). CONCLUSIONS: BMI was not associated with AMH levels in the general population of infertile women or in patients without PCOS. However, BMI appeared to be significantly and inversely correlated with AMH in women with PCOS. PMID- 26238388 TI - Impact of the cryopreservation technique and vascular bed on ovarian tissue transplantation in cynomolgus monkeys. AB - PURPOSE: The aim of this study was to determine the best combination in terms of cryopreservation techniques and vascular bed preparation before grafting in order to obtain functional ovarian tissue after transplantation. METHODS: Five cynomolgus monkeys were used. Strips from 10 ovaries were cryopreserved, 5 by vitrification (V), and 5 by slow-freezing (SF). Pieces of fresh ovarian tissue were used for controls. After 1 month, the strips were autografted to two different vascular beds, healed (HB) or freshly decorticated (FDB), constituting four study groups: SF-HB, SF-FDB, V-HB, and V-FDB. These were compared to fresh tissue. After 6 months, the ovaries were removed and several parameters analyzed: follicle quality, stage, density, proliferation, apoptosis, functionality, vascularization, and fibrosis. Mixed effect linear regression models were built to assess the impact of cryopreservation and vascular bed preparation on ovarian tissue viability and functionality. p values were adjusted for multiple testing using the Benjamini-Hochberg method, and q values < 0.20 were considered significant in order to achieve a 20% false discovery rate. RESULTS: Compared to fresh tissue, no difference was observed in the percentage of morphologically normal follicles, while a significant increase was noted in the follicle proliferation rate (41%, q = 0.19), percentage of antral follicles (12%, q = 0.14), and number of vessels per area (3.3 times, q = 0.07) in the V-FDB group. CONCLUSIONS: Vitrification associated with FDB vascular bed preparation is the best combination to obtain functional autografted ovarian tissue. Further studies are nevertheless required, with confirmed pregnancies and live births before introducing the procedure into clinical practice. PMID- 26238389 TI - Slow freezing should not be totally substituted by vitrification when applied to day 3 embryo cryopreservation: an analysis of 5613 frozen cycles. AB - PURPOSE: This study aimed to compare slow freezing (SF) and vitrification (VT) techniques for day 3 embryo cryopreservation in infertile couples. METHODS: This retrospective cohort study enrolled 5613 infertile patients, with 7862 frozen thawed day 3 embryos and 3845 vitrified-warmed day 3 embryos, from 2010 to 2014, at a single center. The rates of embryo survival, pregnancy, implantation, miscarriage, live birth, and live birth weight were compared between the two groups. RESULTS: A total of 5613 cycles with 5520 transfers were analyzed. Using SF, the rates of overall embryo survival and fully intact blastomeres were lower than those in VT (91.5 vs. 97.4 % and 68.7 vs. 92.3 %, respectively). The rate of good quality embryos after thawing/warming was lower in SF than in VT. In single frozen embryo transfer cycles (FETs), the pregnancy and implantation rates were similar between the two groups (35.0 vs. 40.8 % and 34.6 vs. 35.9 %, respectively). In double FETs, the pregnancy rate per cycle was also similar between the groups (58.8 vs. 58.4 %). The implantation rate per embryo transfer was significantly higher with SF than with VT (38.8 vs. 34.6 %). With adjustment for maternal age and the number of good quality embryos, differences in implantation rate remained significant (adjusted P value, SF vs. VT P < 0.05). No independent effect was found for the method of cryopreservation on the pregnancy rate. No significant differences in the rates of miscarriage, live birth, and live birth weight were observed between the two techniques. CONCLUSIONS: Despite the significantly low embryo survival rate, fully intact blastomere rate, and good quality embryo rate in SF, the pregnancy and implantation rates were not adversely affected in single and double FETs. SF yielded an equivalent miscarriage rate, live birth rate, and live birth weight compared with VT. The SF protocol to cryopreserve day 3 embryos still should be considered. PMID- 26238390 TI - Serum progesterone levels greater than 20 ng/dl on day of embryo transfer are associated with lower live birth and higher pregnancy loss rates. AB - BACKGROUND: Progesterone (P4) is essential for support of the endometrium and implantation of an embryo in the normal menstrual cycle. In programed frozen embryo transfer cycles using exogenous P4 is necessary, as the endogenous production of P4 requires a functioning corpus luteum that is not present in programed cycles. To date, there is continuing debate about ideal serum estradiol and P4 values in frozen embryo transfer cycles. METHODS: Patients underwent single euploid embryo frozen transfer cycles from 2010 to 2013 at a single large academic center. Patients using donor oocytes and patients with changes in progesterone dose during the cycles in question were excluded. All cycles were programed and intramuscular P4 was used exclusively. Only patients administering the same daily dose of P4 throughout the cycle were included (N = 213 patients). Main outcomes were ongoing pregnancy/live birth rates (OPR/LBR), clinical pregnancy rates (CPR), and spontaneous abortions/biochemical pregnancies. CPR was defined by the presence of a sac on 1st trimester ultrasound. Missed abortions were calculated per pregnancy with a sac. Receiver operator characteristic curves (ROC curves) and chi-squared tests were performed for statistical analysis. RESULTS: Two groups based on day 19 P4 levels were compared (group A, P4 < 20 ng/ml; group B, P4 > 20 ng/ml). OPR/LBRs were 65 vs. 49 %, group A vs. B, p value = 0.02, RR = 1.33 (1.1-1.7). Missed abortion and biochemical rates were higher in group B as opposed to group A, 27 vs. 12 %, p = 0.01, RR = 0.45(0.24-0.86). When P4 was stratified into five groups based on nanogram per milliliter of progesterone on day 19 (10-15, 15-20, 20-30, 30-40, and >40), there was a trend downward in OPR/LBR (70, 62, 52, 50, and 33 %, respectively). There was also an increase in missed abortion/biochemical rates (7, 15, 27, 32, and 20 %, respectively). Multiple logistic regression showed an increase in OPR/LBR when accounting for age, day 2 FSH, weight, number of embryos biopsied, and number of euploid embryos. CONCLUSION: P4 levels >20 ng/ml on the day of transfer (during frozen single euploid embryo transfer cycles) were associated with decreased OPR/LBR. PMID- 26238391 TI - Double-strand DNA breaks and repair response in human immature oocytes and their relevance to meiotic resumption. AB - PURPOSE: Only 50-60 % of immature human oocytes attain the mature stage in vitro. Such a deficiency may be a reflection of inadequate conditions of in vitro maturation (IVM) or a manifestation of intrinsic oocyte defects. In the present study, we explored the possibility that the DNA of immature oocytes may be damaged and that such a condition, or inability to trigger a repair action, is associated to germinal vesicle (GV) arrest. METHODS: Immature oocytes (GV-stage oocytes) were obtained from women undergoing stimulated (Stim-C) or IVM (IVM-C) cycles. GV oocytes obtained from stimulated cycles were fixed for successive analysis either after recovery (T0) or following 30 h (T30) of culture if still arrested at the GV stage. Oocytes retrieved in IVM cycles were used only if they were found arrested at the GV stage after 30 h (T30) of culture. All oocytes were fixed and stained to detect chromatin and actin. They were also assessed for positivity to gammaH2AX and Rad51, markers revealing the presence of double strand DNA breaks and the activation of a DNA repair response, respectively. Labelled oocytes were analysed using a Leica TCS SP2 laser scanning confocal microscope. RESULTS: In Stim-C oocytes, gammaH2AX positivity was 47.5 and 81.5 % in the T0 and T30 groups, respectively (P = 0.003), while gammaH2AX-positive oocytes were 58.3 % in the IVM-C T30 group (Stim-C T0 vs. IVM-C T30, P = 0.178; Stim-C T30 vs. IVM-C T30, P = 0.035). Positivity for nuclear staining to Rad51 occurred in 42.1 and 74.1 % of Stim-C in the T0 and T30 subgroups, respectively (T = 0.006), while 66.7 % of IVM-C T30 oocytes resulted positive for a DNA repair response (Stim-C T0 vs. IVM-C T30, P = 0.010; Stim-C T30 vs. IVM-C T30, P = 0.345). CONCLUSIONS: The present data document the existence of double-strand DNA breaks (DSBs) in human immature oocytes. Also, they are consistent with the hypothesis that insults to DNA integrity may be an important factor affecting meiotic resumption. PMID- 26238392 TI - Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy. AB - The grim prognosis for patients diagnosed with malignant gliomas necessitates the development of new therapeutic strategies for localized and sustained drug delivery to combat tumor drug resistance and regrowth. Here we introduce drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy (DREAM BIG therapy). DREAM BIG therapy is envisioned to deliver three chemotherapeutics, temporally staged over one year, via a bioadhesive, biodegradable spray directly to the brain surgical site after tumor excision. In this proof-of-principle article exploring key components of the DREAM BIG therapy prototype, rhodamine B (RB) encapsulated poly(lactic-co-glycolic acid) and immunoglobulin G (IgG) encapsulated poly(lactic acid) microspheres were formulated and characterized. The encapsulation efficiency of RB and IgG and the release kinetics of the model drugs from the microspheres were elucidated in addition to the release kinetics of RB from poly(lactic-co-glycolic acid) microspheres formulated in a degradable poly(N-isopropylacrylamide) solution. The successful aerosolized application onto brain tissue ex-vivo demonstrated the conformal adhesion of the RB encapsulated poly(lactic-co-glycolic acid) microspheres to the convoluted brain surface mediated by the thermoresponsive carrier, poly(N-isopropylacrylamide). These preliminary results suggest the potential of the DREAM BIG therapy for future use with multiple chemotherapeutics and microsphere types to combat gliomas at a localized site. PMID- 26238393 TI - Ionizing radiation induces a motile phenotype in human carcinoma cells in vitro through hyperactivation of the TGF-beta signaling pathway. AB - Radiotherapy, a major treatment modality against cancer, can lead to secondary malignancies but it is uncertain as to whether tumor cells that survive ionizing radiation (IR) treatment undergo epithelial-mesenchymal transition (EMT) and eventually become invasive or metastatic. Here, we have tested the hypothesis that the application of IR (10 MeV photon beams, 2-20 Gy) to lung and pancreatic carcinoma cells induces a migratory/invasive phenotype in these cells by hyperactivation of TGF-beta and/or activin signaling. In accordance with this assumption, IR induced gene expression patterns and migratory responses consistent with an EMT phenotype. Moreover, in A549 cells, IR triggered the synthesis and secretion of both TGF-beta1 and activin A as well as activation of intracellular TGF-beta/activin signaling as evidenced by Smad phosphorylation and transcriptional activation of a TGF-beta-responsive reporter gene. These responses were sensitive to SB431542, an inhibitor of type I receptors for TGF beta and activin. Likewise, specific antibody-mediated neutralization of soluble TGF-beta, or dominant-negative inhibition of the TGF-beta receptors, but not the activin type I receptor, alleviated IR-induced cell migration. Moreover, the TGF beta-specific approaches also blocked IR-dependent TGF-beta1 secretion, Smad phosphorylation, and reporter gene activity, collectively indicating that autocrine production of TGF-beta(s) and subsequent activation of TGF-beta rather than activin signaling drives these changes. IR strongly sensitized cells to further increase their migration in response to recombinant TGF-beta1 and this was accompanied by upregulation of TGF-beta receptor expression. Our data raise the possibility that hyperactivation of TGF-beta signaling during radiotherapy contributes to EMT-associated changes like metastasis, cancer stem cell formation and chemoresistance of tumor cells. PMID- 26238394 TI - Impact of a private sector living wage intervention on depressive symptoms among apparel workers in the Dominican Republic: a quasi-experimental study. AB - OBJECTIVES: Poverty reduction interventions through cash transfers and microcredit have had mixed effects on mental health. In this quasi-experimental study, we evaluate the effect of a living wage intervention on depressive symptoms of apparel factory workers in the Dominican Republic. SETTING: Two apparel factories in the Dominican Republic. PARTICIPANTS: The final sample consisted of 204 hourly wage workers from the intervention (99) and comparison (105) factories. INTERVENTIONS: In 2010, an apparel factory began a living wage intervention including a 350% wage increase and significant workplace improvements. The wage increase was plausibly exogenous because workers were not aware of the living wage when applying for jobs and expected to be paid the usual minimum wage. These individuals were compared with workers at a similar local factory paying minimum wage, 15-16 months postintervention. PRIMARY OUTCOME MEASURES: Workers' depressive symptoms were assessed using the Center for Epidemiologic Studies-Depression Scale (CES-D). Ordinary least squares and Poisson regressions were used to evaluate treatment effect of the intervention, adjusted for covariates. RESULTS: Intervention factory workers had fewer depressive symptoms than comparison factory workers (unadjusted mean CES-D scores: 10.6 +/- 9.3 vs 14.7 +/- 11.6, p = 0.007). These results were sustained when controlling for covariates (beta = -5.4, 95% CI -8.5 to -2.3, p = 0.001). In adjusted analyses using the standard CES-D clinical cut-off of 16, workers at the intervention factory had a 47% reduced risk of clinically significant levels of depressive symptoms compared with workers at the comparison factory (23% vs 40%). CONCLUSIONS: Policymakers have long grappled with how best to improve mental health among populations in low-income and middle-income countries. We find that providing a living wage and workplace improvements to improve income and well being in a disadvantaged population is associated with reduced depressive symptoms. PMID- 26238395 TI - Protocol--the RAMESES II study: developing guidance and reporting standards for realist evaluation. AB - INTRODUCTION: Realist evaluation is an increasingly popular methodology in health services research. For realist evaluations (RE) this project aims to: develop quality and reporting standards and training materials; build capacity for undertaking and critically evaluating them; produce resources and training materials for lay participants, and those seeking to involve them. METHODS: To achieve our aims, we will: (1) Establish management and governance infrastructure; (2) Recruit an interdisciplinary Delphi panel of 35 participants with diverse relevant experience of RE; (3) Summarise current literature and expert opinion on best practice in RE; (4) Run an online Delphi panel to generate and refine items for quality and reporting standards; (5) Capture 'real world' experiences and challenges of RE-for example, by providing ongoing support to realist evaluations, hosting the RAMESES JISCmail list on realist research, and feeding problems and insights from these into the deliberations of the Delphi panel; (6) Produce quality and reporting standards; (7) Collate examples of the learning and training needs of researchers, students, reviewers and lay members in relation to RE; (8) Develop, deliver and evaluate training materials for RE and deliver training workshops; and (9) Develop and evaluate information and resources for patients and other lay participants in RE (eg, draft template information sheets and model consent forms) and; (10) Disseminate training materials and other resources.Planned outputs: (1) Quality and reporting standards and training materials for RE. (2) Methodological support for RE. (3) Increase in capacity to support and evaluate RE. (4) Accessible, plain-English resources for patients and the public participating in RE. DISCUSSION: The realist evaluation is a relatively new approach to evaluation and its overall place in the is not yet fully established. As with all primary research approaches, guidance on quality assurance and uniform reporting is an important step towards improving quality and consistency. PMID- 26238396 TI - Expression of cortactin in human gliomas and its effect on migration and invasion of glioma cells. AB - The aim of the present study was to investigate the role of cortactin in the infiltrative behavior of glioma cells and the potential mechanism of cortactin in promoting the migration and invasion of glioma cells. The expression of cortactin was detected by immunohistochemistry in 40 human glioma specimens and 8 non-tumor brain specimens. U251, LN229 and SNB19 glioma cells were employed for the in vitro study and assigned into the siRNA-cortactin (transfected with siRNA specific to cortactin), siRNA-NC (transfected with negative control RNA sequence) and siRNA-N (transfected with empty vector) groups. The expression of cortactin in different treated glioma cell groups was detected using western blot analysis and RT-qPCR. The migration and invasion of glioma cells under different treatments were assessed using a wound-healing assay and Transwell-chamber invasion assay, respectively. The lamellipodia of glioma cells following treatment were observed by immunofluorescence (IF) and changes of lamellipodia over time were imaged using an inverted microscope. The distribution of cortactin and the actin-related protein 2/3 (Arp2/3) complex in glioma cells were observed after IF detection. The expression of cortactin in the glioma specimens was significantly higher than that in non-tumor brain tissue (P<0.05) and positively correlated with the malignancy of glioma specimens (r=0.912, P=0.00). The cortactin expression in glioma cells was markedly inhibited (P<0.05) and their migration and invasion ability was also impaired significantly following treatment with siRNA (P<0.05) compared with the other two groups. The size and persistence time of lamellipodia were reduced after cortactin expression was inhibited in glioma cells. Cortactin and the Arp2/3 complex were co-localized in the front of glioma cells, where actin was polymerized and lamellipodia formed. Thus, the results revealed that, cortactin is crucial in invasion and migration of glioma cells, which may promote the migration and invasion of glioma cells by regulating lamellipodia formation, a process requiring the combination of cortactin and the Arp2/3 complex. PMID- 26238397 TI - Risk factors for reoperation due to chronic groin postherniorrhaphy pain. AB - BACKGROUND: Chronic groin postherniorrhaphy pain (CGPP) is common and sometimes so severe that surgical treatment is necessary. The aim of this study was to identify risk factors for being reoperated due to CGPP. METHODS: All 195,707 repairs registered in the Swedish Hernia Register between 1999 and 2011 were included in the study. Out of these, 28,947 repairs were excluded since they were registered as procedures on the same patient after a previous repair. Age, gender, hernia anatomy (indirect reference), method of repair (anterior sutured repair reference) and postoperative complications were included in a multivariate Cox analysis with reoperation due to CGPP as endpoint. RESULTS: Of the patients included in the study cohort, 218 (0.13%) later underwent reoperation due to CGPP, including 31 (14%) women. Median age at the primary repair was 61.5 years. Risk factors for being reoperated were age < median [hazard ratio (HR) 3.03, 95% confidence interval (CI) 2.22-4.12], female gender (HR 2.13, CI 1.41-3.21), direct hernia (HR 1.35, CI 1.003-1.81), other hernia (HR 6.03, CI 3.08-11.79), Lichtenstein repair (HR 2.22, CI 1.16-4.25), plug repair (HR 3.93, CI 1.96-7.89), other repair (HR 2.58, CI 1.08-6.19), bilateral repair (HR 2.58, CI 1.43-4.66) and postoperative complication (HR 4.40, CI 3.25-5.96). CONCLUSIONS: Risk factors for being reoperated due to CGPP in this cohort included low age, female gender, a direct hernia, a previous Lichtenstein or plug repair, bilateral repair and postoperative complications. Further research on how to avoid CGPP and explore the effectiveness of surgery for CGPP is necessary. PMID- 26238398 TI - TEP and Lichtenstein anatomy: does simulation accelerate acquisition among interns? AB - PURPOSE: The anatomy of the inguinal region is notoriously challenging to master. We sought to teach open inguinal hernia (OIH) and totally extraperitoneal (TEP) anatomy with simulation models among general surgery (GS) interns. METHODS: Low fidelity OIH and TEP models were constructed out of cardboard, plastic bins, fabric, and yarn. GS interns (n = 30) participated in a 3-h hernia session including a pretest, anatomy lecture, simulated OIH and TEP hernia repair, and posttest. Pre- and posttest scores were based on a difficult 30-point exam which included didactic questions (10 points), drawing relevant TEP (10 points), and OIH (10 points) anatomy. Participants were surveyed following the session. RESULTS: Median pretest scores were 13 % (range 0-60 %). Median posttest scores improved to 47 % (range 20-93 %, p < 0.001). Median number of structures drawn in the TEP image improved from 2 (range 0-14) to 11 (range 1-21, p < 0.001). Median number of structures drawn in the OIH image improved from 3 (range 0-15) to 7 (range 1-19, p < 0.001). 67 % (12/18) demonstrated improvement in knowledge of abdominal wall layers. 23 % (7/30) knew the triangles of pain/doom on the pretest vs. 77 % (23/30) on the posttest. Mean Likert scores favored session enjoyability (4.5), not a waste of training time (4.4), and improved understanding of OIH and TEP anatomy (4.4, 4.2). CONCLUSIONS: Low-fidelity simulators can be used to teach and assess knowledge of TEP and OIH anatomy. While enjoyable and useful, one 3-h session does not create master hernia surgeons or expert anatomists out of novice trainees. PMID- 26238399 TI - Comment to: Meta-analysis and systematic review of laparoscopic versus open mesh repair for elective incisional hernia. Awaiz A et al. Hernia 2015;19:449-463. PMID- 26238400 TI - Synergistic neuroprotective effect of microglial-conditioned media treated with geniposide and ginsenoside Rg1 on hypoxia injured neurons. AB - The synergistic mechanism underlying the effects of multi-component combined drug use for complex diseases remains to be fully elucidated. Microglial activation following ischemia can either affect neural survival or cause neuronal injury. The aim of the present study was to determine the synergistic effect of geniposide and ginsenoside Rg1, based on microglial-neuronal communication. N2a neuronal cells were divided into the following seven groups: Control group; normal cultured microglial cells in conditioned medium (N-MG-CM) group; oxygen glucose deprivation (OGD) model group; OGD-injured MG-CM (I-MG-CM) group; geniposide-treated MG-CM (G-MG-CM) group; ginsenoside Rg1-treated MG-CM (R-MG-CM) group; and combination-treated MG-CM (C-MG-CM) group. A series of assays were used to detect the effects of the different MG-CM on neurons in terms of: (i) cell viability, determined using a Cell Counting Kit-8; (ii) lactate dehydrogenase (LDH) leakage rate; (iii) expression of NMDAR1 and activated caspase-3, detected using western blotting; (iv) mitochondrial transmembrane potential, determined by JC-1; and (v) mitochondrial ultrastructural features, determined using electron microscopy. The experimental results demonstrated that MG-CM including the integrated use of geniposide and ginsenoside Rg1 significantly protected neuronal cell viability and inhibited LDH leakage, suppressed the expression of N-methyl-D-aspartate receptor subunit 1 and activated caspase-3, increased the mitochondrial transmembrane potential and improved the mitochondrial ultrastructure. MG-CM from separately used geniposide or ginsenoside Rg1 demonstrated differential neuroprotection at different levels. These findings revealed that the synergistic drug combination of geniposide and ginsenoside Rg1 in the treatment of stroke is a feasible approach for use. PMID- 26238401 TI - Expansion of CRISPR/Cas9 genome targeting sites in zebrafish by Csy4-based RNA processing. PMID- 26238402 TI - Substrate-bound structure of the E. coli multidrug resistance transporter MdfA. AB - Multidrug resistance is a serious threat to public health. Proton motive force driven antiporters from the major facilitator superfamily (MFS) constitute a major group of multidrug-resistance transporters. Currently, no reports on crystal structures of MFS antiporters in complex with their substrates exist. The E. coli MdfA transporter is a well-studied model system for biochemical analyses of multidrug-resistance MFS antiporters. Here, we report three crystal structures of MdfA-ligand complexes at resolutions up to 2.0 A, all in the inward-facing conformation. The substrate-binding site sits proximal to the conserved acidic residue, D34. Our mutagenesis studies support the structural observations of the substrate-binding mode and the notion that D34 responds to substrate binding by adjusting its protonation status. Taken together, our data unveil the substrate binding mode of MFS antiporters and suggest a mechanism of transport via this group of transporters. PMID- 26238403 TI - Trace elements and heavy metals in the Grand Bay National Estuarine Reserve in the northern Gulf of Mexico. AB - The objectives of this study are to investigate distribution of trace elements and heavy metals in the salt marsh and wetland soil and biogeochemical processes in the Grand Bay National Estuarine Research Reserve of the northern Gulf of Mexico. The results show that Hg, Cd and to some extent, As and Pb have been significantly accumulated in soils. The strongest correlations were found between concentrations of Ni and total organic matter contents. The correlations decreased in the order: Ni>Cr>Sr>Co>Zn, Cd>Cu>Cs. Strong correlations were also observed between total P and concentrations of Ni, Co, Cr, Sr, Zn, Cu, and Cd. This may be related to the P spilling accident in 2005 in the Bangs Lake site. Lead isotopic ratios in soils matched well those of North American coals, indicating the contribution of Pb through atmospheric fallout from coal power plants. PMID- 26238404 TI - Hyperlipidemia exacerbates cerebral injury through oxidative stress, inflammation and neuronal apoptosis in MCAO/reperfusion rats. AB - Recent studies showed that hyperglycemia enhanced brain damage when subjected to transient cerebral ischemic stroke. However, the etiologic link between them has been less known. In the present study, based on an experimental rat's model of hyperlipidemia combined with cerebral ischemia-reperfusion injury (I/R), we herein showed that hyperlipidemia induced by high-fat diet (HFD) resulted in considerable increase in serum triglycerides, cholesterol and low-density lipoprotein cholesterol, and remarkable decrease in serum high-density lipoprotein cholesterol, which associated with an exacerbation on neurological deficit, cerebral infarct and terminal deoxynucleotidyl transferase-mediated nick end labeling-positive cells in the ischemic hemisphere of cerebral I/R rats treated with HFD diet. The data showed that serum superoxide dismutase activity and glutathione peroxides content were significantly decreased, while malondialdehyde level was obviously increased by hyperlipidemia or cerebral I/R alone, especially by coexistence of hyperlipidemia and cerebral I/R; meantime, hyperlipidemia also enhanced cerebral I/R-induced protein expression of cytochrome P450 2E1 (CYP2E1) and the levels of pro-inflammatory factors tumor necrosis factor-alpha and IL-6 in the ischemic hemispheres. Furthermore, the combined action of hyperlipidemia and cerebral I/R resulted in a protein increase expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 compared to hyperlipidemia or cerebral I/R alone. Meanwhile, this study also showed that hyperlipidemia significantly enhanced cerebral I/R-induced transfer of cytochrome c from mitochondria to cytosolic and the protein expressions of Apaf-1 and caspase-3, but also decreased cerebral I/R-induced bcl 2 protein expression. The results reveal that hyperlipidemia exacerbates cerebral I/R-induced injury through the synergistic effect on CYP2E1 induction, which further induces reactive oxygen species formation, oxidative stress, inflammation and neuronal apoptosis by coexistence of hyperlipidemia and cerebral I/R. PMID- 26238405 TI - Is there a link between sensorimotor coordination and inter-manual coordination? Differential effects of auditory and/or visual rhythmic stimulations. AB - The purpose of this study was to test how the sensory modality of rhythmic stimuli affects the production of bimanual coordination patterns. To this aim, participants had to synchronize the taps of their two index fingers with auditory and visual stimuli presented separately (auditory or visual) or simultaneously (audio-visual). This kind of task requires two levels of coordination: (1) sensorimotor coordination, which can be measured by the mean asynchrony between the beat of the stimulus and the corresponding tap and by mean asynchrony stability, and (2) inter-manual coordination, which can be assessed by the accuracy and stability of the relative phase between the right-hand and left-hand taps. Previous studies show that sensorimotor coordination is better during the synchronization with auditory or audio-visual metronomes than with visual metronome, but it is not known whether inter-manual coordination is affected by stimulation modalities. To answer this question, 13 participants were required to tap their index fingers in synchrony with the beat of auditory and/or visual stimuli specifying three coordination patterns: two preferred inphase and antiphase patterns and a non-preferred intermediate pattern. A first main result demonstrated that inphase tapping had the best inter-manual stability, but the worst asynchrony stability. The second main finding revealed that for all patterns, audio-visual stimulation improved the stability of sensorimotor coordination but not of inter-manual coordination. The combination of visual and auditory modalities results in multisensory integration, which improves sensorimotor coordination but not inter-manual coordination. Both results suggest that there is dissociation between processes underlying sensorimotor synchronization (anticipation or reactivity) and processes underlying inter manual coordination (motor control). This finding opens new perspectives to evaluate separately the possible sensorimotor and inter-manual coordination deficits present in movement disorders. PMID- 26238406 TI - Subliminal presentation of emotionally negative vs positive primes increases the perceived beauty of target stimuli. AB - Emotions have a profound influence on aesthetic experiences. Studies using affective priming procedures demonstrate, for example, that inducing a conscious negative emotional state biases the perception of abstract stimuli towards the sublime (Eskine et al. Emotion 12:1071-1074, 2012. doi: 10.1037/a0027200). Moreover, subliminal happy facial expressions have a positive impact on the aesthetic evaluation of abstract art (Flexas et al. PLoS ONE 8:e80154, 2013). Little is known about how emotion influences aesthetic perception of non abstract, representational stimuli, especially those that are particularly relevant for social behaviour, like human bodies. Here, we explore whether the subliminal presentation of emotionally charged visual primes modulates the explicit subjective aesthetic judgment of body images. Using a forward/backward masking procedure, we presented subliminally positive and negative, arousal matched, emotional or neutral primes and measured their effect on the explicit evaluation of perceived beauty (high vs low) and emotion (positive vs negative) evoked by abstract and body images. We found that negative primes increased subjective aesthetic evaluations of target bodies or abstract images in comparison with positive primes. No influence of primes on the emotional dimension of the targets was found, thus ruling out an unspecific arousal effect and strengthening the link between emotional valence and aesthetic appreciation. More specifically, that subliminal negative primes increase beauty ratings compared to subliminal positive primes indicates a clear link between negative emotions and positive aesthetic evaluations and vice versa, suggesting a possible link between negative emotion and the experience of sublime in art. The study expands previous research by showing the effect of subliminal negative emotions on the subjective aesthetic evaluation not only of abstract but also of body images. PMID- 26238408 TI - Global state of women's health: should we be content? PMID- 26238407 TI - Complex regional pain syndrome (CRPS) or continuous unilateral distal experimental pain stimulation in healthy subjects does not bias visual attention towards one hemifield. AB - In natural life pain automatically draws attention towards the painful body part suggesting that it interacts with different attentional mechanisms such as visual attention. Complex regional pain syndrome (CRPS) patients who typically report on chronic distally located pain of one extremity may suffer from so-called neglect like symptoms, which have also been linked to attentional mechanisms. The purpose of the study was to further evaluate how continuous pain conditions influence visual attention. Saccade latencies were recorded in two experiments using a common visual attention paradigm whereby orientating saccades to cued or uncued lateral visual targets had to be performed. In the first experiment saccade latencies of healthy subjects were measured under two conditions: one in which continuous experimental pain stimulation was applied to the index finger to imitate a continuous pain situation, and one without pain stimulation. In the second experiment saccade latencies of patients suffering from CRPS were compared to controls. The results showed that neither the continuous experimental pain stimulation during the experiment nor the chronic pain in CRPS led to an unilateral increase of saccade latencies or to a unilateral increase of the cue effect on latency. The results show that unilateral, continuously applied pain stimuli or chronic pain have no or only very limited influence on visual attention. Differently from patients with visual neglect, patients with CRPS did not show strong side asymmetries of saccade latencies or of cue effects on saccade latencies. Thus, neglect-like clinical symptoms of CRPS patients do not involve the allocation of visual attention. PMID- 26238409 TI - Qualitative Study Exploring the Meaning of Knee Symptoms to Adults Ages 35-65 Years. AB - OBJECTIVE: While osteoarthritis (OA) has mainly been viewed as a disease affecting older people, its prevalence in younger adults is substantial. However, there is limited research on how younger adults understand knee symptoms. This article explores the meaning of knee symptoms to adults ages 35-65 years. METHODS: This qualitative study comprised 6 focus groups and 10 one-on-one interviews with 51 participants (median age 49, 61% female), who self-reported knee OA or reported knee symptoms (i.e., pain, aching, or stiffness) on most days of the past month. Constructivist grounded theory guided the sampling, data collection, and analysis. Data were analyzed using a constant comparative method. RESULTS: Central to participants' understanding of knee symptoms was the perception that symptoms were preventable, meaning that there was the potential to prevent the onset of symptoms and to alter the course of symptoms. This understanding was demonstrated in participants' explanation of symptoms. Participants commented on the cause, prevention, and course of symptoms. Moreover, participants reflected on their experience with symptoms, indicating that symptoms made them feel older than their current age. However, they did not perceive their symptoms as normal or acceptable. CONCLUSION: Participants interpreted knee symptoms as potentially preventable, suggesting that they may be open to primary and secondary prevention strategies. PMID- 26238410 TI - An in vitro study of peptide-loaded alginate nanospheres for antagonizing the inhibitory effect of Nogo-A protein on axonal growth. AB - The adult mammalian central nervous system has limited ability to regenerate after injury. This is due, in part, to the presence of myelin-associated axon growth inhibitory proteins such as Nogo-A that bind and activate the Nogo receptor, leading to profound inhibition of actin-based motility within the growing axon tip. This paper presents an in vitro study of the use of a Nogo receptor-blocking peptide to antagonize the inhibitory effect of Nogo-A on axon growth. Alginate nanospheres were fabricated using an emulsion technique and loaded with Nogo receptor-blocking peptide, or with other model proteins. Protein release profiles were studied, and retention of the bioactivity of released proteins was verified. Primary dorsal root ganglion neurons were cultured and their ability to grow neurites was challenged with Nogo-A chimeric protein in the absence or presence of Nogo receptor antagonist peptide-loaded alginate nanospheres. Our results demonstrate that peptide released from alginate nanospheres could overcome the growth inhibitory effect of Nogo-A, suggesting that a similar peptide delivery strategy using alginate nanospheres might be used to improve axon regeneration within the injured central nervous system. PMID- 26238411 TI - The new insight on the regulatory role of the vitamin D3 in metabolic pathways characteristic for cancerogenesis and neurodegenerative diseases. AB - Apart from the classical function of regulating intestinal, bone and kidney calcium and phosphorus absorption as well as bone mineralization, there is growing evidence for the neuroprotective function of vitamin D3 through neuronal calcium regulation, the antioxidative pathway, immunomodulation and detoxification. Vitamin D3 and its derivates influence directly or indirectly almost all metabolic processes such as proliferation, differentiation, apoptosis, inflammatory processes and mutagenesis. Such multifactorial effects of vitamin D3 can be a profitable source of new therapeutic solutions for two radically divergent diseases, cancer and neurodegeneration. Interestingly, an unusual association seems to exist between the occurrence of these two pathological states, called "inverse comorbidity". Patients with cognitive dysfunctions or dementia have considerably lower risk of cancer, whereas survivors of cancer have lower prevalence of central nervous system (CNS) disorders. To our knowledge, there are few publications analyzing the role of vitamin D3 in biological pathways existing in carcinogenic and neuropathological disorders. PMID- 26238412 TI - HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen. AB - The human epidermal growth factor receptor (HER) 4 is a relative of HER2 and has been associated to endocrine breast cancer and prediction of tamoxifen response. In addition to PI3K/Akt and MAPK pathway activation, ligand binding to HER4 triggers proteolytic cleavage and release of an intracellular receptor domain (4ICD) with signaling properties. The aim of the present study was to analyze HER4 protein expression and intracellular localization in breast cancer tissue from patients randomized to treatment with or without adjuvant tamoxifen. To investigate HER4 expression and localization in response to estradiol (E2) and 4 hydroxytamoxifen (4-OHT) exposure, we also performed in vitro studies. Cytoplasmic, nuclear and membrane expression of HER4 protein was evaluated by immunohistochemical staining in tumor tissue from 912 breast cancer patients. Three different breast epithelia cancer cell lines were exposed to E2 and 4-OHT and mRNA expression was analyzed using qPCR. Further, nuclear and cytoplasmic proteins were separated and analyzed with western blotting. We found an association between nuclear HER4 protein expression and ER-positivity (P=0.004). Furthermore, significant association was found between cytoplasmic HER4 and ER negativity (P<0.0005), PgR-negativity (P<0.0005), tumor size >20 mm (P=0.001) and HER2-negativity (P=0.008). However, no overall significance of HER4 on recurrence free survival was found. After E2 exposure, HER4 mRNA and protein expression had decreased in two cell lines in vitro yet no changes in nuclear or cytoplasmic protein fractions were seen. In conclusion, nuclear HER4 seem to be co-located with ER, however, we did not find support for overall HER4 expression in independently predicting response of tamoxifen treatment. The possible influence of separate isoforms was not tested and future studies may further evaluate HER4 significance. PMID- 26238413 TI - Metastatic metaplastic breast carcinoma mimicking pulmonary squamous cell carcinoma on fine-needle aspiration. AB - Metaplastic squamous cell carcinoma (SCC) of the breast is a rare type of breast cancer. Metastases to the lung, which can be a major site of second primary tumor development among breast cancer patients, are difficult to distinguish from primary SCC of the lung and present a unique challenge for pathologists. There are few available discriminating immunohistochemical markers as squamous differentiation typically leads to loss of expression of characteristic primary epithelial cell markers of both breast and lung origin. GATA protein binding 3 (GATA-3) is a useful marker of breast origin in metastatic ductal and lobular carcinomas including poorly differentiated triple-negative carcinomas and some metaplastic carcinomas. Here, we present a case of metastatic SCC presenting as a solitary lung mass with regional lymph node metastases and a single satellite lesion in a patient with a history of metaplastic SCC of the breast. In addition to the routine markers of squamous differentiation, the metastases were also positive for estrogen receptor (ER) and GATA-3 on cytologic material obtained by transbronchial FNA. This suggests that immunoreactivity for ER and GATA-3 may support a diagnosis of metastatic SCC in the context of a prior metaplastic SCC of the breast. PMID- 26238414 TI - Identification of educational needs in the management of overweight and obesity: results of an international survey of attitudes and practice. AB - Despite the availability of a growing range of interventions to assist control of body weight for people with excess weight or obesity, only a small proportion of people achieve their weight loss goals and are able to maintain body weight reductions in the long term. Negative attitudes and beliefs are often found among physicians and others involved in treating obesity and may adversely impact the effectiveness of management. In this international study, healthcare professionals were invited to complete an online survey of their attitudes and practice in the management of excess body weight. A total of 335 clinicians completed the survey of whom approximately half were based in Europe. A key finding from the survey is that, while participants are generally confident in their ability to manage overweight and obesity effectively, they also report that most of their patients are not successful in achieving their weight loss goals. At the same time, participants tended to overestimate the effectiveness of current medical management in maintaining reductions in body weight. Educational initiatives addressing the real-life effectiveness of different weight control interventions may help to close the gap between clinicians' perceptions and reality in the management of excess body weight. PMID- 26238415 TI - 3-O-Hydroxytyrosol glucuronide and 4-O-hydroxytyrosol glucuronide reduce endoplasmic reticulum stress in vitro. AB - Endoplasmic reticulum (ER) stress is important for atherosclerosis development and is mediated by the unfolded protein response (UPR). In this work, we synthesized two among the most physiologically-prominent hydroxytyrosol HT hepatic metabolites, i.e. 3-O-HT glucuronide and 4-O-HT glucuronide and we tested their activities on ER stress (in human hepatocarcinoma HepG2 cells), to gain further insight into the cardiopreventive properties of HT, extra virgin olive oil, and the Mediterranean diet. We report that 3-O-HT glucuronide and 4-O-HT glucuronide inhibit tunicamycin-induced ER stress. As compared with the effects of the parent molecule, 3-O-HT glucuronide and 4-O-HT glucuronide at 10 MUM and 25 MUM alone induced a milder change in mRNA expression levels of both CCAAT enhancer-binding protein homologous protein (CHOP) and glucose regulated protein GRP78 immunoglobulin heavy chain binding protein (BiP). In conclusion, we add further evidence to the hypothesis that the HT intake might be atheroprotective and reiterate the usefulness to preferably use high-quality, high-(poly)phenol extra virgin olive oil as a prominent condiment. PMID- 26238416 TI - Chemically Altering the Solubility and Durability of Dyes for Sensitized Solar Cells. AB - By designing dyes with fluoroalkyl groups, the optical and electronic properties of the alkyl analogue were maintained while dramatically altering the solubility. Dyes, F-TABTA (8) and its masked derivative F-TABTSi (9), that enable them to be deposited under conventional organic solvent and scCO2 conditions, respectively, were developed. In liquid DSSC devices, the fluoroalkyl dye (F-TABTA, 8) performs slightly better than its alkyl analogue (D21L6, 10), and interestingly, it was found that the former device showed better stability over time. Deploying the silyl-masked precursor F-TABTSi (9), this dye was deposited onto TiO2 photoanodes from scCO2 in very short contact times (2.5 h), and ECEs of 7.70% were obtained that exceed the performance of the alkyl dye when deposited by conventional methods. PMID- 26238417 TI - Defecating disorders: a common cause of constipation in women. AB - Defecating disorders are a common and complex problem. There are a range of anatomical and functional bowel abnormalities that can lead to this condition. Treatment is difficult and needs a multidisciplinary approach. First line treatment for defecating disorders is conservative. For those that fail conservative treatment, some may respond to surgical therapy but with variable results. The aim of this review is to offer an overview of defecating disorders as well as provide an algorithm on how to diagnose and treat them with the help of a multidisciplinary and multimodal approach. PMID- 26238418 TI - Caring for cancer survivors: more than just checking the blood pressure and measuring the ejection fraction. PMID- 26238419 TI - Muscle strength recovery versus semitendinosus and gracilis tendon regeneration after harvesting for anterior cruciate ligament reconstruction. AB - Twenty consecutive, chronic and isolated anterior cruciate ligament (ACL) lesions that underwent reconstruction with quadrupled semitendinosus (ST) and gracilis (G) were prospectively examined to compare tendon regeneration and muscle strength recovery. Twenty consecutive axial nuclear magnetic resonance (NMR) scans were done after 1 month, 6 months and 2 years from surgery. A CybexII was used to evaluate concentric strength deficits both in flexion and in internal tibia rotation at 6 months and 2 years. At 2 years, an NMR signal comparable to the contralateral was present in 14 (70%) cases and absent in 6 (30%). Semitendinosus tendon exceeded the meniscal plateau since the first month, while the G tendon crossed the joint line only after 6 months. However, the distal-end insertions of both tendons were always significantly more proximal than the contralateral normal side (ST: P = .002; G: P = .003). In case of tendon regeneration, flexion deficit was not significant after 6 months, while internal tibia rotation deficit became not significant only after 2 years. In case of non regeneration, a flexion deficit was present after 6 months [15.5% (P = .05)] but not after 2 years, while internal tibial rotation deficit was significant both after 6 months [30.3% (P < .001)] and 2 years [24.3% (P = .03)]. In case of tendon regeneration, isokinetic evaluation showed a non-significant deficit in both flexion and internal rotation strength after ACL reconstruction with ST and G. At the 2-year follow-up, none of the 6 patients without tendon regeneration found any impairment in their sport activities despite the loss of internal rotation strength. PMID- 26238420 TI - Mass Spectrometric and Computational Investigation of the Protonated Carnosine Carboplatin Complex Fragmentation. AB - Platinum(II)-based anticancer drugs are square-planar d(8) complexes that, activated by hydrolysis, cause cancer cell death by binding to nuclear DNA and distorting its structure. For that reason, interactions of platinum anticancer drugs with DNA have been extensively investigated, aiming at disentangling the mechanism of action and toxicity. Less attention, however, has been devoted to the formation of adducts between platinum drugs with biological ligands other than DNA. These adducts can cause the loss and deactivation of the drug before it arrives at the ultimate target and are also thought to contribute to the drug's toxicity. Here are reported the outcomes of electrospray ionization mass spectrometry experiments and density functional theory (DFT) computations carried out to investigate the fragmentation pathways of the protonated carnosine carboplatin complex, [Carnosine + CarbPt + H](+). DFT calculations at the B3LYP/LANL2DZ level employed to probe fragmentation mechanisms account for all experimental data. Because of the relative rigidity of the structure of the most stable 1A conformer, stabilized by three strong hydrogen bonds, the first step of all of the examined fragmentation pathways is the interconversion of the 1A conformer into the less stable structure 1B. Formation of the [Carnosine + H](+) fragment from the precursor ion, [Carnosine + CarbPt + H](+), is calculated to be the lowest-energy process. At slightly higher energies, the loss of two amino groups is observed to produce the [Carnosine + (CarbPt - NH3) + H](+) and [Carnosine + (CarbPt - 2NH3) + H](+) ions. At significantly higher energies, the loss of CO2 occurs, yielding the final [Carnosine + (CarbPt - NH3) - CO2 + H](+) and [Carnosine + (CarbPt - 2NH3) - CO2 + H](+) products. Formation of the [CarbPt + H](+) fragment from [Carnosine + CarbPt + H](+), even if not hampered by a high activation barrier, is calculated to be very unfavorable from a thermodynamic point of view. PMID- 26238421 TI - Evaluation of reference gene suitability for quantitative expression analysis by quantitative polymerase chain reaction in the mandibular condyle of sheep. AB - Reference genes are commonly used as a reliable approach to normalize the results of quantitative polymerase chain reaction (qPCR), and to reduce errors in the relative quantification of gene expression. Suitable reference genes belonging to numerous functional classes have been identified for various types of species and tissue. However, little is currently known regarding the most suitable reference genes for bone, specifically for the sheep mandibular condyle. Sheep are important for the study of human bone diseases, particularly for temporomandibular diseases. The present study aimed to identify a set of reference genes suitable for the normalization of qPCR data from the mandibular condyle of sheep. A total of 12 reference genes belonging to various functional classes were selected, and the expression stability of the reference genes was determined in both the normal and fractured area of the sheep mandibular condyle. RefFinder, which integrates the following currently available computational algorithms: geNorm, NormFinder, BestKeeper, and the comparative DeltaCt method, was used to compare and rank the candidate reference genes. The results obtained from the four methods demonstrated a similar trend: RPL19, ACTB, and PGK1 were the most stably expressed reference genes in the sheep mandibular condyle. As determined by RefFinder comprehensive analysis, the results of the present study suggested that RPL19 is the most suitable reference gene for studies associated with the sheep mandibular condyle. In addition, ACTB and PGK1 may be considered suitable alternatives. PMID- 26238422 TI - Exercise-induced bronchoconstriction diagnosis in asthmatic children: comparison of treadmill running and eucapnic voluntary hyperventilation challenges. AB - BACKGROUND: Exercise-induced bronchoconstriction (EIB) occurs in up to 90% of young people with asthma and can be diagnosed using serial measurements of forced expiratory volume in 1 second (FEV1) after standardized exercise, usually treadmill running (TR). Eucapnic voluntary hyperventilation (EVH) is a guideline recommended alternative challenge for EIB diagnosis. The 2 methods have not been compared for EIB diagnosis in this population. OBJECTIVE: To compare 2 methods of EIB diagnosis in children and adolescents with asthma. METHODS: Thirty-four children 8 to 18 years of age attending the allergy clinic of the Hospital das Clinicas (Recife, Brazil) from September through December 2013 were examined. All underwent a basal FEV1 determination followed by TR for 8 minutes or EVH for 6 minutes on consecutive days. The first challenge was chosen at random. Serial FEV1 determinations were obtained at 3, 5, 7, 10, 15, and 30 minutes after the challenge and the test result was considered positive if at least 2 consecutive FEV1 measurements decreased at least 10% below the basal value. RESULTS: Thirteen patients responded to the 2 challenges, 6 only after TR and 4 exclusively after EVH (agreement 71%, kappa = 0.41). The 95% limits of agreement of FEV1 decreasing after the challenges were widely spread (mean 0.1%, limits 19.8% to -19.6%). CONCLUSION: The 2 tests cannot be used interchangeably and the reproducibility of the FEV1 response to the EVH challenge has to be properly evaluated to better understand its role in EIB diagnosis. PMID- 26238423 TI - Acupuncture for seasonal allergic rhinitis: is it ready for prime time? PMID- 26238424 TI - Phase II study of a combination regimen of gefitinib and pemetrexed as first-line treatment in patients with advanced non-small cell lung cancer harboring a sensitive EGFR mutation. AB - PURPOSE: Patients with advanced non-small cell lung cancer (NSCLC) harboring a sensitive epidermal growth factor receptor (EGFR) mutation have been shown to exhibit a marked response to EGFR-tyrosine kinase inhibitor (TKI) treatment. Pemetrexed and gefitinib were reported to have a schedule-dependent cytotoxic synergism. We evaluated the efficacy and safety of a combination regimen of gefitinib and pemetrexed as first-line chemotherapy in EGFR-mutated NSCLC patients. PATIENTS AND METHODS: Systemic therapy-naive patients with advanced non squamous NSCLC harboring a sensitive EGFR mutation were included in this study. Pemetrexed was administered on day 1 at a dose of 500 mg/m(2), and gefitinib was sequentially administered on days 2-16. This treatment regimen was repeated every 3 weeks until disease progression. RESULTS: Twenty-six patients were enrolled in this study. The median number of treatment cycles was 16 (range, 1-35). The overall response rate (ORR) was 84.6% (95% confidence interval [CI], 70.7-98.5%), and the disease control rate (DCR) was 96.2% (95% CI, 88.9-100%). Grade 3/4 hematological toxicities included neutropenia (15.4%), leukopenia (7.7%), and anemia (3.8%). No grade 4 non-hematological toxicities were observed. The main grade 3 non-hematological toxicities were infection (11.5%), increased alanine aminotransferase (11.5%) and aspartate aminotransferase (7.7%) levels, fatigue (3.8%), diarrhea (3.8%), and pneumonitis (3.8%). We observed a median progression free survival (PFS) of 18.0 months (95% CI, 15.0-21.0 months) and a median survival time (MST) of 32.0 months (95% CI, 28.5-35.5 months). There were no treatment-related deaths. CONCLUSIONS: The combination regimen used in this study showed a high ORR, long median PFS, and acceptable toxicity. A future randomized trial on pemetrexed plus gefitinib compared with gefitinib alone is warranted. PMID- 26238425 TI - RNF111/Arkadia is regulated by DNA methylation and affects TGF-beta/Smad signaling associated invasion in NSCLC cells. AB - OBJECTIVES: RNF111/Arkadia is a critical regulator of TGF-beta signaling, being required for SMAD3-mediated responses such as TGF-beta-induced repression of E cadherin. Previous studies show that mutations in RNF111 in human cancers are rare and RNF111 promotes lung tumor metastasis. However, the epigenetic mechanisms underlying the role of RNF111 in non-small cell lung cancer (NSCLC) metastasis remain unknown. Here, we mainly focused on low- (95C) and high metastatic (95D) NSCLC cell lines, which share a similar genetic background, and investigated the methylation-based regulation of RNF111 expression. MATERIALS AND METHODS: Clonal bisulfite sequencing, real-time qRT-PCR, western blot analysis, luciferase reporter assays, RNA interference, chromatin immunoprecipitation (ChIP) assay and transwell migration and invasion assays were performed on human NSCLC cell lines 95C and 95D. RESULTS: RNF111 was high-expressed in 95D cells, which showed low-level methylation at -459CpG site in RNF111 promoter. The opposite results were obtained in 95C cells. Cell-based and biochemical assays revealed that -459CpG methylation can inhibit RNF111 transcriptional expression by interfering with the recruitment of Sp1 to RNF111 promoter. On TGF-beta stimulation, siRNA-mediated RNF111 knockdown inhibited TGF-beta/Smad signaling activity and Snail (an inducer of metastasis) expression, and enhanced E-cadherin (an epithelial-to-mesenchymal transition marker) expression in 95C and 95D cells. Furthermore, demethylation-induced upregulation of RNF111 enhanced phosphorylation of SMAD3 and Snail expression, and repressed E-cadherin expression in 95C cells expressing low RNF111. CONCLUSIONS: Our results suggest that -459CpG methylation in Sp1-binding site of RNF111 promoter transcriptionally decreases RNF111 expression, which inhibits TGF-beta/Smad signaling associated invasion in NSCLC cells. PMID- 26238426 TI - Peroxisome proliferator-activated receptor gamma prevents the production of NOD like receptor family, pyrin domain containing 3 inflammasome and interleukin 1beta in HK-2 renal tubular epithelial cells stimulated by monosodium urate crystals. AB - Recent evidence showed that peroxisome proliferator-activated receptor gamma (PPARgamma) ameliorates a variety of inflammatory conditions. The present study aimed to investigate the role of PPARgamma in regulating NOD-like receptor family, pyrin domain containing 3 (NALP3) inflammasome and interleukin (IL)-1beta levels during monosodium urate (MSU) crystal-induced inflammation. HK-2 cells were incubated with or without 200 ug/ml MSU crystals, and mRNA and protein levels of PPARgamma were determined using reverse transcription quantitative polymerase chain reaction and western blot analysis, respectively. To verify the role of PPARgamma, HK-2 cells were pre-treated with PPARgamma agonist pioglitazone, and the levels of NALP3 inflammasome and IL-1beta were detected by western blot analysis and ELISA. The results showed that MSU crystals increased PPARgamma expression in HK-2 cells at 24 h, while the expression decreased to normal levels at 48 h. It was also demonstrated that although the PPARgamma agonist pioglitazone did not alter the mRNA and protein levels of PPARgamma, it significantly reduced the MSU crystal-induced production of NALP3 inflammasome and IL-1beta in HK-2 cells, possibly by increasing the level of PPARgamma activity. In conclusion, the results of the present study indicated that PPARgamma prevented NALP3 inflammasome formation and IL-1beta production in HK-2 cells stimulated by MSU crystals, which indicated that PPARgamma may represent a novel target for the treatment of hyperuricemic nephropathy. PMID- 26238427 TI - Mesenteric fibromatosis with complete aortic thrombosis as an indication for intestinal transplant. PMID- 26238428 TI - Tuberculous periportal lymphadenitis: A diagnostic challenge. PMID- 26238429 TI - Conservative treatment of hepatic inflammatory pseudotumor. PMID- 26238430 TI - Highly Sensitive Electrochemical Biosensor for Evaluation of Oxidative Stress Based on the Nanointerface of Graphene Nanocomposites Blended with Gold, Fe3O4, and Platinum Nanoparticles. AB - High levels of H2O2 pertain to high oxidative stress and are associated with cancer, autoimmune, and neurodegenerative disease, and other related diseases. In this study, a sensitive H2O2 biosensor for evaluation of oxidative stress was fabricated on the basis of the reduced graphene oxide (RGO) nanocomposites decorated with Au, Fe3O4, and Pt nanoparticles (RGO/AuFe3O4/Pt) modified glassy carbon electrode (GCE) and used to detect the released H2O2 from cancer cells and assess the oxidative stress elicited from H2O2 in living cells. Electrochemical behavior of RGO/AuFe3O4/Pt nanocomposites exhibits excellent catalytic activity toward the relevant reduction with high selection and sensitivity, low overpotential of 0 V, low detection limit of ~0.1 MUM, large linear range from 0.5 MUM to 11.5 mM, and outstanding reproducibility. The as-prepared biosensor was applied in the measurement of efflux of H2O2 from living cells including healthy normal cells and tumor cells under the external stimulation. The results display that this new nanocomposites-based biosensor is a promising candidate of nonenzymatic H2O2 sensor which has the possibility of application in clinical diagnostics to assess oxidative stress of different kinds of living cells. PMID- 26238432 TI - Associations Do Not Equal Causation: Clinical Relevance of Statistical Associations of Phosphodiesterase Type 5 Inhibitors with Prostate Cancer Progression and Melanoma. PMID- 26238433 TI - Computer simulations of single particles in external electric fields. AB - Applying electric fields is an attractive way to control and manipulate single particles or molecules, e.g., in lab-on-a-chip devices. However, the response of nanosize objects in electrolyte solution to external fields is far from trivial. It is the result of a variety of dynamical processes taking place in the ion cloud surrounding charged particles and in the bulk electrolyte, and it is governed by an intricate interplay of electrostatic and hydrodynamic interactions. Already systems composed of one single particle in electrolyte solution exhibit a complex dynamical behaviour. In this review, we discuss recent coarse-grained simulations that have been performed to obtain a molecular-level understanding of the dynamic and dielectric response of single particles and single macromolecules to external electric fields. We address both the response of charged particles to constant fields (DC fields), which can be characterized by an electrophoretic mobility, and the dielectric response of both uncharged and charged particles to alternating fields (AC fields), which is described by a complex polarizability. Furthermore, we give a brief survey of simulation algorithms and highlight some recent developments. PMID- 26238431 TI - Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer. AB - BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25-50% of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking. OBJECTIVE: To discover and validate biomarkers predictive of response to NAC for MIBC. DESIGN, SETTING, AND PARTICIPANTS: Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments-certified laboratory. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. RESULTS AND LIMITATIONS: Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p=0.024) and validation (p=0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p<0.001; 87% sensitivity, 100% specificity) and better overall survival (p=0.007). This test remained predictive for pathologic response in the validation set (p=0.033), with a trend towards better overall survival (p=0.055). These results require further validation in additional sample sets. CONCLUSIONS: Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. PATIENT SUMMARY: Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended. PMID- 26238435 TI - A Cross-Sectional Study of Psychological Comparison Processes That May Underlie the Acceptance of Chronic Pain. AB - : Acceptance of chronic pain varies between patients but may also be expected to develop and change within patients. In this latter framework, the present study explored three psychological processes that may contribute to changes in acceptance: social comparisons, temporal comparisons and counterfactual comparisons. In general, these comparisons are used to cope with negative life events, and they may also play a role in acceptance of pain. In this study, the two subscales of the Chronic Pain Acceptance Questionnaire (Activity Engagement and Pain Willingness) were complemented with a scale of Affective Acceptance. Using linear regression analyses, data from these three acceptance scales were regressed on three scales of temporal comparison processes, four scales of social comparison processes and one scale of counterfactual comparisons. The results showed that the comparison processes explained up to 37% of the variance in acceptance, especially a higher frequency of thinking of one's present condition in relation to a condition in the past, and feeling bad when comparing with others who are doing better, were consistently related to lower acceptance. These explorative results may inspire experimental studies to influence comparison processes and, eventually, to address those comparison processes in interventions for patients with chronic pain to improve acceptance. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: In addition to beliefs indicating Activity Engagement and Pain Willingness, Affective acceptance of pain may also be a relevant dimension and manifestation of acceptance Social comparisons, temporal comparisons and counterfactual comparisons are related to acceptance of pain In patients with pain psychological comparison processes can be relevant in diagnosing possible causes of non-optimal acceptance of chronic pain Practitioners may try to influence each of the three types of psychological comparison processes in individuals and observe the effects. PMID- 26238434 TI - Spatiotemporal regulation of Heterochromatin Protein 1-alpha oligomerization and dynamics in live cells. AB - Heterochromatin protein 1 (HP1) is a central factor in establishing and maintaining the heterochromatin state. As consequence of playing a structural role in heterochromatin, HP1 proteins can have both an activating as well as repressive function in gene expression. Here we probe how oligomerisation of the HP1-alpha isoform modulates interaction with chromatin, by spatially resolved fluorescence correlation spectroscopy (FCS). We find from fluctuation analysis of HP1-alpha dynamics that this isoform exists as a dimer around the periphery of heterochromatin foci and these foci locally rotate with characteristic turn rates that range from 5-100 ms. From inhibition of HP1-alpha homo-oligomerization we find the slow turn rates (20-100 ms) are dimer dependent. From treatment with drugs that disrupt or promote chromatin compaction, we find that HP1-alpha dimers spatially redistribute to favor fast (5-10 ms) or slow (20-100 ms) turn rates. Collectively our results demonstrate HP1-alpha oligomerization is critical to the maintenance of heterochromatin and the tunable dynamics of this HP1 isoform. PMID- 26238436 TI - Droplets move over viscoelastic substrates by surfing a ridge. AB - Liquid drops on soft solids generate strong deformations below the contact line, resulting from a balance of capillary and elastic forces. The movement of these drops may cause strong, potentially singular dissipation in the soft solid. Here we show that a drop on a soft substrate moves by surfing a ridge: the initially flat solid surface is deformed into a sharp ridge whose orientation angle depends on the contact line velocity. We measure this angle for water on a silicone gel and develop a theory based on the substrate rheology. We quantitatively recover the dynamic contact angle and provide a mechanism for stick-slip motion when a drop is forced strongly: the contact line depins and slides down the wetting ridge, forming a new one after a transient. We anticipate that our theory will have implications in problems such as self-organization of cell tissues or the design of capillarity-based microrheometers. PMID- 26238437 TI - Clinical utility of genetic signatures in selecting adjuvant treatment: Risk stratification for early vs. late recurrences. AB - Adjuvant endocrine therapy (ET) reduces the odds of distant recurrence and mortality by nearly one-half in women with hormone receptor (HR) positive early stage breast cancer. While the risk of recurrence is lower for HR positive than negative patients during the first 5-7 years, HR positive patients suffer ongoing recurrences between 0.5 and 2% year over subsequent years. Extended adjuvant ET further reduces recurrence during this late phase of follow-up. ET is associated with post-menopausal side effects (hot flashes, sexual dysfunction, mood changes, and weight gain), and occasional major toxicities (thrombosis and endometrial cancer with tamoxifen; bone mineral loss and possibly heart disease with AIs) persist throughout therapy. Accurate and reliable estimates of the risk of recurrence after five years of ET for women with prior HR positive breast cancer would permit appropriate extended ET decisions. The risk of long-term relapse is related to lymph node status and size of tumor, but these are relatively crude. Several groups have investigated whether multi-parameter tumor biomarker tests might identify those patients whose risk of recurrence is so low that extended ET is not justified. These assays include IHC4, the 21-gene "OncotypeDX", the 12 gene "Endopredict," the PAM50, and the 2-gene "Breast Cancer Index (BCI)" assays. The clinical validity of all these tests for this use context have been established, with at least one paper for each that shows a statistically significant difference in risk of distant recurrence during the 5-10 years after the initial five years of adjuvant endocrine therapy. However, the stakes are high, and although each of these represents a "prospective retrospective" study, they require further validation in subsequent datasets before they should be considered to have "clinical utility" and are used to withhold potentially life saving treatment. Perhaps more importantly, the clinical breast cancer community, and especially the patient, need to determine how low the risk of late recurrence needs to be to forego the toxicities and side effects of extended adjuvant ET. PMID- 26238438 TI - Targeting bone microenvironment: Clinical implications. PMID- 26238439 TI - What to expect from high throughput genomics in metastatic breast cancers? AB - Breast cancer is a heterogeneous disease and its genomic characteristics have been widely studied in the last years. Although several progresses have been made, metastatic disease is still incurable in the majority of patients. Recent genomic studies have shown that a large number of candidate targets exist in breast cancer. Currently only two drivers have been validated (ER and HER2), but several others seem to be associated with objective response, such as PIK3CA mutations, FGFR1 amplifications, AKT1 mutations, EGFR amplifications and ERBB2 mutations. Beside driver identification, many other applications can be developed for genomics such as identification of lethal subclones, DNA repair defects or immune response against tumor. Most of the precision medicine programs currently use targeted sequencing. Nevertheless, whole exome sequencing, RNA sequencing, gene expression analysis, phosphoprotein detection, SNP arrays and ctDNA sequencing have been also proposed in clinical trials. PMID- 26238440 TI - Phase I clinical trial of 99mTc-etarfolatide, an imaging agent for folate receptor in healthy Japanese adults. AB - OBJECTIVE: Technetium etarfolatide ((99m)Tc-EF) is a radioactive diagnostic imaging agent that was developed to assess the expression of folate receptors in tumors. Administering folic acid prior to the administration of (99m)Tc-EF has been shown to improve SPECT images. Here, we conducted a phase I clinical trial to assess the safety, pharmacokinetics, and radiation dosimetry of (99m)Tc-EF injection following pre-administration of folic acid in healthy Japanese male adults. METHODS: Six healthy Japanese male adults were enrolled in the study. Folic acid was intravenously administered, followed 1-3 min later by an intravenous injection of (99m)Tc-EF (740 MBq +/- 20 %). Assessments of subjective symptoms and objective findings, electrocardiograms, physical examination, and laboratory tests were performed before and up to 7 days after the injection to assess the safety of (99m)Tc-EF. Blood and urine collections and whole-body planar imaging were conducted at various time points up to 24 h after the injection to assess the pharmacokinetics of (99m)Tc-EF. The internal radiation dosimetry was calculated based on the pharmacokinetics results using the MIRD method. RESULTS: Five adverse events were observed in three subjects (50 %) after administration of the folic acid and (99m)Tc-EF, while these events were mild and non-serious. Of those five events, three were considered to be related to the administered agents. The radioactivity in blood rapidly decreased and showed a biphasic profile. The activity of (99m)Tc-EF at 5 min post injection was largest in the bone marrow, followed by the liver and kidneys, and had decreased within 24 h in all organs/tissues without appreciable retention. The pharmacokinetics results suggested that (99m)Tc-EF was mainly eliminated by kidney. The results also suggested that when administered at 925 MBq of (99m)Tc-EF, which is the maximum dose generally used for clinical trials in other countries, the corresponding effective dose of (99m)Tc-EF is equal to or less than those determined for the current radioactive diagnostic imaging agents. CONCLUSIONS: The results of this study assessing the safety and radiation dosimetry of (99m)Tc EF with folic acid pre-administration suggested that folic acid and (99m)Tc-EF should be appropriate for further studies. No pharmacokinetics concerns were noted. PMID- 26238441 TI - Identification of promising host-induced silencing targets among genes preferentially transcribed in haustoria of Puccinia. AB - BACKGROUND: The cereal rust fungi are destructive pathogens that affect grain production worldwide. Although the genomic and transcript sequences for three Puccinia species that attack wheat have been released, the functions of large repertories of genes from Puccinia still need to be addressed to understand the infection process of these obligate parasites. Host-induced gene silencing (HIGS) has emerged a useful tool to examine the importance of rust fungus genes while growing within host plants. In this study, HIGS was used to test genes from Puccinia with transcripts enriched in haustoria for their ability to interfere with full development of the rust fungi. RESULTS: Approximately 1200 haustoria enriched genes from Puccinia graminis f. sp. tritici (Pgt) were identified by comparative RNA sequencing. Virus-induced gene silencing (VIGS) constructs with fragments of 86 Puccinia genes, were tested for their ability to interfere with full development of these rust fungi. Most of the genes tested had no noticeable effects, but 10 reduced Pgt development after co-inoculation with the gene VIGS constructs and Pgt. These included a predicted glycolytic enzyme, two other proteins that are probably secreted and involved in carbohydrate or sugar metabolism, a protein involved in thiazol biosynthesis, a protein involved in auxin biosynthesis, an amino acid permease, two hypothetical proteins with no conserved domains, a predicted small secreted protein and another protein predicted to be secreted with similarity to bacterial proteins involved in membrane transport. Transient silencing of four of these genes reduced development of P. striiformis (Pst), and three of also caused reduction of P. triticina (Pt) development. CONCLUSIONS: Partial suppression of transcripts involved in a large variety of biological processes in haustoria cells of Puccinia rusts can disrupt their development. Silencing of three genes resulted in suppression of all three rust diseases indicating that it may be possible to engineer durable resistance to multiple rust pathogens with a single gene in transgenic wheat plants for sustainable control of cereal rusts. PMID- 26238442 TI - Hypofractionated irradiation in elderly patients with breast cancer after breast conserving surgery and mastectomy : Analysis of 205 cases. AB - BACKGROUND: Several randomized trials and meta-analyses confirmed a wide benefit of radiotherapy (RT), both after breast conserving surgery (BCS) and mastectomy. However, many elderly women don't receive RT. Hypofractionated (HF) RT allows " simplified " and more accessible treatments with equivalent results to classic RT in three large randomized trials. However, there are few available data on HF-RT for nodal irradiation, as well as for the boost. METHODS: We evaluated patients treated for IBC by HF-RT between 2004 and 2012 in two regional cancer centres. We used an original scheme delivering 45 Gy in 15 fractions three times a week, both after BCS or mastectomy, with or without nodal irradiation. After BCS, a 9 Gy boost in 3 fractions was delivered. Local, regional and distant recurrences were assessed, as well as acute and late cutaneous, cardiac or pulmonary toxicities. RESULTS: 205 patients were analysed, 116 after BCS (57 %) and 89 after mastectomy (43 %). Median age was 81 years (range: 52-91); 44 % had axillary nodal involvement (pN+). The Nottingham Prognostic Index (NPI) scored 0, 1, 2 and 3 in 10 %, 27 %, 44 % and 19 % of the cases. A nodal HF-RT was delivered in 65 patients (32 %) and boost in 98 patients (84 % of BCS) by 9 Gy/3 fr scheme. Fifty (24 %) patients underwent chemotherapy and 156 (75 %) hormonal treatment. With a 49-month median follow-up, 3/116 (2.6 %) patients and 4/89 (4.5 %) had local recurrence (LR) after BCS and mastectomy, respectively. The overall 5-year LR rate was 4.4 %. In univariate and multivariate analysis, LR risk factors were: high NPI (HR 5.46; p = 0.028), and triple negative tumour (HR 9.78; p = 0.006). Only 8 (4.5 %) patients had grade III skin toxicity; 29 (14 %) late fibrosis and 16 (8 %) telangiectasia. No pulmonary or cardiac toxicity was observed. CONCLUSION: Our HF-RT scheme (with or without nodal irradiation) confirms in elderly patients the data from randomized trials, both after BCS or mastectomy. Toxicity seems very acceptable but requires a longer follow-up. A larger evaluation is still ongoing in several other centres in France. PMID- 26238443 TI - Adrenal histopathology in primary aldosteronism: is it time for a change? PMID- 26238444 TI - Noninvasive renal denervation for resistant hypertension using high-intensity focused ultrasound. PMID- 26238445 TI - Dose-Dependent Bidirectional Effect of Angiotensin IV on Abdominal Aortic Aneurysm via Variable Angiotensin Receptor Stimulation. AB - Angiotensin IV (Ang IV), as an effector peptide of the rennin-angiotensin system, possesses many biological properties yet not completely known. In this study, we aimed to investigate the role of Ang IV in the development of Ang II-induced abdominal aortic aneurysm (AAA) in apolipoprotein E-knockout mice. We used Ang II infusion to induce AAA, and animals were treated with Ang II (1.44 mg/kg per day) plus no treatment, Ang II (1.44 mg/kg per day) plus low-, medium-, and high-dose Ang IV (0.72, 1.44, and 2.88 mg/kg per day, respectively). The incidence of AAA was 87.5%, 66.7%, 37.5%, and 83.3% in the no treatment, the low-, medium-, or high-dose Ang IV group, respectively. Compared with the no treatment group, medium-dose Ang IV treatment markedly reduced macrophage infiltration; levels of proinflammatory cytokines, including monocyte chemoattractant protein 1, interleukin 6, and intercellular adhesion molecule 1; the expression and activity of metalloproteinases 2 and 9; but increased smooth muscle cells, and collagen content in AAA. However, high-dose Ang IV treatment did not have obvious protective effect. The beneficial effect of medium-dose Ang IV may be contributed to the stimulation of type 4 angiotensin receptor (AT4R) and AT2R with suppression of AT1R, activation of Akt, and inhibition of nuclear factor-kappaB, as these beneficial effects were largely reversed by cotreatment with the AT4R antagonist divalinal-Ang IV in Ang II-infused mice or with the Akt inhibitor A6730 in Ang II-stimulated human smooth muscle cells. Therefore, medium dose of Ang IV may provide a novel and promising approach to the treatment of AAA. PMID- 26238446 TI - Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension. AB - Hypertensive cardiac remodeling is accompanied by molecular inflammation and fibrosis, 2 mechanisms that finally affect cardiac function. At cardiac level, aldosterone promotes inflammation and fibrosis, although the precise mechanisms are still unclear. Galectin-3 (Gal-3), a beta-galactoside-binding lectin, is associated with inflammation and fibrosis in the cardiovascular system. We herein investigated whether Gal-3 inhibition could block aldosterone-induced cardiac inflammation and fibrosis and its potential role in cardiac damage associated with hypertension. Aldosterone-salt-treated rats presented hypertension, cardiac inflammation, and fibrosis that were prevented by the pharmacological inhibition of Gal-3 with modified citrus pectin. Cardiac inflammation and fibrosis presented in spontaneously hypertensive rats were prevented by modified citrus pectin treatment, whereas Gal-3 blockade did not modify blood pressure levels. In the absence of blood pressure modifications, Gal-3 knockout mice were resistant to aldosterone-induced cardiac inflammation. In human cardiac fibroblasts, aldosterone increased Gal-3 expression via its mineralocorticoid receptor. Gal-3 and aldosterone enhanced proinflammatory and profibrotic markers, as well as metalloproteinase activities in human cardiac fibroblasts, effects that were not observed in Gal-3-silenced cells treated with aldosterone. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac inflammation and fibrosis, alterations that were prevented by Gal-3 blockade independently of blood pressure levels. These data suggest that Gal-3 could be a new molecular mechanism linking cardiac inflammation and fibrosis in situations with high-aldosterone levels, such as hypertension. PMID- 26238447 TI - High salt intake: independent risk factor for obesity? AB - High salt intake is the major cause of raised blood pressure and accordingly leads to cardiovascular diseases. Recently, it has been shown that high salt intake is associated with an increased risk of obesity through sugar-sweetened beverage consumption. Increasing evidence also suggests a direct link. Our study aimed to determine whether there was a direct association between salt intake and obesity independent of energy intake. We analyzed the data from the rolling cross sectional study-the UK National Diet and Nutrition Survey 2008/2009 to 2011/2012. We included 458 children (52% boys; age, 10+/-4 years) and 785 adults (47% men; age, 49+/-17 years) who had complete 24-hour urine collections. Energy intake was calculated from 4-day diary and misreporting was assessed by Goldberg method. The results showed that salt intake as measured by 24-hour urinary sodium was higher in overweight and obese individuals. A 1-g/d increase in salt intake was associated with an increase in the risk of obesity by 28% (odds ratio, 1.28; 95% confidence interval, 1.12-1.45; P=0.0002) in children and 26% (odds ratio, 1.26; 95% confidence interval, 1.16-1.37; P<0.0001) in adults, after adjusting for age, sex, ethnic group, household income, physical activity, energy intake, and diet misreporting, and in adults with additional adjustment for education, smoking, and alcohol consumption. Higher salt intake was also significantly related to higher body fat mass in both children (P=0.001) and adults (P=0.001) after adjusting for age, sex, ethnic group, and energy intake. These results suggest that salt intake is a potential risk factor for obesity independent of energy intake. PMID- 26238448 TI - Tenascin-C may accelerate cardiac fibrosis by activating macrophages via the integrin alphaVbeta3/nuclear factor-kappaB/interleukin-6 axis. AB - Tenascin-C (TN-C) is an extracellular matrix protein not detected in normal adult heart, but expressed in several heart diseases closely associated with inflammation. Accumulating data suggest that TN-C may play a significant role in progression of ventricular remodeling. In this study, we aimed to elucidate the role of TN-C in hypertensive cardiac fibrosis and underlying molecular mechanisms. Angiotensin II was administered to wild-type and TN-C knockout mice for 4 weeks. In wild-type mice, the treatment induced increase of collagen fibers and accumulation of macrophages in perivascular areas associated with deposition of TN-C and upregulated the expression levels of interleukin-6 and monocyte chemoattractant protein-1 as compared with wild-type/control mice. These changes were significantly reduced in TN-C knockout/angiotensin II mice. In vitro, TN-C accelerated macrophage migration and induced accumulation of integrin alphaVbeta3 in focal adhesions, with phosphorylation of focal adhesion kinase (FAK) and Src. TN-C treatment also induced nuclear translocation of phospho-NF-kappaB and upregulated interleukin-6 expression of macrophages in an NF-kappaB-dependent manner; this being suppressed by inhibitors for integrin alphaVbeta3 and Src. Furthermore, interleukin-6 upregulated expression of collagen I by cardiac fibroblasts. TN-C may enhance inflammatory responses by accelerating macrophage migration and synthesis of proinflammatory/profibrotic cytokines via integrin alphaVbeta3/FAK-Src/NF-kappaB, resulting in increased fibrosis. PMID- 26238449 TI - Progesterone elevation on the day of human chorionic gonadotropin administration adversely affects the outcome of IVF with transferred embryos at different developmental stages. AB - BACKGROUND: The effect of progesterone elevation (PE) on the day of human chorionic gonadotropin (hCG) administration on the pregnancy outcomes of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles is a matter of ongoing debate. The replacement of cleavage-stage embryos with blastocyst-stage embryos for transfer was proposed to avoid the possible impairment of PE in fresh cycles. This study aimed to assess the association between PE on the day of human chorionic gonadotropin (hCG) administration and clinical pregnancy rates (CPRs) in IVF/ICSI cycles with embryos transferred at different developmental stages (cleavage and blastocyst). Moreover, a secondary aim was to determine the thresholds at which PE has a detrimental effect on CPRs. METHODS: This single center retrospective cohort study included more than 10,000 patients undergoing day 3 cleavage-stage embryo transfer (ET) and 1146 patients undergoing day 5 blastocyst-stage embryo transfer (ET) using gonadotropin and GnRH agonist for controlled ovarian stimulation. RESULTS: Serum PE was inversely associated with CPRs in both cleavage- and blastocyst-stage ET cycles. In the day 3 ET cycles, CPRs (progesterone levels < 0.5 ng/ml, 49.2 %) significantly declined when the progesterone concentration reached 1.0 ng/ml (45.5 %) and decreased further when the progesterone concentration increased to 1.5 ng/ml (36.2 %). In the day 5 blastocyst-stage ET cycles, patients with serum progesterone levels >=1.75 ng/ml had significantly lower CPRs (31.3 % VS. 41.4 %, p < 0.001) compared to patients with serum progesterone levels <1.75 ng/ml. The negative association of PE with CPRs was noted in both ET groups, even after adjusting for confounders. Furthermore, the developmental stage of the transferred embryos was not linked to the effect of PE on CPRs because the interaction between the developmental stage of the transferred embryos and PE was not significant. CONCLUSIONS: PE on the day of hCG administration is associated with decreased CPRs in GnRH agonist IVF/intracytoplasmic sperm injection (ICSI) cycles regardless of the developmental stage of the transferred embryos (cleavage versus blastocyst stage). PMID- 26238450 TI - The therapeutic response in Gorham's syndrome to the beta-blocking agent propranolol is correlated to VEGF-A, but not to VEGF-C or FLT1 expression. AB - BACKGROUND: Gorham's syndrome is a rare illness of unknown etiology. It is characterized by a local proliferation of blood or lymphatic vessels that in bones leads to progressive resorption and destruction. The cause of the disease is not elucidated, and therapeutic options remain limited. CASE PRESENTATION: We report herein the case of a young female Caucasian patient aged 18 years with diffuse Gorham syndrome. In tissue specimens angiogenesis and massive lymphangiogenesis as well as the expression of vascular endothelial growth factor A (VEGF-A) and neuropilins was observed. Lymphangiogenesis is a prominent feature of the disease and a number of lymphatic markers were found to be expressed, however only VEGF-A, but not vascular endothelial growth factor-C (VEGF-C) was found to be elevated in the circulation. Circulating levels of soluble VEGF receptor-1 were also not elevated. Furthermore, the patient responded favorably and the disease was stabilized following treatment with the beta-blocking agent Propranolol alone which acts on VEGF-A alone, but not on soluble VEGF receptor-1 levels. CONCLUSION: This suggests that the disease is dependent on VEGF-A, but on neither VEGF-C, the major driver of lymphangiogenesis, nor FLT1. Furthermore, Propranolol acts on VEGF-A but not FLT1 expression. PMID- 26238451 TI - Marital Status, Relationship Distress, and Self-rated Health: What Role for "Sleep Problems"? AB - This paper analyzes data from a nationally representative survey of adults in the United Kingdom (Understanding Society, N = 37,253) to explore the marital status/health nexus (using categories that include a measure of relationship distress) and to assess the role that sleep problems play as a potential mediator. Findings indicate how it is not just the "form" marital status takes but also the absence or presence of relationship distress that is essential to self-rated health. We demonstrate two further findings that: (1) sleep problems act as a mediator of the link between marital status/relationship distress and self-rated health, most notably for those in cohabiting relationships with medium/high distress or who have a history of relationship loss, and (2) the mediating role of sleep problems differs for divorced men and women. PMID- 26238452 TI - SerpentinaDB: a database of plant-derived molecules of Rauvolfia serpentina. AB - BACKGROUND: Plant-derived molecules (PDMs) are known to be a rich source of diverse scaffolds that could serve as a basis for rational drug design. Structured compilation of phytochemicals from traditional medicinal plants can facilitate prospection for novel PDMs and their analogs as therapeutic agents. Rauvolfia serpentina is an important medicinal plant, endemic to Himalayan mountain ranges of Indian subcontinent, reported to be of immense therapeutic value against various diseases. DESCRIPTION: We present SerpentinaDB, a structured compilation of 147 R. serpentina PDMs, inclusive of their plant part source, chemical classification, IUPAC, SMILES, physicochemical properties, and 3D chemical structures with associated references. It also provides refined search option for identification of analogs of natural molecules against ZINC database at user-defined cut-off. CONCLUSION: SerpentinaDB is an exhaustive resource of R. serpentina molecules facilitating prospection for therapeutic molecules from a medicinally important source of natural products. It also provides refined search option to explore the neighborhood of chemical space against ZINC database to identify analogs of natural molecules obtained as leads. In a previous study, we have demonstrated the utility of this resource by identifying novel aldose reductase inhibitors towards intervention of complications of diabetes. PMID- 26238455 TI - Adipose Derived Stromal Cell (ADSC) Injections for Pain Management of Osteoarthritis in the Human Knee Joint. AB - BACKGROUND: This safety and feasibility study used autologous adipose-derived stromal vascular cells (the stromal vascular fraction [SVF] of adipose tissue), to treat 8 osteoarthritic knees in 6 patients of grade I to III (K-L scale) with initial pain of 4 or greater on a 10-point Visual Analog Scale (VAS). OBJECTIVES: The primary objective of the study was evaluation of the safety of intra articular injection of SVF. The secondary objective was to assess initial feasibility for reduction of pain in osteoarthritic knees. METHODS: Adipose derived SVF cells were obtained through enzymatic disaggregation of lipoaspirate, resuspension in 3 mL of Lactated Ringer's Solution, and injection directly into the intra-articular space of the knee, with a mean of 14.1 million viable, nucleated SVF cells per knee. Metrics included monitoring of adverse events and preoperative to postoperative changes in the Western Ontario and McMaster Universities Arthritis Index (WOMAC), the VAS pain scale, range of motion (ROM), timed up-and-go (TUG), and MRI. RESULTS: No infections, acute pain flares, or other adverse events were reported. At 3-months postoperative, there was a statistically significant improvement in WOMAC and VAS scores (P < .02 and P < .001, respectively), which was maintained at 1 year. Physical therapy measurements for ROM and TUG both improved from preoperative to 3-months postoperative. Standard MRI assessment from preoperative to 3-months postoperative showed no detectable structural differences. All patients attained full activity with decreased knee pain. CONCLUSIONS: Autologous SVF was shown to be safe and to present a new potential therapy for reduction of pain for osteoarthritis of the knee. LEVEL OF EVIDENCE 4: Therapeutic. PMID- 26238454 TI - Relation of atherogenic lipoproteins with estimated glomerular filtration rate decline: a longitudinal study. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with dyslipidemia, but the role of atherogenic lipid fractions in CKD progression remains unclear. Here we assess whether baseline plasma levels of lipoprotein(a) [Lp(a)] and apolipoprotein C-III (apoC-III), causal cardiovascular (CV) risk factors being studied as therapeutic targets, are associated with decreasing estimated glomerular filtration rate (eGFR) over time. METHODS: In the Penn Diabetes Heart Study (PDHS), a single-center observational cohort of type 2 diabetes patients without clinical CV disease or pre-existing CKD, we performed linear mixed effects modeling with incremental multivariable analysis to evaluate the effects of baseline plasma Lp(a) and apoC-III on the slope of eGFR over time for subjects with longitudinal data (N = 400). RESULTS: Each two-fold higher plasma Lp(a) level was associated with an additional decline in eGFR by 0.50 mL/min/year in the fully adjusted model (p < 0.001). Baseline Lp(a) levels greater than the atherogenic cut-point of 30 mg/dL were associated with a decline in eGFR by 2.75 mL/min/year compared to 1.01 mL/min/year in subjects with baseline Lp(a) less than 30 mg/dL (p < 0.001). Although each two-fold higher apoC-III level was also associated with statistically significant decline in eGFR over time, as expected the association was attenuated after adjusting for baseline triglycerides, the key lipid intermediary regulated by apoC-III in circulation. CONCLUSIONS: Elevated baseline plasma Lp(a) levels are associated with a decrease in eGFR over time independent of race, lipid medication use, and albuminuria, whereas elevated baseline apoC-III levels are associated with eGFR decline in a triglyceride dependent fashion. PMID- 26238456 TI - Topographical pressure pain sensitivity maps of the shoulder region in individuals with subacromial pain syndrome. AB - BACKGROUND: Topographical pain maps (TPM) are useful tools to assess deep tissue sensitivity in musculoskeletal pain conditions. There is evidence suggesting bilateral sensitivity in subacromial pain syndrome (SAPS), although it is not widely accepted. No previous study has investigated TPM of the shoulder in SAPS. OBJECTIVE: To investigate whether differences for TPM of the shoulder are evident among patients with unilateral SAPS and controls. METHODS: Pressure pain thresholds (PPTs) were assessed 3 times at each point and there was a 20 s rest period between each one. The TPM were calculated using 29 pre-determined points on both shoulders in all groups by inverse distance weighted interpolation of PPT data. Multivariate Analysis of Covariance was applied to detect differences in PPTs between groups, sides, points (gender as covariate). RESULTS: The results revealed significant differences between points and genders (both, P < 0.001), but not between groups (P = 0.243) and sides (P = 0.812). Heterogeneous distribution of mechanical pain sensitivity was found in both groups as the PPTs were lower on the root spine of the scapula and the posterior border of the acromion (points 5-8, P < 0.05), glenohumeral joint (points 17-20, P < 0.01) and the anterior deltoid muscle (points 21-25, P < 0.001) compared to the average of the other sites on the shoulder. Women exhibited bilateral lower PPTs in all points than men in both groups (all, P < 0.01). CONCLUSIONS: This study revealed no differences for mechanical pain sensitivity in patients with SAPS experiencing lower levels of pain compared with matched controls, but showed heterogeneous distribution of PPTs in the shoulder. PMID- 26238457 TI - Prediction of concurrent endometrial carcinoma in women with endometrial hyperplasia. AB - OBJECTIVE: Although a fraction of endometrial hyperplasia cases have concurrent endometrial carcinoma, patient characteristics associated with concurrent malignancy are not well described. The aim of our study was to identify predictive clinico-pathologic factors for concurrent endometrial carcinoma among patients with endometrial hyperplasia. METHODS: A case-control study was conducted to compare endometrial hyperplasia in both preoperative endometrial biopsy and hysterectomy specimens (n=168) and endometrial carcinoma in hysterectomy specimen but endometrial hyperplasia in preoperative endometrial biopsy (n=43). Clinico-pathologic factors were examined to identify independent risk factors of concurrent endometrial carcinoma in a multivariate logistic regression model. RESULTS: The most common histologic subtype in preoperative endometrial biopsy was complex hyperplasia with atypia [CAH] (n=129) followed by complex hyperplasia without atypia (n=58) and simple hyperplasia with or without atypia (n=24). The majority of endometrial carcinomas were grade 1 (86.0%) and stage I (83.7%). In multivariate analysis, age 40-59 (odds ratio [OR] 3.07, p=0.021), age>=60 (OR 6.65, p=0.005), BMI>=35kg/m(2) (OR 2.32, p=0.029), diabetes mellitus (OR 2.51, p=0.019), and CAH (OR 9.01, p=0.042) were independent predictors of concurrent endometrial carcinoma. The risk of concurrent endometrial carcinoma rose dramatically with increasing number of risk factors identified in multivariate model (none 0%, 1 risk factor 7.0%, 2 risk factors 17.6%, 3 risk factors 35.8%, and 4 risk factors 45.5%, p<0.001). Hormonal treatment was associated with decreased risk of concurrent endometrial cancer in those with >=3 risk factors. CONCLUSIONS: Older age, obesity, diabetes mellitus, and CAH are predictive of concurrent endometrial carcinoma in endometrial hyperplasia patients. PMID- 26238459 TI - DNA barcode and evolutionary relationship within Laemolyta Cope 1872 (Characiformes: Anostomidae) through molecular analyses. AB - The Laemolyta genus is a monophyletic group with five valid species. Phylogenetic relationships among the species of this genus are unknown. We analyzed four nominal Laemolyta species. The COI gene for all individuals was amplified and the genetic distances were estimated. We performed genetic distance analyses to determine the different MOTUs. Two mitochondrial (COI and CytB) and three nuclear (Myh6, RAG1 and RAG2) markers were amplified for one individual of each identified MOTU. Maximum Parsimony and Maximum Likelihood were conducted using concatenate alignment. In addition, multilocus Bayesian species tree was carried out. By using DNA barcode, we identified six different MOTUs. The COI inter-MOTU distances ranged from 0.92% to 5.76%. The normalized mean intra-MOTU distance was 0.13%. The DNA barcode was useful to diagnose all species. Two clades showing distinct color patterns were recovered in all molecular phylogenetic trees. Clade A joined fishes with no vertical bars (L. garmani, L. taeniata 1 and L. taeniata 2) and clade B, fishes with vertical dark bars (L. fernandezi Araguaia, L. fernandezi Xingu, and L. proxima). The results were able to identify the cryptic biodiversity within the group and obtained the most complete Laemolyta phylogeny. PMID- 26238458 TI - Alteration of amino acid and biogenic amine metabolism in hepatobiliary cancers: Findings from a prospective cohort study. AB - Perturbations in levels of amino acids (AA) and their derivatives are observed in hepatocellular carcinoma (HCC). Yet, it is unclear whether these alterations precede or are a consequence of the disease, nor whether they pertain to anatomically related cancers of the intrahepatic bile duct (IHBC), and gallbladder and extrahepatic biliary tract (GBTC). Circulating standard AA, biogenic amines and hexoses were measured (Biocrates AbsoluteIDQ-p180Kit) in a case-control study nested within a large prospective cohort (147 HCC, 43 IHBC and 134 GBTC cases). Liver function and hepatitis status biomarkers were determined separately. Multivariable conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI) for log-transformed standardised (mean = 0, SD = 1) serum metabolite levels and relevant ratios in relation to HCC, IHBC or GBTC risk. Fourteen metabolites were significantly associated with HCC risk, of which seven metabolites and four ratios were the strongest predictors in continuous models. Leucine, lysine, glutamine and the ratio of branched chain to aromatic AA (Fischer's ratio) were inversely, while phenylalanine, tyrosine and their ratio, glutamate, glutamate/glutamine ratio, kynurenine and its ratio to tryptophan were positively associated with HCC risk. Confounding by hepatitis status and liver enzyme levels was observed. For the other cancers no significant associations were observed. In conclusion, imbalances of specific AA and biogenic amines may be involved in HCC development. PMID- 26238460 TI - The gene tree delusion. AB - Higher-level relationships among placental mammals are mostly resolved, but several polytomies remain contentious. Song et al. (2012) claimed to have resolved three of these using shortcut coalescence methods (MP-EST, STAR) and further concluded that these methods, which assume no within-locus recombination, are required to unravel deep-level phylogenetic problems that have stymied concatenation. Here, we reanalyze Song et al.'s (2012) data and leverage these re analyses to explore key issues in systematics including the recombination ratchet, gene tree stoichiometry, the proportion of gene tree incongruence that results from deep coalescence versus other factors, and simulations that compare the performance of coalescence and concatenation methods in species tree estimation. Song et al. (2012) reported an average locus length of 3.1 kb for the 447 protein-coding genes in their phylogenomic dataset, but the true mean length of these loci (start codon to stop codon) is 139.6 kb. Empirical estimates of recombination breakpoints in primates, coupled with consideration of the recombination ratchet, suggest that individual coalescence genes (c-genes) approach ~12 bp or less for Song et al.'s (2012) dataset, three to four orders of magnitude shorter than the c-genes reported by these authors. This result has general implications for the application of coalescence methods in species tree estimation. We contend that it is illogical to apply coalescence methods to complete protein-coding sequences. Such analyses amalgamate c-genes with different evolutionary histories (i.e., exons separated by >100,000 bp), distort true gene tree stoichiometry that is required for accurate species tree inference, and contradict the central rationale for applying coalescence methods to difficult phylogenetic problems. In addition, Song et al.'s (2012) dataset of 447 genes includes 21 loci with switched taxonomic names, eight duplicated loci, 26 loci with non-homologous sequences that are grossly misaligned, and numerous loci with >50% missing data for taxa that are misplaced in their gene trees. These problems were compounded by inadequate tree searches with nearest neighbor interchange branch swapping and inadvertent application of substitution models that did not account for among-site rate heterogeneity. Sixty-six gene trees imply unrealistic deep coalescences that exceed 100 million years (MY). Gene trees that were obtained with better justified models and search parameters show large increases in both likelihood scores and congruence. Coalescence analyses based on a curated set of 413 improved gene trees and a superior coalescence method (ASTRAL) support a Scandentia (treeshrews)+Glires (rabbits, rodents) clade, contradicting one of the three primary systematic conclusions of Song et al. (2012). Robust support for a Perissodactyla+Carnivora clade within Laurasiatheria is also lost, contradicting a second major conclusion of this study. Song et al.'s (2012) MP-EST species tree provided the basis for circular simulations that led these authors to conclude that the multispecies coalescent accounts for 77% of the gene tree conflicts in their dataset, but many internal branches of their MP-EST tree are stunted by an order of magnitude or more due to wholesale gene tree reconstruction errors. An independent assessment of branch lengths suggests the multispecies coalescent accounts for ? 15% of the conflicts among Song et al.'s (2012) 447 gene trees. Unfortunately, Song et al.'s (2012) flawed phylogenomic dataset has been used as a model for additional simulation work that suggests the superiority of shortcut coalescence methods relative to concatenation. Investigator error was passed on to the subsequent simulation studies, which also incorporated further logical errors that should be avoided in future simulation studies. Illegitimate branch length switches in the simulation routines unfairly protected coalescence methods from their Achilles' heel, high gene tree reconstruction error at short internodes. These simulations therefore provide no evidence that shortcut coalescence methods out-compete concatenation at deep timescales. In summary, the long c-genes that are required for accurate reconstruction of species trees using shortcut coalescence methods do not exist and are a delusion. Coalescence approaches based on SNPs that are widely spaced in the genome avoid problems with the recombination ratchet and merit further pursuit in both empirical systematic research and simulations. PMID- 26238461 TI - Novel Two-Dimensional Mechano-Electric Generators and Sensors Based on Transition Metal Dichalcogenides. AB - Transition metal dichalcogenides (TMDCs), such as MoS2 and WSe2, provide two dimensional atomic crystals with semiconductor band gap. In this work, we present a design of new mechano-electric generators and sensors based on transition metal dichalcogenide nanoribbon PN junctions and heterojunctions. The mechano-electric conversion was simulated by using a first-principle calculation. The output voltage of MoS2 nanoribbon PN junction increases with strain, reaching 0.036 V at 1% strain and 0.31 V at 8% strain, much larger than the reported results. Our study indicates that the length, width and layer number of TMDC nanoribbon PN junctions have an interesting but different impact on the voltage output. Also, the results indicate that doping position and concentration only cause a small fluctuation in the output voltage. These results have been compared with the mechano-electric conversion of TMDC heterojunctions. Such novel mechano-electric generators and sensors are very attractive for applications in future self powered, wearable electronics and systems. PMID- 26238462 TI - Gefitinib Approved for EGFR-Mutated NSCLC. PMID- 26238463 TI - Effect of intramuscular interferon beta-1a on gray matter atrophy in relapsing remitting multiple sclerosis: A retrospective analysis. AB - BACKGROUND: Changes in gray matter (GM) volume may be a useful measure of tissue loss in multiple sclerosis (MS). OBJECTIVES: To investigate the rate, patterns, and disability correlates of GM volume change in an MS treatment clinical trial. METHODS: Patients (n=140) with relapsing-remitting MS were randomized to intramuscular (IM) interferon (IFN) beta-1a or placebo. Treatment effects on GM fraction (GMF) and white matter (WM) fraction (WMF) changes, differences in rates of GMF and WMF change in year one and two on treatment, and differences in atrophy rates by disease progression status were assessed retrospectively. RESULTS: Significantly less GM atrophy (during year two), but not WM atrophy (at any point), was observed with IM IFN beta-1a compared with placebo. Pseudoatrophy effects were more apparent in WM than in GM; in year one, greater WM volume loss was observed with IM IFN beta-1a than with placebo, whereas GM volume loss was similar between groups. Risk of sustained disability progression was significantly associated with GM, but not WM, atrophy. CONCLUSIONS: These results suggest that GMF change is more meaningful than WMF as a marker of tissue loss and may be useful to augment whole brain atrophy measurements in MS clinical trials. PMID- 26238464 TI - Validating Neuro-QoL short forms and targeted scales with people who have multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic, progressive, and disabling disease of the central nervous system with dramatic variations in the combination and severity of symptoms it can produce. The lack of reliable disease-specific health-related quality of life (HRQL) measures for use in clinical trials prompted the development of the Neurology Quality of Life (Neuro-QOL) instrument, which includes 13 scales that assess physical, emotional, cognitive, and social domains, for use in a variety of neurological illnesses. OBJECTIVE: The objective of this research paper is to conduct an initial assessment of the reliability and validation of the Neuro-QOL short forms (SFs) in MS. METHODS: We assessed reliability, concurrent validity, known groups validity, and responsiveness between cross-sectional and longitudinal data in 161 recruited MS patients. RESULTS: Internal consistency was high for all measures (alpha = 0.81-0.95) and ICCs were within the acceptable range (0.76-0.91); concurrent and known groups validity were highest with the Global HRQL question. Longitudinal assessment was limited by the lack of disease progression in the group. CONCLUSIONS: The Neuro QOL SFs demonstrate good internal consistency, test-re-test reliability, and concurrent and known groups validity in this MS population, supporting the validity of Neuro-QOL in adults with MS. PMID- 26238465 TI - Atrophy of reward-related striatal structures in fatigued MS patients is independent of physical disability. AB - BACKGROUND: MRI studies have shown gray-matter abnormalities in fatigued multiple sclerosis (MS) patients. However, given that physical disability is highly correlated to MS fatigue, it is often difficult to disentangle its effect in these MRI findings. OBJECTIVE: The objective of this research paper is to investigate gray-matter damage in mildly disabled MS patients, addressing which variables were better related to fatigue while controlling for physical disability and depression. METHODS: Forty-nine relapsing-remitting MS (RRMS) patients and 30 controls underwent MRI (3T). Fatigue was assessed using the Fatigue Severity Scale (FSS). Multivariate logistic regression was performed to assess the contribution of clinical and MRI metrics to fatigue. Statistical analyses were performed controlling for disability and depression. RESULTS: Fatigue was present in 22 (44.9%) patients. FSS score was highly correlated with EDSS (p = 0.00001). Patients with fatigue had lower brain cortical and subcortical gray-matter volumes. However, after controlling for EDSS, only the caudate and the accumbens volumes remained statistically significant. CONCLUSIONS: Fatigued MS patients have a global cortical and subcortical gray matter atrophy that seems largely related to higher physical disability. However, striatal structures involved in effort-reward functions exhibited smaller volumes in fatigued patients, independently of physical disability and depressive symptoms, supporting the theory of cortico-striatal network impairment in MS fatigue. PMID- 26238466 TI - Epigenetic Changes in the Methylation Patterns of KCNQ1 and WT1 after a Weight Loss Intervention Program in Obese Stroke Patients. AB - Ischemic stroke patients often show high concentrations of circulating inflammatory markers that are associated with increased risk of recurrence. Epigenetic mechanisms could be involved in obesity, inflammation and stroke. The objective of this research was to investigate, in obese patients suffering a previous stroke, the effects of a nutritional program on anthropometric and biochemical variables, and on the methylation patterns of two stroke-related genes (KCNQ1: potassium channel, voltage gated KQT-like subfamily Q, member 1; and WT1: Wilms tumor 1). Twenty-two ischemic stroke patients were compared with a control group composed of eighteen obese subjects with similar age and body mass index ranges. Both groups followed a 20-week nutritional program based on an energy-restricted balanced diet with high adherence to the Mediterranean dietary pattern. The intervention significantly improved anthropometric and metabolic variables, such as the Homeostatic Model Assessment of Insulin Resistance (HOMA IR) and C-reactive protein concentration, in ischemic stroke patients, and was accompanied by changes in the methylation patterns of both stroke-related genes, which correlated with anthropometric and biochemical variables. PMID- 26238467 TI - Utilizing Ultrasound to Transiently Increase Blood-Brain Barrier Permeability, Modulate of the Tight Junction Proteins, and Alter Cytoskeletal Structure. AB - The central nervous system is protected by the blood-brain barrier (BBB). The tight junction (TJ) proteins claudin-5 and zonula occludens-1 (ZO-1) as well as the cytoskeletal component F-actin play key roles in maintaining homeostasis of the BBB. Increases in BBB permeability may be beneficial for the delivery of pharmacological substances into the brain. Therefore, here, we assessed the use of ultrasound to induce transient enhancement of BBB permeability. We used fluorescein isothiocyanate (FITC)-dextran 40 to detect changes in the membrane permeability of bEnd.3 cells during ultrasound treatment. Ultrasound increased FITC-dextran 40 uptake into bEnd.3 cells for 2-6 h after treatment; however, normal levels returned after 24 h. An insignificant increase in lactate dehydrogenase (LDH) leakage also occurred 3 and 6 h after ultrasound treatment, whereas at 24 h, LDH leakage was indistinguishable between the control and treatment groups. Expression of claudin-5, ZO-1, and F-actin at the messenger RNA (mRNA) and protein levels was assessed with real-time polymerase chain reaction and western blotting. Ultrasound induced a transient decrease in claudin-5 mRNA and protein expression within 2 h of treatment; however, no significant changes in ZO-1 and F-actin expression were observed. Claudin-5, ZO-1, and F-actin immunofluorescence demonstrated that the cellular structures incorporating these proteins were transiently impaired by ultrasound. In conclusion, our ultrasound technique can temporarily increase BBB permeability without cytotoxicity to exposed cells, and the method can be exploited in the delivery of drugs to the brain with minimal damage. PMID- 26238468 TI - A High Burden of Ischemic Stroke in Regions of Eastern/Central Europe is Largely Due to Modifiable Risk Factors. AB - Incidence and mortality of ischemic stroke in Croatia is significantly higher than in many other developed European countries. Here, we aimed to evaluate underlying conditions of this unacceptably high disease burden. An observational prospective cohort study of first-ever ischemic stroke patients identified in a population-based incidence study (N=751) (study 1, S1) and a concurrent case control trial (215 patients, 125 controls, S2) were conducted in the county of Varazdin from 2007-2010. Atrial fibrillation (AF) was common (36.1% in S1, 40.9% in S2) and mostly (>50%) unrecognized before the index event. In a multivariate analysis, odds of stroke increased with tobacco smoking (OR=3.95, 95%CI 1.33 10.8), unhealthy diet (OR=2.12, 1.12-4.01) and AF (OR=9.40, 4.01-22.0), and decreased with higher education (OR=0.33, 0.11-0.98), moderate alcohol consumption (OR=0.48, 0.25-0.93), higher fasting HDL (OR=0.14, 0.07-0.30) and pre stroke use of anticoagulants (OR=0.09, 0.01-0.59), antihypertensive drugs (OR=0.52, 0.27-1.00) and statins (OR=0.29, 0.12-0.69). Fourteen-day case fatality was 10.8% (S1) and 6.1% (S2) and the risk was higher with AF, cardioembolic stroke, older age, higher fasting serum glucose, and lower with acute aspirin. Among the acute phase survivors, 30.9% died over the subsequent 1-3 years (p<0.05). We conclude that the incidence of ischemic stroke in Croatia is related to conventional risk factors and largely due to a high rate of unawareness and inadequate treatment of predisposing morbidity. PMID- 26238469 TI - Intravenous Fosfomycin Treatment for Carbapenem-Resistant Klebsiella pneumoniae in the United States. PMID- 26238470 TI - New Insulin Glargine 300 U/mL for the Treatment of Type 1 and Type 2 Diabetes Mellitus. AB - OBJECTIVE: To describe the studies evaluating the efficacy and safety of new insulin glargine 300 U/mL (Gla-300) as a basal insulin in the treatment of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. DATA SOURCES: A literature search of MEDLINE was conducted (January 2008-June 2015) using the terms U300, Gla-300, and insulin glargine 300 units/mL and supplemented with congress abstracts published in 2014 and 2015. STUDY SELECTION AND DATA EXTRACTION: All English language studies assessing the efficacy and/or safety of Gla-300 were evaluated. DATA SYNTHESIS: The efficacy and safety of once-daily Gla-300 has been compared with insulin glargine 100 U/mL (Gla-100) in the EDITION trials, 6 phase-3, multinational, open-label studies in T1DM and T2DM. Across these studies, Gla-300 consistently demonstrated glycemic control comparable to Gla-100; a mean (standard error) change in glycated hemoglobin A1c of -1.02% (0.03) with both Gla 100 (n = 1235) and Gla-300 (n = 1239) was seen in a patient-level meta-analysis. Gla-300 was associated with comparable or reduced nocturnal hypoglycemia compared with Gla-100; the relative risk for nocturnal hypoglycemia with Gla-300 versus Gla-100 was 0.75 (95% CI = 0.68 to 0.83) in a patient-level meta-analysis. There is also some evidence for less weight gain with Gla-300 compared with Gla-100, despite a higher insulin dose. Gla-300 was well tolerated, with the number of adverse events being comparable to that with Gla-100. CONCLUSIONS: These results suggest that Gla-300 may have a place as an alternative, long-acting basal insulin for patients with T1DM or T2DM, with the possibility for improved tolerability. PMID- 26238471 TI - PDK1: A signaling hub for cell migration and tumor invasion. AB - The ability of cells to migrate is essential for different physiological processes including embryonic development, angiogenesis, tissue repair and immune response. In the context of cancer such abilities acquire dramatic implications, as they are exploited by tumor cells to invade neighboring or distant healthy tissues. 3-Phosphoinositide dependent protein kinase-1 (PDK1 or PDPK1) is an ancient serine-threonine kinase belonging to AGC kinase family. An increasing amount of data points at a pivotal role for PDK1 in the regulation of cell migration. PDK1 is a transducer of PI3K signaling and activates multiple downstream effectors, thereby representing an essential hub coordinating signals coming from extracellular cues to the cytoskeletal machinery, the final executor of cell movement. Akt, PAK1, beta3 integrin, ROCK1, MRCKalpha and PLCgamma1 are, according to the literature, the signaling transducers through which PDK1 regulates cell migration. In addition, PDK1 contributes to tumor cell invasion by regulating invadopodia formation and both amoeboid and collective cancer cell invasion. This and other pieces of evidence, such as its reported overexpression across several tumor types, corroborate a PDK1 role tumor aggressiveness. Altogether, these findings indicate the possibility to rationally target PDK1 in human tumors in order to counteract cancer cell dissemination in the organism. PMID- 26238473 TI - Selection on incremental variation of eye size in a wild population of Daphnia. AB - Several studies of eye morphology have analysed macroevolutionary patterns in the diversity of eyes, and although these studies are often linked to environment or behaviour, they provide only indirect evidence of selection. Specific data to show the microevolutionary potential for adaptation by natural selection in eye morphology have been lacking. We document directional selection on eye size, an important determinant of visual capabilities, in a wild population of the freshwater microcrustacean Daphnia. We show that even slight changes in eye size may have major consequences for fitness. An increase in eye diameter of 19.9 MUm slightly more than one standard deviation - is associated with an increase in clutch size of one egg, or an increase of nearly 20% of the mean clutch size. Furthermore, relative eye size is genetically variable and thus could evolve in response to the observed selective pressure. We conclude that selection on incremental variation in eye size may have led to differences observed on broader taxonomic scales. PMID- 26238472 TI - Laparoscopic resection with natural orifice specimen extraction versus conventional laparoscopy for colorectal disease: a meta-analysis. AB - PURPOSE: We wished to determine the effects of laparoscopic resection using natural orifice specimen extraction (NOSE) for patients with colorectal disease through a meta-analysis. METHODS: A study search was undertaken in PubMed, EMBASE, and Cochrane databases for eligible studies until December 2014. Duration of hospital stay, operation time, time to first flatus, pain score, cosmetic result, postoperative complications, and disease-free survival (DFS) were the main endpoints. The results were analyzed using RevMan v5.3. RESULTS: Nine clinical studies involving 837 patients were included for final analyses. Laparoscopic resection with NOSE had a shorter duration of hospital stay (weighted mean difference (WMD) = -0.62 days, 95 % confidence interval (CI) [ 0.95, -0.28], p < 0.01) and time to first flatus (WMD = -0.59 days, 95 % CI [ 0.78, -0.41], p < 0.01), less postoperative pain (WMD = -1.43, 95 % CI [-1.95, 0.90], p < 0.01), and postoperative complications (odds ratio (OR) = 0.51, 95 % CI [0.36, 0.74], p < 0.01) with better cosmetic result (WMD = 1.37, 95 % CI [0.59, 2.14], p < 0.01). However, the operation time was significantly longer in the NOSE group (WMD = 20.97 min, 95 % CI [4.33, 37.62], p = 0.01). No significant difference was observed in DFS (hazard ratio (HR) = 0.88, 95 % CI [0.49, 1.57], p = 0.67). CONCLUSION: Our meta-analysis supported the notion that laparoscopic resection with NOSE for colorectal disease can significantly reduce the duration of hospital stay, accelerate postoperative recovery with better cosmetic results, and in particular, result in less postoperative pain and fewer complications. PMID- 26238474 TI - HCV vertical transmission in pregnancy: New horizons in the era of DAAs. PMID- 26238475 TI - Homeless Caseload is Associated with Behavioral Health and Case Management Staffing in Health Centers. AB - Community health centers provide co-located medical, behavioral, and case management services to meet the unique and complex needs of the underserved, including homeless individuals. Multivariate analysis of staffing patterns in health centers serving high homeless caseloads highlights above-average behavioral and case management staffing, regardless of Health Care for the Homeless funding status. Rural health centers and those in the South had lower behavioral health and enabling services staffing. Implications include the need to monitor disparities, link health centers with available technical assistance, and emphasize integrating co-located behavioral health, enabling, and medical services through grant oversight mechanisms. PMID- 26238477 TI - Surgery of the primary tumor in de novo metastatic breast cancer: To do or not to do? AB - Approximately five percent of all breast cancer patients in developed countries present with distant metastases at initial diagnosis. Due to its incurability, metastatic breast cancer is generally treated with systemic therapies to achieve disease control and reduce tumor-related symptoms. Primary treatments for metastatic breast cancer are chemotherapy, endocrine- and biologic therapy, whereas surgery with or without radiotherapy is usually performed to treat impending wound issues. Since 2002, several retrospective non-randomized clinical studies have shown that extirpation of the primary tumor correlates with a significantly improved survival in patients with primary metastatic breast cancer. Others have argued that this survival benefit associated with surgery may be due to selection biases. Therefore, in the absence of published results from randomized controlled trials carried out in India and Turkey and completion of a trial in the United States, there is no clear conclusion on whether surgical excision of the primary breast cancer translates into a survival benefit for patients with de novo metastatic disease. Furthermore, timing and type of surgical procedure, as well as selection of patients who could benefit the most from this approach, represent additional points of uncertainty. Despite the epidemiological burden of this condition, there are no guidelines on how to manage breast cancer patients presenting with de novo metastatic breast cancer; and decisions are often left to provider and patient preferences. Here, we present a critical overview of the literature focusing on the rationale and potential role of primary tumour excision in patients with de novo metastatic breast cancer. PMID- 26238476 TI - Spatiotemporal regulation of GLI target genes in the mammalian limb bud. AB - GLI proteins convert Sonic hedgehog (Shh) signaling into a transcriptional output in a tissue-specific fashion. The Shh pathway has been extensively studied in the limb bud, where it helps regulate growth through a SHH-FGF feedback loop. However, the transcriptional response is still poorly understood. We addressed this by determining the gene expression patterns of approximately 200 candidate GLI-target genes and identified three discrete SHH-responsive expression domains. GLI-target genes expressed in the three domains are predominately regulated by derepression of GLI3 but have different temporal requirements for SHH. The GLI binding regions associated with these genes harbor both distinct and common DNA motifs. Given the potential for interaction between the SHH and FGF pathways, we also measured the response of GLI-target genes to inhibition of FGF signaling and found the majority were either unaffected or upregulated. These results provide the first characterization of the spatiotemporal response of a large group of GLI target genes and lay the foundation for a systems-level understanding of the gene regulatory networks underlying SHH-mediated limb patterning. PMID- 26238478 TI - An improved technique for bladder cancer: Pure laparoscopic radical cystectomy with orthotopic U-shape ileal neobladder using titanium staples. AB - OBJECTIVE: To report our experience with an improved technique of laparoscopic radical cystectomy (LRC) and orthotopic ileal neobladder reconstruction, evaluating the perioperative and pathological outcomes. METHODS: We retrospectively reviewed the data of 56 cases who underwent radical cystoprostatectomy followed by construction of an orthotopic U-shaped ileal neobladder between August 2010 and December 2014. These data include intraoperative data, early and long-term postoperative complications, neobladder function, urinary continence and oncologic results. Also the key innovative procedure was introduced with details. RESULTS: The median time of the overall procedure was 212 min. The median estimated blood loss was 171 ml. The median hospitalization time after the operation was 21 days. Complications included two cases of unilateral ureter-pouch anastomotic strictures, one case of bilateral ureteral stricture, three cases of vesicourethral anastomotic strictures and three cases of vesicourethral leakage. The mean maximum pouch capacity was 446 +/ 32 ml, and pouch pressure at capacity was 18.1 +/- 2.6 cm H2O. The Qmax was 14 +/- 1.2 ml/s, and the mean postvoid residual was 25 +/- 10 ml. There were 9 cases of night-time incontinence at 3 months post-operatively. Negative surgical margins of the bladder specimens were achieved in all patients. During a follow up period of 3-44 months (average 32.6 months), local recurrence was found in two patients and distant metastasis was occurred in another 3 patients. CONCLUSIONS: Our preliminary experience showed that pure LRC with nonabsorbable titanium staples assisted orthotopic U-shape ileal neobladder reconstruction is feasible based on perioperative data and oncologic features. PMID- 26238479 TI - Using non-Markovian measures to evaluate quantum master equations for photosynthesis. AB - When dealing with system-reservoir interactions in an open quantum system, such as a photosynthetic light-harvesting complex, approximations are usually made to obtain the dynamics of the system. One question immediately arises: how good are these approximations, and in what ways can we evaluate them? Here, we propose to use entanglement and a measure of non-Markovianity as benchmarks for the deviation of approximate methods from exact results. We apply two frequently-used perturbative but non-Markovian approximations to a photosynthetic dimer model and compare their results with that of the numerically-exact hierarchy equation of motion (HEOM). This enables us to explore both entanglement and non-Markovianity measures as means to reveal how the approximations either overestimate or underestimate memory effects and quantum coherence. In addition, we show that both the approximate and exact results suggest that non-Markonivity can, counter intuitively, increase with temperature, and with the coupling to the environment. PMID- 26238480 TI - The impact of cryoballoon-based catheter ablation on left atrial structural and potential electrical remodeling in patients with paroxysmal atrial fibrillation. AB - BACKGROUND: While atrial fibrillation (AF) begets AF via structural, contractile, and electrical remodeling, it was shown that successful radiofrequency ablation of AF has effectively reversed left atrial (LA) remodeling. However, there was little data regarding the efficacy of cryoablation on LA remodeling. Herein, we aimed to assess the impact of cryoablation on LA structural and potential electrical remodeling in paroxysmal AF patients. METHODS: A total of 41 symptomatic patients with non-valvular paroxysmal AF underwent their first catheter ablation via cryoballoon technique. All patients had transthoracic echocardiography before, 6 and 12 months after cryoablation. LA volume index (LAVI), left intra-, right intra-, and inter-atrial electromechanical conduction delay (AEMD) were calculated in all patients. Postprocedural first 3 months was accepted as blanking period. RESULTS: All 179 pulmonary veins were isolated successfully in 41 patients with no major complication. During median 18 months (12-20 months) follow-up, recurrent atrial arrhythmia was found in nine patients (21.9%). In multivariate Cox regression analysis, only early recurrence was found as the independent predictor of late recurrence. At 12th month visit compared to baseline, there was no change in LAVI (p = 0.647) but significant increase in left intra- and inter-AEMD (p < 0.05). However, in non-recurrent group, both LAVI (30.63 +/- 3.6 to 28.42 +/- 3.63, p < 0.001), left intra-AEMD (18.75 +/- 8.77 to 12.5 +/- 4.65, p < 0.001), and inter-AEMD (25.2 +/- 13.2 to 18.84 +/- 8.52, p < 0.001) were significantly decreased. CONCLUSIONS: Our study findings revealed that successful cryoballoon-based AF ablation yields LA structural and potential electrical reverse remodeling. However, LA remodeling process cannot be halted by cryoablation in patients with AF recurrence during follow-up. PMID- 26238481 TI - Heavy metals in marine fish meat and consumer health: a review. AB - The numerous health benefits provided by fish consumption may be compromised by the presence of toxic metals and metalloids such as lead, cadmium, arsenic and mercury, which can have harmful effects on the human body if consumed in toxic quantities. The monitoring of metal concentrations in fish meat is therefore important to ensure compliance with food safety regulations and consequent consumer protection. The toxicity of these metals may be dependent on their chemical forms, which requires metal speciation processes for direct measurement of toxic metal species or the identification of prediction models in order to determine toxic metal forms from measured total metal concentrations. This review addresses various shortcomings in current knowledge and research on the accumulation of metal contaminants in commercially consumed marine fish globally and particularly in South Africa, affecting both the fishing industry as well as fish consumers. PMID- 26238482 TI - Gene expression profiling in myelodysplastic syndrome after SPARC overexpression associated with Ara-C. AB - Secreted protein acidic and rich in cysteine (SPARC) is involved in many biological processes, including erythropoiesis and cell proliferation. However, the role of SPARC in myelodysplastic syndrome (MDS) remains to be elucidated. Pyrimidine analogue cytosine arabinoside (Ara-C) is among the most effective agents used in the treatment of acute leukemia. The aim of the present study was to determine whether the chemotherapeutic activity of Ara-C was enhanced by the overexpression of SPARC. DNA microarray technology and RNA sequencing were employed to examine differential gene expression in the apoptosis signaling pathway after gene change occurred in cells following drug treatment. The results showed that upregulation of the expression of SPARC induced SKM-1 cell death and inhibited proliferation. Additionally, the apoptotic rate of SPARC overexpression combined with Ara-C increased significantly. Transcription factors CPBP and ZNF333 regulated the 69 genes and long non-coding RNA (lncRNA). Moreover, the mRNA and protein expression of apoptosis-related genes in the DNA microarray results were increased. These results suggest that SPARC expression changes with Ara-C, revealing a possible application in the treatment of MDS. PMID- 26238483 TI - Composite Superior Gluteal Artery Perforator Flaps for Unilateral Breast Reconstruction: A Case Report. PMID- 26238484 TI - Best bang for your buck: GPU nodes for GROMACS biomolecular simulations. AB - The molecular dynamics simulation package GROMACS runs efficiently on a wide variety of hardware from commodity workstations to high performance computing clusters. Hardware features are well-exploited with a combination of single instruction multiple data, multithreading, and message passing interface (MPI) based single program multiple data/multiple program multiple data parallelism while graphics processing units (GPUs) can be used as accelerators to compute interactions off-loaded from the CPU. Here, we evaluate which hardware produces trajectories with GROMACS 4.6 or 5.0 in the most economical way. We have assembled and benchmarked compute nodes with various CPU/GPU combinations to identify optimal compositions in terms of raw trajectory production rate, performance-to-price ratio, energy efficiency, and several other criteria. Although hardware prices are naturally subject to trends and fluctuations, general tendencies are clearly visible. Adding any type of GPU significantly boosts a node's simulation performance. For inexpensive consumer-class GPUs this improvement equally reflects in the performance-to-price ratio. Although memory issues in consumer-class GPUs could pass unnoticed as these cards do not support error checking and correction memory, unreliable GPUs can be sorted out with memory checking tools. Apart from the obvious determinants for cost-efficiency like hardware expenses and raw performance, the energy consumption of a node is a major cost factor. Over the typical hardware lifetime until replacement of a few years, the costs for electrical power and cooling can become larger than the costs of the hardware itself. Taking that into account, nodes with a well balanced ratio of CPU and consumer-class GPU resources produce the maximum amount of GROMACS trajectory over their lifetime. PMID- 26238485 TI - The synergistic effect of VEGF and biomorphic silicon carbides topography on in vivo angiogenesis and human bone marrow derived mesenchymal stem cell differentiation. AB - Topographical features of biomaterials are able to modulate cell attachment, spreading and differentiation. The addition of growth factors to implantable biomaterials can modify these cellular responses, enhancing their therapeutic potential. The aim of this research is to establish the influence of biomorphic silicon carbide ceramics (bioSiCs) surface topography on the proliferation and osteoblastic differentiation of mesenchymal stem cells and the potential synergistic effect of the ceramic porous structure together with vascular endothelial growth factor loading (VEGF) on the surface mediated osteoblastic differentiation. Three porous bioSiCs with important differences in their microstructure were obtained from different natural precursors. Samples loaded with or without VEGF through ionic interactions were cultured with human umbilical vein endothelial cells (HUVEC) or bone marrow derived mesenchymal stem cells (hMSCs). Cell behaviour and protein activity with regard to bioSiC porous structure and surface properties were analysed. An in vivo model (Chick Chorioallantoic Membrane; CAM) was used to assess the capability of the VEGF loaded systems to promote angiogenesis. Experimental data show that loaded systems were able to control the release of VEGF for up to 15 d ensuring the activity of the protein, increasing the proliferation of HUVECs and the formation of new blood vessels in the CAM. It was found that the selection of bioSiCs with a higher pore size promoted a higher concentration of osteoblastic differentiation markers of MSCs cultured on the surface of bioSiCs. Furthermore, the addition of VEGF to the systems was able to promote a faster osteoblastic differentiation according to the qPCR results, suggesting a synergy between both the surface properties and the controlled release of the growth factor. The VEGF loaded sapelli bioSiC was found to be the most promising material for bone tissue engineering applications. PMID- 26238486 TI - mTOR Inhibition Per Se Induces Nuclear Localization of FOXP3 and Conversion of Invariant NKT (iNKT) Cells into Immunosuppressive Regulatory iNKT Cells. AB - CD1d-restricted activation of invariant NKT (iNKT) cells results in the abundant production of various types of cytokines and the subsequent modulation of immune responses. This has been shown to be relevant in several clinical disorders, including cancer, autoimmunity, and graft tolerance. Although it is well known that the suppressive function of regulatory T cells is critically dependent on the FOXP3 gene, FOXP3 can also be expressed by conventional human T cells upon activation, indicating the lack of specificity of FOXP3 as a marker for suppressive cells. In this study, we report that the mammalian target of rapamycin (mTOR) inhibitor rapamycin and IL-10, but not TGF-beta, can induce FOXP3 expression in iNKT cell lines. Importantly, however, FOXP3(+) iNKT cells only acquired suppressive abilities when cultured in the presence of the mTOR inhibitor rapamycin. Suppression of responder T cell proliferation by FOXP3(+) iNKT cells was found to be cell contact-dependent and was accompanied by a reduced capacity of iNKT cells to secrete IFN-gamma. Notably, imaging flow cytometry analysis demonstrated predominant nuclear localization of FOXP3 in suppressive FOXP3(+) iNKT cells, whereas nonsuppressive FOXP3(+) iNKT cells showed a predominance of cytoplasmically localized FOXP3. In conclusion, whereas IL-10 can enhance FOXP3 expression in iNKT cells, mTOR inhibition is solely required for promoting nuclear localization of FOXP3 and the induction of suppressive FOXP3(+) iNKT cells. PMID- 26238489 TI - Endothelial LSP1 Modulates Extravascular Neutrophil Chemotaxis by Regulating Nonhematopoietic Vascular PECAM-1 Expression. AB - During inflammation, leukocyte-endothelial cell interactions generate molecular signals that regulate cell functions. The Ca(2+)- and F-actin-binding leukocyte specific protein 1 (LSP1) expressed in leukocytes and nonhematopoietic endothelial cells is pivotal in regulating microvascular permeability and leukocyte recruitment. However, cell-specific function of LSP1 during leukocyte recruitment remains elusive. Using intravital microscopy of cremasteric microvasculature of chimeric LSP1-deficient mice, we show that not neutrophil but endothelial LSP1 regulates neutrophil transendothelial migration and extravascular directionality without affecting the speed of neutrophil migration in tissue in response to CXCL2 chemokine gradient. The expression of PECAM-1 sensitive alpha6beta1 integrins on the surface of transmigrated neutrophils was blunted in mice deficient in endothelial LSP1. Functional blocking studies in vivo and in vitro elucidated that alpha6beta1 integrins orchestrated extravascular directionality but not the speed of neutrophil migration. In LSP1 deficient mice, PECAM-1 expression was reduced in endothelial cells, but not in neutrophils. Similarly, LSP1-targeted small interfering RNA silencing in murine endothelial cells mitigated mRNA and protein expression of PECAM-1, but not ICAM 1 or VCAM-1. Overexpression of LSP1 in endothelial cells upregulated PECAM-1 expression. Furthermore, the expression of transcription factor GATA-2 that regulates endothelial PECAM-1 expression was blunted in LSP1-deficient or LSP1 silenced endothelial cells. The present study unravels endothelial LSP1 as a novel cell-specific regulator of integrin alpha6beta1-dependent neutrophil extravascular chemotactic function in vivo, effective through GATA-2-dependent transcriptional regulation of endothelial PECAM-1 expression. PMID- 26238487 TI - The Raf Kinase Inhibitor Sorafenib Inhibits JAK-STAT Signal Transduction in Human Immune Cells. AB - Sorafenib is an oral multikinase inhibitor that was originally developed as a Raf kinase inhibitor. We hypothesized that sorafenib would also have inhibitory effects on cytokine signaling pathways in immune cells. PBMCs from normal donors were treated with varying concentrations of sorafenib and stimulated with IFN alpha or IL-2. Phosphorylation of STAT1 and STAT5 was measured by flow cytometry and confirmed by immunoblot analysis. Changes in IFN-alpha- and IL-2-stimulated gene expression were measured by quantitative PCR, and changes in cytokine production were evaluated by ELISA. Cryopreserved PBMCs were obtained from cancer patients before and after receiving 400 mg sorafenib twice daily. Patient PBMCs were thawed, stimulated with IL-2 or IFN-alpha, and evaluated for phosphorylation of STAT1 and STAT5. Pretreatment of PBMCs with 10 MUM sorafenib decreased STAT1 and STAT5 phosphorylation after treatment with IFN-alpha or IL-2. This inhibitory effect was observed in PBMCs from healthy donors over a range of concentrations of sorafenib (5-20 MUM), IL-2 (2-24 nM), and IFN-alpha (10(1)-10(6) U/ml). This effect was observed in immune cell subsets, including T cells, B cells, NK cells, regulatory T cells, and myeloid-derived suppressor cells. Pretreatment with sorafenib also inhibited PBMC expression of IFN-alpha- and IL-2-regulated genes and inhibited NK cell production of IFN-gamma, RANTES, MIP1-alpha, and MIG in response to IFN-alpha stimulation. PBMCs from patients receiving sorafenib therapy showed decreased responsiveness to IL-2 and IFN-alpha treatment. Sorafenib is a Raf kinase inhibitor that could have off-target effects on cytokine-induced signal transduction in immune effector cells. PMID- 26238488 TI - Modulation of the IL-6 Receptor alpha Underlies GLI2-Mediated Regulation of Ig Secretion in Waldenstrom Macroglobulinemia Cells. AB - Ig secretion by terminally differentiated B cells is an important component of the immune response to foreign pathogens. Its overproduction is a defining characteristic of several B cell malignancies, including Waldenstrom macroglobulinemia (WM), where elevated IgM is associated with significant morbidity and poor prognosis. Therefore, the identification and characterization of the mechanisms controlling Ig secretion are of great importance for the development of future therapeutic approaches for this disease. In this study, we define a novel pathway involving the oncogenic transcription factor GLI2 modulating IgM secretion by WM malignant cells. Pharmacological and genetic inhibition of GLI2 in WM malignant cells resulted in a reduction in IgM secretion. Screening for a mechanism identified the IL-6Ralpha (gp80) subunit as a downstream target of GLI2 mediating the regulation of IgM secretion. Using a combination of expression, luciferase, and chromatin immunoprecipitation assays we demonstrate that GLI2 binds to the IL-6Ralpha promoter and regulates its activity as well as the expression of this receptor. Additionally, we were able to rescue the reduction in IgM secretion in the GLI2 knockdown group by overexpressing IL-6Ralpha, thus defining the functional significance of this receptor in GLI2-mediated regulation of IgM secretion. Interestingly, this occurred independent of Hedgehog signaling, a known regulator of GLI2, as manipulation of Hedgehog had no effect on IgM secretion. Given the poor prognosis associated with elevated IgM in WM patients, components of this new signaling axis could be important therapeutic targets. PMID- 26238490 TI - Store-Operated Ca2+ Release-Activated Ca2+ Channels Regulate PAR2-Activated Ca2+ Signaling and Cytokine Production in Airway Epithelial Cells. AB - The G-protein-coupled protease-activated receptor 2 (PAR2) plays an important role in the pathogenesis of various inflammatory and auto-immune disorders. In airway epithelial cells (AECs), stimulation of PAR2 by allergens and proteases triggers the release of a host of inflammatory mediators to regulate bronchomotor tone and immune cell recruitment. Activation of PAR2 turns on several cell signaling pathways of which the mobilization of cytosolic Ca(2+) is likely a critical but poorly understood event. In this study, we show that Ca(2+) release activated Ca(2+) (CRAC) channels encoded by stromal interaction molecule 1 and Orai1 are a major route of Ca(2+) entry in primary human AECs and drive the Ca(2+) elevations seen in response to PAR2 activation. Activation of CRAC channels induces the production of several key inflammatory mediators from AECs including thymic stromal lymphopoietin, IL-6, and PGE2, in part through stimulation of gene expression via nuclear factor of activated T cells (NFAT). Furthermore, PAR2 stimulation induces the production of many key inflammatory mediators including PGE2, IL-6, IL-8, and GM-CSF in a CRAC channel-dependent manner. These findings indicate that CRAC channels are the primary mechanism for Ca(2+) influx in AECs and a vital checkpoint for the induction of PAR2-induced proinflammatory cytokines. PMID- 26238491 TI - Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling. AB - Cellular FLIP (c-FLIP) specifically inhibits caspase-8 and suppresses death receptor-induced apoptosis. c-FLIP has also been reported to transmit activation signals. In this study, we report a novel function of c-FLIP involving inhibition of myeloid cell activation through antagonizing the selective innate signaling pathway. We found that conditional knockout of c-FLIP in dendritic cells (DCs) led to neutrophilia and splenomegaly. Peripheral DC populations, including CD11b(+) conventional DCs (cDCs), CD8(+) cDCs, and plasmacytoid DCs, were not affected by c-FLIP deficiency. We also found that c-FLIP knockout cDCs, plasmacytoid DCs, and bone marrow-derived DCs (BMDCs) displayed enhanced production of TNF-alpha, IL-2, or G-CSF in response to stimulation of TLR4, TLR2, and dectin-1. Consistent with the ability of c-FLIP to inhibit the activation of p38 MAPK, the enhanced activation of c-FLIP-deficient BMDCs could be partly linked to an elevated activation of p38 MAPK after engagement of innate receptors. Increased activation was also found in c-FLIP(+/-) macrophages. Additionally, the increased activation in c-FLIP-deficient DCs was independent of caspase-8. Our results reveal a novel inhibitory role of c-FLIP in myeloid cell activation and demonstrate the unexpected anti-inflammatory activity of c-FLIP. Additionally, our observations suggest that cancer therapy targeting c-FLIP downregulation may facilitate DC activation and increase T cell immunity. PMID- 26238493 TI - Adding of ascorbic acid to the culture medium influences the antioxidant status and some biochemical parameters in the hen granulosa cells. AB - OBJECTIVES: The aim of the present study was to determine the activity of superoxide dismutase (SOD), total antioxidant status (TAS) of the hen granulosa cells, and selected biochemical parameters, including calcium, phosphorus, sodium, potassium, glucose, cholesterol, proteins, in the culture medium of granulosa cells after exposing them to ascorbic acid in vitro conditions. METHODS: Ovarian granulosa cells of hens were incubated with various doses of ascorbic acid (E1 0.09 mg/ml, E2 0.13 mg/ml, E3 0.17 mg/ml, E4 0.33 mg/ml, E5 0.5 mg/ml). RESULTS: Ascorbic acid did not manifest antioxidant potential and higher doses of ascorbic acid (0.17; 0.33 and 0.5 mg/ml) decreased the activity of SOD in granulosa cells. Vitamin application resulted in a significantly (p<0.05) higher accumulation of Na+ and K+ in culture media of granulosa cells and decreased the concentration of glucose and proteins. CONCLUSION: These results indicate that ascorbic acid might be involved in the regulation of selected biochemical and physiological processes in ovarian granulosa cells. PMID- 26238492 TI - Th Cell Diversity in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. AB - Multiple sclerosis (MS) is believed to be initiated by myelin-reactive CD4(+) Th cells. IL-12-polarized Th1 cells, IL-23-polarized Th17 cells, and Th17 cells that acquire Th1 characteristics were each implicated in autoimmune pathogenesis. It is debated whether Th cells that can drive the development of demyelinating lesions are phenotypically diverse or arise from a single lineage. In the current study, we assessed the requirement of IL-12 or IL-23 stimulation, as well as Th plasticity, for the differentiation of T cells capable of inducing CNS axon damage. We found that stable murine Th1 and Th17 cells independently transfer experimental autoimmune encephalomyelitis (widely used as an animal model of MS) in the absence of IL-23 and IL-12, respectively. Plastic Th17 cells are particularly potent mediators of demyelination and axonopathy. In parallel studies, we identified MS patients who consistently mount either IFN-gamma- or IL 17-skewed responses to myelin basic protein over the course of a year. Brain magnetic resonance imaging revealed that patients with mixed IFN-gamma and IL-17 responses have relatively high T1 lesion burden, a measure of permanent axon damage. Our data challenge the dogma that IL-23 and Th17 plasticity are universally required for the development of experimental autoimmune encephalomyelitis. This study definitively demonstrates that autoimmune demyelinating disease can be driven by distinct Th-polarizing factors and effector subsets, underscoring the importance of a customized approach to the pharmaceutical management of MS. PMID- 26238494 TI - Does radio frequency radiation induce micronuclei frequency in exfoliated bladder cells of diabetic rats? AB - OBJECTIVE: For many years there has been a discussion among both experts and the general public regarding the effects of radio frequency (RF) radiation on the human organism. The purpose of the present study was to evaluate the relationship of micronucleui (MN) frequency and RF radiation in exfoliated bladder cells of non-diabetic and diabetic rats. METHODS: Three groups were used in the experiment: Group I (n=6): diabetic group without RF exposure; Group II (n=6): diabetic group exposed 2100 MHz RF radiation and Group III (n=6): control animals (non-diabetic group, no RF exposure). RF exposure in the experiment resulted in a whole body average SAR of 0.24 W/kg with an ERMS field of 17.5 V/m in non-thermal levels. RESULT: Results showed that there was no statistically important differences between non-RF exposed diabetes group and control group; Group I and Group III (p>0.05). There was no statistically important differences between diabetes group and diabetes+RF exposed group (Group I and Group II) (p>0.05). RF exposure did not result in increased MN frequencies in exfoliated bladder cells of diabetic rats with respect to control animals (Group II and Group III), either and this result found no statistically important (p>0.05). CONCLUSIONS: This study suggested no possible genotoxic effects of RF radiation among human beings especially with chronic disorders, such as diabetes. PMID- 26238495 TI - Inhibition of fatty-acid amide hydrolyse (FAAH) exerts cognitive improvements in male but not female rats. AB - OBJECTIVES: The endocannabinoid system is implicated in the regulation of various brain functions including cognition, memory, and behavior. It has been shown that inhibition of the endocannabinoid-degrading enzyme fatty acid amid hydrolase (FAAH) enhances the memory and learning in males. Given the fact that sexual dimorphism exists in the different components of the endocannabinoid system, the aim of this study was to test the hypothesis that cognition enhancing effect of the acute inhibition of FAAH by URB597 is gender dependent. METHODS: In the study, 32 adult male and female Sprague-Dawley rats were used. They were treated with a single intraperitoneal injection of FAAH inhibitor URB597 (0.3 mg/kg) or vehicle 40 min before behavioral testing. The novel object recognition test was used as a working memory task to assess cognitive performance. RESULTS: Neither the treatment nor the gender significantly affected the velocity, the total distance travelled and the time spent exploring the familiar object. The recognition of the object was influenced by both URB597 and gender. Male rats treated with URB597 displayed significantly increased novel object exploration compared to males treated with vehicle as well as to female rats treated with URB597. Single administration of URB597 significantly enhanced the recognition index in male, but not female rats. CONCLUSIONS: The results demonstrate that the positive effects of FAAH inhibition on the cognition are gender dependent. It is likely that male rats are more vulnerable to the modulation of the endocannabinoid system than female rats. PMID- 26238497 TI - Potential biomarkers of exosomal cargo in endocrine signaling. AB - Cancer represents one of the leading cause of morbidity and mortality worldwide, with approximately 14 million new cases every year and more than 8 million cancer related deaths. In men, lung cancer is the most frequently diagnosed cancer type, followed by the prostate, colorectal, and gastric cancer; in woman, the most frequent cancer is the breast cancer, followed by the colorectal, lung, cervical, and stomach cancer. During the second half of the twentieth century the efforts to evaluate the importance of the solid tumor cells present in the circulating blood have been made. Similarly, long time ago in 1948, extracellular nucleic acids (circulating free DNA) floating around in human blood plasma were discovered. Exosomes were disclosed as the last component of this "triumvirate" present in the blood and applicable for diagnostics. The exosomal cargo consists of bioactive molecules from donor cells that can be transferred to recipient cells and modulate their intracellular signaling. Thus, exosomes can provide autocrine (local signals between the same cell type), paracrine (local signals between different cell types), and endocrine (distant signals between any types of cells) type of signals. PMID- 26238496 TI - Age of obesity onset in MC4R mutation carriers. AB - OBJECTIVES: The mutations in gene for the melanocortin-4 receptor (MC4R) are the most common etiology factors of monogenic obesity development. Recently, it has been shown that current life style has a significant impact on the phenotype of MC4R mutation carriers - increases the penetrance of the mutations. We aimed to study the impact of the current age on the time of obesity onset among MC4R mutation carriers. METHODS: DNA analysis of the MC4R gene was performed in 268 unrelated Slovak and Moravian obese children and adolescents 18 years and 28 blood relatives >18 years of the probands with a mutation. RESULTS: Three different previously described heterozygous loss of function MC4R mutations (p.Ser19Alafs*34, p.Ser127Leu, and p.Gly181Asp) were found in 3 <18 years probands, 3 adult probands, and 6 adult obese/overweight family relatives. The age of obesity onset in mutation carriers was 1 year in all probands in the children group and 1-35 years (median 11 years) in adults. The age of the obesity onset significantly correlated (R=0.809, p=0.028) with the current age in all of the MC4R mutation carriers. CONCLUSIONS: The age of obesity onset in the present child generation of MC4R mutation carriers is decreasing compared to the age of onset in their parents' generation. This is in agreement with similarly increasing penetrance of obesity in MC4R mutation carriers and it points out to escalation of obesogenic potential of environment. PMID- 26238498 TI - Exercise associated hormonal signals as powerful determinants of an effective fat mass loss. AB - Obesity management for achieving an effective weight loss includes dietary modification and exercise [resistance (strength), endurance (cardiovascular) or intervals training (high-intensity intermittent exercise)]. Regular exercise acutely increases fat oxidation, which induces loss of fat mass and increases energy expenditure. Moreover, it has a positive effect on the physical (improved insulin sensitivity, lipid profile, etc.) and mental health (mood, cognition, memory, sleep, etc.). Endocrine responses to muscle actions are affected by many factors, including the exercise muscle groups (lower and upper body), load/volume, time-under tension, and rest-period intervals between sets, training status, gender, and age. The aim of this review is to summarize, evaluate, and clarify the literature data focusing on the endocrine responses to different types of exercise, including the frequency, intensity, and type of movement with regard to the fat loss strategies. Many studies have investigated anabolic [growth hormone, insulin-like growth factor-1 (IGF-1), testosterone] and gluco- and appetite- regulatory (insulin, cortisol, ghrelin) hormone responses and adaptations of skeletal muscles to exercise. Muscle tissue is a critical endocrine organ, playing important role in the regulation of several physiological and metabolic events. Moreover, we are also describing the response of some other substances to exercise, such as myokines [irisin, apelin, brain derived neurotrophic factor (BDNF), myostatin, and fibroblast growth factor 21 (FGF21)]. It is proposed that reducing intra-abdominal fat mass and increasing cardiorespiratory fitness through improving nutritional quality, reducing sedentary behavior, and increase the participation in physical activity/exercise, might be associated with clinical benefits, sometimes even in the absence of weight loss. PMID- 26238499 TI - Molecular-genetic aspects of familial hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is the world's most abundant and the most common heritable disorder of lipid metabolism. The prevalence of the disease in general population is 1:500. Therefore the approximate number of FH patients all over the world is 14 million. From the genetic point of view the disease originates as a result of mutations in genes affecting the processing of LDL particles from circulation, resulting in an increase in LDL cholesterol and hence total cholesterol. These are mutations in genes encoding LDL receptor, apolipoprotein B, proprotein convertase subtilisin/kexin 9 and LDL receptor adaptor protein 1. Cholesterol depositing in tissues and blood vessels of individuals creates tendon xanthoma, xanthelesma and arcus lipoides cornae. Due to the increased deposition of cholesterol in blood vessels, atherosclerosis process is accelerated, what leads to a significantly higher risk of premature cardiovascular diseases. Therefore, early clinical diagnosis confirmed by the DNA analysis, and effective treatment are crucial to reduce the mortality and high risk of premature atherosclerotic complications. PMID- 26238500 TI - On the threshold of adulthood: A new approach for the use of maturation indicators to assess puberty in adolescents from medieval England. AB - OBJECTIVES: This study provides the first large scale analysis of the age at which adolescents in medieval England entered and completed the pubertal growth spurt. This new method has implications for expanding our knowledge of adolescent maturation across different time periods and regions. METHODS: In total, 994 adolescent skeletons (10-25 years) from four urban sites in medieval England (AD 900-1550) were analyzed for evidence of pubertal stage using new osteological techniques developed from the clinical literature (i.e., hamate hook development, cervical vertebral maturation (CVM), canine mineralization, iliac crest ossification, and radial fusion). RESULTS: Adolescents began puberty at a similar age to modern children at around 10-12 years, but the onset of menarche in girls was delayed by up to 3 years, occurring around 15 for most in the study sample and 17 years for females living in London. Modern European males usually complete their maturation by 16-18 years; medieval males took longer with the deceleration stage of the growth spurt extending as late as 21 years. CONCLUSIONS: This research provides the first attempt to directly assess the age of pubertal development in adolescents during the 10th-17th centuries. Poor diet, infections, and physical exertion may have contributed to delayed development in the medieval adolescents, particularly for those living in the city of London. This study sheds new light on the nature of adolescence in the medieval period, highlighting an extended period of physical and social transition. PMID- 26238501 TI - meso-2'-Linked porphyrin-BODIPY hybrids: synthesis and efficient excitation energy transfer. AB - Three meso-2'-linked porphyrin-BODIPY hybrids which contain one, two, and four BODIPY units (, , and ), respectively, were synthesized. Their photophysical properties were investigated by UV-vis and fluorescence spectroscopy, cyclic voltammetry, and femtosecond transient absorption spectroscopy, as well as by theoretical calculations. The electronic properties of the constituent chromophores were found to be largely retained in these hybrids. Meanwhile, efficient and rapid energy transfers from (1)* to were evaluated to be 1.2 * 10(11), 1.5 * 10(11), and 1.1 * 10(11) s(-1), respectively. PMID- 26238502 TI - Neuropsychiatric manifestations in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic disease characterized by persistent synovitis, systemic inflammation, and the presence of autoantibodies. Neuropsychiatric manifestations are quite common in RA, including depression, cognitive dysfunction, behavior changes, spinal cord compression and peripheral nerve involvement. Potential causes include systemic inflammatory process, neural compression due to bone and joint destruction, side effects of medications and copying difficulties due to the chronicity of the disease. A high level of suspicious is required for an adequate diagnosis and treatment. In this review, we will discuss topographically the main neuropsychiatric manifestations described in RA patients, in an attempt to help in the management of these complex and multifaceted disease. PMID- 26238503 TI - Yiqi Huaju formula, a Chinese herbal medicine, reduces arterial pressure in salt sensitive hypertension by inhibiting renin-angiotensin system activation. AB - Hypertension is a chronic disease with a high prevalence, and is associated with a high risk of vascular disease and premature death. Traditional Chinese medicine has been administered to treat hypertension for many years. In the present study, the effects of Yiqi Huaju formula (YQ; a compound used in traditional Chinese herbal medicine) were observed in salt-sensitive hypertension, which was induced by a high-salt and high-fat (HSF) diet and the potential mechanism was investigated. YQ was prepared from five plant extracts and was dissolved in normal sodium chloride prior to use. Male Sprague-Dawley rats were randomly divided into three groups, and fed either a normal diet (control), an HSF diet or an HSF diet with YQ. At week eight, blood pressure was measured and 24-h urine samples were collected from all of the rats. The rats were subsequently sacrificed, and their blood was collected for biochemical analyses and kidney tissue samples were dissected for the immunohistochemical assay. YQ was observed to decrease the high arterial pressure and serum total cholesterol level, which had been induced by the HSF diet. It also enhanced the excretion of urinary angiotensinogen, Na+, and decreased the loss of urinary aldosterone, K+ and microalbuminuria. In addition, YQ inhibited the high mRNA expression level of renal renin, angiotensin II (Ang II), and Ang II receptor, type 1 (AT1R), and inhibited the protein expression of renal AT1R and Ang II receptor type 2, which had been induced by the HSF diet. These results indicate that YQ may reduce the arterial pressure in salt-sensitive hypertension via the inhibition of renin angiotensin system activation. PMID- 26238504 TI - Prevalence of perceived cognitive dysfunction in survivors of a wide range of cancers: results from the 2010 LIVESTRONG survey. AB - PURPOSE: With cancer survivors now numbering over 13 million in the United States, and expected to continue to increase, it is important to consider the needs of this growing population. In the literature, one of the most common complaints by cancer survivors is perceived cognitive dysfunction. Since the preponderance of the research has focused on breast cancer survivors, the purpose of the present study was to explore the prevalence and correlates of perceived cognitive dysfunction in a large sample of cancer survivors with representation across a wide range of different types of cancer. METHODS: A sample of 3108 post treatment cancer survivors completed the 2010 LIVESTRONG survey as part of a larger study of cancer survivorship. Respondents completed standardized questions regarding current and past perceived cognitive dysfunction, as well as depressive symptoms, and demographic and medical variables. RESULTS: Current perceived cognitive dysfunction was reported by nearly half of respondents (45.7%), across a wide range of cancer types, with the highest prevalence among survivors of central nervous system cancers. Receiving chemotherapy and current report of depressive symptoms were both strongly associated with current perceived cognitive dysfunction. CONCLUSION: These findings contribute to a growing appreciation of the high prevalence of perceived cognitive dysfunction in survivors of a wide range of cancer types and the potential interactive effect of concurrent symptoms of depression. These findings highlight a need to develop more effective means of preventing or reducing cognitive dysfunction in cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Perceived cognitive dysfunction was reported in a wide range of cancer survivors. The potential interactive effect of symptoms of depression suggests the need to develop interventions targeting both cognitive dysfunction and depression to achieve improvements in cognitive functioning. PMID- 26238505 TI - Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening. AB - Microglia are a proliferative population of resident brain macrophages that under physiological conditions self-renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as 'priming'. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first-generation G1 mTerc(-/-) )- and late-generation (third-generation G3 and G4 mTerc(-/-) ) telomerase-deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late generation mTerc(-/-) microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc(-/-) microglia are comparable with microglia derived from G1 mTerc(-/-) mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc(-/-) microglia mice show an enhanced pro-inflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age-associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood-brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening. PMID- 26238506 TI - Structural analysis of a type 1 ribosome inactivating protein reveals multiple L asparagine-N-acetyl-D-glucosamine monosaccharide modifications: Implications for cytotoxicity. AB - Pokeweed antiviral protein (PAP) belongs to the family of type I ribosome inactivating proteins (RIPs): Ribotoxins, which function by depurinating the sarcin-ricin loop of ribosomal RNA. In addition to its antibacterial and antifungal properties, PAP has shown promise in antiviral and targeted tumor therapy owing to its ability to depurinate viral RNA and eukaryotic rRNA. Several PAP genes are differentially expressed across pokeweed tissues, with natively isolated seed forms of PAP exhibiting the greatest cytotoxicity. To help elucidate the molecular basis of increased cytotoxicity of PAP isoenzymes from seeds, the present study used protein sequencing, mass spectroscopy and X-ray crystallography to determine the complete covalent structure and 1.7 A X-ray crystal structure of PAP-S1aci isolated from seeds of Asian pokeweed (Phytolacca acinosa). PAP-S1aci shares ~95% sequence identity with PAP-S1 from P. americana and contains the signature catalytic residues of the RIP superfamily, corresponding to Tyr72, Tyr122, Glu175 and Arg178 in PAP-S1aci. A rare proline substitution (Pro174) was identified in the active site of PAP-S1aci, which has no effect on catalytic Glu175 positioning or overall active-site topology, yet appears to come at the expense of strained main-chain geometry at the pre-proline residue Val173. Notably, a rare type of N-glycosylation was detected consisting of N-acetyl-D-glucosamine monosaccharide residues linked to Asn10, Asn44 and Asn255 of PAP-S1aci. Of note, our modeling studies suggested that the ribosome depurination activity of seed PAPs would be adversely affected by the N glycosylation of Asn44 and Asn255 with larger and more typical oligosaccharide chains, as they would shield the rRNA-binding sites on the protein. These results, coupled with evidence gathered from the literature, suggest that this type of minimal N-glycosylation in seed PAPs and other type I seed RIPs may serve to enhance cytotoxicity by exploiting receptor-mediated uptake pathways of seed predators while preserving ribosome affinity and rRNA recognition. PMID- 26238507 TI - The Focinator - a new open-source tool for high-throughput foci evaluation of DNA damage. AB - BACKGROUND: The quantitative analysis of foci plays an important role in many cell biological methods such as counting of colonies or cells, organelles or vesicles, or the number of protein complexes. In radiation biology and molecular radiation oncology, DNA damage and DNA repair kinetics upon ionizing radiation (IR) are evaluated by counting protein clusters or accumulations of phosphorylated proteins recruited to DNA damage sites. Consistency in counting and interpretation of foci remains challenging. Many current software solutions describe instructions for time-consuming and error-prone manual analysis, provide incomplete algorithms for analysis or are expensive. Therefore, we aimed to develop a tool for costless, automated, quantitative and qualitative analysis of foci. METHODS: For this purpose we integrated a user-friendly interface into ImageJ and selected parameters to allow automated selection of regions of interest (ROIs) depending on their size and circularity. We added different export options and a batch analysis. The use of the Focinator was tested by analyzing gamma-H2.AX foci in murine prostate adenocarcinoma cells (TRAMP-C1) at different time points after IR with 0.5 to 3 Gray (Gy). Additionally, measurements were performed by users with different backgrounds and experience. RESULTS: The Focinator turned out to be an easily adjustable tool for automation of foci counting. It significantly reduced the analysis time of radiation-induced DNA-damage foci. Furthermore, different user groups were able to achieve a similar counting velocity. Importantly, there was no difference in nuclei detection between the Focinator and ImageJ alone. CONCLUSIONS: The Focinator is a costless, user-friendly tool for fast high-throughput evaluation of DNA repair foci. The macro allows improved foci evaluation regarding accuracy, reproducibility and analysis speed compared to manual analysis. As innovative option, the macro offers a combination of multichannel evaluation including colocalization analysis and the possibility to run all analyses in a batch mode. PMID- 26238509 TI - Optimization of the Electroformation of Giant Unilamellar Vesicles (GUVs) with Unsaturated Phospholipids. AB - Giant unilamellar vesicles (GUV) are widely used cell membrane models. GUVs have a cell-like diameter and contain the same phospholipids that constitute cell membranes. The most frequently used protocol to obtain these vesicles is termed electroformation, since key steps of this protocol consist in the application of an electric field to a phospholipid deposit. The potential oxidation of unsaturated phospholipids due to the application of an electric field has not yet been considered even though the presence of oxidized lipids in the membrane of GUVs could impact their permeability and their mechanical properties. Thanks to mass spectrometry analyses, we demonstrated that the electroformation technique can cause the oxidation of polyunsaturated phospholipids constituting the vesicles. Then, using flow cytometry, we showed that the amplitude and the duration of the electric field impact the number and the size of the vesicles. According to our results, the oxidation level of the phospholipids increases with their level of unsaturation as well as with the amplitude and the duration of the electric field. However, when the level of lipid oxidation exceeds 25 %, the diameter of the vesicles is decreased and when the level of lipid oxidation reaches 40 %, the vesicles burst or reorganize and their rate of production is reduced. In conclusion, the classical electroformation method should always be optimized, as a function of the phospholipid used, especially for producing giant liposomes of polyunsaturated phospholipids to be used as a cell membrane model. PMID- 26238508 TI - Nuclear factor of activated T-cell isoform expression and regulation in human myometrium. AB - BACKGROUND: During pregnancy, myometrial gene and protein expression is tightly regulated to accommodate fetal growth, promote quiescence and ultimately prepare for the onset of labour. It is proposed that changes in calcium signalling, may contribute to regulating gene expression and that nuclear factor of activated T cell (NFAT) transcription factors (isoforms c1-c4) may be involved. Currently, there is little information regarding NFAT expression and regulation in myometrium. METHODS: This study examined NFAT isoform mRNA expression in human myometrial tissue and cells from pregnant women using quantitative PCR. The effects of the Ca(2+) ionophore A23187 and in vitro stretch (25 % elongation, static strain; Flexercell FX-4000 Tension System) on NFAT expression were determined in cultured human myometrial cells. RESULTS: Human myometrial tissue and cultured cells expressed NFATc1-c4 mRNA. NFATc2 gene expression in cultured cells was increased in response to 6 h stretch (11.5 fold, P < 0.001, n = 6) and calcium ionophore (A23187, 5 MUM) treatment (20.6 fold, P < 0.001, n = 6). This response to stretch was significantly reduced (90 %, P < 0.001, n = 10) in the presence of an intracellular calcium chelator, BAPTA-AM (20 MUM). CONCLUSIONS: These data suggest that NFATc2 expression is regulated by intracellular calcium and in vitro stretch, and that the stretch response in human myometrial cells is dependent upon intracellular calcium signalling pathways. Our findings indicate a potentially unique role for NFATc2 in mediating stretch-induced gene expression per se and warrant further exploration in relation to the mechanisms promoting uterine smooth muscle growth in early pregnancy and/or labour. PMID- 26238510 TI - Estimation of the planning organ at risk volume for the lenses during radiation therapy for nasal cavity and paranasal sinus cancer. AB - INTRODUCTION: To establish the optimal planning risk volume (PRV) of the lenses for patients who are receiving radiotherapy to the nasal cavity and paranasal sinus (NCPSC). METHODS: Geometrical uncertainties of the lenses were evaluated for a prospective group of patients (G1). Differences between planned and delivered maximum doses to the lenses were evaluated for every fraction. The relationship between dose differences and geometrical uncertainties were analysed to establish an optimal PRV for the lenses. Obtained results were verified in the second group (G2) of patients for whom calculated PRV was applied. RESULTS: Data of 426 observations for 15 patients from G1 were investigated. The systematic and random errors equalled, respectively, 0.6 mm and 2.3 mm in the medio-lateral direction; 0.8 mm and 1.6 mm in the cranio-caudal direction; and 0.4 mm and 1.5 mm in the anterio-posterior direction. The clinical PRV for the lenses was established at 2 mm. Applied margin was evaluated for 10 patients from G2. The dose distribution in the planning target volume (PTV) for G1 and for G2 was comparable (P = 0.122), whereas the differences between planned and delivered doses in the lenses were significantly smaller for G2 (P = 0.013). CONCLUSION: The study showed that for radiotherapy of NCPSC, the PRV for the lenses could be defined as 2 mm. This margin does not affect the dose distribution in the PTV and effectively reduces the differences between planned and delivered doses in the lenses. PMID- 26238511 TI - Increased urothelial cancer associated 1 is associated with tumor proliferation and metastasis and predicts poor prognosis in colorectal cancer. AB - Long non-coding RNA, urothelial cancer associated 1 (UCA1), is reported to play a critical role in progression of carcinogenesis. In the present study, we identified differential expression of UCA1 in colorectal cancer (CRC) and paired peritumoral tissues using gene expression microarray analyses. qPCR analysis confirmed that UCA1 was upregulated in CRC (p<0.001) and the expression of UCA1 was statistically correlated with lymph node metastasis (P=0.040), distant metastasis (P=0.043) and tumor stage (P=0.010). Kaplan-Meier analysis indicated that patients with high UCA1 expression had a poor prognosis. Moreover, multivariate analysis identified UCA1 overexpression as an independent predictor for CRC. We also found that knockdown of UCA1 significantly suppressed cell proliferation and metastasis in CRC cells. Flow cytometry assays showed UCA1 silencing induced G0/G1 growth arrest and apoptosis of CRC cells. To further investigate the regulatory mechanisms of UCA1, we identified that Ets-2 bound to the UCA1 core promoter using luciferase assays. Collectively, our findings suggested that UCA1 might be an important prognostic indicator in CRC and may be a potential target for diagnosis and gene therapy. PMID- 26238512 TI - Smartphone usage in the 21st century: who is active on WhatsApp? AB - BACKGROUND: Mounting evidence shows that smartphone usage heavily disrupts our work life and social activities. Moreover, it is possible that overuse could resemble addictive tendencies. A key contributing factor to smartphone overuse seems to be usage of the messaging application WhatsApp. Although WhatsApp is one of the most commonly used communication applications on smartphones, research in this area is scarce. Given the huge societal debate on the impact of smartphone usage on our daily lives, the present study undertook a large-scale investigation in order to provide numbers on smartphone usage generally-and use of WhatsApp in particular, with the aim of providing a basis for a scientific debate. METHODS: In a large sample of N = 2,418 users, we recorded WhatsApp behaviour over a 4 week period. RESULTS: Our data show that use of WhatsApp accounted for 19.83% (= 32.11 min) of all smartphone behaviour (compare: Facebook only 9.38% = 15.19 min). The mean of general daily smartphone usage was 161.95 min. Females used WhatsApp for significantly longer periods of time than males and younger age was associated with longer duration of WhatsApp use. While the personality trait Extraversion was positively associated with daily WhatsApp use, Conscientiousness showed an inverse correlation with the length of daily WhatsApp use. CONCLUSIONS: The numbers on smartphone usage in the present study show that the smartphone dominates our daily life. In particular WhatsApp is a driving force, here. Given the length of daily smartphone and WhatsApp usage, more studies need to be conducted to better understand smartphone usage. PMID- 26238513 TI - Single and combined effects of peppermint and thyme essential oils on productive performance, egg quality traits, and blood parameters of laying hens reared under cold stress condition (6.8 +/- 3 degrees C). AB - This study was conducted to evaluate the effects of adding peppermint essential oil (PEO), thyme essential oil (TEO), or their combination to diet on productive performance, egg quality traits, and blood parameters of laying hens reared under cold stress condition (6.8 +/- 3 degrees C). Feed intake (FI), feed conversion ratio (FCR), egg weight (EW), egg production (EP), and egg mass (EM) were evaluated during the 56-day trial period using 120 Lohmann LSL-lite laying hens. Significant interactions between PEO and TEO on FCR, EP, and EM were observed (P < 0.05). The EP and EM increased, whereas FCR decreased (P < 0.05) in the hens fed the diets supplemented by the combined form of PEO and TEO compared to those fed the basal diet. Also, increased EW and FI were observed in the laying hens fed the diet added by PEO compared to the birds fed the basal diet. There were significant interactions between PEO and TEO on the serum level of cholesterol, shell thickness, and Hough unit of egg (P < 0.05), so that serum content of cholesterol decreased, but egg shell thickness and Hough unit increased in the hens fed the diet supplemented by the combined form of PEO and TEO compared to those fed the basal diet. From the results of the present experiment, it can be concluded that diet supplementation by combined form of PEO and TEO could have beneficial effects on performance parameters of hens reared under cold stress condition. PMID- 26238515 TI - Isolation of methyl gamma linolenate from Spirulina platensis using flash chromatography and its apoptosis inducing effect. AB - BACKGROUND: Isolation of methyl gamma linolenate from Spirulina platensis using flash chromatography and its apoptosis inducing effect against human lung carcinoma A- 549 cell lines. METHODS: Gamma linolenic acid is an important omega 6 polyunsaturated fatty acid (PUFA) of medicinal interest was isolated from microalgae Spirulina platensis using flash chromatography system (Isolera system) as its methyl ester. The isolated methyl gamma linolenate was characterized by IR, (1)H NMR, (13)C NMR and mass spectral analysis and the data were consistent with the structure. RESULTS: The percentage yield of isolated methyl gamma linolenate is found to be 71% w/w, which is a very good yield in comparison to other conventional methods. It was subjected to in-vitro cytotoxic screening on A 549 lung cancer cell lines using SRB assay and result was compared with standard rutin. CONCLUSION: It may be concluded that the Flash chromatography system plays a major role in improving the yield for the isolation of methyl gamma linoleate from Spirulina platensis and the isolated molecule is a potent cytotoxic agent towards human lung carcinoma cell lines, however it may be further taken up for an extensive study. PMID- 26238514 TI - Mutations in ARID2 are associated with intellectual disabilities. AB - The etiology of intellectual disabilities (ID) remains unknown for the majority of patients. Due to reduced reproductive fitness in many individuals with ID, de novo mutations account for a significant portion of severe ID. The ATP-dependent SWI/SNF chromatin modifier has been linked with neurodevelopmental disorders including ID and autism. ARID2 is an intrinsic component of polybromo-associated BAF (PBAF), the SWI/SNF subcomplex. In this study, we used clinical whole exome sequencing (WES) in proband-parent-trios to identify the etiology of ID. We identified four independent, novel, loss of function variants in ARID2 gene in four patients, three of which were confirmed to be de novo. The patients all have ID and share other clinical characteristics including attention deficit hyperactivity disorder, short stature, dysmorphic facial features, and Wormian bones. All four novel variants are predicted to lead to a premature termination with the loss of the two conservative zinc finger motifs. This is the first report of mutations in ARID2 associated with developmental delay and ID. PMID- 26238516 TI - [Pulmonary fibrosis]. PMID- 26238518 TI - Engineered Nanostructured Facial Lipopeptide as Highly Efficient Molecular Transporter. AB - Designing an effective peptide based molecular transporter for the intracellular delivery of hydrophilic therapeutic biomacromolecules remains a considerable challenge. Highly basic oligoarginine and lipidated arginine rich cell penetrating peptides have been reported in the literature as molecular transporters, which were extensively used for cellular internalization of significantly large biopharmaceuticals. However, oligoarginine based molecular transporters with l-arginine residues pose significant challenges due to proteolytic instability and limited stability of noncovalent peptide-cargo nanocomplexes. Exploiting the rational peptide designing strategy, we have engineered protease-resistant facial lipopeptide based molecular transporter having arginine-sarcosine-arginine moiety to minimize adjacent arginine-arginine pair repulsion. N-Methylated amino acid sarcosine was incorporated as a spacer between two adjacent arginine residues, which provides proteolytic stability to the designed peptide and minimizes intermolecular aggregation of peptides. Two stearyl moieties were incorporated to facilitate cellular internalization. Interestingly, our designed lipopeptide exhibits significantly enhanced cellular internalization with only six l-arginine residues compared to stearylated oligo nona-arginine. Additionally, enhanced proteolytic stability of such class of molecular transporter enables increased cargo internalization, and we anticipate that our engineered multifunctional, proteolytically stable, nanostructured facial lipopeptide based molecular transporter can have major impact in advancing drug delivery technologies. PMID- 26238520 TI - Outcomes of sustained low efficiency dialysis versus continuous renal replacement therapy in critically ill adults with acute kidney injury: a cohort study. AB - BACKGROUND: Sustained low efficiency dialysis (SLED) is increasingly used as a renal replacement modality in critically ill patients with acute kidney injury (AKI) and hemodynamic instability. SLED may reduce the hemodynamic perturbations of intermittent hemodialysis, while obviating the resource demands of CRRT. Although SLED is being increasingly used, few studies have evaluated its impact on clinical outcomes. METHODS: We conducted a cohort study comparing SLED (target 8 h/session, blood flow 200 mL/min, predominantly without anticoagulation) to CRRT in four ICUs at an academic medical centre. The primary outcome was mortality 30 days after RRT initiation, adjusted for demographics, comorbidity, baseline kidney function, and Sequential Organ Failure Assessment score. Secondary outcomes were persistent RRT dependence at 30 days and early clinical deterioration, defined as a rise in SOFA score or death 48 h after starting RRT. RESULTS: We identified 158 patients who initiated treatment with CRRT and 74 with SLED. Mortality at 30 days was 54 % and 61 % among SLED- and CRRT-treated patients, respectively [adjusted odds ratio (OR) 1.07, 95 % CI 0.56-2.03, as compared with CRRT]. Among SLED recipients, the risk of RRT dependence at 30 days (adjusted OR 1.36, 95 % CI 0.51-3.57) and early clinical deterioration (adjusted OR 0.73, 95 % CI 0.40-1.34) were not different as compared to patients who initiated CRRT. CONCLUSIONS: Notwithstanding the limitations of this small non randomized study, we found similar clinical outcomes for patients treated with SLED and CRRT. While we await the completion of a trial that will definitively assess the non-inferiority of SLED as compared to CRRT, SLED appears to be an acceptable alternative form of renal support in hemodynamically unstable patients with AKI. PMID- 26238519 TI - The complete mitochondrial genome sequence of the green microalga Lobosphaera (Parietochloris) incisa reveals a new type of palindromic repetitive repeat. AB - BACKGROUND: Lobosphaera incisa, formerly known as Myrmecia incisa and then Parietochloris incisa, is an oleaginous unicellular green alga belonging to the class Trebouxiophyceae (Chlorophyta). It is the richest known plant source of arachidonic acid, an omega-6 poly-unsaturated fatty acid valued by the pharmaceutical and baby-food industries. It is therefore an organism of high biotechnological interest, and we recently reported the sequence of its chloroplast genome. RESULTS: We now report the complete sequence of the mitochondrial genome of L. incisa from high-throughput Illumina short-read sequencing. The circular chromosome of 69,997 bp is predicted to encode a total of 64 genes, some harboring specific self-splicing group I and group II introns. Overall, the gene content is highly similar to that of the mitochondrial genomes of other Trebouxiophyceae, with 34 protein-coding, 3 rRNA, and 27 tRNA genes. Genes are distributed in two clusters located on different DNA strands, a bipartite arrangement that suggests expression from two divergent promoters yielding polycistronic primary transcripts. The L. incisa mitochondrial genome contains families of intergenic dispersed DNA repeat sequences that are not shared with other known mitochondrial genomes of Trebouxiophyceae. The most peculiar feature of the genome is a repetitive palindromic repeat, the LIMP (L. Incisa Mitochondrial Palindrome), found 19 times in the genome. It is formed by repetitions of an AACCA pentanucleotide, followed by an invariant 7-nt loop and a complementary repeat of the TGGTT motif. Analysis of the genome sequencing reads indicates that the LIMP can be a substrate for large-scale genomic rearrangements. We speculate that LIMPs can act as origins of replication. Deep sequencing of the L. incisa transcriptome also suggests that the LIMPs with long stems are sites of transcript processing. The genome also contains five copies of a related palindromic repeat, the HyLIMP, with a 10-nt motif related to that of the LIMP. CONCLUSIONS: The mitochondrial genome of L. incisa encodes a unique type of repetitive palindromic repeat sequence, the LIMP, which can mediate genome rearrangements and play a role in mitochondrial gene expression. Experimental studies are needed to confirm and further characterize the functional role(s) of the LIMP. PMID- 26238521 TI - Social penalty promotes cooperation in a cooperative society. AB - Why cooperation is well developed in human society is an unsolved question in biological and human sciences. Vast studies in game theory have revealed that in non-cooperative games selfish behavior generally dominates over cooperation and cooperation can be evolved only under very limited conditions. These studies ask the origin of cooperation; whether cooperation can evolve in a group of selfish individuals. In this paper, instead of asking the origin of cooperation, we consider the enhancement of cooperation in a small already cooperative society. We ask whether cooperative behavior is further promoted in a small cooperative society in which social penalty is devised. We analyze hawk-dove game and prisoner's dilemma introducing social penalty. We then expand it for non cooperative games in general. The results indicate that cooperation is universally favored if penalty is further imposed. We discuss the current result in terms of the moral, laws, rules and regulations in a society, e.g., criminology and traffic violation. PMID- 26238522 TI - Inhibitory effect of 2-mercaptoethane sulfonate on the formation of Escherichia coli biofilms in vitro. AB - The biofilms (BF) formed by Escherichia coli (E. coli) is an important cause of chronic and recurrent infections due to its capacity to persist on medical surfaces and indwelling devices, demonstrating the importance of inhibiting the formation of E. coli BF and reducing BF infection. Although 2-mercaptoethane sulfonate (MESNA) exhibits a marked mucolytic effect clinically, the effect of MESNA on the inhibition of E. coli BF formation remains to be elucidated. The present study investigated whether MESNA inhibits the formation of E. coli BF in vitro. The minimum inhibitory concentration of MESNA on E. coli was determined to be 10 mg/ml. Subsequently, the effect of MESNA on BF early adhesion, extracellular polysaccharide (EPS) and extracellular protein were detected. The effect of a subinhibitory concentration of MESNA on BF formation was evaluated, and the inhibitory potency of MESNA against matured BF was assayed. The results revealed that MESNA inhibited early stage adhesion and formation of the E. coli BF, destroyed the mature BF membrane and reduced the EPS and extracellular proteins levels of the BF. In addition, the present study investigated the effects of MESNA on the expression of EPS- and adhesion protein-associated genes using quantitative polymerase chain reaction analysis, which demonstrated that MESNA effectively inhibited the expression of these genes. These results suggested that MESNA possesses anti-BF formation capability on E. coli in vitro and may be used as a potential reagent for the clinical treatment of E. coli BF associated infections. PMID- 26238524 TI - Erratum to: Production of carotenoids by microalgae: achievements and challenges. PMID- 26238523 TI - Effect of Raf kinase inhibitor protein expression on malignant biological behavior and progression of colorectal cancer. AB - The Raf kinase inhibitor protein (RKIP) is a novel metastasis suppressor. RKIP was previously found to have low expression in a colorectal cancer (CRC) patient cohort by immunohistochemistry. However, the role of RKIP in CRC remains undetermined. In the present study, immunohistochemistry was performed to compare RKIP expression between 129 paired stage II CRC and adjacent non-tumorous tissues. The correlations between clinical parameters, prognosis and RKIP expression were evaluated. To investigate the effect of RKIP on proliferation and metastasis, RKIP was overexpressed and knocked down in colon cancer cell lines. 3 (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Transwell and wound-healing assays were performed. Murine models were established to confirm the influence of RKIP on malignant tumor phenotypes in vivo. Our results showed that RKIP expression was significantly decreased in the CRC tissues compared to the adjacent non-cancerous tissues (p<0.001) and was correlated with the risk of relapse in stage II CRC (p<0.05). Overexpression of RKIP suppressed HCT116 cell metastasis in vitro and in vivo, whereas knockdown of RKIP expression in SW480 cells and its murine model increased metastatic ability (p<0.05). No effect of RKIP on cell proliferation in CRC was observed. These data suggest that RKIP is an important metastasis-suppressor gene in CRC. The re-expression of RKIP could be a potential therapeutic target for antimetastatic strategies for CRC. PMID- 26238525 TI - Chirality amplification and detection by tactoids of lyotropic chromonic liquid crystals. AB - Detection of chiral molecules requires amplification of chirality to measurable levels. Typically, amplification mechanisms are considered at the microscopic scales of individual molecules and their aggregates. Here we demonstrate chirality amplification and visualization of structural handedness in water solutions of organic molecules that extends over the scale of many micrometers. The mechanism is rooted in the long-range elastic nature of orientational order in lyotropic chromonic liquid crystals (LCLCs) formed in water solutions of achiral disc-like molecules. The nematic LCLC coexists with its isotropic counterpart, forming elongated tactoids; the spatial confinement causes a structural twist even when the material is nonchiral. Minute quantities of chiral molecules such as the amino acid l-alanine and limonene transform the racemic array of left- and right-twisted tactoids into a homochiral set. The left and right chiral enantiomers are readily distinguished from each other as the induced structural handedness is visualized through a simple polarizing microscope observation. The effect is important for developing our understanding of chirality amplification mechanisms; it also might open up new possibilities in biosensing. PMID- 26238526 TI - Shear Bond Strength of a Self-adhering Flowable Composite and a Flowable Base Composite to Mineral Trioxide Aggregate, Calcium-enriched Mixture Cement, and Biodentine. AB - INTRODUCTION: The purpose of this study was to investigate the shear bond strength (SBS) of a self-adhering flowable composite (Vertise Flow; Kerr, Orange, CA) and a flowable composite (X-tra base; Voco GmbH, Cuxhaven, Germany) to mineral trioxide aggregate (MTA), Biodentine (Septodent, Saint-Maur-des-Fosses Cedex, France), and calcium-enriched mixture (CEM; Yektazist Dandan, Tehran, Iran). METHODS: Sixty cylindric acrylic blocks with a hole (3 mm in diameter and 1.5 mm in height) were prepared. The acrylic blocks were filled with MTA, Biodentine, and CEM (n = 20) and accordingly allocated into 3 groups. The specimens were stored for 72 hours at 37 degrees C and 100% humidity. Then, each group was divided into 2 subgroups according to the composite resin type used (n = 10). Vertise Flow and X-tra base were applied over MTA, Biodentine, and CEM and then polymerized. SBS was tested in a universal testing machine with a crosshead speed of 1 mm/min. Data were analyzed using 2-way analysis of variance and the Tukey test. RESULTS: The Vertise Flow-CEM and X-tra base-MTA groups showed significantly higher SBS values than the group made of Vertise flow-Biodentine (P < .05). There were no statistically significant differences among the other groups (P > .05). CONCLUSIONS: MTA and CEM exhibited higher SBS than Biodentine; therefore, they could be preferred under flowable composites. PMID- 26238527 TI - Ultrasonically Activated Irrigation to Remove Calcium Hydroxide from Apical Third of Human Root Canal System: A Systematic Review of In Vitro Studies. AB - INTRODUCTION: The aim of this systematic review was to summarize the outcomes of in vitro studies comparing ultrasonically activated irrigation versus other irrigation techniques for removing calcium hydroxide (Ca[OH]2) from the apical third of root canals. METHODS: The research question was developed according to the PICO strategy. A comprehensive literature search was performed. The Medline, Embase, and TRIP electronic databases were searched. A hand search of the reference lists of identified articles was performed to isolate relevant articles. Two reviewers critically assessed the studies against our inclusion and exclusion criteria. Evaluation of the risk of bias of the studies was performed independently by the 2 reviewers. RESULTS: After study selection, 62 were assessed for eligibility. Of these, 9 met the inclusion criteria and were included in the systematic review. Because considerable heterogeneity was found in the methodologies, it was not possible to combine the results of studies in a meta-analysis. Ultrasonically activated irrigation was found to be superior to syringe irrigation and apical negative pressure irrigation, but insufficient evidence was found to indicate its superiority over the other irrigation techniques such as sonically activated irrigation, the Self-Adjusting File, (ReDent-Nova, Ra'anana, Israel) and the RinsEndo, (Durr Dental, Bietigheim, Germany). CONCLUSIONS: On the basis of available evidence, we determined the effectiveness of ultrasonically activated irrigation compared with syringe and apical negative pressure irrigation. Because of the small sample sizes, low number of included studies, and limitations, further research is needed to confirm our results. PMID- 26238528 TI - A Micro-computed Tomographic Assessment of Root Canal Preparation with a Novel Instrument, TRUShape, in Mesial Roots of Mandibular Molars. AB - INTRODUCTION: A novel S-shaped rotary file was developed to conform to nonround canal cross sections. However, the instrument should also perform well in small curved canals. This study used micro-computed tomographic scans to test the effects of TRUShape (Dentsply Tulsa Dental Specialties, Tulsa, OK) and a conventional rotary on canal geometry. METHODS: Twenty mandibular molars with independent mesial canals were submitted to preoperative micro-computed tomographic scans (20-MUm resolution). Canals were randomly allocated to 2 groups using Vortex (Dentsply Tulsa Dental Specialties) and TRUShape for shaping according to the directions for use. Scans were obtained after size 20/.06 and 30/.06; the following outcome variables were calculated: dentin volume, smallest radicular wall thickness, treated canal surface, canal transportation, and accumulated hard tissue debris. The number of preparation errors was tabulated; data were statistically contrasted using repeated measures and factorial analyses of variance. RESULTS: The initial canal sizes were similar in both groups. Both instruments promoted preparation with no overt procedural errors. Vortex removed significantly more dentin both at size #20 and #30 (P < .02). Significantly (P < .02) more radicular wall dentin remained toward the furcation in the TRUShape group (1.02 +/- 0.25 mm vs 0.94 +/- 0.22 mm). The untreated surface at size #20 was 28.5 +/- 13.9 and 19.4 +/- 8.9 (P < .05), and it was 15.1 +/- 8.5 and 11.3 +/ 4.9 (P > .05) at size #30 for TRUShape and Vortex, respectively. Canal transportation at size #30 varied between 85 +/- 57 MUm and 179 +/- 65 MUm; the overall transportation scores were significantly lower for TRUShape (P < .05). CONCLUSIONS: TRUShape provided conservation of dentin by limiting dentin removal and in the absence of substantial canal transportation. In the present study, the use of TRUShape in the mesial canals of mandibular molars did not result in decreased amounts of unprepared canal surface. PMID- 26238529 TI - Do the Sealer Solvents Used Affect Apically Extruded Debris in Retreatment? AB - INTRODUCTION: We evaluated apically extruded debris in the retreatment of root canals filled with different root canal sealers and gutta-percha using different solvents. METHODS: Ninety human mandibular central and lateral teeth were prepared using the Reciproc #25 .08 nickel-titanium system (VDW GmbH, Munich, Germany) and were divided randomly into 6 groups. In groups 1, 2, and 3, root canals were filled with epoxy resin-based sealer and gutta-percha, and in groups 4, 5, and 6, root canals were filled with zinc oxide-eugenol-based sealer and gutta-percha. Each tooth was placed in a glass vial experimental apparatus. All root canal fillings were removed with the ProTaper Retreatment nickel-titanium system (Dentsply Maillefer, Ballaigues, Switzerland). During the retreatment procedure, in group 1, Resosolv (Pierre Rolland, Merignac, France) was used; in group 4, Endosolv E (Septodont, Paris, France) was used; and in groups 2 and 5, Guttasolv (Septodont) was used as the solvent. In the control groups (groups 3 and 6), no solvent was used. Reciproc #40 .06 was used for the final preparation. The times required for retreatments were recorded. RESULTS: The weight of the extruded debris and the time required for retreatment were decreased significantly in the groups in which a solvent that was intended specifically for the root canal sealer was used (groups 1 and 4). In the Guttasolv groups (groups 2 and 5), the amount of apically extruded debris and the time required decreased for both root canal sealers. CONCLUSIONS: The amount of apically extruded debris and the duration of retreatment were reduced by the use of a solvent specific to the sealer compared with a gutta-percha solvent or no solvent. PMID- 26238530 TI - TiO2 nanoparticles-induced apoptosis of primary cultured Sertoli cells of mice. AB - Titanium dioxide nanoparticles (TiO2 NPs), as largest production and use of nanomaterials, have been demonstrated to have a potential toxicity on reproductive system. However, the mechanism underlying male reproductive toxicity of TiO2 NPs remains limited. Thus, our study was designed to examine the cellular viability, apoptosis, oxidative stress, antioxidant capacity, and expression of apoptotic cytokines in primary cultured Sertoli cells isolated from mice under TiO2 NPs exposure. Results showed that TiO2 NPs exposure from 5 to 30 MUg/mL resulted in reduction of cell viability, lactate dehydrogenase release, and induction of apoptosis or death on Sertoli cells. TiO2 NPs could migrate to Sertoli cells, which induced mitochondria-mediated or endoplasmic-reticulum mediated apoptotic changes including elevation in reactive oxygen species (ROS) generation and reductions in superoxide dismutase, catalase, and glutathione peroxidase activities, decreases in mitochondrial membrane potential (DeltaPsim), and releases of cytochrome c into the cytosol. In addition, upregulation of cytochrome c, Bax, caspase-3, glucose-regulated protein 78, and C/EBP homologous protein and caspase-12 protein expression, and downregulation of bcl-2 protein expression in primary cultured Sertoli cells induced by TiO2 NPs treatment. All of the results suggested that ROS generation may play a critical role in the initiation of TiO2 NPs-induced apoptosis by mediation of the disruption of DeltaPsim, the cytochrome c release, and further the activation of caspase cascade and unfolded protein response signaling pathway. PMID- 26238531 TI - Tridentate Complexes of Palladium(II) and Platinum(II) Bearing bis-Aryloxide Triazole Ligands: A Joint Experimental and Theoretical Investigation. AB - A novel class of palladium(II) and platinum(II) complexes bearing tridentate bis aryloxide triazole ligands was prepared by using straightforward and high yielding synthetic routes. The complexes were fully characterized and the molecular structures of four derivatives were unambigously determined by single crystal X-ray diffractometric analyses. For the most promising luminescent Pt(II) derivatives, further experimental investigations were carried out to characterize their photophysical features and to ascertain the nature of the emitting excited state by means of electronic absorption, steady-state, and time-resolved emission techniques in different conditions. In degassed fluid solution the complexes displayed broad and featureless photoluminescence with lambda(em) =522-585 nm, excited-state lifetime up to few microseconds and quantum yield (PLQY) up to 17%, depending on the nature of both ancillary ligand and substituent on the tridentate ligand. Computational investigation using density functional theory and time-dependent DFT were performed to gain insight into the electronic processes responsible for optical transitions and structure-photoluminescence relationship. Jointly, experimental and theoretical characterization indicated that the radiative transition arises from an excited state with admixed triplet manifold metal-to-ligand charge transfer and ligand-centered ((3)MLCT/(3)LC) character. We elucidated the modulation of the photophysical properties upon variation of substituents for this new family of complexes. PMID- 26238532 TI - MicroRNA-145 inhibits migration and invasion via inhibition of fascin 1 protein expression in non-small-cell lung cancer cells. AB - MicroRNA (miR)-145 has been shown to act as a suppressor in numerous cancer types, including non-small-cell lung cancer (NSCLC). Fascin 1 (FSCN1), an actin bundling protein, has been implicated in NSCLC. However, the detailed role of miR 145 as well as the association between miR-145 and FSCN1 in the regulation of migration and invasion in NSCLC cells has remained elusive. The present study revealed that miR-145 was downregulated and FSCN1 was upregulated in NSCLC tissues and cell lines. Further investigation showed that overexpression of miR 145 markedly inhibited the protein expression of FSCN1, while knockdown of miR 145 upregulated the protein (but not mRNA) levels of FSCN1 in the NSCLC cell line H129. Moreover, a luciferase reporter assay indicated that FSCN1 is a direct target of miR-145 in NSCLC H129 cells. Furthermore, overexpression of miR-145 markedly inhibited the migration and invasion of NSCLC cells, similar to the effect of small interfering RNA-mediated FSCN1 inhibition in H129 cells. In addition, the inhibitory effect of miR-145 overexpression on migration and invasion was reversed by FSCN1 upregulation in H129 cells. These findings suggested that miR-145 has an inhibitory effect on the migration and invasion in NSCLC cells, at least in part through suppressing the protein expression of its target FSCN1. Therefore, miR-145/FSCN1 may be used as a potential target for the treatment of NSCLC. PMID- 26238533 TI - Seasonal variation in nutritional status and anemia among lactating mothers in two agro-ecological zones of rural Ethiopia: A longitudinal study. AB - OBJECTIVE: The aim of this study was to determine seasonal and agro-ecological variations in nutritional status, anemia, and associated factors among lactating women in rural Ethiopia. METHODS: We conducted a longitudinal study with 216 mothers in pre- and postharvest seasons in two agro-ecological zones of rural Ethiopia. We conducted interviews using a structured questionnaire, anthropometric measurements, and blood tests for anemia. We used multivariable linear regression models to identify independent predictors. RESULTS: The prevalence of anemia increased from postharvest (21.8%) to preharvest seasons (40.9%). Increases were from 8.6% to 34.4% in midland and from 34.2% to 46.3% in lowland agro-ecological zones. Of the mothers, 15% were anemic during both seasons. The prevalence of undernutrition, assessed using body mass index (BMI) < 18.5 kg/m(2), increased from 41.7% to 54.7% between the two seasons. Prevalence of maternal mid upper arm circumferences <22 cm also increased from 43.1% to 55.2% during the preharvest season. The seasonal effect was generally more pronounced in the midland community for all forms of malnutrition. Predictors of anemia were high parity of mother and low dietary diversity. Parity, number of children under the age of 5 y, and regional variation were predictors of low BMI among lactating mothers. CONCLUSION: The magnitude of malnutrition and anemia was significantly influenced by variations in season and agro-ecological zones. Interventions focused on agro-ecology and seasonal variation should be considered in addition to current strategies to alleviate malnutrition in lactating mothers. PMID- 26238534 TI - Vitamin D and diabetic nephropathy: A systematic review and meta-analysis. AB - OBJECTIVE: There has been a long history documenting the use of different vitamin D derivatives as therapy for renal diseases. However, to our knowledge, there is no comprehensive assessment of the relation between vitamin D deficiency and risk for diabetic nephropathy (DN). Additionally, the effect of vitamin D supplementation on DN is still unclear. The aim of this meta-analysis was to assess these issues by pooling together the results from cross-sectional studies and clinical trials. METHODS: A systematic literature search of PubMed, Scopus, and Google Scholar was conducted, ending in September 2014. For cross-sectional studies, odds ratio was used as a measure of the association between vitamin D status and risk for DN; for clinical trials, mean and SD of the main outcome (urine albumin-to-creatinine ratio [UACR]) in intervention and placebo groups were considered for analysis. RESULTS: The final selected articles were published between 2009 and 2014. In all, 3700 and 219 patients were enrolled in observational and interventional studies, respectively. The pooled odds ratio from six cross-sectional studies was 1.80 (95% confidence interval [CI], 1.25 2.59; P = 0.002), indicating a significant inverse association between serum vitamin D status and risk for nephropathy in patients with diabetes. However, the pooled data of UACR levels in clinical trials suggested no significant change following vitamin D supplementation (17.98; 95% CI, -35.35 to 71.32; P = 0.51). CONCLUSION: This meta-analysis showed the higher risk for nephropathy in vitamin D-deficient patients with diabetes. Pooling the results of available clinical trials after vitamin D supplementation did not support causality in this association. PMID- 26238535 TI - The role of folate receptor autoantibodies in preterm birth. AB - OBJECTIVE: Cellular uptake of folate is mediated by folate receptor (FR)alpha. Prior studies indicate that a FRalpha autoantibody (FRAb) is implicated in poor pregnancy outcomes. The aims of this study were to determine the prevalence of FRAbs in women with preterm and term pregnancies, and to investigate the role of maternal FRAbs in preterm birth. METHODS: This prospective observational study included 23 mothers and 25 preterm infants (two twin births) born at gestational age (GA) <=32 wk and/or birth weight <=1500 g (group 1) and 25 mother-term infant pairs (infants born at GA >=37 wk, group 2). Blocking and binding FRAbs in maternal and in cord blood were determined. The association between maternal FRAbs and pregnancy outcome was measured using multiple logistic regression, adjusted for maternal age and previous preterm birth. RESULTS: The prevalence of FRAbs was 65.2% in women with preterm birth, which was twofold higher than in those with term pregnancy (28%; relative risk [RR], 2.3; 95% confidence interval [CI], 1.2-4.7). The prevalence of FRAbs in preterm infants (64%) was significantly higher than in term infants (24%; RR, 2.7; 95% CI, 1.3-5.7). Pregnant women with positive FRAbs had 4.9 times higher odds of having preterm birth (odds ratio, 4.9; 95% CI, 1.4-17.7), adjusted for maternal age and previous preterm birth. CONCLUSIONS: These findings suggest that the presence of FRAbs might be a contributing factor to preterm birth, which could be prevented with appropriate testing and therapeutic interventions. Further studies are warranted to investigate the possible mechanisms of fetal sensitization resulting in FRAb production in utero and its possible clinical correlates. PMID- 26238536 TI - Supramolecular nanoreactors for intracellular singlet-oxygen sensitization. AB - An amphiphilic polymer with multiple decyl and oligo(ethylene glycol) chains attached to a common poly(methacrylate) backbone assembles into nanoscaled particles in aqueous environments. Hydrophobic anthracene and borondipyrromethene (BODIPY) chromophores can be co-encapsulated within the self-assembling nanoparticles and transported across hydrophilic media. The reversible character of the noncovalent bonds, holding the supramolecular containers together, permits the exchange of their components with fast kinetics in aqueous solution. Incubation of cervical cancer (HeLA) cells with a mixture of two sets of nanoparticles, pre-loaded independently with anthracene or BODIPY chromophores, results in guest scrambling first and then transport of co-entrapped species to the intracellular space. Alternatively, incubation of cells with the two sets of nanocarriers in consecutive steps permits the sequential transport of the anthracene and BODIPY chromophores across the plasma membrane and only then allows their co-encapsulation within the same supramolecular containers. Both mechanisms position the two sets of chromophores with complementary spectral overlap in close proximity to enable the efficient transfer of energy intracellularly from the anthracene donors to the BODIPY acceptors. In the presence of iodine substituents on the BODIPY platform, intersystem crossing follows energy transfer. The resulting triplet state can transfer energy further to molecular oxygen with the concomitant production of singlet oxygen to induce cell mortality. Furthermore, the donor can be excited with two near-infrared photons simultaneously to permit the photoinduced generation of singlet oxygen intracellularly under illumination conditions compatible with applications in vivo. Thus, these supramolecular strategies to control the excitation dynamics of multichromophoric assemblies in the intracellular environment can evolve into valuable protocols for photodynamic therapy. PMID- 26238537 TI - Adhesive behaviour and virulence of coagulase negative staphylococci isolated from Italian cheeses. AB - Coagulase-negative staphylococci (CoNS) belong to saprophytic microbiota on the skin and mucous membranes of warm-blooded animals and humans, but are also isolated from foodstuffs such as meat, cheese, and milk. In other circumstances, some CoNS can act as pathogens. Thus the presence of CoNS may not be an immediate danger to public health, but can become a risk factor. In particular antibiotic resistant genes could be transferred to other potentially pathogenic microorganisms. Furthermore, CoNS are known to be strong biofilm producers and this is also a risk factor for public health. The aim of the present work was to determine the genotypic and phenotypic profiles of 106 CoNS belonging to four different species isolated from five different Italian cheeses for the presence of some adhesion and virulence features. In order to verify a possible correlation between the formation of biofilm and staphylococcal virulence factors, we checked the presence of adhesin genes by PCR and we investigated the ability of these strains to make biofilm at different temperatures. Furthermore, in some conditions, we analyzed surface proteins and autolytic pattern of selected strains. In conclusion, we checked the presence of norA and mecA genes responsible for fluoroquinolones and methicillin resistance, respectively. We found resistant genes in a proportion of the food isolates in amounts of 9.4% (mecA) and 5.7% (norA). These data support the importance to continuously examine the microbiota not only for the creation of a database but also to safeguard public health. PMID- 26238538 TI - Innovative Anthocyanin/Anthocyanidin Formulation Protects SK-N-SH Cells Against the Amyloid-beta Peptide-Induced Toxicity: Relevance to Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder of aging. It is a multifactorial disease with several overlapping pathways. Therefore, successful therapy should target several pathological features simultaneously. In this regard, cumulative data have demonstrated that polyphenols can display neuroprotective effects through different mechanisms. In this study, we tested the hypothesis that a mixture of anthocyanins/anthocyanidins presents in the formulation MAF14001 may mitigate the amyloid-beta peptide (Abeta) toxicity. Anthocyanins are a class of polyphenols capable to cross the blood brain barrier and their intake is associated to a reduced risk of some several chronic diseases. Our results showed that the formulation MAF14001 can protect SK-N-SH cells against Abeta-induced toxicity. From 5 uM, MAF14001 protected SK-N-SH cells against Abeta toxicity by preventing oxidative stress, mitochondrial dysfunction and apoptosis. Furthermore, MAF14001 might directly interact with Abeta to prevent its aggregation process, a key process on Abeta-induced oxidative stress. Indeed, in the presence of MAF14001, Abeta was less susceptible to fibrillation. Finally, MAF14001 decreased the tau phosphorylation (Ser-202) induced by Abeta. Altogether, these results demonstrated that MAF14001 could target multiple mechanisms involved in the etiology of AD and could be useful in preventing and treating AD. PMID- 26238539 TI - Normalization of circulating microRNA expression data obtained by quantitative real-time RT-PCR. AB - The high-throughput analysis of microRNAs (miRNAs) circulating within the blood of healthy and diseased individuals is an active area of biomarker research. Whereas quantitative real-time reverse transcription polymerase chain reaction (qPCR)-based methods are widely used, it is yet unresolved how the data should be normalized. Here, we show that a combination of different algorithms results in the identification of candidate reference miRNAs that can be exploited as normalizers, in both discovery and validation phases. Using the methodology considered here, we identify normalizers that are able to reduce nonbiological variation in the data and we present several case studies, to illustrate the relevance in the context of physiological or pathological scenarios. In conclusion, the discovery of stable reference miRNAs from high-throughput studies allows appropriate normalization of focused qPCR assays. PMID- 26238540 TI - Pathogenetic and prognostic roles of bloodborne fibrocytes in asthma. AB - Bloodborne fibrocytes are cells mobilized from the bone marrow, which express surface antigens commonly ascribed to hematopoietic progenitors and have phenotypic and functional characteristics similar to those of immature mesenchymal cells. They exhibit predominant proinflammatory or profibrotic activities at tissue sites, depending on the host's response to environmental insults and on the characteristics of the cell infiltrate and cytokine milieu. In patients with allergic asthma, fibrocytes egress from the bone marrow and are recruited into the airways after every allergen exposure and during viral infections. Recruited fibrocytes amplify the inflammatory responses driven by T helper type 2 lymphokines and favor viral replication and further inflammation on respiratory virus infections. Persistently elevated blood fibrocyte counts and persisting airway fibrocytosis are present in patients with chronically undertreated or corticosteroid-insensitive asthma, and are linked to an enhanced risk of adverse outcomes because of the major involvement of fibrocytes in the development of structural abnormalities that lead to chronic airflow obstruction in these patients. Consequently, blood fibrocyte count is an emerging biomarker of asthma control and disease progression and its clinical applicability as a new outcome measure deserves further evaluation in large clinical trials. PMID- 26238541 TI - Numerical magnitude processing in abacus-trained children with superior mathematical ability: an EEG study. AB - Distance effect has been regarded as the best established marker of basic numerical magnitude processes and is related to individual mathematical abilities. A larger behavioral distance effect is suggested to be concomitant with lower mathematical achievement in children. However, the relationship between distance effect and superior mathematical abilities is unclear. One could get superior mathematical abilities by acquiring the skill of abacus-based mental calculation (AMC), which can be used to solve calculation problems with exceptional speed and high accuracy. In the current study, we explore the relationship between distance effect and superior mathematical abilities by examining whether and how the AMC training modifies numerical magnitude processing. Thus, mathematical competencies were tested in 18 abacus-trained children (who accepted the AMC training) and 18 non-trained children. Electroencephalography (EEG) waveforms were recorded when these children executed numerical comparison tasks in both Arabic digit and dot array forms. We found that: (a) the abacus-trained group had superior mathematical abilities than their peers; (b) distance effects were found both in behavioral results and on EEG waveforms; (c) the distance effect size of the average amplitude on the late negative-going component was different between groups in the digit task, with a larger effect size for abacus-trained children; (d) both the behavioral and EEG distance effects were modulated by the notation. These results revealed that the neural substrates of magnitude processing were modified by AMC training, and suggested that the mechanism of the representation of numerical magnitude for children with superior mathematical abilities was different from their peers. In addition, the results provide evidence for a view of non-abstract numerical representation. PMID- 26238542 TI - Development of a test strip for rapid detection of lactoperoxidase in raw milk. AB - Traditional methods for detecting lactoperoxidase (LP) are complex and time consuming, so a test strip was made based on the enzymatic reaction principle to enable quick and convenient detection of LP in raw milk. In this study 0.1 mol/L citric acid (CA)/0.2 mol/L disodium hydrogen phosphate (NaP) buffer solution (pH 5.0), 22 mmol/L 3,3',5,5'-tetramethylbenzidine (TMB), 0.6 mmol/L hydrogen peroxide (H2O2), and 0.5% Tween-20 or 0.3% cetyltrimethyl ammonium bromide (CTAB) were optimal for preparing a quick, sensitive, and accurate LP test strip. The coefficient of variation (CV) of the estimated LP concentrations ranged from 2.47% to 6.72% and the minimum LP concentration detected by the test strip was 1 2 mg/L. Estimates of active LP in sixteen raw milk samples obtained using the test strip or the TMB method showed a good correlation (r=0.9776). So the test strip provides a quick, convenient, and accurate method for detecting the LP concentration of raw milk. PMID- 26238543 TI - Cytotoxicity and effect of extraction methods on the chemical composition of essential oils of Moringa oleifera seeds. AB - Renewed interest in natural materials as food flavors and preservatives has led to the search for suitable essential oils. Moringa oleifera seed essential oil was extracted by solvent-free microwave and hydrodistillation. This study assessed its chemical constituents. Cytotoxicity of the oils was investigated using hatchability and lethality tests on brine shrimps. A total of 16 and 26 compounds were isolated from the hydrodistillation extraction (HDE) and solvent free microwave extraction (SME) oils, respectively, which accounted for 97.515% and 97.816% of total identifiable constituents, respectively. At 24 h when the most eggs had hatched, values of the SME (56.7%) and HDE (60.0%) oils were significantly different (P<0.05) from those of sea water (63.3%) and chloramphenicol (15.0%). Larva lethality was different significantly (P<0.05) between HDE and SME oils at different concentrations and incubation periods. The median lethal concentration (LC50) of the oils was >1000 mg/ml recommended as an index for non-toxicity, which gives the oil advantage over some antioxidant, antimicrobial, therapeutic, and preservative chemicals. PMID- 26238544 TI - Microcalorimetry studies of the antimicrobial actions of Aconitum alkaloids. AB - The metabolic activity of organisms can be measured by recording the heat output using microcalorimetry. In this paper, the total alkaloids in the traditional Chinese medicine Radix Aconiti Lateralis were extracted and applied to Escherichia coli and Staphylococcus aureus. The effect of alkaloids on bacteria growth was studied by microcalorimetry. The power-time curves were plotted with a thermal activity monitor (TAM) air isothermal microcalorimeter and parameters such as growth rate constant (MU), peak-time (Tm), inhibitory ratio (I), and enhancement ratio (E) were calculated. The relationships between the concentration of Aconitum alkaloids and MU of E. coli or S. aureus were discussed. The results showed that Aconitum alkaloids had little effect on E. coli and had a potentially inhibitory effect on the growth of S. aureus. PMID- 26238545 TI - Leaf and root glucosinolate profiles of Chinese cabbage (Brassica rapa ssp. pekinensis) as a systemic response to methyl jasmonate and salicylic acid elicitation. AB - Glucosinolates (GSs) are an important group of defensive phytochemicals mainly found in Brassicaceae. Plant hormones jasmonic acid (JA) and salicylic acid (SA) are major regulators of plant response to pathogen attack. However, there is little information about the interactive effect of both elicitors on inducing GS biosynthesis in Chinese cabbage (Brassica rapa ssp. pekinensis). In this study, we applied different concentrations of methyl jasmonate (MeJA) and/or SA onto the leaf and root of Chinese cabbage to investigate the time-course interactive profiles of GSs. Regardless of the site of the elicitation and the concentrations of the elicitors, the roots accumulated much more GSs and were more sensitive and more rapidly responsive to the elicitors than leaves. Irrespective of the elicitation site, MeJA had a greater inducing and longer lasting effect on GS accumulation than SA. All three components of indole GS (IGS) were detected along with aliphatic and aromatic GSs. However, IGS was a major component of total GSs that accumulated rapidly in both root and leaf tissues in response to MeJA and SA elicitation. Neoglucobrassicin (neoGBC) did not respond to SA but to MeJA in leaf tissue, while it responded to both SA and MeJA in root tissue. Conversion of glucobrassicin (GBC) to neoGBC occurred at a steady rate over 3 d of elicitation. Increased accumulation of 4-methoxy glucobrassicin (4-MGBC) occurred only in the root irrespective of the type of elicitors and the site of elicitation. Thus, accumulation of IGS is a major metabolic hallmark of SA- and MeJA-mediated systemic response systems. SA exerted an antagonistic effect on the MeJA-induced root GSs irrespective of the site of elicitation. However, SA showed synergistic and antagonistic effects on the MeJA-induced leaf GSs when roots and leaves are elicitated for 3 d, respectively. PMID- 26238546 TI - Rumen fermentation and acetogen population changes in response to an exogenous acetogen TWA4 strain and Saccharomyces cerevisiae fermentation product. AB - The presence of yeast cells could stimulate hydrogen utilization of acetogens and enhance acetogenesis. To understand the roles of acetogens in rumen fermentation, an in vitro rumen fermentation experiment was conducted with addition of acetogen strain (TWA4) and/or Saccharomyces cerevisiae fermentation product (XP). A 2*2 factorial design with two levels of TWA4 (0 or 2*10(7) cells/ml) and XP (0 or 2 g/L) was performed. Volatile fatty acids (VFAs) were increased (P<0.05) in XP and TWA4XP, while methane was increased only in TWA4XP (P<0.05). The increase rate of microorganisms with formyltetrahydrofolate synthetase, especially acetogens, was higher than that of methanogens under all treatments. Lachnospiraceae was predominant in all acetogen communities, but without close acetyl-CoA synthase (ACS) amino acid sequences from cultured isolates. Low-Acetitomaculum ruminis like ACS was predominant in all acetogen communities, while four unique phylotypes in XP treatment were all amino acid identified low-Eubacterium limosum like acetogens. It differs to XP treatment that more low-A. ruminis-like and less low-E. limosum-like sequences were identified in TWA4 and TWA4XP treatments. Enhancing acetogenesis by supplementation with an acetogen strain and/or yeast cells may be an approach to mitigate methane, by targeting proper acetogens such as uncultured low-E. limosum-like acetogens. PMID- 26238547 TI - Evaluation of efficacy of resin hemoperfusion in patients with acute 2,4 dinitrophenol poisoning by dynamic monitoring of plasma toxin concentration. AB - OBJECTIVE: The intoxications caused by 2,4-dinitrophenol (2,4-DNP), even death, have been frequently reported in recent years. This study aims to investigate the dynamic changes of plasma toxin concentration and explore the clinical value of resin hemoperfusion (HP) in the treatment of patients with acute 2,4-DNP poisoning. METHODS: We reported 16 cases of acute 2,4-DNP poisoning through occupational exposure due to ignoring the risk of poisoning. The blood samples were collected from the 14 survivors. According to the different treatments of resin HP, the survivors were divided into routine HP (n=5) and intensive HP (n=9) groups. Ultra high performance liquid chromatography/ tandem mass spectroscopy (UPLC-MS/MS) was used to detect the 2,4-DNP concentration in plasma in this study. RESULTS: The 14 survivors recovered very well after treatment. The initial plasma 2,4-DNP concentrations (C1) of survivors ranged from 0.25 to 41.88 ug/ml (mean (12.56+/-13.93) ug/ml). A positive correlation existed between initial plasma 2,4-DNP concentration (C1) and temperature. The elimination of 2,4-DNP was slow and persistent, and the total clearance rates of plasma toxin from the 1st to 3rd day (R3), the 3rd to 7th day (R3-7), and the 1st to 7th day (R7), were only (53.03+/-14.04)%, (55.25+/-10.50)%, and (78.29+/-10.22)%, respectively. The plasma toxin was cleared up to 25 d after poisoning in most of the patients. The R3, R3-7, and R7 in the intensive HP group were all apparently higher than those in the routine HP group, with statistical significance (P<0.05). Simultaneously, the elimination half-life (t1/2) of 2,4-DNP in the intensive HP group was apparently shorter than that in the routine HP group, with statistical significance (P<0.05). CONCLUSIONS: The clinicians should be aware of this slow and persistent process in the elimination of plasma 2,4-DNP. Higher initial plasma toxin concentration resulted in a more severe fever for the patient. According to the limited data, longer and more frequent resin HP may accelerate to eliminate the poison. PMID- 26238548 TI - Screening for simple sequence repeat markers in Puccinia striiformis tritici based on genomic sequence. AB - Puccinia striiformis f. sp. tritici (Pst) is the obligate biotrophic fungus responsible for stripe rust wheat. In this study, we developed and characterized 20 polymorphic microsatellite markers from the genomic sequence of an isolate of Chinese Pst race CY32. Polymorphism at each simple sequence repeat (SSR) locus was determined using 32 Pst isolates from 7 countries. The number of alleles varied from 2 to 7 across isolates, and the observed and expected heterozygosities ranged from 0.33 to 0.97 (mean 0.62) and 0.23 to 0.73 (mean 0.51), respectively. As expected the genomic SSR markers were more polymorphic than the expressed sequence tag (EST)-SSR markers developed previously. These markers will be more useful for population genetics and molecular genetics studies in Pst. PMID- 26238549 TI - Natural and induced antibodies contribute to differential susceptibility to secondary cystic echinococcosis of Balb/c and C57Bl/6 mice. AB - Antibodies are key immune players in several helminth infections and animal models have been central for the identification of their mechanisms of protection. Murine secondary cystic echinococcosis is a useful model for studying Echinococcus granulosus immunobiology, being the immune profile mounted by the experimental host a determinant of parasite success or failure in infection establishment. In the present study, we analyzed infection outcome using Balb/c and C57Bl/6 mice strains, and compared their antibody responses in terms of quality and intensity. Our results showed that Balb/c is a highly susceptible strain to secondary cystic echinococcosis, while C57Bl/6 mice are quite resistant. Moreover, significant differences between strains were observed in natural and induced antibodies recognizing E. granulosus antigens, both at the systemic and peritoneal levels. Natural cross-reacting IgM, IgG2b and IgG3 antibodies were detected in sera from both strains but with different intensities, and - remarkably - natural IgG2b showed to be an intrinsic correlate of protection in both mice strains. Interestingly, naive C57Bl/6 serum displayed a higher protoscolicidal activity, and heterologous - but not homologous - transference of C57Bl/6 naive serum into Balb/c mice, significantly reduced their infection susceptibility. In the peritoneal cavity, different levels of natural cross-reacting IgM and IgG3 antibodies were detected in both mice strains, while cross-reacting IgG2b was detected only in C57Bl/6 mice. On the other hand, infected mice from both strains developed isotype-mixed antibody responses, with Balb/c mice biasing their response towards high avidity IgG1 and C57Bl/6 mice showing a predominance of mixed IgM/IgG2c/IgG2b/IgG3. In this regard, IgG1 levels showed to be a correlate of susceptibility in both mice strains. In conclusion, our results suggest that antibodies - either natural or induced - play a role in the susceptibility degree to murine secondary cystic echinococcosis. PMID- 26238550 TI - Effect of Synthetic Levers on Nickel Phosphide Nanoparticle Formation: Ni5P4 and NiP2. AB - Due to their unique catalytic, electronic, and redox processes, Ni5P4 and NiP2 nanoparticles are of interest for a wide-range of applications from the hydrogen evolution reaction to energy storage (batteries); yet synthetic approaches to these materials are limited. In the present work, a phase-control strategy enabling the arrested-precipitation synthesis of nanoparticles of Ni5P4 and NiP2 as phase-pure samples using different Ni organometallic precursors and trioctylphosphine (TOP) is described. The composition and purity of the product can be tuned by changing key synthetic levers, including the Ni precursor, the oleylamine (OAm) coordinating solvent and TOP concentrations, temperature, time, and the presence or absence of a moderate temperature soak step to facilitate formation of Ni and/or Ni-P amorphous nanoparticle intermediates. Notably, the 230 degrees C intermediate step favors the ultimate formation of Ni2P and hinders further phosphidation to form Ni5P4 or NiP2 as phase-pure products. In the absence of this step, increasing the P/Ni ratio (13-20), reaction temperature (350-385 degrees C), and time (10-48 h) favors more P-rich phases, and these parameters can be adjusted to generate either Ni5P4 or NiP2. The phase of the obtained particles can also be tuned between pure Ni2P to Ni5P4 and NiP2 by simply decreasing the OAm/TOP ratio and/or changing the nickel precursor (nickel(II)acetylacetonate, nickel(II)acetate tetrahydrate, or bis(cyclooctadiene)nickel(0)). However, at high concentrations of OAm, the product formed is the same regardless of Ni precursor, suggesting the formation of a uniform Ni intermediate (an Ni-oleylamine complex) under these conditions that is responsible for product distribution. Intriguingly, under the extreme phosphidation conditions required to favor Ni5P4 and NiP2 over Ni2P (large excess of TOP), the 20-30 nm crystallites assemble into supraparticles with diameters of 100-500 nm. These factors are discussed in light of a comprehensive synthetic scheme utilized to control P incorporation in nickel phosphides. PMID- 26238552 TI - A Polymer Lithium-Oxygen Battery. AB - Herein we report the characteristics of a lithium-oxygen battery using a solid polymer membrane as the electrolyte separator. The polymer electrolyte, fully characterized in terms of electrochemical properties, shows suitable conductivity at room temperature allowing the reversible cycling of the Li-O2 battery with a specific capacity as high as 25,000 mAh gC(-1) reflected in a surface capacity of 12.5 mAh cm(-2). The electrochemical formation and dissolution of the lithium peroxide during Li-O2 polymer cell operation is investigated by electrochemical techniques combined with X-ray diffraction study, demonstrating the process reversibility. The excellent cell performances in terms of delivered capacity, in addition to its solid configuration allowing the safe use of lithium metal as high capacity anode, demonstrate the suitability of the polymer lithium-oxygen as high-energy storage system. PMID- 26238553 TI - DNA methylation detection with end-to-end nanorod assembly-enhanced surface plasmon resonance. AB - The Au nanorod (AuNR) assembly-enhanced surface plasmon resonance (SPR) system coupling with polymerization and nicking reactions was developed for amplified detection of DNA methylation and adenine methylation (Dam) methyltransferase (MTase) activity assay. The biosensor showed a good linear relationship between the SPR angle shift and the Dam MTase concentration over a range from 0.5 to 120 U mL(-1), with a detection limit of 0.2 U mL(-1). This study provided a sensitive platform to screen inhibitors for Dam MTase with great potential to be further applied in early clinical diagnosis. PMID- 26238554 TI - Effectiveness of Nonpharmacologic Interventions for Decreasing Fatigue in Adults With Systemic Lupus Erythematosus: A Systematic Review. AB - OBJECTIVE: Survival of patients with systemic lupus erythematosus (SLE) has significantly improved over the past decades. As SLE patients live longer they inevitably experience a range of clinical manifestations and somatic symptoms. Quality of life may also be impacted through a range of subjective indicators. Among these parameters, fatigue is the most prevalent complaint. Nonpharmacologic strategies seem regularly utilized for fatigue management in SLE; however, their real effects are not known. METHODS: A systematic review was conducted to analyze the effectiveness of nonpharmacologic interventions to reduce fatigue in SLE patients. Medline/PreMedline, Embase, PsycINFO, SCI-EXPANDED, Social Sciences Citation Index, and the Cochrane Library were searched (June 2014). Studies were included and assessed for quality if they fulfilled prespecified criteria. RESULTS: A total of 12 studies were finally included (n = 549): 7 randomized trials, 1 nonrandomized trial, and 4 prospective observational studies. They assessed 5 main intervention categories: exercise, behavioral and psychological approaches, diets, acupuncture, and phototherapy. All interventions produced reductions in fatigue, as measured using at least 1 instrument. Aerobic exercise was found to be effective and suitable for reducing fatigue, but results were not always consistent across instruments used. The diversity of psychological interventions limits the significance of the results; however, data point to a positive impact on fatigue. There are still few data on the effect of acupuncture, diets, and ultraviolet A radiation. CONCLUSION: Studies are few and heterogeneous; however, nonpharmacologic interventions applied to SLE patients can be effective in reducing fatigue. PMID- 26238555 TI - Vitroprocines, new antibiotics against Acinetobacter baumannii, discovered from marine Vibrio sp. QWI-06 using mass-spectrometry-based metabolomics approach. AB - A robust and convenient research strategy integrating state-of-the-art analytical techniques is needed to efficiently discover novel compounds from marine microbial resources. In this study, we identified a series of amino-polyketide derivatives, vitroprocines A-J, from the marine bacterium Vibrio sp. QWI-06 by an integrated approach using imaging mass spectroscopy and molecular networking, as well as conventional bioactivity-guided fractionation and isolation. The structure-activity relationship of vitroprocines against Acinetobacter baumannii is proposed. In addition, feeding experiments with (13)C-labeled precursors indicated that a pyridoxal 5'-phosphate-dependent mechanism is involved in the biosynthesis of vitroprocines. Elucidation of amino-polyketide derivatives from a species of marine bacteria for the first time demonstrates the potential of this integrated metabolomics approach to uncover marine bacterial biodiversity. PMID- 26238556 TI - Increased BMI during pregnancy: how do midwife lead maternity carers respond? AB - AIM: To determine the knowledge base of midwife lead maternity carers (LMCs) and explore their adjustments in practice for obese women. MATERIALS & METHODS: A nationwide cohort study of LMC midwives in New Zealand concerning obesity in pregnancy using an electronic survey. RESULTS: A total of 428 LMCs responded. Most respondents were aware of the risks of obesity during pregnancy. Midwives felt it was important to provide customized care. Various barriers to accessing support for obese women within the health system were identified. Discussing weight and obesity was acknowledged as a sensitive issue for both the woman and the midwife. CONCLUSION: This study highlights the need to improve access to and availability of supportive maternity services and resources for pregnant women with increased BMI. PMID- 26238558 TI - Factors associated with type-specific persistence of high-risk human papillomavirus infection: A population-based study. AB - Persistent genital infection with high-risk (HR) human papillomavirus (HPV) is a prerequisite for cervical cancer development. The aim of this study was to identify factors associated with type-specific persistence of HR HPV infections. From a population-based cohort of 40,399 women participating in cervical cancer screening established during 2002-2005, we selected all HR HPV-positive women (N = 7,778). During follow-up (2005-2008), we collected cervical samples from these women and tested them for HPV DNA to determine type-specific HR HPV persistence in the interval 1-4.5 years after enrolment. Data on hospitalisations, prescriptions and socioeconomic factors were obtained from nationwide registers. Women with abnormal cytology at baseline or who had undergone conisation during follow-up were excluded. Factors associated with persistence were identified by logistic regression analysis. The overall rate of HR HPV persistence was 31.4%. The risk for persistence was significantly increased among women with a previous episode of genital warts (OR, 1.35; 95% CI, 1.04-1.74), current use of oral contraceptives (OR, 1.35; 95% CI, 1.13-1.63) or use of systemic glucocorticoids (OR, 2.04; 95% CI, 1.16-3.56). The number of pregnancies or births or use of a hormonal intrauterine device, hormonal therapy or nonsteroidal anti-inflammatory drugs was not associated with risk for HR HPV persistence. A history of genital warts and current use of oral contraceptives or systemic glucocorticoids increased the risk, potentially indicating a decreased immune response to HPV infection. These findings suggest that host immune response characteristics are important in HR HPV persistence and consequently in cervical cancer development. PMID- 26238557 TI - The influence of area-level education on body mass index, waist circumference and obesity according to gender. AB - OBJECTIVES: The aim of this study was to analyze the association between area level education and body mass index (BMI), waist circumference (WC) and obesity controlling for individual demographic and socioeconomic characteristics. METHODS: A cross-sectional population-based study was carried out with 1720 adults aged 20-59 in southern Brazil. We used multilevel modeling techniques to test whether area-level education was associated with BMI, WC and obesity regardless of individual-level characteristics. RESULTS: We observed a significant between-groups variance for both BMI and WC. Among women, area-level education explained 27.6 and 30.0% of the between-groups variance of BMI and WC, respectively. In the fully adjusted model, the WC was 4.67 cm higher (p < 0.05) and the BMI was 1.12 kg/m(2) higher (p < 0.05) in the women residents of low education neighborhoods compared to the residents of high education areas. In the same group, the chance of central obesity and general obesity was, respectively, 2.05 (IC95% 1.19-3.52) and 1.85 (IC95% 1.04-3.29) times higher. CONCLUSIONS: The findings suggest that neighborhood characteristics play an important role in the distribution of obesity and must be addressed by policy makers. PMID- 26238559 TI - Latin America multidisciplinary research on heat shock proteins and cell stress: proceedings of the first conference of the Latin America Chapter of the Cell Stress Society International. AB - The First Conference of the Latin America Chapter of the Cell Stress Society International (CSSI) organized by CSSI was held in Montevideo, Uruguay, on March 11-14, 2014. The Latin America Chapter of the CSSI (LAC-CSSI) was established at the Workshop on the Molecular Biology of the Stress Response, Porto Alegre, Brazil, May 2012. The chapter's first meeting took place in the beautiful city of Montevideo and was chaired by the first (LAC-CSSI) elected president Professor Maria Bausero. Forty-two invited speakers presented their work to more than 100 scientists. The first day of the conference was dedicated to an introductory program for students, young investigators, and participants new to the field of molecular chaperones and the stress response. These seminars were held in the Pasteur Institute of Montevideo and the Faculty of Sciences of the University of the Republic. These institutions were carefully selected to give foreign participants a broad view of the diversity of students and institutions doing research in Uruguay, as well as an opportunity for direct interaction with our scientists and students. Invited speakers for the seminar series were Dr. Wolfgang Schumann, Dr. Cristina Bonorino, Dr. Antonio De Maio, Dr. Ian Brown, Dr. Rafael Radi, Dr. Daniel Ciocca, and Dr. Celia Quijano. The remaining days of the conference took place at the Sheraton Hotel in Montevideo, and the scientific sessions are discussed below. PMID- 26238560 TI - Serendipity and technical considerations for the measurement of serum heat shock protein HSP27 in patients with COPD and lung cancer. PMID- 26238562 TI - Commentary to: 'A comparison of two commercially available ELISA methods for the quantification of human plasma heat shock protein 70 during rest and exercise stress' by Lee et al. 2015. PMID- 26238561 TI - Transcriptome response to heat stress in a chicken hepatocellular carcinoma cell line. AB - Heat stress triggers an evolutionarily conserved set of responses in cells. The transcriptome responds to hyperthermia by altering expression of genes to adapt the cell or organism to survive the heat challenge. RNA-seq technology allows rapid identification of environmentally responsive genes on a large scale. In this study, we have used RNA-seq to identify heat stress responsive genes in the chicken male white leghorn hepatocellular (LMH) cell line. The transcripts of 812 genes were responsive to heat stress (p < 0.01) with 235 genes upregulated and 577 downregulated following 2.5 h of heat stress. Among the upregulated were genes whose products function as chaperones, along with genes affecting collagen synthesis and deposition, transcription factors, chromatin remodelers, and genes modulating the WNT and TGF-beta pathways. Predominant among the downregulated genes were ones that affect DNA replication and repair along with chromosomal segregation. Many of the genes identified in this study have not been previously implicated in the heat stress response. These data extend our understanding of the transcriptome response to heat stress with many of the identified biological processes and pathways likely to function in adapting cells and organisms to hyperthermic stress. Furthermore, this study should provide important insight to future efforts attempting to improve species abilities to withstand heat stress through genome-wide association studies and breeding. PMID- 26238563 TI - Multimodality assessment and treatment of chemotherapy-induced cardiotoxicity. PMID- 26238564 TI - Synaptic generation of an intracellular retrograde signal requires activation of the tyrosine kinase and mitogen-activated protein kinase signaling cascades in Aplysia. AB - Cellular changes underlying memory formation can be generated in an activity dependent manner at specific synapses. Thus an important question concerns the mechanisms by which synaptic signals communicate with the cell body to mediate these cellular changes. A monosynaptic circuit that is enhanced by sensitization in Aplysia is well-suited to study this question because three different subcellular compartments: (i) the sensorimotor SN-MN synapses, (ii) the SN projections to MNs via axonal connections, (iii) the SN cell bodies, can all be manipulated and studied independently. Here, we report that activity-dependent (AD) training in either the entire SN-MN circuit or in only the synaptic compartment, activates MAPK in a temporally and spatially specific pattern. Specifically, we find (i) MAPK activation is first transiently generated at SN-MN synapses during training, (ii) immediately after training MAPK is transiently activated in SN-MN axonal connections and persistently activated in SN cell bodies, and finally, (iii) MAPK is activated in SN cell bodies and SN-MN synapses 1h after training. These data suggest that there is an intracellularly transported retrograde signal generated at the synapse which is later responsible for delayed MAPK activation at SN somata. Finally, we find that this retrograde signal requires activation of tyrosine kinase (TK) and MEK signaling cascades at the synapses. PMID- 26238565 TI - Montane forest ecotones moved downslope in northeastern USA in spite of warming between 1984 and 2011. AB - Ecotones are transition zones that form, in forests, where distinct forest types meet across a climatic gradient. In mountains, ecotones are compressed and act as potential harbingers of species shifts that accompany climate change. As the climate warms in New England, USA, high-elevation boreal forests are expected to recede upslope, with northern hardwood species moving up behind. Yet recent empirical studies present conflicting findings on this dynamic, reporting both rapid upward ecotonal shifts and concurrent increases in boreal species within the region. These discrepancies may result from the limited spatial extent of observations. We developed a method to model and map the montane forest ecotone using Landsat imagery to observe change at scales not possible for plot-based studies, covering mountain peaks over 39 000 km(2) . Our results show that ecotones shifted downward or stayed stable on most mountains between 1991 and 2010, but also shifted upward in some cases (13-15% slopes). On average, upper ecotone boundaries moved down -1.5 m yr(-1) in the Green Mountains, VT, and -1.3 m yr(-1) in the White Mountains, NH. These changes agree with remeasured forest inventory data from Hubbard Brook Experimental Forest, NH, and suggest that processes of boreal forest recovery from prior red spruce decline, or human land use and disturbance, may swamp out any signal of climate-mediated migration in this ecosystem. This approach represents a powerful framework for evaluating similar ecotonal dynamics in other mountainous regions of the globe. PMID- 26238566 TI - Using conjoint analysis to develop a system of scoring policymakers' use of research in policy and program development. AB - BACKGROUND: The importance of utilising the best available research evidence in the development of health policies, services, and programs is increasingly recognised, yet few standardised systems for quantifying policymakers' research use are available. We developed a comprehensive measurement and scoring tool that assesses four domains of research use (i.e. instrumental, conceptual, tactical, and imposed). The scoring tool breaks down each domain into its key subactions like a checklist. Our aim was to develop a tool that assigned appropriate scores to each subaction based on its relative importance to undertaking evidence informed health policymaking. In order to establish the relative importance of each research use subaction and generate this scoring system, we conducted conjoint analysis with a sample of knowledge translation experts. METHODS: Fifty four experts were recruited to undertake four choice surveys. Respondents were shown combinations of research use subactions called profiles, and rated on a 1 to 9 scale whether each profile represented a limited (1-3), moderate (4-6), or extensive (7-9) example of research use. Generalised Estimating Equations were used to analyse respondents' choice data, which calculated a utility coefficient for each subaction. A large utility coefficient indicated that a subaction was particularly influential in guiding experts' ratings of extensive research use. RESULTS: Utility coefficients were calculated for each subaction, which became the points assigned to the subactions in the scoring system. The following subactions yielded the largest utilities and were regarded as the most important components of each research use domain: using research to directly influence the core of the policy decision; using research to inform alternative perspectives to deal with the policy issue; using research to persuade targeted stakeholders to support a predetermined decision; and using research because it was a mandated requirement by the policymaker's organisation. CONCLUSIONS: We have generated an empirically derived and context-sensitive means of measuring and scoring the extent to which policymakers used research to inform the development of a policy document. The scoring system can be used by organisations to not only quantify the extent of their research use, but also to provide them with insights into potential strategies to improve subsequent research use. PMID- 26238567 TI - Survey of clustered regularly interspaced short palindromic repeats and their associated Cas proteins (CRISPR/Cas) systems in multiple sequenced strains of Klebsiella pneumoniae. AB - BACKGROUND: In recent years the emergence of multidrug resistant Klebsiella pneumoniae strains has been an increasingly common event. This opportunistic species is one of the five main bacterial pathogens that cause hospital infections worldwide and multidrug resistance has been associated with the presence of high molecular weight plasmids. Plasmids are generally acquired through horizontal transfer and therefore is possible that systems that prevent the entry of foreign genetic material are inactive or absent. One of these systems is CRISPR/Cas. However, little is known regarding the clustered regularly interspaced short palindromic repeats and their associated Cas proteins (CRISPR/Cas) system in K. pneumoniae. The adaptive immune system CRISPR/Cas has been shown to limit the entry of foreign genetic elements into bacterial organisms and in some bacteria it has been shown to be involved in regulation of virulence genes. Thus in this work we used bioinformatics tools to determine the presence or absence of CRISPR/Cas systems in available K. pneumoniae genomes. RESULTS: The complete CRISPR/Cas system was identified in two out of the eight complete K. pneumoniae genomes sequences and in four out of the 44 available draft genomes sequences. The cas genes in these strains comprises eight cas genes similar to those found in Escherichia coli, suggesting they belong to the type I E group, although their arrangement is slightly different. As for the CRISPR sequences, the average lengths of the direct repeats and spacers were 29 and 33 bp, respectively. BLAST searches demonstrated that 38 of the 116 spacer sequences (33%) are significantly similar to either plasmid, phage or genome sequences, while the remaining 78 sequences (67%) showed no significant similarity to other sequences. The region where the CRISPR/Cas systems were located is the same in all the Klebsiella genomes containing it, it has a syntenic architecture, and is located among genes encoding for proteins likely involved in metabolism and resistance to antibiotics. CONCLUSIONS: The CRISPR/Cas system is not widely distributed in K. pneumoniae genomes, those present most likely belong to type I E with few differences from the arrangement of the cse3 gene and most of the spacers have not been are not described yet. Given that the CRISPR/Cas system is scarcely distributed among K. pneumoniae genomes it is not clear whether it is involved in either immunity against foreign genetic material or virulence. We consider that this study represents a first step to understand the role of CRISPR/Cas in K. pneumoniae. PMID- 26238568 TI - Effect of Achillea Millefolium on Relief of Primary Dysmenorrhea: A Double-Blind Randomized Clinical Trial. AB - INTRODUCTION: Primary dysmenorrhea occurs in as many as 50% of postmenarche women and is characterized by a particularly intense pain that is localized in the abdominal inferior quadrants and radiates to the inner thigh. This study assessed the effectiveness of Achillea millefolium on relief of primary dysmenorrhea. MATERIALS AND METHODS: The clinical trial was conducted at Islamic Azad, Toyserkan Branch in western Iran from July 10 to November 18, 2013. It consisted of female students from the university who had primary dysmenorrhea. The subjects were randomly divided into 2 equal groups and were given either placebo or A millefolium in teabag form for 3 days in 2 menstruation cycles. They graded the severity of their pain by using a visual analog scale. RESULTS: The severity of pain in the 2 groups was compared using t test. The mean change in pain score in the A millefolium group was significantly greater than that in the placebo group at 1 month (P = .001) and 2 months (P < .0001) after treatment. CONCLUSION: A millefolium is effective in minimizing the pain severity in primary dysmenorrhea. PMID- 26238569 TI - Fasting Glucose Changes in Adolescents with Polycystic Ovary Syndrome Compared with Obese Controls: A Retrospective Cohort Study. AB - STUDY OBJECTIVE: To compare changes in fasting glucose among adolescents with polycystic ovary syndrome (PCOS) with those in obese adolescents without PCOS. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 310 adolescents with PCOS and 250 obese adolescents (age range 13 to 18 years) seen at Mayo Clinic, Rochester, MN, from 1996 to 2012. METHODS: Included for analysis were 98 adolescents with PCOS and 150 obese adolescents who had 2 or more fasting glucose measurements separated by at least 6 months. Adolescents with impaired fasting glucose (IFG) or diabetes were excluded. Multivariate models were used to assess predictors of change in fasting glucose. RESULTS: At diagnosis, adolescents with PCOS had lower body mass index (BMI) (kg/m(2)) and older age than obese adolescents (P < .001). Adolescents with PCOS had shorter follow-up (P = .02). Baseline fasting glucose was not different between groups. Mean change in fasting glucose was 2.4 +/- 9.4 mg/dL per year for PCOS and 2.2 +/- 6.2 mg/dL per year for obese adolescents (P = .83). Significant predictors for change in fasting glucose were BMI and fasting glucose at diagnosis (P < .01). Within the PCOS cohort, BMI was a significant predictor for development of IFG (P = .003). Prevalence of hypertension increased in the PCOS cohort from baseline to follow up (P = .02). PCOS and BMI were significantly associated with development of HTN in the entire cohort. CONCLUSION: Adolescent girls with PCOS do not show a significant change in fasting glucose or an increased risk for the development of IFG compared with obese adolescents. BMI, not PCOS status, was the strongest predictor for changes in fasting glucose and development of IFG over time. PMID- 26238570 TI - Impact of smoking on the age at diagnosis of upper tract urothelial carcinoma: Subanalysis of the Japanese Urological Association multi-institutional national database. AB - OBJECTIVES: To examine the influence of smoking history on the diagnosis and other tumor characteristics of upper tract urothelial carcinoma in Japan. METHODS: A total of 1509 patients with upper tract urothelial carcinoma who were diagnosed in 2005 from 348 Japanese institutions were registered using the multi institutional national database of the Japanese Urological Association and included in this analysis. Clinical data of the patients were collected in 2011. The associations between the patients' self-reported smoking history and their age at the diagnosis of upper tract urothelial carcinoma, sex, pathological T stage and tumor grade were analyzed. RESULTS: The mean age at the diagnosis of upper tract urothelial carcinoma was approximately 5 years earlier for the 238 current smokers than for the 618 current non-smokers (P < 0.0001). Similar associations between smoking and the early diagnosis of upper tract urothelial carcinoma were shown in the sex subgroups and in subgroups stratified by pathological T stages. Among the current smokers, the age at diagnosis for the smoking >= 20 cigarettes per day group was 6.5 years lower than that of the < 20 cigarettes per day group, which was significantly different (P < 0.0001). CONCLUSION: Current smoking is a significant risk factor for the earlier diagnosis of upper tract urothelial carcinoma. The finding is important from the perspective of both healthcare and medical economies. PMID- 26238571 TI - Plantar-flexion of the ankle joint complex in terminal stance is initiated by subtalar plantar-flexion: A bi-planar fluoroscopy study. AB - Gross motion of the ankle joint complex (AJC) is a summation of the ankle and subtalar joints. Although AJC kinematics have been widely used to evaluate the function of the AJC, the coordinated movements of the ankle and subtalar joints are not well understood. The purpose of this study was to accurately quantify the individual kinematics of the ankle and subtalar joints in the intact foot during ground walking by using a bi-planar fluoroscopic system. Bi-planar fluoroscopic images of the foot and ankle during walking and standing were acquired from 10 healthy subjects. The three-dimensional movements of the tibia, talus, and calcaneus were calculated with a three-dimensional/two-dimensional registration method. The skeletal kinematics were quantified from 9% to 86% of the full stance phase because of the limited camera speed of the X-ray system. At the beginning of terminal stance, plantar-flexion of the AJC was initiated in the subtalar joint on average at 75% ranging from 62% to 76% of the stance phase, and plantar flexion of the ankle joint did not start until 86% of the stance phase. The earlier change to plantar-flexion in the AJC than the ankle joint due to the early plantar-flexion in the subtalar joint was observed in 8 of the 10 subjects. This phenomenon could be explained by the absence of direct muscle insertion on the talus. Preceding subtalar plantar-flexion could contribute to efficient and stable ankle plantar-flexion by locking the midtarsal joint, but this explanation needs further investigation. PMID- 26238572 TI - Can dosimetric parameters predict acute hematologic toxicity in rectal cancer patients treated with intensity-modulated pelvic radiotherapy? AB - BACKGROUND: To identify dosimetric parameters associated with acute hematologic toxicity (HT) in rectal cancer patients undergoing concurrent chemotherapy and intensity-modulated pelvic radiotherapy. METHODS: Ninety-three rectal cancer patients receiving concurrent capecitabine and pelvic intensity-modulated radiation therapy (IMRT) were analyzed. Pelvic bone marrow (PBM) was contoured for each patient and divided into three subsites: lumbosacral spine (LSS), ilium, and lower pelvis (LP). The volume of each site receiving 5-40 Gy (V 5, V10, V15, V20, V30, and V40, respectively) as well as patient baseline clinical characteristics was calculated. The endpoint for hematologic toxicity was grade >= 2 (HT2+) leukopenia, neutropenia, anemia or thrombocytopenia. Logistic regression was used to analyze correlation between dosimetric parameters and grade >= 2 hematologic toxicity. RESULTS: Twenty-four in ninety-three patients experienced grade >= 2 hematologic toxicity. Only the dosimetric parameter V40 of lumbosacral spine was correlated with grade >= 2 hematologic toxicity. Increased pelvic lumbosacral spine V40 (LSS-V40) was associated with an increased grade >= 2 hematologic toxicity (p = 0.041). Patients with LSS-V40 >= 60 % had higher rates of grade >= 2 hematologic toxicity than did patients with lumbosacral spine V40 < 60 % (38.3 %, 18/47 vs.13 %, 6/46, p =0.005). On univariate and multivariate logistic regression analysis, lumbosacral spine V40 and gender was also the variable associated with grade >= 2 hematologic toxicity. Female patients were observed more likely to have grade >= 2 hematologic toxicity than male ones (46.9 %, 15/32 vs 14.8 %, 9/61, p =0.001). CONCLUSIONS: Lumbosacral spine -V40 was associated with clinically significant grade >= 2 hematologic toxicity. Keeping the lumbosacral spine -V40 < 60 % was associated with a 13 % risk of grade >= 2 hematologic toxicity in rectal cancer patients undergoing concurrent chemoradiotherapy. PMID- 26238573 TI - Developing core competencies for monitoring and evaluation tracks in South Asian MPH programs. AB - BACKGROUND: Monitoring and evaluation (M&E) provides vital information for decision-making and its structures, systems and processes are expected to be integrated throughout the life-cycle of public health programs. The acquisition of these skills should be developed in a structured manner and needs educational systems to identify core competencies in M&E teaching. This article presents our work on harmonizing M&E competencies for Masters level programs in the South Asian context and undertaking the global review of M&E track/ concentration offered in various Masters of Public Health (MPH) programs. METHODS: Through an online search and snow-balling, we mapped institutions offering M&E tracks/ concentrations in Masters of Public Health (MPH) programs globally. We obtained detailed information about their M&E curriculum from university websites and brochures. The data on curricular contents was extracted and compiled. We analyzed the curricular contents using the framework for core competencies developed by the Association of Schools of Public Health (ASPH); and the Miller's triangle. This data was then used to inform a consultative exercise aimed at identifying core competencies for an M&E track/ concentration in MPH programs in the South Asian context. RESULTS: Our curricular review of M&E content within MPH programs globally showed that different domains or broad topic areas relating to M&E are covered differently across the programs. The quantitative sciences (Biostatistics and Epidemiology) and Health Policy and Management are covered in much greater depth than the other two domains (Social & Behavioral Sciences and Environmental Health Sciences). The identification of core competencies for an M&E track/ concentration in the South Asian context was undertaken through a consultative group exercise involving representation from 11 institutions across Bangladesh, India, Nepal and Sri Lanka. During the consultation, the group engaged in a focused discussion to reach consensus on a set of 15 core competencies for an M&E track in South Asian MPH programs. CONCLUSION: This work presents an opportunity for institutions to identify and re-examine their M&E competencies as a part of their specialized tracks within MPH programs. Our curricular analysis approach has the potential for adaptation and further use in curriculum analysis across different academic specialties. PMID- 26238574 TI - Rescue of long-term memory after reconsolidation blockade. AB - Memory reconsolidation is considered to be the process whereby stored memories become labile on recall, allowing updating. Blocking the restabilization of a memory during reconsolidation is held to result in a permanent amnesia. The targeted knockdown of either Zif268 or Arc levels in the brain, and inhibition of protein synthesis, after a brief recall results in a non-recoverable retrograde amnesia, known as reconsolidation blockade. These experimental manipulations are seen as key proof for the existence of reconsolidation. However, here we demonstrate that despite disrupting the molecular correlates of reconsolidation in the hippocampus, rodents are still able to recover contextual memories. Our results challenge the view that reconsolidation is a separate memory process and instead suggest that the molecular events activated initially at recall act to constrain premature extinction. PMID- 26238575 TI - Boundary primacy in spatial mapping: Evidence from zebrafish (Danio rerio). AB - The ability to map locations in the surrounding environment is crucial for any navigating animal. Decades of research on mammalian spatial representations suggest that environmental boundaries play a major role in both navigation behavior and hippocampal place coding. Although the capacity for spatial mapping is shared among vertebrates, including birds and fish, it is not yet clear whether such similarities in competence reflect common underlying mechanisms. The present study tests cue specificity in spatial mapping in zebrafish, by probing their use of various visual cues to encode the location of a nearby conspecific. The results suggest that untrained zebrafish, like other vertebrates tested so far, rely primarily on environmental boundaries to compute spatial relationships and, at the same time, use other visible features such as surface markings and freestanding objects as local cues to goal locations. We propose that the pattern of specificity in spontaneous spatial mapping behavior across vertebrates reveals cross-species commonalities in its underlying neural representations. PMID- 26238577 TI - Editorial: anti-secretory therapy prior to anti-reflux surgery. Does dose matter? PMID- 26238576 TI - Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients. AB - INTRODUCTION: EXPEDITION and EXPEDITION2 were identically designed placebo controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-beta peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published. METHODS: Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed. RESULTS: In the mild AD population, less cognitive and functional decline was observed with solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study-Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study-Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. DISCUSSION: These findings describe solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate solanezumab's effects in a mild AD population. PMID- 26238578 TI - Editorial: anti-secretory therapy prior to anti-reflux surgery. Does dose matter? Authors' reply. PMID- 26238579 TI - Letter: oesophageal eosinophilia must be excluded before determining prevalence of eosinophilic oesophagitis. PMID- 26238580 TI - Letter: oesophageal eosinophilia must be excluded before determining prevalence of eosinophilic oesophagitis--authors' reply. PMID- 26238581 TI - Letter: PNPLA3, metabolic syndrome and NAFLD status in obese subjects--authors' reply. PMID- 26238582 TI - Letter: PNPLA3, metabolic syndrome and NAFLD status in obese subjects. PMID- 26238583 TI - Letter: clarithromycin dose for H. pylori therapy remains unresolved. PMID- 26238584 TI - Letter: clarithromycin dose for H. pylori therapy remains unresolved--authors' reply. PMID- 26238585 TI - Letter: serum vitamin D levels in primary biliary cirrhosis. PMID- 26238586 TI - Letter: serum vitamin D levels in primary biliary cirrhosis--authors' reply. PMID- 26238587 TI - [Not Available]. PMID- 26238588 TI - Editorial overview: Molecular imaging: Cellular imaging approaches. PMID- 26238589 TI - [Amyand's hernia and complicated appendicitis; case presentation and surgical treatment choice]. AB - BACKGROUND: A caecal appendix within an inguinal hernia, with or without appendicitis, is defined as Amyand's hernia. In 1% of inguinal hernias an appendix without inflammation can be found, however, the prevalence of appendicitis in a hernia sac is only 0.08-0.13%. CLINICAL CASE: Male of 43 years old, began two days before admission with pain in the right inguinal region. He was scheduled for surgery due to a complication of a right inguinal hernia. The surgical findings were Amyand's hernia, necrotic spermatic cord, and perforated appendix. Surgical repair was performed with a favourable outcome, and he was discharged on the fourth postoperative day. DISCUSSION: Most of Amyand's hernia exhibit characteristics of incarcerated or strangulated inguinal hernia. Even acute appendicitis or perforated appendix within the hernia sac does not reflect specific symptoms or signs, therefore, a preoperative clinical diagnosis of Amyand's hernia is difficult to achieve. In our case, the patient had perforated appendicitis, developing necrosis of the spermatic cord. Orchiectomy, appendectomy, and inguinal hernia repair was performed without placing mesh. Due to the controversy on the use of mesh in contaminated abdominal wall defects, it was not indicated here, due to the high risk of wound infection and appendicular fistula. CONCLUSION: An extremely rare condition is presented, with a surgical choice that led to a favourable outcome. PMID- 26238590 TI - [Laparoscopic gastric sleeve in gastric volvulus secondary to diaphragmatic eventration in an adult patient]. AB - BACKGROUND: Acute gastric volvulus is a rare, but potentially life-threatening, cause of upper gastrointestinal obstruction. CLINICAL CASE: Male of 60 years old with severe epigastric pain and abdominal distension with haematemesis on two occasions. The patient was haemodynamically stable, with abdominal distension and palpable epigastric fullness. Hematic cytology showed: haemoglobin 8.2g/dl and haematocrit 27%. Abdominal X-ray showed an elevation of left diaphragm with a hugely dilated stomach. A nasogastric tube was inserted. Endoscopy was performed. There was no active bleeding, but it was impossible to reach the duodenum due to the stomach distortion. The upper gastrointestinal X-ray study showed the appearance of an inverted stomach in the chest and an organoaxial gastric torsion. The CT scans of thorax and abdomen showed a gastric ascent into the thoracic cavity. Laparoscopic surgery was performed, finding the left hemi diaphragm elevated, and the stomach, splenic angle of the colon, the spleen and tail of the pancreas were also raised. A linear gastrectomy (gastric sleeve) was performed. The postoperative progress was satisfactory. Oral feeding was started 72 hours after surgery, and the patient was discharged, and has remained asymptomatic during the following by 8 years. CONCLUSIONS: Emergency physicians must maintain a high level of suspicion in patients that present with signs and symptoms suggesting upper digestive tract occlusion. The gastric sleeve is an excellent alternative to avoid recurrence of gastric volvulus. PMID- 26238591 TI - [Multiple aneurysms splenic; surgical exclusion with conservation of the spleen]. AB - BACKGROUND: Aneurysm of the splenic artery is diagnosed when the diameter of the splenic artery is greater than 1cm. It occupies third place among abdominal aneurysms. It is more frequent in women (4:1). It is associated with trauma, haemodynamics and local hormonal effects during pregnancy, portal hypertension (including the Caroli syndrome), arterial degeneration, atherosclerosis, and liver transplantation. It is difficult to diagnose, and it generally presents as ruptured, thus once the diagnosis is made, the surgical approach is indicated due to its high mortality. CLINICAL CASE: Female of 66 years of age with a diagnosis of splenic artery aneurysm, with pulsing sensation at epigastric level of 8 months onset. On physical examination there is a palpable throbbing mass of 9 cm of diameter approximately, for which she was admitted. The computed tomography angiography with reconstruction showed three splenic aneurysms. Two were tied and the larger one was repaired by endo-aneurysmorrhaphy. DISCUSSION: Visceral aneurysms are extremely rare. They are currently increasing and are the third leading cause of cardiovascular death, as morbidity/mortality is high. The surgical treatment must be done selectively according to their size. Selection of the surgical techniques depends on the anatomic location and the need for revascularisation, the aetiology and the experience of the surgeon. CONCLUSION: A review has been presented on the advances in diagnostic, and management, concluding that the best is to preserve the spleen, and whatever the technique it must be performed by trained surgeons. PMID- 26238592 TI - [Triple synchronous primary gynaecological tumours. A case report]. AB - BACKGROUND: Synchronous multiple primary malignancies in the female genital tract are infrequent. From 50 to 70% of them corresponds to synchronous cancers of the endometrium and ovary. To our knowledge, this is only the third case report in the international literature of three concurrent gynaecological cancers of epithelial origin. A case is presented, as well as a literature review due to the infrequency of its diagnosis and the lack of information on the subject. CLINICAL CASE: A 49-year-old woman, with previous gynaecological history of ovarian endometriosis. She underwent a hysterectomy and bilateral oophorectomy, as she had been diagnosed with endometrial hyperplasia with atypia. The final histopathology reported synchronous ovarian, Fallopian tube, and endometrial cancer. An extension study and complete surgical staging was performed, both being negative. She received adjuvant treatment of chemotherapy and radiotherapy. She is currently free of disease. CONCLUSIONS: The aetiology is uncertain. There is controversy relating to increased susceptibility of synchronous neoplasms to pelvic endometriosis and inherited genetic syndromes. Its diagnosis needs to differentiate them from metastatic disease. Additionally, they are problematical from a clinical, diagnostic, therapeutic, and prognostic point of view. The presentation of more cases of triple synchronous cancers is necessary for a complete adjuvant and surgical treatment. PMID- 26238593 TI - GSK1838705A, an IGF-1R inhibitor, inhibits glioma cell proliferation and suppresses tumor growth in vivo. AB - Glioma is a type of primary malignant tumor of the central nervous system in humans. At present, standard treatment involves surgical resection, followed by radiation therapy and chemotherapy. However, the prognosis is poor and the long term survival rate remains low. An improved understanding of the molecular basis for glioma tumorigenesis is in urgently required. The pro-survival effect of the insulin-like growth factor (IGF) signaling pathway has been implicated in progression of the glioma disease state. GSK1838705A is a novel, small molecule kinase inhibitor of IGF-IR, which inhibits IGF signal transduction and downstream target activation. Its anti-proliferative activity has been demonstrated in various tumor cell lines. The present study investigated the potential use of GSK1838705A for the treatment of glioma. Human U87MG glioma cells were used to examine the inhibitory activity of GSK1838705A in cell proliferation, migration and apoptosis. The antitumor activity of GSK1838705A was assessed in a xenograft mouse model. GSK1838705A inhibited the growth and induced the apoptosis of the U87MG glioma cells in a dose-dependent manner. The GSK1838705A-treated cells exhibited reduced migratory activity in response to chemoattractants. The present study further demonstrated the antitumor activity of GSK1838705A in vivo. The administration of GSK1838705A significantly inhibited the growth of glioma tumors by inducing the apoptosis of tumor cells. These results suggested that targeting IGF signaling with GSK1838705A may be a promising therapeutic strategy for the treatment of patients with glioma. PMID- 26238594 TI - Pattern and presentation of cardiac diseases among patients with chronic kidney disease attending a national referral hospital in Uganda: a cross sectional study. AB - BACKGROUND: Chronic kidney disease is a risk factor for development of cardiovascular diseases. Cardiovascular diseases are the primary cause of morbidity and mortality in patients with chronic kidney disease. There is limited data on cardiovascular diseases among chronic kidney disease patients in resource limited settings including Uganda. We determined the prevalence and patterns of cardiac diseases among patients with chronic kidney disease attending the nephrology outpatient clinic in Mulago National Referral Hospital in Uganda. METHODS: This was a cross sectional study in which two hundred seventeen patients with chronic kidney disease were recruited over a period of 9 months. Data on demographic characteristics and risk factors for cardiovascular diseases were collected using a standardized questionnaire. Cardiac evaluation was done using resting electrocardiography and transthoracic echocardiography performed for all study participants and findings entered into a data sheet. RESULTS: One hundred eleven (51.2 %) of the 217 participants were male. Mean age was 42.8 years. One hundred eighteen (54.4 %) of patients had either eccentric or concentric left ventricular hypertrophy. Patients with left ventricular hypertrophy were more likely to be hypertensive (p < 0.001) or anemic (p = 0.034). Up to 9.2 % of study subjects had valvular heart disease (rheumatic or degenerative) and 22 % had pericarditis. Forty one patients (18.9 %) had left ventricular systolic failure (Ejection fraction < 50 %). There was a higher prevalence of systolic failure in patients with left ventricular hypertrophy (21 % vs. 16 %) although this was not statistically significant, p = 0.346. Thirty eight participants (17.5 %) had diastolic failure while 2 % had cardiac rhythm abnormalities. CONCLUSION: Cardiac abnormalities are common in a predominantly young African population with CKD. Clinicians should routinely screen and manage cardiovascular disease in CKD patients. PMID- 26238596 TI - Characterization of GnRH-like peptides from the nerve ganglia of Yesso scallop, Patinopecten yessoensis. AB - There is yet no firm experimental evidence that the evolutionary ancient gonadotropin-releasing hormone GnRH (i.e., GnRH1) also acts in invertebrate gametogenesis. The objective of this paper is to characterize candidate invGnRH peptides of Yesso scallop Patinopecten yessoensis (i.e., peptide identification, immunohistochemical localization, and immunoquantification) in order to reveal their bioactive form in bivalves. Using mass spectrometry (MS), we identified two invGnRH (py-GnRH) peptides from the scallop nerve ganglia: a precursor form of py GnRH peptide (a non-amidated dodecapeptide; py-GnRH12aa-OH) and a mature py-GnRH peptide (an amidated undecapeptide; py-GnRH11aa-NH2). Immunohistochemical staining allowed the localization of both py-GnRH peptides in the neuronal cell bodies and fibers of the cerebral and pedal ganglia (CPG) and the visceral ganglion (VG). We found that the peptides showed a dimorphic distribution pattern. Notably, the broad distribution of mature py-GnRH in neuronal fibers elongating to peripheral organs suggests that it is multi-functional. Time resolved fluorescent immunoassays (TR-FIA) enabled the quantification of each py GnRH form in the single CPG or VG tissue obtained from one individual. In addition, we observed greater abundance of mature py-GnRH in VG compared with its level in CPG, suggesting that VG is the main producing organ of mature py-GnRH peptide and that py-GnRH may play a central regulatory role in neurons of scallops. Our study provides evidence, for the first time, for the presence of precursor and mature forms of invGnRH peptides in the nerve ganglia of an invertebrate. PMID- 26238595 TI - RNA-seq for gene identification and transcript profiling in relation to root growth of bermudagrass (Cynodon dactylon) under salinity stress. AB - BACKGROUND: Soil salinity is one of the most significant abiotic stresses affecting plant shoots and roots growth. The adjustment of root architecture to spatio-temporal heterogeneity in salinity is particularly critical for plant growth and survival. Bermudagrass (Cynodon dactylon) is a widely used turf and forage perennial grass with a high degree of salinity tolerance. Salinity appears to stimulate the growth of roots and decrease their mortality in tolerant bermudagrass. To estimate a broad spectrum of genes related to root elongation affected by salt stress and the molecular mechanisms that control the positive response of root architecture to salinity, we analyzed the transcriptome of bermudagrass root tips in response to salinity. RESULTS: RNA-sequencing was performed in root tips of two bermudagrass genotypes contrasting in salt tolerance. A total of 237,850,130 high quality clean reads were generated and 250,359 transcripts were assembled with an average length of 1115 bp. Totally, 103,324 unigenes obtained with 53,765 unigenes (52 %) successfully annotated in databases. Bioinformatics analysis indicated that major transcription factor (TF) families linked to stress responses and growth regulation (MYB, bHLH, WRKY) were differentially expressed in root tips of bermudagrass under salinity. In addition, genes related to cell wall loosening and stiffening (xyloglucan endotransglucosylase/hydrolases, peroxidases) were identified. CONCLUSIONS: RNA seq analysis identified candidate genes encoding TFs involved in the regulation of lignin synthesis, reactive oxygen species (ROS) homeostasis controlled by peroxidases, and the regulation of phytohormone signaling that promote cell wall loosening and therefore root growth under salinity. PMID- 26238597 TI - Antifungal activity of cathelicidin peptides against planktonic and biofilm cultures of Candida species isolated from vaginal infections. AB - Vulvovaginal candidiasis (VVC) is a frequent gynecological condition caused by Candida albicans and a few non-albicans Candida spp. It has a significant impact on the quality of life of the affected women also due to a considerable incidence of recurrent infections that are difficult to treat. The formation of fungal biofilm may contribute to the problematic management of recurrent VVC due to the intrinsic resistance of sessile cells to the currently available antifungals. Thus, alternative approaches for the prevention and control of biofilm-related infections are urgently needed. In this regard, the cationic antimicrobial peptides (AMPs) of the innate immunity are potential candidates for the development of novel antimicrobials as many of them display activity against biofilm formed by various microbial species. In the present study, we investigated the in vitro antifungal activities of the cathelicidin peptides LL 37 and BMAP-28 against pathogenic Candida spp. also including C. albicans, isolated from vaginal infections, and against C. albicans SC5314 as a reference strain. The antimicrobial activity was evaluated against planktonic and biofilm grown Candida cells by using microdilution susceptibility and XTT [2,3-bis(2 methoxy-4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5-carboxanilide] reduction assays and, in the case of established biofilms, also by CFU enumeration and fluorescence microscopy. BMAP-28 was effective against planktonically grown yeasts in standard medium (MIC range, 2-32MUM), and against isolates of C. albicans and Candida krusei in synthetic vaginal simulated fluid (MIC range 8 32MUM, depending on the pH of the medium). Established 48-h old biofilms formed by C. albicans SC5314 and C. albicans and C. krusei isolates were 70-90% inhibited within 24h incubation with 16MUM BMAP-28. As shown by propidium dye uptake and CFU enumeration, BMAP-28 at 32MUM killed sessile C. albicans SC5314 by membrane permeabilization with a faster killing kinetics compared to 32MUM miconazole (80-85% reduced biofilm viability in 90min vs 48h). In addition, BMAP 28 at 16MUM prevented Candida biofilm formation on polystyrene and medical grade silicone surfaces by causing a >90% reduction in the viability of planktonic cells in 30min. LL-37 was overall less effective than BMAP-28 against planktonic Candida spp. (MIC range 4->=64MUM), and was ineffective against established Candida biofilms. However, LL-37 at 64MUM prevented Candida biofilm development by inhibiting cell adhesion to polystyrene and silicone surfaces. Finally, Candida adhesion was strongly inhibited when silicone was pre-coated with a layer of BMAP-28 or LL-37, encouraging further studies for the development of peptide based antimicrobial coatings. PMID- 26238598 TI - Defining the minimal clinically important difference (MCID) of the Heinrichs carpenter quality of life scale (QLS). AB - To determine the Minimal Clinically Important Difference (MCID) of the Heinrichs Carpenter Quality of Life Scale (QLS). Data from the "Schizophrenia Trial of Aripiprazole" (STAR) study were used in this analysis. The MCID value of the QLS total score was estimated using the anchor-based method. These findings were substantiated/validated by comparing the MCID estimate to other measurements collected in the study. Half of the patients (49%) showed improvement in Clinical Global Impressions of Severity (CGI-S) during the trial. The estimated MCID of the QLS total score was 5.30 (standard error: 2.60; 95% confidence interval: [0.16; 10.43]; p < 0.05). Patients were divided into two groups: "QLS improvers" (QLS total score increased >= six points) and "non-improvers". The QLS improvers had significantly better effectiveness and reported significantly higher levels of preference for their current medications. There was a statistically significant difference between the two groups in the change in two of the four domains of QLS; "Interpersonal relations" and "Intrapsychic foundations" domains during the study. These findings support the value of the estimated MCID for the QLS and may be a useful tool in evaluating antipsychotic treatment effects and improving long-term patient outcomes in schizophrenia. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26238599 TI - Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling. AB - Functional assays, such as the "migration inhibition of neural crest cells" (MINC) developmental toxicity test, can identify toxicants without requiring knowledge on their mode of action (MoA). Here, we were interested, whether (i) inhibition of migration by structurally diverse toxicants resulted in a unified signature of transcriptional changes; (ii) whether statistically-identified transcript patterns would inform on compound grouping even though individual genes were little regulated, and (iii) whether analysis of a small group of biologically-relevant transcripts would allow the grouping of compounds according to their MoA. We analyzed transcripts of 35 'migration genes' after treatment with 16 migration-inhibiting toxicants. Clustering, principal component analysis and correlation analyses of the data showed that mechanistically related compounds (e.g. histone deacetylase inhibitors (HDACi), PCBs) triggered similar transcriptional changes, but groups of structurally diverse toxicants largely differed in their transcriptional effects. Linear discriminant analysis (LDA) confirmed the specific clustering of HDACi across multiple separate experiments. Similarity of the signatures of the HDACi trichostatin A and suberoylanilide hydroxamic acid to the one of valproic acid (VPA), suggested that the latter compound acts as HDACi when impairing neural crest migration. In conclusion, the data suggest that (i) a given functional effect (e.g. inhibition of migration) can be associated with highly diverse signatures of transcript changes; (ii) statistically significant grouping of mechanistically-related compounds can be achieved on the basis of few genes with small regulations. Thus, incorporation of mechanistic markers in functional in vitro tests may support read-across procedures, also for structurally un-related compounds. PMID- 26238601 TI - Different origin of adipogenic stem cells influences the response to antiretroviral drugs. AB - Lipodystrophy (LD) is a main side effect of antiretroviral therapy for HIV infection, and can be provoked by nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs). LD exists in different forms, characterized by fat loss, accumulation, or both, but its pathogenesis is still unclear. In particular, few data exist concerning the effects of antiretroviral drugs on adipocyte differentiation. Adipose tissue can arise either from mesenchymal stem cells (MSCs), that include bone marrow-derived MSCs (hBM-MSCs), or from ectodermal stem cells, that include dental pulp stem cells (hDPSCs). To analyze whether the embryonal origin of adipocytes might impact the occurrence of different phenotypes in LD, we quantified the effects of several antiretroviral drugs on the adipogenic differentiation of hBM-MSCs and hDPSCs. hBM-MSCs and hDPSCs were isolated from healthy donors. Cells were treated with 10 and 50 MUM stavudine (d4T), efavirenz (EFV), atazanavir (ATV), ritonavir (RTV), and ATV boosted RTV. Viability and adipogenesis were evaluated by staining with propidium iodide, oil red, and adipoRed; mRNA levels of genes involved in adipocyte differentiation, i.e. CCAAT/enhancer-binding protein alpha (CEBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma), and in adipocyte functions, i.e. fatty acid synthase (FASN), fatty acid binding protein-4 (FABP4), perilipin-1 (PLIN1) and 1-acylglycerol-3-phosphate O-acyltransferase-2 (AGPAT2), were quantified by real time PCR. We found that ATV, RTV, EFV, and ATV-boosted RTV, but not d4T, caused massive cell death in both cell types. EFV and d4T affected the accumulation of lipid droplets and induced changes in mRNA levels of genes involved in adipocyte functions in hBM-MSCs, while RTV and ATV had little effects. All drugs stimulated the accumulation of lipid droplets in hDPSCs. Thus, the adipogenic differentiation of human stem cells can be influenced by antiretroviral drugs, and depends, at least in part, on their embryonal origin. PMID- 26238602 TI - Dietary Quality of Americans by Supplemental Nutrition Assistance Program Participation Status: A Systematic Review. AB - CONTEXT: The Supplemental Nutrition Assistance Program (SNAP) is an effective component in reducing food insecurity in the U.S. In the discussion of strategies to also help SNAP participants maximize diet quality, it is important to know their current dietary patterns and food choices. This paper provides a systematic review of recent U.S. studies on dietary quality, food consumption, and spending among SNAP participants as compared to income-eligible and higher-income nonparticipants. EVIDENCE ACQUISITION: The review, completed in 2014, summarized studies that were peer-reviewed, published between January 2003 and August 2014, and provided data on dietary quality and intake of SNAP participants and nonparticipants. EVIDENCE SYNTHESIS: Twenty-five studies were included in this review. Daily caloric, macronutrient, and micronutrient intake of SNAP participants did not differ systematically from those of income-eligible nonparticipants; however, differences in dietary quality emerged. Adult SNAP participants scored lower on the Healthy Eating Index than either group of nonparticipants. Children's diets were similar among SNAP participants and low income nonparticipants, but were less nutritious than diets of higher-income children. The evidence regarding sugar-sweetened beverage consumption was mixed, with most studies indicating significantly higher beverage intake among SNAP participants compared with higher-income nonparticipants, but no difference compared to income-eligible nonparticipants. CONCLUSIONS: SNAP effectively alleviates food insecurity in terms of caloric, macronutrient, and micronutrient intake. Still, SNAP participants are struggling more than income-eligible and higher-income nonparticipants to meet key dietary guidelines. Future policies should ensure that this vital food assistance program addresses diet quality while reducing food insecurity. PMID- 26238603 TI - Influenza Vaccination Coverage Among People With High-Risk Conditions in the U.S. AB - INTRODUCTION: During annual influenza epidemics, rates of serious illness and death are higher among those who have medical conditions, such as pulmonary disease, diabetes, or heart disease, which place them at increased risk of influenza complications. Annual influenza vaccination was recommended for people with high-risk conditions as early as 1960. METHODS: Data from the 2012-2013 Behavioral Risk Factor Surveillance System were analyzed in 2014 to estimate national and state-specific influenza vaccination coverage among people aged 18 64 years with high-risk conditions. Prevalence ratios adjusted for demographic and access-to-care characteristics were calculated using logistic regression and predictive marginal models. RESULTS: Unadjusted influenza vaccination coverage was 45.4% among adults aged 18-64 years with at least one high-risk condition, compared with 32.9% among those with no high-risk conditions (p<0.05). Among adults aged 18-64 years with multiple conditions (at least two high-risk conditions), vaccination coverage was 53.2%. Coverage was 43.9% for those with pulmonary diseases, 52.7% for those with diabetes, 48.1% for those with heart disease, and 45.0% for those with cancer. Individuals with high-risk conditions were more likely to receive an influenza vaccine than those with no high-risk conditions, even after controlling for demographic and access-to-care characteristics. CONCLUSIONS: Despite ongoing influenza vaccination recommendations for adults with high-risk conditions, coverage was below the Healthy People 2020 target; only about half were vaccinated. Primary care providers and subspecialists should ensure routine assessment of vaccination status every fall and winter and recommend vaccination to people with high-risk conditions. PMID- 26238604 TI - Coating of beta-tricalcium phosphate scaffolds-a comparison between graphene oxide and poly-lactic-co-glycolic acid. AB - Bone regeneration in critical size defects is a major challenge in oral and maxillofacial surgery, and the gold standard for bone reconstruction still requires the use of autologous tissue. To overcome the need for a second intervention and to minimize morbidity, the development of new biomaterials with osteoinductive features is the focus of current research. As a scaffolding material, beta-tricalcium phosphate (beta-TCP) is suitable for bone regeneration purposes, although it does not carry any functional groups for the covalent immobilization of molecules. The aim of the present study was to establish effective coating variants for beta-TCP constructs to enable the biofunctionalization of anorganic blocks with different osteogenic molecules in future studies. We established working protocols for thin surface coatings consisting of polylactic-co-glycolic acid (PLGA) and graphene oxide (GO) by varying parameters. Surface properties such as the angularity and topography of the developed scaffolds were analyzed. To examine biological functionality, the adhesion and proliferation behavior of jaw periosteal cells (JPCs) were tested on the coated constructs. Our results suggest that PLGA is the superior material for surface coating of beta-TCP matrices, leading to higher JPC proliferation rates and providing a more suitable basis for further biofunctionalization in the field of bone tissue engineering. PMID- 26238605 TI - Transcriptome sequencing of the anterior cingulate in bipolar disorder: dysregulation of G protein-coupled receptors. AB - OBJECTIVE: Gene expression dysregulation in the brain has been associated with bipolar disorder through candidate gene and microarray expression studies, but questions remain about isoform-specific dysregulation and the role of noncoding RNAs whose importance in the brain has been suggested recently but not yet characterized for bipolar disorder. METHOD: The authors used RNA sequencing, a powerful technique that captures the complexity of gene expression, in postmortem tissue from the anterior cingulate cortex from 13 bipolar disorder case subjects and 13 matched comparison subjects. Differential expression was computed, and a global pattern of downregulation was detected, with 10 transcripts significant at a false discovery rate <=5%. Importantly, all 10 genes were also replicated in an independent RNA sequencing data set (N=61) from the anterior cingulate cortex. RESULTS: Among the most significant results were genes coding for class A G protein-coupled receptors: SSTR2 (somatostatin receptor 2), CHRM2 (cholinergic receptor, muscarinic 2), and RXFP1 (relaxin/insulin-like family peptide receptor 1). A gene ontology analysis of the entire set of differentially expressed genes pointed to an overrepresentation of genes involved in G protein-coupled receptor regulation. The top genes were followed up by querying the effect of treatment with mood stabilizers commonly prescribed in bipolar disorder, which showed that these drugs modulate expression of the candidate genes. CONCLUSIONS: By using RNA sequencing in the postmortem bipolar disorder brain, an interesting profile of G protein-coupled receptor dysregulation was identified, several new bipolar disorder genes were indicated, and the noncoding transcriptome in bipolar disorder was characterized. These findings have important implications with regard to fine-tuning our understanding of the bipolar disorder brain, as well as for identifying potential new drug target pathways. PMID- 26238606 TI - Pregnancy Complications Following Prenatal Exposure to SSRIs or Maternal Psychiatric Disorders: Results From Population-Based National Register Data. AB - OBJECTIVE: Using national register data, the authors examined the relationship between prenatal selective serotonin reuptake inhibitor (SSRI) treatment and pregnancy complications, accounting for psychiatric diagnoses related to SSRI use. METHOD: This was a population-based prospective birth cohort study using national register data. The sampling frame included 845,345 offspring, representing all singleton live births in Finland between 1996 and 2010. Pregnancies were classified as exposed to SSRIs (N=15,729), unexposed to SSRIs but with psychiatric diagnoses (N=9,652), and unexposed to medications and psychiatric diagnoses (N=31,394). Pregnancy outcomes in SSRI users were compared with those in the unexposed groups. RESULTS: Offspring of mothers who received SSRI prescriptions during pregnancy had a lower risk for late preterm birth (odds ratio=0.84, 95% CI=0.74-0.96), for very preterm birth (odds ratio=0.52, 95% CI=0.37-0.74), and for cesarean section (odds ratio=0.70, 95% CI=0.66-0.75) compared with offspring of mothers unexposed to medications but with psychiatric disorders. In contrast, in SSRI-treated mothers, the risk was higher for offspring neonatal complications, including low Apgar score (odds ratio=1.68, 95% CI=1.34-2.12) and monitoring in a neonatal care unit (odds ratio=1.24, 95% CI=1.14-1.35). Compared with offspring of unexposed mothers, offspring of SSRI treated mothers and mothers unexposed to medications but with psychiatric disorders were both at increased risk of many adverse pregnancy outcomes, including cesarean section and need for monitoring in a neonatal care unit. CONCLUSIONS: In a large national birth cohort, treatment of maternal psychiatric disorders with SSRIs during pregnancy was related to a lower risk of preterm birth and cesarean section but a higher risk of neonatal maladaptation. The findings provide novel evidence for a protective role of SSRIs on some deleterious reproductive outcomes, possibly by reducing maternal depressive symptoms. The divergent findings suggest that clinical decisions on SSRI use during pregnancy should be individualized, taking into account the mother's psychiatric and reproductive history. PMID- 26238607 TI - Thermal Transport in Fullerene Derivatives Using Molecular Dynamics Simulations. AB - In order to study the effects of alkyl chain on the thermal properties of fullerene derivatives, we perform molecular dynamics (MD) simulations to predict the thermal conductivity of fullerene (C60) and its derivative phenyl-C61-butyric acid methyl ester (PCBM). The results of non-equilibrium MD simulations show a length-dependent thermal conductivity for C60 but not for PCBM. The thermal conductivity of C60, obtained from the linear extrapolation of inverse conductivity vs. inverse length curve, is 0.2 W m(-1) K(-1) at room temperature, while the thermal conductivity of PCBM saturates at ~0.075 W m(-1) K(-1) around 20 nm. The different length-dependence behavior of thermal conductivity indicates that the long-wavelength and low-frequency phonons have large contribution to the thermal conduction in C60. The decrease in thermal conductivity of fullerene derivatives can be attributed to the reduction in group velocities, the decrease of the frequency range of acoustic phonons, and the strong scattering of low frequency phonons with the alkyl chains due to the significant mismatch of vibrational density of states in low frequency regime between buckyball and alkyl chains in PCBM. PMID- 26238608 TI - Formation of social and household skills in children with hand defects. AB - PURPOSE: The aim of this study was to consider the peculiarities of forming social and household skills, and the criteria for their evaluation, as well as an assessment of functional capacity, in children with hand defects both before and after surgical treatment and rehabilitation courses using a system of games. METHODS: We elaborated and implemented a program of social rehabilitation of preschool children with congenital and acquired hand defects for the development of their functional capabilities and the formation of social and household skills after surgical treatment and prosthetics using play therapy methods. As part of this work, 140 preschool children aged 3-7 years underwent social rehabilitation. Most of the children had congenital hand defects-122 children (87 %): 96 children (79 %) with ectrodactylia, adactylia, hypoplasia, aplasia, hand splitting, club hand, or partial gigantism; 26 children (21 %) with congenital syndactylism and constricted bonds and 18 children (13 %) with acquired defects (burn deformity, amputation). 110 children (79 %) had reached the stage of surgical correction; 30 children (21 %) reached the stage of prosthetics. Most of the children participating in the experiment (78 children, 56 %) had defects of fingers on one hand. The program aimed at solving specific rehabilitation tasks: formation and improvement of all possible types of grip under the existing defect including those after surgery and prosthetics; development of tactile sensations in fingers; development of fine motor skills; increase in range of motion in all joints of the damaged hand; development of attention and concentration; formation of social and household skills appropriate to age; and development of the ability to achieve the set task. RESULTS: Analysis of the level of social and household skills of children with hand defects undergoing rehabilitation treatment at the hospital depending on the age prior to medical and social rehabilitation showed that preschool children with hand defects in the age category of 3 years demonstrated the highest results in the level of social and household skills (31 %) as compared with children in other age categories. The indicators for children aged 4 and 5 years were slightly lower, 25 and 26 %, respectively. The lowest values were recorded among children aged 6: 20 %. CONCLUSION: Statistically significant parameters of the level of functional capacity of hand grip and social and household skills in children with hand defects obtained in the course of the investigation indicated that the use of play therapy measures significantly increased the effect of medical treatment irrespective of the type of defect. These data indicate that play therapy measures given immediately after surgery or prosthetics can significantly increase the efficiency of rehabilitation even in its early stages. PMID- 26238609 TI - Island nail flap in the treatment of foot macrodactyly of the first ray in children: report of two cases. AB - PURPOSE: We evaluated the result of a combined single-stage surgery in the treatment of first ray macrodactyly in children. INTRODUCTION: Macrodactyly is a rare congenital abnormality that involves thickening of both the soft tissue and bone of the affected digits. It is more frequent in fingers than toes, where there is less neural involvement. Increased growth is also seen in neurofibromatosis, hemangiomatosis, arteriovenous malformations, congenital lymphedema, and syndromes such as Klippel-Trenaunay-Weber syndrome and Proteus syndrome. The goal of treatment is to obtain a pain-free, functional foot that can accommodate normal shoes. Treatment of macrodactyly of the first ray generates numerous difficulties since ray resection, which has been recommended for other toes as a means to of shortening and narrowing the foot, cannot be performed. In addition to this, cosmetic results are better if the nail is preserved. METHODS: We retrospectively reviewed our cases of first ray macrodactyly treated by a single-stage multiple-technique procedure. RESULTS: We obtained satisfactory results, in that same-sized shoes could be worn on by our patients and patients and family were happy with the outcome. However, one of our cases patients lost the nail 10 months postoperatively. CONCLUSIONS: We believe that island-nail transfer in children obtains excellent results. PMID- 26238610 TI - Risk factors for complications and readmission after operative fixation of pediatric femur fractures. AB - PURPOSE: Operative fixation of pediatric femur fractures with intramedullary implants has grown in popularity in recent decades. However, risk factors for short-term adverse events and readmission have not been well studied. METHODS: Pediatric patients who underwent intramedullary nailing of a femur fracture between 2012 and 2013 were identified from the American College of Surgeons National Surgical Quality Improvement Program database. Risk factors for any adverse event (AAE) and readmission after intramedullary nailing were evaluated using univariate and multivariate analysis. RESULTS: A total of 522 pediatric patients who underwent intramedullary nailing of the femur during the study period were identified. The mean age of this patient cohort was 10.2 +/- 3.8 years. Review of the cases revealed that 18 (3.4 %) patients had AAE and that 20 (3.8 %) patients were readmitted, of whom 13 (2.5 %) underwent a reoperation. Independent risk factors for AAE were a cardiac comorbidity [odds ratio (OR) 12.7, 95 % confidence interval (CI) 1.5, 103.7], open fracture (OR 10.2, 95 % CI 1.4, 74.4), and prolonged operative time (OR 17.5, 95 % CI 6.1, 50.5). Independent risk factors for readmission were a central nervous system disorder (OR 4.5, 95 % CI 1.3, 16.2) and a seizure disorder (OR 4.9, 95 % CI 1.0, 23.5). CONCLUSIONS: The results of the multivariate analysis suggest that cardiac comorbidities, open fractures, and prolonged operative time increase the risk for AAE and that central nervous system disorders and seizure disorders may increase the risk for readmission. Surgeons should be aware of these risk factors and counsel the families of pediatric patients who undergo intramedullary nailing of femur fractures. PMID- 26238611 TI - Facing challenges in an ageing world. PMID- 26238612 TI - Novel quinazoline derivatives exhibit antitumor activity by inhibiting JAK2/STAT3. AB - Quinazoline core-containing compounds such as gefitinib and erlotinib constitute an important group of antitumor drugs that act as receptor tyrosine kinase inhibitors against epidermal growth factor receptor (EGFR) kinase activity. We investigated a group of recently prepared 2-alkyl-substituted quinazolines (2 ASQs) for their antitumor activity against non-small cell lung carcinoma (NSCLC) cells. The compounds showed antitumor activity against A549, H1299, and H460 cells by induction of apoptosis. The IC50 values for (E)-2-propyl-4 styrylquinazoline (compound #4) and (E)-2-cyclopropyl-4-styrylquinazoline (compound #7) against these cell lines were 2-5 times lower than that of gefitinib. Unlike gefitinib that blocks EGFR phosphorylation, these compounds showed no activity against EGFR activation. Instead, the compounds suppressed both constitutive and IL-6-induced activation of JAK2/STAT3 phosphorylation and downstream gene expression. Transient expression of a constitutively active mutant of STAT3 reversed the pro-apoptotic effect of compound #7. Using a nude mouse model bearing A549 xenografts, we showed that administration of #7 at 15 and 30 mg/kg suppressed tumor growth. The present study therefore demonstrated that 2-alkyl substituted quinazolines target the JAK2/STAT3 pathway for their antitumor activity. PMID- 26238613 TI - Elastic large muscular vessel wall engineered with bone marrow-derived cells under pulsatile stimulation in a bioreactor. AB - Bone marrow-derived cells (BMCs) have demonstrated their ability to differentiate into multiple cell lineages and may be a promising cell source for vascular tissue engineering. Although much progress has been made in the engineering of small blood vessels (<6 mm in diameter) with biodegradable materials such as polyglycolic acid (PGA), it remains a challenge to engineer large vessels (>6 mm in diameter) due to unsatisfactory biomechanical properties. The present study was to engineered an elastic large vessel wall (6 mm in diameter) using a PGA unwoven fibre scaffold covered with BMCs from canine humeri. The cell-PGA sheet was then loaded into a bioreactor designed for the present study, with dynamic pulsatile culture conditions to mimic the physiological vessel environment. After four weeks of the pulsatile stimuli culture, an elastic vessel wall was formed. Histological analyses demonstrated that layers of smooth muscle-like cells and well-oriented collagenous fibres were evenly oriented in the dynamic group. By contrast, disorganised cells and randomly collagenous fibres were apparent in the static group. Furthermore, the engineered vessel wall in the dynamic group exhibited significantly improved biomechanical properties compared with those in static culture group. The approach developed in the present study was demonstrated to have promising potential to be used for the engineering of large vessel as well as other smooth muscle cell-containing tissues, including bladder, urethral and intestinal tissues. PMID- 26238614 TI - PROTEOMICS - Clinical Applications Reviews 2009. PMID- 26238615 TI - Protein microarrays as an application for disease biomarkers. AB - Protein microarrays are an increasingly powerful technology in the hunt for new and novel diagnostic and prognostic biomarkers. Lending credit to the highly established DNA microarray, protein microarrays are versatile tools that utilize a variety of formats to facilitate the discovery of new biomarkers and our understanding of disease pathways. The aims of this review are: to detail a variety of protein microarray technologies currently used, including forward phase technologies and reverse-phase technologies useful in both the discovery and validation of candidate biomarkers; to explore the strengths and weaknesses of various proteomic microarray platforms; to explain how bioinformatics helps compare data between microarray data sets; and to discuss the downstream applications of such technologies as they relate to the development of a highly personalized approach to medicine. PMID- 26238616 TI - Two-dimensional gel electrophoresis and mass spectrometry for biomarker discovery. AB - The proteome project, initiated in 1995, was made possible by 2-DE combined with MS. The project main objective was and remains the identification of all proteins expressed by a cell, tissue or organism in a given time and condition. Following this objective, the global profiling of proteins in health versus pathological state by the 2-DE/MS-based proteomic approach has contributed to the elucidation of the basic mechanisms of disease by discovering candidate disease biomarkers and disease targets for new drug development. This review will briefly summarize the historical evolution of 2-DE up to today, and review 2-DE/MS technology and its specific methods of study of immunoresponse (immunoproteomics), PTM of proteins, complex protein-protein interactions (interactome), the proteome of cell membrane and intracellular proteome turnover in disease biomarker discovery. PMID- 26238617 TI - Sources of error and its control in studies on the diagnostic accuracy of " omics" technologies. AB - Analyses of errors in diagnostic studies have led to improvements in the methodological quality of traditional laboratory research. However, since features of genomics and proteomics research ("-omics") differ from those of traditional research, sources of error are also likely to be distinct. We examine the main sources of error that are particularly relevant to "-omics"-based diagnostic techniques through the analysis of primary research papers which address these potential errors, their solutions, and the resulting spurious effect on diagnostic accuracy prediction. The main sources of error described in "-omics"-based research are mainly associated with chance: overfitting and inadequate sample size; variation: preanalytical variation (specimen collection and management), analytical variation (test procedures and reproducibility) and biological variation. We conclude that "-omics"-based research is prone to several errors. We have characterized them and shown the range of available solutions. This is a key step in the application of genomic discoveries to clinical and public health practice. PMID- 26238618 TI - Proteomics in gastric cancer research: Benefits and challenges. AB - Among various cancers, gastric cancer (GC) exhibits relatively high morbidity and mortality rate worldwide. The lack of effective methods in early detection and diagnosis, and immediate therapies makes treating such disease a challenge for both clinicians and oncologists. Proteomics has emerged as a promising technology platform for rationally identifying biomarkers and novel therapeutic targets for GC, as well as discovering underlying mechanisms of carcinogenesis. Its application has greatly benefited mechanistic studies of this disease. This review will demonstrate the applications of proteomic technology in GC research. The advantages and shortcomings of this technology, as reflected by current studies, will also be discussed to improve and expand its application in the field of cancer research. PMID- 26238619 TI - Prostate cancer proteomics: The urgent need for clinically validated biomarkers. AB - Prostate cancer (PCa) is the most common cancer diagnosis and the second most common cause of cancer-related deaths in men. Currently, serum prostate-specific antigen (PSA) is the only biomarker widely used in the diagnosis and management of patients with PCa. However, PSA lacks diagnostic sensitivity and specificity, leading to false-negative and false-positive test results. PSA cannot distinguish indolent from aggressive disease, leading to many patients being over-treated with associated side-effects. Furthermore, PSA is unable to identify which tumors are likely to become unresponsive to treatment at an early stage. Thus, there is an urgent need for clinically validated biomarkers which will improve the diagnosis and management of PCa. Given the heterogeneity of PCa it is likely that a panel of biomarkers will be required. In the quest for PCa biomarkers, a wide range of samples including urine, serum, tissues, and cell lines have been studied using proteomic approaches such as 2-DE, SELDI-TOF, SILAC, ICAT, iTRAQ, and MALDI-IMS. The value of these technologies, and other emerging platforms such as selected reaction monitoring (SRM) and multiple reaction monitoring (MRM), are discussed in the context of biomarker discovery, validation and addressing the "bottle-necks" that exist prior to clinical translation. PMID- 26238620 TI - Novel biomarkers of atherosclerosis and cardiovascular risk in autoimmune diseases: Genomics and proteomics approaches. AB - Atherosclerosis (AT) and cardiovascular disease (CVD) are enhanced in autoimmune diseases such as antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). The reason for this accelerated process is still debatable and, although traditional risk factors are more prevalent in those patients than in general population, they do not fully explain that enhanced risk. Inflammatory components of the immune response, mainly interleukins, TNF-alpha, and IFN-gamma, as well as some autoantibodies, including anti-oxidized low density lipoproteins (anti-oxLDL), anti-beta-2-Glycoprotein 1 (anti- beta2GPI), anti-Heat shock proteins 60/65 (anti-HSP60/65), and anti oxLDL/beta2GPI have been shown to play a leading role in the pathogenesis of both, AT and CVD. However, the role of the autoantibodies in accelerated AT in autoimmune disease patients is still controversial. Recently, DNA microarray and proteomic-based approaches have made substantial breakthrough into the study of various rheumatic diseases, thus allowing for the discovery of previously unknown proteins involved in CVD including some that may be suitable to be used as biomarkers. Herein, we review recent genomics and proteomic approaches that have been applied to the study of autoimmune diseases with atherosclerotic and CV risk. The pharmacogenomics and pharmacoproteomics studies given over to the analysis of ancient and new drugs used to relieve the physiopathology associated to these complex diseases are also discussed. PMID- 26238621 TI - Proteomics: New insights into rheumatic diseases. AB - Tremendous advances undergone in electrophoresis, chromatography, and MS have led proteomic research to unprecedented achievement over the last decade. Proteomics is presently employed for assessing protein expression levels, for monitoring cellular activities and for determination of biochemical pathways, revolutionizing the way we study disease by opening up the possibility to decipher the pathogenesis of clinical manifestations. Over 200 disorders including osteoarthritis (OA), rheumatoid arthritis (RA), and osteoporosis are considered rheumatic diseases (RDs), which affect the musculoskeletal system (joints and other supporting structures of the body such as muscles, tendons, ligaments, and bones) and are a leading cause of disability among older adults. Despite that an autoimmune origin has been proposed for some RDs like RA, the pathogenesis of most of these diseases is still unclear. Therefore, proteomic research on RDs, notably OA and RA, can help clarify underlying disease mechanisms, develop biomarkers to improve early detection, measure response to treatment, and devise new therapies. Achievements in the field of proteomics research on RDs are summarized in this work. PMID- 26238622 TI - Modern strategies to identify new molecular targets for the treatment of liver diseases: The promising role of Proteomics and Redox Proteomics investigations. AB - Oxidative stress, due to an imbalance between the generation of ROS and the antioxidant defense capacity of the cell, is a major pathogenetic event occurring in several liver diseases, ranging from metabolic to proliferative. Main sources of ROS are represented by mitochondria and cytochrome P450 enzymes in the hepatocytes, Kuppfer cells, and neutrophils. Oxidative stress affects major cellular components including lipids, DNA, and proteins. Through modulation of protein structure/function, ROS can influence gene expression profile by affecting intracellular signal transduction pathways. While several enzymatic and nonenzymatic markers of chronic oxidative stress are well known in liver, early protein targets of oxidative injury are yet poorly defined. Identification of these biomarkers will enable early detection of liver diseases and will allow monitoring the degree of liver damage, the response to pharmacological therapies, and the development of new therapeutic approaches. In the era of molecular medicine, new proteomic methodologies promise to establish a relationship between pathological hallmarks of the disease and protein structural/functional modifications, thus allowing a better understanding and a more rational therapy on liver disorders. Purpose of this review is to critically analyze the application of proteomic and redox proteomic approaches to the study of oxidative stress-linked liver diseases. PMID- 26238623 TI - Proteomics in obesity research. AB - Obesity has emerged as one of the major global epidemics of the 21st century and is now reaching alarming proportions. Obese subjects have an increased morbidity and mortality, decreased quality of life and a major risk of developing pathologies such as diabetes mellitus, insulin resistance and cardiovascular disease. Obesity is a complex disease characterised by an increase in body fat mass resulting from an imbalance between energy intake and expenditure. Signal integration between adipose tissue, other peripheral organs and the CNS seems to regulate energy homeostasis. Proteomics may be useful in unravelling the pathogenesis of obesity, since a combination of genetic predisposition and environmental factors account for its development. Most of the proteomic studies performed to date have focused on protein profiling of adipose tissue in different models of experimental obesity and the study of the adipocyte differentiation process. Another issue that has recently attracted attention is the characterisation of the adipocyte secretome, which may be important in signalling to other organs and in regulating energy balance. Target identification of potential therapies has also been investigated by proteomics. This review focuses on the contributions of proteomics to understanding the molecular mechanisms of obesity and their potential therapies. PMID- 26238624 TI - Post-translational modifications of orphan nuclear receptor TR2 - new insights into drug targets for stem cell therapy and the effect of retinoic acid. AB - Testicular receptor 2 (TR2) belongs to the nuclear receptor superfamily that constitutes one of the largest transcription factor families. Due to the lack of specific ligands for TR2 and because TR2 gene knockout mice exhibited no apparent pathological phenotypes in laboratories, it has been a challenge to pursue studies of this mysterious nuclear receptor. Recently, using gene knockdown approaches, we were able to detect its specific biological activity, primarily, in the maintenance of proliferation potential of embryonic stem cells. Further, with proteomic approaches, we have uncovered extensive PTMs of TR2. Specific PTMs of TR2 could differentially regulate its biological activity mediated by multiple signaling pathways including one elicited by the nongenomic action of retinoic acid. These PTMs are involved in TR2 activation, repression, DNA-binding, protein stability, and subcellular distribution. The confirmed PTMs that have a functional consequence on the activity/property of TR2 include phosphorylation, ubiquitination, and SUMOylation. This review summarizes the effects of PTMs, as well as their signaling pathways, on TR2 receptor protein stability, recruitment of coregulators, and subcellular partition, and discusses the potential of developing therapeutics targeting at the regulatory components of stem/precursor cells. PMID- 26238625 TI - Photodynamic therapy in colorectal cancer treatment--The state of the art in preclinical research. AB - BACKGROUND: Photodynamic therapy (PDT) is used in many different oncologic fields. Also in gastroenterology, where have been a few attempts to treat both the premalignant lesion and advanced colorectal cancer (CRC). This review aims to give a general overview of preclinical photodynamic studies related to CRC cells and animal studies of photodynamic effects related to CRC treatment to emphasize their potential in study of PDT mechanism, safety and efficiency to translate these results into clinical benefit in CRC treatment. MATERIALS AND METHOD: Literature on in vitro preclinical photodynamic studies related to CRC cells and animal studies of photodynamic effects related to CRC treatment with the fallowing medical subject headings search terms: colorectal cancer, photodynamic therapy, photosensitizer(s), in vitro, cell culture(s), in vivo, animal experiment(s). The articles were selected by their relevance to the topic. RESULTS: The majority of preclinical studies concerning possibility of PDT application in colon and rectal cancer is focused on phototoxic action of photosensitizers toward cultured colorectal tumor cells in vitro. The purposes of animal experiments are usually elucidation of mechanisms of observed photodynamic effects in scale of organism, estimation of PDT safety and efficiency and translation of these results into clinical benefit. CONCLUDING REMARKS: In vitro photodynamic studies and animal experiments can be useful for studies of mechanisms and efficiency of photodynamic method as a start point on PDT clinical research. The primary disadvantage of in vitro experiments is a risk of over interpretation of their results during extrapolation to the entire CRC. PMID- 26238626 TI - The Importance of the Lateral Prefrontal Cortex for Strategic Decision Making in the Prisoner's Dilemma. AB - Previous functional imaging studies investigating the neural basis of strategic decision making in the prisoner's dilemma reported a correlation between cooperative behavior and dorsolateral prefrontal cortex (DLPFC) activity; however, the precise function of the DLPFC in establishing cooperation remains unclear so far. The present study investigated the causal role of the DLPFC in an iterative prisoner's dilemma game with transcranial magnetic stimulation (TMS). We discovered that disrupting the DLPFC with TMS decreased cooperation rates in comparison to control conditions, with this effect being most pronounced when the partner had defected previously. Thus, the current results suggest that the DLPFC contributes to strategic decision making in the prisoner's dilemma game. PMID- 26238627 TI - Epithelioid Glioblastomas and Anaplastic Epithelioid Pleomorphic Xanthoastrocytomas--Same Entity or First Cousins? AB - Epithelioid glioblastoma (eGBM) and pleomorphic xanthoastrocytoma (PXA) with anaplastically transformed foci (ePXA) show overlapping features. Eleven eGBMs and 5 ePXAs were reviewed and studied immunohistochemically. Fluorescence in situ hybridization for EGFR amplification, PTEN deletion and ODZ3 deletion was also performed, with Ilumina 450 methylome analysis obtained in five cases. The average age for eGBM was 30.9 (range 2-79) years, including five pediatric cases and a M : F ratio of 4.5. The ePXA patients had a M : F ratio of 4 and averaged 21.2 (range 10-38) years in age, including two pediatric cases. Six eGBMs and two ePXAs recurred (median recurrence interval of 12 and 3.3 months, respectively). All tumors were composed of solid sheets of loosely cohesive, "melanoma-like" cells with only limited infiltration. ePXAs showed lower grade foci with classic features of PXA. Both tumor types showed focal expression of epithelial and glial markers, retained INI1 and BRG1 expression, occasional CD34 positivity, and lack of mutant IDH1 (R132H) immunoreactivity. BRAF V600E mutation was present in four eGBMs and four ePXAs. ODZ3 deletion was detected in seven eGBMs and two ePXAs. EGFR amplification was absent. Methylome analysis showed that one ePXA and one eGBM clustered with PXAs, one eGBM clustered with low-grade gliomas, and two eGBMs clustered with pediatric-type glioblastomas. Common histologic, immunohistochemical, molecular and clinical features found in eGBM and ePXA suggest that they are closely related or the same entity. If the latter is true, the nomenclature and WHO grading remains to be resolved. PMID- 26238628 TI - Towards a better understanding of the relationship between side effects of analgesia and quality of life in patients with multiple myeloma. PMID- 26238629 TI - Contrast-induced nephropathy in patients with active cancer undergoing contrast enhanced computed tomography. AB - PURPOSE: This study was performed to measure the incidence and identify potential predictors of contrast-induced nephropathy (CIN) in cancer patients without chronic kidney disease and with normal or near-normal baseline serum creatinine measures who underwent contrast-enhanced computed tomography (CECT). Severity of CIN was reported based on the RIFLE (risk, injury, failure, loss of kidney function, and end-stage renal disease) classification of acute kidney injury. METHODS: A retrospective analysis was performed on 820 cancer patients who presented at our emergency department from October 2014 to March 2015. CIN was defined as an increase in creatinine concentration of >=0.5 mg/dL or >=25 % above baseline that occurred 48 to 72 h after CECT. RESULTS: The incidence of CIN was 8.0%. Serial CT examination [odds ratio (OR) 4.09; 95% confidence interval (CI) 1.34-12.56], hypotension before the CT scan (OR 3.95; 95% CI 1.77-8.83), liver cirrhosis (OR 2.82; 95% CI 1.06-7.55), BUN/creatinine >20 (OR 2.54; 95% CI 1.44 4.46), and peritoneal carcinomatosis (OR 1.75; 95% CI 1.01-3.00) were independently associated with CIN. Of 66 CIN patients, 44 met any of the severity criteria of the RIFLE classification. Five of these patients died during hospitalization but only one death was related to renal failure. CONCLUSIONS: Even when the baseline serum creatinine is <=1.5 mg/dL, a significant portion of cancer patients are still at risk of CIN. Consecutive CECT examinations, hypotension before CT, liver cirrhosis, dehydration, and peritoneal carcinomatosis seem to predispose patients to CIN. PMID- 26238630 TI - Chondrogenic differentiation of bone marrow-derived stem cells cultured in the supernatant of elastic cartilage cells. AB - Repair of cartilage defects remains a challenge for surgeons, owing to its poor self-repairing capacity. Cartilage tissue engineering, particularly marrow stem cell-based cartilage regeneration, provides a promising option for the regeneration of damaged cartilage. Although producing tissue-engineered cartilage from marrow stem cells appeared to be a feasible method, constructing certain sub types of cartilage, including elastic cartilage, remains difficult. Therefore, the present study explored the feasibility of constructing elastic cartilage by culturing bone marrow-derived stem cells (BMSCs) in the supernatant of elastic cartilage cells to generate elastic cartilage. The elastic cartilage cells were obtained from the auricle cartilage of a newborn pig, and BMSCs were isolated from pig bone marrow aspirate. The supernatant of the chondrocytes was collected and then used to the culture BMSCs. At various time-points, the differentiation of BMSCs was evaluated by gross view, histological examination and quantitative polymerase chain reaction. BMSCs changed from spindle-shaped cells into polygonal cells with increasing culture time. The expression of collagen II and elastin was observed in the cells cultured in the supernatant of elastic chondrocytes, while no expression was observed in the control cells. Furthermore, the expression of collagen I and collagen X was downregulated in the cells cultured in the supernatant of elastic cartilage cells. The supernatant of elastic cartilage cells promoted the differentiation of BMSCs into elastic cartilage cells, which may be a promising method for constructing certain sub-types of tissue-engineered cartilage. PMID- 26238632 TI - Tyrosylprotein sulfotransferase 1 expression is negatively correlated with c-Met and lymph node metastasis in human lung cancer. AB - The present study aimed to test the expression of tyrosylprotein sulfotransferase 1 (TPST-1) in human lung cancer and to analyze the correlation with clinicopathologic features and c-Met expression levels. Expression levels of TPST 1 and c-Met were analyzed by immunohistochemistry in 50 lung cancer tissues. Non neoplastic tissues 5 cm from the cancer tissues were collected as controls. The association between TPST-1 and c-Met expression and TPST-1 and clinicopathologic parameters was then analyzed. TPST-1 was expressed in all normal tissue samples, but only in 60% of lung cancer tissues. In tumor tissues, they appeared to be significantly lower than those in matched control lung tissues. The expression of TPST-1 was significantly correlated with the tumor-node-metastasis (TNM) stage and lymph node metastasis and was significantly inversely associated with c-Met expression. In conclusion, the present study demonstrated that TPST-1 expression was associated with the TNM stage and lymph node metastasis in patients with lung cancer. TPST-1 was significantly negatively correlated with the expression of c Met in lung cancer and may be a negative prognostic biomarker of lung cancer. PMID- 26238633 TI - Advances in Prevention and Treatment of Chronic Obstructive Pulmonary Disease. PMID- 26238631 TI - PEA3 transcription factors are downstream effectors of Met signaling involved in migration and invasiveness of Met-addicted tumor cells. AB - Various solid tumors including lung or gastric carcinomas display aberrant activation of the Met receptor which correlates with aggressive phenotypes and poor prognosis. Although downstream signaling of Met is well described, its integration at the transcriptional level is poorly understood. We demonstrate here that in cancer cells harboring met gene amplification, inhibition of Met activity with tyrosine kinase inhibitors or specific siRNA drastically decreased expression of ETV1, ETV4 and ETV5, three transcription factors constituting the PEA3 subgroup of the ETS family, while expression of the other members of the family were less or not affected. Similar link between Met activity and PEA3 factors expression was found in lung cancer cells displaying resistance to EGFR targeted therapy involving met gene amplification. Using silencing experiments, we demonstrate that the PEA3 factors are required for efficient migration and invasion mediated by Met, while other biological responses such as proliferation or unanchored growth remain unaffected. PEA3 overexpression or silencing revealed that they participated in the regulation of the MMP2 target gene involved in extracellular matrix remodeling. Our results demonstrated that PEA3-subgroup transcription factors are key players of the Met signaling integration involved in regulation of migration and invasiveness. PMID- 26238634 TI - Epidemiology of Chronic Obstructive Pulmonary Disease: Prevalence, Morbidity, Mortality, and Risk Factors. AB - Chronic obstructive pulmonary disease (COPD) remains a common and important cause of morbidity and mortality both in the United States and globally. The increasing trends of COPD prevalence, morbidity, and mortality seen in the later part of last century have not continued in the United States. COPD prevalence, hospitalizations, and deaths have remained stable or are decreasing over the last decade. This is likely a function of the overall decreasing prevalence of tobacco use over the past 50 years, along with improved therapies for COPD. Future trends in COPD will probably be driven by factors in addition to tobacco use, such as longer survival in the population, other occupational and environmental exposures, and the increasing prevalence of asthma. Globally, factors such as air pollution and chronic respiratory infections, such as tuberculosis, will remain important predictors of future trends. PMID- 26238635 TI - Treatment of Alpha-1 Antitrypsin Deficiency. AB - Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disease that creates multiple unique phenotypes of chronic obstructive pulmonary disease. While bronchospasm, cough, dyspnea, and sputum production all occur with AATD, the phenotypic differences require a computed tomographic (CT) scan to decipher. The availability of augmentation therapy in the United States since 1989 has generated both controversy and evidence that informs the science of usual chronic obstructive pulmonary disease (COPD). Because of the predominance of emphysema in AATD, much of the best evidence concerning biomarkers of emphysema progression comes from this population. Imaging measurement of emphysema progression, impact of emphysema phenotypes on hyperinflation and dynamic hyperinflation, and correlation with traditional spirometric measures of COPD progression are required to understand the impact of AAT therapies. These studies are important for better understanding of usual COPD pathogenesis. Significantly, there are no adequately powered research studies to determine if augmentation therapy is helpful for the non-emphysema phenotypes of AATD. Specifically, phenotypes of chronic bronchitis, asthma predominant disease, and bronchiectasis will require targeted research studies to define optimal therapy. PMID- 26238636 TI - The Promise of Observational Studies (ECLIPSE, SPIROMICS, and COPDGene) in Achieving the Goal of Personalized Treatment of Chronic Obstructive Pulmonary Disease. AB - Personalized medicine is based on the concept that individuals differ from one another. Chronic obstructive pulmonary disease (COPD) is particularly in need of a personalized medicine strategy. However, while the COPD population is characterized by a marked degree of heterogeneity at the etiologic, mechanistic, physiologic, and clinical levels, efforts to cluster COPD patients into meaningful groups that can guide therapy have been limited. Three large observational studies-the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE), the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS), and COPDGene-are underway and/or being analyzed. These studies have accumulated a uniquely rich set of clinical and biological data on relatively large cohorts of patients who have already influenced the way in which COPD is viewed. These studies have great potential to advance understanding of COPD so that the goal of personalized treatment can be pursued. PMID- 26238637 TI - Smoking Cessation in Chronic Obstructive Pulmonary Disease. AB - Smoking cessation is the most effective strategy for slowing down the progression of chronic obstructive pulmonary disease (COPD) and reducing mortality in the approximately 50% of patients with diagnosed COPD who continue to smoke. While behavioral interventions (including simple advice) have modest efficacy in improving smoking quit rates, the combination of counseling and pharmacotherapy is more effective than either alone. When combined with even brief counseling, nicotine replacement therapy (NRT), bupropion SR, and varenicline have all been shown to be effective in promoting smoking cessation and sustained abstinence in smokers with COPD to a degree comparable to that observed in the general smoking population. However, the recidivism rate is high after initial quitting so that at the end of 1 year, approximately 80% or more of patients are still smoking. Thus, new approaches to smoking cessation are needed. One approach is to combine different pharmacotherapies, for example, nicotine patch plus rapidly acting NRT (e.g., gum or nasal spray) and/or bupropion or even varenicline plus either NRT or bupropion, in a stepwise approach over a varying duration depending on the severity of nicotine dependence and nicotine withdrawal symptoms during the quit attempt, as proposed in the American College of Chest Physicians Tobacco Dependence Took Kit. Electronic (e)-cigarettes, which deliver vaporized nicotine without most of the noxious components in the smoke from burning tobacco cigarettes, also has potential efficacy as a smoking cessation aid, but their efficacy and safety as either substitutes for regular cigarettes or smoking cessation aids require additional study. This task is complicated because e cigarettes are currently unregulated and hundreds of different brands are currently available. PMID- 26238638 TI - Identifying Molecular Targets for New Drug Development for Chronic Obstructive Pulmonary Disease: What Does the Future Hold? AB - There is an urgent need to develop more effective therapies for chronic obstructive pulmonary disease (COPD) that target the underlying inflammatory disease process. Current therapies with long-acting bronchodilators and inhaled corticosteroids fail to prevent either disease progression or mortality, as they do not suppress the underlying inflammation. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several new therapeutic targets have been identified. Several mediator antagonists or inhibitors tested in COPD have so far been disappointing. Broad-spectrum anti inflammatory drugs may be more effective, and include inhibitors of the proinflammatory enzymes phosphodiesterase-4, p38 mitogen-activated protein kinase, Janus-activated kinases, NF-kappaB kinase, and PI3kinase-gamma and delta, but side effects after oral administration are a major limitation; therefore, in future inhaled delivery may be necessary. A new promising approach is reversal of corticosteroid resistance through increasing histone deacetylase-2 activity. This might be achieved by existing treatments such as theophylline, nortriptyline, and macrolides, or more selectively by PI3kinase-delta inhibitors. Other treatments in development target oxidative stress, the failure to resolve inflammation, aberrant repair mechanisms, and accelerated lung aging. PMID- 26238639 TI - New Pharmacotherapeutic Approaches for Chronic Obstructive Pulmonary Disease. AB - The last 5 years have seen a proliferation of data about the best way to treat chronic obstructive pulmonary disease (COPD). New long-acting inhaled beta agonist and antimuscarinic drugs have been developed as a once-daily inhaled corticosteroid. Studies have tested whether these agents are safe and effective alone or in combination. Alternative strategies to treatment including phosphodiesterase-4 inhibition and long-term antibiotic treatment have become reasonable alternatives to more established approaches, at least in terms of preventing COPD exacerbations. New data are beginning to define which patients benefit from which treatments and this will help us develop more appropriate treatment regimes. These topics are considered in this review which provides an overview of the latest data and some direction as to how these findings can be applied in practice. PMID- 26238640 TI - Novel Aerosol Delivery Devices. AB - Delivery of medication to sites of action through airways has been used for centuries but has gained momentum in recent decades. Currently available modes of aerosol delivery offer advantages but still there are shortcomings. Delivery of active agents to sites of action is affected by many factors beyond the characteristics of the delivery devices, including the coordination between inhalation and actuation and dependence on the patient's inspiratory flow and breathing pattern. Recent advances in drug delivery focus around changes in the generation of particle size with better penetration to the targeted sites, easier activation of the device with inspiratory flow, ease of use including fewer steps in using the device, and better portability. Availability of computer chips allows for smart delivery devices to tailor delivery to the patient's breathing pattern and lung function. Further, smart devices can provide feedback to patients. Novel inhaler technologies, separately or in combination with new therapeutic agents, are in development not only for respiratory diseases but also for diseases of other systems. This article reviews some of the recent clinically relevant advances in aerosol delivery devices. PMID- 26238641 TI - Supplemental Oxygen Therapy for Patients with Chronic Obstructive Pulmonary Disease. AB - Oxygen is necessary for aerobic metabolism. Since the human body cannot produce or store oxygen, a continuous and adequate delivery of oxygen needs to be secured by oxygen uptake from inhaled air via the respiratory system and oxygen delivery to body tissues via the circulation. Severely reduced lung function in advanced chronic obstructive pulmonary disease (COPD) may be a limiting factor for adequate oxygen uptake and patients with this disease may require supplemental oxygen therapy. While the methodology of oxygen delivery in home settings represents a continuously evolving field, oxygen therapy itself has been an integral part of the management of severely hypoxemic patients with COPD for more than 50 years despite the lack of full understanding of its effects and the relative paucity of clinical evidence supporting its use. In this article, we review the physiological effects and discuss the clinical benefits of oxygen therapy. We also evaluate the evidence supporting and arguing against its use in the published literature, discuss its risks and benefits, define criteria for prescribing oxygen therapy, and review methods of oxygen delivery in home settings. PMID- 26238642 TI - Chronic Obstructive Pulmonary Disease-Evolving Concepts in Treatment: Advances in Pulmonary Rehabilitation. AB - Over the past three decades, pulmonary rehabilitation has risen to the stature as a gold standard for the treatment of chronic obstructive pulmonary disease (COPD). This rise is owing to both the development of science explaining mechanisms underlying its effectiveness and the demonstration of its substantial benefits across multiple outcome areas of importance to patients. Arguably, pulmonary rehabilitation provides the greatest improvements of any therapy in the areas of dyspnea-relief, exercise performance, and functional and health status. Emerging science also indicates that it reduces subsequent health care utilization and-when administered in the perihospital period-mortality risk. These beneficial effects are realized despite the fact that pulmonary rehabilitation has virtually no direct effect on lung function in COPD. Instead, this comprehensive, patient-centered intervention reduces the negative effects from systemic morbidity (such as muscle wasting) and comorbidity (such as depression and anxiety) that frequently accompany COPD. Two major components of pulmonary rehabilitation are exercise training and behavioral interventions. An example of the latter is a collaborative action plan for the early recognition and prompt treatment of the COPD exacerbation. Innovation in pulmonary rehabilitation includes (1) expanding its applicability, such as demonstrating effectiveness in the non-COPD respiratory patient, in milder COPD, in the periexacerbation period, and its provision in the home and community settings; (2) improving its process, such as refining the self-management and behavioral interventions, and the promotion of physical activity in the home and community settings; and (3) promoting its accessibility, such as exploring its potential usefulness in nontraditional settings (the home and community) and developing technology to assist in its implementation. PMID- 26238644 TI - Surgical Approaches to Treating Emphysema: Lung Volume Reduction Surgery, Bullectomy, and Lung Transplantation. AB - Chronic obstructive pulmonary disease (COPD) is a common and morbid progressive disease where treatment is focused on improving dyspnea, reducing exacerbations, attenuating comorbidities, and improving quality of life. Surgical therapy can be beneficial to a carefully selected subset of individuals and is the subject of this review. The National Emphysema Treatment Trial (NETT) has not only demonstrated the efficacy of lung volume reduction surgery (LVRS) but has also provided many lessons regarding advanced emphysema. NETT demonstrated that LVRS improves exercise performance, quality of life, and pulmonary function in those with upper lobe predominant emphysema in the setting of advanced disease. Those with upper lobe predominant emphysema and low exercise tolerance also had a survival advantage compared with maximal medical therapy. Careful patient selection is paramount to success, as there clearly are patients in whom LVRS increases mortality. Giant bullae are rare, but bullectomy has been demonstrated to improve dyspnea and lung function in cases where the bulla occupies at least one-third of the hemithorax and compresses some adjacent lung tissue. For patients with chronic respiratory failure due to COPD who have not improved despite maximal surgical and medical therapy, lung transplantation remains an option in those without significant comorbid conditions. PMID- 26238645 TI - Novel Endoscopic Approaches to Treating Chronic Obstructive Pulmonary Disease and Emphysema. AB - Chronic obstructive pulmonary disease (COPD) is a widespread disease associated with high morbidity and mortality. The principal aim of therapy is preventing disease progression. Besides rehabilitation and pharmacological treatment, different endoscopic approaches were developed in the past decade extending the therapeutic spectrum. Various endoscopic lung volume reduction (ELVR) techniques are available that differ in the implementation, mechanism of action, complication spectrum, and reversibility. So far, the data on efficacy and safety are variable and still very limited. The most comprehensive data are available for endoscopic valve therapy. This reversible technique leads to lobar atelectasis and thus significant lobar volume reduction in patients with severe emphysema and low collateral ventilation. Implantation of coils leading to parenchymal compression and bronchoscopic thermal vapor ablation inducing an inflammatory reaction are nonblocking ELVR techniques and thus independent of collateral ventilation. Besides ELVR techniques, targeted lung denervation has evolved as the latest development in the field of endoscopic therapy in COPD. The aim of this endoscopic method is sustainable bronchodilation by minimizing the influence of parasympathetic pulmonary nerves on smooth muscles of the airways. This review summarizes the different endoscopic procedures, their mechanism of action, and the results of the clinical trials including efficacy and safety. PMID- 26238646 TI - The Role of Noninvasive Ventilation in the Hospital and Outpatient Management of Chronic Obstructive Pulmonary Disease. AB - Positive pressure noninvasive ventilation (NIV) has become widely accepted in the treatment of both hospitalized and outpatient subjects with chronic obstructive pulmonary disease (COPD). The support has evolved over the past two decades to be part of first-line management in acute exacerbations of COPD and is also instrumental in discontinuing mechanical ventilation in COPD patients with acute respiratory failure. It is also suitable for treatment of COPD with other associated conditions including pneumonia, following lung resectional surgery, with concomitant obstructive sleep apnea and as part of end-of-life care. Short term application can also facilitate some endoscopic procedures that may otherwise require endotracheal intubation. Outpatient use of NIV in COPD has garnered much attention, but the support has not been as robust as with NIV in hospitalized patients. However, an approach with higher pressures with a goal of significant reduction in daytime PaCO2 may be an effective strategy. NIV can also facilitate exercise training in pulmonary rehabilitation. A portable device which can augment tidal volume during ambulation and other activities of daily living may further expand the use of NIV in COPD patients. PMID- 26238647 TI - Comprehensive Self-Management Strategies. AB - In this article, we provide a review of the literature on self-management interventions and we are giving some thought to how, when, and by whom they should be offered to patients. The present literature based on randomized clinical trials has demonstrated benefits (reduced hospital admissions and improved health status) for chronic obstructive pulmonary disease (COPD) patients undergoing self-management interventions, although there are still problems with the heterogeneity among interventions, study populations, follow-up time, and outcome measures that make generalization difficult in real life. Key to the success, self-management intervention has to target behavior change. Proper self management support is a basic prerequisite, for example, techniques and skills used by health care providers "case manager" to instrument patients with the knowledge, confidence, and skills required to effectively self-manage their disease. To improve health behaviors and engagement in self-management, self management interventions need to target enhancing intrinsic motivation to change. This will best be done using client-centered communication (motivational communication) that encourages patients to express what intrinsically motivates them (e.g., consistent with their values or life goals) to adopt certain health behavior, with the goal of helping them overcome their ambivalence about change. Finally, if we want to be able to design and implement self-management interventions that are integrated, coherent, and have a strong likelihood of success, we need to take a more careful look and give more attention at the case manager, the patient (patient evaluation), and the quality assurance. PMID- 26238643 TI - Comorbidities and Chronic Obstructive Pulmonary Disease: Prevalence, Influence on Outcomes, and Management. AB - Comorbidities impact a large proportion of patients with chronic obstructive pulmonary disease (COPD), with over 80% of patients with COPD estimated to have at least one comorbid chronic condition. Guidelines for the treatment of COPD are just now incorporating comorbidities to their management recommendations of COPD, and it is becoming increasingly clear that multimorbidity as well as specific comorbidities have strong associations with mortality and clinical outcomes in COPD, including dyspnea, exercise capacity, quality of life, healthcare utilization, and exacerbation risk. Appropriately, there has been an increased focus upon describing the burden of comorbidity in the COPD population and incorporating this information into existing efforts to better understand the clinical and phenotypic heterogeneity of this group. In this article, we summarize existing knowledge about comorbidity burden and specific comorbidities in COPD, focusing on prevalence estimates, association with outcomes, and existing knowledge about treatment strategies. PMID- 26238648 TI - Associations between adult attachment and: oral health-related quality of life, oral health behaviour, and self-rated oral health. AB - PURPOSE: Although adult attachment theory has been revealed as a useful theoretical framework for understanding a range of health parameters, the associations between adult attachment patterns and a range of oral health parameters have not yet been examined. The aim of this study was to examine potential associations between attachment insecurity and: (1) oral health-related quality of life (OHRQoL), (2) oral health behaviours, and (3) self-rated oral health. In association with this aim, sample characteristics were compared with normative data. METHODS: The sample in this cross-sectional study was comprised of 265 healthy adults, recruited via convenience sampling. Data were collected on attachment patterns (Experiences in Close Relationships Scale-Short Form, ECR-S), OHRQoL (Oral Health Impact Profile-14, OHIP-14), oral health behaviours (modified Dental Neglect Scale, m-DNS), and self-rated oral health (one-item global rating of oral health). Multivariate regression models were performed. RESULTS: Both dimensions of attachment insecurity were associated with lowered use of favourable dental visiting behaviours, as well as decreased OHRQoL for both overall well-being and specific aspects of OHRQoL. Attachment avoidance was linked with diminished self-rated oral health. CONCLUSIONS: This study supports the potential value of an adult attachment framework for understanding a range of oral health parameters. The assessment of a client's attachment pattern may assist in the identification of people who are at risk of diminished OHRQoL, less adaptive dental visiting behaviours, or poorer oral health. Further research in this field may inform ways in which attachment approaches can enhance oral health related interventions. PMID- 26238649 TI - Quality-of-life measures as predictors of post-esophagectomy survival of patients with esophageal cancer. AB - PURPOSE: Improving survival after esophagectomy is an important issue in treating patients with esophageal cancer (EC). In addition to standard hospitalization management, periodic assessment of quality-of-life (QOL) measures may be useful to detect disease progression from patients' subjective reports. Therefore, this prospective longitudinal study was undertaken to identify prognostic factors for 3-year survival of EC patients after esophagectomy and to evaluate the impact of QOL measures on these prognostic factors. METHODS: Patients with EC (n = 67) who had a complete tumor resection and were alive 6 months after esophagectomy were followed in this study for 3 years. Data were collected on patients' sociodemographics, cancer characteristics, adjuvant therapy, general QOL and EC specific QOL (before esophagectomy and 6 months afterward), cancer recurrence, and death. Patients' independent risk factors for 3-year survival were investigated by multivariate Cox regression analysis. RESULTS: Of the 67 participants with EC, 26 had late mortality, with a median survival for the whole cohort of 38.2 months (95 % CI 31.97-44.35). Independent predictors of early death were early cancer recurrence (within 6 months after surgery), poor cognitive function (95 % CI 1.020-1.041), and worse dyspnea (95 % CI 1.007 1.034). CONCLUSIONS: The most predictive factor for early death in EC patients after esophagectomy was cancer recurrence within 6 months after surgery. However, QOL measures could be a tool to provide clinical information from patients' perspective suggesting cancer recurrence. PMID- 26238650 TI - DNA-hypomethylating agent, 5'-azacytidine, induces cyclooxygenase-2 expression via the PI3-kinase/Akt and extracellular signal-regulated kinase-1/2 pathways in human HT1080 fibrosarcoma cells. AB - The cytosine analogue 5'-azacytidine (5'-aza) induces DNA hypomethylation by inhibiting DNA methyltransferase. In clinical trials, 5'-aza is widely used in epigenetic anticancer treatments. Accumulated evidence shows that cyclooxygenase 2 (COX-2) is overexpressed in various cancers, indicating that it may play a critical role in carcinogenesis. However, few studies have been performed to explore the molecular mechanism underlying the increased COX-2 expression. Therefore, we tested the hypothesis that 5'-aza regulates COX-2 expression and prostaglandin E2 (PGE2) production. The human fibrosarcoma cell line HT1080, was treated with various concentrations of 5'-aza for different time periods. Protein expressions of COX-2, DNA (cytosine-5)-methyltransferase 1 (DNMT1), pAkt, Akt, extracellular signal-regulated kinase (ERK), and phosphorylated ERK (pERK) were determined using western blot analysis, and COX-2 mRNA expression was determined using RT-PCR. PGE2 production was evaluated using the PGE2 assay kit. The localization and expression of COX-2 were determined using immunofluorescence staining. Treatment with 5'-aza induces protein and mRNA expression of COX-2. We also observed that 5'-aza-induced COX-2 expression and PGE2 production were inhibited by S-adenosylmethionine (SAM), a methyl donor. Treatment with 5'-aza phosphorylates PI3-kinase/Akt and ERK-1/2; inhibition of these pathways by LY294002, an inhibitor of PI3-kinase/Akt, or PD98059, an inhibitor of ERK-1/2, respectively, prevents 5'-aza-induced COX-2 expression and PGE2 production. Overall, these observations indicate that the hypomethylating agent 5'-aza modulates COX-2 expression via the PI3-kinase/Akt and ERK-1/2 pathways in human HT1080 fibrosarcoma cells. PMID- 26238651 TI - Carbon monoxide as stunning/killing method on farmed Atlantic salmon (Salmo salar): effects on lipid and cholesterol oxidation. AB - BACKGROUND: Carbon monoxide (CO) has been recently utilized as a new stunning/killing procedure for Atlantic salmon (Salmo salar). Its effects on lipid and cholesterol oxidation of farmed Atlantic salmon fillets were evaluated at two times of refrigerated (2.5 degrees C) storage, T0 (64 h after death) and T14 (14 days from T0). The use of CO was compared with the commonly utilized percussion (P) method. RESULTS: Fatty acid profile, primary (conjugated dienes) and secondary (TBARS) oxidation products, cholesterol oxidation products (COPs) and carotenoids were unaffected by the killing method. Despite the low oxidative status of lipid (0.66 and 0.60 mg malondialdehyde kg(-1) muscle in P and CO fish respectively), cholesterol was found to be highly oxidized (0.17 and 0.13 mg COPs kg(-1) ). Storage significantly affected oxidative stability of fish muscle by increasing oxidation products. Interestingly, TBARS content doubled while the increase for COPs was not homogeneous: alpha- and beta-epoxycholesterol increased by 25%, whereas triol and 7-ketocholesterol increased by 48 and 62% respectively. CONCLUSION: The quality of salmon fillets just after slaughtering and after 14 days of refrigerated storage at 2.5 degrees C did not change, irrespective of the killing method adopted, suggesting that the CO method may be applied without any detrimental effect on the quality of fish fillets. (c) 2015 Society of Chemical Industry. PMID- 26238653 TI - Major complications of high-energy microwave ablation for percutaneous CT-guided treatment of lung malignancies: Single-centre experience after 4 years. AB - PURPOSE: To evaluate the rate of major complications related to percutaneous computed tomography (CT)-guided microwave ablation (MWA) of primary and secondary lung malignancies performed at our institution over a 4-year period. METHODS: From May 2010 to September 2014, 70 MWAs were performed on 51 patients. All major intra- and post-procedural complications (as defined by the classification proposed by the Society of Interventional Radiology) were retrospectively analysed. The results were correlated with a systematic review of the available literature on MWA in the lung. RESULTS: Major complications were encountered in 14 out of 70 ablations (20%). Twenty-one separate major complications were encountered (some ablations lead to more than one major complication). One death occurred within 30 days of ablation, though the relationship to the procedure remains uncertain. Other major complications included: nine pneumothoraces requiring drain insertion (12.9%), four cases of large effusion requiring drainage (5.7%), two cases of significant pulmonary haemorrhage altering clinical management (2.9%), two infections (2.9%), one case of mechanical failure (1.4%), one chest wall burn (1.4%) and one case of pleural seeding (1.4%). Major complications were much more likely to occur if the nodule was located within 7 mm from the pleura. CONCLUSION: MWA of pulmonary tumours carries moderate risk; nevertheless, the usually manageable complications should not deter from undertaking a potentially curative therapy for poor surgical candidates. PMID- 26238652 TI - CD59 mediates cartilage patterning during spontaneous tail regeneration. AB - The regeneration-competent adult animals have ability to regenerate their lost complex appendages with a near-perfect replica, owing to the positional identity acquired by the progenitor cells in the blastema, i.e. the blastemal cells. CD59, a CD59/Ly6 family member, has been identified as a regulator of positional identity in the tail blastemal cells of Gekko japonicus. To determine whether this function of CD59 is unique to the regenerative amniote(s) and how CD59 mediates PD axis patterning during tail regeneration, we examined its protective role on the complement-mediated cell lysis and intervened CD59 expression in the tail blastemal cells using an in vivo model of adenovirus transfection. Our data revealed that gecko CD59 was able to inhibit complement-mediated cell lysis. Meanwhile, CD59 functioned on positional identity through expression in cartilage precursor cells. Intervening positional identity by overexpression or siRNA knockdown of CD59 resulted in abnormal cartilaginous cone patterning due to the decreased differentiation of blastemal cells to cartilage precursor cells. The cartilage formation-related genes were found to be under the regulation of CD59. These results indicate that CD59, an evolutionarily transitional molecule linking immune and regenerative regulation, affects tail regeneration by mediating cartilage patterning. PMID- 26238654 TI - Toxoplasma gondii in horse meat intended for human consumption in Romania. AB - The prevalence of Toxoplasma gondii, an economically important zoonotic protozoan, was investigated in horses slaughtered for export and human consumption in the North of Romania. Pairs of samples, sera and heart tissues, were collected from 82 slaughtered horses. Examination of horse sera by ELISA at a dilution of 1:10, and by modified agglutination test (MAT) at a dilution of 1:6, revealed that 32 (39%) and 31(37.8%) horses, respectively, had antibodies against T. gondii. Using polymerase chain reaction (PCR) analysis, T. gondii DNA was not found in any heart sample collected from horses. By bioassay in mice, we obtained viable isolates of T. gondii from two of ten horses determined to be strongly positive by serological assay/ELISA. The prevalence estimated in horses highlighted the potential risk for human contamination by consumption of raw or undercooked meat. PMID- 26238656 TI - Frequency of cattle farms with ivermectin resistant gastrointestinal nematodes in Veracruz, Mexico. AB - This study reports the percentage of cattle farms with ivermectin (IVM) resistant gastrointestinal nematodes (GINs) in Veracruz, Mexico, and identifies the GIN genera involved in the resistances. It also describes management practices of anthelmintic (AH) use on the surveyed farms. Twenty-one farms were assessed by means of the faecal egg count reduction test using the McMaster technique. Only two farms had GIN populations susceptible to IVM (9.5%). The proportion of farms with IVM resistant GIN was 71.4% (15/21). Seven of these farms had less than 80% egg count reductions. Haemonchus and Cooperia were the genera most commonly found in the resistant populations, followed by Oesophagostomum. Inappropriate AH treatment practices were identified from the completed questionnaires. Further management practices such as selective treatment and quarantine treatments are proposed to further reduce the spread of IVM resistance between farms. PMID- 26238655 TI - Diagnosis before treatment: Identifying dairy farmers' determinants for the adoption of sustainable practices in gastrointestinal nematode control. AB - Anthelmintic resistance is emerging in dairy cattle and this can result in a lack of effective control and production losses. Therefore, sustainable control strategies, such as targeted treatments (TT) and targeted selected treatments (TST), should be adopted by the industry. TT and TST approaches require the use of diagnostic methods to take informed treatment decisions. To understand the factors affecting the farmers' intention to adopt diagnostic methods before implementing anthelmintic drugs ('adoption intention'), a cross-sectional survey was carried out in dairy farms in Belgium (Flanders). A framework was constructed to predict adoption intentions based on two fundamental theories in the field of behavioural psychology and health psychology: the Theory of Planned Behaviour and the Health Belief Model. In the tested model, adoption intentions were predicted based on attitudes towards anthelminthics, attitudes towards diagnostic methods, subjective norms, behavioural control and perceived risk. Structural equation modelling was used for analyses. The model fitted the data well and explained 46% of the variance in adoption intention of diagnostics. The factors 'attitude towards diagnostic methods' and 'subjective norm'; i.e. the influence of significant others, had the strongest, positive influence on adoption intention of diagnostic methods. 'Perceived behavioural control' had a weak, positive effect on intention. Further, 'attitude towards the use of anthelmintic drugs' had a negative effect on adoption intention of the diagnostic methods. This implicates an effect of current behaviour on future adoption, which should be considered in future research. Factors measuring risk perception of anthelmintic resistance; perceived severity and perceived susceptibility, had no effect on the adoption intention of diagnostic methods. The threat of anthelmintic resistance is perceived to be low for dairy herds. The study further did not find any differences in the effects of the predictors for young stock and adult dairy cows. The results of this study can be used to develop communication strategies to advertise sustainable nematode control on dairy farms. PMID- 26238657 TI - New insights into the molecular epidemiology of Trichinella infection in domestic pigs, wild boars, and bears in Romania. AB - Trichinellosis is a food-borne zoonosis caused by the parasitic nematode Trichinella, characterized by an extremely wide host range and geographical distribution. In Romania, it is recognized as one of the most serious zoonotic diseases. A cross-sectional study, covering all regions of Romania, was conducted in 2014 to investigate and update the prevalence of Trichinella infection among domestic pigs, wild boars, and bears. Additional, molecular identification of Trichinella species circulating among these animals was performed in order to establish the biogeography of Trichinella species within the seven geographical regions of Romania. For this, a total of 113,383 pigs raised in non-controlled housing conditions (backyards), 5596 hunted wild boars and 147 hunted bears were subjected to Trichinella analysis. The highest prevalence of Trichinella infections was found in bears (12.93%), followed by wild boars (1.66%) and domestic pigs (0.20%). Of 294 Trichinella isolates that tested positive by multiplex PCR, 219 (74.49%) were identified as Trichinella spiralis, 66 (22.45%) as Trichinella britovi, and 9 isolates (3.06%) as mixed infections of T. spiralis and T. britovi. T. spiralis was more prevalent in domestic pigs (165/228; 72.37%) than in game (63/228; 27.63%), while T. britovi showed a higher prevalence in game (50/75; 66.66%) than in domestic pigs (25/75; 33.33%). Moreover, the present study revealed a significant host- and area- related distribution of Trichinella species within the seven regions of Romania. Therefore, these findings are of epidemiological relevance, updating data on the prevalence and distribution of Trichinella species circulating among domestic and wild animals in South-Eastern Europe. PMID- 26238658 TI - Inhibiting GLUT-1 expression and PI3K/Akt signaling using apigenin improves the radiosensitivity of laryngeal carcinoma in vivo. AB - Hypoxia is an important factor in radioresistance of laryngeal carcinoma. Glucose transporter-1 (GLUT-1) is an important hypoxic marker in malignant tumors, including laryngeal carcinoma. Apigenin is a natural phytoestrogen flavonoid that has potential anticancer effects. Various studies have reported that the effects of apigenin on lowering GLUT-1 expression were involved in downregulation of the PI3K/Akt pathway. Thus, apigenin may improve the radiosensitivity of laryngeal carcinoma by suppressing the expression of GLUT-1 via the PI3K/Akt pathway. The effect of GLUT-1 and PI3K/Akt pathway-related factor expressions by apigenin or antisense oligonucleotides (AS-ODNs) on the radiosensitivity of laryngeal carcinoma in vivo was assessed. The xenograft volume, xenograft weight and apoptosis detection were performed to determine radiosensitivity. The results showed that apigenin or apigenin plus GLUT-1 AS-ODNs improved the radiosensitivity of xenografts. Apigenin or apigenin plus GLUT-1 reduced the expression of GLUT-1, Akt, and PI3K mRNA after X-ray radiation. We found similar results at the protein level. The results suggest that the effects of apigenin on inhibiting xenograft growth and enhancing xenograft radiosensitivity may be associated with suppressing the expression of GLUT-1 via the PI3K/Akt pathway. In addition, apigenin may enhance the effects of GLUT-1 AS-ODNs via the same mechanism. PMID- 26238659 TI - Fenofibrate suppresses cellular metabolic memory of high glucose in diabetic retinopathy via a sirtuin 1-dependent signalling pathway. AB - Inflammation is a major contributing factor in the development of diabetic microvascular complications, regardless of whether improved glycaemic control is achieved. Studies have increasingly indicated that fenofibrate, a lipid-lowering therapeutic agent in clinical use, exerts a potential anti-inflammatory effect, which is mediated by sirtuin 1 (SIRT1; an NAD+-dependent deacetylase) in endothelial cells. The aim of the present study was to investigate the inhibitory effect of fenofibrate on metabolic memory (via the regulation of SIRT1), and inflammatory responses in cell and animal models of diabetic retinopathy (DR). The data demonstrated that high glucose treatment in human retinal endothelial cells (HRECs) inhibited the expression and deacetylase activity of SIRT1. The reduction of SIRT1 expression and deacetylase activity persisted following a return to normal glucose levels. Furthermore, nuclear factor-kappaB expression was observed to be negatively correlated with SIRT1 expression and activity in HRECs under high glucose levels and the subsequent return to normal glucose levels. Fenofibrate treatment abrogated these changes. Knockdown of SIRT1 attenuated the effect of fenofibrate on high glucose-induced NF-kappaB expression. In addition, fenofibrate upregulated SIRT1 expression through peroxisome proliferator-activated receptor alpha in high glucose-induced metabolic memory. These findings indicate that fenofibrate is important in anti inflammatory processes and suppresses the cellular metabolic memory of high glucose-induced stress via the SIRT1-dependent signalling pathway. Thus, treatment with fenofibrate may offer a promising therapeutic strategy for halting the development of DR and other complications of diabetes. PMID- 26238660 TI - Platform-Switching for Cemented Versus Screwed Fixed Dental Prostheses: Reliability and Failure Modes: An In Vitro Study. AB - PURPOSE: The aim of this study was to evaluate the probability of survival of cemented and screwed three-unit implant-supported fixed dental prostheses (ISFDP) using different implant-abutment horizontal matching configurations (regular vs switching platforms). METHODS: One hundred and sixty-eight implants with internal hexagon connection (4 mm diameter, 10 mm length, Emfils; Colosso Evolution System, Itu, SP, Brazil) were selected for this study according to the horizontal implant-abutment matching configuration (regular or switching) and retention method and divided in four groups (n = 21 per group) as follows: 1) regular platform cemented (IRC); 2) or screw-retained (IRS); 3) switched-platform cemented (ISC); or 4) screw-retained (ISS). Regular and platform-switched abutments (Colosso evolution, 4 mm and 3.3 mm, respectively) were torqued, and 84 three-unit metal bridges were fabricated (first molar pontic). Implants were embedded in polymethyl-methacrylate resin and subjected to step-stress accelerated life testing in water. Weibull distribution was used to determine the probability of survival for a mission of 100,000 cycles at 400 N (90% two-sided confidence intervals). Polarized light and scanning electron microscopes were used for fractographic analysis. RESULTS: The beta values of 0.50, 1.19, 1.25, and 1.95 for groups IRC, IRS, ISC, and ISS respectively, indicated that fatigue accelerated the failure for all groups, except IRC. The cement-retained groups presented significantly higher probability of survival (IRC - 98%, ISC - 59%) than screw-retained groups (IRS - 23% and ISS - 0%). Screw-retained FDPs exclusively failed by abutment-screw fractures, whereas cement-retained presented implant/screw/abutment fractures. CONCLUSIONS: The probability of survival of cement-retained ISFDP was higher than screw-retained, irrespective of implant abutment horizontal configuration. PMID- 26238661 TI - Rare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome. AB - Klippel-Feil syndrome is a rare disorder represented by a subgroup of segmentation defects of the vertebrae and characterized by fusion of the cervical vertebrae, low posterior hairline, and short neck with limited motion. Both autosomal dominant and recessive inheritance patterns were reported in families with Klippel-Feil. Mutated genes for both dominant (GDF6 and GDF3) and recessive (MEOX1) forms of Klippel-Feil syndrome have been shown to be involved in somite development via transcription regulation and signaling pathways. Heterotaxy arises from defects in proteins that function in the development of left-right asymmetry of the developing embryo. We describe a consanguineous family with a male proband who presents with classical Klippel-Feil syndrome together with heterotaxy (situs inversus totalis). The present patient also had Sprengel's deformity, deformity of the sternum, and a solitary kidney. Using exome sequencing, we identified a homozygous frameshift mutation (c.299delT; p.L100fs) in RIPPLY2, a gene shown to play a crucial role in somitogenesis and participate in the Notch signaling pathway via negatively regulating Tbx6. Our data confirm RIPPLY2 as a novel gene for autosomal recessive Klippel-Feil syndrome, and in addition-from a mechanistic standpoint-suggest the possibility that mutations in RIPPLY2 could also lead to heterotaxy. (c) 2015 Wiley Periodicals, Inc. PMID- 26238662 TI - Outbreak of extended-spectrum beta-lactamase-producing Escherichia coli transmitted through breast milk sharing in a neonatal intensive care unit. AB - BACKGROUND: Routine surveillance in a neonatal intensive care unit (NICU) showed an increased detection of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (ESBL-E. coli) in August 2012, following nearly a year without detection. AIM: To describe the investigation and interventions by a hospital infection control team of an outbreak of ESBL-E. coli in a NICU. METHODS: Six neonates with positive cultures of ESBL-E. coli (five with respiratory colonization, one with a urinary tract infection), control infants who were negative for ESBL-E. coli during the study period, and mothers who donated their breast milk were included. A case-control study was performed to identify possible risk factors for positive ESBL-E. coli cultures and molecular typing of isolated strains by pulsed-field gel electrophoresis. FINDINGS: The odds ratio for ESBL-E. coli infection after receiving shared unpasteurized breast milk during the study period was 49.17 (95% confidence interval: 6.02-354.68; P < 0.05). The pulsed-field gel electrophoresis pattern showed that all strains were identical, and the same pathogen was detected in freshly expressed milk of a particular donor. After ceasing the breast milk sharing, the outbreak was successfully terminated. CONCLUSION: This outbreak indicates that contamination of milk packs can result in transmission of a drug-resistant pathogen to newborn infants. Providers of human breast milk need to be aware of the necessity for low temperature pasteurization and bacterial cultures, which should be conducted before and after freezing, before prescribing to infants. PMID- 26238663 TI - Visible-wavelength two-photon excitation microscopy for fluorescent protein imaging. AB - The simultaneous observation of multiple fluorescent proteins (FPs) by optical microscopy is revealing mechanisms by which proteins and organelles control a variety of cellular functions. Here we show the use of visible-light based two photon excitation for simultaneously imaging multiple FPs. We demonstrated that multiple fluorescent targets can be concurrently excited by the absorption of two photons from the visible wavelength range and can be applied in multicolor fluorescence imaging. The technique also allows simultaneous single-photon excitation to offer simultaneous excitation of FPs across the entire range of visible wavelengths from a single excitation source. The calculation of point spread functions shows that the visible-wavelength two-photon excitation provides the fundamental improvement of spatial resolution compared to conventional confocal microscopy. PMID- 26238664 TI - Stable and efficient colour enrichment powders of nonpolar nanocrystals in LiCl. AB - In this work, we propose and develop the inorganic salt encapsulation of semiconductor nanocrystal (NC) dispersion in a nonpolar phase to make a highly stable and highly efficient colour converting powder for colour enrichment in light-emitting diode backlighting. Here the wrapping of the as-synthesized green emitting CdSe/CdZnSeS/ZnS nanocrystals into a salt matrix without ligand exchange is uniquely enabled by using a LiCl ionic host dissolved in tetrahydrofuran (THF), which simultaneously disperses these nonpolar nanocrystals. We studied the emission stability of the solid films prepared using NCs with and without LiCl encapsulation on blue LEDs driven at high current levels. The encapsulated NC powder in epoxy preserved 95.5% of the initial emission intensity and stabilized at this level while the emission intensity of NCs without salt encapsulation continuously decreased to 34.7% of its initial value after 96 h of operation. In addition, we investigated the effect of ionic salt encapsulation on the quantum efficiency of nonpolar NCs and found the quantum efficiency of the NCs-in-LiCl to be 75.1% while that of the NCs in dispersion was 73.0% and that in a film without LiCl encapsulation was 67.9%. We believe that such ionic salt encapsulated powders of nonpolar NCs presented here will find ubiquitous use for colour enrichment in display backlighting. PMID- 26238665 TI - Impact of gender, work, and clinical presentation on diagnostic delay in Italian patients with primary ankylosing spondylitis. AB - The variability of demographic, social, genetic, and clinical factors might influence the time between the onset of symptoms and the diagnosis [diagnostic delay (DD)] of ankylosing spondylitis (AS) in different geographic areas. Different clinical manifestations in men and women affected by AS might indicate a possible role of gender in DD. The aim of the present study was to investigate the influence of demographic, social, genetic, and clinical factors on DD and the differences of DD between men and women related to the presence of different demographic, social, clinical, and genetic parameters in an Italian cohort of primary AS patients. A total of 135 Italian primary AS patients (45 female and 90 male, 27.9 +/- 0.89 years old at onset) were studied. The DD, gender, education and work (manual or non-manual) levels, and type of first clinical presentation (inflammatory back pain, arthritis, enthesitis) at onset, family history of AS, and HLA B27 presence were analyzed. The DD (8.744 mean +/-0.6869) was significantly higher in men (p = 0.0023), in axial presentation (p = 0.0021), and in manual work (even if with low significance, p = 0.047). The lower DD in women in comparison to that in men was likely related to higher education (p = 0.0045) and work (p = 0.0186) levels, peripheral involvement (p = 0.0009), and HLA B27 positivity (p = 0.0231). DD was higher in AS patients: male, employed in manual jobs, and with axial symptoms at onset. In men, DD seemed to be negatively influenced by lower level of education and work, axial clinical presentation, and HLA B27. PMID- 26238667 TI - Effect of GSTM1 and GSTT1 Polymorphisms on Genetic Damage in Humans Populations Exposed to Radiation From Mobile Towers. AB - All over the world, people have been debating about associated health risks due to radiation from mobile phones and mobile towers. The carcinogenicity of this nonionizing radiation has been the greatest health concern associated with mobile towers exposure until recently. The objective of our study was to evaluate the genetic damage caused by radiation from mobile towers and to find an association between genetic polymorphism of GSTM1 and GSTT1 genes and DNA damage. In our study, 116 persons exposed to radiation from mobile towers and 106 control subjects were genotyped for polymorphisms in the GSTM1 and GSTT1 genes by multiplex polymerase chain reaction method. DNA damage in peripheral blood lymphocytes was determined using alkaline comet assay in terms of tail moment (TM) value and micronucleus assay in buccal cells (BMN). There was a significant increase in BMN frequency and TM value in exposed subjects (3.65 +/- 2.44 and 6.63 +/- 2.32) compared with control subjects (1.23 +/- 0.97 and 0.26 +/- 0.27). However, there was no association of GSTM1 and GSTT1 polymorphisms with the level of DNA damage in both exposed and control groups. PMID- 26238668 TI - Reproductive hormones and schizophrenia. PMID- 26238666 TI - Thirty-day complications in rheumatoid patients following total knee arthroplasty. AB - Although total knee arthroplasty (TKA) is highly successful for patients with end stage rheumatoid arthritis (RA), the risks and complications associated with surgery in this cohort are less defined. The objectives of our study were to analyze the demographic and perioperative factors of RA patients that may affect post-TKA outcomes, as well as to assess the 30-day complication rates compared to osteoarthritis patients. We retrospectively evaluated the National Surgical Quality Improvement Program (NSQIP) database from 2006 to 2012 to assess all patients who underwent a primary TKA and had a diagnosis of rheumatoid arthritis (n = 141) or primary knee osteoarthritis (n = 7125). We evaluated and compared the demographic factors, social factors, preoperative factors, operative factors, and postoperative complications. The RA cohort had a lower mean age and body mass index than patients in the OA group. There was also a significantly higher incidence of women and Hispanics in the RA cohort. There was a lower incidence of diabetes and hypertension requiring medication in the rheumatoid cohort, but also a higher incidence of bleeding disorders. The RA cohort had an increased proportion of patients requiring blood transfusions and had a longer mean length of stay. The incidence of pneumonia and postoperative bleeding that required transfusion was also higher in RA patients. Rheumatoid patients had higher rates of wound infections, pulmonary embolisms, and deep vein thrombosis; however, these findings were not significant. Although RA patients with end-stage knee arthritis may benefit from TKA, these patients should be preoperatively optimized to minimize complication risks. PMID- 26238670 TI - Conjugated Polymer Nanoparticles for Fluorescence Imaging and Sensing of Neurotransmitter Dopamine in Living Cells and the Brains of Zebrafish Larvae. AB - Nanoscale materials are now attracting a great deal of attention for biomedical applications. Conjugated polymer nanoparticles have remarkable photophysical properties that make them highly advantageous for biological fluorescence imaging. We report on conjugated polymer nanoparticles with phenylboronic acid tags on the surface for fluorescence detection of neurotransmitter dopamine in both living PC12 cells and brain of zebrafish larvae. The selective enrichment of dopamine and fluorescence signal amplification characteristics of the nanoparticles show rapid and high-sensitive probing such neurotransmitter with the detection limit of 38.8 nM, and minimum interference from other endogenous molecules. It demonstrates the potential of nanomaterials as a multifunctional nanoplatform for targeting, diagnosis, and therapy of dopamine-relative disease. PMID- 26238671 TI - CACUL1/CAC1 Regulates the Antioxidant Response by Stabilizing Nrf2. AB - Nrf2 is the pre-dominant transcription activator responsible for coordinated up regulation of ARE-driven antioxidant and detoxification genes. The activity of Nrf2 is tightly regulated at basal levels through its ubiquitination by Cul3 Keap1 and consequential degradation. Upon exposure to stress, the Cul3-Keap1 ligase is inhibited, leading to Nrf2 stabilization and activation. Here we describe CACUL1/CAC1 as a positive regulator of the Nrf2 pathway. We found that CACUL1 is up-regulated by Nrf2-activating oxidative stresses in cells and in mice. The association of CACUL1 with the Cul3-Keap1 complex led to a decrease in Nrf2 ubiquitination levels at non-stressed as well as stressed conditions, and sensitized cells for higher Nrf2 activation. Furthermore, CACUL1 knock-down led to a decrease in Nrf2 activity and cell viability under stress. Our results show that CACUL1 is a regulator of Nrf2 ubiquitination, adding another regulatory layer to the Nrf2 antioxidant stress response. PMID- 26238673 TI - Impacts of global warming on residential heating and cooling degree-days in the United States. AB - Climate change is expected to decrease heating demand and increase cooling demand for buildings and affect outdoor thermal comfort. Here, we project changes in residential heating degree-days (HDD) and cooling degree-days (CDD) for the historical (1981-2010) and future (2080-2099) periods in the United States using median results from the Climate Model Intercomparison Project phase 5 (CMIP5) simulations under the Representation Concentration Pathway 8.5 (RCP8.5) scenario. We project future HDD and CDD values by adding CMIP5 projected changes to values based on historical observations of US climate. The sum HDD + CDD is an indicator of locations that are thermally comfortable, with low heating and cooling demand. By the end of the century, station median HDD + CDD will be reduced in the contiguous US, decreasing in the North and increasing in the South. Under the unmitigated RCP8.5 scenario, by the end of this century, in terms of HDD and CDD values considered separately, future New York, NY, is anticipated to become more like present Oklahoma City, OK; Denver, CO, becomes more like Raleigh, NC, and Seattle, WA, becomes more like San Jose, CA. These results serve as an indicator of projected climate change and can help inform decision-making. PMID- 26238672 TI - Certolizumab Pegol Efficacy Across Methotrexate Regimens: A Pre-Specified Analysis of Two Phase III Trials. AB - OBJECTIVE: Anti-tumor necrosis factor (anti-TNF) agents are frequently used in combination with methotrexate (MTX) to treat rheumatoid arthritis (RA). We investigated the effect of a background MTX dose, in combination with anti-TNF certolizumab pegol (CZP), on treatment efficacy and safety in RA patients. METHODS: A pre-specified subgroup analysis comparing 2 MTX dosage categories (<15 mg/week and >=15 mg/week) was carried out using data pooled from phase III clinical trials, Rheumatoid Arthritis Prevention of Structural Damage 1 (RAPID 1) and RAPID 2, according to treatment group: CZP 200 mg, CZP 400 mg, or placebo, every 2 weeks. Inclusion criteria required MTX dosage >=10 mg/week. Efficacy end points included week 24 American College of Rheumatology criteria for 20%, 50%, and 70% improvement (ACR20/50/70) responses analyzed by logistic regression, and changes from baseline in the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) and the modified Sharp/van der Heijde score (SHS) were analyzed by analysis of covariance. Incidence rates of treatment emergent adverse events (TEAEs) were categorized by baseline MTX dose. Post hoc sensitivity analysis investigated 3 MTX dose categories: <=10 mg/week, >10 and <=15 mg/week, and >15 mg/week. RESULTS: A total of 638, 635, and 325 patients received CZP 200 mg, CZP 400 mg, and placebo, respectively. At week 24, treatment responses in both CZP groups were uninfluenced by baseline MTX dose category, and were superior to the placebo group for all investigated end points: ACR20/50/70, DAS28-ESR, and SHS. TEAE incidence rates were higher in patients receiving MTX >=15 mg/week for most TEAE types across treatment groups. CONCLUSION: CZP efficacy was not affected by background MTX dose category. It can be hypothesized that to minimize TEAEs, background MTX doses could be tailored to individual patient tolerance without affecting CZP efficacy. PMID- 26238674 TI - Sphingolipids--who's controlling who in disease? PMID- 26238675 TI - First observation on neustonic plastics in waters off NW Spain (spring 2013 and 2014). AB - This paper examines the presence and distribution of plastic particles in waters off the NW Spanish Atlantic coast. A pilot sampling program was initiated in 2013 to study the presence of plastic particles in surface waters. A total of 41 neuston samples were collected using a manta trawl fitted with a 333 MUm mesh (21 samples in 2013 and 20 samples in 2014). Several types of plastic particles were observed in 95% of the stations. A total of 1463 plastic microparticles (<5 mm; mps) and 208 mesoparticles (>5 mm and <20 mm; MPS) were counted. Average concentrations recorded were 0.034 +/- 0.032 and 0.176 +/- 0.278 mps m(-2) and 0.005 +/- 0.005 and 0.028 +/- 0.043 MPS m(-2), respectively for 2013 and 2014. Results on this emerging topic are discussed as a preliminary step towards implementation of the Marine Strategy Framework Directive in the region. Harmonization of protocols for determination of plastic particles is urgently needed in order to compare results between regions and to ensure coherence in the implementation of the MSFD. This aspect is also important at a worldwide scale. PMID- 26238676 TI - Combating Superbug Without Antibiotic on a Postamputation Wound in a Patient with Diabetic Foot. AB - Diabetic foot is a kind of limb- and life-threatening complication that is difficult to treat with conventional therapy, especially when accompanied with peripheral arterial insufficiency and severe infection. We present a diabetic patient with a postamputation wound infected by multidrug-resistant Acinetobacter baumannii/haemolyticus, which was resistant to almost all antibiotics. As the clinical response to antimicrobial therapy was poor, antibiotic was discontinued. Autologous platelet-rich gel with anticoagulation, negative pressure wound therapy, and improvement of microcirculation were used successfully to eradicate infection of the superbug and achieve final wound closure. PMID- 26238677 TI - Drug therapy for an overactive bladder. PMID- 26238678 TI - Delivery Systems for Biopharmaceuticals. Part I: Nanoparticles and Microparticles. AB - Pharmaceutical biotechnology has been showing therapeutic success never achieved with conventional drug molecules. Therefore, biopharmaceutical products are currently well-established in clinic and the development of new ones is expected. These products comprise mainly therapeutic proteins, although nucleic acids and cells are also included. However, according to their sensitive molecular structures, the efficient delivery of biopharmaceuticals is challenging. Several delivery systems (e.g. microparticles and nanoparticles) composed of different materials (e.g. polymers and lipids) have been explored and demonstrated excellent outcomes, such as: high cellular transfection efficiency for nucleic acids, cell targeting, increased proteins and peptides bioavailability, improved immune response in vaccination, and viability maintenance of microencapsulated cells. Nonetheless, important issues need to be addressed before they reach clinics. For example, more in vivo studies in animals, accessing the toxicity potential and predicting in vivo failure of these delivery systems are required. This is the Part I of two review articles, which presents the state of the art of delivery systems for biopharmaceuticals. Part I deals with microparticles and polymeric and lipid nanoparticles. PMID- 26238679 TI - The Effect in Topical Use of Lycogen(TM) via Sonophoresis for Anti-aging on Facial Skin. AB - BACKGROUND: Anti-aging skin care is a growing popular topic in cosmetic and aesthetic fields, and skin care rather then makeup tips draw more attention nowadays. The phenomenon of skin aging includes thinning of skin losses of elasticity and moisture, pigmented spot formation, and wrinkle development. Along with growth in age, the decreased rates of epithelium renewal and cellular recovery as well as the reduced contents of elastin, collagen, and glycosaminoglycans all contribute to creases or folds of skin. Available strategies for wrinkle treatments include topical use of skin care products with anti-aging contents, dermabrasion, laser, Botox injection, fillers injection, and facelift. Though all of these above options can provide different degrees of improvement in facial wrinkles, the cost-effect, pain of intervention therapy, and necessity of repetitive treatment may impact on choices made. Topical use of anti-aging skin products is the most convenient and cheap way to achieve skin anti-aging effect. Lycogen(TM) is an antioxidant, which can prevent the downregulation of pro-collagen I, intracellular accumulation of malondialdehyde (MDA) and achieve the aim of skin rejuvenation. METHODS: Twenty-six female patients were included in our study with ages between 30 and 45. They were randomly assigned to two groups: the vehicle control group and the experimental group. Patients in the control group applied a skin care product without Lycogen(TM)to the face via sonophoresis after facial cleanser use in the morning and at night. The experimental group applied a Lycogen(TM) -containing skin care product via sonophoresis in the same time schedule. We evaluated results, including pigmented spots, wrinkles, texture, pores, and red area by VISIA on weeks 0, 1, 2, 4, 6, 8, and 10 respectively. RESULTS: In the aspect of pigmented spots, the experimental group showed significant difference in comparison with the vehicle control group on weeks 2, 6, 8, and 10. For wrinkles, the experimental group had better results on weeks 1, 2, 4, 8, and 10. Measured by texture, the experimental group had better results on weeks 1, 2, 4, 6, 8, and 10. Determined by pores, the experimental group had better results on weeks 2, 4, 6, 8, and 10. Concerning red areas, the experimental group had better results on weeks 6, 8, and 10. (p < 0.05). CONCLUSION: In our study, we applied a Lycogen(TM)- containing product by sonophoresis as the experimental group in comparison with a skin care product without LycogenTM. VISIA (Canfield Imaging Systems, Fairfield, NJ) was used to evaluate facial skin in aspects of pigmented spots, wrinkles, texture, pores, and red area. Overall, Lycogen(TM) had proven effectiveness on anti-oxidation as patients who used the Lycogen TM -containing product had better outcomes. PMID- 26238680 TI - Natural Products Mediated Regulation of Oxidative Stress and DNA Damage in Ultraviolet Exposed Skin Cells. AB - Data obtained through high-throughput technologies have gradually revealed that a unique stratified epithelial architecture of human skin along with the antioxidant-response pathways provided vital defensive mechanisms against UV radiation. However, it is noteworthy that skin is a major target for toxic insult by UV radiations that can alter its structure and function. Substantial fraction of information has been added into the existing pool of knowledge related to natural products mediated biological effects in UV exposed skin cells. Accumulating evidence has started to shed light on the potential of these bioactive ingredients as protective natural products in cosmetics against UV photodamage by exerting biological effects mainly through wide ranging intracellular signalling cascades of oxidative stress and modulation of miRNAs. In this review, we have summarized recently emerging scientific evidences addressing underlying mechanisms of UV induced oxidative stress and deregulation of signalling cascades and how natural products can be used tactfully to protect against UV induced harmful effects. PMID- 26238681 TI - Characterization and antiherpetic activity of native and chemically sulfated polysaccharide from Adenanthera pavonina. AB - The herpes simplex virus (HSV) is a widespread human pathogen and for many reasons the development of anti-herpetic drugs from natural products has been encouraged. Adenanthera pavonina (Ap) is a medicinal plant widely used in Brazil, among other uses. Herein, a native Ap seed polysaccharide (PLSAp) and its chemically sulfated derivate (SPLSAp) were studied by Fourier transform IR spectra (FT-IR), gel permeation chromatography (GPC) for molar mass determination and their intrinsic viscosity [eta]. Biologically, the compounds were evaluated for anti-HSV activity, in HEp2 cell cultures. The cytotoxic concentrations (CC50) and the inhibitory concentrations (IC(50)) of the polysaccharides were determined by the colorimetric assay (dimethyl-thiazolyl-diphenyltetrazolium bromide) and plaque reduction assay (PRA), respectively. The SPLSAp showed a better antiviral activity when compared to the PLSAp with a CC(50) of 500 MUg/ml, the IC(50) equal to 15 MUg/ml and the selectivity index (SI) of 33.3. The time-of-addition and the time-of-removal assays demonstrated the highest inhibitory activity between 8-16h after the infection. The inhibition of viral DNA and protein syntheses by SPLSAp monitored by PCR and immunofluorescence assay (IFA), respectively, has also demonstrated. These findings demonstrated that the SPLSAp inhibited HSV-1 infection in different steps of the replication and, therefore, represents a valuable compound for preclinical studies in anti-herpetic therapy. PMID- 26238682 TI - Engineering of Escherichia coli for Lycopene Production Through Promoter Engineering. AB - The control of gene expression is critical for metabolic engineering. The multi copy plasmids has been widely used for high-level expression of genes. However, plasmid-based expression systems are liable to genetic instability and require a selective pressure to assure plasmid stability. In this study, we first constructed a lycopene producer Escherichia coli through promoter engineering. Saccharomyces cerevisiae mevalonate (MEV) pathway was also optimized to balance expression of the top and bottom MEV pathway by using the different strength promoters. The chromosomal heterologous expression of the optimized S. cerevisiae MEV pathway can further improved lycopene production. The final engineered strain, E. coli LYCOP 20, produced lycopene of 529.45 mg/L and 20.25 mg per gram of dry cell weight in the fed-batch culture. The engineered strain does not have a plasmid or antibiotic marker. This strategy used in this study can be applied in pathway engineering of E. coli and other bacteria. PMID- 26238683 TI - Effects of facial expression on working memory. AB - In long-term memory (LTM) emotional content may both enhance and impair memory, however, disagreement remains whether emotional content exerts different effects on the ability to maintain and manipulate information over short intervals. Using a working-memory (WM) recognition task requiring the monitoring of faces displaying facial expressions of emotion, participants judged each face as identical (target) or not (non-target) to that presented 2 trials back (2-back). Negative expression was better and faster recognised, illustrated by higher target discriminability and target detection. Positive and negative expressions also induced a more liberal detection bias compared with neutral. Taking the preceding item into account, additional accuracy impairment (negative preceding negative target) and enhancement effects (negative or positive preceding neutral target) appeared. This illustrates a differential modulation of WM based on the affective tone of the target (mirroring LTM enhancement- and recognition bias effects), and of the preceding item (enhanced and impaired target detection). PMID- 26238684 TI - An Indian pediatric emergency weight estimation tool: prospective adjustment of the Broselow tape. AB - BACKGROUND: This study aims to remodel the Broselow Pediatric Emergency Tape for the Indian pediatric population. The Broselow tape overestimates the heights of the Indian pediatric population and remits inaccurate predicted weights for all color zones with varying degrees and could result in overresuscitation of Indian children in emergency settings. The Indian children are underweight for their age and height. METHODS: We prospectively collected cross-sectional data on a sample of 1185 children aged 1 month to 12 years old in Chennai, India. The Broselow tape was used for length-based weight estimation, and actual weight was recorded by a weighing scale. In the first stage, we recruited 769 children. With univariate linear regression, we adjusted the Broselow tape by an 8 % correction factor to enhance accuracy and created a new tape with new weight and height ranges. In the second stage, we recruited 416 children and tested the new ranges for accuracy. RESULTS: The Broselow tape overestimates weights with a mean percentage difference of 5-15 % depending on the color zone. Accuracy of the Broselow tape by color-coded zone was between 33-86.6 %, with higher weight color zones showing lower accuracy. The new Indian pediatric weight estimation tool (IPWET), based on the Broselow tape has a weight range of 4-36 kg and height range of 50-150 cm (Broselow tape, 3-36 kg, 46-146.5 cm) and an improved accuracy between 51-97.8 %. CONCLUSIONS: A remodeled Broselow tape can predict weights with higher accuracy in the Indian pediatric population. PMID- 26238685 TI - SIV-induced Translocation of Bacterial Products in the Liver Mobilizes Myeloid Dendritic and Natural Killer Cells Associated With Liver Damage. AB - Disruption of the mucosal epithelium during lentivirus infections permits translocation of microbial products into circulation, causing immune activation and driving disease. Although the liver directly filters blood from the intestine and is the first line of defense against gut-derived antigens, the effects of microbial products on the liver are unclear. In livers of normal macaques, minute levels of bacterial products were detectable, but increased 20-fold in simian immunodeficiency virus (SIV)-infected animals. Increased microbial products in the liver induced production of the chemoattractant CXCL16 by myeloid dendritic cells (mDCs), causing subsequent recruitment of hypercytotoxic natural killer (NK) cells expressing the CXCL16 receptor, CXCR6. Microbial accumulation, mDC activation, and cytotoxic NK cell frequencies were significantly correlated with markers of liver damage, and SIV-infected animals consistently had evidence of hepatitis and fibrosis. Collectively, these data indicate that SIV-associated accumulation of microbial products in the liver initiates a cascade of innate immune activation, resulting in liver damage. PMID- 26238686 TI - Impact of Placental Malaria and Hypergammaglobulinemia on Transplacental Transfer of Respiratory Syncytial Virus Antibody in Papua New Guinea. AB - BACKGROUND: Passively acquired respiratory syncytial virus (RSV) neutralizing antibody protects against RSV-associated lower respiratory infections, but placental malaria (PM) and maternal hypergammaglobulinemia might interfere with transplacental immunoglobulin transport. METHODS: We measured RSV plaque reduction neutralization (PRN) antibody in 300 full-term maternal/cord serum pairs in 2 cohorts in malaria-endemic Papua New Guinea: Alexishafen (2005-2008) and the Fetal Immunity Study (FIS) (2011-2013). We defined impaired transport as a cord-to-maternal titer ratio <1.0 and a protective RSV PRN titer (PRNT) >=1:200. RESULTS: PM and hypergammaglobulinemia occurred in 60% and 54% of Alexishafen mothers versus 8% and 9% of FIS mothers, respectively. 34% of Alexishafen and 32% of FIS pairs demonstrated impaired transport. Multivariate modeling revealed significant associations between increasing maternal IgG (log2) and impaired transport (adjusted OR, Alexishafen: 2.68 [1.17-6.14], FIS: 6.94 [1.94-24.8]) but no association with PM. 34% of Alexishafen and 31% of FIS cord PRNTs were <1:200. CONCLUSIONS: Impaired RSV antibody transport was observed in approximately one-third of maternal/cord pairs. Hypergammaglobulinemia, but not PM, was associated with impaired transport, particularly among women with low RSV PRNT. Detection of RSV PRNT <1:200 in one-third of cord sera confirms the need to increase levels of RSV neutralizing antibody in pregnant women through maternal immunization. PMID- 26238687 TI - Sex Hormones Coordinate Neutrophil Immunity in the Vagina by Controlling Chemokine Gradients. AB - Estradiol-based contraceptives and hormonal replacement therapy predispose women to Candida albicans infections. Moreover, during the ovulatory phase (high estradiol), neutrophil numbers decrease in the vaginal lumen and increase during the luteal phase (high progesterone). Vaginal secretions contain chemokines that drive neutrophil migration into the lumen. However, their expression during the ovarian cycle or in response to hormonal treatments are controversial and their role in vaginal defense remains unknown.To investigate the transepithelial migration of neutrophils, we used adoptive transfer of Cxcr2(-/-) neutrophils and chemokine immunofluorescence quantitative analysis in response to C. albicans vaginal infection in the presence of hormones.Our data show that the Cxcl1/Cxcr2 axis drives neutrophil transepithelial migration into the vagina. Progesterone promotes the Cxcl1 gradient to favor neutrophil migration. Estradiol disrupts the Cxcl1 gradient and favors neutrophil arrest in the vaginal stroma; as a result, the vagina becomes more vulnerable to pathogens. PMID- 26238688 TI - Comparative analysis of extractable proteins from Clostridium perfringens type A and type C strains showing varying degree of virulence. AB - The prevailing scenario of bioterrorism warrants development of medical countermeasures with expanded coverage of select agents. Clostridium perfringens is a pathogen of medical, veterinary and military importance, and has been listed as Validated Biological Agent. We employed 2DE-MS approach to identify a total of 134 unique proteins (529 protein spot features) from the extractable proteome of four type A and type C strains. Proteins showing altered expression under host simulated conditions from virulent type A strain (ATCC13124) were also elucidated. Significant among the differentially expressed proteins were elongation factor, molecular chaperones, ribosomal proteins, carbamoyl phosphate synthase, clpB protein, choloylglycine hydrolase, phosphopyruvate hydratase, and trigger factor. Predictive elucidation, of putative virulence associated proteins and sequence conservation pattern of selected candidates, was carried out using homologous proteins from other bacterial select agents to screen for the commonality of putative antigenic determinants. Pathogens (17 select agents) were observed to form three discrete clusters; composition of I and II being consistent in most of the phylogenetic reconstructions. This work provides a basis for further validation of putative candidate proteins as prophylactic agents and for their ability to provide protection against clusters of pathogenic select bacterial agents; aimed at mitigating the shadows of biothreat. PMID- 26238689 TI - Improving prediction of cardiovascular complications of cancer therapy: what does the future hold? PMID- 26238690 TI - Eight decades of sampling reveal a contemporary novel fish assemblage in coastal nursery habitats. AB - In order to adequately monitor biodiversity trends through time and their responses to natural or anthropogenic impacts, researchers require long time series that are often unavailable. This general lack of datasets that are several decades or longer makes establishing a background or baseline of diversity metrics difficult - especially when attempting to understand species composition changes against a backdrop of climate and ecological variability. Here, we present an analysis of a community of juvenile nearshore fishes based on nearly 8 decades of highly standardized Norwegian survey records. Using multivariate statistical techniques, we: (i) characterize the change in taxonomic community composition through time, (ii) determine whether there has been an increase in warm-water affinity species relative to their cold water affinity counterparts, and (iii) characterize the temporal change in the species' functional trait assemblage. Our results strongly indicate a shift toward a novel fish assemblage between the late 1990s and 2000s. The context of changes within the most recent two decades is in stark contrast to those during the 1960s and 1970s, but similar to those during the previous warm period during the 1930s and 1940s. This novel assemblage is tightly linked to the warming temperatures in the region portrayed by the increased presence of warm-water species and a higher incidence of pelagic, planktivorous species. The results indicate a clear influence of ocean temperature on the region's juvenile fish community that points to climate mediated effects on the species assemblages of an important fish nursery area. PMID- 26238691 TI - Editorial Comment from Dr Presicce et al. to Emerging links between non neurogenic lower urinary tract symptoms secondary to benign prostatic obstruction, metabolic syndrome and its components: A systematic review. PMID- 26238692 TI - Endoport-assisted surgery for the management of spontaneous intracerebral hemorrhage. AB - The aim of this retrospective study is to report our initial experience with endoport-assisted microsurgical evacuation (EAME) of intracerebral hemorrhages (ICH). Neurosurgical intervention has not been shown to significantly improve patient outcomes after spontaneous ICH. Minimally invasive technologies, such as endoport systems, may offer a better risk to benefit profile for ICH evacuation than conventional approaches. We performed a retrospective review of all patients who underwent EAME of ICH from January 2013 to February 2015 using the BrainPath endoport system (NICO, Indianapolis, IN, USA). The baseline and follow-up patient and ICH characteristics were analyzed. Of the 11 patients included for analysis, seven were women (64%), and the median age was 65 years (range: 23-84). The ICH was supratentorial in nine patients (82%), and the median ICH score was 2 (range: 1-4). The median preoperative and postoperative ICH volumes were 51 cm(3) (range: 8-168) and 10 cm(3) (range: 0.4-59), respectively, with a median reduction in ICH volume of 87% (range: 38-99). The median preoperative and postoperative amounts of midline shift were 6.7 mm (range: 4.9-14.3) and 3.7 mm (range: 2.2-8.9), respectively, with a median reduction in midline shift of 38% (range: 18-61). At the 90 day follow-up, four patients (36%) were functionally independent (modified Rankin Scale 0-2). Four patients had ICH-related mortalities (36%). EAME appears to be a safe and effective treatment option for ICH. Further studies are necessary to assess the comparative effectiveness of EAME in relation to medical therapy or other interventional techniques, for the management of ICH patients. PMID- 26238693 TI - The Presto 1000: A novel automated transcranial Doppler ultrasound system. AB - We examined the reliability and ease of use of a novel automated transcranial Doppler (TCD) system in comparison to a conventional TCD system. TCD ultrasound allows non-invasive monitoring of cerebral blood flow, and can predict arterial vasospasm after a subarachnoid hemorrhage (SAH). The Presto 1000 TCD system (PhysioSonics, Bellevue, WA, USA) is designed for monitoring flow through the M1 segment of the middle cerebral artery (MCA) via temporal windows. The Presto 1000 system was tested across multiple preclinical and clinical settings in parallel with a control predicate TCD system. In a phantom flow generating device, both the Presto 1000 and Spencer system (Spencer Technologies, Redmond, WA, USA) were able to detect velocities with high accuracy. In nine volunteer patients, the Presto system was able to locate the MCA in 14 out of 18 temporal windows, in an average of 12.5s. In the SAH cohort of five patients with a total of 25 paired measurements, the mean absolute difference in flow velocities of the M1 segment, as measured by the two systems, was 17.5 cm/s. These data suggest that the Presto system offers an automated TCD that can reliably localize and detect flow of the MCA, with relative ease of use. The system carries the additional benefit of requiring minimal training for the operator, and can be used by many providers across multiple bedside settings. The mean velocities that were generated warrant further validation across an extended group of patients, and the predictive value for vasospasm should be checked against the current standard of angiography. PMID- 26238694 TI - Ethanol exposure and isolated traumatic brain injury. AB - This study aims to investigate an association between ethanol exposure and in hospital mortality among patients with isolated traumatic brain injury (iTBI). Ethanol exposure is associated with a substantially increased risk of sustaining an iTBI. However, once an iTBI has been sustained, it is unclear whether ethanol exposure is neuroprotective or harmful. We conducted a retrospective review of patients who presented between 2006 and 2012 and were entered into the Alfred Hospital trauma registry. The patients who presented with iTBI, as defined by a head abbreviated injury scale (AIS) score ?3 and all other body regions with AIS<3, and who had ethanol levels recorded on admission, were eligible for inclusion. The association between ethanol exposure as a continuous variable, and in-hospital mortality, was explored using multivariable logistic regression analysis. There were 1688 patients with iTBI who met the inclusion criteria, 577 (34.2%) of whom tested positive for ethanol. Ethanol exposure was not significantly associated with a change in the in-hospital mortality rate (adjusted odds ratio 1.01; 95% confidence interval 1.00-1.02; p=0.19). A substantial proportion of patients with iTBI were exposed to ethanol, but ethanol exposure was not independently associated with a change in mortality rate following iTBI. Any neuroprotection or harm from ethanol exposure was not conclusive, requiring further prospective trials. PMID- 26238695 TI - Food and drink purchasing habits out of school at lunchtime: a national survey of secondary school pupils in Scotland. AB - BACKGROUND: Food and drink purchasing habits of pupils out of school at lunchtime may be contributing to poor dietary intakes and overweight and obesity. The aim of this study was to identify the places from which purchases were made, types of food and drinks purchased and, the reasons for purchasing food or drinks out of school. METHODS: A survey of the food and drinks purchasing habits of secondary school pupils (11-16 yrs) out of school at lunchtime was conducted in Scotland in 2010. A face-to-face interview and a self-completion questionnaire was designed to identify the food outlets used at lunchtime, types of food and drinks purchased and pupils' reasons for purchasing food or drinks out of school. Height and weight were measured and BMI centiles used to classify pupils as normal weight, overweight or obese. Results were compared by age group, sex, BMI group and level of socio-economic deprivation. RESULTS: Of the 612 pupils who completed the survey, 97 % reported having access to places selling food or drinks out of school at lunchtime, and of these 63 % made purchases. A higher proportion of pupils from more deprived areas reported purchasing food or drinks out of school, but the proportion making purchases did not differ significantly by sex or BMI group. Supermarkets were the outlets from which pupils reported most often making purchases, with fewer purchasing food or drinks from fast food takeaways, and this did not differ significantly by socio-economic deprivation. Reasons for making purchases included availability of preferred food and drinks, some of which are restricted for sale in schools, and social reasons, such as wanting to be with friends. Sandwiches and non-diet soft drinks were items most commonly purchased, followed by confectionery and diet soft drinks. However, less than 10 % of all the secondary school pupils reported purchasing these foods every day. CONCLUSIONS: Supermarkets, not just fast food outlets, should be considered when developing strategies to improve the dietary habits of pupils at lunchtime. The importance of food preferences and social reasons for purchasing food and drinks need to be acknowledged and integrated in future interventions. PMID- 26238696 TI - Abdominal wall abscess after cholecystectomy. AB - BACKGROUND: Laparoscopic cholecystectomy is one of the most frequently performed surgical interventions nowadays in developed countries. While lost gallstones during the procedure represent a commonly encountered issue, there is an ongoing debate whether split gallstones imperatively need to be extracted during the same procedure. The reported case of a wall abscess several years after follow-up lights up this debate. CASE PRESENTATION: A 75-year-old male Caucasian with a history of rheumatoid arthritis and congestive heart failure presented with a recurrent subcutaneous abdominal wall abscess with occasional, spontaneous drainage of pus. He underwent laparoscopic cholecystectomy for acute calculous cholecystitis 3 years ago with uneventful and prompt recovery. A computed tomography scan showed a cavity in the periumbilical abdominal wall with peripheral contrast-enhancing, next to a calcified foreign body between the rectus muscle sheets. Wound exploration under general anaesthesia was performed with drainage of the cavity, extraction of the foreign body and closure of the anterior rectus sheet over a drainage catheter. The foreign body turned out to be a gallstone lost in the periumbilical port site during the procedure. Antibiotic treatment with co-amoxiclav was continued for 14 days. The patient was discharged 9 days postoperatively with a clean wound. CONCLUSION: This case and short review of the literature is a reminder of the importance of careful extraction of split gallstones during cholecystectomy in order to avoid early or late complications. This is especially important in the light of one of the most commonly performed surgical procedures in developed countries with generally low morbidity. PMID- 26238697 TI - Optimal speed estimation in natural image movies predicts human performance. AB - Accurate perception of motion depends critically on accurate estimation of retinal motion speed. Here we first analyse natural image movies to determine the optimal space-time receptive fields (RFs) for encoding local motion speed in a particular direction, given the constraints of the early visual system. Next, from the RF responses to natural stimuli, we determine the neural computations that are optimal for combining and decoding the responses into estimates of speed. The computations show how selective, invariant speed-tuned units might be constructed by the nervous system. Then, in a psychophysical experiment using matched stimuli, we show that human performance is nearly optimal. Indeed, a single efficiency parameter accurately predicts the detailed shapes of a large set of human psychometric functions. We conclude that many properties of speed selective neurons and human speed discrimination performance are predicted by the optimal computations, and that natural stimulus variation affects optimal and human observers almost identically. PMID- 26238699 TI - The fatty acid binding protein 2 (FABP2) polymorphism Ala54Thr and obesity in Pakistan: A population based study and a systematic meta-analysis. AB - The prevalence of obesity has increased worldwide and it has been designated as a global epidemic by WHO. In Pakistan, recent decades have seen an explosion of obesity, but the research in the field of obesity genetics is limited. We aimed to determine the allele/genotype frequencies of Ala54Thr polymorphism of the FABP2 gene that affects fatty acid metabolism and look for its association on serum biochemical parameters in the Pakistani population. A total of 569 obese and 446 non obese controls were genotyped by PCR-RFLP method. Serum parameters were determined by commercially available kits. Results showed a higher allele frequency of Thr54 allele in cases (0.424) as well as controls (0.331) than Caucasians (0.271). The risk allele was significantly associated with obesity (p=0.002) and there was a significant difference in allele and genotype frequencies among cases and controls (p=0.002). The risk allele is significantly associated with serum total cholesterol and LDL-c but not triglycerides, HDL-c, leptin, systolic/diastolic blood pressure and insulin. The Ala54Thr polymorphism has a high prevalence in the Pakistani population and may play a considerable role in the development of obesity. The effect on obesity may be in part mediated through changing serum cholesterol levels. We then performed a systematic search for any previous reports on the association of the variant with obesity. We identified 5 studies for Ala54Thr association with obesity in Asian subjects. The meta-analysis revealed a significant association of the variant with obesity (Thr allele: OR=1.15, CI=1.02-1.30 and p-value=0.02). PMID- 26238700 TI - Molecular and functional characterization of the ecdysone receptor isoform-A from the cotton mirid bug, Apolygus lucorum (Meyer-Dur). AB - We cloned the cDNA of the ecdysone receptor (EcR) isoform-A from the mirid bug, Apolygus lucorum (AlEcR-A). The AlEcR-A cDNA has an open reading frame of 1410 bp with a conserved sequence of approximately 20 amino acids at the carboxyl-end of its A/B-specific domain. Phylogenetic analysis showed that AlEcR-A is very similar to the EcR-A genes of other Hemiptera species. AlEcR-A mRNA was detected at all developmental stages of A. lucorum with peaks correlating to ecdysteroid pulses. AlEcR-A was also expressed in all analyzed tissues with maximum expression in the epidermis and fat body. An AlEcR-A mRNA of size 1.8 kb was detected in all tissues by northern blot analysis. We investigated the functions of AlEcR-A in A. lucorum growth and development using RNAi in vivo. Weights of fifth instar nymphs were significantly decreased in insects treated with AlEcR-A specific anti-sense RNA. Mortality from third instar nymphs to adults increased significantly along with a significant increase in instar duration. PMID- 26238701 TI - Molecular evolution of cryptochromes in fishes. AB - Circadian rhythmicity is an endogenous biological cycle of about 24h, which exists in cyanobacteria and fungi, plants and animals. Circadian rhythms improve the adaptability of organisms in both constant and changing environments. The cryptochrome (CRY) is a key element of the circadian system in various animal groups including fishes. We studied evolution of cryptochromes in the phylogenetically and ecologically diverse fish taxa. The phylogenetic tree of fish Cry features two major clades: Cry1 and Cry2. Teleosts possess extra copies of Cry1 due to the genome duplication, which resulted in 3 main paralogous subfamilies (1A, 1B and 1C). Cry1 experienced further diversification through additional duplications in some taxa. 1A of Cry1 is more conserved than the other paralogs (dN=0.010 +/- 0.003, pi=0.119 +/- 0.058). The analysis of selection indicated that, while the Cry homologs in fish evolved under the different levels of selection pressure, strong purifying selection (average omega=0.017) dominated in their evolution. PMID- 26238698 TI - Malignant hyperthermia: a review. AB - Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. The incidence of MH reactions ranges from 1:10,000 to 1: 250,000 anesthetics. However, the prevalence of the genetic abnormalities may be as great as one in 400 individuals. MH affects humans, certain pig breeds, dogs and horses. The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. The syndrome is likely to be fatal if untreated. An increase in end-tidal carbon dioxide despite increased minute ventilation provides an early diagnostic clue. In humans the syndrome is inherited in an autosomal dominant pattern, while in pigs it is autosomal recessive. Uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation leads to the pathophysiologic changes. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 400 variants have been identified in the RYR1 gene located on chromosome 19q13.1, and at least 34 are causal for MH. Less than 1 % of variants have been found in CACNA1S but not all of these are causal. Diagnostic testing involves the in vitro contracture response of biopsied muscle to halothane, caffeine, and in some centres ryanodine and 4-chloro-m-cresol. Elucidation of the genetic changes has led to the introduction of DNA testing for susceptibility to MH. Dantrolene sodium is a specific antagonist and should be available wherever general anesthesia is administered. Increased understanding of the clinical manifestation and pathophysiology of the syndrome, has lead to the mortality decreasing from 80 % thirty years ago to <5 % in 2006. PMID- 26238702 TI - Adapting the adult social care outcomes toolkit (ASCOT) for use in care home quality monitoring: conceptual development and testing. AB - BACKGROUND: Alongside an increased policy and practice emphasis on outcomes in social care, English local authorities are now obliged to review quality at a service level to help in their new role of ensuring the development of diverse and high-quality care markets to meet the needs of all local people, including self-funders. The Adult Social Care Outcomes Toolkit (ASCOT) has been developed to measure the outcomes of social care for individuals in a variety of care settings. Local authorities have expressed an interest in exploring how the toolkit might be used for their own purposes, including quality monitoring. This study aimed to explore how the care homes version of the ASCOT toolkit might be adapted for use as a care home quality indicator and carry out some preliminary testing in two care homes for older adults. METHODS: Consultations were carried out with professional and lay stakeholders, with an interest in using the tool or the ratings it would produce. These explored demand and potential uses for the measure and fed into the conceptual development. A draft toolkit and method for collecting the data was developed and the feasibility of using it for quality monitoring was tested with one local authority quality monitoring team in two homes for older adults. RESULTS: Stakeholders expressed an interest in care home quality ratings based on residents' outcomes but there were tensions around who might collect the data and how it might be shared. Feasibility testing suggested the measure had potential for use in quality monitoring but highlighted the importance of training in observational techniques and interviewing skills. The quality monitoring officers involved in the piloting recommended that relatives' views be collected in advance of visits, through surveys not interviews. CONCLUSIONS: Following interest from another local authority, a larger evaluation of the measure for use in routine quality monitoring is planned. As part of this, the ratings made using this measure will be validated against the outcomes of individual residents and compared with the quality ratings of the regulator, the Care Quality Commission. PMID- 26238703 TI - A study of human colonic motility in healthy and constipated subjects using the wireless capsule. AB - Constipation is a common and distressing condition that has been linked to major morbidity, burdens the health care system, and impacts patients' quality of life. However, there is no perfect method for diagnosing and treating constipation. The purpose of this paper is to develop an automatic algorithm to identify patients with constipation from healthy subjects. Data from 12 healthy subjects and 10 patients with constipation were analyzed. The key challenges for data processing were data filtering, feature extraction, information evaluation, and providing the reference conclusion; these were resolved by employing the phase space reconstruction (PSR), independent component analysis (ICA), dynamic feature extraction algorithm, and the Wilcoxon rank sum test. The contractile frequency (Fr), motility index per unit time (MIU), average peak of peristaltic wave (Pave) and variance (Var) were extracted as dynamic parameters and analyzed. Results between groups were compared with the Wilcoxon rank sum test. There were statistically significant differences between healthy subjects and patients with constipation for Fr and MIU (P<0.05), whereas there was no statistically difference for Var. Moreover, the Fr and MIU of patients with normal transit constipation (NTC) are significantly lower compared to healthy subjects, whereas patients with slow transit constipation (STC) did not show significant differences. The proposed algorithms were able to differentiate between healthy subjects and patients with constipation based on the colonic motility profiles. PMID- 26238705 TI - Electronic health record usage behaviors in primary care medical practices: A survey of family physicians in Canada. AB - OBJECTIVE: The importance and potential value of office-based electronic health record (EHR) systems is being recognized internationally. We thus sought to better understand how EHRs are actually being used by family physicians and what they perceive to be the main performance outcomes for themselves and their medical practices. METHODS: We conducted a survey of family physicians practicing in medical practices in Quebec, Canada (n =331). Bivariate and multivariate statistical analyses were conducted to characterize EHR usage behaviors and assess the perceived performance outcomes of these systems. RESULTS: EHR systems "as-used" vary substantively from one family physician to another in terms of the capabilities that are actually mobilized by them. Significant differences between "basic" and "advanced" users were observed in terms of the EHR system's characteristics and perceived performance outcomes. Physicians were also clustered under three profiles that could be clearly distinguished from one another, in terms of the extent to which their performance and their practice's performance was impacted by their EHR usage. Physicians that are "highly impacted" by their EHR system are those who have the longest usage experience and make the most extended use of their system's capabilities. CONCLUSIONS: Our study indicates that only a minority of family physicians in our sample use most of the features available in their EHR system. Consequently, few physicians perceive gaining significant performance improvements from such systems. Future research must identify the factors that motivate primary care physicians to assimilate EHR systems in a more extensive manner. PMID- 26238704 TI - Barriers to using eHealth data for clinical performance feedback in Malawi: A case study. AB - INTRODUCTION: Sub-optimal performance of healthcare providers in low-income countries is a critical and persistent global problem. The use of electronic health information technology (eHealth) in these settings is creating large-scale opportunities to automate performance measurement and provision of feedback to individual healthcare providers, to support clinical learning and behavior change. An electronic medical record system (EMR) deployed in 66 antiretroviral therapy clinics in Malawi collects data that supervisors use to provide quarterly, clinic-level performance feedback. Understanding barriers to provision of eHealth-based performance feedback for individual healthcare providers in this setting could present a relatively low-cost opportunity to significantly improve the quality of care. OBJECTIVE: The aims of this study were to identify and describe barriers to using EMR data for individualized audit and feedback for healthcare providers in Malawi and to consider how to design technology to overcome these barriers. METHODS: We conducted a qualitative study using interviews, observations, and informant feedback in eight public hospitals in Malawi where an EMR system is used. We interviewed 32 healthcare providers and conducted seven hours of observation of system use. RESULTS: We identified four key barriers to the use of EMR data for clinical performance feedback: provider rotations, disruptions to care processes, user acceptance of eHealth, and performance indicator lifespan. Each of these factors varied across sites and affected the quality of EMR data that could be used for the purpose of generating performance feedback for individual healthcare providers. CONCLUSION: Using routinely collected eHealth data to generate individualized performance feedback shows potential at large-scale for improving clinical performance in low-resource settings. However, technology used for this purpose must accommodate ongoing changes in barriers to eHealth data use. Understanding the clinical setting as a complex adaptive system (CAS) may enable designers of technology to effectively model change processes to mitigate these barriers. PMID- 26238706 TI - Classification of antecedents towards safety use of health information technology: A systematic review. AB - OBJECTIVES: This paper provides a systematic review of safety use of health information technology (IT). The first objective is to identify the antecedents towards safety use of health IT by conducting systematic literature review (SLR). The second objective is to classify the identified antecedents based on the work system in Systems Engineering Initiative for Patient Safety (SEIPS) model and an extension of DeLone and McLean (D&M) information system (IS) success model. METHODS: A systematic literature review (SLR) was conducted from peer-reviewed scholarly publications between January 2000 and July 2014. SLR was carried out and reported based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. The related articles were identified by searching the articles published in Science Direct, Medline, EMBASE, and CINAHL databases. Data extracted from the resultant studies included are to be analysed based on the work system in Systems Engineering Initiative for Patient Safety (SEIPS) model, and also from the extended DeLone and McLean (D&M) information system (IS) success model. RESULTS: 55 articles delineated to be antecedents that influenced the safety use of health IT were included for review. Antecedents were identified and then classified into five key categories. The categories are (1) person, (2) technology, (3) tasks, (4) organization, and (5) environment. Specifically, person is attributed by competence while technology is associated to system quality, information quality, and service quality. Tasks are attributed by task-related stressor. Organisation is related to training, organisation resources, and teamwork. Lastly, environment is attributed by physical layout, and noise. CONCLUSIONS: This review provides evidence that the antecedents for safety use of health IT originated from both social and technical aspects. However, inappropriate health IT usage potentially increases the incidence of errors and produces new safety risks. The review cautions future implementation and adoption of health IT to carefully consider the complex interactions between social and technical elements propound in healthcare settings. PMID- 26238708 TI - [Autoinflammatory syndromes in childhood]. AB - Systemic autoinflammatory diseases are a group of hereditary and non-hereditary diseases of the innate immune system, characterized by inflammation with no apparent cause, recurrence at irregular intervals and manifestation on the skin, mucous membranes, joints, bone, gastrointestinal tract, blood vessels and the central nervous system (CNS). Amyloidosis and other possibly severe long-term complications are important. Advances in genetics and molecular biology have improved understanding of the pathogenesis of these diseases, including familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome and improved others. The vast majority of these diseases are based on activation of the interleukin-1 (IL-1) pathway, so that inhibition of IL-1 provides a therapeutic option. Other syndromes are characterized by a granulomatous inflammation. Newer autoinflammatory diseases, such as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) and stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) are, however, driven by interferons. PMID- 26238709 TI - [Treat to participation : Position paper of the German Society for Rheumatology on sustained improvement of functional health of patients with rheumatic and musculoskeletal diseases]. AB - From the perspective of patients with rheumatic diseases, the reduction of inflammatory disease activity alone is not a sufficient treatment goal. In addition the functional health and participation also have to be improved. Starting with the first symptoms the empowerment for the self-management of the disease is important for the patients; therefore, the established treat to target strategy has to be expanded by the functional dimension to treat to participation. The position paper of the German Society for Rheumatology (GSR) summarizes the relevant fields of the multiprofessional action that is frequently necessary. This includes the acquirement of function-related competencies during training, further education and advanced training as well as implementation in the everyday practice of patient care. Furthermore, the GSR acknowledges the need for research related to functional and sociomedical consequences of rheumatic diseases and to individual and combined function-related programs in outpatient and inpatient care in rheumatology. PMID- 26238710 TI - Fibronectin Binding Proteins SpsD and SpsL Both Support Invasion of Canine Epithelial Cells by Staphylococcus pseudintermedius. AB - In this study, we investigated the cell wall-anchored fibronectin-binding proteins SpsD and SpsL from the canine commensal and pathogen Staphylococcus pseudintermedius for their role in promoting bacterial invasion of canine progenitor epidermal keratinocytes (CPEK). Invasion was examined by the gentamicin protection assay and fluorescence microscopy. An DeltaspsD DeltaspsL mutant of strain ED99 had a dramatically reduced capacity to invade CPEK monolayers, while no difference in the invasion level was observed with single mutants. Lactococcus lactis transformed with plasmids expressing SpsD and SpsL promoted invasion, showing that both proteins are important. Soluble fibronectin was required for invasion, and an RGD-containing peptide or antibodies recognizing the integrin alpha5beta1 markedly reduced invasion, suggesting an important role for the integrin in this process. Src kinase inhibitors effectively blocked internalization, suggesting a functional role for the kinase in invasion. In order to identify the minimal fibronectin-binding region of SpsD and SpsL involved in the internalization process, recombinant fragments of both proteins were produced. The SpsD520-846 and SpsL538-823 regions harboring the major fibronectin-binding sites inhibited S. pseudintermedius internalization. Finally, the effects of staphylococcal invasion on the integrity of different cell lines were examined. Because SpsD and SpsL are critical factors for adhesion and invasion, blocking these processes could provide a strategy for future approaches to treating infections. PMID- 26238707 TI - Randomised clinical trial: alisporivir combined with peginterferon and ribavirin in treatment-naive patients with chronic HCV genotype 1 infection (ESSENTIAL II). AB - BACKGROUND: Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. AIM: To evaluate efficacy and safety of ALV plus peginterferon-alpha2a and ribavirin (PR) in treatment-naive patients with chronic HCV genotype 1 infection. METHODS: Double-blind, randomised, placebo-controlled, Phase 3 study evaluating ALV 600 mg once daily [response-guided therapy (RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received >=12 weeks and 20% had received >=24 weeks of ALV/PR triple therapy. RESULTS: A total of 1081 patients were randomised (12% cirrhosis, 55% CT/TT IL28B). Addition of ALV to PR improved virological response in a dose dependent fashion. Overall, sustained virological response (SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension. CONCLUSIONS: Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment-naive patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon-free combination regimens. PMID- 26238711 TI - Streptolysin S Promotes Programmed Cell Death and Enhances Inflammatory Signaling in Epithelial Keratinocytes during Group A Streptococcus Infection. AB - Streptococcus pyogenes, or group A Streptococcus (GAS), is a pathogen that causes a multitude of human diseases from pharyngitis to severe infections such as toxic shock syndrome and necrotizing fasciitis. One of the primary virulence factors produced by GAS is the peptide toxin streptolysin S (SLS). In addition to its well-recognized role as a cytolysin, recent evidence has indicated that SLS may influence host cell signaling pathways at sublytic concentrations during infection. We employed an antibody array-based approach to comprehensively identify global host cell changes in human epithelial keratinocytes in response to the SLS toxin. We identified key SLS-dependent host responses, including the initiation of specific programmed cell death and inflammatory cascades with concomitant downregulation of Akt-mediated cytoprotection. Significant signaling responses identified by our array analysis were confirmed using biochemical and protein identification methods. To further demonstrate that the observed SLS dependent host signaling changes were mediated primarily by the secreted toxin, we designed a Transwell infection system in which direct bacterial attachment to host cells was prevented, while secreted factors were allowed access to host cells. The results using this approach were consistent with our direct infection studies and reveal that SLS is a bacterial toxin that does not require bacterial attachment to host cells for activity. In light of these findings, we propose that the production of SLS by GAS during skin infection promotes invasive outcomes by triggering programmed cell death and inflammatory cascades in host cells to breach the keratinocyte barrier for dissemination into deeper tissues. PMID- 26238712 TI - Comparative Genomics Provides Insight into the Diversity of the Attaching and Effacing Escherichia coli Virulence Plasmids. AB - Attaching and effacing Escherichia coli (AEEC) strains are a genomically diverse group of diarrheagenic E. coli strains that are characterized by the presence of the locus of enterocyte effacement (LEE) genomic island, which encodes a type III secretion system that is essential to virulence. AEEC strains can be further classified as either enterohemorrhagic E. coli (EHEC), typical enteropathogenic E. coli (EPEC), or atypical EPEC, depending on the presence or absence of the Shiga toxin genes or bundle-forming pilus (BFP) genes. Recent AEEC genomic studies have focused on the diversity of the core genome, and less is known regarding the genetic diversity and relatedness of AEEC plasmids. Comparative genomic analyses in this study demonstrated genetic similarity among AEEC plasmid genes involved in plasmid replication conjugative transfer and maintenance, while the remainder of the plasmids had sequence variability. Investigation of the EPEC adherence factor (EAF) plasmids, which carry the BFP genes, demonstrated significant plasmid diversity even among isolates within the same phylogenomic lineage, suggesting that these EAF-like plasmids have undergone genetic modifications or have been lost and acquired multiple times. Global transcriptional analyses of the EPEC prototype isolate E2348/69 and two EAF plasmid mutants of this isolate demonstrated that the plasmid genes influence the expression of a number of chromosomal genes in addition to the LEE. This suggests that the genetic diversity of the EAF plasmids could contribute to differences in the global virulence regulons of EPEC isolates. PMID- 26238713 TI - Toll-Like Receptor 9 Contributes to Defense against Acinetobacter baumannii Infection. AB - Acinetobacter baumannii is a common nosocomial pathogen capable of causing severe diseases associated with significant morbidity and mortality in impaired hosts. Pattern recognition receptors, such as the Toll-like receptors (TLRs), play a key role in pathogen detection and function to alert the immune system to infection. Here, we examine the role for TLR9 signaling in response to A. baumannii infection. In a murine model of A. baumannii pneumonia, TLR9(-/-) mice exhibit significantly increased bacterial burdens in the lungs, increased extrapulmonary bacterial dissemination, and more severe lung pathology compared with those in wild-type mice. Following systemic A. baumannii infection, TLR9(-/-) mice have significantly increased bacterial burdens in the lungs, as well as decreased proinflammatory cytokine and chemokine production. These results demonstrate that TLR9-mediated pathogen detection is important for host defense against the opportunistic pathogen Acinetobacter baumannii. PMID- 26238714 TI - Chitinase 3-Like 1 Promotes Candida albicans Killing and Preserves Corneal Structure and Function by Controlling Host Antifungal Responses. AB - Chitinase 3-like 1 (CHI3L1) has been shown to play a role in promoting antibacterial responses, decreasing tissue injury, and enhancing pulmonary repair. This study sought to elucidate the role of CHI3L1 in augmenting the corneal innate immune response to Candida albicans infection in an animal model of fungal keratitis. Flagellin applied topically 24 h prior to C. albicans inoculation significantly protected the corneal from C. albicans and induced CHI3L1 expression in C57BL/6 mouse corneas. CHI3L1, however, played a detectable but minor role in flagellin-induced protection. While C. albicans keratitis was more severe in the corneas treated with Chi3l1 small interfering RNA (siRNA), corneas treated with recombinant CHI3L1 before C. albicans inoculation had markedly ameliorated keratitis, reduced fungal load, and decreased polymorphonucleocyte (PMN) infiltration in an interleukin 13 receptor alpha2 (IL 13Ralpha2)-dependent manner. CHI3L1 treatment resulted in the induction of the antimicrobial peptides beta-defensin 3, CRAMP, and chemokine CXCL10 and its receptor CXCR3 in corneal epithelial cells. Importantly, CHI3L1 administered after C. albicans inoculation also had strong protection against fungal keratitis, suggesting a therapeutic window. This is the first report demonstrating that CHI3L1 is induced during fungal infection, where it acts as an immunomodulator to promote fungal clearance and to regulate antifungal innate immune responses in the cornea. PMID- 26238716 TI - Retraction Note: Species-specific chemosensory gene expression in the olfactory organs of the malaria vector Anopheles gambiae. PMID- 26238715 TI - Similar Neutrophil-Driven Inflammatory and Antibacterial Responses in Elderly Patients with Symptomatic and Asymptomatic Bacteriuria. AB - Differential diagnosis of asymptomatic bacteriuria (ASB) and urinary tract infection (UTI) is based on the presence of diverse symptoms, including fever (>=38.5 degrees C), rigors, malaise, lethargy, flank pain, hematuria, suprapubic discomfort, dysuria, and urgent or frequent urination. There is consensus in the medical community that ASB warrants antibiotic treatment only for patients undergoing urological procedures that lead to mucosal bleeding, catheterized individuals whose ASB persists for more than 48 h after catheter removal, and pregnant women. Pyuria is associated with UTI and implicates host immune responses via release of antibacterial effectors and phagocytosis of pathogens by neutrophils. Such responses are not sufficiently described for ASB. Metaproteomic methods were used here to identify the pathogens and evaluate molecular evidence of distinct immune responses in cases of ASB compared to UTI in elderly patients who were hospitalized upon injury. Neutrophil-driven inflammatory responses to invading bacteria were not discernible in most patients diagnosed with ASB compared to those with UTI. In contrast, proteomic urine analysis for trauma patients with no evidence of bacteriuria, including those who suffered mucosal injuries via urethral catheterization, rarely showed evidence of neutrophil infiltration. The same enzymes contributing to the synthesis of leukotrienes LTB4 and LTC4, mediators of inflammation and pain, were found in the UTI and ASB cohorts. These data support the notion that the pathways mediating inflammation and pain in most elderly patients with ASB are not quantitatively different from those seen in most elderly patients with UTI and warrant larger clinical studies to assess whether a common antibiotic treatment strategy for elderly ASB and UTI patients is justified. PMID- 26238717 TI - Vascular calcification burden of Chinese patients with chronic kidney disease: methodology of a cohort study. AB - BACKGROUND: Vascular calcification is a common complication associated with chronic kidney disease and the major cause of cardiovascular disease in patients with end-stage renal disease. The vascular calcification risk burden is still unknown in China. This study aims to investigate the prevalence of vascular calcification and assess the predictive value of vascular calcification in patients with stage 5 chronic kidney disease on dialysis in China. METHODS/DESIGN: This is a national, multicenter, non-interventional, prospective cohort study planning to recruit 1520 patients with end-stage renal disease receiving hemodialysis or peritoneal dialysis for at least 6 months in 24 dialysis centers in China. All the patients provided written informed consents before participating in this study. It will include a baseline visit and 24 months follow-up period with 4 other visits at 6-month intervals. Vascular calcification images will be obtained to determine the prevalence of vascular calcification, coronary artery calcification, abdominal aortic calcification and cardiac valve calcification. Association between vascular calcification and all cause and cardiovascular disease mortality and non-fatal cardiovascular events will be assessed. Disease management, as assessed by serum level of calcium, phosphorus and intact parathyroid hormone and its impact on vascular calcification, will also be surveyed. DISCUSSION: The new results gained from this study will supplement limited current available data and provide better clinical decisions in Chinese patients with chronic kidney disease on dialysis. PMID- 26238718 TI - Activation of Toll-like receptor 7 inhibits the proliferation and migration, and induces the apoptosis of pancreatic cancer cells. AB - Pancreatic cancer is one of the most malignant types of tumor and has a poor prognosis. Toll-like receptor 7 (TLR7) has been found to be present and have different roles in different types of cancer cells. In the present study, the roles of TLR7 in BxPC-3 cells, a human pancreatic adenocarcinoma cell line, were investigated. The cells were treated with gardiquimod, an agonist of TLR7, following which the properties of the cells, including proliferation, migration, cell cycle and apoptosis, were analyzed. It was revealed that activation of TLR7 by gardiquimod inhibited cell proliferation and migration, and induced apoptosis of the cells. In addition, gardiquimod downregulated the expression levels of cyclin B1, cyclin E and B-cell lymphoma 2, while upregulating the expression of B cell-associated X protein. These results suggested that the activation of TLR7 suppresses the progression of pancreatic cancer. PMID- 26238719 TI - In vitro activity of minocycline alone or in combination in multidrug-resistant Acinetobacter baumannii isolates. AB - Minocycline (MIN) usually shows good activity against Acinetobacter baumannii strains. The reintroduction to the market of intravenous MIN provides an additional agent to the limited options for the treatment of A. baumannii infections. The activity of MIN as a single agent and in combination with rifampicin (RIF), colistin (COL) or imipenem (IMI) was evaluated by means of killing curves and 24 h-time-kill curves in five A. baumannii isolates which were selected on the basis of different antimicrobial resistance profiles. MIN showed bacteriostatic activity in three isolates (2 * or 16 * MIC) and bactericidal activity in the other isolates (64 * MIC). In isolates harbouring the tetB gene, the associations studied were always indifferent. However, in isolates not harbouring tetB, the use of MIN in combination showed a rapid synergistic effect (at 4 h) in four out of nine combinations (two with RIF and one each with IMI and COL). At 24 h, this effect was observed in six out of nine combinations (two in each association). MIN in combination with RIF, IMI and COL showed bactericidal synergy in most of the isolates which did not harbour the tetB gene, but the combinations were not synergistic in tetB-positive isolates. PMID- 26238720 TI - Incidence of narcolepsy before and after MF59-adjuvanted influenza A(H1N1)pdm09 vaccination in South Korean soldiers. AB - BACKGROUND: Previous reports mostly from Europe suggested an association between an occurrence of narcolepsy and an influenza A(H1N1)pdm09 vaccine adjuvanted with AS03 (Pandemrix((r))). During the 2009 H1N1 pandemic vaccination campaign, the Korean military performed a vaccination campaign with one type of influenza vaccine containing MF59-adjuvants. This study was conducted to investigate the background incidence rate of narcolepsy in South Korean soldiers and the association of the MF59-adjuvanted vaccine with the occurrence of narcolepsy in a young adult group. METHODS: To assess the incidence of narcolepsy, we retrospectively reviewed medical records of suspicious cases of narcolepsy in 2007-2013 in the whole 20 military hospitals of the Korean military. The screened cases were classified according to the Brighton Collaboration case definition of narcolepsy. After obtaining the number of confirmed cases of narcolepsy per 3 months in 2007-2013, we compared the crude incidence rate of narcolepsy before and after the vaccination campaign. RESULTS: We included 218 narcolepsy suspicious cases in the initial review, which were screened by the diagnostic code on the computerized disease registry in 2007-2013. Forty-one cases were finally diagnosed with narcolepsy in 2007-2013 (male sex, 95%; median age, 21 years). The average background incidence rate of narcolepsy in Korean soldiers was 0.91 cases per 100,000 persons per year. During the 9 months before vaccination implementation (April to December 2009), 6 narcolepsy cases occurred, whereas during the next 9 months (January to September 2010) including the 3 month vaccination campaign, 5 cases occurred. CONCLUSIONS: The incidence of narcolepsy in South Korean soldiers was not increased after the pandemic vaccination campaign using the MF59-adjuvanted vaccine. Our results suggest that the MF59-adjuvanted H1N1 vaccine did not contribute to the occurrence of narcolepsy in this young adult group. PMID- 26238721 TI - Reduction of avian influenza virus shedding by administration of Toll-like receptor ligands to chickens. AB - Avian influenza viruses (AIV) are of concern to the poultry industry. Outbreaks of AIV highlight the urgent need for effective control measures. Prophylactic strategies should be explored that rapidly elicit immunity against the virus. Toll-like receptors (TLRs) are innate immune molecules that can induce anti-viral responses, therefore the application of TLR ligands as prophylactic agents in chickens is gaining more attention. We hypothesized that treatment of chickens with TLR ligands reduces the shedding of AIV from infected birds. In addition, the effects of TLR ligand dose and route of administration on the efficiency of TLR ligands to reduce AIV shedding were examined. Chickens were treated with TLR2, 4, 7 and 21 ligands using different doses and routes of administration, 18h before AIV infection. Moreover, the expression of several candidate genes, such as type I interferons, PKR, OAS, viperin and IFITM3 was quantified at 3, 8 and 18h post-treatment with TLR ligands. The results revealed that route of administration and dosage affect the efficacy of TLR ligands to reduce virus shedding. Furthermore, varying effects were observed when different ligands were applied. Our results demonstrated that all TLR ligand treatments reduced AIV shedding, with the CpG-ODN 1826 being the most efficacious to reduce oral virus shedding, whereas LPS from Escherichia coli 026:B6 resulted in the largest reduction in cloacal virus shedding. Moreover, TLR ligands induced the expression of genes involved in antiviral responses such as type I interferons and interferon-stimulated genes in chicken trachea and cecal tonsils. These results raise the possibility of treatment of chickens with TLR ligands as anti-viral agents. PMID- 26238722 TI - Live attenuated Salmonella enterica serovar Choleraesuis vaccine vector displaying regulated delayed attenuation and regulated delayed antigen synthesis to confer protection against Streptococcus suis in mice. AB - Salmonella enterica serotype Choleraesuis (S. Choleraesuis) and Streptococcus suis (S. suis) are important swine pathogens. Development of a safe and effective attenuated S. Choleraesuis vaccine vector would open a new window to prevent and control pig diseases. To achieve this goal, the mannose and arabinose regulated delayed attenuated systems (RDAS), Deltapmi and DeltaPcrp::TT araC PBADcrp, were introduced into the wild type S. Choleraesuis strain C78-3. We also introduced DeltarelA::araC PBADlacI TT to achieve regulated delayed antigen synthesis and DeltaasdA to constitute a balanced-lethal plasmid system. The safety and immunogenicity of the resulted RDAS S. Choleraesuis strain rSC0011 carrying 6 phosphogluconate dehydrogenase (6-PGD) of S. suis serotype 2 (SS2) were evaluated in vitro and in vivo. Compared with the wild type parent strain C78-3 and vaccine strain C500, a live attenuated S. Choleraesuis vaccine licensed for piglet in China, the results showed that the survival curves of the vaccine strain rSC0011 were similar to those of strains C78-3 and C500 at the early stage of infection, but lower than those of C78-3 and higher than those of C500 at the later stage in both porcine alveolar macrophages and peripheral porcine monocytes. The LD50 of the RDAS strains rSC0011 by oral route in mice was close to that of C500 and 10,000-fold higher than that of C78-3. Similar results were achieved by intraperitoneal (i.p.) route, suggesting that the RDAS strains rSC0011 achieved similar attenuation as C500. However, the RDAS strain rSC0011 was superior to C500 in colonization of Peyer's patches. Adult mice orally immunized with strain rSC0011 carrying a plasmid expression 6-phosphogluconate dehydrogenase (6-PGD) gene from SS2 developed strong immune responses against 6-PGD and Salmonella antigens, and conferred high protection against i.p. challenge with SS2. PMID- 26238723 TI - Perinatal survival and health after maternal influenza A(H1N1)pdm09 vaccination: A cohort study of pregnancies stratified by trimester of vaccination. AB - Large cohort studies demonstrated the safety of vaccination with the AS03 adjuvanted pandemic influenza vaccine, but data on first trimester vaccination safety are limited. We conducted a nationwide register-based retrospective cohort study in Finland, included singleton pregnancies present on 01 November 2009 and followed them from 01 November 2009 until delivery. Pregnancies with abortive outcome, pregnancies that started before 01 February 2009 and pregnancies of women, who received the AS03 adjuvanted pandemic influenza vaccine prior to the onset of pregnancy, were excluded. Our main outcome measures were hazard ratios comparing the risk of stillbirth, early neonatal death, moderately preterm birth, very preterm birth, moderately low birth weight, very low birth weight, and being small for gestational age between pregnancies exposed and unexposed to maternal influenza A(H1N1)pdm09 vaccination. The study population comprised 43,604 pregnancies; 34,241 (78.5%) women were vaccinated at some stage during pregnancy. The rates of stillbirth, early neonatal death, moderately preterm birth, and moderately low birth weight were similar between pregnant women exposed and unexposed to influenza A(H1N1)pdm09 vaccination. After adjusting for known risk factors, the relative rates were 0.90 (95% confidence interval 0.55-1.45) for very preterm birth, 0.84 (0.61-1.16) for very low birth weight, and 1.17 (0.98 1.40) for being small for gestational age. Also, in the subanalysis of 7839 women vaccinated during the first trimester, the rates did not indicate that maternal vaccination during the first trimester had any adverse impact on perinatal survival and health. The risk of adverse pregnancy outcomes was not associated with the exposure to the AS03 adjuvanted pandemic influenza vaccine. This study adds reassuring evidence on the safety of AS03 adjuvanted influenza vaccines when given in the first trimester and supports the recommendation of influenza vaccination to all pregnant women through all stages of pregnancy. PMID- 26238724 TI - Influenza vaccination type, live, attenuated influenza vaccine (LAIV) versus inactivated influenza vaccine (IIV), received by children, United States, 2011-12 through 2013-14 influenza seasons. AB - BACKGROUND: Influenza vaccines available for children in the United States include inactivated influenza vaccine (IIV) and live, attenuated influenza vaccine (LAIV). Objectives of this study were to quantify proportions of IIV and LAIV received by vaccinated children, and examine associations between vaccine type received and demographic characteristics. METHODS: National Immunization Survey-Flu (NIS-Flu) parental reported data for the 2011-12 through 2013-14 influenza seasons were used to estimate proportions of vaccinated children 2-17 years who received IIV and LAIV. Tests of association between vaccination type and demographic variables were conducted using Wald chi-square tests and pair wise comparison t-tests. Multivariable logistic regression was used to determine variables independently associated with receipt of LAIV versus IIV. RESULTS: In the 2013-14 season, 33.3% of vaccinated children received LAIV, similar to the proportion in the 2011-12 (32.2%) and 2012-13 (32.1%) seasons. Across all seasons studied, the strongest observed association was between vaccination type and child's age, with children 2-8 years (Adjusted Prevalence Ratio (95% confidence interval) [APR(95% CI)] 1.41(1.27-1.56), 1.46(1.34-1.59), and 1.50(1.38-1.63) for 2011-12, 2012-13, and 2013-14) and 9-12 years (APR(95% CI) 1.37(1.23-1.54), 1.38(1.26-1.51), and 1.50(1.38-1.63) for 2011-12, 2012-13, and 2013-14) being more likely to have received LAIV than children 13-17 years. Among those vaccinated, whites were more likely to have received LAIV compared with blacks (APR(95% CI) 1.19(1.05-1.35), 1.24(1.10-1.39), and 1.22(1.11-1.34) for 2011-12, 2012-13, and 2013-14), and children living above poverty (annual income >$75,000) were more likely to have received LAIV than those living at or below poverty (APR(95% CI) 1.43(1.23-1.67), 1.13(1.02-1.26), and 1.16(1.06-1.28) for 2011-12, 2012-13, and 2013-14). CONCLUSIONS: This study provides a baseline of the extent and patterns of LAIV uptake that can be used to measure the impact of relevant public health policy. Additional research is needed to investigate parental and provider preferences and barriers regarding LAIV. PMID- 26238725 TI - Current methods of epitope identification for cancer vaccine design. AB - The importance of the immune system in tumor development and progression has been emerging in many cancers. Previous cancer vaccines have not shown long-term clinical benefit possibly because were not designed to avoid eliciting regulatory T-cell responses that inhibit the anti-tumor immune response. This review will examine different methods of identifying epitopes derived from tumor associated antigens suitable for immunization and the steps used to design and validate peptide epitopes to improve efficacy of anti-tumor peptide-based vaccines. Focusing on in silico prediction algorithms, we survey the advantages and disadvantages of current cancer vaccine prediction tools. PMID- 26238726 TI - Comparison of the efficacy of Neethling lumpy skin disease virus and x10RM65 sheep-pox live attenuated vaccines for the prevention of lumpy skin disease - The results of a randomized controlled field study. AB - Lumpy skin disease (LSD) is a viral disease of cattle and buffalo, caused by a Capripox virus. A field study was performed during an LSD epidemic which occurred in 2012-2013 in Israel, in order to assess the efficacy of two commercial vaccines for protection against LSD. Fifteen dairy herds, vaccinated 2-5 months prior to study onset with a single dose of 10(2.5) TCID50 of RM65 attenuated sheep-pox vaccine, and not affected previously, were enrolled in the study. 4694 cows were randomized to be either vaccinated with a 10(3.5) TCID50/dose of RM65 vaccine (x10RM65) or with a same dose of an attenuated Neethling LSD virus vaccine. A case of LSD was defined as the appearance of at least 5 lesions typical to LSD and a severe case was defined if this sign was accompanied by either fever (>39.5 degrees C) or/and a 20% reduction in milk production. Deep lesion biopsies and blood samples were collected from 64.5% of the cases in an attempt to detect DNA of LSD virus by PCR and to differentiate between the wild strain and the vaccine Neethling strain. Seventy-six cows were affected by LSD in 8 herds with an incidence of 0.3-5.7%. Mantel-Haenszel relative risk (RRMH) for LSD morbidity at least 15 days after vaccination in x10RM65 vs. Neethling was 2.635 (CI95%=1.44-4.82) and 11.2 (2.3-54.7) for severe morbidity. RRMH for laboratory confirmed cases was 4.28 (1.59-11.53). An incidence of 0.38% (9/2356) of Neethling associated disease was observed among Neethling vaccinated cows while no such disease occurred in x10RM65 vaccinated cows. We conclude that the Neethling vaccine is significantly more effective than x10RM65 in preventing LSD morbidity, though it might cause a low incidence of Neethling associated disease. No transmission of the Neethling strain to non-Neethling vaccinated cows was observed in this study. PMID- 26238727 TI - Comparison of unbiased estimation of neuronal number in the rat hippocampus with different staining methods. AB - BACKGROUND: NeuN and Nissl staining (toluidine blue, cresyl violet staining) are routinely used methods in unbiased stereological estimation of the total number of hippocampal neurons. NEW METHOD: In the present study, we stained serial frozen coronal sections from 5 normal adult male Sprague-Dawley rat brains with different methods, measured the deformation of hippocampal area in brain sections and estimated the total number of hippocampal neurons using the optical fractionator. RESULTS: The deformation in x, y-axis was not obviously different with different staining protocols, but shrinkage in z-axis was significant after staining (p < 0.001). NeuN staining produced significant higher estimate number than cresyl violet staining by 24% (p = 0.002), however, NeuN and Cresyl Violet staining showed a high degree of correlation in quantification of total neuronal numbers and both methods are suitable for unbiased stereological estimation. COMPARISON WITH EXISTING METHOD (S): NeuN is more reliable but if time is limited or the number of animals used in experiments is high, cresyl violet staining may be a feasible method. CONCLUSIONS: Compared with previous estimates of the neurons number in rat hippocampus, our present data is reliable and the stereological analysis based on our system is a cost-effective unbiased method for estimation of neuron number. PMID- 26238728 TI - A novel 3D method of locomotor analysis in adult zebrafish: Implications for automated detection of CNS drug-evoked phenotypes. AB - BACKGROUND: Expanding the spectrum of organisms to model human brain phenotypes is critical for our improved understanding of the pathobiology of neuropsychiatric disorders. Given the clear limitations of existing mammalian models, there is an urgent need for low-cost, high-throughput in-vivo technologies for drug and gene discovery. NEW METHOD: Here, we introduce a new automated method for generating 3D (X,Y,Z) swim trajectories in adult zebrafish (Danio rerio), to improve their neurophenotyping. RESULTS: Based on the Track3D module of EthoVision XT video tracking software (Noldus Information Technology), this tool enhances the efficient, high-throughput 3D analyses of zebrafish behavioral responses. Applied to adult zebrafish behavior, this 3D method is highly sensitive to various classes of psychotropic drugs, including selected psychostimulant and hallucinogenic agents. COMPARISON WITH EXISTING METHODS: Our present method offers a marked advance in the existing 2D and 3D methods of zebrafish behavioral phenotyping, minimizing research time and recording high resolution, automatically synchronized videos with calculated, high-precision object positioning. CONCLUSIONS: Our novel approach brings practical simplicity and 'integrative' capacity to the often complex and error-prone quantification of zebrafish behavioral phenotypes. Illustrating the value of 3D swim path reconstructions for identifying experimentally-evoked phenotypic profiles, this method fosters innovative, ethologically relevant, and fully automated small molecule screens using adult zebrafish. PMID- 26238729 TI - Transdermal spinal catheter placement in piglets: Description and validation of the technique. AB - BACKGROUND: The swine species represents a perfect model for translational medicine due to its physiological and anatomical resemblance to humans. The development of techniques for spinal catheter insertion in swine is significantly useful but, at the moment, the only technique described requires laminectomy as a surgical approach. NEW METHOD: The proposed techniques represent a transdermal approach for catheter placement in piglets. The study was divided into Phase I (anatomical study on 8 cadavers) and Phase II (in vivo application of the technique in 20 anaesthetised 30-day old piglets). A spinal needle was introduced between the L2 and L3 spinous processes with a ventro-cranial orientation until cerebro-spinal fluid leakage. It was then replaced with a Tuohy needle, used to introduce the catheter into the intrathecal space. Before inserting the catheter, the approximate length from the insertion point to the external projection of the Cisterna Magna was measured using the gradation markings on the device. RESULTS: The technique described allowed spinal catheter placement in all piglets. In Phase I, the correct placement was confirmed using fluoroscopy while, in Phase II, cerebrospinal fluid leakage from the needle was relied on. No clinical alterations were detected either during the procedure or during the following days. COMPARISON WITH EXISTING METHOD: This technique is easy and requires less skilled operators when compared to the other existing method which involves a surgical approach. Moreover, being less invasive, it potentially leads to fewer complications. CONCLUSIONS: In conclusion, the technique can be performed safely in piglets, and provides an easier and less invasive approach for spinal catheter insertion. PMID- 26238730 TI - The Bankart Performance Metrics Combined With a Cadaveric Shoulder Create a Precise and Accurate Assessment Tool for Measuring Surgeon Skill. AB - PURPOSE: To determine if previously validated performance metrics for an arthroscopic Bankart repair (ABR) coupled with a cadaveric shoulder are a valid assessment tool with the ability to discriminate between the performances of experienced and novice surgeons and to establish a proficiency benchmark for an ABR using a cadaveric shoulder. METHODS: Ten master/associate master faculty from an Arthroscopy Association of North America Resident Course (experienced group) were compared with 12 postgraduate year 4 and postgraduate year 5 orthopaedic residents (novice group). Each group was instructed to perform a diagnostic arthroscopy and a 3 suture anchor Bankart repair on a cadaveric shoulder. The procedure was videotaped in its entirety and independently scored in blinded fashion by a pair of trained reviewers. Scoring was based on defined and previously validated metrics for an ABR and included steps, errors, "sentinel" (more serious) errors, and time. RESULTS: The inter-rater reliability was 0.92. Novice surgeons made 50% more errors (5.86 v 2.95, P = .013), showed more performance variability (SD, 1.86 v 0.55), and took longer to perform the procedure (45.5 minutes v 25.9 minutes, P < .001). The greatest difference in errors related to suture delivery and management (exclusive of knot tying) (1.95 v 0.45, P = .024). CONCLUSIONS: The assessment tool composed of validated arthroscopic Bankart metrics coupled with a cadaveric shoulder accurately distinguishes the performance of experienced from novice orthopaedic surgeons. A benchmark based on the mean performance of the experienced group includes completion of a 3-anchor Bankart repair, and enacting no more than 3 total errors and 1 sentinel error. CLINICAL RELEVANCE: Validated procedural metrics combined with the use of a cadaveric shoulder can be used to assess the performance of an ABR. The methodology used may serve as a template for outcomes-based procedural skills training in general. PMID- 26238731 TI - Effects of dietary boron and phytase supplementation on growth performance and mineral profile of broiler chickens fed on diets adequate or deficient in calcium and phosphorus. AB - 1. Two experiments were designed to determine the effect of dietary boron (B) in broiler chickens. In Experiment 1, a 2 * 4 factorial arrangement of treatments was used to investigate the effect of dietary calcium (Ca) and available phosphorus (aP) (adequate or deficient) and supplemental B (0, 20, 40, and 60 mg/kg diet). In Experiment 2, B, at 20 mg/kg, and phytase (PHY) (500 FTU/kg diet) were incorporated into a basal diet deficient in Ca and aP, either alone or in combination. 2. The parameters that were measured were growth performance indices, serum biochemical activity as well as ash and mineral (i.e. Ca, P, Mg, Fe, Cu and Zn) content of tibia, breast muscle and liver. 3. Results indicated that both supplemental B and dietary Ca and aP had marginal effects on performance indices of chickens grown for 42 d. 4. There were positive correlations (linear effect) between B concentrations of serum, bone, breast muscle and liver and the amount of B consumed. 5. Serum T3 and T4 activities increased linearly with higher B supplementation. 6. Increasing supplemental B had significant implications on breast muscle and liver mineral composition. Lowering dietary Ca and aP level increased Cu content in liver and both Fe and Zn retention in breast muscle. Tibia ash content and mineral composition did not respond to dietary modifications with either Ca-aP or B. 7. The results also suggested that dietary contents of Ca and aP do not affect the response to B regarding tissue mineral profile. Dietary combination with B and PHY did not create a synergism with regard to growth performance and bioavailability of the minerals. PMID- 26238732 TI - 3D cell culture and osteogenic differentiation of human bone marrow stromal cells plated onto jet-sprayed or electrospun micro-fiber scaffolds. AB - A major limitation of the 2D culture systems is that they fail to recapitulate the in vivo 3D cellular microenvironment whereby cell-cell and cell-extracellular matrix (ECM) interactions occur. In this paper, a biomaterial scaffold that mimics the structure of collagen fibers was produced by jet-spraying. This micro fiber polycaprolactone (PCL) scaffold was evaluated for 3D culture of human bone marrow mesenchymal stromal cells (MSCs) in comparison with a commercially available electrospun scaffold. The jet-sprayed scaffolds had larger pore diameters, greater porosity, smaller diameter fibers, and more heterogeneous fiber diameter size distribution compared to the electrospun scaffolds. Cells on jet-sprayed constructs exhibited spread morphology with abundant cytoskeleton staining, whereas MSCs on electrospun scaffolds appeared less extended with fewer actin filaments. MSC proliferation and cell infiltration occurred at a faster rate on jet-sprayed compared to electrospun scaffolds. Osteogenic differentiation of MSCs and ECM production as measured by ALP, collagen and calcium deposition was superior on jet-sprayed compared to electrospun scaffolds. The jet-sprayed scaffold which mimics the native ECM and permits homogeneous cell infiltration is important for 3D in vitro applications such as bone cellular interaction studies or drug testing, as well as bone tissue engineering strategies. PMID- 26238733 TI - Measuring localized viscoelasticity of the vitreous body using intraocular microprobes. AB - Vitrectomy is a standard ophthalmic procedure to remove the vitreous body from the eye. The biomechanics of the vitreous affects its duration (by changing the removal rate) and the mechanical forces transmitted via the vitreous on the surrounding tissues during the procedure. Biomechanical characterization of the vitreous is essential for optimizing the design and control of instruments that operate within the vitreous for improved precision, safety, and efficacy. The measurements are carried out using a magnetic microprobe inserted into the vitreous, a method known as magnetic microrheology. The location of the probe is tracked by a microscope/camera while magnetic forces are exerted wirelessly by applied magnetic fields. In this work, in vitro artificial vitreous, ex vivo human vitreous and ex vivo porcine vitreous were characterized. In addition, in vivo rabbit measurements were performed using a suturelessly injected probe. Measurements indicate that viscoelasticity parameters of the ex vivo human vitreous are an order of magnitude different from those of the ex vivo porcine vitreous. The in vivo intra-operative measurements show typical viscoelastic behavior of the vitreous with a lower compliance than the ex vivo measurements. The results of the magnetic microrheology measurements were validated with those obtained by a standard atomic force microscopy (AFM) method and in vitro artificial vitreous. This method allows minimally-invasive characterization of localized mechanical properties of the vitreous in vitro, ex vivo, and in vivo. A better understanding of the characteristics of the vitreous can lead to improvements in treatments concerning vitreal manipulation such as vitrectomy. PMID- 26238734 TI - GABAergic interneuronal loss and reduced inhibitory synaptic transmission in the hippocampal CA1 region after mild traumatic brain injury. AB - Patients that suffer mild traumatic brain injuries (mTBI) often develop cognitive impairments, including memory and learning deficits. The hippocampus shows a high susceptibility to mTBI-induced damage due to its anatomical localization and has been implicated in cognitive and neurological impairments after mTBI. However, it remains unknown whether mTBI cognitive impairments are a result of morphological and pathophysiological alterations occurring in the CA1 hippocampal region. We investigated whether mTBI induces morphological and pathophysiological alterations in the CA1 using the controlled cortical impact (CCI) model. Seven days after CCI, animals subjected to mTBI showed cognitive impairment in the passive avoidance test and deficits to long-term potentiation (LTP) of synaptic transmission. Deficiencies in inducing or maintaining LTP were likely due to an observed reduction in the activation of NMDA but not AMPA receptors. Significant reductions in the frequency and amplitude of spontaneous and miniature GABAA receptor mediated inhibitory postsynaptic currents (IPSCs) were also observed 7 days after CCI. Design-based stereology revealed that although the total number of neurons was unaltered, the number of GABAergic interneurons is significantly reduced in the CA1 region 7 days after CCI. Additionally, the surface expression of alpha1, beta2/3, and gamma2 subunits of the GABAA receptor were reduced, contributing to a reduced mIPSC frequency and amplitude, respectively. Together, these results suggest that mTBI causes a significant reduction in GABAergic inhibitory transmission and deficits to NMDA receptor mediated currents in the CA1, which may contribute to changes in hippocampal excitability and subsequent cognitive impairments after mTBI. PMID- 26238735 TI - Rapid changes in expression of class I and IV histone deacetylases during epileptogenesis in mouse models of temporal lobe epilepsy. AB - A prominent role of epigenetic mechanisms in manifestation of epilepsy has been proposed. Thus altered histone H3 and H4 acetylation has been demonstrated in experimental models of temporal lobe epilepsy (TLE). We now investigated changes in the expression of the class I and class IV histone deacetylases (HDAC) in two complementary mouse TLE models. Unilateral intrahippocampal injection of kainic acid (KA) induced a status epilepticus lasting 6 to 24h, development of spontaneous limbic seizures (2 to 3 days after KA injection) and chronic epilepsy, as revealed by telemetric recordings of the EEGs. Mice were killed at different intervals after KA injection and expression of HDAC mRNAs was investigated by in situ hybridization. We observed marked decreases in the expression of HDACs 1, 2 and 11 (by up to 75%) in the granule cell and pyramidal cell layers of the hippocampus during the acute status epilepticus (2 to 6h after KA injection). This was followed by increased expression of all class I HDAC mRNAs in all principal cell layers of the hippocampus after 12 to 48 h. In the chronic phase, 14 and 28 days after KA, only modest increases in the expression of HDAC1 mRNA were observed in granule and pyramidal cells. Immunohistochemistry using an antibody detecting HDAC2 revealed results consistent with the mRNA data and indicates also expression in glial cells on the injection side. Similar changes as seen in the KA model were observed after a pilocarpine-induced status epilepticus except that decreases in HDACs 2, 3 and 8 were also seen at the chronic 28 day interval. The prominent decreases in HDAC expression during status epilepticus are consistent with the previously demonstrated increased expression of numerous proteins and with the augmented acetylation of histone H4. It is suggested that respective putative gene products could facilitate proconvulsive as well as anticonvulsive mechanisms. The increased expression of all class I HDACs during the "silent phase", on the other hand, may be related to decreased histone acetylation, which could cause a decrease in expression of certain proteins, a mechanism that could also promote epileptogenesis. Thus, addressing HDAC expression may have a therapeutic potential in interfering with a status epilepticus and with the manifestation of TLE. PMID- 26238736 TI - Expression profile analysis of microRNAs and downregulated miR-486-5p and miR-30a 5p in non-small cell lung cancer. AB - Lung cancer is the leading cause of cancer-related mortality worldwide and although there have been improvements in treatment there is a low survival rate. The aim of the present study was to investigate the effect of microRNA (miRNA) on cell pathways. A miRNA microarray was used to profile miRNAs of lung cancer tissues. It was identified that 33 miRNAs with >2.0-fold change and FDR <0.05 were differentially expressed between the adjacent non-cancerous lung tissues and non-small cell lung cancers NSCLCs (P<0.005). The data were optimized in combination with physical interaction analysis to obtain crucial miRNAs. The results showed that differentially expressed miRNAs were associated with biological processes such as cell migration, protein phosphorylation and neuron differentiation, and signaling pathways such as MAPK, TGF-beta and PI3K/Akt signaling pathways. Validation of significant miRNAs in independent 40 paired NSCLC tissues demonstrated that the expression level of miR-486-5p and miR-30a-5p was significantly downregulated in another 40 paired lung cancer tissues. Taken together, the results provided strong evidence of the possible involvement of miRNAs in the development and progression of NSCLC. Thus, the results are of importance for clinical investigators and for those who design miRNA-based novel cancer therapeutics. PMID- 26238737 TI - Interface Engineering through Atomic Layer Deposition towards Highly Improved Performance of Dye-Sensitized Solar Cells. AB - A composite photoanode comprising ultralong ZnO nanobelts and TiO2 nanoparticles was prepared and its performance in dye-sensitized solar cells (DSSCs) was optimized and compared to the photoanode consisting of conventional TiO2 nanoparticles. The ultralong ZnO nanobelts were synthesized in high yield by a facile solution approach at 90 degrees C followed by annealing at 500 degrees C. The effect of the ratio of ZnO nanobelts to TiO2 nanoparticles on the light scattering, specific surface area, and interface recombination were investigated. An optimum amount of ZnO nanobelts enhanced the photon-conversion efficiency by 61.4% compared to that of the conventional TiO2 nanoparticles. To further reduce the recombination rate and increase the carrier lifetime, Atomic Layer Deposition (ALD) technique was utilized to coat a continuous TiO2 film surrounding the ZnO nanobelts and TiO2 nanoparticles, functioning as a barrier-free access of all electrons to conductive electrodes. This ALD treatment improved the interface contact within the whole photoanode system, finally leading to significant enhancement (137%) in the conversion efficiency of DSSCs. PMID- 26238739 TI - Novel Approaches to the Management of Advanced Peripheral Artery Disease: Perspectives on Drug-Coated Balloons, Drug-Eluting Stents, and Bioresorbable Scaffolds. AB - Introducing anti-restenotic drug-based treatment modalities in femoropopliteal interventions is the potential revolutionizing reperfusion treatment of peripheral artery disease. Durability of recanalization procedures using drug coated balloons (DCB) and drug-eluting stents (DES) yields in excellent mid-term and long-term technical and clinical outcomes and may be cost saving on the long term as compared to traditional treatment modalities such as plain old balloon angioplasty (POBA) and bare metal nitinol stent implantation. Drug-eluting bioresorbable scaffolds are another drug-based promising treatment option but are still investigational. In particular, DCB provide a novel method to locally deliver paclitaxel into the arterial wall without the need of a chronically implanted delivery system or even if those devices will be indicated, they can be delivered focally. Following the first positive pilot studies, two large pivotal trials have confirmed superiority of DCB over plain old balloon angioplasty (POBA) in the treatment of TASC II A and B femoropopliteal lesions. Even for more complex femoropopliteal lesions such as long lesions and instent restenosis, single center studies and small randomized studies have shown promising mid-term technical and clinical results. For DES, follow-up data for the only commercially available device are now presented up to 5 years with excellent clinical outcome regarding freedom from target lesion revascularization and improvement of walking capacity. This review article summarizes the current knowledge and perspectives of drug-based endovascular treatment modalities in femoropopliteal interventions and discusses still unresolved needs. PMID- 26238738 TI - Renal Artery Stenosis: Optimal Therapy and Indications for Revascularization. AB - Atherosclerotic renal artery stenosis (ARAS) is associated with increased cardiovascular risk and overall mortality. Manifestations of ARAS include resistant or malignant hypertension, progressive deterioration of renal function, and cardiac dysfunction syndromes of flash pulmonary edema and angina. Diagnosis rests upon non-invasive studies such as duplex ultrasonography and is confirmed using invasive renal arteriography. Regardless of the severity of ARAS, management of this entity has been a topic of contentious debate. For over two decades, the use of percutaneous revascularization to treat ARAS has been studied with various clinical trials. Though case series seem to demonstrate favorable clinical response to revascularization, the overwhelming majority of randomized clinical trials have not mirrored a robust outcome. In these trials, poor correlation is noted between the reduction of stenosis and the improvement of renovascular hypertension and glomerular filtration rate, and decrease in cardiovascular outcomes and mortality. With dichotomizing results, the explanation for these discrepant findings has been attributed to improper trial design and inappropriate patient selection. An overview of the treatment options available will be provided, with a focus on the methodology and design of clinical trials investigating the efficacy of percutaneous revascularization. Emphasis is placed on appropriate patient selection criteria, which may necessitate the use of hemodynamic lesion assessment and clinical correlation based on individualized care. When clinical equipoise exists between optimal medical therapy and revascularization, the current paradigm supports ongoing medical therapy as the treatment of choice. However, renal artery stenting remains a viable therapeutic option for those who continue to have clinical syndromes consistent with renal hypoperfusion while adequately treated with optimal medical therapy. Despite observational studies suggesting clinical benefit for this specific patient population, there remains a paucity of randomized clinical trial data. Further trials targeting the patients who are inadequately treated with optimal medical therapy need to be undertaken to confirm the efficacy of revascularization. PMID- 26238740 TI - Carotid Disease Management: Surgery, Stenting, or Medication. AB - Internal carotid artery stenosis accounts for about 7-10 % of ischemic strokes. Conventional risk factors such as aging, hypertension, diabetes mellitus, and smoking increase the risk for carotid atherosclerosis. All patients with carotid stenosis should receive aggressive medical therapy. Carotid revascularization with either endarterectomy or stenting can benefit select patients with severe stenosis. New clinical trials will examine the contemporary role of carotid revascularization relative to optimal medical therapy. PMID- 26238741 TI - New Oral Anticoagulants: How Do We Use Them Wisely? AB - The relative efficacy and safety of new oral anticoagulants (NOAC) have been consistent across a wide range of patients in clinical trials. On the one hand, they have offered new therapeutic options for stroke prevention in patients with atrial fibrillation (AF) and patients do like the experience of no need of frequent blood draws. On the other hand, their expensive prices, different formulary plans from different insurance companies, lack of antidote, and no method of monitoring the therapy are some of the challenges on their use in clinical practice. This narrative review aims to help clinicians understand these new oral anticoagulants better and choose them wisely according to their indications. In addition, other issues related to the use of NOAC, such as cost and methods of reversing their effects in hemorrhagic conditions, are also discussed. PMID- 26238742 TI - Cannabis, Cannabinoids, and Cerebral Metabolism: Potential Applications in Stroke and Disorders of the Central Nervous System. AB - No compound has generated more attention in both the scientific and recently in the political arena as much as cannabinoids. These diverse groups of compounds referred collectively as cannabinoids have both been vilified due to its dramatic and potentially harmful psychotropic effects and glorified due to its equally dramatic and potential application in a number of acute and chronic neurological conditions. Previously illegal to possess, cannabis, the plant where natural form of cannabinoids are derived, is now accepted in a growing number of states for medicinal purpose, and some even for recreational use, increasing opportunities for more scientific experimentation. The purpose of this review is to summarize the growing body of literature on cannabinoids and to present an overview of our current state of knowledge of the human endocannabinoid system in the hope of defining the future of cannabinoids and its potential applications in disorders of the central nervous system, focusing on stroke. PMID- 26238743 TI - Treatment of Intracranial Aneurysms: Clipping Versus Coiling. AB - Intracranial aneurysms (IAs) have an estimated incidence of up to 10 % and can lead to serious morbidity and mortality. Because of this, the natural history of IAs has been studied extensively, with rupture rates ranging from 0.5 to 7 %, depending on aneurysm characteristics. The spectrum of presentation of IAs ranges from incidental detection to devastating subarachnoid hemorrhage. Although the gold standard imaging technique is intra-arterial digital subtraction angiography, other modalities such as computed tomography angiography (CTA) and magnetic resonance angiography (MRA) are being increasingly used for screening and treatment planning. Management of these patients depends upon a number of factors including aneurysmal, patient, institutional, and operator factors. The ultimate goal of treating patients with IAs is complete and permanent occlusion of the aneurysm sac in order to eliminate future hemorrhagic risk, while preserving or restoring the patient's neurological function. The most common treatment approaches include microsurgical clipping and endovascular coiling, and multiple studies have compared these two techniques. To date, three large prospective, randomized studies have been done: a study from Finland, International Subarachnoid Aneurysm Trial (ISAT), and the Barrow Ruptured Aneurysm Trial (BRAT). Despite differences in methodology, the results were similar: in patients undergoing coiling, although rates of rebleeding and retreatment are higher, the overall rate of poor outcomes at 12 months was significantly lower. As minimally invasive procedures and devices continue to be refined, endovascular strategies are likely to increase in popularity. However, as long-term outcome studies become available, it is increasingly apparent that they are complementary treatment strategies, with patient selection of critical importance. PMID- 26238744 TI - Work Stress as a Risk Factor for Cardiovascular Disease. AB - The role of psychosocial work stress as a risk factor for chronic disease has been the subject of considerable debate. Many researchers argue in support of a causal connection while others remain skeptical and have argued that the effect on specific health conditions is either negligible or confounded. This review of evidence from over 600,000 men and women from 27 cohort studies in Europe, the USA and Japan suggests that work stressors, such as job strain and long working hours, are associated with a moderately elevated risk of incident coronary heart disease and stroke. The excess risk for exposed individuals is 10-40 % compared with those free of such stressors. Differences between men and women, younger versus older employees and workers from different socioeconomic backgrounds appear to be small, indicating that the association is robust. Meta-analyses of a wider range of health outcomes show additionally an association between work stress and type 2 diabetes, though not with common cancers or chronic obstructive pulmonary disease, suggesting outcome specificity. Few studies have addressed whether mitigation of work stressors would reduce the risk of cardiovascular disease. In view of the limited interventional evidence on benefits, harms and cost-effectiveness, definitive recommendations have not been made (e.g. by the US Preventive Services Taskforce) for the primary prevention of cardiovascular disease via workplace stress reduction. Nevertheless, governments are already launching healthy workplace campaigns, and preventing excessive work stress is a legal obligation in several countries. Promoting awareness of the link between stress and health among both employers and workers is an important component of workplace health promotion. PMID- 26238745 TI - Management of Multivessel Coronary Disease in ST-segment Elevation Myocardial Infarction. AB - Primary PCI of infarct-related arteries is the preferred reperfusion strategy in patients presenting with ST-segment elevation myocardial infarction (STEMI). Up to 40 % of such patients demonstrate evidence of multivessel, non-infarct-related artery coronary disease. Previous non-randomised observational studies and their associated meta-analyses have suggested that in such cases only the culprit infarct-related artery (IRA) lesion should be treated. However, recent randomised controlled trials have demonstrated improved clinical outcomes with lower major adverse cardiovascular events (MACE) rates when complete revascularisation is undertaken either at index primary percutaneous coronary intervention (PPCI) or during index admission. These trials suggest that current guidelines pertaining to treatment of non-infarct-related artery (N-IRA) lesions in STEMI patients with multivessel disease may need to be reconsidered depending on future trials. However, issues remain around timing of N-IRA intervention, the use of fractional flow reserve (FFR) or intravascular imaging to guide intervention in N-IRA lesions and the need to demonstrate reductions in hard clinical endpoints (death and MI) after complete revascularisation; these issues will need to be addressed through future trials. Clinicians must judge on the currently available data, whether it is still safer to leave important stenosis in N-IRA untreated. PMID- 26238747 TI - Spontaneous and induced labour are associated with different myometrial proteomes in the human. AB - Human myometrium undergoes a major phenotypic change at labour likely involving modifications to key regulatory proteins. In some cases, the myometrium fails to activate normally and medical intervention is required to induce labour. In this study, 2-D DIGE was used to examine changes in the myometrial proteome at the time of spontaneous (SL) and induced labour (IL). Proteomic profiles of nonlabouring term myometria (NL, n = 6) were quantitatively compared to SL (n = 6) and prostaglandin/oxytocin-IL term myometria (n = 6). In SL samples, 23 differentially expressed protein spots were detected (9 increased/14 decreased compared to NL, p<0.05). In IL samples, 59 differentially expressed spots were observed (13 increased/46 decreased compared to NL). Comparison of SL and IL proteomes revealed 69 differentially expressed proteins (7 increased/62 decreased). Two proteins consistently decreased in SL and IL samples were identified as transgelin (1.98- and 1.97-fold decrease in SL and IL, respectively) and alphaB-crystallin (3.27- and 2.49-fold decrease). Levels of desmin and cytosolic phospholipase A2 beta were decreased 2.9- and 2.65-fold, respectively only in IL samples. Our results show human labour is accompanied by general downregulation of specific myometrial proteins. Differences exist between SL and IL myometrial proteomes indicating divergence of underlying processes and highlighting the importance of distinguishing these groups in future studies of parturition. Our findings underscore the utility of discovery approaches in investigations of organ-wide protein changes that underlie discrete physiological events including human labour. PMID- 26238746 TI - Autophagy inhibition enhances isorhamnetin-induced mitochondria-dependent apoptosis in non-small cell lung cancer cells. AB - Isorhamnetin (ISO) is a flavonoid from plants of the Polygonaceae family and is also an immediate metabolite of quercetin in mammals. To date, the anti-tumor effects of ISO and the underlying mechanisms have not been elucidated in lung cancer cells. The present study investigated the inhibitory effects of ISO on the growth of human lung cancer A549 cells. Treatment of the lung cancer cells with ISO significantly suppressed cell proliferation and colony formation. ISO treatment also resulted in a significant increase in apoptotic cell death of A549 cells in a time- and dose-dependent manner. Further investigation showed that the apoptosis proceeded via the mitochondria-dependent pathway as indicated by alteration of the mitochondrial membrane potential, the release of cytochrome C and caspase activation. Of note, treatment with ISO also induced the formation of autophagosomes and light chain 3-II protein in A549 cells. Furthermore, co treatment with autophagy inhibitors 3-methyladenine and hydroxychloroquine significantly inhibited the ISO-induced autophagy and enhanced the ISO-induced apoptotic cell death in vitro as well as in vivo. Thus, the results of the present study suggested that ISO is a potential anti-lung cancer agent. In addition, the results indicated that the inhibition of autophagy may be a useful strategy for enhancing the chemotherapeutic effect of ISO on lung cancer cells. PMID- 26238748 TI - Protein content in aqueous humor from patients with pseudoexfoliation (PEX) investigated by capillary LC MALDI-TOF/TOF MS. AB - Analysis of proteins in human body fluids is challenging since the composition of the sample often is rather complex. Here we present a method for analysis of proteins in aqueous humor from two groups of cataract patients, with and without pseudoexfoliation (PEX). Aqueous humor is an extracellular fluid contained in the anterior chamber of the eye between the cornea and iris. The limited volume of sample requires sophisticated analysis techniques. Our method is based on a total tryptic digestion of the sample followed by capillary LC-MALDI MS and MS/MS analysis of the peptides. The method is rapid, efficient and suitable as a complement or alternative to more commonly used methods based on gel electrophoretic experiments. With this method we found and unambiguously identified 30 nonredundant proteins. Proteins found include general transport proteins such as albumin and apolipoprotein A1 but also specific proteins involved in immune response, such as complement factors. Cystatin C, clusterin, and crystallins were also found. Although the number of proteins was roughly the same in both groups there was a significant difference in their identities. These findings may give some new insights into the pathophysiology of the PEX syndrome. PMID- 26238749 TI - Proteomics analysis of liver pathological calcification suggests a role for the IQ motif containing GTPase activating protein 1 in myofibroblast function. AB - To date the cellular and molecular mechanisms by which liver pathological calcifications occur and are regulated are poorly investigated. To study the mechanisms linked to their appearance, we performed a proteomics analysis of calcified liver samples. To this end, human liver biopsies collected in noncalcified (N), precalcified (P), and calcified (C) areas of the liver were subjected to weak ion exchange chromatography, SDS-PAGE, and LC-ESI MS/MS analyses. As we previously demonstrated that alpha-smooth muscle actin (alpha SMA) expressing myofibroblasts were involved in liver pathological calcification, we performed a targeted analysis of actin cytoskeleton remodeling-related proteins. This revealed dramatic changes in protein expression patterns in the periphery of the calcified areas. More particularly, we found that IQGAP1 and IQGAP2 proteins were subjected to major expression changes. We show that IQGAP1 expression within P and C areas of the liver correlates with the high abundance of myofibroblasts and that IQGAP1 is specifically expressed in these cells. In addition, we find that IQGAP1 is part of a protein complex including beta-catenin and Rac1 mainly in P and C regions of the liver. These results suggest that IQGAP1 may play a critical role in the regulation of cytoskeleton remodeling in liver myofibroblasts in response to liver injury and consequently impact on their function. PMID- 26238750 TI - Comparative proteomic analysis of differentially expressed proteins in an in vitro cellular carcinogenesis model of oral squamous cell carcinoma. AB - In vitro cellular model is an important tool to be used to investigate the cellular events related to pathophysiological conditions in humans. We have developed an in vitro cellular carcinogenesis model of oral squamous cell carcinoma (OSCC). In this study, we performed comparative proteomic analysis using 2-DE and LC-tandem mass chromatography to separate and identify differentially expressed proteins. Forty-five proteins were identified, including 24 proteins with decreased expression and 19 proteins with increased expression during carcinogenesis from immortalized oral epithelial cells to squamous cancerous cells. The identified known proteins were classified into three ontologies of cellular component, molecular function, and biological process. Further validation of five identified proteins (ANXA1, ANXA2, CTSB, KRT17, and S100A6) in the cellular carcinogenesis model and cancerous tissues from OSCC patients confirmed the comparative proteomic results. Moreover, Annexin A1 and A2 expression levels correlated with the pathological differentiation grade of cancerous tissues. Thus, this work provides a dynamic protein file of differentially expressed proteins in oral squamous carcinoma cells, which could provide clues to study the mechanisms of OSCC carcinogenesis and possibly be developed as potential biomarkers for clinical diagnosis or prognostic monitoring. PMID- 26238751 TI - Protein carbonylation in kidney medulla of the spontaneously hypertensive rat. AB - Enhanced generation of ROS has been reported in models of hypertension such as the spontaneously hypertensive rat (SHR). Impairment of kidney function has been implicated in development and progression of hypertension, and the renal medulla appears to play an important role in regulating long-term blood pressure. A key biomarker of oxidative stress is the formation of protein carbonyls, which we set out to characterize in the SHR medulla. We identified 11 proteins that were differentially carbonylated in SHR medulla in comparison to normotensive wistars including enolase 1, catalase, carbonic anhydrase II, transferrin and members of the aldo-keto-reductase family. This enhanced protein oxidation was not only accompanied by an increase in intracellular iron deposition, but aldo-keto reductase activity was also significantly less in SHR medulla than in normotensive Wistars. Oxidative stress appears selectively to target a subset of proteins in SHR kidney and modification of these proteins may in turn contribute to the renopathy associated with hypertension. PMID- 26238752 TI - Multidimensional protein identification technology analysis highlights mitoxantrone-induced expression modulations in the primary prostate cancer cell proteome. AB - Chemotherapeutic agents as they are used today have limited effectiveness against prostate cancer, but may potentially be used in new combinations with more efficacious results. Mitoxantrone, used for palliation of prostate cancer, has recently been found by our group to improve the susceptibility of primary prostate cancer cells to killing through the Fas-mediated death pathway. Here we used a shotgun proteomics approach to first profile the entire prostate cancer proteome and then identify specific factors involved in this mitoxantrone response. Peptides derived from primary prostate cancer cells treated with or without 100 nM mitoxantrone were analyzed by multidimensional protein identification technology (MudPIT). Strict limits and data filtering hierarchies were applied to identify proteins with high confidence. We identified 1498 proteins belonging to the prostate cancer proteome, 83 of which were significantly upregulated and 27 of which were markedly downregulated following mitoxantrone treatment. These proteins perform diverse functions, including ceramide production, tumour suppression, and oxidative reduction. Detailed proteomic analyses of prostate cancer cells and their response to mitoxantrone will further our understanding of its mechanisms of action. Identification of proteins influenced by treatment with mitoxantrone or other compounds may lead to the development of more effective drug combinations against prostate cancer. PMID- 26238753 TI - Quantitative nuclear proteomics reveals new phenotypes altered in lymphoblastoid cells. AB - B-lymphocytes are essential for the production of antibodies to fight pathogens and are the cells of origin in 95% of human lymphomas. During their activation, and immortalisation by Epstein-Barr virus (EBV) which contributes to human cancers, B-lymphocytes undergo dramatic changes in cell size and protein content. This study was initiated to compare the proteome of two B-cell lines, from the same individual, that reflect different patterns of activation, one is EBV negative and the other is EBV positive. Using isobaric tags, LC-MALDI TOF-TOF and subcellular fractionation, we quantified 499 proteins from B-cells. From a detergent lysed protein extract, we identified 34 proteins that were differentially expressed in EBV-immortalised B-cells. By analysing a nuclear extract, we identified a further 29 differentially expressed proteins with only four proteins shared between the two extracts, illustrating the benefit of subcellular fractionation. This analysis has identified proteins involved in the cytoskeletal phenotype of activated B-cells and the increased antigen recognition in EBV-immortalised cells. Importantly, we have also identified new regulators of transcription and changes in ribonuclear proteins that may contribute to the increased cell size and immortalisation of lymphoblastoid cells. PMID- 26238754 TI - Dynamic urinary proteomic analysis reveals stable proteins to be potential biomarkers. AB - Human urinary proteome analysis is a convenient and efficient approach for understanding disease processes affecting the kidney and urogenital tract. Many potential biomarkers have been identified in previous differential analyses; however, dynamic variations of the urinary proteome have not been intensively studied, and it is difficult to conclude that potential biomarkers are genuinely associated with disease rather then simply being physiological proteome variations. In this paper, pooled and individual urine samples were used to analyze dynamic variations in the urinary proteome. Five types of pooled samples (first morning void, second morning void, excessive water-drinking void, random void, and 24 h void) collected in 1 day from six volunteers were used to analyze intra-day variations. Six pairs of first morning voids collected a week apart were used to study inter-day, inter-individual, and inter-gender variations. The intra-day, inter-day, inter-individual, and inter-gender variation analyses showed that many proteins were constantly present with relatively stable abundances, and some of these had earlier been reported as potential disease biomarkers. In terms of sensitivity, the main components of the five intra-day urinary proteomes were similar, and the second morning void is recommended for clinical proteome analysis. The advantages and disadvantages of pooling samples are also discussed. The data presented describe a pool of stable urinary proteins seen under different physiological conditions. Any significant qualitative or quantitative changes in these stable proteins may mean that such proteins could serve as potential urinary biomarkers. PMID- 26238755 TI - Considerations for powering a clinical proteomics study: Normal variability in the human plasma proteome. AB - Proteomics is increasingly being applied to the human plasma proteome to identify biomarkers of disease for use in non-invasive assays. 2-D DIGE, simultaneously analysing thousands of protein spots quantitatively and maintaining protein isoform information, is one technique adopted. Sufficient numbers of samples must be analysed to achieve statistical power; however, few reported studies have analysed inherent variability in the plasma proteome by 2-D DIGE to allow power calculations. This study analysed plasma from 60 healthy volunteers by 2-D DIGE. Two samples were taken, 7 days apart, allowing estimation of sensitivity of detection of differences in spot intensity between two groups using either a longitudinal (paired) or non-paired design. Parameters for differences were: two fold normalised volume change, alpha of 0.05 and power of 0.8. Using groups of 20 samples, alterations in 1742 spots could be detected with longitudinal sampling, and in 1206 between non-paired groups. Interbatch gel variability was small relative to the detection parameters, indicating robustness and reproducibility of 2-D DIGE for analysing large sample sets. In summary, 20 samples can allow detection of a large number of proteomic alterations by 2-D DIGE in human plasma, the sensitivity of detecting differences was greatly improved by longitudinal sampling and the technology was robust across batches. PMID- 26238756 TI - Contents: Proteomics - Clinical Applications 3/2009. PMID- 26238757 TI - In this issue: Proteomics - Clinical Applications 3/2009. AB - In this issue of Proteomics - Clinical Applications you will find the following highlighted articles: http://doi.wiley.com/10.1002/prca.200800050Labour isn't just a British party If you ask a woman who's had labor induced at the end of a normal pregnancy about the experience, she will probably flinch at the memory, which is not to say that spontaneous labor is a picnic. MacIntyre et al. report here on the proteomic analysis of the differences between spontaneous (SL) and induced (IL) labor in the myometrium. Applying 2-D DIGE to the question, they found 23 significant differences between SL and NL (non-laboring) myometria, and 59 differences between IL and NL samples. Comparison of SL to IL revealed 69 differences. Only two proteins showed the same changes for SL and IL vs, NL, suggesting that there might be more than one route to the same end. MacIntyre, D. A. et al., Proteomics Clin. Appl. 2009, 3, 288-298. Fresh mud for prostate info, not for spa facial Prostate cancer is one of the more challenging cancers to treat. It is not susceptible to any conventional chemotherapeutics, one of the most common approaches is implantation of radioactive "seeds" in the tumor. One chemotherapeutic agent that shows some promise when administered in combination with other therapies is mitoxantrone (MTXT). Symes et al. looked at proteomic changes in primary prostate cancer biopsy cultures with or without 100 nM MTXT, using MudPIT technology. Approximately 110 of 1500 proteins changed levels significantly. Among the up-regulated proteins were a number of membrane proteins - fatty acid synthase, caveolin-1 et al. - interesting targets for the combination therapy. Symes, J. et al., Proteomics Clin. Appl. 2009, 3, 347-358. Alien morph virus invasion We'll leave the royalty rights issue to the lawyers but if I were a wagering man, I'd put my money on the virus. We're talking about the battle between Epstein-Barr virus (EBV) and B-lymphocytes, the antibody boys. Once EBV gets into a lymphocyte it is immortalized, its cytoskeleton reshaped, its transcription control rewired and a variety of other changes implemented. Brennan et al. tackle this morass with all the proteomic tools at their call - MALDI-TOF/TOF, iTRAQ, 1- and 2-DE, Western blotting. In this paper they found 59 proteins with shifted expression in EBV-immortalized lymphoblastoid cells when compared to control Burkitt's lymphoma cells. Brennan, P. et al., Proteomics Clin. Appl. 2009, 3, 359-369. PMID- 26238758 TI - A synergistic effect of albumin and H2O2 accelerates corrosion of Ti6Al4V. AB - The synergistic effect of albumin and H2O2 on corrosion of titanium alloy Ti6Al4V in physiological saline was investigated with long-term immersion tests and electrochemical methods. It was found that in the presence of both albumin and H2O2, the rate of metal release in immersion tests was far higher than in the presence of either species alone. Electrochemical polarisation curves and potentiostatic tests showed that H2O2 increased both the rates of the anodic and cathodic reactions, whilst albumin significantly decreased the rate of the cathodic reaction and slightly decreased the rate of the anodic reaction. The synergistic effect of albumin and H2O2 during immersion tests was attributed to the effect of adsorption of albumin in lowering the rate of the cathodic reaction and thus lowering the open circuit potential into the active region of titanium where complexation by H2O2 increased the corrosion rate. The corrosion attack was found to be greater in the beta-phase of the alloy. The findings suggest that current standard tests in physiological or phosphate-buffered saline may underestimate the rate of corrosion in the peri-implant environment, in which albumin is the predominant protein, and reactive oxygen species such as H2O2 can occur as a result of inflammatory reactions in response to surgery, infection, or implant corrosion products. STATEMENT OF SIGNIFICANCE: Corrosion of many biomedical implant materials occurs in the body leading to adverse biological responses. Several components of the environment into which a metal implant is placed including proteins and products of cellular physiology, been shown to modify corrosion resistance. Previously all studies on such components including the common protein albumin and the inflammatory product H2O2 have considered the effects of these species in isolation. For the first time we report a synergistic interaction between albumin and H2O2 significantly accelerating corrosion of Ti6Al4V at physiological pH and temperature. This is attributed to an increased rate of the anodic reaction caused by H2O2 complexation of Ti, suppression of cathodic reaction by albumin adsorption shifting OCP to the active region of Ti6Al4V. PMID- 26238759 TI - Continuity of cognitive change across adulthood. AB - Although cross-sectional (between-person) comparisons consistently reveal age related cognitive declines beginning in early adulthood, significant declines in longitudinal (within-person) comparisons are often not apparent until age 60 or later. The latter results have led to inferences that cognitive change does not begin until late middle age. However, because mean change reflects a mixture of maturational and experiential influences whose contributions could vary with age, it is important to examine other properties of change before reaching conclusions about the relation of age to cognitive change. The present study was designed to examine measures of the stability, variability, and reliability of change, as well as correlations of changes in memory with changes in speed in 2,330 adults between 18 and 80 years of age. Despite substantial power to detect small effects, the absence of significant age differences in these properties suggests that cognitive change represents a qualitatively similar phenomenon across a large range of adulthood. PMID- 26238760 TI - Action video game training reduces the Simon Effect. AB - A number of studies have shown that training on action video games improves various aspects of visual cognition including selective attention and inhibitory control. Here, we demonstrate that action video game play can also reduce the Simon Effect, and, hence, may have the potential to improve response selection during the planning and execution of goal-directed action. Non-game-players were randomly assigned to one of four groups; two trained on a first-person-shooter game (Call of Duty) on either Microsoft Xbox or Nintendo DS, one trained on a visual training game for Nintendo DS, and a control group who received no training. Response times were used to contrast performance before and after training on a behavioral assay designed to manipulate stimulus-response compatibility (the Simon Task). The results revealed significantly faster response times and a reduced cost of stimulus-response incompatibility in the groups trained on the first-person-shooter game. No benefit of training was observed in the control group or the group trained on the visual training game. These findings are consistent with previous evidence that action game play elicits plastic changes in the neural circuits that serve attentional control, and suggest training may facilitate goal-directed action by improving players' ability to resolve conflict during response selection and execution. PMID- 26238761 TI - Effect of dexmedetomidine on the QT interval in pediatric patients undergoing general anesthesia. AB - BACKGROUND: Recent years have seen an increase in the use of dexmedetomidine in pediatric patients presenting for surgical procedures. However, only a limited number of studies have evaluated its effects on the QT interval in this patient group. To address this lack of knowledge, we have evaluated the effects of dexmedetomidine on the QT interval in children receiving sevoflurane anesthesia. METHODS: This study was a prospective case-control study in which pediatric patients presenting for anesthetic care were divided into two groups--the dexmedetomidine (D) and control (C) groups. Three electrocardiograms (ECGs) were obtained on each patient, including a baseline ECG (T1) prior to anesthetic induction and an ECG after the induction of anesthesia with sevoflurane (T2). In group D, the third ECG was obtained 2 min after the administration of dexmedetomidine, which in turn was started immediately after the T2 ECG reading (T3D); in group C, it was obtained 2 min after the T2 reading (T3C). Statistical analysis was performed using analysis of variance to compare the QT intervals at the three time points outlined above. RESULTS: A total of 50 patients were recruited to the study, ranging in age from 1 to 16 [mean 7.9 +/- 4.1 (SD) years]. There were 25 patients in group C and 25 in group D. There were no statistical differences in the demographics between the 2 groups. In group C, the QTc was noted to increase progressively with the administration of sevoflurane (T3C vs. T1; P = 0.006). In group D, following the administration of dexmedetomidine, there was a significant decrease in the QTc relative to the post induction value [436 +/- 25 (T2) vs. 418 +/- 17 ms (T3D); P < 0.01]. CONCLUSION: A progressive lengthening of the QTc interval following the administration of sevoflurane was observed in the control group. In the dexmedetomidine group, there was a significant shortening of the QTc interval following the administration of dexmedetomidine compared to the length of the post-induction QTc interval and when compared to the control group. PMID- 26238762 TI - Nuclear transcription factor CDX2 inhibits gastric cancer-cell growth and reverses epithelial-to-mesenchymal transition in vitro and in vivo. AB - The epithelial-to-mesenchymal transition (EMT) has been noted as a critical event in the early step of cancer metastasis. Recent studies showed that nuclear transcription factor caudal type homeobox transcription factor 2 (CDX2) is a prognostic factor, which acts as a marker of good outcome in gastric cancer (GC) patients. However, the association between CDX2 expression and EMT has remained to be fully elucidated. The present study reported that forced overexpression of CDX2 in MKN45/CDX2 cells inhibited GC-cell growth and proliferation, and attenuated migration and invasion in vitro. Furthermore, MKN45/CDX2 cells exhibited a significant upregulation of E-cadherin protein and a significant downregulation of vimentin protein expression. These results were further supported by in vivo tumorigenicity assays, which showed that CDX2 suppressed gastric tumor xenograft growth and inhibited EMT in nude mice. These results indicated that CDX2 is capable of inhibiting GC-cell growth and invasion. CDX2 may participate in the process of EMT of GC cells by regulating the expression of the epithelial and mesenchymal proteins E-cadherin and vimentin. PMID- 26238763 TI - Age-related cleavages of crystallins in human lens cortical fiber cells generate a plethora of endogenous peptides and high molecular weight complexes. AB - Low molecular weight peptides derived from the breakdown of crystallins have been reported in adult human lenses. The proliferation of these LMW peptides coincides with the earliest stages of cataract formation, suggesting that the protein cleavages involved may contribute to the aggregation and insolubilization of crystallins. This study reports the identification of 238 endogenous LMW crystallin peptides from the cortical extracts of four human lenses representing young, middle and old-age human lenses. Analysis of the peptide terminal amino acids showed that Lys and Arg were situated at the C-terminus with significantly higher frequency compared to other residues, suggesting that trypsin-like proteolysis may be active in the lens cortical fiber cells. Selected reaction monitoring analysis of an endogenous alphaA-crystallin peptide (alphaA(57-65)) showed that the concentration of this peptide in the human lens increased gradually to middle age, after which the rate of alphaA(57-65) formation escalated significantly. Using 2D gel electrophoresis/nanoLC-ESI-MS/MS, 12 protein complexes of 40-150 kDa consisting of multiple crystallin components were characterized from the water soluble cortical extracts of an adult human lens. The detection of these protein complexes suggested the possibility of crystallin cross-linking, with these complexes potentially acting to stabilize degraded crystallins by sequestration into water soluble complexes. PMID- 26238764 TI - [From synthetic biology to synthetic humankind]. AB - In this paper, we propose an historical survey of the expression "synthetic biology" in order to identify its main philosophical components. The result of the analysis is then used to investigate the meaning of the notion of "synthetic man". It is shown that both notions share a common philosophical background that can be summed up by the short but meaningful assertion: "biology is technology". The analysis allows us to distinguish two notions that are often confused in transhumanist literature: the notion of synthetic man and the notion of renewed man. The consequences of this crucial distinction are discussed. PMID- 26238765 TI - [About moral enhancement]. AB - First, a short summary of the moral enhancement debate is drawn up. Then an argument first put forward by J. Harris is explored: this argument is directly related to I. Perrson's and J. Savulescu's conception of moral life. To conclude, it is suggested that they advocate a naive idea of technology, conceived as a neutral means for value loaded ends. PMID- 26238766 TI - [Promises and limits of genomics and its applications]. AB - This text traces the extraordinary advances made in genomics for 40 years: recombinant DNA, transgenesis or genetic sequencing. In recent years, the model "all genetics" was questioned and post-genomics emerged in the molecular landscape. The promises of medical advances are many and the ethical issues that accompany them are challenges. Advances in synthetic biology are a relevant illustration of these promises and challenges. PMID- 26238767 TI - Decoy receptor 3 regulates the expression of tryptophan hydroxylase 1 in rheumatoid synovial fibroblasts. AB - Decoy receptor 3 (DcR3) is expressed in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and downregulates the expression of tryptophan hydroxylase 1 (TPH1), which is the rate-limiting enzyme in serotonin synthesis. The aim of the present study was to determine the specificity of the effects of DcR3 on TPH1 in RA-FLS, and therefore determine whether DcR3 had the potential to modulate the pathogenesis of RA. The present study also aimed to compare the effects of DcR3 and inflammatory cytokines on the expression of TPH1 in RA-FLS and osteoarthritis (OA)-FLS. Primary cultured RA- or OA-FLS were incubated with 1.0 ug/ml DcR3-Fc protein or 1.0 ug/ml control immunoglobulin G (IgG)1 for 12 h, or with 1.0 ng/ml tumor necrosis factor (TNF)alpha, 1.0 ng/ml interleukin (IL)-1beta or serum-free Opti-MEM only, for 24 h. The relative mRNA expression levels of TPH1 were subsequently quantified using reverse transcription-polymerase chain reaction. The expression of serotonin in RA or OA synovial tissue was detected using immunohistochemistry. The mRNA expression of TPH1 was observed in both RA- and OA FLS and was significantly decreased following treatment with DcR3 in the RA-FLS, however, not in the OA-FLS. The mRNA expression of TPH1 was significantly decreased following treatment with TNFalpha or IL-1beta in both the RA- and OA FLS. The expression of serotonin in the multi-layered lining synovial cells of RA and the outer layer lining synovial cells of OA was detected using immunohistochemistry. The present study is the first, to the best of our knowledge, to demonstrate that the expression of TPH1 in FLS is downregulated by inflammatory cytokines, and that DcR3 suppressed the expression of TPH1 in RA-FLS in a disease-specific manner. These results suggested that synovial serotonin may be involved in the pathogenesis of RA, and that TPH1 and DcR3 may be potential therapeutic targets for the treatment of RA. PMID- 26238768 TI - Risk Factors for Revision Anterior Cruciate Ligament Reconstruction. AB - Purpose The purpose of this study was to identify risk factors for revision surgery following primary anterior cruciate ligament (ACL) reconstruction. Methods A retrospective analysis of 2,965 patients who underwent a primary ACL reconstruction were separated into two groups: those who returned to our center for revision of their reconstruction (n = 67) and those who did not return to our center for revision of their reconstruction (n = 2,898). Patient characteristics assessed at the time of primary reconstruction include age, gender, graft type, graft source, meniscal and/or chondral injury, sport, side of effected extremity, level of competition, and surgeon. Multivariable analyses were performed to identify significant, independent associations with the need for revision. Results The portion of patients who returned for revision reconstruction after primary ACL reconstruction was 2.3% (67/2,965). Age (p < 0.001), sport type (p = 0.007), and level of participation (p < 0.001) were significantly different between the nonrevision and revision patients. Graft type preferences varied among surgeons (p < 0.001). Accounting for sport type or level of competition, age (p = 0.014) and surgeon (p = 0.041) were independently associated with revision. Gender, extremity (R vs. L), meniscal or chondral injury, and graft characteristics were not associated with revision. Conclusion Revision of primary ACL reconstructions is independently associated with age and choice of surgeon at the time of primary reconstruction. PMID- 26238769 TI - Impact of regular physical activity on weekly warfarin dose requirement. AB - Warfarin is an oral anticoagulant agent with a narrow therapeutic index. There is a marked inter- and intra-patient variability in warfarin dose requirement. All factors influencing warfarin response are not known and this study aims to evaluate if regular physical activity (RPA) is a determining factor. RPA level was collected with the Stanford Brief Activity Survey in 1064 incident warfarin users, as part of the Quebec Warfarin Cohort (QWC), and with the Global Physical Activity Questionnaire in 618 patients from the Montreal Heart Institute (MHI) Biobank. Linear regression was performed to model relationship of warfarin dose after 3 months of therapy in the QWC with RPA, while controlling for height, weight, age, CYP2C9 (*2 and *3 alleles) and VKORC1 (*2 allele) genotype. Warfarin dose of prevalent users was modeled in the MHI Biobank for replication. A higher level of physical activity was associated with higher doses of warfarin in both cohorts. In the QWC, physical activity could explain 5.4 % (P < 0.001) and 0.9 % (P = 3.23 * 10(-5)) of variance in dose, in univariate and multivariable models, respectively. Similarly, RPA was found to be associated with 1.7 % (P = 0.0012) and 0.5 % (P = 0.0391) of inter-individual variability in warfarin dose requirement before and after adjustment for other covariables, respectively. RPA is associated with higher warfarin dose requirement. The relevance of clinical recommendations on RPA to maintain a steady response to warfarin should be assessed in further studies. PMID- 26238770 TI - Influence of chronic kidney disease on anticoagulation levels and bleeding after primary percutaneous coronary intervention in patients treated with unfractionated heparin. AB - Unfractionated heparin (UFH) plasma protein binding and elimination might be impaired in patients with chronic kidney disease (CKD-defined as creatinine clearance <60 ml/min). It is currently unknown at which UFH bolus dose persistent prolongation of activated partial thromboplastin time (aPTT) occurs in ST-segment elevation myocardial infarction (STEMI) patients with CKD. We investigated the effect of different UFH bolus doses on the first aPTT measured within 6 and 12 h after PPCI in 1071 STEMI patients with and without CKD undergoing primary percutaneous coronary intervention (PPCI) between 1-1-2003 and 31-07-2008. In the first 6 h after PPCI, aPTT ratio was 5.1 for patients with CKD versus 3.4 for those without (p < 0.001). The proportion of patients with markedly high aPTTs (aPTT ratio >= 4 times control) increased with increasing heparin bolus and beyond 130 IU/kg there was a marked difference between patients with and without CKD (74.1 and 42.3 % respectively, p < 0.001). By multivariable analysis, CKD was associated with an increased risk of markedly high aPTTs (odds ratio (OR) 2.04; 95 % confidence interval (CI) 1.27-3.27), driven largely by an increased risk of aPTT prolongation in patients treated with UFH boluses >=130 IU/kg (OR 3.69; 95 % CI 1.85-7.36; p for interaction = 0.009). In conclusion, CKD is associated with severe persistent aPTT prolongation in STEMI patients undergoing PPCI, possibly due to impaired plasma protein binding and reduced UFH elimination. A lower heparin bolus dose might result in lower aPTTs and less bleeding complications in patients with CKD undergoing PPCI. PMID- 26238771 TI - MicroRNA-146a inhibits epithelial mesenchymal transition in non-small cell lung cancer by targeting insulin receptor substrate 2. AB - During cancer progression, some tumor cells show changes in their plasticity by morphological and phenotypical conversions, as an expression of mesenchymal markers and loss of epithelial markers, collectively referred to as epithelial mesenchymal transition (EMT). EMT has been increasingly recognized as a critical phenomenon in lung cancer progression. The goal of this study was to identify microRNAs involved in lung cancer progression. A microarray and qRT-PCR were performed to investigate the miRNA expression profiles in mesenchymal-like lung cancer cells. The role of miR-146a in lung cancer progression was measured by invasion and migration assays in vitro. Bioinformatics and luciferase report assays were used to identify the target of miR-146a. The expression of miR-146a was reduced in mesenchymal-like lung cancer cell lines. The overexpression of miR 146a induced a marked reduction of the mesenchymal marker and increase the epithelial marker in lung cancer cell lines. Moreover, the overexpression of miR 146a suppressed lung cancer cell migration and invasion. Co-treatment with miR 146a and gefitinib treatment showed a significant reduction of invasion in the resistant lung cancer cells induced by EMT. The expression of miR-146a was downregulated in advanced lung cancer tissues. Insulin receptor substrate 2 (IRS2), an adaptor protein that modulates normal growth, metabolism, survival, and differentiation, was identified as a target of miR-146a. miR-146a regulated the expression of IRS2 at the mRNA and protein levels. These data demonstrate for the first time that miR-146a suppresses lung cancer progression by repressing IRS2 expression. This provides new insight into the post-transcriptional regulation of lung cancer progression by miRNAs, a potential approach for the treatment of lung cancer. PMID- 26238773 TI - When a 520 million-year-old Chengjiang fossil meets a modern micro-CT--a case study. AB - The 520 million-year-old Chengjiang biota of China (UNESCO World Heritage) presents the earliest known evidence of the so-called Cambrian Explosion. Studies, however, have mainly been limited to the information exposed on the surface of the slabs. Thus far, structures preserved inside the slabs were accessed by careful removal of the matrix, in many cases with the unfortunate sacrifice of some "less important" structures, which destroys elements of exceptionally preserved specimens. Here, we show for the first time that microtomography (micro-CT) can reveal structures situated inside a Chengjiang fossil slab without causing any damage. In the present study a trilobitomorph arthropod (Xandarella spectaculum) can be reliably identified only with the application of micro-CT. We propose that this technique is an important tool for studying three-dimensionally preserved Chengjiang fossils and, most likely, also those from other biota with a comparable type of preservation, specifically similar iron concentrations. PMID- 26238772 TI - Scientific basis of personalised tomographic radiation planning for radioembolisation: A form of brachytherapy planning. AB - Today's tomographic imaging techniques such as catheter-directed CT and single photon emission computed tomography with integrated computed tomography may be used for pre-therapy radiation planning for radioembolisation based on prospective calculation of tissue radiation absorbed doses. We outline the scientific concepts that underlie modern personalised tomographic radiation planning for radioembolisation and highlight its similarities to brachytherapy planning. PMID- 26238774 TI - Harnessing the microbiome in glaucoma and uveitis. PMID- 26238775 TI - Curcumin alters gene expression-associated DNA damage, cell cycle, cell survival and cell migration and invasion in NCI-H460 human lung cancer cells in vitro. AB - Lung cancer is the most common cause of cancer mortality and new cases are on the increase worldwide. However, the treatment of lung cancer remains unsatisfactory. Curcumin has been shown to induce cell death in many human cancer cells, including human lung cancer cells. However, the effects of curcumin on genetic mechanisms associated with these actions remain unclear. Curcumin (2 uM) was added to NCI-H460 human lung cancer cells and the cells were incubated for 24 h. Total RNA was extracted from isolated cells for cDNA synthesis, labeling, microarray hybridization and flour-labeled cDNA hybridized on chip. Localized concentrations of fluorescent molecules were detected and quantified using Expression Console software (Affymetrix) with default RMA parameters. GeneGo software was used for the key genes involved and their possible interaction pathways. The results showed that ~170 genes were significantly upregulated and 577 genes were significantly downregulated in curcumin-treated cells. Specifically, the up- and downregulated genes included CCNE2, associated with DNA damage; ID3, associated with cell survival and 146 genes with a >2- to 3-fold change including the TP53INP1 gene, associated with DNA damage; CDC6, CDCA5, TAKMIP2, CDK14, CDK5, CDCA76, CDC25A, CDC5L and SKP2, associated with cell cycle; the CARD6, ID1 and ID2 genes, associated with cell survival and the BRMS1L, associated with cell migration and invasion. Additionally, 59 downregulated genes exhibited a >4-fold change, including the DDIT3 gene, associated with DNA damage; while 97 genes had a >3- to 4-fold change including the DDIT4 gene, associated with DNA damage; the CCPG1 gene, associated with cell cycle and 321 genes with a >2- to 3-fold including the GADD45A and CGREF1 genes, associated with DNA damage; the CCPG1 gene, associated with cell cycle, the TNFRSF10B, GAS5, TSSC1 and TNFRSF11B gene, associated with cell survival and the ARHAP29 and CADM2 genes, associated with cell migration and invasion. In conclusion, gene alterations provide information regarding the cytotoxic mechanism of curcumin at the genetic level and provide additional biomarkers or targets for the treatment of human lung cancer. PMID- 26238776 TI - Small interfering RNA-induced silencing of galectin-3 inhibits the malignant phenotypes of osteosarcoma in vitro. AB - Osteosarcoma (OS) is the most common malignant tumor of bone. It has recently been demonstrated that galectin-3, a multifunctional beta-galactoside-binding, is significantly upregulated in OS tissues, and is correlated with its progression and metastasis. However, the detailed role of galectin-3 in the regulation of cellular biological processes in OS cells has remained to be elucidated. The present study reported that the mRNA and protein levels of galectin-3 were significantly increased in OS tissues compared to those in their matched normal adjacent tissues. Furthermore, galectin-3 was upregulated in three OS cell lines, Saos-2, MG63 and U2OS, when compared with that in the human osteoblast cell line hFOB1.19. Knockdown of galectin-3 by galectin-3-specific small interfering RNA markedly inhibited OS-cell proliferation and induced cell apoptosis. Furthermore, silencing of galectin-3 expression significantly inhibited OS cell migration and invasion, accompanied with a marked decrease in the protein expression of matrix metalloproteinase 2 and -9. Mechanistic investigation suggested that the mitogen activated protein kinase kinase/extracellular signal-regulated protein kinase signaling pathway may be involved in the galectin-3-mediated OS cell invasion. In conclusion, the present study was the first to report that silencing of galectin 3 inhibited the malignant phenotypes of osteosarcoma in vitro. Therefore, galectin-3 may serve as a potential therapeutic target for OS. PMID- 26238777 TI - Self-assembly of pH-sensitive fluorinated peptide dendron functionalized dextran nanoparticles for on-demand intracellular drug delivery. AB - In this study, the amphiphilic fluorinated peptide dendrons functionalized dextran (FPD-HZN-Dex) via an acid-sensitive hydrazone linkage was successfully designed and prepared for the first time. We demonstrated a spontaneous self assembly of amphiphilic FPD-HZN-Dex into the well-defined nanoparticles with the core-shell architecture in aqueous media, which is attributed to the efficient amphiphilic functionalization of dextran by the hydrophobic fluorinated peptide dendrons. The spherical morphology, uniform particle size and good storage stability of the prepared FPD-HZN-Dex nanoparticles were characterized by dynamic light scattering and transmission electron microscopy, respectively. In vitro drug release studies showed a controlled and pH dependent hydrophobic drug release profile. The cell viability assays show excellent biocompatibility of the FPD-HZN-Dex nanoparticles for both normal cells and tumor cells. Moreover, the FPD-HZN-Dex self-assembled systems based on pH-sensitive hydrazone linkage also can serve as stimulus bioresponsive carriers for on-demand intracellular drug delivery. These self-assembled nanoparticles exhibit a stimulus-induced response to endo/lysosome pH (pH 5.0) that causes their disassembly over time, enabling controlled release of encapsulated DOX. This work has unveiled a unique non covalent interaction useful for engineering amphiphilic dendrons or dendrimers self-assembled systems. PMID- 26238778 TI - Impact of Quetiapine Treatment on Duration of Hypoactive Delirium in Critically Ill Adults: A Retrospective Analysis. AB - STUDY OBJECTIVE: Because delirium remains a common consequence of critical illness, and reducing its duration has been shown to have a positive impact on patient outcomes during and after an intensive care unit (ICU) stay, we sought to determine whether treatment of hypoactive delirium with quetiapine reduces the duration of delirium compared with no pharmacologic treatment. DESIGN: Retrospective cohort study. SETTING: Three medical-surgical ICUs within the two main campuses of an academic tertiary care hospital system. PATIENTS: A total of 113 adults with documented hypoactive delirium during an ICU length of stay (LOS) of at least 72 hours between August 2013 and September 2014; 52 patients received at least one dose of quetiapine during their hypoactive delirium course, and 61 patients received no pharmacologic delirium treatment. MEASUREMENTS AND MAIN RESULTS: Patients were screened for hypoactive delirium using the Confusion Assessment Method-ICU (CAM-ICU) and the Richmond Agitation Sedation Scale (RASS). The primary outcome was time to first resolution of delirium, and secondary outcomes included ICU and hospital LOS, and duration of mechanical ventilation. To assess potential adverse effects of quetiapine, the number of RASS assessments deeper than goal and the total number of RASS assessments documented during the delirium course were recorded for all patients. Daily progress notes and discharge documentation were surveyed to assess for new onset of extrapyramidal symptoms or torsade de pointes. Median duration of hypoactive delirium was shorter in the quetiapine-treated group compared with the no-quetiapine group (1.5 vs 2.0 days, p=0.04), and time to extubation after screening positive for delirium trended favorably toward quetiapine-treated patients (3 vs 5 days, p=0.08). There were no significant differences in ICU or hospital LOS, and safety outcomes were similar between groups. CONCLUSION: In this mixed ICU population, treatment of hypoactive delirium with quetiapine was safe and reduced the duration of delirium compared with standard care alone. Prospective placebo controlled studies are needed to further assess the role of antipsychotics in hypoactive delirium. PMID- 26238779 TI - A Prospective Longitudinal Study on Implant Prosthetic Rehabilitation in Controlled HIV-Positive Patients with 1-Year Follow-Up: The Role of CD4+ Level, Smoking Habits, and Oral Hygiene. AB - BACKGROUND: A recent study showed that implant-prosthetic rehabilitation in well controlled HIV patients gave slightly worse results than in an healthy population, and failures were all linked to infection. PURPOSE: The aim of this study was to examine the associations between the success of implant-prosthetic treatment and systemic CD4+ level, smoking habits, and oral hygiene. MATERIALS AND METHODS: This mono-centric study included HIV patients with a stable disease and good oral hygiene requiring implant rehabilitation. Each patient received at least one dental implant. Prosthesis were delivered after 90 days in the upper jaw and 60 days in the lower jaw. Primary outcome measures were prosthetic failures, implant failures, peri-implant marginal bone level changes, and biological complications (peri-implantitis, pus, pain, paresthesia). The possible association with CD4 count, smoking habits, and oral hygiene was analyzed. RESULTS: Sixty-eight patients received 194 implants, and 66 patients (190 implants) were followed for 1 year. No significant associations were found between CD4+ count, oral hygiene-associated variables, and any of the outcome measures. If compared with nonsmoking/light smoking patients, patients who smoked >10 cigarettes/day suffered a statistically significant greater number of implant failures (p <= .005), presented a comparatively higher number of peri-implantitis (p < .001), as well as a higher frequency of pus (p <= .007), and reported pain (p <= .009). CONCLUSION: Within the limitation of the present study, placement of dental implants in HIV-positive patients with stable disease seems a reasonable treatment option, regardless of CD4+ cell count, provided that they are in a normal range. Oral hygiene variables were not influent in this group of patient following recall appointments, while HIV-positive heavy smokers (>10 cigarettes/day) demonstrated an increased risk of early implant failure, peri implantitis, episodes of pus, and self-reported pain. PMID- 26238780 TI - Colon Cancer Growth and Dissemination Relies upon Thrombin, Stromal PAR-1, and Fibrinogen. AB - Thrombin-mediated proteolysis is a major determinant of metastasis, but is not universally important for primary tumor growth. Here, we report that colorectal adenocarcinoma represents one important exception whereby thrombin-mediated functions support both primary tumor growth and metastasis. In contrast with studies of multiple nongastrointestinal cancers, we found that the growth of primary tumors formed by murine and human colon cancer cells was reduced in mice by genetic or pharmacologic reduction of circulating prothrombin. Reduced prothrombin expression was associated with lower mitotic indices and invasion of surrounding tissue. Mechanistic investigations revealed that thrombin-driven colonic adenocarcinoma growth relied upon at least two targets of thrombin mediated proteolysis, protease-activated receptor-1 (PAR-1) expressed by stromal cells and the extracellular matrix protein, fibrinogen. Colonic adenocarcinoma growth was reduced in PAR-1-deficient mice, implicating stromal cell-associated PAR-1 as one thrombin target important for tumor outgrowth. Furthermore, tumor growth was dramatically impeded in fibrinogen-deficient mice, offering the first direct evidence of a critical functional role for fibrinogen in malignant tumor growth. Tumors harvested from fibrinogen-deficient mice displayed a relative reduction in cell proliferative indices, as well as increased tumor necrosis and decreased tumor vascular density. Collectively, our findings established a functional role for thrombin and its targets PAR-1 and fibrinogen in the pathogenesis of colonic adenocarcinoma, supporting tumor growth as well as local invasion and metastasis. PMID- 26238781 TI - Ceacam1L Modulates STAT3 Signaling to Control the Proliferation of Glioblastoma Initiating Cells. AB - Glioblastoma-initiating cells (GIC) are a tumorigenic cell subpopulation resistant to radiotherapy and chemotherapy, and are a likely source of recurrence. However, the basis through which GICs are maintained has yet to be elucidated in detail. We herein demonstrated that the carcinoembryonic antigen related cell adhesion molecule Ceacam1L acts as a crucial factor in GIC maintenance and tumorigenesis by activating c-Src/STAT3 signaling. Furthermore, we showed that monomers of the cytoplasmic domain of Ceacam1L bound to c-Src and STAT3 and induced their phosphorylation, whereas oligomerization of this domain ablated this function. Our results suggest that Ceacam1L-dependent adhesion between GIC and surrounding cells play an essential role in GIC maintenance and proliferation, as mediated by signals transmitted by monomeric forms of the Ceacam1L cytoplasmic domain. PMID- 26238783 TI - A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis. AB - Relationships between genetic alterations, such as co-occurrence or mutual exclusivity, are often observed in cancer, where their understanding may provide new insights into etiology and clinical management. In this study, we combined statistical analyses and computational modeling to explain patterns of genetic alterations seen in 178 patients with bladder tumors (either muscle-invasive or non-muscle-invasive). A statistical analysis on frequently altered genes identified pair associations, including co-occurrence or mutual exclusivity. Focusing on genetic alterations of protein-coding genes involved in growth factor receptor signaling, cell cycle, and apoptosis entry, we complemented this analysis with a literature search to focus on nine pairs of genetic alterations of our dataset, with subsequent verification in three other datasets available publicly. To understand the reasons and contexts of these patterns of associations while accounting for the dynamics of associated signaling pathways, we built a logical model. This model was validated first on published mutant mice data, then used to study patterns and to draw conclusions on counter-intuitive observations, allowing one to formulate predictions about conditions where combining genetic alterations benefits tumorigenesis. For example, while CDKN2A homozygous deletions occur in a context of FGFR3-activating mutations, our model suggests that additional PIK3CA mutation or p21CIP deletion would greatly favor invasiveness. Furthermore, the model sheds light on the temporal orders of gene alterations, for example, showing how mutual exclusivity of FGFR3 and TP53 mutations is interpretable if FGFR3 is mutated first. Overall, our work shows how to predict combinations of the major gene alterations leading to invasiveness through two main progression pathways in bladder cancer. PMID- 26238782 TI - The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma. AB - Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine tumor. Merkel cell polyomavirus (MCPyV) may contribute to tumorigenesis in a subset of tumors via inhibition of tumor suppressors such as retinoblastoma (RB1) by mutated viral T antigens, but the molecular pathogenesis of MCPyV-negative MCC is largely unexplored. Through our MI-ONCOSEQ precision oncology study, we performed integrative sequencing on two cases of MCPyV negative MCC, as well as a validation cohort of 14 additional MCC cases (n = 16). In addition to previously identified mutations in TP53, RB1, and PIK3CA, we discovered activating mutations of oncogenes, including HRAS and loss-of-function mutations in PRUNE2 and NOTCH family genes in MCPyV-negative MCC. MCPyV-negative tumors also displayed high overall mutation burden (10.09 +/- 2.32 mutations/Mb) and were characterized by a prominent UV-signature pattern with C > T transitions comprising 85% of mutations. In contrast, mutation burden was low in MCPyV positive tumors (0.40 +/- 0.09 mutations/Mb) and lacked a UV signature. These findings suggest a potential ontologic dichotomy in MCC, characterized by either viral-dependent or UV-dependent tumorigenic pathways. PMID- 26238784 TI - VR23: A Quinoline-Sulfonyl Hybrid Proteasome Inhibitor That Selectively Kills Cancer via Cyclin E-Mediated Centrosome Amplification. AB - The proteasome is clinically validated as a target for cancer therapeutics. However, proteasome-inhibitory agents that are cancer selective have yet to be developed. In this study, we report the identification of a safe and effective proteasome inhibitor with selective anticancer properties. We screened a chemical library constructed using a hybrid approach that incorporated a 4 piperazinylquinoline scaffold and a sulfonyl phamarcophore. From this library, we identified 7-chloro-4-(4-(2,4-dinitrophenylsulfonyl)piperazin-1-yl)quinoline (VR23) as a small molecule that potently inhibited the activities of trypsin-like proteasomes (IC50 = 1 nmol/L), chymotrypsin-like proteasomes (IC50 = 50-100 nmol/L), and caspase-like proteasomes (IC50 = 3 MUmol/L). Data from molecular docking and substrate competition assays established that the primary molecular target of VR23 was beta2 of the 20S proteasome catalytic subunit. Notably, VR23 was structurally distinct from other known proteasome inhibitors and selectively killed cancer cells by apoptosis, with little effect on noncancerous cells. Mechanistic investigations showed that cancer cells exposed to VR23 underwent an abnormal centrosome amplification cycle caused by the accumulation of ubiquitinated cyclin E. In combinations with the clinically approved chymotrypsin like proteasome inhibitor bortezomib, VR23 produced a synergistic effect in killing multiple myeloma cells, including those that were resistant to bortezomib. VR23 was effective in vivo in controlling multiple myelomas and metastatic breast cancer cells, in the latter case also enhancing the antitumor activity of paclitaxel while reducing its side effects. Overall, our results identify VR23 as a structurally novel proteasome inhibitor with desirable properties as an anticancer agent. PMID- 26238786 TI - Self-Reported Versus Performance-Based Assessments of a Simple Mobility Task Among Older Adults in the Emergency Department. AB - STUDY OBJECTIVE: Accurate information about the mobility of independently living older adults is essential in determining whether they may be safely discharged home from the emergency department (ED). We assess the accuracy of self-reported ability to complete a simple mobility task among older ED patients. METHODS: This was a cross-sectional study of cognitively intact patients aged 65 years and older who were neither nursing home residents nor critically ill, conducted in 2 academic EDs. Consenting participants were asked whether they could get out of bed, walk 10 feet, turn around, and get back in bed without assistance, and if not, whether they could perform this task with a cane, walker, or assistance. Each participant was then asked to perform the task and was provided with a mobility device or assistance as needed. RESULTS: Of 272 patients who met eligibility criteria and answered the physical task question, 161 (59%) said they could do the task unassisted, 45 (17%) said they could do it with a cane or walker, 21 (8%) said they could do it with assistance, and 45 (17%) said they would be unable to do it even with assistance. Among those who said they could do the task either with or without assistance and who were subsequently willing to attempt the task (N=172), discrepancies between self-reported ability and actual performance were common. Of those who said they could perform the task without assistance, 12% required some assistance or were unable to complete the task. Of those who said they could perform the task with a cane or walker, 48% required either assistance or were unable to perform the task. Of those who said they could perform the task with assistance, 24% were unable to perform the task even with assistance. CONCLUSION: In this sample of older adults receiving care in the ED, the accuracy of their self-reported ability to perform a simple mobility task was poor, particularly for those who reported some need for assistance. For older adults being considered for discharge who report a need for assistance with mobility, direct observation of the patient's mobility by a member of the emergency care team should be considered. PMID- 26238787 TI - Silver-Rusell syndrome caused by epigenetic alteration in a child conceived by intrauterine insemination from donor sperm. PMID- 26238785 TI - Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages. AB - Triple-negative breast cancer (TNBC) patients have the highest risk of recurrence and metastasis. Because they cannot be treated with targeted therapies, and many do not respond to chemotherapy, they represent a clinically underserved group. TNBC is characterized by reduced expression of metastasis suppressors such as Raf kinase inhibitory protein (RKIP), which inhibits tumor invasiveness. Mechanisms by which metastasis suppressors alter tumor cells are well characterized; however, their ability to regulate the tumor microenvironment and the importance of such regulation to metastasis suppression are incompletely understood. Here, we use species-specific RNA sequencing to show that RKIP expression in tumors markedly reduces the number and metastatic potential of infiltrating tumor associated macrophages (TAM). TAMs isolated from nonmetastatic RKIP(+) tumors, relative to metastatic RKIP(-) tumors, exhibit a reduced ability to drive tumor cell invasion and decreased secretion of prometastatic factors, including PRGN, and shed TNFR2. RKIP regulates TAM recruitment by blocking HMGA2, resulting in reduced expression of numerous macrophage chemotactic factors, including CCL5. CCL5 overexpression in RKIP(+) tumors restores recruitment of prometastatic TAMs and intravasation, whereas treatment with the CCL5 receptor antagonist Maraviroc reduces TAM infiltration. These results highlight the importance of RKIP as a regulator of TAM recruitment through chemokines such as CCL5. The clinical significance of these interactions is underscored by our demonstration that a signature comprised of RKIP signaling and prometastatic TAM factors strikingly separates TNBC patients based on survival outcome. Collectively, our findings identify TAMs as a previously unsuspected mechanism by which the metastasis suppressor RKIP regulates tumor invasiveness, and further suggest that TNBC patients with decreased RKIP activity and increased TAM infiltration may respond to macrophage-based therapeutics. PMID- 26238788 TI - Towards optimal design of sport footwear based on muscle activity and minimum loading rate using simplified model. AB - Recently, researchers have been looking for a model to relate the ground reaction force to the vibration parameters of sport shoes. A 4-degrees-of-freedom mass spring-damper model and a dimensionless objective function have been used in the literature in order to simulate the functionality of the central nervous system based on muscle tuning paradigm. In this study, a two-phase optimization method was proposed in order to better simulate the functionality of the central nervous system. A comparison between the results of this method and those in the literature demonstrates more accuracy. Additionally, it has been reported that the loading rate in the time history of the ground reaction force has a role in overuse injuries in the tibia and tarsals; therefore, in order to introduce an optimum design for sport shoes, in this study, a new objective function was introduced and the proposed method was used in order to find the best possible range of shoe parameters for pre-fatigued and post-fatigued conditions. Results indicated that there is no possible solution which brings the loading rate to the desired value; however, the region in which the least values for the objective function achieved was introduced as the safe region. It was shown that the size of this safe region shrinks as muscles fatigue. The results also demonstrated high dependency of the safe region to the mass distribution and touchdown velocities of the lower extremities. PMID- 26238789 TI - The influence of flow diverter's angle of curvature across the aneurysm neck on its haemodynamics. AB - Flow diverter stents have provided a new method of endovascular reconstruction for large and complex aneurysms. Understanding the impact of the flow diverter's angle of curvature across the neck and its metal coverage rate on the haemodynamics of aneurysm is crucial to maximize the mass flow reduction inside the aneurysm, post-deployment. The aim of this study is to understand the correlation between the angle of curvature of flow diverter across the aneurysm neck and the metal coverage rate, and the aneurysm's haemodynamics, using computational fluid dynamics. Varying the flow diverter angle resulted in varying metal coverage rate across the aneurysm neck for two patient vessel geometries, A (straight artery) and B (curved artery) with aspect ratios of 3.1 and 2.9, respectively. The results indicate that there exists a relationship between the aneurysm's haemodynamics and the flow diverter's angle of curvature across its neck. Moreover, the calculations indicated that cases with a moderately curved flow diverter, with an associated metal coverage rate of 50%-60%, achieve maximum flow reduction inside the aneurysm due to a stable flow resistance in the direction normal to the blood flow. PMID- 26238790 TI - A novel simulator for mechanical ventilation in newborns: MEchatronic REspiratory System SImulator for Neonatal Applications. AB - Respiratory problems are among the main causes of mortality for preterm newborns with pulmonary diseases; mechanical ventilation provides standard care, but long term complications are still largely reported. In this framework, continuous medical education is mandatory to correctly manage assistance devices. However, commercially available neonatal respiratory simulators are rarely suitable for representing anatomical and physiological conditions; a step toward high-fidelity simulation, therefore, is essential for nurses and neonatologists to acquire the practice needed without any risk. An innovative multi-compartmental infant respirator simulator based on a five-lobe model was developed to reproduce different physio-pathological conditions in infants and to simulate many different kinds of clinical scenarios. The work consisted of three phases: (1) a theoretical study and modeling phase, (2) a prototyping phase, and (3) testing of the simulation software during training courses. The neonatal pulmonary simulator produced allows the replication and evaluation of different mechanical ventilation modalities in infants suffering from many different kinds of respiratory physio-pathological conditions. In particular, the system provides variable compliances for each lobe in an independent manner and different resistance levels for the airway branches; moreover, it allows the trainer to simulate both autonomous and mechanically assisted respiratory cycles in newborns. The developed and tested simulator is a significant contribution to the field of medical simulation in neonatology, as it makes it possible to choose the best ventilation strategy and to perform fully aware management of ventilation parameters. PMID- 26238791 TI - Head injury predictors in sports trauma--a state-of-the-art review. AB - Head injuries occur in a great variety of sports. Many of these have been associated with neurological injuries, affecting the central nervous system. Some examples are motorsports, cycling, skiing, horse riding, mountaineering and most contact sports such as football, ice and field hockey, soccer, lacrosse, etc. The outcome of head impacts in these sports can be very severe. The worst-case scenarios of permanent disability or even death are possibilities. Over recent decades, many In recent decades, a great number of head injury criteria and respective thresholds have been proposed. However, the available information is much dispersed and a consensus has still not been achieved regarding the best injury criteria or even their thresholds. This review paper gives a thorough overview of the work carried out by the scientific community in the field of impact biomechanics about head injuries sustained during sports activity. The main goal is to review the head injury criteria, as well as their thresholds. Several are reviewed, from the predictors based on kinematics to the ones based on human tissue thresholds. In this work, we start to briefly introduce the head injuries and their mechanisms commonly seen as a result of head trauma in sports. Then, we present and summarize the head injury criteria and their respective thresholds. PMID- 26238792 TI - Developmental stress impairs performance on an association task in male and female songbirds, but impairs auditory learning in females only. AB - In songbirds, early-life environments critically shape song development. Many studies have demonstrated that developmental stress impairs song learning and the development of song-control regions of the brain in males. However, song has evolved through signaller-receiver networks and the effect stress has on the ability to receive auditory signals is equally important, especially for females who use song as an indicator of mate quality. Female song preferences have been the metric used to evaluate how developmental stress affects auditory learning, but preferences are shaped by many non-cognitive factors and preclude the evaluation of auditory learning abilities in males. To determine whether developmental stress specifically affects auditory learning in both sexes, we subjected juvenile European starlings, Sturnus vulgaris, to either an ad libitum or an unpredictable food supply treatment from 35 to 115 days of age. In adulthood, we assessed learning of both auditory and visual discrimination tasks. Females reared in the experimental group were slower than females in the control group to acquire a relative frequency auditory task, and slower than their male counterparts to acquire an absolute frequency auditory task. There was no difference in auditory performance between treatment groups for males. However, on the colour association task, birds from the experimental group committed more errors per trial than control birds. There was no correlation in performance across the cognitive tasks. Developmental stress did not affect all cognitive processes equally across the sexes. Our results suggest that the male auditory system may be more robust to developmental stress than that of females. PMID- 26238793 TI - The Natural History of Atrioventricular Valve Regurgitation Throughout Fetal Life in Patients with Atrioventricular Canal Defects. AB - Atrioventricular valve regurgitation (AVVR) influences morbidity and mortality in the atrioventricular canal defect (AVC). Fetal cardiac structures are subject to hemodynamic changes, as well as growth and maturation during gestation, which may alter the degree of AVVR and affect prognosis. We sought to investigate the frequency of change in degree of AVVR documented by fetal echocardiography (echo) between different periods of gestational age. Subjects with AVC seen in the Fetal Heart Program between January 2008 and September 2010 were identified. Degree of AVVR was assessed by color Doppler imaging and categorized as Grade 0 (no AVVR), Grade 1 (hemodynamically insignificant AVVR = trivial or mild), and Grade 2 (hemodynamically important AVVR = >=moderate). Levels of AVVR between periods were compared. Forty-three fetuses were analyzed. Overall, 60% had no change, 14% had a decrease, and 26% had an increase in AVVR grade. Two fetuses progressed from Grade 0 or 1 to Grade 2, while one fetus decreased from Grade 2 to Grade 0. Trisomy 21 and heterotaxy syndrome were not risk factors for AVVR progression. Transitional and incomplete canal defects may be more susceptible to AVVR progression. Sixty percent of fetuses with AVC will not exhibit progression of AVVR between the second and third trimesters of gestation. In those who exhibit change, it is most often within a hemodynamically insignificant range between none and mild regurgitation (Grades 0 and 1). These findings have implications for the counseling, follow-up, and delivery plans of the fetus with AVC defect. PMID- 26238796 TI - The Association Between Stalking and Violence in a Sample of Spanish Partner Violence Cases. AB - The present descriptive study analyzes stalking in a sample of 278 Spanish court cases involving partner violence and contrasts the benefits of the new bill article 172ter, which criminalizes stalking, compared with the Organic Law 1/2004 on partner violence. Thirty-seven percent (37%) of the total sample included stalking behaviors, which manifested in intimidatory (60%) and controlling (45%) unwanted verbal communications (62%) and physical approaches (42%) that ended violently in a third of the cases (35%). Cases involving violent stalking, non violent stalking, and physical violence without stalking were compared. A closer look at violent stalking cases uncovered that intimacy-seeking stalking behavior was concurrent with face-to-face aggression with a sharp object, whereas pursuit/control and invasive behavior were associated with property invasion and damage. Data not only support the contention that stalking should be criminalized regardless of the type of stalking behavior but also indicate that differences in the behavior might warrant different management interventions. PMID- 26238794 TI - Hepatitis B Virus and Hepatitis D Virus Entry, Species Specificity, and Tissue Tropism. AB - Entry of hepatitis B (HBV) and hepatitis D viruses (HDV) into a host cell represents the initial step of infection. This process requires multiple steps, including the low-affinity attachment of the virus to the cell surface, followed by high-affinity attachment to specific receptor(s), and subsequent endocytosis mediated internalization. Within the viral envelope, the preS1 region is involved in receptor binding. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as an entry receptor of HBV and HDV by affinity purification using a preS1 peptide. NTCP is mainly or exclusively expressed in the liver, and this membrane protein is at least one of the factors determining the narrow species specificity and hepatotropism of HBV and HDV. However, there are likely other factors that mediate the species and tissue tropism of HBV. This review summarizes the current understanding of the mechanisms of HBV/HDV entry. PMID- 26238797 TI - Bioinspired Lotus-like Self-Illuminous Coating. AB - The sensitivity of long persistent phosphor materials (LPP) to moisture greatly limits their applications especially in humid environments, which cause the hydrolysis of LPP and shorten their lifetime. In this work, a facile, environmentally friendly, and low-cost method was developed to prevent the infiltration of water or moisture to the LPP by doping LPP with SiO2 nanoparticles to form a superhydrophobic coating. The superhydrophobic coating provided a stable environment to the self-illuminous system, which not only can resist the infiltration of water but also can have good self-cleaning property, similar to the lotus leaf effect. This facile method will be very beneficial for expending further application of LPP especially in high humidity. PMID- 26238799 TI - A Surface-Enhanced Raman Scattering Sensor Integrated with Battery-Controlled Fluidic Device for Capture and Detection of Trace Small Molecules. AB - For surface-enhanced Raman scattering (SERS) sensors, one of the important issues is the development of substrates not only with high SERS-activity but also with strong ability to capture analytes. However, it is difficult to achieve the two goals simultaneously especially when detecting small molecules. Herein a compact battery-controlled nanostructure-assembled SERS system has been demonstrated for capture and detection of trace small molecule pollutants in water. In this SERS fluidic system, an electrical heating constantan wire covered with the vertically aligned ZnO nanotapers decorated with Ag-nanoparticles is inserted into a glass capillary. A mixture of thermo-responsive microgels, Au-nanorods colloids and analyte solution is then filled into the remnant space of the capillary. When the system is heated by switching on the battery, the thermo-responsive microgels shrink, which immobilizes the analyte and drives the Au-nanorod close to each other and close to the Ag-ZnO nanotapers. This process has also created high density "hot spots" due to multi-type plasmonic couplings in three-dimensional space, amplifying the SERS signal. This integrated device has been successfully used to measure methyl parathion in lake water, showing a great potential in detection of aquatic pollutants. PMID- 26238800 TI - Antecedents of intra/intergroup friendships and stress levels among ethnic and religious minority members. AB - Two studies tested a model, whereby, identification with the minority group was predicted to impact on acculturation preferences, which in turn were proposed to impact involvement in intragroup friendships with other minority members, intergroup friendships with majority members and stress experienced by minority members. A direct path from minority identification to stress was also included in the model. The model was tested using structural equation modelling on survey data collected from Muslim women (N = 250) and from Somali minority members (N = 198) in Britain. Results supported predictions and revealed that identification was associated with more culture maintenance preference and less culture adoption preference. Culture maintenance preference was associated with involvement in intragroup friendships, and culture adoption preference was associated with involvement in intergroup friendships and increased stress. Practical applications of the findings are discussed. PMID- 26238798 TI - Approaching rational epitope vaccine design for hepatitis C virus with meta server and multivalent scaffolding. AB - Development of a prophylactic vaccine against hepatitis C virus (HCV) has been hampered by the extraordinary viral diversity and the poor host immune response. Scaffolding, by grafting an epitope onto a heterologous protein scaffold, offers a possible solution to epitope vaccine design. In this study, we designed and characterized epitope vaccine antigens for the antigenic sites of HCV envelope glycoproteins E1 (residues 314-324) and E2 (residues 412-423), for which neutralizing antibody-bound structures are available. We first combined six structural alignment algorithms in a "scaffolding meta-server" to search for diverse scaffolds that can structurally accommodate the HCV epitopes. For each antigenic site, ten scaffolds were selected for computational design, and the resulting epitope scaffolds were analyzed using structure-scoring functions and molecular dynamics simulation. We experimentally confirmed that three E1 and five E2 epitope scaffolds bound to their respective neutralizing antibodies, but with different kinetics. We then investigated a "multivalent scaffolding" approach by displaying 24 copies of an epitope scaffold on a self-assembling nanoparticle, which markedly increased the avidity of antibody binding. Our study thus demonstrates the utility of a multi-scale scaffolding strategy in epitope vaccine design and provides promising HCV immunogens for further assessment in vivo. PMID- 26238802 TI - Erratum to: Re-irradiation with cetuximab or cisplatin-based chemotherapy for recurrent squamous cell carcinoma of the head and neck. PMID- 26238801 TI - Investigations of Potential Phenotypes of Foot Osteoarthritis: Cross-Sectional Analysis From the Clinical Assessment Study of the Foot. AB - OBJECTIVE: To investigate the existence of distinct foot osteoarthritis (OA) phenotypes based on pattern of joint involvement and comparative symptom and risk profiles. METHODS: Participants ages >=50 years reporting foot pain in the previous year were drawn from a population-based cohort. Radiographs were scored for OA in the first metatarsophalangeal (MTP) joint, first and second cuneometatarsal, navicular first cuneiform, and talonavicular joints according to a published atlas. Chi-square tests established clustering, and odds ratios (ORs) examined symmetry and pairwise associations of radiographic OA in the feet. Distinct underlying classes of foot OA were investigated by latent class analysis (LCA) and their association with symptoms and risk factors was assessed. RESULTS: In 533 participants (mean age 64.9 years, 55.9% female) radiographic OA clustered across both feet (P < 0.001) and was highly symmetrical (adjusted OR 3.0, 95% confidence interval 2.1, 4.2). LCA identified 3 distinct classes of foot OA: no or minimal foot OA (64%), isolated first MTP joint OA (22%), and polyarticular foot OA (15%). After adjustment for age and sex, polyarticular foot OA was associated with nodal OA, increased body mass index, and more pain and functional limitation compared to the other classes. CONCLUSION: Patterning of radiographic foot OA has provided insight into the existence of 2 forms of foot OA: isolated first MTP joint OA and polyarticular foot OA. The symptom and risk factor profiles in individuals with polyarticular foot OA indicate a possible distinctive phenotype of foot OA, but further research is needed to explore the characteristics of isolated first MTP joint and polyarticular foot OA. PMID- 26238803 TI - Two new flavonoids from Selaginella uncinata. AB - Two new flavonoids, uncinataflavones A (1) and B (2), along with one known compound 6-(5-carboxyl-2-methoxyphenyl)-apigenin (3), were isolated from Selaginella uncinata (Desv.) Spring. All these compounds belong to apigenin derivatives with aryl substituents at C-6 position. The structures of new compounds were elucidated on the basis of comprehensive spectroscopic analyses (UV, IR, 1D, and 2D NMR as well as HR-ESI-MS). PMID- 26238804 TI - 'Superficial' anastomoses in monochorionic placentas are not always superficial. AB - Arterioarterial (AA) and venovenous (VV) anastomoses in monochorionic (MC) placentas lie on the placental surface and are termed as superficial anastomoses. The purpose of this study is to report the occurrence of an atypical form of superficial anastomoses which are partially hidden. Partially-hidden superficial anastomoses were defined as vascular anastomoses without visible direct connection on placental surface but with clear mixing of dye after colored dye injection. With analyzing 270 MC placentas, we found a prevalence of partially hidden AA and VV anastomose of 3% and 5%, respectively. In conclusion, partially hidden superficial anastomose are not infrequent in MC placentas. PMID- 26238805 TI - QbD-Enabled Development of Novel Stimuli-Responsive Gastroretentive Systems of Acyclovir for Improved Patient Compliance and Biopharmaceutical Performance. AB - The current studies entail systematic quality by design (QbD)-based development of stimuli-responsive gastroretentive drug delivery systems (GRDDS) of acyclovir using polysaccharide blends for attaining controlled drug release profile and improved patient compliance. The patient-centric quality target product profile was defined and critical quality attributes (CQAs) earmarked. Risk assessment studies, carried out through Ishikawa fish bone diagram and failure mode, effect, and criticality analysis, helped in identifying the plausible risks or failure modes affecting the quality attributes of the drug product. A face-centered cubic design was employed for systematic development and optimization of the concentration of sodium alginate (X 1) and gellan (X 2) as the critical material attributes (CMAs) in the stimuli-responsive formulations, which were evaluated for CQAs viz. viscosity, gel strength, onset of floatation, and drug release characteristics. Mathematical modeling was carried out for generation of design space, and optimum formulation was embarked upon, exhibiting formulation characteristics marked by excellent floatation and bioadhesion characteristics along with promising drug release control up to 24 h. Drug-excipient compatibility studies through FTIR and DSC revealed absence of any interaction(s) among the formulation excipients. In vivo pharmacokinetic studies in Wistar rats corroborated extension in the drug absorption profile from the optimized stimuli responsive GR formulations vis-a-vis the marketed suspension (ZOVIRAX(r)). Establishment of in vitro/in vivo correlation (IVIVC) revealed a high degree of correlation between the in vitro and in vivo data. In a nutshell, the present investigations report the successful development of stimuli-responsive GRDDS of acyclovir, which can be applicable as a platform approach for other drugs too. PMID- 26238807 TI - A new arthroscopic classification of degenerative medial meniscus root tear that correlates with meniscus extrusion on magnetic resonance imaging. AB - BACKGROUND: To determine a new classification system for medial meniscus root tears (MMRT) based on arthroscopic findings. METHODS: 24 knees (55%) belonged to the nondisplaced or overlapped group, and 20 knees (45%) to the widely displaced group. Absolute meniscal extrusion was defined as distance between outer edge of the articular cartilage of tibial plateau and meniscal outer edge. Relative extrusion was defined as extruded meniscus width divided by entire meniscal width, multiplied by 100. The proportion of knees with major (>3 mm) extrusion were compared in two groups, as were the severity of chondral wear and osteoarthritic change. RESULTS: Absolute (4.6 mm vs. 3.7 mm, P=0.006) and relative (46% vs. 39%, P=0.042) extrusion of the medial meniscus were greater in widely displaced than in nondisplaced or overlapped group. Medial joint space width was significantly narrower in the widely displaced than in the nondisplaced or overlapped group (3.0 mm vs. 4.0 mm, P=0.007). The widely displaced group had a 4 degrees greater varus deformity, and higher rates of major extrusion (>3 mm), grade III or IV chondral wear in the medial femoral condyle (60% vs. 29%, P=0.039) and medial compartment osteoarthritis (75% vs. 21%, P=0.001) than did the nondisplaced or overlapped group. CONCLUSIONS: Widely displaced MMRT had greater meniscal extrusion and more severe chondral wear and osteoarthritis than did nondisplaced or overlapped MMRT. In this novel classification system, the stage of MMRT severity was associated with tear site displacement. LEVEL OF EVIDENCE: Case series (level IV). PMID- 26238808 TI - Editorial Comment from Dr Kim and Dr Ku to Prognostic factors of recurrent disease in upper urinary tract urothelial cancer after radical nephroureterectomy: Subanalysis of the multi-institutional national database of the Japanese Urological Association. PMID- 26238806 TI - Development of Solid Self-Emulsifying Formulation for Improving the Oral Bioavailability of Erlotinib. AB - To improve the solubility and oral bioavailability of erlotinib, a poorly water soluble anticancer drug, solid self-emulsifying drug delivery system (SEDDS) was developed using solid inert carriers such as dextran 40 and Aerosil(r) 200 (colloidal silica). The preliminary solubility of erlotinib in various oils, surfactants, and co-surfactants was determined. Labrafil M2125CS, Labrasol, and Transcutol HP were chosen as the oil, surfactant, and co-surfactant, respectively, for preparation of the SEDDS formulations. The ternary phase diagram was evaluated to show the self-emulsifying area. The formulations were optimized using the droplet size and polydispersity index (PDI) of the resultant emulsions. Then, the optimized formulation containing 5% Labrafil M2125CS, 65% Labrasol, and 30% Transcutol was spray dried with dextran or Aerosil(r) and characterized for surface morphology, crystallinity, and pharmacokinetics in rats. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) exhibited the amorphous form or molecular dispersion of erlotinib in the formulations. The pharmacokinetic parameters of the optimized formulations showed that the maximum concentration (C max) and area under the curve (AUC) of erlotinib were significantly increased, compared to erlotinib powder (p < 0.05). Thus, this SEDDS could be a promising method for enhancing the oral bioavailability of erlotinib. PMID- 26238809 TI - Intensive Care Utilization for Hematopoietic Cell Transplant Recipients. AB - Blood and marrow transplantation (BMT) is a potentially curative therapy for a number of malignant and nonmalignant diseases. Multiple variables, including age, comorbid conditions, disease, disease stage, prior therapies, degree of donor recipient matching, type of transplantation, and dose intensity of the preparative regimen, affect both morbidity and mortality. Despite tremendous gains in supportive care, BMT remains a high-risk medical therapy. A critically ill BMT recipient may require transfer to an intensive care unit (ICU) and the specialized medical and nursing care that can be provided, such as mechanical ventilation and vasopressor support. Mortality for BMT recipients requiring care in an ICU is high. This paper will describe the experience of the Stanford Blood and Marrow Transplant Program in developing and implementing guidelines to maximize the benefit of intensive care for critically ill BMT recipients. PMID- 26238812 TI - Mental Training for Cognitive Improvement in Elderly People: What have We Learned from Clinical and Neurophysiologic Studies? AB - Cognitive impairment is a major concern in elderly people, and a variety of nonpharmacological therapies (NPTs) have been developed to help with cognitive decline. One of the most popular therapies is cognitive training, which includes pencil-and-paper puzzles, computerized games, or the combination of the two. Training is designed to have participants perform diverse exercises in one or more cognitive domains. Most clinical training trials indicate that well organized tasks are clinically effective for cognitive improvement. Neural plasticity is a probable explanation for positive training effects. EEG and fMRI research show that the electrical activity and metabolism of specific brain areas are changed, and these changes are retained for a long period after training. Studies on mice to uncover the cellular and molecular changes underlying neural connectivity have found effective changes in brain networks after learning or training. Rac1 and NMDA receptors are thought to be involved in hippocampal neurogenesis, which is induced by learning. Here we review clinical trials of cognitive training, published during the last five years, and summarized some important characteristics of training tasks design. The probable role of neuronal plasticity and molecular mechanisms in training effects also are discussed. Most importantly, we discuss key ways to modifying the design of tasks based on studies we review. This review mainly identifies and discusses the reasons for positive training effects on cognition from clinical and neurophysiological perspectives. Based on the findings and their related mechanisms, further studies should design more effective and specific training tasks. PMID- 26238813 TI - Differential Influence of Carotid Stenosis and White Matter Disease on Motor and Cognitive Activation. AB - BACKGROUND: Cognitive and motor performance can be supported, especially in older subjects, by different types of brain activations, which can be accurately studied by functional magnetic resonance imaging (fMRI). Vascular risk factors (VRFs) are extremely important in the development of cognitive impairment, but few studies have focused on the fMRI cortical activation characteristics of healthy subjects with and without silent cerebrovascular disease including white matter hyperintensities (WMH) and carotid stenosis (CS) performing cognitive tasks. METHODS: Thirty-five volunteers with and without asymptomatic unilateral carotid stenosis above 70% and variable degrees of WMH underwent performance of a simple motor and cognitive task during an fMRI session. RESULTS: While the performance of the motor task resulted in a cortical activation dependent of age but not of WMH and carotid stenosis, performance of the cognitive task was accompanied by a significantly increased activation independently correlated with age, presence of WMH as well as of carotid stenosis. CONCLUSIONS: in this study, cognitive domains regulating attention and working memory appear to be activated with a pattern influenced by the presence of carotid stenosis as well as by white matter hyperintensities. The impairment of these cognitive abilities is of high relevance in Alzheimer's disease pathology. The fMRI pattern shown in patients with asymptomatic but significant carotid stenosis might be related to chronic cerebrovascular hypoperfusion, a critical pathophysiological mechanisms in AD. In these patients, carotid endoarterectomy should be considered also for AD prevention and might be recommended. PMID- 26238810 TI - High Disease-Free Survival with Enhanced Protection against Relapse after Double Unit Cord Blood Transplantation When Compared with T Cell-Depleted Unrelated Donor Transplantation in Patients with Acute Leukemia and Chronic Myelogenous Leukemia. AB - Double-unit cord blood (DCB) grafts are a rapidly available stem cell source for adults with high-risk leukemias. However, how disease-free survival (DFS) after DCB transplantation (DCBT) compares to that of unrelated donor transplantation (URDT) is not fully established. We analyzed 166 allograft recipients (66 8/8 HLA matched URDT, 45 7/8 HLA-matched URDT, and 55 DCBT) ages 16 to 60 years with high risk acute leukemia or chronic myelogenous leukemia (CML). URDT and DCBT recipients were similar except DCBT recipients were more likely to have lower weight and non-European ancestry and to receive intermediate-intensity conditioning. All URDT recipients received a CD34(+) cell-selected (T cell depleted) graft. Overall, differences between the 3-year transplantation-related mortality were not significant (8/8 URDT, 18%; 7/8 URDT, 39%; and DCBT, 24%; P = .108), whereas the 3-year relapse risk was decreased after DCBT (8/8 URDT, 23%; 7/8 URDT, 20%; and DCBT 9%, P = .037). Three-year DFS was 57% in 8/8 URDT, 41% in 7/8 URDT, and 68% in DCBT recipients (P = .068), and the 3-year DFS in DCBT recipients was higher than that of 7/8 URDT recipients (P = .021). In multivariate analysis in acute leukemia patients, factors adversely associated with DFS were female gender (hazard ratio [HR], 1.68; P = .031), diagnosis of acute lymphoblastic leukemia (HR, 2.09; P = .004), and 7/8 T cell-depleted URDT (HR, 1.91; P = .037). High DFS can be achieved in adults with acute leukemia and CML with low relapse rates after DCBT. Our findings support performing DCBT in adults in preference to HLA-mismatched T cell-depleted URDT and suggest DCBT is a readily available alternative to T cell-depleted 8/8 URDT, especially in patients requiring urgent transplantation. PMID- 26238814 TI - Integration of Cognitive Tests and Resting State fMRI for the Individual Identification of Mild Cognitive Impairment. AB - BACKGROUND: Resting-state functional magnetic resonance imaging (RS-fMRI) appears as a promising imaging technique to identify early biomarkers of Alzheimer type neurodegeneration, which can be more sensitive to detect the earliest stages of this disease than structural alterations. Recent findings have highlighted interesting patterns of alteration in resting-state activity at the mild cognitive impairment (MCI) prodromal stage of Alzheimer's disease. However, it has not been established whether RS-fMRI alterations may be of any diagnostic use at the individual patient level and whether parameters derived from RS-fMRI images add any quantitative predictive/classificatory value to standard cognitive tests (CTs). METHODS: We computed a set of 444 features based on RS-fMRI and used 21 variables obtained from a neuropsychological assessment battery of tests in 29 MCI patients and 21 healthy controls. We used these indices to evaluate their impact on MCI/healthy control classification using machine learning algorithms and a 10-fold cross validation analysis. RESULTS: A classification accuracy (sensitivity/ specificity/area under curve/positive predictive value/negative predictive value) of 0.9559 (0.9620/0.9470/ 0.9517/0.9720/0.9628) was achieved when using both sets of indices. There was a statistically significant improvement over the use of CTs only, highlighting the superior classificatory role of RS-fMRI. CONCLUSIONS: RS-fMRI provides complementary information to CTs for MCI-patient/healthy control individual classification. PMID- 26238815 TI - Non-plasmonic nanoantennas for surface enhanced spectroscopies with ultra-low heat conversion. AB - Nanoplasmonics has recently revolutionized our ability to control light on the nanoscale. Using metallic nanostructures with tailored shapes, it is possible to efficiently focus light into nanoscale field 'hot spots'. High field enhancement factors have been achieved in such optical nanoantennas, enabling transformative science in the areas of single molecule interactions, highly enhanced nonlinearities and nanoscale waveguiding. Unfortunately, these large enhancements come at the price of high optical losses due to absorption in the metal, severely limiting real-world applications. Via the realization of a novel nanophotonic platform based on dielectric nanostructures to form efficient nanoantennas with ultra-low light-into-heat conversion, here we demonstrate an approach that overcomes these limitations. We show that dimer-like silicon-based single nanoantennas produce both high surface enhanced fluorescence and surface enhanced Raman scattering, while at the same time generating a negligible temperature increase in their hot spots and surrounding environments. PMID- 26238816 TI - Thiomers: Influence of molecular mass and thiol group content of poly(acrylic acid) on efflux pump inhibition. AB - The aim of the present study was to investigate the influence of molecular mass and thiol group content of poly(acrylic acid)-cysteine conjugates on the permeation of sulforhodamine 101 and penicillin G. acting as substrates for multidrug resistance-associated protein 2 efflux pump. Poly(acrylic acids) of 2 kDa, 100 kDa, 250 kDa, 450 kDa and 3000 kDa were conjugated with cysteine. The thiol group content of all these polymers was in the range from 343.3 +/- 48.4 MUmol/g to 450.3 +/- 76.1 MUmol/g. Transport studies were performed on rat small intestine mounted in Ussing-type chambers. Since 250 kDa poly(acrylic acid) showed the highest permeation enhancing effect, additionally thiolated 250 kDa polyacrylates displaying 157.2 MUmol/g, 223.0 +/- 18.1 and 355.9 MUmol/g thiol groups were synthesized in order to investigate the influence of thiol group content on the permeation enhancement. The permeation of sulforhodamine was 3.93- and 3.85-fold improved using 250 kDa poly(acrylic acid)-cysteine conjugate exhibiting 355.9 +/- 39.5 MUmol/g and 223.0 +/- 18.1 MUmol/g thiol groups. Using the same conjugates the permeation of penicillin G was 1.70- and 1.59-fold improved, respectively. The study demonstrates that thiolated poly(acrylic acid) inhibits Mrp2 mediated transport and that the extent of inhibition depends on the molecular mass and degree of thiolation of the polymer. PMID- 26238817 TI - Gastroretentive montmorillonite-tetracycline nanoclay for the treatment of Helicobacter pylori infection. AB - The paper aims to explore the potential benefits provided by an organically modified montmorillonite (nanoclay) in the problematic management of the Helicobacter pylori gastric infection that is one of the most prevalent infectious diseases worldwide. Two nanoclay samples were produced by the intercalation of tetracycline (TC) into the interlayer of montmorillonite (MM) under two different pH reaction conditions (pH 3.0 and 8.7). MM/TC nanoclays were characterized by EDX, XRD, FTIR, DSC, drug adsorption extent, in vitro mucoadhesiveness and desorption in simulated gastric media. The reaction between MM and TC led to a complete MM cation (Na(+) and Ca(2+)) exchange process, an increase of MM characteristic interlayer spacing as well as an involvement of NHR3(+) group of TC, regardless of the reaction pH value. However, MM/TC nanoclay obtained under alkaline conditions provided a lower TC adsorption as well as a drug fraction weakly linked to MM in comparison with the nanoclay obtained in acidic conditions. Both the nanoclays exhibited good mucoadhesion properties to porcine mucin and TC desorption occurring mainly via a cation exchange process by H(+) ions. Based on the results obtained, TC intercalation into MM nanoplatelets could represent a potential advantageous approach allowing the antibiotic to distribute homogeneously on the gastric mucosa, diffuse through the gastric mucus layer and achieve the microorganism localization. PMID- 26238818 TI - Stereotactic body radiotherapy for second pulmonary nodules after operation for an initial lung cancer. AB - OBJECTIVE: A second lung cancer is occasionally observed in patients who underwent surgical resection of the index lung cancer. The purpose of this study is to evaluate stereotactic body radiation therapy for second lung cancer. METHODS: Fifty-one medically inoperable patients who underwent stereotactic body radiation therapy for second lung cancer were the subjects: 31 cases of multiple primary lung cancer and 20 of pulmonary metastasis from the index cancer. Clinical stage was T1a in 27 patients, T1b in 13 patients and T2a in 11 patients, and 70% of subjects had impaired respiratory function. Histology of second lung cancer was adenocarcinoma in 16 patients, squamous cell carcinoma in 9 patients and not assessed in 25 patients. The interval between index cancer operation and stereotactic body radiation therapy was 31 months (range: 4-171). The total stereotactic body radiation therapy doses were 48 Gy in 4 fractions or 60 Gy in 10 fractions. RESULTS: With the median follow-up of 36 months, 3-year overall survival rates were 62% with the median survival time of 46 months. Cause specific survival was 73% at 3 years. Overall survival for multiple primary lung cancer and pulmonary metastasis was quite similar: 62 and 61% at 3 years, respectively. Three-year overall survival was 77% for T1a and 43% for T1b or T2a. Grade 2 pulmonary toxicities occurred in five patients and one patient died of Grade 5 pneumonitis. CONCLUSIONS: Even though the subjects were medically inoperable, the survival outcomes of stereotactic body radiation therapy were favorable. Furthermore, having acceptable toxicity, stereotactic body radiation therapy is feasible and could be an option for multiple primary lung cancer and pulmonary metastasis after surgical resection for the index cancer. PMID- 26238819 TI - Anterior cerebral artery dissection diagnosed using high-resolution MRI. PMID- 26238820 TI - Adiponectin and leptin levels in migraineurs in the Atherosclerosis Risk in Communities Study. PMID- 26238821 TI - Preoperative factors of apathy in subthalamic stimulated Parkinson disease: a PET study. PMID- 26238822 TI - Emerging subspecialties in neurology: neurorehabilitation. PMID- 26238823 TI - Teaching NeuroImages: epilepsia partialis continua revealing PML after allogenic stem cell transplantation. PMID- 26238824 TI - Elastic Recoil Revisited. PMID- 26238825 TI - Hydraulic Fracturing (Fracking) and the Clean Air Act. PMID- 26238826 TI - Pepsin: A Silent Biomarker for Reflux Aspiration or an Active Player in Extra Esophageal Mucosal Injury? PMID- 26238827 TI - Learning to Look Through the Bronchoscope. PMID- 26238828 TI - Organ Donors: Making the Most of What Is Offered. PMID- 26238829 TI - POINT: Does Laboratory Polysomnography Yield Better Outcomes Than Home Sleep Testing? Yes. PMID- 26238830 TI - COUNTERPOINT: Does Laboratory Polysomnography Yield Better Outcomes Than Home Sleep Testing? No. PMID- 26238831 TI - Rebuttal From Dr Pack. PMID- 26238832 TI - Rebuttal From Dr Freedman. PMID- 26238833 TI - Correction to Table in: Poor Symptom Control Is Associated With Reduced CT Scan Segmental Airway Lumen Area in Smokers With Asthma. PMID- 26238834 TI - Use of Lenalidomide in 5q-Myelodysplastic Syndrome Provides Novel Treatment Prospects in Management of Pulmonary Sarcoidosis. AB - We present the case of a 71-year-old woman with a long-standing history of refractory pulmonary sarcoidosis, who, upon commencement of treatment with lenalidomide for her newly diagnosed 5q-myelodysplastic syndrome, showed a remarkable, immediate, unexpected response and recovery of her sarcoidosis related symptoms, improvement of her vital capacity, and complete clearance of her bibasal alveolor infiltrates. To our knowledge, this is the first case to report on the significant and immediate efficacy of lenalidomide in the management of pulmonary sarcoidosis. It provides a potential role for the use of lenalidomide as a novel therapeutic agent in patients with refractory pulmonary sarcoidosis. PMID- 26238835 TI - A 73-Year-Old Man With Left Lung "White Out". PMID- 26238836 TI - A 72-Year-Old Woman With Previous Pulmonary Metastasis and New Peripheral Nodule. AB - A 72-year-old female nonsmoker was admitted to our Thoracic Surgery Unit in 2013 because of a lesion detected on chest CT scan during oncologic follow-up. Her medical history was significant for the development of a single pulmonary metastasis discovered 1 year after sigmoidectomy for colic adenocarcinoma. At that time, the patient was treated with six cycles of neoadjuvant chemotherapy followed by left lower lobectomy. Histologic examination demonstrated a pulmonary metastasis of colic adenocarcinoma with diffuse necrotic areas. The patient underwent subsequent adjuvant chemotherapy with capecitabine and was followed annually with biohumoral oncologic screening (carcinoembryonic antigen, carbohydrate antigen 19-9), chest-abdomen CT scan, and colonoscopy. PMID- 26238837 TI - An 18-Year-Old Woman With Snoring and Refractory Epilepsy. AB - An 18-year-old woman with a history of refractory complex partial epilepsy presented for evaluation of snoring and episodes of gasping for air during sleep. She had uncontrolled epilepsy since the age of 8 years despite trial of multiple antiepileptic medications. She eventually underwent an implantation of a vagus nerve stimulator (VNS) device (model 103; Cyberonics Inc) with gradual adjustment of the VNS settings for better seizure control. PMID- 26238838 TI - A 37-Year-Old Man With Nonresolving Pneumonia and Endobronchial Lesion. AB - A previously healthy, immunocompetent 37-year-old man was hospitalized with a 3 month history of intermittent fevers and cough with mucopurulent sputum preceded by flu-like symptoms. Five episodes of similar symptoms had prompted two hospitalizations and three courses of outpatient antibiotics. The fever would subside with treatment but intermittent dry cough persisted. There was no history of weight loss, night sweats, wheezing, arthralgia, skin rash, hemoptysis, recent travel, sick contacts, or high-risk sexual behavior. He was a nonsmoker with no alcohol or recreational drug use. He was an accountant in the military with no history of significant organic or inorganic dust exposures. PMID- 26238839 TI - Cultural Differences in Palliative Care in Patients With Idiopathic Pulmonary Fibrosis. PMID- 26238840 TI - Response. PMID- 26238841 TI - In Defense of Medical Education. PMID- 26238842 TI - Performing Pulmonary Interventions: Pulmonologist or Pulmonary Interventionist. PMID- 26238843 TI - Response. PMID- 26238844 TI - Association Between Postdischarge Pulmonologist Visit and Hospital Readmission. PMID- 26238845 TI - Response. PMID- 26238846 TI - Caring for Critically Ill Patients Infected With the Ebola Virus: Logistic and Human Challenges. PMID- 26238847 TI - Response. PMID- 26238848 TI - Another Meaningful End Point for Nighttime Intensivist Coverage. PMID- 26238849 TI - Should Quality of Care Provided by Nighttime Intensivists Be Judged by Mortality? PMID- 26238850 TI - Response. PMID- 26238851 TI - Brain Death: Legal Duties to Accommodate Religious Objections. PMID- 26238852 TI - The US Uniform Determination of Death Act: Will It Survive a Constitutional Challenge? PMID- 26238853 TI - Response. PMID- 26238854 TI - Visualizing spikes in source-space: Rapid and efficient evaluation of magnetoencephalography. AB - OBJECTIVE: Reviewing magnetoencephalography (MEG) recordings is time-consuming: signals from the 306 MEG-sensors are typically reviewed divided into six arrays of 51 sensors each, thus browsing each recording six times in order to evaluate all signals. A novel method of reconstructing the MEG signals in source-space was developed using a source-montage of 29 brain-regions and two spatial components to remove magnetocardiographic (MKG) artefacts. Our objective was to evaluate the accuracy of reviewing MEG in source-space. METHODS: In 60 consecutive patients with epilepsy, we prospectively evaluated the accuracy of reviewing the MEG signals in source-space as compared to the classical method of reviewing them in sensor-space. RESULTS: All 46 spike-clusters identified in sensor-space were also identified in source-space. Two additional spike-clusters were identified in source-space. As 29 source-channels can be easily displayed simultaneously, MEG recordings had to be browsed only once. Yet, this yielded a global coverage of the recorded signals and enhanced detectability of epileptiform discharges because MKG-artefacts were suppressed and did not impede evaluation in source space. CONCLUSIONS: Our results show that reviewing MEG recordings in source space is accurate and much more rapid than the classical method of reviewing in sensor-space. SIGNIFICANCE: This novel method facilitates the clinical use of MEG. PMID- 26238855 TI - Neurophysiological studies of brainstem functions and reflexes: Publications from the Brainstem Society Meeting. Berlin, March 2014. PMID- 26238856 TI - Universal automated high frequency oscillation detector for real-time, long term EEG. AB - OBJECTIVE: Interictal high frequency oscillations (HFOs) in intracranial EEG are a potential biomarker of epilepsy, but current automated HFO detectors require human review to remove artifacts. Our objective is to automatically redact false HFO detections, facilitating clinical use of interictal HFOs. METHODS: Intracranial EEG data from 23 patients were processed with automated detectors of HFOs and artifacts. HFOs not concurrent with artifacts were labeled quality HFOs (qHFOs). Methods were validated by human review on a subset of 2000 events. The correlation of qHFO rates with the seizure onset zone (SOZ) was assessed via (1) a retrospective asymmetry measure and (2) a novel quasi-prospective algorithm to identify SOZ. RESULTS: Human review estimated that less than 12% of qHFOs are artifacts, whereas 78.5% of redacted HFOs are artifacts. The qHFO rate was more correlated with SOZ (p=0.020, Wilcoxon signed rank test) and resected volume (p=0.0037) than baseline detections. Using qHFOs, our algorithm was able to determine SOZ in 60% of the ILAE Class I patients, with all algorithmically determined SOZs fully within the resected volumes. CONCLUSIONS: The algorithm reduced false-positive HFO detections, improving the precision of the HFO biomarker. SIGNIFICANCE: These methods provide a feasible strategy for HFO detection in real-time, continuous EEG with minimal human monitoring of data quality. PMID- 26238857 TI - MiR-106b induces cell radioresistance via the PTEN/PI3K/AKT pathways and p21 in colorectal cancer. AB - BACKGROUND: Radioresistance is a challenge in the treatment of patients with colorectal cancer (CRC). Individuals display different therapeutic responses to preoperative radiotherapy, and the need of targeted therapies is urgent. MicroRNAs (miRNAs) are involved in essential biological activities, including chemoresistance and radioresistance. Several research studies have indicated that miRNA played an important role in sensitizing cells to ionizing radiation (IR). MiR-106b, a member of the miR-106b-25 cluster, is frequently dysregulated in many human cancers, including CRC. However, the function of miR-106b in radioresistance is currently poorly understood. METHODS: A series of in vitro and in vivo studies were performed to investigate the roles of miR-106b on cell radioresistance in CRC. RESULTS: We found overexpression of miR-106b could induce resistance to IR in vitro and in vivo in SW620 cells. Correspondingly, knocking down miR-106b in SW480 yielded the opposite effect. In addition, overexpression of miR-106b could enhance the tumour-initiating cell capacity without or with IR condition, such as the colony sphere formation capacity and the upregulation of stemness-related genes (CD133, Sox2). We further identified PTEN and p21 as novel direct targets of miR-106b by using target prediction algorithms and a luciferase assay. Overexpression of miR-106b reduced the expression of PTEN and p21 and increased the expression of p-AKT, which is a downstream of PTEN. Restoring the expression of PTEN or p21 in stably miR-106b-overexpressed cells could rescue the effect of miR-106b on cell radioresistance. Together, the acquisition of tumour initiating cell capacity endowed CRC cells with the potential of resistance to irradiation. CONCLUSIONS: These observations illustrated that miR-106b could induce cell radioresistance by directly targeting PTEN and p21, this process was accompanied by tumour-initiating cell capacity enhancement, which is universally confirmed to be associated with radioresistance. Our data suggested that miR-106b at least partly induces cell radioresistance in CRC. PMID- 26238858 TI - Colloidal bismuth subcitrate impedes proton entry into Helicobacter pylori and increases the efficacy of growth-dependent antibiotics. AB - BACKGROUND: Successful eradication of Helicobacter pylori is becoming more difficult, mainly due to emerging antibiotic resistance. Treatment regimens containing bismuth have increased efficacy, but the mechanism is unknown. Helicobacter pylori is a neutralophile adapted to survive the acidic gastric environment via acid acclimation, but demonstrates more robust growth at neutral pH. Many antibiotics used to treat H. pylori rely on bacterial growth. AIM: To investigate the mechanism of increased efficacy of bismuth-containing H. pylori treatment regimens. METHODS: RNAseq and qPCR, urease activity in permeabilised and intact bacteria, internal pH and membrane potential were measured with and without colloidal bismuth subcitrate (CBS). Bacterial survival was assessed with CBS and/or ampicillin. RESULTS: Genes involved with metabolism and growth were upregulated in the presence of CBS at acidic pH. Urease activity of permeabilised H. pylori at pH 7.4 and 4.5 decreased in the presence of CBS, but intact urease activity decreased only at acidic pH. The fall in cytoplasmic pH with external acidification was diminished by CBS. The increase in membrane potential in response to urea addition at acidic medium pH was unaffected by CBS. The impact of CBS and ampicillin on H. pylori survival was greater than either agent alone. CONCLUSIONS: Bismuth is not acting directly on urease or the urea channel. Colloidal bismuth subcitrate impedes proton entry into the bacteria, leading to a decrease in the expected fall in cytoplasmic pH. With cytoplasmic pH remaining within range for increased metabolic activity of a neutralophile, the efficacy of growth-dependent antibiotics is augmented. PMID- 26238860 TI - Comments Concerning "Comparison of Airway and Systemic Malondialdehyde Levels for Assessment of Oxidative Stress in Cystic Fibrosis". PMID- 26238859 TI - Current State of Pediatric Lung Transplantation. AB - Cardiothoracic transplantation has significantly impacted the lives of pediatric patients with advanced cardiopulmonary failure. The current state of lung transplantation in children as well as its ongoing and future challenges are discussed. PMID- 26238862 TI - 16S rDNA PCR-DGGE and sequencing in the diagnosis of neonatal late-onset septicemia. AB - The 16S rDNA polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) and sequencing method has been demonstrated to be valuable in detecting pathogens in the blood of patients suffering from fever or neutropenia. However, its use in the diagnosis of neonatal late-onset septicemia (LOS) has not yet been reported. The aim of the present study was to investigate the efficiency of this method in detection of the type of bacterial infection in neonatal LOS. Blood specimens from 60 neonates in whom LOS was suspected were collected. Fourteen culture positive blood samples and 24 spiked 'infected' blood samples were analyzed by the 16S rDNA PCR-DGGE and sequencing method or by pathogen-specific PCR. Only in 5 of the 14 cases did the results of 16S rDNA PCR DGGE and sequencing match with the results of blood culturing. In the other 9 cases, the blood culture failed to detect bacteria, such as Neisseria sp. and Moraxella sp., which were detected by 16S rDNA PCR-DGGE and sequencing. Furthermore, the 16S rDNA PCR-DGGE and sequencing failed to detect blood culture proven bacteria, such as Klebsiella pneumonia. A competitive inhibitory effect in 16S rDNA PCR amplification may lead to the discrepancy between pathogen-specific PCR and spiked 'infected' blood samples. When a certain species of bacteria was detected by 16S rDNA PCR, the competitive inhibitory effect presented a higher sensitivity in detecting this species in the blood samples that contained bacterial DNA only from this species compared with the blood samples that were blended with other bacterial DNAs. In conclusion, 16S rDNA PCR-DGGE and sequencing can detect a more comprehensive spectrum of pathogens than blood culture. However, the competitive inhibitory effect, which may lead to false negative results should be taken into consideration when the 16S rDNA PCR-DGGE and sequencing method is applied to the diagnosis of neonatal LOS. PMID- 26238861 TI - CRISPR/Cas9: a powerful genetic engineering tool for establishing large animal models of neurodegenerative diseases. AB - Animal models are extremely valuable to help us understand the pathogenesis of neurodegenerative disorders and to find treatments for them. Since large animals are more like humans than rodents, they make good models to identify the important pathological events that may be seen in humans but not in small animals; large animals are also very important for validating effective treatments or confirming therapeutic targets. Due to the lack of embryonic stem cell lines from large animals, it has been difficult to use traditional gene targeting technology to establish large animal models of neurodegenerative diseases. Recently, CRISPR/Cas9 was used successfully to genetically modify genomes in various species. Here we discuss the use of CRISPR/Cas9 technology to establish large animal models that can more faithfully mimic human neurodegenerative diseases. PMID- 26238863 TI - The making of local hospital discharge arrangements: specifying the role of professional groups. AB - BACKGROUND: Timely discharge is a key component of contemporary hospital governance and raises questions about how to move to more explicit discharge arrangements. Although associated organisational changes closely intersect with professional interests, there are relatively few studies in the literature on hospital discharge that explicitly examine the role of professional groups. Recent contributions to the literature on organisational studies of the professions help to specify how professional groups in hospitals contribute to the introduction and routinisation of discharge arrangements. This study builds on a view of organisational and professional projects as closely intertwined, where professionals take up organising roles and where organisations shape professionalism. METHODS: The analysis is based on a case study of the introduction and routinisation of explicit discharge arrangements for patients with prostate cancer in two hospitals in Denmark. This represents a typical case that involves changes in professional practice without being first and foremost a professional project. The multiple case design also makes the findings more robust. The analysis draws from 12 focus groups with doctors, nurses and secretaries conducted at two different stages in the process of the making of the local discharge arrangements. RESULTS: From the analysis, two distinct local models of discharge arrangements that connect more or less directly to existing professional practice emerge: an 'add-on' model, which relies on extra resources, special activities and enforced change; and an 'embedded model', which builds on existing ways of working, current resources, and perspectives of professional groups. The two models reveal differences in the roles of professional groups in terms of their stakes and involvement in the process of organisational change: whereas in the 'add on' model the professional groups remain at a distance, in the 'embedded model' they are closely engaged. CONCLUSIONS: In terms of understanding the making of hospital discharge arrangements, the study contributes two sets of insights into the specific roles of professional groups. First, professional interests are an important driver for health professionals to engage in adapting discharge arrangements; and second, professional practice offers a powerful lever for turning new discharge arrangements into organisational routines. PMID- 26238864 TI - Azithromycin is not associated with QT prolongation in hospitalized patients with community-acquired pneumonia. AB - PURPOSE: Large data-based studies have reported excess cardiovascular mortality in high-risk patients treated with azithromycin, but whether or not azithromycin causes QT prolongation remains controversial. The purpose of this study was to examine the association of azithromycin treatment on QT prolongation in a cohort of patients hospitalized with community-acquired pneumonia (CAP) METHODS: One hundred twenty-two hospitalized patients with CAP were enrolled in the study. We compared the baseline QTc, with daily post antibiotic QTc. Other risk factors for QT prolongation such as medication or electrolyte abnormalities were recorded. RESULTS: Ninety (73.8%) patients were treated with azithromycin (usually in combination with ceftriaxone), and 32 (26.2%) patients with other antibiotics (ampicillin-clavulanate, chloramphenicol, doxcycline, or ceftriaxone); 72.1% (88) of the cohort experienced QT lengthening; 72.7% with QT lengthening had a normal baseline QTc. Azithromycin was not associated with the post-antibiotic QTc. Wide (pathological) post-antibiotic QTc was associated with the pneumonia score. Every 10-point increase in the pneumonia score raised the risk for a pathological post antibiotic QTc by 1.249 (95%CI: 1.050-1.486). Analysis of patients with non pathological baseline QTc revealed that pathological post-antibiotic QTc was only associated with previous stroke and not with the type of antibiotic. CONCLUSIONS: Azithromycin treatment was not associated with QT prolongation in patients with severe CAP. Nonetheless, in a large majority of hospitalized CAP patients, QT prolongation and pathological QTc develop regardless of the antibiotic used, especially in patients with previous stroke or a higher pneumonia score. PMID- 26238865 TI - Chlorhexidine decontamination of sputum for culturing Mycobacterium tuberculosis. AB - BACKGROUND: Culture of Mycobacterium tuberculosis is the gold standard method for the laboratory diagnosis of pulmonary tuberculosis, after effective decontamination. RESULTS: We evaluated squalamine and chlorhexidine to decontaminate sputum specimens for the culture of mycobacteria. Eight sputum specimens were artificially infected with 10(5) colony-forming units (cfu)/mL Mycobacterium tuberculosis and Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans as contaminants. In the second step, we tested chlorhexidine based decontamination on 191 clinical specimens, (Chlorhexidine, 0.1, 0.5 and 0.7 %). In a last step, growth of contaminants and mycobacteria was measured in 75 consecutive sputum specimens using the routine NALC-NaOH decontamination protocol or with 0.7 % chlorhexidine decontamination and an inoculation on Coletsos medium. In the artificially model, contaminants grew in 100 % of the artificially infected sputum specimens decontaminated using 100 mg/mL squalamine, in 62.5 % of specimens decontaminated using N-Acetyl-L-Cysteine-Sodium Hydroxide (NALC-NaOH), and in 0 % of specimens decontaminated using 0.1 %, 0.35 %, or 1 % chlorhexidine (P < 0.05). These specimens yielded <10(2) cfu M. tuberculosis using NALC-NaOH and > 1.4.10(2) cfu M. tuberculosis when any concentration of chlorhexidine was used (P < 0.05). In the second step we found that 0.7 %-chlorhexidine yielded 0 % contamination rate, 3.2 % for 0.5 %-chlorhexidine and 28.3 % for 0.1 % chlorhexidine. As for the 75 specimens treated in parallel by both methods we found that when using the standard NALC-NaOH decontamination method, 8/75 (10.7 %) specimens yielded M. tuberculosis colonies with a time to detection of 17.5 +/ 3 days and an 8 % contamination rate. Additionally, 14 specimens yielded mycobacteria colonies (12 M. tuberculosis, and 2 Mycobacterium bolletii) (18.7 %) (P = 0.25), which has yielded a 100 % sensitivity for the chlorhexidine protocol. Time to detection was of 15.86 +/- 4.7 days (P = 0.39) and a 0 % contamination rate (P < 0.05) using the 0.7 %-chlorhexidine protocol. CONCLUSION: In our work we showed for the first time that chlorhexidine based decontamination is superior to the standard NALC-NaOH method in the isolation of M. tuberculosis from sputum specimens. We currently use 0.7 %-chlorhexidine for the routine decontamination of sputum specimens for the isolation of M. tuberculosis and non-tuberculosis mycobacteria on egg-lecithin containing media. PMID- 26238867 TI - Interdisciplinary Laboratory Course Facilitating Knowledge Integration, Mutualistic Teaming, and Original Discovery. AB - Experiencing the thrill of an original scientific discovery can be transformative to students unsure about becoming a scientist, yet few courses offer authentic research experiences. Increasingly, cutting-edge discoveries require an interdisciplinary approach not offered in current departmental-based courses. Here, we describe a one-semester, learning laboratory course on organismal biomechanics offered at our large research university that enables interdisciplinary teams of students from biology and engineering to grow intellectually, collaborate effectively, and make original discoveries. To attain this goal, we avoid traditional "cookbook" laboratories by training 20 students to use a dozen research stations. Teams of five students rotate to a new station each week where a professor, graduate student, and/or team member assists in the use of equipment, guides students through stages of critical thinking, encourages interdisciplinary collaboration, and moves them toward authentic discovery. Weekly discussion sections that involve the entire class offer exchange of discipline-specific knowledge, advice on experimental design, methods of collecting and analyzing data, a statistics primer, and best practices for writing and presenting scientific papers. The building of skills in concert with weekly guided inquiry facilitates original discovery via a final research project that can be presented at a national meeting or published in a scientific journal. PMID- 26238866 TI - A prospective web-based patient-centred interactive study of long-term disabilities, disabilities perception and health-related quality of life in patients with multiple sclerosis in The Netherlands: the Dutch Multiple Sclerosis Study protocol. AB - BACKGROUND: In the past two decades the widespread use of disease modifying drugs with moderate to strong efficacy has changed the natural course of multiple sclerosis (MS). Health care professionals, researchers, patient organizations and health authorities are in need of recent information about the objectified and subjective long-term clinical outcomes in MS patients. Such information is scarce. METHODS/DESIGN: We started a prospective, web-based, patient-centred, interactive study of long-term disabilities, disabilities perception and health related quality of life (HRQoL) in MS patients in The Netherlands (Dutch Multiple Sclerosis Study). The study has an on online patient-driven inclusion and online acquisition of patient-reported outcomes (PROs). At six-months intervals participants complete the Multiple Sclerosis Impact Profile (MSIP) (disabilities and disabilities perception in seven domains and four symptoms), the Multiple Sclerosis Quality of Life-54 items (MSQoL-54), the Modified Fatigue Impact Scale 5 items (MFIS-5) and the Leeds Multiple Sclerosis Quality of Life-8 items (LMSQoL) questionnaires, and a Medication and Adherence Inventory. Every three years the Expanded Disability Status Scale (EDSS) score is assessed by phone. The monthly completion of the MFIS-5, LMSQoL and Medication and Adherence Inventory is optional. Completed questionnaires and inventories, and automatically generated scores are made available online to patients for self-monitoring and self-management purposes, and to authorized health care professionals for the evaluation of disease activity and of the effectiveness of treatments. Study duration is planned to be 15 years. Results will be analyzed periodically using means and standard deviations for continuous variables, and frequencies for categorical variables. Relations between time points, variables, patient and treatment characteristics will be evaluated in random effects repeated measures models. DISCUSSION: The Dutch Multiple Sclerosis Study is characterized by online patient-driven inclusion; online data acquisition; the use of PROs; the optional monthly completion of short questionnaires; the interactive use of personal study data by patients and authorized health care professionals for self-monitoring, self-management and multidisciplinary care; the expected representativeness of the study sample; and a long-term time horizon. The study will provide valuable data on long-term disabilities, disabilities perceptions and HRQoL in MS patients in The Netherlands. PMID- 26238868 TI - Predominance of PCR-ribotypes, 018 (smz) and 369 (trf) of Clostridium difficile in Japan: a potential relationship with other global circulating strains? AB - Global spread and evolutionary links of an epidemic Clostridium difficile strain (PCR-ribotype 027) have been noted in recent decades. However, in Japan, no outbreaks caused by type 027 have been reported to date. A total of 120 C. difficile isolates from patients at 15 hospitals during non-outbreak seasons between 2011 and 2013 as well as 18 and 21 isolates collected from two hospitals in 2010 and 2009, respectively, in outbreak periods in Japan, were examined. Among these 120 isolates, Japan-ribotypes smz and ysmz (subtype variant of smz) were the most predominant (39.2 %) followed by Japan-ribotype trf (15.8 %). Types smz/ysmz and trf were also concurrently predominant at two hospitals in the outbreak settings. Out of the five binary toxin-positive isolates observed, only one was PCR-ribotype 027 and another PCR-ribotype 078. Type smz was later found to correspond to PCR-ribotype 018. High rates of resistance against gatifloxacin, moxifloxacin, erythromycin and clindamycin were observed in the PCR-ribotype 018 isolates. Interestingly, all trf isolates were toxin A-negative, toxin B positive, but they did not correspond to PCR-ribotype 017, thus being assigned a new ribotype (PCR-ribotype 369). In conclusion, PCR-ribotypes 018 (smz) and 369 (trf) were identified as major circulating strains in both outbreak and non outbreak settings in Japan. Given their epidemiological relevance, molecular investigations are warranted to clarify potential evolutionary links with related strains found elsewhere, such as PCR-ribotypes 018 and 017 from Europe and North America. PMID- 26238869 TI - Even a low-dose of moderate-to-vigorous physical activity reduces mortality by 22% in adults aged >=60 years: a systematic review and meta-analysis. AB - BACKGROUND: The health benefits of 150 min a week of moderate-to-vigorous intensity physical activity (MVPA) in older adults, as currently recommended, are well established, but the suggested dose in older adults is often not reached. OBJECTIVES: We aimed to determine whether a lower dose of MVPA was effective in reducing mortality, in participants older than 60 years. METHODS: The PubMed and Embase databases were searched from inception to February 2015. Only prospective cohorts were included. Risk ratios of death were established into four doses based on weekly Metabolic Equivalent of Task (MET)-minutes, defined as inactive (reference), low (1-499), medium (500-999) or high (>=1000). Data were pooled and analysed through a random effects model using comprehensive meta-analysis software. RESULTS: Of the 835 reports screened, nine cohort studies remained, totalling 122 417 participants, with a mean follow-up of 9.8+/-2.7 years and 18 122 reported deaths (14.8%). A low dose of MVPA resulted in a 22% reduction in mortality risk (RR=0.78 (95% CI 0.71 to 0.87) p<0.0001). MVPA beyond this threshold brought further benefits, reaching a 28% reduction in all-cause mortality in older adults who followed the current recommendations (RR=0.72 (95% CI 0.65 to 0.80) p<0.0001) and a 35% reduction beyond 1000 MET-min per week (RR=0.65 (95% CI 0.61 to 0.70) p<0.0001). CONCLUSIONS: A dose of MVPA below current recommendations reduced mortality by 22% in older adults. A further increase in physical activity dose improved these benefits in a linear fashion. Older adults should be encouraged to include even low doses of MVPA in their daily lives. PMID- 26238870 TI - Two factors that may underpin outstanding outcomes after ACL rehabilitation. PMID- 26238871 TI - Dinosaurs among us causing chaos and confusion. PMID- 26238872 TI - The Cover Page. PMID- 26238873 TI - Neurosurgical Education: Some thoughts. PMID- 26238874 TI - Neurosurgery: A legacy of excellence. AB - Neurosurgeons are often identified with traits such as arrogance and hubris. However, the true legacy of neurosurgeons is excellence. Harvey Cushing, the pioneering neurosurgeon of the United States, is largely responsible for this legacy of excellence. Eminent personalities have agreed that sincere and hard work is necessary to achieve excellence. Excellence in neurosurgery in the domains of surgical work and research will be discussed in the article. Excellence in surgical work should be measured comprehensively and over long follow-up periods using tools such as functional outcomes and quality of life instruments besides morbidity and mortality. For excellence in neurosurgical research, one can use the help of indices such as the h-index and i10 index. No single measure, whether for surgical excellence or excellence in research, however, incorporates a measure of qualities such as empathy, integrity and mentorship. These intangible qualities should be an integral part of the assessment of a neurosurgeon and his/her work. Cushing's attributes of meticulous record keeping, attention to detail, and maximal utilization of opportunities should guide us in our pursuit of excellence. In recent years, it has been suggested that excellence is not the result of an innate talent but can be aspired to by anyone willing to adopt a work ethic that involves several hours of "deliberate practice," feedback and passion. Neurosurgeons should continue to pursue the legacy of Cushing especially in present times when medical professionals are frequently depicted as being driven more by avarice than by Hippocratic principles. PMID- 26238875 TI - Fyodor Mikhailovich Dostoyevsky and his epilepsy. PMID- 26238876 TI - Are we ready to replace dynamic contrast-enhanced perfusion with tissue similarity measures derived perfusion magnetic resonance imaging in glioma grading? PMID- 26238877 TI - Brain tumor magnetic resonance imaging - so near yet so far. PMID- 26238878 TI - Vasospasm: The enigma of subarachnoid hemorrhage. PMID- 26238879 TI - Importance of anthropometric indices in subarachnoid hemorrhage. PMID- 26238880 TI - Correlation of adiposity and muscle catabolism with clinical vasospasm and mortality after subarachnoid hemorrhage. PMID- 26238881 TI - Meningiomas decoded: Looking beyond microsurgery. PMID- 26238882 TI - Metabolic syndrome: A smoldering risk to the cognition of the ageing Indian? PMID- 26238883 TI - Limb girdle muscular dystrophies in India. PMID- 26238884 TI - Dengue-associated neuromuscular complications. AB - Dengue is associated with many neurological dysfunctions. Up to 4% of dengue patients may develop neuromuscular complications. Muscle involvement can manifest with myalgias, myositis, rhabdomyolysis and hypokalemic paralysis. Diffuse myalgia is the most characteristic neurological symptom of dengue fever. Dengue associated myositis can be of varying severity ranging from self-limiting muscle involvement to severe dengue myositis. Dengue-associated hypokalemic paralysis often has a rapidly evolving course; benign nature; excellent response to potassium; and, often leads to diagnostic confusion with other dengue-associated neuromuscular disorders. Rhabdomyolysis is the most severe form of muscle involvement and may be life-threatening. Guillain-Barriota syndrome is another frequent neuromuscular dengue-associated complication. Dengue-associated Guillain Barriota syndrome responds very well to intravenous immunoglobulins. Predominant spinal gray matter involvement has been reported in a patient presenting with areflexic paraparesis. Mononeuropathies often manifest with paralysis of the diaphragm due to phrenic nerve dysfunction. Brachial plexopathy, in the form of neuralgic amyotrophy, has been described much more frequently than lumbo-sacral plexopathy. Early recognition of these neuromuscular complications is needed for successful treatment and to prevent further disabilities. PMID- 26238885 TI - Chromosomal aberrations in atypical and anaplastic meningiomas: A fluorescence in situ hybridization study. AB - OBJECTIVE: There is significant variability in the biologic behavior of meningiomas, especially of atypical and anaplastic meningiomas, that cannot be accounted for by just histology and grade of excision. The aim of our study was to analyze deletions in regions 22q, 18p11, 1p32, and 14q32 in grade II and grade III meningiomas and their correlation with tumor grade and recurrence. MATERIALS AND METHODS: A total of 59 samples from 50 cases of grade II and grade III meningiomas were analyzed with fluorescence in situ hybridization (FISH) technique with locus specific probes. The types of aberrations and deletions were analyzed and correlated with the tumor status. RESULTS: There was a statistically significant increase in deletions in recurrences when compared to primary surgeries. The mean mitotic index was higher in patients with deletions. Patients with 18p deletions tended to be younger and had a significant association with sheeting. 22q deletions were associated with hypercellular tumors. 1p, 14q, and 1p14q codeletion had a significant association with mitosis >=7. CONCLUSION: This is a first study from India analyzing all these four sites for deletions using the FISH technique. Recurrent tumors and tumors with tendency to recur have a higher frequency of deletions. The FISH study can be used to predict the behavior of meningiomas if significant association is found. Further studies in larger sets of patients along with their clinical correlation would help in categorizing patients who have a higher risk of recurrence and help in guiding their clinical management. PMID- 26238886 TI - Feasibility of tissue similarity map-based relative cerebral blood volume assessment in the evaluation of gliomas. AB - OBJECTIVE: To investigate the feasibility of tissue similarity map (TSM)-based relative cerebral blood volume (rCBV) assessment in evaluating the hemodynamic characteristics of gliomas and in differentiating high-grade gliomas from low grade ones without concentration time curve (CTC). MATERIALS AND METHODS: TSM based rCBV (rCBV TSM ) and conventional rCBV (rCBV PWI ) maps were generated (n = 35). The differences in percentage and concordance correlation coefficient (CCC) of the rCBV TSM and rCBV PWI ratios were calculated. The Mann-Whitney test and the receiver operating characteristic (ROC) curve analysis were also performed to examine the relationships of rCBV ratios between high- and low-grade gliomas. The improvement factors of signal to noise ratio (SNR) of rCBV TSM maps were also calculated. RESULTS: The mean difference in percentage between rCBV TSM and rCBV PWI ratios was 4.29 +/- 2.62%. The CCC of rCBV TSM and rCBV PWI ratios was 0.9974, with 95% confidence interval of 0.9948, 0.9987, which implied a high agreement between them. The Mann-Whitney test suggested that the rCBV TSM and rCBV PWI ratios of high-grade gliomas were significantly different from those of low-grade gliomas (P < 0.001). The improvement factors of SNR of the rCBV TSM map were 1.31 +/- 0.24 for glioma and 1.28 +/- 0.24 for normal white matter. CONCLUSION: It is feasible to use rCBV TSM in the evaluation of hemodynamic characteristics of gliomas and differentiation of high- and low-grade gliomas without CTC. Moreover, rCBV TSM maps possess a higher SNR, which allows potentially more accurate diagnosis compared with the conventional ones. PMID- 26238887 TI - Study of trends in anthropometric nutritional indices and the impact of adiposity among patients of subarachnoid hemorrhage. AB - BACKGROUND: Nutritional status and adiposity have not been studied to a significant extent in subarachnoid hemorrhage (SAH). The aim of this study was to determine the trends in anthropometric indices and assess their impact on patients with SAH. METHODS: We prospectively studied in 56 patients with SAH, the triceps skinfold thickness (TSF), mid-arm circumference (MAC), mid-arm muscle circumference (MAMC), and other factors, and their relationship to clinical vasospasm and mortality. RESULTS: The median MAC decreased significantly from 29.3 cm (interquartile range [IQR] 28-31 cm) at admission to 27 cm (IQR 26-29 cm) at 1-week (P < 0.001). The median TSF decreased significantly from 34 mm (IQR 30 40 mm) at admission to 30 mm (IQR 25-35 mm) at 1-week (P < 0.001). MAMC values did not show a significant change over a week. The patients who developed clinical vasospasm had significantly higher median admission TSF of 40 mm (IQR 35 45 mm), compared to the median admission TSF of 35 mm (IQR 30-40 mm) among those who did not develop vasospasm (P = 0.03). MAMC values did not differ significantly in relation to vasospasm. Patients who expired by 3 months had significantly greater fall in median MAMC values at 1-week (7.7% [IQR 5.2 11.5%]), compared to the fall in median MAMC values at 1-week among those who were alive at 3 months (2.6% [IQR 2.1-6.6%]) [P = 0.03]. However, the fall in TSF values did not differ significantly in relation to mortality. In multivariate analysis, only the admission TSF, Hunt and Hess and Fisher grades had a significant association with vasospasm. This association was independent of other prognostic factors and of each other. CONCLUSION: Excessive adiposity of patients, measured as an increased TSF value, is significantly associated with clinical vasospasm independent of other prognostic factors, while fall in MAMC, indicating somatic protein catabolism, has some impact on mortality. PMID- 26238888 TI - A study on cognitive decline with respect to metabolic syndrome and inflammation in elderly Indians. AB - BACKGROUND: This study was undertaken to find out if metabolic syndrome (MetS) in the elderly was associated with cognitive decline and also if this association was modified by the presence of inflammation. MATERIALS AND METHODS: 100 patients more than 60 years of age were divided into 2 groups of 50 each and were age and sex matched. Group 1 and 2 had patients with and without MetS, respectively. The individual components of MetS were measured in each patient. Cognitive decline was measured by Modified Mini-Mental Score (3MS) of Teng. Inflammation was measured by high-sensitivity C-reactive protein (hs-CRP). RESULTS: Fasting hyperglycemia was the most common component of MetS (60% of group 1). The mean serum hs-CRP in patients of group 1 was 6.56 +/- 9.72 while that in the patients of group 2 was 1.95 +/- 1.93. In the group-1, 36% (n = 18) patients were having a decreased 3MS, whereas in group-2, 22% (n = 11) were having a decreased 3MS. MetS was associated with an odd's ratio of 1.99 for developing cognitive decline. 3MS had a negative correlation with hs-CRP values. Regression analysis showed a significant association of hs-CRP and MetS with cognitive decline in the elderly population. CONCLUSION: Cognitive decline in the elderly is associated with the presence of inflammation and MetS. Hence, early identification of the high-risk groups may offer benefit by disease course modification and better caregiving. PMID- 26238889 TI - Stuck with a drowsy patient, evoke the Percheron. AB - BACKGROUND: Strokes caused by normal variants of the cerebral circulation can be difficult to diagnose, hence a high index of suspicion is needed. This case series discusses the clinical and radiological aspects of one such stroke caused by occlusion of the artery of Percheron (AOP). MATERIALS AND METHODS: Computerized discharge summaries, outpatient records and imaging from picture archiving and communication system (PACS, GE), of patients with AOP infarction over a period of 12-years (2002-2014) were identified and their clinical and radiological features analyzed. RESULTS: Of 3589 strokes (both ischemic and hemorrhagic), 17 (0.47%) were due to AOP infarction. Their mean age was 50 years (range: 31-72 years). Disorders of consciousness (94%) were the most common presenting symptoms followed by gaze (53%) and memory impairment (24%). At follow up, 2/17 (12%) patients developed extrapyramidal features. All patients had bilateral paramedian thalamic infarcts on magnetic resonance imaging (MRI). Associated anterior thalamic (5/17; 30%) and mid brain (10/17; 59%) infarcts were also seen. CT scan done in 11/17 patients prior to the MRI picked up only 6/11 (55%) of these infarcts. The most common etiological factors detected using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria were cardio embolic (8/17; 47%) followed by small vessel occlusion (7/17; 41%). Mortality occurred in 2/17 (12%) patients. At 6 months, a modified Rankin score of 2 or less was seen in 8/17 (47%) patients. CONCLUSIONS: Artery of Percheron infarcts should be considered in the differential diagnosis of patients presenting with sudden alterations in consciousness. MRI should be the investigation of choice. An embolic etiology should be actively looked for. PMID- 26238890 TI - A prospective study on the immunophenotypic characterization of limb girdle muscular dystrophies 2 in India. AB - OBJECTIVE: In this prospective study conducted over 2 years, 300 nonconsecutive cases of autosomal recessive limb girdle muscular dystrophies (AR-LGMD) were characterized, based on phenotypic features, biochemical findings, electrophysiological studies, muscle immunohistochemistry (IHC), and western blot (WB) analysis. METHODS: Muscle biopsy was performed in 280 index cases. 226 biopsies were subjected for IHC, and, 176 of these for WB analysis. RESULTS: A total of 246 patients were finally analyzed. This figure included 20 affected siblings. LGMD2B was the most common form and comprised of 33.3% (n = 82) of the entire cohort. This was followed by alpha-dystroglycanopathies with 61 (24.79%) patients (LGMD2I in 15, 2K in 10 and combined deficiency of both in the remaining). LGMD 2C-F was present in 35 (14.23%) cases and LGMD2A in 22 (10.2%) cases, and were identified by routine WB, densitometry method and autocatalytic assay. LGMD2G was present in 8 patients (3.25%), and LGMD2H and 2J in 2 cases each, respectively. CONCLUSIONS: For the first time, we have identified patients with LGMD2G, 2H, 2I, and 2K by the WB technique. These may be the common forms of autosomal recessive (AR)-LGMD's among Indian patients and need identification for prognostication and appropriate counseling. Although not a nationwide study, our data is sufficient to provide information about the relative proportions of various LGMD2 subtypes in India. Diagnosing LGMD2 based on classical clinical features, IHC and WB is fairly sensitive and specific; however, further genetic studies are required to confirm the diagnosis. PMID- 26238891 TI - Rare case of myasthenia gravis associated with situs inversus totalis: Implications in management. AB - A rare case of simultaneous occurrence of myasthenia gravis and situs inversus totalis is reported. The implications of the presence of these two entities on management are discussed. PMID- 26238892 TI - Intraventricular silicone oil mimicking a colloid cyst. AB - We report a case where intraventricular migration of silicone oil occurred into the third ventricle, mimicking the presence of a colloid cyst. To the best of our knowledge, this is the first case reported where intraventricular silicone oil (SiO) presented at the foramen of Monro, resembling the radiological appearance of a colloid cyst. The systemic dissemination of silicone oil is a very rare complication of intravitreal SiO administration that is used for providing a mechanical tamponade that maintains the retinal attachment following repair of a retinal detachment. The imaging findings that are characteristic of the presence of intraventricular silicone oil are its usual dissemination in a nondependent location and the accompaniment of changes in its location based on changes in the patient's position. PMID- 26238893 TI - Papillary tumor of the pineal region-report of three cases with literature review. AB - Papillary tumor of the pineal region (PTPR) is a rare tumor of the pineal region. Not much is known about the pathogenesis, prognosis, and treatment protocol of this uncommon entity. We present three cases of PTPR with follow-up from 8 months to 98 months. All patients presented with headache and visual disturbance. One patient also had amenorrhea. Radiology revealed an heterogeneously enhancing mass arising from the pineal region with associated hydrocephalus. Histopathologically, all cases showed the papillary architecture, strong pan cytokeratin and cytokeratin 18 positivity, and faint positivity for synaptophysin and neuron-specific enolase. All cases received postoperative radiotherapy. One case showed tumor recurrence after 7 years. Other two cases did not show any recurrence till the last follow-up. PMID- 26238894 TI - Endoscopic epilepsy surgery: Emergence of a new procedure. AB - BACKGROUND: The use of minimally invasive endoscopic surgery is fast emerging in many subspecialties of neurosurgery as an effective alternative to the open procedures. OBJECTIVE: The author describe a novel technique of using an endoscope for performing a corpus callosotomy and hemispherotomy. A description of endoscopic disconnection for a hypothalamic hamartoma (HH) and a review of the literature is also presented. MATERIALS AND METHODS: Thirty four patients underwent endoscopic procedures between January 2010 and March 2015. These included endoscopic-assisted inter-hemispheric trans-callosal hemispherotomy (EH; n = 11), endoscopic-assisted corpus callosotomy with anterior/posterior commissurotomy (CCWC; n = 16), and endoscopic disconnection for HH (n = 7). EH and CCWC were performed with the use of a small craniotomy (4 cm * 3 cm). The surgeries were performed using a rigid high-definition endoscope, bayonetted self irrigating bipolar forceps, and other standard endoscopic instruments along with the guidance of intra-operative magnetic resonance imaging and neuronavigation. HH disconnection was performed using endoscopic neuronavigation through a burr hole. RESULTS: Hemispherotomy: Sequelae of middle cerebral artery infarct (5), Rasmussen's syndrome (3), and hemimegalencephaly (3). OUTCOME: Class I Engel (9) and class II (2), mean follow-up of 8.4 months, range: 3-18 months. Mean blood loss: 85 cc, mean operating time: 210 min. CCWC: All had a diagnosis of Lennox Gastaut syndrome (LGS), with etiologies of hypoxic insult (10), lissencephaly (2), bilateral band heterotropia (2), microgyria and pachygyria (2). Mean follow up: 18 +/- 4.7 (16-27 months). Drop attacks stopped in all the patients. Seizure frequency and duration decreased >90% (11) and >50% (5). HH: Type II (2), Type III (2), Type IV (3). 5 had IA outcome. CONCLUSION: The article emphasizes the role of endoscopic procedures for epilepsy surgery and provides a review of literature. This experience may subserve to coin the term "endoscopic epilepsy surgery" for a fast emerging subspeciality in the field of epilepsy surgery. PMID- 26238895 TI - Neurorestorative strategies for Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by beta-amyloid plaques and neurofibrillary tangles that cause devastating cognitive and memory deficits. AD is known to be associated with neuronal death and synaptic loss. Thus, methods to retard the progression of the disease and to promote neuro-regeneration are vital for the prevention of advancement of AD. The recent trend is to decipher the molecular mechanisms of AD, and further aim at neuro-restorative mechanisms such as neuro-protection, neuro-modulation, and neuro-regeneration. In this review, we provide an overview of the recent studies describing various neuro-restorative strategies for AD and mainly focus on stem cell and neuro-modulation therapies. Furthermore, we briefly refer to the other neurorestorative treatments including medications, bioengineering, and gene therapies for AD. Although most of them remain in an experimental phase, neuro-restorative strategies may have the potential for clinical use in the management of this debilitative disease. PMID- 26238896 TI - Neurosurgery at All India Institute of Medical Sciences, a center of excellence: A success story. AB - The department of neurosurgery at All India Institute of Medical Sciences (AIIMS) started its humble beginning in 1965. With the untiring and selfless hard work of Prof. P N Tandon and Prof. A K Banerji, the department progressed over time to become a center of excellence in the subcontinent. To establish a neurosciences center at AIIMS was an uphill task, which was accomplished with great efforts. The department has established itself as one of the highest centers of learning in the country with its vast infrastructure and diversity in all fields of neurosurgery. AIIMS, New Delhi was established by an act of the parliament in 1956. It was started with a grant from the Government of New Zealand under the "Colombo Plan." It was the vision of Rajkumari Amrita Kaur, the first Health Minister of India, that led to the establishment of a medical institute of international repute in India. AIIMS, New Delhi is an autonomous institute and is governed by the AIIMS Act, 1956. The department of neurosurgery at AIIMS was started in March 1965 with Prof. P.N. Tandon as the Head of the Department. Prof. A.K. Banerji joined him a few months later. The Department celebrated its golden jubilee in the year 2015, and has tremendously grown in stature from its humble beginnings to being a center of excellence with world-wide recognition. PMID- 26238897 TI - A summary of some of the recently published seminal papers in Neuroscience. PMID- 26238898 TI - Transient global amnesia with intracranial vertebral artery dissection and hippocampal CA1 lesion. PMID- 26238899 TI - A report of intracranial aneurysmal coil rotation. PMID- 26238900 TI - Multimodal management of a complex indirect carotid cavernous fistula. PMID- 26238901 TI - Posterior reversible encephalopathy syndrome as a rare presenting feature of acute intermittent porphyria. PMID- 26238902 TI - Epithelioid hemangioma of the thoracic spine. PMID- 26238903 TI - Commentary: Epithelioid hemangioma of spine. PMID- 26238904 TI - Mucopolysaccharidosis type I with craniosynostosis. PMID- 26238905 TI - Asymmetric lumbosacral radiculoplexopathy: Rare presentation of sarcoidosis. PMID- 26238906 TI - Dorsal spine involvement in Takayasu arteritis. PMID- 26238907 TI - Intrathecal baclofen pump implantation in a patient 2 years following a traumatic brain injury resulted in regained oratory capabilities. PMID- 26238908 TI - Lateral ventricular cystic choroid plexus papilloma presenting with recurrent drop attacks: A rare manifestation of a rare variant. PMID- 26238909 TI - Familial Mediterranean fever with convulsions: A rare association in a child. PMID- 26238910 TI - Intrapleural migration of distal ventriculoperitoneal shunt catheter. PMID- 26238911 TI - Magnetic resonance neurography identifies involvement of plexuses in leprous neuropathy. PMID- 26238912 TI - Niemann-Pick type C disease in a 13-year-old boy from Nepal: A genetically confirmed case. PMID- 26238913 TI - An interesting case of super-refractory status epilepticus. PMID- 26238914 TI - Chewing induced dystonia: Report of a case and the review of literature. PMID- 26238915 TI - Epilepsy associated with Turner syndrome. PMID- 26238916 TI - NAMASTE for stroke awareness. PMID- 26238917 TI - Malignant peripheral nerve sheath tumor arising in a skull-vault defect. PMID- 26238918 TI - Fetal hemimegalencephaly. PMID- 26238919 TI - Magnetic resonance imaging of sciatic nerve crush injury. PMID- 26238920 TI - E-learning in neurology. PMID- 26238921 TI - Deciding on the study design. PMID- 26238922 TI - Use of mobile applications in neurosurgery: Are we compromising on patient confidentiality and privacy? PMID- 26238923 TI - Rapid generation of fowl adenovirus 9 vectors. AB - Fowl adenoviruses (FAdV) have the largest genomes of any fully sequenced adenovirus genome, and are widely considered as excellent platforms for vaccine development and gene therapy. As such, there is a strong need for stream-lined protocols/strategies for the generation of recombinant adenovirus genomes. Current genome engineering strategies rely upon plasmid based homologous recombination in Escherichia coli BJ5183. This process is time-consuming, involves multiple cloning steps, and low efficiency recombination. This report describes a novel system for the more rapid generation of recombinant fowl adenovirus genomes using the lambda Red recombinase system in E. coli DH10B. In this strategy, PCR based amplicons with around 50 nt long homologous arms, a unique SwaI site and a chloramphenicol resistance gene fragment (CAT cassette), are introduced into the FAdV-9 genome in a highly efficient and site-specific manner. To demonstrate the efficacy of this system we generated FAdV-9 ORF2, and FAdV-9 ORF11 deleted, CAT marked and unmarked FAdV-9 infectious clones (FAdmids), and replaced either ORF2 or ORF11, with an EGFP expression cassette or replaced ORF2 with an EGFP coding sequence via the unique SwaI sites, in approximately one month. All recombinant FAdmids expressed EGFP and were fully infectious in CH-SAH cells. PMID- 26238924 TI - Inhibition of porcine reproductive and respiratory syndrome virus replication with exosome-transferred artificial microRNA targeting the 3' untranslated region. AB - Porcine reproductive and respiratory syndrome (PRRS) is an economically important swine disease. As part of the development of RNA interference (RNAi) strategy against the disease, in this study a recombinant adenovirus (rAd) expressing the artificial microRNA (amiRNA) targeting the 3' untranslated region (UTR) was used to investigate the exosome-mediated amiRNA transfer from different pig cell types to porcine alveolar macrophages (PAMs). Quantitative RT-PCR showed that the sequence-specific amiRNA was expressed in and secreted via exosomes from the rAd transduced pig kidney cell line PK-15, PAM cell line 3D4/163, kidney fibroblast cells (PFCs) and endometrial endothelial cells (PEECs) with different secretion efficiencies. Fluorescent microscopy revealed that the dye-labeled amiRNA containing exosomes of different cell origins were efficiently taken up by all of the five types of pig cells tested, including primary PAMs. Quantitative RT-PCR showed that the amiRNA-containing exosomes of different cell origins were taken up by primary PAMs in both time- and dose-dependent manners. Both quantitative RT PCR and viral titration assays showed that the exosome-delivered amiRNA had potent anti-viral effects against three different PRRSV strains. These data suggest that the exosomes derived from pig cells could serve as an efficient miRNA transfer vehicle, and that the exosome-delivered amiRNA had potent anti viral effects against different PRRSV strains. PMID- 26238925 TI - [DEFI-ALPHA cohort and POLYGEN DEFI-ALPHA clinical research hospital programme. A study about clinical, biological and genetics factors associated with the occurrence and the evolution of hepatic complications in children with alpha-1 antitrypsin deficiency]. AB - INTRODUCTION: The alpha-1 antitrypsin (alpha1-AT) deficiency, most frequently caused by homozygosity for the Z variant (SERPINA1: c.1096 G>A; Glu342Lys), can give rise to two clinical patterns: (i) respiratory impairment with emphysema (mainly in adulthood) because of a pulmonary quantitative defect in anti-elastase activity; (ii) hepatic impairment (mainly in childhood) due to the misfolding of the PiZ protein which accumulates in hepatocytes thus providing cytotoxicity. CURRENT KNOWLEDGE: To date, the clinical and genetic factors responsible for the development of major hepatic injuries (fibrosis and portal hypertension) during childhood in PiZ patients are not known. METHODS: The DEFI-ALPHA cohort, created in 2008, aims to inventory and prospectively study all alpha1-AT deficient children diagnosed and included after occurrence of a hepatic sign. The POLYGEN DEFI-ALPHA PHRC has recently (2013) been added to the project to identify modifiers genes by two complementary approaches: (i) the candidate genes strategy with the SERPINA1, CFTR (cystic fibrosis gene), MAN1B1 and SORL1 genes, these two latter being implied in the degradation of misfolding proteins; (ii) the whole exome sequencing (WES) strategy in families in which the PiZ proband has a PiZ brother or sister free of any hepatic sign. EXPECTED RESULTS: The clinical parameter we want to explain is the apparition of a portal hypertension in PiZ children. In the DEFI-ALPHA project, three criteria will be tested: (i) age of inclusion in the cohort, (ii) the way of inclusion (neo-natal icterus or later hepatic impairment) and (iii) treatment or not with ursodesoxycholic acid and, if so, its duration. Genetically, polymorphisms on the SERPINA1 and MAN1B1 genes have already been associated in the literature with different clinical evolutions of the A1ATD but very inconstantly. Our study thus aims to confirm or not this association. The CFTR and SORL1 genes have never been studied in the alpha1-AT deficiency. Finally, the whole exome sequencing strategy could allow the discovery of new unexpected modifiers genes in this disease. PMID- 26238926 TI - [Pulmonary Mycobacterium abscessus sensu lato infection in patients without cystic fibrosis]. AB - INTRODUCTION: Infection with Mycobacterium abscessus sensu lato is uncommon in patients without cystic fibrosis. We are interested in these patients and have collected cases in Finistere between 2007 and 2011. CASE REPORTS: Four patients met the infection criteria recommended by the American Thoracic Society in 2007. Among them, all had Aspergillus spp. in sputum, 3 had gastroesophageal reflux and two had the criteria for allergic bronchopulmonary aspergillosis. We identified Mycobacterium massiliense in the single patient in our series whose therapeutic outcome was successful. CONCLUSION: By comparing these data with those in the literature, we believe that the search for allergic bronchopulmonary aspergillosis and gastroesophageal reflux is necessary in these patients and that species identification is essential for prognosis. PMID- 26238927 TI - Quality of Cancer Care in Patients with Cirrhosis and Hepatocellular Carcinoma. AB - Hepatocellular carcinoma is the most common primary liver cancer in patients with cirrhosis and is the leading cause of mortality in these patients. Despite existence of robust clinical practice guidelines for surveillance, diagnosis, and management for hepatocellular carcinoma (HCC), the quality of care received by patients with HCC has been inconsistent. Several studies have reported disappointingly low surveillance rates in high-risk groups which likely contribute to most HCC cases being diagnosed at advanced stages. There is also data from large studies showing that significant under-referral to specialists and delay in initiation of treatment are linked to poor clinical outcomes. Given above circumstances, it is very important to perform studies which can identify areas in need of improvement in the care processes of HCC and design interventions to enhance quality of care. Unfortunately, data on validated quality indicators and quality metrics for HCC are non-existent. In this article, we review the existing literature pertaining to this issue and identify areas that need further research. PMID- 26238928 TI - Identification of a thioredoxin peroxidase gene involved in resistance to nucleopolyhedrovirus infection in Helicoverpa armigera with RNA interference. AB - Thioredoxin peroxidases (Tpxs) play a crucial role in protection against oxidative damage in several insect species. However, studies on the characteristics and functions of Tpxs in Helicoverpa armigera are lacking. In this study, a novel 2-Cys Tpx gene from H. armigera (HaTpx) was identified. Sequence analysis revealed that HaTpx is highly conserved and shares two catalysis regions (VCP) with other insect species. HaTpx mRNA was found to be expressed in an age-dependent manner and was ubiquitous in all tissues examined. Hormone treatment showed that the expression of HaTpx is clearly induced by 20 hydroxyecdysone but repressed by Juvenile hormone. Additionally, extreme temperature, ultraviolet light, mechanical injury, Escherichia coli, Metarhizium anisopliae, nucleopolyhedrovirus (NPV) infection, and H2O2 treatment markedly induced HaTpx gene expression. Reactive oxygen species (ROS) levels in hemocytes and MDA concentrations in the hemolymph after NPV infection were evaluated, and the results indicated that NPV infection causes excessive ROS generation. After knockdown of HaTpx by RNA interference, the expression of three antioxidant genes (Cu/ZnSOD, Trx, and TrxR) was increased, whereas two antioxidant genes (CAT and GPX) showed decreased expression. Moreover, the susceptibility of H. armigera to NPV infection increased after HaTpx knockdown. These results indicated that HaTpx contributes to the susceptibility of H. armigera to NPV, and the results also provide a theoretical basis for a novel strategy for developing new chemicals and microbial pesticides that target HaTpx gene for controlling H. armigera. PMID- 26238929 TI - Proteomic analysis of ofloxacin-mono resistant Mycobacterium tuberculosis isolates. AB - Drug resistance particularly, multi drug resistance tuberculosis (MDR-TB) has emerged as a major problem in the chemotherapy of tuberculosis. Ofloxacin (OFX) has been used as second-line drug against MDR-TB. The principal target of the OFX is DNA gyrase encoded by gyrA and gyrB genes. Many explanations have been proposed for drug resistance to OFX but still some mechanisms are unknown. As proteins manifest most of the biological processes, these are attractive targets for developing drugs and diagnostics/therapeutics. We examined the OFX resistant Mycobacterium tuberculosis isolates by proteomic approach (2DE-MALDI-TOF-MS) and bioinformatic tools under OFX induced conditions. Our study showed fourteen proteins (Rv0685, Rv0363c, Rv2744c, Rv3803c, Rv2534c, Rv2140c, Rv1475c, Rv0440, Rv2245, Rv1436, Rv3551, Rv0148, Rv2882c and Rv0733) with increased intensities in OFX resistant and OFX induced as compared to susceptible isolates. Bioinformatic analysis of hypothetical proteins (Rv2744c, Rv2140c, Rv3551 and Rv0148) revealed the presence of conserved motifs and domains. Molecular docking showed proper interaction of OFX with residues of conserved motifs. These proteins might be involved in the OFX modulation/neutralization and act as novel resistance mechanisms as well as potential for diagnostics and drug targets against OFX resistance. This article is part of a Special Issue entitled: Proteomics in India. PMID- 26238931 TI - SSIEM 2015 Annual Symposium : Lyon, France, August 2015. PMID- 26238930 TI - Targeting effect of PEGylated liposomes modified with the Arg-Gly-Asp sequence on gastric cancer. AB - Previous studies have demonstrated that the alpha5beta1 integrin-mediated interaction with fibronectin (FN) occurs through the Arg-Gly-Asp (RGD) cell binding sequence in repeat III10. Indocyanine green (ICG) is a near-infrared (NIR) optical dye that has been approved by the US Food and Drug Administration. In the present study, we developed an RGD-modified PEGylated liposome encapsulated ICG (RGD-PLS-ICG) system mediated by integrin. RGD was conjugated covalently to the distal end of DSPE-PEG2000-NH2 lipid by amide binding. The characteristics and stability of the prepared liposomes were assessed. In vitro, SGC7901 cells with high expression of integrin alpha5beta1 were selected by polymerase chain reaction (PCR) and western blotting. To confirm the targeting efficacies to gastric cancer, coumarin-6 was encapsulated as a fluorescent probe for in vitro study, and the targeting effect of RGD was detected by flow cytometry and confocal microscopy. In vivo, the bio distribution of RGD-PLS-ICG was studied by an in vivo imaging system in the tumor model. RGD-PLS-ICG and PLS ICG had a higher UV absorbance spectrum and stability than free-ICG. Confocal microscopy and flow cytometry demonstrated that RGD-PLS-encapsulated coumarin-6 was efficiently associated with the SGC7901 cells, while limited interaction was found for the other groups. Moreover, the in vivo imaging of the liposomes indicated that RGD-PLS-ICG achieved more accumulation in the tumor tissues when compared with PLS-ICG. The significant in vitro and in vivo results suggest that RGD-PLS-ICG may be a promising fluorescent dye delivery system for targeting gastric cancer cell overexpression of integrin. PMID- 26238932 TI - Electric field modification of magnetism in Au/La2/3Ba1/3MnO3/Pt device. AB - The La2/3Ba1/3MnO3 film is deposited in a CMOS-compatible Pt/Ti/SiO2/Si substrate with the oxygen pressure of 10 Pa for investigating magnetoelectric effect. Bipolar resistive switching effect with excellent endurance and retention is observed in this Au/La2/3Ba1/3MnO3/Pt device. Through this effect, a significant nonvolatile change of magnetization is obtained in this device as well. The change of magnetization can be understood by the break and repair of the -Mn(3+) O(2-)-Mn(4+)- chains induced by the electric field through the oxygen vacancies migration. The resistance and magnetization of the Au/La2/3Ba1/3MnO3/Pt device can be simultaneously manipulated by the electric field, which makes it to be a promising candidate for the multifunctional memory devices. PMID- 26238933 TI - Direct Production of 5-Hydroxymethylfurfural via Catalytic Conversion of Simple and Complex Sugars over Phosphated TiO2. AB - A water-THF biphasic system containing N-methyl-2-pyrrolidone (NMP) was found to enable the efficient synthesis of 5-hydroxymethylfurfural (HMF) from a variety of sugars (simple to complex) using phosphated TiO2 as a catalyst. Fructose and glucose were selectively converted to HMF resulting in 98 % and 90 % yield, respectively, at 175 degrees C. Cellobiose and sucrose also gave rise to high HMF yields of 94 % and 98 %, respectively, at 180 degrees C. Other sugar variants such as starch (potato and rice) and cellulose were also investigated. The yields of HMF from starch (80-85 %) were high, whereas cellulose resulted in a modest yield of 33 %. Direct transformation of cellulose to HMF in significant yield (86 %) was assisted by mechanocatalytic depolymerization-ball milling of acid-impregnated cellulose. This effectively reduced cellulose crystallinity and particle size, forming soluble cello-oligomers; this is responsible for the enhanced substrate-catalytic sites contact and subsequent rate of HMF formation. During catalyst recyclability, P-TiO2 was observed to be reusable for four cycles without any loss in activity. We also investigated the conversion of the cello oligomers to HMF in a continuous flow reactor. Good HMF yield (53 %) was achieved using a water-methyl isobutyl ketone+NMP biphasic system. PMID- 26238934 TI - Pravastatin inhibits fibrinogen- and FDP-induced inflammatory response via reducing the production of IL-6, TNF-alpha and iNOS in vascular smooth muscle cells. AB - Atherosclerosis is a chronic inflammatory response of the arterial wall to pro atherosclerotic factors. As an inflammatory marker, fibrinogen directly participates in the pathogenesis of atherosclerosis. Our previous study demonstrated that fibrinogen and fibrin degradation products (FDP) produce a pro inflammatory effect on vascular smooth muscle cells (VSMCs) through inducing the production of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS). In the present study, the effects of pravastatin on fibrinogen- and FDP-induced expression of IL-6, TNF-alpha and iNOS were observed in VSMCs. The results showed that pravastatin dose-dependently inhibited fibrinogen- and FDP-stimulated expression of IL-6, TNF-alpha and iNOS in VSMCs at the mRNA and protein level. The maximal inhibition of protein expression of IL-6, TNF-alpha and iNOS was 46.9, 42.7 and 49.2% in fibrinogen stimulated VSMCs, and 50.2, 49.8 and 53.6% in FDP-stimulated VSMCs, respectively. This suggests that pravastatin has the ability to relieve vascular inflammation via inhibiting the generation of IL-6, TNF-alpha and iNOS. The results of the present study may aid in further explaining the beneficial effects of pravastatin on atherosclerosis and related cardiovascular diseases. In addition, they suggest that application of pravastatin may be beneficial for prevention of atherosclerosis formation in hyperfibrinogenemia. PMID- 26238935 TI - Parental Well-being Surrounding First Birth as a Determinant of Further Parity Progression. AB - A major component driving cross-country fertility differences in the developed world is differences in the probability of having additional children among those who have one. Why do people stop at having only one child? We hypothesize that the experience of the transition to parenthood is an important determinant of further fertility. Analyzing longitudinal data from Germany, we find that the experience during the transition to parenthood, as measured by changes in subjective well-being, predicts further parity progression. A drop in well-being surrounding first birth predicts a decreased likelihood of having another child. The association is particularly strong for older parents and those with higher education: these characteristics may be related to the ability or willingness to revise fertility plans based on prior experiences. Parents' experience with the first birth is an important and understudied factor in determining completed family size, and policy-makers concerned about low fertility should pay attention to factors that influence the well-being of new parents. PMID- 26238936 TI - Changes in perfusion and diffusion in the endplate regions of degenerating intervertebral discs: a DCE-MRI study. AB - PURPOSE: Dynamic contrast-enhanced MRI (DCE-MRI) was used to investigate the associations between intervertebral disc degeneration and changes in perfusion and diffusion in the disc endplates. METHODS: 56 participants underwent MRI scans. Changes in DCE-MRI signal enhancement in the endplate regions were analyzed. Also, a group template was generated for the endplates and enhancement maps were registered to this template for group analysis. RESULTS: DCE-MRI enhancement changed significantly in cranial endplates with increased degeneration. A similar trend was observed for caudal endplates, but it was not significant. Group-averaged enhancement maps revealed major changes in spatial distribution of endplate perfusion and diffusion with increasing disc degeneration especially in peripheral endplate regions. CONCLUSIONS: Increased enhancement in the endplate regions of degenerating discs might be an indication of ongoing damage in these tissues. Therefore, DCE-MRI could aid in understanding the pathophysiology of disc degeneration. Moreover, it could be used in the planning of novel treatments such as stem cell therapy. PMID- 26238937 TI - Family Accommodation of Child and Adolescent Anxiety: Mechanisms, Assessment, and Treatment. AB - TOPIC: Anxiety disorders are the most common mental health concern for youth. Unfortunately, a substantial number of children and adolescents do not respond positively to current evidence-based interventions and/or relapse. As pediatric anxiety disorders are fundamentally a systemic phenomenon, focusing on the ways in which parents become involved in their children's anxiety symptoms may be a promising alternative approach to treatment. PURPOSE: To inform psychiatric mental health nurse practitioners (PMHNPs) about the phenomenology, associated neurobiology, and assessment of family accommodation (FA) as well as clinical interventions targeting FA. FA refers to ways that parents adapt their own behaviors to reduce their children's anxiety-related distress. SOURCES USED: A literature search was performed using Psyc-INFO and PubMed. CONCLUSIONS: Current findings indicate a high prevalence of FA associated with pediatric anxiety disorders. FA has a potentially deleterious impact on course of illness and treatment response and is associated with greater caregiver burden. Potential neurobiological underpinnings of FA include dysregulation of parent cortico limbic circuitry and the oxytocinergic system. PMHNPs are in a unique position to identify families engaged in problematic FA, educate their clientele, provide psychotherapy services with the goal of reducing FA, and consult with multidisciplinary team members. PMID- 26238938 TI - Oxidative damage to human parametrial ligament fibroblasts induced by mechanical stress. AB - The aim of the present study was to explore the underlying mechanisms of the roles of mechanical factors in the pathogenesis of pelvic organ prolapse (POP). The experiments were performed on fibroblasts derived from uterosacral ligaments and cardinal ligaments of patients who received total hysterectomy due to benign disease excluding POP. Fibroblasts were cultured after collagenase digestion and identified by morphological observation and immunocytochemical methods. A four point bending device was used to subject fibroblasts at passage 4-6 to strains of 0, 1,333 u (1 mm), 2,666 u (2 mm) or 5,333 u (4 mm) at a frequency of 0.1 Hz for 4 h. Intracellular reactive oxygen species (ROS) were quantified using the fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate. Changes in the mitochondrial membrane potential were verified using the fluorescent dye JC-1, and apoptosis was detected using Annexin V/propidium iodide staining and flow cytometric analysis. Mechanical strain changed the morphology and adherence ability of parametrial ligament fibroblasts. Furthermore, the production of ROS was significantly increased and the mitochondrial membrane potential obviously declined with the enhancement of mechanical stress loading. In addition, the apoptotic rate of fibroblasts subjected to high mechanical strain was significantly increased compared with that in fibroblast under low-intensity strain. In conclusion, the present study showed that mechanical strain enhanced intracellular ROS levels, decreased the mitochondrial membrane potential and increased the apoptotic rate in human parametrial ligament fibroblasts, which may contribute to POP. PMID- 26238939 TI - Surgical Treatment Alone of Cerebral Aspergillosis in Immunocompetent Patient. AB - Aspergillosis is a disease that predominantly affects immunocompromised patients. The incidence in immunocompetents is rare, and manifestation is generally pulmonary. Few reports in the literature refer to isolated cerebral aspergillosis in individuals with no chronic comorbidities. We describe a case of a 59-year-old rural worker without previous pathologies who had a partial convulsive crisis in a subtle form, with self-limiting and nonrecurrent secondary generalization. Diagnostic investigation demonstrated a subcortical tumorlike lesion in the right precentral gyrus by nuclear magnetic resonance that allowed en bloc microsurgical resection, with histopathologic findings indicating cerebral aspergillosis. Because of the delay in obtaining the result of the biopsy due to technical difficulties with analysis, the diagnosis was delayed. The patient was clinically stable, with imaging without modifications and with negative serologic tests, so it was decided to follow the patient without antifungal therapy, which was successful. This was a case of isolated cerebral aspergillosis in an immunocompetent individual who was successfully treated by complete resection of the lesion alone, without combined antifungal therapy. PMID- 26238940 TI - The Usefulness of Spinal Cord Stimulation for Chronic Pain Due to Combined Vasospastic Prinzmetal Angina and Diabetic Neuropathic Pain of the Lower Limbs. AB - OBJECTIVE: To describe an unusual case of combined neuropathic and ischemia induced chronic pain in a patient who was treated with one high thoracic paddle lead. BACKGROUND: To the best of our knowledge, the use of spinal cord stimulation (SCS) utilizing a single lead as a treatment strategy for combined Prinzmetal angina, a cardiac ischemia-induced disturbance of nociceptive perception, and diabetic neuropathy of the lower limbs has rarely been described. CASE REPORT: The underlying pain conditions and SCS technique used to treat both types of pain-Prinzmetal angina and lower-limb diabetic neuropathy-in a 73-year old patient experiencing medical or interventional refractory complex pain syndrome are described. The SCS electrode was placed in the anatomical midline with a T2- to T3-level laminotomy and externalized for postoperative trial stimulation with systemic antibiotic administration. RESULTS: After 8 months, stable pain control was achieved. No complications occurred. CONCLUSION: We present a chronic pain syndrome due to combined Prinzmetal angina and diabetic neuropathy of the lower limbs with sustained pain relief utilizing a single SCS lead. PMID- 26238941 TI - Open Traumatic Brain Injury Is a Strong Predictor for Aseptic Bone Necrosis after Cranioplasty Surgery: A Retrospective Analysis of 219 Patients. AB - OBJECTIVE: To investigate whether independent predictors of complications after cranioplasty are identifiable. METHODS: Parameters that could predict the occurrence of complications were analyzed retrospectively. The end point of the study was the explantation of the bone flap. RESULTS: A total of 219 patients with a mean age of 42.8 years (standard deviation: 17.89) were included. History of trauma and especially open traumatic brain injury (TBI) were associated with a higher complication rate (p = 0.01 and p = 0.02, respectively). Multivariate testing showed that fragmented bone flap resulted in a more frequent occurrence of bone flap necrosis (p = 0.014). The risk of complications following cranioplasty was higher if a ventriculoperitoneal (VP) shunt was placed at the same time (p = 0.01). Longer duration of the cranioplasty procedure was significantly associated with a higher postoperative complication rate (p = 0.001). Subsequent rehabilitation is more frequent if patients develop a complication. CONCLUSIONS: To avoid complications after cranial vault reconstruction, indications for simultaneous VP shunt implantation should be carefully evaluated. The implantation of traumatically fragmented bone flaps should be avoided. Patients after open TBI should either primarily be treated with an allogenic graft or they should be carefully followed up because they are prone to develop aseptic necrosis. PMID- 26238942 TI - MicroRNA-20a promotes the proliferation and cell cycle of human osteosarcoma cells by suppressing early growth response 2 expression. AB - MicroRNAs (miRNAs) are crucial in cancer development. However, the underlying mechanisms of miRNAs in osteosarcoma (OS) remain largely uncharacterized. The present study investigated the role of miR-20a in OS cell proliferation. It was determined that miR-20a expression is markedly upregulated in OS tissues and cells compared with the matched adjacent normal tissues and h-FOB human osteoblast cell lines. Ectopic expression of miR-20a promoted the proliferation and anchorage-independent growth of OS cells, whereas inhibition of miR-20a reduced this effect. Bioinformatics analysis further revealed early growth response 2 (EGR2), as a potential target of miR-20a. Data from luciferase reporter assays showed that miR-20a directly binds to the 3'-untranslated region (3'-UTR) of EGR2 mRNA and represses expression at the transcriptional and translational levels. In functional assays, miR-20a promoted OS cell proliferation and the cell cycle, which could be suppressed by an inhibitor of miR-20a. In conclusion, the data provide compelling evidence that miR-20a functions as an onco-miRNA, which is important in promoting cell proliferation in OS, and its oncogenic effect is mediated primarily through direct suppression of EGR2 expression. PMID- 26238943 TI - A systematic review of recent clinical practice guidelines and best practice statements for the evaluation of the infertile male. AB - PURPOSE: We systematically identified and reviewed the methods and consistency of recommendations of recently developed clinical practice guidelines (CPG) and best practice statements (BPS) on the evaluation of the infertile male. METHODS: MEDLINE and related engines as well as guidelines' Web sites were searched for CPG and BPS written in English on the general evaluation of male infertility published between January 2008 and April 2015. RESULTS: Four guidelines were identified, all of which reported to have been recently updated. Systematic review was not consistently used in the BPS despite being reported in the CPG. Only one of them reported having a patient representative in its development team. The CPG issued by the European Association of Urology (EAU) graded some recommendations and related that to levels (but not quality) of evidence. Overall, the BPS issued respectively by the American Urological Association and American Society for Reproductive Medicine concurred with each other, but both differed from the EAU guidelines with regard to methods of collection, extraction and interpretation of data. None of the guidelines incorporated health economics. Important specific limitations of conventional semen analysis results were ignored by all guidelines. Besides variation in the methodological quality, implementation strategies were not reported in two out of four guidelines. CONCLUSIONS: While the various panels of experts who contributed to the development of the CPG and BPS reviewed should be commended on their tremendous efforts aiming to establish a clinical standard in both the evaluation and management of male infertility, we recognized inconsistencies in the methodology of their synthesis and in the contents of their final recommendations. These discrepancies pose a barrier in the general implementation of these guidelines and may limit their utility in standardizing clinical practice or improving health-related outcomes. Continuous efforts are needed to generate high-quality evidence to allow further development of these important guidelines for the evaluation and management of males suffering from infertility. PMID- 26238944 TI - A practical solution that bypasses the altruism versus incentives debate. PMID- 26238945 TI - The first fistula: influence of location on catheter use and the influence of catheter use on maturation. AB - BACKGROUND: The forearm location for the initial vascular access has traditionally been considered the most desirable; however, recent advances in our understanding the physiology of fistula development suggest that the larger proximal vessels with higher blood flows may be associated with increased wall stress and faster fistula development. We examined whether the location of a first fistula had any relationship to the incidence and duration of catheter use. METHODS: This was an observational study of 808 patients who underwent the creation of an autologous arteriovenous fistula for their first hemodialysis access who were evaluated for the length of use of a temporary catheter. The variables studied for their effect upon catheter use included: location in the forearm or upper arm, age, the presence of diabetes, vascular disease or smoking history. RESULTS: Despite being younger (P < 0.0001), nondiabetics (P < 0.0001), without vascular disease (P < 0.0001), and placed longer before initiation of dialysis (P = 0.03), the patients with forearm fistulas were significantly more likely to need a catheter to start dialysis (P < 0.0001) and the length of use was significantly longer than in upper arm fistulas. Fistulas place prior to initiation of dialysis required shorter maturation time. CONCLUSION: The upper arm as the initial site for fistula creation was associated with a significantly reduced incidence and prevalence of catheter use when the patients began dialysis. Fistulas placed prior to the initiation of dialysis had significantly shorter maturation times than those created after a catheter had been inserted which might be due to delayed maturation caused by the catheter. PMID- 26238946 TI - Association of genetic variants with dyslipidemia. AB - Although genetic variants, which regulate lipid metabolism, have been extensively investigated in Caucasian populations, the genes, which confer susceptibility to dyslipidemia in Japanese individuals, remain to be elucidated. The aim of the present study was to examine a possible association among hypertriglyceridemia, hypo-high density lipoprotein (HDL)-cholesterolemia or hyper-low density lipoprotein (LDL)-cholesterolemia in Japanese individuals with 29 polymorphisms observed to confer susceptibility for coronary heart disease. This was performed through meta-analyses of genome-wide association studies in Caucasian populations. The study population comprised 2,354 individuals with dyslipidemia (hypertriglyceridemia, hypo-HDL-cholesterolemia or hyper-LDL-cholesterolemia) and 3,106 control individuals. To compensate for multiple comparisons of genotypes, a false discovery rate (FDR) of <0.05 was adopted to determine the statistical significance of the associations. Comparisons of allele frequencies using the chi2 test revealed that rs964184 of zinc finger gene (ZPR1; FDR=2.1x10-7), rs4845625 of interleukin 6 receptor (IL6R; FDR=0.032), rs46522 of ubiquitin conjugating enzyme E2Z gene (UBE2Z; FDR=0.032) and rs17514846 of furin (FDR=0.041) were significantly associated with hypertriglyceridemia. The chi2 test revealed that rs599839 of proline/serine-rich coiled-coil 1 (PSRC1; FDR=0.004) and rs2075650 of translocase of outer mitochondrial membrane 40 homolog (TOMM40; FDR=0.004) were significantly associated with hyper-LDL cholesterolemia. Multivariate logistic regression analysis with adjustment for age, gender and body mass index revealed that rs964184 of ZPR1 (P=5.1x10-7; odds ratio, 1.37; dominant model), rs4845625 of IL6R (P=0.0019, odds ratio, 1.25; dominant model) and rs46522 of UBE2Z (P=0.0039, odds ratio, 1.19; dominant model) were significantly associated with hypertriglyceridemia, and that rs599839 of PSRC1 (P=0.0004, odds ratio, 0.70; dominant model) and rs2075650 of TOMM40 (P=0.0004, odds ratio, 1.43; dominant model) were significantly associated with hyper-LDL-cholesterolemia. Therefore, ZPR1, IL6R, and UBE2Z may be susceptibility loci for hypertriglyceridemia, whereas PSRC1 and TOMM40 may be such loci for hyper-LDL-cholesterolemia in Japanese individuals. PMID- 26238947 TI - Influence of kidney disease on drug disposition: An assessment of industry studies submitted to the FDA for new chemical entities 1999-2010. AB - In 1998, the United States Food and Drug Administration (FDA) released the first guidance for industry regarding pharmacokinetic (PK) studies in renally impaired patients. This study aimed to determine if the FDA renal PK guidance influenced the frequency and rigor of renal studies conducted for new chemical entities (NCEs). FDA-approved package inserts (APIs) and clinical pharmacology review documents were analyzed for 194 NCEs approved from 1999 to 2010. Renal studies were conducted in 71.6% of NCEs approved from 1999 to 2010, a significant increase over the 56.3% conducted from 1996 to 1997 (P = .0242). Renal studies were more likely to be completed in highly renally excreted drugs (fe >= 30%) compared with drugs with low renal excretion, fe < 30% (89.6% vs 65.8%, P = .0015). PK studies to assess the impact of dialysis were conducted for 31.7% of NCEs that had a renal study: a greater proportion of high fe NCEs were studied (44.2% vs 26.0%, P = .0335). No significant change in frequency or rigor of PK studies was detected over time. The majority of NCEs (76.3%) with a renal study provided specific dosing recommendations in the API. The adoption of the 1998 FDA guidance has resulted in improved availability of PK and drug-dosing recommendations, particularly for high fe drugs. PMID- 26238948 TI - Washout of hepatocellular carcinoma on portal venous phase of multidetector computed tomography in a pre-transplant population. AB - INTRODUCTION: Washout is an important diagnostic imaging feature of hepatocellular carcinoma (HCC) on computed tomography (CT). The primary aim of this study is to evaluate the prevalence and the interobserver variation in the detection of portal venous phase (PVP) washout of HCCs using CT in a transplant population. The secondary aim is to evaluate factors influencing the detection of PVP washout. METHODS: Forty-five patients who underwent CT liver imaging within the 60 days before transplantation had viable HCCs confirmed on pathology. Two radiologists retrospectively reviewed the images for HCCs including features of arterial enhancement and PVP washout. Clinical data, peak kilovoltage, imaging features of portal hypertension, region of interest attenuation measurements of the individual lesions, background liver parenchyma and portal vein were obtained. Liver to lesion attenuation ratio was also calculated. Statistical analysis was performed. RESULTS: The two readers identified 50 arterially enhancing HCCs in 45 patients. In consensus, the two readers identified washout in 60% of the HCCs with a substantial interobserver agreement (kappa = 0.633). PVP washout was associated with larger lesion size, increased background liver parenchyma attenuation, increased liver to lesion attenuation ratio, increased portal vein attenuation and hepatitis B viral status (P = 0.027, 0.008, 0.014, 0.017 and 0.037 respectively). CONCLUSION: In our transplant population, portal venous phase washout was seen in 60% of the hypervascular HCCs. Factors influencing the presence of PVP washout include lesion size as well as the liver and portal vein attenuation reflective of the portal haemodynamics. PMID- 26238949 TI - OsPRR37 and Ghd7 are the major genes for general combining ability of DTH, PH and SPP in rice. AB - Artificial selection of high yield crops and better livestock is paramount importance in breeding programs. Selection of elite parents with preferred traits from a phalanx of inbred lines is extremely laborious, time-consuming and highly random. General combining ability (GCA) was proposed and has been widely used for the evaluation of parents in hybrid breeding for more than half a century. However, the genetic and molecular basis of GCA has been largely overlooked. Here, we present two pleotropic QTLs are accounting for GCA of days to heading (DTH), plant height (PH) and spikelet per panicle (SPP) using an F2-based NCII design, the BC3F2 population as well as a set of nearly isogenic lines (NILs) with five testers. Both GCA1 and GCA2 were loss-of-function gene in low-GCA parent and gain-of-function gene in high-GCA parent, encoding the putative Pseudo Response Regulators, OsPRR37 and Ghd7, respectively. Overexpression of GCA1 in low-GCA parent significantly increases GCA effects in three traits. Our results demonstrate that two GCA loci associate with OsPRR37 and Ghd7 and reveal that the genes responsible for important agronomic traits could simultaneously account for GCA effects. PMID- 26238950 TI - miR-519d-mediated downregulation of STAT3 suppresses breast cancer progression. AB - MicroRNAs (miRNAs) play important roles in the the gene regulation of carcinogenesis including breast cancer. miR-519d has been studied in various types of cancer, but its role in breast cancer remains unclear. In the present study, we investigated the expression and biological function of miR-519d in breast cancer. Using quantitative RT-PCR (RT-qPCR) analysis, we analyzed the expression of miR-519d in breast cancer tissues and cell lines. It was shown that miR-519d expression was decreased in cancer tissues and cell lines compared with their controls. Overexpression of miR-519d inhibited cell proliferation and invasion, and induced apoptosis of breast cancer cells. Signal transducer and activator of transcription 3 (STAT3) was predicted as a target gene of miR-519d and it was verified by the luciferase reporter assay. Additionally, STAT3 mRNA and protein expression levels were downregulated in the cells with miR-519d overexpression as determined by RT-qPCR and western blotting. Taken together, the results indicated that miR-519d functions as a tumor suppressor in breast cancer by suppressing STAT3 expression. PMID- 26238951 TI - High-Dose-Rate Brachytherapy as Monotherapy for Intermediate- and High-Risk Prostate Cancer: Clinical Results for a Median 8-Year Follow-Up. AB - PURPOSE: To present mature results of high-dose-rate brachytherapy (HDR-BT) as monotherapy for intermediate- and high-risk prostate cancer. METHODS AND MATERIALS: From 1995 through 2012, 190 patients, 79 with intermediate-risk and 111 with high-risk prostate cancer, were treated with HDR-BT alone using 48 Gy/8 fractions, 54 Gy/9 fractions, or 45.5 Gy/7 fractions over 4 to 5 days. Neoadjuvant with or without adjuvant androgen deprivation therapy was administered to 139 patients, 35 intermediate- and 104 high-risk. RESULTS: Median follow-up time was 92 months (range, 10-227 months), with a minimum of 2 years for surviving patients. Respective rates of cause-specific survival, overall survival, metastasis-free survival, and biochemical no evidence of disease for the intermediate-risk patients were 100%, 100%, 96%, and 93% at 5 years, and 100%, 96%, 91%, and 91% at 8 years. Corresponding rates for the high-risk patients were 97%, 93%, 84%, and 81% at 5 years, and 93%, 81%, 74%, and 77% at 8 years. The cumulative incidence of late grade 2 to 3 genitourinary toxicity was 5% at 5 years and 10% at 8 years, and that of late grade 3 was 0 at 5 years and 1% at 8 years. The cumulative incidence of late grade 2-3 gastrointestinal toxicity was 4% at 5 years and 6% at 8 years, and that of late grade 3 was 0 at 5 years and 2% at 8 years. No grade 4 or 5 toxicity was detected. CONCLUSIONS: Our single-institution study with a median 8-year follow-up showed that HDR-BT as monotherapy was safe and effective for patients with intermediate- and high-risk prostate cancer. PMID- 26238953 TI - A Quantitative Analysis of the Relationship Between Radiation Therapy Use and Travel Time. AB - PURPOSE: To model and quantify the relationship between radiation therapy (RT) use and travel time to RT services. METHODS AND MATERIALS: Population-based registries and databases were used to identify both incident cancer patient and patients receiving RT within 1 year of diagnosis (RT1y) in British Columbia, Canada, between 1992 and 2011. The effects of age, gender, diagnosis year, income, prevailing wait time, and travel duration for RT on RT1y were assessed. Significant factors from univariate analyses were included in a multivariable logistic regression model. The shape of the travel time-RT1y curve was represented by generalized additive and segmented regression models. Analyses were conducted for breast, lung, and genitourinary cancer separately and for all cancer sites combined. RESULTS: After adjustment for age, gender, diagnosis year, income, and prevailing wait times, increasing travel time to the closest RT facility had a negative impact RT1y. The shape of the travel time-RT1y curve varied with cancer type. For breast cancer, the odds of RT1y were constant for the first 2 driving hours and decreased at 17% per hour thereafter. For lung cancer, the odds of RT1y decreased by 16% after 20 minutes and then decreased at 6% per hour. Genitourinary cancer RT1y was relatively independent of travel time. For all cancer sites combined, the odds of RT1y were constant within the first 2 driving hours and decreased at 7% per hour thereafter. CONCLUSIONS: Travel time to receive RT has a different impact on RT1y for different tumor sites. The results provide evidence-based insights for the configuration of catchment areas for new and existing cancer centers providing RT. PMID- 26238952 TI - Reverse-Contrast Imaging and Targeted Radiation Therapy of Advanced Pancreatic Cancer Models. AB - PURPOSE: To evaluate the feasibility of delivering experimental radiation therapy to tumors in the mouse pancreas. Imaging and treatment were performed using combined CT (computed tomography)/orthovoltage treatment with a rotating gantry. METHODS AND MATERIALS: After intraperitoneal administration of radiopaque iodinated contrast, abdominal organ delineation was performed by x-ray CT. With this technique we delineated the pancreas and both orthotopic xenografts and genetically engineered disease. Computed tomographic imaging was validated by comparison with magnetic resonance imaging. Therapeutic radiation was delivered via a 1-cm diameter field. Selective x-ray radiation therapy of the noninvasively defined orthotopic mass was confirmed using gammaH2AX staining. Mice could tolerate a dose of 15 Gy when the field was centered on the pancreas tail, and treatment was delivered as a continuous 360 degrees arc. This strategy was then used for radiation therapy planning for selective delivery of therapeutic x-ray radiation therapy to orthotopic tumors. RESULTS: Tumor growth delay after 15 Gy was monitored, using CT and ultrasound to determine the tumor volume at various times after treatment. Our strategy enables the use of clinical radiation oncology approaches to treat experimental tumors in the pancreas of small animals for the first time. We demonstrate that delivery of 15 Gy from a rotating gantry minimizes background healthy tissue damage and significantly retards tumor growth. CONCLUSIONS: This advance permits evaluation of radiation planning and dosing parameters. Accurate noninvasive longitudinal imaging and monitoring of tumor progression and therapeutic response in preclinical models is now possible and can be expected to more effectively evaluate pancreatic cancer disease and therapeutic response. PMID- 26238955 TI - Delayed Workforce Entry and High Emigration Rates for Recent Canadian Radiation Oncology Graduates. AB - PURPOSE: To determine the employment status and location of recent Canadian radiation oncology (RO) graduates and to identify current workforce entry trends. METHODS AND MATERIALS: A fill-in-the-blank spreadsheet was distributed to all RO program directors in December 2013 and June 2014, requesting the employment status and location of their graduates over the last 3 years. Visa trainee graduates were excluded. RESULTS: Response rate from program directors was 100% for both survey administrations. Of 101 graduates identified, 99 (98%) had known employment status and location. In the December survey, 5 2013 graduates (16%), 17 2012 graduates (59%), and 18 2011 graduates (75%) had permanent staff employment. Six months later, 5 2014 graduates (29%), 15 2013 graduates (48%), 24 2012 graduates (83%), and 21 2011 graduates (88%) had secured staff positions. Fellowships and temporary locums were common for those without staff employment. The proportion of graduates with staff positions abroad increased from 22% to 26% 6 months later. CONCLUSIONS: Workforce entry for most RO graduates was delayed but showed steady improvement with longer time after graduation. High emigration rates for jobs abroad signify domestic employment challenges for newly certified, Canadian-trained radiation oncologists. Coordination on a national level is required to address and regulate radiation oncologist supply and demand disequilibrium in Canada. PMID- 26238954 TI - A Preliminary Study on Racial Differences in HMOX1, NFE2L2, and TGFbeta1 Gene Polymorphisms and Radiation-Induced Late Normal Tissue Toxicity. AB - PURPOSE: This study tested whether racial differences in genetic polymorphisms of 4 genes involved in wound repair and response to radiation can be used to predict the occurrence of normal tissue late effects of radiation therapy and indicate potential therapeutic targets. METHODS AND MATERIALS: This prospective study examined genetic polymorphisms that modulate the expression of 4 genes involved in inflammation and fibrosis and response to radiation (HMOX1, NFE2L2, NOS3, and TGFbeta1). DNA from blood samples of 179 patients (~ 80% breast and head and neck) collected at the time of diagnosis by their radiation oncologist as exhibiting late normal tissue toxicity was used for the analysis. Patient demographics were as follows: 56% white, 43% African American, 1% other. Allelic frequencies of the different polymorphisms of the participants were compared with those of the general American population stratified by race. Twenty-six additional patients treated with radiation, but without toxicity at 3 months or later after therapy, were also analyzed. RESULTS: Increased frequency of a long GT repeat in the HMOX1 promoter was associated with late effects in both African American and white populations. The single nucleotide polymorphisms (SNP) rs1800469 in the TGFbeta1 promoter and the rs6721961 SNP in the NFE2L2 promoter were also found to significantly associate with late effects in African Americans but not whites. A combined analysis of these polymorphisms revealed that >90% of African American patients with late effects had at least 1 of these minor alleles, and 58% had 2 or more. No statistical significance was found relating the studied NOS3 polymorphisms and normal tissue toxicity. CONCLUSIONS: These results support a strong association between wound repair and late toxicities of radiation. The presence of these genetic risk factors can vary significantly among different ethnic groups, as demonstrated for some of the SNPs. Future studies should account for the possibility of such ethnic heterogeneity in the late toxicities of radiation. PMID- 26238956 TI - 1q21.1 microduplication in a patient with mental impairment and congenital heart defect. AB - 1q21.1 duplication is a rare copy number variant with multiple congenital malformations, including developmental delay, autism spectrum disorder, dysmorphic features and congenital heart anomalies. The present study described a Chinese female patient (age, four years and eight months) with multiple malformations, including congenital heart defect, mental impairment and developmental delay. The parents and the monozygotic twin sister of the patient, however, were physically and psychologically normal. High-resolution genome-wide single nucleotide polymorphism array revealed a 1.6-Mb duplication in chromosome region 1q21.1. This chromosome region contained HFE2, a critical gene involved in hereditary hemochromatosis. However, the parents and monozygotic twin sister of the patient did not carry this genomic lesion. To the best of our knowledge, the present study was the first to report on a 1q21.1 duplication patient in mainland China. PMID- 26238957 TI - Decrypting Cryptic Click Beetle Species by Analysis of Sex Pheromones. AB - Despite sex pheromones being highly species specific, their use as phylogenetic characters and a tool for the verification of species status are still relatively few compared to use of morphological and molecular characters. Earlier studies revealed that within the click beetle species Idolus picipennis, two types can be separated based on pheromone composition. Gas chromatography/mass spectrometry analysis of pheromone from a third type of Idolus revealed the presence of geranyl hexanoate and geranyl octanoate in a ratio of ca. 1:9. Neryl esters and farnesyl esters, present in the glands of the other two species, are absent in this type. In field experiments, males of all three types were attracted specifically to synthetic mixtures of pheromone resembling their own females. This suggests that cross attraction among different types is unlikely and indicates that they are likely distinct species. Using the large numbers of male beetles caught in pheromone traps, morphological differences between the species were studied and an identification key derived. This study highlights the role of sex pheromones as a powerful tool in integrative taxonomy and systematics to study the phylogenetic position and evolution of taxa and to determine the taxonomic status of cryptic species. PMID- 26238958 TI - Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. AB - The propensity score is defined as a subject's probability of treatment selection, conditional on observed baseline covariates. Weighting subjects by the inverse probability of treatment received creates a synthetic sample in which treatment assignment is independent of measured baseline covariates. Inverse probability of treatment weighting (IPTW) using the propensity score allows one to obtain unbiased estimates of average treatment effects. However, these estimates are only valid if there are no residual systematic differences in observed baseline characteristics between treated and control subjects in the sample weighted by the estimated inverse probability of treatment. We report on a systematic literature review, in which we found that the use of IPTW has increased rapidly in recent years, but that in the most recent year, a majority of studies did not formally examine whether weighting balanced measured covariates between treatment groups. We then proceed to describe a suite of quantitative and qualitative methods that allow one to assess whether measured baseline covariates are balanced between treatment groups in the weighted sample. The quantitative methods use the weighted standardized difference to compare means, prevalences, higher-order moments, and interactions. The qualitative methods employ graphical methods to compare the distribution of continuous baseline covariates between treated and control subjects in the weighted sample. Finally, we illustrate the application of these methods in an empirical case study. We propose a formal set of balance diagnostics that contribute towards an evolving concept of 'best practice' when using IPTW to estimate causal treatment effects using observational data. PMID- 26238959 TI - In reference to: Endoscopic transcanal removal of symptomatic external auditory canal exostoses. PMID- 26238960 TI - [Airway management in Ludwig's angina - a challenge: case report]. AB - BACKGROUND: Ludwig's angina (LA) is an infection of the submandibular space, first described by Wilhelm Frederick von Ludwig in 1836. It represents an entity difficult to manage due to the rapid progression and difficulty in maintaining airway patency, a major challenge in medical practice, resulting in asphyxia and death in 8-10% of patients. OBJECTIVE: Describe a case of a patient with Ludwig's angina undergoing surgery, with emphasis on airway management, in addition to reviewing the articles published in the literature on this topic. CASE REPORT: Male patient, 21 years, drug addict, admitted by the emergency department and diagnosed with LA. Difficult airway was identified during the anesthetic examination. In additional tests, significant deviation from the tracheal axis was seen. Undergoing bilateral thoracoscopic pleural drainage, we opted for airway management through tracheal intubation using fiberoptic bronchoscopy, and balanced general anesthesia was proposed. There were no complications during the surgical-anesthetic act. After the procedure, the patient remained intubated and mechanically ventilated in the intensive care unit. CONCLUSIONS: Airway management in patients with Ludwig's angina remains challenging. The choice of the safest technique should be based on clinical signs, technical conditions available, and the urgent need to preserve the patient's life. PMID- 26238961 TI - A novel 2q37 microdeletion containing human neural progenitors genes including STK25 results in severe developmental delay, epilepsy, and microcephaly. AB - 2q37 microdeletion syndrome is a rare syndrome characterized by neurodevelopmental delay, bone, cardiovascular, and neurological alterations. This syndrome is typically associated with loss of genetic material of approximately 100 genes in the 2q37 band. However, the genes associated with neurodevelopmental phenotype in this syndrome are still unknown. We identified a deleted region of 496 kb by whole genome array CGH in a patient who fulfilled criteria for 2q37 microdeletion syndrome with developmental delay, microcephaly, hypoplasia of the corpus callosum, hand wringing, toe walking, and seizures. The deleted segment contains genes that are highly expressed in the developing human cortical plate and the subventricular zone (SVZ) in vivo and human neural progenitors in vitro, including SEPT2, THAP4, ATG4B, PPP1R7, and STK25. Network analysis revealed that STK25 was the most interacting gene associated with neural development in this deletion. Our report narrows the likely causative genomic region for microcephaly and neurodevelopmental delay in 2q37 microdeletion syndrome to a small genomic region enriched with neural progenitor genes that may represent an important locus for the development of the human cortex and corpus callosum. PMID- 26238962 TI - Aminoboration: Addition of B-N sigma Bonds across C-C pi Bonds. AB - This communication demonstrates the first catalytic aminoboration of C-C pi bonds by B-N sigma bonds and its application to the synthesis of 3-borylated indoles. The regiochemistry and broad functional group compatibility of this addition reaction enable substitution patterns that are incompatible with major competing technologies. This aminoboration reaction effects the formation of C-B and C-N bonds in a single step from aminoboronic esters, which are simple starting materials available on the gram scale. This reaction generates synthetically valuable N-heterocyclic organoboron compounds as potential building blocks for drug discovery. The working mechanistic hypothesis involves a bifunctional Lewis acid/base catalysis strategy involving the combination of a carbophilic gold cation and a trifluoroacetate anion that activate the C-C pi bond and the B-N sigma bond simultaneously. PMID- 26238963 TI - Motor unit firing pattern: evidence for motoneuronal or axonal discharge origin? AB - In neuromuscular diseases, a fasciculation origin is disputed. In some reports, it was suggested that motor unit firing pattern alone is evidence for motoneuronal or axonal fasciculations; namely interspike intervals of approximately 5 ms (doublet intervals) provide evidence for the axonal firing. To clarify the reliability of the suggestion, we compared doublet intervals originated in motoneurons and their axons in healthy humans. For this aim, the H reflex and M-response of single motor units were elicited during gentle voluntary muscle contractions. Peri-stimulus time histograms allowed reliable judgment about a doublet origin: motoneuronal (at the H-reflex latency) or axonal (at the M-response latency). Significant difference between motoneuronal and axonal doublet intervals was absent. It was concluded that doublet interval alone cannot be the reliable criterion for an axonal firing origin; additional evidences are needed for this conclusion, for example, the appearance of the F-wave. The approach may be used as an additional estimation of mechanisms underlying motor unit diseases. PMID- 26238964 TI - Representation and Incorporation of Close Others' Responses: The RICOR Model of Social Influence. AB - We propose a new model of social influence, which can occur spontaneously and in the absence of typically assumed motives. We assume that perceivers routinely construct representations of other people's experiences and responses (beliefs, attitudes, emotions, and behaviors), when observing others' responses or simulating the responses of unobserved others. Like representations made accessible by priming, these representations may then influence the process that generates perceivers' own responses, without intention or awareness, especially when there is a strong social connection to the other. We describe evidence for the basic properties and important moderators of this process, which distinguish it from other mechanisms such as informational, normative, or social identity influence. The model offers new perspectives on the role of others' values in producing cultural differences, the persistence and power of stereotypes, the adaptive reasons for being influenced by others' responses, and the impact of others' views about the self. PMID- 26238965 TI - Magnetic gold nanotriangles by microwave-assisted polyol synthesis. AB - Simple approaches to synthesize hybrid nanoparticles with magnetic and plasmonic functionalities, with high control of their shape and avoiding cytotoxic reactants, to target biomedical applications remain a huge challenge. Here, we report a facile, fast and bio-friendly microwave-assisted polyol route for the synthesis of a complex multi-material consisting of monodisperse gold nanotriangles around 280 nm in size uniformly decorated by superparamagnetic iron oxide nanoparticles of 5 nm. These nanotriangles are readily dispersible in water, display a strong magnetic response (10 wt% magnetic fraction) and exhibit a localized surface plasmon resonance band in the NIR region (800 nm). Moreover, these hybrid particles can be easily self-assembled at the liquid-air interfaces. PMID- 26238966 TI - Value of diffusion-weighted imaging when added to magnetic resonance enterographic evaluation of Crohn disease in children. AB - BACKGROUND: MR enterography is increasingly utilized for noninvasive evaluation of disease activity in young patients with Crohn disease and has great impact on clinical management. Diffusion-weighted imaging (DWI) is a rapid MR imaging technique that measures molecular diffusion of water and is sensitive to the inflammatory process; however, its value to MR enterography has not been rigorously evaluated. OBJECTIVE: To determine whether the addition of DWI to MR enterography is helpful in evaluating Crohn disease activity in young patients when compared to a histological reference. MATERIALS AND METHODS: In this single institution retrospective study, we searched an imaging database for the period January 2010 to December 2012 to identify patients age 19 years and younger who had MR enterography with diffusion-weighted imaging (DWI). We used an electronic medical record search to identify those who had MR enterography and colonoscopy performed within 28 days of each other. All MR enterography scans were performed on a 1.5-T or 3-T clinical MR scanner with phased-array torso coil configuration using standard pulse sequences as well as axial DWI with b values of 50, 400 and 800. Bowel segments were evaluated for disease activity based on standard MR enterography sequences; in addition, segmental apparent diffusion coefficient (ADC) values were calculated based on DWI. Histological reference for disease activity was based on assessment for mucosal inflammatory changes on endoscopic biopsy. MR enterography and DWI evaluation were performed in a blinded fashion with respect to histological results. RESULTS: We included imaging of 78 bowel segments from 27 patients (mean age 14.5 +/- 3.02 years) with known Crohn disease in the study. The mean ADC for bowel segments with active disease was 1.56 +/- 0.7 * 10(3) mm(2)/s compared with 2.58 +/- 1.4 * 10(3) mm(2)/s for segments without active disease, a difference that was statistically significant (P < 0.01, Student's t-test). Using a threshold value of 2.0 * 10(3) mm(2)/s, DWI demonstrated lower accuracy (64.1%) but higher sensitivity (78.8%) for detecting active disease compared with standard MR enterography (69.2% and 54.6%, respectively). Combining DWI with MR enterography, using DWI as the initial screen and MR enterography afterward to reduce false negativity, led to a significant increase in accuracy (76.9%; P = 0.03, McNemar's test) compared with either imaging technique alone. CONCLUSION: Although DWI does not perform as well as standard MR enterography for detection of active Crohn disease, the combination of DWI and MR enterography increases imaging accuracy for determining disease activity compared with either technique alone. These results indicate that DWI adds value to MR enterography and supports the incorporation of DWI into MR enterography protocols for evaluation of Crohn disease in young patients. PMID- 26238967 TI - Paradoxical centrally increased diffusivity in perinatal arterial ischemic stroke. AB - BACKGROUND: Restricted diffusion on acute MRI is the diagnostic standard for perinatal arterial ischemic stroke. In a subset of children with perinatal arterial ischemic stroke, primarily those with large infarct volumes, we noted a core of centrally increased diffusivity with a periphery of restricted diffusion. OBJECTIVE: Given the paradoxical diffusion-weighted imaging (DWI) appearance observed in some children with perinatal arterial ischemic stroke, we sought to determine its significance and hypothesized that: (1) centrally increased diffusivity is associated with larger infarcts in perinatal arterial ischemic stroke and (2) this tissue is irreversibly injured (infarcted). MATERIALS AND METHODS: We reviewed all perinatal arterial ischemic stroke cases in a prospective cohort study from Aug. 1, 2000, to Jan. 1, 2012. Infarct volumes were measured by drawing regions of interest around the periphery of the area of restricted diffusion on DWI. The Mann-Whitney U test was used to compare means between groups. RESULTS: Of 25 eligible cases, centrally increased diffusivity was seen in 4 (16%). Cases with centrally increased diffusivity had larger average infarct volumes (mean 117,182 mm(3) vs. 36,995 mm(3); P = 0.008), higher average apparent diffusion coefficient (ADC) values in the infarct core (1,679 * 10(-6) mm(2)/s vs. 611 * 10(-6) mm(2)/s, P < 0.0001), and higher ADC ratio (1.2 vs. 0.5, P < 0.0001). At last clinical follow-up, children with perinatal arterial ischemic stroke and centrally increased diffusivity were more often treated for ongoing seizures (75% vs. 0%; P < 0.001) than those without. CONCLUSION: Centrally increased diffusivity was associated with larger stroke volume and the involved tissue was confirmed to be infarcted on follow-up imaging. Radiologists should be aware of this unusual appearance of perinatal arterial ischemic stroke in order to avoid underestimating infarct volume or making an incorrect early diagnosis. PMID- 26238968 TI - Effects of post-extinction l-DOPA administration on the spontaneous recovery and reinstatement of fear in a human fMRI study. AB - Relapse is a pertinent problem in the treatment of anxiety disorders. In the laboratory, relapse is modeled as return of conditioned fear responses after successful fear extinction and is explained by insufficient retrieval and/or expression of the fear-inhibitory extinction memory that is generated during extinction learning. We have shown in mice and humans that return of fear can be prevented by administration of a single dose of the dopamine precursor l-3,4 dihydroxyphenylalanine (l-DOPA) immediately after extinction. In mice, this effect could be attributed to an enhancement of extinction memory consolidation. In our human study, we could not exclude that l-DOPA might have acted by interfering with the consolidation of the original fear memory. In the present study, we therefore used a combined differential cue and context conditioning paradigm where initial fear conditioning and extinction were conducted one day apart, in analogy to previous mouse studies. l-DOPA (N=21) or placebo (N=19) were administered after extinction, precluding any action on fear memory consolidation. In the return-of-fear test conducted one week later, drug effects on conditioned skin conductance responses were absent. However, we found evidence indicative of reduced neural activity, measured with functional magnetic resonance imaging (fMRI), in the l-DOPA group in areas related to conditioned fear and return of fear (amygdala, posterior hippocampus) and enhanced activity in a key area of extinction retrieval/expression (ventromedial prefrontal cortex), relative to placebo controls. These findings require further corroboration in additional experiments. Implications for further investigations on the role of the dopamine system in extinction and on the neuropharmacological augmentation of extinction-based therapies are discussed. PMID- 26238969 TI - Recurrence rates in bipolar disorder: Systematic comparison of long-term prospective, naturalistic studies versus randomized controlled trials. AB - Bipolar disorder (BD) is a recurrent, lifelong illness with high risks of disability and excess mortality. Despite many treatment options with demonstrated short-term efficacy, evidence concerning long-term treatment effectiveness in BD remains limited and the relative value of naturalistic studies versus randomized, controlled trials (RCTs) in its assessment, uncertain. Systematic computer searching yielded 10 naturalistic studies and 15 RCTs suitable for analysis of recurrence rates and their association with treatments and selected clinical factors. In naturalistic studies (3904 BD subjects, 53.3% women, 85.8% BD-I, mean onset age 29.1, followed up to 2.1 years), the pooled recurrence rate was 55.2% (26.3%/year). In RCTs (4828 subjects, 50.9% women, 96.0% BD-I, mean onset age 23.1, followed up to 1.9 years), the pooled recurrence rate was 39.3% (21.9%/year) with mood-stabilizing drug-treatment versus 60.6% (31.3%/year) with placebo; drug-versus-placebo outcomes favored antipsychotics over lithium, and disfavor an approved anticonvulsant. Depressive episode-polarity increased from 27.7% at intake to 52.0% at first-recurrence (p<0.0001). Recurrence rate (%/year) did not differ by study-type, was greater with younger onset and rapid-cycling, and paradoxically declined with longer observation. In short, recurrences of major affective episodes up to two years during putative mood-stabilizing treatment of BD patients in prospective, naturalistic studies and RCTs were substantial and similar (26.3 vs. 21.9%/year). Episode-polarity shifted strongly toward depressive first-recurrences. These findings support the value of naturalistic studies to complement long-term RCTs, and add to indications that control of depression in BD remains particularly unsatisfactory. PMID- 26238970 TI - Maximal rectification ratios for idealized bi-segment thermal rectifiers. AB - Thermal rectifiers whose forward heat fluxes are greater than reverse counterparts have been extensively studied. Here we have discovered, idealized, and derived the ultimate limit of such rectification ratios, which are partially validated by numerical simulations, experiments, and micro-scale Hamiltonian oscillator analyses. For rectifiers whose thermal conductivities (kappa) are linear with the temperature, this limit is simply a numerical value of 3. For those whose conductivities are nonlinear with temperatures, the maxima equal kappamax/kappamin, where two extremes denote values of the solid segment materials that can be possibly found or fabricated within a reasonable temperature range. Recommendations for manufacturing high-ratio rectifiers are also given with examples. Under idealized assumptions, these proposed rectification limits cannot be defied by any bi-segment thermal rectifiers. PMID- 26238972 TI - Practice type effects on head impact in collegiate football. AB - OBJECT IVE: This study directly compares the number and severity of subconcussive head impacts sustained during helmet-only practices, shell practices, full-pad practices, and competitive games in a National Collegiate Athletic Association (NCAA) Division I-A football team. The goal of the study was to determine whether subconcussive head impact in collegiate athletes varies with practice type, which is currently unregulated by the NCAA. METHODS: Over an entire season, a cohort of 20 collegiate football players wore impact-sensing mastoid patches that measured the linear and rotational acceleration of all head impacts during a total of 890 athletic exposures. Data were analyzed to compare the number of head impacts, head impact burden, and average impact severity during helmet-only, shell, and full-pad practices, and games. RESULTS: Helmet-only, shell, and full-pad practices and games all significantly differed from each other (p <= 0.05) in the mean number of impacts for each event, with the number of impacts being greatest for games, then full-pad practices, then shell practices, and then helmet-only practices. The cumulative distributions for both linear and rotational acceleration differed between all event types (p < 0.01), with the acceleration distribution being similarly greatest for games, then full-pad practices, then shell practices, and then helmet-only practices. For both linear and rotational acceleration, helmet-only practices had a lower average impact severity when compared with other event types (p < 0.001). However, the average impact severity did not differ between any comparisons of shell and full-pad practices, and games. CONCLUSIONS: Helmet-only, shell, and full-pad practices, and games result in distinct head impact profiles per event, with each succeeding event type receiving more impacts than the one before. Both the number of head impacts and cumulative impact burden during practice are categorically less than in games. In practice events, the number and cumulative burden of head impacts per event increases with the amount of equipment worn. The average severity of individual impacts is relatively consistent across event types, with the exception of helmet only practices. The number of hits experienced during each event type is the main driver of event type differences in impact burden per athletic exposure, rather than the average severity of impacts that occur during the event. These findings suggest that regulation of practice equipment could be a fair and effective way to substantially reduce subconcussive head impact in thousands of collegiate football players. PMID- 26238973 TI - A novel gene THSD7A is associated with obesity. AB - Body mass index (BMI) is a non-invasive measurement of obesity. It is commonly used for assessing adiposity and obesity-related risk prediction. Genetic differences between ethnic groups are important factors, which contribute to the variation in phenotypic effects. India inhabited by the first out-of-Africa human population and the contemporary Indian populations are admixture of two ancestral populations; ancestral north Indians (ANI) and ancestral south Indians (ASI). Although ANI are related to Europeans, ASI are not related to any group outside Indian-subcontinent. Hence, we expect novel genetic loci associated with BMI. In association analysis, we found eight genic SNPs in extreme of distribution (P?3.75 * 10(-5)), of which WWOX has already been reported to be associated with obesity-related traits hence excluded from further study. Interestingly, we observed rs1526538, an intronic SNP of THSD7A; a novel gene significantly associated with obesity (P=2.88 * 10(-5), 8.922 * 10(-6) and 2.504 * 10(-9) in discovery, replication and combined stages, respectively). THSD7A is neural N glycoprotein, which promotes angiogenesis and it is well known that angiogenesis modulates obesity, adipose metabolism and insulin sensitivity, hence our result find a correlation. This information can be used for drug target, early diagnosis of obesity and treatment. PMID- 26238975 TI - Aerogel Poly(butylene succinate) Biomaterial Substrate for RF and Microwave Applications. AB - Polybutylene succinate (PBS) has become a potential candidate, similar to polypropylene (PP) and acrylonitrile butadiene styrene (ABS), for use as an organic plastic material due to its outstanding mechanical properties as well as high thermal deformation characteristics. A new composition of silica aerogel nanoparticles extracted from rice waste with PBS is proposed for use as a dielectric (epsilonr = 4.5) substrate for microwave applications. A microstrip patch antenna was fabricated on the proposed dielectric substrate for multi resonant ultra-wideband (UWB) applications. The performance characteristics of the proposed biomaterial-based antenna were investigated in a far-field measurement environment. The results indicate that the proposed biocompatible material-based antenna covered a bandwidth of 9.4 (2.3-11.7) GHz with stop bands from 5.5 GHz to 5.8 GHz and 7.0 GHz to 8.3 GHz. Peak gains of 9.82 dBi, 7.59 dBi, 8.0 dBi and 7.68 dBi were measured at resonant frequencies of 2.7 GHz, 4.6 GHz, 6.3 GHz and 9.5 GHz, respectively. PMID- 26238976 TI - Virtual Reality in Health System: Beyond Entertainment. A Mini-Review on the Efficacy of VR During Cancer Treatment. AB - Virtual reality (VR), a computer-generated virtual environment, has been increasingly used in the entertainment world becoming a very new evolving field, but VR technology has also found a variety of applications in the biomedical field. VR can offer to subjects a safe environment within which to carry on different interventions ranging from the rehabilitation of discharged patients directly at home, to the support of hospitalized patients during different procedures and also of oncological inpatient subjects. VR appears as a promising tool for support and monitoring treatments in cancer patients influencing psychological and physiological functions. The aim of this systematic review is to provide an overview of all the studies that used VR intervention on cancer patients and analyze their main findings. Nineteen studies across nearly a thousand articles were identified that explored effects of VR interventions on cancer patients. Although these studies varied greatly in setting and design, this review identified some overarching themes. Results found that VR improved patients' emotional well-being, and diminished cancer-related psychological symptoms. The studies explored various relevant variables including different types of settings (i.e., during chemotherapy, during pain procedures, during hospitalization). Here, we point to the need of a global and multi-disciplinary approach aimed at analyzing the effects of VR taking advantage of the new technology systems like biosensors as well as electroencephalogram monitoring pre, during, and after intervention. Devoting more attention to bio-physiological variables, standardized procedures, extending duration to longitudinal studies and adjusting for motion sickness related to VR treatment need to become standard of this research field. PMID- 26238974 TI - Effects of Achieving Target Measures in Rheumatoid Arthritis on Functional Status, Quality of Life, and Resource Utilization: Analysis of Clinical Practice Data. AB - OBJECTIVE: To evaluate associations between achieving guideline-recommended targets of disease activity, defined by the Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) <2.6, the Simplified Disease Activity Index (SDAI) <=3.3, or the Clinical Disease Activity Index (CDAI) <=2.8, and other health outcomes in a longitudinal observational study. METHODS: Other defined thresholds included low disease activity (LDA), moderate (MDA), or severe disease activity (SDA). To control for intraclass correlation and estimate effects of independent variables on outcomes of the modified Health Assessment Questionnaire (M-HAQ), the EuroQol 5-domain (EQ-5D; a quality-of-life measure), hospitalization, and durable medical equipment (DME) use, we employed mixed models for continuous outcomes and generalized estimating equations for binary outcomes. RESULTS: Among 1,297 subjects, achievement (versus nonachievement) of recommended disease targets was associated with enhanced physical functioning and lower health resource utilization. After controlling for baseline covariates, achievement of disease targets (versus LDA) was associated with significantly enhanced physical functioning based on SDAI <=3.3 (DeltaM-HAQ -0.047; P = 0.0100) and CDAI <=2.8 (-0.073; P = 0.0003) but not DAS28-CRP <2.6 (-0.022; P = 0.1735). Target attainment was associated with significantly improved EQ-5D (0.022-0.096; P < 0.0030 versus LDA, MDA, or SDA). Patients achieving guideline-recommended disease targets were 36-45% less likely to be hospitalized (P < 0.0500) and 23 45% less likely to utilize DME (P < 0.0100). CONCLUSION: Attaining recommended target disease-activity measures was associated with enhanced physical functioning and health-related quality of life. Some health outcomes were similar in subjects attaining guideline targets versus LDA. Achieving LDA is a worthy clinical objective in some patients. PMID- 26238977 TI - Does unemployment affect child abuse rates? Evidence from New York State. AB - This article used child maltreatment reports from New York State from 2000 to 2010 to investigate the relationship between county level unemployment and county level child maltreatment rates. Models showed that a 1 percentage point increase in unemployment rates reduced the child report rate by approximately 4.25%. Report rates for young children (children under the age of 6) and older children (children ages 6 and over) responded similarly to changes in local unemployment, but the relationship between unemployment rates and child maltreatment reports did vary by a county's metropolitan designation. The negative relationship between unemployment and child maltreatment reports was largely contained to metropolitan counties. The relationship between unemployment and child maltreatment reports in non-metropolitan counties was often positive but not statistically significant. These findings were robust to a number of specifications. In alternate models, the county's mandated reporter employment rate was added as a control; the inclusion of this variable did not alter the results. PMID- 26238979 TI - Subjective analysis of exercise-induced changes in back dimensions of the horse: The influence of saddle-fit, rider skill and work quality. AB - Recommendations concerning saddle-fit are empirical rather than based on scientific information. A saddle needs to fit the horse in motion, but there has been no investigation of whether the thoracolumbar region changes in dimensions in association with exercise. The objectives of this study were to quantify exercise-induced back dimension changes and to describe the association with work quality, saddle-fit and rider skill. Sixty-three sports horses in regular work were assessed prospectively in a non-random, cross-sectional survey. Thoracolumbar dimensions/symmetries were measured at predetermined sites before and immediately after a 30 min exercise period; widths for two levels at each site were measured and the shape-ratio calculated. The work quality and rider skill were graded and the presence of lameness and saddle-fit were recorded. Descriptive statistics, univariable and multivariable mixed-effect linear regression were performed to assess the relationship between horse-saddle-rider factors and changes in back dimensions. The mean back width after ridden exercise was greater compared with before exercise. Mean changes were greater in horses working correctly vs. those not working correctly, in those with correctly fitting vs. ill-fitting saddles, and in horses ridden by good > moderately > poorly skilled riders. Back-width changes were significantly associated with saddle-fit. The back dimensions of horses working correctly change transiently with work. If a saddle does not fit properly before exercise, this increase in size does not occur. Saddle-fit should be assessed both before and after exercise to ensure correct fit. PMID- 26238978 TI - Oncologic and clinical outcomes in pelvic primary bone sarcomas treated with limb salvage surgery. AB - PURPOSE: We propose to study a group of patients with primary bone sarcoma of the pelvis treated with limb salvage surgery and analyze overall survival, local recurrence rates and functional outcomes. METHODS: A retrospective review was performed, and all patients diagnosed with pelvic primary bone sarcomas between 1990 and 2012 were analyzed. Patients treated with limb salvage surgery and with a minimum of 12-month follow-up for patients alive were included. The overall survival and the local recurrence rate were calculated for the assessment of oncological results. The associations with gender, age, histological grade, type of surgery, margins chemotherapy response and use of navigation were examined. RESULTS: Fifty-two patients were included in the study. The mean age was 37 years (range 10-82), and mean follow-up was 44 months (range 8-189). Forty-five (86 %) tumors were histologically classified as high-grade sarcomas, four (8 %) as low grade sarcomas and three (6 %) as dedifferentiated sarcomas. Cancer-specific overall survival was 37.5 % for 5 years and 31 % for 10 years. Local recurrence rate was 30 %. High-grade tumors and chemotherapy necrosis below 90 % were negative prognosis factor. Postoperative complication rate was 34.5 % (n:18), being deep infection the most prevalent (n:13). Reconstruction of the pelvis after an oncology resection for primary pelvic sarcomas increased the incidence of complication significantly (p < 0.001). CONCLUSION: Primary bone sarcomas involving the pelvis are suggestive of a high-grade tumor and present poor oncologic outcomes. Pelvic reconstruction after a limb salvage surgery is associated with a high risk of complication. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 26238980 TI - Discovery of a series of novel compounds with moderate anti-hepatitis C virus NS3 protease activity in vitro. AB - The hepatitis C virus (HCV) NS3/4A protease that plays an important role in the viral life cycle has been proven to be an excellent target for the discovery of anti-HCV drugs. Enlightened by some P2-triazole and amide compounds, which had been found as HCV NS3 protease inhibitors, we designed and synthesized a series of novel compounds by incorporating different amino acid residues in P1/P1' and P3/P3' position to develop novel antiviral agents. The result of enzyme inhibition assay indicated that all the designed compounds showed moderate anti HCV NS3 protease activity. On the basis of the biological result, a detailed structure-activity relationship (SAR) was derived and discussed. PMID- 26238981 TI - Role of targeted therapy in combination with surgery in renal cell carcinoma. AB - Surgical complete resection is the only curative treatment of renal cell carcinoma including patients with locally advanced disease and those with limited metastatic disease. Patients at high risk of recurrence after complete resection might theoretically benefit from adjuvant and neoadjuvant systemic treatment strategies to prolong disease-free survival and ultimately overall survival. Another rationale for using targeted therapy includes downsizing/downstaging of surgically complex locally advanced renal cell carcinoma to facilitate complete resection or primary tumors to allow for nephron-sparing strategies. Unfortunately, a considerable percentage of patients are diagnosed with metastatic disease at first presentation. Although large population-based studies consistently show a survival benefit after cytoreductive nephrectomy in the targeted therapy era, confounding factors preclude definite conclusions for this heterogeneous patient group until ongoing phase III trials are published. Presurgical targeted therapy has been proposed to identify patients with clinical benefit and potentially long-term survival after cytoreductive nephrectomy. Recently, the use of targeted therapy before or after local treatment of metastases has been reported in small retrospective series. The present review revisits the current evidence base of targeted therapy in combination with surgery for the various disease stages in renal cell carcinoma. PMID- 26238982 TI - Detection of parasite-specific IgG and IgA in paired serum and saliva samples for diagnosis of human strongyloidiasis in northern Parana state, Brazil. AB - Human strongyloidiasis is an infection caused by the helminth Strongyloides stercoralis that can be fatal, especially in immunosuppressed patients. The aim of this study is to evaluate parasite-specific IgG and IgA levels using S. venezuelensis third-stage (L3) infective larvae alkaline extract as a heterologous antigen by ELISA in paired serum and saliva samples with improved sensitivity and specificity. Individuals from northern Parana state, Brazil were divided into three groups: 30 patients copropositive for S. stercoralis (Group I); 30 clinically healthy individuals (Group II); and 30 patients copropositive for other parasites (Group III). The area under ROC curve (AUC), an overall index of diagnostic accuracy, and Kappa index were calculated. Data were analyzed using analysis of variance (ANOVA) followed by a Kruskal-Wallis test. Probability (p) values of <0.05 were regarded as significant. In Group I, IgG was detected in 96.7% serum and in 6.7% saliva samples. IgG was not detected in Group II. In Group III, cross-reactivity was observed for serum IgG in 26.7% and in 6.7% for saliva samples. In Group I, IgA was detected in 76.7% serum and 56.7% saliva samples. In Group II, 3.3% were positive for IgA in serum, whereas IgA was not detected in any saliva samples. Group III showed 6.7% serum and 26.7% saliva positive samples. The sensitivity values for detection of IgG and IgA in serum samples were 96.7% and 76.7%, respectively. In saliva samples, the sensitivity values for detection of IgG and IgA were 6.7% and 56.7%, respectively. The specificity value was 100% for the detection of IgG in serum and for detection of IgG and IgA in saliva, and 96.7% for detection of IgA in serum samples. The proper choice of immunological diagnosis to supplement parasitological methods is essential to estimate the true prevalence of the parasite, and will permit analysis of population immune response profiles, particularly in northern Parana state, where there are no previous reports. PMID- 26238983 TI - Tauroursodeoxycholic acid suppresses endoplasmic reticulum stress in the chondrocytes of patients with osteoarthritis. AB - The main pathogenic events in osteoarthritis (OA) include loss and abnormal remodeling of cartilage extracellular matrix. The present study aimed to evaluate the protective effect of tauroursodeoxycholic acid on chondrocyte apoptosis induced by endoplasmic reticulum (ER) stress. Articular cartilage tissues were collected from 18 patients who underwent total knee arthroplasty and were analyzed histologically. Subsequently, chondrocyte apoptosis was assessed by TUNEL. Quantitative polymerase chain reaction and western blot analysis were employed to evaluate gene and protein expression, respectively, of ER stress markers, including glucose-regulated protein 78 (GRP78), growth arrest and DNA damage-inducible gene 153 (GADD153) and caspase-12 along with type II collagen. Chondrocytes obtained from osteoarthritis patients at different stages were cultured in three conditions including: No treatment (CON group), tunicamycin treatment to induce ER stress (ERS group) and tauroursodeoxycholic acid treatment after 4 h of tunicamycin (TDA group); and cell proliferation, apoptosis, function and ER stress level were assessed. Degradation of cartilage resulted in histological damage with more apoptotic cartilage cells observed. Of note, GRP78, GADD153 and caspase-12 mRNA and protein expression increased gradually from grade I to III cartilage tissue, while type II collagen expression decreased. Tunicamycin induced ER stress, as shown by a high expression of ER stress markers, reduced cell proliferation, increased apoptosis and decreased synthesis of type II collagen. Notably, tauroursodeoxycholic acid treatment resulted in the improvement of tunicamycin-induced ER stress. These results indicated that ER stress is highly involved in the tunicamycin-induced apoptosis in chondrocytes, which can be prevented by tauroursodeoxycholic acid. PMID- 26238984 TI - Stiff-person syndrome with central sleep apnea after thymoma excision: report of the first known case. PMID- 26238985 TI - The role of mammalian sirtuins in cancer metabolism. AB - Metabolic reprogramming has recently emerged as a key feature of cancer cells, which need to rewire their cellular metabolism in order to sustain their faster proliferation and growth. New insight into the molecular mechanisms governing this metabolic reprogramming has implicated mammalian sirtuins as important regulators of cancer metabolism. Sirtuins are NAD(+)-dependent protein deacylases involved in a variety of biological functions, including life span and health span regulation, genomic stability, tumorigenesis, inflammation, and metabolism. Due to the requirement of NAD(+) for their function, sirtuins can act as sensors of the metabolic state of the cell and regulate core metabolic pathways in response to cellular stresses, thus being good candidates to control the reprogramming of cellular metabolism that occurs during tumorigenesis. Here, we summarize our current knowledge of the roles of mammalian sirtuins in cancer metabolism, and discuss their implication in controlling this metabolic shift during aging and aging-associated cancers. PMID- 26238986 TI - Primary cutaneous adenoid cystic carcinoma with brain metastases: case report and literature review. AB - Primary cutaneous adenoid cystic carcinoma (ACC) is a rare skin tumor that is unlikely to metastasize. We present a case of primary cutaneous ACC in a 67-year old male with axillary lymph node, pulmonary and brain metastases. To the best of our knowledge, this is the first reported case of cutaneous ACC with distant metastases to the brain. PMID- 26238987 TI - Molecular cytogenetic characterization of novel wheat-Thinopyrum bessarabicum recombinant lines carrying intercalary translocations. AB - Thinopyrum bessarabicum (2n = 2x = 14, JJ or E(b)E(b)) is a valuable source of genes for bread wheat (2n = 6x = 42) improvement because of its salinity tolerance and disease resistance. Development of wheat-Th. bessarabicum translocation lines by backcrossing the amphiploid in the absence of the Ph1 gene (allowing intergenomic recombination) can assist its utilization in wheat improvement. In this study, six novel wheat-Th. bessarabicum translocation lines involving different chromosome segments (T4BS.4BL-4JL, T6BS.6BL-6JL, T5AS.5AL 5JL, T5DL.5DS-5JS, T2BS.2BL-2JL, and the whole arm translocation T1JS.1AL) were identified and characterized using genomic in situ hybridization (GISH) and fluorescent in situ hybridization (FISH). No background translocations between wheat genomes were observed. The involvement of five of the seven chromosomes and small terminal segments of Th. bessarabicum chromosome arm were important, contributing to both reduced linkage drag of the derived lines by minimizing agronomically deleterious genes from the alien species and high stability including transmission of the alien segment. All three wheat genomes were involved in the translocations with the alien chromosome, and GISH showed the Th. bessarabicum genome was more closely related to the D genome in wheat. All the introgression lines were disomic, stable, and with good morphological characters. PMID- 26238988 TI - Editorial: Off-label Treatments for Mental Health: Inappropriate or Unavoidable? A Special Issue to Help Get Through the Maze. PMID- 26238989 TI - What is in a name? Causative explanatory models of postpartum psychosis among patients and caregivers in India. AB - BACKGROUND: Explanatory models (EMs) influence decision-making related to treatment and compliance. There is little knowledge about belief systems related to postpartum psychosis in different cultures. AIMS: To study EMs of illness among women with postpartum psychosis and their family members in India. METHOD: A total of 123 women with postpartum psychosis and their caregivers were assessed to understand their beliefs regarding causes of postpartum psychosis using Short Explanatory Model Interview (SEMI). Local names were listed and emerging themes were analysed. RESULTS: Respondents often held more than one EM and only one third held a biomedical EM. Other common models included stressors unique to childbirth, marital stress and supernatural causes. Local names reflected the underlying models. CONCLUSION: Non-biomedical EMs are common in women with postpartum psychosis. Cultural and social factors unique to childbirth appear to influence these models. There is a need to enhance awareness and knowledge about this serious disorder in the community. PMID- 26238990 TI - How do young people in Cambodia perceive the impact of societal attitudes, media and religion on suicidal behaviour? AB - BACKGROUND: Young people in low and middle income countries (LMICs) in societal transitions with rapidly changing norms face an increased risk of suicide. This study explores how young people in Cambodia understand the impact on suicidal behaviour from societal attitudes, media and religion. MATERIAL: Focus group discussions were held with school students from a suburban area. Thematic analysis was used to interpret the data. DISCUSSION: Participants perceived the prevailing suicide-stigmatizing societal attitudes, the double-edged media and suicide-ambiguity in Buddhist religion as challenging. Globalization was recognized as contradicting with traditional Cambodian norms and values. CONCLUSION: Suicide prevention programmes should take into consideration the complex picture of suicide that young people are exposed to. PMID- 26238991 TI - Lentiviral-mediated growth-associated protein-43 modification of bone marrow mesenchymal stem cells improves traumatic optic neuropathy in rats. AB - The aim of the present study was to examine the effect of growth-associated protein-43 (GAP-43) on bone marrow mesenchymal stem cell (BMSC) differentiation in a rat model of traumatic optic neuropathy (TON). GAP-43 and short hairpin (sh)RNA-GAP-43 were inserted into pGLV5 and pGLV3 lentiviral vectors, respectively. The stable control, GAP-43-overexpression and GAP-43-knockdown cell lines (GFP/BMSCs, GAP-43/BMSCs and shGAP-43/BMSCs, respectively) were established. The expression of GAP-43, neuron-specific enolase (NSE), nestin, neurofilament (NF), neuron-specific nuclear-binding protein (NeuN) and betaIII tubulin were detected in the GAP-43/BMSCs and shGAP-43/BMSCs with retinal cell conditioned differentiation medium using semi-quantitative polymerase chain reaction (PCR), western blotting and cell immunofluorescence. In addition, the BMSCs were observed under fluorescence microscopy. The Sprague-Dawley rat models of TON were established and identified by retrograde labeling of retinal ganglion cells (RGCs) with fluoroGold (FG). The lentiviral-mediated GAP-43-modified BMSCs were then transplanted into the rat model of TON. The expression of GAP-43 was detected in the retinal tissues using qPCR and western blotting. The histopathology of the retinal tissues was observed using hematoxylin and eosin (H&E) staining. The GAP-43/BMSCs exhibited positive expression of NSE, NF, nestin and betaIII-tubulin, and exhibited a neuronal phenotype. The shGAP-43/BMSCs markedly inhibited expression of NeuN, NSE, NF, nestin and betaIII-tubulin induced by retinal cell-conditioned differentiation medium. The FG staining revealed that the number of labeled RGCs were significantly decreased in the TON model rats, compared with normal rats (P<0.05). The H&E staining revealed that the degree of pathological changes was improved in the GAP-43/BMSC group, compared with the GFP/BMSC and shGAP-43/BMSC groups. In conclusion, GAP-43 promoted BMSC differentiation into neuron-like cells, and intravitreally injected GAP-43/BMSCs promoted the process of nerve repair in a rat model of TON. PMID- 26238993 TI - Health screening of free-ranging European brown hares (Lepus europaeus) on the German North-Sea island Pellworm. AB - BACKGROUND: A sudden decline of the European brown hare (Lepus europaeus) population in one of the best hunting districts for small game species in northern Germany, the German North-Sea island Pellworm, in the years 2007/08 following marked habitat changes led to the implementation of a thorough health assessment program of the population. 110 animals were collected during the normal hunting season in the years 2010 and 2011. A post-mortem examination and histopathological investigation was performed on all animals. Additionally, routine bacteriology of the small intestine and parasitology were carried out. Sera of hares were tested for European Brown Hare Syndrome (EBHS) by enzyme linked immunosorbent assay, and for Treponema sp. by indirect immunofluorescent test. Additional testing was performed when deemed necessary. RESULTS: The most striking result was a shift in the intestinal bacterial flora towards Gram negative Enterobacteriaceae with a predominance of either Escherichia coli, or Aeromonas sp., or a high-grade double-infection with these two pathogens with subsequent catarrhal enteritis. Additionally, a marked coccidiosis, and varying infestations with the nematode Trichostrongylus retortaeformis were found. The sero-prevalence for EBHS was 78.1%, and for Treponema 43.9%. CONCLUSIONS: The shift and decrease in diversity of the intestinal flora was the main and most consistent result found. In the authors' opinion the change of the habitat combined with other stressors increased the animals' sensitivity to ubiquitous bacterial species and parasites which usually would not have such fatal effects. PMID- 26238992 TI - Decreased long noncoding RNA SPRY4-IT1 contributing to gastric cancer cell metastasis partly via affecting epithelial-mesenchymal transition. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) are emerging as key regulators governing fundamental biological processes, and their disorder expression involves in tumorigenesis. SPRY4-IT1 (SPRY4 intronic transcript 1), a lncRNA derived from an intron within SPRY4 gene, involves in multiple cancers development. However, the expression pattern and biological function of SPRY4-IT1 in gastric cancer is still not well documented. Hence, we carried out the present study to investigate the potential role of SPRY4-IT1 in gastric carcinogenesis. METHODS: QRT-PCR was performed to detect the expression of SPRY4-IT1 in 61 pairs of gastric cancer samples. Over-expression and RNA interference (RNAi) approaches were used to investigate the biological functions of SPRY4-IT1. The effect of SPRY4-IT1 on proliferation was evaluated by MTT and colony formation assays. Gastric cancer cells transfected with pCDNA-SPRY4-IT1 were injected into nude mice to study the effect of SPRY4-IT1 on tumorigenesis and metastasis in vivo. Protein levels of SPRY4-IT1 targets were determined by western blot or fluorescence immunohistochemistry. ChIP assays were performed to investigate the effect of DNMT1 on SPRY4-IT1 expression. Differences between groups were tested for significance using Student's t test (two-tailed). RESULTS: SPRY4-IT1 expression is decreased in gastric cancer tissues and associated with larger tumor size, advanced pathological stage, deeper depth of invasion and lymphatic metastasis. Patients with lower SPRY4-IT1 expression had a relatively poor prognosis. DNA methylation may be a key factor in controlling the SPRY4-IT1 expression. Furthermore, SPRY4-IT1 contributed to gastric cancer cells metastasis might partly via regulating epithelial-mesenchymal transition (EMT) process. CONCLUSION: Low expression of SPRY4-IT1 is involved in progression and metastasis of gastric cancer and may represent a novel biomarker of poor prognosis in patients with gastric cancer. PMID- 26238994 TI - Management of serum calcium reductions among patients on hemodialysis following cinacalcet initiation. AB - PURPOSE: Cinacalcet is indicated for treatment of secondary hyperparathyroidism in patients receiving hemodialysis. Cinacalcet reduces serum calcium concentrations by decreasing parathyroid hormone secretion, but the frequency and degree of calcium reduction following cinacalcet initiation, subsequent physician response, and ultimate calcium recovery in clinical practice are not well described. METHODS: Patients receiving hemodialysis at a large dialysis organization who enrolled in the organization's prescription benefits service and initiated cinacalcet at serum calcium >=8.4 mg/dL were studied (N = 13 723). Patients were categorized by whether they experienced a reduction in calcium to <8.4 mg/dL and to what level (<7.5, 7.5-7.9, and 8.0-8.3 mg/dL). Baseline characteristics, frequency of subsequent intervention, and calcium recovery were compared. RESULTS: Of those who experienced a reduction in calcium to <8.4 mg/dL (n = 6437 [46.9%]), 6.6% had calcium <7.5 mg/dL and 24.5% had calcium 7.5-7.9 mg/dL, while the majority (68.9%) had a level of 8-8.3 mg/dL. Higher baseline parathyroid hormone and alkaline phosphatase were associated with lower resultant calcium. Among patients with calcium reductions, 45.6-63.5% received one or more directed clinical therapeutic responses, including 15.6-28.4% for whom cinacalcet was discontinued; the majority of patients recovered to calcium >=8.4 mg/dL within 90 days of first detection. Only modest differences in recovery were noted between patients who did and did not receive any therapeutic response and patients who did and did not discontinue cinacalcet. CONCLUSION: Serum calcium reductions following cinacalcet initiation were common; declines <7.5 mg/dL were infrequent. Calcium recovery occurred in the majority of patients, with or without therapeutic intervention. PMID- 26238995 TI - Label-free LC-MS analysis of HER2+ breast cancer cell line response to HER2 inhibitor treatment. AB - BACKGROUND: Human epidermal growth-factor receptor (HER)-2 is overexpressed in 25 % of breast-cancers and is associated with an aggressive form of the disease with significantly shortened disease free and overall survival. In recent years, the use of HER2-targeted therapies, monoclonal-antibodies and small molecule tyrosine kinase inhibitors has significantly improved the clinical outcome for HER2 positive breast-cancer patients. However, only a fraction of HER2-amplified patients will respond to therapy and the use of these treatments is often limited by tumour drug insensitivity or resistance and drug toxicities. Currently there is no way to identify likely responders or rational combinations with the potential to improve HER2-focussed treatment outcome. METHODS: In order to further understand the molecular mechanisms of treatment-response with HER2 inhibitors, we used a highly-optimised and reproducible quantitative label-free LC-MS strategy to characterize the proteomes of HER2-overexpressing breast-cancer cell-lines (SKBR3, BT474 and HCC1954) in response to drug-treatment with HER2 inhibitors (lapatinib, neratinib or afatinib). RESULTS: Following 12 ours treatment with different HER2-inhibitors in the BT474 cell-line; compared to the untreated cells, 16 proteins changed significantly in abundance following lapatinib treatment (1 MUM), 21 proteins changed significantly following neratinib treatment (150 nM) and 38 proteins changed significantly following afatinib treatment (150 nM). Whereas following 24 hours treatment with neratinib (200 nM) 46 proteins changed significantly in abundance in the HCC1954 cell-line and 23 proteins in the SKBR3 cell-line compared to the untreated cells. Analysing the data we found that, proteins like trifunctional-enzyme subunit-alpha, mitochondrial; heterogeneous nuclear ribonucleoprotein-R and lamina-associated polypeptide 2, isoform alpha were up-regulated whereas heat shock cognate 71 kDa protein was down-regulated in 3 or more comparisons. CONCLUSION: This proteomic study highlights several proteins that are closely associated with early HER2 inhibitor response and will provide a valuable resource for further investigation of ways to improve efficacy of breast-cancer treatment. PMID- 26238996 TI - Cancer care coordinators in stage III colon cancer: a cost-utility analysis. AB - BACKGROUND: There is momentum internationally to improve coordination of complex care pathways. Robust evaluations of such interventions are scarce. This paper evaluates the cost-utility of cancer care coordinators for stage III colon cancer patients, who generally require surgery followed by chemotherapy. METHODS: We compared a hospital-based nurse cancer care coordinator (CCC) with 'business-as usual' (no dedicated coordination service) in stage III colon cancer patients in New Zealand. A discrete event microsimulation model was constructed to estimate quality-adjusted life-years (QALYs) and costs from a health system perspective. We used New Zealand data on colon cancer incidence, survival, and mortality as baseline input parameters for the model. We specified intervention input parameters using available literature and expert estimates. For example, that a CCC would improve the coverage of chemotherapy by 33% (ranging from 9 to 65%), reduce the time to surgery by 20% (3 to 48%), reduce the time to chemotherapy by 20% (3 to 48%), and reduce patient anxiety (reduction in disability weight of 33%, ranging from 0 to 55%). RESULTS: Much of the direct cost of a nurse CCC was balanced by savings in business-as-usual care coordination. Much of the health gain was through increased coverage of chemotherapy with a CCC (especially older patients), and reduced time to chemotherapy. Compared to 'business-as-usual', the cost per QALY of the CCC programme was $NZ 18,900 (~ $US 15,600; 95% UI: $NZ 13,400 to 24,600). By age, the CCC intervention was more cost-effective for colon cancer patients < 65 years ($NZ 9,400 per QALY). By ethnicity, the health gains were larger for Maori, but so too were the costs, meaning the cost-effectiveness was roughly comparable between ethnic groups. CONCLUSIONS: Such a nurse-led CCC intervention in New Zealand has acceptable cost-effectiveness for stage III colon cancer, meaning it probably merits funding. Each CCC programme will differ in its likely health gains and costs, making generalisation from this evaluation to other CCC interventions difficult. However, this evaluation suggests that CCC interventions that increase coverage of, and reduce time to, effective treatments may be cost-effective. PMID- 26238997 TI - Receptor interacting protein 3-induced RGC-5 cell necroptosis following oxygen glucose deprivation. AB - BACKGROUND: Necroptosis is a type of regulated form of cell death that has been implicated in the pathogenesis of various diseases. Receptor-interacting protein 3 (RIP3), a member of the RIP family of proteins, has been reported as an important necroptotic pathway mediator in regulating a variety of human diseases, such as myocardial ischemia, inflammatory bowel disease, and ischemic brain injury. Our previous study showed that RIP3 was expressed in rat retinal ganglion cells (RGCs), where it was significantly upregulated during the early stage of acute high intraocular pressure. Furthermore, RIP3 expression was co-localized with propidium iodide (PI)-positive staining (necrotic cells). These results suggested that RIP3 up-regulation might be involved in the necrosis of injured RGCs. In this study, we aimed to reveal the possible involvement of RIP3 in oxygen glucose deprivation (OGD)-induced retinal ganglion cell-5 (RGC-5) necroptosis. METHODS: RGC-5 cells were cultured in Dulbecco's-modified essential medium and necroptosis was induced by 8 h OGD. PI staining and flow cytometry were performed to detect RGC-5 necrosis. RIP3 expression was detected by western blot and flow cytometry was used to detect the effect of RIP3 on RGC-5 necroptosis following OGD in rip3 knockdown cells. Malondialdehyde (MDA) lipid peroxidation assay was performed to determine the degree of oxidative stress. RESULTS: PI staining showed that necrosis was present in the early stage of OGD induced RGC-5 cell death. The presence of RGC-5 necroptosis after OGD was detected by flow cytometry using necrostatin-1, a necroptosis inhibitor. Western blot demonstrated that RIP3 up-regulation may be involved in RGC-5 necroptosis. Flow cytometry revealed that the number of OGD-induced necrotic RGC-5 cells was reduced after rip3 knockdown. Furthermore, MDA levels in the normal RGC-5 cells were much higher than in the rip3-knockdown cells after OGD. CONCLUSIONS: Our findings suggest that RGC-5 cell necroptosis following OGD is mediated by a RIP3 induced increase in oxidative stress. PMID- 26238998 TI - Development of a markerless gene deletion system for Bacillus subtilis based on the mannose phosphoenolpyruvate-dependent phosphotransferase system. AB - To optimize Bacillus subtilis as a production strain for proteins and low molecular substances by genome engineering, we developed a markerless gene deletion system. We took advantage of a general property of the phosphoenolpyruvate-dependent phosphotransferase system (PTS), in particular the mannose PTS. Mannose is phosphorylated during uptake by its specific transporter (ManP) to mannose 6-phosphate, which is further converted to fructose 6-phosphate by the mannose-6-phosphate isomerase (ManA). When ManA is missing, accumulation of the phosphorylated mannose inhibits cell growth. This system was constructed by deletion of manP and manA in B. subtilis Delta6, a 168 derivative strain with six large deletions of prophages and antibiotic biosynthesis genes. The manP gene was inserted into an Escherichia coli plasmid together with a spectinomycin resistance gene for selection in B. subtilis. To delete a specific region, its up and downstream flanking sites (each of approximately 700 bp) were inserted into the vector. After transformation, integration of the plasmid into the chromosome of B. subtilis by single cross-over was selected by spectinomycin. In the second step, excision of the plasmid was selected by growth on mannose. Finally, excision and concomitant deletion of the target region were verified by colony PCR. In this way, all nine prophages, seven antibiotic biosynthesis gene clusters and two sigma factors for sporulation were deleted and the B. subtilis genome was reduced from 4215 to 3640 kb. Despite these extensive deletions, growth rate and cell morphology remained similar to the B. subtilis 168 parental strain. PMID- 26238999 TI - Agreement between self-reported perinatal outcomes and administrative data in New South Wales, Australia. AB - BACKGROUND: Many epidemiological studies that focus on pregnancy rely on maternal self-report of perinatal outcomes. The aim of this study was to evaluate the agreement between self-reported perinatal outcomes (gestational hypertension with or without proteinuria, gestational diabetes, premature birth and low birth weight) in a longitudinal study and linked to administrative data (medical records). METHODS: Self-reported survey data from the Australian Longitudinal Study on Women's Health was linked with the New South Wales Perinatal Data Collection. Agreement between the two sources was evaluated using percentage agreement and kappa statistics. Analyses were conducted at two levels by: i) the mother and ii) each individual child. RESULTS: Women reliably self-report their perinatal outcomes (>= 87 % agreement). Gestational hypertension with or without proteinuria had the lowest level of agreement. Mothers' reports of perinatal outcomes were more reliable when evaluated by child. Restricting the analysis to complete and consistent reporting further strengthened the reliability of the child-specific data, increasing the agreement from >92 to >95 % for all outcomes. CONCLUSIONS: The present study offers a high degree of confidence in the use of maternal self-reports of the perinatal outcomes gestational hypertension, gestational diabetes, preterm birth and low birth weight in epidemiological research, particularly when reported on a per child basis. Furthermore self report offers a cost-effective and convenient method for gathering detailed maternal perinatal histories. PMID- 26239000 TI - Preoperative Lumbar Drain Use During Acoustic Neuroma Surgery and Effect on CSF Leak Incidence. AB - OBJECTIVE: To determine if preoperative lumbar drain (LD) use reduces the incidence of postoperative cerebrospinal fluid (CSF) leak in patients undergoing acoustic neuroma resection. METHODS: Retrospective review of 282 patients presenting for acoustic neuroma resection between 2005 and 2014. RESULTS: Two hundred and eighty-two patients had a mean tumor size of 19.1 mm +/- 10.2 mm. Twenty-nine (10.3%) patients developed a postoperative CSF leak. Two hundred and twenty patients (78.0%) received a preoperative LD, and 20 (9.1%) developed a CSF leak. Sixty-two (22.0%) patients did not receive a preoperative LD, and 9 (14.5%) developed a CSF leak. No significant difference in CSF leak frequency was observed with use versus no use of a LD (P = .23). Fifteen (5.3%) patients with an LD placed had a complication related to the LD. No significant difference in CSF leak frequency was observed with patient age, neurofibromatosis type-2 diagnosis, tumor size, or sidedness. CONCLUSIONS: Postoperative CSF leaks are among the most common complications of acoustic neuroma microsurgery. No formal guidelines exist for elective placement of a preoperative LD to lower the incidence of CSF leaks. Our reported CSF leak incidence with preoperative LD placement is not significantly lower than without LD use, and there is a complication rate associated with LD use. PMID- 26239001 TI - Environment-contact administration of rotenone: A new rodent model of Parkinson's disease. AB - Epidemiological studies suggest an association between pesticides and the incidence of Parkinson's disease (PD). Individuals are likely to be exposed to numerous natural or synthetic environmental agents by ingestion, inhalation, or skin contact. Here, we describe a novel environment-contact administration of rotenone model, in which male C57BL/6 mice (15 per group per time-point) were placed in one bedding-free, rotenone-applied cage for 2h every day over a period of 2-6 weeks, mimicking the common ways a person may be exposed to pesticides. Our results showed that rotenone exposure had no detrimental effect on body weights of mice during 6 weeks, nor did it cause systemic toxicity (HPLC analysis of rotenone in blood and brain, as well as complex I activity measurements in brain and muscle), but it caused significant impairments in motor function (open field test, pole test, and rotarod test) from 4 weeks that were responsive to apomorphine. Accordingly, rotenone caused significant dopamine depletion from the striatum (HPLC analysis), nigrostriatal degeneration (quantitative tyrosine hydroxylase immunohistochemistry and western blot), and accumulation of alpha synuclein in the substantia nigra and striatum (alpha-synuclein immunohistochemistry) in a time-dependent manner. In addition, rotenone-exposed mice also developed deficits in gastrointestinal and olfactory function (fecal pellet output and buried food pellet test) prior to the motor dysfunction. Furthermore, we observed that alpha-synuclein accumulated in the anterior olfactory nucleus and the enteric nervous system at 2 weeks. In summary, this novel rotenone model was able to reproduce many key aspects of PD progression. Therefore, it provides new insight into how environmental factors could trigger PD and provides a useful tool for studying PD pathogenesis and testing neuroprotective strategies. PMID- 26239003 TI - Cardiovascular Disease Susceptibility and Resistance in Circumpolar Inuit Populations. AB - Cardiovascular disease (CVD) is a major public health issue in indigenous populations in the Arctic. These diseases have emerged concomitantly with profound social changes over the past 60 years. The aim of this study was to summarize the literature on CVD risk among Arctic Inuit. Literature on prevalence, incidence, and time trends for CVD and its risk factors in Arctic Inuit populations was reviewed. Most evidence supports a similar incidence of coronary heart disease and a higher incidence of cerebrovascular disease among Arctic Inuit than seen in western populations. Factors that may increase CVD risk include aging of the population, genetic susceptibility, and a rapid increase in obesity, diabetes, and hypertension in parallel with decreasing physical activity and deterioration of the lipid profile. In contrast, and of great importance, there has been a decrease in smoking and alcohol intake (at least documented in Greenland), and contaminant levels are declining. Although there have been marked socioeconomic and dietary changes, it remains unsolved and to some extent controversial how this may have influenced cardiovascular risk among Arctic Inuit. The increase in life expectancy, in combination with improved prognosis for patients with manifest CVD, will inevitably lead to a large increase in absolute numbers of individuals affected by CVD in Arctic Inuit populations, exacerbated by the rise in most CVD risk factors over the past decades. For preventive purposes and for health care planning, it is crucial to carefully monitor disease incidence and trends in risk factors in these vulnerable Arctic populations. PMID- 26239004 TI - Family History of Sudden Death Should Be a Primary Indication for Implantable Cardioverter Defibrillator in Hypertrophic Cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden death in young patients. A number of noninvasive clinical markers, including family history, have formed the basis for a risk stratification strategy aimed at identifying high-risk patients with HCM. The observation that sudden death can occur in multiple relatives of the same family, and clinical studies in which a family history of HCM-related sudden death emerges as an independent predictor of sudden death, support the principle that family history should be considered a risk factor which, in the appropriate clinical scenario, can form the basis for recommending prophylactic implantable cardioverter defibrillator therapy. PMID- 26239002 TI - Short-term, high-dose administration of corticosterone by injection facilitates trace eyeblink conditioning in young male rats. AB - Glucocorticoids released as part of the physiological response to stress are known to affect cognitive function, presumably via effects on the hippocampus. Trace classical eyeblink conditioning is an associative learning task which depends on the hippocampus and has been used to examine the development of learning processes in young mammals. Previously, we demonstrated deficits in trace eyeblink conditioning associated with postnatal administration of the glucocorticoid corticosterone by creating a sustained elevation with methods such as subcutaneous timed-release pellets and osmotic mini-pumps which were active over several days. In the present study, we examined the effects of an oscillating pattern of corticosterone elevation on subsequent trace eyeblink conditioning. Twice daily corticosterone injections (high, low, or vehicle) were administered over a 3-day period, starting at postnatal day 15. Then, on postnatal day 28, animals underwent trace classical eyeblink conditioning to examine the possible influence of earlier corticosterone elevations on the development of learning and memory. Eyeblink conditioning was affected by corticosterone treatments, but only for males, and only very early in acquisition; Males receiving the high dose of corticosterone exhibited facilitation of learning relative to controls. These data demonstrate that oscillating corticosterone elevations produce opposite effects on this associative learning task than do sustained elevations. PMID- 26239005 TI - Usefulness of Cardiovascular Magnetic Resonance Indices to Rule In or Rule Out Precapillary Pulmonary Hypertension. AB - BACKGROUND: Various cardiovascular magnetic resonance (CMR) imaging indices are used to assess pulmonary hypertension (PH; mean pulmonary artery pressure >= 25 mm Hg). We compared the value of CMR indices to diagnose precapillary PH in treatment-naive patients evaluated for the first time for known or suspected pulmonary vascular disease. METHODS: Right heart catheterization and CMR were performed within 48 hours of each other in 85 consecutive subjects. The tricuspid annular plane systolic excursion, right ventricular (RV) fractional area change (RVFAC), RV ejection fraction, systolic eccentricity index, and RV end-diastolic area over left ventricular end-diastolic area ratio were calculated. The pulmonary artery trunk diameter, main pulmonary artery relative area change, and mean flow velocity were also calculated. RESULTS: There were 20 non-PH subjects (14 women/6 men, 55 +/- 14 years of age, mean pulmonary artery pressure [mPAP] = 20 +/- 4 mm Hg) and 65 precapillary PH subjects (32 women/33 men, 60 +/- 15 years of age; P = not significant; mPAP = 46 +/- 12 mm Hg; 54% with chronic thromboembolic PH). All CMR indices showed essentially the same (good) value to rule in precapillary PH. The RV end-diastolic area over left ventricular end diastolic area ratio and RVFAC, which are relatively easy to measure, had a large area under the receiver operating characteristic curve (0.93, with optimal cut off > 0.96, and 0.92, with optimal cut-off <= 35%, respectively), not significantly different from RV ejection fraction. In addition, RVFAC > 45% was documented in none of 65 PH and in 10 of 20 non-PH; thus, in a population similar to ours, RVFAC measurement could potentially have avoided unnecessary catheterization in 50% of non-PH subjects. CONCLUSIONS: In treatment-naive subjects in whom pulmonary vascular disease is highly suspected, right-sided CMR indices distinguish between PH and non-PH patients. RVFAC might have particular value in excluding precapillary PH. PMID- 26239006 TI - Ethnic Differences in Cardiovascular Disease Risk Factors: A Systematic Review of North American Evidence. AB - BACKGROUND: Canada is often referred to as a 'land of immigrants,' and the high level of immigration has resulted in significant ethnic diversity in Canada. METHODS: We performed a systematic review of the literature published from 2000 onward to summarize the evidence on ethnic differences in cardiovascular disease (CVD) risk factors; by comparing the presence of CVD risk factors of Arab, black, Chinese, Hispanic, indigenous, and Filipino ethnic groups with that of CVD risk factors in the white ethnic group. RESULTS: One hundred ten studies met the inclusion criteria for this review. Evidence consistently reported greater prevalence of hypertension in black individuals, greater prevalence of diabetes, overall and abdominal obesity and smoking in indigenous people, greater prevalence of diabetes in Hispanic individuals, and lower prevalence of overall obesity and smoking in Chinese individuals compared with their white counterparts. Although inconsistent, most evidence also indicated higher diastolic blood pressure in black individuals, higher hypertension prevalence in indigenous people, higher prevalence of obesity and diabetes in black individuals, and lower prevalence of smoking in Filipino and Hispanic individuals compared with white individuals. The evidence on ethnic differences in CVD risk factors in Arab, Chinese, and Filipino individuals compared with white individuals is limited. CONCLUSIONS: We observed significant ethnic differences in CVD risk factors. However, because most studies were of cross-sectional design and many of them explored the ethnic differences in CVD risk factors without adjustment for potential confounders, more robust designs are needed to get a better insight into where the true differences lie, what factors they are attributed to, and whether they persist or change over time. PMID- 26239008 TI - The Relationship Between Trimethylamine-N-Oxide and Prevalent Cardiovascular Disease in a Multiethnic Population Living in Canada. AB - BACKGROUND: Microflora-dependent trimethylamine-N-oxide (TMAO) formation, which results from intake of choline and L-carnitine-rich food, shows promise as a predictor of cardiovascular disease (CVD) risk, but these associations have not been examined in ethnically diverse populations. In a multiethnic population based study of adults in Canada, we assessed the stability of TMAO and L carnitine in stored serum samples and their association with intimal medial thickness, prevalent risk factors, and clinical events. METHODS: In a randomly sampled cross-sectional study of 1286 Canadians, fasting serum samples were collected and stored. In 292 consecutive individuals (99 CVD cases and 193 unmatched control subjects), L-carnitine and TMAO concentrations were assessed using validated analytical approaches. RESULTS: The mean (+/- SD) TMAO level was 1.998 +/- 3.13 MUM and L-carnitine was 42.29 +/- 11.35 MUM. The relative levels of the samples did not appreciably change after 3 freeze-thaw cycles (coefficient of variation, 5.6% and 4.7%, respectively). No significant association between L carnitine levels and prevalent CVD was found, with adjustment for covariates (odds ratio, 1.57; 95% confidence interval, 0.58-4.26; P trend = 0.65), for highest vs lowest quintile group. TMAO levels showed a significant, graded association with prevalent CVD (odds ratio, 3.17; 95% confidence interval, 1.05 9.51; P trend = 0.02). After further adjustment for diabetes status, meat, fish, and cholesterol intake, the association remained significant. No significant association between carotid intimal medial thickness and L-carnitine (P = 0.64) or TMAO (P = 0.18) was found. CONCLUSIONS: Serum TMAO and L-carnitine analysis on stored samples is reliable. Our findings support an association between TMAO with prevalent CVD in a multiethnic population. This finding requires replication in larger studies in which dietary intake and stored serum samples exist. PMID- 26239007 TI - Resilience in Vulnerable Populations With Type 2 Diabetes Mellitus and Hypertension: A Systematic Review and Meta-analysis. AB - BACKGROUND: Patients with chronic conditions and limited access to health care experience stressful challenges resulting from the burden of managing both their conditions and their daily life demands. Resilience provides a mechanism of adapting to stressful experiences. We conducted a systematic review and meta analysis to synthesize the evidence about interventions to enhance resiliency in managing hypertension or type 2 diabetes in vulnerable populations and to assess the efficacy of these interventions on clinical outcomes. METHODS: We searched multiple databases from early inception through February 2015 including randomized controlled trials that enrolled patients with type 2 diabetes or hypertension. All interventions that targeted resilience in vulnerable populations were included. Data were synthesized to describe the characteristics and efficacy of resiliency interventions. We pooled the total effects by calculating standardized mean difference using the random-effects model. RESULTS: The final search yielded 17 studies. All studies were conducted in the United States and generally targeted minority participants. Resiliency interventions used diverse strategies; discussion groups or workshops were the most common approach. CONCLUSIONS: Interventions aimed at enhancing the resiliency of patients from vulnerable groups are diverse. Outcomes were not fully conclusive. There was some evidence that resiliency interventions had a positive effect on hemoglobin A1C levels but not blood pressure. The incorporation of resiliency oriented interventions into the arsenal of preventing and managing chronic conditions appears to be an opportunity that remains to be better investigated and exploited, and there is need to pursue further understanding of the core components of any intervention that claims to enhance resilience. PMID- 26239009 TI - Recent advances in the development of a chemically synthesised anti-malarial vaccine. AB - INTRODUCTION: Obtaining an effective antimalarial vaccine has represented one of the biggest public health challenges over the last 50 years. Despite efforts by many laboratories around the world using whole-organism, recombinant proteins and genome-based approaches, the results have been disappointing. One of the main problems when designing an antimalarial vaccine is the poor immunogenicity induced by the functionally relevant and conserved protein regions of the parasite. AREAS COVERED: This review focuses on the logical and rational methodology followed to identify Plasmodium falciparum conserved functional regions with the ability to bind to target cells conserved high activity binding peptides (cHABPs) and the physicochemical and immunological characteristics that should be taken into account for modifying them into highly immunogenic and protection-inducing peptides (mHABPs) into highly immunogenic and protection inducing in Aotus monkeys. EXPERT OPINION: The functional approach taken to develop a fully protective, minimal subunit-based, multiantigenic, multistage and synthetic peptide-based antimalarial vaccine has shown promising results. The clear relationship observed between mHABPs structure and their immunological properties highlights the challenges and opportunities arising from this methodology, as well as the universal principles and rules derived therefrom. PMID- 26239011 TI - Construction of a Genetic System for Streptomyces albulus PD-1 and Improving Poly(epsilon-L-lysine) Production Through Expression of Vitreoscilla Hemoglobin. AB - Poly(epsilon-L-lysine) (epsilon-PL) is a novel bioactive polymer secreted by filamentous bacteria. Owing to lack of a genetic system for most epsilon-PL producing strains, very little research on enhancing epsilon-PL biosynthesis by genetic manipulation has been reported. In this study, an effective genetic system was established via intergeneric conjugal transfer for Streptomyces albulus PD-1, a famous epsilon-PL-producing strain. Using the established genetic system, the Vitreoscilla hemoglobin (VHb) gene was integrated into the chromosome of S. albulus PD-1 to alleviate oxygen limitation and to enhance the biosynthesis of epsilon-PL in submerged fermentation. Ultimately, the production of epsilon-PL increased from 22.7 g/l to 34.2 g/l after fed-batch culture in a 5 L bioreactor. Determination of the oxygen uptake rate, transcriptional level of epsilon-PL synthetase gene, and ATP level unveiled that the expression of VHb in S. albulus PD-1 enhanced epsilon-PL biosynthesis by improving respiration and ATP supply. To the best of our knowledge, this is the first report on enhancing epsilon-PL production by chromosomal integration of the VHb gene in an epsilon-PL-producing strain, and it will open a new avenue for epsilon-PL production. PMID- 26239010 TI - The Role of Residues 103, 104, and 278 in the Activity of SMG1 Lipase from Malassezia globosa: A Site-Directed Mutagenesis Study. AB - The SMG1 lipase from Malassezia globosa is a newly found mono- and diacylglycerol (DAG) lipase that has a unique lid in the loop conformation that differs from the common alpha-helix lid. In the present study, we characterized the contribution of three residues, L103 and F104 in the lid and F278 in the rim of the binding site groove, on the function of SMG1 lipase. Sitedirected mutagenesis was conducted at these sites, and each of the mutants was expressed in the yeast Pichia pastoris, purified, and characterized for their activity toward DAG and pnitrophenol (pNP) ester. Compared with wild-type SMG1, F278A retained approximately 78% of its activity toward DAG, but only 11% activity toward pNP octanoate (pNP-C8). L103G increased its activity on pNP-C8 by approximately 2 fold, whereas F104G showed an approximate 40% decrease in pNP-C8 activity, and they both showed decreased activity on the DAG emulsion. The deletion of 103-104 retained approximately 30% of its activity toward the DAG emulsion, with an almost complete loss of pNP-C8 activity. The deletion of 103-104 showed a weaker penetration ability to a soybean phosphocholine monolayer than wild-type SMG1. Based on the modulation of the specificity and activity observed, a pNP-C8 binding model for the ester (pNP-C8, N102, and F278 form a flexible bridge) and a specific lipidanchoring mechanism for DAG (L103 and F104 serve as "anchors" to the lipid interface) were proposed. PMID- 26239012 TI - Production of (R)-Ethyl-4-Chloro-3-Hydroxybutanoate Using Saccharomyces cerevisiae YOL151W Reductase Immobilized onto Magnetic Microparticles. AB - For the synthesis of various pharmaceuticals, chiral alcohols are useful intermediates. Among them, (R)-ethyl-4-chloro-3-hydroxybutanoate ((R)-ECHB) is an important building block for the synthesis of L-carnitine. (R)-ECHB is produced from ethyl-4-chloro-3-oxobutanoate (ECOB) by a reductase-mediated, enantioselective reduction reaction. The Saccharomyces cerevisiae YOL151W reductase that is expressed in Escherichia coli cells exhibited an enantioselective reduction reaction toward ECOB. By virtue of the C-terminal His tag, the YOL151W reductase was purified from the cell-free extract using Ni(2+) NTA column chromatography and immobilized onto Ni(2+)-magnetic microparticles. The physical properties of the immobilized reductase (Imm-Red) were measured using electron microscopy, a magnetic property measurement system, and a zeta potential system; the average size of the particles was approximately 1 MUm and the saturated magnetic value was 31.76 emu/g. A neodymium magnet was used to recover the immobilized enzyme within 2 min. The Imm-Red showed an optimum temperature at 45 degrees C and an optimum pH at 6.0. In addition, Bacillus megaterium glucose dehydrogenase (GDH) was produced in the E. coli cells and was used in the coupling reaction to regenerate the NADPH cofactor. The reduction/oxidation coupling reaction composed of the Imm-Red and GDH converted 20 mM ECOB exclusively into (R)- ECHB with an e.e.p value of 98%. PMID- 26239013 TI - Development of a Recombinant Protein Vaccine Based on Cell-Free Protein Synthesis for Sevenband Grouper Epinephelus septemfasciatus Against Viral Nervous Necrosis. AB - Sevenband grouper, Epinephelus septemfasciatus, is becoming an important aquaculture species in Korea. However, viral nervous necrosis disease is a large problem causing mass mortality in sevenband grouper aquaculture. Recombinant protein vaccines are one of the best methods to reduce these economic losses. However, the cell-based expression method mainly produces inclusion bodies and requires additional procedures. In this study, we expressed a recombinant viral coat protein of sevenband grouper nervous necrosis virus (NNV) using a cell-free protein synthesis system. The purified recombinant NNV coat protein (rNNV-CP) was injected into sevenband grouper at different doses followed by a NNV challenge. Nonimmunized fish in the first trial (20 MUg/fish) began to die 5 days post challenge and reached 70% cumulative mortality. In contrast, immunized fish also starting dying 5 days postchallenge but lower cumulative mortality (10%) was observed. Cumulative morality in the second trial with different doses (20, 4, and 0.8 MUg/fish) was 10%, 40%, and 50%, respectively. These results suggest that rNNV-CP can effectively immunize sevenband grouper depending on the dose administered. This study provides a new approach to develop a recombinant vaccine against NNV infection for sevenband grouper. PMID- 26239014 TI - Advances in the management of chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH), a potentially curable form of pulmonary hypertension with pulmonary thromboendarterectomy surgery, has been the focus of significant medical advances. In addition to new imaging modalities that are now used to help recognize and diagnose CTEPH, additional treatment options have emerged for inoperable cases. These include a newly approved medical therapy for inoperable disease or persistent/recurrent CTEPH as well as percutaneous balloon angioplasty of the pulmonary arteries. In this article, we summarize these recent advances in the field and review the related literature. PMID- 26239015 TI - Perkinsosis in the clams Ruditapes decussatus and R. philippinarum in the Northeastern Atlantic and Mediterranean Sea: A review. AB - Perkinsosis is a disease of gastropod and bivalve molluscs caused by protozoan parasites of the Perkinsus genus. These parasites have been responsible for mass mortalities worldwide, with a significant impact in both fisheries and aquaculture, and resulting in severe economic losses. This review focuses mainly on current knowledge of diagnostic methods and on the distribution of Perkinsus spp. in the Northeastern Atlantic and Mediterranean Sea, which infect the grooved carpet shell clam Ruditapes decussatus and the Japanese carpet shell clam Ruditapes philippinarum. The association between perkinsosis and high mortality rates of R. decussatus and R. philippinarum in southern European countries such as Portugal and Italy is discussed as is the role of environmental factors in those mortality outbreaks. The putative introduction of Perkinsus olseni into the Northeastern Atlantic and Mediterranean Sea is also discussed, as are management strategies that could be used to mitigate the impact of perkinsosis in production of R. decussatus and R. philippinarum. PMID- 26239016 TI - Models of marine molluscan diseases: Trends and challenges. AB - Disease effects on host population dynamics and the transmission of pathogens between hosts are two important challenges for understanding how epizootics wax and wane and how disease influences host population dynamics. For the management of marine shellfish resources, marine diseases pose additional challenges in early intervention after the appearance of disease, management of the diseased population to limit a decline in host abundance, and application of measures to restrain that decline once it occurs. Mathematical models provide one approach for quantifying these effects and addressing the competing goals of managing the diseased population versus managing the disease. The majority of models for molluscan diseases fall into three categories distinguished by these competing goals. (1) Models that consider disease effects on the host population tend to focus on pathogen proliferation within the host. Many of the well-known molluscan diseases are pandemic, in that they routinely reach high prevalence rapidly over large geographic expanses, are characterized by transmission that does not depend upon a local source, and exert a significant influence on host population dynamics. Models focused on disease proliferation examine the influence of environmental change on host population metrics and provide a basis to better manage diseased stocks. Such models are readily adapted to questions of fishery management and habitat restoration. (2) Transmission models are designed to understand the mechanisms triggering epizootics, identify factors impeding epizootic development, and evaluate controls on the rate of disease spread over the host's range. Transmission models have been used extensively to study terrestrial diseases, yet little attention has been given to their potential for understanding the epidemiology of marine molluscan diseases. For management of diseases of wild stocks, transmission models open up a range of options, including the application of area management, manipulation of host abundance, and use of scavengers and filter feeders to limit the concentration of infective particles. (3) The details of host population processes and pathogen transmission dynamics are blended in models that evaluate the effects of natural selection and/or genetic modification in developing disease resistance in the host population. Application of gene-based models to marine diseases is only now beginning and represents a promising approach that may provide a mechanistic basis for managing marine diseases and their host populations. Overall disease models remain both uncommon and underutilized in addressing the needs for managing molluscan diseases and their host populations. PMID- 26239017 TI - Effect of extremely low frequency magnetic fields on cell proliferation and gene expression. AB - Owing to concerns regarding possible effects of extremely low frequency magnetic fields (ELF-MF) on human health, many studies have been conducted to elucidate whether ELF-MF can induce modifications in biological processes. Despite this, controversies regarding effects of ELF-MF are still rife. In this study, we investigated biological effects of ELF-MF on MCF10A, MCF7, Jurkat, and NIH3T3 cell lines. ELF-MF with a magnetic flux density of 1 mT at 60 Hz was employed to stimulate cells for 4 or 16 h, after which the effects of ELF-MF on cell proliferation, cell death, cell viability, and DNA synthesis rates were assessed. Whereas Jurkat and NIH3T3 cells showed no consistent variation in cell number, cell viability, and DNA synthesis rate, MCF10A and MCF7 cells showed consistent and significant decreases in cell number, cell viability, and DNA synthesis rates. However, there was no effect of ELF-MF on cell death in any of tested cell lines. Next, to investigate the effect of ELF-MF on gene expression, we exposed MCF7 cells to 2 mT at 60 Hz for 16 h and examined transcriptional responses by using gene expression array. We found a gene, PMAIP1, that exhibited statistically significant variation using two-fold cut-off criteria and certified its expression change by using semi-quantitative and quantitative reverse transcription polymerase chain reaction. From these results, we concluded that ELF-MF could induce the delay of cell cycle progression in MCF7 and MCF10A cells in a cell context-specific manner and could up-regulate PMAIP1 in MCF7 cells. PMID- 26239018 TI - Primary Cerebellar Gliosarcoma with Extracranial Metastases: An Orphan Differential Diagnosis. AB - BACKGROUND: Gliosarcomas are rare, malignant primary brain tumors, most commonly located in the temporal lobe, that contain both glial and mesenchymal elements. Gliosarcomas located within the cerebellum are exceedingly rare. The previously unreported finding of a cerebellar gliosarcoma concurrently with an extracranial metastasis to the lungs is discussed here. CASE DESCRIPTION: A 57-year-old man presented with a 3-month history of chest pain, weight loss, headaches, and vomiting. Physical examination revealed a left cerebellar dysfunction, and the radiological work-up revealed a 6 * 6-cm right apical pulmonary tumor and a 4 * 3.5 * 3.8-cm peripherally enhancing left cerebellar mass. On the basis of a smoking history in the setting of a lung lesion and cerebellar mass, the presumptive diagnosis was primary lung cancer with metastasis to the cerebellum. Gross total resection of a firm pseudo-encapsulated cerebellar mass was performed. The microscopic features and the immunohistochemical profile confirmed the diagnosis of Gliosarcoma. The thoracic lesion was removed subsequently, and pathology confirmed it as an extracranial metastasis from the cerebellar gliosarcoma. Adjuvant radiation and chemotherapy were then administered. No clinical or radiographic evidence of recurrence was observed during one year of follow-up monitoring. CONCLUSIONS: To the best of our knowledge, a primary infratentorial gliosarcoma with extracranial metastases has not been previously described. PMID- 26239019 TI - Twist induces epithelial-mesenchymal transition in cervical carcinogenesis by regulating the TGF-beta/Smad3 signaling pathway. AB - Epithelial-mesenchymal transition (EMT) is associated with the metastasis and poor prognosis of cervical cancer. However, the underlying mechanisms are poorly defined. In the present study, we investigated whether Twist plays a direct role in human cervical cancer using immunohistochemical and western blot analyses. Immunohistochemical analysis revealed that Twist is highly expressed in cervical cancer, which correlates with poor tumor pathological differentiation or lymph node metastasis (P<0.05). Depletion of Twist by stable shRNA-mediated knockdown decreased the migratory ability of cancer cell lines in vitro. Suppression or overexpression of Twist also resulted in an altered expression of the molecular mediators of EMT. Furthermore, exogenous TGF-beta promoted EMT by upregulating the expression of Twist through the TGF-beta/Smad3 pathway, and this effect was eliminated by Twist depletion in cancer cells as demonstrated in the in vitro study. The use of in vivo models revealed a decreased tumor proliferation potential in Twist-depleted cancer cells. The results suggested a novel function for Twist in the promotion of EMT via TGF-beta/Smad3 signaling pathway. Thus, Twist constitutes a potential therapeutic target in human cervical cancer. PMID- 26239020 TI - Cognitive Bias by Gender Interaction on N170 Response to Emotional Facial Expressions in Major and Minor Depression. AB - States of depression are considered to relate to a cognitive bias reactivity to emotional events. Moreover, gender effect may influence differences in emotional processing. The current study is to investigate whether there is an interaction of cognitive bias by gender on emotional processing in minor depression (MiD) and major depression (MaD). N170 component was obtained during a visual emotional oddball paradigm to manipulate the processing of emotional information in 33 MiD, 36 MaD, and 32 controls (CN). Compared with CN, in male, both MiD and MaD had lower N170 amplitudes for happy faces, but MaD had higher N170 amplitudes for sad faces; in female, both MiD and MaD had lower N170 amplitudes for happy and neutral faces, but higher N170 amplitudes for sad faces. Compared with MaD in male, MiD had higher N170 amplitudes for happy faces, lower N170 amplitudes for sad faces; in female, MiD only had higher N170 amplitudes for sad faces. Interestingly, a negative relationship was observed between N170 amplitude and the HDRS score for identification of happy faces in depressed patients while N170 amplitude was positively correlated with the HDRS score for sad faces identification. These results provide novel evidence for the mood-brightening effect with an interaction of cognitive bias by gender on emotional processing. It further suggests that female depression may be more vulnerable than male during emotional face processing with the unconscious negative cognitive bias and depressive syndromes may exist on a spectrum of severity on emotional face processing. PMID- 26239021 TI - Ideal Spintronics in Molecule-Based Novel Organometallic Nanowires. AB - With the purpose of searching for new intriguing nanomaterial for spintronics, a series of novel metalloporphyrin nanowires (M-PPNW, M = Cr, Mn, Fe, Co, Ni, Cu and Zn) and hybrid nanowires fabricated by metalloporphyrin and metal phthalocyanine (M-PCNW) are systematically investigated by means of first principles calculations. Our results indicate that the transition metal atoms (TMs) embedded in the frameworks distribute regularly and separately, without any trend to form clusters, thus leading to the ideally ordered spin distribution. Except for the cases embedded with Ni and Zn, the others are spin-polarized. Remarkably, the Mn-PPNW, Mn-PCNW, MnCu-PPNW, MnCr-PCNW, and MnCu-PCNW frameworks all favor the long-ranged ferromagnetic spin ordering and display half-metallic nature, which are of greatest interest and importance for electronics and spintronics. The predicted Curie temperature for the Mn-PCNW is about 150 K. In addition, it is found that the discrepancy in magnetic coupling for these materials is related to the competition mechanisms of through-bond and through space exchange interactions. In the present work, we propose not only two novel sets of 1D frameworks with appealing magnetic properties, but also a new strategy in obtaining the half-metallic materials by the combination of different neighboring TMs. PMID- 26239022 TI - Introduction: Mental health counseling in third party reproduction. AB - Mental health professionals serve an important role in guiding intended parents through a myriad of considerations from donor or surrogate selection to issues of disclosure with children. This role has evolved due to many considerations including evolving practice and ethics guidelines, as well as other factors such as access to the internet. This Views and Reviews will explore how team care, inclusive of the mental health professional, serves the interests of patients and provides a strong foundation for families created with the help of donors and/or surrogates. PMID- 26239023 TI - Subclinical hypothyroidism in the infertile female population: a guideline. AB - There is controversy regarding whether to treat subtle abnormalities of thyroid dysfunction in the infertile female patient. This guideline document reviews the risks and benefits of treating subclinical hypothyroidism in female patients with a history of infertility and miscarriage, as well as obstetrical and neonatal outcomes in this population. PMID- 26239025 TI - Carbazole Dye-Sensitized Solar Cells Studied from Femtoseconds to Seconds-Effect of Additives in Cobalt- and Iodide-Based Electrolytes. AB - Comprehensive studies of all charge-separation processes in efficient carbazole dye-sensitized solar cells are correlated with their photovoltaic parameters. An important role of partial, fast electron recombination from the semiconductor nanoparticles to the oxidized dye is revealed; this takes place on the picosecond and sub-nanosecond timescales. The charge-transfer dynamics in cobalt tris(bipyridyl) based electrolytes and iodide-based electrolyte is observed to depend on potential-determining additives in a similar way. Upon addition of 0.5 M 4-tert-butylpiridine to both types of electrolytes, the stability of the cells is greatly improved; the cell photovoltage increases by 150-200 mV, the electron injection rate decreases about five times (from 5 to 1 ps(-1) ), and fast recombination slows down about two to three times. Dye regeneration proceeds at a rate of about 1 MUs(-1) in all electrolytes. Electron recombination from titania to cobalt electrolytes is much faster than that to iodide ones. PMID- 26239026 TI - Telogen elongation in the hair cycle of ob/ob mice. AB - Alopecia impairs the physical and mental health of patients. We have previously shown that 8-week-old ob/ob mice have no reactivity to depilation, which is a stimulus that induces anagen transition in normal mice, while no hair cycle abnormalities have been reported in other studies until mice reach 7 weeks of age. Therefore, we hypothesized that ob/ob mice have abnormalities in hair cycle progression beyond 7 weeks of age. We examined 6- to 24-week-old ob/ob and 6- to 10-week-old normal mice. After acclimation, the dorsal skin was harvested and the hair cycle phase was identified histologically and immunohistochemically. Normal mice showed catagen-telogen and telogen-anagen transitions at 6 and 8-9 weeks old, respectively. In contrast, the anagen-catagen transition was observed in 7 week-old mice and the telogen phase was maintained from 10 to 24 weeks in most ob/ob mice. These results suggests that ob/ob mice are a possible model animal for telogen effluvium. PMID- 26239024 TI - Aberrant expression and localization of deoxyribonucleic acid methyltransferase 3B in endometriotic stromal cells. AB - OBJECTIVE: To define the expression and function of DNA methyltransferases (DNMTs) in response to decidualizing stimuli in endometriotic cells compared with healthy endometrial stroma. DESIGN: Basic science. SETTING: University research center. PATIENT(S): Premenopausal women with or without endometriosis. INTERVENTION(S): Primary cultures of stromal cells from healthy endometrium (E IUM) or endometriomas (E-OSIS) were subjected to in vitro decidualization (IVD) using 1 MUM medroxyprogesterone acetate, 35 nM 17beta-estradiol, and 0.05 mM 8-Br cAMP. MAIN OUTCOME MEASURE(S): Expression of DNMT1, DNMT3A, and DNMT3B in E-IUM and E-OSIS were assessed by quantitative real-time polymerase chain reaction and immunoblotting. Recruitment of DNMT3B to the promoters of steroidogenic factor 1 (SF-1) and estrogen receptor alpha (ESR1) was examined by chromatin immunoprecipitation. RESULT(S): IVD treatment reduced DNMT3B messenger RNA (74%) and protein levels (81%) only in E-IUM; DNMT1 and DNMT3A were unchanged in both cell types. Significantly more DNMT3B bound to the SF-1 promoter in E-IUM compared with E-OSIS, and IVD treatment reduced binding in E-IUM to levels similar to those in E-OSIS. Enrichment of DNMT3B across 3 ESR1 promoters was reduced in E-IUM after IVD, although the more-distal promoter showed increased DNMT3B enrichment in E-OSIS after IVD. CONCLUSION(S): The inability to downregulate DNMT3B expression in E-OSIS may contribute to an aberrant epigenetic fingerprint that misdirects gene expression in endometriosis and contributes to its altered response to steroid hormones. PMID- 26239027 TI - Ponicidin suppresses HT29 cell growth via the induction of G1 cell cycle arrest and apoptosis. AB - Ponicidin is a diterpenoid extracted from the Chinese herb Isodon adenolomus, which has been reported as a therapeutic cytotoxic drug that may be used to treat various types of human cancer. The present study aimed to determine the antitumor effects of ponicidin, and to investigate its underlying mechanisms in colorectal cancer. The HT29 colorectal cancer cell line was used to detect the cytotoxicity of various doses of ponicidin. Cell proliferation was measured using a Cell Counting kit-8 assay. Cell cycle and apoptosis analyses were performed using flow cytometry and fluorescent microscopy. Western blot analysis was used to measure the expression levels of apoptosis-associated proteins following treatment with ponicidin. Treatment with ponicidin significantly suppressed HT29 cell growth by inducing G1 cell cycle arrest and apoptosis. The AKT and MEK signaling pathways were also suppressed by ponicidin; however, the p38 signaling pathway was significantly activated. The expression levels of caspase 3 and Bax protein were markedly upregulated following treatment with ponicidin. These results suggest that ponicidin exerts significant antitumor effects via the induction of cell cycle arrest and apoptosis in colorectal cells. In conclusion, ponicidin acted as an inducer of apoptosis, and may be used as a therapeutic cytotoxic drug to treat human cancer, including colorectal cancer. PMID- 26239028 TI - Time reversal and charge conjugation in an embedding quantum simulator. AB - A quantum simulator is an important device that may soon outperform current classical computations. A basic arithmetic operation, the complex conjugate, however, is considered to be impossible to be implemented in such a quantum system due to the linear character of quantum mechanics. Here, we present the experimental quantum simulation of such an unphysical operation beyond the regime of unitary and dissipative evolutions through the embedding of a quantum dynamics in the electronic multilevels of a (171)Yb(+) ion. We perform time reversal and charge conjugation, which are paradigmatic examples of antiunitary symmetry operators, in the evolution of a Majorana equation without the tomographic knowledge of the evolving state. Thus, these operations can be applied regardless of the system size. Our approach offers the possibility to add unphysical operations to the toolbox of quantum simulation, and provides a route to efficiently compute otherwise intractable quantities, such as entanglement monotones. PMID- 26239029 TI - Redox mediators modify end product distribution in biomass fermentations by mixed ruminal microbes in vitro. AB - The fermentation system of mixed ruminal bacteria is capable of generating large amounts of short-chain volatile fatty acids (VFA) via the carboxylate platform in vitro. These VFAs are subject to elongation to larger, more energy-dense products through reverse beta-oxidation, and the resulting products are useful as precursors for liquid fuels production. This study examined the effect of several redox mediators (neutral red, methyl viologen, safranin O, tannic acid) as alternative electron carriers for mixed ruminal bacteria during the fermentation of biomass (ground switchgrass not subjected to other pretreatments) and their potential to enhance elongation of end-products to medium-chain VFAs with no additional run-time. Neutral red (1 mM) in particular facilitated chain elongation, increasing average VFA chain length from 2.42 to 2.97 carbon atoms per molecule, while simultaneously inhibiting methane accumulation by over half yet maintaining total C in end products. The ability of redox dyes to act as alternative electron carriers suggests that ruminal fermentation is inherently manipulable toward retaining a higher fraction of substrate energy in the form of VFA. PMID- 26239030 TI - Bacterial secretion of soluble and functional trivalent scFv-based N-terminal trimerbodies. AB - Recombinant antibodies are used with great success in many different diagnostic and therapeutic applications. A variety of protein expression systems are available, but nowadays almost all therapeutic antibodies are produced in mammalian cell lines due to their complex structure and glycosylation requirements. However, production of clinical-grade antibodies in mammalian cells is very expensive and time-consuming. On the other hand, Escherichia coli (E. coli) is known to be the simplest, fastest and most cost-effective recombinant expression system, which usually achieves higher protein yields than mammalian cells. Indeed, it is one of the most popular host in the industry for the expression of recombinant proteins. In this work, a trivalent single-chain fragment variable (scFv)-based N-terminal trimerbody, specific for native laminin 111, was expressed in human embryonic kidney 293 cells and in E. coli. Mammalian and bacterially produced anti-laminin trimerbody molecules display comparable functional and structural properties, although importantly the yield of trimerbody expressed in E. coli was considerably higher than in human cells. These results demonstrated that E. coli is a versatile and efficient expression system for multivalent trimerbody-based molecules that is suitable for their industrial production. PMID- 26239031 TI - An Assessment and Diagnosis Case Study Is Not a Closed Case. AB - PROBLEM: The presenting problem of anxiety is found to be one of many psychiatric symptoms resulting in a lack of clarity in diagnosis and treatment. METHOD: The case of a 17-year-old reporting escalating anxiety and migraine headaches is presented. A mental health assessment, parental information, screening tools, the Personality Assessment Inventory, ongoing observation, review of treatment regimens, consultation, and test results from other healthcare professionals are included in the ongoing assessment. FINDINGS: Symptoms including anxiety, auditory and tactile hallucinations, mood alterations, substance use, insomnia, and hypomanic symptoms are identified. The symptoms are suggestive of various diagnostic categories/diagnoses: mood disorder, prodromal schizophrenia, schizoaffective disorder, and generalized anxiety disorder. CONCLUSION: A thorough assessment does not necessarily lead to clarity of a diagnosis or diagnoses. Clarity may evolve over time; however, this does not eliminate the responsibility to treat the patient. It is important to consider and utilize evidence-based treatments for the symptomatology and possible diagnoses. PMID- 26239032 TI - Changing trends of total knee replacement utilization over more than a decade. AB - BACKGROUND: Osteoarthritis of the knee causes significant disability amongst the elderly, and total knee replacement remains the only effective intervention for pain relief and functional improvement. Using data from single military healthcare institutional records in India, we estimated the utilization rates of total knee replacement by age, gender and rank profile. METHODS: All the data were retrieved manually from institutional records as the institutional databases are yet to be digitized. The information on the study subjects was retrospectively retrieved from the records of the Department of Orthopaedics from the year 1997 to 2012. Trends were estimated by using two 6-year periods separated by a decade, i.e. 1997-2002 and 2007-2012. We estimated age-, gender- and rank-specific rates of TKR utilization in these years. RESULTS: From 1997 to 2002, 37 TKRs were performed as compared to 800 during 2007-2012, showing a more than 20 times increase. During 1997-2002, the mean age was 62.6 years (SD-9.224) compared to 65.8 years (SD-7.05). There was significant disparity in TKR utilization rates on the basis of rank with officers and their dependent, showing much higher utilization rates in both year groups which is possibly explained by the higher level of awareness about the procedure, higher education levels and higher acceptability of the procedure by the officers as compared to PBORs. The rate of TKR was marginally higher amongst women as compared to men. CONCLUSION: The TKR utilization rates have increased tremendously over a decade. In view of this huge increase, future planning is essential to enable optimal material and human resource allocation as well as training to meet future challenges. PMID- 26239033 TI - Networks of micrornas and genes in acute lymphoblastic leukemia. AB - In the present study, three regulatory networks, including a network of differentially expressed factors, a related network and a global network, were constructed hierarchically in order to analyze the association between genes, micro (mi)RNAs and transcriptional factors (TFs) in a systematical approach, rather than focusing on only one or several miRNAs or TFs. By analyzing and comparing the similarities and differences among these three networks, a number of key pathways were highlighted. In addition, identifying the upstream and the downstream nodes, which were composed of differentially expressed genes and miRNAs in the networks provided assistance in identifying associations between circle-regulations or self-adaptation regulations among these elements. In the present study, the TP53 gene and the TP53 pathway were observed to be important in acute lymphoblastic leukemia (ALL). However, the predicted transcriptional factors, including EFKB1 and E2F1, which were found with self-adaptaion associations and certain abnormally expressed miRNAs in the network of differentially expressed factors, requires further examination in further investigations of the pathogenesis of ALL. The confirmation of these factors may be of significance to ALL. PMID- 26239034 TI - Impact of the thickness of the subcutaneous tissue at the site of injection as measured by ultrasound on the therapeutic response to subcutaneous anti-tumor necrosis factor drugs. PMID- 26239035 TI - Multifunctional Thrombin-Activatable Polymer Capsules for Specific Targeting to Activated Platelets. AB - Smart poly(2-oxazoline) (POx)-based multifunctional polymer capsules that specifically target glycoprotein (GP) IIb/IIIa on the surface of activated platelets are degraded by the serine protease thrombin and release the urokinase plasminogen activator loaded into the polymer capsules, only in the area of acute thrombosis. PMID- 26239036 TI - Editorial: Impact of Racial Differences on Brain Health among the Oldest Old. PMID- 26239037 TI - Brain Aging in African-Americans: The Atherosclerosis Risk in Communities (ARIC) Experience. AB - Reported rates of dementia differ by race, although most studies have not focused on carefully measured outcomes, confounding by education or other demographic factors, nor have they studied other outcomes other than dementia. In this review we will discuss the experience in the Atherosclerosis Risk in Communities (ARIC) study evaluating racial disparities relating to stroke, subclinical brain infarction, leukoaraiosis, as well as cognitive change and dementia. ARIC is a biracial cohort of 15,792 participants from four U.S. communities, initially recruited in 1987-1989, and seen at a total of 5 in-person visits (most recently seen in 2011-2013) with annual follow-up phone calls. We will provide evidence from ARIC studies that disproportionate rates of vascular risk factors explain at least some of these observed disparities by race, but particular risk factors, including diabetes, may differentially affect the brain in African-American versus white participants. In addition, we will review some of the disparities by race in studies focusing on the genetics of stroke, small vessel disease, and dementia. PMID- 26239038 TI - Stability in Cognitive Function Over 18 Years: Prevalence and Predictors among Older Mexican Americans. AB - PURPOSE: Numerous studies have examined the association of physical, behavioral and social factors with cognitive decline in older adults. Less attention has been placed on factors associated with long-term maintenance of intact cognition even into very old age. A greater understanding of those factors can inform the development of activities for maintaining cognitive strength. METHODS: Using a sample from the Hispanic Established Populations for Epidemiologic Study of the Elderly, a population-based study of non-institutionalized Mexican Americans aged 65 and older from five Southwestern states (N = 2767), latent class mixture models were developed to identify subgroups of cognitive change over time. RESULTS: Three distinct trajectories of cognitive change were identified and characterized as stable, slow decline and rapid decline. Compared to the rapid decline group, a higher proportion of the stable cognition group were women, had high school education, were married and attended church one or more times per week. Regular church attendance had a significant positive impact in the stable group (beta = 0.64, p <0.01), the slow decline group (beta = 0.84, p <0.001) and the rapid decline group (beta = 2.50, p <0.001). Activity limitations had a consistently negative association with cognition in the stable, slow decline and rapid decline groups (beta = -0.37, p <0.001; beta = -0.85, p <0.001; and beta = 1.58, p <0.001 respectively). CONCLUSION: Substantial heterogeneity exists in rates of cognitive decline among older Mexican Americans. Interventions targeting cognitive maintenance may benefit from increased focus on factors associated with continued social engagement. PMID- 26239039 TI - Social Determinants, Race, and Brain Health Outcomes: Findings from the Chicago Health and Aging Project. AB - The broad spectrum of economic and cultural diversity in the U.S. population correlates with and affects the study of behavioral aspects of health. The purpose of this article is to provide a selective overview of research findings from the Chicago Health and Aging Project (CHAP), which covers a socio demographically diverse population in Chicago, with a focus on role-related psychosocial factors and observed racial/ethnic differences in aging outcomes. CHAP is a longitudinal, epidemiological study of common chronic conditions of aging with an emphasis on medical, psychosocial, and environmental risk factors for the decline in cognitive function across the older adult lifespan. We briefly summarize the study design and methods used in the CHAP study and characterize the study population and describe the psychosocial data, noting black-white associations as they relate to three common brain health outcomes: cognitive function and Alzheimer's Disease, stroke, and subclinical vascular disease as noted on neuroimaging. PMID- 26239041 TI - Pharmaceutical policies: effects of financial incentives for prescribers. AB - BACKGROUND: The proportion of total healthcare expenditures spent on drugs has continued to grow in countries of all income categories. Policy-makers are under pressure to control pharmaceutical expenditures without adversely affecting quality of care. Financial incentives seeking to influence prescribers' behaviour include budgetary arrangements at primary care and hospital settings (pharmaceutical budget caps or targets), financial rewards for target behaviours or outcomes (pay for performance interventions) and reduced benefit margin for prescribers based on medicine sales and prescriptions (pharmaceutical reimbursement rate reduction policies). This is the first update of the original version of this review. OBJECTIVES: To determine the effects of pharmaceutical policies using financial incentives to influence prescribers' practices on drug use, healthcare utilisation, health outcomes and costs (expenditures). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (searched 29/01/2015); MEDLINE, Ovid SP (searched 29/01/2015); EMBASE, Ovid SP (searched 29/01/2015); International Network for Rational Use of Drugs (INRUD) Bibliography (searched 29/01/2015); National Health Service (NHS) Economic Evaluation Database (searched 29/01/2015); EconLit - ProQuest (searched 02/02/2015); and Science Citation Index and Social Sciences Citation Index, Institute for Scientific Information (ISI) Web of Knowledge (citation search for included studies searched 10/02/2015). We screened the reference lists of relevant reports and contacted study authors and organisations to identify additional studies. SELECTION CRITERIA: We included policies that intend to affect prescribing by means of financial incentives for prescribers. Included in this category are pharmaceutical budget caps or targets, pay for performance and drug reimbursement rate reductions and other financial policies, if they were specifically targeted at prescribing or drug utilisation. Policies in this review were defined as laws, rules, regulations and financial and administrative orders made or implemented by payers such as national or local governments, non government organisations, private or social insurers and insurance-like organisations. One of the following outcomes had to be reported: drug use, healthcare utilisation, health outcomes or costs. The study had to be a randomised or non-randomised trial, an interrupted time series (ITS) analysis, a repeated measures study or a controlled before-after (CBA) study. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed eligibility for inclusion of studies and risks of bias using Cochrane Effective Practice and Organisation of Care (EPOC) criteria and extracted data from the included studies. For CBA studies, we reported relative effects (e.g. adjusted relative change). The review team re-analysed all ITS results. When possible, the review team also re-analysed CBA data as ITS data. MAIN RESULTS: Eighteen evaluations (six new studies) of pharmaceutical policies from six high-income countries met our inclusion criteria. Fourteen studies evaluated pharmaceutical budget policies in the UK (nine studies), two in Germany and Ireland and one each in Sweden and Taiwan. Three studies assessed pay for performance policies in the UK (two) and the Netherlands (one). One study from Taiwan assessed a reimbursement rate reduction policy. ITS analyses had some limitations. All CBA studies had serious limitations. No study from low-income or middle-income countries met the inclusion criteria.Pharmaceutical budgets may lead to a modest reduction in drug use (median relative change -2.8%; low-certainty evidence). We are uncertain of the effects of the policy on drug costs or healthcare utilisation, as the certainty of such evidence has been assessed as very low. Effects of this policy on health outcomes were not reported. Effects of pay for performance policies on drug use and health outcomes are uncertain, as the certainty of such evidence has been assessed as very low. Effects of this policy on drug costs and healthcare utilisation have not been measured. Effects of the reimbursement rate reduction policy on drug use and drug costs are uncertain, as the certainty of such evidence has been assessed as very low. No included study assessed the effects of this policy on healthcare utilisation or health outcomes. Administration costs of the policies were not reported in any of the included studies. AUTHORS' CONCLUSIONS: Although financial incentives are considered an important element in strategies to change prescribing patterns, limited evidence of their effects can be found. Effects of policies, including pay for performance policies, in improving quality of care and health outcomes remain uncertain. Because pharmaceutical policies have uncertain effects, and because they might cause harm as well as benefit, proper evaluation of these policies is needed. Future studies should consider the impact of these policies on health outcomes, drug use and overall healthcare expenditures, as well as on drug expenditures. PMID- 26239040 TI - What Metabolic Syndrome Contributes to Brain Outcomes in African American & Caucasian Cohorts. AB - Metabolic syndrome (MetS), i.e., meeting criteria for any three of the following: hyperglycemia, hypertension, hypertriglyceridemia, low high-density lipoprotein and/or abdominal obesity, is associated with negative health outcomes. For example, MetS negatively impacts cognition; however, less is known about incremental MetS risk, i.e., meeting 1 or 2 as opposed to 3 or more criteria. We hypothesized incremental MetS risk would negatively contribute to cognition and relevant neuroanatomy, e.g., memory and hippocampal volumes, and that this risk extends to affective functioning. 119 non-demented/non-depressed participants (age=60.1+12.9;~50% African American) grouped by incremental MetS risk-no (0 criteria met), low (1-2 criteria met), or high (3+ criteria met)-were compared across cognition, affect and relevant neuroanatomy using multivariable linear regressions. Exploratory analyses, stratified by race, consider the role of health disparities in disease severity of individual MetS component (e.g., actual blood pressure readings) on significant results from primary analyses. Incremental MetS risk contributed to depressive symptomatology (nolow=high) after controlling for age, race (n.s.) and IQ. Different indices of disease severity contributed to different aspects of brain structure and function by race providing empirical support for future studies of the impact distinct health disparities in vascular risk have on brain aging. MetS compromised mood, cognition and hippocampal structure with incremental risk applying to some but not all of these outcomes. Care providers may wish to monitor a broader spectrum of risk including components of MetS like blood pressure and cholesterol levels when considering brain-behavior relationships in adults from diverse populations. PMID- 26239043 TI - Characterisation and diagnosis of frangipani mosaic virus from India. AB - Frangipani mosaic virus (FrMV) is known to infect frangipani tree (Plumeria rubra f. acutifolia) in India but the virus has not been characterized at genomic level and diagnosis is not available. In the present study, an isolate of FrMV (FrMV Ind-1) showing greenish mosaic and vein-banding symptoms in P. rubra f. acutifolia in New Delhi was characterized based on host reactions, serology and genome sequence. The virus isolate induced local symptoms on several new experimental host species: Capsicum annuum (chilli), Nicotiana benthamiana, Solanum lycopersicum and S. melongena. N. benthamiana could be used as an efficient propagation host as it developed systemic mottle mosaic symptoms all round the year. The genome of FrMV-Ind-1 was 6643 (JN555602) nucleotides long with genome organization similar to tobamoviruses. The Indian isolate of FrMV shared a very close genome sequence identity (98.3 %) with the lone isolate of FrMV-P from Australia. FrMV-Ind-1 together with FrMV-P formed a new phylogenetic group i.e. Apocynaceae-infecting tobamovirus. The polyclonal antiserum generated through the purified virus preparation was successfully utilized to detect the virus in field samples of frangipani by ELISA. Of the eight different tobamoviruses tested, FrMV-Ind-1 shared distant serological relationships with only cucumber green mottle mosaic virus, tobacco mosaic virus, bell pepper mottle virus and kyuri green mottle mosaic virus. RT-PCR based on coat protein gene primer successfully detected the virus in frangipani plants. This study is the first comprehensive description of FrMV occurring in India. PMID- 26239042 TI - Effects of brain-derived neurotrophic factor and neurotrophin-3 on the neuronal differentiation of rat adipose-derived stem cells. AB - Tissue engineering is a promising method that may be used to treat spinal cord injury (SCI). The underlying repair mechanism of tissue engineering involves the stable secretion of neurotrophins from seed cells, which eventually differentiate into neurons; therefore, the selection of appropriate seed cells, which stably secrete neurotrophins that easily differentiate into neurons requires investigation. Adipose-derived stem cells (ADSCs), which are adult SCs, are advantageous due to convenience sampling and easy expansion; therefore, ADSCs are currently the most popular type of seed cell. Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) possess superior properties, when compared with other neurotrophic factors, in the maintenance of neuronal survival and promotion of SC differentiation into neurons. The present study used two lentiviruses, which specifically express BDNF and NT-3 [Lenti-BDNF-green fluorescent protein (GFP), Lenti-NT-3-red fluorescent protein (RFP)], to transfect third-generation ADSCs. Three types of seed cell were obtained: i) Seed cells overexpressing BDNF (ADSC/Lenti-BDNF-GFP); ii) seed cells overexpressing NT-3 (ADSC/Lenti-NT-3-RFP); and iii) seed cells overexpressing BDNF and NT-3 (ADSC/Lenti-BDNF-GFP and NT-3 RFP). The transfected cells were then induced to differentiate into neurons and were divided into a further four groups: i) The BDNF and NT-3 co-overexpression group; ii) the BDNF overexpression group; iii) the NT-3 overexpression group; and iv) the control group, which consisted of untransfected ADSCs. The results of the present study demonstrate that BDNF and NT-3 expression was higher 10 days after induction, as detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Neuron-specific enolase is a neuronal marker, the expression of which was highest in the BDNF and NT-3 co overexpression group, followed by the BDNF overexpression group and then by the NT-3 overexpression group. The lowest expression levels of NSE were detected in the control group, as determined by RT-qPCR, western blotting and immunofluorescent staining. These results indicate that BDNF and NT-3 exert a synergistic effect, which may promote the neuronal differentiation of ADSCs. The present study provides a solid theoretical foundation for future experiments regarding the use of tissue engineering technology for the treatment of SCI. PMID- 26239044 TI - Stimulation of RAW264.7 macrophages by sulfated Escherichia coli K5 capsular polysaccharide in vitro. AB - The aim of the present study was to explore the immunomodulatory effects of sulfated K5 polysaccharide derivatives on RAW264.7 macro-phage cells, and to further elucidate the structure-activity relationship. In the present study, chemically sulfated polysaccharides were derived from Escherichia coli K5 capsular polysaccharide (K5PS), and molecular weight determination, sugar analysis, and other physical and chemical characterizations were performed on the derived polysaccharides. Enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction analyses demonstrated that K5-OS2 stimulated murine RAW264.7 macrophage cells to release TNF-alpha and IL-1beta proinflammatory cytokines. K5-OS2 also induced the expression of inducible nitric oxide synthase iNOS, which is responsible for the production of nitric oxide. In addition, K5-OS2 markedly induced macrophage-mediated cytotoxicity against cancer cells and promoted the phagocytic activity of the RAW264.7 cells. Therefore, K5 OS2 activated macrophages and acted as a potent immunomodulator. Observations of the present study also indicated that sulfation modification enhanced the immune enhancing activity of K5PS, and that the high sulfation in the O-position of K5PS may be required for the immunomodulatory activities of the Escherichia coli K5 capsular polysaccharide. PMID- 26239045 TI - Impact of cytochrome P450 2C19 polymorphisms on the pharmacokinetics of tacrolimus when coadministered with voriconazole. AB - This study evaluated the effects of cytochrome P450 (CYP) 2C19 polymorphisms on tacrolimus pharmacokinetics when coadministered with voriconazole. Eighteen healthy volunteers, including 6 individuals in each CYP2C19 genotype (extensive metabolizers [EMs], intermediate metabolizers [IMs], and poor metabolizers [PMs]), received a single oral dose of 3 mg tacrolimus alone or in combination with 200 mg voriconazole twice daily at steady state. When tacrolimus was coadministered with voriconazole, a significant increase in area under its concentration-time curve (AUC0-24 ) was observed for all genotypes. AUC0-12 of voriconazole in IMs and PMs were significantly higher than that in EMs (P < .05 and P < .01, respectively). Consequently, AUC0-24 of tacrolimus in combination with voriconazole in IMs and PMs were also significantly higher than that in EMs (P < .05). These results demonstrate that CYP2C19 genotypes influenced the exposure of tacrolimus when coadministered with voriconazole, although tacrolimus is mainly metabolized by CYP3A. PMID- 26239046 TI - Down-regulation of HMGB1 expression by shRNA constructs inhibits the bioactivity of urothelial carcinoma cell lines via the NF-kappaB pathway. AB - The high mobility group box 1 (HMGB1), which is a highly conserved and evolutionarily non-histone nuclear protein, has been shown to associate with a variety of biological important processes, such as transcription, DNA repair, differentiation, and extracellular signalling. High HMGB1 expression has been reported in many cancers, such as prostate, kidney, ovarian, and gastric cancer. However, there have been few studies of the function of HMGB1 in the malignant biological behaviour of bladder urothelial carcinoma (BUC), and the potential mechanism of HMGB1 in the pathogenesis of BUC remains unclear. Thus, in this study, we constructed plasmid vectors that are capable of synthesizing specific shRNAs targeting HMGB1 and transfected them into BUC cells to persistently suppress the endogenous gene expression of HMGB1. The expression of HMGB1, the bioactivity of BUC cells, including proliferation, apoptosis, cell cycle distribution, migration and invasion, and the effects of HMGB1 knockdown on downstream signalling pathways were investigated. Our data suggest that HMGB1 promotes the malignant biological behaviour of BUC, and that this effect may be partially mediated by the NF-kappaB signalling pathway. HMGB1 may serve as a potential therapeutic target for BUC in the future. PMID- 26239047 TI - Obstetric risk factors and time trends of neurodevelopmental outcome at 2 years in very-low-birthweight infants: a single institution study. AB - AIM: To assess the time trends of neonatal survival and infant neurodevelopmental outcome in very-low-birthweight children at 24 months corrected age over a 20 year period. METHOD: The study cohort comprised 857 infants (439 males and 418 females) weighing less than 1500g at birth or delivered before 32 weeks gestational age in the period 1989 to 2008. Neurological examination and cognitive assessment of the infants (Bayley Scales of Infant Development and Griffiths Mental Developmental Scale) were performed at 24 months corrected age. RESULTS: The prevalence of neonatal survival with normal neurodevelopmental outcome increased from 55.3% (104/188) in 1989 to 1993, to 61.4% in 1994-1998 (116/189), 68.3% in 1999 to 2003 (138/202), and 84.5% in 2004 to 2008 (235/278) (annual increase=1%, 95% CI 2.1-4.1; p<0.001). In logistic models, the increase in the rate of normal neurodevelopmental outcome during the periods studied was consistent across the categories of birthweight (<=1000g as opposed to >1000g), gestational age (<=28wks as opposed to >28wks), and clinical characteristics (pre eclampsia/growth restriction as opposed to spontaneous prematurity/rupture of membranes). INTERPRETATION: The increased rate of normal neurodevelopmental outcome at 2 years among very-low-birthweight infants is independent of obstetric risk factors. PMID- 26239048 TI - Cholestane-3beta,5alpha,6beta-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency. AB - Niemann-Pick type C (NPC) is a progressive neurodegenerative disease characterized by lysosomal/endosomal accumulation of unesterified cholesterol and glycolipids. Recent studies have shown that plasma cholestane-3beta,5alpha,6beta triol (CT) and 7-ketocholesterol (7-KC) could be potential biomarkers for the diagnosis of NPC patients. We aimed to know the sensitivity and specificity of these biomarkers for the diagnosis of NPC compared with other diseases that can potentially lead to oxysterol alterations. We studied 107 controls and 122 patients including 16 with NPC, 3 with lysosomal acid lipase (LAL) deficiency, 8 with other lysosomal diseases, 5 with galactosemia, 11 with cerebrotendinous xanthomatosis (CTX), 3 with Smith-Lemli-Opitz, 14 with peroxisomal biogenesis disorders, 19 with unspecific hepatic diseases, 13 with familial hypercholesterolemia, and 30 with neurological involvement and no evidence of an inherited metabolic disease. CT and 7-KC were analyzed by HPLC-ESI-MS/MS as mono dimethylglycine derivatives. Levels of 7-KC were high in most of the studied diseases, whereas those of CT were only high in NPC, LAL, and CTX patients. Consequently, although CT is a sensitive biomarker of NPC disease, including those cases with doubtful filipin staining, it is not specific. 7-KC is a very unspecific biomarker. PMID- 26239049 TI - An LC-MS/MS method to quantify acylcarnitine species including isomeric and odd numbered forms in plasma and tissues. AB - Acylcarnitines are intermediates of fatty acid and amino acid oxidation found in tissues and body fluids. They are important diagnostic markers for inherited diseases of peroxisomal and mitochondrial oxidation processes and were recently described as biomarkers of complex diseases like the metabolic syndrome. Quantification of acylcarnitine species can become challenging because various species occur as isomers and/or have very low concentrations. Here we describe a new LC-MS/MS method for quantification of 56 acylcarnitine species with acyl chain lengths from C2 to C18. Our method includes amino acid-derived positional isomers, like methacrylyl-carnitine (2-M-C3:1-CN) and crotonyl-carnitine (C4:1 CN), and odd-numbered carbon species, like pentadecanoyl-carnitine (C15:0-CN) and heptadecanoyl-carnitine (C17:0-CN), occurring at very low concentrations in plasma and tissues. Method validation in plasma and liver samples showed high sensitivity and excellent accuracy and precision. In an application to samples from streptozotocin-treated diabetic mice, we identified significantly increased concentrations of acylcarnitines derived from branched-chain amino acid degradation and of odd-numbered straight-chain species, recently proposed as potential biomarkers for the metabolic syndrome. In conclusion, the LC-MS/MS method presented here allows robust quantification of isomeric acylcarnitine species and extends the palette of acylcarnitines with diagnostic potential derived from fatty acid and amino acid metabolism. PMID- 26239050 TI - Simultaneous quantification of cholesterol sulfate, androgen sulfates, and progestagen sulfates in human serum by LC-MS/MS. AB - Steroids are primarily present in human fluids in their sulfated forms. Profiling of these compounds is important from both diagnostic and physiological points of view. Here, we present a novel method for the quantification of 11 intact steroid sulfates in human serum by LC-MS/MS. The compounds analyzed in our method, some of which are quantified for the first time in blood, include cholesterol sulfate, pregnenolone sulfate, 17-hydroxy-pregnenolone sulfate, 16-alpha-hydroxy dehydroepiandrosterone sulfate, dehydroepiandrosterone sulfate, androstenediol sulfate, androsterone sulfate, epiandrosterone sulfate, testosterone sulfate, epitestosterone sulfate, and dihydrotestosterone sulfate. The assay was conceived to quantify sulfated steroids in a broad range of concentrations, requiring only 300 MUl of serum. The method has been validated and its performance was studied at three quality controls, selected for each compound according to its physiological concentration. The assay showed good linearity (R(2) > 0.99) and recovery for all the compounds, with limits of quantification ranging between 1 and 80 ng/ml. Averaged intra-day and between-day precisions (coefficient of variation) and accuracies (relative errors) were below 10%. The method has been successfully applied to study the sulfated steroidome in diseases such as steroid sulfatase deficiency, proving its diagnostic value. This is, to our best knowledge, the most comprehensive method available for the quantification of sulfated steroids in human blood. PMID- 26239051 TI - Omental adipocyte hypertrophy relates to coenzyme Q10 redox state and lipid peroxidation in obese women. AB - Occurrence of oxidative stress in white adipose tissues contributes to its dysfunction and the development of obesity-related metabolic complications. Coenzyme Q10 (CoQ10) is the single lipophilic antioxidant synthesized in humans and is essential for electron transport during mitochondrial respiration. To understand the role of CoQ10 in adipose tissue physiology and dysfunction, the abundance of the oxidized and reduced (CoQ10red) isoforms of the CoQ10 were quantified in subcutaneous and omental adipose tissues of women covering the full range of BMI (from 21.5 to 53.2 kg/m(2)). Lean women displayed regional variations of CoQ10 redox state between the omental and subcutaneous depot, despite similar total content. Obese women had reduced CoQ10red concentrations in the omental depot, leading to increased CoQ10 redox state and higher levels of lipid hydroperoxide. Women with low omental CoQ10 content had greater visceral and subcutaneous adiposity, increased omental adipocyte diameter, and higher circulating interleukin-6 and C-reactive protein levels and were more insulin resistant. The associations between abdominal obesity-related cardiometabolic risk factors and CoQ10 content in the omental depot were abolished after adjustment for omental adipocyte diameter. This study shows that hypertrophic remodeling of visceral fat closely relates to depletion of CoQ10, lipid peroxidation, and inflammation. PMID- 26239052 TI - Dendritic cells combined with anti-GITR antibody produce antitumor effects in osteosarcoma. AB - We attempted to enhance the antitumor effects of tumor lysate-pulsed dendritic cells by eliminating regulatory T cells. The combinatorial effects of dendritic cells and agonist anti-glucocorticoid-induced tumor necrosis factor receptor (anti-GITR) antibodies were investigated with respect to enhancement of the systemic immune response, elimination of regulatory T cells, and inhibition of tumor growth. To determine whether the combination of dendritic cells and anti GITR antibodies could enhance systemic immune responses and inhibit primary tumor growth in a murine osteosarcoma (LM8) model. We established the following 4 groups of C3H mice (20 mice in total): i), control IgG-treated mice; ii), tumor lysate-pulsed dendritic cell-treated mice; iii), agonist anti-GITR antibody treated mice; and iv), agonist anti-GITR antibody- and tumor lysate-pulsed dendritic cell-treated mice.The mice that received the agonist anti-GITR antibodies and tumor lysate-pulsed dendritic cells displayed inhibited primary growth, prolonged life time, reduced numbers of regulatory T lymphocytes in the spleen, elevated serum interferon-gamma levels, increased number of CD8+ T lymphocytes. The mice that received combined therapy had reduced level of immunosuppressive cytokines in tumor tissue and serum. Combining agonist anti GITR antibodies with tumor lysate-pulsed dendritic cells enhanced the systemic immune response. These findings provide further support for the continued development of agonist anti-GITR antibodies as an immunotherapeutic strategy for osteosarcoma. We suggest that our proposed immunotherapy could be developed further to improve osteosarcoma treatment. PMID- 26239053 TI - [Molecular basis of Rett syndrome: A current look]. AB - Rett syndrome (RS) is a neurodevelopmental disorder that exclusively affects girls, and occurs along with autism. It is very uncommon, and has five distinct forms, one classic and the others atypical, which generally compromise manual skills, language, and mobility, and widely associated with the appearance of stereotypy and early epilepsy. With the aim of updating the information about RS, a search was performed in the computer data bases of PubMed, Hinari, SCIELO and Medline, as well as consulting other web sites including OMIM, ORPHANET, GeneMap, Genetests, Proteins and Gene, using the descriptors "Sindrome de Rett", "genes y Sindrome de Rett", "Rett Syndrome gene", "Rett Syndrome", "Rett Syndrome gene therapy", and "Rett Syndrome review". Of the 1,348 articles found, 42 articles were selected, which reported 3 genes causing the syndrome: MECP2, CDKL5 and FOXG. The MECP2 gene is mutated in 80% of patients with classic RS, as well as in 40% of those affected by any of its atypical forms. RS with early epilepsy and the congenital variant are mainly due to variations in the CDKL5 and FOXG1 genes, respectively. CONCLUSIONS: The diagnosis of RS is based on clinical criteria. However, the advances in molecular biology and genetics have opened a wide range of possibilities for diagnosing the different clinical forms that could not be classified before. Molecular analysis can help confirm the clinical criteria and provided information as regards the prognosis of the patient. PMID- 26239054 TI - Selective FFA2 Agonism Appears to Act via Intestinal PYY to Reduce Transit and Food Intake but Does Not Improve Glucose Tolerance in Mouse Models. AB - Free fatty acid receptor 2 (FFA2) is expressed on enteroendocrine L cells that release glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) when activated by short-chain fatty acids (SCFAs). Functionally GLP-1 and PYY inhibit gut transit, increase glucose tolerance, and suppress appetite; thus, FFA2 has therapeutic potential for type 2 diabetes and obesity. However, FFA2-selective agonists have not been characterized in vivo. Compound 1 (Cpd 1), a potent FFA2 agonist, was tested for its activity on the following: GLP-1 release, modulation of intestinal mucosal ion transport and transit in wild-type (WT) and FFA2(-/-) tissue, and food intake and glucose tolerance in lean and diet-induced obese (DIO) mice. Cpd 1 stimulated GLP-1 secretion in vivo, but this effect was only detected with dipeptidyl peptidase IV inhibition, while mucosal responses were PYY, not GLP-1, mediated. Gut transit was faster in FFA2(-/-) mice, while Cpd 1 slowed WT transit and reduced food intake and body weight in DIO mice. Cpd 1 decreased glucose tolerance and suppressed plasma insulin in lean and DIO mice, despite FFA2(-/-) mice displaying impaired glucose tolerance. These results suggest that FFA2 inhibits intestinal functions and suppresses food intake via PYY pathways, with limited GLP-1 contribution. Thus, FFA2 may be an effective therapeutic target for obesity but not for type 2 diabetes. PMID- 26239055 TI - TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic beta-Cells. AB - Pancreatic beta-cells are destroyed by an autoimmune attack in type 1 diabetes. Linkage and genome-wide association studies point to >50 loci that are associated with the disease in the human genome. Pathway analysis of candidate genes expressed in human islets identified a central role for interferon (IFN) regulated pathways and tyrosine kinase 2 (TYK2). Polymorphisms in the TYK2 gene predicted to decrease function are associated with a decreased risk of developing type 1 diabetes. We presently evaluated whether TYK2 plays a role in human pancreatic beta-cell apoptosis and production of proinflammatory mediators. TYK2 silenced human beta-cells exposed to polyinosinic-polycitidilic acid (PIC) (a mimick of double-stranded RNA produced during viral infection) showed less type I IFN pathway activation and lower production of IFNalpha and CXCL10. These cells also had decreased expression of major histocompatibility complex (MHC) class I proteins, a hallmark of early beta-cell inflammation in type 1 diabetes. Importantly, TYK2 inhibition prevented PIC-induced beta-cell apoptosis via the mitochondrial pathway of cell death. The present findings suggest that TYK2 regulates apoptotic and proinflammatory pathways in pancreatic beta-cells via modulation of IFNalpha signaling, subsequent increase in MHC class I protein, and modulation of chemokines such as CXCL10 that are important for recruitment of T cells to the islets. PMID- 26239057 TI - Vitamin C attenuates the toxic effect of aristolochic acid on renal tubular cells via decreasing oxidative stress-mediated cell death pathways. AB - Aristolochic acid (AA) is a component of Chinese medicinal herbs, including asarum and aristolochia and has been used in Traditional Chinese Medicine for a long time. Recent studies found that AA has a cytotoxic effect resulting in nephropathy. These studies indicated that AA-induced cytotoxicity is associated with increases in oxidative stress and caspase-3 activation. The present study further demonstrated that AA mainly elevates the H2O2 ratio, leading to increases in oxidative stress. Furthermore, the results indicated that AA induces cell death can via caspase-dependent and -independent pathways. It is desirable to identify means of inhibiting AA-induced renal damage; therefore, the present study applied an anti-oxidative nutrient, vitamin C, to test whether it can be employed to reduce AA-induced cell cytotoxicity. The results showed that vitamin C decreased AA-induced H2O2 levels, caspase-3 activity and cytotoxicity in renal tubular cells. In conclusion, the present study was the first to demonstrate that AA-induced increases of the H2O2 ratio resulted in renal tubular cell death via caspase-dependent and -independent pathways, and that vitamin C can decrease AA induced increases in H2O2 levels and caspase-3 activity to attenuate AA-induced cell cytotoxicity. PMID- 26239056 TI - Type 2 Diabetes-Associated K+ Channel TALK-1 Modulates beta-Cell Electrical Excitability, Second-Phase Insulin Secretion, and Glucose Homeostasis. AB - Two-pore domain K+ (K2P) channels play an important role in tuning beta-cell glucose-stimulated insulin secretion (GSIS). The K2P channel TWIK-related alkaline pH-activated K2P (TALK)-1 is linked to type 2 diabetes risk through a coding sequence polymorphism (rs1535500); however, its physiological function has remained elusive. Here, we show that TALK-1 channels are expressed in mouse and human beta-cells, where they serve as key regulators of electrical excitability and GSIS. We find that the rs1535500 polymorphism, which results in an alanine-to glutamate substitution in the C-terminus of human TALK-1, increases channel activity. Genetic ablation of TALK-1 results in beta-cell membrane potential depolarization, increased islet Ca2+ influx, and enhanced second-phase GSIS. Moreover, mice lacking TALK-1 channels are resistant to high-fat diet-induced elevations in fasting glycemia. These findings reveal TALK-1 channels as important modulators of second-phase insulin secretion and suggest a clinically relevant mechanism for rs1535500, which may increase type 2 diabetes risk by limiting GSIS. PMID- 26239058 TI - Depressive Symptoms and Gambling Behavior: Mediating Role of Coping Motivation and Gambling Refusal Self-Efficacy. AB - Understanding the variables that contribute to the comorbidity of depression and gambling behaviors is important in developing effective intervention strategies for those who experience gambling-related problems. The purpose of this study was to implement core concepts from Jacob's general theory of addiction and the social cognitive theory in a multiple mediation model. Specifically, we tested two models to examine whether coping motivation and refusal self-efficacy mediated the relationship between depressive symptoms, gambling related problems, and days gambled. Data was collected from 333 undergraduate students at a large public Midwest university, participating in a larger clinical trial. Analyses indicated a direct effect between depressive symptoms and gambling related problems. Depressive symptoms were found to have a significant indirect effect through coping motivation and gambling refusal self-efficacy on gambling related problems and days gambled. These results provide further support regarding the mechanisms through which depressive symptoms may increase risk for problematic gambling behavior. PMID- 26239059 TI - Growing thrombi release increased levels of CD235a(+) microparticles and decreased levels of activated platelet-derived microparticles. Validation in ST elevation myocardial infarction patients. AB - BACKGROUND: Local fluid dynamics and exposed atherosclerotic lesions regulate thrombus formation. Activated cells in the attached thrombi release microparticles to the circulation (circulating microparticles [cMPs]); however, their phenotype is unknown. OBJECTIVES: To investigate the specific phenotype of the cMPs released by growing thrombi. METHODS/PATIENTS: cMPs released by thrombi growing in different well-characterized thrombogenic conditions were investigated. cMP contents just before and immediately after perfusion of the thrombogenic surfaces were analyzed by triple-labeling flow cytometry. cMPs were tested for their thrombin-generating capacity. The cMPs identified in the ex vivo perfusion experiments were validated in blood of ST-elevation myocardial infarction (STEMI) patients undergoing thrombectomy and percutaneous coronary intervention. Culprit coronary blood (STEMI-CCB) and peripheral artery blood (STEMI-PAB) were simultaneously analyzed and compared with peripheral artery blood from age-matched controls (C-PAB) and peripheral artery blood from patients who had recovered from acute coronary syndrome (ACS) (pSTEMI-PAB). RESULTS: The levels of annexin V(+) cMPs significantly increased in blood collected after perfusion of the exposed thrombogenic surfaces. cMP release was directly related to the formed thrombus mass and the plasma procoagulant activity. Post-thrombus blood showed higher thrombin generation potential and contained higher levels of cMPs carrying glycophorin-A (CD235a(+) ; erythrocyte-derived microparticles [ErMPs]) than preperfusion blood (P < 0.05), whereas the levels of cMPs carrying activated and adhesion platelet markers were decreased. STEMI-CCB and STEMI-PAB had significantly higher ErMP levels than control blood (P < 0.005). ErMP levels were also significantly higher in STEMI-PAB than in pSTEMI-PAB, validating the experimental mechanistic studies and suggesting that ErMPs are markers of ongoing coronary thrombosis (C-statistics: 0.950; 95% confidence interval 0.889-1.000; P < 0.001). CONCLUSION: Glycophorin-A-rich microparticles are released from evolving growing thrombi into the distal perfusing blood, and can be measured in peripheral blood. CD235a(+) cMPs may constitute a novel systemic biomarker of ongoing thrombosis. PMID- 26239060 TI - A penalized robust semiparametric approach for gene-environment interactions. AB - In genetic and genomic studies, gene-environment (G*E) interactions have important implications. Some of the existing G*E interaction methods are limited by analyzing a small number of G factors at a time, by assuming linear effects of E factors, by assuming no data contamination, and by adopting ineffective selection techniques. In this study, we propose a new approach for identifying important G*E interactions. It jointly models the effects of all E and G factors and their interactions. A partially linear varying coefficient model is adopted to accommodate possible nonlinear effects of E factors. A rank-based loss function is used to accommodate possible data contamination. Penalization, which has been extensively used with high-dimensional data, is adopted for selection. The proposed penalized estimation approach can automatically determine if a G factor has an interaction with an E factor, main effect but not interaction, or no effect at all. The proposed approach can be effectively realized using a coordinate descent algorithm. Simulation shows that it has satisfactory performance and outperforms several competing alternatives. The proposed approach is used to analyze a lung cancer study with gene expression measurements and clinical variables. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26239061 TI - [Transient global amnesia: A descriptive study of 12 Polynesian patients]. AB - INTRODUCTION: According to the criteria of Hodges and Warlow, transient global amnesia is defined by sudden onset of isolated anterograde amnesia of spontaneous resolution within one to twenty-four hours. Its pathophysiological mechanisms are still uncertain. METHODS: In a retrospective study, we have analyzed epidemiological, clinical and MRI data from twelve patients admitted to the only neurological department of French Polynesia for transient global amnesia corresponding to the criteria of Hodges and Warlow between January 2010 and December 2013. RESULTS: The median age of the cohort was 61.5 (53-72), the sex ratio was 1. Ten patients had one or more cardiovascular risk factors, 3 had migraine headaches and 3 had anxiodepressive disorders. Among triggers found, the occurrence during the rest was noted in one case. Retrograde amnesia was observed in 42% of cases, repetitive questioning in 75% of cases, anxious bewilderment in 67% of cases and disorientation in 33% of cases. The median episode duration was 9 hours and the duration of hospitalization was 3 days. Three patients had a recurrence. MRI was abnormal in all patients and showed diffusion-weighted hyperintensities in right (n=8), left (n=3) and bilateral (n=1) hippocampi. CONCLUSION: Epidemiological, clinical and MRI data from our cohort are similar to those from the literature except for the highest prevalence of cardiovascular risk factors and the most frequent right hippocampus involvement. Transient global amnesia occurring exceptionally while sleeping was also observed in one of our patients. PMID- 26239062 TI - One-year prevalence of migraine using a validated extended French version of the ID MigraineTM: A Belgian population-based study. AB - BACKGROUND: Country-specific prevalence data on migraine and comorbidities are vital to assess the public health burden of migraine and the corresponding resources required for proper management. Considering the absence of reliable statistics, this study aimed to estimate the one-year prevalence of migraine in Wallonia (Belgium) in relation to socio-demographic factors and several health indicators. METHODS: Among the 1071 people aged 20-69 years who participated in the NESCaV survey, 751 (70.1%) were screened for one-year migraine attacks using the "ef-ID Migraine", a validated, extended French version of the self administered ID MigraineTM questionnaire. Socio-demographic and health data were collected with a self-administered questionnaire and a physical examination. RESULTS: The overall one-year prevalence of migraine was 25.8%; 40.8% of migraineurs reported visual symptoms compatible with an aura. The prevalence was higher in women than in men (33.9% vs. 17.9%, P<0.0001) and declined markedly after the age of 50 (P=0.005). Importantly, migraine was associated with the subjective feeling of poorer health (P=0.0004). No other socio-demographic factor or health indicator studied was significantly correlated with migraine. CONCLUSIONS: High prevalence of migraine and strong association with feeling of poor health should incite health authorities to institute more active public health and management policies with regards to the migraine problem. PMID- 26239063 TI - New insights into central nervous system involvement in FOP: Case report and review of the literature. AB - Fibrodyspasia ossificans progressiva is an autosomal dominant disease due to activating mutations in activin receptor type IA and characterized by progressive heterotopic ossification. Recently, the same non-synonymous heterozygous somatic mutations of ACVR1 have been identified in brain biopsies or autopsy of 24-27% of patients with a rare cerebral tumor, the diffuse intrinsic pontine glioma. We report the first case of a patient with FOP with incidental findings of an abnormal soft tissue mass surrounding the brainstem and causing obstructive hydrocephalus, associated with bilateral dentate lesions. Clinico-radiological course during 10 years of follow-up was consistent with a benign lesion, excluding an oncogenic role of ACVR1 mutations. PMID- 26239065 TI - Electrical-field-driven metal-insulator transition tuned with self-aligned atomic defects. AB - Recently, significant attention has been paid to the resistance switching (RS) behaviour in Fe3O4 and it was explained through the analogy of the electrically driven metal-insulator transition based on the quantum tunneling theory. Here, we propose a method to experimentally support this explanation and provide a way to tune the critical switching parameter by introducing self-aligned localized impurities through the growth of Fe3O4 thin films on stepped SrTiO3 substrates. Anisotropic behavior in the RS was observed, where a lower switching voltage in the range of 10(4) V cm(-1) is required to switch Fe3O4 from a high conducting state to a low conducting state when the electrical field is applied along the steps. The anisotropic RS behavior is attributed to a high density array of anti phase boundaries (APBs) formed at the step edges and thus are aligned along the same direction in the film which act as a train of hotspot forming conduits for resonant tunneling. Our experimental studies open an interesting window to tune the electrical-field-driven metal-insulator transition in strongly correlated systems. PMID- 26239064 TI - Emergence of concurrent infections with colistin-resistant ESBL-positive Klebsiella pneumoniae and OXA-23-producing Acinetobacter baumannii sensitive to colistin only in a Romanian cardiac intensive care unit. AB - We report the emergence and analysis of a cluster of concurrent infections/colonisations with colistin-resistant Klebsiella pneumoniae and OXA-23 carbapenemase-producing Acinetobacter baumannii in patients who had undergone cardiac surgery. We describe the emergence of colistin-resistant K. pneumoniae harbouring blaCTX-M-15, blaSHV-11, blaOXA-1, blaTEM-1 beta-lactamases and aac(6') Ib-cr fluoroquinolone resistance. Colistin-resistant K. pneumoniae infections (pneumonia, wound infection, urinary tract infections and bacteraemia) occurred in critically ill patients previously treated with colistin for post-surgery infections with carbapenem-resistant Pseudomonas aeruginosa and/or A. baumannii. Although the cause of death could not be directly attributed to a single pathogen, three patients co-infected/colonised with K. pneumoniae, P. aeruginosa and/or A. baumannii died, whilst a fourth patient who had a mono-microbial infection with colistin-resistant K. pneumoniae only survived. The use of mobile intubation equipment in patients that shared the same ward, the clustering of cases over a short period of time, as well as the pulsed-field gel electrophoresis (PFGE) data all suggest cross-contamination between patients, either through equipment or by staff contact transmission. This report presents the 'worst-case scenario' where concurrent infection/colonisation with pathogens exhibiting resistance to different types of last-resort antimicrobials occurred in some of the most debilitated intensive care unit (ICU) patients. PMID- 26239066 TI - Bioremediation strategies for removal of residual atrazine in the boreal groundwater zone. AB - Strategies for bioremediation of atrazine, a pesticide commonly polluting groundwater in low concentrations, were studied in two boreal nonagricultural soils. Atrazine was not mineralized in soil without bioremediation treatments. In biostimulation treatment with molasses, up to 52% of atrazine was mineralized at 10 degrees C, even though the degradation gene copy numbers did not increase. Incubations with radioactively labeled atrazine followed by microautoradiographic analysis revealed that bioremediation strategies increased the relative proportion of active degraders from 0.3 up to 1.9% of the total bacterial count. These results indicate that atrazine degradation might not solely be facilitated by atzA/trzN-atzB genes. In combined biostimulation treatment using citrate or molasses and augmentation with Pseudomonas citronellolis ADP or Arthrobacter aurescens strain TC1, up to 76% of atrazine was mineralized at 30 degrees C, and the atrazine degradation gene numbers increased up to 10(7) copies g(-1) soil. Clone libraries from passive samplers in groundwater monitoring wells revealed the presence of phylogenetic groups formerly shown to include atrazine degraders, and the presence of atrazine degradation genes atzA and atzB. These results show that the mineralization of low concentrations of atrazine in the groundwater zone at low temperatures is possible by bioremediation treatments. PMID- 26239067 TI - Prolyl-specific peptidases for applications in food protein hydrolysis. AB - Various food proteins including, e.g. gluten, collagen and casein are rich in L proline residues. Due to the cyclic structure of proline, these proteins are well protected from enzymatic degradation by typical digestive enzymes. Proline specific peptidases (PsP) belong to different families of hydrolases acting on peptide bonds (EC 3.4.x.x). They occur in various organisms including bacteria, fungi, plants and insects. Based on their biochemical characteristics, PsP type enzymes are further grouped into different subclasses of which prolyl aminopeptidases (EC 3.4.11.5, PAP), prolyl carboxypeptidases (EC 3.4.17.16, PCP) and prolyl oligopeptidases/prolyl endopeptidases (EC 3.4.21.26, POP/PEP) are of major interest for applications in food biotechnology. This mini review summarises the biochemical assays employed for these subclasses of PsP and their structural properties and the reaction mechanisms. A special focus was set on PsP derived from fungi and insects and important industrial applications in the field of food biotechnology. The degradation of gluten and collagen as well as the hydrolysis of bitter peptides are discussed. PMID- 26239068 TI - Improved insecticidal activity of a recombinant baculovirus expressing spider venom cyto-insectotoxin. AB - Baculoviruses have a long history of safe use as specific, environmentally friendly insecticides that provide alternatives to chemical pesticides for controlling insect pests. However, their use has been limited by several factors, particularly their slow pathogenicity. In this study, we constructed a recombinant Bombyx mori nucleopolyhedrovirus (BmNPV) and an Autographa californica multiple nucleopolyhedrovirus (AcMNPV) that expressed an insect specific cyto-insectotoxin (Cit1a) from the venom of the central Asian spider Lachesana tarabaevi. Cit1a is a comparatively long linear cytolytic molecule that contains a predicted alpha-helix structure composed of two short membrane-acting antimicrobial peptides (MAMPs) that are joined together in a "head-to-tail" shape. Cit1a fused to polyhedrin gene (polh) (polh-cit1a) was expressed in the nuclei as polyhedra in silkworm larvae, Bm5 and Sf9 cells. An early death of Bm5 and Sf9 cells by recombinant BmNPV/Polh-Cit1a and AcMNPV/Polh-Cit1a was observed compared with control viruses that lacked the toxin gene. The infected cells showed a loss of cytoplasm, membrane integrity, and structural changes, suggesting that recombinant baculovirus-infected cells were killed by the necrosis caused by Cit1a. In addition, the BmNPV/Polh-Cit1a showed a significant reduction in the median lethal time (LT50) against silkworm larvae compared with those of control BmNPV that lacked the cit1a gene. PMID- 26239069 TI - Improvement of oxidized glutathione fermentation by thiol redox metabolism engineering in Saccharomyces cerevisiae. AB - Glutathione is a valuable tripeptide widely used in the pharmaceutical, food, and cosmetic industries. In industrial fermentation, glutathione is currently produced primarily using the yeast Saccharomyces cerevisiae. Intracellular glutathione exists in two forms; the majority is present as reduced glutathione (GSH) and a small amount is present as oxidized glutathione (GSSG). However, GSSG is more stable than GSH and is a more attractive form for the storage of glutathione extracted from yeast cells after fermentation. In this study, intracellular GSSG content was improved by engineering thiol oxidization metabolism in yeast. An engineered strain producing high amounts of glutathione from over-expression of glutathione synthases and lacking glutathione reductase was used as a platform strain. Additional over-expression of thiol oxidase (1.8.3.2) genes ERV1 or ERO1 increased the GSSG content by 2.9-fold and 2.0-fold, respectively, compared with the platform strain, without decreasing cell growth. However, over-expression of thiol oxidase gene ERV2 showed almost no effect on the GSSG content. Interestingly, ERO1 over-expression did not decrease the GSH content, raising the total glutathione content of the cell, but ERV1 over expression decreased the GSH content, balancing the increase in the GSSG content. Furthermore, the increase in the GSSG content due to ERO1 over-expression was enhanced by additional over-expression of the gene encoding Pdi1, whose reduced form activates Ero1 in the endoplasmic reticulum. These results indicate that engineering the thiol redox metabolism of S. cerevisiae improves GSSG and is critical to increasing the total productivity and stability of glutathione. PMID- 26239070 TI - Microencapsulation of new probiotic formulations for gastrointestinal delivery: in vitro study to assess viability and biological properties. AB - The paper describes the preparation of new probiotic formulations based on chitosan-coated alginate microcapsules containing three different probiotic strains, Lactobacillus plantarum PBS067, Lactobacillus rhamnosus PBS070, and Bifidobacterium animalis subsp. lactis PBS075 taken individually and as a mixture of them. The effects of microencapsulation on the viability of the strains in conditions simulating the gastrointestinal tract and under industrial processes conditions were studied. In addition, an evaluation of their probiotic properties was also investigated by in vitro tests on the human intestinal cell line HT-29 to explore the effect of microencapsulation on health beneficial effect of the considered strains. Non-encapsulated cells were completely destroyed when exposed to simulated gastric juice and other stress conditions, while encapsulated cells exhibited a significantly higher resistance to artificial intestinal juice and heat and osmotic treatment. Moreover, in this study, the effect of the various microencapsulated probiotic strain formulations was compared with analogous formulations also containing the beta-glucan Pleuran. The microencapsulation effectively protected the selected bacteria, as single strain and as a mixture of the three strains in both the formulations with and without Pleuran, from simulating gastrointestinal tract and industrial process conditions in delivering the viable cells without any significant adverse effect on their functionalities. The comparative study of the immunomodulatory properties of each single strain and the mixture of the three strains revealed a synergistic effect of the probiotic mixture, but no appreciable difference between the two kinds of formulations could be detected, as the effect of Pleuran is covered by the higher potential of the probiotic strains. PMID- 26239071 TI - Secreted expression of Leuconostoc mesenteroides glucansucrase in Lactococcus lactis for the production of insoluble glucans. AB - We expressed a glucansucrase, DsrI, from Leuconostoc mesenteroides that catalyzes formation of water-insoluble glucans from sucrose using a nisin-controlled gene expression system in Lactococcus lactis. These polymers have potential for production of biodegradable gels, fibers, and films. We optimized production of DsrI using several different background vectors, signal peptides, strains, induction conditions, and bioreactor parameters to increase extracellular accumulation. Optimal production of the enzyme utilized a high-copy plasmid, pMSP3535H3, which contains a nisin immunity gene, L. lactis LM0230, and bioreactors maintained at pH 6.0 to stabilize the enzyme. We were able to significantly improve growth using the lactic acid inhibitor heme and by continuous removal of lactic acid with anion exchange resins, but enzyme production was less than the controls. The recombinant enzyme under optimized conditions accumulated in the culture medium to approximately 380 mg/L, which was over 150-fold higher compared to the native L. mesenteroides strain. Methods are also included for purification of DsrI utilizing the glucan-binding domain of the enzyme. PMID- 26239072 TI - Perspective of harnessing energy from landfill leachate via microbial fuel cells: novel biofuels and electrogenic physiologies. AB - Organic carbon, nitrogen, and sulfur are highly concentrated in municipal solid waste (MSW) landfill leachate, which usually frustrates conventional leachate treatment technologies from the perspective of energy costs. Therefore, the possibility of converting leachate to a new energy source via microbial fuel cell (MFC) technology has been examined recently. This paper summarizes the power output and energy recovery efficiency of the leachate-fed MFCs according to different feeding patterns, cell structures, and loading rates. Also, we assess potential energy-generating chemicals in leachate like nitrogen and sulfur compounds and propose alternative pathways, which may lift strict ratios between organic carbon and nitrogen content in conventional denitrification of leachate and are expected to achieve a higher voltage than traditional organic-oxygen based cells. Although currently power output of leachate-fed MFCs is limited, it seems well possible that dynamic characteristics of MSW leachates and microbial physiologies underlying some bio-electrochemically efficient activities (e.g., direct interspecies electron transfer) could be stimulated in MFC systems to improve the present status. PMID- 26239073 TI - Erratum to: Visualization and analysis of EPS glycoconjugates of the thermoacidophilic archaeon Sulfolobus metallicus. PMID- 26239074 TI - Inactivation of the virulence factors from 2,3-butanediol-producing Klebsiella pneumoniae. AB - The microbiological production of 2,3-butanediol (2,3-BDO) has attracted considerable attention as an alternative way to produce high-value chemicals from renewable sources. Among the number of 2,3-BDO-producing microorganisms, Klebsiella pneumoniae has been studied most extensively and is known to produce large quantity of 2,3-BDO from a range of substrates. On the other hand, the pathogenic characteristics of the bacteria have limited its industrial applications. In this study, two major virulence traits, outer core LPS and fimbriae, were removed through homologous recombination from 2,3-BDO-producing K. pneumoniae 2242 to expand its uses to the industrial scale. The K. pneumoniae 2242 ?wabG mutant strain was found to have an impaired capsule, which significantly reduced its ability to bind to the mucous layer and evade the phagocytic activity of macrophage. The association with the human ileocecal epithelial cell, HCT-8, and the bladder epithelial cell, T-24, was also reduced dramatically in the K. pneumoniae 2242 ?fimA mutant strain that was devoid of fimbriae. However, the growth rate and production yield for 2,3-BDO were unaffected. The K. pneumoniae strains developed in this study, which are devoid of the major virulence factors, have a high potential for the efficient and sustainable production of 2,3-BDO. PMID- 26239077 TI - Clinical pharmacokinetics of amoxicillin in neonates. PMID- 26239075 TI - Glucocorticoid affects dendritic transport of BDNF-containing vesicles. AB - Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival, differentiation, and functions in the central nervous system (CNS). Because BDNF protein is sorted into secretory vesicles at the trans-Golgi network in the cell body after translation, transport of BDNF-containing vesicles to the secretion sites is an important process for its function. Here we examined the effect of dexamethasone (DEX), a synthetic glucocorticoid, on BDNF-containing vesicle transport and found that DEX decreased the proportion of stationary vesicles and increased velocity of the microtubule-based vesicle transport in dendrites of cortical neurons. Furthermore, DEX increased huntingtin (Htt) protein levels via glucocorticoid receptor (GR) activation, and reduction in the amount of Htt by a specific shRNA reversed the action of DEX on BDNF vesicle transport. Given that Htt protein is a positive regulator for the microtubule-dependent vesicular transport in neurons, our data suggest that glucocorticoid stimulates BDNF vesicle transport through upregulation of Htt protein levels. PMID- 26239078 TI - Physical Functioning and Prediction of Physical Activity After Total Hip Arthroplasty: Five-Year Followup of a Randomized Controlled Trial. AB - OBJECTIVE: To examine whether the 1-year effects from a previous walking skill training program on walking and stair climbing still persist 5 years following total hip arthroplasty (THA), to examine recovery of physical functioning from before to 5 years after surgery, and to identify predictors of physical activity 5 years after THA from preoperative measures. METHODS: We performed a 5-year followup of a randomized controlled trial and a longitudinal study. Sixty participants with a mean age of 70 years (range 50-87 years; 95% confidence interval 68, 72 years) were assessed. Outcome measures were the 6-minute walk test, the stair climbing test (SCT), active hip range of motion (ROM), self efficacy, Hip Dysfunction and Osteoarthritis Outcome Score (HOOS), and University of California, Los Angeles (UCLA) activity scale. Data were analyzed by Student's t-tests, generalized linear model, and multivariate regression analyses. RESULTS: The training and control groups were approximately equal on outcome measures of physical functioning, pain, and self-efficacy at 5 years (P > 0.05). In the total group, the recovery course was unchanged from 1 to 5 years (P > 0.05), except for 9% improvement in ROM (P < 0.001) and an increase in time on SCT of 18% (P = 0.004). Preoperative HOOS pain (P = 0.022) and HOOS sport (P = 0.019) predicted UCLA activity scale 5 years after THA. CONCLUSION: At 5 years after THA, the control group had caught up with the training group on physical functioning, and the participants led an active lifestyle. Those with worse preoperative scores on pain and physical functioning in sport were at risk of being less physically active in the long term following THA. PMID- 26239080 TI - Advances in the Treatment of Borderline Personality Disorder: An Introduction to the Special Issue. AB - The past few decades have seen major progress in the treatment of borderline personality disorder (BPD), a condition that historically has been viewed as difficult to treat. Currently, several evidence-based psychotherapies are available that have generated excitement and hope, yet these developments have also raised new problems that must be addressed. In this special issue, experts in the field of BPD have been invited to share their ideas on some viable directions in the treatment field. This commentary reviews the challenges we currently face and describes the treatment directions presented by the contributors. PMID- 26239081 TI - [Not Available]. PMID- 26239079 TI - Variability in hepatic expression of organic anion transporter 7/SLC22A9, a novel pravastatin uptake transporter: impact of genetic and regulatory factors. AB - Human organic anion transporter 7 (OAT7, SLC22A9) is a hepatic transport protein poorly characterized so far. We therefore sought to identify novel OAT7 substrates and factors contributing to variable hepatic OAT7 expression. Using OAT7-expressing cells, pravastatin was identified as a substrate. Hepatic SLC22A9/OAT7 mRNA and protein expression varied 28-fold and 15-fold, respectively, in 126 Caucasian liver samples. Twenty-four variants in SLC22A9 were genotyped, including three rare missense variants (rs377211288, rs61742518, rs146027075), which occurred only heterozygously. No variant significantly affected hepatic SLC22A9/OAT7 expression. The three missense variants, however, showed functional consequences when expressed in vitro. Hepatic nuclear factor 4 alpha (HNF4alpha) emerged as a major transcriptional regulator of SLC22A9 by a series of in silico and in vitro analyses. In conclusion, pravastatin is the first identified OAT7 drug substrate. Substantial inter-individual variability in hepatic OAT7 expression, majorly driven by HNF4alpha, may contribute to pravastatin drug disposition and might affect response.The Pharmacogenomics Journal advance online publication, 4 August 2015; doi:10.1038/tpj.2015.55. PMID- 26239082 TI - Architecture of Chimeric Spheroids Controls Drug Transport. AB - It is well-established that upregulation of drug efflux pumps leads to multi-drug resistance. Less is known about the role of the architecture of the tumor microenvironment in this process: how the location of pump expressing cells influences drug exposure to cancerous as well as non-cancerous cells. Here, we report a 3D in vitro model of spheroids with mixtures of cells expressing high and low levels of ABCG2, quantifying pump activity by the ability to reject the fluorescent dye Hoechst 33342. With respect to the organization of the mixed spheroids, three different architectures were observed: 1) high-expressing ABCG2 cells located in the spheroid core surrounded by low-expressing cells, 2) high expressing ABCG2 cells intermixed with low-expressing cells and 3) high expressing ABCG2 cells surrounding a core of low-expressing cells. When high expressing ABCG2 cells were in the core or intermixed, Hoechst uptake was directly proportional to the percentage of ABCG2 cells. When high-expressing ABCG2 cell formed an outer coating surrounding spheroids, small numbers of ABCG2 cells were disproportionately effective at inhibiting uptake. Specific inhibitors of the ABCG2 transporter eliminated the effect of this coating. Confocal microscopy of spheroids revealed the location of high- and low-expressing cells, and Hoechst fluorescence revealed that the ABCG2-dependant drug concentration in the cancer microenvironment is influenced by pump expression level and distribution among the cells within a tissue. In addition to providing a 3D model for further investigation into multicellular drug resistance, these data show that the location of ABCG2-expressing cells can control drug exposure within the tumor microenvironment. PMID- 26239083 TI - Refractory absence seizures: An Italian multicenter retrospective study. AB - BACKGROUND: To evaluate evidence and prognosis of refractory cases of absence seizures. METHODS: Subjects with refractory absence seizures were identified retrospectively in 17 Italian epilepsy pediatrics Centers. We analyzed age at onset, family history, presence of myoclonic components, seizure frequency, treatment with antiepileptic drugs (AEDs), interictal electroencephalography (EEG) and neuropsychological assessment. Two subgroups were identified: one with patients with current absence seizures and another with patients that had become seizure free with or without AED treatment. The chi-square test was applied. RESULTS: A total of 92 subjects with drug-resistant absence seizures were analyzed. 45 subjects still show absence seizures (49%) and the other 47 became seizure free (51%) after a period of drug-resistance. The statistical analysis between these two groups showed no correlation between age of onset, family history and abnormalities at interictal EEG. Statistically significant differences were observed with regard to the number of AEDs used and intellectual disability. CONCLUSION: Typical absence epilepsy classifiable as Childhood Absence Epilepsy could not be considered so "benign", as suggested in literature. A longer duration of disease and a higher frequency of seizure seem to be correlated with a higher presence of cognitive impairment. No significant risk factor was observed to allow the faster and better recognition of patients with worse prognosis. PMID- 26239084 TI - Heterogeneous response of cardiac sympathetic function to cardiac resynchronization therapy in heart failure documented by 11[C]-hydroxy-ephedrine and PET/CT. AB - INTRODUCTION: Cardiac resynchronization therapy (CRT) is an accepted treatment in patients with end-stage heart failure. PET permits the absolute quantification of global and regional homogeneity in cardiac sympathetic innervation. We evaluated the variation of cardiac adrenergic activity in patients with idiopathic heart failure (IHF) disease (NYHA III-IV) after CRT using (11)C-hydroxyephedrine (HED) PET/CT. METHODS: Ten IHF patients (mean age = 68; range = 55-81; average left ventricular ejection fraction 26 +/- 4%) implanted with a resynchronization device underwent three HED PET/CT studies: PET 1 one week after inactive device implantation; PET 2, one week after PET 1 under stimulated rhythm; PET 3, at 3 months under active CRT. A dedicated software (PMOD 3.4 version) was used to estimate global and regional cardiac uptake of HED through 17 segment polar maps. RESULTS: At baseline, HED uptake was heterogeneously distributed throughout the left ventricle with a variation coefficient of 18 +/- 5%. This variable markedly decreased after three months CRT (12 +/- 5%, p < 0.01). Interestingly, subdividing the 170 myocardial segments (17 segments of each patient multiplied by the number of patients) into two groups, according to the median value of tracer uptake expressed as % of maximal myocardial uptake (76%), we observed a different behaviour depending on baseline innervation: HED uptake significantly increased only in segments with "impaired innervation" (SUV 2.61 +/- 0.92 at PET1 and 3.05 +/- 1.67 at three months, p < 0.01). CONCLUSION: As shown by HED PET/CT uptake and distribution, improvement in homogeneity of myocardial neuronal function reflected a selective improvement of tracer uptake in regions with more severe neuronal damage. ADVANCES IN KNOWLEDGE: These finding supported the presence of a myocardial regional variability in response of cardiac sympathetic system to CRT and a systemic response involving remote tissues with rich adrenergic innervation. IMPLICATION FOR PATIENT CARE: This work might contribute to identify imaging parameters that could predict the response to CRT therapy. PMID- 26239085 TI - Copper-64-labeled anti-bcl-2 PNA-peptide conjugates selectively localize to bcl-2 positive tumors in mouse models of B-cell lymphoma. AB - INTRODUCTION: The bcl-2 gene is overexpressed in non-Hodgkin's lymphoma (NHL). We have reported micro-SPECT/CT imaging of Mec-1 human lymphoma xenografts in SCID mice, using [(111)In]DOTA-anti-bcl-2-PNA-Tyr(3)-octreotate. In order to reduce normal organ accumulation and improve imaging contrast, modified monomers with neutral hydrophilic (serine, TS) or negatively charged (aspartic acid, TD) residues were synthesized as substitutes for glycine at T(14) in the PNA sequence. The parent and modified PNA-peptide conjugates were labeled with (64)Cu and evaluated in biodistribution studies and high resolution PET/CT imaging of SCID mice bearing bcl-2-positive Mec-1 xenografts as well as bcl-2-negative Ramos xenografts. METHODS: Mice were administered the (64)Cu-labeled conjugates for biodistribution and imaging studies. Biodistributions were obtained from 1 to 48 h post-injection. Mice were imaged from 1 to 48 h post-injection. RESULTS: The parent glycine conjugate and two modified conjugates all showed selective tumor uptake in Mec-1 xenografts. The liver uptake of the serine conjugate was significantly reduced compared to the two other PNA conjugates. Its kidney uptake was highest of the three at 47.1% ID/g at 1h and dropped to 20.6% ID/g at 24h. [Copper-64]DOTA-anti-bcl-2-TS-PNA-Tyr(3)-octreotate showed tumor uptake of 1.38% ID/g at 1h and 1.06% ID/g at 24h. The tumor-to-blood ratio was increased by factor of 2 from 1h to 24h. This compound detected Mec-1 tumors by micro-PET/CT as early as 1h post-injection and at time points out to 48 h. However, the negative control Ramos tumor could not be detected. CONCLUSIONS: These (64)Cu labeled, amino acid-modified PNA conjugates showed selective tumor targeting in vivo, and tumor xenografts were detected by micro-PET/CT as early as 1h post injection, suggesting that bcl-2 expression at the mRNA level can detected by PET in mouse models of NHL. Advances in knowledge and implications for patient care Down-regulating bcl-2, an anti-apoptotic proto-oncogene, is a mechanism to reverse chemotherapy resistance in humans with NHL. Thus, bcl-2 overexpression might be considered a new independent prognostic parameter in NHL, aiding in the identification of patients at risk for treatment failure. We have developed [(64)Cu]DOTA-anti-bcl-2-PNA-Tyr(3)-octreotate conjugates for targeted antisense PET imaging. Our preclinical studies identified an effective combination of antisense and radionuclide imaging, with the goal of future clinical trials in patients. This imaging modality may improve clinical care by identifying patients who might respond better to conventional chemotherapy. PMID- 26239086 TI - Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. AB - This phase 3 trial evaluated the safety and hemostatic efficacy of a recombinant von Willebrand factor (rVWF) for treatment of bleeds in severe von Willebrand disease (VWD). rVWF was initially administered together with recombinant factor VIII (rFVIII) and subsequently alone, as long as hemostatic factor VIII activity (FVIII : C) levels were maintained. Pharmacokinetics (PK) were evaluated in a randomized cross-over design (rVWF vs rVWF:rFVIII at 50 IU VWF:ristocetin cofactor activity [RCo]/kg). Bleed control for all treated bleeds (N = 192 bleeds in 22 subjects) was rated good or excellent (96.9% excellent; 119 of 122 minor, 59 of 61 moderate, and 6 of 7 major bleeds) on a 4-point scale (4 = none to 1 = excellent). A single infusion was effective in 81.8% of bleeds. Treatment success, defined as the number of subjects with a mean efficacy rating of <2.5, was 100%. The PK profile of rVWF was not influenced by rFVIII (mean VWF:RCo terminal half-life: 21.9 hours for rVWF and 19.6 hours for rVWF:rFVIII). FVIII : C levels increased rapidly after rVWF alone, with hemostatic levels achieved within 6 hours and sustained through 72 hours after infusion. Eight adverse events (AEs; 6 nonserious AEs in 4 subjects and 2 serious AEs [chest discomfort and increased heart rate, without cardiac symptomatology] concurrently in 1 subject) were associated with rVWF. There were no thrombotic events or severe allergic reactions. No VWF or FVIII inhibitors, anti-VWF binding antibodies, or antibodies against host cell proteins were detected. These results show that rVWF was safe and effective in treating bleeds in VWD patients and stabilizes endogenous FVIII : C, which may eliminate the need for rFVIII after the first infusion. This trial was registered at www.clinicaltrials.gov as #NCT01410227. PMID- 26239087 TI - Prognostic value of circulating Bcl-2/IgH levels in patients with follicular lymphoma receiving first-line immunochemotherapy. AB - Bcl-2/IgH rearrangements can be quantified in follicular lymphoma (FL) from peripheral blood (PB) by polymerase chain reaction (PCR). The prognostic value of Bcl-2/IgH levels in FL remains controversial. We therefore prospectively studied PB Bcl-2/IgH levels from 173 first-line FL patients who were consecutively enrolled, randomized, and treated within the multicenter phase 3 clinical trial NHL1-2003 comparing bendamustine-rituximab (B-R) with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. From April 2005 to August 2008, 783 pre- and posttreatment PB samples were quantified by quantitative PCR. At inclusion, 114 patients (66%) tested positive and 59 (34%) were negative for Bcl-2/IgH. High pretreatment Bcl-2/IgH levels had an adverse effect on progression-free survival (PFS) compared with intermediate or low levels (high vs intermediate: hazard [HR], 4.28; 95% confidence interval [CI], 1.70-10.77; P = .002; high vs low: HR, 3.02; 95% CI, 1.55-5.86; P = .001). No PFS difference between treatment arms was observed in Bcl-2/IgH-positive patients. A positive posttreatment Bcl-2/IgH status was associated with shorter PFS (8.7 months vs not reached; HR, 3.15; 95% CI, 1.51-6.58; P = .002). By multivariate analysis, the pretreatment Bcl-2/IgH level was the strongest predictor for PFS. Our data suggest that pre- and posttreatment Bcl-2/IgH levels from PB have significant prognostic value for PFS in FL patients receiving first-line immunochemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT00991211 and at the German Federal Institute for Drugs and Medical Devices as #BfArM-4021335. PMID- 26239089 TI - Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. AB - The risk of central nervous system (CNS) dissemination in mantle cell lymphoma (MCL) is low and occurs late in the course of the disease. However, prognosis in such cases remains extremely poor despite high-dose antimetabolite chemotherapy. Among novel drugs used to treat relapsing MCL patients, ibrutinib, an oral inhibitor of Bruton tyrosine kinase, shows great promise. Here we report the clinical observation of 3 MCL patients with symptomatic CNS relapse treated with single-agent ibrutinib. All 3 patients had dramatic and rapid responses with almost immediate recovery from symptoms. We also confirmed that ibrutinib crosses the blood-brain barrier with parallel pharmacokinetic analyses in plasma and cerebrospinal fluid using a validated LC-MS/MS method. All responses were ongoing after 2 months to 1 year of follow-up. PMID- 26239088 TI - Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. AB - Programmed cell death ligand 1 (PD-L1) is expressed on both select diffuse large B-cell lymphoma (DLBCL) tumor cells and on tumor-infiltrating nonmalignant cells. The programmed cell death 1 (PD-1)/PD-L1 pathway inhibits host antitumor responses; however, little is known about how this pathway functions in the tumor microenvironment. The aim of this study was to determine the clinicopathological impact of PD-L1(+) DLBCL. We performed PD-L1/PAX5 double immunostaining in 1253 DLBCL biopsy samples and established a new definition of PD-L1(+) DLBCL. We also defined the criteria for microenvironmental PD-L1(+) (mPD-L1(+)) DLBCL (ie, PD L1(-) DLBCL in which PD-L1(+) nonmalignant cells are abundant in the tumor microenvironment). Of the 273 patients whose clinical information was available, quantitative analysis of PD-1(+) tumor-infiltrating lymphocytes (TILs) was performed. The prevalence rates of PD-L1(+) and mPD-L1(+) DLBCL were 11% and 15.3%, respectively. Both PD-L1(+) and mPD-L1(+) DLBCL were significantly associated with non-germinal center B-cell (GCB) type and Epstein-Barr virus positivity. The number of PD-1(+) TILs was significantly higher in GCB-type tumors and lower in mPD-L1(-) and PD-L1(+) DLBCL. Patients with PD-L1(+) DLBCL had inferior overall survival (OS) compared with that in patients with PD-L1(-) DLBCL (P = .0009). In contrast, there was no significant difference in OS between mPD-L1(+) and mPD-L1(-) DLBCL (P = .31). The expression of PD-L1 maintained prognostic value for OS in multivariate analysis (P = .0323). This is the first report describing the clinicopathological features and outcomes of PD-L1(+) DLBCL. Immunotherapy targeting the PD-1/PD-L1 pathway should be considered in this distinct DLBCL subgroup. PMID- 26239090 TI - Monitoring unfractionated heparin in children: a parallel-cohort randomized controlled trial comparing 2 dose protocols. AB - Monitoring unfractionated heparin (UFH) is crucial to prevent over- or under anticoagulation. However, the optimal parameters for monitoring UFH in children are not well established. The study objectives were to investigate (1) the relationship between UFH dose and its anticoagulant effect as assessed by anti Xa, activated partial thromboplastin time (aPTT) and activated clotting time (ACT); (2) other factors influencing UFH effect; (3) the agreement between the assays; and (4) the association between UFH effect and clinical outcome. HEARTCAT was a parallel-cohort randomized controlled trial comparing high-dose (100 U/kg bolus followed by age-based continuous infusion in randomized children) vs low dose UFH (50 U/kg bolus) during cardiac catheterization in children. Blood samples were drawn before and after UFH administration at 30, 60, and 90 minutes. Four-hundred and two samples of 149 patients were evaluable. Anti-Xa, aPTT, and ACT all showed good discrimination between UFH doses. Regression models demonstrated the following determinants of UFH effect: UFH dose, age, baseline antithrombin (for anti-Xa), and baseline levels of aPTT and ACT, respectively. UFH effects were lower in infants compared with older children, which was more pronounced at low-dose than at high-dose UFH. Agreement between the 3 assays was poor. Most aPTT values were above therapeutic range or beyond measuring limit and thus of limited value for UFH monitoring. No association of UFH dose or effect with clinical outcome could be observed. In conclusion, all assays reflected a significant UFH dose-effect relationship, however, with poor agreement between the respective tests. The age-dependency of UFH effect was confirmed. Notably, the influence of age on UFH effect was dose-dependent. PMID- 26239091 TI - Cell surface-associated aggregation-promoting factor from Lactobacillus gasseri SBT2055 facilitates host colonization and competitive exclusion of Campylobacter jejuni. AB - Campylobacter jejuni, one of the most common causes of gastroenteritis worldwide, is transmitted to humans through poultry. We previously reported that Lactobacillus gasseri SBT2055 (LG2055) reduced C. jejuni infection in human epithelial cells in vitro and inhibited pathogen colonization of chickens in vivo. This suggested that the LG2055 adhesion and/or co-aggregation phenotype mediated by cell-surface aggregation-promoting factors (APFs) may be important for the competitive exclusion of C. jejuni. Here, we show that cell surface associated APF1 promoted LG2055 self-aggregation and adhesion to human epithelial cells and exhibited high affinity for the extracellular matrix component fibronectin. These effects were absent in the apf1 knockout mutant, indicating the role of APF1 in LG2055-mediated inhibition of C. jejuni in epithelial cells and chicken colonization. Similar to APF1, APF2 promoted the co-aggregation of LG2055 and C. jejuni but did not inhibit C. jejuni infection. Our data suggest a pivotal role for APF1 in mediating the interaction of LG2055 with human intestinal cells and in inhibiting C. jejuni colonization of the gastrointestinal tract. We thus provide new insight into the health-promoting effects of probiotics and mechanisms of competitive exclusion in poultry. Further research is needed to determine whether the probiotic strains reach the epithelial surface. PMID- 26239092 TI - An Evidence-based Guide for Obesity Treatment in Primary Care. AB - On behalf of the Society of Behavioral Medicine, we present a model of obesity management in primary care based on the 5As counseling framework (Assess, Advise, Agree, Assist, and Arrange). Primary care physicians can use the 5As framework to build and coordinate a multidisciplinary team that: 1) addresses patients' psychosocial issues and medical and psychiatric comorbidities associated with obesity treatment failure; 2) delivers intensive counseling that consists of goal setting, self-monitoring, and problem solving; and 3) connects patients with community resources to assist them in making healthy lifestyle changes. This paper outlines reimbursement guidelines and weight-management counseling strategies, and provides a framework for building a multidisciplinary team to maximize the patient's success at weight management. PMID- 26239093 TI - Low Cobalamin Levels as Predictors of Cobalamin Deficiency: Importance of Comorbidities Associated with Increased Oxidative Stress. AB - BACKGROUND: Cobalamin (B12) deficiency can lead to irreversible neurocognitive changes if unrecognized. Screening involves measurement of serum cobalamin levels, but the sensitive metabolic indicators of cobalamin deficiency, methylmalonic acid (MMA) and homocysteine (HCys), may be normal when cobalamin values are low and elevated when cobalamin values are normal. Because cobalamin is inactivated by oxidation, the relationship between these metabolites and comorbidities associated with increased oxidative stress (oxidant risks) in subjects with low and low-normal cobalamin levels was studied. METHODS: A retrospective record-review was conducted of community-dwelling adults evaluated for cobalamin deficiency during a 12-year period with serum cobalamin values in the low (<= 200 pg/mL; n = 49) or low-normal (201-300 pg/mL; n = 187) range and concurrent measurement of MMA. RESULTS: When "No" oxidant risk was present, elevated MMA (>250 nmol/L) and HCys (>12.1 MUmol/L) values occurred in 50% and 30% of subjects, respectively (P <.01). In contrast, when "Three or More" oxidant risks were present, mean MMA and HCys values were significantly higher, and elevated MMA and HCys values occurred in 84% and 78% of these subjects, respectively (P <=.012). Pharmacologic doses of cyanocobalamin significantly decreased metabolite values in >= 94% of treated subjects. CONCLUSION: In subjects with low or low-normal cobalamin values, metabolic evidence of cobalamin deficiency is more frequent when 3 or more oxidant risks are present. Thus, defining a low serum cobalamin level to screen for cobalamin deficiency may be a "moving target" due to the variable presence and severity of often subtle, confounding clinical conditions in individual subjects. PMID- 26239094 TI - Antithrombotic Treatment Patterns in Patients with Newly Diagnosed Nonvalvular Atrial Fibrillation: The GLORIA-AF Registry, Phase II. AB - BACKGROUND: The Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) was designed to provide prospectively collected information on patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke, with the aim of addressing treatment patterns and questions of effectiveness and safety. METHODS AND RESULTS: In this predefined analysis from GLORIA-AF, the baseline characteristics and initial antithrombotic management of the first 10,000 patients in Phase II of this large Registry Program are presented. Overall, 32.3% of patients received vitamin K antagonists (VKAs) and 47.7% received non-VKA oral anticoagulants (NOACs), while 12.3% received antiplatelet treatment and 7.6% did not receive any antithrombotic treatment. Among patients with CHA2DS2-VASc score >=2, 6.7% received no antithrombotic treatment and 10.0% received aspirin. In Europe, treatment with dabigatran was as common as treatment with VKAs (38.8% and 37.8%, respectively). More than half of the patients were treated with NOACs (52.4%), while antiplatelet treatment was given to 5.7%, and 4.1% did not receive any antithrombotic treatment. In North America, treatment with dabigatran (25.0%) was as common as with VKAs (26.1%), but overall NOAC use was more common (52.1%) than with VKAs (26.1%); however, 14.1% received antiplatelet treatment, while 7.6% received no antithrombotic treatment. In Asia, treatment with VKAs (31.9%) was more prevalent than NOACs (25.5%), but antiplatelet treatment was given to 25.8%, and 16.9% did not receive any antithrombotic treatment. In Asia, only 60.7% of patients with high stroke risk received oral anticoagulants (OACs). Paroxysmal atrial fibrillation and minimally symptomatic (or asymptomatic) patients were often undertreated with OACs. CONCLUSION: In this analysis, OAC use was high in Europe and North America, with overall NOAC use higher than VKA use. A considerable percentage of high-risk patients in North America still received antiplatelet treatment or were untreated, while Asian patients had a high proportion of aspirin use and nontreatment. PMID- 26239096 TI - The Forgotten Lead: aVR in Left Main Disease. PMID- 26239095 TI - Tropheryma whipplei Endocarditis: A Two-patient Case Series. AB - BACKGROUND: Whipple endocarditis is caused by Tropheryma whipplei and is a well described complication of Whipple's disease. Limited and small case series have been published regarding the presentation, diagnosis, and clinical course of this disease. METHODS/RESULTS: We describe 2 cases of patients with T. whipplei endocarditis, one of which underwent a successful heart transplant. CONCLUSION: In both cases of Whipple's endocarditis, there was a subacute prodromal phase followed by an acute rapid decompensation with severe destruction of the aortic valve, heart failure, and embolism. Because the diagnosis of T. whipplei endocarditis is typically not made until pathological examination of tissue, clinicians must have a high suspicion for it in the absence of other offending organisms, especially among middle-aged white males with sub-acute symptoms and embolic complications. PMID- 26239098 TI - Stereoselective synthesis of vinylphosphonates and phosphine oxides via silver catalyzed phosphorylation of styrenes. AB - An efficient and stereoselective synthesis of vinylphosphonates and phosphine oxides was developed starting from styrenes using AgNO3 as the catalyst and K2S2O8 as the oxidant. The success of the reaction was found to be critically dependent on the use of TEMPO as the additive. PMID- 26239097 TI - Cordyceps sinensis oral liquid prolongs the lifespan of the fruit fly, Drosophila melanogaster, by inhibiting oxidative stress. AB - This study investigated the effect of Cordyceps sinensis oral liquid (CSOL) on the lifespan of Drosophila melanogaster (fruit fly). Following the lifelong treatment of fruit flies with CSOL, lifespan was examined. The activity of copper zinc-containing superoxide dismutase 1 (SOD1), manganese-containing superoxide dismutase 2 (SOD2) and catalase (CAT), as well as the lipofuscin (LF) content were determined. The mRNA levels of SOD1, SOD2 and CAT were quantified by qPCR. Hydrogen peroxide (H2O2) and paraquat were used to mimic the effects of damage caused by acute oxidative stress. D-galactose was used to mimic chronic pathological aging. CSOL significantly prolonged the lifespan of the fruit flies under physiological conditions. The activity of SOD1 and CAT was upregulated, and LF accumulation was inhibited by CSOL. CSOL had no effect on the transcriptional levels (mRNA) of these enzymes. The survival time of the fruit flies which were negatively affected by exposure to H2O2 or paraquat was significantly prolonged by CSOL. In fruit flies pathologically aged by epxosure to D-galactose, CSOL also significantly prolonged their lifespan, upregulated the activity of SOD1 and CAT, and inhibited LF accumulation. The findings of our study indicate that CSOL prolongs the lifespan of fruit flies through an anti-oxidative stress pathway involving the upregulation of SOD1 and CAT activity and the inhibition of LF accumulation. CSOL may thus be explored as a novel agent for slowing the human aging process. PMID- 26239099 TI - Few-layered MoSe2 nanosheets as an advanced electrode material for supercapacitors. AB - We report the synthesis of few-layered MoSe2 nanosheets using a facile hydrothermal method and their electrochemical charge storage behavior. A systematic study of the structure and morphology of the as-synthesized MoSe2 nanosheets was performed. The downward peak shift in the Raman spectrum and the high-resolution transmission electron microscopy images confirmed the formation of few-layered nanosheets. The electrochemical energy-storage behavior of MoSe2 nanosheets was also investigated for supercapacitor applications in a symmetric cell configuration. The MoSe2 nanosheet electrode exhibited a maximum specific capacitance of 198.9 F g(-1) and the symmetric device showed 49.7 F g(-1) at a scan rate of 2 mV s(-1). A capacitance retention of approximately 75% was observed even after 10 000 cycles at a high charge-discharge current density of 5 A g(-1). The two-dimensional MoSe2 nanosheets exhibited a high specific capacitance and good cyclic stability, which makes it a promising electrode material for supercapacitor applications. PMID- 26239100 TI - Safety and immunogenicity of an attenuated Salmonella enterica serovar Paratyphi A vaccine candidate. AB - Enteric fever caused by Salmonella enterica serovar Paratyphi A has progressively increased in recent years and became a global health issue. Currently licensed typhoid vaccines do not confer adequate cross-immunoprotection against S. Paratyphi A infection. Therefore, vaccines specifically against enteric fever caused by S. Paratyphi A are urgently needed. In the present study, an attenuated vaccine strain was constructed from S. Paratyphi A CMCC50093 by the deletions of aroC and yncD. The obtained strain SPADD01 showed reduced survival within THP-1 cells and less bacterial burden in spleens and livers of infected mice compared with the wild-type strain. The 50% lethal doses of SPADD01 and the wild-type strain were assessed using a murine infection model. The virulence of SPADD01 is approximately 40,000-fold less than that of the wild-type strain. In addition, SPADD01 showed an excellent immunogenicity in mouse model. Single intranasal inoculation elicited striking humoral and mucosal immune responses in mice and yielded effective protection against lethal challenge of the wild-type strain. A high level of cross-reactive humoral immune response against LPS of Salmonella enterica serovar Typhi was also detected in immunized mice. However, SPADD01 vaccination only conferred a low level of cross-protection against S. Typhi. Our data suggest that SPADD01 is a promising vaccine candidate against S. Paratyphi A infection and deserves further evaluation in clinical trial. To date, no study has demonstrated a good cross-protection between serovars of S. Typhi and S. Paratyphi A, suggesting that the dominant protective antigens of both serovars are likely different and need to be defined in future study. PMID- 26239101 TI - Cytological analyses of the karyotypes and chromosomes of three Colletotrichum species, C. orbiculare, C. graminicola and C. higginsianum. AB - In contrast to the recent accomplishments of genome projects, cytological information on chromosomes and genomes of the genus Colletotrichum is very scarce. In this study, we performed mitotic cytological karyotyping for the three species, C. orbiculare, C. graminicola, and C. higginsianum by fluorescence microscopy and compared the results with those from genome projects. Chromosome number (CN) of C. orbiculare was determined for the first time to be n=10 with no minichromosomes (MCs) in the genome, while CNs of C. graminicola and C. higginsianum were consistent with those from their genome project including the number of MCs. Regarding chromosome features, C. orbiculare was peculiar in that each chromosome was distinctly partitioned into a highly AT-rich pericentromeric region and the remaining highly GC-rich regions, and the pericentromeric region was judged to be constitutive heterochromatin. Integrating all the discernible morphological characteristics such as chromosome length, nucleolar organizing region, and DAPI-stained regions, idiograms were constructed for the three species. The overall cytological features of the chromosomes and genomes fit well with the data from the genome projects in terms of genome size, GC-content, and the occurrence of AT-rich regions. This study represents the most comprehensive and detailed mitotic cytological karyotyping of fungi ever reported. PMID- 26239102 TI - Diagnostic utility of 5-hydroxymethylcytosine immunohistochemistry in melanocytic proliferations. AB - Decreased hydroxymethylated cytosine (5-hydroxymethycytosine, 5-hmC) is reported to correlate with melanocyte dysplasia. The purpose of this study was to assess the diagnostic utility of this observation. 5-hmC immunohistochemistry was performed on tissue microarrays containing 171-melanocytic lesions from two different institutions. An immunohistochemical staining score representing the percentage and intensity of nuclear staining was assigned. The performance characteristics of 5-hmC immunohistochemistry for discriminating between a nevus and melanoma were determined. Additional cases of melanoma arising in a nevus (n = 8), nodal nevi (n = 5) and melanoma micrometastases to a lymph node (n = 6) were also assessed. Pronounced 5-hmC loss was observed in melanomas when compared with nevi (mean +/- standard deviation = 6.71 +/- 11.78 and 55.19 +/- 23.66, respectively, p < 0.0001). While the mean immunohistochemical staining score values for melanocytic nevi and melanoma were distinct, there was considerable variability in immunohistochemical staining score within a single diagnostic category. The sensitivity and specificity of this assay for nevus vs. melanoma is 92.74 and 97.78%, respectively. Distinct biphasic staining patterns were observed in cases of melanoma arising in association with a nevus. Relative changes of 5 hmC expression within a single lesion may be more informative than absolute values when using 5-hmC as a diagnostic adjunct. PMID- 26239103 TI - Modeling internal ballistics of gas combustion guns. AB - Potato guns are popular homemade guns which work on the principle of gas combustion. They are usually constructed for recreational rather than criminal purposes. Yet some serious injuries and fatalities due to these guns are reported. As information on the internal ballistics of homemade gas combustion powered guns is scarce, it is the aim of this work to provide an experimental model of the internal ballistics of these devices and to investigate their basic physical parameters. A gas combustion gun was constructed with a steel tube as the main component. Gas/air mixtures of acetylene, hydrogen, and ethylene were used as propellants for discharging a 46-mm caliber test projectile. Gas pressure in the combustion chamber was captured with a piezoelectric pressure sensor. Projectile velocity was measured with a ballistic speed measurement system. The maximum gas pressure, the maximum rate of pressure rise, the time parameters of the pressure curve, and the velocity and path of the projectile through the barrel as a function of time were determined according to the pressure-time curve. The maximum gas pressure was measured to be between 1.4 bar (ethylene) and 4.5 bar (acetylene). The highest maximum rate of pressure rise was determined for hydrogen at (dp/dt)max = 607 bar/s. The muzzle energy was calculated to be between 67 J (ethylene) and 204 J (acetylene). To conclude, this work provides basic information on the internal ballistics of homemade gas combustion guns. The risk of injury to the operator or bystanders is high, because accidental explosions of the gun due to the high-pressure rise during combustion of the gas/air mixture may occur. PMID- 26239104 TI - Inactivation of INK4a and ARF induces myocardial proliferation and improves cardiac repair following ischemia-reperfusion. AB - The growth of the heart during mammalian embryonic development is primarily dependent on an increase in the number of cardiomyocytes (CM). However, shortly following birth, CMs cease proliferating and further growth of the myocardium is achieved via hypertrophic expansion of the existing CM population. The cyclin dependent kinase inhibitor 2A (Cdkn2a) locus encodes overlapping genes for two tumor suppressor proteins, p16INK4a and p19 alternative reading frame (ARF). To determine whether decreased Cdkn2a gene expression results in improved cardiac regeneration in vitro and in vivo following cardiac injury, the proliferation of CMs isolated from Cdkn2a knockout (KO) and wild-type (WT) mice in vitro and in vivo were evaluated following generation of ischemia reperfusion (IR) injury. The KO mice demonstrated enhanced CM proliferation not only in vitro, but also in vivo. Furthermore, heart function was improved and scar size was decreased in the KO mice compared with that of the WT mice. The results also indicated that microRNA (miR)-1 and miR-195 expression levels associated with cell proliferation were reduced following IR injury in KO mice compared with those of WT mice. These results suggested that the inactivation of INK4a and ARF stimulated CM proliferation and promoted cardiac repair. PMID- 26239105 TI - A problem of overlap. AB - Here we propose that earlier-demonstrated details in the primate visual cortical map may account for an otherwise puzzling (and problematic) finding in the current human fMRI literature. Specifically, the well-known regions LO and MT(+) reportedly overlap in the human cortical visual map, when those two regions are localized using standard stimulus comparisons in conventional fMRI experiments. Here we describe evidence supporting the idea that the apparent functional overlap between LO and MT arises from a third area (the MT crescent: "MTc"), which is well known to surround posterior MT based on earlier histological, neuroanatomical, and electrophysiological studies in nonhuman primates. If we assume that MTc also exists in human visual cortex, and that it has a location and functional properties intermediate to those in LO and MT, simplistic modeling confirmed that this arrangement could produce apparent overlap between localizers for LO and MT in conventional fMRI maps in human visual cortex. PMID- 26239106 TI - Why Sexual Economics Theory Is Patriarchal: Reply to Vohs and Baumeister's (2015) Comment on Rudman and Fetterolf (2014). PMID- 26239107 TI - Correcting Some Misrepresentations About Gender and Sexual Economics Theory: Comment on Rudman and Fetterolf (2014). PMID- 26239108 TI - Concreteness and Psychological Distance in Natural Language Use. AB - Existing evidence shows that more abstract mental representations are formed and more abstract language is used to characterize phenomena that are more distant from the self. Yet the precise form of the functional relationship between distance and linguistic abstractness is unknown. In four studies, we tested whether more abstract language is used in textual references to more geographically distant cities (Study 1), time points further into the past or future (Study 2), references to more socially distant people (Study 3), and references to a specific topic (Study 4). Using millions of linguistic productions from thousands of social-media users, we determined that linguistic concreteness is a curvilinear function of the logarithm of distance, and we discuss psychological underpinnings of the mathematical properties of this relationship. We also demonstrated that gradient curvilinear effects of geographic and temporal distance on concreteness are nearly identical, which suggests uniformity in representation of abstractness along multiple dimensions. PMID- 26239109 TI - In vivo imaging of the lung inflammatory response to Pseudomonas aeruginosa and its modulation by azithromycin. AB - BACKGROUND: Chronic inflammation of the airways is a central component in lung diseases and is frequently associated with bacterial infections. Monitoring the pro-inflammatory capability of bacterial virulence factors in vivo is challenging and usually requires invasive methods. METHODS: Lung inflammation was induced using the culture supernatants from two Pseudomonas aeruginosa clinical strains, VR1 and VR2, isolated from patients affected by cystic fibrosis and showing different phenotypes in terms of motility, colony characteristics and biofilm production as well as pyoverdine and pyocyanine release. More interesting, the strains differ also for the presence in supernatants of metalloproteases, a family of virulence factors with known pro-inflammatory activity. We have evaluated the benefit of using a mouse model, transiently expressing the luciferase reporter gene under the control of an heterologous IL-8 bovine promoter, to detect and monitoring lung inflammation. RESULTS: In vivo imaging indicated that VR1 strain, releasing in its culture supernatant metalloproteases and other virulence factors, induced lung inflammation while the VR2 strain presented with a severely reduced pro-inflammatory activity. The bioluminescence signal was detectable from 4 to 48 h after supernatant instillation. The animal model was also used to test the anti-inflammatory activity of azithromycin (AZM), an antibiotic with demonstrated inhibitory effect on the synthesis of bacterial exoproducts. The inflammation signal in mice was in fact significantly reduced when bacteria grew in the presence of a sub-lethal dose of AZM causing inhibition of the synthesis of metalloproteases and other bacterial elements. The in vivo data were further supported by quantification of immune cells and cytokine expression in mouse broncho-alveolar lavage samples. CONCLUSIONS: This experimental animal model is based on the transient transduction of the bovine IL 8 promoter, a gene representing a major player during inflammation, essential for leukocytes recruitment to the inflamed tissue. It appears to be an appropriate molecular read-out for monitoring the activation of inflammatory pathways caused by bacterial virulence factors. The data presented indicate that the model is suitable to functionally monitor in real time the lung inflammatory response facilitating the identification of bacterial factors with pro-inflammatory activity and the evaluation of the anti-inflammatory activity of old and new molecules for therapeutic use. PMID- 26239110 TI - Seroprevalence of Toxoplasma gondii in free-ranging wild boars hunted for human consumption in Estonia. AB - BACKGROUND: Although the prevalence of human Toxoplasma gondii infections is high in Estonia, no information is available on the prevalence of infections in the local animal populations. Wild boars are a good indicator species for estimating the prevalence and spread of T. gondii and were thus investigated in this nationwide cross-sectional study. Volunteer hunters sampled cardiac or skeletal muscle of 471 wild boars legally hunted for human consumption in Estonia during the hunting season of 2012-2013. Serosanguineous meat juice samples were obtained from thawed tissue samples, diluted 1:40, and screened for specific anti-T. gondii IgG antibodies with a commercial direct agglutination test. RESULTS: Almost one-quarter (113; 24%) of the wild boars examined were seropositive for T. gondii. The seroprevalence did not differ significantly between age groups or sexes. The seroprevalence was lowest in Viljandimaa, which is located in the southern part of Estonia. In other counties, the infection was evenly prevalent. CONCLUSIONS: In Estonia, wild boars are commonly exposed to T. gondii, which is endemic and widespread. The consumption of raw or undercooked meat of Estonian wild boars may pose an infection risk to humans and other hosts. PMID- 26239111 TI - Testing the Independence of Multiple Personality Factors in Relation to Health Among Community-Dwelling Older Men. AB - OBJECTIVE: We assessed associations between specific personality factors and health, and tested whether specific personality factors were related to health outcomes independent of each other. METHOD: We performed cross-sectional analyses of personality and health among a sample of community-dwelling older men (n = 613, M age = 81.4, SD = 5.04 years) living in Pittsburgh, Pennsylvania. RESULTS: Personality factors (dispositional optimism, conscientiousness, and goal adjustment) were crudely related to both physical and mental health, but adjusting for other personality factors completely attenuated several of these associations. Conscientiousness remained uniquely related to every physical and mental health outcome. Optimism remained uniquely related to all health outcomes, except physical activity (which was more highly related to conscientiousness and goal adjustment). Associations between goal adjustment and probable depression appeared to be explained by conscientiousness and optimism. DISCUSSION: Correlations among multiple aspects of personality may mask unique associations of specific personality aspects with successful aging. PMID- 26239112 TI - Symptoms, Diagnosis, and Treatment of Cow's Milk Allergy. AB - INTRODUCTION: The diagnosis and management of cow's milk allergy (CMA) is a topic of debate because there are no specific symptoms and reliable diagnostic tests. METHOD: Literature was searched using databases to find original papers and reviews on this topic. RESULTS: A "challenge test" is still recommended as the most specific and sensitive diagnostic test, although a positive challenge test does not proof the involvement of the immune system. Only in the rare case of anaphylaxis, the challenge tests is not recommended. The Cow's Milk Symptom Score (CoMiSS) is an awareness tool for health care professionals to better recognize symptoms caused by the ingestion of cow's milk, but still needs validation. Today, the recommended diagnostic approach consists of an elimination diet with an extensive cow's milk based hydrolysate, followed by a challenge test. Amino acid based formula is reserved for the severe cases. Rice hydrolysates are gaining popularity, because they have been shown to be effective, have a better acceptability, and to be cheaper than the extensive cow's milk based hydrolysates. Soy infant formula may offer an additional alternative option as reviews concluded that about 10-15% of infants allergic to cow's milk will also react to soy. Gastro-intestinal microbiota manipulation may be of additional benefit in the treatment of CMA. CONCLUSION: The development of rice hydrolysates challenge the use of Today, extensive cow's milk based extensive hydrolysates remain the first option for the majority of patients and amino acid formula for the most severe cases. Rice hydrolysates and soy infant formula are considered as second choice options. PMID- 26239113 TI - How Much Iron is Needed for Breastfeeding Infants? AB - The iron requirement for breastfed infants remains controversial. Given the impact of iron on neurodevelopmental outcomes and the questionable impact of iron supplements after iron deficiency has occurred, its importance as a nutrient in this population cannot be down played. Infants are born with relatively large body stores of iron that are marginally related to maternal iron status in developed countries. Delayed cord clamping may increase these fetal stores, but at the present time this is only recommended for preterm infants who are born with low iron stores. The diagnosis of iron deficiency (ID) and iron deficiency anemia (IDA) remains problematic though new laboratory tests (measures of reticulocyte hemoglobin concentration and serum transferrin receptor) hold promise in developed countries. The present evidence supports the potential benefits of iron supplementation of exclusively breastfed infants after 4 months of age, by which time the iron stores present at birth are depleted. This deficit cannot be made up even if the small amounts of iron in human milk are completely absorbed. PMID- 26239114 TI - Reduction of mixed Mn-Zr oxides: in situ XPS and XRD studies. AB - A series of mixed Mn-Zr oxides with different molar ratios Mn/Zr (0.1-9) have been prepared by coprecipitation of manganese and zirconium nitrates and characterized by X-ray diffraction (XRD) and BET methods. It has been found that at concentrations of Mn below 30 at%, the samples are single-phase solid solutions (MnxZr1-xO2-delta) based on a ZrO2 structure. X-ray photoelectron spectroscopy (XPS) measurements showed that manganese in these solutions exists mainly in the Mn(4+) state on the surface. An increase in Mn content mostly leads to an increase in the number of Mn cations in the structure of solid solutions; however, a part of the manganese cations form Mn2O3 and Mn3O4 in the crystalline and amorphous states. The reduction of these oxides with hydrogen was studied by a temperature-programmed reduction technique, in situ XRD, and near ambient pressure XPS in the temperature range from 100 to 650 degrees C. It was shown that the reduction of the solid solutions MnxZr1-xO2-delta proceeds via two stages. During the first stage, at temperatures between 100 and 500 degrees C, the Mn cations incorporated into the solid solutions MnxZr1-xO2-delta undergo partial reduction. During the second stage, at temperatures between 500 and 700 degrees C, Mn cations segregate on the surface of the solid solution. In the samples with more than 30 at% Mn, the reduction of manganese oxides was observed: Mn2O3 -> Mn3O4 -> MnO. PMID- 26239115 TI - Everolimus plus exemestane versus bevacizumab-based chemotherapy for second-line treatment of hormone receptor-positive metastatic breast cancer in Greece: An economic evaluation study. AB - BACKGROUND: The objective of our study was to conduct a cost-effectiveness (CE) study of combined everolimus (EVE) and exemestane (EXE) versus the common clinical practice in Greece for the treatment of postmenopausal women with HR+/HER2- advanced breast cancer (BC) progressing on nonsteroidal aromatase inhibitors (NSAI). The combinations of bevacizumab (BEV) plus paclitaxel (PACL) and BEV plus capecitabine (CAPE) were selected as comparators. METHOD: A Markov model, consisting of three health states, was used to describe disease progression and evaluate the CE of the comparators from a third-party payer perspective over a lifetime horizon. Efficacy and safety data as well as utility values considered in the model were extracted from the relevant randomized Phase III clinical trials and other published studies. Direct medical costs referring to the year 2014 were incorporated in the model. A probabilistic sensitivity analysis was conducted to account for uncertainty and variation in the parameters of the model. Primary outcomes were patient survival (life-years), quality adjusted life years (QALYs), total direct costs and incremental cost effectiveness ratios (ICER). RESULTS: The discounted quality-adjusted survival of patients treated with EVE plus EXE was greater by 0.035 and 0.004 QALYs, compared to BEV plus PACL and BEV plus CAPE, respectively. EVE plus EXE was the least costly treatment in terms of drug acquisition, administration, and concomitant medications. The total lifetime cost per patient was estimated at ?55,022, ?67,980, and ?62,822 for EVE plus EXE, BEV plus PACL, and BEV plus CAPE, respectively. The probabilistic analysis confirmed the deterministic results. CONCLUSION: Our results suggest that EVE plus EXE may be a dominant alternative relative to BEV plus PACL and BEV plus CAPE for the treatment of HR+/HER2- advanced BC patients failing initial therapy with NSAIs. PMID- 26239116 TI - FKBP25 and FKBP38 regulate non-capacitative calcium entry through TRPC6. AB - Non-capacitative calcium entry (NCCE) contributes to cell activation in response to the occupation of G protein-coupled membrane receptors. Thrombin administration to platelets evokes the synthesis of diacylglycerol downstream of PAR receptor activation. Diacylglycerol evokes NCCE through activating TRPC3 and TRPC6 in human platelets. Although it is known that immunophilins interact with TRPCs, the role of immunophilins in the regulation of NCCE remains unknown. Platelet incubation with FK506, an immunophilin antagonist, reduced OAG-evoked NCCE in a concentration-dependent manner, an effect that was independent on the inactivation of calcineurin (CaN). FK506 was unable to reduce NCCE evoked by OAG in platelets from TRPC6-/- mice. In HEK-293 cells overexpressing TRPC6, currents through TRPC6 were altered in the presence of FK506. We have found interaction between FKBP38 and other FKBPs, like FKBP25, FKBP12, and FKBP52 that were not affected by FK506, as well as with calmodulin (CaM). FK506 modified the pattern of association between FKBP25 and TRPCs as well as impaired OAG-evoked TRPC3 and TRPC6 coupling in both human and mouse platelets. By performing biotinylation experiments we have elucidated that FKBP25 and FKBP38 might be found at different cellular location, the plasma membrane and the already described intracellular locations. Finally, FKBP25 and FKBP38 silencing significantly inhibits OAG-evoked NCCE in MEG-01 and HEK293 cells, while overexpression of FKBP38 does not modify NCCE in HEK293 cells. All together, these findings provide strong evidence for a role of immunophilins, including FKBP25 and FKBP38, in NCCE mediated by TRPC6. PMID- 26239117 TI - A Tat menage a trois--The role of Bacillus subtilis TatAc in twin-arginine protein translocation. AB - The twin-arginine translocation system (Tat) is a protein transport system that moves fully folded and cofactor-containing proteins across membranes of bacteria, archaea and thylakoids. The minimal Tat pathway is composed of two subunits, TatA and TatC. In some organisms TatA has been duplicated and evolved to form a third specialized subunit, TatB. The Bacillus subtilis genome encodes two TatC subunits (TatCd and TatCy) and three TatA subunits (TatAd, TatAy and TatAc). These subunits combine to form two parallel minimal pathways, TatAy-TatCy and TatAd TatCd. The purpose and role of the third TatA component, TatAc, has remained ambiguous. In this study we examined the translocation of two natively expressed TatAy-TatCy-dependent substrates, EfeB and QcrA, in various Tat-deficient genetic backgrounds. More specifically, we examined the ability of different mutated TatAy subunits to complement for the absence of wild-type TatAy. We further detailed a graded growth phenotype associated with the functional translocation of EfeB. We found that in various instances where specific amino acid substitutions were made in TatAy, a definite TatAc-associated growth phenotype occurred in genetic backgrounds lacking TatAc. Altogether, our findings show that TatAy and TatAc interact and that this TatAy-TatAc interaction, although not essential, supports the translocation of the Tat substrate EfeB when TatAy function is compromised. This implies that the third TatA-like protein in B. subtilis could represent an intermediate evolutionary step in TatA-TatB specialization. PMID- 26239118 TI - DNAJB1 negatively regulates MIG6 to promote epidermal growth factor receptor signaling. AB - Mitogen-inducible gene 6 (MIG6) is a tumor suppressor implicated in the development of human cancers; however, the regulatory mechanisms of MIG6 remain unknown. Here, using a yeast two-hybrid screen, we identified DnaJ homolog subfamily B member I (DNAJB1) as a novel MIG6-interacting protein. We found that DNAJB1 binds to and decreases MIG6 protein, but not mRNA, levels. DNAJB1 overexpression dosage-dependently decreased MIG6 protein levels. Conversely, DNAJB1 knockdown increased MIG6 protein levels. DNAJB1 destabilizes MIG6 by enhancing K48-linked ubiquitination of MIG6. However, knocking-down of DNAJB1 reduced the ubiquitination of MIG6. DNAJB1 positively regulates the epidermal growth factor receptors (EGFR) signaling pathway via destabilization of MIG6; however, DNAJB1 knockdown diminishes activation of EGFR signaling as well as elevation of MIG6. Importantly, the increased levels of MIG6 by DNAJB1 knockdown greatly enhanced the gefitinib sensitivity in A549 cells. Thus, our study provides a new molecular mechanism to regulate EGFR signaling through modulation of MIG6 by DNAJB1 as a negative regulator. PMID- 26239119 TI - Colchicine as an anti-inflammatory and cardioprotective agent. AB - INTRODUCTION: Colchicine has been successfully used for the treatment of neutrophilic disorders such as familial Mediterranean fever (FMF), Behcet disease (BD) and gout. There is a growing interest in its cardiovascular effects. AREAS COVERED: A MEDLINE/PubMed search for English articles published from January 1972 to June 2015 was completed using the following terms: therapy, pharmacokinetics, efficiency, side effects, toxicity, heart, colchicine, inflammation, FMF, amyloidosis, BD, gout, cardiovascular disorders, pericarditis, arrhythmias, inflammation, neutrophils, platelets. EXPERT OPINION: By targeting neutrophils, endothelial cells and platelets, inhibiting mitosis, vascular hyperplasia and fibrosis, colchicine improves outcomes of pericarditis, myocardial ischemia and coronary interventions. Studies in neutrophilic rheumatic diseases and cardiovascular disorders demonstrated that oral colchicine at doses of 0.5 - 2.5 mg/daily is useful for treating pericarditis, myocardial ischemia and coronary occlusion. In rheumatic and cardiovascular disorders, therapeutic doses of the drug reduce C-reactive protein to levels below 2 mg/L, prevent myocardial damage and preserve normal values of atrial and ventricular impulse generation. One of the drug's frequent side effects is diarrhea, which is treated by diet modification or temporary discontinuation of the therapy. Certain drugs (macrolides, statins), comorbidities and certain genetic factors increase risk of colchicine toxicity. PMID- 26239120 TI - Proteomics analysis reveals differentially activated pathways that operate in peanut gynophores at different developmental stages. AB - BACKGROUND: Cultivated peanut (Arachis hypogaea. L) is one of the most important oil crops in the world. After flowering, the peanut plant forms aboveground pegs (gynophores) that penetrate the soil, giving rise to underground pods. This means of reproduction, referred to as geocarpy, distinguishes peanuts from most other plants. The molecular mechanism underlying geocarpic pod development in peanut is poorly understood. RESULTS: To gain insight into the mechanism of geocarpy, we extracted proteins from aerial gynophores, subterranean unswollen gynophores, and gynophores that had just started to swell into pods. We analyzed the protein profiles in each of these samples by combining 1 DE with nanoLC-MS/MS approaches. In total, 2766, 2518, and 2280 proteins were identified from the three samples, respectively. An integrated analysis of proteome and transcriptome data revealed specifically or differentially expressed genes in the different developmental stages at both the mRNA and protein levels. A total of 69 proteins involved in the gravity response, light and mechanical stimulus, hormone biosynthesis, and transport were identified as being involved in geocarpy. Furthermore, we identified 91 genes that were specifically or abundantly expressed in aerial gynophores, including pectin methylesterase and expansin, which were presumed to promote the elongation of aerial gynophores. In addition, we identified 35 proteins involved in metabolism, defense, hormone biosynthesis and signal transduction, nitrogen fixation, and transport that accumulated in subterranean unswellen gynophores. Furthermore, 26 specific or highly abundant proteins related to fatty acid metabolism, starch synthesis, and lignin synthesis were identified in the early swelling pods. CONCLUSIONS: We identified thousands of proteins in the aerial gynophores, subterranean gynophores, and early swelling pods of peanut. This study provides the basis for examining the molecular mechanisms underlying peanut geocarpy pod development. PMID- 26239121 TI - Incorporating the Six Core Elements of Health Care Transition Into a Medicaid Managed Care Plan: Lessons Learned From a Pilot Project. AB - This pediatric-to-adult health care transition pilot project describes the process and results of incorporating the "Six Core Elements of Health Care Transition (2.0)" into a Medicaid managed care plan with a group of 35 18-23 year olds who have chronic mental health, developmental, and complex medical conditions. The pilot project demonstrated an effective approach for customizing and delivering recommended transition services. At the start of the 18-month project, the Medicaid plan was at the basic level (1) of transition implementation of the Six Core Elements with no transition policy, member transition readiness assessment results, health care transition plans of care, updated medical summaries, transfer package for the adult-focused provider, and assurance of transfer completion and consumer feedback. At the conclusion of the pilot project, the plan scored at level 3 on each core element. The primary reason for not scoring at the highest level (4) was because the transition elements have not been incorporated into services for all enrollees within the plan. Future efforts in managed care will benefit from starting the transition process much earlier (ages 12-14), expanding the role of nurse care managers and participating pediatric and adult-focused clinicians in transition, and offering payment incentives to clinicians to implement the Six Core Elements of Health Care Transition. PMID- 26239122 TI - Relationships Between Clinical Decision-Making Patterns and Self-Efficacy and Nursing Professionalism in Korean Pediatric Nurses. AB - As pediatric nurses must make decisions on a regular basis when caring for hospitalized children, clinical decision-making abilities are necessary in this profession. In the present study, we explored clinical decision-making patterns and their association with self-efficacy and nursing professionalism in pediatric nurses. We surveyed 173 pediatric nurses and analyzed the relationships between their clinical decision-making patterns and self-efficacy and nursing professionalism. Factor analysis identified 5 clinical decision-making patterns: patient-family-nurse collaborative (PNC), individual patient-oriented (IP), nurse model-oriented (NM), pattern-oriented intuitive (PI), and nursing knowledge oriented (NK). The most frequently observed clinical decision-making pattern was the PNC. The self-efficacy and nursing professionalism were found to be higher in pediatric nurses using the IP and NM, and were lower for those using the PNC. Thus, the present results suggest that pediatric nurses' clinical decision-making patterns are influenced by nursing professionalism and self-efficacy. Therefore, intervention programs focusing on these variables might improve clinical decision making in pediatric nurses. PMID- 26239123 TI - The role of husbands in maternal health and safe childbirth in rural Nepal: a qualitative study. AB - BACKGROUND: The role of husbands in maternal health is often overlooked by health programmes in developing countries and is an under-researched area of study globally. This study examines the role of husbands in maternity care and safe childbirth, their perceptions of the needs of women and children, the factors which influence or discourage their participation, and how women feel about male involvement around childbirth. It also identifies considerations that should be taken into account in the development of health education for husbands. METHODS: This qualitative study was conducted in four rural hill villages in the Gorkha district of Nepal. Semi-structured, in-depth interviews were conducted with husbands (n = 17), wives (n = 15), mothers-in-law (n = 3), and health workers (n = 7) in Nepali through a translator. Interviews were transcribed and analysed using axial coding. RESULTS: We found that, in rural Nepal, male involvement in maternal health and safe childbirth is complex and related to gradual and evolving changes in attitudes taking place. Traditional beliefs are upheld which influence male involvement, including the central role of women in the domain of pregnancy and childbirth that cannot be ignored. That said, husbands do have a role to play in maternity care. For example, they may be the only person available when a woman goes into labour. Considerable interest for the involvement of husbands was also expressed by both expectant mothers and fathers. However, it is important to recognise that the husbands' role is shaped by many factors, including their availability, cultural beliefs, and traditions. CONCLUSIONS: This study shows that, although complex, expectant fathers do have an important role in maternal health and safe childbirth. Male involvement needs to be recognised and addressed in health education due to the potential benefits it may bring to both maternal and child health outcomes. This has important implications for health policy and practice, as there is a need for health systems and maternal health interventions to adapt in order to ensure the appropriate and effective inclusion of expectant fathers. PMID- 26239124 TI - Inefficient translation of nsrR constrains behaviour of the NsrR regulon in Escherichia coli. AB - The NsrR protein of Escherichia coli is a transcriptional repressor that contains an [Fe-S] cluster that is the binding site for nitric oxide (NO). Reaction of NsrR with NO leads to de-repression of its target genes, which include those encoding an NO scavenging flavohaemoglobin and the RIC (repair of iron centres) protein involved in the repair of NO-damaged [Fe-S] clusters. The nsrR gene is promoter proximal in a transcription unit with rnr, encoding the cold shock inducible RNase R. Here, we show that nsrR is expressed from a strong promoter, but that its translation is extremely inefficient, leading to a low cellular NsrR concentration. Conversion of the nsrR start codon from the wild-type GUG to AUG increased the efficiency of translation (which, nevertheless, remained extremely low) and had measurable effects on the expression of some NsrR-regulated genes. We conclude that NsrR abundance in the cell is such that promoters with low affinity NsrR binding sites may partially escape NsrR-mediated repression. Expression profiling confirmed that genes regulated by NsrR (whether directly or indirectly) tend to express lower mRNA levels when the nsrR start codon is AUG than when it is GUG. Transcriptomics data implicated the pyruvate oxidase gene poxB as a novel NsrR target, which we confirmed and showed to be due to read through transcription from the upstream hcp-hcr genes. We also present evidence to suggest that NsrR is a regulator of the sufABCDSE genes, which encode the components of an [Fe-S] cluster biogenesis and repair system. PMID- 26239125 TI - Interventions to Increase Treatment Adherence in Pediatric Atopic Dermatitis: A Systematic Review. AB - Poor adherence to treatment is a major factor limiting treatment outcomes in patients with atopic dermatitis. The purpose of our systematic review is to identify techniques that have been tested to increase treatment adherence in atopic dermatitis. A MEDLINE search was performed for clinical trials focusing on interventions used to increase adherence in atopic dermatitis. Four articles were retrieved. References of these studies were analyzed yielding three more trials. The seven results were evaluated by comparing the intervention used to improve adherence, how adherence was assessed, and the outcome of the intervention tested. Different approaches to increase adherence such as written eczema action plans, educational workshops, extra office visits, and use of an atopic dermatitis educator were evaluated. All interventions increased adherence rates or decreased severity in patients, except for two. The MEDLINE search yielded limited results due to a lack of studies conducted specifically for atopic dermatitis and adherence was measured using different methods making the studies difficult to compare. Interventions including patient education, eczema action plans, and a quick return for a follow-up visit improve adherence, but based on the lack of clinical trials, developing new techniques to improve adherence could be as valuable as developing new treatments. PMID- 26239126 TI - Myogenic Precursors from iPS Cells for Skeletal Muscle Cell Replacement Therapy. AB - The use of adult myogenic stem cells as a cell therapy for skeletal muscle regeneration has been attempted for decades, with only moderate success. Myogenic progenitors (MP) made from induced pluripotent stem cells (iPSCs) are promising candidates for stem cell therapy to regenerate skeletal muscle since they allow allogenic transplantation, can be produced in large quantities, and, as compared to adult myoblasts, present more embryonic-like features and more proliferative capacity in vitro, which indicates a potential for more self-renewal and regenerative capacity in vivo. Different approaches have been described to make myogenic progenitors either by gene overexpression or by directed differentiation through culture conditions, and several myopathies have already been modeled using iPSC-MP. However, even though results in animal models have shown improvement from previous work with isolated adult myoblasts, major challenges regarding host response have to be addressed and clinically relevant transplantation protocols are lacking. Despite these challenges we are closer than we think to bringing iPSC-MP towards clinical use for treating human muscle disease and sporting injuries. PMID- 26239127 TI - HPV Carcinomas in Immunocompromised Patients. AB - Human papillomavirus (HPV) infection is the most common sexually transmitted disease worldwide and can result in pre-malignancies or overt malignancies of the skin and mucosal surfaces. HPV-related illnesses are an important personal and public health problem causing physical, mental, sexual and financial detriments. Moreover, this set of malignancies severely affects the immunosuppressed population, particularly HIV-positive patients and organ-transplant recipients. There is growing incidence of HPV-associated anogenital malignancies as well as a decrease in the average age of affected patients, likely related to the rising number of high-risk individuals. Squamous cell carcinoma is the most common type of HPV-related malignancy. Current treatment options for HPV infection and subsequent disease manifestations include imiquimod, retinoids, intralesional bleomycin, and cidofovir; however, primary prevention with HPV vaccination remains the most effective strategy. This review will discuss anogenital lesions in immunocompromised patients, cutaneous warts at nongenital sites, the association of HPV with skin cancer in immunocompromised patients, warts and carcinomas in organ-transplant patients, HIV-positive patients with HPV infections, and the management of cutaneous disease in the immunocompromised patient. PMID- 26239128 TI - Tapping Stem Cells to Target AMD: Challenges and Prospects. AB - Human pluripotent stem cells (hPSCs) are increasingly gaining attention in biomedicine as valuable resources to establish patient-derived cell culture models of the cell type known to express the primary pathology. The idea of "a patient in a dish" aims at basic, but also clinical, applications with the promise to mimic individual genetic and metabolic complexities barely reflected in current invertebrate or vertebrate animal model systems. This may particularly be true for the inherited and complex diseases of the retina, as this tissue has anatomical and physiological aspects unique to the human eye. For example, the complex age-related macular degeneration (AMD), the leading cause of blindness in Western societies, can be attributed to a large number of genetic and individual factors with so far unclear modes of mutual interaction. Here, we review the current status and future prospects of utilizing hPSCs, specifically induced pluripotent stem cells (iPSCs), in basic and clinical AMD research, but also in assessing potential treatment options. We provide an outline of concepts for disease modelling and summarize ongoing and projected clinical trials for stem cell-based therapy in late-stage AMD. PMID- 26239129 TI - Potential Role of Induced Pluripotent Stem Cells (IPSCs) for Cell-Based Therapy of the Ocular Surface. AB - The integrity and normal function of the corneal epithelium are crucial for maintaining the cornea's transparency and vision. The existence of a cell population with progenitor characteristics in the limbus maintains a dynamic of constant epithelial repair and renewal. Currently, cell-based therapies for bio replacement-cultured limbal epithelial transplantation (CLET) and cultured oral mucosal epithelial transplantation (COMET)-present very encouraging clinical results for treating limbal stem cell deficiency (LSCD) and restoring vision. Another emerging therapeutic approach consists of obtaining and implementing human progenitor cells of different origins in association with tissue engineering methods. The development of cell-based therapies using stem cells, such as human adult mesenchymal or induced pluripotent stem cells (IPSCs), represent a significant breakthrough in the treatment of certain eye diseases, offering a more rational, less invasive, and better physiological treatment option in regenerative medicine for the ocular surface. This review will focus on the main concepts of cell-based therapies for the ocular surface and the future use of IPSCs to treat LSCD. PMID- 26239131 TI - What Should General Practice Trainees Learn about Atopic Eczema? AB - Effective atopic eczema (AE) control not only improves quality of life but may also prevent the atopic march. The Royal College of General Practitioners' (RCGP) curriculum does not currently provide specific learning outcomes on AE management. We aimed to gain consensus on learning outcomes to inform curriculum development. A modified Delphi method was used with questionnaires distributed to gather the views of a range of health care professionals (HCPs) including general practitioners (GPs), dermatologists, dermatology nurses and parents of children with AE attending a dedicated paediatric dermatology clinic. Ninety-one questionnaires were distributed to 61 HCPs and 30 parents; 81 were returned. All agreed that learning should focus on the common clinical features, complications and management of AE and the need to appreciate its psychosocial impact. Areas of divergence included knowledge of alternative therapies. Parents felt GPs should better understand how to identify, manage and refer severe AD and recognized the value of the specialist eczema nurse. Dermatologists and parents highlighted inconsistencies in advice regarding topical steroids. This study identifies important areas for inclusion as learning outcomes on AE management in the RCGP curriculum and highlights the importance of patients and parents as a valuable resource in the development of medical education. PMID- 26239130 TI - Age-Related Macular Degeneration: Advances in Management and Diagnosis. AB - Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in older populations in industrialized nations. AMD is a late onset deterioration of photoreceptors and retinal pigment epithelium in the central retina caused by various environmental and genetic factors. Great strides in our understanding of AMD pathogenesis have been made in the past several decades, which have translated into revolutionary therapeutic agents in recent years. In this review, we describe the clinical and pathologic features of AMD and present an overview of current diagnosis and treatment strategies. PMID- 26239132 TI - The Importance of Colonization with Clostridium difficile on Infection and Transmission. AB - Clostridium difficile infections (CDI) are the most common cause of healthcare associated infections (HAI) in the USA, accounting for 12 % of all HAIs [1]. Reasons for such an increase are unknown but may relate to antibiotic use and evolution of a new, pathogenic strain, NAP1/BI/027. The Centers for Disease Control and Prevention (CDC) identifies C. difficile as one of only three organisms to be assigned a designation of an "urgent" threat level. Asymptomatic colonization with C. difficile is much more common than symptomatic CDI and has been documented to contribute to new cases of CDI. Despite this knowledge, approaches to managing and preventing transmission from asymptomatically colonized patients are lacking. Enhanced cleaning, avoidance of unnecessary antimicrobials, and use of gowns and gloves for patients with CDI are the cornerstone of C. difficile management in patients with known disease. Infection control interventions to prevent transmission from asymptomatically colonized patients have not been determined. PMID- 26239133 TI - The mammalian target of rapamycin modulates the immunoproteasome system in the heart. AB - The mammalian target of rapamycin (mTOR) plays an important role in cardiac development and function. Inhibition of mTOR by rapamycin has been shown to attenuate pathological cardiac hypertrophy and improve the function of aging heart, accompanied by an inhibition of the cardiac proteasome activity. The current study aimed to determine the potential mechanism(s) by which mTOR inhibition modulates cardiac proteasome. Inhibition of mTOR by rapamycin was found to reduce primarily the immunoproteasome in both H9c2 cells in vitro and mouse heart in vivo, without significant effect on the constitutive proteasome and protein ubiquitination. Concurrent with the reduction of the immunoproteasome, rapamycin reduced two important inflammatory response pathways, the NF-kappaB and Stat3 signaling. In addition, rapamycin attenuated the induction of the immunoproteasome in H9c2 cells by inflammatory cytokines, including INFgamma and TNFalpha, by suppressing NF-kappaB signaling. These data indicate that rapamycin indirectly modulated immunoproteasome through the suppression of inflammatory response pathways. Lastly, the role of the immunoproteasome during the development of cardiac hypertrophy was investigated. Administration of a specific inhibitor of the immunoproteasome ONX 0914 attenuated isoproterenol-induced cardiac hypertrophy, suggesting that the immunoproteasome may be involved in the development of cardiac hypertrophy and therefore could be a therapeutic target. In conclusion, rapamycin inhibits the immunoproteasome through its effect on the inflammatory signaling pathways and the immunoproteasome could be a potential therapeutic target for pathological cardiac hypertrophy. PMID- 26239134 TI - Imaging of atherosclerosis. AB - Cardiovascular disease (CVD) is a major health concern worldwide and atherosclerosis is the main cause of CVD. Atherosclerosis is a systemic and chronic inflammatory disease, which is characterized by plaque formation and can affect different vascular beds. Imaging of atherosclerosis could guide therapeutic interventions. Ultrasound, computed tomography, magnetic resonance imaging (MRI), positron emission tomography (PET) and interventional angiography are the main imaging modalities available for the assessment of atherosclerotic burden and for potential prediction of future events. In addition, the introduction of new hybrid imaging techniques like PET/MRI allow for the simultaneous evaluation of anatomical and metabolic characteristics tissues. This article provides an overview of coronary and non-coronary atherosclerosis and summarizes the current understanding of different available imaging techniques. The integration of these techniques in clinical practice may allow for superior risk stratification and therapeutic planning as well as monitoring of interventional and medication based treatment strategies. PMID- 26239135 TI - Arterial stiffness as a predictor of recovery of left ventricular systolic function after acute myocardial infarction treated with primary percutaneous coronary intervention. AB - Left ventricular ejection fraction (LVEF) and pulse wave velocity (PWV) are acknowledged as independent risk factors in different high-risk populations. We investigated the effects of arterial stiffness on LV function at 3 and 6 months after acute myocardial infarction. Changes in LVEF were evaluated in 136 consecutive patients who were diagnosed with ST-segment elevation coronary syndrome and treated with primary percutaneous coronary intervention. Doppler guided by 2D ultrasound was used to measure carotid-femoral PWV. According to tertiles of arterial stiffness, a significant correlation between higher PWV and worse recovery in LVEF was found (3 months EF change: 9.9 +/- 5.0% vs 5.9 +/- 3.4 vs 3.8 +/- 1.6; p < 0.001 and 6 months EF change: 18.5 +/- 7.0% vs 11.5 +/- 5.2 vs 7.3 +/- 3.0; p = 0.002). In the multivariate analysis PWV showed the ability to predict the outcome in terms of EF recovery at 3 and 6 months also after any correction for age and other variables (beta = -0.566, p < 0.001). Arterial stiffening may result in a less effective recovery of LV function after acute myocardial infarction. PMID- 26239136 TI - miR-138 suppresses the proliferation of oral squamous cell carcinoma cells by targeting Yes-associated protein 1. AB - Aberrant microRNA expression has been suggested to be an important event in the pathologies of various types of cancer. MicroRNA-138 (miR-138) has been reported to be frequently downregulated in various types of human cancer, including oral squamous cell carcinoma (OSCC). However, the precise molecular mechanism of miR 138 underlying OSCC remains largely unknown. The aim of the present study was to investigate the expression of miR-138 in OSCC tumor tissues and several OSCC cell lines and validated its interaction with the 3'-untranslated region (3'-UTR) of Yes-associated protein 1 (YAP1). The results showed that, miR-138 was significantly downregulated in OSCC tumor tissues and cell lines. Overexpression of miR-138 inhibited cell proliferation of OSCC cells whereas the downregulation of miR-138 promoted cell proliferation. A direct interaction between miR-138 and 3'-UTR of YAP1 was validated by dual-luciferase reporter assay. Moreover, overexpression of miR-138 in OSCC cells significantly decreased the expression of YAP1 and downregulation of miR-138 inhibited the expression of YAP1. Specifically, the inhibitory effect of miR-138 on the proliferation of OSCC cells was eliminated by transfection with YAP1 overexpression vectors that did not harbor any specific miR-138 binding specific sequences in 3'-UTR. In addition, the miR-138-overexpressing OSCC cells exhibited a low growth rate in the xenograft tumor assay with a decreased expression of YAP1 in tumor tissues. The results suggest that miR-138 is a tumor suppressor miRNA in OSCC through targeting YAP1, which serves as a promising therapeutic target for the treatment of OSCC. PMID- 26239138 TI - Bullying-related behaviour in a mainstream high school versus a high school for autism: Self-report and peer-report. AB - This study examined the frequency of bullying, victimisation and defending behaviours among children with autism spectrum disorder and normal intelligence, using both self-report and peer-report information. Peer-report and self-report data were collected on a single classroom of 26 early adolescent boys attending a special school for children with autism and compared with 23 typically developing boys attending a single mainstream secondary school. Results showed that self- and peer-reported bully and victimisation rates did not differ between boys with autism spectrum disorder and typically developing boys. However, self-reported defending behaviour was less likely to be reported by boys in the autism spectrum disorder school compared to boys in the mainstream school, although there was no such difference for peer-reported defending. PMID- 26239137 TI - Association of three SNPs in TOX3 and breast cancer risk: Evidence from 97275 cases and 128686 controls. AB - The associations of SNPs in TOX3 gene with breast cancer risk were investigated by some Genome-wide association studies and epidemiological studies, but the study results were contradictory. To derive a more precise estimate of the associations, we conducted a meta-analysis. ORs with 95% CI were used to assess the strength of association between TOX3 polymorphisms and breast cancer risk in fixed or random effect model. A total of 37 publications with 97275 cases and 128686 controls were identified. We observed that the rs3803662 C > T, rs12443621 A > G and rs8051542 C > T were all correlated with increased risk of breast cancer. In the stratified analyses by ethnicity, significantly elevated risk was detected for all genetic models of the three SNPs in Caucasians. In Asian populations, there were significant associations of rs3803662 and rs8051542 with breast cancer risk. Whereas there was no evidence for statistical significant association between the three SNPs and breast cancer risk in Africans. Additionally, we observed different associations of rs3803662 with breast cancer risk based on different ER subtype and BRCA1/BRCA2 mutation carriers. In conclusion, the meta-analysis suggested that three SNPs in TOX3 were significantly associated with breast cancer risk in different populations. PMID- 26239139 TI - Uncovering the natural history of cancer from post-mortem cross-sectional diameters of hepatic metastases. AB - We develop a mathematical and statistical methodology for estimation of important unobservable characteristics of the individual natural history of cancer from a sample of cross-sectional diameters of liver metastases measured at autopsy. Estimation of the natural history of cancer is based on a previously proposed stochastic model of cancer progression tailored to this type of observations. The model accounts for primary tumour growth, shedding of metastases, their selection, latency and growth in a given secondary site. The model was applied to the aforementioned data on 428 liver metastases detected in one untreated small cell lung cancer patient. Identifiable model parameters were estimated by the method of maximum likelihood and through minimizing the [Formula: see text] distance between theoretical and empirical cumulative distribution functions. The model with optimal parameters provided an excellent fit to the data. Results of data analysis support, if only indirectly, the hypothesis of the existence of stem-like cancer cells in the case of small cell lung carcinoma and point to the possibility of suppression of metastatic growth by a large primary tumour. They also lead to determination of the lower and upper bounds for the age of cancer onset and expected duration of metastatic latency. Finally, model-based inference on the patient's natural history of cancer allowed us to conclude that resection of the primary tumour would most likely not have had a curative effect. PMID- 26239140 TI - MicroRNA-19a mediates gastric carcinoma cell proliferation through the activation of nuclear factor-kappaB. AB - In gastric carcinoma, the nuclear factor-kappaB (NF-kappaB) signaling pathway is highly active, and the constitutive activation of NF-kappaB prompts malignant cell proliferation. MicroRNAs are considered to be important mediators in the regulation of the NF-kappaB signaling pathway. The present study predominantly focussed on the effects of microRNA (miR)-19a on NF-kappaB activation. Reverse transcription-quantitative polymerase chain reaction was used to quantify the relative levels of miR-19a in gastric carcinoma cells. MTT assays were used to determine the effect of miR-19a on cellular proliferation. To detect the activation of NF-kappaB, western blotting was performed to measure the protein levels of NF-kappaB and the products of its downstream target genes. To define the target genes, luciferase reporter assays were used. miR-19a was found to be markedly upregulated in gastric carcinoma cells. The overexpression of miR-19a resulted in proliferation and enhanced migratory capabilities of the MGC-803 gastric carcinoma cell line. The results of the western blot analysis demonstrated that the protein levels of p65 increased when the MGC-803 cells were transfected with miR-19a mimics. In addition, the downstream target genes of miR 19a, including intercellular adhesion molecule, vascular cell adhesion molecule and monocyte chemoattractant protein-1, were upregulated. The results of the luciferase assay indicated that IkappaB-alpha was the target gene of miR-19a. Therefore, the results of the present study suggested that miR-19a enhances malignant gastric cell proliferation by constitutively activating the NF-kappaB signaling pathway. PMID- 26239141 TI - Diabetes associated with dominant insulin gene mutations: outcome of 24-month, sensor-augmented insulin pump treatment. PMID- 26239142 TI - Impact of body weight on antidiabetic treatment and predictors of weight control under real-world conditions: a 2-year follow-up of DiaRegis cohort. AB - AIMS: Treatment strategies for obese patients with type 2 diabetes mellitus aim to increase physical activity, reduce body weight, and improve glucose control using weight-beneficial antidiabetic drugs. The objective of this study was to determine whether these strategies are implemented, and to identify factors predictive of glucose control and body weight management in a large, real-world patient population. METHODS: The prospective DiaRegis cohort study included 3807 patients with type 2 diabetes in whom the treating physician decided to intensify and optimize treatment because of insufficient glucose control. RESULTS: Antidiabetic treatment of overweight and obese patients was compared with that of normal-weight patients over a 2-years follow-up period, and multivariate analyses were performed to identify predictors of body weight loss. Among the 3807 participants, 92.5 % were overweight or obese. Normal-weight participants were more often treated with sulfonylureas or insulin, and overweight and obese patients with metformin or glucagon-like peptide (GLP)-1 analogues. Predictors of weight loss were body mass index (BMI) >=30 kg/m(2) and any reported physical activity. CONCLUSIONS: DiaRegis study shows that under real-world conditions, antidiabetic drug therapy is performed dependent on body weight. This strategy results in adequate glucose control and moderate weight reductions in overweight and obese patients. Weight loss is affected by treatment with weight-beneficial drugs, but also by any reported physical activity. However, only a small subgroup of patients perform physical activity. Initiation and maintenance of a physically active lifestyle remains a significant challenge for physicians, and patients with type 2 diabetes. PMID- 26239143 TI - Lower limbs edema by insulin glargine treatment: two other cases in pediatrics. PMID- 26239145 TI - Testing the implementation of an electronic process-of-care checklist for use during morning medical rounds in a tertiary intensive care unit: a prospective before-after study. AB - BACKGROUND: To improve the delivery of important care processes in the ICU, morning ward round checklists have been implemented in a number of intensive care units (ICUs) internationally. Good quality evidence supporting their use as clinical support tools is lacking. With increased use of technology in clinical settings, integration of such tools into current work practices can be a challenge and requires evaluation. Having completed preliminary work revealing variations in practice and evidence supporting the construct validity of a process-of-care checklist, the need to develop, test and further validate an e(lectronic)-checklist in an ICU was identified. METHODS: A prospective, before after study was conducted in a 19-bed general ICU within a tertiary hospital. Data collection occurred during baseline and intervention periods for 6 weeks each, with education and training conducted over a 4-week period prior to intervention. The e-checklist was used at baseline by ICU research nurses conducting post-ward round audits. During intervention, senior medical staff completed the e-checklist after patient assessments during the morning ward rounds, and research staff conducted post-ward round audits for validity testing (via concordance measurement). To examine changes in compliance over time, checklist-level data were analysed using generalised estimating equations that factored in confounding variables, and statistical process control charts were used to evaluate unit-level data. Established measures of concordance were used to evaluate e-checklist validity. RESULTS: Compliance with each care component improved significantly over time; the largest improvement was for pain management (42% increase; adjusted odds ratio = 23, p < 0.001), followed by glucose management (22% increase, p < 0.001) and head-of-bed elevation (19% increase, p < 0.001), both with odds ratios greater than 10. Most detected omissions were corrected by the following day. Control charts illustrated reduced variability in care compliance over time. There was good concordance between physician and auditor e-checklist responses; seven out of nine cares had kappa values above 0.8. CONCLUSION: Improvements in the delivery of essential daily care processes were evidenced after the introduction of an e-checklist to the morning ward rounds in an ICU. High levels of agreement between physician and independent audit responses lend support to the validity of the e-checklist. PMID- 26239144 TI - Glutamic acid decarboxylase autoantibodies are dominant but insufficient to identify most Chinese with adult-onset non-insulin requiring autoimmune diabetes: LADA China study 5. AB - AIMS: Adult-onset autoimmune diabetes is prevalent in China, in contrast to childhood-onset type 1 diabetes mellitus. Islet autoantibodies are the most important immune biomarkers to diagnose autoimmune diabetes. We assayed four different islet autoantibodies in recently diagnosed adult non-insulin-requiring diabetes Chinese subjects to investigate the best antibody assay strategy for the correct diagnosis of these subjects. METHODS: LADA China study is a nation-wide multicenter study conducted in diabetes patients from 46 university-affiliated hospitals in China. Non-insulin-treated newly diagnosed adult diabetes patients (n = 2388) were centrally assayed for glutamic acid decarboxylase autoantibody (GADA), protein tyrosine phosphatase-2 autoantibody (IA-2A), and zinc transporter 8 autoantibody (ZnT8A) by radioligand assay and insulin autoantibody (IAA) by microtiter plate radioimmunoassay. Clinical data were determined locally. RESULTS: Two hundred and six (8.63 %) subjects were autoantibody positive, of which GADA identified 5.78 % (138/2388) of the total, but only 67 % (138/206) of the autoimmune cases. IA-2A, ZnT8A, and IAA were found in 1.51, 1.84, and 1.26 % of the total study subjects, respectively. When assaying three islet autoantibodies, the most effective strategy was the combination of GADA, ZnT8A, and IAA, which could identify 92.2 % (190/206) autoimmune diabetes patients. The clinical data showed that those subjects with positive GADA had lower random C peptide than autoantibody negative subjects (P < 0.05). CONCLUSIONS: As with Europeans, GADA is the dominant autoantibody in this form of autoimmune diabetes in China, but in contrast to Europeans, screening should include other diabetes associated autoantibodies. PMID- 26239147 TI - Successful use of ultrasound-guided caudal catheter in a child with a very low termination of dural sac and Opitz-GBBB syndrome: a case report. AB - We report a 2-year-old patient with Opitz-GBBB syndrome scheduled for a posterior sagittal anorectoplasty (PSARP). The ultrasound scan revealed the inferior end of dural sac just below sacrococcygeal membrane, although the patient had previously two successful caudal epidural blocks. Consequently, the epidural catheter was inserted under a real-time ultrasound guidance without dural puncture. Our patient had excellent pain relief without any side effects. PMID- 26239146 TI - Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial beta1 integrin recycling. AB - Anti-angiogenic drugs targeting vascular endothelial cell growth factor receptor have provided modest clinical benefit, in part, owing to the actions of additional angiogenic factors that stimulate tumour neoangiogenesis in parallel. To overcome this redundancy, approaches targeting these other signalling pathways are required. Here we show, using endothelial cell-targeted mice, that the small GTPase Arf6 is required for hepatocyte growth factor (HGF)-induced tumour neoangiogenesis and growth. Arf6 deletion from endothelial cells abolishes HGF stimulated beta1 integrin recycling. Pharmacological inhibition of the Arf6 guanine nucleotide exchange factor (GEF) Grp1 efficiently suppresses tumour vascularization and growth. Grp1 as well as other Arf6 GEFs, such as GEP100, EFA6B and EFA6D, regulates HGF-stimulated beta1 integrin recycling. These findings provide insight into the mechanism of HGF-induced tumour angiogenesis and offer the possibility that targeting the HGF-activated Arf6 signalling pathway may synergize with existing anti-angiogenic drugs to improve clinical outcomes. PMID- 26239148 TI - Transrectal ultrasound-guided prostate biopsy in Taiwan: A nationwide database study. AB - BACKGROUND: For patients with an elevated prostate specific antigen (PSA) level or a suspected lesion detected by digital rectal examination, transrectal ultrasound-guided (TRUS) prostate biopsy is the standard procedure for prostate cancer diagnoses. In Taiwan, TRUS prostate biopsy has not been well-studied on a nationwide scale. This article aimed to study TRUS prostate biopsy in Taiwan and its related complications, according to the claims generated through the National Health Insurance (NHI) program. METHODS: We applied for access to claims from the NHI Research Database of Taiwan of all patients who visited the urology clinic during the period of 2006 to 2010. In the 5-year urology profile, we obtained all records, which included admission and ambulatory clinical records. The definition of TRUS biopsy included codes for ultrasound-guided procedure and for prostate puncture; other codes involving complications such as postbiopsy voiding difficulty, significant bleeding, or infection requiring treatment were also included. Risk factors included age, diagnosis of prostate cancer, hospitalization or nonhospitalization, and the Charlson Comorbidity Index (CCI; with a value of 0, 1, 2 or >= 3). Descriptive and comparative analyses were also performed. RESULTS: In the 5-year urology profile, 12,968 TRUS biopsies performed of which 6885 were in-patient procedures and 6083 were ambulatory clinic procedures. After the procedures, 1266 (9.76%) biopsies were associated with voiding difficulty; 148 (1.14%) biopsies, with significant bleeding; and 855 (6.59%) biopsies, with infection that required treatment. The prostate cancer diagnosis rate was 36.02%. The overall biopsy-related mortality rate within 30 days was 0.25%, and the postbiopsy sepsis-related mortality rate was 0.13%. Age, diagnosis of cancer, hospitalization, and CCI value >= 1 were all significant factors in univariate analysis and multivariate analysis for postbiopsy voiding difficulty and severe infection. A diagnosis of cancer and a CCI value >= 2 were significant factors for significant bleeding after biopsy. Patients diagnosed as having prostate cancer had fewer bleeding complications after biopsy. CONCLUSION: The most frequent complication was postbiopsy voiding difficulty, followed by infection that required treatment and significant bleeding. The sepsis-related mortality rate was 0.13%. Significant risk factors for postbiopsy complications included age, diagnosis of prostate cancer, hospitalization, and the CCI value. PMID- 26239149 TI - Assessment of acute and subacute toxic effects of the Saudi folk herb Retama raetam in rats. AB - BACKGROUND: Retama raetam (RR) fruit is used in traditional Saudi folk medicine as a hypoglycemic herb. However, the potential toxicity of RR has not been fully investigated. The current study aimed to explore the potential acute and subacute toxicities of the methanolic extract of RR fruit in male and female rats. METHODS: The extent of acute toxicity of RR was tested 14 days after a single oral dose was administered (250 mg/kg, 500 mg/kg, or 750 mg/kg). Additionally, subacute toxicity was tested 28 days after an oral dose of 250 mg/kg/d, 500 mg/kg/d, or 750 mg/kg/d was administered for 4 weeks. RESULTS: Subsequent to variable dosage testing, oral LD50 of RR was found to be 1995 mg/kg in rats. Oral doses of 500 mg/kg and 750 mg/kg significantly decreased body weight gain. Subacute administration (750 mg/kg) was associated with significant manifestations of toxicity. Additionally, subacute administration of the extract at doses of 500 mg/kg or 750 mg/kg significantly elevated alanine transaminase and aspartate transaminase activities. Hepatotoxicity of RR was confirmed with histopathological findings. Subacute administration of RR (500 mg/kg) showed histopathological changes in the liver as indicated by degenerated hepatocytes and early fibrosis, while a dosage of 750 mg/kg showed congested central vein and vascular degeneration. Moreover, subacute administration of the extract at doses of 250 mg/kg, 500 mg/kg, or 750 mg/kg showed histopathological alterations in rat kidney that ranged from mild interstitial congestion to tubular degeneration. The extract showed positive result in the Ames test. CONCLUSION: Repeated administration of methanolic extract of RR (250 mg/kg) has a low nephrotoxic subacute toxicity potential, while it might have hepatotoxic, nephrotoxic, and mutagenic effects at higher doses. PMID- 26239150 TI - In vitro effects of estrogen and progesterone containing drugs on human erythrocyte carbonic anhydrase I and II isozymes in women smokers and nonsmokers. AB - BACKGROUND: Carbonic anhydrases (CAs), a group of metalloenzymes, are involved in numerous physiological and pathological processes such as acid-base balance, gluconeogenesis, lipogenesis, ureagenesis, electrolyte secretion in various tissues, bone resorption and calcification, and tumorigenicity. In the current study, we aimed to determine and compare possible alterations in the activity of carbonic anhydrase I (CA I) and carbonic anhydrase II (CA II) isozymes by using estrogens and progestagens in female smokers and nonsmokers. METHODS: Blood samples from 30 smoker and 30 nonsmoker volunteers were drawn after obtaining informed consent. The blood samples were centrifuged to separate the plasma and erythrocytes. Thereafter, hemolysate was prepared from the red cells. CA I and CA II were purified from human erythrocytes with a simple one-step procedure using Sepharose 4B-l-tyrosine-sulfonamide affinity column. CAI and CA II isozymes were treated with estrogen and progesterone-containing drugs, after which the inhibition or activation of the enzyme was determined. RESULTS: CA I and CA II enzyme activity was observed to be increased in female smokers. The results of this study show that dienogest is the most effective inhibitor for human erythrocytes CA I when compared with micronized progesterone, hydroxyprogesterone caproate, estradiol valerate, and estradiol hemihydrate in both female smokers and nonsmokers. All active ingredients have been shown to have a stronger inhibition in smokers than nonsmokers for CA I activity. Additionally, estradiol valerate and hydroxyprogesterone caproate have stronger inhibition against CA II enzyme activity in women who smoke. CONCLUSION: The results of the current study provide important information to clinicians about how to consider the possible adverse effects of these drugs which are produced as a result of inhibition of CA I and CA II enzyme. Clinicians should take into consideration the side effects caused by CA I and CA II enzyme inhibition when prescribing these drugs in the treatment of different clinical conditions, especially in women who smoke. PMID- 26239151 TI - Notch Signaling in Cancer: Rationale and Strategies for Targeting. AB - The Notch signaling pathway is a highly conserved system that controls embryonic cell fate decisions and the maintenance of adult stem cells through affecting communication between adjacent cells. The pathway is linked to the development of various cancers owing to increased cell proliferation and tumor blood perfusion in addition to inhibition of apoptosis. Pharmaceutical agents that suppress overactive Notch signaling may be of benefit in the treatment of patients with various cancers. These targeted therapies confer several advantages over conventional anticancer therapies including reduced deleterious effects on normal cells. In this review, we explore the rationale for targeting the Notch signaling pathway in cancer along with different investigational strategies designed to block the pathway. PMID- 26239152 TI - Common and unique mechanisms of Chinese herbal remedies on ischemic stroke mice revealed by transcriptome analyses. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Four traditional Chinese herbal remedies (CHR) including Buyang Huanwu decoction (BHD), Xuefu Zhuyu decoction (XZD), Tianma Gouteng decoction (TGD) and Shengyu decoction (SYD) are popular used in treating brain-related dysfunction clinically with different syndrome/pattern based on traditional Chinese medicine (TCM) principles, yet their neuroprotective mechanisms are still unclear. MATERIALS AND METHODS: Mice were subjected to an acute ischemic stroke to examine the efficacy and molecular mechanisms of action underlying these CHR. RESULTS: CHR treatment significantly enhanced the survival rate of stroke mice, with BHD being the most effective CHR. All CHR were superior to recombinant tissue-type plasminogen activator (rt-PA) treatment in successfully ameliorating brain function, infarction, and neurological deficits in stroke mice that also paralleled to improvements in blood-brain barrier damage, inflammation, apoptosis, and neurogenesis. Transcriptome analyses reveals that a total of 774 ischemia-induced probe sets were significantly modulated by four CHR, including 52 commonly upregulated genes and 54 commonly downregulated ones. Among them, activation of neurogenesis-associated signaling pathways and down-regulating inflammation and apoptosis pathways are key common mechanisms in ischemic stroke protection by all CHR. Besides, levels of plasma CX3CL1 and S100a9 in patients could be used as biomarkers for therapeutic evaluation before functional recovery could be observed. CONCLUSION: Our results suggest that using CHR, a combinatory cocktail therapy, is a better way than rt-PA for treating cerebral ischemic-associated diseases through modulating a common as well as a specific group of genes/pathways that may partially explain the syndrome differentiation and treatment principle in TCM. PMID- 26239153 TI - In vitro antiprotozoal activity and cytotoxicity of extracts and fractions from the leaves, root bark and stem bark of Isolona hexaloba. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Isolona hexaloba (Pierre) Engl. and Diels (Annonaceae) is traditionally used in D.R. Congo against parasitic diseases including malaria. MATERIALS AND METHODS: Two crude aqueous extracts, 3 crude methanol extracts and 3 crude 80% ethanol extracts from the leaves, root bark and stem bark together with 12 subfractions from the crude 80% ethanol extracts were evaluated in vitro for their antiprotozoal activity against Trypanosoma brucei brucei, T. cruzi, Leishmania infantum and the chloroquine and pyrimethamine resistant K1 strain of Plasmodium falciparum. Their cytotoxic effects against MRC 5 cell lines were also assessed. RESULTS: Results indicated that the most pronounced activities against T. b. brucei were recorded for the crude methanol extracts of root bark (IC50=1.97 ug/ml; SI>32.49) and leaves (IC50=2.65 ug/ml; SI>24.15). Three samples displayed good activity against T. cruzi: the 80% methanol extract of leaves (IC50=8.33 ug/ml; SI>3.92), its petroleum ether fraction (IC50=8.50 ug/ml; SI=2.52) and the crude aqueous extract of the stem bark (IC50=9.31 ug/ml; SI=3.46). The crude aqueous extract of the leaves exhibited a pronounced and selective activity against L. infantum (IC50=2.00 ug/ml; SI>32). The crude methanol extract of leaves (IC50=6.35 ug/ml; SI>10.10) and the 2 dichloromethane soluble fractions of the 80% ethanol extracts from root bark (IC50=6.96 ug/ml; SI=6.1) and stem bark (IC50=8 ug/ml; SI>8.00) showed good activity and selectivity against L. infantum. The most active samples against Plasmodium falciparum K1 were the leaves crude 80% ethanol extract (0.92 ug/ml) and its fractions: alkaline aqueous (IC50=0.27 ug/ml), 90% methanol (0.90 ug/ml) and dichloromethane (1.04 ug/ml), respectively, with promising selectivity indexes of 350.05). Besides, SNX inhibited the contraction triggered by NE in endothelium denuded rings in Ca(2+)-free medium. SNX also produced rightward parallel displacement of CaCl2 curves. CONCLUSIONS: These results suggest that SNX can induce less endothelium-dependent and more endothelium-independent vascular relaxation. The NO/cGMP and HO/CO pathways, blockade of Ca(2+) channels are inhibition of IP3R mediated Ca(2+) mobilization from intracellular stores, are likely involved in this relaxation. Furthermore, the underlying mechanisms of combined compositions in SNX await further investigations. PMID- 26239155 TI - Ethnobotany of medicinal plants used in Antakya: A multicultural district in Hatay Province of Turkey. AB - ETHNOPHARMACOLOGICAL RELEVANCE: We have compiled information about the medicinal plants used in folk medicine in the district of Antakya. Since its establishment by King Seleucus I in 300 B.C., Antakya (old Antioch) has hosted nearly 20 civilizations. Antakya, neighboring Northwestern Syria, is located on the western end of the "Silk Road" and was one of the great centers of Graeco-Roman world. Today, Antakya is a cosmopolitan city in which Arabic and Turkish are widely spoken, and where distinct ethnic and religious communities, such as Arab Alawite, Arab Christian, Arab Sunni, Turk Sunni, Armenian, and Jewish, have been living together in harmony for centuries. In addition, the rich flora in the vicinity of Antakya also renders the area interesting in terms of ethnobotanical fieldwork. AIM OF THE STUDY: This study aimed to compile the information about plants used for medicinal purposes by local people in the district of Antakya. This city is a significant region in terms of ethnobotanical fieldwork, owing to its cosmopolitan structure, long history, relatively preserved traditional community structure, and rich flora. Furthermore, we sought to compare the ethnomedicinal data geographically, cross-culturally, and historically. MATERIALS AND METHODS: The ethnobotany of medicinal plants used in the district of Antakya has been investigated through two separate studies; one was conducted in 1975, interviewing 29 people, and the other was conducted in 2011-2013, interviewing 182 people. The use value (UV) and informant consensus factor (FIC) values of the plants were calculated. In order to interpret the authenticity and sources of the compiled ethnomedicinal information, previous publications that contain information about the similar medicinal uses of plants identified in our region were reviewed and evaluated meticulously. A comparison with the data obtained from other regions of Turkey and from other Mediterranean regions, as well as a cross-cultural analysis between the ethnic groups within the study area, was performed by implementation of the Jaccard index (JI) RESULTS: Throughout the study, information about 202 medicinal plant taxa was compiled. Among these plants, 39 have either not yet been mentioned in ethnobotanical or medicinal studies, or have been used for a medicinal purpose other than those encountered in the literature review. The ethnomedicinal information we gathered from the study area exhibits close similarities to the ethnomedicinal information of other Southern and Eastern Mediterranean countries where Arabic is spoken, as well as to that of Northern and Western Mediterranean countries where Latin languages are spoken. In addition to these similarities, in most cases, this ethnomedicinal information shows hybrid features of ethnomedicinal knowledge from Eastern and Western Mediterranean countries. CONCLUSION: Based on a literature survey, we found that the cited medicinal uses for 43 plants have also been corroborated by other various biological testings. This finding strongly suggests the importance of ethnobotanical studies in the development of new medicines. We believe that this study has compiled rich ethnomedicinal information that reflects the cosmopolitan structure of Antakya in a very good way. PMID- 26239156 TI - Moonlighting Metals: Insights into Regulation of Cyclization Pathways in Fungal Delta(6) -Protoilludene Sesquiterpene Synthases. AB - Fungal 1,11 cyclizing sesquiterpene synthases are product specific under typical reaction conditions. However, in vivo expression of certain Delta(6) protoilludene synthases results in dual 1,11 and 1,10 cyclization. To determine the factors regulating this mechanistic variation, in-depth in vitro characterization of Delta(6)-protoilludene synthases was conducted. Divalent metal ions determine cyclization specificity and this product variability. Promiscuity in metal binding is mediated by secondary metal-binding sites away from the conserved D(D/E)XX(D/E) motif in sesquiterpene synthases. Phylogenetic analysis revealed a divergent evolution of Basidiomycota trans-humulyl cation producing sesquiterpene synthases, results that indicate a wider diversity in function than previously predicted. This study provides key insights into the function and evolution of 1,11 cyclizing fungal sesquiterpene synthases. PMID- 26239158 TI - Measles vaccine: Past, present, and future. PMID- 26239157 TI - Influence of Electronic Effects on the Reactivity of Triazolylidene-Boryl Radicals: Consequences for the use of N-Heterocyclic Carbene Boranes in Organic and Polymer Synthesis. AB - A small library of triazolylidene-boranes that differ only in the nature of the aryl group on the external nitrogen atom was prepared. Their reactivity as hydrogen-atom donors, as well as that of the corresponding N-heterocyclic carbene (NHC)-boryl radicals toward methyl acrylate and oxygen, was investigated by laser flash photolysis, molecular orbital calculations, and ESR spin-trapping experiments, and benchmarked relative to the already known dimethyltriazolylidene borane. The new NHC-boranes were also used as co-initiators for the Type I photopolymerization of acrylates. This allowed a structure-reactivity relationship with regard to the substitution pattern of the NHC to be established and the role of electronic effects in the reactivity of NHC-boryl radicals to be probed. Although their rate of addition to methyl acrylate depends on their electronegativity, the radicals are all nucleophilic and good initiators for photopolymerization reactions. PMID- 26239159 TI - Developmental energetics, sibling death, and parental instability as predictors of maturational tempo and life history scheduling in males from Cebu, Philippines. AB - OBJECTIVES: Cross-species comparisons show that high extrinsic mortality favors the evolution of "faster" life histories. There is interest in applying this principle to human life history plasticity, based on the idea that psychosocial stressors that correlate with extrinsic mortality accelerate reproductive pace. Most prior studies have been conducted in settings in which psychosocial stressors co-occur with the maturation-accelerating influence of nutritional abundance. MATERIALS AND METHODS: We evaluate cues of local mortality (sibling death) or low parental investment (paternal instability; maternal absence) and energetic measures during development as predictors of life history scheduling among males (n = 754) in a Philippine population with marginal developmental nutritional. RESULTS: Males who had more favorable nutritional status during childhood, as reflected in linear growth, skinfold thickness, and caloric intake, were more maturationally advanced in adolescence (all P < 0.05). Taller stature and higher caloric intake during childhood also predicted earlier ages at first sex (both P < 0.01), which persisted after controlling for the effect of nutrition on pubertal maturation. While psychosocial stressors did not predict accelerated maturation, males who as children grew up with an unstable paternal presence had sex earlier (P < 0.05) and tended to become fathers sooner than those with a stable fatherly presence. Those who had a sibling die became fathers sooner than those who did not (P < 0.05). DISCUSSION: Our findings point to important energetic constraints on the onset of reproductive maturity, while psychosocial stressors accelerate entry to parenthood, which may be comparatively more socially, rather than biologically, constrained. Am J Phys Anthropol 158:175 184, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26239160 TI - Roles of microRNA-146a and microRNA-181b in regulating the secretion of tumor necrosis factor-alpha and interleukin-1beta in silicon dioxide-induced NR8383 rat macrophages. AB - Despite increasing evidence to suggest that microRNA (miR)-146a and miR-181b are involved in the regulation of immune responses and tumor progression, their roles in silicosis remain to be fully elucidated. Therefore, the present study examined the roles of miR-146a and miR-181b in inflammatory responses, and their effect on the expression of the tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) inflammatory chemokines in silicon dioxide (SiO2)-induced NR8383 rat macrophages. Alterations in the expression levels of miR-146a and miR-181b in rats with silicosis have been previously investigated using miRNA arrays. In the present study, the expression levels of miR-146a and miR-181b were assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The NR8383 cells were transfected with miRNA-146a and miR-181b mimics or inhibitors, and the cells and culture supernatants were collected following SiO2 treatment for 12 h. The expression levels of TNF-alpha and IL-1beta were detected using western blotting, RT-qPCR and ELISA. Analysis of variance and Student's two tailed t-test were used to perform statistical analyses. The expression level of miR-146a was significantly increased, while the expression level of miR-181b was significantly decreased in the fibrotic lungs of the rats with silicosis, compared with the levels in the normal rats. It was observed that, following treatment of the NR8383 cells with SiO2 for 12 h, the levels of TNF-alpha were significantly increased following miR-181b knockdown and the levels of IL-1beta were significantly increased following miR-146a knockdown, compared with the inhibitor-treated controls (P<0.05). By contrast, miR-181b mimic transfection led to a significant reduction in the levels of TNF-alpha (P<0.05), and miR-146a mimics were responsible for the decrease in IL-1beta (P<0.05). The results of the present study provide evidence supporting the roles of miR-146a and miR-181b in the pathogenesis of silicosis, and suggest that they may be candidate therapeutic target in this disease. PMID- 26239161 TI - Visceral fat area is associated with HbA1c but not dialysate-related glucose load in nondiabetic PD patients. AB - Factors associated with increased visceral fat area (VFA) have been well documented in the general population but rarely explored in nondiabetic individuals on peritoneal dialysis (PD). As glycosylated hemoglobin (HbA1c) is positively correlated with VFA in diabetic patients, we hypothesized that the same correlation would exist in nondiabetic PD patients. We enrolled 105 nondiabetic patients who had undergone chronic PD for more than 3 months. Each subject underwent an abdominal computed tomography (CT) scan, and the umbilicus cut was analyzed for VFA. VFA values, corrected for body mass index and subjected to natural logarithm transformations, were examined to determine whether they were correlated with HbA1c and other parameters. PD dialysates prescribed at the time of enrollment were recorded to calculate glucose load. We found that when 105 nondiabetic PD patients were classified according to tertiles of HbA1c, higher HbA1c was associated with larger VFA. Multiple linear regression analysis revealed that HbA1c was an independent determinant of VFA, while glucose load and other PD-specific factors were not. In summary, HbA1c, but not PD-related glucose load, was positively correlated with VFA in nondiabetic PD patients, suggesting clinical utility of HbA1c in the PD population. PMID- 26239162 TI - Facial emotion recognition system for autistic children: a feasible study based on FPGA implementation. AB - Children with autism spectrum disorder have difficulty in understanding the emotional and mental states from the facial expressions of the people they interact. The inability to understand other people's emotions will hinder their interpersonal communication. Though many facial emotion recognition algorithms have been proposed in the literature, they are mainly intended for processing by a personal computer, which limits their usability in on-the-move applications where portability is desired. The portability of the system will ensure ease of use and real-time emotion recognition and that will aid for immediate feedback while communicating with caretakers. Principal component analysis (PCA) has been identified as the least complex feature extraction algorithm to be implemented in hardware. In this paper, we present a detailed study of the implementation of serial and parallel implementation of PCA in order to identify the most feasible method for realization of a portable emotion detector for autistic children. The proposed emotion recognizer architectures are implemented on Virtex 7 XC7VX330T FFG1761-3 FPGA. We achieved 82.3% detection accuracy for a word length of 8 bits. PMID- 26239163 TI - Specimen-specific vertebral fracture modeling: a feasibility study using the extended finite element method. AB - Osteoporotic vertebral body fractures are an increasing clinical problem among the aging population. Specimen-specific finite element models, derived from quantitative computed tomography (QCT), have the potential to more accurately predict failure loads in the vertebra. Additionally, the use of extended finite element modeling (X-FEM) allows for a detailed analysis of crack initiation and propagation in various materials. Our aim was to study the feasibility of QCT/X FEM analysis to predict fracture properties of vertebral bodies. Three cadaveric specimens were obtained, and the L3 vertebrae were excised. The vertebrae were CT scanned to develop computational models and mechanically tested in compression to measure failure load, stiffness and to observe crack location. One vertebra was used for calibration of the material properties from experimental results and CT gray-scale values. The two additional specimens were used to assess the model prediction. The resulting QCT/X-FEM model of the specimen used for calibration had 2 and 4% errors in stiffness and failure load, respectively, compared with the experiment. The predicted failure loads of the additional two vertebrae were larger by about 41-44% when compared to the measured values, while the stiffness differed by 129 and 40%. The predicted fracture patterns matched fairly well with the visually observed experimental cracks. Our feasibility study indicated that the QCT/X-FEM method used to predict vertebral compression fractures is a promising tool to consider in future applications for improving vertebral fracture risk prediction in the elderly. PMID- 26239164 TI - Transplantation of vascular endothelial growth factor 165-transfected endothelial progenitor cells for the treatment of limb ischemia. AB - The present study aimed to investigate the effects of neovascularization in rabbits with limb ischemia transplanted with vascular endothelial growth factor (VEGF)165-transfected endothelial progenitor cells (EPC). Bone marrow mononuclear cells were isolated by gradient centrifugation, cultured in M199 culture medium and induced into EPCs using VEGF, basic fibroblast growth factor, and insulin like growth factor-1, and subsequently identified. The EPCs were transfected with Adv-green fluorescent protein-VEGF165 and the proliferation potential of the cells was determined using an MTT assay. The protein expression levels of VEGF were measured by detecting its concentration levels in the supernatant using an ABC-ELISA assay. A rabbit hind limb ischemic model was established and randomly divided into three groups: (A) Control group, (B) EPC-transplanted group, and (C) Ad-VEGF165/EPCs-transplanted group. The effects of transplantation and the levels of recanalization were detected. Incorporation of the transplanted cells into the ischemic region was confirmed by 5-bromodeoxyuridine staining, and the levels of recanalization were measured by computer tomography ateriography and immunohistochemical staining. Bone marrow-derived EPCs were induced, cultivated, and successfully identified. The results of the present study determined the optimum transfection ratio that promoted the growth of EPCs. The EPCs were successfully transfected with VEGF165, and EPC proliferation was not affected by the transfection. The supernatant protein concentration levels of VEGF were markedly higher in the VEGF165-transfected group, as compared with those of the control group. Introduction of the transplanted cells into the ischemic region of group C occurred more efficiently, as compared with groups A and B. The recanalization capillary density in group C was significantly higher, as compared with groups A and B. VEGF gene transfection was able to improve the quality of EPCs, and the response of rabbits with limb ischemia to transplantation with VEGF transfected EPCs was significantly better, as compared with transplantation with EPCs alone. PMID- 26239165 TI - Gremlin 2 inhibits adipocyte differentiation through activation of Wnt/beta catenin signaling. AB - The primary function of white adipose tissues is to store excess energy. The current study aimed to investigate the roles of Gremlin 2 (Grem2), a glycoprotein in adipogenesis. Using polymerase chain reaction-based microarrays, it was determined that Grem2 was markedly downregulated in adipose tissues from obese animals and humans. In addition, 3T3-L1 cells were used to investigate the details of the mechanisms underlying the anti-adipogenic effects of Grem2. Grem2 expression was markedly decreased upon the induction of adipocyte differentiation, as demonstrated by reverse transcription-quantitative polymerase chain reaction and western blot analysis. Notably, Grem2 overexpression inhibited adipogenesis, while knockdown of Grem2 led to an increase in adipogenesis. At the molecular level, Grem2 promotes nuclear translocation of beta-catenin, an integral Wnt signaling component. Consistently, inhibition of Wnt/beta-catenin signaling using a retrovirus targeting the beta-catenin coding region attenuated the anti-adipogenic effects of Grem2. Therefore, to the best of our knowledge, the current study shows for the first time that Grem2 may be an important regulator of adipocyte differentiation. PMID- 26239166 TI - Shortened dental arch and body mass index in adults 45-65 years of age: results from National Health and Nutrition Examination Survey 2005-2008. AB - OBJECTIVE: Many people have dental arches with unrestored edentulous areas posterior to natural teeth. One dental pattern is the shortened dental arch (SDA). As a result of the lack of teeth, individuals with an SDA may eat a restricted diet, including soft, highly processed foods. Such diets may increase the risk of being overweight or of obesity. We examined whether there was an association between SDA and body mass index (BMI) in adults 45-65 years of age. METHODS: The data for this study were US National Health and Nutrition Examination Survey (NHANES) 2005-2008 merged files. There were 5,773 eligible participants. The data were examined for frequencies, and the results were analysed using the chi-square test and logistic regression. RESULTS: There were 69.3% participants with a shortened mandibular arch and a BMI of >=25 compared with 71.8% of participants who had a complete mandibular dental arch and a BMI of >=25 (P=0.7246). There were 70.6% of participants with a shortened maxillary arch and a BMI of >=25 compared with 71.9% of participants who had a complete maxillary dental arch and a BMI of >=25 (P=0.8859). The adjusted odds ratio for shortened mandibular dental arch was 0.70 (95% CI: 0.46-1.08) for a BMI of >=25 as compared with individuals with a BMI<25. The adjusted odds ratio for shortened maxillary dental arch was 1.06 (95% CI: 0.63-1.78) as compared with individuals with a BMI<25. CONCLUSIONS: The research hypothesis that an SDA was related to higher BMI, and the corollary that restored or complete dentition had better odds of a lower BMI, were not supported. PMID- 26239167 TI - Inhibition of sphingosine-1-phosphate phosphatase 1 promotes cancer cells migration in gastric cancer: Clinical implications. AB - Sphingosine-1-phosphate (S1P) plays an important role in regulating many biological processes. Sphingosine-1-phosphate phosphatase 1 (SGPP1) can dephosphorylate S1P into sphingosine and tip the balance of sphingosine-S1P. Increased levels of sphingosine leads to a decrease in the ability of cell invasion as well as an increase in the ability of cell apoptosis. However, little is known regarding the effects of SGPP1 in gastric cancer. The present study examined the function of SGPP1 on gastric cancer cell lines as well as its clinical relevance in gastric cancer progression. Using immunohistochemistry and RT-qPCR techniques, the clinical significance of SGPP1 expression was analyzed in 288 paraffin-embedded gastric tissue specimens and 219 fresh gastric tissues, respectively. Transgenes encoding ribozymes to specifically target human SGPP1 (pEF-SGPP1) was constructed. Human gastric cancer cell lines (AGS and HGC27) were transfected with pEF-SGPP1 transgene and examined by functional analysis. SGPP1 was downregulated in gastric cancer tissues, compared with adjacent normal gastric tissues (p=0.034). SGPP1 mRNA levels in gastric cancer tissues were significantly decreased when compared with their adjacent non-cancerous tissues (p<0.001). Weakly expressed SGPP1 was positively correlated with the lymph node metastasis (p=0.005) and distant metastasis (p=0.031). Kaplan-Meier survival curves revealed that patients with SGPP1 positive expression had a significant increase in overall survival (OS) (p=0.034) and progression-free survival (PFS) (p=0.041). Multivariate analysis indicated the expression of SGPP1 was an independent prognostic factor in gastric cancer patients (p=0.041). In vitro experiments showed that knockdown of SGPP1 resulted in an increase in the invasion (2-fold) and migration (5-fold) of AGS and HGC27. The two gastric cancer cells transfected with pEF-SGPP1 exhibited a slower rate of growth with less adhesion. Thus, our findings provided evidence that SGPP1 may serve as a prognostic biomarker for patients with advanced gastric cancers. PMID- 26239168 TI - Bouveret's syndrome: An unusual cause of duodenal obstruction. PMID- 26239169 TI - The dark story of the yellow rose: A case report of hepatotoxicity associated with Cochlospermum vitifolium consumption as an herbal remedy. PMID- 26239170 TI - Acute gastric dilation after trauma. PMID- 26239171 TI - MicroRNA-214 promotes proliferation and inhibits apoptosis via targeting Bax in nasopharyngeal carcinoma cells. AB - The deregulation of microRNAs (miRNAs) is involved in the development and progression of various types of human malignancy. Previously, it has been suggested that miR-214 has an oncogenic role in nasopharyngeal carcinoma. However, the detailed molecular mechanisms remain to be elucidated. In the present study, reverse transcription-quantitative polymerase chain reaction and western blot analysis were conducted to determine the relative mRNA and protein levels, respectively. The MTT assay was performed to examine cell proliferation. Flow cytometry was conducted to determine cell apoptosis level. In the present study, the expression of miR-214 was found to be notably upregulated in nasopharyngeal carcinoma tissues and cell lines. Further investigation demonstrated that inhibition of miR-214 inhibited proliferation and promoted apoptosis in nasopharyngeal carcinoma cells. By contrast, overexpression of miR 214 promoted nasopharyngeal carcinoma cell proliferation and inhibited cell apoptosis. Bcl-2-associated X protein (Bax) was then identified as a novel target of miR-214. miR-214 negatively regulated the protein expression of Bax in nasopharyngeal carcinoma cells. siRNA-induced Bax inhibition attenuated the promoting effect of miR-214 downregulation on nasopharyngeal carcinoma cell apoptosis, suggesting that Bax acts as a downstream effector in miR-214-mediated nasopharyngeal carcinoma cell proliferation and apoptosis. Finally, the present study demonstrated that the expression level of Bax was downregulated in nasopharyngeal carcinoma tissues. In conclusion, the present study suggests that miR-214 may be a potential target for the treatment of nasopharyngeal carcinoma. PMID- 26239172 TI - Culture and Dehydration: A Comparative Study of Caida de la Mollera (Fallen Fontanel) in Three Latino Populations. AB - A sunken soft-spot or fontanel is a sign for dehydration in infants. Around the world, folk illnesses, such as caida de la mollera in some Latin American cultures, often incorporate this sign as a hallmark of illness, but may or may not incorporate re-hydration therapies in treatment strategies. This report describes a study of lay descriptions of causes, symptoms, and treatments for caida de la mollera in three diverse Latin American populations. A mixed-methods approach was used. Representative community-based samples were interviewed in rural Guatemala, Guadalajara, Mexico, and Edinburgh, Texas, with a 132 item questionnaire on the causes, susceptibility, symptoms, and therapies for caida de la mollera. Cultural consensus analysis was used to estimate community beliefs about caida. Interviews conducted in rural Guatemala (n = 60), urban Mexico (n = 62), and rural Texas on the Mexican border (n = 61) indicated consistency in thematic elements within and among these three diverse communities. The high degree of consistency in the illness explanatory models indicated shared beliefs about caida de la mollera in each of the communities and a core model shared across communities. However, an important aspect of the community beliefs was that rehydration therapies were not widely endorsed. The consistency in explanatory models in such diverse communities, as well as the high degree of recognition and experience with this illness, may facilitate communication between community members, and health care providers/public health intervention planners to increase use of rehydration therapies for caida de la mollera. Recommendations for culturally informed and respectful approaches to clinical communication are provided. PMID- 26239173 TI - Flexible regression models for ROC and risk analysis, with or without a gold standard. AB - A novel semiparametric regression model is developed for evaluating the covariate specific accuracy of a continuous medical test or biomarker. Ideally, studies designed to estimate or compare medical test accuracy will use a separate, flawless gold-standard procedure to determine the true disease status of sampled individuals. We treat this as a special case of the more complicated and increasingly common scenario in which disease status is unknown because a gold standard procedure does not exist or is too costly or invasive for widespread use. To compensate for missing data on disease status, covariate information is used to discriminate between diseased and healthy units. We thus model the probability of disease as a function of 'disease covariates'. In addition, we model test/biomarker outcome data to depend on 'test covariates', which provides researchers the opportunity to quantify the impact of covariates on the accuracy of a medical test. We further model the distributions of test outcomes using flexible semiparametric classes. An important new theoretical result demonstrating model identifiability under mild conditions is presented. The modeling framework can be used to obtain inferences about covariate-specific test accuracy and the probability of disease based on subject-specific disease and test covariate information. The value of the model is illustrated using multiple simulation studies and data on the age-adjusted ability of soluble epidermal growth factor receptor - a ubiquitous serum protein - to serve as a biomarker of lung cancer in men. SAS code for fitting the model is provided. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26239174 TI - Progressive age-related changes in sleep and EEG profiles in the PLB1Triple mouse model of Alzheimer's disease. AB - Sleep disturbances are common in Alzheimer's disease (AD) and now assumed to contribute to disease onset and progression. Here, we investigated whether activity, sleep/wake pattern, and electroencephalogram (EEG) profiles are altered in the knock-in PLB1Triple mouse model from 5 to 21 months of age. PLB1Triple mice displayed a progressive increase in wakefulness and non-rapid eye movement sleep fragmentation from 9 months onward, whereas PLB1WT wild type controls showed such deterioration only at 21 months. Impaired habituation to spatial novelty was also detected in PLB1Triple mice. Hippocampal power spectra of transgenic mice revealed progressive, vigilance stage-, brain region-, and age specific changes. Age had an impact on EEG spectra in both cohorts but led to accelerated genotype-dependent differences, ultimately affecting all bands at 21 months. Overall, although PLB1Triple animals display only subtle amyloid and tau pathologies, robust sleep-wake and EEG abnormalities emerged. We hypothesize that such endophenotypes are sensitive, noninvasive, and reliable biomarker to identify onset and progression of AD. PMID- 26239175 TI - Heritability of telomere length in a study of long-lived families. AB - Chromosomal telomere length shortens with repeated cell divisions. Human leukocyte DNA telomere length (LTL) has been shown to shorten during aging. LTL shortening has correlated with decreased longevity, dementia, and other age associated processes. Because LTL varies widely between individuals in a given age group, it has been hypothesized to be a marker of biological aging. However, the principal basis for the variation of human LTL has not been established, although various studies have reported heritability. Here, we use a family-based study of longevity to study heritability of LTL in 3037 individuals. We show that LTL is shorter in older individuals, and in males, and has a high heritability (overall h(2) = 0.54). In the offspring generation, who are in middle-life, we find an ordinal relationship: persons more-closely-related to elderly probands have longer LTL than persons less-closely-related, who nonetheless have longer LTL than unrelated spouses of the offspring generation. These results support a prominent genetic underpinning of LTL. Elucidation of such genetic bases may provide avenues for intervening in the aging process. PMID- 26239177 TI - The APP A673T frequency differs between Nordic countries. AB - A coding gene variant A673T (rs63750847) in the APP gene has recently been recognized as a protective variant of late-onset Alzheimer's Disease in a large Icelandic population and has been observed recurrently in populations from Nordic countries. The variant also was related to longevity in the Icelandic population. However, because of the extreme rarity of A673T in non-Nordic populations, the association with Alzheimer's disease has not yet been formally replicated. Because the variant has not been reported among the Danes, we aimed to study its frequency among healthy middle-age twins and oldest-old singletons and explore the possible effects on longevity and cognitive abilities. Surprisingly, only 1 of 3487 unrelated Danes carried the A673T variant, (0.014% [95% CI 0.000-0.080]), which was significantly lower than in the other Nordic countries averaging to 0.43% (95% CI 0.40-0.46). In conclusion, the A673T variant is rarer in Danes than other Nordic countries, thus precluding assessment of association with longevity or cognitive functioning. PMID- 26239179 TI - Inherited mtDNA variations are not strong risk factors in human prion disease. AB - Aside from variation in the prion protein gene, genetic risk factors for sporadic Creutzfeldt-Jakob disease remain elusive. Given emerging evidence implicating mitochondrial dysfunction in the pathogenesis of the disorders, we studied the role of inherited mitochondrial DNA variation in a 2255 sporadic prion disease cases and 3768 controls. Our analysis indicates that inherited mitochondrial DNA variation does not have a major role in the risk of developing the disorder. PMID- 26239176 TI - Cerebral amyloid angiopathy and its co-occurrence with Alzheimer's disease and other cerebrovascular neuropathologic changes. AB - We examined the relationship between cerebral amyloid angiopathy (CAA), Alzheimer's disease neuropathologic changes, other vascular brain pathologies, and cognition in a large multicenter autopsy sample. Data were obtained from the National Alzheimer's Coordinating Center on autopsied subjects (N = 3976) who died between 2002 and 2012. Descriptive statistics and multivariable regression models estimated the associations between CAA and other pathologies, and between CAA severity and cognitive test scores proximal to death. CAA tended to co-occur with Alzheimer's disease neuropathologic changes but a minority of cases were discrepant. CAA was absent in 22% (n = 520) of subjects with frequent neuritic plaques but present in 20.9% (n = 91) of subjects with no neuritic plaques. In subjects with no/sparse neuritic plaques, nonhemorrhagic brain infarcts were more common in those with CAA pathology than without (p = 0.007). In subjects without the APOE epsilon4 allele, CAA severity was associated with lower cognition proximal to death, factoring in other pathologies. The presence of CAA in patients without Alzheimer's disease may indicate a distinct cerebrovascular condition. PMID- 26239178 TI - Nonlinear cerebral atrophy patterns across the Alzheimer's disease continuum: impact of APOE4 genotype. AB - The progression of Alzheimer's disease (AD) is characterized by complex trajectories of cerebral atrophy that are affected by interactions with age and apolipoprotein E allele epsilon4 (APOE4) status. In this article, we report the nonlinear volumetric changes in gray matter across the full biological spectrum of the disease, represented by the AD-cerebrospinal fluid (CSF) index. This index reflects the subject's level of pathology and position along the AD continuum. We also evaluated the associated impact of the APOE4 genotype. The atrophy pattern associated with the AD-CSF index was highly symmetrical and corresponded with the typical AD signature. Medial temporal structures showed different atrophy dynamics along the progression of the disease. The bilateral parahippocampal cortices and a parietotemporal region extending from the middle temporal to the supramarginal gyrus presented an initial increase in volume which later reverted. Similarly, a portion of the precuneus presented a rather linear inverse association with the AD-CSF index whereas some other clusters did not show significant atrophy until index values corresponded to positive CSF tau values. APOE4 carriers showed steeper hippocampal volume reductions with AD progression. Overall, the reported atrophy patterns are in close agreement with those mentioned in previous findings. However, the detected nonlinearities suggest that there may be different pathological processes taking place at specific moments during AD progression and reveal the impact of the APOE4 allele. PMID- 26239181 TI - Safe and effective management of esophageal coins in children with bougienage. AB - BACKGROUND: Coins are the foreign body most commonly ingested in infants and children. Coins retained in the esophagus require intervention to prevent complications. Management of retained esophageal coins remains variable both between and within institutions. We hypothesize that the incorporation of bougienage in the management of pediatric esophageal coins is safe and more cost effective compared with traditional management strategies that use endoscopy. METHODS: We conducted a retrospective review of infants and children diagnosed with an esophageal foreign body managed at Children's Hospital of Wisconsin between January 2003 and June 2012. Pediatric otolaryngologists (ear-nose-throat, ie, ENTs) or pediatric surgeons manage all children with esophageal foreign bodies in a prospective call schedule that alternates weekly. RESULTS: During an 8.5-year period, 1,642 children were diagnosed with esophageal foreign bodies and 518 had a retained coin. For esophageal coins, ENT managed 218 cases and pediatric surgery managed 300. ENTs preferentially used endoscopy for coin removal, whereas pediatric surgeons used either endoscopy or esophageal bougienage for selected children meeting specific criteria. Bougienage was successful at advancing the coin into the stomach in 94% of patients, and endoscopy was successful at removing the coin from the esophagus in 100% of patients. The mean duration of stay was 0.6 days for endoscopy by ENT, 0.6 days for endoscopy by pediatric surgery, and 0.1 days for bougienage (P < .05). The median hospital charge was $4,593 for endoscopy by ENT, $5,379 for endoscopy by pediatric surgery, and $579 for bougienage (P < .05). There were 3 complications each in the endoscopy group for ENT and pediatric surgery. There were no complications in children undergoing bougienage. CONCLUSION: This is the first case series evaluating the management of children with esophageal coins using a prospective assignment to endoscopy versus endoscopy or bougienage. Our data support bougienage as a safe and cost-effective treatment for managing retained esophageal coins in selected children. PMID- 26239182 TI - Menkes disease with discordant phenotype in female monozygotic twins. AB - Menkes disease (MD) is a rare X-linked recessive disorder caused by mutations in the ATP7A gene. This neurodegenerative disorder typically affects males and is characterized by impaired copper distribution and the malfunction of several copper-dependent enzymes. We report clinically discordant female monozygotic twins (MZT) with a heterozygous ATP7A mutation. One twin girl is healthy at the current age of 4 years, whereas the other twin girl developed classical MD, showed disease stabilization under copper histidine treatment but died at the age of 3 years. Presumably, the affected girl developed MD due to skewed X inactivation, although this could not be demonstrated in two tissues (blood, buccal mucosa). This case is a rare example of an affected girl with MD and shows the possibility of a discordant phenotype in MZT girls. As speculated in other X linked diseases, the process of monozygotic twinning may be associated with skewed X inactivation leading to a discordant phenotype. PMID- 26239184 TI - Organophosphonate bridged anatase mesocrystals: low temperature crystallization, thermal growth and hydrogen photo-evolution. AB - The sol-gel co-condensation of organo-phosphonates to titanium alkoxides enables access to novel organic-inorganic hybrids based on phosphonate-bridged titanium dioxide. In this contribution, we bring new perspectives to the long established sol-gel mineralization of titanium alkoxide species, by harnessing the virtues of the well-designed phosphonate-terminated phosphorus dendrimers as reactive amphiphilic nanoreactor, confined medium and cross-linked template to generate discrete crystalline anatase nanoparticles at low temperature (T = 60 degrees C). An accurate investigation on several parameters (dendrimer generation, dendrimer-to-titanium alkoxide ratio, precursor reactivity, temperature, solvent nature, salt effect) allows a correlation between the network condensation, the opening porous framework and the crystalline phase formation. The evolution of the dendrimer skeleton upon heat treatment has been deeply monitored by means of (31)P NMR, XPS and Raman spectroscopy. Increasing the heteroatom content within a titania network provides the driving force for enhancing their photocatalytic water splitting ability for hydrogen production. PMID- 26239183 TI - Neurite outgrowth stimulation by n-3 and n-6 PUFAs of phospholipids in apoE containing lipoproteins secreted from glial cells. AB - PUFAs, which account for 25-30% of the total fatty acids in the human brain, are important for normal brain development and cognitive function. However, it remains unclear how PUFAs are delivered to neurons and exert their effects. In this study, we demonstrated that n-3 and n-6 PUFAs added to the medium are incorporated into membrane phospholipids of primary glial cells from rat cortices, and then secreted as the fatty acid moiety of phospholipids in apoE containing lipoproteins (LpEs). Tandem mass spectrometry analysis further showed that LpEs secreted from glial cells contain a variety of metabolites of PUFAs produced in glial cells by elongation and unsaturation. LpEs are absorbed by endocytosis into neurons via LDL receptor-related protein 1. LpE-containing n-3 and n-6 PUFAs exhibit a strong effect on neurite outgrowth of hippocampal neurons by increasing the number of branches. This study sheds light on the novel role of LpEs in the central nervous system and also a novel pathway in which PUFAs act on neurons. PMID- 26239185 TI - Multidrug Resistance-Associated Protein 4 (MRP4/ABCC4) Controls Efflux Transport of Hesperetin Sulfates in Sulfotransferase 1A3-Overexpressing Human Embryonic Kidney 293 Cells. AB - Sulfonation is an important metabolic pathway for hesperetin. However, the mechanisms for the cellular disposition of hesperetin and its sulfate metabolites are not fully established. In this study, disposition of hesperetin via the sulfonation pathway was investigated using human embryonic kidney (HEK) 293 cells overexpressing sulfotransferase 1A3. Two monosulfates, hesperetin-3'-O-sulfate (H 3'-S) and hesperetin-7-O-sulfate (H-7-S), were rapidly generated and excreted into the extracellular compartment upon incubation of the cells with hesperetin. Regiospecific sulfonation of hesperetin by the cell lysate followed the substrate inhibition kinetics (Vmax = 0.66 nmol/min per mg, Km = 12.9 MUM, and Ksi= 58.1 MUM for H-3'-S; Vmax = 0.29 nmol/min per mg, Km = 14.8 MUM, and Ksi= 49.1 MUM for H-7-S). The pan-multidrug resistance-associated protein (MRP) inhibitor MK-571 at 20 MUM essentially abolished cellular excretion of both H-3'-S and H-7-S (the excretion activities were only 6% of the control), whereas the breast cancer resistance protein-selective inhibitor Ko143 had no effects on sulfate excretion. In addition, knockdown of MRP4 led to a substantial reduction (>47.1%; P < 0.01) in sulfate excretion. Further, H-3'-S and H-7-S were good substrates for transport by MRP4 according to the vesicular transport assay. Moreover, sulfonation of hesperetin and excretion of its metabolites were well characterized by a two-compartment pharmacokinetic model that integrated drug uptake and sulfonation with MRP4-mediated sulfate excretion. In conclusion, the exporter MRP4 controlled efflux transport of hesperetin sulfates in HEK293 cells. Due to significant expression in various organs/tissues (including the liver and kidney), MRP4 should be a determining factor for the elimination and body distribution of hesperetin sulfates. PMID- 26239186 TI - Identification of Single-Locus PCR-Based Markers Linked to Shell Background Color in the Pacific Oyster (Crassostrea gigas). AB - A number of Pacific oyster (Crassostrea gigas) with golden shell background color were obtained which show great potential to develop a niche market. To improve the selective breeding progress of true-breeding strains with complete golden oysters, research was conducted to identify genetic markers linked to the shell color locus. An F1-segregating population was obtained by crossing two oysters with golden shell and white shell. Genomic DNA from eight progenies with golden shell and eight progenies with white shell were equally pooled for amplified fragment length polymorphism (AFLP) screening. In bulked segregant analysis, six out of 225 selective primer pair combinations produced seven polymorphic fragments tightly linked to shell color across the segregating population. The seven AFLP markers were all derived from the golden dam and mapped onto a single linkage group flanking the shell color locus. In conversion of the AFLPs into single-locus PCR-based markers, a sequence-characterized amplified region (SCAR) marker, named SCARJ8-2, a single nucleotide polymorphism (SNP) marker, named SNPL2-4, and a simple sequence repeat (SSR) marker, named SSRO11-2, were obtained. These markers obtained in this study will be useful for marker-assisted selection of the Pacific oyster. PMID- 26239187 TI - Low-Toxicity Diindol-3-ylmethanes as Potent Antifouling Compounds. AB - In the present study, eight natural products that belonged to di(1H-indol-3 yl)methane (DIM) family were isolated from Pseudovibrio denitrificans UST4-50 and tested for their antifouling activity against larval settlement (including both attachment and metamorphosis) of the barnacle Balanus (=Amphibalanus) amphitrite and the bryozoan Bugula neritina. All diindol-3-ylmethanes (DIMs) showed moderate to strong inhibitory effects against larval settlement of B. amphitrite with EC50 values ranging from 18.57 to 1.86 MUM and could be considered as low-toxicity antifouling compounds since their LC50/EC50 ratios were larger than 15. Furthermore, the DIM- and 4-(di(1H-indol-3-yl)methyl)phenol (DIM-Ph-4-OH)-treated larvae completed normal settlement when they were transferred to clean seawater after being exposed to those compounds for 24 h. DIM also showed comparable antifouling performance to the commercial antifouling biocide Sea-Nine 211(TM) in the field test over a period of 5 months, which further confirmed that DIMs can be considered as promising candidates of environmentally friendly antifouling compounds. PMID- 26239188 TI - Functional Sperm of the Yellowtail (Seriola quinqueradiata) Were Produced in the Small-Bodied Surrogate, Jack Mackerel (Trachurus japonicus). AB - Production of xenogeneic gametes from large-bodied, commercially important marine species in closely related smaller surrogates with short generation times may enable rapid domestication of the targeted species. In this study, we aimed to produce gametes of Japanese yellowtail (Seriola quinqueradiata) using jack mackerel (Trachurus japonicus) as a surrogate with a smaller body size and shorter maturation period. Donor spermatogonia were collected from the testes of yellowtail males and transferred into the peritoneal cavity of 10- and 12-day-old jack mackerel larvae. Twenty days later, 59.5% of the recipients survived of which 88.2% had donor-derived germ cells in their gonads. One year later, genomic DNA templates were prepared from the semen of 96 male recipients and subjected to polymerase chain reaction (PCR) analyses using primers specific for the yellowtail vasa sequence, resulting in the detection of positive signals in semen from two recipients. The milt collected from the recipients was used for fertilization with yellowtail eggs. Of eight hatchlings obtained from the crosses, two were confirmed to be derived from donor yellowtail by DNA markers, although the others were gynogenetic diploids. These findings indicate that it is possible to produce donor-derived sperm in xenogeneic recipients with a smaller body size and shorter generation time by transplanting spermatogonia. Thus, the xenogeneic transplantation of spermatogonia might be a potential tool to produce gametes of large-bodied, commercially important fish, although the efficiency of the method requires further improvement. This is the first report demonstrating that donor-derived sperm could be produced in xenogeneic recipient via spermatogonial transplantation in carangid fishes. PMID- 26239189 TI - (Ti/Zr,N) codoped hematite for enhancing the photoelectrochemical activity of water splitting. AB - In this theoretical study, first-principles calculations were carried out to explore the photocatalytic activity of cation (Ti or Zr) and anion (N) compensated codoped hematite based on density functional theory (DFT). For (Ti/Zr,N) codoped hematite, the band edges of the conduction band and the valence band move close to each other, leading to an obvious bandgap reduction. Compared with the pure hematite, the optical absorption coefficient of codoped hematite is significantly enhanced in the visible light region. The charge distribution at the conduction band minimum (CBM) and valence band maximum (VBM) is spatially separated after codoping, which is beneficial for extending the carrier lifetime. More interestingly, the CBM becomes electronically delocalized in (Ti,N) doped hematite, which indicates better carrier transport properties in the bulk system. Due to these special features of (Ti/Zr,N) codoped hematite, an improved photocatalytic performance can be expected. PMID- 26239190 TI - The pharmacokinetic basis of oral valacyclovir treatment of herpes simplex virus (HSV) or varicella zoster virus (VZV) meningitis, meningoencephalitis or encephalitis in adults. PMID- 26239192 TI - Influence of electroosmotic flow on the ionic current rectification in a pH regulated, conical nanopore. AB - The ionic current rectification (ICR) is studied theoretically by considering a pH-regulated, conical nanopore. In particular, the effect of electroosmotic flow (EOF), which was often neglected in previous studies, is investigated by solving a set of coupled Poisson, Nernst-Planck, and Navier-Stokes equations. The behaviors of ICR under various conditions are examined by varying solution pH, bulk ionic concentration, and applied electric potential bias. We show that the EOF effect is significant when the bulk ionic concentration is medium high, the pH is far away from the iso-electric point, and the electric potential bias is high. The percentage deviation in the current rectification ratio arising from neglecting the EOF effect can be on the order of 100%. In addition, the behavior of the current rectification ratio at a high pH taking account of EOF is different both qualitatively and quantitatively from that without taking account of EOF. PMID- 26239191 TI - Validation of a new radiographic measurement of acetabular version: the transverse axis distance (TAD). AB - OBJECTIVES: This study has three aims: (1) validate a new radiographic measure of acetabular version, the transverse axis distance (TAD) by showing equivalent TAD accuracy in predicting CT equatorial acetabular version when compared to a previously validated, but more cumbersome, radiographic measure, the p/a ratio; (2) establish predictive equations of CT acetabular version from TAD; (3) calculate a sensitive and specific cut point for predicting excessive CT acetabular anteversion using TAD. MATERIALS AND METHODS: A 14-month retrospective review was performed of patients who had undergone a dedicated MSK CT pelvis study and who also had a technically adequate AP pelvis radiograph. Two trained observers measured the radiographic p/a ratio, TAD, and CT acetabular equatorial version for 110 hips on a PACS workstation. Mixed model analysis was used to find prediction equations, and ROC analysis was used to evaluate the diagnostic accuracy of p/a ratio and TAD. RESULTS: CT equatorial acetabular version can accurately be predicted from either p/a ratio (p < 0.001) or TAD (p < 0.001). The diagnostic accuracies of p/a ratio and TAD are comparable (p =0.46). Patients whose TAD is higher than 17 mm may have excessive acetabular anteversion. For that cutpoint, the sensitivity of TAD is 0.73, with specificity of 0.82. CONCLUSION: TAD is an accurate radiographic predictor of CT acetabular anteversion and provides an easy-to-use and intuitive point-of-care assessment of acetabular version in patients with hip pain. PMID- 26239194 TI - Time cost of a nonclosing intravenous thrombolysis service for acute ischemic stroke. AB - BACKGROUND/PURPOSE: Intravenous thrombolysis for ischemic stroke saves societal costs. The aim of this study was to investigate the cost burden that hospitals may shoulder. METHODS: Stroke code activations between May 2009 and April 2011 were recorded and divided into groups based on work and duty time, as well as the period of the day or season. "Time cost of nonclosing service" (TCNS) per stroke code activation or intravenous thrombolysis treatment was calculated by dividing the time by the number of activations or thrombolysis treatments during that period. Comparisons were made among groups. RESULTS: There were a total of 634 stroke code activations in a period of 2 years, and intravenous thrombolysis was used in 132 (20.8%) of these cases. The rates of thrombolysis were not statistically different between the groups. Overall, the average TCNS for the stroke team was 27.6 hours per code activation and 132.7 hours per thrombolysis treatment. The TCNS during duty time was 1.38 times that during work time per stroke code activation and 1.46 times per thrombolysis treatment. In summer, the TCNS was 1.6 times that in winter per code activation and 2.2 times per thrombolysis treatment. During the late night hours, the TCNS was four times that of early night hours per code activation and 9.8 times per thrombolysis treatment. CONCLUSION: Our results demonstrate a large variation in the time cost of a nonclosing service for intravenous thrombolysis. Payment based on piece-rate compensation may not be appropriate and requires improvement. PMID- 26239193 TI - Risk factors of distant metastasis in the follicular variant of papillary thyroid carcinoma. AB - BACKGROUND/PURPOSE: The follicular variant of papillary thyroid carcinoma (FVPTC) is the most common variant of papillary thyroid carcinoma (PTC). A previous population-based study revealed its clinical behavior as a mix of classic papillary thyroid carcinoma (C-PTC) and follicular thyroid carcinoma. Whereas locoregional extension was lower in FVPTC than in C-PTC, the distant metastasis rate was higher in FVPTC than in C-PTC. The aim of this study was to evaluate the risk factors of distant metastasis in FVPTC postoperatively. METHODS: A retrospective review of 359 patients with final pathological diagnosis of FVPTC treated at Chang Gung Memorial Hospital between January 2000 and January 2014 was performed. After excluding patients who had inadequate pathological data for analysis or did not attend regular follow up for >1 year, 346 patients were included in this study. Univariate and multivariate statistical analyses were performed to determine the significance of various factors. RESULTS: Of the 346 patients with FVPTC, 19 (5.5%) had lymph node metastases and 32 (9.2%) had distant metastases. Two positive and one negative risk factors were predictive for distant metastasis using multivariate analysis: angiolymphatic invasion [odds ratio (OR), 3.085; 95% confidence interval (CI), 1.008-9.442], extrathyroidal extension (OR, 3.929; 95% CI, 1.330-11.602), and encapsulation (OR, 0.361; 95% CI, 0.154-0.850). CONCLUSION: The presence of angiolymphatic invasion, extrathyroidal extension, or nonencapsulation was associated with distant metastasis in FVPTC in this study. In FVPTC patients, postoperative investigation for distant metastasis may be warranted by the presence of these two positive risk factors or the absence of the one negative risk factor. PMID- 26239195 TI - Robust quantum control using smooth pulses and topological winding. AB - The greatest challenge in achieving the high level of control needed for future technologies based on coherent quantum systems is the decoherence induced by the environment. Here, we present an analytical approach that yields explicit constraints on the driving field which are necessary and sufficient to ensure that the leading-order noise-induced errors in a qubit's evolution cancel exactly. We derive constraints for two of the most common types of noise that arise in qubits: slow fluctuations of the qubit energy splitting and fluctuations in the driving field itself. By theoretically recasting a phase in the qubit's wavefunction as a topological winding number, we can satisfy the noise cancelation conditions by adjusting driving field parameters without altering the target state or quantum evolution. We demonstrate our method by constructing robust quantum gates for two types of spin qubit: phosphorous donors in silicon and nitrogen-vacancy centers in diamond. PMID- 26239196 TI - Exercise Medicine for Osteoarthritis: Research Strategies to Maximize Effectiveness. PMID- 26239197 TI - Pharmacological inhibition of fatty-acid oxidation synergistically enhances the effect of l-asparaginase in childhood ALL cells. AB - l-asparaginase (ASNase), a key component in the treatment of childhood acute lymphoblastic leukemia (ALL), hydrolyzes plasma asparagine and glutamine and thereby disturbs metabolic homeostasis of leukemic cells. The efficacy of such therapeutic strategy will depend on the capacity of cancer cells to adapt to the metabolic challenge, which could relate to the activation of compensatory metabolic routes. Therefore, we studied the impact of ASNase on the main metabolic pathways in leukemic cells. Treating leukemic cells with ASNase increased fatty-acid oxidation (FAO) and cell respiration and inhibited glycolysis. FAO, together with the decrease in protein translation and pyrimidine synthesis, was positively regulated through inhibition of the RagB-mTORC1 pathway, whereas the effect on glycolysis was RagB-mTORC1 independent. As FAO has been suggested to have a pro-survival function in leukemic cells, we tested its contribution to cell survival following ASNase treatment. Pharmacological inhibition of FAO significantly increased the sensitivity of ALL cells to ASNase. Moreover, constitutive activation of the mammalian target of rapamycin pathway increased apoptosis in leukemic cells treated with ASNase, but did not increase FAO. Our study uncovers a novel therapeutic option based on the combination of ASNase and FAO inhibitors. PMID- 26239198 TI - Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism. AB - Bispecific T-cell engagers (BiTEs) are very effective in recruiting and activating T cells. We tested the cytotoxicity of the CD33/CD3 BiTE antibody construct AMG 330 on primary acute myeloid leukemia (AML) cells ex vivo and characterized parameters contributing to antileukemic cytolytic activity. The E:T ratio and the CD33 expression level significantly influenced lysis kinetics in long-term cultures of primary AML cells (n=38). AMG 330 induced T-cell-mediated proinflammatory conditions, favoring the upregulation of immune checkpoints on target and effector cells. Although not constitutively expressed at the time of primary diagnosis (n=123), PD-L1 was strongly upregulated on primary AML cells upon AMG 330 addition to ex vivo cultures (n=27, P<0.0001). This phenomenon was cytokine-driven as the sole addition of interferon (IFN)-gamma and tumor necrosis factor-alpha also induced expression. Through blockade of the PD-1/PD-L1 interaction, AMG 330-mediated lysis (n=9, P=0.03), T-cell proliferation (n=9, P=0.01) and IFN-gamma secretion (n=8, P=0.008) were significantly enhanced. The combinatorial approach was most beneficial in settings of protracted AML cell lysis. Taken together, we have characterized a critical resistance mechanism employed by primary AML cells under AMG 330-mediated proinflammatory conditions. Our results support the evaluation of checkpoint molecules in upcoming clinical trials with AMG 330 to enhance BiTE antibody construct-mediated cytotoxicity. PMID- 26239199 TI - Altered mesenchymal niche cells impede generation of normal hematopoietic progenitor cells in leukemic bone marrow. AB - Degeneration of normal hematopoietic cells is a shared feature of malignant diseases in the hematopoietic system. Previous studies have shown the exhaustion of hematopoietic progenitor cells (HPCs) in leukemic marrow, whereas hematopoietic stem cells (HSCs) remain functional upon relocation to non-leukemic marrow. However, the underlying cellular mechanisms, especially the specific niche components that are responsible for the degeneration of HPCs, are unknown. In this study, we focused on murine bone mesenchymal stem cells (MSCs) and their supporting function for normal hematopoietic cells in Notch1-induced acute T-cell lymphocytic leukemia (T-ALL) mice. We demonstrate that the proliferative capability and differentiation potential of T-ALL MSCs were impaired due to accelerated cellular senescence. RNA-seq analysis revealed significant transcriptional alterations in leukemic MSCs. After co-cultured with the MSCs from T-ALL mice, a specific inhibitory effect on HPCs was defined, whereas in vivo repopulating potential of normal HSCs was not compromised. Furthermore, osteoprotegerin was identified as a cytokine to improve the function of T-ALL MSCs and to enhance normal HPC output via the p38/ERK pathway. Therefore, this study reveals a novel cellular mechanism underlying the inhibition of HPC generation in T-ALL. Leukemic MSCs may serve as a cellular target for improving normal hematopoietic regeneration therapeutically. PMID- 26239200 TI - Coexpression of auxiliary subunits KChIP and DPPL in potassium channel Kv4 positive nociceptors and pain-modulating spinal interneurons. AB - Subthreshold A-type K(+) currents (ISA s) have been recorded from the somata of nociceptors and spinal lamina II excitatory interneurons, which sense and modulate pain, respectively. Kv4 channels are responsible for the somatodendritic ISA s. Accumulative evidence suggests that neuronal Kv4 channels are ternary complexes including pore-forming Kv4 subunits and two types of auxiliary subunits: K(+) channel-interacting proteins (KChIPs) and dipeptidyl peptidase like proteins (DPPLs). Previous reports have shown Kv4.3 in a subset of nonpeptidergic nociceptors and Kv4.2/Kv4.3 in certain spinal lamina II excitatory interneurons. However, whether and which KChIP and DPPL are coexpressed with Kv4 in these ISA -expressing pain-related neurons is unknown. In this study we mapped the protein distribution of KChIP1, KChIP2, KChIP3, DPP6, and DPP10 in adult rat dorsal root ganglion (DRG) and spinal cord by immunohistochemistry. In the DRG, we found colocalization of KChIP1, KChIP2, and DPP10 in the somatic surface and cytoplasm of Kv4.3(+) nociceptors. KChIP3 appears in most Abeta and Adelta sensory neurons as well as a small population of peptidergic nociceptors, whereas DPP6 is absent in sensory neurons. In the spinal cord, KChIP1 is coexpressed with Kv4.3 in the cell bodies of a subset of lamina II excitatory interneurons, while KChIP1, KChIP2, and DPP6 are colocalized with Kv4.2 and Kv4.3 in their dendrites. Within the dorsal horn, besides KChIP3 in the inner lamina II and lamina III, we detected DPP10 in most projection neurons, which transmit pain signal to brain. The results suggest the existence of Kv4/KChIP/DPPL ternary complexes in ISA expressing nociceptors and pain-modulating spinal interneurons. PMID- 26239202 TI - [Medicolegal aspects of treating children]. PMID- 26239203 TI - Basal cell carcinoma: Epidemiology, clinical and histologic features, and basic science overview. PMID- 26239201 TI - Daptomycin for Gram-positive Infections in Patients with Neutropenia: Clinical Experience from a European Outcomes Registry. AB - INTRODUCTION: The aim of this analysis was to describe in real-world settings the clinical outcomes and safety associated with daptomycin treatment in patients with neutropenia and Gram-positive infections. METHODS: Patients with an absolute neutrophil count (ANC) <=1000 cells/mm(3) who received at least one dose of daptomycin between 2006 and 2012 were selected from a non-interventional, multicenter, retrospective registry (European Cubicin((r)) Outcome Registry and Experience; EU-CORE(SM)). RESULTS: Of the 6075 patients enrolled in EU-CORE, 446 (7.3%) had an ANC <= 1000 cells/mm(3) at baseline or during daptomycin therapy; they were all included in efficacy and safety populations. Half of the patients had severe neutropenia (ANC <= 100 cells/mm(3)). Most patients had hematologic malignancy (60.5%), an immunosuppressed state (39.7%) or had undergone a transplant (27.8%). The most common primary infections were bacteremia (42.2%) and complicated skin and soft tissue infection (13.9%). Cultures were positive for 68.6% (254/370) of patients with available culture results; coagulase negative staphylococci (43.7%; 111/254) and Staphylococcus aureus (18.9%; 48/254) were the most commonly isolated primary pathogens. Median duration of daptomycin therapy was 10.0 (range 1-98) days. Most patients (82.8%) received antibiotics concomitantly with daptomycin; the most common were carbapenems (51.2%), penicillins (42.1%), and aminoglycosides (19.9%). The overall clinical success rate (cured or improved) associated with daptomycin was 77.1%. Adverse events possibly related to daptomycin treatment were reported in seven (1.6%) patients and led to drug discontinuation in 27 (6.1%) patients. CONCLUSION: The study results suggest that daptomycin is an effective therapeutic option for the treatment of a broad range of Gram-positive infections in patients with neutropenia, and has a good safety profile. FUNDING: This study was funded by Novartis Pharma AG. PMID- 26239204 TI - Cutaneous squamous cell carcinoma and related entities: Epidemiology, clinical and histological features, and basic science overview. PMID- 26239205 TI - Ophthalmic manifestations and outcomes after cavernous sinus thrombosis in children. AB - PURPOSE: To review the causes, treatment, and outcomes of cavernous sinus thrombosis (CST) in children. METHODS: The medical records of children (<18 years of age) diagnosed with thrombophlebitis of an intracranial venous sinus were reviewed to identify cases of CST presenting to Children's Hospital Colorado from January 2000 through January 2013. Cases were evaluated for etiology, symptoms, imaging characteristics, treatment, and outcomes. RESULTS: A total of 110 children with a venous thrombus of an intracranial sinus were included. Of these, 9 had a CST. All cases were confirmed by magnetic resonance imaging. All 9 had sinusitis, 4 had orbital involvement, and 1 resulted from a nasal septal abscess. Eight cases presented with ophthalmoplegia, and 5 presented with decreased vision. Every patient underwent sinus surgery: 4 underwent orbitotomy for abscess drainage, and 1 required bilateral exenteration. Cultures were inconclusive in 2 cases, and 2 cases were culture positive rhino-orbital mucormycosis. There was 1 case of methicillin-resistant Staphylococcus aureus. Of the 9 cases, 4 returned to normal vision and ocular motility; 5 had permanent ophthalmoplegia and vision loss. There were no cases of mortality. CONCLUSIONS: CST is a rare complication of orbital and sinus disease. High clinical suspicion, early neurologic imaging, and a multidisciplinary approach to management are key factors in reducing morbidity and mortality from CST in children. PMID- 26239206 TI - Higher-order aberrations and best-corrected visual acuity in Native American children with a high prevalence of astigmatism. AB - PURPOSE: To determine whether higher-order aberrations (HOAs) in children from a highly astigmatic population differ from population norms and whether HOAs are associated with astigmatism and reduced best-corrected visual acuity. METHODS: Subjects were 218 Tohono O'odham Native American children 5-9 years of age. Noncycloplegic HOA measurements were obtained with a handheld Shack-Hartmann sensor (SHS). Signed (z06s to z14s) and unsigned (z06u to z14u) wavefront aberration Zernike coefficients Z(3,-3) to Z(4,4) were rescaled for a 4 mm diameter pupil and compared to adult population norms. Cycloplegic refraction and best-corrected logMAR letter visual acuity (BCVA) were also measured. Regression analyses assessed the contribution of astigmatism (J0) and HOAs to BCVA. RESULTS: The mean root-mean-square (RMS) HOA of 0.191 +/- 0.072 MUm was significantly greater than population norms (0.100 +/- 0.044 MUm). All unsigned HOA coefficients (z06u to z14u) and all signed coefficients except z09s, z10s, and z11s were significantly larger than population norms. Decreased BCVA was associated with astigmatism (J0) and spherical aberration (z12u) but not RMS coma, with the effect of J0 about 4 times as great as z12u. CONCLUSIONS: Tohono O'odham children show elevated HOAs compared to population norms. Astigmatism and unsigned spherical aberration are associated with decreased acuity, but the effects of spherical aberration are minimal and not clinically significant. PMID- 26239207 TI - Serum neutrophil-to-lymphocyte ratio in retinopathy of prematurity. AB - PURPOSE: To evaluate the relationship between serum neutrophil-to-lymphocyte ratio (NLR) and development of retinopathy of prematurity (ROP). METHODS: Infants with a gestational age of <=32 week were screened for ROP. Complete blood cell, high-sensitivity C-reactive protein, and interleukin 6 levels of subjects were measured within the first 24 hours of life. The NLR was calculated by dividing neutrophil count by lymphocyte count. The association between other risk factors and the development of ROP were analyzed using univariate analysis and multivariate logistic regression analysis. RESULTS: A total of 100 infants were included: 80 with ROP and 20 without ROP. The NLR values differed significantly between the ROP group (median, 0.67; interquartile range, 0.38-1.09) and non-ROP group (median, 0.32; interquartile range, 0.22-0.79; P = 0.02). The lymphocyte count in the ROP group (4.01 +/- 1.89) compared to that of the non-ROP group (5.69 +/- 2.16) was significantly lower (P = 0.001). In multivariate analysis, lymphocyte count remained an independent predictor of ROP (OR = 0.599; 95% CI, 0.430-0.836; P = 0.003). CONCLUSIONS: The NLR seems not to be an independent predictor of development of ROP. Lymphocyte count is inversely associated with ROP. PMID- 26239208 TI - Plateau iris in children. AB - Narrow iridocorneal angles, a very rare condition in the pediatric population, can lead to visual loss through angle closure glaucoma. In the workup for patients with narrow iridocorneal angles, plateau iris must be considered in the differential diagnosis. We describe 5 children with plateau iris, the youngest 5 years of age. All were confirmed using ultrasound biomicroscopy and were offered iridotomy for treatment. PMID- 26239209 TI - Solar retinopathy in children. AB - PURPOSE: To describe the visual acuity, fundus appearance, and spectral domain optical coherence tomography (SD-OCT) findings in 5 eyes of 3 children with foveal damage from solar retinopathy. METHODS: This was a prospective, observational case series of children who presented to the emergency department at the Royal Victorian Eye and Ear Hospital after having directly viewed the Sun during the transit of Venus on June 6, 2012, or the partial eclipse of the Sun on November 14, 2012. All patients underwent visual acuity testing, dilated fundus examination, and SD-OCT imaging. RESULTS: The 3 patients' ages at presentation were 8, 10, and 11 years. Best-corrected visual acuity in the affected eyes ranged from 20/20 to 20/40 on presentation. Significant foveal pathology was identified on SD-OCT in all 5 eyes, even when visual acuity was normal. At presentation, all eyes showed disruption of the photoreceptor ellipsoid zone and the interdigitation zone on SD-OCT. Additionally, in those eyes with decreased visual acuity, there was disruption of the outer nuclear layer and/or external limiting membrane. At 3-5 months' follow-up, the outer nuclear layer and external limiting membrane lesions had resolved; however, in some eyes the ellipsoid and interdigitation zone abnormalities persisted at 5 months' follow-up, even in the presence of best-corrected visual acuity as good as 20/12.5. CONCLUSIONS: Solar retinopathy in children can cause persistent damage to multiple retinal layers despite recovery of good visual acuity. PMID- 26239210 TI - Surgical management of monocular elevation deficiency combined with inferior rectus restriction. AB - PURPOSE: To evaluate the results of ipsilateral inferior rectus (IR) recession, when performed alone or in combination with contralateral superior rectus (SR) recession in patients with monocular elevation deficiency (MED) and IR tightness. METHODS: The medical records of patients with MED and tight IR muscle were retrospectively reviewed. Patients underwent either ipsilateral IR recession alone (IR group) or combined with contralateral SR recession (IR+SR group). Pre- and postoperative ocular motility and alignment and fundus torsion were analyzed. Abnormal head posture was recorded. All patients were followed for at least 6 months. RESULTS: A total of 23 patients were identified. Mean patient age at time of surgery was 9.8 +/- 8.7 years (range, 3-45 years). Ten patients underwnet ipsilateral IR recession 5-8 mm; 13 patients, 4 mm ipsilateral IR recession combined with 5-12 mm contralateral SR recession. Both groups experienced marked improvement in ocular alignment in the primary position (P = 0.34). However, there was a statistically better ocular alignment in both upgaze (P = 0.03) and downgaze (P < 0.01) in the IR+SR group, with a lower degree of fundus intorsion (P < 0.01). An ipsilateral head tilt developed in 70% of patients in the IR group and in 54% of patients in the IR+SR group. CONCLUSIONS: In this patient cohort, combined contralateral SR recession with ipsilateral IR recession reduced postoperative IR underaction and achieved better ocular alignment in upgaze and downgaze. PMID- 26239211 TI - A new surgical "noose" technique for excision of pediatric ocular adnexal and anterior orbital cysts. AB - We describe a "noose technique" that facilitates complete surgical excision of all forms of pediatric adnexal and anterior orbital extraocular cysts, including conjunctival retention cysts, parasitic cysts involving the conjunctiva, Tenon's capsule, or rectus muscle, superficial cysts, and deep dermoid cysts. The technique provides good exposure and facilitates handling of tissues, maintains surgical planes, minimizes bleeding, decreases injury to collateral tissues, reduces surgical time, allows for utilization of less skilled assistants, and ensures complete excision in most cases. The noose technique is a versatile procedure that can be applied to extraocular cysts of any location or size both in children and adults. We demonstrate the technique in 3 different pediatric extraocular cysts. PMID- 26239212 TI - The concept of teamwork does not fully explain how interprofessional work occurs in intensive care. PMID- 26239213 TI - Chlorpromazine-Induced Hyperprolactinemia on Rat's Uterus. AB - BACKGROUND: Hyperprolactinemia is a common side effect of antipsychotic drugs that requires further investigation. The current study was designed to evaluate dose-dependent effect of chlorpromazine (CPZ) on hormonal changes and uterine horn histological structure in rats. Moreover, the mammary glands were analyzed to show hyperprolactinemia-induced histological changes. METHODS: Albino Wistar rats (n = 32) were divided into four groups. The first group was set as a control. In the three drug-treated groups (eight rats in each group), CPZ was administered by a gavage at doses of 3, 10, and 30 mg/kg/day for 28 days. One day after the last administration of the drug, the animals were sacrificed. Histopathological and histomorphometrical analyses of the uterine horns and mammary glands were carried out to evaluate dose-dependent effect of CPZ on histological structure. Serum levels of prolactin (PRL), estradiol, progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were also evaluated. RESULTS: Remarkable (P < 0.05) elevation was observed in CPZ administrated animals' uterine horn endometrium, myometrium, and perimetrium thicknesses, and the mammary glands were observed with galactorrhea features. The serum level of progesterone and PRL significantly (P < 0.05) increased, while the serum concentration of LH, FSH, and estradiol was notably (P < 0.05) decreased depending on administrated CPZ dose. No histological and biological changes were occurred in the control animals. CONCLUSION: The present findings suggest that CPZ-induced disturbances not only depend on PRL level and increased PRL level largely depends on administrated doses of the CPZ. PMID- 26239214 TI - Denatured state aggregation parameters derived from concentration dependence of protein stability. AB - Protein aggregation is a major issue affecting the long-term stability of protein preparations. Proteins exist in equilibrium between the native and denatured or partially denatured conformations. Often denatured or partially denatured conformations are prone to aggregate because they expose to solvent the hydrophobic core of the protein. The aggregation of denatured protein gradually shifts the protein equilibrium toward increasing amounts of denatured and ultimately aggregated protein. Recognizing and quantitating the presence of denatured protein and its aggregation at the earliest possible time will bring enormous benefits to the identification and selection of optimal solvent conditions or the engineering of proteins with the best stability/aggregation profile. In this article, a new approach that allows simultaneous determination of structural stability and the amount of denatured and aggregated protein is presented. This approach is based on the analysis of the concentration dependence of the Gibbs energy (DeltaG) of protein stability. It is shown that three important quantities can be evaluated simultaneously: (i) the population of denatured protein, (ii) the population of aggregated protein, and (iii) the fraction of denatured protein that is aggregated. PMID- 26239215 TI - Quantification of amyloid fibrils using size exclusion chromatography coupled with online fluorescence and ultraviolet detection. AB - An amyloid fibrils investigation within biofilm samples requires distinguishing the amyloid beta-sheet structure of these proteins and quantifying them. In this study, the property of amyloids to incorporate the fluorescent dye Thioflavin T has been exploited to propose a method of quantification. The experimental protocol includes the preparation of amyloids from commercial kappa-casein (kappaCN) and their fractionation through size exclusion chromatography (SEC) to provide calibration curves from fluorescence and absorbance signals. Finally, a bacterial biofilm extract was injected into SEC, and the amyloid fibrils could be expressed as equivalent kappaCN, representing approximately 21% of the total proteins. PMID- 26239216 TI - Cefepime, a fourth-generation cephalosporin, in complex with manganese, inhibits proteasome activity and induces the apoptosis of human breast cancer cells. AB - Cefepime (FEP), which is a member of the fourth-generation cephalosporin class, has been extensively studied as a biochemical and antimicrobial reagent in recent years. Manganese (Mn) is important in the biochemical and physiological processes of many living organisms, and it is also high expressed in some tumor tissues. In the present study, we aimed to investigate the proteasome-inhibitory and anti proliferative properties of 8 metal complexes (FEP-Cu, FEP-Zn, FEP-Co, FEP-Ni, FEP-Cd, FEP-Cr, FEP-Fe, FEP-Mn) in MDA-MB-231 human breast cancer cells. The FEP Mn complex was found to be more potent in its ability to inhibit cell proliferation and proteasome activity than the other compounds tested. Moreover, the FEP-Mn complex inhibited proteasomal chymotrypsin-like (CT-like) activity and induced the apoptosis of breast cancer cells in a dose-and time-dependent manner. Furthermore, the MCF-10A cells were much less sensitive to the FEP complexes compared with the MDA-MB-231 breast cancer cells. These results demonstrated that the FEP-Mn(II) complex has the potential to act as a proteasome inhibitor and apoptosis inducer and therefore has possible future applications in cancer chemotherapy. PMID- 26239217 TI - Shoulder function and scapular position in boxers. AB - OBJECTIVES: To investigate differences in strength, shoulder range of motion and scapula position in a cohort of boxers in comparison with a control group of non boxers. DESIGN: Cross-sectional study. PARTICIPANTS: 18 boxers with 3 or more years of experience (years = 5.5 +/- 3.1, sessions per week = 4.3 +/- 0.7, age = 27.0 +/- 6.8) and 20 control participants (age = 28.3 +/- 4.6). EXPERIMENTAL PROTOCOL: The participants were tested for isometric internal and external rotation strength measured with a hand held dynamometer, passive internal and external rotation measured via 2D video using a digital camera, and scapular function measured with a scoliometer and visual inspection by a trained researcher. Both arms (dominant and non-dominant) were tested to allow for comparison. Magnitude based inferences were used to find meaningful differences intra and inter group. RESULTS: Boxers had greater scapular dyskinesis (hazard ratio (HR) = 2.73 *// 3.37) and increased external rotation in the dominant arm (effect size (ES) = 0.70 +/- 0.68) when compared to the non-boxer group. CONCLUSION: Boxers with 3 or more years of experience displayed symptoms that increase their risk of upper limb injury when compared to a control group. PMID- 26239218 TI - The use of a pitch count estimator to calculate exposure in collegiate baseball pitchers. AB - OBJECTIVE: Excessive pitch counts have been associated with arm pain in pitchers. Tracking of exposure is difficult based on participation on multiple teams and variability in organizational rules. Statisticians have estimated exposure for professional pitchers using pitch count estimators. Our objective was to determine the utility of pitch count estimators at the collegiate level. DESIGN AND PARTICIPANTS: Cohort; 29 collegiate pitchers. METHODS: The team athletic trainer collected game pitch count data. The total number of batters faced (PA), strike outs (SO), and walks (BB) were recorded from the box score and entered into the pitch count formula (3.3*PA + 1.5*SO + 2.2*BB) to estimate pitch counts. Intraclass correlation coefficients (ICCs(2,1)) and standard error of measurement (SEM), were used to examine the agreement between actual and estimated pitch counts. RESULTS: The mean pitch count was correlated with the estimated pitch count (628 +/- 476 vs.603 +/- 426; r = .99, p < .001). The actual and estimated pitch counts per season demonstrated excellent agreement (ICC(2,1) = 0.99; SEM = 56 pitches). The ICC(2,1) calculated to compare actual and estimated pitch counts for starters and relievers (ICC(2,1) = 0.98; SEM = 77; 0.98; SEM = 39) reflect good agreement. CONCLUSIONS: The estimator provides a method of quantifying exposure for pitchers to help plan safe participation and control for confounding factors when attempting to understand the risks of pitching. PMID- 26239219 TI - Claudins in a primary cultured puffer fish (Tetraodon nigroviridis) gill epithelium model alter in response to acute seawater exposure. AB - Gill epithelium permeability and qualitative/quantitative aspects of gill claudin (cldn) tight junction (TJ) protein transcriptomics were examined with a primary cultured model gill epithelium developed using euryhaline puffer fish (Tetraodon nigroviridis) gills. The model was prepared using seawater-acclimated fish gills and was cultured on permeable cell culture filter supports. The model is composed of 1-2 confluent layers of gill pavement cells (PVCs), with the outer layer exhibiting prominent apical surface microridges and TJs between adjacent cells. During development of electrophysiological characteristics, the model exhibits a sigmoidal increase in transpithelial resistance (TER) and plateaus around 30 kOmegacm(2). At this point paracellular movement of [(3)H]polyethylene glycol (PEG) 4000 was low at ~1.75 cm s(-1)*10(-7). When exposed to apical seawater (SW) epithelia exhibit a marked decrease in TER while PEG flux remained unchanged for at least 6 h. In association with this, transcript encoding cldn TJ proteins cldn3c, -23b, -27a, -27c, -32a and -33b increased during the first 6 h while cldn11a decreased. This suggests that these proteins are involved in maintaining barrier properties between gill PVCs of SW fishes. Gill cldn mRNA abundance also altered 6 and 12 h following abrupt SW exposure of puffer fish, but in a manner that differed qualitatively and quantitatively from the cultured model. This most likely reflects the cellular heterogeneity of whole tissue and/or the contribution of the endocrine system in intact fish. The current study provides insight into the physiological and transcriptomic response of euryhaline fish gill cells to a hyperosmotic environment. PMID- 26239220 TI - Digestive enzyme activities in the guts of bonnethead sharks (Sphyrna tiburo) provide insight into their digestive strategy and evidence for microbial digestion in their hindguts. AB - Few investigations have studied digestive enzyme activities in the alimentary tracts of sharks to gain insight into how these organisms digest their meals. In this study, we examined the activity levels of proteases, carbohydrases, and lipase in the pancreas, and along the anterior intestine, spiral intestine, and colon of the bonnethead shark, Sphyrna tiburo. We then interpreted our data in the context of a rate-yield continuum to discern this shark's digestive strategy. Our data show anticipated decreasing patterns in the activities of pancreatic enzymes moving posteriorly along the gut, but also show mid spiral intestine peaks in aminopeptidase and lipase activities, which support the spiral intestine as the main site of absorption in bonnetheads. Interestingly, we observed spikes in the activity levels of N-acetyl-beta-D-glucosaminidase and beta-glucosidase in the bonnethead colon, and these chitin- and cellulose-degrading enzymes, respectively, are likely of microbial origin in this distal gut region. Taken in the context of intake and relatively long transit times of food through the gut, the colonic spikes in N-acetyl-beta-D-glucosaminidase and beta-glucosidase activities suggest that bonnetheads take a yield-maximizing strategy to the digestive process, with some reliance on microbial digestion in their hindguts. This is one of the first studies to examine digestive enzyme activities along the gut of any shark, and importantly, the data match with previous observations that sharks take an extended time to digest their meals (consistent with a yield maximizing digestive strategy) and that the spiral intestine is the primary site of absorption in sharks. PMID- 26239221 TI - Vestibular-evoked myogenic potentials in central vestibular disorders. AB - Vestibular-evoked myogenic potentials (VEMPs) are short latency manifestations of vestibulo-ocular and vestibulocollic reflexes that originate from the utricle and saccule. Although cervical and ocular VEMPs have mostly been applied to peripheral vestibular disorders, the characteristics and the diagnostic values of VEMPs have been expanded to assess the function of the central otolithic pathways. In the central nervous system, the cervical VEMPs (cVEMPs) are mediated by the vestibular nuclei and uncrossed medial vestibulospinal tract descending in the lower brainstem and spinal cord. In contrast, the ocular VEMPs (oVEMPs) reflect the function of the vestibular nuclei and the crossed vestibulo-ocular reflex (VOR) pathways, mostly contained in the medial longitudinal fasciculus (MLF). Therefore, lesions involving the vestibular nuclei can present abnormalities of both cVEMPs and oVEMPs. The medullary lesions involving the descending MLF or the spinal accessory nucleus impair cVEMPs. In contrast, the lesions involving the MLF, the crossed ventral tegmental tract, oculomotor nuclei and the interstitial nucleus of Cajal can impair oVEMPs. Patients with unilateral cerebellar infarctions may show abnormal VEMPs especially when they have the ocular tilt reaction. Delayed responses of VEMPs are characteristic of multiple sclerosis (MS). Reduced VEMP responses can be observed in patients with vestibular migraine. VEMPs are useful in evaluating central as well as peripheral otolithic function that are not readily defined by conventional vestibular function tests, and can aid in detecting and localizing central lesions, especially silent brainstem lesions such as tiny infarctions or MS plaques. PMID- 26239222 TI - Predictors of disease activity in 857 patients with MS treated with interferon beta-1b. AB - Multiple sclerosis (MS) is a chronic demyelinating neurodegenerative disease of the CNS that requires long-term treatment. The identification of patient characteristics that can help predict disease outcomes could improve care for patients with MS. The objective of this study is to identify predictors of disease activity in patients from the BEYOND trial. This regression analysis of patients with relapsing-remitting MS from BEYOND examined the predictive value of patient characteristics at baseline and after 1 year of treatment with interferon beta-1b 250 MUg every other day for clinical and MRI outcomes after year 1 of the study. 857 and 765 patients were included in the analyses of clinical and MRI outcomes, respectively. In multivariate analyses of age, a higher number of relapses in the past 2 years, >=3 new MRI lesions in the first year, and, especially, a higher number of relapses in year 1 predicted the future occurrence of relapses. By contrast, age, MRI activity, and the presence of neutralizing antibodies in the first year were principally predictive of future MRI activity. In patients with continued clinical disease activity or substantial MRI activity on therapy, an alternative therapeutic approach should be strongly considered. PMID- 26239224 TI - Did the Millennium Development Goals Change Trends in Child Mortality? AB - There has been little assessment of the role the Millennium Development Goals (MDGs) have had in progressing international development. There has been a 41% reduction in the under-five mortality rate worldwide from 1990 to 2011 and an acceleration in the rate of reduction since 2000. This paper explores why this has occurred, and results for all developing countries indicate that it is not due to more healthcare or public health interventions but is driven by a coincidental burst of economic growth. Although the MDGs are considered to have played an important part in securing progress against poverty, hunger and disease, there is very little evidence to back this viewpoint up. A thorough analysis of the successes and failures of the MDGs is therefore necessary before embarking on a new round of global goals. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26239223 TI - Walking improvements with nabiximols in patients with multiple sclerosis. AB - Recently, nabiximols was approved as a treatment in MS spasticity. Data leading to approval and clinical use of nabiximols, although widely recognised, are based on subjective scales. Movement analysis procedures would obtain more detailed data about the impact on mobility. The aim of the study was to quantitatively assess the functional modification of gait patterns induced by nabiximols in MS. We evaluated three-dimensional gait analysis (spatial-temporal and kinematic) variation by means of one-way ANOVA. Twenty patients were enrolled-9 male and 11 female-with mean EDSS of 5.3 (SD +/- 0.81) and mean reduction of numerical rating scale during nabiximols treatment of 1.88. The spatial-temporal parameters of gait revealed an increased speed (+15 %, p < 0.001), cadence (+6 %, p < 0.001) and stride length (+10 %, p < 0.001) after treatment. Regarding the kinematics data, the Gait Profile Score after treatment was reduced by 10 % (p < 0.001): Significant changes involved the pelvic area, hip rotation and knee flexion extension. We found that nabiximols is able to improve the speed, cadence and stride length. Furthermore, the dynamics of the proximal segment of the legs and the knee movement results after treatment are closer to the physiologic values. PMID- 26239225 TI - MicroRNA-133a and microRNA-326 co-contribute to hepatocellular carcinoma 5 fluorouracil and cisplatin sensitivity by directly targeting B-cell lymphoma extra large. AB - Chemotherapy is one of the most common treatments used for hepatocellular carcinoma (HCC), which effectively improves outcome and reduces tumor recurrence. However, the drug resistance mechanisms involved in chemotherapy, which is the predominant challenge in HCC treatment, remain to be fully elucidated. Therefore, there is an urgent requirement for the identification of novel therapeutic strategies or drugs. MicroRNAs (miRs) have become an area of interest, and in the present study, the effects of miR-133a and miR-326 on HepG2 cells, and their function on B-cell lymphoma-extra large (Bcl-xl) in HepG2 cells were investigated. Using computational programs, Bcl-xl was predicted as the common target gene of miR-133a and miR-326. A dual-luciferase reporter assay was used to verify the target genes of miRs. The mRNA and protein levels of Bcl-xl were observed to be downregulated following transfection with miR-133a or miR-326 mimics. Combining miR-133a or miR-326 with 5-fluorouracil (5-FU) or cisplatin (DDP) resulted in increased cell death. The results of the present study indicated that miR-133a, miR-326 and Bcl-xl acted protectively against the apoptosis, induced by 5-FU or DDP, in HepG2 cells. This suggested the potential use of miRs either as ancillary anti-cancer drugs or as anti-cancer drugs themselves. PMID- 26239226 TI - Marginal kidneys for transplantation. PMID- 26239227 TI - Prolonged diet-induced obesity in mice modifies the inflammatory response and leads to worse outcome after stroke. AB - BACKGROUND: Obesity increases the risk for ischaemic stroke and is associated with worse outcome clinically and experimentally. Most experimental studies have used genetic models of obesity. Here, a more clinically relevant model, diet induced obesity, was used to study the impact of obesity over time on the outcome and inflammatory response after stroke. METHODS: Male C57BL/6 mice were maintained on a high-fat (60% fat) or control (12% fat) diet for 2, 3, 4 and 6 months when experimental stroke was induced by transient occlusion of the middle cerebral artery (MCAo) for either 20 (6-month diet) or 30 min (2-, 3-, 4- and 6 month diet). Ischaemic damage, blood-brain barrier (BBB) integrity, neutrophil number and chemokine expression in the brain were assessed at 24 h. Plasma chemokine levels (at 4 and 24 h) and neutrophil number in the liver (at 24 h) were measured. Physiological parameters (body weight and blood glucose) were measured in naive control- and high-fat-fed mice at all time points and blood pressure at 3 and 6 months. Blood cell counts were also assessed in naive 6-month control- and high-fat-fed mice. RESULTS: Mice fed a high-fat diet for 6 months had greater body weight, blood glucose and white and red blood cell count but no change in systolic blood pressure. After 4 and 6 months of high-fat feeding, and in the latter group with a 30-min (but not 20-min) occlusion of the MCA, obese mice had greater ischaemic brain damage. An increase in blood-brain barrier permeability, chemokine expression (CXCL-1 and CCL3), neutrophil number and microglia/macrophage cells was observed in the brains of 6-month high-fat-fed mice after 30-min MCAo. In response to stroke, chemokine (CXCL-1) expression in the plasma and liver was significantly different in obese mice (6-month high-fat fed), and a greater number of neutrophils were detected in the liver of control but not obese mice. CONCLUSIONS: The detrimental effects of diet-induced obesity on stroke were therefore dependent on the severity of obesity and length of ischaemic challenge. The altered inflammatory response in obese mice may play a key role in its negative impact on stroke. PMID- 26239228 TI - Function Self-Efficacy Scale-FSES: Development, Evaluation, and Contribution to Well-Being. AB - This article describes the development and validation of the Function Self Efficacy Scale (FSES) for assessing the degree of confidence in self-functioning while facing decline in health and function (DHF). The FSES was evaluated in two studies of older Israelis, aged 75+ years. Data were collected by structured home interviews. Exploratory factor analyses conducted in both studies clearly revealed two underlying factors: emotion self-efficacy and action self-efficacy. Confirmatory factor analyses resulted in acceptable model fit criteria. The shortened final 13-item FSES had good internal consistency and satisfactory criterion and convergent validity. Multiple regression analyses, conducted to predict subjective well-being in each of the studies, showed that function self efficacy had a positive and significant contribution to the explanation of well being, while controlling for general self-efficacy, self-rated health, and sociodemographic variables. We propose that appropriate interventions can strengthen function self-efficacy, thus improving the well-being of elderly persons and their ability to cope with DHF. PMID- 26239229 TI - Anti-leukemic activity of axitinib against cells harboring the BCR-ABL T315I point mutation. AB - The BCR-ABL; breakpoint cluster region-Abelson point mutation T315I is resistant to ABL tyrosine kinase inhibitors. However, axitinib, a vascular endothelial growth factor receptor inhibitor, is effective against this mutation. In this study, we investigated axitinib activity against ponatinib-resistant cells and found that axitinib inhibited cellular growth and apoptosis in Ba/F3 T315I-mutant cells and T315I-mutant primary samples, but not in ponatinib-resistant Ba/F3 cells and primary samples. Thus, an alternative strategy may be required to improve the prognosis of Philadelphia-chromosome-positive leukemia patients harboring BCR-ABL point mutations. PMID- 26239230 TI - Continuous gas fermentation by Acetobacterium woodii in a submerged membrane reactor with full cell retention. AB - Acetogenic bacteria like Acetobacterium woodii represent an ancient group of anaerobic microorganisms which use hydrogen and carbon dioxide to produce acetate. Cell concentrations and space-time yields are usually low in gas fermentations. A standard stirred-tank bioreactor with continuous gas supply was equipped with a customized submerged microfiltration unit. A. woodii showed similar growth behavior with an initial maximal growth rate of 1.2 d(-1) in continuous gas fermentations with full cell retention and varying dilution rates. A steady increase of cell mass concentrations was observed with the highest biomass formation at the highest dilution rate. By contrast the final acetate concentrations were lowest at the highest dilution rate. The highest final acetate space-time yield of 148 g l(-1) d(-1) was measured at the highest dilution rate (increase by factor 8 compared to a standard batch process or by factor 37 compared to published data). The highest reported cell concentration of A. woodii in gas fermentations of nearly 14 g l(-1) cell dry weight was achieved in the submerged membrane bioreactor with increased yeast extract concentrations in the feed medium. Product inhibition was observed when acetate concentrations exceeded 8-12 g l(-1) causing a steady decrease in cell mass specific acetate production rates. PMID- 26239231 TI - Efficient biosynthesis of rare natural product scopolamine using E. coli cells expressing a S14P/K97A mutant of hyoscyamine 6beta-hydroxylase AaH6H. AB - Hyoscyamine 6beta-hydroxylase (H6H, EC 1.14.11.11), an alpha-ketoglutarate dependent dioxygenase catalyzes the hydroxylation of (-)-hyoscyamine and the subsequent epoxidation of 6beta-hydroxyhyoscyamine to form scopolamine, a valuable natural alkaloid. In this study, random mutagenesis and site-directed saturation mutagenesis were used to enhance the hydroxylation activity of H6H from Anisodus acutangulus (AaH6H). A double mutant, AaH6HM1 (S14P/K97A), showed a 3.4-fold improved hydroxylation activity compared with the wild-type enzyme, and the in vivo epoxidation activity was also improved by 2.3 times. After 34h cultivation of Escherichia coli cells harboring Aah6hm1 in a 5-L bioreactor with a working volume of 3L, scopolamine was produced via a single-enzyme-mediated two step transformation from 500mgL(-1) (-)-hyoscyamine in 97% conversion, and 1.068g of the product were isolated, corresponding to a space-time yield of 251mgL(-1)d( 1). This study shows that the protein engineering of some key enzymes is a promising and effective way for improving the production of rare natural products such as scopolamine. PMID- 26239232 TI - Renal Vasoconstriction Occurs Early During Shockwave Lithotripsy in Humans. AB - INTRODUCTION: In animal models, pretreatment with low-energy shock waves and a pause decreased renal injury from shockwave lithotripsy (SWL). This is associated with an increase in perioperative renal resistive index (RI). A perioperative rise is not seen without the protective protocol, which suggests that renal vasoconstriction during SWL plays a role in protecting the kidney from injury. The purpose of our study was to investigate whether there is an increase in renal RI during SWL in humans. MATERIALS AND METHODS: Subjects were prospectively recruited from two hospitals. All subjects received an initial 250 shocks at low setting, followed by a 2-minute pause. Treatment power was then increased. Measurements of the renal RI were taken before start of procedure, at 250, after 750, after 1500 shocks, and at the end of the procedure. A linear mixed-effects model was used to compare RIs at the different time points. RESULTS: Fifteen patients were enrolled. Average treatment time was 46 +/- 8 minutes. Average RI at pretreatment, after 250, after 750, after 1500 shocks, and post-treatment was 0.67 +/- 0.06, 0.69 +/- 0.08, 0.71 +/- 0.07, 0.73 +/- 0.07, and 0.74 +/- 0.06, respectively. In adjusted analyses, RI was significantly increased after 750 shocks compared with pretreatment (p = 0.05). CONCLUSION: Renal RI increases early during SWL in humans with the protective protocol. Monitoring for a rise in RI during SWL is feasible and may provide real-time feedback as to when the kidney is protected. PMID- 26239233 TI - Better Axial Stiffness of a Bicortical Screw Construct Compared to a Cable Construct for Comminuted Vancouver B1 Proximal Femoral Fractures. AB - The aim of this study was to biomechanically evaluate the Locking attachment plate (LAP) construct in comparison to a Cable plate construct, for the fixation of periprosthetic femoral fractures after cemented total hip arthroplasty. Each construct incorporated a locking compression plate with bi-cortical locking screws for distal fixation. In the Cable construct, 2 cables and 2 uni-cortical locking screws were used for proximal fixation. In the LAP construct, the cables were replaced by a LAP with 4 bi-cortical locking screws. The LAP construct was significantly stiffer than the cable construct under axial load with a bone gap (P=0.01). The LAP construct offers better axial stiffness compared to the cable construct in the fixation of comminuted Vancouver B1 proximal femoral fractures. PMID- 26239234 TI - Effects of Reduction Osteotomy on Gap Balancing During Total Knee Arthroplasty for Severe Varus Deformity. AB - This study aimed to assess the effects of down-sizing and lateralizing of the tibial component (reduction osteotomy) on gap balancing in TKA, and the clinical feasibility of an uncemented modular trabecular metal tibial tray in this technique. Reduction osteotomy was performed for 39 knees of 36 patients with knee OA with a mean tibiofemoral angle of 21 degrees varus. In 20 knees, appropriate gap balance was achieved by release of the deep medial collateral ligament alone. Flexion gap imbalance could be reduced by approximately 1.7 degrees and 2.8 degrees for 4-mm osteotomy and 8-mm osteotomy, respectively. Within the first postoperative year, clinically-stable tibial component subsidence was observed in 9 knees, but it was not progressive, and the clinical results were excellent at a mean follow-up of 3.3 years. PMID- 26239235 TI - Histopathological Evaluation of the Anterior Cruciate Ligament in Patients Undergoing Primary Total Knee Arthroplasty. AB - This study assessed gross and histopathological ACL changes in arthritic knees (n=174) undergoing total knee arthroplasty. Histopathological changes were assessed and graded as absent (0), mild (1), moderate (2), or marked (3). These were correlated to demographic and clinical factors, and radiographic evaluations. The ACL was intact in 43, frayed in 85, torn in 15, and absent in 31 knees. Eighty-five percent had histological changes. Overall, there were significant associations between greater age and BMI, and histological changes. Grade IV knees had significantly greater calcium pyrophosphate deposits, microcyst formation, and number of pathologic changes. These correlations may aid decision-making when determining suitability for unicompartmental or bicruciate retaining arthroplasties, though further studies should correlate these histological findings to mechanical and functional knee status. PMID- 26239236 TI - Preparation and Administration of I-125 Labeled Seeds for Localization of Nonpalpable Breast Lesions. AB - Radioactive seed localization (RSL) is a new technique for surgical identification of non-palpable breast lesions. We describe the preparation of the needle with I-125 seeds for ultrasound-guided deposition in breast lesions. In a feasibility study we investigated the minimum activity amount needed for reliable gamma probe identification of the seeds and the levels of exposure to the staff. METHODS: 11 patients received a seed, which was manually placed in an 18 gauge needle with bone wax occluding the tip, and the radiologist introduced it into the breast tissue guided by ultra-sound. The seed was located during the operation with a handheld gamma probe. The activity amount required was studied in a water bath. Radiation exposure to the fingertips of pathologists was measured by a thermoluminescent dosemeter. RESULTS: All seeds were successfully prepared, positioned in the breast lesion, and easily identified. The surgeon removed the seeds together with the breast lesions, and they were identified by the pathologist. There were no unexpected adverse drug reactions. Water bath studies suggest that 1-3 MBq I-125 was sufficient for precise identification, regardless of the presence of conventional Tc- 99m activity from sentinel node injection. The total finger dose exposure to the pathologists for the 8 procedures was below the detection limit of 0.1 mSv. CONCLUSION: I-125 seeds for ultrasound-guided deployment and surgical identification of breast lesions were successfully prepared and identified for this promising new radioguided surgical technique. The radiation exposure to staff involved is considerably below the permissible limits and almost negligible. PMID- 26239237 TI - Optimising the Azeotropic Drying of 18F-Fluorine Wayto Improve the 18F Fluorocholine Radiochemical Yield. AB - BACKGROUND AND OBJECTIVE: 18F-Fluorocholine has been suggested as one of the reputable imaging tracers for diagnosis of prostate tumour in Positron Emission Tomography / Computed Tomography (PET/CT) modality. Nevertheless, it has never been synthesised in Malaysia. We acknowledged that the major problem with 18F Fluorocholine is due to its relatively low radiochemical yield at the end of synthesis (EOS). Therefore, this article presents improved 18FFluorocholine radiochemical yields after carrying out optimisation on azeotropic drying of 18F Fluorine. METHODS: In the previous study, the azeotropic drying of non-carrier added (n.c.a) 18F-Fluorine in the reactor was conducted at atmospheric pressure (0 atm) and shorter duration time. In this study, however, the azeotropic drying of non-carried-added (n.c.a) 18FFluorine was made at a high vacuum pressure (- 0.65 to - 0.85 bar) with an additional time of 30 seconds. At the end of the synthesis, the mean radiochemical yield was statistically compared between the two azeotropic drying conditions so as to observe whether the improvement made was significant to the radiochemical yield. RESULTS: From the paired sample t test analysis, the improvement done to the azeotropic drying of non-carrier-added (n.c.a) 18F-Fluorine was statistically significant (p < 0.05). With the improvement made, the 18F-Fluorcholine radiochemical yield was found to have increase by one fold. CONCLUSION: Improved 18F-Fluorocholine radiochemical yields were obtained after the improvement had been done to the azeotropic drying of non carrier-added (n.c.a) 18F-Fluorine. It was also observed that improvement made to the azeotropic drying of non-carrier-added (n.c.a) 18F-Fluorine did not affect the 18F-Fluorocholine quality control analysis. PMID- 26239238 TI - Automatic 3D Cell Analysis in High-Throughput Microarray Using Micropillar and Microwell Chips. AB - Area-based and intensity-based 3D cell viability measurement methods are compared in high-throughput screening in order to analyze their effects on the assay results (doubling time and IC50) and their repeatability. Many other 3D cell based high-throughput screening platforms had been previously introduced, but these had not clearly addressed the effects of the two methods on the assay results and assay repeatability. In this study, the optimal way to analyze 3D cultured cells is achieved by comparing day-to-day data of doubling times and IC50 values obtained from the two methods. In experiments, the U251 cell line is grown in chips. The doubling time, based on the area of the 3D cells, was 27.8 +/ 1.8 h (standard deviation: 6.6%) and 27.8 +/- 3.8 h (standard deviation: 13.7%) based on the intensity of the 3D cells. The doubling time calculated by area shows a smaller standard deviation than one calculated by intensity. IC50 values calculated by both methods are very similar. The standard deviations of IC50 values for the two methods were within +/- 3-fold. The IC50 variations of the 12 compounds were similar regardless of the viability measurement methods and were highly related to the shape of the dose-response curves. PMID- 26239239 TI - What Drives Variation in Episode-of-care Payments for Primary TKA? An Analysis of Medicare Administrative Data. AB - BACKGROUND: Episode-of-care payments are defined as a single lump-sum payment for all services associated with a single medical event or surgery and are designed to incentivize efficiency and integration among providers and healthcare systems. A TKA is considered an exemplar for an episode-of-care payment model by many policymakers, but data describing variation payments between hospitals for TKA are extremely limited. QUESTIONS/PURPOSES: We asked: (1) How much variation is there between hospitals in episode-of-care payments for primary TKA? (2) Is variation in payment explained by differences in hospital structural characteristics such as teaching status or geographic location, patient factors (age, sex, ethnicity, comorbidities), and discharge disposition during the postoperative period (home versus skilled nursing facility)? (3) After accounting for those factors, what proportion of the observed variation remains unexplained? METHODS: We used Medicare administrative data to identify fee-for-service beneficiaries who underwent a primary elective TKA in 2009. After excluding low volume hospitals, we created longitudinal records for all patients undergoing TKAs in eligible hospitals encompassing virtually all payments by Medicare for a 120-day window around the TKA (30 days before to 90 days after). We examined payments for the preoperative, perioperative, and postdischarge periods based on the hospital where the TKA was performed. Confounding variables were controlled for using multivariate analyses to determine whether differences in hospital payments could be explained by differences in patient demographics, comorbidity, or hospital structural factors. RESULTS: There was considerable variation in payments across hospitals. Median (interquartile range) hospital preoperative, perioperative, postdischarge, and 120-day payments for patients who did not experience a complication were USD 623 (USD 516-768), USD 13,119 (USD 12,165 14,668), USD 8020 (USD 6403-9933), and USD 21,870 (USD 19,736-25,041), respectively. Variation cannot be explained by differences in hospital structure. Median (interquartile range) episode payments were greater for hospitals in the Northeast (USD 26,291 [22,377-30,323]) compared with the Midwest, South, and West (USD 20,614, [USD 18,592-22.968]; USD 21,584, [USD 19,663-23,941]; USD 22,421, [USD 20,317-25,860]; p < 0.001) and for teaching compared with nonteaching hospitals (USD 23,152 [USD 20,426-27,127] versus USD 21,336 [USD 19,352-23,846]; p < 0.001). Patient characteristics explained approximately 15% of the variance in hospital payments, hospital characteristics (teaching status, geographic region) explained 30% of variance, and approximately 55% of variance was not explained by either factor. CONCLUSIONS: There is much unexplained variation in episode-of-care payments at the hospital-level, suggesting opportunities for enhanced efficiency. Further research is needed to ensure an appropriate balance between such efficiencies and access to care. LEVEL OF EVIDENCE: Level II, economic analysis. PMID- 26239240 TI - Health-care services utilization and costs associated with radical cystectomy for bladder cancer: a descriptive population-based study in the province of Quebec, Canada. AB - BACKGROUND: Bladder cancer (BC) has the highest lifetime treatment costs per patient of all cancers. The objective of this study was to characterize the use of health-care services and costs associated with BC among patients who underwent radical cystectomy (RC) in the province of Quebec. METHODS: We conducted a descriptive study in a retrospective cohort of patients who underwent RC for BC between 2000 and 2009. Data was obtained from two health administrative databases (RAMQ and ISQ). We calculated average costs per patient and total costs in 2014 Canadian dollars for the following components of costs: 1) Pre-surgery costs (pre and post-urologist consultations, urologist consultations, cystoscopies, TURBTs, imaging procedures); 2) Costs of radical cystectomy and 3) Post-surgery costs (urologist consultations, post-operative consultations, medical oncologist consultations, imaging procedures and post-operative complication management). ARIMA models were used to evaluate trends in average costs per patient over the study period. RESULTS: Among 2759 patients included in the study (75% men), average pre-surgery costs, RC costs, and post-surgery costs were estimated at 3762$, 18979$ and 4770$, respectively. RC cost was responsible for 69% of total costs, followed by post-operative consultations (7.8%), post-operative complications and TURBTs (6% of total costs, each). Academic hospitals performed RC at a lower average cost, compared to community hospitals (difference of $1000, p < .0001). A decreased trend in post-surgery costs was detected in the year 2009. CONCLUSIONS: Costs of RC, TURBT, consultations and post-operative complications were the most important economic components of total RC cost per patient in Quebec. Academic hospitals performed RC at a lower cost, compared to community hospitals. PMID- 26239241 TI - An internet-based self-administered intervention for promoting healthy habits and weight loss in hypertensive people who are overweight or obese: a randomized controlled trial. AB - BACKGROUND: The prevalence of overweight and obesity is on the rise worldwide with severe physical and psychosocial consequences. One of the most dangerous is hypertension. Lifestyle changes related to eating behaviour and physical activity are the critical components in the prevention and treatment of hypertension and obesity. Data indicates that the usual procedures to promote these healthy habits in health services are either insufficient or not efficient enough. Internet has been shown to be an effective tool for the implementation of lifestyle interventions based on this type of problem. This study aims to assess the efficacy of a totally self-administered online intervention programme versus the usual medical care for obese and overweight participants with hypertension (from the Spanish public health care system) to promote healthy lifestyles (eating behaviour and physical activity). METHOD: A randomized controlled trial will be conducted with 100 patients recruited from the hypertension unit of a public hospital. Participants will be randomly assigned to one of two conditions: a) SII: a self-administered Internet-based intervention protocol; and b) MUC-medical usual care. The online intervention is an Internet-delivered, multimedia, interactive, self-administered programme, composed of nine modules designed to promote healthy eating habits and increase physical activity. The first five modules will be activated at a rate of one per week, and access for modules 5 to 9 will open every two weeks. Patients will be assessed at four points: before the intervention, after the intervention (3 months), and at 6 and 12 months (follow up). The outcome variables will include blood pressure, and Body Mass Index, as primary outcome measures, and quality of life and other lifestyle and anthropometrical variables as secondary outcome measures. DISCUSSION: The literature highlights the need for more studies on the benefits of using the Internet to promote lifestyle interventions. This study aims to investigate the efficiency of a totally self-administered Internet - +based programme for promoting healthy habits and improving the medical indicators of a hypertensive and overweight population. TRIAL REGISTRATION: NCT02445833. PMID- 26239242 TI - Satisfaction with fertility- and sexuality-related information in young women with breast cancer--ELIPPSE40 cohort. AB - BACKGROUND: Young breast cancer survivors are often dissatisfied with the information provided on fertility and sexuality. Our aim was to discuss possible contributing factors and to propose strategies to increase patient satisfaction with such information. METHODS: Using the French National Health Insurance System database, we constituted the ELIPPSE40 regional cohort of 623 women, aged 18-40, diagnosed with breast cancer between 2005 and 2011. As of January 2014, 319 women had taken part in the 10-, 16-, 28 and 48-month telephone interviews. Satisfaction with the information provided about the potential impact of cancer and its treatment on fertility and sexuality was assessed at 48 months after diagnosis on 5-point Likert scales. RESULTS: Four years after diagnosis, only 53.0 and 42.6% of women were satisfied with fertility- and sexuality-related information, respectively, without any significant change over the 2009-2014 period (P = 0.585 and P = 0.676 respectively). The two issues were moderately correlated (rho = 0.60; P <0.001). General satisfaction with medical follow-up was the only common correlate. Irrespective of sociodemographic and medical characteristics, satisfaction with fertility-related information was greater among women with a family history of breast/ovarian cancer who had the opportunity to ask questions at the time of cancer disclosure. Satisfaction with sexuality-related information increased with the spontaneous provision of information by physicians at cancer disclosure. CONCLUSIONS: Promoting both patients' question asking behavior and more systematic information could improve communication between caregivers and young breast cancer survivors and address distinct unmet needs regarding fertility- and sexuality- related information. PMID- 26239243 TI - P53 Regulates Rapid Apoptosis in Human Pluripotent Stem Cells. AB - Human pluripotent stem cells (hPSCs) are sensitive to DNA damage and undergo rapid apoptosis compared to their differentiated progeny cells. Here, we explore the underlying mechanisms for the increased apoptotic sensitivity of hPSCs that helps to determine pluripotent stem cell fate. Apoptosis was induced by exposure to actinomycin D, etoposide, or tunicamycin, with each agent triggering a distinct apoptotic pathway. We show that hPSCs are more sensitive to all three types of apoptosis induction than are lineage-non-specific, retinoic-acid differentiated hPSCs. Also, Bax activation and pro-apoptotic mitochondrial intermembrane space protein release, which are required to initiate the mitochondria-mediated apoptosis pathway, are more rapid in hPSCs than in retinoic acid-differentiated hPSCs. Surprisingly, Bak and not Bax is essential for actinomycin-D-induced apoptosis in human embryonic stem cells. Finally, P53 is degraded rapidly in an ubiquitin-proteasome-dependent pathway in hPSCs at steady state but quickly accumulates and induces apoptosis when Mdm2 function is impaired. Rapid degradation of P53 ensures the survival of healthy hPSCs but avails these cells for immediate apoptosis upon cellular damage by P53 stabilization. Altogether, we provide an underlying, interconnected molecular mechanism that primes hPSCs for quick clearance by apoptosis to eliminate hPSCs with unrepaired genome alterations and preserves organismal genomic integrity during the early critical stages of human embryonic development. PMID- 26239245 TI - A Case of Midbrain and Thalamic Infarction Involving Artery of Percheron. AB - Blood supply to the thalamus and brainstem have frequent anatomic variations. One of these is where all the perforators to the above areas arise from a single branch of the posterior cerebral artery commonly known as the artery of Percheron. Infarction involving this artery leading to bilateral thalamic and midbrain lesions is not uncommon, but can cause diagnostic difficulties due to the varying clinical presentations possible and the wide differentials. Early brain imaging and diagnosis is important for initiating appropriate treatment. In this case report, we discuss a patient who presented with an artery of Percheron related stroke affecting the mid brain and paramedian thalamic areas. We also discuss the differentials of presentations with similar symptoms. PMID- 26239244 TI - Oxygen-Glucose Deprivation (OGD) Modulates the Unfolded Protein Response (UPR) and Inflicts Autophagy in a PC12 Hypoxia Cell Line Model. AB - Hypoxia is the lack of sufficient oxygenation of tissue, imposing severe stress upon cells. It is a major feature of many pathological conditions such as stroke, traumatic brain injury, cerebral hemorrhage, perinatal asphyxia and can lead to cell death due to energy depletion and increased free radical generation. The present study investigates the effect of hypoxia on the unfolded protein response of the cell (UPR), utilizing a 16-h oxygen-glucose deprivation protocol (OGD) in a PC12 cell line model. Expression of glucose-regulated protein 78 (GRP78) and glucose-regulated protein 94 (GRP94), key players of the UPR, was studied along with the expression of glucose-regulated protein 75 (GRP75), heat shock cognate 70 (HSC70), and glyceraldehyde 3-phosphate dehydrogenase, all with respect to the cell death mechanism(s). Cells subjected to OGD displayed upregulation of GRP78 and GRP94 and concurrent downregulation of GRP75. These findings were accompanied with minimal apoptotic cell death and induction of autophagy. The above observation warrants further investigation to elucidate whether autophagy acts as a pro-survival mechanism that upon severe and prolonged hypoxia acts as a concerted cell response leading to cell death. In our OGD model, hypoxia modulates UPR and induces autophagy. PMID- 26239247 TI - Hypercalcemia Associated with Calcium Supplement Use: Prevalence and Characteristics in Hospitalized Patients. AB - BACKGROUND: The ingestion of large amounts of milk and antacids to treat peptic ulcer disease was a common cause of hypercalcemia in the past (the "milk-alkali syndrome"). The current popularity of calcium and supplements has given rise to a similar problem. OBJECTIVES: To evaluate the prevalence and characteristics of hypercalcemia induced by calcium intake ("calcium supplement syndrome"; or CSS) in hospitalized patients. METHODS: We conducted a retrospective; electronic health record (EHR)-based review of patients with hypercalcemia over a 3-year period. Diagnosis of CSS was based on the presence of hypercalcemia; a normal parathyroid hormone (PTH) level; renal insufficiency; metabolic alkalosis; a history of calcium intake; and documented improvement with treatment. RESULTS: Of the 72 patients with non-PTH mediated hypercalcemia; 15 (20.8%) satisfied all the criteria for the diagnosis of CSS. Calcium; vitamin D; and multivitamin ingestion were significantly associated with the diagnosis (p values < 0.0001; 0.014; and 0.045 respectively); while the presence of hypertension; diabetes; and renal insufficiency showed a trend towards statistical significance. All patients received intravenous fluids; and six (40%) received calcium-lowering drugs. The calcium level at discharge was normal 12 (80%) of patients. The mean serum creatinine and bicarbonate levels decreased from 2.4 and 35 mg/dL on admission respectively; to 1.6 mg/dL and 25.6 mg/dL at discharge respectively. CONCLUSION: The widespread use of calcium and vitamin D supplementation can manifest as hypercalcemia and worsening of kidney function in susceptible individuals. Awareness among health care professionals can lead to proper patient education regarding these health risks. PMID- 26239248 TI - Treatment of Acute Myeloid Leukemia in Adolescent and Young Adult Patients. AB - The objectives of this review were to discuss standard and investigational treatment strategies for adolescent and young adult with acute myeloid leukemia, excluding acute promyelocytic leukemia. Acute myeloid leukemia (AML) in adolescent and young adult patients (AYAs) may need a different type of therapy than those currently used in children and older patients. As soon as AML is diagnosed, AYA patient should be offered to participate in well-designed clinical trials. The standard treatment approach for AYAs with AML is remission induction chemotherapy with an anthracycline/cytarabine combination, followed by either consolidation chemotherapy or stem cell transplantation, depending on the ability of the patient to tolerate intensive treatment and cytogenetic features. Presently, continuing progress of novel drugs targeting specific pathways in acute leukemia may bring AML treatment into a new era. PMID- 26239246 TI - Neuroendocrine Disorders in Pediatric Craniopharyngioma Patients. AB - Childhood-onset craniopharyngiomas are partly cystic embryonic malformations of the sellar/parasellar region. The therapy of choice in patients with favorable tumor localization is complete resection with a specific focus on maintaining optical and hypothalamic neuroendocrine functions. In patients with unfavorable tumor localization (i.e., hypothalamic involvement), a limited hypothalamus sparing surgical strategy followed by local irradiation is recommended. Involvement and/or surgical lesions of posterior hypothalamic areas cause major neuroendocrine sequelae. The overall survival rates are high (92%) but neuroendocrine disorders such as obesity and metabolic syndrome due to involvement and/or treatment-related hypothalamic lesions have major negative impact on survival and quality of life. Recurrences and progressions are frequent post-surgical events. Because irradiation is efficient in preventing tumor progression, appropriate timing of post-surgical irradiation is currently under investigation in a randomized multinational trial (KRANIOPHARYNGEOM 2007). Childhood-onset craniopharyngioma should be recognized as a chronic disease requiring treatment and constant monitoring of the clinical and quality of life consequences, frequently impaired due to neuroendocrine disorders, by experienced multidisciplinary teams in order to provide optimal care of surviving patients. PMID- 26239249 TI - Molecular Genetic Markers in Acute Myeloid Leukemia. AB - Genetics play an increasingly important role in the risk stratification and management of acute myeloid leukemia (AML) patients. Traditionally, AML classification and risk stratification relied on cytogenetic studies; however, molecular detection of gene mutations is playing an increasingly important role in classification, risk stratification, and management of AML. Molecular testing does not take the place of cytogenetic testing results, but plays a complementary role to help refine prognosis, especially within specific AML subgroups. With the exception of acute promyelocytic leukemia, AML therapy is not targeted but the intensity of therapy is driven by the prognostic subgroup. Many prognostic scoring systems classify patients into favorable, poor, or intermediate prognostic subgroups based on clinical and genetic features. Current standard of care combines cytogenetic results with targeted testing for mutations in FLT3, NPM1, CEBPA, and KIT to determine the prognostic subgroup. Other gene mutations have also been demonstrated to predict prognosis and may play a role in future risk stratification, although some of these have not been confirmed in multiple studies or established as standard of care. This paper will review the contribution of cytogenetic results to prognosis in AML and then will focus on molecular mutations that have a prognostic or possible therapeutic impact. PMID- 26239250 TI - New Developments in Biomarkers for Atopic Dermatitis. AB - The application of biomarkers in medicine is evolving. Biomarkers do not only give us a better understanding of pathogenesis, but also increase treatment efficacy and safety, further enabling more precise clinical care. This paper focuses on the current use of biomarkers in atopic dermatitis, new developments and future perspectives. Biomarkers can be used for many different purposes, including the objective determination of disease severity, confirmation of clinical diagnosis, and to predict response to treatment. In atopic dermatitis, many biomarkers have been investigated as a marker for disease severity. Currently serum thymus and activation-regulated chemokine (TARC) is the superior biomarker for assessing disease severity. However, we have recently shown that the use of a panel of serum biomarkers is more suitable for assessing disease severity than an individual biomarker. In this overview, we will discuss alternative sources for biomarkers, such as saliva and capillary blood, which can increase the user friendliness of biomarkers in atopic dermatitis (AD). Both methods offer simple, non-invasive and cost effective alternatives to venous blood. This provides great translational and clinical potential. Biomarkers will play an increasingly important role in AD research and personalized medicine. The use of biomarkers will enhance the efficacy of AD treatment by facilitating the individualization of therapy targeting the patients' specific biological signature and also by providing tools for predicting and monitoring of therapeutic response. PMID- 26239251 TI - Effects of T-Cell Depletion on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in AML Patients. AB - Graft versus host disease (GVHD) remains one of the leading causes of morbidity and mortality associated with conventional allogeneic hematopoietic stem cell transplantation (HCT). The use of T-cell depletion significantly reduces this complication. Recent prospective and retrospective data suggest that, in patients with AML in first complete remission, CD34+ selected grafts afford overall and relapse-free survival comparable to those observed in recipients of conventional grafts, while significantly decreasing GVHD. In addition, CD34+ selected grafts allow older patients, and those with medical comorbidities or with only HLA mismatched donors to successfully undergo transplantation. Prospective data are needed to further define which groups of patients with AML are most likely to benefit from CD34+ selected grafts. Here we review the history of T-cell depletion in AML, and techniques used. We then summarize the contemporary literature using CD34+ selection in recipients of matched or partially mismatched donors (7/8 or 8/8 HLA-matched), and provide a summary of the risks and benefits of using T-cell depletion. PMID- 26239252 TI - Optional real-time display of intraoperative neurophysiological monitoring in the microscopic field of view: avoiding communication failures in the operating room. AB - BACKGROUND: The use of intraoperative neurophysiological monitoring (IONM) in neurosurgery has improved patient safety and outcomes. However, a pitfall in the use of IONM remains unsolved. Currently, there is no feasible way for surgeons to interpret IONM waves themselves during operations. Instead, they have to rely on verbal feedback from a neurophysiologist. This method is prone to communication failures, which can lead to delayed or false interpretation of the data. Direct visualization of IONM waves is a way to alleviate this problem and make IONM more effective. METHODS: Microscope-integrated IONM (MI-IONM) was used in 163 cranial and spinal cases. We evaluated the feasibility, system stability and how well the system integrated into the surgical workflow. We used an IONM system that was connected to a surgical microscope. All IONM modalities used at our institution could be visualized as required, superimposed on the surgical field in the eyepiece of the microscope without obstructing the surgeon's field of vision. RESULTS: Use of MI-IONM was safe and reliable. It furthermore provided valuable intraoperative information. The system merely required a short learning curve. Only minor system problems without impact on surgical workflow occurred. MI-IONM proved to be especially useful in surgical cases where careful monitoring of nerve function is required, e.g., cerebellopontine angle surgery. Here, direct assessment of surgical action and IONM wave change was provided to the surgeon, if necessary (on-off control). CONCLUSION: MI-IONM is a useful extension of conventional IONM that provides optional real-time functional information to the surgeon on demand. PMID- 26239253 TI - Individualization of deep brain stimulation targets for movement disorders. PMID- 26239254 TI - Transcriptional regulation of nucleoredoxin-like genes takes place on a daily basis in the retina and pineal gland of rats. AB - The nucleoredoxin-like gene Nxnl1 (Txnl6) and its paralogue Nxnl2 encode the rod derived cone viability factors (RdCVF and RdCVF2), which increase the resistance to photooxidative damage and have therapeutic potential for the survival of cones in retinitis pigmentosa. In this study, the transcription of Nxnl genes was investigated as a function of the day/night cycle in rats. The transcript levels of Nxnl1 and Nxnl2 were seen to display daily rhythms with steadily increasing values during the light phase and peak expression around dark onset in preparations of whole retina, photoreceptor cells and-but only in regard to Nxnl1 in photoreceptor-related pinealocytes. The cycling of Nxnl1 but not that of Nxnl2 persisted in constant darkness in the retina. This suggests that daily regulation of Nxnl1 is driven by a circadian clock, whereas that of Nxnl2 is promoted by environmental light. The present data indicate clock- and light-dependent regulations of nucleoredoxin-like genes that may be part of a protective shield against photooxidative damage. PMID- 26239255 TI - Designing an Internationally Accessible Web-Based Questionnaire to Discover Risk Factors for Amyotrophic Lateral Sclerosis: A Case-Control Study. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a typical survival of three to five years. Epidemiological studies using paper-based questionnaires in individual countries or continents have failed to find widely accepted risk factors for the disease. The advantages of online versus paper-based questionnaires have been extensively reviewed, but few online epidemiological studies into human neurodegenerative diseases have so far been undertaken. OBJECTIVE: To design a Web-based questionnaire to identify environmental risk factors for ALS and enable international comparisons of these risk factors. METHODS: A Web-based epidemiological questionnaire for ALS has been developed based on experience gained from administering a previous continent-wide paper-based questionnaire for this disease. New and modified questions have been added from our previous paper based questionnaire, from literature searches, and from validated ALS questionnaires supplied by other investigators. New criteria to allow the separation of familial and sporadic ALS cases have been included. The questionnaire addresses many risk factors that have already been proposed for ALS, as well as a number that have not yet been rigorously examined. To encourage participation, responses are collected anonymously and no personally identifiable information is requested. The survey is being translated into a number of languages which will allow many people around the world to read and answer it in their own language. RESULTS: After the questionnaire had been online for 4 months, it had 379 respondents compared to only 46 respondents for the same initial period using a paper-based questionnaire. The average age of the first 379 web questionnaire respondents was 54 years compared to the average age of 60 years for the first 379 paper questionnaire respondents. The questionnaire is soon to be promoted in a number of countries through ALS associations and disease registries. CONCLUSIONS: Web-based questionnaires are a time- and resource efficient method for performing large epidemiological studies of neurodegenerative diseases such as ALS. The ability to compare risk factors between different countries using the same analysis tool will be of particular value for finding robust risk factors that underlie ALS. PMID- 26239256 TI - Emergence of Multiple Superconducting Phases in (NH3)yMxFeSe (M: Na and Li). AB - We previously discovered multiple superconducting phases in the ammoniated Na doped FeSe material, (NH3)yNaxFeSe. To clarify the origin of the multiple superconducting phases, the variation of Tc was fully investigated as a function of x in (NH3)yNaxFeSe. The 32 K superconducting phase is mainly produced in the low-x region below 0.4, while only a single phase is observed at x = 1.1, with Tc = 45 K, showing that the Tc depends significantly on x, but it changes discontinuously with x. The crystal structure of (NH3)yNaxFeSe does not change as x increases up to 1.1, i.e., the space group of I4/mmm. The lattice constants, a and c, of the low-Tc phase (Tc = 32.5 K) are 3.9120(9) and 14.145(8) A, respectively, while a = 3.8266(7) A and c = 17.565(9) A for the high-Tc phase (~46 K). The c increases in the high Tc phase, implying that the Tc is directly related to c. In (NH3)yLixFeSe material, the Tc varies continuously within the range of 39 to 44 K with changing x. Thus, the behavior of Tc is different from that of (NH3)yNaxFeSe. The difference may be due to the difference in the sites that the Na and Li occupy. PMID- 26239257 TI - Cytotoxic and apoptogenic effects of Strobilanthes crispa Blume extracts on nasopharyngeal cancer cells. AB - The chemotherapeutic agents used to treat nasopharyngeal cancer (NPC) exhibit low efficacy. Strobilanthes crispa Blume is widely used for its anticancer, diuretic and anti-diabetic properties. The present study aimed to determine the cytotoxic and apoptogenic effects of S. crispa on CNE-1 NPC cells. A 3-(4,5-dimethylthiazol 2-yl)-2,5 diphenyl tetrazolium bromide assay was used to evaluate the cytotoxic effects of S. crispa against CNE-1 cells. The rate of apoptosis was determined using propidium iodide staining and caspase assays. Ethyl acetate, hexane and chloroform extracts of S. crispa leaves all exhibited cytotoxic effects on CNE-1 cells, at a half maximal inhibitory concentration (IC50) of 119, 123.5 and 161.7 ug/ml, respectively. In addition, hexane, chloroform and ethyl acetate extracts of S. crispa stems inhibited CNE-1 cell proliferation, at a IC50 of 49.4, 148.3 and 163.5 ug/ml, respectively. Flow cytometric analysis revealed an increased proportion of cells in the sub G1 phase and a decreased proportion of cells in the G2/M phase, following treatment with the extracts. However, the extracts did not alter the activities of caspase -3/7, -8 and -9. No cytotoxic effect was observed when the cells were treated with the methanol and water extracts of S. crispa stems and leaves. In conclusion, the S. crispa extracts were cytotoxic against CNE-1 cells and these extracts were able to induce apoptosis, independent of caspase activation. PMID- 26239259 TI - Most Heart Failure Patients Die from Pump Failure: Implications for Therapy. AB - Careful review of the literature of the last 20 years since the appearance of the first positive trials in heart failure indicates an evolution in the mode of death moving from sudden death to a predominance of pump failure death (i.e., death due to progression of heart failure). Pump failure is becoming a leading cause of mortality in a range of patient profiles, including patients with newly diagnosed or severe heart failure, patients with devices, and patients with heart failure associated with Chagas' disease. Indeed, the evidence suggests that modern management strategies, such as beta-blockers and devices, are successful in preventing sudden death. However, this means that optimally treated patients are at greater risk for the consequences of pump failure (death, hospitalization, and reduced quality of life). This highlights a new important unmet need in heart failure, and a priority for current research should be therapies that reduce pump failure death and hospitalization for more cost-effective management of the disease. Insofar as one-third of heart failure patients do not survive more than 3 years after diagnosis, properly addressing pump failure is an essential target in heart failure. PMID- 26239258 TI - Harmonic force spectroscopy measures load-dependent kinetics of individual human beta-cardiac myosin molecules. AB - Molecular motors are responsible for numerous cellular processes from cargo transport to heart contraction. Their interactions with other cellular components are often transient and exhibit kinetics that depend on load. Here, we measure such interactions using 'harmonic force spectroscopy'. In this method, harmonic oscillation of the sample stage of a laser trap immediately, automatically and randomly applies sinusoidally varying loads to a single motor molecule interacting with a single track along which it moves. The experimental protocol and the data analysis are simple, fast and efficient. The protocol accumulates statistics fast enough to deliver single-molecule results from single-molecule experiments. We demonstrate the method's performance by measuring the force dependent kinetics of individual human beta-cardiac myosin molecules interacting with an actin filament at physiological ATP concentration. We show that a molecule's ADP release rate depends exponentially on the applied load, in qualitative agreement with cardiac muscle, which contracts with a velocity inversely proportional to external load. PMID- 26239260 TI - Valproic acid suppresses the self-renewal and proliferation of head and neck cancer stem cells. AB - Emerging evidence suggests that cancer cells present profound epigenetic alterations in addition to featuring classic genetic mutations. Valproic acid (VPA), a histone deacetylase inhibitor, can potently inhibit tumor growth and induce differentiation. However, the effect and underlying mechanism of VPA on head and neck squamous cell carcinoma (HNSCC) cancer stem cells (CSCs) remain unclear. In the present study we investigated the effects of VPA on the characteristics of HNSCC CSCs in vitro and in vivo. As a result, VPA inhibited the self-renewal abilities of HNSCC CSCs during two serial passages and decreased the expression of stem cell markers, such as Oct4, Sox2 and CD44. VPA also potentiated the cytotoxic effect of cisplatin by suppressing the ABCC2 and ABCC6 transporters as well as by inducing caspase-mediated apoptosis. In addition, the combination of VPA and cisplatin attenuated tumor growth and induced apoptosis in a xenograft model. Our results suggest that VPA might be a potential therapeutic strategy in combination with conventional cisplatin for HNSCC patients by elimination of CSC traits. PMID- 26239261 TI - Middle finger length-based tracheal intubation depth improves the rate of appropriate tube placement in children. AB - BACKGROUND: It is challenging for anesthetists to determine the optimal tracheal intubation depth in children. We hypothesize that a measure three times the length of the middle finger can be used for predicting tracheal tube depth in children. METHODS: Eighty-six children (4-14 years of age) were included in this study. After the children were anesthetized, a fiberoptic bronchoscope (FOB) was inserted into the trachea, the lengths from the upper incisor teeth to carina and vocal cords were measured, and a suitably sized cuffed tracheal tube was inserted into the trachea. Age-based and middle finger length-based formulas were used to determine the tracheal intubation depth. RESULTS: All 86 children enrolled were included in this study. Compared with the age-based intubation, the rate of appropriate tube placement was higher for middle finger length-based intubation (88.37% vs 66.28%, P = 0.001). The proximal intubation rate was lower in middle finger length-based intubation (4.65% vs 32.56%, P < 0.001). There was only weak evidence for a difference in the distal intubation rate between the two methods (6.97% vs 1.16%, P = 0.054). The correlation coefficient between middle finger length and optimal tracheal tube depth was larger than that between age and optimal tracheal tube depth (0.883 vs 0.845). CONCLUSIONS: Our data indicate that the appropriate tube placement rate can be improved by using three times the middle finger length as the tracheal intubation depth in children. PMID- 26239262 TI - Exercise training attenuates age-dependent elevation of angiotensin II type 1 receptor and Nox2 signaling in the rat heart. AB - Fibrosis of the aging heart impedes cardiac function and increases the risk of arrhythmias and heart disease. Previously, we demonstrated that exercise-induced reduction of collagen I in the aging heart was linked to a suppression of oxidative stress and transforming growth factor-beta (TGF-beta). The renin angiotensin II system (RAS) increases oxidative stress via NADPH oxidase-2 (Nox2) and thus elevates TGF-beta and collagen accumulation. Therefore, we tested the hypothesis that exercise training would alleviate age-related upregulation of the angiotensin II receptor I (AT1R) and NADPH oxidase-2 (Nox2), concomitant with suppression of TGF-beta and fibrosis. Young (3 months, n=20) and old (31 months, n=20) Fischer 344 *B rown Norway F1 (FBNF1) hybrid rats were assigned into sedentary and exercise groups, with exercise training rats training on a treadmill 45 min/day, 5 days/week for the next 12 weeks. Exercise training mitigated age-related upregulation of AT1R, Nox2 activity, and Nox2 subunits gp91phox and p47phox. Exercise training also attenuated TGF-beta positive staining and downstream effectors of fibrosis in the aging heart: connective tissue growth factor, phosphorylation of Smad2 at Ser423, myofibroblast proliferation, and collagen I-positive staining. Our results are consistent with the hypothesis that exercise training protects against age-dependent cardiac fibrosis by suppressing AT1R and Nox2 as part of a RAS-Nox2-TGF-beta pathway. PMID- 26239263 TI - A Fluorescent 1,3-Diaminonaphthalimide Conjugate of Calix[4]arene for Sensitive and Selective Detection of Trinitrophenol: Spectroscopy, Microscopy, and Computational Studies, and Its Applicability using Cellulose Strips. AB - A new fluorescent 1,3-diaminonaphthalimide conjugate of calix[4]arene receptor (R) was synthesized and characterized. The receptor displays good selectivity towards trinitrophenol (TNP) over other explosive aromatic- and aliphatic-nitro compounds by exhibiting changes in its fluorescence emission. Receptor-coated cellulose paper strips are equally effective in terms of their selective detection of TNP over other aromatic- and aliphatic-nitro compounds. When used in solution or on cellulose paper strips, R can detect up to submicromolar concentration of TNP by exhibiting changes in its fluorescence emission and in its supramolecular structure upon interaction. Interestingly, the microscopy features of R, TNP, and {R+TNP} are quite distinct, indicating the interactions present between R and TNP, as studied by using AFM and TEM. Computationally modeled complexes of receptor with TNP and TNT show enormous difference in their interaction energies in the favor of TNP by showing the host-guest interaction of cation???anion type in the presence of TNP but not TNT. This is because the receptor adopts an "arms-open"-type structure in the case of the TNP complex, whereas it adopts an "arms-closed"-type structure in the presence of TNT. Both the experimental and the computational studies reveal that the receptor selectively binds to TNP over TNT. Thus, R-coated Whatman No.1 filter paper strips provide easy, rapid, and economical detection of trace amounts of TNP both by visual and spectral measurement. PMID- 26239264 TI - Spectroscopic Observation of the Hydroxy Position in Butanol Hydrates and Its Effect on Hydrate Stability. AB - In this study, we investigate the crystal structures and phase equilibria of butanols+CH4 +H2 O systems to reveal the hydroxy group positioning and its effects on hydrate stability. Four clathrate hydrates formed by structural butanol isomers are identified with powder X-ray diffraction (PXRD). In addition, Raman spectroscopy is used to analyze the guest distributions and inclusion behaviors of large alcohol molecules in these hydrate systems. The existence of a free OH indicates that guest molecules can be captured in the large cages of structure II hydrates without any hydrogen-bonding interactions between the hydroxy group of the guests and the water-host framework. However, Raman spectra of the binary (1-butanol+CH4 ) hydrate do not show the free OH signal, indicating that there could be possible hydrogen-bonding interactions between the guests and hosts. We also measure the four-phase equilibrium conditions of the butanols+CH4 +H2 O systems. PMID- 26239265 TI - Practical assessment of the quantification of atherosclerotic lesions in apoE-/- mice. AB - Genetic manipulations have enabled the mouse to be widely used as an animal model for investigating the mechanisms of human atherosclerotic disease. However, there is no standard method for quantifying atherosclerotic lesions among different laboratories. The present study introduces a thorough and precise quantitative assessment of atherosclerotic lesions in mice. In the present study, 6-week-old apoE-/- mice were fed either a chow diet or a high-fat diet (HFD) for 12 weeks. Plasma lipid levels were measured every four weeks. Aortic atherosclerotic lesions were quantified and analyzed using an image analysis system. The aortic tree was isolated and stained with Oil Red O to measure the gross lesion area. The heart was removed and divided into sequential cross sections, which were then assessed for microscopic intimal lesions in the aortic root as follows: (1) Elastic van Gieson staining was performed to determine the area of the atherosclerotic lesion; (2) cross sections were stained with hematoxylin and eosin for histological analysis; and (3) cross sections were stained with Oil Red O and immunohistochemical staining for quantitative analysis of the cellular components within the lesions. ApoE-/- mice fed with either the chow diet or HFD developed severe atherosclerosis in the aortic root, however, there were few lesions in the remainder of the aortic tree. Compared with the control group, the HFD apoE-/- mice had increased plasma lipid levels and increases in the gross lesion area in the aortic tree, the microscopic lesion area in the aortic root and the number of macrophages, vascular smooth muscle cells and neutral lipids present within the lesions. HFD feeding in the apoE-/- mice accelerated the development of atherosclerosis. The quantitative method described in the present study may be used to assist in future investigations of atherosclerosis in mice. PMID- 26239266 TI - Pharmacokinetics of serelaxin in patients with severe renal impairment or end stage renal disease requiring hemodialysis: A single-dose, open-label, parallel group study. AB - Serelaxin, a recombinant human relaxin-2 hormone, is in clinical development for treating acute heart failure. This open-label, parallel-group study investigated serelaxin pharmacokinetics (PK) after a single 4-hour intravenous infusion (10 ug/kg) in patients with severe renal impairment (n = 6) or end-stage renal disease (ESRD) requiring hemodialysis (PK on the day of dialysis [n = 6] or during dialysis-free interval [n = 6]), compared with matched healthy subjects (n = 18). In all participants, serum serelaxin concentration peaked at the end of infusion and subsequently declined with mean terminal elimination half-life of 6.5-8.8 hours. Compared with healthy subjects, a moderate decrease in serelaxin systemic clearance (37%-52%) and increase in its exposure (30%-115%) were observed in all patients. During the 4-hour hemodialysis in ESRD patients, 30% serelaxin was removed, with hemodialysis clearance constituting approximately 52% of total systemic clearance. Serelaxin was well tolerated with no deaths, serious adverse events (AE), or AE-related discontinuations. Antiserelaxin antibodies were not detected in any participant. Given the shallow dose-response relationship observed with serelaxin in clinical studies and its wide therapeutic window, the observed PK differences in patients with severe renal impairment compared with healthy subjects are unlikely to pose a safety risk and do not warrant a predefined dosage adjustment in such patients. PMID- 26239267 TI - Clavicular curvature and locomotion in anthropoid primates: A 3D geometric morphometric analysis. AB - OBJECTIVES: As a component of the primate shoulder, the clavicle is expected to reflect locomotor adaptations. Whereas previous work has generally focused on clavicular length and torsion, the shape of clavicular curvature may better distinguish taxa and provide additional information about upper limb use in locomotion. This study uses three-dimensional geometric morphometrics to analyze shape differences in the curvatures of the clavicle in different locomotor groups of anthropoid primates. METHODS: Sliding semi-landmarks were placed on clavicles of 10 Anthropoid primate species (total n = 85) that display a range of locomotor behaviors. Landmarks (k = 39) were chosen to capture the overall curvature of the clavicle in three dimensions. RESULTS: The degree of ventral curvature in the clavicle represents a gradient from most-curved in suspensory genera (e.g., Ateles, Hylobates, and Pongo) to least-curved in genera that are rarely suspensory (e.g., Papio and Gorilla). This curvature may allow an increased range of craniodorsal movement without the clavicle impinging on the thoracic outlet. An inferior curvature of the medial clavicle is found in hominoids and brachiators. This curvature could help stabilize the shoulder and prevent superior dislocation of the clavicle in suspension. Finally, a superior curvature in the lateral part of the clavicle, most pronounced in quadrupedal monkeys, may be related to the relative position of the scapula and sternum. CONCLUSIONS: Patterns of clavicular curvature in anthropoid primates reflect locomotor behavior and successfully distinguished among taxonomic and locomotor groups. In the future, this method could be used to assess locomotor behavior in fossil primates. Am J Phys Anthropol 158:257-268, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26239268 TI - New generation of two-dimensional spintronic systems realized by coupling of Rashba and Dirac fermions. AB - Intriguing phenomena and novel physics predicted for two-dimensional (2D) systems formed by electrons in Dirac or Rashba states motivate an active search for new materials or combinations of the already revealed ones. Being very promising ingredients in themselves, interplaying Dirac and Rashba systems can provide a base for next generation of spintronics devices, to a considerable extent, by mixing their striking properties or by improving technically significant characteristics of each other. Here, we demonstrate that in BiTeI@PbSb2Te4 composed of a BiTeI trilayer on top of the topological insulator (TI) PbSb2Te4 weakly- and strongly-coupled Dirac-Rashba hybrid systems are realized. The coupling strength depends on both interface hexagonal stacking and trilayer stacking order. The weakly-coupled system can serve as a prototype to examine, e.g., plasmonic excitations, frictional drag, spin-polarized transport, and charge-spin separation effect in multilayer helical metals. In the strongly coupled regime, within ~100 meV energy interval of the bulk TI projected bandgap a helical state substituting for the TI surface state appears. This new state is characterized by a larger momentum, similar velocity, and strong localization within BiTeI. We anticipate that our findings pave the way for designing a new type of spintronics devices based on Rashba-Dirac coupled systems. PMID- 26239269 TI - Dickkopf-related protein 1 induces angiogenesis by upregulating vascular endothelial growth factor in the synovial fibroblasts of patients with temporomandibular joint disorders. AB - Angiogenesis has an important role in the progression of temporomandibular joint disorders (TMD). The aim of the present study was to explore the association between dickkopf-related protein 1 (DKK-1) and angiogenesis in TMD. The expression levels of DKK-1 and vascular endothelial growth factor (VEGF) were quantified by an ELISA assay of the synovial fluid from patients with TMD. The correlation between DKK-1 and VEGF was analyzed by Pearson correlation test. Synovial fibroblasts were isolated from patients with TMD and were subsequently treated with recombinant human DKK-1, anti-DKK-1 antibody, hypoxia inducible factor-1alpha (HIF-1alpha), or small interfering RNA (siRNA). The expression levels of DKK-1, HIF-1alpha, and VEGF were subsequently quantified. The present study also investigated the effects of DKK-1 on the migration of human umbilical vein endothelial cells (HUVEC). Increased expression levels of DKK-1 were concordant with increased expression levels of VEGF in the synovial fluid from patients with TMD. In the synovial fibroblasts, DKK-1 increased the expression levels of VEGF, and promoted HIF-1alpha nuclear localization. In addition, DKK-1 induced HUVEC migration, and HIF-1alpha siRNA inhibited DKK-1-induced cell migration. The results of the present study indicate that DKK-1 is associated with angiogenesis in the synovial fluid of patients with TMD. Furthermore, HIF 1alpha may be associated with DKK-1-induced HUVEC activation. PMID- 26239270 TI - A genome-wide study of DNA methylation modified by epigallocatechin-3-gallate in the CAL-27 cell line. AB - In order to gain greater understanding of the mechanisms underlying the effect of epigallocatechin-3-gallate (EGCG) on DNA methylation and its chemopreventative action in oral squamous cell carcinoma (OSCC), a genome-wide methylation and mRNA expression screen was performed in the CAL-27 cell line with and without EGCG (100 uM) treatment. A total of 761 differentially methylated gene loci were identified following treatment with EGCG. Comparison of gene expression profiling in OSCC samples revealed 184 transcripts with a significant difference (P<0.05) and a fold change difference >2 compared with controls. Gene ontology analysis of differentially methylated loci and functional annotation of the differentially expressed genes indicated that the main pathways involved were metabolic, mitogen activated protein kinase (MAPK), wnt, and cell cycle pathways. In conclusion, the present study indicates that EGCG can affect the methylation status and gene expression in the CAL-27 cell line. Additionally, the changes in several important signaling pathways may reveal the antitumor mechanism of EGCG. PMID- 26239271 TI - Cool tadpoles from Arctic environments waste fewer nutrients - high gross growth efficiencies lead to low consumer-mediated nutrient recycling in the North. AB - Endothermic organisms can adapt to short growing seasons, low temperatures and nutrient limitation by developing high growth rates and high gross growth efficiencies (GGEs). Animals with high GGEs are better at assimilating limiting nutrients and thus should recycle (or lose) fewer nutrients. Longer guts in relation to body mass may facilitate higher GGE under resource limitation. Within the context of ecological stoichiometry theory, this study combines ecology with evolution by relating latitudinal life-history adaptations in GGE, mediated by gut length, to its ecosystem consequences, such as consumer-mediated nutrient recycling. In common garden experiments, we raised Rana temporaria tadpoles from two regions (Arctic/Boreal) under two temperature regimes (18/23 degrees C) crossed with two food quality treatments (high/low-nitrogen content). We measured tadpole GGEs, total nutrient loss (excretion + egestion) rates and gut length during ontogeny. In order to maintain their elemental balance, tadpoles fed low nitrogen (N) food had lower N excretion rates and higher total phosphorous (P) loss rates than tadpoles fed high-quality food. In accordance with expectations, Arctic tadpoles had higher GGEs and lower N loss rates than their low-latitude conspecifics, especially when fed low-N food, but only in ambient temperature treatments. Arctic tadpoles also had relatively longer guts than Boreal tadpoles during early development. That temperature and food quality interacted with tadpole region of origin in affecting tadpole GGEs, nutrient loss rates and relative gut length, suggests evolved adaptation to temperature and resource differences. With future climate change, mean annual temperatures will increase. Additionally, species and genotypes will migrate north. This will change the functioning of Boreal and Arctic ecosystems by affecting consumer-mediated nutrient recycling and thus affect nutrient dynamics in general. Our study shows that evolved latitudinal adaption can change key ecosystem functions. PMID- 26239272 TI - Enrichment and characterization of cancer stem cells from a human non-small cell lung cancer cell line. AB - Tumor cells from the same origin comprise different cell populations. Among them, cancer stem cells (CSCs) have higher tumorigenicity. It is necessary to enrich CSCs to determine an effective way to suppress and eliminate them. In the present study, using the non-adhesive culture system, tumor spheres were successfully generated from human A549 non-small cell lung cancer (NSCLC) cell line within 2 weeks. Compared to A549 adherent cells, sphere cells had a higher self-renewal ability and increased resistance to cytotoxic drugs. Sphere cells were more invasive and expressed stem cell markers including octamer-binding transcription factor 4 (Oct4) and sex-determining region Y-box 2 (Sox2) at high levels. CD133, a disputed marker of lung CSCs, was also upregulated. Tumor sphere cells showed higher tumorigenic ability in vivo, indicating that more CSCs were enriched in the sphere cells. More blood vessels were formed in the tumor generated by sphere cells suggesting the interaction between CSCs and blood vessel. A reliable model of enriching CSCs from the human A549 NSCLC cell line was established that was simple and cost-effective compared to other methods. PMID- 26239273 TI - The Effect of pH on Globular State of Lipase-3646; an Appropriate Model for Molten Globule Investigations. AB - Secondary structure content of proteins in molten globule state is relatively constant while the quantity of tertiary structures clearly declines due to alterations in side-chain packing. In the present study, we analyze the MG state of lipase-3646 for the first time. We introduce lipase-3646 as an appropriate model for investigating the properties and behavior of a protein in MG state as well as folding pathway. Applying fluorescence spectroscopy we measured both intrinsic and extrinsic fluorescence of lipase-3646 in a pH range from 1.0 to 12.0. It was found that at pH 3.0 the protein acquires a MG state. Applying far UV circular dichroism (CD), our analysis on the secondary structure of lipase 3646 revealed a slight change in the MG state intermediate (pH 3.0) compared to the native state (pH 8.5), which this amount of change is common for MG. Measurements in near-UV CD also showed a significant change in the enzyme conformation at pH 3.0 in comparison with the pH 8.5 wherein the protein acquires its native structure. Quenching the fluorescence by applying acrylamide, the amount 23 and 35 M(-1) were measured at pHs 8.5 and 3.0 respectively for stern volmer constant (KSV). An increase in the enzyme molecular volume in the MG state was confirmed by gel filtration chromatography. PMID- 26239274 TI - N-Myc downstream-regulated gene 2 suppresses the proliferation of T24 human bladder cancer cells via induction of oncosis. AB - Previous studies have reported the antitumor activity of N-Myc downstream regulated gene 2 (NDRG2), a novel p53-inducible gene, in several types of cancer. The present study aimed to investigate the effects of NDRG2 expression on the proliferation of a human bladder cancer cell line. NDRG2 and control green fluorescent protein (GFP) recombinant adenovirus plasmids were constructed and transfected into a bladder cancer cell line with mutant p53 (T24 cells). NDRG2 expression was analyzed using western blot analysis and immunofluorescence assay (IFA); in addition, the subcellular localization of NDRG2 was detected using a confocal microscope. The proliferation rate of cells was measured using colony formation and MTT assays. Furthermore, the cell cycle of transfected T24 cells was detected by flow cytometry. The results indicated that T24 cells expressed low levels of NDRG2 prior to infection with GFP-NDRG2 recombinant adenovirus; by contrast, following infection, NDRG2 was primarily overexpressed in mitochondria. The proliferation rate of T24 cells was significantly reduced by NDRG2 expression (P<0.01). In addition, 82.1% of NDRG2-expressing cells were in S-phase, compared to 74.4% in the control virus-infected cells (P<0.05). Furthermore, upregulation of NDRG2 induced an increase in oncosis, rather than apoptosis, in T24 cell. In conclusion, the results of the present study indicated that NDRG2 expression in mitochondria may arrest bladder cancer cells in S-phase as well as decrease cell proliferation through inducing oncosis. It was therefore proposed that NDRG2 was not only a biomarker, but also a tumor suppressor for bladder cancer. PMID- 26239276 TI - Data Resource Profile: The Japan National Health and Nutrition Survey (NHNS). PMID- 26239275 TI - Latent class instrumental variables: a clinical and biostatistical perspective. AB - In some two-arm randomized trials, some participants receive the treatment assigned to the other arm as a result of technical problems, refusal of a treatment invitation, or a choice of treatment in an encouragement design. In some before-and-after studies, the availability of a new treatment changes from one time period to this next. Under assumptions that are often reasonable, the latent class instrumental variable (IV) method estimates the effect of treatment received in the aforementioned scenarios involving all-or-none compliance and all or-none availability. Key aspects are four initial latent classes (sometimes called principal strata) based on treatment received if in each randomization group or time period, the exclusion restriction assumption (in which randomization group or time period is an instrumental variable), the monotonicity assumption (which drops an implausible latent class from the analysis), and the estimated effect of receiving treatment in one latent class (sometimes called efficacy, the local average treatment effect, or the complier average causal effect). Since its independent formulations in the biostatistics and econometrics literatures, the latent class IV method (which has no well-established name) has gained increasing popularity. We review the latent class IV method from a clinical and biostatistical perspective, focusing on underlying assumptions, methodological extensions, and applications in our fields of obstetrics and cancer research. PMID- 26239277 TI - Exploratory survey study of long-term users of nicotine replacement therapy in Danish consumers. AB - BACKGROUND: Long-term use of nicotine replacement therapy (NRT) has been approved in several countries for smokers who are unable or unwilling to quit smoking. However, information on basic characteristics, degree of nicotine dependence, health status and contentment with long-term use of NRT is scarce. The aim of this study was to collect information on the characteristics of long-term NRT users, having used NRT for at least 12 months, reasons for, and contentment with, their continued use of NRT including reasons for wishing to quit or sustain use and an estimation of their degree of nicotine dependence. METHOD: Through advertisements in three national Danish newspapers, long-term NRT users were recruited to answer a short questionnaire about basic characteristics, health status and satisfaction with using NRT. A modified version of the Heaviness of Smoking Index (HSI) questionnaire was applied to estimate nicotine dependence. Linear regression was used to test association between time to first NRT and daily dosage of NRT. RESULTS: A total of 92 respondents were included in the data analysis. A majority of 88% wished to quit NRT for the following reasons: costs of NRT, being tired of feeling addicted and fear of adverse health effects. Scoring on the modified HSI scale was 22.0% low, 68.0% moderate and 9.3% high dependent. Of the respondents, 67.0% used NRT within the first 30 min after waking. A validation check found a significant linear association between the two items in the modified HSI. CONCLUSION: A significant majority of users wished to quit NRT because of the cost of products, being tired of feeling addicted and fear of adverse health consequences. The majority of these users were moderate to high nicotine dependent. The strong association found between time to first NRT and NRT dosages used per day gives reason to believe the validity of the modified HSI. Further studies are required for confirmation. Better counselling of long term users on the benefits of using NRT compared to smoking should be provided, for those who are chronically dependent, as well as support to stop long-term use of NRT if wanted. PMID- 26239278 TI - Attitudes of students of health sciences towards the older persons. AB - OBJECTIVES: The purpose of this study was to evaluate and compare attitudes towards the elderly of Turkish students of various disciplines in health sciences at the level of associate and bachelor degree. METHODS: 685 students participated in this descriptive study. Data were collected with a questionnaire administered to the students and the Turkish version of Kogan's Attitudes Towards Old People Scale (KAOP). Statistical evaluation of the data was included in percentage, mean, median, t-test, and one-way variance analysis. RESULTS: The average age of the students was 20.91+/-2.25years, and mean and median scores of KAOP for these students were 131.21+/-14.403 and 130, respectively. The attitudes of physiotherapy students towards older people were better than students in other health disciplines (p<0.05), and there were no differences in the attitudes of health science students towards the older persons in eastern and western cities of Turkey (p<0.05). DISCUSSION: The attitudes of the health science professionals of tomorrow towards older people should be evaluated currently to be able to improve the provision of health care standards and to prevent possible negative beliefs and opinions in the future. PMID- 26239279 TI - Progressive hip joint subluxation in Saul-Wilson syndrome. AB - Saul-Wilson syndrome (SWS) is a rare congenital skeletal syndrome characterized by postnatal onset of short stature, relative microcephaly, frontal bossing, prominent eyes with shallow orbits, midface hypoplasia, cataract, and generalized skeletal changes, including spondylar dysplasia, overtubulation of the long bones with metaphyseal flaring and megaepiphyses, coxa valga, elbow deformity, and brachydactyly. We describe a boy with the overall clinical and radiological features fitting the characteristics of SWS, although cataract, elbow deformity, and overt brachydactyly were not seen. He presented with painful hip joint due to hip subluxation in late childhood, which exacerbated with age and ultimately, required surgical intervention. Awareness of this orthopedic complication in SWS is essential in the management of patients with SWS. PMID- 26239281 TI - Effects of constituent ions of a phosphonium-based ionic liquid on molecular organization of H2O as probed by 1-propanol: tetrabutylphosphonium and trifluoroacetate ions. AB - Aqueous solutions of tetrabutylphosphonium trifluoroacetate, [P4444]CF3COO, exhibit a liquid-liquid phase transition with a lower critical solution temperature. Herein, we characterized the constituent ions, [P4444](+) and CF3COO(-), in terms of their effects on the molecular organization of H2O on the basis of 1-propanol probing methodology devised by Koga et al. The resulting characterization of the hydrophobicity/hydrophilicity is displayed on a two dimensional map together with previous results, for a total of four cations and nine anions of typical ionic liquid (IL) constituents. The results indicate that [P4444](+) is the most significant amphiphile with strong hydrophobic and equally strong hydrophilic contributions among the group of constituent cations of ILs studied so far. The hydration number for [P4444](+) was evaluated to be nH = 72, which is three times larger than that of a typical imidazolium-based cation, [C4mim](+). Self-aggregation of [P4444](+) was found to occur in an aqueous solution of [P4444]CF3COO above 0.0080 mole fraction of the IL. PMID- 26239280 TI - Expected 10-year treatment cost of breast cancer detected within and outside a public screening program in Norway. AB - BACKGROUND: The shift towards earlier stages of disease advancement at diagnosis when introducing mammography screening is expected to affect the treatment costs of breast cancer. MATERIALS AND METHODS: We collected data on hospital resource use in Norway following a breast cancer diagnosis for the period 1 January, 2008 through 31 December, 2009 for women aged 50-69 years, diagnosed with breast cancer during the period 1 January, 1999 through 31 December, 2009. We estimated treatment costs using a function that included the probability of being at risk for receiving treatment, estimated by means of the Cox proportional hazard model. RESULTS: In total, 16,045 patients were included for the analyses among which 10.5 % died during the study period. The mean 10-year per-person treatment cost was ?31,940 (95 % CI ?31,030-32,880), and lower for cancers detected within the public screening program (?30,730) than for those detected elsewhere (?36,230). For ductal carcinoma in situ (DCIS) and cancers in stages I thru IV, treatment costs were ?15,740, ?23,570, ?46,550, ?55,230 and ?60,430, respectively. Interval cancers occurring within the screening program were generally more resource demanding than both cancers detected at screening or elsewhere. CONCLUSIONS: Ten year treatment costs increased by increasing stage at diagnosis. Patients whose cancer was detected within the public screening program had lower treatment costs than those detected elsewhere. Interval cancers had higher costs than others. PMID- 26239282 TI - Neoadjuvant, anthracycline-free chemotherapy with carboplatin and docetaxel in triple-negative, early-stage breast cancer: a multicentric analysis of rates of pathologic complete response and survival. AB - INTRODUCTION: Triple-negative breast cancer (TNBC) has the highest mortality rates of all subtypes. Anthracycline and taxane regimens yield unsatisfactorily low rates of pathologic complete response (pCR) and are often not feasible in cardiac comorbidity. This study seeks to increase pCR and survival by introducing platin agents. PATIENTS AND METHODS: In this multicentric, open-label study with six cycles of docetaxel (75 mg/m(2)) and carboplatin AUC 6 q3w, patients were unwilling or unsuitable for anthracycline-based regimens. Primary endpoint was pCR (ypT0/ypTis ypN0) and survival. RESULTS: pCR rate was 50%. After 2 and 5 years, overall survival (OS) was 96.7 and 89.7%, disease-free-survival (DFS) 96.7 and 85.7%, DDFS 96.7 and 89.6%. Grade 3/4 toxicities were rare. Ninety-three per cent of patients completed six cycles. No toxicity-related treatment discontinuation or febrile neutropaenia was recorded. CONCLUSION: This regimen is highly effective and feasible in TNBC and may be combined with anthracyclines. PMID- 26239283 TI - Cerium anomaly at microscale in fossils. AB - Patterns in rare earth element (REE) concentrations are essential instruments to assess geochemical processes in Earth and environmental sciences. Excursions in the "cerium anomaly" are widely used to inform on past redox conditions in sediments. This proxy resources to the specificity of cerium to adopt both the +III and +IV oxidation states, while most rare earths are purely trivalent and share very similar reactivity and transport properties. In practical terms, the level of cerium anomaly is established through elemental point quantification and profiling. All these models rely on a supposed homogeneity of the cerium oxidation state within the samples. However, this has never been demonstrated, whereas the cerium concentration can significantly vary within a sample, as shown for fossils, which would vastly complicate interpretation of REE patterns. Here, we report direct micrometric mapping of Ce speciation through synchrotron X-ray absorption spectroscopy and production of local rare earth patterns in paleontological fossil tissues through X-ray fluorescence mapping. The sensitivity of the approach is demonstrated on well-preserved fishes and crustaceans from the Late Cretaceous (ca. 95 million years (Myr) old). The presence of Ce under the +IV form within the fossil tissues is attributed to slightly oxidative local conditions of burial and agrees well with the limited negative cerium anomaly observed in REE patterns. The [Ce(IV)]/[Ce(tot)] ratio appears remarkably stable at the microscale within each fossil and is similar between fossils from the locality. Speciation maps were obtained from an original combination of synchrotron microbeam X-ray fluorescence, absorption spectroscopy, and diffraction, together with light and electron microscopy. This work also highlights the need for more systematic studies of cerium geochemistry at the microscale in paleontological contexts, in particular across fossil histologies. PMID- 26239284 TI - Concerning pretreatment 18F-FDG PET/CT imaging in patients with large or locally advanced breast cancer. PMID- 26239285 TI - Photoelectrochemical etching and energy gap control of silver clusters. AB - An energy gap of Ag clusters is controlled on the basis of photoinduced electron transfer from the clusters to TiO2. With 2.6 eV light irradiation, Ag32 clusters on TiO2 are oxidized and disappear. With <1.6 eV light, the energy gap of Ag32 is changed from ~1.4 to ~1.7 eV because of photoetching. PMID- 26239286 TI - Epitaxial diamond-hexagonal silicon nano-ribbon growth on (001) silicon. AB - Silicon crystallizes in the diamond-cubic phase and shows only a weak emission at 1.1 eV. Diamond-hexagonal silicon however has an indirect bandgap at 1.5 eV and has therefore potential for application in opto-electronic devices. Here we discuss a method based on advanced silicon device processing to form diamond hexagonal silicon nano-ribbons. With an appropriate temperature anneal applied to densify the oxide fillings between silicon fins, the lateral outward stress exerted on fins sandwiched between wide and narrow oxide windows can result in a phase transition from diamond-cubic to diamond-hexagonal Si at the base of these fins. The diamond-hexagonal slabs are generally 5-8 nm thick and can extend over the full width and length of the fins, i.e. have a nano-ribbon shape along the fins. Although hexagonal silicon is a metastable phase, once formed it is found being stable during subsequent high temperature treatments even during process steps up to 1050 oC. PMID- 26239287 TI - [Extensive swelling reaction after a pentavalent vaccination]. AB - Injection site reactions (ISRs) are quite common side effects defined by a local adverse drug reaction directly caused by a vaccine. Twenty-four hours after an intramuscular injection (in the deltoid muscle) of the diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis, Haemophilus influenza type b (DTPCa-Hib) combined vaccine, a 3-year-old boy developed fever. A few hours later, local redness and swelling appeared at the injection site, with rapid extension to the entire limb, it was pain-free, and no other clinical anomalies were present. The patient received intravenous antibiotics for suspected cellulitis. The progression was favorable in 12h (apyrexia and decreased limb swelling), allowing the intravenous antibiotic treatment to be discontinued. Since the child was in excellent general health and recovery was fast, an ISR was diagnosed. Extensive limb swelling is frequent, mostly after the fourth dose of DTPCa-Hib. Deltoid muscle injection of DTP vaccine increases the risk of ISR compared to injection in the thigh, before the age of 3 years. The introduction of acellular pertussis vaccine decreased the risk of general side effects but may increase the risk of ISR. These reactions disappear with symptomatic treatment and do not contraindicate the product. PMID- 26239288 TI - Evaluating Adherence to a Treat-to-Target Protocol in Recent-Onset Rheumatoid Arthritis: Reasons for Compliance and Hesitation. AB - OBJECTIVE: To evaluate rheumatologists' adherence to a low Disease Activity Score (DAS)-steered treat-to-target (T2T) strategy in treatment of patients with rheumatoid arthritis (RA) and to assess associated conditions. METHODS: Data of the BeSt study were used, a multicenter T2T strategy trial with 10-year followup. During 3 monthly visits, the physician answered questions about satisfaction with level of RA suppression, agreement with the study protocol, and agreement with the DAS. Associations between the answers and nonadherence were evaluated. RESULTS: Protocol adherence decreased over time from 100% to 60% per visit, with an average over time of 79%. Rheumatologists mostly agreed with the DAS (80-90% of visits over time) and were satisfied with the treatment steps (75-90%) and with the level of RA suppression (85-90%). The odds for protocol violation were higher when the rheumatologist disagreed with the DAS (odds ratio [OR] 2.3, 95% confidence interval [95% CI] 2.0-2.7 when they thought the DAS overestimated actual disease activity; OR 2.5, 95% CI 2.0-3.1 when they thought the DAS underestimated actual disease activity) or with the next required treatment step (OR 3.0, 95% CI 2.5-3.5), and when the physician was dissatisfied with disease suppression (OR 1.3, 95% CI 1.1-1.6). CONCLUSION: Rheumatologists generally agreed with and followed a 10-year followup DAS-steered T2T strategy. Disagreement with the DAS or the required treatment and dissatisfaction with the level of disease suppression were risk factors for nonadherence. These results indicate the feasibility of continued protocol-driven T2T therapy. For daily practice, adherence to T2T therapy might be improved by adopting the structure components of a clinical trial. PMID- 26239289 TI - Evidence of CNIH3 involvement in opioid dependence. AB - Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55-0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP's in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system. PMID- 26239290 TI - The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens. AB - Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse. PMID- 26239291 TI - Nonmuscle myosin IIB as a therapeutic target for the prevention of relapse to methamphetamine use. AB - Memories associated with drug use increase vulnerability to relapse in substance use disorder (SUD), and there are no pharmacotherapies for the prevention of relapse. Previously, we reported a promising finding that storage of memories associated with methamphetamine (METH), but not memories for fear or food reward, is vulnerable to disruption by actin depolymerization in the basolateral amygdala complex (BLC). However, actin is not a viable therapeutic target because of its numerous functions throughout the body. Here we report the discovery of a viable therapeutic target, nonmuscle myosin IIB (NMIIB), a molecular motor that supports memory by directly driving synaptic actin polymerization. A single intra-BLC treatment with Blebbistatin (Blebb), a small-molecule inhibitor of class II myosin isoforms, including NMIIB, produced a long-lasting disruption of context induced drug seeking (at least 30 days). Further, postconsolidation genetic knockdown of Myh10, the heavy chain of the most highly expressed NMII in the BLC, was sufficient to produce METH-associated memory loss. Blebb was found to be highly brain penetrant. A single systemic injection of the compound selectively disrupted the storage of METH-associated memory and reversed the accompanying increase in BLC spine density. This effect was specific to METH-associated memory, as it had no effect on an auditory fear memory. The effect was also independent of retrieval, as METH-associated memory was disrupted 24 h after a single systemic injection of Blebb delivered in the home cage. Together, these results argue for the further development of small-molecule inhibitors of NMII as potential therapeutics for the prevention of SUD relapse triggered by drug associations. PMID- 26239292 TI - Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders. AB - With an onset under the age of 3 years, autism spectrum disorders (ASDs) are now understood as diseases arising from pre- and/or early postnatal brain developmental anomalies and/or early brain insults. To unveil the molecular mechanisms taking place during the misshaping of the developing brain, we chose to study cells that are representative of the very early stages of ontogenesis, namely stem cells. Here we report on MOlybdenum COfactor Sulfurase (MOCOS), an enzyme involved in purine metabolism, as a newly identified player in ASD. We found in adult nasal olfactory stem cells of 11 adults with ASD that MOCOS is downregulated in most of them when compared with 11 age- and gender-matched control adults without any neuropsychiatric disorders. Genetic approaches using in vivo and in vitro engineered models converge to indicate that altered expression of MOCOS results in neurotransmission and synaptic defects. Furthermore, we found that MOCOS misexpression induces increased oxidative-stress sensitivity. Our results demonstrate that altered MOCOS expression is likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders. We anticipate our discovery to be a fresh starting point for the study on the roles of MOCOS in brain development and its functional implications in ASD clinical symptoms. Moreover, our study suggests the possible development of new diagnostic tests based on MOCOS expression, and paves the way for drug screening targeting MOCOS and/or the purine metabolism to ultimately develop novel treatments in ASD. PMID- 26239293 TI - A genome-wide analysis of putative functional and exonic variation associated with extremely high intelligence. AB - Although individual differences in intelligence (general cognitive ability) are highly heritable, molecular genetic analyses to date have had limited success in identifying specific loci responsible for its heritability. This study is the first to investigate exome variation in individuals of extremely high intelligence. Under the quantitative genetic model, sampling from the high extreme of the distribution should provide increased power to detect associations. We therefore performed a case-control association analysis with 1409 individuals drawn from the top 0.0003 (IQ >170) of the population distribution of intelligence and 3253 unselected population-based controls. Our analysis focused on putative functional exonic variants assayed on the Illumina HumanExome BeadChip. We did not observe any individual protein-altering variants that are reproducibly associated with extremely high intelligence and within the entire distribution of intelligence. Moreover, no significant associations were found for multiple rare alleles within individual genes. However, analyses using genome-wide similarity between unrelated individuals (genome-wide complex trait analysis) indicate that the genotyped functional protein-altering variation yields a heritability estimate of 17.4% (s.e. 1.7%) based on a liability model. In addition, investigation of nominally significant associations revealed fewer rare alleles associated with extremely high intelligence than would be expected under the null hypothesis. This observation is consistent with the hypothesis that rare functional alleles are more frequently detrimental than beneficial to intelligence. PMID- 26239295 TI - Tau hyperphosphorylation in synaptosomes and neuroinflammation are associated with canine cognitive impairment. AB - Canine cognitive impairment syndrome (CDS) represents a group of symptoms related to the aging of the canine brain. These changes ultimately lead to a decline of memory function and learning abilities, alteration of social interaction, impairment of normal housetraining, and changes in sleep-wake cycle and general activity. We have clinically examined 215 dogs, 28 of which underwent autopsy. With canine brains, we performed extensive analysis of pathological abnormalities characteristic of human Alzheimer's disease and frontotemporal lobar degeneration, including beta-amyloid senile plaques, tau neurofibrillary tangles, and fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP43) inclusions. Most demented dogs displayed senile plaques, mainly in the frontal and temporal cortex. Tau neurofibrillary inclusions were found in only one dog. They were identified with antibodies used to detect tau neurofibrillary lesions in the human brain. The inclusions were also positive for Gallyas silver staining. As in humans, they were distributed mainly in the entorhinal cortex, hippocampus, and temporal cortex. On the other hand, FUS and TDP43 aggregates were not present in any of the examined brain samples. We also found that CDS was characterized by the presence of reactive and senescent microglial cells in the frontal cortex. Our transcriptomic study revealed a significant dysregulation of genes involved in neuroinflammation. Finally, we analyzed tau phosphoproteome in the synaptosomes. Proteomic studies revealed a significant increase of hyperphosphorylated tau in synaptosomes of demented dogs compared with nondemented dogs. This study suggests that cognitive decline in dogs is related to the tau synaptic impairment and neuroinflammation. J. Comp. Neurol. 524:874 895, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26239296 TI - Retinochoroidal toxoplasmosis in a patient with cerebral post-transplant lymphoproliferative disease of Hodgkin's type: a diagnostic challenge. AB - Toxoplasmosis is a relatively rare complication in renal transplant patients and can pose diagnostic challenges, especially when it manifests as an ocular inflammation. Authors hereby report an unusual case of a 57-year-old male who developed retinochoroidal toxoplasmosis after 15 years of renal transplant, the diagnoses of which were challenging as the patient was also a known case of cerebral post-transplant lymphoproliferative disease (PTLD) of Hodgkin's type, which misled the ophthalmologists towards a clinical diagnosis of ocular PTLD. Histopathology examination of the enucleated eye revealed numerous toxoplasmosis cysts within the retina and choroid. No ocular PTLD was observed. PMID- 26239297 TI - [Instability of the distal radioulnar joint: Treatment options for ulnar lesions of the triangular fibrocartilage complex]. AB - Injuries of the triangular fibrocartilage complex (TFCC) may be fatal to the distal radioulnar joint (DRUJ). This structure is one of the crucial stabilizers and guarantees unrestricted pronosupination of the forearm. A systematic examination is mandatory to diagnose DRUJ instability reliably. A clinical examination in comparison to the contralateral side is obligatory. Plain radiographs are required to exclude osseous lesions or deformities. Computed tomography of both wrists in neutral, pronation and supination is necessary to verify DRUJ instability in ambiguous situations. Based on a systematic examination wrist and DRUJ arthroscopy identify lesions clearly. Injuries of the radioulnar ligaments which entail DRUJ instability, should be reconstructed preferably anatomically. Ulnar-sided TFCC lesions may often cause DRUJ instability. Osseous ligament avulsions are mostly treated osteosynthetically. Ligament tears may be refixated using anchor or transosseous sutures. Tendon transplants are necessary for an anatomical reconstruction in cases of irreparable ruptures. PMID- 26239298 TI - [Cardiac post-resuscitation care. An indication for trauma whole-body CT?]. AB - We report the case of a 51-year-old male patient who sustained a liver rupture following mechanical cardiopulmonary resuscitation (CPR) with the LUCAS(r) system. The patient was under anticoagulation and developed an abdominal compartment syndrome. Although the use of mechanical CPR devices, such as the LUCAS(r) system and the load distributing band (Autopulse(r)), is becoming more common, there are specific complications described in the literature, which are associated with mechanical CPR. It is important to differentiate between general complications associated with CPR and those which can be attributed to the application of mechanical CPR devices. Using the example of the presented case, this article outlines and discusses these points based on the currently available literature. It should also be noted that mechanical CPR can act in a similar way to chest trauma and can necessitate an investigation with contrast enhanced computed tomography. PMID- 26239299 TI - Telomerase reverse transcriptase promoter mutations in glandular lesions of the urinary bladder. AB - Glandular lesions of the urinary bladder include a broad spectrum of entities ranging from completely benign to primary and secondary malignancies. The accurate diagnosis of these lesions is both important and challenging. Recently, studies suggest that telomerase reverse transcriptase (TERT) promoter mutations could be a biomarker for urothelial carcinoma (UC). We hypothesized that these mutations can distinguish UC with glandular differentiation from nephrogenic adenoma, primary adenocarcinoma of the urinary bladder (PAUB), or secondary malignancies. Twenty-five cases of benign glandular lesions (including nephrogenic adenoma); 29 cases of UC with glandular differentiation; 10 cases of PAUB; and 10 cases each of metastatic colon cancer, prostatic carcinoma, and carcinoma from Mullerian origin were collected. Slides were reviewed and selected to make sure the lesion was at least 10% to 20% of all tissue. Macrodissection was performed in some of cases, and genomic DNA was extracted from the tissue. Telomerase reverse transcriptase promoter mutations were determined by standard polymerase chain reaction sequencing. Twenty-one cases (72%) of UC with glandular differentiation were positive for TERT promoter mutations. However, none of the remaining cases (total 65 cases of benign lesions, PAUB, and metastatic carcinomas) was positive for TERT promoter mutation. Telomerase reverse transcriptase promoter mutations were highly associated with UC including UC with glandular differentiation but not other glandular lesions of bladder. Therefore, in conjunction with morphologic features, Immunohistochemistry stain profile, and clinical information, TERT promoter mutations could distinguish UC with glandular differentiation from other bladder glandular lesions. In addition, lack of TERT promoter mutations in primary adenocarcinoma of bladder suggests that this entity may have different origin or carcinogenesis from those of UC. PMID- 26239300 TI - A family of low molecular-weight, organic catalysts for reductive C-C bond formation. AB - Hydrazines form a new family of low molecular-weight reducing agents for diazonium salts. Using only small amounts of hydrazine catalyst, the coupling of diazonium salts to a variety of reactive partners has been achieved, without the requirement for either metal adjuvants or irradiation with visible or ultraviolet light. The generality of the concept proposed herein as well as its advantages in the preparative scale is outlined and discussed. PMID- 26239294 TI - Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. AB - The common nonsynonymous variant rs16969968 in the alpha5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerstrom Test for Nicotine Dependence score?4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)?0.05), aggregate low frequency variants (0.05>MAF?0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 * coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 * 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking related diseases such as lung cancer. PMID- 26239301 TI - New heart failure treatment and nursing care. PMID- 26239302 TI - Changes in Cerebellar Activation After Onabotulinumtoxin A Injections for Spasticity After Chronic Stroke: A Pilot Functional Magnetic Resonance Imaging Study. AB - OBJECTIVE: To investigate the effect of reducing spasticity via onabotulinumtoxin A (Obtx-A) injection on cerebellar activation after chronic stroke during unilateral gripping. DESIGN: Pre-post, case series. SETTING: Outpatient spasticity clinic. PARTICIPANTS: Individuals with chronic spasticity (N=4). INTERVENTIONS: Upper-limb Obtx-A injection. MAIN OUTCOME MEASURES: Functional magnetic resonance imaging (fMRI) was used to measure changes in cerebellar activation before and after upper-limb Obtx-A injection. During fMRI testing, participants performed the same motor task before and after injection, which was 15% and 30% of maximum voluntary isometric gripping measured before Obtx-A injection. RESULTS: After Obtx-A injection, cerebellar activation increased bilaterally during gripping with the paretic hand and during rest. During both pre- and postinjection scans, the paretic hand showed larger cerebellar activation during gripping compared with the nonparetic hand. Cerebellar activation during gripping with the nonparetic hand did not change significantly after Obtx-A injection. CONCLUSIONS: Reducing spasticity via Obtx-A injection may increase cerebellar activation both during gripping tasks with the paretic hand and during rest. To our knowledge, this is the first study that examines changes in cerebellar activation after spasticity treatment with Obtx-A. PMID- 26239303 TI - In-depth analysis of the critical genes and pathways in colorectal cancer. AB - The present study aimed to investigate the molecular targets for colorectal cancer (CRC). Differentially expressed genes (DEGs) were screened between CRC and matched adjacent noncancerous samples. GENETIC_ASSOIATION_DB_DISEASE analysis was performed to identify CRC genes from the identified DEGs using the Database for Annotation, Visualization and Integrated Discovery, followed by Gene Omicronntology (GO) and Kyoto Encyclopedia of Genes and Genomes analysis for the CRC genes. A protein-protein interaction (PPI) network was constructed for the CRC genes, followed by determination and analysis of the hub genes, in terms of the protein domains and spatial structure. In total, 35 CRC genes were determined, including 19 upregulated and 16 downregulated genes. Downregulated N acetyltransferase (NAT)1 and NAT2 were enriched in the caffeine metabolism pathway. The downregulated and upregulated genes were enriched in a number of GO terms and pathways, respectively. Cyclin D1 (CCND1) and proliferating cell nuclear antigen (PCNA) were identified as the hub genes in the PPI network. The C terminal and N-terminal domains were similar in PCNA, but different in CCND1. The results suggested PCNA, CCND1, NAT1 and NAT2 for use as biomarkers to enable early diagnosis and monitoring of CRC. These results form a basis for developing therapies, which target the unique protein domains of PCNA and CCND1. PMID- 26239304 TI - NETs and traps delay wound healing in diabetes. AB - Diabetes is associated with dire peripheral sequelae including foot ulcers and amputations. A recent article by Wong et al. demystifies this connection by demonstrating that the neutrophil defense mechanism of extruding decondensed chromatin, termed NETosis, mediates delayed wound healing in diabetes and provides a therapeutic strategy for this indication. PMID- 26239305 TI - alpha-channel and calcium-channel blockers are ineffective as medical expulsive therapy for ureteral stones regardless of size and location. PMID- 26239306 TI - In knee osteoarthritis, pharmacological interventions, with the exception of acetaminophen, significantly improve pain; with intra-articular administration being more effective. PMID- 26239307 TI - A novel endoscopic marker for radiological localization and image-guided radiotherapy in esophageal and gastric cancers (with video). AB - BACKGROUND AND AIMS: Radiotherapy is an accepted modality in the treatment of esophageal cancers and is currently being evaluated in conjunction with chemotherapy for the neoadjuvant treatment of gastric cancers. Our aim was to assess whether a novel endoscopically inserted marker can be used to improve radiological assessment of the primary cancer and allow for image-guided radiotherapy. METHODS: A phase II feasibility study was conducted at a tertiary care center. Twenty-six consecutive adult patients with esophagogastric cancers underwent endoscopic marking of the tumor margins with a novel radiopaque marker (mixture of lipiodol and n-butyl 2-cyanoacrylate). The main outcome measure was the successful insertion of the marker based on a combination of radiological, endoscopic, and histological assessment. RESULTS: A total of 92 markers were inserted in 26 patients. Twenty-two (88%) had follow-up imaging to assess the 81 markers inserted, 79 of which (97.5%) were visible. There were no postprocedural adverse events noted in our cohort. Radiological assessment of tumor size improved such that it was in line with the endoscopic evaluation after marker placement in 18 of 21 patients (85.7%) who had appropriate follow-up radiology imaging. Ten patients (38.5%) from our cohort underwent image-guided radiotherapy (IGRT) by using the endoscopically inserted markers. CONCLUSION: Within the limitations of our small pilot study, endoscopic placement of our novel marker was successful in the majority of our cohort without significant adverse events. Marker placement resulted in improved radiological localization in the majority of our cohort and allowed for IGRT. (Australian New Zealand Clinical Trials Registry: ACTRN12613000239763.). PMID- 26239308 TI - FE, a phloem-specific Myb-related protein, promotes flowering through transcriptional activation of FLOWERING LOCUS T and FLOWERING LOCUS T INTERACTING PROTEIN 1. AB - In many flowering plants, the transition to flowering is primarily affected by seasonal changes in day length (photoperiod). An inductive photoperiod promotes flowering via synthesis of a floral stimulus, called florigen. In Arabidopsis thaliana, the FLOWERING LOCUS T (FT) protein is an essential component of florigen, which is synthesized in leaf phloem companion cells and is transported through phloem tissue to the shoot apical meristem where floral morphogenesis is initiated. However, the molecular mechanism involved in the long-distance transport of FT protein remains elusive. In this study, we characterized the classic Arabidopsis mutant fe, which is involved in the photoperiodic induction of flowering, and showed that FE encodes a phloem-specific Myb-related protein that was previously reported as ALTERED PHLOEM DEVELOPMENT. Phenotypic analyses of the fe mutant showed that FT expression is reduced in leaf phloem companion cells. In addition, the transport of FT protein from leaves to the shoot apex is impaired in the fe mutant. Expression analyses further demonstrated that FE is also required for transcriptional activation of FLOWERING LOCUS T INTERACTING PROTEIN 1 (FTIP1), an essential regulator for selective trafficking of the FT protein from companion cells to sieve elements. These findings indicate that FE plays a dual role in the photoperiodic induction of flowering: as a transcriptional activator of FT on the one hand, and its transport machinery component, FTIP1, on the other hand. Thus, FE is likely to play a role in regulating FT by coordinating FT synthesis and FT transport in phloem companion cells. PMID- 26239309 TI - Taurine deficiency, synthesis and transport in the mdx mouse model for Duchenne Muscular Dystrophy. AB - The amino acid taurine is essential for the function of skeletal muscle and administration is proposed as a treatment for Duchenne Muscular Dystrophy (DMD). Taurine homeostasis is dependent on multiple processes including absorption of taurine from food, endogenous synthesis from cysteine and reabsorption in the kidney. This study investigates the cause of reported taurine deficiency in the dystrophic mdx mouse model of DMD. Levels of metabolites (taurine, cysteine, cysteine sulfinate and hypotaurine) and proteins (taurine transporter [TauT], cysteine deoxygenase and cysteine sulfinate dehydrogenase) were quantified in juvenile control C57 and dystrophic mdx mice aged 18 days, 4 and 6 weeks. In C57 mice, taurine content was much higher in both liver and plasma at 18 days, and both cysteine and cysteine deoxygenase were increased. As taurine levels decreased in maturing C57 mice, there was increased transport (reabsorption) of taurine in the kidney and muscle. In mdx mice, taurine and cysteine levels were much lower in liver and plasma at 18 days, and in muscle cysteine was low at 18 days, whereas taurine was lower at 4: these changes were associated with perturbations in taurine transport in liver, kidney and muscle and altered metabolism in liver and kidney. These data suggest that the maintenance of adequate body taurine relies on sufficient dietary intake of taurine and cysteine availability and metabolism, as well as retention of taurine by the kidney. This research indicates dystrophin deficiency not only perturbs taurine metabolism in the muscle but also affects taurine metabolism in the liver and kidney, and supports targeting cysteine and taurine deficiency as a potential therapy for DMD. PMID- 26239310 TI - Pulse waveform analysis of optic nerve head circulation for predicting carotid atherosclerotic changes. AB - PURPOSE: To evaluate the relationship between the parameters of pulse waveform analysis in the optic nerve head using laser speckle flowgraphy (LSFG) and intima media thickness (IMT) and severity of carotid arterial plaque. DESIGN: Prospective and cross-sectional study. METHODS: One hundred seventy-six subjects were studied. Mean IMT and plaque score obtained from high-resolution B-mode ultrasound were evaluated. If mean IMT was 1 mm or greater, abnormal carotid artery thickening was diagnosed; if the plaque score exceeded 10, severe atherosclerosis was diagnosed. Blowout time and blowout score, which are parameters of pulse waveform analysis using LSFG, were evaluated. Logistic regression analyses determined the independent factors for abnormal carotid artery thickening and severe atherosclerosis. The cutoff levels for abnormal carotid artery thickening and severe atherosclerosis were analyzed using a conventional receiver operating characteristic (ROC) curve. RESULTS: Logistic regression analysis showed that blowout time and body mass index contributed independently to abnormal carotid artery thickening, and blowout score contributed independently to severe atherosclerosis. The ROC curve showed that sensitivity and specificity of the blowout time and blowout score were equivalent to or greater than those of other factors. The cutoff level of the blowout time for abnormal carotid artery thickening was 46.4; the cutoff level of the blowout score for severe atherosclerosis was 71.8. CONCLUSIONS: Measurement of blowout time and blowout score in the optic nerve head by LSFG can be useful for evaluating mean IMT and plaque score, which are parameters of carotid atherosclerosis. PMID- 26239311 TI - Physician Payment Contracts in the Presence of Moral Hazard and Adverse Selection: The Theory and Its Application in Ontario. AB - We develop a stylized principal-agent model with moral hazard and adverse selection to provide a unified framework for understanding some of the most salient features of the recent physician payment reform in Ontario and its impact on physician behavior. These features include the following: (i) physicians can choose a payment contract from a menu that includes an enhanced fee-for-service contract and a blended capitation contract; (ii) the capitation rate is higher, and the cost-reimbursement rate is lower in the blended capitation contract; (iii) physicians sort selectively into the contracts based on their preferences; and (iv) physicians in the blended capitation model provide fewer services than physicians in the enhanced fee-for-service model. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26239312 TI - Association between xanthine dehydrogenase tag single nucleotide polymorphisms and essential hypertension. AB - The present study aimed to investigate the association between xanthine dehydrogenase (XDH) gene polymorphism and essential hypertension in the rural Han Chinese population of Fuxin, Liaoning. Han Chinese individuals, who had lived in rural areas of Fuxin, were selected as subjects for the present study. A total of 521 unrelated patients with hypertension were selected, along with a further 533 unrelated individuals with normal blood pressure, in order to serve as controls. Five tag single nucleotide polymorphisms (SNP) of the XDH gene were selected. An estimation of SNP allele frequency was determined using DNA pooling and pyrosequencing methods. Prior to Bonferroni correction, T allele frequency for rs206811 was significantly higher in patients with hypertension, as compared with the controls (64.1 vs. 59.4%; P=0.031); C allele frequency for rs1042039 was significantly higher in patients with hypertension, as compared with the controls (66.1 vs. 60.6%; P=0.011), C allele frequency for rs1054889 was significantly lower in patients with hypertension, as compared with the controls (38.8 vs. 44.8%; P=0.007); and A allele frequency for rs2073316 was significantly lower in patients with hypertension, as compared with the controls (29.2 vs. 34.4%; P=0.013). However, once a Bonferroni correction for multiple testing was applied, the XDH gene polymorphisms rs1042039, rs1054889, and rs2073316 were shown to be associated with hypertension (P=0.044, 0.035, and 0.039, respectively). These results suggest that the XDH gene polymorphisms rs1042039, rs1054889, and rs2073316 may be associated with hypertension in the rural Han Chinese population. PMID- 26239313 TI - Level of Serum Enzymes and Electrocardiogram in Healthy Rabbits after Injection of ICD-85 as an Anticancer Agent. AB - BACKGROUND: Our previous in vivo studies confirmed that ICD-85, as an anticancer agent, was able to prevent further growth of breast tumors and expand the life expectancy of mice with breast cancer. METHODS: Blood collection was carried out before, 1, 3, and 6 hours after ICD-85 injection. Sera were used to determinate the cardio and hepatic enzymes levels, including ALT, AST, LDH, CPK, and Ck-MB. Coagulation factors such as PT and PTT were also assayed. ECGs of all rabbits were recorded during the experiment. RESULTS: ECG results showed that the injection of 50 and 100 ug/kg ICD-85 into healthy rabbits has no significant effect on heart function while the injection of 150 to 200 ug/kg ICD-85 caused ECG wave changes and mild bradycardia without toxic effects on heart. After ICD 85 injection (concentrations below 100 ug/kg), no significant increase was observed in liver and cardiac enzymes (ALT, AST, LDH, CPK, and CK-MB). However, the concentration of 150 ug/kg and above caused a rise in the enzymes. Comparison of the PT and PTT before and after ICD-85 injection showed no significant clotting time at any concentrations below 200 ug/kg. CONCLUSION: Based on the results obtained in the present study as well as our previous reports, ICD-85 at concentrations below 100 ug/kg seems to have no significant effect on the serum enzymes as indicators of hepatotoxicity and cardiotoxicity in healthy rabbits. However, to confirm this conclusion, more detailed surveys on heart and liver is needed to be carried out. PMID- 26239314 TI - Management Strategies for Vitamin K Antagonists Reversal in Patients With Major Bleeding: A Survey of Italian Emergency Departments. AB - OBJECTIVE: Emergency physicians frequently deal with patients on vitamin K antagonists (VKAs) suffering major bleeding events, and rapid reversal of anticoagulation in this setting is of paramount importance. In Italy, given the absence of specific national guidelines, local policies are likely to differ, possibly impacting on clinical outcomes. We decided to perform a telephone survey among Italian emergency physicians to evaluate management strategies for VKAs reversal in patients with major bleeding. METHODS: We conducted a computer assisted, 10-minute telephone survey of 15 questions, focusing on the local prevalence, assessment, and management strategies of major and intracranial hemorrhage (ICH) occurring in patients on VKAs. We planned to interview a sample of 320 Italian emergency physicians. Institutions from all geographic areas of Italy were to participate in the survey. RESULTS: Of the 320 physicians contacted, 150 (47%) completed the survey, 95% being employed in public hospitals. Focusing on ICH, only 29% of the responders stated they would reverse anticoagulation irrespective of the international normalized ratio value, and only 27% would use prothrombin-complex concentrate as first-line agent. In patients needing urgent neurosurgical operation, less than 50% would administer prothrombin-complex concentrate before surgery. CONCLUSION: The average knowledge of management strategies for reversal of anticoagulation displayed by Italian emergency physicians appears to be unsatisfactory. The need for an extensive educational program and for the implementation of specific guidelines, possibly endorsed by Scientific Societies, cannot be underemphasized. PMID- 26239315 TI - Home treatment of deep venous thrombosis in the era of new oral anticoagulants. AB - This is a retrospective cohort study of adults with a primary diagnosis of deep venous thrombosis (DVT) unaccompanied by pulmonary embolism (PE), seen in 4 emergency departments in 2013 and part of 2014. The purpose was to assess the prevalence of home treatment of DVT in the present era of new oral anticoagulants. Among 96 patients with DVT and no PE, 85 (88.5%) were hospitalized and 11 (11.5%) were discharged to home. Most of the patients discharged to home received low-molecular-weight heparin, 9 (81.8%) of 11. None were prescribed new oral anticoagulants. Early discharge in <=2 days occurred 28 (32.9%) of 85 patients. Most (64.3%) received enoxaparin and/or warfarin at early discharge. Rivaroxaban was prescribed in 7 (25.0%) of those discharged in <=2 days. We conclude that in some emergency departments, patients with DVT are uncommonly discharged to home even though new oral anticoagulants are available. PMID- 26239316 TI - Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy. AB - Hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal, multifactorial disorder, which may present with thrombocytopenia, hemolysis, acute renal failure, mental status changes and involvement of other organs. The pathogenesis of TA-TMA is complex and includes multiple risk factors such as certain conditioning regimens, calcineurin inhibitors (CNIs), graft versus-host disease (GVHD), human leukocyte antigen mismatch, and opportunistic infections. The end result of these insults is endothelial injury in the kidney and other organs. Recent studies also indicate a role of complement activation in tissue damage. The lack of sensitive and specific diagnostic tests for TA-TMA often results in delayed diagnosis. Biopsy is not always possible for diagnosis because of the risk of complications such as bleeding. Recently, an emerging role of renal-centered screening approach has been demonstrated, which utilize the monitoring of blood pressure, urine protein, serum lactate dehydrogenase and hemogram for early detection. Therapeutic options are limited, and plasma exchange plays a minor role. Withdrawal of offending agent such as CNIs and the use of rituximab can be effective in some patients. However, the current treatment strategy is suboptimal and associated with high mortality rate. Recently, eculizumab has been utilized in a few patients with good outcomes. Patients, who develop TA-TMA, are also at an increased risk of GVHD, infection, renal, cardiovascular, and other complications, which can contribute to high mortality. Better understanding of molecular pathogenesis, improvement in posttransplant management, leading to early diagnosis, and management of TA-TMA are required to improve outcomes of this fatal entity. PMID- 26239317 TI - Real-World Impact of Setting a Narrow International Normalized Ratio Target Range in the Management of Older Adult Patients on Warfarin. AB - INTRODUCTION: Elderly patients intrinsically have higher bleeding risks, deterring clinicians from prescribing them oral anticoagulants. Setting a narrow international normalized ratio (INR) target range might potentially mitigate some of these risks. This study sought to compare the outcomes of elderly patients who were assigned to either a narrow INR target range or the conventional INR target range in a real-world environment. METHODS: This was a retrospective cohort study with the primary and secondary outcomes being the mean percentage time above INR 3.0 and the mean percentage time below INR 2.0 and the incidents of bleeding and thromboembolism associated with oral anticoagulant therapy, respectively. Patients and health care workers managing them had no prior knowledge of this study. RESULTS: Data of 150 patients with a narrow INR target range (2.0-2.5) and 164 patients with a conventional INR target range (2.0-3.0) were collected and analyzed. The narrow INR group had significantly higher underlying risks of bleeding than the conventional INR group. Patients in the narrow INR group had a significantly lower percentage time above INR 3.0 but no significant difference in the percentage time below INR 2.0. Adjusted incidence rate ratio (IRR) for bleeding events was significantly lower for the narrow INR group, while the adjusted IRR for thromboembolic events between both groups was similar. CONCLUSION: Patients assigned to a narrow INR target range in real-world practice spent a significantly lower amount of time below an INR of 3.0 compared to conventional INR target range with lower incidents of bleeding complications and no increase in subtherapeutic INRs. PMID- 26239318 TI - Expression of antigenic epitopes of porcine reproductive and respiratory syndrome virus (PRRSV) in a modified live-attenuated porcine circovirus type 2 (PCV2) vaccine virus (PCV1-2a) as a potential bivalent vaccine against both PCV2 and PRRSV. AB - Co-infection of pigs in the field with porcine circovirus type 2 (PCV2) and porcine reproductive and respiratory syndrome virus (PRRSV) is common and poses a major concern in effective control of PCV2 and PRRSV. We previously demonstrated that insertion of foreign epitope tags in the C-terminus of PCV2 ORF2 produced infectious virions that elicited humoral immune responses against both PCV2 capsid and inserted epitope tags. In this study, we aimed to determine whether the non-pathogenic chimeric virus PCV1-2a, which is the basis for the licensed PCV2 vaccine Fostera PCV, can express PRRSV antigenic epitopes, thus generating dual immunity as a potential bivalent vaccine against both PCV2 and PPRSV. Four different linear B-cell antigenic epitopes of PRRSV were inserted into the C terminus of the capsid gene of the PCV1-2a vaccine virus. We showed that insertion of 12 (PRRSV-GP2 epitope II, PRRSV-GP3 epitope I, and PRRSV-GP5 epitope I), and 14 (PRRSV-GP5 epitope IV) amino acid residues did not impair the replication of the resulting PCV1-2a-PRRSVEPI chimeric viruses in vitro. The four chimeric PCV1-2a viruses expressing PRRSV B-cell linear epitopes were successfully rescued and characterized. An immunogenicity study in pigs revealed that two of the four chimeric viruses, PCV1-2a-PRRSVEPIGP3IG and PCV1-2a PRRSVEPIEPIGP5IV, elicited neutralizing antibodies against PRRSV VR2385 as well as PCV2 (strains PCV2a, PCV2b, and mPCV2b). The results have important implications for exploring the potential use of PCV1-2a vaccine virus as a live virus vector to develop bivalent MLVs against both PCV2 and PRRSV. PMID- 26239319 TI - The role of long non-coding RNAs in hepatitis B virus-related hepatocellular carcinoma. AB - Chronic infection with hepatitis B virus (HBV) is a major risk for development of hepatocellular carcinoma (HCC), which is the fifth most common cancer and a leading global cause of mortality. Long noncoding RNAs (lncRNAs) are regulators of complex biological processes and their functional disruption is implicated in the etiology of many cancers including HCC. Several lncRNAs have been shown to have oncogenic or tumor suppressive roles and have recently become the focus of intense investigation. However, the contributions of lncRNAs to HBV-related HCC remain to be fully elucidated. In this review we concentrate on the functional roles of various lncRNAs in HBV-associated HCC. Their involvement in viral replication, the specific association of certain lncRNAs with HBV-related HCC, potential utility as therapeutic targets and diagnostic markers are discussed. PMID- 26239320 TI - Electromagnetic radiation at 900 MHz induces sperm apoptosis through bcl-2, bax and caspase-3 signaling pathways in rats. AB - BACKGROUND: The decreased reproductive capacity of men is an important factor contributing to infertility. Accumulating evidence has shown that Electromagnetic radiation potentially has negative effects on human health. However, whether radio frequency electromagnetic radiation (RF-EMR) affects the human reproductive system still requires further investigation. Therefore, The present study investigates whether RF-EMR at a frequency of 900 MHz can trigger sperm cell apoptosis and affect semen morphology, concentration, and microstructure. METHODS: Twenty four rats were exposed to 900 MHz electromagnetic radiation with a special absorption rate of 0.66 +/- 0.01 W/kg for 2 h/d. After 50d, the sperm count, morphology, apoptosis, reactive oxygen species (ROS), and total antioxidant capacity (TAC), representing the sum of enzymatic and nonenzymatic antioxidants, were investigated. Western blotting and reverse transcriptase PCR were used to determine the expression levels of apoptosis-related proteins and genes, including bcl-2, bax, cytochrome c, and capase-3. RESULTS: In the present study, the percentage of apoptotic sperm cells in the exposure group was significantly increased by 91.42% compared with the control group. Moreover, the ROS concentration in exposure group was increased by 46.21%, while the TAC was decreased by 28.01%. Radiation also dramatically decreased the protein and mRNA expression of bcl-2 and increased that of bax, cytochrome c, and capase-3. CONCLUSION: RF-EMR increases the ROS level and decreases TAC in rat sperm. Excessive oxidative stress alters the expression levels of apoptosis-related genes and triggers sperm apoptosis through bcl-2, bax, cytochrome c and caspase-3 signaling pathways. PMID- 26239322 TI - Interpreting raised serum ferritin levels. PMID- 26239321 TI - Dalbavancin for the treatment of acute bacterial skin and skin structure infections. AB - INTRODUCTION: Acute bacterial skin and skin structure infections (ABSSSI) have increased in incidence and severity. The involvement of resistant organisms, particularly methicillin-resistant Staphylococcus aureus, presents additional challenges. The lipoglycopeptide dalbavancin has a prolonged half-life, high protein binding, and excellent tissue levels which led to its development as a once-weekly treatment for ABSSSI. In the pivotal DISCOVER 1 and DISCOVER 2 trials, dalbavancin proved non-inferior to vancomycin followed by linezolid when used sequentially for ABSSSI, forming the basis for its recent approval in the US and Europe for ABSSSI. AREAS COVERED: A literature search of published pharmacologic and clinical data was conducted to review the chemistry, pharmacodynamics, and pharmacokinetics of dalbavancin. We also discuss its development process, highlighting efficacy and safety data from pertinent clinical trials and the role it could play in the current clinical landscape. EXPERT OPINION: DISCOVER 1 and DISCOVER 2 demonstrated dalbavancin's non inferiority to vancomycin followed by linezolid for ABSSSI and confirmed its safety and tolerability. They were among the first trials to use new, early primary efficacy endpoints, and dalbavancin was among the first agents designated a Qualified Infectious Disease Product for expedited review. Dalbavancin may prove to be a valuable option for ABSSSI patients in whom conventional therapy is limited. PMID- 26239323 TI - Continuous infusion vs intermittent vancomycin in neurosurgical intensive care unit patients. AB - PURPOSE: Target plasma level achievement has remained a challenge in neurosurgical intensive care unit patients receiving intravenous vancomycin. We evaluated continuous infusion (CI) and intermittent vancomycin dosing strategies in these patients. METHODS: This retrospective cohort compared CI vancomycin (target random levels, 20-30 mg/L) to intermittent vancomycin (target troughs, 15 20 mg/L) in regards to achievement of target plasma levels, nephrotoxicity, pharmacodynamic target attainment, and cost savings in 130 patients. RESULTS: Continuous infusion resulted in greater achievement of goal plasma concentrations at the first steady-state level (40 vs 21.5%, P = .02), more rapid achievement of goal plasma concentrations (2.04 vs 3.76 days, P < .0001), and increased time within therapeutic range (55% vs 34%, P < .0001) but no significant difference in nephrotoxicity (15.4% vs 21.5%, P = .5). Continuous infusion improved pharmacodynamic target attainment (92.3% vs 30.8%, P < .0001) and also reduced levels drawn (3.8 vs 5.7, P = .0007), dose adjustments (1.4 vs 2.4, P = .0006), days of therapy (10.4 vs 14.1, P = .01), and mean total daily dose requirements (33 vs 35.7 mg/kg, P < .0001) per patient. CONCLUSIONS: Continuous infusion appears beneficial for improving attainment of target plasma concentrations, pharmacodynamic goals, and financial burden, without increasing risk of acute kidney injury. PMID- 26239324 TI - Overexpression of TMEM158 contributes to ovarian carcinogenesis. AB - BACKGROUND: Transmembrane protein 158 (TMEM158) is a recently identified upregulated gene during Ras-induced senescence. Its association with various cancers has been recently reported. However, the expression and biological function of TMEM158 in ovarian cancer is still unclear. This study was aimed to elucidate the roles of TMEM158 in cell proliferation, adhesion and cell invasion of ovarian cancer cells. METHODS: We analyzed TMEM158 mRNA level in ovarian cancer tissues and adjacent no-tumorous tissues by real-time PCR. We then suppressed TMEM158 expression of ovarian cancer cells by RNA interference and examined the effects of TMEM158 knockdown on cancerous transformation of ovarian cancer cells. RESULTS: The RNA-sequencing data of the ovarian cancer cohort from The Cancer Genome Atlas project (TCGA) and our real-time PCR data showed that TMEM158 was overexpressed in ovarian cancer. Knockdown of TMEM158 by RNA interference in ovarian cancer cells significantly inhibited cell proliferation, which may be due to the increase of G1-phase arrest. Silencing of TMEM158 also inhibited cell adhesion, cell invasion as well as tumorigenicity in nude mice. Moreover, knockdown of TMEM158 notably repressed cell adhesion via down regulating the expression intercellular adhesion molecule1 (ICAM1) and vascular cell adhesion molecule1 (VCAM1). Transforming Growth Factor-beta (TGF-beta) signaling pathway was also remarkably impaired by TMEM158 silencing. CONCLUSIONS: Our data suggests that TMEM158 may work as an oncogene for ovarian cancer and that inhibition of TMEM158 may be a therapeutic strategy for ovarian cancer. PMID- 26239325 TI - [Antihistamines for the treatment of urticaria in Mexico]. AB - There are four types of histamine receptors. Allergic symptoms, especially those in rhinoconjunctivitis and urticaria, are mainly caused by activation of histamine receptor 1 (H1). Consequently, oral H1-antihistamines form and integral part of the treatment of these diseases. Antihistamines are inverse agonists that stabilize the non-active configuration of the histamine receptor. First generation H1-antihistamines cause a variety of adverse effects via several mechanisms: sedation (accumulation in the central nervous system), dry mouth, urinary retention, weight gain (low selectivity: stimulation of serotonin/muscarinic/alpha-adrenergic receptors) and drug interactions (substrate of CYP450-3A4). Generally second generation H1-antihistamines have a better safety profile. New guidelines on allergic rhinitis and urticaria recommend second generation H1-antihistamines as first line drugs, with -if necessary- four times updosing to obtain control in urticaria. The enhanced efficacy of quadruple doses in urticaria, while maintaining a good safety profile, has been shown for bilastine, desloratadine and levocetirizine (rupatadine). For ebastine and fexofenadine only the safety of quadruple doses has been shown till now. Extreme precaution should be taken with astemizol and terfenadine that never should be up dosed, as high serum concentrations can cause potentially fatal ventricular tachycardia. First generation antihistamines are not recommended as first line treatment and updosing is not safe. PMID- 26239326 TI - [Usefulness of studies looking for autoimmunity in patients with spontaneous chronic urticaria]. AB - BACKGROUND: Chronic spontaneous urticaria (CSU) is a common condition in adults, especially among women; this entity is frequently associated with autoimmune diseases. Our goal is to assess through laboratory studies whether patients with autoimmune CSU presented data. MATERIAL AND METHOD: A cross-sectional study of 35 patients was done in the area of Allergy and Immunology at Hospital Juarez de Mexico diagnosed with CSU. We performed the following tests: complete blood count, thyroid antibodies (antiperoxidase and thyroglobulin), antinuclear antibodies, rheumatoid factor, lupus anticoagulant, LE cells Autologous Serum Skin Test (ASST), add (C3 and C4). In addition, we made Helicobacter pylori test, thyroid hormones (T3, T4, TSH) and D-dimer. RESULTS: We evaluated 35 adult patients, 27 female; ASST was positive in 4 patients, negative antinuclear antibodies in all cases, but positive anti thyroid (AAT) antibodies in 4. The LE cell, lupus anticoagulant, complement, dimer D, thyroid and Helicobacter pylori profile were normal or negative and rheumatoid factor was positive in one patient. All AAT-positive patients were women, but 26 of them had negative ASST. The correlation between ASST and AAT was not significant. CONCLUSION: Most patients were women UCE and only 4 had positive ASST, but this does not correlate with the presence of anti-thyroid antibodies. Most studies were normal, so we suggest not making unnecessary laboratory studies in this disease. PMID- 26239327 TI - [Prevalence of allergic sensitization to bee, mosquito and red ant in children with allergic disease]. AB - BACKGROUND: The allergic sensitization to insects of the Hymenoptera and Culicidae order in pediatric population is studied with low frequency. OBJECTIVE: To determine the prevalence of sensitization to bees, mosquito and fire ants in children with allergic diseases. MATERIAL AND METHOD: A retrolective and descriptive study was carried out in a pediatric allergy service. The registers of the cutaneous reactivity to bees, mosquitos and fire ants done among January 2009 to December 2011 were analyzed. The frequency of sensitization to insects and its confidence interval to 95% was estimated. RESULTS: The sample included 613 patients, 41% were girls. The age average of the group was 6.2 +/- 3.7 years. The allergic sensitization to mosquito was 15% (CI 95%: 12.4-18.1), bees 14.2% (CI 95%: 11.4-16.9) and fire ants 6% (CI 95%: 6.0-6.8) older that non-sensitized, 7.1 vs 6.0 years old (p=0.011) and 7.4 vs 6.1 years old (p=0.042), respectively. During fall and winter seasons, fire ant sensitization was observed with more frequency. CONCLUSION: In our knowledge this is the first report in Mexico related with sensitization frequency to bees, mosquitos and fire ants carried out on children. Also, our results suggest that sensitization to these insects should be identified more often. PMID- 26239328 TI - [Type I hypersensitivity to nocturnal Lepidoptera in a Costa Rican allergic population]. AB - BACKGROUND: Allergic patients are routinely tested for various allergens including molds, food, pollen, cockroaches and house dust mites; however, there are patients who present allergy symptoms but show negative results in Prick tests with the available allergens. OBJECTIVE: To determine the percentage of patients sensitized to the nocturnal Lepidoptera and its role as an important environmental allergen. MATERIAL AND METHOD: A retrospective analysis was carried out in which we determined the percentage of patients allergic to nocturnal Lepidoptera, house dust mites (Blomia tropicalis, Dermatophagoides pteronyssinus, Dermatophagoides farinae and Tyrophagus putrescentiae) and insects (Periplaneta americana and Musca domestica). Also, we analyzed the demographics and symptoms of the patients. RESULTS: 63% of the patients were allergic to house dust mites, 39% to nocturnal Lepidoptera, 28% to Periplaneta americana and 24% to Musca domestica. Also, 2% of the patients allergic to only one allergen were mono sensitized to nocturnal Lepidoptera. CONCLUSIONS: We strongly recommend that allergists constantly test for nocturnal Lepidoptera, because most of the studied patients had allergy to these insects. PMID- 26239329 TI - [Prevalence of rhinitis allergic in populations of several states of Mexico]. AB - BACKGROUND: Allergic rhinitis is an inflammatory disorder of the nasal mucosa, characterized by symptoms of itching, rhinorrhea, nasal congestion and sneezing induced by an IgE-mediated response. In Mexico we have reports of prevalence, with fluctuations of 5.5% to 47.7% with the question of rhinitis symptoms the past 12 months. OBJECTIVE: To determine the prevalence of allergic rhinitis in schoolchildren from various states of Mexico. MATERIAL AND METHOD: A descriptive study of prevalence in which a questionnaire was applied to preschool, elementary , middle- and high-school population. It was performed in four cities in four states of Mexico: Puebla, Puebla, Tulancingo, Hidalgo, Tlaxcala, Tlaxcala and Cancun, Quintana Roo. Parents answered questionnaires of preschool and elementary school and middle- and high-school students answered their questionnaires. The study was conducted from June 2014 to January 2015. The instrument used was: questionnaire diagnosis of allergic rhinitis for epidemiological studies. RESULTS: Of the surveys, 8,159 completed questionnaires were obtained, in the city of Puebla: 2,267, Tulancingo, Hidalgo: 2,478, Tlaxcala, Tlaxcala: 2,574, Cancun, Quintana Roo: 840; total male: 4,190 (51%). The overall average rate of prevalence of allergic rhinitis among four states including all respondents ages was 15%. CONCLUSIONS: With the use of the questionnaire diagnosis of allergic rhinitis for epidemiological studies in the four cities in four different states, we found a prevalence of allergic rhinitis of 15% in >=13 yearpopulation and 13% in <=12 year-old children. PMID- 26239330 TI - [Prevalence of intolerance to salicylates in patients with nasal polyposis]. AB - BACKGROUND: Salicylates intolerance is related to alteration in the metabolism of arachidonic acid leading to increased leukotrienes. The condition may be manifested with respiratory, skin or systemic symptoms or associated with sinonasal polyposis. Salicylates are present in anti-inflammatory drugs, cosmetics products and food. OBJECTIVE: To determine the prevalence of salicylates intolerance in patients with sinonasal polyposis presenting to Clinical Immunology and Allergy and Otolaryngology Service, CMN 20 Noviembre, Mexico City. MATERIAL AND METHOD: An observational, descriptive, cross sectional study included patients with sinonasal polyposis. The sample size was 49 patients, and variables were compared using STATISTICA 8.0. RESULTS: The prevalence of sinonasal polyposis was 4% of the study group, predominantly in females; only 24% of the population had an ideal weight, the salicylates intolerance prevalence was 53%, and the Samter triad was 31%. CONCLUSIONS: Sinonasal polyposis has an inflammatory disease pattern. Its pathophysiology is not yet fully established and in this study was related to obesity and persistent sinusitis. The most feared complication recurrence is associated with salicylates intolerance. The study found a slight increase of recurrence in the group of intolerance, with no statistically significant difference, possibly related to the sample size. PMID- 26239331 TI - [Radiographic changes in children with primary immunodeficiency]. AB - BACKGROUND: Although we have epidemiological information on primary immunodeficiencies (PID), the available information is meager in Mexico. OBJECTIVE: To provide epidemiological information on the delay in the diagnosis of PID and its correlation to chronic lung damage. MATERIAL AND METHOD: A retrospective, analytical study was done in patients 0-18 year old age diagnosed with PID for 11 years at the HIMFG (Hospital Infantil de Mexico Federico Gomez). The variables studied were: age at symptom onset, age at diagnosis, time from onset of symptoms to diagnosis, number of previous pneumonias and studies with radiographic chronic lung damage data. RESULTS: 48 patients were obtained after meeting inclusion criteria; 33 showed lung damage at diagnosis, antibody deficiency being the most affected group. Relating age of onset of symptoms and the time difference of the onset of symptoms to diagnosis showed a strong correlation (p < 0.001, Rho > 0.80). A moderate correlation between the observed time difference vs number of pneumonias (p=0.005, Rho=0.495) and correlation between number of pneumonia and lung damage was highly significant (p <0.001, Rho=0.704). CONCLUSION: A strong relationship between the elapsed time from onset of symptoms and the number of pneumonia with lung injury time was found. So, the recurrent pneumonia (> 2) must make suspect the diagnosis of PID, as recommended in the literature. PMID- 26239332 TI - [Research groups in biomedical sciences. Some recommendations]. AB - Despite the growing number of scientific publications reflecting a greater number of people interested in the biomedical sciences, many research groups disappear secondary to poor internal organization. From the review of the available literature, we generate a series of recommendations that may be useful for the creation of a research group or to improve the productivity of an existing group. Fluid communication between its members with a common overall policy framework allows the creation of a good foundation that will lead to the consolidation of the group. PMID- 26239333 TI - [Key points for the management of dermatitis in Latin America. The SLAAI Consensus]. AB - The incidence of atopic dermatitis in Latin America, as in other regions, has been increasing in recent years. The SLAAI consensus is based on a systematic search for articles related to dermatitis, with focus in the pathophysiology and treatment and its impact on Latin America, and reviewed using the Delphi methodology (Revista Alergia Mexico 2014;61:178-211). In this article we highlight the key points of consensus and particular considerations in Latin America. PMID- 26239334 TI - [Allergy to egg proteins in children]. AB - Food allergy prevalence has increased during the last years, affecting 15-20% of children, in this case, egg allergy affects from 0.5-2.5%. Most of the egg allergic reactions are type I or IgE mediated antibodies against egg proteins. Five major proteins have been identified: ovomucoid (Gal d1), ovoalbumin (Gal d2), ovotransferrin (Gal d3), lysozyme (Gal d4) and albumin (Gal d5). Ovomucoid protein, which is found in the egg white, is heat resistant and enzyme resistant. This protein is the most allergenic and the most common in egg composition. Clinical diagnosis requires a detailed questionnaire. Skin prick test or Ige specific diagnosis are made as first choice. Skin prick tests are quick and useful to determine the presence of IgE specific antibodies to egg. Specific IgE for egg can be measured using standarized IgE studies in vitro, making a quantitative measure. Traditionally with the clinical history a diagnosis can be made. Standarized oral double blinded-placebo controlled challenge continues to be the gold standard for food allergy diagnosis. The identification and elimination of egg proteins from the diet is the primary treatment and the only one validated to this food, but there are more studies needed to stablish protocols for each specific egg allergen before the oral inmunotherapy becomes a routine practice. PMID- 26239335 TI - [Desensitization to darunavir in a pediatric patient]. AB - Treatment of HIV infection requires the combination of multiple antiretroviral drugs, known as highly active antiretroviral therapy (HAART); however, up to 84% of patients experience adverse drug effects that lead to discontinuation within first months of treatment. Skin manifestations are reported to 22% of patients. The severity of these is variable, such as erythema multiforme, rash, hives and severe skin reactions at less than 2%. Mild rashes, usually transient and self limiting, while severe reactions require immediately remove the drug involved to prevent progression of the reaction. Only in those cases where the offending drug does not have another alternative and documented the reaction is mediated type I hypersensitivity mechanisms, can be performed desensitization protocol. PMID- 26239336 TI - Hydrogen Sulfide Treatment Mitigates Renal Allograft Ischemia-Reperfusion Injury during Cold Storage and Improves Early Transplant Kidney Function and Survival Following Allogeneic Renal Transplantation. AB - PURPOSE: Ischemia-reperfusion injury is unavoidable during organ transplantation. Prolonged ischemia-reperfusion injury is detrimental to short-term and long-term graft function and survival. H2S is a recently characterized, endogenously produced gaseous molecule with important physiological roles that has been shown to be cytoprotective during tissue ischemia-reperfusion injury. The current study aimed to determine whether H2S could mitigate cold renal ischemia-reperfusion injury in the clinically relevant context of allogeneic renal transplantation. MATERIALS AND METHODS: Following bilateral native nephrectomy Lewis rats underwent renal transplantation with kidneys from Brown Norway donor rats that were flushed with cold (4C) standard University of Wisconsin preservation solution (University of Wisconsin preservation solution group) or cold University of Wisconsin preservation solution plus 150 MUM NaHS (H2S group) solution. Kidneys were stored for 6 hours at 4C in the same solution. Recipient animals were monitored for 14 days or until sacrifice using metabolic cages to assess various parameters of renal graft function. RESULTS: H2S treatment improved early allograft survival and function, and decreased early levels of necrosis, apoptosis and Kim-1 compared to University of Wisconsin preservation solution alone. H2S treatment did not affect allograft rejection. Rather, it modulated the early allograft transcriptome to decrease the expression of renal injury, coagulation and cellular stress response genes, and increase the expression of cellular proliferation and Ifn-gamma induced genes compared to University of Wisconsin preservation solution alone. CONCLUSIONS: To our knowledge our findings are the first to show that H2S protects donor kidneys against cold ischemia reperfusion injury in the context of allogeneic renal transplantation. This potentially represents a novel cost-effective therapeutic solution to mitigate ischemia-reperfusion injury and improve the clinical outcomes of renal transplantation. PMID- 26239337 TI - No Detrimental Effect of a Positive Family History on Long-Term Outcomes Following Radical Prostatectomy. AB - PURPOSE: Overall 1 in 5 patients with prostate cancer has a positive family history. In this report we evaluated the association between family history and long-term outcomes following radical prostatectomy. MATERIALS AND METHODS: Patients treated with radical prostatectomy were identified from a German registry, and separated into positive first-degree family history vs negative family history (strictly negative, requiring at least 1 male first-degree relative older than 60 years and no prostate cancer in the family). Kaplan-Meier curves and Cox proportional hazards models were used for association analyses with biochemical recurrence-free and prostate cancer specific survival. RESULTS: Median followup for 7,690 men included in the study was 8.4 years. Of the 754 younger patients less than 55 years old 50.9% (384) had a family history compared to 40.4% of the older patients (2,803; p <0.001). The 10-year biochemical recurrence-free (62.5%) and prostate cancer specific survival (96.1%) rates did not differ between patients with vs without a family history, nor between the younger vs older patient groups (all p >0.05). Prostate specific antigen, pathological stage, node stage and Gleason score were the only significant predictors for biochemical recurrence-free survival, while pathological stage, node stage (all p <0.005) and Gleason score (Gleason 7 vs 6 or less-HR 1.711, 95% CI 1.056-2.774, p = 0.03; Gleason 8 or greater vs 6 or less-HR 4.516, 95% CI 2.776-7.347, p <0.0001) were the only predictors for prostate cancer specific survival. CONCLUSIONS: A family history of prostate cancer has no bearing on long term outcomes after radical prostatectomy. PMID- 26239339 TI - Addendum to: Deep-sequencing of dsRNAs recovered from mosaic-diseased pigeonpea reveals the presence of a novel emaravirus: pigeonpea sterility mosaic virus 2. PMID- 26239340 TI - Antiviral effect of lithium chloride on feline calicivirus in vitro. AB - Feline calicivirus (FCV) is a highly contagious pathogen that causes oral and upper respiratory tract disease in cats. Despite widespread vaccination, the prevalence of FCV remains high. Furthermore, a high gene mutation rate has led to the emergence of variants, and some infections are lethal. To date, there is no effective antiviral drug available for treating FCV infection. Here, we show that lithium chloride (LiCl) effectively suppresses the replication of FCV strain F9 in Crandell-Reese feline kidney (CRFK) cells. The antiviral activity of LiCl occurred primarily during the early stage of infection and in a dose-dependent manner. LiCl treatment also inhibited the cytopathic effect. LiCl treatment exhibited a strong inhibitory effect against a panel of other two reference strains and two recent FCV isolates from China. These results demonstrate that LiCl might be an effective anti-FCV drug for controlling FCV disease. Further studies are required to explore the antiviral activity of LiCl against FCV replication in vivo. PMID- 26239341 TI - Comparative analysis of the replication of bovine herpesvirus 1 (BHV1) and BHV5 in bovine-derived neuron-like cells. AB - Members of the subfamily Alphaherpesvirinae use the epithelium of the upper respiratory and/or genital tract as preferential sites for primary replication. However, bovine herpesvirus 5 (BoHV5) is neurotropic and neuroinvasive and responsible for meningoencephalitis in cattle and in animal models. A related virus, BoHV1 has also been occasionally implicated in natural cases of neurological infection and disease in cattle. The aim of the present study was to assess the in vitro effects of BoHV1 and BoHV5 replication in neuron-like cells. Overall, cytopathic effects, consisting of floating rounded cells, giant cells and monolayer lysis, induced by both viruses at 48 h postinfection (p.i.) resulted in a loss of cell viability and high virus titres (r = 0.978). The BoHV1 Cooper strain produced the lowest titres in neuron-like cells, although viral DNA was detected in infected cells during all experiments. Virus replication in infected cells was demonstrated by immunocytochemistry, flow cytometry and qPCR assays. BoHV antigens were better visualized at 48 h p.i. and flow cytometry analysis showed that SV56/90 and Los Angeles antigens were present at higher levels. In spite of the fact that BoHV titres dropped at 48 h p.i, viral DNA remained detectable until 120 h p.i. Sensitive TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) and annexin V assays were used to identify apoptosis. BoHV5 induced death in approximately 50% of cells within 24 h p.i., similar to what has been observed for BoHV1 Los Angeles. Infection with the BoHV1 Cooper strain resulted in 26.37% of cells being in the early stages of apoptosis; 63.69% of infected cells were considered viable. Modulation of mitochondrial function, as measured by mitochondrial membrane depolarization, was synchronous with the virus replication cycle, cell viability and virus titres at 48 h p.i. Our results indicate that apoptosis plays an important role in preventing neuronal death and provides a bovine-derived in vitro system to study herpesvirus-neuron interactions. PMID- 26239338 TI - Phytoconstituents as apoptosis inducing agents: strategy to combat cancer. AB - Advancement in the field of cancer molecular biology has aided researchers to develop various new chemopreventive agents which can target cancer cells exclusively. Cancer chemopreventive agents have proficiency to inhibit, reverse and delay process of carcinogenesis during its early and later course. Chemopreventive agents can act as antioxidative, antimutagenic/antigenotoxic, anti-inflammatory agents or via aiming various molecular targets in a cell to induce cell death. Apoptosis is a kind of cell death which shows various cellular morphological alterations such as cell shrinkage, blebbing of membrane, chromatin condensation, DNA fragmentation, formation of apoptotic bodies etc. Nowadays, apoptosis is being one of the new approaches for the identification and development of novel anticancer therapies. For centuries, plants are known to play part in daily routine from providing food to management of human health. In the last two decades, diverse phytochemicals and various botanical formulations have been characterized as agents that possess potential to execute cancer cells via inducing apoptosis. Data obtained from the research carried out globally pointed out that natural products are the potential candidates which have capability to combat cancer. In the present review, we surveyed literature on natural products which throws light on the mechanism through which these phytochemicals induce apoptosis in cancer cells. PMID- 26239342 TI - Identification of recombination between Muscovy duck parvovirus and goose parvovirus structural protein genes. AB - Waterfowl parvoviruses are divided into Muscovy duck parvoviruses (MDPVs) and goose parvoviruses (GPVs). Phylogenetic analysis based on structural gene nucleotide sequences showed that the strains of three GPVs (DY, PT and D strains) and two MDPVs (GX5 and SAAH-SHNH) are closely related and formed one cluster. Recombination analysis showed that recombination between GPV-GDFsh and MDPV 89384/FRANCE strains led to five recombinant strains: GPV-DY, GPV-PT, GPV-D, MDPV GX5 and MDPV-SAAH-SHNH. The recombinant event was confirmed using the Simplot program and phylogenetic analysis. This is the first comprehensive investigation of recombination between MDPV and GPV structural genes. PMID- 26239343 TI - Horizontal study of vaccinia virus infections in an endemic area: epidemiologic, phylogenetic and economic aspects. AB - Vaccinia virus (VACV), the etiological agent of bovine vaccinia (BV), is widespread in Brazil and present in most of the milk-producing regions. We conducted a horizontal study of BV in Bahia, a state of Brazil in which the production of milk is increasing. During 2011, human and bovine clinical samples were collected during outbreaks for BV diagnosis, virus isolation and molecular analysis. We collected data for epidemiological inferences. Vaccinia virus was detected in 87.7% of the analyzed outbreaks, highlighting the effective circulation of VACV in Bahia. The molecular data showed the spreading of group 1 Brazilian VACV to Bahia. We observed a seasonal profile of BV, with its peak in the drier and cooler season. Manual milking was observed in 96 % of the visited properties, showing its importance to viral spread in herds. Under-notification of BV, ineffective animal trade surveillance, and bad milking practices have contributed to the spread of VACV in Brazil. PMID- 26239345 TI - Sick Leave and Factors Influencing Sick Leave in Adult Patients with Atopic Dermatitis: A Cross-Sectional Study. AB - BACKGROUND: Little is known about the prevalence of sick leave due to atopic dermatitis (AD). The current literature on factors influencing sick leave is mostly derived from other chronic inflammatory diseases. This study aimed to determine the prevalence of sick leave due to AD and to identify influencing factors. METHODS: A cross-sectional study was carried out in adult patients with AD. OUTCOME MEASURES: sick leave during the two-week and one-year periods, socio demographic characteristics, disease severity, quality of life and socio occupational factors. Logistic regression analyses were used to determine influencing factors on sick leave over the two-week period. RESULTS: In total, 253 patients were included; 12% of the patients had to take sick leave in the last two weeks due to AD and 42% in the past year. A higher level of symptom interference (OR 1.26; 95% CI 1.13-1.40) or perfectionism/diligence (OR 0.90; 95% CI 0.83-0.96) may respectively increase or decrease the number of sick leave days. CONCLUSION: Sick leave in patients with AD is a common problem and symptom interference and perfectionism/diligence appeared to influence it. Novel approaches are needed to deal with symptoms at work or school to reduce the amount of sick leave due to AD. PMID- 26239346 TI - Using iPS Cells toward the Understanding of Parkinson's Disease. AB - Cellular reprogramming of somatic cells to human pluripotent stem cells (iPSC) represents an efficient tool for in vitro modeling of human brain diseases and provides an innovative opportunity in the identification of new therapeutic drugs. Patient-specific iPSC can be differentiated into disease-relevant cell types, including neurons, carrying the genetic background of the donor and enabling de novo generation of human models of genetically complex disorders. Parkinson's disease (PD) is the second most common age-related progressive neurodegenerative disease, which is mainly characterized by nigrostriatal dopaminergic (DA) neuron degeneration and synaptic dysfunction. Recently, the generation of disease-specific iPSC from patients suffering from PD has unveiled a recapitulation of disease-related cell phenotypes, such as abnormal alpha synuclein accumulation and alterations in autophagy machinery. The use of patient specific iPSC has a remarkable potential to uncover novel insights of the disease pathogenesis, which in turn will open new avenues for clinical intervention. This review explores the current Parkinson's disease iPSC-based models highlighting their role in the discovery of new drugs, as well as discussing the most challenging limitations iPSC-models face today. PMID- 26239344 TI - The Potential of Vitamin D-Regulated Intracellular Signaling Pathways as Targets for Myeloid Leukemia Therapy. AB - The current standard regimens for the treatment of acute myeloid leukemia (AML) are curative in less than half of patients; therefore, there is a great need for innovative new approaches to this problem. One approach is to target new treatments to the pathways that are instrumental to cell growth and survival with drugs that are less harmful to normal cells than to neoplastic cells. In this review, we focus on the MAPK family of signaling pathways and those that are known to, or potentially can, interact with MAPKs, such as PI3K/AKT/FOXO and JAK/STAT. We exemplify the recent studies in this field with specific relevance to vitamin D and its derivatives, since they have featured prominently in recent scientific literature as having anti-cancer properties. Since microRNAs also are known to be regulated by activated vitamin D, this is also briefly discussed here, as are the implications of the emerging acquisition of transcriptosome data and potentiation of the biological effects of vitamin D by other compounds. While there are ongoing clinical trials of various compounds that affect signaling pathways, more studies are needed to establish the clinical utility of vitamin D in the treatment of cancer. PMID- 26239347 TI - Patient-Specific iPSC-Derived RPE for Modeling of Retinal Diseases. AB - Inherited retinal diseases, such as age-related macular degeneration and retinitis pigmentosa, are the leading cause of blindness in the developed world. Currently, treatments for these conditions are limited. Recently, considerable attention has been given to the possibility of using patient-specific induced pluripotent stem cells (iPSCs) as a treatment for these conditions. iPSCs reprogrammed from adult somatic cells offer the possibility of generating patient specific cell lines in vitro. In this review, we will discuss the current literature pertaining to iPSC modeling of retinal disease, gene therapy of iPSC derived retinal pigmented epithelium (RPE) cells, and retinal transplantation. We will focus on the use of iPSCs created from patients with inherited eye diseases for testing the efficacy of gene or drug-based therapies, elucidating previously unknown mechanisms and pathways of disease, and as a source of autologous cells for cell replacement. PMID- 26239348 TI - The Interaction between Human Immunodeficiency Virus and Human Papillomaviruses in Heterosexuals in Africa. AB - Sub-Saharan Africa has the highest incidence of human papillomavirus (HPV) and cervical cancer in the world, which is further aggravated by the burden of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) disease with invasive cervical cancer being an AIDS-defining cancer. The prevalence of HPV infection and associated disease is very high in HIV-infected people and continues to be a problem even after anti-retroviral therapy. In the genital tract, the interaction between HPV and HIV is complex, with infection with multiple HPV types reported to make both women and men more susceptible to HIV infection. Besides the national programmes to vaccinate girls against HPV and screen women for cervical cancer, there should be targeted cervical cancer screening, treatment and prevention programmes introduced into HIV treatment centres. There is evidence that in high HIV prevalence areas, HIV-positive women could cause increases in the prevalence of genital HPV infection in HIV-negative men and so increase the HPV circulating in the community. Condom use and circumcision reduce the acquisition of HIV-1, and also to some extent of HPV. This review will highlight what is known about the interaction of HIV and HPV, with an emphasis on research in Africa. PMID- 26239349 TI - Biological Treatments in Atopic Dermatitis. AB - Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases that affect both children and adults with a prevalence of 30% and 10%, respectively. Even though most of patients respond satisfactory to topical anti inflammatory drugs, about 10% require one or more systemic treatments to achieve good control of their illness. The progressive and increasingly detailed knowledge in the immunopathogenesis of AD has allowed research on new therapeutic targets with very promising results in the field of biological therapy. In this article, we will review the different biological treatments with a focus on novel drugs. Their mechanism of action, current status and results from clinical trials and observational studies will be specified. PMID- 26239350 TI - Safety and Efficacy Data on Vaccines and Immunization to Human Papillomavirus. AB - Since the discovery of the causal association between human papillomavirus (HPV) and cervical cancer, efforts to develop an effective prophylactic vaccine to prevent high-risk HPV infections have been at the forefront of modern medical research. HPV causes 530,000 cervical cancer cases worldwide, which is the second most common cause of cancer deaths in women; a worldwide collaboration among epidemiologists, molecular biologists, vaccinologists, virologists, and clinicians helped lead to the development of two highly effective prophylactive HPV vaccines. The first, Gardasil, is a quadrivalent vaccine made up of recombinant HPV L1 capsid proteins from the two high-risk HPV types (16/18) responsible for 70% of cervical cancer cases as well as two low-risk HPV types (6/11) which are the causative agent for genital warts. The second, Cervarix, is a bivalent vaccine that was FDA approved three years after Gardasil and is also composed of L1 capsid proteins from HPV types 16/18. This review article focuses on the safety and efficacy data of both FDA-approved vaccines, as well as highlighting a few advances in future HPV vaccines that show promise in becoming additional treatment options for this worldwide disease. PMID- 26239351 TI - Concise Review: Methods and Cell Types Used to Generate Down Syndrome Induced Pluripotent Stem Cells. AB - Down syndrome (DS, trisomy 21), is the most common viable chromosomal disorder, with an incidence of 1 in 800 live births. Its phenotypic characteristics include intellectual impairment and several other developmental abnormalities, for the majority of which the pathogenetic mechanisms remain unknown. Several models have been used to investigate the mechanisms by which the extra copy of chromosome 21 leads to the DS phenotype. In the last five years, several laboratories have been successful in reprogramming patient cells carrying the trisomy 21 anomaly into induced pluripotent stem cells, i.e., T21-iPSCs. In this review, we summarize the different T21-iPSCs that have been generated with a particular interest in the technical procedures and the somatic cell types used for the reprogramming. PMID- 26239353 TI - Histamine and Skin Barrier: Are Histamine Antagonists Useful for the Prevention or Treatment of Atopic Dermatitis? AB - Atopic Dermatitis (AD), the most common chronic inflammatory skin disease, is characterized by an overactive immune response to a host of environmental allergens and dry, itchy skin. Over the past decade important discoveries have demonstrated that AD develops in part from genetic and/or acquired defects in the skin barrier. Histamine is an aminergic neurotransmitter involved in physiologic and pathologic processes such as pruritus, inflammation, and vascular leak. Enhanced histamine release has been observed in the skin of patients with AD and antihistamines are often prescribed for their sedating and anti-itch properties. Recent evidence suggests that histamine also inhibits the terminal differentiation of keratinocytes and impairs the skin barrier, raising the question whether histamine might play a role in AD barrier impairment. This, coupled with the notion that histamine's effects mediated through the recently identified histamine receptor H4R, may be important in allergic inflammation, has renewed interest in this mediator in allergic diseases. In this paper we summarize the current knowledge on histamine and histamine receptor antagonists in AD and skin barrier function. PMID- 26239352 TI - Endoplasmic Reticulum Stress in the Diabetic Kidney, the Good, the Bad and the Ugly. AB - Diabetic kidney disease is the leading worldwide cause of end stage kidney disease and a growing public health challenge. The diabetic kidney is exposed to many environmental stressors and each cell type has developed intricate signaling systems designed to restore optimal cellular function. The unfolded protein response (UPR) is a homeostatic pathway that regulates endoplasmic reticulum (ER) membrane structure and secretory function. Studies suggest that the UPR is activated in the diabetic kidney to restore normal ER function and viability. However, when the cell is continuously stressed in an environment that lies outside of its normal physiological range, then the UPR is known as the ER stress response. The UPR reduces protein synthesis, augments the ER folding capacity and downregulates mRNA expression of genes by multiple pathways. Aberrant activation of ER stress can also induce inflammation and cellular apoptosis, and modify signaling of protective processes such as autophagy and mTORC activation. The following review will discuss our current understanding of ER stress in the diabetic kidney and explore novel means of modulating ER stress and its interacting signaling cascades with the overall goal of identifying therapeutic strategies that will improve outcomes in diabetic nephropathy. PMID- 26239354 TI - Bioengineering and Stem Cell Technology in the Treatment of Congenital Heart Disease. AB - Congenital heart disease places a significant burden on the individual, family and community despite significant advances in our understanding of aetiology and treatment. Early research in ischaemic heart disease has paved the way for stem cell technology and bioengineering, which promises to improve both structural and functional aspects of disease. Stem cell therapy has demonstrated significant improvements in cardiac function in adults with ischaemic heart disease. This finding, together with promising case studies in the paediatric setting, demonstrates the potential for this treatment in congenital heart disease. Furthermore, induced pluripotent stems cell technology, provides a unique opportunity to address aetiological, as well as therapeutic, aspects of disease. PMID- 26239355 TI - Dementia and intentional and unintentional poisoning in older people: a 10 year review of hospitalization records in New South Wales, Australia. AB - BACKGROUND: Medicinal substances have been identified as common agents of both unintentional and intentional poisoning among older people, including those with dementia. This study aims to compare the characteristics of poisoning resulting in hospitalization in older people with and without dementia and their clinical outcomes. METHODS: A retrospective cohort study involving an examination of poisoning by intent involving individuals aged 50+ years with and without dementia using linked hospitalization and mortality records during 2003-2012. Individuals who had dementia were identified from hospital diagnoses and unintentional and intentional poisoning was identified using external cause classifications. The epidemiological profile (i.e. individual and incident characteristics) of poisoning by intent and dementia status was compared, along with clinical outcomes of hospital length of stay (LOS), 28-day readmission and 30-day mortality. RESULTS: The hospitalization rate for unintentional and intentional poisoning for individuals with dementia was double and 1.5 times higher than the rates for individuals without dementia (69.5 and 31.6 per 100,000) and (56.4 and 32.5 per 100,000). [corrected]. The home was the most common location of poisoning. Unintentional poisoning was more likely to involve individuals residing in aged care facilities (OR 2.12; 95%CI 1.70-2.63) or health service facilities (OR 4.56; 95%CI 4.06-5.13). [corrected]. There were higher mortality rates and longer length of stay [corrected] for unintentional poisoning for individuals with dementia. CONCLUSIONS: Clinicians need to be aware of the risks of poisoning for individuals with dementia and care is required in appropriate prescription, safe administration, and potential for self-harm with commonly used medications, such as anticholinesterase medications, antihypertensive drugs, and laxatives. PMID- 26239356 TI - Big or fast: two strategies in the developmental control of body size. AB - Adult body size is controlled by the mechanisms that stop growth when a species characteristic size has been reached. The mechanisms by which size is sensed and by which this information is transduced to the growth regulating system are beginning to be understood in a few species of insects. Two rather different strategies for control have been discovered; one favors large body size and the other favors rapid development. PMID- 26239357 TI - Chlorophyll catalyse the photo-transformation of carcinogenic benzo[a]pyrene in water. AB - Algal blooms cause great damage to water quality and aquaculture. However, this study showed that dead algal cells and chlorophyll could accelerate the photo transformation of benzo[a]pyrene (BaP), a ubiquitous and persistent pollutant with potently mutagenic and carcinogenic toxicities, under visible light irradiation. Chlorophyll was found to be the major active substance in dead algal cells, and generated a high level of singlet oxygen to catalyse the photo transformation of BaP. According to various BaP metabolites formed, the degradation mechanism was proposed as that chlorophyll in dead algal cells photo oxidized BaP to quinones via photocatalytic generation of singlet oxygen. The results provided a good insight into the role of chlorophyll in the photo transformation of organic contaminants and could be a possible remediation strategy of organic pollutants in natural environment. PMID- 26239358 TI - Cost-effectiveness of sofosbuvir-based treatments for chronic hepatitis C in the US. AB - BACKGROUND: The standard care of treatment of interferon plus ribavirin (plus protease inhibitor for genotype 1) are effective in 50 % to 70 % of patients with CHC. Several new treatments including Harvoni, Olysio + Sovaldi, Viekira Pak, Sofosbuvir-based regimens characterized with potent inhibitors have been approved by the Food and Drug Administration (FDA) providing more options for CHC patients. Trials have shown that the new treatments increased the rate to 80% to 95%, though with a substantial increase in cost. In particular, current market pricing of a 12-week course of sofosbuvir is approximately US$84,000. We determine the cost-effectiveness of new treatments in comparison with the standard care of treatments. METHODS: A Markov simulation model of CHC disease progression is used to evaluate the cost-effectiveness of different treatment strategies based on genotype. The model calculates the expected lifetime medical costs and quality adjusted life years (QALYs) of hypothetical cohorts of identical patients receiving certain treatments. For genotype 1, we compare: (1) peginterferon + ribavirin + telaprevir for 12 weeks, followed by 12 or 24 weeks treatment of peginterferon + ribavirin dependent on HCV RNA level at week 12; (2) Harvoni treatment, 12 weeks; (3) Olysio + Sovaldi, 12 weeks for patients without cirrhosis, 24 weeks for patients with cirrhosis; (4) Viekira Pak + ribavirin, 12 weeks for patients without cirrhosis, 24 weeks for patients with cirrhosis; (5) sofosbuvir + peginterferon + ribavirin, 12 weeks for patients with or without cirrhosis. For genotypes 2 and 3, treatment strategies include: (1) peginterferon + ribavirin, 24 weeks for treatment-naive patients; (2) sofosbuvir + ribavirin, 12 weeks for patients with genotype 2, 24 weeks for genotype 3; (3) peginterferon + ribavirin as initial treatment, 24 weeks for patients with genotype 2/3, follow up treatment with sofosbuvir + ribavirin for 12/16 weeks are performed on non responders and relapsers. RESULTS: Viekira Pak is cost-effective for genotype 1 patients without cirrhosis, whereas Harvoni is cost-effective for genotype 1 patients with cirrhosis. Sofosbuvir-based treatments for genotype 1 in general are not cost-effective due to its substantial high costs. Two-phase treatments with 12-week and 16-week follow-ups are cost-effective for genotype 3 patients and for genotype 2 patients with cirrhosis. The results were shown to be robust over a broad range of parameter values through sensitivity analysis. CONCLUSIONS: For genotype 1, sofosbuvir-based treatments are not cost-effective compared to Viekira Pak and Harvoni, although a 30% reduction in sofosbuvir price would change this result. Sofosbuvir + ribavirin are cost-effective as second-phase treatments following peginterferon + ribavirin initial treatment for genotypes 2 and 3. However, there is limited data on sofosbuvir-involved treatment, and the results obtained in this study must be interpreted within the model assumptions. PMID- 26239359 TI - Prevalence and characteristics of suicide attempters and ideators among acutely admitted psychiatric hospital patients in northwest Russia and northern Norway. AB - BACKGROUND: More knowledge about suicidality and suicide risk profiles in acute psychiatric hospital patients (both first-time and chronic patients) is needed. While numerous factors are associated with suicidality in such populations, these may differ across cultures. Better understanding of factors underlying suicide risk can be informed by cross-cultural studies, and can aid development of therapeutic and preventive measures. METHODS: An explorative, cross-sectional cohort study was carried out. Acutely admitted patients at one psychiatric hospital in northwest Russia and two in northern Norway were included. At admission, demographic, clinical, and service use data were collected, in addition to an assessment of suicidal ideation and attempts, comprising five dichotomic questions. Data from 358 Norwegian and 465 Russian patients were analyzed with univariate and multivariate statistics. Within each cohort, attempters and ideators were compared with patients not reporting any suicidality. RESULTS: The observed prevalence of suicidal ideation and attempts was significantly higher in the Norwegian cohort than in the Russian cohort (chi(2) = 168.1, p < 0,001). Norwegian suicidal ideators and attempters had more depressed moods, more personality disorders, and greater problems with alcohol/drugs, but fewer psychotic disorders, cognitive problems or overactivity than non-suicidal patients. Russian suicidal ideators and attempters were younger, more often unemployed, had more depressed mood and adjustment disorders, but had fewer psychotic disorders and less alcohol/drug use than the non-suicidal patients. CONCLUSIONS: Rates of suicidal ideation and non-fatal attempts in Norwegian patients were intermediate between those previously reported for patients admitted for the first time and those typical of chronic patients. However, the significantly lower rates of suicidal ideation and non-fatal attempts in our Russian cohort as compared with the Norwegian, contrasted with what might be expected in a region with much higher suicide rates than in northern Norway. We suggest that suicide-related stigma in Russia may reduce both patient reporting and clinicians' recognition of suicidality. In both cohorts, overlapping risk profiles of ideators and attempters may indicate that ideators should be carefully evaluated and monitored, particularly those with depressed moods, alcohol/substance abuse disorders, and inadequate treatment continuity. PMID- 26239360 TI - Effect of thymosin alpha1 on the phenotypic and functional maturation of dendritic cells from children with acute lymphoblastic leukemia. AB - To determine the effect of thymosin alpha1 (Talpha1) on the phenotypic and functional maturation of HL-60 cells, freeze-thaw antigen-loaded dendritic cells (DCs) were derived from peripheral blood mononuclear cells (PBMCs) of children with acute lymphoblastic leukemia (ALL). The DCs were generated from the PBMC samples that were collected from the PB of 10 consecutive ALL children. On day 3 of culturing, the cells in the antigen + no Talpha1 (AN) and antigen + Talpha1 (AT) groups were incubated with 100 ul lysates obtained from freeze-thaw cycling. After 5 days of incubation, the AT group was administered with 100 ng/ml Talpha1. On day 8, the DCs were stained with fluorescein isothiocyanate-conjugated cluster of differentiation (CD)1a, CD83 and HLA-DR antibodies and analyzed by flow cytometry. In addition, the killing activity of cytotoxic T lymphocytes (CTLs) from the different groups on wild-type leukemia cells was measured. The DCs in the AT group exhibited more apparent, characteristic dendritic morphologies than the control and AN group DCs. Furthermore, the lowest expression level of CD1a, and the highest expression of CD83 and HLA-DR were observed in the AT group when compared with the AN and control groups (P<0.05). The lactate dehydrogenase release assay demonstrated that the killing rate of CTL in the AT group was significantly higher than that in the control and AN groups (P<0.01). Thus, Talpha1 may markedly promote the phenotypic and functional maturation of DCs, and may serve as a suitable immunomodulator of DC-based immunotherapy for treatment of hematological malignancies. PMID- 26239361 TI - A Systematic Review of Economic Evaluations of the Use of Robotic Assisted Laparoscopy in Surgery Compared with Open or Laparoscopic Surgery. AB - BACKGROUND: Robot assisted laparoscopic (RAL) surgery developed to overcome the limitations of laparoscopy to assist in surgical procedures, has high capital and operating costs. Systematically assembled evidence demonstrating its clinical and cost effectiveness would be helpful for its adoption by decision makers. OBJECTIVE: To summarise the evidence on the cost-effectiveness of robot-assisted laparoscopic (RAL) surgery compared with relevant alternatives. Methods and results of identified studies were assessed to identify the deficiencies in evidence and areas for further research. METHODS: Studies reporting both costs and outcomes for comparisons of RAL with laparoscopy and/or open surgery were systematically identified. Searches were conducted in February 2015 on MEDLINE, EMBASE and NHS EED. Quality of the included studies was assessed against a standard checklist for economic analyses. Length of hospital stay and operating time (determinants of cost), cost of intervention, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were extracted. To aid comparison, costs were converted into a common currency and price year (2014 US dollars). RESULTS: Forty-seven eligible studies were identified (full economic evaluation n = 6 and cost analysis n = 41). Economic models were used in 11 (23%) studies. Only three studies used a model considered representative of the disease and clinical pathway with a time-horizon allowing capture of relevant differences in outcomes across strategies. The cost of RAL varied substantially between uses, ranging from US$7011 for hysterectomy to over US$30,000 for radical cystectomy. The majority of estimates were between US$15,000 and US$25,000 per person. In part this difference is explained by the difference between studies in which costs were included. It was also identified to have higher costs than the alternatives it was compared against. Incremental cost per QALY for RAL radical prostatectomy was US$28,801-$31,763 over a 10-year period assuming 200 cases per annum. CONCLUSION: The clinical evidence available for RAL overall and used within included studies is limited. RAL surgery costs were consistently higher than open and laparoscopic surgery. Therefore, in adopting the robotic technology decision makers need to take into account the cost effectiveness within their own systems. Economic models generated and published for radical prostatectomy and hysterectomy may be adapted to other health systems if the care pathway is similar to provide locally relevant data. PMID- 26239363 TI - Indoxyl sulphate and kidney disease: Causes, consequences and interventions. AB - In the last decade, chronic kidney disease (CKD), defined as reduced renal function (glomerular filtration rate (GFR) < 60 mL/min per 1.73 m(2) ) and/or evidence of kidney damage (typically manifested as albuminuria) for at least 3 months, has become one of the fastest-growing public health concerns worldwide. CKD is characterized by reduced clearance and increased serum accumulation of metabolic waste products (uremic retention solutes). At least 152 uremic retention solutes have been reported. This review focuses on indoxyl sulphate (IS), a protein-bound, tryptophan-derived metabolite that is generated by intestinal micro-organisms (microbiota). Animal studies have demonstrated an association between IS accumulation and increased fibrosis, and oxidative stress. This has been mirrored by in vitro studies, many of which report cytotoxic effects in kidney proximal tubular cells following IS exposure. Clinical studies have associated IS accumulation with deleterious effects, such as kidney functional decline and adverse cardiovascular events, although causality has not been conclusively established. The aims of this review are to: (i) establish factors associated with increased serum accumulation of IS; (ii) report effects of IS accumulation in clinical studies; (iii) critique the reported effects of IS in the kidney, when administered both in vivo and in vitro; and (iv) summarize both established and hypothetical therapeutic options for reducing serum IS or antagonizing its reported downstream effects in the kidney. PMID- 26239362 TI - A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models. AB - Packaging clinically relevant hydrophobic drugs into a self-assembled nanoparticle can improve their aqueous solubility, plasma half-life, tumour specific uptake and therapeutic potential. To this end, here we conjugated paclitaxel (PTX) to recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into ~60 nm near-monodisperse nanoparticles that increased the systemic exposure of PTX by sevenfold compared with free drug and twofold compared with the Food and Drug Administration-approved taxane nanoformulation (Abraxane). The tumour uptake of the CP-PTX nanoparticle was fivefold greater than free drug and twofold greater than Abraxane. In a murine cancer model of human triple-negative breast cancer and prostate cancer, CP-PTX induced near complete tumour regression after a single dose in both tumour models, whereas at the same dose, no mice treated with Abraxane survived for >80 days (breast) and 60 days (prostate), respectively. These results show that a molecularly engineered nanoparticle with precisely engineered design features outperforms Abraxane, the current gold standard for PTX delivery. PMID- 26239364 TI - The novel mTOR inhibitor Torin-2 induces autophagy and downregulates the expression of UHRF1 to suppress hepatocarcinoma cell growth. AB - Mammalian target of rapamycin (mTOR) is frequently upregulated in hepatocellular carcinoma (HCC). Blockage of mTOR was found to induce marked reduction in HCC growth in preclinical models. In the present study, we tested a novel mTOR inhibitor, Torin-2, for its antitumor efficacy in HCC cell lines Hep G2, SNU-182 and Hep 3B2.1-7. The HCC cell lines were cultured in vitro. These cells were treated with Torin-2. Cell apoptosis was evaluated by Annexin V staining. Cell proliferation and cell cycle progression were determined by Ki67 staining and propidium iodide staining, respectively. mTOR signaling, autophagy induction and expression of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) were assessed by western blot analysis. The UHRF1 mRNA level was determined by real-time PCR. We found that Torin-2 effectively suppressed the growth and survival of HCC cell lines, demonstrated by reduced proliferation and a high rate of apoptosis. Further study elucidated that in addition to blocking mTOR complex 1 (mTORC1)-associated cell cycle progression and induction of autophagy, Torin-2 downregulated transcription of UHRF1, an essential regulator of DNA methylation that is highly expressed in HCC cell lines. Consistently, the level of DNA (cytosine-5)-methyltransferase 1 (DNMT1) was higher after treatment of the HCC cell lines with Torin-2. The downregulation of UHRF1 by Torin-1 was partially due to a decrease in the UHRF1 mRNA level. Torin-2 effectively inhibited HCC cell proliferation through induction of autophagy. Torin-2-induced downregulation of UHRF1 expression may also contribute to its antitumor effect. Our research provides new clues regarding the antitumor effects of Torin-2 and sheds light on a novel therapeutic approach for HCC. PMID- 26239365 TI - Structure-function discrepancy in Clostridium botulinum C3 toxin for its rational prioritization as a subunit vaccine. AB - Clostridium botulinum is anaerobic pathogenic bacterium causing food-born botulism in human and animals by producing botulinum neurotoxins A-H, C2, and C3 cytotoxins. Physiological group III strains (type C and D) of this bacterium are capable of producing C2 and C3 toxins in cattle and avian. Herein, we have revealed the structure-function disparity of C3 toxins from two different C. botulinum type C phage (CboC) and type D phage (CboD) to design avirulent toxins rationally. Structure-function discrepancy of the both toxins was computationally evaluated from their homology models based on the conservation in sequence structure-function relationships upon covariation and point mutations. It has shown that 8 avirulent mutants were generated from CboC of 34 mutants while 27 avirulent mutants resulted from CboD mutants. No major changes were found in tertiary structure of these toxins; however, some structural variations appeared in the coiled and loop regions. Correlated mutation on the first residue would disorder or revolutionize the hydrogen bonding pattern of the coevolved pairs. It suggested that the residues coupling in the local structural environments were compensated with coevolved pairs so as to preserve a pseudocatalytic function in the avirulent mutants. Avirulent mutants of C3 toxins have shown a stable structure with a common blue print of folding process and also attained a near native backrub ensemble. Thus, we concluded that selecting the site-directed mutagenesis sites are very important criteria for designing avirulent toxins, in development of rational subunit vaccines, to cattle and avian, but the vaccine specificity can be determined by the C3 toxins of C. botulinum harboring phages. PMID- 26239366 TI - Meta-analysis of molecular targetted agents in the treatment of elderly patients with metastatic colorectal cancer: does the age matter? AB - AIM: Patients aged 65 years and older are often under-represented in clinical trials of metastatic colorectal cancer (mCRC) and probably undertreated in clinical practice. We performed a meta-analysis of randomized controlled trials to assess the efficacy of molecular targetted agents (MTAs) in this population. METHODS: A comprehensive literature search for studies published up to December 2014 was performed. The endpoints were overall survival (OS) and progression-free survival (PFS). The pooled hazard ratio (HR) and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS: Eleven randomized controlled trials involved 8,488 patients were ultimately identified. The pooled analysis demonstrated that the use of MTAs in elderly patients with mCRC significantly improved OS (HR 0.84, 95% CI: 0.76-0.92, p < 0.001) and PFS (HR 0.78, 95% CI: 0.64-0.96, p = 0.017) when compared to MTAs-free therapies. Similar results of OS were observed in sub-group analysis according to treatment line and regimes. No publication bias was detected by Begg's and Egger's tests. CONCLUSIONS: The introduction of MTAs to therapies offers a survival benefit in elderly patients with mCRC. Further studies aimed at this specific patient population are still needed to monitor potential treatment-related toxicities to optimize the use of these drugs. PMID- 26239367 TI - TiO2 nanoparticles functionalized monolithic capillary microextraction online coupled with inductively coupled plasma mass spectrometry for the analysis of Gd ion and Gd-based contrast agents in human urine. AB - In this work, a novel method of TiO2 nanoparticles (NPs) functionalized monolithic capillary microextraction (CME) online coupling with inductively coupled plasma mass spectrometry (ICPMS) was developed for the sequential determination of Gd(3+) and Gd-based contrast agents in human urine samples. The monolithic capillary was prepared by embedding anatase TiO2 NPS in the poly(methacrylic acid-ethylene glycol dimethacrylate) (MAA-EDMA) framework. The Gd(3+) and Gd-based contrast agents (such as gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) and Gd-DTPA-bismethylamide (Gd-DTPA-BMA)) display different adsorption behaviors on the prepared monolithic capillary which possesses the adsorption properties of both anatase TiO2 NPS and poly(MAA-EDMA) monolith. Under the optimized conditions, the limits of detection (LODs) were found to be 3.6, 3.2, and 4.5 ng L(-1) for Gd(3+), Gd-DTPA, and Gd-DTPA-BMA, respectively, which are the lowest up to date. The enrichment factor was 25-fold with the sample throughput of 5 h(-1). The proposed method was validated by the analysis of Gd(3+) and Gd-DTPA in the healthy human urine samples as well as Gd(3+) and Gd-DTPA-BMA in patient urine samples. It was found that only a small amount of the free Gd(3+) was released from Gd-DTPA-BMA, and accurate results could be obtained since no oxidation/reduction or subtraction is involved in this method. This method is simple, sensitive, and rapid and provides a very attractive nonchromatography strategy for the speciation of Gd(3+) and Gd-based contrast agents in urine samples. PMID- 26239368 TI - The barber's pole worm CAP protein superfamily--A basis for fundamental discovery and biotechnology advances. AB - Parasitic worm proteins that belong to the cysteine-rich secretory proteins, antigen 5 and pathogenesis-related 1 (CAP) superfamily are proposed to play key roles in the infection process and the modulation of immune responses in host animals. However, there is limited information on these proteins for most socio economically important worms. Here, we review the CAP protein superfamily of Haemonchus contortus (barber's pole worm), a highly significant parasitic roundworm (order Strongylida) of small ruminants. To do this, we mined genome and transcriptomic datasets, predicted and curated full-length amino acid sequences (n=45), undertook systematic phylogenetic analyses of these data and investigated transcription throughout the life cycle of H. contortus. We inferred functions for selected Caenorhabditis elegans orthologs (including vap-1, vap-2, scl-5 and lon-1) based on genetic networking and by integrating data and published information, and were able to infer that a subset of orthologs and their interaction partners play pivotal roles in growth and development via the insulin like and/or the TGF-beta signalling pathways. The identification of the important and conserved growth regulator LON-1 led us to appraise the three-dimensional structure of this CAP protein by comparative modelling. This model revealed the presence of different topological moieties on the canonical fold of the CAP domain, which coincide with an overall charge separation as indicated by the electrostatic surface potential map. These observations suggest the existence of separate sites for effector binding and receptor interactions, and thus support the proposal that these worm molecules act in similar ways as venoms act as ligands for chemokine receptors or G protein-coupled receptor effectors. In conclusion, this review should guide future molecular studies of these molecules, and could support the development of novel interventions against haemonchosis. PMID- 26239369 TI - The electrical conductivity of Al2O3 under shock-compression. AB - Sapphire (Al2O3) crystals are used below 100 GPa as anvils and windows in dynamic compression experiments because of their transparency and high density. Above 100 GPa shock pressures, sapphire becomes opaque and electrically conducting because of shock-induced defects. Such effects prevent temperature and dc conductivity measurements of materials compressed quasi-isentropically. Opacities and electrical conductivities at ~100 GPa are non-equilibrium, rather than thermodynamic parameters. We have performed electronic structure calculations as a guide in predicting and interpreting shock experiments and possibly to discover a window up to ~200 GPa. Our calculations indicate shocked sapphire does not metallize by band overlap at ~300 GPa, as suggested previously by measured non equilibrium data. Shock-compressed Al2O3 melts to a metallic liquid at ~500 GPa and 10,000 K and its conductivity increases rapidly to ~2000 Omega(-1)cm(-1) at ~900 GPa. At these high shock temperatures and pressures sapphire is in thermal equilibrium. Calculated conductivity of Al2O3 is similar to those measured for metallic fluid H, N, O, Rb, and Cs. Despite different materials, pressures and temperatures, and compression techniques, both experimental and theoretical, conductivities of all these poor metals reach a common end state typical of strong-scattering disordered materials. PMID- 26239370 TI - Erratum to: Interactive X-ray and proton therapy training and simulation. PMID- 26239371 TI - Laser-assisted flat-detector CT-guided intracranial access. AB - PURPOSE: Flat-detector CT can be integrated with C-arm fluoroscopy for CT-guided neurosurgical and endovascular procedures. We studied the accuracy of this technique with laser assistance in targeting intracranial lesions in a cranial model. METHODS: An acrylic scale-model skull containing foam parenchyma was embedded with 2.16-mm-diameter targets. A flat-detector CT was acquired and registered to the skull's position. Ten targets were accessed with biopsy needles under fluoroscopic guidance, flat-detector CT overlay, and laser assistance. Accuracy was measured from the needle tip to the target center using flat detector CT. RESULTS: Ten targets were accessed successfully using XperGuide software. Needles were placed within 1.30 [Formula: see text] 0.63 mm of target isocenter. Accuracy did not vary by entry site, operator, location, or lesion depth. CONCLUSIONS: Laser-assisted flat-detector CT-guided targeting of all intracranial targets was successful with excellent accuracy. This technique can be applied to other minimally invasive neurosurgical procedures. PMID- 26239372 TI - Pattern recognition for cache management in distributed medical imaging environments. AB - PURPOSE: Traditionally, medical imaging repositories have been supported by indoor infrastructures with huge operational costs. This paradigm is changing thanks to cloud outsourcing which not only brings technological advantages but also facilitates inter-institutional workflows. However, communication latency is one main problem in this kind of approaches, since we are dealing with tremendous volumes of data. To minimize the impact of this issue, cache and prefetching are commonly used. The effectiveness of these mechanisms is highly dependent on their capability of accurately selecting the objects that will be needed soon. METHODS: This paper describes a pattern recognition system based on artificial neural networks with incremental learning to evaluate, from a set of usage pattern, which one fits the user behavior at a given time. The accuracy of the pattern recognition model in distinct training conditions was also evaluated. RESULTS: The solution was tested with a real-world dataset and a synthesized dataset, showing that incremental learning is advantageous. Even with very immature initial models, trained with just 1 week of data samples, the overall accuracy was very similar to the value obtained when using 75% of the long-term data for training the models. Preliminary results demonstrate an effective reduction in communication latency when using the proposed solution to feed a prefetching mechanism. CONCLUSIONS: The proposed approach is very interesting for cache replacement and prefetching policies due to the good results obtained since the first deployment moments. PMID- 26239373 TI - Experimental investigation of intravascular OCT for imaging of intracranial aneurysms. AB - PURPOSE: Rupture risk assessment of an intracranial aneurysm (IA) is an important factor for indication of therapy. Until today, there is no suitable objective prediction method. Conventional imaging modalities cannot assess the IA's vessel wall. We investigated the ability of intravascular optical coherence tomography (OCT) as a new tool for the characterization and evaluation of IAs. MATERIALS AND METHODS: An experimental setup for acquisition of geometrical aneurysm parameters was developed. Object of basic investigation was a silicone phantom with six IAs from patient data. For structural information, three circle of Willis were dissected and imaged postmortem. All image data were postprocessed by medical imaging software. RESULTS: Geometrical image data of a phantom with six different IAs were acquired. The geometrical image data showed a signal loss, e.g., in aneurysms with a high bottleneck ratio. Imaging data of vessel specimens were evaluated with respect to structural information that is valuable for the characterization of IAs. Those included thin structures (intimal flaps), changes of the vessel wall morphology (intimal thickening, layers), adjacent vessels, small vessel outlets, arterial branches and histological information. CONCLUSION: Intravascular OCT provides new possibilities for diagnosis and rupture assessment of IAs. However, currently used imaging system parameters have to be adapted and new catheter techniques have to be developed for a complete assessment of the morphology of IAs. PMID- 26239374 TI - A simple approach to harvest of the pedicled descending branch muscle-sparing latissimus dorsi flap. PMID- 26239375 TI - Correlation between indocyanine green (ICG) patterns and real-time elastography images in lower extremity lymphedema patients. AB - BACKGROUND/AIM: Indocyanine green (ICG) lymphography is becoming a popular modality, but unfortunately it is not available in all institutions. Elastography is a relatively new ultrasonographic technique to evaluate tissue elasticity, which visualizes fluid retention as a red region in lymphedema patients. The aim of this study was to evaluate the correlation between elastography and ICG lymphology. METHODS: Thirty-six legs in 18 patients with secondary lower extremity lymphedema (LEL) and 20 legs in 10 healthy volunteers were examined using elastography. Thirty-six legs in 18 secondary LEL patients were examined using ICG lymphography. Elastography was performed on both legs at the following three sites: medial thigh (MT), medial leg (ML), and anterior ankle (AA). The area of the red region in the subcutaneous tissue demonstrated by elastography was calculated using Image software. ICG lymphography findings were classified into the following four patterns: linear (ICG1), splash (ICG2), stardust (ICG3), and diffuse (ICG4) patterns. RESULTS: As ICG pattern progressed, the red region area was likely to increase. There was a correlation between ICG patterns and red region area according to the severity at bilateral MT (rs = 0.665), ML (rs = 0.623), and AA (rs = 0.668). Significant difference was demonstrated among group means of the red region area by analysis of variance (healthy vs. ICG1 vs. ICG2 vs. ICG3 vs. ICG 4: 14.4 +/- 5.7 vs. 15.1 +/- 10.3 vs. 25.2 +/- 6.2 vs. 30.8 +/- 9.4 vs. 35.0 +/- 2.8; P < 0.001). CONCLUSIONS: The area of the red region in the subcutaneous tissue shown using elastography, which represents fluid, increases with the aggravation of lymphedema demonstrated by ICG patterns. As elastography is performed by ultrasonography, which is available in most institutions, elastography could be a useful alternative evaluation for lymphedema severity when ICG lymphography is not available. PMID- 26239376 TI - Diagnosis of trauma-induced lymphedema using indocyanine green lymphography. PMID- 26239377 TI - Internal reliability of the alcohol-related visual probe task is increased by utilising personalised stimuli and eye-tracking. AB - BACKGROUND: In the current study, we investigated whether the internal reliability of the visual probe task measure of attentional bias for substance related cues could be improved by incorporating eye-tracking methods and personalised stimuli. METHOD: Sixty social drinkers completed two visual probe tasks: one with a broad range of different alcohol pictures, the other containing only images of the participants' preferred drink. Attentional bias was inferred from manual reaction times to probes replacing the pictures, and from the duration of eye movement fixations towards the pictures (gaze dwell time). RESULTS: Internal reliability was highest for personalised (versus general) alcohol stimuli, and for eye-tracking (versus manual reaction time) measures of attentional bias. The internal reliability of both reaction time (alpha=.73) and gaze dwell time measures (alpha=.76) of attentional bias for personalised alcohol stimuli was acceptable. Internal reliability of indices of attentional bias for general alcohol stimuli was inferior, although better for the gaze dwell time (alpha=.51) compared to the reaction time measure (alpha=.19). Attentional bias towards personalised stimuli was larger than bias to general stimuli, but only for the reaction time measure. There were no statistically significant associations between measures of attentional bias and alcohol consumption or craving. CONCLUSIONS: Adopting personalised stimuli and eye movement monitoring significantly improves the internal reliability of the alcohol-related visual probe task. PMID- 26239379 TI - One-Dimensional Self-Standing TiO2 Nanotube Array Layers Designed for Perovskite Solar Cell Applications. AB - Nanotube (NT) layers of TiO2 are important one-dimensional nanostructures for advanced applications. ZnO nanowire arrays prepared through electrochemical deposition with tuned morphological properties are converted into anatase TiO2 NTs by using a titanate solution adjusted to an ad hoc pH. The tubes are polycrystalline and their diameter and length can be tuned to obtain nanostructures of tailored dimensions. The layers are integrated in CH3 NH3 PbI3 perovskite solar cells (PSCs). Their morphology is optimized for maximum performance and is compared to mesoscopic TiO2 PSCs. As compared to the latter, the use of NTs improved the perovskite absorbance in the green-to-near-infrared solar spectral region. Moreover, it is shown that the surface treatment of the TiO2 NTs with TiCl4 optimizes the interface between the oxide and CH3 NH3 PbI3 , which leads to better charge injection between the perovskite layer and the TiO2 NTs. The current density-voltage curve hysteresis index is low for the best NT morphology and significantly increases with tube length and diameter. PMID- 26239378 TI - Functional and protein-protein interaction network analysis of colorectal cancer induced by ulcerative colitis. AB - Colorectal cancer (CRC) is a well-recognized complication of ulcerative colitis (UC), and patients with UC have a higher incidence of CRC, compared with the general population. However, the properties of CRC induced by UC have not been clarified using an interaction network to analyze and compare gene sets. In the present study, six microarray datasets of CRC and UC were extracted from the Array Express database, and gene signatures were identified using the genome-wide relative significance (GWRS) method. Functional analysis was performed based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Prediction of the genes and microRNA were performed using a hypergeometric method. A protein protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/proteins, and clusters were obtained through the Molecular Complex Detection algorithm. Topological centrality and a novel analyzing method, based on the rank value of GWGS, were used to characterize the biological importance of the clusters. A total of 217 differentially expressed (DE) genes of CRC were identified, 341 DE genes were identified in UC, and 62 common genes existed in the two. Several KEGG pathways were the same in CRC and UC. Collagenase, progesterone, heparin, urokinase, nadh and adenosine drugs demonstrated potential for use in treatment of CRC and UC. In the PPI network of CRC, 210 nodes and 752 edges were observed, wheras 314 nodes and 882 edges were identified in UC. Cluster 3 in UC had the highest GWGS, while the topological centrality of Cluster 3 in UC had the lowest degree and betweenness. PPI network analysis provided an effective way to estimate and understand the likelihood of the potential connections between proteins/genes. The results obtained following the use of GWGS to analyze differences between clusters did not agree with the topological degree and betweenness centrality, which indicated that gene fold change based GWGS was controversial with degree here in CRC and UC. PMID- 26239380 TI - A multiscale mechanobiological model of bone remodelling predicts site-specific bone loss in the femur during osteoporosis and mechanical disuse. AB - We propose a multiscale mechanobiological model of bone remodelling to investigate the site-specific evolution of bone volume fraction across the midshaft of a femur. The model includes hormonal regulation and biochemical coupling of bone cell populations, the influence of the microstructure on bone turnover rate, and mechanical adaptation of the tissue. Both microscopic and tissue-scale stress/strain states of the tissue are calculated from macroscopic loads by a combination of beam theory and micromechanical homogenisation. This model is applied to simulate the spatio-temporal evolution of a human midshaft femur scan subjected to two deregulating circumstances: (i) osteoporosis and (ii) mechanical disuse. Both simulated deregulations led to endocortical bone loss, cortical wall thinning and expansion of the medullary cavity, in accordance with experimental findings. Our model suggests that these observations are attributable to a large extent to the influence of the microstructure on bone turnover rate. Mechanical adaptation is found to help preserve intracortical bone matrix near the periosteum. Moreover, it leads to non-uniform cortical wall thickness due to the asymmetry of macroscopic loads introduced by the bending moment. The effect of mechanical adaptation near the endosteum can be greatly affected by whether the mechanical stimulus includes stress concentration effects or not. PMID- 26239381 TI - Large-amplitude, short-wave peristalsis and its implications for transport. AB - Valveless, tubular pumps are widespread in the animal kingdom, but the mechanism by which these pumps generate fluid flow is often in dispute. Where the pumping mechanism of many organs was once described as peristalsis, other mechanisms, such as dynamic suction pumping, have been suggested as possible alternative mechanisms. Peristalsis is often evaluated using criteria established in a technical definition for mechanical pumps, but this definition is based on a small-amplitude, long-wave approximation which biological pumps often violate. In this study, we use a direct numerical simulation of large-amplitude, short-wave peristalsis to investigate the relationships between fluid flow, compression frequency, compression wave speed, and tube occlusion. We also explore how the flows produced differ from the criteria outlined in the technical definition of peristalsis. We find that many of the technical criteria are violated by our model: Fluid flow speeds produced by peristalsis are greater than the speeds of the compression wave; fluid flow is pulsatile; and flow speed have a nonlinear relationship with compression frequency when compression wave speed is held constant. We suggest that the technical definition is inappropriate for evaluating peristalsis as a pumping mechanism for biological pumps because they too frequently violate the assumptions inherent in these criteria. Instead, we recommend that a simpler, more inclusive definition be used for assessing peristalsis as a pumping mechanism based on the presence of non-stationary compression sites that propagate unidirectionally along a tube without the need for a structurally fixed flow direction. PMID- 26239382 TI - The Picture-Word Interference Paradigm: Grammatical Class Effects in Lexical Production. AB - Four picture-word interference experiments aimed to test the role of grammatical class in lexical production. In Experiment 1 target nouns and verbs were produced in presence of semantically unrelated distractors that could also be nouns and verbs. Participants were slower when the distractor was of the same grammatical category of the target. To rule out the semantic hypothesis that the effects were due to objects versus actions semantic dichotomy rather than to grammatical class, Experiment 2 was conducted. Participants named target verbs in presence of unrelated action nouns and verbs. The results evidenced a grammatical category effect. Finally, in Experiments 3 and 4, morphologically not derived materials were used to verify the role of morphological information. The results evidenced a syntactic effect independent from morphology. Taken together the results supported the hypothesis that grammatical class information plays a crucial role in lexical production. PMID- 26239383 TI - Coupled aggregation of mitochondrial single-strand DNA-binding protein tagged with Eos fluorescent protein visualizes synchronized activity of mitochondrial nucleoids. AB - Oligomer aggregation of green-to-red photoconvertible fluorescent protein Eos (EosFP) is a natural feature of the wild-type variant. The aim of the present study was to follow up mitochondrial nucleoid behavior under natural conditions of living cells transfected with mitochondrial single-strand DNA-binding protein (mtSSB) conjugated with EosFP. HEPG2 and SH-SY5Y cells were subjected to lentiviral transfection and subsequently immunostained with anti-DNA, anti transcription factor A, mitochondrial (TFAM) or anti-translocase of the inner membrane 23 antibodies. Fluorescent microscopy, conventional confocal microscopy, superresolution biplane fluorescence photo-activation localization microscopy and direct stochastic optical reconstruction microscopy were used for imaging. In the two cell types, apparent couples of equally-sized mtSSB-EosFP-visualized dots were observed. During the time course of the ongoing transfection procedure, however, a small limited number of large aggregates of mtSSB-EosFP-tagged protein started to form in the cells, which exhibited a great co-localization with the noted coupled positions. Antibody staining and 3D immunocytochemistry confirmed that nucleoid components such as TFAM and DNA were co-localized with these aggregates. Furthermore, the observed reduction of the mtDNA copy number in mtSSB EosFP-transfected cells suggested a possible impairment of nucleoid function. In conclusion, the present study demonstrated that coupled nucleoids are synchronized by mtSSB-EosFP overexpression and visualized through their equal binding capacity to mtSSB-EosFP-tagged protein. This observation suggested parallel replication and transcription activity of nucleoid couples native from a parental one. Preserved coupling in late stages of artificial EosFP-mediated aggregation of tagged proteins suggested a rational manner of mitochondrial branching that may be cell-type specifically dependent on hierarchical nucleoid replication. PMID- 26239384 TI - The complex liaison between cachexia and tumor burden (Review). AB - Cachexia is a wasting syndrome that afflicts end-stage cancer patients. Whereas a consensus statement for a definition of cachexia recently has been accomplished, a useful measurement for this condition at present is lacking. The aim of the present review is to discuss the advantage of introducing the measurement of tumor burden for a better overall evaluation of cachexia. Our suggestion ensues from a somewhat novel perspective in the field of infectious disease research where a careful measurement of the pathogen load, between i.e. different host genotypes, leads to the definition of the concept of tolerance to the infectious insult. Indeed tolerance concurs, together the more classical resistance, in maintaining the host reproductive fitness or health state. Noticeably a similar reasoning may apply to tumor biology as well. Whereas the extent of cachexia increases with tumor burden, the relationship between these two correlates of tumor progression fluctuates in a broad range. We have selected from the literature studies in the rodent model where significant variation in the course of the wasting illness during cancer was observed and quantitatively assessed comparing experimental groups marked by different genotype, drug treatment, diet or gender. These studies may be further classified in two categories: the former where the experimental condition associated to milder cachexia is accompanied to a lesser tumor burden, the latter where the inhibition of cachexia results disentangled from the tumor burden, that is the whole number of cancer cells results unchanged or even, paradoxically, is increased. In addition we survey, even in the context of human malignancy, the significance and feasibility of plotting quantitative estimates of cachexia against the whole tumor burden. Ultimately, the principal endeavor of introducing the measurement of tumor burden, in both experimental and clinical oncology, may be to achieve a better assessment of the inter-individual variation in the host vulnerability to cancer cachexia. PMID- 26239385 TI - Concentration Threshold and Amplification Exhibited by a Helicene Oligomer during Helix-Dimer Formation: A Proposal on How a Cell Senses Concentration Changes of a Chemical. AB - Sulfonamidohelicene tetramer (M)-1 exhibits a concentration threshold and amplification phenomena in solution during helix-dimer formation from a random coil. The (M)-tetramer is a random-coil below a threshold concentration, and the concentration of the helix-dimer is irreversibly amplified once the threshold concentration is exceeded. For example, a 15% increase in (M)-tetramer total concentration from 0.6 to 0.7 mM induces an 8-fold increase in the concentration of the helix-dimer, being 8:0.15=53-fold amplification, under temperature oscillation conditions between 47 and 49 degrees C. Experiments without oscillation also exhibit concentration amplification. The threshold and amplification phenomenon involves concentration hysteresis, being away from equilibrium, and self-catalysis. On the basis of this study, a proposal on how a biological cell senses concentration changes of a chemical substance is provided. PMID- 26239386 TI - Potential Therapy for Rheumatoid Arthritis and Sjogren Syndrome With Human Chorionic Gonadotropin. AB - Autoimmune diseases such as rheumatoid arthritis (RA) and Sjogren syndrome (SS) ameliorate during pregnancy, through dampening (immunotolerance) of the maternal immune system which protects the fetus from rejection. A large number of studies have shown that human chorionic gonadotropin (hCG) contributes to this tolerance. Studies on animal models have reaffirmed that hCG treatment mimics the benefits of pregnancy. Based on the scientific evidence, randomized clinical trials comparing hCG with current therapies and/or placebo are recommended for RA, SS, and for other autoimmune diseases such as, type 1 diabetes and ankylosing spondylitis, which also get better during pregnancy and hCG treatment seems to help. PMID- 26239387 TI - Levels of Regulatory Proteins Associated With Cell Proliferation in Endometria From Untreated Patients Having Polycystic Ovarian Syndrome With and Without Endometrial Hyperplasia. AB - Polycystic ovarian syndrome (PCOS) has been associated with endometrial hyperplasia and cancer. The aim of this study was to establish whether the expression of proliferation regulatory proteins in the endometria of patients having PCOS, with or without hyperplasia, differs from control women. Control endometria (CE), patients having PCOS without and with endometrial hyperplasia (PCOSE and HPCOSE, respectively), and that of women with endometrial hyperplasia (HE) were used. The phosphorylated estrogen receptor form (pERalpha), similar to mother against decapentaplegic (SMAD) 2, SMAD3, and SMAD4, vascular epithelial growth factor (VEGF), and phosphorylated SMAD (pSMAD) 2 and pSMAD3 were detected by immunohistochemistry or Western blot. The results show higher levels of pERalpha in HE versus CE (P < .05), while higher VEGF levels were found in PCOSE and HE (P < .05) compared to CE; SMAD2 diminished in HE (P < .05) versus CE. Consequently, the higher levels of VEGF and pERalpha in PCOSE could represent early changes in the progression of PCOSE toward hyperplasia and cancer, whereas changes observed in SMAD proteins support the differential origin of the pathologies of HPCOSE and HE. PMID- 26239388 TI - Cytokine Profiling in the Eutopic Endometrium of Adenomyosis During the Implantation Window After Ovarian Stimulation. AB - In this study, we aimed to clarify the inflammatory cytokine profile of endometrium in patients with adenomyosis during the implantation window after ovarian stimulation. Eighteen patients with adenomyosis and 24 control patients undergoing in vitro fertilization treatment were included in this prospective case-control study. Regular gonadotropin-releasing hormone antagonist protocol was used for ovarian stimulation. Endometrial samples were obtained 7 days after human chorionic gonadotropin (hCG) injection (hCG + 7). Cytokine levels in endometrium secretions from women with and without adenomyosis were assayed by multiplex immunoassay, levels of interleukin (IL) 6 (25.9 +/- 6.6 vs 12.4 +/- 3.4 pg/mL; P = .001), IL-10 (10.4 +/- 2.9 vs 15.6 +/- 4.2 pg/mL; P = .001), IL-17 (11.9 +/- 3.0 vs 14.2 +/- 3.9 pg/mL; P = .046), interferon-gamma (11.7 +/- 3.5 vs 8.0 +/- 3.4 pg/mL; P = .001), and monocyte chemoattractant protein-1 (MCP-1; 37.1 +/- 6.5 vs 16.4 +/- 3.2 pg/mL; P = .001) were significantly different between patients with adenomyosis and control groups, respectively. Immunohistochemistry and quantitative real-time polymerase chain reaction showed that CD-68+, IL-6, and MCP-1 expression were higher and IL-10 was lower in adenomyosis endometrium epithelia compared to controls. In conclusion, within the implantation window of ovarian stimulation cycles, macrophages, IL-6, IL-10, and MCP-1 are expressed differently in the endometrium of women with adenomyosis, which may correlate with compromised endometrium receptivity. We postulated that cytokines of endometrial secretions expressed differently in patients with adenomyosis may contribute to impaired endometrium receptivity in these patients. PMID- 26239389 TI - Differing In Vitro Potencies of Tocolytics and Progesterone in Myometrium From Singleton and Twin Pregnancies. AB - We compared the relaxant effect of 2 known tocolytics; indomethacin and atosiban and progesterone, on pregnant human myometrial spontaneous and oxytocin-induced contractions from singleton and twin pregnancies. All agents exerted a concentration-dependent relaxant effect on myometrial contractions. There was no significant difference in the concentration-response curves between singletons and twins for progesterone or indomethacin on spontaneous contractions or atosiban on oxytocin-induced contraction. Under oxytocin however, the concentration-response curves for indomethacin and progesterone were significantly shifted to the right for both amplitude of contraction (P < .01) and activity integral (P < .01). When compared to singleton myometrium however, the concentration-response curves were significantly shifted to the right in the twin myometrium group (P < .05 progesterone and P < .001 indomethacin). We conclude that a greater concentration of progesterone and indomethacin is required to inhibit oxytocin-induced myometrial contractions in twins compared to singletons in vitro. The differences noted in the tissue pharmacologies may have implications for the successful prevention or inhibition of preterm labor in twin pregnancy. PMID- 26239390 TI - Initial inhomogeneity-induced crazy-clock behavior in the iodate-arsenous acid reaction in a buffered medium under stirred batch conditions. AB - It is unambiguously demonstrated that in the case of an autocatalytic reaction, initial inhomogeneities induced by the imperfectly mixed part of the overall volume may result in a serious irreproducibility of the individual kinetic runs. A statistically meaningful number of repetitions, however, gives rise to a reproducible cumulative probability distribution curve often referred to as a support of the stochastic feature. The iodate-arsenous acid reaction being autocatalytic with respect to both iodide and hydrogen ions displays clock behavior. However, the time lag necessary for the appearance of iodine, even in buffered solution, varies in an apparently random manner. Careful analysis of the variation of the different parameters like stirring rate, overall volume, geometry of the reactor and the way of mixing the reactants led us to conclude that the fate of the individual samples is determined at the initial stage when the reacting system is per se inhomogeneous. The place, the size of the so-called ignition volume, where the reacting system is imperfectly stirred, as well as the residence time spent there by the imperfectly mixed reactants all seem to depend on external factors. PMID- 26239391 TI - Genetic diversity of Italian goat breeds assessed with a medium-density SNP chip. AB - BACKGROUND: Among the European countries, Italy counts the largest number of local goat breeds. Thanks to the recent availability of a medium-density SNP (single nucleotide polymorphism) chip for goat, the genetic diversity of Italian goat populations was characterized by genotyping samples from 14 Italian goat breeds that originate from different geographical areas with more than 50 000 SNPs evenly distributed on the genome. RESULTS: Analysis of the genotyping data revealed high levels of genetic polymorphism and an underlying North-south geographic pattern of genetic diversity that was highlighted by both the first dimension of the multi-dimensional scaling plot and the Neighbour network reconstruction. We observed a moderate and weak population structure in Northern and Central-Southern breeds, respectively, with pairwise FST values between breeds ranging from 0.013 to 0.164 and 7.49 % of the total variance assigned to the between-breed level. Only 2.11 % of the variance explained the clustering of breeds into geographical groups (Northern, Central and Southern Italy and Islands). CONCLUSIONS: Our results indicate that the present-day genetic diversity of Italian goat populations was shaped by the combined effects of drift, presence or lack of gene flow and, to some extent, by the consequences of traditional management systems and recent demographic history. Our findings may constitute the starting point for the development of marker-assisted approaches, to better address future breeding and management policies in a species that is particularly relevant for the medium- and long-term sustainability of marginal regions. PMID- 26239392 TI - Three new HLA-C alleles (HLA-C*14:02:13, HLA-C*15:72 and HLA-C*15:74) in Saudi bone marrow donors. AB - Three new HLA-C alleles were identified by sequence-based typing method (SBT) in donors for the Saudi Bone Marrow Donor Registry (SBMDR). HLA-C*14:02:13 differs from HLA-C*14:02:01 by a silent G to A substitution at nucleotide position 400 in exon 2, where lysine at position 66 remains unchanged. HLA-C*15:72 differs from HLA-C*15:22 by a nonsynonymous C to A substitution at nucleotide position 796 in exon 3, resulting in an amino acid change from phenylalanine to leucine at position 116. HLA-C*15:74 differs from HLA-C*15:08 by a nonsynonymous C to T substitution at nucleotide position 914 in exon 3, resulting in an amino acid change from arginine to tryptophan at position 156. PMID- 26239393 TI - Platelet response to increased aspirin dose in patients with persistent platelet aggregation while treated with aspirin 81 mg. AB - This study demonstrates that patients who are taking 81 mg of aspirin and are nonresponsive benefit from a dose of 162 mg or greater vs a different antiplatelet therapy. We identified 100 patients who were nonresponsive to aspirin 81 mg via whole blood aggregometry and observed how many patients became responsive at a dose of 162 mg or greater. Platelet nonresponsiveness was defined as >10 Omega of resistance to collagen 1 ug/mL and/or an ohms ratio of collagen 1 ug/mL to collagen 5 ug/mL >0.5 and/or >6 Omega to arachidonate. Borderline response was defined as an improvement in 1 but not both of the above criteria. Of the initial 100 patients who were nonresponsive to an aspirin dose of 81 mg, 79% became responsive at a dose of 162 mg or >162 mg. Only 6% did not respond to any increase in dose. We believe that patients treated with low-dose aspirin who have significant risk for secondary vascular events should be individually assessed to determine their antiplatelet response. Those found to have persistent platelet aggregation despite treatment with 81 mg of aspirin have a higher likelihood of obtaining an adequate antiplatelet response at a higher aspirin dose. PMID- 26239394 TI - New tools (DNA barcoding), old hypothesis: the case of the taxonomic identity of the Argentine hakes (Actinopterygii: Merluccius). AB - The present study evaluated the possible occurrence of cryptic species among Merluccidae from Argentina by examining sequences of cytochrome c oxidase subunit I (coI) mtDNA. This approach can discriminate Merluccius hubbsi and Merluccius australis; specimens with morphological diagnostic characters of Merluccius patagonicus formed a cohesive cluster with M. hubbsi specimens. BIN analysis confirmed the effectiveness of barcoding within a global context. PMID- 26239396 TI - Evaluating the efficiency of different recording protocols for entheseal changes in regards to expressing activity patterns using archival data and cross sectional geometric properties. AB - OBJECTIVES: In the past decade there have been extensive discussions on the potential utility of entheseal changes (EC) as activity markers. Nevertheless, no study to date has compared different EC recording protocols with respect to their correlation to activity patterns. MATERIALS AND METHODS: This article records changes on fibrocartilaginous entheses of the upper limbs of 90 male skeletons from the documented Athens Collection using the Hawkey and Merbs (Int J Osteoarchaeol 5 (1995) 324-338), Mariotti et al. (Collegium Antropol 28 (2004) 145-159), and Villotte et al. (Am J Phys Anthropol 142 (2010) 224-234) recording schemes in order to determine which one exhibits the highest correlation with activity. Activity is assessed by means of the recorded profession of each individual, as well as employing cross-sectional geometric properties. Generalized Linear Models are used to explore the impact of age, body mass, and activity on EC expression. RESULTS: Our results agree with previous studies that age is the primary factor determining EC, whereas body mass is the second most influential factor. In contrast, activity in the form of profession or cross sectional geometry rarely showed a significant correlation to EC expression and no clear pattern could be discerned irrespective of the recording technique. However, bilateral differences in the impact of age and body mass in EC expression were traced and may relate to activity patterns. CONCLUSIONS: The differences found in the bilateral impact of age and body mass highlight the fact that the activity patterns of the individuals under examination must play an underlying role to EC expression, though current recording schemes for EC do not capture this, rendering further work in the direction of developing more elaborate recording standards imperative. PMID- 26239395 TI - Molecular docking to explore the possible binding mode of potential inhibitors of thioredoxin glutathione reductase. AB - Praziquantel (PZQ) is the treatment of choice for schistosomiasis, one of the most important but neglected tropical diseases. Recently, however, Schistosoma have exhibited reduced susceptibility to PZQ, and an urgent need to develop new drugs to treat schistosomiasis has emerged. Thioredoxin glutathione reductase (TGR) plays a crucial role in the redox balance of the parasite, combining glutaredoxin (Grx), glutathione reductase and thioredoxin reductase (TR) activities. Several compounds, including oxadiazole 2-oxides, phosphinic acid amides, isoxazolones and phosphoramidites, have been identified as agents that inhibit TGR from Schistosoma mansoni (smTGR) and exhibit anti-schistosomal activity. 4-Phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide has also been shown to be active against TGR from Schistosoma japonicum (sjTGR). The binding sites of these inhibitors, however, remain unclear. To explore the binding interactions of these compounds, we selected six compounds to dock into the NADPH binding site, the active site of the TR domain and the Grx active site of both smTGR and sjTGR using AutoDock 4.2.5.1. The results suggested that the most favoured binding site for all compounds in either sjTGR or smTGR was the oxidised glutathione-binding pocket of the TR domain. Although all of the compounds could fit into the sjTGR site, the inhibition efficiency of these compounds towards sjTGR was marginally lower than it was towards smTGR, suggesting that it would be necessary to design specific inhibitors of TGR for different Schistosoma species. The docking results showed that all compounds docking in smTGR and sjTGR adopted similar binding modes in the TR domain. Two peptide fragments from another subunit, Phe505' Leu508' and Pro572'-Thr577', played a critical role in the interactions with the inhibitors. In conclusion, the present study has revealed binding mechanisms for potential inhibitors of Schistosoma TGRs and could lead to structure-based ligand design and the development of new anti-schistosomiasis drugs. PMID- 26239397 TI - Beyond hepatic hemangiomas: the diverse appearances of gastrointestinal and genitourinary hemangiomas. AB - Hemangiomas are common lesions, best known for their appearance in the liver. Their appearance in less common locations, such as the gastrointestinal and genitourinary tracts, is less well known. We will review the typical and atypical appearance of hemangiomas in these locations on sonography, CT, and MRI. PMID- 26239398 TI - A structured approach to reporting rectal cancer with magnetic resonance imaging. AB - OBJECTIVE: Rectal cancers are the second most common GI carcinoma. Prognosis and therapeutic decisions hinge on the extent of disease. We present a comprehensive structured approach for staging rectal cancer using MRI to ensure the clear, concise, and standardized communication of disease extent to guide optimal treatment planning. CONCLUSION: MRI is crucial for local staging of rectal cancer. A standardized approach to reporting of rectal MRI focused on communication of essential treatment planning and prognostic indicators ensures maximal added value to referring physicians to guide appropriate management. PMID- 26239399 TI - Does focal incidental 18F-FDG PET/CT uptake in the prostate have significance? AB - PURPOSE: (18)F-FDG PET/CT is used to characterize many malignancies, but is not recommended for localized prostate cancer. This study explores the value of multi parametric MRI (mpMRI) in characterizing incidental prostate (18)F-FDG uptake. METHODS: Thirty-one patients who underwent (18)F-FDG PET/CT for reasons unrelated to prostate cancer and prostate mpMRI were eligible for this retrospective study. The mpMRI included T2-weighted (T2W), dynamic contrast enhancement (DCE), apparent diffusion coefficient (ADC), and MR spectroscopy (MRS) sequences. Fourteen patients were excluded (n = 8 insufficient histopathology, n = 6 radical prostatectomy before PET), and final analysis included 17 patients. A nuclear medicine physician, blinded to clinicopathologic findings, identified suspicious areas and maximum standardized uptake values (SUV max) on (18)F-FDG PET/CT. Sector-based imaging findings were correlated with annotated histopathology from whole-mount or MRI/transrectal ultrasound fusion biopsy samples. Positive predictive values (PPVs) were estimated using generalized estimating equations with logit link. Results were evaluated with Kruskal-Wallis and Dunn's multiple comparisons tests. RESULTS: The PPV of (18)F-FDG PET alone in detecting prostate cancer was 0.65. Combining (18)F-FDG PET as a base parameter with mpMRI (T2W, DCE, ADC, and MRS) increased the PPV to 0.82, 0.83, 0.83, and 0.94, respectively. All benign lesions had SUV max < 6. Malignant lesions had higher SUV max values that correlated with Gleason scores. There was a significant difference in SUV max per prostate between the Gleason >= 4 + 5 and benign categories (p = 0.03). CONCLUSIONS: Focal incidental prostate (18)F-FDG uptake has low clinical utility alone, but regions of uptake may harbor high-grade prostate cancer, especially if SUV max > 6. Using mpMRI to further evaluate incidental (18)F-FDG uptake aids the diagnosis of prostate cancer. PMID- 26239400 TI - Wolf-Hirschhorn syndrome: A review and update. AB - Since 4p- was first described in 1961, significant progress has been made in our understanding of this classic deletion disorder. We have been able to establish a more complete picture of the WHS phenotype associated with distal 4p monosomy, and we are working to delineate the phenotypic effects when each gene on distal 4p is hemizygous. Our aim is to provide genotype-specific anticipatory guidance and recommendations to families of individuals with a diagnosis of WHS. In addition, establishing the molecular underpinnings of the disorder will potentially suggest targets for molecular treatments. Thus, the next step is to determine the precise effects of specific gene deletions. As we look forward to deepening our understanding of distal 4p deletion, our focus will continue to be on the establishment of robust genotype-phenotype correlations and the penetrance of these phenotypes. We will continue to follow our WHS cohort closely as they age to determine the presence or absence of some of these comorbidities, including hepatic neoplasms, hematopoietic dysfunction, and recurrence of seizures. We will also continue to refine the critical regions for other phenotypes as we enroll additional (hopefully informative) participants into the research study and as the mechanisms of the genes in these regions are elucidated. New animal models will also be developed to further our understanding of the effects of hemizygosity as well as to serve as models for treatment development. PMID- 26239402 TI - Beyond catheter tip and radiofrequency lesion delivery: the role of robotics in ablation of ventricular tachycardia. PMID- 26239401 TI - Reduction of butyrate- and methane-producing microorganisms in patients with Irritable Bowel Syndrome. AB - The pathophysiology of irritable bowel syndrome (IBS) remains unclear. Here we investigated the microbiome of a large cohort of patients to identify specific signatures for IBS subtypes. We examined the microbiome of 113 patients with IBS and 66 healthy controls. A subset of these participants provided two samples one month apart. We analyzed a total of 273 fecal samples, generating more than 20 million 16S rRNA sequences. In patients with IBS, a significantly lower microbial diversity was associated with a lower relative abundance of butyrate-producing bacteria (P = 0.002; q < 0.06), in particular in patients with IBS-D and IBS-M. IBS patients who did not receive any treatment harboured a lower abundance of Methanobacteria compared to healthy controls (P = 0.005; q = 0.05). Furthermore, significant correlations were observed between several bacterial taxa and sensation of flatulence and abdominal pain (P < 0.05). Altogether, our findings showed that IBS-M and IBS-D patients are characterized by a reduction of butyrate producing bacteria, known to improve intestinal barrier function, and a reduction of methane producing microorganisms a major mechanism of hydrogen disposal in the human colon, which could explain excess of abdominal gas in IBS. PMID- 26239403 TI - Optimization of Analgesics for Greater Exercise Therapy Participation Among Patients With Knee Osteoarthritis and Severe Pain: A Feasibility Study. AB - OBJECTIVE: Severe pain in patients with knee osteoarthritis (OA) hampers the ability to exercise. A protocol for the standardized optimization of analgesics in combination with exercise therapy was developed. The purpose of this protocol was to reduce pain, thereby allowing the patient to participate in exercise therapy. The objective of the present study was to evaluate the feasibility and outcome of the protocol. METHODS: Forty-nine patients with knee OA and severe knee pain (numerical rating scale for pain >=7) were included. Analgesics were prescribed following an incremental protocol. After 6 weeks, a 12-week exercise therapy program was added. Information about analgesic use and exercise therapy content was recorded. Knee pain and activity limitations were assessed at baseline, after 6 weeks, and after 18 weeks. RESULTS: Statistically significant improvements in pain and activity limitations were found in intent-to-treat analysis after 6 weeks of analgesic use and after the intervention was completed. Mean improvements from baseline were 30% (P < 0.001) for pain and 17% (P < 0.001) for activity limitations after the intervention was completed. Seventy-eight percent of the patients were able to exercise according to the protocol. In these patients, exercise therapy following 6 weeks of analgesic use resulted in a further improvement of activity limitations of 10% (P = 0.004). CONCLUSION: The combined intervention of standardized analgesic prescription and exercise therapy allows most patients with knee OA and severe pain to participate in exercise therapy, leading to reduction of pain and activity limitations. These promising results need to be confirmed in a randomized controlled trial. PMID- 26239404 TI - The Birmingham parallel genetic algorithm and its application to the direct DFT global optimisation of Ir(N) (N = 10-20) clusters. AB - A new open-source parallel genetic algorithm, the Birmingham parallel genetic algorithm, is introduced for the direct density functional theory global optimisation of metallic nanoparticles. The program utilises a pool genetic algorithm methodology for the efficient use of massively parallel computational resources. The scaling capability of the Birmingham parallel genetic algorithm is demonstrated through its application to the global optimisation of iridium clusters with 10 to 20 atoms, a catalytically important system with interesting size-specific effects. This is the first study of its type on Iridium clusters of this size and the parallel algorithm is shown to be capable of scaling beyond previous size restrictions and accurately characterising the structures of these larger system sizes. By globally optimising the system directly at the density functional level of theory, the code captures the cubic structures commonly found in sub-nanometre sized Ir clusters. PMID- 26239405 TI - Incorporating the sampling design in weighting adjustments for panel attrition. AB - We review weighting adjustment methods for panel attrition and suggest approaches for incorporating design variables, such as strata, clusters, and baseline sample weights. Design information can typically be included in attrition analysis using multilevel models or decision tree methods such as the chi-square automatic interaction detection algorithm. We use simulation to show that these weighting approaches can effectively reduce bias in the survey estimates that would occur from omitting the effect of design factors on attrition while keeping the resulted weights stable. We provide a step-by-step illustration on creating weighting adjustments for panel attrition in the Galveston Bay Recovery Study, a survey of residents in a community following a disaster, and provide suggestions to analysts in decision-making about weighting approaches. PMID- 26239406 TI - Crosstalk between the TNF and IGF pathways enhances NF-kappaB activation and signaling in cancer cells. AB - BACKGROUND: The receptor for type I insulin like growth factor (IGF-IR) and NFkappaB signaling both play essential roles in cancer initiation and progression but relatively little is known about possible crosstalk between these pathways. We have shown that the IGF-IR could rescue lung and colon carcinoma cells from Tumor necrosis factor -alpha (TauNuF-alpha)-induced apoptosis by activating autocrine, pro-survival IL-6/gp130/STAT3 signaling, suggesting that IGF-IR expression could alter NF-kappaB signaling that is required for transcriptional activation of IL-6. OBJECTIVE: Here we sought to determine if and how IGF-IR signaling promotes TNF-alpha-induced NFkappaB activation. DESIGN: We used lung carcinoma M-27 and colon carcinoma MC-38 cells to investigate IGF-IR-induced changes to the IKK/IkappaBalpha/NFkappaB pathway by a combination of qPCR, Western blotting, electrophoretic mobility shift assay, a reporter assay and gene silencing. RESULTS: We show that in the presence of increased IGF-IR expression or activation levels, nuclear translocation of NFkappaB in response to TNF-alpha was enhanced in lung and colon carcinoma cells and this was due to accelerated phosphorylation and degradation of IkappaBalpha. This effect was AKT-dependent and mediated via mitogen-activated protein kinase kinase kinase 3(MEKK3) activation. CONCLUSION: The results suggest that ligand-mediated activation of IGF-IR alters NF-kappaB signaling in cancer cells in an AKT/MEKK3-dependent manner and that temporal aspects of NF-kappaB activation can regulate the cytokine profile of the tumor cells and thereby, their interaction with the microenvironment. PMID- 26239407 TI - Breeding patterns and cultivated beets origins by genetic diversity and linkage disequilibrium analyses. AB - KEY MESSAGE: Genetic diversity in worldwide population of beets is strongly affected by the domestication history, and the comparison of linkage disequilibrium in worldwide and elite populations highlights strong selection pressure. Genetic relationships and linkage disequilibrium (LD) were evaluated in a set of 2035 worldwide beet accessions and in another of 1338 elite sugar beet lines, using 320 and 769 single nucleotide polymorphisms, respectively. The structures of the populations were analyzed using four different approaches. Within the worldwide population, three of the methods gave a very coherent picture of the population structure. Fodder beet and sugar beet accessions were grouped together, separated from garden beets and sea beets, reflecting well the origins of beet domestication. The structure of the elite panel, however, was less stable between clustering methods, which was probably because of the high level of genetic mixing in breeding programs. For the linkage disequilibrium analysis, the usual measure (r (2)) was used, and compared with others that correct for population structure and relatedness (r S (2) , r V (2) , r VS (2)). The LD as measured by r (2) persisted beyond 10 cM within the elite panel and fell below 0.1 after less than 2 cM in the worldwide population, for almost all chromosomes. With correction for relatedness, LD decreased under 0.1 by 1 cM for almost all chromosomes in both populations, except for chromosomes 3 and 9 within the elite panel. In these regions, the larger extent of LD could be explained by strong selection pressure. PMID- 26239408 TI - The genetic basis of flecking and its relationship to disease resistance in the IBM maize mapping population. AB - KEY MESSAGE: In this paper, we determine the genetic architecture controlling leaf flecking in maize and investigate its relationship to disease resistance and the defense response. Flecking is defined as a mild, often environmentally dependent lesion phenotype observed on the leaves of several commonly used maize inbred lines. Anecdotal evidence suggests a link between flecking and enhanced broad-spectrum disease resistance. Neither the genetic basis underlying flecking nor its possible relationship to disease resistance has been systematically evaluated. The commonly used maize inbred Mo17 has a mild flecking phenotype. The IBM-advanced intercross mapping population, derived from a cross between Mo17 and another commonly used inbred B73, has been used for mapping a number of traits in maize including several related to disease resistance. In this study, flecking was assessed in the IBM population over 6 environments. Several quantitative trait loci for flecking were identified, with the strongest one located on chromosome 6. Low but moderately significant correlations were observed between stronger flecking and higher disease resistance with respect to two diseases, southern leaf blight and northern leaf blight and between stronger flecking and a stronger defense response. PMID- 26239409 TI - Genomic approaches to selection in outcrossing perennials: focus on essential oil crops. AB - The yield of essential oil in commercially harvested perennial species (e.g. 'Oil Mallee' eucalypts, Tea Trees and Hop) is dependent on complex quantitative traits such as foliar oil concentration, biomass and adaptability. These often show large natural variation and some are highly heritable, which has enabled significant gains in oil yield via traditional phenotypic recurrent selection. Analysis of transcript abundance and allelic diversity has revealed that essential oil yield is likely to be controlled by large numbers of quantitative trait loci that range from a few of medium/large effect to many of small effect. Molecular breeding techniques that exploit this information could increase gains per unit time and address complications of traditional breeding such as genetic correlations between key traits and the lower heritability of biomass. Genomic selection (GS) is a technique that uses the information from markers genotyped across the whole genome in order to predict the phenotype of progeny well before they reach maturity, allowing selection at an earlier age. In this review, we investigate the feasibility of genomic selection (GS) for the improvement of essential oil yield. We explore the challenges facing breeders selecting for oil yield, and how GS might deal with them. We then assess the factors that affect the accuracy of genomic estimated breeding values, such as linkage disequilibrium (LD), heritability, relatedness and the genetic architecture of desirable traits. We conclude that GS has the potential to significantly improve the efficiency of selection for essential oil yield. PMID- 26239410 TI - Fine genetic mapping of the white immature fruit color gene w to a 33.0-kb region in cucumber (Cucumis sativus L.). AB - KEY MESSAGE: The white immature fruit color gene w was rapidly mapped to a 33.0 kb region to identify a valuable candidate gene that encodes peroxidase. The skin color of immature fruit is a crucial external trait of cucumbers, and white skin is shared by limited numbers of commercial cultivars. Herein, one BC1 population and two F2 segregating populations were constructed using four inbred parental lines (WD3 * B-2-2 and Q30 * Q24) to investigate the inheritance patterns and chromosomal locations of immature fruit color genes in cucumbers. Consequently, a single recessive gene, w, was identified that controls white immature fruit color. A total of 526 markers, which were derived from published genetic maps, two reference cucumber genomes ("9930" and GY14), and two parents (Q30 and Q24) for which whole-genome sequence information is available, were used to map the target gene w to a 33.0-kb region flanked by two SNP-based markers, ASPCR39262 and ASPCR39229, which are physically located at 39262450 and 39229482 of chromosome 3 ("9930" draft genome assembly), respectively. Gene prediction indicated that four potential genes were located in the target region. One gene that encodes peroxidase is likely to be a valuable candidate gene because quantitative real-time PCR revealed an eightfold difference in its transcriptional level, and several amino acid variations were found when the deduced amino acid sequence was aligned. A co-segregating marker was used synergistically to test its ability to predict the skin colors of 83 dark green/white germplasms, and the validity of its utility in marker-assisted selection was confirmed. Fine mapping of this locus will assist in cloning the gene and in marker-assisted breeding to develop dark green/white cucumber cultivars. PMID- 26239411 TI - Characterization of recombinants of the Aegilops peregrina-derived Lr59 translocation of common wheat. AB - KEY MESSAGE: A compensating, recombined Lr59 translocation with greatly reduced alien chromatin was identified. Microsatellite locus Xdupw217 occurs within the remaining segment and can be used as a co-dominant marker for Lr59. In earlier studies, leaf rust (caused by Puccinia triticina Eriks.) resistance gene Lr59 was transferred from Aegilops peregrina (Hackel) Maire et Weiler to chromosome arm 1AL of common wheat (Triticum aestivum L.). The resistance gene was then genetically mapped on the translocated chromosome segment following homoeologous pairing induction. Eight recombinants that retained the least alien chromatin apparently resulted from crossover within a terminal region of the translocation that was structurally different from 1AL. These recombinants could not be differentiated by size, and it was not clear whether they were compensating in nature. The present study determined that the distal part of the original translocation has group 6 chromosome homoeology and a 6BS telomere (with the constitution of the full translocation chromosome being 1AS.1L(P).6S(P) .6BS). During the allosyndetic pairing induction experiment to map and shorten the full size translocation, a low frequency of quadrivalents involving 1A, the 1A translocation, and two 6B chromosomes was likely formed. Crossover within such quadrivalents apparently produced comparatively small compensating alien chromatin inserts within the 6BS satellite region on chromosome 6B of seven of the eight recombinants. It appears that the Gli-B2 storage protein locus on 6BS has not been affected by the recombination events, and the translocations are therefore not expected to affect baking quality. Simple sequence repeat marker results showed that Lr59-151 is the shortest recombinant, and it will therefore be used in breeding. Marker DUPW217 detects a homoeo-allele within the remaining alien chromatin that can be used for marker-assisted selection of Lr59. PMID- 26239412 TI - Detailed insight into the ultrafast photoconversion of the cyanobacteriochrome Slr1393 from Synechocystis sp. AB - The initial light-induced processes of the photochromic, phycocyanobilin-binding GAF domain of Slr1393 from Synechocystis sp. PCC6803 have been studied by ultrafast transient absorption spectroscopy. We use lifetime density analysis as a model-independent method for the evolution of the experimental data, which gives a comprehensive overview of the excitation wavelength dependence of the photoconversion kinetics. The method is particularly suitable for this highly complex and not purely exponential kinetics. In contrast to previously studied cyanobacteriochromes (CBCRs), here both the red- and the green-absorbing forms show significantly slower reaction dynamics, which proceed also via ground state intermediates. The photoconversion of the green-absorbing form is faster than that of the red state, which allowed a clear detection of the primary photoproduct Lumi-G. Strong coherent oscillations of the recorded transient absorption due to wavepacket motion on the excited state potential energy surface were observed and analyzed for both (red and green) forms of Slr1393g3. The vibrational modes responsible for the coherent oscillations could play a role in the dynamics of the initially heterogeneous excited state (ES) population and direct the system towards the minima on the potential energy surface that determine the ES decay pathway. Furthermore, the coherent oscillations appear to be a common feature of bilin-based photoreceptors and thus deserve further attention. The investigated CBCR exhibits an extraordinary high level of heterogeneity due to the remarkable flexibility of the phycocyanobilin and the protein binding pocket. These properties should allow spectrally tuned response to the light stimuli and thus have significant biological implications. PMID- 26239413 TI - Lipopolysaccharide (LPS) exposure differently affects allergic asthma exacerbations and its amelioration by intranasal curcumin in mice. AB - AIM: Lipopolysaccharide (LPS) is ubiquitous in the environment and can therefore, exacerbate allergic responses. Studies have suggested immunoregulatory effects of LPS according to route, dose and stage of exposure. Present study has examined whether dose and stage of LPS exposure (during sensitization and challenge with OVA) exacerbates airway inflammations, antigen specific-IgE level, histamine release, Th1/Th2 cytokine response. Further, anti-asthmatic potential of curcumin, through intranasal route has been evaluated for the first time in LPS induced airway inflammation in an ovalbumin (OVA)-challenged mouse asthma model. METHODS: Balb/c mice were first sensitized with OVA on 1st and 8th day and exposed to two LPS doses (0.1/1.0 MUg) separately on 2nd day and then further exposed to LPS with OVA-aerosol (from 9 to 14 day). Further, lower LPS dose (0.1 MUg) was chosen for OVA exposed mouse model of asthma exacerbation study. Intranasal curcumin was administered from 9th to 14th day before every LPS exposure. RESULTS: Exposure to LPS (0.1 MUg) exacerbates airway inflammations in terms of IgE level, Th2-cytokine response (IL-4 and IL-5), histamine release, EPO and MPO activities and oxidative stress. Intranasal curcumin has effectively ameliorated airway exacerbations whereas dexamethasone, a known glucocorticosteroid, was not promising as compared to intranasal curcumin. CONCLUSION: Schedule and dose of LPS exposure determines asthma exacerbations and intranasal curcumin could be better immunomodulatory agent in LPS exposed asthma exacerbations. PMID- 26239414 TI - Plasmodium berghei ANKA infection results in exacerbated immune responses from C57BL/6 mice displaying hypothalamic obesity. PMID- 26239415 TI - Transforming growth factor beta 1 (TGF-beta1) modulates Epstein-Barr virus reactivation in absence of Helicobacter pylori infection in patients with gastric cancer. AB - BACKGROUND: Transforming growth factor-beta 1 (TGF-beta1), a multifunctional cytokine, acts as a key factor for Epstein-Barr virus (EBV) reactivation. We investigated the role of TGF-beta1 in latent and lytic stages of EBV in relation to Helicobacter pylori infection among patients with gastric cancer (GC) and peptic ulcer disease (PUD). METHOD: Gastric mucosal TGF-beta1 expression was determined in 95 EBV positive patients with gastroduodenal pathology [GC 40, PUD 19 and non-ulcer dyspepsia (NUD) 36] by quantitative real time PCR. Presence of H. pylori infection was diagnosed when either culture or any two of three tests (RUT, histopathology and specific ureA PCR) were positive. Serum level of TGF beta1 was detected among 60 patients using ELISA. RESULTS: Mucosal TGF-beta1 mRNA expression was detected in 85 of 95 EBV positive patients and it was significantly higher in patients with GC (p=0.042). TGF-beta1 expression tended to be higher among H. pylori non-infected than infected patients (3.80+/-6.24 vs. 2.07+/-2.50, p=0.085). Both mRNA and serum level had significant association with lytic stage of EBV in absence of H. pylori infection when compared with its presence (5.21+/-4.00 vs. 2.29+/-2.89, p=0.040 and 842.00 [669.55] vs. 662.63 [628.76], p=0.049; respectively). CONCLUSION: TGF-beta1 expression was significantly associated with GC. TGF-beta1 was higher both at expression and translational levels in lytic EBV infection without H. pylori suggests that H. pylori infection might play important role in preventing EBV reactivation through attenuated TGF-beta1 expression. This might be a "wise host defense against EBV reactivation". PMID- 26239416 TI - IL-23, rather than IL-17, is crucial for the development of ovalbumin-induced allergic rhinitis. AB - Interleukin-23 (IL-23) and IL-17 are involved in the pathogenesis of allergic rhinitis (AR). However, the roles of IL-23 and IL-17 in ovalbumin (OVA)-induced AR remain unclear. Therefore in this study we aim to investigate the precise roles of IL-23 and IL-17 in a mouse model of OVA-induced AR. We found that during OVA-induced AR, eosinophil and goblet cells in the nose were significantly decreased in IL-23-deficient, but not in IL-17-deficient mice. However, there was no difference in the serum IgE and IgG1 levels between IL-23-deficient or IL-17 deficient and wild-type mice. Moreover, IL-4 levels in lymph node cell culture supernatants were significantly decreased in IL-23-deficient, but not IL-17 deficient, compared with wild-type mice. Furthermore, OVA-induced AR developed similarly in wild-type mice transferred with either IL-23-deficient BM cells or wild-type BM cells. These findings suggest that IL-23, but not IL-17 is crucial for the development of OVA-induced AR, and IL-23 neutralization may be a potential approach for treatment of OVA-induced AR in humans. PMID- 26239417 TI - HLA-B polymorphisms and intracellular assembly modes. AB - Human leukocyte antigen (HLA) class I molecules are ligands for antigen receptors of cytotoxic T cells (CTL) and inhibitory receptors of natural killer (NK) cells. The high degree of HLA class I polymorphism allows for the selection of distinct and diverse sets of antigenic peptide ligands for presentation to CTL. The extensive polymorphisms of the HLA class I genes also result in large variations in their intracellular folding and assembly characteristics. Recent findings indicate that North American HLA-B variants differ significantly in the stabilities of their peptide-deficient forms and in the requirements for the endoplasmic reticulum (ER)-resident factor tapasin for proper assembly. In HIV infected individuals, the presence of tapasin-independent HLA-B allotypes links to more rapid progression to death. Further studies are important to better understand how the intrinsic structural characteristics of HLA class I folding intermediates affect immune responses mediated by CTL and NK cells. PMID- 26239418 TI - Secretory leukocyte protease inhibitor inhibits expression of polymeric immunoglobulin receptor via the NF-kappaB signaling pathway. AB - Polymeric immunoglobulin receptor (pIgR) plays an important role in mucosal immune systems. Secretory immunoglobulin A, composed of secretory component of pIgR and a dimeric form of immunoglobulin A, is secreted on mucosal surfaces and serves as a biological defense factor. pIgR gene expression is reportedly induced by activation of the transcription factor nuclear factor (NF)-kappaB. On the other hand, secretory leukocyte protease inhibitor (SLPI) is a glycoprotein that functions as a serine protease inhibitor. In alveolar epithelial cells, SLPI increases the level of IkappaBbeta, which indicates that it is an inhibitor of NF kappaB at the protein level. Taken together, SLPI may regulate pIgR expression; however, the specific mechanism by which this occurs is unclear. Therefore, the aim of this study was to elucidatethe influence of SLPI on pIgR expression.SLPI and pIgR localized in goblet cells and ciliated epithelial cells of the gastrointestinal tract, respectively. No cells were detected in which SLPI and pIgR were co-expressed. In addition, recombinant human SLPI stimulation of an epithelial cell line (HT-29) decreased the pIgR expression. The pIgR expression was also higher in SLPI-deficient Ca9-22 cells than in wild-type Ca9-22 cells. Furthermore, a luciferase assay using a NF-kappaB reporter plasmid and real-time RT-PCR analysis indicated that when SLPI was present, the transcriptional activity of NF-kappaB protein was suppressed, which was accompanied by anincrease in the protein, but not the mRNA,expression of IkappaBbeta. These results demonstrate that SLPI down-regulates pIgR expression through the NF-kappaB signaling pathway by inhibiting degradation of IkappaBbeta protein. PMID- 26239419 TI - Shikonin reduces TGF-beta1-induced collagen production and contraction in hypertrophic scar-derived human skin fibroblasts. AB - Hypertrophic scarring/hypertrophic scars (HS) is a highly prevalent condition following burns and trauma wounds. Numerous studies have demonstrated that transforming growth factor-beta1 (TGF-beta1) plays an essential role in the wound healing process by regulating cell differentiation, collagen production and extracellular matrix degradation. The increased expression of TGF-beta1 is believed to result in the formation of HS. Shikonin (SHI), an active component extracted from the Chinese herb, Radix Arnebiae, has previously been found to downregulate the expression of TGF-beta1 in keratinocyte/fibroblast co-culture conditioned medium. In view of this, in this study, we aimed to further investigate the effects of SHI on TGF-beta1-stimulated hypertrophic scar-derived human skin fibroblasts (HSFs) and examined the underlying mechanisms. Cell viability and proliferation were measured using alamarBlue and CyQUANT assays. The total amount of collagen and cell contraction were examined using Sirius red staining and the cell contraction assay kit. Gene expression and signalling pathway activation were detected using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Our results revealed that SHI reduced TGF-beta1-induced collagen production through the ERK/Smad signalling pathway and attenuated TGF-beta1-induced cell contraction by downregulating alpha smooth muscle actin (alphaSMA) expression in the HSFs. The data from this study provide evidence supporting the potential use of SHI as a novel treatment for HS. PMID- 26239420 TI - The Methodological Quality of Systematic Reviews and Meta-Analyses on the Effectiveness of Non-pharmacological Cancer Pain Management. AB - This study used the Assessment of Multiple Systematic Reviews (AMSTAR) to determine how the quality of methodologies in systematic reviews (SRs) and meta analyses (MAs) impacts the effectiveness of nonpharmacological cancer pain management. The authors searched 11 electronic databases for published and unpublished studies (in English and Korean) on SRs and MAs relating to "cancer" and "pain management" that were released prior to May 7, 2014. The findings from 17 SRs and MAs were scored for quality using AMSTAR and coded by management type and value of effect size. Only one article was deemed high quality; five were considered to be of low quality. The mean score was 5.47 (SD = 2.03), indicating moderate quality. Among the items we tested via AMSTAR, zero studies stated whether they have a conflict of interest in their covered studies, but every study established the research question and inclusion criteria before constructing the review. Rigorous assessment of nonpharmacological cancer pain management using AMSTAR might contribute to healthcare providers making more informed clinical decisions when it comes to handling pain. Based on the finding, researchers should abide by reporting guidelines for SRs and MAs to ensure that research is more rigorously synthesized. PMID- 26239421 TI - The effectiveness of a 'Code Red' transfusion request policy initiated by pre hospital physicians. AB - BACKGROUND: Major trauma is a leading cause of mortality and serious morbidity. Recent approaches to life-threatening traumatic haemorrhage have emphasized the importance of early blood product transfusion. We have implemented a pre-hospital transfusion request policy where a pre-hospital physician can request the presence of a major transfusion pack on arrival at the destination trauma centre. OBJECTIVES: This study was performed to establish whether three simple criteria (1) suspicion or evidence of active haemorrhage (2) systolic BP<90 mmHg (3) failure of blood pressure to respond to an intravenous fluid bolus) which were used to activate a pre-hospital 'Code Red' transfusion request accurately identified seriously injured patients who required transfusion on arrival at hospital. METHODS: Prospective evaluation of all pre-hospital 'Code Red' requests over a 30-month period (August 2008-May 2011) was performed for patients transported to a major trauma centre. Mechanism of injury, Injury Severity Score, hospital mortality, and use of blood products were recorded. Patients were followed up to hospital discharge. RESULTS: 176 'Code Red' activations were made in the study period. 129 patients were transported to the Trauma Centre. Mechanism of injury was penetrating trauma in 39 (30%) cases, road traffic collision in 58 (45%), falls in 18 (14%) and 'other' in 14 (10.8%). Complete data was available for 126 patients. Of the patients reaching hospital, 20 died in the emergency department or operating theatre, 22 died following admission and 84 survived to hospital discharge. Mean Injury Severity Score (ISS) was 29.1. (range 0-66). Overall, 115 (91%) of the patients declared 'Code Red' pre-hospital received blood product transfusion after arrival in hospital. Eleven patients did not receive any blood products following hospital admission. In patients declared 'Code Red' pre-hospital, mean packed red blood cell transfusion in the first 24-h was 10.4 unit (95% CI 8.4-12.3 unit). CONCLUSIONS: The use of simple pre-hospital criteria allowed physicians to successfully identify trauma patients with severe injury and a requirement for blood product transfusion. This allowed blood products to be ready on the patient's arrival in a major trauma centre with the potential for earlier transfusion. PMID- 26239422 TI - Displaced intracapsular neck of femur fractures in the elderly: bipolar hemiarthroplasty may be the treatment of choice; a case control study. AB - Management of the mobile elderly patient who sustains an intra-capsular neck of femur fracture remains controversial. Current evidence is mixed as to whether total hip arthroplasty (THA), which confers higher surgical and dislocation risk, is significantly superior in function and in reduced rates of reoperation when compared to bipolar hemi-arthroplasty. A group of 110 patients with an intra capsular NOF fracture who had undergone either THA or Bipolar hemi-arthroplasty and were still alive at the time of follow up were retrospectively identified and matched using the National Hip Fracture Database. Matching criteria included ASA, age, sex, pre-op mobility, pre-op AMTS and source of admission. Follow up was by postal questionnaire. Mean follow up was 24 months in both groups (Range; Bipolar 12-36 months, THA 12-38 months). There was no significant difference in pre operative Tonnis grade, postoperative Oxford Hip Score (OHS) or Short Form 36 (SF 36) scores between the two groups. 12 dislocations in 5 patients occurred in the THA group and none in the bipolar group. 33/55 Bipolar patients were discharged to their own home compared to 35/55 in the THA group. None of the bipolar hemi arthroplasties were revised to THA. Higher complication rates were experienced in the THA group with no increase in function. PMID- 26239423 TI - Chemical Penetration Enhancers for Transdermal Drug Delivery - Success and Challenges. AB - Chemical penetration enhancers (CPEs), which are also referred to as sorption promoters or accelerants have several advantages in transdermal drug delivery. These are painlessness, noninvasiveness and the capacity to increase in transdermal flux in comparison with passive diffusion. Several investigators have used a number of chemical enhancers to demonstrate these important properties. Studies have also been carried out to have a better understanding of the mechanisms of penetration enhancement. It has been postulated that these compounds can enhance transdermal drug delivery by perturbing the stratum corneum, increasing partition coefficient or increasing solubility. In this paper, several compounds used in facilitating percutaneous penetration of drugs have been described and the potential of using them for transdermal drug delivery highlighted. Special attention has been paid to cell-penetrating proteins (protein transduction domains) as well as skin penetrating peptides. Ironically, these are substances that possess high molecular weight themselves but are capable of creating pores through which drugs can penetrate into and through the skin. Concerns relating to irritation and cytotoxicity and efforts to overcome them are discussed. PMID- 26239424 TI - Burnout among psychosocial oncologists: an application and extension of the effort-reward imbalance model. AB - OBJECTIVES: Burnout is a significant problem among healthcare professionals working within the oncology setting. This study aimed to investigate predictors of emotional exhaustion (EE) and depersonalisation (DP) in psychosocial oncologists, through the application of the effort-reward imbalance (ERI) model with an additional focus on the role of meaningful work in the burnout process. METHODS: Psychosocial oncology clinicians (n = 417) in direct patient contact who were proficient in English were recruited from 10 international psychosocial oncology societies. Participants completed an online questionnaire, which included measures of demographic and work characteristics, EE and DP subscales of the Maslach Burnout Inventory-Human Services Survey, the Short Version ERI Questionnaire and the Work and Meaning Inventory. RESULTS: Higher effort and lower reward were both significantly associated with greater EE, although not DP. The interaction of higher effort and lower reward did not predict greater EE or DP. Overcommitment predicted both EE and DP but did not moderate the impact of effort and reward on burnout. Overall, the ERI model accounted for 33% of the variance in EE. Meaningful work significantly predicted both EE and DP but accounted for only 2% more of the variance in EE above and beyond the ERI model. CONCLUSIONS: The ERI was only partially supported as a useful framework for investigating burnout in psychosocial oncology professionals. Meaningful work may be a viable extension of the ERI model. Burnout among health professionals may be reduced by interventions aimed at increasing self-efficacy and changes to the supportive work environment. PMID- 26239425 TI - beta- and gamma-Actins in the nucleus of human melanoma A375 cells. AB - Actin is a highly conserved protein that is expressed in all eukaryotic cells and has essential functions in the cytoplasm and the nucleus. Nuclear actin is involved in transcription by all three RNA polymerases, chromatin remodelling, RNA processing, intranuclear transport, nuclear export and in maintenance of the nuclear architecture. The nuclear actin level and polymerization state are important factors regulating nuclear processes such as transcription. Our study shows that, in contrast to the cytoplasm, the majority of endogenous nuclear actin is unpolymerized in human melanoma A375 cells. Most mammalian cells express the two non-muscle beta- and gamma-actin isoforms that differ in only four amino acids. Despite their sequence similarity, studies analysing the cytoplasmic functions of these isoforms demonstrated that beta- and gamma-actins show differences in localization and function. However, little is known about the involvement of the individual actin isoforms in nuclear processes. Here, we used the human melanoma A375 cell line to analyse actin isoforms in regard to their nuclear localization. We show that both beta- and gamma-non-muscle actin isoforms are present in nuclei of these cells. Immunolocalization studies demonstrate that both isoforms co-localize with RNA polymerase II and hnRNP U. However, we observe differences in the ratio of cytoplasmic to nuclear actin distribution between the isoforms. We show that beta-actin has a significantly higher nucleus-to-cytoplasm ratio than gamma-actin. PMID- 26239427 TI - From a reactive to a proactive safety approach. Analysis of medication errors in chemotherapy using general failure types. AB - A better understanding of why medication errors (MEs) occur will mean that we can work proactively to minimise them. This study developed a proactive tool to identify general failure types (GFTs) in the process of managing cytotoxic drugs in healthcare. The tool is based on Reason's Tripod Delta tool. The GFTs and active failures were identified in 60 cases of MEs reported to the Swedish national authorities. The most frequently encountered GFTs were defences, procedures, organisation and design. Working conditions were often the common denominator underlying the MEs. Among the active failures identified, a majority were classified as slips, one-third as mistakes, and for a few no active failure or error could be determined. It was found that the tool facilitated the qualitative understanding of how the organisational weaknesses and local characteristics influence the risks. It is recommended that the tool be used regularly. We propose further development of the GFT tool. We also propose a tool to be further developed into a proactive self-evaluation tool that would work as a complement to already incident reporting and event and risk analyses. PMID- 26239426 TI - Crosstalk between SOXB1 proteins and WNT/beta-catenin signaling in NT2/D1 cells. AB - During early vertebrate embryogenesis, the expression of SOXB1 proteins is precisely regulated by a number of different mechanisms, including Wnt/beta catenin signaling. This is essential for controlling the balance between stemness and differentiation in embryonic stem cells. In the present study, we analyzed the molecular mechanism of LiCl action in NT2/D1 cells and examined the crosstalk between SOXB1 proteins and Wnt signaling in this model system. We have shown that LiCl increases beta-catenin level, induces its translocation to the nucleus and consequently up-regulates beta-catenin/Tcf-dependent transcription in NT2/D1 cells. Our results also suggest that LiCl treatment leads to increased expression of SOX2 and SOX3 proteins in NT2/D1 cells through activation of canonical Wnt signaling. Finally, we have detected a negative feedback loop between beta catenin and SOX2 expression in NT2/D1 cells. Since beta-catenin and SOX2 have been linked to processes of self-renewal and pluripotency, our results have implications for future research on the maintenance of stemness and lineage commitment of embryonic stem cells. PMID- 26239428 TI - Improving chemical safety in the life sciences industry. PMID- 26239429 TI - Clinical correlation of peripheral CD4+-cell sub-sets, their imbalance and Parkinson's disease. AB - Emerging evidence suggests that the peripheral immune system has an active role in the progression of Parkinson's disease (PD). The finding of T-helper (Th; CD4+) cells infiltrating into the substantia nigra in PD patients demonstrated that Th cells are involved in PD. However, the association between peripheral T helper cell sub-sets (Th1, Th2, Treg and Th17) and the sub-set balance (Th1/Th2 and Th17/Treg) and PD has remained elusive. In the present study, sixty PD patients of the First Affiliated Hospital of Bengbu Medical College as well as 40 age- and environment-matched healthy individuals were enrolled. The fraction of CD4+ T cells in the peripheral blood was assessed by automated hematology analysis and its sub-sets (Thl, Th2, Thl7, Treg) were quantified by flow cytometry. The results showed that in the PD group, the proportion of Th1 and Th17 cells was increased, while that of Th2 and Treg cells was decreased. Compared with the control group, the Th1/Th2 and Th17/Treg ratios were significantly enhanced, and shifted towards Th1 and Th17, respectively. Furthermore, this Th1-type response (Th1/Th2 balance shifting towards Th1) were associated with motor function scores determined by Unified Parkinson's Disease Rating Scale III (UPDRS-III) scores. However, no correlation was found between the change in the Th17/Treg cell balance (Th17/Treg balance shifting towards Th1) and UPDRS-III scores. These data supported that chronic immune stimulation, specifically CD4+-cell sub-set imbalance, is linked to PD pathobiology and disease severity. CD4+-cell sub-sets and their imbalance may therefore represent novel biomarkers or therapeutic targets for PD. PMID- 26239430 TI - Live imaging of transgene expression in Cloudman S91 melanoma cells after polyplex-mediated gene delivery. AB - Utilizing nanoparticles made of cationic polymers as gene carriers is a promising approach in cancer gene therapy. One of the major requirements for successful gene delivery is DNA translocation into the nuclei of cancer cells. Nuclear envelope breakdown during mitosis has been considered as the most favorable opportunity for DNA translocation to the nucleus. Here, we aimed to study the influence of mitosis on polyplex-mediated gene delivery using time-lapse microscopy as a safe and accurate tool. Studying of reporter gene expression on a single cell level enabled to confirm the significance of cell division for gene delivery to Cloudman S91 melanoma cells, in spite of minor mitosis-independent transfection, and to discover some important details of polyplex delivery process. We have found that cell division can result in only one post-mitotic transfected cell of the two that could indicate non-uniform distribution of a very small number of intact plasmid DNA between daughter cells. According to our data, the shorter the time interval from polyplex addition to cell division, the longer time is required for the start of reporter gene expression after completed cytokinesis that presumably is a result of gradual polyplex dissociation in cell. Most probably, the development of new gene delivery carriers which would combine the strong ability to protect DNA and ability to release it during mitosis can provide an increase in intact DNA molecule number per cell, uniform DNA distribution between two post-mitotic cells, and fast reporter gene expression resulting in superior transfection of proliferating cells. PMID- 26239431 TI - The link between lipids, statins and cancer: is there a role for cardio-oncology? PMID- 26239433 TI - Corrigendum. AB - Stefan Seidel, Andreas Bock, Werner Schlegel, Arzu Kilic, Gudrun Wagner, Gloria Gelbmann, Almut Hubenthal, Incifer Kanbur, Sofia Natriashvili, Andreas Karwautz, Christian Wober and Cicek Wober-Bingol. Increased RLS prevalence in children and adolescents with migraine: A case-control study. Cephalalgia 2012; 32: 693-699. DOI: 10.1177/0333102412446207. In the published version of this article, Table 2 was printed incorrectly. The authors apologize for this mistake. PMID- 26239432 TI - Role of capsid proteins in parvoviruses infection. AB - The parvoviruses are widely spread in many species and are among the smallest DNA animal viruses. The parvovirus is composed of a single strand molecule of DNA wrapped into an icosahedral capsid. In a viral infection, the massy capsid participates in the entire viral infection process, which is summarized in this review. The capsid protein VP1 is primarily responsible for the infectivity of the virus, and the nuclear localization signal (NLS) of the VP1 serves as a guide to assist the viral genome in locating the nucleus. The dominant protein VP2 provides an "anti-receptor", which interacts with the cellular receptor and leads to the further internalization of virus, and, the N-terminal of VP2 also cooperates with the VP1 to prompt the process of nucleus translocation. Additionally, a cleavage protein VP3 is a part of the capsid, which exists only in several members of the parvovirus family; however, the function of this cleavage protein remains to be fully determined. Parvoviruses can suffer from the extreme environmental conditions such as low pH, or even escape from the recognition of pattern recognition receptors (PRRs), due to the protection of the stable capsid, which is thought to be an immune escape mechanism. The applications of the capsid proteins to the screening and the treatment of diseases are also discussed. The processes of viral infection should be noted, because understanding the virus-host interactions will contribute to the development of therapeutic vaccines. PMID- 26239435 TI - WMA to challenge Indian Medical Association over its support of top Indian doctor for president. PMID- 26239434 TI - Beclin-1 expression is retained in high-grade serous ovarian cancer yet is not essential for autophagy induction in vitro. AB - BACKGROUND: Autophagy is a conserved cellular self-digestion mechanism that can either suppress or promote cancer in a context-dependent manner. In ovarian cancer, prevalent mono-allelic deletion of BECN1 (a canonical autophagy-inducer) suggests that autophagy is impaired to promote carcinogenesis and that Beclin-1 is a haploinsufficient tumor suppressor. Nonetheless, autophagy is known to be readily inducible in ovarian cancer cells. We sought to clarify whether Beclin-1 expression is in fact disrupted in ovarian cancer and whether this impacts autophagy regulation. METHODS: BECN1 expression levels were assessed using The Cancer Genome Atlas (TCGA) datasets from 398 ovarian high-grade serous cystadenocarcinomas (HGSC) and protein immunoblot data from HGSC samples obtained at our institution. Knockdown of BECN1 and other autophagy-related gene expression was achieved using siRNA in established human ovarian cancer cell lines (CaOV3, OVCAR8, SKOV3, and HeyA8) and a novel early-passage, ascites derived cell line (iOvCa147-E2). LC3 immunoblot, autophagic flux assays, transmission electron microscopy and fluorescence microscopy were used to assess autophagy. RESULTS: We observed prevalent mono-allelic BECN1 gene deletion (76%) in TCGA tumors, yet demonstrate for the first time that Beclin-1 protein expression remains relatively unaltered in these and additional samples generated at our institution. Surprisingly, efficient siRNA-mediated Beclin-1 knockdown did not attenuate autophagy induction, whereas knockdown of other autophagy-related genes blocked the process. Beclin-1 knockdown instead decreased cell viability without inducing apoptosis. CONCLUSIONS: Taken together, these data demonstrate that despite its sustained expression, Beclin-1 is dispensable for autophagy induction in ovarian tumor cells in vitro, yet may be retained to promote cell viability by a mechanism independent of autophagy or apoptosis regulation. Overall, this work makes novel observations about tumor expression of Beclin-1 and challenges the accepted understanding of its role in regulating autophagy in ovarian cancer. PMID- 26239436 TI - Molecular and biochemical evidences on the protective effects of triiodothyronine against phosphine-induced cardiac and mitochondrial toxicity. AB - AIM: Aluminum phosphide (AlP) is a widely used fumigant and rodenticide. While AlP ingestion leads to high mortality, its exact mechanism of action is unclear. There are ample evidences suggesting cardioprotective effects of triiodothyronine (T3). In this study, we aimed to examine the potential of T3 in the protection of a rat model of AlP induced cardiotoxicity. MAIN METHODS: In order to induce AlP intoxication animals were intoxicated with AlP (12 mg/kg; LD50) by gavage. In treatment groups, T3 (1, 2 and 3 MUg/kg) was administered intra-peritoneally 30 min after AlP administration. Animals were connected to the electronic cardiovascular monitoring device simultaneously after T3 administration. Then, electrocardiogram (ECG), blood pressure (BP), and heart rate (HR) were monitored for 180 min. Additionally, 24h after AlP intoxication, rats were deceased and the hearts were dissected out for evaluation of oxidative stress, cardiac mitochondrial function (complexes I, II and IV), ATP/ADP ratio, caspases 3 & 9, and apoptosis by flow cytometry. KEY FINDINGS: The results demonstrated that AlP intoxication causes cardiac toxicity presenting with changes in ECG patterns such as decrement of HR, BP and abnormal QRS complexes, QTc and ST height. T3 at a dose of 3 MUg/kg significantly improved ECG and also oxidative stress parameters. Furthermore, T3 administration could increase mitochondrial function and ATP levels within the cardiac cells. In addition, administration of T3 showed a reduction in apoptosis through diminishing the caspase activities and improving cell viability. SIGNIFICANCE: Overall, the present data demonstrate the beneficial effects of T3 in cardiotoxicity of AlP. PMID- 26239437 TI - Regulating G protein activity by lipase-independent functions of phospholipase C. AB - The phosphatidylinositol-specific phospholipase C (PLC) family is known to regulate physiological response through an increase in the levels of cytosolic Ca(2+). PLC hydrolyzes phosphatidylinositol-4, 5-bisphosphate (PIP2) to inositol 1, 4, 5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 releases the stored pool of Ca(2+). DAG stimulates protein kinase C (PKC) activity. An intriguing story is that some PLCs are also GTPase activating proteins (GAPs) or guanine nucleotide exchange factors (GEFs) to regulate the activity of their G protein. GEF and GAPs modulate the G protein GTPase cycle. GEFs catalyze the replacement of GDP with GTP to activate the G protein. GAPs accelerate the GTPase cycle to limit signaling upon removal of the activating ligand. It is not known whether GAP/GEF activity is coupled to the lipase activity of PLC, nor is it clear whether or how lipid factors may contribute to this synergistic interaction. While lipase activity is subject to allosteric regulation by mechanisms that include the signaling phospholipid, phosphatidic acid, regulation of the lipase associated GAP/GEF activity remains unexplored. This review explores the possibilities and evidence that support synergistic lipase-G protein regulatory activity in the PLC-beta, PLC-delta, PLC-epsilon and PLC-gamma subfamilies that may be mediated, in part, through phosphatidic acid. Understanding the full spectrum of PLC activities, and their regulation, is necessary to drive innovation in medicine by identifying novel targets. PMID- 26239438 TI - Sensitivity of glioma initiating cells to a monoclonal anti-EGFR antibody therapy under hypoxia. AB - AIMS: Glioma initiating cells (GICs) represent a subpopulation of tumor cells endowed with self-renewal and multilineage differentiation capacity but also with innate resistance to cytotoxic agents, a feature likely to pose major clinical challenges towards the complete eradication of minimal residual disease in glioma patients. MATERIALS AND METHODS: In this work, GICs were obtained from two patient-derived high-grade gliomas xenograft model, expressing differently EGFR. GICs were exposed to anti-EGFR monoclonal antibody cetuximab during 48h in 1% or 21% oxygen tension. Cell viability and self-renewal capacity were then evaluated as well as their angiogenic properties. KEY FINDINGS: GICs were sensitive to cetuximab only in normoxic condition whatever the EGFR status. Nevertheless, under hypoxia cetuximab was able to decrease the self-renewal capacity as well as the expression of CD133 while expression of GFAP increased. Moreover, cetuximab decreased the effect of GICs on endothelial cell migration under hypoxia. SIGNIFICANCE: Consequently, anti-EGFR therapy can be envisaged to target specifically GICs in order to limit the tumor recurrence. PMID- 26239439 TI - Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management. AB - Long-acting anticoagulant rodenticides (LAARs) inhibit vitamin K epoxide reductase (VKOR). Related bleeding may present a diagnostic challenge and require administration of blood component therapy, hemostatic agents, and vitamin K. This article intends to provide the reader a comprehensive understanding of LAAR poisoning. An exhaustive literature search of PubMed, Science Direct, US National Library of Medicine Toxicology Data Network, and Google Scholar yielded 174 reported cases of LAAR poisoning from which clinical data were extracted and reviewed. In addition, 25 years of epidemiologic data from the American Association of Poison Control Centers was reviewed. In the United States, on average, there were 10413 exposures reported with 2750 patients treated annually. For 25 years, there were 315951 exposures reported with nearly 90% among children and more than 100000 patients treated in a health care facility. Fortunately, only 2% of all exposures result in morbidity or mortality. Inhalational, transcutaneous, and oral routes of exposure have been documented. Most exposures are unintentional. The most frequently reported bleeding sites are mucocutaneous, with hematuria being the most common feature. Deaths were most commonly associated with intracranial hemorrhage. Long-acting anticoagulant rodenticide induced paradoxical thrombosis and thrombotic complications accompanying hemostatic therapy have also been observed. Most patients present with coagulation assay values beyond measurable limits. Long-acting anticoagulant rodenticides have an extremely high affinity for VKOR compared with warfarin, characterized by rebound coagulopathy and bleeding after initial treatment and the need for high-dose, long-term therapy with vitamin K1. Treatment of acute hemorrhagic symptoms often required intravenous vitamin K1 in excess of 50 to 100 mg; chronic maintenance with 100 mg PO vitamin K1 daily was the most frequently used dose required to suppress coagulopathy. Treatment courses averaged 168 days. Adjunctive hemostatic therapy with recombinant factor VIIa and prothrombin complex concentrate has been reported, and phenobarbital has been used to expedite LAAR metabolism. PMID- 26239440 TI - Relationship of proteomic variation and toxin synthesis in the dinoflagellate Alexandrium tamarense CI01 under phosphorus and inorganic nitrogen limitation. AB - Paralytic shellfish toxins (PSTs) are originated from cyanobacteria and dinoflagellates, including Alexandrium tamarense, the common dinoflagellate species. In this study, a toxic dinoflagellate strain of A. tamarense CI01 was selected for studying the PSTs' concentration and the related protein variation during the whole cell cycle under different nutrient conditions. High-performance liquid chromatography, 2-D DIGE and Western blotting were used collectively for protein profiling and identification. Results showed that the toxin content was suppressed under nitrogen limiting condition, but enhanced in phosphorous limiting medium. Based on the results of proteomics analysis, 7 proteins were discovered to be related to the PSTs biosynthesis of A. tamarense CI01, including S-adenosylhomocysteine hydrolase, ornithine cyclodeaminase, argininosuccinate synthase, methyluridine methyltransferase cystine ABC transporter, phosphoserine phosphatase, argininosuccinate synthase and acyl-CoA dehydrogenase, which corresponds to the metabolism of the methionine, cysteine, ornithine, arginine and proline. Moreover, some photosynthesis relating proteins also increased their expression during PST synthesis period in A. tamarense CI01, such as phosphoenolpyruvate carboxylase, chloroplast phosphoglycerate kinase, peridinin chlorophyll alpha-binding protein, Mg(2+) transporter protein and chloroplast phosphoglycerate kinase. The above findings are in support of our hypothesis that these proteins are involved in toxin biosynthesis of A. tamarense CI01, but cause and-effect mechanisms need to be investigated in further studies. PMID- 26239441 TI - Efficient Surface Display of Diisopropylfluorophosphatase (DFPase) in E. coli for Biodegradation of Toxic Organophosphorus Compounds (DFP and Cp). AB - Compounds including organophosphorus pesticides (OPs) and chemical nerve agents are toxic compounds synthesized recently which disrupt the mechanisms of neural transmission. Therefore, a critical requirement is the development of a bio refining technology to facilitate the biodegradation of organophosphorus pollutants. The diisopropylfluorophosphatase (DFPase, EC 3.1.8.2) from the ganglion and brain of Loligo vulgaris acts on P-F bonds present in some OPs. Intracellular production of OPs-degrading enzymes or the use of native bacteria and fungi leads to a low degradation rate of OPs due to a mass transfer issue which reduces the overall catalytic efficiency. To overcome this challenge, we expressed DFPase on the surface of E. coli for the first time by employing the N terminal domain of the ice nucleation protein (InaV-N) as an anchoring motif. Tracking the recombinant protein confirmed that DFPase is successfully located on the outer membrane. Further studies on its activity to degrade diisopropylfluorophosphate (DFP) showed its significant ability for the biodegradation of diisopropylfluorophosphate (DFP) with a specific activity of 500 U/mg of wet cell weight. Recombinant cells could also degrade chlorpyrifos (Cp) with an activity equivalent to a maximum value of 381.44 U/ml with a specific activity of 476.75 U/mg of cell, analyzed using HPLC technique. The optimum activity of purified DFPase was found at 30 degrees C. A more increased activity was also obtained in the presence of glucose-mineral-salt (GMS) supplemented with tryptone and 100 mg/L Co(2+) ion. These results highlight the high potential of the InaV-N anchoring domain to produce an engineered bacterium that can be used in the bioremediation of pesticide-contaminated environments. PMID- 26239442 TI - Immobilization of Acidithiobacillus ferrooxidans on Cotton Gauze for the Bioleaching of Waste Printed Circuit Boards. AB - The bioleaching parameters of metal concentrates from waste printed circuit boards by Acidithiobacillus ferrooxidans immobilized on cotton gauze in a two step reactor were investigated in this study. The results indicated that an average ferrous iron oxidation rate of 0.54 g/(L.h) and a ferrous iron oxidation ratio of 96.90 % were obtained after 12 h at aeration rate of 1 L/min in bio oxidation reactor. After 96 h, the highest leaching efficiency of copper reached 91.68 % under the conditions of the content of the metal powder 12 g/L, the retention time 6 h, and the aeration rate 1 L/min. The bioleaching efficiency of copper could be above 91.12 % under repeated continuous batch operation. Meanwhile, 95.32 % of zinc, 90.32 % of magnesium, 86.31 % of aluminum, and 59.07 % of nickel were extracted after 96 h. All the findings suggested that the recovery of metal concentrates from waste printed circuit boards via immobilization of A. ferrooxidans on cotton gauze was feasible. PMID- 26239443 TI - Probing Phosphorus Efficient Low Phytic Acid Content Soybean Genotypes with Phosphorus Starvation in Hydroponics Growth System. AB - Phosphorus is an essential nutrient required for soybean growth but is bound in phytic acid which causes negative effects on both the environment as well as the animal nutrition. Lowering of phytic acid levels is associated with reduced agronomic characteristics, and relatively little information is available on the response of soybean plants to phosphorus (P) starvation. In this study, we evaluated the effects of different P starvation concentrations on the phytic acid content, growth, and yield of seven mutant genotypes along with the unirradiated control, JS-335, in a hydroponics growth system. The low phytic acid containing mutant genotypes, IR-JS-101, IR-DS-118, and IR-V-101, showed a relatively high growth rate in low P concentration containing nutrient solution (2 MUM), whereas the high P concentration (50 MUM) favored the growth of IR-DS-111 and IR-DS-115 mutant genotypes containing moderate phytate levels. The mutant genotypes with high phytic acid content, IR-DS-122, IR-DS-114, and JS-335, responded well under P starvation and did not have any significant effect on the growth and yield of plants. Moreover, the reduction of P concentration in nutrient solution from 50 to 2 MUM also reduced the phytic acid content in the seeds of all the soybean genotypes under study. The desirable agronomic performance of low phytic acid containing mutant genotype IR-DS-118 reported in this study suggested it to be a P-efficient genotype which could be considered for agricultural practices under P limiting soils. PMID- 26239444 TI - Characterization of Hyaluronan-Degrading Enzymes from Yeasts. AB - Hyaluronidases (HAases) from yeasts were characterized for the first time. The study elucidated that hyaluronate 4-glycanohydrolase and hyaluronan (HA) lyase can be produced by yeasts. Six yeasts producing HAases were found through express screening of activities. The extracellular HAases from two of the yeast isolates, Pseudozyma aphidis and Cryptococcus laurentii, were characterized among them. P. aphidis HAase hydrolyzed beta-1,4 glycosidic bonds of HA, yielding even-numbered oligosaccharides with N-acetyl-D-glucosamine at the reducing end. C. laurentii produced hyaluronan lyase, which cleaved beta-1,4 glycosidic bonds of HA in beta elimination reaction, and the products of HA degradation were different-sized even-numbered oligosaccharides. The shortest detected HA oligomer was dimer. The enzymes' pH and temperature optima were pH 3.0 and 37-45 degrees C (P. aphidis) and pH 6.0 and 37 degrees C (C. laurentii), respectively. Both HAases showed good thermostability. PMID- 26239445 TI - Changes in Concentration and Distribution of Biomarkers in Biodegraded Oils from Dongying Depression, China. AB - The alkane fraction of 11 biodegraded oils and five non-biodegraded oils from the Dongying Depression, Bohai Bay Basin, eastern China, were analyzed by gas chromatography-mass spectrometry to investigate the biomarker alteration caused by biodegradation. Results indicated that the concentration of 25-norhopanes was correlated with increased biodegradation. The oil samples showed an increase in the C31 and C32 hopane 22S/(22S + 22R), C29 sterane C2920S/(20S + 20R), and C29betabeta/(betabeta + alphaalpha) thermal maturity parameters in the heavily biodegraded oils. Oleanane was preferentially biodegraded compared with C3017alpha-hopane, which was preferentially biodegraded compared with C2917alpha, 21beta-norhopane, C30 moretane, and C29 25-norhopane. The selective depletion of C27-C29 steranes followed the order alphaalphaalpha 20R > alphaalphaalpha 20S + alphabetabeta 20R > alphabetabeta 20S and C27 > C29 > C28, and the diasteranes and C20-C21 steranes were much more resistant to biodegradation than regular C27 C29 steranes. The steranes were generally preferentially biodegraded compared with the hopanes in this study. PMID- 26239446 TI - Low-Transition-Temperature Mixtures (LTTMs) for Dissolving Proteins and for Drug Formulation. AB - Several diverse proteins are found to readily dissolve in neat low-transition temperature mixtures (LTTMs). They undergo no irreversible denaturation in such unusual solvents, and the resistance of hen egg-white lysozyme against thermoinactivation in LTTMs is greater than in aqueous solution at extreme pHs. Separately, the water-sensitive drug aspirin is found to form concentrated transparent LTTMs, where it is some 10-fold more stable against cleavage than in water. PMID- 26239447 TI - Pea aphid infestation induces changes in flavonoids, antioxidative defence, soluble sugars and sugar transporter expression in leaves of pea seedlings. AB - The perception of aphid infestation induces highly coordinated and sequential defensive reactions in plants at the cellular and molecular levels. The aim of the study was to explore kinetics of induced antioxidative defence responses in leaf cells of Pisum sativum L.cv. Cysterski upon infestation of the pea aphid Acyrthosiphon pisum at varying population sizes, including accumulation of flavonoids, changes of carbon metabolism, and expression of nuclear genes involved in sugar transport. Within the first 96 h, after A. pisum infestation, flavonoid accumulation and increased peroxidase activity were observed in leaves. The level of pisatin increased after 48 h of infestation and reached a maximum at 96 h. At this time point, a higher concentration of flavonols was observed in the infested tissue than in the control. Additionally, strong post-infestation accumulation of chalcone synthase (CHS) and isoflavone synthase (IFS) transcription products was also found. The levels of sucrose and fructose in 24-h leaves infested by 10, 20, and 30 aphids were significantly lower than in the control. Moreover, in leaves infested by 30 aphids, the reduced sucrose level observed up to 48 h was accompanied by a considerable increase in the expression level of the PsSUT1 gene encoding the sucrose transporter. In conclusion, A. pisum infestation on pea leads to stimulation of metabolic pathways associated with defence. PMID- 26239449 TI - Advancements in the Management of HPV-Associated Head and Neck Squamous Cell Carcinoma. AB - Head and neck carcinomas have long been linked to alcohol and tobacco abuse; however, within the last two decades, the human papillomavirus (HPV) has emerged as a third etiology and is specifically associated with head and neck squamous cell carcinomas (HNSCC). In this anatomical region, the oncogenic HPV-16 mediates transformation and immortalization of epithelium, most commonly in the oropharynx. Nevertheless, the recent identification of novel HPV mechanisms thought to be specific to oropharyngeal carcinogenesis has coincided with observations that HPV-associated HNSCC has differing clinical behavior-in terms of natural history, therapeutic response, and prognosis-than HPV-negative head and neck tumors. Taken together with the growing incidence of HPV transmission in younger populations, these discoveries have sparked a rapid expansion in both laboratory and clinical studies on the infection and disease. Herein, we review the clinical characteristics of HPV-associated HNSCC, with particular emphasis on recent advancements in our understanding of the management of this infectious malignancy. PMID- 26239450 TI - Advancements in Pharmacotherapy for Noncancerous Manifestations of HPV. AB - Human papillomavirus (HPV) is the most common sexually transmitted disease. Via infection of the basal epithelial cells, HPV causes numerous malignancies and noncancerous cutaneous manifestations. Noncancerous cutaneous manifestations of HPV, including common, plantar, plane, and anogenital warts, are among the most common reasons for an office visit. Although there are various therapies available, they are notoriously difficult to treat. HPV treatments can be grouped into destructive (cantharidin, salicylic acid), virucidal (cidofovir, interferon alpha), antimitotic (bleomycin, podophyllotoxin, 5-fluorouracil), immunotherapy (Candida antigen, contact allergen immunotherapy, imiquimod) or miscellaneous (trichloroacetic acid, polyphenon E). The mechanism of action, recent efficacy data, safety profile and recommended regimen for each of these treatment modalities is discussed. PMID- 26239448 TI - Polypoidal Choroidal Vasculopathy in Asians. AB - Age related macular degeneration (AMD) in Asians has been suggested to differ from their Western counterparts in terms of epidemiology, pathogenesis, clinical presentation and treatment. In particular, polypoidal choroidal vasculopathy (PCV) appears to be the predominant subtype of exudative AMD in Asian populations, in contrast to choroidal neovascularization secondary to AMD (CNV AMD) in Western populations. Epidemiological data on PCV has been largely limited to hospital-based studies and there are currently no data on the incidence of PCV. Similarities and differences in risk factor profile between PCV and CNV-AMD point to some shared pathogenic mechanisms but also differential underlying mechanisms leading to the development of each phenotype. Serum biomarkers such as CRP, homocysteine and matrix metalloproteinases suggest underlying inflammation, atherosclerosis and deranged extracellular matrix metabolism as possible pathogenic mechanisms. In addition, recent advances in genome sequencing have revealed differences in genetic determinants of each subtype. While the standard of care for CNV-AMD is anti-vascular endothelial growth factor (VEGF) therapy, photodynamic therapy (PDT) has been the mainstay of treatment for PCV, although long-term visual prognosis remains unsatisfactory. The optimal treatment for PCV requires further clarification, particularly with different types of anti-VEGF agents and possible benefits of reduced fluence PDT. PMID- 26239451 TI - Neuroendocrine Disturbances after Brain Damage: An Important and Often Undiagnosed Disorder. AB - Traumatic brain injury (TBI) is a common and significant public health problem all over the world. Until recently, TBI has been recognized as an uncommon cause of hypopituitarism. The studies conducted during the last 15 years revealed that TBI is a serious cause of hypopituitarism. Although the underlying pathophysiology has not yet been fully clarified, new data indicate that genetic predisposition, autoimmunity and neuroinflammatory changes may play a role in the development of hypopituitarism. Combative sports, including boxing and kickboxing, both of which are characterized by chronic repetitive head trauma, have been shown as new causes of neuroendocrine abnormalities, mainly hypopituitarism, for the first time during the last 10 years. Most patients with TBI-induced pituitary dysfunction remain undiagnosed and untreated because of the non-specific and subtle clinical manifestations of hypopituitarism. Replacement of the deficient hormones, of which GH is the commonest hormone lost, may not only reverse the clinical manifestations and neurocognitive dysfunction, but may also help posttraumatic disabled patients resistant to classical treatment who have undiagnosed hypopituitarism and GH deficiency in particular. Therefore, early diagnosis, which depends on the awareness of TBI as a cause of neuroendocrine abnormalities among the medical community, is crucially important. PMID- 26239452 TI - Immune Pathways in Atopic Dermatitis, and Definition of Biomarkers through Broad and Targeted Therapeutics. AB - Atopic dermatitis (AD) is the most common inflammatory skin disease. Recent research findings have provided an insight into the complex pathogenic mechanisms involved in this disease. Despite a rising prevalence, effective and safe therapeutics for patients with moderate-to-severe AD are still lacking. Biomarkers of lesional, nonlesional skin, and blood have been developed for baseline as well as after treatment with broad and specific treatments (i.e., cyclosporine A and dupilumab). These biomarkers will help with the development of novel targeted therapeutics and assessment of disease reversal, with the promise of a more personalized treatment approach. Since AD involves more than one subtype (i.e., intrinsic/extrinsic, pediatric/adult, etc.), these molecular fingerprints needs to be validated in all subpopulations with AD. PMID- 26239453 TI - Can Novel Treatment of Age-Related Macular Degeneration Be Developed by Better Understanding of Sorsby's Fundus Dystrophy. AB - Sorsby's Fundus Dystrophy (SFD) is a rare autosomal dominant maculopathy that shares many clinical features with Age-Related Macular Degeneration (AMD). It is caused by a mutation in a single gene, TIMP-3, which accumulates in Bruch's membrane (BM). BM thickening and TIMP-3 accumulation can also be found in AMD. From our understanding of the pathophysiology of SFD we hypothesize that BM thickening could be responsible for making the elastic layer vulnerable to invasion by choriocapillaris, thereby leading to choroidal neovascularization in some cases of AMD, whilst in others it could deprive the retinal pigment epithelium of its blood supply, thereby causing geographic atrophy. PMID- 26239454 TI - Diagnosis of Atopic Dermatitis: Mimics, Overlaps, and Complications. AB - Atopic dermatitis (AD) is one of the most common skin diseases affecting infants and children. A smaller subset of adults has persistent or new-onset AD. AD is characterized by pruritus, erythema, induration, and scale, but these features are also typical of several other conditions that can mimic, coexist with, or complicate AD. These include inflammatory skin conditions, infections, infestations, malignancies, genetic disorders, immunodeficiency disorders, nutritional disorders, graft-versus-host disease, and drug eruptions. Familiarity of the spectrum of these diseases and their distinguishing features is critical for correct and timely diagnosis and optimal treatment. PMID- 26239455 TI - Current Cervical Carcinoma Screening Guidelines. AB - A formidable threat to the health of women, cervical carcinoma can be prevented in many cases with adequate screening. The current guidelines for cervical carcinoma screening were created as joint recommendations of the American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP) and the American Society for Clinical Pathology (ASCP) in 2012, and later accepted and promoted by the American Congress of Obstetricians and Gynecologists (ACOG). The 2012 recommendations underscore the utility of molecular testing as an adjunct to cytology screening for certain women and provide guidance to clinicians based on different risk-benefit considerations for different ages. This manuscript will review screening techniques and current recommendations for cervical cancer screening and human papilloma virus (HPV) testing, as well as possible future screening strategies. PMID- 26239456 TI - Hyponatremia Associated with Heart Failure: Pathological Role of Vasopressin Dependent Impaired Water Excretion. AB - An exaggerated increase in circulatory blood volume is linked to congestive heart failure. Despite this increase, reduction of the "effective circulatory blood volume" in congestive heart failure is associated with decreased cardiac output, and can weaken the sensitivity of baroreceptors. Thereafter, tonic inhibition of the baroreceptor-mediated afferent pathway of vagal nerves is removed, providing an increase in non-osmotic release of arginine vasopressin (AVP). In the renal collecting duct, the aquaporin-2 (AQP2) water channel is regulated by sustained elevation of AVP release, and this leads to augmented hydroosmotic action of AVP, that results in exaggerated water retention and dilutional hyponatremia. Hyponatremia is also a predictor for worsening heart failure in patients with known/new onset heart failure. Therefore, such a dilutional hyponatremia associated with organ damage is predictive of the short- and long-term outcome of heart failure. PMID- 26239458 TI - Addisonian Crisis after Missed Diagnosis of Posttraumatic Hypopituitarism. AB - We report a case of a previously undiagnosed panhypopituitarism initially presenting as a full-blown Addisonian crisis with hypoglycemia, hyponatremia, hypotension and neuropsychological symptoms, more than 30 years after a severe traumatic brain injury (TBI). The patient also displayed clearly visible pathognomonic clinical signs of long-standing pituitary dysfunction. The case highlights the importance of being aware of endocrine sequelae even decades after serious TBI. PMID- 26239457 TI - Hypoglycemia in Patients with Diabetes and Renal Disease. AB - This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetic kidney disease and reviews therapeutic limitations in this situation. PMID- 26239459 TI - The Importance of Acidification in Atopic Eczema: An Underexplored Avenue for Treatment. AB - Atopic dermatitis is a form of dermatitis commonly seen in children and adults. Its pathophysiology is complex and is centered on the barrier function of the epidermis. An important aspect of the skin's barrier is pH, which in turn affects a number of parameters such as the skin flora, protease function, and mediators of inflammation and pruritus. Normal pH for non-neonatal skin is acidic and ranges from 4 to 6. Skin pH in atopic dermatitis patients is often increased into the neutral to basic range, and the resulting cascade of changes contributes to the phenotype of atopic dermatitis. Therefore, the maintenance of normal skin pH remains an important topic in understanding and treating atopic dermatitis. This article will review skin pH and its impact on normal barrier function, pathological pH changes in atopic dermatitis, and the therapeutic considerations related to restoring and maintaining pH balance. PMID- 26239460 TI - Clinical Characteristics, Treatments, and Prognosis of Atopic Eczema in the Elderly. AB - Atopic eczema (AE) in the elderly is gradually increasing and has been added to the classification of AE in recent years. This investigation retrospectively analyzed 60 patients with elderly AE. Among the clinical characteristics, a male predominance, existence of several patterns of onset and clinical course, and associations with immunoglobulin (Ig)E-allergic-status and asthmatic complication were observed. The highest positive-rate and positive-score for serum-specific IgE against Dermatophagoides farinae were 83.8% and 2.65 in patients with IgE allergic AE, and a lower incidence of lichenified eczema in the elbow and knee folds were observed. In terms of treatments and outcomes, clinical improvement and clinical remission were observed in 80.8% and 36.5% of cases, respectively, using standard treatments and combined therapy with oral corticosteroid in severe cases. As for complications and final prognosis, most elderly AE patients reached the end of life with AE, but patients with IgE-allergic AE showed significantly lower incidences of complications of malignancy and death from malignancy. These results indicate that AE in the elderly represents a new subgroup of AE with specific features. PMID- 26239461 TI - Renal Biopsy in Type 2 Diabetic Patients. AB - The majority of diabetic patients with renal involvement are not biopsied. Studies evaluating histological findings in renal biopsies performed in diabetic patients have shown that approximately one third of the cases will show pure diabetic nephropathy, one third a non-diabetic condition and another third will show diabetic nephropathy with a superimposed disease. Early diagnosis of treatable non-diabetic diseases in diabetic patients is important to ameliorate renal prognosis. The publication of the International Consensus Document for the classification of type 1 and type 2 diabetes has provided common criteria for the classification of diabetic nephropathy and its utility to stratify risk for renal failure has already been demonstrated in different retrospective studies. The availability of new drugs with the potential to modify the natural history of diabetic nephropathy has raised the question whether renal biopsies may allow a better design of clinical trials aimed to delay the progression of chronic kidney disease in diabetic patients. PMID- 26239462 TI - Biomarkers of Renal Disease and Progression in Patients with Diabetes. AB - Diabetes prevalence is increasing worldwide, mainly due to the increase in type 2 diabetes. Diabetic nephropathy occurs in up to 40% of people with type 1 or type 2 diabetes. It is important to identify patients at risk of diabetic nephropathy and those who will progress to end stage renal disease. In clinical practice, most commonly used markers of renal disease and progression are serum creatinine, estimated glomerular filtration rate and proteinuria or albuminuria. Unfortunately, they are all insensitive. This review summarizes the evidence regarding the prognostic value and benefits of targeting some novel risk markers for development of diabetic nephropathy and its progression. It is focused mainly on tubular biomarkers (neutrophil-gelatinase associated lipocalin, kidney injury molecule 1, liver-fatty acid-binding protein, N-acetyl-beta-d-glucosaminidase), markers of inflammation (pro-inflammatory cytokines, tumour necrosis factor-alpha and tumour necrosis factor-alpha receptors, adhesion molecules, chemokines) and markers of oxidative stress. Despite the promise of some of these new biomarkers, further large, multicenter prospective studies are still needed before they can be used in everyday clinical practice. PMID- 26239463 TI - Hypothalamic-Pituitary Autoimmunity and Traumatic Brain Injury. AB - BACKGROUND: Traumatic brain injury (TBI) is a leading cause of secondary hypopituitarism in children and adults, and is responsible for impaired quality of life, disabilities and compromised development. Alterations of pituitary function can occur at any time after the traumatic event, presenting in various ways and evolving during time, so they require appropriate screening for early detection and treatment. Although the exact pathophysiology is unknown, several mechanisms have been hypothesized, including hypothalamic-pituitary autoimmunity (HP-A). The aim of this study was to systematically review literature on the association between HP-A and TBI-induced hypopituitarism. Major pitfalls related to the HP-A investigation were also discussed. METHODS: The PubMed database was searched with a string developed for this purpose, without temporal or language limits, for original articles assessing the association of HP-A and TBI-induced hypopituitarism. RESULTS: Three articles from the same group met the inclusion criteria. Anti-pituitary and anti-hypothalamic antibodies were detected using indirect immunofluorescence in a significant number of patients with acute and chronic TBI. Elevated antibody titer was associated with an increased risk of persistent hypopituitarism, especially somatotroph and gonadotroph deficiency, while no correlations were found with clinical parameters. CONCLUSION: HPA seems to contribute to TBI-induced pituitary damage, although major methodological issues need to be overcome and larger studies are warranted to confirm these preliminary data. PMID- 26239464 TI - Vitamin D and the Development of Atopic Eczema. AB - A "vitamin D hypothesis" has been proposed to explain the increased prevalence of eczema in regions with higher latitude. This review focuses on the current available evidence with regard to the possible effect of vitamin D on the development of atopic eczema. Observational studies have indicated a link between vitamin D status and eczema outcomes, including lower serum vitamin D levels associated with increased incidence and severity of eczema symptoms. Vitamin D is known to have a regulatory influence on both the immune system and skin barrier function, both critical in the pathogenesis of eczema. However heterogeneous results have been found in studies to date investigating the effect of vitamin D status during pregnancy and infancy on the prevention of eczema outcomes. Well designed, adequately powered, randomised controlled trials are needed. The study design of any new intervention trials should measure vitamin D levels at multiple time points during the intervention, ultraviolet (UV) radiation exposure via the use of individual UV dosimeters, and investigate the role of individual genetic polymorphisms. In conclusion, the current available evidence does not allow firm conclusions to be made on whether vitamin D status affects the development of atopic eczema. PMID- 26239465 TI - Neuropsychology of Neuroendocrine Dysregulation after Traumatic Brain Injury. AB - Endocrine dysfunction is a common effect of traumatic brain injury (TBI). In addition to affecting the regulation of important body functions, the disruption of endocrine physiology can significantly impair mental functions, such as attention, memory, executive function, and mood. This mini-review focuses on alterations in mental functioning that are associated with neuroendocrine disturbances in adults who suffered TBI. It summarizes the contribution of hormones to the regulation of mental functions, the consequences of TBI on mental health and neuroendocrine homeostasis, and the effects of hormone substitution on mental dysfunction caused by TBI. The available empirical evidence suggests that comprehensive assessment of mental functions should be standard in TBI subjects presenting with hormone deficiency and that hormone replacement therapy should be accompanied by pre- and post-assessments. PMID- 26239466 TI - Individualized Treatment of Neovascular Age-Related Macular Degeneration: What are Patients Gaining? Or Losing? AB - The widespread use of drugs that bind diffusible vascular endothelial growth factor (VEGF) has revolutionized the treatment of neovascular age-related macular degeneration (AMD). The pivotal ranibizumab and aflibercept registration trials featured monthly intravitreal injections for 12 months, during which visual acuities and macular edema rapidly improved for the first 3 months and modest gains or stabilization continued until the primary endpoint. In many subsequent trials, patients were evaluated monthly and treated as-needed (PRN) according to the results of visual acuity (VA) testing, fundus examinations and optical coherence tomography scans. Compared to monthly-treated control groups, PRN treated patients require fewer injections during the first year but they also experience smaller VA gains (1-3 letters). A small number of prospective trials that directly compared monthly with PRN therapy showed that VA gains with discontinuous therapy lag slightly behind those achieved with monthly injections. Physicians recognize that monthly office visits with frequent intraocular injections challenge patients' compliance, accrue high drug and professional service costs, and clog office schedules with frequently returning patients. To decrease the numbers of both office visits and anti-VEGF injections without sacrificing VA gains, physicians have embraced the treat-and-extend strategy. Treat-and-extend has not been studied as rigorously as PRN but it has become popular among both vitreoretinal specialists and patients. Despite the possible risks associated with discontinuous therapy (decreased VA and increased macular fluid), most physicians individualize treatment (PRN or treat-and-extend) for the majority of their patients. This review chapter explores the many advantages of individualized therapy, while balancing these against suboptimal responses due to the decreased frequency of anti-VEGF injections. PMID- 26239467 TI - Intracranial CNS Manifestations of Myeloid Sarcoma in Patients with Acute Myeloid Leukemia: Review of the Literature and Three Case Reports from the Author's Institution. AB - Myeloid sarcoma (MS) of the central nervous system (CNS) is a rare presentation of leukemic mass infiltration outside of the bone marrow. It may involve the subperiosteum and dura mater and, on rare occasions, can also invade the brain parenchyma. The disease is most commonly seen in children or young adults; however, it has been described in multiple age groups. MS can be seen in patients with acute myeloid leukemia (AML), chronic myeloid leukemia and other myeloproliferative disorders. This entity has the potential to be underdiagnosed if the MS appearance precedes the first diagnosis of leukemia. The main reason is that their appearance on CT and MRI has a broad differential diagnosis, and proper diagnosis of MS can only be made if the imaging findings are correlated with the clinical history and laboratory findings. Herein, we describe the intracranial CNS manifestations of MS in patients with AML on CT and MRI involving the brain and/or meninges. This study is based on a systematic review of the literature. In addition, three case reports from the author's institution with AML and intracranial involvement of MS are included. Our aim is to enhance the awareness of this entity among both clinicians and radiologists. PMID- 26239468 TI - Pattern of Investigation Reflects Risk Profile in Emergency Medical Admissions. AB - Demand for hospital resources may increase over time; we have examined all emergency admissions (51,136 episodes) from 2005 to 2013 for underlying trends and whether resource utilization and clinical risk are correlated. We used logistic regression of the resource indicator against 30-day in-hospital mortality and adjusted this risk estimate for other outcome predictors. Generally, resource indicators predicted an increased risk of a 30-day in hospital death. For CT Brain the Odds Ratio (OR) was 1.37 (95% CI: 1.27, 1.50), CT Abdomen 3.48 (95% CI: 3.02, 4.02) and CT Chest, Thorax, Abdomen and Pelvis 2.50 (95% CI: 2.10, 2.97). Services allied to medicine including Physiotherapy 2.57 (95% CI: 2.35, 2.81), Dietetics 2.53 (95% CI: 2.27, 2.82), Speech and Language 5.29 (95% CI: 4.57, 6.05), Occupational Therapy 2.65 (95% CI: 2.38, 2.94) and Social Work 1.65 (95% CI: 1.48, 1.83) all predicted an increased risk. The in-hospital 30-day mortality increased with resource utilization, from 4.7% (none) to 27.0% (five resources). In acute medical illness, the use of radiological investigations and allied professionals increased over time. Resource utilization was calibrated from case complexity/30-day in-hospital mortality suggesting that complexity determined the need for and validated the use of these resources. PMID- 26239471 TI - Directionality Effect in Double Conditionals. AB - Directionality effect in deductive reasoning is a very well-known phenomenon that shows that the percentage of forward or backward inferences that participants make depends on the conditional form used. A new extension of the semantic hypothesis (Oberauer & Wilhelm, 2000) is presented to explain the directionality effect in double conditionals with different directionality. This hypothesis claims that the directional effect depends on which term plays the role of relatum. It also makes several novel claims which have been confirmed in three experiments: Experiments 1 and 2 showed there were more forward than backward inferences when the end-term that played the role of relatum was in the first premise, experiment 1: t (45) = 2.73, p < .01, experiment 2: t (38) = 12.06, p < .05, but there were more backward than forward inferences when the end-term that played the role of relatum was in the second premise, experiment 1: t (45) = 2.84, p < .01, experiment 2: t (38) = 2.21, p < .04. Experiment 3 showed that there was no directional effect when both end-terms played the role of relatum, t (34) = 1.39, p = .17, or when both middle-terms (or neither of the end-terms) played the role of relatum, t (34) = .78, p = .44. These experiments confirmed the predictions of the new extension of the semantic hypothesis. PMID- 26239470 TI - A Review of Multidisciplinary Interventions in Atopic Dermatitis. AB - Multidisciplinary interventions have been developed for patients with atopic dermatitis (AD) and their families, with the aim of improving outcomes such as disease control, adherence, and quality of life. We reviewed the content of different multidisciplinary approaches to intervention for AD and evidence for their impact on key outcome measures. We also provided data from our multidisciplinary outpatient program for pediatric AD. Studies included in the review suggest benefits of multidisciplinary interventions as models of treatment or adjuncts to standard medical care, with a positive impact on outcomes including disease severity and itching/scratching. There were limitations to existing studies, including heterogeneous methods used to assess quality of life outcomes across studies and lack of controlled studies assessing the outcome of clinical care programs. Further research will be useful in assessing the impact of multidisciplinary interventions on important outcomes such as treatment adherence and sleep, identifying the elements of multidisciplinary interventions that are most critical for improved outcomes, and identifying the best candidates for multidisciplinary intervention approaches. PMID- 26239472 TI - Cardiac magnetic resonance image-based classification of the risk of arrhythmias in post-myocardial infarction patients. AB - INTRODUCTION: Patients surviving myocardial infarction (MI) can be divided into high and low arrhythmic risk groups. Distinguishing between these two groups is of crucial importance since the high-risk group has been shown to benefit from implantable cardioverter defibrillator insertion; a costly surgical procedure with potential complications and no proven advantages for the low-risk group. Currently, markers such as left ventricular ejection fraction and myocardial scar size are used to evaluate arrhythmic risk. METHODS: In this paper, we propose quantitative discriminative features extracted from late gadolinium enhanced cardiac magnetic resonance images of post-MI patients, to distinguish between 20 high-risk and 34 low-risk patients. These features include size, location, and textural information concerning the scarred myocardium. To evaluate the discriminative power of the proposed features, we used several built-in classification schemes from matrix laboratory (MATLAB) and Waikato environment for knowledge analysis (WEKA) software, including k-nearest neighbor (k-NN), support vector machine (SVM), decision tree, and random forest. RESULTS: In Experiment 1, the leave-one-out cross-validation scheme is implemented in MATLAB to classify high- and low-risk groups with a classification accuracy of 94.44%, and an AUC of 0.965 for a feature combination that captures size, location and heterogeneity of the scar. In Experiment 2 with the help of WEKA, nested cross validation is performed with k-NN, SVM, adjusting decision tree and random forest classifiers to differentiate high-risk and low-risk patients. SVM classifier provided average accuracy of 92.6%, and AUC of 0.921 for a feature combination capturing location and heterogeneity of the scar. Experiment 1 and Experiment 2 show that textural features from the scar are important for classification and that localization features provide an additional benefit. CONCLUSION: These promising results suggest that the discriminative features introduced in this paper can be used by medical professionals, or in automatic decision support systems, along with the recognized risk markers, to improve arrhythmic risk stratification in post-MI patients. PMID- 26239469 TI - Human Papillomavirus: Current and Future RNAi Therapeutic Strategies for Cervical Cancer. AB - Human papillomaviruses (HPVs) are small DNA viruses; some oncogenic ones can cause different types of cancer, in particular cervical cancer. HPV-associated carcinogenesis provides a classical model system for RNA interference (RNAi) based cancer therapies, because the viral oncogenes E6 and E7 that cause cervical cancer are expressed only in cancerous cells. Previous studies on the development of therapeutic RNAi facilitated the advancement of therapeutic siRNAs and demonstrated its versatility by siRNA-mediated depletion of single or multiple cellular/viral targets. Sequence-specific gene silencing using RNAi shows promise as a novel therapeutic approach for the treatment of a variety of diseases that currently lack effective treatments. However, siRNA-based targeting requires further validation of its efficacy in vitro and in vivo, for its potential off target effects, and of the design of conventional therapies to be used in combination with siRNAs and their drug delivery vehicles. In this review we discuss what is currently known about HPV-associated carcinogenesis and the potential for combining siRNA with other treatment strategies for the development of future therapies. Finally, we present our assessment of the most promising path to the development of RNAi therapeutic strategies for clinical settings. PMID- 26239473 TI - Accreditation and improvement in process quality of care: a nationwide study. AB - OBJECTIVE: To examine whether performance measures improve more in accredited hospitals than in non-accredited hospital. DESIGN AND SETTING: A historical follow-up study was performed using process of care data from all public Danish hospitals in order to examine the development over time in performance measures according to participation in accreditation programs. PARTICIPANTS: All patients admitted for acute stroke, heart failure or ulcer at Danish hospitals. INTERVENTION: Hospital accreditation by either The Joint Commission International or The Health Quality Service. MEASUREMENTS: The primary outcome was a change in opportunity-based composite score and the secondary outcome was a change in all or-none scores, both measures were based on the individual processes of care. These processes included seven processes related to stroke, six processes to heart failure, four to bleeding ulcer and four to perforated ulcer. RESULTS: A total of 27 273 patients were included. The overall opportunity-based composite score improved for both non-accredited and accredited hospitals (13.7% [95% CI 10.6; 16.8] and 9.9% [95% 5.4; 14.4], respectively), but the improvements were significantly higher for non-accredited hospitals (absolute difference: 3.8% [95% 0.8; 8.3]). No significant differences were found at disease level. The overall all-or-none score increased significantly for non-accredited hospitals, but not for accredited hospitals. The absolute difference between improvements in the all or-none score at non-accredited and accredited hospitals was not significant (3.2% [95% -3.6:9.9]). CONCLUSIONS: Participating in accreditation was not associated with larger improvement in performance measures for acute stroke, heart failure or ulcer. PMID- 26239474 TI - Quality of primary care by advanced practice nurses: a systematic review. AB - PURPOSE: To conduct a systematic review of randomized controlled trials (RCTs) of the safety and effectiveness of primary care provided by advanced practice nurses (APNs) and evaluate the potential of their deployment to help alleviate primary care shortages. DATA SOURCES: PubMed, Medline and the Cumulative Index to Nursing and Allied Health Literature. STUDY SELECTION: RCTs and their follow-up reports that compared outcomes of care provided to adults by APNs and physicians in equivalent primary care provider roles were selected for inclusion. DATA EXTRACTION: Ten articles (seven RCTs, plus two economic evaluations and one 2 year follow-up study of included RCTs) met inclusion criteria. Data were extracted regarding study design, setting and outcomes across four common categories. RESULTS OF DATA SYNTHESIS: The seven RCTs include data for 10 911 patients who presented for ongoing primary care (four RCTs) or same-day consultations for acute conditions (three RCTs) in the primary care setting. Study follow-up ranged from 1 day to 2 years. APN groups demonstrated equal or better outcomes than physician groups for physiologic measures, patient satisfaction and cost. APNs generally had longer consultations compared with physicians; however, two studies reported that APN patients required fewer consultations over time. CONCLUSION: There were few differences in primary care provided by APNs and physicians; for some measures APN care was superior. While studies are needed to assess longer term outcomes, these data suggest that the APN workforce is well-positioned to provide safe and effective primary care. PMID- 26239475 TI - Why do outcomes of CABG care vary between urban and rural areas in Taiwan? A perspective from quality of care. AB - OBJECTIVE: This study explores the association between coronary artery bypass surgery (CABG) patients' residence and quality of care in terms of 30-day mortality. DESIGN: A retrospective, multilevel study design was conducted using claims data from Taiwan's Universal Health Insurance Scheme. Hospital and surgeon's CABG operation volume, risk-adjusted surgical site infection rate and risk-adjusted 30-day mortality rate in the previous year were adopted as performance indicators, and the level of quality was evaluated via K-means clustering algorithm. Baron and Kenny's procedures for mediation effect were conducted. SETTING: Hospitals in Taiwan. PARTICIPANTS: Patients who underwent CABG surgeries from 1 January 2008 to 30 September 2011 were identified in this study. However, patients who were under the age of 18 years or above the age of 85(n = 164), with missing data for gender (n = 3) or received surgeries from surgeons who never performed any CABG surgeries (n = 27), were excluded. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Thirty-day mortality. RESULTS: There were 9973 CABG surgeries included in this study. Patients who lived in urban areas received better quality of care (28.90 vs. 21.57%) and enjoyed better outcome (4.33 vs. 6.84%). After the procedure of mediation effect testing, the results showed that the relationship between patient residence's urbanization level and 30-day mortality was partially mediated by patterns of quality of care. CONCLUSIONS: The rural-dwelling CABG patients are less likely to approach the better performing healthcare providers, and this tendency indirectly affects their treatment outcomes. Policymakers still need to develop strategies to ensure better equity in access to quality health care. PMID- 26239478 TI - Improving Drug Penetrability with iRGD Leverages the Therapeutic Response to Sorafenib and Doxorubicin in Hepatocellular Carcinoma. AB - iRGD is a derivative of the integrin-binding peptide RGD, which selectively increases the penetrability of tumor tissue to various coadministered substances in several preclinical models. In this study, we investigated the ability of iRGD to improve the delivery of sorafenib and doxorubicin therapy in hepatocellular carcinoma (HCC) using established mouse models of the disease. A contrast enhanced MRI method was developed in parallel to assess the in vivo effects of iRGD in this setting. We found that iRGD improved the delivery of marker substances to the tumors of HCC-bearing mice about three-fold without a parallel increase in normal tissues. Control peptides lacking the critical CendR motif had no effect. Similarly, iRGD also selectively increased the signal intensity from tumors in Gd-DTPA-enhanced MRI. In terms of antitumor efficacy, iRGD coadministration significantly augmented the individual inhibitory effects of sorafenib and doxorubicin without increasing systemic toxicity. Overall, our results offered a preclinical proof of concept for the use of iRGD coadministration as a strategy to widen the therapeutic window for HCC chemotherapy, as monitored by Gd-DTPA-enhanced MRI as a noninvasive, clinically applicable method to identify iRGD-reactive tumors. PMID- 26239479 TI - Thickness controlled proximity effects in C-type antiferromagnet/superconductor heterostructure. AB - Modulation of the superconducting state possessing a C-type antiferromagnetic phase in the Nd0.35Sr0.65MnO3/YBa2Cu3O7 heterostructure is investigated, with the Nd0.35Sr0.65MnO3 thickness (t) varying from 40 to 200 nm. Both the superconducting transition temperature and the upper critical field along the c axis decrease with increasing t; while the in-plane coherence length increases from 2.0 up to 3.6 nm. Meanwhile, the critical current density exhibits a field independent behavior, indicating an enhanced flux pinning effect. Furthermore, low-temperature spin canting induces a breakdown and re-entrance of the superconductivity, demonstrating a dynamic completion between the superconducting pairing and the exchange field. An unexpected colossal magnetoresistance is observed below the superconducting re-entrance temperature at t = 200 nm, which is attributed to the dominant influence of the exchange field over the pairing energy. PMID- 26239477 TI - Cytomegalovirus Immediate-Early Proteins Promote Stemness Properties in Glioblastoma. AB - Glioblastoma (GBM) is the most common and aggressive human brain tumor. Human cytomegalovirus (HCMV) immediate-early (IE) proteins that are endogenously expressed in GBM cells are strong viral transactivators with oncogenic properties. Here, we show how HCMV IEs are preferentially expressed in glioma stem-like cells (GSC), where they colocalize with the other GBM stemness markers, CD133, Nestin, and Sox2. In patient-derived GSCs that are endogenously infected with HCMV, attenuating IE expression by an RNAi-based strategy was sufficient to inhibit tumorsphere formation, Sox2 expression, cell-cycle progression, and cell survival. Conversely, HCMV infection of HMCV-negative GSCs elicited robust self renewal and proliferation of cells that could be partially reversed by IE attenuation. In HCMV-positive GSCs, IE attenuation induced a molecular program characterized by enhanced expression of mesenchymal markers and proinflammatory cytokines, resembling the therapeutically resistant GBM phenotype. Mechanistically, HCMV/IE regulation of Sox2 occurred via inhibition of miR-145, a negative regulator of Sox2 protein expression. In a spontaneous mouse model of glioma, ectopic expression of the IE1 gene (UL123) specifically increased Sox2 and Nestin levels in the IE1-positive tumors, upregulating stemness and proliferation markers in vivo. Similarly, human GSCs infected with the HCMV strain Towne but not the IE1-deficient strain CR208 showed enhanced growth as tumorspheres and intracranial tumor xenografts, compared with mock-infected human GSCs. Overall, our findings offer new mechanistic insights into how HCMV/IE control stemness properties in GBM cells. PMID- 26239480 TI - Characterization of fluorescent NBD-cholesterol efflux in THP-1-derived macrophages. AB - Macrophage cholesterol efflux is important in maintaining cellular lipid homeostasis and preventing the formation of lipid-laden foam cells. Although radioactive [3H]-cholesterol is widely used as a tracer in cholesterol efflux assays, the lengthy and labor-intensive assay procedure, and the radioactivity disposal procedure limit the use of this assay for high-throughput screening. In the present study, a novel procedure using fluorescent N-(7-nitrobenz-2-oxa-1,3 diazol-4-yl)amino)-23,24-bisnor-5-xholen-3beta-ol (NBD)-cholesterol was developed as a substitute for [3H]-cholesterol for the measurement of cholesterol efflux in THP-1-derived macrophages. NBD-cholesterol uptake and metabolism in the THP-1 cells were characterized using fluorescent microscopy and spectrophotometry. NBD cholesterol distributed rapidly into the cell organelles, with the exception of the nucleus. The uptake of NBD-cholesterol in the THP-1 macrophages was concentration- and time-dependent, and reached a plateau following 4 h incubation. The present study subsequently investigated whether NBD-cholesterol efflux was correlated with [3H]-cholesterol efflux in THP-1 derived macrophages and in human peripheral blood mononuclear cells (PBMCs). The results demonstrated that the percentage of efflux of NBD-cholesterol in the THP-1 cells was significantly correlated with that of [3H]-cholesterol, at various concentrations of HDL or apoA-1 as lipid acceptors (R2=0.876 for HDL; R2=0.837 for apoA-1; P<0.001). In the PBMCs, NBD-cholesterol efflux also correlated significantly with [3H]-cholesterol efflux (R2=0.887 for HDL; R2=0.872 for apoA-1; P<0.001). Furthermore, NBD-cholesterol efflux in the THP-1 cells exhibited a similar trend to that obseved in the PBMCs. In conclusion, the results of the present study suggested that fluorescent NBD-cholesterol can be used as a sensitive and specific probe in cholesterol efflux assays in THP-1-derived macrophages. PMID- 26239483 TI - Could in situ DNA-hybridization chain reaction enable simple and effective detection of identity and function in whole cell hybridizations? PMID- 26239482 TI - The effect of caffeine and albuterol on body composition and metabolic rate. AB - OBJECTIVE: Caffeine and ephedrine was an effective combination therapy for weight loss until ephedrine was removed from the market due to safety concerns. This study investigated the combination of caffeine and albuterol as a possibly safer alternative to ephedrine. METHODS: In a series of experiments using cultured adipocytes, rat models, and humans, the effects of caffeine and albuterol on lipolysis, metabolic rate, food intake, and body composition were evaluated. RESULTS: Both caffeine and albuterol enhanced lipolysis in cultured adipocytes. Acute treatment of humans with caffeine and/or albuterol increased resting metabolic rate. Longer-term studies of rats revealed a trend for increased metabolic rate with albuterol treatment. There was increased lean mass gain concurrent with decreased fat mass gain with caffeine/albuterol treatment that was greater than albuterol treatment alone. CONCLUSIONS: In rats, albuterol with caffeine produced significantly greater increases in lean body mass and reductions in fat mass without changes in food intake after 4-8 weeks of treatment. Since caffeine and albuterol are approved for the treatment of asthma in children and adolescents at the doses tested and change body composition without changing food intake, this combination may deserve further exploration for use in treating pediatric obesity. PMID- 26239481 TI - The impact of multimorbidity on adult physical and mental health in low- and middle-income countries: what does the study on global ageing and adult health (SAGE) reveal? AB - BACKGROUND: Chronic diseases contribute a large share of disease burden in low- and middle-income countries (LMICs). Chronic diseases have a tendency to occur simultaneously and where there are two or more such conditions, this is termed as 'multimorbidity'. Multimorbidity is associated with adverse health outcomes, but limited research has been undertaken in LMICs. Therefore, this study examines the prevalence and correlates of multimorbidity as well as the associations between multimorbidity and self-rated health, activities of daily living (ADLs), quality of life, and depression across six LMICs. METHODS: Data was obtained from the WHO's Study on global AGEing and adult health (SAGE) Wave-1 (2007/10). This was a cross-sectional population based survey performed in LMICs, namely China, Ghana, India, Mexico, Russia, and South Africa, including 42,236 adults aged 18 years and older. Multimorbidity was measured as the simultaneous presence of two or more of eight chronic conditions including angina pectoris, arthritis, asthma, chronic lung disease, diabetes mellitus, hypertension, stroke, and vision impairment. Associations with four health outcomes were examined, namely ADL limitation, self-rated health, depression, and a quality of life index. Random intercept multilevel regression models were used on pooled data from the six countries. RESULTS: The prevalence of morbidity and multimorbidity was 54.2 % and 21.9 %, respectively, in the pooled sample of six countries. Russia had the highest prevalence of multimorbidity (34.7 %) whereas China had the lowest (20.3 %). The likelihood of multimorbidity was higher in older age groups and was lower in those with higher socioeconomic status. In the pooled sample, the prevalence of 1+ ADL limitation was 14 %, depression 5.7 %, self-rated poor health 11.6 %, and mean quality of life score was 54.4. Substantial cross-country variations were seen in the four health outcome measures. The prevalence of 1+ ADL limitation, poor self-rated health, and depression increased whereas quality of life declined markedly with an increase in number of diseases. CONCLUSIONS: Findings highlight the challenge of multimorbidity in LMICs, particularly among the lower socioeconomic groups, and the pressing need for reorientation of health care resources considering the distribution of multimorbidity and its adverse effect on health outcomes. PMID- 26239484 TI - Current Advances in Biochemistry, Medicinal Chemistry and Drug Development Strategies for Age-Related Neurodegenerative Diseases. PMID- 26239485 TI - Contrast-enhanced ultrasonography diagnosis of fundal localized type of gallbladder adenomyomatosis. AB - BACKGROUND: Adenomyomatosis of gallbladder is an acquired hyperplastic lesion, characterized by focal or diffuse thickening of the gallbladder with intramural cysts or echogenic areas with comet tail on ultrasonography. But in some cases, especially in the localized fundal type of adenomyomatosis, the intramural anechoic cystic spaces are uncertainty which causes difficult to differential adenomyomatosis from GB cancer. The purpose of this study was to determine the accuracy of real-time contrast-enhanced ultrasonography(CEUS) in the diagnosis of the fundal localized type of gallbladder adenomyomatosis. METHODS: We performed a retrospective study of 21 patients with pathologically proven fundal localized type of gallbladder (GB) adenomyomatosis. All patients underwent preoperative grayscale ultrasound (US) and real-time CEUS examination. The study's reviewers made the diagnosis of adenomyomatosis according to the presence of the focal thickening of the fundal gallbladder wall with intramural cyst or intramural echogenic foci on grayscale US or CEUS. The diagnostic accuracy of US and CEUS was compared. The enhanced pattern and degree of intactness of the GB wall were also recorded. RESULTS: The fundal portion of the GB wall showed localized thickness in all 21 patients. Small anechoic spaces or intramural echogenic foci were detected in 14 (66.7%) and 21 (100 %) of cases respectively, and the intactness of the GB wall's outer hyper-echoic layer was demonstrated in 17 (81%) and 20 (95%) on grayscale US and CEUS, respectively. The accuracy rate of the above two examination modalities was significantly different (p < 0.05). In the arterial phase of the CEUS, areas of focal thickened GB wall were iso-enhanced in 18 cases and hyper-enhanced in 3 cases. All 21 cases appeared to show heterogeneous enhancement with small non-enhancement spaces. The mucosal and serosal layers of the GB wall surrounding the lesions were enhanced, which presented as two "hyper-echoic lines" in the arterial phase of CEUS. In the venous phase of the CEUS, 19 lesions were iso-enhanced and 2 lesions were hypo enhanced. The small non-enhancement spaces were more clearly during the venous phase. CONCLUSION: The small non-enhancement space is a characteristic finding of the fundal localized type of gallbladder adenomyomatosis on CEUS. CEUS could increase the degree of visualization of Rokitansky-Aschoff sinuses (RAS) and intactness of the GB wall, which play an important role in differential diagnosis. PMID- 26239486 TI - Relationship of insight with medication adherence and the impact on outcomes in patients with schizophrenia and bipolar disorder: results from a 1-year European outpatient observational study. AB - BACKGROUND: Many patients with schizophrenia and bipolar disorder have impaired insight and low medication adherence. The aim of this post hoc analysis was to explore the relationship between insight and medication adherence. METHODS: We included 903 patients with schizophrenia or bipolar disorder who participated in an observational study conducted in Europe on the outcomes of patients treated with two oral formulations of olanzapine over a 1-year period. Evaluations included Clinical Global Impression (CGI), Global Assessment of Functioning (GAF), insight (Scale to Assess Unawareness of Mental Disorder, SUMD) medication adherence (Medication Adherence Rating Scale, MARS), and therapeutic alliance (Working Alliance Inventory, WAI). RESULTS: Medication adherence was higher in bipolar patients (mean MARS score (SD) 6.5 (2.8) versus 5.8 (2.7) in schizophrenia; p < 0.001). Patients with schizophrenia had lower insight (i.e., SUMD item 1, unawareness of mental disorder, mean (SD) of 2.5 (1.3) in schizophrenia versus 1.9 (1.2) in bipolar, p < 0.001). Better insight was associated with higher adherence (Spearman Correlation Coefficient, SCC, ranging from 0.39 to 0.49 for the three SUMD general items, p < 0.0001 in all cases). Higher insight was related to a stronger therapeutic alliance (SCC ranging from 0.38 to 0.48, p < 0.0001). A path analysis revealed a positive impact of insight on adherence and alliance and that stronger alliance was related to lower clinical severity (lower CGI score). CONCLUSION: Insight and adherence were found to be closely related. Insight impacts on the therapeutic alliance with mental health professionals. These factors are associated to treatment outcomes. PMID- 26239487 TI - Children Experiencing First-Time or Prolonged Febrile Seizure Are Prone to Stress Hyperglycemia. AB - The risk factors and clinical implications of stress hyperglycemia in children with febrile seizure remain uncertain. Among 479 children with febrile seizure, the prevalence of the stress hyperglycemia (blood glucose concentration >= 150 mg/dL) was 10.0%. Stress hyperglycemia group included larger proportion of first time febrile seizure, prolonged febrile seizure, and smaller proportion of short febrile seizure in comparison with the non-stress hyperglycemia group. Stress hyperglycemia group demonstrated a lower pH and higher lactate levels than the non-stress hyperglycemia group. Multivariate analysis revealed that first-time febrile seizure (aOR = 3.741, P = .004) and prolonged febrile seizure (aOR = 12.855, P < .001) were significant risk factors for stress hyperglycemia. The rate of early febrile seizure recurrence in the emergency department was not different between the groups. These findings suggest that children experiencing first-time or prolonged febrile seizure are prone to stress hyperglycemia, and this can be related to febrile seizure severity. However, stress hyperglycemia is not predictive of early febrile seizure recurrence in the emergency department. PMID- 26239488 TI - Skin Ulcers and Mortality Among Adolescents and Young Adults With Spina Bifida in South Carolina During 2000-2010. AB - The authors investigated 48 deaths (7% death rate) among 690 adolescents and young adults with spina bifida in South Carolina during 2000-2010. The authors used Medicaid and other administrative data and a retrospective cohort design that included people with spina bifida identified using ICD-9 codes. Cox regression models with time-dependent and time-invariant covariates, and Kaplan Meier survival curves were constructed. The authors found that 21.4% of the study group had a skin ulcer during the study period and individuals with skin ulcers had significantly higher mortality than those without ulcers (P < .0001). People who had their first skin ulcer during adolescence had higher mortality than those who had the first skin ulcer during young adulthood (P = .0002; hazard ratio = 10.70, 95% confidence interval for hazard ratio: 3.01, 38.00) and those without skin ulcers, controlling for other covariates. This study showed that age at which individuals first had a skin ulcer was associated with mortality. PMID- 26239489 TI - A Single-Center Experience of CNS Anomalies or Neural Tube Defects in Patients With Jarcho-Levin Syndrome. AB - Jarcho-Levin syndrome (JLS) is a genetic disorder characterized by distinct malformations of the ribs and vertebrae, and/or other associated abnormalities such as neural tube defect, Arnold-Chiari malformation, renal and urinary abnormalities, hydrocephalus, congenital cardiac abnormalities, and extremity malformations. The study included 12 cases at 37-42 weeks of gestation and diagnosed to have had Jarcho-Levin syndrome, Arnold-Chiari malformation, and meningmyelocele. All cases of Jarcho-Levin syndrome had Arnold-Chiari type 2 malformation; there was corpus callosum dysgenesis in 6, lumbosacral meningmyelocele in 6, lumbal meningmyelocele in 3, thoracal meningmyelocele in 3, and holoprosencephaly in 1 of the cases. With this article, the authors underline the neurologic abnormalities accompanying Jarcho-Levin syndrome and that each of these abnormalities is a component of Jarcho-Levin syndrome. PMID- 26239490 TI - Dysregulation of FMRP/mTOR Signaling Cascade in Hypoxic-Ischemic Injury of Premature Human Brain. AB - In this study the authors investigated whether dysregulation of the fragile X mental retardation protein and mammalian target of rapamycin signaling cascade can have a role in the pathogenesis of encephalopathy of prematurity following perinatal hypoxia-ischemia. The authors examined the brain tissue of newborns with encephalopathy and compared it to age-matched controls with normal brain development and adults. In normal controls, the fragile X mental retardation protein expression in cortical gray matter spiked 4-fold during 36-39 gestational weeks compared to the adult, with a concomitant suppression of p70S6K and S6. In encephalopathy cases, the developmental spike of fragile X mental retardation protein was not observed, and fragile X mental retardation protein levels remained significantly lower than in normal controls. Importantly, this fragile X mental retardation protein downregulation was followed by a significant overexpression of p70S6K and S6. These novel findings thus suggest that premature hypoxic-ischemic brain injury can affect the fragile X mental retardation protein/mammalian target of rapamycin pathway, as otherwise observed in inherited syndromes of cognitive disability and autism spectrum disorders. PMID- 26239491 TI - Pediatric Gliomatosis Cerebri: A Review of 15 Years. AB - Gliomatosis cerebri is a rare glial tumor that carries a poor prognosis. Seen in both adults and children, gliomatosis cerebri appears to differ in these populations as with adult versus pediatric glioblastoma. We present 10 children who either presented to the Weill Cornell Medical College or enrolled in the institution's Gliomatosis Cerebri International Registry alongside a cohort of 89 pediatric patients reported in the literature between 2000 and 2014. Age ranged from 4 months to 21 years, with a male to female ratio of 1.71. Median overall survival for patients in the registry cohort was 17 months (n = 10) and for the historic cohort was 13 months (n = 52). Overall survival was analyzed for the combined cohort and was significantly longer when presenting at age >= 10 (20 vs 10 months), for boys (18 vs 11 months), and with low-grade pathology (26.5 vs 12 months) but did not vary significantly by treatment approach. PMID- 26239492 TI - Outcomes of Botulinum Toxin Type A Injection Followed by Rehabilitation in Cases of Cerebral Palsy With Upper Extremity Involvement. AB - We evaluated the efficiency of botulinum toxin type A injection followed by a rehabilitation program including individual therapy, group therapy, and occupational therapy in cases of cerebral palsy with upper extremity involvement. A total of 29 injections were performed on 25 patients, and the patients were placed on rehabilitation program. At 3-month and 6-month assessments, there was a significant improvement in lateral grip strength, 9 Hole Peg test, Upper Limb Physician's Rating Scale and pediatric functional independence measure total scores. There were significant decreases in active range of motion in elbow extension, supination, and wrist extension, and Modified Ashworth Scale in elbow flexion, elbow pronation, and wrist flexion at 6-week, 3-month, and 6-month assessments. Combination of group therapy with traditional therapy methods after injection is effective in cases of cerebral palsy with upper extremity involvement. PMID- 26239493 TI - Age at Referral of Children for Initial Diagnosis of Cerebral Palsy and Rehabilitation: Current Practices. AB - OBJECTIVES: This study describes current practices in the age at referral for diagnosis of cerebral palsy and factors that influence earlier referral. STUDY DESIGN: Retrospective chart review (2002-2012). RESULTS: Of 103 children referred for diagnosis, 81 were referred to a neurologist by other medical specialists at a mean of 13.6 +/- 15.7 months, whereas primary care providers referred much later (mean = 28.8 +/- 27.1 months). Children admitted to the neonatal intensive care unit were referred earlier (mean = 9.3 +/- 10.2 months) than those not (28.1 +/- 24.9 months). Referral to rehabilitation was similarly delayed. CONCLUSIONS: Primary care providers generated a minority of referrals, of concern given their role in developmental surveillance. Remarkably high variability suggests knowledge of cerebral palsy attributes varies widely among service providers. Half of children with cerebral palsy do not have a complicated birth history; subsequently, referrals for diagnosis and management are often delayed. New strategies are needed to optimize prompt referral by primary care providers. PMID- 26239495 TI - An epilogue to lung function and lung disease: state-of-the-art 2015. PMID- 26239496 TI - Editorial Comment. PMID- 26239494 TI - Relative Timing Between Kappa Opioid Receptor Activation and Cocaine Determines the Impact on Reward and Dopamine Release. AB - Negative affective states can increase the rewarding value of drugs of abuse and promote drug taking. Chronic cocaine exposure increases levels of the neuropeptide dynorphin, an endogenous ligand at kappa opioid receptors (KOR) that suppresses dopamine release in the nucleus accumbens (NAc) and elicits negative affective states upon drug withdrawal. However, there is evidence that the effects of KOR activation on affective state are biphasic: immediate aversive effects are followed by delayed increases in reward. The impact of KOR-induced affective states on reward-related effects of cocaine over time is not known. We hypothesize that the initial aversive effects of KOR activation increase, whereas the delayed rewarding effects decrease, the net effects of cocaine on reward and dopamine release. We treated rats with cocaine at various times (15 min to 48 h) after administration of the selective KOR agonist salvinorin A (salvA). Using intracranial self-stimulation and fast scan cyclic voltammetry, we found that cocaine-induced increases in brain stimulation reward and evoked dopamine release in the NAc core were potentiated when cocaine was administered within 1 h of salvA, but attenuated when administered 24 h after salvA. Quantitative real-time PCR was used to show that KOR and prodynorphin mRNA levels were decreased in the NAc, whereas tyrosine hydroxylase and dopamine transporter mRNA levels and tissue dopamine content were increased in the ventral tegmental area 24 h post-salvA. These findings raise the possibility that KOR activation-as occurs upon withdrawal from chronic cocaine-modulates vulnerability to cocaine in a time dependent manner. PMID- 26239498 TI - MicroRNA-210 is upregulated by hypoxia-inducible factor-1alpha in the stromal cells of giant cell tumors of bone. AB - To date, little is known regarding the molecular mechanisms underlying the deregulation of the giant cell tumor of bone (GCTB). Hypoxia has been confirmed to be a characteristic observed in a variety of types of cancer, and a pivotal role for hypoxia-inducible factor-1alpha (HIF-1alpha) has previously been indicated in the hypoxia adaptation of GCTBs. However, another key regulator, microRNA (miR)-210, which is closely correlated with HIF-1alpha, has not previously been identified in GCTBs. The present study therefore selected miR 210, the most significantly upregulated miRNA in hypoxic subtypes of cancer, for investigation in GCTB tissues. Reverse transcription-quantitative polymerase chain reaction was used to evaluate miR-210 expression levels in GCTB tissues and primary GCTB stromal cells. It was revealed that miR-210 and HIF-1alpha were upregulated in GCTB specimens and in primary GCTB stromal cells under hypoxia, and a positive correlation was identified between the two molecules. Furthermore, the promotion of miR-210 expression in primary GCTB stromal cells by hypoxia was HIF-1alpha-dependent. To the best of our knowledge, the present study was the first to identify the overexpression of miR-210 in an HIF-1alpha-dependent manner in GCTB specimens, suggesting an adaptive response to hypoxia in GCTB. PMID- 26239499 TI - Visualizing fluoride ion in mitochondria and lysosome of living cells and in living mice with positively charged ratiometric probes. AB - Two ratiometric probes fluoride ion, Mito-F and Lyso-F, were rationally designed and synthesized with positive charges at physiological conditions. The positive charges functioned as target moieties for subcellular mitochondria and lysosome of living cells, and effective sequesters of fluoride ion for fast and efficient fluorescent detection. In addition, in vivo imaging of fluoride ion in living mice was successfully achieved for the first time using probe Mito-F. PMID- 26239500 TI - Ovarian cancer in BRCA1/2 mutation carriers: The impact of mutation position and family history on the cancer risk. AB - OBJECTIVES: Assessing the combined impact of mutation position, regarding the ovarian cancer cluster region (OCCR), and type of cancer family history (FH) on age-related penetrance of ovarian cancer (OC) in women from BRCA1/2 families from the northern Netherlands. STUDY DESIGN: A consecutive series of 1763 mutation carriers and their first-degree relatives from 355 proven BRCA1/2 families with a history of breast and/or ovarian cancer with in total 248 OC cases was included. Mutations were stratified for gene (BRCA1 or BRCA2) and location (within or outside the OCCR). FH was stratified for type of cancer occurring in first and second-degree relatives (OC only, breast cancer (BC) only or both OC and BC). MAIN OUTCOME MEASURES: Cox-proportional hazard models were applied to estimate the OCCR effect, including and excluding a FH of cancer. RESULTS: Among BRCA1 families, OC risks were higher in women with OCCR mutations versus those with non OCCR mutations (HR=1.59, 95%CI=1.19-2.12). This effect remained significant after adjustment for the type of FH (HR=1.50, 95%CI=1.11-2.01). In BRCA2 families, mutation position did not significantly affect the OC risk (HR=1.50, 95%CI=0.74 3.04). However, in the BRCA2 group, a FH including only OC presented by itself a strong impact on OC risk (HR=4.63, 95%CI=2.38-9.02), which remained stable after adjustment for mutation position (HR=4.48, 95%CI=2.28-8.81). CONCLUSION: OCCR mutations significantly increased the OC risk in BRCA1 families regardless of the type of FH, but in BRCA2 families, type of FH seems to have a higher impact than mutation position on OC risk. PMID- 26239502 TI - Joint interaction of ethidium bromide and methylene blue with DNA. The effect of ionic strength on binding thermodynamic parameters. AB - Large amount of data of experimental and theoretical studies have shown that ethidium bromide (EtBr) and methylene blue (MB) may bind to nucleic acids via three modes: intercalation between two adjacent base pairs, insertion into the plane between neighboring bases in the same strand (semi-intercalation), and outside binding with negatively charged backbone phosphate groups. The aim of the given research is to examine the behavior of these two ligands at both separate and joint DNA binding. The obtained experimental data show that the effect of simultaneous binding of EtBr and MB on double-stranded DNA has a non-additive effect of separate binding. The analyses of the melting thermodynamic parameters of DNA complexes with two bound ligands suggest competitive mechanism of interaction. PMID- 26239503 TI - Drug-Polymer Interactions in Hydrogel-based Drug-Delivery Systems: An Experimental and Theoretical Study. AB - In drug-delivery systems, drug transport is a key step, but the interpretation of the transport mechanism is still controversial. Here, we investigated a promising hydrogel library loaded with the anticonvulsant drug ethosuximide (ESM). The self diffusion coefficient of ESM was measured using two methods: a direct and advanced measurement with a pulsed field gradient spin-echo (PFGSE) method, using an NMR spectrometer equipped with high-resolution magic angle spinning (HR-MAS) probe, and an indirect one based on fitting in vitro drug-delivery data. Starting from the experimental data a mathematical model without fitted parameters was developed and all the phenomena involved, that is, adsorption and diffusion, were considered. At low drug concentrations, adsorption prevails and consequently the diffusivity in the gels is lower than that in water. At high drug concentrations, where all adsorption sites are saturated, the diffusion in the gels is similar to that in a water solution. This study may pave the way for better device design. PMID- 26239504 TI - Human recombinant endostatin Endostar attenuates hepatic sinusoidal endothelial cell capillarization in CCl4-induced fibrosis in mice. AB - The aim of the present study was to detect the effect of the recombinant human endostatin Endostar on hepatic sinusoidal capillarization in CCl4-induced murine models of liver fibrosis. The liver fibrosis model was induced in BALB/c mice using intraperitoneal injection of CCl4 for 6 weeks. Animals were divided into the following six treatment groups: Group 1, normal animals; group 2, CCl4 induced liver fibrosis; group 3, CCl4+Endostar 20 mg/kg/day for 6 weeks; group 4, CCl4+Endostar 10 mg/kg/day for 6 weeks; group 5, CCl4+Endostar 20 mg/kg/day for 4 weeks; and group 6, CCl4+Endostar 10 mg/kg/day for 4 weeks. The average number of fenestrae per hepatic sinusoid was determined using transmission electron microscopy. Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) 1 and 2 expression was detected by western blot analysis. There were significant differences in the number of fenestrae per sinusoid between the normal control and untreated model fibrotic mice (P<0.01), and between the untreated model and Endostar-treated mice (P<0.05). Endostar treatment was associated with reduced levels of VEGFR1 and VEGFR2 in liver tissues (P<0.01), as well as with decreased hepatic sinusoidal endothelial cell capillarization in CCl4-induced mouse models of liver fibrosis, and this effect may involve the VEGF pathway. However, further studies are required to confirm its involvement in other causes of liver fibrosis. PMID- 26239501 TI - Alternative Sampling Strategies for Cytochrome P450 Phenotyping. AB - Interindividual variability in the expression and function of drug metabolizing cytochrome P (CYP) 450 enzymes, determined by a combination of genetic, non genetic and environmental parameters, is a major source of variable drug response. Phenotyping by administration of a selective enzyme substrate, followed by the determination of a specific phenotyping metric, is an appropriate approach to assess the in vivo activity of CYP450 enzymes as it takes into account all influencing factors. A phenotyping protocol should be as simple and convenient as possible. Typically, phenotyping metrics are determined in traditional matrices, such as blood, plasma or urine. Several sampling strategies have been proposed as an alternative for these traditional sampling techniques. In this review, we provide a comprehensive overview of available methods using dried blood spots (DBS), hair, oral fluid, exhaled breath and sweat for in vivo CYP450 phenotyping. We discuss the relation between phenotyping metrics measured in these samples and those in conventional matrices, along with the advantages and limitations of the alternative sampling techniques. Reliable phenotyping procedures for several clinically relevant CYP450 enzymes, including CYP1A2, CYP2C19 and CYP2D6, are currently available for oral fluid, breath or DBS, while additional studies are needed for other CYP450 isoforms, such as CYP3A4. The role of hair analysis for this purpose remains to be established. Being non- or minimally invasive, these sampling strategies provide convenient and patient-friendly alternatives for classical phenotyping procedures, which may contribute to the implementation of CYP450 phenotyping in clinical practice. PMID- 26239505 TI - Low-field Switching Four-state Nonvolatile Memory Based on Multiferroic Tunnel Junctions. AB - Multiferroic tunneling junction based four-state non-volatile memories are very promising for future memory industry since this kind of memories hold the advantages of not only the higher density by scaling down memory cell but also the function of magnetically written and electrically reading. In this work, we demonstrate a success of this four-state memory in a material system of NiFe/BaTiO3/La0.7Sr0.3MnO3 with improved memory characteristics such as lower switching field and larger tunneling magnetoresistance (TMR). Ferroelectric switching induced resistive change memory with OFF/ON ratio of 16 and 0.3% TMR effect have been achieved in this multiferroic tunneling structure. PMID- 26239506 TI - Opinions of Social Workers in Turkey About the Principles on Die with Dignity. AB - The conditions how people will spend their very last moments are an increasingly debated topic in Turkey. This study is planned to learn the opinions of Social Workers in Turkey on "Principles of a good death." The results of this study reveal that social workers in Turkey agree with principles of a good death in general. The degree of support for some specific principles changes by the sex and age of the participants. Despite the significant support given to principles by social workers, majority of them do not think that these principles are currently followed in medical and care institutions in Turkey. PMID- 26239507 TI - Knees Shaking Uncontrollably. AB - A prose poem about the power of intergenerational psychological and spiritual healing. PMID- 26239508 TI - Patterns of Phrenic Nerve Discharge after Complete High Cervical Spinal Cord Injury in the Decerebrate Rat. AB - Studies conducted since the second half of the 19th century have revealed spontaneous as well as pharmacologically induced phasic/rhythmic discharge in spinal respiratory motor outputs of cats, dogs, rabbits, and neonatal rats following high cervical transection (Tx). The extent to which these various studies validate the existence of a true spinal respiratory rhythm generator remains debated. In this set of studies, we seek to characterize patterns of spontaneous phasic/rhythmic, asphyxia-induced, and pharmacologically induced activity occurring in phrenic nerve (PhN) discharge after complete high cervical (C1-C2) spinal cord transection. Experiments were performed on 20 unanesthetized decerebrate Sprague-Dawley adult male rats. Patterns of spontaneous activity after spinalization included tonic, phasic, slow oscillatory, and long-lasting tonic discharges. Topical application of antagonists of GABAA and glycine receptors to C1- and C2- spinal segments induced left-right synchronized phasic decrementing activity in PhN discharge that was abolished by an additional C2Tx. Asphyxia elicited increases in tonic activity and left-right synchronized gasp like bursts in PhN discharge, demonstrating the presence of spinal circuits that may underlie a spinal gasping-like mechanism. We conclude that intrinsic slow oscillators and a phasic burst/rhythm generator exist in the spinal cord of the adult rat. If present in humans, this mechanism may be exploited to recover respiratory function in patients sustaining severe spinal cord injury. PMID- 26239509 TI - Self-Assembled Boronic Ester Cavitand Capsules with Various Bis(catechol) Linkers: Cavity-Expanded and Chiral Capsules. AB - Two molecules of cavitand tetraboronic acid and four molecules of various bis(catechol) linkers self-assemble into capsules through the formation of eight dynamic boronic ester bonds. Each capsule has a different cavity size depending on the linker used, and shows particular guest encapsulation selectivity. A chiral capsule made up of the cavitand and a chiral bis(catechol) linker was also constructed. This capsule induces supramolecular chirality with respect to a prochiral biphenyl guest by diastereomeric encapsulation through the asymmetric suppression of rotation around the axis of the prochiral biphenyl moiety. PMID- 26239510 TI - Solid-state NMR as a probe of anion binding: molecular dynamics and associations in a [5]polynorbornane bisurea host complexed with terephthalate. AB - A range of solid-state NMR techniques is used to characterise a molecular host:guest complex consisting of a [5]polynorbornane bisurea host binding a terephthalate dianion guest. Detailed information is obtained on the molecular dynamics and associations from the point of view of both the host and guest molecules. The formation of the complex in the solid state is confirmed using (1)H 2D exchange NMR, and the 180 degrees flipping of the (2)H-labelled terephthalate guest and its eventual expulsion from the complex at elevated temperatures are quantified using variable-temperature (2)H spin-echo experiments. Two-dimensional (1)H-(13)C HETCOR spectra obtained under fast magic angle spinning conditions (60 kHz) show a high resolution despite the poor crystallinity of the solid complex, and clearly reveal changes in the rigidity of the host molecule when complexed. Short-range intra- and intermolecular (1)H-(1)H proximities are also detected using 2D SQ-DQ correlation methods, providing insight into the molecular packing in the solid phase. PMID- 26239511 TI - Inhibitory effects of 3-bromopyruvate in human nasopharyngeal carcinoma cells. AB - Tumor cells depend on aerobic glycolysis for adenosine triphosphate (ATP) production, which is therefore targeted by therapeutic agents. The compound 3 bromopyruvate (3-BrPA), a strong alkylating agent and hexokinase inhibitor, inhibits tumor cell glycolysis and the production of ATP, causing apoptosis. 3 BrPA induces apoptosis of nasopharyngeal carcinoma (NPC) cell lines HNE1 and CNE 2Z, which may be related to its molecular mechanisms. In the present study, we investigated the effects of 3-BrPA on the viability, reactive oxygen species (ROS), apoptosis and other types of programmed cell death in NPC cells in vitro and in vivo. PI staining showed significant apoptosis in NPC cells accompanied by the overproduction of ROS and downregulation of mitochondrial membrane potential (MMP, DeltaPsim) by 3-BrPA. However, the ROS scavenger N-acetyl-L-cysteine (NAC) significantly reduced 3-BrPA-induced apoptosis by decreasing ROS and facilitating the recovery of MMP. We elucidated the molecular mechanisms underlying 3-BrPA activity and found that it caused mitochondrial dysfunction and ROS production, leading to necroptosis of NPC cells. We investigated the effects of the caspase inhibitor z-VAD-fmk, which inhibits apoptosis but promotes death domain receptor (DR)-induced NPC cell necrosis. Necrostatin-1 (Nec-1) inhibits necroptosis, apparently via a DR signaling pathway and thus abrogates the effects of z-VAD fmk. In addition, we demonstrated the effective attenuation of 3-BrPA-induced necrotic cell death by Nec-1. Finally, animal studies proved that 3-BrPA exhibited significant antitumor activity in nude mice. The present study is the first demonstration of 3-BrPA-induced non-apoptotic necroptosis and ROS generation in NPC cells and provides potential strategies for developing agents against apoptosis-resistant cancers. PMID- 26239513 TI - Mobile MAX-DOAS observation of NO2 and comparison with OMI satellite data in the western coastal areas of the Korean peninsula. AB - Ground-based MAX-DOAS measurements have been used to retrieve column densities of atmospheric absorbers such as NO2, SO2, HCHO, and O3. In this study, mobile MAX DOAS measurements were conducted to map the 2-D distributions of atmospheric NO2 in the western coastal areas of the Korean peninsula. A Mini-MAX-DOAS instrument was mounted on the rooftop of a mobile lab vehicle with a telescope mounted parallel to the driving direction, pointing forward. The measurements were conducted from 21 to 24 December 2010 along the western coastal areas from Gomso harbor (35.59N, 126.61E) to Gunsan harbor (35.98N, 126.67E). During mobile MAX DOAS observations, high elevation angles were used to avoid shades from nearby obstacles. For the determination of the tropospheric vertical column density (VCD), the air mass factor (AMF) was retrieved by the so-called geometric approximation. The NO2 VCDs from 20 and 45 degree elevation angles were retrieved from mobile MAX-DOAS measurements. The tropospheric NO2 VCDs derived from mobile MAX-DOAS measurements were compared directly to those retrieved by the OMI satellite observations. Mobile MAX-DOAS VCD was in good agreement with OMI tropospheric VCD on most days. However, OMI tropospheric VCD was much higher than that of mobile MAX-DOAS on 23 December 2010. One probable reason for this difference is that OMI retrieval might overestimate NO2 VCD under haze conditions, when a pollution plume was transported over the measurement site. The mobile MAX-DOAS observations reveal much finer spatial patterns of NO2 distributions, which can provide useful information for the validation of satellite observation of atmospheric trace gases. PMID- 26239512 TI - Ethyl acetate extract of Hypericum japonicum induces apoptosis via the mitochondria-dependent pathway in vivo and in vitro. AB - The widely-used Chinese medicinal herb Hypericum japonicum, also known as Hypericum japonicum Thunb or Tianjihuang, displays potent anti-carcinogenic effects against liver cancer. However, the molecular mechanism underlying the therapeutic effects of Hypericum japonicum remains to be elucidated. The present study investigated the in vivo efficacy of ethyl acetate extract of Hypericum japonicum (EAEHJ) against tumor growth in an H22 cell-bearing liver cancer mouse model. Treatment with EAEHJ significantly reduced tumor weight, but had no effect on murine body weight. The results of the present study also showed that EAEHJ induced H22 cell apoptosis in vivo. In addition, the anti-carcinogenic effects of EAEHJ were investigated in vitro. The results of the present study demonstrate that both phospholipid asymmetry in the plasma membrane and mitochondrial membrane potential were deregulated in HepG2 human hepatoma cells, following treatment with EAEHJ. Treatment with EAEHJ also increased the ratio of pro apoptotic B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax) to anti-apoptotic Bcl-2, and activated the caspase-9 signaling pathway. These results suggest that EAEHJ is able to trigger the apoptosis of liver cancer cells via the mitochondria dependent pathway. PMID- 26239514 TI - Negative-Pressure Wound Therapy in the Management of High-Grade Ventral Hernia Repairs. AB - BACKGROUND: Despite improved operative techniques, open ventral hernia repair (VHR) surgery in high-risk, potentially contaminated patients remains challenging. As previously reported by our group, the use of a modified negative pressure wound therapy system (hybrid-VAC or HVAC) in patients with grade 2 hernias is associated with lower surgical site occurrence (SSO) and surgical site infection (SSI) rates. Accordingly, the authors aim to evaluate whether the HVAC would similarly improve surgical site outcomes following VHR in patients with grade 3 hernias. METHODS: A 4-year retrospective review (2011-2014) was conducted of all consecutive, modified ventral hernia working group (VHWG) grade 3 hernia repairs with HVAC closure performed by a single surgeon (FEE) at a single institution. Operative data and 90-day outcomes were evaluated. Overall outcomes (e.g., recurrence, reoperation, mortality) were reviewed for the study group. RESULTS: A total of 117 patients with an average age of 56.7 +/- 11.9 years were classified as grade 3 hernias and underwent open VHR with subsequent HVAC closure. Fifty patients were male (42.7 %), the mean BMI was 35.2 (+/-9.5), and 60.7 % had a history of prior hernia repair. The average fascial defect size was 201.5 (+/-167.3) cm(2) and the mean length of stay was 14.2 (+/-9.3) days. Ninety day outcomes showed an SSO rate of 20.7 % and an SSI rate of 5.2 %. The overall hernia recurrence rate was 4.2 % (n=6) with a mean follow-up of 11 +/- 7.3 months. CONCLUSION: Modified VHWG grade 3 ventral hernias are associated with significant morbidity. In our series utilizing the HVAC system after VHR, the observed rate of SSO and SSI compared favorably to reported series. Further prospective cost-effective studies are warranted to validate these findings. PMID- 26239515 TI - A NSQIP Review of Major Morbidity and Mortality of Synchronous Liver Resection for Colorectal Metastasis Stratified by Extent of Liver Resection and Type of Colorectal Resection. AB - INTRODUCTION: Safety of synchronous hepatectomy and colorectal resection (CRR) for metastatic colorectal cancer remains controversial. We hypothesized that both the extent of hepatectomy and CRR influences postoperative outcomes. METHODS: Prospective 2005-2013 ACS-NSQIP data were retrospectively reviewed for mortality and major morbidity (MM) after (1) isolated hepatectomy, (2) isolated CRR, and (3) synchronous resection for colorectal cancer. Hepatectomy and CRR risk categories were created based on mortality and MM of respective isolated resections. The synchronous cohort was then stratified based on risk categories. Cumulative asynchronous mortality and MM were estimated compared to that observed in the synchronous cohort via unadjusted relative risk and risk difference. RESULTS: There were 43,408 patients identified. Among isolated hepatectomy patients (N = 6,661), trisectionectomy and right hepatectomy experienced the greatest mortality and were defined as "major" hepatectomy. Among isolated CRR patients (N = 35,825), diverted left colectomy, abdominoperineal resection, total abdominal colectomy, and total abdominal proctocolectomy experienced the greatest MM and were defined as "high risk" CRR. Synchronous patients (N = 922) were stratified by hepatectomy and CRR risk categories; mortality and MM varied from 0.9 to 5.0 % and 25.5 to 55.0 %, respectively. Mortality and MM were greatest for patients undergoing "high risk" CRR and "major" hepatectomy and lowest for synchronous CRR and "minor" hepatectomy. As both CRR and hepatectomy risk categories increased, there was a significant trend in increasing mortality and MM in synchronous patients. Additionally, comparison of the synchronous resections versus the estimated cumulative asynchronous outcomes showed that (1) mortality was significantly less after synchronous minor hepatectomy and either low or high risk CRR, and (2) neither mortality nor major morbidity differed significantly after major hepatectomy with either high or low risk CRR. CONCLUSION: Major morbidity after synchronous hepatic and colorectal resections vary incrementally and are related to both the risk of hepatectomy and CRR. Stratification of outcomes by the hepatectomy and CRR components may reflect a more accurate description of risks. Comparison of synchronous and combined outcomes of individual operations supports a potential benefit for synchronous resections with minor hepatectomy. PMID- 26239516 TI - The Prognostic Importance of the Number of Metastatic Lymph Nodes for Patients Undergoing Curative Resection Followed by Adjuvant Chemoradiotherapy for Extrahepatic Bile Duct Cancer. AB - BACKGROUND: Current nodal staging system for extrahepatic bile duct (EHBD) cancer is controversial. The number of metastatic lymph nodes (mLN) and lymph node ratio (LNR) has been studied for the assessment of the nodal status in many other gastrointestinal cancers, but there are few studies on assessing the prognostic impact of these parameters in EHBD cancer. METHODS: We retrospectively reviewed 239 consecutive patients who underwent curative resection followed by adjuvant chemoradiotherapy for adenocarcinoma of EHBD from 1995 to 2009 in our institution. The prognostic value of the number of mLN and LNR was evaluated by adjusting for other known factors. Optimal cutoff points were determined using maximally selected chi-square test. RESULTS: Lymph node metastasis was found in 77 (32 %) patients. Univariate analysis for overall survival (OS) revealed both the number of mLN (0 vs. 1-3 vs. >=4; p < 0.001) and LNR (<0.2 vs. >=0.2; p < 0.001) as significant prognosticators. Multivariate analysis demonstrated that the number of mLN was an independent prognostic factor, whereas LNR was not. The estimated 5-year OS was 48.7 % for patients with negative nodes, 33.4 % for patients with 1-3 mLN, and 9.1 % for patients with 4 or more mLN (p < 0.001). CONCLUSIONS: The number of mLN is a powerful parameter to predict survival in the EHBD cancer, which is more reliable than LNR. As for many other gastrointestinal cancers, further classification of node positive patients based on the number of mLN seems to be useful and may provide precise information. PMID- 26239517 TI - miR-126 inhibits papillary thyroid carcinoma growth by targeting LRP6. AB - microRNA-126 (miR-126) has been reported to play tumor suppressor roles in various types of cancers. Although it has been reported that miR-126 expression is downregulated in papillary thyroid carcinoma (PTC), the precise role and underlying molecular mechanism of miR-126 in PTC remains unclear. Therefore, the aims of the present study were to investigate the role and potential mechanism of miR-126 in tumorigenicity of PTC in vivo and in vitro. We observed that the miR 126 expression level was significantly downregulated in PTC tissue and PTC cell lines, the aberrant expression of miR-126 was correlated with lymph node metastasis, tumor size and TNM stage. We also showed that restoration of miR-126 in PTC cells inhibited cell proliferation, colony formations, migration and invasion, promoted cell apoptosis and cell cycle arrest at G1 stage in vitro, as well as inhibited tumor growth and decreased tumor volume and weight in vivo. Furthermore, low-density lipoprotein receptor-related protein 6 (LRP6), a regulator of the Wnt/beta-catenin signaling cascade, was identified as a crucial target gene of miR-126. Overexpression of miR-126 inhibited LP6 expression on mRNA and protein levels, and deactivate Wnt/beta-catenin signaling pathway. These results suggested that miR-126 functions as a tumor-suppressive miRNA by targeting LRP6 regulating Wnt/beta-catenin signaling pathway and represents a therapeutic target for PTC. PMID- 26239518 TI - Erratum to: A Segmentation Framework of Pulmonary Nodules in Lung CT Images. PMID- 26239520 TI - Beauty and the Eye of the Beholder: Gender and Attractiveness Affect Judgments in Teacher Sex Offense Cases. AB - The present study investigated the effects of gender and attractiveness on judgments of bail requirements, incarceration, and sex offender registration lengths, and attitudes toward offenders and victims in a teacher-student sexual perpetration scenario. Researchers presented 432 undergraduate students at a large southwestern university with one of four vignettes detailing a sexual relationship between a 35-year-old teacher and a 14-year-old student. Vignettes varied by both attractiveness and gender of the offender (using heterosexual offender-victim dyads). Results indicate that both gender and attractiveness affect judgments of sex offenders; specifically, female sexual offenders were viewed more leniently and judged less punitively than male sexual offenders. Although attractive female sexual offenders were given particularly lenient treatment, attractiveness did not affect judgments toward male sex offenders. In addition, although male and female participants tended to rate male offenders similarly, male participants were more lenient toward female offenders than were female participants. Finally, post hoc analyses revealed that, for many variables, unattractive female sexual offenders may not be viewed differently from male sexual offenders. These results have serious implications for the legal system, sex offender management, and societal views regarding male and female sexual offenders and their victims. PMID- 26239519 TI - Analysis of phylogenomic datasets reveals conflict, concordance, and gene duplications with examples from animals and plants. AB - BACKGROUND: The use of transcriptomic and genomic datasets for phylogenetic reconstruction has become increasingly common as researchers attempt to resolve recalcitrant nodes with increasing amounts of data. The large size and complexity of these datasets introduce significant phylogenetic noise and conflict into subsequent analyses. The sources of conflict may include hybridization, incomplete lineage sorting, or horizontal gene transfer, and may vary across the phylogeny. For phylogenetic analysis, this noise and conflict has been accommodated in one of several ways: by binning gene regions into subsets to isolate consistent phylogenetic signal; by using gene-tree methods for reconstruction, where conflict is presumed to be explained by incomplete lineage sorting (ILS); or through concatenation, where noise is presumed to be the dominant source of conflict. The results provided herein emphasize that analysis of individual homologous gene regions can greatly improve our understanding of the underlying conflict within these datasets. RESULTS: Here we examined two published transcriptomic datasets, the angiosperm group Caryophyllales and the aculeate Hymenoptera, for the presence of conflict, concordance, and gene duplications in individual homologs across the phylogeny. We found significant conflict throughout the phylogeny in both datasets and in particular along the backbone. While some nodes in each phylogeny showed patterns of conflict similar to what might be expected with ILS alone, the backbone nodes also exhibited low levels of phylogenetic signal. In addition, certain nodes, especially in the Caryophyllales, had highly elevated levels of strongly supported conflict that cannot be explained by ILS alone. CONCLUSION: This study demonstrates that phylogenetic signal is highly variable in phylogenomic data sampled across related species and poses challenges when conducting species tree analyses on large genomic and transcriptomic datasets. Further insight into the conflict and processes underlying these complex datasets is necessary to improve and develop adequate models for sequence analysis and downstream applications. To aid this effort, we developed the open source software phyparts ( https://bitbucket.org/blackrim/phyparts ), which calculates unique, conflicting, and concordant bipartitions, maps gene duplications, and outputs summary statistics such as internode certainy (ICA) scores and node-specific counts of gene duplications. PMID- 26239521 TI - Nomenclature for factors of the HLA system, update June 2015. PMID- 26239522 TI - Evidence-based choice of ritonavir as index CYP3A inhibitor in drug-drug interaction studies. PMID- 26239523 TI - A Great Time for Food Science in New Zealand. PMID- 26239525 TI - Origin of anomalous giant dielectric performance in novel perovskite: Bi(0.5 x)LaxNa(0.5-x)LixTi(1-y)MyO3 (M = Mg2+, Ga3+). AB - Dielectric properties and dielectric relaxation behaviors of A/B sites co substituted Bi0.5Na0.5TiO3 perovskite-type ferroelectrics are reported. The Bi(0.5-x)LaxNa(0.5-x)LixTi(1-y)MyO3 (M = Mg(2+), Ga(3+)) exhibits anomalous giant dielectric permittivity (epsilon') of ~10(5) under a heterogeneous constitution with easily discernible grain and grain boundary conductivity. The lone pairs substitution theory as well as extrinsic disorders are used to clarify the significant structural evolution and the origin of the dielectric performance. A bigger free volume promotes the anomalous relaxation between oxygen sites, and the polarization direction on the nanoscale deviates from the average polarization direction at its ferroelectric state. Furthermore, no obvious phase transition indicates the considerable static substitutional disorder at the Bi/Na sites, which facilitates delocalized conduction of oxygen ions in the intermediate temperature range. PMID- 26239524 TI - Post-Traumatic Stress Disorder and Risk for Incident Rheumatoid Arthritis. AB - OBJECTIVE: To examine the association between symptoms of post-traumatic stress disorder (PTSD) and rheumatoid arthritis (RA) risk in a prospective cohort and to characterize the role of smoking in this relationship. METHODS: A subset (n = 54,224) of the Nurses' Health Study II, a prospective cohort of female nurses, completed the Brief Trauma Questionnaire and a screen for PTSD symptoms. Participants were categorized based on trauma exposure and number of PTSD symptoms. Incident RA cases (n = 239) from 1989 to 2011 were identified. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) between PTSD symptoms and incident RA. To identify the impact of smoking, secondary and subgroup analyses were performed. In all analyses, PTSD and smoking were lagged 2 years before the development of RA. RESULTS: Compared to no history of trauma/PTSD symptoms, the HR for >=4 PTSD symptoms and incident RA was 1.76 (95% CI 1.16-2.67) in models adjusted for age, race, and socioeconomic status. The risk for RA increased with an increasing number of PTSD symptoms (P = 0.01). When smoking was added to the model, the HR for RA remained elevated (HR 1.60 [95% CI 1.05-2.43]). In a subgroup analysis, excluding women who smoked before PTSD onset, results were unchanged (HR 1.68 [95% CI 1.04-2.70]). CONCLUSION: This study suggests that women with high PTSD symptomatology have an elevated risk for RA, independent of smoking, adding to emerging evidence that stress is an important determinant of physical health. PMID- 26239526 TI - Effect of FTY720-phosphate on the expression of inflammation-associated molecules in astrocytes in vitro. AB - FTY720 is a new oral immunomodulatory therapy for the treatment of multiple sclerosis (MS). There is strong evidence that FTY720 has direct effects on brain resident cells such as astrocytes acting via sphingosine-1-phosphate (S1P) receptors. In the present study, the mRNA expression of S1P receptors as well as selected cytokines, chemokines and growth factors were investigated in primary murine astrocytes under inflammatory conditions in the presence or absence of the phosphorylated form of FTY720 (FTY720-P). Following stimulation with either the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) or with bacterial lipopolysaccharide, there was an increased expression of the receptors S1P1 and S1P3, the cytokines and chemokines interleukin (IL)-1beta, chemokine (C C-motif) ligand 2 (CCL-2), CCL-20 and chemokine (C-X-C-motif) ligand 12 as well as the growth factors insulin-like growth factor-1, ciliary neurotrophic factor and glial cell line-derived neurotrophic factor (GDNF). FTY720-P led to an increased expression of IL-1beta and GDNF at distinct time points following co stimulation with TNF-alpha compared with TNF-alpha treatment alone. However, the presence of FTY720-P did not have any further significant effects on the expression of S1P receptors, cytokines or growth factors, suggesting that the regulation of these target genes in astrocytes is not likely to be a major mechanism underlying the effect of FTY720-P in diseases such as MS. PMID- 26239527 TI - Condensing chromosome condensation. AB - Mitotic chromosome condensation has fascinated biologists since Flemming's early illustrations of mitosis in the late nineteenth century. Now--130 years later- chromatid condensation is reconstituted in vitro with the minimum components. The results are remarkably and beautifully simple, requiring only core histones, three histone chaperones, topoisomerase II and condensin I. PMID- 26239528 TI - Building stomach in a dish. AB - Modelling organs in culture has great potential to improve our understanding of development, organogenesis and disease. While some endodermal derived organs have been modelled, the corpus region of the stomach, where acid-producing cells reside, remained an invincible target. A 60-day differentiation protocol now enables the generation of functional acid-producing cells in culture, conquering the challenge. PMID- 26239529 TI - RB-loss puts focus on Myc. AB - Activator E2Fs and Myc cooperate as master regulators of proliferation. A new study sheds light on one of the fundamental questions in cancer biology: how do oncogenic changes, such as Retinoblastoma (RB)-mutation, modify E2F and Myc activity? PMID- 26239531 TI - Corrigendum: Selective autophagy degrades DICER and AGO2 and regulates miRNA activity. PMID- 26239532 TI - Is honey a fallback food for wild chimpanzees or just a sweet treat? AB - OBJECTIVES: Honey is a highly nutritious resource for any primate able to exploit it. Wild chimpanzees exploit nests of honey-making bees (Apini and Meliponini) for honey and brood, typically using tools to overcome the bees' defences. The universality of honey-gathering among modern human foragers in tropical climates and chimpanzees suggests energy-rich honey, acquired with tools, was likely a regular food for ancestral hominins. However, few studies have assessed its role in seasonal foraging strategies of chimpanzees. This study asks whether honey serves as a high-quality fallback food for chimpanzees at Bulindi, Uganda. MATERIALS AND METHODS: Honey consumption was investigated via fecal analysis over 22 months during two studies (Study 1: 2007-2008; Study 2: 2012-2014). Additionally, flower and fruit phenology was measured during Study 1; peak flowering intensity was expected to facilitate increased honey and/or brood production by bees. RESULTS: Chimpanzees consumed honey (and/or brood) at low frequencies year-round, but bees/beeswax appeared in feces at higher frequencies with decreasing fruit availability (Study 1). Honey consumption was unrelated to flowering and chimpanzees did not consume honey more frequently during the "honey season" when local people harvest beehives. Moreover, consumption was inversely related to fruit intake (both study periods). DISCUSSION: Although honey fits the functional definition of a filler fallback food at Bulindi, the chimpanzees unlikely depend on honey to replace nutrients provided by fruit. Overall, honey best qualifies as an energy-dense "treat" during low fruiting months. The data lend support to the hypothesis that tools can facilitate chimpanzees' access to high-quality fallbacks including insect foods when fruit availability is low. PMID- 26239530 TI - Erratum: Proteostasis control by the unfolded protein response. PMID- 26239533 TI - Managing septic arthritis after knee ligament reconstruction. AB - PURPOSE: Joint infection after anterior cruciate ligament (ACL) reconstruction is uncommon but has potentially serious consequences for the graft and articular cartilage. Most recently published series are in agreement that an urgent arthroscopic washout and antibiotic treatment are mandatory to preserve both graft and cartilage. However, several questions have not as yet been touched upon. METHODS: We performed a literature review to assess the most interesting series published about this issue. RESULTS: In this review, a management protocol is first presented that discusses the different diagnostic parameters to consider and surgical and antibiotic treatment suggested according to the literature. Outcomes published in different series are also discussed. PMID- 26239534 TI - A novel combination of computer-assisted reduction technique and three dimensional printed patient-specific external fixator for treatment of tibial fractures. AB - PURPOSE: Good reduction and appropriate fixation are critical for long bone fractures, however, neither has been addressed satisfactorily. Robotic and navigation techniques can help improve the reduction accuracy. However, their clinical applications are limited by high cost and complexity in operation. The aim of this study was to discuss the feasibility of a customized external fixator in treating long bone fractures. METHODS: We combined a computer-assisted reduction technique with 3D printing to develop a customized external fixator for treating three cases of tibial fractures. The reduction accuracy and fixation results were discussed in terms of operation time, X-ray examinations after operation, and limb function recovery. RESULTS: Good reduction results were obtained on all three tibial fractures with an average lateral displacement of 2.04 mm (+/-1.53) and an angulation of 2.54 degrees (+/-1.33). The surgery was not experience-dependent, and no intra-operative X-ray examinations were conducted. The average operative time was 8.67 minutes (+/-0.58). CONCLUSIONS: A novel customized external fixator for the treatment of tibial fractures has the advantages of easy manipulation, accurate reduction, appropriate fixation, minimal invasion and experience-independence, and therefore has huge potential in clinical applications. PMID- 26239535 TI - Effects of stacking order, layer number and external electric field on electronic structures of few-layer C2N-h2D. AB - Recently, a new type of two-dimensional layered material, i.e. a nitrogenated holey two-dimensional structure C2N-h2D, has been synthesized using a simple wet chemical reaction and used to fabricate a field-effect transistor device (Nat. Commun., 2015, 6, 6486). Here we have performed a first-principles study of the electronic properties of few-layer C2N-h2D with different stacking orders and layer numbers. Because of the interlayer coupling mainly in terms of the orbital interaction, band structure of this system, especially splitting of the bands and band gap, depends on its stacking order between the layers, and the band gap exhibits monotonically decreasing behavior as the layer number increases. All the few-layer C2N-h2D materials have characteristics of direct band gap, irrespective of the stacking order and layer number examined in our calculations. And bulk C2N h2D has an indirect or direct band gap, depending on the stacking order. Besides, when we apply an out-of-plane electric field on few-layer C2N-h2D, its band gap will decrease as the electric field increases due to a giant Stark effect except for the monolayer case, and even a semiconductor-to-metal transition may occur for few-layer C2N-h2D with more layers under an appropriate electric field. Owing to their tunable band gaps in a wide range, the layered C2N-h2D materials will have tremendous opportunities to be applied in nanoscale electronic and optoelectronic devices. PMID- 26239537 TI - Human lactoferricin derived di-peptides deploying loop structures induce apoptosis specifically in cancer cells through targeting membranous phosphatidylserine. AB - Host defense-derived peptides have emerged as a novel strategy for the development of alternative anticancer therapies. In this study we report on characteristic features of human lactoferricin (hLFcin) derivatives which facilitate specific killing of cancer cells of melanoma, glioblastoma and rhabdomyosarcoma compared with non-specific derivatives and the synthetic peptide RW-AH. Changes in amino acid sequence of hLFcin providing 9-11 amino acids stretched derivatives LF11-316, -318 and -322 only yielded low antitumor activity. However, the addition of the repeat (di-peptide) and the retro-repeat (di-retro-peptide) sequences highly improved cancer cell toxicity up to 100% at 20 MUM peptide concentration. Compared to the complete parent sequence hLFcin the derivatives showed toxicity on the melanoma cell line A375 increased by 10-fold and on the glioblastoma cell line U-87mg by 2-3-fold. Reduced killing velocity, apoptotic blebbing, activation of caspase 3/7 and formation of apoptotic DNA fragments proved that the active and cancer selective peptides, e.g. R-DIM-P-LF11 322, trigger apoptosis, whereas highly active, though non-selective peptides, such as DIM-LF11-318 and RW-AH seem to kill rapidly via necrosis inducing membrane lyses. Structural studies revealed specific toxicity on cancer cells by peptide derivatives with loop structures, whereas non-specific peptides comprised alpha-helical structures without loop. Model studies with the cancer membrane mimic phosphatidylserine (PS) gave strong evidence that PS only exposed by cancer cells is an important target for specific hLFcin derivatives. Other negatively charged membrane exposed molecules as sialic acid, heparan and chondroitin sulfate were shown to have minor impact on peptide activity. PMID- 26239536 TI - Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. AB - OBJECTIVE: An extensive analysis of white matter plaques in a large sample of multiple sclerosis (MS) autopsies provides insights into the dynamic nature of MS pathology. METHODS: One hundred twenty MS cases (1,220 tissue blocks) were included. Plaque types were classified according to demyelinating activity based on stringent criteria. Early active, late active, smoldering, inactive, and shadow plaques were distinguished. A total of 2,476 MS white matter plaques were identified. Plaque type distribution was analyzed in relation to clinical data. RESULTS: Active plaques were most often found in early disease, whereas at later stages, smoldering, inactive, and shadow plaques predominated. The presence of early active plaques rapidly declined with disease duration. Plaque type distribution differed significantly by clinical course. The majority of plaques in acute monophasic and relapsing-remitting MS (RRMS) were active. Among secondary progressive MS (SPMS) cases with attacks, all plaque types could be distinguished including active plaques, in contrast to SPMS without attacks, in which inactive plaques predominated. Smoldering plaques were frequently and almost exclusively found in progressive MS. At 47 years of age, an equilibrium was observed between active and inactive plaques, whereas smoldering plaques began to peak. Men displayed a higher proportion of smoldering plaques. INTERPRETATION: Disease duration, clinical course, age, and gender contribute to the dynamic nature of white matter MS pathology. Active MS plaques predominate in acute and early RRMS and are the likely substrate of clinical attacks. Progressive MS transitions to an accumulation of smoldering plaques characterized by microglial activation and slow expansion of pre-existing plaques. Whether current MS therapeutics impact this pathological driver of disease progression remains uncertain. PMID- 26239538 TI - Short course palliative radiotherapy in the management of choroidal metastasis: An effective technique since ages. AB - PURPOSE: Uveal tract is the most common site of intra-ocular metastasis. Overall, the reported prevalence of clinically evident uveal metastases in patients with cancer ranges from 2% to 9%, with the majority of the cases being due to breast cancer. We aimed at evaluating the role of palliative radiotherapy in the management of choroidal metastasis from carcinoma breast. MATERIALS AND METHODS: We describe the clinico-pathologic features, treatment and outcome of ten patients of carcinoma breast who presented to the ophthalmology department at our institution with ocular symptoms attributable to choroidal metastasis. RESULTS: Nine of the patients were female while one was male. All of them presented with painless progressive diminution of vision. Median duration of symptoms was 2.25 months. Five patients had associated lung metastasis while bone and brain metastases were seen in three and two patients respectively. All of them received palliative radiotherapy (RT) to the involved eye (or eye+brain) by 3D-CRT (n=7), or 2 Dimensional technique (n=2) or electron therapy (n=1). Doses prescribed were 30 Gy/10#/2 weeks (n=8); 20 Gy/5 #/1 week (n=2). Simultaneously they received hormonal therapy (n=6) or systemic chemotherapy (n=3). After a median follow up of 18 months seven patients had complete resolution and two patients had partial resolution of the metastases. CONCLUSION: Short course palliative radiation therapy is an effective modality for the management of choroidal metastasis in patients of carcinoma breast. In the current report it led to formidable local control with acceptable radiation induced toxicity. PMID- 26239539 TI - Annotation of Stress-Responsive Candidate Genes in Peanut ESTs. AB - Peanut (Arachis hypogaea L.) is an internationally important crop for human consumption as a good source of protein and vegetable oil. Peanut is widely cultivated around the world in tropical, subtropical and warm temperate climate. Because of its huge genome size (2.8 Gb) and unsequenced genome, studies on genomics and genetic modification of peanut are less as compared to other model crops. As peanut can be cultivated in arid and semiarid regions, its growth is drastically affected by various stresses that reduce the yield. Therefore, study on stress-responsive genes and its regulation is very much important. Here we report about the identification and annotation of some stress-responsive candidate genes using peanut expressed sequence tags (ESTs). The selection of genes was based on the publically available expression data. Due to good expression data and lack of available literature in peanut, some of the stress responsive genes were screened. Individual EST of the said group was further searched in peanut ESTs (1,78,490 whole EST sequences) using computational approach. Various tools like VecScreen, RepeatMasker, EST trimmer, DNA Baser and Wise2 were being used for stress-responsive gene identification and annotation. Research progress made toward contig assembly, determination of biological function of genes, and prediction of domain as well as 3D structure for related protein are included. PMID- 26239540 TI - Prediction of (13)C NMR Chemical Shift Sum Using Topological Indices: Role of Recently Introduced Balaban F and G Indices. AB - Present paper deals with the examination of Balaban F and G indices for estimating (13)C NMR chemical shift sums of alkanes. Set of 66 alkanes were used for this purpose, which have been divided into training set (50 compounds) and test set (16 compounds). The results have shown that Balaban G Index along with connectivity indices yields the best model. The model is analyzed for the defect due to colinearity using Ridge parameters. The most appropriate model is a three parametric model found containing [Formula: see text], [Formula: see text], and G as correlating parameters. The results have been critically examined based on variety of statistical parameters. PMID- 26239541 TI - In Silico Structural, Virtual Screening and Docking Studies of Human Cytochrome P450 2A7 Protein. AB - Among CYPs, CYP2A sub-family is well known for its function to metabolise xenobiotics. CYP2A includes three members: CYP2A6, CYP2A7 and CYP2A13. Of these three proteins, structure and function of CYP2A6 and CYP2A13 are widely studied, whereas very little study has been carried out on CYP2A7. In the initial in vitro studies on CYP2A7, full protein in its active form could not be expressed. The exact structure and function of CYP2A7 is still not revealed. However, up regulation of CYP2A7 has been reported in malignant oesophageal cells and colon cancer cells. In the present study, we generated the structure of CYP2A7 protein. The modelled proteins were validated and subjected to molecular docking analyses. The energy and RMSD calculations demonstrated that the protein is highly conserved in nature, i.e., the protein is not much flexible. Here the ligand molecules of NCI Diversity Set II from the ZINC database against the active site of the CYP2A7 protein were screened. Five compounds that possess good inhibitory activity against CYP2A7 active site were identified. The top ranking molecule (ZINC01572309) has a minimum energy score of -12.0 kcal/Mol. This compound is thus a good starting point for further development of strong inhibitors. Our in silico approach could help in better structural and functional analysis of CYP2A7. Apart from structural description of CYP2A7, elaboration of binding sites for inhibitors provides us with an opportunity to utilise binding pockets in targeted inactivation of this protein for further research. PMID- 26239542 TI - [Biomaterials in orthopedics]. AB - Biomaterials are artificial or natural materials, which are used in living organisms for a wide variety of reasons. Currently, there are biomaterials available for practically all types of tissue and can fulfill temporary and permanent functions. Ideally, materials used for temporary roles should be completely resorbed after the fulfilling the function and those with a permanent role should remain stable within the body. Many of the currently available biomaterials do not possess these optimal features. Those with temporary roles often remain unchanged within the organism or only induce an incomplete regeneration and those with permanent roles suffer biological alterations which reduce the function. Despite the enormous number of biomaterials, it must always be considered whether the therapeutic target can be achieved without using an implant. PMID- 26239543 TI - The effects of vitamin D3 on lipogenesis in the liver and adipose tissue of pregnant rats. AB - Obesity is a worldwide individual and public health issue, and contributes to the development of numerous chronic diseases. In particular, maternal obesity has harmful effects on both the mother and child during and after pregnancy. The digestion and metabolism of food are controlled by endocrine factors, including insulin, glucagon and estrogen. These hormonal factors are differentially regulated during pregnancy due to the specialized hormonal environment during this period. In the present study, we examined the effects of 1,25 dihydroxyvitamin D3 (VD3), an active hormonal form of nutritional vitamin D3, on lipid metabolism in pregnant rats. The body weight of rats treated with VD3 was significantly reduced compared to that of the rats in the control group. In addition, histological analysis demonstrated that the amount of fat stored in adipocytes was reduced by treatment with VD3. To determine the role of VD3 in lipid metabolism, the expression levels of lipid metabolism-associated genes were measured in the rat adipose tissue and liver. VD3 negatively regulated the expression of various lipogenic genes, including fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1) and acetyl-CoA carboxylase 1 (ACC1), in both the adipose tissue and liver. However, the regulators of lipogenic enzymes such as, sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator activated receptor-gamma (PPAR-gamma) and insulin-induced gene 2 (INSIG2) were differentially regulated by VD3 in a tissue-specific manner. On the whole, these findings suggest that VD3 regulates lipid metabolism and deposition in the liver and adipose tissue, and thereby reduces fat in pregnant animals, as well as body weight. Our results suggest that the alteration of lipogenesis through the administration of VD3 may help to reduce excessive weight gain during pregnancy and prevent obesity-related pregnancy complications such as pre-eclampsia, gestational diabetes, hypertension and issues with labor. PMID- 26239544 TI - Oxidative DNA cleavage by Cu(II) complexes: Effect of periphery substituent groups. AB - A series of structurally-related [Cu(R-benzyl-dipicolylamine)(NO3)2] complexes, where R=methoxy- (1), methyl- (2), H- (3), fluoro- (4), and nitro-group (5), were synthesized, and their activity on DNA cleavage was investigated by linear dichroism (LD) and electrophoresis. The addition of a benzyl group to the dipicolylamine ligand of the [Cu(dipicolylamine)(NO3)2] complex (A), i.e., the [Cu(benzyl-dipicolylamine)(NO3)2] complex (3), caused significant enhancement in the efficiency of oxidative cleavage of both super-coiled (sc) and double stranded (ds) DNA, as evidenced by the electrophoresis pattern and faster decrease in the LD intensity at 260nm. The efficiency in DNA cleavage was also altered with further modifications of the benzyl group by the introduction of various substituents at the para-position. The cleavage efficiency appeared to be the largest when the methyl group was attached. The order of efficiency in DNA cleavage was methyl>methoxy~H>fluoro~nitro group. When an electron-withdrawing group was introduced, the cleavage efficiency decreased remarkably. The reactive oxygen species involved in the cleavage process were the superoxide radical and singlet oxygen. A possible mechanism for this variation in the DNA cleavage efficiency was proposed. PMID- 26239545 TI - Interactions of carboplatin and oxaliplatin with proteins: Insights from X-ray structures and mass spectrometry studies of their ribonuclease A adducts. AB - Oxaliplatin and carboplatin are two platinum(II) drugs in widespread clinical use for the treatment of various types of cancers; yet, structural information on their interactions with proteins is scarce. Here, the X-ray structures of the adducts formed upon reaction of carboplatin and oxaliplatin with bovine pancreatic ribonuclease (RNase A) are reported and compared with results obtained for the structure of the RNase A-cisplatin adduct derived from isomorphous crystals, under the same experimental conditions. Additional details on the binding mode of these metallodrugs toward RNase A are provided by electrospray ionization mass spectrometry (ESI MS) measurements, thus offering insight on the occurring metal-protein interactions. Notably, while carboplatin and cisplatin mainly bind the side chain of Met29, oxaliplatin also binds the side chains of Asp14, of catalytically important His119 and, to a lesser extent, of His105. On the basis of the available data, a likely mechanism for oxaliplatin hydrolysis and binding to the protein is proposed. These results are potentially useful for a better understanding of the biological chemistry, toxicity and side effects of this important class of antitumor agents. PMID- 26239546 TI - Metal coordination and tyrosinase inhibition studies with Kojic-betaAla-Kojic. AB - Kojic acid is a natural antifungal and antibacterial agent that has been extensively studied for its tyrosinase inhibitory and metal coordination properties. Tyrosinase is a metalloenzyme with two copper ions in the active site. It is widely accepted that the tyrosinase inhibitory activity of kojic acid is related to its ability to coordinate metals. Over the past five years, we have used kojic acid to synthesize new and efficient bis-kojic acid chelators of iron and aluminium. In parallel, we investigated whether the de novo designed ligands could interfere with proper tyrosinase functioning. The present study combines our experience with inhibition and coordination studies of the new ligand: Kojic betaAla-Kojic. Research aimed at the assembly of a new potent tyrosinase inhibitor was based on the well-known crystal structure of the enzyme. Two questions were whether two kojic acids could act better than one and to what extent the length and kind of linker could ameliorate metal coordination, and inhibitory activity. Our results show that Kojic-betaAla-Kojic has high affinity for Fe(III), Al(III), Zn(II), and Cu(II) and strong tyrosinase inhibitory effect and it can be proposed for use in industrial and pharmaceutical applications. PMID- 26239547 TI - Guanine nucleobase adducts formed by a monofunctional complex: [Pt(N-(6-methyl-2 picolyl)-N-(2-picolyl)amine)Cl]Cl. AB - Monofunctional Pt(II) complexes bind to G residues in DNA and, if the carrier ligands are bulky, cause DNA structural distortions that lead to anticancer activity. We assessed the steric effects of the tridentate carrier ligand, N(H)6 Medpa (N-(6-methyl-2-picolyl)-N-(2-picolyl)amine), bearing a 6-methyl group and a 6'-proton projecting toward the nucleobase in Pt(N(H)6-Medpa)G adducts (G=9 ethylguanine, 3'-GMP, 5'-GMP, 5'-GTP). Pt(N(H)6-Medpa)G adducts form syn and anti rotamers with the guanine O6 and the central N-H of N(H)6-Medpa on the same or opposite side of the coordination plane, respectively. Pt(N(H)6-Medpa)G adducts have some properties (ease of rotamer interchange and extent of conversion to bis adducts, Pt(N(H)6-Medpa)G2) intermediate to properties reported for analogs having a tridentate ligand with zero or two methyl groups. However, in comparison, the syn rotamer of Pt(N(H)6-Medpa)G adducts has an unexpectedly high abundance. This result is attributable to guanine base canting, such that the 6 membered guanine ring is positioned away from the bulky 6-Me group. This canting both relieves electrostatic repulsion between the partially positive H6' and the guanine H8 protons and creates a favorable electrostatic attraction between the H6' proton and the partially negative guanine O6. This combined information provides insight useful for designing monofunctional anticancer agents. PMID- 26239548 TI - Hochu-ekki-to (Bu-zhong-yi-qi-tang), a herbal medicine, enhances cisplatin induced apoptosis in HeLa cells. AB - Hochu-ekki-to (HET), a Kampo herbal medicine composed of ten medicinal plants, is traditionally used to improve the general state of patients with malignant diseases such as cancer. Recent studies showed that HET had an anti-cancer effect against several cancer cell lines in vitro by inducing apoptosis. However, high doses of HET may have cytotoxic effects attributed to saponins or detergent-like compounds. Therefore, the present study used low doses of HET (50 ug/ml), which did not affect cell viability, to evaluate its synergistic anti-cancer effects with cisplatin. HeLa cells were cultured for 24 h with 50 ug/ml HET, followed by cisplatin treatment for 24 h at various concentrations. Subsequently, the sensitivity of the cells to cisplatin was assessed using a colony survival and a crystal violet cell viability assay. Furthermore, cisplatin-induced apoptosis was analyzed by flow cytometry. Proteins associated with cell viability and apoptosis, including phosphorylated (p-)Akt, p53, B-cell lymphoma 2 (Bcl-2), Bcl 2-associated X protein (Bax) and active caspase-3 were analyzed by immunoblotting. The present study revealed that cell survival was decreased and apoptosis was increased in HeLa cells pre-treated with HET prior to cisplatin treatment compared with HET-untreated cells. Furthermore, protein expression of p53 and active caspase-3 was increased, while the expression of p-Akt as well as the Bcl-2/Bax ratio, an index of survival activity in cells, were decreased in the HET-pre-treated cells compared with those in HET-untreated cells following incubation with cisplatin. In conclusion, the present study indicated that HET enhanced cisplatin-induced apoptosis of HeLa cells and that the administration of HET may therefore be clinically beneficial alongside apoptosis-inducing chemotherapy. PMID- 26239549 TI - Intertemporal choice behavior is constrained by brain structure in healthy participants and pathological gamblers. AB - The steepness of the delay discounting function shows considerable interindividual differences. Moreover, faster devaluation of future rewards has been consistently observed in pathological gamblers (PGs). Here, we asked whether variability in delay discounting is at least partially driven by differences in the anatomy of gray and white matter. For 40 healthy young subjects (study 1) as well as 15 PG and 15 age-matched healthy controls (HCs, study 2), the individual discounting parameter k was obtained. Based on 3D T1-weighted high-resolution magnetic resonance scans and diffusion tensor imaging, we performed voxel-based morphometry and tract-based spatial statistics, respectively, to examine the relation of gray matter volume (GMV) and white matter properties (as indicated by fractional anisotropy, FA) to k. Healthy groups from both studies showed a negative correlation between k and FA for the superior longitudinal fascicle and inferior longitudinal fascicle, whereas a positive correlation was found in the PG group for the inferior longitudinal fascicle and left inferior fronto occipital fascicle. The latter also was significantly different between HC and PG in the group statistics (albeit on the right side), thus suggesting that this is a significant structure for the development of pathological gambling. GMV of the right frontal orbital cortex, left insular cortex and right lateral occipital cortex showed a positive correlation to k HC (studies 1 and 2) and PG, whereas a negative correlation was found for the left frontal pole in all three groups. Group comparison of GMV (study 2) revealed a decrease in PG for several cortical and subcortical areas. PMID- 26239550 TI - Managing anthracycline-induced cardiotoxicity: beginning with the end in mind. PMID- 26239551 TI - Human IL-21+IFN-gamma+CD4+ T cells in nasal polyps are regulated by IL-12. AB - In the previous study, we found that the levels of IL-21 in nasal polyps (NPs) were significantly increased and associated with polyp size and recurrence. However, it is unclear that the cell source of IL-21 and the regulation of IL-21 in NP tissues. In the present study, we isolated the lymphocytes from NP tissues, uncinate tissues and peripheral blood of patients with NPs. The cells were analyzed for cell surface markers, cytokines and transcriptional factors by flow cytometry. The results indicated that CD4(+) T cells were the major IL-21 expressing cells in NP tissues and the majority of IL-21 producing CD4(+) T cells co-expressed IFN-gamma or IL-17A. IL-21(+)IFN-gamma(+)CD4(+) T cells in NP tissues exhibited the features of both Tfh and Th1 cells which co-expressed significantly higher amount of CXCR5, ICOS, PD-1, Bcl-6 and T-bet than did IL 21(+)IFN-gamma(-)CD4(+) T cells (p < 0.05). Treatment of the lymphocytes from NP tissues with IL-12 enhanced the production of IL-21 and IFN-gamma, especially the frequency of IL-21(+)IFN(-)gamma(+)CD4(+) T cells (p < 0.05). The blockade of IL 12 inhibited the production of IL-21 and IFN-gamma (p < 0.05). These findings indicated that IL-12 positively enhanced the generation of IL-21(+)IFN gamma(+)CD4(+) T cells having the features of both Tfh and Th1 cells in NP tissues. PMID- 26239552 TI - Endothelin Blockade in Diabetic Kidney Disease. AB - Diabetic kidney disease (DKD) remains the most common cause of chronic kidney disease and multiple therapeutic agents, primarily targeted at the renin angiotensin system, have been assessed. Their only partial effectiveness in slowing down progression to end-stage renal disease, points out an evident need for additional effective therapies. In the context of diabetes, endothelin-1 (ET 1) has been implicated in vasoconstriction, renal injury, mesangial proliferation, glomerulosclerosis, fibrosis and inflammation, largely through activation of its endothelin A (ETA) receptor. Therefore, endothelin receptor antagonists have been proposed as potential drug targets. In experimental models of DKD, endothelin receptor antagonists have been described to improve renal injury and fibrosis, whereas clinical trials in DKD patients have shown an antiproteinuric effect. Currently, its renoprotective effect in a long-time clinical trial is being tested. This review focuses on the localization of endothelin receptors (ETA and ETB) within the kidney, as well as the ET-1 functions through them. In addition, we summarize the therapeutic benefit of endothelin receptor antagonists in experimental and human studies and the adverse effects that have been described. PMID- 26239553 TI - The Possible Future Roles for iPSC-Derived Therapy for Autoimmune Diseases. AB - The ability to generate inducible pluripotent stem cells (iPSCs) and the potential for their use in treatment of human disease is of immense interest. Autoimmune diseases, with their limited treatment choices are a potential target for the clinical application of stem cell and iPSC technology. IPSCs provide three potential ways of treating autoimmune disease; (i) providing pure replacement of lost cells (immuno-reconstitution); (ii) through immune-modulation of the disease process in vivo; and (iii) for the purposes of disease modeling in vitro. In this review, we will use examples of systemic, system-specific and organ-specific autoimmunity to explore the potential applications of iPSCs for treatment of autoimmune diseases and review the evidence of iPSC technology in auto-immunity to date. PMID- 26239554 TI - The Concept and the Epidemiology of Diabetic Nephropathy Have Changed in Recent Years. AB - Diabetes Mellitus (DM) is a growing worldwide epidemic. It was estimated that more than 366 million people would be affected. DM has spread its presence over the world due to lifestyle changes, increasing obesity and ethnicities, among others. Diabetic nephropathy (DN) is one of the most important DM complications. A changing concept has been introduced from the classical DN to diabetic chronic kidney disease (DCKD), taking into account that histological kidney lesions may vary from the nodular or diffuse glomerulosclerosis to tubulointerstitial and/or vascular lesions. Recent data showed how primary and secondary prevention were the key to reduce cardiovascular episodes and improve life expectancy in diabetic patients. A stabilization in the rate of end stage kidney disease has been observed in some countries, probably due to the increased awareness by primary care physicians about the prognostic importance of chronic kidney disease (CKD), better control of blood pressure and glycaemia and the implementation of protocols and clinical practice recommendations about the detection, prevention and treatment of CKD in a coordinated and multidisciplinary management of the DM patient. Early detection of DM and DCKD is crucial to reduce morbidity, mortality and the social and economic impact of DM burden in this population. PMID- 26239555 TI - The Role of Malassezia spp. in Atopic Dermatitis. AB - Malassezia spp. is a genus of lipophilic yeasts and comprises the most common fungi on healthy human skin. Despite its role as a commensal on healthy human skin, Malassezia spp. is attributed a pathogenic role in atopic dermatitis. The mechanisms by which Malassezia spp. may contribute to the pathogenesis of atopic dermatitis are not fully understood. Here, we review the latest findings on the pathogenetic role of Malassezia spp. in atopic dermatitis (AD). For example, Malassezia spp. produces a variety of immunogenic proteins that elicit the production of specific IgE antibodies and may induce the release of pro inflammatory cytokines. In addition, Malassezia spp. induces auto-reactive T cells that cross-react between fungal proteins and their human counterparts. These mechanisms contribute to skin inflammation in atopic dermatitis and therefore influence the course of this disorder. Finally, we discuss the possible benefit of an anti-Malassezia spp. treatment in patients with atopic dermatitis. PMID- 26239556 TI - Cutaneous Squamous Cell Carcinomas in Organ Transplant Recipients. AB - Non-melanoma skin cancers represent a major cause of morbidity after organ transplantation. Squamous cell carcinomas (SCC) are the most common cutaneous malignancies seen in this population, with a 65-100 fold greater incidence in organ transplant recipients compared to the general population. In recent years, human papillomaviruses (HPV) of the beta genus have been implicated in the pathogenesis of post-transplant SCCs. The underlying mechanism of carcinogenesis has been attributed to the E6 and E7 proteins of HPV. Specific immunosuppressive medications, such as the calcineurin inhibitors and azathioprine, are associated with a higher incidence of post-transplant SCCs compared to other immunosuppressive agents. Compared to other immunosuppressives, mTOR inhibitors and mycophenolate mofetil have been associated with a decreased risk of developing post-transplant non-melanoma skin cancers. As a result, they may represent ideal immunosuppressive medications in organ transplant recipients. Treatment options for post-transplant SCCs include surgical excision, Mohs micrographic surgery, systemic retinoid therapy, adjunct topical therapy, electrodessication and curettage, and radiation therapy. This review will discuss the epidemiology, risk factors, and management options of post-transplant SCCs. In addition, the underlying mechanisms of beta-HPV mediated carcinogenesis will be discussed. PMID- 26239557 TI - Alternative Donor Transplantation for Acute Myeloid Leukemia. AB - Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for adult patients with acute myeloid leukemia (AML), but its use for consolidation therapy after first remission with induction chemotherapy used to be limited to younger patients and those with suitable donors. The median age of AML diagnosis is in the late 60s. With the introduction of reduced intensity conditioning (RIC), many older adults are now eligible to receive allo HCT, including those who are medically less fit to receive myeloablative conditioning. Furthermore, AML patients commonly have no human leukocyte antigen (HLA)-identical or medically suitable sibling donor available to proceed with allo-HCT. Technical advances in donor matching, suppression of alloreactivity, and supportive care have made it possible to use alternative donors, such as unrelated umbilical cord blood (UCB) and partially HLA-matched related (haploidentical) donors. Outcomes after alternative donor allo-HCT are now approaching the outcomes observed for conventional allo-HCT with matched related and unrelated donors. Thus, with both UCB and haploidentical donors available, lack of donor should rarely be a limiting factor in offering an allo-HCT to adults with AML. PMID- 26239558 TI - Kidney Transplantation in the Diabetic Patient. AB - Diabetes mellitus is one of the most important causes of chronic kidney disease (CKD). In patients with advanced diabetic kidney disease, kidney transplantation (KT) with or without a pancreas transplant is the treatment of choice. We aimed to review current data regarding kidney and pancreas transplant options in patients with both type 1 and 2 diabetes and the outcomes of different treatment modalities. In general, pancreas transplantation is associated with long-term survival advantages despite an increased short-term morbidity and mortality risk. This applies to simultaneous pancreas kidney transplantation or pancreas after KT compared to KT alone (either living donor or deceased). Other factors as living donor availability, comorbidities, and expected waiting time have to be considered whens electing one transplant modality, rather than a clear benefit in survival of one strategy vs. others. In selected type 2 diabetic patients, data support cautious utilization of simultaneous pancreas kidney transplantation when a living kidney donor is not an option. Pancreas and kidney transplantation seems to be the treatment of choice for most type 1 diabetic and selected type 2 diabetic patients. PMID- 26239559 TI - Association between Osteopontin Promoter Gene Polymorphisms and Haplotypes with Risk of Diabetic Nephropathy. AB - BACKGROUND: Osteopontin (OPN) C-443T promoter polymorphism has been shown as a genetic risk factor for diabetic nephropathy (DN) in type 2 diabetic patients (T2D). METHODS: In the present study we investigated the association of three functional promoter gene polymorphisms C-443T, delG-156G, and G-66T and their haplotypes with the risk of DN and estimated Glomerular Filtration Rate (eGFR) in Asian Indians T2D patients using Real time PCR based Taqman assay. A total of 1165 T2D patients, belonging to two independently ascertained Indian Asian cohorts, were genotyped for three OPN promoter polymorphisms C-443T (rs11730582), delG-156G (rs17524488) and G-66T (rs28357094). RESULTS: -156G allele and GG genotypes (delG-156G) and haplotypes G-C-G and T-C-G (G-66T, C-443T, delG-156G) were associated with decreased risk of DN and higher eGFR. Haplotype G-T-delG and T-T-delG (G-66T, C-443T, delG-156G) were identified as risk haplotypes, as shown by lower eGFR. CONCLUSION: This is the first study to report an association of OPN promoter gene polymorphisms; G-66T and delG-156G and their haplotypes with DN in T2D. Our results suggest an association between OPN promoter gene polymorphisms and their haplotypes with DN. PMID- 26239561 TI - How Often Do Comparative Randomised Controlled Trials in the Field of Eczema Fail to Directly Compare the Treatments Being Tested? AB - The objective of the study was to identify all parallel design randomised controlled trials (RCTs) comparing treatments for eczema in recent dermatology literature that have failed to report a between-group analysis. The GREAT database (www.greatdatabase.org.uk) was searched to identify parallel group RCTs comparing two or more interventions published in the English language in the last decade, 2004 to 2013. The primary outcome was the number of studies that had not reported a between-group analysis for any of the outcomes. Where possible we re analysed the data to determine whether a between-group analysis would have given a different conclusion to that reported. Out of a total of 304 RCTs in the study period, 173 (56.9%) met the inclusion criteria. Of the 173 eligible studies, 12 (6.9%) had not conducted a between-group analysis for any of the reported outcomes. There was no clear improvement over time. Five of the eight studies that were re-analysed yielded non-significant between-group differences yet reported significant within-group comparisons. All but one of the 12 studies implied that the experimental intervention was successful despite not undertaking any between-group comparisons. Although the proportion of all RCTs that fail to report an appropriate between-group analysis is small, the fact that any scientist who purports to compare one treatment against another then chooses to omit the key comparison statistic is worrying. PMID- 26239560 TI - Role of Neuropilin-1 in Diabetic Nephropathy. AB - Diabetic nephropathy (DN) often develops in patients suffering from type 1 or type 2 diabetes mellitus. DN is characterized by renal injury resulting in proteinuria. Neuropilin-1 (NRP-1) is a single-pass transmembrane receptor protein devoid of enzymatic activity. Its large extracellular tail is structured in several domains, thereby allowing the molecule to interact with multiple ligands linking NRP-1 to different pathways through its signaling co-receptors. NRP-1's role in nervous system development, immunity, and more recently in cancer, has been extensively investigated. Although its relation to regulation of apoptosis and cytoskeleton organization of glomerular vascular endothelial cells was reported, its function in diabetes mellitus and the development of DN is less clear. Several lines of evidence demonstrate a reduced NRP-1 expression in glycated-BSA cultured differentiated podocytes as well as in glomeruli from db/db mice (a model of type 2 Diabetes) and in diabetic patients diagnosed with DN. In vitro studies of podocytes implicated NRP-1 in the regulation of podocytes' adhesion to extracellular matrix proteins, cytoskeleton reorganization, and apoptosis via not completely understood mechanisms. However, the exact role of NRP-1 during the onset of DN is not yet understood. This review intends to shed more light on NRP-1 and to present a link between NRP-1 and its signaling complexes in the development of DN. PMID- 26239563 TI - Sex differences in prevalence of overweight and obesity, and in extent of overweight index, in children and adolescents (3-18 years) from Krakow, Poland in 1983, 2000 and 2010. AB - OBJECTIVE: The increasing prevalence of overweight and obesity among children is now an important health problem. This fact, however, does not reflect the scale of the problem. The aim of the present study was to find how much the BMI threshold was exceeded in a population from Krakow. DESIGN: The study was based on three cross-sectional surveys conducted in 1983, 2000 and 2010. The prevalence of overweight and obesity was estimated based on the International Obesity Task Force cut-off points. In addition to these, an extent of overweight (EOW) index was calculated. SETTING: Poland. SUBJECTS: Children aged 3-18 years (n 14 534) from Krakow. RESULTS: Between the populations examined in 1983 and 2010, the EOW index in boys rose by almost 10 %, and the prevalence of overweight and obesity by 39 %. In girls, however, the EOW index decreased by 45 %, while the prevalence of overweight and obesity remained at similar levels. Analyses in separate age groups showed that the EOW index increased only among early adolescents (150 % for boys, 94 % for girls) and late adolescents (390 % and 64 %, respectively). CONCLUSIONS: The observed increased prevalence of overweight and obesity mainly concerned boys and was accompanied by an increase in the amount by which the BMI threshold values were exceeded. PMID- 26239562 TI - Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade. AB - Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways. Among agents currently undergoing trials that may modify the clinical practice on top of RAS blockade in a 5-year horizon, anti-inflammatory agents currently hold the most promise while anti-fibrotic agents have so far disappointed. Pentoxifylline, an anti-inflammatory agent already in clinical use, was recently reported to delay estimated glomerular filtration rate (eGFR) loss in chronic kidney disease (CKD) stage 3-4 diabetic kidney disease when associated with RAS blockade and promising phase 2 data are available for the pentoxifylline derivative CTP-499. Among agents targeting chemokines or chemokine receptors, the oral small molecule C-C chemokine receptor type 2 (CCR2) inhibitor CCX140 decreased albuminuria and eGFR loss in phase 2 trials. A dose-finding trial of the anti-IL-1beta antibody gevokizumab in diabetic kidney disease will start in 2015. However, clinical development is most advanced for the endothelin receptor A blocker atrasentan, which is undergoing a phase 3 trial with a primary outcome of preserving eGFR. The potential for success of these approaches and other pipeline agents is discussed in detail. PMID- 26239565 TI - Predictive Value of D-Dimer Levels and Tissue Doppler Mitral Annular Systolic Velocity for Detection of Left Atrial Appendage Thrombus in Patients with Mitral Stenosis in Sinus Rhythm. AB - BACKGROUND: Transesophageal echocardiogram (TEE) is a gold standard test for diagnosis of left atrial (LA) thrombus, but it has limited sensitivity for identification of small thrombi within side lobes. Thus, the absence of visualizing a left atrial appendage (LAA) thrombus does not equate with the absence of a LAA thrombus. AIM: To assess the predictive value of mitral annular systolic velocity (Sa) and D-dimer for the detection of LA thrombus and spontaneous echocardiographic contrast (SEC) in mitral stenosis (MS) patients with sinus rhythm (SR). METHODS: Transthoracic echocardiogram, TEE, and D-dimer analysis were performed in 104 severe MS patients and divided them into three groups: Group I:no LA thrombus or SEC; Group II:LA SEC only; and Group III:LA thrombus. RESULTS: Group III had more severe New York Heart Association (NYHA) class (III-IV) dyspnea and lower Sa (6.9 +/- 0.7 vs.10.0 +/- 1.2 cm/sec), lower LAA late emptying velocity (17.7 +/- 2.1 vs. 24.4 +/- 4.2 cm/sec), larger LA transverse dimension, and LAA area (LAAA) than group I+II. Mean D-dimer levels were higher in groups III and II than in group I. In multivariate analysis Sa, D dimer levels, LAAA, and NYHA class were independent predictors of LA thrombus. ROC curve analysis revealed that higher Sa >8 cm/sec and lower D-dimer levels <370 MUg/L predict the absence of LA thrombus and lower Sa <8 cm/sec and higher D dimer levels >510 MUg/L predict the presence of LA thrombus. CONCLUSION: Measurement of Sa and D-dimer levels is necessary for better assessment of LA thrombus and SEC, for identification of patients who are at high risk for LA thrombus formation and for initiation of prophylactic anticoagulation. PMID- 26239564 TI - Association between liver X receptor-alpha and neuron-derived orphan nuclear receptor-1 in Kupffer cells of C57BL/6 mice during inflammation. AB - The liver X receptor (LXR) isoform LXR-alpha has a significant role in lipid metabolism and innate immunity. Overexpression of neuron-derived orphan nuclear receptor-1 (NOR-1) in macrophages reduces the synthesis of inflammatory cytokines and chemokines. However, to date, the mechanisms via which NOR-1 inhibits lipopolysaccharide (LPS)-induced inflammation in Kupffer cells (KCs) via LXR alpha have not been elucidated. T0901317 is the most potent LXR-alpha ligand, leading to its activation. In the present study, KCs were isolated from C57BL/6 mice and randomly divided into five groups: Control, T0901317, LPS, LPS + T0901317 and LPS + T0901317 + NOR-1 small hairpin (sh)RNA groups. In order to investigate the role of NOR-1 in inflammation, shRNA targeting NOR-1 was used to specifically knock down NOR-1 mRNA in KCs. The expression levels of LXR-alpha and NOR-1 in KCs were determined by reverse transcription quantitative polymerase chain reaction and western blot analyses. The protein levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 in the supernatant of KCs were evaluated by ELISA. The results revealed that LXR-alpha expression in the T0901317 group was higher than that in the control group; furthermore, LXR-alpha expression was higher in KCs treated with LPS + T0901317 compared with that in KCs treated with LPS only. The expression levels of NOR-1 in each group showed a similar trend. shRNA targeting of NOR-1 suppressed the mRNA expression of NOR-1, but had no influence on LXR-alpha mRNA expression. NOR-1 protein expression was augmented in the LPS + T0901317 group compared with that in the LPS + T09 + shRNA group. In the supernatant of KCs, the TNF-alpha levels in the LPS + T0901317 group were lower than those in the LPS group, whereas the IL-10 levels were higher in the LPS + T0901317 group compared with those in the LPS group. The results of the present study suggested that ligand T0901317 promotes LXR-alpha expression, which consequently suppresses LPS-induced inflammation by elevating NOR-1 expression in KCs. PMID- 26239566 TI - Matrix metalloproteinase 9 expression and survival of patients with osteosarcoma: a meta-analysis. AB - Several studies have evaluated the effect of matrix metalloproteinase-9 (MMP-9) expression on the overall survival of patients with osteosarcoma, but the results remain conflicting. To examine the prognostic significance of MMP-9 expression in osteosarcoma risk, we conducted this meta-analysis to systematically review the published studies. We searched the commonly used electronic databases updated to September 2013 for relevant studies which evaluated the correction between MMP-9 expression and survival of patients with osteosarcoma. Overall, a total of eight studies including 437 cases were screened out. No significant heterogeneity was observed between studies. The MMP-9 was expressed in 73.9% (323/437) of cases, and the results showed that MMP-9 expression was associated with increased mortality rate of osteosarcoma during the follow-up (risk ratio = 2.79, 95% confidence interval, CI = 1.96-3.97, P < 0.00001). By ethnicity analysis, a significant correction was also found between MMP-9 expression and osteosarcoma risk among Asian and non-Asian population (P < 0.001), indicating that MMP-9 was an indicator of prognosis of osteosarcoma. In conclusion, this meta-analysis indicated that MMP-9 expression might be a biomarker of poor prognosis for patients with osteosarcoma. However, the prognostic value of MMP-9 on survival of osteosarcoma patients still needs further large-scale trials to be clarified. PMID- 26239567 TI - Plasma EGFR Mutation Detection Associated With Survival Outcomes in Advanced Stage Lung Cancer. AB - We confirmed the performance of an array method for plasma epidermal growth factor receptor (EGFR) mutation detection and showed the association of plasma EGFR mutation with survival outcomes. BACKGROUND: Noninvasive detection of epidermal growth factor receptor (EGFR) mutation in plasma is feasible and could be adjunct for therapeutic monitoring especially when repeated biopsy of tumor tissue is challenging. The aims of this study were to establish the diagnostic performance of peptide nucleic acid-locked nucleic acid polymerase chain reaction followed by custom array for plasma EGFR mutation and to evaluate the association of detection with clinical characteristics and survival outcomes. MATERIALS AND METHODS: Plasma genomic DNA from consecutive advanced lung cancer subjects was tested for EGFR mutations before anticancer treatment, and compared with mutation status in tumor tissue. Clinical characteristics were compared between patients who were EGFR-mutant and wild type; and within EGFR mutants, whether EGFR mutations could be detected in plasma. RESULTS: In 74 lung cancer patients, the sensitivity, specificity, and positive and negative predictive values of plasma EGFR detection were 79.1%, 96.8%, 97.1%, and 76.9%, respectively. EGFR mutants with concomitant detection of plasma EGFR mutation showed worse survival compared with mutants with no concomitant plasma mutation detected in biopsy specimens. CONCLUSION: Plasma EGFR mutation detected using this method demonstrated high diagnostic performance. In EGFR mutants, plasma EGFR mutation detection correlated not only EGFR mutation status in biopsy but was also associated with worse prognosis compared with EGFR mutant without plasma EGFR mutation detection. PMID- 26239568 TI - Structural changes in response to bioaccumulation of iron and mercury in Chromolaena odorata (L.) King & Robins. AB - A comparative study was designed to elucidate the effect of iron and mercury on the morphological and anatomical changes as well as bioaccumulation potential in Chromolaena odorata. Plants were grown in half-strength Hoagland nutrient medium artificially contaminated with known quantities of HgCl2 (15 MUM) and FeCl3 (1000 MUM). Bioaccumulation of Hg and Fe was maximum in the root, and comparatively reduced bioaccumulation was recorded in the stem and leaves. Microscopic studies on morphology and anatomy revealed development of trichomes and lenticels on the stem and modified trichomes on leaves. Localized deposits of stained masses in various internal parts of the root, stem and leaf also were observed. Differential adaptation/strategy of C. odorata to attain tolerance towards Hg and Fe and phytoremediation potential of the plant is discussed. PMID- 26239569 TI - Annual ecosystem respiration variability of alpine peatland on the eastern Qinghai-Tibet Plateau and its controlling factors. AB - Peatlands are widely developed in the eastern Qinghai-Tibet Plateau, but little is known about carbon budgets for these alpine peatland ecosystems. In this study, we used an automatic chamber system to measure ecosystem respiration in the Hongyuan peatland, which is located in the eastern Qinghai-Tibet Plateau. Annual ecosystem respiration measurements showed a typical seasonal pattern, with the peak appearing in June. The highest respiration was 10.43 MUmol CO2/m(2)/s, and the lowest was 0.20 MUmol CO2/m(2)/s. The annual average ecosystem respiration was 2.06 MUmol CO2/m(2)/s. The total annual respiration was 599.98 g C/m(2), and respiration during the growing season (from May to September) accounted for 78 % of the annual sum. Nonlinear regression revealed that ecosystem respiration has a significant exponential correlation with soil temperature at 10-cm depth (R (2) = 0.98). The Q 10 value was 3.90, which is far higher than the average Q 10 value of terrestrial ecosystems. Ecosystem respiration had an apparent diurnal variation pattern in growing season, with peaks and valleys appearing at approximately 14:00 and 10:00, respectively, which could be explained by soil temperature and soil water content variation at 10-cm depth. PMID- 26239570 TI - A multivariate statistical approach to identify the spatio-temporal variation of geochemical process in a hard rock aquifer. AB - A study has been carried out in crystalline hard rock aquifers of Madurai district, Tamil Nadu, to identify the spatial and temporal variations and to understand sources responsible for hydrogeochemical processes in the region. Totally, 216 samples were collected for four seasons [premonsoon (PRM), southwest monsoon (SWM), northeast monsoon (NWM), and postmonsoon (POM)]. The Na and K ions are attributed from weathering of feldspars in charnockite and fissile hornblende gneiss. The results also indicate that monsoon leaches the U ions in the groundwater and later it is reflected in the (222)Rn levels also. The statistical relationship on the temporal data reflects the fact that Ca, Mg, Na, Cl, HCO3, and SO4 form the spinal species, which are the chief ions playing the significant role in the geochemistry of the region. The factor loadings of the temporal data reveal the fact that the predominant factor is anthropogenic process and followed by natural weathering and U dissolution. The spatial analysis of the temporal data reveals that weathering is prominent in the NW part and that of distribution of U and (222)Rn along the NE part of the study area. This is also reflected in the cluster analysis, and it is understood that lithology, land use pattern, lineaments, and groundwater flow direction determine the spatial variation of these ions with respect to season. PMID- 26239571 TI - Statistical analysis of the influence of major tributaries to the eco-chemical status of the Danube River. AB - We have assembled and assessed the statistical procedure which is capable to objectively explore influence of the Danube's major tributaries (the Rivers Tisa, Sava, and Velika Morava) to its eco-chemical status. Procedure contains several tests for measurement of central tendencies: one-way analysis of variance (ANOVA), repeated measures ANOVA, and nonparametric Kruskal-Wallis and Mann Whitney tests. Various nuisance factors, (outliers, departures from normality, seasonality, and heteroscedasticity) which are present in large data bases, affect the objectivity of central tendency tests; therefore, it was important not only to estimate their robustness, but also to apply proper procedures for detection of the nuisance factors (Grubbs', generalized ESD-extreme Studentized deviate, Kolmogorov-Smirnov, Shapiro-Wilk, turning point, Wald-Wolfowitz runs, Kendall rank, and Levene's tests) and to mitigate their influence (outlier exclusion, Box-Cox, and logarithmic transformations). The analysis of selected eco-chemical parameters: biological oxygen demand-5, chemical oxygen demand, UV extinction at 254 nm, dissolved oxygen, oxygen saturation, total dissolved solids, electrical conductivity, suspended matter, total phosphorus, phosphates, nitrates, ammonia, pH, total alkalinity, m-2p alkalinity, CO2, and temperature, was performed for 15 years period. The Tisa was the most polluted tributary, but its pollution load was not substantial enough to exceed the Danube self purification potential. The City of Belgrade was also identified as serious pollution source. Assessment of assembled statistical procedure, which was based on the real environmental data, indicates that proposed tests are sufficiently robust to the observed level of nuisance factors with the exception of pronounced seasonality. PMID- 26239572 TI - Hepatic and visceral adipose tissue 11betaHSD1 expressions are markers of body weight loss after bariatric surgery. AB - OBJECTIVE: Cortisolemia and 11betaHSD1 in liver and adipose tissue are altered in obesity. However, their participation in the development of obesity remains unclear. This study analyzed these parameters in the transition from morbid to type 1 obesity after bariatric surgery. METHODS: A group of 34 patients with morbid obesity and 22 nonobese subjects were recruited. Initial hypothalamus pituitary-adrenal (HPA) basal activity and 11betaHSD1 mRNA expression in liver, subcutaneous (SAT), and visceral adipose tissue (VAT) were evaluated. A year after bariatric surgery (weight loss of 48 kg), these parameters were reappraised in plasma, SAT, and liver. RESULTS: Body weight loss was accompanied by a downshift in basal HPA activity and 11betaHSD1 expression in SAT. In patients with morbid obesity, 11betaHSD1 expression correlated positively with BMI in VAT and negatively in liver at 6 and 12 months after surgery. In SAT, a correlation was observed with body weight only when patients showed type 1 obesity. Insulin, glucose, and HOMA correlated positively with all the HPA indicators and 11betaHSD1 expression in SAT. CONCLUSIONS: Body weight loss after bariatric surgery is accompanied by a downshift in basal HPA activity. Hepatic and VAT 11betaHSD1 expressions in morbid obesity are predictors of body weight loss. PMID- 26239573 TI - Effect of transcatheter arterial chemoembolization on cellular immune function and regulatory T cells in patients with hepatocellular carcinoma. AB - The present study aimed to investigate changes in cellular immune function and regulatory T cells (Tregs) in patients with hepatocellular carcinoma (HCC) prior to and following transcatheter arterial chemoembolization (TACE) and their clinical significance. The proportion of CD4+ and CD8+ T cells and Tregs in the peripheral blood between healthy volunteers and patients with HCC were detected by flow cytometry prior to (1 day) and one month following TACE. The level of interleukin (IL)-35 in the peripheral blood was examined by ELISA. In the peripheral blood of patients with HCC, the proportion of CD4+ T cells in the total T lymphocytes was significantly lower compared with that of healthy volunteers (26.71 +/- 5.57, vs. 34.74 +/- 2.86%; P<0.05) and the ratio of CD4+/CD8+ T lymphocytes in patients with HCC was lower compared with that of healthy adults prior to TACE (1.03 +/- 0.14, vs. 1.68 +/- 0.16, P<0.05). The ratio markedly increased following TACE treatment (30.52 +/- 4.19, vs. 1.29 +/- 0.14). The percentage of CD4+CD25+ Treg cells in the total CD4+ T cells isolated from the patients with HCC was markedly higher compared with that of healthy adults prior to TACE (11.12 +/- 3.58%, vs. 4.98 +/- 1.45%, P<0.05) and it was significantly decreased following TACE (7.58+/-2.65%; P<0.05). No statistically significant difference in the expression of IL-35 was detected prior to or following TACE in patients with HCC and healthy adults (369.66 +/- 95.53, 352.28 +/- 107.50 and 316.24 +/- 89.21 pg/ml, respectively). The level of AFP, an oncofetal protein of ~72 kDa, which is produced by normal gastrointestinal cells, yolk sac cells and fetal hepatocytes immediately following birth, was increased in patients with HCC (1674 +/- 1649 ng/ml) and was significantly decreased following TACE (827 +/- 981 ng/ml). Treg cells changed in positive correlation with the change of AFP, with a correlation coefficient of 0.401. TACE markedly improved the immune function of patients with HCC. PMID- 26239574 TI - Assessment of the Cadmium Exposure in the Blood, Diet, and Water of the Pumi People in Yunnan, China. AB - Cadmium (Cd) is considered as one of the most toxic and carcinogenic heavy metals. Accumulation of Cd in the human body can cause multiorgan dysfunction. Long-term irrational mining activities have led to serious Cd pollution in soil, water, and even agricultural products. Therefore, evaluating the Cd exposure levels of people living in mining areas is of great importance. In the current study, we chose the Pumi people who lived in Jinding and Tongdian towns of Lanping county in Yunnan province, China, to do the on-site nutritional epidemiology investigation and laboratory detection. We analyzed the content of the Cd in peripheral blood and mixed dietary, as well as water samples in the Pumi residents of the two towns. Results showed that the blood Cd levels of people in Jinding town, which is nearer the mining district, were statistically significantly higher than those in Tongdian town. The P 50 of blood Cd level of the two towns was 0.64 ng/mL. In addition, the P 50 of the mixed diet of the two towns was 8.32 MUg/kg. There was a weak correlation between blood Cd levels and Cd exposure in the mixed diet, PTDI, and PTWI of the Pumi people. In addition, higher concentrations of Cd were observed in the water of Jinding town, indicating people in Jinding town risking more Cd exposure. These results indicated that diet and water are critical factors of Cd exposure for the residents and the nearer people living to mining district risking the more Cd exposure. PMID- 26239576 TI - Reducing research waste and improving research impact. PMID- 26239575 TI - Relationship between pathological findings and enzymes of the energy metabolism in liver of rats infected by Trypanosoma evansi. AB - The aim of this study was to investigate the activities of important enzymes involved in the energetic metabolism in the liver of rats experimentally infected by Trypanosoma evansi. Adenylate kinase (AK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) in liver homogenate, as well as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and clotting time in plasma were evaluated at 5 and 15 days post-infection (PI). The activities of the respiratory chain complexes and of Na(+), K(+)-ATPase were also evaluated. This study demonstrates energetic metabolism impairment in rats infected by T. evansi. A reduced energy metabolism in the liver of rats infected by T. evansi was observed, demonstrated by AK decreased and PK increased activities at 5 days PI, a mechanism known as energetic compensation. However, at 15 days PI a decrease of AK and PK activities were observed. In addition, an increase in the activities of respiratory chain complexes II, II-III and IV in infected rats at 15 days PI, and a decrease of Na(+), K(+)-ATPase activities in infected rats on days 5 and 15 PI were verified. In the plasma, we observed an increase in ALT and AST activities on days 5 and 15 PI, and increase in clotting time in infected rats. The changes caused by T. evansi infection on the activity of enzymes of hepatic energy metabolism can corroborate to elucidate the mechanisms that lead to liver injury and inflammatory infiltration verified in T. evansi infected rats. Therefore, these alterations are directly related to disease pathogenesis. PMID- 26239577 TI - The NHMRC Road Map 'benchmark' principles: a formal evaluation process is needed to improve their application. PMID- 26239579 TI - Usefulness of the Red Blood Cell Distribution Width to Predict Heart Failure in Patients With a Fontan Circulation. AB - The red blood cell distribution width (RDW) is a quantitative measure of the variability in the size of circulating erythrocytes. We aimed to study whether higher levels of the RDW were associated with heart failure in a Fontan circulation and to analyze its clinical value compared to brain natriuretic peptide. This retrospective study included 38 consecutive pediatric patients with a Fontan circulation who underwent routine cardiac catheterization at the International Medical Center, Saitama Medical University from October 2010 to July 2014. We assessed the relation between the RDW and catheterization data such as the central venous pressure (CVP), mixed venous oxygen saturation (SvO2), and cardiac index (CI). The RDW was positively correlated with the CVP (p = 0.0002). The elevated RDW group had a significantly greater CVP than the normal RDW group (p = 0.0003). Also, the RDW was negatively correlated with the SvO2 (p = 0.0004). The elevated RDW group had a significantly less SvO2 than the normal RDW group (p <0.0001). The CI in the elevated RDW group was lower than that in the normal RDW group (p = 0.0421). In the multivariate regression analysis, the RDW was a significant independent predictor of the CVP and SvO2. The BNP level did not have any significant relation with the CVP, SvO2, or CI. The RDW is a convenient and powerful marker for detecting heart failure in a Fontan circulation. PMID- 26239580 TI - Comparison of Outcomes in Patients With Nonobstructive, Labile-Obstructive, and Chronically Obstructive Hypertrophic Cardiomyopathy. AB - Patients with nonobstructive hypertrophic cardiomyopathy (HC) are considered low risk, generally not requiring aggressive intervention. However, nonobstructive and labile-obstructive HC have been traditionally classified together, and it is unknown if these 2 subgroups have distinct risk profiles. We compared cardiovascular outcomes in 293 patients HC (96 nonobstructive, 114 labile obstructive, and 83 obstructive) referred for exercise echocardiography and magnetic resonance imaging and followed for 3.3 +/- 3.6 years. A subgroup (34 nonobstructive, 28 labile-obstructive, 21 obstructive) underwent positron emission tomography. The mean number of sudden cardiac death risk factors was similar among groups (nonobstructive: 1.4 vs labile-obstructive: 1.2 vs obstructive: 1.4 risk factors, p = 0.2). Prevalence of late gadolinium enhancement (LGE) was similar across groups but more non-obstructive patients had late gadolinium enhancement >=20% of myocardial mass (23 [30%] vs 19 [18%] labile obstructive and 8 [11%] obstructive, p = 0.01]. Fewer labile-obstructive patients had regional positron emission tomography perfusion abnormalities (12 [46%] vs nonobstructive 30 [81%] and obstructive 17 [85%], p = 0.003]. During follow-up, 60 events were recorded (36 ventricular tachycardia/ventricular fibrillation, including 30 defibrillator discharges, 12 heart failure worsening, and 2 deaths). Nonobstructive patients were at greater risk of VT/VF at follow-up, compared to labile obstructive (hazed ratio 0.18, 95% confidence interval 0.04 to 0.84, p = 0.03) and the risk persisted after adjusting for age, gender, syncope, family history of sudden cardiac death, abnormal blood pressure response, and septum >=3 cm (p = 0.04). Appropriate defibrillator discharges were more frequent in nonobstructive (8 [18%]) compared to labile-obstructive (0 [0%], p = 0.02) patients. In conclusion, nonobstructive hemodynamics is associated with more pronounced fibrosis and ischemia than labile-obstructive and is an independent predictor of VT/VF in HC. PMID- 26239581 TI - Neuropeptide S Increases locomotion activity through corticotropin-releasing factor receptor 1 in substantia nigra of mice. AB - Neuropeptide S (NPS), the endogenous ligand of NPS receptor (NPSR), was reported to be involved in the regulation of arousal, anxiety, locomotion, learning and memory. The basal ganglia play a crucial role in regulating of locomotion-related behavior. Here, we found that NPSR protein of mouse was distributed in the substantia nigra (SN) and globus pallidus (LGP) by immunohistochemical analysis. However, less is known about the direct locomotion-related effects of NPS in both SN and LGP. Therefore, we investigated the role of NPS in locomotion processes, using the open field test. The results showed that NPS infused into the SN (0.03, 0.1, 1nmol) or LGP (0.01, 0.03, 0.1nmol) dose-dependently increased the locomotor activity in mice. SHA 68 (50mg/kg), an antagonist of NPSR, blocked the locomotor stimulant effect of NPS in both nuleus. Meanwhile, these effects of NPS were also counteracted by the CRF1 receptor antagonist antalarmin (30mg/kg, i.p.). In addition, we found that the expression of c-Fos was significantly increased after NPS was delivered into SN. In conclusion, these results indicate that NPS-NPSR system may regulate locomotion together with the CRF1 system in SN. PMID- 26239582 TI - Maternal-infant mental health: postpartum group intervention. AB - Dyadic interactions associated with maternal depression and anxiety may perpetuate maternal mental illness and impact infant attachment. Individual and maternal-dyadic therapies are effective but resource intensive. We assessed feasibility, acceptability, and preliminary efficacy of a newly developed maternal-infant dyadic group therapy intervention. This was an open-label pilot study targeting mothers with mood or anxiety disorders, and their infants aged 6 to 12 months. We conducted three 12-week groups combining evidence-based maternal and mother-infant dyadic strategies to enhance mood, insight, parenting, and mentalizing capacity. We measured recruitment and retention rates, reasons for nonparticipation, and missed sessions. Acceptability of the intervention was assessed via questionnaires and semi-structured interviews. Efficacy outcomes were the Parenting Stress Index (PSI), Edinburgh Postnatal Depression Scale (EDPS), and the Beck Anxiety Inventory (BAI), measured pretreatment and posttreatment. The feasibility and acceptability were excellent. There was a significant reduction in mean depressive symptom scores (t 3.31; p 0.008 sig) and a trend toward decreasing anxiety scores (t 1.96; p 0.08). The total PSI score decreased, approaching statistical significance (t 2.23; p 0.057). Enhanced insight, parenting capacity, affect regulation, and positive interaction with baby were supported with self-report surveys and interviews. This resource efficient novel mother-baby dyadic group intervention shows excellent feasibility, acceptability, and has good preliminary efficacy results. It has the potential to improve depression, anxiety, affect regulation, parenting, and maternal mentalization. PMID- 26239583 TI - Multiple gait patterns within the same Winters class in children with hemiplegic cerebral palsy. AB - BACKGROUND: Previous literature hypothesized that Winters type I are mainly characterized by a hypo-activation of dorsiflexors and type II by hyperactivation of plantarflexors around initial contact. However, it is currently not known if hemiplegic children belonging to the same Winters class really share the same muscle activation patterns, although this information might have relevant clinical implications in the patient management. METHODS: Gait data of 38 hemiplegic cerebral palsy children (16 Winters type I, 22 Winters type II) were analyzed, focusing on the foot and shank. A 2.5-minute walk test was considered, corresponding to more than 100 gait cycles for each child, analyzing the muscle activation patterns of tibialis anterior and gastrocnemius lateralis. The large stride-to-stride variability of gait data was handled in an innovative way, processing separately: 1) distinct foot-floor contact patterns, and for each specific foot-floor contact pattern 2) distinct muscle "activation modalities", averaging only across gait cycles with the same number of activations, and obtaining, in both cases, the pattern frequency-of-occurrence. FINDINGS: At least 2 representative foot-floor contact patterns within each Winters group, and up to 4-5 distinct muscle activation patterns were documented. INTERPRETATION: It cannot be defined a predominant muscle activation pattern specific for a Winters group. For a correct clinical assessment of a hemiplegic child, it is advisable to record and properly analyze gait signals during a longer period of time (2-3 min), rather than (subjectively) selecting a few "clean" gait cycles, since these cycles may not be representative of the patient's gait. PMID- 26239584 TI - Global threshold dynamics of an SIVS model with waning vaccine-induced immunity and nonlinear incidence. AB - Vaccination is the most effective method of preventing the spread of infectious diseases. For many diseases, vaccine-induced immunity is not life long and the duration of immunity is not always fixed. In this paper, we propose an SIVS model taking the waning of vaccine-induced immunity and general nonlinear incidence into consideration. Our analysis shows that the model exhibits global threshold dynamics in the sense that if the basic reproduction number is less than 1, then the disease-free equilibrium is globally asymptotically stable implying the disease dies out; while if the basic reproduction number is larger than 1, then the endemic equilibrium is globally asymptotically stable indicating that the disease persists. This global threshold result indicates that if the vaccination coverage rate is below a critical value, then the disease always persists and only if the vaccination coverage rate is above the critical value, the disease can be eradicated. PMID- 26239585 TI - Robotic-assisted laparoscopic hysterectomy seems safe in women with early-stage endometrial cancer. AB - INTRODUCTION: Robotic surgery is increasingly used in the management of endometrial cancer; and although it is known that minimally invasive surgery reduces post-operative morbidity, the outcomes of this novel treatment should be monitored carefully. The aim of this study was to examine the incidence of complications according to the Clavien-Dindo scale after robotic-assisted laparoscopic hysterectomy (RALH) for early-stage endometrial cancer and atypical complex hyperplasia. The Clavien-Dindo scale grades the severity of complications. METHODS: This was a retrospective, descriptive cohort study of 235 women with endometrial cancer or atypical complex hyperplasia who had RALH. Surgeries were stratified into two groups: with or without pelvic lymphadenectomy. RESULTS: A total of 6% developed a grade 3 or higher complication with no significant difference (p = 0.24) between the groups. The overall incidence of complications was 15%, also with no significant difference between groups (p = 0.32). The most frequent complications were urinary tract infections (6%) and port site/wound infections (3%). A total of 21% of the women who had lymphadenectomy developed lymphoedema within 12 months. CONCLUSION: The types and frequency of complications observed in this study resemble those reported in similar studies of RALH for malignant gynaecologic conditions. Health care professionals treating and caring for women with early-stage endometrial cancer should know of the types and frequency of post-operative complications following RALH. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26239586 TI - Increased health-care utilisation in international adoptees. AB - INTRODUCTION: Several studies have documented that international adoptees have an increased occurrence of health problems and contacts to the health-care system after arriving to their new country of residence. This may be explained by pre adoption adversities, especially for the period immediately after adoption. Our study aimed to the assess health-care utilisation of international adoptees in primary and secondary care for somatic and psychiatric diagnoses in a late post adoption period. Is there an increased use of the health-care system in this period, even when increased morbidity in the group of international adoptees is taken into consideration? METHODS: This was a Danish register-based cohort study examining health-care utilisation in a multivariable two-part model. The prevalence of selected outcomes and the quantity of use were assessed in a late (year three, four and five) post-adoption period. The cohort comprised internationally adopted children (n = 6,820), adopted between 1994 and 2005, and all non-adopted children (n = 492,374) who could be matched with the adopted children on sex, age, municipality and family constellation at the time of adoption. RESULTS: International adoption increased the use of all services in primary care, while in secondary care only few areas showed an increased long term morbidity. CONCLUSION: International adoptees use medical services in primary care at a higher rate than non-adoptees some years after adoption. Excess use of services in secondary care is also present, but only exists in selected areas. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26239587 TI - Increased conjugated bilirubin is sufficient to initiate screening for biliary atresia. AB - INTRODUCTION: Biliary atresia is the leading cause of liver transplantation in children. It affects 1:15,000 in Denmark. With a national birth rate of 60,000, four children are born every year with biliary atresia. Early correction of biliary obstruction is essential to prevent fatal biliary cirrhosis. The Danish Health and Medicines Authority (DHMA) demands diagnostic evaluation of children with elevated level of serum bilirubin after two weeks of age. Biliary atresia has to be excluded if conjugated bilirubin level is above than 20 MUmol/l, and/or more than 20% of total bilirubin. This percentage value has caused diagnostic trouble over the years. The objective of the present study was to investigate the possibility of changing the recommendations. METHODS: This was a retrospective analysis of the medical records of children operated for biliary atresia in the 1993-2012 period. RESULTS: During the period, 73 patients where operated with a portoenterostomy ad modum Kasai. Patients older than 84 days at the time of operation were excluded, 54 patients were available for analysis. Conjugated bilirubin in MUmol/l and the percentage value were significantly above the DHMA threshold limit: mean 129.7 MUmol/l (42-334 MUmol/l) and 73% (28-97%), respectively. CONCLUSION: The total amount of conjugated bilirubin above 20 MUmol/l is sufficient to require further evaluation for biliary atresia. The percentage value is unnecessary and may cause confusion. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26239588 TI - Oral iron absorption test should not be performed with iron drops containing ferric iron. AB - INTRODUCTION: In an oral iron absorption test (OIAT), the rise in plasma iron concentration after oral ingestion of iron is a measure of intestinal iron absorption. We describe results of the OIAT using two different formulations of oral iron drops. METHODS: The study included all patients who had an OIAT performed at the Department of Internal Medicine, Farso, Aalborg University Hospital, Denmark, from 1 January 2013 to 17 June 2014 (n = 24) using ferrous iron drops "Glycifer" and from 18 June to 3 November 2014 (n = 17) using ferric iron drops "Medic". A venous blood sample was drawn before and then 90, 180 and 240 min. after the intake of 9 ml iron drops of the "Glycifer" brand (270 mg ferrous iron) or the intake of 11 ml iron drops of the "Medic" brand (264 mg ferric iron). RESULTS: The patient characteristics (ferrous versus ferric iron drops) were similar in terms of gender, age, haemoglobin, ferritin and previous gastric bypass surgery. The fasting baseline plasma iron concentration was median 5 MUmol/l in both groups (p = 0.4). The maximum plasma iron concen-tration increase from baseline after oral intake of the iron drops was median 2 MUmol/l (range: 0-8 MUmol/l) in the group given ferric iron drops and 48 MUmol/l (range: 14-78 MUmol/l) when ferrous iron drops were used (p < 0.001). CONCLUSION: OIAT performed with ferrous or ferric iron drops showed very different results with a lack of plasma iron concentration increase after ingestion of ferric iron drops. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26239589 TI - Classification of drugs with different risk profiles. AB - INTRODUCTION: A risk stratification approach is needed to identify patients at high risk of medication errors and a resulting high need of medication review. The aim of this study was to perform risk stratification (distinguishing between low-risk, medium-risk and high-risk drugs) for drugs found to cause serious adverse reactions due to medication errors. The study employed a modified Delphi technique. METHODS: Drugs from a systematic literature search were included into two rounds of a Delphi process. A panel of experts was asked to evaluate each identified drug's potential for harm and for clinically relevant drug-drug interactions on a scale from 1 (low risk) to 9 (high risk). RESULTS: A total of 36 experts were appointed to serve on the panel. Consensus was reached for 29/57 (51%) drugs or drug classes that cause harm, and for 32/57 (56%) of the drugs or drug classes that cause interactions. For the remaining drugs, a decision was made based on the median score. Two lists, one stating the drugs' potential for causing harm and the other stating clinically relevant drug-drug interactions, were stratified into low-risk, medium-risk and high-risk drugs. CONCLUSION: Based on a modified Delphi technique, we created two lists of drugs stratified into a low-risk, a medium-risk and a high-risk group of clinically relevant interactions or risk of harm to patients. The lists could be incorporated into a risk-scoring tool that stratifies the performance of medication reviews according to patients' risk of experiencing adverse reactions. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26239590 TI - Women referred for occupational risk assessment in pregnancy have no increased risk of adverse obstetric outcomes. AB - INTRODUCTION: Our aim was to study the association between pregnant women's referral status for occupational risk assessment, and their risk of preterm delivery (< 37 weeks), low birth weight (LBW) (< 2,500 g) and small for gestational age (SGA). METHODS: In a cohort study, 1,202 deliveries among pregnant women referred to two Danish clinics of occupational medicine (Copenhagen and Aarhus) from 1984 to 2010 were compared with the referred women's 1,077 non-referred pregnancy outcomes and with the pregnancy outcomes of 345,467 gainfully employed women from the same geographical areas and time period. Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI). Calculations were adjusted for the mother's age at delivery, parity, ethnicity, socioeconomic status, smoking, and in supplementary analyses for year of birth. RESULTS: Referred women gave birth to children with a higher birth weight than the average employee (difference 47.8 g; 95% CI: 19.9-75.6), but the outcomes did not differ with respect to gestational age (difference 0.05 weeks; 95% CI: -0.06-0.17), preterm delivery (OR: 0.8; 95% CI: 0.62-1.04), LBW (OR: 0.81; 95% CI: 0.52-1.26) or SGA (OR: 0.92; 95% CI: 0.72-1.17). CONCLUSION: The women who are referred for occupational risk assessment at two large occupational university departments are not at an increased risk of preterm birth or of delivering low birth weight children. This may reflect that reproductive hazards in Danish workplaces are limited and/or that the occupational risk assessment and counselling of pregnant women are preventing these selected adverse pregnancy outcomes. FUNDING: The Research Unit at Department of Occupational and Environmental Medicine at Bispebjerg Hospital supported the study financially. TRIAL REGISTRATION: not relevant. The study was conducted using systematically collected data including the refereed women's occupational exposure codes, which were anonymised and linked to national registries at Statistic Denmark. The Danish Data Protection Agency approved the study (R. no. 2012-41-1267). PMID- 26239591 TI - Risk factors and mortality among patients with severe muco-cutaneous drug reactions. AB - INTRODUCTION: The aim of this study was to examine risk factors and mortality among patients with erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). METHODS: This was a retrospective evaluation of the med-ical records of 250 patients from two Danish tertiary dermatological departments during a ten-year period. RESULTS: In a total of 192 cases (77.4%), the primary diagnosis of EM (66.5%), SJS (62.2%) and TEN (100%) was confirmed, whereas the remaining cases (22.6%) were diagnosed differently. Antibiotics and allopurinol were predominantly associated with TEN, whereas SJS was associated with a broad spectrum of drugs. EM was related mainly to viral infections, predominantly herpes (30.6%); 38.2% of the causes of EM remained unknown. Patients with TEN had the highest mortality; i.e. 60% in the course of the ten year study period: adjusted hazard ratio (HR) = 11.2 (95% confidence interval (CI): 3.65-34.35); p < 0.001 compared with EM patients. The risk of death was also increased among patients with SJS relative to patients with EM: HR = 2.60 (95% CI: 1.10-6.16); p = 0.030; however, this did not remain statistically significant after adjustment for age, co-morbidity, infection, cancer and polypharmacy, HR = 0.99 (95% CI: 0.38-2.57); p = 0.976. CONCLUSION: We validated diagnoses in 250 patients with EM, SJS and TEN diagnosed during a ten-year period. The survival of patients with TEN was expectedly low compared with patients with EM. We extend previous findings by showing that after adjustment for confounders, the survival rates of SJS and EM are comparable. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26239592 TI - Bronchoscopy in patients with haemoptysis and normal computed tomography of the chest is unlikely to result in significant findings. AB - INTRODUCTION: The standard evaluation of haemoptysis in a department of respiratory medicine would currently consist of chest radiography, contrast enhanced computed tomography (CT) and fibre-optic bronchoscopy (FOB), regardless of the result of the CT. Our aim was to evaluate whether patients presenting with haemoptysis but no positive finding on a contrast-enhanced CT of the chest are at risk for having serious disease, first of all lung cancer, and thus whether FOB is mandatory for such patients. METHODS: We searched the literature and retrospectively reviewed all records of patients referred with haemoptysis between 2000 and 2010 at the Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Denmark. RESULTS: A total of 379 patient records were reviewed for inclusion in the clinical part of the study. Of these, 269 had the information required for the study and had been examined with CT. In all, 16 of the 269 patients were diagnosed with lung cancer. In all of these, a tumour or other findings indicating a possible tumour were seen on the chest CT. No additional cases of lung cancer were discovered during FOB, and no cases had been missed by the CT. CONCLUSION: CT should be used as first-line examination in patients with a history of haemoptysis. Furthermore, in patients above 40 years of age with positive findings of any kind on the CT, further examination with FOB is indicated. However, if the chest CT is without pathological findings, it is most unlikely that FOB will reveal anything of significance. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26239593 TI - Vabrasio is a reliable test to rule out endometrial cancer. AB - INTRODUCTION: Endometrial cancer is the most common gynaecological cancer in Denmark, and its incidence peaks in the postmenopausal years. The aim of the present study was to evaluate the effectiveness of vacuum aspirator (vabrasio) for the detection of endometrial cancer in terms of sensitivity, specificity and predictive value. METHODS: A cohort counting 503 women who had vabrasio was evaluated retrospectively. The women included were consecutive patients who had received vabrasio at the Department of Gynaecology and Obstetrics at Herning Hospital, Denmark, during a two-year period. They were identified by searching the hospital database for the International Classification of Diseases, tenth version (ICD-10) code for vabrasio. RESULTS: The indications for vabrasio were postmenopausal bleeding (45%), meno/metrorrhagia (43%) and thickened endometrium/polyp (6%). The first evaluation by vabrasio was normal in 381 women (76%), insufficient in 83 women (17%), 22 (4%) had endometrial cancer and 17 (3%) had another non-malignant diagnosis. The first evaluation for cancer with vabrasio had a sensitivity of 81%, a specificity of 100% and predictive values of 100% (positive) and 99% (negative). CONCLUSION: Vabrasio has a good diagnostic reliability with respect to endometrial cancer, but has some shortcomings due to insufficient sampling for diagnosis. FUNDING: none. TRIAL REGISTRATION: not relevant. Danish Data Protection Agency: case no.: 1-16-02-601-14. PMID- 26239594 TI - Comparable effect of partly supervised and self-administered exercise programme in early rheumatoid arthritis--a randomised, controlled trial. AB - INTRODUCTION: There is a need to establish a framework and exercise level for patients with early rheumatoid arthritis (RA). The aim of this study was to compare the effect of a partly supervised and a self-administered exercise programme for patients with early RA. METHODS: A total of 51 patients with early (<= 5 years) RA were randomised to either a six-week supervised, progressive, high-intensity exercise programme followed by a six-week self-administered exercise programme or a 12-week self-administered exercise programme. RESULTS: A total of 36 patients completed the study. Following the 12 weeks of exercises, patients in the two groups had improved both their muscle strength and their physical fitness. There was a significant difference in Disease Activity Score in 28 joints calculated with C-reactive protein between the two exercise groups, but no significant differences in physical fitness, pain perception, Health Assessment Questionnaire, Short Form 36 health survey questionnaire, Fear Avoidance Beliefs Questionnaire, or in muscle strength, except from a significant difference in trunk extensors. The dropout was 40% in the supervised group versus 20% in the self-administered group. CONCLUSION: A progressive, high-intensity exercise programme is feasible for patients with early RA, although we observed an elevated number of dropouts for reasons not related to the intervention. The partly supervised exercise programme with follow-up after 12 weeks does not seem to be more effective than the self-administered exercise programme. FUNDING: none. TRIAL REGISTRATION: The trial was registered with www.clinicaltrials.gov (NCT01553305). PMID- 26239595 TI - Neuromuscular blockade during laparoscopic ventral herniotomy: protocol for a randomised controlled trial. AB - INTRODUCTION: Laparoscopic herniotomy is the preferred technique for some ventral hernias. Several factors may influence the surgical conditions, one being the depth of neuromuscular blockade (NMB) applied. We hypothesised that deep neuromuscular blockade defined as a post-tetanic count below eight would provide a better surgical workspace. METHODS: This was an investigator-initiated, assessor- and patient-blinded randomised cross-over study. A total of 34 patients with planned laparoscopic umbilical, incisional and linea alba herniotomy were studied. Patients would be randomised to receive deep NMB followed by no NMB, or no NMB followed by deep NMB. Our primary outcome was improvement of the surgical workspace (rated on a five-point scale) estimated as the difference between the workspace during deep NMB and the workspace without NMB. Secondary outcomes included, among others, surgeon's rating of surgical conditions during suturing, duration of surgery and duration of the suturing of the hernia. CONCLUSION: This randomised cross-over study investigated a potential effect on the surgical workspace in laparoscopic ventral herniotomy using deep NMB compared with no NMB. The study may provide knowledge relevant to other laparoscopic techniques. FUNDING: The study is funded by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp. TRIAL REGISTRATION: NCT02247466. PMID- 26239596 TI - Elucidating the immunological effects of 5-azacytidine treatment in patients with myelodysplastic syndrome and identifying new conditional ligands and T-cell epitopes of relevance in melanoma. AB - This review is focused on research within three different areas of tumor immunology: discovery of new T-cell epitopes and a new immunological antigen (reported in Paper I and II), elucidation of the immunological effects of treatment with a hypomethylating drug (reported in Paper III) and discovery of new conditional ligands (reported in Paper IV). Many melanoma-associated T-cell epitopes have been described, but 45% of these are restricted to human leukocyte antigen (HLA)-A2, leaving the remaining 36 different HLA molecules with only a few described T-cell epitopes each. Therefore we wanted to expand the number of T cell epitopes restricted to HLA-A1, -A3, -A11 and -B7, all HLA molecules frequently expressed in Caucasians in Western Europe and Northern America. In Paper I we focused on the proteins gp100, Mart1, MAGE-A3, NY-ESO-1, tyrosinase and TRP-2, all melanoma-associated antigens frequently recognized by T cells from HLA-A2 patients. On contrary, in Paper II we wanted to investigate the protein Nodal as a novel immunological target. We took advantage of a T-cell epitope mapping platform in which HLA ligands are predicted by computer-based algorithms, further tested in the laboratory by an ELISA-based method and used for flow cytometry-based detection of specific T-cell responses by use of combinatorial encoded major histocompatibility (MHC) class I multimers. This procedure resulted in 127 (Paper I) and 32 (Paper II) confirmed HLA ligands, respectively, which we used for screening of the T-cell recognition within peripheral blood mononuclear cell samples from melanoma patients. As spontaneous tumor-specific T-cell responses tend to be of very low frequency and probably below the detection threshold of the method, we incorporated a T-cell enrichment step prior to the detection of these responses. Our screening of 39 melanoma patients resulted in 26 (17 different) T-cell responses against the common melanoma-associated antigens and 10 (8 different) T-cell responses against Nodal. We were further able to show processing and presentation on the cell-surface in K562 and melanoma cells expressing relevant protein and HLA molecules of four of these peptide sequences from tyrosinase, gp100 (2 peptides) and Nodal, respectively. However, one of the gp100 peptides has previously been described as a T-cell epitope. In addition to identifying new melanoma-associated T-cell epitopes we could thus describe Nodal as a new immunological antigen found of relevance in melanoma patients. In Paper III we wanted to investigate if the hypomethylating drug 5 azactytidine (Vidaza, Celgene Inc.) modulates the immune system in patients with myeloproliferative diseases. It has previ-ously been shown that 5-azacytidine mediated demethylation of gene promoter regions results in enhanced transcription and expression of tumor suppressor genes and cancer-testis antigens. Cancer testis antigens have frequently been recognized by T-cells in many cancers, and we hypothesized that 5-azacytidine treat-ment in the clinic would increase their frequency with resulting enhanced anti-tumor reactivity. We investigated separately the effect on T cells and tumor cells, and found that tumor cells af fected by the treatment were better recognized, resulting in higher numbers of activated T cells, than tumor cells not exposed to 5-azacytidine. No effects were observed on the T-cell population. A screen of the T-cell recognition of 43 cancer-testis antigens in blood from our patients revealed increased T-cell recognition upon start of therapy which, though, stabilized or declined at later time points. We further investigated the general immune effector and inhibitory cell populations and found only minor effects of drug exposure, suggesting that 5 azacytidine primarily affects the tumor cells. From these results we are currently initiating a phase I clinical trial of cancer-testis antigen-peptide vaccination in combination with 5-azacytidine therapy for patients with myeloproliferative diseases. In Paper IV we wanted to expand the library of conditional ligands for use with the UV light-mediated peptide-exchange method. This method enables high-throughput generation of MHC class I molecules with different peptide-specificities. These MHC monomers can be multimerized and used for detection of specific T cell populations by flow or mass cytometry. The HLA molecules are highly genetically variable and this necessitates unique design of conditional ligands for each HLA molecule. Thus, to screen for the T-cell recognition in a given setting within all patients or healthy donors present in a cohort, a broad library of conditional ligands is needed. We designed and evaluated conditional ligands for HLA-B*08:01, HLA-B*35:01 and HLA-B*44:02/03/05, all HLA-B molecules present in high frequency among Caucasians. In addition, we provided proof for the use of a conditional ligand first designed for HLA-B*15:02 in complex with HLA-B*15:01. We compared the staining patterns of HLA-B*15:01 and HLA-B*15:02 MHC multimers and found remarkable dissimilarities, although the two heavy chains in these MHC molecules only differ in a few amino acid positions. PMID- 26239597 TI - Hemostasis and endothelial damage during sepsis. AB - The sepsis syndrome represents a disease continuum, including severe sepsis and septic shock associated with high mortality. One of the main problems in severe sepsis and septic shock, resulting in organ failure and death, are disturbances in the hemostasis due to sepsis-related coagulopathy. Sepsis-related coagulopathy affects not only traditional coagulation factors, but also the platelets and endothelium. Functional testing of the hemostatic system has found application in critical illness. Thrombelastography (TEG) provides an overview of the hemostatic system allowing for an evaluation of interactions between coagulation factors and platelets. Additionally, the role of the endothelium during sepsis can be explored through testing of biomarkers of endothelial damage. The three studies comprising this PhD thesis all investigate important aspects of the disturbed hemostasis during sepsis, including endothelial damage. Together, the specific findings from the three studies improve the existing understanding of sepsis related coagulopathy, and the possible influences of some of the treatments offered these patients. The first study investigates the occurrence of antimicrobial-induced thrombocytopenia among critically ill patients. In sepsis, thrombocytopenia is a predictor of poor outcome, and reports, of mainly casuistic nature, have previously hypothesized that specific antimicrobial agents could induce in sepsis-related thrombocytopenia. This hypothesis was tested using a randomized designed set-up, encompassing 1147 critically ill patients, and no significant difference in risk of thrombocytopenia was observed among patients receiving large amounts of antimicrobials vs. patients receiving standard-of care. As a consequence, the risk of antimicrobial-induced thrombocytopenia in the general population of critically ill patients seemingly does not represent a substantial problem and thrombocytopenia during critical illness is most likely due to other factors such as infection severity. In the second study of the thesis, the role of endothelial damage during sepsis was explored. Levels of biomarkers of superficial and profound endothelial damage (syndecan-1 and soluble thrombomodulin (sTM), respectively) were determined in a cohort of 1103 critically ill patients. The results showed that only high levels of sTM were associated with a markedly increased risk of 90-day mortality, as well as multi organ failure. The finding suggests that profound damage to the endothelium is centrally involved in the pathogenesis of death in sepsis. Thus, the endothelium may be a target for new interventions against sepsis. In the third study, we investigated, using a randomized controlled trial, how mild induced hypothermia (cooling to 32-34 degrees C for 24 hours, MIH) influenced sepsis-related coagulopathy using TEG; functional coagulopathy improved in patients exposed to the intervention compared with the control group. This improvement of coagulopathy parameters during MIH persisted after rewarming. These results not only add to the understanding of the effect of hypothermia on the hemostatic system, but indicate that MIH reduces sepsis-related coagulopathy assessed by TEG. Overall, this thesis emphasizes that the role of the hemostatic system during sepsis is not only complex, but centrally involved in disease severity and prognosis. The endothelium seems to play a central role in the morbidity and mortality of sepsis, which cannot be explained simply by the presences of organ failure. Thus, restoring the broken endothelium and reducing coagulopathy appears to be essential in order to significantly improve sepsis out-comes. MIH could be a promising intervention in sepsis, in part due to the improvement of the coagulopathy. Despite the increased focus on the hemostatic system during sepsis, it seems that continued research on restoring disrupted hemostasis - including endothelial damage - is needed. PMID- 26239598 TI - Investigations of functional and structural changes in migraine with aura by magnetic resonance imaging. AB - Migraine sufferers with aura often report visual discomfort outside of attacks and many consider bright or flickering light an attack-precipitating factor. The nature of this visual hypersensitivity and its relation to the underlying pathophysiology of the migraine aura is unknown. A useful technology to study these features of migraine with aura (MA) is functional magnetic resonance imaging (fMRI), which has the potential not only to detect, but also to localize hypersensitive cortex. The main objective of this thesis was to investigate the cortical responsivity of patients with MA during visual stimulation using fMRI. To optimize sensitivity, we applied a within-patient design by assessing functional interhemispheric differences in patients consistently experiencing visual aura in the same visual hemifield. To validate our data analysis methods, we initially studied healthy volunteers using single hemifield visual stimulation and compared the "stimulated" hemispheres (i.e. hemispheres contralateral to the visual stimulation) to the "non-stimulated" hemispheres. We then applied this validated method of interhemispheric comparison of fMRI-blood oxygenation level dependent (BOLD) activation to compare left versus right hemisphere responses to symmetric full-field visual stimulation in 54 healthy subjects (study I). This study concluded that, a) the applied visual stimulation is effective in activating large expanses of visual cortex, b) interhemispheric differences in fMRI-BOLD activation can be determined using the proposed method, and c) visual responses to symmetric full-field visual stimulation are asymmetrically distributed between the cerebral hemispheres. We investigated the effects of migraine aura, by including 20 patients with frequent side-fixed visual aura attacks, i.e. >== 90% of auras occurring in the same visual hemifield (study II). To circumvent bias relating to differences between right and left hemispheres (e.g. caused by physiological left/right bias, asymmetry of the visual stimulation or magnetic field inhomogeneity of the scanner), we included an equal number of patients with right- and left-sided symptoms. Further, we included 20 individually matched healthy controls with no history (including family history) of migraine. We compared the fMRI-BOLD responses to visual stimulation between symptomatic and asymptomatic hemispheres during the interictal phase and between migraine patients and controls. BOLD responses were selectively increased in the symptomatic hemispheres and localized in the inferior parietal lobule, the inferior frontal gyrus and the superior parietal lobule. The affected cortical areas comprise a visually driven functional network involved in oculomotor control, guidance of movement, motion perception, visual attention, and visual spatial memory. The patients also had significantly increased response in the same cortical areas when compared to controls. Since these findings theoretically could depend on aura-related differences in brain structure, we performed additional analyses (study III) to determine the relation between migraine aura and structural, cortical and subcortical, grey matter abnormalities. We analyzed structural MRI data from the same 20 patients and applied voxel-based morphometry and surface-based morphometry on a whole-hemisphere level and for specific anatomical regions of interest. Within-subject comparisons were made with regard to aura symptoms (N = 20 vs 20) and with regard to headache (N = 13 vs 13). We found no differences in grey matter structure with regard to aura symptoms in MA patients. Comparing the typical migraine headache side of the patients to the contralateral side revealed a difference in cortical thickness in the inferior frontal gyrus, which correlated significantly with the migraine attack frequency. In conclusion, we validated a method of interhemispheric comparison of fMRI-BOLD responses to visual stimulation. By using this method we discovered a lateralized alteration of a visually driven functional network in patients with side-fixed aura. These findings suggest a hyperexcitability of the visual system in the interictal phase of migraine with visual aura. Further, this abnormal function is not dependent on lateralized abnormalities of gray matter structure. However, alteration of the inferior frontal cortex related to headache lateralization could indicate structural reorganization of pain inhibitory circuits in response to the repeated intense nociceptive input due to the headache attacks. PMID- 26239599 TI - Sphingosine 1-phosphate receptor modulators in multiple sclerosis. AB - Sphingosine 1-phosphate (S1P) receptor modulators possess a unique mechanism of action as disease-modifying therapy for multiple sclerosis (MS). Subtype 1 S1P receptors are expressed on the surfaces of lymphocytes and are important in regulating egression from lymph nodes. The S1P receptor modulators indirectly antagonize the receptor's function and sequester lymphocytes in lymph nodes. Fingolimod was the first S1P agent approved in the USA in 2010 for relapsing MS after two phase III trials (FREEDOMS and TRANSFORMS) demonstrated potent efficacy, and good safety and tolerability. Post-marketing experience, as well as a third phase III trial (FREEDOMS II), also showed favorable results. More selective S1P receptor agents-ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303-are still in relatively early stages of development, but phase I and II trials showed promising efficacy and safety. However, these observations have yet to be reproduced in phase III clinical trials. PMID- 26239602 TI - [Serum Clara cell 16-kDa protein (CC16) levels and lung impairment in systemic sclerosis patients]. AB - OBJECTIVE: To assess clinical utility of serum Clara cell 16-kDa protein (CC16) measurements in relation with staging system for systemic sclerosis associated interstitial lung disease (SSc-ILD). MATERIALS AND METHODS: Serum levels of CC16 were determined by ELISA in 28 SSc patients and 30 healthy controls, and correlated with staging system for SSc-ILD in SSc patients. Lung involvement was assessed functionally (body plethysmography, diffusing capacity of the lung for carbon monoxide) and radiologically (an average disease extent on high resolution computed tomography of the lungs, HRCT) in SSc patients. RESULTS: We observed statistically significant differences in serum CC16 levels between SSc patients and healthy controls only in non-smokers. However, serum CC16 concentrations were significantly elevated in patients with HRCT extent>20% in comparison to patients with HRCT extent<20% (p=0.01). They correlated positively with average disease extent on HRCT (p=0.04), an extent of a reticular pattern on HRCT (p<0.01), and negatively with a total lung capacity (TLC) (p=0.03) and the results of the 6-min walk test (p<0.01). CONCLUSIONS: CC16 levels can be considered as a supplemental serum biomarker for SSc-ILD. PMID- 26239604 TI - [Idiopathic musculoskeletal pain in Indian Children-prevalence and impact on daily routine]. AB - OBJECTIVES: To study the prevalence of idiopathic musculoskeletal pain (IMSP) in school going children and its impact on daily life. METHODS: One thousand eighteen apparently healthy school children aged 5-16 years were assessed and analysed for IMSP and its associated problems. Standard tests for significance were applied. RESULTS: One hundred and sixty five (16.2%) children mostly males (55.2%) reported IMSP. Lower limbs (52.1%) were the most common location of pain. More than 1 year of pain history was present in 15%. Thirty seven percent children complained of discomfort during walking, 30.9%, had pain during physical exercise, 29.2% had difficulty attending lessons and 4.2% had interference in pursuing hobbies. The children were also further sub grouped into preadolescents and adolescents. There was significant difference in pain duration and duration of each pain episode in the two groups (p=0.01). A significant number of children (21.2%) with IMSP reported school absenteeism (p<0.001). A significant number of adolescents had history positive for contact sports (p=0.001). Sleep disturbances were also reported to be higher in children with IMSP (29% vs. 5.7%, p=0.001). Other associated problems in children with IMSP found were day time tiredness (51.1%), headache (47.3%) and abdominal pain (24.8%). CONCLUSIONS: Prevalence of IMSP in school children aged 5-16 yrs was found to be 16.2% and a significant percentage of these children experience interference with daily activities including school absenteeism. PMID- 26239605 TI - Borax-Loaded PLLA for Promotion of Myogenic Differentiation. AB - Boron is an essential metalloid, which plays a key role in plant and animal metabolisms. It has been reported that boron is involved in bone mineralization, has some uses in synthetic chemistry, and its potential has been only recently exploited in medicinal chemistry. However, in the area of tissue engineering, the use of boron is limited to works involving certain bioactive glasses. In this study, we engineer poly(l-lactic acid) (PLLA) substrates with sustained release of boron. Then, we analyze for the first time the uniqueness effects of boron in cell differentiation using murine C2C12 myoblasts and discuss a potential mechanism of action in cooperation with Ca(2+). Our results demonstrate that borax-loaded materials strongly enhance myotube formation at initial steps of myogenesis. Furthermore, we demonstrate that Ca(2+) plays an essential role in combination with borax as chelating or blocking Ca(2+) entry into the cell leads to a detrimental effect on myoblast differentiation observed on borax-loaded materials. This research identifies borax-loaded materials to trigger differentiation mechanisms and it establishes a new tool to engineer microenvironments with applications in regenerative medicine for muscular diseases. PMID- 26239606 TI - High-content screening imaging and real-time cellular impedance monitoring for the assessment of chemical's bio-activation with regards hepatotoxicity. AB - Testing hepatotoxicity is a crucial step in the development and toxicological assessment of drugs and chemicals. Bio-activation can lead to the formation of metabolites which may present toxicity for the organism. Classical cytotoxic tests are not always appropriate and are often insufficient, particularly when non metabolically-competent cells are used as the model system, leading to false positive or false-negative results. We tested over 24 h the effects of eight reference compounds on two different cell models: primary cultures of rat hepatocytes and FAO hepatoma cells that lack metabolic properties. We performed inter-assay validation between three classical cytotoxicity assays and real-time cell impedance data. We then complemented these experiments with high-content screening (HCS) to determine the cell function disorders responsible for the observed effects. Among the different assays used, the neutral red test seemed to be well suited to our two cell models, coupled with real-time cellular impedance which proved useful in the detection of bio-activation. Indeed, impedance monitoring showed a high sensitivity with interesting curve profiles yet seemed unsuitable for evaluation of viability on primary culture. Finally, HCS in the evaluation of hepatotoxicity is likely to become an essential tool for use in parallel to a classical cytotoxic assay in the assessment of drugs and environmental chemicals. PMID- 26239607 TI - Stem cells: Donor-derived bone marrow cells become adipocytes in recipients. PMID- 26239608 TI - Transplantation: Sustained benefits of islet transplants for T1DM. PMID- 26239610 TI - Endocrine disruptors: DDT, endocrine disruption and breast cancer. PMID- 26239611 TI - Factors Affecting Exclusive Breastfeeding among Women in Muheza District Tanga Northeastern Tanzania: A Mixed Method Community Based Study. AB - OBJECTIVES: Estimates shows exclusive breastfeeding (EBF) has the potential to prevent 11.6% of all under-five deaths in developing countries. Prevalence of EBF is low globally (35%), and in sub Saharan Africa ranges between 22 and 33%. Like other developing countries the prevalence of EBF is 50% in Tanzania. There is limited information in Tanzania on factors influencing EBF apart from information specific for HIV positive women. This study aimed at examining factors that affect EBF practice among women in Muheza district, Tanga region, northeastern Tanzania. METHODS: A community based cross-sectional study using both qualitative and quantitative methods was conducted from April to June 2014. To collect relevant information, a total of 316 women with infants aged 6-12 months were interviewed using a questionnaire and 12 key informants using in-depth interview guide. Qualitative data was analyzed using thematic analysis while bivariate and multivariate logistic regression analysis were used assess association between EBF and predictor variables. RESULTS: The prevalence of EBF was 24.1%. The perception that mothers' breast milk is insufficient for child's growth, child being thirsty and the need to introduce herbal medicine for cultural purposes were among the important factors for early mixed feeding. In multivariate analysis advanced maternal age (OR 2.6; 95% CI 1.18-5.59) and knowledge on EBF duration and advantages (OR 2.2; 95% CI 1.2-3.8) remained significantly associated with EBF practice. CONCLUSIONS: The prevalence of EBF in our study is low compared with the national prevalence. Strategies to target beliefs that breast milk is insufficient for growth need to be strengthened in the community. Furthermore opportunity to increase EBF training during ante and postnatal visits for women should be enhanced as more than 90% of women in the district use skilled attendants during pregnancy and delivery. PMID- 26239612 TI - Detection of volatile organic compounds released by wood furniture based on a cataluminescence test system. AB - Wood furniture is an important source of indoor air pollution. To date, the detection of harmful substances in wood furniture has relied on the control of a single formaldehyde component, therefore the detection and evaluation of pollutants released by wood furniture are necessary. A novel method based on a cataluminescence (CTL) sensor system generated on the surface of nano-3TiO2 2BiVO4 was proposed for the simultaneous detection of pollutants released by wood furniture. Formaldehyde and benzene were selected as a model to investigate the CTL-sensing properties of the sensor system. Field emission scanning electronic microscopy (FESEM), transmission electron microscopy (TEM) and X-ray diffraction (XRD) were employed to characterize the as-prepared samples. The results showed that the as-prepared test system exhibited outstanding CTL properties such as stable intensity, a high signal-to-noise ratio, and short response and recovery times. In addition, the limit of detection for formaldehyde and benzene was below the standard permitted concentrations. Moreover, the sensor system showed outstanding selectivity for formaldehyde and benzene compared with eight other common volatile organic compounds (VOCs). The performance of the sensor system will enable furniture VOC limit emissions standards to be promulgated as soon as possible. PMID- 26239609 TI - Congenital generalized lipodystrophies--new insights into metabolic dysfunction. AB - Congenital generalized lipodystrophy (CGL) is a heterogeneous autosomal recessive disorder characterized by a near complete lack of adipose tissue from birth and, later in life, the development of metabolic complications, such as diabetes mellitus, hypertriglyceridaemia and hepatic steatosis. Four distinct subtypes of CGL exist: type 1 is associated with AGPAT2 mutations; type 2 is associated with BSCL2 mutations; type 3 is associated with CAV1 mutations; and type 4 is associated with PTRF mutations. The products of these genes have crucial roles in phospholipid and triglyceride synthesis, as well as in the formation of lipid droplets and caveolae within adipocytes. The predominant cause of metabolic complications in CGL is excess triglyceride accumulation in the liver and skeletal muscle owing to the inability to store triglycerides in adipose tissue. Profound hypoleptinaemia further exacerbates metabolic derangements by inducing a voracious appetite. Patients require psychological support, a low-fat diet, increased physical activity and cosmetic surgery. Aside from conventional therapy for hyperlipidaemia and diabetes mellitus, metreleptin replacement therapy can dramatically improve metabolic complications in patients with CGL. In this Review, we discuss the molecular genetic basis of CGL, the pathogenesis of the disease's metabolic complications and therapeutic options for patients with CGL. PMID- 26239613 TI - 12-Deoxyphorbol 13-palmitate inhibits the expression of VEGF and HIF-1alpha in MCF-7 cells by blocking the PI3K/Akt/mTOR signaling pathway. AB - Vascular endothelial growth factor (VEGF) is an essential component for angiogenesis, and hypoxia-inducible factor-1alpha (HIF-1alpha), which controls the switch of glycolytic and oxidative metabolism, activates the transcription of VEGF. 12-Deoxyphorbol 13-palmitate (DP) is a compound isolated from the roots of Euphorbia fischeriana, and has been revealed to possess anticancer activity. In the present study, we found that DP is an effective inhibitor of VEGF and HIF 1alpha in MCF-7 cells. DP markedly reduced cell viability as determined by MTT assay. ELISA, western blotting and RT-qPCR assays indicated that DP significantly decreased the protein and mRNA expression of VEGF and the protein expression of HIF-1alpha, while HIF-1alpha mRNA remained unchanged. In addition, the entrance of HIF-1alpha into the nucleus was blocked after DP treatment as detected by immunofluorescence analysis. In a further study, we proved that the effects mentioned above were associated with constitutive interference of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. DP effectively inhibited the phosphorylation of PI3K and its downstream factors p-Akt and p-mTOR, oppositely enhanced the expression of TSC1 (hamartin) and TSC2 (tuberin), which could be reversed by the co-treatment with the PI3K inhibitor wortmannin. Moreover, the addition of wortmanin further downregulated the protein levels of VEGF and HIF-1alpha. The results revealed that DP inhibited the expression of VEGF and HIF-1alpha through the PI3K/Akt/mTOR signaling pathway, confirming that DP may be a potential therapeutic candidate for breast cancer. PMID- 26239614 TI - MicroRNA-205 inhibits the proliferation and invasion of breast cancer by regulating AMOT expression. AB - It has been reported that the expression of angiomotin (AMOT) is upregulated in breast cancer. However, the regulatory mechanism remains unknown. In the present study, we aimed to ascertain whether the expression of AMOT is regulated by microRNAs (miRNAs) in breast cancer. In the present study, miR-205 was significantly downregulated in breast cancer samples and it was identified to directly target the 3'-untranslated region (3'-UTR) of AMOT in breast cancer MCF 7 cells by luciferase assay. miR-205 and small interfering RNA (siRNA)-mediated AMOT-knockdown experiments revealed that miR-205 significantly inhibited the proliferation and the invasion of MCF-7 cells through a decrease in the expression of AMOT, yet had no effect on apoptosis. Furthermore, we observed that the overexpression of AMOT partially reversed the inhibitory effect of miR-205 on the growth and the invasion of MCF-7 cells. The data indicated that miR-205 regulated the proliferation and the invasion of breast cancer cells through suppression of AMOT expression, at least partly. Therefore, the disordered decreased expression of miR-205 and the resulting AMOT upregulation contributes to breast carcinogenesis, and miR-205-AMOT represents a new potential therapeutic target for the treatment of breast carcinoma. PMID- 26239615 TI - Metal-Free Oxidative C-C Bond Formation through C-H Bond Functionalization. AB - The formation of C-C bonds embodies the core of organic chemistry because of its fundamental application in generation of molecular diversity and complexity. C-C bond-forming reactions are well-known challenges. To achieve this goal through direct functionalization of C-H bonds in both of the coupling partners represents the state-of-the-art in organic synthesis. Oxidative C-C bond formation obviates the need for prefunctionalization of both substrates. This Minireview is dedicated to the field of C-C bond-forming reactions through direct C-H bond functionalization under completely metal-free oxidative conditions. Selected important developments in this area have been summarized with representative examples and discussions on their reaction mechanisms. PMID- 26239616 TI - MeCP2 controls hippocampal brain-derived neurotrophic factor expression via homeostatic interactions with microRNA-132 in rats with depression. AB - Major depressive disorder (MDD) is a considerable public health concern, which affects patients worldwide. MDD is associated with psychosocial impairment, poor quality of life, and significant disability, morbidity and mortality. Stress is a major factor in depression, which impairs the structural and functional plasticity of the hippocampus. Previous studies have demonstrated that chronic unpredictable mild stress is able to downregulate the expression of brain-derived neurotrophic factor (BDNF) and methyl-CpG-binding protein 2 (MeCP2), and alter the expression levels of certain microRNAs (miR). The aim of the present study was to investigate the regulatory association between BDNF, MeCP2 and miR-132 in an animal model of chronic stress-induced depression. ELISA, western blot and qPCR were used to detect the expression levels of BDNF, MeCP2 and miR-132 in the peripheral blood samples of patients with MDD and in the hippocampi of depressed animals. In addition, a dual luciferase reporter gene system was used to determine whether miR-132 directly targets BDNF or MeCP2. The present study demonstrated that, as compared with normal subjects, miR-132 expression was increased in the peripheral blood samples of patients with MDD, whereas the expression of MeCP2 and BDNF was decreased; thus, the expression levels of MeCP2 and BDNF were negatively correlated with those of miR-132. In addition, in an animal model of chronic stress-induced depression, increased expression levels of miR-132, and decreased levels of MeCP2 and BDNF were detected in the hippocampi. Furthermore, knockdown of MeCP2 expression in primary hippocampal neurons increased the expression of miR-132 and decreased the expression levels of BDNF. The results of the present study demonstrated that miR-132 may directly target MeCP2, but not BDNF, and control its expression at the transcriptional and translational level. miR-132 was also shown to negatively regulate BDNF expression. The reduced expression levels of BDNF, as induced by MeCP2 knockdown, were enhanced by miR-132 mimics, and were rescued by miR-132 inhibitors. These results suggested that homeostatic interactions between MeCP2 and miR-132 may regulate hippocampal BDNF levels, which may have a role in the pathogenesis of MDD. PMID- 26239617 TI - Hereditary multiple exostoses and solitary osteochondroma associated with growth hormone deficiency: to treat or not to treat? AB - BACKGROUND: Osteochondroma generally occurs as a single lesion and it is not a heritable disease. When two or more osteochondroma are present, this condition represents a genetic disorder named hereditary multiple exostoses (HME). Growth hormone deficiency (GHD) has rarely been found in HME patients and a few data about growth therapy (GH) therapy effects in development/growth of solitary or multiple exostoses have been reported. CASE PRESENTATION: We describe the clinical features of 2 patients (one with osteochondroma and one with HME) evaluated before and after GH therapy. In the first patient, the single osteochondroma was noticed after the start of treatment; the other patient showed no evidence of significant increase in size or number of lesions related to GH therapy. CONCLUSION: It is necessary to investigate GH secretion in patients with osteochondroma or HME and short stature because they could benefit from GH replacement therapy. Moreover, careful clinical and imaging follow-up of exostoses is mandatory. PMID- 26239618 TI - Comparative proteomics analysis of Spodoptera frugiperda cells during Autographa californica multiple nucleopolyhedrovirus infection. AB - BACKGROUND: Increasing evidence sugggest that in addition of balculovirus controling insect host, host cells also responds to balculovirus infection. However, compared to existing knowledge on virus gene, host cell responses are relatively poorly understood. METHODS: In this study, Spodoptera frugiperda (Sf9) cells were infected with Autographa californica multiple nucleopolyhedrovirus (AcMNPV). The protein composition and protein changes of Spodoptera frugiperda (Sf9) cells of different infection stages were analysed by isobaric tag for relative and absolute quantification (iTRAQ) techniques. RESULTS: A total of 4004 Sf9 proteins were identified by iTRAQ and 413 proteins were found as more than 1.5-fold changes in abundance. The 413 proteins were categorised according to GO classification for insects and were categorised into: biological process, molecular function and cellular component. CONCLUSIONS: The determination of the protein changes in infected Sf9 cells would help to better understanding of host cell responses and facilitate better design of this virus-host cell interaction in pest insect control and other related fields. PMID- 26239619 TI - Induction of microRNA-146a is involved in curcumin-mediated enhancement of temozolomide cytotoxicity against human glioblastoma. AB - MicroRNA (miR)-146a is a negative regulator of nuclear factor-kappaB (NF-kappaB) signaling that affects tumor growth and survival. The present study was undertaken to determine whether the cytotoxicity of curcumin (diferuloylmethane), a natural polyphenolic compound isolated from turmeric (Curcuma longa Linn), in glioblastoma cells is mediated through upregulation of miR-146a. Human U-87 MG glioblastoma cells were treated with curcumin and temozolomide (TMZ) alone or in combination, and cell proliferation and apoptosis were assessed. The involvement of miR-146a and NF-kappaB signaling in curcumin-mediated chemosensitization was explored. Curcumin exposure led to upregulation of miR-146a in U-87 MG cells. Combined curcumin and TMZ treatment significantly (P<0.05) inhibited U-87 MG cell proliferation and induced apoptotic death, compared with each alone. Notably, curcumin-mediated enhancement of TMZ-induced apoptosis was blocked by depletion of miR-146a. By contrast, miR-146a overexpression enhanced apoptosis and suppressed NF-kappaB activation in TMZ-treated cells. Additionally, pharmacological inhibition of NF-kappaB signaling significantly increased TMZ induced apoptosis. To the best of our knowledge, the present study provides the first evidence that upregulation of miR-146a and inactivation of NF-kappaB signaling mediates the sensitization of human glioblastoma cells to TMZ-induced apoptosis by curcumin. PMID- 26239620 TI - A family of Fe(3+) based double-stranded helicates showing a magnetocaloric effect, and Rhodamine B dye and DNA binding activities. AB - Herein, the synthesis, structural characterization, magnetic properties and guest binding activities of four Fe(3+) based double-stranded helicates namely; [Fe2(L)2](ClO4)(Cl).4(CH3OH).2(H2O) (), [Fe2(L)2](BF4)2.2(H2O) (), [Fe2(L)2](NO3)2.3(CH3OH).2(H2O) (), and [Fe2(L)2](Cl)2.2(CH3OH).4(H2O) () are reported. Complexes have been synthesized using the hydrazide-based ligand H2L (H2L = N'1,N'4-bis(2-hydroxybenzylidene)succinohydrazide) and the corresponding Fe(2+) salts. Each of the independent cationic complexes [Fe2(L)2](2+) shows double-stranded helicates from the self-assembly of the ligand and metal ions in a 2 : 2 ratio, where the individual Fe(3+) centre is lying on a C2-axis and the ligand strands wrap around it. In , ligand L adopts "pseudo-C" conformations and forms a double-stranded dinuclear helicate with a small cage in between them. Moreover, in , each of the independent cationic complexes [Fe2L2](2+) is inherently chiral and possesses P for right-hand and M for left-hand helicity and as a consequence is a racemic solid. Detailed magnetic studies of all the complexes reveal that the Fe(3+) centres are magnetically isolated and isotropic in nature. Estimation of the Magnetocaloric Effect (MCE) from magnetization data unveils a moderate MCE at a temperature of 3 K with magnetic entropy changes ( DeltaSm) of 22.9, 27.7, 24.1, 26.5 J kg(-1) K(-1) at a magnetic field of 7 T for complexes , respectively. Also, the variation of the -DeltaSm values was justified by considering the parameter of magnetization per unit mass. Stability of all the complexes in solution phase was confirmed by ESI-mass spectrometric analysis and liquid phase FT-IR spectroscopy. Further, the interaction of the complexes with Rhodamine B dye was examined by UV-vis and fluorescence spectroscopic study. The observed blue-shift in the fluorescence study and hyperchromicity and hypochromicity with the appearance of two isosbestic points in the UV-vis study ascertain the interactions of the dye with the complexes. A DNA binding study by absorption spectral titration suggests the weak external intercalation of complex within the nucleotide of calf thymus DNA. Computational study supports the isotropic nature of the metal centres and the consequent high spin multiplicity, which assists the complexes to show significant magnetic entropy changes. PMID- 26239622 TI - Fascin expression in undifferentiated and dedifferentiated endometrial carcinoma. AB - The actin-binding protein fascin promotes cellular invasion, and increased fascin expression correlates with adverse prognostic factors in a variety of tumors. Fascin up-regulation may also be associated with epithelial-mesenchymal transition in neoplastic epithelial cells. This study investigated fascin expression in undifferentiated and dedifferentiated endometrial carcinoma (UEC), a clinically aggressive variant of endometrial neoplasia. Twenty-two UECs, 5 of which were entirely undifferentiated and 17 dedifferentiated, were examined. In the dedifferentiated group, staining was compared between the differentiated and undifferentiated tumor components. Where applicable, fascin expression was noted in foci of lymphovascular space invasion. The mean age was 67.6 years, and 11 patients (50%) presented with stage III or IV disease. The undifferentiated tumor component showed diffuse fascin expression in 20 cases (91%) including 4 of 5 pure undifferentiated carcinomas and 16 of 17 dedifferentiated carcinomas. In contrast, the low-grade endometrioid carcinoma component of 13 (77%) of 17 dedifferentiated carcinomas was fascin negative or showed only focal staining. Intravascular undifferentiated tumor cells were identified in 16 cases, and these were consistently fascin positive, whereas low-grade intravascular tumor cells, present in 2 cases, were not stained. Fascin up-regulation may be a contributory factor toward the highly invasive character of UEC and could represent an epithelial-mesenchymal transition-like process in these tumors. Fascin expression in intravascular tumor cells may be permissive toward intravascular survival and metastatic risk. PMID- 26239621 TI - A Systems Level Analysis of Vasopressin-mediated Signaling Networks in Kidney Distal Convoluted Tubule Cells. AB - The kidney distal convoluted tubule (DCT) plays an essential role in maintaining body sodium balance and blood pressure. The major sodium reabsorption pathway in the DCT is the thiazide-sensitive NaCl cotransporter (NCC), whose functions can be modulated by the hormone vasopressin (VP) acting via uncharacterized signaling cascades. Here we use a systems biology approach centered on stable isotope labeling by amino acids in cell culture (SILAC) based quantitative phosphoproteomics of cultured mouse DCT cells to map global changes in protein phosphorylation upon acute treatment with a VP type II receptor agonist 1 desamino-8-D-arginine vasopressin (dDAVP). 6330 unique proteins, containing 12333 different phosphorylation sites were identified. 185 sites were altered in abundance following dDAVP. Basophilic motifs were preferential targets for upregulated sites upon dDAVP stimulation, whereas proline-directed motifs were prominent for downregulated sites. Kinase prediction indicated that dDAVP increased AGC and CAMK kinase families' activities and decreased activity of CDK and MAPK families. Network analysis implicated phosphatidylinositol-4,5 bisphosphate 3-kinase or CAMKK dependent pathways in VP-mediated signaling; pharmacological inhibition of which significantly reduced dDAVP induced increases in phosphorylated NCC at an activating site. In conclusion, this study identifies unique VP signaling cascades in DCT cells that may be important for regulating blood pressure. PMID- 26239623 TI - Fibroblast growth factor receptor 1 gene amplification in gastric adenocarcinoma. AB - Gastric adenocarcinomas are associated with a poor prognosis due to the fact that the tumor has often metastasized by the time of diagnosis. Thus, identification of novel therapeutic targets is highly desirable. Here, we examined gene copy number of fibroblast growth factor receptor 1 (FGFR1), a potential target for tyrosine kinase inhibitors, and clinicopathologic parameters in a large cohort of gastric adenocarcinomas. We performed fluorescence in situ hybridization analysis of 293 gastric adenocarcinomas using tissue microarrays. Amplification of the FGFR1 gene is a rare but noticeable event that can be found in 2% (6/293) of cases and was associated with poor 10-year survival (median 15.3 months in FGFR1 amplified cases versus 36 months in nonamplified cases, P = .047) and a higher rate of distant metastasis (P = .025). FGFR1 appears to represent a potential new therapeutic target in a subset of patients with gastric carcinoma. Identification of gastric cancers harboring FGFR1 amplification may be important in preselecting patients and/or interpreting clinical studies using tyrosine kinase inhibitors. PMID- 26239624 TI - Clinicopathological and immunohistochemical characteristics of papillary renal cell carcinoma with emphasis on subtyping. AB - Papillary renal cell carcinoma (PRCC), a morphologically and genetically distinct subtype of RCC, is morphologically separated into 2 subtypes for therapeutic and prognostic purposes. Type 2 tumors are generally believed to have a poorer prognosis than type 1 tumors. In spite of multiple studies, many clinicopathological issues about PRCC remain vague. We studied the clinicopathological features associated with type 1 versus type 2 PRCC, and we compared the immunohistochemical profiles in both subtypes of PRCC. We identified a total of 144 cases (74 type 1, 46 type 2, and 24 mixed), 29 female and 115 male. Mean age was 56 years for type 1 and 59 years for type 2. Mean tumor size was 3.6 cm for type 1 and 4.6 cm for type 2. Type 1 tumors were more likely to have nuclear grade 2 and less, whereas type 2 tumors were more likely to have nuclear grade 3 and above (P = .0001). There was no significant association between tumor type and renal sinus fat invasion, invasion of muscular branches of renal vein, perinephric fat invasion, microvascular angiolymphatic invasion, and main renal vein invasion. Type 2 tumors have higher nuclear grades than type 1 tumors. Based on long follow-up data, both subtypes appear to have excellent prognosis when diagnosed at early stage. The immunohistochemical profiles of both types 1 and 2 PRCC are essentially the same. The similar immunohistochemical profile suggests that PRCC is one entity with divergent histologic features. PMID- 26239625 TI - A prospective registry evaluating the epidemiology and clinical care of traumatic brain injury patients presenting to a regional referral hospital in Moshi, Tanzania: challenges and the way forward. AB - Traumatic brain injury (TBI) is the most common cause of death and disability globally disproportionately affecting low- and middle-income countries where increasing injury rates are compounded by limited quality care. The objective of this study is to describe quality of care for TBI patients who presented to Kilimanjaro Christian Medical Center, Moshi, Tanzania. We evaluated a prospective quality improvement TBI registry that enrolled consecutive patients with acute TBI. Descriptive statistics and qualitative comparative analysis was performed. Overall, 893 TBI patients were enrolled during the study period, with a mean age of 32.1 years and who were mostly (80%) male. 12.9% suffered severe TBI (GCS < 9). Most injuries were road traffic (66%) especially motorcyclists (49%) and 26.8% were alcohol related. One intubation occurred, and 22.9% of hypoxic patients received oxygen. Severe TBI mortality was 47%. TBI affects men 15-45 years old in traffic crashes with high mortality for severe TBI (47%) patients. Care addressing secondary injury, hypoxemia, and hypotension is limited. PMID- 26239626 TI - The springtail cuticle as a blueprint for omniphobic surfaces. AB - Omniphobic surfaces found in nature have great potential for enabling novel and emerging products and technologies to facilitate the daily life of human societies. One example is the water and even oil-repellent cuticle of springtails (Collembola). The wingless arthropods evolved a highly textured, hierarchically arranged surface pattern that affords mechanical robustness and wetting resistance even at elevated hydrostatic pressures. Springtail cuticle-derived surfaces therefore promise to overcome limitations of lotus-inspired surfaces (low durability, insufficient repellence of low surface tension liquids). In this review, we report on the liquid-repellent natural surfaces of arthropods living in aqueous or temporarily flooded habitats including water-walking insects or water spiders. In particular, we focus on springtails presenting an overview on the cuticular morphology and chemistry and their biological relevance. Based on the obtained liquid repellence of a variety of liquids with remarkable efficiency, the review provides general design criteria for robust omniphobic surfaces. In particular, the resistance against complete wetting and the mechanical stability strongly both depend on the topographical features of the nano- and micropatterned surface. The current understanding of the underlying principles and approaches to their technological implementation are summarized and discussed. PMID- 26239627 TI - Malignant tumors of the heart. AB - Primary malignant cardiac tumors are rare, and mostly manifest as sarcomas in various types. As non-invasive diagnostic modalities, e.g. echocardiography and magnetic resonance imaging, have become more sensitive, there is a marked increase in the number of patients diagnosed. Nevertheless, most patients die within one year of initial diagnosis, either because of the often asymptomatic presentation of cardiac tumors until advanced disease, or a low index of suspicion on the part of the physician. The presenting symptoms, treatment options and, indeed, prognosis are largely controlled by the tumor's anatomic location. Cardiac sarcomas may present with a variety of symptoms and are known to be great mimickers. A quick diagnosis facilitates the initiation of a proper treatment (surgical resection, adjuvant chemotherapy), which may in turn improve the prognosis. Metastases to the heart are far more common, unfortunately, clinical manifestations are mainly dominated by generalized tumor spread. The article summarizes epidemiology, symptoms, diagnostic modalities, and possible treatment options. PMID- 26239628 TI - Capsule Commentary on Baig et al., Picture Good Health: A Church-Based Self Management Intervention among Latino Adults with Diabetes. PMID- 26239629 TI - Good Intentions, Unintended Consequences, and Unrealized Benefits. PMID- 26239630 TI - Effect of T2* correction on contrast kinetic model analysis using a reference tissue arterial input function at 7 T. AB - OBJECTIVES: We aimed to investigate the effect of T2* correction on estimation of kinetic parameters from T1-weighted dynamic contrast enhanced (DCE) MRI data when a reference-tissue arterial input function (AIF) is used. MATERIALS AND METHODS: DCE-MRI data were acquired from seven mice with 4T1 mouse mammary tumors using a double gradient echo sequence at 7 T. The AIF was estimated from a region of interest in the muscle. The extended Tofts model was used to estimate pharmacokinetic parameters in the enhancing part of the tumor, with and without T2* correction of the lesion and AIF. The parameters estimated with T2* correction of both the AIF and lesion time-intensity curve were assumed to be the reference standard. RESULTS: For the whole population, there was significant difference (p < 0.05) in transfer constant (K(trans)) between T2* corrected and not corrected methods, but not in interstitial volume fraction (ve). Individually, no significant differences were found in K(trans) and ve of four and six tumors, respectively, between the T2* corrected and not corrected methods. In contrast, K(trans) was significantly underestimated, if the T2* correction was not used, in other tumors for which the median K(trans) was larger than 0.4 min(-1). CONCLUSION: T2* effect on tumors with high K(trans) may not be negligible in kinetic model analysis, even if AIF is estimated from reference tissue where the concentration of contrast agent is relatively low. PMID- 26239631 TI - Active decoupling of RF coils using a transmit array system. AB - OBJECTIVE: Implementation of a decoupling method for isolation of transmit and receive radio frequency (RF) coils for concurrent excitation and acquisition (CEA) MRI in samples with ultra-short T2*. MATERIALS AND METHODS: The new phase and amplitude (PA) decoupling method is implemented in a clinical 3T-MRI system equipped with a parallel transmit array system. For RF excitation, two transmit coils are used in combination with a single receive coil. The transmit coil is geometrically decoupled from the receive coil, and the remaining B 1-induced voltages in the receive coil during CEA are minimized by the second transmit coil using a careful adjustment of the phase and amplitude settings in this coil. Isolation of the decoupling scheme and transmit noise behavior are analyzed for different loading conditions, and a CEA MRI experiment is performed in a rubber phantom with sub-millisecond T2* and in an ex vivo animal. RESULTS: Geometrical (20 dB) and PA decoupling (50 dB) provided a total isolation of 70 dB between the transmit and receive coils. Integration of a low-noise RF amplifier was necessary to minimize RF transmit noise. CEA MR images could be reconstructed from a rubber phantom and an ex vivo animal. CONCLUSION: CEA MRI can be implemented in clinical MRI systems using active decoupling with parallel transmit array capabilities with minor hardware modifications. PMID- 26239634 TI - Delhi hospital's call for special treatment for VIPs sparks criticism. PMID- 26239633 TI - You are invited to submit.... AB - The academic community is under great pressure to publish. This pressure is compounded by high rejection rates at many journals. A more recent trend is for some journals to send invitations directly to researchers inviting them to submit a manuscript to their journals. Many researchers find these invitations annoying and unsure how best to respond to them. We collected electronic invitations to submit a manuscript to a journal between April 1, 2014, and March 31, 2015. We analyzed their content and cross-tabulated them against journals listed in Beall's list of potential predatory journals. During this time period, 311 invitations were received for 204 journals, the majority of which were in Beall's list (n = 244; 79%). The invitations came throughout the calendar year and some journals sent up to six invitations. The majority of journals claimed to provide peer review (n = 179; 57.6%) although no mention was made of expedited review process. Similarly, more than half of the journals claimed to be open access (n = 186; 59.8%). The majority of invitations included an unsubscribe link (n = 187; 60.1%). About half of the invitations came from biomedical journals (n = 179). We discuss strategies researchers and institutions can consider to reduce the number of invitations received and strategies to handle those invitations that make it to the recipients' inbox, thus helping to maintain the credibility and reputation of researchers and institutions. PMID- 26239632 TI - A thorough QTc study demonstrates that olmesartan medoxomil does not prolong the QTc interval. AB - Two studies (ROADMAP and ORIENT) evaluating the renoprotective effects of olmesartan medoxomil (OM) in patients with type 2 diabetes suggested OM is associated with increased cardiovascular mortality. We conducted a thorough QTc study to evaluate the effects of OM on cardiac repolarization. A randomized, double-blind, phase 1 study was conducted per E14 Guidance to assess the effects of single doses of OM therapeutic dose (40 mg), OM supratherapeutic dose (160 mg), placebo, or moxifloxacin (MOXI; 400 mg) on QTc in 56 healthy subjects. The primary endpoint was the baseline-adjusted, placebo-corrected QTc interval using Fridericia's formula (DeltaDeltaQTcF) for OM and MOXI. Assay sensitivity was concluded if lower limit of 1-sided 95%CI > 5 milliseconds of DeltaDeltaQTcF for MOXI. No threshold pharmacologic effect for OM was concluded if upper limit of 1 sided 95%CI <10 milliseconds for DeltaDeltaQTcF at any timepoint. Pharmacokinetics, ECGs, and safety were assessed. Assay sensitivity was demonstrated. The largest upper limit of the 1-sided 95%CI for DeltaDeltaQTcF was <5 milliseconds for OM. No clinically significant changes were observed in ECGs. Pharmacokinetics and safety profile were consistent with previous data. Therapeutic and supratherapeutic OM doses had no clinically significant effect on cardiac repolarization and were well tolerated. PMID- 26239635 TI - Psychometric properties of the Chinese version of the Obsessive Beliefs Questionnaire-44 (OBQ-44). AB - BACKGROUND: The Obsessive Beliefs Questionnaire-44 (OBQ-44) is originally developed by the Obsessive Compulsive Cognitions Working Group and has been translated into several languages. This paper is aimed to investigate the psychometric properties of the Chinese version of the Obsessive Beliefs Questionnaire-44 (OBQ-44) in both clinical and non-clinical samples. METHODS: Five hundred and sixty-nine undergraduate volunteers and sixty-six OCD patients were included in the study. All participants have completed Chinese version of OBQ-44, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and Beck Depression Inventory (BDI). Confirmatory factor analysis was conducted to examine the construct validity of Chinese version of OBQ-44. The internal consistency and test-retest reliabilities at 4-week interval were examined in both non-clinical and clinical groups. RESULTS: The confirmatory factor analysis of the non clinical sample confirmed a 3-factor model which was suggested by the original authors of the instrument (chi (2)/d.f = 2.96, GFI = 0.83, NFI = 0.82, CFI = 0.88 and RMSEA = 0.06). The internal consistency and test-retest reliability were at an acceptable range for the two samples. CONCLUSIONS: The Chinese version of OBQ 44 is a valid and reliable instrument for assessing dysfunctional beliefs related to the etiology and maintenance of obsessions and compulsions. PMID- 26239636 TI - Interobserver and intraobserver agreement for gastric mucosa atrophy. AB - BACKGROUND: The grade of gastric mucosa atrophy caused by Helicobacter pylori (H. pylori) infection is closely associated with the risk of gastric cancer, especially of the intestinal type. Interobserver and intraobserver agreement for endoscopic gastric mucosa atrophy in subjects with H. pylori-uninfected, currently infected and past infected was investigated. METHODS: Endoscopic images of 91 patients, 34 images per patient, were assessed. The assessors were 4 endoscopist groups: Japanese and Vietnamese experienced (>=7, <= 15 year experience with endoscopy) and Japanese and Vietnamese beginner (<= 3 year experience) groups. Each group comprised 3 endoscopists. The grades of atrophy were classified as 3: none to mild (C-0 and C-1), moderate (C-2 and C-3), and severe (O-1, O-2, and O-3) using the Kimura-Takemoto Classification. After a period of 2 weeks, images of all patients were reevaluated by the investigators. Interobserver and intraobserver agreement was calculated by kappa statistics. RESULTS: The kappa values for the interobserver agreement in the groups of Japanese and Vietnamese experienced, and Japanese and Vietnamese beginner were 0.474, 0.408, 0.291, and 0.373, respectively. The kappa value of intraobsever agreement in the Japanese and Vietnamese experienced endoscoists ranged from 0.585 to 0.871. On the other hand, the value in the beginner endoscopists ranged wider than that in experienced endoscopists, from 0.264 to 0.866. CONCLUSIONS: Our results indicated that, although intraobserver agreement for gastric mucosa atrophy was good to excellent, interobserver agreement was moderate in experienced endoscopists. This suggests that better guidelines and firm criteria may be needed to properly diagnose and grade gastric atrophy. PMID- 26239637 TI - Effects of Mad Honey on Some Biochemical Parameters in Rats. AB - The aims of this study were to determine grayanotoxin (GTX-III) toxin level in mad honey using liquid chromatography-tandem mass spectrometry and examine the dynamic changes of certain biochemical parameters in blood serum of rats that consumed mad honey. For the experimental animal study, 20 Sprague-Dawley female rats were divided into 5 groups of 4 rats each, with one group being the control group (Group 1) and the others being the experimental groups (Groups 2-5). Groups 2, 3, 4, and 5 were, respectively, given mad honey extract at doses of 0.3, 0.6, 1.2, and 2.4 mg/g body weight/day via oral gavage for 8 days. According to results, the quantity of GTX-III found in the honey sample as 39.949 +/- 0.020 MUg GTX-III/g honey, and the biochemical analysis of the tested parameters (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, creatine kinase, and creatine kinase muscle and brain) showed a significant elevation with increasing concentration of honey. In conclusion, the use of increasing concentrations of Rhododendron honey was seen as a source of enzymatic symptoms. PMID- 26239638 TI - Editorial: Combination Therapy of Vascular Diseases and Fangjiomics: When West Meets East in the Era of Phenomics. PMID- 26239639 TI - An insertion/deletion polymorphism at the microRNA-122 binding site in the interleukin-1alpha 3'-untranslated region is associated with a risk for osteoarthritis. AB - Polymorphisms located at microRNA (miRNA) binding sites may affect the expression of genes. The present study aimed to identify the association between an insertion/deletion (Ins/Del) polymorphism (rs3783553) in the 3'-untranslated region (3'-UTR) of interleukin-1alpha (IL-1A) and the risk for osteoarthritis (OA). Using a luciferase reporter system, IL-1A was identified in the present study as an effective target gene of miR-122 in synovial cells that were obtained from patients who had received a synovectomy. This finding was verified further by the observation that exogenous over-expression of miR-122 in the synovial cells significantly downregulated the expression of IL-1A in the cells with Ins/Ins and Ins/Del genotypes, but not in the cells with Del/Del genotypes. Patients with OA (n=931) and OA-free volunteers (n=952) were enrolled in the study. Compared with the Del/Del genotype, patients possessing the Ins/Del or Ins/Ins genotype were associated with a lower risk for OA [odds ratio (OR)=0.67, P=0.0051; OR=0.65, P=0.0031, respectively], and the association was even stronger in young subjects (<62 years) (OR=0.53; P<0.001). Additionally, it was found that genotype was associated with radiographic severity (OR=0.72; P=0.023). The synovial fluid (SF) concentrations of IL-1A and miR-122 were measured in 75 OA patients. While the miR-122 concentrations were found to be comparable between each genotype group, the SF concentration of IL-1A in the Del/Del group was significantly higher than in the Ins/Del and Ins/Ins genotype groups. Therefore, the present study identified that the Ins/Del polymorphism in the 3'-UTR of IL-1A may affect genetic expression and, to the best of our knowledge, is the first study to demonstrate that the minor allele (Del) is associated with an elevated risk for OA and disease severity. PMID- 26239640 TI - Utility and Associated Risk of Pulmonary Embolism Computed Tomography Scans in the Michigan Lupus Cohort. AB - OBJECTIVE: Systemic lupus erythematosus patients are frequently evaluated for chest pain and may have multiple pulmonary embolism (PE) computed tomography (CT) scans. This study was undertaken to determine the incidence of pulmonary embolism in the University of Michigan Lupus Cohort patients who have undergone PE CT scans and to estimate the associated increased risk of breast and lung cancer from radiation exposure. METHODS: We reviewed records of patients in the University of Michigan Lupus Cohort (n = 854) and determined the number and outcome of PE CT scans. Radimetrics software was used to perform individualized calculations of radiation dose to the lung and breast of each patient. We used this dose information, the patient's age at the time of scan, and risks according to the Biological Effects of Ionizing Radiation, report VII, to estimate the increased incidence risks of breast and lung cancer. RESULTS: A total of 182 of 856 patients (21%) underwent 357 PE CT scans. The overall rate of positivity was 7.5%. For patients undergoing their first through third scans, the rate of positivity for PE was 8.8%, whereas patients undergoing their fourth through tenth scans had 1.6% positivity. The highest increase in incidence risk was 0.87% for breast and 0.62% for lung. CONCLUSION: Patients with multiple previous PE CT scans had lower likelihood of a positive result on subsequent scans and higher risks of malignancy. The magnitude of risk should not discourage performance of PE CT when clinically indicated. PMID- 26239641 TI - A Simple and Green Route for Room-Temperature Synthesis of Gold Nanoparticles and Selective Colorimetric Detection of Cysteine. AB - Gold nanoparticles (AuNPs) were synthesized at room temperature following a simple, rapid, and green route using fresh-squeezed apple juice as a reducing reagent. The optimal AuNPs, based on the particle color, stability, and color change suitable for colorimetric detection of cysteine (Cys), are synthesized using 5 mL of 10% apple juice, 1 mL of 10 mM gold precursor solution, and 1 mL of 0.1 M NaOH. Under this set of parameters, the AuNPs are synthesized within 30 min at room temperature. The average size (11.1 +/- 3.2 nm) and zeta potential (-36.5 mV) of the AuNPs synthesized were similar to those of AuNPs prepared via the conventional citrate-reduction method. In the presence of Cys, unlike with any other amino acid, the AuNPs aggregated, possibly due to the gold-sulfur covalent interaction, yielding red-to-purple color change of the sample solution. The red shift of the localized surface plasmon resonance peak of the AuNPs responsible for the color change was recorded by UV-vis spectrometer. The effect of other potential interferents such as glucose, ascorbic acid, K(+) , Na(+) , Ca(2+) , Zn(2+) , Ag(+) , Ni(2+) , Cu(2+) , Co(2+) , and Hg(2+) were also examined. The results show that AuNPs can be used to selectively detect and measure Cys with a linear dependency in the range of 2 to 100 MUM and a limit of detection (signal to-noise ratio > 3) of 50 nM. The results suggest that the green-synthesized AuNPs are useful for simple, rapid, and sensitive colorimetric detection of Cys, which is an essential amino acid in food and biological systems. PMID- 26239642 TI - Importance of presenting the variability of the false discovery rate control. AB - BACKGROUND: Multiple hypothesis testing is a pervasive problem in genomic data analysis. The conventional Bonferroni method which controls the family-wise error rate is conservative and with low power. The current paradigm is to control the false discovery rate. RESULTS: We characterize the variability of the false discovery rate indices (local false discovery rates, q-value and false discovery proportion) using the bootstrapped method. A colon cancer gene-expression data and a visual refractive errors genome-wide association study data are analyzed as demonstration. We found a high variability in false discovery rate controls for typical genomic studies. CONCLUSIONS: We advise researchers to present the bootstrapped standard errors alongside with the false discovery rate indices. PMID- 26239643 TI - The Fukushima Health Management Survey: estimation of external doses to residents in Fukushima Prefecture. AB - The Fukushima Health Management Survey (including the Basic Survey for external dose estimation and four detailed surveys) was launched after the Fukushima Dai ichi Nuclear Power Plant accident. The Basic Survey consists of a questionnaire that asks Fukushima Prefecture residents about their behavior in the first four months after the accident; and responses to the questionnaire have been returned from many residents. The individual external doses are estimated by using digitized behavior data and a computer program that included daily gamma ray dose rate maps drawn after the accident. The individual external doses of 421,394 residents for the first four months (excluding radiation workers) had a distribution as follows: 62.0%, <1 mSv; 94.0%, <2 mSv; 99.4%, <3 mSv. The arithmetic mean and maximum for the individual external doses were 0.8 and 25 mSv, respectively. While most dose estimation studies were based on typical scenarios of evacuation and time spent inside/outside, the Basic Survey estimated doses considering individually different personal behaviors. Thus, doses for some individuals who did not follow typical scenarios could be revealed. Even considering such extreme cases, the estimated external doses were generally low and no discernible increased incidence of radiation-related health effects is expected. PMID- 26239644 TI - PLAP-1/Asporin Positively Regulates FGF-2 Activity. AB - PLAP-1 is an extracellular matrix protein that is predominantly expressed in the periodontal ligament within periodontal tissue. It was previously revealed that PLAP-1 negatively regulates bone morphogenetic protein 2 and transforming growth factor beta activity through direct interactions. However, the interaction between PLAP-1 and other growth factors has not been defined. Here, we revealed that PLAP-1 positively regulates the activity of fibroblast growth factor 2 (FGF 2), a critical growth factor in tissue homeostasis and repair. In this study, we isolated mouse embryonic fibroblasts (MEFs) from Plap-1(-/-) mice generated in our laboratory. Interestingly, Plap-1(-/-) MEFs exhibited enhanced responses to bone morphogenetic protein 2 but defective responses to FGF-2, and Plap-1 transfection into Plap-1(-/-) MEFs rescued these defective responses. In addition, binding assays revealed that PLAP-1 promotes FGF-2-FGF receptor 1 (FGFR1) complex formation by direct binding to FGF-2. Immunocytochemistry analyses revealed colocalization of PLAP-1 and FGF-2 in wild-type MEFs and reduced colocalization of FGF-2 and FGFR1 in Plap-1(-/-) MEFs compared with wild type MEFs. Taken together, PLAP-1 positively regulates FGF-2 activity through a direct interaction. Extracellular matrix-growth factor interactions have considerable effects; thus, this approach may be useful in several regenerative medicine applications. PMID- 26239646 TI - Closing the drug lag for new drug submission and review in Japan: An industry perspective. AB - Previous publications have focused on drug lag in Japan and the government's initiatives to address the situation.(1) Japan is the third largest pharmaceutical market, and yet has experienced significant drug lag for many years. This article reviews the progress resulting from industry adaptation of new regulatory paradigms that include Japan in global drug development programs. PMID- 26239647 TI - Should Exotic Eucalyptus be Planted in Subtropical China: Insights from Understory Plant Diversity in Two Contrasting Eucalyptus Chronosequences. AB - Although Eucalyptus is widely planted in South China, whose effects on native biodiversity are unclear. The objective of this study was to quantify the richness and composition of understory plants in two contrasting Eucalyptus chronosequences in South China. One was in Zhangzhou City with plantation age of 2, 4, and 6 years after clear-cutting Chinese fir forests, while the other was in Heshan City with plantation age of 2, 3, and 24 years that reforested on barren lands. Results showed that the richness of understory plants and functional groups was not significantly altered in the Zhangzhou chronosequence, while increased in the 24-year-old plantations, with a significantly larger proportion of woody plants than the younger plantations for the Heshan chronosequence. Moreover, a higher richness of woody plants accompanied by a lower richness of herbaceous species was detected in the Zhangzhou chronosequence compared with the Heshan one. To balance the need for pulp production and plant diversity conservation, we suggest that intercropping approaches between exotic Eucalyptus plantations and native forests should be considered in the fast rotation Eucalyptus plantations. However, Eucalyptus plantations may be used as pioneer species to sustain ecosystem functioning for the degraded lands. PMID- 26239648 TI - The Socio-ecological Fit of Human Responses to Environmental Degradation: An Integrated Assessment Methodology. AB - The scientific and policy interest in the human responses to environmental degradation usually focuses on responses sensu stricto and 'best practices' that potentially abate degradation in affected areas. The transfer of individual, discrete instruments and 'best practices' to different contexts is challenging, however, because socio-ecological systems are complex and environmental degradation is contextual and contingent. To sensibly assess the effectiveness of formal and informal interventions to combat environmental degradation, the paper proposes an integrative, non-reductionist analytic, the 'response assemblage', for the study of 'responses-in-context,' i.e., products of human decisions to utilize environmental resources to satisfy human needs in socio-ecological systems. Response assemblages are defined as geographically and historically unique, provisional, open, territorial wholes, complex compositions emerging from processes of assembling biophysical and human components, including responses sensu stricto, from affected focal and other socio-ecological systems, to serve human goals, one of which may be combatting environmental degradation. The degree of match among the components, called the socio-ecological fit of the response assemblage, indicates how effectively their contextual and contingent interactions maintain the socio-ecological resilience, promote sustainable development, and secure the continuous provision of ecosystem services in a focal socio-ecological system. The paper presents a conceptual approach to the analysis of the socio-ecological fit of response assemblages and details an integrated assessment methodology synthesizing the resilience, assemblage, and 'problem of fit' literature. Lastly, it summarizes the novelty, value, and policy relevance of conceptualizing human responses as response assemblages and of the integrated assessment methodology, reconsiders 'best practices' and suggests selected future research directions. PMID- 26239649 TI - Cost-Effectiveness Analysis of Surface Flow Constructed Wetlands (SFCW) for Nutrient Reduction in Drainage Discharge from Agricultural Fields in Denmark. AB - Constructed wetlands have been proposed as cost-effective and more targeted technologies in the reduction of nitrogen and phosphorous water pollution in drainage losses from agricultural fields in Denmark. Using two pig farms and one dairy farm situated in a pumped lowland catchment as case studies, this paper explores the feasibility of implementing surface flow constructed wetlands (SFCW) based on their cost effectiveness. Sensitivity analysis is conducted by varying the cost elements of the wetlands in order to establish the most cost-effective scenario and a comparison with the existing nutrients reduction measures carried out. The analyses show that the cost effectiveness of the SFCW is higher in the drainage catchments with higher nutrient loads. The range of the cost effectiveness ratio on nitrogen reduction differs distinctively with that of catch crop measure. The study concludes that SFCW could be a better optimal nutrients reduction measure in drainage catchments characterized with higher nutrient loads. PMID- 26239650 TI - Assessing the Social Carrying Capacity of Diving Sites in Mabul Island, Malaysia. AB - This study has explored social carrying capacity of an underwater environment based on divers' perceived crowding. Two dimensions were assessed, the number of divers seen and the proximity of diver. Data were obtained from a survey of 132 divers dived in Mabul Island, Malaysia during 2013-2014. Photographs depicting four levels of diver number and four levels of diver proximity in different combinations were shown to the respondents for assessing their acceptability. Between the two variables, the "number of divers" was the most influential factor for divers' perceived crowding. Divers would start to feel unacceptably crowded if 8-9 divers were visible to them at one time. Based on this, it is likely that the use level of diving sites in Mabul Island has already exceeded its social carrying capacity. Implications for future research and diving tourism management for Mabul Island are also discussed in the paper. PMID- 26239651 TI - PEGylated Biopharmaceuticals: Current Experience and Considerations for Nonclinical Development. AB - PEGylation (the covalent binding of one or more polyethylene glycol molecules to another molecule) is a technology frequently used to improve the half-life and other pharmaceutical or pharmacological properties of proteins, peptides, and aptamers. To date, 11 PEGylated biopharmaceuticals have been approved and there is indication that many more are in nonclinical or clinical development. Adverse effects seen with those in toxicology studies are mostly related to the active part of the drug molecule and not to polyethylene glycol (PEG). In 5 of the 11 approved and 10 of the 17 PEGylated biopharmaceuticals in a 2013 industry survey presented here, cellular vacuolation is histologically observed in toxicology studies in certain organs and tissues. No other effects attributed to PEG alone have been reported. Importantly, vacuolation, which occurs mainly in phagocytes, has not been linked with changes in organ function in these toxicology studies. This article was authored through collaborative efforts of industry toxicologists/nonclinical scientists to address the nonclinical safety of large PEG molecules (>10 kilo Dalton) in PEGylated biopharmaceuticals. The impact of the PEG molecule on overall nonclinical safety assessments of PEGylated biopharmaceuticals is discussed, and toxicological information from a 2013 industry survey on PEGylated biopharmaceuticals under development is summarized. Results will contribute to the database of toxicological information publicly available for PEG and PEGylated biopharmaceuticals. PMID- 26239645 TI - Rare coding variants and X-linked loci associated with age at menarche. AB - More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ~3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 * 10(-8)). In addition, we identify common X chromosome loci at IGSF1 (rs762080, P=9.4 * 10(-13)) and FAAH2 (rs5914101, P=4.9 * 10(-10)). Highlighted genes implicate cellular energy homeostasis, post transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 * 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ~0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait. PMID- 26239652 TI - Fifteen-minute consultation for a child not attending school: a structured approach to school refusal. AB - Paediatric consultations in school refusal cases need to explore the presenting medical symptoms and discuss with families any psychological function of the problems that have led to non-attendance. Understanding possible reinforcements of the child's avoidant behaviour, liaising with school and reassurance of the parents are often enough to manage the situation. However, more chronic and persistent refusal often require support from an extended team around the child, often requiring input from mental health professionals. Behavioural strategies are the recommended approach to improve school attendance and to tackle the underlying anxiety or depression, or both, that may be the root cause of their non-attendance. PMID- 26239653 TI - Haemolytic anaemia: don't leave it out in the cold. AB - This clinical case highlights the diagnostic odyssey of an adolescent girl presenting to A&E with non-specific headaches and chest pain. The case will describe the steps in decision making from admission to follow-up. PMID- 26239655 TI - Human epicardial adipose tissue has a specific transcriptomic signature depending on its anatomical peri-atrial, peri-ventricular, or peri-coronary location. AB - AIMS: Human epicardial adipose tissue (EAT) is a visceral and perivascular fat that has been shown to act locally on myocardium, atria, and coronary arteries. Its abundance has been linked to coronary artery disease (CAD) and atrial fibrillation. However, its physiological function remains highly debated. The aim of this study was to determine a specific EAT transcriptomic signature, depending on its anatomical peri-atrial (PA), peri-ventricular (PV), or peri-coronary location. METHODS AND RESULTS: Samples of EAT and thoracic subcutaneous fat, obtained from 41 patients paired for cardiovascular risk factors, CAD, and atrial fibrillation were analysed using a pangenomic approach. We found 2728 significantly up-regulated genes in the EAT vs. subcutaneous fat with 400 genes being common between PA, PV, and peri-coronary EAT. These common genes were related to extracellular matrix remodelling, inflammation, infection, and thrombosis pathways. Omentin (ITLN1) was the most up-regulated gene and secreted adipokine in EAT (fold-change >12, P < 0.0001). Among EAT-enriched genes, we observed different patterns depending on adipose tissue location. A beige expression phenotype was found in EAT but PV EAT highly expressed uncoupled protein 1 (P = 0.01). Genes overexpressed in peri-coronary EAT were implicated in proliferation, O-N glycan biosynthesis, and sphingolipid metabolism. PA EAT displayed an atypical pattern with genes implicated in cardiac muscle contraction and intracellular calcium signalling pathway. CONCLUSION: This study opens new perspectives in understanding the physiology of human EAT and its local interaction with neighbouring structures. PMID- 26239656 TI - Regulation of PHLDA1 Expression by JAK2-ERK1/2-STAT3 Signaling Pathway. AB - Toll-like receptor 2 (TLR2)-mediated signaling cascades and gene regulation are mainly involved in diseases, such as immunity and inflammation. In this study, microarray analysis was performed using bone marrow-derived macrophages (BMDM) and Raw 264.7 cells to identify novel proteins involved in the TLR2-mediated cellular response. We found that pleckstrin homology-like domain family, member 1 (PHLDA1) is a novel gene up-regulated by TLR2 stimulation and determined the unique signaling pathway for its expression. Treatment with TLR2 agonist Pam3 CSK4 increased mRNA, protein, and fluorescence staining of PHLDA1. Induction of PHLDA1 by TLR2 stimulation disappeared from TLR2 KO mice-derived BMDM. Among janus kinase (JAK) family members, JAK2 was involved in TLR2-stimulated PHLDA1 expression. Signal transducer and activator of transcription 3 (STAT3) also participated in PHLDA1 expression downstream of the JAK2. Interestingly, ERK1/2 was an intermediate between JAK2 and STAT3. In silico analysis revealed the presence of highly conserved gamma-activated sites within mouse PHLDA1 promoter and confirmed the JAK2-STAT3 pathway is important to Pam3 CSK4 -induced PHLDA1 transcription. These findings suggest that the JAK2-ERK1/2-STAT3 pathway is an important signaling pathway for PHLDA1 expression and that these proteins may play a critical role in eliciting TLR2-mediated immune and inflammatory response. PMID- 26239657 TI - Circadian rhythm of RNA N6-methyladenosine and the role of cryptochrome. AB - Methylation of RNA N(6)-methyladenosine has fundamental cellular functions, including translation regulation, RNA export, and stem cells renewal. However, the regulation of RNA N(6)-methyladenosine methylation is poorly understood. Here, we observed a robust circadian rhythm in N(6)-methyladenosine modifications of RNA. Deficiency of core mammalian clock genes, cryptochromes, decreased the levels of N(6)-methyladenosine in RNA. Cryptochrome1/2 knockout mice had significantly lower N(6)-methyladenosine methylation of RNA and lost the circadian rhythm of N(6)-methyladenosine levels in RNA. Global analysis of the circadian methylomes of N(6)-methyladenosine in RNA revealed that gene transcription, translation regulation, and RNA metabolism were highly correlated with N(6)-methyladenosine oscillation. Our findings extended a fundamental link between the circadian rhythm and N(6)-methyladenosine modification of RNA and suggested that this link is critical in controlling post-transcriptional gene expression and RNA metabolism. PMID- 26239654 TI - Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation. AB - Gene therapy is a promising modality for the treatment of inherited and acquired cardiovascular diseases. The identification of the molecular pathways involved in the pathophysiology of heart failure and other associated cardiac diseases led to encouraging preclinical gene therapy studies in small and large animal models. However, the initial clinical results yielded only modest or no improvement in clinical endpoints. The presence of neutralizing antibodies and cellular immune responses directed against the viral vector and/or the gene-modified cells, the insufficient gene expression levels, and the limited gene transduction efficiencies accounted for the overall limited clinical improvements. Nevertheless, further improvements of the gene delivery technology and a better understanding of the underlying biology fostered renewed interest in gene therapy for heart failure. In particular, improved vectors based on emerging cardiotropic serotypes of the adeno-associated viral vector (AAV) are particularly well suited to coax expression of therapeutic genes in the heart. This led to new clinical trials based on the delivery of the sarcoplasmic reticulum Ca(2+)-ATPase protein (SERCA2a). Though the first clinical results were encouraging, a recent Phase IIb trial did not confirm the beneficial clinical outcomes that were initially reported. New approaches based on S100A1 and adenylate cyclase 6 are also being considered for clinical applications. Emerging paradigms based on the use of miRNA regulation or CRISPR/Cas9-based genome engineering open new therapeutic perspectives for treating cardiovascular diseases by gene therapy. Nevertheless, the continuous improvement of cardiac gene delivery is needed to allow the use of safer and more effective vector doses, ultimately bringing gene therapy for heart failure one step closer to reality. PMID- 26239658 TI - Low-magnitude mechanical vibration regulates expression of osteogenic proteins in ovariectomized rats. AB - OBJECTIVE: The present study aimed to investigate the impact of low-magnitude and high-frequency mechanical vibration with various lengths of resting period incorporated between loading cycles on the expression of osteogenesis-related proteins in a rat model of osteoporosis. METHODS: The rats in the mechanical loading groups received low-magnitude and high-frequency vibration (35 Hz and acceleration of 0.25 g, 15 min/day) for 8 weeks. Bilateral humeral heads and femoral heads were then isolated, and protein levels of bone morphogenetic protein 2 (BMP-2), extracellular signal-regulated kinase 1/2 (ERK1/2), phosphorylated ERK1/2 (p-ERK1/2), runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) were determined by Western blotting. RESULTS: Increased levels of BMP-2, Runx2 and OCN were observed in rats receiving mechanical vibration. Total ERK1/2 protein remained unchanged, whereas the level of activated ERK1/2 (p ERK1/2) increased after mechanical vibration. Vibration with incorporated resting period, regardless of length, was more effective in inducing expression of these osteogenic proteins, and the vibration with 7-day resting period had the most profound impact. CONCLUSION: Signals from low-magnitude and high-frequency mechanical vibration upregulated the expression of BMP-2 and Runx2, activated the ERK1/2 signaling pathway, and consequently led to increased expression of OCN. The anabolic effect of mechanical stimulation was enhanced with incorporation of resting period between loadings, and the one with 7-day resting period exhibited the strongest effect among all. Our results could provide a reference for development of mechanical stimulation as a non-pharmacological intervention for osteoporosis. PMID- 26239659 TI - GABAB receptors inhibit low-voltage activated and high-voltage activated Ca(2+) channels in sensory neurons via distinct mechanisms. AB - Growing evidence suggests that mammalian peripheral somatosensory neurons express functional receptors for gamma-aminobutyric acid, GABAA and GABAB. Moreover, local release of GABA by pain-sensing (nociceptive) nerve fibres has also been suggested. Yet, the functional significance of GABA receptor triggering in nociceptive neurons is not fully understood. Here we used patch-clamp recordings from small-diameter cultured DRG neurons to investigate effects of GABAB receptor agonist baclofen on voltage-gated Ca(2+) currents. We found that baclofen inhibited both low-voltage activated (LVA, T-type) and high-voltage activated (HVA) Ca(2+) currents in a proportion of DRG neurons by 22% and 32% respectively; both effects were sensitive to Gi/o inhibitor pertussis toxin. Inhibitory effect of baclofen on both current types was about twice less efficacious as compared to that of the MU-opioid receptor agonist DAMGO. Surprisingly, only HVA but not LVA current modulation by baclofen was partially prevented by G protein inhibitor GDP beta-S. In contrast, only LVA but not HVA current modulation was reversed by the application of a reducing agent dithiothreitol (DTT). Inhibition of T-type Ca(2+) current by baclofen and the recovery of such inhibition by DTT were successfully reconstituted in the expression system. Our data suggest that inhibition of LVA current in DRG neurons by baclofen is partially mediated by an unconventional signaling pathway that involves a redox mechanism. These findings reinforce the idea of targeting peripheral GABA receptors for pain relief. PMID- 26239660 TI - Aspartic cathepsin D degrades the cytosolic cysteine cathepsin inhibitor stefin B in the cells. AB - Stefin B is the major general cytosolic protein inhibitor of cysteine cathepsins. Its main function is to protect the organism against the activity of endogenous potentially hazardous proteases accidentally released from lysosomes. In this study, we investigated the possible effect of endosomal/lysosomal aspartic cathepsins D and E on stefin B after membrane permeabilization. Loss of membrane integrity of lysosomes and endosomes was induced by a lysosomotropic agent L Leucyl-L-leucine methyl ester (Leu-Leu-OMe). The rat thyroid cell line FRTL-5 was selected as a model cell line owing to its high levels of proteases, including cathepsin D and E. Permeabilization of acid vesicles from FRTL-5 cells induced degradation of stefin B. The process was inhibited by pepstatin A, a potent inhibitor of aspartic proteases. However, degradation of stefin B was prevented by siRNA-mediated silencing of cathepsin D expression. In contrast, cathepsin E silencing had no effect on stefin B degradation. These results showed that cathepsin D and not cathepsin E degrades stefin B. It can be concluded that the presence of cathepsin D in the cytosol affects the inhibitory potency of stefin B, thus preventing the regulation of cysteine cathepsin activities in various biological processes. PMID- 26239661 TI - Baicalin attenuates angiotensin II-induced endothelial dysfunction. AB - Angiotensin II (Ang II) has been shown to activate multiple downstream pathways resulting in endothelial dysfunction and oxidative stress. Baicalin, a natural flavone, exerts anti-oxidant and anti-apoptotic effects in cardiovascular diseases. In the present study, we hypothesized that baicalin has beneficial effects in Ang II-induced endothelial cells injury. Here, we shown that baicalin improved endothelial fuction impaired by Ang II through promoting endothelial dependent vasodilation and suppressing the apoptosis of HUVECs in which baicalin decreased the expression of bax and cleaved caspase-3, and increased bcl-2 expression. Additionally, baicalin significantly conversed Ang II to angiotensin 1-7 [Ang-(1-7)] by activating angiotensin-converting enzyme 2 (ACE2) and Mas receptor mRNA expression and protein expression. Moreover, treatment with baicalin significantly reduced cell oxidative damage induced by Ang II through MDA/ROS decrease and NO/T-AOC increase. This antioxidant capacity was related to the increases of PI3K, phosphor-AKT (Ser-473) and phosphor-eNOS (Ser-1177). In conclusion, our results implicate that baicalin could protect endothelial cells from Ang II-induced endothelial dysfunction and oxidative stress via modulating the expression of bax, bcl-2 and cleaved caspase-3, activating ACE2/Ang-(1-7)/Mas axis and up-regulating PI3K/AKT/eNOS pathway. PMID- 26239662 TI - Repeated stress-induced expression pattern alterations of the hippocampal chloride transporters KCC2 and NKCC1 associated with behavioral abnormalities in female mice. AB - The balance of cation-chloride co-transporters, particularly KCC2 and NKCC1, is critical for GABAergic inhibitory signaling. However, KCC2/NKCC1 balance is disrupted in many neurodegenerative diseases. Moreover, correlations between chronic stress, KCC2 and NKCC1 in the hippocampus remain poorly understood. Despite the fact that emotional disorders in humans are far more prevalent in women, there have been relatively few studies about female subjects. Here we investigated behaviors and expression patterns of KCC2 and NKCC1 in the hippocampi of female mice under chronic stress. Repeated stress (RS) was induced in experimental mice by repeated forced water administration. Then, expression patterns of GABAergic signaling molecules were identified by immunohistochemical analysis and performance was assessed using several behavioral tests. The results of semi-quantitative analysis showed that RS decreased KCC2 expression and increased NKCC1 expression in membranes of granular and pyramidal cells in the hippocampus. The novel object recognition (NOR) test and sociability test revealed that RS induced cognitive and sociability deficits, whereas RS increased the time spent in the open arms of the elevated plus maze test and induced attention deficits in other tests. In summary, RS induced alterations in membrane KCC2/NKCC1 balance in the hippocampus of female mice, which may contribute to GABAergic disinhibition associated with cognitional, sociability and attention deficits. PMID- 26239663 TI - Volume-targeted versus pressure-limited ventilation in infants born at or near term. AB - Our aims were to determine whether volume-targeted ventilation (VTV) or pressure limited ventilation (PLV) reduced the time to successful extubation and if any difference was explained by a lower work of breathing (WOB), better respiratory muscle strength or less thoracoabdominal asynchrony (TAA) and associated with fewer hypocarbic episodes. Infants born at >=34 weeks of gestational age were randomised to VTV or PLV. The WOB was assessed by the transdiaphragmatic pressure time product, respiratory muscle strength by the maximum inflation (Pimax) and expiratory (Pemax) pressures and TAA assessed using uncalibrated respiratory inductance plethysmography. Forty infants, median gestational age of 39 (range 34 42) weeks, were recruited. The time to successful extubation did not differ between the two groups (median 25, range 2.5-312 h (VTV) versus 33.5, 1.312 h (PLV)) (p = 0.461). There were no significant differences between the groups with regard to the WOB, respiratory muscle strength or the TAA results. The median number of hypocarbic episodes was 1.5 (range 0-8) in the VTV group versus 4 (range 1-13) in the PLV group (p = 0.005). CONCLUSION: In infants born at or near term, VTV compared to PLV did not reduce the time to successful extubation but was associated with significantly fewer hypocarbic episodes. WHAT IS KNOWN: In prematurely born infants, volume-targeted ventilation (VTV) compared to pressure limited ventilation (PLV) reduces bronchopulmonary dysplasia or death. In addition, VTV is associated in prematurely born infants with lower incidences of pneumothorax, intraventricular haemorrhage and hypocarbic episodes. WHAT IS NEW: Despite a high morbidity, few studies have investigated optimum ventilation strategies for infants born at or near term. In a RCT, we have demonstrated VTV versus PLV in infants >=34 weeks gestation was associated with significantly fewer hypocarbic episodes. PMID- 26239664 TI - Inferior vena cava filter migration during the prone position for spinal surgery: a case report. AB - PURPOSE: Inferior vena cava (IVC) filters have been used as an alternative therapy for patients with a contraindication to anticoagulation. We present a case of an IVC filter migration to the right ventricle occurring while a trauma patient was undergoing spinal surgery in the prone position. The patient provided written consent to describe this case. CLINICAL FEATURES: A 54-yr-old multiple trauma male patient with an unstable fracture of the T6 vertebra and a stable fracture of the T10 vertebra developed a pulmonary embolism secondary to a left common femoral deep vein thrombosis. An IVC filter was placed so that an intravenous unfractionated heparin infusion could be stopped two days before scheduled spinal surgery. Intraoperatively, the patient was placed in the prone position on conventional convex support pads. At the end of the procedure, he developed ventricular trigeminy which lasted three minutes. During the next 48 hr, the patient developed a fever of 39 degrees C. An echocardiogram was performed to rule out endocarditis, and results showed that the IVC filter had migrated into the right ventricle. After a failed attempt at percutaneous removal of the filter in the catheterization laboratory, the patient was transferred to the operating room and the IVC filter was extracted through a midline sternotomy under cardiopulmonary bypass. CONCLUSIONS: The prone position during surgery can induce anatomic and hemodynamic changes in the IVC. This may contribute to the migration of IVC filters--especially flexible retrievable filters. Careful handling and positioning of patients with IVC filters is recommended to avoid a sudden increase in IVC pressure that may predispose to IVC filter migration. PMID- 26239665 TI - Limiting the accessibility of cost-prohibitive drugs reduces overall anesthetic drug costs: a retrospective before and after analysis. AB - PURPOSE: Cost effectiveness is becoming increasingly important in today's healthcare environment. Remifentanil, dexmedetomidine, and desflurane are costly agents that often have suitable alternatives to their use. We sought to identify changes in cost and outcomes following interventions that limited the availability of these drugs. METHODS: We calculated anesthetic drug costs for all operating room procedures performed before and after the accessibility interventions. We retrospectively compared drug costs per case and the frequency of agent use before and after the interventions. In addition, we analyzed the incidence of adverse outcomes, including delayed out-of-room times, postoperative nausea and vomiting (PONV), unplanned intubations, use of naloxone, and reintubations. Wilcoxon-Mann-Whitney and Chi square analyses were used to quantify differences in cost, use, and outcomes between cohorts. RESULTS: Of the 27,233 cases we identified, 24,201 cases were analyzed. The mean anesthetic drug costs per case were significantly lower after the interventions vs before at ($21.44 vs $32.39, respectively), a cost savings of $10.95 (95% confidence interval, $9.86 to $12.04; P < 0.001). Additionally, a comparison of data after vs before the interventions revealed the following results: remifentanil use was significantly lower (3.5% vs 9.2% of cases; P < 0.001). Dexmedetomidine use did not differ significantly (0.4% vs 0.5% of cases; P = 0.07), and desflurane use was significantly lower (0.6% vs 20.2% of cases; P < 0.001). There was no significant relationship between the interventions and the frequency of delayed out-of-room times (15.5% vs 15.9%; P = 0.41), unplanned intubations (0.02% vs 0.03%; P = 0.60), and reintubations (0.01% vs 0.03%; P = 0.28). Postoperative nausea and vomiting decreased significantly after the interventions (22.8% vs 24.4%; P = 0.003), and naloxone use showed a significant increase (0.22% vs 0.11% of cases; P = 0.04). CONCLUSIONS: Reducing the accessibility of these cost prohibitive agents resulted in significant anesthetic drug cost savings and decreased utilization of remifentanil and desflurane. The interventions had no significant effect on patient recovery time, incidence of unplanned intubations, or incidence of reintubation, but they were associated with a decrease in PONV and an increase in naloxone use. PMID- 26239666 TI - Curtailing the cost of anesthetic drugs: prudent economics or an infringement of clinical autonomy? PMID- 26239667 TI - Reviving older drugs to deal with anesthesia drug shortages. PMID- 26239668 TI - Point-of-care ultrasound defines gastric content and changes the anesthetic management of elective surgical patients who have not followed fasting instructions: a prospective case series. AB - PURPOSE: Pulmonary aspiration of gastric contents is a major cause of anesthesia morbidity and mortality. Point-of-care gastric ultrasound provides information regarding the type and volume of gastric content. The hypothesis of this prospective cohort study was that the addition of point-of-care gastric ultrasound to standard patient assessment results in changes in anesthetic management in at least 30% of elective surgical patients who do not follow fasting instructions. METHODS: Following Research Ethics Board approval and informed consent, elective surgical patients who did not follow fasting instructions were included in this prospective study. Documentation included the type of food ingested, the timing of the ingestion relative to the planned surgical time, and the treating anesthesiologist's management plan based on history alone. Next, an independent anesthesiologist not involved in the medical decision-making performed a focused gastric ultrasound examination. The results of the ultrasound exam were documented in a standardized fashion and made available to the attending anesthesiologist who then confirmed or revised the initial management plan. The treating anesthesiologist's actual (post-test) patient management was documented in a standardized fashion and compared with the initial (pre-test) management plan. RESULTS: Thirty-eight patients were included in this case series. Following point-of-care gastric ultrasound, there was a change in either the timing of anesthesia or the anesthetic technique (or both) in 27 patients (71%), with a net change towards a lower incidence of surgical delays. CONCLUSIONS: This prospective case series suggests that a standardized point-of care gastric ultrasound examination informs anesthesiologists' perceived level of aspiration risk and leads to changes in anesthetic management in a significant proportion of elective patients who did not follow fasting instructions. PMID- 26239669 TI - Memristive crypto primitive for building highly secure physical unclonable functions. AB - Physical unclonable functions (PUFs) exploit the intrinsic complexity and irreproducibility of physical systems to generate secret information. The advantage is that PUFs have the potential to provide fundamentally higher security than traditional cryptographic methods by preventing the cloning of devices and the extraction of secret keys. Most PUF designs focus on exploiting process variations in Complementary Metal Oxide Semiconductor (CMOS) technology. In recent years, progress in nanoelectronic devices such as memristors has demonstrated the prevalence of process variations in scaling electronics down to the nano region. In this paper, we exploit the extremely large information density available in nanocrossbar architectures and the significant resistance variations of memristors to develop an on-chip memristive device based strong PUF (mrSPUF). Our novel architecture demonstrates desirable characteristics of PUFs, including uniqueness, reliability, and large number of challenge-response pairs (CRPs) and desirable characteristics of strong PUFs. More significantly, in contrast to most existing PUFs, our PUF can act as a reconfigurable PUF (rPUF) without additional hardware and is of benefit to applications needing revocation or update of secure key information. PMID- 26239670 TI - [Update of diabetic retinopathy for Primary Care physicians: Towards an improvement of telematic medicine]. AB - Diabetic retinopathy (DR) is considered the most common cause of blindness in the working-age population in industrialised countries, with diabetic macular oedema being the most common reason of decreased visual acuity in diabetics. According to the results of large multicentre studies, blindness prevention for RD involves conducting periodic check-ups, which include examinations of the back of the eye, so they can be treated in time. The use of non-mydriatic cameras and telemedicine have been shown to be useful in this regard (sensitivity>80% and specificity>90%). If this procedure is followed, the first retinography should be performed 5 years from diagnosis in type 1 diabetics and immediately after diagnosis in type 2 diabetics. Therefore the role of the Primary Care physician is crucial to enable early diagnosis of this disease. PMID- 26239671 TI - [Breast cancer and Mondor's disease: A curious couple]. PMID- 26239672 TI - [Low back pain during pregnancy. Multidisciplinary approach]. AB - After explaining that low back pain is considered the most common pregnancy complication, its pathogenesis, risk factors and the clinical characteristics of the very painful symptoms of this condition are described. As for its approach, it is stressed that it must be multidisciplinary, introducing very important preventive measures, including proper postural hygiene. For its treatment, the methods may be based on non-surgical or pharmacological interventions of a conservative non-invasive nature. Thus, physiotherapy, osteopathic manipulation, multimodal intervention (exercise and education), exercises performed in water environment, acupuncture, etc., have proven to be effective. Finally, it is emphasised that given the significant impact on their quality of life, different health professionals must be proactive and treat the lumbar disease in pregnant women. PMID- 26239673 TI - [Isolated hepatic sarcoidosis, an unusual form of presentation of a systemic disease]. PMID- 26239674 TI - MEN1 c.825-1G>A mutation in a family with multiple endocrine neoplasia type 1: A case report. AB - Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease characterized by combined occurrence of tumors and hyperplasia in tissues including the parathyroid, gastrointestinal endocrine tissue and anterior pituitary. Heterozygous germline mutation of the tumor suppressor gene MEN1 is the cause of the disease. Treatment and long-term follow up of patients with MEN1 are rarely reported in the literature due to the relative rarity of the disease; thus, there is limited understanding of tumor biology and behavior, and heterogeneous clinical presentation. This case report observed a family that presented with MEN1 c.825-1G>A mutation. The clinical features and treatment were followed up for >20 years. Detailed family history of this pedigree was investigated and followed up. Genomic DNA was extracted by standard methods from peripheral leukocytes. The coding sequence, including 9 coding exons and 16 splice junctions of the MEN1 gene of leukocyte DNA was determined. The proband presented with gastrinoma, pituitary tumors, hyperparathyroidism, thymoma and lung carcinoid tumors, and was followed from age 35 to 54 years old. During the 20 years, the patient underwent four surgeries: Trans-sphenoidal adenomectomy, followed by post operative radiotherapy at 39 years; hyperplasia parathyroid gland resection at 40 years; removal of pancreatic, head and neck, duodenal, gallbladder, bile duct, subtotal gastric (4/5) and pyloric region lymph nodes at age 41; and a thymectomy and left lung carcinoid tumor removal procedure at the age of 49. The patient died of unrelated trauma and had a relatively stable illness course. DNA sequence analysis revealed MEN1 gene c.825-1G>A or IVS 5-1G>A mutation in the family. Two carriers in the pedigree were identified and followed up. Data indicated that although MEN1 is a complex disease involving multiple organs and systems, MEN1 tumors should be considered surgically curable. If patients are properly cared for by multidisciplinary teams comprising of relevant specialists with experience in the diagnosis and treatment of patients with endocrine tumors, patients may have a relatively positive prognosis. PMID- 26239675 TI - Lanthanide mixed-ligand complexes of the [Ln(CAPh)3(Phen)] and [LaxEu1 x(CAPh)3(Phen)] (CAPh = carbacylamidophosphate) type. A comparative study of their spectral properties. AB - A series of complexes Ln(Pip)3(Phen) (Ln(iii) = La, Ce-Nd, Sm-Lu, Y; HPip (CAPh type ligand) = 2,2,2-trichloro-N-(dipiperidin-1-yl-phosphoryl)acetamide, Phen = 1,10-phenanthroline) has been synthesized. The lanthanum(iii) doped europium(iii) complexes ([LaxEu1-x(Pip)3(Phen)], x = 0.99, 0.95, 0.50) have been obtained by the co-crystallization method. The complexes have been characterized by means of X-ray diffraction, IR, (1)H and (31)P-NMR and absorption spectroscopy. Emission and excitation luminescence spectra were recorded at 295 and 77 K. The lifetime values (tau) for the emission of all europium complexes were determined. The (5)D0 luminescence quantum efficiency is 73-89%. The symmetries of the nearest europium surrounding in pure and doped complexes were evaluated from the Stark splitting of (5)D0-(7)FJ transitions. Crystal structures of [Ln(Pip)3(Phen)] (Ln = Nd (1), Eu (2) and Tb (3)) have been determined. Lattice parameters of the [Ln(Pip)3(Phen)] (Ln = Tb, Yb) and the doped [LaxEu1-x(Pip)3(Phen)] (x = 0.99, 0.95, 0.50) complexes have been measured. The presence of four polymorphs within a number of rare earth elements has been estimated: two in triclinic (Ln1 = La, Nd; Ln2 = Eu), one in the monoclinic (Ln3 = Tb) and one in the rhombic (Ln4 = Tb, Yb) symmetry. Complex 3 can be obtained in two crystal modifications: monoclinic and orthorhombic ones. PMID- 26239676 TI - N-trans-rho-caffeoyl tyramine isolated from Tribulus terrestris exerts anti inflammatory effects in lipopolysaccharide-stimulated RAW 264.7 cells. AB - Inflammation is induced by the expression of cyclooxygenase-2 (COX-2), which is an important mediator of chronic inflammatory diseases, such as rheumatoid arthritis, asthma and inflammatory bowel disease. Tribulus terrestris (T. terrestris) is known to have a beneficial effect on inflammatory diseases. In this study, we investigated the effects of N-trans-rho-caffeoyl tyramine (CT) isolated from T. terrestris on the production of nitric oxide (NO), and the expression of pro-inflammatory cytokines and COX-2 in lipopolysaccharide (LPS) stimulated RAW 264.7 cells. We also aimed to elucidate the molecular mechanisms involved. We found that the ethanolic extract of T. terrestris (EETT) and CT inhibited the production of NO, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-10 in the LPS-stimulated RAW 264.7 cells in a dose dependent manner. They were determined by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). In addition, CT markedly suppressed the expression of COX-2 and the production of prostaglandin E2 (PGE2) in response to LPS stimulation. Furthermore, CT markedly decreased p-c Jun N-terminal kinase (p-JNK) protein expression in LPS-stimulated RAW 264.7 cells. COX-2 and p-JNK were measured by western blot analysis. Taken together, these findings indicate that CT isolated from T. terrestris is a novel and potent modulator of inflammatory responses. Thus, it may prove benefiical to further evaluate CT as a possible treatment for chronic inflammatory diseases. PMID- 26239677 TI - Building bridges: the emerging field of cardio-oncology. PMID- 26239678 TI - Lymphoid lineage differentiation potential of mouse nuclear transfer embryonic stem cells. AB - Stem cells therapy is considered as an efficient strategy for the treatment of some diseases. Nevertheless, some obstacles such as probability of rejection by the immune system limit applications of this strategy. Therefore, several efforts have been made to overcome this among which using the induced pluripotent stem cells (iPSCs) and nuclear transfer embryonic stem cell (nt-ESCs) are the most efficient strategies. The objective of this study was to evaluate the differentiation potential of the nt-ESCs to lymphoid lineage in the presence of IL-7, IL-3, FLT3-ligand and TPO growth factors in vitro. To this end, the nt-ESCs cells were prepared and treated with aforementioned growth factors for 7 and 14 days. Then, the cells were examined for expression of lymphoid markers (CD3, CD25, CD127 and CD19) by quantitative PCR (q-PCR) and flow cytometry. An increased expression of CD19 and CD25 markers was observed in the treated cells compared with the negative control samples by day 7. After 14 days, the expression level of all the tested CD markers significantly increased in the treated groups in comparison with the control. The current study reveals the potential of the nt-ESCs in differentiation to lymphoid lineage in the presence of defined growth factors. PMID- 26239679 TI - The patterning mechanism of carbon nanotubes using surface acoustic waves: the acoustic radiation effect or the dielectrophoretic effect. AB - In this study, we present a simple technique capable of assembling and patterning suspended CNTs using a standing surface acoustic wave (SSAW) field. Individual CNTs could be assembled into larger CNT bundles and patterned in periodic positions on a substrate surface. The mechanism of the SSAW-based patterning technique has been investigated using both numerical simulation and experimental study. It has been found that the acoustic radiation effect due to the acoustic pressure field and the dielectrophoretic (DEP) effect induced by the electric field co-existing in the patterning process however play different roles depending on the properties of the suspended particles and the suspension medium. In the SSAW-based patterning of highly conductive CNTs with high aspect ratio geometry, the positive DEP effect dominates over the acoustic radiation effect. In contrast, the acoustic radiation effect dominates over the DEP effect when manipulating less conductive, spherical or low aspect ratio particles or biological cells. These results provide a meaningful insight into the mechanism of SSAW-based patterning, which is of great help to guide the effective use of this patterning technique for various applications. PMID- 26239680 TI - Diabetic Nephropathy and CKD-Analysis of Individual Patient Serum Creatinine Trajectories: A Forgotten Diagnostic Methodology for Diabetic CKD Prognostication and Prediction. AB - Creatinine is produced in muscle metabolism as the end-product of creatine phosphate and is subsequently excreted principally by way of the kidneys, predominantly by glomerular filtration. Blood creatinine assays constitute the most common clinically relevant measure of renal function. The use of individual patient-level real-time serum creatinine trajectories provides a very attractive and tantalizing methodology in nephrology practice. Topics covered in this review include acute kidney injury (AKI) with its multifarious rainbow spectrum of renal outcomes; the stimulating vicissitudes of the diverse patterns of chronic kidney disease (CKD) to end-stage renal disease (ESRD) progression, including the syndrome of rapid onset end stage renal disease (SORO-ESRD); the syndrome of late onset renal failure from angiotensin blockade (LORFFAB); and post-operative AKI linked with the role of intra-operative hypotension in patients with diabetes mellitus and suspected diabetic nephropathy with CKD. We conclude that the study of individual patient-level serum creatinine trajectories, albeit a neglected and forgotten diagnostic methodology for diabetic CKD prognostication and prediction, is a most useful diagnostic tool, both in the short-term and in the long-term practice of nephrology. The analysis of serum creatinine trajectories, both in real time and retrospectively, indeed provides supplementary superior diagnostic and prognostic insights in the management of the nephrology patient. PMID- 26239681 TI - A Circulating MicroRNA Signature as a Biomarker for Prostate Cancer in a High Risk Group. AB - INTRODUCTION: Mi(cro)RNAs are small non-coding RNAs whose differential expression in tissue has been implicated in the development and progression of many malignancies, including prostate cancer. The discovery of miRNAs in the blood of patients with a variety of malignancies makes them an ideal, novel biomarker for prostate cancer diagnosis. The aim of this study was to identify a unique expression profile of circulating miRNAs in patients with prostate cancer attending a rapid access prostate assessment clinic. METHODS: To conduct this study blood and tissue samples were collected from 102 patients (75 with biopsy confirmed cancer and 27 benign samples) following ethical approval and informed consent. These patients were attending a prostate assessment clinic. Samples were reverse-transcribed using stem-loop primers and expression levels of each of 12 candidate miRNAs were determined using real-time quantitative polymerase chain reaction. miRNA expression levels were then correlated with clinicopathological data and subsequently analysed using qBasePlus software and Minitab. RESULTS: Circulating miRNAs were detected and quantified in all subjects. The analysis of miRNA mean expression levels revealed that four miRNAs were significantly dysregulated, including let-7a (p = 0.005) which has known tumour suppressor characteristics, along with miR-141 (p = 0.01) which has oncogenic characteristics. In 20 patients undergoing a radical retropubic-prostatectomy, the expression levels of miR-141 returned to normal at day 10 post-operatively. A panel of four miRNAs could be used in combination to detect prostate cancer with an area under the curve (AUC) of 0.783 and a PPV of 80%. CONCLUSION: These findings identify a unique expression profile of miRNA detectable in the blood of prostate cancer patients. This confirms their use as a novel, diagnostic biomarker for prostate cancer. PMID- 26239682 TI - Long-Term Visual Outcomes for a Treat and Extend Anti-Vascular Endothelial Growth Factor Regimen in Eyes with Neovascular Age-Related Macular Degeneration. AB - With the advent of anti-vascular endothelial growth factor (VEGF) therapy, clinicians are now focused on various treatment strategies to better control neovascular age-related macular degeneration (NVAMD), a leading cause of irreversible blindness. Herein, we retrospectively reviewed consecutive patients with treatment-naive NVAMD initially classified based on fluorescein angiography (FA) alone or with an anatomic classification utilizing both FA and optical coherence tomography (OCT) and correlated long-term visual outcomes of these patients treated with an anti-VEGF Treat-and-Extend Regimen (TER) with baseline characteristics including neovascular phenotype. Overall, 185 patients (210 eyes) were followed over an average of 3.5 years (range 1-6.6) with a retention rate of 62.9%, and visual acuity significantly improved with a TER that required a mean number of 8.3 (+/-1.6) (+/- standard deviation) intravitreal anti-VEGF injections/year (range 4-13). The number of injections and the anatomic classification were independent predictors of visual acuity at 6 months, 1, 2, 3 and 4 years. Patients with Type 1 neovascularization had better visual outcomes and received more injections than the other neovascular subtypes. There were no serious adverse events. A TER provided sustained long-term visual gains. Eyes with Type 1 neovascularization had better visual outcomes than those with other neovascular subtypes. PMID- 26239683 TI - Diabetic Nephropathy without Diabetes. AB - Diabetic nephropathy without diabetes (DNND), previously known as idiopathic nodular glomerulosclerosis, is an uncommon entity and thus rarely suspected; diagnosis is histological once diabetes is discarded. In this study we describe two new cases of DNND and review the literature. We analyzed all the individualized data of previous publications except one series of attached data. DNND appears to be favored by recognized cardiovascular risk factors. However, in contrast with diabetes, apparently no factor alone has been demonstrated to be sufficient to develop DNND. Other factors not considered as genetic and environmental factors could play a role or interact. The most plausible hypothesis for the occurrence of DNND would be a special form of atherosclerotic or metabolic glomerulopathy than can occur with or without diabetes. The clinical spectrum of cardiovascular risk factors and histological findings support this theory, with hypertension as one of the characteristic clinical features. PMID- 26239684 TI - Mitochondrial Glutathione in Diabetic Nephropathy. AB - Although there are many etiologies for diabetic nephropathy (DN), one common characteristic of all cases involves mitochondrial oxidative stress and consequent bioenergetic dysfunction. As the predominant low-molecular-weight, intramitochondrial thiol reductant, the mitochondrial glutathione (mtGSH) pool plays important roles in how this organelle adapts to the chronic hyperglycemia and redox imbalances associated with DN. This review will summarize information about the processes by which this important GSH pool is regulated and how manipulation of these processes can affect mitochondrial and cellular function in the renal proximal tubule. Mitochondria in renal proximal tubular (PT) cells do not appear to synthesize GSH de novo but obtain it by transport from the cytoplasm. Two inner membrane organic anion carriers, the dicarboxylate carrier (DIC; Slc25a10) and 2-oxoglutarate carrier (OGC; Slc25a11) are responsible for this transport. Genetic modulation of DIC or OGC expression in vitro in PT cells from diabetic rats can alter mitochondrial function and susceptibility of renal PT cells to oxidants, with overexpression leading to reversion of bioenergetic conditions to a non-diabetic state and protection of cells from injury. These findings support the mtGSH carriers as potential therapeutic targets to correct the underlying metabolic disturbance in DN. PMID- 26239685 TI - Diabetes Insipidus after Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a significant cause of morbidity and mortality in many age groups. Neuroendocrine dysfunction has been recognized as a consequence of TBI and consists of both anterior and posterior pituitary insufficiency; water and electrolyte abnormalities (diabetes insipidus (DI) and the syndrome of inappropriate antidiuretic hormone secretion (SIADH)) are amongst the most challenging sequelae. The acute head trauma can lead (directly or indirectly) to dysfunction of the hypothalamic neurons secreting antidiuretic hormone (ADH) or of the posterior pituitary gland causing post-traumatic DI (PTDI). PTDI is usually diagnosed in the first days after the trauma presenting with hypotonic polyuria. Frequently, the poor general status of most patients prevents adequate fluid intake to compensate the losses and severe dehydration and hypernatremia occur. Management consists of careful monitoring of fluid balance and hormonal replacement. PTDI is associated with high mortality, particularly when presenting very early following the injury. In many surviving patients, the PTDI is transient, lasting a few days to a few weeks and in a minority of cases, it is permanent requiring management similar to that offered to patients with non traumatic central DI. PMID- 26239686 TI - Impaired Pituitary Axes Following Traumatic Brain Injury. AB - Pituitary dysfunction following traumatic brain injury (TBI) is significant and rarely considered by clinicians. This topic has received much more attention in the last decade. The incidence of post TBI anterior pituitary dysfunction is around 30% acutely, and declines to around 20% by one year. Growth hormone and gonadotrophic hormones are the most common deficiencies seen after traumatic brain injury, but also the most likely to spontaneously recover. The majority of deficiencies present within the first year, but extreme delayed presentation has been reported. Information on posterior pituitary dysfunction is less reliable ranging from 3%-40% incidence but prospective data suggests a rate around 5%. The mechanism, risk factors, natural history, and long-term effect of treatment are poorly defined in the literature and limited by a lack of standardization. Post TBI pituitary dysfunction is an entity to recognize with significant clinical relevance. Secondary hypoadrenalism, hypothyroidism and central diabetes insipidus should be treated acutely while deficiencies in growth and gonadotrophic hormones should be initially observed. PMID- 26239687 TI - Hypopituitarism in Traumatic Brain Injury-A Critical Note. AB - While hypopituitarism after traumatic brain injury (TBI) was previously considered rare, it is now thought to be a major cause of treatable morbidity among TBI survivors. Consequently, recommendations for assessment of pituitary function and replacement in TBI were recently introduced. Given the high incidence of TBI with more than 100 pr. 100,000 inhabitants, TBI would be by far the most common cause of hypopituitarism if the recently reported prevalence rates hold true. The disproportion between this proposed incidence and the occasional cases of post-TBI hypopituitarism in clinical practice justifies reflection as to whether hypopituitarism has been unrecognized in TBI patients or whether diagnostic testing designed for high risk populations such as patients with obvious pituitary pathology has overestimated the true risk and thereby the disease burden of hypopituitarism in TBI. The findings on mainly isolated deficiencies in TBI patients, and particularly isolated growth hormone (GH) deficiency, raise the question of the potential impact of methodological confounding, determined by variable test-retest reproducibility, appropriateness of cut-off values, importance of BMI stratified cut-offs, assay heterogeneity, pre-test probability of hypopituitarism and lack of proper individual laboratory controls as reference population. In this review, current recommendations are discussed in light of recent available evidence. PMID- 26239688 TI - Urinary MicroRNA Profiling Predicts the Development of Microalbuminuria in Patients with Type 1 Diabetes. AB - Microalbuminuria provides the earliest clinical marker of diabetic nephropathy among patients with Type 1 diabetes, yet it lacks sensitivity and specificity for early histological manifestations of disease. In recent years microRNAs have emerged as potential mediators in the pathogenesis of diabetes complications, suggesting a possible role in the diagnosis of early stage disease. We used quantiative polymerase chain reaction (qPCR) to evaluate the expression profile of 723 unique microRNAs in the normoalbuminuric urine of patients who did not develop nephropathy (n = 10) relative to patients who subsequently developed microalbuminuria (n = 17). Eighteen microRNAs were strongly associated with the subsequent development of microalbuminuria, while 15 microRNAs exhibited gender related differences in expression. The predicted targets of these microRNAs map to biological pathways known to be involved in the pathogenesis and progression of diabetic renal disease. A microRNA signature (miR-105-3p, miR-1972, miR-28-3p, miR-30b-3p, miR-363-3p, miR-424-5p, miR-486-5p, miR-495, miR-548o-3p and for women miR-192-5p, miR-720) achieved high internal validity (cross-validated misclassification rate of 11.1%) for the future development of microalbuminuria in this dataset. Weighting microRNA measurements by their number of kidney relevant targets improved the prognostic performance of the miRNA signature (cross-validated misclassification rate of 7.4%). Future studies are needed to corroborate these early observations in larger cohorts. PMID- 26239689 TI - Renal Replacement Therapy: Purifying Efficiency of Automated Peritoneal Dialysis in Diabetic versus Non-Diabetic Patients. AB - BACKGROUND: In order to reduce the cardiovascular risk, morbidity and mortality of peritoneal dialysis (PD), a minimal level of small-solute clearances as well as a sodium and water balance are needed. The peritoneal dialysis solutions used in combination have reduced the complications and allow for a long-time function of the peritoneal membrane, and the preservation of residual renal function (RRF) in patients on peritoneal dialysis (PD) is crucial for the maintenance of life quality and long-term survival. This retrospective cohort study reviews our experience in automatic peritoneal dialysis (APD) patients, with end-stage renal disease (ESRD) secondary to diabetic nephropathy (DN) in comparison to non diabetic nephropathy (NDN), using different PD solutions in combination. DESIGN: Fifty-two patients, 29 diabetic and 23 non-diabetic, were included. The follow-up period was 24 months, thus serving as their own control. RESULTS: The fraction of renal urea clearance (Kt) relative to distribution volume (V) (or total body water) (Kt/V), or creatinine clearance relative to the total Kt/V or creatinine clearance (CrCl) decreases according to loss of RRF. The loss of the slope of RRF is more pronounced in DN than in NDN patients, especially at baseline time interval to 12 months (loss of 0.29 mL/month vs. 0.13 mL/month, respectively), and is attenuated in the range from 12 to 24 months (loss of 0.13 mL/month vs. 0.09 mL/month, respectively). Diabetic patients also experienced a greater decrease in urine output compared to non-diabetic, starting from a higher baseline urine output. The net water balance was adequate in both groups during the follow up period. Regarding the balance sodium, no inter-group differences in sodium excretion over follow up period was observed. In addition, the removal of sodium in the urine output decreases with loss of renal function. The average concentration of glucose increase in the cycler in both groups (DN: baseline 1.44 +/- 0.22, 12 months 1.63 +/- 0.39, 24 months 1.73 +/- 0.47; NDN: baseline 1.59 +/ 0.40, 12 months 1.76 +/- 0.47, 24 months 1.80 +/- 0.46), in order to maintain the net water balance. The daytime dwell contribution, the fraction of day and the renal fraction of studies parameters provide sustained benefit in the follow up time, above 30%. CONCLUSIONS: The wet day and residual renal function are determinants in the achievement of the objective dose of dialysis, as well as in the water and sodium balance. The cause of chronic kidney disease (CKD) does not seem to influence the cleansing effectiveness of the technique. PMID- 26239690 TI - Impact of Current Antipsychotic Medications on Comparative Mortality and Adverse Events in People With Parkinson Disease Psychosis. AB - OBJECTIVES: To establish the mortality risk and adverse events associated with the use of atypical antipsychotic medications in people with Parkinson disease psychosis (PDP) in a clinically defined trial cohort. DESIGN: Post hoc analysis of data from a multicenter, open-label extension study of pimavanserin comparing people taking and not taking current antipsychotics. SETTING: Primary and secondary care medical centers in the United States, Canada, Europe, and India. PARTICIPANTS: A total of 459 people with PDP enrolled in the extension study. Participants were between ages 30 and 80 years, and had an established diagnosis of idiopathic Parkinson disease and moderate to severe psychosis. INTERVENTIONS: Participants were categorized into 2 groups: those receiving concomitant antipsychotic medications ("concurrent APD") and those who did not take antipsychotic medications at any time during the study ("no APD"). Participants were receiving 40 mg pimavanserin daily in addition to concurrent antipsychotics and Parkinson disease medications. MAIN OUTCOME MEASURES: Safety assessments at 2 weeks; 1, 3, 6, 9, and 12 months; and every 6 months thereafter, including evaluation of adverse events (AEs), vital signs, weight, physical examinations, 12-lead electrocardiograms, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and the Unified Parkinson's Disease Rating Scale Parts II and III (UPDRS-II+III, activities of daily living and motor impairment, respectively). Differences between participants taking and not taking current antipsychotics were evaluated using incidence rate ratios (IRRs) with 95% confidence intervals (CIs). RESULTS: There was significant increase in the mortality rate for participants taking concurrent antipsychotics compared with the group not taking antipsychotic medications (IRR 4.20, 95% CI 2.13-7.96). Participants who received a concurrent antipsychotic were also significantly more likely to experience overall a serious AE (IRR 2.95, 95% CI 2.02-4.24), any antipsychotic-related event (IRR 1.66, 95% CI 1.18-2.29), cognition-related events (IRR 2.70, 95% CI 1.19-5.58), infections (IRR 1.97, 95% CI 1.17-3.16), and edema (IRR 2.61, 95% CI 1.09-5.59). The risk of falls, stroke, sedation, orthostatic hypotension, and thromboembolic events was also increased in these individuals but this was not significant. CONCLUSIONS: This study highlights a significant risk of mortality, and severe AEs in patients with Parkinson disease receiving atypical antipsychotics. This is similar to or greater than the risks seen in people with Alzheimer disease, although with a less clear-cut risk of stroke and a longer delay to increased mortality. PMID- 26239692 TI - In utero arsenic exposure in mice and early life susceptibility to cancer. AB - In its review of the U.S. Environmental Protection Agency's toxicological review of inorganic arsenic (iAs), the National Academy of Sciences identified carcinogenic endpoints among the highest priority health effects of concern and stated the need to consider evidence that early life exposures may increase the risk of adverse health effects. Recent studies in mice suggest that in utero exposure to arsenic increases susceptibility to cancer later in life. These data are striking in light of the general lack of evidence for carcinogenicity in rodents exposed to iAs. To evaluate the transplacental carcinogenic potential of iAs, a detailed analysis of the toxicology literature evaluating the role of in utero arsenic exposure in carcinogenesis was conducted. Bladder, lung, and skin tumors, which are the tumor types most consistently reported in humans exposed to high arsenic levels, were not consistently increased in mouse studies. There was also a lack of concordance across studies for other tumor types not typically reported in humans. Therefore, we considered methodological and other critical issues that may have contributed to variable results and we suggest additional studies to address these issues. It was concluded that the available data do not provide evidence of a causal link between in utero arsenic exposure and cancer or indicate early life-stage susceptibility to arsenic-induced cancer, particularly at environmentally relevant doses. PMID- 26239691 TI - Present and future therapies of hepatitis B: From discovery to cure. AB - Hepatitis B virus (HBV) is a significant global pathogen, infecting more than 240 million people worldwide. While treatment for HBV has improved, HBV patients often require lifelong therapies and cure is still a challenging goal. Recent advances in technologies and pharmaceutical sciences have heralded a new horizon of innovative therapeutic approaches that are bringing us closer to the possibility of a functional cure of chronic HBV infection. In this article, we review the current state of science in HBV therapy and highlight new and exciting therapeutic strategies spurred by recent scientific advances. Some of these therapies have already entered into clinical phase, and we will likely see more of them moving along the development pipeline. CONCLUSION: With growing interest in developing and efforts to develop more effective therapies for HBV, the challenging goal of a cure may be well within reach in the near future. PMID- 26239693 TI - Manufacturing doubt about endocrine disrupter science--A rebuttal of industry sponsored critical comments on the UNEP/WHO report "State of the Science of Endocrine Disrupting Chemicals 2012". AB - We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption is based on incomplete and misleading quoting of the report through omission of qualifying statements and inaccurate description of study objectives, results and conclusions. Lamb et al. define extremely narrow standards for synthesizing evidence which are then used to dismiss the UNEP/WHO 2013 report as flawed. We show that Lamb et al. misuse conceptual frameworks for assessing causality, especially the Bradford-Hill criteria, by ignoring the fundamental problems that exist with inferring causality from empirical observations. We conclude that Lamb et al.'s attempt of deconstructing the UNEP/WHO (2013) report is not particularly erudite and that their critique is not intended to be convincing to the scientific community, but to confuse the scientific data. Consequently, it promotes misinterpretation of the UNEP/WHO (2013) report by non-specialists, bureaucrats, politicians and other decision makers not intimately familiar with the topic of endocrine disruption and therefore susceptible to false generalizations of bias and subjectivity. PMID- 26239694 TI - Risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a 30 year semi-prospective analysis. AB - BRCA1 and BRCA2 mutation carriers have an increased risk of contralateral breast cancer after primary breast cancer. Risk reduction strategies are discussed after assessment of risk factors for developing contralateral breast cancer. We assessed potential risk factors that could be of use in clinical practice, including the novel use of single nucleotide polymorphisms (SNP) testing. 506 BRCA1 and 505 BRCA2 mutation carriers with a diagnosis of breast cancer were observed for up to 30 years. The risk of a contralateral breast cancer is approximately 2-3% per year, remaining constant for at least 20 years. This was similar in both BRCA1 and BRCA2 carriers. Initial breast cancer before age 40 years was a significant risk factor, which was more pronounced in BRCA1 patients. The effect of risk-reducing oophorectomy on contralateral breast cancer risk may be overestimated because of bias. No significant association was found between overall breast cancer risk SNP score and contralateral breast cancer development. Young mutation carriers, particularly those with BRCA1 mutations, who develop breast cancer have a significantly higher risk of developing contralateral breast cancer, remaining constant for over 20 years. Contralateral risk-reducing mastectomy should be considered in this group, in particular as there is a survival benefit. Caution is advised when counselling women considering risk reducing oophorectomy as, after accounting for statistical bias, the associated risk reduction was found to be non-significant, and potentially smaller than has been previously reported. SNP testing did not add any further discriminatory information when assessing contralateral breast cancer risk. PMID- 26239695 TI - In diabetic Charcot neuroarthropathy impaired microvascular function is related to long lasting metabolic control and low grade inflammatory process. AB - AIMS: The aim of this study was to assess microvascular function associated with the occurrence of Charcot neuroarthropathy (CN) in patients with diabetes. METHODS: We evaluated 70 diabetic patients (54 men) with Charcot neuroarthropathy (CN-DM), median age 59 (IQR: 51-62), mean disease duration 16+/-8years. The control group were 70 subjects with diabetes and without Charcot neuroarthropathy (DM), 54 men, median age 60 (54-62), mean diabetes duration 15+/-7years. We assessed metabolic control of diabetes, serum C-reactive protein concentration (CRP) and cardiovascular autonomic neuropathy (CAN). We used AGE-Reader to measure skin autofluorescence (AF) associated with accumulation of advanced glycation end products that reflects long lasting metabolic control. Microvascular function was examined by laser Doppler flowmetry (PERIFLUX 5000) with thermal hyperemia (TH) and postocclusive reactive hyperemia (PORH). RESULTS: CN-DM patients as compared to DM subjects had lower HbA1c level [7.6 (6.6-8.4) vs 8.4 (7.3-9.7)%, p<0.001], lower eGFR [75.9+/-24.1 vs 86.6+/-17.8ml/min/1.73m(2), p=0.003], higher CRP serum concentration [3.8 (2.3-10.1) vs 1.9 (0.8-4.4)mg/l, p<0.001] and higher skin autofluorescence [2.8 (2.5-3.1) vs 2.6 (2.3-2.9)AU, p=0.03]. The cardiovascular autonomic neuropathy (CAN) was more frequently diagnosed in CN-DM subjects [59 vs 27%, p<0.001]. The peak flow during thermal hyperemia (THmax) was lower in CN-DM subjects as compared to DM group [156 (93 240) vs 235 (155-300)PU, p=0.001]. We found negative correlation between THmax and CRP concentration (Rs=-0.34, p=0.003), TG concentration (Rs=-0.37, p=0.002) and skin AF (Rs=-0.32, p=0.04) and positive correlation between THmax and HDL cholesterol level (Rs=0.42, p<0.001) in CN-DM patients. There was also a positive correlation between PORHpeak and HDL cholesterol level (Rs=-0.23, p=0.04). CONCLUSION: Deterioration of microvascular function and autonomic system dysfunction are present in Charcot neuroarthropathy. Impaired microvascular reactivity is associated with worse long lasting metabolic control of diabetes and low grade inflammatory process. PMID- 26239696 TI - Loss of RUNX3 expression promotes cancer-associated bone destruction by regulating CCL5, CCL19 and CXCL11 in non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) frequently metastasizes to bone, which is associated with significant morbidity and a dismal prognosis. RUNX3 functions as a tumour suppressor in lung cancer and loss of expression occurs more frequently in invasive lung adenocarcinoma than in pre-invasive lesions. Here, we show that RUNX3 and RUNX3-regulated chemokines are linked to NSCLC-mediated bone resorption. Notably, the receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) ratio, an index of osteoclastogenic stimulation, was significantly increased in human osteoblastic cells treated with conditioned media derived from RUNX3-knockdown NSCLC cells. We aimed to identify RUNX3 regulated factors that modify the osteoblastic RANKL/OPG ratio and found that RUNX3 knockdown led to CCL5 up-regulation and down-regulation of CCL19 and CXCL11 in NSCLC cells. Tumour size was noticeably increased and more severe osteolytic lesions were induced in the calvaria and tibiae of mice that received RUNX3 knockdown cells. In response to RUNX3 knockdown, serum and tissue levels of CCL5 increased, whereas CCL19 and CXCL11 decreased. Furthermore, CCL5 increased the proliferation, migration, and invasion of lung cancer cells in a dose-dependent manner; however, CCL19 and CXCL11 did not show any significant effects. The RANKL/OPG ratio in osteoblastic cells was increased by CCL5 but reduced by CCL19 and CXCL11. CCL5 promoted osteoclast differentiation, but CCL19 and CXCL11 reduced osteoclastogenesis in RANKL-treated bone marrow macrophages. These findings suggest that RUNX3 and related chemokines are useful markers for the prediction and/or treatment of NSCLC-induced bone destruction. PMID- 26239697 TI - Exploring the copper(II)-aminotriazole complex-binding sites of human serum albumin. AB - The potential impact on human exposure to aminotriazole (ATA) and heavy metal in the environment becomes a concerning issue. In the current study, a water-soluble Cu(II)-aminotriazole complex [Cu(II)-ATA] was synthesized. To explore the binding mechanism of the complex with human serum albumin (HSA), their effects on conformation and activity of HSA by multispectroscopic approach and molecular modeling were investigated. Further fluorescent tests revealed that the quenching mechanism of HSA by Cu(II)-ATA was overall static. Meanwhile, the obtained binding constant and thermodynamic parameters on complex-HSA interaction showed that the types of interaction force of Cu(II)-ATA and HSA were hydrogen bonding, van der Waals and electrostatic. The analysis of three-dimensional fluorescence, circular dichroism and Fourier transform infrared spectroscopy showed that Cu(II) ATA induced the changes in the secondary structure of HSA. Molecular docking simulation was performed and docking model suggested that the complex docked into HSA at subdomain IIA. Furthermore, amino group and attractive electrostatic interaction of Cu(II)-ATA greatly contributed to the hydrogen bonding, van der Waals and electrostatic interaction between Cu(II)-ATA and HSA, as confirmed by experimental data. PMID- 26239698 TI - Direct determination of fatty acid esters of 3-chloro-1, 2-propanediol in edible vegetable oils by isotope dilution - ultra high performance liquid chromatography - triple quadrupole mass spectrometry. AB - A selective and sensitive ultra-high performance liquid chromatography - triple quadrupole mass spectrometry (UHPLC-MS/MS) method coupled with matrix solid phase dispersion (MSPD) extraction was developed for the direct determination of fatty acid esters of 3-chloro-1,2-propanediol (3-MCPD esters) in edible vegetable oils. The method integrated the isotope dilution technique, MSPD extraction and UHPLC - MS/MS analysis with multi-reaction monitoring mode (MRM). Matrix-matched calibration curves showed good linearity within the range of 0.01-10mgL(-1) with the correlation coefficient not less than 0.999. Limits of detection (LODs) and limit of quantification (LOQs) of the 3-MCPD esters fell into the range of 0.0001 0.02mgkg(-1) and 0.0004-0.05mgkg(-1), respectively. The recoveries for the spiked extra virgin olive oils ranged from 94.4% to 108.3%, with the relative standard deviations (RSD) ranging from 0.6% to 10.5%. The method was applied for the oil sample (T2642) of the official Food Analysis Performance Assessment Scheme (FAPAS) in 2014 and other real samples from supermarket, and the results showed that the present method was comparative to the gas chromatography-mass spectrometry (GC-MS) method based on the improved German Society for Fat Science (DGF) standard method C-III 18 (09) except for palm oil. PMID- 26239699 TI - Measurement of breakthrough volumes of volatile chemical warfare agents on a poly(2,6-diphenylphenylene oxide)-based adsorbent and application to thermal desorption-gas chromatography/mass spectrometric analysis. AB - To establish adequate on-site solvent trapping of volatile chemical warfare agents (CWAs) from air samples, we measured the breakthrough volumes of CWAs on three adsorbent resins by an elution technique using direct electron ionization mass spectrometry. The trapping characteristics of Tenax((r)) TA were better than those of Tenax((r)) GR and Carboxen((r)) 1016. The latter two adsorbents showed non-reproducible breakthrough behavior and low VX recovery. The specific breakthrough values were more than 44 (sarin) L/g Tenax((r)) TA resin at 20 degrees C. Logarithmic values of specific breakthrough volume for four nerve agents (sarin, soman, tabun, and VX) showed a nearly linear correlation with the reciprocals of their boiling points, but the data point of sulfur mustard deviated from this linear curve. Next, we developed a method to determine volatile CWAs in ambient air by thermal desorption-gas chromatography (TD-GC/MS). CWA solutions that were spiked into the Tenax TA((r)) adsorbent tubes were analyzed by a two-stage TD-GC/MS using a Tenax((r)) TA-packed cold trap tube. Linear calibration curves for CWAs retained in the resin tubes were obtained in the range between 0.2pL and 100pL for sarin, soman, tabun, cyclohexylsarin, and sulfur mustard; and between 2pL and 100pL for VX and Russian VX. We also examined the stability of CWAs in Tenax((r)) TA tubes purged with either dry or 50% relative humidity air under storage conditions at room temperature or 4 degrees C. More than 80% sarin, soman, tabun, cyclohexylsarin, and sulfur mustard were recovered from the tubes within 2 weeks. In contrast, the recoveries of VX and Russian VX drastically reduced with storage time at room temperature, resulting in a drop to 10-30% after 2 weeks. Moreover, we examined the trapping efficiency of Tenax TA((r)) adsorbent tubes for vaporized CWA samples (100mL) prepared in a 500mL gas sampling cylinder. In the concentration range of 0.2-2.5mg/m(3), >50% of sarin, soman, tabun, cyclohexylsarin, and HD were recovered, whereas <1% of VX and Russian VX were recovered in the same concentration range. The results indicate that CWA vapors, with the exception of VX and Russian VX, can be measured by an on-site collection procedure using the Tenax((r)) TA resin tubes, followed by a subsequent TD-GC/MS analysis. PMID- 26239700 TI - Possibilities of retention prediction in fast gradient liquid chromatography. Part 3: Short silica monolithic columns. AB - We studied possibilities of prediction of the gradient elution data for alkylbenzenes, flavones and phenolic acids on two short octadecyl silica gel monolithic columns, namely a Chromolith Flash C18, 25*4.6mm, and a "new generation" Chromolith High Resolution C18, 50*4.6mm, in fast 1-2min gradients. With fixed short gradient times and varying gradient ranges of acetonitrile concentration in water, high flow rates of the mobile phase (3-5mL/min) could be used. The gradient elution data were predicted from four gradient models based on two-parameter and three-parameter isocratic retention equations. Various gradient retention models can be used for prediction of chromatograms and optimization of separation within a fixed gradient time. A two-parameter log-log model introduced in 1974 and a three-parameter model introduced in 1980 provided slightly more accurate prediction than the Linear Solvent Strength (LSS) semi-logarithmic two parameter model, most frequently used in reversed-phase LC. A three-parameter model introduced in 1978 provided slightly improved accuracy of prediction of gradient data with respect to two-parameter models, in contrast to another, more recent three-parameter empirical model introduced in 2010 (which failed for gradients starting at a non-zero concentration of acetonitrile). Both a longer (5cm) and more efficient Chromolith HR column and a shorter (2.5cm) slightly less efficient Chromolith Flash column provide useful separations in fast gradients (1 2min) at high flow rates (3.5-5mL/min), especially in second dimension of two dimensional LC*LC, in combination with HILIC separation on monolithic microcolumn in D1. PMID- 26239701 TI - Simvastatin promotes alveolar epithelial cell proliferation and attenuates cigarette smoke-induced emphysema in rats. AB - Current treatments for chronic obstructive pulmonary disease (COPD) cannot reverse the pathological process of the disease, therefore, the development of novel agents and strategies for COPD treatment is required. The aim of the present study was to investigate the potential therapeutic value of simvastatin (SmSt) in cigarette smoke-induced emphysema in rats. A total of 24 male and female Wistar rats were randomly divided into four groups. The levels of vascular endothelial growth factor (VEGF) in the lung tissues and bronchoalveolar lavage (BAL) fluid of each group were measured using an enzyme-linked immunoassay. The mRNA expression of VEGF was assessed using reverse transcription-quantitative polymerase chain reaction. The protein expression levels of VEGF and proliferating cell nuclear antigen (PCNA) were determined using immunohistochemical assays. Histological scoring revealed that simvastatin reduced the total inflammatory scores significantly more in the simvastatin treated smoke-exposed group, compared with the smoke exposed (Sm) group. Significant differences in the average inter-alveolar septal wall distance and mean alveolar numbers were also observed between the SmSt and Sm groups. The levels of VEGF in the BAL fluid and lung tissue homogenates of the SmSt group were similar to those in the simvostatin-only (St) and control (CtL) groups, and significantly higher compared with those in the Sm group. The expression of VEGF in the alveolar and bronchial epithelial cells of the SmSt group was similar to that in the CtL group, and significantly higher compared with that of the Sm group. The percentage of PCNA-positive alveolar epithelial cells was significantly higher in the SmSt group compared with the Sm and CtL groups. Simvastatin exerted a significant impact on the expression of VEGF and attenuated cigarette smoke-induced emphysema in rats. Therefore simvastatin may have beneficial effects in patients with COPD. PMID- 26239702 TI - Severe Aortic Regurgitation Caused by Unicuspid Aortic Valve Based on Quadricuspid Aortic Valve. PMID- 26239703 TI - Assessment of liver fat content using quantitative ultrasonography to evaluate risks for metabolic diseases. AB - OBJECTIVE: The ultrasound quantitative method for liver fat content (LFC) is a recent established method for non-invasive assessment of liver steatosis. Its use in clinical practice is further explored by investigating the quantitative relationships between LFC measured by quantitative ultrasonography and metabolic diseases in a middle-aged and elderly Chinese population. METHODS: Liver fat content was measured by the quantitative ultrasound method in 4,916 participants from the Shanghai Changfeng Community Study. The anthropometric and serum biochemical parameters related to glucose and lipid metabolism were detected for each participant. The carotid artery intima-media thickness (CIMT) was measured by ultrasonography. RESULTS: The LFC displayed a non-Gaussian and positively skewed distribution in the community population and was significantly correlated with body weight, serum glucose, lipid profile, and CIMT. The 95th percentile of LFC in the subgroup of participants without any metabolic disease was 10.8%, and a LFC >= 10% was correlated with remarkable increases in the risks for glucose and lipid metabolic diseases. CONCLUSIONS: The quantitative ultrasound method that was developed for measuring LFC was useful in a population study. A LFC >= 10% might help to identify the subjects with an increased risk for metabolic diseases. PMID- 26239704 TI - Complex antibodies provide a simple explanation for the plurality of clinical presentations in the Guillain Barre syndromes. PMID- 26239705 TI - Rose myrtle (Rhodomyrtus tomentosa) extract and its component, piceatannol, enhance the activity of DNA polymerase and suppress the inflammatory response elicited by UVB-induced DNA damage in skin cells. AB - A number of naturally occurring agents are hypothesized to protect against ultraviolet (UV)-induced skin damage. The present study screened >50 plant extracts for inhibitors of UVB-induced cytotoxicity, using cultured normal human epidermal keratinocytes (NHEK), and identified that the fruit of rose myrtle (Rhodomyrtus tomentosa) was the most marked inhibitor of cell death. The protective effect of rose myrtle extract and the two key components, piceatannol and piceatannol-4'-O-beta-D-glucopyranoside, on UVB-induced damage and inflammation in cultured NHEK was investigated. The 80% ethanol extract from rose myrtle fruit with piceatannol exhibited protection of UVB-induced cytotoxicity in NHEK; however, piceatannol-4'-O-beta-D-glucopyranoside exhibited no protection, as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. This extract and piceatannol reduced the production of UVB-induced cyclobutane pyrimidine dimers and enhanced the cellular enzyme activity of the DNA polymerases in UVB-irradiated NHEK, suggesting that UVB-stimulated DNA damage was repaired by the polymerases. In addition, the secretion of prostaglandin E2, which is an inflammatory mediator, was decreased. These results indicated that rose myrtle fruit extract and its key constituent, piceatannol, are potential photoprotective candidates for UV-induced skin damage. PMID- 26239706 TI - Controversies in venous thromboembolism--2015. AB - Venous thromboembolism is commonly encountered both in the community and the in patient setting. Despite major advances in diagnosis and treatment, there remain challenges in several clinical areas as a result of insufficient evidence to guide practice. This review covers six controversial topics, summarizes the best available evidence, and presents recommendations for practice. The clinical relevance of calf vein thrombosis and sub-segmental pulmonary embolism are often questioned; this has implications for both their diagnosis and management. The role of thrombolysis for the treatment of deep vein thrombosis (DVT) is discussed in consideration of the potential benefits and risks. Residual vein obstruction has been proposed as a predictor of recurrent thrombosis; we consider its relevance when determining the duration of anticoagulant treatment. The post thrombotic syndrome (PTS) can be a disabling and costly consequence of DVT with limited options for prevention and treatment. We review the available evidence related to compression stockings for PTS prevention. Finally, the relationship between cancer and VTE is well recognized and this review considers the value of screening for occult cancer in patients with unprovoked VTE. PMID- 26239707 TI - Phylogenetic analysis of avian infectious bronchitis virus S1 glycoprotein regions reveals emergence of a new genotype in Moroccan broiler chicken flocks. AB - BACKGROUND: Infectious bronchitis virus (IBV), a major pathogen of commercial poultry flocks, circulates in the form of several serotypes/genotypes. Only a few amino-acid changes in the S1 subunit of wild-type IBVS proteins may result in mutants unaffected by current vaccines. METHODS: Partial S1 gene sequences of 3 IBV isolates of the Moroccan Italy 02 genotype from vaccinated and unvaccinated broiler chicken flocks, located in southern and central regions of Morocco, were amplified by RT-PCR, sequenced, and aligned for phylogenetic and amino-acid similarity analyses. RESULTS: The three isolates were found genetically highly distant from known avian IBV based on partial sequences of their S1 genes: gammaCoV/chicken/Morocco/I01/2011(IBV/Morocco/01), gammaCoV/chicken/Morocco/I30/2010 (IBV/Morocco/30), and gammaCoV/chicken/Morocco/I38/2013 (IBV/Morocco/38), nucleotide sequence identities reached 89.5 % to 90.9 % among the three isolates. The deduced protein sequence identities ranged from 29.7 % (between IBV/Morocco/38 and Egypt SCU 14/2013-1) to 78.2 % (between IBV/Morocco/01 and Spain/05/866). Amino acid sequence comparison and phylogenetic analysis indicated the emergence of a new Moroccan genotype, clustering with regionally related isolates from Spain (Spain/05/866) and belonging to a new sub-genotype. CONCLUSION: Our sequencing results demonstrate a co-circulation of wild-type infectious bronchitis viruses in broiler chickens. These results justify permanent monitoring of circulating strains in order to rationally modify vaccination strategies to make them appropriate to the evolving field situation. PMID- 26239708 TI - Methicillin-resistant Staphylococcus aureus mandibular osteomyelitis in an extremely low birth weight preterm infant. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an established nosocomial pathogen with frequent multidrug resistance. The immaturity of the immune system along with intravascular lines and empirical antibiotic treatments place hospitalized preterm infants at major risk of MRSA infection.We report a case of MRSA mandibular osteomyelitis complicating a persistent S. aureus bacteremia in a 23-week preterm infant. From the first weeks of life, the infant showed recurrent C-reactive protein (CRP) elevation, associated with S. aureus bacteremia. Antibiotic courses, including vancomycin and linezolid, were performed with transitory normalization of blood parameters. On day 74, the infant suddenly deteriorated and showed a significant increase of both CRP and procalcitonin. Empiric vancomycin and piperacillin-tazobactam treatment was started; nevertheless, she developed a progressive hard swelling of neck and mandible. Radiological evaluation revealed a mandibular osteomyelitis complicated by an abscess, whose culture grew MRSA. Vancomycin was thus changed to teicoplanin and complete clinical and radiological healing was gradually achieved.In the presence of major risk factors, persistent bacteremia and nonspecific symptoms, a localized focus of infection should be suspected. Microbiological diagnosis should always be attempted and antibiotic treatment should be guided by both susceptibility results and clinical response. PMID- 26239709 TI - A feedback protocol improves the diagnostic performance of MR arthrography by experienced musculoskeletal radiologists in patients with traumatic anterior shoulder instability. AB - PURPOSE: To prospectively evaluate the diagnostic performance of magnetic resonance-arthrography (MRA) by experienced musculoskeletal radiologists in patients with traumatic-anterior-shoulder-instability (TASI), after feedback protocol execution. MATERIALS AND METHODS: Forty-five surgically confirmed MRA's were used to enhance personal feedback, to discuss differences in outcome between MRA assessment and surgical findings and to fine-tune definition interpretation agreement of 7 different TASI-related lesions, between experienced musculoskeletal radiologists and experienced orthopaedic shoulder surgeons. After execution of the feedback protocol 20 new, surgically confirmed, MRA's were assessed by 2 experienced musculoskeletal radiologists using a seven-lesion standardized scoring form. Kappa coefficients, sensitivity, specificity, and differences in percentage agreement or correct diagnosis (p-value, McNemar's test) were calculated per lesion and overall per 7 lesion types to assess whether diagnostic reproducibility and accuracy was improved. RESULTS: Per 7 lesion types, the overall kappa and percentage of agreement, between the 2 radiologists, were dramatically increased in comparison with our former study (k=0.81 versus k=0.48 and 90.7% versus 78.2%, respectively). The overall sensitivity of radiologist 1 increased from 45.9% to 87.8%, the overall sensitivity of radiologist 2 increased from 63.5% to 79.6% and the overall specificity of radiologist 2 increased from 80.1% to 85.7%. Furthermore, the overall percentage of correct diagnosis of both radiologist was also exceedingly higher (85.7% and 83.6%) compared to our former study (74.4% and 74.8%). CONCLUSION: The implementation of our feedback protocol dramatically improved the reproducibility and accuracy of high field MRA by experienced musculoskeletal radiologist in patients with traumatic anterior shoulder instability. PMID- 26239710 TI - Posterior ankle impingement in athletes: Pathogenesis, imaging features and differential diagnoses. AB - Posterior ankle impingement is a clinical diagnosis which can be seen following a traumatic hyper-plantar flexion event and may lead to painful symptoms in athletes such as female dancers ('en pointe'), football players, javelin throwers and gymnasts. Symptoms of posterior ankle impingement are due to failure to accommodate the reduced interval between the posterosuperior aspect of the talus and tibial plafond during plantar flexion, and can be due to osseous or soft tissue lesions. There are multiple causes of posterior ankle impingement. Most commonly, the structural correlates of impingement relate to post-traumatic synovitis and intra-articular fibrous bands-scar tissue, capsular scarring, or bony prominences. The aims of this pictorial review article is to describe different types of posterior ankle impingement due to traumatic and non-traumatic osseous and soft tissue pathology in athletes, to describe diagnostic imaging strategies of these pathologies, and illustrate their imaging features, including relevant differential diagnoses. PMID- 26239712 TI - Transcription: Stress unleashes the DoGs. PMID- 26239711 TI - Return of genetic testing results in the era of whole-genome sequencing. AB - Genetic testing based on whole-genome sequencing (WGS) often returns results that are not directly clinically actionable as well as raising the possibility of incidental (secondary) findings. In this article, we first survey the laws and policies guiding both researchers and clinicians in the return of results for WGS based genetic testing. We then provide an overview of the landscape of international legislation and policies for return of these results, including considerations for return of incidental findings. Finally, we consider a range of approaches for the return of results. PMID- 26239713 TI - Systems biology: MoA on DeMAND. PMID- 26239714 TI - Microbial genetics: C. parvum gets the CRISPR upgrade. PMID- 26239716 TI - Inhibitory effect of zinc on the advanced glycation end product-induced apoptosis of mouse osteoblastic cells. AB - Osteoporosis and diabetes have become serious health problems worldwide. Previous studies have suggested that diabetes is associated with osteoporosis and increased fracture risk. However, the mechanism underlying diabetes-induced osteoporosis remains to be elucidated. Therefore, the present study aimed to examine the mechanism underlying diabetes-induced osteoporosis, and determine the protective effects of zinc, which is known to be closely associated with osteoporosis and diabetes. The results of the present study demonstrated that zinc inhibited advanced glycation end product (AGE)-induced MC3T3-E1 cell apoptosis by attenuating the production of reactive oxygen species, inhibiting caspase-3 and caspase-9 activation, and inhibiting the release of cytochrome c from between the mitochondria and the cytosol. Furthermore, zinc was found to protect cells against AGE-induced apoptosis via the mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/AKT signaling pathways. In conclusion, these findings enable a better understanding of the mechanism underlying diabetes-induced osteoporosis, and may indicate a novel target for its prevention and treatment. PMID- 26239717 TI - First homoleptic MIC and heteroleptic NHC-MIC coordination cages from 1,3,5 triphenylbenzene-bridged tris-MIC and tris-NHC ligands. AB - The preparation of a triphenylbenzene-bridged tris-(1,2,3-triazolium) salt allowed us to obtain the first homoleptic tris-MIC cylinder-like cages of Ag and Au. The silver MIC-based cage reacts with the tris-NHC-Ag analogue to form the corresponding heteroleptic NHC-MIC silver cage in an unusual reaction involving the simultaneous exchange of the tris-NHC and tris-MIC ligands. PMID- 26239715 TI - Vaccine-Drug Interactions: Cytokines, Cytochromes, and Molecular Mechanisms. AB - Vaccinations are recommended throughout life to reduce the risk of vaccine preventable diseases and their sequelae. Vaccines are often administered in patients with chronic diseases who are likely to be treated with several drugs. A growing number of clinical observations have indicated the possibility of interactions between vaccines and drugs, leading to changes in drug metabolism after vaccination. These interactions represent a significant concern because of the increasing use of vaccines in older patients who are likely to be treated with several drugs. Because of the possible implications of adverse reactions in terms of public health, several studies were performed to verify the risk posed by these interactions and to clarify the biologic mechanisms that drive these events. Of the several mechanisms proposed to be at the basis of vaccine-drug interactions, the most convincing evidence suggests a role of inflammatory cytokines on the regulation of specific cytochrome P450 enzymes in the liver. Differences in the cytochrome P450 enzymes involved in the metabolism of these drugs could explain these contrasting results and provide important insights to fully understand the clinical importance of these events. Further studies are required to verify whether vaccine-drug interactions may occur in other clinical settings, especially the ones for which patients are required to be vaccinated against specific diseases. PMID- 26239718 TI - Ethnicity and prostate cancer: the way to solve the screening problem? AB - In their analysis in BMC Medicine, Lloyd et al. provide individual patient lifetime risks of prostate cancer diagnosis and prostate cancer death stratified by ethnicity. This easy to understand information is helpful for men to decide whether to start prostate-specific antigen testing (i.e. screening). A higher lifetime risk of prostate cancer death in some ethnic groups is not automatically a license to start screening. The potential benefit in the form of reducing metastases and death should still be weighed against the potential risk of over diagnosis. In case of ethnicity, this harm-to-benefit ratio does not differ between groups. Stratifying men for screening based on ethnicity is therefore not optimal and will not solve the current screening problem. Other methods for risk stratifying men have been proven to produce a more optimal harm-to-benefit ratio. Please see related article: http://www.biomedcentral.com/1741-7015/13/171. PMID- 26239719 TI - A ratiometric fluorescent probe for alkaline phosphatase via regulation of excited-state intramolecular proton transfer. AB - A ratiometric fluorescent probe 2-(benzimidazol-2-yl)phenyl phosphoric acid (1) for alkaline phosphatase (ALP) is designed and synthesized. The method employs the modulation of the excited-state intramolecular proton transfer (ESIPT) process of 2-(2'-hydroxyphenyl)benzimidazole (HPBI) through the hydroxyl group protection/deprotection reaction. Upon phosphorylated with POCl3 , HPBI shows only an emission peak at 363 nm due to the blockage of ESIPT. However, once selective enzymatic hydrolysis with alkaline phosphatase (ALP) in Tris-HCl buffer occurs, the probe 1 is returned to HPBI and the ESIPT process is switched on, which results in a decrease in the emission band at 363 nm and an increase in a new fluorescence peak around 430 nm. The fluorescence intensity ratio at 430 and 360 nm (I430/I360) increases linearly with the activity of ALP up to 0.050 U/mL and the detection limit is 0.0013 U/mL. The proposed probe shows excellent specificity toward ALP. PMID- 26239720 TI - Expression of immune checkpoint molecules of T cell immunoglobulin and mucin protein 3/galectin-9 for NK cell suppression in human gastrointestinal stromal tumors. AB - Monoclonal antibody therapy for immune checkpoint blockade has achieved promising results for several types of malignant tumors. For the future treatment of gastrointestinal stromal tumors (GISTs) by immune checkpoint blockade, expression of immune checkpoint-related molecules that suppress antitumor immunity in GISTs was examined. Infiltration of immune cell types into 19 GIST tissues was analyzed by immunohistochemistry, and expression of T cell immunoglobulin and mucin protein 3 (Tim-3) and programmed cell death-1 (PD-1) in the infiltrated immune cells was examined by immunofluorescence microscopy. The expression status of galectin-9 in the GIST tumor cells was also determined by immunohistochemistry. All the GIST tissues showed CD8+ T cell infiltration and 8 showed CD56+ natural killer (NK) cell infiltration, and the numbers of infiltrated CD8+ T and NK cells were strongly correlated. However, these CD8+ T and NK cells were CD69-negative inactivated cells. Tim-3 was expressed in the infiltrated NK cells in 6/8 (75%) of the GIST tissues. Expression of galectin-9, a ligand of Tim-3, was observed in 13/19 (68.4%) GIST tissues and all of the GIST tissues with Tim-3+ NK cell infiltration showed positive galectin-9 expression. No PD-1 expression in the infiltrated NK cells and neither Tim-3 nor PD-1 expression was observed in the infiltrated CD8+ T cells. Interaction between Tim-3 in infiltrated NK cells and galectin-9 in tumor cells may be involved in an immune checkpoint mechanism for suppression of antitumor immunity in GISTs. Blockade of the Tim-3/galectin-9 pathway may become a new strategy for GIST treatment. PMID- 26239721 TI - Prolonged cholinergic effects after the reversal of neuromuscular blockade with neostigmine. PMID- 26239722 TI - Sigmoid to scrotal fistula secondary to mesh erosion: a rare complication of inguinal hernia repair in a patient on anticoagulation. AB - BACKGROUND: Few reports from the medical literature have presented severe mesh related complications following laparoscopic repair of inguinal hernia. One of these complications is being mesh erosion into bowel, resulting in fistulous tract with subsequent abscess formation. CASE PRESENTATION: A 75-year-old patient, status post laparoscopic bilateral inguinal hernia repair, and on anticoagulation for dual prosthetic heart valves, presented with a unique case of sigmoid to scrotal fistula, post mesh erosion, resulting in sepsis. The patient presented in septic shock, necessitating an individualized surgical approach. Given the septic picture of our patient, the surgical approach was truncated. Initially the sepsis from the scrotum was drained and debrided. A watermelon seed was noted in the scrotum. After stabilization, the second stage approach was performed, were a laparotomy was performed, followed by division of the sigmoid to internal ring fistula, and reperitonealization of the mesh. Mesh removal was delayed as the risk of bleeding into the peritoneum was high, once anticoagulation needed to be resumed. Because of a persistent wound sinus tract, several months later, the mesh was removed, in a third stage, from an inguinal incision. Albeit meticulous dissection and homeostasis, a postoperative extraperitoneal inguinal hematoma developed, as expected, on day 2, once anticoagulation was resumed. CONCLUSION: Sigmoid to inguinoscrotal fistula is a rare, yet serious, complication of mesh infection and erosion. This can be obviated by preventing serosal tear, and proper peritonealization of the mesh. Fistulectomy alone with primary repair turned out to be a valid approach in our patient. Retaining the mesh could be an alternative for avoiding bleeding in patients on anticoagulation; despite that a persistent indolent infection and sinus tract will necessitate mesh removal afterwards. PMID- 26239723 TI - Two novel compound heterozygous mutations in the BCKDHB gene that cause the intermittent form of maple syrup urine disease. AB - Intermittent maple syrup urine disease (MSUD) is a potentially life-threatening metabolic disorder caused by a deficiency of branched chain alpha-ketoacid dehydrogenase (BCKD) complex. In contrast to classic MSUD, children with the intermittent form usually have an atypical clinical manifestation. Here, we describe the presenting symptoms and clinical course of a Chinese boy with intermittent MSUD. Mutation analysis identified two previously unreported mutations in exon 7 of the BCKDHB gene: c.767A > G (p.Y256C) and c.768C > G (p.Y256X); the parents were each heterozygous for one of these mutations. In silico analysis predicted Y256C probably affects protein structure; Y256X leads to a premature stop codon. This case demonstrates intermittent MSUD should be suspected in cases with symptoms of recurrent encephalopathy, especially ataxia or marked drowsiness, which usually present after the neonatal period and in conjunction with infection. symmetrical basal ganglia damage but normal myelination in the posterior limb will assist differential diagnosis; alloisoleucine is a useful diagnostic marker and mutation analysis may be of prognostic value. These novel mutations Y256C and Y256X result in the clinical manifestation of a variant form of MSUD, expanding the mutation spectrum of this disease. PMID- 26239724 TI - Teenagers and young adults with cancer in Europe: from national programmes to a European integrated coordinated project. AB - Over 14 000 patients aged 15-24 are estimated to be diagnosed with cancer in the European Union (EU) each year. Teenagers and young adults (TYA) often fall down gaps between children's and adults cancer services. The specific challenges of providing optimal care to them are described, but we present a summary of recent progress. Progress to overcome these challenges is happening at different rates across Europe. We summarise the European national projects in this field but more recently we have seen the beginnings of European coordination. Within the EU 7th Funding Programme (FP7) European Network for Cancer Research in Children and Adolescents programme (ENCCA), a specific European Network for Teenagers and Young Adults with Cancer has held a series of scientific meetings, including professionals, patients and caregivers. This group has proposed unanswered research questions and agreed key features of a high-quality service that can improve outcomes for TYA with cancer, including the primacy of collaboration between adult and paediatric services to eliminate the gap in the management of TYA with cancer. PMID- 26239725 TI - microRNA-22 downregulation of galectin-9 influences lymphocyte apoptosis and tumor cell proliferation in liver cancer. AB - Galectin-9 (Gal-9) plays an important role in both the immune response and tumor progression, while microRNAs act as tumor regulators to mediate tumorigenesis. However, the underlying molecular mechanisms remain unknown. In the present study, we investigated the relationship between Gal-9 and microRNA-mediated regulation in liver cancer. We examined Gal-9 expression using qRT-PCR and western blot analysis and found that it was markedly upregulated in human liver cancer cells compared with the level in normal hepatocytes. We co-cultured peripheral blood mononuclear cells (PBMCs) and tumor cells and observed that Gal 9 induced lymphocyte apoptosis and tumor cell immune escape using flow cytometric analysis and WST-1 assay. We found that miR-22 was downregulated in liver cancer tissues and cell lines and confirmed that miR-22 directly targeted the Gal-9 3'UTR and negatively regulated Gal-9 expression by luciferase reporter assay and transfection of microRNA mimics. We also observed that the Gal-9/miR-22 axis may influence lymphocyte apoptosis and tumor cell proliferation. These studies contribute to a further understanding of the microRNA-mediated regulation of the Gal-9 pathway and elucidate novel therapeutic targets for liver cancer. PMID- 26239727 TI - High-flow oxygen therapy in cancer patients with acute respiratory failure. PMID- 26239728 TI - Geographical variation in use of intensive care: a nationwide study. AB - PURPOSE: To examine whether there is geographical variation in the use of intensive care resources in Denmark concerning both intensive care unit (ICU) admission and use of specific interventions. Substantial variation in use of intensive care has been reported between countries and within the US, however, data on geographical variation in use within more homogenous tax-supported health care systems are sparse. METHODS: We conducted a population-based cross-sectional study based on linkage of national medical registries including all Danish residents between 2008 and 2012 using population statistics from Statistics Denmark. Data on ICU admissions and interventions, including mechanical ventilation, noninvasive ventilation, acute renal replacement therapy, and treatment with inotropes/vasopressors, were obtained from the Danish Intensive Care Database. Data on patients' residence at the time of admission were obtained from the Danish National Registry of Patients. RESULTS: The overall age- and gender standardized number of ICU patients per 1000 person-years for the 5-year period was 4.3 patients (95 % CI, 4.2; 4.3) ranging from 3.7 (95 % CI, 3.6; 3.7) to 5.1 patients per 1000 person-years (95 % CI, 5.0; 5.2) in the five regions of Denmark and from 2.8 (95 % CI, 2.8; 3.0) to 23.1 patients per 1000 person-years (95 % CI, 13.0; 33.1) in the 98 municipalities. The age-, gender-, and comorbidity standardized proportion of use of interventions among ICU patients also differed across regions and municipalities. CONCLUSIONS: There was only minimal geographical variation in the use of intensive care admissions and interventions at the regional level in Denmark, but more pronounced variation at the municipality level. PMID- 26239726 TI - The complete genome sequence of Dickeya zeae EC1 reveals substantial divergence from other Dickeya strains and species. AB - BACKGROUND: Dickeya zeae is a bacterial species that infects monocotyledons and dicotyledons. Two antibiotic-like phytotoxins named zeamine and zeamine II were reported to play an important role in rice seed germination, and two genes associated with zeamines production, i.e., zmsA and zmsK, have been thoroughly characterized. However, other virulence factors and its molecular mechanisms of host specificity and pathogenesis are hardly known. RESULTS: The complete genome of D. zeae strain EC1 isolated from diseased rice plants was sequenced, annotated, and compared with the genomes of other Dickeya spp.. The pathogen contains a chromosome of 4,532,364 bp with 4,154 predicted protein-coding genes. Comparative genomics analysis indicates that D. zeae EC1 is most co-linear with D. chrysanthemi Ech1591, most conserved with D. zeae Ech586 and least similar to D. paradisiaca Ech703. Substantial genomic rearrangement was revealed by comparing EC1 with Ech586 and Ech703. Most virulence genes were well-conserved in Dickeya strains except Ech703. Significantly, the zms gene cluster involved in biosynthesis of zeamines, which were shown previously as key virulence determinants, is present in D. zeae strains isolated from rice, and some D. solani strains, but absent in other Dickeya species and the D. zeae strains isolated from other plants or sources. In addition, a DNA fragment containing 9 genes associated with fatty acid biosynthesis was found inserted in the fli gene cluster encoding flagellar biosynthesis of strain EC1 and other two rice isolates but not in other strains. This gene cluster shares a high protein similarity to the fatty acid genes from Pantoea ananatis. CONLUSION: Our findings delineate the genetic background of D. zeae EC1, which infects both dicotyledons and monocotyledons, and suggest that D. zeae strains isolated from rice could be grouped into a distinct pathovar, i.e., D. zeae subsp. oryzae. In addition, the results of this study also unveiled that the zms gene cluster presented in the genomes of D. zeae rice isolates and D. solani strains, and the fatty acid genes inserted in the fli gene cluster of strain EC1 were likely derived from horizontal gene transfer during later stage of bacterial evolution. PMID- 26239729 TI - Gain-of-function single nucleotide variants of the CYP2C19 gene (CYP2C19*17) can identify subtherapeutic voriconazole concentrations in critically ill patients: a case series. PMID- 26239730 TI - ICU-acquired candidemia within selective digestive decontamination studies: a meta-analysis. AB - PURPOSE: To estimate the direct and indirect (contextual) effects of the factorized constituents of selective digestive decontamination and selective oropharyngeal decontamination (SDD/SOD), being topical antibiotic (TA) and protocolized antifungal prophylaxis (PAFP), on ICU-acquired candidemia. METHODS: A broad range of ICU candidemia incidence studies were sourced to serve as points of reference. The candidemia incidence was extracted from component (control and intervention) groups decanted from studies of various designs (concurrent or non concurrent) and whether investigating SDD/SOD versus non-TA methods of ICU infection prevention. The candidemia incidences were summarized in regression models using generalized estimating equation (GEE) methods. Groups derived from observational studies (no prevention method under study) provided an overarching external benchmark candidemia incidence for calibration. RESULTS: Within studies investigating SDD/SOD, the mean (and 95% confidence interval) candidemia incidence among concurrent component groups (40 control; 2.4%; 1.7-3.2% and 43 intervention groups; 2.4%; 1.6-3.1%), but not non-concurrent control groups (11 groups; 1.6%; 0.1-2.7%), is higher than that of the benchmark candidemia incidence derived from 54 observational groups (1.5%; 1.2-1.9%). The TA constituent within SDD/SOD has significant direct and indirect (contextual) effects in GEE models even after adjusting for the publication year and the group wide presence of either candidemia risk factors or PAFP use. CONCLUSION: The TA constituent of SDD/SOD is associated with a contextual effect on candidemia incidence which is similar in magnitude to that of the conventional candidemia risk factors and against which PAFP partially attenuates. This increase is inapparent within individual SDD/SOD studies examined in isolation. PMID- 26239731 TI - Genotyping of common SIRPB1 copy number variant using Paralogue Ratio Test coupled to MALDI-MS quantification. AB - Copy number variant (CNV) regions have been proven to have a significant impact on gene expression. Some of them have been also found to be associated to different human diseases. CNV genotyping is often prone to error and cross validation with independent methods is frequently required. The platform of choice depends on whether it is a genome-wide discovery screening or a candidate CNV study, the cohort size and the number of CNVs included in the assay and, finally, the budget available. Here we illustrate a affordable approach to determine the CNV genotype using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) and based on the quantitative determination of single nucleotide duplicated mismatches (SNDM) mapping the CNV region and a paralogue genomic region that is used as a two-copy reference. We have genotyped nsv436327, a common CNV mapping SIRPB1 intron 1 that has been associated to human personality behavior. SIRP cluster region was subjected to several ancestral duplication events what makes SIRPB1 CNV genotyping technically challenging. We designed three sets of primer pairs that amplified paralogue regions inside and outside the CNV, containing three SNDMs. Post-PCR extension analyses of sequencing oligonucleotides mapping immediately upstream each SNDM allowed us to quantify using MALDI-MS the proportion of PCR products derived from the CNV region versus the external reference. In contrast to other approaches, setting up this genotyping method requires an affordable investment. PMID- 26239733 TI - Margaret McCartney: Perfect people. PMID- 26239732 TI - Early virological response may predict treatment response in sofosbuvir-based combination therapy of chronic hepatitis c in a multi-center "real-life" cohort. AB - BACKGROUND: The combination of sofosbuvir (SOF), ribavirin (RBV) and peg interferon-alfa-2a (peg-IFN-alfa-2a) as well as the combination of SOF and RBV for the treatment of patients infected with hepatitis c virus (HCV) has improved rates of sustained virological response (SVR) considerably in recent trials. However, there is only limited data concerning the efficacy and safety in a "real life" cohort. METHODS: We analyzed a cohort of 119 patients with chronic HCV infection treated at four investigational sites in Germany. All patients received either a combination treatment of SOF, RBV and peg-IFN-alfa-2a or SOF and RBV. RESULTS: The rates of SVR at 12 weeks after end of treatment (SVR 12) were as follows: Among 76 patients with genotype 1 infection the SVR 12 rate was 74% (n = 56), among 14 patients with genotype 2 infection the SVR 12 rate was 79% (n = 11), among 24 patients with genotype 3 infection the SVR 12 rate was 92% (n = 22) and among 5 patients with genotype 4 infection the SVR 12 rate was 80% (n = 4). Of all 26 patients with a relapse in our cohort, 69% (n = 18) of these patients presented with liver cirrhosis and 58% (n = 15) were treatment experienced. Notably, the level of HCV-RNA after 4 weeks of treatment was a significant predictor of treatment response in genotype 1 patients. Patients with HCV-RNA levels >= 12 IU ml-1 after 4 weeks of treatment achieved SVR 12 only in 30% (n = 17/56, p < 0.0001) of cases and treatment response was even lower with SVR 12 of 25% (n = 5/20, p = 0.0016) in the subgroup of patients with cirrhosis. CONCLUSION: We observed a high rate of SVR 12 with SOF-based treatment regimes, however probably due to the high number of patients with liver cirrhosis and prior treatment experience, treatment response rates were lower than in previously published trials. In genotype 1 patients the analysis of early virological response may predict treatment response in SOF-based combination therapies. PMID- 26239734 TI - Arsenic Keratosis in a Patient from Newfoundland and Labrador, Canada: Case Report and Review. AB - BACKGROUND AND OBJECTIVE: Millions of people worldwide suffer from chronic arsenic poisoning due to contaminated drinking water. The devastating effects of chronic arsenic ingestion are multisystem, but depending on the dose and frequency of exposure, may take many years to become clinically apparent. The earliest and most common manifestations are dermatological, and therefore, recognition of hallmark lesions is key. In this report, we describe a suspected case of palmoplantar arsenical keratosis in a patient from Newfoundland, Canada. METHODS: Case report and review of relevant literature via PubMed search. RESULTS: A 64-year-old fisherman from rural Newfoundland presented with a 12-year history of hyperkeratotic palmoplantar papules/plaques. The lesions first appeared on the sole of his left foot but gradually extended to involve the sole of his right foot and palms. Numerous violaceous keratotic papules with erosions were observed. Both the patient and his wife were found to have elevated blood arsenic levels, and the arsenic concentration in their artesian well was 14.2 ug/L (maximum acceptable concentration: 10 ug/L). Interestingly, biopsy showed a lichen-sclerosis-like inflammatory pattern that seems to deviate from the classic histologic description. The patient is being treated with oral acitretin, and minor improvement has been noted. CONCLUSION: It is important to consider arsenic exposure whenever a patient presents with acral hyperkeratosis. Further research is needed to develop more effective treatments for chronic arsenicism and to determine the effects of very low-dose exposure and what truly constitutes a safe level. PMID- 26239735 TI - Therapeutic value of combined therapy with deferiprone and silymarin as iron chelators in Egyptian children with beta thalassemia major. AB - BACKGROUND: Beta Thalassemia is inherited anemia characterized by absent or reduced synthesis of beta-globin chains of hemoglobin, caused by beta-globin gene mutations resulting in chronic hemolytic anemia that requires 'repeated blood transfusion with resulting iron overload'. Silymarin has iron chelating activity in thalassemic patients with iron overload. AIM OF THE WORK: was to study the therapeutic value of combined therapy of Deferiprone and silymarin as iron chelators in Egyptian children with beta thalassemia with iron overload'. PATIENTS AND METHODS: 'This study was conducted on 80 beta thalassemic children with their serum ferritin more than 1000 ng/ml who were divided into two groups'. Group I included 40 patients who were treated with oral Deferiprone and silymarin for 9 months. Group II included 40 patients who were treated with oral Deferiprone and placebo for 9 months. RESULTS: 'There were no significant differences in serum ferritin, iron and TIBC between group I and group II before the study but after regular chelation therapy, serum ferritin and iron were significantly lower in group I than group II. No statistically significant differences in serum creatinine, blood urea, ALT, AST and bilirubin levels between Group I and Group II before and after chelation therapy were observed'. CONCLUSION: Deferiprone in combination with silymarin are better iron chelators than Deferiprone and placebo. RECOMMENDATIONS: 'Extensive multicenter studies in large number of patients with longer follow up period and more advanced methods of assessment of iron status to clarify the exact role of silymarin in reduction of iron over load in thalassemic children'. PMID- 26239736 TI - [Seizures and respiratory failure following local anaesthesia administered for circumcision]. AB - We present two cases in which two boys of four weeks and four and a half months, respectively, experienced seizures and respiratory insufficiency as complications to the local anaesthesia administered for ritual circumcision. They both needed intubation and anticonvulsive therapy and acquired an aspiration pneumonia, which was treated with antibiotics. Both recovered without sequelae. Surgeons should be careful with calculating the maximum safe dose of local anaesthesia for young children and should be prepared to treat complications. PMID- 26239737 TI - [Missing cuff from the oro-tracheal tube during percutaneous dilatation tracheotomy]. AB - During a percutaneous dilatation tracheotomy (PDT) performed at the intensive care unit of a regional hospital, subsequent to completion of the PDT a small segment of the cuff from the oro-tracheal tube was found missing, once the oro tracheal tube was removed. The oto-rhino-laryngologist was called upon to carry out a flexible bronchoscopy and laryngoscopic examination of the patient. After deflation, the missing piece was located at the level of the tracheal tube cuff and removed successfully. We recommend examining the condition of the oro tracheal tube cuff upon completion of the PDT procedure. PMID- 26239738 TI - [Cerebral infarction can be a consequence of anaesthesia in beach chair position]. AB - Performing orthopaedic surgery in beach chair position (BCP) is a common procedure in Denmark. In this case report we present a patient, who underwent standard procedure with no variations according to the general anaesthesia. The arterial blood pressure after entering BCP and during surgery was acceptable. In the recovery phase the patient did not gain full consciousness, his blood pressure turned high and he developed seizures. A. cerebri media infarction was identified, and severe brain damage was the consequence. We question the rationale for using BCP as well as the use of phenylephrine for the cerebral hypoperfusion. PMID- 26239739 TI - [Clinical molecular genetics diagnostics of Rett syndrome in Denmark]. AB - The neurodevelopmental disorder Rett syndrome was first described in 1966 by Andreas Rett, who described girls with loss of speech and hand use displaying characteristic hand stereotypies. Since then, the disease has been linked to mutations in the gene MECP2. However, the basis of the diagnosis is still clinical as defined by the latest clinical criteria as proposed by Neul and colleagues in 2010. This article presents a short clinical and molecular overview of the latest in Rett syndrome with emphasis on the Danish patients, headlines for making the diagnosis, differential diagnoses and molecular diagnostic possibilities. PMID- 26239740 TI - [Intestinal tuberculosis--a rare differential diagnosis of Crohn's disease in an ethnic Danish woman]. AB - We report a case of intestinal tuberculosis in a 42-year-old Danish woman with stomach pain, weight loss and diarrhoea for months suspective of Crohn's disease. She underwent hysterectomy where white, small nodules were found on the small intestine. Biopsies showed non-necrotizing granulomatous inflammation. Gastroscopy and colonoscopy were normal. Capsule endoscopy revealed small intestine ulcers and a stenosis. A CT scan of the abdomen confirmed stenosis and inflammation of terminal ileum. QuantiFERON-TB Gold Test was positive and Mycobacterium tuberculosis was detected in faeces cultures. PMID- 26239741 TI - [Cancer in pregnancy]. AB - Cancer in pregnancy occurs in about one in 1,000 pregnancies. Recent reports have shown that most treatment regimes in second and third trimester are safe for the mother and the child. This has led to a paradigm shift in treating pregnant women with cancer. The management of the pregnant woman should be in a multidisciplinary setting, and delivery should be postponed to avoid very preterm delivery and planned 2-3 weeks after the last chemotherapeutic treatment allowing both maternal and foetal bone marrow to recover. PMID- 26239742 TI - Decreased expression levels of Nurr1 are associated with chronic inflammation in patients with type 2 diabetes. AB - Chronic inflammation is associated with insulin resistance, a characteristic of type 2 diabetes (T2D). Nuclear receptor-related protein 1 (Nurr1) can regulate inflammation, dependent on the nature of individual diseases. However, whether Nurr1 regulates chronic inflammation during the pathogenic process of T2D in humans remains to be fully elucidated. The present study aimed to investigate the potential association between the expression of Nurr1 in peripheral blood mononuclear cells (PBMCs) and inflammation in patients with T2D. The levels of plasma tumor necrosis factor (TNF)alpha and interleukin (IL)-6, the relative expression levels of Nurr1, and glycogen synthase kinase (GSK)-3beta phosphorylation in PBMCs from 40 patients with T2D and 40 healthy controls (HC group) were examined, and their potential association with clinical measures were analyzed. The expression levels of Nurr1, induced by high glucose and palmitic acid, were assessed in the PBMCs from the HC group. Compared with the HC group, significantly higher levels of plasma TNFalpha and IL-6 were correlated positively with the degree of insulin resistance in the T2D patients. However, significantly lower expression levels of Nurr1 and GSK-3beta phosphorylation in the PBMCs were correlated negatively with the levels of TNFalpha, IL-6, fasting insulin and insulin resistance in the T2D patients. Treatment of the PBMCs with high glucose or palmitic acid inhibited the expression of Nurr1 in a dose- and time-dependent manner. Therefore, decreased expression levels of Nurr1 were associated with chronic inflammation and insulin resistance in patients with T2D. PMID- 26239743 TI - Gender comparison of factors associated with age-related differences in bone mineral density. AB - We found that age-related decline in bone mineral density (BMD) is more pronounced in women than in men, that lean mass was the most important determinant of BMD in all age groups in both sexes, and that different factors may be important for bone health of men and women and at different ages. INTRODUCTION: Multiple factors may affect bone mineral density (BMD). Our objective was to identify the correlates of age-related differences in BMD among men and women. METHODS: We performed a cross-sectional study involving 490 men and 517 women between the age of 29 and 87 years that were free of medication and diseases known to affect bone metabolism. BMD was measured at various sites using dual-energy X-ray absorptiometry, and factors possibly associated with skeletal status were assessed by direct measurements and a detailed questionnaire. RESULTS: BMD was lower with advancing age at all BMD measurement sites, the greatest difference being for the femoral neck where in women BMD was 37.5 % lower in the oldest compared to that in the youngest age group, but the difference was 22.9 % in men. Levels of free estradiol were sharply lower after age of 40 among women; free testosterone declined gradually with age among men but was not independently associated with BMD. Factors including lean mass, physical activity, ionized calcium, C-terminal telopeptide (CTX), serum sodium, free estradiol, and smoking explained a large fraction of difference in BMD in different age groups but to a varying degree in men and women. Lean mass was the strongest independent factor associated with BMD at all sites among men and women. CONCLUSIONS: Age-related decline in BMD is more pronounced in women than in men, but determinants of BMD are multiple and interrelated. Our study indicates that different factors may be important for bone health of men and women and at different ages. PMID- 26239744 TI - Studies of a Diazo Cyclopropanation Strategy for the Total Synthesis of (-) Lundurine A. AB - The bioactive Kopsia alkaloids lundurines A-D are the only natural products known to contain indolylcyclopropane. Achieving their syntheses can provide important insights into their biogenesis, as well as novel synthetic routes for complex natural products. Asymmetric total synthesis of (-)-lundurine A has previously been achieved through a Simmons-Smith cyclopropanation strategy. Here, the total synthesis of (-)-lundurine A was carried out using a metal-catalyzed diazo cyclopropanation strategy. In order to avoid a carbene C?H insertion side reaction during cyclopropanation of alpha-diazo- carboxylates or cyanides, a one pot, copper-catalyzed Bamford-Stevens diazotization/diazo decomposition/cyclopropanation cascade was developed, involving hydrazone. This approach simultaneously generates the C/D/E ring system and the two chiral quaternary centers at C2 and C7. PMID- 26239745 TI - Hydrogel Microencapsulated Insulin-Secreting Cells Increase Keratinocyte Migration, Epidermal Thickness, Collagen Fiber Density, and Wound Closure in a Diabetic Mouse Model of Wound Healing. AB - Wound healing is a hierarchical process of intracellular and intercellular signaling. Insulin is a potent chemoattractant and mitogen for cells involved in wound healing. Insulin's potential to promote keratinocyte growth and stimulate collagen synthesis in fibroblasts is well described. However, there currently lacks an appropriate delivery mechanism capable of consistently supplying a wound environment with insulin; current approaches require repeated applications of insulin, which increase the chances of infecting the wound. In this study, we present a novel cell-based therapy that delivers insulin to the wound area in a constant or glucose-dependent manner by encapsulating insulin-secreting cells in nonimmunogenic poly(ethylene glycol) diacrylate (PEGDA) hydrogel microspheres. We evaluated cell viability and insulin secretory characteristics of microencapsulated cells. Glucose stimulation studies verified free diffusion of glucose and insulin through the microspheres, while no statistical difference in insulin secretion was observed between cells in microspheres and cells in monolayers. Scratch assays demonstrated accelerated keratinocyte migration in vitro when treated with microencapsulated cells. In excisional wounds on the dorsa of diabetic mice, microencapsulated RIN-m cells accelerated wound closure by postoperative day 7; a statistically significant increase over AtT-20ins treated and control groups. Histological results indicated significantly greater epidermal thickness in both microencapsulated RIN-m and AtT-20ins-treated wounds. The results suggest that microencapsulation enables insulin-secreting cells to persist long enough at the wound site for a therapeutic effect and thereby functions as an effective delivery vehicle to accelerate wound healing. PMID- 26239746 TI - Reflecting microscope system with a 0.99 numerical aperture designed for three dimensional fluorescence imaging of individual molecules at cryogenic temperatures. AB - We have developed a cryogenic fluorescence microscope system, the core of which is a reflecting objective that consists of spherical and aspherical mirrors. The use of an aspherical mirror allows the reflecting objective to have a numerical aperture (NA) of up to 0.99, which is close to the maximum possible NA of 1.03 in superfluid helium. The performance of the system at a temperature of 1.7 K was tested by recording a three-dimensional fluorescence image of individual quantum dots using excitation wavelengths (lambdaex) of 532 nm and 635 nm. At 1.7 K, the microscope worked with achromatic and nearly diffraction-limited performance. The 1/e(2) radius (Gamma) of the point spread function of the reflecting objective in the lateral (xy) direction was 0.212 +/- 0.008 MUm at lambdaex = 532 nm and was less than 1.2 times the simulated value for a perfectly polished objective. The radius Gamma in the axial (z) direction was 0.91 +/- 0.04 MUm at lambdaex = 532 nm and was less than 1.4 times the simulated value of Gamma. The chromatic aberrations between the two wavelengths were one order of magnitude smaller than Gamma in each direction. PMID- 26239747 TI - Reply. PMID- 26239748 TI - Feasibility of Using Electronic Medical Record Data for Tracking Quality Indicators in Adults with Congenital Heart Disease. AB - BACKGROUND: In order to determine the feasibility of tracking quality of care in adults with congenital heart disease (ACHD), we aimed to estimate the availability of relevant data in electronic medical records (EMR) used in North American ACHD centers. METHODS: Previously proposed quality indicators (QIs) were reviewed to consider what types of data would be required for each. ACHD program directors were surveyed about the nature of electronic data in existing EMRs. From the survey, the availability of data types needed for the denominator and numerator of each QI were estimated, and an overall estimate of data availability was calculated for each QI. These estimates were adjusted by the sensitivity of identifying the patients through administrative codes. Analysis was repeated for scenarios in which various data type estimates were hypothetically dropped by half to determine the overall impact of each data type. RESULTS: A total of 64 ACHD program directors responded to the survey. Of 55 QIs, average estimated data availability was 67%. QIs for tetralogy of Fallot had the highest estimated data availability (mean 88%), whereas those for atrial septal defect were lowest (mean 23%), reflecting both the need for interpretation of imaging studies and the lower reliability of billing codes for identification of ACHD patients. QIs with highest estimates were based largely on administrative data, which had the biggest impact on overall estimates. QIs needing interpretation of imaging findings had the lowest estimates, as well as certain overuse measures. CONCLUSIONS: For a wide range of ACHD programs, data for proposed QIs based on administrative data are most likely to be obtainable through EMR. Data related to imaging interpretation or overuse measures are least likely. Our findings can inform future efforts to establish registry efforts or data reporting tools to track these indicators. PMID- 26239750 TI - Footbridges as elements for urban rehabilitation and renewal. AB - When a bridge is designed, we start from the basis that it is visible in all its parts. In actual fact, due to the position and speed of the observer, the bridge can be perceived partially and for a limited period of time. The area and time within which the bridge can be perceived are entities that can be quantified and, therefore, measured (Perceptive quantity). Italian legislation about infrastructures distinguishes between two forms of quality: internal, also referred to as technical performance and, more general, work function apply; and external, namely connected with the social-economic, environmental and landscape impact of the work. Footbridges make it possible to create closer relations between the user and the work, as walking on them implies moving at a slower pace. The aim of this paper was to understand how the perception of a footbridge can prove to be an effective knowledge base for planning, and an instrument for urban rehabilitation. This paper will also explore the ways in which existing footbridges can change the perception and the meaning of a place. It will also investigate the connection between the design of footbridges and planning tools. The results involve the study of the effects that a footbridge may have on the urban landscape, taking the relationship between the internal and external quality of the work into consideration. PMID- 26239749 TI - Incidence of End-Stage Renal Disease Among Newly Diagnosed Systemic Lupus Erythematosus Patients: The Georgia Lupus Registry. AB - OBJECTIVE: To estimate and identify factors associated with the incidence of all cause end-stage renal disease (ESRD) among newly diagnosed systemic lupus erythematosus (SLE) patients. METHODS: Data from a national registry of treated ESRD were linked to data from a lupus registry of SLE patients who were newly diagnosed and living in Atlanta, Georgia, 2002-2004 (median followup 7.8 years). Cumulative incidence and incidence rates (ESRD treatment initiations per 1,000 patient-years) were calculated, and age- and race-adjusted Poisson models were used to calculate incidence rate ratios (IRRs). RESULTS: Among 344 newly diagnosed SLE patients, 29 initiated ESRD treatment over 2,603.8 years of followup. Incidence rates were 13.8 (95% confidence interval [95% CI] 9.4-20.3) among black patients and 3.3 (95% CI 0.8-13.0) among white patients, per 1,000 patient-years; corresponding 5-year cumulative incidence was 6.4% and 2.5% among black and white patients, respectively. Lupus nephritis documented prior to 2005, which occurred in 80% of those who progressed to ESRD, was the strongest risk factor for incident ESRD (IRR 6.7 [95% CI 2.7-16.8]; incidence rate 27.6 per 1,000 patient-years). Results suggested that patients who were black versus white (IRR 3.9 [95% CI 0.9-16.4]) or <18 years old (versus >=30 years old) at diagnosis (IRR 2.1 [95% CI 0.9-5.3]) may be more likely to progress to ESRD, but incidence did not differ by sex or other characteristics. CONCLUSION: The incidence of all cause ESRD among patients with a recent diagnosis of SLE is high in Georgia. Interventions to decrease ESRD incidence among newly diagnosed SLE patients should target young and black patients, as well as patients with lupus nephritis. PMID- 26239751 TI - Anticipatory eye movements in sensorimotor actions: on the role of guiding fixations during learning. AB - During object-based sensorimotor tasks, humans look at target locations for subsequent hand actions. These anticipatory eye movements or guiding fixations seem to be necessary for a successful performance. By practicing such a sensorimotor task, humans become faster and perform fewer guiding fixations (Foerster and Schneider, In Prep; Foerster et al. in J Vis 11(7):9:1-16, 2011). We aimed at clarifying whether this decrease in guiding fixations is the cause or effect of faster task completion time. Participants may learn to use less visual input (fewer fixations) allowing shorter completion times. Alternatively, participants may speed up their hand movements (e.g., more efficient motor control) leaving less time for visual intake. The latter would imply that the number of fixations is directly connected to task speed. We investigated the relationship between the number of fixations and task speed in a computerized version of the number connection task (Foerster and Schneider in Ann N Y Acad Sci 2015. doi: 10.1111/nyas.12729 ). Eye movements were recorded while participants clicked in ascending order on nine numbered circles. In 90 learning trials, they clicked the sequence with a constant spatial configuration as fast as possible. In the subsequent experimental phase, they should perform 30 trials again under high-speed instruction and 30 trials under slow-speed instruction. During slow speed instruction, fixation rates were lower with longer fixation durations and more fixations were performed than during high-speed instruction. The results suggest that the number of fixations depends on both the need for visual intake and task completion time. It seems that the decrease in anticipatory eye movements through sensorimotor learning is at the same time a result and a cause of faster task performance. PMID- 26239752 TI - Representation of impossible worlds in the cognitive map. AB - It is often assumed that humans represent large-scale spatial environments as cognitive maps, but the exact features of these representations are still unclear. We investigate the structure of this representation with the impossible worlds paradigm by testing whether the information provided by virtual environments (VEs) with arbitrary violations of geometrical rules is rectified ("distorted") to become compatible with a map-like structure. The experiments were conducted in virtual reality using a natural locomotion interface. The subjects' task was to explore possible and impossible VEs carefully to achieve a "full understanding". After each trial, they had to "blindly" reproduce the path through the environment from memory in a VE with impoverished visual cues. We have found no evidence for angular or configurational distortions or alterations in the blind reproductions of impossible VEs. Blind reproduction indicates that impossible VEs do not require a transformation into a "possible" format to make them fit into the cognitive map. This suggests that the representation may not be similar to a map in a bounded sense of interpretation but requires more generalized concepts for its understanding. PMID- 26239753 TI - Gender-specific effects of emotional modulation on visual temporal order thresholds. AB - Emotions affect temporal information processing in the low-frequency time window of a few seconds, but little is known about their effect in the high-frequency domain of some tens of milliseconds. The present study aims to investigate whether negative and positive emotional states influence the ability to discriminate the temporal order of visual stimuli, and whether gender plays a role in temporal processing. Due to the hemispheric lateralization of emotion, a hemispheric asymmetry between the left and the right visual field might be expected. Using a block design, subjects were primed with neutral, negative and positive emotional pictures before performing temporal order judgment tasks. Results showed that male subjects exhibited similarly reduced order thresholds under negative and positive emotional states, while female subjects demonstrated increased threshold under positive emotional state and reduced threshold under negative emotional state. Besides, emotions influenced female subjects more intensely than male subjects, and no hemispheric lateralization was observed. These observations indicate an influence of emotional states on temporal order processing of visual stimuli, and they suggest a gender difference, which is possibly associated with a different emotional stability. PMID- 26239754 TI - Confirmatory factor analysis for indicators of perceived environmental quality of the stadium (IPEQS). AB - Studies conducted in the 1980s (see Canter et al. in Football in its place. An environmental psychology of football grounds. Routledge, London, 1989) highlighted the prominent role of the spatial-physical features of football grounds in influencing users' perception of safety, comfort, and general satisfaction towards the stadium experience. In particular, the importance of fulfilling the spectators' needs of personal space (e.g. presence of an open view, proper distance between the seats) and movement opportunity was analysed. The aim of this study is to confirm the factorial structure of a set of indicators--the IPEQS--concerning the perceived quality of an array of aspects (i.e. architectural, social, functional, and safety issues) related to the stadium design. Participants (N = 255), who were selected on the basis of their stadium experience, filled in a self-report questionnaire measuring a set of indicators developed on the basis of both validated tools [i.e. the perceived residential environment quality indicators (PREQIs): Bonaiuto et al. in J Environ Psychol 19:331-352, 1999] and outcomes of semi-structured interviews. Confirmatory factor analyses (CFA) were performed for each scale, and reliability assessments were then carried out for each indicator. IPEQS' factorial structures found through the CFA procedure substantially confirm the results of exploratory factor analyses run with previous data. Outcomes of this study should provide a useful tool for managers and designers of football grounds, in order to improve the overall experience of the spectators. PMID- 26239755 TI - Does the road go up the mountain? Fictive motion between linguistic conventions and cognitive motivations. AB - Fictive motion (FM) characterizes the use of dynamic expressions to describe static scenes. This phenomenon is crucial in terms of cognitive motivations for language use; several explanations have been proposed to account for it, among which mental simulation (Talmy in Toward a cognitive semantics, vol 1. MIT Press, Cambridge, 2000) and visual scanning (Matlock in Studies in linguistic motivation. Mouton de Gruyter, Berlin and New York, pp 221-248, 2004a). The aims of this paper were to test these competing explanations and identify language specific constraints. To do this, we compared the linguistic strategies for expressing several types of static configurations in four languages, French, Italian, German and Serbian, with an experimental set-up (59 participants). The experiment yielded significant differences for motion-affordance versus no motion affordance, for all four languages. Significant differences between languages included mean frequency of FM expressions. In order to refine the picture, and more specifically to disentangle the respective roles of language-specific conventions and language-independent (i.e. possibly cognitive) motivations, we completed our study with a corpus approach (besides the four initial languages, we added English and Polish). The corpus study showed low frequency of FM across languages, but a higher frequency and translation ratio for some FM types--among which those best accounted for by enactive perception. The importance of enactive perception could thus explain both the universality of FM and the fact that language-specific conventions appear mainly in very specific contexts--the ones furthest from enaction. PMID- 26239756 TI - Configurational salience of landmarks: an analysis of sketch maps using Space Syntax. AB - We conducted a visibility graph analysis (a Space Syntax method) of a virtual environment to examine how the configurational salience of global and local landmarks (i.e., their relative positions in the environment) as compared to their visual salience affects the probability of their depiction on sketch maps. Participants of two experimental conditions produced sketch maps from memory after exploration with a layout map or without a map, respectively. Participants of a third condition produced sketch maps in parallel to exploration. More detailed sketch maps were produced in the third condition, but landmarks with higher configurational salience were depicted more frequently across all experimental conditions. Whereas the inclusion of global landmarks onto sketch maps was best predicted by their size, both visual salience and isovist size (i.e., the area a landmark was visible from) predicted the frequency of depiction for local landmarks. Our findings imply that people determine the relevance of landmarks not only by their visual, but even more by their configurational salience. PMID- 26239757 TI - An in vitro investigation into the role of bone marrow-derived mesenchymal stem cells in the control of disc degeneration. AB - Excessive apoptosis and high expression levels of interleukin-1beta (IL-1beta) in disc cells have been reported to serve important roles in intervertebral disc degeneration (IVDD). Previous studies investigating mesenchymal stem cells (MSCs) have indicated potential for their use in the treatment of IVDD. However, the therapeutic potential and anti-apoptotic ability of MSCs remains to be fully elucidated. The present study aimed to establish an in vitro model for bone marrow-derived MSC (BMSC) therapy by investigating the anti-apoptotic effects, in addition to the migration of BMSCs to nucleus pulposus (NP) cells stimulated by IL-1beta. A co-culture system of BMSCs and NP cells was founded. Following inflammatory stimulation, the NP cells exhibited increased indexes for inflammation-induced degeneration. The degenerative and apoptotic indexes were significantly reduced when NP cells were co-cultured with BMSCs. Compared with the indirect co-culture group, the direct co-culture group exhibited an improved capacity for anti-apoptosis. In addition, IL-1beta-stimulated NP cells attracted and mediated the migration of BMSCs. Mitochondrial transfer from BMSCs to NP cells by tunneling nanotubes was also observed. In conclusion, the anti-apoptosis and the migration, in addition to mitochondrial transfer associated with BMSC treatments in IVDD, were investigated in vitro in the present study. The interaction between stimulated NP cells and BMSCs is likely involved in to simulating the in vivo process of stem cell-mediated repair. PMID- 26239758 TI - Forensic Potential of MMPs and CC Chemokines for Wound Age Determination. AB - In this study, we investigated time-dependent expression of matrix metalloproteases (MMP)-2, MMP-9, chemokine CC motif ligand (CCL)-2, CCL-3, CCL-5, IL-1beta, IL-6, and TNF-alpha mRNA at the skin injury site and sought their forensic potentials during the skin wound repair process. The tested wound ages in 42 mouse skin wounds were distributed at 0d, 1d, 3d, 5d, 7d, 10d, and 14d, respectively and then followed by real-time polymerase chain reaction. Ultimately, MMP-2 played an important role in the inflammation phase. On the contrary, MMP-9 became involved at a later phase during wound healing. Meanwhile, CCL-2 and CCL-3 were active throughout almost all of the process. However, CCL-5 mRNA had no significance. Collectively, an MMP-9/MMP-2 ratio of over 0.84 indicated that skin wound healing age was strongly 5 days or less. So elevated gene expressions of cytokines and chemokines in different phases of wound ages implied that combined exploration could make wound age determination more accurate and objective. PMID- 26239759 TI - Reactive atmospheric pressure plasma for highly efficient removal of structure directing agents from zeolite thin films. AB - We present a novel approach to remove the structure-directing agent (SDA) from as synthesized zeolites using an atmospheric pressure plasma jet (APPJ). This reduces the time required to less than 60 seconds as compared to the existing thermal calcination, whose durations range from hours to days. The highly reactive plasma also results in a pronounced Q(3)-to-Q(4) transformation in the pure-silica zeolite MFI. PMID- 26239760 TI - Implementation challenges of a TB programme in rural northern mozambique: evaluation of 2012-2013 outcomes. AB - BACKGROUND: We aimed to identify challenges and to propose solutions for the implementation of tuberculosis (TB) programmes in rural Sub-Saharan Africa (SSA) by evaluating the outcomes of the TB programme in the Ancuabe district in rural Northern Mozambique. METHODS: Retrospective descriptive study of the patients included in the TB programme in 2012-2013. Follow-up was continued till June 2014. RESULTS: Three hundred nineteen patients were registered, 62.1% male, mean age 36.3 (SD 14.4), estimated case detection rate (eCDR) of 24.24%. Two hundred seventy-two were new cases, 21 transferred-in, 11 back after lost to follow-up (LTFU), 10 relapsing TB, 5 previous treatment failures. 94.4% were tested for Human immunodeficiency virus (HIV), 41.9% HIV-positive. 87.5% of the new cases were pulmonary TB (PTB), 43.4% were HIV co-infected. Initial sputum results were available in 207 cases, with 145 smear-positive (SP) cases. Outcomes of new cases: 122 (44.9%) LTFU, 55 (20.2%) cured, 43 (15.8%) treatment completed (98-36% treatment success), 31 (11.4%) died, 19 (7%) transferred out and 2 (0.7%) failures. CONCLUSIONS: A low eCDR and high proportion of LTFU demonstrate that few patients were identified and had a low probability of complete treatment, suggesting a fragile health system. This raises the hypothesis that, probably, to improve TB health care in rural SSA, interventions should aim at improving health systems. Special attention should be given to social protection and compensation of the financial burden associated with TB. PMID- 26239761 TI - Biodegradation of ionic liquids--a critical review. AB - The importance of biodegradation data as part of the design of safer chemicals is presented using ionic liquids (ILs) as a model study. Structural features that promote/impede IL biodegradation, IL design strategies, methods of biodegradation analysis, properties of IL/surfactant derivatives and computational methods of predicting biodegradation are discussed. The importance of metabolite studies as part of biodegradation assays is highlighted. The relevance of applying the lessons learned developing biodegradable ILs to other chemical classes is proposed. A comprehensive appendix of IL biodegradation data published since 2010 (~300 ILs) has been compiled. PMID- 26239763 TI - Caudal regression syndrome with diastematomyelia, multiple vertebral anomalies, and rotoscoliosis in an adult. PMID- 26239762 TI - Surgery for metastatic spine tumors in the elderly. Advanced age is not a contraindication to surgery! AB - BACKGROUND: With recent advances in oncologic treatments, there has been an increase in patient survival rates and concurrently an increase in the number of incidence of symptomatic spinal metastases. Because elderly patients are a substantial part of the oncology population, their types of treatment as well as the possible impact their treatment will have on healthcare resources need to be further examined. PURPOSE: We studied whether age has a significant influence on quality of life and survival in surgical interventions for spinal metastases. STUDY DESIGN: We used data from a multicenter prospective study by the Global Spine Tumor Study Group (GSTSG). This GSTSG study involved 1,266 patients who were admitted for surgical treatments of symptomatic spinal metastases at 22 spinal centers from different countries and followed up for 2 years after surgery. PATIENT SAMPLE: There were 1,266 patients recruited between March 2001 and October 2014. OUTCOME MEASURES: Patient demographics were collected along with outcome measures, including European Quality of Life-5 Dimensions (EQ-5D), neurologic functions, complications, and survival rates. METHODS: We realized a multicenter prospective study of 1,266 patients admitted for surgical treatment of symptomatic spinal metastases. They were divided and studied into three different age groups: <70, 70-80, and >80 years. RESULTS: Despite a lack of statistical difference in American Society of Anesthesiologists (ASA) score, Frankel neurologic score, or Karnofsky functional score at presentation, patients >80 years were more likely to undergo emergency surgery and palliative procedures compared with younger patients. Postoperative complications were more common in the oldest age group (33.3% in the >80, 23.9% in the 70-80, and 17.9% for patients <70 years, p=.004). EQ-5D improved in all groups, but survival expectancy was significantly longer in patients <70 years old (p=.02). Furthermore, neurologic recovery after surgery was lower in patients >80 years old. CONCLUSIONS: Surgeons should not be biased against operating elderly patients. Although survival rates and neurologic improvements in the elderly patients are lower than for younger patients, operating the elderly is compounded by the fact that they undergo more emergency and palliative procedures, despite good ASA scores and functional status. Age in itself should not be a determinant of whether to operate or not, and operations should not be avoided in the elderly when indicated. PMID- 26239764 TI - Osteolytic vascular lesion of upper cervical spine. PMID- 26239765 TI - Schwann Cells Increase Prostate and Pancreatic Tumor Cell Invasion Using Laminin Binding A6 Integrin. AB - Human pancreatic and prostate cancers metastasize along nerve axons during perineural invasion. The extracellular matrix laminin class of proteins is an abundant component of both myelinated and non-myelinated nerves. Analysis of human pancreatic and prostate tissue revealed both perineural and endoneural invasion with Schwann cells surrounded or disrupted by tumor, respectively. Tumor and nerve cell co-culture conditions were used to determine if myelinating or non myelinating Schwann cell (S16 and S16Y, respectively) phenotype was equally likely to promote integrin-dependent cancer cell invasion and migration on laminin. Conditioned medium from S16 cells increased tumor cell (DU145, PC3, and CFPAC1) invasion into laminin approximately 1.3-2.0 fold compared to fetal bovine serum (FBS) treated cells. Integrin function (e.g., ITGA6p formation) increased up to 1.5 fold in prostate (DU145, PC3, RWPE-1) and pancreatic (CFPAC1) cells, and invasion was dependent on ITGA6p formation and ITGB1 as determined by function-blocking antibodies. In contrast, conditioned medium isolated from S16Y cells (non-myelinating phenotype) decreased constitutive levels of ITGA6p in the tumor cells by 50% compared to untreated cells and decreased ITGA6p formation 3.0 fold compared to S16 treated cells. Flow cytometry and western blot analysis revealed loss of ITGA6p formation as reversible and independent of overall loss of ITGA6 expression. These results suggest that the myelinating phenotype of Schwann cells within the tumor microenvironment increased integrin-dependent tumor invasion on laminin. PMID- 26239766 TI - Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine in humans. AB - Pramipexole is a D3 dopamine receptor-preferring agonist indicated for the treatment of Parkinson disease. Studies associate pramipexole with pathological gambling and impulse control disorders suggesting a role for D3 receptors in reinforcement processes. Clinical studies showed pramipexole decreased cocaine craving and reversed central deficits in individuals with cocaine use disorder. Preclinical studies have shown acute administration of pramipexole increases cocaine's reinforcing effects whereas other reports suggest chronic pramipexole produces tolerance to cocaine. In a randomized, double-blind, placebo-controlled study we examined the impact of pramipexole treatment on the subjective effects produced by cocaine in volunteers with cocaine use disorder. Volunteers received pramipexole titrated up to 3.0mg/d or placebo over 15 days. Participants then received intravenous cocaine (0, 20 and 40mg) on day 15. Cardiovascular and subjective effects were obtained with visual analog scales at time points across the session. Pramipexole alone increased peak heart rate following saline and diastolic blood pressure following cocaine. Pramipexole produced upwards of two fold increases in positive subjective effects ratings following cocaine. These results indicate that chronic D3 receptor activation increases the subjective effects of cocaine in humans. Caution should be used when prescribing pramipexole to patients that may also use cocaine. PMID- 26239767 TI - Effects of a single bout of maximal aerobic exercise on BDNF in bipolar disorder: A gender-based response. AB - Acute exercise increases brain-derived neurotrophic factor (BDNF) serum levels in majorly depressed and anxious patients. However, to the best of our knowledge, no study has evaluated the acute effects of exercise on BDNF serum levels in Bipolar Disorder (BD). The objective of the present study was to evaluate the peripheral BDNF serum response to a single maximum session of exercise in BD participants and age- and gender-matched healthy participants. BD participants (n=18) and age- and gender-matched healthy participants (n=18) were recruited to perform a single bout of maximal exercise on a cycle ergometer. Blood samples were collected prior to and immediately after the exercise protocol. There was a significant group effect and a significant group x time x gender interaction. BD participants presented significantly higher BDNF serum levels when compared to their healthy control counterparts. Exercise increases the BDNF levels of BD women, but not men. PMID- 26239768 TI - Bright light therapy for the treatment of night eating syndrome: A pilot study. AB - The effect of bright light therapy (BLT) on the symptoms of night eating syndrome was evaluated. Fifteen adults completed two weeks of daily 10,000 lux BLT administered in the morning. Significant reductions were found pre-to-post treatment in night eating symptomatology, mood disturbance, and sleep disturbance. This pilot trial provides preliminary support for the efficacy of BLT for the treatment of night eating syndrome. PMID- 26239769 TI - Association between GABA(A) receptor subunit polymorphisms and autism spectrum disorder (ASD). AB - ASD might be associated with alterations in excitation/inhibition ratio and GABA(A) has been implicated since it mediates synaptic inhibition. Polymorphisms in GABA receptor (GABAR) were studied: significant differences in allele and genotype frequencies observed between cases and controls (rs1912960, GABRA4). Haplotype analysis: rs1912960 (GABRA4) and rs211037 (GABRG2) overrepresented in cases. Rs1912960 has been associated with ASD and rs211037 with epilepsy. GABRA4 is associated with autism in the Argentinean dataset independently or in combination with GABRG2. PMID- 26239770 TI - Clinical course of psychiatric disorders in patients with cervical dystonia. AB - We assessed the course of psychiatric disorders in 23 cervical dystonia patients by using the structured clinical interview for DSM-IV and different rating scales. Patients were studied on two occasions 5 years apart. There were no differences in psychiatric disorders and severity of psychiatric symptoms between the two evaluations, whereas the severity of dystonia was milder at the second evaluation. Psychiatric symptoms likely represent a primary disorder in cervical dystonia patients. PMID- 26239771 TI - Understanding complete oxidation of methane on spinel oxides at a molecular level. AB - It is crucial to develop a catalyst made of earth-abundant elements highly active for a complete oxidation of methane at a relatively low temperature. NiCo2O4 consisting of earth-abundant elements which can completely oxidize methane in the temperature range of 350-550 degrees C. Being a cost-effective catalyst, NiCo2O4 exhibits activity higher than precious-metal-based catalysts. Here we report that the higher catalytic activity at the relatively low temperature results from the integration of nickel cations, cobalt cations and surface lattice oxygen atoms/oxygen vacancies at the atomic scale. In situ studies of complete oxidation of methane on NiCo2O4 and theoretical simulations show that methane dissociates to methyl on nickel cations and then couple with surface lattice oxygen atoms to form -CH3O with a following dehydrogenation to -CH2O; a following oxidative dehydrogenation forms CHO; CHO is transformed to product molecules through two different sub-pathways including dehydrogenation of OCHO and CO oxidation. PMID- 26239772 TI - A Tool for Predicting Regulatory Approval After Phase II Testing of New Oncology Compounds. AB - We developed an algorithm (ANDI) for predicting regulatory marketing approval for new cancer drugs after phase II testing has been conducted, with the objective of providing a tool to improve drug portfolio decision-making. We examined 98 oncology drugs from the top 50 pharmaceutical companies (2006 sales) that first entered clinical development from 1999 to 2007, had been taken to at least phase II development, and had a known final outcome (research abandonment or regulatory marketing approval). Data on safety, efficacy, operational, market, and company characteristics were obtained from public sources. Logistic regression and machine-learning methods were used to provide an unbiased approach to assess overall predictability and to identify the most important individual predictors. We found that a simple four-factor model (activity, number of patients in the pivotal phase II trial, phase II duration, and a prevalence-related measure) had high sensitivity and specificity for predicting regulatory marketing approval. PMID- 26239773 TI - World Health Assembly Resolution WHA68.15: "Strengthening Emergency and Essential Surgical Care and Anesthesia as a Component of Universal Health Coverage" Addressing the Public Health Gaps Arising from Lack of Safe, Affordable and Accessible Surgical and Anesthetic Services. AB - On May 22 2015, the 68th World Health Assembly (WHA) adopted resolution WHA68.15, "Strengthening emergency and essential surgical care and anesthesia as a component of universal health coverage (UHC)." For the first time, governments worldwide acknowledged and recognized surgery and anesthesia as key components of UHC and health systems strengthening. The resolution details and outlines the highest level of political commitments to address the public health gaps arising from lack of safe, affordable, and accessible surgical and anesthetic services in an integrated approach. This article reviews the background of resolution WHA68.15 and discusses how it can be of use to surgeons, anesthetists, advanced practice clinicians, nurses, and others caring for the surgical patients, especially in low- and middle-income countries. PMID- 26239774 TI - Modified Anterior Approach for the ALPPS Procedure: How We Do It. AB - BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a highly complex operation that demands a thorough understanding of the intrahepatic vascular anatomy and skills in parenchymal transection for the in situ split procedure. In order to minimize adhesion formation after the stage I operation and to avoid iatrogenic tumor rupture during right liver mobilization in large tumors, anterior approach appears to be a logical approach for the in situ split procedure. However, in contrast to the anterior approach adopted for the usual right hepatectomy, the right hepatic artery and biliary pedicle remain intact and undivided during the first operation. To address this issue, we hereby reported our experience of the modified 'anterior approach' for the ALPPS procedure that facilitates a complete in situ parenchymal split. METHODS: Prospectively collected data of 13 patients who underwent the ALPPS procedure by the modified anterior approach for hepatocellular carcinoma from October 2013 to October 2014 were reviewed. RESULTS: The baseline future liver remnant volume (FLR) was 286 ml. The median tumor size was 6.0 cm. After a median of 8 days from stage I operation, the left FLR hypertrophied by 52.7 % in volume to 482 ml. All patients proceeded to second stage hepatectomy (extended right hepatectomy, n = 5; right hepatectomy, n = 6; right trisectionectomy, n = 2) without significant adhesion encountered. The overall morbidity and mortality rates were 7.7 % (n = 1) and 7.7 % (n = 1), respectively. CONCLUSION: The modified anterior approach is safe and feasible for complete in situ split in the ALPPS procedure. PMID- 26239775 TI - Commentary on "Myths and Misinformation About Gunshot Wounds may Adversely Affect Proper Treatment". PMID- 26239776 TI - Additional Imaging in Alert Trauma Patients with Cervical Spine Tenderness and a Negative Computed Tomographic Scan: Is it Needed? AB - BACKGROUND: The value of additional imaging in clearing the cervical spine (C spine) of alert trauma patients with tenderness on clinical exam and a negative computed tomographic (CT) scan is still unclear. METHODS: All adult trauma patients with a Glasgow Coma Scale of 15, C-spine tenderness in the absence of neurologic signs, and a negative C-spine CT were included. The study period extended from September 2011 to June 2012. C-spine CT scans were interpreted in detail and considered negative in the absence of any findings indicating bony, ligamentous, or soft tissue injury around the C-spine. The incidence of C-spine injury was evaluated using early (<24 h) repeat physical examination, MRI, and/or flexion-extension films. RESULTS: Of 2015 patients with a C-spine CT, 383 (19 %) fulfilled the inclusion criteria. The median age was 43 (IQR: 30-53) and 44.7 % were female. Thirty-six patients (9.4 %) underwent MRI (3.7 %), flexion-extension imaging (5.2 %), or both (0.5 %), with no significant injuries identified and subsequent removal of the collar allowed. The remaining patients were clinically cleared within 24 h of presentation. None of the patients developed neurological signs following removal of the collar. On bivariate analysis, no variable except for evaluation by trauma surgery was associated with performance of additional imaging. CONCLUSION: C-spine precautions can be withdrawn without additional imaging in most blunt trauma patients with C-spine tenderness but negative neurologic evaluation and C-spine CT. Focus should be placed on the detailed and comprehensive interpretation of the C-spine CT. PMID- 26239777 TI - Erratum for Petry et al. Phytic acid concentration influences iron bioavailability from biofortified beans in Rwandese women with low iron status. J Nutr 2014;144:1681-7. PMID- 26239779 TI - Effect of CoCl2 on fracture repair in a rat model of bone fracture. AB - Low oxygen availability is known to activate the hypoxia-inducible factor-1alpha (HIF-1alpha) pathway, which is involved in the impairment of fracture healing. However, the role of low oxygen in fracture healing remains to be fully elucidated. In the present study, rats were divided into two groups and treated with CoCl2 or saline, respectively. Mice with tibial fractures were sacrificed at 14, 28 and 42 days subsequent to fracture. Autoradiography was performed to measure healing of the bone tissue. In addition, the effects of cobalt chloride (CoCl2) on the expression of two major angiogenic mediators, HIF-1alpha and vascular endothelial growth factor (VEGF), as well as the osteoblast markers runt related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and osteocalcin (OC) were determined at mRNA and protein levels by reverse transcription-quantitative polymerase chain reaction, western blot analysis and immunohistochemistry. Systemic administration of CoCl2 (15 mg/kg/day intraperitoneally) significantly promoted fracture healing and mechanical strength. The present study demonstrated that in rats treated with CoCl2, the expression of HIF-1alpha, VEGF, Runx2, ALP and OC was significantly increased at mRNA and protein levels, and that CoCl2 treatment enhances fracture repair in vivo. PMID- 26239780 TI - Learning the Language of Copernicus. AB - The Copernicus Initiative was a bold and important undertaking by the Arthroscopy Association of North America to help further our learning the art of arthroscopy in a controlled setting. Understanding arthroscopic learning, training, and simulation research requires mastery of a lexicon of new terms, which AANA Copernicus researchers define in a glossary. Learning requires practice to develop proficiency. Developing new ability is a rewarding challenge. Metrics may be used to quantitatively measure objective performance, and is a key component of the Copernicus Initiative. A dedicated group of AANA researchers and educators have taken on an important and challenging task to help us improve in the realm of surgical education. PMID- 26239781 TI - Dry Arthroscopy of the Elbow and Basic Hip Arthroscopy Positioning. AB - In Arthroscopy Techniques, dry arthroscopy of the elbow is well-illustrated, and hip arthroscopy patient positioning including fluoroscopic examination under anesthesia is critically reviewed. PMID- 26239782 TI - Authors' Reply. PMID- 26239783 TI - Considerations for Chondrolysis After Hip Arthroscopy. PMID- 26239784 TI - Magellan and Copernicus: Arthroscopy Association of North America Seeking Excellence in Education. PMID- 26239785 TI - Metric Development for an Arthroscopic Bankart Procedure: Assessment of Face and Content Validity. AB - PURPOSE: To establish the metrics (operational definitions) necessary to characterize a reference arthroscopic Bankart procedure, and to seek consensus from experienced shoulder arthroscopists on the appropriateness of the steps, as well as errors identified. METHODS: Three experienced arthroscopic shoulder surgeons and an experimental psychologist (comprising the Metrics Group) deconstructed an arthroscopic Bankart procedure. Fourteen full-length videos were analyzed to identify the essential steps and potential errors. Sentinel (i.e., more serious) errors were defined as either (1) potentially jeopardizing the procedure outcome or (2) creating iatrogenic damage to the shoulder. The metrics were stress tested for clarity and the ability to be scored in binary fashion during a video review as either occurring or not occurring. The metrics were subjected to analysis by a panel of 27 experienced arthroscopic shoulder surgeons to obtain face and content validity using a modified Delphi Panel methodology (consensus opinion of experienced surgeons rendered by cyclical deliberations). RESULTS: Forty-five steps and 13 phases characterizing an arthroscopic Bankart procedure were identified. Seventy-seven procedural errors were specified, with 20 designated as sentinel errors. The modified Delphi Panel deliberation created the following changes: 2 metrics were deleted, 1 was added, and 5 were modified. Consensus on the resulting Bankart metrics was obtained and face and content validity verified. CONCLUSIONS: This study confirms that a core group of experienced arthroscopic surgeons is able to perform task deconstruction of an arthroscopic Bankart repair and create unambiguous step and error definitions (metrics) that accurately characterize the essential components of the procedure. Analysis and revision by a larger panel of experienced arthroscopists were able to validate the Bankart metrics. CLINICAL RELEVANCE: The ability to perform task deconstruction and validate the resulting metrics will play a key role in improving surgical skills training and assessing trainee progression toward proficiency. PMID- 26239786 TI - Editorial Commentary: Arthroscopic Training and Proficiency Assessment Are Hot Topics. AB - Methods to measure operative skill are improving in quality. Arthroscopic surgical training and arthroscopic proficiency assessment are hot topics. PMID- 26239788 TI - The Winning Team. PMID- 26239787 TI - Editorial Commentary: "Arthroscop*". AB - Bibliometric analysis methods demonstrate that Arthroscopy: The Journal of Arthroscopic and Related Surgery is ranked number 1 among journals publishing arthroscopic and related research. PMID- 26239789 TI - What I Have Seen and Learned Since Looking Through an Arthroscope: 43 Years and Counting. PMID- 26239790 TI - Editorial Commentary: Biomechanical Data Does Not Translate to Clinical Rerupture Rates After Shoulder Rotator Cuff Repair Using Different Suture Techniques. AB - Biomechanical data does not translate to clinical re-rupture rates after shoulder rotator cuff repair using different suture techniques stratified by method of repair and tear size. Explanations include reporting and selection bias. PMID- 26239791 TI - Editorial Commentary: Ankle Anterior Impingement Is Common in Athletes and Could Be Under-Recognized. AB - Arthroscopic treatment of anterior ankle pain shows good results, with high patient satisfaction and low complication rates. Anterior pain with ankle hyperdorsiflexion, restriction of dorsiflexion, and swelling, particularly in a soccer player or ballet dancer, is a classic presentation. Ankle anterior impingement is common in athletes and could be under-recognized. PMID- 26239792 TI - Editorial Commentary: Smoking is Hazardous to Shoulder Health. AB - It is no controversy that smoking is hazardous to one's shoulder health. Arthroscopic shoulder surgery complications are common in patients with age greater than 60 years, COPD, cancer, and in cases where surgical time is greater than 90 minutes. PMID- 26239793 TI - Editorial Commentary: Effects of PRP on Cartilage Repair Using Scaffolds Are Inconclusive. AB - Effects of PRP on cartilage repair using scaffolds are, in the clinical setting, inconclusive. Biologics research is confounded by the variety and heterogeneity of stem cells, scaffolds, PRP preparations, other growth factors, and other biological stimulants. PMID- 26239794 TI - Correction: Iron-doping-enhanced photoelectrochemical water splitting performance of nanostructured WO3: a combined experimental and theoretical study. AB - Correction for 'Iron-doping-enhanced photoelectrochemical water splitting performance of nanostructured WO3: a combined experimental and theoretical study' by Teng Zhang et al., Nanoscale, 2015, 7, 2933-2940. PMID- 26239795 TI - Differential effect of the 17beta-aminoestrogens prolame, butolame and pentolame in anxiety and depression models in rats. AB - Estrogens of clinical use produce consistent antidepressant- and anxiolytic-like effects in animal models of menopause. Regulation of the hypothalamic-pituitary adrenal (HPA) or stress axis, has been proposed as a pathway through which estrogens improve affective-like behaviors. Anticoagulant 17beta-aminoestrogens (17beta-AEs) butolame and pentolame mimic some effects of estradiol (E2), i.e., on female rodent sexual behavior, with opposite actions on coagulation. However, their psychoactive actions have not been explored. On the basis of similitude with E2's effects, we hypothesized that these 17beta-AEs would induce anxiolytic- and antidepressant-like effects, which would be reflected in a reduction of activity in the HPA axis. In ovariectomized female rats, chronic treatment with prolame (60 MUg/kg), butolame (65 MUg/kg) and pentolame (70 MUg/kg) reduced anxiety-like behavior in the elevated plus maze (evidenced by an increase in time in open arms, E2 (40 MUg/kg) +176%; prolame +201%; butolame, +237%; and pentolame +295%, in comparison to the control vehicle group 100%). Pentolame also decreased significantly anxiety-like behavior in the burying behavior test. Prolame and E2 produced a significantly antidepressant-like action, which was not induced by butolame and pentolame. Behavioral effects of 17beta-AEs (and E2) on anxiety and depression did not follow the same pattern than corticosterone or E2 levels; they also were associated to changes in locomotor activity, evaluated by the open field test. These results constitute the first evidence of specific and selective actions of butolame and pentolame as anxiolytics for females with a hypoestrogenic condition. Results also confirm the potential of prolame as an antidepressant steroid with equivalent actions to E2. Psychoactive properties of 17beta-AEs in combinations with reduced adverse effects on coagulation, suggest that 17beta-AEs may be a good alternative replacement therapy for women with symptoms associated with menopause. PMID- 26239796 TI - An Update on Methods for Revascularization and Expansion of the TASC Lesion Classification to Include Below-the-Knee Arteries: A Supplement to the Inter Society Consensus for the Management of Peripheral Arterial Disease (TASC II). AB - The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) guidelines were last updated in 2007 (TASC II) and represented the collaboration of international vascular specialties involved in the management of patients with peripheral arterial disease (PAD). Since the publication of TASC II, there have been innovations in endovascular revascularization strategies for patients with PAD. The intent of this publication is to provide a complete anatomic lower limb TASC lesion classification, including the infrapopliteal segment, and an updated literature review of new endovascular techniques and practice patterns employed by vascular specialists today. PMID- 26239797 TI - Commentary: TASC II Anatomic Classification for Infrapopliteal Arterial Disease: A Framework for Clinical Practice and Future Research. PMID- 26239798 TI - Development and evaluation of PCR methods based on cytochrome c oxidase subunit one (cox1) and NADH dehydrogenase subunit one gene (nad1) to detect Opisthorchis viverrini in human fecal samples. AB - Opisthorchis viverrini is highly prevalent throughout Southeast Asia. Chronic infection of this parasite leads to cholangiocarcinoma (CCA), a fatal bile duct cancer. The early and accurate detection of this parasite is very important; therefore, new PCR methods targeting cytochrome c oxidase subunit one and NADH dehydrogenase subunit one gene to detect O. viverrini in fecal specimens have been developed. Ninety O. viverrini-positive human fecal samples were used in this study. The PCR sensitivity of both genes was compared with internal transcribe spacer 2 (ITS2)-PCR. The sensitivity of cox1-PCR and nad1-PCR was 66.7 and 50 %, respectively. The sensitivity of cox1-PCR and nad1-PCR achieved 89.1 and 71.7 % in specimens containing O. viverrini eggs of >100 eggs per gram (EPG). Additionally, these primers can be used to provide the information on genetic diversity from mitochondrial genes of O. viverrini. PMID- 26239799 TI - Morphological and molecular characterization of Henneguya bicaudi n. sp. (Myxosporea: Myxobolidae) infecting gills of Cirrhinus mrigala (Ham.) in Harike Wetland, Punjab (India). AB - In the present study, Henneguya bicaudi n. sp. infecting gills of Cirrhinus mrigala (Ham.) an Indian major carp from Harike Wetland in Punjab, India, has been described on the basis of myxospore morphology and partial amplification of the SSU rRNA gene. The pseudocysts of H. bicaudi n. sp. were located within the gill filament, whitish with round to irregular outer margin and 0.5-0.7 mm in diameter, 3-4 pseudocysts each containing about 50-100 myxospores were detected per gill. Mature myxospores were oblongate, 21.0 * 6.2 MUm had a caudal appendage bifurcating into two thin thread-like branches starting posterior to middle of its length. The two equal polar capsules were 3.14 * 2.02 MUm. The present species was compared morphologically with 21 species of the genus Henneguya infecting fresh water fishes in India and related geographical area. H. bicaudi n. sp. differed in having a peculiar oblongate shape and size of the myxospore, equal polar capsules, and also by the location of the point of bifurcation of the caudal appendage. 18S rDNA sequences of H. bicaudi n. sp. obtained revealed 96% homogeneity with H. pseudorhinogobi (Kageyama et al., Fish Sci 75:657-663, 2009) infecting gill filaments of Rhinogobius sp. (Rutter, PANS Philad 56-90, 1897) in Japan. The intensity of infection was determined by the gill pseudocyst index (GPI) based on the number of countable pseudocysts by stereo zoom trinocular microscopy per gill (on one side). PMID- 26239800 TI - Efficiency of liposomal albendazole for the treatment of the patients with complex alveolar echinococcosis: a comparative analysis of CEUS, CT, and PET/CT. AB - We aim to investigate the efficiency of liposomal albendazole (L-ABZ) for the treatment of complex alveolar echinococcosis (CAE) using contrast-enhanced ultrasonography (CEUS), computed tomography (CT), and positron emission tomography (PET)/CT. Twelve patients with CAE admitted to our hospital between June 2000 and June 2011 were included in this retrospective study. CEUS, CT, and PET/CT were used to evaluate the clinical efficiency of L-ABZ for these patients. Effectiveness was defined as significant response after chemotherapy. Effectiveness with clinical significance was defined as complete response after chemotherapy, and non-effectiveness was defined as no response after chemotherapy. Patients were followed up for 3-11 years. Ten patients (83.3%) had a ratio of averaged gray scale in the enhanced band to that of hepatic tissues of <=1.1, and six patients (50.0%) had a ratio of <=0.9 as revealed by CEUS. CT scanning results indicated an effective rate of 91.6%. PET/CT indicated a maximal standard uptake (SUVmax) of <2.5 in nine patients (75.0%), which was considered to be effective. A high uptake of fluorodeoxyglucose was observed in three patients (25.0%) with SUVmax >=2.5, which was considered to be non-effective. Taken together, CEUS, CT, and PET/CT provide objective evaluation of the clinical efficiency of L-ABZ for the treatment of CAE. PMID- 26239801 TI - Plant-borne ovicides in the fight against mosquito vectors of medical and veterinary importance: a systematic review. AB - Mosquitoes (Diptera: Culicidae) are a huge threat for millions of people worldwide, since they act as vectors for devastating parasites and pathogens. Culicidae control is of crucial importance. Mosquito eggs, larvae, and pupae are usually targeted using organophosphates, insect growth regulators, and microbial agents. Indoor residual spraying and insecticide-treated bed nets are also employed. However, these chemicals have negative effects on human health and the environment, and induce resistance in a number of species. Eco-friendly tools have been recently implemented against mosquito vectors, including botanical insecticides. The majority of researches focused on larvicides (745 SCOPUS results, July 2015) and adult repellents (434 SCOPUS results), while limited efforts were conducted to identify effective ovicides of botanical origin (59 SCOPUS results). Here, I review current knowledge on the effectiveness of plant borne ovicides against major mosquito vectors of medical and veterinary importance. The majority of researches focused on the toxicity of crude extracts, their fractions, or essential oils against three important mosquito vectors, Anopheles stephensi, Aedes aegypti, and Culex quinquefasciatus. As a general trend, C. quinquefasciatus eggs were the most resistant to botanical ovicides. Five studies proposed selected compounds from plant extracts and essential oils as ovicides effective at few parts per million. However, no efforts were conducted to shed light on possible mechanisms underlying the toxicity of plant borne ovicides. In the final section, a number of hot issues needing further research and cooperation among parasitologists, entomologists, and researchers working in natural product chemistry are outlined. PMID- 26239802 TI - Meclizine, a pregnane X receptor agonist, is a direct inhibitor and mechanism based inactivator of human cytochrome P450 3A. AB - Meclizine is an agonist of human pregnane X receptor (PXR). It increases CYP3A4 mRNA expression, but decreases CYP3A-catalyzed testosterone 6beta-hydroxylation in primary cultures of human hepatocytes, as assessed at 24h after the last dose of meclizine. Therefore, the hypothesis to be tested is that meclizine inactivates human CYP3A enzymes. Our findings indicated that meclizine directly inhibited testosterone 6beta-hydroxylation catalyzed by human liver microsomes, recombinant CYP3A4, and recombinant CYP3A5. The inhibition of human liver microsomal testosterone 6beta-hydroxylation by meclizine occurred by a mixed mode and with an apparent Ki of 31+/-6MUM. Preincubation of meclizine with human liver microsomes and NADPH resulted in a time- and concentration-dependent decrease in testosterone 6beta-hydroxylation. The extent of inactivation required the presence of NADPH, was unaffected by nucleophilic trapping agents or reactive oxygen species scavengers, attenuated by a CYP3A substrate, and not reversed by dialysis. Meclizine selectively inactivated CYP3A4, but not CYP3A5. In contrast to meclizine, which has a di-substituted piperazine ring, norchlorcyclizine, which is a N-debenzylated meclizine metabolite with a mono-substituted piperazine ring, did not inactivate but directly inhibited hepatic microsomal CYP3A activity. In conclusion, meclizine inhibited human CYP3A enzymes by both direct inhibition and mechanism-based inactivation. In contrast, norchlorcyclizine is a direct inhibitor but not a mechanism-based inactivator. Furthermore, a PXR agonist may also be an inhibitor of a PXR-regulated enzyme, thereby giving rise to opposing effects on the functional activity of the enzyme and indicating the importance of measuring the catalytic activity of nuclear receptor-regulated enzymes. PMID- 26239803 TI - Characterization of native PfABCG protein in Plasmodium falciparum. AB - The Plasmodium falciparum genome encodes 16 members of ABC proteins, with one member of the ABCG subfamily (PfABCG). Analysis of PfABCG amino acid sequence shows equal sequence identity to hsABCG1 and G2. Using N-terminal directed antibody against a recombinant fragment of PfABCG, we show that PfABCG migrates with an apparent molecular mass of 65KDa polypeptide on SDS-PAGE. PfABCG is expressed in all four stages of the parasite erythrocytic life cycle, with lower and higher expression in ring and late trophozoite stages, respectively. The protein localizes to the plasma membrane and a novel spherical structure beneath the cell membrane. Similar localization is also observed in gametocytes where PfABCG is highly expressed. Analysis of PfABCG genomic sequences for polymorphisms and changes in protein expression between different strains of P. falciparum revealed identical nucleotide sequence among the different strains, but variable protein expression. PfABCG expression is least in HB3 chloroquine sensitive strain, while higher expression levels are seen in other chloroquine sensitive and -resistant strains, with highest levels of expression in 7G8. The differential expression of PfABCG in three chloroquine-sensitive strains (e.g., 3D7, HB3 and D10) predicts the sensitivity of the different strains to ketotifen, an anti-histaminic drug, whereby low expression is associated with decreased sensitivity to ketotifen. Taken together, the results in this report provide the first description of native PfABCG expression and subcellular localization in asexual stages of the parasite and its localization in gametocytes. It remains to be determined if PfABCG is functionally equivalent to mammalian ABCG1, ABCG2 or both. PMID- 26239804 TI - Unknown unknowns in biomedical research: does an inability to deal with ambiguity contribute to issues of irreproducibility? AB - The credibility and consequent sustainability of the biomedical research "ecosystem" is in jeopardy, in part due to an inability to reproduce data from the peer-reviewed literature. Despite obvious and relatively inexpensive solutions to improve reproducibility-ensuring that experimental reagents, specifically cancer cell lines and antibodies, are authenticated/validated before use and that best practices in statistical usage are incorporated into the design, analysis, and reporting of experiments-these are routinely ignored, a reflection of hubris and a comfort with the status quo on the part of many investigators. New guidelines for the peer review of publications and grant applications introduced in the past year, while well-intended, lack the necessary consequences, e.g., denial of funding, that would result in sustained improvements when scientific rigor is lacking and/or transparency is, at best, opaque. An additional factor contributing to irreproducibility is a reductionist mindset that prioritizes certainty in research outcomes over the ambiguity intrinsic to biological systems that is often reflected in "unknown unknowns". This has resulted in a tendency towards codifying "rules" that can provide "yes no" outcomes that represent a poor substitute for the intellectual challenge and skepticism that leads to an awareness and consideration of "unknown unknowns". When acknowledged as potential causes of unexpected experimental outcomes, these can often transition into the "knowns" that facilitate positive, disruptive innovation in biomedical research like the human microbiome. Changes in investigator mindset, both in terms of validating reagents and embracing ambiguity, are necessary to aid in reducing issues with reproducibility. PMID- 26239805 TI - Low molecular weight heparin tinzaparin antagonizes cisplatin resistance of ovarian cancer cells. AB - Low molecular weight heparin (LMWH) is routinely used for antithrombotic treatment of cancer patients. Preclinical- and clinical data suggest that LMWH has beneficial effects for cancer patients beyond the prevention of thrombosis, i.e. by inhibiting metastasis. It is, however, unclear whether heparin has an impact on the efficiency of chemotherapy in cancer patients. Here we show that a therapeutic dosage of LMWH tinzaparin reverses cisplatin resistance of A2780cis human ovarian cancer cells to the level of sensitive cells. This novel activity of tinzaparin is associated with intense transcriptional reprogramming. Our gene expression profiling experiments revealed that 3776 genes responded to tinzaparin treatment. For this reason tinzaparin has a complex impact on diverse biological processes. We discovered that tinzaparin inhibits the expression of genes that mediate cisplatin resistance of A2780cis cells. In contrast tinzaparin induced the expression of genes that antagonize drug resistance. This activity of tinzaparin is mediated by cell surface proteoglycans, since enzymatic cleavage of heparan sulfates prevented the reversal of cisplatin resistance. These data indicate that cell surface heparan sulfate proteoglycans play an important role for chemotherapy resistance. The results of this study shed a new light on LMWH application in cancer therapy and suggest tinzaparin as promising treatment option of ovarian cancer patients in combination with anticancer drugs. Future clinical trials are needed to validate these findings. PMID- 26239806 TI - miR-485-5p inhibits bladder cancer metastasis by targeting HMGA2. AB - MicroRNA (miRNA or miR)-485 is a functional miRNA which has received much attention in recent years. However, little is known about the expression of miR 485 or the role it plays in bladder cancer [namely in metastasis and epithelial mesenchymal transition (EMT)]. Thus, in the present study, we aimed to detect the expression of miR-485 in human bladder cancer tissues and bladder cancer cell lines, and to examine the effects of miR-485-5p on bladder cancer cell metastasis and EMT. We found that the expression of miR-485-5p was downregulated in the human bladder cancer tissues and different bladder cancer cell lines compared with the normal tissues and cell lines, as demonstrated by reverse transcription quantitative polymerase chain reaction (RT-qPCR). We enforced the expression of miR-485-5p in T24 cells and inhibited the expression of miR-485-5p in SW780 cells by transfection with miR-485-5p mimic or miR-485-5p inhibitor, respectively. The ectopic expression of miR-485-5p was shown to inhibit cell metastasis and EMT, whereas the inhibition of miR-485-5p expression promoted cell metastasis and EMT, as shown by transwell-matrigel assay, cell adhesion assay and western blot analysis. Furthermore, a luciferase reporter assay revealed that high mobility group AT-hook 2 (HMGA2) was a direct target of miR-485-5p and that the overexpression of HMGA2 reversed the effects of miR-485-5p on cell metastasis and EMT. In conclusion and to the very best of our knowledge, the present study, for the first time, identified miR-485-5p as a suppressive miRNA in human bladder cancer, and demonstrated that miR-485-5p inhibits cell metastasis and EMT at least partly through the suppression of HMGA2 expression. PMID- 26239807 TI - Genome-wide hydroxymethylcytosine pattern changes in response to oxidative stress. AB - The TET enzymes convert methylcytosine to the newly discovered base hydroxymethylcytosine. While recent reports suggest that TETs may play a role in response to oxidative stress, this role remains uncertain, and results lack in vivo models. Here we show a global decrease of hydroxymethylcytosine in cells treated with buthionine sulfoximine, and in mice depleted for the major antioxidant enzymes GPx1 and 2. Furthermore, genome-wide profiling revealed differentially hydroxymethylated regions in coding genes, and intriguingly in microRNA genes, both involved in response to oxidative stress. These results thus suggest a profound effect of in vivo oxidative stress on the global hydroxymethylome. PMID- 26239808 TI - Broadband Epsilon-Near-Zero Perfect Absorption in the Near-Infrared. AB - Perfect absorption (PA) of incident light is important for both fundamental light matter interaction studies and practical device applications. PA studies so far have mainly used resonant nanostructures that require delicate structural patterning. Here, we realize tunable and broadband PA in the near-infrared region using relatively simple thin film coatings. We adjust the growth condition of an ITO film and control its epsilon-near-zero (ENZ) wavelength. We show that this results in highly tunable PA in the telecommunication window. Then, using an ITO multilayer of different ENZ wavelengths, we demonstrate broadband PA that covers a wide range of near-infrared wavelengths. The use of ENZ coatings makes PA adjustable during the film growth and does not require any structural patterning afterward. It also facilitates the chip-scale integration of perfect absorbers with other device components. Broadband PA relaxes the single wavelength condition in previous PA studies, and thus it is suitable for many practical device applications, including sensors, photodetectors, and energy harvesting devices. PMID- 26239809 TI - Strain imaging to detect cancer therapeutics-related cardiac dysfunction: are we there yet? PMID- 26239810 TI - Effects of glucomannan/spirulina-surimi on liver oxidation and inflammation in Zucker rats fed atherogenic diets. AB - Cholesterolemia is associated with pro-oxidative and proinflammatory effects. Glucomannan- or glucomannan plus spirulina-enriched surimis were included in cholesterol-enriched high-saturated diets to test the effects on lipemia; antioxidant status (glutathione status, and antioxidant enzymatic levels, expressions and activities); and inflammation biomarkers (endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-alpha)) in Zucker fa/fa rats. Groups of eight rats each received diet containing squid-surimi (C), squid-surimi cholesterol-enriched diet (HC), glucomannan-squid-surimi cholesterol-enriched diet (HG), or glucomannan spirulina-squid-surimi cholesterol-enriched diet (HGS) over a period of 7 weeks. HC diet induced severe hyperlipemia, hepatomegalia, increased inflammation markers, and impaired antioxidant status significantly (at least p < 0.05) vs. C diet. HG diet decreased lipemia and liver size and normalized antioxidant status to C group levels, but increased TNF-alpha with respect to HC diet (p < 0.05). In general terms, 3 g/kg of spirulina in diet maintained the positive results observed in the HG diet but, in addition, increased inflammation index [eNOS/(eNOS + iNOS)] and decreased plasma TNF-alpha (both p < 0.05). In conclusion, glucomannan plus a small amount of spirulina blocks negative effects promoted by hypercholesterolemic diets. Although more studies are needed, present results suggest the utility of including glucomannan and/or spirulina as functional ingredients into fish derivates to be consumed by people on metabolic syndrome risk. PMID- 26239811 TI - Translational research has come of age and colorectal surgeons need to claim their part. PMID- 26239816 TI - Data supporting updating estimates of the prevalence of chronic hepatitis B and C in the United States. PMID- 26239817 TI - The genomic birthday paradox: how much is enough? AB - Genomic matchmaking databases (GMDs) allow participants to submit genomic and phenotypic data with the goal of identifying previously uncharacterized disease associated genes by "matching" to other comparable cases. Current estimates suggest that there are at least 3,000 Mendelian disease-associated genes that have not yet been characterized as such, but the true number may be substantially higher. Therefore, GMDs are addressing a pressing medical need, and it is important to ask how they should be designed and how much data they should strive to contain in order to identify a certain number of these genes. In this work, we argue that genomic matchmaking has similarities to the so-called "birthday paradox," which refers to the observation that within a group of just 23 persons, two people will have the same birthday with probability greater than 50%. We develop a series of simulations to provide a rough estimate of the number of cases required and to explore the influence of parameters such as genetic heterogeneity, mode of inheritance, background variation, precision of phenotypic descriptions, disease prevalence, and the accuracy of bioinformatics pathogenicity prediction programs on the performance of genomic matchmaking. PMID- 26239819 TI - Osmotic Virial Coefficients as Access to the Protein Partitioning in Aqueous Two Phase Systems. AB - A promising alternative to state of the art chromatographic separations of therapeutic proteins is the extraction of the target protein using an aqueous two phase system (ATPS). The use of an additional salt working as a displacement agent can influence the protein partitioning behavior in ATPS and thus enable a selective purification of the target protein. The selection of a suitable ATPS for protein extraction requires information concerning the protein-protein interactions (second osmotic virial coefficient B22 ) as well as the interactions between protein and solute (displacement agent and phase-forming components) (cross virial coefficient B23 ). In this work, the partitioning behavior and the precipitation affinity of immunoglobulin G (IgG) is considered within a polyethylene glycol (PEG)-phosphate ATPS. The influence on IgG partitioning upon addition of NaCl and (NH4)2 SO4 was investigated. In order to access the IgG precipitation affinity and the IgG partitioning behavior, the B22 and B23 values were determined for several combinations of solute [PEG, phosphate buffer, NaCl, and (NH4)2 SO4 ] and IgG based on static light scattering measurements. A qualitative estimation of the IgG precipitation affinity and the suitability of a solute as potential displacement agent within the PEG-phosphate ATPS on the basis of the measured B22 and B23 values is presented. PMID- 26239818 TI - Retinal ganglion cell neuroprotection induced by activation of alpha7 nicotinic acetylcholine receptors. AB - The alpha7nAChR agonist, PNU-282987, has previously been shown to have a neuroprotective effect against loss of retinal ganglion cells (RGCs) in an in vivo glaucoma model when the agent was injected into the vitreous chamber of adult Long Evans rat eyes. Here, we characterized the neuroprotective effect of PNU-282987 at the nerve fiber and retinal ganglion cell layer, determined that neuroprotection occurred when the agonist was applied as eye drops and verified detection of the agonist in the retina, using LC/MS/MS. To induce glaucoma-like conditions in adult Long Evans rats, hypertonic saline was injected into the episcleral veins to induce scar tissue and increase intraocular pressure. Within one month, this procedure produced significant loss of RGCs compared to untreated conditions. RGCs were quantified after immunostaining with an antibody against Thy 1.1 and imaged using a confocal microscope. In dose-response studies, concentrations of PNU-282987 were applied to the animal's right eye two times each day, while the left eye acted as an internal control. Eye drops of PNU 282987 resulted in neuroprotection against RGC loss in a dose-dependent manner using concentrations between 100 MUM and 2 mM PNU-282987. LC/MS/MS results demonstrated that PNU-282987 was detected in the retina when applied as eye drops, relatively small amounts of PNU-282987 were measured in blood plasma and no PNU-282987 was detected in cardiac tissue. These results support the hypothesis that eye drop application of PNU-282987 can prevent loss of RGCs associated with glaucoma, which can lead to neuroprotective treatments for diseases that involve alpha7nAChRs. PMID- 26239820 TI - Identification of embryonic stem cell activities in an embryonic cell line derived from marine medaka (Oryzias dancena). AB - This study was conducted to identify embryonic stem cell (ESC) activities of a long-term cultured embryonic cell line previously derived from blastula-stage Oryzias dancena embryos. Five sub-cell lines were established from the embryonic cell line via clonal expansion of single cells. ESC activities, including clonogenicity, alkaline phosphatase (AP) activity, and differentiation capacity, were examined in the five sub-cell lines. We observed both clonogenicity and AP activity in all five sub-cell lines, but the proportion of cells that exhibited both properties was significantly different among them. Even though we detected different formation rates and sizes of embryoid body (EB) among these cells, all lines were stably able to form EBs and further induction for differentiation showed their capability to differentiate into other cell types in a spontaneous manner. From this study, we determined that the embryonic cell lines examined possessed heterogeneous ESC activities and can be utilized as a marine model system for fish ESC-based research. PMID- 26239821 TI - Cytotoxicity and apoptosis induction by e-cigarette fluids in human gingival fibroblasts. AB - OBJECTIVES: Electronic cigarettes (e-cigarettes) are generally acknowledged as a safer alternative to the use of combusted tobacco products. Nevertheless, there are increasing conflicting claims concerning the effect of these novel industrial products on the health of e-cigarettes users. The aim of this work was to investigate the effects of the liquids of e-cigarettes on human gingival fibroblasts (HGFs) and to compare the effects of nicotine-containing fluid to the fluid itself. MATERIALS AND METHODS: HGFs were treated with different concentrations (0-5 mg/mL) of fluids of e-cigarettes for different times (0-72 h) and cytotoxicity was analyzed by MTT assay. Fluids were administered also after being vaped (e.g., warmed into the cartomizer). Apoptosis occurrence and Bax expression were evaluated by flow cytometry; ROS production was analyzed by fluorescence optical microscopy. RESULTS: Both nicotine-containing and nicotine free fluids induced an increased ROS production after 24 h, along with an increased Bax expression, followed by apoptosis occurrence after 48 h of exposure. CONCLUSIONS: The cytotoxicity exerted on HGFs by e-cigarettes fluids is not entirely ascribable to nicotine. Since the e-cigarettes are advertised as a safer alternative to traditional ones, especially for the possibility of "smoking" nicotine-free fluids, further studies are necessary to clarify the mechanism involved in the occurrence of cytotoxicity exerted by such compounds. CLINICAL RELEVANCE: Our results suggest a role for e-cigarette fluids in the pathogenesis of oral diseases, such as periodontitis. PMID- 26239823 TI - Paced QRS predictors of left ventricular lead location and prognosis. PMID- 26239822 TI - Low expression of DLC1 is predictive of poor therapeutic efficiency of fluoropyrimidine and oxaliplatin as adjuvant chemotherapy in gastric cancer. AB - The Rho-GTPase-activating protein, deleted in liver cancer-1 (DLC1), has been reported to be a tumor suppressor. However, the prognostic value of DLC1 in gastric cancer (GC) remains to be fully elucidated. Fluoropyrimidine-oxaliplatin (FP-LOHP) combination therapy has been widely used for the adjuvant chemotherapy of GC, however, no reliable marker has been identified to determine its efficiency. Thus, the present study performed a retrospective investigation involving 251 patients with stage IB-III GC, who received adjuvant chemotherapy following radical resection and 37 patients with stage IV GC, who underwent palliative resection. The expression of DLC1 was found to be reduced in the majority of GC samples (212/288 pairs of samples), compared with normal mucosa, in immunohistochemical analyses. Lower expression levels of DLC1 indicated a more advanced tumor-node-metastasis stage, increased lymph node metastasis, deeper tumor invasion, increased tumor size and a higher rate of distant metastasis. By contrast, relatively increased expression levels of DLC1 indicated a longer time to recurrence (TTR) [hazard ratio (HR), 2.232; P=0.004] and overall survival (OS) rate (HR, 2.910; P=0.001). Patients receiving FP-LOHP adjuvant chemotherapy were significantly less likely to suffer GC recurrence (P=0.001) and succumb to mortality (P=0.004), compared with those who received alternative chemotherapies. However, only the patients with DLC1-positive GC receiving FP-LOHP [DLC1 (+)/FP LOHP (+)] exhibited a more favorable TTR and OS, compared with the patients with DLC1 (+)/FP-LOHP (-) (TTR, P=0.001; OS, P=0.020). No significant improvement in clinical outcome was observed in GC patients with low DLC1 receiving FP-LOHP treatment (TTR, P=0.270; OS, P=0.197). In conclusion, low expression of DLC1 correlated with GC progression and is predictive of higher rates of recurrence and mortality. Only patients with DLC1-positive GC may have an improved treatment outcome from the use of FP-LOHP as adjuvant chemotherapy. PMID- 26239824 TI - Hepatocytes in liver injury: Victim, bystander, or accomplice in progressive fibrosis? AB - Chronic liver disease causes significant morbidity and mortality through progressive fibrosis, cirrhosis, and liver cancer. The classical theory of fibrogenesis has hepatic stellate cells (HSCs) as the principal and only significant source of abnormal extracellular matrix (ECM). Further, HSCs have the major role in abnormal ECM turnover. It is the death of hepatocytes, as the initial target of injury, that initiates a sequence of events including the recruitment of inflammatory cells and activation of HSCs. Following this initial response, the ongoing insult to hepatocytes is regarded as perpetuating injury, but otherwise, hepatocytes are regarded as "victims" and "bystanders" in progressive fibrosis. Recent developments, however, challenge this view and suggest the concept of the hepatocyte being an active participant in liver injury. It is clear now that hepatocytes undergo phenotypic changes, adapt to injury, and react to the altered microenvironment. In this review, we describe studies showing that hepatocytes contribute to progressive fibrosis by direct manipulation of the surrounding ECM and through signaling to effector cells, particularly HSCs and intrahepatic immune cells. Together, these findings suggest an active "accomplice" role for the hepatocyte in progressive liver fibrosis and highlight novel pathways that could be targeted for development of future anti fibrotic therapies. PMID- 26239826 TI - Application of recombinant severe fever with thrombocytopenia syndrome virus nucleocapsid protein for the detection of SFTSV-specific human IgG and IgM antibodies by indirect ELISA. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging disease that was first reported in China in 2011. It is caused by SFTS virus (SFTSV) which is a member of the Phlebovirus genus in the Bunyaviridae family. SFTSV has been classified as a BSL3 pathogen. There is a need to develop safe and affordable serodiagnostic methods for proper clinical management of infected patients. METHODS: The full length nucleocapsid (N) gene of SFTSV Yamaguchi strain was amplified by RT-PCR and cloned to an expression vector pQE30. The recombinant (r) SFTSV-N protein was expressed by using Escherichia coli (E. coli) expression system and purified under native conditions. rSFTSV-N protein based indirect IgG and IgM enzyme linked immunosorbent assay (ELISA) systems were established to detect specific human IgG and IgM antibodies, respectively. One hundred fifteen serum samples from clinically suspected-SFTS patients were used to evaluate the newly established systems and the results were compared with the total antibody detecting sandwich ELISA system. RESULTS: The native form of recombinant (r) SFTSV-N protein was expressed and purified. Application of the rSFTSV-N protein based indirect IgG ELISA to the 115 serum samples showed results that perfectly matched those of the total antibody sandwich ELISA with a sensitivity and specificity of 100 %. The rSFTSV-N protein based indirect IgM ELISA missed 8 positive samples that were detected by the total antibody sandwich ELISA. The sensitivity and specificity of rSFTSV-N-IgM capture ELISA were 90.59 and 100 %, respectively. CONCLUSIONS: The rSFTSV-N protein is highly immunoreactive and a good target for use as an assay antigen in laboratory diagnosis. Its preparation is simpler in comparison with that used for the total antibody sandwich system. Our rSFTSV-N protein-based IgG and IgM ELISA systems have the advantage of distinguishing two types of antibodies and require small volume of serum sample only. They are safe to use for diagnosis of SFTS virus infection and especially fit in large-scale epidemiological investigations. PMID- 26239829 TI - Development of a valid simplified Chinese version of the Osteoarthritis of Knee and Hip Quality of Life (OAKHQOL) in patients with knee or hip osteoarthritis. AB - RATIONALE, AIMS AND OBJECTIVES: As the first specific questionnaire for knee or hip osteoarthritis (OA) patients' condition assessment, the Osteoarthritis of Knee and Hip Quality of Life (OAKHQOL) questionnaire is widely used and its original version is French. Although it has already been translated into multiple languages, a Chinese version is still unpublished, despite the fact that China has the largest population of OA patients in the world. The objectives of our study were to adapt the OAKHQOL questionnaire into simplified Chinese and to assess its psychometric properties in Chinese patients with knee or hip OA. METHODS: First, we developed the simplified Chinese version of OAKHQOL (SC OAKHOQL) in a five-step procedure of translation and cross-cultural adaptation. Next, we calculated the Cronbach's alpha, intraclass correlation coefficient (ICC), Pearson's correlation coefficient (r), effect size (ES) and standardized response mean (SRM) to evaluate the reliability, validity and responsiveness of the SC-OAKHQOL, respectively. Unidimensionality of subscales was assessed by the principal component analysis (PCA) of residuals. RESULTS: Overall, 144 knee or hip OA patients successfully completed all of the questionnaires. Excellent or good internal consistency (alpha = 0.826-0.964) was found in the SC-OAKHQOL, as well as excellent test-retest reliability (ICC = 0.888-0.944). Good correlations were also obtained among physical subscales (r = 0.646-0.934), as well as mental subscales (r = 0.786-0.874) in the SC-OAKHQOL and other questionnaires, on which excellent or good validity of the SC-OAKHQOL shall be based. With the exception of the social support subscale, all others contained excellent or good responsiveness (ES, SRM = 1.02-2.92). The unidimensionality of five subscales was respected according to the PCA of residuals. CONCLUSION: The SC-OAKHQOL questionnaire is reliable, valid and responsive for the evaluation of Chinese osteoarthritis patients of the knee or hip, and it would be an effective instrument. PMID- 26239827 TI - Neuropathic Pain due to Small Fiber Neuropathy in Aging: Current Management and Future Prospects. AB - Over the last 10 years, the diagnosis small fiber neuropathy (SFN) has gained recognition worldwide. Patients often suffer from severe neuropathic pain that may be difficult to treat. A substantial subset of patients with SFN is aged 65 years or older, and these patients often exhibit comorbidities and usage of multiple drugs, making neuropathic pain treatment more challenging. In this review, we highlight relevant pathophysiological aspects and discuss currently used therapeutic strategies for neuropathic pain. Possible pitfalls in neuropathic pain treatment in the elderly will be underlined. PMID- 26239828 TI - Giant Cell Arteritis: Beyond Corticosteroids. AB - Giant cell arteritis (GCA) is a large-vessel vasculitis predominantly affecting older people, with a peak incidence between 70 and 79 years of age. If untreated, ischaemic complications can be catastrophic for the patient, including blindness. We review the current treatment paradigms for this condition, the mainstay of which is immediate high-dose glucocorticoid therapy with a gradual dose tapering. Adverse events of glucocorticoid therapy are often observed after 12-24 months and corticosteroid-sparing adjuvant therapies are used in severe disease, multiple flares or patients at high risk of prolonged therapy. The current understanding of the pathogenesis of GCA is explored. This has informed the identification of new potential targets and approaches to treatment. Blockade of interleukin (IL)-6 (tocilizumab) and IL-1 (gevokizumab) are being evaluated in phase III clinical trials. It is hoped that improved risk stratification of organ damage and relapses will be developed using imaging and biomarkers, allowing for individualised treatment for patients; however, there remains further work to be done before this becomes a reality. PMID- 26239830 TI - Transfer hydrogenation promoted by N-heterocyclic carbene and water. AB - N-Heterocyclic carbenes (NHCs) promote the transfer hydrogenation of various activated C=C, C=N, and N=N bonds with water as the proton source. The NHCs act as reducing reagents to be converted into their oxides. A detailed reaction mechanism is proposed on the basis of deuterium-labeling experiments. PMID- 26239831 TI - A high-protein breakfast prevents body fat gain, through reductions in daily intake and hunger, in "Breakfast skipping" adolescents. AB - OBJECTIVE: The purpose of this study was to examine whether the daily consumption of normal-protein (NP) vs. high-protein (HP) breakfast meals improves appetite control, food intake, and body composition in "breakfast skipping" young people with overweight/obesity. METHODS: Fifty-seven adolescents (age: 19 +/- 1 years; BMI: 29.7 +/- 4.6 kg m(-2)) completed a 12-week randomized controlled trial in which the adolescents consumed either a 1,464 kJ NP breakfast (13 g protein) or a HP breakfast (35 g protein) or continued to skip breakfast (CON). Pre- and post study appetite, food intake, body weight, and body composition were assessed. RESULTS: Time-by-group interactions (P < 0.05) were detected for body fat mass, daily intake, and perceived hunger. Specifically, HP prevented fat mass gains over the 12 weeks (-0.4 +/- 0.5 kg) vs. CON (+1.6 +/- 0.9 kg; P = 0.02), whereas NP did not (+0.3 +/- 0.5 kg). HP led to reductions in daily intake (-1,724 +/- 954 kJ) vs. CON (+1,556 +/- 745 kJ; P = 0.03), whereas NP did not (+494 +/- 213 kJ). Lastly, only the HP group experienced reductions in daily hunger vs. CON (P < 0.05). However, when directly comparing the HP vs. NP groups, no differences were detected in any outcomes. CONCLUSIONS: The daily addition of a HP breakfast improved indices of weight management as illustrated by the prevention of body fat gain, voluntary reductions in daily intake, and reductions in daily hunger in breakfast skipping adolescents with overweight/obesity. PMID- 26239832 TI - Effects of dietary resveratrol on excess-iron-induced bone loss via antioxidative character. AB - Estrogen deficiency has been considered to be a major cause of osteoporosis, but recent epidemiological evidence and mechanistic studies have indicated that aging and the associated increase in reactive oxygen species (ROS) are the proximal pathogenic factors. Through ROS-mediated reactions, iron can induce disequilibrium of oxidation and antioxidation and can cause bone loss in mice. Therefore, we investigated the effects of resveratrol (RES) on bone mineral density, bone microstructure and the osteoblast functions under iron-overload conditions. Excess iron disrupted the antioxidant/prooxidant equilibrium of the mice and induced the defect and the lesion of the bone trabecula as well as disequilibrium between bone formation and bone resorption in iron-overload mice. Oral administration of RES significantly prevented bone loss in the osteoporotic mice. RES reversed the reduction of Runx2, OCN and type I collagen from excess iron; up-regulated the level of FOXO1; and maintained the antioxidant/prooxidant equilibrium in the mice. RES also reduced the ratio of OPG/RANKL in MC3T3-E1 cells and in mice and significantly inhibited subsequent osteoclastogenesis. These results provide new insights into the antiosteoporosis mechanisms of RES through antioxidative effects, suggesting that RES can be considered a potential natural resource for developing medicines or dietary supplements to prevent and treat osteoporosis. PMID- 26239833 TI - Gaseous pollutants on rural and urban nursery schools in Northern Portugal. AB - Indoor air quality in nursery schools is different from other schools and this has been largely ignored, particularly in rural areas. Urban and rural nursery schools have different environmental characteristics whose knowledge needs improvement. Thus, this study aimed to evaluate continuously the concentrations of CO2, CO, NO2, O3, CH2O and total VOC in three rural nursery schools and one urban, being the only one comparing urban and rural nurseries with continuous measurements, thus considering occupation and non-occupation periods. Regarding CO2, urban nursery recorded higher concentrations (739-2328 mg m(-3)) than rural nurseries (653-1078 mg m(-3)). The influence of outdoor air was the main source of CO, NO2 and O3 indoor concentrations. CO and NO2 concentrations were higher in the urban nursery and O3 concentrations were higher in rural ones. CH2O and TVOC concentrations seemed to be related to internal sources, such as furniture and flooring finishing and cleaning products. PMID- 26239834 TI - Roles of heat shock factor 1 in isoproterenol-induced myocardial fibrosis in mice. AB - Although it is well known that isoproterenol (ISO) causes myocardial hypertrophy and myocardial fibrosis in rats, it has remained elusive whether heat shock factor 1 (HSF1) has a role in this process. The present study aimed to investigate the possible roles of HSF1 in ISO-induced fibrosis in mice. It was found that after administration of ISO in Kunming and HSF1-/+ mice, there was a large number of fibers deposited around blood vessels and among cardiocytes, accompanied with an obvious increase in the protein expressions of type I or III collagen and heat shock protein 47 (HSP47), as indicated by western blot analysis. After intervention with insulin-like growth factor 1 (IGF-1), myocardial fibrosis was significantly attenuated, with a paralleled decrease in the expression of collagen and HSP47 in the mice. However, in HSF1-/- mice, fiber hyperplasy was not observed after injection of ISO, and the levels of type I or III collagen and HSP47 were not significantly increased at the protein and mRNA level. Furthermore, it was demonstrated that after subcutaneous injection of ISO into the back of Kunming and HSF1-/+ mice, large amounts of HSF1 protein were localized to the nucleus, and there was an increase in phosphorylated HSF1 as indicated by western blot and immunohistochemical analysis, respectively. Intervention with IGF-1 inhibited HSF1 activation mediated by ISO. These results suggested that HSF1 is required for myocardial fibrosis in ISO-treated mice, and the underlying molecular mechanism may involve the regulation of HSP47. PMID- 26239835 TI - FoxO1 Inhibitors: The Future Medicine for Metabolic Disorders? AB - FoxO1, one of the most widely expressed sub-families of the winged helix forkhead factors, is biologically 'omni-functional' owing to its far-flung roles in metabolism, cell cycle, tissue differentiation and development and oxidative stress response. The knowledge of involvement of FoxO1 in metabolic disorders has long been there, but the potential target remained underutilized due to unavailability of specific and potent inhibitors. The review provides an insight into the role of FoxO1 in orchestrating metabolic diseases' pathogenesis (including diabetes, its secondary complications and obesity) and compiles the literature on FoxO1 inhibitors. The emergence of various natural molecules and synthesized small molecules like AS1842856 as FoxO1 inhibitors urges us to think further and decide the future course of drug development for the management of metabolic disorders. PMID- 26239836 TI - Subpath analysis of each subtype of head and neck cancer based on the regulatory relationship between miRNAs and biological pathways. AB - The aim of the present study was to explore the potential mechanisms involved in each subtype of head and neck squamous cell carcinoma (HNSCC) via subpath analysis and to investigate their relevance in the prevention of HNSCC. Gene expression profiles of GSE6631 and GSE39366 containing 44 and 168 HNSCC samples, respectively, were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) from samples in GSE6631 and GSE393666 were screened using the Detection of Imbalanced Differential Signal (DIDS) method respectively. DEGs in GSE39366 were matched with the DEGs in GSE6631 and were used to classify the subtypes of HNSCC based on hierarchical clustering analysis. Furthermore, DEGs were separated into different subtypes and then the pathway information was analyzed. The regulated miRNAs for the DEGs in each subtype were analyzed to select the significant subpaths. Totally, 1,095 DEGs from GSE6631 and 2,528 DEGs from GSE39366 were screened. Samples in GSE39366 were separated into four subtypes. Specific genes in each subtype and DEGs in the common gene set involved in a variety of pathways were identified. In addition, the significant miRNA-target-pathway subpath of each subtype of HNSCC and the common gene set of HNSCC were also enriched. Our data suggest that human papillomavirus (HPV) is positively correlated with HNSCC in subtype 2. Several miRNAs (miRLet-7A, miR-1, miR-206, miR-153, miR-519A and miR-506) and their target genes (CYP46A1, BPNT1, MCM7 and COL5A1) are crucial for HNSCC prevention via different pathways and may provide further knowledge of the mechanisms involved in the progression of HNSCC. PMID- 26239838 TI - Nutrition-based interventions to address metabolic syndrome in the Navajo: a systematic review. AB - AIMS AND OBJECTIVES: The objective of this systematic review is to identify nutrition-based interventions that may be effective for the prevention and treatment of metabolic syndrome in the Navajo. BACKGROUND: Metabolic syndrome, a major risk factor for cardiovascular disease, affects almost half of the Navajo population. The diet of the Navajo, heavy in fat and refined carbohydrates, has been identified as an important contributing factor to the high rates of metabolic syndrome in this population. DESIGN: A search was conducted on PubMed, EMBASE and CINAHL to identify studies published before October, 2013, involving nutrition-based interventions in adult populations similar to the Navajo targeting at least one measure of metabolic syndrome. METHODS: Data on efficacy and participation were gathered and synthesised qualitatively. RESULTS: Out of 19 studies included in this systematic review, 11 interventions were identified to be effective at improving at least one measure of metabolic syndrome. Level of exposure to the intervention, frequency of intervention activities, family and social support, cultural adaptation and case management were identified as factors that may improve the efficacy of an intervention. CONCLUSIONS: Multiple nutrition-based interventions have been found to be effective in populations similar to the Navajo. RELEVANCE TO CLINICAL PRACTICE: Development of a strategy to address metabolic syndrome in the Navajo may involve aspects from multiple interventions to increase efficacy and maximise participation. PMID- 26239839 TI - Investigation into the interaction of methylparaben and erythromycin with human serum albumin using multispectroscopic methods. AB - In this paper, the interaction of methylparaben and erythromycin with human serum albumin (HSA) was studied for the first time using spectroscopic methods including Fourier transform infrared (FTIR) spectroscopy and UV absorption spectroscopy in combination with fluorescence quenching under physiological conditions. The binding parameters were evaluated using a fluorescence quenching method. Based on Forster's theory of non-radiation energy transfer, the binding average distance, r between the donor (HSA) and the acceptor (methylparaben and erythromycin) was evaluated. UV/vis absorption, FTIR, synchronous and 3D spectral results showed that the conformation of HSA was changed in the presence of methylparaben and erythromycin. The thermodynamic parameters were calculated according to the van't Hoff equation and are discussed. The effect of some biological metal ions and site probes on the binding of methylparaben and erythromycin to HSA were further examined. PMID- 26239837 TI - Alterative effects of an oral alginate extract on experimental rabbit osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is a common joint disease that causes disabilities in elderly. However, few agents with high efficacy and low side effects have been developed to treat OA. In this study, we evaluated the effects of the alginate extract named CTX in OA cell and rabbit models. RESULTS: CTX was formulated by hydrolyzing sodium alginate polymers with alginate lyase and then mixing with pectin. HPLC was used to analyze the CTX content. Human chondrosarcoma SW1353 cells treated with interleukin-1beta were used as OA model cells to investigate the effects of CTX on chondrocyte inflammation and anabolism. CTX at concentrations up to 1000 MUg/ml exerted low cytotoxicity. It inhibited the gene expression of proinflammatory matrix metalloproteinases (MMPs) including MMP1, MMP3 and MMP13 in a dose-dependent manner and increased the mRNA level of aggrecan, the major proteoglycan in articular cartilage, at 1000 MUg/ml. Thirteen-week-old New Zealand White rabbits underwent a surgical anterior cruciate ligament transection and were orally treated with normal saline, glucosamine or CTX for up to 7 weeks. Examinations of the rabbit femur and tibia samples demonstrated that the rabbits taking oral CTX at a dosage of 30 mg/kg/day suffered lesser degrees of articular stiffness and histological cartilage damage than the control rabbits. CONCLUSIONS: The gene expression profiles in the cell and the examinations done on the rabbit cartilage suggest that the alginate extract CTX is a pharmaco-therapeutic agent applicable for OA therapy. PMID- 26239841 TI - The ethical challenges of the clinical introduction of mitochondrial replacement techniques. AB - Mitochondrial DNA (mtDNA) diseases are a group of neuromuscular diseases that often cause suffering and premature death. New mitochondrial replacement techniques (MRTs) may offer women with mtDNA diseases the opportunity to have healthy offspring to whom they are genetically related. MRTs will likely be ready to license for clinical use in the near future and a discussion of the ethics of the clinical introduction of MRTs is needed. This paper begins by evaluating three concerns about the safety of MRTs for clinical use on humans: (1) Is it ethical to use MRTs if safe alternatives exist? (2) Would persons with three genetic contributors be at risk of suffering? and (3) Can society trust that MRTs will be made available for humans only once adequate safety testing has taken place, and that MRTs will only be licensed for clinical use in a way that minimises risks? It is then argued that the ethics debate about MRTs should be reoriented towards recommending ways to reduce the possible risks of MRT use on humans. Two recommendations are made: (1) licensed clinical access to MRTs should only be granted to prospective parents if they intend to tell their children about their MRT conception by adulthood; and (2) sex selection should be used in conjunction with the clinical use of MRTs, in order to reduce transgenerational health risks. PMID- 26239840 TI - Production of recombinant VP1-derived virus-like particles from novel human polyomaviruses in yeast. AB - BACKGROUND: Eleven new human polyomaviruses (HPyVs) have been identified in the last decade. Serological studies show that these novel HPyVs sub-clinically infect humans at an early age. The routes of infection, entry pathways, and cell tropism of new HPyVs remain unknown. VP1 proteins of polyomaviruses can assembly into virus-like particles (VLPs). As cell culturing systems for HPyV are currently not available, VP1-derived VLPs may be useful tools in basic research and biotechnological applications. RESULTS: Recombinant VP1-derived VLPs from 11 newly identified HPyVs were efficiently expressed in yeast. VP1 proteins derived from Merkel cell polyomavirus (MCPyV), trichodysplasia spinulosa-associated polyomavirus (TSPyV), and New Jersey polyomavirus (NJPyV) self-assembled into homogeneous similarly-sized VLPs. Karolinska Institutet polyomavirus (KIPyV), HPyV7, HPyV9, HPyV10, and St. Louis polyomavirus (STLPyV) VP1 proteins formed VLPs that varied in size with diameters ranging from 20 to 60 nm. Smaller-sized VLPs (25-35 nm in diameter) predominated in preparations from Washington University polyomavirus (WUPyV) and HPyV6. Attempts to express recombinant HPyV12 VP1-derived VLPs in yeast indicate that translation of VP1 might start at the second of two potential translation initiation sites in the VP1-encoding open reading frame (ORF). This translation resulted in a 364-amino acid-long VP1 protein, which efficiently self-assembled into typical PyV VLPs. MCPyV-, KIPyV-, TSPyV-, HPyV9-, HPyV10-, and HPyV12-derived VLPs showed hemagglutination (HA) assay activity in guinea pig erythrocytes, whereas WUPyV-, HPyV6-, HPyV7-, STLPyV and NJPyV-derived VP1 VLPs did not. CONCLUSIONS: The yeast expression system was successfully utilized for high-throughput production of recombinant VP1-derived VLPs from 11 newly identified HPyVs. HPyV12 VP1-derived VLPs were generated from the second of two potential translation initiation sites in the VP1-encoding ORF. Recombinant VLPs produced in yeast originated from different HPyVs demonstrated distinct HA activities and may be useful in virus diagnostics, capsid structure studies, or investigation of entry pathways and cell tropism of HPyVs until cell culture systems for new HPyVs are developed. PMID- 26239842 TI - Genetically modified human placenta-derived mesenchymal stem cells with FGF-2 and PDGF-BB enhance neovascularization in a model of hindlimb ischemia. AB - Ischemic diseases represent a challenging worldwide health burden. The current study investigated the therapeutic potential of genetically modified human placenta-derived mesenchymal stem cells (hPDMSCs) with basic fibroblast growth factor (FGF2) and platelet-derived growth factor-BB (PDGF-BB) genes in hindlimb ischemia. Mesenchymal stem cells obtained from human term placenta were transfected ex vivo with adenoviral bicistronic vectors carrying the FGF2 and PDGF-BB genes (Ad-F-P). Unilateral hindlimb ischemia was surgically induced by excision of the right femoral artery in New Zealand White rabbits. Ad-F-P genetically modified hPDMSCs, Ad-null (control vector)-modified hPDMSCs, unmodified hPDMSCs or media were intramuscularly implanted into the ischemic limbs 7 days subsequent to the induction of ischemia. Four weeks after cell therapy, angiographic analysis revealed significantly increased collateral vessel formation in the Ad-F-P-hPDMSC group compared with the control group. Histological examination revealed markedly increased capillary and arteriole density in the Ad-F-P-hPDMSC group. The xenografted hPDMSCs survived in the ischemic tissue for at least 4 weeks subsequent to cell therapy. The current study demonstrated that the combination of hPDMSC therapy with FGF2 and PDGF-BB gene therapy effectively induced collateral vessel formation and angiogenesis, suggesting a novel strategy for therapeutic angiogenesis. PMID- 26239843 TI - Genetic analysis of Verticillium wilt resistance in a backcross inbred line population and a meta-analysis of quantitative trait loci for disease resistance in cotton. AB - BACKGROUND: Verticillium wilt (VW) and Fusarium wilt (FW), caused by the soil borne fungi Verticillium dahliae and Fusarium oxysporum f. sp. vasinfectum, respectively, are two most destructive diseases in cotton production worldwide. Root-knot nematodes (Meloidogyne incognita, RKN) and reniform nematodes (Rotylenchulus reniformis, RN) cause the highest yield loss in the U.S. Planting disease resistant cultivars is the most cost effective control method. Numerous studies have reported mapping of quantitative trait loci (QTLs) for disease resistance in cotton; however, very few reliable QTLs were identified for use in genomic research and breeding. RESULTS: This study first performed a 4-year replicated test of a backcross inbred line (BIL) population for VW resistance, and 10 resistance QTLs were mapped based on a 2895 cM linkage map with 392 SSR markers. The 10 VW QTLs were then placed to a consensus linkage map with other 182 VW QTLs, 75 RKN QTLs, 27 FW QTLs, and 7 RN QTLs reported from 32 publications. A meta-analysis of QTLs identified 28 QTL clusters including 13, 8 and 3 QTL hotspots for resistance to VW, RKN and FW, respectively. The number of QTLs and QTL clusters on chromosomes especially in the A-subgenome was significantly correlated with the number of nucleotide-binding site (NBS) genes, and the distribution of QTLs between homeologous A- and D- subgenome chromosomes was also significantly correlated. CONCLUSIONS: Ten VW resistance QTL identified in a 4-year replicated study have added useful information to the understanding of the genetic basis of VW resistance in cotton. Twenty-eight disease resistance QTL clusters and 24 hotspots identified from a total of 306 QTLs and linked SSR markers provide important information for marker-assisted selection and high resolution mapping of resistance QTLs and genes. The non-overlapping of most resistance QTL hotspots for different diseases indicates that their resistances are controlled by different genes. PMID- 26239844 TI - Factors affecting post-embolization fever and liver failure after trans-arterial chemo-embolization in a cohort without background infective hepatitis- a prospective analysis. AB - BACKGROUND: Transarterial-chemo-embolization (TACE) is used for palliation of unresectable hepatocellular carcinoma (HCC). We studied the tolerability of TACE in a cohort of patients with NASH and alcoholic cirrhosis related HCC. METHODS: Of 290 patients with HCC (July 2011 - December 2014), 84 underwent TACE. They were monitored for post-TACE complications: postembolization fever (PEF), nausea and vomiting (NV), abdominal pain, infection, acute hepatic decompensation (AHD) and acute kidney injury (AKI). RESULTS: 84 patients [90.5% males, 89.2% cirrhotics, 89.2% nodular HCC, median age 63 (34-84) years] underwent 111 TACE sessions. All were Child class A [69.4% sessions (n = 77)] or B; ascites and portal vein invasion was present in 18 (16.2%) and 15 (13.6%), respectively. 42 (38.2%) TACE procedures resulted in complications [PEF 28 (25.2%), NV 4 (3.6%), abdominal pain 9 (8.1%), infection 7 (6.3 %), AHD 13 (11.7%), AKI 3 (2.7 %)]. There were no immediate post-TACE deaths. On univariate analysis elevated serum bilirubin (p = 0.046) and low serum albumin (p = 0.035) predicted PEF while low serum albumin (p = 0.021) and low platelet counts (p = 0.041) predicted AHD. In the multivariate model, factors with p < 0.200 on univariate analysis and factors derived from the previous literature were considered covariates. Female gender (p = 0.029, OR = 1.412), ascites (p = 0.030, OR = 1.212), elevated serum bilirubin (p = 0.007, OR = 4.357) and large tumour size (p = 0.036, OR = 3.603) were independent risk factors for PEF. Tumour diameter >5 cm (p = 0.049, OR = 2.410) and elevated serum bilirubin (p = 0.036, OR = 1.517) predicted AHD. CONCLUSION: In NASH and alcoholic cirrhosis related HCC patients pre-procedure serum bilirubin, ascites, tumour size and female gender predicted PEF post-TACE. Tumours larger 5 cm with elevated bilirubin predicted AHD post-TACE. PMID- 26239845 TI - NASH: CX3CR1-a direct line to gut-liver crosstalk? PMID- 26239846 TI - Incubation time of Mycobacterium tuberculosis complex sputum cultures in BACTEC MGIT 960: 4weeks of negative culture is enough for physicians to consider alternative diagnoses. AB - We retrospectively analyzed time to detection of 3747 positive MGIT sputum cultures at a laboratory in a country with heavy burden of tuberculosis. Ninety nine percent of diagnostic cultures turned positive within 28days, suggesting that physicians may consider alternative diagnoses if sputum cultures remain negative after 4weeks of incubation. PMID- 26239847 TI - High Court rules that Health Research Authority acted unlawfully over trial transparency. PMID- 26239848 TI - A Need for Renewed and Cohesive US Policy on Cord Blood Banking. AB - Stem cells obtained from umbilical cord blood (CB) are used to treat more than 80 different diseases and are a standard treatment for many types of leukemias, lymphomas, myelodysplasias, and inherited immune system disorders. CB transplants have been carried out in humans for over 25 years, and hundreds of clinical trials are currently underway investigating CB's therapeutic potential for a wide range of disorders, including autism, diabetes, cerebral palsy, and spinal cord injury. Extensive storage facilities have been established in the United States and around the world to collect, test, and freeze CB for later use in medical procedures. However, a divide between two different banking models-public versus private-has emerged, presenting several policy challenges. While the Food and Drug Administration currently regulates CB storage and use in the United States, other state and federal guidelines on CB education, awareness, and ethical considerations remain variable, and no mandatory international guidelines exist. In addition, federal funding for an important CB collection initiative that specifically targets minority populations is set to expire by the end of FY2015. To help organize and coordinate efforts across the United States and other nations, policymakers should implement regulations for: high quality standards for both private and public CB banks, a commitment to ethical practices, and an investment in educational campaigns and training programs for all steps of the CB banking process. PMID- 26239849 TI - Derivation and growth characteristics of dental pulp stem cells from patients of different ages. AB - The dental pulp contains a relatively low number of stem cells; however, it is considered to be a promising source of stem cells for use in regenerative therapy. To date, it has remained elusive whether there are certain differences in the dental pulp stem cells (DPSCs) from donors of different ages. In the present study, DPSC lines were derived using teeth from children, adolescents, adults and aged donors. The derivation efficiency, the proliferative and apoptotic rate, cell marker expression and the differentiation capacity were investigated and compared among these DPSC lines. The derivation efficacy was decreased with increasing donor age. Although a large part of cell surface markers was expressed in all DPSC lines, the expression of CD29 was downregulated in the DPSCs from aged teeth. In addition, the doubling time of DPSCs from aged teeth was prolonged and the number of apoptotic cells was increased with the propagation. These DPSCs were able to differentiate into a neuronal linage, which positively expressed the neuron-specific class III beta-tubulin and microtubule associated protein 2, as well as into an osteogenic lineage, which positively expressed CD45; however, these DPSCs from aged teeth were completely or partially deprived of differentiation capacity. By contrast, DPSCs from younger teeth displayed significantly higher vitality and a higher potential for use in dental regenerative medicine. PMID- 26239850 TI - Effect of Verbascum thapsus ethanol extract on induction of apoptosis in Trichomonas vaginalis in vitro. AB - Trichomoniasis is a sexually transmitted disease (STD) caused by a tiny parasite called Trichomonas vaginalis. Metronidazole is used as routine treatment of disease. Some reports have confirmed the potential carcinogenic and teratogenic effects of this drug on fetus and indication of drug resistance. Verbascum thapsus belongs to the family of Scorphulariaceae. Its antiinflammatory properties, disinfectant and skin healing effects are well known. This plant has been used to treat diarrhea and genitourinary infection in traditional medicine. Effects of different concentrations of the Verbascum thapsus extract were tested on the growth and motility of T. vaginalis trophozoites. To evaluate the toxicity of extract, their effects on mice macrophages were measured by MTT([3-(4,5 dimethyl thiazolyl-2)- 2,5-diphenyle tetrazolium bromide ])assay. In this experimental study the effect of Verbascum thapsus ethanol extract on induction apoptosis in T. vaginalis was determined by Flow Cytometry. Results were analyzed by Flow Jo software and the degree of apoptosis was determined. Toxicity percentage of 25-800 MUg/ml concentrations of Verbascum thapsus alcoholic extract for mice macrophages was observed between 0.17-0.25 after 12 hours and they were between 0.25-0.42 and0.45-0.95 after 24 and 48h respectively. IC50 (inhibitory concentration, 50%) of Verbascum thapsus ethanol extract and metronidazole after 24h was 39.17 and 0.0326 MUg/ml respectively. Flow cytometry results showed the percent of apoptosis following treatment of trophozoites with different concentrations of Verbascum thapsus ethanol extract (25, 50,100,200,400 MUg/ml), were 20.7, 37.04, 47.5, 62.72 and 86.35 respectively, while in control group was 2.9. According to this study, Verbascum thapsus extract induces programmed death in T. vaginalis. It is recommended that Verbascum thapsus extract can be considered as a suitable choice for Medical Studies. PMID- 26239851 TI - [In Process Citation]. PMID- 26239852 TI - [In Process Citation]. PMID- 26239853 TI - [In Process Citation]. PMID- 26239854 TI - [Challenges when improving surgical conditions by use of neuromuscular blockade]. AB - Neuromuscular blockade (NMB) may pose a clinical dilemma between surgeons' requirements of muscle relaxation and the risk of residual blockade. This review has aimed at describing the challenges when using NMB for optimizing surgical conditions and reasons for inadequate relaxation despite use of NMB. Interdisciplinary collaboration, proper neuromuscular monitoring, knowledge on differences in pharmacodynamics and pharmacokinetics of NMB are essential factors when optimizing surgical conditions by use of NMB. PMID- 26239855 TI - [Non-invasive prenatal testing is a breakthrough in prenatal screening]. AB - Non-invasive prenatal testing (NIPT) using cell-free fetal DNA from the peripheral blood of the pregnant woman has become a possibility within recent years, but is not yet implemented in Denmark. NIPT has proven to be very efficient in the screening for especially trisomi 21. This article summarizes the basics behinds the most used NIPT techniques and describes which genetic conditions this method may detect. Finally, the future aspects of implementing NIPT in the prenatal screening programme in Denmark are discussed. PMID- 26239856 TI - [Acute pancreatitis after ingestion of ibuprofen in a 16-year-old boy]. AB - This is a case report of a 16-year-old boy with possible drug-induced pancreatitis (DIP) caused by ibuprofen. The patient had a history of psychiatric, but no somatic, disease, and he was admitted with a clinical presentation consistent with acute pancreatitis after a bolus ingestion of 10 g of ibuprofen in a suicidal attempt. No evidence of other causality for acute pancreatitis was identified. The patient was treated with a standard pancreatitis treatment regime and was discharged against medical advice after four days. The case represents a possible causality between ibuprofen and DIP. PMID- 26239857 TI - [Effective rehabilitation of hospitalized patients with multiple sclerosis]. AB - Globally, the number of people suffering from multiple sclerosis (MS) is more than two million, and MS is characterized by increasing symptom development over time. The socio-economic costs are enormous. Therefore, effective management of MS is of great importance. Multidisciplinary rehabilitation (MR) seeks to prevent and stop loss of function and trains the patients to deal with symptoms and challenges that will arise in the future. Because there is a need for high quality evidence of the effectiveness of MR, the MS hospitals in Denmark have initiated the largest study of its kind on MR. PMID- 26239858 TI - [Allergic rhinoconjunctivitis caused by occupational exposure to ginger]. AB - We present a case report of occupational allergic rhinoconjunctivitis after exposure to dust from ginger-containing herbal medicine. The likelihood of an aetiological connection between exposure and the patient's symptoms was supported by a temporal association, positive specific IgE, positive histamine release test, positive prick test, and positive acoustic rhinometry test. Occupational allergy to ginger has rarely been reported. The cases described - including the one we present - suggest that work-related IgE-mediated allergy is associated with exposure to dry aerosols/dust. PMID- 26239859 TI - A web-based, patient-centered toolkit to engage patients and caregivers in the acute care setting: a preliminary evaluation. AB - We implemented a web-based, patient-centered toolkit that engages patients/caregivers in the hospital plan of care by facilitating education and patient-provider communication. Of the 585 eligible patients approached on medical intensive care and oncology units, 239 were enrolled (119 patients, 120 caregivers). The most common reason for not approaching the patient was our inability to identify a health care proxy when a patient was incapacitated. Significantly more caregivers were enrolled in medical intensive care units compared with oncology units (75% vs 32%; P < .01). Of the 239 patient/caregivers, 158 (66%) and 97 (41%) inputted a daily and overall goal, respectively. Use of educational content was highest for medications and test results and infrequent for problems. The most common clinical theme identified in 291 messages sent by 158 patients/caregivers was health concerns, needs, preferences, or questions (19%, 55 of 291). The average system usability scores and satisfaction ratings of a sample of surveyed enrollees were favorable. From analysis of feedback, we identified barriers to adoption and outlined strategies to promote use. PMID- 26239860 TI - Prospective multifactorial analysis of preseason risk factors for shoulder and elbow injuries in high school baseball pitchers. AB - PURPOSE: To prospectively identify preseason physical factors for shoulder and elbow injuries during the season in high school baseball pitchers. METHODS: The study included 105 high school baseball pitchers [median age 16 (15-17) years]. The range of motion of the shoulder (90 degrees abducted external and internal rotation) and elbow (extension/flexion), shoulder muscle strength (abduction and prone internal and external rotation), shoulder and elbow laxity, horizontal flexion, and scapular dyskinesis were assessed. After the season, the participants completed questionnaires regarding shoulder and/or elbow injuries, with injury defined as an inability to play for >=1 week due to elbow/shoulder problems. The results of two groups (injured and noninjured) were compared using t tests and Chi-square analyses. Stepwise forward logistic regression models were developed to identify risk factors. RESULTS: Twenty-one injuries were observed. In univariate analysis, 90 degrees abducted internal rotation and total arc of the dominant shoulder and the ratio of prone external rotation in the dominant to nondominant sides in the injured group were significantly less than those in the noninjured group (P = 0.02, 0.04, and 0.01, respectively). In logistic regression analysis, 90 degrees abducted internal rotation in the dominant shoulder and prone external rotation ratio were significantly associated with injuries (P = 0.02 and 0.03, respectively). CONCLUSION: A low prone external rotation ratio and decreased 90 degrees abducted internal rotation in the dominant shoulder in the preseason were significant risk factors for shoulder and elbow injuries in high school baseball pitchers. The results may contribute to reduce the incidence of these injuries. LEVEL OF EVIDENCE: II. PMID- 26239861 TI - The natural history of donor hamstrings unit after anterior cruciate ligament reconstruction: a prospective MRI scan assessment. AB - PURPOSE: The aim of this prospective study was to assess the natural history of the donor hamstrings, compared to the contralateral knee and thigh. METHODS: In 47 patients who had ACL reconstruction (hamstrings technique), bilateral knees and thighs were investigated using MRI scans, up to 2 years post-operatively. RESULTS: Tendon regeneration below the knee joint line of the semitendinosus occurred in 30/47 (64 %) patients and of the gracilis tendon in 17/47 (36 %) patients. Insertion of both tendons at the "pes anserinus", with normal anatomic relations, was observed in 5/47 (11 %) patients. Semitendinosus and gracilis donor muscles were found retracted in 41/47 (87 %) patients. In 25/47 (53 %) patients, there was evidence of fatty infiltration of the semitendinosus muscle. All (47/47) (100 %) patients showed semitendinosus muscle atrophy and 41/47 (87 %) patients showed gracilis muscle atrophy, compared to the contralateral limb. High signal intensity on STIR images was observed in the semitendinosus in 22/47 (46 %) patients and in the gracilis muscle in 30/47 (64 %) patients, on MRI examination performed up to 24 months post-operatively. CONCLUSIONS: The "regenerated" hamstrings tendons most commonly do not regenerate fully anatomically, so they should not be considered as a first choice for re harvesting in revision ACL reconstruction. The "donor hamstrings muscles" are found to be shorter, contracted, thinner and with a long-term abnormal MRI signal, features which are considered to be related to reduced muscle performance (knee flexion and internal rotation) post-operatively. LEVEL OF EVIDENCE: II. PMID- 26239862 TI - Knee joint kinematics after dynamic intraligamentary stabilization: cadaveric study on a novel anterior cruciate ligament repair technique. AB - PURPOSE: Dynamic intraligamentary stabilization (DIS) has been introduced for the repair of acute anterior cruciate ligament (ACL) tears as an alternative to delayed reconstruction. The aim of the present study was to compare knee joint kinematics after DIS to those of the ACL-intact and ACL-deficient knee under simulated Lachman/KT-1000 and pivot-shift tests. We hypothesized that DIS provides knee joint kinematics equivalent to an intact ACL. METHODS: With the use of a robotic knee simulator, knee kinematics were determined in simulated Lachman/KT-1000 and pivot-shift tests at 0 degrees , 15 degrees , 30 degrees , 60 degrees , and 90 degrees of flexion in eight cadaveric knees under the following conditions: (1) intact ACL, (2) ACL deficiency, (3) DIS with a preload of 60 N, and (4) DIS with a preload of 80 N. Statistical analyses were performed using two factor repeated-measures analysis of variance. The significance level was set at a p value of <0.05. RESULTS: After DIS with a preload of either 60 N or 80 N, the anterior translation was significantly reduced in the simulated Lachman/KT-1000 and pivot-shift tests when compared to the ACL-deficient knee (p < 0.05). No significant differences were observed between the DIS reconstruction with a preload of 80 N and the intact ACL with regard to anterior laxity in either test. However, DIS with a preload of only 60 N was not able to restore knee joint kinematics to that of an intact knee in all degrees of flexion. CONCLUSION: DIS with a preload of 80 N restores knee joint kinematics comparable to that of an ACL-intact knee and is therefore capable of providing knee joint stability during ACL healing. DIS therefore provides a new technique for primary ACL repair with superior biomechanical properties in comparison with other techniques that have been described previously, although further clinical studies are required to determine its usefulness in clinical settings. PMID- 26239863 TI - MRI injury patterns in surgically confirmed and reconstructed posterolateral corner knee injuries. AB - PURPOSE: The posterolateral corner (PLC) of the knee is anatomically complex with similarly complex MR imaging findings in acutely injured knees. The purpose of this study was to define the MRI pattern of injury in cases of PLC disruption requiring surgery because of clinical instability. METHODS: The knee MRIs of 22 patients who underwent surgical repair and/or reconstruction of PLC injury were retrospectively reviewed. The fibular collateral ligament (FCL), popliteus tendon (PT), biceps femoris (BF), popliteofibular ligament (PFL), arcuate ligament (AL), and fabellofibular ligament (FFL) were evaluated and graded as follows: complete tear, high-grade partial tear, low-grade partial tear, and normal. RESULTS: In the 22 cases of PLC injury that necessitated surgery, a constellation of findings involving the larger structures of the PLC was identified. Of the FCL, PT, and BF (considered larger structures), at least two were abnormal in all 22 injury cases. Of the PFL, AL, and FFL (considered smaller structures), the PFL appeared abnormal in 19 cases, yet neither the AL nor FFL were confidently characterized in the injury group. CONCLUSION: The larger structures of the PLC are easily evaluated using standard MRI techniques. This study identified a predictable pattern of imaging findings involving these more easily assessed structures in those patients who were felt to be clinically unstable and underwent surgical reconstruction, as at least two were abnormal in all 22 cases. The smaller structures of the PLC are difficult to assess with MRI; however, direct visualization of their involvement on MRI is not necessary to report a clinically unstable PLC injury. Emphasis of this simplified but critical analysis of the FCL, BF and PT on MRI scans reviewed by radiologists and orthopaedic surgeons may help to prevent delayed diagnosis of unstable PLC injuries. LEVEL OF EVIDENCE: III. PMID- 26239864 TI - Contraception Practices and Pregnancy Outcome in Patients after Fontan Operation. AB - OBJECTIVE: The feasibility and safety of pregnancy after the Fontan operation is not well understood. We sought to determine contraception practices and early and late outcomes of pregnancy after the Fontan operation. DESIGN: We performed a retrospective review of medical records to identify women of childbearing age from the Mayo Clinic Fontan database. A follow-up questionnaire was mailed to all patients not known to be deceased at the time of study. Patients with available contraception and pregnancy data were included in the study. RESULTS: Of the 138 women with available contraception data, 44% used no contraception, 12% each used barrier methods, combination hormone therapy or sterilization, 8% used Depo Provera, 7% had intrauterine devices, 4% had a partner with a vasectomy and 1% used progestin pills. Six women had thrombotic complications (only one using oral contraceptives). Thirty-five women had pregnancy data available. Prior to the Fontan operation there were 10 pregnancies (8 miscarriages, 2 therapeutic abortions, and no live births). After the Fontan operation there were 70 pregnancies resulting in 35 miscarriages (50%), 29 live births (41%), and 6 therapeutic abortions (9%). There were no maternal deaths during pregnancy. During long-term follow up (26 +/- 6 years since the Fontan), 1 death, and 1 cardiac transplant occurred. Mean gestational age of the newborns (n = 22/29) was 33.1 +/- 4.0 weeks; mean birth weight (n = 20/29) was 2086 +/- 770 g. There was 1 neonatal death because of prematurity and two children were born with congenital heart disease (one patent ductus arteriosus and one membranous ventricular septal defect). CONCLUSIONS: Pregnancy after the Fontan operation is associated with a high rate of miscarriages, preterm delivery, and low birth weight. Further studies are needed to identify specific variables influencing risk stratification of pregnancy in this patient population. PMID- 26239865 TI - [Effect of removing the ischaemia tourniquet on the transfusion needs of the patient undergoing primary knee arthroplasty]. AB - OBJECTIVE: To determine the influence of the timing of the removal of the ischaemia tourniquet on the transfusion needs in primary knee arthroplasty and its influence on post-operative complications. MATERIAL AND METHOD: A retrospective analysis was performed on 201 primary knee arthroplasties. The patients were divided into 2 groups: group A (101 patients), where the tourniquet was removed before surgical closure, and group B (100 patients), where the tourniquet was removed after the surgical closure. A comparison was made of the blood transfusions (pools of red corpuscles) received by both groups, along with the surgical time, and the post-operative complications. RESULTS: The mean number of packed red cells transfused in group A was 0.62, while in the group B it was 0.61 (P=.831). The mean time in the surgery in group A was 111 min, and in group B it was 98 min (P<.05), with no significant difference between the surgical time and the number of packed cells transfused (P=.055). The post-operative complications in the group A were 8, and in the B were 10 (P=.79). DISCUSSION: There were no differences between removing the tourniquet before or after surgical closure or in the transfusion needs or in the post-operative complications. Traditionally, the greater blood loss due to the removal of the tourniquet before surgical closure has been explained as due to the longer surgery time required. However, in the present study, this fact was not associated with greater transfusion needs, or with more post-operative complications. PMID- 26239866 TI - A Versatile Organocatalytic Approach for the Synthesis of Enantioenriched gem Difluorinated Compounds. AB - The combination of a practical and highly enantioselective organocatalytic reaction, which allows the stereoselective introduction of a benzodithiol group, with a fluorination step, gives a new and effective strategy for the stereoselective synthesis of difluorinated building blocks. The benzodithiol group is a versatile and chameleonic group that can be further functionalized before fluorination, giving customized and tailored useful synthetic strategies. As an example of the application of this facile strategy, the effective enantioselective synthesis of difluoroarundic acid is described. PMID- 26239868 TI - Low Work-function Poly(3,4-ethylenedioxylenethiophene): Poly(styrene sulfonate) as Electron-transport Layer for High-efficient and Stable Polymer Solar Cells. AB - Low-work-function poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) ( PEDOT: PSS) modified with polyethylenimine (PEIE) was used as an electron transport layer (ETL) for polymer solar cells (PSCs). A thin layer of PEIE film was spin-coated onto the surface on the PEDOT: PSS films, thus substantially changing their charge selectivity from supporting hole transport to supporting electron transport. It was also found that the PEDOT: PSS/PEIE ETL exhibited higher interfacial contact, a more favorable active morphology, and improved charge mobility. By virtue of these beneficial properties, inverted PSCs based on low-bandgap semiconducting photoactive layers achieved a notably improved power conversion efficiency (PCE) of 7.94%, superior even to the corresponding performance of devices with only a ZnO layer. Surpassing our expectations, compared with the extreme degradation of device stability observed when pure PEDOT: PSS is used, PEIE-modified PEDOT: PSS can considerably suppress device degradation because of the hydrophobic and alkaline nature of PEIE, which not only reduces the hygroscopicity of the PEDOT: PSS but also neutralizes the acidic PEDOT: PSS and thus prevents the corrosion of the ITO cathode. These results demonstrate the potential of PEIE-modified PEDOT: PSS for use as an efficient ETL in commercial printed electronic devices. PMID- 26239867 TI - Neurotoxicity of FireMaster 550(r) in zebrafish (Danio rerio): Chronic developmental and acute adolescent exposures. AB - BACKGROUND: FireMaster(r) 550 (FM 550) is the second most commonly used flame retardant (FR) product in consumer goods and has been detected in household dust samples. However, neurobehavioral effects associated with exposure have not been characterized in detail. We investigated the behavioral effects of FM 550 in zebrafish to facilitate the integration of the cellular and molecular effects of FM 550 with its behavioral consequences. The effects of developmental FM 550 exposure on zebrafish larvae swimming shortly after the end of exposure as well as the persisting effects of this exposure on adolescent behavior were studied. In addition, the acute effects of FM 550 on behavior with exposure during adolescence in zebrafish were studied. METHODS: Developmental exposure to 0, 0.01, 0.1 or 1 mg/L of FM 550 via immersion spanned 0-5 days post fertilization, with larval testing on day 6 and adolescent testing on days 40-45. Acute adolescent (45 dpf) exposure was to 0, 1.0 or 3.0 mg/L of FM 550 via immersion, for 24 h, with testing 2 h or 1 week later. The vehicle condition was colony tank water with .0004% (developmental) or .0012% (adolescent) DMSO. Zebrafish behavior was characterized across several domains including learning, social affiliation, sensorimotor function, predator escape, and novel environment exploration. RESULTS: Persisting effects of developmental FM 550 exposure included a significant (p<0.01) reduction in social behavior among all dose groups. Acute FM 550 exposure during adolescence caused hypoactivity and reduced social behavior (p's<0.05) when the fish were tested 2 h after exposure. These effects were attenuated at the 1 week post exposure testing point DISCUSSION: Taken together, these data indicate that FM 550 may cause persisting neurobehavioral alterations to social behavior in the absence of perturbations along other behavioral domains and that developmental exposure is more costly to the organism than acute adolescent exposure. PMID- 26239873 TI - Discontinuation of oral anticoagulation preceding acute ischemic stroke- prevalence and outcomes: Comprehensive chart review. AB - INTRODUCTION: Oral anticoagulants (OAC) are the therapy of choice to prevent thromboembolism in patients at risk. Discontinuation of OAC prior to elective medical and surgical procedures may reduce the risk of bleeding, but may expose patients to increased risk of thromboembolism and ischemic stroke. The current public health burden of ischemic strokes associated with OAC discontinuation is unknown. We aimed to study the prevalence OAC discontinuation in patients who presented with acute ischemic stroke as well as the outcomes of these strokes. METHODS: Retrospective cross-sectional study by intensive chart review of all acute ischemic stroke patients over 6 months in a large tertiary care community hospital. RESULTS: A total of 431 patients with acute ischemic stroke were admitted during study period, of which 11 (2.6%) had OAC discontinuation within 120 days prior to the index admission. Several strokes occurred after relatively brief discontinuations. The patient group with discontinuation was older, had higher comorbidities and also had a clinically significant stroke and resulting higher mortality and morbidity. CONCLUSION: About 2.6% or 1 in every 38 of all ischemic stokes occurred after OAC discontinuation. Strokes occurring after OAC discontinuation also have higher mortality and morbidity. Our data suggest that any planned discontinuation of OAC, however brief, should be carefully considered. PMID- 26239874 TI - Comment on: In Vivo Evaluation of Electrospun Polycaprolactone Graft for Anterior Cruciate Ligament Engineering. Tissue Eng Part A. 2015;21(7-8):1228-1236. PMID- 26239875 TI - Understanding and exploiting nanoparticles' intimacy with the blood vessel and blood. AB - While the blood vessel is seldom the target tissue, almost all nanomedicine will interact with blood vessels and blood at some point of time along its life cycle in the human body regardless of their intended destination. Despite its importance, many bionanotechnologists do not feature endothelial cells (ECs), the blood vessel cells, or consider blood effects in their studies. Including blood vessel cells in the study can greatly increase our understanding of the behavior of any given nanomedicine at the tissue of interest or to understand side effects that may occur in vivo. In this review, we will first describe the diversity of EC types found in the human body and their unique behaviors and possibly how these important differences can implicate nanomedicine behavior. Subsequently, we will discuss about the protein corona derived from blood with foci on the physiochemical aspects of nanoparticles (NPs) that dictate the protein corona characteristics. We would also discuss about how NPs characteristics can affect uptake by the endothelium. Subsequently, mechanisms of how NPs could cross the endothelium to access the tissue of interest. Throughout the paper, we will share some novel nanomedicine related ideas and insights that were derived from the understanding of the NPs' interaction with the ECs. This review will inspire more exciting nanotechnologies that had accounted for the complexities of the real human body. PMID- 26239876 TI - Dissolvable base scaffolds allow tissue penetration of high-aspect-ratio flexible microneedles. AB - Microscale needle technology is important in electrophysiological studies, drug/chemical delivery systems, optogenetic applications, and so on. In this study, dissolvable needle-base scaffold realizes penetration of high-aspect-ratio flexible microneedles (e.g., <5 MUm diameter and >500 MUm length) into biological tissues. This methodology, which is applicable to numerous high-aspect-ratio flexible microneedles, should reduce the invasiveness and provide safer tissue penetrations than conventional approaches. PMID- 26239877 TI - Copper-Assisted Direct Growth of Vertical Graphene Nanosheets on Glass Substrates by Low-Temperature Plasma-Enhanced Chemical Vapour Deposition Process. AB - Vertical graphene (VG) nanosheets are directly grown below 500 degrees C on glass substrates by a one-step copper-assisted plasma-enhanced chemical vapour deposition (PECVD) process. A piece of copper foil is located around a glass substrate as a catalyst in the process. The effect of the copper catalyst on the vertical graphene is evaluated in terms of film morphology, growth rate, carbon density in the plasma and film resistance. The growth rate of the vertical graphene is enhanced by a factor of 5.6 with the copper catalyst with denser vertical graphene. The analysis of optical emission spectra suggests that the carbon radical density is increased with the copper catalyst. Highly conductive VG films having 800 Omega/? are grown on glass substrates with Cu catalyst at a relatively low temperature. PMID- 26239878 TI - Pd nanoparticle-modified electrodes for nonenzymatic hydrogen peroxide detection. AB - A hydrogen peroxide (H2O2) sensor based on Pd nanoparticles (NPs) and glassy carbon electrodes (GCEs) is fabricated. Pd NPs are deposited on GCEs by using a gas phase cluster beam deposition technique. The NP-deposited electrodes show enhanced electrocatalytic activity in reduction of H2O2. The electrode with an optimized NP coverage of 85 % has a high selective and stable nonenzymatic sensing ability of H2O2 with a low detection limit (3.4 * 10(-7) M), high sensitivity (50.9 MUA mM(-1)), and a wide linear range (from 1.0 * 10(-6) to 6.0 * 10(-3) M). The reduction peak potential of the electrode is close to -0.12 V, which enables high selective amperometric detection of H2O2 at a low applied potential. PMID- 26239880 TI - High spatial resolution mapping of individual and collective localized surface plasmon resonance modes of silver nanoparticle aggregates: correlation to optical measurements. AB - Non-isolated nanoparticles show a plasmonic response that is governed by the localized surface plasmon resonance (LSPR) collective modes created by the nanoparticle aggregates. The individual and collective LSPR modes of silver nanoparticle aggregated by covalent binding by means of bifunctional molecular linkers are described in this study. Individual contributions to the collective modes are investigated at nanometer scale by means of energy-filtering transmission electron microscopy and compared to ultraviolet-visible spectroscopy. It is found that the aspect ratio and the shape of the clusters are the two main contributors to the low-energy collective modes. PMID- 26239881 TI - Bronsted acid-catalyzed 1,2-fluorine migration with fluoroepoxides. AB - A catalytic 1,2-fluorine migration reaction with simple fluoroepoxides at room temperature is reported. Under Bronsted acid catalysis, alpha-fluorinated ketones are efficiently constructed in the absence of an external fluorine source through a 1,2-fluorine migration reaction. The experimental results indicate that the present 1,2-fluorine migration reaction proceeds via a carbocation intermediate. PMID- 26239879 TI - Comparison of Infectious Agents Susceptibility to Photocatalytic Effects of Nanosized Titanium and Zinc Oxides: A Practical Approach. AB - Nanotechnology contributes towards a more effective eradication of pathogens that have emerged in hospitals, veterinary clinics, and food processing plants and that are resistant to traditional drugs or disinfectants. Since new methods of pathogens eradication must be invented and implemented, nanotechnology seems to have become the response to that acute need. A remarkable achievement in this field of science was the creation of self-disinfecting surfaces that base on advanced oxidation processes (AOPs). Thus, the phenomenon of photocatalysis was practically applied. Among the AOPs that have been most studied in respect of their ability to eradicate viruses, prions, bacteria, yeasts, and molds, there are the processes of TiO2/UV and ZnO/UV. Titanium dioxide (TiO2) and zinc oxide (ZnO) act as photocatalysts, after they have been powdered to nanoparticles. Ultraviolet (UV) radiation is an agent that determines their excitation. Methods using photocatalytic properties of nanosized TiO2 and ZnO prove to be highly efficient in inactivation of infectious agents. Therefore, they are being applied on a growing scale. AOP-based disinfection is regarded as a very promising tool that might help overcome problems in food hygiene and public health protection. The susceptibility of infectious agents to photocatalylic processes can be generally arranged in the following order: viruses > prions > Gram-negative bacteria > Gram-positive bacteria > yeasts > molds. PMID- 26239882 TI - Platelet reactivity in MitraClip patients. AB - BACKGROUND: Common complications during MitraClip procedure are bleeding and ischemic events. The right strategy of platelet inhibition is unknown and challenging, as there are substantial interindividual response-variabilities to antiplatelet drugs and additionally, many MitraClip patients are on permanent oral anticoagulation because of atrial fibrillation. We aimed to investigate the incidence of (i) high- and low on-treatment platelet reactivity (HTPR, LTPR) to antiplatelet medication and (ii) clinical complications in MitraClip patients. METHODS: In an observational single-center cohort study we investigated 73 patients who underwent MitraClip implantation. Clopidogrel effects were measured using the vasodilator-stimulated protein phosphorylation (VASP) assay, aspirin effects by light-transmission aggregometry (LTA). Clinical complications were investigated during six-month follow-up. RESULTS: HTPR to clopidogrel was observed in 44 patients, LTPR to clopidogrel in 6 patients. 16 patients had HTPR to aspirin. Major complications occurred in 12 patients, overall bleeding complications in 27 patients, overall ischemic events in two patients. The incidence of HTPR/LTPR did not differ between patients with- vs. without clinical complications. Bleeding complications were not more frequent in patients with additional oral anticoagulation. CONCLUSIONS: In this study, the incidence of HTPR to clopidogrel was very high (60% of patients). Despite these insufficient clopidogrel antiplatelet effects, ischemic events were rare and bleeding complications more frequent. Additionally, many patients undergoing MitraClip procedure were on permanent oral anticoagulation because of atrial fibrillation. The optimal antithrombotic regiment should be investigated in large scale clinical trials under consideration of the high incidence of HTPR to clopidogrel medication in MitraClip patients. PMID- 26239883 TI - Camptothecin promotes the production of nitric oxide that triggers subsequent S nitrosoproteome-mediated signaling cascades in endothelial cells. AB - Camptothecin (CPT) has been used for colorectal cancer therapy. At low concentration of 10-9M, CPT modulates endothelial nitric oxide production following the phosphorylation of LKB1 Ser431, AMPK-alpha Thr172, eNOS Ser633 and Ser1177. Elevated nitric oxide (NO) was observed by FA-OMe fluorescent probe. 726 S-nitrosoproteins were identified by iTRAQ quantitative proteomics. IPA analysis indicated that ERK/MAPK was closely linked in the signaling network. Further studies showed that CPT phosphorylated p38 MAPK Thr180/Tyr182 and dephosphorylated Tau Ser199/202. CPT also suppressed the TNF-alpha-induced expression of the inflammasome and cyclooxygenase 2. All this suggests that in addition to the original character of CPT in attenuating the binding of topoisomerase I and DNA in cancer cells, the role of CPT in triggering NO production and the subsequent S-nitrosylated signaling including anti inflammatory effects in endothelial cells are proposed here. CPT, therefore, provides a potential application addition in preventing vascular disorders. PMID- 26239884 TI - Methylthiouracil, a new treatment option for sepsis. AB - The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases. Inhibition of high mobility group box 1 (HMGB1) and restoration of endothelial integrity are emerging as an attractive therapeutic strategies in the management of severe sepsis or septic shock. Here, we examined the effects of methylthiouracil (MTU), used as antithyroid drug, by monitoring the effects on lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-mediated release of HMGB1, and on the modulation of HMGB1-mediated inflammatory responses. The anti-inflammatory activities of MTU were determined by measuring permeability, leukocyte adhesion and migration, and the activation of pro-inflammatory proteins in HMGB1-activated HUVECs and mice. MTU inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. MTU also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with MTU reduced CLP-induced release of HMGB1 and sepsis-related mortality and pulmonary injury. Our results indicate that MTUs could be candidate therapeutic agents for various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway. PMID- 26239886 TI - Single vs Dual Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation: A Systematic Review. AB - There is wide variability in prescribing of antiplatelet regimens following transcatheter aortic valve implantation (TAVI). The objective of this review was to evaluate published and unpublished reports regarding the efficacy and safety of dual antiplatelet therapy (DAPT) compared with a single antiplatelet agent in patients undergoing TAVI. We searched MEDLINE, CENTRAL, Embase, and unpublished sources of literature from inception to December 2014 using terms synonymous with TAVI and DAPT. We included randomized controlled trials (RCTs) and cohort or case control studies that compared DAPT with a single antiplatelet agent post-TAVI. Four articles met the inclusion criteria (2 RCTs, 2 cohort studies), of which all were deemed to be at high risk of bias, for a total of 662 patients. Compared with a single antiplatelet agent, DAPT did not significantly reduce all-cause mortality (risk ratio: 1.22, 95% confidence interval: 0.72-2.09, I(2) = 0%). Due to selective outcome reporting and variable follow-up, other outcomes of interest could not be meta-analyzed; however, evaluation of individual studies demonstrated no significant reduction in thrombotic events with DAPT and a similar or higher risk of bleeding. Current evidence, though limited by low methodological quality, suggests a lack of benefit and potential harm with DAPT compared with a single antiplatelet agent in patients post-TAVI. Therefore, clinicians should evaluate the use of DAPT in patients post-TAVI on a case-by case basis until more robust evidence is available to guide practice. PMID- 26239885 TI - A pharmacologic activator of endothelial KCa channels increases systemic conductance and reduces arterial pressure in an anesthetized pig model. AB - SKA-31, an activator of endothelial KCa2.3 and KCa3.1 channels, reduces systemic blood pressure in mice and dogs, however, its effects in larger mammals are not well known. We therefore examined the hemodynamic effects of SKA-31, along with sodium nitroprusside (SNP), in anesthetized, juvenile male domestic pigs. Experimentally, continuous measurements of left ventricular (LV), aortic and inferior vena cava (IVC) pressures, along with flows in the ascending aorta, carotid artery, left anterior descending coronary artery and renal artery, were performed during acute administration of SKA-31 (0.1, 0.3, 1.0, 3.0 and 5.0mg/ml/kg) and a single dose of SNP (5.0 MUg/ml/kg). SKA-31 dose-dependently reduced mean aortic pressure (mPAO), with the highest dose decreasing mPAO to a similar extent as SNP (-23 +/- 3 and -28 +/- 4 mmHg, respectively). IVC pressure did not change. Systemic conductance and conductance in coronary and carotid arteries increased in response to SKA-31 and SNP, but renal artery conductance was unaffected. There was no change in either LV stroke volume (SV) or heart rate (versus the preceding control) for any infusion. With no change in SV, drug evoked decreases in LV stroke work (SW) were attributed to reductions in mPAO (SW vs. mPAO, r(2)=0.82, P<0.001). In summary, SKA-31 dose-dependently reduced mPAO by increasing systemic and arterial conductances. Primary reductions in mPAO by SKA-31 largely account for associated decreases in SW, implying that SKA-31 does not directly impair cardiac contractility. PMID- 26239887 TI - Nuclear respiratory factor-2alpha and adenosine triphosphate synapses in rat primary cortical neuron cultures: The key role of adenosine monophosphate activated protein kinase. AB - Nuclear respiratory factor-2alpha (NRF-2alpha) is an important transcription factor that regulates mitochondrial oxidative phosphorylation and regeneration. NRF-2alpha regulates mitochondrial transcription factors (mTF)A and B, and mitochondrial DNA by indirectly regulating the mitochondrial respiratory enzyme chain subunit. In addition, NRF-2alpha is involved in the mitochondrial energy metabolism. Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), is an important transcription coactivator of NRF-2alpha. Adenosine monophosphate-activated protein kinase (AMPK) is considered an important effector in the regulation of the energy metabolism balance of nervous system microenvironments. However, the signaling mechanism underlying the energy coupling of PGC-1alpha and NRF-2alpha in visual cortical neurons remains to be elucidated. The present study used a primary culture system of rat visual cortical neurons in order to investigate whether AMPK is involved in the regulation of NRF-2alpha and PGC-1alpha expression in cortical neurons. The results of the present study indicated that KCl depolarization rapidly activated AMPK, and significantly increased the expression levels of PGC-1alpha, NRF-2alpha and mtTFA, as well as adenosine triphosphate production in cultured neurons. Similarly, the AMPK agonists 5-aminoimidazole-4-carboxamide riboside and resveratrol significantly increased the mRNA expression levels of PGC-1alpha and NRF-2alpha in cultured neurons. These responses were blocked by compound C, an AMPK inhibitor. In conclusion, AMPK is an important transcriptional regulator of the neuronal excitation response, and exerts its regulatory effects via the PGC 1alpha/NRF-2alpha signaling pathway. PMID- 26239888 TI - Analysis of the integration of human papillomaviruses in head and neck tumours in relation to patients' prognosis. AB - Integration, which leads to the disruption of the circular HPV genome, is considered as a critical, albeit not obligatory, step in carcinogenic progression. Although cervical carcinomas with extrachromosomal HPV plasmid genomes have been described, the virus is integrated in 70% of HPV16-positive cervical tumours. Limited information is available about HPV integration in head and neck tumours (HNC). In this study, we have characterised the physical status of HPV in a set of tonsillar tumour samples using different methods--the mapping of E2 integration breakpoint at the mRNA level, the 3' RACE based Amplification of Papillomavirus Oncogene Transcripts (APOT) assay and Southern blot. Furthermore, the impact of HPV integration on patients' prognosis has been evaluated in a larger set of 186 patients with head and neck cancer. Based on the analysis of E2 mRNA, HPV was integrated in the host genome in 43% of the HPV positive samples. Extrachromosomal or mixed form was present in 57%. In fresh frozen samples, the APOT and E2 mapping results were in agreement. The results were confirmed using Southern blotting. Furthermore, the type and exact site of integration were determined. The survival analysis of 186 patients revealed HPV positivity, tumour size and lymph node positivity as factors that influence disease specific survival. However, no statistically significant difference was found in disease specific survival between patients with HPV-positive integrated vs. extrachromosomal/mixed forms of the virus. PMID- 26239889 TI - Diurnal intraocular pressure changes in eyes affected with acute primary angle closure and fellow eyes after laser peripheral iridotomy. AB - PURPOSE: To evaluate diurnal curves of intraocular pressure (IOP) in eyes affected with unilateral acute primary angle closure (APAC) after laser peripheral iridotomy (LPI), and fellow eyes. METHODS: The medical records of 22 female patients (44 eyes) with unilateral APAC and LPI performed OU were reviewed along with those of 48 normal control subjects (48 eyes). None of the subjects used glaucoma medications after LPI. IOP was measured with a Goldman applanation tonometer during waking hours and in a sitting position every 2 h between 09:00 and 23:00. IOP profiles were compared including the means, peaks, trough IOPs, and IOP fluctuations of the affected, fellow, and normal eyes. RESULTS: The IOPs of the affected eyes were significantly higher than those of normal eyes at every time point measured, including peak and trough IOPs. The diurnal IOPs of fellow eyes were higher than those of normal eyes, though not significantly. There were no significant differences in IOP fluctuation between the affected, fellow, and normal eyes. IOP diurnal curves for APAC affected, fellow, and normal eyes were not statistically different (repeated measures ANOVA, p = 0.865). The mean coefficient of IOP in affected and fellow eyes ranged from 0.486 to 0.604. CONCLUSIONS: There were no clinically significant differences among the three groups in terms of IOP diurnal curves, and thus LPI did not have a significant effect on diurnal patterns of IOP. Though the diurnal IOPs of affected eyes after LPI was significantly higher than those of normal eyes, the IOP range was not acute. PMID- 26239890 TI - Effects of Polyhexamethylene Biguanide and Polyquaternium-1 on Phospholipid Bilayer Structure and Dynamics. AB - Multipurpose solutions (MPS) are a single solution that functions to simultaneously rinse, disinfect, clean, and store soft contact lenses. Several commercial MPS products contain polyhexamethylene biguanide (PHMB) and/or polyquaternium-1 (PQ-1) as antimicrobial agents. In this paper we have created an in vitro small unilamellar vesicle (SUV) model of the corneal epithelial surface, and we have assessed the interactions of PHMB and PQ-1 with several model biomembranes by using fluorescence spectroscopy, dynamic light scattering (DLS), and liquid chromatography-mass spectrometry (LC-MS). Steady-state and time resolved fluorescence were used to assess the membrane acyl chain and polar headgroup region local microenvironment as a function of added PHMB or PQ-1. DLS was used to detect and quantify SUV aggregation induced by PHMB and PQ-1. LC-MS was used to determine the liposomal composition from any precipitated materials in comparison to the as-prepared SUVs. The results are consistent with PHMB adsorbing onto and PQ-1 intercalating into the biomembrane structure. The differences between the two interaction mechanisms have substantial impacts on the biomembrane dynamics and stability. PMID- 26239891 TI - Design of aqueous redox-enhanced electrochemical capacitors with high specific energies and slow self-discharge. AB - Electrochemical double-layer capacitors exhibit high power and long cycle life but have low specific energy compared with batteries, limiting applications. Redox-enhanced capacitors increase specific energy by using redox-active electrolytes that are oxidized at the positive electrode and reduced at the negative electrode during charging. Here we report characteristics of several redox electrolytes to illustrate operational/self-discharge mechanisms and the design rules for high performance. We discover a methyl viologen (MV)/bromide electrolyte that delivers a high specific energy of ~14 Wh kg(-1) based on the mass of electrodes and electrolyte, without the use of an ion-selective membrane separator. Substituting heptyl viologen for MV increases stability, with no degradation over 20,000 cycles. Self-discharge is low, due to adsorption of the redox couples in the charged state to the activated carbon, and comparable to cells with inert electrolyte. An electrochemical model reproduces experiments and predicts that 30-50 Wh kg(-1) is possible with optimization. PMID- 26239892 TI - Nano-level position resolution for particle tracking in digital in-line holographic microscopy. AB - Three-dimensional particle tracking in biological systems is a quickly growing field, many techniques have been developed providing tracking characters. Digital in-line holographic microscopy is a valuable technique for particle tracking. However, the speckle noise, out-of-focus signals and twin image influenced the particle tracking. Here an adaptive noise reduction method based on bidimensional ensemble empirical mode decomposition is introduced into digital in-line holographic microscopy. It can eliminate the speckle noise and background of the hologram adaptively. Combined with the three-dimensional deconvolution approach in the reconstruction, the particle feature would be identified effectively. Tracking the fixed beads on the cover-glass with piezoelectric stage through multiple holographic images demonstrate the tracking resolution, which approaches 2 nm in axial direction and 1 nm in transverse direction. This would facilitate the development and use in the biological area such as living cells and single molecule approaches. PMID- 26239893 TI - Anti-inflammatory properties and expression in selected organs of canine interleukin-1beta splice variant 1. AB - The IL-1beta gene can be also be spliced with the intron 4 retention; the result is a IL-1beta splice variant 1 (IL-1betasv1), which was significantly up regulated in failing myocardium of dogs suffering from chronic degenerative valvular disease (CDVD). Expression of IL-1betasv1 was assessed, at both RNA and protein levels, in organs affected by heart failure, namely, kidneys, liver, and lungs from 35 dogs suffering chronic degenerative valvular disease (CDVD) and in 20 disease free control dogs. IL-1betasv1 RNA was detected in the dogs from both groups. In the CDVD group, the highest RNA and protein IL-1betasv1 levels were observed in lungs, followed, in that order, by the liver and kidneys. IL-1betasv1 protein was found in the cytoplasm of hepatocytes and IL-1betasv1-overexpressing DH82 cells. In lungs, IL-1betasv1 was localized in the cytoplasm and in the nuclei of bronchiolar epithelial and smooth-muscle cells. Cytoplasmic and nuclear IL-1betasv1 expression was observed in macrophages, and a strong nuclear signal was detected in epithelial cells of the alveolar sacs. Following lipopolysaccharide (LPS) stimulation, overexpression of IL-1betasv1 in DH82 cells decreased the pro-inflammatory response. Our results indicate that IL-1betasv1 is constitutively expressed in both normal tissues and in tissues from cases of heart failure. The presence of IL-1betasv1 in tissues exposed to invading agents and its anti-inflammatory activity in DH82 cells may point to its immunomodulatory role in vivo. PMID- 26239894 TI - Inactivation of Bacteria on Explanted Dialysis Catheter Lumens with Fiber Optically Delivered Ultraviolet Light. AB - PURPOSE: To evaluate the germicidal effect of fiber optically delivered ultraviolet (UV) light on colonized explanted dialysis catheters. MATERIALS AND METHODS: Explanted dialysis catheters were screened for intraluminal colonization by culturing 1 mL of a saline flush. Catheters growing >10 colony-forming units were treated with doses of fiber optically delivered UV light (range, 40-1,300 mJ/cm2). For each UV-treated catheter, an unexposed segment was first cut and set aside as a control sample. A sterile optical fiber was inserted into the catheter hub and advanced to the catheter tip. The fiber was slowly withdrawn at a constant rate while exposing the inner lumen to UV light. A second UV-exposed segment was then removed. The UV-exposed and control segments were split and sonicated to remove the adherent bacteria. The bacteria were counted and identified. RESULTS: There were 14 colonized catheters treated with UV light. The catheters were primarily colonized with coagulase-negative staphylococci (60%) and Staphylococcus aureus (33%). There was a significant reduction in viable bacteria between the UV-treated versus untreated segments of each infected catheter (P = .04). In the seven treated catheters with >100,000 colony-forming units per cm2 of luminal surface area, there was a >99.5% reduction of viable bacteria in all UV-exposed samples, with no residual viable bacteria in four of seven (57%) of the samples. CONCLUSIONS: This study demonstrates the technical feasibility and benchtop efficacy of using fiber optics to deliver UV light into the lumen of a colonized dialysis catheter and inactivating bacteria on the intraluminal surface. PMID- 26239895 TI - Initial Clinical Experience: Symmetric-Tip Dialysis Catheter with Helical Flow Characteristics Improves Patient Outcomes. AB - PURPOSE: To report preliminary clinical experience with a new symmetric-tip dialysis catheter compared with a conventional split-tip catheter. MATERIALS AND METHODS: Over a 5-month period, patients requiring a tunneled catheter for hemodialysis or undergoing exchange of a dysfunctional dialysis catheter at a tertiary academic medical center were retrospectively analyzed. Patients underwent placement of a VectorFlow or Ash Split Cath catheter at the discretion of the inserting interventional radiologist. Patient demographics, catheter patency, mean blood flow rate, and arterial and venous pressures were compared according to catheter type. Catheter failure was analyzed based on clinical and anatomic variables by using a multivariate Cox proportional-hazards model. RESULTS: A total of 33 VectorFlow and 46 Ash Split Cath catheters were placed. Patients in the VectorFlow group had significantly higher body mass index (P = .013) and Charlson Comorbidity Index (P = .049), as well as more non-internal jugular vein placements. At 120 days, 89% of VectorFlow catheters remained functional, compared with 45% of Ash Split Cath catheters (P = .046). The VectorFlow catheter was associated with 16% lower arterial pressures during dialysis (P = .009); mean blood flow rate was equivalent. On multivariate analysis, the risk of catheter failure was 13.3 times higher in the Ash Split Cath group compared with the VectorFlow group (P = .004). Left-sided catheters were also predictive of catheter failure (relative risk = 5.5; P = .02). CONCLUSIONS: The VectorFlow catheter was associated with a significant increase in intervention-free catheter patency compared with the Ash Split Cath catheter, with equivalent flow at lower arterial pressures during dialysis. PMID- 26239896 TI - Root Cause Analysis of Rebleeding Events following Transjugular Intrahepatic Portosystemic Shunt Creation for Variceal Hemorrhage. AB - PURPOSE: To identify fundamental causes underlying recurrent variceal hemorrhage (VH) after transjugular intrahepatic portosystemic shunt (TIPS) to ascertain opportunities for improvement of TIPS-based management of VH and prevention of rebleeding. MATERIALS AND METHODS: This single-center retrospective study comprised 166 patients (male-to-female ratio 101:65; median age, 52 y; median Model for End-Stage Liver Disease score, 14) who had TIPS created for VH in 1998 2014. Medical record review was used to identify patients who had recurrent VH events, and root cause analysis allowed identification of the most probable causal factors. A 5-person interventional radiology physician group generated quality improvement (QI) recommendations for process changes to address causal factors, with consensus achieved using a modified Delphi method. RESULTS: Variceal rebleeding occurred after TIPS in 25 (15%) patients. The 1-, 3-, and 5 year variceal rebleeding incidence was 17%, 21%, and 21%, respectively. Variceal rebleeding was associated with high 90-day all-cause mortality incidence (10/25; 40%). Male sex (P = .018) and Model for End-Stage Liver Disease score (P = .009) were statistically associated with variceal rebleeding. The most common primary and secondary causes of recurrent VH were lack of or insufficient variceal embolization (64%). Other causal factors included TIPS stenosis or occlusion (28%) with recurrent portosystemic gradient (PSG) elevation (20%), severe coagulopathy (20%), inadequate portosystemic gradient reduction (12%), and TIPS underdilation (4%). To potentially address variceal rebleeding, 14 preventive QI recommendations were developed. CONCLUSIONS: Although recurrent VH rates after TIPS are not trivial, rebleeding may be related to addressable underlying causal factors. Further investigation may assess the efficacy of QI-based procedure methodologic enhancements in reducing rebleeding incidence after TIPS. PMID- 26239897 TI - Morphological concordance between CBCT and MDCT: a paranasal sinus-imaging anatomical study. AB - PURPOSE: Cone-beam computed tomography (CBCT) is an imaging technique, first developed for use during oral and pre-implant surgery. In sinonasal surgery, CBCT might represent a valuable tool for anatomical research given its high spatial resolution and low irradiation dose. However, clinical and anatomical evidence pertaining to its efficacy is lacking. This study assessed the morphological concordance between CBCT and multislice detector computed tomography (MDCT) in the context of sinonasal anatomy. METHODS: We performed an anatomical study using 15 fresh cadaver heads. Each head underwent both CBCT and MDCT. Two independent reviewers evaluated 26 notable anatomical landmarks. The primary outcome was the overall morphological concordance between the two imaging techniques. Secondary objectives included assessment of inter-rater agreement and comparison of the radiation doses received by different parts of the anatomy. RESULTS: Overall morphological concordance between the two imaging techniques was excellent (>98 %); the inter-rater agreement for CBCT was approximately 97 %, which is highly similar to MDCT, but achieved using a significantly decreased irradiation dose. CONCLUSION: Our preliminary study indicates that CBCT represents a valid, reproducible, and safe technique for the identification of relevant sinonasal anatomical structures. Further research, particularly in pathological contexts, is required. PMID- 26239898 TI - Synthesis and biological evaluation of conformationally restricted adenine bicycloribonucleosides. AB - We prepared a novel series of conformationally restricted bicyclonucleosides and nucleotides. The synthetic approach employed a ring closing metathesis to provide access to both 6 and 7 membered saturated and unsaturated rings linking the 3' to 5' methylene groups of the sugar. The bicyclonucleosides were also transformed to the corresponding phosphoramidate prodrugs by an innovative one-pot protocol of boronate ester protection, coupling of the phosphoryl chloridate and deprotection of the boronate. A similar strategy was also employed for the synthesis of the corresponding monophosphates as crucial intermediates for the synthesis of selected triphosphates. The biological properties of the nucleosides and monophosphate prodrugs were assessed for antiviral and cytostatic activities in cell based assays whilst the triphosphates were evaluated in enzymatic assays. The lack of significant effects suggests that the linkage of the 3' to 5'via a ring system and the subsequent conformational restriction of the ribose ring to the South conformation are incompatible with the kinases and polymerases that recognize nucleosides and their metabolites. PMID- 26239899 TI - Echocardiography in the Management of Patients with Left Ventricular Assist Devices: Recommendations from the American Society of Echocardiography. PMID- 26239900 TI - Guidelines for the Echocardiographic Assessment of Atrial Septal Defect and Patent Foramen Ovale: From the American Society of Echocardiography and Society for Cardiac Angiography and Interventions. PMID- 26239901 TI - "Keeping Up" without being "Held Up". PMID- 26239903 TI - Evolutions in Quality in Training and Accreditation for Vascular Imaging. PMID- 26239904 TI - TBL2 Associates With ATF4 mRNA Via Its WD40 Domain and Regulates Its Translation During ER Stress. AB - PKR-like ER-resident kinase (PERK) phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2alpha) under endoplasmic reticulum (ER) stress; this results in repression of general translation and induction of specific gene expression, such as activating transcription factor 4 (ATF4). We previously showed that, upon ER stress, transducin (beta)-like 2 (TBL2) was an ER-localized transmembrane protein and interacted with PERK and that TBL2 was involved in ATF4 expression and cell survival. Here, we show that TBL2 is able to associate with ATF4 mRNA and regulate its translation. The RNA-immunoprecipitation analysis using several TBL2 deletion mutants revealed that the WD40 domain was essential for association with ATF4 mRNA. Importantly, suppression of TBL2 by knockdown or overexpression of the TBL2 mutant with a defective WD40 domain diminished ATF4 induction at the translational level. Thus, our findings indicate that, under ER stress, TBL2 participates in ATF4 translation through its association with the mRNA. PMID- 26239905 TI - A novel expression cassette delivers efficient production of exclusively tetrameric human butyrylcholinesterase with improved pharmacokinetics for protection against organophosphate poisoning. AB - Butyrylcholinesterase is a stoichiometric bioscavenger against poisoning by organophosphorus pesticides and nerve agents. The low level of expression and extremely rapid clearance of monomeric recombinant human butyrylcholinesterase (rhBChE) from bloodstream (t1/2~2 min) limits its pharmaceutical application. Recently (Ilyushin at al., PNAS, 2013) we described a long-acting polysialylated recombinant butyrylcholinesterase (rhBChE-CAO), stable in the bloodstream, that protects mice against 4.2 LD50 of VR. Here we report a set of modifications of the initial rhBChE expression vector to improve stability of the enzyme in the bloodstream and increase its production in CHO cells by introducing in the expression cassette: (i) the sequence of the natural human PRAD-peptide in frame with rhBChE gene via "self-processing" viral F2A peptide under control of an hEF/HTLV promoter, and (ii) previously predicted in silico MAR 1-68 and MAR X-29 sequences. This provides fully tetrameric rhBChE (4rhBChE) at 70 mg/l, that displays improved pharmacokinetics (t1/2 = 32 +/- 1.2 h, MRT = 43 +/- 2 h). 3D Fluorescent visualization and distribution of (125)I-labeled enzyme reveals similar low level 4rhBChE and rhBChE-CAO accumulation in muscle, fat, and brain. Administered 4rhBChE was mainly catabolized in the liver and breakdown products were excreted in kidney. Injection of 1.2 LD50 and 1.1 LD50 of paraoxon to BALB/c and knockout BChE-/- mice pre-treated with 4rhBChE (50 mg/kg) resulted in 100% and 78% survival, respectively, without perturbation of long-term behavior. In contrast, 100% mortality of non-pre-treated mice was observed. The high expression level of 4rhBChE in CHO cells permits consideration of this new expression system for manufacturing BChE as a biopharmaceutical. PMID- 26239906 TI - A comparative study of acellular nerve xenografts and allografts in repairing rat facial nerve defects. AB - Acellular nerves are composed of a basal lamina tube, which retains sufficient bioactivity to promote axon regeneration, thereby repairing peripheral nerve gaps. However, the clinical application of acellular allografts has been restricted due to its limited availability. To investigate whether xenografts, a substitute to allograft acellular nerves in abundant supply, could efficiently promote nerve regeneration, rabbit and rat acellular nerve grafts were used to reconstruct 1 cm defects in Wistar rat facial nerves. Autologous peroneal nerve grafts served as a positive control group. A total of 12 weeks following the surgical procedure, the axon number, myelinated axon number, myelin sheath thickness, and nerve conduction velocity of the rabbit and rat-derived acellular nerve grafts were similar, whereas the fiber diameter of the rabbit-derived acellular xenografts decreased, as compared with those of rat-derived acellular allografts. Autografts exerted superior effects on nerve regeneration; however, no significant difference was observed between the axon number in the autograft group, as compared with the two acellular groups. These results suggested that autografts perform better than acellular nerve grafts, and chemically extracted acellular allografts and xenografts have similar effects on the regeneration of short facial nerve defects. PMID- 26239908 TI - Subclinical atherosclerosis in Behcet's disease: A systematic review and meta analysis. AB - OBJECTIVE: To evaluate subclinical atherosclerosis in Behcet disease (BD), we performed a systematic review and meta-analysis of studies where atherosclerosis was determined by flow-mediated dilatation (FMD) and endothelial-mediated dilatation (EMD) and by measurement of intima media thickness (IMT) of carotid arteries. METHODS: Systematic search of EMBASE and PubMed databases from January 2000 to January 2014 according to PRISMA guidelines. RESULTS: Nine studies met the inclusion criteria on FMD/EMD, 11 on IMT and 4 on both. BD had lower FMD than controls (SMD = -0.89, 95% CI: -0.660 to -1.11, p < 0.001), which was confirmed by subgroup analyses on active and inactive patients (SMD = -1.17, 95% CI: -1.45 to -0.89 and SMD = -0.72, 95% CI: -0.97 to -0.46, p = 0.0001 for both). EMD was lower in BD but with a large estimate (SMD = 0.38, 95% CI: -0.79 to -0.03, p = 0.06, I(2) = 82.2%). IMT was greater in BD and the large estimate (SMD = 0.95, 95% CI: 0.63-1.28, p < 0.0001, I(2) = 87.6%) persisted after subgroup analysis on active and inactive patients (I(2) = 88.4% and 86.7%, respectively). Pooling IMT studies by a Newcastle Ottawa Scale of 5 and 6/7 yielded lower estimates (SMD = 0.54, 95% CI: 0.32-0.75, p < 0.0001, I(2) = 58.7% and SMD = 1.72, 95% CI: 1.35 2.09 p < 0.05, I(2) = 48.6%). CONCLUSIONS: FMD is impaired in BD even in inactive state and IMT is greater despite a degree of statistical heterogeneity that reflects the clinical heterogeneity of BD. Future prospective studies should account for risk stratification of atherosclerosis in BD. PMID- 26239907 TI - Oxalate nephropathy in systemic sclerosis: Case series and review of the literature. AB - OBJECTIVE: To increase awareness of oxalate nephropathy as a cause of acute kidney injury (AKI) among systemic sclerosis patients with small intestinal dysmotility and malabsorption, and to prompt consideration of dietary modification and early treatment of predisposing causes of oxalate nephropathy in this population. METHODS: Two cases of biopsy-proven oxalate nephropathy were identified among systemic sclerosis patients in the course of direct clinical care. Subsequently, a retrospective search of the Johns Hopkins Pathology databases identified a third patient with systemic sclerosis who developed oxalate nephropathy. RESULTS: Among the three patients with qualifying biopsies, all three had systemic sclerosis with lower gastrointestinal involvement. All three presented with diarrhea, malabsorption, and AKI. In two of the three patients, diarrhea was present for at least 2 years before the development of AKI; in the third, incidental oxalate nephropathy was noted 3 years before she developed AKI and extensive oxalate nephropathy in the setting of a prolonged mycobacterium avium-intracellulare enteritis. In the first case, oxalate crystals were present by urinalysis months before diagnosis by biopsy; in the second, hyperoxaluria was diagnosed by urine collection immediately after; and in the third, oxalate crystals had been noted incidentally on post-transplant renal biopsy 3 years before the development of fulminant oxalate nephropathy. All three patients died within a year after diagnosis. CONCLUSIONS: Patients with systemic sclerosis and bowel dysmotility associated with chronic diarrhea and malabsorption may be at risk for an associated oxalate nephropathy. Regular screening of systemic sclerosis patients with small bowel malabsorption syndromes through routine urinalysis or 24-h urine oxalate collection, should be considered. Further studies defining the prevalence of this complication in systemic sclerosis, the benefit of dietary modification on hyperoxaluria, the effect of treating small intestinal bowel overgrowth with antibiotics, and the effectiveness of probiotics, calcium supplements, or magnesium supplements to prevent hyperoxaluria-associated renal disease in these patients, are warranted. PMID- 26239909 TI - Morphological analysis of Francisella novicida epithelial cell infections in the absence of functional FipA. AB - Francisella novicida is a surrogate pathogen commonly used to study infections by the potential bioterrorism agent, Francisella tularensis. One of the primary sites of Francisella infections is the liver where >90% of infected cells are hepatocytes. It is known that once Francisella enter cells it occupies a membrane bound compartment, the Francisella-containing vacuole (FCV), from which it rapidly escapes to replicate in the cytosol. Recent work examining the Francisella disulfide bond formation (Dsb) proteins, FipA and FipB, have demonstrated that these proteins are important during the Francisella infection process; however, details as to how the infections are altered in epithelial cells have remained elusive. To identify the stage of the infections where these Dsbs might act during epithelial infections, we exploited a hepatocyte F. novicida infection model that we recently developed. We found that F. novicida DeltafipA-infected hepatocytes contained bacteria clustered within lysosome associated membrane protein 1-positive FCVs, suggesting that FipA is involved in the escape of F. novicida from its vacuole. Our morphological evidence provides a tangible link as to how Dsb FipA can influence Francisella infections. PMID- 26239910 TI - Proteomics of post-translational modifications of mammalian spermatozoa. AB - It is hard to fathom that one of the most highly differentiated cells in the body, the spermatozoon, spends over half of its developmental life without the capacity for nuclear protein biosynthesis. This is even more incredible when considering that protein synthesis is switched off long before the sperm is mature. As such, in order to obtain full functionality, spermatozoa rely on post translational modifications (PTM) of existing proteins. Many PTM have been shown to play a role in the development of a sperm cell. These include phosphorylation and glycosylation events that occur both in the epididymis and during capacitation. In addition, several other PTM such as disulfide cross-linking, ubiquitination, acetylation and methylation all play a role to both develop and enable a spermatozoon to achieve its final destiny. PMID- 26239911 TI - Adipose tissue macrophages in non-rodent mammals: a comparative study. AB - The stromal vascular fraction (SVF) of adipose tissue in rodents and primates contains mesenchymal stem cells and immune cells. SVF cells have complex metabolic, immune and endocrine functions with biomedical impact. However, in other mammals, the amount of data on SVF stem cells is negligible and whether the SVF hosts immune cells is unknown. In this study, we show that the SVF is rich in immune cells, with a dominance of adipose tissue macrophages (ATMs) in cattle (Bos primigenius taurus), domestic goat (Capra aegagrus hircus), domestic sheep (Ovis aries), domestic cat (Felis catus) and domestic dog (Canis familiaris). ATMs of these species are granulated lysosome-rich cells with lamellipodial protrusions and express the lysosome markers acid phosphatase 5 (ACP-5) and Mac 3/Lamp-2. Using ACP-5 and Mac-3/Lamp-2 as markers, we additionally detected ATMs in other species, such as the domestic horse (Equus ferus caballus), wild boar (Sus scrofa) and red fox (Vulpes vulpes). Feline and canine ATMs also express the murine macrophage marker F4/80 antigen. In the lean condition, the alternative macrophage activation marker CD206 is expressed by feline and canine ATMs and arginase-1 by feline ATMs. Obesity is associated with interleukin-6 and interferon gamma expression and with overt tyrosine nitration in both feline and canine ATMs. This resembles the obesity-induced phenotype switch of murine and human ATMs. Thus, we show, for the first time, that the presence of ATMs is a general trait of mammals. The interaction between the adipose cells and SVF immune cells might be evolutionarily conserved among mammals. PMID- 26239913 TI - Deleterious impacts of a 900-MHz electromagnetic field on hippocampal pyramidal neurons of 8-week-old Sprague Dawley male rats. AB - Children are at potential risk due to their intense use of mobile phones. We examined 8-week-old rats because this age of the rats is comparable with the preadolescent period in humans. The number of pyramidal neurons in the cornu ammonis of the Sprague Dawley male rat (8-weeks old, weighing 180-250 g) hippocampus following exposure to a 900 MHz (MHz) electromagnetic field (EMF) were examined. The study consisted of control (CN-G), sham exposed (SHM-EG) and EMF exposed (EMF-EG) groups with 6 rats in each. The EMF-EG rats were exposed to 900 MHz EMF (1h/day for 30 days) in an EMF jar. The SHM-EG rats were placed in the EMF jar but not exposed to the EMF (1h/day for 30 days). The CN-G rats were not placed into the exposure jar and were not exposed to the EMF during the study period. All animals were sacrificed at the end of the experiment, and their brains were removed for histopathological and stereological analysis. The number of pyramidal neurons in the cornu ammonis of the hippocampus was estimated on Cresyl violet stained sections of the brain using the optical dissector counting technique. Histopathological evaluations were also performed on these sections. Histopathological observation showed abundant cells with abnormal, black or dark blue cytoplasm and shrunken morphology among the normal pyramidal neurons. The largest lateral ventricles were observed in the EMF-EG sections compared to those from the other groups. Stereological analyses showed that the total number of pyramidal neurons in the cornu ammonis of the EMF-EG rats was significantly lower than those in the CN-G (p<0.05) and the SHM-EG (p<0.05). In conclusion, our results suggest that pyramidal neuron loss and histopathological changes in the cornu ammonis of 8-week-old male rats may be due to the 900-MHz EMF exposure. PMID- 26239912 TI - Regenerative cellular therapies for neurologic diseases. AB - The promise of stem cell regeneration has been the hope of many neurologic patients with permanent damage to the central nervous system. There are hundreds of stem cell trials worldwide intending to test the regenerative capacity of stem cells in various neurological conditions from Parkinson's disease to multiple sclerosis. Although no stem cell therapy is clinically approved for use in any human disease indication, patients are seeking out trials and asking clinicians for guidance. This review summarizes the current state of regenerative stem cell transplantation divided into seven conditions for which trials are currently active: demyelinating diseases/spinal cord injury, amyotrophic lateral sclerosis, stroke, Parkinson's disease, Huntington's disease, macular degeneration and peripheral nerve diseases. This article is part of a Special Issue entitled SI: PSC and the brain. PMID- 26239914 TI - Cell therapy for Parkinson's disease: Functional role of the host immune response on survival and differentiation of dopaminergic neuroblasts. AB - Parkinson's disease (PD) is a neurodegenerative disorder, whose cardinal pathology is the loss of dopaminergic neurons in the substantia nigra. Current treatments for PD have side effects in the long term and do not halt disease progression or regenerate dopaminergic cell loss. Attempts to compensate neuronal cell loss by transplantation of dopamine-producing cells started more than 30 years ago, leading to several clinical trials. These trials showed safety and variable efficacy among patients. In addition to variability in efficacy, several patients developed graft-induced dyskinesia. Nevertheless, they have provided a proof of concept that motor symptoms could be improved by cell transplantation. Cell transplantation in the brain presents several immunological challenges. The adaptive immune response should be abolished to avoid graft rejection by the host. In addition, the innate immune response will always be present after transplanting cells into the brain. Remarkably, the innate immune response can have dramatic effects on the survival, differentiation and proliferation of the transplanted cells, but has been hardly investigated. In this review, we analyze data on the functional effects of signals from the innate immune system on dopaminergic differentiation, survival and proliferation. Then, we discussed efforts on cell transplantation in animal models and PD patients, highlighting the immune response and the immunomodulatory treatment strategies performed. The analysis of the available data lead us to conclude that the modulation of the innate immune response after transplantation can increase the success of future clinical trials in PD by enhancing cell differentiation and survival. This article is part of a Special Issue entitled SI: PSC and the brain. PMID- 26239916 TI - A highly sensitive and specific method for the screening detection of genetically modified organisms based on digital PCR without pretreatment. AB - Digital PCR has developed rapidly since it was first reported in the 1990 s. It was recently reported that an improved method facilitated the detection of genetically modified organisms (GMOs). However, to use this improved method, the samples must be pretreated, which could introduce inaccuracy into the results. In our study, we explored a pretreatment-free digital PCR detection method for the screening for GMOs. We chose the CaMV35s promoter and the NOS terminator as the templates in our assay. To determine the specificity of our method, 9 events of GMOs were collected, including MON810, MON863, TC1507, MIR604, MIR162, GA21, T25, NK603 and Bt176. Moreover, the sensitivity, intra-laboratory and inter-laboratory reproducibility of our detection method were assessed. The results showed that the limit of detection of our method was 0.1%, which was lower than the labeling threshold level of the EU. The specificity and stability among the 9 events were consistent, respectively. The intra-laboratory and inter-laboratory reproducibility were both good. Finally, the perfect fitness for the detection of eight double-blind samples indicated the good practicability of our method. In conclusion, the method in our study would allow more sensitive, specific and stable screening detection of the GMO content of international trading products. PMID- 26239917 TI - Event Documentation and Transfer of Care After Severe Contrast Reactions. AB - PURPOSE: Radiology residencies are increasingly using clinical simulation to teach contrast reaction management. The aim of this study was to evaluate resident documentation of management and transfer of care in severe contrast reactions after a clinical simulation. METHODS: After a high-fidelity mannequin simulation of contrast-induced anaphylactic shock, residents (n = 18) were asked to document the event in a progress note and transfer care to a receiving medical team. A total of 22 prospectively determined criteria were selected, and notes were analyzed by a blinded reviewer. RESULTS: Notes contained between 12 and 21 of the prospectively determined 22 criteria (54%-95%). The median number of criteria contained in a note was 16. None of the notes fulfilled all 22 criteria. However, consistent deficiencies were found in documenting prior reaction to contrast (28%) and transfer-of-care criteria (22%-44%). CONCLUSIONS: Although standards for the documentation of advanced cardiovascular life support codes and other emergencies have been devised, no such standards exist for documentation in the management of contrast reactions. The results of this study suggest the need to develop a standardized documentation system for severe contrast-induced reactions. Education regarding transfer of care and documentation should be emphasized during clinical simulation. PMID- 26239915 TI - The cnidarian origin of the proto-oncogenes NF-kappaB/STAT and WNT-like oncogenic pathway drives the ctenophores (Review). AB - The cell survival pathways of the diploblastic early multicellular eukaryotic hosts contain and operate the molecular machinery resembling those of malignantly transformed individual cells of highly advanced multicellular hosts (including Homo). In the present review, the STAT/NF-kappaB pathway of the cnidarian Nematostella vectensis is compared with that of human tumors (malignant lymphomas, including Reed-Sternberg cells) pointing out similarities, including possible viral initiation in both cases. In the ctenophore genome and proteome, beta-catenin gains intranuclear advantages due to a physiologically weak destructive complex in the cytoplasm, and lack of natural inhibitors (the dickkopfs). Thus, a scenario similar to what tumor cells initiate and achieve is presented through several constitutive loss-of-function type mutations in the destructive complex and in the elimination of inhibitors. Vice versa, malignantly transformed individual cells of advanced multicellular hosts assume pheno genotypic resemblance to cells of unicellular or early multicellular hosts, and presumably to their ancient predecessors, by returning to the semblance of immortality and to the resumption of the state of high degree of resistance to physicochemical insults. Human leukemogenic and oncogenic pathways are presented for comparisons. The supreme bioengineers RNA/DNA complex encoded both the malignantly transformed immortal cell and the human cerebral cortex. The former generates molecules for the immortality of cellular life in the Universe. The latter invents the inhibitors of the process in order to gain control over it. PMID- 26239919 TI - The Curious Case of the Limping Toddler. PMID- 26239918 TI - Systematically Prioritizing Functional Differentially Methylated Regions (fDMRs) by Integrating Multi-omics Data in Colorectal Cancer. AB - While genome-wide differential DNA methylation regions (DMRs) have been extensively identified, the comprehensive prioritization of their functional importance is still poorly explored. Here, we aggregated multiple data resources rooted in the genome, epigenome and transcriptome to systematically prioritize functional DMRs (fDMRs) in colorectal cancer (CRC). As demonstrated, the top ranked fDMRs from all of the data resources showed a strong enrichment for known methylated genes. Additionally, we analyzed those top 5% DMR-coupled coding genes using functional enrichment, which resulted in significant disease-related biological functions in contrast to the tail 5% genes. To further confirm the functional importance of the top-ranked fDMRs, we applied chromatin modification alterations of CRC cell lines to characterize their functional regulation. Specifically, we extended the utility of the top-ranked DMR-coupled genes to serve as classification and survival biomarkers, which showed a robust performance across diverse independent data sets. Collectively, our results established an integrative framework to prioritize fDMRs, which could help characterize aberrant DNA methylation-induced potential mechanisms underlying tumorigenesis and uncover epigenome-based biomarkers for clinical diagnosis and prognosis. PMID- 26239920 TI - The Therapy Beneath the Fun: Medical Clowning During Invasive Examinations on Children. AB - OBJECTIVE: The qualitative research presented here is part of a larger project on the significance of medical clowning during invasive examinations in children in the Department of Gastroenterology and the Center for the Sexually Abused in a hospital in Israel. It investigated what makes up the essence of medical clowning, what skills and techniques are used by medical clowns, and whether their work contains therapeutic elements. METHODS: A total of 9 children undergoing invasive examinations and 9 of their accompanying parents participated in semistructured interviews, which were analyzed using a thematic analysis methodology assisted by an Atlas-ti software program. RESULTS: The interviews revealed that the medical clowning intervention during invasive examinations was essentially therapeutic, with the clown using theatrical and clowning tools to incorporate therapeutic elements such as empowerment, reversal of role, reframing, and building a therapeutic alliance. In addition, during the invasive examinations, the medical clowning followed the model of brief crisis intervention therapy. CONCLUSION: The study advances the need to incorporate medical clowns as an integral part of medical teams performing invasive procedures and to include clowns in all stages of the hospital visit when children undergo invasive examinations. PMID- 26239921 TI - Developing Case Definitions for Health Care-Associated Infections for Pediatric Long-Term Care Facilities. PMID- 26239923 TI - Glycome characterization of immunoglobulin G from buffalo (Bubalus bubalis) colostrum. AB - Immunoglobulin G (IgG) is a major glycoprotein in ruminant colostrum. First day buffalo colostrum protein was purified on Sephadex G-100 and its mass was determined by MALDI-TOF as 147.848 KDa. The PMF data of protein subunits revealed its homology to IgG, which was supported by the identification of peptide sequences LLIYGATSR and VYNEYLPAPIVR corresponding to light and heavy chains of IgG by CID MS/MS analysis. The N-glycan microheterogeneity was established based on chemoselective glycoblotting technique with the identification of high mannose, neutral complex/hybrid and sialylated complex/hybrid glycans. A complete structural assignment of 54 N-linked oligosaccharides were identified and the ratio of sialyl oligosaccharides was found to be higher compared to neutral saccharides. The fucosylation observed in more than 20 oligosaccharides, high mannose and trisialyl oligosaccharides were present in diminutive amount. The high non-fucosyl and sialyl oligosaccharides in buffalo colostrum IgG provide ample scope for its utilization in targeted therapies to elicit effective ADCC and anti-inflammatory responses. PMID- 26239925 TI - The shear effort of measurement of portal hypertension. PMID- 26239926 TI - Racial and Ethnic Disparities among Pediatric Patients at Community Health Centers. AB - OBJECTIVES: To assess racial/ethnic disparities in pediatric utilization of community health centers (CHCs) among a nationally representative sample. STUDY DESIGN: Using the 2009 Health Center Patient Survey, a nationally representative sample of CHC patients, demographic characteristics, health conditions, and service utilization were examined for patients under 18 years old (n = 590). Negative binomial and logistic regression models assessed disparities in access to routine care, ambulatory service intensity, and hospital utilization. RESULTS: Racial/ethnic disparities were not present for well-child visits or dental checkups. However, disparities in ambulatory care service intensity and hospital use were observed. Compared with white children, Hispanic children had fewer CHC visits (incidence rate ratio [IRR] 0.62; 95% CI 0.41-0.95), and fewer visits to other ambulatory providers (IRR 0.30; 95% CI 0.15-0.61). Black children had fewer CHC visits (IRR 0.46; 95% CI 0.31-0.70) and fewer visits to other ambulatory providers (IRR 0.23; 95% CI 0.06-0.91), and were also less likely to have been hospitalized (OR 0.04; 95% CI 0.01-0.26). CONCLUSIONS: Study limitations included the cross-sectional study design, the self-reported data, and the age of the data. Nevertheless, this study demonstrates that there are fewer disparities among children who visit CHCs in comparison with national trends, but there is still room for improvement. Future initiatives should address remaining challenges in ensuring access to care for all children in underserved communities. PMID- 26239924 TI - Fluorescently labelled glycans and their applications. AB - This review summarises the literature on the synthesis and applications of fluorescently labelled carbohydrates. Due to the sensitivity of fluorescent detection, this approach provides a useful tool to study processes involving glycans. A few general categories of labelling are presented, in situ labelling of carbohydrates with fluorophores, fluorescently labelled glycolipids, fluorogenic glycans, pre-formed fluorescent glycans for intracellular applications, glycan-decorated fluorescent polymers, fluorescent glyconanoparticles, and other functional fluorescent glycans. PMID- 26239927 TI - Bilirubin Concentrations in Jaundiced Neonates with Conjunctival Icterus. AB - OBJECTIVES: To assess the total serum bilirubin (TSB) levels at which conjunctival icterus is observed in neonates of >=34 weeks gestation during the first week of life. STUDY DESIGN: Two convenience samples of neonates were examined for conjunctival icterus within 4 hours of TSB measurements. A concurrent assessment of cephalopedal cutaneous icterus was performed and the TSB characterized using the Bhutani hour-specific risk zone nomogram. RESULTS: Two hundred forty neonates were studied of which 76 had conjunctival icterus. Conjunctival icterus was always accompanied by cutaneous jaundice to at least the chest and more often than not a TSB >14.9 mg/dL (255 umol/L) consistently in the 76th%-95th% to >95th% range on the Bhutani nomogram. Only a few infants with TSB in the range of 10-14.9 mg/dL (171-255 umol/L) had conjunctival icterus. CONCLUSIONS: Conjunctival icterus was observed in a subset of jaundiced neonates and associated with elevated hour-specific TSB levels frequently >95th% on the Bhutani nomogram. Conjunctival icterus is a sign of clinically relevant hyperbilirubinemia that merits a TSB measurement and evaluation of the infant. PMID- 26239928 TI - Natural History of Patent Ductus Arteriosus in Very Low Birth Weight Infants after Discharge. AB - Data on the natural history of infants discharged with patent ductus arteriosus is sparse. We report on the 36-months follow-up after hospitalization in 68 infants discharged with an open ductus arteriosus. Notwithstanding a high spontaneous closure rate, catheter intervention in 5 infants illustrates a critical need for cardiologic follow-up. PMID- 26239922 TI - Exploring the role and diversity of mucins in health and disease with special insight into non-communicable diseases. AB - Mucins are major glycoprotein components of the mucus that coats the surfaces of cells lining the respiratory, digestive, gastrointestinal and urogenital tracts. They function to protect epithelial cells from infection, dehydration and physical or chemical injury, as well as to aid the passage of materials through a tract i.e., lubrication. They are also implicated in the pathogenesis of benign and malignant diseases of secretory epithelial cells. In Human there are two types of mucins, membrane-bound and secreted that are originated from mucous producing goblet cells localized in the epithelial cell layer or in mucous producing glands and encoded by MUC gene. Mucins belong to a heterogeneous family of high molecular weight proteins composed of a long peptidic chain with a large number of tandem repeats that form the so-called mucin domain. The molecular weight is generally high, ranging between 0.2 and 10 million Dalton and all mucins contain one or more domains which are highly glycosylated. The size and number of repeats vary between mucins and the genetic polymorphism represents number of repeats (VNTR polymorphisms), which means the size of individual mucins can differ substantially between individuals which can be used as markers. In human it is only MUC1 and MUC7 that have mucin domains with less than 40% serine and threonine which in turn could reduce number of PTS domains. Mucins can be considered as powerful two-edged sword, as its normal function protects from unwanted substances and organisms at an arm's length while, malfunction of mucus may be an important factor in human diseases. In this review we have unearthed the current status of different mucin proteins in understanding its role and function in various non-communicable diseases in human with special reference to its organ specific locations. The findings described in this review may be of direct relevance to the major research area in biomedicine with reference to mucin and mucin associated diseases. PMID- 26239929 TI - Skin Plaques Mimicking Psoriasis. PMID- 26239931 TI - Erratum to: Differential susceptibility to maternal expressed emotion in children with ADHD and their siblings? Investigating plasticity genes, prosocial and antisocial behaviour. PMID- 26239932 TI - Monte Carlo validation and optimisation of detector packaging for spectroscopic dosimetry for in vivo urethral dosimetry during low dose rate brachytherapy. AB - The urethral mini-dosimeter, developed by the Centre for Medical Radiation Physics, University of Wollongong, uses spectroscopic dosimetry to provide real time point dose measurements along the urethra during low dose rate prostate brachytherapy. Spectroscopic dosimetry uses the measured spectrum of the treatment isotope to estimate the dose rate at the point of measurement, however, the silicon mini-detectors employed in the urethral mini-dosimeter require water proof encapsulation which must be capable of providing electromagnetic shielding without greatly increasing the size of the probe. The introduction of non-tissue equivalent materials within the encapsulation can change the spectrum of radiation incident on the detector, which may influence the application of spectroscopic dosimetry within the urethral dosimeter. The Monte Carlo code Geant4 was adopted to study the effect of encapsulation on the operation of the urethral mini-dosimeter, as well as to determine whether an appropriate thickness of aluminium shielding was possible for electromagnetic screening. The depth dose response and angular dependence of the urethral mini-dosimeter with three thicknesses of aluminium shielding (20, 50, 100 um) was compared with the urethral mini-dosimeter without aluminium shielding. The aluminium shielding had the effect of increasing the depth dose response (up to 3% within 30 mm and up to 5% within 50 mm), slightly reduced the azimuth angular dependence and slightly increased the polar angular dependence. The 100 um thick shielding provided the least azimuth angular dependence (+/-2 %) and provided a polar angular dependence of +/-1.4 % within the angles of -45 degrees to 45 degrees . PMID- 26239933 TI - Population Pharmacokinetics of Vancomycin in Postoperative Neurosurgical Patients. AB - Neurosurgical procedures may damage the blood-brain barrier to allow more vancomycin distribution into the cerebrospinal fluid (CSF) from blood after intravenous administration. However, a large intersubject variability in CSF vancomycin concentration was observed. We aimed to develop a population pharmacokinetic model to guide vancomycin dosing in patients after neurosurgical operation. Blood and CSF samples were collected and determined from postoperative neurosurgical patients after vancomycin administration. A three-compartment (central, peripheral, and CSF) model was proposed to characterize the pharmacokinetics of vancomycin. A nonlinear mixed-effects modeling approach was applied to fit the blood and CSF data simultaneously. The covariate analysis found that the CSF albumin level was strongly associated with the clearance between central and CSF compartment. Visual predictive check indicated that the proposed population pharmacokinetic model agrees well with the observed vancomycin concentrations. Individualized vancomycin dosage regimens could be developed for postoperative neurosurgical patients with different CSF albumin levels through model simulations. The CSF albumin level is a determinant of CSF vancomycin concentration. PMID- 26239935 TI - Commercial-scale recycling of NdFeB-type magnets with grain boundary modification yields products with 'designer properties' that exceed those of starting materials. AB - NdFeB-type magnets dominate the market for high performance magnetic materials, yet production of 'virgin' magnets via mining is environmentally, financially and energetically costly. Hence, interest is growing in 'magnet to magnet' recycling schemes that offer the potential for cheaper, more environmentally-friendly solutions to the world's growing appetite for rare-earth based magnetic materials. Unfortunately, previously described recycling processes only partially capitalise on this potential, because the methods described to date are limited to 'laboratory scale' or operate only under ideal conditions and result in products that fail to recapture the coercivity of the starting, scrap materials. Herein, we report a commercial scale process (120 kg batches) that completely recovers the properties of the starting scrap magnets. Indeed, 'grain boundary modification', via careful addition of a proprietary mix of blended elements, produces magnets with 'designer properties' that can exceed those of the starting materials and can be closely tailored to meet a wide variety of end-user applications, including high-coercivity (>2000 kA/m), sintered magnets suitable for motor applications. PMID- 26239934 TI - [Moderate preterm birth 34-37 weeks: Description of immediate neonatal causes and consequences in a level 2 maternity]. AB - OBJECTIVES: In France, 75% of annual preterm births happen between 34 and 36 weeks+6 days. This study's goal is to describe the main causes and short-term consequences. METHODS: Two hundred and ninety-seven computerized files of patients who gave birth between 34 and 36 weeks+6 days at the hospital Foch's maternity were analyzed retrospectively. Descriptive statistical analysis was done with XLSTAT 2008. RESULTS: Among the 6028 births, 4.9% happened between 34 and 36 weeks+6 days and 43.1% of these births were medically induced. The two main causes of induced late preterm birth were: pre-eclampsia (28.9%) and premature rupture of membranes (25%). In spontaneous deliveries, newborns less often require respiratory support at birth (17.2% vs 31%; P=0.02) and are significantly less likely to be hospitalized in neonatology (54% vs 72.3%; P<0.01). C-section rates (71.1% vs 17.75%; P<0.01) and post-partum hemorrhages' probability (10.2% vs 3%; P<0.01) are significantly higher than for medically induced deliveries. CONCLUSION: Better knowledge of late prematurity causes and consequences would help limit medically induced births after 34 weeks. PMID- 26239936 TI - Materials recovery from waste liquid crystal displays: A focus on indium. AB - In the present work the recovery of indium and of the polarizing film from waste liquid crystal displays was experimentally investigated in the laboratory. First of all, the polarizing film was removed by employing a number of different techniques, including thermal and chemical treatments. Leaching of indium was then performed with HCl 6N, which allowed solubilisation of approximately 90% In (i.e. 260 mg In per kg of glass) at room temperature, without shredding. Indium recovery from the aqueous phase was then investigated through solvent extraction with polyethylene glycol (PEG)-based aqueous biphasic systems. Indium extraction tests through the PEG-ammonium sulphate-water system were conducted as a function of PEG concentration, salt concentration and molecular weight of PEG, using 1,10 phenanthroline as a ligand. The experimental results demonstrated that indium partitioning between the bottom (salt-rich) and the top (PEG-rich) phase is quite independent on the composition of the system, since 80-95% indium is extracted in the bottom phase and 5-20% in the top phase; it was also found that when PEG concentration is increased, the ratio between the bottom and the upper phase volumes decreases, resulting in an increase of indium concentration in the bottom phase (at [PEG]=25% w/w, indium concentration in the bottom phase is ~30% higher than the initial concentration before the extraction). PMID- 26239937 TI - Agricultural waste utilisation strategies and demand for urban waste compost: Evidence from smallholder farmers in Ethiopia. AB - The use of agricultural waste for soil amendment is limited in developing countries. Competition between fuel and feed is the major cause for the insufficient application of agricultural waste on cropland. The aims of this study were therefore (i) to investigate variation in agricultural waste allocation between groups of farmers with different livelihood strategies and link this allocation with the nutrient balances of their production systems, (ii) to identify farm characteristics that influence utilisation of agricultural waste for soil amendment, and (iii) to assess demand for urban waste compost. A total of 220 farmers were selected randomly and interviewed using standardised semi structured questionnaires. Four groups of farmers, namely (i) field crop farmers, (ii) vegetable producers, (iii) ornamental-plant growers, and (iv) farmers practising mixed farming, were identified using categorical principal component and two-step cluster analyses. Field crop farmers produced the largest quantity of agricultural waste, but they allocated 80% of manure to fuel and 85% of crop residues to feed. Only <10% of manure and crop residues were applied on soils. Farmers also sold manure and crop residues, and this generated 5-10% of their annual income. Vegetable and ornamental-plant growers allocated over 40% of manure and crop residues to soil amendment. Hence, nutrient balances were less negative in vegetable production systems. Education, farm size, land tenure and access to extension services were the variables that impeded allocation of agricultural waste to soil amendment. Replacement of fuel and feed through sustainable means is a viable option for soil fertility management. Urban waste compost should also be used as alternative option for soil amendment. Our results showed variation in compost demand between farmers. Education, landownership, experience with compost and access to extension services explained variation in compost demand. We also demonstrated that labour availability should be used to estimate compost demand beside cash. PMID- 26239938 TI - Nitrification of leachates from manure composting under field conditions and their use in horticulture. AB - This work aimed to demonstrate the feasibility of nitrification applied to the treatment of leachates formed during composting of cattle and pig manure in order to promote their further use as liquid fertilizer in horticulture. Nitrification trials were successfully conducted in summer and winter seasons under Mediterranean climate conditions. Subsequently, effect of using the nitrified effluents as nutritive solution in the fertigation of lettuce (Lactuca sativa L.) was assessed in terms of productivity and nutrient uptake. Similar productivities were obtained when using the nitrified effluents and a standard nutritive solution. However, results also evidenced high nutrient uptake, which indicates that dosage should be adjusted to culture requirements. PMID- 26239939 TI - Endophthalmitis After Intravitreal Injections: Incidence, Presentation, Management, and Visual Outcome. PMID- 26239940 TI - Serum cobalamin concentrations and small intestinal ultrasound changes in 75 cats with clinical signs of gastrointestinal disease: a retrospective study. AB - Objectives The aim of the study was to evaluate ultrasonographic changes in the small intestine of cats with clinical signs of gastrointestinal disease and low or low-normal serum cobalamin concentrations. Methods Records for client-owned cats presenting to the small animal hospital with signs of gastrointestinal disease and in which serum cobalamin concentrations were measured from 2000-2013 were reviewed. Inclusion criteria were cobalamin concentrations <500 ng/l, abdominal ultrasound within 1 month of cobalamin testing and definitive diagnosis. Results Of 751 serum cobalamin measurements, hypocobalaminemia or low normal cobalamin was identified in 270 cats, abdominal ultrasound was performed in 207 of those cats and a diagnosis was available for 75 of them. Small intestinal ultrasound changes were detected in 49/75 (65%) cats. Abnormalities included thickening, loss of wall layer definition, echogenicity alterations and discrete masses. Serum cobalamin concentrations <500 ng/l were observed with diagnoses of inflammatory disease, neoplasia, infectious disease and normal histopathology. Cobalamin concentration was significantly lower in cats with lymphoma or inflammatory bowel disease compared with other gastrointestinal neoplasia ( P = 0.031). No difference was found between cobalamin concentration and the presence of ultrasound abnormalities, specific ultrasound changes or albumin concentration. Conclusions and relevance One-third of symptomatic cats with hypocobalaminemia or low-normal cobalamin concentrations may have an ultrasonographically normal small intestine. For the majority of cats in this study, histopathologic abnormalities were observed in the small intestine, regardless of ultrasound changes. These findings suggest gastrointestinal disease should not be excluded based on low-normal cobalamin concentrations, even with a concurrent normal ultrasound examination. Additional studies are needed in cats with low-normal serum cobalamin concentrations, as a definitive diagnosis was not pursued consistently in those cats. However, data from this study suggest that careful monitoring, histopathologic evaluation and future cobalamin supplementation may be warranted. PMID- 26239941 TI - Retrospective assessment of peripheral nerve block techniques used in cats undergoing hindlimb orthopaedic surgery. AB - OBJECTIVES: The aim of this study was to assess retrospectively the efficacy and complication rate of hindlimb peripheral nerve blocks (PNBs) in cats. METHODS: Clinical records of cats that received PNBs and underwent hindlimb orthopaedic surgery from February 2010 to October 2014 were examined. Type of PNB, type and dose of local anaesthetic used, end-expiratory fraction of isoflurane (FE'Iso) administered, additional intraoperative analgesia, incidence of hypotension, postoperative opioid requirement, postoperative contralateral limb paralysis and neurological complications at the 6 week re-examination were investigated. RESULTS: Eighty-nine records were retrieved but only 69 were analysed. Four combinations of PNBs were used: 34 lateral preiliac (LPI) approach to lumbar plexus (LP) associated with lumbar paravertebral approach to sciatic nerve (SN); 20 LPI-LP associated with the lateral approach to SN; three LPI-LP associated with gluteal approach to SN; 12 dorsal-paravertebral (DPV) approach to LP associated with lateral SN. Levobupivacaine was used for the majority of PNBs. The mean intraoperative FE'Iso was 1.15%; hypotension was documented in 55.1% of anaesthetics, while 31.8% of cats received fentanyl and/or ketamine intraoperatively. Postoperatively, 72.7% of cats received at least one dose of opioid, while five cats required further postoperative analgesia (ketamine constant rate infusion and/or gabapentin). No cats showed contralateral limb paralysis and neurological complications at the 6 week re-examination. No differences were found when comparing the different PNBs used. CONCLUSIONS AND RELEVANCE: PNBs contributed to perioperative anaesthesia/analgesia in cats undergoing hindlimb orthopaedic surgery. However, the clinical relevance of intraoperative hypotension needs further investigation. PMID- 26239942 TI - Ultrastructure of dermal denticles in sharpnose shark (Rhizoprionodon lalandii) (Elasmobranchii, Carcharhinidae). AB - The presence of denticles in the external surface, oral cavity, fins, and clasper of Elasmobranchii has been widely reported. These structures, called body denticles, may be observed on the body surface of sharks. Dermal and oral denticles are made up by a basal plate that is embedded in the dermis, forming a peduncle that grows from the base to the crown. These denticles may protect the skin against abrasion, and improve hydrodynamics and gill arches function. Rhizoprionodon lalandii is a widely distributed and very common species in Brazilian coastal areas. The aims of this study was to compare the morphology of oral and body denticles of R. lalandii to understand the implications of these structures in the behavior of these animals. Morphological analysis showed that there are differences between dermal and oral denticles, which are related to their role in different body regions. Body denticles have three cusps, and well defined crests and ridges, and literature data suggest that suggest that hydrodynamics is their main function. Most of the oral denticles have only one cusp, and their morphology and distribution showed that their main functions are preparing food to be swallowed and protecting the oral cavity against abrasion. PMID- 26239943 TI - Anodic electrogenerated chemiluminescence of self-assembled peptide nanotubes in an aqueous system. AB - Anodic electrogenerated chemiluminescence (ECL) of the self-assembled peptide nanotube (PNT) modified electrode in an aqueous system was observed for the first time using tri-n-propylamine (TPrA) as the coreactant. The potential application of ECL PNTs in analytical chemistry was also demonstrated using Cu(2+) as an example. PMID- 26239944 TI - Visceral adiposity in persons with chronic spinal cord injury determined by dual energy X-ray absorptiometry. AB - OBJECTIVE: To determine visceral adipose tissue (VAT) volume (VATvol) by dual energy X-ray absorptiometry (DXA) in spinal cord injured (SCI) and able-bodied (AB) participants and to explore the relationships between VATvol and routine anthropometric measures. METHODS: Sixty-three subjects with SCI and 126 healthy male AB controls were stratified as low risk [LR: waist circumference (WC) < 102 cm] and moderate to high risk (MHR: WC >= 102 cm) for identification of risk for cardiometabolic disease: AB-LR, SCI-LR, AB-MHR, and SCI-MHR. Anthropometrics and standard body composition measurements by DXA with analysis to derive VATvol were performed. RESULTS: Comparison of the four subgroups demonstrated the highest subcutaneous adipose tissue volume (SATvol) in the AB-MHR group (P < 0.01), and the highest VATvol in the SCI-MHR group (P < 0.01). Furthermore, when compared to the AB group, participants with SCI had a 27% increase in VATvol for every centimeter increase in WC and a 20% increase in VATvol for every unit increase in BMI. CONCLUSIONS: Because cutoff values for the routine surrogate measures of adiposity underestimate visceral adiposity in persons with SCI, the risk of adverse metabolic consequences would also be underestimated, which necessitates adjustment of the these cutoff values or, preferably, to perform its direct measurement. PMID- 26239945 TI - Effect of quantum dots on the biological behavior of the EJ human bladder urothelial carcinoma cell line. AB - Quantum dots (QDs) are a type of fluorescent label with applications in biological molecules, cells and in vivo imaging. The current study investigated the effect of QDs on the toxicity, proliferation, migration and invasion of the EJ human bladder cancer cell line in vitro. The cell counting kit-8 test was used to measure the survival rate of EJ cells following incubation with varying concentrations of QDs. Additionally, the effect of QDs on tumor cell migration and invasion was evaluated using the Transwell chamber assay, and cell proliferation rate was assessed using a hemocytometer. Data from the current study demonstrated no significant differences in survival rate between the experimental and control groups with the conventionally used concentrations (5, 10 and 20 nM) of QD605 (P>0.05). However, with high concentrations of QD605 (40 and 80 nM), significant differences were observed (P<0.001). The survival rate of EJ cells, however, remained at 92.6%. In addition, no significant differences were observed between the EJ cells labeled with transactivator of transcription (TAT)-QD605 and the unlabeled EJ cells with regard to proliferation, migration and invasion (P>0.05). Thus, the results of the current study indicate that QDs exhibit a certain degree of influence on the activity of the EJ bladder cancer cell line at high concentrations. However, at the concentrations that QDs are conventionally used, there was little impact on the survival of the EJ cells. In addition, the proliferation, migration and invasion abilities of the EJ cells were not affected by TAT-QDs. Therefore, the peptide-conjugated QDs have potential to be applied in the imaging and tracking of live cells in vitro and of animals in vivo. Notably, QDs may provide the foundation for a novel, non invasive imaging strategy for the early diagnosis of tumors. PMID- 26239946 TI - Contemporary faces of diabetes care for youth and young adults in the 21st century: evolution in the roles of patients and families, healthcare providers and systems, behavioral health, and the online community. PMID- 26239947 TI - Differential optimal dopamine levels for set-shifting and working memory in Parkinson's disease. AB - Parkinson's disease (PD) is an important model for the role of dopamine in supporting human cognition. However, despite the uniformity of midbrain dopamine depletion only some patients experience cognitive impairment. The neurocognitive mechanisms of this heterogeneity remain unclear. A genetic polymorphism in the catechol O-methyltransferase (COMT) enzyme, predominantly thought to exert its cognitive effect through acting on prefrontal cortex (PFC) dopamine transmission, provides us with an experimental window onto dopamine's role in cognitive performance in PD. In a large cohort of PD patients (n=372), we examined the association between COMT genotype and two tasks known to implicate prefrontal dopamine (spatial working memory and attentional set-shifting) and on a task less sensitive to prefrontal dopamine (paired associates learning). Consistent with the known neuroanatomical locus of its effects, differences between the COMT genotype groups were observed on dopamine-dependant tasks, but not the paired associates learning task. However, COMT genotype had differential effects on the two prefrontal dopamine tasks. Putative prefrontal dopamine levels influenced spatial working memory in an 'Inverted-U'-shaped fashion, whereas a linear, dose dependant pattern was observed for attentional set-shifting. Cumulatively, these results revise our understanding of when COMT genotype modulates cognitive functioning in PD patients by showing that the behavioural consequences of genetic variation vary according to task demands, presumably because set-shifting and working memory have different optimal dopamine levels. PMID- 26239948 TI - Ferric Citrate, an Iron-Based Phosphate Binder, Reduces Health Care Costs in Patients on Dialysis Based on Randomized Clinical Trial Data. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) require phosphate binders for hyperphosphatemia and erythropoiesis-stimulating agents (ESAs) and intravenous (i.v.) iron for anemia. Ferric citrate (FC) is a novel, iron-based phosphate binder that increases iron stores and decreases i.v. iron and ESA usage while maintaining hemoglobin levels, and may decrease the cost of ESRD care. The study objectives were to (1) quantify differences in ESA and i.v. iron usage among ESRD patients receiving FC compared with active control (AC) (sevelamer carbonate and/or calcium acetate) on the basis of data from a 52-week phase III clinical trial and (2) standardize trial data to the general United States (US) ESRD population and calculate the potential impact of FC on ESRD cost/patient/year in the USA. STUDY DESIGN: The study was a randomized, controlled clinical trial. SETTING AND POPULATION: A total of 441 adult subjects with ESRD who received FC or AC for 52 weeks were included. MODEL, PERSPECTIVE, AND TIMELINE: Differences in ESA and i.v. iron usage between the treatment groups were modeled over time using generalized linear mixed models and zero-inflated Poisson models. Trends were modeled via logarithmic curves, and utilization patterns were applied to the general dialysis population to estimate expected resource savings. OUTCOMES: Study outcomes were costs saved/patient/year using FC versus AC (US dollars). RESULTS: Our model suggests an annual decrease of 129,106 U of ESAs and 1960 mg of i.v. iron per patient in the second year after a switch from AC to FC. Applying 2013 Medicare pricing, this would save $1585 in ESAs and $516 in i.v. iron: a total of $2101/patient/year; these savings would be expected to double for managed care plans. LIMITATIONS: The projections were made on 1 year of trial data. CONCLUSIONS: Phosphate binding with FC reduces i.v. iron and ESA usage. Given the high cost burden of ESRD, our model demonstrates significant potential cost savings. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01191255) http://clinicaltrials.gov/ct2/show/NCT01191255 . PMID- 26239949 TI - Involvement of adenosine monophosphate-activated protein kinase in the influence of timed high-fat evening diet on the hepatic clock and lipogenic gene expression in mice. AB - A high-fat diet may result in changes in hepatic clock gene expression, but potential mechanisms are not yet elucidated. Adenosine monophosphate-activated protein kinase (AMPK) is a serine/threonine protein kinase that is recognized as a key regulator of energy metabolism and certain clock genes. Therefore, we hypothesized that AMPK may be involved in the alteration of hepatic clock gene expression under a high-fat environment. This study aimed to examine the effects of timed high-fat evening diet on the activity of hepatic AMPK, clock genes, and lipogenic genes. Mice with hyperlipidemic fatty livers were induced by orally administering high-fat milk via gavage every evening (19:00-20:00) for 6 weeks. Results showed that timed high-fat diet in the evening not only decreased the hepatic AMPK protein expression and activity but also disturbed its circadian rhythm. Accordingly, the hepatic clock genes, including clock, brain-muscle-Arnt like 1, cryptochrome 2, and period 2, exhibited prominent changes in their expression rhythms and/or amplitudes. The diurnal rhythms of the messenger RNA expression of peroxisome proliferator-activated receptoralpha, acetyl-CoA carboxylase 1alpha, and carnitine palmitoyltransferase 1 were also disrupted; the amplitude of peroxisome proliferator-activated receptorgammacoactivator 1alpha was significantly decreased at 3 time points, and fatty liver was observed. These findings demonstrate that timed high-fat diet at night can change hepatic AMPK protein levels, activity, and circadian rhythm, which may subsequently alter the circadian expression of several hepatic clock genes and finally result in the disorder of hepatic lipogenic gene expression and the formation of fatty liver. PMID- 26239950 TI - Reduced linoleic acid intake in early postnatal life improves metabolic outcomes in adult rodents following a Western-style diet challenge. AB - The global increase in dietary n-6 polyunsaturated fatty acid (PUFA) intake has been suggested to contribute to the rise in obesity incidence. We hypothesized that reduced n-6 PUFA intake during early postnatal life improves adult body composition and metabolic phenotype upon a Western diet challenge. Male offspring of C57Bl/6j mice and Wistar rats were subjected to a control diet (CTRL; 3.16 En% linoleic acid [LA]) or a low n-6 PUFA diet (low LA; 1.36 En% LA) from postnatal days (PNs) 2 to 42. Subsequently, all animals were switched to a Western-style diet (2.54 En% LA) until PN98. We monitored body composition by dual-energy x-ray absorptiometry and glucose homeostasis by an intravenous glucose and insulin tolerance test in rats and by the homeostasis model assessment of insulin resistance (HOMA-IR) in mice. At PN98, plasma lipids, glucose, insulin, and adipokines were measured and adipocyte number and size were analyzed. In mice, the postnatal low-LA diet decreased fat accumulation during the adult Western style diet challenge (-27% compared with CTRL, P < .001). Simultaneously, it reduced fasting triglyceride levels and lowered fasting resistin and leptin levels. In rats, the low-LA diet did not affect adult body composition, but decreased the number of retroperitoneal adipocytes and increased the number of large adipocytes. In conclusion, lowering dietary n-6 PUFA intake in early life protected against detrimental effects of an obesogenic diet in adulthood on metabolic homeostasis and fat mass accumulation. PMID- 26239952 TI - A patient request for some "deprescribing". PMID- 26239953 TI - Real-Time MRI-Guided Catheter Tracking Using Hyperpolarized Silicon Particles. AB - Visualizing the movement of angiocatheters during endovascular interventions is typically accomplished using x-ray fluoroscopy. There are many potential advantages to developing magnetic resonance imaging-based approaches that will allow three-dimensional imaging of the tissue/vasculature interface while monitoring other physiologically-relevant criteria, without exposing the patient or clinician team to ionizing radiation. Here we introduce a proof-of-concept development of a magnetic resonance imaging-guided catheter tracking method that utilizes hyperpolarized silicon particles. The increased signal of the silicon particles is generated via low-temperature, solid-state dynamic nuclear polarization, and the particles retain their enhanced signal for >= 40 minutes- allowing imaging experiments over extended time durations. The particles are affixed to the tip of standard medical-grade catheters and are used to track passage under set distal and temporal points in phantoms and live mouse models. With continued development, this method has the potential to supplement x-ray fluoroscopy and other MRI-guided catheter tracking methods as a zero-background, positive contrast agent that does not require ionizing radiation. PMID- 26239954 TI - Response to the Letter to the Editor by Waarsenburg et al. PMID- 26239955 TI - Pelvic floor symptoms in female cyclists and possible remedies: a narrative review. AB - INTRODUCTION AND HYPOTHESIS: Cycling has become a popular athletic activity worldwide and can lead to genital and pelvic floor dysfunction. This review summarizes the current body of evidence about the epidemiology of genital and pelvic floor symptoms in female cyclists, the therapy, and preventive interventions. METHODS: Two electronic meta-databases, OvidSPTM and Deutsches Institut fur Medizinische Dokumentation und Information (DIMDI), comprising 40 individual databases, were searched for studies that described genital and pelvic floor symptoms in association with cycling and studies that tested possible therapies and prophylactic measures. For the literature search we explored the search terms "female", "bicycling", "pelvic floor", "lower urinary tract symptoms", and "vulvar diseases". RESULTS: The search retrieved 1,219 articles, leaving 763 articles after removal of duplicates, and finally 12 articles eligible for review. We assessed 10 observational and 2 experimental studies. Genital and pelvic floor symptoms related to bicycling were pain, tenderness, neuropathy, urological dysfunction and skin lesions. Broader and conventionally shaped saddles were associated with fewer symptoms compared with cut-out saddle designs. CONCLUSION: The quality of existing studies is generally low, but there is evidence that female cyclists suffer from similar problems to male cyclists, ranging from minor skin lesions to severe sequelae such as pain and neurological deficiencies. PMID- 26239957 TI - Comments on Lone et al.: One-year prospective comparison of vaginal pessaries and surgery for pelvic organ prolapse using the validated ICIQ-VS and ICIQ-UI (SF) questionnaires. PMID- 26239956 TI - The "1-3-5 cough test": comparing the severity of urodynamic stress incontinence with severity measures of subjective perception of stress urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: The purpose of the study was to examine whether a test performed during urodynamics, the "1-3-5 cough test", could determine the severity of urodynamic stress incontinence (USI). METHODS: We included women referred for urodynamics who were diagnosed with USI. The "1-3-5 cough test" was performed to grade the severity of USI at the completion of filling cystometry. A diagnosis of "severe", "moderate" or "mild" USI was given if urine leakage was observed after one, three or five consecutive coughs respectively. We examined the associations between grades of USI severity and measures of subjective perception of stress urinary incontinence (SUI): International Consultation of Incontinence Modular Questionnaire-Female Lower Urinary Tract Symptom (ICIQ FLUTS), King's Health Questionnaire (KHQ), Urinary Distress Inventory-6 (UDI-6), Urinary Impact Questionnaire-7 (UIQ-7). RESULTS: A total of 1,181 patients completed the ICIQ-FLUTS and KHQ and 612 completed the UDI-6 and UIQ-7 questionnaires. There was a statistically significant association of higher grades of USI severity with higher scores of the incontinence domain of the ICIQ FLUTS. The scores of the UDI-6, UIQ-7 and of all KHQ domains (with the exception of general health perception and personal relationships) had statistically significant larger mean values for higher USI severity grade. Groups of higher USI severity had statistically significant associations with higher scores of most of the subjective measures of SUI. CONCLUSIONS: Severity of USI, as defined by the "1-3-5 cough test", was associated with the severity of subjective measures of SUI. This test may be a useful tool for the objective interpretation of patients with SUI who undergo urodynamics. PMID- 26239958 TI - GALNT2 mRNA levels are associated with serum triglycerides in humans. PMID- 26239959 TI - [Acute disseminated encephalomyelitis is an important differential diagnosis in the acutely affected child]. AB - Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory paediatric disorder of the central nervous system (CNS). ADEM primarily affects the white matter of the brain and spinal cord. The aetiology of ADEM is unknown, but the illness is often precipitated by an infection, less often by vaccination. ADEM is characterized by acute polyfocal CNS deficit, including encephalopathy. This can be seen on MRI as simultaneously occurring multifocal lesions. Empirical treatment with steroids or immunoglobulins is often used. The prognosis of ADEM is usually favourable. This article describes two Danish cases both demonstrating trait characteristics of ADEM as well as the importance of an MRI considering an ADEM diagnosis early in the course of the illness. PMID- 26239960 TI - [Patients with basal cell naevus syndrome should be offered an early multidisciplinary follow-up and treatment]. AB - Basal cell naevus syndrome (Gorlin-Goltz syndrome) is a rare, autosomal dominantly inherited condition with a wide range of developmental and multiple organ-related anomalies. Cardinal features include multiple basal cell carcinomas, jaw cysts, palmoplantar pits and calcification of the falx cerebri. Other important clinical features are skeletal abnormalities and facial dysmorphism including macrocephaly. Germ-line mutations are found in PTCH1. Management of the syndrome requires a multidisciplinary approach, and in this article management guidelines are reviewed and discussed. PMID- 26239961 TI - [Detection of occult cancer in patients with idiopathic venous thrombosis]. AB - Idiopathic venous thrombosis (VTE) is frequently associated with underlying malignancy. Thus, it is tempting to search for underlying cancer in these patients. However, extensive screening is cost-intensive and no survival benefit has been demonstrated. Based on a review of the literature, we recommend the performance of a thorough medical history and physical examination in addition to basic biochemical screening and a chest X-ray in patients with idiopathic VTE. Only specific symptoms or findings should lead to a more extensive work-up. PMID- 26239962 TI - [Improved immunologic response after laparoscopic versus open colorectal cancer surgery]. AB - Laparoscopic colorectal cancer surgery results in a reduced impact on the immune system compared with open surgery. This is important when taken into consideration that the immune system may have an instrumental role in the advancement of cancer in the perioperative period. Several studies have shown that the perioperative period is characterized by an immune incompetent period, which is believed to favour tumour metastasis. In this paper factors associated with the cellular and innate immune response in relation to laparoscopic and open colorectal cancer surgery are reviewed. PMID- 26239963 TI - [The Masquelet procedure used after an open femur fracture with infection and osteomyelitis]. AB - The treatment of patients with larger bone defects due to infections, trauma or tumours is a challenge in orthopaedic surgery. In 1986 Alain Charles Masquelet introduced a new technique using a two-step procedure, in which cement and bone graft is used to reconstruct the defect. The Masquelet procedure is an effective alternative to methods formerly used in Denmark, but is still rarely used and unknown by many. In this case report we present a young woman with a large bone defect due to infection after an open femur fracture, who was successfully treated using this method. PMID- 26239964 TI - Dynamism of the aortic annulus: Effect of diastolic versus systolic CT annular measurements on device selection in transcatheter aortic valve replacement (TAVR). AB - BACKGROUND: Annular dimensions, including cross-sectional area, perimeter and subsequently derived diameters, are subject to dynamic changes throughout the cardiac cycle. There is ongoing controversy as to whether perimeter measurement changes between systole and diastole are too small to impact on valve sizing. OBJECTIVES: To assess both the variability of aortic annular dimensions throughout the cardiac cycle across a range of sub-annular calcification using computed tomography (CT) and the impact of this variability on device size selection for balloon-expandable valves in a large, all-comer multi-center cohort. METHODS: ECG-gated CT data of 507 patients (mean 81 +/- 7.5 years, 60.1% male) were analyzed in this retrospective, multicenter analysis. Aortic annulus dimensions were assessed on pre-specified systolic and diastolic phases by planimetry, yielding both area and perimeter. Contour smoothing was employed to avoid artificial increase in perimeter values by uneven contours. The extent of subannular calcification was graded semi-quantitatively and assessed in relation to the degree of annular dynamism. Hypothetical device sizing was undertaken to assess the impact of using systolic and diastolic measurements on valve selection. RESULTS: Mean annular dimensions were larger during systole than diastole (area: 474.4 +/- 87.4 mm(2) vs. 438.3 +/- 84.3 mm(2) or 8.23%, p < 0.001; perimeter: 78.5 +/- 7.2 mm vs. 75.9 +/- 7.2 mm or 3.36%, p < 0.001). The magnitude of annular area and perimeter change (systolic minus diastolic measurement) was greater among patients without calcification compared to patients with grade 3 calcification. Using diastolic rather than systolic data for device sizing resulted in a change of the recommended valve size in nearly half of patients for both annular area and perimeter. CONCLUSIONS: The systematic differences between systolic and diastolic annular measurements for cross sectional area and perimeter have implications for device sizing with potential for valve under-sizing if diastolic annular dimensions are employed. PMID- 26239965 TI - Higher screen time is associated with overweight, poor dietary habits and physical inactivity in Brazilian adolescents, mainly among girls. AB - OBJECTIVES: To analyse the associations between high screen time and overweight, poor dietary habits and physical activity in adolescents according to sex. METHODS: The study comprised 515 boys and 716 girls aged 14-17 years from Londrina, Brazil. Nutritional status (normal weight or overweight/obese) was assessed by calculating the body mass index. Eating habits and time spent in physical activity were reported using a questionnaire. The measurement of screen time considered the time spent watching television, using a computer and playing video games during a normal week. Associations between high screen time and dependent variables (nutritional status, eating habits and physical activity levels) were assessed by binary logistic regression, adjusted for sociodemographic and lifestyle variables. RESULTS: Most adolescents (93.8% of boys and 87.2% of girls) spent more than 2 hours per day in screen-time activities. After adjustments, an increasing trend in the prevalence of overweight and physical inactivity with increasing time spent on screen activities was observed for both sexes. Screen times of >4 hours/day compared with <2 hours/day were associated with physical inactivity, low consumption of vegetables and high consumption of sweets only in girls and the consumption of soft drinks in both sexes. CONCLUSIONS: The frequency of overweight and physical inactivity increased with increasing screen time in a trending manner and independently of the main confounders. The relationship between high screen time and poor eating habits was particularly relevant for adolescent girls. PMID- 26239966 TI - Genome expression of Thermococcus barophilus and Thermococcus kodakarensis in response to different hydrostatic pressure conditions. AB - Transcriptomes were analyzed for two related hyperthermophilic archaeal species, the piezophilic Thermococcus barophilus strain MP and piezosensitive Thermococcus kodakarensis strain KOD1 subjected to high hydrostatic pressures. A total of 378 genes were differentially expressed in T. barophilus cells grown at 0.1, 40 and 70 MPa, whereas 141 genes were differentially regulated in T. kodakarensis cells grown at 0.1 and 25 MPa. In T. barophilus cells grown under stress conditions (0.1 and 70 MPa), 178 upregulated genes were distributed among three clusters of orthologous groups (COG): energy production and conversion (C), inorganic ion transport and metabolism (P) and carbohydrate transport and metabolism (G), whereas 156 downregulated genes were distributed among: amino acid transport and metabolism (E), replication, recombination and repair (L) and nucleotide transport and metabolism (F). The expression of 141 genes was regulated in T. kodakarensis cells grown under stress conditions (25 MPa); 71 downregulated genes belong to three COG: energy production and conversion (C), amino acid transport and metabolism (E) and transcription (K), whereas 70 upregulated genes are associated with replication, recombination and repair (L), coenzyme transport (H) and defense mechanisms (V). PMID- 26239967 TI - Light-Induced C-H Arylation of (Hetero)arenes by In Situ Generated Diazo Anhydrides. AB - Diazo anhydrides (Ar-N=N-O-N=N-Ar) have been known since 1896 but have rarely been used in synthesis. This communication describes the development of a photochemical catalyst-free C-H arylation methodology for the preparation of bi(hetero)aryls by the one-pot reaction of anilines with tert-butyl nitrite and (hetero)arenes under neutral conditions. The key step in this procedure is the in situ formation and subsequent photochemical (>300 nm) homolytic cleavage of a transient diazo anhydride intermediate. The generated aryl radical then efficiently reacts with a (hetero)arene to form the desired bi(hetero)aryls producing only nitrogen, water, and tert-butanol as byproducts. The scope of the reaction for several substituted anilines and (hetero)arenes was investigated. A continuous-flow protocol increasing selectivity and safety has been developed enabling the experimentally straightforward preparation of a variety of substituted bi(hetero)aryls within 45 min of reaction time. PMID- 26239968 TI - Colchicine derivative as a potential anti-glioma compound. AB - Colchicine, an anti-microtubule and antimitotic drug, is a common therapeutically agent for gout, which is thought to have potential anti-tumor effects. Owing to concerns of colchicines poisoning, the development of derivatives with low dose efficacy and less side effects is of obvious interest. In this study, we characterized the inhibitory effects of a colchicine derivative named AD1 on the cell proliferation of human malignant glioblastoma (MG) cell lines, U87MG and U373MG. We found that 50 % of U87MG and U373MG cells were reduced in the cultures after exposure to AD1 for 24 h at 10 and 50 nM, respectively. Moreover, alpha tubulin immunostaining indicated that AD1 induced the disruption of the microtubule polymerization in glioma cells with apoptotic features including membrane budding/blebbing or fragmented nuclei. Increased levels of reactive oxygen species (ROS) were also detected in AD1-treated U87MG and U373MG cells compared to that observed in the control culture. Moreover, examination of microtubule-associated protein 1A/1B-light chain 3 (LC3I)/LC3II conversion and acridine orange staining for autophagic vesicles, combined with flow cytometry, showed that treatment with AD1 induced the autophagic pathway in U87MG and U373MG cells. Furthermore, we found that the intermittent intravenous administration of AD1 suppressed glioma growth in rat brain receiving intracerebral injection with rat C6 glioma cells. Taken together, our findings reveal that treatment with AD1 at nanomolar scales can reduce glioma cell viability effectively, with the occurrence of a rise in ROS and cellular autophagy. In conjunction with the observations from in vivo study, the colchicine derivative AD1 has chemotherapeutic potential to suppress glioma progression. PMID- 26239969 TI - Imaging and Analysis of Human Vocal Fold Vibration Using Two-Dimensional (2D) Scanning Videokymography. AB - OBJECTIVE: Laryngeal videokymography and high-speed digital kymography are the currently available techniques for studying aperiodic vibration of the vocal folds. However, videokymography has a fundamental limitation that only linear portions of the vocal fold mucosa can be visualized, whereas high-speed digital kymography has the disadvantages of lack of immediate feedback during examination and considerable waiting time before kymographic visualization. We developed a new system, two-dimensional (2D) scanning videokymography, that provides a possible alternative for evaluation of the vibratory pattern of the vocal folds. Herein, we report the application of 2D scanning videokymography for visualization of vocal fold vibration in humans and an analysis of its parameters. MATERIALS AND METHODS: Two young healthy volunteers (one man and one woman) took part in this study. The vibratory patterns of their vocal folds were evaluated using 2D scanning videokymography and laryngeal stroboscopy. RESULTS: Two-dimensional scanning videokymography provided a high-definition image of the vibratory movements of the vocal folds. In analysis of the images acquired by the device, various parameters including fundamental frequency; ratio of the vibratory phases; phase, amplitude, and glottal area symmetry; and cycle-to-cycle variability were extracted. CONCLUSIONS: Our results indicate that 2D scanning videokymography is a useful and promising tool for visualization of the vibratory movement of the vocal folds. This new technique might improve our understanding of the mechanism of vocal fold vibration and contribute to voice research as well as clinical practice. PMID- 26239970 TI - Refractory Dysphonia Due to Isolated Cricothyroid Muscle Dystonia. AB - OBJECTIVE: To demonstrate the utility of electromyography (EMG) in the evaluation and management of treatment-resistant dysphonia. METHOD: We report a case of refractory dysphonia in which EMG was used to identify and treat isolated cricothyroid (CT) dystonia. RESULTS: The patient, a healthy 43-year-old woman, presented with 9 months of progressive hoarseness. Her symptoms were present across vocal tasks but were particularly bothersome while dictating. On presentation, her voice was rated grade 3, roughness 3, breathiness 1, asthenia 0, and strain 3 (G3R3B1A0S3). Videostroboscopy was remarkable for hyperfunction. Voice therapy was not beneficial despite appropriate effort. Microdirect laryngoscopy revealed no evidence of structural pathology. The patient was referred for EMG because of her normal examination and failure to improve with therapy. The CT muscle demonstrated an increased latency of 750 ms in all vocal tasks. One month after CT injection with 3 units of botulinum toxin (BTX), her voice was improved. Perceptual voice evaluation was rated G1R1B0A0S1. Voice Handicap Index improved from 87 to 35. CONCLUSIONS: In the absence of structural pathology, EMG can be a useful adjunct in the diagnosis of dysphonia that persists despite adequate trials of voice therapy. To our knowledge, this is the only report of laryngeal dystonia due to isolated CT dysfunction successfully treated with BTX. PMID- 26239971 TI - Editorial: genomic advances in systemic sclerosis: it is time for precision. PMID- 26239972 TI - Comparison of Different Time of Flight-Mass Spectrometry Modes for Small Molecule Quantitative Analysis. AB - Currently, the use of time of flight (TOF)-mass spectrometry (MS) in quantitative analysis of small molecules is rare. Recently, the quantitative performance of TOF mass analyzers has improved due to the advancements in TOF technology. We evaluated a Q-TOF-MS in different modes, i.e., Q-TOF-full scan (Q-TOF-FS), Q-TOF enhanced-full scan (Q-TOF-En-FS), MS(E), Q-TOF-targeted (Q-TOF-TGT), Q-TOF enhanced-targeted (Q-TOF-En-TGT), and compared their quantitative performance against a unit resolution LC-MS-MS (tandem quadrupole) platform. The five modes were investigated for sensitivity, linearity, signal-to-noise ratio, recovery and precision using 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH) as a model compound in electrospray ionization (ESI) with negative polarity. Preliminary studies indicated that Q-TOF-FS mode was the least linear and precise; hence, it was eliminated from further investigation. Total imprecision in remaining four modes was <10%. The Q-TOF-En-FS and Q-TOF-En-TGT showed better signal intensity than their respective modes without enhancement. Overall, peak signal intensity was the highest in MS(E) mode, whereas the signal-to-noise ratio was the best in the Q-TOF-En-TGT mode. Relatively, MS(E) and Q-TOF-En-TGT modes were the best overall performers compared with the other modes. Both MS(E) and Q TOF-En-TGT modes showed excellent precision (coefficient of variation <6%), patient correlation (r > 0.99) and linearity (range, 5-455 ng/mL) for THC-COOH analysis when compared with LC-MS-MS. We also investigated the performance of the same four modes using methamphetamine in positive ESI. Quantitative data obtained by Q-TOF-En-TGT and MS(E), using both positive and negative ESI, suggest that these modes performed better than the other modes. While unit resolution LC-MS-MS remains the optimal technique for quantification, our data showed that Q-TOF-MS can also be used to quantify small molecules in complex biological specimens. PMID- 26239973 TI - Potent In Vitro Antiproliferative Synergism of Combinations of Ergosterol Biosynthesis Inhibitors against Leishmania amazonensis. AB - Leishmaniases comprise a spectrum of diseases caused by protozoan parasites of the Leishmania genus. Treatments available have limited safety and efficacy, high costs, and difficult administration. Thus, there is an urgent need for safer and more-effective therapies. Most trypanosomatids have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. In previous studies, we showed that Leishmania amazonensis is highly susceptible to aryl-quinuclidines, such as E5700, which inhibit squalene synthase, and to the azoles itraconazole (ITZ) and posaconazole (POSA), which inhibit C-14alpha demethylase. Herein, we investigated the antiproliferative, ultrastructural, and biochemical effects of combinations of E5700 with ITZ and POSA against L. amazonensis. Potent synergistic antiproliferative effects were observed against promastigotes, with fractional inhibitory concentration (FIC) ratios of 0.0525 and 0.0162 for combinations of E5700 plus ITZ and of E5700 plus POSA, respectively. Against intracellular amastigotes, FIC values were 0.175 and 0.1125 for combinations of E5700 plus ITZ and E5700 plus POSA, respectively. Marked alterations of the ultrastructure of promastigotes treated with the combinations were observed, in particular mitochondrial swelling, which was consistent with a reduction of the mitochondrial transmembrane potential, and an increase in the production of reactive oxygen species. We also observed the presence of vacuoles similar to autophagosomes in close association with mitochondria and an increase in the number of lipid bodies. Both growth arrest and ultrastructural/biochemical alterations were strictly associated with the depletion of the 14-desmethyl endogenous sterol pool. These results suggest the possibility of a novel combination therapy for the treatment of leishmaniasis. PMID- 26239974 TI - Pharmacokinetic Modeling of Lamivudine and Zidovudine Triphosphates Predicts Differential Pharmacokinetics in Seminal Mononuclear Cells and Peripheral Blood Mononuclear Cells. AB - The male genital tract is a potential site of viral persistence. Therefore, adequate concentrations of antiretrovirals are required to eliminate HIV replication in the genital tract. Despite higher zidovudine (ZDV) and lamivudine (3TC) concentrations in seminal plasma (SP) than in blood plasma (BP) (SP/BP drug concentration ratios of 2.3 and 6.7, respectively), we have previously reported lower relative intracellular concentrations of their active metabolites, zidovudine triphosphate (ZDV-TP) and lamivudine triphosphate (3TC-TP), in seminal mononuclear cells (SMCs) than in peripheral blood mononuclear cells (PBMCs) (SMC/PBMC drug concentration ratios of 0.36 and 1.0, respectively). Here, we use population pharmacokinetic (PK) modeling-based methods to simultaneously describe parent and intracellular metabolite PK in blood, semen, and PBMCs and SMCs. From this model, the time to steady state in each matrix was estimated, and the results indicate that the PK of 3TC-TP and ZDV-TP in PBMCs are different from the PK of the two in SMCs and different for the two triphosphates. We found that steady-state conditions in PBMCs were achieved within 2 days for ZDV-TP and 3 days for 3TC-TP. However, steady-state conditions in SMCs were achieved within 2 days for ZDV-TP and 2 weeks for 3TC-TP. Despite this, or perhaps because of it, ZDV-TP in SMCs does not achieve the surrogate 50% inhibitory concentration (IC50) (as established for PBMCs, assuming SMC IC50 = PBMC IC50) at the standard 300-mg twice-daily dosing. Mechanistic studies are needed to understand these differences and to explore intracellular metabolite behavior in SMCs for other nucleoside analogues used in HIV prevention, treatment, and cure. PMID- 26239975 TI - Effects of Iron Chelators on the Formation and Development of Aspergillus fumigatus Biofilm. AB - Iron acquisition is crucial for the growth of Aspergillus fumigatus. A. fumigatus biofilm formation occurs in vitro and in vivo and is associated with physiological changes. In this study, we assessed the effects of Fe chelators on biofilm formation and development. Deferiprone (DFP), deferasirox (DFS), and deferoxamine (DFM) were tested for MIC against a reference isolate via a broth macrodilution method. The metabolic effects (assessed by XTT [2,3-bis[2-methoxy-4 nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt]) on biofilm formation by conidia were studied upon exposure to DFP, DFM, DFP plus FeCl3, or FeCl3 alone. A preformed biofilm was exposed to DFP with or without FeCl3. The DFP and DFS MIC50 against planktonic A. fumigatus was 1,250 MUM, and XTT gave the same result. DFM showed no planktonic inhibition at concentrations of <=2,500 MUM. By XTT testing, DFM concentrations of <1,250 MUM had no effect, whereas DFP at 2,500 MUM increased biofilms forming in A. fumigatus or preformed biofilms (P < 0.01). DFP at 156 to 2,500 MUM inhibited biofilm formation (P < 0.01 to 0.001) in a dose-responsive manner. Biofilm formation with 625 MUM DFP plus any concentration of FeCl3 was lower than that in the controls (P < 0.05 to 0.001). FeCl3 at >=625 MUM reversed the DFP inhibitory effect (P < 0.05 to 0.01), but the reversal was incomplete compared to the controls (P < 0.05 to 0.01). For preformed biofilms, DFP in the range of >=625 to 1,250 MUM was inhibitory compared to the controls (P < 0.01 to 0.001). FeCl3 at >=625 MUM overcame inhibition by 625 MUM DFP (P < 0.001). FeCl3 alone at >=156 MUM stimulated biofilm formation (P < 0.05 to 0.001). Preformed A. fumigatus biofilm increased with 2,500 MUM FeCl3 only (P < 0.05). In a strain survey, various susceptibilities of biofilms of A. fumigatus clinical isolates to DFP were noted. In conclusion, iron stimulates biofilm formation and preformed biofilms. Chelators can inhibit or enhance biofilms. Chelation may be a potential therapy for A. fumigatus, but we show here that chelators must be chosen carefully. Individual isolate susceptibility assessments may be needed. PMID- 26239976 TI - Antischistosomal Activity of Oxindolimine-Metal Complexes. AB - In recent years, a class of oxindole-copper and -zinc complex derivatives have been reported as compounds with efficient proapoptotic activity toward different tumor cells (e.g., neuroblastomas, melanomas, monocytes). Here we assessed the efficacy of synthesized oxindole-copper(II), -zinc(II), and -vanadyl (VO(2+)) complexes against adult Schistosoma mansoni worms. The copper(II) complexes (50% inhibitory concentrations of 30 to 45 MUM) demonstrated greater antischistosomal properties than the analogous zinc and vanadyl complexes regarding lethality, reduction of motor activity, and oviposition. PMID- 26239977 TI - Oritavancin Pharmacokinetics and Bone Penetration in Rabbits. AB - The pharmacokinetics and bone concentrations of oritavancin were investigated after a single intravenous dose was administered to rabbits. The pharmacokinetic profile of oritavancin in rabbits showed that it is rapidly distributed to bone tissues, with concentrations remaining stable for up to 168 h, the last measured time point. Based on these findings, further evaluation of oritavancin for the treatment of infections in bone tissues is warranted. PMID- 26239978 TI - Evaluation of Gallium Citrate Formulations against a Multidrug-Resistant Strain of Klebsiella pneumoniae in a Murine Wound Model of Infection. AB - Skin and soft tissue infections (SSTIs) are a common occurrence in health care facilities with a heightened risk for immunocompromised patients. Klebsiella pneumoniae has been increasingly implicated as the bacterial agent responsible for SSTIs, and treatment can be challenging as more strains become multidrug resistant (MDR). Therefore, new treatments are needed to counter this bacterial pathogen. Gallium complexes exhibit antimicrobial activity and are currently being evaluated as potential treatment for bacterial infections. In this study, we tested a topical formulation containing gallium citrate (GaCi) for the treatment of wounds infected with K. pneumoniae. First, the MIC against K. pneumoniae ranged from 0.125 to 2.0 MUg/ml GaCi. After this in vitro efficacy was established, two topical formulations with GaCi (0.1% [wt/vol] and 0.3% [wt/vol]) were tested in a murine wound model of MDR K. pneumoniae infection. Gross pathology and histopathology revealed K. pneumoniae-infected wounds appeared to close faster with GaCi treatment and were accompanied by reduced inflammation compared to those of untreated controls. Similarly, quantitative indications of infection remediation, such as reduced weight loss and wound area, suggested that treatment improved outcomes compared to those of untreated controls. Bacterial burdens were measured 1 and 3 days following inoculation, and a 0.5 to 1.5 log reduction of CFU was observed. Lastly, upon scanning electron microscopy analysis, GaCi treatment appeared to prevent biofilm formation on dressings compared to those of untreated controls. These results suggest that with more preclinical testing, a topical application of GaCi may be a promising alternative treatment strategy for K. pneumoniae SSTI. PMID- 26239979 TI - Rapid, Semiquantitative Assay To Discriminate among Compounds with Activity against Replicating or Nonreplicating Mycobacterium tuberculosis. AB - The search for drugs that can kill replicating and nonreplicating Mycobacterium tuberculosis faces practical bottlenecks. Measurement of CFU and discrimination of bacteriostatic from bactericidal activity are costly in compounds, supplies, labor, and time. Testing compounds against M. tuberculosis under conditions that prevent the replication of M. tuberculosis often involves a second phase of the test in which conditions are altered to permit the replication of bacteria that survived the first phase. False-positive determinations of activity against nonreplicating M. tuberculosis may arise from carryover of compounds from the nonreplicating stage of the assay that act in the replicating stage. We mitigate these problems by carrying out a 96-well microplate liquid MIC assay and then transferring an aliquot of each well to a second set of plates in which each well contains agar supplemented with activated charcoal. After 7 to 10 days-about 2 weeks sooner than required to count CFU-fluorometry reveals whether M. tuberculosis bacilli in each well have replicated extensively enough to reduce a resazurin dye added for the final hour. This charcoal agar resazurin assay (CARA) distinguishes between bacterial biomasses in any two wells that differ by 2 to 3 log10 CFU. The CARA thus serves as a pretest and semiquantitative surrogate for longer, more laborious, and expensive CFU-based assays, helps distinguish bactericidal from bacteriostatic activity, and identifies compounds that are active under replicating conditions, nonreplicating conditions, or both. Results for 14 antimycobacterial compounds, including tuberculosis (TB) drugs, revealed that PA-824 (pretomanid) and TMC207 (bedaquiline) are largely bacteriostatic. PMID- 26239980 TI - Copper(II)-Bis(Thiosemicarbazonato) Complexes as Antibacterial Agents: Insights into Their Mode of Action and Potential as Therapeutics. AB - There is increasing interest in the use of lipophilic copper (Cu)-containing complexes to combat bacterial infections. In this work, we showed that Cu complexes with bis(thiosemicarbazone) ligands [Cu(btsc)] exert antibacterial activity against a range of medically significant pathogens. Previous work using Neisseria gonorrhoeae showed that Cu(btsc) complexes may act as inhibitors of respiratory dehydrogenases in the electron transport chain. We now show that these complexes are also toxic against pathogens that lack a respiratory chain. Respiration in Escherichia coli was slightly affected by Cu(btsc) complexes, but our results indicate that, in this model bacterium, the complexes act primarily as agents that deliver toxic Cu ions efficiently into the cytoplasm. Although the chemistry of Cu(btsc) complexes may dictate their mechanism of action, their efficacy depends heavily on bacterial physiology. This is linked to the ability of the target bacterium to tolerate Cu and, additionally, the susceptibility of the respiratory chain to direct inhibition by Cu(btsc) complexes. The physiology of N. gonorrhoeae, including multidrug-resistant strains, makes it highly susceptible to damage by Cu ions and Cu(btsc) complexes, highlighting the potential of Cu(btsc) complexes (and Cu-based therapeutics) as a promising treatment against this important bacterial pathogen. PMID- 26239981 TI - Protective effect of Qnr on agents other than quinolones that target DNA gyrase. AB - Qnr is a plasmid-encoded and chromosomally determined protein that protects DNA gyrase and topoisomerase IV from inhibition by quinolones. Despite its prevalence worldwide and existence prior to the discovery of quinolones, its native function is not known. Other synthetic compounds and natural products also target bacterial topoisomerases. A number were studied as molecular probes to gain insight into how Qnr acts. Qnr blocked inhibition by synthetic compounds with somewhat quinolone-like structure that target the GyrA subunit, such as the 2 pyridone ABT-719, the quinazoline-2,4-dione PD 0305970, and the spiropyrimidinetrione pyrazinyl-alkynyl-tetrahydroquinoline (PAT), indicating that Qnr is not strictly quinolone specific, but Qnr did not protect against GyrA targeting simocyclinone D8 despite evidence that both simocyclinone D8 and Qnr affect DNA binding to gyrase. Qnr did not affect the activity of tricyclic pyrimidoindole or pyrazolopyridones, synthetic inhibitors of the GyrB subunit, or nonsynthetic GyrB inhibitors, such as coumermycin A1, novobiocin, gyramide A, or microcin B17.Thus, in this set of compounds the protective activity of Qnr was confined to those that, like quinolones, trap gyrase on DNA in cleaved complexes. PMID- 26239982 TI - Antitrypanosomal Treatment with Benznidazole Is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease. AB - Two CYP51 inhibitors, posaconazole and the ravuconazole prodrug E1224, were recently tested in clinical trials for efficacy in indeterminate Chagas disease. The results from these studies show that both drugs cleared parasites from the blood of infected patients at the end of the treatment but that parasitemia rebounded over the following months. In the current study, we sought to identify a dosing regimen of posaconazole that could permanently clear Trypanosoma cruzi from mice with experimental Chagas disease. Infected mice were treated with posaconazole or benznidazole, an established Chagas disease drug, and parasitological cure was defined as an absence of parasitemia recrudescence after immunosuppression. Twenty-day therapy with benznidazole (10 to 100 mg/kg of body weight/day) resulted in a dose-dependent increase in antiparasitic activity, and the 100-mg/kg regimen effected parasitological cure in all treated mice. In contrast, all mice remained infected after a 25-day treatment with posaconazole at all tested doses (10 to 100 mg/kg/day). Further extension of posaconazole therapy to 40 days resulted in only a marginal improvement of treatment outcome. We also observed similar differences in antiparasitic activity between benznidazole and posaconazole in acute T. cruzi heart infections. While benznidazole induced rapid, dose-dependent reductions in heart parasite burdens, the antiparasitic activity of posaconazole plateaued at low doses (3 to 10 mg/kg/day) despite increasing drug exposure in plasma. These observations are in good agreement with the outcomes of recent phase 2 trials with posaconazole and suggest that the efficacy models combined with the pharmacokinetic analysis employed here will be useful in predicting clinical outcomes of new drug candidates. PMID- 26239983 TI - Antibacterial Action of Nitric Oxide-Releasing Chitosan Oligosaccharides against Pseudomonas aeruginosa under Aerobic and Anaerobic Conditions. AB - Chitosan oligosaccharides were modified with N-diazeniumdiolates to yield biocompatible nitric oxide (NO) donor scaffolds. The minimum bactericidal concentrations and MICs of the NO donors against Pseudomonas aeruginosa were compared under aerobic and anaerobic conditions. Differential antibacterial activities were primarily the result of NO scavenging by oxygen under aerobic environments and not changes in bacterial physiology. Bacterial killing was also tested against nonmucoid and mucoid biofilms and compared to that of tobramycin. Smaller NO payloads were required to eradicate P. aeruginosa biofilms under anaerobic versus aerobic conditions. Under oxygen-free environments, the NO treatment was 10-fold more effective at killing biofilms than tobramycin. These results demonstrate the potential utility of NO-releasing chitosan oligosaccharides under both aerobic and anaerobic environments. PMID- 26239984 TI - Use of a Combination Biomarker Algorithm To Identify Medical Intensive Care Unit Patients with Suspected Sepsis at Very Low Likelihood of Bacterial Infection. AB - Sepsis remains a diagnostic challenge in the intensive care unit (ICU), and the use of biomarkers may help in differentiating bacterial sepsis from other causes of systemic inflammatory syndrome (SIRS). The goal of this study was to assess test characteristics of a number of biomarkers for identifying ICU patients with a very low likelihood of bacterial sepsis. A prospective cohort study was conducted in a medical ICU of a university hospital. Immunocompetent patients with presumed bacterial sepsis were consecutively enrolled from January 2012 to May 2013. Concentrations of nine biomarkers (alpha-2 macroglobulin, C-reactive protein [CRP], ferritin, fibrinogen, haptoglobin, procalcitonin [PCT], serum amyloid A, serum amyloid P, and tissue plasminogen activator) were determined at baseline and at 24 h, 48 h, and 72 h after enrollment. Performance characteristics were calculated for various combinations of biomarkers for discrimination of bacterial sepsis from other causes of SIRS. Seventy patients were included during the study period; 31 (44%) had bacterial sepsis, and 39 (56%) had other causes of SIRS. PCT and CRP values were significantly higher at all measured time points in patients with bacterial sepsis. A number of combinations of PCT and CRP, using various cutoff values and measurement time points, demonstrated high negative predictive values (81.1% to 85.7%) and specificities (63.2% to 79.5%) for diagnosing bacterial sepsis. Combinations of PCT and CRP demonstrated a high ability to discriminate bacterial sepsis from other causes of SIRS in medical ICU patients. Future studies should focus on the use of these algorithms to improve antibiotic use in the ICU setting. PMID- 26239985 TI - U.S.-Based National Sentinel Surveillance Study for the Epidemiology of Clostridium difficile-Associated Diarrheal Isolates and Their Susceptibility to Fidaxomicin. AB - In 2011 a surveillance study for the susceptibility to fidaxomicin and epidemiology of Clostridium difficile isolates in the United States was undertaken in seven geographically dispersed medical centers. This report encompasses baseline surveillance in 2011 and 2012 on 925 isolates. A convenience sample of C. difficile isolates or toxin positive stools from patients were referred to a central laboratory. Antimicrobial susceptibility was determined by agar dilution (CLSI M11-A8). Clinical and Laboratory Standards Institute (CLSI), Food and Drug Administration, or European Union of Clinical Antimicrobial Susceptibility Testing (EUCAST) breakpoints were applied where applicable. Toxin gene profiles were characterized by multiplex PCR on each isolate. A random sample of 322 strains, stratified by institution, underwent restriction endonuclease analysis (REA). The fidaxomicin MIC90 was 0.5 MUg/ml for all isolates regardless of REA type or toxin gene profile, and all isolates were inhibited at <=1.0 MUg/ml. By REA typing, BI strains represented 25.5% of the isolates. The toxin gene profile of tcdA, tcdB, and cdtA/B positive with a tcdC 18-bp deletion correlated with BI REA group. Moxifloxacin and clindamycin resistance was increased among either BI or binary toxin-positive isolates. Metronidazole and vancomycin showed reduced susceptibility (EUCAST criteria) in these isolates. Geographic variations in susceptibility, REA group and binary toxin gene presence were observed. Fidaxomicin activity against C. difficile isolated in a national surveillance study did not change more than 1 year after licensure. This analysis provides baseline results for future comparisons. PMID- 26239986 TI - Lumefantrine and Desbutyl-Lumefantrine Population Pharmacokinetic-Pharmacodynamic Relationships in Pregnant Women with Uncomplicated Plasmodium falciparum Malaria on the Thailand-Myanmar Border. AB - Artemether-lumefantrine is the most widely used antimalarial artemisinin-based combination treatment. Recent studies have suggested that day 7 plasma concentrations of the potent metabolite desbutyl-lumefantrine correlate better with treatment outcomes than those of lumefantrine. Low cure rates have been reported in pregnant women with uncomplicated falciparum malaria treated with artemether-lumefantrine in northwest Thailand. A simultaneous pharmacokinetic drug-metabolite model was developed based on dense venous and sparse capillary lumefantrine and desbutyl-lumefantrine plasma samples from 116 pregnant patients on the Thailand-Myanmar border. The best model was used to evaluate therapeutic outcomes with a time-to-event approach. Lumefantrine and desbutyl-lumefantrine concentrations, implemented in an Emax model, both predicted treatment outcomes, but lumefantrine provided better predictive power. A combined model including both lumefantrine and desbutyl-lumefantrine did not improve the model further. Simulations suggested that cure rates in pregnant women with falciparum malaria could be increased by prolonging the treatment course. (These trials were registered at controlled-trials.com [ISRCTN 86353884].). PMID- 26239988 TI - First Report and Molecular Characterization of a Campylobacter jejuni Isolate with Extensive Drug Resistance from a Travel-Associated Human Case. PMID- 26239987 TI - How Robust Are Malaria Parasite Clearance Rates as Indicators of Drug Effectiveness and Resistance? AB - Artemisinin-based combination therapies (ACTs) are currently the first-line drugs for treating uncomplicated falciparum malaria, the most deadly of the human malarias. Malaria parasite clearance rates estimated from patients' blood following ACT treatment have been widely adopted as a measure of drug effectiveness and as surveillance tools for detecting the presence of potential artemisinin resistance. This metric has not been investigated in detail, nor have its properties or potential shortcomings been identified. Herein, the pharmacology of drug treatment, parasite biology, and human immunity are combined to investigate the dynamics of parasite clearance following ACT. This approach parsimoniously recovers the principal clinical features and dynamics of clearance. Human immunity is the primary determinant of clearance rates, unless or until artemisinin killing has fallen to near-ineffective levels. Clearance rates are therefore highly insensitive metrics for surveillance that may lead to overconfidence, as even quite substantial reductions in drug sensitivity may not be detected as lower clearance rates. Equally serious is the use of clearance rates to quantify the impact of ACT regimen changes, as this strategy will plausibly miss even very substantial increases in drug effectiveness. In particular, the malaria community may be missing the opportunity to dramatically increase ACT effectiveness through regimen changes, particularly through a switch to twice-daily regimens and/or increases in artemisinin dosing levels. The malaria community therefore appears overreliant on a single metric of drug effectiveness, the parasite clearance rate, that has significant and serious shortcomings. PMID- 26239989 TI - Purification Methodology for Viable and Infective Plasmodium vivax Gametocytes That Is Compatible with Transmission-Blocking Assays. AB - Significant progress toward the control of malaria has been achieved, especially regarding Plasmodium falciparum infections. However, the unique biology of Plasmodium vivax hampers current control strategies. The early appearance of P. vivax gametocytes in the peripheral blood and the impossibility of culturing this parasite are major drawbacks. Using blood samples from 40 P. vivax-infected patients, we describe here a methodology to purify viable gametocytes and further infect anophelines. This method opens new avenues to validate transmission blocking strategies. PMID- 26239990 TI - Population Pharmacokinetics of Fosfomycin in Critically Ill Patients. AB - This study describes the population pharmacokinetics of fosfomycin in critically ill patients. In this observational study, serial blood samples were taken over several dosing intervals of intravenous fosfomycin treatment. Blood samples were analyzed using a validated liquid chromatography-tandem mass spectrometry technique. A population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Five hundred fifteen blood samples were collected over one to six dosing intervals from 12 patients. The mean (standard deviation) age was 62 (17) years, 67% of patients were male, and creatinine clearance (CLCR) ranged from 30 to 300 ml/min. A two-compartment model with between-subject variability on clearance and volume of distribution of the central compartment (Vc) described the data adequately. Calculated CLCR was supported as a covariate on fosfomycin clearance. The mean parameter estimates for clearance on the first day were 2.06 liters/h, Vc of 27.2 liters, intercompartmental clearance of 19.8 liters/h, and volume of the peripheral compartment of 22.3 liters. We found significant pharmacokinetic variability for fosfomycin in this heterogeneous patient sample, which may be explained somewhat by the observed variations in renal function. PMID- 26239991 TI - MALDI-TOF MS as a Tool To Detect a Nosocomial Outbreak of Extended-Spectrum-beta Lactamase- and ArmA Methyltransferase-Producing Enterobacter cloacae Clinical Isolates in Algeria. AB - Enterobacter cloacae is among the most important pathogens responsible for nosocomial infections and outbreaks. In this study, 77 Enterobacter isolates were collected: 27 isolates from Algerian hospitals (in Constantine, Annaba, and Skikda) and 50 isolates from Marseille, France. All strains were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Antibiotic susceptibility testing was performed by the disk diffusion method. PCR was used to detect extended-spectrum-beta-lactamase (ESBL) encoding, fluoroquinolone resistance-encoding, and aminoglycoside-modifying enzyme (AME) genes. Epidemiological typing was performed using MALDI-TOF MS with data mining approaches, along with multilocus sequence typing (MLST). Sixty-eight isolates (27 from Algeria, 41 from Marseille) were identified by MALDI-TOF MS as E. cloacae. Resistance to antibiotics in the Algerian isolates was significantly higher than that in the strains from Marseille, especially for beta-lactams and aminoglycosides. Eighteen of the 27 Algerian isolates and 11 of the 41 Marseille isolates possessed at least one ESBL-encoding gene: blaCTX-M and/or blaTEM. AME genes were detected in 20 of the 27 Algerian isolates and 8 of the 41 Marseille isolates [ant(2")-Ia, aac(6')-Ib-cr, aadA1, aadA2, and armA]. Conjugation experiments showed that armA was carried on a transferable plasmid. MALDI-TOF typing showed three separate clusters according to the geographical distribution and species level. An MLST-based phylogenetic tree showed a clade of 14 E. cloacae isolates from a urology unit clustering together in the MALDI-TOF dendrogram, suggesting the occurrence of an outbreak in this unit. In conclusion, the ability of MALDI-TOF to biotype strains was confirmed, and surveillance measures should be implemented, especially for Algerian patients hospitalized in France. PMID- 26239992 TI - Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 3. Tobramycin. AB - The aim of this study was to determine the biopharmaceutical characteristics of tobramycin (TOB) after nebulization in rats. TOB was administered by intravenous (i.v.) bolus or intratracheal nebulization (3 mg . kg(-1)), and concentrations were determined in plasma and epithelial lining fluid (ELF) by liquid chromatography-tandem mass spectrometry. The ratio of the TOB concentration in ELF to the plasma area under the curve (AUC) was more than 200 times as high after NEB as after i.v. bolus administration, indicating that TOB nebulization offers a biopharmaceutical advantage over i.v. administration. PMID- 26239993 TI - Altering Antimalarial Drug Regimens May Dramatically Enhance and Restore Drug Effectiveness. AB - There is considerable concern that malaria parasites are starting to evolve resistance to the current generation of antimalarial drugs, the artemisinin-based combination therapies (ACTs). We use pharmacological modeling to investigate changes in ACT effectiveness likely to occur if current regimens are extended from 3 to 5 days or, alternatively, given twice daily over 3 days. We show that the pharmacology of artemisinins allows both regimen changes to substantially increase the artemisinin killing rate. Malaria patients rarely contain more than 10(12) parasites, while the standard dosing regimens allow approximately 1 in 10(10) parasites to survive artemisinin treatment. Parasite survival falls dramatically, to around 1 in 10(17) parasites if the dose is extended or split; theoretically, this increase in drug killing appears to be more than sufficient to restore failing ACT efficacy. One of the most widely used dosing regimens, artemether-lumefantrine, already successfully employs a twice-daily dosing regimen, and we argue that twice-daily dosing should be incorporated into all ACT regimen design considerations as a simple and effective way of ensuring the continued long-term effectiveness of ACTs. PMID- 26239994 TI - Antileishmanial Activity of Disulfiram and Thiuram Disulfide Analogs in an Ex Vivo Model System Is Selectively Enhanced by the Addition of Divalent Metal Ions. AB - Current treatments for cutaneous and visceral leishmaniasis are toxic, expensive, difficult to administer, and limited in efficacy and availability. Disulfiram has primarily been used to treat alcoholism. More recently, it has shown some efficacy as therapy against protozoan pathogens and certain cancers, suggesting a wide range of biological activities. We used an ex vivo system to screen several thiuram disulfide compounds for antileishmanial activity. We found five compounds (compound identifier [CID] 7188, 5455, 95876, 12892, and 3117 [disulfiram]) with anti-Leishmania activity at nanomolar concentrations. We further evaluated these compounds with the addition of divalent metal salts based on studies that indicated these salts could potentiate the action of disulfiram. In addition, clinical studies suggested that zinc has some efficacy in treating cutaneous leishmaniasis. Several divalent metal salts were evaluated at 1 MUM, which is lower than the normal levels of copper and zinc in plasma of healthy individuals. The leishmanicidal activity of disulfiram and CID 7188 were enhanced by several divalent metal salts at 1 MUM. The in vitro therapeutic index (IVTI) of disulfiram and CID 7188 increased 12- and 2.3-fold, respectively, against L. major when combined with ZnCl2. The combination of disulfiram with ZnSO4 resulted in a 1.8-fold increase in IVTI against L. donovani. This novel combination of thiuram disulfides and divalent metal ions salts could have application as topical and/or oral therapies for treatment of cutaneous and visceral leishmaniasis. PMID- 26239995 TI - In Vitro Activities of Eight Antifungal Drugs against a Global Collection of Genotyped Exserohilum Isolates. AB - The in vitro susceptibilities of 24 worldwide Exserohilum isolates belonging to 10 species from human and environmental sources were determined for eight antifungal drugs. The strains were characterized by internal transcribed spacer (ITS) sequencing and amplified fragment length polymorphism fingerprinting. Posaconazole had the lowest geometric mean MIC (0.16 MUg/ml), followed by micafungin (0.21 MUg/ml), amphotericin B (0.24 MUg/ml), itraconazole (0.33 MUg/ml), voriconazole (0.8 MUg/ml), caspofungin (1.05 MUg/ml), isavuconazole (1.38 MUg/ml), and fluconazole (15.6 MUg/ml). PMID- 26239996 TI - N-Chlorotaurine Exhibits Fungicidal Activity against Therapy-Refractory Scedosporium Species and Lomentospora prolificans. AB - N-Chlorotaurine (NCT), a well-tolerated endogenous long-lived oxidant that can be applied topically as an antiseptic, was tested on its fungicidal activity against Scedosporium and Lomentospora, opportunistic fungi that cause severe infections with limited treatment options, mainly in immunocompromised patients. In quantitative killing assays, both hyphae and conidia of Scedosporium apiospermum, Scedosporium boydii, and Lomentospora prolificans (formerly Scedosporium prolificans) were killed by 55 mM (1.0%) NCT at pH 7.1 and 37 degrees C, with a 1 to 4-log10 reduction in CFU after 4 h and a 4- to >6-log10 reduction after 24 h. The addition of ammonium chloride to NCT markedly increased this activity. LIVE/DEAD staining of conidia treated with 1.0% NCT for 0.5 to 3 h increased the permeability of the cell wall and membrane. Preincubation of the test fungi in 1.0% NCT for 10 to 60 min delayed the time to germination of conidia by 2 h to >12 h and reduced their germination rate by 10.0 to 100.0%. Larvae of Galleria mellonella infected with 1.0 * 10(7) conidia of S. apiospermum and S. boydii died at a rate of 90.0 to 100% after 8 to 12 days. The mortality rate was reduced to 20 to 50.0% if conidia were preincubated in 1.0% NCT for 0.5 h or if heat inactivated conidia were used. Our study demonstrates the fungicidal activity of NCT against different Scedosporium and Lomentospora species. A postantifungal effect connected with a loss of virulence occurs after sublethal incubation times. The augmenting effect of ammonium chloride can be explained by the formation of monochloramine. PMID- 26239998 TI - The relationship between hallucinations and FDG-PET in dementia with Lewy bodies. AB - Visual hallucinations are common in dementia with Lewy bodies (DLB), although their etiology is unclear. This study aimed to investigate the relationship between severity and frequency of hallucinations and regional brain glucose metabolism. We performed brain FDG-PET scanning on 28 subjects with DLB (mean age 76). The neuropsychiatric index (NPI) was used to assess frequency and severity of hallucinations. We used the SPM package to investigate voxelwise correlations between NPI hallucination score (severity x frequency) and FDG uptake relative to the cerebellum. There was a bilateral medial occipital region where reduced FDG was associated with increased hallucination severity and frequency. We conclude that the reduced occipital metabolism frequently seen in DLB is associated with frequency and severity of visual hallucinations. Further studies are required to investigate whether this is the result of deficits in top-down or bottom-up visual processing pathways. PMID- 26239997 TI - Cardiorespiratory fitness and white matter integrity in Alzheimer's disease. AB - The objective of this study was to investigate the relationship between cardiorespiratory (CR) fitness and the brain's white matter tract integrity using diffusion tensor imaging (DTI) in the Alzheimer's disease (AD) population. We recruited older adults in the early stages of AD (n = 37; CDR = 0.5 and 1) and collected cross-sectional fitness and diffusion imaging data. We examined the association between CR fitness (peak oxygen consumption [VO2peak]) and fractional anisotropy (FA) in AD-related white matter tracts using two processing methodologies: a tract-of-interest approach and tract-based spatial statistic (TBSS). Subsequent diffusivity metrics (radial diffusivity [RD], mean diffusivity [MD], and axial diffusivity [A * D]) were also correlated with VO2peak. The tract of-interest approach showed that higher VO2peak was associated with preserved white matter integrity as measured by increased FA in the right inferior fronto occipital fasciculus (p = 0.035, r = 0.36). We did not find a significant correlation using TBSS, though there was a trend for a positive association between white matter integrity and higher VO2peak measures (p < 0.01 uncorrected). Our findings indicate that higher CR fitness levels in early AD participants may be related to preserved white matter integrity. However to draw stronger conclusions, further study on the relationship between fitness and white matter deterioration in AD is necessary. PMID- 26239999 TI - Synergistic antitumor responses by combined GITR activation and sunitinib in metastatic renal cell carcinoma. AB - Sunitinib, a multitargeted tyrosine kinase inhibitor, is the frontline therapy for renal and gastrointestinal cancers. In view of its well-documented proapoptotic and immunoadjuvant properties, we speculate that combination of Sunitinib and immunotherapy would provide a synergistic antitumor effect. Here, we report that a remarkably synergistic antitumor responses elicited by the combined treatment of Sunitinib and an agonistic antibody against glucocorticoid induced TNFR related protein (GITR) in a model of metastatic renal cell carcinoma. Sunitinib significantly increased the infiltration, activation, and proliferation and/or cytotoxicity of CD8(+) T cells and NK cells in liver metastatic foci when combined with the anti (alpha)-GITR agonist, which was associated with treatment-induced prominent upregulation of Th1-biased immune genes in the livers from mice receiving combined therapy versus single treatment. Sunitinib/alpha-GITR treatment also markedly promoted the maturation, activation and cytokine production of liver-resident macrophages and DCs compared with that achieved by alpha-GITR or Sunitinib treatment alone in mice. Cell depletion experiments demonstrated that CD8(+) T cells, NK cells and macrophage infiltrating liver metastatic foci all contribute to the antitumor effect induced by combined treatment. Furthermore, mechanistic investigation revealed that Sunitinib treatment reprograms tumor-associated macrophages toward classically activated or "M1" polarization upon GITR stimulation and consequently mounts an antitumor CD8(+) T and NK cell response via inhibiting STAT3 activity. Thus, our findings provide a proof of concept that Sunitinib can synergize with alpha-GITR treatment to remodel the tumor immune microenvironment to trigger regressions of an established metastatic cancer. PMID- 26240005 TI - Proton Pump Inhibitors Reduce the Frequency of Phlebotomy in Patients With Hereditary Hemochromatosis. AB - BACKGROUND & AIMS: Patients with hereditary hemochromatosis (HH) need frequent phlebotomies to reduce iron overload. Proton pump inhibitors (PPIs) were reported to reduce the need for phlebotomies in patients homozygous for the C282Y mutation in HFE. We investigated the effects of PPI treatment on numbers of phlebotomies in these patients. METHODS: We conducted a retrospective study of patients with HH homozygous for the C282Y mutation by using the database and medical records from Atrium Medical Centrum Parkstad in Brunssum, The Netherlands. In a paired group analysis of 12 patients, we compared mean serum levels of ferritin and number of phlebotomies needed each year during the periods of 3 years before and 3 years after the start of PPI therapy. We compared these results with those from a group who received PPIs for at least 2 years (n = 9) and a group who never received PPIs (n = 36). RESULTS: We found a significant reduction in median number of phlebotomies after patients began taking PPIs vs. before (0.50 vs. 3.17, P < .002). Patients who received PPIs for at least 2 years needed significantly fewer phlebotomies than patients in the paired group before they started taking PPIs (1.25 vs. 3.17, P < .001). The number of phlebotomies in the group who never received PPIs was significantly higher than in the paired group after they started taking PPIs (3.0 vs. 0.5, P < .001). CONCLUSIONS: On the basis of a retrospective analysis, in patients with HH homozygous for the C282Y mutation in HFE, treatment with PPIs for 2 or more years significantly reduced the number of phlebotomies required to maintain serum levels of ferritin below 100 MUg/L. PMID- 26240006 TI - Pernicious Anemia: Time to Justify Endoscopic Monitoring? PMID- 26240007 TI - Is it Time to Rethink Screening of Individuals With Symptoms of Irritable Bowel Syndrome for Celiac Disease? PMID- 26240008 TI - True Nonceliac Gluten Sensitivity in Real Patients. PMID- 26240009 TI - Downsizing Chemotherapy for Initially Unresectable Locally Advanced Biliary Tract Cancer Patients Treated with Gemcitabine Plus Cisplatin Combination Therapy Followed by Radical Surgery. AB - BACKGOUND: We have treated patients with initially unresectable locally advanced biliary tract cancer (BTC) by administering gemcitabine and have found that surgical resection became feasible in some downsized patients. The aim of this study was to investigate the usefulness of downsizing combination chemotherapy using gemcitabine plus cisplatin to treat initially unresectable locally advanced BTC. METHODS: The subjects of the study were 150 consecutive patients who were treated for BTC between October 2011 and April 2014. Downsizing chemotherapy was carried out for 39 patients (26.0 %) whose lesions were unresectable because of locally advanced BTC. RESULTS: Reduction in tumor size with downsizing chemotherapy was seen in 18 patients, and surgical resection was performed in 10 of 39 patients (25.6 %). Median survival time in patients with surgical resection following downsizing chemotherapy and those with chemotherapy alone was 17.9 and 12.4 months, respectively (p = 0.0378). According to the historical comparison between gemcitabine and gemcitabine plus cisplatin chemotherapy, there is no significant difference in overall survival. However, there was a significant difference for the pathologic response rate (>=Grade III) to be higher in patients with gemcitabine plus cisplatin chemotherapy compared with gemcitabine monotherapy. CONCLUSIONS: Preoperative downsizing chemotherapy with gemcitabine plus cisplatin provides longer survival by the conversion to the surgical resection in patients with initially unresectable locally advanced BTC. It may have the potential for disease eradication as a new multidisciplinary approach for initially unresectable locally advanced BTC. PMID- 26240010 TI - An International Multicenter Review of the Malignancy Rate of Excised Papillomatous Breast Lesions. AB - BACKGROUND: Papillary lesions of the breast are a relatively rare, but heterogeneous group ranging from benign to atypical and malignant. Debate exists regarding the optimal management of these lesions. In the absence of more accurate risk-stratification models, traditional management guidelines recommend surgical excision, despite the majority of lesions proving benign. This study sought to determine the rate of malignancy in excised breast papillomas and to elucidate whether there exists a population in which surgical excision may be unnecessary. METHODS: A multicenter international retrospective review of core biopsy diagnosed breast papillomas and papillary lesions was performed between 2009 and 2013, following institutional ethical approval. Patient demographics, histopathological, and radiological findings were recorded. All data was tabulated, and statistical analysis performed using Stata. RESULTS: A total of 238 patients were included in the final analysis. The age profile of those with benign pathology was significantly younger than those with malignant pathology (p < 0.001). Atypia on core needle biopsy was significantly associated with a final pathological diagnosis of malignancy (OR = 2.73). The upgrade rate from benign core needle biopsy to malignancy on the final pathological sample was 14.4 %; however, only 3.7 % had invasive cancer. CONCLUSIONS: This international dataset is one of the largest in the published literature relating to breast papillomas. The overall risk of malignancy is significantly associated with older age and the presence of atypia on core needle biopsy. It may be possible to stratify higher risk patients according to age and core needle biopsy findings, thereby avoiding surgery on low-risk patients. PMID- 26240011 TI - Polytopic bis(oxazoline)-based ligands for recoverable catalytic systems applied to the enantioselective Henry reaction. AB - Several kinds of polytopic chiral ligands (including ditopic, tritopic and tetratopic), based on the bis(oxazoline) and azabis(oxazoline) motifs, have been tested in the preparation of recoverable catalytic systems for the Henry reaction. The results obtained with the different ligands are, in general, good, but they point to the existence of a delicate balance between the coordinating ability of the ligand, the catalytic activity and the recovery of the catalyst by formation of the coordination polymer, related to the easiness to form oligomeric species in solution. PMID- 26240012 TI - Late occurrence of Epstein-Barr virus-associated lymphoproliferative disorder in a patient with follicular lymphoma treated with bendamustine and rituximab. PMID- 26240013 TI - Neuroprotective Effects of Castanea sativa Mill. Bark Extract in Human Neuroblastoma Cells Subjected to Oxidative Stress. AB - One of the major features of neurodegenerative disease is the selective vulnerability of different neuronal populations that are affected in a progressive and often stereotyped manner. Despite the susceptible neuronal population varies between diseases, oxidative stress is implicated as the major pathogenic process in all of them. Natural Extract of Castanea sativa Mill. bark (ENC), recently characterized in its phenolic composition, acts as antioxidant and cardioprotective agent. Its neuroprotettive properties, however, have never been investigated. The aim of this study was to assess neuroprotection of ENC in in vitro models of oxidative-stress-mediate injury. Human neuroblastoma SH-SY5Y cells treated with glutamate (50 mM for 24 h) or hydrogen peroxide (25 MUM for 1 h followed by 24 with medium) were used. The results showed that the addition of ENC (1-50 MUg/ml) to cell medium before the neuronal damage provided neuroprotection in both experimental models used, while its addition after the injury was ineffective. In conclusion, the present results suggest that ENC could be a valuable support as dietary supplement, combining beneficial preventive neuroprotettive effects with a high antioxidant activity. PMID- 26240014 TI - Universal self-field critical current for thin-film superconductors. AB - For any practical superconductor the magnitude of the critical current density, Jc, is crucially important. It sets the upper limit for current in the conductor. Usually Jc falls rapidly with increasing external magnetic field, but even in zero external field the current flowing in the conductor generates a self-field that limits Jc. Here we show for thin films of thickness less than the London penetration depth, lambda, this limiting Jc adopts a universal value for all superconductors-metals, oxides, cuprates, pnictides, borocarbides and heavy Fermions. For type-I superconductors, it is Hc/lambda where Hc is the thermodynamic critical field. But surprisingly for type-II superconductors, we find the self-field Jc is Hc1/lambda where Hc1 is the lower critical field. Jc is thus fundamentally determined and this provides a simple means to extract absolute values of lambda(T) and, from its temperature dependence, the symmetry and magnitude of the superconducting gap. PMID- 26240015 TI - Atg5 siRNA inhibits autophagy and enhances norcantharidin-induced apoptosis in hepatocellular carcinoma. AB - Cantharidin is a terpenoid isolated from Chinese blister beetles, and norcantharidin (NCTD) is a demethylated analog of cantharidin. It has been reported that cantharidin and norcantharidin have anticancer activities. Growing evidence suggests that inhibiting autophagy can induce apoptosis in the human hepatoma cell line HepG2. The objective of the present study was to determine whether inhibition of autophagy enhances NCTD-induced apoptosis in HepG2 cells. HepG2 cells were cultured in DMEM containing NCTD. Autophagy was upregulated in the presence of HBSS media supplemented with Ca2+ and Mg2+ and 10 mM HEPES and downregulated in the presence of 3-methyladenine (3-MA) and Atg5 siRNA. Autophagy, cell viability, and the expression of apoptotic proteins were assessed in HepG2 cells. Our data showed that cell apoptosis generally increased after norcantharidin treatment in HepG2 cells. Expression of LC3-II, an autophagosome marker, increased when cells were treated with HBSS media. It also increased cell viability. However, in the presence of 3-MA and Atg5 siRNA, autophagy was inhibited, LC3-II expression decreased and cell apoptosis increased. There was increased expression of Bax, cytochrome c, cleaved caspase-3, caspase-9 and PARP and the mitochondrial membrane potential was disrupted. Additionally, increased apoptosis was accompanied by increased reactive oxygen species (ROS) production. NCTD has anticancer activity, and Atg5 siRNA-mediated downregulation of autophagy enhanced its anticancer actions due to ROS generation and activation of the mitochondrial apoptosis pathway. PMID- 26240016 TI - USP18 negatively regulates NF-kappaB signaling by targeting TAK1 and NEMO for deubiquitination through distinct mechanisms. AB - Nuclear factor kappaB (NF-kappaB) is a key transcription factor in inflammatory immune responses and cell survival. Multiple types of ubiquitination play critical roles in the activation of NF-kappaB signaling, yet the molecular mechanisms responsible for their reversible deubiquitination are still poorly understood. In this study, we identified a member of the deubiquitinases family, ubiquitin-specific protease 18 (USP18), as a novel negative regulator in Toll like receptor (TLR)-mediated NF-kappaB activation in human macrophages. USP18 is an interferon inducible gene, which is also upregulated by various TLR ligands in human monocytes and macrophages. Knockdown of USP18 enhanced the phosphorylation of IKK, the degradation of IkappaB, and augmented the expression of pro inflammatory cytokines. Furthermore, USP18 interacted with TAK1-TAB1 complex and IKKalpha/beta-NEMO complex, respectively. USP18 cleaved the K63-linked polyubiquitin chains attached to TAK1 in a protease-dependent manner. Moreover, USP18 targeted the IKK complex through the regulatory subunit NEMO of IKK, and specifically inhibited K63-linked ubiquitination of NEMO. Mutation analysis revealed direct binding of USP18 to the UBAN motif of NEMO. Our study has identified a previously unrecognized role for USP18 in the negative regulation of NF-kappaB activation by inhibiting K63-linked ubiquitination of TAK1 and NEMO through distinct mechanisms. PMID- 26240018 TI - Repurposing an old drug: A low-cost allergy medication provides new hope for hepatitis C patients. PMID- 26240017 TI - IRF6 is the mediator of TGFbeta3 during regulation of the epithelial mesenchymal transition and palatal fusion. AB - Mutation in interferon regulatory factor 6 (IRF6) is known to cause syndromic and non-syndromic cleft lip/palate in human. In this study, we investigated the molecular mechanisms related to IRF6 during palatal fusion using palatal shelves organ culture. The results showed that ablation of Irf6 resulted in a delay in TGFbeta3-regulated palatal fusion. Ectopic expression of IRF6 was able to promote palatal fusion and rescue shTgfbeta3-induced fusion defect. These findings indicate that IRF6 is involved in TGFbeta3-mediated palatal fusion. Molecular analysis revealed that ectopic expression of IRF6 increased the expression of SNAI2, an epithelial mesenchymal transition (EMT) regulator, and diminished the expression of various epithelial markers, such as E-cadherin, Plakophilin and ZO 1. In addition, knockdown of Irf6 expression decreased SNAI2 expression, and restored the expression of ZO-1 and Plakophilin that were diminished by TGFbeta3. Blocking of Snai2 expression delayed palatal fusion and abolished the IRF6 rescuing effect associated with shTgfbeta3-induced fusion defect. These findings indicate that TGFbeta3 increases IRF6 expression and subsequently regulates SNAI2 expression, and IRF6 appears to regulate EMT during palatal fusion via SNAI2. Taken together, this study demonstrates that IRF6 is a mediator of TGFbeta3, which regulates EMT and fusion process during the embryonic palate development. PMID- 26240019 TI - A Progressively Realizable Right to Health and Global Governance. AB - A moral right to health or health care is a special instance of a right to fair equality of opportunity. Nation-states generally have the capabilities to specify the entitlements of such a right and to raise the resources needed to satisfy those entitlements. Can these functions be replicated globally, as a global right to health or health care requires? The suggestion that "better global governance" is needed if such a global right is to be claimed requires that these two central capabilities be present. It is unlikely that nation-states would concede these two functions to a form of global governance, for doing so would seriously compromise the authority that is generally included in sovereignty. This claim is a specification of what is often recognized as the "sovereignty problem." The argument of this paper is not an "impossibility" claim, but a best guess about whether the necessary conditions for better global governance that supports a global right to health or health care can be achieved. PMID- 26240020 TI - Interdependence, Human Rights and Global Health Law. AB - The connection between health and human rights continues to play a prominent role within global health law. In particular, a number of theorists rely on the claim that there is a relation of interdependence between health and human rights. The nature and extent of this relation, however, is rarely defined, developed or defended in a conceptually robust way. This paper seeks to explore the source, scope and strength of this putative relation and what role it might play in developing a global health law framework. PMID- 26240021 TI - A Troubled Past? Reassessing Ethics in the History of Tissue Culture. AB - Recent books, articles and plays about the 'immortal' HeLa cell line have prompted renewed interest in the history of tissue culture methods that were first employed in 1907 and became common experimental tools during the twentieth century. Many of these sources claim tissue cultures like HeLa had a "troubled past" because medical researchers did not seek informed consent before using tissues in research, contravening a long held desire for self-determination on the part of patients and the public. In this article, I argue these claims are unfair and misleading. No professional guidelines required informed consent for tissue culture during the early and mid twentieth century, and popular sources expressed no concern at the widespread use of human tissues in research. When calls for informed consent did emerge in the 1970s and 1980s, moreover, they reflected specific political changes and often emanated from medical researchers themselves. I conclude by arguing that more balanced histories of tissue culture can make a decisive contribution to public debates today: by refuting a false dichotomy between science and its publics, and showing how ethical concepts such as informed consent arise from a historically specific engagement between professional and social groups. PMID- 26240023 TI - Polymerase chain reaction-based screening method applicable universally to environmental haloarchaea and halobacteria for identifying polyhydroxyalkanoate producers among them. AB - The existing techniques for detection of polyhydroxyalkanoates (PHA) in halophilic archaea/bacteria are either imprecise or require prior PHA production before screening. The proposed method involves amplification of the approximately 280-300 bp conserved region of Class III PHA synthase (phaC) gene of halophiles using the primers codehopCF and codehopCR (Han et al. Appl Environ Microb 76:7811 7819, 2010). In this study, the best reaction condition was ascertained after repeated trials. This developed method was tested on nine haloarchaeal and halobacterial type strains and 28 environmental halophilic archaea and bacteria isolated from the salt pans of the east and west coasts of India. 29 strains were found to be phaC-positive, while eight were found to be phaC-negative although they appeared PHA positive through conventional Nile Red staining. 16S rRNA-based phylogenetic analysis identified 9 haloarchaeal and 9 halobacterial species as novel PHA producers. Multiple sequence alignment of the phaC gene-derived amino acid sequences showed that only 7 amino acid residues were conserved within all four classes of phaC enzymes, whereas 61 amino acids were identical among the phaC enzyme specific to the haloarchaeal and halobacterial strains presently investigated. All phaC-positive strains produced PHA in standard nutrient deficient medium, whereas the phaC-negative strains did not accumulate any PHA as detected by gas chromatography and nuclear magnetic resonance analyses, thus proving the precision of the developed method and elimination of false positives seen with the traditional Nile Red staining procedure. PMID- 26240024 TI - The ubiquitin ligase RNF43 downregulation increases membrane expression of frizzled receptor in pancreatic ductal adenocarcinoma. AB - RNF43 is a novel tumor suppressor protein and known to be expressed in a multitude of tissue and dysregulated in cancers of these organs including ovarian and colorectal tissues. RNF43 expression has been shown to be expressed in mutated forms in several pancreatic cell lines. RNF43, by virtue of being an ubiquitin ligase, has the potential to ubiquitinylate membrane receptors like frizzled that subserves sensing Wnt soluble signals at the cell membrane. Thus, normally, RNF43 downregulates Wnt signaling by removing frizzled receptor from the membrane. In the present study, the expression of the tumor suppressor RNF43 was examined in human patient samples of pancreatic ductal adenocarcinoma (PDAC). Reduced levels of expression of RNF43 in PDAC were demonstrated by Western blotting. We incorporated membrane biotinylation assay to examine the expression of frizzled6 receptor in the membrane and demonstrated that it is significantly increased in PDAC tissues. This may be responsible for enhanced Wnt/beta-catenin signaling and provides the first level of evidence of a possible role of this well-known pathway in pancreatic exocrine carcinogenesis. We have utilized appropriate controls to ensure the true positivity of the findings of the present study. The contribution of Wnt/beta-catenin/RNF43 pathway in pancreatic carcinogenesis may provide for utilization of pharmacologic resources for precision-based approaches to treat pancreatic ductal adenocarcinoma. PMID- 26240025 TI - Serum lactate dehydrogenase levels at presentation in stage IV non-small cell lung cancer: predictive value of metastases and relation to survival outcomes. AB - This study aimed to evaluate the clinical correlations between serum lactate dehydrogenase (LDH) levels and tumor characteristics and to investigate the prognostic impact of serum LDH levels in advanced non-small cell lung cancer (NSCLC). A total of 394 patients were included in the present study between June 2007 and January 2013. All eligible patients had serum LDH levels available before treatment, and whole-body metastatic extent was measured using whole-body metastatic scores, as determined by 18(F)-fludeoxyglucose positron emission tomography scans from 1 to 7 as the sum of each metastatic region. The diagnostic cutoff value for an abnormal serum LDH level was 450 IU/L. The median serum LDH level was 477 IU/L (range, 113-2850), and 224 (56.9 %) patients had abnormal serum LDH levels. The serum LDH levels showed no significant associations with age, gender, histology, tumor differentiation, and smoking history. However, the proportion of patients with abnormal serum LDH levels was statistically significantly higher in the high total metastatic score group (scores 3-7) than in the low total metastatic score group (scores 1-2) (65.3 vs 50.4 %, p = 0.001). In a multivariate survival analysis, age (p = 0.001), gender (p = 0.001), histology (p = 0.003), tumor differentiation (p = 0.001), Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.001), LDH levels (p = 0.046), and treatment factors (p = 0.001) proved to be independent prognostic factors for survival outcomes. The results of this study suggest that the serum LDH levels at presentation may be significantly correlated with whole-body tumor extent and might independently but modestly prognosticate OS in stage IV NSCLC. PMID- 26240026 TI - Mutant-specific BRAF and CD117 immunocytochemistry potentially facilitate risk stratification for papillary thyroid carcinoma in fine-needle aspiration biopsy specimens. AB - The study aims to test whether combination of mutant-specific BRAF and CD117 immunocytochemical (ICC) staining stratifies probability for papillary thyroid carcinoma (PTC) in thyroid fine-needle aspiration biopsy (FNAB) specimens. A consecutive cohort of cases diagnosed as atypia of undetermined significance (AUS) or suspicious for malignancy-suspicious for papillary thyroid carcinoma (SM SPTC) from 30 December, 2011 to 23 October, 2014 in a single institute was enrolled. Forty cytologically benign and 50 cytologically diagnosed PTC within the same time span were also included. CD117 and mutant-specific BRAF (BRAF VE1) ICC staining was performed. Association of BRAF VE1 and CD117 expression with final diagnosis was analyzed. Both BRAF VE1 and CD117 showed good performance in distinguishing PTC from benign nodules. Combination of BRAF VE1 and CD117 stratified 180 cases into three categories: BRAF VE1 positive regardless of CD117 expression (ICC-malignant), BRAF VE1 negative plus low level of CD117 expression (ICC-intermediate), and BRAF VE1 negative plus high level of CD117 expression (ICC-benign), which was associated with 100, 75.6, and 0 % of malignancy. Combination of mutant-specific BRAF and CD117 ICC may potentially facilitate the PTC risk stratification in FNAB thyroid nodule specimens. PMID- 26240028 TI - Mitral valve disease and acute coronary syndromes. PMID- 26240027 TI - An assessment of feeding jejunostomy tube placement at the time of resection for gastric adenocarcinoma: A seven-institution analysis of 837 patients from the U.S. gastric cancer collaborative. AB - BACKGROUND: Jejunostomy feeding tubes (J-tubes) are often placed during resection for gastric adenocarcinoma (GAC). Their effect on postoperative complications and receipt of adjuvant therapy is unclear. METHODS: Patients who underwent curative intent resection of GAC at seven institutions of the U.S. Gastric Cancer Collaborative from 2000 to 2012 were identified. The associations of J-tubes with postoperative complications and receipt of adjuvant therapy were determined. RESULTS: Of 837 patients, 265 (32%) received a J-tube. Patients receiving J-tubes demonstrated greater incidence of preoperative weight loss, lower BMI, greater extent of resection, and more advanced TNM stage. J-tube placement was associated with increased infectious complications (36% vs. 19%; P < 0.001), including surgical-site (14% vs. 6%; P < 0.001) and deep intra-abdominal (11% vs. 4%; P < 0.001) infections. On multivariate analysis, J-tubes remained independently associated with increased risk of infectious complications (all: HR = 1.93; P = 0.001; surgical-site: HR = 2.85; P = 0.001; deep intra-abdominal: HR = 2.13; P = 0.04). J-tubes were not associated with increased receipt of adjuvant therapy (HR = 0.82; P = 0.34). Subset analyses of patients undergoing total and subtotal gastrectomy similarly demonstrated an association of J-tubes with increased risk of infectious outcomes and no association with increased receipt of adjuvant therapy. CONCLUSIONS: J-tube placement after resection of gastric adenocarcinoma is associated with increased postoperative infectious outcomes and is not associated with increased receipt of adjuvant therapy. Selective use of J-tubes is recommended. PMID- 26240029 TI - Hand grip strength predicts myocardial infarction and stroke. PMID- 26240030 TI - Stress and strain distribution in demineralized enamel: A micro-CT based finite element study. AB - Physiological oral mechanical forces may play a role on the progression of enamel carious lesions to cavitation. Thus, the aim of this study was to describe, by 3D finite element analysis, stress, and strain patterns in sound and carious enamel after a simulated occlusal load. Micro-CT based models were created and meshed with tetrahedral elements (based on an extracted third molar), namely: a sound (ST) and a carious tooth (CT). For the CT, enamel material properties were assigned according to the micro-CT gray values. Below the threshold corresponding to the enamel lesion (2.5 g/cm(3) ) lower and isotropic elastic modulus was assigned (E = 18 GPa against E1 = 80 GPa, E2 = E3 = 20 GPa for sound enamel). Both models were imported into a FE solver where boundary conditions were assigned and a pressure load (500 MPa) was applied at the occlusal surface. A linear static analysis was performed, considering anisotropy in sound enamel. ST showed a more efficient transfer of maximum principal stress from enamel to the dentin layer, while for the CT, enamel layer was subjected to higher and concentrated loads. Maximum principal strain distributions were seen at the carious enamel surface, especially at the central fossa, correlating to the enamel cavity seen at the original micro-CT model. It is possible to conclude that demineralized enamel compromises appropriate stress transfer from enamel to dentin, contributing to the odds of fracture and cavitation. Enamel fracture over a dentin lesion may happen as one of the normal pathways to caries progression and may act as a confounding factor during clinical diagnostic decisions. PMID- 26240031 TI - Glycan reducing end dual isotopic labeling (GREDIL) for mass spectrometry-based quantitative N-glycomics. AB - A general and effective enzymatic labeling method, termed glycan reducing end dual isotopic labeling (GREDIL), was developed for mass spectrometry-based quantitative N-glycomics. PMID- 26240032 TI - Evaluation of adherence by elderly nursing home patients to regular consumption of apple compote enriched with protein and soluble fiber. AB - BACKGROUND: An increase in daily doses of protein and fiber for the elderly is relevant in preventing sarcopenia and preserving intestinal balance. However, such intake of supplements is often compromised by the lack of adherence among the elderly. OBJECTIVES: The main objective was to evaluate the perception of the hedonic qualities of compote enriched with NUTRALYS((r)) pea protein, NUTRALYS((r))W hydrolyzed wheat gluten and NUTRIOSE((r)) soluble fiber and the changes in that perception due to repeated consumption. The secondary objectives were to evaluate the evolution in the quantity of compote eaten, satisfaction with consumption and any changes in fatigue, digestive comfort and digestive tolerance when eating compote every other day for 3 weeks. METHOD: An observational study was conducted in nursing homes on volunteers aged 70-90 years. The compote was proposed as a lunchtime dessert every two days for a period of three consecutive weeks. All criteria were evaluated at days D0 and/or D1, D7, D15 and D21, except for the amount of compote eaten, evaluated after each meal at which it was served. RESULTS: When first tasted, the compote was judged 'rather pleasant' to 'very pleasant' by 91.6 % and this rating held up at 79.2 % (p = 0.1797) after 1 week, 83.3 % (p = 0.3173) after 2 weeks and 79.2 % (p = 0.2568) after 3 weeks. Average consumption of compote was stable and varied between a maximum of 79.5 % of the total quantity at inclusion to a minimum of 61.5 % recorded on D17. The other parameters did not change significantly. CONCLUSION: Pea protein, hydrolyzed wheat gluten and soluble fiber seem to provide an appropriate form of protein and fiber supplementation in the diets of elderly people in nursing homes. PMID- 26240033 TI - Classification of Chinese herbs based on the cluster analysis of delayed luminescence. AB - Traditional Chinese material medica are an important component of the Chinese pharmacopeia. According to the traditional Chinese medicinal concept, Chinese herbal medicines are classified into different categories based on their therapeutic effects, however, the bioactive principles cannot be solely explained by chemical analysis. The aim of this study is to classify different Chinese herbs based on their therapeutic effects by using delayed luminescence (DL). The DL of 56 Chinese herbs was measured using an ultra-sensitive luminescence detection system. The different DL parameters were used to classify Chinese herbs according to a hierarchical cluster analysis. The samples were divided into two groups based on their DL kinetic parameters. Interestingly, the DL classification results were quite consistent with classification according to the Chinese medicinal concepts of 'cold' and 'heat' properties. In this paper, we show for the first time that by using DL technology, it is possible to classify Chinese herbs according to the Chinese medicinal concept and it may even be possible to predict their therapeutic properties. PMID- 26240034 TI - Multiple sclerosis: 7 T MRI reveals cortical lesions associated with disability in MS. PMID- 26240037 TI - Motor neuron disease: Brain transcriptome profiling reveals involvement of divergent pathways in C9orf72-associated and sporadic ALS. PMID- 26240036 TI - Cell-based therapies for Parkinson disease-past insights and future potential. AB - Parkinson disease (PD) is characterized by loss of the A9 nigral neurons that provide dopaminergic innervation to the striatum. This discovery led to the successful instigation of dopaminergic drug treatments in the 1960s, although these drugs were soon recognized to lose some of their efficacy and generate their own adverse effects over time. Despite the fact that PD is now known to have extensive non-nigral pathology with a wide range of clinical features, dopaminergic drug therapies are still the mainstay of therapy, and work well for many years. Given the success of pharmacological dopamine replacement, pursuit of cell-based dopamine replacement strategies seemed to be the next logical step, and studies were initiated over 30 years ago to explore the possibility of dopaminergic cell transplantation. In this Review, we outline the history of this therapeutic approach to PD and highlight the lessons that we have learned en route. We discuss how the best clinical outcomes have been obtained with fetal ventral mesencephalic allografts, while acknowledging inconsistencies in the results owing to problems in trial design, patient selection, tissue preparation, and immunotherapy used post-grafting. We conclude by discussing the challenges of bringing the new generation of stem cell-derived dopamine cells to the clinic. PMID- 26240038 TI - Diterpenoid alkaloids of Aconitum laciniatum and mitigation of inflammation by 14 O-acetylneoline in a murine model of ulcerative colitis. AB - Aconitum laciniatum is used in Bhutanese traditional medicine for treating various chronic infections and inflammatory conditions. We carried out in-depth isolation and characterization of the phytochemicals from the root component and determined the anti-inflammatory effects of the isolated compounds against chemically-induced colitis in mice. Five diterpenoid alkaloids - pseudaconitine, 14-veratroylpseudaconine, 14-O-acetylneoline, neoline, and senbusine A - were isolated from A. laciniatum for the first time. Two of the alkaloids were tested for anti-inflammatory properties in the TNBS-induced colitis model in mice. Various parameters were measured to assess pathology including weight loss, clinical and macroscopic scores, histological structure and IFN-gamma production in the gut. Of the two alkaloids tested, 14-O-acetylneoline showed significant protection against different parameters of colitic inflammation. Compared to control mice that received TNBS alone, mice treated with 14-O-acetylneoline experienced significantly less weight loss and had significantly lower clinical scores, macroscopic pathology and grades of histological inflammation. Moreover, colonic IFN-gamma mRNA levels were significantly reduced in mice that received 14 O-acetylneoline compared to control mice that received TNBS alone. This alkaloid is now considered a novel anti-colitis drug lead compound. PMID- 26240039 TI - Self-Care Practices of Baccalaureate Nursing Students. AB - PURPOSE: The aim of the study was to investigate baccalaureate nursing student perspectives of self-care practices to gain understanding of their value in health promotion. DESIGN: A descriptive, quantitative tool developed by Chow and Grant Kalischuk (2008), Self-Care & Complementary Therapies Survey, was adapted to measure the self-care practices of nursing students. METHODS: A convenience sample of students (n = 119) enrolled in a 3-year baccalaureate nursing program at a public university were sent the Self-Care & Complementary Therapies Survey online. Fifty-three (44.5%) students participated in the survey. Collection of data occurred over a 30-day period in spring of 2014. FINDINGS: Year in the program did not appear to impact self-care practices or knowledge of complementary alternative therapies (CAM). Diet, exercise, and sleep correlated with perceived health status. General health by students was rated as 7.18 using a scale from 0 to 10 (O being poor health and 10 excellent). Students reported feeling comfortable caring for clients who use CAM yet rated their knowledge as average. CONCLUSION: Although based on a relatively small sample size, the findings support education and interventions addressing areas of general health, diet and hydration, exercise, reduction of stress, and increased knowledge of CAM in baccalaureate nursing. PMID- 26240041 TI - [In Process Citation]. PMID- 26240040 TI - Picroside II Inhibits the MEK-ERK1/2-COX2 Signal Pathway to Prevent Cerebral Ischemic Injury in Rats. AB - The objective of this study is to explore the neuroprotective effect and mechanism of picroside II on ERK1/2-COX2 signal transduction pathway after cerebral ischemic injury in rats. Focal cerebral ischemic models were established by inserting monofilament threads into the middle cerebral artery in 200 Wistar rats. Twenty four rats were randomly selected into control group, while the other rats were randomly divided into six groups: model group, picroside group, lipopolysaccharide (LPS) with picroside group, U0126 with picroside group, LPS group, and U0126 group with each group containing three subgroups with ischemia at 6, 12, and 24 h. Neurobehavioral function in the rats was evaluated by modified neurological severity score points (mNSS) test; structure of neurons was observed using hematoxylin-eosin (HE) staining; apoptotic cells were counted using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay; expressions of phosphorylated mitogen/extracellular signal-regulated kinase kinas1/2 (pMEK1/2), phosphorylated extracellular signal-regulated protein kinase1/2 (pERK1/2), and cyclooxygenase (COX2) in the cortex were determined using immunohistochemistry (IHC) and Western blot (WB); and real-time PCR was used to determine the level of COX2 mRNA. The neurological behavioral malfunction appeared in all rats with middle cerebral artery occlusion (MCAO). In the model group, neuron damage was extensive, while the neurobehavioral function score, apoptotic cell index, expression of pMEK1/2, pERK1/2, and COX2 and the level of COX2 mRNA increased significantly when compared to the control group. The peak COX2 mRNA level was in ischemia 12 h, prior to the peak in COX2 protein expression. In the picroside and U0126 groups, the neurological behavioral function was improved, and the number of apoptotic cells and the expression of pMEK1/2, pERK1/2, and COX2 decreased significantly when compared to the model group. In the LPS with picroside group, at ischemia 6 h neuron damage was extensive, and pMEK1/2, pERK1/2, and COX2 expression were much higher than in the model group. But at ischemia 12 and 24 h, the expression of pMEK1/2, pERK1/2, and COX2 decreased slightly, and the neurobehavioral function also improved slightly. In LPS group, neuron damage was extensive, pMEK1/2, pERK1/2, and COX2 expression was still at a high level, and COX2 mRNA peak arrived at ischemic 12 h. Picroside II downregulates COX2 expression after MCAO by inhibiting MEK-ERK1/2 in rats to protect neurons from apoptosis and inflammation. PMID- 26240042 TI - [In Process Citation]. PMID- 26240043 TI - [In Process Citation]. PMID- 26240044 TI - [Schnitzler syndrome is a diagnostic challenge]. AB - Schnitzler syndrome (SS) is a rare autoinflammatory disorder characterized by a chronic urticarial rash and a monoclonal immunoglobulin M gammopathy, accompanied by recurrent fever, lymphadenopathy, arthralgia or arthritis, hepato- or splenomegaly and elevated levels of markers of systemic inflammation. Because patients often present to various specialists with different symptoms the syndrome is often undiagnosed, and it can take years before the correct diagnosis is made. Treatment with interleukin-1 receptor antagonists has a rapid effect on SS. PMID- 26240046 TI - [Perianal abscesses in twins]. AB - Perianal abscesses (PA) are relatively common in children, especially in infants. The aetiology of PA is still unknown but several factors point toward a congenital aetiology: 1) it is almost exclusively seen in infants, 2) with a male predominance, 3) predilection sites at 3 and 9 o'clock, 4) the finding of abnormal Morgagni crypts and 5) aberrant epithelial lining. Traditionally, incision and drainage has been the treatment of choice, but several studies suggest conservative management. The effect of antibiotics has not been proven. In this case report we present two 29-day-old monozygous twin boys with PA. PMID- 26240045 TI - [The use of an inspiratory impedance valve during cardiopulmonary resuscitation does not improve long-term survival or neurologic outcome]. AB - The impedance threshold device (ITD) works by increasing negative intrathoracic pressure, venous return and cardiac output during cardiopulmonary resuscitation. Although animal studies have shown promising results on haemodynamics, randomized studies and metaanalyses in humans have not shown better long-term survival or neurologic outcome. No studies have been done on the use of the ITD during in hospital cardiac arrest. The ITD combined with active compression-decompression cardiopulmonary resuscitation may result in a better outcome. PMID- 26240047 TI - [A patient diagnosed herself with erythropoietic protoporphyria after googling photosensitivity]. AB - Erythropoietic protoporphyria (EPP) is rare genetic disease caused by decreased activity of the eighth enzyme in the haem synthesis. Patients are photosensitive, getting stinging and burning sensations in the skin after sun exposure. Delayed diagnosis of these patients is not seldom because of the rarity in combination with not always visible skin symptoms. This is a case report of a 43-year-old woman who diagnosed herself with EPP after googling photosensitivity. Genetic testing revealed a formerly undescribed mutation, c. 1096-3C>G in combination with the polymorphism, c.333-48T>C. PMID- 26240048 TI - [High volume exercise can be unhealthy]. AB - There are positive health effects of exercise performed at regular intervals also in high volume exercisers. However, at present there is no exact definition of the optimal dose or the maximal safe dose of exercise, nor can the level of exercise to induce increased risk of harmful effects be defined. People who often exercise with a high volume and intensity should therefore individually consider the health-related effects and possible risks of their training as well as the physical or psychological warning signals. PMID- 26240049 TI - [No evidence that formalized triage is superior to informally structured triage]. AB - Formalized triage has been implemented in all Danish emergency departments. The validation behind formalized triage has focused on investigating predictive validity, i.e. correspondence between triage category and different outcome measures. Reliability is primarily investigated in terms of inter-rater reliability on written patient cases, and several studies have methodological limitations questioning their clinical relevance. Currently, there is no evidence establishing that formalized triage is superior to informally structured triage with regards to clinical end points. PMID- 26240050 TI - Is Intake of Flavonoid-Based Food Supplements During Pregnancy Safe for the Developing Child? A Literature Review. AB - Due to potential health benefits and the general assumption that natural products are safe, there is an increasing trend in the general population - including pregnant women - to supplement their diet with flavonoid-based food supplements. In addition, preclinical studies aim to prevent developmental adverse effects induced by toxic substances, infections, maternal or genetic diseases of the unborn child by administration of flavonoids at doses far above those reached by normal diets. Because these substances do not undergo classical risk assessment processes, our aim was to review the available literature on the potential adverse effects of maternal diet supplementation with flavonoid-based products for the developing child. A systematic literature search was performed in three databases and screened following four exclusion criteria. Selected studies were classified into two groups: 1. Studies on the developmental toxicity of single flavonoids in vitro or in animals in vivo, and 2. Studies on the developmental toxicity of single flavonoids or on flavonoid-mixtures in humans. The data collected indicate that there is a concern for the safety of some flavonoids within realistic human exposure scenarios. This concern is accompanied by a tremendous lack of studies on safety of these compounds during development making definite safety decisions impossible. Besides studies of survival, especially the more specific developmental processes like nervous system development need to be addressed experimentally. Before new high-dose, flavonoid-based therapeutic strategies are developed for pregnant women further research on the safety of these compounds is clearly needed. PMID- 26240051 TI - Molecular Pharmacology of Malignant Pleural Mesothelioma: Challenges and Perspectives From Preclinical and Clinical Studies. AB - Malignant pleural mesothelioma (MPM) is one of the deadliest and most heterogeneous tumors, highly refractory to multimodal therapeutic approach, including surgery, chemo- and radiotherapy. Preclinical and clinical studies exploring the efficacy of drugs targeting tyrosine kinases, angiogenesis and histone deacetylases, did not fulfil the expected clinical benefits. Thus, novel molecular targets should be identified from a definite knowledge of the unique biology and most relevant transduction pathways of MPM cells. Cancer stem cells (CSCs) are a subset of malignant precursors responsible for initiation, progression, resistance to cytotoxic drugs, recurrence and metastatic diffusion of tumor cells. CSCs are putative driving factors for MPM development and contribute to its clinical and biological heterogeneity; hence, targeted eradication of CSCs represents an ineludible goal to counteract MPM aggressiveness. In this context, innovative preclinical models could be exploited to identify novel intracellular pathway inhibitors able to target CSC viability. Novel drug targets have been identified among key factors responsible for the oncogenic transformation of mesothelial cells, often directly induced by asbestos. These include mitogenic and anti-apoptotic signaling that may also be activated by autocrine and paracrine cytokine pathways controlling cell plasticity. Both signaling pathways affecting proto-oncogene and transcription factor expression, or genetic and epigenetic alterations, such as mutations in cell cycle genes and silencing of tumor suppressor genes, represent promising disease-specific targets. In this review we describe current knowledge of MPM cell biology, focusing on potential targets to be tested in pharmacological studies, and highlighting results and challenges of clinical translation. PMID- 26240052 TI - Targeting Interferon Regulatory Factor for Cardiometabolic Diseases: Opportunities and Challenges. AB - BACKGROUND: The pathological activation of innate immune system may contribute to the development of cardiometabolic diseases. The interferon regulatory factor (IRF) family members, which are the major transcription factors in innate immune signaling, are implicated in cardiometabolic diseases. OBJECTIVE: The aim of this review is to summary the current knowledge of the biological functions of IRFs in innate immune responses and immune cell development, and highlight our contemporary understanding of the functions and molecular mechanisms of IRFs in metabolic diseases, cardiovascular remodeling, and stroke. RESULTS: IRFs are the essential regulators of cardiometabolic diseases via immune-dependent and - independent manners. CONCLUSION: IRFs signaling is the promising target to manage the initiation and progression of cardiometabolic disorders. PMID- 26240053 TI - Nano-Based Anti-Tubercular Drug Delivery and Therapeutic Interventions in Tuberculosis. AB - Nanotechnology has shown great promise in health care offering numerous possibilities to significantly improve diagnosis of many dreadful diseases including Tuberculosis (TB). Nanomedicine has made the current drug regimen more effective against diseases particularly TB with attributes like sustained release, increased half life, higher drug concentrations at target sites, reduced toxicity and lesser side effects. However because of the severity of the disease, there is a strong urge to develop better approaches with some concomitant regimens using nano-particles to diagnose, treat and manage TB patients. The current review highlights some of the evolving strategies in the field of nanomedicine particularly drug delivery offering promising alternative for the current TB regimens. The study also emphasizes upon the need to design more effective nanocarriers which are highly specific, biocompatible and biodegradable as well. PMID- 26240054 TI - Chemokines in the Pathogenesis and as Therapeutical Markers and Targets of HCV Chronic Infection and HCV Extrahepatic Manifestations. AB - Cytokines and chemokines, hepatitis C virus (HCV) infection-induced, participate in viral control and liver damage. The complex cytokine network, operating during initial infection allows a coordinated and effective development of innate and adaptive immune responses. "HCV interferes with cytokines at various levels and escapes immune response by inducing a T helper (Th)2/T cytotoxic 2 cytokine profile". A predominance of the Th1 immune response (and related cytokines) has been evidenced in chronic hepatitis C infection and in extrahepatic manifestations. Interferon (IFN)-gamma and IFN-gamma-inducible chemokine (C-X-C motif) ligand (CXCL)9, -10 and -11 recruit inflammatory infiltrates into the liver parenchyma due to the incapability to control the infection process, resulting in extensive liver damage and liver cirrhosis. "The most important systemic HCV-related extrahepatic diseases - mixed cryoglobulinemia, lymphoproliferative disorders, diabetes and autoimmune thyroid disorders - are associated with a complex dysregulation of the cytokine/chemokine network and involve pro-inflammatory and Th1 chemokines. The therapeutical administration of cytokines such as IFN-alpha may result in viral clearance during persistent infection and reverts this process" reducing circulating CXCL10 levels. "Several studies have reported interleukin (IL)-28B polymorphisms, and circulating CXCL10, may be prognostic markers for HCV treatment efficacy in HCV infection". Other studies have also shown that HCV clearance by directly acting antiviral agents therapy decreases circulating CXCL10 levels. "Theoretically agents that selectively neutralize CXCL10 could increase patient responsiveness to traditional IFN-based HCV therapy", simultaneously reducing inflammatory immune cell activation. PMID- 26240055 TI - Endothelial Cell Senescence and Inflammaging: MicroRNAs as Biomarkers and Innovative Therapeutic Tools. AB - Aging is accompanied by a progressive decline of endothelial function and a progressive drift toward a systemic pro-inflammatory status that has been designated "inflammaging". Both phenomena are accelerated and exacerbated in patients with the most common age-related diseases (ARDs), including cancer. The finding that chronic cell stress activates a pro-inflammatory program leading to acquisition of the senescence-associated secretory phenotype (SASP) and to the propagation of senescence to surrounding cells through the secretome, suggests that cell senescence may have a role in both processes. Here we: i) describe the role of cell senescence in endothelial dysfunction, ii) emphasize the contribution of the endothelial cell SASP to inflammaging, and iii) suggest that selective removal of senescent endothelial cells may not only hinder such harmful processes, but also reduce the risk of developing ARDs and their complications. Although in vivo detection and targeting of senescent endothelial cells are still being investigated, it is likely that therapeutic strategies based on antioxidant and anti-inflammatory compounds would involve generalized anti-aging effects also benefiting endothelial cells. MicroRNA (miRNAs) - single-stranded, non-coding RNAs expressed by all living cells and involved in the epigenetic modulation of all transcriptional programs - may constitute an innovative, valuable tool to detect and target senescent endothelial cells and to devise treatments that can slow down the pro-inflammatory program activated in senescent endothelial cells. PMID- 26240056 TI - Green Template-Free Synthesis of Hierarchical Shuttle-Shaped Mesoporous ZnFe2 O4 Microrods with Enhanced Lithium Storage for Advanced Li-Ion Batteries. AB - Invited for the cover of this issue is Changzhou Yuan and co-workers at the Anhui University of Technology. The image depicts hierarchical shuttle-shaped mesoporous ZnFe2 O4 micro-rods, as a low-cost yet high-performance anode, for advanced next-generation Li-ion batteries. Read the full text of the article at 10.1002/chem.201501876. PMID- 26240059 TI - Rash on the arms and legs. PMID- 26240057 TI - Involuntary, Forced and Voluntary Exercises Equally Attenuate Neurocognitive Deficits in Vascular Dementia by the BDNF-pCREB Mediated Pathway. AB - A rat model of vascular dementia was used to compare the effects of involuntary exercise induced by functional electrical stimulation (FES), forced exercise and voluntary exercise on the recovery of cognitive function recovery and its underlying mechanisms. In an involuntary exercise (I-EX) group, FES was used to induce involuntary gait-like running on ladder at 12 m/min. A forced exercise group (F-EX) and a voluntary exercise group (V-EX) exercised by wheel running. The Barnes maze was used for behavioral assessment. Brain-derived neurotrophic factor (BDNF), phosphorylated extracellular signal-regulated kinase 1 and 2 (ERK1/2) and cAMP response element binding protein (CREB) positive cells in hippocampal CA1, CA2/3 and dentate gyrus (DG) regions were evaluated using immunohistochemical methods. Western blotting was used to assess the levels of BDNF, phosphorylated protein kinase B (Akt), tropomyosin receptor kinase B (TrkB), mitogen-activated protein kinase 1 and 2 (MEK1/2), ERK1/2 and CREB in BDNF-pCREB signaling in the hippocampus and prefrontal cortex. Involuntary, forced and voluntary exercises were all found to reverse the cognitive deficits of vascular dementia with about equal effectiveness. The number of BDNF, pCREB and pERK1/2 immunopositive cells was significantly increased in the hippocampal CA1, CA2/3 and DG regions in all three exercise groups. In addition, involuntary exercise activated BDNF and the phosphorylation of Akt, TrkB, MEK1/2, ERK1/2 and CREB in the hippocampus and prefrontal cortex equally as well as voluntary or forced exercise. These results suggest that involuntary exercise induced by FES may be as beneficial for alleviating cognitive deficits after cerebral ischemia. PMID- 26240058 TI - A longitudinal biomarker for the extent of skin disease in patients with diffuse cutaneous systemic sclerosis. AB - OBJECTIVE: To define a pharmacodynamic biomarker based on gene expression in skin that would provide a biologic measure of the extent of disease in patients with diffuse cutaneous systemic sclerosis (dcSSc) and could be used to monitor skin disease longitudinally. METHODS: Skin biopsy specimens obtained from a cohort of patients with dcSSc (including longitudinal specimens) were analyzed by microarray. Expression of genes correlating with the modified Rodnan skin thickness score (MRSS) were examined for change over time using a NanoString platform, and a generalized estimating equation (GEE) was used to define and validate longitudinally measured pharmacodynamic biomarkers composed of multiple genes. RESULTS: Microarray analysis of genes parsed to include only those correlating with the MRSS revealed prominent clusters of profibrotic/transforming growth factor beta-regulated, interferon-regulated/proteasome, macrophage, and vascular marker genes. Using genes changing longitudinally with the MRSS, we defined 2 multigene pharmacodynamic biomarkers. The first was defined mathematically by applying a GEE to longitudinal samples. This modeling method selected cross-sectional THBS1 and longitudinal THBS1 and MS4A4A. The second model was based on a weighted selection of genes, including additional genes that changed statistically significantly over time: CTGF, CD163, CCL2, and WIF1. In an independent validation data set, biomarker levels calculated using both models correlated highly with the MRSS. CONCLUSION: Skin gene expression can be used effectively to monitor changes in SSc skin disease over time. We implemented 2 relatively simple models on a NanoString platform permitting highly reproducible assays that can be applied directly to samples from patients or collected as part of clinical trials. PMID- 26240060 TI - Lysine-specific demethylase-1 contributes to malignant behavior by regulation of invasive activity and metabolic shift in esophageal cancer. AB - Lysine-specific demethylase-1 (LSD1) removes the methyl groups from mono- and di methylated lysine 4 of histone H3. Previous studies have linked LSD1 to malignancy in several human tumors, and LSD1 is considered to epigenetically regulate the energy metabolism genes in adipocytes and hepatocellular carcinoma. This study investigates the function of LSD1 in the invasive activity and the metabolism of esophageal cancer cells. We investigated whether LSD1 immunohistochemical expression levels are related to clinical and pathological features, including the maximum standard uptake value in fluorodeoxyglucose positron emission tomography assay. The influence of LSD1 on cell proliferation, invasion and glucose uptake was evaluated in vitro by using specific small interfering RNA for LSD1, and an LSD1 inhibitor. We also evaluated two major energy pathways (glycolytic pathway and mitochondrial respiration) by measuring the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) with an extracellular flux analyzer. High LSD1 immunohistochemical expression was significantly associated with high tumor stage, lymphovascular invasion, poor prognosis, and high maximum standard uptake value in esophageal cancer patients. In the in vitro analysis, LSD1 knockdown significantly suppressed the invasive activity and glucose uptake of cancerous cells, reduced their ECAR and increased their OCR and OCR/ECAR. LSD1 may contribute to malignant behavior by regulating the invasive activity and metabolism, activating the glycolytic pathway and inhibiting the mitochondrial respiration of esophageal cancer cells. The results support LSD1 as a potential therapeutic target. PMID- 26240061 TI - Towards Predicting Patient-Specific Flow-Diverter Treatment Outcomes for Bifurcation Aneurysms: From Implantation Rehearsal to Virtual Angiograms. AB - Despite accounting for the majority of all cerebral aneurysm cases, bifurcation aneurysms present many challenges to standard endovascular treatment techniques. This study examines the treatment of bifurcation aneurysms endovascularly with flow-diverting stents and presents an integrative computational modeling suite allowing for rehearsing all aspects of the treatment. Six bifurcation aneurysms are virtually treated with 70% porosity flow-diverters. Substantial reduction (>50%) in aneurysm inflow due to device deployment is predicted in addition to reductions in peak and average aneurysm wall shear stress to values considered physiologically normal. The subsequent impact of flow-diverter deployment on daughter vessels that are jailed by the device is investigated further, with a number of simulations conducted with increased outlet pressure conditions at jailed vessels. Increased outlet pressures at jailed daughter vessels are found to have little effect on device-induced aneurysm inflow reduction, but large variation (13-86%) is seen in the resulting reduction in daughter vessel flow rate. Finally, we propose a potentially powerful approach for validation of such models, by introducing an angiographic contrast model, with contrast transport modeled both before and after virtual treatment. Virtual angiograms and contrast residence curves are created, which offer unique clinical relevance and the potential for future in vivo verification of simulated results. PMID- 26240062 TI - Determining Tension-Compression Nonlinear Mechanical Properties of Articular Cartilage from Indentation Testing. AB - The indentation test is widely used to determine the in situ biomechanical properties of articular cartilage. The mechanical parameters estimated from the test depend on the constitutive model adopted to analyze the data. Similar to most connective tissues, the solid matrix of cartilage displays different mechanical properties under tension and compression, termed tension-compression nonlinearity (TCN). In this study, cartilage was modeled as a porous elastic material with either a conewise linear elastic matrix with cubic symmetry or a solid matrix reinforced by a continuous fiber distribution. Both models are commonly used to describe the TCN of cartilage. The roles of each mechanical property in determining the indentation response of cartilage were identified by finite element simulation. Under constant loading, the equilibrium deformation of cartilage is mainly dependent on the compressive modulus, while the initial transient creep behavior is largely regulated by the tensile stiffness. More importantly, altering the permeability does not change the shape of the indentation creep curves, but introduces a parallel shift along the horizontal direction on a logarithmic time scale. Based on these findings, a highly efficient curve-fitting algorithm was designed, which can uniquely determine the three major mechanical properties of cartilage (compressive modulus, tensile modulus, and permeability) from a single indentation test. The new technique was tested on adult bovine knee cartilage and compared with results from the classic biphasic linear elastic curve-fitting program. PMID- 26240063 TI - Differential roles of resident microglia and infiltrating monocytes in murine CNS autoimmunity. AB - Macrophages can be of dual origin. Most tissue-resident macrophage compartments are generated before birth and subsequently maintain themselves independently from each other locally in healthy tissue. Under inflammatory conditions, these cells can however be complemented by macrophages derived from acute monocyte infiltrates. Due to the lack of suitable experimental systems, differential functional contributions of central nervous system (CNS)-resident microglia and monocyte-derived macrophages (MoMF) to CNS inflammation, such as experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis (MS), remain poorly understood. Here, we will review recent progress in this field that suggest distinct roles of microglia and MoMF in disease induction and progression, capitalizing on novel transgenic mouse models. The latter finding could have major implications for the rationale development of therapeutic approaches to the management of brain inflammation and MS therapy. PMID- 26240065 TI - Cognitive Function: Is There More to Anticoagulation in Atrial Fibrillation Than Stroke? PMID- 26240068 TI - Sexual Violence in the Context of Drug Use Among Young Adult Opioid Users in New York City. AB - Drug and alcohol use have been associated with increased risk for sexual violence, but there is little research on sexual violence within the context of drug use among young adult opioid users. The current mixed-methods study explores young adult opioid users' sexual experiences in the context of their drug use. Forty-six New York City young adults (ages 18-32) who reported lifetime nonmedical use of prescription opioids (POs) completed in-depth, semistructured interviews, and 164 (ages 18-29) who reported heroin and/or nonmedical PO use in the past 30 days completed structured assessments that inquired about their drug use and sexual behavior and included questions specific to sexual violence. Participants reported frequent incidents of sexual violence experienced both personally and by their opioid using peers. Participants described sexual violence, including sexual assault, as occurring within a context characterized by victimization of users who were unconscious as a result of substance use, implicit and explicit exchanges of sex for drugs and/or money that increased risk for sexual violence, negative sexual perceptions ascribed to drug users, and participants' own internalized stigma. Recommendations to reduce sexual violence among young adult opioid users include education for users and service providers on the risk of involvement in sexual violence within drug using contexts and efforts to challenge perceptions of acceptability regarding sexual violence. PMID- 26240067 TI - E-cadherin can limit the transforming properties of activating beta-catenin mutations. AB - Wnt pathway deregulation is a common characteristic of many cancers. Only colorectal cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of the pancreas) have activating mutations in beta-catenin (CTNNB1). We have compared the dynamics and the potency of beta-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of beta-catenin took much longer to achieve Wnt deregulation and acquire a crypt-progenitor cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of beta-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of beta-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E cadherin:beta-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of beta-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of beta-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated beta-catenin. PMID- 26240069 TI - Reversal of the Drug Binding Pocket Defects of the AcrB Multidrug Efflux Pump Protein of Escherichia coli. AB - The AcrB protein of Escherichia coli, together with TolC and AcrA, forms a contiguous envelope conduit for the capture and extrusion of diverse antibiotics and cellular metabolites. In this study, we sought to expand our knowledge of AcrB by conducting genetic and functional analyses. We began with an AcrB mutant bearing an F610A substitution in the drug binding pocket and obtained second-site substitutions that overcame the antibiotic hypersusceptibility phenotype conferred by the F610A mutation. Five of the seven unique single amino acid substitutions--Y49S, V127A, V127G, D153E, and G288C--mapped in the periplasmic porter domain of AcrB, with the D153E and G288C mutations mapping near and at the distal drug binding pocket, respectively. The other two substitutions--F453C and L486W--were mapped to transmembrane (TM) helices 5 and 6, respectively. The nitrocefin efflux kinetics data suggested that all periplasmic suppressors significantly restored nitrocefin binding affinity impaired by the F610A mutation. Surprisingly, despite increasing MICs of tested antibiotics and the efflux of N-phenyl-1-naphthylamine, the TM suppressors did not improve the nitrocefin efflux kinetics. These data suggest that the periplasmic substitutions act by influencing drug binding affinities for the distal binding pocket, whereas the TM substitutions may indirectly affect the conformational dynamics of the drug binding domain. IMPORTANCE: The AcrB protein and its homologues confer multidrug resistance in many important human bacterial pathogens. A greater understanding of how these efflux pump proteins function will lead to the development of effective inhibitors against them. The research presented in this paper investigates drug binding pocket mutants of AcrB through the isolation and characterization of intragenic suppressor mutations that overcome the drug susceptibility phenotype of mutations affecting the drug binding pocket. The data reveal a remarkable structure-function plasticity of the AcrB protein pertaining to its drug efflux activity. PMID- 26240070 TI - Opposite and Coordinated Rotation of Amphitrichous Flagella Governs Oriented Swimming and Reversals in a Magnetotactic Spirillum. AB - Current knowledge regarding the mechanism that governs flagellar motor rotation in response to environmental stimuli stems mainly from the study of monotrichous and peritrichous bacteria. Little is known about how two polar flagella, one at each cell pole of the so-called amphitrichous bacterium, are coordinated to steer the swimming. Here we fluorescently labeled the flagella of Magnetospirillum magneticum AMB-1 cells and took advantage of the magnetically controllable swimming of this bacterium to investigate flagellar rotation in moving cells. We identified three motility behaviors (runs, tumbles, and reversals) and two characteristic fluorescence patterns likely corresponding to flagella rotating in opposite directions. Each AMB-1 locomotion mode was systematically associated with particular flagellar patterns at the poles which led us to conclude that, while cell runs are allowed by the asymmetrical rotation of flagellar motors, their symmetrical rotation triggers cell tumbling. Our observations point toward a precise coordination of the two flagellar motors which can be temporarily unsynchronized during tumbling. IMPORTANCE: Motility is essential for bacteria to search for optimal niches and survive. Many bacteria use one or several flagella to explore their environment. The mechanism by which bipolarly flagellated cells coordinate flagellar rotation is poorly understood. We took advantage of the genetic amenability and magnetically controlled swimming of the spirillum-shaped magnetotactic bacterium Magnetospirillum magneticum AMB-1 to correlate cell motion with flagellar rotation. We found that asymmetric rotation of the flagella (counterclockwise at the lagging pole and clockwise at the leading pole) enables cell runs whereas symmetric rotation triggers cell tumbling. Taking into consideration similar observations in spirochetes, bacteria possessing bipolar ribbons of periplasmic flagella, we propose a conserved motility paradigm for spirillum-shaped bipolarly flagellated bacteria. PMID- 26240072 TI - US healthcare spending will reach 20% of GDP by 2024, says report. PMID- 26240071 TI - An Essential Poison: Synthesis and Degradation of Cyclic Di-AMP in Bacillus subtilis. AB - Gram-positive bacteria synthesize the second messenger cyclic di-AMP (c-di-AMP) to control cell wall and potassium homeostasis and to secure the integrity of their DNA. In the firmicutes, c-di-AMP is essential for growth. The model organism Bacillus subtilis encodes three diadenylate cyclases and two potential phosphodiesterases to produce and degrade c-di-AMP, respectively. Among the three cyclases, CdaA is conserved in nearly all firmicutes, and this enzyme seems to be responsible for the c-di-AMP that is required for cell wall homeostasis. Here, we demonstrate that CdaA localizes to the membrane and forms a complex with the regulatory protein CdaR and the glucosamine-6-phosphate mutase GlmM. Interestingly, cdaA, cdaR, and glmM form a gene cluster that is conserved throughout the firmicutes. This conserved arrangement and the observed interaction between the three proteins suggest a functional relationship. Our data suggest that GlmM and GlmS are involved in the control of c-di-AMP synthesis. These enzymes convert glutamine and fructose-6-phosphate to glutamate and glucosamine-1-phosphate. c-di-AMP synthesis is enhanced if the cells are grown in the presence of glutamate compared to that in glutamine-grown cells. Thus, the quality of the nitrogen source is an important signal for c-di-AMP production. In the analysis of c-di-AMP-degrading phosphodiesterases, we observed that both phosphodiesterases, GdpP and PgpH (previously known as YqfF), contribute to the degradation of the second messenger. Accumulation of c-di-AMP in a gdpP pgpH double mutant is toxic for the cells, and the cells respond to this accumulation by inactivation of the diadenylate cyclase CdaA. IMPORTANCE: Bacteria use second messengers for signal transduction. Cyclic di-AMP (c-di-AMP) is the only second messenger known so far that is essential for a large group of bacteria. We have studied the regulation of c-di-AMP synthesis and the role of the phosphodiesterases that degrade this second messenger. c-di-AMP synthesis strongly depends on the nitrogen source: glutamate-grown cells produce more c-di AMP than glutamine-grown cells. The accumulation of c-di-AMP in a strain lacking both phosphodiesterases is toxic and results in inactivation of the diadenylate cyclase CdaA. Our results suggest that CdaA is the critical diadenylate cyclase that produces the c-di-AMP that is both essential and toxic upon accumulation. PMID- 26240073 TI - Gingerol Inhibits Serum-Induced Vascular Smooth Muscle Cell Proliferation and Injury-Induced Neointimal Hyperplasia by Suppressing p38 MAPK Activation. AB - PURPOSE: Gingerol inhibits growth of cancerous cells; however, its role in vascular smooth muscle cell (VSMC) proliferation is not known. The present study investigated the effect of gingerol on VSMC proliferation in cell culture and during neointima formation after balloon injury. METHOD AND RESULTS: Rat VSMCs or carotid arteries were harvested at 15 minutes, 30 minutes, 1, 6, 12, and 24 hours of fetal bovine serum (FBS; 10%) stimulation or balloon injury, respectively. Gingerol prevented FBS (10%)-induced proliferation of VSMCs in a dose-dependent manner (50 MUmol/L-400 MUmol/L). The FBS-induced proliferating cell nuclear antigen (PCNA) upregulation and p27(Kip1) downregulation were also attenuated in gingerol (200 MUmol/L) pretreated cells. Fetal bovine serum-induced p38 mitogen activated protein kinase (MAPK) activation, PCNA upregulation, and p27(Kip1) downregulation were abrogated in gingerol (200 MUmol/L) and p38 MAPK inhibitor (SB203580, 10 MUmol/L) pretreated cells. Balloon injury induced time-dependent p38 MAPK activation in the carotid artery. Pretreatment with gingerol (200 MUmol/L) significantly attenuated injury-induced p38 MAPK activation, PCNA upregulation, and p27(Kip1) downregulation. After 14 days of balloon injury, intimal thickening, neointimal proliferation, and endothelial dysfunction were significantly prevented in gingerol pretreated arteries. In isolated organ bath studies, gingerol (30 nmol/L-300 MUmol/L) inhibited phenylephrine-induced contractions and induced dose-dependent relaxation of rat thoracic aortic rings in a partially endothelium-dependent manner. CONCLUSION: Gingerol prevented FBS induced VSMC proliferation and balloon injury-induced neointima formation by regulating p38 MAPK. Vasodilator effect of gingerol observed in the thoracic aorta was partially endothelium dependent. Gingerol is thus proposed as an attractive agent for modulating VSMC proliferation, vascular reactivity, and progression of vascular proliferative diseases. PMID- 26240074 TI - Oxygen in the Setting of Acute Myocardial Infarction: Is It Really a Breath of Fresh Air? AB - INTRODUCTION: Supplemental oxygen has been used in the setting of acute myocardial infarction (AMI). Once an official recommendation in the guidelines for the management of acute ST-segment elevation myocardial infarction, it is now mentioned as an intervention to be considered. Data for the use of supplemental oxygen or AMI are limited, and some data have suggested associated harm. METHODS: We performed a systematic review of the literature and a subsequent meta-analysis of the data to determine the effect of high concentration oxygen versus titrated oxygen or room air in the setting of AMI. The following end points were studied: in-hospital mortality, opiate use, percentage of infarcted myocardium by magnetic resonance imaging (MRI), and mass of infarcted myocardium by MRI. RESULTS: No significant difference was noted with end points when comparing those randomized to high-concentration oxygen versus those randomized to titrated oxygen or room air in the setting of AMI. No significant publication bias was identified although this could not be assessed for all end points. CONCLUSION: High concentration oxygen may not offer any benefit when compared to titrated oxygen or room air. A large, randomized trial is warranted to further delineate these differences with respect to multiple end points. PMID- 26240075 TI - Sex-specific predictors of improved walking with step-monitored, home-based exercise in peripheral artery disease. AB - The aim of this study was to determine whether baseline clinical characteristics and the duration and intensity of ambulation during our step-monitored home-based exercise program were predictive of changes in ambulatory outcomes at completion of the program in symptomatic patients with peripheral artery disease (PAD). Twenty-two men (ankle-brachial index (ABI) = 0.71 +/- 0.19) and 24 women (ABI = 0.66 +/- 0.23) completed the home exercise program, consisting of intermittent walking to mild-to-moderate claudication pain for 3 months. Ambulatory outcome measures were peak walking time (PWT) and claudication onset time (COT) during a treadmill test, and the distance recorded during a 6-minute walk distance test (6MWD). Men experienced significant increases (p<0.01) in COT, PWT, and 6MWD following the home exercise program, and women had significant increases in 6MWD (p<0.01) and PWT (p<0.05). In women, average exercise cadence during the home exercise sessions was the only predictor that entered the model for change in COT (p=0.082), and was the first predictor in the model for change in PWT (p=0.029) and 6MWD (p=0.006). In men, the ABI was the only predictor that entered the model for change in 6MWD (p=0.002), and ABI was a predictor along with metabolic syndrome in the model for change in COT (p=0.003). No variables entered the model for change in PWT. Faster ambulatory cadence during the step-monitored home-based exercise program may predict greater improvements in ambulatory function in women, whereas having less severe PAD and comorbid burden at baseline may predict greater improvements in ambulatory function in men. ClinicalTrials.gov Identifier: NCT00618670. PMID- 26240077 TI - Disclosing payments from drug companies should be mandatory for doctors, says academy. PMID- 26240076 TI - Origin and interpretation of cancer transcriptome profiling: the essential role of the stroma in determining prognosis and drug resistance. PMID- 26240078 TI - What is the proper attire for a Paediatric Emergency Medicine (PEM) consultant? PMID- 26240083 TI - From the Exhibitors' Hall: SNMMI Annual Meeting 2015. PMID- 26240085 TI - SNMMI 2015 Image of the Year. PMID- 26240087 TI - Significant Improvements of EEG and Clinical Findings With Oral Lacosamide in a Patient With Ring Chromosome 20. PMID- 26240088 TI - Are There Any Specific EEG Findings in Autoimmune Epilepsies? AB - This study evaluated the EEG findings of patients whose seizures were associated with a possible autoimmune etiology. Our aim was to find clues to distinguish patients with antineuronal antibodies (Ab) through EEG studies. We reviewed our database and identified antineuronal Ab positive epilepsy patients with or without autoimmune encephalitis. These patients had Abs to N-methyl-d-aspartate receptor (NMDAR) (n = 5), glycine receptor (GLY-R) (n = 5), contactin-associated protein-like 2 (CASPR-2) (n = 4), uncharacterized voltage-gated potassium channel complex (VGKC) antigens (n = 2), glutamic acid decarboxylase (GAD) (n = 2), Hu (n = 1), and amphiphysin (n = 1). The control group consisted of 21 seronegative epilepsy or encephalopathy patients with similar clinical features. EEG findings were compared between the groups in a blindfolded design. We did not find any significant difference in EEG findings between antineuronal Ab positive epilepsy patients and seronegative control group. It was remarkable that four seropositive but none of the seronegative patients presented with nonconvulsive status epilepticus (NCSE) or focal motor status epilepticus. Continuous theta and delta rhythms were observed in 5 (71%) seropositive patients with autoimmune encephalitis and 2 (25%) seronegative patients. Eight (40 %) seropositive patients showed a frontal intermittent rhythmic delta activity (FIRDA) pattern as opposed to 5 (24%) seronegative patients. Two patients with NMDAR Ab positivity showed rhythmic delta waves superimposed with beta frequency activity resembling "delta brush" pattern. EEG seems as a limited diagnostic tool in differentiating epilepsy and/or encephalopathy patients with a possible autoimmune etiology from those without. However, antineuronal Abs associated with encephalitis should be considered in the etiology of status epilepticus forms. A possible autoimmune etiology for seizures may be considered in the presence of continuous slow waves, FIRDA, and delta brush pattern in the EEG. PMID- 26240089 TI - Diagnostic labelling influences self-rated health. A prospective cohort study: the HUNT Study, Norway. AB - BACKGROUND: Studies have shown an independent association between poor self-rated health (SRH) and increased mortality. Few studies, however, have investigated any possible impact on SRH of diagnostic labelling. OBJECTIVE: To test whether SRH differed in persons with known and unknown hypothyroidism, diabetes mellitus (DM) or hypertension, opposed to persons without these conditions, after 11-year follow-up. METHODS: Prospective population-based cohort study in North-Trondelag County, Norway, HUNT2 (1995-97) to HUNT3 (2006-08). All inhabitants aged 20 years and older were invited. The response rate was 69.5% in HUNT2 and 54.1% in HUNT3. In total, 34144 persons aged 20-70 years were included in the study population. The outcome was poor SRH. RESULTS: Persons with known disease had an increased odds ratio (OR) to report poor SRH at follow-up; figures ranging from 1.11 (0.68 1.79) to 2.52 (1.46-4.34) (men with hypothyroidism kept out owing to too few numbers). However, in persons not reporting, but having laboratory results indicating these diseases (unknown disease), no corresponding associations with SRH were found. Contrary, the OR for poor SRH in women with unknown hypothyroidism and unknown hypertension was 0.64 (0.38-1.06) and 0.89 (0.79 1.01), respectively. CONCLUSIONS: Awareness opposed to ignorance of hypothyroidism, DM and hypertension seemed to be associated with poor perceived health, suggesting that diagnostic labelling could have a negative effect on SRH. This relationship needs to be tested more thoroughly in future research but should be kept in mind regarding the benefits of early diagnosing of diseases. PMID- 26240091 TI - Notes From the Field: Secondary Task Precision for Cognitive Load Estimation During Virtual Reality Surgical Simulation Training. AB - Cognitive load (CL) theory suggests that working memory can be overloaded in complex learning tasks such as surgical technical skills training, which can impair learning. Valid and feasible methods for estimating the CL in specific learning contexts are necessary before the efficacy of CL-lowering instructional interventions can be established. This study aims to explore secondary task precision for the estimation of CL in virtual reality (VR) surgical simulation and also investigate the effects of CL-modifying factors such as simulator integrated tutoring and repeated practice. Twenty-four participants were randomized for visual assistance by a simulator-integrated tutor function during the first 5 of 12 repeated mastoidectomy procedures on a VR temporal bone simulator. Secondary task precision was found to be significantly lower during simulation compared with nonsimulation baseline, p < .001. Contrary to expectations, simulator-integrated tutoring and repeated practice did not have an impact on secondary task precision. This finding suggests that even though considerable changes in CL are reflected in secondary task precision, it lacks sensitivity. In contrast, secondary task reaction time could be more sensitive, but requires substantial postprocessing of data. Therefore, future studies on the effect of CL modifying interventions should weigh the pros and cons of the various secondary task measurements. PMID- 26240090 TI - Ever and Annual Use of Prostate Cancer Screening in African American Men. AB - Since prostate cancer continues to disproportionately affect African American men in terms of incidence, morbidity, and mortality, prostate-specific antigen (PSA) screening plays an important role in early detection, especially when men engage in informed decision making to accept or decline this test. The authors evaluated utilization of PSA testing among African American men based on factors that are important components of making informed decisions. Utilization of PSA testing was evaluated based on whether men had ever had PSA testing and PSA testing during the past year in a community-based sample of African American men ages 50 to 75 ( n = 132). Overall, 64% of men ( n = 85) reported that they had ever had a PSA test; the mean ( SD) age for first use of PSA testing was 47.7 ( SD = 7.4). The likelihood of ever having a PSA test increased significantly with physician communication (odds ratio [OR] = 14.2; 95% confidence interval [CI] = 4.20, 48.10; p = .0001) and with having an annual household income that was greater than $20,000 (OR = 9.80; 95% CI = 3.15, 30.51; p = .0001). The odds of ever having a PSA test were also decreased with each unit increase in future temporal orientation (OR = 0.66; 95% CI = 0.47, 0.93; p = .02). Of the men who had ever had PSA testing, 57% were screened during the past year. Only health insurance status had a significant independent association with having annual PSA testing (OR = 5.10; 95% CI = 1.67, 15.60; p = .004). Different factors were associated significantly with ever having PSA testing and annual testing among African American men. African American men may not be making an informed decision about prostate cancer screening. PMID- 26240092 TI - Immune-mediated necrotising myopathy associated with antibodies to the signal recognition particle treated with a combination of rituximab and cyclophosphamide. AB - A 50-year-old man presented with dysphagia and proximal muscle weakness. He was diagnosed with immune-mediated necrotising myopathy associated with antibodies to the signal recognition particle. After an initial response following treatment with high-dose steroids, intravenous immunoglobulin and methotrexate, there was a relapse of the immune condition. The clinical deterioration occurred less than 2 months after disease onset. The refractoriness of this disease was characterised by an increase of the already severe muscle wasting that led to respiratory failure and progressive dysphagia, regardless of the immunosuppressant treatment. At this time the patient was referred to our department. He was restarted on intravenous pulses of methylprednisolone associated with intravenous cyclophosphamide, but with no effect. After 3 weeks, rituximab was started with a dramatic and progressive improvement. There were no complications associated with rituximab/cyclophosphamide treatment and the disease has been kept in remission, for the last 3 years. PMID- 26240093 TI - Brown tumours of the tibia and second metacarpal bone in a woman with severe vitamin D deficiency. AB - Brown tumours caused by vitamin D deficiency are rare. Most cases are caused by primary hyperparathyroidism, and are rarely caused by secondary hyperparathyroidism in cases of renal failure. We present a case of Brown tumours of the tibia and second metacarpal bone in a 50-year-old woman who had a low dietary intake of vitamin D and had worn a veil for most of her adult life. The Brown tumours were caused by vitamin D deficiency and secondary hyperparathyroidism. The patient improved on treatment with vitamin D3 and calcium supplements. This is a rare case and the first, to our knowledge, with a Brown tumour of the tibia caused by vitamin D deficiency due to decreased dietary intake and decreased exposure to sunlight. The course of treatment and investigations of the patient are described. PMID- 26240094 TI - Disseminated tuberculosis in an HIV-infected child: rifampicin resistance detected by GeneXpert in a lymph node aspirate but not in cerebrospinal fluid. AB - A 9-year-old HIV-infected child previously treated with inadequate doses of antitubercular drugs based on weight was admitted 5 months after initial tuberculosis (TB) diagnosis with acute hemiplegia and inguinal lymphadenopathies in a rural hospital in Tanzania. He was diagnosed with TB meningitis and lymphadenitis using Xpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) assay. Rifampicin resistance was detected in the lymph node aspirate but not in the cerebrospinal fluid. His TB therapy was optimised based on available medications and antiretroviral treatment was initiated 6 weeks later. Despite these efforts, the clinical evolution was poor and the child died 12 weeks after admission. PMID- 26240095 TI - Gastric pneumatosis in a small-for-gestational-age neonate. AB - We describe a dysmature (small-for-gestational-age) neonate born at term with multiple congenital defects, who presented with bloody diarrhoea. The abdominal X ray showed gastric pneumatosis. The patient was treated conservatively with intravenous fluids and antibiotics, and recovered uneventfully. The patient underwent genetic investigation, and was diagnosed with Cornelia de Lange syndrome. Gastric pneumatosis is rare, and may be the result of neonatal sepsis, gastritis, pyloric stenosis, necrotising enterocolitis of the stomach, misplacement of nasogastric tubes, or non-invasive positive pressure ventilation. Furthermore, it is speculated that gastric pneumatosis might more frequently occur with congenital, cardiac or genetic disorders. PMID- 26240096 TI - Frontal lobotomy: a vanishing but important radiological finding. PMID- 26240097 TI - Leiomyoma in the thumb causing trigger finger. AB - Leiomyoma is a generally benign tumour and common in the uterine smooth muscle. In some cases, it is found in other parts of the human body. In our study, we report the case of a 61-year-old woman with a painless cystic lesion on the first left thumb associated with trigger finger. The first diagnostic hypotheses were ganglionic cyst and giant cell tumour, however, after surgical excision and histological analysis, it was revealed to be a rare leiomyoma of the hand. We report a clinical case and detailed histopathological study, with 12 high resolution images stained with: H&E, Smooth Muscle Actin, Desmin, S-100 and CD34. PMID- 26240098 TI - Two typical cases of pseudoankylosis of the jaw: same treatment, different outcome. AB - Pseudoankylosis of the temporomandibular joint is a rare, extra-articular form of ankylosis of the jaw. It is characterised by limited mandibular movement caused by an extrinsic condition of the joint leading to fusion between the coronoid process and temporal, zygomatic or maxillary bone. Pseudoankylosis is less frequent than the intracapsular form. Extracapsular ankylosis can be congenital or acquired; approximately 70% of cases are associated with trauma. A CT scan is usually requested to achieve a diagnosis. CT can detect bony fusion, thus differentiating pseudoankylosis from true ankylosis. Once symptomatic bone ankylosis is diagnosed, surgery with postoperative physiotherapy is the recommended treatment. The ankylotic bone is removed together with the coronoid process and the mouth is forced open under general anaesthesia. Two cases of post traumatic pseudoankylosis of the jaw treated with bilateral coronoidectomy and postoperative physiotherapy are described. PMID- 26240099 TI - Masquerading optic neuritis. AB - A 54-year-old woman presented to the ophthalmology emergency department with a 10 day history of blurred vision. The best-corrected visual acuities and Ishihara colour vision were bilaterally reduced with a left relative afferent pupillary defect. Slit-lamp examination was otherwise normal. Retrobulbar optic neuritis (ON) was presumed as she had suffered with this previously and was known to have multiple sclerosis (MS). She was recalled the following week for visual field (VF) testing, which was not available at the time of presentation. VFs demonstrated an incongruous left homonymous hemianopia. She was immediately referred to the medical team to investigate for a stroke, which was subsequently excluded. Thereafter, a trial of pulsed methylprednisolone was commenced, resulting in near complete resolution of the hemianopia. This case demonstrates not only the importance of VF testing, but also how ON may present with any field defect, including mimicking a stroke, a point valuable to ophthalmologists and medics alike. PMID- 26240100 TI - Lingual thyroid: can we 'wait and see'? AB - A 42-year-old Caucasian woman presented with a sensation of fullness in the throat and dry cough of 1-month duration. Physical examination showed a mass located in the midline of the tongue base. Cervical ultrasound confirmed the absence of thyroid gland tissue in the normal position. MRI of the neck showed a mass suggestive of lingual thyroid and scintigraphy confirmed the diagnosis. Thyroid function was normal. Despite normal thyroid function, to decrease the size of the mass and perhaps solve the problem, we decided to start levothyroxine suppression therapy. The patient had palpitations and one episode of angina pectoris as a side effect, resulting in the medication being interrupted. After 3 years of follow-up, she remains in clinical surveillance and without symptoms. PMID- 26240101 TI - Addison's disease in a patient with hypothyroidism: autoimmune polyglandular syndrome type 2. AB - A 57-year-old Caucasian woman with known autoimmune hypothyroidism diagnosed in 2006 presented to hospital with flu-like symptoms and circulatory collapse. She reported weight loss and gradual increase in her skin pigmentation over a 1-year period. Aggressive fluid resuscitation was instituted. Hormonal tests showed primary adrenal insufficiency. Appropriate steroid replacement was started with rapid clinical response. Subsequent antibody tests confirmed the diagnosis of autoimmune polyglandular type 2 (Schmidt's) syndrome. The adrenal crisis had been precipitated by influenza virus type B infection. PMID- 26240102 TI - An unusual cause of pancreatitis in a 46-year-old returning traveller. AB - A 46-year-old previously fit and well man, travelled to Jhelum, Pakistan for 6 weeks in early 2015. Four weeks after returning to the UK, he developed sudden onset epigastric pain, vomiting and fever. C reactive protein was 232 mg/L and amylase was 2061 U/L. He was treated conservatively as pancreatitis, with peripancreatic streaking and left colic gutter fluid on a CT abdominal scan. He was discharged and later attended the Hospital for Tropical Diseases, after coughing up an 8 cm male ascaris worm. He was treated for acute ascariasis infection, complicated by resolved mild-moderate pancreatitis, a common complication in the developing world but rarely seen among travellers. PMID- 26240103 TI - Recurrent angioleiomyoma of the middle turbinate. AB - We present a case of a middle-aged woman with a history of not only progressive nasal obstruction, facial pain, hyposmia and epistaxis, but also excision of the nasal mass diagnosed as a vascular leiomyoma. On examination, a smooth bulge was seen over the middle turbinate. Surgical excision along with histopathology and immunohistochemistry revealed a diagnosis of recurrent vascular leiomyoma of the middle turbinate. PMID- 26240104 TI - Ulcerated tophaceous gout. AB - Gout is an inflammatory arthritis characterised by hyperuricemia, which, if poorly controlled, can lead to the development of tophi. We report the case of a 60-year-old Caucasian man with poorly controlled polyarticular tophaceous gout with multiple comorbidities (including renal failure) who presented with tophaceous ulcers of the upper extremity. These ulcers caused extreme pain, requiring chronic opiate medications, and were associated with decreased sensation and reduced ability to move the extremity. His hospital course was complicated by acute kidney injury, haemolytic anaemia and Clostridium difficile infection. He required 1 month of antibiotics and intensive wound care for his ulcers. This case highlights the diagnosis, natural history and management of an unusual complication of hyperuricemia. PMID- 26240105 TI - Atypical cytomegalovirus retinitis in non-Hodgkin's lymphoma. AB - A 54-year-old woman, a known case of non-Hodgkin's lymphoma (NHL) in complete remission, presented with floaters and diminution of vision in her left eye. The eye had vitritis with non-haemorrhagic retinitis mimicking intraocular lymphoma and acute retinal necrosis. A vitreous sample was positive for cytomegalovirus (CMV) and herpes simplex virus 1 (HSV-1) DNA by PCR. The possibility of intraocular lymphoma was not confirmed by the immunohistochemistry of the vitreous sample. The patient had a relapse of NHL along with rapid deterioration of vision in her left eye to no perception of light, due to optic nerve involvement. The right eye developed a new patch of focal haemorrhagic retinitis threatening the fovea. Based on the laboratory results and the clinical findings, she was successfully managed as a case of bilateral CMV retinitis and the vision in her right eye was salvaged. PMID- 26240106 TI - Dermatological sequela of a car accident: acquired Port-wine stain (Fegeler syndrome). PMID- 26240107 TI - Acute unilateral vision loss with optic disc oedema in retinitis pigmentosa. AB - A 36-year-old woman presented with acute vision loss and was found to have disc oedema and retinitis pigmentosa (RP). She presented with a history of acute, painless vision loss in her left eye over a period of 10 days. Her best-corrected visual acuity was 20/50, N6 in the right eye (OD) and 20/160, N6 in the left eye (OS). She was found to have a swollen optic disc and the examination of her fundus showed changes suggestive of RP. The diagnosis of RP was confirmed by electroretinogram, and after ruling out demyelinating changes in the central nervous system and other possible infectious causes of papillitis, she was treated with intravenous steroids followed by a course of oral steroid therapy. Following treatment, her visual acuity improved to 20/60. Acute vision loss may occur in patients with RP and prompt steroid therapy may result in partial visual recovery. PMID- 26240108 TI - Solitary osteochondroma of the trapezoid disguised as a tooth fragment. AB - Fight bite injuries of the hand are common presentations in A&E departments and usually result from a fist blow to the mouth. The authors report a case of a 24 year-old man who presented 6 weeks after an injury to his right wrist following an altercation. Radiographic examination and CT scans were in keeping with a tooth fragment embedded in the trapezoid. However, post excision histology subsequently revealed the lesion to be a solitary osteochondroma of the trapezoid. Osteochondromas are benign lesions of bony or cartilaginous origin and are usually found in the metaphyseal region of long bones. They represent by far the most common primary bone tumours. However, osteochondromas arising from the carpal bones are extremely rare with very few cases reported in the literature. This case illustrates the need to include 'tumour' as a differential diagnosis in every unusual appearing bony lesion, even if there is a history of trauma. PMID- 26240109 TI - An epibulbar chocolate cyst: a rare complication of silicone-based scleral buckle. AB - A patient with a history of vitreoretinal surgery presented with nasal dystopia, diplopia and epibulbar bluish black mass simulating a chocolate cyst in the right eye. After a non-conclusive ocular examination, he underwent CT of the orbit along with volume rendition and three-dimensional reconstruction, which demonstrated intact globe with laterally displaced band-buckle assembly along with peri-scleral buckle element (SBE) soft tissue proliferation. Imaging assisted exploration of the lesion was performed and retained scleral buckle element (SBE) was removed in toto; thus relieving the patient long-standing dystopia. PMID- 26240110 TI - Severely calcified peritoneal metastases masquerading as retained barium on CT scan. PMID- 26240111 TI - Hepatic portal venous gas complicating Bickerstaff's encephalitis with Guillain Barre overlap. PMID- 26240112 TI - Superficial siderosis of the central nervous system. PMID- 26240113 TI - Severe micrognathia with rib dysplasia: cerebro-costo-mandibular syndrome. PMID- 26240114 TI - Don't stop now? How long should resuscitation continue at birth in the absence of a detectable heartbeat? PMID- 26240115 TI - The blocking of angiotensin II type 1 receptor and RhoA/Rho kinase activity in hypertensive patients: Effect of olmesartan medoxomil and implication with cardiovascular-renal remodeling. AB - HYPOTHESIS/INTRODUCTION: The pathophysiological role of oxidative stress (OxSt) in hypertension and target organ damage is recognized. Angiotensin II (Ang II) induces OxSt via NAD(P)H oxidase activation and production of proinflammatory cytokines/growth factors leading to cardiovascular-renal remodeling. Ang II stimulates the RhoA/Rho kinase (ROCK) pathway, which is deeply involved in the development of cardiovascular-renal remodeling via OxSt induction. Olmesartan, an Ang II type 1 receptor blocker, possesses antioxidant and activating nitric oxide system-related effects, which we have shown in terms of p22(phox) reduction, heme oxygenase-1 and calcitonin gene-related peptide increase. This study evaluates in 15 untreated hypertensive patients the effect of olmesartan treatment on p63RhoGEF, key in Ang II-induced ROCK activation, and MYPT-1 phosphorylation, a marker of ROCK activity. MATERIALS AND METHODS: The p63RhoGEF protein level and MYPT-1 phosphorylation (Western blot) were evaluated at baseline, and after three and six months of olmesartan treatment. RESULTS: Olmesartan normalized systolic and diastolic BP (p < 0.001), reduced p63RhoGEF level: 1.3+/-0.25 d.u. (baseline) vs 1.0+/-0.29 (three months), p < 0.0001 vs 1.0+/-0.22, (six months), p < 0.0001 and MYPT-1 phosphorylation: 1.2 +/-0.14 (baseline) vs 0.9+/-0.19 (three months), p = 0.008, vs 0.8+/-0.16 (six months), p = 0.001. CONCLUSIONS: These data added to our previous results further provide a mechanistic rationale for olmesartan's antioxidant/anti-inflammatory potential translation, in the long term, toward anti-atherosclerotic/anti-remodeling effects reported by clinical trials. PMID- 26240116 TI - Association of the angiotensinogen M235T polymorphism with recurrence after catheter ablation of acquired atrial fibrillation. AB - PURPOSE: Previous studies showed that genetic variants of the angiotensinogen (AGT) gene conferred higher risk for acquired atrial fibrillation (AF). The present study investigated whether AGT variants correlate with the clinical outcome in patients with acquired AF after catheter ablation (CA). METHODS: A total of 150 acquired symptomatic drug-refractory AF patients (mean age 63.7+/ 11.0 years, 24.6% non-paroxysmal AF) with acquired AF underwent a single CA procedure in our department and were included in this retrospective analysis. Eight tagging single nucleotide polymorphisms (tSNPs) in the AGT gene were genotyped. Standard electrocardiographs (ECGs) and 24-hour Holter recordings were performed during a median follow-up period of 57.5 months to detect AF recurrence. RESULTS: Sixty-one patients (40.7%) suffered AF recurrences after a single CA procedure during follow up. Of the eight tSNPs, the frequency of the M allele of M235T was significantly higher in the recurrence group (28%) compared to the non-recurrence group (18%) (p=0.042). The recurrence rates of patients with the TT, MT, and MM genotypes were 34.4%, 50%, and 55.6%, respectively (ptrend=0.049). After adjusting for age, sex, body mass index, hypertension, left atrial volume index (LAVI) and other covariates, M235T increased the risk of AF recurrence in additive and dominant models with odds ratios of 2.023 (95% confidence interval (CI): 1.034-3.926, p=0.033) and 2.601 (95% CI: 1.102-6.056, p=0.025), respectively. However, in multiple correction analyses, the p values of multiple comparisons were not statistically significant (pcorrect>0.05). CONCLUSIONS: The M allele of M235T might be associated with an increased risk of AF recurrence after CA. Genotyping may thus be helpful on identifying patients with higher risks of AF recurrence after CA and developing optimal follow-up strategies. These strategies may differ and should be individualized according to patients' genotype. Future studies are warranted to validate the potential effect of AGT M235T on AF recurrence post CA. PMID- 26240117 TI - Wandering spleen: a surgical enigma. AB - Wandering spleen, also referred to as 'ptotic spleen', is a rare clinical condition characterized by splenic migration form its normal left hypochondrial position to any other abdominal or pelvic position. Among the multifactorial etiologies proposed, laxity of the spleen's primary supporting ligaments is the most agreed-upon hypothesis. We present one rare case of wandering spleen in an 11-year-old girl who presented with recurrent abdominal pain with no localizing features. Her abdominal examination revealed an intra-abdominal left iliac fossa lump with restricted mobility, which was confirmed as a wandering spleen by abdominal sonography and contrast-enhanced computed tomography. Intraoperatively, an infarcted spleen was encountered with tortuous, elongated, torsional splenic pedicle and a single dense adhesive band with descending colon. Splenectomy was offered to the patient. Post-operatively, the patient is healthy and symptom free at one-year follow-up. The rare clinical diagnosis of this condition, particularly in the paediatric age-group, makes it an enigma for the surgical world. PMID- 26240118 TI - Work-Related Health Complaints and Injuries, and Health and Safety Perceptions of Latino Day Laborers. AB - This study describes socio-demographic, health, and work factors as well as health and safety perceptions of day laborers who reported work-related health complaints and injuries. The researchers completed a secondary data analysis of 217 interviews conducted in 2009 with day laborers in a large city. The participants reported 83 health complaints or injuries (38%) that had occurred during the prior 12 months, with 57 of these complaints or injuries resulting in lost work time. Pain and soreness of the back were the most prevalent health complaints or injuries; 66% of participants did not report their injuries, 62% reported no health and safety training, 96% reported they needed personal protective equipment (PPE), and 63% were provided with PPE. Latino day laborers reported a high 12-month prevalence of work-related health complaints and injuries. Ongoing policy work is needed to encourage injury reporting by day laborers and the provision of health and safety training and PPE to this group of workers. PMID- 26240119 TI - Boot Camp for Occupational Health Nurses: Understanding Social Media. AB - Social media is a buzzword frequently referred to in marketing materials, general media, and personal conversations. Although many refer to the term social media, some individuals do not understand its meaning or how it affects their daily lives at work and home. Since the expansion of the Internet to web 2.0, multiple platforms of communication occur virtually through various social media. Understanding and learning how to use these platforms are essential to stay connected with friends, family, and colleagues; advance connections to professional organizations; and extend educational opportunities. This article presents basic information for occupational health nurses to improve their understanding of social media and how to communicate virtually using different platforms safely and securely. PMID- 26240121 TI - Sarcoidosis. AB - Sarcoidosis was revealed by a worker in an initial post-offer examination. This disorder requires careful review prior to workers being in hot or cold environments, using respirators, or traveling internationally. To protect worker health, occupational health nurses must understand the pathophysiology and risks associated with sarcoidosis. PMID- 26240122 TI - In this issue of Occupational Medicine : https://youtu.be/HV2RIyPb6sw. PMID- 26240123 TI - Wither or whither now training in occupational medicine? PMID- 26240124 TI - Mellifluous. PMID- 26240125 TI - Edmund C. Thompson assisted by George T. Capstick, Speed - the Modern Mercury 1931. PMID- 26240126 TI - Fifty years ago: 'The teaching of occupational medicine to undergraduate medical students'. PMID- 26240127 TI - Fifty years ago: 'Height, Weight and Obesity in an Industrial Population'. PMID- 26240128 TI - Noise-induced hearing loss and combined noise and vibration exposure. PMID- 26240129 TI - Serial peak flow measurements in allergic alveolitis. PMID- 26240130 TI - Epworth Sleepiness Scale. PMID- 26240131 TI - Breast Cancer Disparities: A Multicenter Comparison of Tumor Diagnosis, Characteristics, and Surgical Treatment in China and the U.S. AB - BACKGROUND AND OBJECTIVE: Incidence of and mortality rates for breast cancer continue to rise in the People's Republic of China. The purpose of this study was to analyze differences in characteristics of breast malignancies between China and the U.S. METHODS: Data from 384,262 breast cancer patients registered in the U.S. Surveillance, Epidemiology, and End Results (SEER) program from 2000 to 2010 were compared with 4,211 Chinese breast cancer patients registered in a Chinese database from 1999 to 2008. Outcomes included age, race, histology, tumor and node staging, laterality, surgical treatment method, and reconstruction. The Pearson chi-square and Fisher's exact tests were used to compare rates. RESULTS: Infiltrating ductal carcinoma was the most common type of malignancy in the U.S. and China. The mean number of positive lymph nodes was higher in China (2.59 vs. 1.31, p < .001). Stage at diagnosis was higher in China (stage IIA vs. I, p < .001). Mean size of tumor at diagnosis was higher in China (32.63 vs. 21.57 mm). Mean age at diagnosis was lower in China (48.28 vs. 61.29 years, p < .001). Moreover, 2.0% of U.S. women underwent radical mastectomy compared with 12.5% in China, and 0.02% in China underwent reconstructive surgery. CONCLUSION: Chinese women were diagnosed at younger ages with higher stage and larger tumors and underwent more aggressive surgical treatment. Prospective trials should be conducted to address screening, surgical, and tumor discrepancies between China and the U.S. IMPLICATIONS FOR PRACTICE: Breast cancer patients in China are diagnosed at later stages than those in America, which might contribute to different clinical management and lower 5-year survival rate. This phenomenon suggests that an earlier detection and treatment program should be widely implemented in China. By comparing the characteristics of Chinese and Chinese American patients, we found significant differences in tumor size, lymph nodes metastasis, and age at diagnosis. These consequences indicated that patients with similar genetic backgrounds may have different prognoses due to the influence of environment and social economic determinates. PMID- 26240132 TI - Algorithms in the First-Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma--Analysis Using Diagnostic Nodes. AB - BACKGROUND: With the advent of targeted therapies, many treatment options in the first-line setting of metastatic clear cell renal cell carcinoma (mccRCC) have emerged. Guidelines and randomized trial reports usually do not elucidate the decision criteria for the different treatment options. In order to extract the decision criteria for the optimal therapy for patients, we performed an analysis of treatment algorithms from experts in the field. MATERIALS AND METHODS: Treatment algorithms for the treatment of mccRCC from experts of 11 institutions were obtained, and decision trees were deduced. Treatment options were identified and a list of unified decision criteria determined. The final decision trees were analyzed with a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees. The most common treatment recommendations were determined, and areas of discordance were identified. RESULTS: The analysis revealed heterogeneity in most clinical scenarios. The recommendations selected for first-line treatment of mccRCC included sunitinib, pazopanib, temsirolimus, interferon-alpha combined with bevacizumab, high-dose interleukin-2, sorafenib, axitinib, everolimus, and best supportive care. The criteria relevant for treatment decisions were performance status, Memorial Sloan Kettering Cancer Center risk group, only or mainly lung metastases, cardiac insufficiency, hepatic insufficiency, age, and "zugzwang" (composite of multiple, related criteria). CONCLUSION: In the present study, we used diagnostic nodes to compare treatment algorithms in the first-line treatment of mccRCC. The results illustrate the heterogeneity of the decision criteria and treatment strategies for mccRCC and how available data are interpreted and implemented differently among experts. IMPLICATIONS FOR PRACTICE: The data provided in the present report should not be considered to serve as treatment recommendations for the management of treatment-naive patients with multiple metastases from metastatic clear cell renal cell carcinoma outside a clinical trial; however, the data highlight the different treatment options and the criteria used to select them. The diversity in decision making and how results from phase III trials can be interpreted and implemented differently in daily practice are demonstrated. PMID- 26240133 TI - The Prognostic Impact of Type 2 Diabetes Mellitus on Early Cervical Cancer in Asia. AB - BACKGROUND: Many studies have shown that type 2 diabetes mellitus (DM) increases the risk for several types of cancer but not cervical cancer (CC). Although DM and insulin-like growth factor 1 have preclinical and clinical implications for CC, less is known about the prognostic impact of DM on patients with early stage CC. PATIENTS AND METHODS: We used the nationwide Taiwan Cancer Registry database to collect the characteristics of stage I-IIA cervical cancer patients diagnosed between 2004 and 2008. DM and other comorbidities were retrieved from the National Health Insurance database. Cervical cancer-specific survival (CSS) and overall survival (OS) times of patients according to DM status were estimated using the Kaplan-Meier method. We used a Cox proportional hazards model to calculate adjusted hazard ratios (HRs) for the effects of DM and other risk factors on mortality. RESULTS: A total of 2,946 patients had primary stage I-IIA CC and received curative treatments, and 284 (9.6%) had DM. The 5-year CSS and OS rates for patients with DM were significantly lower than those without DM (CSS: 85.4% vs. 91.5%; OS: 73.9% vs. 87.9%). After adjusting for clinicopathologic variables and comorbidities, DM remained an independent unfavorable prognostic factor for CSS (adjusted HR: 1.46) and OS (adjusted HR: 1.55). CONCLUSION: In Asian patients with early cervical cancer, DM is an independent unfavorable prognostic factor influencing both OS and CSS, even after curative treatments. IMPLICATIONS FOR PRACTICE: Type 2 diabetes mellitus (DM) increases the incidence of several types of cancer but not cervical cancer (CC); however, less is known about the impact of DM on patients who already have CC. This study suggests that DM may increase the risk of cancer recurrence and death for early stage CC patients, even after curative treatments. Incorporating DM control should be considered part of the continuum of care for early stage CC patients, and close surveillance during routine follow-up in this population is recommended. PMID- 26240134 TI - Variation in the Attitudes of Medical Oncologists Toward Research Biopsies in Patients With Metastatic Breast Cancer. AB - BACKGROUND: Tissue from research biopsies provides access to insights into tumor biology. We aimed to determine medical oncologists' (MOs') attitudes toward research biopsies in patients with metastatic breast cancer (MBC). MATERIALS AND METHODS: A total of 309 breast MOs from National Cancer Institute (NCI) designated cancer centers were invited to complete a self-administered survey about their attitudes toward approaching patients for research purpose-only biopsies (RPOBs), performed as a standalone procedure, or additional biopsies, performed with a clinically indicated biopsy. The MOs were asked to predict what proportion of their MBC patients would consider undergoing research biopsies. RESULTS: Of the 309 MOs, 221 (72%) responded. Of these 221 MOs, 30 were ineligible, leaving 191 eligible responders. Nearly all the MOs reported they were comfortable approaching patients regarding research biopsies of blood or skin. One fifth of MOs were uncomfortable approaching patients for RPOBs of the breast. One half of MOs were uncomfortable approaching patients for RPOBs of the liver. A significant variation was found in the perceptions by MOs of their patients' willingness to undergo research biopsies. The factors associated with increased comfort in approaching patients for research biopsies included fewer years in practice, caring for patients who had undergone recent research biopsies, and the predicted willingness of patients to consent to biopsies. The risk of a biopsy and biopsy-related pain were the most common reasons for reluctance to refer patients for research biopsies. CONCLUSION: Significant variation exists, even at NCI centers, in the comfort level of MOs in approaching MBC patients for research biopsies. MOs' attitudes toward research biopsies might be a modifiable factor in increasing tissue collection for research. IMPLICATIONS FOR PRACTICE: Tissue-based research is critical in advancing our understanding of cancer biology, and obtaining tissue from a research biopsy provides an essential resource. This study demonstrates the variability of oncologists' attitudes toward research biopsies and elicits factors associated with increased comfort levels with approaching patients for research biopsies. Biopsy risk and biopsy related pain were commonly cited reasons not to refer patients for research biopsies. If the risk of a research biopsy is deemed sufficiently low enough to be acceptable, oncologists' attitudes might be a potential target for education and change, which may assist in increasing the availability of tissue for cancer research. PMID- 26240135 TI - Continuous Trastuzumab Therapy in Breast Cancer Patients With Asymptomatic Left Ventricular Dysfunction. AB - BACKGROUND: Adjuvant trastuzumab is a highly effective targeted treatment that improves survival for patients with HER2-positive breast cancer. However, trastuzumab interruption is recommended for patients who develop treatment induced cardiotoxicity (i.e., decline in left ventricular ejection fraction [LVEF], with or without symptoms) and can lead to an incomplete course of treatment. We studied the cardiac safety of continuous trastuzumab therapy among patients with asymptomatic declines in LVEF. METHODS: We retrospectively evaluated patients with HER2-positive breast cancer treated with adjuvant trastuzumab at our institution between 2005 and 2010. Treatment-induced cardiotoxicity was defined by an absolute decrease in LVEF of >=10% to below 55% or an absolute decrease of >=16%. Logistic regression was used to determine the association between candidate risk factors and treatment-induced cardiotoxicity. RESULTS: Among 573 patients, 92 (16%) developed treatment-induced cardiotoxicity. Trastuzumab was continued without interruption in 31 of 92 patients with treatment-induced cardiotoxicity-all were asymptomatic with LVEF of >=50% at cardiotoxicity diagnosis with median LVEF of 53% (range, 50%-63%), and none developed heart failure during follow-up. Risk factors associated with treatment induced cardiotoxicity included age (p = .011), anthracycline chemotherapy (p = .002), and lower pretrastuzumab LVEF (p < .001). CONCLUSION: Among patients who develop asymptomatic treatment-induced cardiotoxicity with LVEF of >=50%, continuous trastuzumab therapy appears to be safe. PMID- 26240136 TI - Perceived acceptability of female smoking in China. AB - BACKGROUND: Female smoking prevalence in China is very low but may rise with increased tobacco marketing towards women and changing norms. However, little is known about current perceptions of women smoking in China. OBJECTIVE: This study sought to examine smokers' and non-smokers' perceived acceptability of female smoking and how it changed over time in China. METHODS: Data come from Waves 1 to 3 (2006-2009) of the International Tobacco Control China Survey, a face-to-face cohort survey of approximately 800 adult smokers and 200 non-smokers in each of seven cities in mainland China. RESULTS: At Wave 3 (2009), about 38% of smokers and 9% of non-smokers agreed that female smoking is acceptable with women being almost twice as likely to do so as men (67% vs 36% and 11% vs 6%, respectively). In addition to women, smokers who were younger and had more positive perceptions of smoking in general were more likely to say that female smoking is acceptable. This perception significantly increased from Wave 1 (2006) to Wave 3 (2009), as did the perception that smoking is a sign of sophistication, but other general perceptions of smoking did not significantly change between 2006 and 2009. CONCLUSIONS: Norms against female smoking appear to remain strong in China, but female smoking may be becoming more acceptable. It is important to monitor these perceptions to prevent a rise in female smoking prevalence along with an increase in tobacco-related death and disease among women in China. PMID- 26240137 TI - Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant. AB - The role of mitochondrial energy metabolism in maintaining lung function is not understood. We previously observed reduced lung function in mice lacking the fatty acid oxidation enzyme long-chain acyl-CoA dehydrogenase (LCAD). Here, we demonstrate that long-chain acylcarnitines, a class of lipids secreted by mitochondria when metabolism is inhibited, accumulate at the air-fluid interface in LCAD(-/-) lungs. Acylcarnitine accumulation is exacerbated by stress such as influenza infection or by dietary supplementation with l-carnitine. Long-chain acylcarnitines co-localize with pulmonary surfactant, a unique film of phospholipids and proteins that reduces surface tension and prevents alveolar collapse during breathing. In vitro, the long-chain species palmitoylcarnitine directly inhibits the surface adsorption of pulmonary surfactant as well as its ability to reduce surface tension. Treatment of LCAD(-/-) mice with mildronate, a drug that inhibits carnitine synthesis, eliminates acylcarnitines and improves lung function. Finally, acylcarnitines are detectable in normal human lavage fluid. Thus, long-chain acylcarnitines may represent a risk factor for lung injury in humans with dysfunctional fatty acid oxidation. PMID- 26240138 TI - MicroRNAs in the Myocyte Enhancer Factor 2 (MEF2)-regulated Gtl2-Dio3 Noncoding RNA Locus Promote Cardiomyocyte Proliferation by Targeting the Transcriptional Coactivator Cited2. AB - Understanding cell cycle regulation in postmitotic cardiomyocytes may lead to new therapeutic approaches to regenerate damaged cardiac tissue. We have demonstrated previously that microRNAs encoded by the Gtl2-Dio3 noncoding RNA locus function downstream of the MEF2A transcription factor in skeletal muscle regeneration. We have also reported expression of these miRNAs in the heart. Here we investigated the role of two Gtl2-Dio3 miRNAs, miR-410 and miR-495, in cardiac muscle. Overexpression of miR-410 and miR-495 robustly stimulated cardiomyocyte DNA synthesis and proliferation. Interestingly, unlike our findings in skeletal muscle, these miRNAs did not modulate the activity of the WNT signaling pathway. Instead, these miRNAs targeted Cited2, a coactivator required for proper cardiac development. Consistent with miR-410 and miR-495 overexpression, siRNA knockdown of Cited2 in neonatal cardiomyocytes resulted in robust proliferation. This phenotype was associated with reduced expression of Cdkn1c/p57/Kip2, a cell cycle inhibitor, and increased expression of VEGFA, a growth factor with proliferation promoting effects. Therefore, miR-410 and miR-495 are among a growing number of miRNAs that have the ability to potently stimulate neonatal cardiomyocyte proliferation. PMID- 26240139 TI - Quercetin-3-rutinoside Inhibits Protein Disulfide Isomerase by Binding to Its b'x Domain. AB - Quercetin-3-rutinoside inhibits thrombus formation in a mouse model by inhibiting extracellular protein disulfide isomerase (PDI), an enzyme required for platelet thrombus formation and fibrin generation. Prior studies have identified PDI as a potential target for novel antithrombotic agents. Using a fluorescence enhancement-based assay and isothermal calorimetry, we show that quercetin-3 rutinoside directly binds to the b' domain of PDI with a 1:1 stoichiometry. The binding of quercetin-3-rutinoside to PDI induces a more compact conformation and restricts the conformational flexibility of PDI, as revealed by small angle x-ray scattering. The binding sites of quercetin-3-rutinoside to PDI were determined by studying its interaction with isolated fragments of PDI. Quercetin-3-rutinoside binds to the b'x domain of PDI. The infusion of the b'x fragment of PDI rescued thrombus formation that was inhibited by quercetin-3-rutinoside in a mouse thrombosis model. This b'x fragment does not possess reductase activity and, in the absence of quercetin-3-rutinoside, does not affect thrombus formation in vivo. The isolated b' domain of PDI has potential as an antidote to reverse the antithrombotic effect of quercetin-3-rutinoside by binding and neutralizing quercetin-3-rutinoside. PMID- 26240140 TI - Phagosomal Acidification Prevents Macrophage Inflammatory Cytokine Production to Malaria, and Dendritic Cells Are the Major Source at the Early Stages of Infection: IMPLICATION FOR MALARIA PROTECTIVE IMMUNITY DEVELOPMENT. AB - Inflammatory cytokines produced at the early stages of malaria infection contribute to shaping protective immunity and pathophysiology. To gain mechanistic insight into these processes, it is important to understand the cellular origin of cytokines because both cytokine input and cytokine-producing cells play key roles. Here, we determined cytokine responses by monocytes, macrophages, and dendritic cells (DCs) to purified Plasmodium falciparum and Plasmodium berghei ANKA, and by spleen macrophages and DCs from Plasmodium yoelii 17NXL-infected and P. berghei ANKA-infected mice. The results demonstrate that monocytes and macrophages do not produce inflammatory cytokines to malaria parasites and that DCs are the primary source early in infection, and DC subsets differentially produce cytokines. Importantly, blocking of phagosomal acidification by inhibiting vacuolar-type H(+)-ATPase enabled macrophages to elicit cytokine responses. Because cytokine responses to malaria parasites are mediated primarily through endosomal Toll-like receptors, our data indicate that the inability of macrophages to produce cytokines is due to the phagosomal acidification that disrupts endosomal ligand-receptor engagement. Macrophages efficiently produced cytokines to LPS upon simultaneously internalizing parasites and to heat-killed Escherichia coli, demonstrating that phagosomal acidification affects endosomal receptor-mediated, but not cell surface receptor-mediated, recognition of Toll-like receptor agonists. Enabling monocytes/macrophages to elicit immune responses to parasites by blocking endosomal acidification can be a novel strategy for the effective development of protective immunity to malaria. The results have important implications for enhancing the efficacy of a whole parasite-based malaria vaccine and for designing strategies for the development of protective immunity to pathogens that induce immune responses primarily through endosomal receptors. PMID- 26240141 TI - Structural Characterization of CalS8, a TDP-alpha-D-Glucose Dehydrogenase Involved in Calicheamicin Aminodideoxypentose Biosynthesis. AB - Classical UDP-glucose 6-dehydrogenases (UGDHs; EC 1.1.1.22) catalyze the conversion of UDP-alpha-d-glucose (UDP-Glc) to the key metabolic precursor UDP alpha-d-glucuronic acid (UDP-GlcA) and display specificity for UDP-Glc. The fundamental biochemical and structural study of the UGDH homolog CalS8 encoded by the calicheamicin biosynthetic gene is reported and represents one of the first studies of a UGDH homolog involved in secondary metabolism. The corresponding biochemical characterization of CalS8 reveals CalS8 as one of the first characterized base-permissive UGDH homologs with a >15-fold preference for TDP Glc over UDP-Glc. The corresponding structure elucidations of apo-CalS8 and the CalS8.substrate.cofactor ternary complex (at 2.47 and 1.95 A resolution, respectively) highlight a notably high degree of conservation between CalS8 and classical UGDHs where structural divergence within the intersubunit loop structure likely contributes to the CalS8 base permissivity. As such, this study begins to provide a putative blueprint for base specificity among sugar nucleotide-dependent dehydrogenases and, in conjunction with prior studies on the base specificity of the calicheamicin aminopentosyltransferase CalG4, provides growing support for the calicheamicin aminopentose pathway as a TDP-sugar dependent process. PMID- 26240142 TI - Enhanced transfer of a photocross-linking N-acetylglucosamine (GlcNAc) analog by an O-GlcNAc transferase mutant with converted substrate specificity. AB - O-Linked beta-N-acetylglucosamine (O-GlcNAc) is a post-translational modification of proteins in multicellular organisms. O-GlcNAc modification is catalyzed by the O-GlcNAc transferase (OGT), which transfers N-acetylglucosamine (GlcNAc) from the nucleotide sugar donor UDP-GlcNAc to serine or threonine residues of protein substrates. Recently, we reported a novel metabolic labeling method to introduce the diazirine photocross-linking functional group onto O-GlcNAc residues in mammalian cells. In this method, cells are engineered to produce diazirine modified UDP-GlcNAc (UDP-GlcNDAz), and the diazirine-modified GlcNAc analog (GlcNDAz) is transferred to substrate proteins by endogenous OGT, producing O GlcNDAz. O-GlcNDAz-modified proteins can be covalently cross-linked to their binding partners, providing information about O-GlcNAc-dependent interactions. The utility of the method was demonstrated by cross-linking highly O-GlcNAc modified nucleoporins to proteins involved in nuclear transport. For practical application of this method to a broader range of O-GlcNAc-modified proteins, efficient O-GlcNDAz production is critical. Here we examined the ability of OGT to transfer GlcNDAz and found that the wild-type enzyme (wtOGT) prefers the natural substrate, UDP-GlcNAc, over the unnatural UDP-GlcNDAz. This competition limits O-GlcNDAz production in cells and the extent of O-GlcNDAz-dependent cross linking. Here we identified an OGT mutant, OGT(C917A), that efficiently transfers GlcNDAz and, surprisingly, has altered substrate specificity, preferring to transfer GlcNDAz rather than GlcNAc to protein substrates. We confirmed the reversed substrate preference by determining the Michaelis-Menten parameters describing the activity of wtOGT and OGT(C917A) with both UDP-GlcNAc and UDP GlcNDAz. Use of OGT(C917A) enhances O-GlcNDAz production, yielding improved cross linking of O-GlcNDAz-modified molecules both in vitro and in cells. PMID- 26240143 TI - Proteomic Analysis of GLUT4 Storage Vesicles Reveals Tumor Suppressor Candidate 5 (TUSC5) as a Novel Regulator of Insulin Action in Adipocytes. AB - Insulin signaling augments glucose transport by regulating glucose transporter 4 (GLUT4) trafficking from specialized intracellular compartments, termed GLUT4 storage vesicles (GSVs), to the plasma membrane. Proteomic analysis of GSVs by mass spectrometry revealed enrichment of 59 proteins in these vesicles. We measured reduced abundance of 23 of these proteins following insulin stimulation and assigned these as high confidence GSV proteins. These included established GSV proteins such as GLUT4 and insulin-responsive aminopeptidase, as well as six proteins not previously reported to be localized to GSVs. Tumor suppressor candidate 5 (TUSC5) was shown to be a novel GSV protein that underwent a 3.7-fold increase in abundance at the plasma membrane in response to insulin. siRNA mediated knockdown of TUSC5 decreased insulin-stimulated glucose uptake, although overexpression of TUSC5 had the opposite effect, implicating TUSC5 as a positive regulator of insulin-stimulated glucose transport in adipocytes. Incubation of adipocytes with TNFalpha caused insulin resistance and a concomitant reduction in TUSC5. Consistent with previous studies, peroxisome proliferator-activated receptor (PPAR) gamma agonism reversed TNFalpha-induced insulin resistance. TUSC5 expression was necessary but insufficient for PPARgamma-mediated reversal of insulin resistance. These findings functionally link TUSC5 to GLUT4 trafficking, insulin action, insulin resistance, and PPARgamma action in the adipocyte. Further studies are required to establish the exact role of TUSC5 in adipocytes. PMID- 26240144 TI - Tim62, a Novel Mitochondrial Protein in Trypanosoma brucei, Is Essential for Assembly and Stability of the TbTim17 Protein Complex. AB - Trypanosoma brucei, the causative agent of human African trypanosomiasis, possesses non-canonical mitochondrial protein import machinery. Previously, we characterized the essential translocase of the mitochondrial inner membrane (TIM) consisting of Tim17 in T. brucei. TbTim17 is associated with TbTim62. Here we show that TbTim62, a novel protein, is localized in the mitochondrial inner membrane, and its import into mitochondria depends on TbTim17. Knockdown (KD) of TbTim62 decreased the steady-state levels of TbTim17 post-transcriptionally. Further analysis showed that import of TbTim17 into mitochondria was not inhibited, but its half-life was reduced >4-fold due to TbTim62 KD. Blue-native gel electrophoresis revealed that TbTim62 is present primarily in ~150-kDa and also in ~1100-kDa protein complexes, whereas TbTim17 is present in multiple complexes within the range of ~300 to ~1100 kDa. TbTim62 KD reduced the levels of both TbTim62 as well as TbTim17 protein complexes. Interestingly, TbTim17 was accumulated as lower molecular mass complexes in TbTim62 KD mitochondria. Furthermore, depletion of TbTim62 hampered the assembly of the ectopically expressed TbTim17-2X-myc into TbTim17 protein complex. Co-immunoprecipitation analysis revealed that association of TbTim17 with mHSP70 was markedly reduced in TbTim62 KD mitochondria. All together our results demonstrate that TbTim62, a unique mitochondrial protein in T. brucei, is required for the formation of a stable TbTim17 protein complex. TbTim62 KD destabilizes this complex, and unassembled TbTim17 degrades. Therefore, TbTim62 acts as a novel regulatory factor to maintain the levels of TIM in T. brucei mitochondria. PMID- 26240145 TI - Demonstration of Lignin-to-Peroxidase Direct Electron Transfer: A TRANSIENT-STATE KINETICS, DIRECTED MUTAGENESIS, EPR, AND NMR STUDY. AB - Versatile peroxidase (VP) is a high redox-potential peroxidase of biotechnological interest that is able to oxidize phenolic and non-phenolic aromatics, Mn(2+), and different dyes. The ability of VP from Pleurotus eryngii to oxidize water-soluble lignins (softwood and hardwood lignosulfonates) is demonstrated here by a combination of directed mutagenesis and spectroscopic techniques, among others. In addition, direct electron transfer between the peroxidase and the lignin macromolecule was kinetically characterized using stopped-flow spectrophotometry. VP variants were used to show that this reaction strongly depends on the presence of a solvent-exposed tryptophan residue (Trp 164). Moreover, the tryptophanyl radical detected by EPR spectroscopy of H2O2 activated VP (being absent from the W164S variant) was identified as catalytically active because it was reduced during lignosulfonate oxidation, resulting in the appearance of a lignin radical. The decrease of lignin fluorescence (excitation at 355 nm/emission at 400 nm) during VP treatment under steady-state conditions was accompanied by a decrease of the lignin (aromatic nuclei and side chains) signals in one-dimensional and two-dimensional NMR spectra, confirming the ligninolytic capabilities of the enzyme. Simultaneously, size-exclusion chromatography showed an increase of the molecular mass of the modified residual lignin, especially for the (low molecular mass) hardwood lignosulfonate, revealing that the oxidation products tend to recondense during the VP treatment. Finally, mutagenesis of selected residues neighboring Trp-164 resulted in improved apparent second-order rate constants for lignosulfonate reactions, revealing that changes in its protein environment (modifying the net negative charge and/or substrate accessibility/binding) can modulate the reactivity of the catalytic tryptophan. PMID- 26240146 TI - Recognition of N-glycoforms in human chorionic gonadotropin by monoclonal antibodies and their interaction motifs. AB - The glycosylation of human chorionic gonadotropin (hCG) plays an important role in reproductive tumors. Detecting hCG N-glycosylation alteration may significantly improve the diagnostic accuracy and sensitivity of related cancers. However, developing an immunoassay directly against the N-linked oligosaccharides is unlikely because of the heterogeneity and low immunogenicity of carbohydrates. Here, we report a hydrogen/deuterium exchange and MS approach to investigate the effect of N-glycosylation on the binding of antibodies against different hCG glycoforms. Hyperglycosylated hCG was purified from the urine of invasive mole patients, and the structure of its N-linked oligosaccharides was confirmed to be more branched by MS. The binding kinetics of the anti-hCG antibodies MCA329 and MCA1024 against hCG and hyperglycosylated hCG were compared using biolayer interferometry. The binding affinity of MCA1024 changed significantly in response to the alteration of hCG N-linked oligosaccharides. Hydrogen/deuterium exchange MS reveals that the peptide beta65-83 of the hCG beta subunit is the epitope for MCA1024. Site-specific N-glycosylation analysis suggests that N-linked oligosaccharides at Asn-13 and Asn-30 on the beta subunit affect the binding affinity of MCA1024. These results prove that some antibodies are sensitive to the structural change of N-linked oligosaccharides, whereas others are not affected by N-glycosylation. It is promising to improve glycoprotein biomarker based cancer diagnostics by developing combined immunoassays that can determine the level of protein and measure the degree of N-glycosylation simultaneously. PMID- 26240147 TI - All-trans-retinoic acid reduces BACE1 expression under inflammatory conditions via modulation of nuclear factor kappaB (NFkappaB) signaling. AB - Insulin resistance and neuroinflammation have emerged as two likely key contributors in the pathogenesis of Alzheimer disease (AD), especially in those sporadic AD cases compromised by diabetes or cardiovascular disease. Amyloid-beta (Abeta) deposition and its associated inflammatory response are hallmarks in sporadic AD brains. Elevated expression and activity of beta-secretase 1 (BACE1), the rate-limiting enzyme responsible for the beta-cleavage of amyloid precursor proteins to Abeta peptides, are also observed in sporadic AD brains. Previous studies have suggested that there is therapeutic potential for retinoic acid in treating neurodegeneration based on decreased Abeta. Here we discovered that BACE1 expression is elevated in the brains of both Tg2576 transgenic mice and mice on high fat diets. These conditions are associated with a neuroinflammatory response. We found that administration of all-trans-retinoic acid (atRA) down regulated the expression of BACE1 in the brains of Tg2576 mice and in mice fed a high fat diet. Moreover, in LPS-treated mice and cultured neurons, BACE1 expression was repressed by the addition of atRA, correlating with the anti inflammatory efficacy of atRA. Mutations of the NFkappaB binding site in BACE1 promoter abolished the suppressive effect of atRA. Furthermore, atRA disrupted LPS-induced nuclear translocation of NFkappaB and its binding to BACE1 promoter as well as promoting the recruitment of the corepressor NCoR. Our findings indicate that atRA represses BACE1 gene expression under inflammatory conditions via the modulation of NFkappaB signaling. PMID- 26240148 TI - High-resolution Digital Mapping of N-Methylpurines in Human Cells Reveals Modulation of Their Induction and Repair by Nearest-neighbor Nucleotides. AB - N-Methylpurines (NMPs), including N(7)-methylguanine (7MeG) and N(3) methyladenine (3MeA), can be induced by environmental methylating agents, chemotherapeutics, and natural cellular methyl donors. In human cells, NMPs are repaired by the multi-step base excision repair pathway initiated by human alkyladenine glycosylase. Repair of NMPs has been shown to be affected by DNA sequence contexts. However, the nature of the sequence contexts has been poorly understood. We developed a sensitive method, LAF-Seq (Lesion-Adjoining Fragment Sequencing), which allows nucleotide-resolution digital mapping of DNA damage and repair in multiple genomic fragments of interest in human cells. We also developed a strategy that allows accurate measurement of the excision kinetics of NMP bases in vitro. We demonstrate that 3MeAs are induced to a much lower level by the SN2 methylating agent dimethyl sulfate and repaired much faster than 7MeGs in human fibroblasts. Induction of 7MeGs by dimethyl sulfate is affected by nearest-neighbor nucleotides, being enhanced at sites neighbored by a G or T on the 3' side, but impaired at sites neighbored by a G on the 5' side. Repair of 7MeGs is also affected by nearest-neighbor nucleotides, being slow if the lesions are between purines, especially Gs, and fast if the lesions are between pyrimidines, especially Ts. Excision of 7MeG bases from the DNA backbone by human alkyladenine glycosylase in vitro is similarly affected by nearest-neighbor nucleotides, suggesting that the effect of nearest-neighbor nucleotides on repair of 7MeGs in the cells is primarily achieved by modulating the initial step of the base excision repair process. PMID- 26240149 TI - Characterization of P4 ATPase Phospholipid Translocases (Flippases) in Human and Rat Pancreatic Beta Cells: THEIR GENE SILENCING INHIBITS INSULIN SECRETION. AB - The negative charge of phosphatidylserine in lipid bilayers of secretory vesicles and plasma membranes couples the domains of positively charged amino acids of secretory vesicle SNARE proteins with similar domains of plasma membrane SNARE proteins enhancing fusion of the two membranes to promote exocytosis of the vesicle contents of secretory cells. Our recent study of insulin secretory granules (ISG) (MacDonald, M. J., Ade, L., Ntambi, J. M., Ansari, I. H., and Stoker, S. W. (2015) Characterization of phospholipids in insulin secretory granules in pancreatic beta cells and their changes with glucose stimulation. J. Biol. Chem. 290, 11075-11092) suggested that phosphatidylserine and other phospholipids, such as phosphatidylethanolamine, in ISG could play important roles in docking and fusion of ISG to the plasma membrane in the pancreatic beta cell during insulin exocytosis. P4 ATPase flippases translocate primarily phosphatidylserine and, to a lesser extent, phosphatidylethanolamine across the lipid bilayers of intracellular vesicles and plasma membranes to the cytosolic leaflets of these membranes. CDC50A is a protein that forms a heterodimer with P4 ATPases to enhance their translocase catalytic activity. We found that the predominant P4 ATPases in pure pancreatic beta cells and human and rat pancreatic islets were ATP8B1, ATP8B2, and ATP9A. ATP8B1 and CDC50A were highly concentrated in ISG. ATP9A was concentrated in plasma membrane. Gene silencing of individual P4 ATPases and CDC50A inhibited glucose-stimulated insulin release in pure beta cells and in human pancreatic islets. This is the first characterization of P4 ATPases in beta cells. The results support roles for P4 ATPases in translocating phosphatidylserine to the cytosolic leaflets of ISG and the plasma membrane to facilitate the docking and fusion of ISG to the plasma membrane during insulin exocytosis. PMID- 26240150 TI - Uptake and Function Studies of Maternal Milk-derived MicroRNAs. AB - MicroRNAs (miRNAs) are important regulators of cell-autonomous gene expression that influence many biological processes. They are also released from cells and are present in virtually all body fluids, including blood, urine, saliva, sweat, and milk. The functional role of nutritionally obtained extracellular miRNAs is controversial, and irrefutable demonstration of exogenous miRNA uptake by cells and canonical miRNA function is still lacking. Here we show that miRNAs are present at high levels in the milk of lactating mice. To investigate intestinal uptake of miRNAs in newborn mice, we employed genetic models in which newborn miR 375 and miR-200c/141 knockout mice received milk from wild-type foster mothers. Analysis of the intestinal epithelium, blood, liver, and spleen revealed no evidence for miRNA uptake. miR-375 levels in hepatocytes were at the limit of detection and remained orders of magnitude below the threshold for target gene regulation (between 1000 and 10,000 copies/cell). Furthermore, our study revealed rapid degradation of milk miRNAs in intestinal fluid. Together, our results indicate a nutritional rather than gene-regulatory role of miRNAs in the milk of newborn mice. PMID- 26240151 TI - Excess Linoleic Acid Increases Collagen I/III Ratio and "Stiffens" the Heart Muscle Following High Fat Diets. AB - Controversy exists on the benefits versus harms of n-6 polyunsaturated fatty acids (n-6 PUFA). Although n-6 PUFA demonstrates anti-atherosclerotic properties, survival following cardiac remodeling may be compromised. We hypothesized that n 6 PUFA like linoleic acid (LA) or other downstream PUFAs like gamma-linolenic acid or arachidonic acid alter the transforming growth factor-beta (TGFbeta) collagen axis in the heart. Excess dietary LA increased the collagen I/III ratio in the mouse myocardium, leading to cardiac "stiffening" characterized by impaired transmitral flow indicative of early diastolic dysfunction within 5 weeks. In vitro, LA under TGFbeta1 stimulation increased collagen I and lysyl oxidase (LOX), the enzyme that cross-links soluble collagen resulting in deposited collagen. Overexpression of fatty acid desaturase 2 (fads2), which metabolizes LA to downstream PUFAs, reduced collagen deposits, LOX maturation, and activity with LA, whereas overexpressing fads1, unrelated to LA desaturation, did not. Furthermore, fads2 knockdown by RNAi elevated LOX activity and collagen deposits in fibroblasts with LA but not oleic acid, implying a buildup of LA for aggravating such pro-fibrotic effects. As direct incubation with gamma-linolenic acid or arachidonic acid also attenuated collagen deposits and LOX activity, we concluded that LA itself, independent of other downstream PUFAs, promotes the pro fibrotic effects of n-6 PUFA. Overall, these results attempt to reconcile opposing views of n-6 PUFA on the cardiovascular system and present evidence supporting a cardiac muscle-specific effect of n-6 PUFAs. Therefore, aggravation of the collagen I/III ratio and cardiac stiffening by excess n-6 PUFA represent a novel pathway of cardiac lipotoxicity caused by high n-6 PUFA diets. PMID- 26240152 TI - Molecular basis for the interaction of the mammalian amino acid transporters B0AT1 and B0AT3 with their ancillary protein collectrin. AB - Many solute carrier 6 (SLC6) family transporters require ancillary subunits to modify their expression and activity. The main apical membrane neutral amino acid transporters in mouse intestine and kidney, B(0)AT1 and B(0)AT3, require the ancillary protein collectrin or ACE2 for plasma membrane expression. Expression and activity of SLC6 neurotransmitter transporters are modulated by interaction with syntaxin 1A. Utilizing monocarboxylate-B(0)AT1/3 fusion constructs, we discovered that collectrin is also necessary for B(0)AT1 and B(0)AT3 catalytic function. Syntaxin 1A and syntaxin 3 inhibit the membrane expression of B(0)AT1 by competing with collectrin for access. A mutagenesis screening approach identified residues on trans-membrane domains 1alpha, 5, and 7 on one face of B(0)AT3 as a key region involved in interaction with collectrin. Mutant analysis established residues that were involved in collectrin-dependent functions as follows: plasma membrane expression of B(0)AT3, catalytic activation, or both. These results identify a potential binding site for collectrin and other SLC6 ancillary proteins. PMID- 26240153 TI - Sphingosine Kinase 1 Protects Hepatocytes from Lipotoxicity via Down-regulation of IRE1alpha Protein Expression. AB - Aberrant deposition of fat including free fatty acids in the liver often causes damage to hepatocytes, namely lipotoxicity, which is a key pathogenic event in the development and progression of fatty liver diseases. This study demonstrates a pivotal role of sphingosine kinase 1 (SphK1) in protecting hepatocytes from lipotoxicity. Exposure of primary murine hepatocytes to palmitate resulted in dose-dependent cell death, which was enhanced significantly in Sphk1-deficient cells. In keeping with this, expression of dominant-negative mutant SphK1 also markedly promoted palmitate-induced cell death. In contrast, overexpression of wild-type SphK1 profoundly protected hepatocytes from lipotoxicity. Mechanistically, the protective effect of SphK1 is attributable to suppression of ER stress-mediated pro-apoptotic pathways, as reflected in the inhibition of IRE1alpha activation, XBP1 splicing, JNK phosphorylation, and CHOP induction. Of note, SphK1 inhibited the IRE1alpha pathway by reducing IRE1alpha expression at the transcriptional level. Moreover, S1P mimicked the effect of SphK1, suppressing IRE1alpha expression in a receptor-dependent manner. Furthermore, enforced overexpression of IRE1alpha significantly blocked the protective effect of SphK1 against lipotoxicity. Therefore, this study provides new insights into the role of SphK1 in hepatocyte survival and uncovers a novel mechanism for protection against ER stress-mediated cell death. PMID- 26240154 TI - Delayed Hemolysis After Parenteral Artesunate Therapy for Severe Malaria in Two Returning Canadian Travelers. AB - Delayed hemolysis after parenteral artesunate has been described in Europe and Asia, but until recently had not been reported in patients receiving the artesunate product used in the United States and Canada. We report two cases of severe delayed hemolysis after the treatment with intravenous artesunate in Canada. PMID- 26240155 TI - An Economic Evaluation of the Posttreatment Prophylactic Effect of Dihydroartemisinin-Piperaquine Versus Artemether-Lumefantrine for First-Line Treatment of Plasmodium falciparum Malaria Across Different Transmission Settings in Africa. AB - Malaria disproportionately affects young children. Clinical trials in African children showed that dihydroartemisinin-piperaquine (DP) is an effective antimalarial and has a longer posttreatment prophylactic (PTP) effect against reinfections than other artemisinin-based combination therapies, including artemether-lumefantrine (AL). Using a previously developed Markov model and individual patient data from a multicenter African drug efficacy trial, we assessed the economic value of the PTP effect of DP versus AL in pediatric malaria patients from health-care provider's perspective in low-to-moderate and moderate-to-high transmission settings under different drug co-payment scenarios. In low-to-moderate transmission settings, first-line treatment with DP was highly cost-effective with an incremental cost-effectiveness ratio of US$5 (95% confidence interval [CI] = -76 to 196) per disability-adjusted life year (DALY) averted. In moderate-to-high transmission settings, DP first-line treatment led to a mean cost saving of US$1.09 (95% CI = -0.88 to 3.85) and averted 0.05 (95% CI = -0.08 to 0.22) DALYs per child per year. Our results suggested that DP might be superior to AL for first-line treatment of uncomplicated childhood malaria across a range of transmission settings in Africa. PMID- 26240157 TI - Seroconversion to Japanese Encephalitis Virus Among U.S. Infantry Forces in Korea. AB - Japanese encephalitis virus (JEV) is endemic in the Republic of Korea (ROK), posing a medical threat to more than 29,000 U.S. Forces military personnel currently deployed in the ROK. The objective of this study was to provide data on the risk of JEV exposure among U.S. Forces in the ROK. One thousand U.S. Army Soldiers were randomly selected for the study from the cohort of infantry Soldiers deployed in the ROK for a period of at least 330 days from 2008 to 2011. Pre- and post-deployment serum specimens were tested for the presence of JEV antibodies by plaque reduction neutralization test. A total of 2/1,000 (0.2%) U.S. Army Soldiers post-deployment specimens tested positive for JEV antibody. Results from the pre-deployment specimens indicated one true seroconversion and one with titers suggestive of a JEV infection. These results indicate a low, but nonzero risk of JEV exposure among U.S. Army Soldiers in the ROK. PMID- 26240156 TI - A Novel Molecular Test to Diagnose Canine Visceral Leishmaniasis at the Point of Care. AB - Dogs are the principal reservoir hosts of zoonotic visceral leishmaniasis (VL) but current serological methods are not sensitive enough to detect all subclinically infected animals, which is crucial to VL control programs. Polymerase chain reaction (PCR) methods have greater sensitivity but require expensive equipment and trained personnel, impairing its implementation in endemic areas. We developed a diagnostic test that uses isothermal recombinase polymerase amplification (RPA) to detect Leishmania infantum. This method was coupled with lateral flow (LF) reading with the naked eye to be adapted as a point-of-care test. The L. infantum RPA-LF had an analytical sensitivity similar to real time-PCR, detecting DNA of 0.1 parasites spiked in dog blood, which was equivalent to 40 parasites/mL. There was no cross amplification with dog or human DNA or with Leishmania braziliensis, Leishmania amazonensis, or Trypanosoma cruzi. The test also amplified Leishmania donovani strains (N = 7). In a group of clinically normal dogs (N = 30), RPA-LF detected more subclinical infections than rK39 strip test, a standard serological method (50% versus 13.3% positivity, respectively; P = 0.005). Also, RPA-LF detected L. infantum in noninvasive mucosal samples of dogs with a sensitivity comparable to blood samples. This novel molecular test may have a positive impact in leishmaniasis control programs. PMID- 26240158 TI - G6PD Deficiency in an HIV Clinic Setting in the Dominican Republic. AB - Because human immunodeficiency virus (HIV)-infected patients receive prophylaxis with oxidative drugs, those with glucose-6-phosphate dehydrogenase (G6PD) deficiency may experience hemolysis. However, G6PD deficiency has not been studied in the Dominican Republic, where many individuals have African ancestry. Our objective was to determine the prevalence of G6PD deficiency in Dominican HIV infected patients and to attempt to develop a cost-effective algorithm for identifying such individuals. To this end, histories, chart reviews, and G6PD testing were performed for 238 consecutive HIV-infected adult clinic patients. The overall prevalence of G6PD deficiency (8.8%) was similar in males (9.3%) and females (8.5%), and higher in Haitians (18%) than Dominicans (6.4%; P = 0.01). By logistic regression, three clinical variables predicted G6PD status: maternal country of birth (P = 0.01) and a history of hemolysis (P = 0.01) or severe anemia (P = 0.03). Using these criteria, an algorithm was developed, in which a patient subset was identified that would benefit most from G6PD screening, yielding a sensitivity of 94.7% and a specificity of 97.2%, increasing the pretest probability (8.8-15.1%), and halving the number of patients needing testing. This algorithm may provide a cost-effective strategy for improving care in resource-limited settings. PMID- 26240161 TI - Corrigendum: MIPSTR: a method for multiplex genotyping of germline and somatic STR variation across many individuals. PMID- 26240159 TI - Association of FcgammaRIIa Polymorphism with Clinical Outcome of Dengue Infection: First Insight from Pakistan. AB - Dengue illness has been a major health concern in Pakistan during the last decade. Dengue infection can result in a spectrum of clinically distinct outcomes, ranging from asymptomatic infection to potentially life-threatening forms of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). A single nucleotide polymorphism in FcgammaRIIa (rs1801274) results in altered affinity of the receptor for different subclasses of immunoglobulin G, and is a key player in determining the susceptibility to or protection from severe clinical infection of dengue. In this study, we analyzed the allelic and genotypic distribution of rs1801274 in subjects of Pakistani origin with subclinical dengue infection (n = 40), dengue fever (DF) (n = 40), and DHF/DSS (n = 30). We found that HH homozygotes and heterozygotes were significantly more likely to develop clinical dengue (odds ratio [OR] = 3.21, 95% confidence interval [CI] = 1.29-7.97, P = 0.009), either DF (OR = 2.82, 95% CI = 1.00-7.97, P = 0.045) or DHF/DSS (OR = 3.90, 95% CI = 1.13-13.07, P = 0.024) than the asymptomatic dengue infection. Results of allelic distribution comparisons and logistic regression analysis also supported the same relationship. The results suggest complex nature of interacting factors in determining the course for severe dengue illness. PMID- 26240162 TI - Bibliometric analysis of poison center-related research published in peer-review journals. AB - Poison centers advance knowledge in the field of toxicology through publication in peer-review journals. This investigation describes the pattern of poison center-related publications. Cases were poison center-related research published in peer-review journals during 1995-2014. These were identified through searching the PubMed database, reviewing the tables of contents of selected toxicology journals, and reviewing abstracts of various national and international meetings. The following variables for each publication were identified: year of publication, journal, type of publication (meeting abstract vs. other, i.e. full article or letter to the editor), and the country(ies) of the poison center(s) included in the research. Of the 3147 total publications, 62.1% were meeting abstracts. There were 263 publications in 1995-1999, 536 in 2000-2004, 999 in 2005-2009, and 1349 in 2010-2014. The publications were in 234 different journals. The journals in which the highest number of research was published were Clinical Toxicology (69.7%), Journal of Medical Toxicology (2.2%), and Veterinary and Human Toxicology (2.1%). The research was reported from 62 different countries. The countries with the highest number of publications were the United States (67.9%), United Kingdom (6.5%), Germany (3.9%), France (2.5%), and Italy (2.4%). The number of publications increased greatly over the 20 years. Although the publications were in a large number of journals, a high proportion of the publications were in one journal. While the research came from a large number of countries, the preponderance came from the United States. PMID- 26240163 TI - Ginsenoside Rg3 attenuated omethoate-induced lung injury in rats. AB - Organophosphorus exposure affects different organs such as the lung, gastrointestinal tract, liver, and brain. The present experiment aimed to evaluate the effect of ginsenoside Rg3 on lung injury induced by acute omethoate poisoning. Rats were administered with omethoate subcutaneously at a single dose of 60 mg/kg, followed by ginsenoside Rg3 (5, 10, or 20 mg/kg) treatment. Histopathological examination of the lung was performed at 24 h after the omethoate exposure. The antioxidative parameters in the lung were also assayed. Moreover, the activities of acetylcholinesterase, myeloperoxidase, and the content of tumor necrosis factor alpha (TNF-alpha) in the lung were determined. The results showed that ginsenoside Rg3 attenuated omethoate-induced lung injury. Ginsenoside Rg3 increased the level of glutathione in the lung (p < 0.05 or p < 0.01). The altered activities of superoxide dismutase and catalase in the lung were also ameliorated by ginsenoside Rg3 treatment (p < 0.05 or p < 0.01). Ginsenoside Rg3 caused significant reductions in the contents of malondialdehyde, TNF-alpha, and the activity of myeloperoxidase (p < 0.05 or p < 0.01). The present study demonstrated that ginsenoside Rg3 had a protective effect against omethoate-induced lung injury in rats, and the mechanisms were related to its antioxidant potential and anti-inflammatory effect. PMID- 26240164 TI - Andrew Ewald takes the helm of first JCS Guest Editorship. PMID- 26240165 TI - Akt-mediated phosphorylation increases the binding affinity of hTERT for importin alpha to promote nuclear translocation. PMID- 26240166 TI - A maternal effect rough deal mutation suggests that multiple pathways regulate Drosophila RZZ kinetochore recruitment. PMID- 26240168 TI - Databases of Conformations and NMR Structures of Glycan Determinants. AB - The present study reports a comprehensive nuclear magnetic resonance (NMR) characterization and a systematic conformational sampling of the conformational preferences of 170 glycan moieties of glycosphingolipids as produced in large scale quantities by bacterial fermentation. These glycans span across a variety of families including the blood group antigens (A, B and O), core structures (Types 1, 2 and 4), fucosylated oligosaccharides (core and lacto-series), sialylated oligosaccharides (Types 1 and 2), Lewis antigens, GPI-anchors and globosides. A complementary set of about 100 glycan determinants occurring in glycoproteins and glycosaminoglycans has also been structurally characterized using molecular mechanics-based computation. The experimental and computational data generated are organized in two relational databases that can be queried by the user through a user-friendly search engine. The NMR ((1)H and (13)C, COSY, TOCSY, HMQC, HMBC correlation) spectra and 3D structures are available for visualization and download in commonly used structure formats. Emphasis has been given to the use of a common nomenclature for the structural encoding of the carbohydrates and each glycan molecule is described by four different types of representations in order to cope with the different usages in chemistry and biology. These web-based databases were developed with non-proprietary software and are open access for the scientific community available at http://glyco3d.cermav.cnrs.fr. PMID- 26240167 TI - Analysis of site-specific N-glycan remodeling in the endoplasmic reticulum and the Golgi. AB - The hallmark of N-linked protein glycosylation is the generation of diverse glycan structures in the secretory pathway. Dynamic, non-template-driven processes of N-glycan remodeling in the endoplasmic reticulum and the Golgi provide the cellular setting for structural diversity. We applied newly developed mass spectrometry-based analytics to quantify site-specific N-glycan remodeling of the model protein Pdi1p expressed in insect cells. Molecular dynamics simulation, mutational analysis, kinetic studies of in vitro processing events and glycan flux analysis supported the defining role of the protein in N-glycan processing. PMID- 26240170 TI - Are cancer outcomes worse in the presence of HIV infection? PMID- 26240171 TI - When is it effective to offer self-sampling to non-attendees--letter. PMID- 26240172 TI - When is it effective to offer self-sampling to non-attendees--response. PMID- 26240173 TI - Calcium intake and prostate cancer--letter. PMID- 26240174 TI - Tropomyosin - master regulator of actin filament function in the cytoskeleton. AB - Tropomyosin (Tpm) isoforms are the master regulators of the functions of individual actin filaments in fungi and metazoans. Tpms are coiled-coil parallel dimers that form a head-to-tail polymer along the length of actin filaments. Yeast only has two Tpm isoforms, whereas mammals have over 40. Each cytoskeletal actin filament contains a homopolymer of Tpm homodimers, resulting in a filament of uniform Tpm composition along its length. Evidence for this 'master regulator' role is based on four core sets of observation. First, spatially and functionally distinct actin filaments contain different Tpm isoforms, and recent data suggest that members of the formin family of actin filament nucleators can specify which Tpm isoform is added to the growing actin filament. Second, Tpms regulate whole organism physiology in terms of morphogenesis, cell proliferation, vesicle trafficking, biomechanics, glucose metabolism and organ size in an isoform specific manner. Third, Tpms achieve these functional outputs by regulating the interaction of actin filaments with myosin motors and actin-binding proteins in an isoform-specific manner. Last, the assembly of complex structures, such as stress fibers and podosomes involves the collaboration of multiple types of actin filament specified by their Tpm composition. This allows the cell to specify actin filament function in time and space by simply specifying their Tpm isoform composition. PMID- 26240177 TI - Endomembrane PtdIns(3,4,5)P3 activates the PI3K-Akt pathway. AB - PKB/Akt activation is a common step in tumour growth, proliferation and survival. Akt activation is understood to occur at the plasma membrane of cells in response to growth factor stimulation and local production of the phosphoinositide lipid phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] following phosphoinositide 3-kinase (PI3K) activation. The metabolism and turnover of phosphoinositides is complex--they act as signalling molecules as well as structural components of biological membranes. The localisation and significance of internal pools of PtdIns(3,4,5)P3 has long been speculated upon. By using transfected and recombinant protein probes for PtdIns(3,4,5)P3, we show that PtdIns(3,4,5)P3 is enriched in the nuclear envelope and early endosomes. By exploiting an inducible dimerisation device to recruit Akt to these compartments, we demonstrate that Akt can be locally activated in a PtdIns(3,4,5)P3-dependent manner and has the potential to phosphorylate compartmentally localised downstream substrates. This could be an important mechanism to regulate Akt isoform substrate specificity or influence the timing and duration of PI3K pathway signalling. Defects in phosphoinositide metabolism and localisation are known to contribute to cancer, suggesting that interactions at subcellular compartments might be worthwhile targets for therapeutic intervention. PMID- 26240176 TI - Vinculin phosphorylation at residues Y100 and Y1065 is required for cellular force transmission. AB - The focal adhesion protein vinculin connects the actin cytoskeleton, through talin and integrins, with the extracellular matrix. Vinculin consists of a globular head and tail domain, which undergo conformational changes from a closed auto-inhibited conformation in the cytoplasm to an open conformation in focal adhesions. Src-mediated phosphorylation has been suggested to regulate this conformational switch. To explore the role of phosphorylation in vinculin activation, we used knock-out mouse embryonic fibroblasts re-expressing different vinculin mutants in traction microscopy, magnetic tweezer microrheology, FRAP and actin-binding assays. Compared to cells expressing wild-type or constitutively active vinculin, we found reduced tractions, cytoskeletal stiffness, adhesion strength, and increased vinculin dynamics in cells expressing constitutively inactive vinculin or vinculin where Src-mediated phosphorylation was blocked by replacing tyrosine at position 100 and/or 1065 with a non-phosphorylatable phenylalanine residue. Replacing tyrosine residues with phospho-mimicking glutamic acid residues restored cellular tractions, stiffness and adhesion strength, as well as vinculin dynamics, and facilitated vinculin-actin binding. These data demonstrate that Src-mediated phosphorylation is necessary for vinculin activation, and that phosphorylation controls cytoskeletal mechanics by regulating force transmission between the actin cytoskeleton and focal adhesion proteins. PMID- 26240175 TI - The Exocyst at a Glance. AB - The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. Spatial and temporal control of exocytosis through the exocyst has a crucial role in a number of physiological processes, such as morphogenesis, cell cycle progression, primary ciliogenesis, cell migration and tumor invasion. In this Cell Science at a Glance poster article, we summarize recent works on the molecular organization, function and regulation of the exocyst complex, as they provide rationales to the involvement of this complex in such a diverse array of cellular processes. PMID- 26240178 TI - The fission yeast cytokinetic contractile ring regulates septum shape and closure. AB - During cytokinesis, fission yeast and other fungi and bacteria grow a septum that divides the cell in two. In fission yeast closure of the circular septum hole by the beta-glucan synthases (Bgs) and other glucan synthases in the plasma membrane is tightly coupled to constriction of an actomyosin contractile ring attached to the membrane. It is unknown how septum growth is coordinated over scales of several microns to maintain septum circularity. Here, we documented the shapes of ingrowing septum edges by measuring the roughness of the edges, a measure of the deviation from circularity. The roughness was small, with spatial correlations indicative of spatially coordinated growth. We hypothesized that Bgs-mediated septum growth is mechanosensitive and coupled to contractile ring tension. A mathematical model showed that ring tension then generates almost circular septum edges by adjusting growth rates in a curvature-dependent fashion. The model reproduced experimental roughness statistics and showed that septum synthesis sets the mean closure rate. Our results suggest that the fission yeast cytokinetic ring tension does not set the constriction rate but regulates septum closure by suppressing roughness produced by inherently stochastic molecular growth processes. PMID- 26240180 TI - Jan van Deursen: From knockout pioneer to antiaging innovator. PMID- 26240179 TI - Accessing Real-Life Episodic Information from Minutes versus Hours Earlier Modulates Hippocampal and High-Order Cortical Dynamics. AB - It is well known that formation of new episodic memories depends on hippocampus, but in real-life settings (e.g., conversation), hippocampal amnesics can utilize information from several minutes earlier. What neural systems outside hippocampus might support this minutes-long retention? In this study, subjects viewed an audiovisual movie continuously for 25 min; another group viewed the movie in 2 parts separated by a 1-day delay. Understanding Part 2 depended on retrieving information from Part 1, and thus hippocampus was required in the day-delay condition. But is hippocampus equally recruited to access the same information from minutes earlier? We show that accessing memories from a few minutes prior elicited less interaction between hippocampus and default mode network (DMN) cortical regions than accessing day-old memories of identical events, suggesting that recent information was available with less reliance on hippocampal retrieval. Moreover, the 2 groups evinced reliable but distinct DMN activity timecourses, reflecting differences in information carried in these regions when Part 1 was recent versus distant. The timecourses converged after 4 min, suggesting a time frame over which the continuous-viewing group may have relied less on hippocampal retrieval. We propose that cortical default mode regions can intrinsically retain real-life episodic information for several minutes. PMID- 26240181 TI - A developmental biologist's "outside-the-cell" thinking. AB - A major gap in our understanding of cell biology is how cells generate and interact with their surrounding extracellular matrix. Studying this problem during development has been particularly fruitful. Recent work on the basement membrane in developmental systems is transforming our view of this matrix from one of a static support structure to that of a dynamic scaffold that is regularly remodeled to actively shape tissues and direct cell behaviors. PMID- 26240182 TI - TPX2 phosphorylation maintains metaphase spindle length by regulating microtubule flux. AB - A steady-state metaphase spindle maintains constant length, although the microtubules undergo intensive dynamics. Tubulin dimers are incorporated at plus ends of spindle microtubules while they are removed from the minus ends, resulting in poleward movement. Such microtubule flux is regulated by the microtubule rescue factors CLASPs at kinetochores and depolymerizing protein Kif2a at the poles, along with other regulators of microtubule dynamics. How microtubule polymerization and depolymerization are coordinated remains unclear. Here we show that TPX2, a microtubule-bundling protein and activator of Aurora A, plays an important role. TPX2 was phosphorylated by Aurora A during mitosis. Its phospho-null mutant caused short metaphase spindles coupled with low microtubule flux rate. Interestingly, phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a. The effect of its mutant in shortening the spindle could be rescued by codepletion of CLASP1 and Kif2a that abolished microtubule flux. Together we propose that Aurora A-dependent TPX2 phosphorylation controls mitotic spindle length through regulating microtubule flux. PMID- 26240183 TI - Rapid pairing and resegregation of distant homologous loci enables double-strand break repair in bacteria. AB - Double-strand breaks (DSBs) can lead to the loss of genetic information and cell death. Although DSB repair via homologous recombination has been well characterized, the spatial organization of this process inside cells remains poorly understood, and the mechanisms used for chromosome resegregation after repair are unclear. In this paper, we introduced site-specific DSBs in Caulobacter crescentus and then used time-lapse microscopy to visualize the ensuing chromosome dynamics. Damaged loci rapidly mobilized after a DSB, pairing with their homologous partner to enable repair, before being resegregated to their original cellular locations, independent of DNA replication. Origin proximal regions were resegregated by the ParABS system with the ParA structure needed for resegregation assembling dynamically in response to the DSB-induced movement of an origin-associated ParB away from one cell pole. Origin-distal regions were resegregated in a ParABS-independent manner and instead likely rely on a physical, spring-like force to segregate repaired loci. Collectively, our results provide a mechanistic basis for the resegregation of chromosomes after a DSB. PMID- 26240186 TI - Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling. PMID- 26240184 TI - MiT/TFE transcription factors are activated during mitophagy downstream of Parkin and Atg5. AB - The kinase PINK1 and ubiquitin ligase Parkin can regulate the selective elimination of damaged mitochondria through autophagy (mitophagy). Because of the demand on lysosomal function by mitophagy, we investigated a role for the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, in this process. We show that during mitophagy TFEB translocates to the nucleus and displays transcriptional activity in a PINK1- and Parkin-dependent manner. MITF and TFE3, homologues of TFEB belonging to the same microphthalmia/transcription factor E (MiT/TFE) family, are similarly regulated during mitophagy. Unlike TFEB translocation after starvation-induced mammalian target of rapamycin complex 1 inhibition, Parkin-mediated TFEB relocalization required Atg9A and Atg5 activity. However, constitutively active Rag guanosine triphosphatases prevented TFEB translocation during mitophagy, suggesting cross talk between these two MiT/TFE activation pathways. Analysis of clustered regularly interspaced short palindromic repeats-generated TFEB/MITF/TFE3/TFEC single, double, and triple knockout cell lines revealed that these proteins partly facilitate Parkin mediated mitochondrial clearance. These results illuminate a pathway leading to MiT/TFE transcription factor activation, distinct from starvation-induced autophagy, which occurs during mitophagy. PMID- 26240187 TI - Retraction. Peroxisome reintroduction in Hansenula polymorpha requires Pex25 and Rho1. PMID- 26240185 TI - PtdIns(4,5)P2 and PtdIns3P coordinate to regulate phagosomal sealing for apoptotic cell clearance. AB - Phagocytosis requires phosphoinositides (PIs) as both signaling molecules and localization cues. How PIs coordinate to control phagosomal sealing and the accompanying switch of organelle identity is unclear. In this study, we followed dynamic changes in PIs during apoptotic cell clearance in Caenorhabditis elegans. We found that phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol-3-phosphate (PtdIns3P), which accumulate transiently on unsealed and fully sealed phagosomes, respectively, are both involved in phagosome closure. We identified PtdIns3P phosphatase MTM-1 as an effector of PtdIns(4,5)P2 to promote phagosomal sealing. MTM-1 coordinates with the class II PI3 kinase PIKI-1 to control PtdIns3P levels on unsealed phagosomes. The SNX9 family protein LST-4 is required for sealing, and its association with unsealed phagosomes is regulated by PtdIns(4,5)P2, PIKI-1, and MTM-1. Loss of LST-4 or its retention on phagosomes disrupts sealing and suppresses PtdIns3P accumulation, indicating close coupling of the two events. Our findings support a coincidence detection mechanism by which phagosomal sealing is regulated and coupled with conversion from PtdIns(4,5)P2 enrichment on unsealed phagosomes to PtdIns3P enrichment on fully sealed phagosomes. PMID- 26240188 TI - The Matrix Polysaccharide (1;3,1;4)-beta-D-Glucan is Involved in Silicon Dependent Strengthening of Rice Cell Wall. PMID- 26240189 TI - Valvular heart disease and the military patient. AB - Valvular heart disease refers to all inherited and acquired abnormalities impairing the function of one or more of the four cardiac valves. Pathology may be of the valve leaflets themselves, of the subvalvular apparatus or of the annulus or other surrounding structures that influences valve function. This paper examines the most common valve lesions, with specific reference to a military population; it focuses on detection and initial management of valve disease in a young adult population and specifically describes how the diagnosis and treatment of valve disease impacts military medical grading. PMID- 26240190 TI - HPLC Determination of Bioactive Flavonoids in Hovenia dulcis Fruit Extracts. AB - A simple, accurate and reproducible reversed-phase liquid chromatographic method was developed for qualitative and quantitative determination of four bioactive flavonoids (ampelopsin, taxifolin, myricetin and quercetin) from the fruit-stalk extract of Hovenia dulcis Thunb. Chromatographic separation was performed on a C18 column (4.6 * 150 mm, 3.5 um) with mobile phase consisting of 0.1% acetic acid and 100% acetonitrile at a flow rate of 1.0 mL/min. The analysis was performed using a diode array detector at 365 nm. The method was validated in terms of selectivity, linearity, accuracy, precision and recovery. Good linearity was observed over the investigated concentration range (10-500 MUg/mL), with correlation coefficient values greater than 0.99. The intra- and inter-day precisions over the concentration range were <3.91% (relative standard deviation), and the accuracy was between 91.57 and 106.66%. The mean recovery for all the analytes was 100.87%. This method was successfully applied in the quality assessment of bioactive flavonoids in the fruit-stalk extract of H. dulcis. PMID- 26240191 TI - Determination of carbon number distributions of complex phthalates by gas chromatography-mass spectrometry with ammonia chemical ionization. AB - An assay method for phthalate esters with a complex mixture of isomer of varying carbon numbers, such as di-isononyl phthalate (DINP) and di-isodecyl phthalate (DIDP), using gas chromatography-mass spectrometry (GC-MS) positive chemical ionization (PCI) with 5% ammonia in methane is described. GC-MS-PCI-NH3, unlike GC-MS electron ionization (EI) (GC-MS-EI) that produces generally m/z 149 ion as the main base peak and low intensity M(+) peaks, produces higher intensity (M + 1) ions that allow the determination of total (R + R') carbon number distributions based on the various R and R' alkyl groups of the di-esters moiety. The technique allows distinguishing among the various commercial DINP and DIDP plasticizers. The carbon number distributions are determined in the acceptable range of <0.1 mole percent to >85 mole percent (m/m). Several examples of analysis made on commercial DINP and DIDP are presented. The use of only 5% instead of 100% ammonia simplifies use of GC-MS-PCI-NH3 but still produces sufficient M + 1 ion intensities that are appropriate for the assay. In addition, use of low concentrations of ammonia mitigates potential safety aspects related to use of ammonia and provides less corrosion for the instrument hardware. PMID- 26240192 TI - Uncertainties of assessing total body vitamin A stores in community settings in low-income countries using the stable-isotope dilution methodology. PMID- 26240193 TI - Reply to G Lietz et al. PMID- 26240196 TI - Characterization of Urinary Phthalate Metabolites Among Custodians. AB - Phthalates, a ubiquitous class of chemicals found in consumer, personal care, and cleaning products, have been linked to adverse health effects. Our goal was to characterize urinary phthalate metabolite concentrations and to identify work and nonwork sources among custodians using traditional cleaning chemicals and 'green' or environmentally preferable products (EPP). Sixty-eight custodians provided four urine samples on a workday (first void, before shift, end of shift, and before bedtime) and trained observers recorded cleaning tasks and types of products used (traditional, EPP, or disinfectant) hourly over the work shifts. Questionnaires were used to assess personal care product use. Four different phthalate metabolites [monoethyl phthalate (MEP), monomethyl phthalate (MMP), mono (2-ethylhexyl) phthalate (MEHP), and monobenzyl phthalate (MBzP)] were quantified using liquid chromatography mass spectrometry. Geometric means (GM) and 95% confidence intervals (95% CI) were calculated for creatinine-adjusted urinary phthalate concentrations. Mixed effects univariate and multivariate modeling, using a random intercept for each individual, was performed to identify predictors of phthalate metabolites including demographics, workplace factors, and personal care product use. Creatinine-adjusted urinary concentrations [GM (95% CI)] of MEP, MMP, MEHP, and MBzP were 107 (91.0-126), 2.69 (2.18-3.30), 6.93 (6.00-7.99), 8.79 (7.84-9.86) ug g(-1), respectively. An increasing trend in phthalate concentrations from before to after shift was not observed. Creatinine adjusted urinary MEP was significantly associated with frequency of traditional cleaning chemical intensity in the multivariate model after adjusting for potential confounding by demographics, workplace factors, and personal care product use. While numerous demographics, workplace factors, and personal care products were statistically significant univariate predictors of MMP, MEHP, and MBzP, few associations persisted in multivariate models. In summary, among this population of custodians, we identified both occupational and nonoccupational predictors of phthalate exposures. Identification of phthalates as ingredients in cleaning chemicals and consumer products would allow workers and consumers to avoid phthalate exposure. PMID- 26240197 TI - The Short-term Protective Effects of 'Non-PPE' Gloves Used by Greenhouse Workers. AB - Task-based worker exposure assessments are used in regulatory product approval for pesticides. Some agricultural workers may be exposed to pesticide residues predominantly via transfer to the hands during plant tending or crop harvesting. They may use thin 'splash-resistant single-use' (SRSU) gloves or cotton gloves as good industry practice, for example, to protect a delicate crop from bruising, rather than specifically for chemical protection. These 'non-personal protective equipment (PPE)' gloves may or may not have been tested for chemical resistance, but can nevertheless give limited protection from chemicals. This paper reports experiments to assess the protection factors (PFs) of 'non-PPE' gloves against chemicals, to better inform the regulatory exposure assessments.One type of lightweight cotton and three types of 0.1 mm SRSU gloves 25cm long (latex, nitrile, and vinyl) that might be used as 'non-PPE' gloves and one type of 0.4 mm PPE nitrile gauntlet 33cm long were worn by 36 volunteers in greenhouses at four nurseries, handling plants sprayed with transferable but non-permeating strontium acetate in four consecutive 1-h sessions, including one session in which no gloves were worn. Dislodgeable foliar residues were measured by rinsing leaves in bags. Each subject carried out their task such as weeding or trimming, for their four sessions on their set of plants. Handwashes followed each session, and the washings were sampled and analysed for strontium. Unprotected hand contamination was taken to be the within-subject 'challenge' in the absence of gloves. It ranged from 166 to 4091 ug equivalent of strontium acetate on the hands and increased with increasing foliar residues. Geometric mean PFs were 60 (95% CI 38 87, n = 22) for PPE gauntlets, 32 (25-41, n = 65) for SRSU gloves and 5.3 (3.5-8, n = 21) for lightweight cotton. The PFs offered by the waterproof gloves (gauntlets and SRSU) increased with challenge, but for the absorbent cotton gloves it decreased. The measurement of protection is restricted by the limit of quantification (LOQ) such that protection must apparently increase with challenge, nevertheless the above trends remained even after removal of data =12 years diagnosed with urogenital MG, and had microbial cure measured within 12 months of treatment. Treatment efficacy was measured as microbial cure at last follow-up after treatment. RESULTS: A total of 21 studies, including 1490 participants, fulfilled the inclusion criteria. Most studies were observational, with only 5 controlled trials identified. The random-effects pooled microbial cure was 77.2% (95% confidence interval [CI], 71.1%-83.4%; I(2) = 80.8%, P < .01). For the 12 studies conducted prior to 2009, pooled microbial cure was 85.3% (CI, 82.3%-88.3%; I(2) = 19.7%, P = .25); for the 9 studies conducted since the beginning of 2009, pooled microbial cure was 67.0% (CI, 57.0%-76.9%; I(2) = 80.9%, P < .01). CONCLUSIONS: The efficacy of a single dose of 1 gram of azithromycin for the treatment of urogenital MG has decreased to approach 60%. Even though most of the available evidence is based on observational studies that have considerable variability in sample size and timing of microbial cure, this low efficacy is of considerable concern. It is vital that new treatment options for MG are investigated. PMID- 26240202 TI - Using immunohistochemistry to assess the accuracy of histomorphologic diagnosis of aspergillosis and mucormycosis. AB - BACKGROUND: Data on the accuracy of conventional histomorphologic diagnosis are limited, especially in mucormycosis. We therefore investigated the accuracy of histomorphologic diagnosis of mucormycosis and aspergillosis, using immunohistochemistry (IHC) tests for mucormycosis and aspergillosis. METHODS: Patients enrolled met the modified criteria for proven and probable mucormycosis (during a 22-year period) or invasive aspergillosis (during a 6-year period) and had formalin-fixed, paraffin-embedded tissues available. We first tested the diagnostic performance of IHC for mucormycosis and aspergillosis in proven cases. Then we determined the accuracy of histomorphologic diagnosis of probable cases, using the IHC tests. RESULTS: In 7 proven cases of mucormycosis, the sensitivity and specificity of mucormycosis IHC were 100% (95% confidence interval, 65%-100%) and 100% (68%-100%), respectively. In 8 proven cases of aspergillosis, and the sensitivity and specificity of aspergillosis IHC staining were 87% (53%-98%) and 100% (65%-100%), respectively. Of 23 probable mucormycosis cases, 20 (87%) were positive with mucormycosis IHC, 2 (9%) were positive with aspergillosis IHC (including 1 positive for both), and 2 were negative with both. Of 16 probable aspergillosis cases, 10 (63%) were positive with aspergillosis IHC, 4 (25%) were positive with mucormycosis IHC, and 2 (13%) were negative with both tests. CONCLUSIONS: Aspergillosis and mucormycosis seem not to be correctly diagnosed morphologically, because some of the probable cases showed either test with both antibodies or failure to stain with the homologous antibody. In the absence of fungal culture results, the IHC tests seem helpful in differentiating between aspergillosis and mucormycosis. PMID- 26240204 TI - Editorial Commentary: Mycoplasma genitalium and Declining Treatment Efficacy of Azithromycin 1 g: What Can We Do? PMID- 26240203 TI - Pretreatment HIV drug resistance increases regimen switches in sub-Saharan Africa. AB - BACKGROUND: After the scale-up of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection in Africa, increasing numbers of patients have pretreatment drug resistance. METHODS: In a large multicountry cohort of patients starting standard first-line ART in six African countries, pol genotyping was retrospectively performed if viral load (VL) >=1000 cps/mL. Pretreatment drug resistance was defined as a decreased susceptibility to >=1 prescribed drug. We assessed the effect of pretreatment drug resistance on all cause mortality, new AIDS events and switch to second-line ART due to presumed treatment failure, using Cox models. RESULTS: Among 2579 participants for whom a pretreatment genotype was available, 5.5% had pretreatment drug resistance. Pretreatment drug resistance was associated with an increased risk of regimen switch (adjusted hazard ratio [aHR] 3.80; 95% confidence interval [CI], 1.49 9.68; P = .005) but was not associated with mortality (aHR 0.75, 95% CI, .24 2.35; P = .617) or new AIDS events (aHR 1.06, 95% CI, .68-1.64; P = .807). During three years of follow up, 106 (4.1%) participants switched to second-line, of whom 18 (17.0%) switched with VL < 1000 cps/mL, 7 (6.6%) with VL >= 1000 cps/mL and no drug resistance mutations (DRMs), 46 (43.4%) with VL >= 1000 cps/mL and >=1 DRMs; no HIV RNA data was available for 32 (30.2%) participants. CONCLUSIONS: Given rising pretreatment HIV drug resistance levels in sub-Saharan Africa, these findings underscore the need for expanded access to second-line ART. VL monitoring can improve the accuracy of failure detection and efficiency of switching practices. PMID- 26240205 TI - Controlling Middle East respiratory syndrome: lessons learned from severe acute respiratory syndrome. PMID- 26240206 TI - Low adherence of HIV providers to practice guidelines for hepatocellular carcinoma screening in HIV/hepatitis B coinfection. AB - BACKGROUND: In the era of combination therapy for human immunodeficiency virus (HIV), liver disease, and hepatocellular carcinoma (HCC) are major causes of death for patients coinfected with HIV and hepatitis B virus (HBV). This study compared HIV provider and hepatologist awareness of and adherence to the American Association for the Study of Liver Diseases (AASLD) practice guidelines for chronic HBV management. The primary endpoint of HIV provider adherence to HCC screening recommendations was compared to that of hepatologists at a large metropolitan academic medical center. METHODS: Medical record database searches by ICD-9 codes were used to identify HIV/HBV coinfected (n = 144) and HBV monoinfected (n = 225) patients who were seen at least twice over a 2-year period in outpatient clinics. Adherence to AASLD guidelines was assessed by chart review. Provider awareness was evaluated through a voluntary anonymous survey with knowledge-based questions. RESULTS: Over a 2-year period, only 36.0% of HIV/HBV coinfected patients seen in HIV practices completed HCC screening compared to 81.8% of HBV monoinfected patients in hepatology practices (P < .00001). Similarly, HIV providers less frequently monitored HBV viral load (P < .0001), HBeAg/anti-HBe (P < .00001), HBsAg/anti-HBs (P < .00001) than hepatologists but screened more often for hepatitis A immunity (P = .028). Self reported adherence and knowledge scores were similar among 19 HIV providers and 16 hepatologists. CONCLUSIONS: HIV providers ordered significantly fewer HCC screening and HBV monitoring tests than hepatologists within a single academic medical center. In the setting of increased reliance on quality indicators for care, both patients and providers will benefit from greater adherence to established guidelines. PMID- 26240207 TI - Coadministration of a 9-Valent Human Papillomavirus Vaccine With Meningococcal and Tdap Vaccines. AB - BACKGROUND: This study in 11- to 15-year-old boys and girls compared the immunogenicity and safety of GARDASIL 9 (9-valent human papillomavirus [9vHPV] vaccine) administered either concomitantly or nonconcomitantly with 2 vaccines routinely administered in this age group (Menactra [MCV4; Neisseria meningitidis serotypes A/C/Y/W-135] or Adacel [Tdap; diphtheria/tetanus/acellular pertussis]). METHODS: Participants received 9vHPV vaccine at day 1 and months 2 and 6; the concomitant group (n = 621) received MCV4/Tdap concomitantly with 9vHPV vaccine at day 1; the nonconcomitant group (n = 620) received MCV4/Tdap at month 1. Antibodies to HPV-, MCV4-, and Tdap-relevant antigens were determined. Injection site and systemic adverse events (AEs) were monitored for 15 days after any vaccination; serious AEs were monitored throughout the study. RESULTS: The geometric mean titers for all HPV types in 9vHPV vaccine 4 weeks after dose 3, proportion of subjects with a fourfold rise or greater in titers for 4 N meningitidis serotypes 4 weeks after injection with MCV4, proportion of subjects with antibody titers to diphtheria and tetanus >=0.1 IU/mL, and geometric mean titers for pertussis antigens 4 weeks after injection with Tdap were all noninferior in the concomitant group compared with the nonconcomitant group. Injection-site swelling occurred more frequently in the concomitant group. There were no vaccine-related serious AEs. CONCLUSIONS: Concomitant administration of 9vHPV vaccine with MCV4/Tdap was generally well tolerated and did not interfere with the antibody response to any of these vaccines. This strategy would minimize the number of visits required to deliver each vaccine individually. PMID- 26240208 TI - Pediatric Traumatic Brain Injury and Attention Deficit. AB - BACKGROUND: We investigated the impact of pediatric traumatic brain injury (TBI) on attention, a prerequisite for behavioral and neurocognitive functioning. METHODS: Children aged 6 to 13 years who were diagnosed with TBI (n = 113; mean 1.7 years postinjury) were compared with children with a trauma control injury (not involving the head) (n = 53). TBI severity was defined as mild TBI with or without risk factors for complicated TBI (mild(RF+) TBI, n = 52; mild(RF-) TBI, n = 24) or moderate/severe TBI (n = 37). Behavioral functioning was assessed by using parent and teacher questionnaires, and the Attention Network Test assessed alerting, orienting, and executive attention. Ex-Gaussian modeling determined the contribution of extremely slow responses (lapses of attention) to mean reaction time (MRT). RESULTS: The TBI group showed higher parent and teacher ratings of attention and internalizing problems, higher parent ratings of externalizing problems, and lower intelligence than the control group (P < .05, d >= 0.34). No effect of TBI on alerting, orienting, and executive attention was observed (P >= .55). MRT was slower in the TBI group (P = .008, d = 0.45), traced back to increased lapses of attention (P = .002, d = 0.52). The mild(RF-) TBI group was unaffected, whereas the mild(RF+) TBI and moderate/severe TBI groups showed elevated parent ratings of behavior problems, lower intelligence, and increased lapses of attention (P <= .03, d >= 0.48). Lapses of attention fully explained the negative relation between intelligence and parent-rated attention problems in the TBI group (P = .02). CONCLUSIONS: Lapses of attention represent a core attention deficit in children with mild(RF+) TBI (even in the absence of intracranial pathology) or moderate/severe TBI, and relate to daily life problems after pediatric TBI. PMID- 26240209 TI - Novel WDR45 Mutation and Pathognomonic BPAN Imaging in a Young Female With Mild Cognitive Delay. AB - beta-propeller protein-associated neurodegeneration (BPAN) is a recently identified X-linked dominant form of neurodegeneration with brain iron accumulation caused by mutations in the WDR45 gene. BPAN commonly presents as global developmental delay in childhood with rapid onset of parkinsonism and dementia in early adulthood and associated pathognomonic changes seen on brain MRI. In this case report, we present a pediatric patient with mild cognitive delay and pathognomonic MRI changes indicative of BPAN preceding neurologic deterioration who is found to have a novel de novo mutation in the WDR45 gene. PMID- 26240211 TI - Prenatal Decision-Making for Myelomeningocele: Can We Minimize Bias and Variability? PMID- 26240210 TI - Suicide Attempts and Childhood Maltreatment Among Street Youth: A Prospective Cohort Study. AB - BACKGROUND: Although suicide is a known leading cause of death among street youth, few prospective studies have explored childhood experiences as risk factors for future suicide attempt in this population. We examined the risk of attempted suicide in relation to childhood maltreatment among street youth. METHODS: From September 2005 to November 2013, data were collected from the At Risk Youth Study (ARYS), a prospective cohort of street youth in Vancouver, Canada. Inclusion criteria were age 14 to 26 years, past-month illicit drug use, and street involvement. Participants completed the Childhood Trauma Questionnaire, an instrument measuring self-reported sexual, physical, and emotional abuse and physical and emotional neglect. Suicide attempts were assessed semiannually. Using Cox regression, we examined the association between the 5 types of maltreatment and suicide attempts. RESULTS: Of 660 participants, 68.2% were male and 24.6% were Aboriginal. Median age was 21.5 years. The prevalence of moderate to extreme childhood maltreatment ranged from 16.8% (sexual abuse) to 45.2% (emotional abuse). Participants contributed 1841 person years, with suicide attempts reported by 35 (5.3%) individuals (crude incidence density: 1.9 per 100 person-years; 95% confidence interval [CI]: 1.4-2.6 per 100 person-years). In adjusted analyses, types of maltreatment associated with suicide attempts included physical abuse (adjusted hazard ratio [HR]: 4.47; 95% CI: 2.12-9.42), emotional abuse (adjusted HR: 4.92; 95% CI: 2.11-11.5), and emotional neglect (adjusted HR: 3.08; 95% CI: 1.05-9.03). CONCLUSIONS: Childhood maltreatment is associated with subsequent risk of suicidal behavior among street youth. Suicide prevention efforts should be targeted toward this marginalized population and delivered from a trauma-informed perspective. PMID- 26240212 TI - Belt Buckles-Increasing Awareness of Nickel Exposure in Children: A Case Report. AB - Children, especially those with atopic dermatitis, are at risk for nickel sensitization and subsequent dermatitis from metal-containing objects, namely belt buckles. We describe allergic contact dermatitis in 12 children with peri umbilical nickel dermatitis (with and without generalized involvement) caused by dimethylglyoxime-positive belt buckles. The patients' symptoms resolved with avoidance of the nickel-containing products. PMID- 26240213 TI - Psychological and Psychosocial Impairment in Preschoolers With Selective Eating. AB - OBJECTIVE: We examined the clinical significance of moderate and severe selective eating (SE). Two levels of SE were examined in relation to concurrent psychiatric symptoms and as a risk factor for the emergence of later psychiatric symptoms. Findings are intended to guide health care providers to recognize when SE is a problem worthy of intervention. METHODS: A population cohort sample of 917 children aged 24 to 71 months and designated caregivers were recruited via primary care practices at a major medical center in the Southeast as part of an epidemiologic study of preschool anxiety. Caregivers were administered structured diagnostic interviews (the Preschool Age Psychiatric Assessment) regarding the child's eating and related self-regulatory capacities, psychiatric symptoms, functioning, and home environment variables. A subset of 188 dyads were assessed a second time ~24.7 months from the initial assessment. RESULTS: Both moderate and severe levels of SE were associated with psychopathological symptoms (anxiety, depression, attention-deficit/hyperactivity disorder) both concurrently and prospectively. However, the severity of psychopathological symptoms worsened as SE became more severe. Impairment in family functioning was reported at both levels of SE, as was sensory sensitivity in domains outside of food and the experience of food aversion. CONCLUSIONS: Findings suggest that health care providers should intervene at even moderate levels of SE. SE associated with impairment in function should now be diagnosed as avoidant/restrictive food intake disorder, an eating disorder that encapsulates maladaptive food restriction, which is new to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. PMID- 26240214 TI - Pediatric Professional Medical Associations and Industry Guideline Compliance. AB - BACKGROUND AND OBJECTIVES: There has been an increasing focus on the relationship between pediatric prescribers and the biomedical industry. There is a lack of research, however, on the biomedical industry's relationship with the professional medical associations (PMAs) of pediatric prescribers. We developed a systematic method to assess this relationship by evaluating PMA transparency and compliance with a set of 2009 best practice guidelines (BPGs). METHODS: Nine PMAs rated as having the greatest influence on pediatric prescribers were examined. Two researchers independently coded publicly accessible information from the PMAs' Web sites for transparency and compliance with 36 BPG recommendations. Using the coded data, an industry relationship index (IRI) score was developed to systematize comparisons across PMAs. RESULTS: The PMAs demonstrated transparency and compliance with less than one-half of the 2009 BPGs (mean +/- SD: 30.2 +/- 15.6; range: 8-51 on the 66-point IRI scale). Two PMAs clustered in the high IRI (more transparent and compliant) group, 3 in the medium group, and 4 in the low group. There was no significant association of IRI group status and the PMAs' number of members or age. PMAs were least compliant with recommendations that prohibit or limit financial relationships with industry. CONCLUSIONS: PMAs with influence on pediatric prescribers have achieved only limited transparency and compliance with a set of 2009 BPGs, particularly with respect to financial separation from industry. Use of quantifiable standards of conduct facilitates comparisons between organizations and may enhance public trust in PMAs, preserving their ability to achieve organizational goals. PMID- 26240215 TI - Up to Speed: A Role for Trainees in Advancing Health Information Technology. PMID- 26240216 TI - Translating Atopic Dermatitis Management Guidelines Into Practice for Primary Care Providers. AB - Atopic dermatitis affects a substantial number of children, many of whom seek initial treatment from their pediatrician or other primary care provider. Approximately two-thirds of these patients have mild disease and can be adequately managed at the primary care level. However, recent treatment guidelines are written primarily for use by specialists and lack certain elements that would make them more useful to primary care providers. This article evaluates these recent treatment guidelines in terms of evaluation criteria, treatment recommendations, usability, accessibility, and applicability to nonspecialists and integrates them with clinical evidence to present a streamlined severity-based treatment model for the management of a majority of atopic dermatitis cases. Because each patient's situation is unique, individualization of treatment plans is critical as is efficient communication and implementation of the plan with patients and caregivers. Specifically, practical suggestions for individualizing, optimizing, implementing, and communicating treatment plans such as choosing a moisturizer formulation, avoiding common triggers, educating patients/caregivers, providing written treatment plans, and scheduling physician follow-up are provided along with a discussion of available resources for patients/caregivers and providers. PMID- 26240217 TI - Academically led clinical trials: challenges and opportunities. PMID- 26240218 TI - Dendritic Cells as Pharmacological Tools for Cancer Immunotherapy. AB - Although the earliest-rudimentary-attempts at exploiting the immune system for cancer therapy can be traced back to the late 18th Century, it was not until the past decade that cancer immunotherapeutics have truly entered mainstream clinical practice. Given their potential to stimulate both adaptive and innate antitumor immune responses, dendritic cells (DCs) have come under intense scrutiny in recent years as pharmacological tools for cancer immunotherapy. Conceptually, the clinical effectiveness of this form of active immunotherapy relies on the completion of three critical steps: 1) the DCs used as immunotherapeutic vehicles must properly activate the antitumor immune effector cells of the host, 2) these immune effector cells must be receptive to stimulation by the DCs and be competent to mediate their antitumor effects, which 3) requires overcoming the various immune-inhibitory mechanisms used by the tumor cells. In this review, following a brief overview of the pivotal milestones in the history of cancer immunotherapy, we will introduce the reader to the basic immunobiological and pharmacological principles of active cancer immunotherapy using DCs. We will then discuss how current research is trying to define the optimal parameters for each of the above steps to realize the full clinical potential of DC therapeutics. Given its high suitability for immune interventions, acute myeloid leukemia was chosen here to showcase the latest research trends driving the field of DC-based cancer immunotherapy. PMID- 26240219 TI - Let It Be Hard. PMID- 26240220 TI - Treatment of Recurrent Endometrial Carcinoma: Progress Toward a More Personalized Approach. PMID- 26240222 TI - Reply to G. Bogani et al. PMID- 26240221 TI - Risk Factors for Melanoma Among Survivors of Non-Hodgkin Lymphoma. AB - PURPOSE: Previous studies have reported that survivors of non-Hodgkin lymphoma (NHL) have an increased risk of developing cutaneous melanoma; however, risks associated with specific treatments and immune-related risk factors have not been quantified. PATIENTS AND METHODS: We evaluated second melanoma risk among 44,870 1-year survivors of first primary NHL diagnosed at age 66 to 83 years from 1992 to 2009 and included in the Surveillance, Epidemiology, and End Results-Medicare database. Information on NHL treatments, autoimmune diseases, and infections was derived from Medicare claims. RESULTS: A total of 202 second melanoma cases occurred among survivors of NHL, including 91 after chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 111 after other NHL subtypes (cumulative incidence by age 85 years: CLL/SLL, 1.37%; other NHL subtypes, 0.78%). Melanoma risk after CLL/SLL was significantly increased among patients who received infused fludarabine-containing chemotherapy with or without rituximab (n=18: hazard ratio [HR], 1.92; 95% CI, 1.09 to 3.40; n=10: HR, 2.92; 95% CI, 1.42 to 6.01, respectively). Significantly elevated risks also were associated with T-cell activating autoimmune diseases diagnosed before CLL/SLL (n=36: HR, 2.27; 95% CI, 1.34 to 3.84) or after CLL/SLL (n=49: HR, 2.92; 95% CI, 1.66 to 5.12). In contrast, among patients with other NHL subtypes, melanoma risk was not associated with specific treatments or with T-cell/B-cell immune conditions. Generally, infections were not associated with melanoma risk, except for urinary tract infections (CLL/SLL), localized scleroderma, pneumonia, and gastrohepatic infections (other NHLs). CONCLUSION: Our findings suggest immune perturbation may contribute to the development of melanoma after CLL/SLL. Increased vigilance is warranted among survivors of NHL to maximize opportunities for early detection of melanoma. PMID- 26240223 TI - Reply to Z. Li et al. PMID- 26240224 TI - Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. AB - PURPOSE: The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify patients with MM. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM). PATIENTS AND METHODS: Clinical and laboratory data from 4,445 patients with NDMM enrolled onto 11 international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival. RESULTS: ISS, CA, and LDH data were simultaneously available in 3,060 of 4,445 patients. We defined the following three groups: revised ISS (R-ISS) I (n = 871), including ISS stage I (serum beta2-microglobulin level < 3.5 mg/L and serum albumin level >= 3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (less than the upper limit of normal range); R-ISS III (n = 295), including ISS stage III (serum beta2-microglobulin level > 5.5 mg/L) and high-risk CA or high LDH level; and R-ISS II (n = 1,894), including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS I, 62% in the R-ISS II, and 40% in the R-ISS III groups; the 5-year PFS rates were 55%, 36%, and 24%, respectively. CONCLUSION: The R-ISS is a simple and powerful prognostic staging system, and we recommend its use in future clinical studies to stratify patients with NDMM effectively with respect to the relative risk to their survival. PMID- 26240225 TI - Germ Cell Cancer and Multiple Relapses: Toxicity and Survival. AB - PURPOSE: A small number of patients with germ cell cancer (GCC) receive more than one line of treatment for disseminated disease. The purpose of this study was to evaluate late toxicity and survival in an unselected cohort of patients who experienced relapse after receiving first-line treatment for disseminated disease. METHODS: From the Danish Testicular Cancer database, we identified all patients who received more than one line of treatment for disseminated disease. Information about late toxicity and mortality was obtained by means of linkage to national registers. Prognostic factors for relapse and death were identified and compared with the International Prognostic Factors Study Group (IPFSG) classification. RESULTS: In total, 268 patients received more than one line of treatment for disseminated GCC. Approximately half of patients (n=136) died as a result of GCC. The 132 remaining patients, compared with patients treated with only orchiectomy, had an increased risk for a second cancer (hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.5), major cardiovascular disease (HR, 1.9; 95% CI, 1.0 to 3.3), pulmonary disease (HR, 2.0; 95% CI, 1.0 to 3.8), GI disease (HR, 7.3; 95% CI, 3.6 to 14.8), renal impairment (HR, 8.3; 95% CI, 3.0 to 23.2), neurologic disorders (HR, 6.3; 95% CI, 3.1 to 12.6), and death as a result of other causes (HR, 2.6; 95% CI, 1.6 to 4.2). In large part, the IPFSG classification was confirmed in our population; however, we could not confirm the primary site and the level of human chorionic gonadotropin as independent factors. We identified increasing age as a possible new prognostic factor for treatment failure after second-line treatment (HR, 1.2 per 10 years; 95% CI, 1.2 to 15). CONCLUSION: Patients with GCC who survive after more than one line of treatment for disseminated disease have a highly increased risk of late toxicity and death as a result of causes other than GCC. Therefore, they should be candidates for life long follow-up. The IPFSG classification was confirmed in this unselected population. PMID- 26240228 TI - Is C-Reactive Protein a Specific Marker in Melanoma? PMID- 26240227 TI - Prediction of Allogeneic Hematopoietic Stem-Cell Transplantation Mortality 100 Days After Transplantation Using a Machine Learning Algorithm: A European Group for Blood and Marrow Transplantation Acute Leukemia Working Party Retrospective Data Mining Study. AB - PURPOSE: Allogeneic hematopoietic stem-cell transplantation (HSCT) is potentially curative for acute leukemia (AL), but carries considerable risk. Machine learning algorithms, which are part of the data mining (DM) approach, may serve for transplantation-related mortality risk prediction. PATIENTS AND METHODS: This work is a retrospective DM study on a cohort of 28,236 adult HSCT recipients from the AL registry of the European Group for Blood and Marrow Transplantation. The primary objective was prediction of overall mortality (OM) at 100 days after HSCT. Secondary objectives were estimation of nonrelapse mortality, leukemia-free survival, and overall survival at 2 years. Donor, recipient, and procedural characteristics were analyzed. The alternating decision tree machine learning algorithm was applied for model development on 70% of the data set and validated on the remaining data. RESULTS: OM prevalence at day 100 was 13.9% (n=3,936). Of the 20 variables considered, 10 were selected by the model for OM prediction, and several interactions were discovered. By using a logistic transformation function, the crude score was transformed into individual probabilities for 100 day OM (range, 3% to 68%). The model's discrimination for the primary objective performed better than the European Group for Blood and Marrow Transplantation score (area under the receiver operating characteristics curve, 0.701 v 0.646; P<.001). Calibration was excellent. Scores assigned were also predictive of secondary objectives. CONCLUSION: The alternating decision tree model provides a robust tool for risk evaluation of patients with AL before HSCT, and is available online (http://bioinfo.lnx.biu.ac.il/~bondi/web1.html). It is presented as a continuous probabilistic score for the prediction of day 100 OM, extending prediction to 2 years. The DM method has proved useful for clinical prediction in HSCT. PMID- 26240226 TI - Cardiovascular Disease Mortality After Chemotherapy or Surgery for Testicular Nonseminoma: A Population-Based Study. AB - PURPOSE: Increased risks of incident cardiovascular disease (CVD) in patients with testicular cancer (TC) given chemotherapy in European studies were largely restricted to long-term survivors and included patients from the 1960s. Few population-based investigations have quantified CVD mortality during, shortly after, and for two decades after TC diagnosis in the era of cisplatin-based chemotherapy. PATIENTS AND METHODS: Standardized mortality ratios (SMRs) for CVD and absolute excess risks (AERs; number of excess deaths per 10,000 person-years) were calculated for 15,006 patients with testicular nonseminoma reported to the population-based Surveillance, Epidemiology, and End Results program (1980 to 2010) who initially received chemotherapy (n=6,909) or surgery (n=8,097) without radiotherapy and accrued 60,065 and 81,227 person-years of follow-up, respectively. Multivariable modeling evaluated effects of age, treatment, extent of disease, and other factors on CVD mortality. RESULTS: Significantly increased CVD mortality occurred after chemotherapy (SMR, 1.36; 95% CI, 1.03 to 1.78; n=54) but not surgery (SMR, 0.81; 95% CI, 0.60 to 1.07; n=50). Significant excess deaths after chemotherapy were restricted to the first year after TC diagnosis (SMR, 5.31; AER, 13.90; n=11) and included cerebrovascular disease (SMR, 21.72; AER, 7.43; n=5) and heart disease (SMR, 3.45; AER, 6.64; n=6). In multivariable analyses, increased CVD mortality after chemotherapy was confined to the first year after TC diagnosis (hazard ratio, 4.86; 95% CI, 1.25 to 32.08); distant disease (P<.05) and older age at diagnosis (P<.01) were independent risk factors. CONCLUSION: This is the first population-based study, to our knowledge, to quantify short- and long-term CVD mortality after TC diagnosis. The increased short-term risk of CVD deaths should be further explored in analytic studies that enumerate incident events and can serve to develop comprehensive evidence-based approaches for risk stratification and application of preventive and interventional efforts. PMID- 26240229 TI - Limited Resection Versus Lobectomy for Older Patients With Early-Stage Lung Cancer: Impact of Histology. AB - PURPOSE: Limited resection has been increasingly used in older patients with stage IA lung cancer. However, the equivalency of limited resection versus lobectomy according to histology is unknown. METHODS: We identified patients older than 65 years with stage IA invasive adenocarcinoma or squamous cell carcinoma <= 2 cm who were treated with limited resection (wedge or segmentectomy) or lobectomy in the Surveillance, Epidemiology, and End Results Medicare database. We estimated propensity scores that predicted the use of limited resection and compared survival of patients treated with limited resection versus lobectomy. Treatments were considered equivalent if the upper 95th percentile of the hazard ratio (HR) for limited resection was <= 1.25. RESULTS: Overall, 27% of 2,008 patients with adenocarcinoma and 32% of 1,139 patients with squamous cell carcinoma underwent limited resection. Survival analyses, adjusted for propensity score by using inverse probability weighting, showed that limited resection was not equivalent to lobectomy in patients with adenocarcinoma (HR, 1.21; upper 95% CI,1.34) or squamous cell carcinoma (HR, 1.21; upper 95% CI, 1.39). Although patients with adenocarcinomas treated with segmentectomy had equivalent survival rates to those treated with lobectomy (HR, 0.97; upper 95% CI, 1.07), outcomes of those treated with wedge resection (HR, 1.29; upper 95% CI, 1.42) did not. Among patients with squamous cell carcinoma, neither wedge resection (HR, 1.34; upper 95% CI, 1.53) nor segmentectomy (HR, 1.19; upper 95% CI, 1.36) were equivalent to lobectomy. CONCLUSION: We found generally that limited resection is not equivalent to lobectomy in older patients with invasive non-small-cell lung cancer <= 2 cm in size, although segmentectomy may be equivalent in patients with adenocarcinoma. PMID- 26240230 TI - Quality of Life and Cost-Effectiveness Assessment of Radioiodine Ablation Strategies in Patients With Thyroid Cancer: Results From the Randomized Phase III ESTIMABL Trial. AB - PURPOSE: In the ESTIMABL phase III trial, the thyroid ablation rate was equivalent for the two thyroid-stimulating hormone (TSH) stimulation methods (thyroid hormone withdrawal [THW] and recombinant human TSH [rhTSH]) and the two iodine-131 ((131)I) activities (1.1 or 3.7 GBq). The objectives of this article were to present health-related quality-of-life (HRQoL) results and a cost effectiveness evaluation performed alongside this trial. PATIENTS AND METHODS: HRQoL and utility were longitudinally assessed, from random assignment to the follow-up visit at 8 +/- 2 months for the 752 patients with thyroid cancer, using the Short Form-36 and the EuroQoL-5D questionnaires, respectively. A cost effectiveness analysis was performed from the societal perspective in the French context. Resource use (hospitalization for (131)I administration, rhTSH, sick leaves, and transportation) was collected prospectively. We used the net monetary benefit approach and computed cost-effectiveness acceptability curves for both TSH stimulation methods and (131)I activities. Sensitivity analyses of the costs of rhTSH were performed. RESULTS: At (131)I administration, THW caused a clinically significant deterioration of HRQoL, whereas HRQoL remained stable with rhTSH. This deterioration was transient with no difference 3 months later. rhTSH was more effective than THW in terms of quality-adjusted life-years (QALYs; +0.013 QALY/patient) but more expensive (+?474/patient). The probability that rhTSH would be cost effective at a ?50,000/QALY threshold was 47% in France. The use of 1.1 GBq of (131)I instead of 3.7 GBq reduced per-patient costs by ?955 (US$1,018) but with slightly decreased efficacy (-0.007 QALY/patient). CONCLUSION: rhTSH avoids the transient THW-induced deterioration of HRQoL but is unlikely to be cost effective at its current price. PMID- 26240232 TI - Pieces of Grief. PMID- 26240231 TI - Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies. AB - PURPOSE: To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers). PATIENTS AND METHODS: Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays. RESULTS: The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B cell-like DLBCL (log-rank P < .001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC positive/BCL2-positive subgroup (log-rank P < .001 for time to progression). CONCLUSION: Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression. PMID- 26240234 TI - Utah Roots ... and Herbs. PMID- 26240233 TI - Use and Effectiveness of Intraperitoneal Chemotherapy for Treatment of Ovarian Cancer. AB - PURPOSE: A 2006 randomized trial demonstrated a 16-month survival benefit with intraperitoneal and intravenous (IP/IV) chemotherapy administered to patients who had ovarian cancer, compared with IV chemotherapy alone, but more treatment related toxicities. The objective of this study was to examine the use and effectiveness of IP/IV chemotherapy in clinical practice. PATIENTS AND METHODS: Prospective cohort study of 823 women with stage III, optimally cytoreduced ovarian cancer diagnosed at six National Comprehensive Cancer Network institutions. We examined IP/IV chemotherapy use in all patients diagnosed between 2003 and 2012 (N = 823), and overall survival and treatment-related toxicities with Cox regression and logistic regression, respectively, in a propensity score-matched sample (n = 402) of patients diagnosed from 2006 to 2012, excluding trial participants, to minimize selection bias. RESULTS: Use of IP/IV chemotherapy increased from 0% to 33% between 2003 and 2006, increased to 50% from 2007 to 2008, and plateaued thereafter. Between 2006 and 2012, adoption of IP/IV chemotherapy varied by institution from 4% to 67% (P < .001) and 43% of patients received modified IP/IV regimens at treatment initiation. In the propensity score-matched sample, IP/IV chemotherapy was associated with significantly improved overall survival (3-year overall survival, 81% v 71%; hazard ratio, 0.68; 95% CI, 0.47 to 0.99), compared with IV chemotherapy, but also more frequent alterations in chemotherapy delivery route (adjusted rates discontinuation or change, 20.4% v 10.0%; adjusted odds ratio, 2.83; 95% CI, 1.47 to 5.47). CONCLUSION: Although the use of IP/IV chemotherapy increased significantly at National Comprehensive Cancer Network centers between 2003 and 2012, fewer than 50% of eligible patients received it. Increasing IP/IV chemotherapy use in clinical practice may be an important and underused strategy to improve ovarian cancer outcomes. PMID- 26240235 TI - Long-Term Course of Patients With Stage IA Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the German Hodgkin Study Group. AB - PURPOSE: The optimal treatment of stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined. Thus, we performed an analysis using the database of the German Hodgkin Study Group. PATIENTS AND METHODS: The long-term outcome of 256 patients with stage IA NLPHL was evaluated. Patients had received combined-modality treatment (CMT; n = 72), extended-field radiotherapy (EF-RT; n = 49), involved-field radiotherapy (IF-RT; n = 108), or four weekly standard doses of rituximab (n = 27) within German Hodgkin Study Group clinical trial protocols between 1988 and 2009. RESULTS: The median age at NLPHL diagnosis was 39 years (range, 16 to 75 years). Most patients were male (76%). The whole patient group had a median follow-up of 91 months (CMT: 95 months; EF-RT: 110 months; IF-RT: 87 months; rituximab: 49 months). At 8 years, progression-free survival and overall survival rates were 88.5% and 98.6% for CMT, 84.3% and 95.7% for EF-RT, and 91.9% and 99.0% for IF-RT, respectively. Patients treated with rituximab had 4-year progression-free and overall survival rates of 81.0% and 100%, respectively. A second malignancy during the course of follow-up was diagnosed in 17 (6.6%) of 256 patients. A total of 12 deaths occurred. However, only one patient died from NLPHL. CONCLUSION: Tumor control in this analysis was equivalent with CMT, EF-RT, and IF-RT. Therefore, IF-RT, which is associated with the lowest risk for the development of toxic effects, should be considered as standard of care for patients with stage IA NLPHL. Rituximab alone is associated with an increased risk of relapse in this patient population. PMID- 26240236 TI - Is young fatherhood causally related to midlife mortality? A sibling fixed-effect study in Finland. AB - BACKGROUND: Previous studies have shown that young fatherhood is associated with higher later-life mortality. It is unclear whether the association is credible, in the sense that mortality and young fatherhood appear to be associated because both are determined by family-related environmental, socioeconomic and genetic characteristics. METHODS: We used a household-based 10% sample drawn from the 1950 Finnish census to estimate all-cause mortality of fathers born during 1940 1950. The fathers were followed from age 45 until death, or the end of age 54. We used a standard Cox model and a sibling fixed-effects Cox model to examine whether the effect of young fatherhood was independent of observed adulthood characteristics and unobserved early-life characteristics shared by brothers. RESULTS: Men who had their first child before the age of 22 or at ages 22-24 had higher mortality as compared with their brothers who had their first child at the median or mean age of 25-26. Men who had their first child later at ages 30-44 had lower mortality than their brothers who had a first child before the age of 25. The pattern of results from a standard model was similar to that obtained from a fixed-effects sibling model. CONCLUSIONS: The findings suggest a causal effect of young fatherhood on mortality and highlight the need to support young fathers in their family life to improve health behaviours and health. PMID- 26240237 TI - Hospital costs and quality. PMID- 26240238 TI - Civil unrest, police use of force, and the public's health. PMID- 26240239 TI - Ambulance diversion associated with reduced access to cardiac technology and increased one-year mortality. AB - Ambulance diversion, which occurs when a hospital emergency department (ED) is temporarily closed to incoming ambulance traffic, is an important system-level interruption that causes delays in treatment and potentially lower quality of care. There is little empirical evidence investigating the mechanisms through which ambulance diversion might affect patient outcomes. We investigated whether ambulance diversion affects access to technology, likelihood of treatment, and ultimately health outcomes for Medicare patients with acute myocardial infarction in twenty-six California counties. We found that patients whose nearest hospital ED had significant ambulance diversions experienced reduced access to hospitals with cardiac technology. This led to a 4.6 percent decreased likelihood of revascularization and a 9.8 percent increase in one-year mortality compared to patients who did not experience diversion. Policy makers may wish to consider creating a policy to specifically manage certain time-sensitive conditions that require technological intervention during periods of ambulance diversion. PMID- 26240240 TI - Assessing Medicare's hospital pay-for-performance programs and whether they are achieving their goals. AB - Three separate pay-for-performance programs affect the amount of Medicare payment for inpatient services to about 3,400 US hospitals. These payments are based on hospital performance on specified measures of quality of care. A growing share of Medicare hospital payments (6 percent by 2017) are dependent upon how hospitals perform under the Hospital Readmissions Reduction Program, the Value-Based Purchasing Program, and the Hospital-Acquired Condition Reduction Program. In 2015 four of five hospitals subject to these programs will be penalized under one or more of them, and more than one in three major teaching hospitals will be penalized under all three. Interactions among these programs should be considered going forward, including overlap among measures and differences in scoring performance. PMID- 26240241 TI - Why Medicare Advantage Plans Pay hospitals traditional Medicare prices. AB - The policy community generally has assumed Medicare Advantage (MA) plans negotiate hospital payment rates similar to those for commercial insurance products and well above those in traditional Medicare. After surveying senior hospital and health plan executives, we found, however, that MA plans nominally pay only 100-105 percent of traditional Medicare rates and, in real economic terms, possibly less. Respondents broadly identified three primary reasons for near-payment equivalence: statutory and regulatory provisions that limit out-of network payments to traditional Medicare rates, de facto budget constraints that MA plans face because of the need to compete with traditional Medicare and other MA plans, and a market equilibrium that permits relatively lower MA rates as long as commercial rates remain well above the traditional Medicare rates. We explored a number of policy implications not only for the MA program but also for the problem of high and variable hospital prices in commercial insurance markets. PMID- 26240242 TI - In California, not-for-profit hospitals spent more operating expenses on charity care than for-profit hospitals spent. AB - In exchange for sizable tax exemptions, not-for-profit hospitals must engage in activities that meet the Internal Revenue Service's community benefit standard. The provision of charity care-free care to those unable to pay-can help meet that standard. Bad debt, the other form of uncompensated care, cannot be used to meet the standard, although Medicaid shortfalls can. However, the ACA lacks guidelines for providing charity care, and federal law sets no minimum requirements for community benefit activities. Using data from California, we examined whether the levels of charity and uncompensated care provided differed across general acute care hospitals by profit status and other characteristics during 2011-13. The mean proportion of total operating expenses spent on charity care differed significantly between not-for-profit (1.9 percent) and for-profit hospitals (1.4 percent), in contrast to the mean proportion spent on uncompensated care. Both types of spending varied widely across hospitals. Policy makers should consider measures that remove disincentives to meeting the persistent considerable need for charity care-for example, increasing supports to offset rising Medicaid shortfalls resulting from program expansion-and facilitate the tracking of ACA impacts on the distribution of charity care and uncompensated care delivery. PMID- 26240243 TI - Hospital board and management practices are strongly related to hospital performance on clinical quality metrics. AB - National policies to improve health care quality have largely focused on clinical provider outcomes and, more recently, payment reform. Yet the association between hospital leadership and quality, although crucial to driving quality improvement, has not been explored in depth. We collected data from surveys of nationally representative groups of hospitals in the United States and England to examine the relationships among hospital boards, management practices of front-line managers, and the quality of care delivered. First, we found that hospitals with more effective management practices provided higher-quality care. Second, higher rated hospital boards had superior performance by hospital management staff. Finally, we identified two signatures of high-performing hospital boards and management practice. Hospitals with boards that paid greater attention to clinical quality had management that better monitored quality performance. Similarly, we found that hospitals with boards that used clinical quality metrics more effectively had higher performance by hospital management staff on target setting and operations. These findings help increase understanding of the dynamics among boards, front-line management, and quality of care and could provide new targets for improving care delivery. PMID- 26240244 TI - For many patients who use large amounts of health care services, the need is intense yet temporary. AB - Patients who accumulate multiple emergency department visits and hospital admissions, known as super-utilizers, have become the focus of policy initiatives aimed at preventing such costly use of the health care system through less expensive community- and primary care-based interventions. We conducted cross sectional and longitudinal analyses of 4,774 publicly insured or uninsured super utilizers in an urban safety-net integrated delivery system for the period May 1, 2011-April 30, 2013. Our analysis found that consistently 3 percent of adult patients met super-utilizer criteria and accounted for 30 percent of adult charges. Fewer than half of super-utilizers identified as such on May 1, 2011, remained in the category seven months later, and only 28 percent remained at the end of a year. This finding has important implications for program design and for policy makers because previous studies may have obscured this instability at the individual level. Our study also identified clinically relevant subgroups amenable to different interventions, along with their per capita utilization and costs before and after being identified as super-utilizers. Future solutions include improving predictive modeling to identify individuals likely to experience sustained levels of avoidable utilization, better classifying subgroups for whom interventions are needed, and implementing stronger program evaluation designs. PMID- 26240245 TI - Prevalence trends for three common medical conditions: treated and untreated. AB - Studies that use the number of individuals treated for a medical condition to investigate its prevalence understate true prevalence and obscure prevalence trends. For example, treated diabetes prevalence was less than half of true prevalence in 1999-2000. Over the ensuing twelve years, the rate of increase in treated prevalence was more than 50 percent higher than that of true prevalence. PMID- 26240246 TI - Waiving the three-day rule: admissions and length-of-stay at hospitals and skilled nursing facilities did not increase. AB - The traditional Medicare program requires an enrollee to have a hospital stay of at least three consecutive calendar days to qualify for coverage of subsequent postacute care in a skilled nursing facility. This long-standing policy, implemented to discourage premature discharges from hospitals, might now be inappropriately lengthening hospital stays for patients who could be transferred sooner. To assess the implications of eliminating the three-day qualifying stay requirement, we compared hospital and postacute skilled nursing facility utilization among Medicare Advantage enrollees in matched plans that did or did not eliminate that requirement in 2006-10. Among hospitalized enrollees with a skilled nursing facility admission, the mean hospital length-of-stay declined from 6.9 days to 6.7 days for those no longer subject to the qualifying stay but increased from 6.1 to 6.6 days among those still subject to it, for a net decline of 0.7 day when the three-day stay requirement was eliminated. The elimination was not associated with more hospital or skilled nursing facility admissions or with longer lengths-of-stay in a skilled nursing facility. These findings suggest that eliminating the three-day stay requirement conferred savings on Medicare Advantage plans and that study of the requirement in traditional Medicare plans is warranted. PMID- 26240247 TI - Federal parity law associated with increased probability of using out-of-network substance use disorder treatment services. AB - The Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 requires commercial insurers providing group coverage for substance use disorder services to offer benefits for those services at a level equal to those for medical or surgical benefits. Unlike previous parity policies instituted for federal employees and in individual states, the law extends parity to out-of-network services. We conducted an interrupted time-series analysis using insurance claims from large self-insured employers to evaluate whether federal parity was associated with changes in out-of-network treatment for 525,620 users of substance use disorder services. Federal parity was associated with an increased probability of using out-of-network services, an increased average number of out-of-network outpatient visits, and increased average total spending on out-of-network services among users of those services. Our findings were broadly consistent with the contention of federal parity proponents that extending parity to out-of-network services would broaden access to substance use disorder care obtained outside of plan networks. PMID- 26240248 TI - Coverage and care consequences for families in which children have mixed eligibility for public insurance. AB - Public health insurance for low-income children in the United States is primarily available through Medicaid and the Children's Health Insurance Program (CHIP). Mixed eligibility occurs when there is a mix of either "Medicaid- and CHIP eligible" children or a mix of "eligible (for public insurance) and ineligible (for public insurance)" children in the family. We used data from the Medical Expenditure Panel Survey (MEPS) Household Component for 2001-12 to examine insurance coverage, access to care, and health care use for eligible children in families with mixed-eligible siblings compared to those in families where all siblings were eligible for one program. We found that mixed eligibility has a significant dampening effect for eligible children in families with a mix of eligible and ineligible siblings. These children were more likely to be uninsured and less likely to have a usual source of care, less likely to have any preventive dental or well-child visits during the year, and less likely to fully adhere to recommended preventive dental and well-child visits than eligible children with all-Medicaid- or all-CHIP-eligible siblings. We found no significant impact for eligible children living in Medicaid-CHIP-mixed families. PMID- 26240249 TI - Medicaid dental coverage alone may not lower rates of dental emergency department visits. AB - Medicaid was expanded to millions of individuals under the Affordable Care Act, but many states do not provide dental coverage for adults under their Medicaid programs. In the absence of dental coverage, patients may resort to costly emergency department (ED) visits for dental conditions. Medicaid coverage of dental benefits could help ease the burden on the ED, but ED use for dental conditions might remain a problem in areas with a scarcity of dentists. We examined county-level rates of ED visits for nontraumatic dental conditions in twenty-nine states in 2010 in relation to dental provider density and Medicaid coverage of nonemergency dental services. Higher density of dental providers was associated with lower rates of dental ED visits by patients with Medicaid in rural counties but not in urban counties, where most dental ED visits occurred. County-level Medicaid-funded dental ED visit rates were lower in states where Medicaid covered nonemergency dental services than in other states, although this difference was not significant after other factors were adjusted for. Providing dental coverage alone might not reduce Medicaid-funded dental ED visits if patients do not have access to dental providers. PMID- 26240250 TI - States with stronger health insurance rate review authority experienced lower premiums in the individual market in 2010-13. AB - States have varying degrees of review authority over health insurance carriers' rates, including prior approval authority over proposed rates and requirements for loss ratios, the proportion of premium revenues spent on medical claims. The Affordable Care Act (ACA) requires carriers in certain categories of health insurance to provide public justification for rate increases of 10 percent or more. We collected data on how states changed their rate review authority and requirements during 2010-13, the years immediately after enactment of the ACA, and we combined these data with carrier filings. We found that adjusted premiums in the individual market in states that had prior-approval authority combined with loss ratio requirements were lower in 2010-13 ($3,489) than premiums in states with no rate review authority or that had only file-and-use regulations, which gave the states no authority to block rate increases ($3,617). Adjusted premiums declined modestly in prior-approval states with loss ratio requirements, from $3,526 in 2010 to $3,452 in 2013, while premiums increased from $3,422 to $3,683 in states with no rate review authority or file-and-use regulations only. Our findings suggest that states with prior approval authority and loss ratio requirements constrained health insurance premium increases. PMID- 26240251 TI - The economic downturn and its lingering effects reduced medicare spending growth by $4 billion in 2009-12. AB - Previous work has found a strong connection between the most recent economic recession and reductions in private health spending. However, the effect of economic downturns on Medicare spending is less clear. In contrast to studies involving earlier time periods, our study found that when the macroeconomy slowed during the Great Recession of 2007-09, so did Medicare spending growth. A small (14 percent) but significant share of the decline in Medicare spending growth from 2009 to 2012 relative to growth from 2004 to 2009 can be attributed to lingering effects of the recession. Absent the economic downturn, Medicare spending would have been $4 billion higher in 2009-12. A major reason for the relatively small impact of the macroeconomy is the relative lack of labor-force participation among people ages sixty-five and older. We estimate that if they had been working at the same rate as the nonelderly before the recession, the effect of the downturn on Medicare spending growth would have been twice as large. PMID- 26240252 TI - Private payers disagree with Medicare over medical device coverage about half the time. AB - There are multiple payers in the US health care system, each making its own coverage determinations for medical technologies. For each of the forty-seven medical devices considered in national coverage determinations (NCDs) of the Centers for Medicare and Medicaid Services (CMS) issued between February 1999 and August 2013, we compared CMS's coverage policy with the policies issued by the largest sixteen private payers that made their decisions publicly available. Overall, we found that NCDs were equivalent to the corresponding private payer policies roughly half of the time, more restrictive approximately a quarter of the time, and less restrictive about a quarter of the time. Our findings indicate that patients may have variable access to medical technology across Medicare and private plans. They also suggest that private plans do not necessarily follow CMS's lead in making coverage decisions. PMID- 26240253 TI - Some state vaccination laws contribute to greater exemption rates and disease outbreaks in the United States. AB - Health officials attest that immunizations are among the most successful interventions in public health. However, there remains a substantial unvaccinated population in the United States. We analyzed how state-level vaccination exemption laws affect immunization rates and the incidence of preventable disease. We measured the association between each component of state kindergarten vaccination exemption laws and state vaccination exemption rates from 2002 to 2012, using the Centers for Disease Control and Prevention's annual school assessment reports. We found that policies such as requiring health department approval of nonmedical exemptions, requiring a physician to sign an exemption application, and having criminal or civil punishments for noncompliance with immunization requirements had a significant effect in reducing vaccine exemptions. Our exemption law effectiveness index identified eighteen states with the most effective laws and nine states with the least effective ones. The most effective states had lower incidences of pertussis, compared to other states. For policy makers interested in decreasing the number of vaccine exemptions in their state, our findings are of particular interest. PMID- 26240254 TI - Intended and unintended consequences of China's zero markup drug policy. AB - Since economic liberalization in the late 1970s, China's health care providers have grown heavily reliant on revenue from drugs, which they both prescribe and sell. To curb abuse and to promote the availability, safety, and appropriate use of essential drugs, China introduced its national essential drug list in 2009 and implemented a zero markup policy designed to decouple provider compensation from drug prescription and sales. We collected and analyzed representative data from China's township health centers and their catchment-area populations both before and after the reform. We found large reductions in drug revenue, as intended by policy makers. However, we also found a doubling of inpatient care that appeared to be driven by supply, instead of demand. Thus, the reform had an important unintended consequence: China's health care providers have sought new, potentially inappropriate, forms of revenue. PMID- 26240255 TI - A failing heart and the downside of life-prolonging technology. AB - For a man with end-stage heart failure, a left ventricular assist device prolongs life but brings dire complications. PMID- 26240258 TI - Buprenorphine waivers for physicians. PMID- 26240259 TI - Buprenorphine waivers: the authors reply. PMID- 26240260 TI - Potentially avoidable hospitalizations in France. PMID- 26240261 TI - Avoidable hospitalizations: the authors reply. PMID- 26240263 TI - Is Cholesteryl Ester Transfer Protein Inhibition an Effective Strategy to Reduce Cardiovascular Risk? CETP Inhibition as a Strategy to Reduce Cardiovascular Risk: The Pro Case. PMID- 26240262 TI - Distinctive Clinical Profile of Blacks Versus Whites Presenting With Sudden Cardiac Arrest. AB - BACKGROUND: Sudden cardiac arrest (SCA) is a major contributor to mortality, but data are limited among nonwhites. Identification of differences in clinical profile based on race may provide opportunities for improved SCA prevention. METHODS AND RESULTS: In the ongoing Oregon Sudden Unexpected Death Study (SUDS), individuals experiencing SCA in the Portland, OR, metropolitan area were identified prospectively. Patient demographics, arrest circumstances, and pre-SCA clinical profile were compared by race among cases from 2002 to 2012 (for clinical history, n=126 blacks, n=1262 whites). Incidence rates were calculated for cases from the burden assessment phase (2002-2005; n=1077). Age-adjusted rates were 2-fold higher among black men and women (175 and 90 per 100 000, respectively) compared with white men and women (84 and 40 per 100 000, respectively). Compared with whites, blacks were >6 years younger at the time of SCA and had a higher prearrest prevalence of diabetes mellitus (52% versus 33%; P<0.0001), hypertension (77% versus 65%; P=0.006), and chronic renal insufficiency (34% versus 19%; P<0.0001). There were no racial differences in previously documented coronary artery disease or left ventricular dysfunction, but blacks had more prevalent congestive heart failure (43% versus 34%; P=0.04) and left ventricular hypertrophy (77% versus 58%; P=0.02) and a longer QTc interval (466+/-36 versus 453+/-41 milliseconds; P=0.03). CONCLUSIONS: In this US community, the burden of SCA was significantly higher in blacks compared with whites. Blacks with SCA had a higher prearrest prevalence of risk factors beyond established coronary artery disease, providing potential targets for race specific prevention. PMID- 26240264 TI - Is Cholesteryl Ester Transfer Protein Inhibition an Effective Strategy to Reduce Cardiovascular Risk? CETP as a Target to Lower CVD Risk: Suspension of Disbelief? PMID- 26240265 TI - ECG Response: August 4, 2015. PMID- 26240266 TI - Three-Dimensional Rotational Angiography-Guided Stent Placement for Treatment of Acquired Supravalvar Aortic Stenosis. PMID- 26240267 TI - Diagnosis of Free-Wall Rupture by Left Ventricular Angiogram After Inferior ST Segment-Elevation Myocardial Infarction. PMID- 26240268 TI - Letter by Abbasi Regarding Article, "Comparison of Lifestyle-Based and Traditional Cardiovascular Disease Prediction in a Multiethnic Cohort of Nonsmoking Women". PMID- 26240269 TI - Letter by Khera et al Regarding Article, "Impact of Annual Operator and Institutional Volume on Percutaneous Coronary Intervention Outcomes: A 5-Year United States Experience (2005-2009)". PMID- 26240270 TI - Response to Letter Regarding Article "Impact of Annual Operator and Institutional Volume on Percutaneous Coronary Intervention Outcomes: A 5-Year United States Experience (2005-2009)". PMID- 26240271 TI - Social Determinants of Risk and Outcomes for Cardiovascular Disease: A Scientific Statement From the American Heart Association. PMID- 26240272 TI - Transcriptomic Profiling of Sequential Tumors from Breast Cancer Patients Provides a Global View of Metastatic Expression Changes Following Endocrine Therapy. AB - PURPOSE: Disease recurrence is a common problem in breast cancer and yet the mechanisms enabling tumor cells to evade therapy and colonize distant organs remain unclear. We sought to characterize global expression changes occurring with metastatic disease progression in the endocrine-resistant setting. EXPERIMENTAL DESIGN: Here, for the first time, RNAsequencing has been performed on matched primary, nodal, and liver metastatic tumors from tamoxifen-treated patients following disease progression. Expression of genes commonly elevated in the metastases of sequenced patients was subsequently examined in an extended matched patient cohort with metastatic disease from multiple sites. The impact of tamoxifen treatment on endocrine-resistant tumors in vivo was investigated in a xenograft model. RESULTS: The extent of patient heterogeneity at the gene level was striking. Less than 3% of the genes differentially expressed between sequential tumors were common to all patients. Larger divergence was observed between primary and liver tumors than between primary and nodal tumors, reflecting both the latency to disease progression and the genetic impact of intervening therapy. Furthermore, an endocrine-resistant in vivo mouse model demonstrated that tamoxifen treatment has the potential to drive disease progression and establish distant metastatic disease. Common functional pathways altered during metastatic, endocrine-resistant progression included extracellular matrix receptor interactions and focal adhesions. CONCLUSIONS: This novel global analysis highlights the influence of primary tumor biology in determining the transcriptomic profile of metastatic tumors, as well as the need for adaptations in cell-cell communications to facilitate successful tumor cell colonization of distant host organs. PMID- 26240273 TI - Preclinical Efficacy and Safety Assessment of an Antibody-Drug Conjugate Targeting the c-RET Proto-Oncogene for Breast Carcinoma. AB - PURPOSE: The RET proto-oncogene has been implicated in breast cancer, and the studies herein describe the preclinical and safety assessment of an anti-RET antibody-drug conjugate (ADC) being developed for the treatment of breast cancer. EXPERIMENTAL DESIGN: RET protein expression was analyzed in breast tumor samples using tissue microarrays. The fully human anti-RET antibody (Y078) was conjugated to the DM1 and DM4 derivatives of the potent cytotoxic agent maytansine using thioether and disulfide linkers, respectively. The resulting compounds, designated Y078-DM1 and Y078-DM4, were evaluated for antitumor activity using human breast cancer cell lines and established tumor xenograft models. A single dose, 28-day, safety study of Y078-DM1 was performed in cynomolgus monkeys. RESULTS: By immunohistochemistry, RET expression was detected in 57% of tumors (1,596 of 2,800 tumor sections) and was most common in HER2-positive and basal breast cancer subtypes. Potent in vitro cytotoxicity was achieved in human breast cancer cell lines that have expression levels comparable with those observed in breast cancer tissue samples. Dose-response studies in xenograft models demonstrated antitumor activity with both weekly and every-3-weeks dosing regimens. In cynomolgus monkeys, a single injection of Y078-DM1 demonstrated dose dependent, reversible drug-mediated alterations in blood chemistry with evidence of on-target neuropathy. CONCLUSIONS: RET is broadly expressed in breast cancer specimens and thus represents a potential therapeutic target; Y078-DM1 and Y078 DM4 demonstrated antitumor activity in preclinical models. Optimization of the dosing schedule or an alternate cytotoxic agent with a different mechanism of action may reduce the potential risk of neuropathy. Clin Cancer Res; 21(24); 5552 62. (c)2015 AACR. PMID- 26240274 TI - Glycogen Synthase Kinase 3 Beta Predicts Survival in Resected Adenocarcinoma of the Pancreas. AB - PURPOSE: GSK3beta is a protein kinase that can suppress a number of key oncoproteins. We have previously shown in preclinical models of pancreatic ductal adenocarcinoma (PDAC) that inhibition of GSK3beta causes stabilization and nuclear translocation of beta-catenin, poor differentiation, proliferation, and resistance to radiation. The objective of this study was to determine its utility as a biomarker of clinical outcomes. EXPERIMENTAL DESIGN: Automated Quantitative Immunofluorescence Analysis (AQUA) of GSK3beta was performed on a tissue microarray with samples from 163 patients treated on RTOG 9704. On the basis of findings in an exploratory cohort, GSK3beta was analyzed as a categorical variable using its upper quartile (>Q3) as a cut point. Overall survival (OS) and disease-free survival (DFS) were estimated with the Kaplan-Meier method, and GSK3beta groupings were compared using the log-rank test. Univariable and multivariable Cox proportional hazards models were used to determine associations between GSK3beta and OS/DFS. RESULTS: The 3-year OS rates for GSK3beta<=Q3 versus GSK3beta >Q3 were 16% (95% confidence intervals; CI, 10%-23%) and 30% (95% CI, 17%-44%), respectively, P = 0.0082. The 3-year DFS rates were 9% (95% CI, 5%-15%) and 20% (95% CI, 9%-33%) respectively, P value = 0.0081. On multivariable analysis, GSK3beta was a significant predictor of OS. Patients with GSK3beta >Q3 had a 46% reduced risk of dying of pancreatic cancer (HR, 0.54; 95% CI, 0.31 0.96, P value = 0.034). The HR for DFS was 0.65 (95% CI, 0.39-1.07; P value = 0.092). CONCLUSIONS: GSK3beta expression is a strong prognosticator in PDAC, independent of other known factors such as tumor (T) stage, nodal status, surgical margins and CA19-9. Clin Cancer Res; 21(24); 5612-8. (c)2015 AACR. PMID- 26240275 TI - Autocrine Signaling by Wnt-5a Deregulates Chemotaxis of Leukemic Cells and Predicts Clinical Outcome in Chronic Lymphocytic Leukemia. AB - PURPOSE: ROR1, a receptor in the noncanonical Wnt/planar cell polarity (PCP) pathway, is upregulated in malignant B cells of chronic lymphocytic leukemia (CLL) patients. It has been shown that the Wnt/PCP pathway drives pathogenesis of CLL, but which factors activate the ROR1 and PCP pathway in CLL cells remains unclear. EXPERIMENTAL DESIGN: B lymphocytes from the peripheral blood of CLL patients were negatively separated using RosetteSep (StemCell) and gradient density centrifugation. Relative expression of WNT5A, WNT5B, and ROR1 was assessed by quantitative real-time PCR. Protein levels, protein interaction, and downstream signaling were analyzed by immunoprecipitation and Western blotting. Migration capacity of primary CLL cells was analyzed by the Transwell migration assay. RESULTS: By analyzing the expression in 137 previously untreated CLL patients, we demonstrate that WNT5A and WNT5B genes show dramatically (five orders of magnitude) varying expression in CLL cells. High WNT5A and WNT5B expression strongly associates with unmutated IGHV and shortened time to first treatment. In addition, WNT5A levels associate, independent of IGHV status, with the clinically worst CLL subgroups characterized by dysfunctional p53 and mutated SF3B1. We provide functional evidence that WNT5A-positive primary CLL cells have increased motility and attenuated chemotaxis toward CXCL12 and CCL19 that can be overcome by inhibitors of Wnt/PCP signaling. CONCLUSIONS: These observations identify Wnt-5a as the crucial regulator of ROR1 activity in CLL and suggest that the autocrine Wnt-5a signaling pathway allows CLL cells to overcome natural microenvironmental regulation. PMID- 26240276 TI - HAGE in Triple-Negative Breast Cancer Is a Novel Prognostic, Predictive, and Actionable Biomarker: A Transcriptomic and Protein Expression Analysis. AB - PURPOSE: The expression of HAGE as a novel prognostic and predictive tool was assessed in 1,079 triple-negative breast cancers (TNBC). EXPERIMENTAL DESIGN: HAGE protein expression was investigated in an early primary TNBC (EP-TNBC; n = 520) cohort who received adjuvant chemotherapy (ACT) and in a locally advanced primary TNBC cohort who received anthracycline combination Neo-ACT (n = 110; AC Neo-ACT). HAGE-mRNA expression was evaluated in the METABRIC-TNBC cohort (n = 311) who received ACT and in a cohort of patients with TNBC who received doxorubicin/cyclophosphamide Neo-ACT, followed by 1:1 randomization to ixabepilone (n = 68) or paclitaxel (n = 64) as part of a phase II clinical trial. Furthermore, a cohort of 128 tumors with integrated HAGE gene copy number changes, mRNA, and protein levels were analyzed. RESULTS: In patients with EP TNBC, who were chemotherapy-naive, high HAGE protein expression (HAGE(+)) was associated with a higher risk of death [HR, 1.3; 95% confidence interval (CI), 1.2-1.5; P = 0.000005] when compared with HAGE(-) cases. Patients who received ACT and expressed mRNA-HAGE(+) were at a lower risk of death than those who were mRNA-HAGE(-) (P = 0.004). The expression of HAGE was linked to the presence of tumor-infiltrating lymphocytes (TIL), and both features were found to be independent predictors for pathologic complete response (pCR, P < 0.001) and associated with prolonged survival (P < 0.01), following AC-Neo-ACT. In patients with residual disease, HAGE(+) had a 2-fold death risk increase (P = 0.018) compared with HAGE(-). CONCLUSIONS: HAGE expression is a potential prognostic marker and a predictor of response to anthracycline treatment in TNBC. A prospective clinical trial to examine the therapeutic value of HAGE for TNBC cases is warranted. PMID- 26240277 TI - Correction for Malik-Soni and Frappier, Proteomic Profiling of EBNA1-Host Protein Interactions in Latent and Lytic Epstein-Barr Virus Infections. PMID- 26240279 TI - Immunosuppression-Independent Role of Regulatory T Cells against Hypertension Driven Renal Dysfunctions. AB - Hypertension-associated cardiorenal diseases represent one of the heaviest burdens for current health systems. In addition to hemodynamic damage, recent results have revealed that hematopoietic cells contribute to the development of these diseases by generating proinflammatory and profibrotic environments in the heart and kidney. However, the cell subtypes involved remain poorly characterized. Here we report that CD39(+) regulatory T (TREG) cells utilize an immunosuppression-independent mechanism to counteract renal and possibly cardiac damage during angiotensin II (AngII)-dependent hypertension. This mechanism relies on the direct apoptosis of tissue-resident neutrophils by the ecto-ATP diphosphohydrolase activity of CD39. In agreement with this, experimental and genetic alterations in TREG/TH cell ratios have a direct impact on tissue resident neutrophil numbers, cardiomyocyte hypertrophy, cardiorenal fibrosis, and, to a lesser extent, arterial pressure elevation during AngII-driven hypertension. These results indicate that TREG cells constitute a first protective barrier against hypertension-driven tissue fibrosis and, in addition, suggest new therapeutic avenues to prevent hypertension-linked cardiorenal diseases. PMID- 26240280 TI - The NF45/NF90 Heterodimer Contributes to the Biogenesis of 60S Ribosomal Subunits and Influences Nucleolar Morphology. AB - The interleukin enhancer binding factors ILF2 (NF45) and ILF3 (NF90/NF110) have been implicated in various cellular pathways, such as transcription, microRNA (miRNA) processing, DNA repair, and translation, in mammalian cells. Using tandem affinity purification, we identified human NF45 and NF90 as components of precursors to 60S (pre-60S) ribosomal subunits. NF45 and NF90 are enriched in nucleoli and cosediment with pre-60S ribosomal particles in density gradient analysis. We show that association of the NF45/NF90 heterodimer with pre-60S ribosomal particles requires the double-stranded RNA binding domains of NF90, while depletion of NF45 and NF90 by RNA interference leads to a defect in 60S biogenesis. Nucleoli of cells depleted of NF45 and NF90 have altered morphology and display a characteristic spherical shape. These effects are not due to impaired rRNA transcription or processing of the precursors to 28S rRNA. Consistent with a role of the NF45/NF90 heterodimer in nucleolar steps of 60S subunit biogenesis, downregulation of NF45 and NF90 leads to a p53 response, accompanied by induction of the cyclin-dependent kinase inhibitor p21/CIP1, which can be counteracted by depletion of RPL11. Together, these data indicate that NF45 and NF90 are novel higher-eukaryote-specific factors required for the maturation of 60S ribosomal subunits. PMID- 26240281 TI - S6 Kinase- and beta-TrCP2-Dependent Degradation of p19Arf Is Required for Cell Proliferation. AB - The kinase mTOR (mammalian target of rapamycin) promotes translation as well as cell survival and proliferation under nutrient-rich conditions. Whereas mTOR activates translation through ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein (4E-BP), how it facilitates cell proliferation has remained unclear. We have now identified p19(Arf), an inhibitor of cell cycle progression, as a novel substrate of S6K that is targeted to promote cell proliferation. Serum stimulation induced activation of the mTOR-S6K axis and consequent phosphorylation of p19(Arf) at Ser(75). Phosphorylated p19(Arf) was then recognized by the F-box protein beta-TrCP2 and degraded by the proteasome. Ablation of beta-TrCP2 thus led to the arrest of cell proliferation as a result of the stabilization and accumulation of p19(Arf). The beta-TrCP2 paralog beta-TrCP1 had no effect on p19(Arf) stability, suggesting that phosphorylated p19(Arf) is a specific substrate of beta-TrCP2. Mice deficient in beta-TrCP2 manifested accumulation of p19(Arf) in the yolk sac and died in utero. Our results suggest that the mTOR pathway promotes cell proliferation via beta TrCP2-dependent p19(Arf) degradation under nutrient-rich conditions. PMID- 26240282 TI - Aurora B Overexpression Causes Aneuploidy and p21Cip1 Repression during Tumor Development. AB - Aurora kinase B, one of the three members of the mammalian Aurora kinase family, is the catalytic component of the chromosomal passenger complex, an essential regulator of chromosome segregation in mitosis. Aurora B is overexpressed in human tumors although whether this kinase may function as an oncogene in vivo is not established. Here, we report a new mouse model in which expression of the endogenous Aurkb locus can be induced in vitro and in vivo. Overexpression of Aurora B in cultured cells induces defective chromosome segregation and aneuploidy. Long-term overexpression of Aurora B in vivo results in aneuploidy and the development of multiple spontaneous tumors in adult mice, including a high incidence of lymphomas. Overexpression of Aurora B also results in a reduced DNA damage response and decreased levels of the p53 target p21(Cip1) in vitro and in vivo, in line with an inverse correlation between Aurora B and p21(Cip1) expression in human leukemias. Thus, overexpression of Aurora B may contribute to tumor formation not only by inducing chromosomal instability but also by suppressing the function of the cell cycle inhibitor p21(Cip1). PMID- 26240284 TI - Histone Deacetylase 10 Regulates the Cell Cycle G2/M Phase Transition via a Novel Let-7-HMGA2-Cyclin A2 Pathway. AB - Histone deacetylase (HDAC) inhibition leads to cell cycle arrest in G1 and G2, suggesting HDACs as therapeutic targets for cancer and diseases linked to abnormal cell growth and proliferation. Many HDACs are transcriptional repressors. Some may alter cell cycle progression by deacetylating histones and repressing transcription of key cell cycle regulatory genes. Here, we report that HDAC10 regulates the cell cycle via modulation of cyclin A2 expression, and cyclin A2 overexpression rescues HDAC10 knockdown-induced G2/M transition arrest. HDAC10 regulates cyclin A2 expression by deacetylating histones near the let-7 promoter, thereby repressing transcription. In HDAC10 knockdown cells, let-7f and microRNA 98 (miR-98) were upregulated and the let-7 family target, HMGA2, was downregulated. HMGA2 loss resulted in enrichment of the transcriptional repressor E4F at the cyclin A2 promoter. These findings support a role for HDACs in cell cycle regulation, reveal a novel mechanism of HDAC10 action, and extend the potential of HDACs as targets in diseases of cell cycle dysregulation. PMID- 26240283 TI - Differential Effects of Hepatocyte Nuclear Factor 4alpha Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells. AB - The nuclear receptor hepatocyte nuclear factor 4alpha (HNF4alpha) is tumor suppressive in the liver but amplified in colon cancer, suggesting that it also might be oncogenic. To investigate whether this discrepancy is due to different HNF4alpha isoforms derived from its two promoters (P1 and P2), we generated Tet On-inducible human colon cancer (HCT116) cell lines that express either the P1 driven (HNF4alpha2) or P2-driven (HNF4alpha8) isoform and analyzed them for tumor growth and global changes in gene expression (transcriptome sequencing [RNA-seq] and chromatin immunoprecipitation sequencing [ChIP-seq]). The results show that while HNF4alpha2 acts as a tumor suppressor in the HCT116 tumor xenograft model, HNF4alpha8 does not. Each isoform regulates the expression of distinct sets of genes and recruits, colocalizes, and competes in a distinct fashion with the Wnt/beta-catenin mediator T-cell factor 4 (TCF4) at CTTTG motifs as well as at AP 1 motifs (TGAXTCA). Protein binding microarrays (PBMs) show that HNF4alpha and TCF4 share some but not all binding motifs and that single nucleotide polymorphisms (SNPs) in sites bound by both HNF4alpha and TCF4 can alter binding affinity in vitro, suggesting that they could play a role in cancer susceptibility in vivo. Thus, the HNF4alpha isoforms play distinct roles in colon cancer, which could be due to differential interactions with the Wnt/beta catenin/TCF4 and AP-1 pathways. PMID- 26240286 TI - ACCESS OF SINGLE WOMEN TO FERTILITY TREATMENT: A CASE OF INCIDENTAL DISCRIMINATION? AB - The purpose of this article is to evaluate the extent to which single women have access to publicly funded fertility treatment. It claims that, despite the fact that great progress has been made in removing gender inequalities in the area of assisted reproduction in England and Wales in recent years, there are points in the regulatory framework that still allow for discrimination against single women. The article builds on recent studies concerning the reforms brought about by the Human Fertilisation and Embryology Act 2008 (HFEA 2008). However, it focusses on publicly funded treatment, thus directing scholarly attention away from the controversies over the amended s 13(5) HFEA 1990. It argues that the primary reason for remaining inequalities can be traced back to (a) the limitations of the current legislative framework; (b) the ambiguities inherent in the regulatory framework, which in the context of publicly funded fertility treatment is determined by the National Institute for Health and Care Excellence clinical guidelines and Clinical Commissioning Groups and Health Boards' resource allocation policies; and (c) the remaining confusion about the relationship between 'welfare of the child' assessments and eligibility criteria in National Health Service rationing decisions. The article argues that the current regulation does not go far enough in acknowledging the inability of single women to conceive naturally, but at the same time that it struggles to address the fluidity of contemporary familial relationships. The analysis presents an opportunity to contribute to debates about the role of law in shaping the scope of reproductive autonomy, gender equality and social justice. PMID- 26240285 TI - Influence of a CTCF-Dependent Insulator on Multiple Aspects of Enhancer-Mediated Chromatin Organization. AB - Developmental stage-specific enhancer-promoter-insulator interactions regulate the chromatin configuration necessary for transcription at various loci and additionally for VDJ recombination at antigen receptor loci that encode immunoglobulins and T-cell receptors. To investigate these regulatory interactions, we analyzed the epigenetic landscape of the murine T-cell receptor beta (TCRbeta) locus in the presence and absence of an ectopic CTCF-dependent enhancer-blocking insulator, H19-ICR, in genetically manipulated mice. Our analysis demonstrated the ability of the H19-ICR insulator to restrict several aspects of enhancer-based chromatin alterations that are observed during activation of the TCRbeta locus for transcription and recombination. The H19-ICR insulator abrogated enhancer-promoter contact-dependent chromatin alterations and additionally prevented Ebeta-mediated histone modifications that have been suggested to be independent of enhancer-promoter interaction. Observed enhancer promoter-insulator interactions, in conjunction with the chromatin structure of the Ebeta-regulated domain at the nucleosomal level, provide useful insights regarding the activity of the regulatory elements in addition to supporting the accessibility hypothesis of VDJ recombination. Analysis of H19-ICR in the heterologous context of the developmentally regulated TCRbeta locus suggests that different mechanisms proposed for CTCF-dependent insulator action might be manifested simultaneously or selectively depending on the genomic context and the nature of enhancer activity being curtailed. PMID- 26240287 TI - Preclinical Evaluation of DMA, a Bisbenzimidazole, as Radioprotector: Toxicity, Pharmacokinetics, and Biodistribution Studies in Balb/c Mice. AB - Radiotherapy, a therapeutic modality of cancer treatment, nonselectively damages normal tissues as well as tumor tissues. The search is ongoing for therapeutic agents that selectively reduce radiation-induced normal tissue injury without reducing tumoricidal effect, thereby increasing the therapeutic ratio of radiation therapy. Our laboratory established 5-(4-methylpiperazin-1-yl)-2-[2' (3,4-dimethoxyphenyl)-5'benzimidazolyl] benzimidazole (DMA) as noncytotoxic radioprotector in mammalian cells. DMA showed an excellent radioprotection in mice at single nontoxic oral dose by a dose-reduction factor of 1.28. An oxygen radical absorbing capacity assay confirmed its free-radical quenching ability. Single bolus dose and 28-days of repeated administration of DMA in mice for toxicity studies determined an LD50 of >2000 mg/kg body weight (bw) and 225 mg/kg bw, respectively, suggesting DMA is safe. Histopathology, biochemical parameters, and relative organ weight analysis revealed insignificant changes in the DMA treated animals. The pharmacokinetic study of DMA at oral and intravenous doses showed its C(max) = 1 hour, bioavailability of 8.84%, elimination half-life of 4 hours, and an enterohepatic recirculation. Biodistribution study in mice with Ehrlich ascites tumors showed that (99m)Tc-DMA achieved its highest concentration in 1 hour and was retained up to 4 hours in the lungs, liver, kidneys, and spleen, and in a low concentration in the tumor, a solicited property of any radioprotector to protect normal cells over cancerous cells. We observed that the single-dose treatment of tumor-bearing mice with DMA 2 hours before 8 Gy total body irradiation showed an impressive rescue of radiation-induced morbidity in terms of weight loss and mortality without a change in tumor response. PMID- 26240289 TI - CCR 20th Anniversary Commentary: A Genetic Mechanism of Imatinib Resistance in Gastrointestinal Stromal Tumor-Where Are We a Decade Later? AB - In the June 1, 2005, issue of Clinical Cancer Research, Antonescu and colleagues defined second-site KIT mutations in gastrointestinal stromal tumor (GIST) as the leading mechanism of acquired resistance to imatinib. Secondary mutations were detectable mainly in KIT exon 11 mutant GISTs after prolonged initial clinical responses. These findings played a critical role in designing the next generation of tyrosine kinase inhibitors. PMID- 26240290 TI - The Evolution of T-cell Therapies for Solid Malignancies. AB - Primary resistant, recurrent, and relapsed solid tumors are often nonresponsive to conventional antineoplastic therapies. Moreover, in responsive tumors, the therapeutic-to-toxic range of these interventions remains quite narrow, such that side effects of therapy are substantial. Targeted therapies, such as adoptive T cell transfer, not only spare normal tissues but also use alternative killing mechanisms to which the tumor cells are usually not immune. Adoptive T-cell transfer for solid tumors faces unique challenges because of the inherent heterogeneity of tumor parenchyma, the complexity of the tumor microenvironment, and tumor occurrence in areas with limited therapeutic accessibility. In this review, we examine the recent evolution of various T-cell-based immunotherapeutics, the mechanisms of action behind their antitumor activity, their increasing complexity, and the prospect of building on previous successes in the treatment of solid tumors. PMID- 26240292 TI - Detecting Plasma Tumor DNA in Early-Stage Breast Cancer-Letter. PMID- 26240291 TI - Identification of a Three-Biomarker Panel in Urine for Early Detection of Pancreatic Adenocarcinoma. AB - PURPOSE: Noninvasive biomarkers for early detection of pancreatic ductal adenocarcinoma (PDAC) are currently not available. Here, we aimed to identify a set of urine proteins able to distinguish patients with early-stage PDAC from healthy individuals. EXPERIMENTAL DESIGN: Proteomes of 18 urine samples from healthy controls, chronic pancreatitis, and patients with PDAC (six/group) were assayed using GeLC/MS/MS analysis. The selected biomarkers were subsequently validated with ELISA assays using multiple logistic regression applied to a training dataset in a multicenter cohort comprising 488 urine samples. RESULTS: LYVE-1, REG1A, and TFF1 were selected as candidate biomarkers. When comparing PDAC (n = 192) with healthy (n = 87) urine specimens, the resulting areas under the receiver-operating characteristic curves (AUC) of the panel were 0.89 [95% confidence interval (CI), 0.84-0.94] in the training (70% of the data) and 0.92 (95% CI, 0.86-0.98) in the validation (30% of the data) datasets. When comparing PDAC stage I-II (n = 71) with healthy urine specimens, the panel achieved AUCs of 0.90 (95% CI, 0.84-0.96) and 0.93 (95% CI, 0.84-1.00) in the training and validation datasets, respectively. In PDAC stage I-II and healthy samples with matching plasma CA19.9, the panel achieved a higher AUC of 0.97 (95% CI, 0.94 0.99) than CA19.9 (AUC = 0.88; 95% CI, 0.81-0.95, P = 0.005). Adding plasma CA19.9 to the panel increased the AUC from 0.97 (95% CI, 0.94-0.99) to 0.99 (95% CI, 0.97-1.00, P = 0.04), but did not improve the comparison of stage I-IIA PDAC (n = 17) with healthy urine. CONCLUSIONS: We have established a novel, three protein biomarker panel that is able to detect patients with early-stage pancreatic cancer in urine specimens. PMID- 26240293 TI - Detecting Plasma Tumor DNA in Early-Stage Breast Cancer--Reply. PMID- 26240294 TI - Correction: Tyrosine Phosphoproteomics Identifies Both Codrivers and Cotargeting Strategies for T790M-Related EGFR-TKI Resistance in Non-Small Cell Lung Cancer. PMID- 26240295 TI - Correction: TMEFF2 Deregulation Contributes to Gastric Carcinogenesis and Indicates Poor Survival Outcome. PMID- 26240296 TI - Performance of cystatin C- and creatinine-based estimated glomerular filtration rate equations depends on patient characteristics. AB - BACKGROUND: The Kidney Disease Improving Global Outcomes (KDIGO) guideline recommends use of a cystatin C-based estimated glomerular filtration rate (eGFR) to confirm creatinine-based eGFR between 45 and 59 mL . min(-1) . (1.73 m(2))( 1). Prior studies have demonstrated that comorbidities such as solid-organ transplant strongly influence the relationship between measured GFR, creatinine, and cystatin C. Our objective was to evaluate the performance of cystatin C-based eGFR equations compared with creatinine-based eGFR and measured GFR across different clinical presentations. METHODS: We compared the performance of the CKD EPI 2009 creatinine-based estimated GFR equation (eGFRCr) and the newer CKD-EPI 2012 cystatin C-based equations (eGFRCys and eGFRCr-Cys) with measured GFR (iothalamate renal clearance) across defined patient populations. Patients (n = 1652) were categorized as transplant recipients (n = 568 kidney; n = 319 other organ), known chronic kidney disease (CKD) patients (n = 618), or potential kidney donors (n = 147). RESULTS: eGFRCr-Cys showed the most consistent performance across different clinical populations. Among potential kidney donors without CKD [stage 2 or higher; eGFR >60 mL . min(-1) . (1.73 m(2))(-1)], eGFRCys and eGFRCr-Cys demonstrated significantly less bias than eGFRCr; however, all 3 equations substantially underestimated GFR when eGFR was <60 mL . min(-1) . (1.73 m(2))(-1). Among transplant recipients with CKD stage 3B or greater [eGFR <45 mL . min(-1) . (1.73 m(2))(-1)], eGFRCys was significantly more biased than eGFRCr. No clear differences in eGFR bias between equations were observed among known CKD patients regardless of eGFR range or in any patient group with a GFR between 45 and 59 mL . min(-1) . (1.73 m(2))(-1). CONCLUSIONS: The performance of eGFR equations depends on patient characteristics that are readily apparent on presentation. Among the 3 CKD-EPI equations, eGFRCr-Cys performed most consistently across the studied patient populations. PMID- 26240297 TI - Cannabinoid concentrations detected in fatal road traffic collision victims compared with a population of other postmortem cases. AB - BACKGROUND: Acute cannabis consumption nearly doubles the risk of motor vehicle collision resulting in injury or death. Limited data have been published regarding the concentrations of cannabinoids associated with fatal road traffic collisions (RTCs), and these have not previously been compared to a population of other postmortem cases. METHODS: We conducted analysis for cannabinoids [Delta(9) tetrahydrocannabinol (THC), 11-hydroxy-THC, 11-nor-THC-9-carboxylic acid, cannabidiol, and cannabinol], drugs, and alcohol on consecutive fatal RTC cases (100) and non-RTC cases (114) from coroners' jurisdictions in London and southeast England and compared the data. RESULTS: The incidence of cannabinoids detected in non-RTC and RTC cases was similar (25% vs 21%, P = 0.44), but THC was detected more frequently (90% vs 59%, P = 0.01) and at significantly higher concentrations in the cannabinoid-positive RTC cases than the non-RTC cases (P = 0.01). The distribution of non-RTC and RTC cases over 4 categories of THC concentration was significantly different (P = 0.004). There was no significant difference in the concentrations of other cannabinoids detected between the 2 groups. Cannabinoids were detected in more fatal RTC cases (21) than alcohol >80 mg/dL (17). Detection of other drugs was low compared to cannabis and alcohol. CONCLUSIONS: These first data on the concentrations of cannabinoids in the postmortem blood of fatal RTC victims compared with a population of other routine coroners' cases highlight the importance of specifically measuring THC concentrations in the blood to aid interpretation of postmortem cases where cannabis may be implicated. PMID- 26240298 TI - Biomarker changes after strenuous exercise can mimic pulmonary embolism and cardiac injury--a metaanalysis of 45 studies. AB - BACKGROUND: Biomarkers are well established for diagnosis of myocardial infarction [cardiac troponins, high-sensitivity cardiac troponins (hs-cTn)], exclusion of acute and chronic heart failure [B-type natriuretic peptide (BNP), N terminal proBNP (NT-proBNP)] and venous thromboembolism (d-dimers). Several studies have demonstrated acute increases in cardiac biomarkers and altered cardiac function after strenuous sports that can pretend a cardiovascular emergency and interfere with state-of-the-art clinical assessment. METHODS: We performed a systematic review and metaanalysis of biomarker and cardiovascular imaging changes after endurance exercise. We searched for observational studies published in the English language from 1997 to 2014 that assessed these biomarkers or cardiac function and morphology directly after endurance exercise. Of 1787 identified abstracts, 45 studies were included. RESULTS: Across all studies cardiac troponin T (cTnT) exceeded the cutoff value (0.01 ng/mL) in 51% (95% CI, 37%-64%) of participants. The measured pooled changes from baseline for high-sensitivity cTnT (hs-cTnT) were +26 ng/L (95% CI, 5.2-46.0), for cTnI +40 ng/L (95% CI, 21.4; 58.0), for BNP +10 ng/L (95% CI, 4.3; 16.6), for NT-proBNP +67 ng/L (95% CI, 49.9; 84.7), and for d-dimer +262 ng/mL (95% CI, 165.9; 358.7). Right ventricular end diastolic diameter increased and right ventricular ejection fraction as well as the ratio of the early to late transmitral flow velocities decreased after exercise, while no significant changes were observed in left ventricular ejection fraction. CONCLUSIONS: Current cardiovascular biomarkers (cTnT, hs-cTnT, BNP, NT-proBNP, and d-dimer) that are used in clinical diagnosis of pulmonary embolism, acute coronary syndrome, and heart failure are prone to alterations due to strenuous exercise. Hence, it is necessary to take previous physical exercise into account when a cardiac emergency is suspected. PMID- 26240300 TI - Umbelopsis longicollis comb. nov. and the synonymy of U. roseonana and U. versiformis with U. nana. AB - Based on maximum growth temperatures, morphological characteristics and multilocus phylogenies (partial 18S and 28S, internal transcribed spacer regions of nuc rDNA and a fragment of an actin gene), Umbelopsis roseonana and U. versiformis are treated as heterotypic synonyms of U. nana, while the phylogenetically closely related U. dimorpha is retained as a separate species. Mortierella longicollis is reclassified as a new combination, U. longicollis. In addition, lectotypes and epitypes for the basionyms of U. longicollis and U. nana are designated here. PMID- 26240299 TI - Meta-Analysis of the Effect of Dietary Sodium Restriction with or without Concomitant Renin-Angiotensin-Aldosterone System-Inhibiting Treatment on Albuminuria. AB - BACKGROUND AND OBJECTIVES: Urinary albumin excretion and/or albumin to creatinine ratio are associated with CKD and higher risk of cardiovascular events. Several studies investigated the effect of reduced dietary sodium intake on urinary albumin excretion and/or albumin to creatinine ratio in adult patient populations, but the majority was inconclusive because of insufficient statistical power. A meta-analysis of the randomized, controlled trials available could overcome this problem and lead to more definitive conclusions. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A systematic search of the online databases available (from 1996 to October of 2014) was conducted of randomized, controlled trials that expressed urinary albumin excretion or albumin to creatinine ratio as the difference between the effects of two different sodium intake regimens. For each study, the mean difference and 95% confidence intervals were pooled using a random effect model. Heterogeneity, publication bias, subgroup, and meta-regression analyses were performed. RESULTS: Eleven studies met the predefined inclusion criteria and provided 23 cohorts with 516 participants and 1-6 weeks of follow-up time. In the pooled analysis, an average reduction in sodium intake of 92 mmol/d was associated with a 32.1% (95% confidence interval, -44.3 to -18.8) reduction in urinary albumin excretion. The effect of sodium restriction was higher in the cohorts including patients on concomitant renin-angiotensin-aldosterone system-blocking therapy, in the studies with intervention lasting at least 2 weeks, and among participants with evidence of kidney damage. A greater reduction of urinary albumin excretion was associated with a higher decrease in BP during the intervention. The analysis of changes in albumin to creatinine ratio provided similar results. CONCLUSIONS: This meta analysis indicates that sodium intake reduction markedly reduces albumin excretion, more so during concomitant renin-angiotensin-aldosterone system blocking therapy and among patients with kidney damage. PMID- 26240301 TI - Ceratocystis tiliae sp. nov., a wound pathogen on Tilia americana. AB - Species in the North American clade (NAC) of the Ceratocystis fimbriata complex are mostly weak pathogens that infect native tree hosts through fresh wounds. Isolations from discolored tissue of wounded Tilia americana (basswood) in Iowa and Nebraska yielded a Ceratocystis species that was similar to but distinct from isolates of C. variospora from other hosts. Sequences of 28S rDNA showed that isolates from basswood did not differ from C. variospora, but there were minor differences in ITS rDNA sequences. The DNA sequences of a portion of the Cerato platanin gene and TEF1alpha showed the basswood fungus to be a unique lineage. Cross inoculations in two experiments showed that the basswood isolates and C. variospora isolates from Quercus spp. were most aggressive to their respective hosts. Isolates from basswood grew slower and were less pigmented than C. variospora isolates from Quercus spp. The basswood fungus thus is distinguished from C. variospora based on phylogenetic analyses and phenotype and is herein described as C. tiliae sp. nov. PMID- 26240302 TI - First comprehensive phylogenetic analysis of the genus Erysiphe (Erysiphales, Erysiphaceae) II: the Uncinula lineage. AB - Phylogenetic relationships of the Uncinula lineage, which is the basal group in the genus Erysiphe, were investigated with 167 sequences of nuc ITS1-5. 8S-ITS2 and the 28S rDNA regions. Backbone tree analyses with six datasets and two tree constructing methods revealed that the Uncinula lineage is divided into seven distinct clades. Clades 1-5 each contained a representative powdery mildew species, namely E. australiana in Clade 1, E. liquidambaris in Clade 2, E. adunca in Clade 3, E. fraxinicola in Clade 4 and E. actinidiae in Clade 5. Clade 6 comprises 71 sequences including the Microsphaera lineage and 17 species of the Uncinula lineage, such as E. carpinicola, E. carpinilaxiflorae, E. miyabei, E. glycines and E. necator. Topology tests supported the Microsphaera lineage forming a monophyletic clade in Clade 6, suggesting that Microsphaera-type appendages appeared only once in this clade to diverge into the Microsphaera lineage. Clade 7 consists of 72 sequences containing 30 species, including species of sects. Californiomyces and Typhulochaeta, four species from Nothofagus, species of sect. Erysiphe parasitising herbaceous plants belonging to the Asteraceae, Rosaceae and Saxifragaceae. Molecular clock analysis suggests that the major seven clades appeared 50-30 million years ago (Ma) in the Paleogene Period. The Microsphaera lineage may have split from the Uncinula lineage at the boundary of the Paleogene and Neogene, when appendages with dichotomously branched tips appeared. The clade of the species on Nothofagus split from the northern hemisphere species about 20-10 million years ago (Ma) in the Miocene Epoch, and host-shift from trees to herbs also might have occurred in this period. PMID- 26240303 TI - Four new species in Leucoagaricus (Agaricaceae, Basidiomycota) from Asia. AB - The genus Leucoagaricus has been well studied in Europe. However, species diversity of Leucoagaricus in Asia remains poorly known, especially in the mountains of southwestern China, a hot spot for biodiversity. Based on morphological characters and molecular data, four new species are described, La. asiaticus, La. subcrystallifer, La. subpurpureolilacinus and La. truncatus. Detailed morphological descriptions, drawings of microstructures for novel taxa and comparisons with closely allied taxa are provided. Phylogenetic analyses inferred from internal transcribed spacer (ITS) and region 6-7 of the gene for the second largest subunit of RNA polymerase II (rpb2) sequences show that the novel taxa are nested within a well-supported clade jointly formed by members of Leucoagaricus section Rubrotincti and subgenus Sericeomyces. PMID- 26240304 TI - Hymenochaetaceae from the Guineo-Congolian rainforest: three new species of Phylloporia based on morphological, DNA sequences and ecological data. AB - Four species are added to Phylloporia. Three species, originating from the western edge of the Guineo-Congolian rainforest in Gabon (central Africa), are described as new. Phylloporia afrospathulata sp. nov. forms seasonal, stipitate, solitary basidiomata emerging from soil, more likely connected to buried roots, and has broadly ellipsoid basidiospores. Phylloporia inonotoides sp. nov. forms seasonal sessile, soft basidiomata, solitary at the base of small-stemmed trees including Crotonogyne manniana (Euphorbiaceae) and Garcinia cf. smeathmannii (Clusiaceae). It has a homogeneous context, large pores (2-3 mm), and oblong ellipsoid to suballantoid basidiospores. Phylloporia fulva sp. nov. forms sessile, conchate, mostly pendant, gregarious basidiomata emerging from the trunk of an unidentified small-stemmed tree and has small, subglobose basidiospores. This species is compared to Polyporus pullus and Phylloporia pulla comb. nov. and proposed based on the study of the type specimen. Phylogenetic inferences using partial nuc 28S DNA sequence data (region including the D1/D2/D3 domains) and the most exhaustive dataset available to date resolved these new morphospecies as three distinct terminal lineages. No sequence data of P. pulla currently is available. The 28S-based phylogenic inferences poorly resolved the interspecific relationships within the Phylloporia clade. PMID- 26240305 TI - Perichaena longipes, a new myxomycete from the Neotropics. AB - A new species of myxomycete, Perichaena longipes, is described from 56 sporocarp specimens that appeared in moist chamber cultures prepared with samples of decaying plant materials collected in Panama, Costa Rica and Brazil. This new species is distinguished from the morphologically similar species P. pedata on the basis of the much longer stipe, lighter peridium and the unique ornamentation of the capillitium. The nuc 18S ribosomal DNA sequences obtained from four specimens of P. longipes support the distinction of this new taxon and its separation from P. pedata. Furthermore, maximum likelihood phylogeny supports earlier evidence that species currently within the genus Perichaena do not form a monophyletic clade. Instead they appear to form three separate branches within the bright-spored clade. The first clade includes P. longipes together with several species of Trichia and Metatrichia, the second includes P. pedata and P. chrysosperma, and the third clade is composed of P. corticalis, P. depressa and P. luteola. PMID- 26240306 TI - A critical revision of the Tubifera ferruginosa complex. AB - Based on a combination of morphological and molecular investigations, a critical revision of the widely distributed myxomycete Tubifera ferruginosa is presented. A phylogeny of the morphospecies, based on partial 18S nuc rDNA sequences, displays several clearly distinct clades, all differing by a genetic distance (p distance) of at least 0.15, with the distance within the clades below 0.11. These molecular differences correlate with morphological characters, such as the shape of sporothecal tips, the color of immature fructifications and the ultrastructure of the inner surface of the peridium. The combination of morphological and molecular data provides evidence that T. ferruginosa is actually a species complex, representing at least seven species. These are T. ferruginosa sensu stricto, T. applanata, T. corymbosa, T. dudkae, T. magna, T. montana and T. pseudomicrosperma. Among these T. applanata and T. dudkae (as Reticularia dudkae) were described recently based on morphological characters and the 18S nuc rDNA phylogeny confirmed their separation. Another four species, T. corymbosa, T. magna, T. montana and T. pseudomicrosperma, are described here. We propose an epitype for T. ferruginosa sensu stricto and recognize subsp. ferruginosa and subsp. acutissima within this species. All studied taxa of the T. ferruginosa complex are shown to lack a capillitium. Structures formerly described as capillitium represent the hyphae of fungi occurring within the fructifications. PMID- 26240307 TI - Lignomyces, a new genus of pleurotoid Agaricomycetes. AB - Collections of a pleurotoid fungus from dead aspen in eastern Russia were initially identified as Lentinus sp., then as Phyllotopsis nidulans. DNA sequencing of cultures derived from these specimens using the nuclear ribosomal 28S (nrLSU) and nuclear ribosomal ITS1-5.8S-ITS2 regions (nrITS) showed that they were neither Lentinus nor Phyllotopsis and were not related to other pleurotoid genera Hohenbuehelia and Pleurotus. Subsequent investigation showed that the Russian fungus was the same as Pleurotus vetlinianus described from Poland. A new genus, Lignomyces, is described and characterized and L. vetlinianus comb. nov. is proposed. PMID- 26240308 TI - Multiple Phytophthora species associated with a single riparian ecosystem in South Africa. AB - The diversity of Phytophthora spp. in rivers and riparian ecosystems has received considerable international attention, although little such research has been conducted in South Africa. This study determined the diversity of Phytophthora spp. within a single river in Gauteng province of South Africa. Samples were collected over 1 y including biweekly river baiting with Rhododendron indicum leaves. Phytophthora isolates were identified with phylogenetic analyses of sequences for the internal transcribed spacer (ITS) region of the ribosomal DNA and the mitochondrial cytochrome oxidase c subunit I (coxI) gene. Eight Phytophthora spp. were identified, including a new taxon, P. taxon Sisulu-river, and two hybrid species from Cooke's ITS clade 6. Of these, species from Clade 6 were the most abundant, including P. chlamydospora and P. lacustris. Species residing in Clade 2 also were encountered, including P. multivora, P. plurivora and P. citrophthora. The detection of eight species in this investigation of Phytophthora diversity in a single riparian river ecosystem in northern South Africa adds to the known diversity of this genus in South Africa and globally. PMID- 26240309 TI - Diversity of Diaporthe species associated with wood cankers of fruit and nut crops in northern California. AB - Diaporthe ampelina, causal agent of Phomopsis cane and leaf spot of grapevine (Vitis vinifera L.) is isolated frequently from grapevine wood cankers, causing Phomopsis dieback. The latter disease is associated with four other Diaporthe species, three of which also are reported from hosts other than grape. To better understand the role of this Diaporthe community in Phomopsis dieback of grapevine and the potential for infection routes among alternate hosts, 76 Diaporthe isolates were recovered from wood cankers of cultivated grape, pear, apricot, almond and the wild host willow in four California counties. Isolates were characterized morphologically and assigned to species based on multigene sequence analyses. This study identified eight Diaporthe species from grapevine and one novel taxon from willow, D. benedicti. We report the first findings of D. australafricana and D. novem in North America. Our findings also expand the host ranges of D. ambigua to apricot and willow, D. australafricana to almond and willow, D. chamaeropis to grapevine and willow, D. foeniculina to willow and D. novem to almond. The generalists D. ambigua and D. eres were the most genetically diverse species, based on high nucleotide and haplotypic diversity, followed by the grapevine specialist D. ampelina. Analyses based on multilocus linkage disequilibrium could not reject the hypothesis of random mating for D. ambigua, which is further supported by relatively high haplotypic diversity, reports of both mating types and reports of successful matings in vitro. Pathogenicity assays revealed that D. ampelina was the most pathogenic species to grapevine wood. PMID- 26240310 TI - Revisiting the morphology and phylogeny of Lactifluus with three new lineages from southern China. AB - As a recent group mainly defined by molecular data the genus Lactifluus is in need of further study to provide insight into the morphological and molecular variation within the genus, species limits and relationships. Phylogenetic analyses of nuc rDNA ITS1-5.8S-ITS2 (ITS), D1 and D2 domains of nuc 28S rDNA (28S), and part of the second largest subunit of the RNA polymerase II (rpb2) (6 7 region) sequences of 28 samples from southern China revealed three new lineages of Lactifluus. Two of them are nested in a major clade that includes the type of Lactifluus and here is treated as two new sections: L. sect. Ambicystidiati and L. sect. Tenuicystidiati. Lactifluus ambicystidiatus, described here as a new species (= sect. Ambicystidiati), has both lamprocystidia and macrocystidia in the hymenium, a unique combination of features within Russulaceae. Furthermore, only remnants of lactiferous hyphae are present in L. ambicystidiatus and our results suggest that the ability to form a lactiferous system has been lost in this lineage. Lactifluus sect. Tenuicystidiati forms a strongly supported monophyletic group as a sister lineage to L. sect. Lactifluus. We recognize it based on the thin-walled macrocystidia and smaller ellipsoid spores with an incomplete reticulum compared with L. sect. Lactifluus. The former placement of L. tenuicystidiatus in the African L. sect. Pseudogymnocarpi is not supported. Using genealogical concordance we recognize five phylogenetic species within L. sect. Tenuicystidiati and describe two of these as new, L. subpruinosus and L. tropicosinicus. The third lineage, represented by L. leoninus, forms a sister group to L. subg. Lactariopsis sensu stricto. The three lineages provide further evidence for morphological features in Lactifluus being homoplasious. Some sections and species complexes are likely to be composed of more species and merit further investigations. Subtropical-tropical Asia is likely a key region for additional sampling. PMID- 26240311 TI - The Phytophthora species assemblage and diversity in riparian alder ecosystems of western Oregon, USA. AB - Phytophthora species were systematically sampled, isolated, identified and compared for presence in streams, soil and roots of alder (Alnus species) dominated riparian ecosystems in western Oregon. We describe the species assemblage and evaluate Phytophthora diversity associated with alder. We recovered 1250 isolates of 20 Phytophthora species. Only three species were recovered from all substrates (streams, soil, alder roots): P. gonapodyides, the informally described "P. taxon Pgchlamydo", and P. siskiyouensis. P. alni ssp. uniformis along with five other species not previously recovered in Oregon forests are included in the assemblage: P.citricola s.l., P. gregata, P. gallica, P. nicotianae and P. parsiana. Phytophthora species diversity was greatest in downstream riparian locations. There was no significant difference in species diversity comparing soil and unwashed roots (the rhizosphere) to stream water. There was a difference between the predominating species from the rhizosphere compared to stream water. The most numerous species was the informally described "P. taxon Oaksoil", which was mainly recovered from, and most predominant in, stream water. The most common species from riparian forest soils and alder root systems was P. gonapodyides. PMID- 26240312 TI - Reply to Brown et al.: Species and places are the priorities for conservation, not economic efficiency. PMID- 26240313 TI - Perceptual transparency from image deformation. AB - Human vision has a remarkable ability to perceive two layers at the same retinal locations, a transparent layer in front of a background surface. Critical image cues to perceptual transparency, studied extensively in the past, are changes in luminance or color that could be caused by light absorptions and reflections by the front layer, but such image changes may not be clearly visible when the front layer consists of a pure transparent material such as water. Our daily experiences with transparent materials of this kind suggest that an alternative potential cue of visual transparency is image deformations of a background pattern caused by light refraction. Although previous studies have indicated that these image deformations, at least static ones, play little role in perceptual transparency, here we show that dynamic image deformations of the background pattern, which could be produced by light refraction on a moving liquid's surface, can produce a vivid impression of a transparent liquid layer without the aid of any other visual cues as to the presence of a transparent layer. Furthermore, a transparent liquid layer perceptually emerges even from a randomly generated dynamic image deformation as long as it is similar to real liquid deformations in its spatiotemporal frequency profile. Our findings indicate that the brain can perceptually infer the presence of "invisible" transparent liquids by analyzing the spatiotemporal structure of dynamic image deformation, for which it uses a relatively simple computation that does not require high-level knowledge about the detailed physics of liquid deformation. PMID- 26240314 TI - RabGDIalpha is a negative regulator of interferon-gamma-inducible GTPase dependent cell-autonomous immunity to Toxoplasma gondii. AB - IFN-gamma orchestrates cell-autonomous host defense against various intracellular vacuolar pathogens. IFN-gamma-inducible GTPases, such as p47 immunity-related GTPases (IRGs) and p65 guanylate-binding proteins (GBPs), are recruited to pathogen-containing vacuoles, which is important for disruption of the vacuoles, culminating in the cell-autonomous clearance. Although the positive regulation for the proper recruitment of IRGs and GBPs to the vacuoles has been elucidated, the suppressive mechanism is unclear. Here, we show that Rab GDP dissociation inhibitor alpha (RabGDIalpha), originally identified as a Rab small GTPase inhibitor, is a negative regulator of IFN-gamma-inducible GTPases in cell autonomous immunity to the intracellular pathogen Toxoplasma gondii. Overexpression of RabGDIalpha, but not of RabGDIbeta, impaired IFN-gamma dependent reduction of T. gondii numbers. Conversely, RabGDIalpha deletion in macrophages and fibroblasts enhanced the IFN-gamma-induced clearance of T. gondii. Furthermore, upon a high dose of infection by T. gondii, RabGDIalpha deficient mice exhibited a decreased parasite burden in the brain and increased resistance in the chronic phase than did control mice. Among members of IRGs and GBPs important for the parasite clearance, Irga6 and Gbp2 alone were more frequently recruited to T. gondii-forming parasitophorous vacuoles in RabGDIalpha deficient cells. Notably, Gbp2 positively controlled Irga6 recruitment that was inhibited by direct and specific interactions of RabGDIalpha with Gbp2 through the lipid-binding pocket. Taken together, our results suggest that RabGDIalpha inhibits host defense against T. gondii by negatively regulating the Gbp2-Irga6 axis of IFN-gamma-dependent cell-autonomous immunity. PMID- 26240316 TI - Breakthrough in the understanding of flaming wildfires. PMID- 26240315 TI - At14a-Like1 participates in membrane-associated mechanisms promoting growth during drought in Arabidopsis thaliana. AB - Limited knowledge of how plants regulate their growth and metabolism in response to drought and reduced soil water potential has impeded efforts to improve stress tolerance. Increased expression of the membrane-associated protein At14a-like1 (AFL1) led to increased growth and accumulation of the osmoprotective solute proline without negative effects on unstressed plants. Conversely, inducible RNA interference suppression of AFL1 decreased growth and proline accumulation during low water potential while having no effect on unstressed plants. AFL1 overexpression lines had reduced expression of many stress-responsive genes, suggesting AFL1 may promote growth in part by suppression of negative regulatory genes. AFL1 interacted with the endomembrane proteins protein disulfide isomerase 5 (PDI5) and NAI2, with the PDI5 interaction being particularly increased by stress. PDI5 and NAI2 are negative regulatory factors, as pdi5, nai2, and pdi5 2nai2-3 mutants had increased growth and proline accumulation at low water potential. AFL1 also interacted with Adaptor protein2-2A (AP2-2A), which is part of a complex that recruits cargo proteins and promotes assembly of clathrin coated vesicles. AFL1 colocalization with clathrin light chain along the plasma membrane, together with predictions of AFL1 structure, were consistent with a role in vesicle formation or trafficking. Fractionation experiments indicated that AFL1 is a peripheral membrane protein associated with both plasma membrane and endomembranes. These data identify classes of proteins (AFL1, PDI5, and NAI2) not previously known to be involved in drought signaling. AFL1-predicted structure, protein interactions, and localization all indicate its involvement in previously uncharacterized membrane-associated drought sensing or signaling mechanisms. PMID- 26240318 TI - Direct calculation of ice homogeneous nucleation rate for a molecular model of water. AB - Ice formation is ubiquitous in nature, with important consequences in a variety of environments, including biological cells, soil, aircraft, transportation infrastructure, and atmospheric clouds. However, its intrinsic kinetics and microscopic mechanism are difficult to discern with current experiments. Molecular simulations of ice nucleation are also challenging, and direct rate calculations have only been performed for coarse-grained models of water. For molecular models, only indirect estimates have been obtained, e.g., by assuming the validity of classical nucleation theory. We use a path sampling approach to perform, to our knowledge, the first direct rate calculation of homogeneous nucleation of ice in a molecular model of water. We use TIP4P/Ice, the most accurate among existing molecular models for studying ice polymorphs. By using a novel topological approach to distinguish different polymorphs, we are able to identify a freezing mechanism that involves a competition between cubic and hexagonal ice in the early stages of nucleation. In this competition, the cubic polymorph takes over because the addition of new topological structural motifs consistent with cubic ice leads to the formation of more compact crystallites. This is not true for topological hexagonal motifs, which give rise to elongated crystallites that are not able to grow. This leads to transition states that are rich in cubic ice, and not the thermodynamically stable hexagonal polymorph. This mechanism provides a molecular explanation for the earlier experimental and computational observations of the preference for cubic ice in the literature. PMID- 26240317 TI - A globally distributed mobile genetic element inhibits natural transformation of Vibrio cholerae. AB - Natural transformation is one mechanism of horizontal gene transfer (HGT) in Vibrio cholerae, the causative agent of cholera. Recently, it was found that V. cholerae isolates from the Haiti outbreak were poorly transformed by this mechanism. Here, we show that an integrating conjugative element (ICE)-encoded DNase, which we name IdeA, is necessary and sufficient for inhibiting natural transformation of Haiti outbreak strains. We demonstrate that IdeA inhibits this mechanism of HGT in cis via DNA endonuclease activity that is localized to the periplasm. Furthermore, we show that natural transformation between cholera strains in a relevant environmental context is inhibited by IdeA. The ICE encoding IdeA is globally distributed. Therefore, we analyzed the prevalence and role for this ICE in limiting natural transformation of isolates from Bangladesh collected between 2001 and 2011. We found that IdeA(+) ICEs were nearly ubiquitous in isolates from 2001 to 2005; however, their prevalence decreased to ~40% from 2006 to 2011. Thus, IdeA(+) ICEs may have limited the role of natural transformation in V. cholerae. However, the rise in prevalence of strains lacking IdeA may now increase the role of this conserved mechanism of HGT in the evolution of this pathogen. PMID- 26240319 TI - Fork rotation and DNA precatenation are restricted during DNA replication to prevent chromosomal instability. AB - Faithful genome duplication and inheritance require the complete resolution of all intertwines within the parental DNA duplex. This is achieved by topoisomerase action ahead of the replication fork or by fork rotation and subsequent resolution of the DNA precatenation formed. Although fork rotation predominates at replication termination, in vitro studies have suggested that it also occurs frequently during elongation. However, the factors that influence fork rotation and how rotation and precatenation may influence other replication-associated processes are unknown. Here we analyze the causes and consequences of fork rotation in budding yeast. We find that fork rotation and precatenation preferentially occur in contexts that inhibit topoisomerase action ahead of the fork, including stable protein-DNA fragile sites and termination. However, generally, fork rotation and precatenation are actively inhibited by Timeless/Tof1 and Tipin/Csm3. In the absence of Tof1/Timeless, excessive fork rotation and precatenation cause extensive DNA damage following DNA replication. With Tof1, damage related to precatenation is focused on the fragile protein-DNA sites where fork rotation is induced. We conclude that although fork rotation and precatenation facilitate unwinding in hard-to-replicate contexts, they intrinsically disrupt normal chromosome duplication and are therefore restricted by Timeless/Tipin. PMID- 26240320 TI - Three types of rescue can avert extinction in a changing environment. AB - Setting aside high-quality large areas of habitat to protect threatened populations is becoming increasingly difficult as humans fragment and degrade the environment. Biologists and managers therefore must determine the best way to shepherd small populations through the dual challenges of reductions in both the number of individuals and genetic variability. By bringing in additional individuals, threatened populations can be increased in size (demographic rescue) or provided with variation to facilitate adaptation and reduce inbreeding (genetic rescue). The relative strengths of demographic and genetic rescue for reducing extinction and increasing growth of threatened populations are untested, and which type of rescue is effective may vary with population size. Using the flour beetle (Tribolium castaneum) in a microcosm experiment, we disentangled the genetic and demographic components of rescue, and compared them with adaptation from standing genetic variation (evolutionary rescue in the strictest sense) using 244 experimental populations founded at either a smaller (50 individuals) or larger (150 individuals) size. Both types of rescue reduced extinction, and those effects were additive. Over the course of six generations, genetic rescue increased population sizes and intrinsic fitness substantially. Both large and small populations showed evidence of being able to adapt from standing genetic variation. Our results support the practice of genetic rescue in facilitating adaptation and reducing inbreeding depression, and suggest that demographic rescue alone may suffice in larger populations even if only moderately inbred individuals are available for addition. PMID- 26240321 TI - Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily. AB - Orthosomycins are oligosaccharide antibiotics that include avilamycin, everninomicin, and hygromycin B and are hallmarked by a rigidifying interglycosidic spirocyclic ortho-delta-lactone (orthoester) linkage between at least one pair of carbohydrates. A subset of orthosomycins additionally contain a carbohydrate capped by a methylenedioxy bridge. The orthoester linkage is necessary for antibiotic activity but rarely observed in natural products. Orthoester linkage and methylenedioxy bridge biosynthesis require similar oxidative cyclizations adjacent to a sugar ring. We have identified a conserved group of nonheme iron, alpha-ketoglutarate-dependent oxygenases likely responsible for this chemistry. High-resolution crystal structures of the EvdO1 and EvdO2 oxygenases of everninomicin biosynthesis, the AviO1 oxygenase of avilamycin biosynthesis, and HygX of hygromycin B biosynthesis show how these enzymes accommodate large substrates, a challenge that requires a variation in metal coordination in HygX. Excitingly, the ternary complex of HygX with cosubstrate alpha-ketoglutarate and putative product hygromycin B identified an orientation of one glycosidic linkage of hygromycin B consistent with metal catalyzed hydrogen atom abstraction from substrate. These structural results are complemented by gene disruption of the oxygenases evdO1 and evdMO1 from the everninomicin biosynthetic cluster, which demonstrate that functional oxygenase activity is critical for antibiotic production. Our data therefore support a role for these enzymes in the production of key features of the orthosomycin antibiotics. PMID- 26240322 TI - Consecutive radical S-adenosylmethionine methylations form the ethyl side chain in thienamycin biosynthesis. AB - Despite their broad anti-infective utility, the biosynthesis of the paradigm carbapenem antibiotic, thienamycin, remains largely unknown. Apart from the first two steps shared with a simple carbapenem, the pathway sharply diverges to the more structurally complex members of this class of beta-lactam antibiotics, such as thienamycin. Existing evidence points to three putative cobalamin-dependent radical S-adenosylmethionine (RS) enzymes, ThnK, ThnL, and ThnP, as potentially being responsible for assembly of the ethyl side chain at C6, bridgehead epimerization at C5, installation of the C2-thioether side chain, and C2/3 desaturation. The C2 substituent has been demonstrated to be derived by stepwise truncation of CoA, but the timing of these events with respect to C2-S bond formation is not known. We show that ThnK of the three apparent cobalamin dependent RS enzymes performs sequential methylations to build out the C6-ethyl side chain in a stereocontrolled manner. This enzymatic reaction was found to produce expected RS methylase coproducts S-adenosylhomocysteine and 5' deoxyadenosine, and to require cobalamin. For double methylation to occur, the carbapenam substrate must bear a CoA-derived C2-thioether side chain, implying the activity of a previous sulfur insertion by an as-yet unidentified enzyme. These insights allow refinement of the central steps in complex carbapenem biosynthesis. PMID- 26240323 TI - Flourishing ocean drives the end-Permian marine mass extinction. AB - The end-Permian mass extinction, the most severe biotic crisis in the Phanerozoic, was accompanied by climate change and expansion of oceanic anoxic zones. The partitioning of sulfur among different exogenic reservoirs by biological and physical processes was of importance for this biodiversity crisis, but the exact role of bioessential sulfur in the mass extinction is still unclear. Here we show that globally increased production of organic matter affected the seawater sulfate sulfur and oxygen isotope signature that has been recorded in carbonate rock spanning the Permian-Triassic boundary. A bifurcating temporal trend is observed for the strata spanning the marine mass extinction with carbonate-associated sulfate sulfur and oxygen isotope excursions toward decreased and increased values, respectively. By coupling these results to a box model, we show that increased marine productivity and successive enhanced microbial sulfate reduction is the most likely scenario to explain these temporal trends. The new data demonstrate that worldwide expansion of euxinic and anoxic zones are symptoms of increased biological carbon recycling in the marine realm initiated by global warming. The spatial distribution of sulfidic water column conditions in shallow seafloor environments is dictated by the severity and geographic patterns of nutrient fluxes and serves as an adequate model to explain the scale of the marine biodiversity crisis. Our results provide evidence that the major biodiversity crises in Earth's history do not necessarily implicate an ocean stripped of (most) life but rather the demise of certain eukaryotic organisms, leading to a decline in species richness. PMID- 26240324 TI - Ubiquitination by March-I prevents MHC class II recycling and promotes MHC class II turnover in antigen-presenting cells. AB - MHC class II (MHC-II)-dependent antigen presentation by antigen-presenting cells (APCs) is carefully controlled to achieve specificity of immune responses; the regulated assembly and degradation of antigenic peptide-MHC-II complexes (pMHC II) is one aspect of such control. In this study, we have examined the role of ubiquitination in regulating pMHC-II biosynthesis, endocytosis, recycling, and turnover in APCs. By using APCs obtained from MHC-II ubiquitination mutant mice, we find that whereas ubiquitination does not affect pMHC-II formation in dendritic cells (DCs), it does promote the subsequent degradation of newly synthesized pMHC-II. Acute activation of DCs or B cells terminates expression of the MHC-II E3 ubiquitin ligase March-I and prevents pMHC-II ubiquitination. Most importantly, this change results in very efficient pMHC-II recycling from the surface of DCs and B cells, thereby preventing targeting of internalized pMHC-II to lysosomes for degradation. Biochemical and functional assays confirmed that pMHC-II turnover is suppressed in MHC-II ubiquitin mutant DCs or by acute activation of wild-type DCs. These studies demonstrate that acute APC activation blocks the ubiquitin-dependent turnover of pMHC-II by promoting efficient pMHC-II recycling and preventing lysosomal targeting of internalized pMHC-II, thereby enhancing pMHC-II stability for efficient antigen presentation to CD4 T cells. PMID- 26240325 TI - Countering antivaccination attitudes. AB - Three times as many cases of measles were reported in the United States in 2014 as in 2013. The reemergence of measles has been linked to a dangerous trend: parents refusing vaccinations for their children. Efforts have been made to counter people's antivaccination attitudes by providing scientific evidence refuting vaccination myths, but these interventions have proven ineffective. This study shows that highlighting factual information about the dangers of communicable diseases can positively impact people's attitudes to vaccination. This method outperformed alternative interventions aimed at undercutting vaccination myths. PMID- 26240326 TI - Effective conservation requires clear objectives and prioritizing actions, not places or species. PMID- 26240327 TI - Spin-liquid polymorphism in a correlated electron system on the threshold of superconductivity. AB - We report neutron scattering measurements which reveal spin-liquid polymorphism in an "11" iron chalcogenide superconductor. It occurs when a poorly metallic magnetic state of FeTe is tuned toward superconductivity by substitution of a small amount of tellurium with isoelectronic sulfur. We observe a liquid-like magnetic response, which is described by the coexistence of two disordered magnetic phases with different local structures whose relative abundance depends on temperature. One is the ferromagnetic (FM) plaquette phase observed in undoped, nonsuperconducting FeTe, which preserves the C4 symmetry of the underlying square lattice and is favored at high temperatures, whereas the other is the antiferromagnetic plaquette phase with broken C4 symmetry, which emerges with doping and is predominant at low temperatures. These findings suggest the coexistence of and competition between two distinct liquid states, and a liquid liquid phase transformation between these states, in the electronic spin system of FeTe(1-x)(S,Se)(x). We have thus discovered the remarkable physics of competing spin-liquid polymorphs in a correlated electron system approaching superconductivity. Our results facilitate an understanding of large swaths of recent experimental data in unconventional superconductors. In particular, the phase with lower C2 local symmetry, whose emergence precedes superconductivity, naturally accounts for a propensity for forming electronic nematic states which have been observed experimentally, in cuprate and iron-based superconductors alike. PMID- 26240328 TI - Linking fecal bacteria in rivers to landscape, geochemical, and hydrologic factors and sources at the basin scale. AB - Linking fecal indicator bacteria concentrations in large mixed-use watersheds back to diffuse human sources, such as septic systems, has met limited success. In this study, 64 rivers that drain 84% of Michigan's Lower Peninsula were sampled under baseflow conditions for Escherichia coli, Bacteroides thetaiotaomicron (a human source-tracking marker), landscape characteristics, and geochemical and hydrologic variables. E. coli and B. thetaiotaomicron were routinely detected in sampled rivers and an E. coli reference level was defined (1.4 log10 most probable number?100 mL(-1)). Using classification and regression tree analysis and demographic estimates of wastewater treatments per watershed, septic systems seem to be the primary driver of fecal bacteria levels. In particular, watersheds with more than 1,621 septic systems exhibited significantly higher concentrations of B. thetaiotaomicron. This information is vital for evaluating water quality and health implications, determining the impacts of septic systems on watersheds, and improving management decisions for locating, constructing, and maintaining on-site wastewater treatment systems. PMID- 26240329 TI - Critical waves and the length problem of biology. AB - It is pointed out that the mystery of how biological systems measure their lengths vanishes away if one premises that they have discovered a way to generate linear waves analogous to compressional sound. These can be used to detect length at either large or small scales using echo timing and fringe counting. It is shown that suitable linear chemical potential waves can, in fact, be manufactured by tuning to criticality conventional reaction-diffusion with a small number substance. Min oscillations in Escherichia coli are cited as precedent resonant length measurement using chemical potential waves analogous to laser detection. Mitotic structures in eukaryotes are identified as candidates for such an effect at higher frequency. The engineering principle is shown to be very general and functionally the same as that used by hearing organs. PMID- 26240330 TI - Siderocalin-mediated recognition, sensitization, and cellular uptake of actinides. AB - Synthetic radionuclides, such as the transuranic actinides plutonium, americium, and curium, present severe health threats as contaminants, and understanding the scope of the biochemical interactions involved in actinide transport is instrumental in managing human contamination. Here we show that siderocalin, a mammalian siderophore-binding protein from the lipocalin family, specifically binds lanthanide and actinide complexes through molecular recognition of the ligands chelating the metal ions. Using crystallography, we structurally characterized the resulting siderocalin-transuranic actinide complexes, providing unprecedented insights into the biological coordination of heavy radioelements. In controlled in vitro assays, we found that intracellular plutonium uptake can occur through siderocalin-mediated endocytosis. We also demonstrated that siderocalin can act as a synergistic antenna to sensitize the luminescence of trivalent lanthanide and actinide ions in ternary protein-ligand complexes, dramatically increasing the brightness and efficiency of intramolecular energy transfer processes that give rise to metal luminescence. Our results identify siderocalin as a potential player in the biological trafficking of f elements, but through a secondary ligand-based metal sequestration mechanism. Beyond elucidating contamination pathways, this work is a starting point for the design of two-stage biomimetic platforms for photoluminescence, separation, and transport applications. PMID- 26240331 TI - Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment. AB - The spindle assembly checkpoint (SAC) is a conserved signaling pathway that monitors faithful chromosome segregation during mitosis. As a core component of SAC, the evolutionarily conserved kinase monopolar spindle 1 (Mps1) has been implicated in regulating chromosome alignment, but the underlying molecular mechanism remains unclear. Our molecular delineation of Mps1 activity in SAC led to discovery of a previously unidentified structural determinant underlying Mps1 function at the kinetochores. Here, we show that Mps1 contains an internal region for kinetochore localization (IRK) adjacent to the tetratricopeptide repeat domain. Importantly, the IRK region determines the kinetochore localization of inactive Mps1, and an accumulation of inactive Mps1 perturbs accurate chromosome alignment and mitotic progression. Mechanistically, the IRK region binds to the nuclear division cycle 80 complex (Ndc80C), and accumulation of inactive Mps1 at the kinetochores prevents a dynamic interaction between Ndc80C and spindle microtubules (MTs), resulting in an aberrant kinetochore attachment. Thus, our results present a previously undefined mechanism by which Mps1 functions in chromosome alignment by orchestrating Ndc80C-MT interactions and highlight the importance of the precise spatiotemporal regulation of Mps1 kinase activity and kinetochore localization in accurate mitotic progression. PMID- 26240332 TI - NLRP12 provides a critical checkpoint for osteoclast differentiation. AB - The alternative or noncanonical nuclear factor kappa B (NF-kappaB) pathway regulates the osteoclast (OC) response to receptor activator of nuclear factor kappa B ligand (RANKL) and thus bone metabolism. Although several lines of evidence support the emerging concept that nucleotide-binding leucine-rich repeat and pyrin domain-containing receptor 12 (NLRP12) impedes alternative NF-kappaB activation in innate immune cells, a functional role for NLRP12 outside an inflammatory disease model has yet to be reported. Our study demonstrates that NLRP12 has a protective role in bone via suppression of alternative NF-kappaB induced osteoclastogenesis and is down-modulated in response to osteoclastogenic stimuli. Here, we show that retroviral overexpression of NLRP12 suppressed RelB nuclear translocation and OC formation. Conversely, genetic ablation of NLRP12 promoted NIK stabilization, RelB nuclear translocation, and increased osteoclastogenesis in vitro. Using radiation chimeras, we demonstrated these in vitro observations dovetail with our in vivo findings that NLRP12 deficiency leads to enhanced OC numbers accompanied by a significant decline in bone mass under physiological conditions. Consistent with the basal bone phenotype, we also observed an enhanced osteolytic response following RANKL injection over the calvaria of NLRP12-deficient chimeric mice compared with wild-type control mice. Thus, modulation of NLRP12 levels controls alternative NF-kappaB signaling in OC precursors, altering bone homeostasis and osteolytic responses. PMID- 26240333 TI - Mapping the conformation of a client protein through the Hsp70 functional cycle. AB - The 70 kDa heat shock protein (Hsp70) chaperone system is ubiquitous, highly conserved, and involved in a myriad of diverse cellular processes. Its function relies on nucleotide-dependent interactions with client proteins, yet the structural features of folding-competent substrates in their Hsp70-bound state remain poorly understood. Here we use NMR spectroscopy to study the human telomere repeat binding factor 1 (hTRF1) in complex with Escherichia coli Hsp70 (DnaK). In the complex, hTRF1 is globally unfolded with up to 40% helical secondary structure in regions distal to the binding site. Very similar conformational ensembles are observed for hTRF1 bound to ATP-, ADP- and nucleotide-free DnaK. The patterns in substrate helicity mirror those found in the unfolded state in the absence of denaturants except near the site of chaperone binding, demonstrating that DnaK-bound hTRF1 retains its intrinsic structural preferences. To our knowledge, our study presents the first atomic resolution structural characterization of a client protein bound to each of the three nucleotide states of DnaK and establishes that the large structural changes in DnaK and the associated energy that accompanies ATP binding and hydrolysis do not affect the overall conformation of the bound substrate protein. PMID- 26240334 TI - FXR1P is a GSK3beta substrate regulating mood and emotion processing. AB - Inhibition of glycogen synthase kinase 3beta (GSK3beta) is a shared action believed to be involved in the regulation of behavior by psychoactive drugs such as antipsychotics and mood stabilizers. However, little is known about the identity of the substrates through which GSK3beta affects behavior. We identified fragile X mental retardation-related protein 1 (FXR1P), a RNA binding protein associated to genetic risk for schizophrenia, as a substrate for GSK3beta. Phosphorylation of FXR1P by GSK3beta is facilitated by prior phosphorylation by ERK2 and leads to its down-regulation. In contrast, behaviorally effective chronic mood stabilizer treatments in mice inhibit GSK3beta and increase FXR1P levels. In line with this, overexpression of FXR1P in the mouse prefrontal cortex also leads to comparable mood-related responses. Furthermore, functional genetic polymorphisms affecting either FXR1P or GSK3beta gene expression interact to regulate emotional brain responsiveness and stability in humans. These observations uncovered a GSK3beta/FXR1P signaling pathway that contributes to regulating mood and emotion processing. Regulation of FXR1P by GSK3beta also provides a mechanistic framework that may explain how inhibition of GSK3beta can contribute to the regulation of mood by psychoactive drugs in mental illnesses such as bipolar disorder. Moreover, this pathway could potentially be implicated in other biological functions, such as inflammation and cell proliferation, in which FXR1P and GSK3 are known to play a role. PMID- 26240335 TI - C-S bond cleavage by a polyketide synthase domain. AB - Leinamycin (LNM) is a sulfur-containing antitumor antibiotic featuring an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18 membered lactam ring. The 1,3-dioxo-1,2-dithiolane moiety is essential for LNM's antitumor activity, by virtue of its ability to generate an episulfonium ion intermediate capable of alkylating DNA. We have previously cloned and sequenced the lnm gene cluster from Streptomyces atroolivaceus S-140. In vivo and in vitro characterizations of the LNM biosynthetic machinery have since established that: (i) the 18-membered macrolactam backbone is synthesized by LnmP, LnmQ, LnmJ, LnmI, and LnmG, (ii) the alkyl branch at C-3 of LNM is installed by LnmK, LnmL, LnmM, and LnmF, and (iii) leinamycin E1 (LNM E1), bearing a thiol moiety at C-3, is the nascent product of the LNM hybrid nonribosomal peptide synthetase (NRPS) acyltransferase (AT)-less type I polyketide synthase (PKS). Sulfur incorporation at C-3 of LNM E1, however, has not been addressed. Here we report that: (i) the bioinformatics analysis reveals a pyridoxal phosphate (PLP)-dependent domain, we termed cysteine lyase (SH) domain (LnmJ-SH), within PKS module-8 of LnmJ; (ii) the LnmJ-SH domain catalyzes C-S bond cleavage by using l-cysteine and l-cysteine S-modified analogs as substrates through a PLP-dependent beta-elimination reaction, establishing l-cysteine as the origin of sulfur at C-3 of LNM; and (iii) the LnmJ-SH domain, sharing no sequence homology with any other enzymes catalyzing C-S bond cleavage, represents a new family of PKS domains that expands the chemistry and enzymology of PKSs and might be exploited to incorporate sulfur into polyketide natural products by PKS engineering. PMID- 26240336 TI - Local generation of multineuronal spike sequences in the hippocampal CA1 region. AB - Sequential activity of multineuronal spiking can be observed during theta and high-frequency ripple oscillations in the hippocampal CA1 region and is linked to experience, but the mechanisms underlying such sequences are unknown. We compared multineuronal spiking during theta oscillations, spontaneous ripples, and focal optically induced high-frequency oscillations ("synthetic" ripples) in freely moving mice. Firing rates and rate modulations of individual neurons, and multineuronal sequences of pyramidal cell and interneuron spiking, were correlated during theta oscillations, spontaneous ripples, and synthetic ripples. Interneuron spiking was crucial for sequence consistency. These results suggest that participation of single neurons and their sequential order in population events are not strictly determined by extrinsic inputs but also influenced by local-circuit properties, including synapses between local neurons and single neuron biophysics. PMID- 26240337 TI - In vivo imaging of axonal transport of mitochondria in the diseased and aged mammalian CNS. AB - The lack of intravital imaging of axonal transport of mitochondria in the mammalian CNS precludes characterization of the dynamics of axonal transport of mitochondria in the diseased and aged mammalian CNS. Glaucoma, the most common neurodegenerative eye disease, is characterized by axon degeneration and the death of retinal ganglion cells (RGCs) and by an age-related increase in incidence. RGC death is hypothesized to result from disturbances in axonal transport and in mitochondrial function. Here we report minimally invasive intravital multiphoton imaging of anesthetized mouse RGCs through the sclera that provides sequential time-lapse images of mitochondria transported in a single axon with submicrometer resolution. Unlike findings from explants, we show that the axonal transport of mitochondria is highly dynamic in the mammalian CNS in vivo under physiological conditions. Furthermore, in the early stage of glaucoma modeled in adult (4-mo-old) mice, the number of transported mitochondria decreases before RGC death, although transport does not shorten. However, with increasing age up to 23-25 mo, mitochondrial transport (duration, distance, and duty cycle) shortens. In axons, mitochondria-free regions increase and lengths of transported mitochondria decrease with aging, although totally organized transport patterns are preserved in old (23- to 25-mo-old) mice. Moreover, axonal transport of mitochondria is more vulnerable to glaucomatous insults in old mice than in adult mice. These mitochondrial changes with aging may underlie the age related increase in glaucoma incidence. Our method is useful for characterizing the dynamics of axonal transport of mitochondria and may be applied to other submicrometer structures in the diseased and aged mammalian CNS in vivo. PMID- 26240338 TI - In situ proteolysis of the Vibrio cholerae matrix protein RbmA promotes biofilm recruitment. AB - The estuarine gram-negative rod and human diarrheal pathogen Vibrio cholerae synthesizes a VPS exopolysaccharide-dependent biofilm matrix that allows it to form a 3D structure on surfaces. Proteins associated with the matrix include, RbmA, RbmC, and Bap1. RbmA, a protein whose crystallographic structure suggests two binding surfaces, associates with cells by means of a VPS-dependent mechanism and promotes biofilm cohesiveness and recruitment of cells to the biofilm. Here, we show that RbmA undergoes limited proteolysis within the biofilm. This proteolysis, which is carried out by the hemagglutinin/protease and accessory proteases, yields the 22-kDa C-terminal polypeptide RbmA*. RbmA* remains biofilm associated. Unlike full-length RbmA, the association of RbmA* with cells is no longer VPS-dependent, likely due to an electropositive surface revealed by proteolysis. We provide evidence that this proteolysis event plays a role in recruitment of VPS(-) cells to the biofilm surface. Based on our findings, we propose that association of RbmA with the matrix reinforces the biofilm structure and leads to limited proteolysis of RbmA to RbmA*. RbmA*, in turn, promotes recruitment of cells that have not yet initiated VPS synthesis to the biofilm surface. The assignment of two functions to RbmA, separated by a proteolytic event that depends on matrix association, dictates an iterative cycle in which reinforcement of recently added biofilm layers precedes the recruitment of new VPS(-) cells to the biofilm. PMID- 26240339 TI - Astrocytes phagocytose focal dystrophies from shortening myelin segments in the optic nerve of Xenopus laevis at metamorphosis. AB - Oligodendrocytes can adapt to increases in axon diameter through the addition of membrane wraps to myelin segments. Here, we report that myelin segments can also decrease their length in response to optic nerve (ON) shortening during Xenopus laevis metamorphic remodeling. EM-based analyses revealed that myelin segment shortening is accomplished by focal myelin-axon detachments and protrusions from otherwise intact myelin segments. Astrocyte processes remove these focal myelin dystrophies using known phagocytic machinery, including the opsonin milk fat globule-EGF factor 8 (Mfge8) and the downstream effector ras-related C3 botulinum toxin substrate 1 (Rac1). By the end of metamorphic nerve shortening, one-quarter of all myelin in the ON is enwrapped or internalized by astrocytes. As opposed to the removal of degenerating myelin by macrophages, which is usually associated with axonal pathologies, astrocytes selectively remove large amounts of myelin without damaging axons during this developmental remodeling event. PMID- 26240340 TI - Identification of a functional hotspot on ubiquitin required for stimulation of methyltransferase activity on chromatin. AB - Ubiquitylation of histone H2B at lysine 120 (H2B-Ub) plays a critical role in transcriptional elongation, chromatin conformation, as well as the regulation of specific histone H3 methylations. Herein, we report a strategy for the site specific chemical attachment of ubiquitin to preassembled nucleosomes. This allowed expedited structure-activity studies into how H2B-Ub regulates H3K79 methylation by the methyltransferase human Dot1. Through an alanine scan of the ubiquitin surface, we identified a functional hotspot on ubiquitin that is required for the stimulation of human Dot1 in vitro. Importantly, this result was validated in chromatin from isolated nuclei by using a synthetic biology strategy that allowed selective incorporation of the hotspot-deficient ubiquitin mutant into H2B. The ubiquitin hotspot additionally impacted the regulation of ySet1 mediated H3K4 methylation but was not required for H2B-Ub-induced impairment of chromatin fiber compaction. These data demonstrate the utility of applying chemical ligation technologies to preassembled chromatin and delineate the multifunctionality of ubiquitin as a histone posttranslational modification. PMID- 26240341 TI - Reply to Zoback and Gorelick: Geologic carbon storage remains a safe strategy to significantly reduce CO2 emissions. PMID- 26240342 TI - To prevent earthquake triggering, pressure changes due to CO2 injection need to be limited. PMID- 26240343 TI - Persistence of the dominant soil phylum Acidobacteria by trace gas scavenging. AB - The majority of microbial cells in global soils exist in a spectrum of dormant states. However, the metabolic processes that enable them to survive environmental challenges, such as nutrient-limitation, remain to be elucidated. In this work, we demonstrate that energy-starved cultures of Pyrinomonas methylaliphatogenes, an aerobic heterotrophic acidobacterium isolated from New Zealand volcanic soils, persist by scavenging the picomolar concentrations of H2 distributed throughout the atmosphere. Following the transition from exponential to stationary phase due to glucose limitation, the bacterium up-regulates by fourfold the expression of an eight-gene operon encoding an actinobacteria-type H2-uptake [NiFe]-hydrogenase. Whole-cells of the organism consume atmospheric H2 in a first-order kinetic process. Hydrogen oxidation occurred most rapidly under oxic conditions and was weakly associated with the cell membrane. We propose that atmospheric H2 scavenging serves as a mechanism to sustain the respiratory chain of P. methylaliphatogenes when organic electron donors are scarce. As the first observation of H2 oxidation to our knowledge in the Acidobacteria, the second most dominant soil phylum, this work identifies new sinks in the biogeochemical H2 cycle and suggests that trace gas oxidation may be a general mechanism for microbial persistence. PMID- 26240344 TI - Dietary changes of large herbivores in the Turkana Basin, Kenya from 4 to 1 Ma. AB - A large stable isotope dataset from East and Central Africa from ca. 30 regional collection sites that range from forest to grassland shows that most extant East and Central African large herbivore taxa have diets dominated by C4 grazing or C3 browsing. Comparison with the fossil record shows that faunal assemblages from ca. 4.1-2.35 Ma in the Turkana Basin had a greater diversity of C3-C4 mixed feeding taxa than is presently found in modern East and Central African environments. In contrast, the period from 2.35 to 1.0 Ma had more C4-grazing taxa, especially nonruminant C4-grazing taxa, than are found in modern environments in East and Central Africa. Many nonbovid C4 grazers became extinct in Africa, notably the suid Notochoerus, the hipparion equid Eurygnathohippus, the giraffid Sivatherium, and the elephantid Elephas. Other important nonruminant C4-grazing taxa switched to browsing, including suids in the lineage Kolpochoerus Hylochoerus and the elephant Loxodonta. Many modern herbivore taxa in Africa have diets that differ significantly from their fossil relatives. Elephants and tragelaphin bovids are two groups often used for paleoecological insight, yet their fossil diets were very different from their modern closest relatives; therefore, their taxonomic presence in a fossil assemblage does not indicate they had a similar ecological function in the past as they do at present. Overall, we find ecological assemblages of C3-browsing, C3-C4-mixed feeding, and C4-grazing taxa in the Turkana Basin fossil record that are different from any modern ecosystem in East or Central Africa. PMID- 26240345 TI - Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells. AB - Tissue homeostasis declines with age partly because stem/progenitor cells fail to self-renew or differentiate. Because mitochondrial damage can accelerate aging, we tested the hypothesis that mitochondrial dysfunction impairs stem cell renewal or function. We developed a mouse model, Tg(KRT14-cre/Esr1) (20Efu/J) * Sod2 (tm1Smel) , that generates mitochondrial oxidative stress in keratin 14 expressing epidermal stem/progenitor cells in a temporally controlled manner owing to deletion of Sod2, a nuclear gene that encodes the mitochondrial antioxidant enzyme superoxide dismutase 2 (Sod2). Epidermal Sod2 loss induced cellular senescence, which irreversibly arrested proliferation in a fraction of keratinocytes. Surprisingly, in young mice, Sod2 deficiency accelerated wound closure, increasing epidermal differentiation and reepithelialization, despite the reduced proliferation. In contrast, at older ages, Sod2 deficiency delayed wound closure and reduced epidermal thickness, accompanied by epidermal stem cell exhaustion. In young mice, Sod2 deficiency accelerated epidermal thinning in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, phenocopying the reduced regeneration of older Sod2-deficient skin. Our results show a surprising beneficial effect of mitochondrial dysfunction at young ages, provide a potential mechanism for the decline in epidermal regeneration at older ages, and identify a previously unidentified age-dependent role for mitochondria in skin quality and wound closure. PMID- 26240346 TI - Synthetic physical interactions map kinetochore regulators and regions sensitive to constitutive Cdc14 localization. AB - The location of proteins within eukaryotic cells is often critical for their function and relocation of proteins forms the mainstay of regulatory pathways. To assess the importance of protein location to cellular homeostasis, we have developed a methodology to systematically create binary physical interactions between a query protein and most other members of the proteome. This method allows us to rapidly assess which of the thousands of possible protein interactions modify a phenotype. As proof of principle we studied the kinetochore, a multiprotein assembly that links centromeres to the microtubules of the spindle during cell division. In budding yeast, the kinetochores from the 16 chromosomes cluster together to a single location within the nucleus. The many proteins that make up the kinetochore are regulated through ubiquitylation and phosphorylation. By systematically associating members of the proteome to the kinetochore, we determine which fusions affect its normal function. We identify a number of candidate kinetochore regulators, including the phosphatase Cdc14. We examine where within the kinetochore Cdc14 can act and show that the effect is limited to regions that correlate with known phosphorylation sites, demonstrating the importance of serine phospho-regulation for normal kinetochore homeostasis. PMID- 26240347 TI - MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation. AB - Inflammatory bowel disease (IBD) is characterized by dysregulated host:microbial interactions and cytokine production. Host pattern recognition receptors (PRRs) are critical in regulating these interactions. Multiple genetic loci are associated with IBD, but altered functions for most, including in the rs713875 MTMR3/HORMAD2/LIF/OSM region, are unknown. We identified a previously undefined role for myotubularin-related protein 3 (MTMR3) in amplifying PRR-induced cytokine secretion in human macrophages and defined MTMR3-initiated mechanisms contributing to this amplification. MTMR3 decreased PRR-induced phosphatidylinositol 3-phosphate (PtdIns3P) and autophagy levels, thereby increasing PRR-induced caspase-1 activation, autocrine IL-1beta secretion, NFkappaB signaling, and, ultimately, overall cytokine secretion. This MTMR3 mediated regulation required the N-terminal pleckstrin homology-GRAM domain and Cys413 within the phosphatase domain of MTMR3. In MTMR3-deficient macrophages, reducing the enhanced autophagy or restoring NFkappaB signaling rescued PRR induced cytokines. Macrophages from rs713875 CC IBD risk carriers demonstrated increased MTMR3 expression and, in turn, decreased PRR-induced PtdIns3P and autophagy and increased PRR-induced caspase-1 activation, signaling, and cytokine secretion. Thus, the rs713875 IBD risk polymorphism increases MTMR3 expression, which modulates PRR-induced outcomes, ultimately leading to enhanced PRR-induced cytokines. PMID- 26240348 TI - Iterative phasing for fluctuation X-ray scattering. AB - Fluctuation X-ray scattering (FXS) is an extension of small- and wide-angle X-ray scattering in which the X-ray snapshots are taken below rotational diffusion times. This technique, performed using a free electron laser or ultrabright synchrotron source, provides significantly more experimental information compared with traditional solution scattering methods. We develop a multitiered iterative phasing algorithm to determine the underlying structure of the scattering object from FXS data. PMID- 26240349 TI - QnAs with Ben Barres. PMID- 26240350 TI - New model to explain tooth wear with implications for microwear formation and diet reconstruction. AB - Paleoanthropologists and vertebrate paleontologists have for decades debated the etiology of tooth wear and its implications for understanding the diets of human ancestors and other extinct mammals. The debate has recently taken a twist, calling into question the efficacy of dental microwear to reveal diet. Some argue that endogenous abrasives in plants (opal phytoliths) are too soft to abrade enamel, and that tooth wear is caused principally by exogenous quartz grit on food. If so, variation in microwear among fossil species may relate more to habitat than diet. This has important implications for paleobiologists because microwear is a common proxy for diets of fossil species. Here we reexamine the notion that particles softer than enamel (e.g., silica phytoliths) do not wear teeth. We scored human enamel using a microfabrication instrument fitted with soft particles (aluminum and brass spheres) and an atomic force microscope (AFM) fitted with silica particles under fixed normal loads, sliding speeds, and spans. Resulting damage was measured by AFM, and morphology and composition of debris were determined by scanning electron microscopy with energy-dispersive X-ray spectroscopy. Enamel chips removed from the surface demonstrate that softer particles produce wear under conditions mimicking chewing. Previous models posited that such particles rub enamel and create ridges alongside indentations without tissue removal. We propose that although these models hold for deformable metal surfaces, enamel works differently. Hydroxyapatite crystallites are "glued" together by proteins, and tissue removal requires only that contact pressure be sufficient to break the bonds holding enamel together. PMID- 26240351 TI - Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities. AB - Obesity and the metabolic syndrome have evolved to be major health issues throughout the world. Whether loss of genome integrity contributes to this epidemic is an open question. DNA polymerase eta (pol eta), encoded by the xeroderma pigmentosum (XP-V) gene, plays an essential role in preventing cutaneous cancer caused by UV radiation-induced DNA damage. Herein, we demonstrate that pol eta deficiency in mice (pol eta(-/-)) causes obesity with visceral fat accumulation, hepatic steatosis, hyperleptinemia, hyperinsulinemia, and glucose intolerance. In comparison to WT mice, adipose tissue from pol eta(-/ ) mice exhibits increased DNA damage and a greater DNA damage response, indicated by up-regulation and/or phosphorylation of ataxia telangiectasia mutated (ATM), phosphorylated H2AX (gammaH2AX), and poly[ADP-ribose] polymerase 1 (PARP-1). Concomitantly, increased cellular senescence in the adipose tissue from pol eta( /-) mice was observed and measured by up-regulation of senescence markers, including p53, p16(Ink4a), p21, senescence-associated (SA) beta-gal activity, and SA secretion of proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) as early as 4 wk of age. Treatment of pol eta(-/-) mice with a p53 inhibitor, pifithrin-alpha, reduced adipocyte senescence and attenuated the metabolic abnormalities. Furthermore, elevation of adipocyte DNA damage with a high-fat diet or sodium arsenite exacerbated adipocyte senescence and metabolic abnormalities in pol eta(-/-) mice. In contrast, reduction of adipose DNA damage with N-acetylcysteine or metformin ameliorated cellular senescence and metabolic abnormalities. These studies indicate that elevated DNA damage is a root cause of adipocyte senescence, which plays a determining role in the development of obesity and insulin resistance. PMID- 26240352 TI - Long-term social dynamics drive loss of function in pathogenic bacteria. AB - Laboratory experiments show that social interactions between bacterial cells can drive evolutionary change at the population level, but significant challenges limit attempts to assess the relevance of these findings to natural populations, where selection pressures are unknown. We have increasingly sophisticated methods for monitoring phenotypic and genotypic dynamics in bacteria causing infectious disease, but in contrast, we lack evidence-based adaptive explanations for those changes. Evolutionary change during infection is often interpreted as host adaptation, but this assumption neglects to consider social dynamics shown to drive evolutionary change in vitro. We provide evidence to show that long-term behavioral dynamics observed in a pathogen are driven by selection to outcompete neighboring conspecific cells through social interactions. We find that Pseudomonas aeruginosa bacteria, causing lung infections in patients with cystic fibrosis, lose cooperative iron acquisition by siderophore production during infection. This loss could be caused by changes in iron availability in the lung, but surprisingly, we find that cells retain the ability to take up siderophores produced by conspecifics, even after they have lost the ability to synthesize siderophores. Only when cooperative producers are lost from the population is the receptor for uptake lost. This finding highlights the potential pitfalls of interpreting loss of function in pathogenic bacterial populations as evidence for trait redundancy in the host environment. More generally, we provide an example of how sequence analysis can be used to generate testable hypotheses about selection driving long-term phenotypic changes of pathogenic bacteria in situ. PMID- 26240353 TI - Flow perfusion effects on three-dimensional culture and drug sensitivity of Ewing sarcoma. AB - Three-dimensional tumor models accurately describe different aspects of the tumor microenvironment and are readily available for mechanistic studies of tumor biology and for drug screening. Nevertheless, these systems often overlook biomechanical stimulation, another fundamental driver of tumor progression. To address this issue, we cultured Ewing sarcoma (ES) cells on electrospun poly(epsilon-caprolactone) 3D scaffolds within a flow perfusion bioreactor. Flow derived shear stress provided a physiologically relevant mechanical stimulation that significantly promoted insulin-like growth factor-1 (IGF1) production and elicited a superadditive release in the presence of exogenous IGF1. This finding is particularly relevant, given the central role of the IGF1/IGF-1 receptor (IGF 1R) pathway in ES tumorigenesis and as a promising clinical target. Additionally, flow perfusion enhanced in a rate-dependent manner the sensitivity of ES cells to IGF-1R inhibitor dalotuzumab (MK-0646) and showed shear stress-dependent resistance to the IGF-1R blockade. This study demonstrates shear stress-dependent ES cell sensitivity to dalotuzumab, highlighting the importance of biomechanical stimulation on ES-acquired drug resistance to IGF-1R inhibition. Furthermore, flow perfusion increased nutrient supply throughout the scaffold, enriching ES culture over static conditions. Our use of a tissue-engineered model, rather than human tumors or xenografts, enabled precise control of the forces experienced by ES cells, and therefore provided at least one explanation for the remarkable antineoplastic effects observed by some ES tumor patients from IGF-1R targeted therapies, in contrast to the lackluster effect observed in cells grown in conventional monolayer culture. PMID- 26240355 TI - Crowded growth leads to the spontaneous evolution of semistable coexistence in laboratory yeast populations. AB - Identifying the mechanisms that create and maintain biodiversity is a central challenge in biology. Stable diversification of microbial populations often requires the evolution of differences in resource utilization. Alternatively, coexistence can be maintained by specialization to exploit spatial heterogeneity in the environment. Here, we report spontaneous diversification maintained by a related but distinct mechanism: crowding avoidance. During experimental evolution of laboratory Saccharomyces cerevisiae populations, we observed the repeated appearance of "adherent" (A) lineages able to grow as a dispersed film, in contrast to their crowded "bottom-dweller" (B) ancestors. These two types stably coexist because dispersal reduces interference competition for nutrients among kin, at the cost of a slower maximum growth rate. This tradeoff causes the frequencies of the two types to oscillate around equilibrium over the course of repeated cycles of growth, crowding, and dispersal. However, further coevolution of the A and B types can perturb and eventually destroy their coexistence over longer time scales. We introduce a simple mathematical model of this "semistable" coexistence, which explains the interplay between ecological and evolutionary dynamics. Because crowded growth generally limits nutrient access in biofilms, the mechanism we report here may be broadly important in maintaining diversity in these natural environments. PMID- 26240354 TI - Heat dissipation guides activation in signaling proteins. AB - Life is fundamentally a nonequilibrium phenomenon. At the expense of dissipated energy, living things perform irreversible processes that allow them to propagate and reproduce. Within cells, evolution has designed nanoscale machines to do meaningful work with energy harnessed from a continuous flux of heat and particles. As dictated by the Second Law of Thermodynamics and its fluctuation theorem corollaries, irreversibility in nonequilibrium processes can be quantified in terms of how much entropy such dynamics produce. In this work, we seek to address a fundamental question linking biology and nonequilibrium physics: can the evolved dissipative pathways that facilitate biomolecular function be identified by their extent of entropy production in general relaxation processes? We here synthesize massive molecular dynamics simulations, Markov state models (MSMs), and nonequilibrium statistical mechanical theory to probe dissipation in two key classes of signaling proteins: kinases and G-protein coupled receptors (GPCRs). Applying machinery from large deviation theory, we use MSMs constructed from protein simulations to generate dynamics conforming to positive levels of entropy production. We note the emergence of an array of peaks in the dynamical response (transient analogs of phase transitions) that draw the proteins between distinct levels of dissipation, and we see that the binding of ATP and agonist molecules modifies the observed dissipative landscapes. Overall, we find that dissipation is tightly coupled to activation in these signaling systems: dominant entropy-producing trajectories become localized near important barriers along known biological activation pathways. We go on to classify an array of equilibrium and nonequilibrium molecular switches that harmonize to promote functional dynamics. PMID- 26240356 TI - Defect tolerance and the effect of structural inhomogeneity in plasmonic DNA nanoparticle superlattices. AB - Bottom-up assemblies of plasmonic nanoparticles exhibit unique optical effects such as tunable reflection, optical cavity modes, and tunable photonic resonances. Here, we compare detailed simulations with experiment to explore the effect of structural inhomogeneity on the optical response in DNA-gold nanoparticle superlattices. In particular, we explore the effect of background environment, nanoparticle polydispersity (>10%), and variation in nanoparticle placement (~5%). At volume fractions less than 20% Au, the optical response is insensitive to particle size, defects, and inhomogeneity in the superlattice. At elevated volume fractions (20% and 25%), structures incorporating different sized nanoparticles (10-, 20-, and 40-nm diameter) each exhibit distinct far-field extinction and near-field properties. These optical properties are most pronounced in lattices with larger particles, which at fixed volume fraction have greater plasmonic coupling than those with smaller particles. Moreover, the incorporation of experimentally informed inhomogeneity leads to variation in far field extinction and inconsistent electric-field intensities throughout the lattice, demonstrating that volume fraction is not sufficient to describe the optical properties of such structures. These data have important implications for understanding the role of particle and lattice inhomogeneity in determining the properties of plasmonic nanoparticle lattices with deliberately designed optical properties. PMID- 26240357 TI - Specific responses of human hippocampal neurons are associated with better memory. AB - A population of human hippocampal neurons has shown responses to individual concepts (e.g., Jennifer Aniston) that generalize to different instances of the concept. However, recordings from the rodent hippocampus suggest an important function of these neurons is their ability to discriminate overlapping representations, or pattern separate, a process that may facilitate discrimination of similar events for successful memory. In the current study, we explored whether human hippocampal neurons can also demonstrate the ability to discriminate between overlapping representations and whether this selectivity could be directly related to memory performance. We show that among medial temporal lobe (MTL) neurons, certain populations of neurons are selective for a previously studied (target) image in that they show a significant decrease in firing rate to very similar (lure) images. We found that a greater proportion of these neurons can be found in the hippocampus compared with other MTL regions, and that memory for individual items is correlated to the degree of selectivity of hippocampal neurons responsive to those items. Moreover, a greater proportion of hippocampal neurons showed selective firing for target images in good compared with poor performers, with overall memory performance correlated with hippocampal selectivity. In contrast, selectivity in other MTL regions was not associated with memory performance. These findings show that a substantial proportion of human hippocampal neurons encode specific memories that support the discrimination of overlapping representations. These results also provide previously unidentified evidence consistent with a unique role of the human hippocampus in orthogonalization of representations in declarative memory. PMID- 26240358 TI - Switching of perpendicularly polarized nanomagnets with spin orbit torque without an external magnetic field by engineering a tilted anisotropy. AB - Spin orbit torque (SOT) provides an efficient way to significantly reduce the current required for switching nanomagnets. However, SOT generated by an in-plane current cannot deterministically switch a perpendicularly polarized magnet due to symmetry reasons. On the other hand, perpendicularly polarized magnets are preferred over in-plane magnets for high-density data storage applications due to their significantly larger thermal stability in ultrascaled dimensions. Here, we show that it is possible to switch a perpendicularly polarized magnet by SOT without needing an external magnetic field. This is accomplished by engineering an anisotropy in the magnets such that the magnetic easy axis slightly tilts away from the direction, normal to the film plane. Such a tilted anisotropy breaks the symmetry of the problem and makes it possible to switch the magnet deterministically. Using a simple Ta/CoFeB/MgO/Ta heterostructure, we demonstrate reversible switching of the magnetization by reversing the polarity of the applied current. This demonstration presents a previously unidentified approach for controlling nanomagnets with SOT. PMID- 26240359 TI - Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock. AB - In mammals, multiple physiological, metabolic, and behavioral processes are subject to circadian rhythms, adapting to changing light in the environment. Here we analyzed circadian rhythms in the fecal microbiota of mice using deep sequencing, and found that the absolute amount of fecal bacteria and the abundance of Bacteroidetes exhibited circadian rhythmicity, which was more pronounced in female mice. Disruption of the host circadian clock by deletion of Bmal1, a gene encoding a core molecular clock component, abolished rhythmicity in the fecal microbiota composition in both genders. Bmal1 deletion also induced alterations in bacterial abundances in feces, with differential effects based on sex. Thus, although host behavior, such as time of feeding, is of recognized importance, here we show that sex interacts with the host circadian clock, and they collectively shape the circadian rhythmicity and composition of the fecal microbiota in mice. PMID- 26240360 TI - Nucleotides regulate the mechanical hierarchy between subdomains of the nucleotide binding domain of the Hsp70 chaperone DnaK. AB - The regulation of protein function through ligand-induced conformational changes is crucial for many signal transduction processes. The binding of a ligand alters the delicate energy balance within the protein structure, eventually leading to such conformational changes. In this study, we elucidate the energetic and mechanical changes within the subdomains of the nucleotide binding domain (NBD) of the heat shock protein of 70 kDa (Hsp70) chaperone DnaK upon nucleotide binding. In an integrated approach using single molecule optical tweezer experiments, loop insertions, and steered coarse-grained molecular simulations, we find that the C-terminal helix of the NBD is the major determinant of mechanical stability, acting as a glue between the two lobes. After helix unraveling, the relative stability of the two separated lobes is regulated by ATP/ADP binding. We find that the nucleotide stays strongly bound to lobe II, thus reversing the mechanical hierarchy between the two lobes. Our results offer general insights into the nucleotide-induced signal transduction within members of the actin/sugar kinase superfamily. PMID- 26240361 TI - SufB intein of Mycobacterium tuberculosis as a sensor for oxidative and nitrosative stresses. AB - Inteins are mobile genetic elements that self-splice at the protein level. Mycobacteria have inteins inserted into several important genes, including those corresponding to the iron-sulfur cluster assembly protein SufB. Curiously, the SufB inteins are found primarily in mycobacterial species that are potential human pathogens. Here we discovered an exceptional sensitivity of Mycobacterium tuberculosis SufB intein splicing to oxidative and nitrosative stresses when expressed in Escherichia coli. This effect results from predisposition of the intein's catalytic cysteine residues to oxidative and nitrosative modifications. Experiments with a fluorescent reporter system revealed that reactive oxygen species and reactive nitrogen species inhibit SufB extein ligation by forcing either precursor accumulation or N-terminal cleavage. We propose that splicing inhibition is an immediate, posttranslational regulatory response that can be either reversible, by inducing precursor accumulation, or irreversible, by inducing N-terminal cleavage, which may potentially channel mycobacteria into dormancy under extreme oxidative and nitrosative stresses. PMID- 26240362 TI - The genetics of human infertility by functional interrogation of SNPs in mice. AB - Infertility is a prevalent health issue, affecting ~15% of couples of childbearing age. Nearly one-half of idiopathic infertility cases are thought to have a genetic basis, but the underlying causes are largely unknown. Traditional methods for studying inheritance, such as genome-wide association studies and linkage analyses, have been confounded by the genetic and phenotypic complexity of reproductive processes. Here we describe an association- and linkage-free approach to identify segregating infertility alleles, in which CRISPR/Cas9 genome editing is used to model putatively deleterious nonsynonymous SNPs (nsSNPs) in the mouse orthologs of fertility genes. Mice bearing "humanized" alleles of four essential meiosis genes, each predicted to be deleterious by most of the commonly used algorithms for analyzing functional SNP consequences, were examined for fertility and reproductive defects. Only a Cdk2 allele mimicking SNP rs3087335, which alters an inhibitory WEE1 protein kinase phosphorylation site, caused infertility and revealed a novel function in regulating spermatogonial stem cell maintenance. Our data indicate that segregating infertility alleles exist in human populations. Furthermore, whereas computational prediction of SNP effects is useful for identifying candidate causal mutations for diverse diseases, this study underscores the need for in vivo functional evaluation of physiological consequences. This approach can revolutionize personalized reproductive genetics by establishing a permanent reference of benign vs. infertile alleles. PMID- 26240363 TI - 21st century United States emissions mitigation could increase water stress more than the climate change it is mitigating. AB - There is evidence that warming leads to greater evapotranspiration and surface drying, thus contributing to increasing intensity and duration of drought and implying that mitigation would reduce water stresses. However, understanding the overall impact of climate change mitigation on water resources requires accounting for the second part of the equation, i.e., the impact of mitigation induced changes in water demands from human activities. By using integrated, high resolution models of human and natural system processes to understand potential synergies and/or constraints within the climate-energy-water nexus, we show that in the United States, over the course of the 21st century and under one set of consistent socioeconomics, the reductions in water stress from slower rates of climate change resulting from emission mitigation are overwhelmed by the increased water stress from the emissions mitigation itself. The finding that the human dimension outpaces the benefits from mitigating climate change is contradictory to the general perception that climate change mitigation improves water conditions. This research shows the potential for unintended and negative consequences of climate change mitigation. PMID- 26240364 TI - Nectar vs. pollen loading affects the tradeoff between flight stability and maneuverability in bumblebees. AB - Bumblebee foragers spend a significant portion of their lives transporting nectar and pollen, often carrying loads equivalent to more than half their body mass. Whereas nectar is stored in the abdomen near the bee's center of mass, pollen is carried on the hind legs, farther from the center of mass. We examine how load position changes the rotational moment of inertia in bumblebees and whether this affects their flight maneuverability and/or stability. We applied simulated pollen or nectar loads of equal mass to Bombus impatiens bumblebees and examined flight performance in a wind tunnel under three conditions: flight in unsteady flow, tracking an oscillating flower in smooth flow, and flower tracking in unsteady flow. Using an inertial model, we estimated that carrying a load on the legs rather than in the abdomen increases a bee's moment of inertia about the roll and yaw axes but not the pitch axis. Consistent with these predictions, we found that bees carrying a load on their legs displayed slower rotations about their roll and yaw axes, regardless of whether these rotations were driven by external perturbations or self-initiated steering maneuvers. This allowed pollen loaded bees to maintain a more stable body orientation and higher median flight speed in unsteady flow but reduced their performance when tracking a moving flower, supporting the concept of a tradeoff between stability and maneuverability. These results demonstrate that the types of resources collected by bees affect their flight performance and energetics and suggest that wind conditions may influence resource selection. PMID- 26240365 TI - Changing central Pacific El Ninos reduce stability of North American salmon survival rates. AB - Pacific salmon are a dominant component of the northeast Pacific ecosystem. Their status is of concern because salmon abundance is highly variable--including protected stocks, a recently closed fishery, and actively managed fisheries that provide substantial ecosystem services. Variable ocean conditions, such as the Pacific Decadal Oscillation (PDO), have influenced these fisheries, while diminished diversity of freshwater habitats have increased variability via the portfolio effect. We address the question of how recent changes in ocean conditions will affect populations of two salmon species. Since the 1980s, El Nino Southern Oscillation (ENSO) events have been more frequently associated with central tropical Pacific warming (CPW) rather than the canonical eastern Pacific warming ENSO (EPW). CPW is linked to the North Pacific Gyre Oscillation (NPGO), whereas EPW is linked to the PDO, different indicators of northeast Pacific Ocean ecosystem productivity. Here we show that both coho and Chinook salmon survival rates along western North America indicate that the NPGO, rather than the PDO, explains salmon survival since the 1980s. The observed increase in NPGO variance in recent decades was accompanied by an increase in coherence of local survival rates of these two species, increasing salmon variability via the portfolio effect. Such increases in coherence among salmon stocks are usually attributed to controllable freshwater influences such as hatcheries and habitat degradation, but the unknown mechanism underlying the ocean climate effect identified here is not directly subject to management actions. PMID- 26240366 TI - Measuring and mitigating agricultural greenhouse gas production in the US Great Plains, 1870-2000. AB - The Great Plains region of the United States is an agricultural production center for the global market and, as such, an important source of greenhouse gas (GHG) emissions. This article uses historical agricultural census data and ecosystem models to estimate the magnitude of annual GHG fluxes from all agricultural sources (e.g., cropping, livestock raising, irrigation, fertilizer production, tractor use) in the Great Plains from 1870 to 2000. Here, we show that carbon (C) released during the plow-out of native grasslands was the largest source of GHG emissions before 1930, whereas livestock production, direct energy use, and soil nitrous oxide emissions are currently the largest sources. Climatic factors mediate these emissions, with cool and wet weather promoting C sequestration and hot and dry weather increasing GHG release. This analysis demonstrates the long term ecosystem consequences of both historical and current agricultural activities, but also indicates that adoption of available alternative management practices could substantially mitigate agricultural GHG fluxes, ranging from a 34% reduction with a 25% adoption rate to as much as complete elimination with possible net sequestration of C when a greater proportion of farmers adopt new agricultural practices. PMID- 26240368 TI - Delicate coordination of TRIM21's dual activity in virus neutralization and signaling. PMID- 26240367 TI - Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice. AB - To better understand human adaptation to stress, and in particular to hypoxia, we took advantage of one of nature's experiments at high altitude (HA) and studied Ethiopians, a population that is well-adapted to HA hypoxic stress. Using whole genome sequencing, we discovered that EDNRB (Endothelin receptor type B) is a candidate gene involved in HA adaptation. To test whether EDNRB plays a critical role in hypoxia tolerance and adaptation, we generated EdnrB knockout mice and found that when EdnrB (-/+) heterozygote mice are treated with lower levels of oxygen (O2), they tolerate various levels of hypoxia (even extreme hypoxia, e.g., 5% O2) very well. For example, they maintain ejection fraction, cardiac contractility, and cardiac output in severe hypoxia. Furthermore, O2 delivery to vital organs was significantly higher and blood lactate was lower in EdnrB (-/+) compared with wild type in hypoxia. Tissue hypoxia in brain, heart, and kidney was lower in EdnrB (-/+) mice as well. These data demonstrate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Transcriptomic profiling of left ventricles revealed three specific genes [natriuretic peptide type A (Nppa), sarcolipin (Sln), and myosin light polypeptide 4 (Myl4)] that were oppositely expressed (q < 0.05) between EdnrB (-/+) and wild type. Functions related to these gene networks were consistent with a better cardiac contractility and performance. We conclude that EDNRB plays a key role in hypoxia tolerance and that a lower level of EDNRB contributes, at least in part, to HA adaptation in humans. PMID- 26240370 TI - Large-scale evidence of dependency length minimization in 37 languages. AB - Explaining the variation between human languages and the constraints on that variation is a core goal of linguistics. In the last 20 y, it has been claimed that many striking universals of cross-linguistic variation follow from a hypothetical principle that dependency length--the distance between syntactically related words in a sentence--is minimized. Various models of human sentence production and comprehension predict that long dependencies are difficult or inefficient to process; minimizing dependency length thus enables effective communication without incurring processing difficulty. However, despite widespread application of this idea in theoretical, empirical, and practical work, there is not yet large-scale evidence that dependency length is actually minimized in real utterances across many languages; previous work has focused either on a small number of languages or on limited kinds of data about each language. Here, using parsed corpora of 37 diverse languages, we show that overall dependency lengths for all languages are shorter than conservative random baselines. The results strongly suggest that dependency length minimization is a universal quantitative property of human languages and support explanations of linguistic variation in terms of general properties of human information processing. PMID- 26240369 TI - Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. AB - Primary aldosteronism (PA) represents the most common cause of secondary hypertension, but little is known regarding its adrenal cellular origins. Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue. PA-causing aldosterone-producing adenomas (APAs) harbor mutations in genes encoding ion channels/pumps that alter intracellular calcium homeostasis and cause renin-independent aldosterone production through increased CYP11B2 expression. Herein, we hypothesized that APCCs have APA-related aldosterone stimulating somatic gene mutations. APCCs were studied in 42 normal adrenals from kidney donors. To clarify APCC molecular characteristics, we used microarrays to compare the APCC transcriptome with conventional adrenocortical zones [zona glomerulosa (ZG), zona fasciculata, and zona reticularis]. The APCC transcriptome was most similar to ZG but with an enhanced capacity to produce aldosterone. To determine if APCCs harbored APA-related mutations, we performed targeted next generation sequencing of DNA from 23 APCCs and adjacent normal adrenal tissue isolated from both formalin-fixed, paraffin-embedded, and frozen tissues. Known aldosterone driver mutations were identified in 8 of 23 (35%) APCCs, including mutations in calcium channel, voltage-dependent, L-type, alpha1D-subunit (CACNA1D; 6 of 23 APCCs) and ATPase, Na(+)/(K+) transporting, alpha1-polypeptide (ATP1A1; 2 of 23 APCCs), which were not observed in the adjacent normal adrenal tissue. Overall, we show three major findings: (i) APCCs are common in normal adrenals, (ii) APCCs harbor somatic mutations known to cause excess aldosterone production, and (iii) the mutation spectrum of aldosterone-driving mutations is different in APCCs from that seen in APA. These results provide molecular support for APCC as a precursor of PA. PMID- 26240371 TI - Essential role for polymerase specialization in cellular nonhomologous end joining. AB - Nonhomologous end joining (NHEJ) repairs chromosome breaks and must remain effective in the face of extensive diversity in broken end structures. We show here that this flexibility is often reliant on the ability to direct DNA synthesis across strand breaks, and that polymerase (Pol) MU and Pol lambda are the only mammalian DNA polymerases that have this activity. By systematically varying substrate in cells, we show each polymerase is uniquely proficient in different contexts. The templating nucleotide is also selected differently, with Pol MU using the unpaired base adjacent to the downstream 5' phosphate even when there are available template sites further upstream of this position; this makes Pol MU more flexible but also less accurate than Pol lambda. Loss of either polymerase alone consequently has clear and distinguishable effects on the fidelity of repair, but end remodeling by cellular nucleases and the remaining polymerase helps mitigate the effects on overall repair efficiency. Accordingly, when cells are deficient in both polymerases there is synergistic impact on NHEJ efficiency, both in terms of repair of defined substrates and cellular resistance to ionizing radiation. Pol MU and Pol lambda thus provide distinct solutions to a problem for DNA synthesis that is unique to this pathway and play a key role in conferring on NHEJ the flexibility required for accurate and efficient repair. PMID- 26240372 TI - Ancient hot and cold genes and chemotherapy resistance emergence. AB - We use a microfabricated ecology with a doxorubicin gradient and population fragmentation to produce a strong Darwinian selective pressure that drives forward the rapid emergence of doxorubicin resistance in multiple myeloma (MM) cancer cells. RNA sequencing of the resistant cells was used to examine (i) emergence of genes with high de novo substitution densities (i.e., hot genes) and (ii) genes never substituted (i.e., cold genes). The set of cold genes, which were 21% of the genes sequenced, were further winnowed down by examining excess expression levels. Both the most highly substituted genes and the most highly expressed never-substituted genes were biased in age toward the most ancient of genes. This would support the model that cancer represents a revision back to ancient forms of life adapted to high fitness under extreme stress, and suggests that these ancient genes may be targets for cancer therapy. PMID- 26240373 TI - Creative template-dependent synthesis by human polymerase mu. AB - Among the many proteins used to repair DNA double-strand breaks by nonhomologous end joining (NHEJ) are two related family X DNA polymerases, Pol lambda and Pol u. Which of these two polymerases is preferentially used for filling DNA gaps during NHEJ partly depends on sequence complementarity at the break, with Pol lambda and Pol u repairing complementary and noncomplementary ends, respectively. To better understand these substrate preferences, we present crystal structures of Pol u on a 2-nt gapped DNA substrate, representing three steps of the catalytic cycle. In striking contrast to Pol lambda, Pol u "skips" the first available template nucleotide, instead using the template base at the 5' end of the gap to direct nucleotide binding and incorporation. This remarkable divergence from canonical 3'-end gap filling is consistent with data on end joining substrate specificity in cells, and provides insights into polymerase substrate choices during NHEJ. PMID- 26240374 TI - RiboAbacus: a model trained on polyribosome images predicts ribosome density and translational efficiency from mammalian transcriptomes. AB - Fluctuations in mRNA levels only partially contribute to determine variations in mRNA availability for translation, producing the well-known poor correlation between transcriptome and proteome data. Recent advances in microscopy now enable researchers to obtain high resolution images of ribosomes on transcripts, providing precious snapshots of translation in vivo. Here we propose RiboAbacus, a mathematical model that for the first time incorporates imaging data in a predictive model of transcript-specific ribosome densities and translational efficiencies. RiboAbacus uses a mechanistic model of ribosome dynamics, enabling the quantification of the relative importance of different features (such as codon usage and the 5' ramp effect) in determining the accuracy of predictions. The model has been optimized in the human Hek-293 cell line to fit thousands of images of human polysomes obtained by atomic force microscopy, from which we could get a reference distribution of the number of ribosomes per mRNA with unmatched resolution. After validation, we applied RiboAbacus to three case studies of known transcriptome-proteome datasets for estimating the translational efficiencies, resulting in an increased correlation with corresponding proteomes. RiboAbacus is an intuitive tool that allows an immediate estimation of crucial translation properties for entire transcriptomes, based on easily obtainable transcript expression levels. PMID- 26240375 TI - ATM-dependent phosphorylation of MRE11 controls extent of resection during homology directed repair by signalling through Exonuclease 1. AB - The MRE11/RAD50/NBS1 (MRN) complex plays a central role as a sensor of DNA double strand breaks (DSB) and is responsible for the efficient activation of ataxia telangiectasia mutated (ATM) kinase. Once activated ATM in turn phosphorylates RAD50 and NBS1, important for cell cycle control, DNA repair and cell survival. We report here that MRE11 is also phosphorylated by ATM at S676 and S678 in response to agents that induce DNA DSB, is dependent on the presence of NBS1, and does not affect the association of members of the complex or ATM activation. A phosphosite mutant (MRE11S676AS678A) cell line showed decreased cell survival and increased chromosomal aberrations after radiation exposure indicating a defect in DNA repair. Use of GFP-based DNA repair reporter substrates in MRE11S676AS678A cells revealed a defect in homology directed repair (HDR) but single strand annealing was not affected. More detailed investigation revealed that MRE11S676AS678A cells resected DNA ends to a greater extent at sites undergoing HDR. Furthermore, while ATM-dependent phosphorylation of Kap1 and SMC1 was normal in MRE11S676AS678A cells, there was no phosphorylation of Exonuclease 1 consistent with the defect in HDR. These results describe a novel role for ATM dependent phosphorylation of MRE11 in limiting the extent of resection mediated through Exonuclease 1. PMID- 26240376 TI - Reassignment of a rare sense codon to a non-canonical amino acid in Escherichia coli. AB - The immutability of the genetic code has been challenged with the successful reassignment of the UAG stop codon to non-natural amino acids in Escherichia coli. In the present study, we demonstrated the in vivo reassignment of the AGG sense codon from arginine to L-homoarginine. As the first step, we engineered a novel variant of the archaeal pyrrolysyl-tRNA synthetase (PylRS) able to recognize L-homoarginine and L-N(6)-(1-iminoethyl)lysine (L-NIL). When this PylRS variant or HarRS was expressed in E. coli, together with the AGG-reading tRNA(Pyl) CCU molecule, these arginine analogs were efficiently incorporated into proteins in response to AGG. Next, some or all of the AGG codons in the essential genes were eliminated by their synonymous replacements with other arginine codons, whereas the majority of the AGG codons remained in the genome. The bacterial host's ability to translate AGG into arginine was then restricted in a temperature-dependent manner. The temperature sensitivity caused by this restriction was rescued by the translation of AGG to L-homoarginine or L-NIL. The assignment of AGG to L-homoarginine in the cells was confirmed by mass spectrometric analyses. The results showed the feasibility of breaking the degeneracy of sense codons to enhance the amino-acid diversity in the genetic code. PMID- 26240378 TI - The conserved 3'X terminal domain of hepatitis C virus genomic RNA forms a two stem structure that promotes viral RNA dimerization. AB - The 3'X domain of hepatitis C virus is a strongly conserved structure located at the 3' terminus of the viral genomic RNA. This domain modulates the replication and translation processes of the virus in conjunction with an upstream 5BSL3.2 stem-loop, and contains a palindromic sequence that facilitates RNA dimerization. Based on nuclear magnetic resonance spectroscopy and gel electrophoresis, we report here that domain 3'X adopts a structure composed of two stem-loops, and not three hairpins or a mixture of folds, as previously proposed. This structure exposes unpaired terminal nucleotides after a double-helical stem and palindromic bases in an apical loop, favoring genomic RNA replication and self-association. At higher ionic strength the domain forms homodimers comprising an intermolecular duplex of 110 nucleotides. The 3'X sequences can alternatively form heterodimers with 5BSL3.2. This contact, reported to favor translation, likely involves local melting of one of the 3'X stem-loops. PMID- 26240377 TI - Telomeric repeat silencing in germ cells is essential for early development in Drosophila. AB - The germline-specific role of telomeres consists of chromosome end elongation and proper chromosome segregation during early developmental stages. Despite the crucial role of telomeres in germ cells, little is known about telomere biology in the germline. We analyzed telomere homeostasis in the Drosophila female germline and early embryos. A novel germline-specific function of deadenylase complex Ccr4-Not in the telomeric transcript surveillance mechanism is reported. Depletion of Ccr4-Not complex components causes strong derepression of the telomeric retroelement HeT-A in the germ cells, accompanied by elongation of the HeT-A poly(A) tail. Dysfunction of transcription factors Woc and Trf2, as well as RNA-binding protein Ars2, also results in the accumulation of excessively polyadenylated HeT-A transcripts in ovaries. Germline knockdowns of Ccr4-Not components, Woc, Trf2 and Ars2, lead to abnormal mitosis in early embryos, characterized by chromosome missegregation, centrosome dysfunction and spindle multipolarity. Moreover, the observed phenotype is accompanied by the accumulation of HeT-A transcripts around the centrosomes in early embryos, suggesting the putative relationship between overexpression of telomeric transcripts and mitotic defects. Our data demonstrate that Ccr4-Not, Woc, Trf2 and Ars2, components of different regulatory pathways, are required for telomere protection in the germline in order to guarantee normal development. PMID- 26240379 TI - Structural basis for DNA strand separation by a hexameric replicative helicase. AB - Hexameric helicases are processive DNA unwinding machines but how they engage with a replication fork during unwinding is unknown. Using electron microscopy and single particle analysis we determined structures of the intact hexameric helicase E1 from papillomavirus and two complexes of E1 bound to a DNA replication fork end-labelled with protein tags. By labelling a DNA replication fork with streptavidin (dsDNA end) and Fab (5' ssDNA) we located the positions of these labels on the helicase surface, showing that at least 10 bp of dsDNA enter the E1 helicase via a side tunnel. In the currently accepted 'steric exclusion' model for dsDNA unwinding, the active 3' ssDNA strand is pulled through a central tunnel of the helicase motor domain as the dsDNA strands are wedged apart outside the protein assembly. Our structural observations together with nuclease footprinting assays indicate otherwise: strand separation is taking place inside E1 in a chamber above the helicase domain and the 5' passive ssDNA strands exits the assembly through a separate tunnel opposite to the dsDNA entry point. Our data therefore suggest an alternative to the current general model for DNA unwinding by hexameric helicases. PMID- 26240380 TI - Functional significance of protein assemblies predicted by the crystal structure of the restriction endonuclease BsaWI. AB - Type II restriction endonuclease BsaWI recognizes a degenerated sequence 5' W/CCGGW-3' (W stands for A or T, '/' denotes the cleavage site). It belongs to a large family of restriction enzymes that contain a conserved CCGG tetranucleotide in their target sites. These enzymes are arranged as dimers or tetramers, and require binding of one, two or three DNA targets for their optimal catalytic activity. Here, we present a crystal structure and biochemical characterization of the restriction endonuclease BsaWI. BsaWI is arranged as an 'open' configuration dimer and binds a single DNA copy through a minor groove contacts. In the crystal primary BsaWI dimers form an indefinite linear chain via the C terminal domain contacts implying possible higher order aggregates. We show that in solution BsaWI protein exists in a dimer-tetramer-oligomer equilibrium, but in the presence of specific DNA forms a tetramer bound to two target sites. Site directed mutagenesis and kinetic experiments show that BsaWI is active as a tetramer and requires two target sites for optimal activity. We propose BsaWI mechanism that shares common features both with dimeric Ecl18kI/SgrAI and bona fide tetrameric NgoMIV/SfiI enzymes. PMID- 26240382 TI - A bacterial regulatory RNA attenuates virulence, spread and human host cell phagocytosis. AB - Staphylococcus aureus pathogenesis is directed by regulatory proteins and RNAs. We report the case of an RNA attenuating virulence and host uptake, possibly to sustain commensalism. A S. aureus sRNA, SprC (srn_3610), reduced virulence and bacterial loads in a mouse infection model. S. aureus deleted for sprC became more virulent and increased bacterial dissemination in colonized animals. Conversely, inducing SprC expression lowered virulence and the bacterial load. Without sprC, S. aureus phagocytosis by monocytes and macrophages was higher, whereas bacteria were internalized at lower yields when SprC expression was stimulated. Without sprC, higher internalization led to a greater number of extracellular bacteria, facilitating colonization. SprC expression decreased after phagocytosis, concurring with the facilitated growth of bacteria lacking the sRNA in the presence of an oxidant. The major staphylococcal autolysin facilitates S. aureus uptake by human phagocytes. ATL proved to be negatively regulated by SprC. The SprC domains involved in pairing with atl mRNA were analyzed. The addition of ATL reduced phagocytosis of bacteria lacking sprC with no effects on wild-type bacterial uptake, implying that SprC influences phagocytosis, at least in part, by controlling ATL. Since the control of SprC on ATL was modest, other factors must contribute to atl regulation. PMID- 26240381 TI - Elongator-dependent modification of cytoplasmic tRNALysUUU is required for mitochondrial function under stress conditions. AB - To gain a wider view of the pathways that regulate mitochondrial function, we combined the effect of heat stress on respiratory capacity with the discovery potential of a genome-wide screen in Saccharomyces cerevisiae. We identified 105 new genes whose deletion impairs respiratory growth at 37 degrees C by interfering with processes such as transcriptional regulation, ubiquitination and cytosolic tRNA wobble uridine modification via 5-methoxycarbonylmethyl-2 thiouridine formation. The latter process, specifically required for efficient decoding of AA-ending codons under stress conditions, was covered by multiple genes belonging to the Elongator (e.g. ELP3) and urmylation (e.g., NCS6) pathways. ELP3 or NCS6 deletants had impaired mitochondrial protein synthesis. Their respiratory deficiency was selectively rescued by overexpression of tRNA(Lys) UUU as well by overexpression of genes (BCK1 and HFM1) with a strong bias for the AAA codon read by this tRNA. These data extend the mitochondrial regulome, demonstrate that heat stress can impair respiration by disturbing cytoplasmic translation of proteins critically involved in mitochondrial function and document, for the first time, the involvement in such process of the Elongator and urmylation pathways. Given the conservation of these pathways, the present findings may pave the way to a better understanding of the human mitochondrial regulome in health and disease. PMID- 26240383 TI - A novel method for the multiplexed target enrichment of MinION next generation sequencing libraries using PCR-generated baits. AB - The enrichment of targeted regions within complex next generation sequencing libraries commonly uses biotinylated baits to capture the desired sequences. This method results in high read coverage over the targets and their flanking regions. Oxford Nanopore Technologies recently released an USB3.0-interfaced sequencer, the MinION. To date no particular method for enriching MinION libraries has been standardized. Here, using biotinylated PCR-generated baits in a novel approach, we describe a simple and efficient way for multiplexed enrichment of MinION libraries, overcoming technical limitations related with the chemistry of the sequencing-adapters and the length of the DNA fragments. Using Phage Lambda and Escherichia coli as models we selectively enrich for specific targets, significantly increasing the corresponding read-coverage, eliminating unwanted regions. We show that by capturing genomic fragments, which contain the target sequences, we recover reads extending targeted regions and thus can be used for the determination of potentially unknown flanking sequences. By pooling enriched libraries derived from two distinct E. coli strains and analyzing them in parallel, we demonstrate the efficiency of this method in multiplexed format. Crucially we evaluated the optimal bait size for large fragment libraries and we describe for the first time a standardized method for target enrichment in MinION platform. PMID- 26240385 TI - Mediator independently orchestrates multiple steps of preinitiation complex assembly in vivo. AB - Mediator is a large multiprotein complex conserved in all eukaryotes, which has a crucial coregulator function in transcription by RNA polymerase II (Pol II). However, the molecular mechanisms of its action in vivo remain to be understood. Med17 is an essential and central component of the Mediator head module. In this work, we utilised our large collection of conditional temperature-sensitive med17 mutants to investigate Mediator's role in coordinating preinitiation complex (PIC) formation in vivo at the genome level after a transfer to a non-permissive temperature for 45 minutes. The effect of a yeast mutation proposed to be equivalent to the human Med17-L371P responsible for infantile cerebral atrophy was also analyzed. The ChIP-seq results demonstrate that med17 mutations differentially affected the global presence of several PIC components including Mediator, TBP, TFIIH modules and Pol II. Our data show that Mediator stabilizes TFIIK kinase and TFIIH core modules independently, suggesting that the recruitment or the stability of TFIIH modules is regulated independently on yeast genome. We demonstrate that Mediator selectively contributes to TBP recruitment or stabilization to chromatin. This study provides an extensive genome-wide view of Mediator's role in PIC formation, suggesting that Mediator coordinates multiple steps of a PIC assembly pathway. PMID- 26240384 TI - Revisiting the structure/function relationships of H/ACA(-like) RNAs: a unified model for Euryarchaea and Crenarchaea. AB - A structural and functional classification of H/ACA and H/ACA-like motifs is obtained from the analysis of the H/ACA guide RNAs which have been identified previously in the genomes of Euryarchaea (Pyrococcus) and Crenarchaea (Pyrobaculum). A unified structure/function model is proposed based on the common structural determinants shared by H/ACA and H/ACA-like motifs in both Euryarchaea and Crenarchaea. Using a computational approach, structural and energetic rules for the guide:target RNA-RNA interactions are derived from structural and functional data on the H/ACA RNP particles. H/ACA(-like) motifs found in Pyrococcus are evaluated through the classification and their biological relevance is discussed. Extra-ribosomal targets found in both Pyrococcus and Pyrobaculum might support the hypothesis of a gene regulation mediated by H/ACA( like) guide RNAs in archaea. PMID- 26240386 TI - Genome-wide analysis of YB-1-RNA interactions reveals a novel role of YB-1 in miRNA processing in glioblastoma multiforme. AB - Altered miRNA expression is believed to play a crucial role in a variety of human cancers; however, the mechanisms leading to the dysregulation of miRNA expression remain elusive. In this study, we report that the human Y box-binding protein (YB 1), a major mRNA packaging protein, is a novel modulator of miRNA processing in glioblastoma multiforme (GBM). Using individual nucleotide-resolution crosslinking immunoprecipitation coupled to deep sequencing (iCLIP-seq), we performed the first genome-wide analysis of the in vivo YB-1-RNA interactions and found that YB-1 preferentially recognizes a UYAUC consensus motif and binds to the majority of coding gene transcripts including pre-mRNAs and mature mRNAs. Remarkably, our data show that YB-1 also binds extensively to the terminal loop region of pri-/pre-miR-29b-2 and regulates the biogenesis of miR-29b-2 by blocking the recruitment of microprocessor and Dicer to its precursors. Furthermore, we show that down-regulation of miR-29b by YB-1, which is up regulated in GBM, is important for cell proliferation. Together, our findings reveal a novel function of YB-1 in regulating non-coding RNA expression, which has important implications in tumorigenesis. PMID- 26240387 TI - Thermodynamic insights into 2-thiouridine-enhanced RNA hybridization. AB - Nucleobase modifications dramatically alter nucleic acid structure and thermodynamics. 2-thiouridine (s(2)U) is a modified nucleobase found in tRNAs and known to stabilize U:A base pairs and destabilize U:G wobble pairs. The recently reported crystal structures of s(2)U-containing RNA duplexes do not entirely explain the mechanisms responsible for the stabilizing effect of s(2)U or whether this effect is entropic or enthalpic in origin. We present here thermodynamic evaluations of duplex formation using ITC and UV thermal denaturation with RNA duplexes containing internal s(2)U:A and s(2)U:U pairs and their native counterparts. These results indicate that s(2)U stabilizes both duplexes. The stabilizing effect is entropic in origin and likely results from the s(2)U induced preorganization of the single-stranded RNA prior to hybridization. The same preorganizing effect is likely responsible for structurally resolving the s(2)U:U pair-containing duplex into a single conformation with a well-defined H bond geometry. We also evaluate the effect of s(2)U on single strand conformation using UV- and CD-monitored thermal denaturation and on nucleoside conformation using (1)H NMR spectroscopy, MD and umbrella sampling. These results provide insights into the effects that nucleobase modification has on RNA structure and thermodynamics and inform efforts toward improving both ribozyme-catalyzed and nonenzymatic RNA copying. PMID- 26240388 TI - Oligonucleotide gap-fill ligation for mutation detection and sequencing in situ. AB - In clinical diagnostics a great need exists for targeted in situ multiplex nucleic acid analysis as the mutational status can offer guidance for effective treatment. One well-established method uses padlock probes for mutation detection and multiplex expression analysis directly in cells and tissues. Here, we use oligonucleotide gap-fill ligation to further increase specificity and to capture molecular substrates for in situ sequencing. Short oligonucleotides are joined at both ends of a padlock gap probe by two ligation events and are then locally amplified by target-primed rolling circle amplification (RCA) preserving spatial information. We demonstrate the specific detection of the A3243G mutation of mitochondrial DNA and we successfully characterize a single nucleotide variant in the ACTB mRNA in cells by in situ sequencing of RCA products generated by padlock gap-fill ligation. To demonstrate the clinical applicability of our assay, we show specific detection of a point mutation in the EGFR gene in fresh frozen and formalin-fixed, paraffin-embedded (FFPE) lung cancer samples and confirm the detected mutation by in situ sequencing. This approach presents several advantages over conventional padlock probes allowing simpler assay design for multiplexed mutation detection to screen for the presence of mutations in clinically relevant mutational hotspots directly in situ. PMID- 26240389 TI - Development and validation of a SYBR Green real-time PCR assay for rapid and quantitative detection of goose interferons and proinflammatory cytokines. AB - Real time quantitative polymerase chain reaction (RT-qPCR) based on SYBR-Green I binding is a quick, reliable, and easy method for analyzing small amounts of mRNA. Viral pathogens are recognized at the time of infection by pattern recognition receptors; thus, the inflammatory cytokines (IL1beta, IL6, and IL18) and antiviral cytokines (IFNalpha, IFNgamma) are secreted by innate immune cells and induced to respond to the pathogens. The objective of this study was to develop an effective and sensitive RT-qPCR assay for the rapid and accurate quantification of goose cytokines: IFNalpha, IFNgamma, IL1beta, IL6, and IL18. Subsequently, the established methods were employed to detect the immune response in agonist-stimulated goose spleen cells in vitro. These data indicated that the established RT-qPCR is a reliable method for determining relative gene expression. The results revealed that Imiquimod led to the significant upregulation of goose IFNalpha (P < 0.01), IFNgamma (P < 0.01), IL1beta (P < 0.01), IL6 (P < 0.01), and IL18 (P < 0.05). The established methods are important for scientific research and clinical applications, which require rapid and accurate results in a short period of time. The technique can potentially be used in the further research of goose molecular immunology, which will help us understand the interactions between hosts and pathogens. PMID- 26240390 TI - Eggshell color in brown-egg laying hens - a review. AB - The major pigment in eggshells of brown-egg laying hens is protoporphyrin IX, but traces of biliverdin and its zinc chelates are also present. The pigment appears to be synthesized in the shell gland. The protoporphyrin IX synthetic pathway is well defined, but precisely where and how it is synthesized in the shell gland of the brown-egg laying hen is still ambiguous. The pigment is deposited onto all shell layers including the shell membranes, but most of it is concentrated in the outermost layer of the calcareous shell and in the cuticle. Recently, the genes that are involved in pigment synthesis have been identified, but the genetic control of synthesis and deposition of brown pigment in the commercial laying hen is not fully understood. The brown coloration of the shell is an important shell quality parameter and has a positive influence on consumer preference. The extent of pigment deposition is influenced by the housing system, hen age, hen strain, diet, stressors, and certain diseases such as infectious bronchitis. In this article, the physiological and biochemical characteristics of the brown pigment in commercial brown-egg layers are reviewed in relation to its various functions in the poultry industry. PMID- 26240391 TI - Effects of dietary fats rich in lauric and myristic acid on performance, intestinal morphology, gut microbes, and meat quality in broilers. AB - This study investigated the hypothesis that dietary fats rich in lauric (C12) and myristic acid (C14) increase broiler performance and that the underlying mechanism involves antimicrobial effects on gut bacteria and changes in gut morphology. One hundred eighty 1-day-old Cobb-500 broilers were allotted to 3 groups. All groups received a basal diet consisting of maize, wheat, soybean meal, and a fat source (4.5, 7.0, 7.6, and 8.0% of fat product in the diet during d 1 to 9, 10 to 17, 18 to 27, and 28 to 35, respectively) until 35 d of age. The diet of the control group contained a fat with 67% of oleic and linoleic acid and 1.4% of C12 and C14 of total fatty acids, that of the esterified lauric and myristic acid (ELA) group a fat with 33% of esterified C12 and C14 and that of the free lauric and myristic acid (FLA) group a fat with 31% of both esterified and free (1:1) C12 and C14 (6 replicates/treatment, 10 birds/replicate). Gain and feed consumption did not differ between groups, but feed:gain was lower in FLA group as compared to the control group (P < 0.05). Carcass weight, liver weight, triglyceride content of liver and muscle, and muscle cholesterol were similar between groups; however, breast muscle weight was higher in the FLA than in the control group (P < 0.05). The villus height:crypt depth ratio of the duodenal wall did not differ between groups, but in the jejunum, it was lower in the FLA group as compared to the control group (P < 0.05). DNA copy numbers of Lactobacillus, Bifidobacteria, Enterobacteria, Escherichia coli, and Campylobacter jejuni in jejunal digesta were similar among groups. The study shows that dietary fats rich in free C12 and C14 improved feed:gain and breast muscle yield, but the observed effects could not be conclusively explained based on the parameters measured. The decreased jejunal villi:crypt ratio may point to changes in gut protein or cell turnover. PMID- 26240392 TI - Eradication of Mycoplasma synoviae from a multi-age broiler breeder farm using antibiotics therapy. AB - Mycoplasma synoviae (MS) is a common respiratory pathogen in the poultry industry. Eradication of MS from broiler breeder flocks is important for reducing economic losses caused by MS-associated diseases on broiler farms. An outbreak of MS infection was detected on a multi-age Korean broiler breeder farm that implements a flock replacement program every 3 to 6 months and uses A-type cages. Continuous administration of tilmicosin after 2 rounds of intensive antibiotics treatment with chlortetracycline, doxycycline, and enrofloxacin reduced MS shedding from the MS-positive flocks and eventually eradicated MS from the farm. Flock 3 was the last MS-positive flock by both PCR and enzyme-linked immunosorbent assay (ELISA), while flocks introduced to the farm after flock 3 were MS-negative by both PCR and ELISA at the time of depletion. This is the first report of successful eradication of MS from a multi-age broiler breeder farm using continuous antibiotic treatments. PMID- 26240393 TI - Effect of dietary probiotic and high stocking density on the performance, carcass yield, gut microflora, and stress indicators of broilers. AB - A study was carried out to evaluate the effect of dietary probiotic supplementation and stocking density on the performance, relative carcass yield, gut microflora, and stress markers of broilers. One-day-old Ross 308 male broiler chickens (n = 480) were allocated to 4 experimental groups for 42 d. Each treatment had 8 replicates of 15 chicks each. Two groups were subjected to a high stocking density (HSD) of 20 birds/m2 and the other 2 groups were kept at low stocking density (LSD) of 10 birds/m2. A basal diet supplemented with probiotic 1 and 0.5 g/kg of diet (in starter and finisher diets, respectively) was fed to 2 treatments, one with HSD and the other with LSD, thereby making a 2 * 2 factorial arrangement. There was no interaction between stocking density (LSD and HSD) and dietary probiotic (supplemented and unsupplemented) for all the variables. Feed intake and weight gain were significantly low and feed conversion ratio was poor in broilers at HSD. Dietary probiotic significantly enhanced the feed intake and weight gain in starter phase only. Dietary probiotic supplementation had no effect (P > 0.05) on total aerobs, Salmonella sp., and Lactobacilli populations in the intestines of broilers. However, HSD reduced the Lactobacilli population only (P < 0.05). Relative breast yields were significantly higher in broilers reared at LSD than HSD. Thigh meat yield was higher in broilers in HSD group compared to LSD. Dietary probiotic did not affect the relative carcass yield and weight of lymphoid organs. Serum malondialdehyde, corticosterone, nitric oxide, and plasma heterophil:lymphocyte ratio were not affected either by stocking density or dietary probiotic supplementation. In conclusion, HSD negatively affected the performance and intestinal Lactobacilli population of broilers only, whereas probiotic supplementation enhanced the performance of broilers during the starter phase only. Total aerobes, Salmonella, Lactobacilli carcass yield, and stress indicators of broilers were not affected by the dietary supplementation of probiotic under the conditions of the present study. PMID- 26240394 TI - Dietary micronized-dehulled white lupin (Lupinus albus L.) in meat-type guinea fowls and its influence on growth performance, carcass traits and meat lipid profile. AB - The present study aimed to evaluate the effects of dietary substitution of soybean meal (SBM) with micronized-dehulled white lupin (Lupinus albus L. cv. Multitalia) in guinea fowl broilers on their growth performance, carcass traits, and meat fatty acids composition. A total of 120 one-day-old guinea fowl females were randomly assigned to 2 treatments which were fed from hatch to 12 wk of age. Birds were fed 2 wheat middlings-based diets comprising of a control treatment which contained SBM (195 g/kg) and a test diet containing micronized-dehulled lupin (240 g/kg) as the main protein source. Replacing SBM with treated lupin had no adverse effect on growth traits, dressing percentage, or breast and thigh muscles relative to the weight of guinea fowls. A decrease (P < 0.05) of abdominal fat was found in guinea fowls fed lupin-diet. Breast muscle from birds fed lupin had higher lightness (L*) (P < 0.01) and redness (a*) (P < 0.05) scores and water-holding capacity (P < 0.05) than the SBM-control diet. Meat from guinea fowls fed lupin had less total lipids (P < 0.05) and cholesterol (P < 0.01), and higher concentrations of phospholipids (P < 0.01). Feeding treated lupin increased polyunsaturated fatty acid (PUFA) levels in breast meat and decreased saturated fatty acid (SFA) concentrations. Our findings suggest that replacing SBM as protein source with micronized-dehulled lupin in meat-type guinea fowl diet can improve carcass qualitative characteristics, enhancing also meat lipid profile with no effect on growth traits. PMID- 26240396 TI - The utilization of the Welfare Quality(r) assessment for determining laying hen condition across three housing systems. AB - The Welfare Quality((r)) Assessment protocol for poultry ( WQA: ) provides animal based measures allowing welfare comparisons across farms and housing systems. It was used to compare Lohmann LSL Classic White hens housed in an enriched colony ( EC: ), aviary ( AV: ), and conventional cage system ( CC: ) on a commercial farm over 2 flock cycles. Hens (n = 100/system) were scored on a variety of measures. A baseline measurement was made at placement at 19 wk of age for 1 flock, since AV hens had been reared in an aviary pullet facility ( AVP: while EC and CC hens were reared in a conventional pullet facility ( CCP: ). Hens in all systems were then assessed at 52 and 72 wk of age. Necropsies were performed on all mortalities 1 wk before and after the WQA sampling. WQAs were analyzed using Mann Whitney U and Kruskal-Wallis tests for prevalence and Fisher's exact tests for severity. There was an effect of rearing, with AVP having shorter claws (P = 0.01), dirtier feathers (P = 0.03), and more keel abnormalities (P < 0.0001) than CCP at placement. For the hens, there were several significant housing system effects across flocks and age periods (all P <= 0.05). AV and EC hens had more keel abnormalities than CC hens. They also had fewer foot abnormalities than CC hens, although those in AV hens were more severe. AV hens had consistently dirtier feathers than EC and CC hens. While AV hens had the best overall feather cover, feather loss patterns suggested that loss was due to head pecking for AV, whereas in EC and CC it was due to cage abrasion. The necropsy findings and the WQA results were similar, except that the WQA failed to find enteritis at 19 wk, although it was detected in the necropsies during this sampling period. These results show that the WQA is a useful tool for detecting hen condition differences across housing systems. PMID- 26240395 TI - Development and nutrient metabolism of embryos from two modern broiler strains. AB - A progressive selection for broiler live and processing performance traits has changed broiler growth patterns during the post hatch period. However, limited information is available to understand whether changes have also occurred during the embryonic stages. This study aims to examine influences of broiler strain on nutrient availability, embryonic development, and nutrient metabolism during incubation. Hatching eggs of Ross 308 and Cobb 500 fast feathering were selected from breeder flocks aged 43 to 46 weeks at an egg weight range of 60 to 63 g. Eggs were obtained in 2 batches, 120 eggs per strain per batch. For each batch, 20 eggs per strain were used to determine egg composition and nutrient availability. The remaining eggs were incubated separately in one of 2 climate respiration chambers at an eggshell temperature of 37.8 degrees C. The results showed that Ross 308 eggs had a higher yolk:albumen ratio with 0.9 g more yolk and 0.7 g less albumen than Cobb 500. Albumen + yolk of Ross 308 eggs had a higher dry matter (Delta = 0.24 g) and crude fat (Delta = 0.23 g) than that of Cobb 500 eggs, but a similar amount of crude protein. Albumen and yolk of Ross 308 eggs had a higher energy content (Delta = 8.9 kJ) compared to Cobb 500 eggs. At 3 h after hatch, Ross 308 chicks were 0.2 cm longer and had a 0.6 g heavier yolk free body mass (YFBM) than Cobb 500 chicks. During incubation, Ross 308 embryos used 13.9 kJ more energy than Cobb 500, and the efficiency of converting energy used to YFBM (EYFB) was approximately 7.6% lower compared to Cobb 500. Ross 308 chicks hatched approximately 4 h later and had less hepatic glycogen (Delta = 5 mg) than Cobb 500 chicks. It can be concluded that, Cobb 500 and Ross 308 differ in egg nutrient availability and have different trajectories for embryonic development and nutrient metabolism during incubation. PMID- 26240397 TI - An individually fitted physical barrier device as a tool to restrict the birds' spatial access: can their use alter behavioral responses? AB - Social interactions have been extensively studied in poultry in a variety of environmental situations. Many studies allow full social contacts between birds, but there are others in which the interactions are tested through barriers (wire mesh or glass). Thus a situation where, according to their needs, some birds can get access to physical contact with conspecifics while others cannot, would be useful to expand the testing options for social interaction studies. We developed an individual physical barrier device (IPB) that is fitted on the birds to delimit their ambulation areas by preventing them from passing across metal mesh boundaries that IPB free counterparts can easily overcome. The prototypes showing greater efficacy consisted of a small metal bar placed in the bird's back perpendicular to the sagittal plane that slightly exceeds body width, held with a harness fitted by 2 elastic fabric bands around the wings' base. To be useful, the IPB should allow natural movements and not affect the expression of behaviors (non-invasive). This study assessed whether the IPB may alter adult Japanese quail behavioral responses using 4 classical test situations: Open-Field, Runway, Time Budget in Home Box, and Mating Interactions. Open-field ambulatory behaviors were affected 1 h, but not 7 d, after IPB was fitted, suggesting that 7 d (or less) are required to habituate to the device. After that time period, IPB fitted birds showed no differences in any of the behaviors registered in the other 3 tests situations when compared to non IPB fitted birds. Findings suggest that after habituation, the IPB does not affect main behaviors in adult quail. Its application could be expanded if an IPB device is also found suitable for other poultry species. PMID- 26240398 TI - Effect of oligosaccharides extract from palm kernel expeller on growth performance, gut microbiota and immune response in broiler chickens. AB - This study examined the prebiotic effects of oligosaccharides extract from palm kernel expeller (OligoPKE) on growth performance, cecal microbiota and immune response of broiler chickens. A total of ninety 1-day-old broiler chicks (Cobb 500) were randomly allocated to three treatment groups of six pens (replicates) with five birds per pen. Dietary treatments were: (i) basal diet as control, (ii) basal diet plus 0.5% OligoPKE, and (iii) basal diet plus 1% OligoPKE. Birds growth traits (ADG, ADFI and G:F) were measured during the starter (1-21 day), finisher (22-35 day) and the entire experimental periods. Blood and cecal digesta samples were collected from chickens at 21 and 35 days of age (DOA). Microbial quantification of the digesta samples, white blood cells including heterophil, lymphocyte, monocyte, eosinophil, basophil counts and immunoglobulin (IgA and IgM) were also determined. OligoPKE had no effect on ADG and ADFI throughout the study period, but chickens fed OligoPKE supplemented diet had better (P < 0.05) G:F during finisher and overall rearing periods. Supplementing OligoPKE did not significantly alter the birds' microbiota of the cecal digesta. At 21 DOA, blood IgA concentration increased significantly when birds fed 1% OligoPKE in diet recorded compared to the control treatment. Similar observations were also recorded in birds at 35 DOA. Hematological data showed that heterophil and basophil counts of chickens fed OligoPKE supplement were lower than those in control group at 21 DOA. Our findings suggested that OligoPKE improved immune responses in broiler chickens, especially at younger age when the immune system is not still fully developed. PMID- 26240399 TI - Analysis of Splicing In Vitro Using Extracts of Saccharomyces cerevisiae. PMID- 26240400 TI - Analysis of Splicing Complexes on Native Gels. PMID- 26240401 TI - Syngeneic Transplants with Modified Chimeric Hematopoietic Tumors. AB - This protocol describes strategies to rapidly transduce tumor cells ex vivo and then transplant modified cells into immunocompetent-recipient mice. Inherent in the definition of a bona fide murine hematopoietic malignancy, unlike a myelo- or lympho-proliferative disease, is the ability to transplant tumors and give rise to a malignancy in recipient animals. This characteristic of hematopoietic disease makes these tumors a tractable model for examining the role of specific genes in tumor growth, dissemination, or therapeutic response. Additionally, because of the systemic nature of hematopoietic malignancies, transplanted tumors are frequently pathologically indistinguishable from donor malignancies-allowing one to perform decisive therapy studies on large cohorts of transplant recipients. Finally, following ex vivo manipulation, transplanted tumors can be made chimeric for the presence of defined retrovirally induced alterations. Thus, these malignancies can be made to resemble genetically heterogeneous human tumors that are in the process of acquiring new capabilities. In these experiments, fluorescent markers serve as a surrogate marker for the expression of a defined alteration, and the change in the percentage of fluorescent cells in a tumor population over time or in response to therapy can be used to gauge the impact of specific alterations on tumor behavior. PMID- 26240402 TI - Loss-of-Function Screening in Hematopoietic Malignancies. AB - Loss-of-function screens can be performed in vivo using retrovirally modified tumor cells. This approach has been used for decades in viral insertional mutagenesis to identify proto-oncogenes. In this approach, tumors are infected with a library of retroviral vectors expressing short-hairpin RNAs (shRNAs), such that each cell receives only a single retroviral insertion, and the representation of proviruses is monitored during ongoing tumor growth or before and after cancer therapy. The resulting tumors are highly chimeric, allowing a large diversity of loss-of-function phenotypes to be monitored simultaneously in an unbiased manner. This approach, used in conjunction with RNAi, can identify genes that are essential for the growth of diverse malignancies in vivo. Here, we outline this approach and discuss key challenges in performing these studies. PMID- 26240403 TI - Rapid Isolation of Nuclei from Cells In Vitro. AB - This protocol presents a rapid, efficient, and practical (REAP) method to separate nuclei from cultured cells in vitro with as little damage and contamination as possible. The REAP procedure is performed at low temperature and takes <2 min, which minimizes protein degradation, protein modification, and diffusion of soluble proteins out of the nuclear compartment while maintaining the integrity of protein complexes. A mild detergent, NP-40, is used together with mild mechanical shearing to disrupt the plasma membrane, leaving the nuclear membrane intact. The REAP method can be used with various cell lines grown in vitro and requires minimal optimization. The isolated nuclei are suitable for numerous downstream applications (e.g., western blotting, 2D gel electrophoresis, and immunoprecipitation). If desired, aliquots of whole-cell lysate and the cytoplasmic fraction can be saved for comparison. PMID- 26240404 TI - Isolation of Pure Nuclei Using a Sucrose Method. AB - This protocol describes a modified version of a widely used method to isolate nuclei from tissue culture cells. It involves mechanical homogenization of cells in isotonic sucrose, followed by velocity centrifugation of nuclei through a denser layer of sucrose. This method, which yields highly pure and intact nuclei, can be optimized for use in various types of tissues and cells. Limitations of the method, alternative options for homogenization, and recommendations for the use of detergents are discussed. PMID- 26240405 TI - Deep Mutational Scanning: Library Construction, Functional Selection, and High Throughput Sequencing. AB - Deep mutational scanning is a highly parallel method that uses high-throughput sequencing to track changes in >10(5) protein variants before and after selection to measure the effects of mutations on protein function. Here we outline the stages of a deep mutational scanning experiment, focusing on the construction of libraries of protein sequence variants and the preparation of Illumina sequencing libraries. PMID- 26240406 TI - Deep Mutational Scanning: Calculating Enrichment Scores for Protein Variants from DNA Sequencing Output Files. AB - During a deep mutational scanning experiment, a collection of variants of a given protein is subjected to high-throughput sequencing before and after selection. The variants that perform well during selection will increase in abundance, whereas those that perform poorly will decrease. Generating a sequence-function map of a protein from a deep mutational scan requires the calculation and comparison of the enrichment scores for each protein variant, based on the results of high-throughput DNA sequencing output files. Here we describe the use of the software program Enrich, which was written specifically for the data analysis phase of a deep mutational scanning experiment. PMID- 26240407 TI - Removal of rRNA from Deproteinized, Phenol-Extracted Total RNA by Hybrid Selection. AB - In this protocol, rRNAs are selectively removed from a total RNA sample by hybridizing the rRNAs to complementary biotinylated oligodeoxynucleotides that can be affinity-purified using streptavidin beads, leaving all other RNAs behind. Although commercially available kits can be used to perform this procedure, they are expensive. We recommend that investigators order species-specific oligodeoxynucleotides for their own applications. There are well-established secondary structure predictions for all rRNAs. PMID- 26240408 TI - Monitoring Autophagic Flux by Using Lysosomal Inhibitors and Western Blotting of Endogenous MAP1LC3B. AB - Assays that monitor autophagic flux, or degradative completion of autophagy, are crucial for the assessment of the dynamic autophagy process in a variety of systems. Such assays help to distinguish between an increase in autophagosomes resulting from induced autophagic activity versus an increase in autophagosomes due to reduced lysosomal turnover. The majority of flux assays use autophagy protein MAP1LC3B (microtubule-associated proteins 1A/1B light chain 3B, here referred to as LC3B) as a marker for autophagy, and most are based on the use of reporters. Here, we describe a method, suitable for monitoring flux in primary cells and/or when reporters are not available or desirable, that uses lysosomal inhibitors and the analysis of endogenous LC3B-II (the lipidated form of LC3B that is associated with autophagosomes) by western blotting. A common application of this method, detailed here, is to test whether a treatment of interest (e.g., chemotherapy drug) induces autophagic flux in the cells of interest. If it is found that there is no difference in LC3B-II levels between treatment with lysosomal inhibitor alone versus drug plus lysosomal inhibitor, then this suggests that the drug is not inducing autophagic flux. Elevated levels of LC3B II in treatments with drug plus lysosomal inhibitor, compared with drug treatment alone and inhibitor treatment alone, indicate that the drug is probably leading to an increase in autophagic flux. PMID- 26240409 TI - Monitoring the Localization of MAP1LC3B by Indirect Immunofluorescence. AB - The autophagy protein MAP1LC3B (microtubule-associated proteins 1A/1B light chain 3B, hereafter referred to as LC3B), which is one of several mammalian homologs of yeast Atg8, is one of the most popular markers for autophagosome formation because its distribution changes from cytosolic/diffuse to punctate upon the induction of autophagy. In many settings, plasmids encoding fluorescently tagged LC3B are introduced into cells, and the subsequent autophagy response is monitored. However, for a variety of reasons, it would be desirable also to have a protocol to monitor the localization of endogenous LC3B under various conditions. This protocol provides such a methodology for the staining of endogenous LC3B by indirect immunofluorescence, such that autophagy responses can be monitored in mammalian cells. PMID- 26240410 TI - Detection of p62 on Paraffin Sections by Immunohistochemistry. AB - The study of autophagy in human disease is a rapidly expanding field. Diagnostic paraffin sections of a variety of patient tissues, including bone marrow, are available to researchers-yet are unsuitable for traditional autophagy quantification methods such as western blot or electron microscopy. This protocol outlines the immunohistochemical detection of the protein p62 (sequestosome-1, encoded by the gene SQSTM1)-an indicator of autophagic degradative activity-in slide-mounted paraffin sections such as bone marrow samples cut by a trephine. The p62 protein is an autophagic cargo adaptor, capable of binding to ubiquitylated proteins as well as autophagosome membrane proteins (LC3B and GABA(A) receptor-associated protein [GABARAP] family members) and hypothesized thus to target protein aggregates for lysosomal degradation. p62 itself is degraded by autophagy, remaining at low levels when autophagy is induced, and has been shown to accumulate when autophagy is deficient. Qualitative assessment and comparison of p62 staining between healthy and disease sections or disease subtypes will help target further investigation into the potential roles for autophagy in a variety of disorders. PMID- 26240411 TI - Ca2+ Uncaging in Nerve Terminals: A Three-Point Calibration Procedure. AB - Ca(2+) uncaging can be used to create a spatially homogenous elevation of the intracellular free Ca(2+) concentration, [Ca(2+)]i, in cells. When applied to nerve terminals or secretory cells, this technique allows one to elicit transmitter release with a [Ca(2+)]i signal of measurable amplitude, and therefore to directly relate the rate of transmitter release to the measured [Ca(2+)]i. When combined with patch-clamp measurements, Ca(2+) uncaging is done by introducing a Ca(2+)-loaded photolyzable Ca(2+) chelator (like DM-nitrophen) into the cell via the whole-cell patch-pipette. A brief light pulse from a flash lamp or a pulsed laser is used to photolyze the DM-nitrophen. The resulting increase in [Ca(2+)]i is measured with ratiometric fluorescent indicators of suitable Ca(2+) affinity, such as Fura-2, Fura-4F, Fura-2FF, or Fura-6F, depending on the postflash [Ca(2+)]i values. To quantitatively measure [Ca(2+)]i, an accurate calibration of the fluorescent indicator in the presence of the photolyzable Ca(2+) chelator is necessary, which will be described here. Ca(2+) uncaging in nerve terminals has proven useful for investigating Ca(2+)-dependent functions like transmitter release, short-term plasticity, and exocytosis endocytosis coupling in the presynaptic compartment of neurons. PMID- 26240412 TI - Chimeric Tumor and Organ Transplantation Models. AB - Mouse models of cancer development and progression provide a means to study tumor response in appropriate physiological contexts. However, mouse cancer progression and therapy models have traditionally suffered from many of the same problems as human clinical cancer research, including genetic heterogeneity and tumor-stage variability at the time of treatment. Additionally, most mouse models are not tractable genetic systems, making it difficult to recapitulate the diverse set of alterations that regularly occur during tumor development. The recent development of chimeric and tumor transplantation techniques address many of the limitations of conventional mouse genetics. These strategies allow for the somatic introduction of complex genetic alterations into a subset of cells in reconstituted tumors or organ systems. Moreover, these different approaches can be combined in such a way that tumors with multiple genotypes are rapidly produced. These matched pairs can be systemically introduced into recipient mice for the rapid ex vivo modification of preestablished malignancies allows the generation of "matched pairs" of tumors differing in a single defined lesion (i.e., aliquots of the same primary malignancy with and without a gene of interest). Thus, treatment studies can be performed (1) in the context of an otherwise normal organ system, (2) on tumors that are in their appropriate anatomical context, and (3) on tumors that are essentially identical besides the presence of defined experimentally introduced alterations. Here, we will introduce procedures for modifying both normal and transformed cells and their adaptation to study in vivo tumor biology. PMID- 26240413 TI - Isolation of Nuclei. AB - The isolation of nuclei is often the first step in studying processes such as nuclear-cytoplasmic shuttling, subcellular localization of proteins, and protein chromatin or nuclear protein-protein interactions in response to diverse stimuli. Therefore, rapidly obtaining nuclei from cells with relatively high purity and minimal subcellular contamination, protein degradation, or postharvesting modification is highly desirable. Historically, the isolation of nuclei involved a homogenization step followed by centrifugation through high-density glycerol or sucrose. Although clean nuclei with little cytoplasmic contamination can be prepared using this method, it is typically time consuming and can allow protein degradation, protein modification, and leaching of components from the nuclei to occur. We have developed a rapid and simple fractionation method that is based on the selective dissolution of the cytoplasmic membrane (but not the nuclear membrane) using a low concentration of a nonionic detergent and rapid centrifugation steps. Here we describe important considerations when isolating nuclei from cells, introduce our rapid method, and compare this method to a more traditional protocol for isolating nuclei, noting the strengths and limitations of each approach. PMID- 26240414 TI - Deep Mutational Scanning: A Highly Parallel Method to Measure the Effects of Mutation on Protein Function. AB - Deep mutational scanning is a method that makes use of next-generation sequencing technology to measure in a single experiment the activity of 10(5) or more unique variants of a protein. Because of this depth of mutational coverage, this strategy provides data that can be analyzed to reveal many protein properties. Deep mutational scanning approaches are particularly amenable to being performed in Saccharomyces cerevisiae, given the extensive toolkit of reagents and technologies available for this organism. PMID- 26240415 TI - Optogenetics in Freely Moving Mammals: Dopamine and Reward. AB - Brain reward systems play a central role in the cognitive and hedonic behaviors of mammals. Multiple neuron types and brain regions are involved in reward processing, posing fascinating scientific questions, and major experimental challenges. Using diverse approaches including genetics, electrophysiology, imaging, and behavioral analysis, a large body of research has focused on both normal functioning of the reward circuitry and on its potential significance in neuropsychiatric diseases. In this introduction, we illustrate a real-world application of optogenetics to mammalian behavior and physiology, delineating procedures and technologies for optogenetic control of individual components of the reward circuitry. We describe the experimental setup and protocol for integrating optogenetic modulation of dopamine neurons with fast-scan cyclic voltammetry, conditioned place preference, and operant conditioning to assess the causal role of well-defined electrical and biochemical signals in reward-related behavior. PMID- 26240416 TI - Expression and functional implications of luteal endothelins in pregnant and non pregnant dogs. AB - Luteal development is regulated by many locally produced mediators, e.g., prostaglandins and angiogenic factors. However, the role and function of vasoactive factors in the canine corpus luteum (CL) remain largely unknown. Consequently, expression of the endothelin (ET) receptors-A and -B (ETA and ETB, revealing vasoconstriction and vasodilator properties respectively), the ET converting enzyme (ECE1) and ET1, -2 and -3 were investigated in CL from non pregnant dogs (days 5, 15, 25, 35, 45 and 65 post-ovulation), and at selected stages of pregnancy (pre-implantation, post-implantation, mid-gestation), and during normal and antigestagen-induced prepartum luteolysis/abortion. The interrelationship between PGE2 and the ET system was investigated in PGE2-treated canine primary lutein cells from early CL. ET1 did not change significantly over time; ET2, ECE1 and ETB were elevated in early CL and were downregulated towards the mid/late-luteal phase. The prepartum increase of ET2 was significant. ET3 increased gradually, and was highest in late CL and/or at prepartum luteolysis. ETA remained constant until the late CL phase and increased only during prepartum luteolysis. ET1 was localized to the luteal cells, and ET2, ET3 and ETA to vascular endothelium. ECE1 and ETB were detected at both locations. Except for upregulated ET1 and lack of effect on ET2, antigestagen applied to mid-pregnant dogs evoked similar changes to those observed during normal luteolysis. PGE2 upregulated ETB in treated cells; ETA and ET1 remained unaffected, and ET2 decreased. A modulatory role of the ETs in canine CL, possibly in association with other factors (e.g., PGE2 and progesterone receptor), is strongly indicated. PMID- 26240417 TI - Understanding the brain by controlling neural activity. AB - Causal methods to interrogate brain function have been employed since the advent of modern neuroscience in the nineteenth century. Initially, randomly placed electrodes and stimulation of parts of the living brain were used to localize specific functions to these areas. Recent technical developments have rejuvenated this approach by providing more precise tools to dissect the neural circuits underlying behaviour, perception and cognition. Carefully controlled behavioural experiments have been combined with electrical devices, targeted genetically encoded tools and neurochemical approaches to manipulate information processing in the brain. The ability to control brain activity in these ways not only deepens our understanding of brain function but also provides new avenues for clinical intervention, particularly in conditions where brain processing has gone awry. PMID- 26240418 TI - Dissecting neural circuits for multisensory integration and crossmodal processing. AB - We rely on rich and complex sensory information to perceive and understand our environment. Our multisensory experience of the world depends on the brain's remarkable ability to combine signals across sensory systems. Behavioural, neurophysiological and neuroimaging experiments have established principles of multisensory integration and candidate neural mechanisms. Here we review how targeted manipulation of neural activity using invasive and non-invasive neuromodulation techniques have advanced our understanding of multisensory processing. Neuromodulation studies have provided detailed characterizations of brain networks causally involved in multisensory integration. Despite substantial progress, important questions regarding multisensory networks remain unanswered. Critically, experimental approaches will need to be combined with theory in order to understand how distributed activity across multisensory networks collectively supports perception. PMID- 26240420 TI - Using perturbations to identify the brain circuits underlying active vision. AB - The visual and oculomotor systems in the brain have been studied extensively in the primate. Together, they can be regarded as a single brain system that underlies active vision--the normal vision that begins with visual processing in the retina and extends through the brain to the generation of eye movement by the brainstem. The system is probably one of the most thoroughly studied brain systems in the primate, and it offers an ideal opportunity to evaluate the advantages and disadvantages of the series of perturbation techniques that have been used to study it. The perturbations have been critical in moving from correlations between neuronal activity and behaviour closer to a causal relation between neuronal activity and behaviour. The same perturbation techniques have also been used to tease out neuronal circuits that are related to active vision that in turn are driving behaviour. The evolution of perturbation techniques includes ablation of both cortical and subcortical targets, punctate chemical lesions, reversible inactivations, electrical stimulation, and finally the expanding optogenetic techniques. The evolution of perturbation techniques has supported progressively stronger conclusions about what neuronal circuits in the brain underlie active vision and how the circuits themselves might be organized. PMID- 26240419 TI - What single-cell stimulation has told us about neural coding. AB - In recent years, single-cell stimulation experiments have resulted in substantial progress towards directly linking single-cell activity to movement and sensation. Recent advances in electrical recording and stimulation techniques have enabled control of single neuron spiking in vivo and have contributed to our understanding of neuronal coding schemes in the brain. Here, we review single neuron stimulation effects in different brain structures and how they vary with artificially inserted spike patterns. We briefly compare single neuron stimulation with other brain stimulation techniques. A key advantage of single neuron stimulation is the precise control of the evoked spiking patterns. Systematically varying spike patterns and measuring evoked movements and sensations enables 'decoding' of the single-cell spike patterns and provides insights into the readout mechanisms of sensory and motor cortical spikes. PMID- 26240421 TI - Playing the electric light orchestra--how electrical stimulation of visual cortex elucidates the neural basis of perception. AB - Vision research has the potential to reveal fundamental mechanisms underlying sensory experience. Causal experimental approaches, such as electrical microstimulation, provide a unique opportunity to test the direct contributions of visual cortical neurons to perception and behaviour. But in spite of their importance, causal methods constitute a minority of the experiments used to investigate the visual cortex to date. We reconsider the function and organization of visual cortex according to results obtained from stimulation techniques, with a special emphasis on electrical stimulation of small groups of cells in awake subjects who can report their visual experience. We compare findings from humans and monkeys, striate and extrastriate cortex, and superficial versus deep cortical layers, and identify a number of revealing gaps in the 'causal map' of visual cortex. Integrating results from different methods and species, we provide a critical overview of the ways in which causal approaches have been used to further our understanding of circuitry, plasticity and information integration in visual cortex. Electrical stimulation not only elucidates the contributions of different visual areas to perception, but also contributes to our understanding of neuronal mechanisms underlying memory, attention and decision-making. PMID- 26240422 TI - Revealing humans' sensorimotor functions with electrical cortical stimulation. AB - Direct electrical stimulation (DES) of the human brain has been used by neurosurgeons for almost a century. Although this procedure serves only clinical purposes, it generates data that have a great scientific interest. Had DES not been employed, our comprehension of the organization of the sensorimotor systems involved in movement execution, language production, the emergence of action intentionality or the subjective feeling of movement awareness would have been greatly undermined. This does not mean, of course, that DES is a gold standard devoid of limitations and that other approaches are not of primary importance, including electrophysiology, modelling, neuroimaging or psychophysics in patients and healthy subjects. Rather, this indicates that the contribution of DES cannot be restricted, in humans, to the ubiquitous concepts of homunculus and somatotopy. DES is a fundamental tool in our attempt to understand the human brain because it represents a unique method for mapping sensorimotor pathways and interfering with the functioning of localized neural populations during the performance of well-defined behavioural tasks. PMID- 26240423 TI - Pulse trains to percepts: the challenge of creating a perceptually intelligible world with sight recovery technologies. AB - An extraordinary variety of sight recovery therapies are either about to begin clinical trials, have begun clinical trials, or are currently being implanted in patients. However, as yet we have little insight into the perceptual experience likely to be produced by these implants. This review focuses on methodologies, such as optogenetics, small molecule photoswitches and electrical prostheses, which use artificial stimulation of the retina to elicit percepts. For each of these technologies, the interplay between the stimulating technology and the underlying neurophysiology is likely to result in distortions of the perceptual experience. Here, we describe some of these potential distortions and discuss how they might be minimized either through changes in the encoding model or through cortical plasticity. PMID- 26240424 TI - Biological and bionic hands: natural neural coding and artificial perception. AB - The first decade and a half of the twenty-first century brought about two major innovations in neuroprosthetics: the development of anthropomorphic robotic limbs that replicate much of the function of a native human arm and the refinement of algorithms that decode intended movements from brain activity. However, skilled manipulation of objects requires somatosensory feedback, for which vision is a poor substitute. For upper-limb neuroprostheses to be clinically viable, they must therefore provide for the restoration of touch and proprioception. In this review, I discuss efforts to elicit meaningful tactile sensations through stimulation of neurons in somatosensory cortex. I focus on biomimetic approaches to sensory restoration, which leverage our current understanding about how information about grasped objects is encoded in the brain of intact individuals. I argue that not only can sensory neuroscience inform the development of sensory neuroprostheses, but also that the converse is true: stimulating the brain offers an exceptional opportunity to causally interrogate neural circuits and test hypotheses about natural neural coding. PMID- 26240425 TI - Contemporary approaches to neural circuit manipulation and mapping: focus on reward and addiction. AB - Tying complex psychological processes to precisely defined neural circuits is a major goal of systems and behavioural neuroscience. This is critical for understanding adaptive behaviour, and also how neural systems are altered in states of psychopathology, such as addiction. Efforts to relate psychological processes relevant to addiction to activity within defined neural circuits have been complicated by neural heterogeneity. Recent advances in technology allow for manipulation and mapping of genetically and anatomically defined neurons, which when used in concert with sophisticated behavioural models, have the potential to provide great insight into neural circuit bases of behaviour. Here we discuss contemporary approaches for understanding reward and addiction, with a focus on midbrain dopamine and cortico-striato-pallidal circuits. PMID- 26240427 TI - Illuminating neural circuits and behaviour in Caenorhabditis elegans with optogenetics. AB - The development of optogenetics, a family of methods for using light to control neural activity via light-sensitive proteins, has provided a powerful new set of tools for neurobiology. These techniques have been particularly fruitful for dissecting neural circuits and behaviour in the compact and transparent roundworm Caenorhabditis elegans. Researchers have used optogenetic reagents to manipulate numerous excitable cell types in the worm, from sensory neurons, to interneurons, to motor neurons and muscles. Here, we show how optogenetics applied to this transparent roundworm has contributed to our understanding of neural circuits. PMID- 26240426 TI - Light, heat, action: neural control of fruit fly behaviour. AB - The fruit fly Drosophila melanogaster has emerged as a popular model to investigate fundamental principles of neural circuit operation. The sophisticated genetics and small brain permit a cellular resolution understanding of innate and learned behavioural processes. Relatively recent genetic and technical advances provide the means to specifically and reproducibly manipulate the function of many fly neurons with temporal resolution. The same cellular precision can also be exploited to express genetically encoded reporters of neural activity and cell signalling pathways. Combining these approaches in living behaving animals has great potential to generate a holistic view of behavioural control that transcends the usual molecular, cellular and systems boundaries. In this review, we discuss these approaches with particular emphasis on the pioneering studies and those involving learning and memory. PMID- 26240430 TI - Agency and intervention. AB - Novel ways to intervene on brain function raise questions about agency and responsibility. Here, I discuss whether direct brain interventions, and in particular, deep brain stimulation, pose a threat to agency in individual cases, or to our general conceptualization of what it is to be a responsible agent. While I do not currently see evidence that these interventions constitute a global challenge to our concept of agency, they do have the potential to diminish agency in individuals. I consider whether the lack of evidence for a global challenge ratifies our folk conceptions, or is a necessary consequence of them. In closing, I propose that our theoretical understanding of agency and our therapeutic approaches could be improved with a more nuanced, multidimensional view of agency. PMID- 26240428 TI - A neurocognitive model for understanding treatment action in depression. AB - The way in which emotion is represented and processed in the human brain is an expanding area of research and has key implications for how we understand and potentially treat affective disorders such as depression. Characterizing the effects of pharmacological manipulations of key neurotransmitter systems can also help reveal the neurochemical underpinnings of emotional processing and how common antidepressant drugs may work in the treatment of depression and anxiety. This approach has revealed that depression is associated with both neural and behavioural biases towards negative over positive stimuli. Evidence from pharmacological challenge studies suggests that antidepressant treatment acts to normalize these biases early on in treatment, resulting in patients experiencing the world in a more positive way, improving their mood over time. This model is supported by evidence from both pharmacological and non-pharmacological interventions. The unique perspective on antidepressant treatment offered by this approach provides some insights into individual response to treatment, as well as novel approaches to drug development. PMID- 26240429 TI - The impact of neuroscience on society: cognitive enhancement in neuropsychiatric disorders and in healthy people. AB - In addition to causing distress and disability to the individual, neuropsychiatric disorders are also extremely expensive to society and governments. These disorders are both common and debilitating and impact on cognition, functionality and wellbeing. Cognitive enhancing drugs, such as cholinesterase inhibitors and methylphenidate, are used to treat cognitive dysfunction in Alzheimer's disease and attention deficit hyperactivity disorder, respectively. Other cognitive enhancers include specific computerized cognitive training and devices. An example of a novel form of cognitive enhancement using the technological advancement of a game on an iPad that also acts to increase motivation is presented. Cognitive enhancing drugs, such as methylphenidate and modafinil, which were developed as treatments, are increasingly being used by healthy people. Modafinil not only affects 'cold' cognition, but also improves 'hot' cognition, such as emotion recognition and task-related motivation. The lifestyle use of 'smart drugs' raises both safety concerns as well as ethical issues, including coercion and increasing disparity in society. As a society, we need to consider which forms of cognitive enhancement (e.g. pharmacological, exercise, lifelong learning) are acceptable and for which groups (e.g. military, doctors) under what conditions (e.g. war, shift work) and by what methods we would wish to improve and flourish. PMID- 26240431 TI - Manipulating neural activity in physiologically classified neurons: triumphs and challenges. AB - Understanding brain function requires knowing both how neural activity encodes information and how this activity generates appropriate responses. Electrophysiological, imaging and immediate early gene immunostaining studies have been instrumental in identifying and characterizing neurons that respond to different sensory stimuli, events and motor actions. Here we highlight approaches that have manipulated the activity of physiologically classified neurons to determine their role in the generation of behavioural responses. Previous experiments have often exploited the functional architecture observed in many cortical areas, where clusters of neurons share response properties. However, many brain structures do not exhibit such functional architecture. Instead, neurons with different response properties are anatomically intermingled. Emerging genetic approaches have enabled the identification and manipulation of neurons that respond to specific stimuli despite the lack of discernable anatomical organization. These approaches have advanced understanding of the circuits mediating sensory perception, learning and memory, and the generation of behavioural responses by providing causal evidence linking neural response properties to appropriate behavioural output. However, significant challenges remain for understanding cognitive processes that are probably mediated by neurons with more complex physiological response properties. Currently available strategies may prove inadequate for determining how activity in these neurons is causally related to cognitive behaviour. PMID- 26240432 TI - AMIGO-Kv2.1 Potassium Channel Complex Is Associated With Schizophrenia-Related Phenotypes. AB - The enormous variability in electrical properties of neurons is largely affected by a multitude of potassium channel subunits. Kv2.1 is a widely expressed voltage dependent potassium channel and an important regulator of neuronal excitability. The Kv2.1 auxiliary subunit AMIGO constitutes an integral part of the Kv2.1 channel complex in brain and regulates the activity of the channel. AMIGO and Kv2.1 localize to the distinct somatodendritic clusters at the neuronal plasma membrane. Here we have created and characterized a mouse line lacking the AMIGO gene. Absence of AMIGO clearly reduced the amount of the Kv2.1 channel protein in mouse brain and altered the electrophysiological properties of neurons. These changes were accompanied by behavioral and pharmacological abnormalities reminiscent of those identified in schizophrenia. Concomitantly, we have detected an association of a rare, population-specific polymorphism of KV2.1 (KCNB1) with human schizophrenia in a genetic isolate enriched with schizophrenia. Our study demonstrates the involvement of AMIGO-Kv2.1 channel complex in schizophrenia related behavioral domains in mice and identifies KV2.1 (KCNB1) as a strong susceptibility gene for schizophrenia spectrum disorders in humans. PMID- 26240433 TI - Transplantation of Epigenetically Modified Adult Cardiac c-Kit+ Cells Retards Remodeling and Improves Cardiac Function in Ischemic Heart Failure Model. AB - Cardiac c-Kit+ cells have a modest cardiogenic potential that could limit their efficacy in heart disease treatment. The present study was designed to augment the cardiogenic potential of cardiac c-Kit+ cells through class I histone deacetylase (HDAC) inhibition and evaluate their therapeutic potency in the chronic heart failure (CHF) animal model. Myocardial infarction (MI) was created by coronary artery occlusion in rats. c-Kit+ cells were treated with mocetinostat (MOCE), a specific class I HDAC inhibitor. At 3 weeks after MI, CHF animals were retrogradely infused with untreated (control) or MOCE-treated c-Kit+ cells (MOCE/c-Kit+ cells) and evaluated at 3 weeks after cell infusion. We found that class I HDAC inhibition in c-Kit+ cells elevated the level of acetylated histone H3 (AcH3) and increased AcH3 levels in the promoter regions of pluripotent and cardiac-specific genes. Epigenetic changes were accompanied by increased expression of cardiac-specific markers. Transplantation of CHF rats with either control or MOCE/c-Kit+ cells resulted in an improvement in cardiac function, retardation of CHF remodeling made evident by increased vascularization and scar size, and cardiomyocyte hypertrophy reduction. Compared with CHF infused with control cells, infusion of MOCE/c-Kit+ cells resulted in a further reduction in left ventricle end-diastolic pressure and total collagen and an increase in interleukin-6 expression. The low engraftment of infused cells suggests that paracrine effects might account for the beneficial effects of c-Kit+ cells in CHF. In conclusion, selective inhibition of class I HDACs induced expression of cardiac markers in c-Kit+ cells and partially augmented the efficacy of these cells for CHF repair. SIGNIFICANCE: The study has shown that selective class 1 histone deacetylase inhibition is sufficient to redirect c-Kit+ cells toward a cardiac fate. Epigenetically modified c-Kit+ cells improved contractile function and retarded remodeling of the congestive heart failure heart. This study provides new insights into the efficacy of cardiac c-Kit+ cells in the ischemic heart failure model. PMID- 26240435 TI - The new emergence of iodine deficiency in the UK: consequences for child neurodevelopment. AB - Adequate iodine intake is important during pregnancy as it is a component of the thyroid hormones that are crucial for fetal brain and neurological development. While randomized controlled trials in severe iodine deficiency have shown that iodine deficiency in pregnancy causes impaired offspring cognition, less is known of the effects in regions of mild/mild-to-moderate deficiency. The United Kingdom is now classified as mildly iodine deficient by the World Health Organization, based on a 2011 national study of 14-15-year-old schoolgirls. As pregnancy is the most critical time for brain development, we evaluated iodine status in pregnant women in Surrey (n = 100) and Oxford (n = 230). The median urinary iodine concentration was 85.3 MUg/L in Surrey women, considerably lower than the WHO/United Nations Children's Fund/International Council for the Control of Iodine Deficiency Disorders cut-off of 150 MUg/L. Oxford women had similarly low status. We investigated whether that level of iodine deficiency was associated with adverse child cognitive effects using stored samples and data from the Avon Longitudinal Study of Parents and Children cohort. In adjusted analyses, we found a significant association between low maternal iodine status in early pregnancy (urinary iodine-to-creatinine ratio <150 MUg/g) such that children had an approximately 60% greater risk of being in the bottom quartile of scores for verbal intelligence quotient, reading accuracy and comprehension. UK women who might become pregnant should ensure they have adequate iodine status to avoid compromising their children's brain development. PMID- 26240434 TI - Cartilage Repair Using Composites of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells and Hyaluronic Acid Hydrogel in a Minipig Model. AB - The cartilage regeneration potential of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) with a hyaluronic acid (HA) hydrogel composite has shown remarkable results in rat and rabbit models. The purpose of the present study was to confirm the consistent regenerative potential in a pig model using three different cell lines. A full-thickness chondral injury was intentionally created in the trochlear groove of each knee in 6 minipigs. Three weeks later, an osteochondral defect, 5 mm wide by 10 mm deep, was created, followed by an 8-mm wide and 5-mm-deep reaming. A mixture (1.5 ml) of hUCB-MSCs (0.5*10(7) cells per milliliter) and 4% HA hydrogel composite was then transplanted into the defect on the right knee. Each cell line was used in two minipigs. The osteochondral defect created in the same manner on the left knee was untreated to act as the control. At 12 weeks postoperatively, the pigs were sacrificed, and the degree of subsequent cartilage regeneration was evaluated by gross and histological analysis. The transplanted knee resulted in superior and more complete hyaline cartilage regeneration compared with the control knee. The cellular characteristics (e.g., cellular proliferation and chondrogenic differentiation capacity) of the hUCB-MSCs influenced the degree of cartilage regeneration potential. This evidence of consistent cartilage regeneration using composites of hUCB-MSCs and HA hydrogel in a large animal model could be a stepping stone to a human clinical trial in the future. SIGNIFICANCE: To date, several studies have investigated the chondrogenic potential of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs); however, the preclinical studies are still limited in numbers with various results. In parallel, in the past several years, the cartilage regeneration potential of hUCB-MSCs with a hyaluronic acid (HA) hydrogel composite have been investigated and remarkable results in rat and rabbit models have been attained. (These experimental results are currently in preparation for publication.) Before applying the cartilage regeneration technique in a human clinical trial, it seemed necessary to confirm the consistent result in a larger animal model. At 12 weeks postoperatively, the minipigs were sacrificed, and the degree of subsequent cartilage regeneration was evaluated by gross and histological analysis. The transplanted knee resulted in superior and more complete hyaline cartilage regeneration compared with the control knee. This evidence of consistent cartilage regeneration with composites of hUCB-MSCs and HA hydrogel in a large animal model could be a stepping stone to a human clinical trial in the future. PMID- 26240436 TI - Analysis of insulin and insulin analogues by mass spectrometry. PMID- 26240437 TI - Decomposition of beech (Fagus sylvatica) and pine (Pinus nigra) litter along an Alpine elevation gradient: Decay and nutrient release. AB - Litter decomposition is an important process for cycling of nutrients in terrestrial ecosystems. The objective of this study was to evaluate direct and indirect effects of climate on litter decomposition along an altitudinal gradient in a temperate Alpine region. Foliar litter of European beech (Fagus sylvatica) and Black pine (Pinus nigra) was incubated in litterbags during two years in the Hochschwab massif of the Northern Limestone Alps of Austria. Eight incubation sites were selected following an altitudinal/climatic transect from 1900 to 900 m asl. The average remaining mass after two years of decomposition amounted to 54% (beech) and 50% (pine). Net release of N, P, Na, Al, Fe and Mn was higher in pine than in beech litter due to high immobilization (retention) rates of beech litter. However, pine litter retained more Ca than beech litter. Altitude retarded decay (mass loss and associated C release) in beech litter during the first year only but had a longer lasting effect on decaying pine litter. Altitude comprises a suite of highly auto-correlated characteristics (climate, vegetation, litter, soil chemistry, soil microbiology, snow cover) that influence litter decomposition. Hence, decay and nutrient release of incubated litter is difficult to predict by altitude, except during the early stage of decomposition, which seemed to be controlled by climate. Reciprocal litter transplant along the elevation gradient yielded even relatively higher decay of pine litter on beech forest sites after a two-year adaptation period of the microbial community. PMID- 26240438 TI - Study of blood flow in several benchmark micro-channels using a two-fluid approach. AB - It is known that in a vessel whose characteristic dimension (e.g., its diameter) is in the range of 20 to 500 microns, blood behaves as a non-Newtonian fluid, exhibiting complex phenomena, such as shear-thinning, stress relaxation, and also multi-component behaviors, such as the Fahraeus effect, plasma-skimming, etc. For describing these non-Newtonian and multi-component characteristics of blood, using the framework of mixture theory, a two-fluid model is applied, where the plasma is treated as a Newtonian fluid and the red blood cells (RBCs) are treated as shear-thinning fluid. A computational fluid dynamic (CFD) simulation incorporating the constitutive model was implemented using OpenFOAM(r) in which benchmark problems including a sudden expansion and various driven slots and crevices were studied numerically. The numerical results exhibited good agreement with the experimental observations with respect to both the velocity field and the volume fraction distribution of RBCs. PMID- 26240439 TI - An Anisotropic Effective Model for the Simulation of Semiflexible Ring Polymers. AB - We derive and introduce anisotropic effective pair potentials to coarse-grain solutions of semiflexible ring polymers of various lengths. The system has been recently investigated by means of full monomer-resolved computer simulations, revealing a host of unusual features and structure formation, which, however, cannot be captured by a rotationally averaged effective pair potential between the rings' centers of mass [Bernabei M.; Soft Matter2013, 9, 1287]. Our new coarse-graining strategy is to picture each ring as a soft, penetrable disk. We demonstrate that for the short- and intermediate-length rings the new model is quite capable of capturing the physics in a quantitative fashion, whereas for the largest rings, which resemble flexible ones, it fails at high densities. Our work opens the way for the physical justification of general, anisotropic penetrable interaction potentials. PMID- 26240440 TI - A scale- and orientation-adaptive extension of Local Binary Patterns for texture classification. AB - Local Binary Patterns (LBPs) have been used in a wide range of texture classification scenarios and have proven to provide a highly discriminative feature representation. A major limitation of LBP is its sensitivity to affine transformations. In this work, we present a scale- and rotation-invariant computation of LBP. Rotation-invariance is achieved by explicit alignment of features at the extraction level, using a robust estimate of global orientation. Scale-adapted features are computed in reference to the estimated scale of an image, based on the distribution of scale normalized Laplacian responses in a scale-space representation. Intrinsic-scale-adaption is performed to compute features, independent of the intrinsic texture scale, leading to a significantly increased discriminative power for a large amount of texture classes. In a final step, the rotation- and scale-invariant features are combined in a multi resolution representation, which improves the classification accuracy in texture classification scenarios with scaling and rotation significantly. PMID- 26240441 TI - Phylogenetic and chemical studies in the potential psychotropic species complex of Psilocybe atrobrunnea with taxonomic and nomenclatural notes. AB - Five Psilocybe species with unresolved systematic position (P. atrobrunnea, P. laetissima, P. medullosa, P. pelliculosa, and P. silvatica) were investigated using four molecular markers (EF1-alpha, ITS, LSU, and IGS). Phylogenetic analysis revealed that with the exception of P. laetissima, which is now rightfully classified in the genus Leratiomyces, all investigated species belong to Psilocybe sect. Psilocybe. For the first time, psychotropic compounds psilocin and psilocybin were detected in P. medullosa using gas chromatography-mass spectrometry. On the contrary, neither psilocin, nor psilocybin was detected in P. atrobrunnea and negative results were also obtained from mycelia grown in vitro on tryptamine/tryptophan-amended media. These results strongly suggest that biosynthesis of these alkaloids was lost in P. atrobrunnea. With the exception of minor differences detected in EF1-alpha marker, all sequences of American and European collections of P. atrobrunnea were identical. On the other hand, a thorough nomenclatural study revealed that the name P. atrobrunnea must be considered dubious; the oldest available candidate name, P. fuscofulva, was therefore adopted. The molecular data suggests that morphologically identical American P. silvatica and European P. medullosa likely represent distinct species; epitypes of both taxa were therefore designated. PMID- 26240442 TI - Phylogeny of Sarocladium (Hypocreales). AB - The circumscription of the genus Acremonium (Hypocreales) was recently reviewed on the basis of a DNA phylogenetic study. Several species were subsequently transferred to Sarocladium, but the relationships between both genera remained unresolved. Based on multilocus phylogenetic inferences combined with phenotypic data, we have revised the species concepts within Sarocladium and some genetically related species of Acremonium. As a result of these studies, six species are described as new, viz. S. bifurcatum, S. gamsii, S. hominis, S. pseudostrictum, S. subulatum and S. summerbellii. In addition, the new combinations S. implicatum and S. terricola are proposed for A. implicatum and A. terricola, respectively. Sarocladium attenuatum is confirmed as synonym of the type species of the genus, S. oryzae. An epitype and neotype are also introduced for S. oryzae and S. implicatum, respectively. Although Sarocladium species have traditionally been considered as important phytopathogens, the genus also contains opportunistic human pathogens. This study extends the spectrum of clinical species that could be diagnosed as causal agents of human infections. PMID- 26240443 TI - Phytopythium: molecular phylogeny and systematics. AB - The genus Phytopythium (Peronosporales) has been described, but a complete circumscription has not yet been presented. In the present paper we provide molecular-based evidence that members of Pythium clade K as described by Levesque & de Cock (2004) belong to Phytopythium. Maximum likelihood and Bayesian phylogenetic analysis of the nuclear ribosomal DNA (LSU and SSU) and mitochondrial DNA cytochrome oxidase subunit 1 (COI) as well as statistical analyses of pairwise distances strongly support the status of Phytopythium as a separate phylogenetic entity. Phytopythium is morphologically intermediate between the genera Phytophthora and Pythium. It is unique in having papillate, internally proliferating sporangia and cylindrical or lobate antheridia. The formal transfer of clade K species to Phytopythium and a comparison with morphologically similar species of the genera Pythium and Phytophthora is presented. A new species is described, Phytopythium mirpurense. PMID- 26240444 TI - Pisorisporiales, a new order of aquatic and terrestrial fungi for Achroceratosphaeria and Pisorisporium gen. nov. in the Sordariomycetes. AB - Four morphologically similar specimens of an unidentified perithecial ascomycete were collected on decaying wood submerged in fresh water. Phylogenetic analysis of DNA sequences from protein-coding and ribosomal nuclear loci supports the placement of the unidentified fungus together with Achroceratosphaeria in a strongly supported monophyletic clade. The four collections are described as two new species of the new genus Pisorisporium characterised by non-stromatic, black, immersed to superficial perithecial ascomata, persistent paraphyses, unitunicate, persistent asci with an amyloid apical annulus and hyaline, fusiform, cymbiform to cylindrical, transversely multiseptate ascospores with conspicuous guttules. The asexual morph is unknown and no conidia were formed in vitro or on the natural substratum. The clade containing Achroceratosphaeria and Pisorisporium is introduced as the new order Pisorisporiales, family Pisorisporiaceae in the class Sordariomycetes. It represents a new lineage of aquatic fungi. A sister relationship for Pisorisporiales with the Lulworthiales and Koralionastetales is weakly supported by Bayesian inference and maximum likelihood analyses. The systematic position of Pisorisporium among morphologically similar perithecial ascomycetes is discussed. PMID- 26240445 TI - Elucidating the Ramularia eucalypti species complex. AB - The genus Ramularia includes numerous phytopathogenic species, several of which are economically important. Ramularia eucalypti is currently the only species of this genus known to infect Eucalyptus by causing severe leaf-spotting symptoms on this host. However, several isolates identified as R. eucalypti based on morphology and on nrDNA sequence data of the ITS region have recently been isolated from other plant hosts, from environmental samples and also from human clinical specimens. Identification of closely related species based on morphology is often difficult and the ITS region has previously been shown to be unreliable for species level identification in several genera. In this study we aimed to resolve this species-complex by applying a polyphasic approach involving morphology, multi-gene phylogeny and matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). Six partial genes (ITS, ACT, TEF1-alpha, HIS3, GAPDH and RPB2) were amplified and sequenced for a total of 44 isolates representing R. eucalypti s.lat. and closely related species. A multi gene Bayesian phylogenetic analysis and parsimony analysis were performed, and both the resulting trees showed significant support for separation of seven species in R. eucalypti s.lat., including two previously described (R. eucalypti and R. miae), four novel species here described (R. haroldporteri, R. glennii, R. mali and R. plurivora) and one undescribed Ramularia species (sterile). Additionally, Mycosphaerella nyssicola is newly combined in Ramularia as R. nyssicola. Main mass spectra (MSPs) of several R. eucalypti s.lat. strains were generated using MALDI-TOF MS and were compared through a Principal Component Analysis (PCA) dendogram. The PCA dendrogram supported three clades containing R. plurivora, R. glenni/R. mali and R. eucalypti/R. miae. Although the dendrogram separation of species differed from the phylogenetic analysis, the clinically relevant strains were successfully identified by MALDI-TOF MS. PMID- 26240446 TI - Application of the consolidated species concept to Cercospora spp. from Iran. AB - The genus Cercospora includes many important plant pathogenic fungi associated with leaf spot diseases on a wide range of hosts. The mainland of Iran covers various climatic regions with a great biodiversity of vascular plants, and a correspondingly high diversity of cercosporoid fungi. However, most of the cercosporoid species found to date have been identified on the basis of morphological characteristics and there are no cultures that support these identifications. In this study the Consolidated Species Concept was applied to differentiate Cercospora species collected from Iran. A total of 161 Cercospora isolates recovered from 74 host species in northern Iran were studied by molecular phylogenetic analysis. Our results revealed a rich diversity of Cercospora species in northern Iran. Twenty species were identified based on sequence data of five genomic loci (ITS, TEF1-alpha, actin, calmodulin and histone H3), host, cultural and morphological data. Six novel species, viz. C. convolvulicola, C. conyzae-canadensis, C. cylindracea, C. iranica, C. pseudochenopodii and C. sorghicola, are introduced. The most common taxon was Cercospora cf. flagellaris, which remains an unresolved species complex with a wide host range. New hosts were recorded for previously known Cercospora species, including C. apii, C. armoraciae, C. beticola, C. cf. richardiicola, C. rumicis, Cercospora sp. G and C. zebrina. PMID- 26240447 TI - Caulicolous Botryosphaeriales from Thailand. AB - Members of Botryosphaeriales are commonly encountered as endophytes or pathogens of various plant hosts. The Botryosphaeriaceae represents the predominant family within this order, containing numerous species associated with canker and dieback disease on a wide range of woody hosts. During the course of routine surveys from various plant hosts in Thailand, numerous isolates of Botryosphaeriaceae, including Aplosporellaceae were collected. Isolates were subsequently identified based on a combination of morphological characteristics and phylogenetic analysis of a combined dataset of the ITS and EF1-alpha gene regions. The resulting phylogenetic tree revealed 11 well-supported clades, correlating with different members of Botryosphaeriales. Other than confirming the presence of taxa such as Lasiodiplodia theobromae, L. pseudotheobromae and Neofusicoccum parvum, new records for Thailand include Pseudofusicoccum adansoniae and P. ardesiacum. Furthermore, four novel species are described, namely Diplodia neojuniperi from Juniperus chinensis, Lasiodiplodia thailandica from Mangifera indica, Pseudofusicoccum artocarpi and Aplosporella artocarpi from Artocarpus heterophyllus, while a sexual morph is also newly reported for L. gonubiensis. Further research is presently underway to determine the pathogenicity and relative importance of these species on different woody hosts in Thailand. PMID- 26240448 TI - Psychrophilic fungi from the world's roof. AB - During a survey of cold-adapted fungi in alpine glaciers on the Qinghai-Tibet Plateau, 1 428 fungal isolates were obtained of which 150 species were preliminary identified. Phoma sclerotioides and Pseudogymnoascus pannorum were the most dominant species. Psychrotolerant species in Helotiales (Leotiomycetes, Ascomycota) were studied in more detail as they represented the most commonly encountered group during this investigation. Two phylogenetic trees were constructed based on the partial large subunit nrDNA (LSU) to infer the taxonomic placements of these strains. Our strains nested in two well-supported major clades, which represented Tetracladium and a previously unknown lineage. The unknown lineage is distant to any other currently known genera in Helotiales. Psychrophila gen. nov. was therefore established to accommodate these strains which are characterised by globose or subglobose conidia formed from phialides on short or reduced conidiophores. Our analysis also showed that an LSU-based phylogeny is insufficient in differentiating strains at species level. Additional analyses using combined sequences of ITS+TEF1+TUB regions were employed to further investigate the phylogenetic relationships of these strains. Together with the recognisable morphological distinctions, six new species (i.e. P. antarctica, P. lutea, P. olivacea, T. ellipsoideum, T. globosum and T. psychrophilum) were described. Our preliminary investigation indicates a high diversity of cold-adapted species in nature, and many of them may represent unknown species. PMID- 26240449 TI - Trichoderma (Hypocrea) species with green ascospores from China. AB - Stromata of Trichoderma species having green ascospores were collected in various regions of China. Based on morphology of the sexual and asexual morph, culture characteristics, and sequence analyses of rpb2 and tef1 genes, 17 species with green ascospores were identified. Among them, Trichoderma rosulatum, T. rufobrunneum and T. stipitatum are described as new species, and seven other species are reported for the first time from China. Trichoderma rosulatum produces small bright yellow or pale greenish stromata with dense dark green ostioles and gliocladium-like conidiophores, shows a close relationship to T. thelephoricola, and belongs to the Chlorospora clade. Trichoderma rufobrunneum, which typically forms reddish brown stromata, is recognised as a member of the Harzianum clade. Trichoderma stipitatum is characterised by turbinate, pale yellow to nearly orange stromata and verticillium-like conidiophores; it forms a distinct, independent lineage with strong bootstrap support in the phylogenetic trees. The distinctions between the new species and their close relatives are discussed, and their phylogenetic positions are explored. PMID- 26240450 TI - Integrative taxonomy reveals an unexpected diversity in Geastrum section Geastrum (Geastrales, Basidiomycota). AB - A revision of the classification of Geastrum sect. Geastrum is presented on the basis of an integrative taxonomic approach, which involves the study of morphological, molecular, ecological, and chorological data. Four DNA regions are analysed: the ITS and LSU nrDNA, rpb1, and atp6. Phylogenetic reconstructions include 95 ingroup samples and show five main clades, which are considered as five subsections, one of them proposed as new (G. subsect. Hungarica), and a total of 27 lineages recognizable at species level. Discriminant function analyses, ANOVAs and Tukey's HSD tests on more than 500 basidiomata reveal the utility of several quantitative morphological characters for species delimitation. As a result of the combination of the different sources of taxonomic information, a revised taxonomy is presented and seven new species, viz., G. austrominimum, G. benitoi, G. britannicum, G. kuharii, G. meridionale, G. papinuttii, and G. thanatophilum, are proposed. PMID- 26240454 TI - The Sendai framework: disaster risk reduction through a health lens. PMID- 26240452 TI - Chakyunglupulins A and B, two novel 4,8,8-trimethylcyclooct-2-enone derivatives from Barleria lupulina. AB - Two novel 4,8,8-trimethylcyclooct-2-enone derivatives, chakyunglupulins A and B, together with six known lignans were isolated from the aerial part of Barleria lupulina. The structures of new compounds were established by extensive spectroscopic data and HR-MS, and their absolute configurations were determined by a combination of NOE experiment and application of the modified Mosher's method. PMID- 26240456 TI - Bridging the language divide in health. PMID- 26240451 TI - Fungal Planet description sheets: 320-370. AB - Novel species of fungi described in the present study include the following from Malaysia: Castanediella eucalypti from Eucalyptus pellita, Codinaea acacia from Acacia mangium, Emarcea eucalyptigena from Eucalyptus brassiana, Myrtapenidiella eucalyptorum from Eucalyptus pellita, Pilidiella eucalyptigena from Eucalyptus brassiana and Strelitziana malaysiana from Acacia mangium. Furthermore, Stachybotrys sansevieriicola is described from Sansevieria ehrenbergii (Tanzania), Phacidium grevilleae from Grevillea robusta (Uganda), Graphium jumulu from Adansonia gregorii and Ophiostoma eucalyptigena from Eucalyptus marginata (Australia), Pleurophoma ossicola from bone and Plectosphaerella populi from Populus nigra (Germany), Colletotrichum neosansevieriae from Sansevieria trifasciata, Elsinoe othonnae from Othonna quinquedentata and Zeloasperisporium cliviae (Zeloasperisporiaceae fam. nov.) from Clivia sp. (South Africa), Neodevriesia pakbiae, Phaeophleospora hymenocallidis and Phaeophleospora hymenocallidicola on leaves of a fern (Thailand), Melanconium elaeidicola from Elaeis guineensis (Indonesia), Hormonema viticola from Vitis vinifera (Canary Islands), Chlorophyllum pseudoglobossum from a grassland (India), Triadelphia disseminata from an immunocompromised patient (Saudi Arabia), Colletotrichum abscissum from Citrus (Brazil), Polyschema sclerotigenum and Phialemonium limoniforme from human patients (USA), Cadophora viticola from Vitis vinifera (Spain), Entoloma flavovelutinum and Bolbitius aurantiorugosus from soil (Vietnam), Rhizopogon granuloflavus from soil (Cape Verde Islands), Tulasnella eremophila from Euphorbia officinarum subsp. echinus (Morocco), Verrucostoma martinicensis from Danaea elliptica (French West Indies), Metschnikowia colchici from Colchicum autumnale (Bulgaria), Thelebolus microcarpus from soil (Argentina) and Ceratocystis adelpha from Theobroma cacao (Ecuador). Myrmecridium iridis (Myrmecridiales ord. nov., Myrmecridiaceae fam. nov.) is also described from Iris sp. (The Netherlands). Novel genera include (Ascomycetes): Budhanggurabania from Cynodon dactylon (Australia), Soloacrosporiella, Xenocamarosporium, Neostrelitziana and Castanediella from Acacia mangium and Sabahriopsis from Eucalyptus brassiana (Malaysia), Readerielliopsis from basidiomata of Fuscoporia wahlbergii (French Guyana), Neoplatysporoides from Aloe ferox (Tanzania), Wojnowiciella, Chrysofolia and Neoeriomycopsis from Eucalyptus (Colombia), Neophaeomoniella from Eucalyptus globulus (USA), Pseudophaeomoniella from Olea europaea (Italy), Paraphaeomoniella from Encephalartos altensteinii, Aequabiliella, Celerioriella and Minutiella from Prunus (South Africa). Tephrocybella (Basidiomycetes) represents a novel genus from wood (Italy). Morphological and culture characteristics along with ITS DNA barcodes are provided for all taxa. PMID- 26240457 TI - Global funding for local health issues. PMID- 26240458 TI - Tuberculosis control and economic recession: longitudinal study of data from 21 European countries, 1991-2012. AB - OBJECTIVE: To investigate whether the economic recession affected the control of tuberculosis in the European Union. METHODS: Multivariate regression models were used to quantify the association between gross domestic product, public health expenditure and tuberculosis case detection rates, using data from 21 European Union member states (1991-2012). The estimated changes in case detection attributable to the recession were combined with mathematical models of tuberculosis transmission, to project the potential influence of the recession on tuberculosis epidemiology until 2030. FINDINGS: Between 1991 and 2007, detection rates for sputum-smear-positive tuberculosis in the European Union were stable at approximately 85%. During the economic recession (2008-2011) detection rates declined by a mean of 5.22% (95% confidence interval, CI: 2.54-7.90) but treatment success rates showed no significant change (P = 0.62). A fall in economic output of 100 United States dollars per capita was associated with a 0.22% (95% CI: 0.05-0.39) mean reduction in the tuberculosis case detection rate. An equivalent fall in spending on public health services was associated with a 2.74% (95% CI: 0.31-5.16) mean reduction in the detection rate. Mathematical models suggest that the recession and consequent austerity policies will lead to increases in tuberculosis prevalence and tuberculosis-attributable mortality that are projected to persist for over a decade. CONCLUSION: Across the European Union, reductions in spending on public health services appear to have reduced tuberculosis case detection and to have increased the long-term risk of a resurgence in the disease. PMID- 26240459 TI - Identifying implementation bottlenecks for maternal and newborn health interventions in rural districts of the United Republic of Tanzania. AB - OBJECTIVE: To estimate effective coverage of maternal and newborn health interventions and to identify bottlenecks in their implementation in rural districts of the United Republic of Tanzania. METHODS: Cross-sectional data from households and health facilities in Tandahimba and Newala districts were used in the analysis. We adapted Tanahashi's model to estimate intervention coverage in conditional stages and to identify implementation bottlenecks in access, health facility readiness and clinical practice. The interventions studied were syphilis and pre-eclampsia screening, partograph use, active management of the third stage of labour and postpartum care. FINDINGS: Effective coverage was low in both districts, ranging from only 3% for postpartum care in Tandahimba to 49% for active management of the third stage of labour in Newala. In Tandahimba, health facility readiness was the largest bottleneck for most interventions, whereas in Newala, it was access. Clinical practice was another large bottleneck for syphilis screening in both districts. CONCLUSION: The poor effective coverage of maternal and newborn health interventions in rural districts of the United Republic of Tanzania reinforces the need to prioritize health service quality. Access to high-quality local data by decision-makers would assist planning and prioritization. The approach of estimating effective coverage and identifying bottlenecks described here could facilitate progress towards universal health coverage for any area of care and in any context. PMID- 26240460 TI - Tobacco smoking and tuberculosis treatment outcomes: a prospective cohort study in Georgia. AB - OBJECTIVE: To assess the effect of tobacco smoking on the outcome of tuberculosis treatment in Tbilisi, Georgia. METHODS: We conducted a prospective cohort study of adults with laboratory-confirmed tuberculosis from May 2011 to November 2013. History of tobacco smoking was collected using a standardized questionnaire adapted from the global adult tobacco survey. We considered tuberculosis therapy to have a poor outcome if participants defaulted, failed treatment or died. We used multivariable regressions to estimate the risk of a poor treatment outcome. FINDINGS: Of the 591 tuberculosis patients enrolled, 188 (31.8%) were past smokers and 271 (45.9%) were current smokers. Ninety (33.2%) of the current smokers and 24 (18.2%) of the participants who had never smoked had previously been treated for tuberculosis (P < 0.01). Treatment outcome data were available for 524 of the participants, of whom 128 (24.4%) - including 80 (32.9%) of the 243 current smokers and 21 (17.2%) of the 122 individuals who had never smoked - had a poor treatment outcome. Compared with those who had never smoked, current smokers had an increased risk of poor treatment outcome (adjusted relative risk, aRR: 1.70; 95% confidence interval, CI: 1.00-2.90). Those who had ceased smoking more than two months before enrolment did not have such an increased risk (aRR: 1.01; 95% CI: 0.51-1.99). CONCLUSION: There is a high prevalence of smoking among patients with tuberculosis in Georgia and smoking increases the risk of a poor treatment outcome. PMID- 26240461 TI - Long-term mortality among older adults with burn injury: a population-based study in Australia. AB - OBJECTIVE: To assess if burn injury in older adults is associated with changes in long-term all-cause mortality and to estimate the increased risk of death attributable to burn injury. METHODS: We conducted a population-based matched longitudinal study - based on administrative data from Western Australia's hospital morbidity data system and death register. A cohort of 6014 individuals who were aged at least 45 years when hospitalized for a first burn injury in 1980 2012 was identified. A non-injury comparison cohort, randomly selected from Western Australia's electoral roll (n = 25 759), was matched to the patients. We used Kaplan-Meier plots and Cox proportional hazards regression to analyse the data and generated mortality rate ratios and attributable risk percentages. FINDINGS: For those hospitalized with burns, 180 (3%) died in hospital and 2498 (42%) died after discharge. Individuals with burn injury had a 1.4-fold greater mortality rate than those with no injury (95% confidence interval, CI: 1.3-1.5). In this cohort, the long-term mortality attributable to burn injury was 29%. Mortality risk was increased by both severe and minor burns, with adjusted mortality rate ratios of 1.3 (95% CI: 1.1-1.9) and 2.1 (95% CI: 1.9-2.3), respectively. CONCLUSION: Burn injury is associated with increased long-term mortality. In our study population, sole reliance on data on in-hospital deaths would lead to an underestimate of the true mortality burden associated with burn injury. PMID- 26240462 TI - Changes in the perceived quality of primary care in Shanghai and Shenzhen, China: a difference-in-difference analysis. AB - OBJECTIVE: To assess changes in the quality of primary care in two megacities following the introduction of health system reforms in China. METHODS: We conducted multistage stratified random face-to-face surveys of patients visiting community health centres in Shanghai in 2011 and 2013, and Shenzhen in 2012 and 2013. Quality of primary care was measured using an assessment tool. Difference in-difference analyses based on multiple linear regressions were used to compare the changes over time, after controlling for potential confounders. FINDINGS: Most (2721) of the 3214 participants used a community health centre as their regular source of care and were included in our analyses. The mean total scores for quality of primary care were similar for Shanghai and Shenzhen at baseline. In Shenzhen, the mean total scores for all participants and those on low incomes had worsened by 0.922 (95% CI: 0.629 to 1.215) and 1.203 (95% CI: 0.397 to 2.009), respectively. In Shanghai, however, there were improvements in the mean total scores which included increases in the scores for first-contact utilization, continuity, coordination of information and comprehensiveness. CONCLUSION: The quality of primary care improved in Shanghai but not in Shenzhen. This may be because, in Shanghai, beneficial long-term relationships between patients and general practitioners were supported by capitation payments and the provision of services tailored to the local health priorities. PMID- 26240464 TI - Quality-of-care audits and perinatal mortality in South Africa. AB - PROBLEM: Suboptimal care contributes to perinatal mortality rates. Quality-of care audits can be used to identify and change suboptimal care, but it is not known if such audits have reduced perinatal mortality in South Africa. APPROACH: We investigated perinatal mortality trends in health facilities that had completed at least five years of quality-of-care audits. In a subset of facilities that began audits from 2006, we analysed modifiable factors that may have contributed to perinatal deaths. LOCAL SETTING: Since the 1990s, the perinatal problem identification programme has performed quality-of-care audits in South Africa to record perinatal deaths, identify modifiable factors and motivate change. RELEVANT CHANGES: Five years of continuous audits were available for 163 facilities. Perinatal mortality rates decreased in 48 facilities (29%) and increased in 52 (32%). Among the subset of facilities that began audits in 2006, there was a decrease in perinatal mortality of 30% (16/54) but an increase in 35% (19/54). Facilities with increasing perinatal mortality were more likely to identify the following contributing factors: patient delay in seeking help when a baby was ill (odds ratio, OR: 4.67; 95% confidence interval, CI: 1.99 10.97); lack of use of antenatal steroids (OR: 9.57; 95% CI: 2.97-30.81); lack of nursing personnel (OR: 2.67; 95% CI: 1.34-5.33); fetal distress not detected antepartum when the fetus is monitored (OR: 2.92; 95% CI: 1.47-5.8) and poor progress in labour with incorrect interpretation of the partogram (OR: 2.77; 95% CI: 1.43-5.34). LESSONS LEARNT: Quality-of-care audits were not shown to improve perinatal mortality in this study. PMID- 26240463 TI - Applying the lessons of maternal mortality reduction to global emergency health. AB - Over the last few decades, maternal health has been a major focus of the international community and this has resulted in a substantial decrease in maternal mortality globally. Although, compared with maternal illness, medical and surgical emergencies account for far more morbidity and mortality, there has been less focus on global efforts to improve comprehensive emergency systems. The thoughtful and specific application of the concepts used in the effort to decrease maternal mortality could lead to major improvements in global emergency health services. The so-called three-delay model that was developed for maternal mortality can be adapted to emergency service delivery. Adaptation of evaluation frameworks to include emergency sentinel conditions could allow effective monitoring of emergency facilities and further policy development. Future global emergency health efforts may benefit from incorporating strategies for the planning and evaluation of high-impact interventions. PMID- 26240465 TI - Improving eye care in Rwanda. AB - PROBLEM: Visual impairment affects nearly 285 million people worldwide. Although there has been much progress in combating the burden of visual impairment through initiatives such as VISION 2020, barriers to progress, especially in African countries, remain high. APPROACH: The Rwandan Ministry of Health has formed partnerships with several nongovernmental organizations and has worked to integrate their efforts to prevent and treat visual impairment, including presbyopia. LOCAL SETTING: Rwanda, an eastern African country of approximately 11 million people. RELEVANT CHANGES: The Rwandan Ministry of Health developed a single national plan that allows key partners in vision care to coordinate more effectively in measuring eye disease, developing eye care infrastructure, building capacity, controlling disease, and delivering and evaluating services. LESSONS LEARNT: Collaboration between stakeholders under a single national plan has ensured that resources and efforts are complementary, optimizing the ability to provide eye care. Improved access to primary eye care and insurance coverage has increased demand for services at secondary and tertiary levels. A comprehensive strategy that includes prevention as well as a supply chain for glasses and lenses is needed. PMID- 26240466 TI - Legionnaire's disease, weather and climate. PMID- 26240467 TI - Gujarat's Chiranjeevi Yojana - a difficult assessment in retrospect. PMID- 26240469 TI - Corrigendum. PMID- 26240468 TI - Government health expenditure in India. PMID- 26240470 TI - Beyond a bigger brain: Multivariable structural brain imaging and intelligence. AB - People with larger brains tend to score higher on tests of general intelligence (g). It is unclear, however, how much variance in intelligence other brain measurements would account for if included together with brain volume in a multivariable model. We examined a large sample of individuals in their seventies (n = 672) who were administered a comprehensive cognitive test battery. Using structural equation modelling, we related six common magnetic resonance imaging derived brain variables that represent normal and abnormal features-brain volume, cortical thickness, white matter structure, white matter hyperintensity load, iron deposits, and microbleeds-to g and to fluid intelligence. As expected, brain volume accounted for the largest portion of variance (~ 12%, depending on modelling choices). Adding the additional variables, especially cortical thickness (+~ 5%) and white matter hyperintensity load (+~ 2%), increased the predictive value of the model. Depending on modelling choices, all neuroimaging variables together accounted for 18-21% of the variance in intelligence. These results reveal which structural brain imaging measures relate to g over and above the largest contributor, total brain volume. They raise questions regarding which other neuroimaging measures might account for even more of the variance in intelligence. PMID- 26240471 TI - Who Am I? Who Do You Think I Am? Stability of Racial/Ethnic Self-Identification among Youth in Foster Care and Concordance with Agency Categorization. AB - While it has been well documented that racial and ethnic disparities exist for children of color in child welfare, the accuracy of the race and ethnicity information collected by agencies has not been examined, nor has the concordance of this information with youth self-report. This article addresses a major gap in the literature by examining: 1) the racial and ethnic self-identification of youth in foster care, and the rate of agreement with child welfare and school categorizations; 2) the level of concordance between different agencies (school and child welfare); and 3) the stability of racial and ethnic self-identification among youth in foster care over time. Results reveal that almost 1 in 5 youth change their racial identification over a one-year period, high rates of discordance exist between the youth self-report of Native American, Hispanic and multiracial youth and how agencies categorize them, and a greater tendency for the child welfare system to classify a youth as White, as compared to school and youth themselves. Information from the study could be used to guide agencies towards a more youth-centered and flexible approach in regards to identifying, reporting and affirming youth's evolving racial and ethnic identity. PMID- 26240472 TI - Dispositional Mindfulness in People with HIV: Associations with Psychological and Physical Health. AB - We used a Stress and Coping model to examine the association of dispositional mindfulness, defined as the tendency to intentionally bring nonjudgmental attention and awareness to one's experience in the present moment, with psychological and physical health in adults with HIV. Data were collected at baseline of a randomized controlled trial of Mindfulness-Based Stress Reduction (MBSR). Four facets of mindfulness (acting with attention/awareness, nonjudging of inner experience, observing, and describing) were examined as correlates of appraisal, positive and negative affect, coping, and indicators of psychological well-being and physical health. We found that mindfulness was inversely related to depression, stress appraisal, and negative affect, and positively related to positive affect. Mindfulness was also inversely related to escape/avoidance and self-blame forms of coping. Mediational analyses indicate that perceived stress and negative affect were the most consistent mediators of the association of mindfulness and psychological well-being. The findings from this paper contribute to a growing understanding of the potential adaptive role of mindfulness in people living with the stress of serious illness. PMID- 26240473 TI - MERS Countermeasures as One of Global Health Security Agenda. PMID- 26240474 TI - Celebrating the Latest Release of the Journal Impact Factors: Thinking Globally, Acting Locally. PMID- 26240475 TI - Treatment of Helicobacter pylori Infection in Korea: A Systematic Review and Meta analysis. AB - The efficacy of seven-day clarithromycin-based standard triple therapy (STT) for Helicobacter pylori has decreased in Korea over the past decade. The aim of this meta-analysis was to clarify the efficacy of first-line and second-line therapies in Korea. This systematic review will provide an overview of H. pylori eradication and present new therapeutic strategies used in Korea. An extensive search of the literature concerning STT, sequential therapy (SET), concomitant therapy (CT), bismuth-containing quadruple therapy (BCQT) and various other therapies used in Korea was performed. All selected studies were randomized controlled trials (RCTs). Eighteen RCTs were eligible for systematic review. The alternative regimens comparing seven-day STT as a first-line therapy include SET, CT, levofloxacin-based therapy (LBT), BCQT, and STT with prolonged duration. The results of the meta-analysis suggest that SET is superior to seven-day STT. The overall eradication rate by intention to treat (ITT) analysis was 69.8% for STT and 79.7% for SET. The overall eradication rate by per-protocol (PP) analysis was 77.0% for STT and 85.0% for SET. The odds ratios for the ITT and PP eradication rate were 0.57 (95% confidence interval [CI], 0.43 to 0.74) and 0.52 (95% CI, 0.35 to 0.76), respectively. In the subgroup analysis, however, there were no significant differences between SET and STT with prolonged durations. Alternative regimens to seven-day BCQT as second-line therapy include LBT, moxifloxacin-based therapy and 14-day BCQT. The eradication rates of these alternative regimens were not superior to that of the conventional treatment. SET is superior to seven-day STT but not to STT with prolonged duration. PMID- 26240476 TI - Publishing Ethics and Predatory Practices: A Dilemma for All Stakeholders of Science Communication. AB - Publishing scholarly articles in traditional and newly-launched journals is a responsible task, requiring diligence from authors, reviewers, editors, and publishers. The current generation of scientific authors has ample opportunities for publicizing their research. However, they have to selectively target journals and publish in compliance with the established norms of publishing ethics. Over the past few years, numerous illegitimate or predatory journals have emerged in most fields of science. By exploiting gold Open Access publishing, these journals paved the way for low-quality articles that threatened to change the landscape of evidence-based science. Authors, reviewers, editors, established publishers, and learned associations should be informed about predatory publishing practices and contribute to the trustworthiness of scholarly publications. In line with this, there have been several attempts to distinguish legitimate and illegitimate journals by blacklisting unethical journals (the Jeffrey Beall's list), issuing a statement on transparency and best publishing practices (the Open Access Scholarly Publishers Association's and other global organizations' draft document), and tightening the indexing criteria by the Directory of Open Access Journals. None of these measures alone turned to be sufficient. All stakeholders of science communication should be aware of multiple facets of unethical practices and publish well-checked and evidence-based articles. PMID- 26240477 TI - Interaction Effect between Weight Perception and Comorbidities on Weight Control Behavior in Overweight and Obese Adults: Is There a Sex Difference? AB - We investigated the interaction effect between body weight perception and chronic disease comorbidities on body weight control behavior in overweight/obese Korean adults. We analyzed data from 9,138 overweight/obese adults >=20 yr of age from a nationally representative cross-sectional survey. Multiple logistic regression using an interaction model was performed to estimate the effect of chronic disease comorbidities on weight control behavior regarding weight perception. Adjusted odds ratios for weight control behavior tended to increase significantly with an increasing number of comorbidities in men regardless of weight perception (P<0.05 for trend), suggesting no interaction. Unlike women who perceived their weight accurately, women who under-perceived their weight did not show significant improvements in weight control behavior even with an increasing number of comorbidities. Thus, a significant interaction between weight perception and comorbidities was found only in women (P=0.031 for interaction). The effect of the relationship between accurate weight perception and chronic disease comorbidities on weight control behavior varied by sex. Improving awareness of body image is particularly necessary for overweight and obese women to prevent complications. PMID- 26240478 TI - Computational Discrimination of Breast Cancer for Korean Women Based on Epidemiologic Data Only. AB - Breast cancer is the second leading cancer for Korean women and its incidence rate has been increasing annually. If early diagnosis were implemented with epidemiologic data, the women could easily assess breast cancer risk using internet. National Cancer Institute in the United States has released a Web-based Breast Cancer Risk Assessment Tool based on Gail model. However, it is inapplicable directly to Korean women since breast cancer risk is dependent on race. Also, it shows low accuracy (58%-59%). In this study, breast cancer discrimination models for Korean women are developed using only epidemiological case-control data (n = 4,574). The models are configured by different classification techniques: support vector machine, artificial neural network, and Bayesian network. A 1,000-time repeated random sub-sampling validation is performed for diverse parameter conditions, respectively. The performance is evaluated and compared as an area under the receiver operating characteristic curve (AUC). According to age group and classification techniques, AUC, accuracy, sensitivity, specificity, and calculation time of all models were calculated and compared. Although the support vector machine took the longest calculation time, the highest classification performance has been achieved in the case of women older than 50 yr (AUC = 64%). The proposed model is dependent on demographic characteristics, reproductive factors, and lifestyle habits without using any clinical or genetic test. It is expected that the model could be implemented as a web-based discrimination tool for breast cancer. This tool can encourage potential breast cancer prone women to go the hospital for diagnostic tests. PMID- 26240479 TI - Association between Promoter Polymorphisms of TFF1, TFF2, and TFF3 and the Risk of Gastric and Diffuse Gastric Cancers in a Korean Population. AB - Gastric cancer is one of the most common cancers in the world. The aims of this study were to evaluate the association between polymorphisms in TFF gene family, TFF1, TFF2, and TFF3 and the risk of gastric cancer (GC) and GC subgroups in a Korean population via a case-control study. The eight polymorphisms in TFF gene family were identified by sequencing and genotyped with 377 GC patients and 396 controls by using TaqMan genotyping assay. The rs184432 TT genotype of TFF1 was significantly associated with a reduced risk of GC (odds ratio, [OR) = 0.45; 95% confidence interval, [CI] = 0.25-0.82; P = 0.009), more protective against diffuse-type GC (OR = 0.20; 95% CI = 0.05-0.89; P = 0.035) than GC (OR = 0.34; 95% CI = 0.14-0.82; P = 0.017) in subjects aged < 60 yr, and correlated with lymph node metastasis negative GC and diffuse-type GC (OR = 0.44; 95% CI = 0.23 0.86; P = 0.016 and OR = 0.20; 95% CI = 0.05-0.87; P = 0.031, respectively). In addition, a decreased risk of lymph node metastasis negative GC and diffuse-type GC was observed for rs225359 TT genotype of TFF1 (OR = 0.46, 95% CI = 0.24-0.88; P = 0.020 and OR = 0.21, 95% CI = 0.05-0.88; P = 0.033, respectively). These findings suggest that the rs184432 and rs225359 polymorphisms in TFF1 have protective effects for GC and contribute to the development of GC in Korean individuals. PMID- 26240480 TI - Predictors of Asthma Control by Stepwise Treatment in Elderly Asthmatic Patients. AB - The geriatric population is increasing, and asthma severity increases with age. We determined the predictors of asthma control, exacerbation, and the factors that affect asthma-specific quality of life (A-QOL) in elderly asthmatic patients. This was a prospective, multicenter, real-life study for 6 months with stepwise pharmacologic treatment based on the Global Initiative for Asthma (GINA) guideline. A total of 296 asthmatic patients aged >= 60 yr were recruited from 5 university centers in Korea. The improved-asthma control group was defined as the group of patients who maintained well-controlled or improved disease and the not improved asthma control group was defined as the remaining patients. Fewer number of medications for comorbidities (2.8 +/- 3.3 in the improved vs. 4.5 +/- 4.4 in the control) and higher physical functioning (PF) scale (89.8 +/- 14.2 in the improved vs. 82.0 +/- 16.4 in the control) were significant predictors in the improved-asthma control group (OR = 0.863, P = 0.004 and OR = 1.028, P = 0.018, respectively). An asthma control test (ACT) score of <= 19 at baseline was a significant predictor of asthma exacerbation (OR = 3.938, P = 0.048). Asthma duration (F = 5.656, P = 0.018), ACT score (F = 12.237, P = 0.001) at baseline, and the presence of asthma exacerbation (F = 5.565, P = 0.019) were significant determinants of changes in A-QOL. The number of medications for comorbidities and performance status determined by the PF scale may be important parameters for assessing asthma control in elderly asthmatic patients. PMID- 26240481 TI - The Effect of Asthma Clinical Guideline for Adults on Inhaled Corticosteroids PrescriptionTrend: A Quasi-Experimental Study. AB - In order to increase inhaled corticosteroid (ICS) use and to reduce hospitalization, emergency department visits and ultimately the economic burden of asthma, "Korean Asthma Management Guideline for Adults 2007" was developed. To assess the guideline effects on physician's ICS prescription for asthma, we conducted segmented regression and multilevel logistic regression using National Health Insurance claims database of outpatient visits from 2003 to 2010. We set each quarter of a year as a time unit and compared ICS prescription between before and after guideline dissemination. A total of 624,309 quarterly visits for asthma was observed. The ICS prescription rate before and after guideline dissemination was 13.3% and 16.4% respectively (P < 0.001). In the segmented regression, there was no significant guideline effect on overall ICS prescription rate. In multilevel logistic regression analyses, the effect of guideline on overall ICS prescription was not significant (odds ratio, 1.03; 95% CI, 1.00 1.06). In subgroup analysis, ICS prescription increased in secondary care hospitals (odds ratio, 1.15; 95% CI, 1.02-1.30) and in general hospitals (odds ratio, 1.10; 95% CI, 1.04-1.16). However, in primary clinics, which covered 81.7% of asthma cases, there was no significant change (odds ratio, 0.98; 95% CI, 0.94 1.02). From the in-depth interview, we could identify that the reimbursement criteria of the Health Insurance Review and Assessment Service and patient's preference for oral drug were barriers for the ICS prescription. The domestic asthma clinical guideline have no significant effect on ICS prescription, especially in primary clinics. PMID- 26240482 TI - Low Hepatic Toxicity in Primary and Metastatic Liver Cancers after Stereotactic Ablative Radiotherapy Using 3 Fractions. AB - This study evaluated the incidence of hepatic toxicity after stereotactic ablative radiotherapy (SABR) using 3 fractions to the liver, and identified the predictors for hepatic toxicity. We retrospectively reviewed 78 patients with primary and metastatic liver cancers, who underwent SABR using 3 fractions between 2003 and 2011. To examine the incidence of hepatic toxicity, we defined newly developed hepatic toxicity>=grade 2 according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 within 3 months after the end of SABR as a significant adverse event. To identify the predictors for hepatic toxicity, we analyzed several clinical and dosimetric parameters (rV5Gy-rV35Gy: normal liver volume receiving =grade 2 occurred in 10 patients (13%): grade 2 in 9 patients and grade 3 in 1 patient. On univariate analysis, baseline Child-Pugh (CP) score (5 vs. 6 8), normal liver volume, and planning target volume were the significant clinical predictors. All dosimetric parameters were significant: rV20Gy was the most significant predictor. On multivariate analysis, baseline CP score (hazard ratio, 0.026; P=0.001) was the only significant predictor. In conclusion, SABR using 3 fractions in primary and metastatic liver cancers produces low hepatic toxicity, especially in patients with a baseline CP score of 5. However, further studies are needed to minimize hepatic toxicity in patients with baseline CP scores>=6. PMID- 26240483 TI - Clinical Significance of Persistent Tumor in Bone Marrow during Treatment of High risk Neuroblastoma. AB - The records of 63 high-risk neuroblastoma patients with bone marrow (BM) tumors at diagnosis were retrospectively reviewed. All patients received nine cycles of induction chemotherapy followed by tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT). Follow-up BM examination was performed every three cycles during induction chemotherapy and every three months for one year after the second HDCT/auto-SCT. BM tumor cells persisted in 48.4%, 37.7%, 23.3%, and 20.4% of patients after three, six, and nine cycles of induction chemotherapy and three months after the second HDCT/auto-SCT, respectively. There was no difference in progression-free survival (PFS) rate between patients with persistent BM tumor and those without during the induction treatment. However, after tandem HDCT/auto-SCT, the PFS rate was worse in patients with persistent BM tumor than in those without (probability of 5-yr PFS 14.7% +/- 13.4% vs. 64.2% +/ 8.3%, P = 0.009). Persistent BM tumor during induction treatment is not associated with a worse prognosis when intensive tandem HDCT/auto-SCT is given as consolidation treatment. However, persistent BM tumor after tandem HDCT/auto-SCT is associated with a worse prognosis. Therefore, further treatment might be needed in patients with persistent BM tumor after tandem HDCT/auto-SCT. PMID- 26240484 TI - Clinical Significance of Substaging and HER2 Expression in Papillary Nonmuscle Invasive Urothelial Cancers of the Urinary Bladder. AB - The study aimed to verify the prognostic utility, therapeutic application and clinical benefits of tumor substaging and HER2 status in papillary non-muscle invasive bladder cancer (NMIBC). Select NMIBC transurethral resection specimens from 141 patients were used to construct tissue microarrays for assessing the substaging, HER2 protein expression by immunohistochemistry (HER2-IHC) and gene amplification by dual-color silver in situ hybridization (HER2-SISH). Substages were identified by the differing depth of tumor invasion (pTa / pT1a / pT1b / pT1c). HER2 protein expression was semiquantitatively analyzed and grouped into negative (score 0, 1+) and positive (score 2+, 3+). Other clinicopathological variables were also investigated. For NMIBC, HER2-IHC and HER2-SISH showed positive results in 6/141 (4.3%) and 4/141 (2.8%) respectively, which correlated well with tumor substaging. In multivariate analysis, substaging, HER2-IHC, and HER2-SISH were found to be independent predictors of progression-free survival (P < 0.001, P < 0.001, P = 0.031). HER2-IHC was the sole independent predictor of recurrent free survival in NMIBC (P = 0.017). It is suggested that tumor substaging and HER2 status are independent predictive markers for tumor progression or recurrence, and thus could be included in diagnostic and therapeutic management for NMIBC. PMID- 26240485 TI - Prevalence of Atrial Fibrillation and Relation to Echocardiographic Parameters in a Healthy Asymptomatic Rural Korean Population. AB - Atrial fibrillation (AF) is the most common arrhythmia worldwide and a potent independent risk factor for stroke. This study aimed to determine the prevalence of AF in a population-based sample of adults in a rural region of Korea. Between January 2005 and December 2009, 4,067 individuals (60.2 +/- 11.2 yr old, M: F = 1,582:2,485) over 21 who were residents of the county of Yangpyeong, Korea, participated in the study. AF was assessed on a resting 12-lead electrocardiogram (ECG) in 4,053 of the participants. Blood tests and transthoracic echocardiography (TTE) were also performed to investigate the relationship between left ventricular mass and AF in the study group. Fifty-four cases (32 men) were diagnosed as AF among the 4,053 subjects. The crude prevalence of AF was 1.3%. It was highest (2.3%) among sixty- and seventy- year olds, and higher in men than women in all age groups over 50. The prevalence in men was 2.0%, and in women 0.9%. In univariate analysis, age, male gender, body mass index, total serum cholesterol, alanine transaminase, serum creatinine, adiponectin level, and ischemic heart disease were associated with AF. Among the TTE parameters, systolic and diastolic left ventricular systolic internal dimension (LVID), and LV ejection fraction were associated with AF. In this relatively healthy population in a rural area of Korea, the prevalence of AF is 1.3%, and increases with age. Of the TTE parameters, systolic and diastolic LVID and left atrial diameter are related to prevalence of AF. PMID- 26240486 TI - Exuberant Vasculoconnective Component in Mediastinal Mixed Germ Cell Tumors. AB - We aimed to evaluate the histologic components of primary mediastinal mixed germ cell tumors. A total of 221 patients diagnosed with a mediastinal germ cell tumor (GCT) were retrospectively reviewed. Among them, 14 patients underwent surgical resection after chemotherapy and 8 patients were diagnosed with mixed GCT, who were then selected for further evaluation. Clinical chart review and histologic review of biopsy and surgical specimens of 8 patients were performed. All 8 patients were young males and showed a mature teratoma or a mature teratoma with a focal immature teratoma in the resected specimens. Serum alpha-feto protein was variably elevated. Seven patients experienced an increase in tumor size after the chemotherapy. In 5 patients, a variable amount of vasculoconnective tissue was found along with the mature teratoma occupying average 66.3% of resected mass, and 3 of them showed an identical vasculoconnective component on biopsy before chemotherapy. We suggest that vasculoconnective tissue might be the intrinsic component of primary mediastinal mixed GCT. When vasculoconnective tissue is obtained on small biopsy of an anterior mediastinal mass of a young male, the possibility of underlying mixed GCT should be considered and further clinical work up should be performed. PMID- 26240487 TI - Routine Screening and Consultation Facilitate Improvement of Metabolic Syndrome. AB - This randomized controlled trial study aimed to investigate the effects of a lifestyle intervention on metabolic syndrome (MetS) among middle-aged Koreans. A total of 243 middle-aged Koreans with MetS were randomly assigned to either of 2 types of lifestyle intervention for MetS and followed for 12 months. Health examinations and interventions were implemented at 16 regional branch facilities of a Korean medical institution from 2010, following the NCEP-ATP III criteria and recommendations. Lifestyle intervention (LI) group (n = 137) participated in a 12-week multi-component intervention including individual counseling, group sessions, and self-help materials. Basic usual intervention (BI) group (n = 106) was provided with one-page health information sheet on MetS and MetS management at baseline. Prevalence of MetS and each of MetS components, except for low HDL cholesterol, in both groups were significantly reduced and maintained after the intervention. Notably, prevalence of hypertension and abdominal obesity continued to improve during the follow-up period. Between-group differences in results were not found. Both interventions were effective when they were accompanied with repeated check-ups and notification of MetS status. It is recommended to design clear guidelines for the notification of MetS after MetS screening and to encourage checking MetS status periodically for effective MetS management (KCT 0000446). PMID- 26240488 TI - Utilizing Genetic Predisposition Score in Predicting Risk of Type 2 Diabetes Mellitus Incidence: A Community-based Cohort Study on Middle-aged Koreans. AB - Contribution of genetic predisposition to risk prediction of type 2 diabetes mellitus (T2DM) was investigated using a prospective study in middle-aged adults in Korea. From a community cohort of 6,257 subjects with 8 yr' follow-up, genetic predisposition score with subsets of 3, 18, 36 selected single nucleotide polymorphisms (SNPs) (genetic predisposition score; GPS-3, GPS-18, GPS-36) in association with T2DM were determined, and their effect was evaluated using risk prediction models. Rs5215, rs10811661, and rs2237892 were in significant association with T2DM, and hazard ratios per risk allele score increase were 1.11 (95% confidence intervals: 1.06-1.17), 1.09 (1.01-1.05), 1.04 (1.02-1.07) with GPS-3, GPS-18, GPS-36, respectively. Changes in AUC upon addition of GPS were significant in simple and clinical models, but the significance disappeared in full clinical models with glycated hemoglobin (HbA1c). For net reclassification index (NRI), significant improvement observed in simple (range 5.1%-8.6%) and clinical (3.1%-4.4%) models were no longer significant in the full models. Influence of genetic predisposition in prediction ability of T2DM incidence was no longer significant when HbA1c was added in the models, confirming HbA1c as a strong predictor for T2DM risk. Also, the significant SNPs verified in our subjects warrant further research, e.g. gene-environmental interaction and epigenetic studies. PMID- 26240489 TI - Lifestyle and Dietary Factors Associated with Serum 25-Hydroxyvitamin D Levels in Korean Young Adults. AB - Inadequate vitamin D status is highly prevalent in the Korean population, especially among young adults. Nonetheless, correlates of suboptimal vitamin D levels in young adults are not well defined. This study aimed to investigate potentially modifiable determinants of vitamin D levels in young adults in Korea. This cross-sectional study was based on health check-up data from 3,450 healthy male and female university students aged 18-29 yr in Seoul between April and May 2013. Serum 25-hydroxyvitamin D [25(OH)D] levels were determined using chemiluminescent immunoassay. Anthropometric data were measured, and lifestyle, dietary, and sociodemographic factors were obtained through self-administered questionnaires. General linear regression was used to assess correlates of serum 25(OH)D levels. The mean serum 25(OH)D level was 11.1 ng/mL, and the prevalence of 25(OH)D levels less than 10 ng/mL was 44.7% (39.5% in men, 50.2% in women). In a final multivariable model, significant positive correlates of serum 25(OH)D were older age, male sex, increased physical activity, sunlight exposure >= 30 min/day, eating breakfast regularly, consumption of dairy and fatty fish, and use of vitamin D-containing supplements. In contrast, significant inverse correlates were obesity (body mass index, BMI >= 25 kg/m(2)) or underweight (BMI < 18.5 kg/m(2)), abdominal obesity, increased sedentary time, and frequent consumption of instant noodles and sugar-sweetened beverages. In conclusion, many modifiable lifestyle and dietary factors were associated with low serum 25(OH)D levels in Korean young adults. Further studies on potential mechanisms of the correlates and optimal strategies to improve vitamin D status in this vulnerable subpopulation are warranted. PMID- 26240490 TI - Clinical Features and Prognosis of Invasive Pulmonary Aspergillosis in Korean Children with Hematologic/Oncologic Diseases. AB - Invasive pulmonary aspergillosis (IPA) is the most frequent form of invasive fungal diseases in immunocompromised patients. However, there are only a few studies on IPA in immunocompromised children in Korea. This study was designed to characterize IPA in Korean children with hematologic/oncologic diseases. Medical records of children with hematologic/oncologic diseases receiving antifungal therapy were reviewed. The enrolled children were divided into the IPA group (proven and probable IPA) and non-IPA group, and the clinical characteristics and prognosis were compared between the two groups. During the study period, 265 courses of antifungal therapy were administered to 166 children. Among them, two (0.8%) episodes of proven IPA, 35 (13.2%) of probable IPA, and 52 (19.6%) of possible IPA were diagnosed. More children in the IPA group suffered from neutropenia lasting for more than two weeks (51.4% vs. 21.9%, P<0.001) and showed halo signs on the chest computed tomography (78.4% vs. 40.7%, P<0.001) than in the non-IPA group. No other clinical factors showed significant differences between the two groups. Amphotericin B deoxycholate was administered as a first line antifungal agent in 33 (89.2%) IPA group episodes, and eventually voriconazole was administered in 27 (73.0%) episodes. Ten (27.0%) children in the IPA group died within 12 weeks of antifungal therapy. In conclusion, early use of chest computed tomography to identify halo signs in immunocompromised children who are expected to have prolonged neutropenia can be helpful for early diagnosis of IPA and improving prognosis of children with IPA. PMID- 26240491 TI - Differences in Features and Course of Mucosal Type Eosinophilic Gastroenteritis between Korean Infants and Children. AB - Eosinophilic gastroenteritis (EGE) is a disorder characterized by eosinophilic infiltration of the bowel wall and various gastrointestinal (GI) manifestations. This study aimed to evaluate the characteristics of EGE in infants and children. A total of 22 patients were diagnosed with histologic EGE (hEGE) or possible EGE (pEGE). Serum specific IgE levels, peripheral eosinophil counts, and endoscopic biopsies were carried out. In the hEGE group (n = 13), initial symptoms included hematemesis, abdominal pain, and vomiting. Three of the subjects had normal endoscopic findings. Eight patients were categorized into the infant group and 5 into the child group. All patients in the infant group showed clinical improvement after switching from cow's milk feeding to special formula or breast feeding. The infant group showed a higher eosinophil count in the gastric mucosal biopsy than the child group. In the pEGE group (n = 9) initial symptoms included hematemesis, abdominal pain, and vomiting. Seven patients in this group showed a good response to treatment with restriction of the suspected foods and/or the administration of ketotifen. Both hEGE and pEGE groups showed clinical improvement after restriction of suspected foods in the majority of cases and also showed a similar clinical course. EGE should be considered in the differential diagnosis of patients with chronic abdominal pain, vomiting, and hematemesis of unknown cause. The infant group may have a better prognosis than the child group if treated properly. PMID- 26240492 TI - Establishment of Reference Ranges for Prostate Volume and Annual Prostate Volume Change Rate in Korean Adult Men: Analyses of a Nationwide Screening Population. AB - We aimed to determine normal reference ranges for prostate volume (PV) and annual PV change rate in a Korean nationwide screening population. Data from men who underwent a routine health check-up were collected from 13 university hospitals. The cohort comprised men aged >=40 yr who had undergone 2 or more serial transrectal ultrasonographies. Men with initial PV>100 mL; serum PSA level>10 ng/mL; PV reduction>20% compared with initial PV, or who had history of prostate cancer or prostate surgery, were excluded. Linear regression and mixed effects regression analyses were used to predict mean PV and longitudinal change in PV over time. A total of 2,967 men formed the study cohort. Age, body mass index (BMI), and serum prostate-specific antigen (PSA) level were found to be significant predictors of PV. A predicted PV table, with a 95% confidence interval (CIs), was developed after adjusting for these 3 variables. Annual PV change rate was 0.51 mL/year (95% CI, 0.47-0.55). Annual PV change rate according to age was 0.68 mL/year, 0.84 mL/year, 1.09 mL/year, and 0.50 mL/year for subjects in their 40s, 50s, 60s, and >=70 yr, respectively. Predicted annual PV change rate differed depending on age, BMI, serum PSA level and baseline PV. From a nationwide screening database, we established age-, PSA-, and BMI-specific reference ranges for PV and annual PV change rate in Korean men. Our newly established reference ranges for PV and annual PV change rate will be valuable in interpreting PV data in Korean men. PMID- 26240493 TI - Survival Outcomes and Predictive Factors for Female Urethral Cancer: Long-term Experience with Korean Patients. AB - The aim of this study was to evaluate female urethral cancer (UCa) patients treated and followed-up during a time period spanning more than 20 yr at single institution in Korea. We reviewed medical records of 21 consecutive patients diagnosed with female UCa at our institution between 1991 and 2012. After exclusion of two patients due to undefined histology, we examined clinicopathological variables, as well as survival outcomes of 19 patients with female UCa. A Cox proportional hazards ratio model was used to identify significant predictors of prognosis according to variables. The median age at diagnosis was 59 yr, and the median follow-up duration was 87.0 months. The most common initial symptoms were voiding symptoms and blood spotting. The median tumor size was 3.4 cm, and 55% of patients had lesions involving the entire urethra. The most common histologic type was adenocarcinoma, and the second most common type was urothelial carcinoma. Fourteen patients underwent surgery, and 7 of these patients received adjuvant radiation or systemic chemotherapy. Eleven patients experienced tumor recurrence after primary therapy. Patients with high stage disease, advanced T stage (>=T3), and positive lymph nodes had worse survival outcomes compared to their counterparts. Particularly, lymph node positivity and advanced T stage were significant predictive factors for all survival outcomes. Tumor location was the only significant predictor for recurrence-free survival. Although our study included a small number of patients, it conveys valuable information about this rare female urologic malignancy in a Korean population. PMID- 26240494 TI - Trends in the Use of Chemotherapy before and after Radical Cystectomy in Patients with Muscle-invasive Bladder Cancer in Korea. AB - We investigated trends in perioperative chemotherapy use, and determined factors associated with neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (AC) use in Korean patients with muscle-invasive bladder cancer (MIBC). We recruited 1,324 patients who had MIBC without nodal invasion or metastases and had undergone radical cystectomies (RC) between 2003 and 2013. The study's cut-off time for AC was three months after surgery, and the study's timespan was divided into three periods based on NAC use, namely, 2003-2005, 2006-2009, and 2010-2013. Complete remission was defined as histologically confirmed T0N0M0 after RC. NAC and AC were administered to 7.3% and 18.1% of the patients, respectively. The median time interval between completing NAC and undergoing RC was 32 days and the mean number of cycles was 3.2. The median time interval between RC and AC was 43 days and the mean number of cycles was 4.1. Gemcitabine and cisplatin were most frequently used in combination for NAC (49.0%) and AC (74.9%). NAC use increased significantly from 4.6% between 2003 and 2005 to 8.4% between 2010 and 2013 (P < 0.05), but AC use did not increase. Only 1.9% of patients received NAC and AC. Complete remission after NAC was achieved in 12 patients (12.5%). Multivariable modeling revealed that an advanced age, the earliest time period analyzed, and clinical tumor stage <= cT2 bladder cancer were negatively associated with NAC use (P < 0.05). While NAC use has slowly increased over time, it remains an underutilized therapeutic approach in Korean clinical practice. PMID- 26240495 TI - Epigenetic Role of Histone 3 Lysine Methyltransferase and Demethylase in Regulating Apoptosis Predicting the Recurrence of Atypical Meningioma. AB - Alteration of apoptosis is related with progression and recurrence of atypical meningiomas (AMs). However, no comprehensive study has been conducted regarding histone modification regulating apoptosis in AMs. This study aimed to determine the prognostic values of certain apoptosis-associated factors, and examine the role of histone modification on apoptosis in AMs. The medical records of 67 patients with AMs, as diagnosed during recent 13 yr, were reviewed retrospectively. Immunohistochemical staining was performed on archived paraffin embedded tissues for pro-apoptotic factors (CASP3, IGFBP, TRAIL-R1, BAX, and XAF1), anti-apoptotic factors (survivin, ERK, RAF1, MDM2, and BCL2), and the histone modifying enzymes (MLL2, RIZ, EZH1, NSD2, KDM5c, JMJD2a, UTX, and JMJD5). Twenty-six (38.8%) patients recurred during the follow-up period (mean duration 47.7 months). In terms of time-to-recurrence (TTR), overexpression of CASP3, TRAIL-R1, and BAX had a longer TTR than low expression, and overexpression of survivin, MDM2, and BCL2 had a shorter TTR than low expression (P<0.05). Additionally, overexpression of MLL2, UTX, and JMJ5 had shorter TTRs than low expression, and overexpression of KDM5c had a longer TTR than low expression. However, in the multi-variate analysis of predicting factors for recurrence, low expression of CASP3 (P<0.001), and BAX (P<0.001), and overexpression of survivin (P=0.007), and MDM2 (P=0.037) were associated with recurrence independently, but any enzymes modifying histone were not associated with recurrence. Conclusively, this study suggests certain apoptosis-associated factors should be associated with recurrence of AMs, which may be regulated epigenetically by histone modifying enzymes. PMID- 26240496 TI - The Korean Version of the Pediatric Symptom Checklist: Psychometric Properties in Korean School-aged Children. AB - Psychosocial problems increase the risk for mental health problems and increase the need for health care services in children and adolescents. Primary care practice is a valuable avenue for identifying the need for more specialized mental health care. We hypothesized that Korean version of the pediatric symptom checklist (PSC) would be a useful tool for early detection of psychosocial problems in children and adolescents in Korea and we aimed to suggest cut-off scores for detecting meaningful psychosocial problems. A total of 397 children with their parents and 97 child patients with their parents were asked to complete the PSC Korean version and the child behavior checklist (CBCL). The internal reliability and test-retest reliability of the PSC as well as the cut off score of the PSC was determined via receiver operating characteristic analysis of the CBCL score, clinical group scores and non-clinical group scores. The internal consistency of the PSC-Korean version was excellent (Cronbach's alpha = 0.95). The test-retest reliability was r = 0.73 (P < 0.001). Using clinical CBCL scores (total score, externalizing score, internalizing score, respectively >= 60) and presence of clinical diagnosis, the recommended cut-off score of the PSC was 14. Using 494 Korean children aged 7-12 yr, the current study assessed the reliability and validity of a Korean version of the PSC and suggested a cut-off for recommending further clinical assessment. The present results suggest that the Korean version of the PSC has good internal consistency and validity using the standard of CBCL scores. PMID- 26240497 TI - Analysis of Predisposing Factors for Hearing Loss in Adults. AB - We aimed to estimate the effects of various risk factors on hearing level in Korean adults, using data from the Korea National Health and Nutrition Examination Survey. We examined data from 13,369 participants collected between 2009 and 2011. Average hearing thresholds at low (0.5, 1, and 2 kHz) and high frequencies (3, 4, and 6 kHz), were investigated in accordance with various known risk factors via multiple regression analysis featuring complex sampling. We additionally evaluated data from 4,810 participants who completed a questionnaire concerned with different types of noise exposure. Low body mass index, absence of hyperlipidemia, history of diabetes mellitus, low incomes, low educational status, and smoking were associated with elevated low frequency hearing thresholds. In addition, male sex, low body mass index, absence of hyperlipidemia, low income, low educational status, smoking, and heavy alcohol consumption were associated with elevated high frequency hearing thresholds. Participants with a history of earphone use in noisy circumstances demonstrated hearing thresholds which were 1.024 dB (95% CI: 0.176 to 1.871; P = 0.018) higher, at low-frequencies, compared to participants without a history of earphone use. Our study suggests that low BMI, absence of hyperlipidemia, low household income, and low educational status are related with hearing loss in Korean adults. Male sex, smoking, and heavy alcohol use are related with high frequency hearing loss. A history of earphone use in noisy circumstances is also related with hearing loss. PMID- 26240498 TI - Dicer Is Down-regulated and Correlated with Drosha in Idiopathic Sudden Sensorineural Hearing Loss. AB - Previously, we reported the expression levels of specific microRNA machinery components, DGCR8 and AGO2, and their clinical association in patients with idiopathic sudden hearing loss (SSNHL). In the present study, we investigated the other important components of microRNA machinery and their association with clinical parameters in SSNHL patients. Fifty-seven patients diagnosed with SSNHL and fifty healthy volunteers were included in this study. We evaluated mRNA expression levels of Dicer and Drosha in whole blood of patients with SSNHL and the control group, using RT & real-time PCR analysis. The Dicer mRNA expression level was down-regulated in patients with SSNHL. However, the Drosha mRNA expression level was not significantly altered in patients with SSNHL. Neither the Dicer nor Drosha mRNA expression level was not associated with any clinical parameters, including age, sex, duration of initial treatment from onset (days), initial Pure tone average, Siegel's criteria, WBC, and Erythrocyte sedimentation rate. However, mRNA expression levels of Dicer and Drosha were positively correlated to each other in patients with SSNHL. In this study, we demonstrated for the first time that the Dicer mRNA expression level was down-regulated in patients with SSNHL, suggesting its important role in pathobiology of SSNHL development. PMID- 26240499 TI - Mechanical Antiallodynic Effect of Intrathecal Nefopam in a Rat Neuropathic Pain Model. AB - Nefopam has a pharmacologic profile distinct from that of opioids or other anti inflammatory drugs. Several recent studies demonstrate that nefopam has a mechanism of action similar to those of anti-depressants and anticonvulsants for treating neuropathic pain. The present study investigates the mechanical antiallodynic effect of nefopam using immunohistochemical study and western blot analysis in a rat neuropathic pain model. Twenty-eight male Sprague-Dawley rats were subjected to left fifth lumbar (L5) spinal nerve ligation and intrathecal catheter implantation, procedures which were not performed on the 7 male Sprague Dawley rats in the sham surgery group (group S). Nefopam, either 10 or 100 ug/kg (group N10 or N100, respectively), and normal saline (group C) were intrathecally administered into the catheter every day for 14 days. The mechanical allodynic threshold of intrathecal nefopam was measured using a dynamic plantar aesthesiometer. Immunohistochemistry targeting cluster of differentiation molecule 11b (CD11b) and glial fibrillary acidic protein (GFAP) was performed on the harvested spinal cord at the level of L5. Extracellular signal-regulated kinase 1/2 (ERK 1/2) and cyclic adenosine monophosphate response element binding protein (CREB) were measured using western blot analysis. The N10 and N100 groups showed improved mechanical allodynic threshold, reduced CD11b and GFAP expression, and attenuated ERK 1/2 and CREB in the affected L5 spinal cord. In conclusion, intrathecal nefopam reduced mechanical allodynia in a rat neuropathic pain model. Its mechanical antiallodynic effect is associated with inhibition of glial activation and suppression of the transcription factors' mitogen-activated protein kinases in the spinal cord. PMID- 26240500 TI - Randomized Comparison of Actual and Ideal Body Weight for Size Selection of the Laryngeal Mask Airway Classic in Overweight Patients. AB - Size selection of the laryngeal mask airway (LMA) Classic based on actual body weight remains a common practice. However, ideal body weight might allow for a better size selection in obese patients. The purpose of our study was to compare the utility of ideal body weight and actual body weight when choosing the appropriate size of the LMA Classic by a randomized clinical trial. One hundred patients with age 20 to 70 yr, body mass index >=25 kg/m(2), and the difference between LMA sizes based on actual weight and ideal weight were allocated to insert the LMA Classic using either actual body weight or ideal body weight in a weight-based formula for size selection. After insertion of the device, several variables including insertion parameters, sealing function, fiberoptic imaging, and complications were investigated. The insertion success rate at the first attempt was lower in the actual weight group (82%) than in the ideal weight group (96%), even it did not show significant difference. The ideal weight group had significantly shorter insertion time and easier placement. However, fiberoptic views were significantly better in the actual weight group. Intraoperative complications, sore throat in the recovery room, and dysphonia at postoperative 24 hr occurred significantly less often in the ideal weight group than in the actual weight group. It is suggested that the ideal body weight may be beneficial to the size selection of the LMA Classic in overweight patients (Clinical Trial Registry, NCT 01843270). PMID- 26240501 TI - Neonatal Iliopsoas Abscess: The First Korean Case. AB - Iliopsoas abscess (IPA) is rare in neonates. We present a case of neonatal IPA that was initially believed to bean inguinal hernia. A 20-day-old male infant was referred to our hospital for herniorrhaphy after a 2-day history of swelling and bluish discoloration of the left inguinal area and leg without limitation of motion. Abdominal and pelvic ultrasonography suggested a femoral hernia, but the anatomy was unclear. Abdominal computed tomography revealed a multi-septated cystic mass extending into the psoas muscle from the lower pole of the left kidney to the femur neck. Broad spectrum antibiotics were initiated, and prompt surgical exploration was planned. After opening the retroperitoneal cavity via an inguinal incision, an IPA was diagnosed and surgically drained. Culture of the abscess fluid detected Staphylococcus aureus, sensitive to methicillin. The patient was discharged without complication on the 17th postoperative day. PMID- 26240502 TI - An Appropriate Lower Respiratory Tract Specimen Is Essential for Diagnosis of Middle East Respiratory Syndrome (MERS). PMID- 26240503 TI - Letter to the editor: Knowledge and Attitude of Nursing Personnel towards Depression in General Hospitals: The Korean Perspective. PMID- 26240504 TI - Clinical Association of Thyroid Stimulating Hormone Receptor Antibody Levels with Disease Severity in the Chronic Inactive Stage of Graves' Orbitopathy. AB - PURPOSE: To investigate associations between serum thyroid stimulating hormone (TSH) receptor antibody (TRAb) levels and Graves' orbitopathy (GO) activity/severity in chronic-stage GO and compare the performance of two newly developed TRAb assays (third-generation TSH-binding inhibition immunoglobulin [TBII] assay versus Mc4 thyroid-stimulating immunoglobulin [TSI] bioassay). METHODS: This study is a retrospective review of medical charts and blood tests from Korean GO patients who first visited the departments of ophthalmology and endocrinology, Yonsei University College of Medicine from January 2008 to December 2011, were diagnosed with GO and Graves' hyperthyroidism, and were followed up for >=18 months. Third-generation M22-TBII and Mc4-TSI assays were performed in the chronic-inactive GO patients in whom euthyroidism status was restored. Patients' GO activity/severity clinical activity scores (CAS), and modified NOSPECS scores were examined for a correlation with TRAb assays. RESULTS: Fifty patients (mean age, 41.3 years; 41 females) were analyzed. The mean duration of Graves' hyperthyroidism symptom was 63 months (range, 18 to 401 months) and that of GO was 46 months (range, 18 to 240 months). All patients had been treated previously with anti-thyroid drugs for a median period of 52.3 months, and two patients underwent either radioiodine therapy or total thyroidectomy. Mean CAS and NOSPECS scores were 0.5 +/- 0.9 (standard deviation) and 4.8 +/- 3.1, respectively. Mean M22-TBII and Mc4-TSI values were 7.5 +/- 10.2 IL/L and 325.9 +/- 210.1 specimen-to-reference control ratio. TSI was significantly correlated with NOSPECS score (R = 0.479, p < 0.001); however, TBII was not associated with NOSPECS score (p = 0.097). Neither TSI nor TBII correlated with CAS (p > 0.05), because GO inflammatory activity subsided in the chronic stages of GO. CONCLUSIONS: In chronic-inactive GO after euthyroid restoration, GO activity score did not associate with serum levels of TRAb or TBII. However, levels of the functional antibody Mc4-TSI did correlate with GO severity. Therefore, the TSI bioassay is a clinically relevant measure of disease severity even in chronic inactive GO. PMID- 26240505 TI - Evaluation of Anterior Segment Parameters in Obesity. AB - PURPOSE: To investigate anterior segment parameters in obese patients in comparison to healthy individuals. METHODS: Thirty-four obese subjects and 34 age sex-matched healthy subjects were enrolled in this prospective cross-sectional study. Ophthalmological examinations including intraocular pressure (IOP), central corneal thickness (CCT), anterior chamber depth (ACD), anterior chamber volume (ACV), anterior chamber angle (ACA), and axial length (AL) measurements were performed on each subject. Height and weight of all subjects were recorded and body mass index (BMI) was calculated. RESULTS: IOP was significantly higher in the obese group (p = 0.003). The mean ACD in obese subjects was significantly lower than that in control subjects (p = 0.036). AL, ACV, ACA and CCT were not significantly different between the groups. There was a positive correlation between BMI and IOP (r = 0.404, p < 0.001). ACD and ACA were negatively correlated with BMI. CONCLUSIONS: IOP was significantly higher and ACD was significantly lower in obese subjects. AL, ACV, ACA and CCT were not significantly different between the groups. The impact of obesity on anterior chamber parameters should be further investigated. PMID- 26240506 TI - Aflibercept Treatment for Neovascular Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy Refractory to Anti-vascular Endothelial Growth Factor. AB - PURPOSE: To report the results of switching treatment to vascular endothelial growth factor (VEGF) Trap-Eye (aflibercept) in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) refractory to anti VEGF (ranibizumab and bevacizumab). METHODS: This is a retrospective study involving 32 eyes from 29 patients; 18 were cases of neovascular AMD and 14 were cases of PCV. The best-corrected visual acuity (BCVA) and central macular thickness (CMT) of spectral-domain optical coherence tomography were evaluated. RESULTS: BCVA and CMT improved from 0.58 to 0.55 (p = 0.005) and from 404 to 321 um (p < 0.001), respectively, after switching to aflibercept. The 14 eyes that received 6 or more aflibercept injections remained stable at 0.81 to 0.81 and 321 to 327 um (p = 1.0, 0.29), respectively, after 3 aflibercept injections. The 10 eyes that received 3 or more bevacizumab injections after 3 or more aflibercept injections worsened, from 0.44 to 0.47 and from 332 to 346 um (p = 0.06, 0.05), respectively. The results showed similar improvement of BCVA and CMT in neovascular AMD and PCV. CONCLUSIONS: Aflibercept seems to be effective for improvement and maintenance of BCVA and CMT for neovascular AMD and PCV refractory to anti-VEGF. Switching from aflibercept back to bevacizumab treatment may not be a proper strategy. PMID- 26240507 TI - Iatrogenic Central Retinal Artery Occlusion Following Retrobulbar Anesthesia for Intraocular Surgery. AB - PURPOSE: To present clinical features of central retinal artery occlusion (CRAO) following retrobulbar anesthesia for intraocular surgery. METHODS: This observational case series describes 5 consecutive patients with acute CRAO following retrobulbar anesthesia for intraocular surgery. Data collected for this study included subject characteristics, retrobulbar anesthesia technique, treatment type, initial and final best-corrected visual acuity, and other ophthalmologic examinations. RESULTS: Mean subject age was 67.0 +/- 8.2 years (range, 53 to 72 years). All patients had one or more vascular risk factors (e.g., hypertension, cerebral infarction, carotid artery stenosis) and presented with acute vision loss 1 day after uneventful intraocular surgery (cataract surgery in 2 eyes and vitrectomy in 3 eyes). All 5 patients received retrobulbar anesthesia during surgery, 4 of which involved the use of a sharp needle. No immediate complications were noted during intraocular surgery. Final visual prognosis was poor (from finger count to no light perception) although intraocular thrombolysis was attempted in 3 patients. CONCLUSIONS: Iatrogenic CRAO is a potential complication of retrobulbar anesthesia for intraocular surgery in elderly patients with vascular risk factors. Unfortunately, this complication can lead to severe vision loss. We conclude that retrobulbar anesthesia for intraocular surgery should be performed with great care and special consideration for elderly patients with vascular risk factors. PMID- 26240508 TI - Ocular Manifestations of Acquired Immunodeficiency Syndrome. AB - PURPOSE: To investigate the patterns and risk factors of the ocular manifestations of acquired immunodeficiency syndrome (AIDS) and their correlation with CD4+ count in the era of highly active antiretroviral therapy (HAART). METHODS: This retrospective study examined 127 AIDS patients who presented to Soonchunhyang University Hospital. Data were collected from patient interviews, clinical examinations, and laboratory investigations. Ophthalmologic examinations included the best-corrected visual acuity, intraocular pressure, anterior segment and adnexal examination, and dilated fundus examination. RESULTS: Of the 127 patients with AIDS, 118 were on HAART and 9 were not. The mean CD4+ count was 266.7 +/- 209.1 cells/uL. There were ocular manifestations in 61 patients (48.0%). The incidence of anterior segment manifestations was higher than posterior segment manifestations at 28.3% and 19.7%, respectively. The mean CD4+ count was significantly (p < 0.05) lower in the patients with posterior versus anterior segment ocular manifestations. The most common ocular manifestation was retinal microvasculopathy (15.0%), followed by keratoconjunctivitis sicca (14.2%), conjunctival microvasculopathy (9.4%), cytomegalovirus retinitis (3.1%), herpes zoster ophthalmicus (2.4%), and blepharitis (1.6%). Retinal microvasculopathy and cytomegalovirus retinitis were common in patients with CD4+ counts <200 cells/uL, while keratoconjunctivitis sicca and conjunctival microvasculopathy were common in patients with CD4+ counts of 200 to 499 cells/uL. There was a significant (p < 0.05) association between ocular manifestation and CD4+ count or age. CONCLUSIONS: The introduction of HAART has changed the landscape of ocular presentations in patients with AIDS. In this study, anterior segment and external ocular manifestations occurred more frequently than posterior segment manifestations. Also, the mean CD4+ count was significantly lower in patients with posterior segment ocular manifestations versus anterior segment ocular manifestations. We found that CD4+ count and age >35 years were independent risk factors for developing ocular manifestations. PMID- 26240509 TI - A Family with Axenfeld-Rieger Syndrome: Report of the Clinical and Genetic Findings. AB - PURPOSE: To describe clinical findings in a Korean family with Axenfeld-Rieger syndrome. METHODS: A retrospective review of clinical data about patients with diagnosed Axenfeld-Rieger syndrome. Five affected members of the family underwent a complete ophthalmologic examination. We screened the forkhead box C1 gene and the pituitary homeobox 2 gene in patients. Peripheral blood leukocytes and buccal mucosal epithelial cells were obtained from seven members of a family with Axenfeld-Rieger syndrome. DNA was extracted and amplified by polymerase chain reaction, followed by direct sequencing. RESULTS: The affected members showed iris hypoplasia, iridocorneal adhesions, posterior embryotoxon, and advanced glaucoma in three generation. None had systemic anomalies. Two mutations including c.1362_1364insCGG and c.1142_1144insGGC were identified in forkhead box C1 in four affected family members. CONCLUSIONS: This study may help to understand clinical findings and prognosis for patients with Axenfeld-Rieger syndrome. PMID- 26240510 TI - Ocular Manifestations of Venomous Snake Bite over a One-year Period in a Tertiary Care Hospital. AB - PURPOSE: Ocular manifestations in snake-bite injuries are quite rare. However, the unusual presentations, diagnosis and their management can pose challenges when they present to the ophthalmologist. Early detection of these treatable conditions can prevent visual loss in these patients who are systemically unstable and are unaware of their ocular condition. To address this, a study was conducted with the aim of identifying the various ocular manifestations of snake bite in a tertiary care center. METHODS: This is a one-year institute-based prospective study report of 12 snake bite victims admitted to a tertiary hospital with ocular manifestations between June 2013 to June 2014, which provides data about the demographic characteristics, clinical profiles, ocular manifestations, and their outcomes. RESULTS: Twelve cases of snake bite with ocular manifestations were included of which six were viper bites, three were cobra bites and three were unknown bites. Six patients presented with bilateral acute angle closure glaucoma (50%), two patients had anterior uveitis (16.6%) of which one patient had concomitant optic neuritis. One patient had exudative retinal detachment (8.3%), one patient had thrombocytopenia with subconjunctival hemorrhage (8.3%) and two patients had external ophthalmoplegia (16.6%). CONCLUSIONS: Bilateral angle closure glaucoma was the most common ocular manifestation followed by anterior uveitis and external ophthalmoplegia. Snake bite can result in significant ocular morbidity in a majority of patients but spontaneous recovery with anti-snake venom, steroids and conservative management results in good visual prognosis. PMID- 26240511 TI - Relationship between Peripapillary Retinal Nerve Fiber Layer Thickness Measured by Optical Coherence Tomography and Visual Field Severity Indices. AB - PURPOSE: Though there are many reports regarding the structure-function relationship in glaucoma, they are too complicated to apply to the routine clinical setting. The aim of this study was to investigate the direct relationship between peripapillary retinal nerve fiber layer (RNFL) thickness measured by optical coherence tomography (OCT) and visual field (VF) severity indices computed by standard automated perimetry. METHODS: This cross-sectional comparative study included 104 glaucomatous patients and 59 healthy subjects. Peripapillary RNFL thickness was measured by spectral domain (SD) and time domain (TD) OCTs. Four glaucoma VF severity indices, including mean deviation (MD), pattern standard deviation (PSD), Collaborative Initial Glaucoma Treatment Study (CIGTS) VF score, and Advanced Glaucoma Intervention Study (AGIS) VF score, were calculated using standard automated perimetry. The Pearson's correlation coefficients (r) between the average and quadrants of peripapillary RNFL thicknesses and the four VF severity indices were calculated. RESULTS: In glaucomatous eyes, the r value between the average RNFL thickness measured by SD OCT and each VF severity index were 0.562, -0.514, -0.577, and -0.567 for the MD, PSD, CIGTS VF score, and AGIS VF score, respectively (all p < 0.001). Among each quadrant, the inferior RNFL thickness showed the largest r value; 0.587, -0.552, 0.613, and -0.598 for the MD, PSD, CIGTS VF score, and AGIS VF score, respectively (all p < 0.001). Measurements by TD OCT showed similar strengths of association with SD OCT. CONCLUSIONS: Moderate correlation was identified between peripapillary RNFL thicknesses measured by SD/TD OCT and glaucoma VF severity indices. Among each quadrant, the inferior RNFL thickness showed the greatest association with glaucoma VF severity indices. There was no significant difference according to the type of VF severity index or the type of OCTs. PMID- 26240513 TI - Uveal Melanoma with Massive Extraocular Extension through the Sclerocorneal Limbus. PMID- 26240512 TI - In Vivo Effects of Preservative-free and Preserved Prostaglandin Analogs: Mouse Ocular Surface Study. AB - PURPOSE: Chronic use of topical hypotensive agents induces several side effects caused by preservatives. The purpose of this study was to evaluate the effects of prostaglandin analogs with varying concentrations of benzalkonium chloride (BAC), preservative-free (PF), and alternative preservatives on mouse corneal tissue. METHODS: Thirty-five, 8- to 10-week-old female C57BL/6 mice (five mice for each group) were used for this study. To the control group, we applied normal saline, and to each drug-treated group we applied 0.02% BAC, bimatoprost 0.01% (with BAC 0.02%), latanoprost 0.005% (with BAC 0.02%), travoprost 0.004% (with 0.001% polyquad) or tafluprost 0.0015% with/without 0.001% BAC, once a day (9 p.m.) for 4 weeks. Corneal fluorescein staining was evaluated in all groups. After harvest, the corneal tissues were embedded in paraffin and then Hematoxylin-Eosin stain was performed for histopathological examination. Immunofluorescence staining was done against TNF-alpha, IL-6, HLA DR, pJNK, and pAkt. RESULTS: In corneal fluorescein staining, severe punctate epithelial keratitis was seen in the groups of 0.02% BAC, 0.02% BAC containing bimatoprost 0.01% and latanoprost 0.005%. The surface desquamation, irregular surface, loss of cell borders, anisocytosis and stromal shrinkage were observed in the groups of BAC-containing eye drops. Moreover, the groups treated with BAC-containing eye drops have high inflammatory markers, significantly decreased cell viability-related signal, pAkt, and higher apoptosis-inducing signal, pJNK, than the control group. On the other hand, travoprost 0.004% and PF tafluprost 0.0015% have less cellular morphologic changes, lower inflammation, and higher cellular viability than BAC-containing formulations. CONCLUSIONS: Corneal damage, increased inflammation and apoptosis and low cell viability were observed in BAC-containing groups. PF or alternatively preserved glaucoma medications seem to be a reasonable and viable alternative to those preserved with BAC. PMID- 26240514 TI - A Case of Congenital Simple Hamartoma of the Retinal Pigment Epithelium and Coats' Disease in the Same Eye. PMID- 26240515 TI - Markov Chain Monte Carlo from Lagrangian Dynamics. AB - Hamiltonian Monte Carlo (HMC) improves the computational e ciency of the Metropolis-Hastings algorithm by reducing its random walk behavior. Riemannian HMC (RHMC) further improves the performance of HMC by exploiting the geometric properties of the parameter space. However, the geometric integrator used for RHMC involves implicit equations that require fixed-point iterations. In some cases, the computational overhead for solving implicit equations undermines RHMC's benefits. In an attempt to circumvent this problem, we propose an explicit integrator that replaces the momentum variable in RHMC by velocity. We show that the resulting transformation is equivalent to transforming Riemannian Hamiltonian dynamics to Lagrangian dynamics. Experimental results suggests that our method improves RHMC's overall computational e ciency in the cases considered. All computer programs and data sets are available online (http://www.ics.uci.edu/~babaks/Site/Codes.html) in order to allow replication of the results reported in this paper. PMID- 26240516 TI - Effects of Behavioral Genetic Evidence on Perceptions of Criminal Responsibility and Appropriate Punishment. AB - Demonstrations of a link between genetic variants and criminal behavior have stimulated increasing use of genetic evidence to reduce perceptions of defendants' responsibility for criminal behavior and to mitigate punishment. However, because only limited data exist regarding the impact of such evidence on decision makers and the public at large, we recruited a representative sample of the U.S. adult population (n=960) for a web-based survey. Participants were presented with descriptions of three legal cases and were asked to: determine the length of incarceration for a convicted murderer; adjudicate an insanity defense; and decide whether a defendant should receive the death penalty. A fully crossed, between-participants, factorial design was used, varying the type of evidence (none, genetic, neuroimaging, both), heinousness of the crime, and past criminal record, with sentence or verdict as the primary outcome. Also assessed were participants' apprehension of the defendant, belief in free will, political ideology, and genetic knowledge. Across all three cases, genetic evidence had no significant effects on outcomes. Neuroimaging data showed an inconsistent effect in one of the two cases in which it was introduced. In contrast, heinousness of the offense and past criminal record were strongly related to participants' decisions. Moreover, participants' beliefs about the controllability of criminal behavior and political orientations were significantly associated with their choices. Our findings suggest that neither hopes that genetic evidence will modify judgments of culpability and punishment nor fears about the impact of genetic evidence on decision makers are likely to come to fruition. PMID- 26240517 TI - TL1A/DR3 axis involvement in the inflammatory cytokine network during pulmonary sarcoidosis. AB - BACKGROUND: TNF-like ligand 1A (TL1A), a recently recognized member of the TNF superfamily, and its death domain receptor 3 (DR3), firstly identified for their relevant role in T lymphocyte homeostasis, are now well-known mediators of several immune-inflammatory diseases, ranging from rheumatoid arthritis to inflammatory bowel diseases to psoriasis, whereas no data are available on their involvement in sarcoidosis, a multisystemic granulomatous disease where a deregulated T helper (Th)1/Th17 response takes place. METHODS: In this study, by flow cytometry, real-time PCR, confocal microscopy and immunohistochemistry analyses, TL1A and DR3 were investigated in the pulmonary cells and the peripheral blood of 43 patients affected by sarcoidosis in different phases of the disease (29 patients with active sarcoidosis, 14 with the inactive form) and in 8 control subjects. RESULTS: Our results demonstrated a significant higher expression, both at protein and mRNA levels, of TL1A and DR3 in pulmonary T cells and alveolar macrophages of patients with active sarcoidosis as compared to patients with the inactive form of the disease and to controls. In patients with sarcoidosis TL1A was strongly more expressed in the lung than the blood, i.e., at the site of the involved organ. Additionally, zymography assays showed that TL1A is able to increase the production of matrix metalloproteinase 9 by sarcoid alveolar macrophages characterized, in patients with the active form of the disease, by reduced mRNA levels of the tissue inhibitor of metalloproteinase (TIMP)-1. CONCLUSIONS: These data suggest that TL1A/DR3 interactions are part of the extended and complex immune-inflammatory network that characterizes sarcoidosis during its active phase and may contribute to the pathogenesis and to the progression of the disease. PMID- 26240518 TI - VideoHacking: Automated Tracking and Quantification of Locomotor Behavior with Open Source Software and Off-the-Shelf Video Equipment. AB - Differences in nervous system function can result in differences in behavioral output. Measurements of animal locomotion enable the quantification of these differences. Automated tracking of animal movement is less labor-intensive and bias-prone than direct observation, and allows for simultaneous analysis of multiple animals, high spatial and temporal resolution, and data collection over extended periods of time. Here, we present a new video-tracking system built on Python-based software that is free, open source, and cross-platform, and that can analyze video input from widely available video capture devices such as smartphone cameras and webcams. We validated this software through four tests on a variety of animal species, including larval and adult zebrafish (Danio rerio), Siberian dwarf hamsters (Phodopus sungorus), and wild birds. These tests highlight the capacity of our software for long-term data acquisition, parallel analysis of multiple animals, and application to animal species of different sizes and movement patterns. We applied the software to an analysis of the effects of ethanol on thigmotaxis (wall-hugging) behavior on adult zebrafish, and found that acute ethanol treatment decreased thigmotaxis behaviors without affecting overall amounts of motion. The open source nature of our software enables flexibility, customization, and scalability in behavioral analyses. Moreover, our system presents a free alternative to commercial video-tracking systems and is thus broadly applicable to a wide variety of educational settings and research programs. PMID- 26240519 TI - ERIN: A Portal to Resources for Higher Education in Neuroscience. AB - ERIN, Educational Resources in Neuroscience, is the Society for Neuroscience's web portal to selected, high-quality materials for higher education. A Board of Editors approves resources after describing them and classifying them by topic, subtopic, media type, author, and appropriate educational level. Some resources are also accompanied by reviews and ratings from faculty who have used the resource. These features make a search of ERIN far more useful than a typical Google search. ERIN's development was funded by the National Science Foundation with a three-year grant to SfN. Along the way, various unexpected problems arose and solutions were found, many of which are described in this overview of ERIN's history and the various decisions that were made in its design and development. PMID- 26240520 TI - Documenting Laboratory Procedures with Video. AB - Demonstrating laboratory procedures in person during class time can be time consuming. When procedures are done under a microscope, live demonstration is also impractical because of the limited number of students who can view the demonstration at once. Creating videos beforehand, which students can watch before class and review during lab sessions, solves both of these problems. This article suggests ways to make and distribute high quality video of microscopic procedures. PMID- 26240521 TI - Retention of Underrepresented Minority Faculty: Strategic Initiatives for Institutional Value Proposition Based on Perspectives from a Range of Academic Institutions. AB - The student and faculty make-up of academic institutions does not represent national demographics. Racial and ethnic minorities are disproportionately underrepresented nationally, and particularly at predominantly white institutions (PWIs). Although significant efforts and funding have been committed to increasing points of access or recruitment of under-represented minority (URM) students and faculty at PWIs, these individuals have not been recruited and retained at rates that reflect their national proportions. Underrepresentation of URMs is particularly prevalent in Science, Technology, Engineering, and Mathematics (STEM) disciplines. This reality represents a national crisis given a predicted shortage of workers in STEM disciplines based on current rates of training of all individuals, majority and URM, and the intersection of this limitation with persistent challenges in the recruitment, training, retention and advancement of URMs who will soon represent the largest pool of future trainees. An additional compounding factor is the increasingly disproportionate underrepresentation of minorities at higher professorial and administrative ranks, thus limiting the pool of potential mentors who are correlated with successful shepherding of URM students through STEM training and development. We address issues related to improving recruitment and retention of URM faculty that are applicable across a range of academic institutions. We describe challenges with recruitment and retention of URM faculty and their advancement through promotion in the faculty ranks and into leadership positions. We offer specific recommendations, including identifying environmental barriers to diversity and implementing strategies for their amelioration, promoting effective and innovative mentoring, and addressing leadership issues related to constructive change for promoting diversity. PMID- 26240522 TI - Intentional Excellence in the Baldwin Wallace University Neuroscience Program. AB - The Society for Neuroscience recognized Baldwin Wallace University's (BWU) undergraduate Neuroscience program as their Program of the Year for 2012. This award acknowledged the "accomplishments of a neuroscience department or program for excellence in educating neuroscientists and providing innovative models to which other programs can aspire." The Neuroscience program grew out of students interested in studying the biological basis of behavior. BWU's neuroscience major is research-intensive, and all students are required to produce an empirically based senior thesis. This requirement challenges program resources, and the demand for faculty attention is high. Thus, we developed an intentional 3-step peer mentoring system that encourages our students to collaborate with and learn from, not only faculty, but each other. Peer mentoring occurs in the curriculum, faculty research labs, and as students complete their senior theses. As the program has grown with over 80 current majors, we have developed a new Neuroscience Methods course to train students on the safety, ethics, and practice of research in the neuroscience laboratory space. Students in this course leave with the skills and knowledge to assist senior level students with their theses and to begin the process of developing their own projects in the laboratory. Further, our students indicate that their "peer mentorship was excellent," "helped them gain confidence," and "allowed them to be more successful in their research." PMID- 26240523 TI - Best Practices: The Neuroscience Program at Central Michigan University. AB - The original design of our program at Central Michigan University (CMU) and its evolving curriculum were directly influenced by Faculty for Undergraduate (FUN) workshops at Davidson College, Oberlin College, Trinity College, and Macalester College. The course content, laboratory exercises, and pedagogy used were informed by excellent articles in the Journal of Undergraduate Neuroscience Education (JUNE) and presentations at these FUN workshops and meetings over the years. Like the program at Baldwin-Wallace College, which was a previous winner of the Undergraduate Neuroscience Program of the Year Award, as selected by the Committee on Neuroscience Departments and Programs (CNDP) of the Society for Neuroscience (SfN, our program stresses the importance of inquiry-based, hands-on research experience for our undergraduates and utilizes a peer-mentoring system. A distinct advantage that is employed at CMU is the use of graduate student mentors, which allows us to expand our peer-mentorship to distinct research teams that are focused on a specific research project. Developing our program was not easy. The present manuscript reviews the long and arduous journey (including ways in which we navigated some difficult internal political issues) we made to build a strong program. Hopefully, this description may prove helpful for other evolving programs, in terms of avoiding certain pitfalls and overcoming obstacles, as well as selecting practices that have proven to be successful at our institution. PMID- 26240524 TI - Career Transitions for Faculty Members committed to Undergraduate Neuroscience Education. AB - This article highlights some of the critical issues that were discussed during a breakout session on career transitions at the 2014 Faculty for Undergraduate Neuroscience (FUN) Workshop at Ithaca College on Undergraduate Neuroscience Education: Challenges and Solutions in Creating and Sustaining Programs. Topics included: (1) transitioning from graduate school or a postdoc position to an assistant professor position; (2) preparing for promotion and tenure decisions; (3) balancing teaching, research, and service during a career in academics; (4) exploring alternative career options, including moving to another institution, taking on an administrative position, and working in industry; and (5) deciding when and how to retire. Much of the discussion focused on special challenges that women and minorities face in the academic environment. Participants offered valuable insights and suggestions for helping new faculty members prepare for reappointment, promotion, and tenure decisions, including utilizing networking connections within FUN for letters of support and collaborative opportunities. These networking opportunities were also valued by participants who were in rather unique positions, such as transitioning from a purely administrative role back to a regular faculty position or handling the extra burden of being a chair or program director with essentially the same research and grant-writing expectations of a regular faculty member. The session proved to be enlightening for most participants and though several questions and concerns remained unanswered, several ideas and insights were shared by the participants and a sense of empathy for the unique circumstances many of the participants were experiencing provided an atmosphere of comradery and support that often emanates from these FUN workshop sessions. PMID- 26240525 TI - Techniques and Technology to Revise Content Delivery and Model Critical Thinking in the Neuroscience Classroom. AB - Undergraduate neuroscience courses typically involve highly interdisciplinary material, and it is often necessary to use class time to review how principles of chemistry, math and biology apply to neuroscience. Lecturing and Socratic discussion can work well to deliver information to students, but these techniques can lead students to feel more like spectators than participants in a class, and do not actively engage students in the critical analysis and application of experimental evidence. If one goal of undergraduate neuroscience education is to foster critical thinking skills, then the classroom should be a place where students and instructors can work together to develop them. Students learn how to think critically by directly engaging with course material, and by discussing evidence with their peers, but taking classroom time for these activities requires that an instructor find a way to provide course materials outside of class. Using technology as an on-demand provider of course materials can give instructors the freedom to restructure classroom time, allowing students to work together in small groups and to have discussions that foster critical thinking, and allowing the instructor to model these skills. In this paper, I provide a rationale for reducing the use of traditional lectures in favor of more student centered activities, I present several methods that can be used to deliver course materials outside of class and discuss their use, and I provide a few examples of how these techniques and technologies can help improve learning outcomes. PMID- 26240526 TI - Light Activated Escape Circuits: A Behavior and Neurophysiology Lab Module using Drosophila Optogenetics. AB - The neural networks that control escape from predators often show very clear relationships between defined sensory inputs and stereotyped motor outputs. This feature provides unique opportunities for researchers, but it also provides novel opportunities for neuroscience educators. Here we introduce new teaching modules using adult Drosophila that have been engineered to express csChrimson, a red light sensitive channelrhodopsin, in specific sets of neurons and muscles mediating visually guided escape behaviors. This lab module consists of both behavior and electrophysiology experiments that explore the neural basis of flight escape. Three preparations are described that demonstrate photo-activation of the giant fiber circuit and how to quantify these behaviors. One of the preparations is then used to acquire intracellular electrophysiology recordings from different flight muscles. The diversity of action potential waveforms and firing frequencies observed in the flight muscles make this a rich preparation to study the ionic basic of cellular excitability. By activating different cells within the giant fiber pathway we also demonstrate principles of synaptic transmission and neural circuits. Beyond conveying core neurobiological concepts it is also expected that using these cutting edge techniques will enhance student motivation and attitudes towards biological research. Data collected from students and educators who have been involved in development of the module are presented to support this notion. PMID- 26240527 TI - Gel Scramble: An E-Tool for Teaching Molecular Neuroscience. AB - In this completely digital teaching module, students interpret the results of two separate procedures: a restriction endonuclease digestion, and a polymerase chain reaction (PCR). The first consists of matching restriction endonuclease digest protocols with images obtained from stained agarose gels. Students are given the sequence of six plasmid cDNAs, characteristics of the plasmid vector, and the endonuclease digest protocols, which specify the enzyme(s) used. Students calculate the expected lengths of digestion products using this information and free tools available on the web. Students learn how to read gels and then match their predicted fragment lengths to the digital images obtained from the gel electrophoresis of the cDNA digest. In the PCR experiment, students are given six cDNA sequences and six sets of primers. By querying NCBI BLAST, students can match the PCR fragments to the lengths of the predicted in silico PCR products. The ruse posed to students is that the gels were inadvertently mislabeled during processing. Although students know the experimental details, they do not know which gel goes with a given restriction endonuclease digest or PCR-they must deduce the answers. Because the gel images are from actual students' experiments, the data sometimes result from mishandling/mislabeling or faulty protocol execution. The most challenging part of the exercise is to explain these errors. This latter aspect requires students to use critical thinking skills to explain aberrant outcomes. This entire exercise is available in a digital format and downloadable for free at http://mdcune.psych.ucla.edu/modules/gel. PMID- 26240528 TI - Neuroscience and Global Learning. AB - Traditional study abroad experiences take a variety of forms with most incorporating extensive cultural emersion and a focus on global learning skills. Here we ask the question: Can this type of experience co-exist with a quality scientific experience and continued progression through a typically rigorous undergraduate neuroscience curriculum? What are the potential costs and benefits of this approach? How do we increase student awareness of study abroad opportunities and inspire them to participate? We outline programs that have done this with some success and point out ways to cultivate this approach for future programs. These programs represent a variety of approaches in both their duration and role in a given curriculum. We discuss a one-week first year seminar program in Berlin, a summer study abroad course in Munich and Berlin, semester experiences and other options offered through the Danish Institute for Study Abroad in Copenhagen. Each of these experiences offers opportunities for interfacing global learning with neuroscience. PMID- 26240529 TI - How to Successfully Incorporate Undergraduate Researchers Into a Complex Research Program at a Large Institution. AB - One feature of the Laboratory for Rational Decision Making at Cornell University is the integration of a large number of undergraduate students into a relatively elaborate research program. We describe our thorough screening process, laboratory structure, and our expectations for undergraduate researchers in our lab. We have a structure in place that helps maintain organization and enhance productivity, including scheduled weekly and monthly meetings, and selecting undergraduate and graduate team leaders to lead each research project. We discuss how it is important to encourage students to aim high and have a good attitude toward learning and problem solving. We emphasize that both initiative and teamwork are important in a large research laboratory. We also discuss the importance of giving students responsibility in connection with research projects our undergraduate researchers engage in data analysis, interpretation of results, and have a high-level understanding of theory. PMID- 26240530 TI - Mission-driven, Manageable and Meaningful Assessment of an Undergraduate Neuroscience Program. AB - Academia has recently been under mounting pressure to increase accountability and intentionality in instruction through development of student "intended learning outcomes" (ILOs) developed at multiple levels (e.g., course, program, major, and even institution). Once these learning goals have been determined, then classroom instruction can be purposefully designed to map onto those intended outcomes in a "backward design" process (Wiggins and McTighe, 2005). The ongoing challenge with any such process, however, is in determining one's effectiveness in achieving these intended learning goals, so it is critical that efficient tools can be developed that enable these goals to be assessed. In addition, an important requirement of any ILOs is that they are mission-driven, meaningful and parsed in such a way that they can be used to obtain evidence in a manageable way. So how can we effectively assess these outcomes in our students? This paper describes key factors to consider in the planning and implementation of assessment for an undergraduate neuroscience program. PMID- 26240531 TI - In Situ Teaching: Fusing Labs & Lectures in Undergraduate Science Courses to Enhance Immersion in Scientific Research. AB - Undergraduate courses in the life sciences at most colleges and universities are traditionally composed of two or three weekly sessions in a classroom supplemented with a weekly three-hour session in a laboratory. We have found that many undergraduates can have difficulty making connections and/or transferring knowledge between lab activities and lecture material. Consequently, we are actively developing ways to decrease the physical and intellectual divides between lecture and lab to help students make more direct links between what they learn in the classroom and what they learn in the lab. In this article we discuss our experiences teaching fused laboratory biology courses that intentionally blurred the distinctions between lab and lecture to provide undergraduates with immersive experiences in science that promote discovery and understanding. PMID- 26240532 TI - In Vivo Time-Lapse Imaging in the Zebrafish Lateral Line: A Flexible, Open-Ended Research Project for an Undergraduate Neurobiology Laboratory Course. AB - The lateral line sensory system in fish detects movements in the water and allows fish to respond to predators, prey, and other stimuli. As the lateral line forms in the first two days of zebrafish development, axons extend caudally along the lateral surface of the fish, eventually forming synapses with hair cells of neuromasts. Growing lateral line axons are located superficially under the skin and can be labeled in living zebrafish using fluorescent protein expression. This system provides a relatively straightforward approach for in vivo time-lapse imaging of neuronal development in an undergraduate setting. Here we describe an upper-level neurobiology laboratory module in which students investigate aspects of axonal development in the zebrafish lateral line system. Students learn to handle and image living fish, collect time-lapse videos of moving mitochondria, and quantitatively measure mitochondrial dynamics by generating and analyzing kymographs of their movements. Energy demands may differ between axons with extending growth cones versus axons that have already reached their targets and are forming synapses. Since relatively little is known about this process in developing lateral line axons, students generate and test their own hypotheses regarding how mitochondrial dynamics may differ at two different time points in axonal development. Students also learn to incorporate into their analysis a powerful yet accessible quantitative tool, the kymograph, which is used to graph movement over time. After students measure and quantify dynamics in living fish at 1 and 2 days post fertilization, this module extends into independent projects, in which students can expand their studies in a number of different, inquiry-driven directions. The project can also be pared down for courses that wish to focus solely on the quantitative analysis (without fish handling), or vice versa. This research module provides a useful approach for the design of open-ended laboratory research projects that integrate the scientific process into undergraduate Biology courses, as encouraged by the AAAS and NSF Vision and Change Initiative. PMID- 26240533 TI - Using the Humanities to Teach Neuroscience to Non-majors. AB - We developed and offered a sequence of neuroscience courses geared toward changing the way non-science students interact with the sciences. Although we accepted students from all majors and at all class levels, our target population was first and second year students who were majoring in the fine arts or the humanities, or who had not yet declared a major. Our goal was to engage these students in science in general and neuroscience in particular by teaching science in a way that was accessible and relevant to their intellectual experiences. Our methodology was to teach scientific principles through the humanities by using course material that is at the intersection of the sciences and the humanities and by changing the classroom experience for both faculty and students. Examples of our course materials included the works of Oliver Sacks, V.S. Ramachandran, Martha Nussbaum, Virginia Woolf and Karl Popper, among others. To change the classroom experience we used a model of team-teaching, which required the simultaneous presence of two faculty members in the classroom for all classes. We changed the structure of the classroom experience from the traditional authority model to a model in which inquiry, debate, and intellectual responsibility were central. We wanted the students to have an appreciation of science not only as an endeavor guided by evidence and experimentation, but also a public discourse driven by creativity and controversy. The courses attracted a significant number of humanities and fine arts students, many of whom had already completed their basic science requirement. PMID- 26240534 TI - Electrophysiology Meets Ecology: Investigating How Vision is Tuned to the Life Style of an Animal using Electroretinography. AB - Students learn best when projects are multidisciplinary, hands-on, and provide ample opportunity for self-driven investigation. We present a teaching unit that leads students to explore relationships between sensory function and ecology. Field studies, which are rare in neurobiology education, are combined with laboratory experiments that assess visual properties of insect eyes, using electroretinography (ERG). Comprised of nearly one million species, insects are a diverse group of animals, living in nearly all habitats and ecological niches. Each of these lifestyles puts different demands on their visual systems, and accordingly, insects display a wide array of eye organizations and specializations. Physiologically relevant differences can be measured using relatively simple extracellular electrophysiological methods that can be carried out with standard equipment, much of which is already in place in most physiology laboratories. The teaching unit takes advantage of the large pool of locally available species, some of which likely show specialized visual properties that can be measured by students. In the course of the experiments, students collect local insects or other arthropods of their choice, are guided to formulate hypotheses about how the visual system of "their" insects might be tuned to the lifestyle of the species, and use ERGs to investigate the insects' visual response dynamics, and both chromatic and temporal properties of the visual system. Students are then guided to interpret their results in both a comparative physiological and ecological context. This set of experiments closely mirrors authentic research and has proven to be a popular, informative and highly engaging teaching tool. PMID- 26240535 TI - Student Friendly Technique to Demonstrate Coordination between Postural (Involuntary) and Voluntary Muscle Contractions. AB - Electromyography is a very useful technique for a number of clinical and research applications in physiology and other life science applications. We have adapted this technique as a student exercise to explore important aspects of postural control. With minimal effort and some mathematical calculations this student friendly technique efficiently demonstrates the interaction of anticipatory, or feedforward, mechanisms and feedback correction from sensory input. PMID- 26240536 TI - The 2014 FUN Achievement Award. PMID- 26240537 TI - Proceedings of the Faculty for Undergraduate Neuroscience Workshops at Ithaca College, Ithaca, NY, July 30 - Aug 3, 2014. PMID- 26240538 TI - Anesthesia for gastrointestinal endoscopy: A subspecialty in evolution? PMID- 26240539 TI - Noninvasive intracranial pressure monitoring via optic nerve sheath diameter for robotic surgery in steep Trendelenburg position. AB - BACKGROUND: Recent reports of increased intracranial pressure (ICP) due to steep Trendelenburg (ST) position causing neurological deterioration, decreased regional cerebral oxygen saturation and postoperative visual loss after robotic urological and gynecological surgeries led us to consider a simple technique of ICP monitoring. Ours is one of the first instances reported of quantitative noninvasive measurement of increase in ICP with ST position by serial measurement of binocular optic nerve sheath diameter (ONSD) in patients undergoing robot assisted urological and gynecological oncosurgery. We tested whether ONSD values rose to above the upper limits of normal and for what length of time they remained elevated. MATERIALS AND METHODS: Prospective, randomized, interventional, parallel group, active control study conducted on 252 American Society of Anesthesiologists I and II patients. ONSD was measured using 7.5 MHz linear ultrasound probe in supine and Trendelenburg positions. STATISTICS: Student's t-test to compare the inter-group mean ONSD and the repetitive t-test for intra-group analysis. RESULT: Comparison of the mean ONSD values of both groups yielded a 2-tailed significance P <0.01 at all compared time points intra- and post-operatively. In Group-O (open surgery; supine position), the baseline mean bilateral ONSD was 4.36 mm, which did not show any statistically significant change throughout open surgery and postoperative period. On de-docking the robot, 6.2 mm was the mean ONSD value in Group-R (robotic group) while 4.3 mm was the corresponding value in control Group-O. CONCLUSION: ONSD evaluation is a simple, quick, safe, readily available, reliable, cost effective, noninvasive, potential standard of care for screening and monitoring of patients undergoing robotic surgery in ST position. PMID- 26240540 TI - Comparative study between sugammadex and neostigmine in neurosurgical anesthesia in pediatric patients. AB - BACKGROUND: Postoperative recurarization remains a risk following the use of the conventional neuromuscular blocking agents. In addition, none of the commonly used reversal agents, such as neostigmine or edrophonium are capable of reliably reversing profound blockade. The present comparative and randomized study investigated the use of sugammadex for reversing profound neuromuscular blockade (NMB) in pediatric neurosurgical patients undergone posterior fossa tumor excision. PATIENTS AND METHODS: Forty pediatric patients undergoing elective craniotomy for posterior fossa tumor excision were randomly divided into either of neostigmine or sugammadex group in which muscle relaxant was reversed at the end of anesthesia either with neostigmine 0.04 mg/kg added to atropine 0.02 mg/kg or sugammadex 4 mg/kg alone, respectively. The primary endpoint was the time from the administration of sugammadex or neostigmine to recovery of the train of four (TOF) ratio to 90% after rocuronium-induced neuromuscular block. Unpaired t-test was used to compare continuous variables between groups. Meanwhile, repeated ANOVA was used to detect intragroup differences. RESULTS: Patients in sugammadex group attained a TOF ratio 90% in statistically shorter time (1.4 +/- 1.2 min) than those in neostigmine group (25.16 +/- 6.49 min) for reversal of the rocuronium. Mean arterial pressure and heart rate were significantly higher in neostigmine group at 2, 5 and 10 min after administration of the reversal agents and returned nonsignificantly different after that. With no recurarization in any patient throughout the study period. CONCLUSION: Sugammadex rapidly and effectively reverses rocuronium-induced NMB in pediatric patients undergoing neurosurgery when administered at reappearance of T2 of TOF at dose 4 mg/kg. PMID- 26240541 TI - Comparison of pregabalin versus ketamine in postoperative pain management in breast cancer surgery. AB - BACKGROUND: Breast surgery compromises one of the most common cancer surgeries in females and commonly followed by acute postoperative pain. Pregabalin and ketamine have been used in many previous studies and was found to have a good analgesic profile. We assumed that pregabalin and ketamine can be used in control of postoperative pain in female patients undergoing breast cancer surgery. MATERIAL AND METHODS: Ninety female patients scheduled for cancer breast surgery were allocated in three groups (30 patients each), control group (group c) received preoperative placebo, pregabalin group (group p) received oral 150 mg pregabalin 1 h before surgery, ketamine group (group k) received intravenous (IV) 0.5 mg/kg ketamine with induction of anesthesia followed by 0.25 mg/kg/h IV throughout the surgery. All patients received general anesthesia and after recovery, the three groups were assessed in the first postoperative 24 h for postoperative visual analog scale (VAS), total 24 h morphine consumption, incidence of postoperative nausea and vomiting (PONV), sedation score >2 and any complications from the drugs used in the study. RESULTS: The use of pregabalin or ketamine was found to reduce total postoperative morphine consumption with P < 0.001. There was no difference between pregabalin and ketamine groups in opioid requirement. There was no difference between the three groups in postoperative VAS scores or incidence of PONV and sedation score >2. CONCLUSION: The use of preoperative oral 150 mg pregabalin 1 h before surgery or IV 0.5 mg ketamine with induction of anesthesia can reduce postoperative opioid consumption in breast cancer surgery without change in sedation or PONV and with a good safety profile. PMID- 26240542 TI - Dexmedetomidine versus propofol in dilatation and curettage: An open-label pilot randomized controlled trial. AB - BACKGROUND: Traditionally propofol has been used for providing sedation in dilatation and curettage (D and C). Recently, dexmedetomidine has been tried, but very little evidence exists to support its use. AIMS: The aim was to compare hemodynamic and recovery profile of both the drugs along with a degree of comfort experienced by patients and the usefulness of the drug to surgeons. SETTINGS AND DESIGN: Tertiary care center and open-label randomized controlled trial. MATERIALS AND METHODS: Patients posted for D and C were enrolled in two groups (25 each). Both groups received fentanyl 1 MUg/kg intravenous (IV) at the beginning of the procedure. Group P received IV propofol in dose of 1.5 mg/kg over 10-15 min and Group D received dexmedetomidine at a loading dose of 1 MUg/kg over 10 min, followed by 0.5 MUg/kg/h infusion until Ramsay sedation score reached 3-4. Hemodynamic vitals were compared during and after the procedure. In the recovery room time to reach modified Aldrete score (MAS) of 9-10 and patient's and surgeon's satisfaction scores were also recorded and compared. RESULTS: In Group D, patients had statistically significant lower heart rate at 2, 5, 10 and 15 min as compared to Group P. Hypotension was present in 52% in Group P and 4% in Group D (P < 0.05). MAS of 9-10 was achieved in 4.4 min in subjects in Group D in contrast to 16.2 min in Group P (P < 0.05). Group D showed higher patient and surgeon satisfaction scores (P < 0.05). CONCLUSION: Dexmedetomidine provide better hemodynamic and recovery profile than propofol. It can be a superior alternative for short surgical day care procedures. PMID- 26240543 TI - Fentanyl versus tramadol with levobupivacaine for combined spinal-epidural analgesia in labor. AB - BACKGROUND: Neuraxial labor analgesia using new local anesthetics such as levobupivacaine has become very popular by virtue of the safety and lesser motor blockade caused by these agents. Combined spinal-epidural analgesia (CSEA) has become the preferred method for labor analgesia as it combines benefits of both spinal analgesia and flexibility of the epidural catheter. Adding opioids to local anesthetic drugs provide rapid onset and prolonged analgesia but may be associated with several maternal and fetal adverse effects. The purpose of this study is to compare fentanyl and tramadol used in CSEA in terms of duration of analgesia and frequency of the adverse fetomaternal outcome. MATERIALS AND METHODS: A total of 60 primiparas with a singleton pregnancy in active labor were given CSEA after randomly allocating them in two groups of 30 each. Group I received intrathecal 2.5 mg levobupivacaine + 25 MUg fentanyl followed by epidural top ups of 20 ml 0.125% solution of the same combination. Group II received 25 mg tramadol instead of fentanyl. Epidural top ups were given when parturient complained of two painful contractions (visual analogue scale >= 4). Data collected were demographic profile of the patients, analgesic qualities, side- effects and the fetomaternal outcome. RESULTS: Patients in Group II had significantly prolonged analgesia (145 +/- 9 minutes) than in Group I (95 +/- 7 minutes). Patients receiving fentanyl showed rapid onset of analgesia, but there were more incidence of side-effects like shivering, pruritus, transient fetal bradycardia, hypotension, nausea and vomiting. Only side-effect in the tramadol group was nausea and vomiting. During labor, maternal satisfaction was excellent. CONCLUSIONS: Adding tramadol to local anesthetic provides prolonged analgesia with minimal side effects. Fentanyl, when used as adjuvant to local anesthetic, has a rapid onset of analgesia but has certain fetomaternal side-effects. PMID- 26240544 TI - Regional anesthesia in transurethral resection of prostate (TURP) surgery: A comparative study between saddle block and subarachnoid block. AB - BACKGROUND: Spinal anesthesia is the technique of choice in transurethral resection of prostate (TURP). The major complication of spinal technique is risk of hypotension. Saddle block paralyzed pelvic muscles and sacral nerve roots and hemodynamic derangement is less. AIMS AND OBJECTIVES: To compare the hemodynamic changes and adequate surgical condition between saddle block and subarachnoid block for TURP. MATERIAL AND METHODS: Ninety patients of aged between 50 to 70 years of ASA-PS I, II scheduled for TURP were randomly allocated into 2 groups of 45 in each group. Group A patients were received spinal (2 ml of hyperbaric bupivacaine) and Group B were received saddle block (2 ml of hyperbaric bupivacaine). Baseline systolic, diastolic and mean arterial pressure, heart rate, oxygen saturation were recorded and measured subsequently. The height of block was noted in both groups. Hypotension was corrected by administration of phenylephrine 50 mcg bolus and total requirement of vasopressor was noted. Complications (volume overload, TURP syndrome etc.) were noted. RESULTS: Incidence of hypotension and vasopressor requirement was less (P < 0.01) in Gr B patients. Adequate surgical condition was achieved in both groups. There was no incidence of volume overload, TURP syndrome, and bladder perforation. CONCLUSION: TURP can be safely performed under saddle block without hypotension and less vasopressor requirement. PMID- 26240545 TI - Effectiveness of intravenous infusion of N-acetylcysteine in cirrhotic patients undergoing major abdominal surgeries. AB - BACKGROUND: Postoperative acute kidney injury (AKI) is common in patients with chronic liver disease. We prospectively evaluated effectiveness of the N acetylcysteine (NAC) in preserving postoperative renal functions in cirrhotic patients undergoing major abdominal surgeries. MATERIALS AND METHODS: A total of 60 cirrhotic patients child A to B were randomized into two groups of 30 each. NAC groupwas received intravenous infusion of NAC (1200 mg/12h starting immediately before surgery and continued for 72h h postoperative) and controls group received a similar volume of glucose 5% solution as a a placebo. Systemic hemodynamics, hepatic and renal functions, serum cystatin C and cystatin C glomerular filtration rate (GFR) (GFR) were compared between both groups. RESULTS: Serum level of cystatin C was raised significantly above the basal value at postoperative day 1 and day 3 associated with significantly decreased in cystatin C GFR below the basal value in the control group (P = 0.001). 6 (20%) (PP = 0.03) in control group developed AKI based on cystatin C GFR criteria (GFR <55 ml/min/1.73m(2)). Mean values of alanine aminotransferase and aspartate aminotransferase were increased significantly above the basal values in both groups, but the increases were significantly lower in NAC group (P = 0.00). Chest infection was significantly lower associated with shorter hospital stay in the NAC group than the control group. CONCLUSION: Intravenous administration of NAC NAC in cirrhotic patients undergoing major abdominal surgeries reduces the incidence of cystatin C GFR-based AKI, postoperative renal and liver functions were well-preserved and improved outcome. PMID- 26240546 TI - Femoral nerve block versus adductor canal block for postoperative pain control after anterior cruciate ligament reconstruction: A randomized controlled double blind study. AB - BACKGROUND: The objective of this study was to evaluate the reliability of the postoperative pain control using adductor canal block (ACB) compared that using the femoral nerve block (FNB) in patients with anterior cruciate ligament reconstructions (ACLR). MATERIALS AND METHODS: One hundred and twenty-eight patients who had been scheduled to patellar graft ACLR were included in this double blind study, and were randomly allocated into two groups; group ACB and group FNB (64 patients each). All patients received general anesthesia. At the end of the surgery, patients in group FNB received a FNB and those in group ACB received an ACB. The postoperative pain (visual analog scale [VAS]) and muscle weakness were assessed in the postoperative care unit and every 6 h thereafter for 24 h. The total morphine requirements were also recorded. RESULTS: Patients in group ACB had significantly higher VAS (at 18 h and 24 h), higher morphine consumption, but significantly less quadriceps weakness than those in group FNB. CONCLUSION: In patients with patellar graft ACLR, the ACB can maintain a higher quadriceps power, but with lesser analgesia compared with the FNB. PMID- 26240547 TI - Evaluation of minimal dose of atracurium for cataract surgery in children: A prospective randomized double-blind study. AB - BACKGROUND: Cataract surgery when performed under general anesthesia, especially without neuromuscular blocking agents, eccentric position of the eye has been reported. However, no evidence exists for the need and optimal dose of neuromuscular blocking agents for surgical reasons when the anesthetic management may be done without its need. We hypothesize that the minimal dose atracurium may accomplish the surgical requirement of cataract surgery in children. MATERIALS AND METHODS: After ethical committee approval, this double-blind, prospective, randomized study was conducted in children scheduled for cataract surgery under general anesthesia. Anesthesia was induced in a standardized manner and using laryngeal mask airway. The patients were randomized into four groups of 55 patients each and atracurium was administered as per group allocation: Group 0: No atracurium was administered; Group 50: Received atracurium at 50% dose of ED95; Group 75: Received atracurium at 75% dose of ED95; Group 100: Received atracurium of 100% dose of ED95. Surgeon was asked to grade surgical condition just after the stab incision in the cornea. The primary outcome variable included the need of atracurium supplementation based on grading of surgical conditions by the operating surgeon who was blinded to the randomized group. RESULTS: The need of atracurium due to unacceptable surgical conditions based on surgeon satisfaction score was statistically significant when compared among the groups being maximum in Group 0 (P < 0.001). Also, the surgeon satisfaction score was statistically significant among the groups (P < 0.0001) with the least satisfaction in Group 0. The laryngeal mask airway (LMA) insertion score was statistically significant in the four groups (P - 0.001). However, number of attempts for LMA placement was comparable among the four groups (P - 0.766). CONCLUSION: We conclude that a balanced anesthetic technique including atracurium provided better surgical condition for cataract procedures in children. The surgical condition improved with increasing dose of atracurium from 25% to 100% ED95 dose. PMID- 26240548 TI - Repeated dose of ketamine effect to the rat hippocampus tissue. AB - AIM: We aimed to determine the neurotoxic effect of repeated ketamine administration on brain tissue and if neurotoxic effect was present, whether this effect continued 16 days later using histological stereological method, a quantitative and objective method. MATERIALS AND METHODS: Female rats were divided into three groups, each containing five rats. Rats in Group I were given 0.9% saline solution 4 times a day for 5 days. The rats in Groups II and III were given ketamine as intraperitoneal injections. Rats in Groups I and II were sacrificed on 5(th) day while the ones in Group III on 21(st) day. Cornu ammonis (CA) and gyrus dentatus (GD) regions in hippocampus tissue of rats were studied using optic fractionation method. FINDINGS: There were significantly less number of cells in hippocampal CA and GD regions of rats from Groups II and III compared to the ones from Group I. Difference in cell number was also significantly higher in Group III than in Group II, but this difference was not as pronounced as the one between Groups III and I. CONCLUSION: Repeated ketamine doses caused neurotoxicity in rat hippocampus. PMID- 26240549 TI - Ultrasound-guided ilioinguinal and iliohypogastric nerve block, a comparison with the conventional technique: An observational study. AB - BACKGROUND: The conventional technique of ilioinguinal and iliohypogastric nerve block may be associated with drug toxicity, block failure and needs large drug volume. The ultrasound-guided (USG) nerve block enables accurate needle positioning that may reduce the chances of drug toxicity, drug dose and block failure. AIM: In this study, we compared the onset and duration of the motor and sensory nerve block, the drug volume required and time to rescue analgesic between USG and conventional technique. SETTINGS AND DESIGN: Sixty male patients aged between 18 and 60 years, belonging to American society of Anesthesiology I II, scheduled for inguinal hernia repair were enrolled in this prospective study and were randomly allocated into two groups of thirty each by computerized method. MATERIALS AND METHODS: Group A patients received hernia block by conventional method using 0.75% ropivacaine 15 ml, and Group B patients were given the block guided by ultrasound using 0.75% ropivacaine, till the nerves were surrounded on all sides by the drug. STATISTICAL ANALYSIS: The data were analyzed using two independent sample t-tests for demographic and hemodynamic parameters. Nonparametric test (Mann-Whitney U-test) was used to find the significance between visual analog scale. RESULTS: There was significantly early onset of sensory block in Group B 14.03 +/- 2.82 min as compared to Group A 15.57 +/- 1.52 min (P = 0.047). The onset of motor block was also earlier in Group B 19.40 +/- 2.85 min as compared to Group A 20.67 +/- 1.90 min. The time to rescue analgesia was more in Group B 7.22 +/- 0.97 h as compared to Group A 6.80 +/- 0.70 h (P = 0.062). The volume of drug required was less with ultrasound guided block. CONCLUSIONS: Ultrasound-guided hernia block thus has the advantage of early onset, less dose requirement and increase in time to rescue analgesia. PMID- 26240550 TI - Efficacy of trans abdominis plane block for post cesarean delivery analgesia: A double-blind, randomized trial. AB - BACKGROUND: The transverse abdominis plane (TAP) block, a regional block provides effective analgesia after lower abdominal surgeries if used as part of multimodal analgesia. In this prospective, randomized double-blind study, we determined the efficacy of TAP block in patients undergoing cesarean section. MATERIALS AND METHODS: Totally, 62 parturients undergoing cesarean section were randomized in a double-blind manner to receive either bilateral TAP block at the end of surgery with 20 ml of 0.25% bupivacaine or no TAP block, in addition to standard analgesic comprising 75 mg diclofenac 8 hourly and intravenous patient-controlled analgesia (PCA) tramadol. Each patient was assessed at 0, 4, 8, 12, 24, 36, and 48 h after surgery by an independent observer for pain at rest and on movement using numeric rating scale of 0-10, time of 1(st) demand for tramadol, total consumption of PCA tramadol, satisfaction with pain management and side effects. RESULTS: Use of tramadol was reduced in patients given TAP block by 50% compared to patients given no block during 48 h after surgery (P < 0.001). Pain scores were lower both on rest and activity at each time point for 24 h in study group (P < 0.001), time of first analgesia was significantly longer, satisfaction was higher, and side effects were less in study group compared to control group. CONCLUSION: Transverse abdominis plane block was effective in providing analgesia with a substantial reduction in tramadol use during 48 h after cesarean section when used as adjunctive to standard analgesia. PMID- 26240551 TI - A survey on postanesthetic patient satisfaction in a university hospital. AB - BACKGROUND AND OBJECTIVES: Patient satisfaction after anesthesia is an important outcome of hospital care. The aim is to evaluate the postoperative patient satisfaction during the patient stay at King Khalid University Hospital in Riyadh, Saudi Arabia. PATIENTS AND METHODS: Three hundred and fifty-three patients who underwent surgery under general/regional anesthesia were surveyed. They were interviewed face to face on the first postoperative day. We recorded pain and pain controls in addition to some common complication of anesthesia like nausea and vomiting (postoperative nausea and vomiting) as a parameter to assess the rate of patient's satisfaction. RESULTS: The overall level of satisfaction was high (95.2%); 17 (4.8%) patients were dissatisfied with their anesthetic care. There was a strong relation between patient dissatisfaction and: (i) Patients with poor postoperative pain control 13 (12.4%), (ii) patients with moderate nausea 8 (11.1%) and (iii) patients with static and dynamic severe pain 6 (21.4). Several factors were associated with dissatisfaction can be prevented, or better treated. CONCLUSION: We concluded that the patient satisfaction was high. Postoperative visit should be routinely performed in order to assess the quality and severity of postoperative pain, nausea and vomiting and the other side-effects postoperatively. PMID- 26240552 TI - Concerns and challenges during anesthetic management of aneurysmal subarachnoid hemorrhage. AB - Anesthetic management of patients with aneurysmal subarachnoid hemorrhage is challenging because of the emergency nature of the presentation, complex pathology, varied intracranial and systemic manifestations and need for special requirements during the course of management. Successful perioperative outcome depends on overcoming these challenges by thorough understanding of pathophysiology of Subarachnoid hemorrhage, knowledge about associated complications, preoperative optimization, choice of definitive therapy, a good anesthetic and surgical technique, vigilant monitoring and optimal postoperative care. Guidelines based on randomized studies and provided by various societies are helpful in the routine management of these patients and wherever there is a lack of high quality evidence, the available data is provided for practical management. PMID- 26240553 TI - Chronic visceral pain secondary to ventral disc herniation: Development of visceral complex regional pain syndrome. AB - When an organ disease is ruled out as the origin of pelvic pain, the superior hypogastric plexus (SHP) injury and consequent dysfunction could be the mechanism of visceral chronic pain perpetuation. As much as a dorsal discus herniation may harm the dorsal or ventral roots, a ventral discus herniation at L4-L5 or L5-S1 may result in direct physical trauma to the SHP, maintaining chronic visceral pain mediated by sympathetic dysfunction, conceivably also afferent fibers dysfunction. We propose that similarly to nociceptive somatic dysfunction named complex regional pain syndrome, the maintained sympathetic pelvic pain secondary to straight physical damage to the SHP characterize in fact the same disease, but in nociceptive visceral tissue, named visceral complex regional pain syndrome, a concept constructed based on the International Association for the Study of Pain criteria (1994). PMID- 26240554 TI - Pediatric patient with Bombay blood group: A rare case report. AB - Bombay blood group is a rare blood group in which there is the absence of H antigen and presence of anti-H antibodies. At the time of blood grouping, this blood group mimics O blood group due to the absence of H antigen, but it shows incompatibility with O group blood during cross matching. Serum grouping or reverse grouping are essential for confirmation of the diagnosis. Patients carrying this blood group can receive blood only from a person with this blood group. Reported cases of anesthesia in the pediatric patient with Bombay blood group are relatively rare. Here, we present successful anesthetic management along with intraoperative blood transfusion in a pediatric patient with Bombay blood group posted for ovarian cystectomy. PMID- 26240555 TI - Fluoroscopy assisted tracheal intubation in a case of anticipated difficult airway: Fail safe devices can also fail. AB - Difficulty in airway management is the most important cause of major anesthesia related morbidity and mortality. Unexpected difficulties may arise even with proper preanesthesia planning. Here, we report a case of anticipated difficult airway primarily planned for flexible fibreoptic bronchoscope assisted intubation, but due to unexpected failure of light source, fluoroscopy was used, and the airway was successfully secured. PMID- 26240556 TI - Muscle relaxant or prone position, which one unfastened the entrapped epidural catheter? AB - Some nonsurgical steps have been introduced to remove an entrapped catheter. But occasionally, the majority of them fail, and we are forced to extract the catheter through an invasive procedure. This article depicts our team's experience on the issue. When we found that the inserted epidural catheter was entrapped, we performed all recommended noninvasive maneuvers to release the catheter, but no progress was achieved. Therefore, after obtaining informed consent, we induced anesthesia and changed her to a prone position to explore her back. The intact catheter was removed easily in this stage. The authors believe, in this process, it would have been better if they had tried pulling the catheter in a prone position as a preliminary step. Furthermore, pulling the catheter in a prone position after injecting a muscle relaxant appeared to be more effective and saved the patient from the scheduled surgery. PMID- 26240557 TI - Airway management in a patient of ankylosing spondylitis with traumatic cervical spine injury. AB - Traumatic cervical lesions compressing the spinal cord pose a significant risk of exacerbating the existing neurological condition during tracheal intubation and subsequent positioning. Preexisting ankylosing spondylitis with spinal column involvement renders the spinal column more rigid and introduces difficulty in airway management of the patient with traumatic cervical spinal cord. To improve ease and success, and reduce cervical spine movement, awake fibreoptic intubation (FOI) is considered the gold standard technique for airway management in such cases. Attaining appropriate position for intubation was challenge in this case due to rigid curvature of the ankylosed spinal column. To prevent neurological injury to the spinal cord and preserve spinal cord function, minimizing movement during intubation and attaining appropriate position was of prime concern. Optimal sedation with self-positioning by the patient in a comfortable posture is quite imperative and assures both airway as well as neurological protection in such expected difficult situations. We report the use of dexmedetomidine for self positioning and awake FOI in a patient with ankylosing spondylitis having traumatic cervical spine who was otherwise neither able to co-operative nor able to give appropriate position for FOI. PMID- 26240558 TI - A delayed spontaneous expulsion of a three teeth bridge after 6 months period of aspiration in the right lung following cardiac surgery. AB - Aspiration of loose teeth is a well-known complication of endo-tracheal intubation hence the importance of oral check by anesthetist prior to ventilation. Artificaial teeth crown (single) or bridges (multiple) can be fixed or removable by the patient. The presence of a foreign body in the lung tissue or airways is a clinical situation that needs aggressive management as it can lead to refractory infections and possible death. We report this unique case of aspirarin of a three bridge teeth (10 mm * 30 mm) following cardiac surgery. The case is complicated by pneumonia, chronic cough and severe bouts of cyanosis and finally removed by spontaneous expulsion after 6 months following forceful cough. PMID- 26240559 TI - A case of anesthesia mumps after sacral laminectomy under general anesthesia. AB - Acute transient parotid gland enlargement in association with general anesthesia is a rare complication and has also been called anesthesia mumps. Unilateral or bilateral parotid or submandibular swelling usually develops during surgery under anesthesia or, a few hours later and usually resolves in a few days with no sequelae. It has been reported as a complication after general anesthesia in patients undergoing spinal surgeries in prone and lateral decubitus position, even after cesarean section in the supine position and also reported in Intensive Care Unit patients. We present a case of a unilateral parotid swelling noticed in immediate postoperative course, in a patient who underwent spine surgery. PMID- 26240560 TI - On table confirmation of the catheter tip: A requirement in times of multiple catheters in the same central vein. PMID- 26240561 TI - Resistant hypercarbia in a patient with interstitial lung disease undergoing resection for right parietoccipital meningioma. PMID- 26240562 TI - Unusual delayed presentation of cauda equina syndrome after failed spinal anesthesia. PMID- 26240563 TI - Anesthetic management of a pregnant female posted for caesarean section with biopsy proven polymyositis. PMID- 26240564 TI - Role of the Surgical Method in Development of Postoperative Cholangiocarcinoma in Todani Type IV Bile Duct Cysts. AB - Background. Our purpose was to investigate the association between the surgical approach for Todani type IV cysts and subsequent malignancy rate. Methods. The records of patients who received cyst excision from 1994 to 2013 were analyzed retrospectively for the following data: demographics, presenting symptoms, postoperative outcomes, malignant transformation, and follow-up reexaminations, including imaging, laboratory, and tumor marker tests. Results. Seven of the 196 patients initially treated at our hospital developed postoperative biliary malignancy, and the surgical approaches were extrahepatic bile duct cyst resection combined with hilar cholangioplasty and Roux-en-Y cystojejunostomy (n = 5), and intra- and extrahepatic bile duct cyst resection and Roux-en-Y hepaticojejunostomy (n = 2). The overall malignancy rate was 3.6% (7/196). Forty eight patients initially treated at other hospitals developed malignancy postoperatively: 15 (31.2%) remained untreated and 33 (68.8%) had undergone incomplete resection procedures. Because Todani type IV cysts were seen in 268 patients, the postoperative malignancy rate of this group of patients was 12.3% (33/268). Conclusions. Radical resection of both intra- and extrahepatic cysts combined with hepatic resection and Roux-en-Y hepaticojejunostomy is associated with a reduced risk of subsequent cancer development. Procedures in which radical cyst excision is not performed are associated with a greater risk of subsequent malignancy. PMID- 26240566 TI - Effect of Umbilical Cord Entanglement and Position on Pregnancy Outcomes. AB - Introduction. To investigate the effect of complex umbilical cord entanglement primarily around the trunk on pregnancy outcomes. Methods. We studied 6307 pregnant women with singleton pregnancies who underwent vaginal delivery of an infant at >=37 weeks of gestation. Cases were classified into no cord, nuchal cord, and body cord groups and defined as cases without umbilical cord entanglement, one or more loops of the umbilical cord around the neck only, and umbilical cord around the trunk only, respectively. Pregnancy outcomes were compared among these three groups. Results. The no cord, nuchal cord, and body cord group included 4733, 1451, and 123 pregnancies, respectively. Although delivery mode was not significantly different among the three groups, 1-minute Apgar scores <7 and umbilical artery (UA) pH <7.10 were significantly more common in the umbilical cord entanglement groups than in the no cord group. In particular, the frequency of 5-minute Apgar scores <7 was significantly higher (P = 0.004), whereas that of UA pH <7.10 tended to be higher (P = 0.057) in the body cord group than in the nuchal cord group. Conclusion. Compared to nuchal cord, umbilical cord entanglement around the trunk was associated with a higher risk of low Apgar scores and low UA pH. PMID- 26240565 TI - Technical Aspects of Laparoscopic Distal Pancreatectomy for Benign and Malignant Disease: Review of the Literature. AB - Distal pancreatectomy is the standard curative treatment for symptomatic benign, premalignant, and malignant disease of the pancreatic body and tail. The most obvious benefits of a laparoscopic approach to distal pancreatectomy include earlier recovery and shorter hospital stay. Spleen-preserving distal pancreatectomy should be attempted in case of benign disease. Spleen preservation can be achieved preferably by preserving the splenic vessels (Kimura technique), but also by resecting the splenic vessels and maintaining vascularity through the short gastric vessels and left gastroepiploic artery (Warshaw technique). Several studies have suggested a higher rate of spleen preservation with laparoscopy. The radical antegrade modular pancreatosplenectomy has become mainstay for treating pancreatic cancer and can be performed laparoscopically as well. Evidence on the feasibility and safety of laparoscopic distal pancreatectomy for cancer is scarce. Despite the obvious advantages of laparoscopic surgery, postoperative morbidity remains relatively high, mainly because of the high incidence of pancreatic fistula. For decades, surgeons have tried to prevent these fistulas but to date no strategy has been confirmed to be effective in 2 consecutive randomized studies. Pragmatic multicenter studies focusing on technical aspects of laparoscopic distal pancreatectomy are lacking and should be encouraged. PMID- 26240567 TI - Pericarditis Epistenocardica or Dressler Syndrome? An Autopsy Case. AB - Postinfarction pericarditis can be classified as "early," referred to as pericarditis epistenocardica, or "delayed," referred to as Dressler syndrome. The incidence of postinfarction pericarditis has decreased to <5% since the introduction of reperfusion therapies and limitation of infarct size. We report on a 57-year-old man who suffered sudden cardiac death as a result of acute myocardial infarction. Autopsy revealed an area of previous infarction and fibrinous pericarditis related to the previous infarction, leading to a diagnosis of Dressler syndrome. PMID- 26240568 TI - Congenital Vallecular Cyst Causing Airway Compromise in a 2-Month-Old Girl. AB - Congenital vallecular cyst is a rare entity and may present with acute airway obstruction. This is a case of congenital vallecular cyst presenting with airway compromise requiring immediate management. The epidemiology, pathogenesis, and clinical presentation of vallecular cysts are discussed as well as the diagnosis and management. PMID- 26240570 TI - Efficacy of Surgery Combined with Autologous Bone Marrow Stromal Cell Transplantation for Treatment of Intracerebral Hemorrhage. AB - Bone marrow stromal cells (BMSCs) may differentiate into nerve cells under a certain condition; however, the clinical application for treating nervous system disease remains unclear. The aim is to assess the safety profile, feasibility, and effectiveness of surgery combined with autologous BMSCs transplantation for treating ICH. 206 ICH patients who had received surgical procedure were divided into transplantation (n = 110) or control group (n = 96). For transplantation group, BMSCs were injected into the perihemorrhage area in the base ganglia through an intracranial drainage tube 5.5 (3.01-6.89) days after surgery, followed by a second injection into the subarachnoid space through lumbar puncture 4 weeks later. Neurologic impairment and daily activities were assessed with National Institute Stroke Scale (NIHSS), Barthel index, and Rankin scale before transplantation and 6 months and 12 months after transplantation. Our results revealed that, compared with control group, NIHSS score and Rankin scale were both significantly decreased but Barthel index was increased in transplantation group after 6 months. Interestingly, no significant difference was observed between 12 months and 6 months. No transplantation-related adverse effects were investigated during follow-up assessments. Our findings suggest that surgery combined with autologous BMSCs transplantation is safe for treatment of ICH, providing short-term therapeutic benefits. PMID- 26240569 TI - Cell Therapy Augments Functional Recovery Subsequent to Spinal Cord Injury under Experimental Conditions. AB - The spinal cord injury leads to enervation of normal tissue homeostasis ultimately leading to paralysis. Until now there is no proper cure for the treatment of spinal cord injury. Recently, cell therapy in animal spinal cord injury models has shown some progress of recovery. At present, clinical trials are under progress to evaluate the efficacy of cell transplantation for the treatment of spinal cord injury. Different types of cells such as pluripotent stem cells derived neural cells, mesenchymal stromal cells, neural stem cells, glial cells are being tested in various spinal cord injury models. In this review we highlight both the advances and lacuna in the field of spinal cord injury by discussing epidemiology, pathophysiology, molecular mechanism, and various cell therapy strategies employed in preclinical and clinical injury models and finally we discuss the limitations and ethical issues involved in cell therapy approach for treating spinal cord injury. PMID- 26240571 TI - Applications of Induced Pluripotent Stem Cells in Studying the Neurodegenerative Diseases. AB - Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons. Incurable neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) show dramatic rising trends particularly in the advanced age groups. However, the underlying mechanisms are not yet fully elucidated, and to date there are no biomarkers for early detection or effective treatments for the underlying causes of these diseases. Furthermore, due to species variation and differences between animal models (e.g., mouse transgenic and knockout models) of neurodegenerative diseases, substantial debate focuses on whether animal and cell culture disease models can correctly model the condition in human patients. In 2006, Yamanaka of Kyoto University first demonstrated a novel approach for the preparation of induced pluripotent stem cells (iPSCs), which displayed similar pluripotency potential to embryonic stem cells (ESCs). Currently, iPSCs studies are permeating many sectors of disease research. Patient sample-derived iPSCs can be used to construct patient-specific disease models to elucidate the pathogenic mechanisms of disease development and to test new therapeutic strategies. Accordingly, the present review will focus on recent progress in iPSC research in the modeling of neurodegenerative disorders and in the development of novel therapeutic options. PMID- 26240572 TI - Adipose-Derived Mesenchymal Stem Cells for the Treatment of Articular Cartilage: A Systematic Review on Preclinical and Clinical Evidence. AB - Among the current therapeutic approaches for the regeneration of damaged articular cartilage, none has yet proven to offer results comparable to those of native hyaline cartilage. Recently, it has been claimed that the use of mesenchymal stem cells (MSCs) provides greater regenerative potential than differentiated cells, such as chondrocytes. Among the different kinds of MSCs available, adipose-derived mesenchymal stem cells (ADSCs) are emerging due to their abundancy and easiness to harvest. However, their mechanism of action and potential for cartilage regeneration are still under investigation, and many other aspects still need to be clarified. The aim of this systematic review is to give an overview of in vivo studies dealing with ADSCs, by summarizing the main evidence for the treatment of cartilage disease of the knee. PMID- 26240573 TI - Noninvasive Optical Imaging and In Vivo Cell Tracking of Indocyanine Green Labeled Human Stem Cells Transplanted at Superficial or In-Depth Tissue of SCID Mice. AB - Stem cell based therapies hold great promise for the treatment of human diseases; however results from several recent clinical studies have not shown a level of efficacy required for their use as a first-line therapy, because more often in these studies fate of the transplanted cells is unknown. Thus monitoring the real time fate of in vivo transplanted cells is essential to validate the full potential of stem cells based therapy. Recent studies have shown how real-time in vivo molecular imaging has helped in identifying hurdles towards clinical translation and designing potential strategies that may contribute to successful transplantation of stem cells and improved outcomes. At present, there are no cost effective and efficient labeling techniques for tracking the cells under in vivo conditions. Indocyanine green (ICG) is a safer, economical, and superior labelling technique for in vivo optical imaging. ICG is a FDA-approved agent and decades of usage have clearly established the effectiveness of ICG for human clinical applications. In this study, we have optimized the ICG labelling conditions that is optimal for noninvasive optical imaging and demonstrated that ICG labelled cells can be successfully used for in vivo cell tracking applications in SCID mice injury models. PMID- 26240574 TI - Oleanolic Acid Induces Differentiation of Neural Stem Cells to Neurons: An Involvement of Transcription Factor Nkx-2.5. AB - Neural stem cells (NSCs) harbor the potential to differentiate into neurons, astrocytes, and oligodendrocytes under normal conditions and/or in response to tissue damage. NSCs open a new way of treatment of the injured central nervous system and neurodegenerative disorders. Thus far, few drugs have been developed for controlling NSC functions. Here, the effect as well as mechanism of oleanolic acid (OA), a pentacyclic triterpenoid, on NSC function was investigated. We found OA significantly inhibited neurosphere formation in a dose-dependent manner and achieved a maximum effect at 10 nM. OA also reduced 5-ethynyl-2'-deoxyuridine (EdU) incorporation into NSCs, which was indicative of inhibited NSC proliferation. Western blotting analysis revealed the protein levels of neuron specific marker tubulin-betaIII (TuJ1) and Mash1 were increased whilst the astrocyte-specific marker glial fibrillary acidic protein (GFAP) decreased. Immunofluorescence analysis showed OA significantly elevated the percentage of TuJ1-positive cells and reduced GFAP-positive cells. Using DNA microarray analysis, 183 genes were differentially regulated by OA. Through transcription factor binding site analyses of the upstream regulatory sequences of these genes, 87 genes were predicted to share a common motif for Nkx-2.5 binding. Finally, small interfering RNA (siRNA) methodology was used to silence Nkx-2.5 expression and found silence of Nkx-2.5 alone did not change the expression of TuJ-1 and the percentage of TuJ-1-positive cells. But in combination of OA treatment and silence of Nkx-2.5, most effects of OA on NSCs were abolished. These results indicated that OA is an effective inducer for NSCs differentiation into neurons at least partially by Nkx-2.5-dependent mechanism. PMID- 26240575 TI - In Vitro Effects of Strontium on Proliferation and Osteoinduction of Human Preadipocytes. AB - Development of tools to be used for in vivo bone tissue regeneration focuses on cellular models and differentiation processes. In searching for all the optimal sources, adipose tissue-derived mesenchymal stem cells (hADSCs or preadipocytes) are able to differentiate into osteoblasts with analogous characteristics to bone marrow mesenchymal stem cells, producing alkaline phosphatase (ALP), collagen, osteocalcin, and calcified nodules, mainly composed of hydroxyapatite (HA). The possibility to influence bone differentiation of stem cells encompasses local and systemic methods, including the use of drugs administered systemically. Among the latter, strontium ranelate (SR) represents an interesting compound, acting as an uncoupling factor that stimulates bone formation and inhibits bone resorption. The aim of our study was to evaluate the in vitro effects of a wide range of strontium (Sr(2+)) concentrations on proliferation, ALP activity, and mineralization of a novel finite clonal hADSCs cell line, named PA20-h5. Sr(2+) promoted PA20-h5 cell proliferation while inducing the increase of ALP activity and gene expression as well as HA production during in vitro osteoinduction. These findings indicate a role for Sr(2+) in supporting bone regeneration during the process of skeletal repair in general, and, more specifically, when cell therapies are applied. PMID- 26240576 TI - Impacting Environmental and Public Health through the Use of Dual Targeted and Tailored Asthma Educational Interventions. AB - Home-based asthma environmental education for parents of asthmatic children is needed since many health professionals lack the time to offer it. However, developing targeted and tailored education is important in order to address the individual needs of participants. This nonrandomized longitudinal study examined knowledge on asthma with an Asthma and Healthy Homes educational intervention training offered to parents of children from low income families who reside in the Rio Grande Valley of Texas. Eighty-nine parents received the training and pre and posttest surveys were used to measure knowledge outcomes. A standardized assessment on asthma triggers was used to identify the different triggers each child was exposed to, and a follow-up survey was conducted 6 months after the educational intervention to identify how many parents reported household and behavior changes as a result of the training. Results showed significant changes in behavior by participants as a result of the training received. This study suggests that these behavioral changes are attributed to the dual "targeted" and "tailored" educational interventions delivered to parents which resulted in a greater understanding of how to manage asthma by eliminating asthma triggers in their respective homes. PMID- 26240577 TI - Impact of Coal Mining on Self-Rated Health among Appalachian Residents. AB - OBJECTIVE: To determine the impact of coal mining, measured as the number of coal mining-related facilities nearby one's residence or employment in an occupation directly related to coal mining, on self-rated health in Appalachia. METHODS: Unadjusted and adjusted ordinal logistic regression models calculated odds ratio estimates and associated 95% confidence intervals for the probability of having an excellent self-rated health response versus another response. Covariates considered in the analyses included number of coal mining-related facilities nearby one's residence and employment in an occupation directly related to coal mining, as well as potential confounders age, sex, BMI, smoking status, income, and education. RESULTS: The number of coal mining facilities near the respondent's residence was not a statistically significant predictor of self rated health. Employment in a coal-related occupation was a statistically significant predictor of self-rated health univariably; however, after adjusting for potential confounders, it was no longer a significant predictor. CONCLUSIONS: Self-rated health does not seem to be associated with residential proximity to coal mining facilities or employment in the coal industry. Future research should consider additional measures for the impact of coal mining. PMID- 26240578 TI - Role of Intravascular Ultrasound in Patients with Acute Myocardial Infarction. AB - Rupture of a vulnerable plaque and subsequent thrombus formation are important mechanisms leading to the development of an acute myocardial infarction (AMI). Typical intravascular ultrasound (IVUS) features of AMI include plaque rupture, thrombus, positive remodeling, attenuated plaque, spotty calcification, and thin cap fibroatheroma. No-reflow phenomenon was attributable to the embolization of thrombus and plaque debris that results from mechanical fragmentation of the vulnerable plaque by percutaneous coronary intervention (PCI). Several grayscale IVUS features including plaque rupture, thrombus, positive remodeling, greater plaque burden, decreased post-PCI plaque volume, and tissue prolapse, and virtual histology-IVUS features such as large necrotic corecontaining lesion and thin-cap fibroatheroma were the independent predictors of no-reflow phenomenon in AMI patients. Non-culprit lesions associated with recurrent events were more likely than those not associated with recurrent events to be characterized by a plaque burden of >=70%, a minimal luminal area of <=4.0 mm(2), or to be classified as thin-cap fibroatheromas. PMID- 26240580 TI - The Theory of Relativity in E (ectopy) and C (coupling): Who Will Prove It? PMID- 26240579 TI - Diabetic Cardiomyopathy; Summary of 41 Years. AB - Patients with diabetes have an increased risk for development of cardiomyopathy, even in the absence of well known risk factors like coronary artery disease and hypertension. Diabetic cardiomyopathy was first recognized approximately four decades ago. To date, several pathophysiological mechanisms thought to be responsible for this new entity have also been recognized. In the presence of hyperglycemia, non-enzymatic glycosylation of several proteins, reactive oxygen species formation, and fibrosis lead to impairment of cardiac contractile functions. Impaired calcium handling, increased fatty acid oxidation, and increased neurohormonal activation also contribute to this process. Demonstration of left ventricular hypertrophy, early diastolic and late systolic dysfunction by sensitive techniques, help us to diagnose diabetic cardiomyopathy. Traditional treatment of heart failure is beneficial in diabetic cardiomyopathy, but specific strategies for prevention or treatment of cardiac dysfunction in diabetic patients has not been clarified yet. In this review we will discuss clinical and experimental studies focused on pathophysiology of diabetic cardiomyopathy, and summarize diagnostic and therapeutic approaches developed towards this entity. PMID- 26240581 TI - Clinical Characteristics and Outcomes of Acute ST-Segment Elevation Myocardial Infarction in Younger Korean Adults. AB - BACKGROUND AND OBJECTIVES: This study aims to investigate the clinical features, angiographic findings, and outcomes of younger Korean ST-segment elevation myocardial infarction (STEMI) patients. SUBJECTS AND METHODS: We analyzed major adverse cardiac events (MACE) in the Korea Acute Myocardial Infarction Registry from November 2005 to October 2010. The registered patients were divided into two groups; young age group (<65 years) and old age group (>=65 years). RESULTS: The young age group included 5281 patients (age, 53+/-7.8 years), and the old age group included 4896 patients (age, 74.3+/-6.5 years). Male gender, smoking, family history, dyslipidemia, and metabolic syndrome were more frequently observed in the young age group than in the old age group (89.5% vs. 59.3%, p<0.001; 77.3% vs. 47.2%, p<0.001; 11% vs. 4.6%, p<0.001; 11.2% vs. 7.7%, p<0.001; 67.6% vs. 62.9%, p<0.001). Most of the young Korean adults with STEMI complained of typical chest pain (89.8%), and they had a shorter symptom-to-door time (12+/-53.2 hours vs. 17.3+/-132 hours, p=0.010). The young age group showed a favorable prognosis, which was represented by the MACE, compared with the old age group at one month (1.8% vs. 2.8%, p=0.028), six months (6.8% vs. 8.2%, p<0.001), and twelve months (10.1% vs. 11.9%, p=0.025). However, there was no significant difference in the adjusted MACE rate at one month {hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.60-1.51, p=0.828} and twelve months (HR 0.86, 95% CI 0.68-1.10, p=0.233). CONCLUSION: Younger Korean adults with STEMI have clinical outcomes similar to old aged patients, and therefore, they should be treated intensively like the elderly patients. PMID- 26240582 TI - The Relationship among N-Terminal Pro-B-Type Natriuretic Peptide, High Sensitivity C-Reactive Protein and Infarct Size in Patients with Acute ST Elevation Myocardial Infarction. AB - BACKGROUND AND OBJECTIVES: We sought to investigate the relationship between levels of high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the infarct size and left ventricular (LV) volume after acute myocardial infarction (MI). SUBJECTS AND METHODS: Eighty-six patients with acute ST-elevation MI underwent delayed enhancement multidetector computed tomography immediately after they underwent percutaneous coronary intervention to determine the infarct size. LV function and remodeling were assessed by echocardiography. Hs-CRP and NT-proBNP were measured at admission, 24 hours and two months later. RESULTS: Both hs-CRP and NT-proBNP at 24 hours showed a positive correlation with infarct size and a negative correlation with LV ejection fraction at the baseline and two months later. NT-proBNP at two months correlated with infarct size, LV ejection fraction, and LV end diastolic and systolic volume indices at two months. In patients with high NT-proBNP levels at 24 hours and two months, infarct size was larger and LV ejection fraction was lower. NT-proBNP was higher in patients who developed LV remodeling at two months: 929 pg/mL vs. 134 pg/mL, p=0.002. In contrast, hs-CRP at two months showed no relationship to infarct size, LV function, or LV volumes at two months. CONCLUSION: Elevated hs-CRP level 24 hours after the onset of acute MI is associated with infarct size and LV dysfunction, whereas elevated levels of NT proBNP 24 hours and two months after the onset of acute MI are both correlated with infarct size, LV dysfunction, and LV remodeling. PMID- 26240583 TI - Coupling Interval Ratio Is Associated with Ventricular Premature Complex-Related Symptoms. AB - BACKGROUND AND OBJECTIVES: Frequent ventricular premature complex (VPC) is one of the most common arrhythmia syndromes. Symptoms observed frequently with this arrhythmia syndrome remain limited. We sought to identify predictors of VPC related symptoms by analyzing demographic information, VPC burden, and VPC surface electrocardiogram characteristics. SUBJECTS AND METHODS: We prospectively enrolled 109 patients with idiopathic outflow tract VPCs (63 males, 49+/-16 years old). They were divided into Group A (n=30, without VPC-related symptoms of palpitations or "dropped beats") and Group B (n=79, with VPC-related symptoms). Measured parameters were sinus and VPC QRS width, coupling interval (CI) between the previous sinus beat and VPC, CI ratio (%, CI/sinus cycle length), post-VPC CI and CI ratio, and VPC amplitude. RESULTS: Both groups had similar age (p=0.22), daily VPC burden (p=0.15), and VPC site of origin (p=0.36). The VPC CI ratio was higher in Group B (60+/-15%) than in Group A (49+/-22%) (p=0.01). CONCLUSION: VPC related symptoms are associated with a higher VPC CI ratio (>50%). The physiologic basis for these results deserves further study. PMID- 26240584 TI - Prognostic Implications of Right and Left Atrial Enlargement after Radiofrequency Catheter Ablation in Patients with Nonvalvular Atrial Fibrillation. AB - BACKGROUND AND OBJECTIVES: The prognostic role of the right atrium (RA) compared with that of the left atrium (LA) is unclear in patients with atrial fibrillation (AF). We assessed structural changes in both atria and determined their association with recurrence of AF after radiofrequency catheter ablation (RFCA). SUBJECTS AND METHODS: All 111 patients with nonvalvular AF (87 men; mean age, 57+/-11 years; 68 with paroxysmal AF) who underwent RFCA were enrolled consecutively. Three-dimensional volumes of both atria measured from computed tomography images were compared between subjects with and without recurrence of AF during the follow-up. RESULTS: Early (<3 months), 6-month, and 1-year recurrence was documented in 26 (24%), 30 (27%), and 36 (32%) patients, respectively. Significantly larger RA and LA volume indices (RAVI and LAVI) were observed in the early, 6-month, and 1-year recurrence groups (p<0.05 for all). In multivariate analysis, Early recurrence was independently associated with RAVI (for each 10 mL/m2 increase; odds ratio [OR], 1.31; 95% confidence interval [CI], 1.03-1.66, p= 0.03), but not with LAVI. However, both RAVI and LAVI failed to predict 6-month outcomes independently. LAVI was the only independent predictor of 1-year recurrence (for each 10 mL/m2 increase; OR, 1.36; 95% CI, 1.08-1.71, p=0.009). CONCLUSION: RA enlargement was more closely related to early recurrence of AF after RFCA than LA size. However, LA size, rather than RA volume, was a determinant of long-term AF prognosis after RFCA. These findings suggest a temporal pattern in the prognostic implication of enlargement in each atrium that switches over time after RFCA for AF. PMID- 26240585 TI - Cognitive Function and Self-Care in Patients with Chronic Heart Failure. AB - BACKGROUND AND OBJECTIVES: This study examined the association of cognitive function with self-care and major adverse cardiac events (MACE) among heart failure (HF) patients. SUBJECTS AND METHODS: In this prospective study, 86 outpatients with HF completed face-to-face interviews including neuropsychological testing to evaluate cognitive function and the use of the Self Care of Heart Failure Index to measure self-care. Functional status was assessed with the New York Heart Association (NYHA) classification. Follow-up data on MACE were obtained at 24 months after enrollment. RESULTS: Compared with the Korean norm values, more than half of the HF patients had cognitive deficits in global function (33.0%), immediate recall (65.1%), delayed recall memory (65.1%), and executive function (60.5%). Patients with symptomatic HF (>=NYHA class II) had the higher risk for substantially poor cognitive function in all areas of cognitive function than asymptomatic HF patients (NYHA class I, p<0.05). Most patients demonstrated poor self-care adequacy in maintenance (84.9%), management of symptoms (100%), and confidence (86.0%). After adjustment for age and gender, memory function was significantly associated with self-care confidence (odds ratio 1.41, 95% confidence interval 1.03-1.92, p=0.033). No relationship was found between cognition and self-care maintenance. There were 19 MACE's during the 24-month follow-up. Patients without MACE had a significantly higher global cognitive function (p=0.024), while no cognitive domains were significant predictors of MACE when adjusted for age and gender. CONCLUSION: HF patients with memory loss have poorer self-care confidence. Studies are warranted to examine the functional implication of cognitive deficits and adverse outcomes in a larger sample. PMID- 26240586 TI - Cardiac Function in Kawasaki Disease Patients with Respiratory Symptoms. AB - BACKGROUND AND OBJECTIVES: Respiratory symptoms are often observed in children with Kawasaki disease (KD) during the acute phase. The association of respiratory viruses in children with KD was investigated using multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) and tissue Doppler echocardiography. SUBJECTS AND METHODS: 138 KD patients were included from January 2010 to June 2013. We compared 3 groups (group 1: n=94, KD without respiratory symptoms; group 2: n=44, KD with respiratory symptoms; and group 3: n=50, febrile patients with respiratory symptoms). Laboratory data were obtained from each patient including N-terminal pro-brain natriuretic peptide (NT-proBNP). Echocardiographic measurements were compared between group 1 and group 2. RT-PCR was performed using nasopharyngeal secretion to screen for the presence of 14 viruses in groups 2 and 3. RESULTS: The incidence of KD with respiratory symptoms was 31.8%. The duration of fever was significantly longer, and coronary artery diameter was larger in group 2 than in group 1. Tei index was significantly higher and coronary artery diameter larger in group 2 than group 1. Coronary artery diameter, C-reactive protein levels, platelet count, alanine aminotransferase levels, and NT-pro BNP levels were significantly higher and albumin levels lower in group 2 compared with group 3. CONCLUSION: NT-pro BNP was a valuable diagnostic tool in differentiating KD from other febrile viral respiratory infections. Some viruses were more frequently observed in KD patients than in febrile controls. Tei index using tissue Doppler imaging was increased in KD patients with respiratory symptoms. PMID- 26240587 TI - Absence of Correlation between Changes in the Number of Endothelial Progenitor Cell Subsets. AB - BACKGROUND AND OBJECTIVES: Previously, various methodologies were used to enumerate the endothelial progenitor cells (EPCs). We now know that these methodologies enumerate at least three different EPC subsets: circulating angiogenic cells (CACs), colony-forming unit endothelial cells (CFU-ECs), and endothelial colony-forming cells (ECFCs). It is not clear whether there is a correlation between changes in the number of these subsets. The aim of the current study is to find an answer to this question. MATERIALS AND METHODS: The number of all EPC subsets was quantified in the peripheral blood of nine pregnant women in their first and third trimesters of pregnancy. We enumerated 14 cell populations by quantitative flow-cytometry using various combinations of the markers, CD34, CD133, CD309, and CD45, to cover most of the reported phenotypes of CACs and ECFCs. Culturing technique was used to enumerate the CFU-ECs. Changes in the number of cells were calculated by subtracting the number of cells in the first trimester peripheral blood from the number of cells in the third trimester peripheral blood, and correlations between these changes were analyzed. RESULTS: The number of CFU-ECs did not correlate with the number of ECFCs and CACs. Also, CACs and ECFCs showed independent behaviors. However, the number of CACs showed a strong correlation with the number of CD133(+)CD309(+) cells (p=0.001) and a moderate correlation with the number of CD34(+)CD309(+) cells (p=0.042). Also, the number of ECFCs was correlated with the number of CD309(+)CD45(-) cells (p=0.029) and CD34(+)CD45(-) cells (p=0.03). CONCLUSION: Our study showed that the three commonly used methods for quantifying EPC subsets represent different cells with independent behaviors. Also, any study that measured the number of EPCs using the flow cytometry method with a marker combination that lacks CD309 may be inaccurate. PMID- 26240588 TI - Constrictive Pericarditis Long after a Gunshot Wound. AB - Constrictive pericarditis is an uncommon post-inflammatory disorder characterized by a variably thickened, fibrotic, and frequently calcified, pericardium. Etiology of the constriction can occur for many reasons. Although foreign bodies are not the common cause of constrictive pericarditis, the long-term presence of foreign bodies, like bullets, is presumed to cause chronic constrictive pericarditis even after a very long asymptomatic period. A 69-year-old patient with atrial flutter was admitted to the hospital. A cardiac computed tomography showed a bullet located adjacent to the right atrium. The transthoracic echocardiography showed a thickened pericardium and septal bouncing motion, which were compatible with constrictive pericarditis. The history of the patient revealed an injury by gunshot during the Korean War in 1950. Radiofrequency ablation of the atrial flutter was performed, and after ablation, the bullet was removed surgically. The patient was discharged home after surgery without complications. PMID- 26240589 TI - Primary Aortoenteric Fistula of a Saccular Aneurysm: Case Study and Literature Review. AB - Primary aortoenteric fistula is a direct communication between the aorta and intestinal lumen and it represents a rare but potentially lethal complication of an abdominal aortic aneurysm. However, it may occur less frequently in a naive non-aneurysmatic aorta. Diagnosis is often difficult and delayed in most cases, unless there is a high level of clinical awareness. Urgent surgery is still the recommended treatment. We describe the case of primary aortoenteric fistula of a saccular aneurysm. A 55-year-old woman was referred to our center with hematemesis, melena, and severe anemia who was dignosed previously with unknown saccular abdominal aneurysm. PMID- 26240590 TI - Ruptured Tricuspid Valve Papillary Muscle in a Neonate with Intractable Persistent Fetal Circulation. AB - Unguarded tricuspid regurgitation (TR) due to a flail tricuspid leaflet is a rare condition of newborn cyanosis. A high perinatal mortality has been associated with this fatal condition. But, there are feasible surgical repairs to improve survival. We report the case of a male full-term neonate with intractable hypoxia. He had profound tricuspid insufficiency and leaflet prolapse caused by a ruptured papillary muscle supporting the anterior leaflet of the tricuspid valve. He presented with severe cyanosis and respiratory distress immediately after birth. Despite medical management, the pulmonary vascular resistance was not decreased and a low cardiac output persisted. Initial stabilization was accomplished with nitric oxide and extracorporeal membrane oxygenation. The tricuspid valve repair surgery was successfully performed subsequently. TR resulting from papillary muscle rupture is a potentially lethal condition. Timely diagnosis and proper surgical treatment can be lifesaving. PMID- 26240591 TI - Transvascular Implantation of an Implantable Cardioverter-Defibrillator in a Patient Who has Undergone One-and-a-Half Ventricle Repair. AB - Implantable cardioverter-defibrillator (ICD) therapy is acknowledged as a valid treatment method for the effective prevention of sudden cardiac death, which is a major cause of mortality in adult congenital heart disease patients. But ICD implantation by the conventional transvascular approach is not always possible in patients who have undergone palliative surgery due to congenital and structural heart disease. Here, we report a case in which an ICD was transvascularly implanted in an arrhythmogenic right ventricular cardiomyopathy patient who had undergone a one-and-a-half ventricle repair. PMID- 26240592 TI - Erratum to: Small Left Atrial Size Complicating Percutaneous Transcatheter Device Closure of Secundum Atrial Septal Defect with Conventional Approach. AB - [This corrects the article on p. 216 in vol. 45, PMID: 26023310.]. PMID- 26240593 TI - Erratum to: Additive Beneficial Effects of Valsartan Combined with Rosuvastatin in the Treatment of Hypercholesterolemic Hypertensive Patients. AB - [This corrects the article on p. 225 in vol. 45, PMID: 26023311.]. PMID- 26240594 TI - A Minireview on Vasopressin-regulated Aquaporin-2 in Kidney Collecting Duct Cells. AB - The kidney collecting duct is an important renal tubular segment for the regulation of body water and salt homeostasis. Water reabsorption in the collecting duct cells is regulated by arginine vasopressin (AVP) via the vasopressin V2-receptor (V2R). AVP increases the osmotic water permeability of the collecting duct cells through aquaporin-2 (AQP2) and aquaporin-3 (AQP3). AVP induces the apical targeting of AQP2 and transcription of AQP2 gene in the kidney collecting duct principal cells. The signaling transduction pathways resulting in the AQP2 trafficking to the apical plasma membrane of the collecting duct principal cells, include AQP2 phosphorylation, RhoA phosphorylation, actin depolymerization and calcium mobilization, and the changes of AQP2 protein abundance in water balance disorders have been extensively studied. These studies elucidate the underlying cellular and molecular mechanisms of body water homeostasis and provide the basis for the treatment of body water balance disorders. PMID- 26240596 TI - Loop Diuretics in Clinical Practice. AB - Diuretics are commonly used to control edema across various clinical fields. Diuretics inhibit sodium reabsorption in specific renal tubules, resulting in increased urinary sodium and water excretion. Loop diuretics are the most potent diuretics. In this article, we review five important aspects of loop diuretics, in particular furosemide, which must be considered when prescribing this medicine: (1) oral versus intravenous treatment, (2) dosage, (3) continuous versus bolus infusion, (4) application in chronic kidney disease patients, and (5) side effects. The bioavailability of furosemide differs between oral and intravenous therapy. Additionally, the threshold and ceiling doses of furosemide differ according to the particular clinical condition of the patient, for example in patients with severe edema or chronic kidney disease. To maximize the efficiency of furosemide, a clear understanding of how the mode of delivery will impact bioavailability and the required dosage is necessary. PMID- 26240595 TI - Salt Sensitivity and Hypertension: A Paradigm Shift from Kidney Malfunction to Vascular Endothelial Dysfunction. AB - Hypertension is a complex trait determined by both genetic and environmental factors and is a major public health problem due to its high prevalence and concomitant increase in the risk for cardiovascular disease. With the recent large increase of dietary salt intake in most developed countries, the prevalence of hypertension increases tremendously which is about 30% of the world population. There is substantial evidence that suggests some people can effectively excrete high dietary salt intake without an increase in arterial BP, and another people cannot excrete effectively without an increase in arterial BP. Salt sensitivity of BP refers to the BP responses for changes in dietary salt intake to produce meaningful BP increases or decreases. The underlying mechanisms that promote salt sensitivity are complex and range from genetic to environmental influences. The phenotype of salt sensitivity is therefore heterogeneous with multiple mechanisms that potentially link high salt intake to increases in blood pressure. Moreover, excess salt intake has functional and pathological effects on the vasculature that are independent of blood pressure. Epidemiologic data demonstrate the role of high dietary salt intake in mediating cardiovascular and renal morbidity and mortality. Almost five decades ago, Guyton and Coleman proposed that whenever arterial pressure is elevated, pressure natriuresis enhances the excretion of sodium and water until blood volume is reduced sufficiently to return arterial pressure to control values. According to this hypothesis, hypertension can develop only when something impairs the excretory ability of sodium in the kidney. However, recent studies suggest that nonosmotic salt accumulation in the skin interstitium and the endothelial dysfunction which might be caused by the deterioration of vascular endothelial glycocalyx layer (EGL) and the epithelial sodium channel on the endothelial luminal surface (EnNaC) also play an important role in nonosmotic storage of salt. These new concepts emphasize that sodium homeostasis and salt sensitivity seem to be related not only to the kidney malfunction but also to the endothelial dysfunction. Further investigations will be needed to assess the extent to which changes in the sodium buffering capacity of the skin interstitium and develop the treatment strategy for modulating the endothelial dysfunction. PMID- 26240597 TI - Abdominal Obesity and Mortality in Continuous Ambulatory Peritoneal Dialysis Patients. AB - BACKGROUND: The relationship between abdominal obesity (AO) and mortality in peritoneal dialysis (PD) patients is controversial. METHODS: The prevalence of AO in 84 PD patients was assessed in a cross-section manner and followed up for 9 years at a single center. AO was defined as a waist circumference (WC) of more than 90 cm in males or more than 80 cm in females. The patients were classified as either with AO(AO group) or without AO(nAO group). RESULTS: The AO group was older, contained more diabetics, more females, and had higher Charlson comorbidity index (aCCI) scores, BMI, and triglyceride and lower serum creatinine than the non-AO subjects. The follow-up duration was 53.2+/-34.4 months. At the end of the follow-up, eighteen patients (21.4%) were dead; 9 died of cardiovascular causes. The five year survival rate was 40.8%. Kaplan-Meier analysis revealed that both all-cause and cardiovascular-cause mortalities were similar in the AO and nAO groups. Multivariate analysis revealed the presence of AO not to be an independent risk factor of all-cause and cardiovascular-cause mortality. CONCLUSION: AO itself might not be a risk factor for mortality in PD patients. Nevertheless, further prospective studies with a large number of patients will be needed to prove this. PMID- 26240598 TI - A Case of Osmotic Demyelination Presenting with Severe Hypernatremia. AB - Osmotic demyelination syndrome is a demyelinating disorder associated with rapid correction of hyponatremia. But, it rarely occurs in acute hypernatremia, and it leads to permanent neurologic symptoms and is associated with high mortality. A 44-year-old woman treated with alternative medicine was admitted with a history of drowsy mental status. Severe hypernatremia (197mEq/L) with hyperosmolality (415mOsm/kgH2O) was evident initially and magnetic resonance imaging revealed a high signal intensity lesion in the pons, consistent with central pontine myelinolysis. She was treated with 0.45% saline and 5% dextrose water and intravenous corticosteroids. Serum sodium normalized and her clinical course gradually improved. Brain lesion of myelinolysis also improved in a follow-up imaging study. This is the first report of a successful treatment of hypernatremia caused by iatrogenic salt intake, and it confirms the importance of adequate fluid supplementation in severe hypernatremia. PMID- 26240599 TI - Complementary and Alternative Therapies for Liver Diseases 2014. PMID- 26240600 TI - In Vitro Evaluation of the Effects of Eurycoma longifolia Extract on CYP-Mediated Drug Metabolism. AB - Eurycoma longifolia (Simaroubaceae) is a popular folk medicine that has traditionally been used in Southeast Asia as an antimalarial, aphrodisiac, antidiabetic, and antimicrobial and in antipyretic remedies. This study evaluates the effects of Eurycoma longifolia extract on cytochrome P450 (CYP) enzyme mediated drug metabolism to predict the potential for herb-drug interactions. Methanolic extract of E. longifolia root was tested at concentrations of 1, 3, 10, 30, 100, 300, and 1000 ug/mL in human liver microsomes or individual recombinant CYP isozymes. The CYP inhibitory activity was measured using the cocktail probe assay based on liquid chromatography-tandem mass spectrometry. E. longifolia showed weak, concentration-dependent inhibition of CYP1A2, CYP2A6, and CYP2C19. The inhibitory effects on these CYP isozymes were further tested using individual recombinant CYP isozymes, showing IC50 values of 324.9, 797.1, and 562.9 MUg/mL, respectively. In conclusion, E. longifolia slightly inhibited the metabolic activities of CYP1A2, CYP2A6, and CYP2C19 but this issue requires careful attention in taking herbal medicines or dietary supplements containing E. longifolia extracts. PMID- 26240601 TI - Research highlights for issue 7: the evolution of invasiveness. PMID- 26240602 TI - Life-history evolution in the anthropocene: effects of increasing nutrients on traits and trade-offs. AB - Variation in life-history traits can have major impacts on the ecological and evolutionary responses of populations to environmental change. Life-history variation often results from trade-offs that arise because individuals have a limited pool of resources to allocate among traits. However, human activities are increasing the availability of many once-limited resources, such as nitrogen and phosphorus, with potentially major implications for the expression and evolution of life-history trade-offs. In this review, we synthesize contemporary life history and sexual selection literature with current research on ecosystem nutrient cycling to highlight novel opportunities presented by anthropogenic environmental change for investigating life-history trait development and evolution. Specifically, we review four areas where nutrition plays a pivotal role in life-history evolution and explore possible implications in the face of rapid, human-induced change in nutrient availability. For example, increases in the availability of nutrients may relax historical life-history trade-offs and reduce the honesty of signaling systems. We argue that ecosystems experiencing anthropogenic nutrient inputs present a powerful yet underexplored arena for testing novel and longstanding questions in organismal life-history evolution. PMID- 26240603 TI - Genomic basis of the differences between cider and dessert apple varieties. AB - Unraveling the genomic processes at play during variety diversification is of fundamental interest for understanding evolution, but also of applied interest in crop science. It can indeed provide knowledge on the genetic bases of traits for crop improvement and germplasm diversity management. Apple is one of the most important fruit crops in temperate regions, having both great economic and cultural values. Sweet dessert apples are used for direct consumption, while bitter cider apples are used to produce cider. Several important traits are known to differentiate the two variety types, in particular fruit size, biennial versus annual fruit bearing, and bitterness, caused by a higher content in polyphenols. Here, we used an Illumina 8k SNP chip on two core collections, of 48 dessert and 48 cider apples, respectively, for identifying genomic regions responsible for the differences between cider and dessert apples. The genome-wide level of genetic differentiation between cider and dessert apples was low, although 17 candidate regions showed signatures of divergent selection, displaying either outlier F ST values or significant association with phenotypic traits (bitter versus sweet fruits). These candidate regions encompassed 420 genes involved in a variety of functions and metabolic pathways, including several colocalizations with QTLs for polyphenol compounds. PMID- 26240604 TI - Morphological and genomic comparisons of Hawaiian and Japanese Black-footed Albatrosses (Phoebastria nigripes) using double digest RADseq: implications for conservation. AB - Evaluating the genetic and demographic independence of populations of threatened species is important for determining appropriate conservation measures, but different technologies can yield different conclusions. Despite multiple studies, the taxonomic status and extent of gene flow between the main breeding populations of Black-footed Albatross (Phoebastria nigripes), a Near-Threatened philopatric seabird, are still controversial. Here, we employ double digest RADseq to quantify the extent of genomewide divergence and gene flow in this species. Our genomewide data set of 9760 loci containing 3455 single nucleotide polymorphisms yielded estimates of genetic diversity and gene flow that were generally robust across seven different filtering and sampling protocols and suggest a low level of genomic variation (theta per site = ~0.00002-0.00028), with estimates of effective population size (N e = ~500-15 881) falling far below current census size. Genetic differentiation was small but detectable between Japan and Hawaii (F ST ~ 0.038-0.049), with no F ST outliers. Additionally, using museum specimens, we found that effect sizes of morphological differences by sex or population rarely exceeded 4%. These patterns suggest that the Hawaiian and Japanese populations exhibit small but significant differences and should be considered separate management units, although the evolutionary and adaptive consequences of this differentiation remain to be identified. PMID- 26240605 TI - Anthropogenic ecosystem fragmentation drives shared and unique patterns of sexual signal divergence among three species of Bahamian mosquitofish. AB - When confronted with similar environmental challenges, different organisms can exhibit dissimilar phenotypic responses. Therefore, understanding patterns of phenotypic divergence for closely related species requires considering distinct evolutionary histories. Here, we investigated how a common form of human-induced environmental alteration, habitat fragmentation, may drive phenotypic divergence among three closely related species of Bahamian mosquitofish (Gambusia spp.). Focusing on one phenotypic trait (male coloration), having a priori predictions of divergence, we tested whether populations persisting in fragmented habitats differed from those inhabiting unfragmented habitats and examined the consistency of the pattern across species. Species exhibited both shared and unique patterns of phenotypic divergence between the two types of habitats, with shared patterns representing the stronger effect. For all species, populations in fragmented habitats had fewer dorsal-fin spots. In contrast, the magnitude and trajectory of divergence in dorsal-fin color, a sexually selected trait, differed among species. We identified fragmentation-mediated increased turbidity as a possible driver of these trait shifts. These results suggest that even closely related species can exhibit diverse phenotypic responses when encountering similar human mediated selection regimes. This element of unpredictability complicates forecasting the phenotypic responses of wild organisms faced with anthropogenic change - an important component of biological conservation and ecosystem management. PMID- 26240606 TI - Patterns of differential gene expression in adult rotation-resistant and wild type western corn rootworm digestive tracts. AB - The western corn rootworm (WCR,Diabrotica virgifera virgifera LeConte) is an important pest of corn. Annual crop rotation between corn and soybean disrupts the corn-dependent WCR life cycle and is widely adopted to manage this pest. This strategy selected for rotation-resistant (RR) WCR with reduced ovipositional fidelity to corn. Previous studies revealed that RR-WCR adults exhibit greater tolerance of soybean diets, different gut physiology, and host-microbe interactions compared to rotation-susceptible wild types (WT). To identify the genetic mechanisms underlying these phenotypic changes, a de novo assembly of the WCR adult gut transcriptome was constructed and used for RNA-sequencing analyses of RNA libraries from different WCR phenotypes fed with corn or soybean diets. Global gene expression profiles of WT- and RR-WCR were similar when feeding on corn diets, but different when feeding on soybean. Using network-based methods, we identified gene modules transcriptionally correlated with the RR phenotype. Gene ontology enrichment analyses indicated that the functions of these modules were related to metabolic processes, immune responses, biological adhesion, and other functions/processes that appear to correlate to documented traits in RR populations. These results suggest that gut transcriptomic divergence correlated with brief soybean feeding and other physiological traits may exist between RR- and WT-WCR adults. PMID- 26240607 TI - Intraspecific variation of a dominant grass and local adaptation in reciprocal garden communities along a US Great Plains' precipitation gradient: implications for grassland restoration with climate change. AB - Identifying suitable genetic stock for restoration often employs a 'best guess' approach. Without adaptive variation studies, restoration may be misguided. We test the extent to which climate in central US grasslands exerts selection pressure on a foundation grass big bluestem (Andropogon gerardii), widely used in restorations, and resulting in local adaptation. We seeded three regional ecotypes of A. gerardii in reciprocal transplant garden communities across 1150 km precipitation gradient. We measured ecological responses over several timescales (instantaneous gas exchange, medium-term chlorophyll absorbance, and long-term responses of establishment and cover) in response to climate and biotic factors and tested if ecotypes could expand range. The ecotype from the driest region exhibited greatest cover under low rainfall, suggesting local adaptation under abiotic stress. Unexpectedly, no evidence for cover differences between ecotypes exists at mesic sites where establishment and cover of all ecotypes were low, perhaps due to strong biotic pressures. Expression of adaptive differences is strongly environment specific. Given observed adaptive variation, the most conservative restoration strategy would be to plant the local ecotype, especially in drier locations. With superior performance of the most xeric ecotype under dry conditions and predicted drought, this ecotype may migrate eastward, naturally or with assistance in restorations. PMID- 26240608 TI - Rapidly shifting maturation schedules following reduced commercial harvest in a freshwater fish. AB - Size-selective harvest of fish stocks can lead to maturation at smaller sizes and younger ages, which may depress stock productivity and recovery. Such changes in maturation may be very slow to reverse, even following complete fisheries closures. We evaluated temporal trends in maturation of five Great Lakes stocks of yellow perch (Perca flavescens Mitchill) using indices that attempt to disentangle plastic and evolutionary changes in maturation: age at 50% maturity and probabilistic maturation reaction norms (PMRNs). Four populations were fished commercially throughout the time series, while the Lake Michigan fishery was closed following a stock collapse. We documented rapid increases in PMRNs of the Lake Michigan stock coincident with the commercial fishery closure. Saginaw Bay and Lake Huron PMRNs also increased following reduced harvest, while Lake Erie populations were continuously fished and showed little change. The rapid response of maturation may have been enhanced by the short generation time of yellow perch and potential gene flow between northern and southern Lake Michigan, in addition to potential reverse adaptation following the fishing moratorium. These results suggest that some fish stocks may retain the ability to recover from fisheries induced life history shifts following fishing moratoria. PMID- 26240609 TI - The effects of spatial structure, frequency dependence and resistance evolution on the dynamics of toxin-mediated microbial invasions. AB - Recent evidence suggests that interference competition between bacteria shapes the distribution of the opportunistic pathogen Staphylococcus aureus in the lower nasal airway of humans, either by preventing colonization or by driving displacement. This competition within the nasal microbial community would add to known host factors that affect colonization. We tested the role of toxin-mediated interference competition in both structured and unstructured environments, by culturing S. aureus with toxin-producing or nonproducing Staphylococcus epidermidis nasal isolates. Toxin-producing S. epidermidis invaded S. aureus populations more successfully than nonproducers, and invasion was promoted by spatial structure. Complete displacement of S. aureus was prevented by the evolution of toxin resistance. Conversely, toxin-producing S. epidermidis restricted S. aureus invasion. Invasion of toxin-producing S. epidermidis populations by S. aureus resulted from the evolution of toxin resistance, which was favoured by high initial frequency and low spatial structure. Enhanced toxin production also evolved in some invading populations of S. epidermidis. Toxin production therefore promoted invasion by, and constrained invasion into, populations of producers. Spatial structure enhanced both of these invasion effects. Our findings suggest that manipulation of the nasal microbial community could be used to limit colonization by S. aureus, which might limit transmission and infection rates. PMID- 26240611 TI - Frailty and the risk of cognitive impairment. AB - Aging occurs as a series of small steps, first causing cellular damage and then affecting tissues and organs. This is also true in the brain. Frailty, a state of increased risk due to accelerated deficit accumulation, is robustly a risk factor for cognitive impairment. Community-based autopsy studies show that frail individuals have brains that show multiple deficits without necessarily demonstrating cognitive impairment. These facts cast a new light on the growing number of risk factors for cognitive impairment, suggesting that, on a population basis, most health deficits can be associated with late-life cognitive impairment. The systems mechanism by which things that are bad for the body are likely to be bad for the brain can be understood like this: the burden of health deficits anywhere indicates impaired ability to withstand or repair endogenous and environmental damage. This in turn makes additional damage more likely. If true, this suggests that a life course approach to preventing cognitive impairment is desirable. Furthermore, conducting studies in highly selected, younger, healthier individuals to provide 'proof of concept' information is now common. This strategy might exclude the very circumstances that are required for disease expression in the people in whom dementia chiefly occurs (that is, older adults who are often in poor health). PMID- 26240613 TI - Minilaparoscopic cholecystectomy - the new non-visible scars technique. Preliminary report of first series. AB - INTRODUCTION: Surgery without scars is the dream of many patients and surgeons as well. It includes many new laparoscopic techniques (LESS, SILS, hybrid NOTES), but data concerning common bile duct (CBD) lesions are unavailable. AIM: To establish the new technique of minilaparoscopic cholecystectomy (MCh): non visible scar intervention without increasing the risk of CBD lesions. MATERIAL AND METHODS: Forty consecutive patients with symptomatic gallbladder lithiasis were qualified for elective laparoscopic cholecystectomy (LCh) using one 10/11 mm umbilical port, one 5 mm right suprapubic port and two minilaparoscopic, disposable, no-port graspers. There were 26 women and 14 men, with the mean age 56 (17-72) years and with the average body mass index 28 (18-33) kg/m(2). CO2 Veress 15 mm Hg pneumoperitoneum was performed after transumbilical incision, and the first 10/11 mm port was inserted at the beginning for the 5 mm laparoscope and finally for typical instruments. Next under camera control, a 5 mm trocar was inserted in the right 'bikini line'. To this port the laparoscope was relocated from the umbilicus, and under its control two minilaparoscopic, disposable, non port graspers were introduced after small, 2 mm skin incisions in the right anterior axillary line and in the right mesogastrium to catch the gallbladder. Next through the umbilical port, using typical instruments, the cystic duct and artery were dissected, clipped and cut. The gallbladder was removed through the umbilical port whole. RESULTS: There was no conversion to open cholecystectomy. In 5 cases drainage of the gallbladder lodge was necessary through a 5 mm port in the right bikini line. The time of the intervention ranged from 90 min during the introduction of the new method to 50 min for the last procedures. No postoperative complications were observed, and all patients were discharged at the same time as after conventional LCh. CONCLUSIONS: Two-port laparoscopic cholecystectomy performed with two minilaparoscopic no-port graspers does not increase the risk of CBD lesions. It provides an excellent cosmetic effect and is very convenient for the surgeon like typical LCh. PMID- 26240612 TI - Minimally invasive pancreatic surgery - a review. AB - During the past 20 years the application of a minimally invasive approach to pancreatic surgery has progressively increased. Distal pancreatectomy is the most frequently performed procedure, because of the absence of a reconstructive phase. However, middle pancreatectomy and pancreatoduodenectomy have been demonstrated to be safe and feasible as well. Laparoscopic distal pancreatectomy is recognized as the gold standard treatment for small tumors of the pancreatic body-tail, with several advantages over the traditional open approach in terms of patient recovery. The surgical treatment of lesions of the pancreatic head via a minimally invasive approach is still limited to a few highly experienced surgeons, due to the very challenging resection and complex anastomoses. Middle pancreatectomy and enucleation are indicated for small and benign tumors and offer the maximum preservation of the parenchyma. The introduction of a robotic platform more than ten years ago increased the interest of many surgeons in minimally invasive treatment of pancreatic diseases. This new technology overcomes all the limitations of laparoscopic surgery, but actual benefits for the patients are still under investigation. The increased costs associated with robotic surgery are under debate too. This article presents the state of the art of minimally invasive pancreatic surgery. PMID- 26240614 TI - Implantation of a new enteral stent in obstructive colorectal cancer using interventional radiology in patients over 70 years of age. AB - INTRODUCTION: Colorectal cancer is the second leading cause of death due to cancer in Poland. The traditional approach to treat patients included a surgical procedure. Irrespective of the surgical method being used, surgical treatment of malignant colorectal obstruction is associated with prolonged hospitalisation, and the postoperative mortality rate is approximately 5-11%. Due to these problems, more interest has been shown in less invasive methods. Prosthesis implantation is a leading endoscopic method used currently in palliative or preoperative treatment. AIM: To compare the results of implantation of traditional stents with the results of implantation of an own stent using minimally invasive methods. MATERIAL AND METHODS: Left-sided colon obstruction due to cancer was an indication for transplantation. All patients were aged over 70 years and had serious concomitant diseases. The control group included 50 patients with colorectal cancer who received traditional stents in the period 2009-2011. Our stent covers only the internal length of a tumour. It is not equipped with anti-migration flares. To minimize the risk of migration it has a system of hooks that are responsible for permanent anchorage of the stent within the tumour mass. RESULTS: Implantation technical and clinical success defined as effective decompression of intestinal obstruction was 100% in both groups. There were 2 cases of stent migration in the control group. CONCLUSIONS: It is possible to achieve a secure surgical anastomosis after intestinal decompression. Stent implantation is fast and safe thanks to the positioning system that was used. The use of labelled hooks is a secure anti-migration solution. PMID- 26240615 TI - Does elevated intra-abdominal pressure during laparoscopic colorectal surgery cause acute gastrointestinal injury? AB - INTRODUCTION: The incidence of acute gastrointestinal injury (AGI) after colorectal surgery is low when laparoscopic techniques are used. While elevated intra-abdominal pressure (IAP) and intra-abdominal hypertension (IAH) are associated with AGI grade II, little is known about the relation between increased IAP during laparoscopy and subsequent AGI. AIM: To assess the impact of increased IAP during laparoscopic colorectal surgery on the incidence of postoperative AGI. MATERIAL AND METHODS: Sixty-six patients (41 men and 25 women) with colorectal cancer undergoing elective laparoscopic colorectal surgery were randomized into 3 groups, according to different IAP levels during CO2 pneumoperitoneum (10 mm Hg, 12 mm Hg and 15 mm Hg). We recorded the incidence of AGI after surgery by assessing the following parameters: time to first flatus/defecation, time to first bowel movement, time to tolerance of semi-liquid food and the occurrence of vomiting/diarrhea. Moreover, inflammatory mediators were measured before the induction of CO2 pneumoperitoneum and on postoperative day 1. RESULTS: Acute gastrointestinal injury occurred in 15 (27.3%) patients. In all 3 study groups, the elevation of IAP during CO2 pneumoperitoneum did not significantly increase the occurrence of symptoms of AGI, vomiting or diarrhea. Lower IAP levels did not significantly accelerate recovery of gastrointestinal function or shorten postoperative hospital stay. The changes in serum IL-6 after surgery did not correlate with the value of IAP. CONCLUSIONS: The level of IAP elevation during laparoscopic colorectal surgery does not increase the occurrence of AGI after surgery. PMID- 26240616 TI - Diagnostic value of preoperative axillary lymph node ultrasound assessment in patients with breast cancer qualified for sentinel lymph node biopsy. AB - INTRODUCTION: Sentinel lymph node biopsy (SLNB) is a standard procedure in the therapeutic management of patients with non-advanced breast cancer. AIM: To analyse the utility of ultrasound scan (USS) examination in the process of patient qualification for SLNB and to estimate the optimal time to perform USS in the clinical preoperational assessment of axillary lymph nodes. MATERIAL AND METHODS: A prospective analysis of 702 patients with invasive breast cancer treated with SLNB between 7.03.2012 and 27.05.2013 was performed. The patients were divided into three groups: I (USS < 8 weeks before SLNB), II (USS > 8 weeks before SLNB and another one on the day before SLNB) and III (USS > 8 weeks before SLNB without perioperative USS). In these patients the percentage of metastases in the sentinel lymph node and the clinical factors influencing the diagnostic value of preoperative ultrasound scan were assessed. RESULTS: Metastatic lesions in sentinel lymph nodes were found in 154 (21.9%) patients. The highest percentage of metastases was noted in patients operated on in the second and third month from the beginning of preoperative diagnostics. None of the factors tested (size of the original tumour, histological malignancy grading, kind of preoperative diagnostics, Ki-67 value, biological type of the tumour, age) had a statistically significant influence on the diagnostic value of perioperative USS examination in the analysed time span. CONCLUSIONS: The lowest percentage of metastases in the sentinel lymph node was noted in the patients qualified for SLNB who had the ultrasound performed directly before the surgical procedure (not more than 4 weeks before the surgery). PMID- 26240617 TI - Changes of size and shape of small, unruptured intracranial aneurysms in repeated computed tomography angiography studies. AB - INTRODUCTION: Unruptured intracranial aneurysms (UIAs) are frequently detected in noninvasive imaging studies such as computed tomography angiography (CTA) or magnetic resonance angiography (MRA). If small, UIAs are observed in these modalities in order to detect growth or shape change, but there are many questions about proper protocol of the follow-up. AIM: To assess changes of small (< 7 mm) UIAs dome size and shape in repeated CTA studies as predictors of growth and rupture. MATERIAL AND METHODS: One hundred and ten UIAs (10 posterior circulation) in 70 patients (55 women) were observed, with a cumulative observation time of 333.32 years. Aneurysms' dome and neck perpendicular dimensions were measured in the first and the last CTA study at least twice with the developed application. Confidence intervals (CI) for measurements and dome shape parameters were calculated. For aneurysms ruptured during follow-up intermediate studies were analyzed. Patients' clinical information was recorded. The aneurysm growth detection algorithm integrated CI and spatial resolution of the CT scanner. RESULTS: Twenty-three aneurysms increased in volume, 10 in height and 14 in dome width. Volume increased in 90% of cases of height and 93% of width increase. Posterior circulation aneurysms grew faster than anterior ones (p < 0.003), but calculated time to significant size increase (eT) did not differ between the groups due to higher CI in the posterior circulation. Analysis of eT with Kaplan-Meier curves showed that 75% of growing aneurysms could be detected in the first 3 years of observation. During the follow-up 3 aneurysms bled, and they grew faster than other growing aneurysms. Two of the bleeding aneurysms formed daughter sacs. CONCLUSIONS: Dome volume assessment is superior to single dimension assessment in aneurysm growth detection. Confidence intervals assessment helps to avoid overestimation of growth. Seventy-five percent of growing aneurysms could be detected in the first 3 years of observation. Daughter sac formation and fast increase in size are strong predictors of aneurysm rupture. PMID- 26240618 TI - Minimally invasive esophagectomy for esophageal cancer - results of surgical therapy. AB - INTRODUCTION: The indication for minimally invasive esophagectomy (MIE) in esophageal cancer has an increasing tendency. AIM: To present our cohort of patients operated on between 2006 and 2012. MATERIAL AND METHODS: A single centre study of 106 consecutive esophagectomies performed for esophageal cancer by a minimally invasive approach in 79 patients was performed. Transhiatal laparoscopic esophagectomy (THLE) was performed in 66 patients, transthoracic esophagectomy (TTE) in 13 patients, with histological findings of squamous cell carcinoma in 28 and adenocarcinoma in 51 patients. RESULTS: The MIE was completed in 76 (96.2%) patients. In cases of TTE, the operation was converted to an open procedure in 3 cases. Operation time ranged from 225 to 370 min (average 256 min). The number of lymph nodes removed was 7-16 (11 on average). The postoperative course was without any complications in 54 (68.3%) patients. Respiratory complications were observed in 14 (17.7%) patients (9 following THLE, 5 following TTE). Other serious complications included acute myocardial infarction (1 patient) and necrosis of the gastroplasty (1 patient). Anastomotic dehiscence was observed in 8 patients, left recurrent laryngeal nerve paralysis in 8 patients, intra-abdominal abscesses in 2 patients, and pleural empyema in 1 case. The overall morbidity of patients operated on by MIE was 31.6%. Thirty-day mortality was 10.1%. CONCLUSIONS: The MIE belongs to the therapeutic portfolio of surgical procedures performed for esophageal cancer. Successful performance requires erudition of the surgical team in both minimally invasive procedures as well as in classical surgical treatment of esophageal cancer; therefore centralization of patients is imperative. PMID- 26240619 TI - Modification of internal hernia classification system after laparoscopic Roux-en Y bariatric surgery. AB - INTRODUCTION: The occurrence of internal hernia is not an uncommon late complication following the laparoscopic bariatric Roux-en-Y gastric bypass procedure. In some instances, it can be life threatening if not treated in a timely manner. Although there are numerous publications in the literature addressing internal hernia, they are mostly retrospective, and focus mainly on describing the different reconstructive orientation as far as the bowel is concerned. AIM: Our study aim is to address the relationship between the three basic elements of internal hernia, namely: intestinal mesentery defect, the involved intestine and herniated loop direction. Although a developed and widely accepted classification system of internal hernia has not been established yet, we hope this study can help the system to be established. MATERIAL AND METHODS: We studied all patients who underwent revision bariatric operations in the Freiburg and Lubeck University Hospitals (2007-2013). A single surgeon performed and documented all revision procedures for internal hernia. The post-operative follow-up period is up to 6 years. All patients with internal hernias were included whether their primary surgery was performed in our center or performed in other institutions, being referred to our center for further management. The presence of hernia defect, the type of herniated intestinal loop and the direction by which the herniated intestinal loop migrated were analyzed. RESULTS: Twenty-five patients with internal hernia were identified; in 2 patients more than one hernia type coexisted. The most frequent constellation of internal hernias was BP limb herniation into the Brolin space and migrating from left to right direction (28%). The highest incidence of internal hernia was found to be following Roux-en-Y gastric bypass (68%); the biliopancreatic limb (BP) limb was the most commonly involved intestine (51.9%). The incidence of Petersen hernia was the highest (59.3%), and left-right direction was more common. The most common hernia direction of the biliopancreatic limb was from left to right (92.6%), but alimentary limb (AL; 57.1%) and common channel (CC; 66.7%) often favor the other course. CONCLUSIONS: There are existing different types of internal hernias after bariatric operations including separate mesenterial spaces, various intestine parts and herniation direction. Our SDL classification system may offer a useful pathway that facilitates the understanding, and systematic approach to internal hernia, which can be used by bariatric quality registers. PMID- 26240620 TI - Colorectal cancer liver metastases: laparoscopic and open radiofrequency-assisted surgery. AB - INTRODUCTION: The liver is the most common site of colorectal metastases (colorectal liver metastases - CLM). Surgical treatment in combination with oncological therapy is the only potentially curative method. Unfortunately, only 10-25% of patients are suitable for surgery. Traditionally, open liver resection (OLR) is usually performed. However, laparoscopic liver resection (LLR) has become popular worldwide in the last two decades. AIM: To evaluate the effectiveness and benefits of radiofrequency minor LLR of CLM in comparison with OLR. MATERIAL AND METHODS: The indication for surgery was CLM and the possibility to perform minor laparoscopic or OLR not exceeding two hepatic segments according to Couinaud's classification. RESULTS: Sixty-six minor liver resections for CLM were performed. Twenty-five (37.9%) patients underwent a laparoscopic approach and 41 (62.1%) patients underwent OLR. The mean operative time was 166.4 min for LLR and 166.8 min for OLR. Average blood loss was 132.3 +/-218.0 ml during LLR and 149.5 +/-277.5 ml during OLR. Length of hospital stay was 8.4 +/-2.0 days for LLR and 10.5 +/-5.8 days for OLR. All resections were R0. There was no case of mortality. Postoperative complications were recognized in 9 (13.6%) patients: 8 in the group of OLR patients and 1 in the LLR group. The median survival time for LLR was 70.5 months and for OLR 61.9 months. The 5-year overall survival rate was higher for LLR vs. OLR - 82.1% vs. 69.8%. The average length of disease-free interval after LLR was greater (52.2 months) in comparison with OLR (49.4%). The 5-year disease-free interval was 63.2% for LLR and 58% for OLR. CONCLUSIONS: Outcomes and oncological radicality of minor laparoscopic liver resections of CLM are comparable to outcomes of OLR. PMID- 26240622 TI - Vascular changes responsible for the reduced effectiveness of obliteration of uterine arteries in women with advanced cervical cancer. AB - INTRODUCTION: Haemorrhages from the genital tract remain a major threat to the life of patients with advanced cervical cancer. It is possible to achieve haemostasis by both surgical techniques and the procedure of endovascular uterine artery embolization. However, in some women with loco-regionally advanced cervical cancer the obliteration of the uterine arteries is not effective. AIM: Evaluation of morphological changes in uterine arteries in patients with advanced cervical cancer and comparison of their changes with the achieved haemostatic effect of obliteration. MATERIAL AND METHODS: The prospective study included a group of 8 women with cervical cancer at a clinical stage of IIB to IIIC according to the FIGO classification. 3D quantitative coronary angiography (QCA) was performed before uterine embolization. The haemostatic effect of uterine artery embolization was compared with observed vascular changes. RESULTS: Mean uterine artery length in patients who achieved complete hemostasis: 39.5 mm - right uterine artery; 38.7 mm - left uterine artery. Mean uterine artery length in patients who achieved partial satisfactory haemostasis: 32 mm - right uterine artery; 30.5 mm - left uterine artery. Mean uterine artery length in patients who achieved unsatisfactory haemostasis: 10.5 mm - right uterine artery; 19 mm - left uterine artery. CONCLUSIONS: Shortening of uterine arteries worsens prognosis of the haemostatic effect of their obliteration in patients with advanced cervical cancer. PMID- 26240621 TI - A prospective evaluation of the influence of three bariatric procedures on insulin resistance improvement. Should the extent of undiluted bile transit be considered a key postoperative factor altering glucose metabolism? AB - INTRODUCTION: Insulin resistance (IR), the essential step in development of type 2 diabetes mellitus (T2DM), resolves quickly after bariatric surgery, but the effectiveness depends on the type of the procedure. Although the long-term influence on IR improvement is well documented, the mechanisms of the ultra-fast response after restrictive and bypass procedures require explanation. AIM: To determine IR evolution from the initial preparative period to 6 months after the operation, exposing the rapid postoperative response while comparing the 3 bariatric methods, with the belief that the metabolic effect may be correlated with anatomical combinations. MATERIAL AND METHODS: From January to December, 2013, a cohort of severely obese, insulin resistant individuals recruited to the prospective study underwent laparoscopic sleeve gastrectomy (SG-30), Roux-en-Y gastric bypass (RYGB-30) and one-anastomosis gastric bypass (OAGB-30). Main laboratory parameters of glucose metabolism were evaluated in fasting patients preoperatively, 4 days and 1, 3 and 6 months after surgery. RESULTS: Within the whole observation period the most significant improvement in homeostasis model assessment for IR (HOMA-IR) was observed in the first 4 days after each operation. The decrease of HOMA-IR was higher (p < 0.0001) in gastric bypass groups than in patients after SG (-41%). The difference between bypass groups favors OAGB over RYGB (63 vs. -56%, p = 0.0489). CONCLUSIONS: Among all bariatric management factors, operation type is the most important in IR improvement. The significant difference in response after SG vs. RYGB and OAGB supports the concept of metabolic competence of duodeno-jejunal exclusion. Altered bile flow after duodeno-jejunal exclusion may be responsible for enhanced glucose metabolism improvement. PMID- 26240623 TI - Usefulness of the Obesity Surgery Mortality Risk Score (OR-MRS) in choosing the laparoscopic bariatric procedure. AB - INTRODUCTION: The most popular scale to stratify the postoperative risk is the Obesity Surgery Mortality Risk Score (OS-MRS). The design and ease of interpretation make the scale a potential tool for clinical use. AIM: To evaluate the usefulness of the OS-MRS scale in the enrollment of patients for laparoscopic bariatric procedures, including laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB). MATERIAL AND METHODS: The medical records of patients who underwent LSG or LRYGB due to obesity between January 2010 and December 2010 were reviewed retrospectively. The decision of choosing the surgical procedure was made on the basis of OS-MRS risk category. The primary endpoint of this study was the 90-day mortality, and the secondary endpoint was the presence of major complications. RESULTS: There were 107 patients including 66 women and 41 men. The OS-MRS classes were A (48%), B (47%) and C (5%). The LSG was applied to patients with higher body mass index and to patients of class C. The secondary endpoints occurred in 6 patients, distributed in 10% of class A, 2% of class B and 0% of class C patients (p < 0.05). In 5 of 6 cases the endpoint was observed after LRYGB. Fatal cases were not observed. CONCLUSIONS: The OS-MRS can be a useful clinical tool for choosing the appropriate laparoscopic bariatric procedure, depending on the risk of postoperative complications. Low risk of postoperative complications should not lower the watchfulness of the surgeon. PMID- 26240624 TI - Endoscopic necrosectomy under fluoroscopic guidance - a single center experience. AB - INTRODUCTION: Our report presents a technique of necrotic tissue removal during transmural drainage of walled-off pancreatic necrosis (WOPN) that is an alternative to the one that has already been described in the literature. AIM: To assess the effectiveness and safety of endoscopic necrosectomy performed during transmural drainage of symptomatic WOPN. MATERIAL AND METHODS: Within the years 2012-2013, 64 patients underwent endoscopic treatment of symptomatic WOPN in our center. Eight patients underwent endoscopic necrosectomy during transmural drainage. Fragments of necrotic tissues were removed from the collection's cavity under fluoroscopic guidance using a Dormia basket. The results and complications of treatment were compared retrospectively. RESULTS: Sixty-four patients with WOPN underwent transmural drainage under endoscopic ultrasonography (EUS) guidance. Eight patients (12.5%, 5 women and 3 men, mean age 57.25 years) were qualified for endoscopic necrosectomy. Transmural transgastric access was made in 7 patients and transduodenal access in 1 patient. Additional percutaneous drainage was used in 2 patients. Active drainage was continued for 24 days (11-44 days). The mean number of endoscopic procedures was 4.75 (3-9). The average number of necrosectomy procedures during drainage was 1.75 (1-4). Complications of endotherapy occurred in 2/8 (25%) patients, and they were not directly connected with necrosectomy. Therapeutic success after the end of active drainage was achieved in all patients. During a 6-month follow-up no recurrence of the collection was observed. CONCLUSIONS: Endoscopic necrosectomy under fluoroscopic guidance is an effective and safe method of minimally invasive treatment in a selected group of patients with symptomatic WOPN. PMID- 26240625 TI - Alternative hybrid and staged interventional treatment of congenital heart defects in critically ill children with complex and non-cardiac problems. AB - INTRODUCTION: An individually designed strategy of comprehensive alternative hybrid and staged interventional treatment (AHASIT) can be a reasonable alternative to conventional treatment of congenital heart defects, reduce the risk of cardiac surgery or interventions performed separately, and give an additional chance for critically ill children. AIM: To present our experience and the results of AHASIT of severely ill or borderline children referred for surgery with the diagnosis of congenital heart defects. MATERIAL AND METHODS: A group of 22 patients with complex cardiac and non-cardiac pathologies was retrospectively selected and analyzed. An individual preoperative severity scale was established for AHASIT patients, with one point for each of the following preoperative complications: prematurity, low body weight, cyanosis, intolerance to drug therapy, failed interventional treatment prior to admission, mechanical ventilation prior to the procedure, chronic respiratory failure and non-cardiac, mainly congenital malformations (congenital diaphragmatic hernia, lower extremity agenesia, duodenal atresia) and acquired problems (newborn edema, necrotic enterocolitis, intracranial hemorrhage, liver and renal failure, anemia and thrombocytopenia, infections or colonization with drug-resistant pathogens). RESULTS: The analysis of the postoperative course showed that the patients with 5 AHASIT points or more had a more complicated postoperative course than the patients with 1 to 4 AHASIT points. CONCLUSIONS: The AHASIT of pediatric congenital heart defects with complex and non-cardiac problems appeared to be an attractive option for selected severely ill patients. The strategy was found to be effective in selected neonates suffering from complex and accompanying non cardiac pathologies, with positive final results of both cardiological intervention and planned surgery. PMID- 26240626 TI - Endoscopic metal enteral stent placement for malignant afferent loop syndrome after pancreaticoduodenectomy. AB - INTRODUCTION: Afferent loop syndrome (ALS) is a rare and dreaded complication after pancreaticoduodenectomy (PD). Malignant ALS after PD is usually difficult to manage due to patients' poor condition. Effective and safe therapeutic strategies for these patients are reported scarcely at present. AIM: To analyze and evaluate the clinical characteristics and treatment of these patients. MATERIAL AND METHODS: We analyzed 3 patients with malignant ALS after PD. They were treated by endoscopic enteral metal stent placement in our hospital. Meanwhile we retrospectively reviewed 49 cases with ALS after PD through available English literature. All these patients' clinical features, laboratory study, treatment and outcome were evaluated. RESULTS: A total of 52 cases were analyzed in the study. The most common presenting symptoms of ALS after PD were jaundice (56.5%), upper abdominal pain (45.7%), fever (26.1%), and vomiting (23.9%). Sixty percent of ALS cases were caused by tumor recurrence. The mean time from prior surgery to diagnosis of ALS was 13.3 months. The rates of treatment with the endoscopic approach, percutaneous stenting or drainage, surgery, and the conservative method were 40.4%, 32.7%, 11.5%, and 15.4%, respectively. Endoscopic enteral metal stent placement proved more effective and less invasive in the treatment of malignant ALS after PD. CONCLUSIONS: Cholangitis and cholangiectasis are the major manifestations of malignant ALS after PD. Invasive interventions are enjoying more and more acceptance for treatment. Endoscopic enteral metal stent placement appears to be a promising technique with effective palliation in these patients. PMID- 26240627 TI - Major vascular injuries complicating knee arthroscopy. AB - Starting with a case report, we made a detailed review of the literature, with the purpose of identifying and analyzing the type of iatrogenic vascular lesion following knee arthroscopy and the method of vascular repair. A PubMed literature search was undertaken to locate all reported cases of major vascular iatrogenic injuries during arthroscopic knee procedures. We identified 39 papers which report a total of 62 cases of major iatrogenic popliteal lesions after knee arthroscopy, between 1985 and 2014. The type of arthroscopic intervention performed, the type of iatrogenic vascular lesion encountered, the time passed until its discovery and treatment, the method of vascular reconstruction, and the postoperative course are presented. Postarthroscopy vascular complications are infrequent but potentially disastrous for the condition of the affected inferior limb. An early diagnosis and reintervention are mandatory for a good postoperative outcome. PMID- 26240628 TI - Reduced port laparoscopic surgery for colon cancer in a patient with tuberculous kyphosis and dwarfism: a rare case and literature review. AB - With accumulated surgical experience, the contraindications to laparoscopic surgery have been decreasing. Reduced port laparoscopic surgery has been widely adopted for a variety of diseases. However, surgery in patients with anatomic deformities are still a challenge for surgeons, specifically abdominal surgery in patients with severe kyphosis. A 71-year-old man with a diagnosis of ascending colon cancer had severe kyphosis with extremely short stature, secondary to tuberculous spondylitis. Laparoscopic right hemicolectomy was successfully performed with a single umbilical incision plus one port. This is the first reported case involving laparoscopic surgery in a patient with tuberculous kyphosis. The purpose of this report is to describe the surgical skills of reduced port laparoscopic surgery in a patient with altered habitus. With proper planning and a meticulous operation, minimally invasive surgery could be safely achieved. PMID- 26240629 TI - Rectal duplication with sciatic hernia. AB - Rectal duplications represent 5% of all duplications in the alimentary tract, and they are very rarely diagnosed during the neonatal period. The authors present the method of investigation and the results of surgical treatment of a full-term neonate with a sciatic hernia containing a rectal duplication. The procedure started with three-port laparoscopy, but excision of the tubular duplication of the rectum was possible only by a transanal endorectal pull-through approach. The sciatic hernia was closed, and plastic sutures on the buttock finished the procedure. The coincidence of sciatic hernia with rectal duplication is extremely rare, and the method of treatment depends exclusively on the anatomical conditions. PMID- 26240630 TI - Ex vivo pyelotomy, nephroscopy and holmium laser lithotripsy of a staghorn stone in a donor kidney prior to renal transplant. AB - This case report presents the diagnostic and treatment procedures of stone removal from the kidney of a 67-year-old donor, the transplantation of the kidney to a 65-year-old recipient, and the postoperative course until the end of hospitalization. Computed tomography performed before collecting the organ showed a staghorn stone in the renal pelvis and lower calyces in the right donor kidney. The stones were removed ex-vivo using a rigid ureteroscope and a holmium laser prior to transplantation. Then the organ was transplanted to the left iliac fossa of a 65-year-old man with end-stage renal failure. The authors think there is a possibility of increasing the kidney pool, by using organs containing large calculi. In such cases stones should be removed before the operation and the patient should be monitored regularly, especially in the first months after the transplant. PMID- 26240631 TI - All dangerous types of endoleaks after endovascular aneurysm repair in a single patient. AB - Endovascular aneurysm repair (EVAR) has become tremendously popular in recent years. However, the long-term results of these stent grafts are uncertain and are still being evaluated. According to some data, the graft-related complication rate after EVAR could be as high as 43% in long-term observation. In this case report, we present a patient who had all dangerous types of endoleaks after EVAR and required sophisticated management including endovascular and open surgical repairs. After repeated invasive treatment, it was possible to exclude all endoleaks, and now the patient is free from graft-related complications. Although EVAR has become very popular, we should remember about possible complications, which could be very severe and life-threatening. For this reason, the choice between endovascular and open repair of abdominal aortic aneurysm should be well considered. PMID- 26240632 TI - Novel combined approach in the management of non-healing solitary rectal ulcer syndrome - laparoscopic resection rectopexy and transanal endoscopic microsurgery. AB - Solitary rectal ulcer syndrome (SRUS) is an uncommon chronic disorder with a wide range of endoscopic findings, clinical presentations and characteristic histopathological features. There is no clear consensus regarding SRUS management, because of its poorly understood pathogenesis and frequent association with various pelvic floor disorders. Laparoscopic resection rectopexy and transanal endoscopic microsurgery (TEM) were used for the treatment of non healing SRUS. The present paper reports a case of non-healing SRUS due to obstructive defecation syndrome based on combined pelvic floor disorders (rectocele, enterocele, internal rectal prolapse and dolichosigma) successfully managed by a novel combined mini-invasive approach which has never been previously reported in the literature (laparoscopic resection rectopexy and TEM). The new minimally invasive concept seems to be safe and feasible - laparoscopic resection rectopexy results in effective correction of the obstructive defecation syndrome, while TEM allows comfortable access for radical resection of a rectal ulcer. PMID- 26240633 TI - Endoscopic vacuum-assisted closure system (E-VAC): case report and review of the literature. AB - Negative pressure wound therapy (NPWT) has become a standard in the treatment of chronic and difficult healing wounds. Negative pressure wound therapy is applied to the wound via a special vacuum-sealed sponge. Nowadays, the endoscopic vacuum assisted wound closure system (E-VAC) has been proven to be an important alternative in patients with upper and lower intestinal leakage not responding to standard endoscopic and/or surgical treatment procedures. Endoscopic vacuum assisted wound closure system provides perfect wound drainage and closure of various kinds of defect and promotes tissue granulation. Our experience has shown that E-VAC may significantly improve the morbidity and mortality rate. Moreover, E-VAC may be useful in a multidisciplinary approach - from upper gastrointestinal to rectal surgery complications. On the other hand, major limitations of the E VAC system are the necessity of repeated endoscopic interventions and constant presence of well-trained staff. Further, large-cohort studies need to be performed to establish the applicability and effectiveness of E-VAC before routine widespread use can be recommended. PMID- 26240634 TI - Laparoscopic removal of gastrointestinal stromal tumors of uncinate process of pancreas. AB - The pancreas is an extremely rare location for gastrointestinal stromal tumors (GIST). We present a case of a patient with a GIST located in the uncinate process of the pancreas that was treated successfully with a laparoscopic technique. Computed tomography, magnetic resonance imaging and scintigraphy suggested a neuroendocrine tumor. Due to the fact that the image suggested a neuroendocrine tumor with a diameter below 2 cm, the patient was qualified for a laparoscopic procedure of tumor enucleation. Postoperative care proceeded in accordance with the principles of the ERAS concept. The postoperative course was uncomplicated. He was discharged home on the second postoperative day. In the obtained histopathology result a GIST was found. During a 6-month observation, including control computed tomography examination, no signs of tumor progression were found. Despite the fact that stromal tumors of the gastrointestinal tract localized in the pancreas are very rare, they should be considered in the differential diagnosis of tumors of this organ. PMID- 26240635 TI - Extracorporeal staple technique: an alternative approach to the treatment of critical colostomy stenosis. AB - We describe an extracorporeal staple technique used to treat severe colostomy stenosis under analgo-sedation, thus avoiding relaparotomy. The surgery is performed under short-term sedation. The orifice of the stoma is widened and overgrowing skin is excised. The volume and diameter of the stoma are assessed. The anvil of a circular stapler device is inserted into the lumen of the colostomy. First bowel layers and then skin are closed with purse-string sutures. One firing of the stapler is used to reshape the stoma. The procedure takes around 20-30 min. One circular stapler is used. The patient can be discharged the same day or a day after surgery. No complications were noted in operated patients. At 6- and 12-month follow-ups, a slight narrowing of the colostomy was visible, but no recurrence of the stricture was noted. The described technique is an interesting, easy and safe alternative to previous methods of treatment for stenosed end-colostomy. Importantly, it is an extra-abdominal procedure and may be offered to patients with a history of multiple abdominal operations or with serious coexisting medical conditions in the one-day surgery setting. PMID- 26240636 TI - Subcapsular liver haematoma as a complication of laparoscopic cholecystectomy. AB - Cholecystectomy is a common procedure for the treatment of symptomatic cholecystitis. A rare complication is the occurrence of subcapsular haematoma of the liver. In the literature, there are only a few case reports of this type. A 25-year-old woman was admitted to the Surgical Department for surgical treatment of cholecystitis. No complications were observed intra-operatively. On the first day after surgery, the patient manifested symptoms of hypovolaemic shock. The patient was qualified for surgical treatment in the mode of emergency surgery - a giant subcapsular haematoma was found. She was referred to the Clinic of General, Transplant and Liver Surgery of the Medical University of Warsaw for further treatment. This case shows the importance of monitoring the life parameters of patients who have undergone laparoscopic surgery due to symptomatic cholecystitis during the first day after surgery. PMID- 26240637 TI - The usefulness of biliopancreatic diversion/Scopinaro operation in treatment of patients with Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS) is the most common form of obesity with a genetic basis. The short expected survival time due to numerous accompanying diseases and their complications is the reason for research on the maximally efficient method of treatment of obesity in this syndrome. Undertaken attempts of conservative treatment, for example with somatostatin, are ineffective. It seems that the only effective treatment of obesity in this syndrome may be surgical. In this article we present 2 cases of patients with PWS who underwent surgery consisting of biliopancreatic diversion (BPD)/Scopinaro procedure. The BPD/Scopinaro operation in selected cases of disciplined patients with a co-operative family, which we find of key importance, can be considered as one option of treatment of this syndrome in patients with prior neglect of conservative treatment. PMID- 26240638 TI - Urgent laparoscopic gastrocystostomy after iatrogenic perforation of pancreatic cyst - case report and literature review. AB - Pancreatic cysts, a common complication of pancreatitis, often require invasive treatment. When possible, endoscopic technique tends to be the procedure of choice. Despite its advantages, most of its complications may require immediate surgical assistance. Experienced surgeons tend to choose a laparoscopic approach bearing in mind its advantages. We present a case of a 71-year-old patient with an idiopathic pancreatic cyst, causing chronic epigastric pain. The attempt of endoscopic drainage led to iatrogenic perforation, which was successfully managed by laparoscopic posterior gastrocystostomy. The postoperative course was uneventful. In our opinion, laparoscopy should always be considered to manage complications caused by endoscopic drainage of a pancreatic pseudocyst. PMID- 26240639 TI - Rare benign pleomorphic adenoma of the nose: short study and literature review. AB - Pleomorphic adenoma is one of the most common benign tumors of the major salivary glands. It can also occur in the minor salivary glands, which exist in the nasal cavity. Intranasal pleomorphic adenoma usually originates from glands of the nasal septum mucosa. We present the results of endoscopic endonasal surgery of this pathology. The aim of the study was to present the endoscopic technique for nasal septum pleomorphic adenoma surgery. The retrospective examination of 3 patients was performed. There were 2 women and 1 man. Age ranged from 15 to 46 years. All the patients presented with nasal obstruction and occasional epistaxis for at least for 6 months. We performed endoscopic surgery to remove the tumors. In all cases we dissected the septal perichondrium to achieved free margins of the tumor. The microscopic examination revealed an epithelial and myoepithelial component with tubular structures composed of two cell layers, ducts, and a solid area found in a loose myxochondroid area. Additionally, immunohistochemical staining was performed using antibodies against cytokeratin, Ki-67, and vimentin. Patients' postoperative course was uneventful, and no complications were encountered. No recurrence was present during patients' postoperative visits. Nasal benign pleomorphic adenoma is a rare tumor which should be taken into consideration in the nasal cavity during surgery. The correct histological diagnosis can be confirmed by additional histological studies. Endoscopic endonasal surgery is reserved for small tumors. PMID- 26240640 TI - Intersphincteric anal lipofilling with micro-fragmented fat tissue for the treatment of faecal incontinence: preliminary results of three patients. AB - Faecal incontinence is a very debilitating problem. Many techniques have been proposed to treat this condition, with controversial results. Autologous transplant of fat tissue is an established procedure used for the repair of tissue damage, and recent studies revealed the potentiality of tissue regeneration by human adipose-derived stem cells. We treated this condition with the injection, in the intersphincteric anal groove, of lipoaspirate processed by an innovative technology (Lipogems). The aim of the study was to evaluate the efficacy of Lipogems injection for the treatment of faecal incontinence. In February 2014 we treated 3 patients with faecal incontinence. The surgical procedure required three phases: lipoaspiration, processing of lipoaspirate with the Lipogems system, and injection of the obtained product in the intersphincteric anal groove. An accurate proctological examination followed at 1 week, 1 month and 6 months after treatment. Each patient reported an improved Wexner incontinence score at 1 month after the procedure. We observed an increase of resting pressure (by at least 10 mm Hg) and thickness of the internal anal sphincter respectively at ano-rectal manometry and by ultrasound (US) evaluation at the sixth month of follow-up. Our preliminary results are encouraging, but multicentric studies with longer follow-up are needed to validate this novel technique for treatment of faecal incontinence. PMID- 26240641 TI - Multiple plastic stents for benign extrahepatic biliary strictures: report of a case. AB - The etiology of benign bile duct strictures is heterogeneous. Many of them may be secondary to intraoperative injury such as injuries occurring during laparoscopic cholecystectomy. The spectrum of symptoms at presentation varies from subclinical disease with elevation of liver function tests to complete biliary obstruction with jaundice and hyperbilirubinemia or external biliary fistula in the case of bile duct injury. Long-term consequences may lead to secondary biliary cirrhosis. This publication reports a case of a 49-year-old woman with symptomatic gallstone disease who underwent a laparoscopic cholecystectomy in November 2006. She underwent endoscopic retrograde cholangio-pancreatography due to jaundice, fever and abdominal pain. Then she underwent left hemi-hepatectomy in October 2008 and transplantation of the liver in January 2014. Traditionally, surgical repair has been the preferred approach in benign biliary strictures, but there is an increasing trend for use of minimally invasive endoscopic therapy in these patients. PMID- 26240642 TI - Spontaneous sphenoid sinus cerebrospinal fluid leak and meningoencephalocele - are they due to patent Sternberg's canal? AB - Sternberg's canal is a congenital bony defect in the lateral wall of the sphenoid sinus. If it persists to adulthood, it may become a source of spontaneous cerebrospinal fluid leak (CSF) and meningoencephalocele. The aim of the study was to describe the authors' experience and review articles related to spontaneous sphenoid sinus CSF leaks and Sternberg's canal. We analysed patients managed surgicallly due to sphenoid sinus CSF leak and performed a PubMed database search. Two female patients with spontaneous CSF leak of sphenoid origin were found. Both patients underwent surgery with the endoscopic endonasal approach, and the defect was closed using the multi-layer technique. Twelve articles related to CSF leaks of sphenoid origin (due to Sternberg's canal) were found in the PubMed database. Lines of lesser resistance within sphenoid bone may underlie CSF leak pathology together with intracranial hypertension. The endoscopic transnasal approach to the sphenoid sinus is an excellent alternative to standard transcranial procedures. PMID- 26240643 TI - Resistance Training with Blood Flow Restriction and Hypertensive Subjects. PMID- 26240644 TI - Biomechanical Analysis of Defensive Cutting Actions During Game Situations: Six Cases in Collegiate Soccer Competitions. AB - The strengths of interpersonal dyads formed by the attacker and defender in one on-one situations are crucial for performance in team ball sports such as soccer. The purpose of this study was to analyze the kinematics of one-on-one defensive movements in soccer competitions, and determine the relationships between lower limb kinematics and the center of mass translation during cutting actions. Six defensive scenes in which a player was responding to an offender's dribble attack were selected for analysis. To reconstruct the three-dimensional kinematics of the players, we used a photogrammetric model-based image-matching technique. The hip and knee kinematics were calculated from the matched skeleton model. In addition, the center of mass height was expressed as a ratio of each participant's body height. The relationships between the center of mass height and the kinematics were determined by the Pearson's product-moment correlation coefficient. The normalized center of mass height at initial contact was correlated with the vertical center of mass displacement (r = 0.832, p = 0.040) and hip flexion angle at initial contact (r = -0.823, p = 0.044). This suggests that the lower center of mass at initial contact is an important factor to reduce the downwards vertical center of mass translation during defensive cutting actions, and that this is executed primarily through hip flexion. It is therefore recommended that players land with an adequately flexed hip at initial contact during one-on-one cutting actions to minimize the vertical center of mass excursion. PMID- 26240645 TI - The Reliability of Electromyographic Normalization Methods for Cycling Analyses. AB - Electromyography (EMG) is normalized in relation to a reference maximum voluntary contraction (MVC) value. Different normalization techniques are available but the most reliable method for cycling movements is unknown. This study investigated the reliability of different normalization techniques for cycling analyses. Twenty-five male cyclists (age 24.13 +/- 2.79 years, body height 176.22 +/- 4.87 cm and body mass 67.23 +/- 4.19 kg, BMI = 21.70 +/- 2.60 kg.m-1) performed different normalization procedures on two occasions, within the same testing session. The rectus femoris, biceps femoris, gastrocnemius and tibialis anterior muscles were examined. Participants performed isometric normalizations (IMVC) using an isokinetic dynamometer. Five minutes of submaximal cycling (180 W) were also undertaken, allowing the mean (DMA) and peak (PDA) activation from each muscle to serve as reference values. Finally, a 10 s cycling sprint (MxDA) trial was undertaken and the highest activation from each muscle was used as the reference value. Differences between reference EMG amplitude, as a function of normalization technique and time, were examined using repeated measures ANOVAs. The test-retest reliability of each technique was also examined using linear regression, intraclass correlations and Cronbach's alpha. The results showed that EMG amplitude differed significantly between normalization techniques for all muscles, with the IMVC and MxDA methods demonstrating the highest amplitudes. The highest levels of reliability were observed for the PDA technique for all muscles; therefore, our results support the utilization of this method for cycling analyses. PMID- 26240646 TI - Effect of Performance Speed on Trunk Movement Control During the Curl-Up Exercise. AB - Trunk exercise speed has significant effects on neuro-mechanical demands; however, the influence of a variety of exercise speeds on motor control of the trunk displacement remains unknown. The aim of this study was to assess the effect of performance speed on trunk motion control during the curl-up exercise by analyzing the kinematic variance about the sagittal trajectory. Seventeen subjects volunteered to perform curl-ups at different cadences controlled by a metronome. Standard deviation (SD) and range (RG) of shoulder girdle medial lateral displacement (SGML) and detrended fluctuation analysis (DFA) of SGML were calculated to examine linear variability and long range autocorrelation of medial lateral upper trunk displacements, respectively. In addition, SD, RG and DFA of centre of pressure medial-lateral displacement (COPML) were performed to analyze the behavior of the motor system while controlling trunk displacement. Although SD and RG of COPML increased as speed increased, the curl-up cadence did not have significant effects on SD and RG of SGML. These results suggest that although high speed curl-ups challenged participants' ability to carry out medial-lateral adjustments, an increase of performance speed did not modify the linear variability about the sagittal trajectory. Regarding DFA, the scaling exponent alpha of SGML and COPML was higher for the fastest movements, mainly in long term fluctuations. Therefore, to maintain the target trajectory, participants used different strategies depending on performance speed. This is to say, there were less trajectory changes when participants performed the fastest exercises. PMID- 26240647 TI - Effects of Unstable Conditions on Kinematics and Performance Variables in Young Handball Players. AB - The execution variability and outcomes found in throwing actions have received special attention in numerous studies in recent years. The aim of this study was to analyze the effect of an unstable condition on velocity, accuracy and kinematics of movement in the seven metres throw in handball. Twenty-five young handball players took part in an experiment, throwing towards a target on a stable and an unstable surface. Each participant performed 32 throws, 16 for each situation. Linear variability of the dominant hand was assessed by 3D Motion Tracking. A radar sports gun was used to record the velocity of the ball and the throws were video recorded to establish their accuracy. Results showed significant decreases in throwing velocity in unstable conditions, but these did not significantly affect the accuracy achieved in performance. Differences were also found in movement kinematics between the two throwing conditions and relationships were found between kinematics, velocity and accuracy. PMID- 26240648 TI - Breast Support Garments are Ineffective at Reducing Breast Motion During an Aqua Aerobics Jumping Exercise. AB - The buoyant forces of water during aquatic exercise may provide a form of 'natural' breast support and help to minimise breast motion and alleviate exercise induced breast pain. Six larger-breasted females performed standing vertical land and water-based jumps, whilst wearing three breast support conditions. Underwater video cameras recorded the motion of the trunk and right breast. Trunk and relative breast kinematics were calculated as well as exercised induced breast pain scores. Key results showed that the swimsuit and sports bra were able to significantly reduce the superioinferior breast range of motion by 0.04 and 0.05 m, respectively, and peak velocity by 0.23 and 0.33 m/s, respectively, during land-based jumping when compared to the bare-breasted condition, but were ineffective at reducing breast kinematics during water-based jumping. Furthermore, the magnitude of the swimsuit superioinferior breast range of motion during water-based jumping was significantly greater than land-based jumping (0.13 m and 0.06 m), yet there were no significant differences in exercise induced breast pain, thus contradicting previously published relationships between these parameters on land. Furthermore, the addition of an external breast support garment was able to reduce breast kinematics on land but not in water, suggesting the swimsuit and sports bras were ineffective and improvements in swimwear breast support garments may help to reduce excessive breast motion during aqua aerobic jumping exercises. PMID- 26240649 TI - Exploratory Investigation of Impact Loads During the Forward Handspring Vault. AB - The purpose of this study was to examine kinematic and kinetic differences in low and high intensity hand support impact loads during a forward handspring vault. A high-speed video camera (500 Hz) and two portable force platforms (500 Hz) were installed on the surface of the vault table. Two-dimensional analyses were conducted on 24 forward handspring vaults performed by 12 senior level, junior Olympic program female gymnasts (16.9 +/-1.4 yr; body height 1.60 +/-0.1 m; body mass 56.7 +/-7.8 kg). Load intensities at impact with the vault table were classified as low (peak force < 0.8 * body weight) and high (peak force > 0.8 * body weight). These vaults were compared via crucial kinetic and kinematic variables using independent t-tests and Pearson correlations. Statistically significant (p < 0.001) differences were observed in peak force (t(24) = 4.75, ES = 3.37) and time to peak force (t(24) = 2.07, ES = 1.56). Statistically significant relationships between the loading rate and time to peak force were observed for high intensity loads. Peak force, time to peak force, and a shoulder angle at impact were identified as primary variables potentially involved in the determination of large repetitive loading rates on the forward handspring vault. PMID- 26240650 TI - Muscle Fatigue in the Three Heads of the Triceps Brachii During a Controlled Forceful Hand Grip Task with Full Elbow Extension Using Surface Electromyography. AB - The objective of the present study was to investigate the time to fatigue and compare the fatiguing condition among the three heads of the triceps brachii muscle using surface electromyography during an isometric contraction of a controlled forceful hand grip task with full elbow extension. Eighteen healthy subjects concurrently performed a single 90 s isometric contraction of a controlled forceful hand grip task and full elbow extension. Surface electromyographic signals from the lateral, long and medial heads of the triceps brachii muscle were recorded during the task for each subject. The changes in muscle activity among the three heads of triceps brachii were measured by the root mean square values for every 5 s period throughout the total contraction period. The root mean square values were then analysed to determine the fatiguing condition for the heads of triceps brachii muscle. Muscle fatigue in the long, lateral, and medial heads of the triceps brachii started at 40 s, 50 s, and 65 s during the prolonged contraction, respectively. The highest fatiguing rate was observed in the long head (slope = -2.863), followed by the medial head (slope = 2.412) and the lateral head (slope = -1.877) of the triceps brachii muscle. The results of the present study concurs with previous findings that the three heads of the triceps brachii muscle do not work as a single unit, and the fiber type/composition is different among the three heads. PMID- 26240651 TI - Nutritional Adaptations in Elite Soccer Referees: First Evidence and Perspectives. AB - Although the physiological cost of refereeing has been already studied in the literature, especially in soccer umpires, it remains unknown whether referees spontaneously adapt their energy intake during game days. Six national soccer referees completed 24-hour dietary recalls (assisted by the SU.VI.MAX copybook) during a control day (CON) and a day with a game (GAME). The stress level and hunger feelings were assessed using visual analogue scales. Total energy intake, energy derived from macronutrients and energy intake at each meal were analyzed using the Bilnuts nutrition software. Total daily energy intake was not significantly different between conditions (CON: 2270 +/- 535 vs. GAME: 2782 +/- 293). Energy derived from fat and protein was not different between conditions but the participants ingested more calories derived from carbohydrates during the GAME day (45.5 +/- 5.9% vs. 54.9 +/- 5.5%, respectively, p<0.05). The calories ingested during snacking were significantly increased during GAME compared with CON (p<0.05). The stress level was significantly higher during GAME and especially before the breakfast, lunch and snack (p<0.05). Hunger feeling was not different between conditions. Referring leads to nutritional adaptations in elite soccer umpires, who tend to increase their energy intake mainly during snacking, by increasing their carbohydrate consumption. PMID- 26240652 TI - The Relationship Between Foot and Pelvic Alignment While Standing. AB - A normal motion and segmental interrelationship has been determined as a significant factor in normal function. Yet, the relationship between distal segments and pelvic alignment needs further investigation. The aim of this study was to investigate the interrelationship between distal and proximal lower extremity segments while standing and during induced feet hyperpronation. Changes in alignment of the pelvis and lower extremities were measured at a gait laboratory using the VICON 612 computerized motion analysis system. Thirty-five healthy volunteer subjects were recruited. Four randomized repeated-measure standing modes were used: standing directly on the floor and then on three wedges angled at 10 degrees , 15 degrees and 20 degrees to induce bilateral hyperpronation for 20 seconds. A significant (p<0.05) bi-variate relationship was found between the anterior pelvic tilt and thigh internal rotation, in all four standing positions (.41<=r<=.46, in all p<0.014). A combined effect of rotational alignment between segments and the cumulative effect of foot hyperpronation on pelvic tilt revealed that only the shank significantly affected pelvic alignment, acting as a mediator between a foot and a thigh with the thigh having a crude significant effect on the pelvis. When internal rotation of the shank occurs, calcaneal eversion couples with thigh internal rotation and anterior pelvic tilt. It can be concluded that in response to induced hyperpronation, the shank is a pivotal segment in postural adjustment. PMID- 26240653 TI - Anthropometric Characteristics of Spanish Professional Basketball Players. AB - The study of elite basketball players' anthropometric characteristics alongside those of body composition contributes significantly to their profiling as professional athletes and plays an important role in the selection process, as these characteristics can have a significant impact on performance. In the current study, 110 professional basketball players from a series of Spanish professional Leagues (ACB, LEB and EBA) and youth level National Teams (U20 and U18) had their anthropometric profiles measured and compared to determine differences between them. Furthermore, all 110 players were divided into three different categories according to their playing position: guards, forwards and centres. The results obtained show no significant differences between players in different competitions in weight, height and the sum of skinfolds. Nonetheless, there were several differences related to body fat content (13.03% in ACB players and 10.52% in the lower categories and National Teams). There were also several differences found between the different playing positions amongst all playing levels in body mass (79.56 +/- 2.41, 91.04 +/- 1.51 and 104.56 +/- 1.73 kg), height (182.28 +/- 0.96, 195.65 +/- 1.00 and 204.08 +/- 0.67 cm), skinfold distribution and perimeters. However, there were no significant differences in body fat content between the different playing positions. The conclusions obtained from this study provide a better understanding to basketball specialists regarding the selection process of players at the elite level, especially on the transition from youth elite programs to men's elite leagues. PMID- 26240654 TI - Acute and Chronic Whole-Body Vibration Exercise does not Induce Health-Promoting Effects on The Blood Profile. AB - Whole-body vibration (WBV) exercise is an alternative, popular and easy exercise that can be followed by general public. Therefore, the aim of the present study was to investigate the influence of acute and chronic WBV exercise on health related parameters. Twenty-eight women were allocated into a control group (n=11, mean +/-SEM: age, 43.5 +/-1.5 yr; body mass, 66.1 +/-3.1 kg; height, 160.6 +/-1.5 cm) and a vibration group (n=17, mean +/-SEM: age, 44.0 +/-1.0 yr; body mass, 67.1 +/-2.2 kg; height, 162.5 +/-1.5 cm). After baseline assessments, participants of the experimental group performed WBV training 3 times/week for 8 weeks. Before and after the chronic WBV exercise, the participants of the vibration group performed one session of acute WBV exercise. Blood chemistry measurements (hematology, creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, C-reactive protein, glucose, insulin, triacylglycerols, total cholesterol, high-density lipoprotein cholesterol, low density lipoprotein cholesterol, apolipoprotein A1, apolipoprotein B and lipoprotein, thiobarbituric-acid reactive substances, protein carbonyls, total antioxidant capacity, uric acid, albumin and bilirubin) were assessed pre exercise and post-exercise at the first and eighth week of WBV exercise in both control and vibration groups. The results failed to support any effect of both acute and chronic WBV exercise on biochemical health-related parameters. However, it seems that WBV exercise is a safe way of training without a negative impact on muscle and liver functionality. PMID- 26240655 TI - The Relationship Between Intensity Indicators in Small-Sided Soccer Games. AB - The aim of the present study was to examine the relationship between different kinds of intensity indicators in small-sided soccer games. This descriptive correlational study included 14 semi-professional male soccer players (21.3 +/- 2.3 years, 174 +/- 4.0 cm, 73.4 +/- 5.1 kg) from the same team. The players were monitored by means of heart rate monitors and GPS devices during 27 small-sided games of nine different formats, yielding a total of 217 recordings. After each game the Borg scale was used to give a rate of perceived exertion (RPE). The internal load indicators were the mean heart rate relative to the individual maximum (%HRmean) and the RPE, while those for the external load were the player load, total distance covered, distance covered in two intensity ranges (>18 km.h 1 and >21 km.h-1), and frequency of effort (in the same two intensity ranges). There was a significant moderate correlation (r=0.506) between the two internal load measurements (%HRmean and RPE). Although there were significant correlations of different degrees between various external load measurements, only the player load was significantly correlated with the internal load indicators (r=0.331 with %HRmean and r=0.218 with RPE). During training programes of this kind, it is necessary to consider a range of intensity indicators so as to obtain complementary information. This will enable coaches to more accurately assess the load imposed on players and therefore optimize the training process. PMID- 26240656 TI - The Relative Age Effect in Spanish Female Soccer Players. Influence of the Competitive Level and a Playing Position. AB - The purposes of the study were to examine relative age effects (RAEs) in Spanish female soccer and to identify the influence of a playing position. The sample comprised all female players (n=4035) of five different competitive levels in the 2010-2013 seasons: First, Second and Third divisions (n=936, n=1711 and n=870, respectively), and National and Regional (n=232 and n=286, respectively) teams were included. Differences between the observed and expected birth-date distributions were tested based on data from the general Spanish population, using the chi-square statistic followed up by calculating odds ratios and 95% confidence intervals. Results revealed that the birth-date distributions of almost all groups of football players showed an overrepresentation of players born in the first quartile. Only in the lowest level was age distribution not significantly different from that of the general population. Moreover, the RAE risk progressively increased with a higher level of involvement. It was also observed that at some playing positions the birth-date distributions were significantly biased. That was the case for goalkeepers and defenders. It could be concluded that in the current structure of Spanish female soccer there is a relative age effect, probably due to the early processes of talent identification. PMID- 26240657 TI - Effects of Sled Towing on Peak Force, the Rate of Force Development and Sprint Performance During the Acceleration Phase. AB - Resisted sprint training is believed to increase strength specific to sprinting. Therefore, the knowledge of force output in these tasks is essential. The aim of this study was to analyze the effect of sled towing (10%, 15% and 20% of body mass (Bm)) on sprint performance and force production during the acceleration phase. Twenty-three young experienced sprinters (17 men and 6 women; men = 17.9 +/- 3.3 years, 1.79 +/- 0.06 m and 69.4 +/- 6.1 kg; women = 17.2 +/- 1.7 years, 1.65 +/- 0.04 m and 56.6 +/- 2.3 kg) performed four 30 m sprints from a crouch start. Sprint times in 20 and 30 m sprint, peak force (Fpeak), a peak rate of force development (RFDpeak) and time to RFD (TRFD) in first step were recorded. Repeated-measures ANOVA showed significant increases (p <= 0.001) in sprint times (20 and 30 m sprint) for each resisted condition as compared to the unloaded condition. The RFDpeak increased significantly when a load increased (3129.4 +/- 894.6 N.s-1, p <= 0.05 and 3892.4 +/- 1377.9 N.s-1, p <= 0.01). Otherwise, no significant increases were found in Fpeak and TRFD. The RFD determines the force that can be generated in the early phase of muscle contraction, and it has been considered a factor that influences performance of force-velocity tasks. The use of a load up to 20% Bm might provide a training stimulus in young sprinters to improve the RFDpeak during the sprint start, and thus, early acceleration. PMID- 26240658 TI - The Effect of the Number of Sets on Power Output for Different Loads. AB - There is much debate concerning the optimal load (OL) for power training. The purpose of this study was to investigate the effect of the number of sets performed for a given load on mean power output (Pmean). Fourteen physically active men performed 3 sets of 3 bench-press repetitions with 30, 40 and 50 kg. The highest mean power value (Pmax) across all loads and Pmean were compared when data were taken from the first set at each absolute load vs. from the best of three sets performed. Pmean increased from the first to the third set (from 5.99 +/- 0.81 to 6.16 +/- 0.96 W.kg(-1), p = 0.017), resulting in a main effect of the set number (p < 0.05). At the 30 kg load Pmean increased from the first to the third set (from 6.01 +/- 0.75 to 6.35 +/- 0.85 W.kg(-1); p < 0.01). No significant effect was observed at 40 and 50 kg loads (p > 0.05). Pmax and velocity were significantly affected by the method employed to determine Pmean at each load (p < 0.05). These results show a positive effect of the number of sets per load on Pmean, affecting Pmax, OL and potentially power training prescription. PMID- 26240659 TI - The Functional Test for Agility Performance is a Reliable Quick Decision-Making Test for Skilled Water Polo Players. AB - The reliability of the Functional Test for Agility Performance has only been evaluated in water polo players in a small group of novice athletes. Thus, the aim of this study was to evaluate the reliability of the Functional Test for Agility Performance in skilled water polo players. Forty-two athletes (17.81 +/- 3.24 years old) with a minimum of 5 years of competitive experience (7.05 +/- 2.84 years) and playing at the national or international level were evaluated. The Functional Test for Agility Performance is characterized as a specific open decision-making test where a tested player moves as quickly as possible in accordance to a pass made by another player. The time spent in the test was measured by two experienced coaches. Descriptive statistics, repeated measures analysis of variance (ANOVA), 95% limit of agreement (LOA), intraclass correlation coefficient (ICC) and standard error of measurements (SEM) were used for data analysis. Athletes completed the Functional Test for Agility Performance in 4.15 0.47 s. The ICC value was 0.87 (95% IC = 0.80-0.92). The SEM varied between 0.24 and 0.38 s. The LOA was 1.20 s and the CV average considering each individual trial was 6%. The Functional Test for Agility Performance was shown to be a reliable quick decision-making test for skilled water polo players. PMID- 26240661 TI - Effects of a Low-Load Gluteal Warm-Up on Explosive Jump Performance. AB - The purpose of this study was to investigate the effects of a low-load gluteal warm-up protocol on countermovement and squat jump performance. Research by Crow et al. (2012) found that a low-load gluteal warm-up could be effective in enhancing peak power output during a countermovement jump. Eleven subjects performed countermovement and squat jumps before and after the gluteal warm-up protocol. Both jumps were examined in separate testing sessions and performed 30 seconds, and 2, 4, 6 & 8 minutes post warm-up. Height jumped and peak ground reaction force were the dependent variables examined in both jumps, with 6 additional variables related to fast force production being examined in the squat jump only. All jumps were performed on a force platform (AMTI OR6-5). Repeated measures analysis of variance found a number of significant differences (p <= 0.05) between baseline and post warm-up scores. Height jumped decreased significantly in both jumps at all rest intervals excluding 8 minutes. Improvement was seen in 7 of the 8 recorded SJ variables at the 8 minute interval. Five of these improvements were deemed statistically significant, namely time to peak GRF (43.0%), and time to the maximum rate of force development (65.7%) significantly decreased, while starting strength (63.4%), change of force in first 100 ms of contraction (49.1%) and speed strength (43.6%) significantly increased. The results indicate that a gluteal warm-up can enhance force production in squat jumps performed after 8 minutes recovery. Future research in this area should include additional warm-up intervention groups for comparative reasons. PMID- 26240662 TI - Connecting Athletes' Self-Perceptions and Metaperceptions of Competence: a Structural Equation Modeling Approach. AB - This study explored the relationships between athletes' competence self perceptions and metaperceptions. Two hundred and fifty one student-athletes (14.26 +/- 1.89 years), members of twenty different teams (basketball, soccer) completed a questionnaire which included the Perception of Success Questionnaire, the Competence subscale of the Intrinsic Motivation Inventory, and modified versions of both questionnaires to assess athletes' metaperceptions. Structural equation modelling analysis revealed that athletes' task and ego metaperceptions positively predicted task and ego self-perceptions, respectively. Competence metaperceptions were strong predictors of competence self-perceptions, confirming the atypical metaperception formation in outcome-dependent contexts such as sport. Task and ego metaperceptions positively predicted athletes' competence metaperceptions. How coaches value their athletes' competence is more influential on what the athletes think of themselves than their own self-perceptions. Athletes' ego and task metaperceptions influenced their competence metaperceptions (how coaches rate their competence). Therefore, athletes build their competence metaperceptions using all information available from their coaches. Finally, only task-self perfections positively predicted athletes' competence self-perceptions. PMID- 26240660 TI - The Effect of a Simulated Basketball Game on Players' Sprint and Jump Performance, Temperature and Muscle Damage. AB - Despite extensive data regarding the demands of playing basketball, the relative importance of factors that cause fatigue and muscle potentiation has been explored only tentatively and remains unclear. The aim of this experimental field study was to assess changes in leg muscle power and relate these changes to body temperature modifications and indices of exercise-induced muscle damage in response to a simulated basketball game. College-level male basketball players (n=10) were divided into two teams to play a simulated basketball game. Ten-meter sprint and vertical counter-movement jump tests, core body temperature and creatine-kinase activity were measured within 48 h after the game. The participants' body temperatures increased after a warm-up (1.9%, p<0.05), continued to increase throughout the game, and reached 39.4 +/- 0.4oC after the fourth quarter (p<0.05). The increase in temperature during the warm-up was accompanied by an improvement in the 10-meter sprint time (5.5%, p<0.05) and jump height (3.8%, p<0.05). The players were able to maintain leg power up to the fourth quarter, i.e., during the major part of the basketball game. There was a significant increase in creatine-kinase at 24 h (>200%, p<0.05) and 48 h (>30%, p<0.05) after the game, indicating damage to the players' muscles. The basketball players' sprint and jump performance appear to be at least in part associated with body temperature changes, which might contribute to counteract fatigue during the larger part of a basketball game. PMID- 26240663 TI - An Examination of Mixed Martial Arts Spectators' Motives and their Sports Media Consumption in Poland. AB - The study attempted to analyse the concept of spectators' motives at mixed martial arts (MMA) events in Poland. In addition, we investigated the relation between motives and sports media consumption. The sample consisted of 273 people attending three similar, regional MMA events. Exploratory factor analysis was used to refine the structure of motives. Confirmatory factor analysis showed a reasonable fit of the obtained model (RMSEA = 0.41). Using ANOVA we found three significant differences in assessment of motives, based on gender. The factor of aesthetics and knowledge was ranked the highest for men and women. Men rated drama and violence, while women perceived socializing and crowd experience, and drama, as the following factors. Path analysis indicated that these motives explained 56% of variance in media consumption for men and 57% for women. The findings showed that the motive of vicarious achievement was the main predictor of media consumption for men, while aesthetics and knowledge were the key predictors for women. The results and ideas for further research are discussed. PMID- 26240664 TI - Temperamental Traits Versus Individual Physical Fitness Components and a Physical Activity Level. AB - The main aim of the study was to examine whether relationships exist between particular temperamental traits within the concept of Regulative Theory of Temperament and components of physical fitness, that are most crucial for success in sport. The research involved 108 individuals including 63 men (age 21.1 +/- 1.6 yrs) and 45 women (age 20.7 +/- 1.3 yrs). None of the respondents were professionally engaged in sport. Components of physical fitness included: aerobic capacity, strength, agility, static-dynamic balance and reaction time. The respondents also completed two questionnaires: the Formal Characteristics of Behaviour - Temperament Inventory and the International Physical Activity Questionnaire. The results indicate that the temperamental traits had average to poor correlations with the components of physical fitness, whereas more statistically significant correlations were observed in women. Negative correlations were obtained between emotional reactivity and agility, which was a result confirmed by previous research. All temperamental traits related with the energetic aspects of behaviour correlated with simple reaction time in women. Physical activity and aerobic capacity did not correlate with any of the studied traits. The results do not allow for any general conclusions to be drawn, but can serve as a reference point for future research on temperamental traits as delineated by Regulative Theory of Temperament and their relationship with the components of physical fitness. PMID- 26240665 TI - The Functional Classification and Field Test Performance in Wheelchair Basketball Players. AB - Wheelchair basketball players are classified in four classes based on the International Wheelchair Basketball Federation (IWBF) system of competition. Thus, the aim of the study was to ascertain if the IWBF classification, the type of injury and the wheelchair experience were related to different performance field-based tests. Thirteen basketball players undertook anthropometric measurements and performance tests (hand dynamometry, 5 m and 20 m sprints, 5 m and 20 m sprints with a ball, a T-test, a Pick-up test, a modified 10 m Yo-Yo intermittent recovery test, a maximal pass and a medicine ball throw). The IWBF class was correlated (p<0.05) to the hand dynamometry (r= 0.84), the maximal pass (r=0.67) and the medicine ball throw (r= 0.67). Whereas the years of dependence on the wheelchair were correlated to the velocity (p<0.01): 5 m (r= -0.80) and 20 m (r= -0.77) and agility tests (r= -0.77, p<0.01). Also, the 20 m sprint with a ball (r= 0.68) and the T-test (r= -0.57) correlated (p<0.05) with the experience in playing wheelchair basketball. Therefore, in this team the correlations of the performance variables differed when they were related to the disability class, the years of dependence on the wheelchair and the experience in playing wheelchair basketball. These results should be taken into account by the technical staff and coaches of the teams when assessing performance of wheelchair basketball players. PMID- 26240666 TI - The Efficiency of a Visual Skills Training Program on Visual Search Performance. AB - In this study, we conducted an experiment in which we analyzed the possibilities to develop visual skills by specifically targeted training of visual search. The aim of our study was to investigate whether, for how long and to what extent a training program for visual functions could improve visual search. The study involved 24 healthy students from the Szczecin University who were divided into two groups: experimental (12) and control (12). In addition to regular sports and recreational activities of the curriculum, the subjects of the experimental group also participated in 8-week long training with visual functions, 3 times a week for 45 min. The Signal Test of the Vienna Test System was performed four times: before entering the study, after first 4 weeks of the experiment, immediately after its completion and 4 weeks after the study terminated. The results of this experiment proved that an 8-week long perceptual training program significantly differentiated the plot of visual detecting time. For the visual detecting time changes, the first factor, Group, was significant as a main effect (F(1,22)=6.49, p<0.05) as well as the second factor, Training (F(3,66)=5.06, p<0.01). The interaction between the two factors (Group vs. Training) of perceptual training was F(3,66)=6.82 (p<0.001). Similarly, for the number of correct reactions, there was a main effect of a Group factor (F(1,22)=23.40, p<0.001), a main effect of a Training factor (F(3,66)=11.60, p<0.001) and a significant interaction between factors (Group vs. Training) (F(3,66)=10.33, p<0.001). Our study suggests that 8 week training of visual functions can improve visual search performance. PMID- 26240667 TI - Self-Determination and Physical Exercise Adherence in the Contexts of Fitness Academies and Personal Training. AB - This research aimed to analyze the validity of the relations hypothesized by the theory of self-determination in predicting adherence to physical exercise in fitness academy users and subjects following personal training. A total of 588 persons from Pelotas / RS / Brazil (405 gym users and 183 subjects following personal training) completed the Portuguese version of the three questionnaires, i.e. the Perceived Autonomy Support Climate Exercise Questionnaire, Basic Psychological Needs in the Exercise Scale and Behavioral Regulation in the Exercise Questionnaire -2. The results support the factorial structure of the questionnaires used in this sample. There was a significant multivariate effect of context on self-determination for physical exercise training [Wilks' lambda = 0.934, F (10, 576.000) = 4.03, p < 0.001, eta(2) = 0.01]. The hypothesized structural equation model, which considered the self-determination theory, showed a good fit to the data (S-B chi(2) = 234.703; p= .001; df = 52; chi(2)/df = 4.514; SRMS = .049; NNFI = .906; CFI = .926; RMSEA = .077; RMSEA 90% CI = .067 - .088). However, in the comparative analysis, the perception of autonomy support, relatedness and competence were significantly higher in the context of personal training, while the amotivation and external regulation were significantly higher in the context of fitness academies. PMID- 26240668 TI - Game-Based Approaches' Pedagogical Principles: Exploring Task Constraints in Youth Soccer. AB - This study tested the use of two pedagogical principles of Game-based approaches, representation and exaggeration, in the context of game performance of U10 soccer players. Twenty-one players participated in two 3 vs. 3 small-sided games. The first small-sided game was modified by representation. The second small-sided game was modified by enhancing the penetration of the defense tactical problem for invasion games. Decision-making and execution were assessed using the Game Performance Evaluation Tool. No significant differences were observed between games in the number of decision-making units related to keeping possession, nor in those related to penetrating the defense. No significant differences were observed in any execution ability (ball control, passing, dribbling and get free movements). The findings suggested that both games could provide similar degeneracy processes to the players for skill acquisition (specific and contextualized task constraints in which they could develop their game performance and the capability to achieve different outcomes in varying contexts). Probably both games had similar learner-environment dynamics leading players to develop their capabilities for adapting their behaviours to the changing performance situations. More research is necessary, from the ecological dynamics point of view, to determine how we should use small-sided games in Game based approaches. PMID- 26240669 TI - Physiological Responses During Multiplay Exergaming in Young Adult Males are Game Dependent. AB - Regular moderate-intensity exercise provides health benefits. The aim of this study was to examine whether the selected exercise intensity and physiological responses during exergaming in a single and multiplayer mode in the same physical space were game-dependent. Ten males (mean +/-SD, age: 23 +/-5 years, body mass: 84.2 +/-15.6 kg, body height: 180 +/-7 cm, body mass index: 26.0 +/-4.0 kg.m(-2)) played the games Kinect football, boxing and track & field (3 * ~10 min, ~ 2 min rest periods) in similar time sequence in two sessions. Physiological responses were measured with the portable Cosmed K4b(2) pulmonary gas exchange system. Single play demands were used to match with a competitive opponent in a multiplay mode. A within-subjects crossover design was used with one-way ANOVA and a post hoc t-test for analysis (p<0.05). Minute ventilation, oxygen uptake and the heart rate were at least 18% higher during a multiplayer mode for Kinect football and boxing but not for track & field. Energy expenditure was 21% higher during multiplay football. Single play track & field had higher metabolic equivalent than single play football (5.7 +/-1.6, range: 3.2-8.6 vs 4.1 +/-1.0, range: 3.0 6.1, p<0.05). Exergaming in a multiplayer mode can provide higher physiological demands but the effects are game-dependent. It seems that exergaming with low intensity in a multiplayer mode may provide a greater physical challenge for participants than in a single play mode but may not consistently provide sufficient intensity to acquire health benefits when played regularly as part of a programme to promote and maintain health in young adults. PMID- 26240670 TI - Timing of Tympanostomy Tube Placement and Efficacy of Palatoplasty Technique on the Resolution of Chronic Otitis Media: A Cross-sectional Analysis. AB - BACKGROUND: Chronic otitis media with effusion is a persistent complication essentially universal in children with cleft palate. The prevalence of chronic otitis media with effusion is hypothesized to be a result of Eustachian tube dysfunction secondary to the anomalous insertion of the palatal musculature. This study was designed to evaluate the timing of tympanostomy tube placement and the effect of primary palatoplasty technique on the recovery of Eustachian tube function and resolution of chronic otitis media with effusion. METHODS: We performed a retrospective, cross-sectional analysis of the previous 99 consecutive patients who underwent a palatoplasty at our institution. Variables included timing of initial tympanostomy tube placement, palatoplasty technique, cleft type, and gender. These were then evaluated to assess their impact on the resolution of chronic otitis media with effusion. Resolution was established as an inverse function of the number of tympanostomy tubes placed in correlation with available audiometric/tympanographic data. For all models, a generalized linear mixed model was applied using a Poisson distribution and a log-link function where the outcome variable was the total number of tympanostomy tubes. For all tests, a P = .05 level of significance was used. RESULTS: Of 99 palatoplasties performed, 94 patients were included in the study. Ninety-one percent of patients had documented chronic otitis media with effusion at the time of palatoplasty. Forty-four percent underwent straight-line repair with aggressive intravelar veloplasty, 36% had Furlow double z-plasty, 20% had straight-line repair without intravelar veloplasty. There was a statistically significant difference (F 2,83 = 5.36, P = .0065) between the 3 types of repair. The mean number of tubes placed was 0.6000 +/- 0.1225, 0.8519 +/- 0.1776, and 1.4737 +/- 0.2785 for intravelar veloplasty, Furlow double z-plasty, and straight line without intravelar veloplasty, respectively . With regard to the timing of tympanostomy tube placement, there was a trend toward statistical significant (F 2,83 = 3.02, P = .0540) in the mean number of tube insertions was 1.4286 +/- 0.4518, 0.6964 +/- 0.1115, and 1.1304 +/- 0.2217 when the initial set was placed before palatoplasty, at the time of palatoplasty, and after palatoplasty, respectively. CONCLUSIONS: Despite its inherent limitations, this study suggests that palatal musculature reconstruction via intravelar veloplasty or reorientation via Furlow double z-plasty may improve Eustachian tube function and lower the need for tympanostomy tubes in this population. In comparison with other time points, patients who underwent initial tympanostomy tube placement at the time of palatoplasty trended toward improved chronic otitis media with effusion. PMID- 26240671 TI - Safety Profile of Amnion-Derived Cellular Cytokine Solution (ACCS) Following Topical Skin Application in Patients Receiving Breast Radiotherapy. AB - OBJECTIVE: To establish a safety profile for amnion-derived cellular cytokine solution following topical application in patients undergoing whole breast radiotherapy for breast cancer. MATERIALS AND METHODS: Twenty female patients with early-stage breast cancer were enrolled in 2 separate cohorts of an institutional review board-approved phase I protocol. Cohort 1 consisted of 10 patients who received topical amnion-derived cellular cytokine solution to the breast immediately following the first 10 fractions of whole breast radiotherapy. Cohort 2 consisted of 10 additional patients who fit the same criteria as the initial cohort but received topical amnion-derived cellular cytokine solution following the development of at least grade I breast erythema. Blood samples were tested for the presence of proteins in amnion-derived cellular cytokine solution as well as routine hematologic functions. RESULTS: Amnion-derived cellular cytokine solution did not induce overproduction of any cytokines sampled, and there was no evidence of "cytokine storm." It also showed no significant absorption systemically following topical delivery. No patients developed an adverse event. There were no patterns of changes in vital signs or clinical laboratory tests that were related to the treatment regimen. CONCLUSION: In this safety trial, the topical application of amnion-derived cellular cytokine solution in both intact and denuded, irradiated skin was found to be safe, and showed no evidence of systemic absorption. No cosmetic changes were identified long term. Patient blood chemistry was not adversely affected, indicating the absence of an anaphylactic response and no evidence "cytokine storm" was identified. Amnion-derived cellular cytokine solution is safe to use topically in clinical protocols. PMID- 26240672 TI - The Real Cost of "Cosmetic Tourism" Cost Analysis Study of "Cosmetic Tourism" Complications Presenting to a Public Hospital. AB - "Cosmetic Tourism," the process of traveling overseas for cosmetic procedures, is an expanding global phenomenon. The model of care by which these services are delivered can limit perioperative assessment and postoperative follow-up. Our aim was to establish the number and type of complications being treated by a secondary referral hospital resulting from "cosmetic tourism" and the cost that has been incurred by the hospital in a 1-year period. Retrospective cost analysis and chart review of patients admitted to the hospital between the financial year of 2012 and 2013 were performed. Twelve "cosmetic tourism" patients presented to the hospital, requiring admission during the study period. Breast augmentation was the most common procedure and infected prosthesis was the most common complication (n = 4). Complications ranged from infection, pulmonary embolism to penile necrosis. The average cost of treating these patients was $AUD 12 597.71. The overall financial burden of the complication to the hospital was AUD$151 172.52. The "cosmetic tourism" model of care appears to be, in some cases, suboptimal for patients and their regional hospitals. In the cases presented in this study, it appears that care falls on the patient local hospital and home country to deal with the complications from their surgery abroad. This incurs a financial cost to that hospital in addition to redirecting medical resources that would otherwise be utilized for treating noncosmetic complications, without any remuneration to the local provider. PMID- 26240673 TI - Inferior Trapezius Myocutaneous Flap as Salvage Procedure for Large Posterior Scalp Defect. PMID- 26240674 TI - Persistent Wrist Pain. PMID- 26240675 TI - FOCUS ON PSORIASIS: A REPORT FROM THE 73RD ANNUAL MEETING OF THE AMERICAN ACADEMY OF DERMATOLOGYPsoriasis-related topics included targeted therapies, safety of biologies, comorbidities. PMID- 26240676 TI - PSORIASIS: FROM GENE TO CLINIC CONGRESS REPORTInternational conference showcases cutting-edge psoriasis research. PMID- 26240677 TI - Returns to Treatment in the Formal Health Care Sector: Evidence from Tanzania. AB - Improving access to the formal health care sector is a primary public health goal in many low-income countries. But the returns to this access are unclear, given that the quality of care at public health facilities is often considered inadequate. We exploit temporal and geographic variation in the cost of traveling to formal sector health facilities to show that treatment at these facilities improves short-term health outcomes for acutely ill children in Tanzania. Our results suggest that these improvements are driven in part by more timely receipt of and better adherence to antimalarial treatment. PMID- 26240678 TI - Enhancing endothelial progenitor cell for clinical use. AB - Circulating endothelial progenitor cells (EPCs) have been demonstrated to correlate negatively with vascular endothelial dysfunction and cardiovascular risk factors. However, translation of basic research into the clinical practice has been limited by the lack of unambiguous and consistent definitions of EPCs and reduced EPC cell number and function in subjects requiring them for clinical use. This article critically reviews the definition of EPCs based on commonly used protocols, their value as a biomarker of cardiovascular risk factor in subjects with cardiovascular disease, and strategies to enhance EPCs for treatment of ischemic diseases. PMID- 26240680 TI - Stem cell autotomy and niche interaction in different systems. AB - The best known cases of cell autotomy are the formation of erythrocytes and thrombocytes (platelets) from progenitor cells that reside in special niches. Recently, autotomy of stem cells and its enigmatic interaction with the niche has been reported from male germline stem cells (GSCs) in several insect species. First described in lepidopterans, the silkmoth, followed by the gipsy moth and consecutively in hemipterans, foremost the milkweed bug. In both, moths and the milkweed bug, GSCs form finger-like projections toward the niche, the apical cells (homologs of the hub cells in Drosophila). Whereas in the milkweed bug the projection terminals remain at the surface of the niche cells, in the gipsy moth they protrude deeply into the singular niche cell. In both cases, the projections undergo serial retrograde fragmentation with progressing signs of autophagy. In the gipsy moth, the autotomized vesicles are phagocytized and digested by the niche cell. In the milkweed bug the autotomized vesicles accumulate at the niche surface and disintegrate. Autotomy and sprouting of new projections appears to occur continuously. The significance of the GSC-niche interactions, however, remains enigmatic. Our concept on the signaling relationship between stem cell niche in general and GSC and niche (hub cells and cyst stem cells) in particular has been greatly shaped by Drosophila melanogaster. In comparing the interactions of GSCs with their niche in Drosophila with those in species exhibiting GSC autotomy it is obvious that additional or alternative modes of stem cell-niche communication exist. Thus, essential signaling pathways, including niche-stem cell adhesion (E-cadherin) and the direction of asymmetrical GSC division - as they were found in Drosophila - can hardly be translated into the systems where GSC autotomy was reported. It is shown here that the serial autotomy of GSC projections shows remarkable similarities with Wallerian axonal destruction, developmental axon pruning and dying-back degeneration in neurodegenerative diseases. Especially the hypothesis of an existing evolutionary conserved "autodestruction program" in axons that might also be active in GSC projections appears attractive. Investigations on the underlying signaling pathways have to be carried out. There are two other well known cases of programmed cell autotomy: the enucleation of erythroblasts in the process of erythrocyte maturation and the segregation of thousands of thrombocytes (platelets) from one megakaryocyte. Both progenitor cell types - erythroblasts and megakaryocytes - are associated with a niche in the bone marrow, erythroblasts with a macrophage, which they surround, and the megakaryocytes with the endothelial cells of sinusoids and their extracellular matrix. Although the regulatory mechanisms may be specific in each case, there is one aspect that connects all described processes of programmed cell autotomy and neuronal autodestruction: apoptotic pathways play always a prominent role. Studies on the role of male GSC autotomy in stem cell-niche interaction have just started but are expected to reveal hitherto unknown ways of signal exchange. Spermatogenesis in mammals advance our understanding of insect spermatogenesis. Mammal and insect spermatogenesis share some broad principles, but a comparison of the signaling pathways is difficult. We have intimate knowledge from Drosophila, but of almost no other insect, and we have only limited knowledge from mammals. The discovery of stem cell autotomy as part of the interaction with the niche promises new general insights into the complicated stem cell-niche interdependence. PMID- 26240679 TI - Importance of being Nernst: Synaptic activity and functional relevance in stem cell-derived neurons. AB - Functional synaptogenesis and network emergence are signature endpoints of neurogenesis. These behaviors provide higher-order confirmation that biochemical and cellular processes necessary for neurotransmitter release, post-synaptic detection and network propagation of neuronal activity have been properly expressed and coordinated among cells. The development of synaptic neurotransmission can therefore be considered a defining property of neurons. Although dissociated primary neuron cultures readily form functioning synapses and network behaviors in vitro, continuously cultured neurogenic cell lines have historically failed to meet these criteria. Therefore, in vitro-derived neuron models that develop synaptic transmission are critically needed for a wide array of studies, including molecular neuroscience, developmental neurogenesis, disease research and neurotoxicology. Over the last decade, neurons derived from various stem cell lines have shown varying ability to develop into functionally mature neurons. In this review, we will discuss the neurogenic potential of various stem cells populations, addressing strengths and weaknesses of each, with particular attention to the emergence of functional behaviors. We will propose methods to functionally characterize new stem cell-derived neuron (SCN) platforms to improve their reliability as physiological relevant models. Finally, we will review how synaptically active SCNs can be applied to accelerate research in a variety of areas. Ultimately, emphasizing the critical importance of synaptic activity and network responses as a marker of neuronal maturation is anticipated to result in in vitro findings that better translate to efficacious clinical treatments. PMID- 26240681 TI - New insights into the epigenetic control of satellite cells. AB - Epigenetics finely tunes gene expression at a functional level without modifying the DNA sequence, thereby contributing to the complexity of genomic regulation. Satellite cells (SCs) are adult muscle stem cells that are important for skeletal post-natal muscle growth, homeostasis and repair. The understanding of the epigenome of SCs at different stages and of the multiple layers of the post transcriptional regulation of gene expression is constantly expanding. Dynamic interactions between different epigenetic mechanisms regulate the appropriate timing of muscle-specific gene expression and influence the lineage fate of SCs. In this review, we report and discuss the recent literature about the epigenetic control of SCs during the myogenic process from activation to proliferation and from their commitment to a muscle cell fate to their differentiation and fusion to myotubes. We describe how the coordinated activities of the histone methyltransferase families Polycomb group (PcG), which represses the expression of developmentally regulated genes, and Trithorax group, which antagonizes the repressive activity of the PcG, regulate myogenesis by restricting gene expression in a time-dependent manner during each step of the process. We discuss how histone acetylation and deacetylation occurs in specific loci throughout SC differentiation to enable the time-dependent transcription of specific genes. Moreover, we describe the multiple roles of microRNA, an additional epigenetic mechanism, in regulating gene expression in SCs, by repressing or enhancing gene transcription or translation during each step of myogenesis. The importance of these epigenetic pathways in modulating SC activation and differentiation renders them as promising targets for disease interventions. Understanding the most recent findings regarding the epigenetic mechanisms that regulate SC behavior is useful from the perspective of pharmacological manipulation for improving muscle regeneration and for promoting muscle homeostasis under pathological conditions. PMID- 26240682 TI - Evaluation of biodegradable electric conductive tube-guides and mesenchymal stem cells. AB - AIM: To study the therapeutic effect of three tube-guides with electrical conductivity associated to mesenchymal stem cells (MSCs) on neuro-muscular regeneration after neurotmesis. METHODS: Rats with 10-mm gap nerve injury were tested using polyvinyl alcohol (PVA), PVA-carbon nanotubes (CNTs) and MSCs, and PVA-polypyrrole (PPy). The regenerated nerves and tibialis anterior muscles were processed for stereological studies after 20 wk. The functional recovery was assessed serially for gait biomechanical analysis, by extensor postural thrust, sciatic functional index and static sciatic functional index (SSI), and by withdrawal reflex latency (WRL). In vitro studies included cytocompatibility, flow cytometry, reverse transcriptase polymerase chain reaction and karyotype analysis of the MSCs. Histopathology of lung, liver, kidneys, and regional lymph nodes ensured the biomaterials biocompatibility. RESULTS: SSI remained negative throughout and independently from treatment. Differences between treted groups in the severity of changes in WRL existed, showing a faster regeneration for PVA CNTs-MSCs (P < 0.05). At toe-off, less acute ankle joint angles were seen for PVA CNTs-MSCs group (P = 0.051) suggesting improved ankle muscles function during the push off phase of the gait cycle. In PVA-PPy and PVA-CNTs groups, there was a 25% and 42% increase of average fiber area and a 13% and 21% increase of the "minimal Feret's diameter" respectively. Stereological analysis disclosed a significantly (P < 0.05) increased myelin thickness (M), ratio myelin thickness/axon diameter (M/d) and ratio axon diameter/fiber diameter (d/D; g-ratio) in PVA-CNT-MSCs group (P < 0.05). CONCLUSION: Results revealed that treatment with MSCs and PVA-CNTs tube-guides induced better nerve fiber regeneration. Functional and kinematics analysis revealed positive synergistic effects brought by MSCs and PVA-CNTs. The PVA-CNTs and PVA-PPy are promising scaffolds with electric conductive properties, bio- and cytocompatible that might prevent the secondary neurogenic muscular atrophy by improving the reestablishment of the neuro-muscular junction. PMID- 26240684 TI - Methods and outcomes of screening for pancreatic adenocarcinoma in high-risk individuals. AB - Pancreatic ductal adenocarcinoma (PDAC) is a lethal neoplasia, for which secondary prevention (i.e., screening) is advisable for high-risk individuals with "familiar pancreatic cancer" and with other specific genetic syndromes (Peutz-Jeghers, p16, BRCA2, PALB and mismatch repair gene mutation carriers). There is limited evidence regarding the accuracy of screening tests, their acceptability, costs and availability, and agreement on whom to treat. Successful target of screening are small resectable PDAC, intraductal papillary mucinous neoplasms with high-grade dysplasia and advanced pancreatic intraepithelial neoplasia. Both magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) are employed for screening, and the overall yield for pre-malignant or malignant pancreatic lesions is of about 20% with EUS and 14% with MRI/magnetic resonance colangiopancreatography. EUS performs better for solid and MRI for cystic lesions. However, only 2% of these detected lesions can be considered a successful target, and there are insufficient data demonstrating that resection of benign or low grade lesions improves survival. Many patients in the published studies therefore seemed to have received an overtreatment by undergoing surgery. It is crucial to better stratify the risk of malignancy individually, and to better define optimal screening intervals and methods either with computerized tools or molecular biomarkers, possibly in large multicentre studies. At the moment, screening should be carefully performed within research protocols at experienced centres, offering involved individuals medical and psychological advice. PMID- 26240683 TI - Mesenchymal stem cells in maxillary sinus augmentation: A systematic review with meta-analysis. AB - AIM: To investigate the effectiveness of mesenchymal stem cells (MSCs) in maxillary sinus augmentation (MSA), with various scaffold materials. METHODS: MEDLINE, EMBASE and SCOPUS were searched using keywords such as sinus graft, MSA, maxillary sinus lift, sinus floor elevation, MSC and cell-based, in different combinations. The searches included full text articles written in English, published over a 10-year period (2004-2014). Inclusion criteria were clinical/radiographic and histologic/ histomorphometric studies in humans and animals, on the use of MSCs in MSA. Meta-analysis was performed only for experimental studies (randomized controlled trials and controlled trials) involving MSA, with an outcome measurement of histologic evaluation with histomorphometric analysis reported. Mean and standard deviation values of newly formed bone from each study were used, and weighted mean values were assessed to account for the difference in the number of subjects among the different studies. To compare the results between the test and the control groups, the differences of regenerated bone in mean and 95% confidence intervals were calculated. RESULTS: Thirty-nine studies (18 animal studies and 21 human studies) published over a 10-year period (between 2004 and 2014) were considered to be eligible for inclusion in the present literature review. These studies demonstrated considerable variation with respect to study type, study design, follow-up, and results. Meta-analysis was performed on 9 studies (7 animal studies and 2 human studies). The weighted mean difference estimate from a random-effect model was 9.5% (95%CI: 3.6%-15.4%), suggesting a positive effect of stem cells on bone regeneration. Heterogeneity was measured by the I (2) index. The formal test confirmed the presence of substantial heterogeneity (I (2) = 83%, P < 0.0001). In attempt to explain the substantial heterogeneity observed, we considered a meta regression model with publication year, support type (animal vs humans) and follow-up length (8 or 12 wk) as covariates. After adding publication year, support type and follow-up length to the meta-regression model, heterogeneity was no longer significant (I (2) = 33%, P = 0.25). CONCLUSION: Several studies have demonstrated the potential for cell-based approaches in MSA; further clinical trials are needed to confirm these results. PMID- 26240685 TI - Staple-line leak after sleve gastrectomy in obese patients: A hot topic in bariatric surgery. AB - Laparoscopic sleeve gastrectomy is a surgical procedure that is being increasingly performed on obese patients. Among its complications, leaks are the most serious and life threatening. The placement of esophageal, covered, self expandable metal stents in these cases has been performed by many authors but reports on the outcome of this procedure are limited and the technical aspects are not well defined. Stent migration is the main complication of the procedure and poses a challenge to the surgeon, with a limited number of options. Here we evaluate the technical and clinical outcome of a new, dedicated, self-expanding metal stent, comparing the advantages of this stent to those traditionally used to treat staple-line leak after sleeve gastrectomy. While published data are limited, they seem support the use of this kind of new stent as the best option for the stenting treatment of a staple-line leak after sleeve gastrectomy, over other kinds of stents. Further studies based on larger series are needed to better evaluate patient outcome. PMID- 26240686 TI - Endoscopic therapy for weight loss: Gastroplasty, duodenal sleeves, intragastric balloons, and aspiration. AB - A new paradigm in the treatment of obesity and metabolic disease is developing. The global obesity epidemic continues to expand despite the availability of diet and lifestyle counseling, pharmacologic therapy, and weight loss surgery. Endoscopic procedures have the potential to bridge the gap between medical therapy and surgery. Current primary endoscopic bariatric therapies can be classified as restrictive, bypass, space-occupying, or aspiration therapy. Restrictive procedures include the USGI Primary Obesity Surgery Endolumenal procedure, endoscopic sleeve gastroplasty using Apollo OverStitch, TransOral GAstroplasty, gastric volume reduction using the ACE stapler, and insertion of the TERIS restrictive device. Intestinal bypass has been reported using the EndoBarrier duodenal-jejunal bypass liner. A number of space-occupying devices have been studied or are in use, including intragastric balloons (Orbera, Reshape Duo, Heliosphere BAG, Obalon), Transpyloric Shuttle, and SatiSphere. The AspireAssist aspiration system has demonstrated efficacy. Finally, endoscopic revision of gastric bypass to address weight regain has been studied using Apollo OverStitch, the USGI Incisionless Operating Platform Revision Obesity Surgery Endolumenal procedure, Stomaphyx, and endoscopic sclerotherapy. Endoscopic therapies for weight loss are potentially reversible, repeatable, less invasive, and lower cost than various medical and surgical alternatives. Given the variety of devices under development, in clinical trials, and currently in use, patients will have multiple endoscopic options with greater efficacy than medical therapy, and with lower invasiveness and greater accessibility than surgery. PMID- 26240687 TI - Serrated polyps of the colon and rectum: Endoscopic features including image enhanced endoscopy. AB - In this review, I outline the characteristic endoscopic findings of serrated lesions of the colorectum based on image enhanced endoscopy (IEE). Histopathologically, lesions with serrated structures are typically classified into the following three types based: hyperplastic polyps (HPs), traditional serrated adenomas (TSAs), and sessile serrated adenoma/polyps (SSA/Ps). Both HP and SSA/P often present as dark-green colors on auto fluorescence imaging (AFI) colonoscopy that are similar to the normal surrounding mucosa. In contrast, TSAs often have elevated shapes and present as magenta colors that are similar to the tubular adenomas. The superficial type of TSA also includes many lesions that present as magenta colors. When SSA/Ps are associated with cytological dysplasia, many lesions present with magenta colors, whereas lesions that are not associated with cytological dysplasia present with dark-green colors. When observed via narrow band imaging (NBI), many SSA/P include lesions with strong mucous adhesions. Because these lesions are observed with reddish mucous adhesions, we refer to them as "red cap sign" and place such signs among the typical findings of SSA/P. Because the dilatation of the pit in SSA/P is observed as a round/oval black dot on magnified observations, we refer to this finding as II-dilatation pit (II-D pit) and also positioned it as a characteristic finding of SSA/P. In contrast, dilatations of the capillary vessels surrounding the glands, such as those that occur in tubular adenoma, are not considered to be useful for differentiating HPs from SSA/Ps. However, in cases in which SSA/P is associated with cytological dysplasia, the dilatation of capillary vessels is observed in the same area. When submucosal layer invasion occurs in the same area, the blood flow presents with irregularities that are similar to those of common colorectal cancer at an early stage and disappears as the invasion proceeds deeply. The surface pattern of invasive cancer that is observed at the tumor surface is also likely to disappear. Based on the above results, we considered that the differentiations between HP and TSA, between TSA and SSA/P, and between HP and SSA/P might become easier due to the concomitant use of white light observation and IEE. We also concluded that AFI and NBI can be useful modalities for SSA/P lesions associated with cytological dysplasia. PMID- 26240688 TI - Recent development of optical coherence tomography for preoperative diagnosis of esophageal malignancies. AB - Endoscopic diagnosis with histological evidence is necessary to decide the best strategy for treating esophageal squamous cell carcinoma and Barrett's-associated neoplasia, and the recent development of endoscopic technologies have made possible real-time information of malignant hallmarks. We focused on the development of optical coherence tomography (OCT), the only technology that can depict real-time cross-sectional images with high resolution. With the improvements in image resolution, acquisition rate and demonstrable area of three dimensional devices with Doppler capability, OCT imaging was shown to enable visualization of structural/functional alterations in the mucosal/submucosal tissue of the esophagus, resulting in more accurate preoperative diagnosis of such malignancies. Moreover, it approved to be useful for targeting malignant areas for biopsy and treatment as well as for predicting the treatment effects. Therefore, further development of this technology is expected to overcome the current clinical issues in management strategies of esophageal malignancies. PMID- 26240689 TI - For "difficult" benign colorectal lesions referred to surgical resection a second opinion by an experienced endoscopist is mandatory: A single centre experience. AB - AIM: To assess how many patients with benign "difficult" colorectal lesions (DCRLs) referred to surgical resection, may be treated with endoscopic resection (ER) rather than surgical resection. METHODS: The prospectively collected colonoscopy database of our Endoscopic Unit was reviewed to identify all consecutive patients who, between July 2011 and August 2013, underwent an endoscopic re-evaluation before surgical resection due to the presence of DCRLs with a histological confirmation of benignancy on forceps biopsy. ER was attempted when the lesion did not have definite features of deeply invasive cancer. The "nonlifting sign" excluded ER only in naive lesions without a prior attempted resection. Lesions were classified, using the Kyoto-Paris classification for mucosal neoplasia. For sessile and non-polypoid lesions the "inject and cut" resection technique was used. Pedunculated and semi-pedunculated lesions were transected at the stalk just below the polyps head and before or after resection, metal clips or a loop were applied on the stalk to prevent bleeding. The lesions were histologically classified according to the Vienna criteria and for the pedunculated lesions the Haggitt classification was used. RESULTS: Eighty-two patients (42 females, mean age 62 years) with 82 lesions (mean size 37 mm) were included in the study. Sixty-nine (84%) lesions were endoscopically resected, while 13 underwent surgical resection since ER was deemed unsuitable. On histology, cancer was found in 21/69 lesions (14 intra mucosal, 7 sub-mucosal) and was associated with the size (P < 0.001) and with type 0-IIa +Is (P = 0.011) and 0-IIa + IIc (P < 0.001) lesions. All patients with sub-mucosal cancer, underwent surgical resection. Complications occurred in 11/69 patients (7 bleedings, 2 transmural burn syndromes, 2 perforations), all managed endoscopically or conservatively, and were associated with presence of invasive cancer (P = 0.021). During follow-up recurrence/residual tissue was found in 14/51 sessile or non-polypoid lesions (13 treated endoscopically, 1 underwent surgical resection) and was associated with type 0-IIa + Is lesions (P = 0.001), piecemeal resections (P = 0.01) and with lesion size (P = 0.004). Overall, 74% of patients avoided surgery. Surgical resection was significantly associated with type 0-IIa + Is (P = 0.01) and 0-IIa + IIc (P = 0.001) lesions, with sub-mucosal invasion on histology (P < 0.001), with presence of the "nonlifting sign" (P < 0.001), and related to the dimension of the lesions (P = 0.001). In the logistic regression analysis, the only independent predictor for surgical resection was the dimension of the lesions (P = 0.002). CONCLUSION: Before submitting patients to surgical resection for a benign DCRL, a second opinion by an experienced endoscopist is mandatory to avoid unnecessary surgery. PMID- 26240690 TI - Comparison of endoscopic stenting for malignant biliary obstruction: A single center study. AB - AIM: To evaluate the efficacy and safety of single-step endoscopic placement of self-expandable metallic stents (SEMS) for treatment of obstructive jaundice. METHODS: A retrospective study was performed among 90 patients who underwent transpapillary biliary metallic stent placement for malignant biliary obstruction (MBO) between April 2005 and October 2012. The diagnosis of primary disease and MBO was based on abdominal ultrasound, computed tomography, magnetic resonance imaging, endoscopic ultrasound, endoscopic retrograde cholangiopancreatography with brush cytology, biopsy, and/or a combination of these modalities. The type of SEMS (covered or non-covered, 8 mm or 10 mm in diameter) was determined by the endoscopist. Ninety patients were divided into two groups: group 1 (49 patients) who underwent a single-step SEMS placement and group 2 (41 patients) who underwent a two-step SEMS placement. The technical success rate, complication rate, stent patency, and patient survival rate were compared between the groups. In addition, to identify the clinical prognostic factors associated with patient survival, the following variables were evaluated in Cox-regression analysis: gender, age, etiology of MBO (pancreatic cancer or non-pancreatic cancer), clinical stage (IVb; with distant metastases or IVa >; without distant metastases), chemotherapy (with or without), patency of the stent, and the use of single-step or two-step SEMS. RESULTS: Immediate technical success was achieved in 93.9% (46/49) in group 1 and in 95.1% (39/41) in group 2, with no significant difference (P = 1.0). Similarly, there was no difference in the complication rates between the groups (group 1, 4.1% and group 2, 4.9%; P = 0.62). Stent failure was observed in 10 cases in group 1 (20.4%) and in 16 cases in group 2 (39.0%). The patency of stent and patient survival revealed no difference between the two groups with Kaplan-Meier analysis, with a mean patency of 111 +/- 17 d in group 1 and 137 +/- 19 d in group 2 (P = 0.91), and a mean survival of 178 +/- 35 d in group 1 and 222 +/- 23 d in group 2 (P = 0.57). On the contrary, the number of days of hospitalization associated with first-time SEMS placement in group 1 was shorter when compared with that number in group 2 (28 vs 39 d; P < 0.05). Multivariate analysis revealed that a clinical stage of IVa > (P = 0.0055), chemotherapy (P = 0.0048), and no patency of the stent (P = 0.011) were independent prognostic factors associated with patient survival. CONCLUSION: Our results showed that single-step endoscopic metal stent placement was safe and effective for treating obstructive jaundice secondary to various inoperable malignancies. PMID- 26240692 TI - Carcinoma in situ in a 7 mm gallbladder polyp: Time to change current practice? AB - Detection of polypoid lesions of the gallbladder is increasing in conjunction with better imaging modalities. Accepted management of these lesions depends on their size and symptomatology. Polyps that are symptomatic and/or greater than 10 mm are generally removed, while smaller, asymptomatic polyps simply monitored. Here, a case of carcinoma-in-situ is presented in a 7 mm gallbladder polyp. A 25 year-old woman, who had undergone a routine cholecystectomy, was found to have an incidental 7 mm polyp containing carcinoma in situ. She had few to no risk factors to alert to her condition. There are few reported cases of cancer transformation in gallbladder polyps smaller than 10 mm reported in the literature. The overwhelming consensus, barring significant risk factors for cancer being present, is that such lesions should be monitored until they become symptomatic or develop signs suspicious for malignancy. In our patient's case this could have led to the possibility of missing a neoplastic lesion, which could then have gone on to develop invasive cancer. As gallbladder carcinoma is an aggressive cancer, this may have led to a tragic outcome. PMID- 26240691 TI - Review on sedation for gastrointestinal tract endoscopy in children by non anesthesiologists. AB - AIM: To present evidence and formulate recommendations for sedation in pediatric gastrointestinal (GI) endoscopy by non-anesthesiologists. METHODS: The databases MEDLINE, Cochrane and EMBASE were searched for the following keywords "endoscopy, GI", "endoscopy, digestive system" AND "sedation", "conscious sedation", "moderate sedation", "deep sedation" and "hypnotics and sedatives" for publications in English restricted to the pediatric age. We searched additional information published between January 2011 and January 2014. Searches for (upper) GI endoscopy sedation in pediatrics and sedation guidelines by non anesthesiologists for the adult population were performed. RESULTS: From the available studies three sedation protocols are highlighted. Propofol, which seems to offer the best balance between efficacy and safety is rarely used by non anesthesiologists mainly because of legal restrictions. Ketamine and a combination of a benzodiazepine and an opioid are more frequently used. Data regarding other sedatives, anesthetics and adjuvant medications used for pediatric GI endoscopy are also presented. CONCLUSION: General anesthesia by a multidisciplinary team led by an anesthesiologist is preferred. The creation of sedation teams led by non-anesthesiologists and a careful selection of anesthetic drugs may offer an alternative, but should be in line with national legislation and institutional regulations. PMID- 26240693 TI - Unusual complication of amebic liver abscess: Hepatogastric fistula. AB - Amebic liver abscess is a parasitic disease which is often encountered in tropical countries. A hepatogastric fistula secondary to an amebic liver abscess is a rare complication of this disease and there are only a handful of reported cases in literature. Here we present a case of an amebic liver abscess which was complicated with the development of a hepatogastric fistula. The patient presented with the Jaundice, pain and distension of abdomen. The Jaundice and pain improved partially after he had an episode of brownish black colored increase in frequency of stools for 5 to 6 d. Patient also had ascites and anemia. He was a chronic alcohol drinker. Esophagogastroduodenoscopy performed in view of the above findings. It showed a fistulous opening with bilious secretions along the lesser curvature of the stomach. On imaging multiple liver abscesses seen including one in sub capsular location. The patient was managed conservatively with antiamebic medications along with proton pump inhibitors. The pigtail drainage of the sub capsular abscess was done. The patient improved significantly. The repeat endoscopy performed after about two months showed reduction in fistula size. A review of the literature shows that hepatogastric fistulas can be managed conservatively with medications and drainage, endoscopically with biliary stenting or with surgical excision. PMID- 26240694 TI - CVD-Enabled Graphene Manufacture and Technology. AB - Integrated manufacturing is arguably the most challenging task in the development of technology based on graphene and other 2D materials, particularly with regard to the industrial demand for "electronic-grade" large-area films. In order to control the structure and properties of these materials at the monolayer level, their nucleation, growth and interfacing needs to be understood to a level of unprecedented detail compared to existing thin film or bulk materials. Chemical vapor deposition (CVD) has emerged as the most versatile and promising technique to develop graphene and 2D material films into industrial device materials and this Perspective outlines recent progress, trends, and emerging CVD processing pathways. A key focus is the emerging understanding of the underlying growth mechanisms, in particular on the role of the required catalytic growth substrate, which brings together the latest progress in the fields of heterogeneous catalysis and classic crystal/thin-film growth. PMID- 26240695 TI - Metabolic surgery: A paradigm shift in type 2 diabetes management. AB - Obesity and type 2 diabetes mellitus (T2DM) are major public health issues globally over the past few decades. Despite dietary interventions, lifestyle modifications and the availability of several pharmaceutical agents, management of T2DM with obesity is a major challenge to clinicians. Metabolic surgery is emerging as a promising treatment option for the management of T2DM in the obese population in recent years. Several observational studies and a few randomised controlled trials have shown clear benefits of various bariatric procedures in obese individuals in terms of improvement or remission of T2DM and multiple other health benefits such as improvement of hypertension, obstructive sleep apnoea, osteoarthritis and non-alcoholic fatty liver disease. Uncertainties about the long-term implications of metabolic surgery such as relapse of T2DM after initial remission, nutritional and psychosocial complications and the optimal body mass index for different ethnic groups exist. The article discusses the major paradigm shift in recent years in the management of T2DM after the introduction of metabolic surgery. PMID- 26240697 TI - Importance of telemedicine in diabetes care: Relationships between family physicians and ophthalmologists. AB - Diabetic retinopathy (DR) is the worldwide leading cause of legal blindness. In 2010, 1.9% of diabetes mellitus (DM) patients were legally blind and 10.2% had visual impairment. The control of DM parameters (glycemia, arterial tension and lipids) is the gold standard for preventing DR complications, although, unfortunately, DR still appeared in a 25% to 35% of patients. The stages of severe vision threading DR, include proliferative DR (6.96%) and diabetic macular edema (6.81%). This review aims to update our knowledge on DR screening using telemedicine, the different techniques, the problems, and the inclusion of different professionals such as family physicians in care programs. PMID- 26240696 TI - Impact of new technologies on diabetes care. AB - Technologies for diabetes management, such as continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) systems, have improved remarkably over the last decades. These developments are impacting the capacity to achieve recommended hemoglobin A1c levels and assisting in preventing the development and progression of micro- and macro vascular complications. While improvements in metabolic control and decreases in risk of severe and moderate hypoglycemia have been described with use of these technologies, large epidemiological international studies show that many patients are still unable to meet their glycemic goals, even when these technologies are used. This editorial will review the impact of technology on glycemic control, hypoglycemia and quality of life in children and youth with type 1 diabetes. Technologies reviewed include CSII, CGM systems and sensor-augmented insulin pumps. In addition, the usefulness of advanced functions such as bolus profiles, bolus calculators and threshold-suspend features will be also discussed. Moreover, the current editorial will explore the challenges of using these technologies. Indeed, despite the evidence currently available of the potential benefits of using advanced technologies in diabetes management, many patients still report barriers to using them. Finally this article will highlight the importance of future studies tailored toward overcome these barriers to optimizing glycemic control and avoiding severe hypoglycemia. PMID- 26240699 TI - Gestational diabetes mellitus: Challenges for different ethnic groups. AB - Ethnicity is defined as "belonging to a social group that has a common national or cultural tradition". Membership of certain ethnic groups has long been associated with increased risk of gestational diabetes mellitus (GDM). Studies that examined ethnic differences amongst women with GDM were often conducted in western countries where women from various ethnic backgrounds were represented. The prevalence of GDM appears to be particularly high among women from South Asia and South East Asia, compared to Caucasian, African-American and Hispanic communities. For some, but not all ethnic groups, the body mass index is a risk factor for the development of GDM. Even within a particular ethnic group, those who were born in their native countries have a different risk profile for GDM compared to those born in western countries. In terms of treatment, medical nutrition therapy (MNT) plays a key role in the management of GDM and the prescription of MNT should be culturally sensitive. Limited studies have shown that women who live in an English-speaking country but predominantly speak a language other than English, have lower rates of dietary understanding compared with their English speaking counterparts, and this may affect compliance to therapy. Insulin therapy also plays an important role and there appears to be variation as to the progression of women who progress to requiring insulin among different ethnicities. As for peri-natal outcomes, women from Pacific Islander countries have higher rates of macrosomia, while women from Chinese backgrounds had lower adverse pregnancy outcomes. From a maternal outcome point of view, pregnant women from Asia with GDM have a higher incidence of abnormal glucose tolerance test results post-partum and hence a higher risk of future development of type 2 diabetes mellitus. On the other hand, women from Hispanic or African American backgrounds with GDM are more likely to develop hypertension post partum. This review highlights the fact that management needs to be individualised and the clinician should be mindful of the impact that differences in ethnicity may have on the clinical characteristics and pregnancy outcomes in women affected by GDM, particularly those living in Western countries. Understanding these differences is critical in the delivery of optimal antenatal care for women from diverse ethnic backgrounds. PMID- 26240698 TI - Respiratory failure in diabetic ketoacidosis. AB - Respiratory failure complicating the course of diabetic ketoacidosis (DKA) is a source of increased morbidity and mortality. Detection of respiratory failure in DKA requires focused clinical monitoring, careful interpretation of arterial blood gases, and investigation for conditions that can affect adversely the respiration. Conditions that compromise respiratory function caused by DKA can be detected at presentation but are usually more prevalent during treatment. These conditions include deficits of potassium, magnesium and phosphate and hydrostatic or non-hydrostatic pulmonary edema. Conditions not caused by DKA that can worsen respiratory function under the added stress of DKA include infections of the respiratory system, pre-existing respiratory or neuromuscular disease and miscellaneous other conditions. Prompt recognition and management of the conditions that can lead to respiratory failure in DKA may prevent respiratory failure and improve mortality from DKA. PMID- 26240700 TI - Exercise guidelines for gestational diabetes mellitus. AB - The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide. This disease has many detrimental consequences for the woman, the unborn foetus and child. The management of GDM aims to mediate the effects of hyperglycaemia by controlling blood glucose levels. Along with pharmacology and dietary interventions, exercise has a powerful potential to assist with blood glucose control. Due to the uncertainty of risks and benefits of exercise during pregnancy, women tend to avoid exercise. However, under adequate supervision exercise is both safe and beneficial in the treatment of GDM. Therefore it is vital that exercise is incorporated into the continuum of care for women with GDM. Medical doctors should be able to refer to competently informed exercise professionals to aid in GDM treatment. It is important that exercise treatment is informed by research. Hence, the development of evidence-based guidelines is important to inform practice. Currently there are no guidelines for exercise in GDM. This review aims to assess the efficacy of exercise for the management of GDM in order to establish an exercise prescription guideline specific to the condition. It is recommended that women with GDM should do both aerobic and resistance exercise at a moderate intensity, a minimum of three times a week for 30-60 min each time. PMID- 26240704 TI - Steroid hyperglycemia: Prevalence, early detection and therapeutic recommendations: A narrative review. AB - Steroids are drugs that have been used extensively in a variety of conditions. Although widely prescribed for their anti-inflammatory and immunosuppressive properties, glucocorticoids have several side effects, being hyperglycemia one of the most common and representative. In the present review, we discuss the main epidemiologic characteristics associated with steroid use, with emphasis on the identification of high risk populations. Additionally we present the pathophysiology of corticosteroid induced hyperglycemia as well as the pharmacokinetics and pharmacodynamics associated with steroid use. We propose a treatment strategy based on previous reports and the understanding of the mechanism of action of both, the different types of glucocorticoids and the treatment options, in both the ambulatory and the hospital setting. Finally, we present some of the recent scientific advances as well as some options for future use of glucocorticoids. PMID- 26240706 TI - Biomechanical Testing of Spinal Segment Fixed by Arcofix System on the Swine Spine. AB - STUDY DESIGN: An in vitro biomechanical study. PURPOSE: To evaluate the mechanical properties of the spinal segment in the intact, injured, and stabilized state after fixation by an Arcofix implant. OVERVIEW OF LITERATURE: Several types of thoracolumbar spine injury necessitates anterior instrumentation. The Arcofix plate represents the latest generation of angular stablity systems. The biomechanical properties of these implants have not been sufficiently studied yet. METHODS: A total of ten porcine specimens (levels Th12 L3) were prepared. The tests were performed for intact, injured, and implanted specimens. In each state, the specimen was subjected to a tension load of a prescribed force, and subsequently, twisted by a given angle. The force load was 200 N. The torsion load had a deformation character, i.e., the control variable was the twisting angle and the measured variable was the moment of a couple. The amplitude of the load alternating cycle was 3 degrees . Another parameter that was evaluated was the area of the hysteresis loop. The area corresponds to the deformation energy which is dissipated during the cycle. RESULTS: A statistically significant difference was found between the intact and injured states as well as between the injured and implanted specimens. The statistical evaluation also showed a statistically different value of the hysteresis loop area. In the case of instability, the area decreased to 33% of the physiological value. For the implanted sample, the area increased to 170% of the physiological value. CONCLUSIONS: The Arcofix implant with its parameters appears to be suitable and sufficiently stable for the treatment of the anterior column of the spine. PMID- 26240705 TI - Rat Notochordal Cells Undergo Premature Stress-Induced Senescence by High Glucose. AB - STUDY DESIGN: In vitro cell culture. PURPOSE: The purpose of the study was to investigate the effect of high glucose on premature stress-induced senescence of rat notochordal cells. OVERVIEW OF LITERATURE: Glucose-mediated increase of oxidative stress is a major causative factor for the development of diseases associated with diabetes mellitus such as senescence. However, no information is available for the effect of high glucose on premature stress-induced senescence of rat notochordal cells. METHODS: Notochordal cells were isolated from 4-week old rats, cultured and placed in either 10% fetal bovine serum (FBS, normal control) or 10% FBS plus two high glucose concentrations (0.1 M and 0.2 M, experimental conditions) for 1 and 3 days. We identified and quantified the mitochondrial damage (mitochondrial transmembrane potential), reactive oxygen species (ROS) and antioxidants, such as manganese superoxide dismutase (MnSOD) and catalase, for each condition. We also identified and quantified senescence and telomerase activity. Finally, we determined the expression of proteins related to replicative senescence (p53-p21-pRB) and stress-induced senescence (p16-pRB) pathways. RESULTS: Two high glucose concentrations enhanced the disruption of mitochondrial transmembrane potential and excessive generation of ROS in notochordal cells for 1 and 3 days, respectively. The expressions of MnSOD and catalase were increased in notochordal cells treated with both high glucose concentrations at 1 and 3 days. The telomerase activity declined at 1 and 3 days. Two high glucose concentrations increased the occurrence of stress-induced senescence of notochordal cells by p16-pRB pathways at 1 and 3 days. CONCLUSIONS: Despite compensatory expression of antioxidants, high glucose-induced oxidative stress accelerates stress-induced senescence in rat notochordal cells. This may result in dysfunction of notochordal cells, leading to accelerated premature disc degeneration. The prevention of excessive generation of oxidative stress by strict blood glucose control is important to prevent or to delay premature disc degeneration in young patients with diabetes mellitus. PMID- 26240701 TI - Indicators of glycemic control in patients with gestational diabetes mellitus and pregnant women with diabetes mellitus. AB - Recently, it has become clear that mild abnormal glucose tolerance increases the incidence of perinatal maternal-infant complications, and so the definition and diagnostic criteria of gestational diabetes mellitus (GDM) have been changed. Therefore, in patients with GDM and pregnant women with diabetes mellitus, even stricter glycemic control than before is required to reduce the incidence of perinatal maternal-infant complications. Strict glycemic control cannot be attained without an indicator of glycemic control; this review proposes a reliable indicator. The gold standard indicator of glycemic control in patients with diabetes mellitus is hemoglobin A1c (HbA1c); however, we have demonstrated that HbA1c does not reflect glycemic control accurately during pregnancy because of iron deficiency. It has also become clear that glycated albumin, another indicator of glycemic control, is not influenced by iron deficiency and therefore might be a better indicator of glycemic control in patients with GDM and pregnant women with diabetes mellitus. However, large-population epidemiological studies are necessary in order to confirm our proposal. Here, we outline the most recent findings about the indicators of glycemic control during pregnancy including fructosamine and 1,5-anhydroglucitol. PMID- 26240702 TI - Is there a relationship between vitamin D with insulin resistance and diabetes mellitus? AB - Available data suggest a possible link between abnormal vitamin D level and abnormal glucose homeostasis, two of the most common chronic medical conditions. Both conditions are associated with inflammation, and the exact mechanism for role of either on the other is not well clear. Literature investigating the link between vitamin D and either pre-diabetic states or diabetes is reviewed. Vitamin D deficiency is detrimental to insulin synthesis and secretion in animal and human studies. In humans, it has been shown by majority of observational studies, that vitamin D is positively correlated with insulin sensitivity and its role is mediated both by direct mechanism through the availability of vitamin D receptors in several tissues and indirectly through the changes in calcium levels. Large number of, but not all, variable samples cross sectional human trials have demonstrated an inverse relation between vitamin D status and impaired glucose tolerance, insulin resistance or diabetes. To compliment this conclusively, evidence from intervention studies is critically warranted before we can frankly state that vitamin D plays a role in diabetes prevention or treatment. Absence of both sizable prospective observational trials utilizing 25(OH)D as the main variable and the non-availability of randomized studies specifically designed to assess the effects of vitamin D on pre-diabetes and diabetes states, are the main obstacles to draw solid and conclusive relationships. PMID- 26240703 TI - Gestational diabetes: A clinical update. AB - Gestational diabetes mellitus (GDM) is increasing in prevalence in tandem with the dramatic increase in the prevalence of overweight and obesity in women of childbearing age. Much controversy surrounds the diagnosis and management of gestational diabetes, emphasizing the importance and relevance of clarity and consensus. If newly proposed criteria are adopted universally a significantly growing number of women will be diagnosed as having GDM, implying new therapeutic challenges to avoid foetal and maternal complications related to the hyperglycemia of gestational diabetes. This review provides an overview of clinical issues related to GDM, including the challenges of screening and diagnosis, the pathophysiology behind GDM, the treatment and prevention of GDM and the long and short term consequences of gestational diabetes for both mother and offspring. PMID- 26240707 TI - The Role of Routine Preoperative Magnetic Resonance Imaging in Idiopathic Scoliosis: A Ten Years Review. AB - STUDY DESIGN: Prospective study. PURPOSE: To determine the role of routine preoperative magnetic resonance imaging (MRI) to detect the incidence and risk factors for intraspinal anomalies in patients with idiopathic scoliosis. OVERVIEW OF LITERATURE: The incidence and risk factors for intraspinal anomalies in patients with idiopathic scoliosis are controversial, and the indications for preoperative MRI in these patients vary among centers. METHODS: Information on patients with idiopathic scoliosis who were surgical candidates over 10 years (age at presentation, sex, magnitude and apex of major curve, intraspinal anomalies detected by MRI, and neurological examination results) were recorded, the patients were grouped according to the intraspinal anomaly, and the data were analyzed. RESULTS: Of the 271 patients with idiopathic scoliosis, 27 had neuroaxial abnormalities (9.9%). Of these 27 patients, 14 (52%) underwent a neurosurgical procedure. Significant differences were observed in the frequency of early disease onset and male sex (p<0.05) between the group of patients with neuroaxial abnormalities on preoperative MRI and those who did not have a cord anomaly. No difference was detected in the magnitude or direction of the curve. CONCLUSIONS: Neuroaxial abnormalities in patients with idiopathic scoliosis and a normal neurological examination were highly frequent (9.9%). Missing these abnormalities before surgery could inflict catastrophic postoperative complications. The incidence of neuroaxial abnormalities was higher in male patients and in those with early onset disease. Thus, MRI is essential for all patients with idiopathic scoliosis who require medical intervention. PMID- 26240708 TI - Efficacy of Antibiotics Sprayed into Surgical Site for Prevention of the Contamination in the Spinal Surgery. AB - STUDY DESIGN: Retrospective study. PURPOSE: To evaluate the effect of intraoperative wound application of vancomycin on preventing surgical wound contamination during instrumented lumbar spinal surgery. OVERVIEW OF LITERATURE: Postoperative infection is the one of the most devastating complications of lumbar surgery. There are a few reports showing the benefits of intraoperative wound application of vancomycin during spinal surgery. However, there is no report about the effectiveness of local vancomycin instillation in prevention of surgical wound contamination. METHODS: Eighty-six patients underwent instrumented lumbar spinal surgery. Mean patient age was 65.19 years (range, 23-83 years). There were 67 females and 19 males. During surgery, vancomycin powder was applied into the surgical site before closure in 43 patients (antibiotic group) and vancomycin powder was not applied into the surgical site before closure in 43 patients (control group). The tip of the surgical drain was cultured to evaluate surgical wound contamination. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured on the first, third, seventh, and fourteenth day after the operation. RESULTS: We found two patients with a positive culture from the tip of surgical drains in the antibiotic group, and one patient with a positive culture from the tip of the surgical drain in the control group. Postoperative ESR and CRP levels did not show significant differences between the two groups. On the third postoperative day, ESR in patients of the antibiotic group was more significantly decreased than that in patients of the control group, while CRP level did not show a significant difference between the two groups. CONCLUSIONS: There was no evidence to suggest that intraoperative vancomycin application is effective in decreasing the risk of postoperative wound infection after instrumented posterior lumbar fusion surgery. PMID- 26240709 TI - Distinctive Characteristic Features of Intramedullary Hemangiopericytomas. AB - STUDY DESIGN: The retrospective analysis of intramedullary hemangiopericytomas (HPCs) was performed, and the entity was discussed in accordance with the literature findings. PURPOSE: This study aimed at defining distinctive characteristic features of intramedullary HPC with respect to surgical approach and prognosis. OVERVIEW OF LITERATURE: Intramedullary HPCs are extremely rare tumors. They originate from capillary pericytes, supposedly follow the vessels over the spinal cord, and infiltrate deep into the spinal cord without a distinct plane. Their treatments and prognosis are not well-defined in the literature. METHODS: Our database was retrospectively reviewed for the cases of HPCs. Later on, a literature search was performed to reveal all reported cases of intramedullary HPCs. The following key words were searched in PubMed databases: "hemangiopericytoma and intramedullary," "hemangiopericytoma and spine (spinal) and intradural," and "hemangiopericytoma and spinal cord." The articles were reviewed for patients' demographics features, imaging characteristics, tumor specific factors (surgical technique, pathological descriptions, and world health organization grades), and postoperative course and prognosis (adjuvant therapies, recurrences, complications, and mortalities). RESULTS: A total of seven patients (three male and four female) was reached, with their ages ranging from 15 to 80 years (mean, 32.5 years). The tumors were located majorly in thoracic region (5/7, 71.4%), and only two cases were in the cervical region (2/7, 28.6%). All tumors were completely removed, and only two cases received radiotherapy. No recurrence was reported. CONCLUSIONS: Complete resection of the intramedullary HPCs seems to be the best management strategy for long-term and recurrence-free survival and in alleviating further need for radiotherapy. PMID- 26240710 TI - Incidence of Pinhole Type Durotomy and Subsequent Cerebrospinal Fluid Leakage Following Simple Laminectomy. AB - STUDY DESIGN: Cross sectional study. PURPOSE: The purpose of this study was to determine the incidence and the associated risk factors of pinhole type of durotomy and cerebrospinal fluid (CSF) leakage following a simple laminectomy for spinal stenosis. OVERVIEW OF LITERATURE: The incidence of spinal stenosis is expected to rise with increasing life expectancy. Moreover, lumbar spinal stenosis is the most common indication for spinal injury in the geriatric population. It is therefore important to identify and prevent the risks associated with laminectomy, the most widely used surgical procedure for spinal stenosis. The serious complication of incidental dural tear or durotomy and subsequent CSF leakage has not been studied in the region of Southeast Asia. METHODS: In this cross sectional study, we included 138 adult patients (age>18 years), who underwent a simple laminectomy for lumbar stenosis between 2011 and 2012. CSF leakage was the main outcome variable. Patients' wounds were examined for CSF leakage up to 1 week postoperatively. RESULTS: The incidence of pinhole type durotomy and subsequent CSF leakage in our region was 8.7%. Univariate analysis showed that hypertension, diabetes and smoking were significantly associated with durotomy and increased CSF leakage by 16.72, 44.25, and 33.71 times, respectively. Multivariate analysis showed that only smoking and diabetes significantly increased the chances of leakage. CONCLUSIONS: Glycemic control and cessation of smoking prior to a simple laminectomy procedure reduced the incidence of a dural tear. Larger clinical studies on this lethal complication are required. PMID- 26240711 TI - Influence of Hamstring Tightness in Pelvic, Lumbar and Trunk Range of Motion in Low Back Pain and Asymptomatic Volunteers during Forward Bending. AB - STUDY DESIGN: Cross-sectional study. PURPOSE: To verify the association of hamstring tightness and range of motion in anterior pelvic tilt (PT), lumbar motion (LM), and trunk flexion (TF) during forward bending. OVERVIEW OF LITERATURE: Increased hamstring stiffness could be a possible contributing factor to low back injuries. Clinical observations have suggested that hamstring tightness influences lumbar pelvic rhythm. Movement restrictions or postural asymmetry likely lead to compensatory movement patterns of the lumbar spine, and subsequently to increased stress on the spinal soft tissues and an increased risk of low back pain (LBP). METHODS: Hamstring muscle tightness was measured using the self-monitored active knee extension (AKE) test. A bubble inclinometer was used to determine the range of motion of PT, LM, and TF during forward bending. Statistical analysis included descriptive statistics, comparisons between groups and a correlation between hamstring tightness (AKE) and anterior PT, TF, and regional LM with p<=0.05. RESULTS: The LBP group was composed of 36 participants, and the asymptomatic group consisted of 32 participants. The mean for PT in the control group was 66.7 degrees , 64.5 degrees for LM and 104.6 degrees for TF. Respective values in the symptomatic group were 57.0 degrees , 79.8 degrees , and 82.2 degrees . CONCLUSIONS: Participants with LBP showed restriction in the pelvis and TF range of motion, but had higher amplitudes in the lumbar spine during forward bending. PMID- 26240712 TI - Normal Values of Diffusion Tensor Magnetic Resonance Imaging Parameters in the Cervical Spinal Cord. AB - STUDY DESIGN: Prospective study. PURPOSE: We evaluated the usefulness of diffusion tensor imaging (DTI) in diagnosing patients with cervical myelopathy by determining the accuracy of normal DTI parameter values. OVERVIEW OF LITERATURE: DTI can visualize white matter tracts in vivo and quantify anisotropy. DTI is known to be more sensitive than conventional magnetic resonance imaging (MRI) in detecting subtle pathological changes of the spinal cord. METHODS: A total of 31 normal subjects (13 men and 18 women; age, 23-87 years; mean age, 46.0 years) were included in this study. The patients had no symptoms of myelopathy or radiculopathy. A Philips Achieva 3-Tesla MRI with SE-type Single Shot EPI was used to obtain diffusion tensor images. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were measured as DTI parameters on axial sections of several cervical levels. Subjects were divided into two groups: >40 years (n=16) and <=40 years (n=15). A paired t-test was used to compare significant differences between the groups. ADC and FA values were most stable on axial sections. RESULTS: For all subjects, mean ADC and FA values were 1.06+/ 0.09*10(-3) mm(2)/sec and 0.68+/-0.05, respectively. ADC was significantly higher in subjects >40 years of age than in those <=40 years. There was no significant difference in FA values between the two groups. The mean ADC value was significantly higher in normal subjects >40 years of age than in those <=40 years. CONCLUSIONS: It is important to consider age when evaluating cervical myelopathy by DTI. PMID- 26240713 TI - Mini Open Foraminotomy for Cervical Radiculopathy: A Comparison of Large Tubular and TrimLine Retractors. AB - STUDY DESIGN: Retrospective chart review. PURPOSE: A comparison of mini open foraminotomy (MOF) for cervical radiculopathy using either large tubular (LT) or TrimLine (TL) retractors. OVERVIEW OF LITERATURE: Posterior foraminotomy relieves compression of the cervical nerve root in radiculopathy patients. However, invasion of the paravertebral muscle may cause major problems in these patients. To address these problems, we performed MOF. METHODS: Twenty cervical radiculopathy patients (16 male and 4 female) who underwent MOF between May 2004 and August 2011 were assigned to LT and TL groups. Each group contained 10 subjects. Surgical and clinical outcomes were compared. RESULTS: The average operating time in the TL group was significantly shorter than that in the LT group. The final follow-up mean neck disability indices significantly improved compared to the preoperative values (LT group, 12.0+/-7.8 vs. 28.0+/-9.4; TL group, 6.0+/-5.9 vs. 21.9+/-10). The final follow-up neck pain visual analog scale (VAS) scores also decreased significantly from the preoperative of 8.0+/ 1.5 and 2.5+/-2.5 to the final follow-up values of 2.2+/-2.2 and 1.0+/-2.5 in the LT and TL groups, respectively. The recovery rate for the neck pain VAS score was 70.0+/-31.9 in the LT group and 87.0+/-32.0 in the TL group, thus suggesting no significant difference between the two groups. CONCLUSIONS: MOF with the TL retractor is an easy and safe procedure. Furthermore, the use of the TL retractor allows for a minimally invasive and effective surgical treatment of cervical radiculopathy patients. PMID- 26240714 TI - The 15-Year Evolution of the Thoracoscopic Anterior Release: Does It Still Have a Role? AB - STUDY DESIGN: Retrospective. PURPOSE: To determine how the indications for anterior thoracoscopic release and fusion have evolved over time. OVERVIEW OF LITERATURE: Anterior release was commonly performed to correct severe spinal deformities before the advent of pedicle screw fixation. The thoracoscopic approach significantly reduced the morbidity, as compared to open thoracotomy procedures. METHODS: We reviewed charts and radiographs of pediatric spinal deformity patients who underwent thoracoscopic release/fusion for their deformity from 1994 to 2008. Indications for the thoracoscopic procedure were assigned to one of the following categories: hyperkyphosis, large/stiff scoliosis, crankshaft prevention, and 'other'. We analysed indications grouped in 3-year intervals to determine how the indications for this procedure evolved over the past 15 years. RESULTS: One hundred and thirty-eight patients (mean age, 15 years; range, 2-28 years) underwent the procedure, with 160 identified indications. The frequency of thoracoscopic anterior release/fusion decreased after peaking in the years 2000 2002. Initially, hyperkyphosis was the most frequent indication (15/33, 45%; 1994 1996), but declined to an intermittent indication since 2006. The use of thoracoscopy to prevent crankshaft has also declined, but remains an indication for the most immature cases (2/17, 12%; 2006-2008). Severe or rigid scoliosis is currently the most common indication for thoracoscopic release/fusion at our center (11/17, 65%; 2006-2008). CONCLUSIONS: The indications for a thoracoscopic anterior release/fusion has evolved with our increased understanding of this procedure and improved posterior fixation with pedicle screw instrumentation. Thoracoscopy in select spinal deformity patients still has an important role despite its less frequent use, as compared to the past decade. PMID- 26240715 TI - A Retrospective Analysis of the Management of Postoperative Discitis: A Single Institutional Experience. AB - STUDY DESIGN: Retrospective study. PURPOSE: The aim of the study was to study the impact and outcome of conservative management and surgical intervention in cases of postoperative discitis. OVERVIEW OF LITERATURE: Postoperative discitis is a rare but often misdiagnosed cause of failed back syndrome. There is paucity of literature regarding management guidelines of postoperative discitis. METHODS: The study was carried out over a period of 6 years. Eighteen patients with postoperative discitis were included in the study. RESULTS: Conservative management with antibiotics, analgesics and bed rest were started in all the study cases. Posterior transpedicular fixation after re-exploration debridement and curettage of disc space granulation tissue was conducted in five patients in whom conservative management failed. CONCLUSIONS: Early diagnosis and appropriate management is the key to effective treatment of postoperative discitis. Conservative management leads to excellent results in majority of cases. Surgical intervention with posterior interbody fusion and debridement is helpful when conservative treatment fails. PMID- 26240716 TI - Mini-Open Anterior Retroperitoneal Lumbar Interbody Fusion: Oblique Lateral Interbody Fusion for Degenerated Lumbar Spinal Kyphoscoliosis. AB - STUDY DESIGN: Prospective case series. PURPOSE: To examine the clinical efficacy of mini-open anterior retroperitoneal lumbar interbody fusion: oblique lateral interbody fusion (OLIF) for degenerated lumbar spinal kyphoscoliosis. OVERVIEW OF LITERATURE: The existing surgical procedures for the treatment of spinal kyphotic deformity, including Smith-Petersen osteotomy, pedicle subtraction osteotomy, and vertebral column resection procedures, are invasive in nature. Extreme lateral interbody fusion to provide less invasive treatment of the deformity has been reported, but complications including spinal nerve and psoas muscle injury have been noted. In the current study, we examined the clinical efficacy and complications of OLIF for degenerated lumbar spinal kyphoscoliosis. METHODS: Twelve patients with degenerated lumbar spinal kyphoscoliosis were examined. All patients underwent OLIF surgery (using a cage and bone graft from the iliac crest) with open pedicle screws or percutaneous pedicle screws, without real-time monitoring by electromyography. Visual analog scale score and Oswestry disability index were evaluated before and 12 months after surgery, and fusion rate at OLIF cage, correction of the deformity, total blood loss, and surgical complications were also evaluated. RESULTS: Pain scores significantly improved after surgery (p<0.05). Fusion rate was found to be 90%, balance parameters also improved after surgery (p<0.05), and average total blood loss was less than 350 mL. There was no spinal nerve, major vessel, peritoneal, or urinary injury, or breakage of instrumentation. CONCLUSIONS: OLIF surgery for degenerated lumbar spinal kyphoscoliosis is less invasive than other procedures and good surgical results were produced without major complications. PMID- 26240717 TI - More than 6 Months of Teriparatide Treatment Was More Effective for Bone Union than Shorter Treatment Following Lumbar Posterolateral Fusion Surgery. AB - STUDY DESIGN: Retrospective case series. PURPOSE: To examine the most effective duration of teriparatide use for spinal fusion in women with postmenopausal osteoporosis. OVERVIEW OF LITERATURE: We reported that daily subcutaneous injection of teriparatide (parathyroid hormone) significantly improved bone union after instrumented lumbar posterolateral fusion (PLF) in women with postmenopausal osteoporosis when compared with oral administration of bisphosphonate. However, the most effective duration of teriparatide use for spinal fusion has not been explored. METHODS: Forty-five women with osteoporosis diagnosed with degenerative spondylolisthesis from one of the three treatment groups were evaluated based on: short-duration treatment (average, 5.5 months; n=15; daily subcutaneous injection of 20 ug teriparatide), long-duration treatment (average, 13.0 months; n=15; daily subcutaneous injection of 20 ug teriparatide), and bisphosphonate treatment (average, 13.0 months; n=15; weekly oral administration of 17.5 mg risedronate). All patients underwent PLF with a local bone graft. Fusion rate and duration of bone union were evaluated 1.5 years after surgery. RESULTS: Bone union rate and average duration for bone union were 92% and 7.5 months in the long-duration treatment group, 80% and 8.5 months in the short-duration treatment group, and 70% and 10.0 months in the bisphosphonate treatment group, respectively. Results of bone union rate and average duration for bone union in the teriparatide treatment groups were significantly superior to those in the bisphosphonate treatment group (p<0.05); whereas, significantly superior results were observed in long-duration treatment group when compared with short-duration treatment group (p<0.05). CONCLUSIONS: Daily injection of teriparatide for bone union was more effective than oral administration of bisphosphonate. Furthermore, a longer period of teriparatide treatment for bone union was more effective than a shorter period of same treatment. PMID- 26240718 TI - Height Restoration after Balloon Kyphoplasty in Rheumatoid Patients with Osteoporotic Vertebral Compression Fracture. AB - STUDY DESIGN: Retrospective study. PURPOSE: This study was conducted to compare vertebral body height restoration rate in rheumatoid arthritis (RA) patients who had undergone percutaneous balloon kyphoplasty (KP) with that of control group who had matched age, sex, body mass index, and bone mineral density. OVERVIEW OF LITERATURE: There is no report on result of KP in RA patients. METHODS: Postoperative height restoration rate of RA group consisting of 15 patients (18 vertebral bodies) who had undergone KP due to osteoporotic vertebral compression fracture with a 30% or higher vertebral compression rate between May 2005 and January 2013 were compared to control group consisting of 38 patients (39 vertebral bodies) who had matched age, sex, body mass index, and bone mineral density. RESULTS: No statically significant difference in age (p=0.846), sex (p=0.366), body mass index (p=0.826), bone mineral density (p=0.349), time to surgery (p=0.528), polymethylmethacrylate injection time (p=0.298), or amount (p=0.830) was found between the RA group and the control group. However, preoperative compression rate in the RA group was significantly (p=0.025) higher compared to that in the control group. In addition, postoperative height restoration rate showed significant correlation with the RA group (p=0.008). Although higher incidence of recollapse occurred in the RA group compared to that in the control group, the difference was not statistically significant (p=0.305). CONCLUSIONS: Compared to the control group, RA patients showed higher compression rate and higher vertebral restoration rate after KP, indirectly indicating weaker bone quality in patients with RA. Higher incidence of recollapse occurred in the RA group compared to that in the control group, although it was not statistically significant. PMID- 26240719 TI - Interrater Reliability of the Postoperative Epidural Fibrosis Classification: A Histopathologic Study in the Rat Model. AB - STUDY DESIGN: Agreement study. PURPOSE: To validate the interrater reliability of the histopathological classification of the post-laminectomy epidural fibrosis in an animal model. OVERVIEW OF LITERATURE: Epidural fibrosis is a common cause of failed back surgery syndrome. Many animal experiments have been developed to investigate the prevention of epidural fibrosis. One of the common outcome measurements is the epidural fibrous adherence grading, but the classification has not yet been validated. METHODS: Five identical sets of histopathological digital files of L5-L6 laminectomized adult Sprague-Dawley rats, representing various degrees of postoperative epidural fibrous adherence were randomized and evaluated by five independent assessors masked to the study processes. Epidural fibrosis was rated as grade 0 (no fibrosis), grade 1 (thin fibrous band), grade 2 (continuous fibrous adherence for less than two-thirds of the laminectomy area), or grade 3 (large fibrotic tissue for more than two-thirds of the laminectomy area). A statistical analysis was performed. RESULTS: Four hundred slides were independently evaluated by each assessor. The percent agreement and intraclass correlation coefficient (ICC) between each pair of assessors varied from 73.5% to 81.3% and from 0.81 to 0.86, respectively. The overall ICC was 0.83 (95% confidence interval, 0.81-0.86). CONCLUSIONS: The postoperative epidural fibrosis classification showed almost perfect agreement among the assessors. This classification can be used in research involving the histopathology of postoperative epidural fibrosis; for example, for the development of preventions of postoperative epidural fibrosis or treatment in an animal model. PMID- 26240720 TI - Combined Video-Assisted Thoracic Surgery and Posterior Spinal Surgery for the Treatment of Dumbbell Tumor of the First Thoracic Nerve Root. AB - Although several cases of a dumbbell tumor of thoracic nerve roots have been reported, reports on the surgical procedures for a dumbbell tumor of the first thoracic (T1) nerve root are rare. Surgeons should be cautious, especially when performing a surgical procedure for a dumbbell tumor of the T1 nerve root because the tumor is anatomically located adjacent to important organs and because the T1 nerve root composes the lower trunk of the brachial plexus with the eighth cervical nerve root. We present cases with dumbbell tumors of the T1 nerve root that were treated with combined surgical treatment to remove the tumor. We first performed video-assisted thoracic surgery (VATS) to release the organs anteriorly and then performed posterior spinal surgery in the prone position. The combined VATS and posterior spinal surgery may become a standard surgical procedure for the treatment of dumbbell tumors of the T1 nerve root. PMID- 26240721 TI - Giant Solitary Anterior Cervical Canal Neurofibroma: Case Report and Surgical Technique. AB - Giant solitary anterior cervical canal neurofibroma (GSACCN) is rarely reported in the literature. When the large lesion is ventrally located to the spinal cord, an anterolateral approach may not be ideal due to various technical challenges. In this report, we describe a case of intradural extramedullary GSACCN located at the cervical region extending from the axis to the sixth cervical vertebrae. Here we also describe a posterior technique successfully used to resect the tumour. Therefore, the posterior approach by En bloc decompressive laminectomy and laminoplasty might be used to adequately treat the lesion. PMID- 26240722 TI - Circumferential Spinal Cord Decompression through a Single Posterior Approach with Microendoscopy for Thoracic and Thoracolumbar Ossification of the Posterior Longitudinal Ligament. AB - Thoracic and thoracolumbar ossification of the posterior longitudinal ligament (OPLL) can be difficult to treat due to the anatomical position. The purpose of this study was to report the significance of a novel surgical technique that represented two cases of thoracic or thoracolumbar OPLL. The first patient was a 72-year-old woman who had a beak-type OPLL at the T11/12. The second was a 45 year-old woman who had a beak-type OPLL at the T12/L1. We performed circumferential spinal cord decompression through a single posterior approach with microendoscopy in both cases. The postoperative computed tomography revealed the complete removal of the OPLL, and the magnetic resonance imaging confirmed adequate decompression of the spinal cord. Preoperative symptoms were substantially improved in both patients. To date, we have used this novel technique to treat five patients with thoracic or thoracolumbar OPLL. This new surgical technique is likely to be useful in patients with a beak-type OPLL of the thoracic or thoracolumbar spine. PMID- 26240723 TI - Anterior Herniation of Partially Calcified and Degenerated Cervical Disc Causing Dysphagia. AB - We report a rare case of anterior cervical disc herniation associated with dysphagia. A 32-year-old man presented with complaints of dysphagia and concomitant pain in the right arm resistant to conservative therapy. On physical examination with respect to the muscle strength, the right shoulder abduction and flexion of the forearm were 3/5. Lateral X-ray revealed calcified osteophytes at the anterior C4-5 level. Magnetic resonance imaging showed soft disc herniation involving the right C6 root at the C5-6 level and anterior herniation of the C4-5 cervical disc. Anterior discectomies for C4-5 and C5-6 levels stabilized and ameliorated the dysphagia and pain. Cervical disc herniation usually presents with radicular findings. However, dysphagia may be an uncommon presentation. Anterior cervical disc herniation should be considered in a patient presenting with dysphagia. PMID- 26240724 TI - A Lethal Sequelae of Spinal Infection Complicating Surgery and Radiotherapy for Head and Neck Cancer. AB - Patients who have undergone neck dissection and radiotherapy are at risk of cervical spine infections. Furthermore, previous radiotherapy and cervical spine infections can lead to fistula formation to the subarachnoid space and intracranial infection. This report discusses the serious consequences of a missed cervical spine infection including cerebrospinal fluid fistula formation and persistent central nervous system infection, and serves as a reminder to clinicians of the possible association between cervical spine infections and prior head and neck surgery and radiotherapy. In all such cases, the posterior pharyngeal wall should be inspected during follow-up. Despite the appearance of an intracranial infection, the cervical spine should be investigated, especially if the response to appropriate antibiotics is suboptimal. PMID- 26240725 TI - Surgical Treatment for Atlanto-Occipital Subluxation due to Destructive Spondyloarthropathy in a Patient Undergoing Long-Term Hemodialysis. AB - Destructive spondyloarthropathy (DSA) has been reported in patients undergoing long-term hemodialysis. Cervical spinal lesions, including those of the upper cervical spine, are reported to be some of the most common. To our knowledge, we report for the first time, a case of atlanto-occipital subluxation requiring surgical treatment due to severe myelopathy and nuchal pain in a patient undergoing long-term hemodialysis. The patient was a 66-year-old woman who had undergone hemodialysis for 40 years. She visited our hospital due to an acute progression of gait disturbance and severe nuchal pain. Computed tomography showed posterior subluxation of the atlanto-occipital joints. DSA was also observed in the lower cervical spine. Magnetic resonance imaging showed spinal canal stenosis at both the upper and lower cervical levels. We performed Oc-C7 fixation, C1 laminectomy, and C3-C7 laminoplasty. We first recognized that the atlanto-occipital subluxation was caused by the extremely long-term, in this case, 40 years, hemodialysis. PMID- 26240726 TI - Post Pregnancy Severe Spinal Osteoporosis with Multiple Vertebral Fractures and Kyphoscoliosis in a Multigravida: A Rare Case with Management. AB - Osteoporosis associated with pregnancy and lactation is a less commonly known condition and often overlooked. The prevalence, exact aetiology and its pathogenesis are unknown. It is commonly seen in first three months after delivery in primigravida. It is often undiagnosed because of it not suspected n and X-rays and densitometry are avoided if possible during pregnancy and lactation. If missed, it can lead to osteoporotic fractures and disability. In this paper, we report a case of a 24-year-old multigravida 4 months after pregnancy with multiple vertebral compression fractures and kyphoscoliosis. Her metabolic workup was normal but bone densitometry revealed severe osteoporosis of the dorso-lumbar spine. Immediate weaning and antiresorptives like bisphosphonates and teriparatide are used as first line drugs to manage postpartum spinal osteoporosis. Our patient presented at 4 month lactation and did not want to wean her infant, so she was treated with total contact orthosis and took vitamin D and calcium. The pain was relieved within 3 months but there was no improvement in bone density. After eight months when the infant was weaned, she was treated with teriparatide. After one year of teriparatide therapy, there were no new fractures and densitometry scores improved. PMID- 26240727 TI - Compression Fractures in the Setting of Diffuse Idiopathic Skeletal Hyperostosis. AB - Compression fractures are the most common vertebral fractures. They involve the anterior column of the spine, and are considered stable fractures due to the presence of intact posterior ligaments that aid in resisting further collapse and deformity. They are thus often managed conservatively. We describe a series of 3 cases that were initially diagnosed as compression fractures and managed conservatively. With the abundance of compression fractures and increase in preference for conservative management of compression fractures, it is of utmost importance to recognize the possibility of other spinal co-pathologies, especially that of hyperostosis of the spine, both by clinical judgment as well as radiological analysis before embarking on conservative management, should there be under-treatment and development of complications that could have otherwise been avoided, as in the cases presented in this series. PMID- 26240728 TI - Craniovertebral Junction Instability: A Review of Facts about Facets. AB - Craniovertebral junction surgery involves an appropriate philosophical, biomechanical and anatomical understanding apart from high degree of technical skill and ability of controlling venous and arterial bleeding. The author presents his 30-year experience with treating complex craniovertebral junction instability related surgical issues. The facets of atlas and axis form the primary site of movements at the craniovertebral junction. All craniovertebral junction instability is essentially localized to the atlantoaxial facet joint. Direct manipulation and fixation of the facets forms the basis of treatment for instability. PMID- 26240730 TI - Hypoglossal Nerve Injury after Cervical Spine Surgery. PMID- 26240729 TI - Low Back Pain: Current Surgical Approaches. AB - Low back pain (LBP) is a worldwide phenomenon. The UK studies place LBP as the largest single cause of absence from work; up to 80% of the population will experience LBP at least once in their lifetime. Most individuals do not seek medical care and are not disabled by their pain once it is managed by nonoperative measures. However, around 10% of patients go on to develop chronic pain. This review outlines the basics of the traditional approach to spinal surgery for chronic LBP secondary to osteoarthritis of the lumbar spine as well as explains the novel concepts and terminology of back pain surgery. Traditionally, the stepwise approach to surgery starts with local anaesthetic and steroid injection followed by spinal fusion. Fusion aims to alleviate pain by preventing movement between affected spinal segments; this commonly involves open surgery, which requires large soft tissue dissection and there is a possibility of blood loss and prolonged recovery time. Established minimally invasive spine surgery techniques (MISS) aim to reduce all of these complications and they include laparoscopic anterior lumbar interbody fusion and MISS posterior instrumentation with pedicle screws and rods. Newer MISS techniques include extreme lateral interbody fusion and axial interbody fusion. The main problem of fusion is the disruption of the biomechanics of the rest of the spine; leading to adjacent level disease. Theoretically, this can be prevented by performing motion preserving surgeries such as total disc replacement, facet arthroplasty, and non fusion stabilisation. We outline the basic concepts of the procedures mentioned above as well as explore some of the novel surgical therapies available for chronic LBP. PMID- 26240731 TI - Response to: Hypoglossal Nerve Unjury after Cervical Spine Surgery. PMID- 26240732 TI - Prevalence of Chronic Kidney Disease and the Incidence of Acute Kidney Injury in Patients with Coronary Artery Disease in Mumbai, India. AB - BACKGROUND AND OBJECTIVE: To determine the prevalence of chronic kidney disease (CKD) and incidence of acute kidney injury (AKI) in patients with coronary artery disease (CAD) demonstrated on coronary angiography. MATERIALS AND METHODS: Totally, 125 patients admitted to Lilavati Hospital and Research Centre, Mumbai, with CAD were included in the study. RESULTS: Left anterior descending artery was the major vessel involved (40%), followed by a circumflex artery (21.6%). 49 out of 125 (39.2%) were found to have underlying CKD. 69% (34) of these CKD patients developed AKI. 21 out of 34 patients who developed AKI required hemodialysis. Only 47.1% (16 out of 34) of CKD patients had complete recovery, 29% had partial recovery, and 23% had no recovery of their renal function from AKI. Statistically significant number of patients in CKD group had no recovery from AKI as compared to non-CKD group (23.5% vs. 0%). CONCLUSION: Our study concludes that there is a very high prevalence of CKD (39.2%) in patients with CAD and AKI is a very important complication (38.4%) in these patients. Considering such a high prevalence of CKD, nephrology referral must be considered in patients with abnormal urinalysis, spot urinary protein to creatinine ratio and in patients whose creatinine clearance is <60 ml/min. PMID- 26240733 TI - Recurrent Hemorrhagic Pericardial Effusion and Tamponade due to Filariasis Successfully Treated with Ivermectin and Albendazole. AB - Filariasis presenting with pericardial effusion with tamponade is rare. We report a case of a 30-year-old female who was admitted with severe dyspnea and chest pain since 2 days. Echocardiogram showed massive pericardial effusion with tamponade. Pericardial fluid aspiration drained 1.2 L of hemorrhagic fluid. Cytology examination revealed microfilaria of Wuchereria bancrofti. She was treated with diethyl carbamazine and discharged. Six weeks later, she presented again with massive pericardial effusion with cardiac tamponade. Pericardiocentesis was done. Cytology examination revealed microfilaria of W. bancrofti. This time she was treated with ivermectin and albendazole and cured. Hemorrhagic effusion resolved completely. Though relatively uncommon, tropical diseases must always be considered in the etiological diagnosis of recurrent pericardial effusion. PMID- 26240734 TI - Percutaneous Closure of an Aortic Prosthetic Paravalvular Leak with Device in a Patient Presenting with Heart Failure. AB - Paravalvular leaks (PVLs) are a well-recognized complication of prosthetic valve replacement. Perivalvular prosthetic regurgitation causes significant morbidity and is associated with high perioperative mortality if open surgical repair is required. PVLs manifest with symptoms of congestive heart failure, hemolysis, or in most cases, the combination of both. In recent years, the development of imaging and device techniques significantly shortened the duration of fluoroscopy and procedure success was achieved. Percutaneous transcatheter closure of PVLs with a specific device causes symptomatic improvement. We present a case of transcatheter closure of aortic paravalvular insufficiency with amplatzer duct occluder 2 device. PMID- 26240735 TI - A Rare Case of Recurrent Pacemaker Allergic Reaction. AB - Allergic reactions to pacemaker device components are uncommon. However, when they occur, they usually mimic pacemaker infection, which results in multiple device replacements and increased morbidity burden. Here we present a 40-year-old female with pacemaker insertion due to complete heart block and who had multiple device replacements because of allergic sensitivity to various pacemaker component-encasing materials, confirmed by allergic testing to these materials. She had complete resolution of her symptoms after replacement with gold-plated device, to which she was not allergic. PMID- 26240736 TI - Primary Synovial Cell Sarcoma of the Heart: A Rare Case. AB - A synovial sarcoma (also known as malignant synovioma) is a rare form of cancer that usually occurs near the joints of the arm, neck, or leg. It is one of the soft tissue sarcomas. Primary cardiac neoplasms are rare. Most common site for synovial sarcoma is lower limb. Synovial sarcoma of the heart is extremely rare. Occurrence of synovial sarcoma at extra synovial site is very uncommon. It is two times common in right side heart than left side so left side synovial sarcoma is rarest of rare, only very limited cases are reported. Here, we report a case of primary synovial cell sarcoma of the left side of the heart in a 26-year-old female. She presented with dyspnea and weakness only. She was operated for left sided mass covering mitral valve; further histo-pathology revealed the mass as synovial cell sarcoma. In Indian scenario, this type of rare case needs documentation. PMID- 26240737 TI - Symptomatic Coronary Cameral Fistula. AB - Coronary cameral fistula is a rare entity and is characterized by an abnormal communication between coronary artery and a cardiac chamber. It is usually congenital and asymptomatic in majority of patients. If symptomatic the patients usually present in childhood. We present a case of 45-year-old male who presented with anginal chest pain and dyspnea on exertion for last 1 year. His exercise treadmill test was positive for ischemic changes and ECG-gated contrast enhanced CT was done for further evaluation. CT showed a large right coronary artery to right atrium fistula. It also ruled out any coronary atherosclerosis as reason for chest pain and ischemic symptoms on exercise treadmill test. The fistula was successfully closed by surgery and there was resolution of chest pain and dyspnea. PMID- 26240738 TI - Surgical Retrieval of Embolized Atrial Septal Defect Closure Device in Right Ventricle. PMID- 26240740 TI - Stem Cell Timeline. PMID- 26240739 TI - Animal-Assisted Therapy. PMID- 26240741 TI - Invader probes: Harnessing the energy of intercalation to facilitate recognition of chromosomal DNA for diagnostic applications. AB - Development of probes capable of recognizing specific regions of chromosomal DNA has been a long-standing goal for chemical biologists. Current strategies such as PNA, triplex-forming oligonucleotides, and polyamides are subject to target choice limitations and/or necessitate non-physiological conditions, leaving a need for alternative approaches. Toward this end, we have recently introduced double-stranded oligonucleotide probes that are energetically activated for DNA recognition through modification with +1 interstrand zippers of intercalator functionalized nucleotide monomers. Here, probes with different chemistries and architectures - varying in the position, number, and distance between the intercalator zippers - are studied with respect to hybridization energetics and DNA-targeting properties. Experiments with model DNA targets demonstrate that optimized probes enable efficient (C50 < 1 MUM), fast (t50 < 3h), kinetically stable (> 24h), and single nucleotide specific recognition of DNA targets at physiologically relevant ionic strengths. Optimized probes were used in non denaturing fluorescence in situ hybridization experiments for detection of gender specific mixed-sequence chromosomal DNA target regions. These probes present themselves as a promising strategy for recognition of chromosomal DNA, which will enable development of new tools for applications in molecular biology, genomic engineering and nanotechnology. PMID- 26240743 TI - Right ventricle failure associated with trastuzumab. AB - Trastuzumab (TZ), a monoclonal antibody against human epidermal growth factor receptor type 2 (HER2), is an important biological agent used for the treatment of positive breast cancer. This paper presents a 46-year-old female patient who developed right heart failure and right ventricular dysfunction while on TZ due to breast cancer, and returned to normal following the discontinuation of the drug. As far as we know, this is the first case report related to a patient presenting with right ventricular dysfunction and induced cardiotoxicity while on TZ. PMID- 26240742 TI - A randomized, crossover, placebo-controlled clinical trial to assess the sensitivity of the CRCDS Mini-Sim to the next-day residual effects of zopiclone. AB - OBJECTIVES: We sought to validate Cognitive Research Corporation's Driving Simulator (CRCDS Mini-Sim) for studies of drug safety with respect to driving ability. METHODS: A total of 30 healthy subjects were randomized to receive placebo or 7.5 mg zopiclone, a hypnotic known to impair driving, in random order during the 2 treatment periods of a 2 period crossover design. RESULTS: Evening administration of 7.5 mg zopiclone increased next-day standard deviation of lateral lane position (SDLP) by 2.62 cm on average compared with evening administration of placebo, and caused significant effects on symmetry analysis. The magnitude of the change in SDLP is highly similar to changes previously observed using on-the-road driving methods. CONCLUSIONS: Further validation of the CRCDS Mini-Sim is warranted to develop this platform for drug safety studies. PMID- 26240744 TI - Safety risks with investigational drugs: Pharmacy practices and perceptions in the veterans affairs health system. AB - OBJECTIVES: Rigorous practices for safe dispensing of investigational drugs are not standardized. This investigation sought to identify error-prevention processes utilized in the provision of investigational drug services (IDS) and to characterize pharmacists' perceptions about safety risks posed by investigational drugs. METHODS: An electronic questionnaire was distributed to an audience of IDS pharmacists within the Veteran Affairs Health System. Multiple facets were examined including demographics, perceptions of medication safety, and standard processes used to support investigational drug protocols. RESULTS: Twenty-one respondents (32.8% response rate) from the Northeast, Midwest, South, West, and Non-contiguous United States participated. The mean number of pharmacist full time equivalents (FTEs) dedicated to the IDS was 0.77 per site with 0.2 technician FTEs. The mean number of active protocols was 22. Seventeen respondents (81%) indicated some level of concern for safety risks. Concerns related to the packaging of medications were expressed, most notably lack of product differentiation, expiration dating, barcodes, and choice of font size or color. Regarding medication safety practices, the majority of sites had specific procedures in place for storing and securing drug supply, temperature monitoring, and prescription labeling. Repackaging bulk items and proactive error identification strategies were less common. Sixty-seven percent of respondents reported that an independent double check was not routinely performed. CONCLUSIONS: Medication safety concerns exist among pharmacists in an investigational drug service; however, a variety of measures have been employed to improve medication safety practices. Best practices for the safe dispensing of investigational medications should be developed in order to standardize these error-prevention strategies. PMID- 26240745 TI - Risk of intracranial hypertension with intrauterine levonorgestrel. AB - OBJECTIVES: The objective of this study was to quantify the risk of intracranial hypertension (ICH) with the intrauterine levonorgestrel (IUL) device Mirena((r)). METHODS: We used the United States Food and Drug Administration's Adverse Events Reporting System (FAERS) database to quantify a reporting odds ratio (ROR) for ICH and Mirena((r)). We also conducted a retrospective cohort study using the IMS LifeLink((r)) database, comparing the risk of two oral contraceptives ethinyl estradiol (EE) with Mirena((r)). A Bayesian sensitivity analysis was performed to account for the effect of body mass index (BMI). RESULTS: The reported odds ratios (ORs) for ICH and papilledema with Mirena((r)) were 1.78 (95% confidence interval [CI] 1.41-2.25) and 1.50 (95% CI 1.10-2.05), respectively. In the cohort study, the OR for ICH and EE-norgestimate and EE-norethindrone compared with Mirena((r)) were 1.29 (95% CI 0.83-2.00) and 0.31 (95% CI 0.04-2.29), respectively. The presence of a strong confounder BMI did not affect the estimated OR (OR = 1.31, 95% CI 0.73-2.41 for EE-norgestimate; OR = 0.18, 95% CI 0.01-1.27 for EE-norethindrone). CONCLUSION: We found a higher than expected number of reports of ICH with Mirena((r)) in the FAERS database. We also found a similar risk of ICH with Mirena((r)) compared with the oral contraceptive EE norgestimate. The higher risk of ICH with EE-norethindrone, another oral contraceptive should be further investigated. PMID- 26240746 TI - Reducing psychotropic pharmacotherapy in patients with severe mental illness: a cluster-randomized controlled intervention study. AB - BACKGROUND: Many patients with mental illness receive psychotropic medicine in high dosages and from more than one drug. One of the consequences of this practice is obesity, which is a contributing factor to increased physical morbidity and premature death. METHODS: Our study was a cluster-randomized intervention study involving 6 facilities and 174 patients diagnosed with severe mental illnesses (73% schizophrenia). The intervention period was 12 months and consisted of teaching sessions with the staff and evaluating the patients' intake of psychotropic medication. At index, 44% met criteria for obesity and 76% met criteria for overweight. Waist circumferences were 108 cm for men and 108 cm for women. Olanzapine, clozapine and quetiapine were the most common prescribed antipsychotics. Mean values of daily doses of antipsychotic were 2.5. RESULTS: The intervention showed no significant differences between the intervention and control group regarding psychotropic treatment. At follow up, independent of intervention, patients receiving antipsychotic polypharmacy had a larger waist circumference compared with patients receiving antipsychotic monotherapy of 9.8 cm (1.5-18.1) (p = 0.028). DISCUSSION AND CONCLUSION: We found both a high prevalence of obesity and that the patients received treatment with antipsychotic polypharmaceutics in high dosages. Active awareness did not change practice and we must think of other ways to restrict treatment with psychotropics in this group of patients. PMID- 26240747 TI - Use of automated medication adherence monitoring in bipolar disorder research: pitfalls, pragmatics, and possibilities. AB - OBJECTIVES: Medication nonadherence occurs in 20-60% of persons with bipolar disorder (BD) and is associated with serious negative outcomes, including relapse, hospitalization, incarceration, suicide and high healthcare costs. Various strategies have been developed to measure adherence in BD. This descriptive paper summarizes challenges and workable strategies using electronic medication monitoring in a randomized clinical trial (RCT) in patients with BD. METHODS: Descriptive data from 57 nonadherent individuals with BD enrolled in a prospective RCT evaluating a novel customized adherence intervention versus control were analyzed. Analyses focused on whole group data and did not assess intervention effects. Adherence was assessed with the self-reported Tablets Routine Questionnaire and the Medication Event Monitoring System (MEMS). RESULTS: The majority of participants were women (74%), African American (69%), with type I BD (77%). Practical limitations of MEMS included misuse in conjunction with pill minders, polypharmacy, cost, failure to bring to research visits, losing the device, and the device impacting baseline measurement. The advantages were more precise measurement, less biased recall, and collecting data from past time periods for missed interim visits. CONCLUSIONS: Automated devices such as MEMS can assist investigators in evaluating adherence in patients with BD. Knowing the anticipated pitfalls allows study teams to implement preemptive procedures for successful implementation in BD adherence studies and can help pave the way for future refinements as automated adherence assessment technologies become more sophisticated and readily available. PMID- 26240748 TI - Clozapine prescribing in the UK: views and experience of consultant psychiatrists. AB - OBJECTIVES: It has been repeatedly shown that clozapine is underutilized and there is delayed use of it in clinical practice. METHOD: An online survey was sent to 2771 consultant psychiatrists registered with the Royal College of Psychiatrists in the UK. A total of 243 responded to this survey. The survey elicited their views and experiences in using clozapine as well as to identify what may be the underlying causes for its underutilization. RESULTS: Over 75% acknowledged that they had good training in using clozapine and about 56% had clozapine-dedicated service. However, 40.5% preferred to use several other antipsychotics prior to considering clozapine. A third felt it was not safe to start clozapine in the community and 42% had less than five patients on clozapine. Eleven possible reasons for clozapine underutilization were identified including concerns about side effects, patients not wanting to have blood tests and lack of experience or knowledge. Knowledge deficiency in certain aspects of clozapine use were identified, e.g. a third of respondents did not know that the risk of agranulocytosis changes with time, 42.7% did not think that clozapine can reduce substance use, while 20% were not aware of its benefit in reducing suicidal risk. CONCLUSIONS: Important areas of concern such as managing side effects and deficiency in evidence-based use of clozapine were identified. These can be targeted in training and professional development programme. PMID- 26240750 TI - Plasma levels of oral risperidone during enteral nutrition in a pregnant schizophrenic patient. PMID- 26240751 TI - Serotonin syndrome with a combination of aripiprazole and fluoxetine: a case report. PMID- 26240752 TI - The simulated early learning of cervical spine manipulation technique utilising mannequins. AB - BACKGROUND: Trivial pain or minor soreness commonly follows neck manipulation and has been estimated at one in three treatments. In addition, rare catastrophic events can occur. Some of these incidents have been ascribed to poor technique where the neck is rotated too far. The aims of this study were to design an instrument to measure competency of neck manipulation in beginning students when using a simulation mannequin, and then examine the suitability of using a simulation mannequin to teach the early psychomotor skills for neck chiropractic manipulative therapy. METHODS: We developed an initial set of questionnaire items and then used an expert panel to assess an instrument for neck manipulation competency among chiropractic students. The study sample comprised all 41 fourth year 2014 chiropractic students at Murdoch University. Students were randomly allocated into either a usual learning or mannequin group. All participants crossed over to undertake the alternative learning method after four weeks. A chi square test was used to examine differences between groups in the proportion of students achieving an overall pass mark at baseline, four weeks, and eight weeks. RESULTS: This study was conducted between January and March 2014. We successfully developed an instrument of measurement to assess neck manipulation competency in chiropractic students. We then randomised 41 participants to first undertake either "usual learning" (n = 19) or "mannequin learning" (n = 22) for early neck manipulation training. There were no significant differences between groups in the overall pass rate at baseline (chi(2) = 0.10, p = 0.75), four weeks (chi(2) = 0.40, p = 0.53), and eight weeks (chi(2) = 0.07, p = 0.79). CONCLUSIONS: This study demonstrates that the use of a mannequin does not affect the manipulation competency grades of early learning students at short term follow up. Our findings have potentially important safety implications as the results indicate that students could initially gain competence in neck manipulation by using mannequins before proceeding to perform neck manipulation on each other. PMID- 26240749 TI - Legal highs: staying on top of the flood of novel psychoactive substances. AB - There has been growing clinical, public, and media awareness and concern about the availability and potential harmfulness of so-called 'legal highs', which are more appropriately called new or novel psychoactive substances (NPS). A cat-and mouse process has emerged wherein unknown chemists and laboratories are producing new, and as yet nonproscribed, compounds for human consumption; and as soon as they are banned, which they inevitably are, slightly modified analogues are produced to circumvent new laws. This rapidly changing environment, 81 new substances were identified in 2013 alone, has led to confusion for clinicians, psychopharmacologists, and the public at large. Our difficulties in keeping up with the process has had a two-fold negative effect: the danger of ignoring what is confusing; and the problem that some of the newer synthesized compounds appear ever more potent. This review aims to circumscribe a quick moving and growing field, and to categorize NPS into five major groups based upon their 'parent' compounds: stimulants similar to cocaine, amphetamines and ecstasy; cannabinoids; benzodiazepine based drugs; dissociatives similar to ketamine and phencyclidine (PCP); and those modelled after classic hallucinogens such as LSD and psilocybin. Pharmacodynamic actions, subjective and physical effects, harmfulness, risk of dependency and, where appropriate, putative clinical potentials are described for each class. Clinicians might encounter NPS in various ways: anecdotal reportage; acute intoxication; as part of a substance misuse profile; and as a precipitant or perpetuating factor for longer-term physical and psychological ill health. Current data are overall limited, and much of our knowledge and treatment strategies are based upon those of the 'parent' compound. There is a critical need for more research in this field, and for professionals to make themselves more aware of this growing issue and how it might affect those we see clinically and try to help: a brave new world of so-called 'psychonauts' consuming NPS will also need informed 'psychotherapeutonauts'. The paper should serve as a primer for clinicians and interested readers, as well as provide a framework into which to place the new substances that will inevitably be synthesized in the future. PMID- 26240753 TI - Contribution of chronic diseases to the mild and severe disability burden in Belgium. AB - BACKGROUND: Population aging accompanied by an increased longevity with disability has raised international concern, especially due to its costs to the health care systems. Chronic diseases are the main causes of physical disability and their simultaneous occurrence in the population can impact the disablement process, resulting in different severity levels. In this study, the contribution of chronic diseases to both mild and severe disability burden in Belgium was investigated. METHODS: Data on 21 chronic diseases and disability from 35,799 individuals aged 15 years or older who participated in the 1997, 2001, 2004, or 2008 Belgian Health Interview Surveys were analysed. Mild and severe disability were defined based on questions related to six activities of daily living and/or mobility limitations. To attribute disability by severity level to selected chronic diseases, multiple additive hazard models were fitted to each disability outcome, separately for men and women. RESULTS: A stable prevalence of mild (5 %) and severe (2-3 %) disability was observed for the Belgian population aged 15 years or older between 1997 and 2008. Arthritis was the most important contributor in women with mild and severe disability. In men, low back pain and chronic respiratory diseases contributed most to the mild and severe disability burden, respectively. The contribution also differed by age: for mild disability, depression and chronic respiratory diseases were important contributors among young individuals, while heart attack had a large contribution for older individuals. For severe disability, neurological diseases and stroke presented a large contribution in young and elderly individuals, respectively. CONCLUSIONS: Our results indicate that the assessment of the contribution of chronic diseases on disability is more informative if different levels of disability are taken into consideration. The identification of diseases which are related to different levels of disability - mild and severe - can assist policymakers in the definition and prioritisation of strategies to tackle disability, involving prevention, rehabilitation programs, support services, and training for disabled individuals. PMID- 26240754 TI - Case report of renal cell carcinoma in automobile manufacturing factory worker due to trichloroethylene exposure in Korea. AB - BACKGROUND: The aim of this paper was report first case of renal cell carcinoma developed in a worker who worked in an automobile manufacture line which handles trichloroethylene in Korea. CASE PRESENTATION: To clarify the relationship between the onset of renal cell carcinoma in 52-years old male worker and the exposure to trichloroethylene, document studies and work environment measurement were done. Past work environment exposure data were reviewed and medical history and surgery records of the worker were also reviewed. The patient had no personal risk factor related to renal cell carcinoma except for his smoking habit of quarter a pack per day for twenty years, and since trichloroethylene was not part of measurement criteria, past work environment risk assessment data could not verify the exposure. The exposure level is deduced by analyzing material exposure level of work environments which has similar processes in data from revised research of chemical exposure standard and work environment validity assessment. Evaluation Committee of Epidemiologic Survey decided that there are relevant relationship between the exposure and the disease, though we do not have exact data during that period, most experts agree that in every factories they used trichloroethylene without any direction. CONCLUSIONS: From the relevant medical history and the results of the usage of trichloroethylene in the relevant industries, and initial discovery of renal cell carcinoma at health inspection sonogram in 2001, it can be concluded that suggests significant causal relationship between the exposure to trichloroethylene and renal cell carcinoma onset, thus reporting it to be the first domestic case declared to be occupational disease. PMID- 26240756 TI - Traumatic Wound Dehiscence after Keratoplasty: Characteristics, Risk Factors, and Visual Outcome. AB - Purpose. The study aimed at evaluating the patients' characteristics, risk factors, complications, and visual outcome of traumatic wound dehiscence after keratoplasty. Patients and Methods. A retrospective case series that included 20 eyes of 20 patients who had undergone a previous keratoplasty procedure followed by traumatic wound dehiscence. Records of the selected patients were reviewed. The mean duration of follow-up after repair was 21 months. Included patients were recalled for the final follow-up visit. Results. The procedure of corneal transplantation was penetrating (PKP) in 16 eyes and deep anterior lamellar keratoplasty (DALK) in 4 eyes. The associated anterior segment injuries included iris prolapse in 17 eyes and lens extrusion in 12 eyes. The associated posterior segment injuries included vitreous hemorrhage in 11 eyes and retinal detachment in 4 eyes. The final BSCVA was 0.1 or better in 5 cases (25 %) and was better than hand motions (HM) to less than 0.1 in 7 cases (35 %). Conclusion. Traumatic wound dehiscence following keratoplasty results in poor visual outcome. Cases following DALK may have less wound extent and better final visual outcome. The dehiscence seems most likely to occur during the first year. PMID- 26240755 TI - Modeling In Vivo Interactions of Engineered Nanoparticles in the Pulmonary Alveolar Lining Fluid. AB - Increasing use of engineered nanomaterials (ENMs) in consumer products may result in widespread human inhalation exposures. Due to their high surface area per unit mass, inhaled ENMs interact with multiple components of the pulmonary system, and these interactions affect their ultimate fate in the body. Modeling of ENM transport and clearance in vivo has traditionally treated tissues as well-mixed compartments, without consideration of nanoscale interaction and transformation mechanisms. ENM agglomeration, dissolution and transport, along with adsorption of biomolecules, such as surfactant lipids and proteins, cause irreversible changes to ENM morphology and surface properties. The model presented in this article quantifies ENM transformation and transport in the alveolar air to liquid interface and estimates eventual alveolar cell dosimetry. This formulation brings together established concepts from colloidal and surface science, physics, and biochemistry to provide a stochastic framework capable of capturing essential in vivo processes in the pulmonary alveolar lining layer. The model has been implemented for in vitro solutions with parameters estimated from relevant published in vitro measurements and has been extended here to in vivo systems simulating human inhalation exposures. Applications are presented for four different ENMs, and relevant kinetic rates are estimated, demonstrating an approach for improving human in vivo pulmonary dosimetry. PMID- 26240757 TI - Predisposition to Cervical Atypia in Systemic Lupus Erythematosus: A Clinical and Cytopathological Study. AB - Introduction. Systemic lupus erythematosus (SLE) is a complex disease with variable presentations, course, and prognosis. The female genital tract may be a potential target organ in SLE since cervical inflammation may be associated with disease activity. An increase in cervical dysplasia, a precursor of cervical cancer, has been reported in females with SLE. Aim of the Work. This work aimed to study the prevalence of abnormal cervicovaginal smears in patients with systemic lupus erythematosus (SLE) and to correlate abnormal smear findings with exposure to infection with human papilloma virus (HPV) in SLE patients. Patients and Methods. Thirty-two patients with SLE, fulfilling the 1997 revised criteria for the classification of SLE, were included in this study. They were subjected to full history taking, clinical examination, laboratory investigations, and cervicovaginal smearing. Twenty healthy subjects not known to suffer from any rheumatological disease were used as controls, and they were subjected to cervicovaginal smearing. Results. Four out of 32 SLE patients showed abnormal Pap smears (12.5%) compared to none showing any cervical changes in the control group (0%). Among these 4 patients, 3 were having ASCU and one was having LSIL (HPV). Conclusion. Cervicovaginal smearing is an easy, economic, safe, repeatable, and noninvasive technique for screening and early detection of cervical neoplastic lesions in SLE. PMID- 26240758 TI - Usefulness of the Pain Tracking Technique in Acute Mechanical Low Back Pain. AB - Objective. To evaluate the usefulness of the pain tracking technique in acute mechanical low back pain. Method. We performed an experimental prospective (longitudinal) explanatory study between January 2011 and September 2012. The sample was randomly divided into two groups. Patients were assessed at the start and end of the treatment using the visual analogue scale and the Waddell test. Treatment consisted in applying the pain tracking technique to the study group and interferential current therapy to the control group. At the end of treatment, cryotherapy was applied for 10 minutes. The Wilcoxon signed-rank test and the Mann Whitney test were used. They were performed with a predetermined significance level of p <= 0.05. Results. Pain was triggered by prolonged static posture and intense physical labor and intensified through trunk movements and when sitting and standing. The greatest relief was reported in lateral decubitus position and in William's position. The majority of the patients had contracture. Pain and disability were modified with the rehabilitation treatment in both groups. Conclusions. Both the pain tracking and interferential current techniques combined with cryotherapy are useful treatments for acute mechanical low back pain. The onset of analgesia is faster when using the pain tracking technique. PMID- 26240759 TI - Evaluation of the Effects of Charged Amino Acids on Uncontrolled Seizures. AB - Introduction. Epilepsy is one of the most common diseases of the central nervous system. The prevalence of epilepsy throughout the world is 0.5 to 1%, and the same rate is 7.8 per 1000 in Kerman. Almost 20 to 30% of epileptic patients do not respond properly to common medications. The present study investigated patients who did not respond to common and, even in some cases, adjuvant therapies, with two seizures or more per week, regardless of the type of the inflicted epilepsy. Methodology. The participants of the present double-blind study were randomly selected into three 10-member groups of uncontrolled epileptic patients (arginine, glutamic acid, and lysine). The patients used amino acid powder dissolved in water (three times the daily need) every day for two weeks before breakfast. The number of seizures was recorded one week prior to commencing amino acid use, as well as the first and the second weeks subsequent to use. Results. A total of 32 patients were studied in three groups. The decline rates of seizures were 53%, 41%, and 13%, and the P value was 0.013, 0.027, and 0.720, respectively. Conclusion. Administration of the charged amino acids, arginine, and glutamic acid can decrease the seizures of patients suffering from uncontrolled epilepsy. PMID- 26240760 TI - Prevalence of Depression and Anxiety among Patients with Multiple Sclerosis Attending the MS Clinic at Sheikh Khalifa Medical City, UAE: Cross-Sectional Study. AB - Depression and anxiety are reported to be prevalent in patients with MS, with prevalence rates ranging from 20% to 50%. Unfortunately, the rates, patterns, and risk factors are not well studied in our Middle East region, and, to our knowledge, not at all in UAE. Using standardized screening tools, we observed that 17% and 20% of 80 patients seen in MS clinic had scores consistent with major depression and anxiety disorders, respectively, at a rate that was not statistically different when compared to age and sex matched controls. None of the studied variables including duration of the disease, EDSS scores, age, gender, and the level of education had any significant correlation with the rates of both disorders. Almost two-thirds of the patients with scores consistent with major depression and anxiety were not on antidepressant and antianxiety medications. PMID- 26240761 TI - Artery to Cystic Duct: A Consistent Branch of Cystic Artery Seen in Laparoscopic Cholecystectomy. AB - Uncontrolled arterial bleeding during laparoscopic cholecystectomy is a serious problem and may increase the risk of bile duct damage. Therefore, accurate identification of the anatomy of the cystic artery is very important. Cystic artery is notoriously known to have a highly variable branching pattern. We reviewed the anatomy of the cystic artery and its branch to cystic duct as seen through the video laparoscope. A single artery to cystic duct with the classical "H-configuration" was demonstrated in 161 (91.47%) patients. This branch may cause troublesome bleeding during laparoscopic dissection in the hepatobiliary triangle. Careful identification of artery to cystic duct is helpful in the proper dissection of Calot's triangle as it reduces the chances of hemorrhage and thus may also be helpful in prevention of extrahepatic biliary radical injuries. PMID- 26240762 TI - Case Report of Multiple Tracheostomy Revisions due to Persistent, Recurrent Cuff Leak. AB - This case is a patient with amyotrophic lateral sclerosis who was unable to be separated from mechanical ventilator support and required a tracheostomy. The patient underwent an initial open tracheostomy utilizing flexible fiberoptic tracheoscopy (FFT) in the operating room (OR). Subsequently, he developed recurrent leaks in the tracheal tube cuff requiring multiple trips back to the operating room. The recurrent cuff leak occurred following each tube placement until the etiology of the leak was discovered during the fourth procedure. In the fourth procedure, the wound was explored more extensively, and it was found that there was a sharp, calcified, aberrant fragment of a tracheal cartilage ring protruding into the tracheal lumen, which was damaging the cuff of each tube. This fragment was not visible by multiple FFTs, nor was it visible in the wound by the surgeons until wider exploration of the wound occurred. The cartilage fragment was ultimately excised and the patient had no further cuff leaks. Aberrant tracheal cartilage should be on the differential diagnosis for cuff leaks subsequent to surgical tracheostomy (ST) or percutaneous dilatational tracheostomy (PDT). PMID- 26240763 TI - Superdominant Right Coronary Artery with Absence of Left Circumflex and Anomalous Origin of the Left Anterior Descending Coronary from the Right Sinus: An Unheard Coronary Anomaly Circulation. AB - Coronary artery anomalies are congenital changes in their origin, course, and/or structure. Most of them are discovered as incidental findings during coronary angiographic studies or at autopsies. We present herein the case of a 70-year-old man with symptomatic severe aortic valvar stenosis whose preoperative coronary angiogram revealed a so far unreported coronary anomaly circulation pattern. PMID- 26240764 TI - Ebstein's Anomaly, Left Ventricular Noncompaction, and Sudden Cardiac Death. AB - Ebstein's anomaly is a congenital disorder characterized by apical displacement of the septal leaflet of the tricuspid valve. Ebstein's anomaly may be seen in association with other cardiac conditions, including patent foramen ovale, atrial septal defect, and left ventricular noncompaction (LVNC). LVNC is characterized by increased trabeculation within the left ventricular apex. Echocardiography is often used to diagnose LVNC; however, magnetic resonance (MR) imaging offers superior characterization of the myocardium. We report a case of sudden cardiac death in a patient with Ebstein's anomaly with unrecognized LVNC noted on post mortem examination with screening documenting the presence of LVNC in one of the patient's twin sons. PMID- 26240765 TI - Oral Manifestations of Crohn's Disease: A Case Report and Review of the Literature. AB - Crohn's disease (CD) is an inflammatory disorder of the gastrointestinal tract that is likely caused by an inappropriate mucosal inflammatory response to intestinal bacteria in a genetically predisposed host. The lesions of CD can involve any region of the GI tract as well as extraintestinal sites such as the skin, joints, and eyes. The most common presenting symptoms are abdominal pain and prolonged diarrhea associated with fevers, fatigue, and malaise. Delayed growth and failure to thrive may also be observed in pediatric patients. Oral manifestations of CD are known as oral CD and may precede GI involvement, thus serving as early markers of this condition. We describe a 6-year-old male who presented with oral lesions as his initial manifestation of disease and review the current literature pertaining to oral CD. PMID- 26240766 TI - Linoleic Acid Induced Acute Hepatitis: A Case Report and Review of the Literature. AB - Several dietary supplements used for weight loss have been reported to cause hepatotoxicity. Conjugated Linoleic Acid (CLA) is a dietary supplement that has been shown to cause reduction in body fat mass. Here, we present the first case of CLA induced acute hepatitis in the United States and only the third case in the worldwide literature along with a brief review of the literature. PMID- 26240767 TI - Denileukin Diftitox (Ontak) as Maintenance Therapy for Peripheral T-Cell Lymphomas: Three Cases with Sustained Remission. AB - Peripheral T-cell lymphomas (PTCL) are rare but markedly aggressive forms of non Hodgkin's lymphoma (NHL). They carry a poor prognosis, with current therapeutic approach being generally ineffective. The most employed first-line treatment is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), which still results in high rates of relapses. Denileukin diftitox is a fusion protein combining the cytotoxic portion of the diphtheria toxin and the receptor-binding domain of the interleukin-2 (IL-2) molecule, thereby targeting cells expressing the IL-2 receptor, including both T-cell and B-cell lymphomas. It has been approved for the treatment of cutaneous T-cell lymphomas, and it has documented activity in PTCL both as a single agent and as part of combination therapy. This report documents three cases of PTCL where denileukin diftitox has been used as long-term maintenance therapy after complete remission was achieved. While the overall survival rate of patients with advanced stage, refractory PTCL is generally poor (with median overall survival of 5.5 months), the three patients described in this report are all experiencing an ongoing complete remission for more than four years. PMID- 26240768 TI - Small Cell Lung Cancer Patient with Profound Hyponatremia and Acute Neurological Symptoms: An Effective Treatment with Fludrocortisone. AB - Hyponatremia is a frequent electrolyte abnormality in patients with small cell lung cancer (SCLC). Being usually asymptomatic, hyponatremia may cause symptoms like nausea, fatigue, disorientation, headache, muscle cramps, or even seizures, particularly if severe and rapid decrease of serum sodium levels occurs. Here we report a case of SCLC patient with severe hyponatremia and acute neurological symptoms that developed 2 days after the first course of second-line chemotherapy, most probably due to the release of antidiuretic hormone (ADH, also known as arginine vasopressin) during lysis of the tumour cells. Initial treatment consisted of continuous administration of hypertonic saline that resulted in improvement of patient's neurological status. However, to obtain a persistent increase in serum sodium level, pharmacological intervention with oral fludrocortisone 0.1 mg twice daily was needed. We can therefore conclude that mineralocorticoids may be used to correct hyponatremia in SCLC patients when appropriate. PMID- 26240769 TI - Biologic Augmentation of the Ulnar Collateral Ligament in the Elbow of a Professional Baseball Pitcher. AB - Tears of the ulnar collateral ligament (UCL) of the elbow are common injuries in overhead athletes. Although surgical reconstruction of the UCL has improved outcomes, not all athletes return to their previous level of competition and when this goal is achieved, the time required averages one to two years. Therefore, additional techniques are needed to further improve return to play and the rate of return to play in overhead athletes. A construct comprising a dermal allograft, platelet rich plasma (PRP), and mesenchymal stem cells (MSCs) has been shown to successfully improve healing in the rotator cuff. Given the promising provisional findings, we postulated that this construct could also improve healing if applied to the UCL. Therefore, the purpose of the present report was to examine the feasibility of utilizing a dermal allograft, PRP, and MSC construct to augment UCL reconstruction in a professional baseball pitcher. No complications were encountered. Although limited to minimal follow-up, the patient has demonstrated excellent progress and has returned to activity. PMID- 26240770 TI - Mature Nasopharyngeal Teratoma in a Child. AB - Teratomas are neoplasms derived from the germ cell with components of all the three embryonic layers. These are rare neoplasms in head and neck region which can occur in any age group but are more prevalent in children. The present case is an 11-year-old girl who was brought with history of painless and progressive swelling in the oropharynx for 3 years with the associated left sided nasal blockage and nasal discharge. CT scan was suggestive of benign nasopharyngeal mass highly suspicious for lipoma. Excision of the mass was done under general anaesthesia. Peroperatively, it was a smooth, pedunculated mass arising from the left lateral wall in the nasopharynx. On cut section, it was solid to cystic mass similar to fatty tissue. Her HPE report came out to be mature teratoma of nasopharynx. PMID- 26240771 TI - Papillary Thyroid Microcarcinoma with a Large Cystic Dilated Lymph Node Metastasis to the Neck Mimicking a Branchial Cleft Cyst: A Potential Pitfall. AB - Lateral cervical cystic mass in a young adult very rarely could be a first sign of an occult thyroid papillary microcarcinoma metastasis. In this paper, we presented a 37-year-old male patient whose preoperative 6 cm left lateral cervical cystic mass was initially diagnosed as branchial cleft cyst, but then the postoperative histopathological examination of the mass was revealed as papillary thyroid carcinoma metastasis. Preoperative fine needle aspiration biopsy was relevant with a branchial cleft cyst. In the left thyroid lobe there were 3 solid nodules with 4, 6, and 12 mm dimensions, respectively. One of the nodules had malignant well-differentiated cells diagnosed after fine needle aspiration biopsy. After total thyroidectomy, histopathologic evaluation of biopsy material's showed papillary thyroid microcarcinomas. This case indicates that especially in a young adult lateral cervical cystic mass should be carefully considered preoperatively for the possibility of metastatic occult thyroid carcinoma, especially for papillary carcinoma in differential diagnosis, and evaluation of the thyroid gland should be taken into account. PMID- 26240772 TI - Ultrasound in Rheumatologic Interstitial Lung Disease: A Case Report of Nonspecific Interstitial Pneumonia in Rheumatoid Arthritis. AB - According to the American Thoracic Society (ATS)/European Respiratory Society consensus classification, idiopathic interstitial pneumonias (IIPs) include several clinic-radiologic-pathologic entities: idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia, acute interstitial pneumonia, respiratory bronchiolitis-associated ILD, desquamative interstitial pneumonia, and lymphoid interstitial pneumonia. Ultrasound Lung Comets (ULCs) are an echographic chest-sonography hallmark of pulmonary interstitial fibrosis. We describe the ultrasound (US) findings in the follow-up of a NSIP's case in rheumatoid arthritis (RA). PMID- 26240773 TI - Anti-Erythropoietin Antibody Associated Pure Red Cell Aplasia Resolved after Liver Transplantation. AB - Patients undergoing antiviral therapy for chronic hepatitis C often develop anemia secondary to ribavirin and interferon. Recombinant erythropoietin has been used to improve anemia associated with antiviral therapy and to minimize dose reductions, which are associated with decreased rates of sustained virologic response. A rare potential side effect of recombinant erythropoietin is anti erythropoietin antibody associated pure red cell aplasia. In chronic kidney disease patients with this entity, there have been good outcomes associated with renal transplant and subsequent immunosuppression. In this case, a chronic liver disease patient developed anti-erythropoietin associated pure red cell aplasia and recovered after liver transplantation and immunosuppression. It is unclear whether it is the transplanted organ, the subsequent immunosuppression, or the combination that contributed to the response. In conclusion, anti-erythropoietin associated pure red cell aplasia is a serious complication of erythropoietin therapy, but this entity should not be considered a contraindication for solid organ transplantation. PMID- 26240774 TI - Transplantation of Horseshoe Kidney from Living, Genetically Unrelated Donor. AB - We report a case of renal transplantation using a horseshoe kidney from a living, genetically unrelated donor. The recipient was a 60-year-old man with diabetic nephropathy, and the donor was the 63-year-old wife of the recipient with a horseshoe kidney free of complications. Computed tomography showed two renal arteries and one renal vein on the left side, and the isthmus was perfused by several accessory arteries and veins. To demarcate the boundary of the isthmus, the left renal artery was ligated and cannulated for in situ perfusion. Furthermore, the isthmus was clamped, and the boundary of the isthmus was confirmed. The kidney was divided at the left margin of the perfused boundary. The cut ends of the isthmus were closed by sutures. The left kidney was transplanted into the right iliac fossa of the recipient. Asymptomatic fluid collection occurred on the cut surface at the isthmus of the donor, and this fluid decreased in due course. On the other hand, the recipient experienced no surgical complication or rejection, while maintaining serum creatinine levels of 2.00-2.20 mg/dL over a 22-month follow-up period. Horseshoe kidneys may be used for transplantation in selected cases after a detailed preoperative evaluation. PMID- 26240775 TI - Systemic Candida parapsilosis Infection Model in Immunosuppressed ICR Mice and Assessing the Antifungal Efficiency of Fluconazole. AB - This study was to establish a systemic C. parapsilosis infection model in immunosuppressed ICR mice induced by cyclophosphamide and evaluate the antifungal efficiency of fluconazole. Three experiments were set to confirm the optimal infectious dose of C. parapsilosis, outcomes of infectious model, and antifungal efficiency of fluconazole in vivo, respectively. In the first experiment, comparisons of survival proportions between different infectious doses treated groups showed that the optimal inoculum for C. parapsilosis was 0.9 * 10(5) CFU per mouse. The following experiment was set to observe the outcomes of infection at a dose of 0.9 * 10(5) CFU C. parapsilosis. Postmortem and histopathological examinations presented fugal-specific lesions in multiorgans, especially in kidneys, characterized by inflammation, numerous microabscesses, and fungal infiltration. The CFU counts were consistent with the histopathological changes in tissues. Th1/Th2 cytokine imbalance was observed with increases of proinflammatory cytokines and no responses of anti-inflammatory cytokines in sera and kidneys. In the last experiment, model based evaluation of fluconazole indicated that there were ideal antifungal activities for fluconazole at dosages of 10-50 mg/kg/d. Data demonstrates that the research team has established a systemic C. parapsilosis infection model in immunosuppressed ICR mice, affording opportunities for increasing our understanding of fungal pathogenesis and treatment. PMID- 26240777 TI - A quantitative study on the formation of Pseudomonas aeruginosa biofilm. AB - Biofilms are bacterial cells in a matrix of extracellular polymeric substance. The formation of biofilm depends on the microenvironment. In this study, the effect of temperature on Pseudomonas aeruginosa biofilm formation was evaluated with respect to three parameters-the mass of biofilm formed, the production of extracellular polysaccharide and the adhesion force. The results indicate that biofilm biomass (2.8, A590), extracellular polysaccharide production (1240 +/- 40 ug) and adhesion force (10.8 +/- 0.2 nN) were highest at 37 degrees C. The results also suggest that biofilms formed at 37 degrees C would have a higher mechanical stability (than biofilms grown at 28, 33 and 42 degrees C). PMID- 26240776 TI - An Online Bystander Intervention Program for the Prevention of Sexual Violence. AB - OBJECTIVE: Because of its high prevalence and serious consequences for victims, sexual violence is a significant problem on college campuses. Sexual assault prevention programs based on the bystander intervention model have been shown to be effective; however, current programs are limited in terms of ease of distribution. To address this issue, we developed and evaluated "Take Care," an online bystander intervention program. To our knowledge, this is the first empirical evaluation of an online bystander intervention program designed to prevent sexual violence. METHOD: Ninety-three participants (80.6% female, 19.4% male) recruited from social psychology classes at a mid-size university were randomly assigned to view one of two online programs: Take Care or a control program on study skills. Before viewing the programs, participants completed measures of bystander behaviors and feelings of efficacy for performing such behaviors. Measures were administered again post-intervention and at a two-month follow-up assessment. RESULTS: Participants who viewed Take Care reported greater efficacy for engaging in bystander behaviors at post-treatment and two months following treatment, compared to those who viewed the control program. In addition, participants who viewed Take Care reported performing relatively more bystander behaviors for friends at the two-month follow-up assessment, compared to participants who viewed the control program. CONCLUSIONS: These results suggest that sexual violence prevention programs may be effectively adapted to an online format. PMID- 26240778 TI - The rs10993994 in the proximal MSMB promoter region is a functional polymorphism in Asian Indian subjects. AB - BACKGROUND: The microseminoprotein gene encoding prostate secretory protein of 94 amino acids (PSP94) harbours a potential risk allele (rs10993994) for prostate cancer (PCa) in its promoter region. However, studies on rs10993994 have been sparse in Asian Indians. METHODS: The present study recruited a sample population of 44 benign prostatic hyperplasia patients, 33 PCa patients and 60 healthy participants, of which, participants without other confounding risk factors for PCa were retained. The serum PSP94 (sPSP94) levels were measured by a serum-based ELISA in an earlier study. A novel RFLP technique was developed to screen for rs10993994 which was validated with direct sequencing. RESULTS: Sequencing showed additional 4 SNPs (rs41274660, rs141211965, rs12770171, rs10669586) and 2 novel variants (GenBank accession nos. KM265191 and KM265192). In silico DNA topographical studies predicted that KM265192 would have higher cleavage intensity and more accessibility for binding of transcription factors. Even though, similar frequencies were observed for all the variants in all the three study groups, the risk allele 'T' (rs10993994) was seen to be associated with reduced PSP94 expression both at mRNA and protein level. Further, mRNA expression as studied by real-time PCR correlated positively with sPSP94 levels. Interestingly, CC genotype of rs10993994 showed highest sPSP94 levels in all the three study groups and was associated with Gleason score <=7 in PCa patients. In contrast, TT genotype of rs10993994 was associated with lesser sPSP94 levels and with aggressiveness of PCa. CONCLUSION: rs10993994 was found to be a functional SNP in the studied Asian Indian population. PMID- 26240779 TI - Quality of life in elderly people at the start of using in-home care. AB - BACKGROUND: Quality of life (QOL) among 200 elderly people planning to use in home care services available to those with severe illness was surveyed to identify the most effective method of improving QOL of the elderly through such care services. RESULTS: QOL was surveyed using a PGC Morale Scale, and factors related to QOL were verified by multivariate analysis. The most relevant factors for QOL among the 11 analyzed were the client's reason for choosing to use in home care services and the client's family structure. The average PGC-MS score was 9.09 +/- 2.6 (mean +/- standard deviation). Analysis of factors significantly affecting PGC-MS score identified treatment history and job type (p < 0.001), family structure (p < 0.009), age (p < 0.008), and years of education (p < 0.029). In addition, after performing multiple regression analysis using treatment history, years of education, employment history, and family structure as independent variables, treatment history (visiting a hospital and receiving treatment but deciding to use in-home care services later) remained significantly related to PGC-MS score (p < 0.001), as did family structure (three-generation families; p < 0.001). Further, with regard to treatment history, PGC-MC scores were higher in those who visited a hospital and received treatment but decided to use in-home care services later than in those who decided to enroll in the care service while still in the hospital. In contrast, with regard to family structure, PGC-MS scores decreased in the order of three-generation families, those living alone, couples, and two-generation families. CONCLUSIONS: QOL of elderly people might be improved by the provision of in-home care services with consideration of consumers' intentions and factors known to influence QOL. PMID- 26240780 TI - Antimicrobial activity of new green-functionalized oxazoline-based oligomers against clinical isolates. AB - BACKGROUND: The search for new antimicrobial compounds able to overcome the global issue of microbial resistance to antibiotics is a priority worldwide. Moreover, several commensal microorganisms have been increasingly associated to opportunistic microbial infections. Having previously disclosed the green synthesis and preliminary characterization of the oligomers [linear oligo(ethylenimine) hydrochloride and oligo(2-methyl-2-oxazoline) quaternized with N,N-dimethyldodecylamine] we herein report on the screening of these oligomers against a battery of 69 clinical isolates of Aerococcus spp., Candida spp., Staphylococcus spp. and Streptococcus spp. FINDINGS: The isolates' susceptibility to both oligomers was evaluated by determining their minimal inhibitory concentration (MIC) and the biocidal effectiveness of each compound was further confirmed through spectrophotometric measurements and fluorescence microscopy. The MIC values of the 69 isolates were highly variable, yet favourably comparable with those of other antimicrobial polymers. The viability assays resulted in 100% of microbial killing rate after only 5 min, highlighting the promising antimicrobial action of these oligomers. CONCLUSIONS: Though further studies are required, evidence suggests that a strong effort should be done in order to confirm these compounds as valid alternatives for several clinical applications. This is reinforced by their well described biocompatibility with human tissues and by their proposed mechanism of action which difficult the development of microbial resistance to these compounds. PMID- 26240781 TI - Constructive techniques for zeros of monotone mappings in certain Banach spaces. AB - Let E be a 2-uniformly convex real Banach space with uniformly Gateaux differentiable norm, and [Formula: see text] its dual space. Let [Formula: see text] be a bounded strongly monotone mapping such that [Formula: see text] For given [Formula: see text] let [Formula: see text] be generated by the algorithm: [Formula: see text]where J is the normalized duality mapping from E into [Formula: see text] and [Formula: see text] is a real sequence in (0, 1) satisfying suitable conditions. Then it is proved that [Formula: see text] converges strongly to the unique point [Formula: see text] Finally, our theorems are applied to the convex minimization problem. PMID- 26240782 TI - Magnetic resonance imaging of uterine fibroids: a preliminary investigation into the usefulness of 3D-rendered images for surgical planning. AB - PURPOSE: This study aimed to assess the efficacy of 3D surface-rendered (SR) magnetic resonance (MR) images for surgical planning of uterine fibroids. METHODS: Ten patients with uterine fibroids underwent 3D volume isotropic turbo spin-echo acquisition (VISTA) sequences in sagittal planes. SR images showing the uterine body, endometrium, and fibroids were extracted from the raw MR data. The preoperative assessment for fertility-preserving fibroid enucleation was independently performed by two gynecologists using 2D sagittal and 3D SR images separately. RESULTS: The required interpretation times [second] for sagittal versus SR images were 19.7 +/- 9.5 versus 10.4 +/- 5.1 for observer 1 (p < 0.05) and 47.5 +/- 12.3 versus 19.7 +/- 9.5 for observer 2 (p < 0.01). The accuracy rates of the planned surgical procedures from sagittal versus SR images were 50 versus 70% for observer 1 and 70 versus 70% for observer 2. The accuracy rates of the numbers of fibroids to be removed from sagittal versus SR images were 70 versus 80% for observer 1 and 70 versus 80% for observer 2. CONCLUSION: Compared with sagittal images, SR images could significantly reduce the time required for surgical planning of uterine fibroids without sacrificing the accuracy of the preoperative assessment. PMID- 26240783 TI - Osteomyelitis due to Clostridium innocuum in a patient with acute lymphoblastic leukemia: case report and literature review. AB - INTRODUCTION: Clostridium innocuum is an anaerobic Gram-positive bacterium, unable to produce toxins and rarely causes infections. We report the first case of C. innocuum osteomyelitis and bacteremia in a patient with acute lymphoblastic leukemia (ALL). Findings were compared with previously reported cases of C. innocuum infections in immunocompromised patients, e.g., patients with acquired immune deficiency syndrome, leukemia, and organ transplantation. CASE DESCRIPTION: A 32-year-old Japanese male was admitted for persistent low-grade fever and purpura lasting for 1 month. Complete blood counts and cytogenetic analysis identified Ph1-positive ALL, which was successfully treated using chemotherapy. However, the patient developed high fever and lumbar pain during complete remission. Fluorodeoxyglucose-positron emission tomography and computed tomography demonstrated osteomyelitis. C. innocuum was identified as the causative agent and the patient was successfully treated using antibiotic therapy. DISCUSSION AND EVALUATION: We performed a literature review revealing a number of common aspects to the clinical presentation of C. innocuum infection and an association with various comorbidities. Further, we highlight the most efficient diagnostic and treatment strategies for C. innocuum osteomyelitis. CONCLUSIONS: Clostridium innocuum can be a causative pathogen of osteomyelitis and bacteremia in immunocompromised patients. PMID- 26240784 TI - Higher locoregional recurrence rate for triple-negative breast cancer following neoadjuvant chemotherapy, surgery and radiotherapy. AB - BACKGROUND: Breast cancer subtype, determined by expression of estrogen/progesterone receptor (ER/PR) and human epidermal growth factor receptor (HER)-2, is predictive for prognosis. The importance of subtype to locoregional recurrence (LRR) following neoadjuvant chemotherapy (NAC) is unknown, particularly after adjuvant radiotherapy (RT). METHODS: We retrospectively identified 160-breast cancer patients registered at Columbia University Medical Center from 1999 to 2012 treated with NAC, surgery and adjuvant RT. RESULTS: Patients were grouped by receptor status: hormone receptor positive (HR+) [(ER or PR+)/HER2-; n = 75], HER2+ (n = 46), or triple-negative (TNBC) [ER (-) PR (-) HER2 (-); n = 36]. The median follow-up was 28 months. 92.0% received an anthracycline-taxane based NAC and 80.4% of HER2+ patients received trastuzumab. All underwent surgical resection followed by RT. 15.6% had a pathologic complete response (pCR): 26% of HER2+, 5% of HR+, and 25% of TN. The actuarial rate of DM was 13.8% for the entire cohort, with equivalent rates by subtypes in non-pCR patients. The overall rate of LRR was 8%. However, the LRR rate was significantly higher for TNBC patients (22.2%) than HER2+ (5.6%) (p = 0.025) or HR+ (3.0%) (p = 0.037) in non-pCR group. In the pCR group, two patients had recurrence; one LRR and one a DM, both had TNBC. All LRR occurred in or near the radiation field. CONCLUSIONS: TNBC patients with < pCR to NAC have a significantly higher LRR rate as compared to other subtypes even with surgery and adjuvant RT. Our data support a need to further intensify local therapy in TNBC patients. PMID- 26240785 TI - Serum estrone concentration, estrone sulfate/estrone ratio and BMI are associated with human epidermal growth factor receptor 2 and progesterone receptor status in postmenopausal primary breast cancer patients suffering invasive ductal carcinoma. AB - BACKGROUND: We investigated in postmenopausal women with primary breast cancer prior to surgical intervention whether, serum levels of different steroid hormones and hormonal precursors associated with tumor tissue estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. METHODS: We enrolled 1,042 patients suffering invasive ductal carcinoma undergoing surgical resection in the National Institute of Oncology, Hungary between 2003 and 2011. Serum parameters were measured by RIA/IRMA assays; tumor tissue ER, PR and HER2 status was assessed histologically. Patients were classified according to tumor receptor status. Case-case analysis subjects were categorized into four subgroups based on serum hormone concentrations in ER, PR and HER2 receptor-negative cases, respectively. RESULTS: Serum estrone sulfate and dehydroepiandrosterone sulfate levels correlated with each other and also with serum estrone and estradiol levels. According to case-case study the odds ratios in the highest quartile were 1.517 (p = 0.0305, Ptrend = 0.0394) for androstenedione, 1.495 (p = 0.0317, Ptrend < 0.0105) for estrone and 0.654 (p = 0.0273, Ptrend < 0.0151) for estrone sulfate/estrone ratio in PR+ vs. PR- tumors. Regarding HER2 status (HER2+ vs. HER2-), the odds ratios for estrone, estrone sulfate and estrone sulfate/estrone ratio were 0.530 (p = 0.0234, Ptrend = 0.0595), 2.438 (p = 0.0042, Ptrend < 0.0066) and 3.118 (p = 0.0001, Ptrend < 0.0001) in the highest quartile, respectively. Of note significantly increased BMI associates with PR+ and ER +/PR+ status while significantly decreased BMI was observed in HER2+ cases. CONCLUSIONS: Taken together, measurement of serum estrone and estrone sulfate concentrations prior to surgical intervention might support the individualization of regime in postmenopausal primary breast cancer patients. PMID- 26240786 TI - Exercise training improves heart rate recovery in women with breast cancer. AB - PURPOSE: To determine whether exercise training improves autonomic function in women with breast cancer (BC). METHODS: Fifty-one patients (aged between 39 and 72 years) with a history of primary invasive BC within the previous 5 years and enrolled in the Mediterranean diet-based DIANA (Diet and Androgens)-5 Trial were subdivided in two groups: a ET group (n = 25) followed a formal ET program of moderate intensity (3 session/week on a bicycle at 60-70% VO2peak for 3 months, followed by one session/week until 1-year follow-up), while a control group (n = 26) did not perform any formal ET. At baseline and after 1-year, all patients underwent cardiopulmonary exercise stress test (CPET). Heart rate recovery (HRR) was calculated as the difference between heart rate at peak exercise and heart rate at first minute of the cool-down period. RESULTS: There were no significant differences between groups in baseline anthropometrical, BC characteristics, metabolic profile, CPET parameters and HRR. Compared to controls, at 1-year follow-up ET group showed a significant improvement in VO2peak (from 12.6 +/- 3.0 to 14.5 +/- 3.3 ml/kg/min, p < 0.001; p < 0.001 between groups); and in HRR (from 17.6 +/- 6.4 to 23.0 +/- 8.3 beats/min, p < 0.001; p < 0.001 between groups). In ET group the changes in HRR directly correlated with changes in VO2peak (r = 0.58, p = 0.002). CONCLUSIONS: Moderate intensity exercise training in BC survivors is associated with improvement of autonomic function. Whether the improvement of sympatho-vagal balance may favorably modulate some of the pathophysiological mechanisms implied in cancer evolution need further investigation. PMID- 26240787 TI - Comparison of the manual, semiautomatic, and automatic selection and leveling of hot spots in whole slide images for Ki-67 quantification in meningiomas. AB - Background. This paper presents the study concerning hot-spot selection in the assessment of whole slide images of tissue sections collected from meningioma patients. The samples were immunohistochemically stained to determine the Ki 67/MIB-1 proliferation index used for prognosis and treatment planning. Objective. The observer performance was examined by comparing results of the proposed method of automatic hot-spot selection in whole slide images, results of traditional scoring under a microscope, and results of a pathologist's manual hot spot selection. Methods. The results of scoring the Ki-67 index using optical scoring under a microscope, software for Ki-67 index quantification based on hot spots selected by two pathologists (resp., once and three times), and the same software but on hot spots selected by proposed automatic methods were compared using Kendall's tau-b statistics. Results. Results show intra- and interobserver agreement. The agreement between Ki-67 scoring with manual and automatic hot-spot selection is high, while agreement between Ki-67 index scoring results in whole slide images and traditional microscopic examination is lower. Conclusions. The agreement observed for the three scoring methods shows that automation of area selection is an effective tool in supporting physicians and in increasing the reliability of Ki-67 scoring in meningioma. PMID- 26240788 TI - Molecular subtyping of leiomyosarcoma with 3' end RNA sequencing. AB - Leiomyosarcoma (LMS) is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for LMS. We performed expression profiling on 99 cases of LMS with 3'end RNA sequencing (3SEQ) and demonstrated the existence of 3 molecular subtypes in this cohort. We consequently showed that these molecular subtypes are reproducible using an independent cohort of 82 LMS cases from TCGA. Two new formalin-fixed, paraffin-embedded (FFPE) tissue-compatible diagnostic immunohistochemical markers were identified for two of the three subtypes: LMOD1 for subtype I LMS and ARL4C for subtype II LMS. Subtype I and subtype II LMS were associated with good and poor prognosis, respectively. Here, we describe the details of LMS diagnosis, RNA isolation, 3SEQ library construction, 3SEQ sequencing data analysis and molecular subtype determination. The 3SEQ data produced in this study was deposited into Gene Expression Omnibus (GEO) under GSE45510. PMID- 26240789 TI - The sticky relationship between allergies and infections. PMID- 26240790 TI - Chronic cough: an Asian perspective. Part 1: Epidemiology. AB - Asia is one of the most diverse and dynamic continents. Due to recent rapid industrialisation and urbanisation, morbidity patterns are likely to be diverse in Asian populations. Chronic cough is a disease condition resulting from host environmental interactions, and is associated with a high global epidemiological burden. However, the underlying epidemiology remains unclear, particularly in Asia. We performed a literature search to identify peer-reviewed articles on chronic cough in community-based adult Asian populations that have been published between January 2000 and June 2015. In this review, we aim to examine the epidemiological characteristics and determinants of chronic cough in several geographical areas of Asia. PMID- 26240791 TI - Association of prevalence of rhinitis, atopic eczema, rhinoconjunctivitis and wheezing with mortality from infectious diseases and with antibiotic susceptibility at a country level. AB - BACKGROUND: It was previously reported that there is a positive correlation between incidence of type 1 diabetes and prevalence of asthma and atopic eczema. A negative correlation between the prevalence of type 1 diabetes and mortality from infectious diseases as well as a positive correlation with antibiotic susceptibility at a country level have also been reported. OBJECTIVE: The aim of this study was to investigate the association between country prevalence of rhinitis, atopic eczema, rhinoconjunctivitis, and wheezing with mortality from infectious diseases and also with antibiotic susceptibility at a country level. METHODS: Data for prevalence of rhinitis, eczema, rhinoconjunctivitis, and wheezing was obtained from the International Study of Asthma and Allergies in Childhood study (ISAAC). ISAAC Phase one was a multicentre multicountry cross sectional study involving over 700,000 children in 2 age groups of school children, 13-14 years old (adolescents) and 6-7 years old (children) in 156 centres from 56 countries. Mortality from infectious diseases was taken from World Health Organisation data. The Alexander project was used to identify antibiotic susceptibilities to common bacteria. RESULTS: There were significant positive correlations between atopic eczema and mortality from all infectious diseases studied, diarrhoeal illness, tropical infections, and childhood infections. A negative correlation exists between the prevalence of rhinitis and Streptococcus pneumoniae susceptibility to penicillin and to erythromycin, rhinitis and Haemophilus influenzae susceptibility to ampicillin and between rhinoconjunctivitis and H. influenzae susceptibility to ampicillin. CONCLUSION: Th1/Th2 responses might influence the pathogenesis of infectious disease mortality, while antibiotic overprescription could explain the negative association between atopy and antibiotic susceptibility. PMID- 26240792 TI - Immunoglobulin E to allergen components of house dust mite in Korean children with allergic disease. AB - BACKGROUND: House dust mites (HDMs) are important sources of indoor allergens. Seventeen components have been identified from Dermatophagoides pteronyssinus (Der p). OBJECTIVE: Our aim was to define the prevalence of specific IgE to components of Der p in Korea and investigate the clinical features of them in children with allergic disease. METHODS: We performed a prospective evaluation of 80 HDM sensitized patients with history of allergic rhinitis (AR), atopic dermatitis (AD), asthma and urticaria (UC). Patients underwent ImmunoCAP for total IgE, Der p, Der f, Der p 1, Der p 2, and Der p 10. RESULTS: Seventy-nine patients had detectable serum IgE to Der p, 80 patients were sensitized to Der f, 66 patients were sensitized to Der p 1, 63 patients to Der p 2, and 7 patients were sensitized to Der p 10. Der p 1 specific IgE was significantly lower in the UC group compared with the AD and AR group. Total IgE was significantly higher in the Der p 10 sensitized group. Der p 10 serum IgE level was highly correlated with crab and shrimp specific IgE. There was a significant positive correlation between total IgE and specific IgE to Der p and its components and Der f. CONCLUSION: Sensitization to HDM and its components in Korea is similar to previous studies from temperate climate. The determination of Der p 1, Der p 2, and Der p 10 specific IgE helps in obtaining additional information in regards to allergic disease. PMID- 26240793 TI - Effect of high-dose sublingual immunotherapy on respiratory infections in children allergic to house dust mite. AB - BACKGROUND: Allergic rhinitis is characterized by eosinophil inflammation. Allergic inflammation may induce susceptibility to respiratory infections (RI). House dust mite (HDM) sensitization is very frequent in childhood. Allergen immunotherapy may cure allergy as it restores a physiologic immune and clinical tolerance to allergen and exerts anti-inflammatory activity. OBJECTIVE: This study investigated whether six-month high-dose, such as 300 IR (index of reactivity), HDM-sublingual immunotherapy (SLIT) could affect RI in allergic children. METHODS: Globally, 40 HDM allergic children (18 males; mean age, 9.3 years) were subdivided in 2 groups: 20 treated by symptomatic drugs (group 1) and 20 by high-dose HDM-SLIT (group 2), since September 2012 to April 2013. The daily maintenance dose of HDM-SLIT was 4 pressures corresponding to 24, 4.8, and 60 ug, respectively of the major allergens Dermatophagoides pteronyssinus (Der p) 1, Der p 2, and Dermatophagoides farinae (Der f) 1. RI was diagnosed when at least 2 symptoms or signs, and fever were present for at least 48 hours. A family pediatrician provided diagnosis on a clinical ground. RESULTS: SLIT-treated children had significantly (p = 0.01) less RI episodes (3.5) than control group (5.45). About secondary outcomes, SLIT-treated children had less episodes of pharyngo-tonsillitis (p < 0.05) and bronchitis (p < 0.005), and snoring (p < 0.05) than control group. In addition, SLIT-treated children had less fever (p < 0.01) and took fewer medications, such as antibiotics (p < 0.05) and fever reducers (p < 0.01), than control group. CONCLUSION: This preliminary study might suggest that also a short course (6 months) of high-dose SLIT, titrated in ug of major allergens, could reduce RI in allergic children. PMID- 26240794 TI - Repeat oral food challenges in peanut and tree nut allergic children with a history of mild/moderate reactions. AB - BACKGROUND: In peanut and tree nut allergic children a history of anaphylaxis is associated with subsequent severe reactions. OBJECTIVE: We aimed to prospectively rechallenge peanut and tree nut allergic children with a history of mild/moderate reactions to assess their allergy over time. METHODS: In this cohort study peanut and tree nut allergic children with a history of mild/moderate reactions during a controlled oral challenge were invited to have a follow-up oral challenge to the same food at least 1 year later. RESULTS: Twenty-six children participated in the study. The mean time interval between the first and second challenge for all participants was 35.5 months. Peanut or tree nut allergy resolved in 38.5% of participants. Those with persistent peanut or tree nut allergy showed a decrease in their reaction threshold and/or increased severity in 81% of cases. There were no demographic features or skin test results that were predictive of changes in severity over time. CONCLUSION: Peanut and tree nut allergic children with a history of mild/moderate reactions who remained allergic demonstrated a high rate of more severe reactions and/or reduced thresholds upon rechallenge over a year later, however, the rate of resolution of allergy in this group may be higher than previously reported. PMID- 26240795 TI - Chlorpheniramine-induced anaphylaxis diagnosed by basophil activation test. AB - Chlorpheniramine is a widely prescribed H1-antihistamine for relieving urticaria or histamine-mediated allergic reactions. However, although rare, it may cause immediate hypersensitivity reactions. The diagnosis is usually made by provocation test, but its application is often limited due to comorbidities or potential risk of severe reactions. In those cases, skin tests and basophil activation tests can be considered as additional diagnostic tests for the drug allergy. Here, we report a 33-year-old female with underlying chronic urticaria, who recurrently developed anaphylaxis after chlorpheniramine administration. Intradermal test showed positive responses in the patient at 0.02 mg/mL of chlorpheniramine, but not in healthy controls. Basophil activation test showed significant up-regulation of CD63 and CD203c by chlorpheniramine. The present case reminds the rare but potential allergic risk of chlorpheniramine, and also suggests the potential utility of basophil activation test in making the diagnosis. PMID- 26240796 TI - Intravenous tacrolimus and cyclosporine induced anaphylaxis: what is next? AB - Tacrolimus and cyclosporine have been used in various formulations, but their hypersensitivity reactions are rare in practice. Castor oil derivatives are nonionic surfactants used in aqueous preparations of hydrophobic active pharmaceutical ingredients. Castor oil derivatives that can be used as additives to tacrolimus and cyclosporine may play a role in the development of hypersensitivity reactions, especially anaphylaxis. Various immunologic and nonimmunologic mechanisms have been implicated in hypersensitivity reactions induced by castor oil derivatives. Physicians should be aware that not only the drug itself, but also its additives or metabolites could induce hypersensitivity reactions. We report a case of anaphylaxis caused by vitamin K (phytonadine), serotonin antagonist (granisetron), intravenous tacrolimus, and cyclosporine. Interestingly, the patient tolerated oral cyclosporine, which did not contain Cremophor EL or polysorbate 80. PMID- 26240797 TI - Gynecomastia induced by H1-antihistamine (ebastine) in a patient with idiopathic anaphylaxis. AB - H1-antihistamine is generally a well-tolerated and safe drug. However, in resemblance with all other drugs, H1-antihistamines can also prompt adverse drug reactions (ADRs). We recently encountered the very unusual ADR of H1 antihistamine-induced gynecomastia. A 21-year-old man with idiopathic anaphylaxis was treated with ebastine (Ebastel), a second-generation H1-antihistamine, for the prevention of anaphylaxis. Three months later, the patient remained well without anaphylaxis, but had newly developed gynecomastia. Because anaphylaxis recurred after the cessation of H1-antihistamine, the preventive medication was changed to omalizumab. A few months later, his gynecomastia had entirely disappeared. Physicians should be aware of this exceptional ADR of H1 antihistamine. PMID- 26240798 TI - Highlights from the 52nd Seminar of the Korean Society of Gastrointestinal Endoscopy. AB - In this July issue of Clinical Endoscopy, state-of-the-art articles selected from the lectures delivered during the 52nd Seminar of the Korean Society of Gastrointestinal Endoscopy (KSGE) on March 29, 2015 are covered, focusing on highlighted educational contents relevant to either diagnostic or therapeutic gastrointestinal (GI) endoscopy. Our society, the KSGE, has continued to host this opportunity for annual seminars twice a year over the last 26 years and it has become a large-scale prestigious seminar accommodating over 4,000 participants. Definitely, the KSGE seminar is considered as one of the premier state-of-the-art seminars dealing with GI endoscopy, appealing to both the beginner and advanced experts. Lectures, live demonstrations, hands-on courses, as well as an editor school, which was an important consensus meeting on how to upgrade our society journal, Clinical Endoscopy, to a Science Citation Index (Expanded) designation were included in this seminar. The 52nd KSGE seminar consisted of more than 20 sessions, including special lectures, concurrent sessions for GI endoscopy nurses, and sessions exploring new technologies. This is a very special omnibus article to highlight the core contents divided into four sessions: upper GI tract, lower GI tract, pancreatobiliary system, and other specialized sessions. PMID- 26240799 TI - Introduction to Starting Upper Gastrointestinal Endoscopy: Proper Insertion, Complete Observation, and Appropriate Photographing. AB - Diagnostic upper gastrointestinal endoscopy is the most basic of endoscopy procedures and is the technique that trainee doctors first learn. Mastering the basics of endoscopy is very important because when this process is imprecise or performed incorrectly, it can severely affect a patient's health or life. Although there are several guidelines and studies that consider these basics, there are still no standard recommendations for endoscopy in Korea. In this review, basic points, including proper endoscope insertion, precise observation without blind spots, and appropriate photographing, for upper gastrointestinal endoscopy will be discussed. PMID- 26240800 TI - Diagnostic and Treatment Approaches for Refractory Peptic Ulcers. AB - Refractory peptic ulcers are defined as ulcers that do not heal completely after 8 to 12 weeks of standard anti-secretory drug treatment. The most common causes of refractory ulcers are persistent Helicobacter pylori infection and use of nonsteroidal anti-inflammatory drugs (NSAIDs). Simultaneous use of two or more H. pylori diagnostic methods are recommended for increased sensitivity. Serologic tests may be useful for patients currently taking proton pump inhibitors (PPIs) or for suspected false negative results, as they are not affected by PPI use. NSAID use should be discontinued when possible. Platelet cyclooxygenase activity tests can confirm surreptitious use of NSAIDs or aspirin. Cigarette smoking can delay ulcer healing. Therefore, patients who smoke should be encouraged to quit. Zollinger-Ellison syndrome (ZES) is a rare but important cause of refractory gastroduodenal ulcers. Fasting plasma gastrin levels should be checked if ZES is suspected. If an ulcer is refractory despite a full course of standard PPI treatment, the dose should be doubled and administration of another type of PPI considered. PMID- 26240801 TI - Improving the Endoscopic Detection Rate in Patients with Early Gastric Cancer. AB - Endoscopists should ideally possess both sufficient knowledge of the endoscopic gastrointestinal disease findings and an appropriate attitude. Before performing endoscopy, the endoscopist must identify several risk factors of gastric cancer, including the patient's age, comorbidities, and drug history, a family history of gastric cancer, previous endoscopic findings of atrophic gastritis or intestinal metaplasia, and a history of previous endoscopic treatments. During endoscopic examination, the macroscopic appearance is very important for the diagnosis of early gastric cancer; therefore, the endoscopist should have a consistent and organized endoscope processing technique and the ability to comprehensively investigate the entire stomach, even blind spots. PMID- 26240802 TI - The Role of Endosonography in the Staging of Gastrointestinal Cancers. AB - Endosonography (EUS) enables the acquisition of clear images of the gastrointestinal tract wall and the surrounding structures. EUS enables much greater accuracy for staging decisions compared to computed tomography. Surgery for esophageal cancer has a high rate of morbidity and mortality, and it is important to decide on an appropriate treatment method through pre-surgical evaluation. Minimal invasive surgery is widely used for the treatment of gastrointestinal cancer, and endoscopic submucosal dissection is a safe treatment method for early cancer of the gastrointestinal tract that does not result in lymph node metastasis. EUS is essential for pre-surgical evaluation for all esophageal cancers. The use of EUS can effectively reduce unnecessary surgeries and thereby allow for appropriate treatment planning for patients. A number of different diagnostic modalities are available, but EUS is still the mainstay for pre-surgical evaluation of esophageal cancer. The role of EUS for early stomach cancer treatment as a tool for determining the need for endoscopic resection and for pre-surgical assessment is increasing. PMID- 26240803 TI - Colorectal Subepithelial Lesions. AB - Most of subepithelial lesion (SEL) being identified was accidentally discovered as small bulging lesion covered with normal mucosa from endoscopic screening. The type of treatment and prognosis vary depending on the type of tumor, it would be crucial to perform an accurate differential diagnosis. Since the differentiation of SEL relied on the indirect findings observed from the mucosal surface using an endoscopy only in the past, it was able to confirm the presence of lesion only but difficult to identify complex detailed nature of the lesion. However, after the endoscopic ultrasonography (EUS) was introduced, it became possible to identify extrinsic compression, and size of intramural tumors, internal properties and contour so that it gets possible to have differential diagnosis of lesions and prediction on the lesion whether it is malignant or benign. In addition, the use of EUS-guided fine needle aspiration and EUS-guided core biopsy made it possible to make histological differential diagnosis. This study intended to investigate endoscopic and EUS findings, histological diagnosis, treatment regimen and impression of colorectal SELs. PMID- 26240804 TI - Endoscopic Ultrasound-Guided Treatment of Pancreatic Cystic and Solid Masses. AB - Pancreatic tumor is one of the most difficult diseases to diagnose and treat because of its anatomical location and characteristics. Recently, there have been several innovative trials on the treatment of pancreatic tumors using endoscopic ultrasound (EUS) because it allows selective access to the difficult to reach target organ along the gastrointestinal tract and can differentiate vessels by color Doppler. Among these trials, several have investigated EUS-guided ethanol lavage with or without paclitaxel for pancreatic cystic tumors. These studies show a 33% to 79% complete resolution rate with a favorable safety profile. Compared to EUS-guided ethanol lavage for pancreatic cystic tumors, EUS-guided radiofrequency ablation is considered a less invasive treatment method for pancreatic cancer. Although there are still several difficulties and concerns about complications, one clinical study reported 72.8% feasibility with favorable safety, and therefore, we anticipate the results of ongoing studies with these new less invasive techniques. PMID- 26240805 TI - Clinical Endoscopy as One of Leading Journals in Gastrointestinal Endoscopy. AB - Clinical Endoscopy (CE) is an official open access journal published bimonthly by the Korean Society of Gastrointestinal Endoscopy (KSGE, http://www.gie.or.kr) and is listed on PMC, PubMed and SCOPUS. The KSGE was established on August 14, 1976, and the journal of the KSGE was published in Korean for the first time in November 1981. The journal was then titled the "Korean Journal of Gastrointestinal Endoscopy" and was published in Korean untill the July 2011 issue. The journal was published in English from the September 2011 issue under the official title of CE. In this review, the past and present of CE are discussed and future perspectives are introduced. In addition, the efforts to progress to a "first come, first served journal" in the field of gastrointestinal endoscopy and to be indexed in Science Citation Index will be described. PMID- 26240806 TI - Evidence of the Internationalization of Clinical Endoscopy Based on Journal Metrics. AB - BACKGROUND/AIMS: This study aims to verify the internationalization of Clinical Endoscopy based on journal metrics after the change to English-only in 2011. The results of this study serve as a starting point for developing strategies to develop Clinical Endoscopy into a top-tier international journal. METHODS: The following journal metrics were analyzed from the journal's homepage or the Web of Science: the number of citable articles, number of countries of affiliation of the contributors, the number of articles supported by research grants, total citations, impact factor, citing journals, countries of citing authors, and the Hirsch index. RESULTS: The number of citable articles in 2011, 2012, 2013, and 2014 was 22, 81, 120, and 95, respectively. The authors were from 11 countries. Twenty-one out of 55 original articles were supported by research grants. The total citations in 2012, 2013, and 2014 were 2, 85, and 213, respectively. The impact factor was 0.670 in 2013 and 0.940 in 2014. The number of countries citing authors were from was 61. The Hirsch index was 6. CONCLUSIONS: The above results demonstrate that Clinical Endoscopy became an international journal, contributing to the propagation of valuable research results through an open access publishing model. PMID- 26240807 TI - Superficial Esophageal Neoplasms Overlying Leiomyomas Removed by Endoscopic Submucosal Dissection: Case Reports and Review of the Literature. AB - The coexistence of an epithelial lesion and a subepithelial lesion is uncommon. In almost all such cases, the coexistence of these lesions appears to be incidental. It is also extremely rare to encounter a neoplasm in the surface epithelium that overlies a benign mesenchymal tumor in the esophagus. Several cases of a coexisting esophageal neoplasm overlying a leiomyoma that is treated endoscopically or surgically have been reported previously. Here, three cases of a superficial esophageal neoplasm that developed over an esophageal leiomyoma and was then successfully removed by endoscopic submucosal dissection are described. PMID- 26240808 TI - Extragastroesophageal Malignancy-Associated Secondary Achalasia: A Rare Association of Pancreatic Cancer Rendering Alarm Manifestation. AB - Secondary achalasia or pseudoachalasia is a rare esophageal motor abnormality, which mimics primary achalasia; it is not easily distinguishable from idiopathic achalasia by manometry, radiological examination, or endoscopy. Although the majority of reported pseudoachalasia cases are associated with neoplasms at or near the esophagogastric (EG) junction, other neoplastic processes or even chronic illnesses such as rheumatoid arthritis can lead to the development of pseudoachalasia, for example, mediastinal masses, gastrointestinal (GI) tumors of the liver and biliary tract, and non-GI malignancies. Therefore, even if a patient presents with the typical findings of achalasia, we should be alert to the possibility of other GI malignancies besides EG tumors. For instance, pancreatic cancer was found in the case reported here; only four such cases have been reported in the literature. A 47-year-old man was admitted to our center with a 3-month history of dysphagia. His endoscopic and esophageal manometric findings were compatible with primary achalasia. However, unresponsiveness to diverse conventional achalasia treatments led us to suspect secondary achalasia. An active search led to a diagnosis of pancreatic mucinous cystadenocarcinoma invading the gastric fundus and EG junction. This rare case of pseudoachalasia caused by pancreatic carcinoma emphasizes the need for suspecting GI malignancies other than EG tumors in patients refractory to conventional achalasia treatment. PMID- 26240809 TI - Simultaneous Esophageal and Gastric Metastases from Lung Cancer. AB - We report of a patient with metastatic adenocarcinoma of the esophagus and stomach from lung cancer. The patient was a 68-year-old man receiving radiotherapy and chemotherapy for stage IV lung cancer, without metastases to the gastrointestinal (GI) tract at the time of the initial diagnosis. During the treatment period, dysphagia and melena newly developed. Upper GI endoscopy revealed geographic erosion at the distal esophagus and multiple volcano-shaped ulcers on the stomach body. Endoscopic biopsy was performed for each lesion. To determine whether the lesions were primary esophageal and gastric cancer masses or metastases from the lung cancer, histopathological testing including immunohistochemical staining was performed, and metastasis from lung cancer was confirmed. The disease progressed despite chemotherapy, and the patient died 5 months after the diagnosis of lung cancer. This is a case report of metastatic adenocarcinoma in the esophagus and stomach, which are very rare sites of spread for lung cancer. PMID- 26240810 TI - A Patient with Duodenal Mucinous Adenocarcinoma Presenting as a Laterally Spreading Tumor. AB - Primary duodenal carcinoma is rare. Duodenal mucinous adenocarcinoma (DMA) is even rarer, and its associated manifestations and typical endoscopic or imaging findings are not well characterized. Herein, we report a case of primary DMA in an asymptomatic 58-year-old man who visited our hospital for a regular health screening. Upper endoscopy revealed an approximately 4-cm lesion in the second portion of the duodenum, but the mass was not visualized on computed tomography. Biopsies revealed a tubular adenoma that was subsequently resected. Frozen biopsies demonstrated DMA with a background of low-grade tubular adenoma for which we performed Roux-en-Y duodenojejunostomy and jejunojejunostomy. To our knowledge, this is the first report of a patient with DMA in Korea. PMID- 26240811 TI - Single Cavernous Hemangioma of the Small Bowel Diagnosed by Using Capsule Endoscopy in a Child with Chronic Iron-Deficiency Anemia. AB - Cavernous hemangiomas of the gastrointestinal tract are extremely rare. In particular, the diagnosis of small bowel hemangiomas is very difficult in children. A 13-year-old boy presented at the outpatient clinic with dizziness and fatigue. The patient was previously diagnosed with iron-deficiency anemia at 3 years of age and had been treated with iron supplements continuously and pure red cell transfusion intermittently. Laboratory tests indicated that the patient currently had iron-deficiency anemia. There was no evidence of gross bleeding, such as hematemesis or bloody stool. Laboratory findings indicated no bleeding tendency. Gastroduodenoscopy and colonoscopy results were negative. To obtain a definitive diagnosis, the patient underwent capsule endoscopy. A purplish stalked mass was found in the jejunum, and the mass was excised successfully. We report of a 13-year-old boy who presented with severe and recurrent iron-deficiency anemia caused by a cavernous hemangioma in the small bowel without symptoms of gastrointestinal bleeding. PMID- 26240812 TI - Could Transgastric Endoscopic Ultrasound-Guided Aspiration Alone Be Effective for the Treatment of Pancreatic Abscesses? AB - Drainage of pancreatic abscesses is required for effective control of sepsis. Endoscopic ultrasound (EUS)-guided endoscopic drainage is less invasive than surgery and prevents local complications related to percutaneous drainage. Endoscopic drainage with stent placement in the uncinate process of the pancreas is a technically difficult procedure. We report a case of pancreatic abscess treated by repeated EUS-guided aspiration and intravenous antibiotics without an indwelling drainage catheter or surgical intervention. PMID- 26240813 TI - An Adult Choledochocele Case Presented with Acute Pancreatitis: Treatment by Endoscopic Sphincterotomy and Cyst Unroofing. PMID- 26240815 TI - Therapeutic Efficacy of E-64-d, a Selective Calpain Inhibitor, in Experimental Acute Spinal Cord Injury. AB - This study aims to investigate the therapeutic effect of calpain inhibitor E-64-d on SCI and to find a new approach to treat SCI. When an SCI rat model was established, it was immediately administered with E-64-d. RT-PCR and Western blotting were used to determine the protein and mRNA levels of calpain 1 and 68 kD NFP. TUNEL staining and NeuN labeling were performed to analyze neuronal apoptosis in the lesion. Immunohistochemistry assay was carried out to observe the expressions of calpain 1 and GFAP. Cyclooxygenase-2 activity was measured to show the immune response status. Locomotor function was evaluated by inclined plane test and Basso, Beattie, and Bresnahan locomotor rating scale. The results showed that calpain 1 was activated after SCI occurred. Treatment with E-64-d decreased expressions of calpain 1 and GFAP, alleviated neuronal apoptosis, inhibited cyclooxygenase-2 activity, and resulted in the promoted locomotor function. Furthermore, combination of E-64-d and MP had better efficacy than did E-64-d or MP alone. E-64-d is expected to be applied to treat SCI, and its alliance with MP may provide a valid strategy for SCI therapy. PMID- 26240816 TI - Immobilization of Yarrowia lipolytica Lipase on Macroporous Resin Using Different Methods: Characterization of the Biocatalysts in Hydrolysis Reaction. AB - To improve the reusability and organic solvent tolerance of microbial lipase and expand the application of lipase (hydrolysis, esterification, and transesterification), we immobilized marine microbial lipase using different methods and determined the properties of immobilized lipases. Considering the activity and cost of immobilized lipase, the concentration of lipase was fixed at 2 mg/mL. The optimal temperature of immobilized lipases was 40 degrees C and 5 degrees C higher than free lipase. The activities of immobilized lipases were much higher than free lipase at alkaline pH (more than 50% at pH 12). The free lipase lost most activity (35.3%) and immobilized lipases retained more than 46.4% of their initial activity after 3 h heat treatment at 70 degrees C. At alkaline pH, immobilized lipases were more stable than free lipase (more than 60% residue activity at pH 11 for 3 h). Immobilized lipases retained 80% of their activity after 5 cycles and increased enzyme activity (more than 108.7%) after 3 h treatment in tert-butanol. Immobilization of lipase which improved reusability of lipase and provided a chance to expand the application of marine microbial lipase in organic system expanded the application range of lipase to catalyze hydrolysis and esterification in harsh condition. PMID- 26240814 TI - Update on Biomarkers for the Detection of Endometriosis. AB - Endometriosis is histologically characterized by the displacement of endometrial tissue to extrauterine locations including the pelvic peritoneum, ovaries, and bowel. An important cause of infertility and pelvic pain, the individual and global socioeconomic burden of endometriosis is significant. Laparoscopy remains the gold standard for the diagnosis of the condition. However, the invasive nature of surgery, coupled with the lack of a laboratory biomarker for the disease, results in a mean latency of 7-11 years from onset of symptoms to definitive diagnosis. Unfortunately, the delay in diagnosis may have significant consequences in terms of disease progression. The discovery of a sufficiently sensitive and specific biomarker for the nonsurgical detection of endometriosis promises earlier diagnosis and prevention of deleterious sequelae and represents a clear research priority. In this review, we describe and discuss the current status of biomarkers of endometriosis in plasma, urine, and endometrium. PMID- 26240817 TI - An Update on Surgical versus Expectant Management of Ovarian Endometriomas in Infertile Women. AB - Ovarian endometriomas are a common manifestation of endometriosis that can represent a more severe stage of the disease. There is much debate over the treatment of these cysts in infertile women, particularly before use of assisted reproductive technologies. Evidence exists that supports surgical excision of ovarian endometriomas, as well as evidence that cautions against surgical intervention. Certain factors need to be examined closely before proceeding with surgery or continuing with expectant management. These include the patient's symptoms, age, ovarian reserve, size and laterality of the cyst, prior surgical treatment, and level of suspicion for malignancy. The most recent evidence appears to suggest that certain patient profiles may benefit from proceeding directly to in vitro fertilization (IVF). These include symptomatic infertile patients, especially those that are older, those that have diminished ovarian reserve, those that have bilateral endometriomas, or those that have had prior surgical treatment. Although endometriomas can be detrimental to the ovarian reserve, surgical therapy may further lower a woman's ovarian reserve. Nevertheless, the presence of an endometrioma does not appear to adversely affect IVF outcomes, and surgical excision of endometriomas does not appear to improve IVF outcomes. Regardless of treatment plan, infertile patients with endometriomas must be counseled appropriately before choosing either treatment path. PMID- 26240818 TI - Bilateral Image Subtraction and Multivariate Models for the Automated Triaging of Screening Mammograms. AB - Mammography is the most common and effective breast cancer screening test. However, the rate of positive findings is very low, making the radiologic interpretation monotonous and biased toward errors. This work presents a computer aided diagnosis (CADx) method aimed to automatically triage mammogram sets. The method coregisters the left and right mammograms, extracts image features, and classifies the subjects into risk of having malignant calcifications (CS), malignant masses (MS), and healthy subject (HS). In this study, 449 subjects (197 CS, 207 MS, and 45 HS) from a public database were used to train and evaluate the CADx. Percentile-rank (p-rank) and z-normalizations were used. For the p-rank, the CS versus HS model achieved a cross-validation accuracy of 0.797 with an area under the receiver operating characteristic curve (AUC) of 0.882; the MS versus HS model obtained an accuracy of 0.772 and an AUC of 0.842. For the z normalization, the CS versus HS model achieved an accuracy of 0.825 with an AUC of 0.882 and the MS versus HS model obtained an accuracy of 0.698 and an AUC of 0.807. The proposed method has the potential to rank cases with high probability of malignant findings aiding in the prioritization of radiologists work list. PMID- 26240819 TI - Tissue Remodelling following Resection of Porcine Liver. AB - AIM: To study genes regulating the extracellular matrix (ECM) and investigate the tissue remodelling following liver resection in porcine. METHODS: Four pigs with 60% partial hepatectomy- (PHx-) induced liver regeneration were studied over six weeks. Four pigs underwent sham surgery and another four pigs were used as controls of the normal liver growth. Liver biopsies were taken upon laparotomy, after three and six weeks. Gene expression profiles were obtained using porcine specific oligonucleotide microarrays. Immunohistochemical staining was performed and a proliferative index was assessed. RESULTS: More differentially expressed genes were associated with the regulation of ECM in the resection group compared to the sham and control groups. Secreted protein acidic and rich in cysteine (SPARC) and collagen 1, alpha 2 (COL1A2) were both upregulated in the early phase of liver regeneration, validated by immunopositive cells during the remodelling phase of liver regeneration. A broadened connective tissue was demonstrated by Masson's Trichrome staining, and an immunohistochemical staining against pan Cytokeratin (pan-CK) demonstrated a distinct pattern of migrating cells, followed by proliferating cell nuclear antigen (PCNA) positive nuclei. CONCLUSIONS: The present study demonstrates both a distinct pattern of PCNA positive nuclei and a deposition of ECM proteins in the remodelling phase of liver regeneration. PMID- 26240820 TI - Inguinal Hernias Represent the Most Frequent Surgical Complication after Kasai in Biliary Atresia Infants. AB - Biliary atresia (BA) is an orphan medical condition of the newborn, resulting in end-stage liver cirrhosis due to obliterative cholangiopathy of the extrahepatic bile duct. Although Kasai's hepatoportoenterostomy (KPE) is the well-established first-line therapy, little is known about its surgical complications. 153 patients receiving open KPE treated at a single center between 1994 and 2014 were analysed retrospectively regarding short-term complications and survival with the native liver. In brief, 40.5% of patients suffered from 1-3 surgical complications, inguinal hernias (IH) being most prevalent (40.0%). In BA patients, incidence of IH was associated with male gender (p = 0.002), the syndromic form of BA (p = 0.038), and percutaneous drainage for ascites (p = 0.002). No association was found with prematurity (p = 0.074) or birth weight (p = 0.912) in our study. In conclusion, IH frequently develops after open KPE of BA patients, but this complication does not negatively affect the patient's outcome. Nevertheless, inspection of the internal inguinal ring and prophylactic closure of inapparent hernias should be discussed in order to prevent secondary surgical procedures. PMID- 26240821 TI - Hijacking of Endocrine and Metabolic Regulation in Cancer and Diabetes. PMID- 26240822 TI - Seroepidemiology of Leptospira Exposure in General Population in Rural Durango, Mexico. AB - The magnitude of Leptospira exposure in rural Mexico is largely unknown. We sought to determine the seroprevalence of Leptospira IgG antibodies in adults in rural Durango, Mexico, and to determine the sociodemographic, behavioral, and housing characteristics of the subjects associated with Leptospira seropositivity. We performed a cross-sectional study in 282 adults living in rural Durango, Mexico. Sera from participants were analyzed for Leptospira IgG antibodies using a commercially available enzyme immunoassay. Seroprevalence association with the characteristics of the subjects was analyzed by bivariate and multivariate analyses. Of the 282 rural subjects (42.91 +/- 17.53 years old) studied, 44 (15.6%) had anti-Leptospira IgG antibodies. Seropositivity to Leptospira was not associated with gender, educational level, employment, socioeconomic status, contact with animals or soil, or type of floors at home. In contrast, multivariate analysis showed that Leptospira exposure was associated with national trips (OR = 2.09; 95% CI: 1.05-4.16; P = 0.03) and poor education of the head of the family (OR = 2.96; 95% CI: 1.51-5.78; P = 0.001). We demonstrated serological evidence of Leptospira exposure in adults in rural northern Mexico. The contributing factors associated with Leptospira exposure found in the present study may be useful for optimal planning of preventive measures against Leptospira infection. PMID- 26240823 TI - How to Develop an Electronic Clinical Endometriosis Research File Integrated in Clinical Practice. AB - Endometriosis is associated with a range of pelvic-abdominal pain symptoms and infertility. It is a chronic disease that can have a significant impact on various aspects of women's lives, including their social and sexual relationships, work, and study. Despite several international guidelines on the management of endometriosis, there is a wide variety of clinical practice in the management of endometriosis, resulting in many women receiving delayed or suboptimal care. In this paper we discuss the possibilities and benefits of using electronic health records for clinical research in the field of endometriosis. The development of a wide range of clinical software for electronic patient records has made the registration of large datasets feasible and the integration of research files and clinical files possible. Integration of global standards on registration of endometriosis care in electronic health records could improve reporting of research data and facilitate the execution of large, multicentre randomized trials on the management of endometriosis. These highly needed trials could bring us the evidence needed for the optimisation of management of women with endometriosis. PMID- 26240824 TI - Endometriosis-Related Infertility: The Role of the Assisted Reproductive Technologies. AB - The assisted reproductive technologies, particularly in vitro fertilization (IVF), represent the most efficient and successful means of overcoming infertility associated with endometriosis. Although older studies suggest that IVF outcomes are compromised in endometriosis patients, more contemporary reports show no differences compared to controls. The exception may be evidence of poorer outcomes and diminished ovarian response in women with advanced disease, particularly those with significant ovarian involvement or prior ovarian surgery. Prolonged pre-IVF cycle suppressive medical therapy, particularly gonadotropin releasing hormone agonists, appears to improve success rates in a subset of endometriosis patients. However, as of yet, there is no diagnostic marker to specifically identify those who would most benefit from this approach. Pre-IVF cycle surgical resection of nonovarian disease has not been consistently shown to improve outcomes with the possible exception of resection of deeply invasive disease, although the data is limited. Precycle resection of ovarian endometriomas does not have benefit and should only be performed for gynecologic indications. Indeed, there is a large body of evidence to suggest that this procedure may have a deleterious impact on ovarian reserve and response. A dearth of appropriately designed trials makes development of definitive treatment paradigms challenging. PMID- 26240825 TI - Cochlear Implant and Its Related Science. PMID- 26240826 TI - Developing a Noninvasive Procedure Using Labeled Monoclonal Antibody Anti-VEGF (Bevacizumab) for Detection of Endometriosis. AB - The off-label use of bevacizumab labeled with 99mTc as a new radiopharmaceutical for imaging of endometriosis is a promising noninvasive, new clinical procedure. The bevacizumab in monoclonal antibodies targeted at vascular endothelial growth factor (VEGF) is superexpressed in cases of endometriosis. In this study we evaluate the imaging of endometriosis lesion in rats (induced to endometriosis) using bevacizumab-99mTc. The results showed that bevacizumab-99mTc imaged the lesion and support his use for Nuclear Medicine applied to gynecology. Also the results appointed that this radiopharmaceutical has a hepatobiliary excretion. It is important to notice that the dose used was almost 0,01% of the usual dose for the bevacizumab. PMID- 26240827 TI - Atrial Fibrillation: Biophysics, Molecular Mechanisms, and Novel Therapies. PMID- 26240828 TI - Abnormal Expression of Prostaglandins E2 and F2alpha Receptors and Transporters in Patients with Endometriosis. AB - OBJECTIVE: To investigate the level of expression of prostaglandin receptivity and uptake factors in eutopic and ectopic endometrium of women with endometriosis. DESIGN: Prospective study. SETTING: Human reproduction research laboratory. PATIENTS: Seventy-eight patients with endometriosis and thirty healthy control subjects. INTERVENTION(S): Endometrial and endometriotic tissue samples were obtained during laparoscopic surgery. MAIN OUTCOME MEASURE(S): Real time polymerase chain reaction assay of mRNA encoding prostaglandin E2 receptors (EP1, EP2, EP3, and EP4), prostaglandin F2alpha receptor (FP), prostaglandin transporter (PGT), and multidrug resistance-associated protein 4 (MRP4); immunohistochemical localization of expressed proteins. RESULTS: Marked increases in receptors EP3, EP4, and FP and transporters PGT and MRP4 in ectopic endometrial tissue were noted, without noticeable change associated with disease stage. An increase in EP3 expression and decreases in FP and PGT were observed in the eutopic endometrium of endometriosis patients in conjunction with the phases of the menstrual cycle. CONCLUSION(S): This study is the first to demonstrate a possible relationship between endometriosis and enhanced prostaglandin activity. In view of the wide range of prostaglandin functions, increasing cell receptivity and facilitating uptake in endometrial tissue could contribute to the initial steps of overgrowth and have an important role to play in the pathogenesis and symptoms of this disease. PMID- 26240830 TI - Enhancing Image Characteristics of Retinal Images of Aggressive Posterior Retinopathy of Prematurity Using a Novel Software, (RetiView). AB - Purpose. To report pilot data from a novel image analysis software "RetiView," to highlight clinically relevant information in RetCam images of infants with aggressive posterior retinopathy of prematurity (APROP). Methods. Twenty-three imaging sessions of consecutive infants of Asian Indian origin with clinically diagnosed APROP underwent three protocols (Grey Enhanced (GE), Color Enhanced (CE), and "Vesselness Measure" (VNM)) of the software. The postprocessed images were compared to baseline data from the archived unprocessed images and clinical exam by the retinopathy of prematurity (ROP) specialist for anterior extent of the vessels, capillary nonperfusion zones (CNP), loops, hemorrhages, and flat neovascularization. Results. There was better visualization of tortuous loops in the GE protocol (56.5%); "bald" zones within the CNP zones (26.1%), hemorrhages (13%), and edge of the disease (34.8%) in the CE images; neovascularization on both GE and CE protocols (13% each); clinically relevant information in cases with poor pupillary dilatation (8.7%); anterior extent of vessels on the VNM protocol (13%) effecting a "reclassification" from zone 1 to zone 2 posterior. Conclusions. RetiView is a noninvasive and inexpensive method of customized image enhancement to detect clinically difficult characteristics in a subset of APROP images with a potential to influence treatment planning. PMID- 26240829 TI - Integrative Analysis with Monte Carlo Cross-Validation Reveals miRNAs Regulating Pathways Cross-Talk in Aggressive Breast Cancer. AB - In this work an integrated approach was used to identify functional miRNAs regulating gene pathway cross-talk in breast cancer (BC). We first integrated gene expression profiles and biological pathway information to explore the underlying associations between genes differently expressed among normal and BC samples and pathways enriched from these genes. For each pair of pathways, a score was derived from the distribution of gene expression levels by quantifying their pathway cross-talk. Random forest classification allowed the identification of pairs of pathways with high cross-talk. We assessed miRNAs regulating the identified gene pathways by a mutual information analysis. A Fisher test was applied to demonstrate their significance in the regulated pathways. Our results suggest interesting networks of pathways that could be key regulatory of target genes in BC, including stem cell pluripotency, coagulation, and hypoxia pathways and miRNAs that control these networks could be potential biomarkers for diagnostic, prognostic, and therapeutic development in BC. This work shows that standard methods of predicting normal and tumor classes such as differentially expressed miRNAs or transcription factors could lose intrinsic features; instead our approach revealed the responsible molecules of the disease. PMID- 26240831 TI - Meat Intake and Insulin Resistance in Women without Type 2 Diabetes. AB - PURPOSE: To examine the relationship between meat intake and insulin resistance (IR) in 292 nondiabetic women. METHODS: IR was evaluated using the homeostasis model assessment (HOMA). Diet was assessed via 7-day weighed food records. Servings of very lean meat (VLM) and regular meat (meat) were indexed using the ADA Exchange Lists Program. Physical activity was assessed using accelerometers and body fat was measured using the Bod Pod. RESULTS: Meat intake was directly related to HOMA (F = 7.4; P = 0.007). Women with moderate or high meat intakes had significantly higher HOMA levels than their counterparts. Adjusting for body fat weakened the relationship (F = 1.0; P = 0.3201). Odds ratio results showed that the low meat quartile had 67% lower odds of being IR (75th percentile) compared to their counterparts (OR = 0.33; 95% CI = 0.16-0.71). These findings changed little after adjusting for all covariates simultaneously (OR = 0.34; 95% CI = 0.14-0.83). Conversely, VLM intake was not related to HOMA, with or without the covariates. CONCLUSION: Moderate and high meat intakes are associated with increased insulin resistance in nondiabetic women. However, differences in body fat contribute significantly to the relationship. VLM is not predictive of IR. Prudence in the amount and type of meat consumed may be helpful in decreasing the likelihood of IR. PMID- 26240833 TI - Optical measurement of dimensional parameters of the breast with subjects in prone position. AB - Various applications require information on breast parameters, such as breast length and volume. An optical system was designed and tested for measuring these parameters with subjects in a prone position. The study results were used for optimizing patient positioning and handling for a future breast computed tomography (BCT) system. Measurements were conducted using an optical measurement system. To test the functionality and accuracy of the system, measurements were performed using reference phantoms. Additionally, 20 women and 5 men were examined to calculate breast parameters in alternative positions and breathing states. The results of the optical measurements were compared with magnetic resonance imaging (MRI) measurements. Volume and length of the reference phantoms were determined with errors below 2%. The patient study demonstrated a mean breast volume of 530.7 ml for women during normal breathing. During an exhalation state, breast volume increased significantly by 17.7 ml in comparison with normal breathing. Differences with MRI measurements were found to be 3% for breast length and 9% for breast volume on average. The proposed optical measurement system was found to be suitable for measuring the dimensional parameters of the breast in a prone position and provides a tool for evaluating breast coverage for BCT. PMID- 26240832 TI - Immune Evasion Strategies of Trypanosoma cruzi. AB - Microbes have evolved a diverse range of strategies to subvert the host immune system. The protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease, provides a good example of such adaptations. This parasite targets a broad spectrum of host tissues including both peripheral and central lymphoid tissues. Rapid colonization of the host gives rise to a systemic acute response which the parasite must overcome. The parasite in fact undermines both innate and adaptive immunity. It interferes with the antigen presenting function of dendritic cells via an action on host sialic acid-binding Ig-like lectin receptors. These receptors also induce suppression of CD4(+) T cells responses, and we presented evidence that the sialylation of parasite-derived mucins is required for the inhibitory effects on CD4 T cells. In this review we highlight the major mechanisms used by Trypanosoma cruzi to overcome host immunity and discuss the role of parasite colonization of the central thymic lymphoid tissue in chronic disease. PMID- 26240835 TI - An Analysis of Transient Overvoltages during the Energization of Electric Ship Propulsion Systems. AB - This paper addresses the resonance phenomena that can occur in an isolated distribution system during transient events such as repeated energizations or power converter switching. In particular, the aim of this study is to analyze the energization of an onboard radial distribution system installed on an electric ship and to determine how the various leakage parameters that can cause resonance problems such as high peak overvoltages when the circuit breaker is closed are relevant. The paper presents a detailed model of whole distribution system, which is validated using infield measurements that refer to a real case in which these events damaged the ships transformers, causing it to be removed from duty. PMID- 26240834 TI - Time Savings and Surgery Task Load Reduction in Open Intraperitoneal Onlay Mesh Fixation Procedure. AB - BACKGROUND: This study assessed the reduction in surgeon stress associated with savings in procedure time for mechanical fixation of an intraperitoneal onlay mesh (IPOM) compared to a traditional suture fixation in open ventral hernia repair. STUDY DESIGN: Nine general surgeons performed 36 open IPOM fixation procedures in porcine model. Each surgeon conducted two mechanical (using ETHICON SECURESTRAP TM Open) and two suture fixation procedures. Fixation time was measured using a stopwatch, and related surgeon stress was assessed using the validated SURG-TLX questionnaire. T-tests were used to compare between-group differences, and a two-sided 95% confidence interval for the difference in stress levels was established using nonparametric methodology. RESULTS: The mechanical fixation group demonstrated an 89.1% mean reduction in fixation time, as compared to the suture group (p < 0.00001). Surgeon stress scores measured using SURG-TLX were 55.5% lower in the mechanical compared to the suture fixation group (p < 0.001). Scores in five of the six sources of stress were significantly lower for mechanical fixation. CONCLUSIONS: Mechanical fixation with ETHICON SECURESTRAP TM Open demonstrated a significant reduction in fixation time and surgeon stress, which may translate into improved operating efficiency, improved performance, improved surgeon quality of life, and reduced overall costs of the procedure. PMID- 26240836 TI - Modeling, Control, and Optimization Technologies in Electric Drive Vehicles. PMID- 26240837 TI - Pruritus in Systemic Diseases: A Review of Etiological Factors and New Treatment Modalities. AB - Pruritus is the most frequently described symptom in dermatology and can significantly impair the patient's quality of life. In 10-50% of adults with persistent pruritus, it can be an important dermatologic clue for the presence of a significant underlying systemic disease such as renal insufficiency, cholestasis, hematologic disorder, or malignancy (Etter and Myers, 2002; Zirwas and Seraly, 2001). This review describes the presence of pruritus in different systemic diseases. It is quite important to discover the cause of pruritus for providing relief for the patients experiencing substantial morbidity caused by this condition. PMID- 26240843 TI - Authors' response. PMID- 26240838 TI - Functionalized alpha-Helical Peptide Hydrogels for Neural Tissue Engineering. AB - Trauma to the central and peripheral nervous systems often lead to serious morbidity. Current surgical methods for repairing or replacing such damage have limitations. Tissue engineering offers a potential alternative. Here we show that functionalized alpha-helical-peptide hydrogels can be used to induce attachment, migration, proliferation and differentiation of murine embryonic neural stem cells (NSCs). Specifically, compared with undecorated gels, those functionalized with Arg-Gly-Asp-Ser (RGDS) peptides increase the proliferative activity of NSCs; promote their directional migration; induce differentiation, with increased expression of microtubule-associated protein-2, and a low expression of glial fibrillary acidic protein; and lead to the formation of larger neurospheres. Electrophysiological measurements from NSCs grown in RGDS-decorated gels indicate developmental progress toward mature neuron-like behavior. Our data indicate that these functional peptide hydrogels may go some way toward overcoming the limitations of current approaches to nerve-tissue repair. PMID- 26240844 TI - [Not Available]. PMID- 26240845 TI - [Nutritional screening in heart failure patients: 5 methods review]. PMID- 26240846 TI - Effectiveness of the Brazilian Conditional Cash Transfer Program--Bolsa Alimentacao--on the variation of linear and ponderal increment in children from northeast of Brazil. AB - BACKGROUND: Social programs can improve the conditions required for families provide sufficient care and attention for an adequate health and nutrition. OBJECTIVE: This study evaluates the effectiveness of the Brazilian's conditional cash transfer program--Bolsa Alimentacao (PBA) on children anthropometric status. METHODS: A cohort of 1847 children, followed for 12 months: 1615 PBA children; 232 non-PBA. There were 316 (14.6%) missing children during the study. A quasi experimental study adopting the before-after strategy was applied and the effectiveness approach was used to assess the impact of the program on children nutritional status. Multilevel analysis with three levels was used in the statistical analysis. The mean increment variations of height-for-age and weight for-age were the outcome variables and the participation in the PBA was the exposition. Four participation groups were established: children not exposed to the program (internal control group); exposed to the program throughout the 12 months, exposed to the program only in the last 6 months; and exposed to the program only in the first 6 months. Repeated measures were obtained at baseline and at 12 months. RESULTS: It was found that the exposure to the program was associated to a mean variation in weight-for-age of 0.34 Z-score (IC = 0.04; 0.63) and height-for-age of 0.38 (IC = 0.05; 0.70) for children who were regular program beneficiaries during the follow-up. The exposure to the program in other periods was not statistically associated with a mean variation in the indicators. CONCLUSIONS: Cash transfers direct to the family were associated to anthropometric deficits reduction in childhood. PMID- 26240847 TI - [Anesthetic cream as anesthesia alternative]. PMID- 26240848 TI - [Fallopian tube under the magnifying glass]. PMID- 26240849 TI - [Difficult differential diagnosis]. PMID- 26240850 TI - Indicators of true intracerebral hemorrhage: hematoidin, siderophage, and erythrophage. PMID- 26240851 TI - Carbon storage in old-growth forests of the Mid-Atlantic: toward better understanding the eastern forest carbon sink. AB - Few old-growth stands remain in the matrix of secondary forests that dominates the eastern North American landscape. These remnant stands offer insight on the potential carbon (C) storage capacity of now-recovering secondary forests. We surveyed the remaining old-growth forests on sites characteristic of the general Mid-Atlantic United States and estimated the size of multiple components of forest C storage. Within and between old-growth stands, variability in C density is high and related to overstory tree species composition. The sites contain 219 +/- 46 Mg C/ha (mean +/- SD), including live and dead aboveground biomass, leaf litter, and the soil O horizon, with over 20% stored in downed wood and snags. Stands dominated by tulip poplar (Liriodendron tulipifera) store the most live biomass, while the mixed oak (Quercus spp.) stands overall store more dead wood. Total C density is 30% higher (154 Mg C/ha), and dead wood C density is 1800% higher (46 Mg C/ha) in the old-growth forests than in the surrounding younger forests (120 and 5 Mg C/ha, respectively). The high density of dead wood in old growth relative to secondary forests reflects a stark difference in historical land use and, possibly, the legacy of the local disturbance (e.g., disease) history. Our results demonstrate the potential for dead wood to maintain the sink capacity of secondary forests for many decades to come. PMID- 26240852 TI - A new probabilistic method for quantifying n-dimensional ecological niches and niche overlap. AB - Considerable progress has been made in the development of statistical tools to quantify trophic relationships using stable isotope ratios, including tools that address size and overlap of isotopic niches. We build upon recent progress and propose a new probabilistic method for determining niche region and pairwise niche overlap that can be extended beyond two dimensions, provides directional estimates of niche overlap, accounts for species-specific distributions in niche space, and, unlike geometric methods, produces consistent and unique bivariate projections of multivariate data. We define the niche region (NR) as a given 95% (or user-defined a) probability region in multivariate space. Overlap is calculated as the probability that an individual from species A is found in the N(R) of species B. Uncertainty is accounted for in a Bayesian framework, and is the only aspect of the methodology that depends on sample size. Application is illustrated with three-dimensional stable isotope data, but practitioners could use any continuous indicator of ecological niche in any number of dimensions. We suggest that this represents an advance in our ability to quantify and compare ecological niches in a way that is more consistent with Hutchinson's concept of an "n-dimensional hypervolume". PMID- 26240853 TI - An open-population hierarchical distance sampling model. AB - Modeling population dynamics while accounting for imperfect detection is essential to monitoring programs. Distance sampling allows estimating population size while accounting for imperfect detection, but existing methods do not allow for estimation of demographic parameters. We develop a model that uses temporal correlation in abundance arising from underlying population dynamics to estimate demographic parameters from repeated distance sampling surveys. Using a simulation study motivated by designing a monitoring program for Island Scrub Jays (Aphelocoma insularis), we investigated the power of this model to detect population trends. We generated temporally autocorrelated abundance and distance sampling data over six surveys, using population rates of change of 0.95 and 0.90. We fit the data generating Markovian model and a mis-specified model with a log-linear time effect on abundance, and derived post hoc trend estimates from a model estimating abundance for each survey separately. We performed these analyses for varying numbers of survey points. Power to detect population changes was consistently greater under the Markov model than under the alternatives, particularly for reduced numbers of survey points. The model can readily be extended to more complex demographic processes than considered in our simulations. This novel framework can be widely adopted for wildlife population monitoring. PMID- 26240854 TI - Modeling false positive detections in species occurrence data under different study designs. AB - The occurrence of false positive detections in presence-absence data, even when they occur infrequently, can lead to severe bias when estimating species occupancy patterns. Building upon previous efforts to account for this source of observational error, we established a general framework to model false positives in occupancy studies and extend existing modeling approaches to encompass a broader range of sampling designs. Specifically, we identified three common sampling designs that are likely to cover most scenarios encountered by researchers. The different designs all included ambiguous detections, as well as some known-truth data, but their modeling differed in the level of the model hierarchy at which the known-truth information was incorporated (site level or observation level). For each model, we provide the likelihood, as well as R and BUGS code needed for implementation. We also establish a clear terminology and provide guidance to help choosing the most appropriate design and modeling approach. PMID- 26240855 TI - Emergent stability in a large, free-flowing watershed. AB - While it is widely recognized that financial stock portfolios can be stabilized through diverse investments, it is also possible that certain habitats can function as natural portfolios that stabilize ecosystem processes. Here we propose and examine the hypothesis that free-flowing river networks act as such portfolios and confer stability through their integration of upstream geological, hydrological, and biological diversity. We compiled a spatially (142 sites) and temporally (1980-present) extensive data set on fisheries, water flows, and temperatures, from sites within one of the largest watersheds in the world that remains without dams on its mainstem, the Fraser River, British Columbia, Canada. We found that larger catchments had more stable fisheries catches, water flows, and water temperatures than smaller catchments. These data provide evidence that free-flowing river networks function as hierarchically nested portfolios with stability as an emergent property. Thus, free-flowing river networks can represent a natural system for buffering variation and extreme events. PMID- 26240856 TI - Ants are less attracted to the extrafloral nectar of plants with symbiotic, nitrogen-fixing rhizobia. AB - Plants simultaneously maintain mutualistic relationships with different partners that are connected through the same host, but do not interact directly. One or more participating mutualists may alter their host's phenotype, resulting in a shift in the host's ecological interactions with all other mutualists involved. Understanding the functional interplay of mutualists associated with the same host remains an important challenge in biology. Here, we show belowground nitrogen-fixing rhizobia on lima bean (Phaseolus lunatus) alter their host plant's defensive mutualism with aboveground ants. We induced extrafloral nectar (EFN), an indirect defense acting through ant attraction. We also measured various nutritive and defensive plant traits, biomass, and counted ants on rhizobial and rhizobia-free plants. Rhizobia increased plant protein as well as cyanogenesis, a direct chemical defense against herbivores, but decreased EFN. Ants were significantly more attracted to rhizobia-free plants, and our structural equation model shows a strong link between rhizobia and reduced EFN as well as between EFN and ants: the sole path to ant recruitment. The rhizobia mediated effects on simultaneously expressed defensive plant traits indicate rhizobia can have significant bottom-up effects on higher trophic levels. Our results show belowground symbionts play a critical and underestimated role in determining aboveground mutualistic interactions. PMID- 26240857 TI - Phenological responses to climate change do not exhibit phylogenetic signal in a subalpine plant community. AB - Phylogenetic relationships may underlie species-specific phenological sensitivities to abiotic variation and may help to predict these responses to climate change. Although shared evolutionary history may mediate both phenology and phenological sensitivity to abiotic variation, few studies have explicitly investigated whether this is the case. We explore phylogenetic signal in flowering phenology and in phenological sensitivity to temperature and snowmelt using a 39-year record of flowering from the Colorado Rocky Mountains, USA that includes dates of first, peak, and last flowering, and flowering duration for 60 plant species in a subalpine plant community. Consistent with other studies, we found evidence in support of phylogenetic signal in first flowering date. However, the strength and significance of that signal were inconsistent across other measures of flowering in this plant community: peak flowering date exhibited the strongest phylogenetic signal, followed by first flowering date; last flowering date and duration of flowering exhibited patterns indistinguishable from random trait evolution. In contrast to first and peak flowering date, phenological sensitivities of all flowering measures to temperature and snowmelt did not exhibit a phylogenetic signal. These findings show that within ecological communities, phylogenetic signal in phenology does not necessarily imply phylogenetic signal in phenological sensitivities to abiotic variation. PMID- 26240858 TI - Egg boons: central components of marine fatty acid food webs. AB - Food web relationships are traditionally defined in terms of the flow of key elements, such as carbon, nitrogen, and phosphorus, and their role in limiting production. There is growing recognition that availability of important biomolecules, such as fatty acids, may exert controls on secondary production that are not easily explained by traditional element-oriented models. Essential fatty acids (EFAs) are required by most organisms for proper physiological function but are manufactured almost entirely by primary producers. Therefore, the flow of EFAs, especially docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (ARA), through aquatic food webs is critical for ecosystem functioning. A meta-analysis of data on the EFA content of marine organisms reveals that individual eggs of marine animals have exceptionally high concentrations of EFAs, and that superabundances of eggs released in temporally and spatially discrete patches create rich, but temporary, nutritional resources for egg predators, called "egg boons." Mortality rates of fish eggs are disproportionately higher than animals of similar size, and those eggs are consumed by predators, both larger and smaller than the adults that produce the eggs. Thus, egg boons are a major trophic pathway through which EFAs are repackaged and redistributed, and they are among the few pathways that run counter to the main direction of trophic flow. Egg boons can transport EFAs across ecosystems through advection of patches of eggs and spawning migrations of adults. Recognizing the significance of egg boons to aquatic food webs reveals linkages and feedbacks between organisms and environments that have important implications for understanding how food webs vary in time and space. Examples are given of top-down, bottom-up, and lateral control mechanisms that could significantly alter food webs through their effects on eggs. Our results suggest that trophodynamic food web models should include EFAs generally, and egg production and egg EFA content in particular. PMID- 26240859 TI - Negative effects of fertilization on plant nutrient resorption. AB - Plants in infertile habitats are thought to have a high rate of nutrient resorption to enable them reuse nutrients more efficiently than those in fertile habitats. However, there is still much debate on how plant nutrient resorption responds to nutrient availability. Here we used a meta-analysis from a global data set of 9703 observations at 306 sites from 508 published articles to examine the effects of nitrogen (N) and phosphorus (P) fertilization on plant foliar N and P concentrations and resorption efficiency. We found that N fertilization enhanced N concentration in green leaves by 27% and P fertilization enhanced green-leaf P by 73% on average. The N and P concentrations in senesced leaves also increased with respective nutrient fertilization. Resorption efficiencies (percentage of nutrient recovered from senescing leaves) of both N and P declined in response to respective nutrient fertilization. Combined N and P fertilization also had negative effects on both N and P resorption efficiencies. Whether nutrient resorption efficiency differs among plant growth types and among ecosystems, however, remains uncertain due to the limited sample sizes when analyzed by plant growth types or ecosystem types. Our analysis indicates that fertilization decreases plant nutrient resorption and the view that nutrient resorption is a critical nutrient conservation strategy for plants in nutrient poor environments cannot be abandoned. The response values to fertilization presented in our analysis can help improve biogeochemical models. PMID- 26240860 TI - Local and regional processes determine plant species richness in a river-network metacommunity. AB - River systems form dendritic ecological networks that influence the spatial structure of riverine communities. Few empirical studies have evaluated how regional, dispersal-related processes and local habitat factors interact to govern network patterns of species composition. We explore such interactions in a boreal watershed and show that riparian plant species richness increases strongly with drainage size, i.e., with downstream position in the network. Assemblage composition was nested, with new species successively added downstream. These spatial patterns in species composition were related to a combination of local and regional processes. Breadth in local habitat conditions increased downstream in the network, resulting in higher habitat heterogeneity and reduced niche overlap among species, which together with similar trends in disturbance, allows more species to coexist. Riparian edaphic conditions were also increasingly favorable to more species within the regional pool along larger streams, with greater nitrogen availability (manifested as lower C:N) and more rapid mineralization of C and N (as indicated by ratios of stable isotopes) observed with downstream position in the network. The number of species with the capacity for water dispersal increased with stream size, providing a mechanistic link between plant traits and the downstream accumulation of species as more propagules arrive from upstream sites. Similarity in species composition between sites was related to both geographical and environmental distance. Our results provide the first empirical evidence that position in the river network drives spatial patterns in riparian plant diversity and composition by the joint influence of local (disturbance, habitat conditions, and habitat breadth) and regional (dispersal) forces. PMID- 26240861 TI - Climate and land use interactively affect lake phytoplankton nutrient limitation status. AB - Climate-change models predict more frequent and intense summer droughts for many areas, including the midwestern United States. Precipitation quantity and intensity in turn drive the rates and ratios at which nitrogen (N) and phosphorus (P) are exported from watersheds into lakes, but these rates and ratios are also modulated by watershed land use. This led us to ask the question, is the effect of precipitation on phytoplankton nutrient limitation dependent on watershed land use? Across 42 lakes, we found that phytoplankton in lakes in agricultural landscapes were usually P limited but shifted to strong N limitation under increased drought intensity, and that droughts promoted N-fixing cyanobacteria. In contrast, phytoplankton in lakes with forested watersheds were consistently N limited, regardless of drought status. This climate-land use interaction suggests that droughts may increase the incidence of N limitation in agriculturally impacted lakes. N limitation would likely impair valuable ecosystem services such as drinking water, fisheries, and recreation by promoting the occurrence and severity of cyanobacterial blooms. PMID- 26240862 TI - Whole-stream 13C tracer addition reveals distinct fates of newly fixed carbon. AB - Many estimates of freshwater carbon (C) fluxes focus on inputs, processing, and storage of terrestrial C; yet inland waters have high rates of internally fixed (autochthonous) C production. Some fraction of newly fixed C may be released as biologically available, dissolved organic C (DOC) and stimulate microbial-driven biogeochemical cycles soon after fixation, but the fate of autochthonous C is difficult to measure directly. Tracing newly fixed C can increase our understanding of fluxes and fate of autochthonous C in the context of freshwater food webs and C cycling. We traced autochthonous C fixation and fate using a dissolved inorganic C stable isotope addition (13C(DIC)). We added 13C(DIC) to North Fork French Creek, Wyoming, USA during two days in August. We monitored changes in 13C pools, fluxes, and storage for 44 d after the addition. Two compartment flux models were used to quantify net release of newly fixed 13C(DOC) and 13C(DIC) into the water column. We compared net 13C fixation with tracer 13C(DIC) removal and gross primary production (GPP) to account for the mass of tracer fixed, released, lost to the atmosphere, and exported downstream. Much of the fixed C turned over rapidly and did not enter longer-term storage pools. Net C fixed was 70% of GPP measured with O2. Algae likely released the remaining 30% via 13C(DOC) exudation and respiration of newly fixed C. Primary producers released 13C(DOC) at rates of up to 16% per day during the 13C addition, but exudation of new labile C declined to near zero by day 6. DIC production from newly fixed C accounted for 21% of ecosystem respiration the day after the 13C addition. All measured organic C (OC) pools were enriched with 13C 1 d after the tracer addition. 20% of fixed 13C remained in benthic OC by day 44, and average residence time of autochthonous C in benthic OC was 62 d. Newly fixed C had two distinct fates: short-term (< 1 week) exudation and respiration or longer-term storage and downstream export. Autochthonous C in streams likely fuels short-term microbial production and biogeochemical cycling, in addition to providing a longer-term resource for consumers. PMID- 26240863 TI - Taking animal tracking to new depths: synthesizing horizontal--vertical movement relationships for four marine predators. AB - In animal ecology, a question of key interest for aquatic species is how changes in movement behavior are related in the horizontal and vertical dimensions when individuals forage. Alternative theoretical models and inconsistent empirical findings mean that this question remains unresolved. Here we tested expectations by incorporating the vertical dimension (dive information) when predicting switching between movement states ("resident" or "directed") within a state-space model. We integrated telemetry-based tracking and diving data available for four seal species (southern elephant, Weddell, antarctic fur, and crabeater) in East Antarctica. Where possible, we included dive variables derived from the relationships between (1) dive duration and depth (as a measure of effort), and (2) dive duration and the postdive surface interval (as a physiological measure of cost). Our results varied within and across species, but there was a general tendency for the probability of switching into "resident" state to be positively associated with shorter dive durations (for a given depth) and longer postdive surface intervals (for a given dive duration). Our results add to a growing body of literature suggesting that simplistic interpretations of optimal foraging theory based only on horizontal movements do not directly translate into the vertical dimension in dynamic marine environments. Analyses that incorporate at least two dimensions can test more sophisticated models of foraging behavior. PMID- 26240864 TI - Dominant predators mediate the impact of habitat size on trophic structure in bromeliad invertebrate communities. AB - Local habitat size has been shown to influence colonization and extinction processes of species in patchy environments. However, species differ in body size, mobility, and trophic level, and may not respond in the same way to habitat size. Thus far, we have a limited understanding of how habitat size influences the structure of multitrophic communities and to what extent the effects may be generalizable over a broad geographic range. Here, we used water-filled bromeliads of different sizes as a natural model system to examine the effects of habitat size on the trophic structure of their inhabiting invertebrate communities. We collected composition and biomass data from 651 bromeliad communities from eight sites across Central and South America differing in environmental conditions, species pools, and the presence of large-bodied odonate predators. We found that trophic structure in the communities changed dramatically with changes in habitat (bromeliad) size. Detritivore : resource ratios showed a consistent negative relationship with habitat size across sites. In contrast, changes in predator: detritivore (prey) ratios depended on the presence of odonates as dominant predators in the regional pool. At sites without odonates, predator: detritivore biomass ratios decreased with increasing habitat size. At sites with odonates, we found odonates to be more frequently present in large than in small bromeliads, and predator: detritivore biomass ratios increased with increasing habitat size to the point where some trophic pyramids became inverted. Our results show that the distribution of biomass amongst food web levels depends strongly on habitat size, largely irrespective of geographic differences in environmental conditions or detritivore species compositions. However, the presence of large-bodied predators in the regional species pool may fundamentally alter this relationship between habitat size and trophic structure. We conclude that taking into account the response and multitrophic effects of dominant, mobile species may be critical when predicting changes in community structure along a habitat-size gradient. PMID- 26240865 TI - Ecological differentiation and local adaptation in two sister species of Neotropical Costus (Costaceae). AB - Reciprocal transplant experiments have often provided evidence of local adaptation in temperate plants, but few such studies have been conducted in the tropics. To enhance our knowledge of local adaptation in tropical plants, we studied natural populations of two recently diverged Neotropical plant species, Costus allenii and C. villosissimus, in central Panama. We found that these species display a parapatric distribution that reflects local environmental differences on a fine geographic scale: C. allenii is found along ravines in the understory of primary forest, while C. villosissimus is found along forest edges. Light availability was lower in C. allenii habitats, while precipitation and soil moisture were lower in C. villosissimus habitats. We carried out reciprocal transplant experiments with seeds and clones of mature plants to test the hypothesis that the parapatric distribution of these species is due to divergent adaptation to their local habitats. We found strong evidence of local adaptation, i.e., when grown in their "home" sites, each species outperformed the species from an "away" site. Our finding that C. allenii and C. villosissimus are mainly isolated by their microhabitats provides a first step toward understanding the mechanisms of adaptation and speciation in the tropics. PMID- 26240866 TI - Density-dependent immunity and parasitism risk in experimental populations of lizards naturally infested by ixodid ticks. AB - When effective immune defenses against parasites are costly and resources limited, individuals are expected to alter their investment in immunity in response to the risk of infection. As an ecological factor that can affect both food abundance and parasite exposure, host density can play an important role in host immunity and host-parasite interactions. High levels of intraspecific competition for food and social stress at high host density may diminish immune defenses and increase host susceptibility to parasites. At the same time, for contagious and environmentally transmitted parasites, parasite exposure often increases with host density, whereas in mobile parasites that actively search for hosts, parasite exposure can decrease with host density due to the "encounter dilution effect." To unravel these multiple and potentially opposing effects of host density on immunity, we manipulated density of the common lizard Zootoca vivipara and measured local inflammation in response to PHA injection and levels of infestation by the tick Ixodes ricinus, a mobile ectoparasite for which we expected an encounter-dilution effect to occur. Local inflammation strongly decreased with lizard density in adults, but not in yearlings. Tick infestation (abundance and prevalence) was negatively correlated with lizard density in both age classes. Using path analyses, we found independent, direct negative density feedbacks on immunity and parasite exposure in adults, supporting the hypothesis of energy constraints and/or physiological stress acting on immunity at high density. In contrast, for yearlings, the best path model showed that density diluted exposure to parasites, which themselves down-regulated immune defenses in lizards. These results highlight the importance of investigating the pathways among host density, host immunity, and parasite infestation, while accounting for relevant individual traits such as age. PMID- 26240867 TI - Decreased competitive interactions drive a reverse species richness latitudinal gradient in subarctic forests. AB - The tendency for species richness to decrease toward the poles is one of the best characterized patterns in biogeography. The mechanisms behind this pattern have received much attention, yet very few studies have investigated very high latitude communities. Here, using data from 134 permanent sample plots from 60 degrees to 68 degrees N, we show that boreal forest plant communities in northwestern Canada increase in richness toward the poles, despite a strong increase in climatic harshness. We hypothesized three possible explanations for this pattern: (1) historical biogeography, (2) reduced competition for light at high latitudes (biotic interactions), and (3) changes in soil characteristics with latitude. We used multidimensional scaling to investigate the community composition at each site and found no clustering of communities by latitude, suggesting that historical biogeography was not constraining site diversity. We then investigated the mechanisms behind this gradient using both abiotic (climate and soil) and biotic (tree stand characteristics) variables in a multiple factor analysis. We found that the best predictor of species richness is an environmental gradient that describes an inverse relationship between temperature and tree-stand density, suggesting that reduced competition for light due to reduced tree growth at low temperatures at higher latitudes allows greater species richness. This study shows that low energy availability and climatic harshness may not be limiting species richness toward the poles, rather, abiotic effects act instead on the strength of biotic interactions. PMID- 26240868 TI - Spatiotemporal variation in deer browse and tolerance in a woodland herb. AB - Herbivory can shape the dynamics of plant populations, including effects on survival and reproduction, and is in turn affected by environmental factors that vary in space and time. White-tailed deer are significant herbivores in North America that have been broadly documented to affect plant reproductive success. If variation in the frequency and impact of herbivory by deer correlates with a broad-scale latitudinal gradient, climactic effects may be important for shaping plant-herbivore interactions, Alternatively, a lack of broad-scale gradients would suggest local factors such as plant community composition and deer densities are affecting herbivory. To investigate broad-scale patterns of deer herbivory, we examined the frequency and reproductive consequences of deer browse over three years in 17 populations of Campanulastrum americanum spanning the latitudinal extent of its range. Even though deer are overabundant throughout the range of C. americanum, we found spatiotemporal variation in deer browse frequency (0-0.96, mean 0.46) and its effects on plant reproductive success. The four southernmost populations experienced high levels of herbivory, and were responsible for generating a negative relationship between latitude and herbivory. In general, patterns of variation in the frequency and impact of herbivory across the entire latitudinal gradient pointed to the importance of local rather than broad-scale factors. Within a population, deer consumed larger plants. Across many populations and years, average fitnesses of browsed and uneaten plants were similar, suggesting that plants are tolerant to browse. However, since large plants have greater reproductive success and are more likely to be browsed, tolerance may be influenced by plant size. When plant size was accounted for, most populations did not fully compensate for browsing. There was no relationship between browsing intensity and tolerance, suggesting that browsing may be too variable to consistently select for tolerance, or that increases in deer density are too recent for increased tolerance to evolve. PMID- 26240869 TI - Female Weddell seals show flexible strategies of colony attendance related to varying environmental conditions. AB - Many animal life cycles involve movements among different habitats to fulfill varying resource demands. There are inherent costs associated with such movements, and the decision to leave or stay at a given location ought to be motivated by the benefits associated with potential target habitats. Because movement patterns, especially those associated with reproduction, can have important implications for the success (survival, reproduction) of individual animals, and therefore a population's dynamics, it is important to identify and understand their sources of variation (environmental and individual). Here, using a mark-recapture, multistate modeling approach, we investigated a set of a priori hypotheses regarding sources and patterns of variation in breeding-colony attendance for Weddell seal (Leptonychotes weddellii) females on sabbatical from pup production. For such females, colony attendance might be motivated by predation avoidance and positive social interactions related to reproduction, but some costs, such as reduced foraging opportunities or aggressive interactions with conspecifics, might also exist. We expected these benefits and costs to vary with a female's condition and the environment. Results revealed that the probability of being absent from colonies was higher (1) in years when the extent of local sea ice was larger, (2) for the youngest and oldest individuals, and (3) for females with less reproductive experience. We also found substantial levels of residual individual heterogeneity in these rates. Based on our a priori predictions, we postulate that the decision to attend breeding colonies or not is directly influenced by an individual's physiological condition, as well as by the ice-covered distance to good foraging areas, availability of predator-free haul out sites, and the level of negative interactions with conspecifics inside colonies. Our results support the idea that in iteroparous species, and colonial animals in particular, seasonal and temporary movements from/to reproductive sites represent flexible behavioral strategies that can play an important role in coping with environmental variability. PMID- 26240870 TI - Parasites of Trinidadian guppies: evidence for sex- and age-specific trait mediated indirect effects of predators. AB - Predation pressure can alter the morphology, physiology, life history, and behavior of prey; each of these in turn can change how surviving prey interact with parasites. These trait-mediated indirect effects may change in direction or intensity during growth or, in sexually dimorphic species, between the sexes. The Trinidadian guppy, Poecilia reticulata presents a unique opportunity to examine these interactions; its behavioral ecology has been intensively studied in wild populations with well-characterized predator faunas. Predation pressure is known to have driven the evolution of many guppy traits; for example, in high-predation sites, females (but not males) tend to shoal, and this anti-predator behavior facilitates parasite transmission. To test for evidence of predator-driven differences in infection in natural populations, we collected 4715 guppies from 62 sites across Trinidad between 2003 and 2009 and screened them for ectosymbionts, including Gyrodactylus. A novel model-averaging analysis revealed that females were more likely to be infected with Gyrodactylus parasites than males, but only in populations with both high predation pressure and high infection prevalence. We propose that the difference in shoaling tendency between the sexes could explain the observed difference in infection prevalence between males and females in high-predation sites. The infection rate of juveniles did not vary with predation regime, probably because juveniles face constant predation pressure from conspecific adults and therefore tend to shoal in both high- and low-predation sites. This represents the first evidence for age- and sex-specific trait-mediated indirect effects of predators on the probability of infection in their prey. PMID- 26240871 TI - Quantifying aquatic insect deposition from lake to land. AB - Adjacent ecosystems are influenced by organisms that move across boundaries, such as insects with aquatic larval stages and terrestrial adult stages, which transport energy and nutrients from water to land. However, the ecosystem-level effect of aquatic insects on land has generally been ignored, perhaps because the organisms themselves are individually small. At the naturally productive Lake Myvatn, Iceland, we used two readily measured quantities: total insect emergence from water and relative insect density on land, to demonstrate an approach for estimating aquatic insect deposition (e.g., kg N x m(-2) x yr(-1)) to shore. Estimates from emergence traps between 2008 and 20.11 indicated a range of 0.15 3.7 g x m(-2) x yr(-1), or a whole-lake emergence of 3.1-76 Mg/yr; all masses are given as dry mass. Using aerial infall trap measurements of midge relative abundance over land, we developed a local-maximum decay function model to predict proportional midge deposition with distance from the lake. The dispersal model predicted midge abundance with R2 = 0.89, a pattern consistent among years, with peak midge deposition occurring 20-25 m inland and 70% of midges deposited within 100 m of shore. During a high-midge year (2008), we estimate midge deposition within the first 50 m of shoreline to be 100 kg xha(-1) x yr(-1), corresponding to inputs of 10 kg N x ha(-1) x yr(-1) and 1 kg P x ha(-1) x yr(-1), or about three to five times above background terrestrial N deposition rates. Consistent with elevated N input where midges are most dense, we observed that soil available nitrate in resin bags decreases with increasing distance from the lake. Our approach, generalizable to other systems, shows that aquatic insects can be a major source of nutrients to terrestrial ecosystems and have the capacity to significantly affect ecosystem processes. PMID- 26240872 TI - Branching angles reflect a trade-off between reducing trail maintenance costs or travel distances in leaf-cutting ants. AB - The design of transport paths in consuming entities that use routes to access food should be under strong selective pressures to reduce costs and increase benefits. We studied the adaptive nature of branching angles in foraging trail networks of the two most abundant tropical leaf-cutting ant species. We mathematically assessed how these angles should reflect the relative weight of the pressure for reducing either trail maintenance effort or traveling distances. Bifurcation angles of ant foraging trails strongly differed depending on the location of the nests. Ant colonies in open areas showed more acute branching angles, which best shorten travel distances but create longer new trail sections to maintain than a perpendicular branch, suggesting that trail maintenance costs are smaller compared to the benefit of reduced traveling distance. Conversely, ant colonies in forest showed less acute branching angles, indicating that maintenance costs are of larger importance relative to the benefits of shortening travel distances. The trail pattern evident in forests may be attributable to huge amounts of litterfall that .increase trail maintenance costs, and the abundant canopy cover that reduces traveling costs by mitigating direct sunlight and rain. These results suggest that branching angles represent a trade-off between reducing maintenance work and shortening travel distances, illustrating how animal constructions can adjust to diverse environmental conditions. This idea may help to understand diverse networks systems, including urban travel networks. PMID- 26240873 TI - Species-area relationships are modulated by trophic rank, habitat affinity, and dispersal ability. AB - In the face of ongoing habitat fragmentation, species-area relationships (SARs) have gained renewed interest and are increasingly used to set conservation priorities. An important question is how large habitat areas need to be to optimize biodiversity conservation. The relationship between area and species richness is explained by colonization-extinction dynamics, whereby smaller sites harbor smaller populations, which are more prone to extinction than the larger populations sustained by larger sites. These colonization-extinction dynamics are predicted to vary with trophic rank, habitat affinity, and dispersal ability of the species. However, empirical evidence for the effect of these species characteristics on SARs remains inconclusive. In this study we used carabid beetle data from 58 calcareous grassland sites to investigate how calcareous grassland area affects species richness and activity density for species differing in trophic rank, habitat affinity, and dispersal ability. In addition, we investigated how SARs are affected by the availability of additional calcareous grassland in the surrounding landscape. Beetle species richness and activity density increased with calcareous grassland area for zoophagous species that are specialists for dry grasslands and, to a lesser extent, for zoophagous habitat generalists. Phytophagous species and zoophagous forest and wet-grassland specialists were not affected by calcareous grassland area. The dependence of species on large single sites increased with decreasing dispersal ability for species already vulnerable to calcareous grassland area. Additional calcareous grassland in the landscape had a positive effect on local species richness of both dry-grassland specialists and generalists, but this effect was restricted to a few hundred meters. Our results demonstrate that SARs are affected by trophic rank, habitat affinity, and dispersal ability. These species characteristics do not operate independently, but should be viewed in concert. In addition, species' responses depend on the landscape context. Our study suggests that the impact of habitat area on trophic interactions may be larger than previously anticipated. In small habitat fragments surrounded by a hostile matrix, food chains may be strongly disrupted. This highlights the need to conserve continuous calcareous grassland patches of at least several hectares in size. PMID- 26240874 TI - Response of beta diversity to pulses of Ordovician-Silurian mass extinction. AB - Ecologists are increasingly using the fossil record of mass extinction to build predictive models for the ongoing biodiversity crisis. During mass extinctions, major depletions in global (i.e., gamma) diversity may reflect decrease in alpha diversity (i.e., local assemblages support fewer taxa), and/or decrease in beta diversity (such that similar pools of taxa are common to a greater number of local areas). Contrasting the effects of extinction on alpha and beta diversity is therefore central to understanding how global richness becomes depleted over these critical events. Here we investigate the spatial effects of mass extinction by examining changes in alpha, beta, and gamma diversity in brachiopod communities over both pulses of Ordovician-Silurian extinction (-445.2 and -438.8 million years ago), which had dramatically different causal mechanisms. We furthermore reconstruct geographic range sizes for brachiopod genera to test competing models for drivers of beta diversity change. We find that: (1) alpha and beta diversity respond differently to extinction; (2) these responses differ between pulses of extinction; (3) changes in beta diversity associated with extinction are accompanied by changes in geographic range size; and (4) changes in global beta diversity were driven by the extinction of taxa with statistically small and large ranges, rather than range expansion/contraction in taxa that survive into the aftermath. A symptom of ongoing biotic crisis may therefore be the extinction of specific narrow- or wide-ranging taxa, rather than the global proliferation of opportunistic and "disaster" forms. In addition, our results illustrate that changes in beta diversity on these longer timescales may largely be dictated by emplacement and removal of barriers to dispersal. Lastly, this study reinforces the utility of the fossil record in addressing questions surrounding the role of global-scale processes (such as mass extinctions) in sculpting and assembling regional biotas. PMID- 26240875 TI - No evidence for leaf-trait dissimilarity effects on litter decomposition, fungal decomposers, and nutrient dynamics. AB - Biodiversity and ecosystem-functioning theory suggest that litter mixtures composed of dissimilar leaf species can enhance decomposition due to species trait complementarity. Here we created a continuous gradient of litter chemistry trait variability within species mixtures to assess effects of litter dissimilarity on three related processes in a natural stream: litter decomposition, fungal biomass accrual in the litter, and nitrogen and phosphorus immobilization. Litter from a pool of eight leaf species was analyzed for chemistry traits affecting decomposition (lignin, nitrogen, and phosphorus) and assembled in all of the 28 possible two-species combinations. Litter dissimilarity was characterized in terms of a range of trait-diversity measures, using Euclidean and Gower distances and dendrogram-based indices. We found large differences in decomposition rates among leaf species, but no significant relationships between decomposition rate of individual leaf species and litter trait dissimilarity, irrespective of whether decomposition was mediated by microbes alone or by both microbes and litter-consuming invertebrates. Likewise, no effects of trait dissimilarity emerged on either fungal biomass accrual or changes during decomposition of nitrogen or phosphorus concentrations in individual leaf species. In line with recent meta-analyses, these results provide support for the contention that litter diversity effects on decomposition, at least in streams, are less pronounced than effects on terrestrial primary productivity. PMID- 26240876 TI - Arbuscular mycorrhizal fungi counteract the Janzen-Connell effect of soil pathogens. AB - Soilborne pathogens can contribute to diversity maintenance in tree communities through the Janzen-Connell effect, whereby the pathogenic reduction of seedling performance attenuates with distance from conspecifics. By contrast, arbuscular mycorrhizal fungi (AMF) have been reported to promote seedling performance; however, it is unknown whether this is also distance dependent. Here, we investigate the distance dependence of seedling performance in the presence of both pathogens and AMF. In a subtropical forest in south China, we conducted a four-year field census of four species with relatively large phylogenetic distances and found no distance-dependent mortality for newly germinated seedlings. By experimentally separating the effects of AMF and pathogens on seedling performance of six subtropical tree species in a shade house, we found that soil pathogens significantly inhibited seedling survival and growth while AMF largely promoted seedling growth, and these effects were host specific and declined with increasing conspecific distance. Together, our field and experimental results suggest that AMF can neutralize the negative effect of pathogens and that the Janzen-Connell effect may play a less prominent role in explaining diversity of nondominant tree species than previously thought. PMID- 26240877 TI - A new twist on a very old binary similarity coefficient. AB - Pairwise similarity coefficients are downward biased when samples only record presences and sampling is partial. A simple but forgotten index proposed by Stephen Forbes in 1907 can help solve this problem. His original equation requires knowing the number of species absent in both samples that could have been present. It is proposed that this count should simply be ignored and that the coefficient should be adjusted using a simple heuristic correction. Four analyses show that the corrected equation outperforms the Dice and Simpson indices, which are highly correlated with many others. In two-sample simulations, similarity is almost always closer to the assumed value when the species pool size and sampling intensity are varied, regardless of whether the underlying abundance distribution is uniform, log-normal, or geometric. The index is also much more robust when sampling is unequal. An analysis of bat samples from peninsular Malaysia buttresses these conclusions. The corrected coefficient also indicates that local assemblages of North American mammals are random subsamples of larger species pools by returning similarity of values of around 1, and it suggests a more consistent relationship between biome-scale comparisons and local scale comparisons. Finally, it yields a better-dispersed pattern when the biome scale inventories are ordinated. If these results are generalizable, then the new and old equation should see wide application, potentially taking the place of the two most commonly used alternatives (the interrelated Dice and Jaccard indices) whenever sampling is incomplete. PMID- 26240878 TI - Pollen limitation and flower abortion in a wind-pollinated, masting tree. AB - Pollen limitation is a key assumption of theories that explain mast seeding, which is common among wind-pollinated and woody plants. In particular, the pollen coupling hypothesis and pollination Moran effect hypothesis assume pollen limitation as a factor that synchronizes seed crops across individuals. The existence of pollen limitation has not, however, been unambiguously demonstrated in wind-pollinated, masting trees. We conducted a two-year pollen supplementation experiment on a masting oak species, Quercus lobata. Supplemental pollen increased acorn set in one year but not in the other, supporting the importance of pollen coupling and pollination Moran effect models of mast seeding. We also tracked the fate of female flowers over five years and found that the vast majority of flowers were aborted for reasons unrelated to pollination, even in the presence of excess pollen. Pollen limitation can reduce annual seed set in a wind-pollinated tree, but factors other than pollen limitation cause the majority of flower abortion. PMID- 26240879 TI - Lifting the veil. PMID- 26240880 TI - Propranolol (Hemangiol) and severe infantile haemangiomas. The drug of first choice. AB - Haemangiomas are benign vascular tumours that generally arise in the skin during the first days of life. They usually grow for a few months before stabilising and regressing over a period of several years, sometimes leaving sequelae. Because of their size or location, some haemangiomas cause: impairment of vital functions (vision, breathing); disfigurement with major problems of self-image; painful skin ulcers; and unsightly scars. When the growth of haemangioma is likely to cause complications, treatment with oral prednisolone at a dose of 2 to 3 mg/kg per day for several months can hasten its regression but carries a risk of numerous adverse effects, including electrolyte disturbances, cardiovascular and musculoskeletal disorders, hypercorticism, behavioural disorders, immunosuppression and growth retardation. Regrowth of the haemangioma sometimes occurs after prednisolone discontinuation. Propranolol, a beta-blocker, has been authorised in the European Union for the treatment of severe infantile haemangiomas, in the form of an oral solution to be used at a dose of 3 mg/kg per day for several months. Two randomised, unblinded trials with low statistical power compared propranolol with prednisolone in respectively 19 and 30 infants treated for several months. No difference in efficacy was observed. Treatment withdrawal seemed less frequent with propranolol. Two randomised, double-blind, placebo-controlled trials tested a 6-month course of propranolol. Propranololled to tumour regression in about half of the infants in one trial but, 17 months after propranolol withdrawal, tumour regrowth occurred in about 40% of the children considered to be in clinical remission. In the other trial, the haemangiomas shrank on average by about 60% with propranolol versus 14% with placebo. The known adverse effects of propranolol differ from those of corticosteroids. They mainly consist of hypoglycaemia, bradycardia, hypotension, bronchospasm, sleep disturbances, and gastrointestinal disorders. In comparative trials, treatment discontinuation because of adverse effects appeared to be less frequent with propranolol than with prednisolone. Severe adverse effects, some of which were fatal, have been reported in infants treated with propranolol. In practice, when medication is warranted for infantile haemangioma, propranolol is the drug of first choice. Parents and healthcare professionals must monitor infants closely for adverse effects. Treatment initiation and each dose increase should take place in hospital. PMID- 26240881 TI - Iomitapide (Lojuxta). Use only in homozygous familial hypercholesterolaemia, with caution. AB - Patients with rare homozygous familial hypercholesterolaemia are at risk of dying at a very young age. When liver transplantation is not feasible, treatment is based on regular LDL apheresis sessions, a burdensome and inconvenient procedure, and on high-dose statins in combination with ezetimibe. Lomitapide acts by inhibiting the synthesis of LDL constituents. It has been granted EU marketing authorisation as adjunctive therapy for homozygous familial hypercholesterolaemia. Clinical evaluation of lomitapide is based on a non comparative trial in 29 adults. When added to standard therapy, lomitapide led to about a 40% reduction in absolute LDL cholesterol levels. Longer follow-up is needed to determine whether this is sufficient to prevent cardiovascular complications. Seven of the 13 patients under-going LDL apheresis were able to increase the interval between sessions or stop them altogether. Nearly all patients treated with lomitapide experienced gastrointestinal adverse effects, including diarrhoea, nausea, vomiting and dyspepsia. Lomitapide was associated with hepatic abnormalities in about one-third of patients in the short-term. It remains to be seen whether the hepatic steatosis observed in some patients progresses to fibrosis or cirrhosis with long-term use. Lomitapide is extensively metabolised by cytochrome P450 isoenzyme CYP3A4 and also inhibits P-glycoprotein, hence a risk of multiple pharmacokinetic interactions. In particular, lomitapide increases the plasma concentrations of statins, and their toxicity. Lomitapide was teratogenic in experimental animals. In practice, lomitapide should be strictly reserved for patients with homozygous familial hypercholesterolaemia. Clinical evaluation must continue in these rare patients at high risk of early death. PMID- 26240883 TI - Urinary continence and incontinence, in brief. PMID- 26240882 TI - Drug-induced urinary incontinence. AB - Urinary incontinence can have a significant impact on patients' quality of life. Some causes involve physiologic and structural disorders of the urinary system. Other causes do not directly affect the urinary system but are related to difficulties in reacting to the urge to urinate or getting to the toilet alone, or an increase in urine output. Toxic substances or drugs are sometimes implicated. Drugs that affect one or more of the components of the normal continence mechanism expose patients to the risk of urinary incontinence. Some of these drugs act on the urinary system, particularly the autonomic nervous system; some increase urine output; some impair physical or cognitive function; and others cause urinary retention, leading to overflow incontinence. Drugs known to cause urinary incontinence are often prescribed for older patients, who are already at increased risk: sedatives, neuroleptics, antidepressants, cholinesterase inhibitors used in Alzheimer's disease, diuretics, alpha blockers used in hypertension or benign prostatic hyperplasia, and menopausal hormone replacement therapy. PMID- 26240884 TI - Misoprostol: serious cardiovascular events, even after a single dose. AB - A French Regional Pharmacovigilance Centre identified serious cardiovascular adverse effects linked to misoprostol and reported worldwide up to the end of 2012. Dozens of cases of myocardial infarction, angina and stroke had been reported, including after a single dose in gynaecology and obstetrics, for instance in elective abortion. This risk appears higher in smokers, women aged over 35 years, obese women, and after high-dose vaginal administration. The incidence is unknown. The bioavailability of misoprostol is higher with the vaginal than the oral route, especially when water is added to the tablet before vaginal administration. In practice, this risk must be taken into account, especially in women with risk factors for cardiovascular disease, or when using high doses or the vaginal route. When a high cardiovascular risk is identified, it is best to warn patients of the cardiac effects of this drug and advise them to consult a doctor if they experience chest tightness, or to propose an alternative method. Whenever possible, these women should not be alone when they take misoprostol. PMID- 26240885 TI - Pharmacology of prostaglandins, in brief. PMID- 26240886 TI - Drugs for hypotension: disproportionate harms with etilefrine and heptaminol. . AB - The French Health Products Agency concluded that etilefrine and heptaminol have an unfavourable harm-benefit balance, and also placed restrictions on the use of midodrine. PMID- 26240887 TI - Cotrimoxazole + an ACE inhibitor or ARB: sudden death. PMID- 26240888 TI - Galantamine: serious skin reactions. PMID- 26240889 TI - Topiramate: visual field defects. PMID- 26240890 TI - Cotrimoxazole: fatal thrombocytopenia. PMID- 26240892 TI - Other adverse effects of screening mammography. PMID- 26240891 TI - Mammographic screening for breast cancer. Overdiagnosis: an insidious adverse effect of screening. AB - Mammographic mass screening for breast cancer sometimes detects tumours that would grow so slowly that the women concerned would die from other causes before developing noteworthy symptoms. This "overdiagnosis" unnecessarily exposes women to cancer treatments and their adverse effects. To assess the risk of overdiagnosis during mammographic mass screening for breast cancer, we conducted a review of the literature using the standard Prescrire methodology. The most reliable estimates of overdiagnosis are obtained by deduction, based on data from randomised trials with lengthy post-screening follow-up. A randomised trial in Sweden and two in Canada compared screening versus no screening, and monitored the women for an average of 15 and 17 years after the end of screening. For every 10 000 women who were screened, there were 63 cases of breast cancer overdiagnosis in the Swedish trial and 26 in the Canadian trials, representing about 25% of all cancers diagnosed by screening. This rate of overdiagnosis is probably on the low side, as about 20% of the women in the unscreened control groups had at least one mammogram. Studies of the general female population confirm that mammographic mass screening leads to overdiagnosis, but the results add little to those of randomised trials. In 2015, the most reliable estimate is that at least 25% of breast cancers detected by screening mammography are overdiagnosed. In France, at least 19 breast cancers would be overdiagnosed for every 1000 women screened during a 20-year period, corresponding to a total of about 3800 overdiagnosed cancers for each year of mass screening. Women must be informed of the risk of overdiagnosis and its consequences in terms of unnecessary treatment, along with other factors influencing the harm-benefit balance. See page 190 for our proposals on how to inform women wondering whether or not to undergo mammographic screening. PMID- 26240893 TI - Sharing relevant information with women to help them decide whether or not to participate in breast cancer screening. PMID- 26240894 TI - Hydroxyzine: choose other treatments. PMID- 26240895 TI - New and little known pholcid spiders (Araneae: Pholcidae) from Laos. AB - Fourteen new species belonging to five pholcid genera are reported from Laos: Belisana champasakensis sp. nov. (male), B. crystallina sp. nov. (male and female), B. gigantea sp. nov. (male and female), B. khanensis sp. nov. (male and female), B. lancea sp. nov. (male), B. martensi sp. nov. (male), B. tadetuensis sp. nov. (male), B. xiangensis sp. nov. (male and female), Calapnita longa sp. nov. (male), Khorata circularis sp. nov. (male and female), K. dupla sp. nov. (male and female), Pholcus arcuatilis sp. nov. (female), P. sublaksao sp. nov. (male and female) and Spermophorafalcata sp. nov. (male and female). The genera Belisana and Spermophora are reported from Laos for the first time. PMID- 26240896 TI - Taxonomic, nomenclatural, and faunistic records for species in tribes Melaenini, Moriomorphini, Pterostichini, Licinini, and Sphodrini (Coleoptera: Carabidae). AB - Mexyclothorax baehri, sp. n. (type locality: Papua New, Guinea, West Sepik Province, summit of Mount Capella, 3960 m), Atrotus indicus, sp. n. (type locality: India, Nilgiri Hills, Coonoor env.), Microzarguspakistanus,sp. n. (type locality: Pakistan, Kaghan Valley, Shogran env.) and Pterostichus (Oreophilus) podgoricensis, sp. n. (type locality: Montenegro, Podgoritsa env.) are described. The following nomenclatural acts are proposed: Hexagonia vartianorum Jedlicka, 1967, syn. n. of Cymbionotum semirubricum (Reitter 1914); Poecilus (Derus) jarkendis (Jedlicka, 1965), comb. n. of Pterostichus (Melanius) jarkendis Jedlicka, 1965; Pterostichus (Pseudorthomus) namrun Jedlicka, 1963, syn. n. of Amphimasoreus amaroides Piochard de la Brulerie, 1875; Synuchus hummeli (Jedlicka, 1935), comb. n. of Pterostichus hummeli Jedlicka, 1935. In addition, new distributional records are recorded for Microzargus hartmanni Sciaky & Facchini, 1997, M. nepalensis Sciaki & Facchini, 1997 and Amphimasoreus amaroides. PMID- 26240897 TI - Six new species of oonopid spiders from Champasak, Laos (Araneae, Oonopidae). AB - Five genera and nine species of oonopid spiders are recorded from Laos, including six new species: Gamasomorpha comosa Tong & Li, 2009, Ischnothyreus corollacous sp. nov., Ischnothyreus tadetu sp. nov., Ischnothyreus tadfane sp. nov., Opopaea cornuta Yin & Wang, 1984, Opopaea lemniscata sp. nov., Opopaea tumida sp. nov., Xestaspis loricata (L. Koch, 1873), and Xyphinus pakse sp. nov. PMID- 26240898 TI - A new species and new records of the genus Hypogastrura Bourlet, 1839 (Collembola, Hypogastruridae) from Iran. AB - Hypogastrura persica sp. nov. is described from the Zagros Mountains (Kermanshah Province, Iran). The new species can be distinguished from two nearest congeners, namely H. exigua Gisin, 1958 (Alps) and H. magistri Babenko, 1994 (Siberia), by the body size, the number of sensilla on antennal segment IV, the number of setae on dens and ventral tube as well as chaetotaxy of abdominal terga IV and V. Three species of the genus, viz. H. martiani Skarzynski & Kaprus', 2009, H. purpurescens (Lubbock, 1867) and H. socialis (Uzel, 1891), have been recorded from Iran for the first time. PMID- 26240899 TI - A new species of the genus Hypleurochilus (Teleostei: Blenniidae) from Trindade Island and Martin Vaz Archipelago, Brazil. AB - A new species of the genus Hypleurochilus, endemic to Trindade Island and Martin Vaz Archipelago, off Brazil, is described. Hypleurochilus brasil sp. n. differs from its congeners in color pattern and anal-ray counts. A recent study shows a close relationship between H. brasil sp. n. and H. fissicornis. This new species is recorded from 3 to 15 m depth, solitary or in small groups (up to 10 individuals), always in small holes or associated with sea-urchins and sponges on the rocky reefs. Hypleurochilus brasil sp. n. is the eleventh recognized species of Hypleurochilus and the third species of this genus reported from the Brazilian Province. PMID- 26240900 TI - Oribatid mites (Acari, Oribatida) of plain area of the Southern European Russia. AB - The paper is devoted to the fauna of oribatid mites (Acari: Oribatida) mostly of a plain area of the Southern European Russia. The most updated taxonomic list of oribatid mite taxa compiled from the original authors' data collected after sam- pling soil, nests and plumage of birds, as well as published sources is presented. It includes 256 species of oribatid mites belonging to 72 families. Twenty species and one family of oribatid mites are recorded for the first time at the research territory. The abundance of mites in the soil is also provided for selected species. PMID- 26240901 TI - The Oriental lanternfly genus Scamandra: new species and taxonomical notes (Hemiptera: Fulgoromorpha: Fulgoridae). AB - Three new species and one new subspecies are described: Scamandra lumawigi sp. n. (Luzon, Philippines), S. huangi sp. n. (Taliabu Island off Sulawesi), S. vanvyvei sp. n. (Sulawesi) and S. vanvyvei pelengana ssp. n. (Peleng Island off Sulawesi). The status of Scamandra mucorea Gerstaecker, 1895 is revised and the species is no more considered a subspecies of S. hermione Stal, 1864. The new name Scamandra stanjakli Constant, 2013 is proposed to replace S. jakli Chew Kea Foo et al., 2010 which is ajunior homonym of S. jakli Rolcik, 2008. Male genitalia are illustrated for S. huangi, S. hermione, S. lumawigi, S. mucorea and S. jakli. Habitus illustrations are provided for all species except S. stanjakli. New distribution records are given for S. mucorea and S. stanjakli. PMID- 26240902 TI - Description of the male, larva and nymphal stages of Cryptocellus iaci (Arachnida, Ricinulei), with an overview of tarsal sensilla and other integumental structures. AB - The male, larva and nymphal stages of Cryptocellus iaci Tourinho, Lo Man-Hung & Bonaldo, 2010, a species previously known only from a single female, are described based on specimens from around the type locality, in an area of both Terra Firme forest and igapo (flooded forests), at the Jufari River, Roraima State, Brazil. The specimens were illustrated using live photography, stereomicroscopy, and scanning electron microscopy, allowing us to examine and describe the large diversity of tarsal sensilla and other integumental structures in Cryptocellus and to compare them to those of the previously studied Pseudocellus. Based on the male somatic characters Cryptocellus iaci is placed in thefoedus species-group. Cryptocellus iaci has two sensilla of type 1 on the distal tarsomeres of legs III (DT III), while only one has been reported for Pseudocellus spp., suggesting a potential value in this type of character for systematic studies of the group. PMID- 26240903 TI - A new species of Homonota (Reptilia: Squamata: Gekkota: Phyllodactylidae) endemic to the hills of Paraje Tres Cerros, Corrientes Province, Argentina. AB - The genus Homonota comprises nine South American species of terrestrial and nocturnal lizards. Homonota lizards lack the femoral pores typical of other South American Phyllodactylidae, and their infradigital lamellas are not expanded. We here describe a new species, Homonota taragui sp. nov., exclusively found on a small group of three hills up to 179 meters above sea level in central eastern Corrientes Province, Argentina. The new species differs from other Homonota species by a combination of characters, including: a well-marked dorsal, reticulate, dark pattern contrasting with a lighter colored background; small, star-shaped chromatophores on the abdomen; the post-orbital region of the head covered by granular scales; the dorsal and anterior regions of the thighs covered by keeled scales interspersed with cycloid scales; and the internasal scale in contact with rostral scales. The conservation status of Homonota taragui sp. nov. may be vulnerable, due to its localized endemism with populations on three small hills surrounded by intense agricultural and livestock activity. Two endemic plant species are known from these hills, and this new lizard represents the first endemic animal species. PMID- 26240904 TI - Collembola Poduromorpha from Guelma Province (Northeastern Algeria), with description of a new Superodontella species (Collembola: Odontellidae). AB - Ten Poduromorpha species have been found in the Taya Region, three of which are new for Algeria: Hypogastrura vernalis (Carl, 1901), Xenylla brevisimilis mediterranea Gama, 1964 and Superodontella tayaensis sp. nov. The new species is morphologically closest to S. subalpina Arbea, 1990, with three subequal dental chaetae. They differ in the number of tibiotarsal chaetae and the sensilar chaetotaxy of Ant IV. PMID- 26240905 TI - The male of Tengella perfuga Dahl, 1901 with re-description of the female and comparisons with T. radiata (Kulczynski, 1909) (Araneae: Tengellidae). AB - Tengellaperfuga Dahl, 1901, is the type species for Tengella, the type genus for the family Tengellidae Dahl, 1908. Here, the males are described for the first time and females re-described based on new specimens collected in Nicaragua. We confirm the species status of T perfuga (instead of previously suggested synonymy with Tengella radiata (Kulczynski, 1909)), since the colour pattern and genitalia of both sexes, particularly the palp RTA and the epigynal median septum, are unique in the genus. Important diagnostic features are illustrated for both males and females. Also new distribution records are reported for T perfuga from Nicaragua and T radiata from Honduras, Nicaragua and Panama. PMID- 26240906 TI - Substrate dependent talitrid amphipods from fragmented beaches on the north coast of Crete (Crustacea, Amphipoda, Talitridae), including a redefinition of the genus Orchestia and descriptions of Orchestia xylino sp. nov. and Cryptorchestia gen. nov. AB - Four species of talitrid amphipods (Orchestia montagui Audouin, 1826, Orchestia stephenseni Cecchini, 1928, Orchestia xylino sp. nov. and Talitrus saltator (Montagu, 1808)) are reported from a set of fragmented pocket beaches to the east of Heraklion on the north coast of Crete. Aside from a previous record of O. stephenseni these are the first records of talitrid amphipods from the island of Crete. 2) Along a coastal segment of only 4.36 km, characterised by habitat fragmentation and substrate patchiness, a clear correlation between talitrid species and beach type is indicated. Talitrus saltator occurs only on sandy beaches. Orchestia montagui and O. xylino occur on banquette beaches and O. montagui, O. stephenseni and O. xylino occur on mixed sand/gravel and cobble beaches. 3) The genus Orchestia is redefined and confined to 15 marine supralittoral species from eastern North America, islands in the North-eastern Atlantic, and western-Europe, including the Baltic and the Mediterranean Seas plus a perplexing group in New Zealand. 4) The new genus Cryptorchestia is described, based on nine terrestrial species previously included in the genus Orchestia and occurring in western Europe, the Mediterranean Sea and the Azores and Canary islands in the North-eastern Atlantic. 5) The new species Orchestia xylino sp. nov. is described. 6) An extensive bibliography for the species in this study is provided. PMID- 26240907 TI - New species for Thraulodes Ulmer, 1920 (Ephemeroptera: Leptophlebiidae: Atalophlebiinae) and the first key to adults from Brazil. AB - Four new species of the mayfly genus Thraulodes Ulmer are described based on imagos from Northeastern and Southern Brazil: Thraulodes luizgonzagai sp. nov., Thraulodes sternimaculatus sp. nov., Thraulodes alapictus sp. nov., and Thraulodes pinhoi sp. nov. The new species can be easily differentiated by the abdominal color pattern and genitalia morphology. The first key to adults from Brazil is provided. PMID- 26240908 TI - New records and geographical distribution of ctenid spiders (Araneae: Ctenidae) in Colombia. AB - This study provides new records, geographical distribution extensions and a checklist of the current ctenids species in Colombia based on the review of four arachnological collections and published literature. A total of 15 new records for Ctenidae in Colombia are reported; nine of these species are new records for the country and the distribution of the remaining six is expanded. The genus Centroctenus Mello-Leitao, 1929 (C. ocelliventer Strand, 1909) is recorded for first time in Colombia and Cupiennius coccineus (F.O. Pickard-Cambridge, 1901) for South America. Due to the strategic geographic position of Colombia, which is a transition zone between Southern and Central American biotas, species inventories in different localities are important to fill distributional gaps. The number of known species of ctenids in Colombia is increased from 16 to 25 and these data will be useful for future studies in taxonomy, systematics and biogeography of this family. PMID- 26240909 TI - A new species of the genus Empitrombium Southcott, 1994 (Acari: Microtrombidiidae) from Turkey. AB - A new species, Empitrombium makolae sp. nov., is described based on active postlarval forms and larvae obtained from adult females kept in the laboratory. Based on the adult morphology of E. makolae, the adult life stage of Platytrombidium littorale (Michener 1946) is moved back to the genus Empitrombium. A key to species of Empitrombium is provided. PMID- 26240910 TI - Two new species of feather mites (Acarina: Analgoidea) from the Moustached Warbler, Acrocephalus melanopogon (Passeriformes, Acrocephalidae), in Romania. AB - Two new species of feather mites Ingrassiella melanopogoni Constantinescu sp. nov. (Xolalgidae) and Trouessartia mironovi Constantinescu sp. nov. (Trouessartiidae) are described from Acrocephalus melanopogon (Passeriformes: Acrocephalidae) from the South-East of Romania. Ingrassiella melanopogoni differs from all species of the genus by having extensions of the posterolateral angles of the prodorsal shield shorter than in other species and not extending to the hysteronotal shield. Trouessartia mironovi is readily distinguished by having an unique combination of characters within the genus: epimerites I are fused in both sexes and epimerites IVa are highly developed in male (coxal fields IV are almost closed). PMID- 26240911 TI - The first goblin spiders of the genus Trilacuna from Vietnam (Araneae, Oonopidae). AB - Two new species of the genus Trilacuna Tong & Li, T. hamata sp. nov. and T. sinuosa sp. nov., are described from Tam Dao National Park, Vietnam. PMID- 26240912 TI - Nine new species of the genus Rosalba (Coleptera, Cerambycidae, Lamiinae, Apomecynini) from South America. AB - New species of Rosalba Thomson, 1864 are described: from Venezuela, R. jolyi sp. nov. (Aragua); from Colombia, R. maculosa sp. nov. (Santander); from Ecuador, R. mediovittata sp. nov. (Manabi), R. cacapyra sp. nov. (Orellana) and R. parvula sp. nov. (province unknown); from Bolivia, R. tanimbuca sp. nov. (Santa Cruz); from Brazil, R. amazonica sp. nov. and R. gounellei sp. nov. (Amazonas) and R. vanini sp. nov. (Rondonia). R. malleri (Melzer, 1934) and R. digna (Melzer, 1934) are illustrated and new records are provided. PMID- 26240913 TI - A new species of Dicranocentrus Schott (Collembola, Entomobryidae, Orchesellinae) from Brazilian Amazon. AB - Orchesellinae specimens are distinguished from other Entomobryidae by a shorter fourth abdominal segment (length at the midline less than 1.8 times the third segment), generally more than four antennal segments, recurved labral setae and the presence of a complex metatrochanteral organ, with at least 11 spine-like setae, (Soto-Adames et al. 2008). Adult Dicranocentrus Schott specimens have the following characters: antennae with six segments, both fifth and sixth antennal segments annulated, 8+8 lenses in the eye patches, absence of a postantennal organ, apically rounded and/or truncated scales, pre-labral setae simple, not bifurcated, rows of spines on dens (present in most but not all species) and mucro bearing two teeth with a basal spine (Mari-Mutt 1976, 1981, Arle & Mendonca 1982, Bellinger et al. 1996-2012). The genus is similar to other scaled Orchesellini genera such as Pseudodicranocentrus Mari-Mutt, 1981 and Dicranorchesella Mari-Mutt, 1977, but differs from these taxa by the presence of simple pre-labral setae (bifurcated in Pseudodicranocentrus) and by rounded and/or truncated scales (fusiform and apically pointed in Dicranorchesella) (Mari Mutt 1977, 1980). Dicranocentrus is holotropical in distribution only four species recorded from Brazil: D. bicolor Handschin, 1924, D. silvestrii Absolon, 1903, D. termitophilus Handschin, 1924 and D. heloisae Arle & Mendonca, 1982 (Abrantes et al. 2012). These species are restricted to northeastern and southeastern Regions (Abrantes et al. 2012). The new species is the first from Brazilian Amazon, north region of Brazil. The dorsal chaetotaxic scheme follows that of Mari-Mutt (1979). PMID- 26240914 TI - A brief review of genus Catopta Staudinger, 1899 (Lepidoptera: Cossidae) with description of a new species from China. AB - A checklist of the genus Catopta Staudinger, 1889 is presented. A new species, C. dusii sp. nov., from the Xiling Xue Shan Mountains of in the Noth West China's Sichuan Province is described. PMID- 26240915 TI - Taxonomic history and invasion biology of two Phyllonorycter leaf miners (Lepidoptera: Gracillariidae) with links to taxonomic and molecular datasets. AB - This paper deals with two European species, Phyllonorycter mespilella (Hubner, 1805) and P. trifasciella (Haworth, 1828), that have colonized the subtropical Canary Islands. The Rosaceae leaf miner, P. mespilella, is recorded for the first time from Lanzarote and La Palma, while the Caprifoliaceae leaf miner, P. trifasciella, is recorded from Tenerife. We present the diagnoses of these species based on morphology, a preliminary DNA barcode (COI) library of congeneric and con-familial species, and discuss the taxonomic position of the colonizers within the blancardella and trifasciella species groups. The recent intensification of anthropogenic disturbance likely accounts for their range expansion, an event that may impact the relict flora present on the Canary Islands. PMID- 26240916 TI - A new species of Parapanteles Ashmead (Hymenoptera: Braconidae) from India reared from Abisara echeria Stoll (Lepidoptera: Riodinidae) with key to the Indian Parapanteles species. AB - A new species of gregarious endoparasitoid, Parapanteles echeriae Gupta, Pereira & Churi, sp. nov., bred from Abisara echeria Stoll (Lepidoptera: Riodinidae) on host plant Embelia sp. (Myrsinaceae), is described and illustrated from Mumbai, Maharashtra, India. Abisara echeria, commonly known as plum judy, is a small striking butterfly prevalent in Asia. This is the first ever record of a parasitic wasp associated with Abisara. Parapanteles echeriae is distinguished from P. sireeshaae Ahmad & Akhtar in having propodeum with areola 1.2x as long as wide; anterior diagonal carina meeting anterior margin of propodeum in one half; veins r and 2RS of fore wing merging in a smooth curve; yellow coloured legs and tegulae brownish black. A key to the Indian species of Parapanteles is also provided. PMID- 26240917 TI - The Cossidae (Lepidoptera) of Malawi with descriptions of two new species. AB - An annotated list of Cossidae of Malawi including 30 species from 13 genera and 3 subfamilies is presented for the first time. Two new species are described: Macrocossus grebennikovi Yakovlev, sp. nov. and Strigocossus elephas Yakovlev, sp. nov. Three new synonyms are established: Strigocossus moderatus (Walker, 1856) = Strigocossus leucopteris Houl- bert, 1916, syn. nov. = Xyleutes sjoestedti vosseleri Gaede, 1930, syn. nov. and Strigocossus capensis (Walker, 1856) Azygophleps kilimandjarae Le Cerf, 1914, syn. nov. PMID- 26240918 TI - A new species of Anchylorhynchus Schoenherr (Coleoptera: Curculionidae) from the Amazon, with a record of a new host palm for the genus. AB - Anchylorhynchus vanini sp. nov. from the Amazon is described, including the mouthparts and male genitalia. The new species is compared with similar species within the genus and the key to the species of Anchylorhynchus provided by Vaurie (1954) is modified to include the new species. Adult specimens were collected in flowers of the palm Syagrus vermicularis Noblick and additional collections in other palms species suggest that this association is specific. This is the first record of the palm Syagrus vermicularis as host for a species of Anchylorhynchus. PMID- 26240919 TI - Planktonic ostracods (Myodocopa: Halocyprididae) from abyssopelagic depths in the Atlantic, North Pacific and Gulf of Oman: Chavturia abyssopelagica (n. gen., n. sp.), Halocypretta profunda (n. sp.), Halocypretta parvirostrata Chavtur and Stovbun, 2008 and Halocypretta striata (Muller, 1906). AB - A novel species and genus of halocyprid ostracod, Chavturia abyssopelagica, and a new species of Halocypretta are described from depths > 3000 m in the Atlantic. The new genus is related to Halocypretta, itself a genus that has only recently been described from deep waters in the North Pacific. Supplementary observations are made on the type species, Halocypretta parvirostrata, based on additional specimens from the North Pacific. Halocypretta striata from the Gulf of Oman is reported for the first time since it was first described and is redescribed in detail. All four species are illustrated and compared using a set of meristic characters. PMID- 26240920 TI - The first troglobitic Cryptops (Trigonocryptops) (Chilopoda: Scolopendromorpha) from South America and the description of a non-troglobitic species from Brazil. AB - Cryptops (Trigonocryptops) iporangensis n. sp., and C. (T) hephaestus n. sp. are described from SE Brazil. C. (T) iporangensis n. sp. presents highly troglomorphic characters and is described from a remarkable cave system located in Sao Paulo State, the Areias cave system, from were other 16 troglobitic species are also known. C. (T) hephaestus n. sp. was described on specimens collected in three caves of the "Quadrilatero Ferrifero" (Iron quadrangle), in Minas Gerais State, but does not presents a clear specialization to subterranean habitat. The new troglobitic species can be separated from other species of Cryptops (T.) from Brazil and all troglobitc species of the genus Cryptops by presenting incomplete paramedian sutures on tergites, antennal article 1 with an inverted Y-shaped suture on its proximal part and distal spinose processes on ultimate leg. C. (T.) hephaestus differs from the other species of Cryptops (Trigonocryptops) from Brazil by presenting anterior oblique sutures on tergites 2-7 and posterior oblique sutures on tergites 1-3. Cryptops (Cryptops) galatheae Meinert, 1886 is moved here to the subgenus Trigonocryptops. PMID- 26240921 TI - Japanagromyza Sasakawa (Diptera: Agromyzidae) of Africa. AB - The African Japanagromyza Sasakawa are revised, including a key and genitalic illustrations, and the limits of the genus are discussed. Nine species are recognized, which include four previously described species and four newly described species: J. crinicolis spec. nov.; J. dolobrata spec. nov.; J. laureata spec. nov.; J. nesiota spec. nov. The ninth species ("female 1") is described but not formally named as it is known only from females. Japanagromyza salicifolii is known from Palaearctic Africa on Populus and Salix. The remaining eight species are known from the Afrotropical Region; of these, only Japanagromyzaparvula Spencer has a known host association [Fabaceae-Crotalaria]. PMID- 26240922 TI - Two new species of the genus Longicheles Valle, 1953 from the Kelkit Valley, Turkey, with redescription Longicheles lagrecai (Valle, 1963) (Acari: Macrochelidae). AB - The Kelkit Valley is geographically a transitional zone between the Middle Black Sea and Inner Anatolia regions in Turkey. Two new species of Macrochelidae are described from this area--Longicheles ozkani sp. nov. and Longicheles ayyildizi sp. nov. Longicheles lagrecai (Valle, 1963) is recorded for the Turkish fauna and redescribed on the basis of specimens collected from the Valley. A world-wide key to species of Longicheles Valle is provided. PMID- 26240923 TI - New species of plant bug associated with pastures in Colombia, and notes on the genera Dolichomiris, Cynodonmiris, and Megaloceroea (Hemiptera: Heteroptera: Miridae). AB - Cynodonmiris corpoicanus, a new species of Miridae belonging to the subfamily Mirinae and the tribe Stenodemini, is described from Colombia. Similarities and differences between Cynodonmiris, Dolichomiris, and Megaloceroea are presented. Geographic distribution of C. corpoicanus and its host plants are given. Diagnoses and illustrations of the female and male genitalia characters are provided to distinguish the Neotropical species of Cynodonmiris and Dolichomiris, and Holarctic Megaloceroea. PMID- 26240924 TI - Description of three new Tetranchyroderma gastrotrichs (Macrodasyida: Thaumastodermatidae) from South Korea. AB - The present paper deals with description of three new marine gastrotrich species belonging to the genus Tetranchyroderma with a new record for Korea of T schizocirratum Chang, Kubota & Shirayama, 2002, on the basis of specimens from the Korean coast. Tetranchyroderma anisoankyrum sp. nov. is differentiated from congeners by its dorsal cuticular armature of pentancres with central tine longer than the others, a pair of rod-like cephalic tentacles, 2 cirratum-type TbDL, 13 14 cirratum-type TbL per side, and a pair of TbL. Tetranchyroderma coreense sp. nov. is distinguished from other pentancrous species by cirratum-type tubes of 2 TbDL, one TbL, 3-4 TbVL, paired foot-type TbV, and absence of cephalic tentacles. Tetranchyroderma oblongum sp. nov. is characterized by the character combination of cuticular armature of tetrancres, 7 dorsolateral and 7-9 lateral cirratum-type tubes, and 33-38 TbVL along whole body. This brings the total number of species in the genus Tetranchyroderma known from South Korea to 12. PMID- 26240925 TI - A new species of the cicada genus Semia Matsumura, 1917 (Hemiptera: Cicadidae) from Vietnam, with a key to the species of the genus. AB - A new species of cicada, Semia gialaiensis, is described from Kon Ka Kinh National Park in central Vietnam. Photos of the adult, illustrations of the male genitalia, a distribution map and biological data are provided. A key to the species of Semia based on the male adults is also given. PMID- 26240926 TI - Taxonomy and distribution of the Afrotropical genus Anchophthalmops Koch, 1956 with a key to species (Coleoptera: Tenebrionidae: Pedinini). AB - The taxonomic and distributional data concerning the representatives of the genus Anchophthalmops were revised. Lectotypes for Anchophthalmopsfoveipennis and A. ventralis were designated to fix the taxonomic status of these species. A. neumanni and A. zablockii were described as new species. Maximum entropy modeling was used to test the probability of occurrence of A. menouxi on Madagascar. An identification key is provided to all known species of Anchophthalmops. PMID- 26240927 TI - Two new species of the spider genus Antoonops (Araneae: Oonopidae), with a key to the known species. AB - Two new species of the goblin spider genus Antoonops are described, bringing the total number of species to six. Antoonops kamieli sp. nov. is described from two males and one female collected in Bouake, Ivory Coast. The species can be easily distinguished from congeners by its large eyes. In addition, the males are characterized by a distinct depression on the ventral abdomen. Antoonops sarae sp. nov. is described from four females collected in Tchabal Mbabo, Cameroon. The species is unusual in having a long postepigastric scutum and a genital duct with finger-like protrusions. A key to the species of Antoonops is provided. PMID- 26240928 TI - A new genus of Thripinae (Thysanoptera, Thripidae) collected from Pandanus in Japan, Malaysia and Australia, with three new species. AB - Pandanothrips gen. n. is described, with three new species inhabiting Pandanus: P. ryukyuensis sp. n. from Japan, P. wangi sp. n. from Malaysia, and P. hallingi sp. n. from Australia. This new genus shows no relationship to Projectothrips Moulton, the only other Thripinae genus known to be associated with Pandanus. Pandanothrips is superficially similar to Danothrips Bhatti, a genus of leaf feeding thrips. The morphological relationships among these genera are discussed, and an illustrated key to the species of Pandanothrips is provided. PMID- 26240929 TI - Lycomimodes, a new generic replacement name for preoccupied Lycomimus Lawrence and Slipinski, 2013 (Insecta: Coleoptera: Ptilodactylidae) non Melzer, 1931 (Insecta: Coleoptera: Cerambycidae). PMID- 26240930 TI - Aradidae from Vietnam II. Longitergus, a new genus and two new species of micropterous Mezirinae (Hemiptera: Heteroptera: Aradidae). AB - A new micropterous flat bug genus, Longitergus n.gen. with the species productus n.sp. and similis n.sp. from Vietnam, is described. A key to related Oriental genera is given and the diagnostic morphological characters of the new genus and species are illustrated. PMID- 26240931 TI - The ants (Hymenoptera:formicidae) of Rawdhat Khorim Nature Preserve, Saudi Arabia, with description of a new species of the genus Tetramorium Mayr. AB - Rawdhat Khorim, a densely vegetated alluvial basin supporting a distinctive floral community in the hyper-arid desert of central Saudi Arabia, is one of the most important protected nature sanctuaries of the country. The ant fauna (Formicidae) of Rawdhat Khorim was sampled and 14 species, including one new species were collected using a variety of sampling methods. The new species, Tetramorium saudicum sp. n., a member of the T. caespitum-group, is described based on the worker caste. Cataglyphis viaticoides (Andre) is recorded for the first time from Saudi Arabia. The information in this paper will allow natural resource managers to establish long-term ecological studies, using sentinel taxa such as ants to evaluate present and future impacts on Rawdhats. PMID- 26240932 TI - A review of the genus Sinodorcadion Gressitt, 1939 with description of three new species from China (Coleoptera: Cerambycidae: Lamiinae). AB - The genus Sinodorcadion Gressitt, 1939 is reviewed. Three new species, S. jiangi sp. nov., S. magnispinicolle sp. nov. and S. punctuscapum sp. nov., are described. A key to all known Sinodorcadion species (five) is presented. PMID- 26240933 TI - A new species of Lappodiamesa Serra-Tosio (Diptera: Chironomidae: Diamesinae) from the Russian Far East, with a key to known species of the genus. AB - The male, pupa, and larva of a new species, Lappodiamesa omelkoi, from the Russian Far East are described and figured. Keys to males, pupae, and fourth instar larvae of known species of the genus are presented. PMID- 26240934 TI - Elucidating Article 45.6 of the International Code of Zoological Nomenclature: a dichotomous key for the determination of subspecific or infrasubspecific rank. AB - We present an overview of the difficulties sometimes encountered when determining whether a published name following a binomen is available or infrasubspecific and unavailable, following Article 45.6 of the International Code of Zoological Nomenclature (ICZN, 1999). We propose a dichotomous key that facilitates this determination and as a preferable method, given the convoluted and subordinate discussion, exceptions, and qualifications laid out in ICZN (1999: 49-50). Examples and citations are provided for each case one can encounter while making this assessment of availability status of names following the binomen. PMID- 26240935 TI - Who gets a fistula? DOPPS research details U.S., international practice patterns on access placement. PMID- 26240936 TI - A closer look at race and access placement. PMID- 26240937 TI - Treating Insomnia: A Review of Patient Perceptions Toward Treatment. AB - Patient views about their treatment for insomnia often dictate outcome. This review explores the literature relating to the patients' global perceptions toward treatment for insomnia. A strategic literature search was conducted using five databases (PubMed, CINAHL, Medline, PsycINFO, and Embase). The 57 research articles included for this review were mapped out chronologically across three key stages of treatment-seeking (pretreatment appraisal, actual treatment experiences, and posttreatment evaluation). Patient perceptions played an important role across these three key stages and influenced subsequent health behaviors such as the initiation of help-seeking, treatment uptake, treatment adherence, and treatment adjustment. Patients' perceptions toward treatment were heavily grounded by their psychosocial contexts. Clinical implications and future directions for including patient-centered metrics in mainstream practice and research are discussed. PMID- 26240938 TI - Development of Activity-Based Probes for Imaging Human alpha-l-Fucosidases in Cells. AB - We have established a concise synthetic route relying on a key base-promoted epimerization step to synthesize two series of activity-based probes carrying a BODIPY fluorophore for alpha-l-fucosidase. The resulting probes were evaluated for labeling performance. The one utilizing an o-fluoromethylphenol derivative as the latent trapping unit was successfully applied for the first time to visualize and locate lysosomal alpha-l-fucosidase activity in human cells. PMID- 26240940 TI - A social network analysis approach to alcohol use and co-occurring addictive behavior in young adults. AB - INTRODUCTION: The current study applied egocentric social network analysis (SNA) to investigate the prevalence of addictive behavior and co-occurring substance use in college students' networks. Specifically, we examined individuals' perceptions of the frequency of network members' co-occurring addictive behavior and investigated whether co-occurring addictive behavior is spread evenly throughout networks or is more localized in clusters. We also examined differences in network composition between individuals with varying levels of alcohol use. METHOD: The study utilized an egocentric SNA approach in which respondents ("egos") enumerated 30 of their closest friends, family members, co workers, and significant others ("alters") and the relations among alters listed. Participants were 281 undergraduates at a large university in the Southeastern United States. RESULTS: Robust associations were observed among the frequencies of gambling, smoking, drinking, and using marijuana by network members. We also found that alters tended to cluster together into two distinct groups: one cluster moderate-to-high on co-occurring addictive behavior and the other low on co-occurring addictive behavior. Lastly, significant differences were present when examining egos' perceptions of alters' substance use between the networks of at-risk, light, and nondrinkers. CONCLUSIONS: These findings provide empirical evidence of distinct clustering of addictive behavior among young adults and suggest the promise of social network-based interventions for this cohort. PMID- 26240939 TI - Early Life Experience and Gut Microbiome: The Brain-Gut-Microbiota Signaling System. AB - BACKGROUND: Over the past decades, advances in neonatal care have led to substantial increases in survival among preterm infants. With these gains, recent concerns have focused on increases in neurodevelopment morbidity related to the interplay between stressful early life experiences and the immature neuroimmune systems. This interplay between these complex mechanisms is often described as the brain-gut signaling system. The role of the gut microbiome and the brain-gut signaling system have been found to be remarkably related to both short- and long term stress and health. Recent evidence supports that microbial species, ligands, and/or products within the developing intestine play a key role in early programming of the central nervous system and regulation of the intestinal innate immunity. PURPOSE: The purpose of this state-of-the-science review is to explore the supporting evidence demonstrating the importance of the brain-gut-microbiota axis in regulation of early life experience. We also discuss the role of gut microbiome in modulating stress and pain responses in high-risk infants. A conceptual framework has been developed to illustrate the regulation mechanisms involved in early life experience. CONCLUSIONS: The science in this area is just beginning to be uncovered; having a fundamental understanding of these relationships will be important as new discoveries continue to change our thinking, leading potentially to changes in practice and targeted interventions. PMID- 26240941 TI - Perceived stress and smoking-related behaviors and symptomatology in male and female smokers. AB - INTRODUCTION: Stress has been found to be a significant risk factor for cigarette smoking. Stress affects males and females differently, as does the use of smoking for stress reduction. Few studies have examined gender differences with the interrelation of perceived stress and smoking behaviors and nicotine related symptomatology. Our study investigates this association, as well as the influence of sociodemographic variables. METHODS: This is a retrospective analysis of 62 smokers (41 males, 21 females) enrolled in a smoking cessation study. At the screening visit sociodemographic information, smoking behaviors and survey measures were completed. These included the Perceived Stress Scale (PSS), Minnesota Nicotine Withdrawal Scale (MNWS), and others. Analyses were conducted using multiple linear regression models. RESULTS: PSS score was found to have a negative association with number of cigarettes smoked in males (slope -0.29+/ 0.08; p=0.0009) and females (slope -0.20+/-0.18; p=0.26) with no difference in effect between genders (p=0.64). Linear regression of MNWS on PSS revealed a positive association for both males (slope 0.41+/-0.068; p<0.0001) and females (slope 0.73+/-0.14; p<0.0001). There was a significant difference in effect between genders (p=0.04). CONCLUSIONS: A strong positive association was observed between perceived stress and nicotine withdrawal symptomatology in smokers of both sexes, with a larger effect seen in women. These findings emphasize the importance of stress reduction in smokers, which may lead to fewer withdrawal symptoms and more effective smoking cessation. PMID- 26240942 TI - Dialectical behavior therapy with American Indian/Alaska Native adolescents diagnosed with substance use disorders: combining an evidence based treatment with cultural, traditional, and spiritual beliefs. AB - This pilot study examined pre to post-change of patients in a substance use residential treatment center that incorporated Dialectical Behavior Therapy with specific cultural, traditional and spiritual practices for American Indian/Alaska Native adolescents. Specifically, the incorporation of cultural, spiritual and traditional practices was done while still maintaining fidelity to the evidence based treatment (DBT). 229 adolescents participated in the study and were given the Youth Outcome Questionnaire-Self-Report version at pre-treatment and post treatment and the total scores were compared. The results of the research study showed that 96% of adolescents were either "recovered" or "improved" using clinical significant change criteria. Additionally, differences between the group's pre-test scores and post-test scores were statistically significant using a matched standard T-test comparison. Finally, the effect size that was calculated using Cohen's criteria was found to be large. The results are discussed in terms of the implication for integrating western and traditional based methods of care in addressing substance use disorders and other mental health disorders with American Indian/Alaska Native adolescents. PMID- 26240943 TI - Prevalence and correlates of electronic cigarette use among adolescents in Greece: a preliminary cross-sectional analysis of nationwide survey data. AB - INTRODUCTION: This study reports the prevalence of electronic cigarette (e cigarette) use among adolescents in Greece and explores how dual smokers of e cigarettes and combustible (conventional) cigarettes differ from smokers of only combustible cigarettes across socio-demographic, familial, psychosomatic health and substance use characteristics. METHODS: Self-reports on smoking were collected from a nationally representative sample of 1320 15-year-old Greek students in the 2014 Health Behaviour in School-aged Children study. Bivariate and multivariable logistic regression analyses were carried out with dependent variables a) lifetime smoking conventional cigarettes and b) lifetime e-cigarette use among lifetime smokers. RESULTS: About 36.9% of 15-year-olds reported lifetime smoking of conventional cigarettes, and 16.6% lifetime use of e cigarettes, mostly experimenting (0.5% reported current e-cigarette use). Six in 7 ever e-cigarette smokers had smoked conventional cigarettes. Peers who smoke and lifetime cannabis use were significant correlates of both lifetime conventional cigarette and e-cigarette smoking, but more strongly for smoking conventional cigarettes. Alcohol use and low parental monitoring correlated with tobacco smoking but not e-cigarette use. Girls were more likely than boys to report lifetime use of tobacco, but, among lifetime smokers, boys had almost seven times the odds of girls of e-cigarette use. In lifetime smokers, low life satisfaction in females and current smoking of conventional tobacco were independently associated with the experimentation with e-cigarettes. CONCLUSIONS: Experimental use of e-cigarettes is relatively widespread among adolescents in Greece. Targeted interventions should focus on male smokers and the role of peer processes and cannabis use in the risk of experimenting with e-cigarettes. PMID- 26240945 TI - Low use of effective and safe therapies for moderate to severe menopausal symptoms: a cross-sectional community study of Australian women. AB - OBJECTIVE: Given the global decline in the use of hormone therapy among women, aimed to determine the prevalence of use of prescription therapies for menopausal symptoms. METHODS: A cross-sectional questionnaire-based study of 2,020 Australian women was conducted between October 2013 and March 2014. Women aged 40 to 65 years who were able to complete a questionnaire in English were recruited from a large dynamic database derived from the Australian electoral roll. The main outcome measures were use of prescription therapies for menopausal symptoms and the Menopause-specific Quality of Life questionnaire. RESULTS: A total of 5,850 women were invited (by telephone) to participate: 2,911 agreed to participate, and 2,020 completed questionnaires were returned. Demographic characteristics show that participants were representative of all Australian women of this age. For this analysis, only 1,491 perimenopausal and postmenopausal women were included. Moderate to severe vasomotor symptoms (VMS) were reported by 17% of women, and 18.3% of women reported moderate to severe sexual symptoms. Among all participants, 11.3% used hormone therapy, mostly oral estrogen (68.5%). Among all women, 1.1% used compounded estrogen and/or compounded progesterone, 0.9% used androgen therapies (dehydroepiandrosterone or testosterone), 0.9% used tibolone, 0.9% used nonhormone therapies, and 4.5% used vaginal estrogen. Hormone therapy use was associated with surgical menopause (adjusted odds ratio [AOR], 3.27; 95% CI, 2.0-5.44), and moderate-severe psychological symptoms (AOR, 1.83; 95% CI, 1.19-2.80. Current smoking (AOR, 0.53; 95% CI, 0.29-0.96) and a BMI >= 40 (AOR, 0.35; 95% CI, 0.14-0.87 were inversely associated with hormone therapy use. Extrapolating our findings to 3.7 million Australian women aged 40 to 64 years, we found that 455,000 women are likely to have moderate to severe VMS, with most women (385,000) remaining untreated. CONCLUSIONS: Most women with severe menopausal symptoms remain untreated despite the availability of safe nonhormone therapies and safer low-dose transdermal hormone therapies. Vaginal estrogen therapy is underprescribed. PMID- 26240944 TI - Rate of nicotine metabolism and smoking cessation outcomes in a community-based sample of treatment-seeking smokers. AB - BACKGROUND: In samples from controlled randomized clinical trials, a smoker's rate of nicotine metabolism, measured by the 3-hydroxycotinine to cotinine ratio (NMR), predicts response to transdermal nicotine. Replication of this relationship in community-based samples of treatment-seeking smokers may help guide the implementation of the NMR for personalized treatment for nicotine dependence. METHODS: Data from a community-based sample of treatment seeking smokers (N=499) who received 8weeks of transdermal nicotine and 4 behavioral counseling sessions were used to evaluate associations between the NMR and smoking cessation. Secondary outcomes included withdrawal and craving, depression and anxiety, side effects, and treatment adherence. RESULTS: The NMR was a significant predictor of abstinence (OR=.56, 95% CI: 0.33-0.95, p=.03), with faster metabolizers showing lower quit rates than slower metabolizers (24% vs. 33%). Faster nicotine metabolizers exhibited significantly higher levels of anxiety symptoms over time during treatment, vs. slower metabolizers (NMR x Time interaction: F[3,357]=3.29, p=.02). NMR was not associated with changes in withdrawal, craving, depression, side effects, and treatment adherence (p's>.05). CONCLUSIONS: In a community-based sample of treatment-seeking smokers, faster nicotine metabolizers were significantly less likely to quit smoking and showed higher rates of anxiety symptoms during a smoking cessation treatment program, vs. slower nicotine metabolizers. These results provide further evidence that transdermal nicotine is less effective for faster nicotine metabolizers and suggest the need to address cessation-induced anxiety symptoms among these smokers to increase the chances for successful smoking cessation. PMID- 26240946 TI - Differences in age at death according to smoking and age at menopause. AB - OBJECTIVE: Younger age at menopause is associated with overall mortality, and cigarette smoking is the only lifestyle factor influencing this association. However, the combined effects of age at menopause and smoking have never been quantified in terms of survival time. Our aim was to evaluate, in a large cohort of Swedish women, differences in age at death according to age at menopause and smoking status. METHODS: Age at menopause and smoking were assessed, using a self administered questionnaire, in a population-based cohort of 25,474 women aged 48 to 83 years. Laplace regression was used to calculate differences in median age at death (50th percentile difference [PD]) according to smoking and age at menopause. RESULTS: Across 16 years of follow-up, 5,942 participants died. The difference in median age at death between women with menopause at 40 years and women with menopause at 60 years was 1.3 years (50th PD, 1.3; 95% CI, 0.3-2.2). Compared with current smokers, former smokers and never smokers had older median age at death-2.5 years (50th PD, 2.5; 95% CI, 1.9-3.1) and 3.6 years (50th PD, 3.6; 95% CI, 3.1-4.1), respectively. When analysis was restricted to current smokers, the difference in age at death between women with menopause at 40 years and women with menopause at 60 years increased to 2.6 years (50th PD, 2.6; 95% CI, 0.8-4.5). No association among never smokers was observed. CONCLUSIONS: Younger age at menopause is linearly associated with shorter survival. This association tends to be stronger among current smokers. PMID- 26240947 TI - Melena as presentation of primary small intestine inflammatory myofibroblastic tumor in an adult woman. A case report. AB - INTRODUCTION: Inflammatory myofibroblastic tumor (IMT), also known as inflammatory pseudotumor, plasma cell granuloma or inflammatory myofibroblastoma, is characterized histopathologically by myofibroblastic spindle cells with inflammatory cell infiltrates ( plasma cell, lymphocytes and eosinophils). Inflammatory myofibroblastic tumor is tipically seen in children or young adults and is most commonly localized in the lung, but it can occur anywhere in the body. CASE REPORT: We present a case in a young woman with severe acute G.I. bleeding, an uncommon presentation of IMT in adults. The patient was admitted to the emergency department for melena. MRI showed a distal jejunum hypervascular mass. Other exams were negative. Surgical excision was recommended, so the patient underwent surgery with complete removal of the tumoral mass. No adjuvant therapy was employed and the patient is asymptomatic after 6 months of follow-up. DISCUSSION: IMT is an rare lesion that mimics malignancy and is accompanied by various clinical manifestations. The treatment of choice is believed to be complete surgical excision and long term follow up. KEY WORDS: Anemia, Inflammatory myofibroblastic tumor (IMT), Small intestine, Surgery. PMID- 26240948 TI - Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: Role of activity at NMDA receptor. AB - Ketamine produces rapid and long-lasting antidepressant effects in patients. The involvement of ketamine metabolites in these actions has been proposed. The effects of ketamine and its metabolites norketamine and dehydronorketamine on ligand binding to 80 receptors, ion channels and transporters was investigated at a single concentration of 10 MUM. The affinities of all three compounds were then assessed at NMDA receptors using [3H]MK-801 binding. The dose-response relationships of all 3 compounds in the forced swim test were also investigated in mice 30 min after IP administration. The effects of ketamine and norketamine (both 50 mg/kg) were then examined at 30 min, 3 days and 7 days post administration. Among the 80 potential targets examined, only NMDA receptors were affected with a magnitude of >50% by ketamine and norketamine at the concentration of 10 MUM. The Ki values of ketamine, norketamine and dehydronorketamine at NMDA receptors were 0.119+/-0.01, 0.97+/-0.1 and 3.21+/-0.3 MUM, respectively. Ketamine and norketamine reduced immobility with minimum effective doses (MEDs) of 10 and 50 mg/kg, respectively; dehydronorketamine did not affect immobility at doses of up to 50 mg/kg. Neither ketamine nor norketamine reduced immobility in the forced swim test 3 and 7 days following administration. Further, oral administration of ketamine (5-50 mg/kg) did not affect immobility. We demonstrate that ketamine and norketamine but not dehydronorketamine given acutely at subanesthetic doses reduced immobility in the forced swim test. These antidepressant-like effects appear attributable to NMDA receptor inhibition. PMID- 26240949 TI - A randomised controlled trial of Outpatient versus inpatient Polyp Treatment (OPT) for abnormal uterine bleeding. AB - BACKGROUND: Uterine polyps cause abnormal bleeding in women and conventional practice is to remove them in hospital under general anaesthetic. Advances in technology make it possible to perform polypectomy in an outpatient setting, yet evidence of effectiveness is limited. OBJECTIVES: To test the hypothesis that in women with abnormal uterine bleeding (AUB) associated with benign uterine polyp(s), outpatient polyp treatment achieved as good, or no more than 25% worse, alleviation of bleeding symptoms at 6 months compared with standard inpatient treatment. The hypothesis that response to uterine polyp treatment differed according to the pattern of AUB, menopausal status and longer-term follow-up was tested. The cost-effectiveness and acceptability of outpatient polypectomy was examined. DESIGN: A multicentre, non-inferiority, randomised controlled trial, incorporating a cost-effectiveness analysis and supplemented by a parallel patient preference study. Patient acceptability was evaluated by interview in a qualitative study. SETTING: Outpatient hysteroscopy clinics and inpatient gynaecology departments within UK NHS hospitals. PARTICIPANTS: Women with AUB - defined as heavy menstrual bleeding (formerly known as menorrhagia) (HMB), intermenstrual bleeding or postmenopausal bleeding - and hysteroscopically diagnosed uterine polyps. INTERVENTIONS: We randomly assigned 507 women, using a minimisation algorithm, to outpatient polypectomy compared with conventional inpatient polypectomy as a day case in hospital under general anaesthesia. MAIN OUTCOME MEASURES: The primary outcome was successful treatment at 6 months, determined by the woman's assessment of her bleeding. Secondary outcomes included quality of life, procedure feasibility, acceptability and cost per quality adjusted life-year (QALY) gained. RESULTS: At 6 months, 73% (166/228) of women who underwent outpatient polypectomy were successfully treated compared with 80% (168/211) following inpatient polypectomy [relative risk (RR) 0.91, 95% confidence interval (CI) 0.82 to 1.02]. The lower end of the CIs showed that outpatient polypectomy was at most 18% worse, in relative terms, than inpatient treatment, within the 25% margin of non-inferiority set at the outset of the study. By 1 and 2 years the corresponding proportions were similar producing RRs close to unity. There was no evidence that the treatment effect differed according to any of the predefined subgroups when treatments by variable interaction parameters were examined. Failure to completely remove polyps was higher (19% vs. 7%; RR 2.5, 95% CI 1.5 to 4.1) with outpatient polypectomy. Procedure acceptability was reduced with outpatient compared with inpatient polyp treatment (83% vs. 92%; RR 0.90, 95% CI 0.84 to 0.97). There were no significant differences in quality of life. The incremental cost-effectiveness ratios at 6 and 12 months for inpatient treatment were L1,099,167 and L668,800 per additional QALY, respectively. CONCLUSIONS: When treating women with AUB associated with uterine polyps, outpatient polypectomy was non-inferior to inpatient polypectomy at 6 and 12 months, and relatively cost-effective. However, patients need to be aware that failure to remove a polyp is more likely with outpatient polypectomy and procedure acceptability lower. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 65868569. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 61. See the NIHR Journals Library website for further project information. PMID- 26240950 TI - Single-Pot Synthesis of ?001?-Faceted N-Doped Nb2O5/Reduced Graphene Oxide Nanocomposite for Efficient Photoelectrochemical Water Splitting. AB - Due to exciting catalytic activity and selectivity, tailoring of nanocatalysts consisting of preferred crystal facets and desired structural properties remains at the forefront of materials engineering. A facile one-step nonhydrolytic solvothermal synthesis of a nanocomposite of reduced graphene oxide and one dimensional nitrogen-doped Nb2O5 (N-NbOx) with exposed ?001? facet is described. Triethylamine performed the dual role as nitrogen source and capping agent to control the size and unidirectional growth of Nb2O5 nanocrystallites. The nanocomposite showed efficient visible-light-mediated (lambda > 420 nm) water splitting in a photoelectrochemical cell. A plausible mechanism for the formation of N-NbOx nanorods and improved photoelectrochemical efficacy in terms of their oriented growth is proposed. PMID- 26240951 TI - Evaluation of the threat of marine CO2 leakage-associated acidification on the toxicity of sediment metals to juvenile bivalves. AB - The effects of the acidification associated with CO2 leakage from sub-seabed geological storage was studied by the evaluation of the short-term effects of CO2 induced acidification on juveniles of the bivalve Ruditapes philippinarum. Laboratory scale experiments were performed using a CO2-bubbling system designed to conduct ecotoxicological assays. The organisms were exposed for 10 days to elutriates of sediments collected in different littoral areas that were subjected to various pH treatments (pH 7.1, 6.6, 6.1). The acute pH-associated effects on the bivalves were observed, and the dissolved metals in the elutriates were measured. The median toxic effect pH was calculated, which ranged from 6.33 to 6.45. The amount of dissolved Zn in the sediment elutriates increased in parallel with the pH reductions and was correlated with the proton concentrations. The pH, the pCO2 and the dissolved metal concentrations (Zn and Fe) were linked with the mortality of the exposed bivalves. PMID- 26240952 TI - Arsenic toxicity effects on microbial communities and nutrient cycling in indoor experimental channels mimicking a fluvial system. AB - The toxicity of chemicals in the environment is influenced by many factors, such as the adsorption to mineral particles, active biological surfaces, biotransformation and/or nutrient concentration. In the present study, a simplified fluvial system including fish, periphyton and sediment was used to investigate the fate and effects of environmentally realistic concentration of arsenic (As) on biofilm growth and nutrient cycling. Total dissolved arsenic concentration decreased exponentially from 120MUg/L to 28.0+/-1.5MUg/L during the experiment (60 days), mostly sinking to the sediment and a smaller percentage accumulated in the periphytic biofilm. Most P and N, which was provided by fish, was also retained in the epipsammic biofilm (growing on sediment grains). We conclude that exposure to this concentration of arsenic under oligotrophic conditions is changing the quality and quantity of the base of the aquatic food chain and its respective contribution to nutrient cycling, and normal functioning of the ecosystem. The effects include lowering the total biomass of biofilm and its potential ability to use organic P (i.e., phosphatase activity), inhibiting algal growth, especially that of diatoms, decreasing nitrogen content, and making the epipsammic biofilm more heterotrophic, thus reducing its ability to oxygenate the aquatic environment. PMID- 26240954 TI - Alignment of centers of mass of body segments with the gravity line. PMID- 26240953 TI - Zebrafish sex differentiation and gonad development after exposure to 17alpha ethinylestradiol, fadrozole and their binary mixture: A stereological study. AB - Current knowledge on zebrafish (Danio rerio) sex determination suggests that this trait has a polygenic genetic basis, although environmental factors, such as endocrine disrupting chemicals (EDC), may also be involved in modeling or disturbing the species sex differentiation and development. This study aimed to assess how sex steroids imbalance triggers impact on sex differentiation and gonad development in zebrafish. Fish where exposed to an estrogen (EE2, i.e. 17alpha-ethinylestradiol, 4ng/L), to an inhibitor of estrogen synthesis (Fad, i.e. fadrozole, 50MUg/L) or to their binary mixture (Mix-EE2+ Fad, 4ng/L+50MUg/L), from 2h to 60 days post-fertilization (dpf). Afterwards, a quantitative (stereological) analysis using light microscopy, based on systematic sampling, was made at 35 and 60dpf, to identify alterations on gonad differentiation and development. During the sex differentiation period, our histological data showed that not all zebrafish males develop a "juvenile ovary", contrarily to what is currently taken for granted. Furthermore, the stereological analysis suggests that EE2 alone enhanced both zebrafish growth and gonad development. On the other hand, exposure to Fad affected the sexual development in zebrafish, inducing masculinization of the specimens, with some degree of intersex observed in males. In addition, the binary mixture allowed identifying sex-dependent roles of steroid hormones in the general growth and gonad development of zebrafish, with estrogens acting as growth promoters in females and being essential for ovary development. Data further support that sex-specific and single EDC impact studies are important, but clearly not sufficient to understand what may occur in the environment. PMID- 26240955 TI - Transannular [4 + 2] Cycloaddition Reactions of Cobalt-Complexed Macrocyclic Dienynes. AB - The first transannular [4 + 2] cycloaddition reactions of macrocyclic dicobalt hexacarbonyl-dienyne complexes were demonstrated. Complexes were conveniently prepared through palladium(II)-catalyzed intramolecular oxidative cyclization of bis(vinylboronate esters) followed by complexation with dicobalt octacarbonyl. Transannular [4 + 2] cycloaddition reactions of the complexes occurred at lower temperatures and shorter times than transannular Diels-Alder reactions of metal free dienynes. Intermolecular control reactions confirmed the effect of cobalt complexation on [4 + 2] cycloaddition reactions of unactivated alkynes and dienes. PMID- 26240956 TI - Pharmacodynamic interaction models in pediatric anesthesia. AB - Pharmacokinetic (PK) and pharmacodynamic (PD) models are important tools for summarizing drug dose, concentration, and effect relationships. Co-administration of drugs may alter PK and PD relationships. Traditional methods of evaluating PD interactions include using isoboles, shifts in dose-response curves, or interaction indices based on parameters of potency derived from separate monotherapy and combination therapy analyses. These methods provide an estimation of the magnitude of effect for dose or concentration combinations, but they do not inform us on the time course of that effect, or its associated variability. A better way to investigate PD interactions is to use modeling, and to take advantage of the benefits of population analyses. A population analysis is a statistical method in which a model describing the typical (or population) response, and the variability between individuals within that population, is developed. Models for monotherapy, derived using a population approach, can be combined and extended to incorporate PD interactions between two or more drugs. The purpose of this article was to provide a general road map for understanding and interpreting PD interaction models, including the 'response surface' models. Several types of response surface models exist, and here we review these with examples taken from the literature. We also consider current and future applications for this type of analysis for clinical anesthesia and pediatrics. PMID- 26240957 TI - Group Singing as a Therapy during Diabetes Training--A Randomized Controlled Pilot Study. AB - Comprehensive diabetes treatment has been shown to reduce quality of life in diabetic patients. However, there is evidence to suggest that group singing can have positive effects on quality of life in various clinical settings. In this randomized controlled pilot study, the effect of singing as a therapy to reduce stress and improve quality of life was investigated in insulin-dependent diabetic patients, undergoing a lifestyle intervention program. Patients from the singing group felt less discontented following treatment. This effect, however, was lost after 3 months. No effect on serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels could be seen when comparing the singing group with the control group, although reduced levels of ACTH and cortisol 3 days after treatment could be found and were still present after 3 months within the group of patients who undertook singing as a therapy. Singing led to an increase in bodyweight, which interestingly had no effect on glucose control or methylglyoxal levels. Therefore, singing during a lifestyle intervention program for insulin dependent diabetic patients had a short lasting and weak effect on patients' mood without affecting glucose control, but no significant effect on stress related hormones. PMID- 26240958 TI - Prevalence of Retinopathy in Adult Patients with GCK-MODY and HNF1A-MODY. AB - We aimed to assess the prevalence of diabetic retinopathy (DR) in adult patients with GCK-MODY and HNF1A-MODY in Poland and to identify biochemical and clinical risk factors associated with its occurrence.We examined 74 GCK mutation carriers, 51 with diabetes and 23 with prediabetes, respectively, and 63 patients with HNF1A-MODY. Retinal photographs, 12 for each patient, were done by a fundus camera. Signs of DR were graded according to the DR disease severity scale. Statistical tests were performed to assess differences between the groups and logistic regression was done for the association with DR.The mean age at examination was 34.5+/-14.8 and 39.9+/-15.2 in the GCK-MODY and HNF1A-MODY groups, respectively. Mild nonproliferative DR (NPDR) was found in one patient with the GCK mutation and likely concomitant type 1 diabetes, whereas DR was diagnosed in 15 HNF1A-MODY patients: 9 with proliferative, 3 with moderate NPDR and 2 with mild NPDR. In univariate logistic regression analysis in the HNF1A MODY group, significant results were found for diabetes duration, fasting glycemia, HbA1c, arterial hypertension, age at the examination, and eGFR. The strongest independent predictors of DR in HNF1A-MODY were markers of glucose control: HbA1c (OR: 2.05, CL%95: 1.2-3.83, p=0.01) and glucose (p=0.006, OR: 1.40, CL%95: 1.12-1.83) analyzed in 2 separated models. Additionally, arterial hypertension independently predicted DR (OR: 9.06, CL%95: 1.19-98.99, p=0.04) in the model with HbA1c as glycaemic control marker.In conclusion, DR of any degree was not present in our GCK-MODY group, while in spite of young age almost every fourth subject with HNF1A-MODY showed signs of this complication. PMID- 26240967 TI - Dasatinib affects focal adhesion and myosin regulation to inhibit matrix contraction by Muller cells. AB - Epiretinal membrane (ERM) contraction is associated with a variety of ocular diseases that cause macular dysfunction. Trans-differentiated Muller cells have been identified in ERMs, and have been implicated to be involved in the contractile process. In this study, we tested the effect of dasatinib, an FDA approved tyrosine kinase inhibitor, on matrix contraction caused by Muller cells, and examined molecular mechanism of action. Type I collagen matrix contraction assays were used to examine the effect of drugs on matrix contraction by trans differentiated Muller cells. Fluophore-conjugated phalloidin was used for the detection of actin cytoskeleton, and Western-blot analyses were carried out to examine protein expression and phosphorylation status. Dasatinib inhibited collagen matrix contraction by trans-differentiated Muller cells that was associated with decreased cell spreading and reduction of actomyosin stress fibers. Concomitantly, dasatinib-treated Muller cells had reduced phosphorylation of Src family kinase, paxillin, as well as myosin II light chain. Specific inhibitors of Rho/ROCK and myosin II confirmed the critical role played by this pathway in Muller cell contraction. Our data demonstrate that dasatinib significantly reduced matrix contraction by Muller cells via inhibition of focal adhesion, as well as actomyosin contraction. PMID- 26240968 TI - An evaluation of the PowerSeqTM Auto System: A multiplex short tandem repeat marker kit compatible with massively parallel sequencing. AB - Capillary electrophoresis (CE) and multiplex amplification with fluorescent tagging have been routinely used for STR typing in forensic genetics. However, CE based methods restrict the number of markers that can be multiplexed simultaneously and cannot detect any intra-repeat variations within STRs. Several studies already have indicated that massively parallel sequencing (MPS) may be another potential technology for STR typing. In this study, the prototype PowerSeq(TM) Auto System (Promega) containing the 23 STR loci and amelogenin was evaluated using Illumina MiSeq. Results showed that single source complete profiles could be obtained using as little as 62 pg of input DNA. The reproducibility study showed that the profiles generated were consistent among multiple typing experiments for a given individual. The mixture study indicated that partial STR profiles of the minor contributor could be detected up to 19:1 mixture. The mock forensic casework study showed that full or partial profiles could be obtained from different types of single source and mixture samples. These studies indicate that the PowerSeq Auto System and the Illumina MiSeq can generate concordant results with current CE-based methods. In addition, MPS-based systems can facilitate mixture deconvolution with the detection of intra-repeat variations within length-based STR alleles. PMID- 26240959 TI - Detection of human bocavirus in nasopharyngeal aspirates versus in broncho alveolar lavage fluids in children with lower respiratory tract infections. AB - To compare the presence of human bocavirus (HBoV) in nasopharyngeal aspirates (NPA) versus broncho-alveolar lavage fluids (BAL) in children with lower respiratory tract infections (LRTIs), as revealed by real-time PCR, in order to confirm the diagnostic validity of NPA samples. A retrospective 5-year study was performed from 2009 to 2014 in 1,194 patients under the age of 17 years (mean age of 3 years) that were diagnosed with LRTIs and from whom both NPA and BAL were obtained. Clinical and demographic data were recorded, and NPA and BAL samples were analyzed for HBoV-positivity by real-time PCR. Of the 1,194 patients enrolled, 65 (5.4%) patients had HBoV detected from NPA, and 61 (5.1%) had HBoV detected from BAL. For HBoV, there was a significant association between the NPA and BAL samples (P < 0.001), but the diagnostic validity was relatively low (kappa = 0.414). When real-time PCR-positivity for HBoV in BAL was used as a reference for diagnosis, NPA had a good specificity and better positive predictive validity in male patients or those younger than 3 years of age. NPA has a similar yield and a good specificity for diagnosis of LRTIs with HBoV compared to BAL. The best diagnostic validity for NPA was detected in male patients or those younger than 3 years old. PMID- 26240969 TI - The effects of metal ion PCR inhibitors on results obtained with the Quantifiler((r)) Human DNA Quantification Kit. AB - Forensic DNA samples may include the presence of PCR inhibitors, even after extraction and purification. Studies have demonstrated that metal ions, co purified at specific concentrations, inhibit DNA amplifications. Metal ions are endogenous to sample types, such as bone, and can be introduced from environmental sources. In order to examine the effect of metal ions as PCR inhibitors during quantitative real-time PCR, 2800 M DNA was treated with 0.0025 18.750 mM concentrations of aluminum, calcium, copper, iron, nickel, and lead. DNA samples, both untreated and metal-treated, were quantified using the Quantifiler((r)) Human DNA Quantification Kit. Quantification cycle (Cq) values for the Quantifiler((r)) Human DNA and internal PCR control (IPC) assays were measured and the estimated concentrations of human DNA were obtained. Comparisons were conducted between metal-treated and control DNA samples to determine the accuracy of the quantification estimates and to test the efficacy of the IPC inhibition detection. This kit is most resistant to the presence of calcium as compared to all metals tested; the maximum concentration tested does not affect the amplification of the IPC or quantification of the sample. This kit is most sensitive to the presence of aluminum; concentrations greater than 0.0750 mM negatively affected the quantification, although the IPC assay accurately assessed the presence of PCR inhibition. The Quantifiler((r)) Human DNA Quantification Kit accurately quantifies human DNA in the presence of 0.5000 mM copper, iron, nickel, and lead; however, the IPC does not indicate the presence of PCR inhibition at this concentration of these metals. Unexpectedly, estimates of DNA quantity in samples treated with 18.750 mM copper yielded values in excess of the actual concentration of DNA in the samples; fluorescence spectroscopy experiments indicated this increase was not a direct interaction between the copper metal and 6-FAM dye used to label the probe that targets human DNA in the Quantifiler((r)) kit. Evidence of inhibition was observed for the human-specific assay at a lower metal concentration than detected by the IPC, for all metals examined except calcium. These results strongly suggest that determination of a "true negative" sample should not be based solely on the failure of the IPC to indicate the presence of a PCR inhibitor and indicate that amplification of all samples should be attempted, regardless of the quantification results. PMID- 26240970 TI - Population genetics data for 21 autosomal STR loci for United Arab Emirates (UAE) population using next generation multiplex STR kit. PMID- 26240972 TI - DNA of ancient wolf-dog pushes back domestication date. PMID- 26240973 TI - Next-generation sequencing to estimate the prevalence of a great unknown: McArdle disease. PMID- 26240974 TI - Response to Nogales-Gadea et al. PMID- 26240975 TI - In sickness and in health: context matters when considering potential benefits and risks of genome-wide sequencing. PMID- 26240976 TI - Response to Strong. PMID- 26240977 TI - Haploinsufficiency of the MYT1L gene causes intellectual disability frequently associated with behavioral disorder. PMID- 26240978 TI - A PMS2-specific colorectal surveillance guideline. PMID- 26240979 TI - Response to ten Broeke and Nielsen. PMID- 26240980 TI - CORRIGENDUM: Treacher Collins syndrome: a clinical and molecular study based on a large series of patients. PMID- 26240982 TI - Changing of the Guard. PMID- 26240981 TI - Comprehensive evaluation of the neuropeptide-Y gene variants in the risk of obesity: a case-control study and meta-analysis. AB - BACKGROUND: Orexigenic actions mediated by neuropeptide-Y (NPY) promote body weight regulation. Genetic variations in the NPY gene could therefore influence susceptibility to obesity, but results have been conflicting. We have carried out, for the first time, a case-control study to examine the effect of NPY rs16147 and rs5574 variants with the risk of obesity in Asians and also a meta analysis to summarize the effect of these variants including that of the widely studied rs16139. MATERIALS AND METHODS: Genotypes and biochemistry data were determined for 942 children (262 cases and 680 controls) recruited from 23 randomly selected schools in Malaysia. Relevant articles were identified from Pubmed, Embase, Web of Science and Google Scholar. Data were extracted and summary estimates of the association between the NPY variants and obesity were examined. RESULTS: The frequency of the rs16147 T allele was significantly higher in the cases than controls (odds ratio 1.27, 95% confidence interval 1.04-1.55, P = 0.022), whereas the rs5574 T allele was significantly higher in the controls (odds ratio 0.76, 95% confidence interval 0.61-0.96, P = 0.020). In addition, NPY rs16147 was significantly correlated with obesity parameters including BMI, waist circumference, triglyceride and body fat percentage (P < 0.05). Meta-analysis including nine case-control studies further confirmed the findings of the association of the two variants with the risk of obesity and also found that rs16139 was associated with increased risk. CONCLUSION: This study suggests that NPY rs16147 T and rs16139 C minor alleles are associated with increased risk, whereas the minor allele T of the rs5574 is associated with a reduced risk of obesity. PMID- 26240984 TI - Introducing the New Faces of Endocrine Reviews. PMID- 26240983 TI - Endocrine Reviews: The Next Generation. PMID- 26240987 TI - The effects of a transition between local and global processing on vigilance performance. AB - Sixty participants performed a sustained attention task in which they were required to perform either global or local feature discrimination. Two groups required just one type of discrimination, while the remaining two groups started on one type of discrimination before transitioning to the other type halfway through. A transition resulted in worse performance when compared to no transition. It was also found that the local discrimination group showed improved performance over time compared to the global discrimination group. Functional near-infrared spectroscopy (fNIRS) was used to measure blood oxygenation during the task and was used as an index of cerebral hemodynamic activity. Total oxygenation was found to increase more in global discrimination tasks. It was also found that the left prefrontal cortex showed little change in nontransition tasks while in transition tasks it followed the same trend as the right prefrontal cortex. Combined with performance data, it suggests that an increased utilization of bilateral resources may in some cases improve performance over time. PMID- 26240988 TI - Nontoxic, Hydrophilic Cationic Polymers-Identified as Class of Antimicrobial Polymers. AB - Amphiphilic polycations are an alternative to biocides but also toxic to mammalian cells. Antimicrobially active hydrophilic polycations based on 1,4 dibromo-2-butene and tetramethyl-1,3-propanediamine named PBI are not hemotoxic for porcine red blood cells with a hemocytotoxicity (HC50) of more than 40,000 MUg . mL(-1). They are quickly killing bacterial cells at their MIC (minimal inhibitory concentration). The highest found selectivity HC50 /MIC is more than 20,000 for S. epidermidis. Investigations on sequentially prepared PBIs with defined molecular weight Mn and tailored end groups revealed that there is a dependence of antimicrobial activity and selectivity on Mn and nature of the end groups. PMID- 26240989 TI - Akt and cAMP response element binding protein mediate 17beta-estradiol regulation of glucose transporter 3 expression in human SH-SY5Y neuroblastoma cell line. AB - Impaired glucose uptake is involved in Alzheimer's disease (AD) and glucose transporter 3 (Glut3) is the major neuronal glucose transporter. Estrogens contribute its theorized protective role against AD. The present studies aimed to examine the effect of 17beta-estradiol (E2, the natural estrogen) on Glut3 expression and the underlying mechanisms by using human SH-SY5Y cell line. The results demonstrated that E2 increased Glut3 expression. E2 could stimulate the activation of Akt signaling pathway and the subsequent phosphorylation of cAMP response element binding protein (CREB). Akt/CREB pathway mediated E2-induced increase in Glut3 expression. These results suggested the mechanisms underlying E2-induced increase in Glut3 expression in human SH-SY5Y cell line and might provide the new data for elucidating the neuroprotective role of E2 against AD. PMID- 26240990 TI - Exon dosage analysis of parkin gene in Chinese sporadic Parkinson's disease. AB - Parkin gene mutations are by far the most common mutations in both familial Parkinson's disease (PD) and sporadic PD. Approximately, 50% of parkin mutations is exon dosage mutations (i.e., deletions and duplications of entire exons). Here, we first established a MLPA assay for quick detection of parkin exon rearrangements. Then, we studied parkin exon dosage mutations in 755 Chinese sporadic PDdisease patients using the established MLPA assay. We found that there were 25 (3.3%) patients with exon dosage alterations including deletions and duplications, 20 (11.4%) patients with exon rearrangements in 178 early-onset patients, and 5 (0.86%) patients with exon rearrangement mutations in 579 later onset patients. The percentage of individuals with parkin dosage mutations is more than 33% when the age at onset is less than 30 years old, but less than 7% when the age at onset is more than 30. In these mutations, deletion is the main mutational style, especially in exon 2-5. Our results indicated that exon dosage mutations in parkin gene might be the main cause for sporadic PD, especially in EOP. PMID- 26240992 TI - Electroencephalographic connectivity analysis in schizophrenia. AB - The aim of the present study was to further investigate the electroencephalogram (EEG) connectivity in schizophrenic patients by means of mutual information (MI), an analysis capable of detecting both the linear and nonlinear components of EEG. 19-lead EEGs were recorded in stable schizophrenic patients (N=17) and healthy controls (N=17) in two different conditions: closed eyes (CE) and open eyes (OE). In patients, higher MI values were observed in temporal-parietal-occipital regions compared with controls. In controls, an increase in brain connectivity in frontal regions was observed in the CE condition. This increase was not present in patients. Our results suggest that patients with schizophrenia present changes of brain connectivity that can be detected through MI analysis. PMID- 26240991 TI - Pain from intra-articular NGF or joint injury in the rat requires contributions from peptidergic joint afferents. AB - Non-physiological stretch of the cervical facet joint's capsular ligament induces persistent behavioral hypersensitivity and spinal neuronal hyperexcitability via an intra-articular NGF-dependent mechanism. Although that ligament is innervated by nociceptors, it is unknown if a subpopulation is exclusively responsible for the behavioral and spinal neuronal responses to intra-articular NGF and/or facet joint injury. This study ablated joint afferents using the neurotoxin saporin targeted to neurons involved in either peptidergic ([Sar(9),Met (O2)(11)] substance P-saporin (SSP-Sap)) or non-peptidergic (isolectin B4-saporin (IB4 Sap)) signaling to investigate the contributions of those neuronal populations to facet-mediated pain. SSP-Sap, but not IB4-Sap, injected into the bilateral C6/C7 facet joints 14 days prior to an intra- articular NGF injection prevents NGF induced mechanical and thermal hypersensitivity in the forepaws. Similarly, only SSP- Sap prevents the increase in mechanical forepaw stimulation- induced firing of spinal neurons after intra-articular NGF. In addition, intra-articular SSP-Sap prevents both behavioral hypersensitivity and upregulation of NGF in the dorsal root ganglion after a facet joint distraction that normally induces pain. These findings collectively suggest that disruption of peptidergic signaling within the joint may be a potential treatment for facet pain, as well as other painful joint conditions associated with elevated NGF, such as osteoarthritis. PMID- 26240993 TI - Increased incidence of intermittent hypoxemia in the Ts65Dn mouse model of Down syndrome. AB - In addition to nervous system, cardiovascular and respiratory systems are primarily affected in Down syndrome (DS). The Ts65Dn mouse model is widely used to recapitulate cognitive dysfunction in DS. While these mice consistently show failure in learning and memory along with functional and structural abnormalities in the hippocampal region, the underlying mechanisms behind cognitive dysfunction remain to be fully elucidated. Convergent evidence implicates chronic episodes of hypoxemia in cognitive dysfunction in people with DS. Using an infra-red detection system to assess oxygen saturation in free-moving mice, we assessed arterial blood oxygenation in both adolescent and adult Ts65Dn mice and found a significant increase in the incidence of hypoxemia in both groups. Notably, the severity of hypoxemia increased during the dark cycle, suggesting a link between hypoxemia and increased motor activity. Postmortem analysis showed significant increase in the expression of mitochondrial Cox4i2, the terminal enzyme of the mitochondrial respiratory chain and oxygen response element. Altogether these data suggest early and chronic occurrence of hypoxemia in the Ts65Dn mouse model of DS, which can contribute to cognitive dysfunction in these mice. PMID- 26240994 TI - Resting-state fMRI reveals enhanced functional connectivity in spatial navigation networks after transcranial direct current stimulation. AB - A number of studies have established that transcranial direct current stimulation (tDCS) modulates cortical excitability. We previously demonstrated polarity dependent changes in parietal lobe blood oxygen level dependent (BOLD) fMRI in a group of young adults during a spatial navigation task [15]. Here we used resting state functional connectivity (rsFC) to examine whether analogous changes were also evident during the resting state. Participants were randomized to either a parietal-anodal, frontal-cathodal (P+F-) or the opposite montage (P-F+) and received 20min of tDCS (2mA) before undergoing resting-state fMRI. rsFC was evaluated between the groups by placing a seed in the medial superior parietal lobule (mSPL), which was under the target electrode. rsFC between the mSPL and a number of other areas involved in spatial navigation, scene processing, and sensorimotor processing was significantly higher in the P+F- than the P-F+ group. Thus, the modulatory effects of tDCS were evident during rest and suggest that stimulation primes not just the underlying neocortex but an extended network that can be recruited as necessary during active task performance. PMID- 26240995 TI - Early treatment with UR13870, a novel inhibitor of p38alpha mitogenous activated protein kinase, prevents hyperreflexia and anxiety behaviors, in the spared nerve injury model of neuropathic pain. AB - Microglia cell activation plays a role in the development of neuropathic pain partly due to the activation of the p38alpha MAPK signaling pathway after nerve injury. In this study we assessed the effect of UR13870, a p38alpha MAPK inhibitor, in the "spared nerve injury" (SNI) model, to study its effects on modulation of spinal microglial activation and to test behavioral hyperreflexia responses and cerebral-mediated pain behavior. The effect of daily administration of UR13870 (10mg/kg p.o.) and Pregabalin (50mg/kg p.o.) on reflex hypersensitivity to mechanical and cold test stimuli and on affective related pain responses measured with the place escape avoidance paradigm and the open field-induced anxiety test, were evaluated after SNI in Sprague Dawley rats. Microglial reactivity in the ipsilateral lumbar laminae I/II dorsal horn was evaluated with OX-42 immunohistochemistry. UR13870 treatment significantly decreased hindlimb hyperreflexia to both mechanical and cold stimuli after SNI without loss of general motor function, in addition to a reduction in pain related anxiety behavior at day 21 after SNI, accompanied by normalization of OX 42 immunoreactivity within the ipsilateral lumbar dorsal horn. Pregabalin treatment only reduced mechanical hyperreflexia and affected general motor function. Oral administration of the p38alpha MAPK inhibitor, UR13870, mediates antinociception to both mechanical and cold stimuli, and significantly restored inner-zone exploration in the open field test, accompanied by normalization in dorsal horn microglial activation in the SNI model. PMID- 26240996 TI - Prior Advance Care Planning Is Associated with Less Decisional Conflict among Surrogates for Critically Ill Patients. AB - RATIONALE: Although numerous studies have documented that family members in intensive care units struggle with end-of-life decisions for incapacitated patients, there is little information about whether prior advance care planning lessens the burden of decision making. OBJECTIVES: We sought to measure decisional conflict in surrogates of critically ill patients and to examine whether prior advance care planning is associated with less decisional conflict. METHODS: We performed a secondary data analysis of a multicenter, prospective cohort study done at five U.S. academic medical centers that included 471 surrogates of 257 patients with acute respiratory distress syndrome. The main outcome was surrogates' burden of decision making as measured using the Decisional Conflict Scale. Surrogates completed a questionnaire item addressing whether they had had any prior advance care planning conversations with their loved ones. We used multilevel linear regression modeling to measure the association between decisional conflict and advance care planning. MEASUREMENTS AND MAIN RESULTS: Moderate or high levels of decisional conflict (Decisional Conflict Scale score>=25) were present in 48% of surrogates. After adjusting for potential confounders, surrogates who had engaged in prior advance care planning conversations had significantly lower levels of decisional conflict than those who had not (mean score 3.3 points lower on the Decisional Conflict Scale; 95% confidence interval, -6.4 to -0.2; P=0.03). CONCLUSIONS: Nearly half of surrogates for critically ill patients have moderate or high levels of decisional conflict. Prior advance care planning was associated with less decisional conflict. These results suggest that the scope of the benefit of advance care planning may extend beyond respecting patients' wishes to also ameliorating the burden on patients' loved ones who act as surrogates. PMID- 26240997 TI - Specific Targeting of Proerythroblasts and Erythroleukemic Cells by the VP1u Region of Parvovirus B19. AB - Viruses are evolutionarily developed cell-entering nanomachines, which are frequently used as gene or drug delivery systems. Parvovirus B19 (B19V) shows a remarkably restricted tropism for erythropoietin-dependent erythroid differentiation stages, and thus this virus provides an opportunity to deliver cargo to these intermediate differentiated cells. Here we report the construction of a delivery system from B19V subunits that maintains the highly selective cell entry of the native virus and offers versatile cargo transport. To obtain this specific carrier, we conjugated the cell-targeting VP1u region of B19V to NeutrAvidin as a loading platform for biotinylated cargos. The VP1u-NeutrAvidin conjugate delivered fluorophores, DNA, and toxic payloads specifically to erythroid cells around the proerythroblast differentiation stage, including erythroleukemic cells. The VP1u-NeutrAvidin represents a unique cell surface marker which exclusively detects intermediate erythroid differentiation stages. Furthermore, the cell-entering property of this viral-based targeting system offers opportunities for erythroid-specific drug delivery or gene therapy. PMID- 26240998 TI - A putative ATPase mediates RNA transcription and capping in a dsRNA virus. AB - mRNA transcription in dsRNA viruses is a highly regulated process but the mechanism of this regulation is not known. Here, by nucleoside triphosphatase (NTPase) assay and comparisons of six high-resolution (2.9-3.1 A) cryo-electron microscopy structures of cytoplasmic polyhedrosis virus with bound ligands, we show that the large sub-domain of the guanylyltransferase (GTase) domain of the turret protein (TP) also has an ATP-binding site and is likely an ATPase. S adenosyl-L-methionine (SAM) acts as a signal and binds the methylase-2 domain of TP to induce conformational change of the viral capsid, which in turn activates the putative ATPase. ATP binding/hydrolysis leads to an enlarged capsid for efficient mRNA synthesis, an open GTase domain for His217-mediated guanylyl transfer, and an open methylase-1 domain for SAM binding and methyl transfer. Taken together, our data support a role of the putative ATPase in mediating the activation of mRNA transcription and capping within the confines of the virus. PMID- 26240999 TI - Risk of Major Abdominal Surgery in an Asian Population-based Crohn's Disease Cohort. AB - BACKGROUND: Crohn's disease (CD) is increasing in incidence and prevalence in Asia, but there is a paucity of population-based studies on risk factors for surgery in Asian patients with CD. This will be useful to identify patients who may benefit from top-down treatment. This study describes the rates of abdominal surgery and identifies associated risk factors in Singaporean patients with CD. METHODS: This was a retrospective observational study. The medical records of Singaporeans diagnosed with CD from 1970 to 2013 were reviewed from 8 different hospitals in Singapore. The cumulative probability of CD-related abdominal surgery was estimated using the Kaplan-Meier method. The logistic regression model was used to assess associations between independent risk factors and surgery. RESULTS: The cohort of 430 Singaporean patients with CD included 63.5% Chinese, 11.9% Malay, and 24.7% Indians, with a male to female ratio of 1.6; median follow-up was 7.3 years (range, 2.9-13.0 yr) and median age at diagnosis 30.5 years (range, 19.5-43.7 yr). One hundred twelve patients (26.0%) required major abdominal surgery: the cumulative risk of surgery was 14.9% at 90 days, 21.2% at 5 years, 28.8% at 10 years, 38.3% at 20 years, and 50.6% at 30 years from diagnosis. Of the surgical patients, 75.0% were Chinese, 10.7% Malays, and 14.3% Indians; 21.4% underwent surgery for inflammatory disease, 40.2% for stricturing disease, and 38.4% for penetrating disease. Age at diagnosis (A2 17 40 yr, OR: 2.75, 95% confidence interval [CI], 1.14-7.76), ileal disease (L1 location, OR: 2.35, 95% CI, 1.14-5.0), stricturing (B2 OR: 6.09, 95% CI, 3.20 11.8), and penetrating behavior (B3 OR: 21.6, 95% CI, 9.0-58.8) were independent risk factors for CD-related abdominal surgery. Indian patients were less likely to require surgery (OR: 0.40, 95% CI, 0.19-0.78). CONCLUSIONS: Age at diagnosis, L1 location, B2, and B3 disease behavior are independent risk factors for abdominal surgery. Interestingly, despite a higher prevalence of CD in Indians, a smaller proportion of Indian patients required surgery. These findings suggest that both environmental and genetic factors contribute to the risk of surgery in Asian patients with CD. PMID- 26241000 TI - Common Genetic Variants Influence Circulating Vitamin D Levels in Inflammatory Bowel Diseases. AB - BACKGROUND: The accuracy and utility of electronic health record (EHR)-derived phenotypes in replicating genotype-phenotype relationships have been infrequently examined. Low circulating vitamin D levels are associated with severe outcomes in inflammatory bowel disease (IBD); however, the genetic basis for vitamin D insufficiency in this population has not been examined previously. METHODS: We compared the accuracy of physician-assigned phenotypes in a large prospective IBD registry to that identified by an EHR algorithm incorporating codified and structured data. Genotyping for IBD risk alleles was performed on the Immunochip and a genetic risk score calculated and compared between EHR-defined patients and those in the registry. Additionally, 4 vitamin D risk alleles were genotyped and serum 25-hydroxy vitamin D [25(OH)D] levels compared across genotypes. RESULTS: A total of 1131 patients captured by our EHR algorithm were also included in our prospective registry (656 Crohn's disease, 475 ulcerative colitis). The overall genetic risk score for Crohn's disease (P = 0.13) and ulcerative colitis (P = 0.32) was similar between EHR-defined patients and a prospective registry. Three of the 4 vitamin D risk alleles were associated with low vitamin D levels in patients with IBD and contributed an additional 3% of the variance explained. Vitamin D genetic risk score did not predict normalization of vitamin D levels. CONCLUSIONS: EHR cohorts form valuable data sources for examining genotype phenotype relationships. Vitamin D risk alleles explain 3% of the variance in vitamin D levels in patients with IBD. PMID- 26241001 TI - Impact of Obesity on the Management and Clinical Course of Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Obesity has been linked with a proinflammatory state and the development of inflammatory diseases. Data on the clinical course and treatment of obese patients with inflammatory bowel disease (IBD) are limited. We used an institutional IBD registry to investigate the impact of obesity on IBD severity and treatment. METHODS: This was a retrospective analysis of prospectively collected data for 3 years (2009-2011). Patients with IBD were categorized by body mass index (BMI). IBD-related quality of life, biochemical markers of inflammation, comorbidities, health care utilization, and treatment were characterized. Obesity was defined as a BMI >=30 (type I: 30-34.9, type II: 35 39.9, and type III >=40). RESULTS: Among 1494 patients with IBD, 71.9% were above their ideal BMI and 31.5% were obese. Obesity was more common in ulcerative colitis compared with patients with Crohn's disease (P = 0.04). Obese class II and class III patients were predominantly female. Obesity in IBD was associated with female gender (P < 0.0001), diabetes mellitus (P < 0.001), hypertension (P < 0.001), hyperlipidemia (P < 0.001), poor quality of life (P < 0.0001), and increased rates of C-reactive protein elevation (P = 0.008). In logistic regression analysis, quality of life and C-reactive protein elevation were not independently correlated with obesity. There was no association between increasing BMI and annual prednisone use, emergency department visits, hospitalization, and surgery. Obesity was associated with lower milligrams per kilogram doses of purine analogs and biologics. CONCLUSIONS: Obesity in IBD is not associated with increased health care utilization and IBD-related surgeries. Optimal regimens for drug dosing in obese patients with IBD have yet to be defined. PMID- 26241002 TI - The search for nucleoside/nucleotide analog inhibitors of dengue virus. AB - Nucleoside analogs represent the largest class of antiviral agents and have been actively pursued for potential therapy of dengue virus (DENV) infection. Early success in the treatment of human immunodeficiency virus (HIV) infection and the recent approval of sofosbuvir for chronic hepatitis C have provided proof of concept for this class of compounds in clinics. Here we review (i) nucleoside analogs with known anti-DENV activity; (ii) challenges of the nucleoside antiviral approach for dengue; and (iii) potential strategies to overcome these challenges. This article forms part of a symposium in Antiviral Research on flavivirus drug discovery. PMID- 26241003 TI - Identification of an HIV-1 replication inhibitor which rescues host restriction factor APOBEC3G in Vif-APOBEC3G complex. AB - HIV-1 Vif protein is one of the most crucial accessory proteins for viral replication. It efficiently counteracts the important host restriction factor APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G, A3G) which is lethal to HIV-1 by causing G to A mutation of viral genome. Vif protein mediates degradation of APOBEC3G via the complicated protein-protein interactions of Vif, APOBEC3G, Elongin C/B and Cullin 5. The importance of Vif APOBEC3G complex makes it a good potential target to develop new therapeutics of HIV-1. We identified a potent HIV-1 replication inhibitor (ZBMA-1, IC50 = 1.01 MUM) that efficiently protected APOBEC3G protein by targeting Vif-APOBEC3G complex. The co-immunoprecipitation and docking studies indicated that compound ZBMA-1 affected the binding of Elongin C with Vif protein. PMID- 26241005 TI - Effects of Ionic Strength on the Colloidal Stability and Interfacial Assembly of Hydrophobic Ethyl Cellulose Nanoparticles. AB - Nanoparticle attachment at a fluid interface is a process that often takes place concurrently with nanoparticle aggregation in the bulk of the suspension. Here we investigate systematically the coupling of these processes with reference to the adsorption of aqueous suspensions of ethyl cellulose (EC) nanoparticles at the air-water interface. The suspension stability is optimal at neutral pH and in the absence of salt, conditions under which the electrostatic repulsion among EC nanoparticles is maximized. Nonetheless, hydrophobic attraction dominates particle-interface interactions, resulting in the irreversible adsorption of EC nanoparticles at the air-water interface. The addition of salt weakens the particle-particle and particle-interface repulsive electrostatic forces. This leads to destabilization of the suspension at ionic strengths of 0.05 M or greater but does not affect nanoparticle adsorption. The energy of adsorption, the surface tension and interface coverage at steady state, and the particle contact angle at the interface all remain unchanged by the addition of salt. These findings contribute to the fundamental understanding of colloidal systems and inform the utilization of EC nanocolloids, in particular for the stabilization of foams and emulsions. PMID- 26241006 TI - Guide for the support of health claims in foods. AB - During the past years there is a rising demand for improving the quality and nutritional value of foods that has encouraged the research and development of new food ingredients and products. Nevertheless, to date, many of the health claim applications evaluating EFSA have been rejected. Hence, it is critical for companies involved in the development of functional foods to be aware of the full flowchart needed for the scientific support of a health claim from the very beginning. This series of articles summarize the conclusions presented in July 2014 during the workshop INCOMES devoted to clarify methodologies for scientific support of health claims in foods/ingredients, in the framework of the XVI Reunion de la Sociedad Espanola de Nutricion, and are intended to be a practical tool, outlining the sections that an application for authorization of a health claim should contain. PMID- 26241004 TI - A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. AB - Tumor metastasis is not only a sign of disease severity but also a major factor causing treatment failure and cancer-related death. Therefore, studies on the molecular mechanisms of tumor metastasis are critical for the development of treatments and for the improvement of survival. The epithelial-mesenchymal transition (EMT) is an orderly, polygenic biological process that plays an important role in tumor cell invasion, metastasis and chemoresistance. The complex, multi-step process of EMT involves multiple regulatory mechanisms. Specifically, the PI3K/Akt signaling pathway can affect the EMT in a variety of ways to influence tumor aggressiveness. A better understanding of the regulatory mechanisms related to the EMT can provide a theoretical basis for the early prediction of tumor progression as well as targeted therapy. PMID- 26241007 TI - Non-clinical toxicity studies on bioactive compounds within the framework of nutritional and health claims. AB - The growing presence of products on the market with added value in terms of health makes essential their regulation and harmonization in critical aspects such as safety. The toxicology applied to the bioactive compounds should demonstrate the absence of toxic effects at doses advised for consumption, as well as evaluate the potential toxic effects in the assumption that the products are used in quantities superior to those recommended. The specific strategy should be defined case by case; therefore, prior to any toxicological development, it is essential to study all the information regarding the bioactive compounds (BACs) characterization, nutridynamics and nutrikinetics, that is available. In this guideline, a general strategy to be applied in the development of BACs is proposed. It includes a first in vitro phase to discard genotoxicity and endocrine effects and a second in vivo phase with different possibilities regarding the duration and the extension of the studies. PMID- 26241008 TI - Nutridynamics: mechanism(s) of action of bioactive compounds and their effects. AB - Mechanism of action of bioactive compounds may be multiple, especially in the food matrix. Therefore, the interplay between these compounds and hosts' physiology, and the consequences of its continuous intake should be considered. In analogy with pharmacodynamics, the bioactive compounds should have both defined targets and mechanisms of action. However, several essential differences arise when considering the heterogeneous nature of the food matrix, the multiplicity of mechanisms and the variety of responses. In order to ascertain a potential mechanism of activity, one should consider both the intended use of the food, the biomarker that will support this claim and previous evidences, examined from current information sources. Once these have been examined, several experimental strategies should be considered, ranging from the choice of preclinical or experimental model, the use of samples from pilot interventional studies and the application of system's biology derived techniques, such as transcriptomics or metabolomics. PMID- 26241009 TI - Discovery of nutritional biomarkers: future directions based on omics technologies. AB - Understanding the interactions between food and human biology is of utmost importance to facilitate the development of more efficient nutritional interventions that might improve our wellness status and future health outcomes by reducing risk factors for non-transmittable chronic diseases, such as cardiovascular diseases, cancer, obesity and metabolic syndrome. Dissection of the molecular mechanisms that mediate the physiological effects of diets and bioactive compounds is one of the main goals of current nutritional investigation and the food industry as might lead to the discovery of novel biomarkers. It is widely recognized that the availability of robust nutritional biomarkers represents a bottleneck that delays the innovation process of the food industry. In this regard, omics sciences have opened up new avenues of research and opportunities in nutrition. Advances in mass spectrometry, nuclear magnetic resonance, next generation sequencing and microarray technologies allow massive genome, gene expression, proteomic and metabolomic profiling, obtaining a global and in-depth analysis of physiological/pathological scenarios. For this reason, omics platforms are most suitable for the discovery and characterization of novel nutritional markers that will define the nutritional status of both individuals and populations in the near future, and to identify the nutritional bioactive compounds responsible for the health outcomes. PMID- 26241010 TI - Characterization and stability studies of bioactive compounds and food matrices as evidence in support of health claims. AB - The characterization and stability evaluation of food and food constituents (chemical active ingredient/microorganism) for which nutrition or health claims want to be requested are essential for the success of an application to EFSA. This work reviews the requirements that must be fulfilled for a full characterization of the active substance, comprising origin, elaboration, or extraction method, and chemical/microbiological composition, using validated analytical methods. The review focuses not only on establishing the specifications of the final active ingredient or food but also on ensuring homogeneity between batches. In addition, the article discusses the methodologies and conditions of the stability studies that need to be performed on food and food constituents to verify that the relevant compounds--chemical and microbiological active ingredients--will get to the consumer in the intended state and concentration to accomplish the claimed health effect over shelf life. PMID- 26241011 TI - Nutrikinetic studies of food bioactive compounds: from in vitro to in vivo approaches. AB - Poor absorption is an important cause of costly late-stage failures in functional food development, and therefore, it has become widely appreciated that pharmacokinetic parameters should be considered as early as possible in the functional food development process. In many cases, the molecular structure of bioactive ingredients is known, but information is lacking on how they interact with other food components, what their fate is upon consumption, what they do in the body and what their target site is. This information is of major importance, as the biological effects of food bioactive compounds (CBAs) are ultimately determined by their bioavailability and their temporal and spatial distribution in the body. In this chapter, we propose the phases to perform nutrikinetic studies of food CBAs from the simplest in vitro assays, applicable in early stages of the development of a functional food, to human intervention studies, which are required by the European Food Safety Authority and are aimed to establish the dose-exposure relationship (pharmacokinetic studies) and at last the exposure-response relationship (pharmacodynamic studies). PMID- 26241012 TI - Cause-effect relationships in nutritional intervention studies for health claims substantiation: guidance for trial design. AB - The growing worldwide interest on functional food research has been accompanied by increasing regulatory guidelines in this area, with the aim of ensuring that any claimed effect in foods, beyond their nutritional role, is based on scientific unequivocal evidence. In order to assess the cause-effect relationship between the regular consumption of a food or a food component and the beneficial outcome for the consumer, an appropriate study design is required. Previous knowledge and research on the specific claimed food or product may be an adequate basis for defining a hypothesis and accurate objectives. Other key factors to take into account are based on the outcomes studied, the length of the trial, sample size and type, as well as the transparency on reporting the results obtained. Based on the Consolidated Standards on Reporting Trials statement (CONSORT), together with the specific guidelines published by the European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies, the present article aims at summarizing key questions conducting to the most appropriate study design for solid health claim substantiation. PMID- 26241013 TI - How does the provision of semantic information influence the lexicalization of new spoken words? AB - The integration of a novel spoken word with existing lexical items can proceed within 24 hours of learning its phonological form. However, previous studies have reported that lexical integration of new spoken words can be delayed if semantic information is provided during learning. One possibility is that this delay in lexical integration reflects reduced phonological processing during learning as a consequence of the need to learn the semantic associations. In the current study, adult participants learnt novel words via a phoneme monitoring task, in which half of the words were associated with a picture referent, and half were phonological forms only. Critically, participants were instructed to learn the forms of the novel words, with no explicit goal to learn the word-picture mappings. Results revealed significant lexical competition effects emerging one week after consolidation, which were equivalent for the picture-present and form only conditions. Tests of declarative memory and shadowing showed equivalent performance for picture-present and form-only words, despite participants showing good knowledge of the picture associations immediately after learning. These data support the contention that provided phonological information is recruited sufficiently well during learning, the provision of semantic information does not slow the time-course of lexical integration. PMID- 26241016 TI - Fibrosis: Targeting EMT to reverse renal fibrosis. PMID- 26241018 TI - Fibrosis: GLI2 inhibition reduces myofibroblast generation and kidney fibrosis. PMID- 26241020 TI - RAS blockade: Nephroprotection by dual RAS blockade--a welcome back. PMID- 26241019 TI - Therapeutic use of human renal progenitor cells for kidney regeneration. AB - The ability of the human kidney to repair itself is limited. Consequently, repeated injury can trigger a maladaptive response that is characterized by fibrosis and loss of renal function. The transcription patterns that characterize nephrogenesis in fetal renal progenitor cells (RPCs) are only partially activated during renal repair in adults. Nevertheless, evidence suggests that segment restricted progenitor resident cells support renal healing in adults. In this Review, we discuss the evidence for the existence of functional human RPCs in adults and their role in renal repair, and consider the controversial issue of whether RPCs are a fixed population or arise through phenotypical plasticity of tubular cells that is mediated by the microenvironment. We also discuss the strategies for generating renal progenitor cells from pluripotent stem cells or differentiated cells and their use in therapy. Finally, we examine preclinical data on the therapeutic use of human fetal cells, adult progenitor cells and adult renal cells. PMID- 26241022 TI - Evaluating hypoxia-inducible factor-1alpha mRNA expression in a pelagic fish, Pacific herring Clupea pallasii, as a biomarker for hypoxia exposure. AB - Hypoxia [dissolved oxygen (DO)<2 mg L(-1)] is a major environmental perturbation for many aquatic ecosystems, particularly highly productive estuaries. Most research attention and understanding about the impacts of hypoxia on estuarine species has focused on the benthos, where hypoxia is most common. Although the pelagic zone is also susceptible to the effects of hypoxia, the biological interactions and consequences are not as well understood in marine environments because documenting exposure or avoidance of hypoxia is often difficult. Physiological biomarkers may provide a way to gain more detailed spatiotemporal information regarding species' exposure to hypoxia. Here, we identified and tested a hypoxia-specific responsive gene, hypoxia-inducible factor-1alpha (hif 1alpha), to evaluate its potential as a biomarker for hypoxia exposure in Pacific herring (Clupea pallasii). We conducted controlled laboratory experiments to establish the level of hepatic hif-1alpha elevated gene expression (>1 sd normoxic mean), exposure amplification (>=2 hours), reduction rate (ca. 24 hours), and some evidence of a lethal hypoxic limit (ca. 2 mg L(-1), >=4 hours). We then used these findings to evaluate the spatiotemporal patterns of hif-1alpha for Pacific herring in a seasonally hypoxia estuary, Hood Canal, Washington, USA. Although expression did not parallel the local hypoxic conditions in the estuary, herring from the more severe hypoxic year (2013) had a higher probability of having elevated mRNA levels. These patterns indicate that hepatic hif-1alpha levels may not be directly indicative of local DO levels for pelagic marine fish, but rather provide insight into hypoxia exposure over broader scales. PMID- 26241023 TI - Inter-individual variability in metacognitive ability for visuomotor performance and underlying brain structures. AB - Metacognition refers to the ability to discriminate between one's own correct and incorrect decisions. The neurobiological underpinnings of metacognition have mainly been studied in perceptual decision-making. Here we investigated whether differences in brain structure predict individual variability in metacognitive sensitivity for visuomotor performance. Participants had to draw straight trajectories toward visual targets, which could unpredictably deviate around detection threshold, report such deviations when detected, and rate their confidence level for such reports. Structural brain MRI analyses revealed that larger gray-matter volume (GMV) in the left middle occipital gyrus, left medial parietal cortex, and right postcentral gyrus predicted higher deviation detection sensitivity. By contrast, larger GMV in the right prefrontal cortex but also right anterior insula and right fusiform gyrus predicted higher metacognitive sensitivity. These results extend past research by linking metacognitive sensitivity for visuomotor behavior to brain areas involved in action agency (insula), executive control (prefrontal cortex) and vision (fusiform). PMID- 26241024 TI - Dissociative absorption: An empirically unique, clinically relevant, dissociative factor. AB - Research of dissociative absorption has raised two questions: (a) Is absorption a unique dissociative factor within a three-factor structure, or a part of one general dissociative factor? Even when three factors are found, the specificity of the absorption factor is questionable. (b) Is absorption implicated in psychopathology? Although commonly viewed as "non-clinical" dissociation, absorption was recently hypothesized to be specifically associated with obsessive compulsive symptoms. To address these questions, we conducted exploratory and confirmatory factor analyses on 679 undergraduates. Analyses supported the three factor model, and a "purified" absorption scale was extracted from the original inclusive absorption factor. The purified scale predicted several psychopathology scales. As hypothesized, absorption was a stronger predictor of obsessive compulsive symptoms than of general psychopathology. In addition, absorption was the only dissociative scale that longitudinally predicted obsessive-compulsive symptoms. We conclude that absorption is a unique and clinically relevant dissociative tendency that is particularly meaningful to obsessive-compulsive symptoms. PMID- 26241025 TI - The frequency of involuntary autobiographical memories and future thoughts in relation to daydreaming, emotional distress, and age. AB - We introduce a new scale, the Involuntary Autobiographical Memory Inventory (IAMI), for measuring the frequency of involuntary autobiographical memories and involuntary future thoughts. Using the scale in relation to other psychometric and demographic measures provided three important, novel findings. First, the frequency of involuntary and voluntary memories and future thoughts are similarly related to general measures of emotional distress. This challenges the idea that the involuntary mode is uniquely associated with emotional distress. Second, the frequency of involuntary autobiographical remembering does not decline with age, whereas measures of daydreaming, suppression of unwanted thoughts and dissociative experiences all do. Thus, involuntary autobiographical remembering relates differently to aging than daydreaming and other forms of spontaneous and uncontrollable thoughts. Third, unlike involuntary autobiographical remembering, the frequency of future thoughts does decrease with age. This finding underscores the need for examining past and future mental time travel in relation to aging and life span development. PMID- 26241026 TI - The role of mTOR in lipid homeostasis and diabetes progression. AB - PURPOSE OF REVIEW: Metabolic diseases, such as type 2 diabetes, cardiac dysfunction, hypertension, and hepatic steatosis, share one critical causative factor: abnormal lipid partitioning, that redistribution of triglycerides from adipocytes to nonadipose peripheral tissues. Lipid overload of these tissues causes a number of pathological effects collectively known as lipotoxicity. If we find the way to correct lipid partitioning, we will restrain metabolic diseases, improve life quality and life expectancy and radically reduce healthcare costs. RECENT FINDINGS: Lipid partitioning in the body is maintained by tightly regulated and balanced rates of de novo lipogenesis, lipolysis, adipogenesis, and mitochondrial oxidation primarily in fat and liver. Recent studies highlighted in this review have established mTOR as a central regulator of lipid storage and metabolism. SUMMARY: Increased activity of mTOR in obesity may compensate for the negative consequences of overnutrition, whereas dysregulation of mTOR may lead to abnormal lipid partitioning and metabolic disease. PMID- 26241028 TI - Glucocorticoids and non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the global obesity and metabolic disease epidemic and is rapidly becoming the leading cause of liver cirrhosis and indication for liver transplantation worldwide. The hallmark pathological finding in NAFLD is excess lipid accumulation within hepatocytes, but it is a spectrum of disease ranging from benign hepatic steatosis to steatohepatitis through to fibrosis, cirrhosis and risk of hepatocellular carcinoma. The exact pathophysiology remains unclear with a multi hit hypothesis generally accepted as being required for inflammation and fibrosis to develop after initial steatosis. Glucocorticoids have been implicated in the pathogenesis of NAFLD across all stages. They have a diverse array of metabolic functions that have the potential to drive NAFLD acting on both liver and adipose tissue. In the fasting state, they are able to mobilize lipid, increasing fatty acid delivery and in the fed state can promote lipid accumulation. Their action is controlled at multiple levels and in this review will outline the evidence base for the role of GCs in the pathogenesis of NAFLD from cell systems, rodent models and clinical studies and describe interventional strategies that have been employed to modulate glucocorticoid action as a potential therapeutic strategy. PMID- 26241029 TI - Regulation of cyclooxygenase-2 expression in rat oviductal epithelial cells: Evidence for involvement of GPR30/Src kinase-mediated EGFR signaling. AB - The oviduct plays a crucial role in female reproduction by regulating gamete transport, providing a specific microenvironment for fertilization and early embryonic development. Cyclooxygenase (COX)-derived prostaglandins play essential role in carrying out these oviduct-specific functions. Estrogen upregulates COX-2 expression in rat oviduct; however, the mechanisms responsible for regulation of COX-2 expression in rat oviductal epithelial cells (OECs) remain unclear. In the present study, we proposed that estrogen induces COX-2 expression via G-protein coupled receptor i.e., GPR30 in OECs. To investigate this hypothesis, we examined the effects of E2-BSA, ICI 182,780, GPR30 agonist and GPR30 antagonist on COX-2 expression and explored potential signaling pathway leading to COX-2 expression. Co-localization experiments revealed GPR30 to be primarily located in the peri nuclear space, which was also the site of E2-BSA-fluorescein isothiocyanate (E2 BSA-FITC) binding. The E2-BSA induced-COX-2 and prostaglandin release were subjected to regulation by both EGFR and PI3K signaling as inhibitors of c-Src kinase (PP2), EGFR (EGFR inhibitor) and PI-3 kinase (LY294002) attenuated E2-BSA mediated effect. These results suggest that EGFR transactivation leading to activation of PI-3K/Akt pathway participates in COX-2 expression in rat OECs. Interestingly, E2-BSA induced COX-2 expression and subsequent prostaglandin release were abolished by NF-kappaB inhibitor. In addition, E2-BSA induced the nuclear translocation of p65-NF-kappaB and up-regulated the NF-kappaB promoter activity in rat OECs. Taken together, results demonstrated that E2-BSA induced the COX-2 expression and consequent PGE2 and PGF2alpha release in rat OECs. These effects are mediated through GPR30-derived EGFR transactivation and PI-3K/Akt cascade leading to NF-kappaB activation. PMID- 26241027 TI - Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges. AB - In the infarcted myocardium, necrotic cardiomyocytes release danger signals, activating an intense inflammatory response. Inflammatory pathways play a crucial role in regulation of a wide range of cellular processes involved in injury, repair, and remodeling of the infarcted heart. Proinflammatory cytokines, such as tumor necrosis factor alpha and interleukin 1, are markedly upregulated in the infarcted myocardium and promote adhesive interactions between endothelial cells and leukocytes by stimulating chemokine and adhesion molecule expression. Distinct pairs of chemokines and chemokine receptors are implicated in recruitment of various leukocyte subpopulations in the infarcted myocardium. For more than the past 30 years, extensive experimental work has explored the role of inflammatory signals and the contributions of leukocyte subpopulations in myocardial infarction. Robust evidence derived from experimental models of myocardial infarction has identified inflammatory targets that may attenuate cardiomyocyte injury or protect from adverse remodeling. Unfortunately, attempts to translate the promising experimental findings to clinical therapy have failed. This review article discusses the biology of the inflammatory response after myocardial infarction, attempts to identify the causes for the translational failures of the past, and proposes promising new therapeutic directions. Because of their potential involvement in injurious, reparative, and regenerative responses, inflammatory cells may hold the key for design of new therapies in myocardial infarction. PMID- 26241030 TI - Estradiol: Mediator of memories, spine density and cognitive resilience to stress in female rodents. AB - Estradiol rapidly activates, within minutes, various physiological functions and behaviors including cognition in rodents. This review describes rapid effects of estradiol on hippocampal dependent learning and memory tasks in rodents. Mechanisms underlying the memory enhancements including the activation of signaling molecules and the enhancement of dendritic spinogenesis are briefly reviewed. In addition, the role of estradiol in the cognitive resilience to chronic stress exhibited only in females is discussed including contributions of ovarian as well as intra-hippocampally derived estrogens to this sex difference. Finally, speculations on possible physiologic functions for rapid mnemonic changes mediated by estrogens are made. Overall, the emergence of a novel and powerful mechanism for regulation of cognition by estradiol is described. PMID- 26241031 TI - Stress-induced mechanisms in mental illness: A role for glucocorticoid signalling. AB - Stress represents the main environmental risk factor for mental illness. Exposure to stressful events, particularly early in life, has been associated with increased incidence and susceptibility of major depressive disorders as well as of other psychiatric illnesses. Among the key players in these events are glucocorticoid receptors. Dysfunctional glucocorticoid signalling may indeed contribute to psychopathology through a number of mechanisms that regulate the response to acute or chronic stress and that affect the function of genes and systems known to be relevant for mood disorders. Indeed, exposure to chronic stress early in life as well as in adulthood has been shown to reduce the expression of glucocorticoid receptors (GR), also through epigenetic mechanisms, and to up-regulate the expression of the co-chaperone gene FKBP5, which restrains GR activity by limiting the translocation of the receptor complex to the nucleus. Another mechanism that contributes to changes in GR responsiveness is the state of receptor phosphorylation that controls activation, subcellular localization as well as its transcriptional activity. Moreover, GR phosphorylation may represent an important mechanism for the cross talk between neurotrophic signalling and GR dependent transcription, bridging two important players for mood disorders. One gene that lies downstream from GR and may contribute to stress-related changes is serum glucocorticoid kinase-1 (SGK1). We have demonstrated that the expression of SGK1 is significantly increased after exposure to chronic stress in rodents as well as in the blood of drug-free depressed patients. We have also shown that SGK1 up-regulation may ultimately reduce hippocampal neurogenesis and contribute to the structural abnormalities that have been reported to occur in depressed patients. In summary, GR signalling may represent a point of convergence as well as of divergence for defects associated with pathologic conditions characterized by heightened vulnerability to stress. The characterization of these abnormalities is crucial to identify novel targets for therapeutic intervention that may counteract more effectively stress-induced neurobiological abnormalities. PMID- 26241032 TI - N-Sulfonyl-aminobiaryls as Antitubulin Agents and Inhibitors of Signal Transducers and Activators of Transcription 3 (STAT3) Signaling. AB - A series of N-sulfonyl-aminobiaryl derivatives have been examined as novel antitubulin agents. Compound 21 [N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy benzenesulfonamide] exhibits remarkable antiproliferative activity against four cancer cell lines (pancreatic AsPC-1, lung A549, liver Hep3B, and prostate PC-3) with a mean GI50 value of 57.5 nM. Additional assays reveal that 21 inhibits not only tubulin polymerization but also the phosphorylation of STAT3 inhibition with an IC50 value of 0.2 MUM. Four additional compounds (8, 10, 19, and 35) are also able to inhibit this phosphorylation. This study describes novel N-sulfonyl aminobiaryl (biaryl-benzenesulfonamides) as potent anticancer agents targeting both STAT3 and tubulin. PMID- 26241033 TI - Total and methylmercury partitioning between colloids and true solution: From case studies in sediment overlying and porewaters to a generalized model. AB - Tangential flow ultrafiltration was used to determine the partitioning of total mercury (THg) and monomethylmercury (MMHg) between colloids and true solution in sediment overlying and porewaters collected in Lake Geneva (Switzerland and France), Venice Lagoon (Italy), and Baihua Reservoir (China). Overlying water and porewater spanned different ranges of THg and MMHg concentrations, redox conditions, and salinity. Total Hg, MMHg, and dissolved organic carbon (DOC) concentrations were measured in filter-passing (<0.45 MUm), colloidal (3 kDa-0.45 MUm), and truly dissolved (<3 kDa) fractions. The percentages of filterable Hg and MMHg associated with colloids (arithmetic means +/-1 standard deviation [SD]) were 29 +/- 11% for THg (range, 4-60%) and 44 +/- 17% for MMHg (range, 15-65%). Ultrafiltration DOC mass balances were often not satisfactory. However, this was apparently without consequences on THg/MMHg fractionation, suggesting that only a part of total DOC controlled THg/MMHg partitioning in overlying water and porewater. Linear relationships existed between filter passing and truly dissolved concentrations of THg and MMHg, suggesting that mechanisms controlling their partitioning are, at least partly, similar across aquatic systems. These linear relationships could be extended to data from published studies and ultrafilterable concentrations often could be predicted, within a factor of 2, from the measurement of filter-passing ones. The possibility to easily model THg/MMHg partitioning across aquatic systems will facilitate its consideration in general biogeochemical THg/MMHg models. PMID- 26241034 TI - Ontogenic retinal changes in three ecologically distinct elopomorph fishes (Elopomorpha:Teleostei) correlate with light environment and behavior. AB - Unlike the mammalian retina, the teleost fish retina undergoes persistent neurogenesis from intrinsic stem cells. In marine teleosts, most cone photoreceptor genesis occurs early in the embryonic and larval stages, and rods are added primarily during and after metamorphosis. This study demonstrates a developmental paradigm in elopomorph fishes in which retinas are rod-dominated in larvae, but undergo periods of later cone genesis. Retinal characteristics were compared at different developmental stages among three ecologically distinct elopomorph fishes-ladyfish (Elops saurus), bonefish (Albula vulpes), and speckled worm eel (Myrophis punctatus). The objectives were to improve our understanding of (1) the developmental strategy in the elopomorph retina, (2) the functional architecture of the retina as it relates to ecology, and (3) how the light environment influences photoreceptor genesis. Photoreceptor morphologies, distributions, and spectral absorption were studied at larval, juvenile, and adult stages. Premetamorphic retinas in all three species are rod-dominated, but the retinas of these species undergo dramatic change over the course of development, resulting in juvenile and adult retinal characteristics that correlate closely with ecology. Adult E. saurus has high rod densities, grouped photoreceptors, a reflective tapetum, and longer-wavelength photopigments, supporting vision in turbid, low-light conditions. Adult A. vulpes has high cone densities, low rod densities, and shorter-wavelength photopigments, supporting diurnal vision in shallow, clear water. M. punctatus loses cones during metamorphosis, develops new cones after settlement, and maintains high rod but low cone densities, supporting primarily nocturnal vision. M. punctatus secondary cone genesis occurs rapidly throughout the retina, suggesting a novel mechanism of vertebrate photoreceptor genesis. Finally, in postsettlement M. punctatus, the continuous presence or absence of visible light modulates rod distribution but does not affect secondary cone genesis, suggesting some degree of developmental plasticity influenced by the light environment. PMID- 26241035 TI - Topographic organization of areas V3 and V4 and its relation to supra-areal organization of the primate visual system. AB - Areas V3 and V4 are commonly thought of as individual entities in the primate visual system, based on definition criteria such as their representation of visual space, connectivity, functional response properties, and relative anatomical location in cortex. Yet, large-scale functional and anatomical organization patterns not only emphasize distinctions within each area, but also links across visual cortex. Specifically, the visuotopic organization of V3 and V4 appears to be part of a larger, supra-areal organization, clustering these areas with early visual areas V1 and V2. In addition, connectivity patterns across visual cortex appear to vary within these areas as a function of their supra-areal eccentricity organization. This complicates the traditional view of these regions as individual functional "areas." Here, we will review the criteria for defining areas V3 and V4 and will discuss functional and anatomical studies in humans and monkeys that emphasize the integration of individual visual areas into broad, supra-areal clusters that work in concert for a common computational goal. Specifically, we propose that the visuotopic organization of V3 and V4, which provides the criteria for differentiating these areas, also unifies these areas into the supra-areal organization of early visual cortex. We propose that V3 and V4 play a critical role in this supra-areal organization by filtering information about the visual environment along parallel pathways across higher order cortex. PMID- 26241036 TI - Traffic-Related Air Pollution, Noise at School, and Behavioral Problems in Barcelona Schoolchildren: A Cross-Sectional Study. AB - BACKGROUND: The available evidence of the effects of air pollution and noise on behavioral development is limited, and it overlooks exposure at schools, where children spend a considerable amount of time. OBJECTIVE: We aimed to investigate the associations of exposure to traffic-related air pollutants (TRAPs) and noise at school on behavioral development of schoolchildren. METHODS: We evaluated children 7-11 years of age in Barcelona (Catalonia, Spain) during 2012-2013 within the BREATHE project. Indoor and outdoor concentrations of elemental carbon (EC), black carbon (BC), and nitrogen dioxide (NO2) were measured at schools in two separate 1-week campaigns. In one campaign we also measured noise levels inside classrooms. Parents filled out the strengths and difficulties questionnaire (SDQ) to assess child behavioral development, while teachers completed the attention deficit/hyperactivity disorder criteria of the DSM-IV (ADHD-DSM-IV) list to assess specific ADHD symptomatology. Negative binomial mixed-effects models were used to estimate associations between the exposures and behavioral development scores. RESULTS: Interquartile range (IQR) increases in indoor and outdoor EC, BC, and NO2 concentrations were positively associated with SDQ total difficulties scores (suggesting more frequent behavioral problems) in adjusted multivariate models, whereas noise was significantly associated with ADHD-DSM-IV scores. CONCLUSION: In our study population of 7- to 11-year-old children residing in Barcelona, exposure to TRAPs at school was associated with increased behavioral problems in schoolchildren. Noise exposure at school was associated with more ADHD symptoms. CITATION: Forns J, Dadvand P, Foraster M, Alvarez-Pedrerol M, Rivas I, Lopez-Vicente M, Suades-Gonzalez E, Garcia-Esteban R, Esnaola M, Cirach M, Grellier J, Basagana X, Querol X, Guxens M, Nieuwenhuijsen MJ, Sunyer J. 2016. Traffic-related air pollution, noise at school, and behavioral problems in Barcelona schoolchildren: a cross-sectional study. Environ Health Perspect 124:529-535; http://dx.doi.org/10.1289/ehp.1409449. PMID- 26241037 TI - Hyperinvasive Meningococci Induce Intra-nuclear Cleavage of the NF-kappaB Protein p65/RelA by Meningococcal IgA Protease. AB - Differential modulation of NF-kappaB during meningococcal infection is critical in innate immune response to meningococcal disease. Non-invasive isolates of Neisseria meningitidis provoke a sustained NF-kappaB activation in epithelial cells. However, the hyperinvasive isolates of the ST-11 clonal complex (ST-11) only induce an early NF-kappaB activation followed by a sustained activation of JNK and apoptosis. We show that this temporal activation of NF-kappaB was caused by specific cleavage at the C-terminal region of NF-kappaB p65/RelA component within the nucleus of infected cells. This cleavage was mediated by the secreted 150 kDa meningococcal ST-11 IgA protease carrying nuclear localisation signals (NLS) in its alpha-peptide moiety that allowed efficient intra-nuclear transport. In a collection of non-ST-11 healthy carriage isolates lacking NLS in the alpha peptide, secreted IgA protease was devoid of intra-nuclear transport. This part of iga polymorphism allows non-invasive isolates lacking NLS, unlike hyperinvasive ST-11 isolates of N. meningitides habouring NLS in their alpha peptide, to be carried asymptomatically in the human nasopharynx through selective eradication of their ability to induce apoptosis in infected epithelial cells. PMID- 26241038 TI - TSPO, a Mitochondrial Outer Membrane Protein, Controls Ethanol-Related Behaviors in Drosophila. AB - The heavy consumption of ethanol can lead to alcohol use disorders (AUDs) which impact patients, their families, and societies. Yet the genetic and physiological factors that predispose humans to AUDs remain unclear. One hypothesis is that alterations in mitochondrial function modulate neuronal sensitivity to ethanol exposure. Using Drosophila genetics we report that inactivation of the mitochondrial outer membrane translocator protein 18kDa (TSPO), also known as the peripheral benzodiazepine receptor, affects ethanol sedation and tolerance in male flies. Knockdown of dTSPO in adult male neurons results in increased sensitivity to ethanol sedation, and this effect requires the dTSPO depletion mediated increase in reactive oxygen species (ROS) production and inhibition of caspase activity in fly heads. Systemic loss of dTSPO in male flies blocks the development of tolerance to repeated ethanol exposures, an effect that is not seen when dTSPO is only inactivated in neurons. Female flies are naturally more sensitive to ethanol than males, and female fly heads have strikingly lower levels of dTSPO mRNA than males. Hence, mitochondrial TSPO function plays an important role in ethanol sensitivity and tolerance. Since a large array of benzodiazepine analogues have been developed that interact with the peripheral benzodiazepine receptor, the mitochondrial TSPO might provide an important new target for treating AUDs. PMID- 26241039 TI - Effect of Common Drinking Water Disinfectants, Chlorine and Heat, on Free Legionella and Amoebae-Associated Legionella. AB - Chlorine and thermal treatments are the most commonly used procedures to control and prevent Legionella proliferation in drinking water systems of large buildings. However, cases of legionellosis still occur in facilities with treated water. The purpose of this work was to model the effect of temperature and free chlorine applied in similar exposure conditions as in drinking water systems on five Legionella spp. strains and two amoebal strains of the genera Acanthamoeba. Inactivation models obtained were used to determine the effectiveness of the treatments applied which resulted more effective against Legionella than Acanthamoeba, especially those in cystic stages. Furthermore, to determine the influence of the relationship between L. pneumophila and Acanthamoeba spp. on the treatment effectiveness, inactivation models of the bacteria-associated amoeba were also constructed and compared to the models obtained for the free living bacteria state. The Legionella-amoeba association did not change the inactivation models, but it reduced the effectiveness of the treatments applied. Remarkably, at the lowest free chlorine concentration, 0.5 mg L-1, as well as at the lowest temperatures, 50 degrees C and 55 degrees C, the influence of the Legionella amoeba associate state was the strongest in reducing the effectiveness of the treatments compared to the free Legionella state. Therefore, the association established between L. pneumophila and amoebae in the water systems indicate an increased health risk in proximal areas of the system (close to the tap) where lower free chlorine concentrations and lower temperatures are commonly observed. PMID- 26241041 TI - Correction: Curcumin Modulates the Inflammatory Response and Inhibits Subsequent Fibrosis in a Mouse Model of Viral-induced Acute Respiratory Distress Syndrome. PMID- 26241040 TI - Comparative Transcriptome Analysis of Differentially Expressed Genes and Signaling Pathways between XY and YY Testis in Yellow Catfish. AB - YY super-males have rarely been detected in nature and only been artificially created in some fish species including tilapia and yellow catfish (Pelteobagrusfulvidraco), which provides a promising model for testis development and spermatogenesis. In our previous study, significant differences in morphology and miRNA expression were detected between XY and YY testis of yellow catfish. Here, solexa sequencing technology was further performed to compare mRNA expression between XY and YY testis. Compared with unigenes expressed in XY testis, 1146 and 1235 unigenes have significantly higher and lower expression in YY testis, respectively. 605 differentially expressed unigenes were annotated to 1604 GO terms with 319 and 286 genes having relative higher expression in XY and YY testis. KEGG analysis suggested different levels of PI3K-AKT and G protein coupled receptor (GPCR) signaling pathways between XY and YY testis. Down regulation of miR-141/429 in YY testis was speculated to promote testis development and maturation, and several factors in PI3K-AKT and GPCR signaling pathways were found as predicted targets of miR-141/429, several of which were confirmed by dual-luciferase reporter assays. Our study provides a comparative transcriptome analysis between XY and YY testis, and reveals interactions between miRNAs and their target genes that are possibly involved in regulating testis development and spermatogenesis. PMID- 26241042 TI - No Effect of Weight on Judgments of Importance in the Moral Domain and Evidence of Publication Bias from a Meta-Analysis. AB - In different cultures, people use the concept of weight to refer to important matters. Recent studies in grounded cognition suggested that experiences of weight affect unrelated judgments of importance in metaphor-congruent ways. Theories in grounded cognition and prime-to-behavior effects state that sensations of weight activate concepts of importance, which may affect morality related variables that are influenced by judgments of importance. The present research aimed to test the effect of carrying a heavy (or light) clipboard on the perceived importance of helping and on the judged severity of moral transgressions. After finding no significant effects in two experiments, a third study explored whether these results were due to a specific lack of effect of weight on morality-related variables or to the concept of importance not being grounded in sensations of weight in Brazilian samples. Specifically, in Study 3 we attempted to replicate two seminal studies but found no significant effects. Together with evidence of publication bias in a meta-analysis of published studies, the current results suggest that the concept of importance may not be as universally grounded in sensations of weight as previously assumed. We discuss the implications of these results for grounded cognition theories and methodological and statistical aspects of priming studies. PMID- 26241043 TI - Rapid Photodegradation of Methyl Orange (MO) Assisted with Cu(II) and Tartaric Acid. AB - Cu(II) and organic carboxylic acids, existing extensively in soil and aquatic environments, can form complexes that may play an important role in the photodegradation of organic contaminants. In this paper, the catalytic role of Cu(II) in the removal of methyl orange (MO) in the presence of tartaric acid with light was investigated through batch experiments. The results demonstrate that the introduction of Cu(II) could markedly enhance the photodegradation of MO. In addition, high initial concentrations of Cu(II) and tartaric acid benefited the decomposition of MO. The most rapid removal of MO assisted by Cu(II) was achieved at pH 3. The formation of Cu(II)-tartaric acid complexes was assumed to be the key factor, generating hydroxyl radicals (*OH) and other oxidizing free radicals under irradiation through a ligand-to-metal charge-transfer pathway that was responsible for the efficient degradation of MO. Some intermediates in the reaction system were also detected to support this reaction mechanism. PMID- 26241044 TI - Smooth Muscle Cell Genome Browser: Enabling the Identification of Novel Serum Response Factor Target Genes. AB - Genome-scale expression data on the absolute numbers of gene isoforms offers essential clues in cellular functions and biological processes. Smooth muscle cells (SMCs) perform a unique contractile function through expression of specific genes controlled by serum response factor (SRF), a transcription factor that binds to DNA sites known as the CArG boxes. To identify SRF-regulated genes specifically expressed in SMCs, we isolated SMC populations from mouse small intestine and colon, obtained their transcriptomes, and constructed an interactive SMC genome and CArGome browser. To our knowledge, this is the first online resource that provides a comprehensive library of all genetic transcripts expressed in primary SMCs. The browser also serves as the first genome-wide map of SRF binding sites. The browser analysis revealed novel SMC-specific transcriptional variants and SRF target genes, which provided new and unique insights into the cellular and biological functions of the cells in gastrointestinal (GI) physiology. The SRF target genes in SMCs, which were discovered in silico, were confirmed by proteomic analysis of SMC-specific Srf knockout mice. Our genome browser offers a new perspective into the alternative expression of genes in the context of SRF binding sites in SMCs and provides a valuable reference for future functional studies. PMID- 26241046 TI - The Characters of Dry Soil Layer on the Loess Plateau in China and Their Influencing Factors. AB - A dry soil layer (DSL) is a common soil desiccation phenomenon that generally forms at a particular depth in the soil profile because of climatic factors and poor land management, and this phenomenon can influence the water cycle and has been observed on the Loess Plateau of China and other similar regions around the world. Therefore, an investigation of the DSL formation depth (DSLFD), thickness (DSLT) and mean water content (MWDSL) on the Loess Plateau can provide valuable information. This paper synthesized 69 recent publications (1,149 observations of DSLs from 73 sites) that focused on DSLs in this region, and the results indicated that DSLs are significantly affected by climatic and vegetation factors. The mean annual precipitation had a significant positive relationship with DSLFD (p = 0.0003) and MWDSL (p<0.0001) and a negative relationship with DSLT (p = 0.0071). Crops had the lowest DSLT and highest MWDSL values compared with other vegetation types. A significant correlation was observed between the occurrence of DSLs and the years since planting for grasses, shrubs, trees and orchards, and the severity of DSLs increased with increasing planting years and wheat yield. Our results suggest that optimizing land-use management can mitigate DSL formation and development on the Loess Plateau. Understanding the dominant factors affecting DSLs will provide information for use in guidelines for the sustainable development of economies and restoration of natural environments experiencing water deficiencies. PMID- 26241047 TI - Sleep Deprivation Reveals Altered Brain Perfusion Patterns in Somnambulism. AB - BACKGROUND: Despite its high prevalence, relatively little is known about the pathophysiology of somnambulism. Increasing evidence indicates that somnambulism is associated with functional abnormalities during wakefulness and that sleep deprivation constitutes an important drive that facilitates sleepwalking in predisposed patients. Here, we studied the neural mechanisms associated with somnambulism using Single Photon Emission Computed Tomography (SPECT) with 99mTc Ethylene Cysteinate Dimer (ECD), during wakefulness and after sleep deprivation. METHODS: Ten adult sleepwalkers and twelve controls with normal sleep were scanned using 99mTc-ECD SPECT in morning wakefulness after a full night of sleep. Eight of the sleepwalkers and nine of the controls were also scanned during wakefulness after a night of total sleep deprivation. Between-group comparisons of regional cerebral blood flow (rCBF) were performed to characterize brain activity patterns during wakefulness in sleepwalkers. RESULTS: During wakefulness following a night of total sleep deprivation, rCBF was decreased bilaterally in the inferior temporal gyrus in sleepwalkers compared to controls. CONCLUSIONS: Functional neural abnormalities can be observed during wakefulness in somnambulism, particularly after sleep deprivation and in the inferior temporal cortex. Sleep deprivation thus not only facilitates the occurrence of sleepwalking episodes, but also uncovers patterns of neural dysfunction that characterize sleepwalkers during wakefulness. PMID- 26241045 TI - A Deluge of Complex Repeats: The Solanum Genome. AB - Repetitive elements have lately emerged as key components of genome, performing varieties of roles. It has now become necessary to have an account of repeats for every genome to understand its dynamics and state. Recently, genomes of two major Solanaceae species, Solanum tuberosum and Solanum lycopersicum, were sequenced. These species are important crops having high commercial significance as well as value as model species. However, there is a reasonable gap in information about repetitive elements and their possible roles in genome regulation for these species. The present study was aimed at detailed identification and characterization of complex repetitive elements in these genomes, along with study of their possible functional associations as well as to assess possible transcriptionally active repetitive elements. In this study, it was found that ~50-60% of genomes of S. tuberosum and S. lycopersicum were composed of repetitive elements. It was also found that complex repetitive elements were associated with >95% of genes in both species. These two genomes are mostly composed of LTR retrotransposons. Two novel repeat families very similar to LTR/ERV1 and LINE/RTE-BovB have been reported for the first time. Active existence of complex repeats was estimated by measuring their transcriptional abundance using Next Generation Sequencing read data and Microarray platforms. A reasonable amount of regulatory components like transcription factor binding sites and miRNAs appear to be under the influence of these complex repetitive elements in these species, while several genes appeared to possess exonized repeats. PMID- 26241048 TI - A Multiplex Label-Free Approach to Avian Influenza Surveillance and Serology. AB - Influenza serology has traditionally relied on techniques such as hemagglutination inhibition, microneutralization, and ELISA. These assays are complex, challenging to implement in a format allowing detection of several types of antibody-analyte interactions at once (multiplex), and troublesome to implement in the field. As an alternative, we have developed a hemagglutinin microarray on the Arrayed Imaging Reflectometry (AIR) platform. AIR provides sensitive, rapid, and label-free multiplex detection of targets in complex analyte samples such as serum. In preliminary work, we demonstrated the application of this array to the testing of human samples from a vaccine trial. Here, we report the application of an expanded label-free hemagglutinin microarray to the analysis of avian serum samples. Samples from influenza virus challenge experiments in mallards yielded strong, selective detection of antibodies to the challenge antigen in most cases. Samples acquired in the field from mallards were also analyzed, and compared with viral hemagglutinin inhibition and microneutralization assays. We find that the AIR hemagglutinin microarray can provide a simple and robust alternative to standard methods, offering substantially greater information density from a simple workflow. PMID- 26241049 TI - Trends in Prevalence, Awareness, Treatment and Control of Hypertension during 2001-2010 in an Urban Elderly Population of China. AB - OBJECTIVE: As the most important risk factors of cardiovascular disease, pre hypertension and hypertension are important public health challenges. Few studies have focused on the trends of pre-hypertension and hypertension specifically for the aging population in China. Given the anticipated growth of the elderly population in China, there is an urgent need to document the conditions of pre hypertension and hypertension in this aging population. METHODS: We conducted two cross-sectional surveys of Chinese adults aged >=60 years in 2001 and 2010. A total of 2,272 (943 males, 1,329 females) and 2,074 (839 males, 1,235 females) participants were included in the two surveys, respectively. RESULTS: The age- and sex-standardized prevalence of hypertension significantly increased from 60.1% to 65.2% from the 2001 to the 2010 survey. Among the participants with hypertension, the awareness, treatment and control of hypertension all significantly increased from 69.8% to 74.5%, 50.3% to 63.7%, and 15.3% to 30.3%, respectively, from 2001 to 2010. A logistic regression showed that a higher education level, a higher BMI, a family history of hypertension and doctor diagnosed cardiovascular disease were significantly associated with hypertension awareness and treatment. CONCLUSION: Hypertension prevalence increased rapidly between the years surveyed. Although the awareness, treatment and control of hypertension improved significantly, the values of these variables remained low. More attention should be given to the elderly because the population is aging worldwide, and urgent action, optimal treatment approaches and proper public health strategies must be taken to prevent and manage hypertension. PMID- 26241050 TI - Historical Perspective and Risk of Multiple Neglected Tropical Diseases in Coastal Tanzania: Compositional and Contextual Determinants of Disease Risk. AB - BACKGROUND: In the past decade, research on neglected tropical diseases (NTDs) has intensified in response to the need to enhance community participation in health delivery, establish monitoring and surveillance systems, and integrate existing disease-specific treatment programs to control overlapping NTD burdens and detrimental effects. In this paper, we evaluated the geographical distribution of NTDs in coastal Tanzania. METHODS AND FINDINGS: We also assessed the collective (compositional and contextual) factors that currently determine risks to multiple NTDs using a cross sectional survey of 1253 individuals in coastal Tanzania. The results show that the effect size in decreasing order of magnitude for non-binary predictors of NTD risks is as follows: NTD comorbidities > poverty > educational attainment > self-reported household quality of life > ethnicity. The multivariate analysis explained 95% of the variance in the relationship between NTD risks and the theoretically-relevant covariates. Compositional (biosocial and sociocultural) factors explained more variance at the neighbourhood level than at the regional level, whereas contextual factors, such as access to health services and household quality, in districts explained a large proportion of variance at the regional level but individually had modest statistical significance, demonstrating the complex interactions between compositional and contextual factors in generating NTD risks. CONCLUSIONS: NTD risks were inequitably distributed over geographic space, which has several important policy implications. First, it suggests that localities of high burden of NTDs are likely to diminish within statistical averages at higher (regional or national) levels. Second, it indicates that curative or preventive interventions will become more efficient provided they can be focused on the localities, particularly as populations in these localities are likely to be burdened by several NTDs simultaneously, further increasing the imperative of multi-disease interventions. PMID- 26241052 TI - Policing Diversity: Examining Police Resistance to Training Reforms for Transgender People in Australia. AB - Using field notes collected from participant observation of Australian police officers training to work with the transgender community, the current research builds on previous work examining social identity theory (Tajfel, 2010) to explain how one training program implemented to educate police about transgender people challenges police culture. This research determines that police culture, training procedures, and stereotypes of gender are equally influential on police perceptions of all transgender people. Overall, the results indicate that negative police perceptions toward police training reforms strengthen in-group identity of police, and negative out-group perceptions of transgender people. PMID- 26241051 TI - Phosphatidylcholine Supply to Peroxisomes of the Yeast Saccharomyces cerevisiae. AB - In the yeast Saccharomyces cerevisiae, phosphatidylcholine (PC), the major phospholipid (PL) of all organelle membranes, is synthesized via two different pathways. Methylation of phosphatidylethanolamine (PE) catalyzed by the methyl transferases Cho2p/Pem1p and Opi3p/Pem2p as well as incorporation of choline through the CDP (cytidine diphosphate)-choline branch of the Kennedy pathway lead to PC formation. To determine the contribution of these two pathways to the supply of PC to peroxisomes (PX), yeast mutants bearing defects in the two pathways were cultivated under peroxisome inducing conditions, i.e. in the presence of oleic acid, and subjected to biochemical and cell biological analyses. Phenotype studies revealed compromised growth of both the cho20Deltaopi3Delta (mutations in the methylation pathway) and the cki1Deltadpl1Deltaeki1Delta (mutations in the CDP-choline pathway) mutant when grown on oleic acid. Analysis of peroxisomes from the two mutant strains showed that both pathways produce PC for the supply to peroxisomes, although the CDP choline pathway seemed to contribute with higher efficiency than the methylation pathway. Changes in the peroxisomal lipid pattern of mutants caused by defects in the PC biosynthetic pathways resulted in changes of membrane properties as shown by anisotropy measurements with fluorescent probes. In summary, our data define the origin of peroxisomal PC and demonstrate the importance of PC for peroxisome membrane formation and integrity. PMID- 26241053 TI - From mice to humans: developments in cancer immunoediting. AB - Cancer immunoediting explains the dual role by which the immune system can both suppress and/or promote tumor growth. Although cancer immunoediting was first demonstrated using mouse models of cancer, strong evidence that it occurs in human cancers is now accumulating. In particular, the importance of CD8+ T cells in cancer immunoediting has been shown, and more broadly in those tumors with an adaptive immune resistance phenotype. This Review describes the characteristics of the adaptive immune resistance tumor microenvironment and discusses data obtained in mouse and human settings. The role of other immune cells and factors influencing the effector function of tumor-specific CD8+ T cells is covered. We also discuss the temporal occurrence of cancer immunoediting in metastases and whether it differs from immunoediting in the primary tumor of origin. PMID- 26241054 TI - Elevated copper impairs hepatic nuclear receptor function in Wilson's disease. AB - Wilson's disease (WD) is an autosomal recessive disorder that results in accumulation of copper in the liver as a consequence of mutations in the gene encoding the copper-transporting P-type ATPase (ATP7B). WD is a chronic liver disorder, and individuals with the disease present with a variety of complications, including steatosis, cholestasis, cirrhosis, and liver failure. Similar to patients with WD, Atp7b-/- mice have markedly elevated levels of hepatic copper and liver pathology. Previous studies have demonstrated that replacement of zinc in the DNA-binding domain of the estrogen receptor (ER) with copper disrupts specific binding to DNA response elements. Here, we found decreased binding of the nuclear receptors FXR, RXR, HNF4alpha, and LRH-1 to promoter response elements and decreased mRNA expression of nuclear receptor target genes in Atp7b-/- mice, as well as in adult and pediatric WD patients. Excessive hepatic copper has been described in progressive familial cholestasis (PFIC), and we found that similar to individuals with WD, patients with PFIC2 or PFIC3 who have clinically elevated hepatic copper levels exhibit impaired nuclear receptor activity. Together, these data demonstrate that copper-mediated nuclear receptor dysfunction disrupts liver function in WD and potentially in other disorders associated with increased hepatic copper levels. PMID- 26241055 TI - Inflammatory IL-15 is required for optimal memory T cell responses. AB - Due to their ability to rapidly proliferate and produce effector cytokines, memory CD8+ T cells increase protection following reexposure to a pathogen. However, low inflammatory immunizations do not provide memory CD8+ T cells with a proliferation advantage over naive CD8+ T cells, suggesting that cell-extrinsic factors enhance memory CD8+ T cell proliferation in vivo. Herein, we demonstrate that inflammatory signals are critical for the rapid proliferation of memory CD8+ T cells following infection. Using murine models of viral infection and antigen exposure, we found that type I IFN-driven expression of IL-15 in response to viral infection prepares memory CD8+ T cells for rapid division independently of antigen reexposure by transiently inducing cell-cycle progression via a pathway dependent on mTOR complex-1 (mTORC1). Moreover, exposure to IL-15 allowed more rapid division of memory CD8+ T cells following antigen encounter and enhanced their protective capacity against viral infection. Together, these data reveal that inflammatory IL-15 promotes optimal responses by memory CD8+ T cells. PMID- 26241056 TI - Advancing the mission. PMID- 26241058 TI - Medicine in 2055. PMID- 26241057 TI - Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action. AB - The thiazide-sensitive NaCl cotransporter (NCC) is important for renal salt handling and blood-pressure homeostasis. The canonical NCC-activating pathway consists of With-No-Lysine (WNK) kinases and their downstream effector kinases SPAK and OSR1, which phosphorylate NCC directly. The upstream mechanisms that connect physiological stimuli to this system remain obscure. Here, we have shown that aldosterone activates SPAK/OSR1 via WNK1. We identified 2 alternatively spliced exons embedded within a proline-rich region of WNK1 that contain PY motifs, which bind the E3 ubiquitin ligase NEDD4-2. PY motif-containing WNK1 isoforms were expressed in human kidney, and these isoforms were efficiently degraded by the ubiquitin proteasome system, an effect reversed by the aldosterone-induced kinase SGK1. In gene-edited cells, WNK1 deficiency negated regulatory effects of NEDD4-2 and SGK1 on NCC, suggesting that WNK1 mediates aldosterone-dependent activity of the WNK/SPAK/OSR1 pathway. Aldosterone infusion increased proline-rich WNK1 isoform abundance in WT mice but did not alter WNK1 abundance in hypertensive Nedd4-2 KO mice, which exhibit high baseline WNK1 and SPAK/OSR1 activity toward NCC. Conversely, hypotensive Sgk1 KO mice exhibited low WNK1 expression and activity. Together, our findings indicate that the proline rich exons are modular cassettes that convert WNK1 into a NEDD4-2 substrate, thereby linking aldosterone and other NEDD4-2-suppressing antinatriuretic hormones to NCC phosphorylation status. PMID- 26241059 TI - A doctor's dilemma: choices amidst change. PMID- 26241061 TI - Potassium, Cesium, and Ammonium Peroxogermanates with Inorganic Hexanuclear Peroxo Bridged Germanium Anion Isolated from Aqueous Solution. AB - Potassium (K6[Ge6(MU-OO)6(MU-O)6(OH)6].14H2O, 1), cesium ammonium (Cs4.2(NH4)1.8[Ge6(MU-OO)6(MU-O)6(OH)6].8H2O, 2), and potassium ammonium (K2.4(NH4)3.6[Ge6(MU-OO)6(MU-O)6(OH)6].6H2O, 3) peroxogermanates were isolated from 3% hydrogen peroxide aqueous solutions of the corresponding hydroxogermanates and characterized by single crystal and powder X-ray diffraction studies and by Raman spectroscopy and thermal analysis. The crystal structure of all three compounds consists of cations of potassium and/or ammonium and cesium, water molecules, and centrosymmetric hexanuclear peroxogermanate anion [Ge6(MU-OO)6(MU-O)6(OH)6](6-) with six MU-oxo- and six MU-peroxo groups. Peroxogermanates demonstrate relatively high thermal stability: the peroxide remains in the structure even after water release after heating to 100-120 degrees C. DFT calculations of the peroxogermanate [Ge6(MU-OO)6(MU-O)6(OH)6](6-) anion confirm its higher thermodynamic stability compared to the hydroperoxo- and oxogermanate analogues. PMID- 26241062 TI - [OCT Angiography - Is this the Future for Macular Diagnosis?]. AB - Recent developements in OCT technology using high speed acquisition and calculation of consecutive scans (SSADA = split spectrum amplitude decorrelation algorithm) have resulted in the possibility to demonstrate retinal and choroidal vessels in the macula. This new technology of "OCT angiography" thus allows the non-invasive and rapid (within seconds) reconstruction of the three-dimensional structure of the retinal and choroidal vascularisation. There are still limitations caused by movement artefacts, superposition of superficial retinal vessels at the RPE level or insufficient three-dimensional imaging, but the first experience with this new method and especially the correlations with the current standard diagnostic procedure fluorescein angiography shows that especially for vascular changes which are predominantly in one retinal layer (e.g., the inner retina) like in diabetic retinopathy or retinal vein occlusions, a very good correlation can be seen. Also in MacTel type 2 patients the proposed vascular changes in the deeper capillary network of the retina can be visualised very well with OCT angiography. In contrast, more three-dimensional vascular changes like the neovascular complex in exsudative AMD need a more sophisticated diagnostic analysis strategy, which has still to be developed. However, the first experience also demonstrates that fluorescein angiographic differentiation can also be seen in OCT angiography. In addition, the new technology gives additional information about the choroidal and outer retinal changes in these pathologies, which may result in a better understanding of the underlying pathologies. PMID- 26241060 TI - Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis. AB - Mitochondrial homeostasis is critical for tissue health, and mitochondrial dysfunction contributes to numerous diseases, including heart failure. Here, we have shown that the transcription factor Kruppel-like factor 4 (KLF4) governs mitochondrial biogenesis, metabolic function, dynamics, and autophagic clearance. Adult mice with cardiac-specific Klf4 deficiency developed cardiac dysfunction with aging or in response to pressure overload that was characterized by reduced myocardial ATP levels, elevated ROS, and marked alterations in mitochondrial shape, size, ultrastructure, and alignment. Evaluation of mitochondria isolated from KLF4-deficient hearts revealed a reduced respiration rate that is likely due to defects in electron transport chain complex I. Further, cardiac-specific, embryonic Klf4 deletion resulted in postnatal premature mortality, impaired mitochondrial biogenesis, and altered mitochondrial maturation. We determined that KLF4 binds to, cooperates with, and is requisite for optimal function of the estrogen-related receptor/PPARgamma coactivator 1 (ERR/PGC-1) transcriptional regulatory module on metabolic and mitochondrial targets. Finally, we found that KLF4 regulates autophagy flux through transcriptional regulation of a broad array of autophagy genes in cardiomyocytes. Collectively, these findings identify KLF4 as a nodal transcriptional regulator of mitochondrial homeostasis. PMID- 26241063 TI - High-Yield Exfoliation of Ultrathin Two-Dimensional Ternary Chalcogenide Nanosheets for Highly Sensitive and Selective Fluorescence DNA Sensors. AB - High-yield preparation of ultrathin two-dimensional (2D) nanosheets is of great importance for the further exploration of their unique properties and promising applications. Herein, for the first time, the high-yield and scalable production of ultrathin 2D ternary chalcogenide nanosheets, including Ta2NiS5 and Ta2NiSe5, in solution is achieved by exfoliating their layered microflakes. The size of resulting Ta2NiS5 and Ta2NiS5 nanosheets ranges from tens of nanometers to few micrometers. Importantly, the production yield of single-layer Ta2NiS5 nanosheets is very high, ca. 86%. As a proof-of-concept application, the single-layer Ta2NiS5 is used as a novel fluorescence sensing platform for the detection of DNA with excellent selectivity and high sensitivity (with detection limit of 50 pM). These solution-processable, high-yield, large-amount ternary chalcogenide nanosheets may also have potential applications in electrocatalysis, supercapacitors, and electronic devices. PMID- 26241064 TI - Sex-Specific Placental Responses in Fetal Development. AB - The placenta is an ephemeral but critical organ for the survival of all eutherian mammals and marsupials. It is the primary messenger system between the mother and fetus, where communicational signals, nutrients, waste, gases, and extrinsic factors are exchanged. Although the placenta may buffer the fetus from various environmental insults, placental dysfunction might also contribute to detrimental developmental origins of adult health and disease effects. The placenta of one sex over the other might possess greater ability to respond and buffer against environmental insults. Given the potential role of the placenta in effecting the lifetime health of the offspring, it is not surprising that there has been a resurging interest in this organ, including the Human Placental Project launched by the National Institutes of Child Health and Human Development. In this review, we will compare embryological development of the laboratory mouse and human chorioallantoic placentae. Next, evidence that various species, including humans, exhibit normal sex-dependent structural and functional placental differences will be examined followed by how in utero environmental changes (nutritional state, stress, and exposure to environmental chemicals) might interact with fetal sex to affect this organ. Recent data also suggest that paternal state impacts placental function in a sex-dependent manner. The research to date linking placental maladaptive responses and later developmental origins of adult health and disease effects will be explored. Finally, we will focus on how sex chromosomes and epimutations may contribute to sex-dependent differences in placental function, the unanswered questions, and future directions that warrant further consideration. PMID- 26241065 TI - Stress and Androgen Activity During Fetal Development. AB - Prenatal stress is known to alter hypothalamic-pituitary-adrenal axis activity, and more recent evidence suggests that it may also affect androgen activity. In animal models, prenatal stress disrupts the normal surge of testosterone in the developing male, whereas in females, associations differ by species. In humans, studies show that (1) associations between prenatal stress and child outcomes are often sex-dependent, (2) prenatal stress predicts several disorders with notable sex differences in prevalence, and (3) prenatal exposure to stressful life events may be associated with masculinized reproductive tract development and play behavior in girls. In this minireview, we examine the existing literature on prenatal stress and androgenic activity and present new, preliminary data indicating that prenatal stress may also modify associations between prenatal exposure to diethylhexyl phthalate, (a synthetic, antiandrogenic chemical) and reproductive development in infant boys. Taken together, these data support the hypothesis that prenatal exposure to both chemical and nonchemical stressors may alter sex steroid pathways in the maternal-placental-fetal unit and ultimately alter hormone-dependent developmental endpoints. PMID- 26241066 TI - Fetal Hematopoietic Stem Cells Are the Canaries in the Coal Mine That Portend Later Life Immune Deficiency. AB - Disorders of the blood system are a significant and growing global health concern and include a spectrum of diseases ranging from aplastic anemia and leukemias to immune suppression. This array of hematological disorders is attributed to the fact that the blood system undergoes a perpetual cycle of turn over with aged and exhausted red and white blood cells undergoing daily replacement. The foundational cells of this replenishment process are comprised of rare hematopoietic stem cells (HSCs) located in the bone marrow that possess the dual function of long-term self-renewal and multilineage differentiation. This constant turnover makes the hematopoietic system uniquely vulnerable to changes in the environment that impact multilineage differentiation, self-renewal, or both. Notably, environmental endocrine-disrupting exposures occurring during development, when HSCs are first emerging, can lead to alterations in HSC programming that impacts the blood and immune systems throughout life. In this review, we describe the process of fetal hematopoiesis and provide an overview of the intrauterine environmental and endocrine-disrupting compounds that disrupt this process. Finally, we describe research opportunities for fetal HSCs as potential sentinels of later-life blood and immune system disorders. PMID- 26241067 TI - Life-Long Implications of Developmental Exposure to Environmental Stressors: New Perspectives. AB - The Developmental Origins of Health and Disease (DOHaD) paradigm is one of the most rapidly expanding areas of biomedical research. Environmental stressors that can impact on DOHaD encompass a variety of environmental and occupational hazards as well as deficiency and oversupply of nutrients and energy. They can disrupt early developmental processes and lead to increased susceptibility to disease/dysfunctions later in life. Presentations at the fourth Conference on Prenatal Programming and Toxicity in Boston, in October 2014, provided important insights and led to new recommendations for research and public health action. The conference highlighted vulnerable exposure windows that can occur as early as the preconception period and epigenetics as a major mechanism than can lead to disadvantageous "reprogramming" of the genome, thereby potentially resulting in transgenerational effects. Stem cells can also be targets of environmental stressors, thus paving another way for effects that may last a lifetime. Current testing paradigms do not allow proper characterization of risk factors and their interactions. Thus, relevant exposure levels and combinations for testing must be identified from human exposure situations and outcome assessments. Testing of potential underpinning mechanisms and biomarker development require laboratory animal models and in vitro approaches. Only few large-scale birth cohorts exist, and collaboration between birth cohorts on a global scale should be facilitated. DOHaD-based research has a crucial role in establishing factors leading to detrimental outcomes and developing early preventative/remediation strategies to combat these risks. PMID- 26241068 TI - Stem Cells as Hormone Targets That Lead to Increased Cancer Susceptibility. AB - Major advances during the past decade have permitted a clearer understanding of processes that regulate stem cell self-renewal and lineage commitment toward differentiated progeny that populate all tissues. Considerable evidence has also accumulated to indicate that aberrations in the stem and progenitor cell populations can lead to increased cancer risk in specific organs systems. It is long recognized that environmental factors play a major role in cancer etiology, and emerging data suggest that endocrine-disrupting chemicals (EDCs) may contribute to an increased cancer risk. Using the prostate gland as a model system, the present review highlights recent data that find that estrogens and EDCs can reprogram prostate stem and progenitor cell populations, leading to increased cancer susceptibility. We propose that stem cell programming during early development in hormone-regulated tissues may lead to heightened sensitivity to early-life EDC exposures and that aberrant stem cell reprogramming by EDCs may contribute to the developmental basis of adult cancer risk. PMID- 26241069 TI - Progesterone and Overlooked Endocrine Pathways in Breast Cancer Pathogenesis. AB - Worldwide, breast cancer incidence has been increasing for decades. Exposure to reproductive hormones, as occurs with recurrent menstrual cycles, affects breast cancer risk, and can promote disease progression. Exogenous hormones and endocrine disruptors have also been implicated in increasing breast cancer incidence. Numerous in vitro studies with hormone-receptor-positive cell lines have provided insights into the complexities of hormone receptor signaling at the molecular level; in vivo additional layers of complexity add on to this. The combined use of mouse genetics and tissue recombination techniques has made it possible to disentangle hormone action in vivo and revealed that estrogens, progesterone, and prolactin orchestrate distinct developmental stages of mammary gland development. The 2 ovarian steroids that fluctuate during menstrual cycles act on a subset of mammary epithelial cells, the hormone-receptor-positive sensor cells, which translate and amplify the incoming systemic signals into local, paracrine stimuli. Progesterone has emerged as a major regulator of cell proliferation and stem cell activation in the adult mammary gland. Two progesterone receptor targets, receptor activator of NfkappaB ligand and Wnt4, serve as downstream paracrine mediators of progesterone receptor-induced cell proliferation and stem cell activation, respectively. Some of the findings in the mouse have been validated in human ex vivo models and by next-generation whole transcriptome sequencing on healthy donors staged for their menstrual cycles. The implications of these insights into the basic control mechanisms of mammary gland development for breast carcinogenesis and the possible role of endocrine disruptors, in particular bisphenol A in this context, will be discussed below. PMID- 26241070 TI - Developmental Origins of Health and Disease: Integrating Environmental Influences. AB - There are now robust data supporting the Developmental Origins of Health and Disease (DOHaD) paradigm. This includes human and animal data focusing on nutrition or environmental chemicals during development. However, the term DOHaD has not been generally accepted as the official term to be used when one is concerned with understanding the pathophysiological basis for how environmental influences acting during early development influence the risk of later noncommunicable diseases. Similarly, there is no global research or public health program built around the DOHaD paradigm that encompasses all aspects of environment. To better inform the global health efforts aimed at addressing the growing epidemic of chronic noncommunicable diseases of environmental origin, we propose a two-pronged approach: first, to make it clear that the current concept of DOHaD comprehensively includes a range of environmental factors and their relevance to disease occurrence not just throughout the life span but potentially across several generations; and second, to initiate the discussion of how adoption of DOHaD can promote a more realistic, accurate, and integrative approach to understanding environmental disruption of developmental programming and better inform clinical and policy interventions. PMID- 26241071 TI - Air Pollution and Neuropsychological Development: A Review of the Latest Evidence. AB - For the last decade, literature on the detrimental impacts of air pollution on brain, cognition and behavior has exponentially increased. Our aim is to review the latest epidemiologic literature on the association between outdoor air pollution and neuropsychological developmental in children. Two independent researchers searched for published studies between January 1, 2012 and June 12, 2015 in MEDLINE, Web of Science, and Science direct using defined keywords on outdoor air pollution and neuropsychological development. Selection of articles was based on study eligibility criteria. We encountered sufficient evidence of detrimental effects of pre- or postnatal exposure to polycyclic aromatic hydrocarbons on global intelligence quotient. The evidence was also sufficient for the association between pre- or postnatal exposure to fine particulate matter (PM2.5) and autism spectrum disorder, and limited evidence was encountered between nitrogen oxides and autism spectrum disorder. For other exposure-outcome associations reviewed, the evidence was inadequate or insufficient. Although evidence is not yet conclusive and further research is needed, the latest epidemiological studies support the hypothesis that pre- or postnatal exposure to ambient pollution, particularly polycyclic aromatic hydrocarbons, PM2.5, and nitrogen oxides has a negative impact on the neuropsychological development of children. The public health impact of air pollutants cannot be ignored and the precautionary principle should be applied to protect children. PMID- 26241073 TI - Prenatal Programming and Toxicity (PPTOX) Introduction. AB - The developmental origin of health and disease hypothesis posits that early-life exposures, including prenatal, can influence disease outcomes throughout the entire lifespan of an organism. Over the past 30 years, scientific researchers have compiled robust epidemiological and mechanistic data showing the effects of early-life nutrition, chemical exposures, and stress on prenatal programing and toxicity. Using novel techniques in genomics and epigenetics, science is now establishing strong links between low-level early-life environmental exposures and the later development of noncommunicable diseases, such as cardiovascular disease, obesity, diabetes, neurodevelopmental and neurodegenerative disease, reproductive effects, immune system function and cancer. Now scientists must engage with communities, industry, policy makers, and clinicians to leverage our newfound understanding of prenatal programing and toxicity into better health outcomes across the lifespan. PMID- 26241072 TI - The Role of Epigenetics in the Latent Effects of Early Life Exposure to Obesogenic Endocrine Disrupting Chemicals. AB - Recent research supports a role for exposure to endocrine-disrupting chemicals (EDCs) in the global obesity epidemic. Obesogenic EDCs have the potential to inappropriately stimulate adipogenesis and fat storage, influence metabolism and energy balance and increase susceptibility to obesity. Developmental exposure to obesogenic EDCs is proposed to interfere with epigenetic programming of gene regulation, partly by activation of nuclear receptors, thereby influencing the risk of obesity later in life. The goal of this minireview is to briefly describe the epigenetic mechanisms underlying developmental plasticity and to evaluate the evidence of a mechanistic link between altered epigenetic gene regulation by early life EDC exposure and latent onset of obesity. We summarize the results of recent in vitro, in vivo, and transgenerational studies, which clearly show that the obesogenic effects of EDCs such as tributyltin, brominated diphenyl ether 47, and polycyclic aromatic hydrocarbons are mediated by the activation and associated altered methylation of peroxisome proliferator-activated receptor gamma, the master regulator of adipogenesis, or its target genes. Importantly, studies are emerging that assess the effects of EDCs on the interplay between DNA methylation and histone modifications in altered chromatin structure. These types of studies coupled with genome-wide rather than gene-specific analyses are needed to improve mechanistic understanding of epigenetic changes by EDC exposure. Current advances in the field of epigenomics have led to the first potential epigenetic markers for obesity that can be detected at birth, providing an important basis to determine the effects of developmental exposure to obesogenic EDCs in humans. PMID- 26241074 TI - Prenatal Programming and Endocrinology. PMID- 26241075 TI - Around Consensual Nonmonogamies: Assessing Attitudes Toward Nonexclusive Relationships. AB - Consensual nonmonogamy is a term used to describe intimate romantic relationships that are sexually and/or emotionally nonexclusive. The present study examined the social norms that are violated by different forms of consensual nonmonogamy and the negative judgments that result. We asked 375 participants to rate hypothetical vignettes of people involved in one of five relationship types (monogamy, polyamory, open relationship, swinging, and cheating) on items related to relationship satisfaction, morality, and cognitive abilities. The monogamous couple was perceived most favorably, followed by the polyamorous couple, then the open and swinging couples who were rated equally. Participants judged the cheating couple most negatively. Although social norms of sexual and emotional monogamy are important, we conclude that the aspect that has the most effect on judgments is whether the relationship structure has been agreed to by all parties. PMID- 26241076 TI - Ruthenium Hydride Catalyzed Silylvinylation of Internal Alkynes Using Ethylene as an Additive. AB - An efficient synthetic strategy for the regiospecific silylvinylation of internal alkynes is described. This transformation is catalyzed by RuHCl(CO)(SIMes)PPh3 and provides a net 5-exo-dig trans-silylvinylation of internal alkynes. Ethylene was used to decrease reaction times and displayed altered selectivity at increased pressure. Furthermore, alkyl-substituted alkynes were acceptable substrates at 80 psi of ethylene. PMID- 26241077 TI - Efficacy of a Low-Tidal Volume Ventilation Strategy to Prevent Reperfusion Lung Injury after Pulmonary Thromboendarterectomy. AB - RATIONALE: Reperfusion lung injury is a postoperative complication of pulmonary thromboendarterectomy that can significantly affect morbidity and mortality. Studies in other postoperative patient populations have demonstrated a reduction in acute lung injury with the use of a low-tidal volume (Vt) ventilation strategy. Whether this approach benefits patients undergoing thromboendarterectomy is unknown. OBJECTIVES: We sought to determine if low-Vt ventilation reduces reperfusion lung injury in patients with chronic thromboembolic pulmonary hypertension undergoing thromboendarterectomy. METHODS: Patients undergoing thromboendarterectomy at one center were randomized to receive either low (6 ml/kg predicted body weight) or usual care Vts (10 ml/kg) from the initiation of mechanical ventilation in the operating room through Postoperative Day 3. The primary endpoint was the onset of reperfusion lung injury. Secondary outcomes included severity of hypoxemia, days on mechanical ventilation, and intensive care unit and hospital lengths of stay. MEASUREMENTS AND MAIN RESULTS: A total of 128 patients were enrolled and included in the analysis; 63 were randomized to the low-Vt group and 65 were randomized to the usual care group. There was no statistically significant difference in the incidence of reperfusion lung injury between groups (32%, n=20 in the low-Vt group vs. 23%, n=15 in the usual care group; P=0.367). Although differences were noted in plateau pressures (17.9 cm H2O vs. 20.1 cm H2O, P<0.001) and peak inspiratory pressures (20.4 cm H2O vs. 23.0 cm H2O, P<0.001) between the low-Vt and usual care groups, respectively, mean airway pressures, PaO2/FiO2, days on mechanical ventilation, and ICU and hospital lengths of stay were all similar between groups. CONCLUSIONS: In patients with chronic thromboembolic pulmonary hypertension undergoing pulmonary thromboendarterectomy, intra- and postoperative ventilation using low Vts (6 mg/kg) compared with usual care Vts (10 mg/kg) does not reduce the incidence of reperfusion lung injury or improve clinical outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT00747045). PMID- 26241078 TI - Biomechanical response of colonic tissue under high-speed traction. PMID- 26241079 TI - A novel approach to classifying postconcussion symptoms: The application of a new framework to the Post-Concussion Symptom Scale. AB - INTRODUCTION: Self-report measures such as the Post-Concussion Symptom Scale (PCSS) are frequently used during baseline and postconcussion testing to evaluate athletes' symptom profiles. However, the common approach of evaluating the total symptom score and/or symptom clusters may not allow for a complete understanding of the nature of athletes' symptom reporting patterns. The primary objective of this study was to apply three "global indices of distress" variables, derived from the Symptom Checklist-90-Revised (SCL-90-R) framework, to the PCSS at baseline and postconcussion. We aimed to evaluate the utility of these symptom indices in relation to four PCSS symptom clusters and the total PCSS symptom score. METHOD: Participants included college athletes evaluated at baseline (N = 846) and postconcussion (N = 86). Athletes underwent neuropsychological testing at both time points, including completion of the PCSS and a paper/pencil and computerized test battery. Eight symptom indices were derived from the PCSS, and a postconcussion neurocognitive composite score was calculated. RESULTS: Results showed that there were significant mean increases from baseline to postconcussion on four of the eight symptom indices evaluated. Furthermore, a significant proportion of athletes showed no change from baseline to postconcussion when evaluating the total symptom score, but showed at least a one standard deviation increase in symptom reporting from baseline to postconcussion when evaluating at least one other symptom index (i.e., a global index of distress or symptom cluster). Finally, the three global indices of distress variables, two of the four symptom clusters, and the total symptom score significantly predicted a postconcussion neurocognitive composite score, such that greater postconcussion symptoms were associated with lower postconcussion neurocognitive performance. CONCLUSIONS: These findings suggest that, in addition to evaluating the postconcussion total symptom score, there may be value in examining more specific symptom indices such as the global indices of distress variables and symptom clusters. PMID- 26241080 TI - Correction to "Single-Molecule FRET Studies of HIV TAR-DNA Hairpin Unfolding Dynamics". PMID- 26241081 TI - Rh(II)-Catalyzed Reactions of Diazoesters with Organozinc Reagents. AB - Rh(II)-catalyzed reactions of diazoesters with organozinc reagents are described. Diorganozinc reagents participate in reactions with diazo compounds by two distinct, catalyst-dependent mechanisms. With bulky diisopropylethyl acetate ligands, the reaction mechanism is proposed to involve initial formation of a Rh carbene and subsequent carbozincation to give a zinc enolate. With Rh2(OAc)4, it is proposed that initial formation of an azine precedes 1,2-addition by an organozinc reagent. This straightforward route to the hydrazone products provides a useful method for preparing chiral quaternary alpha-aminoesters or pyrazoles via the Paul-Knorr condensation with 1,3-diketones. Crossover and deuterium labeling experiments provide evidence for the mechanisms proposed. PMID- 26241082 TI - Synthesis of Zeolitic Imidazolate Framework Core-Shell Nanosheets Using Zinc Imidazole Pseudopolymorphs. AB - Zeolitic imidazolate frameworks (ZIFs) are an emerging class of microporous materials that possess an organic flexible scaffold and zeolite-like topology. The catalytic and molecular-separation capabilities of these materials have attracted considerable attention; however, crystal-shape engineering in ZIF materials remains in its infancy. This is the first study to report an effective method for tailoring the near-spherical crystal morphology of ZIF-8 using its leaf-like pseudopolymorph, ZIF-L. A thin, uniform layer of ZIF-8 is formed on ZIF L through heterogeneous surface growth to produce a ZIF-L@ZIF-8 core-shell nanocomposite. This results in ZIF-8 with a crystal morphology comprising two dimensional nanoflakes. We characterized the resulting core-shell crystals using a number of solid-state techniques, including powder X-ray diffraction, scanning electron microscopy, thermogravimetric analysis, and nitrogen physisorption. Approximately 16 mass% of ZIF-8 in the core-shell composites heterogeneous surfacely grown on ZIF-L core crystals. We also investigated the effects of zinc salts, which were used as a source of zinc in the formation of the ZIF-L@ZIF-8 core-shell nanocomposites. Finally, we assessed the CO2 adsorption properties of ZIF-8, ZIF-L, and ZIF-L@ZIF-8 core-shell crystals, the results of which were used to deduce the dynamic and equilibrium adsorption characteristics of various microporous ZIF crystals. The core-shell materials present hybridized CO2 uptake and diffusivity of the parent crystals. The proposed method for the synthesis of core-shell nanocomposites using pseudopolymorphic crystals is applicable to other ZIF systems. PMID- 26241083 TI - Corrigendum. PMID- 26241084 TI - Thermal Stability Limits of Imidazolium Ionic Liquids Immobilized on Metal Oxides. AB - Thermal stability limits of 33 imidazolium ionic liquids (ILs) immobilized on three of the most commonly used high surface area metal-oxides, SiO2, gamma Al2O3, and MgO, were investigated. ILs were chosen from a family of 13 cations and 18 anions. Results show that the acidity of C2H of an imidazolium ring is one of the key factors controlling the thermal stability. An increase in C2H bonding strength of ILs leads to an increase in their stability limits accompanied by a decrease in interionic energy. Systematic changes in IL structure, such as changes in electronic structure and size of anion/cation, methylation on C2 site, and substitution of alkyl groups on the imidazolium ring with functional groups have significant effects on thermal stability limits. Furthermore, thermal stability limits of ILs are influenced strongly by acidic character of the metal oxide surface. Generally, as the point of zero charge (PZC) of the metal-oxide increases from SiO2 to MgO, the interactions of IL and metal-oxide dominate over interionic interactions, and metal-oxide becomes the significant factor controlling the stability limits. However, thermal stability limits of some ILs show the opposite trend, as the chemical activities of the cation functional group or the electron donating properties of the anion alter IL/metal-oxide interactions. Results presented here can help in choosing the most suitable ILs for materials involving ILs supported on metal-oxides, such as for supported ionic liquid membranes (SILM) in separation applications or for solid catalyst with ionic liquid layer (SCILL) and supported ionic liquid phase (SILP) catalysts in catalysis. PMID- 26241085 TI - Within-Family Discussion on Harmful Effects of Smoking and Intention to Initiate Smoking Among European Adolescents. AB - OBJECTIVE: The main objective of this study was to determine the impact of discussion within family about the harmful effects of smoking on intention to initiate smoking in the long term among nonsmoking adolescents. METHODS: Data from Global Youth Tobacco Survey for 25 European countries were used. The outcomes of interest were, therefore, the intention to initiate smoking 1 and 5 years after the survey. Discussion within family about harmful effect of smoking was the main predictor with age, sex, and smoking status of parents, friends, and classmates as covariates. The association between predictors and outcomes was assessed through multiple regression analysis. RESULTS: A total of 118,703 nonsmoking adolescents were included. Within-family discussion significantly reduced the odds of intention to initiate smoking 1 and 5 years later. Intention to initiate smoking also was significantly associated with the smoking status of friends, classmates, and parents, except for father's smoking status, which was not associated with intention to initiate 1 year later. CONCLUSIONS: This study demonstrated that within-family discussion about the harmful effects of smoking may contribute to reduce the intention to start smoking among adolescents in the long term. Such a discussion was associated with reduced intention to smoke even when adjusting for parent/friend and classmate smoking. PMID- 26241086 TI - Propofol Regulates the Surface Expression of GABAA Receptors: Implications in Synaptic Inhibition. AB - BACKGROUND: The anesthetic propofol is thought to induce rapid hypnotic sedation by potentiating gamma-aminobutyric acid receptor (GABAAR) activity. Little is known about the molecular mechanisms of propofol in modulating inhibitory synaptic transmission. We aimed to investigate the role of propofol in modulating surface expression of GABAARs. METHODS: C57BL/6 mice received an intraperitoneal injection of propofol. Hippocampal pyramidal neurons were prepared from embryonic day-18 mice and were treated with propofol. Proteins on the plasma membrane were analyzed using cell surface biotinylation, immunoblotting and enzyme-linked immunosorbent assay. Electrophysiological activities were recorded from hippocampal cells in acute brain slices of mice. The interaction between GABAARs and clathrin adaptor protein 2 was assessed by immunoprecipitation. Phosphorylation of GABAARs was shown by in vitro kinase assay. RESULTS: Propofol facilitated membrane accumulation of GABAARbeta3 subunits. Propofol mediated phosphorylation of GABAARbeta3 by protein kinase Cepsilon which blocked the interaction between GABAARbeta3 and the beta-adaptin subunit of adaptor protein 2, resulting in an inhibition of the receptor endocytosis in hippocampal pyramidal neurons. Coincident with increased GABAARs surface level, propofol enhanced evoked and miniature synaptic GABA receptor currents. CONCLUSIONS: This study offers new insight on the regulatory mechanism of propofol in inhibiting neuronal excitability. PMID- 26241087 TI - Using fuzzy gap analysis to measure service quality of medical tourism in Taiwan. AB - PURPOSE: The purpose of this paper is intended to create a model to measure quality of service, using fuzzy linguistics to analyze the quality of service of medical tourism in Taiwan so as to find the direction for improvement of service quality in medical tourism. DESIGN/METHODOLOGY/APPROACH: The study developed fuzzy questionnaires based on the characteristics of medical tourism quality of service in Taiwan. Questionnaires were delivered and recovered from February to April 2014, using random sampling according to the proportion of medical tourism companies in each region, and 150 effective samples were obtained. The critical quality of service level is found through the fuzzy gap analysis using questionnaires examining expectations and perceptions of customers, as the direction for continuous improvement. FINDINGS: From the study, the primary five critical service items that improve the quality of service for medical tourism in Taiwan include, in order: the capability of the service provider to provide committed medical tourism services reliably and accurately, facility service providers in conjunction with the services provided, the cordial and polite attitude of the service provider eliciting a sense of trust from the customer, professional ability of medical (nursing) personnel in hospital and reliability of service provider. ORIGINALITY/VALUE: The contribution of this study is to create a fuzzy gap analysis to assess the performance of medical tourism service quality, identify key quality characteristics and provide a direction for improvement and development for medical tourism service quality in Taiwan. PMID- 26241088 TI - Healthy work environment--a challenge? AB - PURPOSE: In Sweden, leave due to sickness was high during the 1990s. The Swedish Social Insurance Agency was able to decrease sick days in the period between 2000 and 2010 but sick days are rising again in Sweden, mostly due to psychological problems among women and partly due to their work environment. It is important to find methods to identify poor work settings to prevent absenteeism due to sickness. The paper aims to discuss these issues. DESIGN/METHODOLOGY/APPROACH: The authors created a web questionnaire focusing on the organizational setting and its impact on employee wellbeing--reported as mental energy, work-related exhaustion and work satisfaction. The questionnaire measures good and poor work environment factors to help managers improve organizational settings. The questionnaire was validated qualitatively and quantitatively. FINDINGS: It is possible to measure individual wellbeing in an organizational context at an early stage. The authors followed a company undergoing organizational change and identified groups at risk of developing illness. PRACTICAL IMPLICATIONS: Managers uncertain about employee mental status can measure employee wellbeing easily and cost effectively to prevent illness. ORIGINALITY/VALUE: The authors created a method, statistically evaluated, to proactively identify good and poor work environments to promote healthy co-workers. PMID- 26241089 TI - Client satisfaction determinants in four Kenyan slums. AB - PURPOSE: In Kenya, gaps exist in health service provision to slum residents, especially service availability and access to quality care. There is also little information on the health status of people living in slums other than in Nairobi. The purpose of this paper is to generate evidence for use in designing interventions to improve health services in four mid-sized slums in Embu, Nyeri and Thika, Kenya. DESIGN/METHODOLOGY/APPROACH: A cross-sectional survey of clients receiving services in health facilities was conducted in the targeted slums. Data were collected through face-to-face interviews. Factor scores were generated using the Rasch model; simple and multivariate logistic regression analyses were done using the R statistical software. FINDINGS: Overall, 81 per cent of the 203 participants reported being satisfied with health services. Most clients (89 per cent) reported that health facility staff greeted them warmly; 82 per cent said their consultation was private. The facility type, waiting time and client experience with service providers determined their satisfaction (p<0.05). PRACTICAL IMPLICATIONS: Healthcare managers can improve client satisfaction levels by understanding the client flow in their facilities and addressing causes of client dissatisfaction, such as long waiting times, while at the same time promoting facilitating factors. ORIGINALITY/VALUE: The authors use latent variable modelling to compute client satisfaction scores, which were dichotomised into two categories and fitted into a logistic regression model to identify factors that influence client satisfaction. Health facility clients in the four slums are satisfied with services and have confidence the providers will serve them in a friendly and professional manner that promotes respect and quality care. The paper recommend healthcare managers in similar settings carry out client flow analysis and institute remedial measures to address long waiting times. Qualitative studies are recommended to determine the reasons behind the high satisfaction levels reported in this study. PMID- 26241090 TI - Factors affecting dental service quality. AB - PURPOSE: Measuring dental clinic service quality is the first and most important factor in improving care. The quality provided plays an important role in patient satisfaction. The purpose of this paper is to identify factors affecting dental service quality from the patients' viewpoint. DESIGN/METHODOLOGY/APPROACH: This cross-sectional, descriptive-analytical study was conducted in a dental clinic in Tehran between January and June 2014. A sample of 385 patients was selected from two work shifts using stratified sampling proportional to size and simple random sampling methods. The data were collected, a self-administered questionnaire designed for the purpose of the study, based on the Parasuraman and Zeithaml's model of service quality which consisted of two parts: the patients' demographic characteristics and a 30-item questionnaire to measure the five dimensions of the service quality. The collected data were analysed using SPSS 21.0 and Amos 18.0 through some descriptive statistics such as mean, standard deviation, as well as analytical methods, including confirmatory factor. FINDINGS: Results showed that the correlation coefficients for all dimensions were higher than 0.5. In this model, assurance (regression weight=0.99) and tangibility (regression weight=0.86) had, respectively, the highest and lowest effects on dental service quality. PRACTICAL IMPLICATIONS: The Parasuraman and Zeithaml's model is suitable to measure quality in dental services. The variables related to dental services quality have been made according to the model. ORIGINALITY/VALUE: This is a pioneering study that uses Parasuraman and Zeithaml's model and CFA in a dental setting. This study provides useful insights and guidance for dental service quality assurance. PMID- 26241091 TI - Key performance measures to control maintenance-associated HAIs. AB - PURPOSE: The purpose of this paper is to improve overall healthcare maintenance (HM) service performance in NHS infection control (IC). Hence, the authors identify critical success factors (CSFs) and key performance measures in maintenance-associated infections. These infections occur because of the poor performance of HM service in IC. DESIGN/METHODOLOGY/APPROACH: In the first Delphi exercise, complete CSFs and performance measures were presented to the Delphi participants for refinement and modification. Delphi round 1 data were analysed manually and used to refine the rounds 2 and 3 Delphi instruments. In subsequent Delphi rounds, the results were analysed through descriptive statistics. FINDINGS: In total, eight CSFs and 53 key performance measures were identified for reducing maintenance-associated infections in hospitals. For example, establishing clear communication between the infection control team (ICT) and HM unit is important for preventing maintenance-associated HAIs. Dust prevention is also identified by the healthcare experts as an important measure to prevent maintenance-associated HAIs in high-risk patient areas. ORIGINALITY/VALUE: The findings provide CSFs and key performance measures for measuring performance in HM in IC. Reducing the rate of maintenance-associated infections will have important socio-economic and health ramifications for hospitals. It will reduce cost and free up additional resources for alternative projects. It will also raise confidence among healthcare users about the quality of services provided by hospitals. PMID- 26241092 TI - Depression screening optimization in an academic rural setting. AB - PURPOSE: Primary care plays a critical role in screening and management of depression. The purpose of this paper is to focus on leveraging the electronic health record (EHR) as well as work flow redesign to improve the efficiency and reliability of the process of depression screening in two adult primary care clinics of a rural academic institution in USA. DESIGN/METHODOLOGY/APPROACH: The authors utilized various process improvement tools from lean six sigma methodology including project charter, swim lane process maps, critical to quality tree, process control charts, fishbone diagrams, frequency impact matrix, mistake proofing and monitoring plan in Define-Measure-Analyze-Improve-Control format. Interventions included change in depression screening tool, optimization of data entry in EHR. EHR data entry optimization; follow up of positive screen, staff training and EHR redesign. FINDINGS: Depression screening rate for office based primary care visits improved from 17.0 percent at baseline to 75.9 percent in the post-intervention control phase (p<0.001). Follow up of positive depression screen with Patient History Questionnaire-9 data collection remained above 90 percent. Duplication of depression screening increased from 0.6 percent initially to 11.7 percent and then decreased to 4.7 percent after optimization of data entry by patients and flow staff. RESEARCH LIMITATIONS/IMPLICATIONS: Impact of interventions on clinical outcomes could not be evaluated. ORIGINALITY/VALUE: Successful implementation, sustainability and revision of a process improvement initiative to facilitate screening, follow up and management of depression in primary care requires accounting for voice of the process (performance metrics), system limitations and voice of the customer (staff and patients) to overcome various system, customer and human resource constraints. PMID- 26241093 TI - The challenges to performance and sustaining mutual health organisations/health institutions: an exploratory study in Ghana. AB - PURPOSE: The purpose of this paper is to explore challenges to the performance and sustainability of mutual health organisations (MHOs) and health institutions towards enhancing access to quality health care (HC) in Ghana. DESIGN/METHODOLOGY/APPROACH: Data were gathered through interviews and documentary review. FINDINGS: Problems with late release of reimbursement funds for discharging with claims by the central government has impacted heavily on the financial and strategic management and decision-making processes of the MHOs and health institutions. RESEARCH LIMITATIONS/IMPLICATIONS: The lack of in-depth analysis of the financial viability of the MHOs; and the limited number of schemes selected. PRACTICAL IMPLICATIONS: Recommends the need to ensure prompt release of reimbursement funds by government to enable the MHOs to reimburse claims to health institutions. SOCIAL IMPLICATIONS: There is a perceived tension between the MHOs and HC institutions due to late release of reimbursement funds by the government. ORIGINALITY/VALUE: Contributes to understanding of how the NHI Act influences the operations of MHOs and health institutions towards increasing access to quality HC and financing. PMID- 26241094 TI - Performance improvement CME for quality: challenges inherent to the process. AB - PURPOSE: The purpose of this paper is to discuss the perspective debates upon the real-time challenges for a three-staged Performance Improvement Continuing Medical Education (PI-CME) model, an innovative and potential approach for future CME, to inform providers to think, prepare and to act proactively. DESIGN/METHODOLOGY/APPROACH: In this discussion, the challenges associated for adopting the American Medical Association's three-staged PI-CME model are reported. FINDINGS: Not many institutions in USA are using a three-staged performance improvement model and then customizing it to their own healthcare context for the specific targeted audience. They integrate traditional CME methods with performance and quality initiatives, and linking with CME credits. PRACTICAL IMPLICATIONS: Overall the US health system is interested in a structured PI-CME model with the potential to improve physicians practicing behaviors. ORIGINALITY/VALUE: Knowing the dearth of evidence for applying this structured performance improvement methodology into the design of CME activities, and the lack of clarity on challenges inherent to the process that learners and providers encounter. This paper establishes all-important first step to render the set of challenges for a three-staged PI-CME model. PMID- 26241095 TI - CONSUMERS' INTENTION TO ATTEND SOCCER EVENTS: APPLICATION AND EXTENSION OF THE THEORY OF PLANNED BEHAVIOR. AB - The purpose of this study was to identify important factors of consumers' intention to attend professional soccer events among Saudi Arabian soccer fans. To explore the decision-making process of this relatively understudied population, the theory of planned behavior was used as theoretical background. Particularly, this study measured the effect of attitude, subjective norm, perceived behavioral control (time and money), and game importance on intention to attend, and examined the moderating role of commitment. Structural equation modeling (SEM) using 231 Saudi university students (M = 21.9 yr., SD = 1.21) indicate that attitude and game importance were significantly related to attendance intention. The effect of subjective norms was significant only for the low commitment group and game importance was more important for the low than the high commitment group. PMID- 26241096 TI - TWO MEASURES FOR CROSS-CULTURAL RESEARCH ON MORALITY: COMPARISON AND REVISION. AB - The current research assessed the reliability and validity of two Western measures of morality in a Chinese sample, namely the Community, Autonomy, and Divinity Scale (CADS) and the Moral Foundations Questionnaire (MFQ). Questionnaires were administered to 274 Chinese participants in Northern China (M age = 25.4 yr., SD = 8.50; 86% women). Confirmatory factor analysis using a structural equation model was conducted to evaluate the construct validity of the two scales. The results indicated a reasonable model fit of both the CADS and the MFQ after certain modifications. The revised versions of both measures had good internal consistency reliabilities. Correlation analysis indicated moderate correlations between the dimensions of the two scales. Regarding the content of morality, Chinese people endorsed more of the traditional ethics and foundations than people from Western cultures in other studies. In addition, participants who reported a religious affiliation scored higher on the Divinity subscale compared to those who claimed to be atheists. PMID- 26241097 TI - EFFECTS OF L2 LEARNING ORIENTATIONS AND IMPLEMENTATION INTENTIONS ON SELF REGULATION. AB - In this study, a classic L2 learning orientation framework and a multi-faceted implementation intention construct were used to predict self-regulation. Attention was particularly paid to the way in which different types of implementation intentions predicted the self-regulatory capacity. A two-phase research design was executed. A pilot was conducted to ensure the reliability and validity of the scales. In the main study, a series of regression analyses examined the links among the variables of interest. The modeling results indicated that the effects of the integrative and instrumental orientations were substantially diminished after the implementation intentions were incorporated into the orientation structure. The empirical findings strongly suggest the need for L2 learners to utilize strategic planning in response to situational and temporal cues in the process of goal pursuit. Further discussions focused on the effects of both orientations and implementation intentions on the self-regulatory capacity in language learning. PMID- 26241098 TI - QUALITY OR SACRIFICE? THE INFLUENCE OF DECISION TASK AND PRODUCT CHARACTERISTICS ON THE DUAL ROLE OF PRICE. AB - People perceive price as a cue of monetary sacrifice, a quality signal, or both. However, this research proposed that the relative salience of these two roles varies with different decision tasks (i.e., selection and rejection). Furthermore, the effect of decision task type on price perception differs by product type (i.e., tangible goods or services). Two experiments show that (1) the price-quality perception under the selection task is higher than that of a rejection task for tangible goods but not for services; and (2) for goods and services, the sacrifice perception is greater in the rejection task than that in a selection task. These findings have important implications for formulating product assortment and marketing communications strategies. PMID- 26241099 TI - EXPLORING THE RELATIONS BETWEEN STUDENT CYNICISM AND STUDENT BURNOUT. AB - Research on the negative effects of student cynicism has been limited, especially regarding its relation to student burnout. This study examined the relations among student cynicism (policy cynicism, academic cynicism, social cynicism, and institutional cynicism) and student burnout, as evidenced by emotional exhaustion, depersonalization, and reduced personal accomplishment, in a sample of 276 Chinese undergraduates. Hierarchical multiple regressions showed that four aspects of student cynicism together explained substantial variance in student burnout. Policy cynicism was the strongest contributor to emotional exhaustion. Social cynicism was the primary contributor to depersonalization, and also to reduced personal accomplishment. Student cynicism overall had the strongest relationship with reduced sense of personal achievement. The findings outline the negative functional relations between student cynicism and student burnout. PMID- 26241100 TI - Metafocusing by a Metaspiral Plasmonic Lens. AB - We designed and realized a metasurface (manipulating the local geometry) spiral (manipulating the global geometry) plasmonic lens, which fundamentally overcomes the multiple efficiency and functionality challenges of conventional in-plane plasmonic lenses. The combination of spirality and metasurface achieves much more efficient and uniform linear-polarization-independent plasmonic focusing. As for functionality, under matched circularly polarized illumination the lens directs all of the power coupled to surface plasmon polaritons (SPPs) into the focal spot, while the orthogonal polarization excites only diverging SPPs that do not penetrate the interior of the lens, achieving 2 orders of magnitude intensity contrast throughout the entire area of the lens. This optimal functional focusing is clearly demonstrated by near-field optical microscopy measurements that are in excellent agreement with simulations and are supported by a detailed theoretical interpretation of the underlying mechanisms. Our results advance the field of plasmonics toward functional detection and the employment of SPPs in smart pixels, near-field microscopy, lithography, and particle manipulation. PMID- 26241101 TI - Degradation and beyond: the macrophage lysosome as a nexus for nutrient sensing and processing in atherosclerosis. AB - PURPOSE OF REVIEW: The ability of macrophage lysosomes to degrade both exogenous and internally derived cargo is paramount to handling the overabundance of lipid and cytotoxic material present in the atherosclerotic plaque. We will discuss recent insights in both classical and novel functions of the lysosomal apparatus, as it pertains to the pathophysiology of atherosclerosis. RECENT FINDINGS: Lipid mediated dysfunction in macrophage lysosomes appears to be a critical event in plaque progression. Consequences include enhanced inflammatory signalling [particularly the inflammasome/interleukin-1beta axis] and an inability to interface with autophagy leading to a proatherogenic accumulation of dysfunctional organelles and protein aggregates. Aside from degradation, several novel functions have recently been ascribed to lysosomes, including involvement in macrophage polarization, generation of lipid signalling intermediates and serving as a nutrient depot for mechanistic target of rapamycin activation, each of which can have profound implications in atherosclerosis. Finally, the discovery of the transcription factor transcription factor EB as a mechanism of inducing lysosomal biogenesis can have therapeutic value by reversing lysosomal dysfunction in macrophages. SUMMARY: Lysosomes are a central organelle in the processing of exogenous and intracellular biomolecules. Together with recent data that implicate the degradation products of lysosomes in modulation of signalling pathways, these organelles truly do lay at a nexus in nutrient sensing and processing. Dissecting the full repertoire of lysosome function and ensuing dysfunction in plaque macrophages is pivotal to our understanding of atherogenesis. PMID- 26241102 TI - Neovascularization of the atherosclerotic plaque: interplay between atherosclerotic lesion, adventitia-derived microvessels and perivascular fat. AB - PURPOSE OF REVIEW: Neovascularization is a prominent feature in advanced human atherosclerotic plaques. This review surveys recent evidence for and remaining uncertainties regarding a role of neovascularization in atherosclerotic plaque progression. Specific emphasis is given to hypoxia, angiogenesis inhibition, and perivascular adipose tissue (PVAT). RECENT FINDINGS: Immunohistochemical and imaging studies showed a strong association between hypoxia, inflammation and neovascularization, and the progression of the atherosclerotic plaque both in humans and mice. Whereas in humans, a profound invasion of microvessels from the adventitia into the plaque occurs, neovascularization in mice is found mainly (peri)adventitially. Influencing neovascularization in mice affected plaque progression, possibly by improving vessel perfusion, but supportive clinical data are not available. Whereas plaque neovascularization contributes to monocyte/macrophage accumulation in the plaque, lymphangiogenesis may facilitate egress of cells and waste products. A specific role for PVAT and its secreted factors is anticipated and wait further clinical evaluation. SUMMARY: Hypoxia, inflammation, and plaque neovascularization are associated with plaque progression as underpinned by recent imaging data in humans. Recent studies provide new insights into modulation of adventitia-associated angiogenesis, PVAT, and plaque development in mice, but there is still a need for detailed information on modulating human plaque vascularization in patients. PMID- 26241103 TI - Eremophilane Sesquiterpenes and Polyketones Produced by an Endophytic Guignardia Fungus from the Toxic Plant Gelsemium elegans. AB - A cultured endophytic fungus, Guignardia mangiferae, isolated from the toxic plant Gelsemium elegans yielded five new sesquiterpenes (1-5), two new polyketones (6 and 7), and two known terpene polyketones (8 and 9). Their structures were elucidated using spectroscopic methods. On the basis of circular dichroism, the absolute configurations of the new compounds were determined. Compounds 1, 3, 4, and 9 inhibited lipopolysaccharide-induced NO production in BV2 cells with IC50 values of 15.2, 6.4, 4.2, and 4.5 MUM, respectively (positive control curcumin, IC50 = 3.9 MUM). PMID- 26241104 TI - Electronic and structural properties of vacancies and hydrogen adsorbates on trilayer graphene. AB - Using ab initio calculations, we study the electronic and structural properties of vacancies and hydrogen adsorbates on trilayer graphene. Those defects are found to share similar low-energy electronic features, since they both remove a p(z) electron from the honeycomb lattice and induce a defect level near the Fermi energy. However, a vacancy also leaves unpaired sigma electrons on the lattice, which lead to important structural differences and also contribute to magnetism. We explore both ABA and ABC stackings and compare properties such as formation energies, magnetic moments, spin density and the local density of states (LDOS) of the defect levels. These properties show a strong sensitivity to the layer in which the defect is placed and smaller sensitivities to sublattice placing and stacking type. Finally, for the ABC trilayer, we also study how these states behave in the presence of an external field, which opens a tunable gap in the band structure of the non-defective system. The p(z) defect states show a strong hybridization with band states as the field increases, with reduction and eventually loss of magnetization, and a non-magnetic, midgap-like state is found when the defect is at the middle layer. PMID- 26241105 TI - In memory of Giovanni Berlinguer. The Man, the Scientist, the Politician. AB - On this occasion I am very grateful to the Academic Authorities for having asked me to illustrate the life of Giovanni Berlinguer as a Researcher, a Professor and a Doctor of Public Health. I will try to fulfill this duty, perhaps with some reservations, because I find it almost impossible to think of Giovanni as a researcher and a professor separately from his complex personality and his role as a politician and a brilliant and prolific writer. This is because Giovanni was an inextricable combination of all these roles, which cannot be described separately. PMID- 26241106 TI - Epidemiological profile of cancer mortality in a province of central Italy for the years 2008 and 2009: preliminary analysis. AB - BACKGROUND: The aim of the study was to perform a preliminary analysis of the mortality data for cancer as widely as possible, in order to obtain useful information for planning specific public health interventions. For this purpose, data on cancer mortality in the province of Rieti (Latium, central Italy) have been collected and analysed. To date, in the Rieti province a Cancer Registry record is not available. METHODS: The study was conducted through statistical analysis of cancer mortality data related to the years 2008 and 2009, obtained from the National Institute of Statistics. Data were cumulative for the province of Rieti and specific for the five districts in which the province is divided. RESULTS: The standardized mortality rates obtained for Rieti province resulted lower than those reported for the other provinces of the Latium region, for Italy and for the European Community, both for 2008 and 2009. In these years, the anatomical areas more affected in terms of mortality were "trachea, bronchus and lung", "colorectal" and "stomach", but gender differences were evidenced. CONCLUSIONS: The present study, also considering the limitation of two years studied only, leads to some basic insights about the importance of updating mortality data to trace an epidemiological profile, to evaluate the presence of risk and protective factors, to program strategically health interventions, and to assess the effectiveness of these interventions. PMID- 26241107 TI - Survey on professional training in three Italian. Post-Graduate Schools of Public Health. AB - BACKGROUND: In 2005 the European Union (EU) recognized the equivalence within its member states of qualifications conferred by post-graduate schools (PGS) in public health. In Italy, ministerial decree no. 176 of 1st August 2005 defined the training goals and the related training programmes (Training Activities) leading to conferral of the qualification of specialist in Public Health and Preventive Medicine (PHPM). This study aimed to develop and validate an assessment tool for professional training programmes. The purpose has been to identify and evaluate their typical features and, at the same time, to enable comparison between Italian PGSs in PHPMs. METHODS: In the first phase, a multiple choice questionnaire was created, using a Likert scale with scores from 1 to 6. This was prepared by post-graduates attending the Milan PGS. This tool was validated by applying it to a pilot sample of post-graduates attending the Milan PGS in PHPM. Following this, a second round of discussion and validation of the model took place, involving 61 post-graduates attending PGSs in PHPM at the Universities of Palermo, Pisa and Turin. A web platform was used that enabled the survey to be created and managed by defining and managing pre-set interview templates. RESULTS: The questionnaire consisted of three sections: Section A - Twenty-eight percent of post-graduates attended their training programme in a university or research centre, 29.8% in a hospital and 35.1% in a Local Health Unit. This training program lasted more than 12 months in 37% of the cases. Section B - The answers were all above pass-level (3 to 4 = satisfactory) except as regards the level of empowerment and the workload, which was judged to be unsatisfactory overall.The skills of the staff present in the facility attended were judged favourably (3.5). Section C - Section C investigates the duration and autonomy of the activities performed during the training programmes aimed at meeting the training requirements set out in ministerial decree no. 176/2005. Among respondents, 87% had taken part in ongoing statistical public health analyses, 81% had given presentations and contributed posters in public health congresses and 79% had planned or implemented an epidemiological survey. CONCLUSIONS: A pre-set form for the assessment of training programmes by the post graduates themselves is a useful tool with which to obtain their feedback. Public health providers must be able to view their training programme as a means of developing the numerous skills the profession requires. Eventually, they must be capable of acting autonomously, and to this end they need to interact with the numerous tutors with whom they come into contact. These latter were judged very favourably by the survey. PMID- 26241108 TI - Exploration study on mortality trends in the territory surrounding an incineration plant of urban solid waste in the municipality of Vercelli (Piedmont, Italy) 1988-2009. AB - BACKGROUND: The places, where the incinerators are located, often present problems of heterogeneous people having different environmental factors. It becomes important to evaluate the possible etiologic role of various environmental risk factors and try to quantify as they affect in the excess epidemiological. METHODS: This study considers the ISTAT index mortality due to all causes occurred from 1988 to 2009 referred to ten municipalities at south of Vercelli (Piedmont, North Western Italy) placed nearby the active incinerator from 1977 (10 latent years). The risks were calculated considering this area at risk versus the municipalities placed at North of Vercelli and versus the Vercelli. RESULTS: Some significant statically excesses emerged in the South area such as neoplasia of nervous system, liver and total of tumours. CONCLUSIONS: The study presents some drawbacks, but it is a work creditable of widening by specific research ad hoc such as cohort and/or control where it is possible to verify various environmental, occupational and occasional factors. PMID- 26241110 TI - Campaigns against smoking: a review of the last ten years in Italy. AB - BACKGROUND: The latest collection of epidemiologic data shows the increased prevalence of smoking among young people and women. The research presents a descriptive analysis of the major anti-smoking campaigns that took place from 2006 to 2014 in Italy by institutions, associations, federations and enterprises who where both nationally and internationally recognized. METHODS: The categories of analysis used were: target, communication strategy, style, website and/or a free number. A qualitative analysis was then conducted on campaigns aimed at women and young people, to identify strengths and weaknesses of the campaigns. RESULTS: In the area of tobacco consumption there are numerous activities of information/awareness/prevention but it is necessary to interfere more directly in young people's lives, and in particular in young women's lives. CONCLUSIONS: The need for more efficacy from campaigns means that they need to be more open to the unconventional social advertising and social network. PMID- 26241109 TI - Feasibility and reliability of a questionnaire for evaluation of the exposure to indoor and outdoor air pollutants, diet and physical activity in 6-8-year-old children. AB - INTRODUCTION: The MAPEC-Life project aims to study the biological effects of early exposure to air pollutants on the oral mucosa cells of school-age children in five Italian cities. A questionnaire was created to evaluate the association between outdoor and indoor airborne pollutants, lifestyle, diet and biomarker effects. The feasibility and reliability of the questionnaire were evaluated. METHODS: A questionnaire was drawn up to be filled in by the parents of 6-8-year old children. It consisted of 148 questions on the children's health, physical activity, environmental exposures and the frequency of food consumption at the main meals. First we conducted a questionnaire feasibility study involving 53 volunteer parents. We then performed a reliability study by administering the questionnaire to a further 156 parents and again one month later (test/retest method). The correlations between answers at the first and second administration of the questionnaire were evaluated using the Kappa statistic and Spearman's coefficient. RESULTS: After verifying the feasibility of the questionnaire, we conducted a reliability analysis on 132 completed questionnaires. The percentage of agreement between the first and the second responses given was over 70%, all K values being greater than 0.6. The analysis of calories and macronutrients also showed good agreement. CONCLUSIONS: The questionnaire drawn up for the study proved to be sufficiently reliable for gathering information about the factors of interest in our study of the relationship between air pollution and early biological effects in children. PMID- 26241111 TI - Violence against women in Rome: An analysis of cases treated in the gynecology emergency department of the hospital Umberto I between 1999 and 2013. AB - BACKGROUND: The gynecological emergency department of the Policlinico Umberto I, Rome sees an average of about 30 cases of violence against females each year. It is stressed that these cases are not representative of all cases of violence against women in Rome and they cannot be used to estimate the prevalence or incidence of the phenomenon, but they may provide some insight on the victims and their aggressors, the use of drugs or alcohol, factors which may affect the decision to report the attack to the police and attacks on children. METHODS: The case records of all 458 females seen in the emergency department between 1999 and 2013 were retrieved, data were extracted and an Excel worksheet was prepared. Temporal variation in the numbers of cases, the types of aggression, the use of drugs or alcohol, reporting the attack to the police and violence against children were specifically investigated using frequency tabulations and appropriate statistical tests. RESULTS: There has been little change in the number of cases seen during the 15 year period; there is no significant seasonal effect or difference between the days of the week. Just over half of the attacks were reported to the police, but this was less likely among the older victims. About 87% of the cases involved vaginal and/or anal penetration. The use of drugs and/or alcohol was most common, 43%, among unmarried women aged 21-25. There were 32 cases of violence against children aged under 16. CONCLUSIONS: There has been little change in the number and characteristics of violent attacks on women seen at this large hospital in Rome over the years 1999-2013.These cases provide little information about the general epidemiology of violence against women, although they do imply that this great social and cultural problem continues unabated in Rome. PMID- 26241112 TI - The Walking Suitability Index of the Territory (T-WSI): a new tool to evaluate urban neighborhood walkability. AB - AIM: To design an easy method to evaluate the walkability of an urban neighborhood, in order to support Public Administrations in the decision making related to urban health policy and local development. METHODS: The tool, called the Walking Suitability Index of the territory (T-WSI), has been further developed by our team. T-WSI is applied to each street of an environmental area. It includes 12 indicators subdivided into 4 categories: practicability, safety, urbanity, pleasurableness. Data collected in each street are inserted in an algoritm to perform weighted sums and to aggregate the indicators and the categories, up to compute the final index. To validate T-WSI an experimental study was carried out in two environmental areas of Rome: "San Saba" and "Sacco Pastore". RESULTS: The average index is: 58.6 for the neighborhood "San Saba" and for 55.1 for "Sacco Pastore. Both results detected gaps in the design for pedestrian use of public spaces. Among the analysed categories, Safety showed the worst results in both neighborhoods, mainly for the lack of "protection from vehicle speed". CONCLUSIONS: The developed tool is easy to use, inexpensive, sensible and reproducible, offering a good basis for urban health policy decisions. The relevance of the tool stands on the survey methodology, based on the direct and objective observation of the context. PMID- 26241113 TI - Do Italian housing regulations and policies protect poor people's health? PMID- 26241114 TI - Long-Term Trends Worldwide in Ambient NO2 Concentrations Inferred from Satellite Observations. AB - BACKGROUND: Air pollution is associated with morbidity and premature mortality. Satellite remote sensing provides globally consistent decadal-scale observations of ambient nitrogen dioxide (NO2) pollution. OBJECTIVE: We determined global population-weighted annual mean NO2 concentrations from 1996 through 2012. METHODS: We used observations of NO2 tropospheric column densities from three satellite instruments in combination with chemical transport modeling to produce a global 17-year record of ground-level NO2 at 0.1 degrees * 0.1 degrees resolution. We calculated linear trends in population-weighted annual mean NO2 (PWMNO2) concentrations in different regions around the world. RESULTS: We found that PWMNO2 in high-income North America (Canada and the United States) decreased more steeply than in any other region, having declined at a rate of -4.7%/year [95% confidence interval (CI): -5.3, -4.1]. PWMNO2 decreased in western Europe at a rate of -2.5%/year (95% CI: -3.0, -2.1). The highest PWMNO2 occurred in high income Asia Pacific (predominantly Japan and South Korea) in 1996, with a subsequent decrease of -2.1%/year (95% CI: -2.7, -1.5). In contrast, PWMNO2 almost tripled in East Asia (China, North Korea, and Taiwan) at a rate of 6.7%/year (95% CI: 6.0, 7.3). The satellite-derived estimates of trends in ground level NO2 were consistent with regional trends inferred from data obtained from ground-station monitoring networks in North America (within 0.7%/year) and Europe (within 0.3%/year). Our rankings of regional average NO2 and long-term trends differed from the satellite-derived estimates of fine particulate matter reported elsewhere, demonstrating the utility of both indicators to describe changing pollutant mixtures. CONCLUSIONS: Long-term trends in satellite-derived ambient NO2 provide new information about changing global exposure to ambient air pollution. Our estimates are publicly available at http://fizz.phys.dal.ca/~atmos/martin/?page_id=232. PMID- 26241115 TI - Queer in STEM: Workplace Experiences Reported in a National Survey of LGBTQA Individuals in Science, Technology, Engineering, and Mathematics Careers. AB - A survey of individuals working in science, technology, engineering, and mathematics (STEM) fields who identify as lesbian, gay, bisexual, trans*, queer, or asexual (LGTBQA) was administered online in 2013. Participants completed a 58 item questionnaire to report their professional areas of expertise, levels of education, geographic location, and gender and sexual identities and rated their work and social communities as welcoming or hostile to queer identities. An analysis of 1,427 responses to this survey provided the first broad portrait of this population, and it revealed trends related to workplace practices that can inform efforts to improve queer inclusivity in STEM workplaces. PMID- 26241116 TI - Externally and Internally Functionalized Copper(II) beta-Diketonate Molecular Squares. AB - Five functionalized bis(beta-diketones) and their Cu(II) molecular squares are described. The new bis(beta-diketones), m-pbhxH2 (3), 5-MeO-m-pbaH2 (4), 5-BuO-m pbaH2 (5), 2-MeO-m-pbaH2 (6), and 2-MeO-m-pbprH2 (7), were prepared by reaction of the corresponding aldehydes with phospholenes, as we previously reported for m pbaH2 (1) and m-pbprH2 (2). Ligand 3 has long alkyl chains in its beta-diketone moieties, while ligands 4-7 have alkoxy substituents on their aromatic rings. When treated with Cu(2+), the new bis(beta-diketones) 3, 4, 5, and 7 afford molecular squares, Cu4(m-pbhx)4 (10), Cu4(5-MeO-m-pba)4 (11), Cu4(5-BuO-m-pba)4 (12), and Cu4(2-MeO-m-pbpr)4 (13), respectively. Two of the new molecular squares, 10 and 12, contain longer-chain substituents and are soluble in a wider range of organic solvents. The other squares, 11 and 13, contain external and internal methoxy groups, respectively, and they show smaller changes in solubility. Single-crystal X-ray analyses are reported for three of the molecular squares without guest molecules, and for five adducts of the squares with sigma- (polypyridine) and pi-bonded (fullerene) guests. The Cu...Cu distances in the "empty" squares range from 14.047 to 14.904 A; those in the adducts vary over a wider range depending on the guest molecule involved. PMID- 26241118 TI - Multiparametric Ultrasound (MPUS) Imaging: Terminology Describing the Many Aspects of Ultrasonography. PMID- 26241119 TI - Normal Doppler Reference Values of the Pericallosal Artery. AB - PURPOSE: To provide the normal reference values of the Doppler flow of the pericallosal artery in relation to gestational age from 18 to 41 weeks of gestation. MATERIALS AND METHODS: The pericallosal artery (PCA) was studied in 466 normal pregnancies. The pulsed Doppler evaluation of the pericallosal artery was done in A3 and A4 segments, and records from PI, RI and Vmax were studied. RESULTS: The resistance index of the pericallosal artery in A3/A4 segments exhibits a plateau from 18 to 31 weeks of gestation. After 31 weeks, a marked decrease becomes apparent. The pulsatility index of the pericallosal artery in A3/A4 segments shows a plateau until 36 weeks of gestation. During the final weeks of gestation, there is a decrease in the pulsatility index. Vmax exhibits a plateau for the maximal flow velocity in A3/A4 segments of the pericallosal artery from 18 to 28 weeks of gestation. After 28 weeks of gestation, there is a slight increase in Vmax. CONCLUSION: Normal reference values of the pericallosal artery might have an impact on clinical judgment during adaptive hemodynamic changes and regarding the progression of the fetal deterioration occurring in the presence of fetal hypoxia. PMID- 26241117 TI - Probing Site-Specific Structural Information of Peptides at Model Membrane Interface In Situ. AB - Isotope labeling is a powerful technique to probe detailed structures of biological molecules with a variety of analytical methods such as NMR and vibrational spectroscopies. It is important to obtain molecular structural information on biological molecules at interfaces such as cell membranes, but it is challenging to use the isotope labeling method to study interfacial biomolecules. Here, by individually (13)C?(16)O labeling ten residues of a peptide, Ovispirin-1, we have demonstrated for the first time that a site specific environment of membrane associated peptide can be probed by the submonolayer surface sensitive sum frequency generation (SFG) vibrational spectroscopy in situ. With the peptide associated with a single lipid bilayer, the sinusoidal trend of the SFG line width and peak-center frequency suggests that the peptide is located at the interface beneath the lipid headgroup region. The constructive interferences between the isotope labeled peaks and the main peptide amide I peak contributed by the unlabeled components were used to determine the membrane orientation of the peptide. From the SFG spectral peak center frequency, line width, and polarization dependence of the isotope labeled units, we deduced structural information on individual units of the peptide associated with a model cell membrane. We also performed molecular dynamics (MD) simulations to understand peptide-membrane interactions. The physical pictures described by simulation agree well with the SFG experimental result. This research demonstrates the feasibility and power of using isotope labeling SFG to probe molecular structures of interfacial biological molecules in situ in real time. PMID- 26241120 TI - Congress Report of the Dreilandertreffen 2014, Innsbruck. Sonography of the Abdomen. PMID- 26241121 TI - Letter to the Editor: Ultrasound Detection of the Disconnected Distal Catheter of a Ventriculoperitoneal Shunt in the Pelvic Region. PMID- 26241123 TI - Improvement of Physical Decline Through Combined Effects of Muscle Enhancement and Mitochondrial Activation by a Gastric Hormone Ghrelin in Male 5/6Nx CKD Model Mice. AB - Because a physical decline correlates with an increased risk of a wide range of disease and morbidity, an improvement of physical performance is expected to bring significant clinical benefits. The primary cause of physical decline in 5/6 nephrectomized (5/6Nx) chronic kidney disease model mice has been regarded as a decrease in muscle mass; however, our recent study showed that a decrease in muscle mitochondria plays a critical role. In the present study, we examined the effects of a gastric hormone ghrelin, which has been reported to promote muscle mitochondrial oxidation, on the physical decline in the chronic kidney disease model mice, focusing on the epigenetic modulations of a mitochondrial activator gene, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC 1alpha). Ghrelin treatment improved a decline in exercise endurance of 5/6Nx mice, associated with an increase in both of the muscle mass and mitochondrial amount. The expression level of PGC-1alpha was decreased in the skeletal muscle of 5/6Nx mice, which was associated with an increase in the methylation ratio of the cytosine residue at 260 base pairs upstream of the initiation point. Conversely, ghrelin treatment de-methylated the cytosine residue and increased the expression of PGC-1alpha. A representative muscle anabolic factor, IGF-1, did not affect the expression of PGC-1alpha and muscle mitochondrial amount, although it increased muscle mass. As a result, IGF-1 treatment in 5/6Nx mice did not increase the decreased exercise endurance as effectively as ghrelin treatment did. These findings indicate an advantage of ghrelin treatment for a recovery of physical decline. PMID- 26241122 TI - A Transcriptome-Led Exploration of Molecular Mechanisms Regulating Somatostatin Producing D-Cells in the Gastric Epithelium. AB - The stomach epithelium contains a myriad of enteroendocrine cells that modulate a range of physiological functions, including postprandial secretion of regulatory peptides, gastric motility, and nutrient absorption. Somatostatin (SST)-producing D-cells are present in the oxyntic and pyloric regions of the stomach, and provide a tonic inhibitory tone that regulates activity of neighboring enteroendocrine cells and gastric acid secretion. Cellular mechanisms underlying the effects of regulatory factors on gastric D-cells are poorly defined due to problems in identifying primary D-cells, and uncertainty remains about which stimuli influence D-cells directly. In this study, we introduce a transgenic mouse line, SST-Cre, which upon crossing with Cre reporter strains, facilitates the identification and purification of gastric D-cells, or cell-specific expression of genetically encoded calcium indicators. Populations of D-cells from the gastric antrum and corpus were isolated and analyzed by RNA sequencing and quantitative RT-PCR. The expression of hormones, hormone receptors, neurotransmitter receptors, and nutrient receptors was quantified. Pyy, Gipr, Chrm4, Calcrl, Taar1, and Casr were identified as genes that are highly enriched in D-cells compared with SST-negative cells. Hormone secretion assays performed in mixed gastric epithelial cultures confirmed that SST secretion is regulated by incretin hormones, cholecystokinin, acetylcholine, vasoactive intestinal polypeptide, calcitonin gene-related polypeptide, oligopetides, and trace amines. Cholecystokinin and oligopeptides elicited increases in intracellular calcium in single-cell imaging experiments performed using cultured D-cells. Our data provide the first transcriptomic analysis and functional characterization of gastric D-cells, and identify regulatory pathways that underlie the direct detection of stimuli by this cell type. PMID- 26241125 TI - Synthesis of Benzofulvene Derivatives from Diarylacetylenes via Pd(II)-Catalyzed Alkyne-Directed C(sp(2))-H Bond Activation. AB - A novel and efficient protocol for the synthesis of benzofulvene derivatives from easily available diarylacetylenes has been developed. The reaction proceeds through rarely reported carboxylate-assisted alkyne-directed ortho-C(sp(2))-H palladation followed by insertion of another diarylacetylene. PMID- 26241124 TI - Age-Related Hearing Loss and Degeneration of Cochlear Hair Cells in Mice Lacking Thyroid Hormone Receptor beta1. AB - A key function of the thyroid hormone receptor beta (Thrb) gene is in the development of auditory function. However, the roles of the 2 receptor isoforms, TRbeta1 and TRbeta2, expressed by the Thrb gene are unclear, and it is unknown whether these isoforms promote the maintenance as well as development of hearing. We investigated the function of TRbeta1 in mice with a Thrb(b1) reporter allele that expresses beta-galactosidase instead of TRbeta1. In the immature cochlea, beta-galactosidase was detected in the greater epithelial ridge, sensory hair cells, spiral ligament, and spiral ganglion and in adulthood, at low levels in the hair cells, support cells and root cells of the outer sulcus. Although deletion of all TRbeta isoforms causes severe, early-onset deafness, deletion of TRbeta1 or TRbeta2 individually caused no obvious hearing loss in juvenile mice. However, over subsequent months, TRbeta1 deficiency resulted in progressive loss of hearing and loss of hair cells. TRbeta1-deficient mice had minimal changes in serum thyroid hormone and thyrotropin levels, indicating that hormonal imbalances were unlikely to cause hearing loss. The results suggest mutually shared roles for TRbeta1 and TRbeta2 in cochlear development and an unexpected requirement for TRbeta1 in the maintenance of hearing in adulthood. PMID- 26241126 TI - The Nature and Impact of Gendered Patterns of Peer Sexual Communications Among Heterosexual Emerging Adults. AB - Although previous research demonstrates that peers serve as top sexual informants and advisers, little is known about how peer sexual communications may be a gendered phenomenon. Do communications about sex and romantic relationships vary according to who is speaking to whom? The current study examined 517 college students' reports of male and female peers' communications of four sexual scripts and the associations between reports of such communications and participants' sexual attitudes and levels of sexual and dating experience. Results suggest that peer messages about sex and relationships vary by the gender of the recipient and the gender of the communicator. Women reported more frequent communications of all sexual scripts from female peers than did men. In terms of male peers' sexual communications, only one gender difference emerged: men reported receiving significantly fewer messages about the relational script than women. Compared to same-sex peer communications, there were more associations between other-sex peer communications and undergraduates' sexual attitudes and levels of sexual and dating experience. Implications for the role of same- and other-sex peers in sexual socialization are discussed. PMID- 26241127 TI - A retrospective clinical study on 37 subtalar arthrodesis patients of nine years follow-up. AB - BACKGROUND: Subtalar arthrodesis is a common therapy for subtalar joint disorders. In this article, we evaluate the effect of subtalar arthrodesis on the ankle and hindfoot joints. METHODS: Fifty patients (33 men and 17 women) underwent subtalar arthrodesis between January 1, 1996, and August 31, 2011. The 36-item Short-Form Health Survey and American Orthopaedic Foot and Ankle Society ankle hindfoot scores were used for clinical evaluation. Radiographic analysis included assessment of degenerative changes and ankle and hindfoot joint function in the frontal and sagittal planes. RESULTS: Thirty-seven patients (27 men and 10 women; mean age, 42.6 years) were followed up for an average of 9.2 years (range, 2-17 years). The mean +/- SD 36-item Short-Form Health Survey score improved from 30.21 +/- 7.19 before surgery to 78.50 +/- 12.23, and the American Orthopaedic Foot and Ankle Society ankle hindfoot score increased from 50.32 +/- 12.39 to 73.14 +/- 15.44. Degenerative changes in the talonavicular, calcaneocuboid, metatarsocuboid, and ankle joints occurred. The talar-vertical angle was positively related to the tibial-plantar minimal angle (affected side: r = 0.56; P < .01; healthy side: r = 0.46; P < .01). The difference in hindfoot height is positively related to the difference in tibial-plantar minimal angle (r = 0.54; P < .01). CONCLUSIONS: Subtalar arthrodesis is effective treatment for subtalar joint disease but could induce joint degeneration and ankle joint motion limitation related to talar declination and hindfoot height. PMID- 26241128 TI - Validity of a musculoskeletal model using two different geometries for estimating hip contact forces during normal walking. PMID- 26241129 TI - Mono- and Dinuclear Heteroleptic Cobalt Complexes with alpha-Diimine and Polyarene Ligands. AB - Reactions of the dimeric cobalt complex [(L(-) Co)2 ] (1, L=[(2,6-iPr2 C6 H3 )NC(Me)]2 ) with polyarenes afforded a series of mononuclear and dinuclear complexes: [LCo(eta(4) -anthracene)] (2), [LCo(MU-eta(4) :eta(4) naphthalene)CoL] (3), and [LCo(MU-eta(4) :eta(4) -phenanthrene)CoL] (4). The pyrene complexes [{Na2 (Et2 O)2 }{LCo(MU-eta(3) :eta(3) -pyrene)CoL}] (5) and [{Na2 (Et2 O)3 }{LCo(eta(3) -pyrene)}] (6) were obtained by treating precursor 1 with pyrene followed by reduction with Na metal. These complexes contain three potential redox active centers: the cobalt metal and both alpha-diimine and polyarene ligands. Through a combination of X-ray crystallography, EPR spectroscopy, magnetic susceptibility measurement, and DFT computations, the electronic configurations of these complexes were studied. It was determined that complexes 2-4 have a high-spin Co(I) center coupled with a radical alpha-diimine ligand and a neutral polyarene ligand. Whereas, the ligand L in complexes 5 and 6 has been further reduced to the dianion, the cobalt remains in a formal (I) oxidation state, and the pyrene molecule is either neutral or monoanionic. PMID- 26241130 TI - Adhesive and Reinforcing Properties of Soluble Cellulose: A Repulpable Adhesive for Wet and Dry Cellulosic Substrates. AB - This work reports, for the first time, the excellent performance of an aqueous alkaline solution of cellulose as an adhesive for wet and dry cellulosic substrates. Uniaxial tensile tests of filter paper and sulfite writing paper strips bonded with this adhesive (5% cellulose and 7% NaOH aqueous solution) show that failure never occurs in the joints but always in the pristine substrate areas, except in butt joint samples prepared with sulfite paper. Tensile test also shows that paper impregnated with cellulose solution is stronger than the original substrate. X-ray microtomography and scanning electron microscopy reveal that dissolved cellulose fills the gaps between paper fibers, providing a morphological evidence for the mechanical interlocking adhesion mechanism, while scanning probe techniques provide a sharp view of different domains in the joints. Additionally, bonded paper is easily reconverted to pulp, which facilitates paper reprocessability, solving a well-known industrial problem related to deposition of adhesive aggregates (stickies) on the production equipment. PMID- 26241131 TI - The MeJA-inducible copper amine oxidase AtAO1 is expressed in xylem tissue and guard cells. AB - Copper amine oxidases oxidize the polyamine putrescine to 4-aminobutanal with the production of the plant signal molecule hydrogen peroxide (H2O2) and ammonia. The Arabidopsis (Arabidopsis thaliana) gene At4g14940 (AtAO1, previously referred to as ATAO1) encodes an apoplastic copper amine oxidase expressed in lateral root cap cells and developing xylem, especially in root protoxylem and metaxylem precursors. In our recent study, we demonstrated that AtAO1 expression is strongly induced in the root vascular tissues by the wound-signal hormone methyl jasmonate (MeJA). Furthermore, we also demonstrated that the H2O2 derived by the AtAO1-driven oxidation of putrescine, mediates the MeJA-induced early protoxylem differentiation in Arabidopsis roots. H2O2 may contribute to protoxylem differentiation by signaling developmental cell death and by acting as co substrate in peroxidase-mediated cell wall stiffening and lignin polymerization. Here, by the means of AtAO1 promoter::green fluorescent protein-beta glucuronidase (AtAO1::GFP-GUS) fusion analysis, we show that a strong AtAO1 gene expression occurs also in guard cells of leaves and flowers. The high expression levels of AtAO1 in tissues or cell types regulating water supply and water loss may suggest a role of the encoded protein in water balance homeostasis, by modulating coordinated adjustments in anatomical and functional features of xylem tissue and guard cells during acclimation to adverse environmental conditions. PMID- 26241132 TI - Open-MRI measures of cam intrusion for hips in an anterior impingement position relate to acetabular contact force. AB - Open MRI in functional positions has potential to directly and non-invasively assess cam femoroacetabular impingement (FAI). Our objective was to investigate whether open MRI can depict intrusion of the cam deformity into the intra articular joint space, and whether intrusion is associated with elevated acetabular contact force. Cadaver hips (9 cam; 3 controls) were positioned in an anterior impingement posture and imaged using open MRI with multi-planar reformatting. The beta-angle (describing clearance between the femoral neck and acetabulum) was measured around the entire circumference of the femoral neck. We defined a binary "MRI cam-intrusion sign" (positive if beta < 0 degrees ). We then instrumented each hip with a piezoresistive sensor and conducted six repeated positioning trials, measuring acetabular contact force (F). We defined a binary "contact-force sign" (positive if F > 20N). Cam hips were more likely than controls to have both a positive MRI cam-intrusion sign (p = 0.0182, Fisher's exact test) and positive contact-force sign (p = 0.0083), which represents direct experimental evidence for cam intrusion. There was also a relationship between the MRI cam-intrusion sign and contact-force sign (p = 0.033), representing a link between imaging and mechanics. Our findings indicate that open MRI has significant potential for in vivo investigation of the cam FAI mechanism. PMID- 26241133 TI - Masquerade. AB - John Skelhorn introduces masquerade, a strategy of prey animals to resemble inanimate (and inedible) objects. PMID- 26241134 TI - Endogenous retroviruses. AB - Endogenous retroviruses are integral features of vertebrate genomes. Here, Hayward and Katzourakis offer a glimpse into the fascinating world of these mysterious partners in our evolution. PMID- 26241135 TI - Human colour perception changes between seasons. PMID- 26241136 TI - Isotropic incorporation of SPD-5 underlies centrosome assembly in C. elegans. PMID- 26241138 TI - Two gut community enterotypes recur in diverse bumblebee species. PMID- 26241137 TI - Different Drosophila cell types exhibit differences in mitotic centrosome assembly dynamics. PMID- 26241139 TI - Chromosome segregation: human female meiosis breaks all the rules. AB - A major hindrance in studying human meiosis has been the inability to assess all four products of female meiosis. Overcoming this hurdle, a new study discovers a high incidence of non-canonical 'reverse meiosis' and a new form of meiotic drive. PMID- 26241140 TI - Centrosome biology: the ins and outs of centrosome assembly. AB - As a microtubule-organizing center, the centrosome undergoes a dramatic increase in size - via expansion of the pericentriolar material - during mitosis. Recent work reveals shared assembly properties of a protein scaffold that facilitates and supports this expansion, a process critical to spindle assembly. PMID- 26241141 TI - Parthenogenesis: birth of a new lineage or reproductive accident? AB - Parthenogenesis - the ability to produce offspring from unfertilized eggs - is widespread among invertebrates and now increasingly found in normally sexual vertebrates. Are these cases reproductive errors or could they be a first step in the emergence of new parthenogenetic lineages? PMID- 26241142 TI - Binocular vision: joining up the eyes. AB - To provide a unitary view of the external world, signals from the two eyes must be combined: a new study pinpoints the location in the human brain where the requisite combination occurs. PMID- 26241143 TI - Chromosome condensation: weaving an untangled web. AB - The compaction of diffuse interphase chromatin into stable mitotic chromosomes enables the segregation of replicated DNA to daughter cells. Two new studies characterise, both in vivo and in vitro, the essential contribution of the vertebrate condensin complex to chromosome organisation. PMID- 26241144 TI - Ecosystems: the rocky road to regime-shift indicators. AB - Ecosystems can undergo dramatic shifts from one stable state to another. While indicators of such shifts are well known, experimental tests are few and far between. A new study on rocky shore ecosystems now offers a test of warning indicators. PMID- 26241145 TI - Neuropsychology: how many emotions are there? AB - Psychological theories disagree on how we attribute emotions to people. A new neuroimaging study shows that such attributions involve a large number of abstract features, rather than a small set of emotion categories. PMID- 26241146 TI - Handedness: what kangaroos tell us about our lopsided brains. AB - Brain asymmetry is widespread, but the presence of handedness in non-human animals is debated. A new study now provides evidence for handedness in bipedal - but not quadrupedal - marsupials. PMID- 26241147 TI - Autism spectrum disorder: sniffing out a new biomarker. AB - Early intervention improves prognosis in autism spectrum disorder, yet diagnosis is very difficult in preverbal children. A new study demonstrates that the automatic adjustments in sniffing patterns to pleasant and unpleasant odors may provide a window into early diagnosis. PMID- 26241148 TI - Coordinating neuronal actin-microtubule dynamics. AB - The growth and migration of neurons require continuous remodelling of the neuronal cytoskeleton, providing a versatile cellular framework for force generation and guided movement, in addition to structural support. Actin filaments and microtubules are central to the dynamic action of the cytoskeleton and rapid advances in imaging technologies are enabling ever more detailed visualisation of the dynamic intracellular networks that they form. However, these filaments do not act individually and an expanding body of evidence emphasises the importance of actin-microtubule crosstalk in orchestrating cytoskeletal dynamics. Here, we summarise our current understanding of the structure and dynamics of actin and microtubules in isolation, before reviewing both the mechanisms and the molecular players involved in mediating actin microtubule crosstalk in neurons. PMID- 26241149 TI - Star-Shaped, Biodegradable, and Elastomeric PLLA-PEG-POSS Hybrid Membrane With Biomineralization Activity for Guiding Bone Tissue Regeneration. AB - Multi-armed biodegradable polymers have attracted much attention in biomedical applications, due to their special structure and properties. However, multi-armed organic-inorganic hybrids with high mechanical properties and biomineralization activity have not been reported yet. Here, star-shaped poly-L-lactide-poly (ethylene glycol)-polyhedral oligomeric silsesquioxane (SPPS) hybrid membranes are fabricated for the first time for guiding bone regeneration applications by a photo-crosslinking method using inositol as a core. SPPS demonstrates tunable mechanical properties (5.8 +/- 0.2 ~ 130 +/- 23 MPa in tensile modulus, 30 +/- 6% ~ 144 +/- 13% in elongation, beyond 90% recovery), biodegradation, biomineralization activity and good osteoblast biocompatibility. These results suggest that our hybrids membrane may have promising applications in guiding bone regeneration. PMID- 26241150 TI - The estimation of prevalence and risk factors of hepatitis B virus infection among blood donors in Chengdu, China. AB - The reported positive rates of hepatitis B virus surface antigen (HBsAg) among Chinese blood donors generally do not include data from pre-donation rapid tests. The aim of this study was to estimate the prevalence of serologic markers for HBsAg and risk factors among blood donors from Chengdu, China. From April 2010 to March 2011, a total of 16,875 blood donors were enrolled. Data from HBsAg tests before and after donations were collected to estimate the prevalence of HBsAg. A case-control study was conducted in 265 unique HBsAg-positive blood donors and 530 seronegative donors between January 2011 and October 2012. The odds ratio (OR) and 95% confidence interval (CI) were calculated using conditional logistic regression. The population attributable risk (PAR) was estimated. The prevalence of HBsAg was 3.17% (95%CI, 2.91-3.43%). The following risk factors were associated with HBV infection: non-vaccination for HBV (OR = 4.236; 95%CI, 2.72 6.60%), razor sharing (OR = 2.370; 95%CI, 1.46-3.84%), dental treatment (OR = 1.714; 95%CI, 1.21-2.43%), acupuncture (OR = 1.983; 95%CI, 1.20-3.28%), a family history of HBV infection (OR = 2.257; 95%CI, 1.32-3.86%), and endoscopy (OR = 2.17; 95%CI, 1.04-4.51%). The PAR values of the risk factors were 42.77%, 31.78%, 13.68%, 6.18%, 6.09%, and 2.85%, respectively, and the total PAR was 68.78%. The prevalence of HBsAg among Chinese blood donors is still high. HBV vaccinations can provide protection. Blood contact from sharing instruments is still a high risk route of transmission for HBV. Immunization programs and behavioral interventions should be used to prevent blood donation infections and improve blood safety. PMID- 26241151 TI - Convex and Concave Encapsulation of Multiple Potassium Ions by Sumanenyl Anions. AB - Herein we report the novel complex consisting of di- and tripotassiumsumanenide, K7(C21H10(2-))2(C21H9(3-)).8THF (2), which was prepared by the treatment of sumanene (C21H12, 1) with excess K metal in THF. The X-ray structural determination revealed unique self-assembly of six potassium ions sandwiched by convex faces of two sumanenyl trianions in addition to novel interaction involving all 15 carbon atoms of three Cp-like moieties on the concave surface of the sumanenyl bowls outside the sandwich. The unique structural features of 2 are rationalized with the help of DFT calculations. PMID- 26241152 TI - Critical Assessment of Endoscopic Techniques for Gastroesophageal Reflux Disease. AB - Over the past 2 decades, a number of new endoscopic techniques have been developed for management of gastroesophageal (GE) reflux disease symptoms as alternatives to medical management and surgical fundoplication. These devices include application of radiofrequency treatment (Stretta), endoscopic plication (EndoCinch, Plicator, Esophyx, MUSE), and injection of bulking agents (Enteryx, Gatekeeper, Plexiglas, Duragel). Their goal was symptom relief through reduction of tissue compliance and enhancement of anatomic resistance at the GE junction. In this review, we critically assess the research behind the efficacy, safety, and durability of these treatments to better understand their roles in contemporary GE reflux disease management. PMID- 26241153 TI - Effects of oxytocin on aggressive responding in healthy adult men. AB - This study investigated the acute effects of oxytocin (OT) on human aggression using a well-established laboratory measure of state (reactive) aggression to test the hypothesis that OT would decrease the frequency of aggressive responding. In a within-subject design, 17 healthy male volunteers received placebo or 24 IU of intranasal OT. Aggression was measured using the Point Subtraction Aggression Paradigm at 30 min before and 30, 60, and 90 min after dose. Acute OT did not produce a significant main effect on aggressive behavior. OT attenuated the expected rise in diastolic blood pressure from morning to early afternoon observed under placebo, providing a possible indication of biological activity. Examination of individual differences showed that aggressive responding following OT dosing (but not placebo) was positively correlated with psychometric measures of interpersonal manipulation and anger (Pearson's r=0.57), indicating that higher scores on these antisocial personality traits were related to increased aggressive behavior following OT administration. These preliminary results stand in contrast to previous work on the prosocial effects of OT and highlight the need for further understanding of individual differences in aggression following OT administration. Such individual differences may have implications for the therapeutic use of OT in individuals with psychiatric disorders and dysfunctional social behavior. PMID- 26241154 TI - RETINOCHOROIDAL MORPHOLOGY DESCRIBED BY WIDE-FIELD MONTAGE IMAGING OF SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: To present baseline images of the vitreous, retina, and choroid from the macula to the periphery in normal patients using a novel montaging technique of spectral domain optical coherence tomography. METHODS: Twenty-six normal eyes of 22 healthy volunteers were enrolled in this study. Montaged images of four radial optical coherence tomography scans through the fovea were obtained from each subject. RESULTS: In the macula, there were six identifiable retinal layers as well as four bands in the outer retina. In the periphery, the ganglion cell layer was not identifiable. The external limiting membrane, the second band, and the retinal pigment epithelium were continuously delineated from the macula to the periphery. The third band was not visible in the periphery. CONCLUSION: Spectral domain optical coherence tomography montaged images provide wide-angle images of the vitreous, retina, and choroid, allowing for evaluation of peripheral findings and examination of relationships between peripheral and posterior disease. The maximum scan length achieved here was 36 mm. The scan length is approximately three times than that provided by conventional posterior scanning and is consistent with known dimensions of the eye. This method is achievable with current commercially available devices and may contribute to decision making in clinical practice. PMID- 26241155 TI - Retinal Toxicity Related to Long-term Use of Ritonavir. PMID- 26241156 TI - Implication of using MRI co-registered with CT in Leksell Gamma Knife((r)) dose planning for patients with vestibular schwannoma. PMID- 26241157 TI - A prospective, randomized, blinded assessment of multitarget thalamic and pallidal deep brain stimulation in a case of hemidystonia. AB - OBJECTIVE: Dystonia is increasingly being interpreted as a multi-nodal "network" disorder. We aimed to investigate multitarget DBS (pallidal and thalamic) versus each target alone in a prospective, randomized, blinded trial in a case of hemidystonia secondary to putaminal stroke. METHODS: DBS leads were implanted in the GPi and Vim/Vop and each stimulation combination (GPi, Vim/Vop, and both) was tested for three months in a single patient. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Short-Form 36 (SF-36) were completed at the end of each trial period. RESULTS: Multitarget (GPi+Vim/Vop) stimulation was clinically the most effective treatment and resulted in the most improvement in function and quality of life. The patient's hemidystonia improved by 25% as measured by the BFMDRS during the multitarget stimulation trial period and at the 6-month follow-up. The patient's quality of life improved by 86% and 59% during the multitarget stimulation trial period and at the 6 month follow-up respectively. CONCLUSION: Multitarget thalamic and pallidal DBS proved to be the most effective therapy for this patient with secondary hemidystonia due to a putaminal stroke. A single-lead approach may not be sufficient in neuromodulating a highly disorganized motor network seen in hemidystonia. Multitarget DBS should be further explored in post stroke dystonia and may offer improved outcome in other forms of secondary dystonia with limited response to GPi DBS. PMID- 26241158 TI - Microelectrode miRNA sensors enabled by enzymeless electrochemical signal amplification. AB - Better detections of circulating microRNAs (miRNAs) as disease biomarkers could advance diseases diagnosis and treatment. Current analysis methods or sensors for research and applications are challenged by the low concentrations and wide dynamic range (from aM to nM) of miRNAs in a physiological sample. Here, we report a one-step label-free electrochemical sensor comprising a triple-stem DNA redox probe structure on a gold microelectrode. A new signal amplification mechanism without the need of a redox enzyme is introduced. The novel strategy overcomes the fundamental limitations of microelectrode DNA sensors that fail to generate detectable current, which is primarily due to the limited amount of redox probes in response to the target analyte binding. By employing a reductant, tris(2-carboxyethyl) phosphine hydrochloride (TCEP) in the detection buffer solution, each redox molecule on the detection probe is cyclically oxidized at the electrode and reduced by the reductant; thus, the signal is amplified in situ during the detection period. The combined merits in the diagnosis power of cyclic voltammetry and the high sensitivity of pulse voltammetry enable parallel analysis for method validation and optimization previously inaccessible. As such, the detection limit of miRNA-122 was 0.1 fM via direct readout, with a wide detection range from sub fM to nM. The detection time is within minutes, which is a significant improvement over other macroscopic sensors and other relevant techniques such as quantitative reverse transcription polymerase chain reaction (qRT-PCR). The high selectivity of the developed sensors is demonstrated by the discrimination against two most similar family sequences: miR-122-3p present in serum and 2-mismatch synthetic RNA sequence. Interference such as nonspecific adsorption, a common concern in sensor development, is reduced to a negligible amount by adopting a multistep surface modification strategy. Importantly, unlike qRT-PCR, the microelectrochemical sensor offers direct absolute quantitative readout that is amenable to clinical and in-home point-of-care (POC) applications. The sensor design is flexible, capable of being tailored for detection of different miRNAs of interest. Combined with the fact that the sensor was constructed at microscale, the method can be generalized for high throughput detection of miRNA signatures as disease biomarkers. PMID- 26241159 TI - New Mechanistic Insights on Na-Ion Storage in Nongraphitizable Carbon. AB - Nongraphitizable carbon, also known as hard carbon, is considered one of the most promising anodes for the emerging Na-ion batteries. The current mechanistic understanding of Na-ion storage in hard carbon is based on the "card-house" model first raised in the early 2000s. This model describes that Na-ion insertion occurs first through intercalation between graphene sheets in turbostratic nanodomains, followed by Na filling of the pores in the carbon structure. We tried to test this model by tuning the sizes of turbostratic nanodomains but revealed a correlation between the structural defects and Na-ion storage. Based on our experimental data, we propose an alternative perspective for sodiation of hard carbon that consists of Na-ion storage at defect sites, by intercalation and last via pore-filling. PMID- 26241160 TI - Predictive behaviors for anxiety and depression in female Wistar rats subjected to cafeteria diet and stress. AB - Obesity and chronic stress have been considered important public health problems that affect millions of people worldwide. Our aim was to analyze the effect of obesity associated with chronic stress on neurobehavioral parameters in female rats, considering that the association of these syndromes can enhance the negative effects on homeostasis. The animals were distributed into standard diet (Std), standard diet+stress (Std+stress), cafeteria diet (Cafe), and cafeteria diet+stress (Cafe+stress) groups. The animals of groups Std and Std+stress were fed with rodent standard feed. Groups Cafe and Cafe+stress, additionally to the standard feed, were offered palatable and calorie-rich processed food and cola type soft drink ad libitum. From the eighth experimental week, groups Std+stress and Cafe+stress were subjected to restraint chronic stress model (50 days). After the stress protocol, predictive anxiety (open-field and elevated plus-maze tests) and depression (forced swim) were applied. The cafeteria diet was effective in inducing obesity. The ratio locomotion in the central quadrants/total locomotion evaluated during the open field test was not indicative of anxiogenic or anxiolytic effect in the animal's behavior. However, the elevated plus maze test showed that obese and stressed animals were prone to higher anxiety levels. In addition, the obese and stressed animals display less climbing behavior than all the other groups, which can be considered an indicator of depression-like behavior. Nevertheless, it is suggested that the mechanisms involved in effects of obesity associated with chronic stress be better investigated in female rats, considering the organic complexity related to these modern illnesses. PMID- 26241161 TI - Mapping and characterizing endometrial implants by registering 2D transvaginal ultrasound to 3D pelvic magnetic resonance images. AB - We propose a new deformable slice-to-volume registration method to register a 2D Transvaginal Ultrasound (TVUS) to a 3D Magnetic Resonance (MR) volume. Our main goal is to find a cross-section of the MR volume such that the endometrial implants and their depth of infiltration can be mapped from TVUS to MR. The proposed TVUS-MR registration method uses contour to surface correspondences through a novel variational one-step deformable Iterative Closest Point (ICP) method. Specifically, we find a smooth deformation field while establishing point correspondences automatically. We demonstrate the accuracy of the proposed method by quantitative and qualitative tests on both semi-synthetic and clinical data. To generate semi-synthetic data sets, 3D surfaces are deformed with 4-40% degrees of deformation and then various intersection curves are obtained at 0-20 degrees cutting angles. Results show an average mean square error of 5.7934+/-0.4615mm, average Hausdorff distance of 2.493+/-0.14mm, and average Dice similarity coefficient of 0.9750+/-0.0030. PMID- 26241162 TI - Mass-spring systems for simulating mitral valve repair using 3D ultrasound images. AB - Mitral valve (MV) diseases are among the most common types of heart diseases, while heart diseases are the most common cause of death worldwide. MV repair surgery is connected to higher survival rates and fewer complications than the total replacement of the MV, but MV repair requires extensive patient-specific therapy planning. The simulation of MV repair with a patient-specific model could help to optimize surgery results and make MV repair available to more patients. However, current patient-specific simulations are difficult to transfer to clinical application because of time-constraints or prohibitive requirements on the resolution of the image data. As one possible solution to the problem of patient-specific MV modeling, we present a mass-spring MV model based on 3D transesophageal echocardiographic (TEE) images already routinely acquired for MV repair therapy planning. Our novel approach to the rest-length estimation of springs allows us to model the global support of the MV leaflets through the chordae tendinae without the need for high-resolution image data. The model is used to simulate MV annuloplasty for five patients undergoing MV repair, and the simulated results are compared to post-surgical TEE images. The comparison shows that our model is able to provide a qualitative estimate of annuloplasty surgery. In addition, the data suggests that the model might also be applied to simulating the implantation of artificial chordae. PMID- 26241163 TI - Current Trends and Investigative Developments in Wheat Allergy. AB - The prevalence of gluten-related diseases is increasing in an alarming rate. The studies regarding wheat allergy in the Southeastern and Central Europe are few. The aim of our study was to discuss the effectiveness of serological tests in detecting the prevalence of specific allergens. PMID- 26241164 TI - The cortical effect of chewing gum during hand movements: A functional MRI study. AB - Nine right-handed normal subjects were recruited for this study. We compared the cortical activation during execution of hand movements (right finger flexion extension) with that during execution of hand movements while chewing gum (right side chewing). We found that execution of hand movements while chewing gum induced less activation in the contralateral SM1 than hand movements alone. Based on our findings, it appears chewing gum during execution of hand movements enhanced the efficiency of hand movements. PMID- 26241165 TI - An innovative and shared methodology for event reconstruction using images in forensic science. AB - This study presents an innovative methodology for forensic science image analysis for event reconstruction. The methodology is based on experiences from real cases. It provides real added value to technical guidelines such as standard operating procedures (SOPs) and enriches the community of practices at stake in this field. This bottom-up solution outlines the many facets of analysis and the complexity of the decision-making process. Additionally, the methodology provides a backbone for articulating more detailed and technical procedures and SOPs. It emerged from a grounded theory approach; data from individual and collective interviews with eight Swiss and nine European forensic image analysis experts were collected and interpreted in a continuous, circular and reflexive manner. Throughout the process of conducting interviews and panel discussions, similarities and discrepancies were discussed in detail to provide a comprehensive picture of practices and points of view and to ultimately formalise shared know-how. Our contribution sheds light on the complexity of the choices, actions and interactions along the path of data collection and analysis, enhancing both the researchers' and participants' reflexivity. PMID- 26241166 TI - Diaphragmatic hernia repair more than four years after severe trauma: Four case reports. AB - INTRODUCTION: Diaphragmatic rupture is an infrequent complication of trauma, occurring in about 5% of those who suffer a severe closed thoracoabdominal injury and about half of the cases are diagnosed early. High morbidity and mortality from bowel strangulation and other sequelae make prompt surgical intervention mandatory. CASE PRESENTATION: Four Brazilian men with a delayed diagnosis of a rare occurrence of traumatic diaphragmatic hernia. Patient one had diaphragmatic rupture on the right side of thorax and the others three patients on the left thoracic side, all they had to approach by a laparotomy and some approach in the chest, either thoracotomy or VATS. This injuries required surgical repositioning of extensively herniated abdominal viscera and intensive postoperative medical management with a careful control of intra-abdominal pressure. DISCUSSION: The negative pressure of the thoracic cavity causes a gradually migration of abdominal contents into the chest; this sequestration reduces the abdomen's ability to maintain the viscera in their normal anatomical position. When the hernia is diagnosed early, the repair is less complicated and requires less invasive surgery. Years after the initial trauma, the diaphragmatic rupture produces dense adhesions between the chest and the abdominal contents. CONCLUSIONS: All cases demonstrated that surgical difficulty increases when diaphragmatic rupture is not diagnosed early. It should be noted that when trauma to the thoraco-abdominal transition area is blunt or penetrating, a thorough evaluation is required to rule out diaphragmatic rupture and a regular follow-up to monitor late development of this comorbidity. PMID- 26241167 TI - Retroperitoneal paraganglioma presenting with pancytopenia: A rare case with rare manifestation. AB - INTRODUCTION: Paragangliomas are tumors that arise from extraadrenal chromaffin cells and most of them are asymptomatic presenting with painless mass. Retroperitoneal paragangliomas are mostly benign with good prognosis; however, they can present with abdominal pain, palpable mass, or hypertensive episodes. Surgical resection is still the main treatment and necessary for histological assessment. CASE REPORT: A 41 year old female patient presented with 6 months of loss of appetite, weight loss, weakness and breathlessness on exertion.. The patient's initial blood examination showed marked anemia, reduced leukocyte count with neutropenia and lymphopenia and a marked reduction in the platelet count. The patient was admitted for evaluation of her pancytopenia. Magnetic resonance imaging revealed a 8*7*8cm sized mass closed to the pancreatic tail invading splenic hilum. A large mass was identified retroperitoneally, closed to the tail of pancreas with a splenic hilum invasion. Total mass resection and splenectomy was performed. DISCUSSION: Complete surgical excision is the treatment of choice for extra-adrenal paragangliomas as well as for recurrent or metastatic neoplasms. Reactive thrombocytosis is a common cause of thrombocytosis. Splenectomy was found to be one of the main causes of extreme reactive thrombocytosis. Reactive thrombocytosis is a predictable finding after splenectomy and management of the thrombocytosis and prevention of complications should be initiated. PMID- 26241168 TI - Pro-arrhythmic action of autoantibodies against the second extracellular loop of beta1-adrenoceptor and its underlying molecular mechanisms. AB - OBJECTIVES: The incidence of arrhythmia is associated with autoantibodies against the second extracellular loop of beta1-adrenergic receptor (beta1-AAbs). The current study was designed to determine the mechanisms by which arrhythmia experimentally might be induced by beta1-AAbs. METHODS: Blood samples were collected from patients with varied arrhythmias or coronary heart disease (CHD) and healthy subjects. The titer of beta1-AAbs was assessed. Passive immunization rat models with beta1-AAbs were established to determine whether beta1-AAbs induced arrhythmia. Conventional intracellular microelectrode technique and whole cell patch clamp were employed to record action potential duration (APD), resting potential (RP), L-type calcium current (ICa-L), sodium-calcium exchange current (INCX), transient outward potassium current (Ito), inward rectifier potassium current (Ik1) and delayed rectifier potassium current (Ik). RESULTS: High levels of beta1-AAbs were found in the sera of heart disease patients, especially in ventricular arrhythmia (VA). Transfusion with beta1-AAbs could induce arrhythmias in normal rats in vivo. beta1-AAbs purified from the sera of active immunized rats induced triggered activity (TA), delayed after depolarization (DAD), and prolonged APD in the papillary muscles of rats. beta1-AAbs prolonged QT interval, increased ICa-L and decreased IK1, Ito and INa-Ca in rat ventricular myocytes in vitro. All these effects can be inhibited by beta1-AR blocker metoprolol. CONCLUSIONS: These results demonstrate for the first time that beta1-AAbs could directly induce ventricular arrhythmia by prolonging QT interval. PMID- 26241169 TI - Personalized approaches to active immunotherapy in cancer. AB - Immunotherapy is emerging as a promising anti-cancer curative modality. However, in contrast to recent advances obtained employing checkpoint blockade agents and T cell therapies, clinical efficacy of therapeutic cancer vaccines is still limited. Most vaccination attempts in the clinic represent "off-the shelf" approaches since they target common "self" tumor antigens, shared among different patients. In contrast, personalized approaches of vaccination are tailor-made for each patient and in spite being laborious, hold great potential. Recent technical advancement enabled the first steps in the clinic of personalized vaccines that target patient-specific mutated neo-antigens. Such vaccines could induce enhanced tumor-specific immune response since neo-antigens are mutation-derived antigens that can be recognized by high affinity T cells, not limited by central tolerance. Alternatively, the use of personalized vaccines based on whole autologous tumor cells, overcome the need for the identification of specific tumor antigens. Whole autologous tumor cells could be administered alone, pulsed on dendritic cells as lysate, DNA, RNA or delivered to dendritic cells in-vivo through encapsulation in nanoparticle vehicles. Such vaccines may provide a source for the full repertoire of the patient-specific tumor antigens, including its private neo-antigens. Furthermore, combining next-generation personalized vaccination with other immunotherapy modalities might be the key for achieving significant therapeutic outcome. PMID- 26241171 TI - Changes in estrogen receptor signaling alters the timekeeping system in male mice. AB - Circadian rhythms are modulated by steroid hormones; however, the mechanisms of this action are not fully understood, particularly in males. In females estradiol regulates activity level, pattern of expression, and free running period (tau). We tested the hypothesis that activity level and distribution in male mice includes both classical and "non-classical" actions of estrogens at the estrogen receptor subtype 1 (ESR1). We used transgenic mice with mutations in their estrogen response pathways: ESR1 knock-out (ERKO) mice lack the ability to respond to estrogens via ESR1. "Non-classical" estrogen receptor knock-in (NERKI) mice have an inserted ESR1 receptor with a mutation in the estrogen-response element binding domain, allowing activation via non-genomic and second messenger pathways. Gonadectomized male NERKI, ERKO, and wildtype (WT) littermates were given oil, or low or high dose estradiol and daily activity parameters were quantified. Estradiol shortened the ratio of activity in the light relative to dark (LD ratio), shortened tau, advanced the time of activity onset, and altered responsiveness to light cues administered in the late subjective night, suggesting modulation by an ESR1-independent mechanism. Estradiol treatment in NERKI but not WT males altered the timing of activity onset, LD ratio, and the behavioral response to light cues. These results may represent disruptions in the balance of genomic/nongenomic or ESR1/ESR2 signaling pathways. We also found a significant genotype effect on total activity, LD ratio, tau, and activity duration. These data provide new information about the role of ESR1-dependent and independent signaling pathways on the timekeeping system in male mice. PMID- 26241172 TI - Higher detection sensitivity of anxiolytic effects of diazepam by ledge-free open arm with opaque walled closed arm elevated plus maze in male rats. AB - The elevated plus maze (EPM) is an established method for testing animal anxiety. However, EPM apparatuses and their features can differ among laboratories, most notably in the presence/absence of ledges on the open arm and/or the transparency/opaqueness of walls on the closed arm. The combined effects of these variable arm features on EPM behavior are not yet fully understood. In the present study, we prepared four types of EPM apparatus - open arms with (0.5 cm) or without (0 cm) ledges*closed arms with transparent or opaque walls - and compared the maze-exploration behavior of male Sprague-Dawley rats. We found that the presence of open arm ledges significantly increased the incidence of open arm exploration. Furthermore, time spent in the distal segment of the open arm was shortest in the apparatus that had open arms with no ledges and opaque closed arms (No-Ledges/Opaque), and was longest in the apparatus that had open arms with ledges and transparent closed arms (Ledges/Transparent). Additionally, the No Ledges/Opaque apparatus could detect the effect of 0.5mg/kg diazepam, an anxiolytic drug, whereas the Ledges/Transparent apparatus could not. These results indicate that arm structure (features of both open and closed arms) significantly influences maze-exploratory behavior in rats, and that No Ledges/Opaque apparatuses have higher detection sensitivity for anxiolytic effects of diazepam than that of Ledges/Transparent apparatuses. PMID- 26241170 TI - Yohimbine reinstates extinguished 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) seeking in rats with prior exposure to chronic yohimbine. AB - Although exposure to acute stress has been shown to reinstate extinguished responding for a wide variety of drugs, no studies have investigated stress induced reinstatement in animals with a history of 3,4 methylenedioxymethamphetamine (MDMA; ecstasy) self-administration. Thus, rats were trained to press a lever for MDMA (0.50 mg/kg/infusion) in daily sessions, and lever pressing was subsequently extinguished in the absence of MDMA and conditioned cues (light and tone). We then tested the ability of acute yohimbine (2.0 mg/kg), a pharmacological stressor, to reinstate lever-pressing under extinction conditions. Additionally, to model chronic stress, some rats were injected daily with yohimbine (5.0 mg/kg * 10 days) prior to reinstatement tests. To assess dopaminergic involvement, chronic yohimbine injections were combined with injections of SCH-23390 (0.0 or 10.0 MUg/kg), a dopamine D1-like receptor antagonist. In a separate experiment, rats with a history of food self administration were treated and tested in the same way. Results showed that acute yohimbine injections reinstated extinguished MDMA and food seeking, but only in rats with a history of chronic yohimbine exposure. Co-administration of SCH-23390 with chronic yohimbine injections prevented the potentiation of subsequent food seeking, but not MDMA seeking. These results suggest that abstinent MDMA users who also are exposed to chronic stress may be at increased risk for future relapse, and also that the effects of chronic stress on relapse may be mediated by different mechanisms depending on one's drug use history. PMID- 26241173 TI - Structural brain abnormalities correlate with clinical features in patients with drug-naive OCD: A DARTEL-enhanced voxel-based morphometry study. AB - BACKGROUND: Abnormal brain structure has been reported in obsessive-compulsive disorder (OCD), but findings from these reports have been inconsistent. This study aimed to gain more detailed insights into gray matter structure and correlate this structure with clinical features in patients with drug-naive OCD using voxel-based morphometry (VBM). METHODS: Voxel-based morphometry and tools of Diffeomorphic Anatomical Registration through Exponentiated Lie Algebra (DARTEL) were used to investigate structural differences in gray matter volume between 26 drug-naive OCD patients and 32 healthy controls. Partial correlation analysis was used to analyze associations of gray matter abnormalities with Yale Brown Obsessive Compulsive Scale (Y-BOCS) scores and illness duration. RESULTS: Compared to healthy controls, drug-naive OCD patients showed significantly smaller gray matter volume in the right dorsolateral prefrontal cortex (DLPFC), left superior temporal gyrus, left precuneus and right precentral gyrus, as well as significantly greater gray matter volume in the left anterior insula and right parahippocampal gyrus (p<0.05, corrected using the familywise error rate). Y-BOCS scores correlated positively with gray matter volume in the left anterior insula, while they correlated negatively with gray matter volume in the right DLPFC. CONCLUSIONS: OCD pathophysiology may involve structural changes in the DLPFC parietal regions, including the dorsolateral prefrontal cortex, precuneus, superior temporal gyrus and connected limbic structures such as the parahippocampal gyrus and anterior insula. Longitudinal studies are needed that integrate anatomical, functional and diffusion MRI data. PMID- 26241174 TI - Conscientious objection to abortion and reproductive healthcare: a review of recent literature and implications for adolescents. AB - PURPOSE OF REVIEW: Conscientious objection to reproductive healthcare (refusal to perform abortion, assisted reproductive technologies, prenatal diagnosis, contraception, including emergency contraception and sterilization, etc.) has become a widespread global phenomenon and constitutes a barrier to these services for many women. Adolescents are a particularly vulnerable group because some providers object to specific aspects of their reproductive healthcare because of their status as minors. RECENT FINDINGS: Recent peer-reviewed publications concerning conscientious objection address provider attitudes to abortion and emergency contraception, ethical arguments against conscientious objection, calls for clarification of the current laws regarding conscientious objection, legal case commentaries, and descriptions of the country-specific impact of policies in Russia and Italy. SUMMARY: Conscientious objection is understudied, complicated, and appears to constitute a barrier to care, especially for certain subgroups, although the degree to which conscientious objection has compromised sexual and reproductive healthcare for adolescents is unknown. Physicians are well positioned to support individual conscience while honoring their obligations to patients and to medical evidence. PMID- 26241175 TI - The Dabbing Dilemma: A Call for Research on Butane Hash Oil and Other Alternate Forms of Cannabis Use. PMID- 26241176 TI - Adenovirus-mediated FIR demonstrated TP53-independent cell-killing effect and enhanced antitumor activity of carbon-ion beams. AB - Combination therapy of carbon-ion beam with the far upstream element-binding protein (FBP)-interacting repressor, FIR, which interferes with DNA damage repair proteins, was proposed as an approach for esophageal cancer treatment with low side effects regardless of TP53 status. In vivo therapeutic antitumor efficacy of replication-defective adenovirus (E1 and E3 deleted adenovirus serotype 5) encoding human FIR cDNA (Ad-FIR) was demonstrated in the tumor xenograft model of human esophageal squamous cancer cells, TE-2. Bleomycin (BLM) is an anticancer agent that introduces DNA breaks. The authors reported that Ad-FIR involved in the BLM-induced DNA damage repair response and thus applicable for other DNA damaging agents. To examine the effect of Ad-FIR on DNA damage repair, BLM, X-ray and carbon-ion irradiation were used as DNA damaging agents. The biological effects of high linear energy transfer (LET) radiotherapy used with carbon-ion irradiation are more expansive than low-LET conventional radiotherapy, such as X rays or gamma rays. High LET radiotherapy is suitable for the local control of tumors because of its high relative biological effectiveness. Ad-FIR enhanced BLM induced DNA damage indicated by gammaH2AX in vitro. BLM treatment increased endogenous nuclear FIR expression in TE-2 cells, and P27Kip1 expression was suppressed by TP53 siRNA and BLM treatment. Further, Ad-FIRDeltaexon2, a dominant negative form of FIR that lacks exon2 transcriptional repression domain, decreased Ku86 expression. The combination of Ad-FIR and BLM in TP53 siRNA increased DNA damage. Additionally, Ad-FIR showed synergistic cell toxicity with X-ray in vitro and significantly increased the antitumor efficacy of carbon-ion irradiation in the xenograft mouse model of TE-2 cells (P=0.03, Mann-Whitney's U test) and was synergistic with the sensitization enhancement ratio (SER) value of 1.15. Therefore, Ad-FIR increased the cell-killing activity of the carbon-ion beam that avoids late-phase severe adverse effects independently of the TP53 status in vitro. Our findings indicated the feasibility of the combination of Ad FIR with DNA damaging agents for future esophageal cancer treatment. PMID- 26241177 TI - Hydrogen sulfide inhalation ameliorates allergen induced airway hypereactivity by modulating mast cell activation. AB - Compelling evidence suggests that hydrogen sulfide represents an important gaseous transmitter in the mammalian respiratory system. In the present study, we have evaluated the role of mast cells in hydrogen sulfide-induced effects on airways in a mouse model of asthma. Mice were sensitized to ovalbumin and received aerosol of a hydrogen sulfide donor (NaHS; 100 ppm) starting at day 7 after ovalbumin challenge. Exposure to hydrogen sulfide abrogated ovalbumin induced bronchial hypereactivity as well as the increase in lung resistance. Concomitantly, hydrogen sulfide prevented mast cell activity as well as FGF-2 and IL-13 upregulation. Conversely, pulmonary inflammation and the increase in plasmatic IgE levels were not affected by hydrogen sulfide. A lack of hydrogen sulfide effects in mast cell deficient mice occurred. Primary fibroblasts harvested from ovalbumin-sensitized mice showed an increased proliferation rate that was inhibited by hydrogen sulfide aerosol. Furthermore, ovalbumin-induced transdifferentiation of pulmonary fibroblasts into myofibroblasts was reversed. Finally, hydrogen sulfide did abrogate in vitro the degranulation of the mast cell-like RBL-2H3 cell line. Similarly to the in vivo experiments the inhibitory effect was present only when the cells were activated by antigen exposure. In conclusion, inhaled hydrogen sulfide improves lung function and inhibits bronchial hyper-reactivity by modulating mast cells and in turn fibroblast activation. PMID- 26241178 TI - Characterization of V0162, a new long-acting antagonist at human M3 muscarinic acetylcholine receptors. AB - The anticholinergic properties of the mequitazine enantiomer V0162 make it a drug candidate for the treatment of chronic obstructive airway diseases. Here, we compared V0162's in vitro pharmacological activity at recombinant human M3 muscarinic acetylcholine receptors (hM3Rs) with that of other anticholinergics, using (i) a radioligand binding assay, (ii) a functional reporter gene assay and (iii) a bronchoconstriction inhibition assay on human bronchial preparations. V0162 had high affinity for hM3Rs, with a pKi varying from 9.01 after a 2 h incubation to 9.21 after 23 h. The other mequitazine enantiomer (V0114) was less potent. V0162 displayed rapid off-kinetics and a biphasic time course of binding. V0162 was found to be an antagonist behaving as an inverse agonist for hM3R mediated reporter gene activation, with much the same efficacy as atropine, ipratropium and tiotropium. However, in contrast to ipratropium and atropine, V0162's inhibitory potency was only slightly affected by compound washout. V0162 antagonized acetylcholine-mediated contractions in a human bronchial preparation; the pA2 values increased with the incubation time (up to 2 h). Moreover, there was a progressive increase in V0162's ability to inhibit electrically-induced contractions, which persisted after compound washout. In conclusion, V0162 is the most active mequitazine enantiomer at hM3Rs and shows a complex pattern of binding to the membrane compartment. These particular features may be of therapeutic value when persistent antagonism at hM3Rs is required. PMID- 26241179 TI - Semaphorin 7a in Herpetic Neurotrophic Keratitis. PMID- 26241180 TI - Evidence for Nontraditional Lymphatics in the Choroid. PMID- 26241181 TI - Development of a new multi-analyte assay for the simultaneous detection of opioids in serum and other body fluids using liquid chromatography-tandem mass spectrometry. AB - A liquid chromatography-tandem mass spectrometry method using electrospray ionization in positive ionization mode was developed for the simultaneous detection of multiple opioid-type drugs in plasma. The presented assay allows the quantitative determination of alfentanil, buprenorphine, codeine, desomorphine, dextromethorphan, dextrorphan, dihydrocodeine, dihydromorphine, ethylmorphine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, naloxone, naltrexone, oxycodone, oxymorphone, pentazocine, pethidine, pholcodine, piritramide, remifentanil, sufentanil, and tramadol as well as the metabolites 6 monoacetylmorphine, bisnortilidine, morphine-3-glucuronide, morphine-6 glucuronide, naltrexol, norbuprenorphine, norfentanyl, norpethidine, nortilidine, and O-desmethyltramadol. Serum and blood samples were purified by solid-phase extraction. The analytes were separated on a phenyl-hexyl (100mm) column by formic acid/acetonitrile gradient elution using an UPLC 1290 Infinity coupled with a 6490 Triple Quadrupole mass spectrometer. The limits of detection ranged from 0.02 to 0.6ng/mL and the lower limits of quantification ranged from 0.1 to 2.0ng/mL. The calibration curves were linear between Calibration Levels 1-6 for all 35 substances. Recovery rates ranged between 51 and 88% for all compounds except alfentanil, bisnortilidine, pethidine, and morphine-3-glucuronide. The matrix effect ranged from 86% for ethylmorphine to 105% for desomorphine. Using the validation procedure proposed by the German Society of Toxicological and Forensic Chemistry, acceptable precision and accuracy data for almost all analytes were obtained. The method was successfully applied to 206 authentic serum samples provided by the palliative and intensive care units of the University Medical Center and the police authorities. Furthermore, a suspected fatal intoxication is demonstrated by an analysis of the sufentanil in post mortem body fluids and tissues. PMID- 26241182 TI - LC-ESI-MS/MS method for bioanalytical determination of osteogenic phytoalexin, medicarpin, and its application to preliminary pharmacokinetic studies in rats. AB - Medicarpin is the active phytoalexin found in the stem bark of Butea monosperma having potent osteogenic activity. An LC-ESI-MS/MS was developed and validated for quantification of medicarpin in rat plasma using liquid-liquid extraction technique and diethyl ether as the extraction solvent. Medicarpin was separated on RP18 column (4.6mm*50mm, 5.0MUm) using methanol and 10mM ammonium acetate (pH 4.0) in the ratio of 80:20 (v/v) as mobile phase. The method was linear within the concentration range of 1-500ng/mL and its sensitivity was 1ng/mL. The precision value for intra- and inter-day assays and stability assays was within 0.88-14.22% while the accuracy ranged between 87.46-116.0% at all four QC levels. The validated method was successfully applied to study the preclinical pharmacokinetics of medicarpin in rats. Medicarpin showed multiple peak phenomenon upon oral administration. Its oral bioavailability was 17.43%. It was found to be a rapidly absorbed (Tmax=15min), 81.61% protein bound and pH stable compound. The present study provides important information regarding preliminary pharmacokinetics of medicarpin for its further exploration as a potential therapeutic agent. PMID- 26241185 TI - Rheumatoid arthritis: Microbiome reflects status of RA and response to therapy. PMID- 26241183 TI - Redox distress and genetic defects conspire in systemic autoinflammatory diseases. AB - Inflammation is initiated by innate immune cell activation after contact with pathogens or tissue injury. An increasing number of observations have suggested that cellular stress, in the absence of infection or evident damage, can also induce inflammation. Thus, inflammation can be triggered by exogenous pathogen associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)-so-called classic inflammation-or by endogenous stress resulting from tissue or cellular dysfunction. External triggers and cellular stress activate the same molecular pathways, possibly explaining why classic and stress-induced inflammation have similar clinical manifestations. In some systemic autoinflammatory diseases (SAIDs), inflammatory cells exhibit reduction-oxidation (redox) distress, having high levels of reactive oxygen species (ROS), which promote proinflammatory cytokine production and contribute to the subversion of mechanisms that self-limit inflammation. Thus, SAIDs can be viewed as a paradigm of stress-related inflammation, being characterized by recurrent flares or chronic inflammation (with no recognizable external triggers) and by a failure to downmodulate this inflammation. Here, we review SAID pathophysiology, focusing on the major cytokines and DAMPs, and on the key roles of redox distress. New therapeutic opportunities to tackle SAIDs by blocking stress-induced pathways and control the response to stress in patients are also discussed. PMID- 26241184 TI - Neurogenic neuroinflammation in fibromyalgia and complex regional pain syndrome. AB - Although fibromyalgia and complex regional pain syndrome (CRPS) have distinct clinical phenotypes, they do share many other features. Pain, allodynia and dysaesthesia occur in each condition and seem to exist on a similar spectrum. Fibromyalgia and CRPS can both be triggered by specific traumatic events, although fibromyalgia is most commonly associated with psychological trauma and CRPS is most often associated with physical trauma, which is frequently deemed routine or minor by the patient. Fibromyalgia and CRPS also seem to share many pathophysiological mechanisms, among which the most important are those involving central effects. Nonetheless, peripheral effects, such as neurogenic neuroinflammation, are also important contributors to the clinical features of each of these disorders. This Review highlights the differing degrees to which neurogenic neuroinflammation might contribute to the multifactorial pathogenesis of both fibromyalgia and CRPS, and discusses the evidence suggesting that this mechanism is an important link between the two disorders, and could offer novel therapeutic targets. PMID- 26241187 TI - Osteoarthritis: Cartilage matrix stiffness regulates chondrocyte metabolism and OA pathogenesis. PMID- 26241186 TI - Pathogenesis and targeted treatment of skin injury in SLE. AB - Skin is the second most common organ (after the kidney) to be affected in patients with systemic lupus erythematosus (SLE), yet the aetiology of skin injury and the mechanisms involved in the development of dermal manifestations of SLE remain unclear. Ultraviolet light (UV), immune cells, cytokines and deposition of immunoglobulins all seem to have a role in the development of skin inflammation and damage in SLE. UV represents the most important environmental factor, and exposure to UV triggers the development of skin lesions in areas where immunoglobulin has been deposited and various other components of the immune system have accumulated. In addition, a number of intracellular kinases and transcription factors have also been demonstrated to be involved in the generation of skin lesions in lupus-prone mice. These molecules can be targeted by small-molecule inhibitors, leading to the prospect that treatments suitable for topical application, and with limited adverse effects, could be developed. Further studies to eliminate the burden of skin inflammation in patients with SLE are clearly required. PMID- 26241188 TI - Therapy: New fusion protein reduces IL-1-mediated inflammation. PMID- 26241189 TI - Modular optimization of multi-gene pathways for fumarate production. AB - Microbial fumarate production from renewable feedstock is a promising and sustainable alternative to petroleum-based chemical synthesis. Here, we report a modular engineering approach that systematically removed metabolic pathway bottlenecks and led to significant titer improvements in a multi-gene fumarate metabolic pathway. On the basis of central pathway architecture, yeast fumarate biosynthesis was re-cast into three modules: reduction module, oxidation module, and byproduct module. We targeted reduction module and oxidation module to the cytoplasm and the mitochondria, respectively. Combinatorially tuning pathway efficiency by constructing protein fusions RoMDH-P160A and KGD2-SUCLG2 and optimizing metabolic balance by controlling genes RoPYC, RoMDH-P160A, KGD2-SUCLG2 and SDH1 expression strengths led to significantly improved fumarate production (20.46 g/L). In byproduct module, synthetizing DNA-guided scaffolds and designing sRNA switchs enabled further production improvement up to 33.13 g/L. These results suggest that modular pathway engineering can systematically optimize biosynthesis pathways to enable an efficient production of fumarate. PMID- 26241190 TI - Recombination radius of a Frenkel pair and capture radius of a self-interstitial atom by vacancy clusters in bcc Fe. AB - The recombination radius of a Frenkel pair is a fundamental parameter for the object kinetic Monte Carlo (OKMC) and mean field rate theory (RT) methods that are used to investigate irradiation damage accumulation in irradiated materials. The recombination radius in bcc Fe has been studied both experimentally and numerically, however there is no general consensus about its value. The detailed atomistic processes of recombination also remain uncertain. Values from 1.0a0 to 3.3a0 have been employed as a recombination radius in previous studies using OKMC and RT. The recombination process of a Frenkel pair is investigated at the atomic level using the self-evolved atomistic kinetic Monte Carlo (SEAKMC) method in this paper. SEAKMC calculations reveal that a self-interstitial atom recombines with a vacancy in a spontaneous reaction from several nearby sites following characteristic pathways. The recombination radius of a Frenkel pair is estimated to be 2.26a0 by taking the average of the recombination distances from 80 simulation cases. In addition, we apply these procedures to the capture radius of a self-interstitial atom by a vacancy cluster. The capture radius is found to gradually increase with the size of the vacancy cluster. The fitting curve for the capture radius is obtained as a function of the number of vacancies in the cluster. PMID- 26241191 TI - A cross-sectional study on knowledge and attitude toward Traditional Chinese Medicine (TCM) among adults in selected regions of Malaysia. AB - BACKGROUND: The objectives of this study were to determine the knowledge and attitude of adult Malaysians about Traditional Chinese Medicine (TCM), to understand the variation in the knowledge and attitude toward TCM among different demographic groups of adult Malaysian population and to determine the pattern of TCM use among adult Malaysians. METHODS: This study was a descriptive, cross sectional survey using the convenience sampling method. A total of 400 adult Malaysians were recruited for this study. An interview-administered questionnaire was used. Descriptive statistics Mann-Whitney U Test and Kruskal-Wallis H test were used to analyze the data. The reliability of survey data in this study may affect since closed-ended questions are used. RESULTS: The more commonly utilized therapy was herbal medicine (n=192, 82.1%), acupuncture (n=79, 33.8%) and oriental massage (n=58, 24.8%). The mean knowledge score and mean attitude score for the respondents were 5.00+/-1.71 and 7.17+/-2.10 respectively. There was a significant difference in the mean knowledge score between genders, among TCM users and non-TCM users, people of different education levels and ethnicity. CONCLUSIONS: There were more TCM users than non-TCM users and the use of TCM was higher in females than males. The most popularly used TCM modalities were herbal medicines and acupuncture. Gender, education, ethnicity and use of TCM had a significant effect on adults' knowledge toward TCM. PMID- 26241192 TI - Smoking and postpartum psychosis. PMID- 26241193 TI - Impact Electrochemistry of Layered Transition Metal Dichalcogenides. AB - Layered transition metal dichalcogenides (TMDs) exhibit paramount importance in the electrocatalysis of the hydrogen evolution reaction. It is crucial to determine the size of the electrocatalytic particles as well as to establish their electrocatalytic activity, which occurs at the edges of these particles. Here, we show that individual TMD (MoS2, MoSe2, WS2, or WSe2; in general MX2) nanoparticles impacting an electrode surface provide well-defined current "spikes" in both the cathodic and anodic regions. These spikes originate from direct oxidation of the nanoparticles (from M(4+) to M(6+)) at the anodic region and from the electrocatalytic currents generated upon hydrogen evolution in the cathodic region. The positive correlation between the frequency of the impacts and the concentration of TMD nanoparticles is also demonstrated here, enabling determination of the concentration of TMD nanoparticles in colloidal form. In addition, the size of individual TMD nanoparticles can be evaluated using the charge passed during every spike. The capability of detecting both the "indirect" catalytic effect of an impacting TMD nanoparticle as well as "direct" oxidation indicates that the frequency of impacts in both the "indirect" and "direct" scenarios are comparable. This suggests that all TMD nanoparticles, which are electrochemically oxidizable (thus capable of donating electrons to electrodes), are also capable of catalyzing the hydrogen reduction reaction. PMID- 26241194 TI - Al3AuIr: A New Compound in the Al-Au-Ir System. AB - A new ternary phase with a composition of Al3AuIr has been found in the Al-rich area of the Al-Au-Ir system. Differential thermal analysis indicates a melting point of 990 degrees C, and single-crystal X-ray diffraction measurements reveal that this ternary phase adopts a Ni2Al3 structure type (space group P3m1) with a = 4.2584(5) A and c = 5.1991(7) A. This compound is isostructural to the Al3Cu1.5Co0.5 phase also found in the Al-rich part of the Al-Cu-Co ternary diagram. Experimental evidence combined with ab initio calculations point toward an Al3AuIr phase stabilized by a Hume-Rothery mechanism. Quantum chemical calculations indicate two-center and multicenter interactions in the Al3AuIr phase. Layered distribution of two-center interactions separated by regions with four- and five-center bonds suggests a preferential cleavage of the material at puckered planes perpendicular to the [001] direction. PMID- 26241196 TI - MOTA: A Many-Objective Tuning Algorithm Specialized for Tuning under Multiple Objective Function Evaluation Budgets. AB - Control parameter studies assist practitioners to select optimization algorithm parameter values that are appropriate for the problem at hand. Parameter values are well suited to a problem if they result in a search that is effective given that problem's objective function(s), constraints, and termination criteria. Given these considerations a many-objective tuning algorithm named MOTA is presented. MOTA is specialized for tuning a stochastic optimization algorithm according to multiple performance measures, each over a range of objective function evaluation budgets. MOTA's specialization consists of four aspects: (1) a tuning problem formulation that consists of both a speed objective and a speed decision variable; (2) a control parameter tuple assessment procedure that utilizes information from a single assessment run's history to gauge that tuple's performance at multiple evaluation budgets; (3) a preemptively terminating resampling strategy for handling the noise present when tuning stochastic algorithms; and (4) the use of bi-objective decomposition to assist in many objective optimization. MOTA combines these aspects together with differential evolution operators to search for effective control parameter values. Numerical experiments consisting of tuning NSGA-II and MOEA/D demonstrate that MOTA is effective at many-objective tuning. PMID- 26241195 TI - Synaptic connections of amacrine cells containing vesicular glutamate transporter 3 in baboon retinas. AB - The goals of these experiments were to describe the morphology and synaptic connections of amacrine cells in the baboon retina that contain immunoreactive vesicular glutamate transporter 3 (vGluT3). These amacrine cells had the morphology characteristic of knotty bistratified type 1 cells, and their dendrites formed two plexuses on either side of the center of the inner plexiform layer. The primary dendrites received large synapses from amacrine cells, and the higher-order dendrites were both pre- and postsynaptic to other amacrine cells. Based on light microscopic immunolabeling results, these include AII cells and starburst cells, but not the polyaxonal amacrine cells tracer-coupled to ON parasol ganglion cells. The vGluT3 cells received input from ON bipolar cells at ribbon synapses and made synapses onto OFF bipolar cells, including the diffuse DB3a type. Many synapses from vGluT3 cells onto retinal ganglion cells were observed in both plexuses. At synapses where vGluT3 cells were presynaptic, two types of postsynaptic densities were observed; there were relatively thin ones characteristic of inhibitory synapses and relatively thick ones characteristic of excitatory synapses. In the light microscopic experiments with Neurobiotin injected ganglion cells, vGluT3 cells made contacts with midget and parasol ganglion cells, including both ON and OFF types. Puncta containing immunoreactive gephyrin, an inhibitory synapse marker, were found at appositions between vGluT3 cells and each of the four types of labeled ganglion cells. The vGluT3 cells did not have detectable levels of immunoreactive gamma-aminobutyric acid (GABA) or immunoreactive glycine transporter 1. Thus, the vGluT3 cells would be expected to have ON responses to light and make synapses onto neurons in both the ON and the OFF pathways. Taken with previous results, these findings suggest that vGluT3 cells release glycine at some of their output synapses and glutamate at others. PMID- 26241197 TI - Analysis of Randomised Search Heuristics for Dynamic Optimisation. AB - Dynamic optimisation is an area of application where randomised search heuristics like evolutionary algorithms and artificial immune systems are often successful. The theoretical foundation of this important topic suffers from a lack of a generally accepted analytical framework as well as a lack of widely accepted example problems. This article tackles both problems by discussing necessary conditions for useful and practically relevant theoretical analysis as well as introducing a concrete family of dynamic example problems that draws inspiration from a well-known static example problem and exhibits a bi-stable dynamic. After the stage has been set this way, the framework is made concrete by presenting the results of thorough theoretical and statistical analysis for mutation-based evolutionary algorithms and artificial immune systems. PMID- 26241198 TI - Neuroendoscopy for Intracranial Arachnoid Cysts in Infants: Therapeutic Considerations. AB - Background The use of the endoscope for various cranial procedures is gradually expanding. Intracranial cystic lesions in the brain are one of the most attractive targets for this minimally invasive procedure, thus avoiding conventional craniotomy. These cystic lesions in the brain, namely arachnoid cysts, are congenital. Surgical treatment depends on clinical presentation, location, and age. Patients A total of 13 patients < 1 year of age with intracranial cysts were operated on between 2005 and 2013. Six presented with hydrocephalus, four presented with seizure, one with abnormal head movement, and two had large asymptomatic cysts. Four children had infratentorial arachnoid cysts; of these, three required a transaqueductal procedure. All the patients underwent endoscopic cystoventriculostomy and/or cystocisternostomy and third ventriculostomy in selected cases with a biopsy from the cyst wall. Results Clinically and radiologically all children showed significant improvement with an average follow-up ranging from 8 months to 6 years. There were no intraoperative complications. Three children developed subdural hygroma that subsided with conservative treatment, and one child with pseudomeningocele required a cystoperitoneal shunt at a later date. Conclusion A symptomatic intracranial arachnoid cyst or a large asymptomatic cyst are indications for neurosurgical intervention, and endoscopy is a good treatment option with the advantage of minimal invasiveness and fewer complications. Endoscopic surgery has to be tailored according to the location and presentation. PMID- 26241200 TI - The long-term impact of combat exposure on health, interpersonal, and economic domains of functioning. AB - PURPOSE: Wartime combat exposure is linked to a broad array of negative outcomes. The current study identified potential differences between middle-to-older aged men exposed to combat and those not exposed for physical health, interpersonal, and economic functioning over 10 years. Post-traumatic stress disorder (PTSD) and social support were examined as moderators between combat exposure and outcomes. METHODS: Data from the National Comorbidity Survey, baseline and 10-year follow up, were utilized. Only men aged 50-65 at follow-up (N = 727) were included. Group differences between combat and non-combat men were examined. Regression analyses were performed to examine relationships between earlier combat and health, interpersonal, and economic outcomes over time, while controlling for important covariates. RESULTS: Combat-exposed men were at increased risk for asthma, arthritis/rheumatism, lung diseases, headaches, and pain; they also had greater marital instability. However, combat-exposed men reported economic advantages, including higher personal earnings at follow-up. For combat-exposed men, PTSD did not increase risk for headaches; however, PTSD in non-combat men was associated with increased risk for headaches at follow-up. Whereas combat exposed men with higher levels of social support were less likely to report chronic pain at follow-up, there were no group differences in pain at lower levels of social support. IMPLICATIONS: Individuals who experience combat may be susceptible to later health and marital problems; however, as combat-exposed men age, they demonstrate some resilience, including in economic domains of life. Given that consequences of combat may manifest years after initial exposure, knowledge of combat exposure is necessary to inform treatments and the delivery of disability benefits. PMID- 26241201 TI - How Common is Men's Self-Reported Sexual Interest in Prepubescent Children? AB - Consistent evidence exists for sexual interest in children in nonclinical/nonforensic male populations. However, prevalences for community men's self-reported sexual interest in children have been based on indiscriminate definitions including postpubescent individuals, age-restricted samples, and/or small convenience samples. The present research assessed men's self-reported sexual interest in children (including child prostitution and child sex tourism) on the community level and examined the link between strictly defined sexual fantasies and behaviors involving prepubescent children. In an online survey of 8,718 German men, 4.1% reported sexual fantasies involving prepubescent children, 3.2% reported sexual offending against prepubescent children, and 0.1% reported a pedophilic sexual preference. Sexual fantasies involving prepubescent children were positively related to sexual offending against prepubescent children. Sexual interest in children was associated with subjectively perceived need for therapeutic help. In contrast to findings from forensic samples, men who reported child pornography use exclusively were identified as a subgroup differing from contact sexual offenders against prepubescent children and men who reported both child pornography use and contact sexual offenses against prepubescent children. The empirical link between child-related sexual fantasies and sexual victimization of prepubescent children and high levels of subjective distress from this inclination underscore the importance of evidence-based child sexual abuse prevention approaches in the community. Findings are discussed in terms of their relation to pedophilic disorder. PMID- 26241202 TI - Relationship between jerk at the L3/L4 intervertebral level and COP mean velocity in bipedal and unipedal standing conditions. PMID- 26241199 TI - What insights can fMRI offer into the structure and function of mid-tier visual areas? AB - Inferring neural responses from functional magnetic resonance imaging (fMRI) data is challenging. Even if we take advantage of high-field systems to acquire data with submillimeter resolution, we are still acquiring data in which a single datum summarizes the responses of tens of thousands of neurons. Excitation and inhibition, spikes and subthreshold membrane potential modulations, local and long-range computations, and tuned and nonselective responses are mixed together in one signal. With a priori knowledge of the underlying neural population responses, careful experiment design allows us to manipulate the experiment or task design so that subpopulations are selectively modulated, and our experiments can reveal those tuning functions. However, because we want to be able to use fMRI to discover new kinds of tuning functions and selectivity, we cannot limit ourselves to experiments in which we already know what we are looking for. Broadly speaking, analyses that rely on classification of responses that are distributed across the local neural population [multi-voxel pattern analyses (MVPA)] offer the ability to discover new kinds of information representation and selectivities in neural subpopulations. There is, however, no way to determine how the information discovered with MVPA or other analyses is related to the underlying neuronal tuning functions. Therefore, we must continue to rely on behavioral, computational, and animal models to develop theories of information representation in mid-tier visual cortical areas. Once encoding models exist, fMRI can be powerful for testing these a priori models of information representation. As an aide in developing these models, an important contribution that fMRI can make to our understanding of mid-tier visual areas is derived from connectivity analyses and experiments that study information sharing between visual areas. This ability to quantify localized population average responses throughout the brain is the strength we can best leverage to discover new properties of local and long-range neural networks. PMID- 26241204 TI - Effects of Governance on Availability of Land for Agriculture and Conservation in Brazil. AB - The 2012 revision of the Brazilian Forest Act changed the relative importance of private and public governance for nature conservation and agricultural production. We present a spatially explicit land-use model for Brazilian agricultural production and nature conservation that considers the spatial distribution of agricultural land suitability, technological and management options, legal command, and control frameworks including the Atlantic Forest Law, the revised Forest Act, and the Amazonian land-titling, "Terra Legal," and also market-driven land use regulations. The model is used to analyze land use allocation under three scenarios with varying priorities among agricultural production and environmental protection objectives. In all scenarios, the legal command and control frameworks were the most important determinants of conservation outcomes, protecting at least 80% of the existing natural vegetation. Situations where such frameworks are not expected to be effective can be identified and targeted for additional conservation (beyond legal requirements) through voluntary actions or self-regulation in response to markets. All scenarios allow for a substantial increase in crop production, using an area 1.5-2.7 times the current cropland area, with much of new cropland occurring on current pastureland. Current public arrangements that promote conservation can, in conjunction with voluntary schemes on private lands where conversion to agriculture is favored, provide important additional nature conservation without conflicting with national agricultural production objectives. PMID- 26241203 TI - Rice bran extract improves mitochondrial dysfunction in brains of aged NMRI mice. AB - OBJECTIVES: Aging represents a major risk factor for neurodegenerative diseases such as Alzheimer's disease. Mitochondria are significantly involved in both the aging process and neurodegeneration. One strategy to protect the brain and to prevent neurodegeneration is a healthy lifestyle including a diet rich in antioxidants and polyphenols. Rice bran extract (RBE) contains various antioxidants including natural vitamin E forms (tocopherols and tocotrienols) and gamma-oryzanol. In this work, we examined the effects of a stabilized RBE on mitochondrial function in 18-month-old Naval Medical Research Institute mice (340 mg/kg body weight/day), which received the extract for 3 weeks via oral gavage. METHODS: Mitochondrial parameters were measured using high-resolution respirometry (Oroboros Oxygraph-2k), Western blot analysis, and photometric methods in dissociated brain cells, isolated mitochondria, and brain homogenate. Vitamin E concentrations in blood plasma and brain tissue were measured using HPLC with fluorescence detection. RESULTS: Aging leads to decreased mitochondrial function (decreased mitochondrial respiration and ATP production) and decreased protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha). RBE administration increased alpha-tocopherol concentrations in the brain and compensated for age-related mitochondrial dysfunction by increasing mitochondrial respiration, membrane potential, PGC1alpha protein expression, and citrate synthase activity. Furthermore, resistance of brain cells to sodium nitroprusside-induced nitrosative stress was improved. DISCUSSION: According to these results, RBE is a promising candidate nutraceutical for the prevention of age-related neurodegenerative diseases. PMID- 26241205 TI - Infrared Detection of a Proton Released from Tyrosine YD to the Bulk upon Its Photo-oxidation in Photosystem II. AB - Photosystem II (PSII) has two symmetrically located, redox-active tyrosine residues, YZ and YD. Whereas YZ mediates the electron transfer from the water oxidizing center to P680 in the main electron transfer pathway, YD functions as a peripheral electron donor to P680. To understand the mechanism of this functional difference between YZ and YD, it is essential to know where the proton is transferred upon its oxidation in the proton-coupled electron transfer process. In this study, we used Fourier transform infrared (FTIR) spectroscopy to examine whether the proton from YD is released from the protein into the bulk. The proton detection method previously used for water oxidation in PSII [Suzuki et al. (2009) J. Am. Chem. Soc. 131, 7849-7857] was applied to YD; a proton released into the bulk upon YD oxidation was trapped by a high-concentration Mes buffer, and the protonation reaction of Mes was monitored by FTIR difference spectroscopy. It was shown that 0.84 +/- 0.10 protons are released into the bulk by oxidation of YD in one PSII center. This result indicates that the proton of YD is not transferred to the neighboring D2-His198 but is released from the protein; this is in sharp contrast to the YZ reaction, in which a proton is transferred to D1-His190 through a strong hydrogen bond. This functional difference is caused by differences in the hydrogen-bonded structures of YD and YZ, which are determined by the hydrogen bond partners at the Npi sites of these His residues, i.e., D2-Arg294 and D1-Asn298, which function as a hydrogen bond donor and acceptor, respectively. This FTIR spectroscopy result supports the recent theoretical prediction [Saito et al. (2013) Proc. Natl. Acad. Sci. U.S.A. 110, 7690-7695] based on the X-ray crystallographic structure of PSII and explains the different rates of the redox reactions of YD and YZ. PMID- 26241206 TI - A Special Focus on Drug Repurposing, Rescue, and Repositioning. PMID- 26241207 TI - Drug Repositioning and Off-Label Use-Finding the Balance and Understanding the Differences: Interview with David Cavalla, MA, PhD, Founder, Numedicus. PMID- 26241208 TI - The NIH-Industry New Therapeutic Uses Pilot Program: Demonstrating the Power of Crowdsourcing. PMID- 26241209 TI - Computational and Practical Aspects of Drug Repositioning. AB - The concept of the hypothesis-driven or observational-based expansion of the therapeutic application of drugs is very seductive. This is due to a number of factors, such as lower cost of development, higher probability of success, near term clinical potential, patient and societal benefit, and also the ability to apply the approach to rare, orphan, and underresearched diseases. Another highly attractive aspect is that the "barrier to entry" is low, at least in comparison to a full drug discovery operation. The availability of high-performance computing, and databases of various forms have also enhanced the ability to pose reasonable and testable hypotheses for drug repurposing, rescue, and repositioning. In this article we discuss several factors that are currently underdeveloped, or could benefit from clearer definition in articles presenting such work. We propose a classification scheme-drug repositioning evidence level (DREL)-for all drug repositioning projects, according to the level of scientific evidence. DREL ranges from zero, which refers to predictions that lack any experimental support, to four, which refers to drugs approved for the new indication. We also present a set of simple concepts that can allow rapid and effective filtering of hypotheses, leading to a focus on those that are most likely to lead to practical safe applications of an existing drug. Some promising repurposing leads for malaria (DREL-1) and amoebic dysentery (DREL-2) are discussed. PMID- 26241210 TI - Antiepileptic Drugs Inhibit Growth, Dimorphism, and Biofilm Mode of Growth in Human Pathogen Candida albicans. AB - Exploring the potential of existing drugs for their unknown properties may offer advantages over conventional drug development by saving time and money. Candida albicans, an important human opportunist, shares many genetic properties with humans. This has encouraged us to study drugs that are not originally antifungals against C. albicans. In the present study, we have tested six antiepileptic drugs for their activities against C. albicans. Their effects on growth, time-dependent killing, yeast-to-hyphal form switching, and biofilms formation by C. albicans were studied. Out of the drugs studied, four drugs, which are gamma-aminobutyric acid (GABA) receptor agonists in humans, inhibited growth, yeast-to-hyphal form switching, and biofilm formation in C. albicans. Lorazepam inhibited growth of C. albicans at 25 MUg/ml, followed by midazolam and diazepam (minimum inhibitory concentrations 100 and 400 MUg/ml, respectively). Members from other group voltage-gated sodium channel blockers failed to inhibit C. albicans. Our study has identified GABA receptor agonists used in epileptic therapy as potential candidates for antifungal drug development against the human pathogen C. albicans. PMID- 26241211 TI - Sources and Targets for Drug Repurposing: Landscaping Transitions in Therapeutic Space. AB - Patent applications provide unique opportunities for landscaping ongoing medical innovation. In this analysis of drug repurposing patent applications published under the international Patent Convention Treaty during the years 2011-2014, we discuss what categories in the World Health Organization's International Classification of Diseases provide drugs and drug candidates for potential second medical uses, and how these proposed repurposed uses relate to each other and the original ones. Also discussed are the geographic origin of the patent assignees and their type and size. Beyond the expected interactions within the field of neuropsychiatry, frequent secondary use claims for oncology compounds to treat noninfectious respiratory diseases, and for cardiovascular compounds to treat neurological conditions, were unexpected findings derived from the repurposing heatmap. The relative absence of repurposing claims to treat parasitic or tropical diseases contrasts sharply with the broad attention this segment receives in the peer-reviewed literature. Equally notable are the dominance of universities and small pharmaceutical companies; a focus of large multinational companies to repurpose their own compounds; and the leading role of European centered entities among the assignees. We believe that this investigation represents the first comprehensive cross-sectional attempt at mapping drug repurposing patterns across therapeutic fields, and could provide important clues that complement those obtained from the peer-reviewed literature. PMID- 26241213 TI - Core-Corona Functionalization of Diblock Copolymer Micelles by Heterogeneous Metal Nanoparticles for Dual Modality in Chemical Reactions. AB - Nanoscale assemblies composed of different types of nanoparticles (NPs) can reveal interesting aspects about material properties beyond the functions of individual constituent NPs. This research direction may also represent current challenges in nanoscience toward practical applications. With respect to the assembling method, synthetic or biological nanostructures can be utilized to organize heterogeneous NPs in specific sites via chemical or physical interactions. However, those assembling methods often encounter uncontrollable particle aggregation or phase separation. In this study, we anticipated that the self-segregating properties of block copolymer micelles could be particularly useful for organizing heterogeneous NPs, because the presence of chemically distinct domains such as the core and the corona can facilitate the selective placement of constituent NPs in separate domains. Here, we simultaneously functionalized the core and the corona of micelles by Au NPs and Ag NPs, which exhibited plasmonic and catalytic functions, respectively. Our primary question is whether these plasmonic and catalytic functions can be combined in the assembled structures to engineer the kinetics of a model chemical reaction. To test this hypothesis, the catalytic reduction of 4-nitrophenol was selected to evaluate the collective properties of the micellar assemblies in a chemical reaction. PMID- 26241214 TI - Pit-a-Pat: A Smart Electrocardiogram System for Detecting Arrhythmia. AB - BACKGROUND: Electrocardiogram (ECG) telemonitoring is one of the most promising applications of medical telemetry. However, previous approaches to ECG telemonitoring have largely relied on public databases of ECG results. MATERIALS AND METHODS: In this article we propose a smart ECG system called Pit-a-Pat, which extracts features from ECG signals and detects arrhythmia. It is designed to run on an AndroidTM (Google, Mountain View, CA) device, without requiring modifications to other software. RESULTS: We implemented the Pit-a-Pat system using a commercial ECG device, and the experimental results demonstrate the effectiveness and accuracy of Pit-a-Pat for monitoring the ECG signal and analyzing the cardiac activity of a mobile patient. CONCLUSIONS: The proposed system allows monitoring of cardiac activity with automatic analysis, thereby providing a convenient, inexpensive, and ubiquitous adjunct to personal healthcare. PMID- 26241215 TI - Novel Asymmetric Formylation of Aromatic Compounds: Enantioselective Synthesis of Formyl 7,8-Dipropyltetrathia[7]helicenes. AB - Asymmetric formylation of aromatic compounds is virtually unexplored. We report the synthesis and evaluation of a library including 20 new chiral formamides in the kinetic resolution of 7,8-dipropyltetrathia[7]helicene, affording the corresponding formyl- or diformylhelicenes in up to 73 % ee, making enantiopure compounds available by recrystallisation. With the N,N-disubstituted formamides used in this study, the best enantioselectivity has been achieved with R(1) =iPr, R(2) =Me, R(3) =H, R(4) =1-naphthyl or its 1-pyrenyl equivalent. PMID- 26241216 TI - Increased expression and activation of cathepsin K in human osteoarthritic cartilage and synovial tissues. AB - Few studies have analyzed Cathepsin K (CatK) expression in human osteoarthritic tissues. We investigated CatK expression and activation in human articular cartilage using clinical specimens. Human osteoarthritic cartilage was obtained during surgery of total hip arthroplasty (n = 10), and control cartilage was from that of femoral head replacement for femoral neck fracture (n = 10). CatB, CatK, CatL, CatS, and Cystatin C (CysC) expressions were evaluated immunohistochemically and by real-time PCR. Intracellular CatK protein was quantified by ELISA. Intracellular CatK activity was also investigated. Osteoarthritis (OA) chondrocytes were strongly stained with CatK, particularly in the superficial layer and more damaged areas. CatB, CatL, CatS, and CysC were weakly stained. CatK mRNA expression was significantly higher in OA group compared to that in control group (p = 0.043), whereas those of CatB, CatL, CatS, and CysC did not differ significantly. Mean CatK concentration (4.83 pmol/g protein) in OA chondrocytes was higher than that (3.91 pmol/g protein) in control chondrocytes (p = 0.001). CatK was enzymatically more activated in OA chondrocytes as compared with control chondrocytes. This study, for the first time, revealed increased CatK expression and activation in human OA cartilage, suggesting possible crucial roles for it in the pathogenesis of osteoarthritic change in articular cartilage. PMID- 26241218 TI - Water-Soluble Gold Nanoparticles: From Catalytic Selective Nitroarene Reduction in Water to Refractive Index Sensing. AB - Water-soluble gold nanoparticles (Au NPs) stabilized by a nitrogen-rich poly(ethylene glycol) (PEG)-tagged substrate have been prepared by reduction of HAuCl4 with NaBH4 in water at room temperature. The morphology and size of the nanoparticles can be controlled by simply varying the gold/stabilizer ratio. The nanoparticles have been fully characterized by TEM, high-resolution (HR) TEM, electron diffraction (ED), energy-dispersive X-ray spectroscopy (EDS), UV/Vis, powder XRD, and elemental analysis. The material is efficient as a recyclable catalyst for the selective reduction of nitroarenes with NaBH4 to yield the corresponding anilines in water at room temperature. Furthermore, the potential ability of the Au NPs as a refractive index sensor owing to their localized surface plasmon resonance (LSPR) effect has also been assessed. PMID- 26241217 TI - Biosynthesis of D-xylulose 5-phosphate from D-xylose and polyphosphate through a minimized two-enzyme cascade. AB - Sugar phosphates cannot be produced easily by microbial fermentation because negatively-charged compounds cannot be secreted across intact cell membrane. D xylulose 5-phosphate (Xu5P), a very expensive sugar phosphate, was synthesized from D-xylose and polyphosphate catalyzed by enzyme cascades in one pot. The synthetic enzymatic pathway comprised of xylose isomerase and xylulokinase was designed to produce Xu5P, along with a third enzyme, polyphosphate kinase, responsible for in site ATP regeneration. Due to the promiscuous activity of the ATP-based xylulokinase from a hyperthermophilic bacterium Thermotoga maritima on polyphosphate, the number of enzymes in the pathway was minimized to two without polyphosphate kinase. The reactions catalyzed by the two-enzyme and three-enzyme pathways were compared for Xu5P production, and the reaction conditions were optimized by examining effects of reaction temperature, enzyme ratio and substrate concentration. The optimized two-enzyme system produced 32 mM Xu5P from 50 mM xylose and polyphosphate after 36 h at 45 degrees C. Biosynthesis of less costly Xu5P from D-xylose and polyphosphate could be highly feasible via this minimized two-enzyme pathway. PMID- 26241219 TI - HHV-6 encephalitis may complicate the early phase after allogeneic hematopoietic stem cell transplantation: Detection by qualitative multiplex PCR and subsequent quantitative real-time PCR. AB - Viral reactivation following hematopoietic stem cell transplantation (HSCT) can cause various complications especially viral encephalitis. In this prospective study, we investigated the correlation of post-HSCT viral reactivation in blood with CNS dysfunction. We employed a multiplex PCR that detects 13 kinds of viruses as a first-line screening test and real-time PCR for subsequent quantitative evaluation. Five hundred ninety-one whole blood samples were collected from 105 patients from before until 42 days after HSCT. Seven patients developed CNS dysfunction such as altered consciousness. In six of the seven, the multiplex PCR test detected HHV-6 DNA in at least one sample. In contrast, DNA from other viruses, such as CMV, EBV, HHV-7, adenovirus, and HBV was never detected in any of the seven patients throughout the study period. Quantitative measurement of whole blood HHV-6 DNA levels demonstrated four of the six HHV-6 DNA loads were elevated at successive time points during the CNS dysfunction. In addition, the virus DNA peaks were temporally associated with the development of CNS dysfunction. CSF was tested in two of the four patients and high HHV-6 DNA levels comparable to those in whole blood were confirmed in both. These four patients were, thus, suspected to have developed HHV-6 encephalitis, a rate of 3.8% in the study population. Our results suggest that early diagnosis of probable HHV-6 encephalitis can be improved by confirming high HHV-6 DNA load in blood. PMID- 26241221 TI - Risky Treatments: A Jewish Medical Ethics Perspective. AB - The Jewish principle concerning a decision with regard to a dangerous treatment is as following: A patient who is estimated to die within 12 months because of a fatal illness is permitted to undergo a treatment that on the one hand may extend his life beyond 12 months, but on the other hand may hasten his death. There are, however, several limitations to this ruling related to the chances of success with the proposed treatment, the nature of the treatment, whether it is intended to be curative or merely to postpone the danger and death, whether the treatment is absolutely necessary, and others. One is not obligated to undergo a dangerous treatment, but one is permitted to do so. The permissibility to forfeit a short life expectancy in order to achieve more prolonged life applies only with the patient's consent. That consent is valid and is not considered a form of attempted suicide. Neither is a refusal to submit to treatment considered an act of suicide; the patient has the right to refuse a dangerous procedure. In all situations where a permissive ruling is granted for a patient to endanger his short life expectancy, the ruling should be arrived at after careful reflection and with the approval of the rabbinic authorities acting on the recommendation of the most expert physicians. PMID- 26241220 TI - Lung Edema Clearance: Relevance to Patients with Lung Injury. AB - Pulmonary edema clearance is necessary for patients with lung injury to recover and survive. The mechanisms regulating edema clearance from the lungs are distinct from the factors contributing edema formation during injury. Edema clearance is effected via vectorial transport of Na(+) out of the airspaces which generates an osmotic gradient causing water to follow the gradient out of the cells. This Na(+) transport across the alveolar epithelium is mostly effected via apical Na(+) and chloride channels and basolateral Na,K-ATPase. The Na,K-ATPase pumps Na(+) out of the cell and K(+) into the cell against their respective gradients in an ATP-consuming reaction. Two mechanisms contribute to the regulation of the Na,K-ATPase activity:recruitment of its subunits from intracellular compartments into the basolateral membrane, and transcriptional/translational regulation. Na,K-ATPase activity and edema clearance are increased by catecholamines, aldosterone, vasopressin, overexpression of the pump genes, and others. During lung injury, mechanisms regulating edema clearance are inhibited by yet unclear pathways. Better understanding of the mechanisms that regulate pulmonary edema clearance may lead to therapeutic interventions that counterbalance the inhibition of edema clearance during lung injury and improve the lungs' ability to clear fluid, which is crucial for patient survival. PMID- 26241222 TI - The Egg and the Nucleus: A Battle for Supremacy. AB - POST-NOBEL PERSPECTIVE: This brief introduction is followed by a published version of my Nobel Laureate lecture, re-published herein with the kind permission of the Nobel Foundation. Much has happened since my original research, for which that prize was awarded. Hence, I am pleased to offer a few thoughts about the future of my research and its possible impact on humankind.Although the original work on nuclear transfer and reprogramming was done over half a century ago, advances continue to be made. In particular the Takahashi and Yamanaka induced pluripotent stem cells (iPS) procedure has opened up the field of cell replacement to a great extent. Now, more recently, further advances make this whole field come closer to actual usefulness for humans. Recently, in the UK, the government approved the use of mitochondrial replacement therapy to avoid the problems associated with genetically defective mitochondria in certain women. Although the House of Commons (members of Parliament) and the House of Lords had to debate and discuss whether to allow this kind of human therapy, I was very pleased to find that both bodies approved this procedure. This means that a patient can choose to make use of the procedure; it does not in any way force an individual to have a procedure that they are not comfortable with. In my view, this is a great advance in respect to giving patients a choice about the treatment they receive. I am told that the UK is the first country in the world to approve mitochondrial replacement therapy.Now that the Clustered Regularly Interspaced Short Palindromic Repeat (CRISPr) technology is being widely used and works well, one can foresee that there will be those who wish to use this technology to make genetic changes to humans. For example, if a human has a gene that makes it susceptible to infection or any other disorder, the removal of that gene might give such a person immunity from that disease. If this gene deletion is done within the germ line, the genetic change will be inherited. However, one can imagine that various people will strongly object and say that this technology should not be allowed. I would very much hope that various regulatory bodies, governments, etc. will allow the choice to remain with the individual. I can see no argument for such bodies to make a law that removes any choice whatsoever by an individual. PMID- 26241223 TI - The Number Needed to Treat: 25 Years of Trials and Tribulations in Clinical Research. AB - The number needed to treat (NNT) is a simple measure of a treatment's impact, increasingly reported in randomized trials and observational studies, but often incorrectly calculated in studies involving varying follow-up times. We discuss the NNT in these contexts and illustrate the concept using several published studies. While the computation of the NNT is founded on the cumulative incidence of the outcome, several published studies use simple proportions that do not account for varying follow-up times, or use incidence rates per person-time. We show how these approaches can lead to erroneous values of the NNT and misleading interpretations. For example, a trial of 3,845 very elderly hypertensives randomized to a diuretic or placebo reported a NNT of 94 treated for 2 years to prevent one stroke, though the correct approach results in a NNT of 63. Also, meta-analyses involving trials of differing lengths often report a single NNT, such as the meta-analysis of 22 trials of the anticholinergic tiotropium in chronic obstructive pulmonary disease that reported a NNT of 16 patients "over one year," even if the trials varied in duration from 3 to 48 months, with the actual NNTs varying widely from 15 to 250. Finally, we describe the value of the NNT in assessing benefit-risk, such as low-dose aspirin use in secondary prevention of mortality assessed against the risk of gastrointestinal bleeding. As the "number needed to treat" becomes increasingly used in the comparative effectiveness and safety of therapies, its accurate estimation and interpretation become crucial to avoid distorting clinical, economic, and public health decisions. PMID- 26241224 TI - Author's Reply to Professionalism-The Role of Quality Improvement. PMID- 26241227 TI - Correction for the Article "MRI-Guided Electrophysiology Intervention" by Henry R. Halperin and Aravindan Kolandaivelu. PMID- 26241226 TI - The Effect of Ivabradine on the Heart Rate and Sympathovagal Balance in Postural Tachycardia Syndrome Patients. AB - BACKGROUND: Postural tachycardia syndrome (POTS) is a common form of chronic orthostatic intolerance. The remarkable increase in heart rate (HR) upon standing is the hallmark of this syndrome. Treatment of POTS patients is challenging and includes drugs that slow the HR. Ivabradine is a selective If channel blocker designed to slow the HR, as an anti-anginal agent. In view of its ability to slow the HR, we posited that ivabradine may be an ideal medication for treating POTS patients. This report provides the results of an investigation in which we studied ivabradine's effect on the hemodynamics and sympathovagal balance in POTS patients. METHODS: An open-label trial, without a placebo control, was performed in eight patients with POTS of two years' standing. Characterization of symptoms, hemodynamics, autonomic function tests, and HR and blood pressure (BP) variability were determined while patients were in a supine position and during a 20-minute head-up tilt before and after a single oral dose of 7.5 mg ivabradine. RESULTS: Ivabradine slowed the HR of POTS patients at rest by 4+/-1 bpm (P<0.05). During a 5-minute head-up tilt, the HR decreased from 118+/-4 bpm to 101+/-5 bpm (P<0.01). Ivabradine did not affect the BP when patients were at rest in a supine position or in head-up tilt position. Cardiovascular vagal and sympathetic tone, extrapolated from the time and frequency domains of the HR and BP variability, were also not affected by ivabradine. CONCLUSIONS: Ivabradine is an effective drug for slowing the HR of POTS patients at rest and during tilting, without producing significant adverse effects. Moreover, ivabradine exerts its effects without influencing the sympathovagal balance. PMID- 26241229 TI - Letter to the Editor: Professionalism-The Role of Quality Improvement. PMID- 26241228 TI - Unusual Manifestations of Monoclonal Gammopathy: I. Ocular Disease. AB - Essential monoclonal gammopathy is usually an asymptomatic condition, the characteristics of which have been defined over approximately 70 years of study. It has a known population-attributable risk of undergoing clonal evolution to a progressive, symptomatic B-cell neoplasm. In a very small fraction of patients, the monoclonal immunoglobulin has biophysical characteristics that can lead to tissue deposition syndrome (e.g. Fanconi renal syndrome) or, by chance, have characteristics of an autoantibody that may inactivate critical proteins (e.g. acquired von Willebrand disease). In this report, we describe the very uncommon forms of ocular injury that may accompany essential monoclonal gammopathy, which include crystalline keratopathy, crystal-storing histiocytosis, hypercupremic keratopathy, and maculopathy. The first three syndromes result from uncommon physicochemical alterations of the monoclonal immunoglobulin that favor crystallization or exaggerated copper binding. The last-mentioned syndrome is of uncertain pathogenesis. These syndromes may result in decreased visual acuity. These ocular findings may lead, also, to the diagnosis of monoclonal gammopathy. PMID- 26241230 TI - Mitochondrial Replacement Therapy: Halachic Considerations for Enrolling in an Experimental Clinical Trial. AB - The transition of new biotechnologies into clinical trials is a critical step in approving a new drug or therapy in health care. Ethically recruiting appropriate volunteers for these clinical trials can be a challenging task for both the pharmaceutical companies and the US Food and Drug Administration. In this paper we analyze the Jewish halachic perspectives of volunteering for clinical trials by focusing on an innovative technology in reproductive medicine, mitochondrial replacement therapy. The halachic perspective encourages individuals to volunteer for such clinical trials under the ethical principles of beneficence and social responsibility, when animal studies have shown that health risks are minimal. PMID- 26241225 TI - The Envy of Scholars: Applying the Lessons of the Framingham Heart Study to the Prevention of Chronic Kidney Disease. AB - During the past 50 years, a dramatic reduction in the mortality rate associated with cardiovascular disease has occurred in the US and other countries. Statistical modeling has revealed that approximately half of this reduction is the result of risk factor mitigation. The successful identification of such risk factors was pioneered and has continued with the Framingham Heart Study, which began in 1949 as a project of the US National Heart Institute (now part of the National Heart, Lung, and Blood Institute). Decreases in total cholesterol, blood pressure, smoking, and physical inactivity account for 24%, 20%, 12%, and 5% reductions in the mortality rate, respectively. Nephrology was designated as a recognized medical professional specialty a few years later. Hemodialysis was first performed in 1943. The US Medicare End-Stage Renal Disease (ESRD) Program was established in 1972. The number of patients in the program increased from 5,000 in the first year to more than 500,000 in recent years. Only recently have efforts for risk factor identification, early diagnosis, and prevention of chronic kidney disease (CKD) been undertaken. By applying the approach of the Framingham Heart Study to address CKD risk factors, we hope to mirror the success of cardiology; we aim to prevent progression to ESRD and to avoid the cardiovascular complications associated with CKD. In this paper, we present conceptual examples of risk factor modification for CKD, in the setting of this historical framework. PMID- 26241232 TI - Unusual Manifestations of Essential Monoclonal Gammopathy. II. Simulation of the Insulin Autoimmune Syndrome. AB - In rare cases, the monoclonal immunoglobulin that characterizes essential monoclonal gammopathy interacts with a self-antigen with functional consequences and a resulting clinical syndrome. This event is presumably random and results from the clone of B lymphocytes making a monoclonal immunoglobulin that simulates an autoimmune antibody. Thus, by chance, the monoclonal immunoglobulin has sufficient affinity for an epitope on a normal protein that functional consequences ensue. One such rare event is the synthesis and secretion of a monoclonal immunoglobulin that binds to human insulin. Inactivation of insulin by antibody results in (1) an early postprandial hyperglycemia, (2) followed by either or both (i) a reactive overshot in insulin secretion, as a result of hypertrophied or hyperplastic islet beta cells, later falling glucose levels, and (ii) an unpredictable dissociation of insulin from the complex, and, several hours later, (3) a resultant increase in free insulin levels and severe hypoglycemia with clinical consequences, ranging from sweating, dizziness, headache, and tremors to confusion, seizures, and unconsciousness. These attacks are invariably responsive to glucose administration. This very uncommon manifestation of a monoclonal gammopathy can occur in patients with essential monoclonal gammopathy or myeloma. The monoclonal anti-insulin immunoglobulin in monoclonal gammopathy has a low affinity for insulin, but has a high capacity for insulin-binding, resulting in the syndrome of episodic hypoglycemic attacks. This phenomenon of an insulin-binding monoclonal immunoglobulin simulates the acquired insulin autoimmune syndrome, although the latter is mediated by a polyclonal antibody response in the majority of cases studied, and has linkage to HLA class II alleles. PMID- 26241233 TI - Fifth Anniversary of Rambam Maimonides Medical Journal: From Concept to Action and Success. PMID- 26241231 TI - Role of Regulatory T Cells (Treg) and the Treg Effector Molecule Fibrinogen-like Protein 2 in Alloimmunity and Autoimmunity. AB - CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) are critical to the maintenance of immune tolerance. Treg are known to utilize a number of molecular pathways to control immune responses and maintain immune homeostasis. Fibrinogen-like protein 2 (FGL2) has been identified by a number of investigators as an important immunosuppressive effector of Treg, which exerts its immunoregulatory activity by binding to inhibitory FcgammaRIIB receptors expressed on antigen-presenting cells including dendritic cells, endothelial cells, and B cells. More recently, it has been suggested that FGL2 accounts for the immunosuppressive activity of a highly suppressive subset of Treg that express T cell immunoreceptor with Ig and ITIM domains (TIGIT). Here we discuss the important role of Treg and FGL2 in preventing alloimmune and autoimmune disease. The FGL2-FcgammaRIIB pathway is also known to be utilized by viruses and tumor cells to evade immune surveillance. Moving forward, therapies based on modulation of the FGL2 FcgammaRIIB pathway hold promise for the treatment of a wide variety of conditions ranging from autoimmunity to cancer. PMID- 26241234 TI - The Long and Winding Road to Innovation. AB - Medicine is developing through biomedical technology and innovations. The goal of any innovation in medicine is to improve patient care. Exponential growth in technology has led to the unprecedented growth of medical technology over the last 50 years. Clinician-scientists need to understand the complexity of the innovation process, from concept to product release, when working to bring new clinical solutions to the bedside. Hence, an overview of the innovation process is provided herein. The process involves an invention designed to solve an unmet need, followed by prototype design and optimization, animal studies, pilot and pivotal studies, and regulatory approval. The post-marketing strategy relative to funding, along with analysis of cost benefit, is a critical component for the adoption of new technologies. Examples of the road to innovation are provided, based on the experience with development of the transcatheter aortic valve. Finally, ideas are presented to contribute to the further development of this worldwide trend in innovation. PMID- 26241235 TI - Dysphonia and Dysphagia: Electrophysiological Techniques From the Laboratory to the Clinical Practice. PMID- 26241236 TI - Laryngeal Electromyography Techniques and Clinical Use. AB - Laryngeal electromyography is considered a valuable diagnostic tool for voice disorders. The technique, described almost 70 years ago, evolved 3 decades later, mainly because of the growing interest of laryngologists and speech pathologists. In the authors' opinion, the reduced number of neurophysiologists involved in laryngeal electromyography groups is, at some instance, related to the difficulty to start the learning process and the multidisciplinary approach the field requires. This review highlights the anatomy and physiology needed to perform laryngeal electromyography and its clinical usefulness in the new field known as neurolaryngology. PMID- 26241239 TI - An Overview of Laryngeal Muscle Single Fiber Electromyography. AB - Needle electromyography is an important tool in the diagnosis of neuromuscular diseases and has also been applied successfully in the evaluation of the vocal cord paralysis. Laryngeal electromyography, initially described by Weddell, is used to determine the cause of vocal cord paralysis and to differentiate organic from nonorganic causes of speech disorders. This test allows the diagnosis of lower motor neuron and nerve paralysis as well as myopathies. Laryngeal electromyography also helps to determine the prognosis of paralysis caused by traumatic injury of the laryngeal nerves and is used for guidance during botulinum toxin injection in spasmodic dysphonias. Single fiber electromyography is used to diagnose abnormalities of neuromuscular transmission and is applied in the study the architecture of the motor unit in muscles. This article reviews the techniques of laryngeal muscles single fiber electromyography, provides limited informative data, and discusses its potential value in the evaluation of patients with dysphonia. PMID- 26241238 TI - Central Nervous System Control of Voice and Swallowing. AB - This review of the central nervous control systems for voice and swallowing has suggested that the traditional concepts of a separation between cortical and limbic and brain stem control should be refined and be more integrative. For voice production, a separation of the nonhuman vocalization system from the human learned voice production system has been posited based primarily on studies of nonhuman primates. However, recent humans studies of emotionally based vocalizations and human volitional voice production have shown more integration between these two systems than previously proposed. Recent human studies have shown that reflexive vocalization as well as learned voice production not involving speech involve a common integrative system. However, recent studies of nonhuman primates have provided evidence that some cortical activity vocalization and cortical changes occur with training during vocal behavior. For swallowing, evidence from the macaque and functional brain imaging in humans indicates that the control for the pharyngeal phase of swallowing is not primarily under brain stem mechanisms as previously proposed. Studies suggest that the initiation and patterning of swallowing for the pharyngeal phase is also under active cortical control for both spontaneous as well as volitional swallowing in awake humans and nonhuman primates. PMID- 26241240 TI - Multi-Motor Unit Potential Analysis and Other Quantitative Techniques for Laryngeal Electromyogram. AB - Reference values for motor unit potentials of laryngeal muscles, the thyroarytenoid (TA) and cricothyroid (CT) muscles, have been collected using multi-motor unit potential quantitative electromyogram analysis technique with concentric quantitative electromyogram-needle electrode type in 40 healthy volunteers. The method is well tolerated, easy to perform, and examination of one muscle takes usually around 5 minutes. The mean motor unit potential amplitude of both muscles was significantly larger in men than in women. The method can safely be used in clinical routine. Other quantitative electromyogram methods are also shortly reviewed. PMID- 26241237 TI - Laryngeal Reflexes: Physiology, Technique, and Clinical Use. AB - This review examines the current level of knowledge and techniques available for the study of laryngeal reflexes. Overall, the larynx is under constant control of several systems (including respiration, swallowing and cough) as well as sensory motor reflex responses involving glossopharyngeal, pharyngeal, laryngeal, and tracheobronchial sensory receptors. Techniques for the clinical assessment of these reflexes are emerging and need to be examined for sensitivity and specificity in identifying laryngeal sensory disorders. Quantitative assessment methods for the diagnosis of sensory reductions and sensory hypersensitivity may account for laryngeal disorders, such as chronic cough, paradoxical vocal fold disorder, and muscular tension dysphonia. The development of accurate assessment techniques could improve our understanding of the mechanisms involved in these disorders. PMID- 26241241 TI - Electrophysiological Techniques to Evaluate Swallowing in Central and Peripheral Nervous System Disorders. AB - Neurogenic dysphagia is a frequent condition that may result in serious complications. Despite high incidence of neurogenic dysphagia, the neurologist is not really interested in its clinical diagnosis and management. In this review, several neurophysiological methods are described to evaluate the neurogenic dysphagia. These kinds of assessment methods are important for early diagnosis and some management strategies against to progressive swallowing pathology. The longitudinal follow-up of the patients also provides data about the prognosis of dysphagia. In our opinion, the neurophysiological methods presented in this review are reliable, cheap, and easy applicable quantitative tests to detect and follow both clinical and subclinical dysphagia. All these electrophysiological techniques can be applied within the discipline of the EMG laboratory. PMID- 26241242 TI - Diagnostic Accuracy of Electrographic Seizure Detection by Neurophysiologists and Non-Neurophysiologists in the Adult ICU Using a Panel of Quantitative EEG Trends. AB - PURPOSE: To evaluate the sensitivity and specificity of a panel of quantitative EEG (qEEG) trends for seizure detection in adult intensive care unit (ICU) patients when reviewed by neurophysiologists and non-neurophysiologists. METHODS: One hour qEEG panels (n = 180) were collected retrospectively from 45 ICU patients and were distributed to 5 neurophysiologists, 7 EEG technologists, and 5 Neuroscience ICU nurses for evaluation of seizures. Each panel consisted of the following qEEG tools, displayed separately for left and right hemisphere electrodes: rhythmicity spectrogram (rhythmic run detection and display; Persyst Inc), color density spectral array, EEG asymmetry index, and amplitude integrated EEG. The reviewers did not have access to the raw EEG data. RESULTS: For the reviewer's ability to detect the presence of seizures on qEEG panels when compared with the gold standard of independent raw EEG review, the sensitivities and specificities are as follows: neurophysiologists 0.87 and 0.61, EEG technologists 0.80 and 0.80, and Neuroscience ICU nurses 0.87 and 0.61, respectively. There was no statistical difference among the three groups regarding sensitivity. CONCLUSIONS: Quantitative EEG display panels are a promising tool to aid detection of seizures by non-neurophysiologists as well as by neurophysiologists. However, even when used as a panel, qEEG trends do not appear to be adequate as the sole method for reviewing continuous EEG data. PMID- 26241243 TI - Intraindividual Variability and Long-Term Changes of Thermal Quantitative Sensory Testing. AB - Thermal threshold examinations are widely used in the clinical setting and in studies to assess the function of the peripheral sensory nervous system. Little is known about the variation from one side of the body to the other and the long term temporal changes and variability. In this study, 134 healthy subjects were stimulated at the dorsum of the hand, lower arm, upper arm, thorax, abdomen, thigh, lower leg, and dorsum of the foot bilaterally to determine the cold detection threshold and the warmth detection threshold. Forty-eight subjects were reexamined after 2 weeks and 26 weeks at the hand and foot. Bilateral stimulations resulted in relative intertrial variations ranging from 19% to 40%. There was no significant temporal change for repeated measures. Analysis of the individual measurements of each subject at baseline and at 26 weeks, however, resulted in relatively large intertrial variations of 19% to 42%. Sample sizes ranging from 42 to 76 subjects in each group would be required to detect a minimal relevant difference of the magnitude of the 95 percentile of the absolute changes. Attention should be given to the relatively large intraindividual variation when used as a tool for diagnosis or monitoring in the clinical setting. Cold and warmth detection threshold are well suited as outcome measures in longitudinal studies. PMID- 26241244 TI - Motor and Sensory Axon Excitability Properties From the Median and Ulnar Nerves and the Effects of Age on These Properties. AB - PURPOSE: Threshold tracking is a new noninvasive approach for detecting axonal excitability changes in vivo. In this study, the authors compared the excitability indices of motor and sensory axons of median and ulnar nerves to determine whether the two nerves behave in a similar or a noninterchangeable way. They also examined whether age affects these indices. METHODS: Seventy normal subjects aged 22-70 years (mean, 36.7 +/- 12.5 years) were recruited. Multiple excitability indices were measured in both motor and sensory axons from median and ulnar nerves. RESULTS: The threshold and rheobase were significantly higher for the ulnar motor axons recorded at the first dorsal interosseous muscle than for the median motor axons at the abductor pollicis brevis muscle. In contrast, the strength-duration time constant was decreased, threshold electrotonus reduction (in both depolarizing and hyperpolarizing directions) was significantly smaller, I/V slope was decreased, and subexcitability was reduced for the ulnar motor axons. Excitability indices measured in the sensory axons of both nerves were not overtly different. In R-square analysis, age had a homogeneous influence on sensory axon excitability but heterogeneous influence on motor axon excitability. CONCLUSIONS: The excitability indices may be interchangeable for sensory axons but not motor axons. The authors therefore recommend recording motor axonal excitability in various muscle groups rather than a single muscle group. PMID- 26241245 TI - What Does One Sleep-Onset REM Period-During Either Nocturnal Polysomnography or Multiple Sleep Latency Test-Mean in Differential Diagnosis of Central Hypersomnias? AB - PURPOSE: The differentiation of narcolepsy without cataplexy from idiopathic hypersomnia is based on the number of sleep-onset rapid eye movement periods (SOREMPs) observed by multiple sleep latency test (MSLT) and nocturnal polysomnography. The main aim of this study was to investigate the utility of SOREMP in differential diagnosis of central hypersomnias. METHODS: The authors retrospectively evaluated consecutive 101 patients with a normal polysomnography other than the presence of SOREMP and/or REM without atonia and a latency of <=8 minutes in MSLT. RESULTS: The authors classified patients as follows: 52 patients had at least 2 SOREMPs (narcolepsy group), 23 had no SOREMPs (idiopathic hypersomnia group), and 26 patients had only 1 SOREMP (intermediate group). In polysomnographic recordings, both mean sleep latency and REM latency were significantly shorter in the narcolepsy (P = 0.012, P < 0.001, respectively) and intermediate groups (P = 0.005 and P = 0.035, respectively) compared with the idiopathic hypersomnia group. In MSLT recordings, sleep latency was 2.7 +/- 2.2 minutes in the narcolepsy group, 3.6 +/- 1.4 minutes in the intermediate group, and 5.2 +/- 2.7 minutes in the idiopathic hypersomnia group (P < 0.001). The mean REM latency and sleep stages SOREMPs arised from were similar between the narcolepsy and intermediate groups. CONCLUSIONS: To date, SOREMPs in MSLT and polysomnography remain the sole electrodiagnostic feature that discriminates narcolepsy without cataplexy from idiopathic hypersomnia. Different parameters or combined criteria are being increasingly investigated to increase the sensitivity and specificity of MSLT. The findings showed an altered instability of REM sleep not only in patients with 2 or more SOREMPs in MSLT but also in patients with one SOREMP. PMID- 26241246 TI - Auditory and Lower Limb Tactile Prepulse Inhibition in Primary Restless Legs Syndrome: Clues to Its Pathophysiology. AB - The resting sensory discomfort transiently relieved upon movement of the affected area in restless legs syndrome suggests that sensorimotor integration mechanisms, specifically gating, may be altered in the disease. The authors sought to determine the effects of prepulse auditory and tactile stimulation applied to lower limbs on the blink reflex of patients with restless legs syndrome and healthy subjects. Seventeen patients with restless legs syndrome and 17 age- and sex-matched healthy controls were investigated. Auditory stimuli and tactile lower limb stimulation were applied as prepulses. The R2 response of the blink reflex induced by electrical stimulation applied to the right supraorbital nerve was selected as the test stimulus. Time intervals between prepulses and response eliciting stimuli were 40, 70, 90, 110, and 200 milliseconds. There were no differences in either the auditory or tactile prepulse conditions between patients and controls and no differences between these measures within subject groups. We concluded that the tactile lower limb and the auditory prepulse effects on the brainstem interneurons mediating the blink reflex share common neural pathways. Because forebrain interneurons mediate these prepulse effects, they are likely not involved in the disordered sensorimotor interaction of restless legs syndrome. PMID- 26241247 TI - Rapid Screening for Carpal Tunnel Syndrome: A Novel Method and Comparison With Established Others. AB - PURPOSE: The authors have observed that in healthy people, the Ulnar wrist-to first dorsal interosseous distal motor latency does not differ significantly compared with median wrist-to-abductor pollicis brevis distal motor latency. The aim of our study was to investigate whether the difference between these two latencies can be used as a screening tool for diagnosing carpal tunnel syndrome and how this technique compares with other established techniques. METHODS: The study was set up as a prospective observational study. As gold standard for the clinical diagnosis of carpal tunnel syndrome, the authors used the opinion of two neurologists who independently examined the patients. A third neurologist, also independently, performed the electrophysiological study. RESULTS: Eighty-four subjects, 42 patients and 42 age- and sex-matched controls, participated in the study. Among all subjects using a receiver operating characteristic curve analysis, the area under the curve was 0.924 (95% CI, 0.857-0.991; SE, 0.034; P < 0.001). To detect carpal tunnel syndrome, at a cutoff score of equal to or greater than 0.575 milliseconds, our technique showed a sensitivity of 91%, a specificity of 93%, a positive predictive value of 93%, and a negative predictive value of 91%. Compared with other "classical" techniques, our technique showed better area under the receiver operating characteristic curve and better Youden index. CONCLUSIONS: The median wrist-to-abductor pollicis brevis motor latency minus ulnar wrist-to-first dorsal interosseous motor latency may be used as a novel rapid screening tool of patients suffering from carpal tunnel syndrome. PMID- 26241248 TI - Intrauterine Device Insertion During Cesarean Delivery: The Rising Tide of the Postdelivery Intrauterine Device. PMID- 26241249 TI - The Evolution of Medication Abortion Care: Using Science to Achieve Quality. PMID- 26241250 TI - Intrauterine Device Placement During Cesarean Delivery and Continued Use 6 Months Postpartum: A Randomized Controlled Trial. AB - OBJECTIVE: To compare intrauterine device (IUD) use at 6 months postpartum among women who underwent intracesarean delivery (during cesarean delivery) IUD placement compared with women who planned for interval IUD placement 6 or more weeks postpartum. METHODS: In this nonblinded randomized trial, women who were undergoing a cesarean delivery and desired an IUD were randomized to intracesarean delivery or interval IUD placement. The primary outcome was IUD use at 6 months postpartum. A sample size of 112 (56 in each group) was planned to detect a 15% difference in IUD use at 6 months postpartum between groups. RESULTS: From March 2012 to June 2014, 172 women were screened and 112 women were randomized into the trial. Baseline characteristics were similar between groups. Data regarding IUD use at 6 months postpartum were available for 98 women, 48 and 50 women in the intracesarean delivery and interval groups, respectively. A larger proportion of the women in the intracesarean delivery group were using an IUD at 6 months postpartum (40/48 [83%]) compared with those in the interval group (32/50 [64%], relative risk 1.3, 95% confidence interval 1.02-1.66). Among the 56 women randomized to interval IUD insertion, 22 (39%) of them never received an IUD; 14 (25%) never returned for IUD placement, five (9%) women declined an IUD, and three (5%) had a failed IUD placement. CONCLUSION: Intrauterine device placement at the time of cesarean delivery leads to a higher proportion of IUD use at 6 months postpartum when compared with interval IUD placement. LEVEL OF EVIDENCE: I. PMID- 26241251 TI - Mifepristone With Buccal Misoprostol for Medical Abortion: A Systematic Review. AB - OBJECTIVE: To summarize clinical outcomes and adverse effects of medical abortion regimens consisting of mifepristone followed by buccal misoprostol in pregnancies through 70 days of gestation. DATA SOURCES: We used PubMed, ClinicalTrials.gov, and reference lists from published reports to identify relevant studies published between November 2005 and January 2015 using the search terms "mifepristone and medical abortion" and "buccal and misoprostol." METHODS OF STUDY SELECTION: Studies were included if they presented clinical outcomes of medical abortion using mifepristone and buccal misoprostol through 70 days of gestation. Studies with duplicate data were excluded. TABULATION, INTEGRATION, AND RESULTS: We included 20 studies with a total of 33,846 women through 70 days of gestation. We abstracted efficacy and ongoing pregnancy rates as an overall rate and by gestational age in days in reference to completed weeks (eg, 49 days or less, 50 56 days, 57-63 days, 64-70 days) and adverse effects when reported. The overall efficacy of mifepristone followed by buccal misoprostol is 96.7% (95% confidence interval [CI] 96.5-96.8%) and the continuing pregnancy rate is 0.8% (95% CI 0.7 0.9%) in approximately 33,000 pregnancies through 63 days of gestation. Only 332 women with pregnancies between 64 and 70 days of gestation are reported in the literature with an overall efficacy of 93.1% (95% CI 89.6-95.5%) and a continuing pregnancy rate of 2.9% (95% CI 1.4-5.7%). Currently available data suggest that regimens with a 24-hour time interval between mifepristone and buccal misoprostol administration are slightly less effective than those with a 24- to 48-hour interval. Rates of surgical evacuation for reasons other than ongoing pregnancy range from 1.8% to 4.2%. Severe adverse events like blood transfusion (0.03-0.6%) and hospitalization (0.04-0.9%) are uncommon. CONCLUSION: Outpatient medical abortion regimens with mifepristone followed in 24-48 hours by buccal misoprostol are highly effective for pregnancy termination through 63 days of gestation. More data are needed to evaluate clinical outcomes with regimens containing mifepristone followed in 24 hours by buccal misoprostol and in pregnancies beyond 63 days of gestation. PMID- 26241252 TI - Medical Compared With Surgical Abortion for Effective Pregnancy Termination in the First Trimester. AB - OBJECTIVE: To compare efficacy between medical and surgical abortion at 9 weeks of gestation or less. METHODS: We performed a retrospective cohort study comparing efficacy of medical compared with surgical abortion before 64 days of gestation at Planned Parenthood, Los Angeles, from November 2010 to August 2013. Electronic medical records were reviewed for ongoing pregnancies after the initial abortion procedure. Data were also collected on complications occurring within the immediate postabortal period (8 weeks postabortal) including unanticipated aspiration and major adverse events (emergency department presentation, hospitalization, perforation, transfusion, infection). Chi square test and logistic regression were used to compare the primary outcomes between cohorts. RESULTS: Data were collected from 30,146 women with pregnancies seeking termination before 64 days of gestation. Sociodemographic and clinical characteristics were similar in the medication and surgical abortion groups. Efficacy of pregnancy termination was 99.6% for medication abortions and 99.8%% for surgical abortions (P<.001). The medication abortion group was more likely to undergo an unanticipated aspiration, for ongoing pregnancy or persistent pain, bleeding, or both (2.1% compared with 0.6%, respectively, odds ratio 1.6, 95% confidence interval 1.1-2.3). These rates were unchanged after controlling for gravidity, parity, and body mass index. There was no difference in major adverse events between the two groups. CONCLUSION: Medication abortion and surgical abortion before 64 days of gestation are both highly effective with low complication rates. LEVEL OF EVIDENCE: II. PMID- 26241253 TI - Ketorolac for Pain Control With Intrauterine Device Placement: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate intramuscular ketorolac compared with placebo saline injection for pain control with intrauterine device (IUD) placement. METHODS: We conducted a randomized, double-blind, placebo-controlled trial between July 2012 and March 2014. Patients received 30 mg ketorolac or placebo saline intramuscular injection 30 minutes before IUD placement. The primary outcome was pain with IUD placement on a 10-cm visual analog scale. Sample size was calculated to provide 80% power to show a 2.0-cm difference (alpha=0.05) in the primary outcome. Secondary outcomes included pain with study drug injection, speculum insertion, tenaculum placement, uterine sounding, and at 5 and 15 minutes after IUD placement. RESULTS: A total of 67 women participated in the study, 33 in the ketorolac arm and 34 in the placebo arm. There were no differences in baseline demographics including age, body mass index, and race. There were no differences in median pain scores for IUD placement in the placebo compared with ketorolac groups (5.2 compared with 3.6 cm, P=.99). There was a decrease in median pain scores at 5 minutes (2.2 compared with 0.3 cm, P<=.001) and 15 minutes (1.6 compared with 0.1 cm, P<=.001) after IUD placement but no difference for all other time points. Nulliparous participants (n=16, eight per arm) had a decrease in pain scores with IUD placement (8.1 compared with 5.4 cm, P=.02). In this study, 22% of participants in the placebo group and 18% in the ketorolac group reported injection pain was as painful as IUD placement. CONCLUSION: Ketorolac does not reduce pain with IUD placement but does reduce pain at 5 and 15 minutes after placement. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; www.clinicaltrials.gov, NCT01664559. LEVEL OF EVIDENCE: I. PMID- 26241254 TI - An Evaluation of Oral Midazolam for Anxiety and Pain in First-Trimester Surgical Abortion: A Randomized Controlled Trial. AB - OBJECTIVE: To estimate the effect of oral midazolam on patient pain and anxiety perception during first-trimester surgical abortion. METHODS: Between May and December 2013, we conducted a randomized, double-blind, placebo-controlled trial. Patients between 6 0/7 and 10 6/7 weeks of gestation received 10 mg oral midazolam or placebo 30-60 minutes before surgical abortion. All patients received ibuprofen and a paracervical block. We powered the study (power=80%; significance level=.025) to detect a 15-mm difference in our two a priori primary outcomes of pain and anxiety with uterine aspiration on a 100-mm visual analog scale. Secondary outcomes were pain and anxiety at additional time points, memory, satisfaction, side effects, and adverse events. RESULTS: Demographics were similar between groups (placebo=62, midazolam=62). Compared with those randomized to placebo, patients who received midazolam had significantly less anxiety preoperatively (room entry: 51.4 mm compared with 34.5 mm, P<.001; positioning: 56.6 mm compared with 45.4 mm, P=.02). There was no difference in pain (P=.28) or anxiety (P=.14) during uterine aspiration or at other procedural time points. A significantly greater number of patients in the midazolam group reported partial amnesia (31/61 compared with 16/61, P=.005) and dizziness (30/61 compared with 18/61, P=.03). Controlling for baseline differences, patients who received midazolam reported more postoperative sleepiness (P<.001) and less postoperative nausea (P=.004). There was no difference in overall satisfaction (P=.88). CONCLUSION: Although oral midazolam reduces preprocedural anxiety, it does not reduce pain or anxiety with uterine aspiration during first-trimester surgical abortions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01830881. LEVEL OF EVIDENCE: I. PMID- 26241256 TI - Four Residents' Narratives on Abortion Training: A Residency Climate of Reflection, Support, and Mutual Respect. AB - The decision on the part of obstetrics and gynecology residents to opt in or out of abortion training is, for many, a complex one. Although the public debate surrounding abortion can be filled with polarizing rhetoric, residents often discover that the boundaries between pro-choice and pro-life beliefs are not so neatly divided. We present narratives from four residents, training at a 32 resident program in the Northeast, who have a range of views surrounding abortion. Their stories reveal how some struggle with the real-life experience of providing abortions, while others feel angst over lacking the skills to terminate a life-threatening pregnancy. These residents have found that close relationships with coworkers from all sides of this issue, along with a residency program that encourages open conversation, have fostered understanding. Their narratives demonstrate that reasonable providers can disagree fundamentally and still work effectively with one another and that the close relationships formed in residency can allow both sides to see beyond the black and white of the public abortion debate. Our objectives in this commentary are to encourage a more nuanced discussion of abortion among obstetrician-gynecologists, to describe the aspects of our residency program that facilitate open dialogue and respect across diverse viewpoints, and to demonstrate that the clear distinction between being pro-life and pro-choice often breaks down when one is immediately responsible for the care of pregnant women. PMID- 26241255 TI - Cost-Effectiveness of Immediate Compared With Delayed Postpartum Etonogestrel Implant Insertion. AB - OBJECTIVE: To evaluate the cost-effectiveness of immediate compared with delayed (6 weeks) postpartum etonogestrel implant insertion in preventing future unintended pregnancy. METHODS: We constructed a decision-analytic model to examine a hypothetical population of women who request a contraceptive implant after giving birth. The timeframe for analysis was from the time of childbirth to 1 year postpartum. Model inputs were derived from a comprehensive literature review. We compared immediate (before discharge from the childbirth hospital stay) compared with delayed (at first postpartum office visit) postpartum placement of the contraceptive implant from a health care system's perspective. Implant insertion and removal, loss to follow-up at the postpartum visit, use of alternative contraceptive methods, and contraceptive failure were incorporated into the model. We calculated the incremental cost of immediate insertion for each pregnancy prevented during the first postpartum year and cost savings associated with pregnancies prevented. One-way sensitivity analyses were also performed. Cost estimates are reported in 2014 U.S. dollars. RESULTS: Immediate postpartum implant insertion is associated with higher expected cost than delayed insertion ($1,091/patient compared with $650/patient) but is more effective in preventing pregnancies (expected pregnancy rate: 2.4% and 21.6%, respectively). This results in an incremental cost-effectiveness ratio of $2,304 per pregnancy prevented. When taking into consideration medical costs of the resulting unintended pregnancies that could be avoided, immediate implant insertion is expected to save $1,263 per patient. CONCLUSION: Immediate postpartum provision of the contraceptive implant is cost-effective in preventing unintended pregnancies and should be provided to women requesting this form of contraception. PMID- 26241257 TI - Second-Trimester Cervical Length Screening Among Asymptomatic Women: An Evaluation of Risk-Based Strategies. AB - OBJECTIVE: To estimate whether there are demographic or clinical characteristics that are associated with the likelihood of having a short cervix and whether these characteristics can be used to optimize cervical length screening. METHODS: This is a cohort study of women with a singleton gestation without a history of spontaneous preterm birth who underwent routine transvaginal second-trimester cervical length screening. Seven risk factors for preterm birth were compared by cervical length status. A multivariable logistic regression was performed to identify independent risk factors for a short cervix (cervical length 2.5 cm or less). Different prediction models for a short cervix, based on the number of risk factors present, were developed and test characteristics for cervical length assessment for different risk-based screening approaches were calculated. RESULTS: Of the 18,250 women screened, 164 (0.9%) had a short cervix. Maternal age and conception by in vitro fertilization were not significantly associated with a short cervix. However, black (adjusted odds ratio [OR] 3.77, 95% confidence interval [CI] 2.42-5.87) and Hispanic (adjusted OR 1.73, 95% CI 1.10 2.74) race-ethnicity, current tobacco use (adjusted OR 3.67, 95% CI 1.56-8.62), prior indicated preterm birth (adjusted OR 2.26, 95% CI 1.26-4.05), and having a prior cervical excisional procedure (adjusted OR 2.96, 95% CI 1.86-4.70) were independent risk factors for a short cervix. If only women with any of these variables present were offered transvaginal cervical length screening, the specificity increases from 62.8% for universal screening to 96.5% with a risk based approach. The sensitivity with one variable present to offer transvaginal scanning was 62.8% and with two factors 14%. CONCLUSION: Limiting cervical length screening to women with at least one of the identified risk factors for a short cervix substantially decreases the number of ultrasonograms for cervical length assessment. However, this strategy results in nearly 40% of women with a short cervix not being ascertained. LEVEL OF EVIDENCE: II. PMID- 26241258 TI - Adverse Pregnancy Outcomes Using The International Association of the Diabetes and Pregnancy Study Groups Criteria: Glycemic Thresholds and Associated Risks. AB - OBJECTIVE: To compare the risks of selected adverse pregnancy outcomes among untreated women who met The International Association of the Diabetes and Pregnancy Study Groups (IADPSG)-defined glucose criteria at two different thresholds. METHODS: A retrospective cohort study of women tested for gestational diabetes mellitus (GDM) with the 75-g 2-hour glucose tolerance test (GTT) who delivered a live singleton neonate. Data of women who were treated because they met institutional criteria defining GDM (at least two GTT results greater than or equal to fasting 100 mg/dL, 1-hour 195 mg/dL, and 2-hour 160 mg/dL) were excluded. The data of the remaining women were analyzed in three groups. The prevalence of selected adverse pregnancy outcomes was compared for those with no GDM ("no GDM," n=7,943); those at least one of whose results were fasting 92-94 mg/dL, 1-hour 180-190 mg/dL, or 2-hour 153-161 mg/dL ("GDM-1," n=771); and those at least one of whose results were greater than or equal to fasting 95 mg/dL, 1 hour 191 mg/dL, or 2-hour 162 mg/dL ("GDM-2," n=1,121). RESULTS: Of the 9,835 women, 1,892 (19.2%) met criteria for GDM, of whom 771 (40.8%) were categorized as GDM-1 and 1,121 (59.2%) GDM-2. After adjustment for confounders, women with GDM-2 were at significantly greater risk for preeclampsia or eclampsia, preterm delivery, primary cesarean delivery, shoulder dystocia, higher birth weight, ponderal index, large for gestational age, transient tachypnea, and neonatal hypoglycemia than women without GDM. Only birth weight and large for gestational age were significantly greater in the GDM-1 compared with the no GDM group. CONCLUSION: Fewer adverse outcomes are found at lower levels of the IADPSG defined glucose intolerance spectrum. Determining whether these patients will benefit from treatment will require a randomized controlled trial. LEVEL OF EVIDENCE: II. PMID- 26241259 TI - Donor Death After Selective Fetoscopic Laser Surgery for Twin-Twin Transfusion Syndrome. AB - OBJECTIVE: To assess the incidence, timing, and risk factors for death of the donor fetus after fetoscopic laser surgery, we evaluated our cohort of patients who underwent the procedure for twin-twin transfusion syndrome. METHODS: This was a prospective cohort study of 166 consecutive patients with twin-twin transfusion syndrome at a single center. Fetal death was diagnosed by ultrasonography after surgery and before onset of labor. Risk factors for death of the donor twin were identified on univariate analysis and then subjected to multivariate, stepwise, logistic regression analysis. RESULTS: Donor demise occurred in 20 (13%) cases and recipient twin death occurred in four (2.6%). The median procedure to death interval was 4 days (range 1-89 days). Risk factors for donor death were fetal growth discordance greater than 30% (odds ratio [OR] 6.7, 95% confidence interval [CI] 2-23), reverse end-diastolic velocity in the donor umbilical artery (OR 25.0, 95% CI 2-290), a marginal and velamentous cord insertion (OR 4.4, 95% CI 1 19), and an increased number of anastomoses (OR 1.2, 95% CI 1.1-1.5). All four donors with both fetal growth discordance greater than 30% and reverse end diastolic velocity in the donor umbilical artery resulted in a demise. CONCLUSION: Four risk factors significantly affecting acute and delayed donor demise after fetoscopic laser surgery were identified. The presence of both fetal growth discordance greater than 30% and reverse end-diastolic velocity in the donor umbilical artery was highly predictive of donor demise in our cohort. Knowledge of these risk factors can aid in counseling and assist patients in choosing the most appropriate intervention in the management of twin-twin transfusion syndrome. LEVEL OF EVIDENCE: III. PMID- 26241260 TI - Nulliparous Women in the Second Stage of Labor: Changes in Delivery Outcomes Between Two Cohorts From 2000 and 2011. AB - OBJECTIVE: To evaluate changes over the past decade in the mode of delivery and second-stage duration in nulliparous women. METHODS: We conducted a retrospective cohort study at a single institution of nulliparous women reaching complete cervical dilation with singleton gestations 36 weeks or greater from January 1, 2011, to December 31, 2012, and compared these with a prior cohort prospectively collected from July 28, 2000, to February 28, 2003. We excluded pregnancies with prenatally diagnosed fetal anomalies. The primary outcome was cesarean delivery. Secondary outcomes included second-stage duration, rates of operative vaginal delivery (forceps and vacuum collectively), and indications for cesarean delivery and operative vaginal delivery. RESULTS: There were 1,023 mother-neonate pairs in the prior cohort and 1,476 in the current cohort. In the prior and current cohorts, respectively, 2% compared with 6% underwent cesarean delivery, 21% compared with 10% underwent operative vaginal delivery, and 77% compared with 84% had spontaneous vaginal delivery (all P<.01). Compared with the prior cohort, the adjusted odds (OR) of cesarean delivery (compared with any vaginal birth) for current patients was 1.74 (95% confidence interval [CI] 1.04-2.91), and in a separate regression model, the adjusted OR of operative vaginal delivery (compared with spontaneous vaginal delivery or cesarean delivery) was 0.42 (95% CI 0.33-0.54). Median (25th, 75th percentile) second-stage duration significantly increased from 38 (20, 71) to 42 (22, 87) minutes (P<.01), but this difference was nullified after adjusting for confounders. CONCLUSION: Comparing cohorts from 2000 and 2011, although the second-stage duration has not changed appreciably, nulliparous women in the second stage of labor at our institution are twice as likely to undergo cesarean delivery and half as likely to undergo operative vaginal delivery. LEVEL OF EVIDENCE: II. PMID- 26241261 TI - Obstructive Sleep Apnea in Pregnancy: Assessment of Current Screening Tools. AB - OBJECTIVE: To estimate the predictive ability of current obstructive sleep apnea (OSA) screening tools and the individual questions in these tools at identifying pregnant women who have OSA. METHODS: A total of 293 third-trimester patients were enrolled between 2010 and 2012, and 248 patients had sleep monitor results. Recruited participants completed a questionnaire consisting of six OSA screening tools and overnight portable sleep monitoring. Predictive ability of the screening tools for OSA compared with results of the diagnosis from overnight sleep monitoring was estimated using the area under receiver operating characteristic curves. RESULTS: Two hundred eighteen (88%) of the patients were OSA-negative, and 30 patients (12%) were OSA-positive based on sleep monitoring results. Compared with OSA-negative patients, OSA-positive patients had greater body mass indices and neck circumferences as well as significantly higher rates of hypertension (chronic and gestational), pregestational diabetes mellitus, asthma, and preeclampsia. The overall predictive ability of the screening tools for OSA was modest (area under receiver operating characteristic curves 0.62 0.695). However, individual components of the questionnaire were strongly associated with OSA. CONCLUSION: We found that none of the studied OSA screening tools accurately detected OSA in pregnant women in the third trimester. We have identified proposed elements of a new screening tool based on promising components from several tools that may more accurately detect patients with OSA. LEVEL OF EVIDENCE: II. PMID- 26241262 TI - Association of 17alpha-Hydroxyprogesterone Caproate and Risk of Infection. AB - OBJECTIVE: To evaluate whether exposure to 17alpha-hydroxyprogesterone caproate is associated with the rate of peripartum infection in women who deliver preterm and their neonates. METHODS: This is a retrospective cohort study of patients who delivered before 37 weeks of gestation at a tertiary care hospital between July 1, 2005, and December 31, 2012. Women in the case group (women exposed to 17alpha hydroxyprogesterone caproate) were matched to women in a control group (unexposed patients) by gestational age and delivery date. The primary outcome was a composite infection rate comprising histologic or clinical chorioamnionitis, endometritis, or early-onset neonatal sepsis. To detect a 15% difference in composite infection rate between women exposed to 17alpha-hydroxyprogesterone caproate and those unexposed (two-tailed alpha=0.05 and power=80%), 183 patients per group were required. Logistic regression was performed to control for a history of prior spontaneous preterm birth and exposure to betamethasone. RESULTS: The primary outcome frequency for women exposed to 17alpha hydroxyprogesterone caproate was 34.6% (64 patients) compared with 33% (61 patients) in those unexposed (P=.74). There was no significant difference between women exposed to 17alpha-hydroxyprogesterone caproate and those unexposed in frequency of clinical chorioamnionitis (1.9% compared with 1.1%, P=.66), histologic chorioamnionitis (39.4% compared with 40%, P=.92), or early-onset neonatal sepsis (2.7% compared with 1.1%, P=.28). A total of 7.1% of women exposed to 17alpha-hydroxyprogesterone caproate developed endometritis compared with 2.7% of those unexposed (P=.05). The adjusted odds ratio for the primary outcome in women exposed to 17alpha-hydroxyprogesterone caproate was 0.65 (95% confidence interval 0.31-1.38). CONCLUSION: Exposure to 17alpha hydroxyprogesterone caproate does not increase the risk of peripartum infection among women who deliver preterm or their neonates. LEVEL OF EVIDENCE: II. PMID- 26241263 TI - Diabetes Screening Reminder for Women With Prior Gestational Diabetes: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate whether an electronic health record (EHR) reminder improves rates of screening for type 2 diabetes in women with prior gestational diabetes. METHODS: We randomly allocated primary care providers (by clinic site) to a reminder for type 2 diabetes screening within the EHR or to usual care. Women with previous gestational diabetes mellitus were identified through an automated search of laboratory results and the problem list. We compared rates of screening during the study period (2010-2012) in women at intervention sites with those at control sites. With a sample size of 850 participants, we had 80% power to detect a 15% difference in screening rates. RESULTS: We included 847 individuals seen at a participating clinic during the study period, of whom 471 were at a reminder clinic and 376 were at a control clinic. A similar proportion of women were screened for type 2 diabetes in both groups (n=265, 56.3% of the reminder group compared with n=206, 54.8% of the control group, P=.67; adjusted odds ratio [OR] 1.04, 95% confidence interval [CI] 0.79-1.38). Patient characteristics associated with risk for diabetes including body mass index (adjusted OR per kg/m 1.05, 95% CI 1.01-1.08) and race (adjusted OR for nonwhite race 2.14, 95% CI 1.57-2.92) were significantly associated with screening. CONCLUSION: A simple EHR reminder did not increase the rate of diabetes screening in women with prior gestational diabetes mellitus. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01288144. LEVEL OF EVIDENCE: I. PMID- 26241264 TI - Outcomes of Term Induction in Trial of Labor After Cesarean Delivery: Analysis of a Modern Obstetric Cohort. AB - OBJECTIVE: To evaluate outcomes of induction of labor, compared with expectant management, in women attempting trial of labor after cesarean delivery (TOLAC) in a large obstetric cohort. METHODS: We performed a secondary analysis of data from the Consortium on Safe Labor that included women with term (37 weeks of gestation or greater) singleton gestations and a history of one prior cesarean delivery who attempted TOLAC. Induction of labor was compared with expectant management by week of gestation from 37 to 40 weeks in both high- and low-risk cohorts. The primary outcome was failed TOLAC. Secondary outcomes included composite maternal morbidity (hysterectomy, transfusion, intensive care unit (ICU) transfer, venous thromboembolism, death), composite neonatal morbidity (5-minute Apgar score less than 5, cord pH less than 7.0, asphyxia, hypoxic ischemic encephalopathy, neonatal death), and neonatal ICU admission. Multivariate logistic regression was performed with adjustment for confounding factors. RESULTS: We identified 6,033 women attempting TOLAC of whom 1,626 (27.0%) underwent induction of labor and 4,407 (73.0%) did not. Compared with expectant management, induction was associated with an increased risk of failed TOLAC at 37-39 weeks of gestation but not at 40 weeks of gestation (37 weeks of gestation, 48.5% compared with 34.3%, adjusted odds ratio [OR] 1.53, 95% confidence interval [CI] 1.02-2.28]; 38 weeks of gestation, 47.0% compared with 33.0%, adjusted OR 1.74, 95% CI 1.29-2.34; 39 weeks of gestation, 45.6% compared with 29.8%, adjusted OR 2.16, 95% CI 1.76 2.67; 40 weeks of gestation, 37.9% compared with 29.4%, adjusted OR 1.21, 95% CI 0.90-1.66). Induction was associated with an increased risk of composite maternal morbidity at 39 weeks of gestation (adjusted OR 1.87, 95% CI 1.22-2.87) and neonatal ICU admission at 37 weeks of gestation (adjusted OR 2.51, 95% CI 1.62 3.90). Induction was not associated with an increased risk of neonatal morbidity. CONCLUSION: Induction of labor in women with one prior cesarean delivery, compared with expectant management, is associated with an increased risk of failed TOLAC. Apart from small increases in maternal morbidity at 39 weeks and neonatal ICU admission at 37 weeks of gestation, induction is not associated with an increased risk of severe maternal or neonatal morbidity. LEVEL OF EVIDENCE: II. PMID- 26241265 TI - Physical Examination-Indicated Cerclage: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To estimate the effectiveness of physical examination-indicated cerclage in the setting of second-trimester cervical dilatation by systematic review and meta-analysis of published studies. DATA SOURCES: We searched MEDLINE, EMBASE, Scopus, ClinicalTrials.gov, Web of Science, and the Cochrane Library for studies published between 1966 and 2014 that evaluated cervical cerclage for the treatment of cervical insufficiency. METHODS OF STUDY SELECTION: The search yielded 6,314 citations. We included cohort studies and randomized controlled trials comparing cerclage placement with expectant management of women with cervical dilatation between 14 and 27 weeks of gestation. Two investigators independently reviewed each citation for inclusion or exclusion and discordant decisions were arbitrated by a third reviewer. Summary estimates were reported as the mean difference and 95% confidence interval (CI) for continuous variables or relative risk and with 95% CI for dichotomous outcomes. Fixed- and random-effects meta-analysis was used, depending on heterogeneity. TABULATION, INTEGRATION, AND RESULTS: Ten studies met inclusion criteria and were included in the final analysis. One was a randomized controlled trial, two were prospective cohort studies, and the remaining seven were retrospective cohort studies. Of the 757 women, 485 (64%) underwent physical examination-indicated cerclage placement and 272 (36%) were expectantly managed. Cerclage was associated with increased neonatal survival (71% compared with 43%; relative risk 1.65, 95% CI 1.19-2.28) and prolongation of pregnancy (mean difference 33.98 days, 95% CI 17.88-50.08). CONCLUSION: Physical examination-indicated cerclage is associated with a significant increase in neonatal survival and prolongation of pregnancy of approximately 1 month when compared with no such cerclage. The strength of this conclusion is limited by the potential for bias in the included studies. PMID- 26241266 TI - Prevalence and Resolution of Auditory Passage of Vaginal Air in Women With Pelvic Floor Disorders. AB - OBJECTIVE: To estimate the prevalence of auditory vaginal air passage among women with and without pelvic organ prolapse (POP) in a population with pelvic floor disorders. METHODS: This prospective cohort study included women with urinary incontinence and POP who sought consultation at a single center from January 2012 to August 2013. Women with rectovaginal fistula, prior surgery for POP or incontinence, and current pregnancy were excluded. Participants completed a nonvalidated questionnaire about auditory vaginal air passage, also known as vaginal wind. The subset who had pelvic reconstructive surgery completed the same questionnaire 6 months postoperatively. Baseline demographic and clinical characteristics and preoperative and postoperative POP quantification data were collected. RESULTS: One hundred thirty-two women were approached for participation, of whom 110 (83%) completed baseline study questionnaires. Of these 110, 59 had POP and 51 had normal pelvic support. The mean age was 55+/-12 years. Sixty-nine percent (76/110, 95% confidence interval [CI] 60-78%) experienced vaginal wind an average of 2.1+/-8.7 times weekly. There was no difference in the prevalence of vaginal wind between women with and without POP. Women with vaginal wind were younger than those without vaginal wind (mean age 52+/-12 years compared with 62+/-11 years, P<.001). The majority with vaginal wind experienced symptoms during intercourse (65/75 [87%], 95% CI 77-93%) and were at least somewhat bothered by it (49/76 [64%], 95% CI 53-75%), but only 22% (17/76, 95% CI 14-33%) reported a negative effect on quality of life. CONCLUSION: Vaginal wind is common among women with pelvic floor disorders but is not associated with POP. LEVEL OF EVIDENCE: II. PMID- 26241267 TI - Association Between Statin Use and Endometrial Cancer Survival. AB - OBJECTIVE: To evaluate the association of 3 hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor (statin) use and concordant polypharmacy with disease specific survival from endometrial cancer. METHODS: A retrospective cohort study was conducted of 985 endometrial cancer cases treated from January 1999 through December 2009 at a single institution. Disease-specific survival was estimated by Kaplan-Meier analyses. A Cox proportional hazards model was used to study factors associated with survival. All statistical tests were two-sided and performed using Stata. RESULTS: At the time of analysis, 230 patients (22% of evaluable patients) died of disease and median follow-up was 3.28 years. Disease-specific survival was greater (179/220 [81%]) for women with endometrial cancer taking statin therapy at the time of diagnosis and staging compared with women not using statins (423/570 [74%]) (log rank test, P=.03). This association persisted for the subgroup of patients with nonendometrioid endometrial tumors who were statin users (59/87 [68%]) compared with nonusers (93/193 [43%]) (log rank test, P=.02). The relationship remained significant (hazard ratio 0.63, 95% confidence interval [CI] 0.40-0.99) after adjusting for age, clinical stage, radiation, and other factors. Further evaluation of polypharmacy showed an association between concurrent statin and aspirin use with an especially low disease-specific mortality (hazard ratio 0.25, 95% CI 0.09-0.70) relative to those who used neither. CONCLUSION: Statin and aspirin use was associated with improved survival from nonendometrioid endometrial cancer. PMID- 26241268 TI - Minilaparoscopic Single-Site Total Hysterectomy. AB - BACKGROUND: Laparoendoscopic single-site surgery and minilaparoscopy (ie, the use of 3-mm instruments) represent two of the most recent advances in ultraminimally invasive surgery. We have combined these two techniques and transvaginal cuff closure to develop a technique for the performance of single-incision, transumbilical, minilaparoscopic hysterectomy. TECHNIQUE: The complete endoscopic detachment of the uterus from its supports and vessels is performed using only two 3-mm minilaparoscopic trocars, both inserted in the umbilicus, with the aid of a uterine manipulator. The procedure was completed with transvaginal extraction of the uterus and transvaginal closure of the vaginal cuff. EXPERIENCE: We performed 20 minilaparoscopic single-site hysterectomies. One (5%) conversion to conventional minilaparoscopic hysterectomy was needed as a result of adhesions. No intraoperative or postoperative complications occurred and all women were discharged home within 30 hours after surgery. Postsurgical pain (measured with a 0-10 visual analog scale administered by an independent observer postoperatively) was very low: 2 (1-3), 2 (1-3), and 0 (0-2) at 1, 3, and 8 hours postoperatively, respectively. CONCLUSION: Single-site total minilaparoscopic hysterectomy using only two 3-mm ports inserted through the umbilicus is feasible and further reduces the incisional trauma of surgery. PMID- 26241269 TI - National Partnership for Maternal Safety: Consensus Bundle on Obstetric Hemorrhage. AB - Hemorrhage is the most frequent cause of severe maternal morbidity and preventable maternal mortality and therefore is an ideal topic for the initial national maternity patient safety bundle. These safety bundles outline critical clinical practices that should be implemented in every maternity unit. They are developed by multidisciplinary work groups of the National Partnership for Maternal Safety under the guidance of the Council on Patient Safety in Women's Health Care. The safety bundle is organized into four domains: Readiness, Recognition and Prevention, Response, and Reporting and System Learning. Although the bundle components may be adapted to meet the resources available in individual facilities, standardization within an institution is strongly encouraged. References contain sample resources and "Potential Best Practices" to assist with implementation. PMID- 26241270 TI - Staging Classification for Cancer of the Ovary, Fallopian Tube, and Peritoneum: Abridged Republication of Guidelines From the International Federation of Gynecology and Obstetrics (FIGO). PMID- 26241271 TI - Single-Nucleotide Polymorphism-Microarray Ploidy Analysis of Paraffin-Embedded Products of Conception in Recurrent Pregnancy Loss Evaluations. AB - OBJECTIVE: To compare the analysis of chromosome number from paraffin-embedded products of conception using single-nucleotide polymorphism (SNP) microarray with the recommended screening for the evaluation of couples presenting with recurrent pregnancy loss who do not have previous fetal cytogenetic data. METHODS: We performed a retrospective cohort study including all women who presented for a new evaluation of recurrent pregnancy loss over a 2-year period (January 1, 2012, to December 31, 2013). All participants had at least two documented first trimester losses and both the recommended screening tests and SNP microarray performed on at least one paraffin-embedded products of conception sample. Single nucleotide polymorphism microarray identifies all 24 chromosomes (22 autosomes, X, and Y). RESULTS: Forty-two women with a total of 178 losses were included in the study. Paraffin-embedded products of conception from 62 losses were sent for SNP microarray. Single-nucleotide polymorphism microarray successfully diagnosed fetal chromosome number in 71% (44/62) of samples, of which 43% (19/44) were euploid and 57% (25/44) were noneuploid. Seven of 42 (17%) participants had abnormalities on recurrent pregnancy loss screening. The per-person detection rate for a cause of pregnancy loss was significantly higher in the SNP microarray (0.50; 95% confidence interval [CI] 0.36-0.64) compared with recurrent pregnancy loss evaluation (0.17; 95% CI 0.08-0.31) (P=.002). Participants with one or more euploid loss identified on paraffin-embedded products of conception were significantly more likely to have an abnormality on recurrent pregnancy loss screening than those with only noneuploid results (P=.028). The significance remained when controlling for age, number of losses, number of samples, and total pregnancies. CONCLUSION: These results suggest that SNP microarray testing of paraffin-embedded products of conception is a valuable tool for the evaluation of recurrent pregnancy loss in patients without prior fetal cytogenetic results. Recommended recurrent pregnancy loss screening was unnecessary in almost half the patients in our study. LEVEL OF EVIDENCE: II. PMID- 26241273 TI - Obstetric Safety and Quality. AB - Obstetric safety and quality is an emerging and important topic not only as a result of the pressures of patient and regulatory expectations, but also because of the genuine interest of caregivers to reduce harm, improve outcomes, and optimize care. Although each seeks to improve care by using scientific approaches beyond human physiology and pathophysiology, patient safety methodologies seek to avoid preventable adverse events, whereas health care quality projects aim to achieve the best possible outcomes. It is well-documented that an increasingly complex medical system controlled by human workers is a circumstance subject to recurrent failure. A safety culture encourages a proactive approach to mitigate failure before, during, and after it occurs. This article highlights the key concepts in health care safety and quality and reviews the background of the quality improvement sciences with particular emphasis on obstetric outcomes and quality measures. PMID- 26241272 TI - Protecting Ovaries During Chemotherapy Through Gonad Suppression: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To estimate whether gonadotropin-releasing hormone (GnRH) analog administration during chemotherapy can protect against development of ovarian toxicity. DATA SOURCES: MEDLINE (1966 to present), EMBASE (1980 to present), Cochrane Central Register of Controlled Trials (CENTRAL), World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov were searched through March 2015 using the phrases: "gonadotropin-releasing hormone," "chemotherapy," and "premature ovarian failure." Hand-search on conference abstracts, SCOPUS, and ISI Web of Science were also searched. METHODS OF STUDY SELECTION: Published English-language randomized controlled trials comparing resumption of ovarian function between GnRH analogs plus chemotherapy with chemotherapy without GnRH analogs were included. Studies including women with pelvic metastases or recent history of receiving chemotherapy were excluded. Accordingly, 10 eligible trials (907 women) were analyzed. TABULATION, INTEGRATION, AND RESULTS: Our primary outcome was the proportion of women with resumed ovarian function (defined as resumption of menstruation, prevention of chemotherapy-induced ovarian failure, or both) at the longest follow-up after the end of chemotherapy. Secondary outcomes were evaluating ovarian reserve parameters and pregnancy. Risk ratio was used to integrate qualitative results and mean difference was used for quantitative data. Gonadotropin-releasing hormone analog cotreatment did not significantly increase ovarian function resumption (320/468 [68.4%] in GnRH analog arm and 263/439 [59.9%] in the chemotherapy alone arm; risk ratio 1.12, 95% confidence interval [CI] 0.99-1.27). No protective effect existed after subgroup analyses (type of malignancy [P=.31], age [P=.14], and GnRH analog type [P=.44]). Gonadotropin releasing hormone analogs did not protect any of ovarian reserve parameters, whether follicle-stimulating hormone (mean difference -2.63, 95% CI -7.33 to 2.07), antral follicle count (mean difference 1.66, 95% CI -0.69 to 4.01), or anti-Mullerian hormone (mean difference 0.31, 95% CI -0.41 to 1.03). Spontaneous pregnancy was also comparable (risk ratio 1.63, 95% CI 0.94-2.82). CONCLUSION: Gonadotropin-releasing hormone analog administration during chemotherapy does not appear to protect the ovaries from gonadal toxicity. It is not a reliable method for fertility preservation. PMID- 26241274 TI - Hepatic Pregnancy Suspected at Term and Successful Delivery of a Live Neonate With Placental Attachment to the Right Lobe of the Liver. AB - BACKGROUND: Hepatic pregnancy is an exceptionally rare form of extrauterine pregnancy. Only 21 cases have been reported in the English medical literature over the past 60 years, of which only 29% progressed beyond the first trimester. CASE: We present a case of advanced hepatic pregnancy that was diagnosed at term. The diagnosis was suspected clinically and on an abdominopelvic ultrasonogram. At laparotomy, the diagnosis of an intrahepatic pregnancy was confirmed. The 2,800-g live neonate was delivered successfully, and the placenta was left in situ. The mother made a full and uneventful recovery. CONCLUSION: This is a very rare case of an advanced hepatic pregnancy that remained undiagnosed until term and resulted in the successful delivery of a live neonate. PMID- 26241275 TI - What Is New in Prenatal Aneuploidy Screening?: Best Articles From the Past Year. AB - This month we focus on current research in prenatal aneuploidy screening. Dr. Norton discusses five recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 26241276 TI - Persistent Occiput Posterior. PMID- 26241277 TI - Persistent Occiput Posterior. PMID- 26241278 TI - In Reply. PMID- 26241279 TI - Prophylactic Use of Negative Pressure Wound Therapy After Cesarean Delivery. PMID- 26241280 TI - In Reply. PMID- 26241281 TI - Pregnancy and Weight Gain: We Have Observed Enough. PMID- 26241282 TI - Evaluation of Third-Degree and Fourth-Degree Laceration Rates as Quality Indicators. PMID- 26241283 TI - In Reply. PMID- 26241284 TI - Suicide Risk Among Perinatal Women Who Report Thoughts of Self-Harm on Depression Screens. PMID- 26241285 TI - In Reply. PMID- 26241291 TI - Committee Opinion No. 637: Marijuana Use During Pregnancy and Lactation. AB - Cannabis sativa (marijuana) is the illicit drug most commonly used during pregnancy. The self-reported prevalence of marijuana use during pregnancy ranges from 2% to 5% in most studies. A growing number of states are legalizing marijuana for medicinal or recreational purposes, and its use by pregnant women could increase even further as a result. Because of concerns regarding impaired neurodevelopment, as well as maternal and fetal exposure to the adverse effects of smoking, women who are pregnant or contemplating pregnancy should be encouraged to discontinue marijuana use. Obstetrician-gynecologists should be discouraged from prescribing or suggesting the use of marijuana for medicinal purposes during preconception, pregnancy, and lactation. Pregnant women or women contemplating pregnancy should be encouraged to discontinue use of marijuana for medicinal purposes in favor of an alternative therapy for which there are better pregnancy-specific safety data. There are insufficient data to evaluate the effects of marijuana use on infants during lactation and breastfeeding, and in the absence of such data, marijuana use is discouraged. PMID- 26241292 TI - ESCAPE ancillary blood pressure measurement study 2: changes in end-digit preference after 2 years of a cluster randomized trial. AB - OBJECTIVE: The aim of the ESCAPE AMPA 2 trial was to describe the evolution of end-digit preference (EDP) practices in primary care after 2 years of trial. METHODS: A descriptive analysis of the EDP in the intervention group (IG) and in the electronic control group (ECG) of the ESCAPE trial and a comparative analysis of EDP changes in blood pressure (BP) measures of both groups were carried out between baseline and 2 years. In the ESCAPE trial, physicians in the IG were new users of electronic devices provided in the trial to measure their patients' BP and physicians in the ECG were former users of electronic devices. Hierarchical mixed-effects models were used for statistical analysis in a pragmatic cluster randomized-controlled trial. RESULTS: After 2 years, the proportion of BP measures ending with a 0 or a 5 was significantly higher in the ECG than in the IG (50.4 vs. 33.4%, P<0.0001). There was no significant change in EDP tendency between baseline and the end of the trial in the ECG (65.6-56.7%, P=0.39) and in the IG (29.6-38.2%, P=0.07), with a between-groups P value of 0.11. Over 2 years, there was no significant change in systematic EDP in the ECG (18.8-20.0%, P=0.29) and in the IG (4.8-10.6%, P=0.01), with a between-groups P value of 0.17. CONCLUSION: EDP is not eliminated by electronic devices and tends to increase with time for new users. PMID- 26241293 TI - The relationship between vitamin D levels and nondipper hypertension. AB - OBJECTIVE: Nondipper hypertension is associated with increased cardiovascular morbidity and mortality. Vitamin D deficiency is associated with cardiovascular diseases such as coronary artery disease, heart failure and hypertension. We aimed to evaluate the effect of vitamin D on nondipper hypertension. DESIGN: This study included total 200 essential hypertensive patients. Twenty-four-hour ambulatory blood pressure monitoring was performed for each patient. In addition to routine tests, vitamin D levels were analysed. RESULTS: The study population was divided into two groups: 100 dipper patients (mean age; 50.6+/-9.9 years, 54 women and 46 men) and 100 nondipper patients (mean age; 49.2+/-8.2 years, 53 women and 47 men). Clinical blood pressures were significantly higher in nondipper hypertensives than dipper hypertensives (systolic blood pressures 141.2+/-5.6 vs. 139.1+/-6.6 mmHg, diastolic blood pressures 88.4+/-2.6 mmHg vs. 87.4+/-3.4, P<0.05, respectively). Nondipper patients showed lower levels of vitamin D compared with dippers (21.1+/-3.5, 31+/-7.1 ng/ml, P<0.001, respectively). A significant positive correlation was observed between vitamin D and the rate of nocturnal systolic and diastolic blood pressure fall (r=0.525, P<0.001 and r=0.512, P<0.001, respectively) CONCLUSION: Vitamin D levels are significantly lower in patients with nondipper hypertension than patients with dipper hypertension. PMID- 26241294 TI - Validation of inflationary noninvasive blood pressure monitoring in the emergency room. AB - OBJECTIVE: The aim of this study was to compare the values of a noninvasive blood pressure (NIBP) measurement during cuff inflation (inflationary NIBP) and deflationary NIBP measurements and to verify whether inflationary NIBP is equivalent to conventional deflationary NIBP and is acceptable for clinical use in the emergency room (ER). MATERIALS AND METHODS: A total of 2981 NIBP data points were collected from 175 patients (age, 56.5+/-22.2 years; range, 7-92 years) who had been treated in the resuscitation area of the ER at Keio University Hospital. The data points were obtained using two alternate algorithms with a standard monitor (BSM-6000). One algorithm consisted of continuous inflationary and deflationary measurements in a single cycle (dual algorithm, 1502 data points); this algorithm was used to verify the success rate and the precision of the data. The second algorithm (1479 data points) consisted of only conventional deflationary measurements and was used to verify the duration of the measurement cycle. RESULTS: The success rate of the inflationary NIBP (completed using only the inflationary method) was 69.0%. Failures in the inflationary measurements were caused by arrhythmia and/or body motions. The mean difference and SD of the systolic pressure and the diastolic pressure between inflationary NIBP and deflationary NIBP were -0.6+/-8.8 and 3.5+/-7.5 mmHg, respectively. The confidence intervals were -0.6 (95% confidence interval=-1.1 to -0.1) and 3.5 (95% confidence interval=3.0 to 4.0) mmHg. The coefficients of correlation were 0.96 and 0.93. Inflationary NIBP was capable of determining the NIBP more quickly compared with deflationary NIBP (average of 15.9 vs. 34.2 s; P<0.05). CONCLUSION: Inflationary NIBP measurements have a reasonable accuracy and a sufficient rapidity, compared with deflationary NIBP measurements, in ER patients. PMID- 26241295 TI - Short-term and Long-term Outcomes Regarding Laparoscopic Versus Open Surgery for Low Rectal Cancer: A Systematic Review and Meta-Analysis. AB - PURPOSE: It is to disclose whether the laparoscopic technique is feasible or not in the treatment of low rectal cancer. MATERIALS AND METHODS: We systematically searched PubMed, Embase, Ovid, Web of Science, Science Direct, SpringerLink, EBSCO, and the Cochrane Library databases for the eligible studies. Review Manager 5.2 was used to test the heterogeneity and to evaluate the overall test performance. RESULTS: Twelve studies met the final inclusion criteria (total n=2973). The pooled analyses showed, despite longer operation times, that there were significantly less blood loss, fewer transfusions, shorter times to bowel function recovery, resumed diet and hospital durations, and lower overall complication and wound infection rates. The compared results of the lymph node harvest number, distal resection margin, circumferential resection margin involvement, local and distant recurrences, disease-free survival, and overall survival were similar between both the groups. CONCLUSION: Laparoscopic surgery is safe and feasible for the treatment of low rectal cancer. PMID- 26241296 TI - A 3-cm Single-port Video-assisted Thoracoscopic Lobectomy for Lung Cancer. AB - Video-assisted thoracoscopic surgery is advantageous over traditional surgical practices, because of a faster postoperative recovery period, less pain, and a shorter hospital length of stay. There is no single standard technique in the video-assisted thoracoscopic surgery approach. Although these "minimally invasive" resections are habitually performed through 3-port or 4-port incision, we performed a left lower lobectomy in a 54-year-old male patient for lung cancer, through a 3-cm single-port incision. PMID- 26241297 TI - The Comparison of 2 New Promising Weapons for the Treatment of Hydatid Cyst Disease: PAIR and Laparoscopic Therapy. AB - BACKGROUND: To compare the effectiveness and safety for hydatid disease treatment, the 2 new minimally invasive therapies: laparoscopic and PAIR (puncture, aspiration, injection, and reaspiration) were compared by systematic meta-analysis. METHODS: A comprehensive analysis of published cases from 1990 to 2014 was performed using PubMed database. A total of 231 publications on laparoscopic treatment of hydatid cysts and 298 publications on the PAIR treatment were identified. Thirty-eight studies involved 1230 laparoscope-treated subjects and 41 involved 2686 PAIR-treated subjects in this review. The effectiveness and safety of emphasis is placed on the recurrence, insufficient response, death, cure, and postoperative complications. Operation time and hospital stay are also discussed as new evaluation index. The stages of cyst are summarized to determine which stage is suitable for PAIR. RESULTS: Clinical and parasitological cure occurred in 98.7% of patients undergoing laparoscopic intervention and in 97.5% of patients receiving PAIR plus chemotherapy (P<0.014). Recurrence occurred in 1.0% and 1.6%, respectively (P<0.087). Insufficient response occurred in 0.16% and 0.9%, respectively (P<0.009); 2 patients died in each group (P<0.594). Allergic reaction/urticarial/anaphylactic shock occurs in 0.14% and 4.24% of patients receiving laparoscopic intervention and PAIR plus chemotherapy, respectively (P<0.001). Infection/abscess (5.37% and 2.57%; P<0.001) and surgical-related complications (7.32% and 3.43%; P<0.001) were seen more frequently in laparoscopic intervention subjects than PAIR plus chemotherapy subjects. CONCLUSIONS: Laparoscopic therapy and PAIR intervention are shown to be safe and effective alternative for open surgery with suitable indication such as cyst type and location. They have different postoperative complication features. The biliary fistula/bile leakage was more frequent in laparoscopic intervention (P<0.001) and fever occurred more in PAIR plus chemotherapy patients. PMID- 26241298 TI - Timing of Cholecystectomy for Biliary Pancreatitis in Chinese Patients. AB - BACKGROUND: The aim of this study was to determine the most feasible and cost effective time of cholecystectomy following gallstone pancreatitis in Chinese patients. MATERIALS AND METHODS: A total of 233 patients who underwent cholecystectomy for biliary pancreatitis (January 2004 to July 2012) were categorized into one of 2 groups: group A patients underwent cholecystectomy during admission (n=123), and group B patients delayed cholecystectomy after discharge from admission (n=110). RESULTS: The groups were comparable in demographics, comorbidities, and disease severity. In total, 100% of patients in group A had a cholecystectomy within 3 weeks after admission, and 60.9% of patients in group B experienced precholecystectomy gallstone-related events (including 15 cases of recurrent pancreatitis) after discharge. The median total length of hospital stay was greater for group B than for group A [12 d (range, 4 to 24 d) vs. 17 d (range, 9 to 39 d), respectively, P=0.000]. The average cost of management was greater in group B than group A [23,036.11 Yuan (range, 9073.53 to 85,132.33 Yuan) vs. 36,643.27 Yuan (range, 14,096.36 to 69,642.02 Yuan), respectively, P=0.000]. CONCLUSION: In Chinese patients, cholecystectomy should be performed within 3 weeks after admission without delay, and is feasible and cost-effective. PMID- 26241299 TI - Laparoscopic Technique and Initial Experiences of Choledocholithotomy Closure With Knotless Unidirectional Barbed Sutures After Surgery for Biliary Stone Disease. AB - BACKGROUND AND AIM: Between January 2012 and June 2013, we performed laparoscopic choledocholithotomy on 10 cases of common bile duct stone disease. Laparoscopic surgery for common duct stone disease is technically demanding. Particularly, laparoscopic intracorporeal suturing and knot tying for repair of choledochotomy are the most difficult skills in this operative procedures. Barbed sutures has recently been proposed to facilitate laparoscopic suturing. This is the first report demonstrating that the barbed suture could potentially improve the efficacy of the intracorporeal repair of choledochotomy following extirpation of biliary tract stones with less time needed to suture. METHODS: Consecutive 10 patients with common bile duct stones who underwent laparoscopic choledocholithotomy were enrolled in this study. Choledochotomy was closed with V Loc sutures (15 cm V-Loc 180 sutures) for 7 patients, and a V-20 needle (26 mm, tapered) for 3 patients. RESULTS: The mean choledochotomy closure time was significantly shorter in the V-Loc group (15.2 +/- 1.6 min) than in the Vicryl group (23.5 +/- 1.5 min). The unidirectional barbed sutures allowed surgeons to use both their hands effectively and to focus exclusively on the placement of the subsequent stitches, without the need to maintain tension on preceding stitches to prevent slippage. And also the unidirectional barbed sutures were able to distribute tension evenly along the suture line, allowing good tissue apposition. CONCLUSION: The knotless unidirectional barbed sutures are a safe and effective tool for choledochotomy repair during surgery for common bile duct stones. PMID- 26241300 TI - A multislice theory of electron scattering in crystals including backscattering and inelastic effects. AB - In the framework of the slice transition operator technique, a general multislice theory for electron scattering in crystals is developed. To achieve this generalization, we combine the approaches for inelastic scattering derived by Yoshioka [J. Phys. Soc. Jpn. 12, 6 (1957)] and backscattering based on the formalism of Chen and Van Dyck [Ultramicroscopy 70, 29-44 (1997)]. A computational realization of the obtained equations is suggested. The proposed computational scheme is tested on elastic backscattering of electrons, where we consider single backscattering in analogy to the computational scheme proposed by Chen and Van Dyck. PMID- 26241301 TI - Signal-to-noise in femtosecond electron diffraction. AB - Pump-probe electron diffraction can directly record atomic-scale motion within molecules or materials. However, the available current in femtosecond experiments is limited, making it challenging to reach the sensitivity required for detecting the fastest structural dynamics, which are encoded in time-dependent diffraction intensities. Here we present a unified analysis of signal-to-noise for an ultrafast electron diffraction apparatus. We characterize the noise of realistic ultrafast electron sources and detectors, test the performance on crystalline and polycrystalline samples and discuss practical approaches for improving measurement sensitivity. The analysis is found sufficient to predict the achievable signal-to-noise ratio in pump-probe electron diffraction before actually starting an investigation. PMID- 26241302 TI - Left atrial appendage closure. AB - Stroke or systemic embolism is a devastating consequence of atrial fibrillation (AF) due to thrombus formation in the left atrial appendage (LAA). AF causes thrombus formation in the LAA due to both the loss of atrial systole and the unique anatomic features of the LAA. Oral anticoagulation is a well established and effective therapy to reduce the risk of stroke in AF patients, albeit with a risk of bleeding. LAA closure is a possible alternative to oral anticoagulation in the prevention of stroke or systemic embolism in AF. PMID- 26241303 TI - The role of left atrial imaging in the management of atrial fibrillation. AB - Atrial fibrillation (AF) is the most commonly encountered sustained cardiac rhythm disorder, is an independent risk factor for stroke, heart failure and death, and its development is promoted by a range of common cardiovascular pathologies. The management of AF is directed at these predisposing conditions, at reducing the risk of systemic thromboembolism, and towards rate or rhythm control of the arrhythmia. Guidelines increasingly support the use of catheter ablation (CA) as an early management strategy, with the efficacy of CA crucially dependent on the extent of left atrial (LA) structural remodeling; LA imaging plays a central role in each of identifying comorbidities, risk stratification for stroke, and identification of suitable candidates for CA. An understanding of the strengths and limitations of various echocardiographic modalities, of cardiac computed tomography and of cardiac magnetic resonance imaging is therefore an increasingly important part of the armory of the electrophysiologist. In particular, individualized use of imaging to select patients more likely to benefit from CA of AF is important, and post-procedural imaging to evaluate the extent of reverse LA remodeling after CA is critical to appropriate decisions regarding ongoing anti-arrhythmic therapy and long-term anticoagulation. PMID- 26241304 TI - Atrial fibrillation ablation: indications, emerging techniques, and follow-up. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia and its prevalence is expected to increase as our population ages. The medical management of AF has yielded only modest success, and over the past 15years, catheter ablation (CA) has become a mainstay in the treatment for AF. Advancements in the tools used for CA have improved outcomes in patients with both paroxysmal and persistent forms of AF. Additionally, the use of various post-procedure ECG monitoring devices is important for guiding the long-term management of patients with AF. However, long term AF control in these patients also requires management of other medical comorbidities and risk factors associated with AF. PMID- 26241305 TI - Two-Dimensional Topological Crystalline Insulator and Topological Phase Transition in TlSe and TlS Monolayers. AB - The properties that distinguish topological crystalline insulator (TCI) and topological insulator (TI) rely on crystalline symmetry and time-reversal symmetry, respectively, which encodes different bulk and surface/edge properties. Here, we predict theoretically that electron-doped TlM (M = S and Se) (110) monolayers realize a family of two-dimensional (2D) TCIs characterized by mirror Chern number CM = -2. Remarkably, under uniaxial strain (~ 1%), a topological phase transition between 2D TCI and 2D TI is revealed with the calculated spin Chern number CS = -1 for the 2D TI. Using spin-resolved edge states analysis, we show different edge-state behaviors, especially at the time reversal invariant points. Finally, a TlBiSe2/NaCl quantum well is proposed to realize an undoped 2D TCI with inverted gap as large as 0.37 eV, indicating the high possibility for room-temperature observation. PMID- 26241307 TI - Acute Appendicitis at Colonoscopy. PMID- 26241306 TI - Hepatitis C virus: why do we need a vaccine to prevent a curable persistent infection? AB - Chronic hepatitis C virus infection is now curable by antiviral therapy but the global burden of liver disease is unlikely to diminish without a vaccine to prevent transmission. The objective of HCV vaccination is not to induce sterilizing immunity, but instead to prevent persistent infection. One vaccine that incorporates only non-structural HCV proteins is now in phase I/II efficacy trials to test the novel concept that T cell priming alone is sufficient for protection. Evidence also suggests that antibodies contribute to infection resolution. Vaccines comprised of recombinant envelope glycoproteins targeted by neutralizing antibodies have been assessed in humans for immunogenicity. Here, we discuss current concepts in protective immunity and divergent approaches to vaccination against a highly mutable RNA virus. PMID- 26241308 TI - Anticipation of Personal Genomics Data Enhances Interest and Learning Environment in Genomics and Molecular Biology Undergraduate Courses. AB - An important discussion at colleges is centered on determining more effective models for teaching undergraduates. As personalized genomics has become more common, we hypothesized it could be a valuable tool to make science education more hands on, personal, and engaging for college undergraduates. We hypothesized that providing students with personal genome testing kits would enhance the learning experience of students in two undergraduate courses at Brigham Young University: Advanced Molecular Biology and Genomics. These courses have an emphasis on personal genomics the last two weeks of the semester. Students taking these courses were given the option to receive personal genomics kits in 2014, whereas in 2015 they were not. Students sent their personal genomics samples in on their own and received the data after the course ended. We surveyed students in these courses before and after the two-week emphasis on personal genomics to collect data on whether anticipation of obtaining their own personal genomic data impacted undergraduate student learning. We also tested to see if specific personal genomic assignments improved the learning experience by analyzing the data from the undergraduate students who completed both the pre- and post-course surveys. Anticipation of personal genomic data significantly enhanced student interest and the learning environment based on the time students spent researching personal genomic material and their self-reported attitudes compared to those who did not anticipate getting their own data. Personal genomics homework assignments significantly enhanced the undergraduate student interest and learning based on the same criteria and a personal genomics quiz. We found that for the undergraduate students in both molecular biology and genomics courses, incorporation of personal genomic testing can be an effective educational tool in undergraduate science education. PMID- 26241309 TI - Structural and Developmental Disparity in the Tentacles of the Moon Jellyfish Aurelia sp.1. AB - Tentacles armed with stinging cells (cnidocytes) are a defining trait of the cnidarians, a phylum that includes sea anemones, corals, jellyfish, and hydras. While cnidarian tentacles are generally characterized as structures evolved for feeding and defense, significant variation exists between the tentacles of different species, and within the same species across different life stages and/or body regions. Such diversity suggests cryptic distinctions exist in tentacle function. In this paper, we use confocal and transmission electron microscopy to contrast the structure and development of tentacles in the moon jellyfish, Aurelia species 1. We show that polyp oral tentacles and medusa marginal tentacles display markedly different cellular and muscular architecture, as well as distinct patterns of cellular proliferation during growth. Many structural differences between these tentacle types may reflect biomechanical solutions to different feeding strategies, although further work would be required for a precise mechanistic understanding. However, differences in cell proliferation dynamics suggests that the two tentacle forms lack a conserved mechanism of development, challenging the textbook-notion that cnidarian tentacles can be homologized into a conserved bauplan. PMID- 26241310 TI - Synchronous Environmental and Cultural Change in the Emergence of Agricultural Economies 10,000 Years Ago in the Levant. AB - The commonly held belief that the emergence and establishment of farming communities in the Levant was a smooth socio-economic continuum during the Pre Pottery Neolithic (ca. 12,000-9,000 cal BP) with only rare minor disruptions is challenged by recently obtained evidence from this region. Using a database of archaeological radiocarbon dates and diagnostic material culture records from a series of key sites in the northern Levant we show that the hitherto apparent long-term continuity interpreted as the origins and consolidation of agricultural systems was not linear and uninterrupted. A major cultural discontinuity is observed in the archaeological record around 10,000 cal BP in synchrony with a Holocene Rapid Climate Change (RCC), a short period of climatic instability recorded in the Northern Hemisphere. This study demonstrates the interconnectedness of the first agricultural economies and the ecosystems they inhabited, and emphasizes the complex nature of human responses to environmental change during the Neolithic period in the Levant. Moreover, it provides a new environmental-cultural scenario that needs to be incorporated in the models reconstructing both the establishment of agricultural economy in southwestern Asia and the impact of environmental changes on human populations. PMID- 26241311 TI - Gut-Microbiota-Metabolite Axis in Early Renal Function Decline. AB - INTRODUCTION: Several circulating metabolites derived from bacterial protein fermentation have been found to be inversely associated with renal function but the timing and disease severity is unclear. The aim of this study is to explore the relationship between indoxyl-sulfate, p-cresyl-sulfate, phenylacetylglutamine and gut-microbial profiles in early renal function decline. RESULTS: Indoxyl sulfate (Beta(SE) = -2.74(0.24); P = 8.8x10-29), p-cresyl-sulfate (-1.99(0.24), P = 4.6x10-16), and phenylacetylglutamine(-2.73 (0.25), P = 1.2x10-25) were inversely associated with eGFR in a large population base cohort (TwinsUK, n = 4439) with minimal renal function decline. In a sub-sample of 855 individuals, we analysed metabolite associations with 16S gut microbiome profiles (909 profiles, QIIME 1.7.0). Three Operational Taxonomic Units (OTUs) were significantly associated with indoxyl-sulfate and 52 with phenylacetylglutamine after multiple testing; while one OTU was nominally associated with p-cresyl sulfate. All 56 microbial members belong to the order Clostridiales and are represented by anaerobic Gram-positive families Christensenellaceae, Ruminococcaceae and Lachnospiraceae. Within these, three microbes were also associated with eGFR. CONCLUSIONS: Our data suggest that indoxyl-sulfate, p-cresyl-sulfate and phenylacetylglutamine are early markers of renal function decline. Changes in the intestinal flora associated with these metabolites are detectable in early kidney disease. Future efforts should dissect this relationship to improve early diagnostics and therapeutics strategies. PMID- 26241312 TI - Urinary Bladder Dysfunction in Transgenic Sickle Cell Disease Mice. AB - BACKGROUND: Urological complications associated with sickle cell disease (SCD), include nocturia, enuresis, urinary infections and urinary incontinence. However, scientific evidence to ascertain the underlying cause of the lower urinary tract symptoms in SCD is lacking. OBJECTIVE: Thus, the aim of this study was to evaluate urinary function, in vivo and ex vivo, in the Berkeley SCD murine model (SS). METHODS: Urine output was measured in metabolic cage for both wild type and SS mice (25-30 g). Bladder strips and urethra rings were dissected free and mounted in organ baths. In isolated detrusor smooth muscle (DSM), relaxant response to mirabegron and isoproterenol (1nM-10MUM) and contractile response to (carbachol (CCh; 1 nM-100MUM), KCl (1 mM-300mM), CaCl2 (1MUM-100mM), alpha,beta methylene ATP (1, 3 and 10 MUM) and electrical field stimulation (EFS; 1-32 Hz) were measured. Phenylephrine (Phe; 10nM-100MUM) was used to evaluate the contraction mechanism in the urethra rings. Cystometry and histomorphometry were also performed in the urinary bladder. RESULTS: SS mice present a reduced urine output and incapacity to produce typical bladder contractions and bladder emptying (ex vivo), compared to control animals. In DSM, relaxation in response to a selective beta3-adrenergic agonist (mirabegron) and to a non-selective beta adrenergic (isoproterenol) agonist were lower in SS mice. Additionally, carbachol, alpha, beta-methylene ATP, KCl, extracellular Ca2+ and electrical field stimulation promoted smaller bladder contractions in SS group. Urethra contraction induced by phenylephrine was markedly reduced in SS mice. Histological analyses of SS mice bladder revealed severe structural abnormalities, such as reductions in detrusor thickness and bladder volume, and cell infiltration. CONCLUSIONS: Taken together, our data demonstrate, for the first time, that SS mice display features of urinary bladder dysfunction, leading to impairment in urinary continence, which may have an important role in the pathogenesis of the enuresis and infections observed the SCD patients. PMID- 26241313 TI - Follicle-Stimulating Hormone Increases the Risk of Postmenopausal Osteoporosis by Stimulating Osteoclast Differentiation. AB - OBJECTIVE: The objectives of this study were to observe the changes in follicle stimulating hormone (FSH) and bone mineral density (BMD) in postmenopausal women, to research the relationship between FSH and postmenopausal osteoporosis, and to observe the effects of FSH on osteoclast differentiation in RAW264.7 cells. METHODS: We analyzed 248 postmenopausal women with normal bone metabolism. A radioimmunoassay (RIA) was used to detect serum FSH, luteinizing hormone (LH), and estradiol (E2). Dual-energy X-ray absorptiometry was used to measure forearm BMD. Then, we analyzed the age-related changes in serum FSH, LH and E2. Additionally, FSH serum concentrations were compared between a group of postmenopausal women with osteoporosis and a control group. Osteoclasts were induced from RAW264.7 cells in vitro by receptor activator of nuclear factor kappa B ligand (RANKL), and these cells were treated with 0, 5, 10, and 20 ng/ml FSH. After the osteoclasts matured, tartrate-resistant acid phosphatase (TRAP) staining was used to identify osteoclasts, and the mRNA expression levels of genes involved in osteoclastic phenotypes and function, such as receptor activator of NF-kappaB (Rank), Trap, matrix metalloproteinase-9 (Mmp-9) and Cathepsin K, were detected in different groups using real-time PCR (polymerase chain reaction). RESULTS: 1. FSH serum concentrations in postmenopausal women with osteoporosis increased notably compared with the control group. 2. RANKL induced RAW264.7 cell differentiation into mature osteoclasts in vitro. 3. FSH increased mRNA expression of genes involved in osteoclastic phenotypes and function, such as Rank, Trap, Mmp-9 and Cathepsin K, in a dose-dependent manner. CONCLUSIONS: The circulating concentration of FSH may play an important role in the acceleration of bone loss in postmenopausal women. FSH increases osteoclastogenesis in vitro. PMID- 26241314 TI - Arsenic pollution and its treatment in Yangzonghai lake in China: In situ remediation. AB - In this study, the effect of direct atomization and spraying a ferric chloride (FeCl3) solution to decrease the arsenic concentration and its pollution in Yangzonghai Lake, China, was investigated. Ten ships were used for spraying 6-8t of FeCl3 in the lake every day since October 2009. After spraying, the average concentration of arsenic in Yangzonghai Lake, which has an area of 31 km(2), an average depth of 20 m, and a water storage capacity of 604 million m(3), started to decrease from 0.117 mg L(-1). On 20 September 2010, the lowest arsenic level of 0.021 mg L(-1) was attained, with an arsenic removal rate as high as 82.0%. However, the source of pollution was not eliminated, and local rainfall mainly occurred in September; hence, arsenic concentration from October to December increased to 0.078 mg L(-1). At the beginning of 2011, the As concentration decreased and remained at 0.025-0.028 mg L(-1) from May to September. During the 2 years of FeCl3 treatment, the water quality improved from V Class to II-III Class of the Chinese standards, which remained consistent for 12 months. The total cost for this in situ water treatment was 29 million RMB, which was less than a hundredth of the expected expenditure of 4-7 billion RMB. The treatment method achieved goals such as high arsenic removal rate, easy operation, low cost, and ecological security. In this study, the changing patterns of the concentration of arsenic in Yangzonghai Lake from June 2008 to December 2014 were analyzed, and the following problems were discussed: the stability of iron arsenic precipitates in the lake, the concentrations of ferric and chloride ions in the lake, the pH of the lake during treatment, the stability of iron-arsenic precipitates in the lakebed sediments, and the variation of phytoplankton species in the lake. PMID- 26241315 TI - Nutritional Status as the Key Modulator of Antioxidant Responses Induced by High Environmental Ammonia and Salinity Stress in European Sea Bass (Dicentrarchus labrax). AB - Salinity fluctuation is one of the main factors affecting the overall fitness of marine fish. In addition, water borne ammonia may occur simultaneously with salinity stress. Additionally, under such stressful circumstances, fish may encounter food deprivation. The physiological and ion-osmo regulatory adaptive capacities to cope with all these stressors alone or in combination are extensively addressed in fish. To date, studies revealing the modulation of antioxidant potential as compensatory response to multiple stressors are rather lacking. Therefore, the present work evaluated the individual and combined effects of salinity challenge, ammonia toxicity and nutritional status on oxidative stress and antioxidant status in a marine teleost, European sea bass (Dicentrarchus labrax). Fish were acclimated to normal seawater (32 ppt), to brackish water (20 ppt and 10 ppt) and to hypo-saline water (2.5 ppt). Following acclimation to different salinities for two weeks, fish were exposed to high environmental ammonia (HEA, 20 mg/L representing 50% of 96h LC50 value for ammonia) for 12 h, 48 h, 84 h and 180 h, and were either fed (2% body weight) or fasted (unfed for 7 days prior to HEA exposure). Results show that in response to decreasing salinities, oxidative stress indices such as xanthine oxidase activity, levels of hydrogen peroxide (H2O2) and lipid peroxidation (malondialdehyde, MDA) increased in the hepatic tissue of fasted fish but remained unaffected in fed fish. HEA exposure at normal salinity (32 ppt) and at reduced salinities (20 ppt and 10 ppt) increased ammonia accumulation significantly (84 h-180 h) in both feeding regimes which was associated with an increment of H2O2 and MDA contents. Unlike in fasted fish, H2O2 and MDA levels in fed fish were restored to control levels (84 h-180 h); with a concomitant increase in superoxide dismutase (SOD), catalase (CAT), components of the glutathione redox cycle (reduced glutathione, glutathione peroxidase and glutathione reductase), ascorbate peroxidase (APX) activity and reduced ascorbate (ASC) content. On the contrary, fasted fish could not activate many of these protective systems and rely mainly on CAT and ASC dependent pathways as antioxidative sentinels. The present findings exemplify that in fed fish single factors and a combination of HEA exposure and reduced seawater salinities (upto 10 ppt) were insufficient to cause oxidative damage due to the highly competent antioxidant system compared to fasted fish. However, the impact of HEA exposure at a hypo-saline environment (2.5 ppt) also defied antioxidant defence system in fed fish, suggesting this combined factor is beyond the tolerance range for both feeding groups. Overall, our results indicate that the oxidative stress mediated by the experimental conditions were exacerbated during starvation, and also suggest that feed deprivation particularly at reduced seawater salinities can instigate fish more susceptible to ammonia toxicity. PMID- 26241316 TI - Attempted Training of Alcohol Approach and Drinking Identity Associations in US Undergraduate Drinkers: Null Results from Two Studies. AB - There is preliminary evidence that approach avoid training can shift implicit alcohol associations and improve treatment outcomes. We sought to replicate and extend those findings in US undergraduate social drinkers (Study 1) and at-risk drinkers (Study 2). Three adaptations of the approach avoid task (AAT) were tested. The first adaptation - the approach avoid training - was a replication and targeted implicit alcohol approach associations. The remaining two adaptations - the general identity and personalized identity trainings - targeted implicit drinking identity associations, which are robust predictors of hazardous drinking in US undergraduates. Study 1 included 300 undergraduate social drinkers. They were randomly assigned to real or sham training conditions for one of the three training adaptations, and completed two training sessions, spaced one week apart. Study 2 included 288 undergraduates at risk for alcohol use disorders. The same training procedures were used, but the two training sessions occurred within a single week. Results were not as expected. Across both studies, the approach avoid training yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes. The general identity training also yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes with one exception; individuals who completed real training demonstrated no changes in drinking refusal self-efficacy whereas individuals who completed sham training had reductions in self-efficacy. Finally, across both studies, the personalized identity training yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes. Despite having relatively large samples and using a well-validated training task, study results indicated all three training adaptations were ineffective at this dose in US undergraduates. These findings are important because training studies are costly and labor-intensive. Future research may benefit from focusing on more severe populations, pairing training with other interventions, increasing training dose, and increasing gamification of training tasks. PMID- 26241319 TI - The family of phytochrome-like photoreceptors: diverse, complex and multi colored, but very useful. AB - Bilin-dependent GAF domain photoreceptors cover the whole spectrum of light with their absorbance properties. They can be divided into three groups according to the domain architecture of their photosensory module. Group I and Group II harbor phytochromes with PAS-GAF-PHY and GAF-PHY domain architecture, respectively. Group III consists of stand-alone GAF domain photoreceptors, the cyanobacteriochromes. Crystal structures of all three groups are now available to shed light on possible downstream signaling pathways. Structures of Group I and III photoreceptors in both states display changes in the secondary structures during photoconversion. The knowledge about the photoconversion in phytochromes and CBCRs make them promising targets for applications in life science and synthetic biology. PMID- 26241317 TI - Large-Scale Transcriptome Analysis of Two Sugarcane Genotypes Contrasting for Lignin Content. AB - Sugarcane is an important crop worldwide for sugar and first generation ethanol production. Recently, the residue of sugarcane mills, named bagasse, has been considered a promising lignocellulosic biomass to produce the second-generation ethanol. Lignin is a major factor limiting the use of bagasse and other plant lignocellulosic materials to produce second-generation ethanol. Lignin biosynthesis pathway is a complex network and changes in the expression of genes of this pathway have in general led to diverse and undesirable impacts on plant structure and physiology. Despite its economic importance, sugarcane genome was still not sequenced. In this study a high-throughput transcriptome evaluation of two sugarcane genotypes contrasting for lignin content was carried out. We generated a set of 85,151 transcripts of sugarcane using RNA-seq and de novo assembling. More than 2,000 transcripts showed differential expression between the genotypes, including several genes involved in the lignin biosynthetic pathway. This information can give valuable knowledge on the lignin biosynthesis and its interactions with other metabolic pathways in the complex sugarcane genome. PMID- 26241318 TI - Structural insights into the regulation of aromatic amino acid hydroxylation. AB - The aromatic amino acid hydroxylases phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase are homotetramers, with each subunit containing a homologous catalytic domain and a divergent regulatory domain. The solution structure of the regulatory domain of tyrosine hydroxylase establishes that it contains a core ACT domain similar to that in phenylalanine hydroxylase. The isolated regulatory domain of tyrosine hydroxylase forms a stable dimer, while that of phenylalanine hydroxylase undergoes a monomer-dimer equilibrium, with phenylalanine stabilizing the dimer. These solution properties are consistent with the regulatory mechanisms of the two enzymes, in that phenylalanine hydroxylase is activated by phenylalanine binding to an allosteric site, while tyrosine hydroxylase is regulated by binding of catecholamines in the active site. PMID- 26241320 TI - The Spalt Transcription Factors Generate the Transcriptional Landscape of the Drosophila melanogaster Wing Pouch Central Region. AB - The Drosophila genes spalt major (salm) and spalt-related (salr) encode Zn-finger transcription factors regulated by the Decapentaplegic (Dpp) signalling pathway in the wing imaginal disc. The function of these genes is required for cell survival and proliferation in the central region of the wing disc, and also for vein patterning in the lateral regions. The identification of direct Salm and Salr target genes, and the analysis of their functions, are critical steps towards understanding the genetic control of growth and patterning of the Drosophila wing imaginal disc by the Dpp pathway. To identify candidate Salm/Salr target genes, we have compared the expression profile of salm/salr knockdown wing discs with control discs in microarray experiments. We studied by in situ hybridization the expression pattern of the genes whose mRNA levels varied significantly, and uncovered a complex transcription landscape regulated by the Spalt proteins in the wing disc. Interestingly, candidate Salm/Salr targets include genes which expression is turned off and genes which expression is positively regulated by Salm/Salr. Furthermore, loss-of-function phenotypic analysis of these genes indicates, for a fraction of them, a requirement for wing growth and patterning. The identification and analysis of candidate Salm/Salr target genes opens a new avenue to reconstruct the genetic structure of the wing, linking the activity of the Dpp pathway to the development of this epithelial tissue. PMID- 26241321 TI - Lysis to Kill: Evaluation of the Lytic Abilities, and Genomics of Nine Bacteriophages Infective for Gordonia spp. and Their Potential Use in Activated Sludge Foam Biocontrol. AB - Nine bacteriophages (phages) infective for members of the genus Gordonia were isolated from wastewater and other natural water environments using standard enrichment techniques. The majority were broad host range phages targeting more than one Gordonia species. When their genomes were sequenced, they all emerged as double stranded DNA Siphoviridae phages, ranging from 17,562 to 103,424 bp in size, and containing between 27 and 127 genes, many of which were detailed for the first time. Many of these phage genomes diverged from the expected modular genome architecture of other characterized Siphoviridae phages and contained unusual lysis gene arrangements. Whole genome sequencing also revealed that infection with lytic phages does not appear to prevent spontaneous prophage induction in Gordonia malaquae lysogen strain BEN700. TEM sample preparation techniques were developed to view both attachment and replication stages of phage infection. PMID- 26241322 TI - Bone Mineral Accrual Is Associated With Parathyroid Hormone and 1,25 Dihydroxyvitamin D Levels in Children and Adolescents. AB - CONTEXT: Rapid bone accrual and calcium demands during puberty may result in compensatory increases in PTH and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels; however, these relations have not been established in longitudinal studies. OBJECTIVE: To determine whether greater bone accrual velocity is associated with greater PTH and 1,25(OH)2D levels in healthy children and adolescents. DESIGN: Prospective cohort study with baseline PTH, 25-hydroxyvitamin D [25(OH)D], and 1,25(OH)2D levels and dual-energy x-ray absorptiometry whole-body bone mineral content (BMC) accrual over 12 months. Secondary analyses examined bone biomarkers and tibia quantitative computed tomography midshaft cortical-BMC. PARTICIPANTS: A total of 594 healthy participants, ages 5-21 years, with longitudinal measures in a subset of 145 participants. MAIN OUTCOME MEASURES: PTH and 1,25(OH)2D levels. RESULTS: PTH levels were higher during Tanner stages 3 and 4 compared to Tanner 1 (P < .05) in males and females and were inversely and significantly associated with 25(OH)D levels and dietary calcium intake. In multivariable analyses, greater bone accrual [measured directly as change in dual-energy x-ray absorptiometry-BMC (P < .001) or quantitative computed tomography-BMC (P < .05), or indirectly as growth velocity (P < .05) or greater bone-formation biomarker level (P < .01)] was associated with higher PTH levels, independent of 25(OH)D level and dietary calcium intake. Similar associations were observed between these direct and indirect indices of bone accrual and 1,25(OH)2D levels. CONCLUSIONS: PTH levels rise in midpuberty, in association with multiple measures of bone accrual. This is consistent with compensatory increases in PTH to drive 1,25(OH)2D production and calcium absorption during periods of increased calcium demands. Additional studies are needed to address PTH effects on bone modeling and remodeling during growth and development. PMID- 26241323 TI - Declining Incidence of Medication-Related Osteonecrosis of the Jaw in Patients With Cancer. AB - CONTEXT: Medication-related osteonecrosis of the jaw (MRONJ) is an infrequent, but severely debilitating condition. Given the significant morbidity attributable to MRONJ and the challenges associated with its management, prevention is crucial. OBJECTIVE: We sought to evaluate the effectiveness of an active dental intervention in reducing MRONJ incidence. DESIGN AND SETTING: We identified all patients who received antiresorptive drug therapy at a specialized cancer center between January 2003 and December 2013 through hospital pharmacy records, whereas confirmed cases of MRONJ were identified through a hospital database. MAIN OUTCOME MEASURES: The incidence of MRONJ before and after the implementation of active dental intervention in July 2008 was quantified and compared. RESULTS: A total of 1243 patients received antiresorptive drug therapy, with 34 confirmed cases of MRONJ (crude overall incidence, 2.7%). The incidence of MRONJ was significantly lower in patients who received antiresorptive therapy after the implementation of guidelines that emphasized active dental input (0.8 vs 4.6%; chi(2) = 16.2; P = .00006). Using a binominal logistic regression model that adjusted for the number of doses of antiresorptive drug received, patients who received active dental input had an odds ratio of developing MRONJ of 0.24 (95% confidence interval, 0.09, 0.61; P = .004). CONCLUSION: The likelihood of developing MRONJ can be minimized through the implementation of prophylactic dental assessment and active dental intervention. This reinforces the importance of increased dental awareness and enhanced dental intervention in the prevention of MRONJ. PMID- 26241324 TI - Elevated Serum Fibroblast Growth Factor 21 Levels in Patients With Hyperthyroidism. AB - CONTEXT: Recent evidence from animal studies indicates that fibroblast growth factor 21 (FGF21), an endocrine hormone that regulates glucose, lipid metabolism, and energy homeostasis, is regulated by T3. However, the role of FGF21 in hyperthyroid patients is unknown. OBJECTIVE: The objective was to study serum FGF21 levels in hyperthyroid patients and the association of serum FGF21 levels with hyperthyroidism. DESIGN AND SETTING: This was a case-control study. PATIENTS AND INTERVENTIONS: A total of 119 hyperthyroid patients and 108 healthy subjects were recruited. Of them, 41 hyperthyroid patients received thionamide treatment for 3 months until euthyroidism was obtained. MAIN OUTCOME MEASURES: Serum FGF21 levels were determined using the ELISA method. RESULTS: Serum FGF21 levels were significantly elevated in hyperthyroid patients as compared with normal subjects [median 290.67 (interquartile range, 156.60-502.33) vs 228.10 (169.85.25-320.10) pg/mL; P < .001]. After thionamide treatment, serum FGF21 levels in hyperthyroid patients declined markedly from 249.10 (139.10-444.00) to 106.90 (38.70-196.15) pg/mL (P < .001). Logistic regression revealed that FGF21, basal metabolic rate, low-density lipoprotein cholesterol, and alanine transaminase were significantly associated with hyperthyroidism. With adjustment for potential confounders, serum FGF21 remained independently associated with hyperthyroidism, with an adjusted odds ratio of 3.123 (95% confidence interval, 1.306-7.468) (P = .010). CONCLUSION: Serum FGF21 levels were elevated in patients with hyperthyroidism and declined after thionamide treatment. And serum FGF21 level was independently associated with hyperthyroidism. PMID- 26241325 TI - Liver Enzymes and Bone Mineral Density in the General Population. AB - CONTEXT: Liver enzyme serum levels within and just above the normal range are strong predictors of incident morbidity and mortality in the general population. However, despite the close links between hepatic pathology and impaired bone health, the association of liver enzymes with osteoporosis has hardly been investigated. OBJECTIVE: The aim of the present study was to clarify whether serum liver enzyme levels in the general population are associated with bone mineral density. DESIGN: This was an observational, cross-sectional study. Participants and Main Outcome: Data on 13 849 adult participants of the Third National Health and Nutrition Examination Survey were used to quantify the independent associations of gamma-glutamyltransferase, alanine transaminase, and aspartate transaminase with femoral neck bone mineral density assessed by dual energy x-ray absorptiometry. RESULTS: In multiple regression models adjusting for numerous confounding variables, gamma-glutamyltransferase showed a weak inverse association with bone mineral density (P = .0063). There also was limited evidence of a nonmonotonous relationship with alanine transaminase, with peak bone mineral density in the second quartile of enzyme activity (P = .0039). No association was found for aspartate transaminase. CONCLUSION: Although mechanistically plausible associations were found in the present study, the rather weak nature of these patterns renders it unlikely that liver enzyme levels could be of substantial use for osteoporosis risk stratification in the general population. PMID- 26241326 TI - The Effect of Glucose on the Release and Bioactivity of Exosomes From First Trimester Trophoblast Cells. AB - CONTEXT: Hyperglycemia and hypoxia are risk factors of metabolic complication during pregnancy. The interactions between oxygen and glucose-sensing pathways that regulate exosome bioactivity from placental cells, however, have not been established. OBJECTIVE: The aim of this study was to test the hypothesis that exosomal signaling by placental cells (defined as the number of exosomes released per unit time and their bioactivity) is responsive to extracellular glucose concentration. METHODS: First-trimester primary trophoblast cells were incubated with D-glucose (5 mM or 25 mM) under 1%, 3%, or 8% O2 for 48 hours. Exosomes were isolated from cell-conditioned media by differential and buoyant density centrifugation. The total number of exosome vesicles was determined by quantifying immunoreactive exosomal CD63. The effect of exosomes on cytokine (granulocyte macrophage colony-stimulating factor, IL-2, IL-4, IL-6. IL-8, IL-10, interferon-gamma, and TNF-alpha) release from endothelial cells was established by a protein solution array analysis. RESULTS: Glucose (25 mM) significantly increased the release of exosomes from trophoblast cells at all oxygen tensions tested (by approximately 2-fold when compared with controls, P < .001). Exosomes (100 MUg/mL exosomal protein) released from trophoblast cells significantly increased (P < .05) the release of all cytokines from human umbilical vein endothelial cells when compared with the control (ie, cells without exosomes), with the exception of IL-2 and IL-10 (P > .05). CONCLUSIONS: The effects of high glucose on exosomes bioactivity may be recapitulated in vivo and is of clinical relevance in association with maternal insulin resistance (resulting in hyperglycemia) and preeclampsia (associated with placental insufficiency and hypoxia). PMID- 26241327 TI - Development of a Weighted Cardiometabolic Disease Staging (CMDS) System for the Prediction of Future Diabetes. AB - CONTEXT: Metabolic syndrome traits are important risk factors for diabetes; however, each trait has different predictive power for future diabetes. Additionally, the impact of insulin resistance on metabolic profile can differ by gender and racial group, suggesting that gender-race specific prediction algorithms for diabetes may be warranted. OBJECTIVE: To develop a quantitative scoring system based on weighting of risk components in the cardiometabolic disease staging (CMDS) system for the prediction of future diabetes. DESIGN, SETTING, AND PARTICIPANTS: We derived the CMDS score in 2857 participants with valid follow-up information on incident diabetes from the Coronary Artery Risk Development in Young Adults study and validated it in 6425 older participants from the Atherosclerosis Risk in Communities study. We assigned a simple integer value for each CMDS risk factor component. MAIN OUTCOME MEASURES: Incident diabetes. RESULTS: Fasting glucose, 2-hour glucose, waist circumference, and blood pressure components contributed similarly for the prediction of future diabetes (CMDS scores, 23, 21, 26, and 20, respectively). The area under the receiver operating characteristic curve was 0.7158 for the CMDS scoring system, whereas it was 0.7053 for the Framingham diabetes score. The CMDS components performed differently for prediction of future diabetes in Black and White men and women. The components with the highest predictive power for diabetes were waist circumference in Black men, 2-hour glucose in Black women, and fasting glucose in both White men and White women. CONCLUSIONS: The weighted CMDS score has high model discrimination power for diabetes and can be used clinically to identify patients for weight loss therapy based on differential risk for future diabetes. PMID- 26241328 TI - Environmental Variables Shaping the Ecological Niche of Thaumarchaeota in Soil: Direct and Indirect Causal Effects. AB - To find environmental variables (EVs) shaping the ecological niche of the archaeal phylum Thaumarchaeota in terrestrial environments, we determined the abundance of Thaumarchaeota in various soil samples using real-time PCR targeting thaumarchaeotal 16S rRNA gene sequences. We employed our previously developed primer, THAUM-494, which had greater coverage for Thaumarchaeota and lower tolerance to nonthaumarchaeotal taxa than previous Thaumarchaeota-directed primers. The relative abundance estimates (RVs) of Thaumarchaeota (RTHAUM), Archaea (RARCH), and Bacteria (RBACT) were subjected to a series of statistical analyses. Redundancy analysis (RDA) showed a significant (p < 0.05) canonical relationship between RVs and EVs. Negative causal relationships between RTHAUM and nutrient level-related EVs were observed in an RDA biplot. These negative relationships were further confirmed by correlation and regression analyses. Total nitrogen content (TN) appeared to be the EV that affected RTHAUM most strongly, and total carbon content (TC), which reflected the content of organic matter (OM), appeared to be the EV that affected it least. However, in the path analysis, a path model indicated that TN might be a mediator EV that could be controlled directly by the OM. Additionally, another path model implied that water content (WC) might also indirectly affect RTHAUM by controlling ammonium nitrogen (NH4+-N) level through ammonification. Thus, although most directly affected by NH4+-N, RTHAUM could be ultimately determined by OM content, suggesting that Thaumarchaeota could prefer low-OM or low-WC conditions, because either of these EVs could subsequently result in low levels of NH4+-N in soil. PMID- 26241329 TI - The Right Tool for the Job: Detection of Soil-Transmitted Helminths in Areas Co endemic for Other Helminths. AB - BACKGROUND: Due to the recent increased use of the McMaster (MM) fecal egg counting method for assessing benzimidazole drug efficacy for treating soil transmitted helminth (STH) infections, the aim of the current study was to determine the operational value of including the MM method alongside the Kato Katz (KK) fecal thick smear to increase the diagnostic sensitivity when STHs are co-endemic with trematode helminths (e.g., Schistosoma mansoni). METHODS: A cross sectional study was conducted in school-aged children aged 4-18 years in the northeastern region of the State of Minas Gerais (Brazil), where Necator americanus, Ascaris lumbricoides, Trichuris trichiura, and S. mansoni are co endemic. One fecal sample from each participant was collected and transported to the field laboratory for analysis. Coprological diagnosis was performed on each fecal sample by three different methods: Formalin-Ether Sedimentation (FES), KK and the MM technique. The diagnostic sensitivity and negative predictive value (NPV) of each technique was calculated using the combination of all three techniques as the composite standard. In order to determine the agreement between the three techniques Fleiss' kappa was used. Both the Cure Rate (CR) and the Fecal Egg Count Reduction (FECR) were calculated using the two quantification techniques (i.e., the MM and KK). RESULTS: Fecal samples from 1260 children were analyzed. The KK had higher diagnostic sensitivity than the MM for the detection of both A. lumbricoides (KK 97.3%, MM 69.5%) and hookworm (KK 95.1%, MM 80.8%). The CR of a single dose of mebendazole varied significantly between the KK and MM for both A. lumbricoides (p = 0.016) and hookworm (p = 0.000), with lower rates obtained with the KK. On the other hand, the FECR was very similar between both techniques for both A. lumbricoides and hookworm. CONCLUSION: The MM did not add any diagnostic value over the KK in areas where both STHs and trematodes were co endemic. The lower sensitivity of the MM would have an important impact on the administration of selective school-based treatment in this area since if only the MM were used, 36 (13.9%) children diagnosed with A. lumbricoides would have gone untreated. PMID- 26241331 TI - Oligomerization state and pigment binding strength of the peridinin-Chl a protein. AB - The peridinin-chlorophyll a-protein (PCP) is one of the major light harvesting complexes (LHCs) in photosynthetic dinoflagellates. We analyzed the oligomeric state of PCP isolated from the dinoflagellate Symbiodinium, which has received increasing attention in recent years because of its role in coral bleaching. Size exclusion chromatography (SEC) and small angle neutron scattering (SANS) analysis indicated PCP exists as monomers. Native mass spectrometry (native MS) demonstrated two oligomeric states of PCP, with the monomeric PCP being dominant. The trimerization may not be necessary for PCP to function as a light-harvesting complex. PMID- 26241332 TI - A modified precise analytical method for anti-malarial screening: Heme polymerization assay. AB - Malarial parasite detoxifies the heme generated in its food vacuole in many ways one of which involves heme polymerization to hemozoin. The existing heme polymerization assays involve use of activators along with buffers for polymerization of heme leading to its precipitation. Such assays then involve special instruments and laborious work of isolating the precipitated polymer and its detection. Simple and precise spectrophotometric and HTS methods were developed for heme polymerization using tween 20 as the activator without isolation of polymerized heme. PMID- 26241330 TI - "PP2C7s", Genes Most Highly Elaborated in Photosynthetic Organisms, Reveal the Bacterial Origin and Stepwise Evolution of PPM/PP2C Protein Phosphatases. AB - Mg+2/Mn+2-dependent type 2C protein phosphatases (PP2Cs) are ubiquitous in eukaryotes, mediating diverse cellular signaling processes through metal ion catalyzed dephosphorylation of target proteins. We have identified a distinct PP2C sequence class ("PP2C7s") which is nearly universally distributed in Eukaryotes, and therefore apparently ancient. PP2C7s are by far most prominent and diverse in plants and green algae. Combining phylogenetic analysis, subcellular localization predictions, and a distillation of publically available gene expression data, we have traced the evolutionary trajectory of this gene family in photosynthetic eukaryotes, demonstrating two major sequence assemblages featuring a succession of increasingly derived sub-clades. These display predominant expression moving from an ancestral pattern in photosynthetic tissues toward non-photosynthetic, specialized and reproductive structures. Gene co expression network composition strongly suggests a shifting pattern of PP2C7 gene functions, including possible regulation of starch metabolism for one homologue set in Arabidopsis and rice. Distinct plant PP2C7 sub-clades demonstrate novel amino terminal protein sequences upon motif analysis, consistent with a shifting pattern of regulation of protein function. More broadly, neither the major events in PP2C sequence evolution, nor the origin of the diversity of metal binding characteristics currently observed in different PP2C lineages, are clearly understood. Identification of the PP2C7 sequence clade has allowed us to provide a better understanding of both of these issues. Phylogenetic analysis and sequence comparisons using Hidden Markov Models strongly suggest that PP2Cs originated in Bacteria (Group II PP2C sequences), entered Eukaryotes through the ancestral mitochondrial endosymbiosis, elaborated in Eukaryotes, then re-entered Bacteria through an inter-domain gene transfer, ultimately producing bacterial Group I PP2C sequences. A key evolutionary event, occurring first in ancient Eukaryotes, was the acquisition of a conserved aspartate in classic Motif 5. This has been inherited subsequently by PP2C7s, eukaryotic PP2Cs and bacterial Group I PP2Cs, where it is crucial to the formation of a third metal binding pocket, and catalysis. PMID- 26241333 TI - Procedural learning and automatization process in children with developmental coordination disorder and/or developmental dyslexia. AB - OBJECTIVE: There is increasing evidence to suggest that developmental dyslexia (DD) and developmental coordination disorder (DCD) actually form part of a broader disorder. Their frequent association could be justified by a deficit of the procedural memory system, that subtends many of the cognitive, motor and linguistic abilities that are impaired in both DD and DCD. However, studies of procedural learning in these two disorders have yielded divergent results, and in any case no studies have so far addressed the issue of automatization (dual-task paradigm). METHODS: We administered a finger tapping task to participants aged 8 12 years (19 DCD, 18 DD, and 22 with both DD and DCD) to explore procedural learning and automatic movements in these three groups of children, comparing motor performances at the prelearning stage, after 2 weeks of training, and in a post-training dual-task condition. RESULTS: First, results indicated that all the children were able to learn a sequence of movements and even automatize their movements. Second, they revealed between-groups differences in procedural/automatization learning abilities, setting the DCD group apart from the other two. Third, contrary to our expectations concerning comorbidity, they suggested that the DD+DCD association does not have an additional impact on behavioral performances. PMID- 26241334 TI - Training to improve manual control in 7-8 and 10-12 year old children: Training eliminates performance differences between ages. AB - Many children have difficulty producing movements well enough to improve in perceptuo-motor learning. We have developed a training method that supports active movement generation to allow improvement in a 3D tracing task requiring good compliance control. We previously tested 7-8 year old children who exhibited poor performance and performance differences before training. After training, performance was significantly improved and performance differences were eliminated. According to the Dynamic Systems Theory of development, appropriate support can enable younger children to acquire the ability to perform like older children. In the present study, we compared 7-8 and 10-12 year old school children and predicted that younger children would show reduced performance that was nonetheless amenable to training. Indeed, the pre-training performance of the 7-8 year olds was worse than that of the 10-12 year olds, but post-training performance was equally good for both groups. This was similar to previous results found using this training method for children with DCD and age-matched typically developing children. We also found in a previous study of 7-8 year old school children that training in the 3D tracing task transferred to a 2D drawing task. We now found similar transfer for the 10-12 year olds. PMID- 26241335 TI - Differential recruitment of brain networks during visuospatial and color processing: Evidence from ERP microstates. AB - Recent functional magnetic resonance imaging (fMRI) studies consistently revealed contributions of fronto-parietal and related networks to the execution of a visuospatial judgment task, the so-called "Clock Task". However, due to the low temporal resolution of fMRI, the exact cortical dynamics and timing of processing during task performance could not be resolved until now. In order to clarify the detailed cortical activity and temporal dynamics, 14 healthy subjects performed an established version of the "Clock Task", which comprises a visuospatial task (angle discrimination) and a control task (color discrimination) with the same stimulus material, in an electroencephalography (EEG) experiment. Based on the time-resolved analysis of network activations (microstate analysis), differences in timing between the angle compared to the color discrimination task were found after sensory processing in a time window starting around 200 ms. Significant differences between the two tasks were observed in an analysis window from 192 ms to 776 ms. We divided this window in two parts: an early phase - from 192 ms to ~440 ms, and a late phase - from ~440 ms to 776 ms. For both tasks, the order of network activations and the types of networks were the same, but, in each phase, activations for the two conditions were dominated by differing network states with divergent temporal dynamics. Our results provide an important basis for the assessment of deviations in processing dynamics during visuospatial tasks in clinical populations. PMID- 26241336 TI - Angiotensin II-induced mouse hippocampal neuronal HT22 cell apoptosis was inhibited by propofol: Role of neuronal nitric oxide synthase and metallothinonein-3. AB - BACKGROUND: The activation of renin angiotensin system is involved in multiple pathological processes. The neuroprotective effect of propofol has been reported. We hypothesized that propofol may attenuate Angiotensin II (Ang II)-induced apoptosis in mouse hippocampal HT22 cells and aimed to identify the underlying mechanisms. METHODS: Mouse hippocampal HT22 cells were pre-treated with propofol, and stimulated with Ang II. Apoptosis was examined by transferase dUTP nick end labeling (TUNEL) staining and caspase-3 activity assay. The effect of propofol on Ang II-modulated neuronal nitric oxide synthase (nNOS) expression, nitric oxide (NO) production, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression and activity, caspase activity and metallothinonein-3 (MT-3) expression were measured. RESULTS: Compared with control, Ang II concentration- and time-dependently induced apoptosis, which was attenuated by propofol in a concentration-dependent manner. Ang II (1 MUM, 3 h) induced the expression of nNOS and NADPH oxidase, caused NO and superoxide anion accumulation, thus leading to excessive oxidative stress. Ang II also induced cytochrome C release and the activation of caspase 9 as well as caspase 3. In addition, Ang II reduced the expression of MT-3. Importantly, these effects were alleviated by 50 MUM propofol, nNOS inhibitor S-methyl-l-thiocitrulline (SMTC) and angiotensin type 1 receptor (AT1R) blocker losartan, but not AT2R blocker PD123319. CONCLUSIONS: Ang II via AT1R induced oxidative stress and apoptosis in hippocampal HT22 cells, and the neuroprotective anti-apoptotic effect of propofol was mediated through inhibiting oxidative stress. PMID- 26241337 TI - The hippocampus in aging and disease: From plasticity to vulnerability. AB - The hippocampus has a pivotal role in learning and in the formation and consolidation of memory and is critically involved in the regulation of emotion, fear, anxiety, and stress. Studies of the hippocampus have been central to the study of memory in humans and in recent years, the regional specialization and organization of hippocampal functions have been elucidated in experimental models and in human neurological and psychiatric diseases. The hippocampus has long been considered a classic model for the study of neuroplasticity as many examples of synaptic plasticity such as long-term potentiation and -depression have been identified and demonstrated in hippocampal circuits. Neuroplasticity is the ability to adapt and reorganize the structure or function to internal or external stimuli and occurs at the cellular, population, network or behavioral level and is reflected in the cytological and network architecture as well as in intrinsic properties of hippocampal neurons and circuits. The high degree of hippocampal neuroplasticity might, however, be also negatively reflected in the pronounced vulnerability of the hippocampus to deleterious conditions such as ischemia, epilepsy, chronic stress, neurodegeneration and aging targeting hippocampal structure and function and leading to cognitive deficits. Considering this framework of plasticity and vulnerability, we here review basic principles of hippocampal anatomy and neuroplasticity on various levels as well as recent findings regarding the functional organization of the hippocampus in light of the regional vulnerability in Alzheimer's disease, ischemia, epilepsy, neuroinflammation and aging. PMID- 26241338 TI - Increased sensitivity to kindling in mice lacking TSP1. AB - The development of a hyperexcitable neuronal network is thought to be a critical event in epilepsy. Thrombospondins (TSPs) regulate synaptogenesis by binding the neuronal alpha2delta subunit of the voltage-gated calcium channel. TSPs regulate synapse formation during development and in the mature brain following injury. It is unclear if TSPs are involved in hyperexcitability that contributes to the development of epilepsy. Here we explore the development of epilepsy using a pentylenetetrazole (PTZ) kindling model in mice lacking TSP1 and TSP2. Unexpectedly, we found increased sensitivity to PTZ kindling in mice lacking TSP1, while mice lacking TSP2 kindled similar to wild-type. We found that the increased seizure susceptibility in the TSP1 knockout (KO) mice was not due to a compensatory increase in TSP2 mRNA as TSP1/2 KO mice were sensitive to PTZ, similar to the TSP1 KO mice. Furthermore, there were similar levels of TGF-B signal activation during kindling in the TSP1 KO mice compared to wild-type. We observed decreased expression of voltage-dependent calcium channel subunit CACNA2D1 mRNA in TSP1, TSP2, and TSP1/2 KO mice. Decreased CACNA2D2 mRNA was only detected in mice that lacked TSP1 and alpha2delta-1/2 protein levels in the cortex were lower in the TSP 1/2 KO mice. CACNA2D2 knockout mice have spontaneous seizures and increased PTZ seizure susceptibility. Here we report similar findings, TSP1, and TSP1/2 KO mice have low levels of CACNA2D2 mRNA expression and alpha2delta-1/2 receptor level in the cortex, and are more susceptible to seizures. CACNA2D2 mutations in mice and humans can cause epilepsy. Our data suggest TSP1 in particular may control CACNA2D2 levels and could be a modifier of seizure susceptibility. PMID- 26241339 TI - Short-term effects of integrated motor imagery practice on muscle activation and force performance. AB - The effect of motor imagery (MI) practice on isometric force development is well documented. However, whether practicing MI during rest periods of physical training improves the forthcoming performance remains unexplored. We involved 18 athletes in a counterbalanced design including three physical training sessions scheduled over five consecutive days. Training involved 10 maximal isometric contractions against a force plate, with the elbow at 90 degrees . During two sessions, we integrated MI practice (focusing on either muscle activation or relaxation) during the inter-trial rest periods. We measured muscle performance from force plate and electromyograms of the biceps brachii and anterior deltoideus. We continuously monitored electrodermal activity (EDA) to control sympathetic nervous system activity. MI of muscle activation resulted in higher isometric force as compared to both MI of muscle relaxation and passive recovery (respectively +2.1% and +3.5%). MI practice of muscle relaxation also outperformed the control condition (+1.9%). Increased activation of the biceps brachii was recorded under both MI practice conditions compared to control. Biceps brachii activation was similar between the two MI practice conditions, but electromyography revealed a marginal trend toward greater activation of the anterior deltoideus during MI practice of muscle activation. EDA and self-reports indicated that these effects were independent from physiological arousal and motivation. These results might account for priming effects of MI practice yielding to higher muscle activation and force performance. Present findings may be of interest for applications in sports training and neurologic rehabilitation. PMID- 26241340 TI - Acidic FGF promotes neurite outgrowth of cortical neurons and improves neuroprotective effect in a cerebral ischemic rat model. AB - Acidic fibroblast growth factor (aFGF) is a neurotrophic factor which is a powerful neuroprotective and neuroregenerative factor of the nervous system. Prior study had shown that levels of FGFs significantly increase following ischemic injury, reflecting a physiological protection mechanism. However, few reports demonstrated the efficacy of applying aFGF in cerebral ischemia. A recent report showed that the intranasal aFGF treatment improved neurological functional recovery; however, it did not significantly reduce the lesion size in ischemic rats. The present study examines the neuroprotective effect of aFGF on cortical neuron-glial cultures under oxygen glucose deprivation (OGD)-induced cell damage and investigates whether epidural application of slow-released aFGF could improve benefit on ischemic stroke injury in conscious rats. We used a topical application of aFGF mixed in fibrin glue, a slow-release carrier, over the peri ischemic cortex and examined such treatment on cerebral infarction and behavioral impairments of rats subjected to focal cerebral ischemia (FCI). Results demonstrate that aFGF effectively protected cortical neuron-glial cultures from OGD-induced neuronal damage. Neurite extension from cortical neurons was significantly enhanced by aFGF, mediated through activation of AKT and ERK. In addition, topical application of fibrin glue-mixed aFGF dose-dependently reduced ischemia-induced brain infarction and improved functional restoration in ischemic stroke rats. Slow-released aFGF not only protected hippocampal and cortical cell loss but reduced microglial infiltration in FCI rats. Our results suggest that aFGF mixed in fibrin glue could prolong the protective/regenerative efficacy of aFGF to the damaged brain tissue and thus improve the functional restorative effect of aFGF. PMID- 26241341 TI - Nucleus accumbens injections of the mGluR2/3 agonist LY379268 increase cue induced sucrose seeking following adult, but not adolescent sucrose self administration. AB - Adolescence is often portrayed as a period of enhanced sensitivity to reward, with long-lasting neurobiological changes upon reward exposure. However, we previously found that time-dependent increases in cue-induced sucrose seeking were more pronounced in rats trained to self-administer sucrose as adults than as adolescents. In addition, adult, but not adolescent sucrose self-administration led to a decreased alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N Methyl-D-aspartate (AMPA/NMDA) ratio in the nucleus accumbens core, suggesting that long-lasting changes in glutamatergic transmission may affect adult processing of natural rewards. Here we tested whether altering glutamatergic transmission in the nucleus accumbens core via local injection of an mGluR2/3 agonist and antagonist affects cue-induced sucrose seeking following abstinence and whether this is different in the two age groups. Rats began oral sucrose self administration training (10 days) on postnatal day (P) 35 (adolescents) or P70 (adults). Following 21 days of abstinence, rats received microinjections of the mGluR2/3 agonist LY379268 (0.3 or 1.0 MUg/side) or vehicle into the nucleus accumbens core, and 15 min later cue-induced sucrose seeking was assessed. An additional group of rats trained as adults received nucleus accumbens core microinjections of the mGluR2/3 antagonist (RS)-alpha-Methyl-4 phosphonophenylglycine (MPPG) (0.12 or 0.5 MUg/side). Confirming our previous results, adult rats earned more sucrose reinforcers, while sucrose intake per body weight was similar across ages. On abstinence day 22, local injection of the mGluR2/3 agonist LY379268 increased cue-induced sucrose seeking only in adult rats, and had no effect in adolescents. Local injections of the mGluR2/3 antagonist MPPG had no effect on sucrose seeking in adult rats. These data suggest an important developmental difference in the neural substrates of natural reward, specifically a difference in glutamatergic transmission in the accumbens in cue-induced responding for sucrose between adolescent and adult rats. PMID- 26241343 TI - Allopregnanolone increases mature excitatory synapses along dendrites via protein kinase A signaling. AB - Allopregnanolone (APalpha; 5alpha-pregnan-3alpha-ol-20-one) is synthesized in both the periphery and central nervous system and is known to be a potent positive allosteric modulator of the GABAA receptor. Because APalpha was suggested to improve the symptoms of depression and Alzheimer's disease (AD), which involve synaptic dysfunction and loss, we examined whether APalpha affects excitatory synapses. Drebrin, which is an actin-binding protein, forms a unique stable actin structure in dendritic spines, and drebrin levels correlate positively with cognitive levels in AD and mild cognitive impairment. We investigated whether APalpha increases excitatory synapse density along dendrites of mature hippocampal neurons using drebrin-imaging-based evaluation of mature synapses. We prepared primary cultures of hippocampal neurons and either transfected them with GFP or immunostained them against drebrin. Morphological analysis of GFP-transfected neurons revealed that a 24-h exposure to 0.3 or 1 MUM APalpha significantly increased dendritic spine density without any morphological changes to spines. Drebrin cluster density was also increased by 0.3 and 1 MUM APalpha. The protein kinase A (PKA) inhibitor H-89 inhibited the APalpha-induced increase in drebrin cluster density. These data demonstrate that APalpha increases mature excitatory synapses via activation of PKA. Therefore, the PKA cAMP response element-binding protein (CREB) signaling pathway is likely to be involved in the APalpha-induced increase of mature excitatory synapses. Another possibility is that the PKA-dependent increase in AMPA receptors at dendritic spines mediates the APalpha function. In conclusion, our study indicates that APalpha may improve neuropsychiatric disorder outcomes via increasing the numbers of mature excitatory synapses. PMID- 26241342 TI - Central fatigue induced by short-lasting finger tapping and isometric tasks: A study of silent periods evoked at spinal and supraspinal levels. AB - The neural substrates of fatigue induced by muscular activity have been addressed in depth in relation to isometric tasks. For these activities, when fatigue develops, it has been noted that the duration of the silent periods (SPs) increases in response to both transcranial magnetic stimulation (TMS) of primary motor cortex or electric cervicomedullary stimulation (CMS). However, fatigue is known to be task-dependent and the mechanisms giving rise to a decrease in motor performance during brief, fast repetitive tasks have been less studied. We hypothesized that fatigue induced by repetitive fast finger tapping may have physiological mechanisms different from those accounting for fatigue during an isometric contraction, even in cases of matched effort durations. In these tasks, we examined the contribution of spinal and supraspinal motor circuits to the production of fatigue. The tapping rate and maximal voluntary contractions (MVC), and TMS- and CMS-evoked SPs were obtained at the time of fatigue, and while subjects maintained maximal muscle activation after fast finger-tapping (or isometric activity) of different durations (10 or 30s). Results showed different mechanisms of fatigue triggered by isometric contraction and repetitive movements, even of short duration. Short-lasting repetitive movements induce fatigue within intracortical inhibitory circuits. They increased TMS-SPs, but not CMS-SPs. On the other hand, isometric contraction had a clear impact on spinal circuits. The consideration of these differences might help to optimize the study of fatigue in physiological conditions and neurological disorders. PMID- 26241344 TI - Negative Secular Trends in Medicine: High CEO Salaries. PMID- 26241345 TI - Electrocardiogram Screening in Athletes: A Good Return on Investment? PMID- 26241346 TI - Variability in United States Allopathic Medical School Tuition. AB - BACKGROUND: Over the course of the last generation, the cost of medical school attendance and medical student debt has increased drastically. Medical student debt has been reported as high as $350,000, and the Association of American Medical Colleges (AAMC) reports that medical school tuition continues to increase annually. The increasing cost of medical education and associated financial burden is now beginning to deter potential applicants from pursuing a career in medicine. In this study we aimed to assess medical school tuition across the US. We hypothesized that the cost of medical school attendance is variable across all regions of the US, and as a result, the financial burden on medical students is inconsistent. METHODS: All 123 allopathic medical schools accredited by the AAMC were assessed in this investigation. In-state and out-of-state tuitions for the year 2016 were obtained from U.S. News and World Report. Additionally, medical school size was collected. Regions were defined according to the US Census Bureau definition, with the US being divided into 4 regions: Northeast, Midwest, South, and West. RESULTS: There was no difference in average medical school size among the 4 regions (P > .05). Average in-state tuition was $38,291.56 +/- $9801.38 (95% confidence interval [CI], $34,658.07-$41,513.46) in the Midwest, $45,923.04 +/- $9178.87 (95% CI, $42,566.28-$49,216.78) in the Northeast, $32,287.78 +/- $12,277.53 (95% CI, $28,581.90-$35,378.68) in the South, and $37,745.40 +/- $11,414.37 (95% CI, $30,063.28-$40,458.99) in the West. In-state tuition in the South was significantly lower than in the Northeast, West, and Midwest (P < .05). In-state tuition in the Northeast was significantly higher than in the South, West, and Midwest (P < .05). Average out-of-state tuition is $54,104.04 +/- $8227.65 (95% CI, $51,207.6-$57,000.39) in the Midwest, $53,180.10 +/- $3963.71 (95% CI, $51,761.71-$54,598.50) in the Northeast, $48,191.86 +/- $12,578.13 (95% CI, $44,595.84-$51,787.89) in the South, and $52,920.47 +/- $7400.83 (95% CI, $49,175.13-$56,665.80) in the West. Out-of-state tuition was significantly lower in the South in comparison with the Midwest and Northeast (P < .05), but was not significantly different than the West (P > .05). CONCLUSION: Despite no significant difference in medical school size among the 4 regions of the US that were assessed, there is significant regional variation in tuition, with higher tuition in private vs public schools. This study suggests that medical schools place a variable financial burden on the medical students based on region. The ongoing increases in medical school tuition are unsustainable, as future trainees will face substantial financial stress as they attempt to pay off their debt while initiating medical practice after residency and fellowship training. PMID- 26241347 TI - Low-grade epithelial ovarian cancer: a number of distinct clinical entities? AB - PURPOSE OF REVIEW: The purpose of this study is to summarize the contemporary understanding of low-grade epithelial ovarian cancers. RECENT FINDINGS: Low-grade serous ovarian cancer is biologically distinct from high-grade serous ovarian cancer. It is associated with a high incidence of K-RAS and B-RAF mutations. Although described as indolent due to median progression-free and overall survivals of 20 and 99 months, respectively, with a median age of diagnosis of 43 years, it accounts for a significant number of patient-years lost. Retrospective studies suggest response rates of 5% for chemotherapy and 9% for antioestrogen therapy. A prospective study of the mitogen-activated protein kinase kinase inhibitor selumetinib (response rate 15%) and retrospective bevacizumab studies suggest that these may be more effective approaches.Limited retrospective clinical data and even more sparse molecular data suggest that similar distinctions may exist between low-grade endometrioid and mucinous ovarian cancers and their respective high-grade counterparts, but more research is required in order to clarify the biological differences and the implications that these have for management. SUMMARY: The results of phase III mitogen-activated protein kinase kinase inhibitor studies in low-grade serous ovarian cancer and further clinical and biological assessment of low-grade endometrioid and mucinous ovarian cancers are urgently required. PMID- 26241348 TI - Cancer stem cells and cell size: A causal link? AB - The majority of normal animal cells are 10-20 MUm in diameter. Many signaling mechanisms, notably PI3K/Akt/mTOR, Myc, and Hippo pathways, tightly control and coordinate cell growth, cell size, cell division, and cell number during homeostasis. These regulatory mechanisms are frequently deregulated during tumorigenesis resulting in wide variations in cell sizes and increased proliferation in cancer cells. Here, we first review the evidence that primitive stem cells in adult tissues are quiescent and generally smaller than their differentiated progeny, suggesting a correlation between small cell sizes with the stemness. Conversely, increased cell size positively correlates with differentiation phenotypes. We then discuss cancer stem cells (CSCs) and present some evidence that correlates cell sizes with CSC activity. Overall, a causal link between CSCs and cell size is relatively weak and remains to be rigorously assessed. In the future, optimizing methods for isolating cells based on size should help elucidate the connection between cancer cell size and CSC characteristics. PMID- 26241349 TI - IL-1beta and BDNF are associated with improvement in hypersomnia but not insomnia following exercise in major depressive disorder. AB - Given the role of sleep in the development and treatment of major depressive disorder (MDD), it is becoming increasingly clear that elucidation of the biological mechanisms underlying sleep disturbances in MDD is crucial to improve treatment outcomes. Sleep disturbances are varied and can present as insomnia and/or hypersomnia. Though research has examined the biological underpinnings of insomnia in MDD, little is known about the role of biomarkers in hypersomnia associated with MDD. This paper examines biomarkers associated with changes in hypersomnia and insomnia and as predictors of improvements in sleep quality following exercise augmentation in persons with MDD. Subjects with non-remitted MDD were randomized to augmentation with one of two doses of aerobic exercise: 16 kilocalories per kilogram of body weight per week (KKW) or 4 KKW for 12 weeks. The four sleep-related items on the clinician-rated Inventory of Depressive Symptomatology (sleep onset insomnia, mid-nocturnal insomnia, early morning insomnia and hypersomnia) assessed self-reported sleep quality. Inflammatory cytokines (tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6) and brain derived neurotrophic factor (BDNF) were assessed in blood samples collected before and following the 12-week intervention. Reduction in hypersomnia was correlated with reductions in BDNF (rho = 0.26, P = 0.029) and IL-1beta (rho = 0.37, P = 0.002). Changes in these biomarkers were not associated with changes in insomnia; however, lower baseline levels of IL-1beta were predictive of greater improvements in insomnia (F = 3.87, P = 0.050). In conclusion, improvement in hypersomnia is related to reductions in inflammatory markers and BDNF in persons with non-remitted MDD. Distinct biological mechanisms may explain reductions in insomnia. PMID- 26241350 TI - Abnormal subcellular localization of GABAA receptor subunits in schizophrenia brain. AB - Inhibitory neurotransmission is primarily mediated by gamma-aminobutyric acid (GABA) activating synaptic GABA type A receptors (GABA(A)R). In schizophrenia, presynaptic GABAergic signaling deficits are among the most replicated findings; however, postsynaptic GABAergic deficits are less well characterized. Our lab has previously demonstrated that although there is no difference in total protein expression of the alpha1-6, beta1-3 or gamma2 GABA(A)R subunits in the superior temporal gyrus (STG) in schizophrenia, the alpha1, beta1 and beta2 GABA(A)R subunits are abnormally N-glycosylated. N-glycosylation is a posttranslational modification that has important functional roles in protein folding, multimer assembly and forward trafficking. To investigate the impact that altered N glycosylation has on the assembly and trafficking of GABA(A)Rs in schizophrenia, this study used western blot analysis to measure the expression of alpha1, alpha2, beta1, beta2 and gamma2 GABA(A)R subunits in subcellular fractions enriched for endoplasmic reticulum (ER) and synapses (SYN) from STG of schizophrenia (N = 16) and comparison (N = 14) subjects and found evidence of abnormal localization of the beta1 and beta2 GABA(A)R subunits and subunit isoforms in schizophrenia. The beta2 subunit is expressed as three isoforms at 52 kDa (beta2(52 kDa)), 50 kDa (beta2(50 kDa)) and 48 kDa (beta2(48 kDa)). In the ER, we found increased total beta2 GABA(A)R subunit (beta2(ALL)) expression driven by increased beta2(50 kDa), a decreased ratio of beta(248 kDa):beta2(ALL) and an increased ratio of beta2(50 kDa):beta2(48 kDa). Decreased ratios of beta1:beta2(ALL) and beta1:beta2(50 kDa) in both the ER and SYN fractions and an increased ratio of beta2(52 kDa):beta(248 kDa) at the synapse were also identified in schizophrenia. Taken together, these findings provide evidence that alterations of N-glycosylation may contribute to GABAergic signaling deficits in schizophrenia by disrupting the assembly and trafficking of GABA(A)Rs. PMID- 26241352 TI - A composite peripheral blood gene expression measure as a potential diagnostic biomarker in bipolar disorder. AB - Gene expression in peripheral blood has the potential to inform on pathophysiological mechanisms and has emerged as a viable avenue for the identification of biomarkers. Here, we aimed to identify gene expression candidate genes and to explore the potential for a composite gene expression measure as a diagnostic and state biomarker in bipolar disorder. First, messenger RNA levels of 19 candidate genes were assessed in peripheral blood mononuclear cells of 37 rapid cycling bipolar disorder patients in different affective states (depression, mania and euthymia) during a 6-12-month period and in 40 age- and gender-matched healthy control subjects. Second, a composite gene expression measure was constructed in the first half study sample and independently validated in the second half of the sample. We found downregulation of POLG and OGG1 expression in bipolar disorder patients compared with healthy control subjects. In patients with bipolar disorder, upregulation of NDUFV2 was observed in a depressed state compared with a euthymic state. The composite gene expression measure for discrimination between patients and healthy control subjects on the basis of 19 genes generated an area under the receiver-operating characteristic curve of 0.81 (P < 0.0001) in sample 1, which was replicated with a value of 0.73 (P < 0.0001) in sample 2, corresponding with a moderately accurate test. The present findings of altered POLG, OGG1 and NDUFV2 expression point to disturbances within mitochondrial function and DNA repair mechanisms in bipolar disorder. Further, a composite gene expression measure could hold promise as a potential diagnostic biomarker. PMID- 26241354 TI - Gene set enrichment ensemble using fold change data only. AB - In a number of biological studies, the raw gene expression data are not usually published due to different causes, such as data privacy and patent rights. Instead, significant gene lists with fold change values are usually provided in most studies. However, due to variations in data sources and profiling conditions, only a small number of common significant genes could be found among similar studies. Moreover, traditional gene set based analyses that consider these genes have not taken into account the fold change values, which may be important to distinguish between the different levels of significance of the genes. Human embryonic stem cell derived cardiomyocytes (hESC-CM) is a good representative of this category. hESC-CMs, with its role as a potentially unlimited source of human heart cells for regenerative medicine, have attracted the attentions of biological and medical researchers. Because of the difficulty of acquiring data and the resulting expenses, there are only a few related hESC CM studies and few hESC-CM gene expression data are provided. In view of these challenges, we propose a new Gene Set Enrichment Ensemble (GSEE) approach to perform gene set based analysis on individual studies based on significant up regulated gene lists with fold change data only. Our approach provides both explicit and implicit ways to utilize the fold change data, in order to make full use of scarce data. We validate our approach with hESC-CM data and fetal heart data, respectively. Experimental results on significant gene lists from different studies illustrate the effectiveness of our proposed approach. PMID- 26241351 TI - Dopamine D2/3 receptor antagonism reduces activity-based anorexia. AB - Anorexia nervosa (AN) is an eating disorder characterized by severe hypophagia and weight loss, and an intense fear of weight gain. Activity-based anorexia (ABA) refers to the weight loss, hypophagia and paradoxical hyperactivity that develops in rodents exposed to running wheels and restricted food access, and provides a model for aspects of AN. The atypical antipsychotic olanzapine was recently shown to reduce both AN symptoms and ABA. We examined which component of the complex pharmacological profile of olanzapine reduces ABA. Mice received 5 HT(2A/2C), 5-HT3, dopamine D1-like, D2, D3 or D2/3 antagonist treatment, and were assessed for food intake, body weight, wheel running and survival in ABA. D2/3 receptor antagonists eticlopride and amisulpride reduced weight loss and hypophagia, and increased survival during ABA. Furthermore, amisulpride produced larger reductions in weight loss and hypophagia than olanzapine. Treatment with either D3 receptor antagonist SB277011A or D2 receptor antagonist L-741,626 also increased survival. All the other treatments either had no effect or worsened ABA. Overall, selective antagonism of D2 and/or D3 receptors robustly reduces ABA. Studies investigating the mechanisms by which D2 and/or D3 receptors regulate ABA, and the efficacy for D2/3 and/or D3 antagonists to treat AN, are warranted. PMID- 26241353 TI - SELENBP1 expression in the prefrontal cortex of subjects with schizophrenia. AB - Selenium binding protein 1 (SELENBP1) messenger RNA (mRNA) has previously been shown to be upregulated in the brain and blood from subjects with schizophrenia. We aimed to validate these findings in a new cohort using real-time PCR in Brodmann's Area (BA) 9, and to determine the disease specificity of increased SELENBP1 expression by measuring SELENBP1 mRNA in subjects with major depressive disorder and bipolar disorder. We then extended the study to include other cortical regions such as BA8 and BA44. SELENBP1 mRNA was higher in BA9 (P = 0.001), BA8 (P = 0.003) and BA44 (P = 0.0007) from subjects with schizophrenia. Conversely, in affective disorders, there was no significant difference in SELENBP1 mRNA in BA9 (P = 0.67), suggesting that the upregulation may be diagnosis specific. Measurement of SELENBP1 protein levels showed that changes in mRNA did not translate to changes in protein. In addition, chronic treatment of rats with antipsychotics did not significantly affect the expression of Selenbp1 in the cortex (P = 0.24). Our data show that elevated SELENBP1 transcript expression is widespread throughout the prefrontal cortex in schizophrenia, and confirm that this change is a consistent feature of schizophrenia and not a simple drug effect. PMID- 26241355 TI - A systematic comparison of feature space effects on disease classifier performance for phenotype identification of five diseases. AB - Automated phenotype identification plays a critical role in cohort selection and bioinformatics data mining. Natural Language Processing (NLP)-informed classification techniques can robustly identify phenotypes in unstructured medical notes. In this paper, we systematically assess the effect of naive, lexically normalized, and semantic feature spaces on classifier performance for obesity, atherosclerotic cardiovascular disease (CAD), hyperlipidemia, hypertension, and diabetes. We train support vector machines (SVMs) using individual feature spaces as well as combinations of these feature spaces on two small training corpora (730 and 790 documents) and a combined (1520 documents) training corpus. We assess the importance of feature spaces and training data size on SVM model performance. We show that inclusion of semantically-informed features does not statistically improve performance for these models. The addition of training data has weak effects of mixed statistical significance across disease classes suggesting larger corpora are not necessary to achieve relatively high performance with these models. PMID- 26241356 TI - In the pursuit of a semantic similarity metric based on UMLS annotations for articles in PubMed Central Open Access. AB - MOTIVATION: Although full-text articles are provided by the publishers in electronic formats, it remains a challenge to find related work beyond the title and abstract context. Identifying related articles based on their abstract is indeed a good starting point; this process is straightforward and does not consume as many resources as full-text based similarity would require. However, further analyses may require in-depth understanding of the full content. Two articles with highly related abstracts can be substantially different regarding the full content. How similarity differs when considering title-and-abstract versus full-text and which semantic similarity metric provides better results when dealing with full-text articles are the main issues addressed in this manuscript. METHODS: We have benchmarked three similarity metrics - BM25, PMRA, and Cosine, in order to determine which one performs best when using concept based annotations on full-text documents. We also evaluated variations in similarity values based on title-and-abstract against those relying on full-text. Our test dataset comprises the Genomics track article collection from the 2005 Text Retrieval Conference. Initially, we used an entity recognition software to semantically annotate titles and abstracts as well as full-text with concepts defined in the Unified Medical Language System (UMLS(r)). For each article, we created a document profile, i.e., a set of identified concepts, term frequency, and inverse document frequency; we then applied various similarity metrics to those document profiles. We considered correlation, precision, recall, and F1 in order to determine which similarity metric performs best with concept-based annotations. For those full-text articles available in PubMed Central Open Access (PMC-OA), we also performed dispersion analyses in order to understand how similarity varies when considering full-text articles. RESULTS: We have found that the PubMed Related Articles similarity metric is the most suitable for full text articles annotated with UMLS concepts. For similarity values above 0.8, all metrics exhibited an F1 around 0.2 and a recall around 0.1; BM25 showed the highest precision close to 1; in all cases the concept-based metrics performed better than the word-stem-based one. Our experiments show that similarity values vary when considering only title-and-abstract versus full-text similarity. Therefore, analyses based on full-text become useful when a given research requires going beyond title and abstract, particularly regarding connectivity across articles. AVAILABILITY: Visualization available at ljgarcia.github.io/semsim.benchmark/, data available at http://dx.doi.org/10.5281/zenodo.13323. PMID- 26241358 TI - Calculation of the specific heat of optimally K-doped BaFe2As2. AB - The calculated specific heat of optimally K-doped BaFe2As2 in density functional theory is about five times smaller than that found in the experiment. We report that by adjusting the potential on the iron atom to be slightly more repulsive for electrons improves the calculated heat capacity as well as the electronic band structure of Ba0.6K0.4Fe2As2. In addition, structural and magnetic properties are moved in the direction of experimental values. Applying the same correction to the antiferromagnetic state, we find that the electron-phonon coupling is strongly enhanced. PMID- 26241357 TI - Alcohol and Drug Use Among Postoperative Bariatric Patients: A Systematic Review of the Emerging Research and Its Implications. AB - BACKGROUND: Emerging research suggests that some bariatric surgery patients are at a heightened risk for developing substance use problems, especially alcohol use problems. METHODS: An exhaustive literature review was conducted in January 2015 to investigate all articles published that included data on postoperative alcohol use, alcohol use disorders, and illicit drug use among bariatric surgery patients. RESULTS: Twenty-three studies reported on alcohol and/or substance use among bariatric patients. Six studies longitudinally assessed alcohol use behaviors; 3 of these studies found an increase in alcohol use following surgery. Six studies were cross-sectional, and 2 studies assessed medical records. Five studies investigated the prevalence of admissions to substance abuse treatment, and 3 studies combined alcohol and drug use data in a single index. Six studies reported on illicit drug use and reported low-postoperative use. The studies' samples were primarily non-Hispanic white females in their upper 40s, and only 11 of the 23 studies utilized validated assessment instruments. CONCLUSIONS: Studies employing longitudinal designs and large sample sizes indicate that bariatric patients who had the gastric bypass procedure are at an elevated risk for alcohol use problems postoperatively. Research also indicates that bariatric surgery patients might be overrepresented in substance abuse treatment facilities. Risk factors for problematic postoperative alcohol use include regular or problematic alcohol use presurgery, male gender, younger age, tobacco use, and symptoms of attention deficient and hyperactivity disorder. As a whole, however, studies indicate bariatric surgery patients demonstrate a low prevalence of problematic alcohol use, and studies about gastric bypass patients are not entirely conclusive. Prospective, longitudinal studies are needed, utilizing standardized and validated alcohol assessment instruments that follow postoperative bariatric patients well beyond 2 years, and account for types of bariatric procedure. Finally, study samples with greater racial/ethnic diversity and wider age ranges are needed. PMID- 26241359 TI - Interhemispheric resting state functional connectivity abnormalities in unipolar depression and bipolar depression. AB - OBJECTIVES: Depression in the context of bipolar disorder (BD) is often misdiagnosed as unipolar depression (UD), leading to mistreatment and poor clinical outcomes. However, little is known about the similarities and differences in interhemispheric functional connectivity between BD and UD. METHODS: Patients with bipolar II disorder (n = 36) and UD (n = 32) during a depressive episode as well as 40 healthy controls underwent resting-state functional magnetic resonance imaging. The functional connectivity between any pair of symmetric interhemispheric voxels (i.e., functional homotopy) was measured by voxel-mirrored homotopic connectivity (VMHC). RESULTS: The three groups showed significant VMHC differences in the posterior cingulate cortex (PCC), fusiform and lingual gyrus, anterior lobe of the cerebellum (CeAL), and posterior lobe of the cerebellum (CePL). In the BD group, the VMHC decreases in the fusiform/lingual gyrus, CeAL, and CePL were shown relative to controls. In the UD group, the VMHC decreases in the PCC, fusiform/lingual gyrus, and CePL were shown relative to controls. No regions of increased VMHC were detected in either patient group. There was no significant difference in the VMHC values in any brain region between the BD group and the UD group. CONCLUSIONS: Depressive episodes in BD and UD have similar impairments of interhemispheric coordination, which might imply an overlap in the neuropathology of depression. PMID- 26241360 TI - [The Current Status of End-of-Life Care in ALS: Progress and Personal Experience from the Past Ten Years in the USA]. AB - End-of-life (EOL) care and management in ALS is one of the least studied subjects within ALS management. In early 2000, Robert Wood Johnson and the ALS Association assembled an advisory committee to develop recommendations for the promotion of excellence during EOL care. We have reviewed this 10-year-old publication1) and describe the progress we have made in 16 different areas of EOL recommendations. Although there are some areas with little progress over the past 10 years, a few areas, particularly those regarding psychosocial management, symptomatic treatments, and ethical issues of EOL, have made major advancements during this time. the statements and recommendations for promoting excellence in EOL made 10 years ago appear to still be valid. We also review hastening death, a newly recognized issue of EOL, and discuss the potential reasons why Japanese and American patients chose tracheostomy-invasive ventilator at different rates. We conclude that EOL management is still evolving and in progress. Until we have a cure for ALS, every effort is being made to improve EOL care for patients with ALS. PMID- 26241361 TI - [Managing End-of-Life Care in ALS and Its Associated Issue]. AB - The neurological disease amyotrophic lateral sclerosis (ALS) requires pain palliation during end-of-life stages. From the view point of a home-care doctor who assists patients with their final wishes to die at home, I summarize the issues involving the section of medical treatments, the extent and frequency of end-of-life pain, the methodology of pain palliation, and the facts of end-of life care at home. I also present several clinical cases of end-of-life home care and discuss its demand and problems. PMID- 26241362 TI - [Palliative Care for Neurological Intractable Diseases and Home Medical Support]. AB - Many medical doctors regard the end stage and palliative care of neurological intractable diseases as the point at which aggressive treatment should be interrupted and death is imminent. However, the definition of health by the World Health Organization as the physical, psychological, and social goal to achieve a fully favorable health condition should be revisited. In the real clinical setting, the health condition, as the ability to adapt and self-manage in the face of social, physical, and emotional challenges with the aim to overcome stress (resilience), is dynamic and involves a healthy condition and satisfaction with one's own living. The most important step in palliative therapy that is shared by neurologists is the maintenance of the health status with the help of multi-disciplinary team with the view to improving the quality of life. PMID- 26241363 TI - [The Terminal Phase of an Intractable Neurological Disease from the Viewpoint of Nursing Care: The Importance of the Promotion of a Barrier-Free Mind for ALS Care]. AB - Amyotrophic lateral sclerosis (ALS) is a particularly serious intractable neurological disease. Patients with ALS have high mortality rates if they are not put on an artificial respirator. Even with an artificial respirator, individuals with ALS are forced to witness their own physical deterioration. Because 24 hour care is usually required, an intense relationship ofter develops between patients with ALS and family caregivers. This relationship forms an invisible barrier and can impede a smooth introduction of external services. As a result, there can be a degradation in the quality of care. The purpose of this paper is to describe the voluntary efforts of patients and family caregivers in order to break down this barrier and to discuss what types of care support are available to promote barrier-free minds. PMID- 26241364 TI - [The Blood-Brain Barrier (BBB) and in vitro BBB Models]. AB - The blood-brain barrier (BBB) is a brain-specific capillary barrier critical for preventing entry of toxic substances into the central nervous system. In contrast to vessels of peripheral organs, the BBB limits the exchange of inflammatory cells and mediators under physiological and pathological conditions. Clarifying these regulation of the BBB would provide new insights into neuroprotective strategies in neuroinflammatory diseases. However, the physiology of the BBB and the pathogenesis of BBB disruption remain incompletely understood. A major limiting factor is the lack of reliable models of the human BBB. Several different in vitro models suggest that there is no perfect model system, with different models advantageous in specific situations. In this review, we summarize the current knowledge on BBB cellular components and in vitro BBB models with a particular focus on novel and recent findings. PMID- 26241365 TI - [Treatment Strategy for Adult Epilepsy: A Current Approach]. AB - The current treatment strategy for adult epilepsy will change significantly in the near future after monotherapy as well as adjunctive therapy using new antiepileptic drugs (AEDs), which have been approved. These new AEDs have unique mechanisms of action with or without a broad spectrum. They have advantages of fewer adverse effects, including central nervous system manifestations and teratogenicity, and fewer or no pharmacokinetic drug interactions, although they lack enhanced efficacy compared to the current AEDs. In addition, the new AEDs do not result in adverse effects associated with the long-term use of the previous AEDs, such as osteoporosis and hyperlipidemia. The use of new AEDs is particularly recommended for elderly patients and young women with epilepsy. Further, their use does not result in seizures or cause adverse effects, which is the goal of epilepsy treatment. PMID- 26241366 TI - [Summary of the Profiles of 22 Children with Traumatic Brain Injury Tacted with the Japanese Version of the WISC-IV]. AB - The Japanese version of the Wechsler intelligence scale for children-fourth edition (WISC-IV) is often used to assess cognitive dysfunction in children with traumatic brain injury (TBI). To reveal the characteristics of cognitive impairment in pediatric TBI, we retrospectively analyzed the results of 22 children with TBI on the WISC-IV that was conducted at the Developmental Evaluation Center of the National Center for Child Health and Development over three years from July 2011 to July 2014. It has been hypothesized that the WISC IV is limited for revealing neuropsychological dysfunction after traumatic brain injury. PMID- 26241367 TI - [A Case of Neuromyelitis Optica with Relapse Symptoms from Paroxysmal Pruritus]. AB - We report the case of a 34-year-old woman who presented with neuromyelitis optica and paroxysmal pruritus. She noticed an itching sensation with no obvious rash in the right postauricular region. Seven days later, the pruritus changed to an abnormal, painful sensation. One month after the onset of the painful sensation, she was hospitalized due to abnormal sensations that extended along the right side of her body and extremities. A hyperintense area on T2-weighted imaging was accompanied by partial enhancement that extended from the lower medulla oblongata to the upper cervical spinal cord. The anti-aquaporin (AQP)-4 antibody was detected in serum. The patient had a history of optic neuritis. Therefore, neuromyelitis optica (NMO) was diagnosed. Her symptoms improved after intravenous and oral corticosteroid treatment. Itching attacks have been occasionally reported with multiple sclerosis, but many of these cases were described before the discovery of the anti-AQP4 antibody. Information on pruritus in serologically confirmed NMO is lacking. We should be aware that patients with NMO can experience recurrence that develops as pruritus. PMID- 26241368 TI - Structural Variations in the Uranyl/4,4'-Biphenyldicarboxylate System. Rare Examples of 2D -> 3D Polycatenated Uranyl-Organic Networks. AB - 4,4'-Biphenyldicarboxylic acid (H2L) was reacted with uranyl ions under solvo hydrothermal conditions with variations in the experimental procedure (organic cosolvent, presence of additional 3d-block metal cations, and N-donor species), thus giving six complexes of the fully deprotonated acid that were characterized by their crystal structure and, in most cases, their emission spectrum. The three complexes [UO2(L)(DMA)] (1), [UO2(L)(NMP)] (2), and [UO2(L)(NMP)] (3) include the cosolvent as a coligand, and they crystallize as two-dimensional (2D) assemblies, with different combinations of the chelating and bridging-bidentate carboxylate coordination modes, resulting in two different topologies. Complex 4, [Ni(bipy)3][(UO2)2(L)2(C2O4)].H2O, includes oxalate coligands generated in situ and contains an anionic planar two-dimensional (2D) assembly with a {6(3)} honeycomb topology. The same hexagonal geometry is found in the homoleptic complexes [Ni(bipy)3][(UO2)2(L)3].6H2O (5) and [Ni(phen)3][(UO2)2(L)3].4H2O (6), but the large size of the hexagonal rings in these cases (~27 A in the longest dimension) allows 2D -> three-dimensional (3D) inclined polycatenation to occur, with the two families of networks either orthogonal in tetragonal complex 5 or at an angle of 73.4 degrees in orthorhombic complex 6. The parallel networks are arranged in closely spaced groups of two, with possible pi...pi stacking interactions, and as many as four rods from four parallel nets pass through each ring of the inclined family of nets, an unusually high degree of catenation. These are the second cases only of 2D -> 3D inclined polycatenation in uranyl organic species. Emission spectra measured in the solid state show the usual vibronic fine structure, with variations in intensity and positions of maxima that are not simply connected with the number of equatorial donors and the presence of additional metal cations. PMID- 26241370 TI - Loading antimalarial drugs into noninfected red blood cells: an undesirable roommate for Plasmodium. PMID- 26241369 TI - The human cortical areas V6 and V6A. AB - In macaque, it has long been known since the late nineties that the medial parieto-occipital sulcus (POS) contains two regions, V6 and V6A, important for visual motion and action. While V6 is a retinotopically organized extrastriate area, V6A is a broadly retinotopically organized visuomotor area constituted by a ventral and dorsal subdivision (V6Av and V6Ad), both containing arm movement related cells active during spatially directed reaching movements. In humans, these areas have been mapped only in recent years thanks to neuroimaging methods. In a series of brain mapping studies, by using a combination of functional magnetic resonance imaging methods such as wide-field retinotopy and task-evoked activity, we mapped human areas V6 (Pitzalis et al., 2006) and V6Av (Pitzalis et al., 2013 d) retinotopically and defined human V6Ad functionally as a pointing selective region situated anteriorly in the close proximity of V6Av (Tosoni et al., 2014). Like in macaque, human V6 is a motion area (e.g., Pitzalis et al., 2010, 2012, 2013 a, b , c ), while V6Av and V6Ad respond to pointing movements (Tosoni et al., 2014). The retinotopic organization (when present), anatomical position, neighbor relations, and functional properties of these three areas closely resemble those reported for macaque V6 (Galletti et al., 1996, 1999 a), V6Av, and V6Ad (Galletti et al., 1999 b; Gamberini et al., 2011). We suggest that information on objects in depth which are translating in space, because of the self-motion, is processed in V6 and conveyed to V6A for evaluating object distance in a dynamic condition such as that created by self-motion, so to orchestrate the eye and arm movements necessary to reach or avoid static and moving objects in the environment. PMID- 26241371 TI - Pharmacokinetics, Biodistribution, Excretion and Plasma Protein Binding Studies of Acteoside in Rats. AB - Acteoside is a representative phenylethanoid glycoside, exhibiting great potency in neurodegenerative diseases treatment, such as Alzheimer's disease. This study was aimed to explore the pharmacokinetic characteristics, tissue distribution, excretion and plasma protein binding of acteoside in Sprague-Dawley rats after oral administration at 20, 40 and 80 mg/kg by a validated LC-MS/MS method. Acteoside was absorbed quickly after oral administration at 3 dose levels. Acteoside reached the peak concentration at 0.29+/-0.17 h, exhibiting a maximum concentration (Cmax) of 312.54+/-44.43 ng/mL after oral administration at 40 mg/kg, and the elimination half-life was 1.05+/-0.23 h. Both the Cmax and AUC showed a linear increase with the oral doses administered. The absolute bioavailability of acteoside was only around 1%. After oral administration, acteoside was extensively and rapidly distributed in most tissues including brain, but little amount of acteoside was excreted in urine, bile or feces. And the rat plasma protein binding ratio with equilibrium dialysis was about 60%. The pharmacokinetic characteristics of the fast gastro-intestinal absorption, the noteworthy distribution in most tissues including brain, the absence of acteoside in urine, bile and feces and valuable plasma protein binding ratio in rats will provide important reference for further research. PMID- 26241372 TI - Rod- and cone-isolated flicker electroretinograms and their response summation characteristics. AB - This study defined the amplitude and phase characteristics of rod- and cone isolated flicker electroretinograms (ERGs) and determined how these responses summate to generate the nonreceptor-specific ERG. Full-field ERGs were obtained from six normally sighted subjects (age 26 to 44 years) using a four-primary LED based photostimulator and standard recording techniques. The four primaries were either modulated sinusoidally in phase to achieve simultaneous rod and cone activation (ERGR+C; nonreceptor-specific) or in different phases to achieve rod isolated (ERGR) and cone-isolated (ERGC) responses by means of triple silent substitution. ERGs were measured at two mean luminance levels (2.4 and 24 cd/m2), two contrasts (20 and 40%), and four temporal frequencies (2-15 Hz). Fundamental amplitude and phase for each condition were derived by Fourier analysis. Response amplitude and phase depended on the stimulus conditions (frequency, mean luminance, and contrast), however, for all conditions: 1) response phase decreased monotonically as stimulus frequency increased; 2) response amplitude tended to decrease monotonically as stimulus frequency increased, with the exception of the 24 cd/m2, 40% contrast ERGR+C that was sharply V-shaped; 3) ERGR phase was delayed (32 to 210 deg) relative to the ERGC phase; 4) ERGR amplitude was typically equal to or lower than the ERGC amplitude, with the exception of the 2.4 cd/m2, 40% contrast condition; and 5) the pattern of ERGR+C responses could be accounted for by a vector summation model of the rod and cone pathway signals. The results show that the ERGR+C amplitude and phase can be predicted from ERGR and ERGC amplitude and phase. For conditions that elicit ERGR and ERGC responses that have approximately equal amplitude and opposite phase, there is strong destructive interference between the rod and cone responses that attenuates the ERGR+C. Conditions that elicit equal amplitude and opposite phase rod and cone responses may be particularly useful for evaluating rod-cone interactions. PMID- 26241374 TI - Comparison between several locations of gyroscope for gait events detection. PMID- 26241373 TI - Contributions of Qualitative Research in Informing HIV/AIDS Interventions Targeting Black MSM in the United States. AB - This article presents a systematic review of qualitative studies focusing on human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) among Black men who have sex with men (BMSM) in the United States. We reviewed studies that were published between 1980 and 2014. Qualitative methods employed in the studies reviewed include in-depth interviews, focus groups, participant observation, and ethnography. We searched several databases (PubMed, PsychINFO, JSTOR, ERIC, Sociological Abstracts, and Google Scholar) for relevant articles using the following broad terms: "Black men" "Black gay/bisexual" or "Black men who have sex with men," and "qualitative" and/or "ethnography." We include 70 studies in this review. The key themes observed across studies were (1) heterogeneity, (2) layered stigma and intersectionality, (3) risk behaviors, (4) mental health, (5) resilience, and (6) community engagement. The review suggests that sexual behavior and HIV-status disclosure, sexual risk taking, substance use, and psychological well-being were contextually situated. Interventions occurring at multiple levels and within multiple contexts are needed to reduce stigma within the Black community. Similarly, structural interventions targeting religious groups, schools, and health care systems are needed to improve the health outcomes among BMSM. Community engagement and using community-based participatory research methods may facilitate the development and implementation of culturally appropriate HIV/AIDS interventions targeting BMSM. PMID- 26241376 TI - Rothia dentocariosa: A Rare Cause of Left-Sided Endocarditis in an Intravenous Drug User. PMID- 26241375 TI - Coping style and memory specificity in adolescents and adults with histories of child sexual abuse. AB - Individuals with histories of childhood trauma may adopt a nonspecific memory retrieval strategy to avoid unpleasant and intrusive memories. In a sample of 93 adolescents and adults with or without histories of child sexual abuse (CSA), we tested the hypothesis that nonspecific memory retrieval is related to an individual's general tendency to use avoidant (i.e., distancing) coping as a personal problem-solving or coping strategy, especially in victims of CSA. We also examined age differences and other individual differences (e.g., trauma related psychopathology) as predictors of nonspecific memories. Distancing coping was significantly associated with less specific autobiographical memory. Younger age, lower vocabulary scores, and non-CSA childhood maltreatment (i.e., physical and emotional abuse) also uniquely predicted less autobiographical memory specificity, whereas trauma-related psychopathology was associated with more specific memory. Implications for the development of autobiographical memory retrieval in the context of coping with childhood maltreatment are discussed. PMID- 26241377 TI - Lifecycle Greenhouse Gas Analysis of an Anaerobic Codigestion Facility Processing Dairy Manure and Industrial Food Waste. AB - Anaerobic codigestion (AcoD) can address food waste disposal and manure management issues while delivering clean, renewable energy. Quantifying greenhouse gas (GHG) emissions due to implementation of AcoD is important to achieve this goal. A lifecycle analysis was performed on the basis of data from an on-farm AcoD in New York, resulting in a 71% reduction in GHG, or net reduction of 37.5 kg CO2e/t influent relative to conventional treatment of manure and food waste. Displacement of grid electricity provided the largest reduction, followed by avoidance of alternative food waste disposal options and reduced impacts associated with storage of digestate vs undigested manure. These reductions offset digester emissions and the net increase in emissions associated with land application in the AcoD case relative to the reference case. Sensitivity analysis showed that using feedstock diverted from high impact disposal pathways, control of digester emissions, and managing digestate storage emissions were opportunities to improve the AcoD GHG benefits. Regional and parametrized emissions factors for the storage emissions and land application phases would reduce uncertainty. PMID- 26241379 TI - Local Field Factors and Dielectric Properties of Liquid Benzene. AB - Local electric field factors are calculated for liquid benzene by combining molecular dynamic simulations with a subsequent force-field model based on a combined charge-transfer and point-dipole interaction model for the local field factor. The local field factor is obtained as a linear response of the local field to an external electric field, and the response is calculated at frequencies through the first absorption maximum. It is found that the largest static local field factor is around 2.4, while it is around 6.4 at the absorption frequency. The linear susceptibility, the dielectric constant, and the first absorption maximum of liquid benzene are also studied. The electronic contribution to the dielectric constant is around 2.3 at zero frequency, in good agreement with the experimental value around 2.2, while it increases to 6.3 at the absorption frequency. The pi -> pi* excitation energy is around 6.0 eV, as compared to the gas-phase value of around 6.3 eV, while the experimental values are 6.5 and 6.9 eV for the liquid and gas phase, respectively, demonstrating that the gas-to-liquid shift is well-described. PMID- 26241378 TI - Design and Characterization of Chemically Stabilized Abeta42 Oligomers. AB - A popular working hypothesis of Alzheimer's disease causation is amyloid beta protein oligomers are the key neuropathogenetic agents. Rigorously elucidating the role of oligomers requires the production of stable oligomers of each size. We previously used zero-length photochemical cross-linking to allow stabilization, isolation, and determination of structure-activity relationships of pure populations of Abeta40 dimers, trimers, and tetramers. We also attempted to study Abeta42 but found that Abeta42 oligomers subjected to the same procedures were not completely stable. On the basis of the fact that Tyr is a critical residue in cross-linking chemistry, we reasoned that the chemical accessibility of Tyr10 in Abeta42 must differ from that in Abeta40. We thus chemically synthesized four singly substituted Tyr variants that placed the Tyr in different positions across the Abeta42 sequence. We then studied the stability of the resulting cross-linked oligomers as well as procedures for fractionating the oligomers to obtain pure populations of different sizes. We found that [Phe(10),Tyr(42)]Abeta42 produced stable oligomers yielding highly pure populations of dimers through heptamers. This provides the means to establish formal structure-activity relationships of these important Abeta42 assemblies. In addition, we were able to analyze the dissociation patterns of non-cross-linked oligomers to produce a model for oligomer formation. This work is relevant to the determination of structure-activity relationships that have the potential to provide mechanistic insights into disease pathogenesis. PMID- 26241380 TI - Awareness of Post-Exposure Prophylaxis (PEP) and Pre-Exposure Prophylaxis (PrEP) Is Low but Interest Is High Among Men Engaging in Condomless Anal Sex With Men in Boston, Pittsburgh, and San Juan. AB - This study examines awareness of and experiences with post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP) among 228 men recruited in Boston, Pittsburgh, and San Juan between 12/2010 and 6/2012. All of them reported having condomless anal sex with a man in the prior year. Overall, 41% had heard of PEP, ranging from 16% in San Juan to 64% in Boston. Only 21% had heard of PrEP, ranging from 8% in San Juan to 36% in Boston. Three had used PEP, and none had used PrEP. After the methods were described to participants, interest in both was high, with intentions to use PEP and PrEP respectively at 9.1 and 7.7 (10-point scale). Increased public education is needed to raise awareness of these HIV prevention methods, especially among MSM who acknowledge potential risk behavior. It also seems likely that many such men would use these methods once they become aware of them. PMID- 26241381 TI - Exploring Social Networking Technologies as Tools for HIV Prevention for Men Who Have Sex With Men. AB - Social networking technologies are influential among men who have sex with men (MSM) and may be an important strategy for HIV prevention. We conducted focus groups with HIV positive and negative participants. Almost all participants used social networking sites to meet new friends and sexual partners. The main obstacle to effective HIV prevention campaigns in social networking platforms was stigmatization based on homosexuality as well as HIV status. Persistent stigma associated with HIV status and disclosure was cited as a top reason for avoiding HIV-related conversations while meeting new partners using social technologies. Further, social networking sites have different social etiquettes and rules that may increase HIV risk by discouraging HIV status disclosure. Overall, successful interventions for MSM using social networking technologies must consider aspects of privacy, stigma, and social norms in order to enact HIV reduction among MSM. PMID- 26241382 TI - Enhancement of a Locally Developed HIV Prevention Intervention for Hispanic/Latino MSM: A Partnership of Community-Based Organizations, a University, and the Centers for Disease Control and Prevention. AB - Hispanic/Latino men who have sex with men (MSM) in the United States are disproportionately affected by HIV and other sexually transmitted diseases (STDs); however, no efficacious behavioral HIV/STD prevention interventions are currently available for use with this vulnerable population. We describe the enhancement of HOLA en Grupos, a community-based behavioral HIV/STD prevention intervention for Spanish-speaking Hispanic/Latino MSM that is currently being implemented and evaluated in North Carolina with support from the Centers of Disease Control and Prevention (CDC). Our intervention enhancement process included incorporating local data on risks and context; identifying community needs and priorities; defining intervention core elements and key characteristics; developing a logic model; developing an intervention logo; enhancing intervention activities and materials; scripting intervention delivery; expanding the comparison intervention; and establishing a materials review committee. If the CDC-sponsored evaluation determines that HOLA en Grupos is efficacious, it will be the first such behavioral HIV/STD prevention intervention to be identified for potential use with Hispanic/Latino MSM, thereby contributing to the body of evidence-based resources that may be used for preventing HIV/STD infection among these MSM and their sex partners. PMID- 26241383 TI - Becoming "Undetectable": Longitudinal Narratives of Gay Men's Sex Lives After a Recent HIV Diagnosis. AB - We explore gay men's sex life narratives following their diagnosis with an acute or recent HIV infection. All participants received an acute (n = 13) or recent (n = 12) HIV diagnosis and completed a series of self-administered questionnaires and in-depth qualitative interviews over a one-year period or longer. Over the course of four qualitative interviews, participants frequently spoke of the role of medications (e.g., decisions to start treatment) and changing viral loads (e.g., discourses of becoming "undetectable") in relation to their sex lives since being diagnosed with HIV. Many men talked about milestones relating to initiating medication and viral load as informing their shifting sexual behaviors and identities as HIV-positive--or "undetectable"--gay men. The narratives of our participants provide insight regarding complex negotiations and processes of decision-making over time related to sex, counseling needs, treatment initiation, viral load, and the significance of undetectability as an emergent identity. PMID- 26241384 TI - Re-Testing and Seroconversion Among HIV Testing and Counseling Clients in Lesotho. AB - HIV testing and counseling (HTC) is an essential component of comprehensive HIV programs. Retrospective HTC program data from 2006 to 2010 were examined to determine patterns of re-testing and seroconversion in Lesotho. Among 104,662 initially negative clients, 6,777 (6.5%) were re-testers. Predictors of re testing included being male, age >= 25 years, divorced/separated, having more than a high school education, being tested as a couple, testing in the year 2006, testing in the capital city, and awareness of partner's recent testing behavior. Among re-testers who seroconverted (N = 259), predictors included being female and having less than a high school education. There is a critical need for more effectively targeting HIV retesting messages to align with WHO (2010) guidelines and identify persons at highest risk for HIV, to increase timely diagnoses and link persons to appropriate HIV prevention, care, and treatment services. PMID- 26241385 TI - Applying Choice Architecture Principles to Understand HIV Testing: Findings From Malawi and Zimbabwe. AB - Improvements spearheaded by the World Health Organization in antenatal HIV counseling in sub-Saharan Africa from 2004 to 2011 have seen a parallel increase in HIV testing. We sought to determine the extent to which the use of choice architecture principles (one that introduces an opt-out option as the default) affect uptake of HIV testing, above and beyond individual-level attitudes and cognitions. Demographic and Health Survey data collected between 2004 and 2011 from Zimbabwe (N = 1,330) and Malawi (N = 4,043)--countries where over 10% of adults have HIV--were analyzed. We explored the influence of demographic variables, modes of knowledge about HIV, stigma against people living with HIV, attitudes about spousal abuse, and whether or not HIV testing had been offered during antenatal visits. Results demonstrated that, taking into account secular trends in higher testing rates, structural-level support was the strongest predictor of HIV testing above and beyond individual-level attitudes and cognitions. PMID- 26241387 TI - Erratum. PMID- 26241386 TI - Gender Differences in Factors Associated With Anal Intercourse Among Heterosexual Adolescents in Singapore. AB - Using a cross-sectional survey, we examined the gender differences in prevalence of and factors associated with anal sex among adolescents attending the only public STI clinic in Singapore. Data were collected from 1035 sexually active adolescents aged 14 to 19 and analyzed using Poisson regression. Prevalence of anal intercourse was 28%, with significantly more females (32%) than males (23%) ever engaged in it. On multivariate analysis, the factors associated with anal intercourse for both genders were oral sex and the nonuse of contraception at last sex. For males, anal intercourse was associated with younger age of sexual debut and greater perceived external control. Among females, it was associated with higher rebellious scores and lack of confidence to resist peer pressure to engage in sex. Consistent condom use for anal sex was 22% and 8% for males and females, respectively. STI prevention programs for adolescents should address anal sex, be gender-specific, and take into consideration individual personality characteristics. PMID- 26241388 TI - Modifying an Insect Cell N-Glycan Processing Pathway Using CRISPR-Cas Technology. AB - Fused lobes (FDL) is an enzyme that simultaneously catalyzes a key trimming reaction and antagonizes elongation reactions in the insect N-glycan processing pathway. Accordingly, FDL function accounts, at least in part, for major differences in the N-glycosylation patterns of glycoproteins produced by insect and mammalian cells. In this study, we used the CRISPR-Cas9 system to edit the fdl gene in Drosophila melanogaster S2 cells. CRISPR-Cas9 editing produced a high frequency of site-specific nucleotide insertions and deletions, reduced the production of insect-type, paucimannosidic products (Man3GlcNAc2), and led to the production of partially elongated, mammalian-type complex N-glycans (GlcNAc2Man3GlcNAc2) in S2 cells. As CRISPR-Cas9 has not been widely used to analyze or modify protein glycosylation pathways or edit insect cell genes, these results underscore its broad utility as a tool for these purposes. Our results also confirm the key role of FDL at the major branch point distinguishing insect and mammalian N-glycan processing pathways. Finally, the new FDL-deficient S2 cell derivative produced in this study will enable future bottom-up glycoengineering efforts designed to isolate insect cell lines that can efficiently produce recombinant glycoproteins with chemically predefined oligosaccharide side-chain structures. PMID- 26241390 TI - Utilization of Active Ni to Fabricate Pt-Ni Nanoframe/NiAl Layered Double Hydroxide Multifunctional Catalyst through In Situ Precipitation. AB - Integration of different active sites into metallic catalysts, which may impart new properties and functionalities, is desirable yet challenging. Herein, a novel dealloying strategy is demonstrated to decorate nickel-aluminum layered double hydroxide (NiAl-LDH) onto a Pt-Ni alloy surface. The incorporation of chemical etching of Pt-Ni alloy and in situ precipitation of LDH are studied by joint experimental and theoretical efforts. The initial Ni-rich Pt-Ni octahedra transform by interior erosion into Pt3 Ni nanoframes with enlarged surface areas. Furthermore, owing to the basic active sites of the decorated LDH together with the metallic sites of Pt3 Ni, the resulting Pt-Ni nanoframe/NiAl-LDH composites exhibit excellent catalytic activity and selectivity in the dehydrogenation of benzylamine and hydrogenation of furfural. PMID- 26241389 TI - Uterine Epithelial Estrogen Receptor-alpha Controls Decidualization via a Paracrine Mechanism. AB - Steroid hormone-regulated differentiation of uterine stromal cells, known as decidualization, is essential for embryo implantation. The role of the estrogen receptor-alpha (ESR1) during this differentiation process is unclear. Development of conditional Esr1-null mice showed that deletion of this gene in both epithelial and stromal compartments of the uterus leads to a complete blockade of decidualization, indicating a critical role of ESR1 during this process. To further elucidate the cell type-specific function of ESR1 in the uterus, we created WE(d/d) mice in which Esr1 is ablated in uterine luminal and glandular epithelia but is retained in the stroma. Uteri of WE(d/d) mice failed to undergo decidualization, indicating that epithelial ESR1 contributes to stromal differentiation via a paracrine mechanism. We noted markedly reduced production of the leukemia inhibitory factor (LIF) in WE(d/d) uteri. Supplementation with LIF restored decidualization in WE(d/d) mice. Our study indicated that LIF acts synergistically with progesterone to induce the expression of Indian hedgehog (IHH) in uterine epithelium and its receptor patched homolog 1 in the stroma. IHH then induces the expression of chicken ovalbumin upstream promoter-transcription factor II, a transcription factor that promotes stromal differentiation. To address the mechanism by which LIF induces IHH expression, we used mice lacking uterine epithelial signal transducer and activator of transcription 3, a well known mediator of LIF signaling. Our study revealed that LIF-mediated induction of IHH occurs without the activation of epithelial signal transducer and activator of transcription 3 but uses an alternate pathway involving the activation of the ERK1/2 kinase. Collectively our results provide unique insights into the paracrine mechanisms by which ESR1 directs epithelial-stromal dialogue during pregnancy establishment. PMID- 26241391 TI - Electrochemical activation of engineered protein switches. AB - Engineered protein switches have a large dynamic range, high specificity for the activating ligand, and a modular architecture, and have been explored for a wide range of applications including biosensors and therapeutics. The ability to externally control switch function is important in extending applications for protein switches. We recently demonstrated that the on/off state could be controlled by the redox state of disulfide bonds introduced into the switches at select locations. Here, we demonstrate that an electrochemical signal can be used as an exogenous input to control switch function via reduction of the engineered disulfide bonds. This study suggests that disulfide-containing protein switch is a potentially useful platform for bioelectronic sensors with remote control of the sensing ability. PMID- 26241393 TI - In Vivo Confocal Microscopy of Corneal Nerves: An Ocular Biomarker for Peripheral and Cardiac Autonomic Neuropathy in Type 1 Diabetes Mellitus. AB - PURPOSE: We investigated the relationship between corneal subbasal nerve (SBN) plexus density, corneal sensitivity, and peripheral and cardiac autonomic neuropathy in patients with type 1 diabetes mellitus. METHODS: We recruited 53 patients with type 1 diabetes mellitus and 40 normal control participants. Corneal in vivo confocal microscopy (IVCM) and sensitivity testing were performed on one eye of each subject. Autonomic function testing was done and an overall neuropathy score obtained from a combination of a symptomatic neuropathy score, clinical assessment, biothesiometry, and nerve conduction tests. RESULTS: The corneal SBN density (P < 0.001) and corneal sensitivity (P < 0.001) were significantly lower in subjects with diabetes compared to controls. A modest negative correlation between total neuropathy score and SBN density was observed (r = -0.33, P = 0.01). A negative correlation between corneal sensitivity and expiration/inspiration component of the autonomic nerve analysis (ANS-EI) also was noted (r = -0.36, P = 0.008). Corneal SBN density was abnormal in 50% of diabetic subjects classified as "Normal" by the clinical and electrophysiological based tests of total neuropathy score. CONCLUSIONS: The correlation of corneal SBN density with total neuropathy score suggests that reduced corneal nerve density reflects peripheral neuropathy in diabetes. Corneal SBN changes precede other clinical and electrophysiology tests of neuropathy supporting a possible role for corneal IVCM and corneal sensitivity testing as surrogate markers in the assessment of diabetic peripheral and cardiac autonomic neuropathy. PMID- 26241394 TI - Corneal Confocal Microscopy and Diabetic Neuropathy. PMID- 26241392 TI - 4-Acetoxyphenol Prevents RPE Oxidative Stress-Induced Necrosis by Functioning as an NRF2 Stabilizer. AB - PURPOSE: Oxidative stress has been suggested to be a major risk factor for the pathogenesis of AMD. Retinal pigment epithelial (RPE) cells are essential for maintaining the homeostasis of the retina, and RPE cell death and the resultant photoreceptor apoptosis have been observed in dry AMD, especially in geographic atrophy. The purpose of this article was to identify and repurpose the Food and Drug Administration-approved natural compound 4-Acetoxyphenol (4-AC), and to evaluate its effect and mechanism in protecting against oxidative stress-induced RPE necrosis. METHODS: We exposed ARPE-19 cells to tert-Butyl hydroperoxide (tBHP) after pretreatment with 4-AC, and measured cell viability by MTT assay. Aggregation of RIPK3 and HMGB1 nuclear release were analyzed by transfected reporter genes. Reactive oxygen species (ROS) were measured using a commercially available ROS detection system. The importance of the NRF2/NQO1/HO-1 pathway in mediating 4-AC function was corroborated by siRNA studies, qRT-PCR, and immunostaining. RESULTS: We have identified a natural antioxidant, 4-AC, which demonstrates strong abilities to protect RPE cells from oxidative stress-induced necrosis. Mechanistically, 4-AC blocked the increase of cellular ROS induced by oxidative stress, and upregulated NQO1 and HO-1 genes by stabilizing and inducing the nuclear translocation of NRF2 transcription factor. The NQO1, HO-1, and NRF2 were further shown to be required for 4-AC protection of RPE cells from death induced by tBHP. The tBHQ, an NRF2 stabilizer, consistently mimicked the protective effect of 4-AC against tBHP-induced RPE death. CONCLUSIONS: The compound 4-AC protects ARPE-19 cells from oxidative stress-induced necrosis through upregulation of NQO1 and HO-1 genes by stabilization of NRF2. PMID- 26241395 TI - Astigmatism of the Ex Vivo Human Lens: Surface and Gradient Refractive Index Age Dependent Contributions. AB - PURPOSE: We estimated the contribution of the gradient refractive index (GRIN) and lens surfaces to lens astigmatism and lens astigmatic angle as a function of age in human donor lenses. METHODS: Human lenses were imaged, ex vivo, with 3D spectral optical coherence tomography (OCT) and their back focal length was measured using laser ray tracing. The contribution of lens surfaces and GRIN to lens astigmatism were evaluated by computational ray tracing on the GRIN lens and a homogenous equivalent index lens. Astigmatism magnitude and relative astigmatic angle of and between lens surfaces, GRIN lens, and lens with homogeneous refractive index were evaluated, and all results were correlated with age. RESULTS: The magnitude of astigmatism in the anterior lens surface decreased with age (slope = -0.005 diopters [D]/y; r = 0.397, P = 0.018). Posterior surface astigmatism and lens astigmatism were not age-dependent. Presence of GRIN did not alter significantly the magnitude or axis of the lens astigmatism. The astigmatism of GRIN lens and lens with homogeneous refractive index correlated with anterior lens surface astigmatism (GRIN, P = 3.9E - 6, r = 0.693; equivalent refractive index lens, P = 4.1E - 4, r = 0.565). The astigmatic angle of posterior surface, GRIN lens, and homogeneous refractive index lens did not change significantly with age. CONCLUSIONS: The axis of lens astigmatism is close to the astigmatic axis of the anterior lens surface. Age-related changes in lens astigmatism appear to be related to changes in the anterior lens astigmatism. The influence of the GRIN on lens astigmatism and the astigmatic axis is minor. PMID- 26241396 TI - Visual Processing in Infantile Nystagmus Is Not Slow. AB - PURPOSE: Treatments for infantile nystagmus (IN) sometimes elicit subjective reports of improved visual function, yet quantifiable improvements in visual acuity, if any, are often negligible. One possibility is that these subjective "improvements" may relate to temporal, rather than spatial, visual function. This study aimed to ascertain the extent to which "time to see" might be increased in nystagmats, as compared to normally sighted controls. By assessing both eye movement and response time data, it was possible to determine whether delays in "time to see" were due solely to the eye movements, or to an underlying deficit in visual processing. METHODS: The time taken to respond to the orientation of centrally and peripherally presented gratings was measured in subjects with IN and normally sighted controls (both groups: n = 11). For each vertically displaced grating, the time until the target-acquiring saccade was determined, as was the time from the saccade until the subject's response. RESULTS: Nystagmats took approximately 60 ms longer than controls to execute target-acquiring saccades to vertically displaced targets (P = 0.010). However, the time from the end of the saccade until subjects responded was not significantly different between groups (P = 0.37). Despite this, nystagmats took longer to respond to gratings presented at fixation. CONCLUSIONS: Individuals with IN took longer to direct their gaze toward objects of interest. However, once a target was foveated, the time taken to process visual information and respond did not appear to differ from that of control subjects. Therefore, conscious visual processing in IN is not slow. PMID- 26241397 TI - Focused Tortuosity Definitions Based on Expert Clinical Assessment of Corneal Subbasal Nerves. AB - PURPOSE: We examined agreement among experts in the assessment of corneal subbasal nerve tortuosity. METHODS: Images of corneal subbasal nerves were obtained from investigators at seven sites (Auckland, Boston, Linkoping, Manchester, Oslo, Rostock, and Sydney) using laser-scanning in vivo confocal microscopy. A set of 30 images was assembled and ordered by increasing tortuosity by 10 expert graders from the seven sites. In a first experiment, graders assessed tortuosity without a specific definition and performed grading three times, with at least 1 week between sessions. In a second experiment, graders assessed the same image set using four focused tortuosity definitions. Intersession and intergrader repeatability for the experiments were determined using the Spearman rank correlation. RESULTS: Expert graders without a specific tortuosity definition had high intersession (Spearman correlation coefficient 0.80), but poor intergrader (0.62) repeatability. Specific definitions improved intergrader repeatability to 0.79. In particular, tortuosity defined by frequent small-amplitude directional changes (short range tortuosity) or by infrequent large-amplitude directional changes (long range tortuosity), indicated largely independent measures and resulted in improved repeatability across the graders. A further refinement, grading only the most tortuous nerve in a given image, improved the average correlation of a given grader's ordering of images with the group average to 0.86 to 0.90. CONCLUSIONS: Definitions of tortuosity specifying short or long-range tortuosity and considering only the most tortuous nerve in an image improved the agreement in tortuosity grading among a group of expert observers. These definitions could improve accuracy and consistency in quantifying subbasal nerve tortuosity in clinical studies. PMID- 26241398 TI - Primary Mechanisms of Thymosin beta4 Repair Activity in Dry Eye Disorders and Other Tissue Injuries. AB - Dry eye disorders are becoming more common due to many causes, including an aging population, increased pollution, and postrefractive surgery. Current treatments include artificial tears; gels; lubricants; tear duct plugs; and anti inflammatory agents such as steroids, doxycycline, and cyclosporine. For more severe forms of the disease, serum tears and scleral contact lenses are employed. Despite these therapies, successful resolution of the problem is limited because none of these treatments fully addresses the underlying causes of dry eye to promote ocular surface repair. Thymosin beta4 (Tbeta4), a small, naturally occurring protein, promotes complete and faster corneal healing than saline alone or prescription agents (doxycycline and cyclosporine) in various animal models of eye injury. In human trials, it improves both the signs and symptoms of moderate to severe dry eye with effects lasting beyond the treatment period. This review will cover the multiple activities of Tbeta4 on cell migration, inflammation, apoptosis, cytoprotection, and gene expression with a focus on mechanisms of cell migration, including laminin-332 synthesis and degradation, that account for this paradigm-shifting potential new treatment for dry eye disorders. We will also speculate on additional mechanisms that might promote eye repair based on data from other tissue injury models. Such studies provide the rationale for use of Tbeta4 in other types of eye disorders beyond dry eye. Finally, we will identify the gaps in our knowledge and propose future research avenues. PMID- 26241399 TI - Ten-Year Incidence of Retinal Nerve Fiber Layer Defects: The Beijing Eye Study 2001/2011. AB - PURPOSE: We examined the 10-year incidence of localized retinal nerve fiber layer defects (RNFLDs) and associated factors in adult Chinese. METHODS: The population based longitudinal Beijing Eye Study, which included 4439 subjects (age, 40+ years) in 2001, was repeated in 2011 with 2695 subjects participating (66.4% of the survivors). Color fundus photographs taken at baseline and 10 years later were examined for localized RNFLDs, defined as wedge-shaped defects running toward the optic disc. RESULTS: Fundus photographs were available for 2422 (89.9%) subjects. Incident-localized RNFLDs were detected in 114/2422 persons (4.7% +/- 0.2%) or 139/4867 eyes (2.9% +/- 0.2%). A total of 25 (22%) persons had incident-localized RNFLDs bilaterally, and 89 (78%) persons unilaterally. Among the 114 persons with incident RNFLDs, 78 persons showed newly developed localized RNFLDs, while 36 subjects showed an enlargement of a preexisting localized RNFLD. In binary logistic regression analysis, a higher 10-year incidence of localized RNFLDs was significantly associated with a higher prevalence of arterial hypertension (P = 0.002; odds ratio [OR], 2.31; 95% confidence interval (CI), 1.35, 3.97), higher diastolic blood pressure (P = 0.02; OR, 1.02; 95% CI, 1.004,1.04), higher prevalence of previous cerebrovascular infarctions (P = 0.007; OR, 2.61; 95% CI, 1.30, 5.22), younger age (P = 0.01; OR, 0.97; 95% CI, 0.94, 0.99), higher prevalence of diabetic retinopathy (P = 0.001; OR, 4.70; 95% CI, 1.92, 11.5), higher prevalence of open-angle (P < 0.001; OR, 39.8; 95% CI, 19.7, 80.5) and angle-closure (P < 0.001; OR, 21.3; 95% CI, 7.90, 57.5) glaucoma, and thinner retinal nerve fiber layer (P < 0.001; OR, 0.97; 95% CI, 0.95, 0.98). CONCLUSIONS: The 10-year incidence of localized RNFLDs in adult Chinese is 4.7% +/- 0.2%. It is strongly associated with arterial hypertension and higher prevalence of cerebrovascular infarcts, in addition to ocular reasons, such as glaucoma and diabetic retinopathy. Ophthalmologically normal subjects with incident-localized RNFLDs may be screened for arterial hypertension and cerebrovascular infarcts. PMID- 26241400 TI - CaV3.1 T-Type Ca2+ Channels Contribute to Myogenic Signaling in Rat Retinal Arterioles. AB - PURPOSE: Although L-type Ca2+ channels are known to play a key role in the myogenic reactivity of retinal arterial vessels, the involvement of other types of voltage-gated Ca2+ channels in this process remains unknown. In the present study we have investigated the contribution of T-type Ca2+ channels to myogenic signaling in arterioles of the rat retinal microcirculation. METHODS: Confocal immunolabeling of whole-mount preparations was used to investigate the localization of CaV3.1-3 channels in retinal arteriolar smooth muscle cells. T type currents and the contribution of T-type channels to myogenic signaling were assessed by whole-cell patch-clamp recording and pressure myography of isolated retinal arteriole segments. RESULTS: Strong immunolabeling for CaV3.1 was observed on the plasma membrane of retinal arteriolar smooth muscle cells. In contrast, no expression of CaV3.2 or CaV3.3 could be detected in retinal arterioles, although these channels were present on glial cell end-feet surrounding the vessels and retinal ganglion cells, respectively. TTA-A2 sensitive T-type currents were recorded in retinal arteriolar myocytes with biophysical properties distinct from those of the L-type currents present in these cells. Inhibition of T-type channels using TTA-A2 or ML-218 dilated isolated, myogenically active, retinal arterioles. CONCLUSIONS: CaV3.1 T-type Ca2+ channels are functionally expressed on arteriolar smooth muscle cells of retinal arterioles and play an important role in myogenic signaling in these vessels. The work has important implications concerning our understanding of the mechanisms controlling blood flow autoregulation in the retina and its disruption during ocular disease. PMID- 26241401 TI - Epigenetic Modification of Mitochondrial DNA in the Development of Diabetic Retinopathy. AB - PURPOSE: Retinal mitochondria are dysfunctional in diabetes, and mitochondrial DNA (mtDNA) is damaged and its transcription is compromised. Our aim was to investigate the role of mtDNA methylation in the development of diabetic retinopathy. METHODS: Effect of high glucose (20 mM) on mtDNA methylation was analyzed in retinal endothelial cells by methylation-specific PCR and by quantifying 5-methylcytosine (5mC). Dnmt1 binding at the D-loop and Cytb regions of mtDNA was analyzed by chromatin immunoprecipitation. The role of mtDNA methylation in transcription and cell death was confirmed by quantifying transcripts of mtDNA-encoded genes (Cytb, ND6, and CoxII) and apoptosis, using cells transfected with Dnmt1-small interfering RNA (siRNA), or incubated with a Dnmt inhibitor. The key parameters were validated in the retinal microvasculature from human donors with diabetic retinopathy. RESULTS: High glucose increased mtDNA methylation, and methylation was significantly higher at the D-loop than at the Cytb and CoxII regions. Mitochondrial accumulation of Dnmt1 and its binding at the D-loop were also significantly increased. Inhibition of Dnmt by its siRNA or pharmacologic inhibitor ameliorated glucose-induced increase in 5mC levels and cell apoptosis. Retinal microvasculature from human donors with diabetic retinopathy presented similar increase in D-loop methylation and decrease in mtDNA transcription. CONCLUSIONS: Hypermethylation of mtDNA in diabetes impairs its transcription, resulting in dysfunctional mitochondria and accelerated capillary cell apoptosis. Regulation of mtDNA methylation has potential to restore mitochondrial homeostasis and inhibit/retard the development of diabetic retinopathy. PMID- 26241403 TI - Amblyopia Reveals the Neuroanatomical Consequences of Prolonged Abnormal Binocular Experience. PMID- 26241402 TI - The Structural Properties of Major White Matter Tracts in Strabismic Amblyopia. AB - PURPOSE: In order to better understand whether white matter structural deficits are present in strabismic amblyopia, we performed a survey of the tissue properties of 28 major white matter tracts using diffusion and quantitative magnetic resonance imaging approaches. METHODS: We used diffusion-based tensor modeling and a new quantitative T1 protocol to measure fractional anisotropy (FA), mean diffusivity (MD), and myelin-sensitive T1 values. We surveyed tracts in the occipital lobe, including the vertical occipital fasciculus (VOF)-a newly rediscovered tract that bridges dorsal and ventral areas of the occipital lobe, as well as tracts across the rest of the brain. RESULTS: Adults with long standing strabismic amblyopia show tract-specific elevations in MD. We rank ordered the tracts on the basis of their MD effect-size. The four most affected tracts were the anterior frontal corpus callosum (ACC), the right VOF, the left inferior longitudinal fasciculus (ILF) and the left optic radiation. CONCLUSIONS: The results suggest that most white matter tissue properties are relatively robust to the early visual insult caused by strabismus. However, strabismic amblyopia does affect MD, not only in occipital tracts, such as the VOF and optic radiation, but also in long range association tracts connecting visual cortex to the frontal and temporal lobes (ILF) and connecting the two hemispheres (ACC). PMID- 26241405 TI - Acinetobacter baumannii as an underestimated pathogen in veterinary medicine. PMID- 26241404 TI - Novel measure of articular instability based on contact stress confirms that the anterior cruciate ligament is a critical stabilizer of the lateral compartment. AB - Knee instability following anterior cruciate ligament (ACL) rupture is common, compromising function, and causing cartilage and meniscal damage. In this study, instability at the level of the articular surfaces was characterized with a new measure: articular instability. Articular instability was defined as the change in location of the center of contact stress per unit of applied load. The effect of ACL-deficiency on articular instability was quantified in response to combined abduction and internal rotation moments simulating the clinical pivot shift, which recreates the sensation of instability. Eleven cadaver knees were loaded using a robotic manipulator and tibiofemoral contact stress was measured using a stress transducer. Sectioning the ACL led to pronounced articular instability on the lateral compartment in 4 of 11 knees. In these 4 knees articular instability increased posteriorly up to 403% and increased laterally up to 754%. Factors driving inter-specimen variations in articular instability might include articular morphology, ligamentous laxity, and the applied loads. This novel description of contact mechanics confirms that the ACL prevents sudden changes in the relative position of the lateral articular surfaces. It is applicable to any loading conditions and provides a unique measure to quantify the effects of ACL injury and reconstruction. PMID- 26241406 TI - Serum level of C-reactive protein is not a parameter to determine the difference between viral and atypical bacterial infections. AB - C-reactive protein (CRP) is an acute-phase reactant that increases in the circulation in response to a variety of inflammatory stimuli. Elevated levels in serum during several infectious diseases have been reported. In this study, a highly sensitive CRP enzyme immunoassay was used to evaluate serum CRP values in patients with viral and atypical bacterial infections. Patients (n = 139) with different viral or atypical bacterial infections (systemic or respiratory) and healthy controls (n = 40) were tested for circulating CRP values. High levels of IgM antibodies against several viruses: Dengue virus (n = 36), Cytomegalovirus (n = 9), Epstein Barr virus (n = 17), Parvovirus B19 (n = 26), Herpes simplex 1 and 2 virus (n = 3) and Influenza A and B (n = 8) and against atypical bacteria: Legionella pneumophila (n = 15), Mycoplasma pneumoniae (n = 21) and Coxiella burnetii (n = 4) were found. High values of CRP in infected patients compared with controls (P < 0.001) were found; however, no significant differences between viral and atypical bacterial infections were found. Low levels of CRP in respiratory and Coxiella burnetii infections compared with exanthematic viral and other atypical bacterial infections were found. This study suggests that CRP values are useful to define viral and atypical bacterial infections compared with normal values, but, it is not useful to define type of infection. PMID- 26241407 TI - Determinants of Treatment-Resistant Depression: The Salience of Benzodiazepines. AB - Treatment-resistant depression (TRD) lacks consensus regarding its definition, despite being common in clinical practice. This study was designed to identify factors contributing to TRD in patients diagnosed with a major depressive disorder. Patients were grouped into "low," "medium," and "high" treatment resistant (TR) groups based on the number of medications that had been prescribed for their depression. We identified a number of factors linked to TRD. The high TR group was generally older, had a longer depressive episode duration, a higher number of comorbid medical and anxiety disorders, a lower education, and were less likely to be in full-time employment. They also reported less trait irritability and were more likely to view medication as being a contributor to their current depression. Some differences between non-melancholic and melancholic subsets were evident and point to the benefits in research on TRD analyzing the two diagnostic groups separately. The most striking finding was benzodiazepine use, which was significantly more common in the high TR group and within both the melancholic and non-melancholic subsets. Some potential explanations for this finding are offered. PMID- 26241409 TI - Cerclage Use Should Be More Evidence-Based. PMID- 26241410 TI - Trends and Predictors of Cerclage Use in the United States From 2005 to 2012. AB - OBJECTIVE: To characterize the use of cervical cerclage on a population basis. METHODS: This population-based study of U.S. natality records from 2005 to 2012 evaluated use of cerclage in singleton and multiple gestation live births. Obstetric, medical, and demographic characteristics were evaluated. A multivariable logistic regression model was developed to determine factors associated with cerclage. Sensitivity analyses were performed to evaluate cerclage placement in multiple gestations. RESULTS: A total of 21,312,920 pregnancies including 71,582 women who underwent cerclage were included in the analysis. The overall rate of cerclage ranged between 0.3% and 0.4% during the study period. Multiple gestation was a leading characteristic associated with cerclage with 0.3% of singleton pregnancies, 1.3% of twins, 7.9% of triplets, and 18.0% of higher-order pregnancies undergoing the procedure. Another leading characteristic associated with cerclage included prior preterm birth (2.4%). In multivariate regression analyses, these factors retained significance. Cerclage use based on specific risk factors did not change appreciably during the study period. CONCLUSION: Cerclage is a commonly performed obstetric procedure that was used in similar clinical scenarios over the course of the study period. Although research evidence is less supportive of cerclage use in particular high-risk groups such as multiple gestations, these findings have not been translated into clinical practice. These findings underscore the importance of society guidelines and other tools to encourage best clinical practices. PMID- 26241411 TI - My Obstetrician Got Me Fired: How Work Notes Can Harm Pregnant Patients and What to Do About It. AB - Prenatal care providers are frequently asked to provide employment notes for their patients requesting medical leave or changes to work duties. Writing employment notes correctly can help patients negotiate for and obtain medically indicated workplace accommodations, allowing them to continue to work and earn an income. However, a poorly written or poorly timed note can jeopardize a patient's employment and salary. This commentary provides an overview of pregnancy-related employment laws and guidance in writing work accommodations letters that allow pregnant women to keep their jobs while maintaining a healthy pregnancy. PMID- 26241412 TI - Search Your Heart: What Press Ganey Can Never Measure. PMID- 26241413 TI - Abortion-Related Mortality in the United States: 1998-2010. AB - OBJECTIVE: To examine characteristics and causes of legal induced abortion related deaths in the United States between 1998 and 2010. METHODS: Abortion related deaths were identified through the national Pregnancy Mortality Surveillance System with enhanced case-finding. We calculated the abortion mortality rate by race, maternal age, and gestational age and the distribution of causes of death by gestational age and procedure. RESULTS: During the period from 1998-2010, of approximately 16.1 million abortion procedures, 108 women died, for a mortality rate of 0.7 deaths per 100,000 procedures overall, 0.4 deaths for non Hispanic white women, 0.5 deaths for Hispanic women, and 1.1 deaths for black women. The mortality rate increased with gestational age, from 0.3 to 6.7 deaths for procedures performed at 8 weeks or less and at 18 weeks or greater, respectively. A majority of abortion-related deaths at 13 weeks of gestation or less were associated with anesthesia complications and infection, whereas a majority of abortion-related deaths at more than 13 weeks of gestation were associated with infection and hemorrhage. In 20 of the 108 cases, the abortion was performed as a result of a severe medical condition where continuation of the pregnancy threatened the woman's life. CONCLUSION: Deaths associated with legal induced abortion continue to be rare events-less than 1 per 100,000 procedures. Primary prevention of unintended pregnancy, including those in women with serious pre-existing medical conditions, and increased access to abortion services at early gestational ages may help to further decrease abortion-related mortality in the United States. LEVEL OF EVIDENCE: III. PMID- 26241415 TI - Metabolic Acidemia in Live Births at 35 Weeks of Gestation or Greater. AB - OBJECTIVE: To estimate the incidence of metabolic acidemia and assess its association with a variety of obstetric complications in a large cohort of singleton live births at 35 weeks of gestation or greater. METHODS: We analyzed obstetric complications and neonatal outcomes associated with metabolic acidemia in singleton newborns delivered at 35 weeks of gestation or greater. Metabolic acidemia was identified as an umbilical artery pH of less than 7.0 and a base deficit of 12 mmol/L or greater from umbilical cord blood gas analyses performed immediately after delivery. The primary outcome of interest was seizures in the immediate newborn period. RESULTS: Between January 1, 1988, and December 31, 2013, a total of 1,265 (3.9/1,000, 95% confidence interval [CI] 3.7-4.1) neonates were identified with metabolic acidemia among 323,027 live births with cord gas analysis. Virtually every recorded obstetric complication was significantly associated with metabolic acidemia. All measures of neonatal morbidity except necrotizing enterocolitis were also significantly increased in the presence of metabolic acidemia. Seizures occurred in 367 of 323,027 (1.1/1,000, 95% CI 1.0 1.3) neonates. Only 19.1% (95% CI 15.2-23.5%) occurred in those with metabolic acidemia. Among the 1,265 with metabolic acidemia, 70 were diagnosed with neonatal seizures, for a prevalence of 5.5% (95% CI 4.3-6.9) in the acidotic group. CONCLUSION: Neonatal acidemia at birth is rare in deliveries occurring at or after 35 weeks of gestation. Seizures occur in less than one in 10 newborns with metabolic acidemia. Approximately 80% of seizures in neonates at this gestational age occur in nonacidemic neonates. LEVEL OF EVIDENCE: III. PMID- 26241414 TI - Calcium Channel Blocker Exposure in Late Pregnancy and the Risk of Neonatal Seizures. AB - OBJECTIVE: To assess whether maternal calcium channel blocker exposure during late pregnancy is independently associated with neonatal seizures after carefully controlling for confounding factors. METHODS: Data were derived from the Medicaid Analytic eXtract for the years 2000-2007 and included 2,529,636 completed pregnancies. We compared the risk of neonatal seizures among neonates who were born to women who took calcium channel blockers in the final month of pregnancy to the risk in neonates born to women who did not use calcium channel blockers. Confounding was addressed through the use of propensity score matching. RESULTS: A total of 22,908 (0.91%) pregnancies included exposure to calcium channel blockers during the final month of pregnancy. Neonatal seizures occurred in 53 (0.23%) neonates born to mothers exposed to calcium channel blockers and in 4,609 (0.18%) neonates of unexposed women (unadjusted odds ratio [OR] 1.26, 95% confidence interval [CI] 0.96-1.65). After accounting for confounders, there was no increase in risk of neonatal seizures associated with calcium channel blocker exposure (OR 0.95, 95% CI 0.70-1.30). This null finding was robust across multiple sensitivity analysis. CONCLUSION: In this large, carefully controlled, population-based cohort study, there was no significant increase in the risk of neonatal seizures in neonates attributable to maternal calcium channel blocker exposure in late pregnancy. The results suggest that calcium channel blockers can be used by obstetricians in late pregnancy without excess concern about this neonatal complication. LEVEL OF EVIDENCE: II. PMID- 26241416 TI - Prevalence, Correlates, and Outcomes of Omphalocele in the United States, 1995 2005. AB - OBJECTIVE: To examine the trends in the prevalence, epidemiologic correlates, and 1-year survival of omphalocele using 1995-2005 data from the National Birth Defects Prevention Network in the United States. METHODS: We examined 2,308 cases of omphalocele over 11 years from 12 state population-based birth defects registries. We used Poisson regression to estimate prevalence and risk factors for omphalocele and Kaplan-Meier survival curves and Cox proportional hazards regression to estimate survival patterns and hazard ratios, respectively, to examine isolated compared with nonisolated cases. RESULTS: Birth prevalence of omphalocele was 1.92 per 10,000 live births with no consistent trend over time. Neonates with omphalocele were more likely to be male (prevalence ratio 1.22, 95% confidence interval [CI] 1.12-1.34), born to mothers 35 years of age or older (prevalence ratio 1.77, 95% CI 1.54-2.04) and younger than 20 years (prevalence ratio 1.34, 95% CI 1.14-1.56), and of multiple births (prevalence ratio 2.22, 95% CI 1.85-2.66). The highest proportion of neonates with omphalocele had congenital heart defects (32%). The infant mortality rate was 28.7%, with 75% of those occurring in the first 28 days. The best survival was for isolated cases and the worst for neonates with chromosomal defects (hazard ratio 7.75, 95% CI 5.40 11.10) and low-birth-weight neonates (hazard ratio 7.51, 95% CI 5.86-9.63). CONCLUSION: Prevalence of omphalocele has remained constant from 1995 to 2005. Maternal age (younger than 20 years and 35 years or older), multiple gestation, and male sex are important correlates of omphalocele, whereas co-occurrence with chromosomal defects and very low birth weight are consistent determinants of 1 year survival among these neonates. LEVEL OF EVIDENCE: II. PMID- 26241417 TI - The Anachronistic Terminology of Gestational Hypertension: Time for a Change. AB - Few conditions in medicine are plagued with as confusing and anachronistic terminology as the clinical variants of pregnancy-induced hypertension and preeclampsia. We propose a simple system of nomenclature that reflects both actual pathophysiology and standard 21st century medical terminology. Such a change would facilitate both rational, evidence-based clinical care, collaboration with other specialties, and research. PMID- 26241418 TI - The Role of Headache in the Classification and Management of Hypertensive Disorders in Pregnancy. AB - Hypertensive disorders of pregnancy remain among the leading causes of maternal morbidity and mortality. The onset of headaches in patients with hypertensive disorders of pregnancy has been considered as a premonitory symptom for eclampsia and other adverse maternal outcomes. Headaches are very common symptoms during pregnancy and the postpartum period with a reported incidence of 39%; however, headache is absent in 30-50% of women before the onset of eclampsia and is a poor predictor of eclampsia and adverse maternal outcomes. If included in the definition of cerebral or visual disturbances, headache may be considered a symptom of preeclampsia, a diagnostic feature of preeclampsia with severe features, a premonitory symptom of eclampsia, and an indication for delivery. Inclusion of this nonspecific symptom in the diagnosis and management of hypertensive disorders of pregnancy in the absence of an evidence basis may lead to unintended consequences including excessive testing, visits to outpatient offices or emergency departments, additional hospitalization, and iatrogenic preterm delivery without proven benefit. If a cerebral disturbance such as severe or persistent headache presents for the first time during pregnancy or postpartum, an evaluation should be performed that considers a broad differential diagnosis, including but not limited to hypertensive disorders of pregnancy, and the diagnostic evaluation is similar to that in nonpregnant adults. This commentary draws attention to the implications of considering the cerebral disturbance of headache as a symptom that portends adverse pregnancy outcome in the current recommendations for diagnosing and managing hypertensive disorders of pregnancy. PMID- 26241419 TI - Glyburide in Women With Mild Gestational Diabetes: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate whether the addition of glyburide to diet therapy modifies pregnancy outcomes in women with mild gestational diabetes. METHODS: Women with at least two abnormal values on a 3-hour, 100-g oral glucose tolerance test according to National Diabetes Data Group criteria and fasting values less than 105 mg/dL between 24 and 30 weeks of gestation were randomized to blinded glyburide or placebo study drug. All women were placed on a 35-kcal/kg diet and recorded four times daily capillary glucose measurements. The study drug was titrated based on weekly maternal capillary glucose values with targets of less than 95 mg/dL (5.3 mmol/L) and 120 mg/dL (6.7 mmol/L) for fasting and 2-hour postprandial glucose measurements, respectively. The primary study outcome was a 200-g birth weight decrement in neonates of women treated with glyburide. The sample size estimate for this outcome was 334 total randomized women with a one to-one allocation. RESULTS: A total of 395 women were enrolled at a single center between September 2008 and October 2012. Women treated with glyburide had a significantly greater decline in fasting glucose values over the course of therapy. However, there was no difference in the primary study outcome. Specifically, the mean birth weight was 33 g lower in the group treated with glyburide (P=.52). Although not powered to examine all outcomes associated with gestational diabetes, treatment with glyburide did not affect need for operative delivery, shoulder dystocia, clavicular fracture, Erb's palsy, or neonatal hypoglycemia. Four women in each group required insulin. CONCLUSION: The addition of glyburide to diet therapy significantly improved maternal glycemic control over time when compared with placebo. However, adding glyburide to diet did not decrease birth weight or improve maternal or neonatal outcomes in women with mild gestational diabetes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00744965. LEVEL OF EVIDENCE: I. PMID- 26241420 TI - Myo-inositol Supplementation for Prevention of Gestational Diabetes in Obese Pregnant Women: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate whether myo-inositol supplementation, an insulin sensitizer, reduces the rate of gestational diabetes mellitus (GDM) and lowers insulin resistance in obese pregnant women. METHODS: In an open-label, randomized trial, myo-inositol (2 g plus 200 micrograms folic acid twice a day) or placebo (200 micrograms folic acid twice a day) was administered from the first trimester to delivery in pregnant obese women (prepregnancy body mass index 30 or greater. We calculated that 101 women in each arm would be required to demonstrate a 65% GDM reduction in the myo-inositol group with a statistical power of 80% (alpha=0.05). The primary outcomes were the incidence of GDM and the change in insulin resistance from enrollment until the diagnostic oral glucose tolerance test. RESULTS: From January 2011 to April 2014, 220 pregnant women at 12-13 weeks of gestation were randomized at two Italian university hospitals, 110 to myo inositol and 110 to placebo. Most characteristics were similar between groups. The GDM rate was significantly reduced in the myo-inositol group compared with the control group, 14.0% compared with 33.6%, respectively (P=.001; odds ratio 0.34, 95% confidence interval 0.17-0.68). Furthermore, women treated with myo inositol showed a significantly greater reduction in the homeostasis model assessment of insulin resistance compared with the control group, -1.0+/-3.1 compared with 0.1+/-1.8 (P=.048). CONCLUSION: Myo-inositol supplementation, started in the first trimester, in obese pregnant women seems to reduce the incidence in GDM through a reduction of insulin resistance. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01047982. PMID- 26241421 TI - Adverse Outcomes and Potential Targets for Intervention in Gestational Diabetes and Obesity. AB - OBJECTIVE: To evaluate the association of obesity with pregnancy outcomes in women with gestational diabetes mellitus (GDM) and identify potentially modifiable risk factors for adverse outcomes in obese women with GDM. METHODS: This was a retrospective cohort study of 1,344 women with GDM who delivered between 2009 and 2012. Demographic data, blood sugar values, gestational weight gain, and maternal and neonatal outcome data were abstracted from the medical record and compared among normal-weight, overweight, and obese women. RESULTS: Overweight and obese women had higher mean fasting and postprandial blood sugars despite higher doses of and more frequent use of medication. Obesity was independently associated with macrosomia (adjusted odds ratio [OR] 2.03, 95% confidence interval [CI] 1.07-3.89, P=.03), indicated preterm birth (adjusted OR 2.21, 95% CI 1.02-4.78, P=.04), and hypertensive disorders of pregnancy (adjusted OR 2.19, 95% CI 1.38-3.49, P=.001). In our stratified analyses, obese women with fasting blood sugars greater than 88.7 mg/dL and postprandial blood sugars greater than 123.8 mg/dL had higher rates of macrosomia (13.1% compared with 5.7%, P=.004 for fasting, 13.0% compared with 6.5%, P=.01 for postprandial blood sugars) and indicated preterm birth (11.4% compared with 6.1%, P=.04 for fasting, 11.9% compared with 5.8%, P=.01 for postprandial blood sugars) when compared with obese women with lower values. Hypertensive disorders of pregnancy were significantly increased in obese women with postdiagnosis weight gain greater than 0.6 lb per week (29.4% compared with 15.2%, P<.001) when compared with obese women with less weight gain. CONCLUSION: Prepregnancy obesity is independently associated with adverse pregnancy outcomes in women with GDM, and interventions to optimize glycemic control and limit weight gain postdiagnosis may improve outcomes in these high-risk women. LEVEL OF EVIDENCE: II. PMID- 26241422 TI - Sleep Duration and Blood Glucose Control in Women With Gestational Diabetes Mellitus. AB - OBJECTIVE: To describe the relationship between objectively assessed sleep and blood glucose in a prospective cohort of women recently diagnosed with gestational diabetes mellitus (GDM). METHODS: Women with GDM were enrolled immediately after attending a GDM education class. All patients were recruited during their first week of attempted dietary management of GDM. They were instructed on the use of a glucometer and on the principles of a GDM diet. Women wore an actigraph and completed a sleep log for 7 consecutive days. Glucose records were compared against the objective sleep data. Linear mixed model analysis was used to estimate the association of sleep duration on morning fasting and 1-hour postprandial blood glucose concentrations. RESULTS: Thirty seven participants provided data for 213 sleep intervals that corresponded to at least one glucose reading. Sleep duration was negatively associated with fasting and 1-hour postprandial blood glucose concentrations In analyses adjusted for age, gestational age, and body mass index, a 1-hour increase in sleep time was associated with statistically significant reductions in fasting glucose (-2.09 mg/dL, 95% confidence interval [CI] -3.98 to -0.20) as well as postprandial glucose concentrations (lunch -4.62 mg/dL, 95% CI -8.75 to -0.50; dinner -6.07 mg/dL, 95% CI -9.40 to -2.73). CONCLUSION: Short sleep durations are associated with worsened glucose control in women with gestational diabetes. Educating women on healthy sleep and screening for and treating sleep disorders during pregnancy may have a role in optimizing blood glucose control in gestational diabetes. LEVEL OF EVIDENCE: II. PMID- 26241423 TI - Association of a Best-Practice Alert and Prenatal Administration With Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccination Rates. AB - OBJECTIVE: To evaluate how implementation of a best-practice alert, a reminder of clinical guidelines within the electronic medical record, in combination with the recommended change in immunization timing from postpartum to antepartum, affected tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) rates, and to examine the association of vaccination with local pertussis attack rates. METHODS: A Tdap best-practice alert was introduced into the electronic prenatal charting system in June 2013. The best-practice alert was designed to appear starting at 32 weeks of gestation and to reappear at every subsequent encounter until vaccine acceptance was recorded or delivery occurred. The overall acceptance rate was then compared with postpartum vaccination rates at our institution from the previous year. Records of pertussis cases in children younger than 2 years of age diagnosed since 2012 in Dallas County were also reviewed to correlate local trends with vaccination efforts. RESULTS: Of the 10,201 women offered Tdap during prenatal care, 9,879 (96.8%) ultimately accepted. This is compared with a 48% (5,064 of 10,600) Tdap postpartum immunization rate in the year prior, before introduction of the best-practice alert. The incidence of pertussis among neonates born to mothers who received prenatal care at Parkland Hospital showed a nonsignificant decline from 13 cases per 10,000 deliveries (19 of 14,834, 95% confidence interval [CI] 7-19) between January 2012 and May 2013 to seven per 10,000 deliveries during the study period (eight of 11,788, 95% CI 2-11, P=.174). CONCLUSION: The use of a best-practice alert, in concert with the recommended change in timing of maternal vaccination from postpartum to antepartum, was associated with an increase in the Tdap immunization rate to 97%. LEVEL OF EVIDENCE: II. PMID- 26241424 TI - California Family Planning Health Care Providers' Challenges to Same-Day Long Acting Reversible Contraception Provision. AB - OBJECTIVE: To assess the extent to which practices offering family planning services are able to offer intrauterine devices (IUDs) and implants in one visit and to identify the reasons why multiple visits may be required. METHODS: In the fall of 2011, 1,000 California family planning providers were asked about their long-acting reversible contraception delivery practices in a probability survey. We used multivariable logistic regression to examine practice characteristics associated with same-day provision of IUDs and implants. RESULTS: Among the 636 responding practices, 67% offered an IUD and 40% offered a contraceptive implant onsite. Among those with onsite provision, the majority required two or more visits to place an IUD (58%); almost half required two visits to place an implant (47%). Nearly all Planned Parenthood practices could place an IUD (95%) or implant (95%) at the initial visit, whereas the majority of all other practice types could not. The main reasons for delaying IUD and contraceptive implant provision included the need to screen and wait for test results (68% and 24%, respectively) and clinic flow and scheduling issues (50% and 64%, respectively). Multivariable analyses indicated that Planned Parenthood practices were significantly more likely than private practices to have same-day insertion protocols. CONCLUSION: Most of the family planning providers surveyed have not adopted same-day long-acting reversible contraception insertion protocols and face barriers to same-day provision. LEVEL OF EVIDENCE: III. PMID- 26241425 TI - Medical and Obstetric Outcomes Among Pregnant Women With Congenital Heart Disease. AB - OBJECTIVE: To estimate nationwide trends in the prevalence of maternal congenital heart disease (CHD) and determine whether women with CHD are more likely than women without maternal CHD to have medical and obstetric complications. METHODS: The 2000-2010 Nationwide Inpatient Sample was queried for International Classification of Diseases, 9th Revision, Clinical Modification codes to identify delivery hospitalizations of women with and without CHD. Trends in the prevalence of CHD were determined and then rates of complications were reported for CHD per 10,000 delivery hospitalizations. For Nationwide Inpatient Sample 2008-2010, logistic regression was used to examine associations between CHD and complications. RESULTS: From 2000 to 2010, there was a significant linear increase in the prevalence of CHD from 6.4 to 9.0 per 10,000 delivery hospitalizations (P<.001). Multivariable logistic regression demonstrated that all selected medical complications, including mortality (17.8 compared with 0.7/10,000 deliveries, adjusted odds ratio [OR] 22.10, 95% confidence interval [CI] 13.96-34.97), mechanical ventilation (91.9 compared with 6.9/10,000, adjusted OR 9.94, 95% CI 7.99-12.37), and a composite cardiovascular outcome (614 compared with 34.3/10,000, adjusted OR 10.54, 95% CI 9.55-11.64) were more likely to occur among delivery hospitalizations with maternal CHD than without. Obstetric complications were also common among women with CHD. Delivery hospitalizations with maternal CHD that also included codes for pulmonary circulatory disorders had higher rates of medical complications compared with hospitalizations with maternal CHD without pulmonary circulatory disorders. CONCLUSION: The number of delivery hospitalizations with maternal CHD in the United States is increasing, and although we were not able to determine whether correction of the cardiac lesion affected outcomes, these hospitalizations have a high burden of medical and obstetric complications. LEVEL OF EVIDENCE: II. PMID- 26241426 TI - Advanced Maternal Age and Stillbirth Risk in Nulliparous and Parous Women. AB - OBJECTIVE: To investigate the association between advanced maternal age and stillbirth risks in first, second, third, and fourth births or more. METHODS: A population-based registry study including all women aged 25 years and older with singleton pregnancies at 28 weeks of gestation and later gave birth in Sweden from 1990 to 2011; 1,804,442 pregnancies were analyzed. In each parity group, the risk of stillbirth at age 30-34 years, 35-39 years, and 40 years and older compared with age 25-29 years was investigated by logistic regression analyses adjusted for sociodemographic factors, smoking, body mass index, history of stillbirth, and interdelivery interval. Also, two low-risk groups were investigated: women with a high level of education and nonsmoking women of normal weight. RESULTS: Stillbirth rates increased by maternal age: 25-29 years 0.27%; 30-34 years 0.31%; 35-39 years 0.40%; and 40 years or older 0.53%. Stillbirth risk increased by maternal age in first births. Compared with age 25-29 years, this increase was approximately 25% at 30-34 years and doubled at age 35 years. In second, third, and fourth birth or more, stillbirth risk increased with maternal age in women with a low and middle level of education, but not in women with high education. In nonsmokers of normal weight, the risk in second births increased from age 35 years or older and in third births or more from age 30 years or older. CONCLUSION: Advanced maternal age is an independent risk factor for stillbirth in nulliparous women. This age-related risk is reduced or eliminated in parous women, possibly as a result of physiologic adaptations during the first pregnancy. LEVEL OF EVIDENCE: II. PMID- 26241427 TI - Contraceptive Use and Unintended Pregnancy in Women With Congenital Heart Disease. AB - OBJECTIVE: To identify patterns of contraceptive use and pregnancy in an academic adult congenital cardiology practice. METHODS: In this cross-sectional study, from October 2013 through March 2014, 100 women with congenital heart disease aged 18-45 years were recruited from an academic congenital heart disease clinic and administered a survey regarding pregnancy history, contraception use, and understanding of pregnancy-related and contraceptive-related risk. The primary outcome was current use of long-acting reversible contraception, including intrauterine devices or subdermal implants. RESULTS: Of 83 sexually active women, 63 (75.9%, 95% confidence interval [CI] 65.3-85.1) reported currently using any contraceptive method, including 30 of 83 (36.1%, 95% CI 25.9-47.4) using tier I methods (typical-use failure rates of less than 1% per year) and 20 of 83 (24.1%, 95% CI 15.4-34.7) using tier II methods (typical-use failure rates of 6-12% per year). Nine of 83 (10.8%, 95% CI 5.1-19.6) reported currently using long-acting reversible contraception. Sixty-four of 141 total pregnancies (45.4%, 95% CI 31.9 58.9) were self-reported by participants as "unexpected" rather than "planned." Only one (1.6%, 95% CI 0-4.6) of the 64 unintended pregnancies occurred when the woman was using a tier I method of contraception at the time of conception. CONCLUSION: Most women with congenital heart disease of childbearing age are sexually active. The high incidence of unintended pregnancy in this group may be related to underuse of highly effective methods of contraception. Specific counseling on tier I methods may reduce unintended pregnancies in women with congenital heart disease. LEVEL OF EVIDENCE: III. PMID- 26241428 TI - Preventing Urinary Incontinence With Supervised Prenatal Pelvic Floor Exercises: A Randomized Controlled Trial. AB - OBJECTIVE: To compare, in an unselected population of nulliparous pregnant women, the postnatal effect of prenatal supervised pelvic floor muscle training with written instructions on postpartum urinary incontinence (UI). METHODS: In a randomized controlled trial in two parallel groups, 282 women were recruited from five university teaching hospitals in France and randomized during the second trimester of pregnancy. The physiotherapy group received prenatal individually supervised exercises. Both groups received written instructions about how to perform exercises at home. Women were blindly assessed at baseline, end of pregnancy, and 2 and 12 months postpartum. The primary outcome measured was UI severity, assessed with an International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form score (range 0-21; 1-5 is slight UI) at 12 months postpartum; other outcomes were UI prevalence and pelvic floor troubles assessed using self-administered questionnaires. To give a 1-point difference in UI severity score, we needed 91 women in each group (standard deviation 2.4, alpha=0.05, beta=0.20, and bilateral analysis). RESULTS: Between February 2008 and June 2010, 140 women were randomized in the physiotherapy group and 142 in the control group. No difference was observed between the two groups in UI severity, prevalence, or pelvic floor troubles at baseline, end of pregnancy, and at 2 and 12 months postpartum. At 12 months postpartum, the primary outcome was available for 190 women (67.4%); mean UI severity was 1.9 in the physiotherapy group compared with 2.1 in the control group (P=.38). CONCLUSION: Prenatal supervised pelvic floor training was not superior to written instructions in reducing postnatal UI. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; www.clinicaltrials.gov, NCT00551551. LEVEL OF EVIDENCE: I. PMID- 26241429 TI - Lactation Duration and Midlife Atherosclerosis. AB - OBJECTIVE: To evaluate lactation duration in relation to subsequent atherosclerosis in women during midlife. METHODS: The Coronary Artery Risk Development in Young Adults study is a multicenter prospective cohort that enrolled 2,787 women in 1985-1986 (ages 18-30 years, 52% black, 48% white), of whom 2,014 (72%) attended the 20-year follow-up examination in 2005-2006. We selected 846 women (46% black) without heart disease or diabetes at baseline who delivered one or more times after the baseline evaluation, had cardiometabolic risk factors measured at baseline, and had maximum common carotid intima-media thickness (mm) measured at the 20-year follow-up examination in 2005-2006. Lactation duration was summed across all postbaseline births for each woman and (n, women) categorized as: 0 to less than 1 month (n=262), 1 to less than 6 months (n=210), 6 to less than 10 months (n=169), and 10 months or greater (n=205). Multiple linear regression models estimated mean common carotid intima media thickness (95% confidence interval) and mean differences among lactation duration groups compared with the 0 to less than 1-month group adjusted for prepregnancy obesity, cardiometabolic status, parity, and other risk factors. RESULTS: Lactation duration had a graded inverse association with common carotid intima-media thickness; mean differences between 10 months or greater compared with 0 to less than 1 month ranged from -0.062 mm for unadjusted models (P trend <.001) to -0.029 mm for models fully adjusted for prepregnancy body mass index (BMI) and cardiometabolic risk factors, parity, smoking, and sociodemographics (P trend=.010). Stepwise addition of potential mediators (BMI, systolic blood pressure at the 20-year follow-up examination) modestly attenuated the lactation and common carotid intima-media thickness association to -0.027 and -0.023 mm (P trend=.019 and .054). CONCLUSION: Shorter lactation duration is associated with subclinical atherosclerosis independent of prepregnancy cardiometabolic risk factors and traditional risk factors. The magnitude of differences in carotid artery intima-media thickness may represent greater vascular aging. Lactation may have long-term benefits that lower cardiovascular disease risk in women. LEVEL OF EVIDENCE: II. PMID- 26241430 TI - Obstacles to Studying Emerging Technologies. AB - Laparoscopic radiofrequency ablation of uterine leiomyomas with a new Federal Drug Administration (FDA)-approved device, a device that delivers radiofrequency energy, is a novel procedure that aims to meet patient and physician demand for effective, minimally invasive leiomyoma treatment. However, as a new procedure, the durability of symptom relief, the safety in widespread use, and ultimately the comparative effectiveness of radiofrequency ablation of leiomyomas need further study. In June 2013, the University of California Fibroid Network, a collaboration of the five University of California Departments of Obstetrics and Gynecology, launched the Uterine Leiomyoma Treatment with Radiofrequency Ablation Study, an investigator-initiated early postmarket approval clinical trial of radiofrequency ablation of leiomyomas. In this commentary, we provide a review of the FDA approval process for medical devices using the device that delivers radiofrequency energy as a case study and describe significant limitations of this process that may adversely affect clinical care. We show how the deficiencies in the FDA process have challenged our ability to conduct independent early postmarket research evaluating the safety and long-term effectiveness of this novel technology. Our experience validates the Institute of Medicine's recommendation that advancements in surgical technology introducing new treatments without long-term effectiveness data, comparative study, or both should emerge onto the market under research conditions. Until the FDA requires more rigorous study of novel devices, we suggest ways of working together as a community of gynecologic surgeons to evaluate promising new technologies in early postmarket studies, putting research before widespread adoption of surgical innovation. PMID- 26241431 TI - Feminism and the Moral Imperative for Contraception. AB - This commentary is adapted from the Irvin M. Cushner Memorial Lecture, "Feminism and the Moral Imperative for Contraception," given at 2014 Annual Clinical Meeting of the American College of Obstetricians and Gynecologists in Chicago. It provides a brief and simplified historical review of the feminist movement, primarily in the United States, focusing on feminism's association with contraception. This commentary reflects the perspective and opinions of the author. Contraception is fundamental to a woman's ability to achieve equality and realize her full social, economic, and intellectual potential. PMID- 26241432 TI - Care of the Pregnant Patient With Inflammatory Bowel Disease. AB - Inflammatory bowel disease affects women in their peak reproductive years. Patients and physicians often have questions regarding the effect of inflammatory bowel disease on a woman's ability to conceive and to carry a pregnancy safely to term as well as the effect of inflammatory bowel disease and the medications used to treat it on pregnancy outcomes. Women with inflammatory bowel disease have the same rates of fertility as women without inflammatory bowel disease unless they have had prior surgery in the pelvis or active disease. However, women with inflammatory bowel disease do have higher rates of adverse pregnancy outcomes. A multidisciplinary approach involving gastroenterologists, obstetricians, and maternal-fetal medicine physicians should focus on preconception planning and disease optimization before pregnancy. Women with inflammatory bowel disease should be followed as high-risk obstetric patients. Most medications used to treat inflammatory bowel disease can be continued safely during pregnancy and lactation. The greatest risk to the pregnancy is active disease, which can be precipitated by discontinuation of effective maintenance medications. Preconception counseling should include education regarding the low risk of most inflammatory bowel disease medications during pregnancy and lactation and the high risk of a significant disease flare during pregnancy. This review outlines important considerations for obstetricians caring for women with inflammatory bowel disease before and during pregnancy and in the postpartum period. PMID- 26241435 TI - Efforts to Improve Perinatal Outcomes for Women Enrolled in Medicaid. AB - Improving women's health and perinatal health outcomes is a high priority for Medicaid, the jointly financed federal-state health coverage program. The authorities provided by the Affordable Care Act give Medicaid new resources and opportunities to improve coverage and perinatal care. Given that the Medicaid program currently covers almost half of all births in the United States, the Centers for Medicare and Medicaid Services, working in partnership with states and other stakeholders, is using new and existing authorities to improve birth outcomes. Quality measurement, quality-improvement projects, and expanded models of care underscore the major quality approach of the center. As an outgrowth of an expert panel that included membership of several state Medicaid medical directors, Medicaid providers, and consumer representatives, the Centers for Medicare and Medicaid Services' Center for Medicaid and CHIP Services launched the Maternal and Infant Health Initiative, which aims to increase postpartum visit rates and the use of effective contraception among women covered by Medicaid. This Initiative provides focus on key opportunities and strategies to improve the rate, measurement, timing, and content of postpartum visits. Additionally, a focus on contraception will serve to improve pregnancy planning and spacing and prevent unintended pregnancy. As the Initiative evolves, the Center for Medicaid and CHIP Services plans to identify policy, service delivery, and reimbursement policies to advance the Initiative's goals and improve outcomes for women covered by Medicaid. PMID- 26241433 TI - Pooled Analysis of Six Pharmacologic and Nonpharmacologic Interventions for Vasomotor Symptoms. AB - OBJECTIVE: To describe the effects of six interventions for menopausal vasomotor symptoms relative to control in a pooled analysis, facilitating translation of the results for clinicians and symptomatic women. The Menopause Strategies: Finding Lasting Answers for Symptoms and Health network tested these interventions in three randomized clinical trials. METHODS: An analysis of pooled individual-level data from three randomized clinical trials is presented. Participants were 899 perimenopausal and postmenopausal women with at least 14 bothersome vasomotor symptoms per week. Interventions included 10-20 mg escitalopram per day, nonaerobic yoga, aerobic exercise, 1.8 g per day omega-3 fatty acid supplementation, 0.5 mg low-dose oral 17-beta-estradiol (E2) per day, and 75 mg low-dose venlafaxine XR per day. The main outcome measures were changes from baseline in mean daily vasomotor symptom frequency and bother during 8-12 weeks of treatment. Linear regression models estimated differences in outcomes between each intervention and corresponding control group adjusted for baseline characteristics. Models included trial-specific intercepts, effects of the baseline outcome measure, and time. RESULTS: The 8-week reduction in vasomotor symptom frequency from baseline relative to placebo was similar for escitalopram at -1.4 per day (95% confidence interval [CI] -2.7 to -0.2), low-dose E2 at -2.4 (95% CI -3.4 to -1.3), and venlafaxine at -1.8 (95% CI -2.8 to -0.8); vasomotor symptom bother reduction was minimal and did not vary across these three pharmacologic interventions (mean -0.2 to -0.3 relative to placebo). No effects on vasomotor symptom frequency or bother were seen with aerobic exercise, yoga, or omega-3 supplements. CONCLUSION: These analyses suggest that escitalopram, low dose E2, and venlafaxine provide comparable, modest reductions in vasomotor symptom frequency and bother among women with moderate hot flushes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00894543 (MsFLASH 01), NCT01178892 (MsFLASH 02), and NCT01418209 (MsFLASH 03). PMID- 26241434 TI - Change in Overactive Bladder Symptoms After Surgery for Stress Urinary Incontinence in Women. AB - OBJECTIVE: To assess change in overactive bladder (OAB) symptoms up to 5 years after surgery and to identify associated predictors of change from baseline. METHODS: This is a secondary analysis of data from three multicenter urinary incontinence (UI) surgical trials of women with stress-predominant mixed UI assigned to Burch colposuspension, autologous fascial sling, or retropubic or transobturator midurethral slings. The primary outcome was improvement of 70% or greater from baseline in symptoms measured by the Urinary Distress Inventory Irritative subscale. Surgical groups were compared within respective trials. Generalized linear models were fit using 1-year and up to 5-year data. RESULTS: Significant improvements in Urinary Distress Inventory-Irritative scores were reported by each surgical group 1 year after surgery (P<.001). Most women (50 71%) reported improvement in OAB symptoms. Improvements were similar between midurethral sling groups at 1 year (65.5% compared with 70.7%, P=.32; odds ratio [OR] 0.83, 95% confidence interval [CI] 0.57-1.20 for retropubic compared with transobturator sling) and throughout the 5-year follow-up period. More women reported OAB symptom improvement after Burch compared with pubovaginal sling (67.9% compared with 56.6%, P=.01; OR 1.59, 95% CI 1.10-2.31 for Burch compared with sling); this group difference at 1 year persisted throughout the 5-year follow-up. At 1-year, 50.0-64.3% of patients reported 70% greater improvement in UI. This proportion declined to 36.5-54.1% at 5 years (P<.001). Preoperative use of anticholinergics and urodynamic parameters was not predictive of OAB symptom change after surgery. CONCLUSION: Most women with stress-predominant mixed UI experienced significant improvement in OAB symptoms after incontinence surgery although this initial improvement diminished over time. Obesity blunted symptom improvement. LEVEL OF EVIDENCE: II. PMID- 26241436 TI - Linking Medicaid Expansion and Cuts to Disproportionate-Share Hospitals: Will Safety Nets Survive? AB - The predominant mechanism by which the health care reforms of the Patient Protection and Affordable Care Act of 2010 are to be financed is through the government's simultaneous defunding of major portions of Medicare and Medicaid, including the reduction of up to 75% of federal payments to disproportionate share hospitals. The justification for curtailment of other public programs is that after Medicaid expansion under the Affordable Care Act, the decrease in the proportion of uninsured among the U.S. population will render disproportionate share hospital payments extraneous and unnecessary. Such justification was reiterated in the recent American College of Obstetricians and Gynecologists Committee Opinion No. 627, entitled Health Care for Unauthorized Immigrants. Herein, the soundness of the Committee Opinion's proposed policy is evaluated by reviewing available literature on the potential effect of Medicaid disproportionate-share hospital cuts with and without concomitant Medicaid expansion. Limitations of Medicaid expansion efforts before and under the Affordable Care Act, the disproportionate-share hospital payment program, and other legislation providing safety net hospitals with (some) relief of financial burdens related to uncompensated care are explicated. Findings raise concern that acceptance of cuts of up to 75% of federal disproportionate-share hospital funds on the premise that nationwide state expansion of Medicaid will offset the difference may be overly optimistic. Indeed, foregoing disproportionate-share hospital payments undercuts the otherwise laudable intent of Committee Opinion No. 627, namely to advocate for universal health care for all women, including undocumented immigrants. PMID- 26241437 TI - What is New in Assisted Reproduction and Multiple Pregnancy Reduction?: Best Articles From the Past Year. PMID- 26241439 TI - Treatment for and Clinical Characteristics of Granulomatous Mastitis. PMID- 26241440 TI - Treatment for and Clinical Characteristics of Granulomatous Mastitis. PMID- 26241441 TI - In Reply. PMID- 26241442 TI - The Sky is not Falling, but it is Severely Drooping for the Specialist Obstetrician-Gynecologist. PMID- 26241443 TI - In Reply. PMID- 26241448 TI - Invertebrates as model organisms for research on aging biology. AB - Invertebrate model systems, such as nematodes and fruit flies, have provided valuable information about the genetics and cellular biology involved in aging. However, limitations of these simple, genetically tractable organisms suggest the need for other model systems, some of them invertebrate, to facilitate further advances in the understanding of mechanisms of aging and longevity in mammals, including humans. This paper introduces 10 review articles about the use of invertebrate model systems for the study of aging by authors who participated in an 'NIA-NIH symposium on aging in invertebrate model systems' at the 2013 International Congress for Invertebrate Reproduction and Development. In contrast to the highly derived characteristics of nematodes and fruit flies as members of the superphylum Ecdysozoa, cnidarians, such as Hydra, are more 'basal' organisms that have a greater number of genetic orthologs in common with humans. Moreover, some other new model systems, such as the urochordate Botryllus schlosseri, the tunicate Ciona, and the sea urchins (Echinodermata) are members of the Deuterostomia, the same superphylum that includes all vertebrates, and thus have mechanisms that are likely to be more closely related to those occurring in humans. Additional characteristics of these new model systems, such as the recent development of new molecular and genetic tools and a more similar pattern to humans of regeneration and stem cell function suggest that these new model systems may have unique advantages for the study of mechanisms of aging and longevity. PMID- 26241449 TI - Oral mucosal precancer and cancer: A helpful discriminating clinical tool. AB - The authors have collaborated with many colleagues in several countries in formulating a useful and practical clinical tool for evaluating oral mucosal findings on routine examination. Consideration of several factors including history, evolution of positive findings and clinical information allows placement of examination results into one of three categories which are graded by a color scheme along a spectrum of concerns (green to red, or no concern to serious concern). Afforded to the clinician is a straightforward grading system as a starting point for office end clinic use for all patients. PMID- 26241450 TI - Use of buccal fat pad to repair post-extraction peri-implant bone defects in the posterior maxilla. A preliminary prospective study. AB - BACKGROUND: Extensive literature exists about the use of the BFP in the treatment of oral defects but, to our knowledge, no article refers to the use of the BFP as a substitute of the membrane barriers for treatment of peri-implant bone defects. The aim was to evaluate the use of the buccal fat pad as a coating material for bone grafting in the peri-implant bone defect regeneration of immediate implants placed in the posterior maxilla. MATERIAL AND METHODS: A preliminary prospective study of patients involving immediate implants in which the buccal fat pad was used as a coating material to peri-implant bone defects was carried out. The outcome measures assessed were: postoperative pain and swelling, complications related to buccal fat pad surgery, implant survival and success rates and peri implant marginal bone loss at 12 months of prosthetic loading. RESULTS: Twenty seven patients (17 women and 10 men) with a mean age of 55.3 +/- 8.9 years, and a total of 43 implants were included. Two-thirds of the patients reported either no pain or only mild intensity pain and moderate inflammation, two days after surgery. Post-operative period was well tolerated by the patients and no serious complications occurred. None wound dehiscence occurred. Implant survival and success rates were 97.6% and the average marginal bone loss 1 year after loading was 0.58 +/- 0.27 mm. CONCLUSIONS: Within the limits of this preliminary study, the use of the buccal fat pad as a coating material for bone grafting in peri implant bone defects placed in the upper posterior maxilla was a well-tolerated technique by patients; high implant success rate was achieved with a minimal peri implant marginal bone loss at 12 months of prosthetic loading. PMID- 26241451 TI - Increased nuclear beta-catenin expression in oral potentially malignant lesions: A marker of epithelial dysplasia. AB - BACKGROUND: Deregulation of beta-catenin is associated with malignant transformation; however, its relationship with potentially malignant and malignant oral processes is not fully understood. The aim of this study was to determine and compare the nuclear beta-catenin expression in oral dysplasia and oral squamous cell carcinoma (OSCC). MATERIAL AND METHODS: Cross sectional study. Immunodetection of beta-catenin was performed on 72 samples, with the following distribution: 21 mild dysplasia, 12 moderate dysplasia, severe dysplasia 3, 36 OSCC including 19 well differentiated, 15 moderately differentiated and 2 poorly differentiated. Through microscopic observation the number of positive cells per 1000 epithelial cells was counted. For the statistical analysis, the Kruskal Wallis test was used. RESULTS: Nuclear expression of beta-catenin was observed in all samples with severe and moderate dysplasia, with a median of 267.5, in comparison to mild dysplasia whose median was 103.75. Only 10 samples (27.7%) with OSCC showed nuclear expression, with statistically significant differences between groups (p < 0.05). CONCLUSIONS: Our results are consistent with most of the reports which show increased presence of beta-catenin in severe and moderate dysplasia compared to mild dysplasia; however the expression of nuclear beta catenin decreased after starting the invasive neoplastic process. This suggests a role for this protein in the progression of dysplasia and early malignant transformation to OSCC. Immunodetection of beta-catenin could be a possible immune marker in the detection of oral dysplasia. PMID- 26241452 TI - Oral cleanliness and gingival health among Special Olympics athletes in Europe and Eurasia. AB - BACKGROUND: Special Olympics athletes, as well as the general population of people with intellectual disabilities, are expected to have poorer gingival health. The aim of the study is to explore the prevalence of gingival signs of inflammation and its relationship to oral cleanliness and age among Special Olympics athletes from Europe and Eurasia. MATERIAL AND METHODS: A retrospective longitudinal study was performed with data collected through standardized oral from 15.941 athletes from annual Special Olympics events held in 49 countries, from Europe and Eurasia between 2007 and 2012. The data was analysed descriptively, with One-Way ANOVA test and Chi-Square test. RESULTS: The level of significance was predetermined at a p value < 0.05. A total of 7,754 athletes presented with gingival signs (48.64%). There were no significant differences (p= 0,095) in mean gingival signs between age groups, however the association between mouth cleaning and age, was statistically significant. CONCLUSIONS: The data suggests that there is a high prevalence of gingival signs among individuals with special needs; over 50% in more than 20 countries. Therefore, there is a serious need for education and preventive programs for the patients, their parents and caregivers. PMID- 26241453 TI - Dental care protocol based on visual supports for children with autism spectrum disorders. AB - BACKGROUND: Subjects with Autism Spectrum Disorders (ASDs) have often difficulties to accept dental treatments. The aim of this study is to propose a dental care protocol based on visual supports to facilitate children with ASDs to undergo to oral examination and treatments. MATERIAL AND METHODS: 83 children (age range 6-12 years) with a signed consent form were enrolled; intellectual level, verbal fluency and cooperation grade were evaluated. Children were introduced into a four stages path in order to undergo: an oral examination (stage 1), a professional oral hygiene session (stage 2), sealants (stage 3), and, if necessary, a restorative treatment (stage 4). Each stage came after a visual training, performed by a psychologist (stage 1) and by parents at home (stages 2, 3 and 4). Association between acceptance rates at each stage and gender, intellectual level, verbal fluency and cooperation grade was tested with chi-square test if appropriate. RESULTS: Seventy-seven (92.8%) subjects overcame both stage 1 and 2. Six (7.2%) refused stage 3 and among the 44 subjects who need restorative treatments, only three refused it. The acceptance rate at each stage was statistically significant associated to the verbal fluency (p=0.02; p=0.04; p=0.01, respectively for stage 1, 3 and 4). In stage 2 all subjects accepted to move to the next stage. The verbal/intellectual/cooperation dummy variable was statistically associated to the acceptance rate (p<0.01). CONCLUSIONS: The use of visual supports has shown to be able to facilitate children with ASDs to undergo dental treatments even in non-verbal children with a low intellectual level, underlining that behavioural approach should be used as the first strategy to treat patients with ASDs in dental setting. PMID- 26241454 TI - Dental extraction in patients receiving dual antiplatelet therapy. AB - BACKGROUND: Dual antiplatelet therapy consists of administering antiplatelet (antiaggregant) drugs (clopidogrel and aspirin) to prevent thrombotic processes, as a preventative measure in patients with acute coronary disease, or in patients subjected to percutaneous coronary intervention. OBJECTIVE: The purpose of this study was to evaluate the efficacy of a protocol for performing dental extraction in patients receiving dual antiplatelet therapy. MATERIAL AND METHODS: Thirty-two patients undergoing dental extractions were included in the study. The variables evaluated were: collagen-epinephrine fraction, collagen- adenosine diphosphate fraction, surgical surface, post-surgical measures, and adverse effects. Alveolar sutures and gauzes impregnated with an antifibrinolytic agent (tranexamic acid), which the patient pressed in place for 30 minutes, were applied to all patients as post-surgical measures. Descriptive statistics were calculated and analyzed with Student's t-test to compare pairs of quantitative variables; simple regression analysis was performed using Pearson's correlation coefficient. Statistical significance was set at p<0.05. RESULTS: Collagen/epinephrine fraction was 264.53+/-55.624 seconds with a range of 135 to 300 seconds, and collagen/ADP fraction was 119.41+/-44.216 seconds, both values being higher than normal. As a result of the post-surgical measures taken, no patients presented post-operative bleeding, hematoma or infection. CONCLUSIONS: Dental extraction was safe for patients receiving dual anti-platelet therapy when using sutures and gauze impregnated with tranexamic acid, which the patient pressed in place for 30 minutes. PMID- 26241455 TI - Influence of perioperative dexamethasone on delayed union in mandibular fractures: A clinical and radiological study. AB - BACKGROUND: The aim was to clarify the occurrence of delayed union after surgical treatment of mandibular fracture and investigate whether an association exists between perioperative use of dexamethasone and delayed union. MATERIAL AND METHODS: Thirty-seven patients were included in a prospective randomized study. Of these patients, 19 (51.4%) were randomized to receive a total dose of 30 mg of dexamethasone and 18 (48.6%) served as controls. Patients underwent clinical and radiological investigation immediately, one month, three months and six months postoperatively. Radiographs were evaluated by an experienced, blinded senior oral radiologist. RESULTS: Delayed fracture union was found in 9 patients (24.3%). It was associated significantly with angle fractures (p=0.012). Delayed union occurred more frequently in patients who received dexamethasone (36.8%) than in those who did not (11.1%) (p=0.068). The association of infection with delayed union was significant (p=0.027). Moreover, dexamethasone was significantly (p=0.019) associated with delayed fracture union with concomitant infection. Gender, age group, smoking habit, treatment delay and duration of surgery were not associated with delayed union. CONCLUSIONS: Infection was associated with delayed union. Short-term high-dose dexamethasone predisposed to complicated fracture union, especially in patients with angle fractures. The relationship between dexamethasone and delayed bone healing without infection remains unresolved. PMID- 26241456 TI - Clinical features and histological description of tongue lesions in a large Northern Italian population. AB - BACKGROUND: Only few studies on tongue lesions considered sizable populations, and contemporary literature does not provide a valid report regarding the epidemiology of tongue lesions within the Italian population. In this report, the histopathological and clinical appearance of 1.106 tongue lesions from northern Italians are described and discussed. MATERIAL AND METHODS: The case records of patients referred for the diagnosis and management of tongue lesions, from October 1993 to October 2013, were reviewed. Histological data were also obtained and blindly re-examined. RESULTS: For instance, a biopsy performed on a lingual ulcer has a strong predicting association with a carcinoma, whereas a biopsy on a white lesion predicts for a leukoplakia or oral lichen planus. Moreover, a biopsy of erosion is representative of bullous diseases, whereas a biopsy on a verrucous papillary lesion is significant for fibroma. Furthermore, carcinomas occur in the majority of cases on the lingual edge or pelvis, oral lichen planus is mainly seen on the edge, and fibromas mostly on the lingual tip. CONCLUSIONS: The high frequency of tongue involvement of such different diseases emphasizes the importance of histological characterization and that some diseases occur more frequently than others, with a peculiar clinical aspect and a more common area. In fact our survey can help the clinician in advancing diagnostic hypothesis, on the basis of the elementary lesion and its site of involvement. PMID- 26241457 TI - Serologic control against hepatitis B virus among dental students of the University of Granada, Spain. AB - BACKGROUND: To evaluate the immunological situation against hepatitis B virus (HBV) of a cohort of dentistry students, to analyze the behavior of the levels of hepatitis B surface antigen (anti-HBs) after the administration of one or three vaccine doses, and to determine the influence of age and sex on the immune response. MATERIAL AND METHODS: This retrospective cohort study included students attending the School of Dentistry of the institution where the study was performed from 2005 to 2012 who had completed the public health vaccination calendar for HBV at the age of 12-13. Data on age, sex, basal anti-HBs levels, post-vaccination anti-HBs results and final anti-HBs levels were collected. Comparisons of the basal and final levels, as well as associations regarding age and sex, were performed by means of the Student t and Chi-square tests. RESULTS: Of the 359 students, 97 (27.02%) had basal antibody concentrations <10 mIU/ml, whereas in 262 the levels of anti-HBs were >=10 mIU/ml (72.98%). Of the 288 participating students who completed the School's protocol for immunization, 287 (99.65%) attained a level of protection >=10 mIU/ml. Globally, there were statistically significant differences between the basal antibody levels and those achieved after administration of the vaccine and booster, but no association with age or sex was observed. CONCLUSIONS: About 70% of dental students vaccinated as pre-adolescents had serologic evidence of protection against HBV. Administering a booster is associated with the presence of an excellent immune memory. There is clearly a need to reinforce control of the antibody levels in groups at risk, such as Dentistry students. PMID- 26241458 TI - Comparison of the efficacy of low doses of methylprednisolone, acetaminophen, and dexketoprofen trometamol on the swelling developed after the removal of impacted third molar. AB - BACKGROUND: The aim of the present study was to compare the efficacy of low doses of methylprednisolone, acetaminophen and dexketoprofen trometamol, which are among the drug groups used in our clinic, on postoperative swelling developing after removal of impacted third molar. MATERIAL AND METHODS: The three group of patients received either 40 mg methylprednisolone or 300 mg acetaminophen or 12.5 mg dexketoprofen trometamol one hour before the procedure, according to the patient groups. The patients in the methylprednisolone group were injected with methylprednisolone at a dose of 20 mg 24 hour after the procedure and prescribed 300 mg acetaminophen as rescue analgesic. During the postoperative period, the doses that were given before the procedure were continued 3 times a day for 2 days in the acetaminophen and dexketoprofen trometamol groups. Maximal swelling was assessed preoperatively and at the postoperative 48 hours by ultrasound images. RESULTS: Swelling was 34% lower in the methylprednisolone than in the other groups; however, no statistically significant difference was found between the groups. The acetaminophen and dexketoprofen trometamol groups exhibited clinical results close to each other. CONCLUSIONS: Combination of low doses of methylprednisolone and acetaminophen provide a safe and adequate clinical success on swelling. PMID- 26241459 TI - Cone beam computed tomographic analysis of maxillary premolars and molars to detect the relationship between periapical and marginal bone loss and mucosal thickness of maxillary sinus. AB - BACKGROUND: This study assessed the relationship between mucosal thickness (MT) of the maxillary sinus and periodontal bone loss (PBL) and periapical condition of related teeth. We also aimed to identify the association between root apices and the inferior wall of the maxillary sinus using Cone beam computed tomography (CBCT). MATERIAL AND METHODS: In this study, CBCT images of 205 patients with 410 maxillary sinuses were examined, retrospectively. A total of 582 maxillary molars and 587 premolars were observed. The relationship of each root with maxillary sinus and apical lesions of these roots were classified, PBL was examined and the situations of adjacent teeth were estimated. The effect of these conditions on sinus mucosal thickness (MT) was evaluated. RESULTS: There was a significant correlation between MT of maxillary sinus and both PBL and age (r = 0.52, p=0.000 and r = 0.111, p= 0.002, respectively). The frequency of MT increased as the severity of apical lesion enlarged. A positive correlation was found between MT and degree of PBL and periapical lesions. To reveal the association between MT and pulpoperiapical condition bivariate correlation was done and a significant relationship between the pulpoperiapical condition and MT was found (r = 0.17, p=0.000). CONCLUSIONS: This retrospective study showed that MT of the maxillary sinus was common among patients with PBL and MT was significantly associated with PBL and apical lesions. The relationship of maxillary sinus to adjacent teeth had also positive correlation with MT. CBCT imaging enabled better evaluation of maxillary sinus, posterior teeth and surrounding structures compared to other imaging tools. PMID- 26241460 TI - Efficacy of mandibular advancement device in the treatment of obstructive sleep apnea syndrome: A randomized controlled crossover clinical trial. AB - BACKGROUND: Evaluation of the efficacy and safety of a mandibular advancement device (MAD) (KlearwayTM) in the treatment of mild-to-moderate obstructive sleep apnea and chronic roncopathy. MATERIAL AND METHODS: A randomized, placebo controlled, double blinded, and crossover clinical trial was conducted. Placebo device (PD) defined as a splint in the centric occlusion that did not induce a mandibular advancement served as a control. The mandible was advanced to the maximum tolerable distance or to a minimum of 65% of the maximum protrusion. After each sequence of treatment, patients were assessed by questionnaires, conventional polysomnography, and objective measurement of snoring at the patient's own home. RESULTS: Forty two patients participated in the study and 38 completed the study. Patients mean age was 46 +/-9 years and the 79% were males. The mean mandibular advancement was 8.6 +/-2.8 mm. Patients used the MAD and the PD for 6.4 +2.4 hours and 6.2 +2.0 hours, respectively. Secondary effects (mostly mild) occurred in the 85.7% and the 86.8% of the users of MAD and PD, respectively. The MAD induced a decrease in the apnea-hypopnea index (AHI) from 15.3 +10.2 to 11.9 +15.5. The 50% reduction in the AHI was achieved in the 46.2% and the 18.4% of the patients treated with MAD and PD, respectively. The use of the MAD induced a reduction in the AHI by 3.4 +15.9 while the PD induced an increase by 10.6 +26.1. The subjective evaluation of the roncopathy indicated an improvement by the MAD and an increase in the perceptive quality of sleep. However, the objective evaluation of the roncopathy did not show significant improvements. CONCLUSIONS: The use of MAD is efficient to reduce the AHI and improve subjectively the roncopathy. MAD could be considered in the treatment of mild-to-moderate OSA and chronic roncopathy. PMID- 26241461 TI - Rechargeable Lithium-Iodine Batteries with Iodine/Nanoporous Carbon Cathode. AB - Rechargeable Li-iodine batteries are attractive electrochemical energy storage systems because iodine cathode provides the possibility of high energy density, wide abundance and low cost. However, the safety risk caused by low thermostability of iodine and the self-discharge reaction due to high solvency of iodine in aprotic solvent are target issues to be considered. Herein, we designed a room-temperature "solution-adsorption" method to prepare a thermostable iodine carbon cathode by utilizing the strong adsorption of nanoporous carbon. Meanwhile, Li-iodine batteries constructed by the as-prepared cathode and ether based electrolyte with the addition of LiNO3 showed negligible self-discharge reaction, high rate and long cycling performance. The reversible reactions of I2/LiI3 and LiI3/LiI in Li-iodine batteries were also proved with in situ Raman measurement. For the demonstration of application, soft-package batteries with Al plastic film were assembled, displaying energy densities of 475 Wh/kg by mass of Li and iodine, and 136 Wh/kg by total mass of the battery. The use of nanoporous carbon to adsorb iodine at room-temperature represents a new and promising direction for realizing high-performance cathode for rechargeable Li-iodine batteries. PMID- 26241462 TI - Spatially-global integration of closed, fragmented contours by finding the shortest-path in a log-polar representation. AB - Finding the occluding contours of objects in real 2D retinal images of natural 3D scenes is done by determining, which contour fragments are relevant, and the order in which they should be connected. We developed a model that finds the closed contour represented in the image by solving a shortest path problem that uses a log-polar representation of the image; the kind of representation known to exist in area V1 of the primate cortex. The shortest path in a log-polar representation favors the smooth, convex and closed contours in the retinal image that have the smallest number of gaps. This approach is practical because finding a globally-optimal solution to a shortest path problem is computationally easy. Our model was tested in four psychophysical experiments. In the first two experiments, the subject was presented with a fragmented convex or concave polygon target among a large number of unrelated pieces of contour (distracters). The density of these pieces of contour was uniform all over the screen to minimize spatially-local cues. The orientation of each target contour fragment was randomly perturbed by varying the levels of jitter. Subjects drew a closed contour that represented the target's contour on a screen. The subjects' performance was nearly perfect when the jitter-level was low. Their performance deteriorated as jitter-levels were increased. The performance of our model was very similar to our subjects'. In two subsequent experiments, the subject was asked to discriminate a briefly-presented egg-shaped object while maintaining fixation at several different positions relative to the closed contour of the shape. The subject's discrimination performance was affected by the fixation position in much the same way as the model's. PMID- 26241463 TI - Relationship between oxygen concentration, shear force and protein oxidation in modified atmosphere packaged pork. AB - Pork loins were stored at 5 degrees C for 14 days to investigate the effect of oxygen concentration in modified atmosphere packaging (MAP) on shear force and oxidation of lipids and proteins. The modified atmosphere contained 0 to 80% O2, 20% CO2, and balanced with N2. The results showed that shear force and thiobarbituric acid-reactive substances (TBARS) values increased with increasing oxygen concentration. Protein oxidation when measured as loss of free thiol groups, was greater in meat packaged under oxygen (20-80%). Myosin heavy chain (MHC) cross-linking, another marker of protein oxidation, was greater in MAP with 80% oxygen than 0% and 20% oxygen. Desmin degradation was not affected by the presence of oxygen, suggesting that the mechanism of oxygen-induced toughening of meat is through protein oxidation leading to cross-linking of structural proteins rather than through inactivation of proteolytic enzymes leading to reduced proteolysis. PMID- 26241464 TI - Antioxidant potential of a unique LAB culture isolated from Harbin dry sausage: In vitro and in a sausage model. AB - The lactic acid bacteria Pediococcus pentosaceus, Lactobacillus curvatus, Lactobacillus brevis, and Lactobacillus fermentum isolated from Harbin dry sausage were evaluated for their potential antioxidant activity. The in vitro results showed that P. pentosaceus had the strongest H2O2 resistance, radical scavenging activity, reducing power, and inhibition of lipid peroxidation (P<0.05). Additionally, superoxide dismutase and glutathione peroxidase activities in P. pentosaceus were higher than those observed in three other strains (P<0.05). The inoculation of P. pentosaceus in dry sausage significantly decreased the quantities of thiobarbituric acid-reactive substance and carbonyl formation, while it also reduced the sulfhydryl loss in sausages (P<0.05). Furthermore, the lower content of volatile compounds that are related to lipid oxidation, such as aldehydes, ketones and hydrocarbons, was observed in the P. pentosaceus inoculated sausage (P<0.05). These results demonstrate that P. pentosaceus has the potential to be employed as an antioxidant starter culture in fermented meat products. PMID- 26241465 TI - Net lactate accumulation and low buffering capacity explain low ultimate pH in the longissimus lumborum of AMPKgamma3 R200Q mutant pigs. AB - Postmortem lactate accumulation in skeletal muscle is linearly associated with the extent of pH decline. Yet, pigs harboring the AMPKgamma3(R200Q) mutation produce meat with similar lactate levels to that of wild-type pigs but have a lower ultimate pH. We hypothesized that lower initial lactate levels and (or) lower buffering capacity in muscle of these pigs may help explain this discrepancy. Longissimus lumborum muscle samples were harvested at 0 and 1440 min postmortem from AMPKgamma3(R200Q) and wild-type pigs. As expected, AMPKgamma3(R200Q) muscle exhibited a lower ultimate pH but similar lactate levels to that of wild-type pigs at 1440 min postmortem. However, the total net lactate produced postmortem was greater in the AMPKgamma3(R200Q) muscle due to lower initial lactate levels at 0 min postmortem. Buffering capacity measured over the pH range of 5.5-7.0 was also lower in AMPKgamma3(R200Q) muscle. Greater net lactate accumulation postmortem (i.e., glycolytic flux) coupled with a lower buffering capacity explains the lower ultimate pH of meat from AMPKgamma3(R200Q) pigs. PMID- 26241466 TI - Seasonal prevalence of potentially positive non-O157 Shiga toxin-producing Escherichia coli (STEC) bovine hides and carcasses in Costa Rica. AB - The prevalence of potentially positive Shiga toxin-producing Escherichia coli (STEC) bovine hides and carcasses in three abattoirs in Costa Rica was estimated. Two export facilities (A and B) and one non-export establishment (C) were visited during the dry and rainy seasons of 2013. Swabs of hides pre-eviscerated and treated (180-220 peroxyacetic acid spray) carcasses were tested for the potential presence of STEC serogroups O26, O45, O103, O111, O121, and O145. The prevalence on hides during the rainy season was 86.7, 96.7 and 96.7% for facilities A, B, and C, respectively. During the dry season, the prevalence on hides was significantly lower in plants A and B (40% and 26.7%, respectively), but was marginally associated with the season in plant C (76.7%, P=0.0523). The prevalence of non-O157 STEC markers on treated carcasses was low (0 to 3.3%), suggesting that all plants were effective in minimizing the target non-O157 STEC in beef destined for export and for domestic consumption. PMID- 26241467 TI - Genetic modulators of the phenotype in the long QT syndrome: state of the art and clinical impact. AB - Long QT syndrome (LQTS) is one the best characterized disorders among all inherited arrhythmogenic syndromes. A multi-parametric risk stratification scheme, which includes clinical variables (QTc, gender) and the main LQTS genotypes, was defined in the early 2000s and is currently used in clinical practice. However, the evidence of a marked phenotypic variability, even in the presence of the same genetic mutation has puzzled many investigators since the discovery of LQTS genes. Practically, variable expression in LQTS often limits the predictive accuracy of risk stratification markers. Therefore, in a subset of cases, the identification of subjects at a high risk of life-threatening arrhythmias and sudden death is difficult. The discovery of common genetic variants that explain the heritable components of the human electrocardiogram, including QT interval, generated the hypothesis that genetic modifiers may account for phenotypical variability in LQTS. Despite the fact that multiple SNPs have been linked to QT interval duration, clinical applications of any findings are limited by the small effect sizes conferred by single SNPs and incomplete knowledge on their functional consequences. Nevertheless, the possibility of introducing SNP genotyping in risk stratification schemes to improve patient specificity is an attractive goal. Here we review the currently available evidence and future perspectives for the inclusion of genetic modifiers in the clinical management of LQTS. PMID- 26241469 TI - A Prolonged Post-Operative Antibiotic Regimen Reduced the Rate of Prosthetic Joint Infection after Aseptic Revision Knee Arthroplasty. AB - BACKGROUND: The aim of this study was to compare the prosthetic joint infection (PJI) rate after knee revision arthroplasty in two consecutive periods with different antibiotic prophylaxis: short (one day) versus long (five days). METHODS: From January 2007 to September 2010 antibiotic prophylaxis consisted of 800 mg of teicoplanin and 2 g of ceftazidime intravenously and 1 g of ceftazidime two hours after the first dose. From October 2010, it was prolonged post operatively using vancomycin and ceftazidime intravenously until the fifth day. RESULTS: During the study period, 341 revision surgeries met the inclusion criteria. The PJI rate was lower in the long-prophylaxis group (2.2% versus 6.9%, p=0.049). Prolonged post-operative antibiotic treatment was the only variable associated independently with a lower rate of PJI (odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.07-0.99). PMID- 26241470 TI - An Evidence-Based Approach To Managing Asymptomatic Elevated Blood Pressure In The Emergency Department. AB - Hypertension is a common chronic illness that affects 50 million individuals in the United States and approximately 30% of adults worldwide. United States emergency departments report > 900,000 annual visits for hypertension-related complaints and studies show that approximately one-third of patients with elevated blood pressure lack a formal prior diagnosis. These patients are at risk for long-term morbidity and mortality from cardiovascular, ocular, and neurological consequences. This review examines the most current evidence regarding emergency department treatment of asymptomatic hypertension, including differentiating hypertensive emergency from poorly controlled hypertension, recommendations for choosing appropriate treatment, determining the need for admission, and guidelines for disposition and follow-up. PMID- 26241468 TI - Insights into blood lipids from rare variant discovery. AB - Large-scale genome wide screens have discovered over 160 common variants associated with plasma lipids, which are risk factors often linked to heart disease. A large fraction of lipid heritability remains unexplained, and it is hypothesized that rare variants of functional consequence may account for some of the missing heritability. Finding lipid-associated variants that occur less frequently in the human population poses a challenge, primarily due to lack of power and difficulties to identify and test them. Interrogation of the protein coding regions of the genome using array and sequencing techniques has led to important discoveries of rare variants that affect lipid levels and related disease risk. Here, we summarize the latest methods and findings that contribute to our current understanding of rare variant lipid genetics. PMID- 26241471 TI - Karyotype Reorganization in the Hokou Gecko (Gekko hokouensis, Gekkonidae): The Process of Microchromosome Disappearance in Gekkota. AB - The Hokou gecko (Gekko hokouensis: Gekkonidae, Gekkota, Squamata) has the chromosome number 2n = 38, with no microchromosomes. For molecular cytogenetic characterization of the gekkotan karyotype, we constructed a cytogenetic map for G. hokouensis, which retains the ancestral karyotype of Gekkota, with 86 functional genes, and compared it with cytogenetic maps for four Toxicofera species that have many microchromosomes (Elaphe quadrivirgata, Varanus salvator macromaculatus, Leiolepis reevesii rubritaeniata, and Anolis carolinensis) and that for a lacertid species (Lacerta agilis) with only one pair of autosomal microchromosomes. Ten pairs of G. hokouensis chromosomes [GHO1, 2, 3, Z(4), 6, 7, 8, 13, 14, and 15] showed highly conserved linkage homology with macrochromosomes and/or macrochromosome arms of the four Toxicofera species and corresponded to eight L. agilis macrochromosomes (LAG). However, GHO5, GHO9, GHO10, GHO11, and LAG6 were composed of chromosome segments that have a homology with Toxicofera microchromosomes, and no homology was found in the chromosomes between G. hokouensis and L. agilis. These results suggest that repeated fusions of microchromosomes may have occurred independently in each lineage of Gekkota and Lacertidae, leading to the disappearance of microchromosomes and appearance of small-sized macrochromosomes. PMID- 26241472 TI - Identification of MicroRNAs in Meloidogyne incognita Using Deep Sequencing. AB - MicroRNAs play important regulatory roles in eukaryotic lineages. In this paper, we employed deep sequencing technology to sequence and identify microRNAs in M. incognita genome, which is one of the important plant parasitic nematodes. We identified 102 M. incognita microRNA genes, which can be grouped into 71 nonredundant miRNAs based on mature sequences. Among the 71 miRANs, 27 are known miRNAs and 44 are novel miRNAs. We identified seven miRNA clusters in M. incognita genome. Four of the seven clusters, miR-100/let-7, miR-71-1/miR-2a-1, miR-71-2/miR-2a-2 and miR-279/miR-2b are conserved in other species. We validated the expressions of 5 M. incognita microRNAs, including 3 known microRNAs (miR-71, miR-100b and let-7) and 2 novel microRNAs (NOVEL-1 and NOVEL-2), using RT-PCR. We can detect all 5 microRNAs. The expression levels of four microRNAs obtained using RT-PCR were consistent with those obtained by high-throughput sequencing except for those of let-7. We also examined how M. incognita miRNAs are conserved in four other nematodes species: C. elegans, A. suum, B. malayi and P. pacificus. We found that four microRNAs, miR-100, miR-92, miR-279 and miR-137, exist only in genomes of parasitic nematodes, but do not exist in the genomes of the free living nematode C. elegans. Our research created a unique resource for the research of plant parasitic nematodes. The candidate microRNAs could help elucidate the genomic structure, gene regulation, evolutionary processes, and developmental features of plant parasitic nematodes and nematode-plant interaction. PMID- 26241473 TI - High Sodium-Induced Oxidative Stress and Poor Anticrystallization Defense Aggravate Calcium Oxalate Crystal Formation in Rat Hyperoxaluric Kidneys. AB - Enhanced sodium excretion is associated with intrarenal oxidative stress. The present study evaluated whether oxidative stress caused by high sodium (HS) may be involved in calcium oxalate crystal formation. Male rats were fed a sodium depleted diet. Normal-sodium and HS diets were achieved by providing drinking water containing 0.3% and 3% NaCl, respectively. Rats were fed a sodium-depleted diet with 5% hydroxyl-L-proline (HP) for 7 and 42 days to induce hyperoxaluria and/or calcium oxalate deposition. Compared to normal sodium, HS slightly increased calcium excretion despite diuresis; however, the result did not reach statistical significance. HS did not affect the hyperoxaluria, hypocalciuria or supersaturation caused by HP; however, it increased calcium oxalate crystal deposition soon after 7 days of co-treatment. Massive calcium oxalate formation and calcium crystal excretion in HS+HP rats were seen after 42 days of treatment. HP-mediated hypocitraturia was further exacerbated by HS. Moreover, HS aggravated HP-induced renal injury and tubular damage via increased apoptosis and oxidative stress. Increased urinary malondialdehyde excretion, in situ superoxide production, NAD(P)H oxidase and xanthine oxidase expression and activity, and decreased antioxidant enzyme expression or activity in the HS+HP kidney indicated exaggerated oxidative stress. Interestingly, this redox imbalance was associated with reduced renal osteopontin and Tamm-Horsfall protein expression (via increased excretion) and sodium-dependent dicarboxylate cotransporter NaDC-1 upregulation. Collectively, our results demonstrate that a HS diet induces massive crystal formation in the hyperoxaluric kidney; this is not due to increased urinary calcium excretion but is related to oxidative injury and loss of anticrystallization defense. PMID- 26241474 TI - An Ideal PPAR Response Element Bound to and Activated by PPARalpha. AB - Peroxisome proliferator-activated receptor-alpha (PPARalpha), a nuclear receptor, plays an important role in the transcription of genes involved in fatty acid metabolism through heterodimerization with the retinoid x receptor (RXR). The consensus sequence of the PPAR response element (PPRE) is composed of two AGGTCA like sequences directionally aligned with a single nucleotide spacer. PPARalpha and RXR bind to the 5' and 3' hexad sequences, respectively. However, the precise sequence definition of the PPRE remains obscure, and thus, the consensus sequence currently available remains AGGTCANAGGTCA with unknown redundancy. The vague PPRE sequence definition poses an obstacle to understanding how PPARalpha regulates fatty acid metabolism. Here we show that, rather than the generally accepted 6-bp sequence, PPARalpha actually recognized a 12-bp DNA sequence, of which the preferred binding sequence was WAWVTRGGBBAH. Additionally, the optimized RXRalpha hexad binding sequence was RGKTYA. Thus, the optimal PPARalpha/RXRalpha heterodimer binding sequence was WAWVTRGGBBAHRGKTYA. The single nucleotide substitution, which reduces binding of RXRalpha to DNA, attenuated PPARalpha induced transcriptional activation, but this is not always true for PPARalpha. Using the definition of the PPRE sequence, novel PPREs were successfully identified. Taken altogether, the provided PPRE sequence definition contributes to the understanding of PPARalpha signaling by identifying PPARalpha direct target genes with functional PPARalpha response elements. PMID- 26241475 TI - Individual Organ Failure and Concomitant Risk of Mortality Differs According to the Type of Admission to ICU - A Retrospective Study of SOFA Score of 23,795 Patients. AB - INTRODUCTION: Organ dysfunction or failure after the first days of ICU treatment and subsequent mortality with respect to the type of intensive care unit (ICU) admission is poorly elucidated. Therefore we analyzed the association of ICU mortality and admission for medical (M), scheduled surgery (ScS) or unscheduled surgery (US) patients mirrored by the occurrence of organ dysfunction/failure (OD/OF) after the first 72h of ICU stay. METHODS: For this retrospective cohort study (23,795 patients; DIVI registry; German Interdisciplinary Association for Intensive Care Medicine (DIVI)) organ dysfunction or failure were derived from the Sequential Organ Failure Assessment (SOFA) score (excluding the Glasgow Coma Scale). SOFA scores were collected on admission to ICU and 72h later. For patients with a length of stay of at least five days, a multivariate analysis was performed for individual OD/OF on day three. RESULTS: M patients had the lowest prevalence of cardiovascular failure (M 31%; ScS 35%; US 38%), and the highest prevalence of respiratory (M 24%; ScS 13%; US 17%) and renal failure (M 10%; ScS 6%; US 7%). Risk of death was highest for M- and ScS-patients in those with respiratory failure (OR; M 2.4; ScS 2.4; US 1.4) and for surgical patients with renal failure (OR; M 1.7; ScS 2.7; US 2.4). CONCLUSION: The dynamic evolution of OD/OF within 72h after ICU admission and mortality differed between patients depending on their types of admission. This has to be considered to exclude a systematic bias during multi-center trials. PMID- 26241477 TI - A Potential Downside to Promoting the Economic Benefits of Palliative Medicine. PMID- 26241476 TI - Disruptions in Resting State Functional Connectivity and Cerebral Blood Flow in Mild Traumatic Brain Injury Patients. AB - Mild traumatic brain injury (mTBI) is often occult to conventional imaging techniques. However, there is growing evidence that mTBI patients who lack evidence of structural intracranial injury may develop post-concussive syndrome (PCS). We investigated longitudinal alterations in resting state functional connectivity (rs-FC) in brain networks in a population of 28 patients compared to 28 matched control participants. Rs-FC and cerebral blood flow (CBF) within the nodes of the Default Mode Network (DMN) and Task Positive Network (TPN) were assessed at three time points including acute, sub-acute, and chronic stages following mTBI. Participants received the Automated Neuropsychological Assessment Metrics (ANAM) to assess cognitive performance. Main findings indicate that despite normalized cognitive performance, chronic mTBI patients demonstrate increased rs-FC between the DMN and regions associated with the salience network (SN) and TPN compared to the control populations, as well as reduced strength of rs-FC within the DMN at the acute stage of injury. In addition, chronic mTBI patients demonstrate an imbalance in the ratio of CBF between nodes of the DMN and TPN. Furthermore, preliminary exploratory analysis suggests that compared to those without chronic PCS, patients with chronic PCS reveal an imbalance in the ratio of CBF between the DMN nodes and TPN nodes across multiple stages of recovery. Findings suggest that the altered network perfusion with the associated changes in rs-FC may be a possible predictor of which mTBI patients will develop chronic PCS. PMID- 26241478 TI - Irisin Induces Angiogenesis in Human Umbilical Vein Endothelial Cells In Vitro and in Zebrafish Embryos In Vivo via Activation of the ERK Signaling Pathway. AB - As a link between exercise and metabolism, irisin is assumed to be involved in increased total body energy expenditure, reduced body weight, and increased insulin sensitivity. Although our recent evidence supported the contribution of irisin to vascular endothelial cell (ECs) proliferation and apoptosis, further research of irisin involvement in the angiogenesis of ECs was not conclusive. In the current study, it was found that irisin promoted Human Umbilical Vein Endothelial Cell (HUVEC) angiogenesis via increasing migration and tube formation, and attenuated chemically-induced intersegmental vessel (ISV) angiogenic impairment in transgenic TG (fli1: GFP) zebrafish. It was further demonstrated that expression of matrix metalloproteinase (MMP) 2 and 9 were also up-regulated in endothelial cells. We also found that irisin activated extracellular signal-related kinase (ERK) signaling pathways. Inhibition of ERK signaling by using U0126 decreased the pro-migration and pro-angiogenic effect of irisin on HUVEC. Also, U0126 inhibited the elevated expression of MMP-2 and MMP-9 when they were treated with irisin. In summary, these findings provided direct evidence that irisin may play a pivotal role in maintaining endothelium homeostasis by promoting endothelial cell angiogenesis via the ERK signaling pathway. PMID- 26241479 TI - Increasing Neonatal Mortality among Palestine Refugees in the Gaza Strip. AB - BACKGROUND: The United Nations Relief and Works Agency for Palestine refugees in the Near East (UNRWA) has periodically estimated infant mortality rates among Palestine refugees in Gaza. These surveys have recorded a decline from 127 per 1000 live births in 1960 to 20.2 in 2008. METHODS: We used the same preceding birth technique as in previous surveys. All multiparous mothers who came to the 22 UNRWA health centres to register their last-born child for immunization were asked if their preceding child was alive or dead. We based our target sample size on the infant mortality rate in 2008 and included 3128 mothers from August until October 2013. We used multiple logistic regression analyses to identify predictors of infant mortality. FINDINGS: Infant mortality in 2013 was 22.4 per 1000 live births compared with 20.2 in 2008 (p = 0.61), and this change reflected a statistically significant increase in neonatal mortality (from 12.0 to 20.3 per 1000 live births, p = 0.01). The main causes of the 65 infant deaths were preterm birth (n = 25, 39%), congenital anomalies (n = 19, 29%), and infections (n = 12, 19%). Risk factors for infant death were preterm birth (OR 9.88, 3.98-24.85), consanguinity (2.41, 1.35-4.30) and high-risk pregnancies (3.09, 1.46-6.53). CONCLUSION: For the first time in five decades, mortality rates have increased among Palestine refugee newborns in Gaza. The possible causes of this trend may include inadequate neonatal care. We will estimate infant and neonatal mortality rates again in 2015 to see if this trend continues and, if so, to assess how it can be reversed. PMID- 26241480 TI - A Cone-Beam Computed Tomographic Study on Mandibular First Molars in a Chinese Subpopulation. AB - The purpose of this study was to conduct a cone-beam computed tomographic (CBCT) investigation on the root and canal configuration of the mandibular first molars, especially the morphology of the disto-lingual (DL) root, in a Chinese subpopulation. A total of 910 CBCT images of the mandibular first molars were collected from 455 patients who underwent CBCT examinations as a preoperative assessment for implants or orthodontic treatment. The following information was analyzed and evaluated: tooth position, gender, root and root canal number per tooth, root canal type of the mesial root(s) and distal root(s), angle of the DL root canal curvature, distance between two distal canal orifices in the teeth with DL root, and angle of disto-buccal canal orifice-disto-lingual canal orifice mesio-lingual canal orifice (DB-DL-ML). Most of the mandibular first molars (64.9%, n = 591) had two roots with three root canals, and most of the mesial root canals (87.7%, n = 798) were type VI. The prevalence of the DL root was 22.1% (n = 201). The right side had a higher prevalence of DL root than the left side (p<0.05). Additionally, the curvature of the DL root canal were greater in the bucco-lingual (BL) orientation (30.10 degrees +/-14.02 degrees ) than in the mesio-distal (MD) orientation (14.03 degrees +/- 8.56 degrees ) (p<0.05). Overall there was a high prevalence of DL root in the mandibular first molars, and most of the DL roots were curved in different degrees. This study provided detailed information about the root canal morphology of the mandibular first molars in a Chinese subpopulation. PMID- 26241481 TI - The Nucleosome Acidic Patch Regulates the H2B K123 Monoubiquitylation Cascade and Transcription Elongation in Saccharomyces cerevisiae. AB - Eukaryotes regulate gene expression and other nuclear processes through the posttranslational modification of histones. In S. cerevisiae, the mono ubiquitylation of histone H2B on lysine 123 (H2B K123ub) affects nucleosome stability, broadly influences gene expression and other DNA-templated processes, and is a prerequisite for additional conserved histone modifications that are associated with active transcription, namely the methylation of lysine residues in H3. While the enzymes that promote these chromatin marks are known, regions of the nucleosome required for the recruitment of these enzymes are undefined. To identify histone residues required for H2B K123ub, we exploited a functional interaction between the ubiquitin-protein ligase, Rkr1/Ltn1, and H2B K123ub in S. cerevisiae. Specifically, we performed a synthetic lethal screen with cells lacking RKR1 and a comprehensive library of H2A and H2B residue substitutions, and identified H2A residues that are required for H2B K123ub. Many of these residues map to the nucleosome acidic patch. The substitutions in the acidic patch confer varying histone modification defects downstream of H2B K123ub, indicating that this region contributes differentially to multiple histone modifications. Interestingly, substitutions in the acidic patch result in decreased recruitment of H2B K123ub machinery to active genes and defects in transcription elongation and termination. Together, our findings reveal a role for the nucleosome acidic patch in recruitment of histone modification machinery and maintenance of transcriptional integrity. PMID- 26241482 TI - Modulation and Apoptosis of Neutrophil Granulocytes by Extracorporeal Photopheresis in the Treatment of Chronic Graft-Versus-Host Disease. AB - Chronic graft-versus-host disease (cGVHD) is a common side effect of allogeneic stem cell transplantation and a major cause of morbidity and mortality in affected patients. Especially skin, eyes and oral mucosa are affected. This can lead to pain and functional impairment. Extracorporeal photopheresis (ECP) is an effective immunomodulatory therapy with minimal side effects but its mode of action is still largely unknown. The objective of the present study was to examine the effects of ECP on neutrophil granulocytes in patients with cGVHD. Analysis of leukocytes from cGVHD patients obtained from the ECP device during treatment showed that neutrophil granulocytes account for the majority of cells treated during ECP. Neutrophils from healthy donors treated in vitro with 8 methoxypsoralen and UVA light as well as neutrophils from buffy coats of patients with cGVHD treated by ECP showed increased apoptosis and decreased half-life. In remaining non-apoptotic cells chemoirradiation resulted in loss of activation markers and reduced effector functions. This was accompanied by an increase in extracellular arginase-1 activity. Additional comparison of neutrophils isolated from blood of cGVHD patients before and 24h after ECP revealed a decreased half life and reduction of effector functions of post-ECP neutrophils ex vivo. These observations strongly suggest that ECP induces both apoptosis and physiological changes in neutrophils and that these changes also take place in vivo. This study is the first to show that ECP modulates apoptosis and inflammatory activity in neutrophil granulocytes, indicating that neutrophils may significantly contribute to the overall immunomodulatory effects attributed to this treatment. PMID- 26241485 TI - Soluble Tetraaminotriptycene Precursors. AB - An efficient route to soluble triptycene tetraamines, shape-persistent molecules containing two ortho-phenylenediamine motifs, is reported. These tetraamines are stable, prepared in good yields, easily purified by column chromatography, and can be readily condensed to give a range of imidazole and pyrazine derivatives. PMID- 26241483 TI - Differential Effects of Dabigatran and Warfarin on Bone Volume and Structure in Rats with Normal Renal Function. AB - BACKGROUND: Warfarin, a widely used anticoagulant, is a vitamin K antagonist impairing the activity of vitamin K-dependent Bone Gla Protein (BGP or Osteocalcin) and Matrix Gla Protein (MGP). Because dabigatran, a new anticoagulant, has no effect on vitamin K metabolism, the aim of this study was to compare the impact of warfarin and dabigatran administration on bone structure and vascular calcification. METHODS: Rats with normal renal function received for 6 weeks warfarin, dabigatran or placebo. Bone was evaluated immuno histochemically and hystomorphometrically after double labelling with declomycin and calcein. Aorta and iliac arteries were examined histologically. RESULTS: Histomorphometric analysis of femur and vertebrae showed significantly decreased bone volume and increased trabecular separation in rats treated with warfarin. Vertebra analysis showed that the trabecular number was higher in dabigatran treated rats. Osteoblast activity and resorption parameters were similar among groups, except for maximum erosion depth, which was higher in warfarin treated rats, suggesting a higher osteoclastic activity. Therefore, warfarin treatment was also associated with higher bone formation rate/bone surface and activation frequency. Warfarin treatment may cause an increased bone turnover characterized by increased remodelling cycles, with stronger osteoclast activity compared to the other groups. There were no differences among experimental groups in calcium deposition either in aortic or iliac arteries. CONCLUSIONS: These findings suggest for the first time that dabigatran has a better bone safety profile than warfarin, as warfarin treatment affects bone by reducing trabecular size and structure, increasing turnover and reducing mineralization. These differences could potentially result in a lower incidence of fractures in dabigatran treated patients. PMID- 26241484 TI - Impact of Community Mass Treatment with Azithromycin for Trachoma Elimination on the Prevalence of Yaws. AB - BACKGROUND: Community mass treatment with 30 mg/kg azithromycin is central to the new WHO strategy for eradicating yaws. Both yaws and trachoma--which is earmarked for elimination by 2020 using a strategy that includes mass treatment with 20 mg/kg azithromycin--are endemic in the Pacific, raising the possibility of an integrated approach to disease control. Community mass treatment with azithromycin for trachoma elimination was conducted in the Solomon Islands in 2014. METHODS: We conducted a study to assess the impact of mass treatment with 20 mg/kg azithromycin on yaws. We examined children aged 5-14 years and took blood and lesion samples for yaws diagnosis. RESULTS: We recruited 897 children, 6 months after mass treatment. There were no cases of active yaws. Serological evidence of current infection was found in 3.6% (95% CI= 2.5-5.0%). This differed significantly between individuals who had and had not received azithromycin (2.8% vs 6.5%, p=0.015); the prevalence of positive serology in 5-14 year-olds had been 21.7% (95% CI=14.6%-30.9%) 6 months prior to mass treatment. Not receiving azithromycin was associated with an odds of 3.9 for infection (p=0.001). National figures showed a 57% reduction in reported cases of yaws following mass treatment. DISCUSSION: Following a single round of treatment we did not identify any cases of active yaws in a previously endemic population. We found a significant reduction in latent infection. Our data support expansion of the WHO eradication strategy and suggest an integrated approach to the control of yaws and trachoma in the Pacific may be viable. PMID- 26241486 TI - Common oxytocin receptor gene variant interacts with rejection sensitivity to influence cortisol reactivity during negative evaluation. AB - The study tested the hypothesis that variation in the oxytocin receptor gene (OXTR rs53576) and self-report of rejection sensitivity are associated with adrenocortical reactivity to social stress. Participants (N=94; 36.17% male; Mage=20.18yrs; 62.8% Caucasian) completed a writing task on a salient problem in society, provided self-report via questionnaire of rejection sensitivity, and were then informed that a committee of peers would evaluate their written comments. Participants received either scripted praise or criticism as a way to induce social evaluative threat. Saliva was collected before and after the stress task and assayed for cortisol. Results revealed that cortisol levels increased in participants with moderate levels of social rejection sensitivity-inferred by rs53576 genotype and reported rejection sensitivity-while cortisol levels decreased in participants with high and low levels of social rejection sensitivity. Our findings suggest a curvilinear relationship between social rejection sensitivity and cortisol reactivity in the context of social rejection, warranting further consideration in future studies. PMID- 26241487 TI - Audio-based detection and evaluation of eating behavior using the smartwatch platform. AB - In recent years, smartwatches have emerged as a viable platform for a variety of medical and health-related applications. In addition to the benefits of a stable hardware platform, these devices have a significant advantage over other wrist worn devices, in that user acceptance of watches is higher than other custom hardware solutions. In this paper, we describe signal-processing techniques for identification of chews and swallows using a smartwatch device's built-in microphone. Moreover, we conduct a survey to evaluate the potential of the smartwatch as a platform for monitoring nutrition. The focus of this paper is to analyze the overall applicability of a smartwatch-based system for food-intake monitoring. Evaluation results confirm the efficacy of our technique; classification was performed between apple and potato chip bites, water swallows, talking, and ambient noise, with an F-measure of 94.5% based on 250 collected samples. PMID- 26241488 TI - Enhanced tocopherol levels during early germination events in Chamaerops humilis var. humilis seeds. AB - Most angiosperms accumulate vitamin E in the form of tocopherols in seeds, exerting a protective antioxidant role. However, several palm trees principally accumulate tocotrienols, rather than tocopherols, in seeds, as it occurs in other monocots. To unravel the protective role of either tocopherols or tocotrienols against lipid peroxidation during seed germination in Chamaerops humilis var. humilis; seed viability, natural and induced germination capacity, seed water content, malondialdehyde levels (as an indicator of the extent of lipid peroxidation) and vitamin E levels (including both tocopherols and tocotrienols) were examined at various germination phases in a simulated, natural seed bank. At the very early stages of germination (operculum removal), malondialdehyde levels increased 2.8-fold, to decrease later up to 74%, thus indicating a transient lipid peroxidation at early stages of germination. Tocopherol levels were absent in quiescent seeds and did not increase during operculum removal, but increased later presumably dampening malondialdehyde accumulation. Thereafter, tocopherols continued increasing, while lipid peroxidation levels decreased. By contrast, tocotrienols levels remained constant or even decreased as germination progressed, showing no correlation with lipid peroxidation levels. We hypothesize that despite their high tocotrienol content, seeds synthesize tocopherols during germination to protect lipids from peroxidation events. PMID- 26241489 TI - Precursors and metabolic pathway for guaiacol production by Alicyclobacillus acidoterrestris. AB - Alicyclobacillus acidoterrestris has recently received much attention due to its implication in the spoilage of pasteurized fruit juices, which was manifested by the production of guaiacol. Vanillic acid and vanillin have been accepted as the biochemical precursors of guaiacol in fruit juices. The purpose of this study was to try to find other precursors and elucidate details about the conversion of vanillic acid and vanillin to guaiacol by A. acidoterrestris. Four potential substrates including ferulic acid, catechol, phenylalanine and tyrosine were analyzed, but they could not be metabolized to guaiacol by all the thirty A. acidoterrestris strains tested. Resting cell studies and enzyme assays demonstrated that vanillin was reduced to vanillyl alcohol by NADPH-dependent vanillin reductase and oxidized to vanillic acid by NAD(P)(+)-dependent vanillin dehydrogenases in A. acidoterrestris DSM 3923. Vanillic acid underwent a nonoxidative decarboxylation to guaiacol. The reversible vanillic acid decarboxylase involved was oxygen insensitive and pyridine nucleotide independent. PMID- 26241490 TI - Production and partial characterization of exopolysaccharides produced by two Lactobacillus suebicus strains isolated from cider. AB - Many lactic acid bacteria synthesize extracellular polysaccharides (exopolysaccharides, EPSs) with a large variation in structure and potential functional properties. Although EPS production can produce detrimental effects in alcoholic beverages, these polymers play an important role in the rheological behavior and texture of fermented products. In this work, EPS production by two Lactobacillus suebicus strains, which were isolated from ropy ciders, was examined in a semidefined medium. The existence of priming glycosyltransferase encoding genes was detected by PCR. In addition, the preliminary characterization of the polymers was undertaken. Molecular masses were determined by size exclusion chromatography revealing the presence of two peaks, corresponding to polymers of high- and low-molecular-weight in all fractions. The composition of the EPS fractions was analyzed by gas chromatography-mass spectrometry after acid hydrolysis, revealing that they contained glucose, galactose, N-acetylglucosamine and phosphate, although in different ratios, suggesting that a mixture of polysaccharides is being synthesized. We also examined the influence of the sugar source (glucose, ribose, xylose, or arabinose) and pH conditions on growth and EPS production. PMID- 26241491 TI - Diversity and dynamics of antibiotic-resistant bacteria in cheese as determined by PCR denaturing gradient gel electrophoresis. AB - This work reports the composition and succession of tetracycline- and erythromycin-resistant bacterial communities in a model cheese, monitored by polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE). Bacterial 16S rRNA genes were examined using this technique to detect structural changes in the cheese microbiota over manufacturing and ripening. Total bacterial genomic DNA, used as a template, was extracted from cultivable bacteria grown without and with tetracycline or erythromycin (both at 25 MUg ml(-1)) on a non selective medium used for enumeration of total and viable cells (Plate Count agar with Milk; PCA-M), and from those grown on selective and/or differential agar media used for counting various bacterial groups; i.e., lactic acid bacteria (de Man, Rogosa and Sharpe agar; MRSA), micrococci and staphylococci (Baird-Parker agar; BPA), and enterobacteria (Violet Red Bile Glucose agar; VRBGA). Large numbers of tetracycline- and erythromycin-resistant bacteria were detected in cheese samples at all stages of ripening. Counts of antibiotic-resistant bacteria varied widely depending on the microbial group and the point of sampling. In general, resistant bacteria were 0.5-1.0 Log10 units fewer in number than the corresponding susceptible bacteria. The PCR-DGGE profiles obtained with DNA isolated from the plates for total bacteria and the different bacterial groups suggested Escherichia coli, Lactococcus lactis, Enterococcus faecalis and Staphylococcus spp. as the microbial types resistant to both antibiotics tested. This study shows the suitability of the PCR-DGGE technique for rapidly identifying and tracking antibiotic resistant populations in cheese and, by extension, in other foods. PMID- 26241492 TI - Down-regulation of superoxide dismutase 1 by PMA is involved in cell fate determination and mediated via protein kinase D2 in myeloid leukemia cells. AB - Myeloid leukemia cells maintain a high intracellular ROS level and use redox signals for survival. The metabolism of ROS also affects cell fate, including cell death and differentiation. Superoxide dismutases (SODs) are major antioxidant enzymes that have high levels of expression in myeloid leukemia cells. However, the role of SODs in the regulation of myeloid leukemia cells' biological function is still unclear. To investigate the function of SODs in myeloid leukemia cell death and differentiation, we used myeloid leukemia cell lines K562, MEG-01, TF-1, and HEL cells for this study. We found that PMA-induced megakaryocytic differentiation in myeloid leukemia cells is accompanied by cell death and SOD1 down-regulation, while SOD2 expression is not affected. The role of SOD1 is verified when ATN-224, a SOD1 specific inhibitor, inhibits cell proliferation and promotes cell death in myeloid leukemia cells without PMA treatment. Moreover, inhibition or silencing of SODs further increases cell death and decreases polyploidization induced by PMA while they were partially reversed by SOD1 overexpression. Thus, SOD1 expression is required for myeloid leukemia cell fate determination. In addition, the knockdown of PKD2 reduces cell death and promotes polyploidization induced by PMA. PMA/PKD2-mediated necrosis via PARP cleavage involves both SOD1-dependent and -independent pathways. Finally, ATN-224 enhanced the inhibition of cell proliferation by Ara-C. Taken together, the results demonstrate that SOD1 regulates cell death and differentiation in myeloid leukemia cells. ATN-224 may be beneficial for myeloid leukemia therapy. PMID- 26241493 TI - A new spermidine macrocyclic alkaloid isolated from Gymnosporia arenicola leaf. AB - The isolation and structural elucidation of a macrocyclic alkaloid, characterized by the presence of a 13-membered macrolactam ring containing a spermidine unit N linked to a benzoyl group is hereby reported. The structure of this previously unknown spermidine alkaloid isolated from Gymnosporia arenicola (Celastraceae) leaves has been elucidated by (1)H and (13)C NMR spectroscopy (including bidimensional analysis) and further characterized by high-resolution mass spectrometry and polarimetry. A route for the biosynthesis of this new bioactive macrocycle is proposed and the cytotoxicity of the compound was evaluated against two ATCC cell lines - one normal-derived (MCF10A) and one cancer-derived cell line (MCF7) - using the MTT assay. The alkaloid revealed to be non-cytotoxic against both cell lines. The IC50 values from the cells were also determined. PMID- 26241494 TI - Pterocarpans and triterpenoids from Gueldenstaedtia verna. AB - Two new pterocarpan glycosides (1-2), five new triterpenoids (3-7), and 13 known analogues (14-20) were isolated from the whole plants of Gueldenstaedtia verna. These new compounds (1-7) were elucidated by extensive spectroscopic techniques including 1D ((1)H and (13)C) and 2D NMR experiments (COSY, HSQC, HMBC and NOESY), HR-ESI-MS and chemical methods. The absolute configuration of 1 was established by the optical rotation, the comparison of experimental and calculated electronic circular dichroism (ECD) spectra and an X-ray diffraction analysis. All the isolates were evaluated for their cytotoxicities against four human cancer cell lines and inhibitory activities on LPS-induced NO production in RAW264.7 cells. PMID- 26241495 TI - Paeoveitols A-E from Paeonia veitchii. AB - Paeoveitols A-E (1-5), involving three monoterpenes and two benzofuran constituents, were isolated from Paeonia veitchii. Their structures were determined based on extensive spectral analyses (IR, UV, MS, 1D and 2D NMR), and the absolute configuration of compound 1 was confirmed by single-crystal X-ray diffraction. By the agitating human melatonin receptor 1 (MT1) assay on HEK293 cell line in vitro, compound 4 showed weak activity with the agitation rate of 22.52% at the concentration of 1.79 mM. PMID- 26241496 TI - Virtual World Currency Value Fluctuation Prediction System Based on User Sentiment Analysis. AB - In this paper, we present a method for predicting the value of virtual currencies used in virtual gaming environments that support multiple users, such as massively multiplayer online role-playing games (MMORPGs). Predicting virtual currency values in a virtual gaming environment has rarely been explored; it is difficult to apply real-world methods for predicting fluctuating currency values or shares to the virtual gaming world on account of differences in domains between the two worlds. To address this issue, we herein predict virtual currency value fluctuations by collecting user opinion data from a virtual community and analyzing user sentiments or emotions from the opinion data. The proposed method is straightforward and applicable to predicting virtual currencies as well as to gaming environments, including MMORPGs. We test the proposed method using large scale MMORPGs and demonstrate that virtual currencies can be effectively and efficiently predicted with it. PMID- 26241497 TI - Exploiting shape, cellular-hitchhiking and antibodies to target nanoparticles to lung endothelium: Synergy between physical, chemical and biological approaches. AB - Delivery of nanoparticles to target specific tissues remains a challenge due to their rapid removal from circulation by the reticuloendothelial (RES) system. The majority of past research has addressed this issue via chemical modification of nanoparticles in the form of hydrophilic coatings which reduces adsorption of opsonins that trigger RES clearance. Recently, additional approaches have been developed which leverage the natural mechanisms our own circulatory cells use to avoid immune system clearance. One such method, called 'cellular-hitchhiking', accomplishes this by non-covalent attachment of nanoparticles to the surface of red blood cells. Concomitantly, approaches that make use of modified nanoparticle geometry, that is rod-shaped nanoparticles, have also been used to avoid immune system clearance and improve tissue targeting. Here, we systematically investigate three approaches and their combinations to improve lung targeting while avoiding RES clearance. Our results show that an approach that combines targeting antibodies (anti-ICAM-1), rod-shaped particles and cellular hitchhiking into one delivery system effectively lowered the accumulated concentration of nanoparticles in RES organs by over two-fold as compared to any other combination or single method, while simultaneously increasing the concentration of accumulated nanoparticles in the lungs from 1.2 to 8.9 fold. The strategy described here offers a novel means that combine chemical, physical and biological approaches to maximize tissue targeting. PMID- 26241498 TI - Mechanoreception at the cell membrane: More than the integrins. AB - A cell receives mechanical cues from its surrounding microenvironment and transduces this mechanical information into a biochemical signal within the cell, ultimately resulting in physiological change. Several molecules within the plasma membrane have been identified that are capable of receiving and translating a mechanical signal. Although integrins are most often discussed as the cell's primary method of mechanoreception at the cell membrane, several non-integrin mechanoreceptors have emerged over the last decade. Specifically, multiple G protein coupled receptors, the glycocalyx, ion channels, lipid rafts and receptor tyrosine kinases have been found to translate mechanical stimuli from the environment into cellular change. This review will discuss these non-integrin mechanoreceptors associated with the plasma membrane, and their impact on cell physiology. PMID- 26241499 TI - Identification of rice Os4BGlu13 as a beta-glucosidase which hydrolyzes gibberellin A4 1-O-beta-d-glucosyl ester, in addition to tuberonic acid glucoside and salicylic acid derivative glucosides. AB - Gibberellin 1-O-beta-d-glucose ester hydrolysis activity has been detected in rice seedling extracts, but no enzyme responsible for this activity has ever been purified and identified. Therefore, gibberellin A4 glucosyl ester (GA4-GE) beta-d glucosidase activity was purified from ten-day rice seedling stems and leaves. The family 1 glycoside hydrolase Os4BGlu13 was identified in the final purification fraction. The Os4BGlu13 cDNA was amplified from rice seedlings and expressed as an N-terminal thioredoxin-tagged fusion protein in Escherichia coli. The purified recombinant Os4BGlu13 protein (rOs4BGlu13) had an optimum pH of 4.5, for hydrolysis of p-nitrophenyl beta-d-glucopyranoside (pNPGlc), which was the best substrate identified, with a kcat/Km of 637 mM(-1) s(-1). rOs4BGlu13 hydrolyzed helicin best among natural glycosides tested (kcat/Km of 74.4 mM(-1) s(-1)). Os4BGlu13 was previously designated tuberonic acid glucoside (TAG) beta glucosidase (TAGG), and here the kcat/Km of rOsBGlu13 for TAG was 6.68 mM(-1) s( 1), while that for GA4-GE was 3.63 mM(-1) s(-1) and for salicylic acid glucoside (SAG) is 0.88 mM(-1) s(-1). rOs4BGlu13 also hydrolyzed oligosaccharides, with preference for short beta-(1 -> 3)-linked over beta-(1 -> 4)-linked glucooligosaccharides. The enzymatic data suggests that Os4BGlu13 may contribute to TAG, SAG, oligosaccharide and GA4-GE hydrolysis in the rice plant, although helicin or a similar compound may be its primary target. PMID- 26241500 TI - New developments in allergen immunotherapy. AB - PURPOSE OF REVIEW: Allergic rhinitis, conjunctivitis, and asthma impact quality of life and cost billions of dollars in lost wages, productivity, and medical expenditures. Allergen immunotherapy is the only therapy that alters the allergen immune response, resulting in fewer symptoms upon natural exposure. This review summarizes recent immunotherapy developments. RECENT FINDINGS: Subcutaneous immunotherapy (SCIT) remains a disease modifying treatment for allergic rhinoconjunctivitis and asthma with rare complications of therapy. Recent evidence suggests that SCIT may be effective in select cases of atopic dermatitis, particularly for patients with dust mite sensitivity. Sublingual immunotherapy (SLIT) tablets are now commercially available for grass and ragweed allergy and appear to have a superior safety profile to SCIT with similar long term effectiveness, because as with SCIT, symptom improvement persists after the SLIT course is completed. SLIT tablets are administered daily at home (after initial supervised dosing) and may be used shortly before and during the target pollen seasons in a precoseasonal fashion (instead of perennial dosing). Research continues into experimental approaches using oral food allergen immunotherapy (OIT) to modify the natural history of food allergies. Although a proportion of patients in OIT trials experience sustained unresponsiveness, many do not and current recommendations limit the use of OIT to research protocols. SUMMARY: Patients have new well tolerated and effective options for more convenient treatment of asthma and allergic rhinoconjunctivitis associated with grass and ragweed allergy. SCIT remains effective for polysensitized patients and may be an option for some patients with atopic dermatitis. Research continues into novel food allergy treatments. PMID- 26241501 TI - The key roles of complement and tissue factor in Escherichia coli-induced coagulation in human whole blood. AB - The complement system and the Toll-like (TLR) co-receptor CD14 play important roles in innate immunity and sepsis. Tissue factor (TF) is a key initiating component in intravascular coagulation in sepsis, and long pentraxin 3 (PTX3) enhances the lipopolysaccharide (LPS)-induced transcription of TF. The aim of this study was to study the mechanism by which complement and CD14 affects LPS- and Escherichia coli (E. coli)-induced coagulation in human blood. Fresh whole blood was anti-coagulated with lepirudin, and incubated with ultra-purified LPS (100 ng/ml) or with E. coli (1 * 10(7) /ml). Inhibitors and controls included the C3 blocking peptide compstatin, an anti-CD14 F(ab')2 antibody and a control F(ab')2 . TF mRNA was measured using quantitative polymerase chain reaction (qPCR) and monocyte TF surface expression by flow cytometry. TF functional activity in plasma microparticles was measured using an amidolytic assay. Prothrombin fragment F 1+2 (PTF1.2) and PTX3 were measured by enzyme-linked immunosorbent assay (ELISA). The effect of TF was examined using an anti-TF blocking antibody. E. coli increased plasma PTF1.2 and PTX3 levels markedly. This increase was reduced by 84->99% with compstatin, 55-97% with anti-CD14 and > 99% with combined inhibition (P < 0.05 for all). The combined inhibition was significantly (P < 0.05) more efficient than compstatin and anti-CD14 alone. The LPS- and E. coli-induced TF mRNA levels, monocyte TF surface expression and TF functional activity were reduced by > 99% (P < 0.05) with combined C3 and CD14 inhibition. LPS- and E. coli-induced PTF1.2 was reduced by 76-81% (P < 0.05) with anti-TF antibody. LPS and E. coli activated the coagulation system by a complement- and CD14-dependent up-regulation of TF, leading subsequently to prothrombin activation. PMID- 26241502 TI - The methylaspartate cycle in haloarchaea and its possible role in carbon metabolism. AB - Haloarchaea (class Halobacteria) live in extremely halophilic conditions and evolved many unique metabolic features, which help them to adapt to their environment. The methylaspartate cycle, an anaplerotic acetate assimilation pathway recently proposed for Haloarcula marismortui, is one of these special adaptations. In this cycle, acetyl-CoA is oxidized to glyoxylate via methylaspartate as a characteristic intermediate. The following glyoxylate condensation with another molecule of acetyl-CoA yields malate, a starting substrate for anabolism. The proposal of the functioning of the cycle was based mainly on in vitro data, leaving several open questions concerning the enzymology involved and the occurrence of the cycle in halophilic archaea. Using gene deletion mutants of H. hispanica, enzyme assays and metabolite analysis, we now close these gaps by unambiguous identification of the genes encoding all characteristic enzymes of the cycle. Based on these results, we were able to perform a solid study of the distribution of the methylaspartate cycle and the alternative acetate assimilation strategy, the glyoxylate cycle, among haloarchaea. We found that both of these cycles are evenly distributed in haloarchaea. Interestingly, 83% of the species using the methylaspartate cycle possess also the genes for polyhydroxyalkanoate biosynthesis, whereas only 34% of the species with the glyoxylate cycle are capable to synthesize this storage compound. This finding suggests that the methylaspartate cycle is shaped for polyhydroxyalkanoate utilization during carbon starvation, whereas the glyoxylate cycle is probably adapted for growth on substrates metabolized via acetyl-CoA. PMID- 26241503 TI - Light microenvironment and single-cell gradients of carbon fixation in tissues of symbiont-bearing corals. AB - Recent coral optics studies have revealed the presence of steep light gradients and optical microniches in tissues of symbiont-bearing corals. Yet, it is unknown whether such resource stratification allows for physiological differences of Symbiodinium within coral tissues. Using a combination of stable isotope labelling and nanoscale secondary ion mass spectrometry, we investigated in hospite carbon fixation of individual Symbiodinium as a function of the local O2 and light microenvironment within the coral host determined with microsensors. We found that net carbon fixation rates of individual Symbiodinium cells differed on average about sixfold between upper and lower tissue layers of single coral polyps, whereas the light and O2 microenvironments differed ~15- and 2.5-fold, respectively, indicating differences in light utilisation efficiency along the light microgradient within the coral tissue. Our study suggests that the structure of coral tissues might be conceptually similar to photosynthetic biofilms, where steep physico-chemical gradients define form and function of the local microbial community. PMID- 26241504 TI - A natural odor attraction between lactic acid bacteria and the nematode Caenorhabditis elegans. AB - Animal predators can track prey using their keen sense of smell. The bacteriovorous nematode Caenorhabditis elegans employs sensitive olfactory sensory neurons that express vertebrate-like odor receptors to locate bacteria. C. elegans displays odor-related behaviors such as attraction, aversion and adaptation, but the ecological significance of these behaviors is not known. Using a combination of food microbiology and genetics, we elucidate a possible predator-prey relationship between C. elegans and lactic acid bacteria (LAB) in rotting citrus fruit. LAB produces the volatile odor diacetyl as an oxidized by product of fermentation in the presence of citrate. We show that C. elegans is attracted to LAB when grown on citrate media or Citrus medica L, commonly known as yuzu, a citrus fruit native to East Asia, and this attraction is mediated by the diacetyl odor receptor, ODR-10. We isolated a wild LAB strain and a wild C. elegans-related nematode from rotten yuzu, and demonstrate that the wild nematode was attracted to the diacetyl produced by LAB. These results not only identify an ecological function for a C. elegans olfactory behavior, but contribute to the growing understanding of ecological relationships between the microbial and metazoan worlds. PMID- 26241505 TI - Competitive strategies differentiate closely related species of marine actinobacteria. AB - Although competition, niche partitioning, and spatial isolation have been used to describe the ecology and evolution of macro-organisms, it is less clear to what extent these principles account for the extraordinary levels of bacterial diversity observed in nature. Ecological interactions among bacteria are particularly challenging to address due to methodological limitations and uncertainties over how to recognize fundamental units of diversity and link them to the functional traits and evolutionary processes that led to their divergence. Here we show that two closely related marine actinomycete species can be differentiated based on competitive strategies. Using a direct challenge assay to investigate inhibitory interactions with members of the bacterial community, we observed a temporal difference in the onset of inhibition. The majority of inhibitory activity exhibited by Salinispora arenicola occurred early in its growth cycle and was linked to antibiotic production. In contrast, most inhibition by Salinispora tropica occurred later in the growth cycle and was more commonly linked to nutrient depletion or other sources. Comparative genomics support these differences, with S. arenicola containing nearly twice the number of secondary metabolite biosynthetic gene clusters as S. tropica, indicating a greater potential for secondary metabolite production. In contrast, S. tropica is enriched in gene clusters associated with the acquisition of growth-limiting nutrients such as iron. Coupled with differences in growth rates, the results reveal that S. arenicola uses interference competition at the expense of growth, whereas S. tropica preferentially employs a strategy of exploitation competition. The results support the ecological divergence of two co-occurring and closely related species of marine bacteria by providing evidence they have evolved fundamentally different strategies to compete in marine sediments. PMID- 26241506 TI - Bioinformatics of antimicrobial resistance in the age of molecular epidemiology. AB - Antimicrobial resistance is a global health challenge and has an evolutionary trajectory ranging from proto-resistance in the environment to untreatable clinical pathogens. Resistance is not static, as pathogenic strains can move among patient populations and individual resistance genes can move among pathogens. Effective treatment of resistant infections, antimicrobial stewardship, and new drug discovery increasingly rely upon genotype information, powered by decreasing costs of DNA sequencing. These new approaches will require advances in microbial informatics, particularly in development of reference databases of molecular determinants such as our Comprehensive Antibiotic Resistance Database and clinical metadata, new algorithms for prediction of resistome and resistance phenotype from genotype, and new protocols for global collection and sharing of high-throughput molecular epidemiology data. PMID- 26241507 TI - Antibiotics and the developing infant gut microbiota and resistome. AB - The microbial communities colonizing the human gut are tremendously diverse and highly personal. The composition and function of the microbiota play important roles in human health and disease, and considerable research has focused on understanding the ecological forces shaping these communities. While it is clear that factors such as diet, genotype of the host, and environment influence the adult gut microbiota community composition, recent work has emphasized the importance of early-life assembly dynamics in both the immediate and long-term personalized nature of the gut microbiota. While the mature adult gut microbiota is believed to be relatively stable, the developing infant gut microbiota (IGM) is highly dynamic and prone to disruption by external factors, including antibiotic exposure. Studies have revealed both transient and persistent alterations to the adult gut microbiota community resulting from antibiotic treatment later in life. As antibiotics are routinely prescribed at a greater rate in the first years of life, the impact of these interventions on the developing IGM is emerging as a key research priority. In addition to understanding the impact of these disruptions on the infant gut microbial architecture and related host diseases, we need to understand the contribution of early life antibiotics to the selection of antibiotic resistance gene reservoirs in the microbiota, and their threat to successful treatment of infectious disease. Here we review the current understanding of the developmental progression of the IGM and the impact of antibiotic therapies on its composition and encoded reservoir of antibiotic resistance genes. PMID- 26241508 TI - Characterization of rock bream (Oplegnathus fasciatus) complement components C1r and C1s in terms of molecular aspects, genomic modulation, and immune responsive transcriptional profiles following bacterial and viral pathogen exposure. AB - The complement components C1r and C1s play a crucial role in innate immunity via activation of the classical complement cascade system. As initiators of the pathogen-induced signaling cascade, C1r and C1s modulate innate immunity. In order to understand the immune responses of teleost C1r and C1s, Oplegnathus fasciatus C1r and C1s genes (OfC1r and OfC1s) were identified and characterized. The genomic sequence of OfC1r was enclosed with thirteen exons that represented a putative peptide with 704 amino acids (aa), whereas eleven exons of OfC1s represented a 691 aa polypeptide. In addition, genomic analysis revealed that both OfC1r and OfC1s were located on a single chromosome. These putative polypeptides were composed of two CUB domains, an EGF domain, two CCP domains, and a catalytically active serine protease domain. Phylogenetic analysis of C1r and C1s showed that OfC1r and OfC1s were evolutionary close to the orthologs of Pundamilia nyererei (identity = 73.4%) and Oryzias latipes (identity = 58.0%), respectively. Based on the results of quantitative real-time qPCR analysis, OfC1r and OfC1s transcripts were detected in all the eleven different tissues, with higher levels of OfC1r in blood and OfC1s in liver. The putative roles of OfC1r and OfC1s in response to pathogenic bacteria (Edwardsiella tarda and Streptococcus iniae) and virus (rock bream iridovirus, RBIV) were investigated in liver and head kidney tissues. The transcription of OfC1r and OfC1s was found to be significantly upregulated in response to pathogenic bacterial and viral infections. Overall findings of the present study demonstrate the potential immune responses of OfC1r and OfC1s against invading microbial pathogens and the activation of classical signaling cascade in rock bream. PMID- 26241509 TI - Scintigraphy Demonstrates High Rate of False-positive Results From Glucose Breath Tests for Small Bowel Bacterial Overgrowth. AB - BACKGROUND & AIMS: Breath tests for hydrogen and/or methane are used to detect small bowel bacterial overgrowth (SBBO), but false-positive results can arise from clinical conditions that accelerate small bowel transit and deliver unabsorbed glucose to the colon. We investigated the prevalence of false-positive results from glucose breath tests by also evaluating patients with scintigraphy. METHODS: In a retrospective study, we reviewed data from glucose breath tests performed with concurrent scintigraphy on 139 patients with suspected SBBO at the Medical College of Wisconsin from January 2003 through July 2013. Results from breath tests were considered abnormal (positive) if there was an increasing curve of hydrogen or methane by >15 parts per million above baseline within 90 minutes. Scintigraphy was used to determine whether this increase occurred before or after the glucose bolus arrived at the cecum. Data from a subset of 45 patients with prior upper gastrointestinal surgery were analyzed separately. RESULTS: Forty-six of the patients (33%) had abnormal results from breath tests. On the basis of scintigraphy findings, 22 of these patients (48%) had false-positive results, which were caused by colon fermentation of unabsorbed glucose. Colon fermentation caused false-positive results in 65% of patients who had undergone upper gastrointestinal surgery and 13% of patients without prior surgery. Patients with false-positive results caused by colonic fermentation had shorter mean oro-cecal transit times (18 minutes) compared with patients with positive breath-test results because of SBBO (79 minutes) or negative results (86 minutes). CONCLUSIONS: Almost half of positive results from glucose breath tests are false because of colonic fermentation. All patients with abnormal results from breath tests should be considered for confirmatory repeat breath testing with concurrent scintigraphy to distinguish SBBO from colonic fermentation. Most patients who have undergone upper gastrointestinal surgery have abnormal results from breath tests and should be assessed by using concurrent scintigraphy with the initial breath test. PMID- 26241510 TI - Effects of Viral Eradication With Ledipasvir and Sofosbuvir, With or Without Ribavirin, on Measures of Fatigue in Patients With Chronic Hepatitis C Virus Infection. AB - BACKGROUND & AIMS: Fatigue is a disturbing symptom of chronic hepatitis C virus (HCV) infection. We assessed the effects of sustained virologic response 12 weeks after the end of therapy (SVR12) on fatigue. METHODS: We performed a retrospective analysis of 100 patients with chronic HCV infection who achieved an SVR12 after treatment with ledipasvir and sofosbuvir, with or without ribavirin. Data were collected on fatigue-related patient-reported outcomes (PROs) and assessed by using the Functional Assessment of Cancer Therapy-Fatigue scoring system and the Vitality subscale of Short Form 36. We measured levels of cytokines and growth factors in frozen serum samples collected at baseline, week 12 of treatment, and 4 weeks after treatment. Central fatigue and peripheral or muscle fatigue (PF) were determined by using items from PROs. Serum levels of cytokines, growth factors, serotonin, alanine aminotransferase, and aspartate aminotransferase were measured by using the Bio-Plex, enzyme-linked immunosorbent, and enzymatic assays. RESULTS: Compared with baseline, 4 weeks after the end of treatment, all fatigue-associated PROs improved significantly. Baseline PROs correlated inversely with serum level of interferon-gamma; level of platelet-derived growth factor correlated with PF, central fatigue, and total fatigue score. Only PF correlated with serum level of serotonin. At baseline, high PF scores correlated with high serum levels of serotonin and low levels of interleukin-10 and tumor necrosis factor-alpha. In multivariate analysis, serum level of interleukin-8 was associated with greater fatigue (P < .02). Reductions in levels of chemokine (C-C motif) ligand 2 (also called monocyte chemotactic protein 1) were associated with fatigue after treatment (P = .0165). CONCLUSIONS: In an analysis of data from patients with chronic HCV infection participating in a clinical trial of ledipasvir and sofosbuvir, SVR12 was associated with reduced fatigue, compared with baseline. High baseline serum levels of interferon-gamma were associated with fatigue. Reductions in levels of chemokine (C-C motif) ligand 2 were associated with persistent fatigue after SVR12. Central and peripheral fatigue each associated with different biomarkers, suggesting different pathogenic pathways. PMID- 26241511 TI - Quality Measurement in Gastroenterology: Confessions of a Realist. AB - Clinicians are required to report their performance on an ever-increasing number of quality measures. However, it is difficult to measure health care quality and it is unclear whether broadly applying accountability measures effectively improves care. This article considers these challenges and includes recommendations that may help gastroenterologists respond to demands for increased quality measurement. PMID- 26241512 TI - [Public Health Genomics]. PMID- 26241513 TI - [Molecular epidemiology in healthcare-associated infections: guidelines of the Italian Society of Hygiene, Preventive Medicine and Public Health (SItI)]. AB - Healthcare-associated infections (HAI) are the most frequent and severe complication acquired in healthcare settings and have a significant impact in terms of morbidity, mortality and costs. This document is aimed at different health professionals and focuses on the role of molecular epidemiology in the prevention and management of these infections. It describes the role of molecular characterization and of bioinformatics archives, the organizational levels of laboratories, the evidence regarding cost-effectiveness, ethical aspects related to HAI, and highlights some specific peculiarities of Italy. Molecular epidemiology is an indispensable tool and should be part of a multidisciplinary approach in the proper management of HAI. PMID- 26241514 TI - [A framework for evaluating ethical issues of public health initiatives: practical aspects and theoretical implications]. AB - The "Framework for the Ethical Conduct of Public Health Initiatives", developed by Public Health Ontario, is a practical guide for assessing the ethical implications of evidence-generating public health initiatives, whether research or non-research activities, involving people, their biological materials or their personal information. The Framework is useful not only to those responsible for determining the ethical acceptability of an initiative, but also to investigators planning new public health initiatives. It is informed by a theoretical approach that draws on widely shared bioethical principles. Two considerations emerge from both the theoretical framework and its practical application: the line between practice and research is often blurred; public health ethics and biomedical research ethics are based on the same common heritage of values. PMID- 26241515 TI - [Defensive Medicine: Defensive Medicine: Overview of the literature]. AB - A literature review was performed on the subject of defensive medicine, in order to gather information and evidence for identifying a shared definition of this phenomenon, identify its causes, quantify its frequency and its economic impact.Results show that defensive medicine is primarily the result of medical professionals adapting to the pressure of litigation risks, and whose behaviour is motivated by fear of malpractice claims rather than by the patient's health. Defensive medicine seems to have become a diffuse phenomenon, afflicting all diagnostic-therapeutic areas and some disciplines to a greater degree, and leading to a large waste of human, organizational and economic resources. PMID- 26241516 TI - Cutaneous Serratia marcescens infections in Korea: A retrospective analysis of 13 patients. AB - Serratia marcescens is a Gram-negative bacillus belonging to the Enterobacteriaceae family. Because of increasing reports of antimicrobial resistance, this bacterium has received considerable attention and has emerged as an important pathogen. In order to reveal clinical and microbiological characteristics of S. marcescens cutaneous infection and to suggest appropriate antibiotic treatment, we retrospectively analyzed 17 strains isolated from wound swabs of Korean patients between November 2005 and March 2014. A total of 13 patients (five men and eight women) were included in our study, with a mean age of 46.3 years (range, 21-82). Based on medical history, seven patients were classified as immunocompromised. Prior predisposing factors for infections were noted in 12 patients, including pre-existing leg ulcers or dermatitis (5/13), preceding cancer surgeries (2/13), plastic surgeries and filler injection (2/13), traumas (2/13) and medical procedures following cutaneous abscess (1/13). Cutaneous infections showed various clinical presentations, including spontaneous dermal abscess, fingernail change, painful nodules and papular erosions. We found that third- and fourth-generation cephalosporins, gentamicin, levofloxacin and meropenem appeared active against all 17 strains in vitro. Clinically, all patients treated with empirical first-generation cephalosporin showed treatment resistance, and oral quinolone monotherapy was the most preferred antibiotic regimen without treatment failure, with an average treatment duration of 25 days (range, 14-42). This study demonstrates the various clinical presentations and treatment responses for cutaneous S. marcescens infection. Moreover, we suggest that initial antibiotic coverage should be broad enough to account for multidrug resistance in this rare pathogen. PMID- 26241517 TI - The evaluation of non-topological components in Berry phase and momentum relaxation time in a gapped 3D topological insulator. AB - The zero gap surface states of a 3D-topological insulator host Dirac fermions with spin locked to the momentum. The gap-less Dirac fermions exhibit electronic behaviour different from those predicted in conventional materials. While calculations based on a simple linear dispersion can account for observed experimental patterns, a more accurate description of the physics of these systems and a better agreement between experimental data theoretical results can be obtained by including higher order k terms in the Hamiltonian. In this work, in presence of a time reversal symmetry breaking external magnetic field and higher order warping term, alteration to the topologically ordained Berry phase of (2n + 1)pi, momentum relaxation time, and the magneto-conductivity tensors is established. The relation between scattering times and the deviations to topological Berry phase of pi is also emphasized. PMID- 26241518 TI - Secretion of matrix metalloproteinase-3 by co-cultured pigmented and non pigmented human trabecular meshwork cells following selective laser trabeculoplasty. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are reported to contribute to the mechanism of argon laser trabeculoplasty, but it is unknown whether they are also secreted after selective laser trabeculoplasty (SLT). The aim of this study was to investigate whether human primary trabecular meshwork (HTM) cells secrete MMP 3 after stimulation by SLT. The relationship between SLT and the two principal forms of cell death, apoptosis and necrosis, was also examined. METHODS: Non pigmented primary HTM cells were challenged with melanin granules to artificially introduce pigmentation. Isolated non-pigmented HTM cells and 1:1 co-cultures of pigmented and non-pigmented cells were treated with 0.5-1.5 mJ SLT. Cellular metabolic activity (CMA) was quantified using the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay. Apoptosis and necrosis were measured using a cell death ELISA and a lactate dehydrogenase assay, respectively. MMP-3 secretion was measured by ELISA. RESULTS: Co-cultures exhibited a dose-dependent decline in CMA and a dose-dependent increase in necrosis 4 and 24 h after SLT. Non-pigmented cells did not undergo necrosis and displayed a trend towards increased CMA. Apoptosis was reduced in non-pigmented cells but elevated in co cultures. Increased MMP-3 secretion was observed from co-cultures but not isolated non-pigmented cells. CONCLUSIONS: Pigmentation is necessary for both post-SLT cell death and MMP-3 secretion. SLT appears to have a hormetic effect on non-pigmented HTM cells. PMID- 26241519 TI - A miniature surface tension-driven robot using spatially elliptical moving legs to mimic a water strider's locomotion. AB - The highly agile and efficient water-surface locomotion of the water strider has stimulated substantial interest in biomimetic research. In this paper, we propose a new miniature surface tension-driven robot inspired by the water strider. A key feature of this robot is that its actuating leg possesses an ellipse-like spatial trajectory similar to that of a water strider by using a cam-link mechanism. Simplified models are presented to discuss the leg-water interactions as well as critical conditions for a leg penetrating the water surface, and simulations are performed on the robot's dynamic properties. The final fabricated robot weighs about 3.9 g, and can freely and stably walk on water at different gaits. The maximum forward and turning speeds of the robot are measured as 16 cm s(-1) and 23 degrees /s, respectively. Furthermore, a similarity analysis with Bond number and Weber number demonstrates that the locomotion of this robot is quite analogous to that of a real water strider: the surface tension force dominates the lifting force and plays a major role in the propulsion force. This miniature surface tension-driven robot might have potential applications in many areas such as water quality monitoring and aquatic search and rescue. PMID- 26241520 TI - Computational Study of Metal-Dinitrogen Keggin-Type Polyoxometalate Complexes [PW11O39M(II)N2)](5-) (M = Ru, Os, Re, Ir): Bonding Nature and Dinitrogen Splitting. AB - Molecular geometry, electronic structure, and metal-dinitrogen bonding nature of a series of metal-dinitrogen derivatives of Keggin-type polyoxometalates (POMs) [PW11O39M(II)N2)](5-) (M = Ru, Os, Re, Ir) have been studied by using a density functional theory (DFT) method with the M06L functional. Among these Keggin-type POM complexes, Os- and Re-substituted POM complexes are the most active for N2 adsorption with considerable adsorption energy. The electronic structure analysis shows that Os(II) and Re(II) centers in their metal-dinitrogen POM complexes possess pi(2)xzpi(2)yzpi(2)xy and pi(2)xzpi(2)yzpi(1)xy configurations, respectively. DFT-M06L calculations show that the possible synthesis routes proposed in this work for the Ru-, Os-, and Re-dinitrogen POM complexes are thermodynamically feasible under various solvent environments. Meanwhile, the Re dinitrogen POM complex was assessed for the direct cleavage of dinitrogen molecule. In the reaction mechanism, a dimeric Keggin-type POM derivative of rhenium could represent the intermediate which undergoes N-N bond scission. The calculated free energy barrier (DeltaG(?)) for a transition state with a zigzag conformation is 16.05 kcal mol(-1) in tetrahydrofuran, which is a moderate barrier for the cleavage of the N-N bond when compared with the literature values. In conclusion, regarding the direct cleavage of the dinitrogen molecule, the findings would be very useful to guide the search for a potential N2 cleavage compound into totally inorganic POM fields. PMID- 26241521 TI - Atomically Precise Growth of Catalytically Active Cobalt Sulfide on Flat Surfaces and within a Metal-Organic Framework via Atomic Layer Deposition. AB - Atomic layer deposition (ALD) has been employed as a new synthetic route to thin films of cobalt sulfide on silicon and fluorine-doped tin oxide platforms. The self-limiting nature of the stepwise synthesis is established through growth rate studies at different pulse times and temperatures. Additionally, characterization of the materials by X-ray diffraction and X-ray photoelectron spectroscopy indicates that the crystalline phase of these films has the composition Co9S8. The nodes of the metal-organic framework (MOF) NU-1000 were then selectively functionalized with cobalt sulfide via ALD in MOFs (AIM). Spectroscopic techniques confirm uniform deposition of cobalt sulfide throughout the crystallites, with no loss in crystallinity or porosity. The resulting material, CoS-AIM, is catalytically active for selective hydrogenation of m-nitrophenol to m-aminophenol, and outperforms the analogous oxide AIM material (CoO-AIM) as well as an amorphous CoSx reference material. These results reveal AIM to be an effective method of incorporating high surface area and catalytically active cobalt sulfide in metal-organic frameworks. PMID- 26241522 TI - Arsenic: A Review of the Element's Toxicity, Plant Interactions, and Potential Methods of Remediation. AB - Arsenic is a naturally occurring element with a long history of toxicity. Sites of contamination are found worldwide as a result of both natural processes and anthropogenic activities. The broad scope of arsenic toxicity to humans and its unique interaction with the environment have led to extensive research into its physicochemical properties and toxic behavior in biological systems. The purpose of this review is to compile the results of recent studies concerning the metalloid and consider the chemical and physical properties of arsenic in the broad context of human toxicity and phytoremediation. Areas of focus include arsenic's mechanisms of human toxicity, interaction with plant systems, potential methods of remediation, and protocols for the determination of metals in experimentation. This assessment of the literature indicates that controlling contamination of water sources and plants through effective remediation and management is essential to successfully addressing the problems of arsenic toxicity and contamination. PMID- 26241523 TI - Viscoelastoplastic model of cell nucleus under compression. PMID- 26241524 TI - Neurologic state transitions in the eye and brain: kinetics of loss and recovery of vision and consciousness. AB - Visual alterations, peripheral light loss (PLL) and blackout (BO), are components of acceleration (+Gz) induced loss of consciousness (LOC) and recovery of consciousness (ROC). The kinetics of loss of vision (LOV) and recovery of vision (ROV) were determined utilizing ocular pressure induced retinal ischemia and compared to the kinetics of LOC and ROC resulting from +Gz-induced cephalic nervous system (CPNS) ischemia. The time from self-induced retinal ischemia in completely healthy subjects (N = 104) to the onset of PLL and complete BO was measured. The time from release of ocular pressure, with return of normal retinal circulation, to the time for complete recovery of visual fields was also measured. The kinetics of pressure induced LOV and ROV was compared with previously developed kinetics of +Gz-induced LOC and ROC focusing on the rapid onset, vertical arm, of the +Gz-induced LOC and ROC curves. The time from onset of increased ocular pressure, immediately inducing retinal ischemia, to PLL was 5.04 s with the time to BO being 8.73 s. Complete recovery of the visual field from BO following release of ocular pressure, immediately abolishing retinal ischemia, was 2.74 s. These results confirm experimental findings that visual loss is frequently not experienced prior to LOC during exposure to rapid onset, high levels of +Gz-stress above tolerance. Offset of pressure induced retinal ischemia to ROV was 2.74 s, while the time from offset of +Gz-induced CPNS ischemia to ROC was 5.29 s. Recovery of retinal function would be predicted to be complete before consciousness is regained following +Gz-induced LOC. Ischemia onset time normalization in neurologic tissues permits comparison between different stress-induced times to altered function. The +Gz-time tolerance curves for LOV and LOC provide comparison and integration of neurologic state transition kinetics in the retina and CPNS. PMID- 26241525 TI - The best prostate biopsy scheme is dictated by the gland volume: a monocentric study. AB - OBJECTIVE: Accuracy of biopsy scheme depends on different parameters. Prostate specific antigen (PSA) level and digital rectal examination (DRE) influenced the detection rate and suggested the biopsy scheme to approach each patient. Another parameter is the prostate volume. Sampling accuracy tends to decrease progressively with an increasing prostate volume. We prospectively observed detection cancer rate in suspicious prostate cancer (PCa) and improved by applying a protocol biopsy according to prostate volume (PV). PATIENTS AND METHODS: Clinical data and pathological features of these 1356 patients were analysed and included in this study. This protocol is a combined scheme that includes transrectal (TR) 12-core PBx (TR12PBx) for PV <= 30 cc, TR 14-core PBx (TR14PBx) for PV > 30 cc but < 60 cc, TR 18-core PBx (TR18PBx) for PV >= 60 cc. RESULTS: Out of a total of 1356 patients, in 111 (8.2%) PCa was identified through TR12PBx scheme, in 198 (14.6%) through TR14PBx scheme and in 253 (18.6%) through TR18PBx scheme. The PCa detection rate was increased by 44% by adding two TZ cores (TR14PBx scheme). The TR18PBx scheme increased this rate by 21.7% vs. TR14PBx scheme. The diagnostic yield offered by TR18PBx was statistically significant compared to the detection rate offered by the TR14PBx scheme (p < 0.003). The biopsy Gleason score and the percentage of core involvement were comparable between PCa detected by the TR14PBx scheme diagnostic yield and those detected by the TR18PBx scheme (p = 0.362). CONCLUSIONS: The only PV parameter, in our opinion, can be significant in choosing the best biopsy scheme to approach in a first setting of biopsies increasing PCa detection rate. PMID- 26241526 TI - Combined treatment of minimally invasive 23-G vitrectomy and chandelier for superior bullous rhegmatogenous retinal detachment. AB - OBJECTIVE: To investigate the clinical efficacy of minimally invasive 23G vitrectomy combined with chandelier for the treatment of superior bullous rhegmatogenous retinal detachment (SBRRD). PATIENTS AND METHODS: A retrospective case series study of 50 patients with SBRRD was conducted. Each of these patients received minimally invasive 23G vitrectomy in one of their eye. A trocar was indwelled with two-step 23-G incision, and the chandelier was inserted in the inferior 6 o'clock pars plana. The tear was closed with 23-G vitrectomy combined with endolaser photocoagulation and infused with perfluoropropane (C3F8) under non-contact wide-angle lens. Postoperative follow-up ranged from 5-49 months (mean 23.9+/-1.3 months). Intraoperative and postoperative complications, postoperative conjunctival hyperemia, eye irritation signs and inflammation reactions, retinal anatomic reduction rate, best corrected visual acuity (BCVA) and intraocular pressure (IOP) changes were analyzed. RESULTS: The intraoperative scleral incision leakage required 17 sutures (34%). No complications, such as iatrogenic retinal breaks and hemorrhage occurred. The postoperative conjunctival hyperemia, eye irritation signs and inflammation reactions were mild. Transient low IOP occurred in one eye (2%) on the first day postoperatively and recovered on the next day. Transient low IOP occurred in eyes of 16 subjects (32%) and recovered after lowering IOP therapy within an average of 4 days. No complications, such as hemorrhage, effusion, choroidal detachment and endophthalmitis were observed. Forty-nine subjects (98%) had retinal reattachment in their eyes after a single surgery, and 100% eyes showed final retinal reattachment. The preoperative and postoperative BCVAs were 4.61+/-0.19 and 4.70+/-0.19, respectively, in 8 patients without detached macula, and the difference was not statistically significant (t = 2.20, p >0.05). CONCLUSIONS: Minimally invasive 23G vitrectomy combined with chandelier is a safe and effective surgical approach for the treatment of SBRRD. PMID- 26241527 TI - An insight into early onset of scoliosis: new update information - a review. AB - Early-onset scoliosis is an onerous challenge to physicians. These patients are young with significant remaining growth potential. Thus, patients are likely to develop progressive deformities, cosmetic disfigurement and cardiopulmonary consequences warrant early intervention in many cases. The purpose of this review is to provide the readers with brief description of the disease, therapeutic modalities available and their indications and use. Publications and abstracts related to EOS in the last decade were carried out and synthesized into a review "an insight into early onset of scoliosis." A comprehensive understanding of the scoliosis, its impact on the thoracic development may guide in treatment, which is often required at a young age in these children to prevent irreversible pulmonary insufficiency. Current treatment techniques are based on multiple factors may include non-surgical strategies, such as Derotational body cast or brace in younger patients with curve <50 degrees. Surgical treatment of spinal deformity should be considered when nonoperative measures are failed to arrest curve progression. Growing rods have been the mainstay treatment of early-onset scoliosis which require repeated surgeries for distraction and are associated with exponential increase in complications. The vertical expandable prosthetic titanium rib may be beneficial for those patients with congenital scoliosis and fused ribs and thoracic insufficiency syndrome. Shilla technique is an alternative to growing rods that avoids the morbidity of repeated lengthening. Growth modulation using staples or tethers shows promise for milder curvatures, but further follow-up is needed to define their use. Although new technologies have improved the treatment of children with EOS but it continues to be challenging with high complication rates. PMID- 26241528 TI - Key pathway to prevent the collapse of femoral head in osteonecrosis. AB - OBJECTIVE: Osteonecrosis of the femoral head (ONFH) is a multifactorial disease, with unclear pathogenesis. The collapse of the femoral head is an important turning point in ONFH, especially for young patients. Many methods have been proposed, but the best treatment lacks consensus among orthopedic surgeons. Thus, understanding the collapse mechanism of the femoral head in ONFH is the key to a successful outcome of joint preservation. This review aims to provide an update of the collapse mechanism of the femoral head in ONFH and to focus on the most appropriate therapeutic strategies to adopt in clinical practice. MATERIALS AND METHODS: We reviewed the international literature to identify studies focusing on ONFH and therapeutic options. PubMed, Medline and Cochrane Library databases were searched for English language papers. RESULTS: An imbalance between bone resorption and bone formation as well as stress distribution on insufficient trabecular bone may be the most important collapse mechanism in ONFH. CONCLUSIONS: Treatment to avoid femoral head collapse should focus on local effective mechanical support with modification of bone remodeling in the femoral head. PMID- 26241529 TI - General anaesthesia is better suitable than epidural anaesthesia for surgical removal of giant intraperitoneal tumours. AB - OBJECTIVE: Our objective was to compare general and epidural anaesthesia for surgical resection of giant intraperitoneal tumours. PATIENTS AND METHODS: 80 patients with giant intraperitoneal tumours were randomly divided into two groups which respectively received general or epidural anaesthesia prior to the surgery. General anaesthesia was done under intubation and mechanical ventilation. RESULTS: Vital signs, including diastolic pressure, systolic pressure, heart rate and oxygen saturation, were not significantly different between two groups before the surgery. Vital signs were decreased in patients of both groups after surgery. However, vital signs in the general anaesthesia group were markedly higher than in the epidural anaesthesia group (p < 0.05), indicating that the changes of vital signs were less pronounced in the general anaesthesia group. Furthermore, the operation time in this group was markedly shorter than in the epidural anaesthesia group, while the success rate was markedly higher. In addition, the intraoperative blood loss and infusion volume were both markedly lower in the general anaesthesia group, as well as the occurrence rate of supine position (p < 0.05 for all comparisons). Occurrence of heart failure, lung edema, altered water electrolyte balance, ECG abnormalities in patients undergoing surgery under general anaesthesia group was significantly lower (p < 0.05 vs. patients under epidural anaesthesia). There were no deaths in either patient group, and all patients were successfully cured and discharged. CONCLUSIONS: General anaesthesia under intubation and mechanical ventilation is better suited for surgical removal of giant intraperitoneal tumours. PMID- 26241530 TI - The importance of the incidental thyroid gland uptake during Tc-99m MIBI myocardial perfusion scintigraphy. AB - OBJECTIVE: The purpose of study was to investigate whether incidental thyroid gland uptake had an important during Tc-99m sestamibi (MIBI) myocardial perfusion scintigraphy (SPECT). PATIENTS AND METHODS: In the presented study, 968 consecutive patients were evaluated for the presence or absence of thyroid gland uptake in the raw data of the Tc-99m MIBI SPECT. All of the patients had thyroid gland uptake of the Tc-99m MIBI underwent laboratory evaluation of thyroid function, ultrasonographic imaging, and hystopathological examination. RESULTS: The thyroid gland uptake was detected in 14 of 968 (1.4%) consecutive patients during the evaluation of raw images of Tc-99m MIBI SPECT studies. Among these 14 patients, 4 had subacute thyroiditis, 7 multinodular goiter, 3 Graves disease by ultrasonographic imaging and hystopathological examination. TSH levels of all of these patients were < 0.01 U/ml. CONCLUSIONS: Tc-99m MIBI uptake by thyroid gland has been explained with associated clinical thyrotoxicosis. Although the primary goal of myocardial perfusion imaging is the evaluation of myocardial perfusion, the interpretation of myocardial perfusion imaging should not be limited to the heart. Because, it is possible to observe extracardiac radioactivity accumulation, which may then lead to the diagnosis of a noncardiac disease during this detailed examination. PMID- 26241531 TI - Enhancement patterns of intrahepatic mass-forming cholangiocarcinoma at multiphasic computed tomography and magnetic resonance imaging and correlation with clinicopathologic features. AB - OBJECTIVE: Incidence of intrahepatic mass-forming cholangiocarcinoma (IMCC) is increasing worldwide, especially in patients with chronic liver disease. The small and the histologically well-differentiated IMCCs in chronic liver disease could be arterially hypervascular lesions with/without washout on computed tomography (CT) and magnetic resonance imaging (MRI), mimicking typical hepatocellular carcinoma (HCC). The aim of this work is to evaluate contrast enhancement (CE) patterns of IMCCs at quadri-phasic multidetector CT (4-MDCT) and MRI, using imaging-clinicopathologic correlation. PATIENTS AND METHODS: The 4 MDCT and MR images of 56 histologically confirmed IMCCs were retrospectively evaluated for tumor morphology and enhancement features. Enhancement pattern was defined according to the behavior of the nodule in arterial (AP), portal venous (PVP) and equilibrium phases (EP), and dynamic pattern was described according to enhancement progression throughout the different phases. Arterial and dynamic enhancement patterns were correlated with chronic liver disease, tumor size and histological differentiation. RESULTS: Most of the nodules were peripherally hyperenhancing (50%) on AP, and partially hyperenhancing on PVP (67.9%) and EP (80.3%). Forty-six (82.1%) IMCCs showed progressive CE, 7 (12.5%) stable CE and 3 (5.4%) wash-out. In normal liver there were 34 nodules with progressive and 3 with stable CE, whereas in chronic liver disease there were 12 IMCCs with progressive, 4 with stable and 3 with washout pattern (p = 0.01); IMCCs with progressive CE were more differentiated than IMCCs with stable CE and wash-out (p = 0.02). CONCLUSIONS: The most prevalent enhancement pattern of IMCCs was arterial rim enhancement followed by progressive and concentric filling. The stable and the washout patterns were more frequent in poorly differentiated IMCCs. Contrast washout was observed only in IMCCs emerging in chronic liver disease with a risk of misdiagnosis with HCC. PMID- 26241532 TI - The role of diffusion weighted MR imaging for differentiation between Graves' disease and Hashimoto thyroiditis. AB - OBJECTIVE: The aim of this study was to evaluate the usefulness of diffusion weighted magnetic resonance imaging (DWMRI) for differentation between Graves' disease and Hashimoto's thyroiditis. PATIENTS AND METHODS: Fifty patients (27 Graves diseases and 23 Hashimoto thyroiditis) and twenty healthy volunteers were examined using T1, T2 and DWMRI. The patients were diagnosed on the basis of physical findings and the results of thyroid function tests and serological tests. Circular ROIs were positioned on the bilateral thyroid lobes and isthmus. All measurements were repeated three different b values including 100, 600 and 1000 s/mm2 in all cases. ADC (Apparent diffusion coefficient) maps were calculated automatically with the MR system. RESULTS: Mean ADC values were 2.93 * 10-3, 1.97 * 10-3 and 1.62 * 10-3 mm2/s in the healthy volunteers; 3.47 * 10-3, 2.25 * 10-3 and 1.64 * 10-3 mm2/s in Graves' disease; 2.53 * 10-3, 1.76 * 10-3, 1.28 * 10-3 mm2/s in Hashimoto thyroiditis for b100, b600 and b1000, respectively. The ADC values of the Graves diseases were higher than healty volunteers and Hashimoto thyroiditis. ADC values were statistically significant for differentation between Hashimoto thyroiditis and Graves' disease all b values (p < 0.05). CONCLUSIONS: DWMRI is fast sequence and does not require contrast agent. Quantitative assessment of the lesion is possible using ADC map. So, DWMRI may be useful differentiation of the Hashimoto thyroiditis and Graves' disease. PMID- 26241533 TI - Sacroiliac pain and CT-guided steroid injection treatment: high-grade arthritis has an adverse effect on outcomes in long-term follow-up. AB - OBJECTIVE: The sacroiliac joint (SIJ) is one of the major sources of low back pain that can lead to severe morbidity. Possible SIJ pain requires a thorough evaluation and treatment option. The purpose of this study was to analyze the possible relationships between computed tomography (CT) grading of SIJ arthritis and the effectiveness of intraarticular steroid injection treatment under CT guidance. PATIENTS AND METHODS: A total of 61 patients with SIJ pain who were treated with CT guided intraarticular steroid injection were retrospectively reviewed. Visual analog scale (VAS) scores for pain control were recorded for short-term (day after injection, first week, third week) and long-term (sixth months and final control) follow-up times. SIJ arthritis was graded using CT images according to the New York criteria. Patients were assigned into low-grade (0, 1 and 2) and high-grade (3 and 4) groups. The relationship between arthritis grades and VAS scores in short and long-term follow-ups were statistically analyzed. RESULTS: Mean age and follow-up was 54.8 years (range: 41-68 years) and 27.8 months (range: 24-36 months), respectively. In 40 patients there was low grade arthritis, while 21 patients were characterized on having high-grade sacroiliac arthritis detected during the radiological evaluation. There was no statistically significant difference between low and high-grade arthritis in regard to short-term VAS scores. On contrary, for long-term VAS scores, there was significant difference between low- and high-grade arthritis. CONCLUSIONS: Steroid injection treatment for SIJ pain is not effective on a long-term basis for patients with high-grade arthritis, and although they have had decreased VAS scores in the short-term, after 2 years of follow-up, their VAS scores significantly increased leading to symptomatic sacroiliac joint pain. PMID- 26241534 TI - The irradiated-fibroblasts elicit immune response against tumor in a murine colon cancer model. AB - OBJECTIVE: The breaking of immune tolerance against tumor stromal fibroblasts should be a useful approach for cancer immunotherapy. The primary objective of this study was to verify whether irradiated-fibroblasts could induce an anti tumor immune response in vivo. MATERIALS AND METHODS: Normal fibroblasts were irradiated with 25Gy; their expressions of a-SMA, HMGB1 and calreticulin were assessed by Western blot. Mice were immunized with irradiated-fibroblasts and then challenged with CT26 colon carcinoma. Auto-antibodies were assessed by flow cytometric. The inhibition of proliferation of tumor cells by purified immunoglobulins was investigated. RESULTS: The irradiated-fibroblasts expressed HMGB1, calreticulin and alpha-SMA. The irradiated-fibroblasts were effective in affording protection from tumor onset and growth. The immunized sera exhibited positive staining for tumor cells in flow cytometric analysis. The purified immunoglobulins from immunized mice inhibited the proliferation of CT26 tumor cells in vitro. CONCLUSIONS: All these suggest that irradiated-fibroblasts could induce an anti-tumor immune response. PMID- 26241535 TI - Helicobacter pylori and mean platelet volume: a relation way before immune thrombocytopenia? AB - OBJECTIVE: Helicobacter pylori is associated with chronic immune thrombocytopenia. Eradication of H. pylori has been related with a platelet response and this treatment has been included within management strategies for a certain group of patients. However, in patients with normal platelet counts, the effects of H. pylori infection on platelet count and mean platelet volume as an important platelet index have not been investigated. In this study, we aimed to assess the relation between platelet indices and H. pylori infection in patients with dyspepsia who have otherwise normal platelet counts. PATIENTS AND METHODS: In a retrospective manner, 4823 patients with dyspeptic complaints who have underwent an upper gastrointestinal endoscopy and a rapid urease test were included. Data of whole blood counts before the procedure were recorded from their files. Patients with normal endoscopic findings or simple gastritis were included. Patients with malignancy, GI bleeding, portal hypertension, liver or kidney disease and taking nonsteroidal anti-inflammatory drugs, proton pump inhibitors, cytotoxic medications were excluded. RESULTS: Mean platelet count in H. pylori positive and negative patients were 246381+/- 92225/mm3 and 258135 +/- 89912/mm3, respectively (p<0.001). Mean MPV was higher in H. pylori positive group (8.9+/- 1.3 vs. 8.23 +/- 0.94, p<0.001). This difference was observed in both genders. MPV was observed to be higher than 10 fL in 20.5% of HP positive patients while in only 2.8% of H. pylori negative patients (p<0.0001). CONCLUSIONS: In patients with H. pylori infection and normal platelet counts, it may be speculated that an ongoing and compensated platelet destruction-production process may be responsible for the increase in MPV. Likewise, in conditions exclusive for the host or the H. pylori strain, platelet destruction may be enhanced leading to immune thrombocytopenia. As our study is the first study to investigate the effect of H. pylori in patients with normal platelet counts, our findings may give way to further prospective researches. PMID- 26241536 TI - Autoimmunity and thyrotropin level in developing thyroid malignancy. AB - OBJECTIVE: Malignancies and autoimmune thyroid disease are still controversial, but recent studies prove that a long lasting thyroid disease may be linked with malignancy, e.g. papillary thyroid carcinoma in patients with Hashimoto thyroiditis. Having in mind that thyrotropin is a thyroid growth factor, the relationship between its serum values, as well as the levels of anti-peroxidase and anti-thyroglobulin antibodies and thyroid malignancy in patients with nodular thyroid goiter was examined. PATIENTS AND METHODS: Six-hundred-thirty-seven medical records, which included the thyroid fine-needle aspiration cytology were retrospectively evaluated. Patients were grouped regarding the levels of thyrotropin, anti-peroxidase and anti-thyroglobulin antibodies (in or out of the reference ranges) and compared with cytology findings for establishing their prognostic potential for malignancy. RESULTS: Elevated serum thyrotropin (>= 4.5 mIU/L) was found in 27.3% of patients with thyroid malignancy compared with 10.8% with benign and 16.1% with unspecified cytology finding (p < 0.01). In the group of patients with malignant cytology findings 7.0% of them had elevated anti peroxidase antibodies level, and 1.4% had anti-peroxidase antibodies level in reference range. In the group of patients with malignant cytology findings 4.2% of them had elevated anti-thyroglobulin antibodies level, and 1.4% had anti thyroglobulin antibodies level in reference range. CONCLUSIONS: In patients with elevated serum thyrotropin concentration and/or chronic thyroiditis the occurrence of thyroid malignancy is increased. PMID- 26241537 TI - Efficacy of mesalazine or beclomethasone dipropionate enema or their combination in patients with distal active ulcerative colitis. AB - OBJECTIVE: Mesalazine or Beclomethasone dipropionate (BDP) enema have been shown effective in treatment of distal active ulcerative colitis (UC). This study was aimed to determine whether the combination of topical mesalazine and BDP is superior to topical mesalazine or BDP used alone in patients with distal active UC. PATIENTS AND METHODS: One-hundred and twenty patients with clinical, endoscopic and histological diagnosis of distal active UC were randomly assigned to a regimen with mesalazine tablets 2.4 g/day associated to either mesalazine enema 4 g/day (group A, n=40), BDP 3 mg/60 ml every day (group B, n=40) or the combination treatment with the two compounds in a single administration (group C, n=40) for eight weeks. After four weeks of treatment all patients underwent clinical controls but only 109 patients returned back for clinical, endoscopic and histological controls at the end of the treatment period. RESULTS: After eight weeks, complete remission rates were of 52%, 47% and 65% respectively, in group A, B and C. From baseline to 4 and 8 weeks the CAI score decreased significantly in all the three groups (p < 0.0001). CONCLUSIONS: All the three combinations achieved equivalent results in terms of symptoms in inducing symptoms relief and mucosa healing in distally active UC. PMID- 26241538 TI - Occupational risk factors in inflammatory bowel disease. AB - OBJECTIVE: Crohn's disease and ulcerative colitis are the two main forms of inflammatory bowel disease (IBD). Although the aetiology of IBD is not completely understood, an interaction between genetic and environmental factors has been proposed. In this context, however, environmental epidemiology lacks a comprehensive evaluation of the possible role of occupational exposures in IBD development and progression. Therefore, aim of our review was to evaluate how certain occupational risk factors may affect IBD pathogenesis, clinical history and severity of disease manifestations. MATERIALS AND METHODS: A critical revision of available literature concerning exposure to groups of potential workplace hazardous agents and IBD, as it appears in Medline and Web of knowledge, was performed. RESULTS: The role of workplace exposures to chemical and biological agents, ionizing or non-ionizing radiations, shift-works, indoor, and sedentary works as well as job strain on IBD has been critically revised. However, the limited number of studies addressing these issues prevented us from extrapolating definite conclusions. CONCLUSIONS: Our review pointed out some critical aspects concerning the relationship between occupational factors and IBD, in terms of causative pathways, hazardous exposure, susceptibility and consequences of IBD functional limitations on career choice and fitness for work that need future investigations. Overall, this seems a challenging public health issue, considering the strong IBD impact on patients' quality of life, work productivity and costs to society. Moreover, this review may encourage concerted actions of health care specialists, occupational physicians, employers and IBD workers to plan preventive and protective measures for "healthier patterns of work" for IBD and to develop innovative perspectives for an integrated management of "IBD at work". PMID- 26241539 TI - Treatment with mild brain hypothermia for cardiopulmonary resuscitation after myoclonic seizures in infant with robertsonian type of trisomy 13. AB - Congenital chromosomal abnormality with trisomy 13 is known to be associated with poor life prognosis and lethal. Therefore, physician advice the patients be kept in intensive treatment with resuscitation and state of the art intensive care when sudden change in the general condition with this trisomy is observed. We report herein, the treatment with mild brain hypothermia therapy for cardiopulmonary resuscitation after myoclonic seizures in infant with Robertsonian type of trisomy 13 in intensive care unit. Our study indicated that brain hypothermia therapy and steroid pulse therapy on an infant who was believed to have post-resuscitation hypoxic encephalopathy was highly effective as the patient's general condition recovered to the original state after four months. PMID- 26241540 TI - 124 cases of clinical analysis of children with viral myocarditis. AB - OBJECTIVE: A study on clinical characteristics, diagnostic methods of children's viral myocarditis (VMC) and analysis of the effect of VMC is carried out. PATIENTS AND METHODS: A retrospective analysis of the clinical data of 124 cases of children with VMC from January 2008 to March 2011 in Xuzhou Children's Hospital is conducted. RESULTS: The age of onset of 1 VMC is less than 1 year old with the majority, fever, precordial pain, and fatigue as the main manifestation, auxiliary examination of abnormal electrocardiogram (ECG) in 110 cases, accounting for 88.71%, the positive rate of dynamic ECG is 92.31%, and abnormal rate of myocardial enzyme examination is 96.77%. The effective rate of treatment is 94.35%, and the effective rate of treatment of creatine phosphate sodium is 100%. CONCLUSIONS: For childhood, especially 1 year old children with viral infection in clinical, attention should be paid to the VMC performance, suspected children should be timely ECG, dynamic ECG and myocardial enzyme examined with diagnosis and early treatment. The myocardial protection of creatine phosphate sodium has definite therapeutic effect on VMC of children. PMID- 26241541 TI - The significance of mild hypothermia therapy on patients with successful resuscitation of cardiac arrest. AB - OBJECTIVE: To investigate the clinical significance of mild hypothermia therapy in patients with resuscitation of cardiac arrest and analyze the possible molecular mechanism. PATIENTS AND METHODS: Ninety-six patients with successful resuscitation of cardiac arrest in ICU were hospitalized from June 2009 to July 2014. They were divided into a control group (n=37 cases) and an observation group (n=59 cases). All patients received high-grade life support treatment immediately after resuscitation. The treatment for the control group was combined with normal temperature treatment while the treatment for the observation group was combined with mild hypothermia therapy. RESULTS: 1. Glasgow coma scale (GCS) scores of the patients in the two groups increased gradually after treatment as the APACHE II scores decreased. Comparisons within the group showed significant differences (p < 0.05). The GCS scores of the observation group were significantly increased compared to those in the control group, and the APACHE score decreased significantly. The differences between the groups were statistically significant (p < 0.05). 2. The serum lactic acid, sCD14, S100 beta protein and TNF-a level of patients in two groups all decreased after treatment. The difference was statistically significant (p < 0.05 =. 3. The 24h and 7d survival rates of patients in the observation group are higher than that in the control group (p < 0.05). CONCLUSIONS: The early treatment of hypothermia, can improve the outcome of patients with cardiac arrest. PMID- 26241542 TI - The effects of estradiol on cardiac muscle electrophysiology in orchiectomized rat model: a new insight to side effects caused by castration. AB - OBJCTIVE: Although the testosterone has a protective effect on heart, patients having maximal androgen blockade due to prostate cancer resembles endothelial dysfunction and cardiac problems when compared to normal population. We aimed to test the effect of 17 beta estradiol on the orchiectomized male rat heart electrophysiology and ion channel expression levels. MATERIALS AND METHODS: This study was conducted on 27 male rats with 4 groups (healthy, orchiectomized, orchiectomized+17 beta estradiol treated and orchiectomized+vehicle treated). Action potentials and contractions were recorded simultaneously, while expressions of the calcium and potassium ion channels were measured. RESULTS: Testosterone depletion for 4 weeks has caused a significant prolongation in the action potential durations and decrease in maximal contraction force as well as a deceleration. While this depletion suppressed expression of potassium channels, it increased the expression of calcium ion channels. Application of estradiol on the other hand, except for the calcium ion channel expression, had no positive effect on the tested parameters. CONCLUSIONS: Testosterone has a markedly important and protective effect on male cardiac muscle preparations while estrogen does not have any. It is predicted that testosterone has showed this effect by means of modulation of some key points of excitation-contraction pairing of cardiac muscle. PMID- 26241543 TI - Mucosolvan serves to optimize perioperative airway management for NSCLC patients in fast track surgery: a randomized placebo controlled study. AB - OBJECTIVE: This study is conducted to investigate whether mucosolvan may offer therapy optimization initiatives for airway perioperative management of patients with non-small cell lung cancer (NSCLC) in fast track surgery (FTS). PATIENTS AND METHODS: The patients in FTS were treated with and without aerosol (90 mg/day) of mucosolvan in combination of intravenous administration of the agent (180 mg/day) for 8 consecutive days. Postoperative complications and length of time of hospital stay were examined in the patients treated with and without mucosolvan. RESULTS: Prevalence rate for the overall postoperative complication was significantly decreased in the mucosolvan-treated patients as compared to the untreated ones (p < 0.05). In further analysis, an appearance of postoperative pulmonary complication was reduced in the treated patients as well (p < 0.05). There was no statistical difference in a morbidity rate of postoperative cardiac complications between these two groups. Furthermore, treatment with mucosolvan resulted in significantly decreasing length of time of hospital stay as compared to the untreated patients (p < 0.05), indicating that this agent may facilitate early recovery of the patients in FTS after major surgical approaches. CONCLUSIONS: Mucosolvan optimizes the perioperative airway management for NSCLC patients in FTS through reducing postoperative complications and shortening time of hospital stay. PMID- 26241544 TI - Prognostic grading after complete resection for thymic malignancies. AB - OBJECTIVE: Despite the World Health Organization (WHO) and Masaoka classifications have been widely accepted as the main describers of prognosis determinants in thymic malignancies, so far, these have been considered independently from one another. We have reviewed our single-centre 40-year results after surgical treatment of thymic malignancies evaluating the inter relationships between the clinical, surgical and pathological variables and investigating their prognostic impact in completely resected patients. PATIENTS AND METHODS: A surgical series of 347 patients was reviewed and, of these, 305 with complete resection enrolled. Long-term and disease-free survival (LTS, DFS) analyses were performed. Kaplan-Meir curves for WHO histotypes and Masaoka-stages were inspected and matched with the log-rank test; the Cox regression analysis was adopted in a multivariable approach. RESULTS: Considered independently, the WHO-histotypes did not differentiate clearly from one to another in terms of LTS and DFS; however, types A-AB-B1-B2 and B3-C clustered in 2, statistically different, malignancy groups (LTS, DFS: Cox-p < 0.001). Masaoka staging was confirmed to be a relevant prognostic determinant, even if no evident difference between stages I vs II and stages III vs IV emerged when the Masaoka classification was factored in. Thus, when investigating 13 surgical and pathological factors of invasiveness, these showed a clustering in 2 groups according to the presence/absence of pathological proven infiltration in the peri thymic structures (LTS, DFS: Cox-p < 0.001). By matching the WHO-malignancy clusters and infiltration clusters, 4 classes may be identified, which proved to have a distinct prognostic significance: (LTS-Cox: stage-I vs stage-II, p = 0.003; III: p < 0.001, IV: p < 0.001; DFS-Cox: stage-I vs stage-II, p < 0.001; III: p < 0.001; IV: p < 0.001). CONCLUSIONS: When analyzing the long-term outcome of patients underwent complete resection for thymic malignancies, the combination between pathological and surgical variables showed accurate prognosis predictability. PMID- 26241545 TI - Role of surgery in the treatment of intrahepatic cholangiocarcinoma. AB - Intrahepatic Cholangiocarcinoma (ICC) is the second most common primary liver cancer, accounting for 10% to 15% of primary hepatic malignancy, and its incidence is increasing in Western Countries. Surgery with curative intent is the only treatment that offers a chance of long-term survival, with a reported 5-year overall survival rate ranging from 17% to 48%. In the most of recent series postoperative mortality is lower than 5% and morbidity varied from 6% to 66%. The macroscopic classification of ICC, proposed by Liver Cancer Study Group of Japan (LCSGJ), reflects different biologic behaviours, pattern of tumor growth and clinicopathological findings. The most important prognostic factors after resection are positive resection margins, lymph-node metastases, tumor size, presence of macrovascular invasion and intrahepatic metastases. Unfortunately, recurrence is still frequent and it is the leading cause of death. The treatment of the recurrence varied according to the location and extension of the disease. Recently, expression of several genes found to be related with the carcinogenesis of ICC. These molecular findings are helpful to differentiate the biological behaviour and will provide evidence for the development of new target therapies. PMID- 26241546 TI - Prognostic significance of DLL4 expression in papillary thyroid cancer. AB - OBJECTIVE: Delta-like ligand 4 (DLL4)-Notch signaling has an important role in tumor neovascular development and angiogenesis during tumor growth. However, the clinical significance of DLL4 expression in papillary thyroid cancer remains unclear to date. PATIENTS AND METHODS: 207 papillary thyroid cancer patients were in the present study. DLL4 expression in papillary thyroid cancer was analyzed and evaluated immunohistochemically. The correlation between DLL4 and clinicopathological factors was also evaluated. RESULTS: DLL4 expression was showed in the cytoplasm of papillary thyroid cancer cells by immunohistochemical staining. DLL4 positivity in papillary thyroid cancer was found in 112 (54%) of the 207 papillary thyroid cancer patients. Papillary thyroid cancer DLL4 expression was significantly correlated with thyroid tumour invasion and metastasis. CONCLUSIONS: Overexpression of DLL4 is associated with thyroid tumour invasion and metastasis and it may be an effective target of anti-DLL4 treatment in papillary thyroid cancer. PMID- 26241547 TI - Acrometastasis: a literature review. AB - OBJECTIVE: Acrometastases are a rare observation, and account for approximately 0.1% of metastases. Every age can be affected, with a male predominance. The most common primary cancer site is the lung, followed by the colo-rectal, breast and genito-urinary tract. They are most commonly seen in pre-terminal patients with wide-spread disseminated disease. Rarely, they may be the first presentation of occult silent cancer, mimicking a benign condition. There is no standard treatment. We reviewed last 20 years literature in order to describe the most common sites of primary tumours and the more commonly used treatments. MATERIALS AND METHODS: We searched the Cochrane Central Library (CENTRAL), MEDLINE/PubMed (from 1940 to February 2014), SCOPUS database, and EMBASE/Ovid using a combination of controlled vocabulary and text word terms. RESULTS: Lung cancer was the first most common cause of acrometastases both in hands and feet, with 32.9% of all the cases; 20% of cases were renal cell cancer (RCC) metastases, followed by breast (12.9%) and colon (10%). Primary malignancies and site of metastasis (hand vs foot) suggest that the tumour cells reach the bones through the circulation and not the lymphatic system; in foot acrometastases Batson's plexus may play a fundamental role in dissemination. CONCLUSIONS: Treatment depends on staging and tumor extent. Amputation or disarticulation is the most common approach. It allows a wide margin resection and pain control. In some cases palliative treatment with radiation therapy, bisphosphonates and chemotherapy have been attempted with good results. The prognosis of the patients with acrometastases is poor; the mean survival time after diagnosis is 7 (+/-7) months. Special reference needs to be made to metastasis from renal cell carcinoma; if treated with radical surgical resection and nephrectomy a better outcome and survival rate shall be expected. PMID- 26241548 TI - Comparison of automatical thoughts among generalized anxiety disorder, major depressive disorder and generalized social phobia patients. AB - OBJECTIVE: Automatic thoughts are measurable cognitive markers of the psychopathology and coping styles of individuals. This study measured and compared the automatic thoughts of patients with generalized anxiety disorder (GAD), major depressive disorder (MDD), and generalized social phobia (GSP). PATIENTS AND METHODS: Fifty-two patients with GAD, 53 with MDD, and 50 with GSP and 52 healthy controls completed the validated Automatic Thoughts Questionnaire (ATQ) and a structured psychiatric interview. Patients with GAD, MDD, and GSP also completed the validated Generalized Anxiety Disorder-7 questionnaire, the Beck Depression Inventory (BDI), and the Liebowitz Social Anxiety Scale (LSAS) to determine the severity of their illnesses. All scales were completed before treatment and after diagnosis. The ATQ scores of all pairs of groups were compared. RESULTS: The ATQ scores of the GAD, MDD, and GSP groups were significantly higher than were those of the control group. We also found significant correlations among scores on the GAD-7, BDI, and LSAS. The mean age of patients with GSP was lower than was that of the other groups (30.90 +/- 8.35). CONCLUSIONS: The significantly higher ATQ scores of the MDD, GAD, and GSP groups, compared with the control group, underscore the common cognitive psychopathology characterizing these three disorders. This finding confirms that similar cognitive therapy approaches should be effective for these patients. This study is the first to compare GAD, MDD, and GSP from a cognitive perspective. PMID- 26241549 TI - Inhibitory effect of group II mGluR agonist 2R, 4R-APDC on cell proliferation in dentate gyrus in rats with epileptic seizure. AB - OBJECTIVE: Epileptic seizure can increase the cell proliferation in dentate gyrus in brain, but the mechanism remains unclear. MATERIALS AND METHODS: In this study, using systemic bromodeoxyuridine (BrdU) to label the dividing cells, the inhibitory effect of group II metabotropic glutamate receptor (mGluR) agonist 2R, 4R-4-aminopyrrolidine-2, 4-dicarboxylate (2R, 4R-APDC) on cell proliferation in dentate gyrus in rats after pilocarpine-induced status epilepticus (SE) was investigated. RESULTS: Results found that, 2R, 4R-APDC could significantly inhibit the behavioral seizure and block the seizure-induced increase of BrdU positive cells in dentate gyrus, especially in hilus. Double-label immunofluorescence staining showed that, 2R, 4R-APDC did not affect the ability of newborn cells to differentiate into neurons or astrocytes. CONCLUSIONS: 2R, 4R APDC not only has anticonvulsant effect on adult rats with pilocarpine-induced SE, but also has neuroprotective effect by reducing the abnormal regeneration of nerves. PMID- 26241551 TI - Paraneoplastic orthostatic hypotension associated with acute myeloid leukemia. AB - Paraneoplastic neuropathies associated with leukemia are rare, and early diagnosis and treatment are crucial due to the potential for irreversible neurological deficits and delay in treatment of the leukemia. This is the first report to describe severe paraneoplastic orthostatic hypotension which resolved after treatment of the acute myeloid leukemia (AML). The patient is a 76 year-old woman who presented with progressive dizziness, anorexia, and fatigue. She had severe orthostatic hypotension (supine systolic blood pressure 186 mmHg and standing 79 mmHg). She was found to have AML, for which azacitidine was initiated, and orthostatic hypotension resolved after initiation of treatment. This case demonstrates a unique example of paraneoplastic sequelae remitting with treatment of the underlying hematologic neoplasm. Physicians should be aware of this unusual occurrence of autonomic neuropathy with AML as delay in treatment of the hematologic malignancy can lead to irreversible neurologic deficit and increased morbidity and mortality. PMID- 26241550 TI - Expression level and distribution of HMGB1 in Sombati's cell model and kainic acid-induced epilepsy model. AB - OBJECTIVE: Observe the expression and distribution of HMGB1 in Sombati's cell model and kainic acid-induced epileptic rats' model. MATERIALS AND METHODS: Dissociated hippocampal neurons from neonatal SD rats and cultured those for 9 days, then changed medium to Mg2+-free medium for 3 hours to induce Sombati's cell model. The expression level of HMGB1 in the neurons was detected at 24h and 72h by Western Blotting. Appropriate kainic acid was injected into the lateral ventricles to induced epileptic rats' model in vivo trial, the expression level and distribution of HMGB1 at 24h and 72h were established by immunohistochemistry. RESULTS: The expression level of HMGB1 showed significantly different between model group and control group both in vitro and in vivo trials. At 24h, the expression level of HMGB1 in the model group was lower than the control group (p < 0.05), and became higher than the control group at 72h (p < 0.05). From the in vivotrial, a nucleus-to-cytoplasm translocation was also discovered. CONCLUSIONS: This investigation indicates that HMGB1 plays a crucial role in the pathophysiology of epilepsy, by altering its quantity and distribution. PMID- 26241552 TI - An investigation of the concomitant use of angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs and diuretics. AB - OBJECTIVE: To determine in retrospective data the prevalence at hospital discharge of co-prescribing angiotensin-converting enzyme inhibitors (ACE-I) and non-steroidal anti-inflammatory drugs (NSAIDs) and ACE-I/NSAIDs and diuretics and to identify factors associated with the co-prescription. Secondary, we evaluated the extent of serum creatinine and potassium monitoring in patients treated with ACE-I and these associations and determined the prevalence of values above the upper normal limit (UNL) in monitored patients. PATIENTS AND METHODS: Hospitalized patients with ACE-I in their therapy at discharge were included in 3 groups as follows: ACE-I, DT (double therapy with ACE-I and NSAIDs) and TT (triple therapy with ACE-I, NSAIDs and diuretics) groups. We evaluated differences on demographic characteristics, co-morbidities, medications, laboratory monitoring and quantified the patients with serum creatinine and potassium levels above the UNL using descriptive statistics. Logistic regression analysis with backward elimination was performed to identify significant predictors of combination therapy. RESULTS: Of 9960 admitted patients, 1214 were prescribed ACE-I, 40 were prescribed ACE-I/NSAIDs and 22 were prescribed ACE I/NSAIDs/diuretics (3.13% and 1.72%, respectively, of the patients prescribed with ACE-I). Serum creatinine and potassium were monitored for the great majority of patients from all groups. The highest percentage of hyperkalemia was found in the DT group (10% of the patients) and of serum creatinine above UNL in the TT group (45.45%). The logistic regression final model showed that younger patients and monitoring for potassium were significantly associated with combination therapy. CONCLUSIONS: The prevalence of patients receiving DT/TT was relatively low and their monitoring during hospitalization was high. Factors associated with the combinations were younger patients and patients not tested for serum potassium. PMID- 26241553 TI - Resolving the organization of the territory of the third visual area: a new proposal. AB - In primates, the cortex adjoining the rostral border of V2 has been variously interpreted as belonging to a single visual area, V3, with dorsal V3 (V3d) representing the lower visual quadrant and ventral V3 (V3v) representing the upper visual quadrant, V3d and V3v constituting separate, incomplete visual areas, V3d and ventral posterior (VP), or V3d being divided into several visual areas, including a dorsomedial (DM) visual area, a medial visual area (M), and dorsal extension of VP (or VLP). In our view, the evidence from V1 connections strongly supports the contention that V3v and V3d are parts of a single visual area, V3, and that DM is a separate visual area along the rostral border of V3d. In addition, the retinotopy revealed by V1 connection patterns, microelectrode mapping, optical imaging mapping, and functional magnetic resonance imaging (fmri) mapping indicates that much of the proposed territory of V3d corresponds to V3. Yet, other evidence from microelectrode mapping and anatomical connection patterns supports the possibility of an upper quadrant representation along the rostral border of the middle of dorsal V2 (V2d), interpreted as part of DM or DM plus DI, and along the midline end of V2d, interpreted as the visual area M. While the data supporting these different interpretations appear contradictory, they also seem, to some extent, valid. We suggest that V3d may have a gap in its middle, possibly representing part of the upper visual quadrant that is not part of DM. In addition, another visual area, M, is likely located at the DM tip of V3d. There is no evidence for a similar disruption of V3v. For the present, we favor continuing the traditional concept of V3 with the possible modification of a gap in V3d in at least some primates. PMID- 26241554 TI - Structure elucidation and NMR assignments of a new 6,9-cyclotetrahydrofuranlignan from Syringa pinnatifolia. AB - A new 6,9-cyclotetrahydrofuranlignan, 3,3'-dimethoxy-4,4'-dihydroxy 8beta,9beta,8'alpha-6,9-cyclotetrahydrofuranlignan, was isolated from the stem of Syringa pinnatifolia Hems1.var. alashanensis MA. et S. Q. ZHOU. Its structures were elucidated on the basis of spectroscopic methods including UV, IR, ESI-MS, 1D NMR and 2D NMR. PMID- 26241555 TI - Effect of Oncoxin Oral Solution in HER2-Overexpressing Breast Cancer. AB - One of the most aggressive breast cancer subtypes includes tumors with high expression of HER2. Gene expression and functional studies have shown a link between HER2 overexpression and oxidative stress. Because of this, we hypothesized that Oncoxin Oral Solution (OOS), a composite product that contains several antioxidants, could have an antitumoral effect against HER2+ tumors. Dose response studies, biochemical and cytometric assessment of the effect of OOS on cell cycle and apoptosis, and drug combination analyses were performed on BT474 and SKBR3 cells, 2 HER2-overexpressing breast cancer cell lines. OOS reduced the proliferation of these cells, and augmented the action of lapatinib, a HER2 inhibitor used in the breast cancer clinic. Moreover, OOS decreased growth of HER2+ tumors in mice. Mechanistically, OOS provoked cell cycle blockade through upregulation of p27 expression and downregulation of cyclin D levels. OOS also caused apoptotic cell death in HER2+ breast cancer cells, as indicated by increases in PARP cleavage as well as upregulation of caspase 8 and caspase 3 activities. These results demonstrate an antitumoral action of OOS in preclinical models of HER2+ breast cancer and suggest that it can be used with anti-HER2 therapies currently adopted as standard of care in the oncology clinic. PMID- 26241556 TI - The association between orthostatic increase in pulse pressure and ischemic heart disease. AB - The clinical meaning of changes in PP with posture remains unclear. We performed treadmill exercise testing on 144 subjects to diagnose ischemic heart disease, and measured the PPs in the supine and standing positions. The differences in the two PPs ranged between -35 and 45 mmHg. Eleven subjects were diagnosed with significant coronary ischemia. The differences in the PPs were significantly increased, and PP in the standing position was significantly elevated in these subjects. A large difference in the PPs in the standing and supine positions was associated with significant coronary ischemia, independent of significant covariables. PMID- 26241559 TI - Neuroleptic Malignant Syndrome Associated With Metoclopramide Use in a Boy: Case Report and Review of the Literature. AB - Neuroleptic malignant syndrome (NMS), an idiosyncratic reaction comprising muscular rigidity, altered level of consciousness, and autonomic dysfunction, is a rare but serious medical condition. It is most commonly precipitated by major tranquilizers such as butyrophenones, phenothiazines, and thioxanthines. Metoclopramide, a chlorbenzamide derivative with antidopaminergic properties, is widely used to treat nausea and emesis. We describe the first reported case of a boy who developed NMS in association with the use of this drug. A 13-year-old boy presented to the emergency department with a history of hyperthermia (42.6 degrees C) and altered level of consciousness. He had recently had acute gastroenteritis and had been treated with metoclopramide 10 mg three times a day for 2 days. Vital signs were notable for hypotension, and physical examination revealed altered mental status with muscle rigidity. Laboratory testing revealed metabolic acidosis and increased prothrombin and partial thromboplastin times. He was actively cooled and received 3 rapid boluses, totaling 60 mL/kg, of isotonic crystalloids, for more than 20 minutes. Sepsis workup revealed no evidence of bacterial infection. He subsequently recovered fully and was discharged home with pediatric follow-up. This case represents the first description of NMS in association with metoclopramide in a healthy boy. It demonstrates the importance of considering this diagnosis early in the course of disease in patients with muscular rigidity, altered level of consciousness and autonomic dysfunction, and the need to rapidly respond to the physiological aberrations. PMID- 26241560 TI - Peptide Anchor for Folate-Targeted Liposomal Delivery. AB - Specific folate receptors are abundantly overexpressed in chronically activated macrophages and in most cancer cells. Directed folate receptor targeting using liposomes is usually achieved using folate linked to a phospholipid or cholesterol anchor. This link is formed using a large spacer like polyethylene glycol. Here, we report an innovative strategy for targeted liposome delivery that uses a hydrophobic fragment of surfactant protein D linked to folate. Our proposed spacer is a small 4 amino acid residue linker. The peptide conjugate inserts deeply into the lipid bilayer without affecting liposomal integrity, with high stability and specificity. To compare the drug delivery potential of both liposomal targeting systems, we encapsulated the nuclear dye Hoechst 34580. The eventual increase in blue fluorescence would only be detectable upon liposome disruption, leading to specific binding of this dye to DNA. Our delivery system was proven to be more efficient (2-fold) in Caco-2 cells than classic systems where the folate moiety is linked to liposomes by polyethylene glycol. PMID- 26241561 TI - Kinetics of Ice Nucleation Confined in Nanoporous Alumina. AB - The nucleation mechanism of water (heterogeneous/homogeneous) can be regulated by confinement within nanoporous alumina. The kinetics of ice nucleation is studied in confinement by employing dielectric permittivity as a probe. Both heterogeneous and homogeneous nucleation, obtained at low and high undercooling, respectively, are stochastic in nature. The temperature interval of metastability extends over ~4 and 0.4 degrees C for heterogeneous and homogeneous nucleation, respectively. Nucleation within a pore is spread to all pores in the template. We have examined a possible coupling of all pores through a heat wave and a sound wave, with the latter being a more realistic scenario. In addition, dielectric spectroscopy indicates that prior to crystallization undercooled water molecules relax with an activation energy of ~50 kJ/mol, and this process acts as precursor to ice nucleation. PMID- 26241562 TI - Idiopathic Pulmonary Fibrosis in United States Automated Claims. Incidence, Prevalence, and Algorithm Validation. AB - RATIONALE: Estimates of idiopathic pulmonary fibrosis (IPF) incidence and prevalence from electronic databases without case validation may be inaccurate. OBJECTIVES: Develop claims algorithms to identify IPF and assess their positive predictive value (PPV) to estimate incidence and prevalence in the United States. METHODS: We developed three algorithms to identify IPF cases in the HealthCore Integrated Research Database. Sensitive and specific algorithms were developed based on literature review and consultation with clinical experts. PPVs were assessed using medical records. A third algorithm used logistic regression modeling to generate an IPF score and was validated using a separate set of medical records. We estimated incidence and prevalence of IPF using the sensitive algorithm corrected for the PPV. MEASUREMENTS AND MAIN RESULTS: We identified 4,598 patients using the sensitive algorithm and 2,052 patients using the specific algorithm. After medical record review, the PPVs of these algorithms using the treating clinician's diagnosis were 44.4 and 61.7%, respectively. For the IPF score, the PPV was 76.2%. Using the clinical adjudicator's diagnosis, the PPVs were 54 and 57.6%, respectively, and for the IPF score, the PPV was 83.3%. The incidence and period prevalences of IPF, corrected for the PPV, were 14.6 per 100,000 person-years and 58.7 per 100,000 persons, respectively. CONCLUSIONS: Sensitive algorithms without correction for false positive errors overestimated incidence and prevalence of IPF. An IPF score offered the greatest PPV, but it requires further validation. PMID- 26241563 TI - A Number to Remember: 741741. PMID- 26241564 TI - "What's New about Freud?". AB - This is a response to a recent Issues in Mental Health Nursing editorial, titled "What's New about Freud?" This response aims to point out the relationship between Freud's psychoanalytic theory; Cowling, Smith, and Watson's (2008) nursing as unitary caring science praxis; and this author's future as a nurse researcher. PMID- 26241565 TI - An Exploration of the Relationships between Attitudes Towards Anger Expression and Personal Style of Anger Expression in Women in the USA and Canada. AB - This study surveyed 228 women, ages 18-75, to assess their attitudes towards anger expression in themselves and other women. Following exposure to an anger inducing vignette, the women were asked to complete the STAXI-2 and evaluate five possible responses based on how appropriate the response was and how likely they felt that other women would respond similarly. Correlation analyses revealed positive and negative relationships between the women's attitudes towards anger expression and their own style of anger expression, as measured by the STAXI-2. The authors discuss implications for practice and future research. PMID- 26241566 TI - Caring Situation, Health, Self-efficacy, and Stress in Young Informal Carers of Family and Friends with Mental Illness in Sweden. AB - This study compared the caring situation, health, self-efficacy, and stress of young (16-25) informal carers (YICs) supporting a family member with mental illness with that of YICs supporting a friend. A sample of 225 carers, assigned to a family group (n = 97) or a friend group (n = 128) completed the questionnaire. It was found that the family group experiences a lower level of support and friends experienced a lower positive value of caring. No other differences in health, general self-efficacy and stress were found. YICs endure different social situations, which is why further study of the needs of YICs, especially those supporting friends, is urgently needed. PMID- 26241567 TI - When It Is Not Postpartum Depression: Understanding the Postpartum Mental Health Needs of Mothers and How They Are Being Met. AB - Although often overlooked, subclinical symptoms of postpartum depression, anxiety, or other mental health symptoms among new mothers increase the risk of more severe problems and can adversely affect maternal and infant health. We conducted focus groups with 92 new mothers and interviews with 20 healthcare providers to elucidate perceptions of mental health needs among first-time mothers and how healthcare providers address these needs. Our findings suggest that a tradition of focusing exclusively on severe presentations of mental health issues may limit maternal and provider ability to address the full spectrum of mental health needs. PMID- 26241568 TI - Towards Effective Management in Psychiatric-Mental Health Nursing: The Dangers and Consequences of Micromanagement. AB - Micromanagement refers to a management style that involves managers exercising control over team members, teams, and also organizations, particularly in relation to the minutiae or minor details of day-to-day operations. While there is no single reason why some managers may choose to micromanage, many micromanagers exhibit similar behavioral traits, a consequence of perfectionism and/or underlying insecurities. In the culture of high performance that characterizes many contemporary mental health contexts, micromanagement also provides one way by which teams can be driven to achieve targets. However, over time, micromanagement leads to reductions in staff morale, creativity, and productivity; and increases in staff turnover. This paper provides an overview of micromanagement, including points of consideration for managers interested in reflecting on their management styles, and strategies for mental health nurses who find themselves working for a micromanager. PMID- 26241569 TI - Comparing Online with Face-to-Face HELPP Intervention in Women Experiencing Intimate Partner Violence. AB - Intimate partner violence (IPV) is a public health problem. The purpose of this study was to compare the effectiveness of the HELPP (Health, Education on Safety, and Legal Support and Resources in IPV Participant Preferred) intervention among IPV survivors. A sequential, transformative mixed-methods design was used. Participants were randomly assigned to one of three study groups: Online (ONL), Face-to-Face (FTF), and Waitlist Control (WLC). The HELPP intervention was offered to 32 adult female participants who were 45.2% Asian, 32.3% White, and 22.5% Black. Outcome measures were anxiety, depression, anger, personal, and social support. In total, 64% (n = 20) of the participants reported having experienced IPV before the age of 18. The anger mean score pre-test to post-test difference was significant for ONL (p < 0.001) and WLC (p = 0.01). The personal and social support pre-test to post-test mean score differences were significant for ONL (p < 0.001; p < 0.001) and WLC (p = 0.01; p = 0.006), respectively. The HELPP intervention (1) decreased anxiety, depression, anger, and (2) increased personal and social support in the ONL group. The HELPP information and intervention was shown to be feasible, acceptable, and effective among IPV survivors compared with participants in the WLC group. The WLC participants displayed (1) increased levels of anxiety, depression, and anger and (2) decreased levels of personal and social support, post-intervention. Further research could be conducted to determine if e-mail alone or e-mail plus mobile devices are more useful modes of delivering interventions. PMID- 26241570 TI - Dementia and Caregiver Stress: An Application of the Reconceptualized Uncertainty in Illness Theory. AB - The Reconceptualized Uncertainty in Illness Theory (RUIT) was used to investigate antecedents to, appraisals of, and ways of coping with stressful caregiving. Four focus groups with caregivers (8 males and 16 females) of relatives with dementia were conducted; 15 cared for their parents and the remainder cared for their spouses. They were recruited from an adult care center and other community settings in a metropolitan area in New England. The discussions were audiotaped and transcribed verbatim. Two researchers independently coded the transcripts. Thematic analysis was structured according to the RUIT. The study is unique in its application to caregivers as opposed to patients and to all of the elements of the RUIT. Caregivers experience uncertainty in similar ways to patients with life-altering illness. Symptom severity--lack of personal boundaries, repetitive and aggressive behaviors, and the need for constant care--was the most frequent source of stress. The appraisals were mostly negative and included feelings of resentment, a lack of support from family members, financial strains, and loss of freedom. Self-improvement and self-care were important aspects of coping. Spirituality and humor were other coping skills that respondents used. Not all respondents said they were coping and some also reported that support from health care providers was not always helpful. Nurses can help improve coping by explaining the factors that contribute to caregiver strain and uncertainty, and by assisting caregivers to anticipate the effects of the caregiving role. PMID- 26241571 TI - Career Choice and Longevity in U.S. Psychiatric-Mental Health Nurses. AB - The demand for mental health services in the United States taxes the existing care continuum and is projected to increase as federal initiatives such as the Affordable Care Act and mental health parity improve access to, and coverage for, mental health services. Quality health care providers, such as psychiatric-mental health nurses, are needed to bolster the mental health system. Prior research has focused on the unpopularity of psychiatric nursing as a career choice for nursing students. The purpose of this study is to understand how seasoned psychiatric nurses came to choose and remain in the specialty; descriptive phenomenology is used. In a face-to-face interview, eight registered nurses described their experiences with psychiatric nursing as a student, their entry into psychiatric nursing, and factors related to their longevity in the specialty. Giorgi's Existential Phenomenological Research Method was employed to analyze the interview data. Three themes emerged related to career choice: Interest Developed Prior to or While in Nursing School, Personal Relevance, and Validation of Potential. Three themes emerged related to retention: Overcoming Stereotypes to Develop Career Pride, Positive Team Dynamics, and Remaining Hopeful. Nurse educators play an important role in identifying talent, validating capability, enhancing interest, and increasing students' confidence to pursue a psychiatric nursing career, while nursing administrators and clinical specialists play a key role in retention. Findings also stimulate pertinent questions surrounding the long-term viability of the psychiatric-mental health nursing specialty. PMID- 26241573 TI - Nursing Care for Lifestyle Behavioral Change. AB - The purpose of this pilot study was to determine if metabolic risk factors can be stabilized or improved with weekly motivational interviewing/coaching and medical follow-up care focused on lifestyle behavioral change in individuals with serious mental illness. Individuals were followed for 18 weeks following discharge from an inpatient psychiatric service. All individuals were prescribed an antipsychotic medication and had at least two risk factors for metabolic syndrome. Weight, waist circumference, blood pressure, LDLs, triglycerides, and blood glucose levels were evaluated during the study period. In addition, each individual selected a lifestyle behavior to improve over the 18-week period. Weekly motivational interviewing, and staggered health promotion appointments were designed to keep individuals focused on health and behavior change. While some individuals showed improvement, others showed deterioration in the physiological markers for metabolic syndrome. Only a small number completed the 18-week study. The nature of current psychiatric care is focused on rapid stabilization and discharge; individuals with serious mental illness may have difficulty focusing on lifestyle behavioral change while transitioning to independent living following an acute exacerbation of mental illness. PMID- 26241572 TI - Korean-Americans' Knowledge about Depression and Attitudes about Treatment Options. AB - The purpose of this pilot study was to explore first-generation Korean-Americans' knowledge about depression and attitudes about depression treatment options. Self report survey data were gathered from 73 first-generation Korean-Americans (KAs) using instruments developed for this study. The data were analyzed using descriptive and inferential statistics including t-tests. Data indicated participants lacked knowledge about depression. Among all depression treatment options, exercise was the option that first-generation KAs were most willing to try and was rated as having the least shame attached to it. Taking an antidepressant was the option KAs reported being most unwilling to try and had the highest shame attached to it. No significant differences in knowledge about depression and attitudes about depression treatment options were found between low and high acculturation groups, with the exception that the high acculturation group demonstrated more agreement than the low acculturation group with the item that emotional symptoms, such as mood changes, can be depression symptoms. These results suggest that initiating depression treatment with exercise may be the most acceptable starting point in treating depression in first-generation KA immigrants. PMID- 26241574 TI - Cognitively Impaired Sexually Abused Women: The Most Vulnerable of All? PMID- 26241577 TI - Corrigendum. AB - Article title: "Trauma-Informed Care: Keeping Mental Health Settings Safe for Veterans". Authors: Ursula Kelly, Mary Ann Boyd, Sharon Valente, and Elizabeth Czekanski. Journal: Issues in Mental Health Nursing. Bibliometrics: Volume 35, Issue 6, pages 413-419. DOI: 10.3109/01612840.2014.881941. The authors acknowledge the contribution of Preston Fitzgerald to an earlier version of their article. PMID- 26241575 TI - The Future of Big Data: Innovative Methodological Approaches. PMID- 26241578 TI - Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury. AB - SB-3CT is a potent and selective inhibitor of matrix metalloproteinase (MMP)-2 and -9, which has shown efficacy in an animal model of severe traumatic brain injury (TBI). However, SB-3CT is poorly water-soluble and is metabolized primarily to p-hydroxy SB-3CT (2), a more potent inhibitor than SB-3CT. We synthesized the O-phosphate prodrug (3) of compound 2 to enhance its water solubility by more than 2000-fold. The prodrug 3 was a poor MMP inhibitor, but readily hydrolyzed to the active 2 in human blood. Pharmacokinetics and brain distribution studies in mice showed that 2 crossed the blood-brain barrier (BBB) and achieved therapeutic concentrations in the brain. The prodrug 3/compound 2 was evaluated in a mouse model of severe TBI and found to significantly decrease the brain lesion volume and improve neurological outcomes. MMP-9 inhibition by a water-soluble thiirane inhibitor is a promising therapy for treatment of TBI. PMID- 26241579 TI - Correlations and Contrasts in Homo- and Heteroleptic Cyclic (Alkyl)(amino)carbene Containing Pt(0) Complexes. AB - An improved synthetic route to homoleptic complex [Pt(CAAC(Me))2] (CAAC = cyclic (alkyl)(amino)carbenes) and convenient routes to new heteroleptic complexes of the form [Pt(CAAC(Me))(PR3)] are presented. Although the homoleptic complex was found to be inert to many reagents, oxidative addition and metal-only Lewis pair (MOLP) formation was observed from one of the heteroleptic complexes. The spectroscopic, structural, and electrochemical properties of the zero-valent complexes were explored in concert with density functional theory (DFT) and time dependent density functional theory (TD-DFT) calculations. The homoleptic [Pt(CAAC)2] and heteroleptic [Pt(CAAC)(PR3)] complexes were found to be similar in their spectroscopic and structural properties, but their electrochemical behavior and reactivity differ greatly. The unusually strong color of the CAAC containing Pt(0) complexes was investigated by TD-DFT calculations and attributed to excitations into the LUMOs of the complexes, which are predominantly composed of bonding pi interactions between Pt and the CAAC carbon atoms. PMID- 26241582 TI - March Through a Swamp in Pursuit of Slaves: John Gabriel Stedman. PMID- 26241583 TI - The Role of University Health Centers in Intervention and Prevention of Campus Sexual Assault. PMID- 26241584 TI - A New Focus on Prescription Drug Spending. PMID- 26241592 TI - The State of the World's Refugees: The Importance of Work, Cash Assistance, and Health Insurance. PMID- 26241593 TI - Sexual Assaults Among University Students: Prevention, Support, and Justice. PMID- 26241594 TI - Physician Counseling on Firearm Safety: A New Kind of Cultural Competence. PMID- 26241595 TI - A PIECE OF MY MIND. Lessons of the Gacaca. PMID- 26241596 TI - Broadening the Approach to Posttraumatic Stress Disorder and the Consequences of Trauma. PMID- 26241597 TI - Mindfulness-Based Stress Reduction for Posttraumatic Stress Disorder Among Veterans: A Randomized Clinical Trial. AB - IMPORTANCE: Mindfulness-based interventions may be acceptable to veterans who have poor adherence to existing evidence-based treatments for posttraumatic stress disorder (PTSD). OBJECTIVE: To compare mindfulness-based stress reduction with present-centered group therapy for treatment of PTSD. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of 116 veterans with PTSD recruited at the Minneapolis Veterans Affairs Medical Center from March 2012 to December 2013. Outcomes were assessed before, during, and after treatment and at 2-month follow up. Data collection was completed on April 22, 2014. INTERVENTIONS: Participants were randomly assigned to receive mindfulness-based stress reduction therapy (n = 58), consisting of 9 sessions (8 weekly 2.5-hour group sessions and a daylong retreat) focused on teaching patients to attend to the present moment in a nonjudgmental, accepting manner; or present-centered group therapy (n = 58), an active-control condition consisting of 9 weekly 1.5-hour group sessions focused on current life problems. MAIN OUTCOMES AND MEASURES: The primary outcome, change in PTSD symptom severity over time, was assessed using the PTSD Checklist (range, 17-85; higher scores indicate greater severity; reduction of 10 or more considered a minimal clinically important difference) at baseline and weeks 3, 6, 9, and 17. Secondary outcomes included PTSD diagnosis and symptom severity assessed by independent evaluators using the Clinician-Administered PTSD Scale along with improvements in depressive symptoms, quality of life, and mindfulness. RESULTS: Participants in the mindfulness-based stress reduction group demonstrated greater improvement in self-reported PTSD symptom severity during treatment (change in mean PTSD Checklist scores from 63.6 to 55.7 vs 58.8 to 55.8 with present-centered group therapy; between-group difference, 4.95; 95% CI, 1.92 7.99; P=.002) and at 2-month follow-up (change in mean scores from 63.6 to 54.4 vs 58.8 to 56.0, respectively; difference, 6.44; 95% CI, 3.34-9.53, P < .001). Although participants in the mindfulness-based stress reduction group were more likely to show clinically significant improvement in self-reported PTSD symptom severity (48.9% vs 28.1% with present-centered group therapy; difference, 20.9%; 95% CI, 2.2%-39.5%; P = .03) at 2-month follow-up, they were no more likely to have loss of PTSD diagnosis (53.3% vs 47.3%, respectively; difference, 6.0%; 95% CI, -14.1% to 26.2%; P = .55). CONCLUSIONS AND RELEVANCE: Among veterans with PTSD, mindfulness-based stress reduction therapy, compared with present-centered group therapy, resulted in a greater decrease in PTSD symptom severity. However, the magnitude of the average improvement suggests a modest effect. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01548742. PMID- 26241598 TI - Brief Motivational Intervention for Intimate Partner Violence and Heavy Drinking in the Emergency Department: A Randomized Clinical Trial. AB - IMPORTANCE: Intimate partner violence (IPV) and heavy drinking are co-occurring public health problems, but integrated brief interventions for these conditions have not been tested. OBJECTIVE: To determine whether a brief motivational intervention provided at the time of an emergency department (ED) visit reduces IPV and heavy drinking. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial conducted at 2 US academic urban EDs between January 2011 and December 2014 to assess the effectiveness of a motivational intervention for IPV-involved female ED patients (ages: 18-64 years; N = 600) who exceeded sex-specific safe drinking limits. All received social service referrals; 2:2:1 to brief intervention (n = 242), assessed control (n = 237), or no-contact control (n = 121). INTERVENTIONS: A 20- to 30-minute manual-guided motivational intervention (recorded and monitored for fidelity) delivered by master's-level therapists with a follow-up telephone booster. The assessed control group received the same number of assessments as the brief intervention group; the no-contact control group was assessed only once at 3 months. MAIN OUTCOMES AND MEASURES: Incidents of heavy drinking and experiencing IPV measured over prespecified, 12 weekly assessments using an interactive voice response system. RESULTS: Of 600 participants, 80% were black women with a mean age of 32 years. Retention was 89% for 2 or more interactive voice response system calls. Seventy-eight percent of women completed the 3-month interview, 79% at 6 months, and 71% at 12 months. During the 12-week period following the brief motivational intervention, there were no significant differences between the intervention group and the assessed control group on weekly assessments for experiencing IPV (odds ratio [OR], 1.02; 95% CI, 0.98-1.06) or heavy drinking (OR, 0.99; 95% CI, 0.96-1.03). From baseline to 12 weeks, the number of women with any IPV in the past week decreased from 57% (134 of 237) in the intervention group to 43% (83 of 194) and from 63% (145 of 231) in the assessed control group to 41% (77 of 187) (absolute difference of 8%). From baseline to 12 weeks, the number of women with past week heavy drinking decreased from 51% (120 of 236) in the intervention group to 43% (83 of 194) and from 46% (107 of 231) in the assessed control group to 41% (77 of 187) (absolute difference of 3%). At 12 months, 43% (71 of 165) of the intervention group and 47% (78 of 165) of the assessed control group reported no IPV during the previous 3 months and 19% (29 of 152) of the intervention group and 24% (37 of 153) of the control group had reduced their alcohol consumption to sex-specific National Institute on Alcohol Abuse and Alcoholism safe drinking levels. CONCLUSIONS AND RELEVANCE: For women experiencing IPV and heavy drinking, the use of a brief motivational intervention in the ED compared with assessed and no-contact controls did not significantly reduce the days of heavy drinking or incidents of IPV. These findings do not support a brief motivational intervention in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifer: NCT01207258. PMID- 26241599 TI - Violence in the United States: Status, Challenges, and Opportunities. AB - IMPORTANCE: Interpersonal violence, which includes child abuse and neglect, youth violence, intimate partner violence, sexual violence, and elder abuse, affects millions of US residents each year. However, surveillance systems, programs, and policies to address violence often lack broad, cross-sector collaboration, and there is limited awareness of effective strategies to prevent violence. OBJECTIVES: To describe the burden of interpersonal violence in the United States, explore challenges to violence prevention efforts and to identify prevention opportunities. DATA SOURCES: We reviewed data from health and law enforcement surveillance systems including the National Vital Statistics System, the Federal Bureau of Investigation's Uniform Crime Reports, the US Justice Department's National Crime Victimization Survey, the National Survey of Children's Exposure to Violence, the National Child Abuse and Neglect Data System, the National Intimate Partner and Sexual Violence Survey, the Youth Risk Behavior Surveillance System, and the National Electronic Injury Surveillance System-All Injury Program. RESULTS: Homicide rates have decreased from a peak of 10.7 per 100,000 persons in 1980 to 5.1 per 100,000 in 2013. Aggravated assault rates have decreased from a peak of 442 per 100,000 in 1992 to 242 per 100,000 in 2012. Nevertheless, annually, there are more than 16,000 homicides and 1.6 million nonfatal assault injuries requiring treatment in emergency departments. More than 12 million adults experience intimate partner violence annually and more than 10 million children younger than 18 years experience some form of maltreatment from a caregiver, ranging from neglect to sexual abuse, but only a small percentage of these violent incidents are reported to law enforcement, health care clinicians, or child protective agencies. Moreover, exposure to violence increases vulnerability to a broad range of mental and physical health problems over the life course; for example, meta-analyses indicate that exposure to physical abuse in childhood is associated with a 54% increased odds of depressive disorder, a 78% increased odds of sexually transmitted illness or risky sexual behavior, and a 32% increased odds of obesity. Rates of violence vary by age, geographic location, sex, and race/ethnicity, and significant disparities exist. Homicide is the leading cause of death for non-Hispanic blacks from age 1 through 44 years, whereas it is the fifth most common cause of death among non-Hispanic whites in this age range. Additionally, efforts to understand, prevent, and respond to interpersonal violence have often neglected the degree to which many forms of violence are interconnected at the individual level, across relationships and communities, and even intergenerationally. The most effective violence prevention strategies include parent and family-focused programs, early childhood education, school-based programs, therapeutic or counseling interventions, and public policy. For example, a systematic review of early childhood home visitation programs found a 38.9% reduction in episodes of child maltreatment in intervention participants compared with control participants. CONCLUSIONS AND RELEVANCE: Progress has been made in reducing US rates of interpersonal violence even though a significant burden remains. Multiple strategies exist to improve violence prevention efforts, and health care providers are an important part of this solution. PMID- 26241600 TI - Psychotherapy for Military-Related PTSD: A Review of Randomized Clinical Trials. AB - IMPORTANCE: Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder common among military personnel and veterans. First-line psychotherapies most often recommended for PTSD consist mainly of "trauma-focused" psychotherapies that involve focusing on details of the trauma or associated cognitive and emotional effects. OBJECTIVE: To examine the effectiveness of psychotherapies for PTSD in military and veteran populations. EVIDENCE REVIEW: PubMed, PsycINFO, and PILOTS were searched for randomized clinical trials (RCTs) of individual and group psychotherapies for PTSD in military personnel and veterans, published from January 1980 to March 1, 2015. We also searched reference lists of articles, selected reviews, and meta-analyses. Of 891 publications initially identified, 36 were included. FINDINGS: Two trauma-focused therapies, cognitive processing therapy (CPT) and prolonged exposure, have been the most frequently studied psychotherapies for military-related PTSD. Five RCTs of CPT (that included 481 patients) and 4 RCTs of prolonged exposure (that included 402 patients) met inclusion criteria. Focusing on intent-to-treat outcomes, within-group posttreatment effect sizes for CPT and prolonged exposure were large (Cohen d range, 0.78-1.10). CPT and prolonged exposure also outperformed waitlist and treatment-as-usual control conditions. Forty-nine percent to 70% of participants receiving CPT and prolonged exposure attained clinically meaningful symptom improvement (defined as a 10- to 12-point decrease in interviewer-assessed or self-reported symptoms). However, mean posttreatment scores for CPT and prolonged exposure remained at or above clinical criteria for PTSD, and approximately two-thirds of patients receiving CPT or prolonged exposure retained their PTSD diagnosis after treatment (range, 60%-72%). CPT and prolonged exposure were marginally superior compared with non-trauma-focused psychotherapy comparison conditions. CONCLUSIONS AND RELEVANCE: In military and veteran populations, trials of the first-line trauma-focused interventions CPT and prolonged exposure have shown clinically meaningful improvements for many patients with PTSD. However, nonresponse rates have been high, many patients continue to have symptoms, and trauma-focused interventions show marginally superior results compared with active control conditions. There is a need for improvement in existing PTSD treatments and for development and testing of novel evidence-based treatments, both trauma-focused and non-trauma-focused. PMID- 26241602 TI - Psychological Treatments for Orphans and Vulnerable Children Affected by Traumatic Events and Chronic Adversity in Sub-Saharan Africa. PMID- 26241601 TI - Does This Patient Have Posttraumatic Stress Disorder?: Rational Clinical Examination Systematic Review. AB - IMPORTANCE: Posttraumatic stress disorder (PTSD) is a relatively common mental health condition frequently seen, though often unrecognized, in primary care settings. Identifying and treating PTSD can greatly improve patient health and well-being. OBJECTIVE: To systematically review the utility of self-report screening instruments for PTSD among primary care and high-risk populations. EVIDENCE REVIEW: We searched MEDLINE and the National Center for PTSD's Published International Literature on Traumatic Stress (PILOTS) databases for articles published on screening instruments for PTSD published from January 1981 through March 2015. Study quality was rated using Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria. STUDY SELECTION: Studies of screening instruments for PTSD evaluated using gold standard structured clinical diagnostic interviews that had interview samples of at least 50 individuals. FINDINGS: We identified 2522 citations, retrieved 318 for further review, and retained 23 cohort studies that evaluated 15 screening instruments for PTSD. Of the 23 studies, 15 were conducted in primary care settings in the United States (n = 14,707 were screened, n = 5374 given diagnostic interview, n = 814 had PTSD) and 8 were conducted in community settings following probable trauma exposure (ie, natural disaster, terrorism, and military deployment; n = 5302 were screened, n = 4263 given diagnostic interview, n = 393 were known to have PTSD with an additional 50 inferred by rates reported by authors). Two screens, the Primary Care PTSD Screen (PC-PTSD) and the PTSD Checklist were the best performing instruments. The 4-item PC-PTSD has a positive likelihood ratio of 6.9 (95% CI, 5.5-8.8) and a negative likelihood ratio of 0.30 (95% CI, 0.21-0.44) using the same score indicating a positive screen as used by the Department of Veterans Affairs in all of its primary care clinics. The 17-item PTSD Checklist has a positive likelihood ratio of 5.2 (95% CI, 3.6-7.5) and a negative likelihood ratio of 0.33 (95% CI, 0.29-0.37) using scores of around 40 as indicating a positive screen. Using the same score employed by primary care clinics in the Department of Veterans Affairs to indicate a positive screen, the 4-item PC-PTSD has a sensitivity of 0.69 (95% CI, 0.55-0.81), a specificity of 0.92 (95% CI, 0.86-0.95), a positive likelihood ratio of 8.49 (95% CI, 5.56-12.96) and a negative likelihood ratio of 0.34 (95% CI, 0.22-0.48). For the 17-item PTSD Checklist, scores around 40 as indicating a positive screen, have a sensitivity of 0.70 (95% CI, 0.64-0.77), a specificity of 0.90 (95% CI, 0.84-0.93), a positive likelihood ratio of 6.8 (95% CI, 4.7-9.9) and a negative likelihood ratio of 0.33 (95% CI, 0.27-0.40). CONCLUSIONS AND RELEVANCE: Two screening instruments, the PC-PTSD and the PTSD Checklist, show reasonable performance characteristics for use in primary care clinics or in community settings with high-risk populations. Both are easy to administer and interpret and can readily be incorporated into a busy practice setting. PMID- 26241603 TI - Effect of Screening for Partner Violence on Use of Health Services at 3-Year Follow-up of a Randomized Clinical Trial. PMID- 26241604 TI - Sexual Violence and HIV Infection Associated With Adolescent vs Adult Entry Into the Sex Trade in Mexico. PMID- 26241605 TI - Medical Scribes and Electronic Health Records. PMID- 26241606 TI - Medical Scribes and Electronic Health Records. PMID- 26241607 TI - Medical Scribes and Electronic Health Records--Reply. PMID- 26241608 TI - Incorrect Figure Label. PMID- 26241610 TI - Psychiatric Evaluation of Those Returning from Combat. PMID- 26241611 TI - JAMA PATIENT PAGE. Posttraumatic Stress Disorder (PTSD). PMID- 26241612 TI - The Acute Effect of Concurrent Training on Running Performance Over 6 Days. AB - PURPOSE: This study examined the effects of strength training on alternating days and endurance training on consecutive days on running performance for 6 days. METHODS: Sixteen male and 8 female moderately trained individuals were evenly assigned into concurrent-training (CCT) and strength-training (ST) groups. The CCT group undertook strength training on alternating days combined with endurance training on consecutive days for 6 days. One week later, the CCT group conducted 3 consecutive days of endurance training only to determine whether fatigue would be induced with endurance training alone (CCT-Con). Endurance training was undertaken to induce endurance-training stimulus and to measure the cost of running (CR), rating of perceived exertion (RPE), and time to exhaustion (TTE). The ST group undertook 3 strength-training sessions on alternating days. Maximal voluntary contraction (MVC), rating of muscle soreness (RMS), and rating of muscle fatigue (RMF) were collected prior to each strength and endurance session. RESULTS: For the CCT group, small differences were primarily found in CR and RPE (ES = 0.17-0.41). However, moderate-to-large reductions were found for TTE and MVC (ES = 0.65-2.00), whereas large increases in RMS and RMF (ES = 1.23-2.49) were found prior to each strength- and endurance-training session. Small differences were found in MVC for the ST group (ES = 0.11) and during CCT-Con for the CCT group (ES = 0.15-0.31). CONCLUSION: Combining strength training on alternating days with endurance training on consecutive days impairs MVC and running performance at maximal effort and increases RMS and RMF over 6 days. PMID- 26241613 TI - Auxiliary proteins that facilitate formation of collagen-rich deposits in the posterior knee capsule in a rabbit-based joint contracture model. AB - Post-traumatic joint contracture is a debilitating consequence of trauma or surgical procedures. It is associated with fibrosis that develops regardless of the nature of initial trauma and results from complex biological processes associated with inflammation and cell activation. These processes accelerate production of structural elements of the extracellular matrix, particularly collagen fibrils. Although the increased production of collagenous proteins has been demonstrated in tissues of contracted joints, researchers have not yet determined the complex protein machinery needed for the biosynthesis of collagen molecules and for their assembly into fibrils. Consequently, the purpose of our study was to investigate key enzymes and protein chaperones needed to produce collagen-rich deposits. Using a rabbit model of joint contracture, our biochemical and histological assays indicated changes in the expression patterns of heat shock protein 47 and the alpha-subunit of prolyl 4-hydroxylase, key proteins in processing nascent collagen chains. Moreover, our study shows that the abnormal organization of collagen fibrils in the posterior capsules of injured knees, rather than excessive formation of fibril-stabilizing cross-links, may be a key reason for observed changes in the mechanical characteristics of injured joints. This result sheds new light on pathomechanisms of joint contraction, and identifies potentially attractive anti-fibrotic targets. PMID- 26241614 TI - Tax secretion from peripheral blood mononuclear cells and Tax detection in plasma of patients with human T-lymphotropic virus-type 1-associated myelopathy/tropical spastic paraparesis and asymptomatic carriers. AB - Human T-lymphotropic virus-type 1 (HTLV-1) is the etiologic agent of the neurologic disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Tax viral protein plays a critical role in viral pathogenesis. Previous studies suggested that extracellular Tax might involve cytokine-like extracellular effects. We evaluated Tax secretion in 18 h-ex vivo peripheral blood mononuclear cells (PBMCs) cultures from 15 HAM/TSP patients and 15 asymptomatic carriers. Futhermore, Tax plasma level was evaluated from other 12 HAM/TSP patients and 10 asymptomatic carriers. Proviral load and mRNA encoding Tax were quantified by PCR and real-time RT-PCR, respectively. Intracellular Tax in CD4(+)CD25(+) cells occurred in 100% and 86.7% of HAM/TSP patients and asymptomatic carriers, respectively. Percentage of CD4(+)CD25(+) Tax+, proviral load and mRNA encoding Tax were significantly higher in HAM/TSP patients. Western blot analyses showed higher secretion levels of ubiquitinated Tax in HAM/TSP patients than in asymptomatic carriers. In HTLV-1-infected subjects, Western blot of plasma Tax showed higher levels in HAM/TSP patients than in asymptomatic carriers, whereas no Tax was found in non-infected subjects. Immunoprecipitated plasma Tax resolved on SDS-PAGE gave two major bands of 57 and 48 kDa allowing identification of Tax and Ubiquitin peptides by mass spectrometry. Relative percentage of either CD4(+)CD25(+) Tax+ cells, or Tax protein released from PBMCs, or plasma Tax, correlates neither with tax mRNA nor with proviral load. This fact could be explained by a complex regulation of Tax expression. Tax secreted from PBMCs or present in plasma could potentially become a biomarker to distinguish between HAM/TSP patients and asymptomatic carriers. PMID- 26241616 TI - Patient Safety: An Important yet Neglected Issue in Nursing Education. PMID- 26241615 TI - In Vitro Reversible Translation Control Using gammaPNA Probes. AB - On-demand regulation of gene expression in living cells is a central goal of chemical biology and antisense therapeutic development. While significant advances have allowed regulatory modulation through inserted genetic elements, on demand control of the expression/translation state of a given native gene by complementary sequence interactions remains a technical challenge. Toward this objective, we demonstrate the reversible suppression of a luciferase gene in cell free translation using Watson-Crick base pairing between the mRNA and a complementary gamma-modified peptide nucleic acid (gammaPNA) sequence with a noncomplementary toehold. Exploiting the favorable thermodynamics of gammaPNA gammaPNA interactions, the antisense sequence can be removed by hybridization of a second, fully complementary gammaPNA, through a strand displacement reaction, allowing translation to proceed. Complementary RNA is also shown to displace the bound antisense gammaPNA, opening up possibilities of in vivo regulation by native gene expression. PMID- 26241617 TI - Intravenous Infiltration Resulting in Compartment Syndrome: A Systematic Review. AB - OBJECTIVE: To determine characteristics of patients who develop compartment syndrome (CS) from IV infiltration requiring surgical intervention. METHODS: A systematic review was conducted of available English literature from 1990 to date. Key terms were entered into a MEDLINE search in addition to searching grey literature and references of included manuscripts. Inclusion criteria were cases of CS requiring surgical intervention from IV infiltration. Exclusions were cases associated with phenytoin because of the unclear mechanism leading to injury (purple glove syndrome). Cases were reviewed for demographics, clinical information, and outcomes. RESULTS: Literature search resulted in 32 manuscripts meeting inclusion with 51 cases. Age ranged from 3 days to 81 years (19.6% age <1 year [10/51], 21.6% age 1-18 years [11/51], and 58.8% age >18 years [30/51]). IV sites were reported in 43 cases: hand 46.5%, forearm 46.5%, foot 4.7%, and leg 2.3% ([20/43], [20/43], [2/43], [1/43]). Of the 42 cases reporting patient mental status, 76.2% (32/42) had impaired mental state or limited communication including young age defined as younger than 3 years. Common associated agents were contrast 36.2%, IV fluid 34%, and mannitol 8.5% ([18/47], [16/47], [4/47]). One patient required hand amputation, 5 had persistent deficits, 36 had no long term deficits, and 9 cases did not report patient outcomes. CONCLUSION: Compartment syndrome affects patients of all ages with a significant number of patients being pediatric and specifically younger than 1 year. Patients at highest risk of developing CS requiring surgery from IV infiltration are likely to have barriers to communication. PMID- 26241618 TI - Is 15q11.2 microdeletion associated with periventricular nodular heterotopia? PMID- 26241619 TI - To Hold Patients Accountable....or Maybe Give Grace. AB - The national agenda for health care includes working with patients to move them to self-efficacy, also known as self-management. Without self-management, patients with chronic conditions will certainly have more emergency department visits and readmissions. Is self-management a realistic and achievable goal? For some, yes; and we must hold them accountable. For others, it is not certain. PMID- 26241620 TI - Psychiatric Case Management in the Emergency Department. AB - PURPOSE: The care of the mentally ill has reached a real crisis in the United States. There were more than 6.4 million visits to emergency departments (EDs) in 2010, or about 5% of total visits, involved patients whose primary diagnosis was a mental health condition or substance abuse (). That is up 28% from just 4 years earlier, according to the latest figures available from the Agency for Healthcare Research and Quality in Rockville, MD. Using a method called scoping, the purpose of this article is to examine the range, extent, and evidence available regarding case management as an intervention in the ED to manage mental health patients, to determine whether there is sufficient quantity and quality of evidence on this topic to conduct a meta-analysis, and to identify relevant studies that balance comprehensiveness with reasonable limitations. PRIMARY PRACTICE SETTINGS: One solution for ensuring that the costs are contained, efficiency is maintained, and quality outcomes are achieved is the placement of a case manager in the ED. According to , because the majority of hospital admissions come through the ED, it makes sense to have case managers located there to act as gatekeepers and ensure that patients who are admitted meet criteria and are placed in the proper bed with the proper status. FINDINGS/CONCLUSIONS: From the scoping techniques implemented in this study, the authors came to the conclusion that case management has been and can be used to effectively treat mental health patients in the emergency room. A good number of patients with psych mental health issues are frequent visitors and repeat visitors. Case management has not been used very often as a strategy for managing patients through the ED or for follow-up after the visit. Hospitals that have developed a protocol for managing these patients outside the main patient flow have had successful results. Staff training and development on psych mental health issues have been helpful in the ED. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: While there are not a large number of studies available on this topic, there is sufficient evidence to warrant further examination of this research topic. The findings in this scoping study have broader implications for research, policy, and practice. The framework of this study involved an outcomes-based approach. Clinical outcomes that positively enhance patient care and save the hospital money are necessary in the current health care environment. PMID- 26241622 TI - The Population Care Coordination Process. AB - PURPOSE/OBJECTIVES: The purpose of the article was to outline a population-based approach to providing care coordination. The Population Care Coordination Process provides a framework for each provider and/or organization to provide multilevel care based on population- and patient-centered principles. PRIMARY PRACTICE SETTING: The Population Care Coordination Process is scalable. It can be utilized in a smaller scale such as single provider office or in a larger scale such as an accountable care organization. FINDINGS/CONCLUSIONS: There are many issues within our current health care structure that must be addressed. Care coordination has been identified as a potential solution to address the needs of complex patients within the system. The expansion to consider populations allows for a more targeted and efficient approach. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: The population care process entails a data-driven approach to care coordination. The inclusion of populations in the care coordination process provides an opportunity to maximize efforts and improve outcomes. PMID- 26241624 TI - Universal Postoperative Hip Instruction Protocol for Rehabilitation in Rural Skilled Nursing Facilities. AB - PURPOSE/OBJECTIVES: Hip fractures among the elderly increase the incidence of mortality and other health-related complications, lead to poor quality of life, and create major economic challenges. Elderly individuals often reside in rural skilled nursing facilities (SNFs) for rehabilitation after undergoing surgical fixation for a hip fracture. Orthopedic providers (OPs) can develop protocols that will encourage continuity of postoperative orthopedic follow-up care, guiding and educating SNF staff in best practices, and encouraging regular communication between SNF staff and OPs. The purpose of this article is to describe how an orthopedic practice developed a universal postoperative hip instruction protocol (UP-HIP) to promote a streamlined approach to postoperative follow-up assessment and rehabilitation for the elderly residing in rural SNFs. The overall goal of the UP-HIP is to provide the OP with assessment findings remotely and avoid putting frail elderly patients at risk by physically transporting them to and from follow-up appointments with the OP. PRIMARY PRACTICE SETTING(S): Orthopedic clinic setting and rural SNFs. FINDINGS/CONCLUSIONS: Comprehensive postoperative protocols focused on elderly patients with hip fracture in rural SNFs serve to improve remote communication during the rehabilitation phase and guide SNF in a coordinated approach to postoperative follow-up care. Future recommendations include the addition of telehealth technology to allow for remote real-time visual assessments by the OP while the elderly patient with hip fracture remains in the SNF environment. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: The UP-HIP allows the OP and case manager to ensure continuity of postoperative care by conducting remote follow-up postoperative visits with elderly patients with hip fracture while they remain in the rural SNF setting. Comprehensive evidence-based protocols assist OPs and case managers with remotely monitoring rehabilitation progress in the rural SNF setting more efficiently and consistently. Telehealth technology added to evidence-based protocols enables the OP and case manager to conduct real-time visual assessments of the patient without the patient having to leave the rural SNF setting. PMID- 26241626 TI - Electronic Cigarettes: An Evidence-Based Analysis. PMID- 26241625 TI - Doubts About the National Agenda of "Self-Managing" Chronic Conditions. AB - What comes to mind when I hear the name Karen Zander: case manager pioneer, brilliant and compassionate nurse leader, articulate teacher, mentor, and friend. Karen has a unique perspective on health care today as a consumer and provider. While she manages through physical limitations, it has never diminished her passion, commitment or can-do spirit. Her contributions to the case management practice are broad based and invaluable. It is with pleasure and gratitude that we welcome Karen as a guest columnist. PMID- 26241627 TI - Why "One" Is the Most Important Number in Case Management. PMID- 26241628 TI - Benefits of Palliative Care. PMID- 26241629 TI - Congenital Absence of Left Atrial Appendage in a Patient with Intracranial Hemorrhage. AB - BACKGROUND: Intracranial hemorrhage is the most serious complication of anticoagulant therapy and is itself an absolute contraindication to further treatment. CASE REPORT: We present the case of a 78-year-old patient with permanent atrial fibrillation and previous intracranial hemorrhage during oral anticoagulation therapy, who was a candidate for percutaneous closure of the left atrial appendage. Transesophageal echocardiography and computed tomography showed absence of the left atrial appendage. The patient continued with single antiplatelet therapy. CONCLUSIONS: Absence of the left atrial appendage is a very rare congenital condition usually found in patients scheduled for cardiovascular procedures and without clinical significance. The risk of thromboembolism is reasonably low but unknown. PMID- 26241631 TI - Nanobubbles at GPa Pressure under Graphene. AB - We provide direct evidence that irradiation of a graphene membrane on Ir with low energy Ar ions induces formation of solid noble-gas nanobubbles. Their size can be controlled by thermal treatment, reaching tens of nanometers laterally and height of 1.5 nm upon annealing at 1080 degrees C. Ab initio calculations show that Ar nanobubbles are subject to pressures reaching tens of GPa, their formation being driven by minimization of the energy cost of film distortion and loss of adhesion. PMID- 26241630 TI - A population-based case-control study of genetic variation in cytokine genes associated with risk of cervical and vulvar cancers. AB - OBJECTIVE: Persistent infection with oncogenic human papillomavirus (HPV) is known to be the necessary cause of cervical cancer and a majority of vulvar cancers. Persistent HPV infections must evade host immune responses, including cytokines released by activated T-helper (Th) cells. In this study, we investigated the risk of cervical and vulvar cancers associated with common genetic variations in 560 tagging single-nucleotide polymorphisms (SNPs) in candidate cytokine genes. METHODS: The study included 399 invasive squamous cell carcinomas (SCCs) and 502 in situ or invasive adenocarcinomas (AC) of the cervix; 357 in situ or invasive vulvar SCC; and 1109 controls from the Seattle-area case control studies of HPV-related cancers. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) using a log additive model, with adjustment for multiple testing. RESULTS: Statistically significant risks were observed for HPV16-containing SCC of the cervix with the variant allele rs879576 in IL17RA and rs2229094 in TNF [OR, 95% CI and multiple-testing corrected p: 1.91 (1.30-2.79), p=0.018 and 0.61 (0.45-0.83), p=0.02, respectively]. We also observed significantly increased risk of HPV-positive vulvar cancers associated with variant alleles in CSF2 (rs25882 and rs27438, 26 28% increased risk) and IL-12B (rs2569254 and rs3181225, 40-41% increased risk) genes. CONCLUSIONS: We found that variation in several Th-cytokine genes is significantly associated with cervical and vulvar cancer risk. The strong association between these HPV-related cancers and common variation in cytokine genes in the Th1 and Th17 pathways may be important for development of new therapies. PMID- 26241632 TI - Locus Coeruleus in time with the making of memories. AB - Over the past decades studies of the neurobiology of memory were largely restricted to consideration of cellular and molecular events taking place immediately or shortly after training, the so-called consolidation period. More recent views have recognized that the memory process includes sensory processing, orienting of attention, retrieval, encoding, and subsequent consolidation. Advances in biotechnology are providing new tools to gain insights at every level of the memory process. New data from experiments employing high definition fMRI are confirming the role of the Locus Coeruleus (LC) noradrenergic system in reorienting of attention and in cognitive flexibility. Electrophysiological studies show new task-related activation of these neurons and learning-related off line activation and suggest a temporal relationship between LC spiking and cortical oscillations in the theta and gamma frequencies. PMID- 26241633 TI - Sleep and need for recovery in shift workers: do chronotype and age matter? AB - This study examined associations of chronotype and age with shift-specific assessments of main sleep duration, sleep quality and need for recovery in a cross-sectional study among N = 261 industrial shift workers (96.6% male). Logistic regression analyses were used, adjusted for gender, lifestyle, health, nap behaviour, season of assessment and shift schedule. Shift workers with latest versus earliest chronotype reported a shorter sleep duration (OR 11.68, 95% CI 3.31-41.17) and more awakenings complaints (OR 4.84, 95% CI 4.45-11.92) during morning shift periods. No associations were found between chronotype, sleep and need for recovery during evening and night shift periods. For age, no associations were found with any of the shift-specific outcome measures. The results stress the importance of including the concept of chronotype in shift work research and scheduling beyond the concept of age. Longitudinal research using shift-specific assessments of sleep and need for recovery are needed to confirm these results. PRACTITIONER SUMMARY: Chronotype seems to better explain individual differences in sleep than age. In view of ageing societies, it might therefore be worthwhile to further examine the application of chronotype for individualised shift work schedules to facilitate healthy and sustainable employment. PMID- 26241634 TI - The same but different: signaling pathways in control of endothelial cell migration. AB - The coordinated migration of endothelial cells (ECs) plays a pivotal role not only in the assembly of the embryonic vasculature, but also during various physiological and pathological processes, such as tissue regeneration and wound healing. Recent reports studying EC migration in distinct vascular beds have revealed common principles, but also surprising differences, in the molecules ECs use to ensure proper migratory behaviors. In addition to genetic cues, hemodynamic forces in perfused blood vessels also affect EC migration, thereby contributing to blood vessel remodeling. In this review, we will discuss the distinct molecules guiding EC migration in different tissues and highlight their modes of action. PMID- 26241635 TI - The importance of China (and Tsung O Cheng, International Consulting Editor for China) to the International Journal of Cardiology. PMID- 26241636 TI - Impact of antiretroviral therapy on serum lipoprotein levels and dyslipidemias: a systematic review and meta-analysis. AB - BACKGROUND: Antiretroviral drugs increase biosynthesis and reduce hepatic clearance of serum cholesterol. It is thus important to evaluate the impact of antiretroviral treatment on serum lipoprotein levels and the risk of dyslipidemia. METHODS: We searched EMBASE and PubMed for articles comparing lipid profiles between HIV-infected adult patients naive and exposed to antiretroviral therapy (ART). Eligible studies were pooled by performing random-effects meta analyses of mean serum lipoprotein levels and prevalence estimates of dyslipidemias. RESULTS: 51 observational studies comprising 37,110 patients were included in the meta-analyses. ART-exposed patients had significantly higher concentrations of total cholesterol (45 studies, mean difference [MD]=29.4mg/dL, 95% confidence interval [CI] 26.5 to 32.4, I(2)=82.2%), low density lipoprotein cholesterol (37 studies, MD=14.9mg/dL, 95% CI 11.2 to 18.5, I(2)=86.1%), and triglycerides (43 studies, MD=46.8mg/dL, 95% CI 37.8 to 55.8, I(2)=97.1%), compared with ART-naive patients. The risks of hypercholesterolemia (25 studies, pooled odds ratio [OR] 3.8, 95% CI 3.1 to 4.7, I(2)=60.0%) and hypertriglyceridemia (21 studies, OR 2.2, 95% CI 1.7 to 2.9, I(2)=81.7%) were also significantly higher among ART-exposed patients, compared with ART-naive patients. CONCLUSION: Antiretroviral therapy is significantly associated with increase in serum lipid levels and increased risk of dyslipidemia. Whether or not these associations are causal should be investigated by future studies. PMID- 26241637 TI - Predictive accuracy of CHA2DS2-VASc and HAS-BLED scores in patients without atrial fibrillation undergoing percutaneous coronary intervention and discharged on dual antiplatelet therapy. AB - BACKGROUND: The CHA2DS2-VASc and HAS-BLED are well-validated stroke risk prediction scores for atrial fibrillation (AF), but their role in risk stratification of major adverse cardiac events (MACEs) and major bleeding for non AF patients undergoing percutaneous coronary intervention (PCI) is unknown. METHODS: Consecutive patients without AF undergoing PCI at two Italian centers were analyzed with different measures of discrimination, net reclassification improvement and net prognostic benefit. MACE included all-cause death, myocardial infarction, destabilizing symptoms leading to hospitalization, and nonfatal stroke. Major bleeding was defined according to the TIMI classification. RESULTS: Of 1437 subjects undergoing PCI, 1330 (mean age 63.6+/-10.9years, 75.7% male) fulfilled the inclusion criteria. During 2.7+/-1.2years of follow-up representing 3539 patient-years at risk, 187 patients had a MACE (5.3%/year) and 48 had a major bleeding (1.4%/year). The cumulative incidences of MACE were significantly stratified by both high CHA2DS2-VASc (P=0.020) or HAS-BLED (P<0.001) scores, whereas major bleeding episodes were not. The CHA2DS2-VASc and the HAS-BLED scores had similar C-statistics for MACE (0.56 vs 0.60; P=0.52) and major bleeding (0.63 vs 0.60; P=0.63). Compared with CHA2DS2-VASc, the HAS-BLED score more accurately reclassified events and no events both for MACE (NRI 8.21%) and major bleeding (NRI 6.85%). CONCLUSIONS: In patients without AF undergoing PCI and discharged on dual antiplatelet therapy, the HAS-BLED score performed better than the CHA2DS2-VASc for the prediction of MACE. Although both scores predict MACE, their discrimination was modest. Conversely, both scores did not significantly predict major bleeding in non-AF patients undergoing PCI. PMID- 26241638 TI - Role of Non-Transferrin-Bound Iron in the pathogenesis of cardiotoxicity in patients with ST-elevation myocardial infarction assessed by Cardiac Magnetic Resonance Imaging. AB - BACKGROUND: Hereditary hemochromatosis, thalassemia and myelodysplastic syndromes represent disease models with evidence of iron-related heart failure. Non Transferrin Bound Iron (NTBI) induces cardiac toxicity through the production of reactive oxygen species and lipid peroxidation. In ST-elevation acute myocardial infarction (STEMI) with evidence of microvascular obstruction (MVO) and hemorrhage (HEM), HEM may be a source of iron-related cardiac toxicity through NTBI and pro-inflammatory mediators. AIM OF THE STUDY: The study aims to assess NTBI in patients with STEMI and its possible relationship with MVO and HEM. METHODS AND RESULTS: NTBI, LPO-Malondialdehyde (MDA) and interleukin-6 (IL-6) were assessed in 15 patients with STEMI immediately before primary percutaneous coronary intervention (PPCI) and at 3, 6, 9, 12, and 24h post-PPCI. Cardiac Magnetic Resonance (CMR) was performed at 5days and 6months after STEMI. Myocardial edema and HEM were assessed by T2 and T2* mapping. MVO and necrotic area were assessed by early and late gadolinium enhancement (LGE). NTBI was detected in 13/15 patients with the highest values in 4 patients with evidence of MVO and HEM. NTBI levels were significantly related to CK-MB and troponin T values. NTBI kinetics appeared to be different in patients with MVO and HEM (7/15 patients), with a peak value at 6h after PCI, in comparison with those with no evidence of MVO and HEM, in whom NTBI values were lower and remained indeterminable after the first 24h. CONCLUSIONS: The detection of elevated NTBI values in patients with STEMI, MVO and HEM suggests a possible role of iron cardiotoxicity in myocardial damage. PMID- 26241639 TI - Coronary anomalies and Brugada Phenocopy, the first documented case in the world. PMID- 26241640 TI - Pharmaco-economics of levosimendan in cardiology: a European perspective. AB - INTRODUCTION: Heart failure places a significant economic burden on health care. Acute heart failure requires hospitalization and often frequent re hospitalization in expensive wards where vasoactive rescue therapy is often added on top of standard medications. In these lean times, there is a growing need for cost-effective therapeutic options that supply superior support and in addition shorten the length of stay in hospital and reduce re-hospitalization rates. The inodilator levosimendan represents the latest addition to the vasoactive treatments of acute heart failure patients, and it appears to meet these expectations. Our aim was to answer the question whether the treatment efficacy of levosimendan - when selected as therapy for patients hospitalized for acute heart failure - brings savings to hospitals in various European countries representing different economies. METHODS AND RESULTS: We took a conservative approach and selected some a fortiori arguments to simplify the calculations. We selected seven European countries to represent different economies: Italy, Spain, Greece, Germany, Sweden, Finland and Israel. Data on the costs of medications and on the cost per day were collected and fed in a simple algorithm to detect savings. These saving varied from country to country, from a minimum of ?0.50 in Germany to a maximum of ?354.64 in Sweden. CONCLUSIONS: The use of levosimendan as a therapy for patients hospitalized for acute heart failure provides a net saving to hospitals driven by a reduction in the length of hospital stay. This finding is true in each of the countries considered in this study. PMID- 26241641 TI - Percutaneous coronary intervention in the elderly. AB - Our population dynamics are changing. The number of octogenarians and older people in the general population is increasing and therefore the number of older patients presenting with acute coronary syndrome or stable angina is increasing. This group has a larger burden of coronary disease and also a greater number of concomitant comorbidities when compared to younger patients. Many of the studies assessing percutaneous coronary intervention (PCI) to date have actively excluded octogenarians. However, a number of studies, both retrospective and prospective, are now being undertaken to reflect the, "real" population. Despite being a higher risk group for both elective and emergency PCIs, octogenarians have the greatest to gain in terms of prognosis, symptomatic relief, and arguably more importantly, quality of life. Important future development will include assessment of patient frailty, encouraging early presentation, addressing gender differences on treatment strategies, identification of culprit lesion(s) and vascular access to minimise vascular complications. We are now appreciating that the new frontier is perhaps recognising and risk stratifying those elderly patients who have the most to gain from PCI. This review article summarises the most relevant trials and studies. PMID- 26241642 TI - Ascending aortic obstruction with hypoplastic innominate artery. PMID- 26241643 TI - Bioresorbable vascular scaffold implantation for the treatment of coronary in stent restenosis: results from a multicenter Italian experience. AB - This multicenter experience sought to investigate the feasibility and safety of BVS for the treatment of ISR. From April 2012 to June 2014, a total of 315 patients (334 lesions) underwent PCI for ISR at the participating centers. Of those, 83 patients (90 lesions) received BVS. Procedural success was achieved in all patients. At a median of 7 (IQR 3-18) months follow-up, MACCE rate was 12%, TLR 7.7%, while one (1.1%) definite BVS-in-stent thrombosis was reported. The results of this multicenter experience suggest that BVS implantation for the treatment of coronary ISR is technically feasible and associated with favorable mid-term clinical results. These data could be considered hypothesis generating for a future randomized clinical trial. PMID- 26241644 TI - Dilation or dilatation: to be or not to be? PMID- 26241645 TI - Opioid Induced Constipation Part I: Established Management Strategies #294. PMID- 26241647 TI - A Quantile Regression Approach to Estimating the Distribution of Anesthetic Procedure Time during Induction. AB - Although procedure time analyses are important for operating room management, it is not easy to extract useful information from clinical procedure time data. A novel approach was proposed to analyze procedure time during anesthetic induction. A two-step regression analysis was performed to explore influential factors of anesthetic induction time (AIT). Linear regression with stepwise model selection was used to select significant correlates of AIT and then quantile regression was employed to illustrate the dynamic relationships between AIT and selected variables at distinct quantiles. A total of 1,060 patients were analyzed. The first and second-year residents (R1-R2) required longer AIT than the third and fourth-year residents and attending anesthesiologists (p = 0.006). Factors prolonging AIT included American Society of Anesthesiologist physical status ? III, arterial, central venous and epidural catheterization, and use of bronchoscopy. Presence of surgeon before induction would decrease AIT (p < 0.001). Types of surgery also had significant influence on AIT. Quantile regression satisfactorily estimated extra time needed to complete induction for each influential factor at distinct quantiles. Our analysis on AIT demonstrated the benefit of quantile regression analysis to provide more comprehensive view of the relationships between procedure time and related factors. This novel two-step regression approach has potential applications to procedure time analysis in operating room management. PMID- 26241646 TI - Deficiency of Nuclear Receptor Nur77 Aggravates Mouse Experimental Colitis by Increased NFkappaB Activity in Macrophages. AB - Nuclear receptor Nur77, also referred to as NR4A1 or TR3, plays an important role in innate and adaptive immunity. Nur77 is crucial in regulating the T helper 1/regulatory T-cell balance, is expressed in macrophages and drives M2 macrophage polarization. In this study we aimed to define the function of Nur77 in inflammatory bowel disease. In wild-type and Nur77-/- mice, colitis development was studied in dextran sodium sulphate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced models. To understand the underlying mechanism, Nur77 was overexpressed in macrophages and gut epithelial cells. Nur77 protein is expressed in colon tissues from Crohn's disease and Ulcerative colitis patients and colons from colitic mice in inflammatory cells and epithelium. In both mouse colitis models inflammation was increased in Nur77-/- mice. A higher neutrophil influx and enhanced IL-6, MCP-1 and KC production was observed in Nur77-deficient colons after DSS-treatment. TNBS-induced influx of T-cells and inflammatory monocytes into the colon was higher in Nur77-/- mice, along with increased expression of MCP-1, TNFalpha and IL-6, and decreased Foxp3 RNA expression, compared to wild type mice. Overexpression of Nur77 in lipopolysaccharide activated RAW macrophages resulted in up-regulated IL-10 and downregulated TNFalpha, MIF-1 and MCP-1 mRNA expression through NFkappaB repression. Nur77 also strongly decreased expression of MCP-1, CXCL1, IL-8, MIP-1alpha and TNFalpha in gut epithelial Caco 2 cells. Nur77 overexpression suppresses the inflammatory status of both macrophages and gut epithelial cells and together with the in vivo mouse data this supports that Nur77 has a protective function in experimental colitis. These findings may have implications for development of novel targeted treatment strategies regarding inflammatory bowel disease and other inflammatory diseases. PMID- 26241648 TI - A Triple Culture Model of the Blood-Brain Barrier Using Porcine Brain Endothelial cells, Astrocytes and Pericytes. AB - In vitro blood-brain barrier (BBB) models based on primary brain endothelial cells (BECs) cultured as monoculture or in co-culture with primary astrocytes and pericytes are useful for studying many properties of the BBB. The BECs retain their expression of tight junction proteins and efflux transporters leading to high trans-endothelial electric resistance (TEER) and low passive paracellular permeability. The BECs, astrocytes and pericytes are often isolated from small rodents. Larger species as cows and pigs however, reveal a higher yield, are readily available and have a closer resemblance to humans, which make them favorable high-throughput sources for cellular isolation. The aim of the present study has been to determine if the preferable combination of purely porcine cells isolated from the 6 months old domestic pigs, i.e. porcine brain endothelial cells (PBECs) in co-culture with porcine astrocytes and pericytes, would compare with PBECs co-cultured with astrocytes and pericytes isolated from newborn rats with respect to TEER value and low passive permeability. The astrocytes and pericytes were grown both as contact and non-contact co-cultures as well as in triple culture to examine their effects on the PBECs for barrier formation as revealed by TEER, passive permeability, and expression patterns of tight junction proteins, efflux transporters and the transferrin receptor. This syngenic porcine in vitro BBB model is comparable to triple cultures using PBECs, rat astrocytes and rat pericytes with respect to TEER formation, low passive permeability, and expression of hallmark proteins signifying the brain endothelium (tight junction proteins claudin 5 and occludin, the efflux transporters P-glycoprotein (PgP) and breast cancer related protein (BCRP), and the transferrin receptor). PMID- 26241649 TI - Characterization of Dynamic Behaviour of MCF7 and MCF10A Cells in Ultrasonic Field Using Modal and Harmonic Analyses. AB - Treatment options specifically targeting tumour cells are urgently needed in order to reduce the side effects accompanied by chemo- or radiotherapy. Differences in subcellular structure between tumour and normal cells determine their specific elasticity. These structural differences can be utilised by low frequency ultrasound in order to specifically induce cytotoxicity of tumour cells. For further evaluation, we combined in silico FEM (finite element method) analyses and in vitro assays to bolster the significance of low-frequency ultrasound for tumour treatment. FEM simulations were able to calculate the first resonance frequency of MCF7 breast tumour cells at 21 kHz in contrast to 34 kHz for the MCF10A normal breast cells, which was due to the higher elasticity and larger size of MCF7 cells. For experimental validation of the in silico determined resonance frequencies, equipment for ultrasonic irradiation with distinct frequencies was constructed. Differences for both cell lines in their response to low-frequent ultrasonic treatment were corroborated in 2D and in 3D cell culture assays. Treatment with ~ 24.5 kHz induced the death of MCF7 cells and MDA-MB-231 metastases cells possessing a similar elasticity; frequencies of > 29 kHz resulted in cytotoxicity of MCF10A. Fractionated treatments by ultrasonic irradiation of suspension myeloid HL60 cells resulted in a significant decrease of viable cells, mostly significant after threefold irradiation in intervals of 3 h. Most importantly in regard to a clinical application, combined ultrasonic treatment and chemotherapy with paclitaxel showed a significantly increased killing of MCF7 cells compared to both monotherapies. In summary, we were able to determine for the first time for different tumour cell lines a specific frequency of low-intensity ultrasound for induction of cell ablation. The cytotoxic effect of ultrasonic irradiation could be increased by either fractionated treatment or in combination with chemotherapy. Thus, our results will open new perspectives in tumour treatment. PMID- 26241650 TI - Thinking Styles and Regret in Physicians. AB - BACKGROUND: Decision-making relies on both analytical and emotional thinking. Cognitive reasoning styles (e.g. maximizing and satisficing tendencies) heavily influence analytical processes, while affective processes are often dependent on regret. The relationship between regret and cognitive reasoning styles has not been well studied in physicians, and is the focus of this paper. METHODS: A regret questionnaire and 6 scales measuring individual differences in cognitive styles (maximizing-satisficing tendencies; analytical vs. intuitive reasoning; need for cognition; intolerance toward ambiguity; objectivism; and cognitive reflection) were administered through a web-based survey to physicians of the University of South Florida. Bonferroni's adjustment was applied to the overall correlation analysis. The correlation analysis was also performed without Bonferroni's correction, given the strong theoretical rationale indicating the need for a separate hypothesis. We also conducted a multivariate regression analysis to identify the unique influence of predictors on regret. RESULTS: 165 trainees and 56 attending physicians (age range 25 to 69) participated in the survey. After bivariate analysis we found that maximizing tendency positively correlated with regret with respect to both decision difficulty (r=0.673; p<0.001) and alternate search strategy (r=0.239; p=0.002). When Bonferroni's correction was not applied, we also found a negative relationship between satisficing tendency and regret (r=-0.156; p=0.021). In trainees, but not faculty, regret negatively correlated with rational-analytical thinking (r= 0.422; p<0.001), need for cognition (r=-0.340; p<0.001), and objectivism (r= 0.309; p=0.003) and positively correlated with ambiguity intolerance (r=0.285; p=0.012). However, after conducting a multivariate regression analysis, we found that regret was positively associated with maximizing only with respect to decision difficulty (r=0.791; p<0.001), while it was negatively associated with satisficing (r=-0.257; p=0.020) and objectivism (r=-0.267; p=0.034). We found no statistically significant relationship between regret and overall accuracy on conditional inferential tasks. CONCLUSION: Regret in physicians is strongly associated with their tendency to maximize; i.e. the tendency to consider more choices among abundant options leads to more regret. However, physicians who exhibit satisficing tendency - the inclination to accept a "good enough" solution - feel less regret. Our observation that objectivism is a negative predictor of regret indicates that the tendency to seek and use empirical data in decision making leads to less regret. Therefore, promotion of evidence-based reasoning may lead to lower regret. PMID- 26241651 TI - Identification of a Male-Produced Pheromone Component of the Citrus Longhorned Beetle, Anoplophora chinensis. AB - The Asian wood-boring beetle Anoplophora chinensis (Forster) (Coleoptera: Cerambycidae) is an important pest of hardwood trees in its native range, and has serious potential to invade other areas of the world through worldwide commerce in woody plants and wood products. This species already has been intercepted in North America, and is the subject of ongoing eradication efforts in several countries in Europe. Attractants such as pheromones would be immediately useful as baits in traps for its detection. Because long-range pheromones are frequently conserved among closely related species of cerambycids, we evaluated two components of the volatile pheromone produced by males of the congener A. glabripennis (Motschulsky), 4-(n-heptyloxy)butan-1-ol and 4-(n-heptyloxy)butanal, as potential pheromones of A. chinensis. Both compounds subsequently were detected in headspace volatiles from male A. chinensis, but not in volatiles from females. Only 4-(n-heptyloxy)butanol elicited responses from beetle antennae in coupled gas chromatography-electroantennogram analyses, and this compound attracted adult A. chinensis of both sexes in field bioassays. These data suggest that 4-(n-heptyloxy)butan-1-ol is an important component of the male-produced attractant pheromone of A. chinensis, which should find immediate use in quarantine monitoring for this pest. PMID- 26241652 TI - Prediction of Peptide and Protein Propensity for Amyloid Formation. AB - Understanding which peptides and proteins have the potential to undergo amyloid formation and what driving forces are responsible for amyloid-like fiber formation and stabilization remains limited. This is mainly because proteins that can undergo structural changes, which lead to amyloid formation, are quite diverse and share no obvious sequence or structural homology, despite the structural similarity found in the fibrils. To address these issues, a novel approach based on recursive feature selection and feed-forward neural networks was undertaken to identify key features highly correlated with the self-assembly problem. This approach allowed the identification of seven physicochemical and biochemical properties of the amino acids highly associated with the self assembly of peptides and proteins into amyloid-like fibrils (normalized frequency of beta-sheet, normalized frequency of beta-sheet from LG, weights for beta-sheet at the window position of 1, isoelectric point, atom-based hydrophobic moment, helix termination parameter at position j+1 and DeltaG degrees values for peptides extrapolated in 0 M urea). Moreover, these features enabled the development of a new predictor (available at http://cran.r project.org/web/packages/appnn/index.html) capable of accurately and reliably predicting the amyloidogenic propensity from the polypeptide sequence alone with a prediction accuracy of 84.9 % against an external validation dataset of sequences with experimental in vitro, evidence of amyloid formation. PMID- 26241653 TI - Differential Migration of Mesenchymal Stem Cells to Ischemic Regions after Middle Cerebral Artery Occlusion in Rats. AB - To evaluate the optimal timing of mesenchymal stem cell (MSC) transplantation following stroke, rats were transplanted with MSCs at 1 (D1), 4 (D4), and 7 days (D7) after middle cerebral artery occlusion (MCAo). Rats in the D1 group showed a better functional recovery than those in the D4 or D7 groups after MCAo. MSCs preferentially migrated to the cortex in the D1 group, while the MSCs in the D4 or D7 groups preferentially migrated to the striatum. Interestingly, the level of monocyte chemotactic protein-1 (MCP-1) in the cortex was highest at 1 day after MCAo, while the level of stromal cell-derived factor-1 (SDF-1) in the striatum was lowest at 1 day after MCAo and then increased over time. The pattern of MCP-1 and SDF-1 level changes according to the time after MCAo was consistent with in vivo and in vitro migration patterns of MSCs. The results suggest that an earlier MSC transplantation is associated with a better functional recovery after stroke, which could be explained by the preferential migration of MSCs to the cortex in the early transplantation group. The time-dependent differential expression of MCP-1 and SDF-1 between ischemic regions seemed to mediate the differential migration of MSCs. Highest level of MCP-1 at one day of stroke may induce preferential migration of MSCs to the cortex, then better functional improvement. PMID- 26241654 TI - Impacts of the 2011 Tsunami on Sediment Characteristics and Macrozoobenthic Assemblages in a Shallow Eutrophic Lagoon, Sendai Bay, Japan. AB - A huge tsunami is one of the greatest disturbance events in coastal benthic communities, although the ecological consequences are not fully understood. Here we examined the tsunami-induced changes in the sediment environment and macrozoobenthic assemblage in a eutrophic brackish lagoon in eastern Japan. The 7.2-m-high tsunami completely replaced muddy sediment with drifting sea sand throughout the lagoon, leading to the drastic changes in quantity and quality of sedimental organic matters, sulfide contents, and sediment redox condition. Intensive physical stress devastated the benthic community, but the disappearance of sulfidic muddy bottoms significantly improved the habitat quality for macrozoobenthos. The re-established macrozoobenthic community after 5 months was characterized by (1) a 2-fold higher total density, but sharp declines in species richness, diversity, and evenness; (2) an increased density of opportunistic taxa (e.g., polychaete Pseudopolydora spp. and amphipod Monocorophium uenoi) in newly created sandy bottoms; and (3) disappearance of several dominant taxa including bivalves and chironomid larvae. These findings indicate that the sensitivity and recovery potential of macrozoobenthos were highly taxa-specific, which was closely related to the taxa's ecological characteristics, including tolerance to physical disturbance, life-history traits, and life form. Our data revealed the rapid recolonization of opportunistic macrozoobenthos after a huge tsunami, which would contribute to the functional recovery of estuarine soft-bottom habitats shortly after a disturbance event. PMID- 26241655 TI - Influence of immunoprotection on genetic variability of cysteine proteinases from Haemonchus contortus adult worms. AB - The limitations associated with the use of anthelmintic drugs in the control of gastrotintestinal nematodosis, such as the emergence of anthelmintic resistance, have stimulated the study of the immunological control of many parasites. In the case of Haemonchus contortus, several vaccination trials using native and recombinant antigens have been conducted. A group of antigens with demonstrated immunoprotective value are cathepsin B - like proteolytic enzymes of the cysteine proteinase type. These enzymes, which have been observed in both excretory secretory products and somatic extracts of H. contortus, may vary among different geographic isolates and on strains isolated from different hosts, or even from the same host, as has been demonstrated in some comparative studies of genetic variability. In the present study, we evaluated the genetic variability of the worms that fully developed their endogenous cycle in immunised sheep and goat in order to identify the alleles of most immunoprotective value. To address these objectives, groups of sheep and goats were immunised with PBS soluble fractions enriched for cysteine proteinases from adult worms of H. contortus from either a strain of H. contortus isolated from goats of Gran Canaria Island (SP) or a strain isolated from sheep of North America (NA). The results confirmed the immunoprophylactic value of this type of enzyme against haemonchosis in both sheep and goats in association with increased levels of specific IgG. The genetic analysis demonstrated that the immunisation had a genetic selection on proteinase encoding genes. In all the immunised animals, allelic frequencies were statistically different from those observed in non-immunised control animals in the four analysed genes. The reduction in the allelic frequencies suggests that parasites expressing these proteases are selectively targeted by the vaccine, and hence they should be considered in any subunit vaccine approach to control haemonchosis in small ruminants. PMID- 26241657 TI - NKP30-B7-H6 Interaction Aggravates Hepatocyte Damage through Up-Regulation of Interleukin-32 Expression in Hepatitis B Virus-Related Acute-On-Chronic Liver Failure. AB - BACKGROUND AND AIMS: Previous work conducted by our group has shown that the accumulation of hepatic natural killer (NK) cells and the up-regulation of natural cytotoxicity receptors (NKP30 and NKP46) on NK cells from patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) were correlated with disease progression in HBV-ACLF. The natural cytotoxicity receptors expressed on NK cells are believed to be probable candidates involved in the NK cell-mediated hepatocyte damage in HBV-ACLF. However, the underlying mechanisms remain to be elucidated. In the present study, we aimed to discover the role of NKP30-B7-H6 interaction in NK cells-mediated hepatocyte damage in HBV ACLF. METHODS: Hepatic expressions of B7-H6 and interleukin-32 (IL-32) were examined by immunochemistry staining in samples from patients with HBV-ACLF or mild chronic hepatitis B (CHB). The cytotoxicity of NK-92 cell against target cells (Huh-7 and LO2) was evaluated by CCK8 assay. Expression of IL-32 in liver NK cell, T cells and NK-92 cell line was detected by the flow cytometric analysis. The effect of IL-32 on the apoptosis of Huh7 cells was evaluated using Annexin V/PI staining analysis. RESULTS: An enhancement of hepatic B7-H6 and IL 32 expression was associated with the severity of liver injury in HBV-ACLF. And there was a positive association between hepatic B7-H6 and IL-32 expression. Expressions of IL-32 in liver NK cells and T cells were increased in HBV-ACLF patients. In vitro NK-92 cells are highly capable of killing the high B7-H6 expressing Huh7 cells and B7-H6-tansfected hepatocyte line LO2 cells dependent on NKP30 and B7-H6 interaction. Furthermore, NK-92 cells exhibited elevated IL-32 expression when stimulated with anti-NKP30 antibodies or when co-cultured with Huh7 cells. IL-32 can induce the apoptosis of Huh7 cells in a dose-dependent manner. CONCLUSION: Our results suggest that NKP30-B7-H6 interaction can aggravate hepatocyte damage, probably through up-regulation of IL-32 expression in HBV-ACLF. PMID- 26241656 TI - Retrohoming of a Mobile Group II Intron in Human Cells Suggests How Eukaryotes Limit Group II Intron Proliferation. AB - Mobile bacterial group II introns are evolutionary ancestors of spliceosomal introns and retroelements in eukaryotes. They consist of an autocatalytic intron RNA (a "ribozyme") and an intron-encoded reverse transcriptase, which function together to promote intron integration into new DNA sites by a mechanism termed "retrohoming". Although mobile group II introns splice and retrohome efficiently in bacteria, all examined thus far function inefficiently in eukaryotes, where their ribozyme activity is limited by low Mg2+ concentrations, and intron containing transcripts are subject to nonsense-mediated decay (NMD) and translational repression. Here, by using RNA polymerase II to express a humanized group II intron reverse transcriptase and T7 RNA polymerase to express intron transcripts resistant to NMD, we find that simply supplementing culture medium with Mg2+ induces the Lactococcus lactis Ll.LtrB intron to retrohome into plasmid and chromosomal sites, the latter at frequencies up to ~0.1%, in viable HEK-293 cells. Surprisingly, under these conditions, the Ll.LtrB intron reverse transcriptase is required for retrohoming but not for RNA splicing as in bacteria. By using a genetic assay for in vivo selections combined with deep sequencing, we identified intron RNA mutations that enhance retrohoming in human cells, but <4-fold and not without added Mg2+. Further, the selected mutations lie outside the ribozyme catalytic core, which appears not readily modified to function efficiently at low Mg2+ concentrations. Our results reveal differences between group II intron retrohoming in human cells and bacteria and suggest constraints on critical nucleotide residues of the ribozyme core that limit how much group II intron retrohoming in eukaryotes can be enhanced. These findings have implications for group II intron use for gene targeting in eukaryotes and suggest how differences in intracellular Mg2+ concentrations between bacteria and eukarya may have impacted the evolution of introns and gene expression mechanisms. PMID- 26241659 TI - Development of a dual-internal-reference technique to improve accuracy when determining bacterial 16S rRNA:16S rRNA gene ratio with application to Escherichia coli liquid and aerosol samples. AB - Accurate enumeration of rRNA content in microbial cells, e.g. by using the 16S rRNA:16S rRNA gene ratio, is critical to properly understand its relationship to microbial activities. However, few studies have considered possible methodological artifacts that may contribute to the variability of rRNA analysis results. In this study, a technique utilizing genomic DNA and 16S rRNA from an exogenous species (Pseudomonas fluorescens) as dual internal references was developed to improve accuracy when determining the 16S rRNA:16S rRNA gene ratio of a target organism, Escherichia coli. This technique was able to adequately control the variability in sample processing and analysis procedures due to nucleic acid (DNA and RNA) losses, inefficient reverse transcription of RNA, and inefficient PCR amplification. The measured 16S rRNA:16S rRNA gene ratio of E. coli increased by 2-3 fold when E. coli 16S rRNA gene and 16S rRNA quantities were normalized to the sample-specific fractional recoveries of reference (P. fluorescens) 16S rRNA gene and 16S rRNA, respectively. In addition, the intra sample variation of this ratio, represented by coefficients of variation from replicate samples, decreased significantly after normalization. This technique was applied to investigate the temporal variation of 16S rRNA:16S rRNA gene ratio of E. coli during its non-steady-state growth in a complex liquid medium, and to E. coli aerosols when exposed to particle-free air after their collection on a filter. The 16S rRNA:16S rRNA gene ratio of E. coli increased significantly during its early exponential phase of growth; when E. coli aerosols were exposed to extended filtration stress after sample collection, the ratio also increased. In contrast, no significant temporal trend in E. coli 16S rRNA:16S rRNA gene ratio was observed when the determined ratios were not normalized based on the recoveries of dual references. The developed technique could be widely applied in studies of relationship between cellular rRNA abundance and bacterial activity. PMID- 26241660 TI - Stimulus generalization and operant context renewal. AB - Context renewal is the relapse of an extinguished response due to changing the stimulus context following extinction. Reinforcing operant responding in Context A and extinguishing in Context B results in relapse when either returning to Context A (ABA renewal) or introducing a novel Context C (ABC renewal). ABA renewal typically is greater than ABC renewal. The present study assessed whether renewal might be conceptualized through excitatory and inhibitory generalization gradients inferred from studies of stimulus generalization. We arranged one keylight-color alternation frequency for pigeons to signal reinforcement in Phase 1 and a different alternation frequency to signal extinction in Phase 2. During a subsequent test in extinction, we presented a range of keylight-alternation frequencies and found renewal to be a function of keylight-alternation frequency. Specifically, Phase-3 responding increased as keylight-alternation frequency differed from that arranged during extinction in Phase 2. Moreover, we observed a shift in the function beyond the originally reinforced keylight-alternation frequency arranged in training (i.e., peak shift). We discuss the relevance of these findings for conceptualizing stimulus-control processes governing generalization gradients for understanding the processes underlying context renewal. PMID- 26241658 TI - SlDEAD31, a Putative DEAD-Box RNA Helicase Gene, Regulates Salt and Drought Tolerance and Stress-Related Genes in Tomato. AB - The DEAD-box RNA helicases are involved in almost every aspect of RNA metabolism, associated with diverse cellular functions including plant growth and development, and their importance in response to biotic and abiotic stresses is only beginning to emerge. However, none of DEAD-box genes was well characterized in tomato so far. In this study, we reported on the identification and characterization of two putative DEAD-box RNA helicase genes, SlDEAD30 and SlDEAD31 from tomato, which were classified into stress-related DEAD-box proteins by phylogenetic analysis. Expression analysis indicated that SlDEAD30 was highly expressed in roots and mature leaves, while SlDEAD31 was constantly expressed in various tissues. Furthermore, the expression of both genes was induced mainly in roots under NaCl stress, and SlDEAD31 mRNA was also increased by heat, cold, and dehydration. In stress assays, transgenic tomato plants overexpressing SlDEAD31 exhibited dramatically enhanced salt tolerance and slightly improved drought resistance, which were simultaneously demonstrated by significantly enhanced expression of multiple biotic and abiotic stress-related genes, higher survival rate, relative water content (RWC) and chlorophyll content, and lower water loss rate and malondialdehyde (MDA) production compared to wild-type plants. Collectively, these results provide a preliminary characterization of SlDEAD30 and SlDEAD31 genes in tomato, and suggest that stress-responsive SlDEAD31 is essential for salt and drought tolerance and stress-related gene regulation in plants. PMID- 26241662 TI - Biological rhythms in bipolar and depressive disorders: A community study with drug-naive young adults. AB - AIM: To assess biological rhythm disruptions among drug-naive young adults with bipolar disorder (BD), major depressive disorder (MDD), and community controls. METHODS: This was a cross-sectional study nested in a population-based study. BD and MDD were diagnosed using the Structured Clinical Interview for DSM-IV. Biological rhythm disruptions were assessed using the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN). RESULTS: Two hundred seventeen subjects were assessed (49 BD, 74 MDD, and 94 community controls). Biological rhythm disruption was higher in subjects with BD (40.32+/-9.92; p<0.001) and MDD (36.23+/-8.71; p<0.001) than community controls (27.67+/-6.88). Subjects with BD had a higher BRIAN total score (p=0.028) and higher disruption in sleep/social domains (p=0.018) as compared to MDD. In addition, the BRIAN scores were higher in current MDD, euthymic BD, and BD in current episode group, as compared to community controls. LIMITATION: Cross-sectional design. Absence of assessment of biomarkers of biological rhythms. CONCLUSION: Bipolar disorder and major depressive disorder are associated with disruption in biological rhythm. In addition, disruption in sleep/social rhythms is higher in subjects with BD when compared to subjects with MDD. We also verified biological rhythm disruption in subjects with BD during euthymic status, but not in remitted MDD. Regulation of biological rhythm may be a means to identify patients with mood disorders and potentially differentiate MDD from BD. PMID- 26241661 TI - Distinguishing Low-Risk Luminal A Breast Cancer Subtypes with Ki-67 and p53 Is More Predictive of Long-Term Survival. AB - Overexpression of p53 is the most frequent genetic alteration in breast cancer. Recently, many studies have shown that the expression of mutant p53 differs for each subtype of breast cancer and is associated with different prognoses. In this study, we aimed to determine the suitable cut-off value to predict the clinical outcome of p53 overexpression and its usefulness as a prognostic factor in each subtype of breast cancer, especially in luminal A breast cancer. Approval was granted by the Institutional Review Board of Samsung Medical Center. We analyzed a total of 7,739 patients who were surgically treated for invasive breast cancer at Samsung Medical Center between Dec 1995 and Apr 2013. Luminal A subtype was defined as ER&PR + and HER2- and was further subclassified according to Ki-67 and p53 expression as follows: luminal A (Ki-67-,p53-), luminal A (Ki-67+, p53-), luminal A (Ki-67 -, p53+) and luminal A (Ki-67+, p53+). Low-risk luminal A subtype was defined as negative for both Ki-67 and p53 (luminal A [ki-67-, p53 ]), and others subtypes were considered to be high-risk luminal A breast cancer. A cut-off value of 10% for p53 was a good predictor of clinical outcome in all patients and luminal A breast cancer patients. The prognostic role of p53 overexpression for OS and DFS was only significant in luminal A subtype. The combination of p53 and Ki-67 has been shown to have the best predictive power as calculated by the area under curve (AUC), especially for long-term overall survival. In this study, we have shown that overexpression of p53 and Ki-67 could be used to discriminate low-risk luminal A subtype in breast cancer. Therefore, using the combination of p53 and Ki-67 expression in discriminating low-risk luminal A breast cancer may improve the prognostic power and provide the greatest clinical utility. PMID- 26241663 TI - Examination of the interrelations between the factors of PTSD, major depression, and generalized anxiety disorder in a heterogeneous trauma-exposed sample using DSM 5 criteria. AB - Exposure to traumatic events places individuals at high risk for multiple psychiatric disorders, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD). The high rates of comorbidity among these conditions merit evaluation in order to improve diagnosis and treatment approaches. The current study evaluated the association between PTSD, MDD, and GAD factors as presented in the DSM 5. 602 trauma-exposed individuals who experienced an event that met Criterion A for the DSM 5 PTSD diagnosis were recruited through Amazon.com, Inc.'s Mechanical Turk (MTurk) to complete an assessment of the impact of stressful events on their lives. High interrelations were detected among the 4 PTSD factors, 2 MDD factors that corresponded to somatic and affective symptoms, and the single GAD factor. The affective factor of MDD was most strongly related to the emotional numbing factor of PTSD, whereas the somatic factor of MDD was most strongly related to the hyperarousal factor of PTSD. The GAD factor was most strongly related to the hyperarousal factor of PTSD, relative to the other PTSD factors. The strength of the interrelations between factors of the three disorders is largely a function of the overlap in symptoms and calls into question the uniqueness of negative affective symptoms of PTSD, MDD and GAD. Results suggest that improved understanding of the trauma reaction requires a focus on the unique presentation of each individual and assessment of multiple disorders. PMID- 26241664 TI - Is religiosity a protective factor against suicidal behavior in bipolar I outpatients? AB - BACKGROUND: Several risk factors have been associated with suicidal behavior (SB) in bipolar disorder (BD), but little is known regarding possible protective factors. Religiosity has been related to favorable outcomes in mental health and to a reduction in the risk of SB, although the relation between BD, religiosity and SB remains under-investigated. The objective of this study was to evaluate the association between religiosity and SB in euthymic bipolar I outpatients. METHOD: In this study, 164 outpatients with BD type I with and without a history of suicide attempts were assessed and compared using a questionnaire to collect clinical and sociodemographic characteristics, the Structured Clinical Interview for DSM-IV, the Hamilton Depression Rating Scale, the Young Mania Rating Scale, the Duke Religious Index, and the Barratt Impulsivity Scale. RESULTS: The suicide attempters (SA) group had more psychiatric comorbidity (p=0.007), more rapid cycling (p=0.004), higher levels of impulsivity in all domains (p=0.000), and less religious affiliation (p=0.006) compared with the non-SA group. In the multivariate analysis, after controlling for covariates, non-organizational religious activities (OR, 0.66; 95% CI, 0.50-0.86) and intrinsic religiosity (OR, 0.70; 95% CI, 0.60-0.81) were associated with less SB. LIMITATIONS: A small sample size, the cross-sectional design that precluded the possibility of assessing cause and effect relationships, and the infeasibility of determining the time lapse between the last suicide attempt and the period when the patients were evaluated. CONCLUSION: Non-organizational religious activities and intrinsic religiosity dimensions exert a protective effect against SB in bipolar I outpatients, even when controlling for variables that may affect the outcome in question. PMID- 26241665 TI - In first-time mothers, post-partum depressive symptom prospectively predict symptoms of post-traumatic stress. AB - BACKGROUND: Symptoms of both depression and Post-Traumatic Stress Disorder (PTSD) are prevalent among first-time mothers following birth. However, the direction of the association between the two types of symptoms is unclear. METHODS: Ninety six first-time mothers giving birth via vaginal delivery (N=38), emergency C-Section (N=27) and planned C-Section (N=21) were assessed for depression and PTSD twice: Six weeks post-partum and six-weeks later. RESULTS: Cross-lagged Structural Equation Modeling (SEM) analyses revealed a prospective effect of depressive symptoms on PTSD symptoms. No moderating factors were identified. LIMITATIONS: A relatively modest sample size and only two assessment waves. CONCLUSIONS: An early detection and intervention with symptoms of post-partum depression might also prevent the development of PTSD symptoms. PMID- 26241666 TI - Did NICE guidelines and the Quality Outcomes Framework change GP antidepressant prescribing in England? Observational study with time trend analyses 2003-2013. AB - BACKGROUND: Both the 2004 NICE depression guidelines and 2006 general practice Quality Outcomes Framework (QOF) encouraged improved targeting of antidepressant treatment for depression. METHODS: Possible effects of the NICE guideline from January 2005, and QOF from April 2006, on rates of GP antidepressant prescribing were examined using time trend analyses of anonymised data from 142 English practices contributing to the Clinical Practice Research Datalink (CPRD), 2003 2013. RESULTS: Sustained reductions were found in the proportion of first-ever depression episodes treated within 12 months, of 4.2% (95% C.I. 1.0-7.3%) following introduction of the NICE guideline, and 4.4% (2.3-6.5%) following introduction of the QOF. Treatment rates for first-ever episodes fell from 72.5% (70.8-74.1%) in Quarter 2 (Q2) 2003 to 61.0% (59.3-62.7%) in Q1 2012, but treatment rates for recurrent episodes increased from 74.3% (72.8-75.8%) to 77.8% (76.5-79.1%), so overall rates remained around 70%. Mean prescriptions per patient per year doubled from 2.06 (2.05-2.07) to 3.98 (3.97-3.99). LIMITATIONS: Participating practices were larger than average and not representative across regions. Inferences of cause and effect from time trend analyses are subject to the possibility of unidentified confounders. No data were available on depression severity or appropriateness of prescribing. CONCLUSIONS: Rates of GP antidepressant treatment for patients with incident depression fell following introduction of NICE depression guidelines and the QOF, but treatment rates for recurrent depression increased. Prescription numbers increased due to longer treatment courses. To impact on antidepressant prescribing rates, guidelines and performance indicators must address recurrent and long-term prescribing, rather than initial treatment decisions. PMID- 26241667 TI - Dimensional structure and correlates of posttraumatic stress symptoms following suspected acute coronary syndrome. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is a heterogeneous construct, and some have suggested that PTSD triggered by acute coronary syndrome (ACS) may differ from PTSD due to prototypical traumas. METHODS: We conducted the first examination of the latent structure of PTSD symptoms after suspected ACS in 399 adults in the REactions to Acute Care and Hospitalization (REACH) study, an observational cohort study of patients recruited from the emergency department during evaluation for ACS. Using confirmatory factor analysis, we compared the 4 factor dysphoria, 4-factor numbing, and 5-factor dysphoric arousal models of PTSD. RESULTS: Although all models fit well, the dysphoria model was selected as the best-fitting model. Further, there was measurement invariance of the dysphoria model by sex. PTSD dimensions evidenced differential associations with indicators of threat perception during ACS evaluation and adherence to cardioprotective medication. LIMITATIONS: One limitation of this investigation is the use of self-report measures. In addition, only one-third of the sample was diagnosed with ACS at discharge; the remaining participants received diagnoses such as chest pain without a cardiac diagnosis, another symptom/disease process (e.g., hypertensive chronic kidney disease), or another cardiac disease. CONCLUSIONS: Findings suggest that suspected ACS-related PTSD symptoms are best represented by a 4-factor structure distinguishing between specific (e.g., re experiencing) and non-specific (dysphoria) symptoms of PTSD that has received support in the broader PTSD literature. PMID- 26241668 TI - Human sperm liver receptor homolog-1 (LRH-1) acts as a downstream target of the estrogen signaling pathway. AB - In the last decade, the study of human sperm anatomy, at molecular level, has revealed the presence of several nuclear protein receptors. In this work, we examined the expression profile and the ultrastructural localization of liver receptor homolog-1 (LRH-1) in human spermatozoa. We evidenced the presence of the receptor by Western blotting and real time-RT-PCR. Furthermore, we used immunogold electron microscopy to investigate the sperm anatomical regions containing LRH-1. The receptor was mainly located in the sperm head, whereas its expression was reduced in the neck and across the tail. Interestingly, we observed the presence of LRH-1 in different stages of testicular germ cell development by immunohistochemistry. In somatic cells, it has been suggested that the LRH-1 pathway is tightly linked with estrogen signaling and the important role of estradiol has been widely studied in sperm cells. To assess the significance of LRH-1 in male gametes and to deepen understanding of the role of estrogens in these cells, we investigated important sperm features such as motility, survival and capacitation. Spermatozoa were treated with 10 nm estradiol and the inhibition of LRH-1 reversed the estradiol stimulatory action. From our data, we discovered that human spermatozoa can be considered a new site of expression for LRH-1, evidencing its role in sperm motility, survival and cholesterol efflux. Furthermore, we may presume that in spermatozoa the LRH-1 effects are closely integrated with the estrogen signaling, supporting LRH-1 as a downstream effector of the estradiol pathway on some sperm functions. PMID- 26241670 TI - Mohs Surgery for Squamous Cell Carcinoma of the Nail Unit: 10 Years of Experience. AB - BACKGROUND: Squamous cell carcinoma (SCC) is the most frequent malignant tumor of the nail unit. OBJECTIVE: The aim of this study was to review the long-term outcome of patients affected by SCC of the nail who underwent Mohs surgery. MATERIALS AND METHODS: Patients affected by nail SCC were enrolled, including cases where x-ray examination had revealed bone changes. The tumor was completely excised and the defect filled with a skin substitute based on hyaluronic acid where bone involvement was not observed. Where Mohs sections indicated bone involvement, the distal phalanx was disarticulated and the remaining end of the digit repaired using a volar/plantar flap. Follow-up was performed every 6 months for 5 years. RESULTS: Mohs technique was performed in 43 cases. Microinvasive SCC was diagnosed in 5 cases, in situ SCC in 7 cases, and invasive SCC in 45 patients. Recurrences were observed in 2 patients (3.5%). Disarticulation was performed in both of them, and no further tumor recurrences were observed in 4 to 5 years of follow-up. CONCLUSION: Mohs surgery provides the highest cure rate for the treatment of nail SCC. It allows the evaluation of periosteal invasion and therefore bone invasion to be reliably distinguished from inflammation or compression. This technique reduces the number of unnecessary amputations, a critical consideration for patient's quality of life. PMID- 26241669 TI - A Novel WRN Frameshift Mutation Identified by Multiplex Genetic Testing in a Family with Multiple Cases of Cancer. AB - Next-generation sequencing technology allows simultaneous analysis of multiple susceptibility genes for clinical cancer genetics. In this study, multiplex genetic testing was conducted in a Chinese family with multiple cases of cancer to determine the variations in cancer predisposition genes. The family comprises a mother and her five daughters, of whom the mother and the eldest daughter have cancer and the secondary daughter died of cancer. We conducted multiplex genetic testing of 90 cancer susceptibility genes using the peripheral blood DNA of the mother and all five daughters. WRN frameshift mutation is considered a potential pathogenic variation according to the guidelines of the American College of Medical Genetics. A novel WRN frameshift mutation (p.N1370Tfs*23) was identified in the three cancer patients and in the youngest unaffected daughter. Other rare non-synonymous germline mutations were also detected in DICER and ELAC2. Functional mutations in WRN cause Werner syndrome, a human autosomal recessive disease characterized by premature aging and associated with genetic instability and increased cancer risk. Our results suggest that the WRN frameshift mutation is important in the surveillance of other members of this family, especially the youngest daughter, but the pathogenicity of the novel WRN frameshift mutation needs to be investigated further. Given its extensive use in clinical genetic screening, multiplex genetic testing is a promising tool in clinical cancer surveillance. PMID- 26241671 TI - Fibrosarcomatous Transformation of a Dermatofibrosarcoma Protuberans During Pregnancy. PMID- 26241672 TI - Upregulation of miR-130b enhances stem cell-like phenotype in glioblastoma by inactivating the Hippo signaling pathway. AB - The Hippo signaling pathway plays a crucial role in suppressing tumorigenesis. Physiologically, The Hippo signaling largely restricts its two downstream effectors, homologous oncoproteins Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), to a low level of activity by the MST1-SAV1 complex-induced kinase cascade. However, how the negative regulation induced by MST1-SAV1 complex is disrupted to exhibit constitutive YAP/TAZ activation in cancer remains unclear. Herein, we reported that miR-130b directly repressed MST1 and SAV1 expression in human glioblastoma cells. Overexpression of miR-130b induced hyperactivation of the YAP/TAZ and enhanced expression of the Hippo signaling downstream genes CTGF and the pluripotency associated markers, including CD133, SOX2, Nanog, MYC and BMI1, leading to promotion of glioblastoma stem cell phenotype. Conversely, inhibition of miR-130b attenuated these effects. These findings provide a novel mechanism for Hippo signaling inactivation in cancer, indicating not only a potentially pivotal role for miR-130b in the progression of glioblastoma, but also may represent a new therapeutic target. PMID- 26241674 TI - Identification and characterization of proliferative retinopathy-related long noncoding RNAs. AB - Proliferative vitreoretinopathy (PVR) is a serious complication of retinal detachment and vitreoretinal surgery, which can lead to severe vision reduction. Long non-coding RNAs (lncRNAs) play critical roles in many biological processes and disease development. We attempted to determine the role of lncRNAs in the setting of PVR. Microarray analysis revealed that 78 lncRNAs were abnormally expressed in the epiretinal membranes (ERMs) of PVR patients, including 48 up regulated and 30 down-regulated lncRNA transcripts. We subsequently focus on one lncRNA, MALAT1, and investigated its expression pattern in the biofluid of PVR patients. MALAT1 was significantly up-regulated in the cellular and plasma fraction of peripheral blood in PVR patients. MALAT1 expression was obviously reduced after PVR operation. In vitro experiments revealed the role of MALAT1 in regulating RPE proliferation and migration, which is critical for ERMs formation. This study suggests that lncRNAs are the potential regulators of PVR pathology. MALAT1 is a potential prognostic indicator and a target for the diagnosis and gene therapy for PVR diseases. PMID- 26241673 TI - A novel cytoplasmic tail motif regulates mouse corin expression on the cell surface. AB - Type II transmembrane serine proteases (TTSPs) are important in many biological processes. Cell surface expression is critical for TTSP activation and function. To date, the mechanism underlying TTSP cell surface expression is poorly understood. Corin is a TTSP and acts as the pro-atrial natriuretic peptide convertase that is essential for sodium homeostasis and normal blood pressure. In this study, we investigated how cytoplasmic tail sequences may regulate corin expression and activation on the cell surface. By site-directed mutagenesis, we made mouse corin proteins with truncations or point-mutations in the cytoplasmic tail. We expressed the mutants in transfected HEK293 cells and analyzed corin cell surface expression and activation by Western blotting and flow cytometry. We found that corin truncation mutants lacking a Lys-Phe-Gln sequence at residues 71 73 had higher levels of cell surface expression and activation compared with that in wild-type corin. When Lys-71, Phe-72 and Gln-73 residues were mutated together, but not individually, in corin with the full-length cytoplasmic tail, increased levels of cell surface expression and zymogen activation were also observed. These results indicate that residues Lys-71, Phe-72 and Gln-73 serve as a novel retention motif in the intracellular pathway to regulate corin cell surface expression and activation. PMID- 26241675 TI - Artificial microRNAs against the viral E6 protein provoke apoptosis in HPV positive cancer cells. AB - High-risk human papillomavirus (HPV) types 16 and 18 are associated with more than 70% of cervical cancer cases. The oncoprotein E6 is multifunctional and has numerous cellular partners. The best-known activity of E6 is the polyubiquination of the pro-apoptotic tumor suppressor p53, targeting it for degradation by the 26S proteasome. Loss of p53 triggers genomic instability and favors cancer development. Here, we generated recombinant adenovirus (Ad) vectors expressing artificial microRNAs directed against HPV16 E6 (Ad16_1) or HPV18 E6 (Ad18_2). E6 knockdown was observed in HeLa after treatment with Ad18_2 and in SiHa with Ad16_1. Western-blot experiments found an increase in p53 levels after treatment in both cell lines. Cell death was observed in both cell lines after knockdown of E6. Further analysis such as cleavage of caspases (3 and 7) as well as of PARP1 indicated that treated HeLa and SiHa cells underwent apoptosis. The growth of HeLa-derived tumors developed in nude mice was significantly reduced after intra tumoral injection of Ad18_2. Therefore, vectorisation of artificial miRNA against E6 oncoprotein by means of recombinant adenoviruses might represent a valuable therapeutic approach for treating HPV-positive cancers. PMID- 26241676 TI - Identification of nucleosome assembly protein 1 (NAP1) as an interacting partner of plant ribosomal protein S6 (RPS6) and a positive regulator of rDNA transcription. AB - The ribosomal protein S6 (RPS6) is a downstream component of the signaling mediated by the target of rapamycin (TOR) kinase that acts as a central regulator of the key metabolic processes, such as protein translation and ribosome biogenesis, in response to various environmental cues. In our previous study, we identified a novel role of plant RPS6, which negatively regulates rDNA transcription, forming a complex with a plant-specific histone deacetylase, AtHD2B. Here we report that the Arabidopsis RPS6 interacts additionally with a histone chaperone, nucleosome assembly protein 1(AtNAP1;1). The interaction does not appear to preclude the association of RPS6 with AtHD2B, as the AtNAP1 was also able to interact with AtHD2B as well as with an RPS6-AtHD2B fusion protein in the BiFC assay and pulldown experiment. Similar to a positive effect of the ribosomal S6 kinase 1 (AtS6K1) on rDNA transcription observed in this study, overexpression or down regulation of the AtNAP1;1 resulted in concomitant increase and decrease, respectively, in rDNA transcription suggesting a positive regulatory role played by AtNAP1 in plant rDNA transcription, possibly through derepression of the negative effect of the RPS6-AtHD2B complex. PMID- 26241677 TI - Intracellular distribution of TM4SF1 and internalization of TM4SF1-antibody complex in vascular endothelial cells. AB - Transmembrane-4 L-six family member-1 (TM4SF1) is a small plasma membrane associated glycoprotein that is highly and selectively expressed on the plasma membranes of tumor cells, cultured endothelial cells, and, in vivo, on tumor associated endothelium. Immunofluorescence microscopy also demonstrated TM4SF1 in cytoplasm and, tentatively, within nuclei. With monoclonal antibody 8G4, and the finer resolution afforded by immuno-nanogold transmission electron microscopy, we now demonstrate TM4SF1 in uncoated cytoplasmic vesicles, nuclear pores and nucleoplasm. Because of its prominent surface location on tumor cells and tumor associated endothelium, TM4SF1 has potential as a dual therapeutic target using an antibody drug conjugate (ADC) approach. For ADC to be successful, antibodies reacting with cell surface antigens must be internalized for delivery of associated toxins to intracellular targets. We now report that 8G4 is efficiently taken up into cultured endothelial cells by uncoated vesicles in a dynamin dependent, clathrin-independent manner. It is then transported along microtubules through the cytoplasm and passes through nuclear pores into the nucleus. These findings validate TM4SF1 as an attractive candidate for cancer therapy with antibody-bound toxins that have the capacity to react with either cytoplasmic or nuclear targets in tumor cells or tumor-associated vascular endothelium. PMID- 26241679 TI - Sustained attention in infancy as a longitudinal predictor of self-regulatory functions. AB - Previous literature suggests that attention processes such as sustained attention would constitute a developmental foundation for the self-regulatory functions executive functioning and effortful control (e.g., Garon, Bryson, & Smith, 2008; Rothbart, Derryberry, & Posner, 1994). Our main aim was to test this hypothesis by studying whether sustained attention at age 1 year can predict individual differences in self-regulatory functions at age 2 years. Longitudinal data from 66 infants and their parents were included in the study. Sustained attention was assessed during free play at age 1 year; executive functioning, measured using an eye-tracking version of the A-not-B task, and effortful control, measured using parental ratings, were assessed at both age 1 and age 2 years. The results did support a longitudinal prediction of individual differences in 2-year-olds' self regulatory functions as a function of sustained attention at age 1 year. We also found significant improvement in both executive functioning and effortful control over time, and the two self-regulatory constructs were related in toddlerhood but not in infancy. The study helps increase our understanding of the early development of self-regulatory functions necessary for identifying developmental risks and, in the future, for developing new interventions. PMID- 26241678 TI - Diet and specific microbial exposure trigger features of environmental enteropathy in a novel murine model. AB - Environmental enteropathy (EE) is a subclinical chronic inflammatory disease of the small intestine and has a profound impact on the persistence of childhood malnutrition worldwide. However, the aetiology of the disease remains unknown and no animal model exists to date, the creation of which would aid in understanding this complex disease. Here we demonstrate that early-life consumption of a moderately malnourished diet, in combination with iterative oral exposure to commensal Bacteroidales species and Escherichia coli, remodels the murine small intestine to resemble features of EE observed in humans. We further report the profound changes that malnutrition imparts on the small intestinal microbiota, metabolite and intraepithelial lymphocyte composition, along with the susceptibility to enteric infection. Our findings provide evidence indicating that both diet and microbes combine to contribute to the aetiology of EE, and describe a novel murine model that can be used to elucidate the mechanisms behind this understudied disease. PMID- 26241680 TI - Real diffusion-weighted MRI enabling true signal averaging and increased diffusion contrast. AB - This project aims to characterize the impact of underlying noise distributions on diffusion-weighted imaging. The noise floor is a well-known problem for traditional magnitude-based diffusion-weighted MRI (dMRI) data, leading to biased diffusion model fits and inaccurate signal averaging. Here, we introduce a total variation-based algorithm to eliminate shot-to-shot phase variations of complex valued diffusion data with the intention to extract real-valued dMRI datasets. The obtained real-valued diffusion data are no longer superimposed by a noise floor but instead by a zero-mean Gaussian noise distribution, yielding dMRI data without signal bias. We acquired high-resolution dMRI data with strong diffusion weighting and, thus, low signal-to-noise ratio. Both the extracted real-valued and traditional magnitude data were compared regarding signal averaging, diffusion model fitting and accuracy in resolving crossing fibers. Our results clearly indicate that real-valued diffusion data enables idealized conditions for signal averaging. Furthermore, the proposed method enables unbiased use of widely employed linear least squares estimators for model fitting and demonstrates an increased sensitivity to detect secondary fiber directions with reduced angular error. The use of phase-corrected, real-valued data for dMRI will therefore help to clear the way for more detailed and accurate studies of white matter microstructure and structural connectivity on a fine scale. PMID- 26241681 TI - Impact of the resolution of brain parcels on connectome-wide association studies in fMRI. AB - A recent trend in functional magnetic resonance imaging is to test for association of clinical disorders with every possible connection between selected brain parcels. We investigated the impact of the resolution of functional brain parcels, ranging from large-scale networks to local regions, on a mass univariate general linear model (GLM) of connectomes. For each resolution taken independently, the Benjamini-Hochberg procedure controlled the false-discovery rate (FDR) at nominal level on realistic simulations. However, the FDR for tests pooled across all resolutions could be inflated compared to the FDR within resolution. This inflation was severe in the presence of no or weak effects, but became negligible for strong effects. We thus developed an omnibus test to establish the overall presence of true discoveries across all resolutions. Although not a guarantee to control the FDR across resolutions, the omnibus test may be used for descriptive analysis of the impact of resolution on a GLM analysis, in complement to a primary analysis at a predefined single resolution. On three real datasets with significant omnibus test (schizophrenia, congenital blindness, motor practice), markedly higher rate of discovery were obtained at low resolutions, below 50, in line with simulations showing increase in sensitivity at such resolutions. This increase in discovery rate came at the cost of a lower ability to localize effects, as low resolution parcels merged many different brain regions together. However, with 30 or more parcels, the statistical effect maps were biologically plausible and very consistent across resolutions. These results show that resolution is a key parameter for GLM connectome analysis with FDR control, and that a functional brain parcellation with 30 to 50 parcels may lead to an accurate summary of full connectome effects with good sensitivity in many situations. PMID- 26241682 TI - Dynamics of respiratory and cardiac CSF motion revealed with real-time simultaneous multi-slice EPI velocity phase contrast imaging. AB - Cerebrospinal fluid (CSF) dynamics have been mostly studied with cardiac-gated phase contrast MRI combining signal from many cardiac cycles to create cine-phase sampling of one time-averaged cardiac cycle. The relative effects of cardiac and respiratory changes on CSF movement are not well understood. There is possible respiration-driven movement of CSF in ventricles, cisterns, and subarachnoid spaces which has not been characterized with velocity measurements. To date, commonly used cine-phase contrast techniques of velocity imaging inherently cannot detect respiratory velocity changes since cardiac-gated data acquired over several minutes randomizes respiratory phase contributions. We have developed an extremely fast, real-time, and quantitative MRI technique to image CSF velocity in simultaneous multi-slice (SMS) echo planar imaging (EPI) acquisitions of 3 or 6 slice levels simultaneously over 30s and observe 3D spatial distributions of CSF velocity. Measurements were made in 10 subjects utilizing a respiratory belt to record respiratory phases and visual cues to instruct subjects on breathing rates. A protocol is able to measure velocity within regions of brain and basal cisterns covered with 24 axial slices in 4 minutes, repeated for 3 velocity directions. These measurements were performed throughout the whole brain, rather than in selected line regions so that a global view of CSF dynamics could be visualized. Observations of cardiac and breathing-driven CSF dynamics show bidirectional respiratory motion occurs primarily along the central axis through the basal cisterns and intraventricular passageways and to a lesser extent in the peripheral Sylvian fissure with little CSF motion present in subarachnoid spaces. During inspiration phase, there is upward (inferior to superior) CSF movement into the cranial cavity and lateral ventricles and a reversal of direction in expiration phase. PMID- 26241684 TI - Implementation of a new parcellation of the orbitofrontal cortex in the automated anatomical labeling atlas. AB - An alternative parcellation of the orbitofrontal cortex is described for the automated anatomical labeling atlas of Tzourio-Mazoyer et al. (2002) (Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. NeuroImage 15:273-289). The new parcellation of the orbitofrontal cortex follows the description provided by Chiavaras, Petrides, and colleagues (2000, 2001). The new atlas is available as a toolbox for SPM at http://www.gin.cnrs.fr/AAL2. PMID- 26241683 TI - Inscapes: A movie paradigm to improve compliance in functional magnetic resonance imaging. AB - The examination of functional connectivity in fMRI data collected during task free "rest" has provided a powerful tool for studying functional brain organization. Limitations of this approach include susceptibility to head motion artifacts and participant drowsiness or sleep. These issues are especially relevant when studying young children or clinical populations. Here we introduce a movie paradigm, Inscapes, that features abstract shapes without a narrative or scene-cuts. The movie was designed to provide enough stimulation to improve compliance related to motion and wakefulness while minimizing cognitive load during the collection of functional imaging data. We compare Inscapes to eyes open rest and to age-appropriate movie clips in healthy adults (Ocean's Eleven, n=22) and a pilot sample of typically developing children ages 3-7 (Fantasia, n=13). Head motion was significantly lower during both movies relative to rest for both groups. In adults, movies decreased the number of participants who self reported sleep. Intersubject correlations, used to quantify synchronized, task evoked activity across movie and rest conditions in adults, involved less cortex during Inscapes than Ocean's Eleven. To evaluate the effect of movie-watching on intrinsic functional connectivity networks, we examined mean functional connectivity using both whole-brain functional parcellation and network-based approaches. Both inter- and intra-network metrics were more similar between Inscapes and Rest than between Ocean's Eleven and Rest, particularly in comparisons involving the default network. When comparing movies to Rest, the mean functional connectivity of somatomotor, visual and ventral attention networks differed significantly across various analyses. We conclude that low demand movies like Inscapes may represent a useful intermediate condition between task-free rest and typical narrative movies while still improving participant compliance. Inscapes is publicly available for download at headspacestudios.org/inscapes. PMID- 26241685 TI - Identifying neural correlates of visual consciousness with ALE meta-analyses. AB - Neural correlates of consciousness (NCC) have been a topic of study for nearly two decades. In functional imaging studies, several regions have been proposed to constitute possible candidates for NCC, but as of yet, no quantitative summary of the literature on NCC has been done. The question whether single (striate or extrastriate) regions or a network consisting of extrastriate areas that project directly to fronto-parietal regions are necessary and sufficient neural correlates for visual consciousness is still highly debated [e.g., Rees et al., 2002, Nat Rev. Neurosci 3, 261-270; Tong, 2003, Nat Rev. Neurosci 4, 219-229]. The aim of this work was to elucidate this issue and give a synopsis of the present state of the art by conducting systematic and quantitative meta-analyses across functional magnetic resonance imaging (fMRI) studies using several standard paradigms for conscious visual perception. In these paradigms, consciousness is operationalized via perceptual changes, while the visual stimulus remains invariant. An activation likelihood estimation (ALE) meta analysis was performed, representing the best approach for voxel-wise meta analyses to date. In addition to computing a meta-analysis across all paradigms, separate meta-analyses on bistable perception and masking paradigms were conducted to assess whether these paradigms show common or different NCC. For the overall meta-analysis, we found significant clusters of activation in inferior and middle occipital gyrus; fusiform gyrus; inferior temporal gyrus; caudate nucleus; insula; inferior, middle, and superior frontal gyri; precuneus; as well as in inferior and superior parietal lobules. These results suggest a subcortical extrastriate-fronto-parietal network rather than a single region that constitutes the necessary NCC. The results of our exploratory paradigm-specific meta-analyses suggest that this subcortical-extrastriate-fronto-parietal network might be differentially activated as a function of the paradigms used to probe for NCC. PMID- 26241686 TI - Surgical Pain Control With Ropivacaine by Atomized Delivery (Spray): A Randomized Controlled Trial. AB - STUDY OBJECTIVE: To investigate the role of intraoperative atomized intraperitoneal ropivacaine (AIR) as an adjuvant to anesthetic agents at the time of minimally invasive pelvic surgery. DESIGN: Double-blind, randomized controlled trial. DESIGN: CLASSIFICATION: Randomized controlled trial (Canadian Task Force classification I). SETTING: Tertiary care teaching hospital. PARTICIPANTS: Fifty five patients who underwent laparoscopic and robotic gynecologic procedures. INTERVENTION: Patients received AIR or atomized intraperitoneal saline (AIS) (dose, 2 mg/kg) immediately after the initiation of pneumoperitoneum. MEASUREMENTS AND MAIN RESULTS: Visual analog scale (VAS) pain scores and narcotic use (in morphine equivalents) were collected and recorded at 2, 4, 8, and 12 hours postoperatively. RESULTS: Fifty-five patients completed the study protocol and data collection, with 30 patients allocated to the AIS group and 25 patients allocated to the AIR group. Demographic and surgical variables did not vary between the groups, with the exception of median operative duration. Postoperative VAS scores at 2, 4, 8, and 12 postoperative hours were higher in the AIS group, but the difference failed to reach statistical significance. Narcotic use was also similar in the 2 groups. CONCLUSION: The use of intraperitoneal ropivacaine was not associated with a statistically significant difference in patients' postoperative VAS scores. Thus, in contrast to findings of similar studies performed in general surgery, AIR might not confer a benefit in women undergoing minimally invasive gynecologic procedures. PMID- 26241687 TI - Laparoscopic Hysterectomy and Urinary Tract Injury: Experience in a Health Maintenance Organization. AB - STUDY OBJECTIVES: To evaluate the incidence, detection, characteristics, and management of urinary tract injury in a cohort undergoing laparoscopic hysterectomy, and to identify potential risk factors for urinary tract injury with laparoscopic hysterectomy. DESIGN: Retrospective analysis (Canadian Task Force classification II-2). SETTING: Kaiser Permanente San Diego Medical Center, 2001 to 2012. PATIENTS: Women who underwent attempted laparoscopic hysterectomy for benign indications. INTERVENTIONS: Total laparoscopic hysterectomy, laparoscopic-assisted vaginal hysterectomy, and laparoscopic supracervical hysterectomy. MEASUREMENTS AND MAIN RESULTS: Demographic and clinical characteristics, surgical techniques, and perioperative complications were abstracted from the medical record. Multivariable logistic regression analysis assessed independent risk factors for ureteral or bladder injury. RESULTS: A total of 3523 patients (mean age, 45.9 +/- 8.0 years; median parity, 2; range, 0 10), with a median body mass index (BMI) of 29 kg/m(2) (range, 16-72 kg/m(2)), underwent laparoscopic hysterectomy; 20% had intraoperative cystoscopy. The incidence of urinary tract injury was 1.3% (46 of 3523); of the 46 patients with injuries, 19 (0.54%) had ureteral injuries, 25 (0.71%) had bladder injuries, and 2 (0.06%) had both types. Of the 21 ureteral injuries, 6 (29%) were diagnosed intraoperatively and 15 (71%) were diagnosed postoperatively, including 4 with normal intraoperative cystoscopy. Of the 27 bladder injuries, 23 (85%) were identified intraoperatively. In multivariable logistic analysis, a BMI of 26 to 30 kg/m(2) (compared with >30 kg/m(2)) was associated with an increased risk of ureteral injury, and a BMI <=25 kg/m(2) (compared with >30 kg/m(2)) and the presence of endometriosis were associated with an increased risk of bladder injury. CONCLUSION: Urinary tract injury occurred in 1.3% of laparoscopic hysterectomies, with ureteral injuries almost as common as bladder injuries. Normal intraoperative cystoscopy findings did not exclude the presence of ureteral injury. PMID- 26241688 TI - Epigallocatechin gallate hinders human hepatoma and colon cancer sphere formation. AB - BACKGROUND AND AIM: The long-term survival of patients with hepatocellular carcinoma remains unsatisfactory because of the presence of cancer stem cells (CSCs), which are responsible for tumor recurrence and chemoresistance after hepatectomy. Drugs that selectively target CSCs thus offer great promise for cancer treatment. Although the antitumor effects of epigallocatechin gallate (EGCG) have been reported in some cancer cells, its effects on CSCs remain poorly studied. In this study, we investigated the effects of EGCG on human hepatoma and colon CSCs. METHODS: HepG2 and HCT-116 cell lines were enriched by sphere formation, and their gene-expression profiles were analyzed by quantitative real time polymerase chain reaction. EGCG-induced growth inhibition in the parental cells was determined by WST-8 assay, and protein expression was assessed by western blotting. Cell cycle profile and apoptosis analysis was performed using flow cytometer. RESULTS: Sphere-derived cells grown in serum-free, nonadherent cultures showed increased expression of stem cell markers, Nek2, and ATP-binding cassette transporter genes, compared with parental cells grown in conventional culture. EGCG induced growth inhibition in the parental cells in a dose-dependent manner. EGCG also inhibited self-renewal in hepatoma and colon CSCs, attenuated the expression of stem cell markers and ATP-binding cassette transporter genes, which are putative molecules associated with treatment resistance in CSCs, and decreased the transcription of Nek2 and p-Akt, resulting in the inhibition of Akt signaling. EGCG also altered cell cycle profile and apoptosis, which may in part play an important role in EGCG-induced cancer cell death. CONCLUSIONS: Overall, these results suggest that EGCG could be a useful chemopreventive agent for targeting hepatocellular carcinoma and colon CSCs, in combination with standard chemotherapies. PMID- 26241689 TI - Three-phonon scattering processes and thermal conductivity in IV-chalocogenides. AB - We present a systematic study of allowed three-phonon scattering processes, involving acoustic and optical branches, and their relative roles in explaining the low thermal conductivity kappa of IV-chalcogenide thermoelectric materials PbTe, PbSe, PbS, and SnTe. Using numerical results for kappa, computed by employing the isotropic continuum scheme, we have examined the extent of the additional contribution the Callaway theory and the Allen theory provide over the single-mode relaxation time theory. Within the Callaway theory, for all these materials the acoustic (TA, LA) and transverse optical (TO) phonons contribute between 10-25% towards kappa at and above room temperature, with kappa(TO) > kappa(TA) > kappa(LA). The longitudinal optical (LO) phonons contribute negligibly (<5%) in Pb-chalogenides, but their contribution is larger (22%) than that of TO phonons (18%) in SnTe. Due to the presence of high defect concentration in these materials, the high temperature conductivity varies less strongly than T(-1). In confirmation with experimental measurements, our study finds that below the Debye temperature the resistivity of SnTe varies as the square-root of the point defect concentration. PMID- 26241690 TI - Energy evaluation of a bio-inspired gait modulation method for quadrupedal locomotion. AB - We have proposed a bio-inspired gait modulation method, by means of which a simulated quadruped model can successfully perform smooth, autonomous gait transitions from a walk to a trot to a gallop, as observed in animals. The model is equipped with a rhythm generator called a central pattern generator (CPG) for each leg. The lateral neighbouring CPGs are mutually and inhibitorily coupled, and the CPG network is hardwired to produce a trot. Adding only the simple feedback of body tilt to each CPG, which was based on input from the postural reflex, led to the emergence of un-programmed walking and galloping at low and high speeds, respectively. Although this autonomous gait transition was a consequence of postural adaptation, it coincidentally also resulted in the minimization of energy consumption, as observed in real animals. In simulations at a variety of constant speeds the energy cost was lower for walking at low speeds and for galloping at high speeds than it was for trotting. Moreover, each gait transition occurred at the optimal speed, such that the model minimised its energy consumption. Thus, gait transitions in simulations that included the bio inspired gait modulation method were similar to those observed in animals, even from the perspective of energy consumption. This method should therefore be a preferred choice for motion generation and control in biomimetic quadrupedal locomotion. PMID- 26241691 TI - Sc2NiMnO6: A Double-Perovskite with a Magnetodielectric Response Driven by Multiple Magnetic Orders. AB - Perovskite materials provide a large variety of interesting physical properties and applications. Here, we report on unique properties of a fully ordered magnetodielectric double-perovskite, Sc2NiMnO6 (space group P21/n, a = 4.99860 A, b = 5.35281 A, c = 7.34496 A, and beta = 90.7915 degrees ), exhibiting sequential magnetic transitions at T1 = 35 K and T2 = 17 K. The transition at T1 corresponds to a single-k antiferromagnetic phase with propagation vector k1 = (1/2, 0, 1/2), while the second transition at T2 corresponds to a 2-k magnetic structure with propagation vectors k1 = (1/2, 0, 1/2) and k2 = (0, 1/2, 1/2). Symmetry analysis suggests that the two ordering wave vectors are independent, and calculations imply that k1 is associated with the Mn sublattice and k2 with the Ni sublattice, suggesting that Mn-Ni coupling is very small or absent. A magnetodielectric anomaly at T2 likely arises from an antiferroelectric ordering that results from the exchange-striction between the two magnetic sublattices belonging to k1 and k2. The behavior of Sc2NiMnO6 demonstrates 3d double-perovskites with small A site cations as a promising avenue in which to search for magnetoelectric materials. PMID- 26241692 TI - Estimation of Hydrogen-Exchange Protection Factors from MD Simulation Based on Amide Hydrogen Bonding Analysis. AB - Hydrogen exchange (HX) studies have provided critical insight into our understanding of protein folding, structure, and dynamics. More recently, hydrogen exchange mass spectrometry (HX-MS) has become a widely applicable tool for HX studies. The interpretation of the wealth of data generated by HX-MS experiments as well as other HX methods would greatly benefit from the availability of exchange predictions derived from structures or models for comparison with experiment. Most reported computational HX modeling studies have employed solvent-accessible-surface-area based metrics in attempts to interpret HX data on the basis of structures or models. In this study, a computational HX MS prediction method based on classification of the amide hydrogen bonding modes mimicking the local unfolding model is demonstrated. Analysis of the NH bonding configurations from molecular dynamics (MD) simulation snapshots is used to determine partitioning over bonded and nonbonded NH states and is directly mapped into a protection factor (PF) using a logistics growth function. Predicted PFs are then used for calculating deuteration values of peptides and compared with experimental data. Hydrogen exchange MS data for fatty acid synthase thioesterase (FAS-TE) collected for a range of pHs and temperatures was used for detailed evaluation of the approach. High correlation between prediction and experiment for observable fragment peptides is observed in the FAS-TE and additional benchmarking systems that included various apo/holo proteins for which literature data were available. In addition, it is shown that HX modeling can improve experimental resolution through decomposition of in-exchange curves into rate classes, which correlate with prediction from MD. Successful rate class decompositions provide further evidence that the presented approach captures the underlying physical processes correctly at the single residue level. This assessment is further strengthened in a comparison of residue resolved protection factor predictions for staphylococcal nuclease with NMR data, which was also used to compare prediction performance with other algorithms described in the literature. The demonstrated transferable and scalable MD based HX prediction approach adds significantly to the available tools for HX-MS data interpretation based on available structures and models. PMID- 26241694 TI - An experimental set-up to assess knee stiffness: a pilot study. PMID- 26241693 TI - Accuracy of Continuous Glucose Monitoring During Three Closed-Loop Home Studies Under Free-Living Conditions. AB - OBJECTIVES: Closed-loop (CL) systems modulate insulin delivery based on glucose levels measured by a continuous glucose monitor (CGM). Accuracy of the CGM affects CL performance and safety. We evaluated the accuracy of the Freestyle Navigator((r)) II CGM (Abbott Diabetes Care, Alameda, CA) during three unsupervised, randomized, open-label, crossover home CL studies. MATERIALS AND METHODS: Paired CGM and capillary glucose values (10,597 pairs) were collected from 57 participants with type 1 diabetes (41 adults [mean+/-SD age, 39+/-12 years; mean+/-SD hemoglobin A1c, 7.9+/-0.8%] recruited at five centers and 16 adolescents [mean+/-SD age, 15.6+/-3.6 years; mean+/-SD hemoglobin A1c, 8.1+/ 0.8%] recruited at two centers). Numerical accuracy was assessed by absolute relative difference (ARD) and International Organization for Standardization (ISO) 15197:2013 15/15% limits, and clinical accuracy was assessed by Clarke error grid analysis. RESULTS: Total duration of sensor use was 2,002 days (48,052 h). Overall sensor accuracy for the capillary glucose range (1.1-27.8 mmol/L) showed mean+/-SD and median (interquartile range) ARD of 14.2+/-15.5% and 10.0% (4.5%, 18.4%), respectively. Lowest mean ARD was observed in the hyperglycemic range (9.8+/-8.8%). Over 95% of pairs were in combined Clarke error grid Zones A and B (A, 80.1%, B, 16.2%). Overall, 70.0% of the sensor readings satisfied ISO criteria. Mean ARD was consistent (12.3%; 95% of the values fall within +/-3.7%) and not different between participants (P=0.06) within the euglycemic and hyperglycemic range, when CL is actively modulating insulin delivery. CONCLUSIONS: Consistent accuracy of the CGM within the euglycemic-hyperglycemic range using the Freestyle Navigator II was observed and supports its use in home CL studies. Our results may contribute toward establishing normative CGM performance criteria for unsupervised home use of CL. PMID- 26241695 TI - Make No Bones about It: Long Bones Scale Isometrically. AB - Long bones are far from being simple cylinders, so how is the relative positioning of their various features maintained during growth? A new study shows that growth is isometric and that drift from the correct position is minimized. Read the Research Article. PMID- 26241697 TI - Photophysics of Derivatives of 3-Hydroxybenzo[c]coumarin. AB - The photophysical studies of two phenols, derivatives of 3 hydroxybenzo[c]coumarin, were performed in n-nonane matrix at 5 K. Unstructured fluorescence spectrum of the derivative bearing a salicylaldehyde moiety, whose onset is shifted by ca. 3000 cm(-1) to lower energy in respect to that of absorption, and short decay time of this emission (0.75 ns) suggested the occurrence of excited-state intramolecular proton transfer (ESIPT). The experimental results were interpreted with the aid of quantum chemistry calculations performed with the DFT and TDDFT/B3LYP/6-31++G(d,p) methods. PMID- 26241696 TI - Circadian clock control of connexin36 phosphorylation in retinal photoreceptors of the CBA/CaJ mouse strain. AB - The gap-junction-forming protein connexin36 (Cx36) represents the anatomical substrate of photoreceptor electrical coupling in mammals. The strength of coupling is directly correlated to the phosphorylation of Cx36 at two regulatory sites: Ser110 and Ser293. Our previous work demonstrated that the extent of biotinylated tracer coupling between photoreceptor cells, which provides an index of the extent of electrical coupling, depends on the mouse strain. In the C57Bl/6J strain, light or dopamine reduces tracer coupling and Cx36 phosphorylation in photoreceptors. Conversely, darkness or a dopaminergic antagonist increases tracer coupling and Cx36 phosphorylation, regardless of the daytime. In the CBA/CaJ strain, photoreceptor tracer coupling is not only regulated by light and dopamine, but also by a circadian clock, a type of oscillator with a period close to 24 h and intrinsic to the retina, so that under prolonged dark-adapted conditions tracer coupling is broader at night compared to daytime. In the current study, we examined whether the modulation of photoreceptor coupling by a circadian clock in the CBA/CaJ mouse photoreceptors reflected a change in Cx36 protein expression and/or phosphorylation. We found no significant change in Cx36 expression or in the number of Cx36 gap junction among the conditions examined. However, we found that Cx36 phosphorylation is higher under dark-adapted conditions at night than in the daytime, and is the lowest under prolonged illumination at any time of the day/night cycle. Our observations are consistent with the view that the circadian clock regulation of photoreceptor electrical coupling is mouse strain-dependent and highlights the critical position of Cx36 phosphorylation in the control of photoreceptor coupling. PMID- 26241698 TI - Post-pyloric versus gastric tube feeding for preventing pneumonia and improving nutritional outcomes in critically ill adults. AB - BACKGROUND: Nutritional support is an essential component of critical care. Malnutrition has been associated with poor outcomes among patients in intensive care units (ICUs). Evidence suggests that in patients with a functional gut, nutrition should be administered through the enteral route. One of the main concerns regarding use of the enteral route is the reduction in gastric motility that is often responsible for limited caloric intake. This increases the risk of aspiration pneumonia as well. Post-pyloric feeding, in which the feed is delivered directly into the duodenum or the jejunum, could solve these issues and provide additional benefits over routine gastric administration of the feed. OBJECTIVES: To evaluate the effectiveness and safety of post-pyloric feeding versus gastric feeding for critically ill adults who require enteral tube feeding. SEARCH METHODS: We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL;2013 Issue 10), MEDLINE (Ovid) (1950 to October 2013), EMBASE (Ovid) (1980 to October 2013) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) via EBSCO host (1982 to October 2013). We reran the search on 4 February 2015 and will deal with the one study of interest when we update the review. SELECTION CRITERIA: Randomized or quasi randomized controlled trials comparing post-pyloric versus gastric tube feeding in critically ill adults. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Anaesthesia, Critical and Emergency Care Group and separately evaluated trial quality and data extraction as performed by each review author. We contacted trials authors to request missing data. MAIN RESULTS: We pooled data from 14 trials of 1109 participants in a meta-analysis. Moderate quality evidence suggests that post-pyloric feeding is associated with low rates of pneumonia compared with gastric tube feeding (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.51 to 0.84). Low-quality evidence shows an increase in the percentage of total nutrient delivered to the patient by post pyloric feeding (mean difference (MD) 7.8%, 95% CI 1.43 to 14.18).Evidence of moderate quality revealed no differences in duration of mechanical ventilation or in mortality. Intensive care unit (ICU) length of stay was similar between the two groups. The effect on the time required to achieve the full nutrition target was uncertain (MD -1.99 hours 95% CI -10.97 to 6.99) (very low-quality evidence). We found no evidence suggesting an increase in the rate of complications during insertion or maintenance of the tube in the post-pyloric group (RR 0.51, 95% CI 0.19 to 1.364; RR1.63, 95% CI 0.93 to 2.86, respectively); evidence was assessed as being of low quality for both.Risk of bias was generally low in most studies, and review authors expressed concern regarding lack of blinding of the caregiver in most trials. AUTHORS' CONCLUSIONS: We found moderate-quality evidence of a 30% lower rate of pneumonia associated with post-pyloric feeding and low-quality evidence suggesting an increase in the amount of nutrition delivered to these participants. We do not have sufficient evidence to show that other clinically important outcomes such as duration of mechanical ventilation, mortality and length of stay were affected by the site of tube feeding.Low-quality evidence suggests that insertion of a post-pyloric feeding tube appears to be safe and was not associated with increased complications when compared with gastric tube insertion. Placement of the post-pyloric tube can present challenges; the procedure is technically difficult, requiring expertise and sophisticated radiological or endoscopic assistance.We recommend that use of a post-pyloric feeding tube may be preferred for ICU patients for whom placement of the post pyloric feeding tube is feasible. Findings of this review preclude recommendations regarding the best method for placing the post-pyloric feeding tube. The clinician is left with this decision, which should be based on the policies of institutional facilities and should be made on a case-by-case basis. Protocols and training for bedside placement by physicians or nurses should be evaluated. PMID- 26241699 TI - Human V4 and ventral occipital retinotopic maps. AB - The ventral surface of the human occipital lobe contains multiple retinotopic maps. The most posterior of these maps is considered a potential homolog of macaque V4, and referred to as human V4 ("hV4"). The location of the hV4 map, its retinotopic organization, its role in visual encoding, and the cortical areas it borders have been the subject of considerable investigation and debate over the last 25 years. We review the history of this map and adjacent maps in ventral occipital cortex, and consider the different hypotheses for how these ventral occipital maps are organized. Advances in neuroimaging, computational modeling, and characterization of the nearby anatomical landmarks and functional brain areas have improved our understanding of where human V4 is and what kind of visual representations it contains. PMID- 26241702 TI - Community-based free clinics: opportunities for interprofessional collaboration, health promotion, and complex care management. AB - OBJECTIVE: Free or outreach clinics offer students the opportunity to work with diverse patient populations. The objective of this study was to describe the demographics and clinical characteristics of a sample of chiropractic patients at a free community-based clinic to assess clinical and educational opportunities for students to work with diverse populations, collaborate with other professions and practice health promotion through patient education. METHODS: This was a prospective, descriptive cross-sectional study conducted over 2 months. Data on demographics, health status, and health risks were collected from patients and their interns. RESULTS: Of the 158 patients, 50.6% were women and 50.6% African American, while only 20.9% were employed full-time. Of the 24.7% tobacco users, 48.7% expressed interest in cessation. Of 80.0% overweight or obese patients, 48.8% expressed interest in weight loss. By self-report, 16.5% were diabetic, 10.1% took hypertension medication, 36.7% used prescription pain medication (9.4% opiate use), 33.5% used nonprescription pain medication, and 9.4% were under the care of a mental health professional. CONCLUSION: This patient population is demographically diverse. A high proportion of patients who used tobacco, or were overweight or obese expressed interest in information on those topics. A substantial proportion reported being under care with a mental health professional. This clinic provides opportunities for students to work with diverse populations, collaborate with other professions, and practice health promotion. PMID- 26241700 TI - CYP24A1 and CYP27B1 Polymorphisms, Concentrations of Vitamin D Metabolites, and Odds of Colorectal Adenoma Recurrence. AB - Development of colorectal adenoma and cancer are associated with low circulating 25-hydroxyvitamin D [25(OH)D] levels. However, less is known regarding colorectal neoplasia risk and variation in CYP27B1 or CYP24A1, genes encoding the enzymes responsible for the synthesis and catabolism of 1alpha,25-hydroxyvitamin D [1,25(OH)2D]. This study examined associations between CYP27B1 and CYP24A1 polymorphisms, circulating 25(OH)D and 1,25(OH)2D concentrations, and colorectal adenoma recurrence in a pooled sample from 2 clinical trials (n = 1,188). Nominal associations were observed between increasing copies of the T allele in CYP24A1 rs927650 and 25(OH)D concentrations (P = 0.02); as well as colorectal adenoma recurrence, with odds ratios (95% confidence intervals) of 1.30 (0.99-1.70) and 1.38 (1.01-1.89) for heterozygotes and minor allele homozygotes, respectively (P = 0.04). In addition, a statistically significant relationship between CYP24A1 rs35051736, a functional polymorphism, and odds for advanced colorectal adenoma recurrence was observed (P < 0.001). Further, nominally statistically significant interactions were observed between rs2296241 and 25(OH)D as well as rs2762939 and 1,25(OH)2D (P(interaction) = 0.10, respectively). Overall, CYP24A1 polymorphisms may influence the development of advanced lesions, and modify the effect of vitamin D metabolites on adenoma recurrence. Further study is necessary to characterize the differences between circulating vitamin D metabolite measurements compared to cellular level activity in relation to cancer risk. PMID- 26241703 TI - Aminocaproic Acid and Tranexamic Acid Fail to Reverse Dabigatran-Induced Coagulopathy. AB - In recent years, dabigatran has emerged as a popular alternative to warfarin for treatment of atrial fibrillation. If rapid reversal is required, however, no reversal agent has clearly been established. The primary purpose of this manuscript was to evaluate the efficacy of tranexamic acid and aminocaproic acid as agents to reverse dabigatran-induced coagulopathy. Rats were randomly assigned to 6 groups. Each rat received either dabigatran or oral placebo, followed by saline, tranexamic acid, or aminocaproic acid. An activated clotting test was used to measure the coagulopathy. Neither tranexamic acid nor aminocaproic acid successfully reversed dabigatran-induced coagulopathy. In this rodent model of dabigatran-induced coagulopathy, neither tranexamic acid nor aminocaproic acid were able to reverse the coagulopathy. PMID- 26241704 TI - Modeling Aggregation of Ionic Surfactants Using a Smeared Charge Approximation in Dissipative Particle Dynamics Simulations. AB - Using dissipative particle dynamics (DPD) simulations, we explore the specifics of micellization in the solutions of anionic and cationic surfactants and their mixtures. Anionic surfactant sodium dodecyl sulfate (SDS) and cationic surfactant cetyltrimethylammonium bromide (CTAB) are chosen as characteristic examples. Coarse-grained models of the surfactants are constructed and parameterized using a combination of atomistic molecular simulation and infinite dilution activity coefficient calibration. Electrostatic interactions of charged beads are treated using a smeared charge approximation: the surfactant heads and dissociated counterions are modeled as beads with charges distributed around the bead center in an implicit dielectric medium. The proposed models semiquantitatively describe self-assembly in solutions of SDS and CTAB at various surfactant concentrations and molarities of added electrolyte. In particular, the model predicts a decline in the free surfactant concentration with the increase of the total surfactant loading, as well as characteristic aggregation transitions in single-component surfactant solutions caused by the addition of salt. The calculated values of the critical micelle concentration reasonably agree with experimental observations. Modeling of catanionic SDS-CTAB mixtures show consecutive transitions to worm like micelles and then to vesicles caused by the addition of CTAB to micellar solution of SDS. PMID- 26241706 TI - Response to Comment on "Improved Calibration of Voltammetric Sensors for Studying Pharmacological Effects on Dopamine Transporter Kinetics in Vivo". PMID- 26241705 TI - Clinical and Immunological Factors in Emphysema Progression. Five-Year Prospective Longitudinal Exacerbation Study of Chronic Obstructive Pulmonary Disease (LES-COPD). AB - RATIONALE: Cross-sectional studies of T-cell responses to self-antigens correlate with baseline emphysema severity. OBJECTIVES: We investigated whether clinical and/or immunological factors could predict disease progression, such as emphysema, FEV1, and 6-minute-walk distance (6MWD), in former and active smokers in a 5-year prospective study. METHODS: We recruited 224 ever smokers over 40 years of age and with greater than a 15 pack-year smoking history. MEASUREMENTS AND MAIN RESULTS: Repeated spirometry, 6MWD, and peripheral blood T-cell cytokine responses to lung elastin fragments were measured. Baseline and repeat chest computed tomography (CT) scans (34 to 65 mo apart) were used to quantify emphysema progression. Of the 141 ever-smokers with baseline and repeat CT scans, the mean (SD) annual rate of change in percent emphysema was +0.46 (0.92), ranging from -1.8 to +4.1. In multivariable analyses, the rate of emphysema progression was greater in subjects who had lower body mass index (BMI) (+0.15 per 5-unit decrease in BMI; 95% confidence interval, +0.03 to +0.29). In active smokers, increased IFN-gamma and IL-6 T-cell responses had a positive association with the annual rate of emphysema progression. Male sex and IL-6 T-cell responses to elastin fragments were significantly associated with annual 6MWD decline, whereas IL-13 was associated with an increase in annual 6MWD. CONCLUSIONS: The rate of emphysema progression quantified by CT scans among ever-smokers was highly variable; clinical factors and biomarkers explained only some of the variability. Aggressive clinical care that targets active smokers with autoreactive T cells and low BMI may temporize progression of emphysema. PMID- 26241707 TI - High-Throughput Cytotoxicity Testing System of Acetaminophen Using a Microfluidic Device (MFD) in HepG2 Cells. AB - A lab-on-a-chip (LOC) is a microfluidic device (MFD) that integrates several lab functions into a single chip of only millimeters in size. LOC provides several advantages, such as low fluidic volumes consumption, faster analysis, compactness, and massive parallelization. These properties enable a microfluidic based high-throughput drug screening (HTDS) system to acquire cell-based abundant cytotoxicity results depending on linear gradient concentration of drug with only few hundreds of microliters of the drug. Therefore, a microfluidic device was developed containing an array of eight separate microchambers for cultivating HepG2 cells to be exposed to eight different concentrations of acetaminophen (APAP) through a diffusive-mixing-based concentration gradient generator. Every chamber array with eight different concentrations (0, 5.7, 11.4, 17.1, 22.8, 28.5, 34.2, or 40 mM) APAP had four replicating cell culture chambers. Consequently, 32 experimental results were acquired with a single microfluidic device experiment. The microfluidic high-throughput cytotoxicity device (MUHTCD) and 96-well culture system showed comparable cytotoxicity results with increasing APAP concentration of 0 to 40 mM. The HTDS system yields progressive concentration-dependent cytotoxicity results using minimal reagent and time. Data suggest that the HTDS system may be applicable as alternative method for cytotoxicity screening for new drugs in diverse cell types. PMID- 26241708 TI - Fucoidan Suppresses the Growth of Human Acute Promyelocytic Leukemia Cells In Vitro and In Vivo. AB - Fucoidan, a natural component of seaweeds, is reported to have immunomodulatory and anti-tumor effects. The mechanisms underpinning these activities remain poorly understood. In this study, the cytotoxicity and anti-tumor activities of fucoidan were investigated in acute myeloid leukemia (AML) cells. The human AML cell lines NB4, KG1a, HL60, and K562 were treated with fucoidan and cell cycle, cell proliferation, and expression of apoptotic pathways molecules were analyzed. Fucoidan suppressed the proliferation and induced apoptosis through the intrinsic and extrinsic pathways in the acute promyelocytic leukemia (APL) cell lines NB4 and HL60, but not in KG1a and K562 cells. In NB4 cells, apoptosis was caspase dependent as it was significantly attenuated by pre-treatment with a pan-caspase inhibitor. P21/WAF1/CIP1 was significantly up-regulated leading to cell cycle arrest. Fucoidan decreased the activation of ERK1/2 and down-regulated the activation of AKT through hypo-phosphorylation of Thr(308) residue but not Ser(473). In vivo, a xenograft model using the NB4 cells was employed. Mice were fed with fucoidan and tumor growth was measured following inoculation with NB4 cells. Subsequently, splenic natural killer (NK) cell cytotoxic activity was also examined. Oral doses of fucoidan significantly delayed tumor growth in the xenograft model and increased cytolytic activity of NK cells. Taken together, these data suggest that the selective inhibitory effect of fucoidan on APL cells and its protective effect against APL development in mice warrant further investigation of fucoidan as a useful agent in treatment of certain types of leukemia. PMID- 26241710 TI - The role of antiplatelet therapy in patients with peripheral artery disease and lower extremity peripheral artery revascularization. AB - PURPOSE OF REVIEW: Although antiplatelet agents are frequently prescribed to patients with lower extremity peripheral artery disease (PAD), there is an overall lack of consensus among published evidence and guidelines with respect to this practice. RECENT FINDINGS: Antiplatelet agents are prescribed to patients with PAD to reduce both cardiovascular and limb-based events during the follow-up period. A large evidence base supports the use of antiplatelet monotherapy with aspirin or clopidogrel in patients with symptomatic PAD or a history of peripheral artery revascularization. However, antiplatelet monotherapy has not proven beneficial in patients with asymptomatic PAD. Dual antiplatelet therapy has not demonstrated a clear benefit in reducing the risk of cardiovascular events in patients with symptomatic PAD. Its role in reducing the risk of adverse limb events following endovascular or surgical revascularization also remains unclear. Recently, the use of vorapaxar in addition to aspirin and/or clopidogrel has been associated with a significant reduction in the need for repeat revascularization procedures and hospitalization for limb ischemia in patients with established PAD. SUMMARY: Eligible patients with symptomatic PAD or with a history of peripheral artery revascularization should be prescribed antiplatelet monotherapy for secondary prevention of both cardiovascular and limb events, using aspirin, clopidogrel, and/or vorapaxar. Given the significant overlap of PAD and coronary artery disease, the evidence presented in this article may have important implications for management of patients with coronary artery disease. PMID- 26241709 TI - High VEGF-D and Low MMP-2 Serum Levels Predict Nodal-Positive Disease in Invasive Bladder Cancer. AB - BACKGROUND: To investigate stromal variables including angiogenesis, lymphangiogenesis, and matrix metalloproteinase (MMP) in the serum of patients with urothelial carcinoma of the bladder (UCB) and to evaluate their association with histopathological characteristics and clinical outcome. MATERIAL AND METHODS: Protein levels of vascular endothelial growth factors-A, -C, -D (VEGF-A/ C/-D), their receptors- VEGF-R2 and -R3 (VEGF-R2/-R3), and matrix metalloproteinases 2, -3, and -7 (MMP-2, MMP-3, MMP-7) were quantified in the blood serum samples of 71 patients with UCB before radical cystectomy (RC). Samples of patients with non-invasive UCB or no history of UCB were investigated as controls (n=20). Protein levels in the serum were measured using a flow cytometric cytokine assay. RESULTS: A positive association for VEGF-D (p<0.001) and an inverse association for MMP-2 (p=0.017) were observed in patients with positive lymph node (LN) status at the time of RC. VEGF-A (p<0.001), VEGF-C (p<0.001), MMP-2 (p<0.001), and MMP-7 (p=0.005) serum levels were different in serum of patients with invasive UCB compared with non-invasive UCB or healthy individuals. None of the serum markers were associated with disease progression. CONCLUSIONS: High VEGF-D and low MMP-2 serum levels predict LN metastasis in patients with UCB at the time of RC. VEGF-A, VEGF-C, MMP-2, and MMP-7 serum levels varied significantly between invasive and non-invasive disease as well as in comparison with healthy individuals. Clinical implementation of these marker serum measurements may be valuable to select high-risk patients with more invasive or nodal-positive disease. PMID- 26241711 TI - Wet-spinnability and crosslinked fibre properties of two collagen polypeptides with varied molecular weight. AB - The formation of naturally derived materials with wet stable fibrous architectures is paramount in order to mimic the features of tissues at the molecular and microscopic scale. Here, we investigated the formation of wet-spun fibres based on collagen-derived polypeptides with comparable chemical composition and varied molecular weight. Gelatin and hydrolysed fish collagen (HFC) were selected as widely available linear amino-acidic chains of high and low molecular weight, respectively, and functionalised in the wet-spun fibre state in order to preserve the material geometry in physiological conditions. Wet spun fibre diameter and morphology were dramatically affected depending on the polypeptide molecular weight, wet-spinning solvent (i.e. 2,2,2-trifluoroethanol and dimethyl sulfoxide) and coagulating medium (i.e. acetone and ethanol), resulting in either bulky or porous internal geometry. Dry-state tensile moduli were significantly enhanced in gelatin and HFC samples following covalent crosslinking with activated 1,3-phenylenediacetic acid (Ph) (E: 726+/-43-844+/ 85MPa), compared to samples crosslinked via intramolecular carbodiimide-mediated condensation reaction (E: 588+/-38MPa). Resulting fibres displayed a dry diameter in the range of 238+/-18-355+/-28MUm and proved to be mechanically stable (E: 230kPa) following equilibration with PBS, whilst a nearly complete degradation was observed after 5-day incubation in physiological conditions. PMID- 26241712 TI - Eczema Herpeticum: Would You Know It If You Saw It? AB - Eczema herpeticum is an easily missed entity most commonly seen in the pediatric population and carries the risk of systemic compromise and a 10% mortality rate. Clinicians should maintain high clinical suspicion when encountering children or young adults with a history of atopic dermatitis or other erosive dermatoses and who present with vesicular lesions, punched-out erosions, and systemic symptoms. We present 3 severe cases of eczema herpeticum that were potentially overlooked and demonstrate the need for elevated awareness to avoid potential pitfalls. PMID- 26241713 TI - Lacticemia After Acute Overdose of Metformin in an Adolescent Managed Without Intravenous Sodium Bicarbonate or Extracorporeal Therapy. AB - Metformin-associated lactic acidosis or lacticemia has been widely reported as an adverse drug effect in diabetic patients with other significant comorbidities and in acute overdose in adults. Lacticemia has been reported twice in a previously healthy pediatric population, both of which were suicide attempts and required hemodialysis. We report a case of a 17-year-old, nondiabetic, healthy adolescent girl with metformin-associated lacticemia who intentionally overdosed on metformin, had no coingestants, and was treated only with crystalloids. Furthermore, she did not require intravenous bicarbonate administration or extracorporeal removal. PMID- 26241714 TI - Point-of-Care Ultrasound for Pediatric Shock. AB - The evaluation of critically ill children in the emergency department is oftentimes challenging. Point-of-care ultrasound is an essential tool in the rapid identification of reversible pathology and provides unique insight into the appropriate treatment approach. In this article, we discuss a straightforward sonographic approach to pediatric patients who present in shock. PMID- 26241716 TI - Emergency Point-of-Care Ultrasound Detection of Cancer in the Pediatric Emergency Department. AB - The use of point-of-care ultrasound in the pediatric emergency department is evolving beyond conventional applications as users become more expert with the technology. In this case series, we describe the potential utility of recognizing abnormal anatomy to impact care in the context of possible cancer in pediatric patients. We describe 4 patients with Langerhans histiocytosis, neuroblastoma, Wilms tumor, and rhabdomyosarcoma, in which point-of-care ultrasound was used to facilitate the diagnoses. PMID- 26241717 TI - Two Year Old With Water Bead Ingestion. AB - Foreign body ingestion is a common pediatric complaint. Two case reports describe intestinal obstruction in children from an ingestion of a single superabsorbent water ball, requiring surgical removal. We describe nonsurgical management of an asymptomatic child who ingested approximately 100 superabsorbent water beads.Because of the risk for subsequent intestinal obstruction, the patient was admitted for whole bowel irrigation. This case report is the first describing use of whole bowel irrigation in the management of an asymptomatic patient with multiple water beads ingestion. PMID- 26241718 TI - ECGs in the ED. PMID- 26241719 TI - Ondasetron Is More Likely Than Ketamine to Cause Ventricular Tachycardia. PMID- 26241720 TI - Observations Regarding Evaluation of an After-Hours Call Center: Are Pediatric Patients Appropriately Referred to the Emergency Department? PMID- 26241721 TI - Regarding Near-Fatal Sodium Phosphate Toxicity in a Child Receiving Sodium Phosphate Enemas. PMID- 26241722 TI - Intensive Care Unit Admissions Among Children After Hematopoietic Stem Cell Transplantation: Incidence, Outcome, and Prognostic Factors. AB - We retrospectively analyzed posttransplantation events in 299 children who underwent hematopoietic stem cell transplantation between 2005 and 2011 in order to ascertain the incidence of life-threatening complications requiring pediatric intensive care unit (PICU) admission, the contributing risk factors, and the patient's long-term survival. Sixty-eight patients (23%) were admitted to the PICU. Risks factors associated with higher cumulative incidence of PICU admission on univariate analysis were nonmalignant disease, status at transplantation, type of transplant, source of stem cell, engraftment syndrome (ES), veno-occlusive disease, acute graft versus host disease (GvHD), chronic GvHD, thrombotic microangiopathy, bronchiolitis obliterans, hemorrhagic cystitis, and posterior reversible encephalopathy syndrome (PRES). On multivariate analysis, only ES, acute GvHD, transplant-associated thrombotic microangiopathy (TA-TMA), and PRES were statistically significant. The variables that had a negative impact on survival, on univariate analysis, were allogeneic transplant, age, male sex, a high O-PRISM score, a high O-PRISM3 score, engraftment failure, acute GvHD, TA TMA, hemorrhagic cystitis, and PRES. On multivariate analysis, only age, allogeneic transplant, engraftment failure, acute GvHD, TA-TMA, and hemorrhagic cystitis had a negative impact on survival. In conclusion, our report provides new findings regarding life-threatening complications after hematopoietic transplantation for PICU admission and survival after that in a pediatric population. PMID- 26241723 TI - Screening Hepatoblastoma in Beckwith-Wiedemann Syndrome: A Complex Issue. PMID- 26241724 TI - Hemophagocytic Lymphohistiocytosis Due to Rickettsia Japonica in a 3-Month-old Infant. PMID- 26241725 TI - Rare Presentation of Supratentorial Primitive Neuroectodermal Tumors Mimicking Bifocal Germ Cell Tumors: 2 Case Reports. AB - Bifocal pineal and suprasellar tumors have only been described in the context of germ cell tumors in the pediatric age group. We report 2 patients with radiologic findings of bifocal pineal and suprasellar lesions, with a histologic diagnosis of supratentorial primitive neuroectodermal tumor. The absence of diabetes insipidus and other endocrine abnormalities was noteworthy in both cases. This observation challenges previous reports on the pathognomonic value of this clinico-radiologic entity. PMID- 26241726 TI - Wiskott-Aldrich Syndrome: Description of a New Gene Mutation With Normal Platelet Volume. AB - Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by an increased incidence of autoimmunity, malignancy, microthrombocytes with thrombocytopenia, eczema, and recurrent infections. In this case report, we present a novel mutation, hemizygous for c.1125_1129delTGGAC mutation in the WAS gene, and a unique clinical presentation. Our patient was initially diagnosed with a milk protein allergy after presenting with a lower gastrointestinal bleed, leukopenia, and thrombocytopenia with normal platelet volume. However, signs of vasculitis and detection of microthrombocytes required additional testing and consideration of WAS. This case report illustrates the importance of retaining a high index of clinical suspicion despite normal platelet volume, as well as adding to the growing number of known mutations associated with WAS. PMID- 26241727 TI - Pilot Feasibility Study of Comprehensive Pulmonary Evaluation Following Lung Radiation Therapy. AB - BACKGROUND: Symptoms of pulmonary injury following lung irradiation may not manifest clinically in childhood. We performed comprehensive pulmonary evaluation of patients who had received lung irradiation for treatment of cancer. MATERIALS AND METHODS: Patients underwent a focused history and physical examination, computed tomography of the chest, pulmonary function test, and cardiopulmonary exercise stress test (CPET). Health-related Quality of Life was also measured. RESULTS: Fourteen patients were recruited with median age of 16 years (range, 6 to 21 y). Median time from pulmonary radiation to testing was 5 years (range, 2 to 11 y). Five patients reported pulmonary symptoms. Twelve patients (85.7%) had at least 1 pulmonary function test abnormality. Nine patients demonstrated CPET abnormalities; 7 patients had abnormal pulmonary limitation to exercise, and 5 patients had exercise-induced bronchospasm. The pulmonary limitations included abnormal ventilatory response to exercise in 5 patients, and gas exchange abnormalities in 4 patients. Chest computed tomography demonstrated grade 1-2 radiation-induced lung changes in 4 patients, and grade 3 abnormalities in 1 patient. CONCLUSIONS: Significant pulmonary dysfunction was observed in childhood cancer survivors who had received lung irradiation. CPET is feasible in childhood cancer survivors and can be valuable for assessment of pulmonary function and exercise capacity. PMID- 26241728 TI - Idiopathic Pulmonary Hemosiderosis With Allergic Asthma Diagnosis in a Pediatric Patient. AB - Idiopathic pulmonary hemosiderosis (IPH) is a rare disorder with unknown pathogenesis that usually presents in the first decade of life. As a result of diffuse alveolar hemorrhage, respiratory symptoms such as cough attacks, hemoptysis, dyspnea, and recurrent and refractory iron-deficiency anemia (IDA) are observed. We present an 8-year-old girl who was followed up with recurrent IDA and allergic asthma and later diagnosed with IPH. IPH was confirmed by the presence of hemosiderin-laden macrophages in bronchoalveolar lavage obtained by bronchoscopy and exclusion of the secondary causes of pulmonary hemosiderosis. Glucocorticoids and iron supplementation were started. Clinical and laboratory improvement was observed with therapy. Our case illustrates that refractory/recurrent IDA with any pulmonary symptoms may be the only presenting feature of IPH. PMID- 26241729 TI - Gastric Schwannoma Without Neurofibromatosis in a 16-Year-Old Adolescent. PMID- 26241730 TI - Interaction of Bile Salts with Model Membranes Mimicking the Gastrointestinal Epithelium: A Study by Isothermal Titration Calorimetry. AB - Bile salts (BS) are biosurfactants synthesized in the liver and secreted into the intestinal lumen where they solubilize cholesterol and other hydrophobic compounds facilitating their gastrointestinal absorption. Partition of BS toward biomembranes is an important step in both processes. Depending on the loading of the secreted BS micelles with endogeneous cholesterol and on the amount of cholesterol from diet, this may lead to the excretion or absorption of cholesterol, from cholesterol-saturated membranes in the liver or to gastrointestinal membranes, respectively. The partition of BS toward the gastrointestinal membranes may also affect the barrier properties of those membranes affecting the permeability for hydrophobic and amphiphilic compounds. Two important parameters in the interaction of the distinct BS with biomembranes are their partition coefficient and the rate of diffusion through the membrane. Altogether, they allow the calculation of BS local concentrations in the membrane as well as their asymmetry in both membrane leaflets. The local concentration and, most importantly, its asymmetric distribution in the bilayer are a measure of induced membrane perturbation, which is expected to significantly affect its properties as a cholesterol donor and hydrophobic barrier. In this work we have characterized the partition of several BS, nonconjugated and conjugated with glycine, to large unilamellar vesicles (LUVs) in the liquid-disordered phase and with liquid-ordered/liquid-disordered phase coexistence, using isothermal titration calorimetry (ITC). The partition into the liquid-disordered bilayer was characterized by large partition coefficients and favored by enthalpy, while association with the more ordered membrane was weak and driven only by the hydrophobic effect. The trihydroxy BS partitions less efficiently toward the membranes but shows faster translocation rates, in agreement with a membrane protective effect of those BS. The rate of translocation through the more ordered membrane was faster, indicating accumulation of BS at specific locations in this membrane. PMID- 26241731 TI - Unusual Enhancement in Intrinsic Thermal Conductivity of Multilayer Graphene by Tensile Strains. AB - Using the Boltzmann-Peierls equation for phonon transport approach with the inputs of interatomic force constants from the self-consistent charge density functional tight binding method, we calculate the room-temperature in-plane lattice thermal conductivities k of multilayer graphene (up to four layers) and graphite under different isotropic tensile strains. The calculated in-plane k of graphite, finite monolayer graphene and 3-layer graphene agree well with previous experiments. For unstrained graphene systems, both the intrinsic k and the extent of the diffusive transport regime present a drastic dimensional transition in going from monolayer to 2-layer graphene and thereafter a gradual transition to the graphite limit. We find a peak enhancement of intrinsic k for multilayer graphene and graphite with increasing strain with the largest enhancement amplitude ~40%. Competition between the decreased mode heat capacities and the increased lifetimes of flexural phonons with increasing strain contribute to this k behavior. Similar k behavior is observed for 2-layer hexagonal boron nitride systems. This study provides insights into engineering k of multilayer graphene and boron nitride by strain and into the nature of thermal transport in quasi-two dimensional and highly anisotropic systems. PMID- 26241732 TI - Activation of transmembrane cell-surface receptors via a common mechanism? The "rotation model". AB - It has long been thought that transmembrane cell-surface receptors, such as receptor tyrosine kinases and cytokine receptors, among others, are activated by ligand binding through ligand-induced dimerization of the receptors. However, there is growing evidence that prior to ligand binding, various transmembrane receptors have a preformed, yet inactive, dimeric structure on the cell surface. Various studies also demonstrate that during transmembrane signaling, ligand binding to the extracellular domain of receptor dimers induces a rotation of transmembrane domains, followed by rearrangement and/or activation of intracellular domains. The paper here describes transmembrane cell-surface receptors that are known or proposed to exist in dimeric form prior to ligand binding, and discusses how these preformed dimers are activated by ligand binding. PMID- 26241733 TI - Longitudinal Trends in Costs of Palliative Radiation for Metastatic Prostate Cancer. AB - BACKGROUND: In recent years, palliative treatment of prostate cancer metastases has been characterized by the use of more complex radiation treatment, despite a lack of evidence demonstrating a clinical benefit of these technologies in the palliative setting. The impact of adoption of these technologies on the costs of palliative radiation treatment in patients with metastatic prostate cancer remains poorly understood in the general patient population. METHODS: The study was a retrospective analysis of Surveillance, Epidemiology and End Results (SEER) Medicare data of men aged 66 and older who died from metastatic prostate cancer between 2000 and 2007 and received radiation therapy for bony metastases in the last year of life. Direct costs were obtained from Medicare carrier and outpatient facility payments for all radiation treatment claims and adjusted to 2008 dollars. RESULTS: A total of 1705 men met study inclusion criteria. Total Medicare payments for radiation therapy for bony metastases in the last year of life increased by 44.4% from an average of $2,763 in 2000 to $3,989 in 2007, with the proportion of all payments accrued within hospital-based settings increasing from 48% to 57%. Complexity of radiation therapy techniques over the same period was characterized by use of less simple (30.1% to 23.3%) and more complex (59.9% versus 66.7%) radiation therapy. From 2000-2003 to 2004-2007, the use of shorter treatment courses (<=5 fractions) decreased from 22% to 14%, and the use of single fraction treatment courses decreased by half (6.3% to 2.9%; P<=.001). CONCLUSIONS: Between 2000 and 2007, palliative radiation therapy for bony prostate cancer metastases was characterized by the use of more advanced treatment technologies and prolonged radiation treatment courses. Further research investigating barriers to cost-effective palliation is warranted. PMID- 26241734 TI - Neutral-carrier ion-selective electrodes assessed by the Nernst-Planck-Poisson model. AB - Ion-selective electrodes (ISEs) containing neutral ionophores are used in clinical, industrial, and environmental analysis. The wide range of applications requires deep theoretical description. This work concentrates on the development of the general approach to the description of electro-diffusion processes, namely, Nernst-Planck-Poisson (NPP) model to allow the description of the time dependent responses in the case of complexation reactions occurring in the ion selective membranes. The impact of the chemical reaction on the calibration curves and apparent selectivity of ISE is discussed. Results obtained using NPP model with time-dependent reaction are compared with those obtained with the Phase Boundary Model (PBM), as well as with the previous solutions of NPP model, using the infinite reaction rates and constant ligand concentration assumption. The validity of these assumptions is investigated and the limitations of PBM in the description of neutral-carrier ISE are discussed. PMID- 26241735 TI - Gold nanoparticles enhanced SERS aptasensor for the simultaneous detection of Salmonella typhimurium and Staphylococcus aureus. AB - Salmonella typhimurium and Staphylococcus aureus are most common causes of food associated disease. A Raman based biosensor was developed for S. typhimurium and S. aureus detection simultaneously. The biosensor was based on nanoparticles enhanced Raman intensity and the specific recognition of aptamer. The Raman signal probe and the capture probe are built. Gold nanoparticles (GNPs) modified with Raman molecules (Mercaptobenzoic acid and 5,5'-Dithiobis(2-nitrobenzoic acid)) and aptamer are used as the signal probe for S. typhimurium and S. aureus, respectively. Fe3O4 magnetic gold nanoparticles (MGNPs) immobilized with both aptamer of S. typhimurium and S. aureus are used as the capture probe. When S. typhimurium and S. aureus are added in the reaction system, the capture probe will capture the target bacteria through the specific binding effect of aptamer. And then the signal probe will be connected to the bacteria also by the effect of aptamer to form the sandwich like detection structure. The Raman intensified spectrum was measured to quantify S. typhimurium and S. aureus. Under optimal conditions, the SERS intensity of MBA at 1582 cm(-1) are used to measure S. typhimurium (y=186.4762+704.8571x, R(2)=0.9921) and the SERS intensity of DNTB at 1333 cm(-1) are used to measure S. aureus (y=135.2381+211.4286x, R(2)=0.9946) in the range of 10(2)-10(7) cfu mL(-1). The LOD is 35 cfu mL(-1) for S. aureus and 15 cfu mL(-1) for S. typhimurium. This method is simple and rapid, results in high sensitivity and specificity, and can be used to detect actual samples. PMID- 26241736 TI - Impedimetric quantification of the formation process and the chemosensitivity of cancer cell colonies suspended in 3D environment. AB - In cancer research, colony formation assay is a gold standard for the investigation of the development of early tumors and the effects of cytotoxic agents on tumors in vitro. Quantification of cancer cell colonies suspended in hydrogel is currently achieved by manual counting under microscope. It is challenging to microscopically quantify the colony number and size without subjective bias. In this work, impedimetric quantification of cancer cell colonies suspended in hydrogel was successfully developed and provides a quantitative and objective method to describe the colony formation process and the development of colony size during the culture course. A biosensor embedded with a pair of parallel plate electrodes was fabricated for the impedimetric quantification. Cancer cell (cell line: Huh-7) were encapsulated in methyl cellulose hydrogel and cultured to gradually form cancer cell colonies suspended in 3D environment. At pre-set schedule during the culture course, small volume (50 MUL) of colonies/MC hydrogel was collected, mixed with measurement hydrogel, and loaded to the biosensor for measurement. Hence, the colony formation process could be quantitatively represented by a colony index and a colony size index calculated from electrical impedance. Based on these developments, chemosensitivity of cancer cell colonies under different concentrations of anti cancer drug, i.e., doxorubicin, was quantitatively investigated to study the efficacy of anti-cancer drug. Also, dose-response curve was constructed to calculate the IC50 value, which is an important indicator for chemosensitivity assay. These results showed the impedimetric quantification is a promising technique for the colony formation assay. PMID- 26241737 TI - Rh(III)-Catalyzed Trifluoromethylthiolation of Indoles via C-H Activation. AB - Cp*Rh(III) complexes have been applied as efficient catalysts for the C-H activation and trifluoromethylthiolation of indoles functionalized with a heterocycle. With N-trifluoromethylthiosaccharin being an electrophilic SCF3 reagent, this C-S coupling occurred selectively at the 2-position with good functional group tolerance. PMID- 26241739 TI - Development of Transcriptomic Markers for Population Analysis Using Restriction Site Associated RNA Sequencing (RARseq). AB - We describe restriction site associated RNA sequencing (RARseq), an RNAseq-based genotype by sequencing (GBS) method. It includes the construction of RNAseq libraries from double stranded cDNA digested with selected restriction enzymes. To test this, we constructed six single- and six-dual-digested RARseq libraries from six F2 pitcher plant individuals and sequenced them on a half of a Miseq run. On average, the de novo approach of population genome analysis detected 544 and 570 RNA SNPs, whereas the reference transcriptome-based approach revealed an average of 1907 and 1876 RNA SNPs per individual, from single- and dual-digested RARseq data, respectively. The average numbers of RNA SNPs and alleles per loci are 1.89 and 2.17, respectively. Our results suggest that the RARseq protocol allows good depth of coverage per loci for detecting RNA SNPs and polymorphic loci for population genomics and mapping analyses. In non-model systems where complete genomes sequences are not always available, RARseq data can be analyzed in reference to the transcriptome. In addition to enriching for functional markers, this method may prove particularly useful in organisms where the genomes are not favorable for DNA GBS. PMID- 26241738 TI - Connective-Tissue Growth Factor (CTGF/CCN2) Induces Astrogenesis and Fibronectin Expression of Embryonic Neural Cells In Vitro. AB - Connective-tissue growth factor (CTGF) is a modular secreted protein implicated in multiple cellular events such as chondrogenesis, skeletogenesis, angiogenesis and wound healing. CTGF contains four different structural modules. This modular organization is characteristic of members of the CCN family. The acronym was derived from the first three members discovered, cysteine-rich 61 (CYR61), CTGF and nephroblastoma overexpressed (NOV). CTGF is implicated as a mediator of important cell processes such as adhesion, migration, proliferation and differentiation. Extensive data have shown that CTGF interacts particularly with the TGFbeta, WNT and MAPK signaling pathways. The capacity of CTGF to interact with different growth factors lends it an important role during early and late development, especially in the anterior region of the embryo. ctgf knockout mice have several cranio-facial defects, and the skeletal system is also greatly affected due to an impairment of the vascular-system development during chondrogenesis. This study, for the first time, indicated that CTGF is a potent inductor of gliogenesis during development. Our results showed that in vitro addition of recombinant CTGF protein to an embryonic mouse neural precursor cell culture increased the number of GFAP- and GFAP/Nestin-positive cells. Surprisingly, CTGF also increased the number of Sox2-positive cells. Moreover, this induction seemed not to involve cell proliferation. In addition, exogenous CTGF activated p44/42 but not p38 or JNK MAPK signaling, and increased the expression and deposition of the fibronectin extracellular matrix protein. Finally, CTGF was also able to induce GFAP as well as Nestin expression in a human malignant glioma stem cell line, suggesting a possible role in the differentiation process of gliomas. These results implicate ctgf as a key gene for astrogenesis during development, and suggest that its mechanism may involve activation of p44/42 MAPK signaling. Additionally, CTGF-induced differentiation of glioblastoma stem cells into a less-tumorigenic state could increase the chances of successful intervention, since differentiated cells are more vulnerable to cancer treatments. PMID- 26241741 TI - Molecular Architecture of Spinal Cord Injury Protein Interaction Network. AB - Spinal cord injury (SCI) is associated with complex pathophysiological processes that follow the primary traumatic event and determine the extent of secondary damage and functional recovery. Numerous reports have used global and hypothesis driven approaches to identify protein changes that contribute to the overall pathology of SCI in an effort to identify potential therapeutic interventions. In this study, we use a semi-automatic annotation approach to detect terms referring to genes or proteins dysregulated in the SCI literature and develop a curated SCI interactome. Network analysis of the SCI interactome revealed the presence of a rich-club organization corresponding to a "powerhouse" of highly interacting hub proteins. Studying the modular organization of the network have shown that rich club proteins cluster into modules that are specifically enriched for biological processes that fall under the categories of cell death, inflammation, injury recognition and systems development. Pathway analysis of the interactome and the rich-club revealed high similarity indicating the role of the rich-club proteins as hubs of the most prominent pathways in disease pathophysiology and illustrating the centrality of pro-and anti-survival signal competition in the pathology of SCI. In addition, evaluation of centrality measures of single nodes within the rich-club have revealed that neuronal growth factor (NGF), caspase 3, and H-Ras are the most central nodes and potentially an interesting targets for therapy. Our integrative approach uncovers the molecular architecture of SCI interactome, and provide an essential resource for evaluating significant therapeutic candidates. PMID- 26241740 TI - CSPP-L Associates with the Desmosome of Polarized Epithelial Cells and Is Required for Normal Spheroid Formation. AB - Deleterious mutations of the Centrosome/Spindle Pole associated Protein 1 gene, CSPP1, are causative for Joubert-syndrome and Joubert-related developmental disorders. These disorders are defined by a characteristic mal-development of the brain, but frequently involve renal and hepatic cyst formation. CSPP-L, the large protein isoform of CSPP1 localizes to microtubule ends of the mitotic mid-spindle and the ciliary axoneme, and is required for ciliogenesis. We here report the microtubule independent but Desmoplakin dependent localization of CSPP-L to Desmosomes in apical-basal polarized epithelial cells. Importantly, siRNA conferred depletion of CSPP-L or Desmoplakin promoted multi-lumen spheroid formation in 3D-cultures of non-ciliated human colon carcinoma Caco-2 cells. Multi-lumen spheroids of CSPP1 siRNA transfectants showed disrupted apical cell junction localization of the cytoskeleton organizing RhoGEF ECT2. Our results hence identify a novel, non-ciliary role for CSPP-L in epithelial morphogenesis. PMID- 26241742 TI - Sexual Networks and HIV Risk among Black Men Who Have Sex with Men in 6 U.S. Cities. AB - BACKGROUND: Sexual networks may place U.S. Black men who have sex with men (MSM) at increased HIV risk. METHODS: Self-reported egocentric sexual network data from the prior six months were collected from 1,349 community-recruited Black MSM in HPTN 061, a multi-component HIV prevention intervention feasibility study. Sexual network composition, size, and density (extent to which members are having sex with one another) were compared by self-reported HIV serostatus and age of the men. GEE models assessed network and other factors associated with having a Black sex partner, having a partner with at least two age category difference (age difference between participant and partner of at least two age group categories), and having serodiscordant/serostatus unknown unprotected anal/vaginal intercourse (SDUI) in the last six months. RESULTS: Over half had exclusively Black partners in the last six months, 46% had a partner of at least two age category difference, 87% had <=5 partners. Nearly 90% had sex partners who were also part of their social networks. Among HIV-negative men, not having anonymous/exchange/ trade partners and lower density were associated with having a Black partner; larger sexual network size and having non-primary partners were associated with having a partner with at least two age category difference; and having anonymous/exchange/ trade partners was associated with SDUI. Among HIV-positive men, not having non-primary partners was associated with having a Black partner; no sexual network characteristics were associated with having a partner with at least two age category difference and SDUI. CONCLUSIONS: Black MSM sexual networks were relatively small and often overlapped with the social networks. Sexual risk was associated with having non-primary partners and larger network size. Network interventions that engage the social networks of Black MSM, such as interventions utilizing peer influence, should be developed to address stable partnerships, number of partners, and serostatus disclosure. PMID- 26241744 TI - Computational Structure-Based De Novo Design of Hypothetical Inhibitors against the Anti- Inflammatory Target COX-2. AB - Cyclooxygenase-2 (COX-2) produces prostaglandins in inflamed tissues and hence has been considered as an important target for the development of anti inflammatory drugs since long. Administration of traditional non-steroidal anti inflammatory drugs (NSAIDs) and other COX-2 selective inhibitors (COXIBS) for the treat of inflammation has been found to be associated with side effects, which mainly includes gastro-intestinal (GI) toxicity. The present study involves developing a virtual library of novel molecules with high druglikeliness using structure-based de novo drug designing and 2D fingerprinting approach. A library of 2657 drug like molecules was generated. 2D fingerprinting based screening of the designed library gave a unique set of compounds. Molecular docking approach was then used to identify two compounds highly specific for COX-2 isoform. Molecular dynamics simulations of protein-ligand complexes revealed that the candidate ligands were dynamically stable within the cyclooxygenase binding site of COX-2. The ligands were further analyzed for their druglikeliness, ADMET properties and synthetic accessibility using knowledge based set of rules. The results revealed that the molecules are predicted to selectively bind to COX-2 enzyme thereby potentially overcoming the limitations posed by the drugs in clinical use. PMID- 26241745 TI - Marteilia spp. parasites in bivalves: A revision of recent studies. AB - Marteilia spp. parasites are Paramyxean organisms that affect several commercial species of molluscs, and thus have a socio-economical impact. These parasites also have an ecological impact on the biodiversity and population dynamics of natural mollusc beds. It has been over forty years since the first description of Marteilia refringens, the first Marteilia species described. Despite four decades of research, the biology, cellular development, as well as the life cycle of Marteilia parasites are not fully understood. In recent years, new studies have reported advances in knowledge of the life cycle, the description of new species, the development of new molecular detection/discrimination tools, new data on biotype geographical distribution, as well as new information on host response and defence mechanisms. Such information is summarized, reported and discussed in the present review in order to facilitate a new overview of the subject. However, numerous knowledge gaps are still unresolved and need to be prioritized in the research and funding institution agendas. PMID- 26241743 TI - Neuroimmune and Neuropathic Responses of Spinal Cord and Dorsal Root Ganglia in Middle Age. AB - Prior studies of aging and neuropathic injury have focused on senescent animals compared to young adults, while changes in middle age, particularly in the dorsal root ganglia (DRG), have remained largely unexplored. 14 neuroimmune mRNA markers, previously associated with peripheral nerve injury, were measured in multiplex assays of lumbar spinal cord (LSC), and DRG from young and middle-aged (3, 17 month) naive rats, or from rats subjected to chronic constriction injury (CCI) of the sciatic nerve (after 7 days), or from aged-matched sham controls. Results showed that CD2, CD3e, CD68, CD45, TNF-alpha, IL6, CCL2, ATF3 and TGFbeta1 mRNA levels were substantially elevated in LSC from naive middle-aged animals compared to young adults. Similarly, LSC samples from older sham animals showed increased levels of T-cell and microglial/macrophage markers. CCI induced further increases in CCL2, and IL6, and elevated ATF3 mRNA levels in LSC of young and middle-aged adults. Immunofluorescence images of dorsal horn microglia from middle-aged naive or sham rats were typically hypertrophic with mostly thickened, de-ramified processes, similar to microglia following CCI. Unlike the spinal cord, marker expression profiles in naive DRG were unchanged across age (except increased ATF3); whereas, levels of GFAP protein, localized to satellite glia, were highly elevated in middle age, but independent of nerve injury. Most neuroimmune markers were elevated in DRG following CCI in young adults, yet middle-aged animals showed little response to injury. No age-related changes in nociception (heat, cold, mechanical) were observed in naive adults, or at days 3 or 7 post-CCI. The patterns of marker expression and microglial morphologies in healthy middle age are consistent with development of a para-inflammatory state involving microglial activation and T-cell marker elevation in the dorsal horn, and neuronal stress and satellite cell activation in the DRG. These changes, however, did not affect the establishment of neuropathic pain. PMID- 26241746 TI - Encapsulation of Living Leishmania Promastigotes in Artificial Lipid Vacuoles. AB - After phagocytosis by mammalian macrophages, promastigote forms of Leishmania parasites settle inside intracellular parasitophorous vacuoles (PVs) in which they transform into amastigote forms and replicate. Here, using a variant of the 'inverted emulsion' method, we succeeded in encapsulating living L. amazonensis parasites in giant artificial liposomes that serve as model PVs. We were able to control the size of liposomes, the pH and the composition of their internal volume, and the number of internalized parasites per liposome. L. amazonensis promastigotes encapsulated in liposomes filled with RPMI-Dextran solution at pH 7.5 or 6.5 survived up to 96 h at 24 degrees C. At 37 degrees C and pH 5.5, parasites survived 48h. This method paves the way to identifying certain effectors secreted by the parasite and to unraveling specific mechanisms of fusion between the PV and intracellular vesicles of the host cell. This method will also facilitate the study of the temporal evolution of biophysical properties of the PV during its maturation. PMID- 26241747 TI - An Investigation on Social Representations: Inanimate Agent Can Mislead Dogs (Canis familiaris) in a Food Choice Task. AB - The nature of mental representation of others plays a crucial role in social interactions. Dogs present an ideal model species for the investigation of such mental representations because they develop social ties with both conspecifics and heterospecifics. Former studies found that dogs' preference for larger food quantity could be reversed by humans who indicate the smaller quantity. The question is whether this social bias is restricted to human partners. We suggest that after a short positive social experience, an unfamiliar moving inanimate agent (UMO) can also change dogs' choice between two food quantities. We tested four groups of dogs with different partners: In the (1) Helper UMO and (2) Helper UMO Control groups the partner was an interactive remote control car that helped the dog to obtain an otherwise unreachable food. In the (3) Non-helper UMO and (4) Human partner groups dogs had restricted interaction with the remote control car and the unfamiliar human partners. In the Human partner, Helper UMO and Helper UMO Control groups the partners were able to revert dogs' choice for the small amount by indicating the small one, but the Non-helper UMO was not. We suggest that dogs are able to generalize their wide range of experiences with humans to another type of agent as well, based on the recognition of similarities in simple behavioural patterns. PMID- 26241748 TI - mTORC1 Prevents Preosteoblast Differentiation through the Notch Signaling Pathway. AB - The mechanistic target of rapamycin (mTOR) integrates both intracellular and extracellular signals to regulate cell growth and metabolism. However, the role of mTOR signaling in osteoblast differentiation and bone formation is undefined, and the underlying mechanisms have not been elucidated. Here, we report that activation of mTOR complex 1 (mTORC1) is required for preosteoblast proliferation; however, inactivation of mTORC1 is essential for their differentiation and maturation. Inhibition of mTORC1 prevented preosteoblast proliferation, but enhanced their differentiation in vitro and in mice. Activation of mTORC1 by deletion of tuberous sclerosis 1 (Tsc1) in preosteoblasts produced immature woven bone in mice due to excess proliferation but impaired differentiation and maturation of the cells. The mTORC1-specific inhibitor, rapamycin, restored these in vitro and in vivo phenotypic changes. Mechanistically, mTORC1 prevented osteoblast maturation through activation of the STAT3/p63/Jagged/Notch pathway and downregulation of Runx2. Preosteoblasts with hyperactive mTORC1 reacquired the capacity to fully differentiate and maturate when subjected to inhibition of the Notch pathway. Together, these findings identified the role of mTORC1 in osteoblast formation and established that mTORC1 prevents preosteoblast differentiation and maturation through activation of the Notch pathway. PMID- 26241749 TI - A quantitative radioluminographic imaging method for evaluating lateral diffusion rates in skin. AB - A method is presented for measuring the lateral diffusion coefficients of exogenously applied compounds on excised skin. The method involves sequential high resolution imaging of the spatial distribution of beta-radiation associated with [(14)C]-labeled compounds to monitor the development of the concentration profile on the skin surface. It is exemplified by measurements made on three radiolabeled test compounds--caffeine, testosterone, and zinc pyrithione (ZnPT)- administered as solutions. Lateral diffusivity is expected to be an important determinant of the topical bioavailability of ZnPT, which is characteristically administered as a fine suspension and must reach microorganisms in molecular form to exert biocidal activity. Application of the test compounds at levels below and above their estimated saturation doses in the upper stratum corneum allows one to distinguish between diffusion-limited and dissolution rate-limited kinetics. The effective lateral diffusivities of the two chemically stable reference compounds, caffeine and testosterone, were (1-4) * 10(-9) cm(2)/s and (3-9) * 10(-9) cm(2)/s, respectively. Lateral transport of [(14)C] associated with ZnPT was formulation-dependent, with effective diffusivities of (1-2) * 10(-9) cm(2)/s in water and (3-9) * 10(-9) cm(2)/s in a 1% body wash solution. These differences are thought to be related to molecular speciation and/or the presence of a residual surfactant phase on the skin surface. All values were greater than those estimated for the transverse diffusivities of these compounds in stratum corneum by factors ranging from 250 to over 2000. Facile lateral transport on skin, combined with a low transdermal permeation rate, may thus be seen to be a key factor in the safe and effective use of ZnPT as a topical antimicrobial agent. PMID- 26241751 TI - Comparison of spray drying, electroblowing and electrospinning for preparation of Eudragit E and itraconazole solid dispersions. AB - Three solvent based methods: spray drying (SD), electrospinning (ES) and air assisted electrospinning (electroblowing; EB) were used to prepare solid dispersions of itraconazole and Eudragit E. Samples with the same API/polymer ratios were prepared in order to make the three technologies comparable. The structure and morphology of solid dispersions were identified by scanning electron microscopy and solid phase analytical methods such as, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Raman chemical mapping. Moreover, the residual organic solvents of the solid products were determined by static headspace-gas chromatography/mass spectroscopy measurements and the wettability of samples was characterized by contact angle measurement. The pharmaceutical performance of the three dispersion type, evaluated by dissolution tests, proved to be very similar. According to XRPD and DSC analyses, made after the production, all the solid dispersions were free of any API crystal clusters but about 10 wt% drug crystallinity was observed after three months of storage in the case of the SD samples in contrast to the samples produced by ES and EB in which the polymer matrix preserved the API in amorphous state. PMID- 26241752 TI - Novel self-assembled nano-tubular mixed micelles of Pluronics P123, Pluronic F127 and phosphatidylcholine for oral delivery of nimodipine: In vitro characterization, ex vivo transport and in vivo pharmacokinetic studies. AB - Subarachnoid hemorrhage (SAH) is a major cause of death in patients suffering from stroke. Nimodipine (NM) is the only FDA-approved drug for treating SAH induced vasospasm. However, NM suffers from poor oral bioavailability (5-13%) due to its low aqueous solubility, extensive first pass metabolism and short elimination half-life (1-2h). The objective of this study was to develop NM loaded Pluronic/phosphatidylcholine/polysorbate 80 mixed micelles (PPPMM) that can solubilize NM in aqueous media even after dilution, prolong its circulation time, improve its bioavailability and eventually help in targeting it to the brain tissue. PPPMM formulations were prepared using the thin film hydration technique, and evaluated for drug payload, solubilization efficiency (SE), micellar size, zeta potential, transmission electron microscopy (TEM) and ex vivo transport through rat intestine. The selected NM-loaded PPPMM, containing PC to Pluronics((r)) molar ratio of 75:25, showed a drug payload, SE, micellar size and zeta potential of 1.06 +/- 0.03 mg/mL, 99.2 +/- 2.01%, 571.5 +/- 11.87 nm and 31.2 +/- 0.06 mv, respectively. The selected formulation had a much larger hydrophobic core volume for solubilization of NM and exhibited the highest NM transport. TEM micrographs illustrated the formation of highly flexible nano tubular mixed micelles (NTMM). The in vivo pharmacokinetic study showed greater bioavailability of NM in plasma (232%) and brain (208%) of rats from NM-loaded PPPMM compared to that of the drug solution due to the efficiency of flexible NTMM to enhance absorption of NM from the intestinal mucosa. The significant increase in drug solubility, enhanced drug absorption and the long circulation time of the NTMM could be promising to improve oral and parenteral delivery of NM. PMID- 26241750 TI - Using exosomes, naturally-equipped nanocarriers, for drug delivery. AB - Exosomes offer distinct advantages that uniquely position them as highly effective drug carriers. Comprised of cellular membranes with multiple adhesive proteins on their surface, exosomes are known to specialize in cell-cell communications and provide an exclusive approach for the delivery of various therapeutic agents to target cells. In addition, exosomes can be amended through their parental cells to express a targeting moiety on their surface, or supplemented with desired biological activity. Development and validation of exosome-based drug delivery systems are the focus of this review. Different techniques of exosome isolation, characterization, drug loading, and applications in experimental disease models and clinic are discussed. Exosome-based drug formulations may be applied to a wide variety of disorders such as cancer, various infectious, cardiovascular, and neurodegenerative disorders. Overall, exosomes combine benefits of both synthetic nanocarriers and cell-mediated drug delivery systems while avoiding their limitations. PMID- 26241753 TI - Kinetics of drug release from ointments: Role of transient-boundary layer. AB - In the current work, an in vitro release testing method suitable for ointment formulations was developed using acyclovir as a model drug. Release studies were carried out using enhancer cells on acyclovir ointments prepared with oleaginous, absorption, and water-soluble bases. Kinetics and mechanism of drug release was found to be highly dependent on the type of ointment bases. In oleaginous bases, drug release followed a unique logarithmic-time dependent profile; in both absorption and water-soluble bases, drug release exhibited linearity with respect to square root of time (Higuchi model) albeit differences in the overall release profile. To help understand the underlying cause of logarithmic-time dependency of drug release, a novel transient-boundary hypothesis was proposed, verified, and compared to Higuchi theory. Furthermore, impact of drug solubility (under various pH conditions) and temperature on drug release were assessed. Additionally, conditions under which deviations from logarithmic-time drug release kinetics occur were determined using in situ UV fiber-optics. Overall, the results suggest that for oleaginous ointments containing dispersed drug particles, kinetics and mechanism of drug release is controlled by expansion of transient boundary layer, and drug release increases linearly with respect to logarithmic time. PMID- 26241754 TI - Preservation of imaging capability in sensitive ultrasound contrast agents after indirect plasma sterilization. AB - Many injectables are not amenable to standard sterilization methods, which destroy sensitive materials. This is particularly true for ultrasound contrast agents (UCA) consisting of gas bubbles stabilized by a surfactant or polymer shell. We investigated a new method to achieve safe and effective sterilization in production by introducing dielectric-barrier discharge non-thermal plasma. A dielectric-barrier discharge was generated to first produce plasma-treated phosphate-buffered saline (PTPBS), which was used as a sterilant solution for our UCA SE61, avoiding direct heat, pressure, chemicals, or radiation. Treated samples were tested for acoustic properties in vitro and in a flow phantom, and for sterility by standard methods. Three minutes plasma treatment of phosphate buffered saline (PBS) proved effective. The samples showed significant inactivation of inoculated bacteria upon PTPBS treatment as compared to un treated-PBS (p=0.0022). The treated and untreated samples showed no statistical significance (p>0.05) in acoustic response or bubble diameter (mean+/-SEM: 2.52+/ 0.31 MUm). Nile Red was used to model intercalation of drug in the hydrophobic shell, intercalated successfully into SE61, and was unaffected by plasma treatment. The PTPBS completely sterilized suspensions of UCA, and it did not compromise the acoustic properties of the agent or its ability to retain a hydrophobic compound. PMID- 26241755 TI - 3-Dimensional spatially organized PEG-based hydrogels for an aortic valve co culture model. AB - Physiologically relevant in vitro models are needed to study disease progression and to develop and screen potential therapeutic interventions for disease. Heart valve disease, in particular, has no early intervention or non-invasive treatment because there is a lack of understanding the cellular mechanisms which lead to disease. Here, we establish a novel, customizable synthetic hydrogel platform that can be used to study cell-cell interactions and the factors which contribute to valve disease. Spatially localized cell adhesive ligands bound in the scaffold promote cell growth and organization of valve interstitial cells and valve endothelial cells in 3D co-culture. Both cell types maintained phenotypes, homeostatic functions, and produced zonally localized extracellular matrix. This model extends the capabilities of in vitro research by providing a platform to perform direct contact co-culture with cells in their physiologically relevant spatial arrangement. PMID- 26241756 TI - Prevalence of Arthritis in Africa: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: In this systematic review, we estimate the prevalence of six types of arthritis in Africa; namely rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, gout, and ankylosing spondylitis. METHODS: We comprehensively searched literature on 31 August 2014 in MEDLINE, EMBASE, Web of Science and the Cochrane Library to identify eligible studies from 1975 up to 31 July 2014. Two review authors independently selected studies, extracted data, and appraised studies. We carried out random effects meta-analysis of prevalence of arthritis and assessed heterogeneity through subgroup analyses. We performed separate analyses for population- and hospital-based studies, as well as rural and urban settings. MAIN FINDINGS: We included 27 cross-sectional studies (20 population-based and 7 hospital-based) from Africa reporting on the prevalence of arthritis. The majority of the studies were from South Africa (44.4%, 12/27). Rheumatoid arthritis in urban settings ranged from 0.1% in Algeria, 0.6% in the DRC, to a meta-analysis overall prevalence of 2.5% in South Africa, and in rural settings ranged from a meta-analysis overall prevalence of 0.07% in South Africa, 0.3% in Egypt, to 0.4% in Lesotho. Osteoarthritis was the most prevalent form of arthritis and in urban settings it was 55.1% in South Africa and in rural settings, all in South Africa, ranged from 29.5%, 29.7%, up to 82.7% among adults aged over 65 years. Other results include highest prevalence of 33.1% for knee osteoarthritis in rural South Africa, 0.1% for ankylosing spondylitis in rural South Africa, 4.4% for psoriatic arthritis in urban South Africa, 0.7% for gout in urban South Africa, and 0.3% for juvenile idiopathic arthritis in urban Egypt. A third of the included studies had a low risk of bias (33.3%, 9/27), 40.8% (11/27) moderate risk, and 25.9% (7/27) had a high risk of bias. CONCLUSIONS: In this systematic review, we have identified the paucity of latest prevalence data on arthritis in Africa. More studies are needed to address the prevalence and the true burden of this disease in Africa. PMID- 26241758 TI - Changes in production of reactive oxygen species in illuminated thylakoids isolated during development and senescence of barley. AB - This paper presents a detailed analysis of thylakoids isolated from secondary barley leaves harvested 18, 22, 25, 29, 32, 35 and 39 days after sowing (DAS). Goal of the analysis was to investigate the production of different reactive oxygen species (ROS) during development and senescence of barley. Generation of superoxide anion (O2-*) and hydrogen peroxide (H2O2) increases during development of barley reaching the highest value right after the onset of senescence (between 25 and 29 DAS), thereafter the levels of both ROS start to decrease until 35 DAS when production of H2O2 increases again. In comparison with O2-* and H2O2, generation of singlet oxygen ((1)O2) showed continuous production of low amounts thought the duration of experiment. Oxidative damage to the thylakoid membrane was assessed by measuring lipid peroxidation. Results showed gradual increase in lipid peroxidation with progress of plant development with highest increase occurring at the late stages of senescence. A possible factor contributing to the elevation in the production of ROS could be an increase in membrane fluidity observed in our previous study. Fluidization of the membrane, allows for better penetration of oxygen inside the membrane, which can lead to an increase in the production of ROS. Indeed, the production of ROS started to increase together with observed fluidization of the membrane from 22 to 29 DAS. Thereafter, production of ROS started to decline till 35th DAS. On the last day of the measurement, chl is at 25% of its initial value, lipid peroxidation reaches the highest value and H2O2 increases again. PMID- 26241757 TI - Partial Loss of Genomic Imprinting Reveals Important Roles for Kcnq1 and Peg10 Imprinted Domains in Placental Development. AB - Mutations in imprinted genes or their imprint control regions (ICRs) produce changes in imprinted gene expression and distinct abnormalities in placental structure, indicating the importance of genomic imprinting to placental development. We have recently shown that a very broad spectrum of placental abnormalities associated with altered imprinted gene expression occurs in the absence of the oocyte-derived DNMT1o cytosine methyltransferase, which normally maintains parent-specific imprinted methylation during preimplantation. The absence of DNMT1o partially reduces inherited imprinted methylation while retaining the genetic integrity of imprinted genes and their ICRs. Using this novel system, we undertook a broad and inclusive approach to identifying key ICRs involved in placental development by correlating loss of imprinted DNA methylation with abnormal placental phenotypes in a mid-gestation window (E12.5 E15.5). To these ends we measured DNA CpG methylation at 15 imprinted gametic differentially methylated domains (gDMDs) that overlap known ICRs using EpiTYPER mass array technology, and linked these epigenetic measurements to histomorphological defects. Methylation of some imprinted gDMDs, most notably Dlk1, was nearly normal in mid-gestation DNMT1o-deficient placentas, consistent with the notion that cells having lost methylation on these DMDs do not contribute significantly to placental development. Most imprinted gDMDs however showed a wide range of methylation loss among DNMT1o-deficient placentas. Two striking associations were observed. First, loss of DNA methylation at the Peg10 imprinted gDMD associated with decreased embryonic viability and decreased labyrinthine volume. Second, loss of methylation at the Kcnq1 imprinted gDMD was strongly associated with trophoblast giant cell (TGC) expansion. We conclude that the Peg10 and Kcnq1 ICRs are key regulators of mid-gestation placental function. PMID- 26241759 TI - Reactive oxygen species mediate axis-cotyledon signaling to induce reserve mobilization during germination and seedling establishment in Vigna radiata. AB - Seeds represent an excellent opportunity to investigate the role of reactive oxygen species (ROS) in control of metabolism during germination and seedling establishment. Cotyledons, the storage organs in Vigna, do not display growth/cell division while the embryonic axis shows rapid growth and intense metabolic activity. The present study investigates the possibility of ROS generated during respiration in the axis serving as messengers guiding storage reserve mobilization from cotyledons at the pre-greening stage. Seeds were germinated in the presence of hydroxyurea to halt cell division in the S-phase and separately in Edaravone, a potent free radical scavenger. Both treatments caused a decrease in germination percentage, seedling growth and protein mobilization. In the growing axis, both treatments resulted in a decrease in hydrogen peroxide (H2O2), total ROS, MDA and protein carbonyls. The picture in cotyledons was quite different, owing to the physiological dissimilarities between the tissues. The status of redox as evident by GSH/GSSG ratios tended toward oxidizing in axis in comparison to the highly reducing environment found in cotyledons. This is construed as a tendency to maintain redox buffering on the oxidizing side in the axis, to facilitate the passage of ROS message. These results strongly indicate that suppression of cell division or scavenging of ROS adversely affects protein reserve mobilization. It is proposed that apart from H2O2 being a transportable signal, the final message perceived in cotyledons also comprises lipid peroxidation, protein carbonylation and alteration of redox status of the glutathione pool. PMID- 26241760 TI - Structure of executive functions in typically developing kindergarteners. AB - Whereas studies of the past 10 years have shown the executive functions (EFs) in adults to be differentiated into at least three principal components (working memory, inhibition, and flexibility), EF structure in children is far less well understood despite a large body of research on the subject. A study was undertaken to test different structural models of EFs through confirmatory factor analysis (CFA) on a large sample of typically developing kindergarteners (N = 272). The method employed sought to remedy the shortcomings of past research in this field such as absence of CFA, insufficient number of EF components tested, insufficient number of indicators per latent variable, and absence of control on processing speed. Children were assessed using a battery of EF tasks developed by the researchers to measure working memory (WM), flexibility, and inhibition (backward word span, backward block span, fruit Stroop, day-night test, hand Stroop, Trails-P, card sort, face sort, and verbal fluency shift). CFA results show the best-fitting model to comprise two factors, namely, an inhibition factor and a WM-flexibility factor. Invariance analyses suggest that this structure is the same for girls and boys and that latent variable means do not differ by sex. These results support the hypothesis of EF differentiation during development. The researchers formulate other hypotheses regarding neurophysiological development. PMID- 26241761 TI - In search of methods enhancing fluency in reading: An examination of the relations between time constraints and processes of reading in readers of German. AB - The attainment of fluency in reading is a major difficulty for reading-disabled people. Manipulations applied on the presentation of texts, leading to "on-line" effects on reading (i.e., while texts are manipulated), are one direction of examinations in search of methods affecting reading. The imposing of time constraints, by deleting one letter after the other from texts presented on a computer screen, has been established as such a method. In an attempt to further understand its nature, we tested the relations between time constraints and processes of reading: phonological decoding of small orthogrpahic units and the addressing of orthographic representations from the mental lexicon. We also examined whether the type of orthogrpahic unit deleted (lexical, sublexical, or nonlexical unit) has any additional effect. Participants were German fifth graders with (n = 29) or without (n = 34) reading disability. Time constraints enhanced fluency in reading in both groups, and to a similar extent, across conditions. Comprehension was unimpaired. These results place the very principle of time constraints, regardless of the orthographic unit manipulated, as a critical factor affecting fluency in reading. However, phonological decoding explained a significant amount of variance in fluency in reading across all conditions in reading-disabled children, whereas the addressing of orthographic representations was the consistent predictor of fluency in reading in regular readers. These results indicate a qualitative difference in the processes explaining the variance in fluency in reading in regular and reading-disabled readers and suggest that time constraints might not have an effect on the relations between these processes and reading performance. PMID- 26241762 TI - Selection of Orthologous Genes for Construction of a Highly Resolved Phylogenetic Tree and Clarification of the Phylogeny of Trichosporonales Species. AB - The order Trichosporonales (Tremellomycotina, Basidiomycota) includes various species that have clinical, agricultural and biotechnological value. Thus, understanding why and how evolutionary diversification occurred within this order is extremely important. This study clarified the phylogenetic relationships among Tricosporonales species. To select genes suitable for phylogenetic analysis, we determined the draft genomes of 17 Trichosporonales species and extracted 30 protein-coding DNA sequences (CDSs) from genomic data. The CDS regions of Trichosporon asahii and T. faecale were identified by referring to mRNA sequence data since the intron positions of the respective genes differed from those of Cryptococcus neoformans (outgroup) and are not conserved within this order. A multiple alignment of the respective gene was first constructed using the CDSs of T. asahii, T. faecale and C. neoformans, and those of other species were added and aligned based on codons. The phylogenetic trees were constructed based on each gene and a concatenated alignment. Resolution of the maximum-likelihood trees estimated from the concatenated dataset based on both nucleotide (72,531) and amino acid (24,173) sequences were greater than in previous reports. In addition, we found that several genes, such as phosphatidylinositol 3-kinase TOR1 and glutamate synthase (NADH), had good resolution in this group (even when used alone). Our study proposes a set of genes suitable for constructing a phylogenetic tree with high resolution to examine evolutionary diversification in Trichosporonales. These can also be used for epidemiological and biogeographical studies, and may also serve as the basis for a comprehensive reclassification of pleomorphic fungi. PMID- 26241763 TI - Chronic postsurgical pain in Europe: An observational study. AB - BACKGROUND: Chronic postsurgical pain (CPSP) is an important clinical problem. Prospective studies of the incidence, characteristics and risk factors of CPSP are needed. OBJECTIVES: The objective of this study is to evaluate the incidence and risk factors of CPSP. DESIGN: A multicentre, prospective, observational trial. SETTING: Twenty-one hospitals in 11 European countries. PATIENTS: Three thousand one hundred and twenty patients undergoing surgery and enrolled in the European registry PAIN OUT. MAIN OUTCOME MEASURES: Pain-related outcome was evaluated on the first postoperative day (D1) using a standardised pain outcome questionnaire. Review at 6 and 12 months via e-mail or telephonic interview used the Brief Pain Inventory (BPI) and the DN4 (Douleur Neuropathique four questions). Primary endpoint was the incidence of moderate to severe CPSP (numeric rating scale, NRS >=3/10) at 12 months. RESULTS: For 1044 and 889 patients, complete data were available at 6 and 12 months. At 12 months, the incidence of moderate to severe CPSP was 11.8% (95% CI 9.7 to 13.9) and of severe pain (NRS >=6) 2.2% (95% CI 1.2 to 3.3). Signs of neuropathic pain were recorded in 35.4% (95% CI 23.9 to 48.3) and 57.1% (95% CI 30.7 to 83.4) of patients with moderate and severe CPSP, respectively. Functional impairment (BPI) at 6 and 12 months increased with the severity of CPSP (P < 0.01) and presence of neuropathic characteristics (P < 0.001). Multivariate analysis identified orthopaedic surgery, preoperative chronic pain and percentage of time in severe pain on D1 as risk factors. A 10% increase in percentage of time in severe pain was associated with a 30% increase of CPSP incidence at 12 months. CONCLUSION: The collection of data on CPSP was feasible within the European registry PAIN OUT. The incidence of moderate to severe CPSP at 12 months was 11.8%. Functional impairment was associated with CPSP severity and neuropathic characteristics. Risk factors for CPSP in the present study were chronic preoperative pain, orthopaedic surgery and percentage of time in severe pain on D1. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01467102. PMID- 26241764 TI - Plasma levels of levobupivacaine during continuous infusion via a wound catheter after major surgery in newborn infants: An observational study. AB - BACKGROUND: Epidurals may be challenging in neonatal patients due to technical difficulties relating to insertion and the risk of local anaesthesia toxicity. The use of wound catheters with an infusion of local anaesthetic has been shown to be well tolerated in adults and older children. There are few data concerning wound catheter techniques in neonatal patients. OBJECTIVES: The primary aim of this study was to analyse plasma levels of levobupivacaine associated with continuous wound infiltration via a catheter following neonatal surgical procedures. Secondary parameters, including the quality of postoperative analgesia and wound healing, were also noted. DESIGN: A prospective, observational study. SETTING: Paediatric ICU at the Karolinska University Hospital, Stockholm, Sweden, from March 2008 to December 2010. PATIENTS: Twenty newborn infants (median weight 3.48 kg) scheduled for major abdominal or thoracic surgery were included. Exclusion criteria were known or suspected hepatic dysfunction. Before skin closure, a subcutaneous catheter was inserted into the wound followed by a 0.5 mg kg(-1) bolus of levobupivacaine (0.125%, 0.4 ml kg( 1)) through the catheter. A continuous infusion was started 20 to 30 min later at a rate of 0.2 mg kg(-1)h(-1) (0.16 ml kg(-1) h(-1)). MAIN OUTCOME MEASURES: Plasma concentrations of levobupivacaine (total and unbound) at 12, 24, 48 and 72 h postoperatively. Morphine consumption, pain scores and wound healing were also analysed. RESULTS: Median concentrations of unbound and total levobupivacaine at 72 h were 0.018 and 1.305 MUg ml(-1), respectively. In 18 out of 20 infants [90%; 95% confidence interval (CI) 68.3 to 98.8], the unbound plasma concentration of levobupivacaine remained relatively stable and below 0.05 MUg ml(-1) throughout the 72 h observation period. Pain scores and morphine consumption levels were low. All wounds except one healed within 10 days. CONCLUSION: The studied infusion regimen was associated with plasma levels of levobupivacaine well below those associated with toxicity. Adequate wound healing, low pain scores and a reduced need for opioids were also noted. PMID- 26241765 TI - Suppressed expression of cystathionine beta-synthase and smaller cerebellum in Wistar Kyoto rats. AB - We previously reported that Wistar Kyoto rats, an animal model of depression, have a characteristically abnormal serine metabolism in the brain, i.e., lower serine and cystathionine, which is a metabolite of serine, concentrations in the brain. To explore the mechanism underlying this abnormality, the expression of cystathionine beta-synthase and serine racemase, which are the enzymes involved in the serine metabolism, was investigated in the cerebellum and hippocampus of Wistar and Wistar Kyoto rats. Wistar Kyoto rats exhibited a significantly lower mRNA expression of cystathionine beta-synthase in the cerebellum in comparison with Wistar rats, while expression levels in the hippocampus did not differ between strains. Previous study indicated that the reduction of cystathionine beta-synthase in the brain induced cerebellar aplasia in mice. Therefore, the cerebellar size was compared between Wistar rats and Wistar Kyoto rats. Wistar Kyoto rats displayed a lower ratio of cerebellum weight to whole-brain weight compared with Wistar rats of the same generation or similar body weight, suggesting that Wistar Kyoto rats exhibit smaller cerebellum. These results suggest that the lower mRNA expression of cystathionine beta-synthase in the cerebellum and the smaller size of cerebellum may be related to the depression like behavior in Wistar Kyoto rats. PMID- 26241767 TI - A Combinational Clustering Based Method for cDNA Microarray Image Segmentation. AB - Microarray technology plays an important role in drawing useful biological conclusions by analyzing thousands of gene expressions simultaneously. Especially, image analysis is a key step in microarray analysis and its accuracy strongly depends on segmentation. The pioneering works of clustering based segmentation have shown that k-means clustering algorithm and moving k-means clustering algorithm are two commonly used methods in microarray image processing. However, they usually face unsatisfactory results because the real microarray image contains noise, artifacts and spots that vary in size, shape and contrast. To improve the segmentation accuracy, in this article we present a combination clustering based segmentation approach that may be more reliable and able to segment spots automatically. First, this new method starts with a very simple but effective contrast enhancement operation to improve the image quality. Then, an automatic gridding based on the maximum between-class variance is applied to separate the spots into independent areas. Next, among each spot region, the moving k-means clustering is first conducted to separate the spot from background and then the k-means clustering algorithms are combined for those spots failing to obtain the entire boundary. Finally, a refinement step is used to replace the false segmentation and the inseparable ones of missing spots. In addition, quantitative comparisons between the improved method and the other four segmentation algorithms--edge detection, thresholding, k-means clustering and moving k-means clustering--are carried out on cDNA microarray images from six different data sets. Experiments on six different data sets, 1) Stanford Microarray Database (SMD), 2) Gene Expression Omnibus (GEO), 3) Baylor College of Medicine (BCM), 4) Swiss Institute of Bioinformatics (SIB), 5) Joe DeRisi's individual tiff files (DeRisi), and 6) University of California, San Francisco (UCSF), indicate that the improved approach is more robust and sensitive to weak spots. More importantly, it can obtain higher segmentation accuracy in the presence of noise, artifacts and weakly expressed spots compared with the other four methods. PMID- 26241766 TI - Dysrhythmia of timed movements in Parkinson's disease and freezing of gait. AB - A well-established motor timing paradigm, the Synchronization-Continuation Task (SCT), quantifies how accurately participants can time finger tapping to a rhythmic auditory beat (synchronization phase) then maintain this rhythm after the external auditory cue is extinguished, where performance depends on an internal representation of the beat (continuation phase). In this study, we investigated the hypothesis that Parkinson's disease (PD) patients with clinical symptoms of freezing of gait (FOG) exhibit exaggerated motor timing deficits. We predicted that dysrhythmia is exacerbated when finger tapping is stopped temporarily and then reinitiated under the guidance of an internal representation of the beat. Healthy controls and PD patients with and without FOG performed the SCT with and without the insertion of a 7-s cessation of motor tapping between synchronization and continuation phases. With no interruption between synchronization and continuation phases, PD patients, especially those with FOG, showed pronounced motor timing hastening at the slowest inter-stimulus intervals during the continuation phase. The introduction of a gap prior to the continuation phase had a beneficial effect for healthy controls and PD patients without FOG, although patients with FOG continued to show pronounced and persistent motor timing hastening. Ratings of freezing of gait severity across the entire sample of PD tracked closely with the magnitude of hastening during the continuation phase. These results suggest that PD is accompanied by a unique dysrhythmia of measured movements, with FOG reflecting a particularly pronounced disruption to internal rhythmic timing. PMID- 26241768 TI - Automatic Segmentation of Spinal Canals in CT Images via Iterative Topology Refinement. AB - Accurate segmentation of the spinal canals in computed tomography (CT) images is an important task in many related studies. In this paper, we propose an automatic segmentation method and apply it to our highly challenging image cohort that is acquired from multiple clinical sites and from the CT channel of the PET-CT scans. To this end, we adapt the interactive random-walk solvers to be a fully automatic cascaded pipeline. The automatic segmentation pipeline is initialized with robust voxelwise classification using Haar-like features and probabilistic boosting tree. Then, the topology of the spinal canal is extracted from the tentative segmentation and further refined for the subsequent random-walk solver. In particular, the refined topology leads to improved seeding voxels or boundary conditions, which allow the subsequent random-walk solver to improve the segmentation result. Therefore, by iteratively refining the spinal canal topology and cascading the random-walk solvers, satisfactory segmentation results can be acquired within only a few iterations, even for cases with scoliosis, bone fractures and lesions. Our experiments validate the capability of the proposed method with promising segmentation performance, even though the resolution and the contrast of our dataset with 110 patient cases (90 for testing and 20 for training) are low and various bone pathologies occur frequently. PMID- 26241769 TI - Unique metabolites protect earthworms against plant polyphenols. AB - All higher plants produce polyphenols, for defence against above-ground herbivory. These polyphenols also influence the soil micro- and macro-fauna that break down plant leaf litter. Polyphenols therefore indirectly affect the fluxes of soil nutrients and, ultimately, carbon turnover and ecosystem functioning in soils. It is unknown how earthworms, the major component of animal biomass in many soils, cope with high-polyphenol diets. Here, we show that earthworms possess a class of unique surface-active metabolites in their gut, which we term 'drilodefensins'. These compounds counteract the inhibitory effects of polyphenols on earthworm gut enzymes, and high-polyphenol diets increase drilodefensin concentrations in both laboratory and field populations. This shows that drilodefensins protect earthworms from the harmful effects of ingested polyphenols. We have identified the key mechanism for adaptation to a dietary challenge in an animal group that has a major role in organic matter recycling in soils worldwide. PMID- 26241770 TI - Performance of a novel microwave-based treatment technology for atrazine removal and destruction: Sorbent reusability and chemical stability, and effect of water matrices. AB - Transition metal-exchanged dealuminated Y zeolites were used to adsorb atrazine from aqueous solutions, followed by regeneration of the sorbents and destruction of the sorbed atrazine with microwave irradiation. Exchange of copper and iron into the zeolite's micropores significantly enhanced its sorption capacity and selectivity toward atrazine, and increased the microwave-induced degradation rate of the sorbed atrazine by 3-4-folds. Both the copper- and iron-exchanged zeolites could be regenerated and reused multiple times, while the catalytic activity of the latter was more robust due to the much greater chemical stability of Fe(3+) species in the micropores. The presence of humic acid, and common cations and anions had little impact on the sorption of atrazine on the transition metal exchanged zeolites. In the treatment of atrazine spiked in natural surface water and groundwater samples, sorptive removal of atrazine was found to be impacted by the level of dissolved organic carbon, probably through competition for the micropore spaces and pore blocking, while the water matrices exhibited no strong effect on the microwave-induced degradation of sorbed atrazine. Overall, iron exchanged dealuminated Y zeolites show great potential for removal and destruction of atrazine from contaminated surface water and groundwater in practical implementation of the novel treatment technology. PMID- 26241771 TI - Influence of co-substrate on textile wastewater treatment and microbial community changes in the anaerobic biological sulfate reduction process. AB - This study investigated the anaerobic treatment of sulfate-rich synthetic textile wastewater in three sulfidogenic sequential batch reactors (SBRs). The experimental protocol was designed to examine the effect of three different co substrates (lactate, glucose, and ethanol) and their concentrations on wastewater treatment performance. Sulfate reduction and dye degradation were improved when lactate and ethanol were used as electron donors, as compared with glucose. Moreover, under co-substrate limited concentrations, color, sulfate, and chemical oxygen demand (COD) removal efficiencies were declined. By reducing co-substrate COD gradually from 3000 to 500 mg/L, color removal efficiencies were decreased from 98.23% to 78.46%, 63.37%, and 69.10%, whereas, sulfate removal efficiencies were decreased from 98.42%, 82.35%, and 87.0%, to 30.27%, 21.50%, and 10.13%, for lactate, glucose, and ethanol fed reactors, respectively. Fourier transform infrared spectroscopy (FTIR) and total aromatic amine analysis revealed lactate to be a potential co-substrate for further biodegradation of intermediate metabolites formed after dye degradation. Pyrosequencing analysis showed that microbial community structure was significantly affected by the co-substrate. The reactor with lactate as co-substrate showed the highest relative abundance of sulfate reducing bacteria (SRBs), followed by ethanol, whereas the glucose-fed reactor showed the lowest relative abundance of SRB. PMID- 26241772 TI - Enhanced visible light-driven photocatalytic performance of ZnO-g-C3N4 coupled with graphene oxide as a novel ternary nanocomposite. AB - This article reports a novel ternary nanocomposite consisting of ZnO, g-C3N4, and graphene oxide (GO) that provides enhanced photocatalytic performance and stability. The ZnO nanospheres disperse evenly and embed themselves in the porous g-C3N4. Composites with various g-C3N4 and GO to ZnO weight ratios were synthesized and characterized systematically. The results indicated that the absorption of binary g-C3N4/ZnO nanocomposites shifted to a lower energy compared to pure ZnO in a fashion consistent with the loading content of g-C3N4. Notably, the loading content of GO in the ZnO-g-C3N4 composite resulted in increased absorption in the visible range and improved charge separation efficiency, thereby drastically improving photocatalytic activity. Successful hybridization of ternary nanocomposite was confirmed by drastic quenching of fluorescence and broader visible light absorption. The optimal content of g-C3N4 in the ZnO-g-C3N4 composite was 50%, which exhibited the effective hybridization between ZnO and g C3N4, and high photocatalytic efficiency. However, the photocatalytic degradation of the ternary nanocomposite showed performance that was two times greater than ZnO-g-C3N4, exhibiting 99.5% degradation efficiency after just 15 min of light irradiation. The combined heterojunction and synergistic effects of this composite account for the improved photocatalytic activity. PMID- 26241773 TI - Field pilot study on emissions, formations and distributions of PCDD/Fs from cement kiln co-processing fly ash from municipal solid waste incinerations. AB - A pilot study was performed to evaluate formation, distribution and emission of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) from cement kilns that co-process fly ash from municipal solid waste incineration (MSWI). Stack gas and particulate samples from multiple stages in the process were collected and analyzed for PCDD/Fs. Stack emissions of PCDD/Fs were below the European Union limit for cement kilns (0.1 ng TEQ m(-3)). PCDD/F concentrations in particulates from the cyclone preheater outlet, suspension preheater boiler, humidifier tower, and back-end bag filter were much higher than in other samples, which suggests that these areas are the major sites of PCDD/F formation. Comparison of PCDD/F homolog and congener profiles from different stages suggested that tetra- and penta-chlorinated furans were mainly formed during cement kiln co-processing of MSWI fly ash. Three lower chlorinated furan congeners, including 2,3,7,8 tetrachlorodibenzofuran, 1,2,3,7,8-pentachlorodibenzo-p-dioxin and 2,3,4,7,8 pentachlorodibenzofuran, were identified as dominant contributors to the toxic equivalents (TEQ) of the PCDD/Fs. The concentration of PCDD/Fs in particulates was correlated with chloride content, which is consistent with its positive effect on PCDD/F formation. This could be mitigated by pretreating the feedstock to remove chloride and metals. Mass balance indicated that cement kilns eliminated about 94% of the PCDD/F TEQ input from the feedstock. PMID- 26241774 TI - Prevalence of radiographic hip osteoarthritis and its association with hip pain in Japanese men and women: the ROAD study. AB - OBJECTIVE: Although hip osteoarthritis (OA) is a major cause of hip pain and disability in elderly people, few epidemiologic studies have been performed. We investigated the prevalence of radiographic hip OA and its association with hip pain in Japanese men and women using a large-scale population of a nationwide cohort study, Research on Osteoarthritis/osteoporosis Against Disability (ROAD). METHODS: From the baseline survey of the ROAD study, 2975 participants (1043 men and 1932 women), aged 23-94 years (mean 70.2 years), living in urban, mountainous, and coastal communities were analyzed. The radiographic severity at both hips was determined by the Kellgren/Lawrence (K/L) grading system. Radiographic hip OA was defined as K/L >= 2, and severe radiographic hip OA as K/L >= 3. RESULTS: The crude prevalence of radiographic hip OA was 18.2% and 14.3% in men and women, respectively, that of severe radiographic hip OA was 1.34% and 2.54%, and that of symptomatic K/L >= 2 OA was 0.29% and 0.99%, respectively. The crude prevalence of hip OA, including severe OA, was not age dependent in men or women. Male sex was a risk factor for radiographic hip OA, whereas female sex was a risk factor for severe radiographic hip OA and hip pain. Compared with K/L = 0/1, hip pain was significantly associated with K/L >= 3, but not with K/L = 2. CONCLUSION: The present cross-sectional study revealed the prevalence of radiographic hip OA and severe hip OA in Japanese men and women. Hip pain was strongly associated with K/L >= 3. PMID- 26241775 TI - The efficacy of non-surgical treatment on pain and sensitization in patients with knee osteoarthritis: a pre-defined ancillary analysis from a randomized controlled trial. AB - OBJECTIVE: To report the efficacy of a 3-month treatment program consisting of neuromuscular exercise, education, diet, insoles and pain medication (MEDIC treatment) compared to usual care (two leaflets with information and treatment advice) in reducing pain-related measures and sensitization in patients with knee osteoarthritis (OA) not eligible for total knee replacement (TKR). METHOD: A pre defined ancillary analysis of the results at 3 months of a randomized controlled trial (RCT) of 100 patients randomized to MEDIC-treatment or usual care. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01535001). Outcomes were sensitization assessed at the knee, the lower leg and forearm using a handheld algometer, peak pain intensity in the previous 24 h, pain intensity after 30 min of walking, pain location and pattern, spreading of pain (a region-divided body chart) and the usage of pain medication. RESULTS: The MEDIC group had larger improvements from baseline to 3 months in peak pain intensity (P = 0.02) and pain after 30 min of walking (P < 0.001) and in the number of body sites with pain (P = 0.04). There was no difference in the change in sensitization from baseline to 3 months between groups (P = 0.87), but sensitization decreased in both groups (P < 0.001). CONCLUSION: A non-surgical treatment program is more efficacious in reducing pain-related measures than usual care, while both are equally efficacious in reducing sensitization, indicating that mechanisms other than pain sensitization contribute to the perceived pain. The patients did not have severe symptomatic knee OA and hence pain sensitization may not yet have developed into a clinically relevant parameter or subgroups with less sensitization may exist. PMID- 26241776 TI - Bone turnover and articular cartilage differences localized to subchondral cysts in knees with advanced osteoarthritis. AB - OBJECTIVE: To investigate changes in bone structure, turnover, and articular cartilage localized in subchondral bone cyst (SBC) regions associated with knee osteoarthritis (OA). METHODS: Tibial plateaus (n = 97) were collected from knee OA patients during total knee arthroplasty (TKA). SBCs were identified using micro-computed tomography, and the specimens were divided into non-cyst (n = 25) and bone cyst (n = 72) groups. Microstructure of subchondral bone was assessed using bone volume fraction (BV/TV), trabecular number (Tb.N), structure model index (SMI) and bone mineral density (BMD). In bone cyst group, the cyst subregion, which contained at least one cyst, and the peri-cyst subregion, which contained no cysts, were further selected for microstructure analysis. Articular cartilage damage was estimated using the Osteoarthritis Research Society International (OARSI) score. The numbers of TRAP(+) osteoclasts, Osterix(+) osteoprogenitors, Osteocalcin(+) osteoblasts and expression of SOX9 were evaluated by immunohistochemistry. RESULTS: Bone cyst group presented higher BV/TV, Tb.N and SMI at subchondral bone than non-cyst group. Furthermore, cyst subregion displayed increased BV/TV and Tb.N but lower BMD and SMI than peri-cyst subregion. Histology revealed a higher OARSI score in bone cyst group. SBC exhibited a weak relationship with BV/TV, etc. The numbers of TRAP(+) osteoclasts, Osterix(+) osteoprogenitors, Osteocalcin(+) osteoblasts and expression of SOX9, were higher in bone cyst group. CONCLUSION: SBCs within knee OA are characterized by focally increased bone turnover, altered bone structure and more severe articular cartilage damage. The increased bone turnover possibly contributes to altered bone structure localized in SBC areas, and thus aggravates articular cartilage degeneration. PMID- 26241777 TI - Limited evidence of chondrocyte outgrowth from adult human articular cartilage. AB - OBJECTIVE: Cellular outgrowth from articular cartilage tissue has been described in a number of recent experimental studies. The aim of this study was to investigate the occurrence of cellular outgrowth from articular cartilage explants isolated from adult human donors. METHOD: Macroscopically intact articular cartilage specimens were isolated from adult human donors and cultured either in their native status, or in a cleansed status achieved by forced washing to minimize attaching cells. Additionally, the effect of chemotactic stimuli including cell lysate, High-Mobility-Group-Protein B1 (HMGB-1), Trefoil-factor 3 (TFF3), bone morphogenetic protein-2 (BMP-2), transforming growth factor-beta1 (TGF-beta1), or three-dimensional fibrin or collagen matrices were investigated. Co-cultures with synovial membrane served as a positive control for a source of migratory cells. The occurrence of cellular outgrowth was analyzed by histological examination after a culture period of 4 weeks. RESULTS: Spontaneous cellular outgrowth from cleansed cartilage specimens was not observed at a relevant level and could not significantly be induced by chemotactic stimuli or three-dimensional matrices either. A forming cartilage-adjoining cell layer was only apparent in the case of native cartilage explants with cellular remnants from surgical isolation or in co-culture experiments with synovial membrane. CONCLUSION: The relevance of cellular outgrowth from cartilage tissue is largely absent in the case of adult human articular cartilage samples. A cartilage adjoining cell layer forming around the explants may instead originate from still attaching cells that remained from surgical isolation. PMID- 26241778 TI - Abnormal perfusion in patellofemoral subchondral bone marrow in the rat anterior cruciate ligament transection model of post-traumatic osteoarthritis: a dynamic contrast-enhanced magnetic resonance imaging study. AB - OBJECTIVE: Although anterior cruciate ligament (ACL) injury is a well-recognized risk factor for developing knee post-traumatic osteoarthritis (PTOA), the process in the patellofemoral (PF) joint after ACL injury is still under-researched. Our aim was to investigate the perfusion changes in PF subchondral bone marrow in the rat ACL transection (ACLX) model of PTOA using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DESIGN: Eighteen male Sprague Dawley rats were randomly separated into three groups (n = 6 each group): a normal control group and groups receiving ACLX and sham-surgery, respectively, in the right knee. Perfusion parameters in the patellar and femoral subchondral bone marrows of all rats were measured on DCE-MRI at 0, 4, 8, and 16 weeks after respective treatment. After the last MRI at week 16, the rats were sacrificed and their right knees were harvested for histologic examination. In addition, to observe the long-term histologic change in PF joints, 9 additional rats (n = 3 in each group) were included and sacrificed at week 32 for histologic examination. RESULTS: In the ACLX group vs the sham and control groups, the perfusion parameters were significantly changed in both patellar and femoral subchondral bone marrows at week 16. Histologic examination revealed cartilage defects in ACLX rats at 32 weeks after surgery. CONCLUSIONS: These data point to a possible functional relationship between subchondral bone marrow perfusion abnormalities and cartilage breakdown in PTOA. Moreover, the perfusion parameters derived from DCE-MRI can potentially serve as biomarkers of early OA. PMID- 26241779 TI - Reciprocal activation of hypoxia-inducible factor (HIF)-2alpha and the zinc-ZIP8 MTF1 axis amplifies catabolic signaling in osteoarthritis. AB - OBJECTIVE: Hypoxia-inducible factor (HIF)-2alpha and the zinc-ZIP8-MTF1 axis in chondrocytes serve as catabolic regulators of osteoarthritic cartilage destruction by regulating the expression of catabolic factor genes. We explored possible crosstalk between these signaling pathways and its biological significance in osteoarthritis (OA). METHODS: Microarray analysis, various mRNA and protein assays were conducted using primary cultured mouse articular chondrocytes and experimental OA cartilage to reveal molecular mechanisms underlying the crosstalk between HIF-2alpha and the zinc-ZIP8-MTF1 axis. Experimental OA in mice was induced by intra-articular (IA) injection of adenovirus expressing HIF-2alpha (Ad-Epas1), ZIP8 (Ad-Zip8), or MTF1 (Ad-Mtf1) in wild-type mice or mice with cartilage-specific conditional knockout of HIF-2alpha (Epas1(fl/fl);Col2a1-Cre), ZIP8 (Zip8(fl/fl);Col2a1-Cre), or MTF1 (Mtf1(fl/fl);Col2a1-Cre). RESULTS: HIF-2alpha activated the zinc-ZIP8-MTF1 axis in chondrocytes by upregulating the Zn(2+) transporter ZIP8, thereby increasing Zn(2+) influx and activating the downstream transcription factor MTF1. The zinc ZIP8-MTF1 axis, in turn, acted as a novel transcriptional regulator of HIF 2alpha. HIF-2alpha-induced activation of the zinc-ZIP8-MTF1 axis amplified HIF 2alpha regulation of OA cartilage destruction by synergistically promoting expression of matrix-degrading enzymes. Thus, HIF-2alpha-induced activation of the zinc-ZIP8-MTF1 axis, together with zinc-ZIP8-MTF1 regulation of HIF-2alpha, acted collectively to synergistically promote expression of matrix-degrading enzymes and OA cartilage destruction. CONCLUSION: Our findings identify a reciprocal activation mechanism involving HIF-2alpha and the zinc-ZIP8-MTF1 axis during OA pathogenesis that amplifies catabolic signaling and cartilage destruction. PMID- 26241780 TI - Quinones as photosensitizer for photodynamic therapy: ROS generation, mechanism and detection methods. AB - Photodynamic therapy (PDT) is based on the dye-sensitized photooxidation of biological matter in the target tissue, and utilizes light activated drugs for the treatment of a wide variety of malignancies. Quinones and porphyrins moiety are available naturally and involved in the biological process. Quinone metabolites perform a variety of key functions in plants which includes pathogen protection, oxidative phosphorylation, and redox signaling. Quinones and porphyrin are biologically accessible and will not create any allergic effects. In the field of photodynamic therapy, porphyrin derivatives are widely used, because it absorb in the photodynamic therapy window region (600-900 nm). Hence, researchers synthesize drugs based on porphyrin structure. Benzoquinone and its simple polycyclic derivatives such as naphthaquinone and anthraquinones absorb at lower wavelength region (300-400 nm), which is lower than porphyrin. Hence they are not involved in PDT studies. However, higher polycyclic quinones absorb in the photodynamic therapy window region (600-900 nm), because of its conjugation and can be used as PDT agents. Redox cycling has been proposed as a possible mechanism of action for many quinone species. Quinones are involved in the photodynamic as well as enzymatic generation of reactive oxygen species (ROS). Generations of ROS may be measured by optical, phosphorescence and EPR methods. The photodynamically generated ROS are also involved in many biological events. The photo-induced DNA cleavage by quinones correlates with the ROS generating efficiencies of the quinones. In this review basic reactions involving photodynamic generation of ROS by quinones and their biological applications were discussed. PMID- 26241781 TI - A comparison of the antibacterial activity of the two methods of photodynamic therapy (using diode laser 810 nm and LED lamp 630 nm) against Enterococcus faecalis in extracted human anterior teeth. AB - BACKGROUND: Failure of endodontic treatment is usually due to an inadequate disinfection of the root canal system. Enterococcus faecalis has been widely used as a valuable microbiological marker for in-vitro studies because of its ability to colonize in a biofilm like style in root canals, invading dentinal tubules and resistance to some endodontic treatments. The aim of this study was to investigate the antibacterial effects of two methods of photodynamic therapy using a light emitting diode lamp (LED lamp, 630 nm) and a diode laser (810 nm) on E. faecalis biofilms in anterior extracted human teeth. METHODS: Fifty six single-rooted extracted teeth were used in this study. After routine root canal cleansing, shaping and sterilization, the teeth were incubated with E. faecalis for a period of two weeks. Teeth were then divided into two experimental groups (nu=23) and two control groups (nu=5). Teeth in one experimental group were exposed to a diode laser (810 nm), and in the other group samples were exposed to a LED lamp (630 nm). Intracanal bacterial sampling was done, and bacterial survival rate was then evaluated for each group. RESULTS: The Colony Forming Unit (CFU) in LED group (log10 CFUs=4.88+/-0.82) was significantly lower than the laser group (log CFUs=5.49+/-0.71) (p value=0.021). CFUs in positive control group (Log10 CFUs=10.96+/-0.44) were significantly higher than the treatment group (p?0.001). No bacterial colony was found in negative control group. CONCLUSION: The results of this research show that photodynamic therapy could be an effective supplement in root canal disinfection. PDT using LED lamp was more effective than diode laser 810 nm in reducing CFUs of E. faecalis in human teeth. PMID- 26241782 TI - Protective activity of salidroside against ethanol-induced gastric ulcer via the MAPK/NF-kappaB pathway in vivo and in vitro. AB - Salidroside (Sal) is a traditional Chinese medicine with various pharmacological effects. The present study aimed to investigate the protective effect of Sal on ethanol-induced acute gastric ulcer and H2O2-induced gastric epithelial cell damage. 0.2 ml ethanol and 400 MUM H2O2 were applied to establish a gastric ulcer model in vivo and in vitro respectively. The production of interleukin (IL)-6, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha was analyzed, as well as myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD). MTT assay was used to detect cell viability. In addition, MAPK/NF-kappaB signal pathway-related proteins p-ERK, p-JNK, p-p38, p-IkappaBalpha and p-NF kappaBp65 were analyzed to determine the underlying protective mechanism. Downstream genes such as cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and leukotrienes B4 (LTB4) were also measured. Obtained data indicated that Sal inhibited the overproduction of pro-inflammatory cytokines and enhanced antioxidant activity. Collectively, it is assumed that Sal could alleviate ethanol-induced acute gastric ulcer and H2O2-induced gastric epithelial cell damage through the MAPK/NF-kappaB pathway. PMID- 26241783 TI - Silver nanoparticles rapidly induce atypical human neutrophil cell death by a process involving inflammatory caspases and reactive oxygen species and induce neutrophil extracellular traps release upon cell adhesion. AB - Inflammation is one of the major toxic effects reported in response to in vitro or in vivo nanoparticle (NP) exposure. Among engineered NPs, silver nanoparticles (AgNPs) are very attractive for the development of therapeutic strategies, especially because of their antimicrobial properties. In humans, neutrophils, key players in inflammation, are the most abundant blood leukocytes that spontaneously undergo apoptosis, a central cell death mechanism regulating inflammation. The aim of this study was to evaluate the effect of AgNPs on neutrophil apoptosis. Transmission electronic microscopy reveals that AgNPs rapidly penetrate inside neutrophils. AgNPs induced atypical cell death where the cell volume increased and the cell surface expression of CD16 remained unaltered unlike apoptotic neutrophils where cell shrinkage and loss of CD16 are typically observed. The AgNP-induced atypical cell death is distinct from necrosis and reversed by a pancaspase inhibitor or by inhibitors of the inflammatory caspase-1 and caspase-4. In addition, AgNPs induced IL-1beta production inhibited by caspase-1 and caspase-4 inhibitors and also induced caspase-1 activity. Reactive oxygen species (ROS) production was increased by AgNPs and the atypical cell death was inhibited by the antioxidant n-acetylcysteine. Under similar experimental conditions, adhesion of neutrophils leads to neutrophil extracellular trap (NET) release induced by AgNPs. However, this process was not reversed by caspase inhibitors. We conclude that AgNPs rapidly induced an atypical cell death in neutrophils by a mechanism involving caspase-1, -4 and ROS. However, in adherent neutrophils, AgNPs induced NET release and, therefore, are novel agents able to trigger NET release. PMID- 26241784 TI - Critical roles of microRNAs in the pathogenesis of systemic sclerosis: New advances, challenges and potential directions. AB - Systemic sclerosis (SSc) is an autoimmune disease characterized by immune disorders, vascular obliteration, excessive extracellular matrix deposition, skin fibrosis, and further pathological change of internal organs. To date, the exact etiology of this complicated disease remains unknown. Over the past few years, the roles of epigenetic modifications caused by environmental factors have been intensively studied in relation to the disease pathogenesis, and important advances have been made. This review focuses on the new advances of microRNAs (miRNAs) in the field of SSc research, including the upstream regulatory factors of miRNAs, the downstream targets, and the feedback mechanisms between miRNAs and their targets. We also discussed the correlation of miRNAs and DNA methylation, the miRNAs and the gene polymorphism. Overall, the findings presented in this review illustrated how miRNAs play important roles in the pathogenesis of SSc. However, several unanswered questions continue to impede our understanding of this complex disease. Future research should focus on the identification of new biomarkers for early diagnosis and prognosis, which will help us improve the clinical treatment of patients with SSc. In addition, we discussed the challenges of miRNA study in SSc in the future. Since the miRNA injection may be a promising therapeutic approach for SSc treatment, one of the challenges in the future is to evaluate the therapeutic effects of miRNA and anti-miRNAs using SSc model animals. In light of the fact that one miRNA can target many mRNAs, and one mRNA is targeted by many miRNAs, the effect of miRNA changes on other gene expression should be investigated to evaluate the treatment safety of miRNA injection in vivo. PMID- 26241786 TI - Study of 57Fe Mossbauer effect in RFe2Zn20 (R = Lu, Yb, Gd). AB - We report measurements of (57)Fe Mossbauer spectra for RFe2Zn20 (R = Lu, Yb, Gd) from ~4.5 K to room temperature. The obtained isomer shift values are very similar for all three compounds, their temperature dependence was analyzed within the Debye model and resulted in an estimate of the Debye temperatures of 450-500 K. The values of quadrupole splitting at room temperature change with the cubic lattice constant a in a linear fashion. For GdFe2Zn20, ferromagnetic order is seen as an appearance of a sextet in the spectra. The (57)Fe site hyperfine field for -> was evaluated to be ~2.4 T. PMID- 26241785 TI - Patterns of Care for Metastatic Colorectal Cancer in Appalachia, and the Clinical, Sociodemographic, and Service Provider Determinants. AB - BACKGROUND: Appalachia has high colorectal cancer (CRC) incidence and mortality, at least in part due to screening disparities. This paper examines patterns and determinants of metastatic colorectal cancer care. METHODS: CRC patients diagnosed in 2006-2008 from 4 cancer registries (Kentucky, Ohio, Pennsylvania, and North Carolina) were linked to Medicare claims (2005-2009.) The final sample after exclusions included 855 stage IV and 590 stages I-III patients with metachronous or synchronous metastases. We estimate bivariate and multivariate analyses for several surgical and chemotherapeutic strategies of care using clinical, sociodemographic, and contextual determinants. RESULTS: Among 1,445 CRC patients, 84% had primary tumor resection and 44% received chemotherapy. Of the chemotherapy patients, 44% received newer systemic agents for at least 75% of the cycles. One year survivors with liver or lung metastases were more likely to have their primary tumor resected immediately (86.1% vs 69.5% for liver, and 78.2% vs 64.9% for lung) and have their metastases resected/ablated (15.7% vs 2.6% for liver and 15.0% vs 0.5% for lung). Patients with stages I-III primary tumors (versus IV) were much more likely to be resected, but they were less likely to receive chemotherapy. Patients with comorbidities (congestive heart failure, dementia, or respiratory disease) had lower odds of chemotherapy. Smaller hospital size and surgical volume had higher odds of immediate versus delayed surgery. The newer chemotherapeutic agents were more common with higher surgical volume. CONCLUSIONS: Metastatic colorectal cancer has clinical, sociodemographic, and service provider determinants. PMID- 26241787 TI - Tactile soft-sparse mean fluid-flow imaging with a robotic whisker array. AB - An array of whiskers is critical to many mammals to survive in their environment. However, current engineered systems generally employ vision, radar or sonar to explore the surroundings, not having sufficiently benefited from tactile perception. Inspired by the whisking animals, we present here a novel tomography based tactile fluid-flow imaging technique for the reconstruction of surroundings with an artificial whisker array. The moment sensed at the whisker base is the weighted integral of the drag force per length, which is proportional to the relative velocity squared on a whisker segment. We demonstrate that the 2D cross sectional mean fluid-flow velocity-field can be successfully mapped out by collecting moment measurements at different angular positions with the whisker array. We use a regularized version of the FOCal underdetermined system solver algorithm with a smoothness constraint to obtain soft-sparse static estimates of the 2D cross-sectional velocity-squared distribution. This new proposed approach has the strong potential to be an alternative environmental sensing technology, particularly in dark or murky environments. PMID- 26241788 TI - Computational Predictions of the Beryllium Analogue of Borole, Cp(+), and the Fluorenyl Cation: Highly Stabilized, non-Lewis Acidic Antiaromatic Ring Systems. AB - A computational study of a set of synthetically unknown beryllium-containing rings, anionic analogues of antiaromatic boroles, has been carried out to investigate their structure, stability, and potential reactivity. The results indicate that these compounds should be electronically viable (as assessed from HOMO-LUMO and singlet-triplet gaps) and therefore potential targets for synthesis. In strong contrast with boroles, these beryllium species are predicted to be not Lewis acidic but rather Lewis basic, with reactivity centered on the endocyclic Be-C bond. PMID- 26241789 TI - A Journey around the Medicinal Chemistry of Hepatitis C Virus Inhibitors Targeting NS4B: From Target to Preclinical Drug Candidates. AB - Hepatitis C virus (HCV) infection is a global health burden with an estimated 130 170 million chronically infected individuals and is the cause of serious liver diseases such as cirrhosis and hepatocellular carcinoma. HCV NS4B protein represents a validated target for the identification of new drugs to be added to the combination regimen recently approved. During the last years, NS4B has thus been the object of impressive medicinal chemistry efforts, which led to the identification of promising preclinical candidates. In this context, the present review aims to discuss research published on NS4B functional inhibitors focusing the attention on hit identification, hit-to-lead optimization, ADME profile evaluation, and the structure-activity relationship data raised for each compound family taken into account. The information delivered in this review will be a useful and valuable tool for those medicinal chemists dealing with research programs focused on NS4B and aimed at the identification of innovative anti-HCV compounds. PMID- 26241791 TI - The influence of an arm sling on sit-to-stand of hemiplegic subjects. PMID- 26241790 TI - The Impact of Insulin Pump Therapy on Glycemic Profiles in Patients with Type 2 Diabetes: Data from the OpT2mise Study. AB - BACKGROUND: The OpT2mise randomized trial was designed to compare the effects of continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) on glucose profiles in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients with glycated hemoglobin (HbA1c) levels of >=8% (64 mmol/mol) and <=12% (108 mmol/mol) despite insulin doses of 0.7-1.8 U/kg/day via MDI were randomized to CSII (n=168) or continued MDI (n=163). Changes in glucose profiles were evaluated using continuous glucose monitoring data collected over 6-day periods before and 6 months after randomization. RESULTS: After 6 months, reductions in HbA1c levels were significantly greater with CSII (-1.1+/-1.2% [ 12.0+/-13.1 mmol/mol]) than with MDI (-0.4+/-1.1% [-4.4+/-12.0 mmol/mol]) (P<0.001). Similarly, compared with patients receiving MDI, those receiving CSII showed significantly greater reductions in 24-h mean sensor glucose (SG) (treatment difference, -17.1 mg/dL; P=0.0023), less exposure to SG >180 mg/dL ( 12.4%; P=0.0004) and SG >250 mg/dL (-5.5%; P=0.0153), and more time in the SG range of 70-180 mg/dL (12.3%; P=0.0002), with no differences in exposure to SG<70 mg/dL or in glucose variability. Changes in postprandial (4-h) glucose area under the curve >180 mg/dL were significantly greater with CSII than with MDI after breakfast (-775.9+/-1,441.2 mg/dL/min vs. -160.7+/-1,074.1 mg/dL/min; P=0.0015) and after dinner (-731.4+/-1,580.7 mg/dL/min vs. -71.1+/-1,083.5 mg/dL/min; P=0.0014). CONCLUSIONS: In patients with suboptimally controlled type 2 diabetes, CSII significantly improves selected glucometrics, compared with MDI, without increasing the risk of hypoglycemia. PMID- 26241793 TI - High feedback versus low feedback of prenatal ultrasound for reducing maternal anxiety and improving maternal health behaviour in pregnancy. AB - BACKGROUND: Prenatal ultrasound is one of many techniques used in screening and diagnosis. It gives parents instant access to the images of the fetus. Receiving information promotes knowledge and understanding, but it may also increase maternal anxiety. OBJECTIVES: To compare high feedback versus low feedback during prenatal ultrasound for reducing maternal anxiety and improving maternal health behaviour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (12 May 2015), the Central Register of Controlled Trials (The Cochrane Library 2015, Issue 5), MEDLINE (January 1966 to 12 May 2015), and the ISRCTN Registry (12 May 2015). We handsearched citation lists of relevant publications. We did not apply any language or date restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) of high feedback (women can see the monitor screen and receive detailed visual and verbal explanations) versus low feedback (women can not see the monitor screen and women are given only a summary statement of the scan) during prenatal ultrasound. The primary outcome measure was maternal state anxiety. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked for accuracy. We have expressed results as risk ratio (RR) or mean differences (MD), together with their 95% confidence intervals (CI). MAIN RESULTS: We included four studies (365 women). Three RCTs (346 participants) reported the effect of high versus low feedback during ultrasound on state anxiety scores (mean difference (MD) 0.92, 95% confidence interval (CI) -0.58 to 2.43; participants = 346; three studies, low quality evidence). Two trials (148 participants) reported women's views of the level of feedback. They do not show that women in the high feedback groups are more likely to choose very positive adjectives to describe their feelings after the scan (risk ratio (RR) 3.30; 95% CI 0.73 to 14.85). Women who had a high feedback during ultrasound were more likely to stop smoking during pregnancy (RR 2.93, 95% CI 1.25 to 6.86; participants = 129; one study; low quality evidence) and to avoid alcohol during pregnancy (RR 2.96, 95% CI 1.15 to 7.60; participants = 129; one study; low quality evidence). Downgrading of evidence was based on the unclear risk of bias of included studies, wide CI crossing the line of no effect or presence of heterogeneity. AUTHORS' CONCLUSIONS: There is insufficient evidence to support either high or low feedback during a prenatal ultrasound to reduce maternal anxiety and promote health behaviour. PMID- 26241794 TI - Paul Newberne, DVM, MSc, PhD. PMID- 26241792 TI - Resolving the organization of the third tier visual cortex in primates: a hypothesis-based approach. AB - As highlighted by several contributions to this special issue, there is still ongoing debate about the number, exact location, and boundaries of the visual areas located in cortex immediately rostral to the second visual area (V2), i.e., the "third tier" visual cortex, in primates. In this review, we provide a historical overview of the main ideas that have led to four models of third tier cortex organization, which are at the center of today's debate. We formulate specific predictions of these models, and compare these predictions with experimental evidence obtained primarily in New World primates. From this analysis, we conclude that only one of these models (the "multiple-areas" model) can accommodate the breadth of available experimental evidence. According to this model, most of the third tier cortex in New World primates is occupied by two distinct areas, both representing the full contralateral visual quadrant: the dorsomedial area (DM), restricted to the dorsal half of the third visual complex, and the ventrolateral posterior area (VLP), occupying its ventral half and a substantial fraction of its dorsal half. DM belongs to the dorsal stream of visual processing, and overlaps with macaque parietooccipital (PO) area (or V6), whereas VLP belongs to the ventral stream and overlaps considerably with area V3 proposed by others. In contrast, there is substantial evidence that is inconsistent with the concept of a single elongated area V3 lining much of V2. We also review the experimental evidence from macaque monkey and humans, and propose that, once the data are interpreted within an evolutionary-developmental context, these species share a homologous (but not necessarily identical) organization of the third tier cortex as that observed in New World monkeys. Finally, we identify outstanding issues, and propose experiments to resolve them, highlighting in particular the need for more extensive, hypothesis-driven investigations in macaque and humans. PMID- 26241795 TI - Explaining retrieval-induced forgetting: A change in mental context between the study and restudy practice phases is not sufficient to cause forgetting. AB - Retrieving information can impair the subsequent recall of related information. Such retrieval-induced forgetting is often attributed to inhibitory mechanisms, but Jonker, MacLeod, and Seli (2013) recently proposed an alternative account. In their view, the study and retrieval-practice phases constitute two disparate contexts, and impairment of unpractised members from practised categories is attributable to their being absent from the retrieval-practice context, which is where, according to Jonker et al., participants preferentially search at the time of final test. In evidence of this account, Jonker et al. showed that even restudy practice-which is assumed by the inhibitory account to be insufficient to cause forgetting (i.e., retrieval-specificity)-can cause forgetting when a mental context change is inserted between study and restudy. The present research sought to replicate this finding while also testing the possibility that a far mental context change would cause more forgetting than a near mental context change. In Experiment 1, participants described a vacation inside the United States (near) or outside the United States (far). In Experiments 2 and 3, participants described the layout of their own home (near) or their parents' home (far). In contrast to the predictions of the context account, however, but consistent with the predictions of the inhibitory account, none of the restudy-plus-context change conditions resulted in significant forgetting. PMID- 26241796 TI - An Empirical Investigation of Defense Interpretation Depth, Defensive Functioning, and Alliance Strength in Psychodynamic Psychotherapy. AB - The present study examined the relationship between depth of defense interpretations by therapists, and patient defensive functioning, on the therapeutic alliance in a sample of 36 patients undergoing short-term dynamic psychotherapy. Defense interpretation depth was defined as the degree to which therapist interpretations contained information regarding the motivation for patient defenses and historical origins of the defensive processes (Greensen, 1967). Mean depth of interpretation was compared between sessions that were identified beforehand as either high-alliance or low-alliance sessions using the Helping Alliance Questionnaire (HAq-II: Luborsky et al., 1996). Results indicated that defensive functioning was correlated to defense interpretation depth in low alliance sessions. Moreover, mean depth of interpretation was also higher in low alliance sessions, pointing to the possible "destabilizing" effects that these interpretations may have on both defensive functioning and the therapeutic alliance. These results are discussed within the context of previous studies of therapeutic technique in dynamic psychotherapy. PMID- 26241797 TI - An Instance of Emotional Absence of a Father Traumatized by War-Clinical Material and Musical Illustration. AB - In his minor essay from 1914, Some Reflections on Schoolboy Psychology, Freud placed immense significance upon the father-son relationship as enabling or inhibiting the individual quest towards a mature, separate, and healthy development. In this essay, I will explore Freud's observations to illuminate the journey taken by Assaff, a 34-year old man who, during the early stages of his adolescence, had a father who was emotionally absent due a traumatic experience during his military service in the Israeli Defense Forces. Through transference work, the impact of the emotional absence will be shown. I will demonstrate how the boy was able unconsciously to use the music of Tommy, a rock opera by the British band The Who, as a transitional object. I will show how that piece of music provided Assaff with the sense of hope that helped during the darker times of his adolescent. PMID- 26241798 TI - Allowing for Psychosis to be Approachable and Understandable as a Human Experience: A Role for the Humanities in Psychotherapy Supervision. AB - Psychiatry and related mental health fields, in particular psychotherapy, have a long history of close ties with the humanities. That bond has weakened, however, over the last few decades as medicalized views of mental health and treatment have emerged. In this paper, we explore the potential of the reintroduction of the humanities, specifically novels and related literary genre, into the supervision of student clinicians working with clients who have psychosis. We believe that incorporation of novels and related literary genre into supervision can lead to unique and deepened understanding of the experience of psychosis, and can create an opportunity for a working therapeutic alliance. The potential mechanisms that create these unique opportunities to understand psychopathology are explored, and considerations for the implications for treatment, training, and future research are presented. PMID- 26241799 TI - The Dual-Dialectical Conceptualization in Psychotherapy. AB - The current paper describes the dual-dialectical conceptualization, a theoretical psychotherapeutic conceptualization based on three major rules: duality, contradiction, and complementarity. The paper surveys these rules with respect to various theoretical approaches in philosophy and psychotherapy. The essential feature of this conceptualization lies in its reinterpretation of problems that patients habitually regard as being one dimensional (e.g., patients are "stuck" in a solely negative attitude). Within the conceptualization, problems are reframed as dual dimensional, thereby offering patients more options and freeing them to better contend with the problems. Introduction of a novel psychotherapeutic tool known as the differentiation/integration approach provides patients with freedom of choice and enables them to distinguish between alternatives in verbal expressions and psychotherapeutic themes. PMID- 26241800 TI - Active Change in Psychodynamic Therapy: Moments of High Receptiveness. AB - This article presents the concept of "moments of high receptiveness" (MoHR or "Momentos de Alta Receptividad"), which is derived from the concept of "experiential coupling" ("Acoplamiento de Experiencias") proposed by Bleichmar (2001). Experiential coupling recently received empirical support by the work of Schiller and colleagues (2010). We will also show the conceptual placing of moments of high receptiveness with respect to the developments of Stern and colleagues (Stern and et al., 1998; Stern, 2004). In order to achieve both objectives, we focus on various clinical vignettes stressing the differences in repercussions of the technique. We describe use of stimuli for active evocation, explain how to identify moments of high receptiveness, and review ways to take advantage of these moments. Lastly, to minimize the risk of iatrogenic symptoms, we examine the role of therapists and some features of the therapeutic process when using this technique. PMID- 26241801 TI - Crystal Growth, Structures, and Properties of the Complex Borides, LaOs2Al2B and La2Os2AlB2. AB - Single crystals of two novel quaternary metal borides, LaOs2Al2B and La2Os2AlB2, have been grown from La/Ni eutectic fluxes. LaOs2Al2B crystallizes in tetragonal space group P4/mmm with the CeCr2Si2C-type structure, and lattice parameters a = 4.2075(6) A and c = 5.634(1) A. La2Os2AlB2 exhibits a new crystal structure in monoclinic space group C2/c with lattice parameters a = 16.629(3) A, b = 6.048(1) A, c = 10.393(2) A, and beta = 113.96(3) degrees . Both structures are three dimensional frameworks with unusual coordination (for solid-state compounds) of the boron atoms by transition metal atoms. The boron atom is square planar in LaOs2Al2B, whereas it exhibits linear and T-shaped geometries in La2Os2AlB2. Electrical resistivity measurements reveal poor metal behavior (rho300 K ~ 900 MUOmega cm) for La2Os2AlB2, consistent with the electronic band structure calculations, which also predict a metallic character for LaOs2Al2B. PMID- 26241803 TI - Epstein-Barr virus infection and nasopharyngeal carcinoma: the other side of the coin. AB - Oncogenic viruses may have a significant impact on the therapeutic management of several malignancies besides their well-known role in tumor pathogenesis. Epstein Barr virus (EBV) induces neoplastic transformation of epithelial cells of the nasopharynx by various molecular mechanisms mostly involving activation of oncogenes and inactivation of tumor-suppressor genes. EBV infection can also induce the expression of several immunogenic peptides on the plasma membrane of the infected cells. Importantly, these virus-related antigens may be used as targets for antitumor immunotherapy-based treatment strategies. Two different immunotherapy strategies, namely adoptive and active immunotherapy, have been developed and strongly improved in the recent years. Furthermore, EBV infection may influence the use of targeted therapies for nasopharyngeal carcinoma (NPC) considering that the presence of EBV can induce important modifications in cell signaling. As an example, latent membrane protein type 1 is a viral transmembrane protein mainly involved in the cancerogenesis process, which can also mediate overexpression of the epidermal growth factor receptor (EGFR) in NPC cells, rendering them more sensitive to anti-EGFR therapy. Finally, EBV may induce epigenetic changes in the infected cells, such as DNA hypermethylation and histone deacetylation, that can sustain tumor growth and can thus be considered potential targets for novel therapies. In conclusion, EBV infection can modify important biological features of NPC cells, rendering them more vulnerable to both immunotherapy and targeted therapy. PMID- 26241802 TI - Isometric Scaling in Developing Long Bones Is Achieved by an Optimal Epiphyseal Growth Balance. AB - One of the major challenges that developing organs face is scaling, that is, the adjustment of physical proportions during the massive increase in size. Although organ scaling is fundamental for development and function, little is known about the mechanisms that regulate it. Bone superstructures are projections that typically serve for tendon and ligament insertion or articulation and, therefore, their position along the bone is crucial for musculoskeletal functionality. As bones are rigid structures that elongate only from their ends, it is unclear how superstructure positions are regulated during growth to end up in the right locations. Here, we document the process of longitudinal scaling in developing mouse long bones and uncover the mechanism that regulates it. To that end, we performed a computational analysis of hundreds of three-dimensional micro-CT images, using a newly developed method for recovering the morphogenetic sequence of developing bones. Strikingly, analysis revealed that the relative position of all superstructures along the bone is highly preserved during more than a 5-fold increase in length, indicating isometric scaling. It has been suggested that during development, bone superstructures are continuously reconstructed and relocated along the shaft, a process known as drift. Surprisingly, our results showed that most superstructures did not drift at all. Instead, we identified a novel mechanism for bone scaling, whereby each bone exhibits a specific and unique balance between proximal and distal growth rates, which accurately maintains the relative position of its superstructures. Moreover, we show mathematically that this mechanism minimizes the cumulative drift of all superstructures, thereby optimizing the scaling process. Our study reveals a general mechanism for the scaling of developing bones. More broadly, these findings suggest an evolutionary mechanism that facilitates variability in bone morphology by controlling the activity of individual epiphyseal plates. PMID- 26241804 TI - A retrospective analysis of trabectedin infusion by peripherally inserted central venous catheters: a multicentric Italian experience. AB - The European Medicines Agency strongly recommends administration of trabectedin through a central venous catheter (CVC) to minimize the risk of extravasation. However, CVCs place patients at risk of catheter-related complications and have a significant budgetary impact for oncology departments. The most frequently used CVCs are subcutaneously implanted PORT-chamber catheters (PORTs); peripherally inserted central venous catheters (PICCs) are relatively new. We reviewed data of trabectedin-treated patients to evaluate the relative cost-effectiveness of the use of PORTs and PICCs in six Italian centres. Data on 102 trabectedin-treated patients (20 with sarcoma, 80 with ovarian cancer and two with cervical cancer) were evaluated. Forty-five patients received trabectedin by a PICC, inserted by trained nurses using an ultrasound-guided technique at the bedside, whereas 57 patients received trabectedin infusion by a PORT, requiring a day surgery procedure in the hospital by a surgeon. Device dislocation and infections were reported in four patients, equally distributed between PORT or PICC users. Thrombosis occurred in a single patient with a PORT. Complications requiring devices removal were not reported during any of the 509 cycles of therapy (median 5; range 1-20). PICC misplacement or early malfunctions were not reported during trabectedin infusion. The cost-efficiency ratio favours PORT over PICC only when the device is used for more than 1 year. Our data suggest that trabectedin infusion by PICC is safe and well accepted, with a preferable cost-efficiency ratio compared with PORT in patients requiring short-term use of the device (<=1 year). PMID- 26241805 TI - A practice-based evaluation of the prevalence and predisposing etiology of white spot lesions. AB - OBJECTIVE: To use an alumni-centered, practice-based research network to evaluate white spot lesions (WSLs) among treated orthodontic patients. MATERIALS AND METHODS: An initial survey was conducted to ascertain whether orthodontic alumni from Texas A&M University Baylor College of Dentistry were willing to participate. Twenty randomly selected alumni participated, providing 158 treated cases. Each alumnus (1) obtained internal review board consent; (2) submitted pre and posttreatment photographs of 10 consecutively finished cases; (3) completed a treatment survey; and (4) had the patient/parent complete the American Dental Association (ADA) Caries Risk Assessment. RESULTS: Almost 90% of the alumni surveyed were willing to participate in the practice-based research, primarily because a fellow alumnus asked them to. Approximately 28% of the patients developed WSLs. The average patient developed 2.4 white spots, affecting 12.7% of the teeth examined. WSLs were significantly (P < .001) more (2.3-3.2 times) likely for patients who were identified on the ADA Caries Risk Assessment. The risk of developing WSLs during treatment was also increased for those with fair (2.7 times) or poor (3.5 times) oral hygiene, poor gingival health (2.3 times), and extended treatment times (2.1 times). CONCLUSIONS: There is a substantial risk of developing WSLs among private practice patients, depending partially on the length of treatment. Patients at greatest risk can be identified prior to treatment based on the ADA Caries Risk Assessment, oral hygiene, and gingival health. PMID- 26241806 TI - Parental Attachment and Adolescents' Perception of School Alienation: The Mediation Role of Self-Esteem and Adjustment. AB - The present study examined the relationship between adolescents' attachment to parents and their feelings of alienation in the school context by considering the mediating role of adjustment and self-esteem. It was proposed that the degree of attachment to one's parents was associated with adjustment and self-esteem, which in turn predicted possible school alienation. A total of 227 students completed self-report measures on parental attachment, adjustment, self-esteem, and alienation from school. Results were consistent with the attachment theory and related literature that posits that (a) secure attachment to parents was associated with adjustment and self-esteem, (b) secure attachment to parents was negatively associated with feelings of school alienation, and (c) adjustment and self-esteem were a crucial mediators between attachment to parents and school alienation. In addition to enhanced adjustment, the self-esteem of adolescents may be an additional factor in reducing alienation at school. The results also supported the mediator role of self-esteem in the relationship between attachment to parents and adjustment. Finally, the relationship between self-esteem and school alienation were shown to be fully mediated by adjustment. The results were discussed in the context of responsibilities of teachers and school counselors, which may provide both students and parents with the skills to improve social functioning in the school context. PMID- 26241807 TI - Retinoblastoma Protein Knockdown Favors Oxidative Metabolism and Glucose and Fatty Acid Disposal in Muscle Cells. AB - Deficiency in the retinoblastoma protein (Rb) favors leanness and a healthy metabolic profile in mice largely attributed to activation of oxidative metabolism in white and brown adipose tissues. Less is known about Rb modulation of skeletal muscle metabolism. This was studied here by transiently knocking down Rb expression in differentiated C2C12 myotubes using small interfering RNAs. Compared with control cells transfected with non-targeting RNAs, myotubes silenced for Rb (by 80-90%) had increased expression of genes related to fatty acid uptake and oxidation such as Cd36 and Cpt1b (by 61% and 42%, respectively), increased Mitofusin 2 protein content (~2.5-fold increase), increased mitochondrial to nuclear DNA ratio (by 48%), increased oxygen consumption (by 65%) and decreased intracellular lipid accumulation. Rb silenced myotubes also displayed up-regulated levels of glucose transporter type 4 expression (~5-fold increase), increased basal glucose uptake, and enhanced insulin-induced Akt phosphorylation. Interestingly, exercise in mice led to increased Rb phosphorylation (inactivation) in skeletal muscle as evidenced by immunohistochemistry analysis. In conclusion, the silencing of Rb enhances mitochondrial oxidative metabolism and fatty acid and glucose disposal in skeletal myotubes, and changes in Rb status may contribute to muscle physiological adaptation to exercise. PMID- 26241808 TI - [Coronary artery anomaly common cause of sudden cardiac death in young people. Unusual diagnosis that requires a targeted investigation in order not to be missed]. AB - 17-year old male was admitted after syncope during exercise, exhibiting transient ST-elevation, raised troponin T levels and regionally hypokinetic myocardium. Further investigation revealed a left main coronary artery arising from the right sinus valsalva, a narrow vessel with an intramural course resulting in compression during systole. The patient had presented previously with chest pain and syncope during physical exercise. After CT-angiography, ECG, Tilt-test and ECHO he was diagnosed with vasomotor induced syncope. Anomalous coronary arteries have been found to be one of the three most common causes of sudden cardiac death in young individuals. Symptomatic individuals present with chest pain and/or syncope on exertion. Diagnosis can be made by coronary angiography or CT angiography. Standard investigation of syncope is likely to miss the diagnosis. The management of left main coronary arising from the right sinus valsalva is generally surgical. PMID- 26241809 TI - [Semi-automatic defibrillators does not always interpret heart rhythms correctly. Five patients were defibrillated despite non-shockable rhythms]. AB - Automated external defibrillators (AED) have become an important part of the "the chain of survival" in case of sudden cardiac arrest (SCA), where early defibrillation is lifesaving. The American Heart Association demands that AEDs have a specificity of >99 % to recognize normal sinus rhythm and >95 % for the other non-shockable rhythms. Reports on their performance in the field are scarce. We present five cases in which AED recommended shock for apparently non shockable rhythms. This indicates the necessity to systematically reevaluate AED performance. PMID- 26241810 TI - [Position statement regarding sex after hip replacement]. PMID- 26241811 TI - [Bed rest when the water breaks early--in accordance with the evidence or old habit?]. AB - Bed rest is often prescribed as part of the treatment plan for women with preterm premature rupture of membranes in the hope of avoid-ing premature birth. The purpose of this study was to determine the routine care of these patients in Swedish hospitals.A survey was sent to all hospitals in Sweden with an obstetrics department (n=45). Out of these, 31 answered our survey (69 %). The women were separated into three groups depending on gestation length (22+0-26+6, 27+0-32+6 and 33+0-36+6).Most hospitals chose to admit the women and to recommend total or partial bed rest. The earlier in the pregnancy the rupture occurred, the more likely the patient was to be confined to total bed rest.The study shows that this topic is controversial. Most hospitals use bed rest even though there is no evidence to support that it is of benefit for the patient. More studies in this area are required in order to find an optimal treatment for this patient group. PMID- 26241812 TI - [Not Available]. PMID- 26241813 TI - [Not Available]. PMID- 26241814 TI - [Informed choices in screening requires more than information]. PMID- 26241815 TI - [Who helps patients with nose bleeds these days?]. PMID- 26241816 TI - Patient-reported sexual toxicity after radiation therapy in long-term prostate cancer survivors. AB - BACKGROUND: To present an overview of patient-reported sexual toxicity in sexually active long-term prostate cancer survivors treated with radiation therapy. METHODS: We used patient-reported outcomes from a study-specific questionnaire surveying symptoms after prostate cancer radiation therapy. Data from 518 men treated at the Sahlgrenska University Hospital in Sweden from 1993 to 2006 were analysed. The men had undergone primary or salvage external beam radiation therapy (EBRT) or EBRT combined with high-dose rate brachytherapy (BT). We also used information from 155 non-treated reference men from the general population with no history of prostate cancer, matched for age and residency. RESULTS: Median time from treatment to follow-up was 5 years (range: 1-14 years). Among the 16 investigated symptoms on erectile function, libido, orgasm, and seminal fluid, 9 symptoms in the primary EBRT group and 10 in both the salvage EBRT and the EBRT+BT groups were statistically significantly more prevalent in survivors than in reference men. Erectile dysfunction was influenced by both age and time to follow-up, whereas symptoms relating to orgasm and seminal fluid were influenced by time to follow-up only. Not being sexually active was almost one and a half times as common in survivors as in reference men. CONCLUSIONS: The presented symptom profiles can help to develop personalized therapy for prostate cancer through a better understanding of which radiation-induced toxicities to be addressed in the clinic and can also assist in identifying suitable interventions for existing symptoms. PMID- 26241818 TI - Polyethyleneimine-modified graphene oxide nanocomposites for effective protein functionalization. AB - A facile method to prepare a biocompatible graphene oxide (GO)-based substrate for protein immobilization was developed to overcome the drawbacks of GO, such as the strong electrostatic and hydrophobic interactions which could potentially alter the conformation and biological activity of proteins. The GO was coated with hydrophilic branched polyethyleneimine (BPEI), while Concanavalin A (Con A) as a model lectin protein was employed to fabricate the functionalized composites to evaluate the feasibility of this strategy. The composites exhibit an extremely high binding capacity for glycoproteins (i.e. IgG 538.3 mg g(-1)), which are superior to other immobilized materials. Moreover, they can work well in 500-fold non-glycoprotein interference and even in complex biological samples. All these data suggest that the GO@BPEI composites will have great potential as scaffolds for proteins fully exerting their biofunctions. PMID- 26241817 TI - Is England closing the international gap in cancer survival? AB - BACKGROUND: We provide an up-to-date international comparison of cancer survival, assessing whether England is 'closing the gap' compared with other high-income countries. METHODS: Net survival was estimated using national, population-based, cancer registrations for 1.9 million patients diagnosed with a cancer of the stomach, colon, rectum, lung, breast (women) or ovary in England during 1995 2012. Trends during 1995-2009 were compared with estimates for Australia, Canada, Denmark, Norway and Sweden. Clinicians were interviewed to help interpret trends. RESULTS: Survival from all cancers remained lower in England than in Australia, Canada, Norway and Sweden by 2005-2009. For some cancers, survival improved more in England than in other countries between 1995-1999 and 2005-2009; for example, 1-year survival from stomach, rectal, lung, breast and ovarian cancers improved more than in Australia and Canada. There has been acceleration in lung cancer survival improvement in England recently, with average annual improvement in 1 year survival rising to 2% during 2010-2012. Survival improved more in Denmark than in England for rectal and lung cancers between 1995-1999 and 2005-2009. CONCLUSIONS: Survival has increased in England since the mid-1990s in the context of strategic reform in cancer control, however, survival remains lower than in comparable developed countries and continued investment is needed to close the international survival gap. PMID- 26241819 TI - Choosing the tool for osteoporosis risk prediction. AB - PURPOSE OF REVIEW: Predicting fracture risk is a major challenge because it allows the prevention of major osteoporotic fracture in high-risk populations. With the aging of the population, this matter will become of even greater importance. In recent years, novel clinical, biochemical, and imaging tools have been developed to improve the assessment of fracture risk. RECENT FINDINGS: The present review summarizes novel clinical strategies, Dual energy X-ray absorptiometry (DXA)-derived tools, imaging techniques, and biochemical markers that have been developed recently to improve fracture risk prediction. SUMMARY: DXA and clinical fracture risk prediction tools are preferential markers of fracture risk. Clinical fracture risk alone might be used if DXA facilities are unavailable. The fracture risk assessment tool may be used in osteoporosis consultation in many countries. Other tools may be used soon after more studies are performed, particularly trabecular bone score, quantitative ultrasound, bone turnover markers. Specific factors for example falls, hip axis length, vertebral fracture assessment could be used in individual patients. This may significantly improve the clinical decision-making. PMID- 26241820 TI - Nutrition and the gastrointestinal tract. PMID- 26241821 TI - THE ENDOPARASITOID Pteromalus puparum INFLUENCES HOST GENE EXPRESSION WITHIN FIRST HOUR OF PARASITIZATION. AB - The small cabbage butterfly, Pieris rapae, is an important pest of cruciferous corps, and Pteromalus puparum is a predominant pupal endoparasitoid wasp of this butterfly. For successful development of parasitoid offspring, female parasitoids usually introduce one or several kinds of maternal factors into the hemocoels during oviposition to suppress host immunity. To investigate the early changes in host immune-related genes following parasitization, we analyzed transcriptomes of parasitized and unparasitized, control, host pupae. Approximately 17.7 and 19.3 million paired-end reads were generated from nonparasitized and parasitized host pupae, and assembled de novo into 45,639 transcripts and 27,659 nonredundant unigenes. The average unigene length was 790 bp. A total 18,377 of 27,659 unigenes were annotated and we identified 557 differentially expressed unigenes in host pupae at 1 h after parasitization, of which 21 were immune-related. Parasitization led to downregulation of most pattern recognition receptors and upregulation of all serine protease inhibitors. The transcirptomic profile of P. rapae is considerably affected by parasitization. This study provides valuable sources for future investigations of the molecular interaction between P. puparum and its host P. rapae. PMID- 26241822 TI - Copper Catalyzed Enantioselective Alkylation of Pyrrole with beta,gamma Unsaturated alpha-Ketoesters: Application to One-Pot Construction of the Seven Membered Ring by Merging a Gold Catalysis. AB - A highly enantioselective Friedel-Crafts alkylation of pyrrole to beta,gamma unsaturated alpha-ketoesters was developed by virtue of a chiral copper complex, affording the alkylated derivatives of pyrrole with good yields and excellent enantioselectivities. Moreover, merging copper catalysis with gold catalysis realized a one-pot construction of the seven-membered ring to give annulated pyrroles with moderate to good yields and high enantiomeric excesses. PMID- 26241823 TI - Hydrogen-Bond Heterogeneity Boosts Hydrophobicity of Solid Interfaces. AB - Experimental and theoretical studies suggest that the hydrophobicity of chemically heterogeneous surfaces may present important nonlinearities as a function of composition. In this article, this issue is systematically explored using molecular simulations. The hydrophobicity is characterized by computing the contact angle of water on flat interfaces and the desorption pressure of water from cylindrical nanopores. The studied interfaces are binary mixtures of hydrophilic and hydrophobic sites, with and without the ability to form hydrogen bonds with water, intercalated at different scales. Water is described with the mW coarse-grained potential, where hydrogen-bonds are modeled in the absence of explicit hydrogen atoms, via a three-body term that favors tetrahedral coordination. We found that the combination of particles exhibiting the same kind of coordination with water gives rise to a linear dependence of contact angle with respect to composition, in agreement with the Cassie model. However, when only the hydrophilic component can form hydrogen bonds, unprecedented deviations from linearity are observed, increasing the contact angle and the vapor pressure above their values in the purely hydrophobic interface. In particular, the maximum enhancement is seen when a 35% of hydrogen bonding molecules is randomly scattered on a hydrophobic background. This effect is very sensitive to the heterogeneity length-scale, being significantly attenuated when the hydrophilic domains reach a size of 2 nm. The observed behavior may be qualitatively rationalized via a simple modification of the Cassie model, by assuming a different microrugosity for hydrogen bonding and non-hydrogen bonding interfaces. PMID- 26241825 TI - Characterization of Paracoccidioides brasiliensis by FT-IR spectroscopy and nanotechnology. AB - Paracoccidioides brasiliensis, the etiological agent of paracoccidioidomycosis, is a dimorphic fungus existing as mycelia in the environment (or at 25 degrees C in vitro) and as yeast cells in the human host (or at 37 degrees C in vitro). Because mycological examination of lesions in patients frequently is unable to show the presence of the fungus and serological tests can misdiagnose the disease with other mycosis, the development of new approach's for molecular identification of P. brasiliensis spurges is needed. This study describes the use of a gold nanoprobe of a known gene sequence of P. brasiliensis as a molecular tool to identify P. brasiliensis by regular polymerase chain reaction (PCR) associated with a colorimetric methods. This approach is suitable for testing in remote areas because it does not require any further step than gene amplification, being safer and cheaper than electrophoresis methods. The proposed test showed a color change of the PCR reaction mixture from red to blue in negative samples, whereas the solution remains red in positive samples. We also performed a Fourier Transform Infrared (FT-IR) Spectroscopy analysis to characterize and compare the chemical composition between yeast and mycelia forms, which revealed biochemical differences between these two forms. The analysis of the spectra showed that differences were distributed in chemical bonds of proteins, lipids and carbohydrates. The most prominent difference between both forms was vibration modes related to 1,3-beta-glucan usually found in mycelia and 1,3-alpha-glucan found in yeasts and also chitin forms. In this work, we introduce FT-IR as a new method suitable to reveal overall differences that biochemically distinguish each form of P. brasiliensis that could be additionally used to discriminate biochemical differences among a single form under distinct environmental conditions. PMID- 26241824 TI - Construction and evaluation of an adenoviral vector for the liver-specific expression of the serine/arginine-rich splicing factor, SRSF3. AB - Serine/arginine-rich splicing factor-3 (SRSF3), alternatively known as SRp20, is a member of the highly-conserved SR protein family of mRNA splicing factors. SRSF3 generally functions as an enhancer of mRNA splicing by binding to transcripts in a sequence-specific manner to both recruit and stabilize the binding of spliceosomal components to the mRNA. In liver, expression of SRSF3 is relatively low and its activity is increased in response to insulin and feeding a high carbohydrate diet. We sought to over-express SRSF3 in primary rat hepatocytes to identify regulatory targets. A standard adenoviral shuttle vector system containing an epitope-tagged SRSF3 under the transcriptional control of the CMV promoter could not be used to produce infectious adenoviral particles. SRSF3 over-expression in the packaging cell line prevented the production of infectious adenovirus particles by interfering with the viral splicing program. To circumvent this issue, SRSF3 expression from the shuttle vector was blocked by placing its expression under the control of the liver-specific albumin promoter. In this system, the FLAG-SRSF3 transgene is only expressed in the target cells (hepatocytes) but not in the packaging cell line. An additional benefit of the albumin promoter is that expression of the transgene does not require the addition of hormones or antibiotics to drive SRSF3 expression in the hepatocytes. Robust expression of FLAG-SRSF3 protein is detected in both HepG2 cells and primary rat hepatocytes infected with adenovirus prepared from this new shuttle vector. Furthermore, abundances of several known and suspected mRNA targets of SRSF3 action are increased in response to over-expression using this virus. This report details the construction of the albumin promoter-driven adenoviral shuttle vector, termed pmAlbAd5-FLAG.SRSF3, that can be used to generate functional adenovirus to express FLAG-SRSF3 specifically in liver. This vector would be suitable for over-expression of other splicing factors that could inhibit virus production. In addition, this vector would allow only liver-specific expression of other cargo genes when used in a whole-animal paradigm. PMID- 26241826 TI - Facile green fabrication of nanostructure ZnO plates, bullets, flower, prismatic tip, closed pine cone: Their antibacterial, antioxidant, photoluminescent and photocatalytic properties. AB - Green synthesis of multifunctional Zinc oxide nanoparticles (NPs) with a variety of morphologies were achieved by low temperature solution combustion route employing neem (Azadirachta indica) extract as fuel. The nanoparticles were characterized by PXRD, FTIR, XPS, Raman and UV-Visible spectroscopic studies. The Morphologies were studied by SEM and TEM analysis. The NPs were subjected for photoluminescence, photocatalytic, antibacterial and antioxidant activity studies. PXRD pattern confirmed the hexagonal wurtzite structure of the product. SEM images indicated the transformation of mushroom like hexagonal disks to bullets, buds, cones, bundles and closed pine cone structured NPs with increase in the concentration of neem extract in reaction mixture. The NPs exhibited prominent green emission due to the presence of intrinsic defect centers. The as formed bullet shaped ZnO with 4ml of neem extract was found to decolorize Methylene blue (MB) under Sunlight and UV light irradiation. The antibacterial studies indicated that ZnO NPs of concentration 500, 750 and 1000MUg resulted in significant antibacterial activity on Klebsiella aerogenes and Staphylococcus aureus but not against Escherichia coli and Pseudomonas aeruginosa in agar well diffusion method. Further, ZnO NPs exhibited significant antioxidant activity against scavenging DPPH free radicals. The current investigation demonstrated green engineering method for the synthesis of multifunctional ZnO NPs with interesting morphologies using neem extract. PMID- 26241827 TI - Spectroscopic studies on the binding interaction of phenothiazinium dyes, azure A and azure B to double stranded RNA polynucleotides. AB - This manuscript presents spectroscopic characterization of the interaction of two phenothiazinium dyes, azure A and azure B with double stranded (ds) ribonucleic acids, poly(A).poly(U), poly(C).poly(G) and poly(I).poly(C). Absorbance and fluorescence studies revealed that these dyes bind to the RNAs with binding affinities of the order 10(6)M(-1) to poly(A).poly(U), and 10(5)M(-1) to poly(C).poly(G) and poly(I).poly(C), respectively. Fluorescence quenching and viscosity data gave conclusive evidence for the intercalation of the dyes to these RNA duplexes. Circular dichroism results suggested that the conformation of the RNAs was perturbed on interaction and the dyes acquired strong induced optical activity on binding. Azure B bound to all the three RNAs stronger than azure A and the binding affinity varied as poly(A).poly(U)>poly(C).poly(G)>poly(I).poly(C) for both dyes. PMID- 26241828 TI - A novel rosamine based fluorescent sensor for Ag(+) recognition. AB - Rosamine derivative, N-(9-(4-(bis(2-(ethylthio)ethyl)amino)phenyl)-6 (diethylamino)-3H-xanthen-3-ylidene)-N-ethylethanaminium hexafluorophosphate, L, bearing an NS2 group as receptor, was synthesized as a turn on chemosensor for silver ion in ethanol solution. Sensor L exhibited high selectivity toward Ag(+) in comparison to other metal cations (Cd(2+), Cu(2+), Hg(2+), Na(+), Mg(2+), Ni(2+), Pb(2+), Fe(3+), and Zn(2+)). The detection limit for Ag(+) was in 10(-7) level. The binding properties between silver ion and L were further studied by (1)HNMR titration experiments. The chemosensor L can be used as a potential material for silver recognition. PMID- 26241829 TI - On-line monitoring the extract process of Fu-fang Shuanghua oral solution using near infrared spectroscopy and different PLS algorithms. AB - An on-line near infrared (NIR) spectroscopy monitoring method with an appropriate multivariate calibration method was developed for the extraction process of Fu fang Shuanghua oral solution (FSOS). On-line NIR spectra were collected through two fiber optic probes, which were designed to transmit NIR radiation by a 2mm flange. Partial least squares (PLS), interval PLS (iPLS) and synergy interval PLS (siPLS) algorithms were used comparatively for building the calibration regression models. During the extraction process, the feasibility of NIR spectroscopy was employed to determine the concentrations of chlorogenic acid (CA) content, total phenolic acids contents (TPC), total flavonoids contents (TFC) and soluble solid contents (SSC). High performance liquid chromatography (HPLC), ultraviolet spectrophotometric method (UV) and loss on drying methods were employed as reference methods. Experiment results showed that the performance of siPLS model is the best compared with PLS and iPLS. The calibration models for AC, TPC, TFC and SSC had high values of determination coefficients of (R(2)) (0.9948, 0.9992, 0.9950 and 0.9832) and low root mean square error of cross validation (RMSECV) (0.0113, 0.0341, 0.1787 and 1.2158), which indicate a good correlation between reference values and NIR predicted values. The overall results show that the on line detection method could be feasible in real application and would be of great value for monitoring the mixed decoction process of FSOS and other Chinese patent medicines. PMID- 26241830 TI - Electrolytic coloration and spectral properties of O(2-)- and Mg(2+)-codoped LiF crystals. AB - O(2-)- and Mg(2+)-codoped (OMC) LiF crystals are colored electrolytically at various temperatures and voltages using a pointed cathode and a flat anode. F, F2, F3(+), Mg-perturbed F and Mg-perturbed F2(+) color centers are produced simultaneously in colored OMC LiF crystals. O(2-)-Va(+), O(2-)-Mg(2+), F, F2, F3(+) and Mg-perturbed F2(+) absorption bands are observed simultaneously in absorption spectrum of colored OMC LiF crystals. O(2-)-Va(+), O(2-)-Va(+) complexes, Mg-perturbed F, F2 and F3(+) fluorescence bands are observed in fluorescence spectra of colored OMC LiF crystals. By using Mollwo-Ivey plot and fluorescence spectroscopy, a room-temperature O(2-)-Va(+) absorption band at 225nm is determined. F3(+) fluorescence of colored OMC LiF crystals is dominant as compared with F2 fluorescence with a single excitation of M-band light. Formation and conversion mechanisms of color centers are discussed. PMID- 26241831 TI - The application of continuous wavelet transform and least squares support vector machine for the simultaneous quantitative spectrophotometric determination of Myricetin, Kaempferol and Quercetin as flavonoids in pharmaceutical plants. AB - Flavonoids are gamma-benzopyrone derivatives, which are highly regarded in these researchers for their antioxidant property. In this study, two new signals processing methods been coupled with UV spectroscopy for spectral resolution and simultaneous quantitative determination of Myricetin, Kaempferol and Quercetin as flavonoids in Laurel, St. John's Wort and Green Tea without the need for any previous separation procedure. The developed methods are continuous wavelet transform (CWT) and least squares support vector machine (LS-SVM) methods integrated with UV spectroscopy individually. Different wavelet families were tested by CWT method and finally the Daubechies wavelet family (Db4) for Myricetin and the Gaussian wavelet families for Kaempferol (Gaus3) and Quercetin (Gaus7) were selected and applied for simultaneous analysis under the optimal conditions. The LS-SVM was applied to build the flavonoids prediction model based on absorption spectra. The root mean square errors for prediction (RMSEP) of Myricetin, Kaempferol and Quercetin were 0.0552, 0.0275 and 0.0374, respectively. The developed methods were validated by the analysis of the various synthetic mixtures associated with a well- known flavonoid contents. Mean recovery values of Myricetin, Kaempferol and Quercetin, in CWT method were 100.123, 100.253, 100.439 and in LS-SVM method were 99.94, 99.81 and 99.682, respectively. The results achieved by analyzing the real samples from the CWT and LS-SVM methods were compared to the HPLC reference method and the results were very close to the reference method. Meanwhile, the obtained results of the one-way ANOVA (analysis of variance) test revealed that there was no significant difference between the suggested methods. PMID- 26241832 TI - Numerical Simulations of the Digital Microfluidic Manipulation of Single Microparticles. AB - Single-cell analysis techniques have been developed as a valuable bioanalytical tool for elucidating cellular heterogeneity at genomic, proteomic, and cellular levels. Cell manipulation is an indispensable process for single-cell analysis. Digital microfluidics (DMF) is an important platform for conducting cell manipulation and single-cell analysis in a high-throughput fashion. However, the manipulation of single cells in DMF has not been quantitatively studied so far. In this article, we investigate the interaction of a single microparticle with a liquid droplet on a flat substrate using numerical simulations. The droplet is driven by capillary force generated from the wettability gradient of the substrate. Considering the Brownian motion of microparticles, we utilize many body dissipative particle dynamics (MDPD), an off-lattice mesoscopic simulation technique, in this numerical study. The manipulation processes (including pickup, transport, and drop-off) of a single microparticle with a liquid droplet are simulated. Parametric studies are conducted to investigate the effects on the manipulation processes from the droplet size, wettability gradient, wetting properties of the microparticle, and particle-substrate friction coefficients. The numerical results show that the pickup, transport, and drop-off processes can be precisely controlled by these parameters. On the basis of the numerical results, a trap-free delivery of a hydrophobic microparticle to a destination on the substrate is demonstrated in the numerical simulations. The numerical results not only provide a fundamental understanding of interactions among the microparticle, the droplet, and the substrate but also demonstrate a new technique for the trap-free immobilization of single hydrophobic microparticles in the DMF design. Finally, our numerical method also provides a powerful design and optimization tool for the manipulation of microparticles in DMF systems. PMID- 26241833 TI - A study on artificial rare earth (RE2O3) based neutron absorber. AB - A new concept of a neutron absorption material (i.e., an artificial rare earth compound) was introduced for criticality control in a spent fuel storage system. In particular, spent nuclear fuels were considered as a potential source of rare earth elements because the nuclear fission of uranium produces a full range of nuclides. It was also found that an artificial rare earth compound (RE2O3) as a High-Level Waste (HLW) was naturally extracted from pyroprocessing technology developed for recovering uranium and transuranic elements (TRU) from spent fuels. In this study, various characteristics (e.g., activity, neutron absorption cross section) were analyzed for validating the application possibility of this waste compound as a neutron absorption material. As a result, the artificial rare earth compound had a higher neutron absorption probability in the entire energy range, and it can be used for maintaining sub-criticality for more than 40 years on the basis of the neutron absorption capability of BoralTM. Therefore, this approach is expected to vastly improve the efficiency of radioactive waste management by simultaneously keeping HLW and spent nuclear fuel in a restricted space. PMID- 26241834 TI - The Act of Hospice: Understanding a Family's Perception of Palliative Care--When You're Family. PMID- 26241835 TI - Broadly available imaging devices enable high-quality low-cost photometry. AB - This paper demonstrates that, for applications in resource-limited environments, expensive microplate spectrophotometers that are used in many central laboratories for parallel measurement of absorbance of samples can be replaced by photometers based on inexpensive and ubiquitous, consumer electronic devices (e.g., scanners and cell-phone cameras). Two devices, (i) a flatbed scanner operating in transmittance mode and (ii) a camera-based photometer (constructed from a cell phone camera, a planar light source, and a cardboard box), demonstrate the concept. These devices illuminate samples in microtiter plates from one side and use the RGB-based imaging sensors of the scanner/camera to measure the light transmitted to the other side. The broadband absorbance of samples (RGB-resolved absorbance) can be calculated using the RGB color values of only three pixels per microwell. Rigorous theoretical analysis establishes a well defined relationship between the absorbance spectrum of a sample and its corresponding RGB-resolved absorbance. The linearity and precision of measurements performed with these low-cost photometers on different dyes, which absorb across the range of the visible spectrum, and chromogenic products of assays (e.g., enzymatic, ELISA) demonstrate that these low-cost photometers can be used reliably in a broad range of chemical and biochemical analyses. The ability to perform accurate measurements of absorbance on liquid samples, in parallel and at low cost, would enable testing, typically reserved for well equipped clinics and laboratories, to be performed in circumstances where resources and expertise are limited. PMID- 26241836 TI - Assessment of meat authenticity using bioinformatics, targeted peptide biomarkers and high-resolution mass spectrometry. AB - In recent years a significant increase of food fraud has been observed, ranging from false label claims to the use of additives and fillers to increase profitability. Recently in 2013 horse and pig DNAs were detected in beef products sold from several retailers. Mass spectrometry (MS) has become the workhorse in protein research, and the detection of marker proteins could serve for both animal species and tissue authentication. Meat species authenticity is performed in this paper using a well-defined proteogenomic annotation, carefully chosen surrogate tryptic peptides and analysis using a hybrid quadrupole-Orbitrap MS. Selected mammalian meat samples were homogenised and proteins were extracted and digested with trypsin. The samples were analysed using a high-resolution MS. Chromatography was achieved using a 30-min linear gradient along with a BioBasic C8 100 * 1 mm column at a flow rate of 75 ul min(-1). The MS was operated in full scan high resolution and accurate mass. MS/MS spectra were collected for selected proteotypic peptides. Muscular proteins were methodically analysed in silico in order to generate tryptic peptide mass lists and theoretical MS/MS spectra. Following a comprehensive bottom-up proteomic analysis, we detected and identified a proteotypic myoglobin tryptic peptide (120-134) for each species with observed m/z below 1.3 ppm compared with theoretical values. Moreover, proteotypic peptides from myosin-1, myosin-2 and beta-haemoglobin were also identified. This targeted method allowed comprehensive meat speciation down to 1% (w/w) of undesired product. PMID- 26241837 TI - Anaerobic digestion of microalgal bacterial flocs from a raceway pond treating aquaculture wastewater: need for a biorefinery. AB - An outdoor raceway pond with microalgal bacterial flocs (MaB-flocs) is a novel sunlight-based system to treat pikeperch aquaculture wastewater while producing biomass. The harvested MaB-floc biomass (33tonTSha(-1)y(-1)) needs further valorization. Therefore, the biochemical methane yield (BMY) of MaB-floc biomass was determined in batch experiments. The results show significant differences between the BMY of MaB-flocs amongst their harvest dates (128-226NLCH4kg(-1)VS), a low anaerobic digestion conversion efficiency (25.0-36.2%), a moderate chlorophyll a removal (51.5-86.9%) and a low biogas profit (<0.01?m( 3)wastewater). None of the pretreatment methods screened (freezing, thermal, microwave, ultrasonic and chlorination, flue gas sparging, and acid) can be recommended due to a low BMY improvement and/or unfavorable energy balance. Therefore, anaerobic digestion of this MaB-floc biomass should only be granted a supporting role within a biorefinery concept. PMID- 26241838 TI - Comprehensive utilization of glycerol from sugarcane bagasse pretreatment to fermentation. AB - In this study, the effects of glycerol pretreatment on subsequent glycerol fermentation and biomass fast pyrolysis were investigated. The liquid fraction from the pretreatment process was evaluated to be feasible for fermentation by Paenibacillus polymyxa and could be an economic substrate. The pretreated biomass was further utilized to obtain levoglucosan by fast pyrolysis. The pretreated sugarcane bagasse exhibited significantly higher levoglucosan yield (47.70%) than that of un-pretreated sample (11.25%). The promotion could likely be attributed to the effective removal of alkali and alkaline earth metals by glycerol pretreatment. This research developed an economically viable manufacturing paradigm to utilize glycerol comprehensively and enhance the formation of levoglucosan effectively from lignocellulose. PMID- 26241839 TI - Characterization of food waste-recycling wastewater as biogas feedstock. AB - A set of experiments was carried out to characterize food waste-recycling wastewater (FRW) and to investigate annual and seasonal variations in composition, which is related to the process operation in different seasons. Year round samplings (n=31) showed that FRW contained high chemical oxygen demand (COD; 148.7+/-30.5g/L) with carbohydrate (15.6%), protein (19.9%), lipid (41.6%), ethanol (14.0%), and volatile fatty acids (VFAs; 4.2%) as major constituents. FRW was partly (62%) solubilized, possibly due to partial fermentation of organics including carbohydrate. Biodegradable portions of carbohydrate and protein were estimated from acidogenesis test by first-order kinetics: 72.9+/-4.6% and 37.7+/ 0.3%, respectively. A maximum of 50% of the initial organics were converted to three major VFAs, which were acetate, propionate, and butyrate. The methane potential was estimated as 0.562L CH4/g VSfeed, accounting for 90.0% of the theoretical maximum estimated by elemental analysis. PMID- 26241840 TI - Nitrogen-removal efficiency of a novel aerobic denitrifying bacterium, Pseudomonas stutzeri strain ZF31, isolated from a drinking-water reservoir. AB - An aerobic denitrifier, identified as Pseudomonas stutzeri strain ZF31, was isolated from the Zhoucun drinking-water reservoir. Strain ZF31 removed 97% of nitrate nitrogen after 16h, without nitrite accumulation. Sequence amplification indicated the presence of the denitrification genes napA, nirS, norB, and nosZ. Nitrogen balance analysis revealed that approximately 75% of the initial nitrogen was removed as gas products. Response surface methodology (RSM) experiments showed that maximum removal of total nitrogen (TN) occurred at pH 8.23, a C/N ratio of 6.68, temperature of 27.72 degrees C, and with shaking at 54.15rpm. The TN removal rate at low C/N ratio (i.e., 3) and low temperature (i.e., 10 degrees C) was 73.30% and 60.08%, respectively. These results suggest that strain ZF31 has potential applications for the bioremediation of slightly polluted drinking water reservoirs. PMID- 26241841 TI - Synergetic deoxy reforming of cellulose and fatty acid esters for liquid hydrocarbon-rich oils. AB - A series of liquid hydrocarbons (alkylbenzenes, alkanes, and alkenes) were obtained by a synergetic deoxy reforming (SDR) process of cellulose and linoleic acid methyl ester (LAME) at 350 degrees C and 4-6MPa in a closed system without external source of hydrogen. The liquid product was obtained with a yield of 15wt% at a LAME/cellulose ratio of 0.2. In contrast, the direct deoxy reforming of cellulose produces oil that contains plenty of phenols and oxygen-containing compounds. Due to the insufficiency of water employed (30wt%), a radical reaction pathway was proposed. Quantum chemical calculations indicate that the radicals from LAME interfere with the reactions of the intermediate products from cellulose, being responsible for the removal of phenols and the formation of hydrocarbons. The SDR process offers an embryonic insight in an alternative technique for preparation of hydrocarbon fuels. PMID- 26241842 TI - High organic loading treatment for industrial molasses wastewater and microbial community shifts corresponding to system development. AB - Molasses wastewater contains high levels of organic compounds, cations, and anions, causing operational problems for anaerobic biological treatment. To establish a high organic loading treatment system for industrial molasses wastewater, this study designed a combined system comprising an acidification tank, a thermophilic multi-stage (MS)-upflow anaerobic sludge blanket (UASB) reactor, mesophilic UASB reactor, and down-flow hanging sponge reactor. The average total chemical oxygen demand (COD) and biochemical oxygen demand removal rates were 85%+/-3% and 95%+/-2%, respectively, at an organic loading rate of 42kgCODcrm(-3)d(-1) in the MS-UASB reactor. By installation of the acidification tank, the MS-UASB reactor achieved low H2-partial pressure. The abundance of syntrophs such as fatty acid-degrading bacteria increased in the MS-UASB and 2nd UASB reactors. Thus, the acidification tank contributed to maintaining a favorable environment for syntrophic associations. This study provides new information regarding microbial community composition in a molasses wastewater treatment system. PMID- 26241843 TI - Determination of dechlorane flame retardants in soil and fish at Guiyu, an electronic waste recycling site in south China. AB - Dechlorane 602 (Dec 602), Dechlorane 603 (Dec 603), Dechlorane 604 (Dec 604), Dechlorane 604 component B (Dec 604 CB) and Dechlorane Plus (DP) were analyzed in soil and fish collected across e-waste recycling sites in Guiyu. The results indicate that soil and fish are contaminated with dechlorane compounds especially Dec 602 and DP which show high concentrations in the samples near recycling sites. Dec 604 and Dec 604 CB are not detected. The photo-degradation experiment indicates that Dec 604 and Dec 604 CB have much faster degradation rates compared to other dechloranes, suggesting they might be more vulnerable to degradation during recycling processes and further studies are needed for assessing the environmental fate and persistence of their degradation products. Dec 602 has not been manufactured in China, the detection of Dec 602 in soil and fish implies that it might be from imports of recyclable materials from developed countries. PMID- 26241844 TI - Hematopoietic progenitors are required for proper development of coronary vasculature. AB - RATIONALE: During embryogenesis, hematopoietic cells appear in the myocardium prior to the initiation of coronary formation. However, their role is unknown. OBJECTIVE: Here we investigate whether pre-existing hematopoietic cells are required for the formation of coronary vasculature. METHODS AND RESULTS: As a model of for hematopoietic cell deficient animals, we used Runx1 knockout embryos and Vav1-cre; R26-DTA embryos, latter of which genetically ablates 2/3 of CD45(+) hematopoietic cells. Both Runx1 knockout embryos and Vav1-cre; R26-DTA embryos revealed disorganized, hypoplastic microvasculature of coronary vessels on section and whole-mount stainings. Furthermore, coronary explant experiments showed that the mouse heart explants from Runx1 and Vav1-cre; R26-DTA embryos exhibited impaired coronary formation ex vivo. Interestingly, in both models it appears that epicardial to mesenchymal transition is adversely affected in the absence of hematopoietic progenitors. CONCLUSION: Hematopoietic cells are not merely passively transported via coronary vessel, but substantially involved in the induction of the coronary growth. Our findings suggest a novel mechanism of coronary growth. PMID- 26241845 TI - STIM1 elevation in the heart results in aberrant Ca2+ handling and cardiomyopathy. AB - Stromal interaction molecule 1 (STIM1) is a Ca(2+) sensor that partners with Orai1 to elicit Ca(2+) entry in response to endoplasmic reticulum (ER) Ca(2+) store depletion. While store-operated Ca(2+) entry (SOCE) is important for maintaining ER Ca(2+) homeostasis in non-excitable cells, it is unclear what role it plays in the heart, although STIM1 is expressed in the heart and upregulated during disease. Here we analyzed transgenic mice with STIM1 overexpression in the heart to model the known increase of this protein in response to disease. As expected, STIM1 transgenic myocytes showed enhanced Ca(2+) entry following store depletion and partial co-localization with the type 2 ryanodine receptor (RyR2) within the sarcoplasmic reticulum (SR), as well as enrichment around the sarcolemma. STIM1 transgenic mice exhibited sudden cardiac death as early as 6weeks of age, while mice surviving past 12weeks of age developed heart failure with hypertrophy, induction of the fetal gene program, histopathology and mitochondrial structural alterations, loss of ventricular functional performance and pulmonary edema. Younger, pre-symptomatic STIM1 transgenic mice exhibited enhanced pathology following pressure overload stimulation or neurohumoral agonist infusion, compared to controls. Mechanistically, cardiac myocytes isolated from STIM1 transgenic mice displayed spontaneous Ca(2+) transients that were prevented by the SOCE blocker SKF-96365, increased L-type Ca(2+) channel (LTCC) current, and enhanced Ca(2+) spark frequency. Moreover, adult cardiac myocytes from STIM1 transgenic mice showed both increased diastolic Ca(2+) and maximal transient amplitude but no increase in total SR Ca(2+) load. Associated with this enhanced Ca(2+) profile was an increase in cardiac nuclear factor of activated T-cells (NFAT) and Ca(2+)/calmodulin-dependent kinase II (CaMKII) activity. We conclude that STIM1 has an unexpected function in the heart where it alters communication between the sarcolemma and SR resulting in greater Ca(2+) flux and a leaky SR compartment. PMID- 26241846 TI - Real-time relationship between PKA biochemical signal network dynamics and increased action potential firing rate in heart pacemaker cells: Kinetics of PKA activation in heart pacemaker cells. AB - cAMP-PKA protein kinase is a key nodal signaling pathway that regulates a wide range of heart pacemaker cell functions. These functions are predicted to be involved in regulation of spontaneous action potential (AP) generation of these cells. Here we investigate if the kinetics and stoichiometry of increase in PKA activity match the increase in AP firing rate in response to beta-adrenergic receptor (beta-AR) stimulation or phosphodiesterase (PDE) inhibition, that alters the AP firing rate of heart sinoatrial pacemaker cells. In cultured adult rabbit pacemaker cells infected with an adenovirus expressing the FRET sensor AKAR3, the EC50 in response to graded increases in the intensity of beta-AR stimulation (by Isoproterenol) the magnitude of the increases in PKA activity and the spontaneous AP firing rate were similar (0.4+/-0.1nM vs. 0.6+/-0.15nM, respectively). Moreover, the kinetics (t1/2) of the increases in PKA activity and spontaneous AP firing rate in response to beta-AR stimulation or PDE inhibition were tightly linked. We characterized the system rate-limiting biochemical reactions by integrating these experimentally derived data into a mechanistic-computational model. Model simulations predicted that phospholamban phosphorylation is a potent target of the increase in PKA activity that links to increase in spontaneous AP firing rate. In summary, the kinetics and stoichiometry of increases in PKA activity in response to a physiological (beta-AR stimulation) or pharmacological (PDE inhibitor) stimuli match those of changes in the AP firing rate. Thus Ca(2+) cAMP/PKA-dependent phosphorylation limits the rate and magnitude of increase in spontaneous AP firing rate. PMID- 26241847 TI - Atrial-selective targeting of arrhythmogenic phase-3 early afterdepolarizations in human myocytes. AB - BACKGROUND: We have previously shown that non-equilibrium Na(+) current (INa) reactivation drives isoproterenol-induced phase-3 early afterdepolarizations (EADs) in mouse ventricular myocytes. In these cells, EAD initiation occurs secondary to potentiated sarcoplasmic reticulum Ca(2+) release and enhanced Na(+)/Ca(2+) exchange (NCX). This can be abolished by tetrodotoxin-blockade of INa, but not ranolazine, which selectively inhibits ventricular late INa. AIM: Since repolarization of human atrial myocytes is similar to mouse ventricular myocytes in that it is relatively rapid and potently modulated by Ca(2+), we investigated whether similar mechanisms can evoke EADs in human atrium. Indeed, phase-3 EADs have been shown to re-initiate atrial fibrillation (AF) during autonomic stimulation, which is a well-recognized initiator of AF. METHODS: We integrated a Markov model of INa gating in our human atrial myocyte model. To simulate experimental results, we rapidly paced this cell model at 10Hz in the presence of 0.1MUM acetylcholine and 1MUM isoproterenol, and assessed EAD occurrence upon return to sinus rhythm (1Hz). RESULTS: Cellular Ca(2+) loading during fast pacing results in a transient period of hypercontractility after return to sinus rhythm. Here, fast repolarization and enhanced NCX facilitate INa reactivation via the canonical gating mode (i.e., not late INa burst mode), which drives EAD initiation. Simulating ranolazine administration reduces atrial peak INa and leads to faster repolarization, during which INa fails to reactivate and EADs are prevented. CONCLUSIONS: Non-equilibrium INa reactivation can critically contribute to arrhythmias, specifically in human atrial myocytes. Ranolazine might be beneficial in this context by blocking peak (not late) atrial INa. PMID- 26241848 TI - Presence of Cleaved Synaptosomal-Associated Protein-25 and Decrease of Purinergic Receptors P2X3 in the Bladder Urothelium Influence Efficacy of Botulinum Toxin Treatment for Overactive Bladder Syndrome. AB - OBJECTIVES: To evaluate whether botulinum toxin A (BoNT-A) injection and Lipotoxin (liposomes with 200 U of BoNT-A) instillation target different proteins, including P2X3, synaptic vesicle glycoprotein 2A, and SNAP-25, in the bladder mucosa, leading to different treatment outcomes. MATERIALS AND METHODS: This was a retrospective study performed in a tertiary teaching hospital. We evaluated the clinical results of 27 OAB patients treated with intravesical BoNT A injection (n = 16) or Lipotoxin instillation (n = 11). Seven controls were treated with saline. Patients were injected with 100 U of BoNT-A or Lipotoxinin a single intravesical instillation. The patients enrolled in this study all had bladder biopsies performed at baseline and one month after BoNT-A therapy. Treatment outcome was measured by the decreases in urgency and frequency episodes at 1 month. The functional protein expressions in the urothelium were measured at baseline and after 1 month. The Wilcoxon signed-rank test and ordinal logistic regression were used to compare the treatment outcomes. RESULTS: Both BoNT-A injection and Lipotoxin instillation treatments effectively decreased the frequency of urgency episodes in OAB patients. Lipotoxin instillation did not increase post-void residual volume. BoNT-A injection effectively cleaved SNAP-25 (p < 0.01). Liposome encapsulated BoNT-A decreased urothelial P2X3 expression in the five responders (p = 0.04), while SNAP-25 was not significantly cleaved. CONCLUSIONS: The results of this study provide a possible mechanism for the therapeutic effects of BoNT-A for the treatment of OAB via different treatment forms. BoNT-A and Lipotoxin treatments effectively decreased the frequency of urgency episodes in patients with OAB. PMID- 26241849 TI - A Highly Stereocontrolled, One-Pot Approach toward Pyrrolobenzoxazinones and Pyrroloquinazolinones through a Lewis Acid-Catalyzed [3 + 2]-Cycloannulation Process. AB - We report herein a stereocontrolled [3 + 2]-cycloheteroannulation of bis-silyl dienediolate 1 with 2-aminobenzoic acid- and 2-aminobenzamide-derived imines to furnish highly substituted pyrrolo[1,2-a]benzoxazinones 3 and pyrrolo[1,2 a]quinazolinones 4, respectively, in good overall yields. This one-pot process rapidly generates molecular complexity and comprises a Lewis acid-catalyzed, vinylogous Mannich reaction of 1 followed by an intramolecular N,O-acetal- and N,N-aminal formation, respectively, which proceeds with good to excellent stereocontrol. PMID- 26241850 TI - Pain Processing after Social Exclusion and Its Relation to Rejection Sensitivity in Borderline Personality Disorder. AB - OBJECTIVE: There is a general agreement that physical pain serves as an alarm signal for the prevention of and reaction to physical harm. It has recently been hypothesized that "social pain," as induced by social rejection or abandonment, may rely on comparable, phylogenetically old brain structures. As plausible as this theory may sound, scientific evidence for this idea is sparse. This study therefore attempts to link both types of pain directly. We studied patients with borderline personality disorder (BPD) because BPD is characterized by opposing alterations in physical and social pain; hyposensitivity to physical pain is associated with hypersensitivity to social pain, as indicated by an enhanced rejection sensitivity. METHOD: Twenty unmedicated female BPD patients and 20 healthy participants (HC, matched for age and education) played a virtual ball tossing game (cyberball), with the conditions for exclusion, inclusion, and a control condition with predefined game rules. Each cyberball block was followed by a temperature stimulus (with a subjective pain intensity of 60% in half the cases). The cerebral responses were measured by functional magnetic resonance imaging. The Adult Rejection Sensitivity Questionnaire was used to assess rejection sensitivity. RESULTS: Higher temperature heat stimuli had to be applied to BPD patients relative to HCs to reach a comparable subjective experience of painfulness in both groups, which suggested a general hyposensitivity to pain in BPD patients. Social exclusion led to a subjectively reported hypersensitivity to physical pain in both groups that was accompanied by an enhanced activation in the anterior insula and the thalamus. In BPD, physical pain processing after exclusion was additionally linked to enhanced posterior insula activation. After inclusion, BPD patients showed reduced amygdala activation during pain in comparison with HC. In BPD patients, higher rejection sensitivity was associated with lower activation differences during pain processing following social exclusion and inclusion in the insula and in the amygdala. DISCUSSION: Despite the similar behavioral effects in both groups, BPD patients differed from HC in their neural processing of physical pain depending on the preceding social situation. Rejection sensitivity further modulated the impact of social exclusion on neural pain processing in BPD, but not in healthy controls. PMID- 26241851 TI - Bacillus cereus ATCC 14579 RpoN (Sigma 54) Is a Pleiotropic Regulator of Growth, Carbohydrate Metabolism, Motility, Biofilm Formation and Toxin Production. AB - Sigma 54 is a transcriptional regulator predicted to play a role in physical interaction of bacteria with their environment, including virulence and biofilm formation. In order to study the role of Sigma 54 in Bacillus cereus, a comparative transcriptome and phenotypic study was performed using B. cereus ATCC 14579 WT, a markerless rpoN deletion mutant, and its complemented strain. The mutant was impaired in many different cellular functions including low temperature and anaerobic growth, carbohydrate metabolism, sporulation and toxin production. Additionally, the mutant showed lack of motility and biofilm formation at air-liquid interphase, and this correlated with absence of flagella, as flagella staining showed only WT and complemented strain to be highly flagellated. Comparative transcriptome analysis of cells harvested at selected time points during growth in aerated and static conditions in BHI revealed large differences in gene expression associated with loss of phenotypes, including significant down regulation of genes in the mutant encoding enzymes involved in degradation of branched chain amino acids, carbohydrate transport and metabolism, flagella synthesis and virulence factors. Our study provides evidence for a pleiotropic role of Sigma 54 in B. cereus supporting its adaptive response and survival in a range of conditions and environments. PMID- 26241852 TI - Comparison of Outcomes and Costs of Ranibizumab and Aflibercept Treatment in Real Life. AB - BACKGROUND: Treatment efficacy and costs of anti-VEGF drugs have not been studied in clinical routine. OBJECTIVE: To compare treatment costs and clinical outcomes of the medications when adjusting for patients' characteristics and clinical status. DESIGN: Comparative study. SETTING: The largest public ophthalmologic clinic in Switzerland. PATIENTS: Health care claims data of patients with age related macular degeneration, diabetic macula edema and retinal vein occlusion were matched to clinical and outcome data. MEASUREMENTS: Patients' underlying condition, gender, age, visual acuity and retinal thickness at baseline and after completing the loading phase, the total number of injections per treatment, the visual outcome and vital status was secured. RESULTS: We included 315 patients (19595 claims) with a follow-up time of 1 to 99 months (mean 32.7, SD 25.8) covering the years 2006-2014. Mean age was 78 years (SD 9.3) and 200 (63.5%) were female. At baseline, the mean number of letters was 55.6 (SD 16.3) and the central retinal thickness was 400.1 MUm (SD 110.1). Patients received a mean number of 15.1 injections (SD 13.7; range 1 to 85). Compared to AMD, adjusted cost per month were significantly higher (+2174.88 CHF, 95%CI: 1094.50-3255.27; p<0.001) for patients with DME, while cost per month for RVO were slightly but not significantly higher. (+284.71 CHF, 95% CI: -866.73-1436.15; p = 0.627). CONCLUSIONS: Patients with DME are almost twice as expensive as AMD and RVO patients. Cost excess occurs with non-ophthalmologic interventions. The currently licensed anti-VEGF medications did not differ in costs, injection frequency and clinical outcomes. Linking health care claims to clinical data is a useful tool to examine routine clinical care. PMID- 26241853 TI - Identification of Candidate Coral Pathogens on White Band Disease-Infected Staghorn Coral. AB - Bacterial diseases affecting scleractinian corals pose an enormous threat to the health of coral reefs, yet we still have a limited understanding of the bacteria associated with coral diseases. White band disease is a bacterial disease that affects the two Caribbean acroporid corals, the staghorn coral Acropora cervicornis and the elkhorn coral A. palmate. Species of Vibrio and Rickettsia have both been identified as putative WBD pathogens. Here we used Illumina 16S rRNA gene sequencing to profile the bacterial communities associated with healthy and diseased A. cervicornis collected from four field sites during two different years. We also exposed corals in tanks to diseased and healthy (control) homogenates to reduce some of the natural variation of field-collected coral bacterial communities. Using a combination of multivariate analyses, we identified community-level changes between diseased and healthy corals in both the field-collected and tank-exposed datasets. We then identified changes in the abundances of individual operational taxonomic units (OTUs) between diseased and healthy corals. By comparing the diseased and healthy-associated bacteria in field-collected and tank-exposed corals, we were able to identify 16 healthy associated OTUs and 106 consistently disease-associated OTUs, which are good candidates for putative WBD pathogens. A large percentage of these disease associated OTUs belonged to the order Flavobacteriales. In addition, two of the putative pathogens identified here belong to orders previously suggested as WBD pathogens: Vibronales and Rickettsiales. PMID- 26241854 TI - Survival and HLA-B*57 in HIV/HCV Co-Infected Patients on Highly Active Antiretroviral Therapy (HAART). AB - BACKGROUND AND AIMS: HLA class I alleles, in particular HLA-B*57, constitute the most consistent host factor determining outcomes in untreated HCV- and HIV infection. In this prospective cohort study, we analysed the impact of HLA class I alleles on all-cause mortality in patients with HIV-, HCV- and HIV/HCV- co infection receiving HAART. METHODS: In 2003 HLA-A and B alleles were determined and patients were prospectively followed in 3-month intervals until 2013 or death. HLA-A and B alleles were determined by strand-specific oligonucleotide hybridisation and PCR in 468 Caucasian patients with HCV- (n=120), HIV- (n=186) and HIV/HCV-infection (n=162). All patients with HIV-infection were on HAART. In each patient group, HLA class I-associated survival was analysed by Kaplan-Meier method and Cox regression analysis. RESULTS: At recruitment the proportion of patients carrying a HLA-B*57 allele differed between HIV- (12.9%) and HCV infection (4.2%). Kaplan Meier analysis revealed significantly increased mortality in HLA-B*57-positive patients with HIV-infection (p=0.032) and HIV/HCV co-infection (p=0.004), which was apparently linked to non-viral infections. Cox logistic regression analysis confirmed HLA-B*57 (p=0.001), serum gamma glutamyltranspeptidase (p=0.003), serum bilirubin (p=0.022) and CD4 counts (p=0.041) as independent predictors of death in HIV-infected patients. CONCLUSION: Differences in the prevalence of HLA-B*57 at study entry between HIV- and HCV- infected patients may reflect immune selection in the absence of antiviral therapy. When patients were treated with HAART, however, HLA-B*57 was associated with increased mortality and risk to die from bacterial infections and sepsis, suggesting an ambiguous role of HLA-B*57 for survival in HIV/HCV infection depending on the circumstances. PMID- 26241855 TI - In Vitro Maturation in Women with vs. without Polycystic Ovarian Syndrome: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To evaluate in vitro maturation (IVM) in sub-fertile women with polycystic ovarian syndrome (PCOS) undergoing in vitro fertilisation (IVF), by comparing outcomes with a control group of non-PCOS. STUDY DESIGN: A search strategy was developed for PubMed and studies reporting rates of the following outcomes (live birth; clinical pregnancy; implantation; cycle cancellation; oocyte maturation; oocyte fertilization; miscarriage) between patients with PCOS, PCO and controls undergoing IVM were deemed eligible. The review was conducted in accordance to the PRISMA guidelines and included studies quality was assessed through the Newcastle-Ottawa Quality scale. ORs with their corresponding 95% CIs were calculated for the main analysis and subgroup analyses were performed for PCOS cases vs. controls and PCOS vs. PCO cases. Alternative analyses were performed for live birth and clinical pregnancy, based on cycles and on women. Subgroup analyses for FSH stimulation, hCG priming and type of procedure (IVF/ICSI) were undertaken for all meta-analyses encompassing at least four study arms. Random effects models were used to calculate pooled effect estimates. RESULTS: Eleven studies were identified. A total of 268 PCOS patients (328 cycles), 100 PCO patients (110 cycles) and 440 controls (480 cycles) were included in the meta-analysis. A borderline trend towards higher birth rates among PCOS patients emerged (pooled OR = 1.74, 95%CI: 0.99-3.04) mainly reflected at the subgroup analysis vs. controls. Clinical pregnancy (pooled OR = 2.37, 95%CI: 1.53-3.68) and implantation rates (pooled OR = 1.73, 95%CI: 1.06-2.81) were higher, while cancellation rates lower (pooled OR = 0.18, 95%CI: 0.06-0.47) among PCOS vs. non-PCOS subjects; maturation and miscarriage rates did not differ between groups, while a borderline trend towards lower fertilization rates among PCOS patients was observed. CONCLUSION: The present meta-analysis provides preliminary evidence on the effectiveness of IVM as a treatment option when offered in sub-fertile PCOS women, as the latter present at least as high outcome rates as those in non-PCOS. PMID- 26241856 TI - Novel Bread Wheat Lines Enriched in Carotenoids Carrying Hordeum chilense Chromosome Arms in the ph1b Background. AB - The use of crop wild relative species to improve major crops performance is well established. Hordeum chilense has a high potential as a genetic donor to increase the carotenoid content of wheat. Crosses between the 7Hch H. chilense substitution lines in wheat and the wheat pairing homoeologous1b (ph1b) mutant allowed the development of wheat-H. chilense translocation lines for both 7Hchalpha and 7Hchbeta chromosome arms in the wheat background. These translocation lines were characterized by in situ hybridization and using molecular markers. In addition, reverse phase chromatography (HPLC) analysis was carried out to evaluate the carotenoid content and both 7Hchalpha?7AL and 7AS?7Hchbeta disomic translocation lines. The carotenoid content in 7Hchalpha?7AL and 7AS?7Hchbeta disomic translocation lines was higher than the wheat-7Hch addition line and double amount of carotenoids than the wheat itself. A proteomic analysis confirmed that the presence of chromosome 7Hch introgressions in wheat scarcely altered the proteomic profile of the wheat flour. The Psy1 (Phytoene Synthase1) gene, which is the first committed step in the carotenoid biosynthetic pathway, was also cytogenetically mapped on the 7Hchalpha chromosome arm. These new wheat-H. chilense translocation lines can be used as a powerful tool in wheat breeding programs to enrich the diet in bioactive compounds. PMID- 26241857 TI - Early Developmental and Evolutionary Origins of Gene Body DNA Methylation Patterns in Mammalian Placentas. AB - Over the last 20-80 million years the mammalian placenta has taken on a variety of morphologies through both divergent and convergent evolution. Recently we have shown that the human placenta genome has a unique epigenetic pattern of large partially methylated domains (PMDs) and highly methylated domains (HMDs) with gene body DNA methylation positively correlating with level of gene expression. In order to determine the evolutionary conservation of DNA methylation patterns and transcriptional regulatory programs in the placenta, we performed a genome wide methylome (MethylC-seq) analysis of human, rhesus macaque, squirrel monkey, mouse, dog, horse, and cow placentas as well as opossum extraembryonic membrane. We found that, similar to human placenta, mammalian placentas and opossum extraembryonic membrane have globally lower levels of methylation compared to somatic tissues. Higher relative gene body methylation was the conserved feature across all mammalian placentas, despite differences in PMD/HMDs and absolute methylation levels. Specifically, higher methylation over the bodies of genes involved in mitosis, vesicle-mediated transport, protein phosphorylation, and chromatin modification was observed compared with the rest of the genome. As in human placenta, higher methylation is associated with higher gene expression and is predictive of genic location across species. Analysis of DNA methylation in oocytes and preimplantation embryos shows a conserved pattern of gene body methylation similar to the placenta. Intriguingly, mouse and cow oocytes and mouse early embryos have PMD/HMDs but their placentas do not, suggesting that PMD/HMDs are a feature of early preimplantation methylation patterns that become lost during placental development in some species and following implantation of the embryo. PMID- 26241858 TI - Genome-Wide Analysis of Hypoxia-Responsive Genes in the Rice Blast Fungus, Magnaporthe oryzae. AB - Rice blast fungus, Magnaporthe oryzae, is the most destructive pathogen in the rice-growing area. This fungus has a biotrophic phase early in infection and later switches to a necrotrophic lifestyle. During the biotrophic phase, the fungus competes with its host for nutrients and oxygen. Continuous uptake of oxygen is essential for successful establishment of blast disease of this pathogen. Here, we report transcriptional responses of the fungus to oxygen limitation. Transcriptome analysis using RNA-Seq identified that 1,047 genes were up-regulated in response to hypoxia. Those genes are involved in mycelial development, sterol biosynthesis, and metal ion transport based on hierarchical GO terms, and are well-conserved among three fungal species. In addition, null mutants of two hypoxia-responsive genes were generated and their roles in fungal development and pathogenicity tested. The mutant for the sterol regulatory element-binding protein gene, MoSRE1, exhibited increased sensitivity to a hypoxia-mimicking agent, increased conidiation, and delayed invasive growth within host cells, which is suggestive of important roles in fungal development. However, such defects did not cause any significant decrease in disease severity. The other null mutant, for the alcohol dehydrogenase gene MoADH1, showed no defect in the hypoxia-mimicking condition (using cobalt chloride) and fungal development. Taken together, this comprehensive transcriptional profiling in response to a hypoxic condition with experimental validations would provide new insights into fungal development and pathogenicity in plant pathogenic fungi. PMID- 26241859 TI - Neurological and cerebellar soft signs do not discriminate schizophrenia from bipolar disorder patients. AB - Patients with schizophrenia (SZ) and bipolar disorder (BD) share subtle motor abnormalities called the neurological soft signs (NSS). Since in both diseases there is evidence for alterations in cerebellar functions, structure and connectivity, we expected that the cerebellar soft signs (CSS), analogue of NSS focusing strictly on cerebellar symptoms, would be also a common trait in SZ and BD. We examined 30 patients with BD, 30 patients with SZ and 28 control subjects using the Neurological Evaluation Scale (NES, for NSS) and International Cooperative Ataxia Rating Scale (ICARS, for CSS). SZ and BD did not differ in total and subscales' scores in both NES and ICARS. Subscale analysis revealed that SZ performed significantly worse than controls in all the subscales of both NES and ICARS. BD patients scored significantly worse than controls in all NES subscales and in oculomotor and kinetic subscales of the ICARS, while other ICARS subscales did not differentiate those two groups. To our knowledge this is the first study to show that CSS constitute common symptoms in BD and SZ. We recommend a special focus on those diseases in further research regarding structural and functional changes of cerebellum and their clinical outcome. PMID- 26241860 TI - The Two-Phase Emergence of Non Pandemic HIV-1 Group O in Cameroon. AB - Unlike the pandemic form of HIV-1 (group M), group O viruses are endemic in west central Africa, especially in Cameroon. However, little is known about group O's genetic evolution, and why this highly divergent lineage has not become pandemic. Using a unique and large set of group O sequences from samples collected from 1987 to 2012, we find that this lineage has evolved in successive slow and fast phases of diversification, with a most recent common ancestor estimated to have existed around 1930 (1914-1944). The most rapid periods of diversification occurred in the 1950s and in the 1980s, and could be linked to favourable epidemiological contexts in Cameroon. Group O genetic diversity reflects this two phase evolution, with two distinct populations potentially having different viral properties. The currently predominant viral population emerged in the 1980s, from an ancient population which had first developed in the 1950s, and is characterized by higher growth and evolutionary rates, and the natural presence of the Y181C resistance mutation, thought to confer a phenotypic advantage. Our findings show that although this evolutionary pattern is specific to HIV-1 group O, it paralleled the early spread of HIV-1 group M in the Democratic Republic of Congo. Both viral lineages are likely to have benefited from similar epidemiological contexts. The relative role of virological and social factors in the distinct epidemic histories of HIV-1 group O and M needs to be reassessed. PMID- 26241862 TI - Interspecific Associations between Cycloneda sanguinea and Two Aphid Species (Aphis gossypii and Hyadaphis foeniculi) in Sole-Crop and Fennel-Cotton Intercropping Systems. AB - Aphids cause significant damage to crop plants. Studies regarding predator-prey relationships in fennel (Foeniculum vulgare Mill.) and cotton (Gossypium hirsutum L.) crops are important for understanding essential ecological interactions in the context of intercropping and for establishing pest management programs for aphids. This study evaluated the association among Hyadaphis foeniculi (Passerini) (Hemiptera: Aphididae), Aphis gossypii Glover (Hemiptera: Aphididae) and Cycloneda sanguinea (L.) (Coleoptera: Coccinellidae) in cotton with coloured fibres, fennel and cotton intercropped with fennel. Association analysis was used to investigate whether the presence or absence of prey and predator species can indicate possible interactions between aphids and ladybugs. Significant associations among both apterous and alate H. foeniculi and C. sanguinea were observed in both the fennel and fennel-cotton intercropping systems. The similarity analysis showed that the presence of aphids and ladybugs in the same system is significantly dependent on the type of crop. A substantial amount of evidence indicates that the presence of the ladybug C. sanguinea, is associated with apterous or alate A. gossypii and H. foeniculi in fennel-cotton intercropping system. We recommend that future research vising integrated aphid management taking into account these associations for take decisions. PMID- 26241861 TI - Optimisations and Challenges Involved in the Creation of Various Bioluminescent and Fluorescent Influenza A Virus Strains for In Vitro and In Vivo Applications. AB - Bioluminescent and fluorescent influenza A viruses offer new opportunities to study influenza virus replication, tropism and pathogenesis. To date, several influenza A reporter viruses have been described. These strategies typically focused on a single reporter gene (either bioluminescent or fluorescent) in a single virus backbone. However, whilst bioluminescence is suited to in vivo imaging, fluorescent viruses are more appropriate for microscopy. Therefore, the idea l reporter virus varies depending on the experiment in question, and it is important that any reporter virus strategy can be adapted accordingly. Herein, a strategy was developed to create five different reporter viruses in a single virus backbone. Specifically, enhanced green fluorescent protein (eGFP), far-red fluorescent protein (fRFP), near-infrared fluorescent protein (iRFP), Gaussia luciferase (gLUC) and firefly luciferase (fLUC) were inserted into the PA gene segment of A/PR/8/34 (H1N1). This study provides a comprehensive characterisation of the effects of different reporter genes on influenza virus replication and reporter activity. In vivo reporter gene expression, in lung tissues, was only detected for eGFP, fRFP and gLUC expressing viruses. In vitro, the eGFP expressing virus displayed the best reporter stability and could be used for correlative light electron microscopy (CLEM). This strategy was then used to create eGFP-expressing viruses consisting entirely of pandemic H1N1, highly pathogenic avian influenza (HPAI) H5N1 and H7N9. The HPAI H5N1 eGFP-expressing virus infected mice and reporter gene expression was detected, in lung tissues, in vivo. Thus, this study provides new tools and insights for the creation of bioluminescent and fluorescent influenza A reporter viruses. PMID- 26241863 TI - Modifications of RNA polymerase II CTD: Connections to the histone code and cellular function. AB - At the onset of transcription, many protein machineries interpret the cellular signals that regulate gene expression. These complex signals are mostly transmitted to the indispensable primary proteins involved in transcription, RNA polymerase II (RNAPII) and histones. RNAPII and histones are so well coordinated in this cellular function that each cellular signal is precisely allocated to specific machinery depending on the stage of transcription. The carboxy-terminal domain (CTD) of RNAPII in eukaryotes undergoes extensive posttranslational modification, called the 'CTD code', that is indispensable for coupling transcription with many cellular processes, including mRNA processing. The posttranslational modification of histones, known as the 'histone code', is also critical for gene transcription through the reversible and dynamic remodeling of chromatin structure. Notably, the histone code is closely linked with the CTD code, and their combinatorial effects enable the delicate regulation of gene transcription. This review elucidates recent findings regarding the CTD modifications of RNAPII and their coordination with the histone code, providing integrative pathways for the fine-tuned regulation of gene expression and cellular function. PMID- 26241864 TI - A Murine Hypertrophic Cardiomyopathy Model: The DBA/2J Strain. AB - Familial hypertrophic cardiomyopathy (HCM) is attributed to mutations in genes that encode for the sarcomere proteins, especially Mybpc3 and Myh7. Genotype phenotype correlation studies show significant variability in HCM phenotypes among affected individuals with identical causal mutations. Morphological changes and clinical expression of HCM are the result of interactions with modifier genes. With the exceptions of angiotensin converting enzyme, these modifiers have not been identified. Although mouse models have been used to investigate the genetics of many complex diseases, natural murine models for HCM are still lacking. In this study we show that the DBA/2J (D2) strain of mouse has sequence variants in Mybpc3 and Myh7, relative to widely used C57BL/6J (B6) reference strain and the key features of human HCM. Four-month-old of male D2 mice exhibit hallmarks of HCM including increased heart weight and cardiomyocyte size relative to B6 mice, as well as elevated markers for cardiac hypertrophy including beta myosin heavy chain (MHC), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and skeletal muscle alpha actin (alpha1-actin). Furthermore, cardiac interstitial fibrosis, another feature of HCM, is also evident in the D2 strain, and is accompanied by up-regulation of type I collagen and alpha-smooth muscle actin (SMA)-markers of fibrosis. Of great interest, blood pressure and cardiac function are within the normal range in the D2 strain, demonstrating that cardiac hypertrophy and fibrosis are not secondary to hypertension, myocardial infarction, or heart failure. Because D2 and B6 strains have been used to generate a large family of recombinant inbred strains, the BXD cohort, the D2 model can be effectively exploited for in-depth genetic analysis of HCM susceptibility and modifier screens. PMID- 26241865 TI - Plasma levels of soluble TNF receptors 1 and 2 after tDCS and sertraline treatment in major depression: Results from the SELECT-TDCS trial. AB - BACKGROUND: The cytokine hypothesis of depression postulates that the pathophysiology of this illness incorporates an increased production of pro inflammatory cytokines, which leads to an over-activation of the hypothalamic pituitary-adrenal axis as well as monoaminergic disturbances. Nevertheless, it remains unclear whether the amelioration of depressive symptoms could decrease cytokine levels. Notwithstanding antidepressant drug therapy might exert anti inflammatory effects, the effects of non-invasive neuromodulatory approaches like transcranial direct current stimulation (tDCS) on pro-inflammatory cytokine networks are largely unknown. METHODS: We evaluated, in the Sertraline vs. Electric Current Therapy for Treating Depression Clinical Study (SELECT-TDCS) trial, whether the plasma levels of the soluble TNF receptors 1 and 2 (sTNFRs) changed after antidepressant treatment in a sample of 73 antidepressant-free patients with unipolar depressive disorder in an episode of at least moderate intensity. RESULTS: Although both tDCS and sertraline exerted antidepressant effects, the plasma levels of sTNFRs did not change over time regardless of the intervention and clinical response. Also, baseline sTNFRs levels did not predict antidepressant response. LIMITATIONS: Our negative findings could be a type II error, as this trial did not use an equivalence design. CONCLUSIONS: To conclude, in this novel placebo-controlled trial prospectively evaluating the changes of sTNFRs in depressed patients, we found that these molecules are not surrogate biomarkers of treatment response of tDCS, whose antidepressant effects occurred regardless of normalization of immunological activity. PMID- 26241866 TI - Evaluation of affective temperament and anxiety-depression levels of patients with polycystic ovary syndrome. AB - BACKGROUND: Women with polycystic ovary syndrome (PCOS) are reported to experience depressive episodes at a higher rate than healthy controls (HC). Affective temperament features are psychiatric markers that may help to predict and identify vulnerability to depression in women with PCOS. Our aim was to evaluate the affective temperaments of women with PCOS and to investigate the association with depression and anxiety levels and laboratory variables in comparison with HC. METHODS: The study included 71 women with PCOS and 50 HC. Hormonal evaluations were performed for women with PCOS. Physical examination, clinical history, Hospital Anxiety and Depression Scale (HADS) and TEMPS-A were performed for all subjects. Differences between groups were evaluated using Student's t-tests and Mann-Whitney U tests. Correlations and logistic regression tests were performed. RESULTS: All temperament subtype scores, except hyperthymic, and HADS anxiety, depression, and total scores were significantly higher in patients with PCOS compared to HC. A statistically significant positive correlation was found between BMI and irritable temperament, and insulin and HADS depression scores in patients with PCOS. Additionally, hirsutism score and menstrual irregularity were correlated with HADS depression, anxiety and total scores in PCOS patients. In logistic regression analysis, depression was not affected by PCOS, hirsutism score or menstrual irregularity. However, HADS anxiety score was associated with hirsutism score. CONCLUSIONS: Our study is the first to evaluate the affective temperament features of women with PCOS. Consequently, establishing affective temperament properties for women with PCOS may help clinicians predict those patients with PCOS who are at risk for depressive and anxiety disorders. PMID- 26241867 TI - The bipolarity of light and dark: A review on Bipolar Disorder and circadian cycles. AB - BACKGROUND: Bipolar Disorder is characterized by episodes running the full mood spectrum, from mania to depression. Between mood episodes, residual symptoms remain, as sleep alterations, circadian cycle disturbances, emotional deregulation, cognitive impairment and increased risk for comorbidities. The present review intends to reflect about the most recent and relevant information concerning the biunivocal relation between bipolar disorder and circadian cycles. METHODS: It was conducted a literature search on PubMed database using the search terms "bipolar", "circadian", "melatonin", "cortisol", "body temperature", "Clock gene", "Bmal1 gene", "Per gene", "Cry gene", "GSK3beta", "chronotype", "light therapy", "dark therapy", "sleep deprivation", "lithum" and "agomelatine". Search results were manually reviewed, and pertinent studies were selected for inclusion as appropriate. RESULTS: Several studies support the relationship between bipolar disorder and circadian cycles, discussing alterations in melatonin, body temperature and cortisol rhythms; disruption of sleep/wake cycle; variations of clock genes; and chronotype. Some therapeutics for bipolar disorder directed to the circadian cycles disturbances are also discussed, including lithium carbonate, agomelatine, light therapy, dark therapy, sleep deprivation and interpersonal and social rhythm therapy. LIMITATIONS: This review provides a summary of an extensive research for the relevant literature on this theme, not a patient-wise meta-analysis. CONCLUSIONS: In the future, it is essential to achieve a better understanding of the relation between bipolar disorder and the circadian system. It is required to establish new treatment protocols, combining psychotherapy, therapies targeting the circadian rhythms and the latest drugs, in order to reduce the risk of relapse and improve affective behaviour. PMID- 26241868 TI - Dynamics of the Heat Stress Response of Ceramides with Different Fatty-Acyl Chain Lengths in Baker's Yeast. AB - The article demonstrates that computational modeling has the capacity to convert metabolic snapshots, taken sequentially over time, into a description of cellular, dynamic strategies. The specific application is a detailed analysis of a set of actions with which Saccharomyces cerevisiae responds to heat stress. Using time dependent metabolic concentration data, we use a combination of mathematical modeling, reverse engineering, and optimization to infer dynamic changes in enzyme activities within the sphingolipid pathway. The details of the sphingolipid responses to heat stress are important, because they guide some of the longer-term alterations in gene expression, with which the cells adapt to the increased temperature. The analysis indicates that all enzyme activities in the system are affected and that the shapes of the time trends in activities depend on the fatty-acyl CoA chain lengths of the different ceramide species in the system. PMID- 26241869 TI - A comparison of respiratory and peripheral muscle strength, functional exercise capacity, activities of daily living and physical fitness in patients with cystic fibrosis and healthy subjects. AB - There are limited reports that compare muscle strength, functional exercise capacity, activities of daily living (ADL) and parameters of physical fitness of cystic fibrosis (CF) patients with healthy peers in the literature. The purpose of this study was to assess and compare respiratory and peripheral muscle strength, functional exercise capacity, ADL and physical fitness in patients with CF and healthy subjects. Nineteen patients with CF (mean forced expiratory volume in one second-FEV1: 86.56+/-18.36%) and 20 healthy subjects were included in this study. Respiratory (maximal inspiratory pressure-MIP and maximal expiratory pressure-MEP) and peripheral muscle strength (quadriceps, shoulder abductors and hand grip strength) were evaluated. Functional exercise capacity was determined with 6min walk test (6MWT). ADL was assessed with Glittre ADL test and physical fitness was assessed with Munich fitness test (MFT). There were not any statistically significant difference in MIP, %MIP, MEP and %MEP values between two groups (p>0.05). %Peripheral muscle strength (% quadriceps and shoulder abductors strength), 6MWT distance and %6MWT distance were significantly lower in patients with CF than those of healthy subjects (p<0.05). Glittre ADL-test time was significantly longer in patients with CF than healthy subjects (p<0.05). According to Munich fitness test, the number of bouncing a ball, hanging score, distance of standing vertical jumping and standing vertical jumping score were significantly lower in patients with CF than those of healthy subjects (p<0.05). Peripheral muscle strength, functional exercise capacity, ADL performance and speed, coordination, endurance and power components of physical fitness are adversely affected in mild-severe patients with CF compared to healthy peers. Evaluations must be done in comprehensive manner in patients with CF with all stages. PMID- 26241870 TI - Nature and reactivity of layered double hydroxides formed by coprecipitating Mg, Al and As(V): Effect of arsenic concentration, pH, and aging. AB - Arsenic (As) co-precipitation is one of the major processes controlling As solubility in soils and waters. When As is co-precipitated with Al and Mg, the possible formation of layered double hydroxides (LDHs) and other nanocomposites can stabilize As in their structures thus making this toxic element less available. We investigated the nature and reactivity of Mg-Al-arsenate [As(V)] co precipitated LDHs formed in solution affected by As concentration, pH, and aging. At the beginning of the co-precipitation process, poorly crystalline LDH and non crystalline Al(Mg)-oxides form. Prolonged aging of the samples promotes crystallization of LDHs, evidenced by an increase in As K XANES intensities and XRD peak intensities. During aging Al- and/or Mg-oxides are likely transformed by dissolution/re-precipitation processes into more crystalline but still defective LDHs. Surface area, chemical composition, reactivity of the precipitates, and anion exchange properties of As(V) in the co-precipitates are influenced by pH, aging, and As concentration. This study demonstrates that (i) As(V) retards or inhibits the formation and transformation of LDHs and (ii) more As(V) is removed from solution if co-precipitated with Mg and Al than by sorption onto well crystallized LDHs. PMID- 26241871 TI - Inoculation with endophytic Bacillus megaterium 1Y31 increases Mn accumulation and induces the growth and energy metabolism-related differentially-expressed proteome in Mn hyperaccumulator hybrid pennisetum. AB - In this study, a hydroponic culture experiment was conducted in a greenhouse to investigate the molecular and microbial mechanisms involved in the endophytic Bacillus megaterium 1Y31-enhanced Mn tolerance and accumulation in Mn hyperaccumulator hybrid pennisetum. Strain 1Y31 significantly increased the dry weights (ranging from 28% to 94%) and total Mn uptake (ranging from 23% to 112%) of hybrid pennisetum treated with 0, 2, and 10mM Mn compared to the control. Total 98 leaf differentially expressed proteins were identified between the live and dead bacterial inoculated hybrid pennisetum. The major leaf differentially expressed proteins were involved in energy generation, photosynthesis, response to stimulus, metabolisms, and unknown function. Furthermore, most of the energy generation and photosynthesis-related proteins were up-regulated, whereas most of the response to stimulus and metabolism-related proteins were down-regulated under Mn stress. Notably, the proportion of indole-3-acetic acid (IAA)-producing endophytic bacteria was significantly higher in the bacterial inoculated plants under Mn stress. The results suggested that strain 1Y31 increased the growth and Mn uptake of hybrid pennisetum through increasing the efficiency of photosynthesis and energy metabolism as well as the proportion of plant growth promoting endophytic bacteria in the plants. PMID- 26241872 TI - Synthesis, crystal structure, spectral characterization and biological exploration of water soluble Cu(II) complexes of vitamin B6 derivative. AB - The synthesis and characterization of Copper(II) complexes of a Schiff base derived from vitamin B6 component (pyridoxal) and ethanol amine [CuL2] (1), and its mixed ligand complexes [Cu(L)(N,N')]NO3, where N,N' is bipyridine (2) and 1,10-phenanthroline (3) are reported, including the X-ray crystal structures of [CuL2] (1). The crystal structure of 1 has square planar geometry with ligand to the metal ratio 2:1. The molecules are assembled in 3D supramolecular structure through hydrogen bonding interactions. DNA is considered as the major pharmacological target of metal based drugs, the objective of the present work includes the understanding of DNA binding mode of the synthesized compounds. The complexes bind with DNA through non intercalative interaction has been evidenced from the results of UV-Visible and fluorescence spectral titrations. It is further validated by molecular docking studies. Bovine serum albumin (BSA) binding studies revealed that the complexes can strongly quench the intrinsic fluorescence of BSA through a static quenching mechanism. The complexes promote the DNA cleavage even in the absence of additives which follows the order 2 > 1 > 3. Further, the complexes show potential cytotoxicity towards human breast cancer cell MCF-7 and induce the cell death. PMID- 26241873 TI - (+)-Dehydroabietylamine derivatives target triple-negative breast cancer. AB - Breast cancer remains the leading cause of cancer-related death among women. The invasive triple-negative subtype is unresponsive to estrogen therapy, and few effective treatments are available. In search of new chemical scaffolds to target this disease, we conducted a phenotypic screen against the human breast carcinoma cell lines MDA-MB-231, MA11, and MCF-7 using terrestrial natural products. Natural products that preferentially inhibited proliferation of triple-negative MDA-MB-231 cells over estrogen receptor-positive cells were further studied; herein we focused on the abietanes. The activity of the abietane carnosol prompted us to generate a focus library from the readily available (+) dehydroabietylamine. The lead compound 61 displayed a promising EC50 of 9.0 MUM against MDA-MB-231 and our mechanistic studies indicate it induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of PARP. Here we describe our current progress towards this promising therapeutic candidate. PMID- 26241874 TI - Design, synthesis and biological activity of new amides derived from 3-methyl-3 phenyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid. AB - A series of new 3-methyl-3-phenyl-2,5-dioxo-pyrrolidin-1-yl-acetamides (6-23) has been synthesized and evaluated for their anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection in mice. The acute neurological toxicity was determined using the rotarod test. The in vivo preliminary pharmacological results showed that in the whole series only two compounds (15, 21) were devoid of activity, whereas other molecules revealed protection in at least one animal model of epilepsy (MES or/and scPTZ). The in vivo quantitative studies in mice showed that in the MES test the most active were 1-{2-[4-(2-methoxyphenyl) piperazin-1-yl]-2-oxo-ethyl}-3-methyl-3-phenyl-pyrrolidine-2,5-dione (17), 1-{2 [4-(4-fluorophenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-3-phenyl-pyrrolidine 2,5-dione (8), and its 2-fluorophenyl analog (7) with ED50 values of 97.51 mg/kg (17), 104.11 mg/kg (8), and 114.68 mg/kg (7), respectively. In the scPTZ screen the most potent were compound 6 with an ED50 = 40.87 mg/kg, and 4 benzylpiperidine derivative 22 - ED50 = 60.00 mg/kg. Furthermore, selected compounds 8, 14, 17, and 23 were tested in the psychomotor seizure 6-Hz test. Compounds 7, 8, and 17 revealed significant analgesic activity in the formalin model of tonic pain in mice, without impairment of the motor coordination in the chimney test. The in vitro binding studies showed that the mechanism of anticonvulsant activity may be partially related with the influence on the voltage-gated sodium and calcium channels. The mutagenic and antimutagenic effects of 13, 17, and 22 were evaluated using the novel Vibrio harveyi assay. PMID- 26241875 TI - Synthesis, estrogenic activity, and anti-osteoporosis effects in ovariectomized rats of resveratrol oligomer derivatives. AB - Three series of resveratrol oligomer derivatives were synthesized, including the indenone-type, indene-type and octahydropentalene-type derivatives, among which ten derivatives were novel compounds. Compounds 2, 14f, and 4d were confirmed as ERbeta agonists by yeast two-hybrid assay, and compound 2 (isopaucifloral F) was further chosen to evaluate its anti-osteoporosis activity in vivo. Compared with the sham-operated and the positive control groups, isopaucifloral F (10 MUg/kg) showed a notable anti-osteoporosis effect in the ovariectomized (OVX) female rats based on a micro-CT analysis and the following measurements: bone mineral density, bone volume/tissue volume, trabecular thickness, trabecular separation/spacing, and the serum biochemical parameters. LD50 of isopaucifloral F was found to be greater than 5 mg/kg and its effective dose (ED) was found to be about 10 MUg/kg. Therefore, isopaucifloral F may be a promising lead compound for the treatment of postmenopausal osteoporosis. PMID- 26241876 TI - Triazine as a promising scaffold for its versatile biological behavior. AB - Among all heterocycles, the triazine scaffold occupies a prominent position, possessing a broad range of biological activities. Triazine is found in many potent biologically active molecules with promising biological potential like anti-inflammatory, anti-mycobacterial, anti-viral, anti-cancer etc. which makes it an attractive scaffold for the design and development of new drugs. The wide spectrum of biological activity of this moiety has attracted attention in the field of medicinal chemistry. Due to these biological activities, their structure activity relationship has generated interest among medicinal chemists and this has culminated in the discovery of several lead molecules. The outstanding development of triazine derivatives in diverse diseases within very short span of time proves its magnitude for medicinal chemistry research. Therefore, these compounds have been synthesized as target structure by many researchers, and were further evaluated for their biological activities. In this review, we have compiled and discussed the biological potential of s-triazine derivatives, which could provide a low-height flying bird's eye view of the triazine derived compounds to a medicinal chemist, for a comprehensive and target oriented information for the development of clinically viable drugs. PMID- 26241877 TI - Modulation of disulfide dual ENKephalinase inhibitors (DENKIs) activity by a transient N-protection for pain alleviation by oral route. AB - The endogenous opioid system, essentially constituted by two opioid receptors which are stimulated by the natural internal effectors enkephalins (Met enkephalin and Leu-enkephalin), is present at the different sites (peripheral, spinal, central) of the control of pain. We have demonstrated that the protection of the enkephalin inactivation by the two metallopeptidases (neprilysin and neutral aminopeptidase) increases their local concentration selectively induced by pain stimuli triggering analgesic responses. With the aim of increasing the orally antinociceptive responses of the previously described disulfide DENKIs ( [Formula: see text] CH(R1)CH2-S-S-CH2-C(R2R3)CONHCH(R4)COOR5), we designed new pro-drugs, in the same chemical series, with a transient protection of the free amino group by an acyloxyalkyl carbamate, giving rise to ((CH3)2CHCO2CH(CH3)OCONHCH(R1)CH2-S-S-CH2-C(R2R3)CONHCH(R4)COOR5) pro-drugs 2a 2g. These compounds were easily prepared from their parent analogs, with a good yield. They were tested per os and shown to be highly efficient in peripherally controlled inflammatory and neuropathic pain with long lasting effects but completely inactive in the acute centrally-controlled hot plate test, a model of pain by excess of nociception. This demonstrates that DENKIs are able to relieve pain at its source thanks to the increase of enkephalin levels. PMID- 26241878 TI - New derivatives of dehydroabietic acid target planktonic and biofilm bacteria in Staphylococcus aureus and effectively disrupt bacterial membrane integrity. AB - The combination of the dehydroabietic acid scaffold with different amino acids resulted in the discovery of a new class of hybrid compounds that targets both planktonic and biofilms bacteria in Staphylococcus aureus strains and are far more potent anti-biofilm agents than conventional antibiotics. Unlike dehydroabietic acid, these compounds can disrupt biofilms within a short time period and compromise the integrity of the bacterial membrane. Two of the compounds identified in our study are the most potent abietane-type anti-biofilm agents reported so far and display robust activity against pre-formed biofilms at concentrations only 3-6-fold higher than those required to inhibit biofilm formation. Their easy preparation based on proteolysis-resistant d- and unusual amino acids makes them useful chemical probes to gain a deeper understanding of bacterial biofilms and outstanding candidates for further development into new drugs to fight infections. PMID- 26241879 TI - How Does Physical Activity Intervention Improve Self-Esteem and Self-Concept in Children and Adolescents? Evidence from a Meta-Analysis. AB - OBJECTIVE: To perform a systematic review and meta-analysis for the effects of physical activity intervention on self-esteem and self-concept in children and adolescents, and to identify moderator variables by meta-regression. DESIGN: A meta-analysis and meta-regression. METHOD: Relevant studies were identified through a comprehensive search of electronic databases. Study inclusion criteria were: (1) intervention should be supervised physical activity, (2) reported sufficient data to estimate pooled effect sizes of physical activity intervention on self-esteem or self-concept, (3) participants' ages ranged from 3 to 20 years, and (4) a control or comparison group was included. For each study, study design, intervention design and participant characteristics were extracted. R software (version 3.1.3) and Stata (version 12.0) were used to synthesize effect sizes and perform moderation analyses for determining moderators. RESULTS: Twenty-five randomized controlled trial (RCT) studies and 13 non-randomized controlled trial (non-RCT) studies including a total of 2991 cases were identified. Significant positive effects were found in RCTs for intervention of physical activity alone on general self outcomes (Hedges' g = 0.29, 95% confidence interval [CI]: 0.14 to 0.45; p = 0.001), self-concept (Hedges' g = 0.49, 95%CI: 0.10 to 0.88, p = 0.014) and self-worth (Hedges' g = 0.31, 95%CI: 0.13 to 0.49, p = 0.005). There was no significant effect of intervention of physical activity alone on any outcomes in non-RCTs, as well as in studies with intervention of physical activity combined with other strategies. Meta-regression analysis revealed that higher treatment effects were associated with setting of intervention in RCTs (beta = 0.31, 95%CI: 0.07 to 0.55, p = 0.013). CONCLUSION: Intervention of physical activity alone is associated with increased self-concept and self-worth in children and adolescents. And there is a stronger association with school-based and gymnasium based intervention compared with other settings. PMID- 26241880 TI - Cost-Effectiveness of Dabigatran Compared to Vitamin-K Antagonists for the Treatment of Deep Venous Thrombosis in the Netherlands Using Real-World Data. AB - BACKGROUND: Vitamin-K antagonists (VKAs) present an effective anticoagulant treatment in deep venous thrombosis (DVT). However, the use of VKAs is limited because of the risk of bleeding and the necessity of frequent and long-term laboratory monitoring. Therefore, new oral anticoagulant drugs (NOACs) such as dabigatran, with lower rates of (major) intracranial bleeding compared to VKAs and not requiring monitoring, may be considered. OBJECTIVES: To estimate resource utilization and costs of patients treated with the VKAs acenocoumarol and phenprocoumon, for the indication DVT. Furthermore, a formal cost-effectiveness analysis of dabigatran compared to VKAs for DVT treatment was performed, using these estimates. METHODS: A retrospective observational study design in the thrombotic service of a teaching hospital (Deventer, The Netherlands) was applied to estimate real-world resource utilization and costs of VKA monitoring. A pooled analysis of data from RE-COVER and RE-COVER II on DVT was used to reflect the probabilities for events in the cost-effectiveness model. Dutch costs, utilities and specific data on coagulation monitoring levels were incorporated in the model. Next to the base case analysis, univariate probabilistic sensitivity and scenario analyses were performed. RESULTS: Real-world resource utilization in the thrombotic service of patients treated with VKA for the indication of DVT consisted of 12.3 measurements of the international normalized ratio (INR), with corresponding INR monitoring costs of ?138 for a standardized treatment period of 180 days. In the base case, dabigatran treatment compared to VKAs in a cohort of 1,000 DVT patients resulted in savings of ?18,900 (95% uncertainty interval (UI) 95,832, 151,162) and 41 (95% UI -18, 97) quality-adjusted life-years (QALYs) gained calculated from societal perspective. The probability that dabigatran is cost-effective at a conservative willingness-to pay threshold of ?20,000 per QALY was 99%. Sensitivity and scenario analyses also indicated cost savings or cost effectiveness below this same threshold. CONCLUSIONS: Total INR monitoring costs per patient were estimated at minimally ?138. Inserting these real-world data into a cost-effectiveness analysis for patients diagnosed with DVT, dabigatran appeared to be a cost-saving alternative to VKAs in the Netherlands in the base case. Cost savings or favorable cost-effectiveness were robust in sensitivity and scenario analyses. Our results warrant confirmation in other settings and locations. PMID- 26241881 TI - Association of E26 Transformation Specific Sequence 1 Variants with Rheumatoid Arthritis in Chinese Han Population. AB - OBJECTIVE: E26 transformation specific sequence 1 (ETS-1) belongs to the ETS family of transcription factors that regulate the expression of various immune related genes. Increasing evidence indicates that ETS-1 could contribute to the pathogenesis of autoimmune disease. Recent research has provided evidence that ETS-1 might correlate with rheumatoid arthritis (RA), but it's not clearly defined. In this study, we aimed to identify whether polymorphisms of ETS-1 play a role in Rheumatoid arthritis (RA) susceptibility and development in Chinese Han population. METHODS: Four single nucleotide polymorphisms (SNPs) within ETS-1 were selected based on HapMap data and previous associated studies. Whole blood and serum samples were obtained from 158 patients with RA and 192 healthy subjects. Genotyping was performed with polymerase chain reaction-high resolution melting (PCR-HRM) assay and the data was analyzed using SPSS17.0. RESULTS: A significantly positive correlation was observed between the SNP rs73013527 of ETS 1 and RA susceptibility, DAS28 and CRP (P<0.001, P = 0.001, and P = 0.028, respectively). Carriers of the haplotype CCT or TCT for rs4937333, rs11221332 and rs73013527 were associated with decreased risk of RA as compared to controls. No statistical significant difference was observed in the distribution of rs10893872, rs4937333 and rs11221332 genotypes between RA patients and controls. CONCLUSIONS: Our data further supports that ETS-1 has a relevant role in the pathogenesis and development of RA. Allele T of rs73013527 plays a protective role in occurrence of RA but a risk factor in the high disease activity. Rs10893872, rs11221332 and rs4937333 are not associated with RA susceptibility and clinical features. PMID- 26241882 TI - Biomembranes research using thermal and cold neutrons. AB - In 1932 James Chadwick discovered the neutron using a polonium source and a beryllium target (Chadwick, 1932). In a letter to Niels Bohr dated February 24, 1932, Chadwick wrote: "whatever the radiation from Be may be, it has most remarkable properties." Where it concerns hydrogen-rich biological materials, the "most remarkable" property is the neutron's differential sensitivity for hydrogen and its isotope deuterium. Such differential sensitivity is unique to neutron scattering, which unlike X-ray scattering, arises from nuclear forces. Consequently, the coherent neutron scattering length can experience a dramatic change in magnitude and phase as a result of resonance scattering, imparting sensitivity to both light and heavy atoms, and in favorable cases to their isotopic variants. This article describes recent biomembranes research using a variety of neutron scattering techniques. PMID- 26241883 TI - Structural determinants of protein partitioning into ordered membrane domains and lipid rafts. AB - Increasing evidence supports the existence of lateral nanoscopic lipid domains in plasma membranes, known as lipid rafts. These domains preferentially recruit membrane proteins and lipids to facilitate their interactions and thereby regulate transmembrane signaling and cellular homeostasis. The functionality of raft domains is intrinsically dependent on their selectivity for specific membrane components; however, while the physicochemical determinants of raft association for lipids are known, very few systematic studies have focused on the structural aspects that guide raft partitioning of proteins. In this review, we describe biophysical and thermodynamic aspects of raft-mimetic liquid ordered phases, focusing on those most relevant for protein partitioning. Further, we detail the variety of experimental models used to study protein-raft interactions. Finally, we review the existing literature on mechanisms for raft targeting, including lipid post-translational modifications, lipid binding, and transmembrane domain features. We conclude that while protein palmitoylation is a clear raft-targeting signal, few other general structural determinants for raft partitioning have been revealed, suggesting that many discoveries lie ahead in this burgeoning field. PMID- 26241884 TI - 2-Deoxy-d-Glucose Sensitizes Human Ovarian Cancer Cells to Cisplatin by Increasing ER Stress and Decreasing ATP Stores in Acidic Vesicles. AB - Cisplatin is a commonly used chemotherapeutic agent; however, the development of acquired resistance limits its application. Here, we demonstrate that 2-deoxy-d glucose (2-DG) enhanced the antitumor effects of cisplatin in SKOV3 cells, which include inhibition of proliferation and promotion of apoptosis. Additionally, either cisplatin or 2-DG alone could upregulate the endoplasmic reticulum (ER) stress-associated protein glucose-regulated protein-78 (GRP78). Moreover, exposure to 2-DG increased the expression of GRP78 induced by cisplatin. Cisplatin also upregulated ER stress-associated apoptotic protein 153/C/EBP homology protein (CHOP) in SKOV3 cells. While treatment with 2-DG alone could not upregulate the CHOP expression, a combination of both 2-DG and cisplatin increased the protein levels of CHOP above those induced by Cisplatin alone. Finally, cisplatin mediated an increase in ATP stores within acidic vesicles, whereas 2-DG decreased this effect. These data demonstrate that 2-DG sensitizes SKOV3 cells to cisplatin by increasing ER stress and decreasing ATP stores in acidic vesicles. PMID- 26241885 TI - Risk factors: Long-term low mortality in patients without coronary artery calcium. PMID- 26241886 TI - Prevention: Guidelines with high statin eligibility target risk and are cost effective. PMID- 26241887 TI - Biodegradation of the herbicide Diuron in a packed bed channel and a double biobarrier with distribution of oxygenated liquid by airlift devices: influence of oxygen limitation. AB - From agricultural soils, where the herbicide Diuron has been frequently applied, a microbial community capable of degrading Diuron and 3,4-dichloroaniline was obtained. The volumetric rates and degradation efficiencies of Diuron and 3,4-DCA were evaluated in two distinct biofilm reactors, which differ in their operating conditions. One is a horizontal fixed bed reactor; plug-flow operated (PF-PBC) with severe limitation of oxygen. In this reactor, the air was supplied to an equalizer reservoir at the start of the PF-PBC reactor. The other is a compartmentalized aerobic biobarrier with internal recirculation of liquid aerated through airlift devices (ALB), continuously or intermittently operated. Both reactors were inoculated with a microbial community capable of degrading Diuron, isolated from a sugarcane field. In the oxygen-limited PF-PBC reactor, 3,4-DCA accumulation was detected, mainly in the middle zone of the packed channel. On the contrary, in the fully aerobic ALB reactor, minimal accumulation of catabolic byproducts was detected, and high Diuron removal efficiencies and removal rates were obtained when it was continuously operated in steady-state conditions. Additionally, the influence of oxygen limitation on the kinetic behavior of the PF-PBC reactor was determined, and a method to estimate the local removal rates of Diuron RV,CD along the plug-flow channel is described. It was observed that the local values of the instantaneous removal rate of Diuron dCD/dt are high in the aerobic region of the PF-PBC reactor; but, suddenly decay in the reactor zones limited by dissolved oxygen. PMID- 26241888 TI - Hershey Kiss and Puberty? PMID- 26241889 TI - Mature Teratoma in a Supernumerary Ovary in a Child: Report of the First Case. AB - BACKGROUND: Supernumerary ovary (ie, ovarian ectopia having no anatomic connection with the normally placed ovaries) is a rare gynecologic condition. To the best of our knowledge, only 1 pediatric case of supernumerary ovary has been reported to date in the English literature. CASE: A 4-year-old girl was assessed for foul-smelling vestibular discharge and was found to have a fistulous tract with opening near the vaginal orifice. Fistuloscopy revealed hair in the lumen of the tract. Computed tomography scan showed a retroperitoneal mass in continuation of the tract. Excision of the mass revealed a mature teratoma in a retroperitoneal supernumerary ovary. SUMMARY AND CONCLUSION: Supernumerary ovary, a gynecologic rarity, is even more uncommon in children. Hence, a thorough clinical-radiological-pathological correlation is mandatory to diagnose extragonadal ovarian tumors arising in supernumerary ovaries. PMID- 26241890 TI - A statistical approach to understand the role of inclusions on the fatigue resistance of superelastic Nitinol wire and tubing. AB - Superelastic wires and diamond-shaped stent surrogates were manufactured from Nitinol rods and tubing, respectively, from five different mill product suppliers - Standard VAR, Standard VIM, Standard VIM+VAR, Process-Optimized VIM+VAR, and High-Purity VAR. High-cycle fatigue tests up to 10(7) cycles were conducted under tension-tension conditions for wires and bending conditions for diamonds. These materials were compared under both testing methods at 37 degrees C with 6% prestrain and 3% mean strain (unloading plateau) with a range of alternating strains. The High-Purity VAR material outperformed all alloys tested with a measured 10(7)-fatigue alternating strain limit of 0.32% for wire and 1.75% for diamonds. Process-Optimized VIM+VAR material was only slightly inferior to the High Purity VAR with a diamond alternating bending strain limit of 1.5%. These two "second generation" Nitinol alloys demonstrated approximately a 2* increase in 10(7)-cycle fatigue strain limit compared to all of the Standard-grade Nitinol alloys (VAR, VIM, and VIM+VAR) that demonstrated virtually indistinguishable fatigue performance. This statistically-significant increase in fatigue resistance in the contemporary alloys is ascribed to smaller inclusions in the Process-Optimized VIM+VAR material, and both smaller and fewer inclusions in the High-Purity VAR Nitinol. PMID- 26241891 TI - Contact damage failure analyses of fretting wear behavior of the metal stem titanium alloy-bone cement interface. AB - Although cemented titanium alloy is not favored currently in the Western world for its poor clinical and radiography outcomes, its lower modulus of elasticity and good biocompatibility are instrumental for its ability supporting and transforming physical load, and it is more suitable for usage in Chinese and Japanese populations due to their lower body weights and unique femoral characteristics. Through various friction tests of different cycles, loads and conditions and by examining fretting hysteresis loops, fatigue process curves and wear surfaces, the current study investigated fretting wear characteristics and wear mechanism of titanium alloy stem-bone cement interface. It was found that the combination of loads and displacement affected the wear quantity. Friction coefficient, which was in an inverse relationship to load under the same amplitude, was proportional to amplitudes under the same load. Additionally, calf serum was found to both lubricate and erode the wear interface. Moreover, cement fatigue contact areas appeared black/oxidative in dry and gruel in 25% calf serum. Fatigue scratches were detected within contact areas, and wear scars were found on cement and titanium surfaces, which were concave-shaped and ring concave/ convex-shaped, respectively. The coupling of thermoplastic effect and minimal torque damage has been proposed to be the major reason of contact damage. These data will be important for further studies analyzing metal-cement interface failure performance and solving interface friction and wear debris production issues. PMID- 26241892 TI - Levers for Language Growth: Characteristics and Predictors of Language Trajectories between 4 and 7 Years. AB - BACKGROUND: Evidence is required as to when and where to focus resources to achieve the greatest gains for children's language development. Key to these decisions is the understanding of individual differences in children's language trajectories and the predictors of those differences. To determine optimal timing we must understand if and when children's relative language abilities become fixed. To determine where to focus effort we must identify mutable factors, that is those with the potential to be changed through interventions, which are associated with significant differences in children's language scores and rate of progress. METHODS: Uniquely this study examined individual differences in language growth trajectories in a population sample of children between 4 and 7 years using the multilevel model for change. The influence of predictors, grouped with respect to their mutability and their proximity to the child (least-mutable, mutable-distal, mutable-proximal), were estimated. RESULTS: A significant degree of variability in rate of progress between 4 and 7 years was evident, much of which was systematically associated with mutable-proximal factors, that is, those factors with evidence that they are modifiable through interventions with the child or family, such as shared book reading, TV viewing and number of books in the home. Mutable-distal factors, such as family income, family literacy and neighbourhood disadvantage, hypothesised to be modifiable through social policy, were important predictors of language abilities at 4 years. CONCLUSIONS: Potential levers for language interventions lie in the child's home learning environment from birth to age 4. However, the role of a family's material and cultural capital must not be ignored, nor should the potential for growth into the school years. Early Years services should acknowledge the effects of multiple, cascading and cumulative risks and seek to promote child language development through the aggregation of marginal gains in the pre-school years and beyond. PMID- 26241893 TI - Area restrictions, risk, harm, and health care access among people who use drugs in Vancouver, Canada: A spatially oriented qualitative study. AB - Area restrictions prohibiting people from entering drug scenes or areas where they were arrested are a common socio-legal mechanism employed to regulate the spatial practices of people who use drugs (PWUD). To explore how socio-spatial patterns stemming from area restrictions shape risk, harm, and health care access, qualitative interviews and mapping exercises were conducted with 24 PWUD with area restrictions in Vancouver, Canada. Area restrictions disrupted access to health and social resources (e.g., HIV care) concentrated in drug scenes, while territorial stigma prevented PWUD from accessing supports in other neighborhoods. Rather than preventing involvement in drug-related activities, area restrictions displaced these activities to other locations and increased vulnerability to diverse risks and harms (e.g., unsafe drug use practices, violence). Given the harms stemming from area restrictions there is an urgent need to reconsider this socio-legal strategy. PMID- 26241894 TI - S-Nitrosylation of Bcl-2 Negatively Affects Autophagy in Lung Epithelial Cells. AB - Autophagy is a catabolic cellular mechanism involving lysosomal degradation of unwanted cellular components. Interaction between Beclin-1 and Bcl-2 proteins is known to play a critical role in the initiation of autophagy. We report that malignantly transformed lung epithelial cells are resistant to autophagy and express lower basal levels of autophagic proteins, Beclin-1 and LC3-II as compared to non-tumorigenic cells. Additionally, increased levels of nitric oxide (NO) and Bcl-2 were observed in transformed cells. Nitric oxide was found to negatively regulate autophagy initiation and autophagic flux by nitrosylating Bcl 2 and stabilizing its interaction with Beclin-1, resulting in inhibition of Beclin-1 activity. An increase in the apoptotic initiator caspase-9 and the apoptosis and autophagy-associated kinase p38/MAPK in both cell types indicated possible autophagy-apoptosis crosstalk. Pre-treatments with ABT-737 (Bcl-2 inhibitor) and aminoguanidine (NO inhibitor), and transfection with a non nitrosylable Bcl-2 cysteine double-mutant plasmid resulted in increased autophagic flux (LC3-II/p62 upregulation) corresponding with decreased S nitrocysteine expression, thus corroborating the regulatory role of Bcl-2 S nitrosylation in autophagy. In conclusion, our study reveals a novel mechanism of autophagy resistance via post-translational modification of Bcl-2 protein by NO, which may be critical in driving cellular tumorigenesis. PMID- 26241895 TI - The Cost-Effectiveness of Low-Cost Essential Antihypertensive Medicines for Hypertension Control in China: A Modelling Study. AB - BACKGROUND: Hypertension is China's leading cardiovascular disease risk factor. Improved hypertension control in China would result in result in enormous health gains in the world's largest population. A computer simulation model projected the cost-effectiveness of hypertension treatment in Chinese adults, assuming a range of essential medicines list drug costs. METHODS AND FINDINGS: The Cardiovascular Disease Policy Model-China, a Markov-style computer simulation model, simulated hypertension screening, essential medicines program implementation, hypertension control program administration, drug treatment and monitoring costs, disease-related costs, and quality-adjusted life years (QALYs) gained by preventing cardiovascular disease or lost because of drug side effects in untreated hypertensive adults aged 35-84 y over 2015-2025. Cost-effectiveness was assessed in cardiovascular disease patients (secondary prevention) and for two blood pressure ranges in primary prevention (stage one, 140-159/90-99 mm Hg; stage two, >=160/>=100 mm Hg). Treatment of isolated systolic hypertension and combined systolic and diastolic hypertension were modeled as a reduction in systolic blood pressure; treatment of isolated diastolic hypertension was modeled as a reduction in diastolic blood pressure. One-way and probabilistic sensitivity analyses explored ranges of antihypertensive drug effectiveness and costs, monitoring frequency, medication adherence, side effect severity, background hypertension prevalence, antihypertensive medication treatment, case fatality, incidence and prevalence, and cardiovascular disease treatment costs. Median antihypertensive costs from Shanghai and Yunnan province were entered into the model in order to estimate the effects of very low and high drug prices. Incremental cost-effectiveness ratios less than the per capita gross domestic product of China (11,900 international dollars [Int$] in 2015) were considered cost-effective. Treating hypertensive adults with prior cardiovascular disease for secondary prevention was projected to be cost saving in the main simulation and 100% of probabilistic simulation results. Treating all hypertension for primary and secondary prevention would prevent about 800,000 cardiovascular disease events annually (95% uncertainty interval, 0.6 to 1.0 million) and was borderline cost-effective incremental to treating only cardiovascular disease and stage two patients (2015 Int$13,000 per QALY gained [95% uncertainty interval, Int$10,000 to Int$18,000]). Of all one-way sensitivity analyses, assuming adherence to taking medications as low as 25%, high Shanghai drug costs, or low medication efficacy led to the most unfavorable results (treating all hypertension, about Int$47,000, Int$37,000, and Int$27,000 per QALY were gained, respectively). The strengths of this study were the use of a recent Chinese national health survey, vital statistics, health care costs, and cohort study outcomes data as model inputs and reliance on clinical-trial-based estimates of coronary heart disease and stroke risk reduction due to antihypertensive medication treatment. The limitations of the study were the use of several sources of data, limited clinical trial evidence for medication effectiveness and harms in the youngest and oldest age groups, lack of information about geographic and ethnic subgroups, lack of specific information about indirect costs borne by patients, and uncertainty about the future epidemiology of cardiovascular diseases in China. CONCLUSIONS: Expanded hypertension treatment has the potential to prevent about 800,000 cardiovascular disease events annually and be borderline cost-effective in China, provided low-cost essential antihypertensive medicines programs can be implemented. PMID- 26241896 TI - Diagnostic Value of Liquid-Based Cytology in Urothelial Carcinoma Diagnosis: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To evaluate the value of liquid-based cytology (LBC) in the diagnosis of urothelial carcinoma. METHOD: Diagnostic studies were searched for the diagnostic value of LBC in urothelial carcinoma in PubMed, Embase, Cochrane Library, Web of Science, CBM and CNKI. The latest retrieval date was September 2014. The data were extracted and the quality of the included studies was independently assessed by 2 reviewers. Stata 13 software was used to perform the statistical analysis. The research was conducted in compliance with the PRISMA statement. RESULT: Nineteen studies, which included 8293 patients, were evaluated. The results of the meta-analysis showed that the pooled sensitivity and specificity of LBC were 0.58 (0.51-0.65) and 0.96 (0.93-0.98), respectively. The diagnostic odds ratio (DOR) was 31 (18-56) and the area under the curve (AUC) of summary receiver operating characteristic (SROC) was 0.83 (0.80-0.86). The post-test probability was 80% when a positive diagnosis was made. Compared with high grade urothelial carcinoma (HGUC), the sensitivity of detecting low-grade urothelial carcinoma (LGUC) was significantly lower, risk ratio of sensitivity was 0.54 (0.43-0.66), P<0.001. However, no significant sensitivity improvement was observed with LBC when compared with traditional cytospin cytology, risk ratio was 1.03 (0.94-1.14), P = 0.524. CONCLUSION: Despite LBC having a pooled 58% positive rate for urothelial carcinoma diagnosis in our meta-analysis, no significant improvement in sensitivity was observed based on the studies evaluated. Further research is needed to validate these findings. PMID- 26241897 TI - Cerebral Perfusion Measurements in Elderly with Hypertension Using Arterial Spin Labeling. AB - PURPOSE: The current study assesses the feasibility and value of crushed cerebral blood flow (CBFcrushed) and arterial transit time (ATT) estimations for large clinical imaging studies in elderly with hypertension. MATERIAL AND METHODS: Two pseudo-continuous arterial spin labeling (ASL) scans with (CBFcrushed) and without flow crushers (CBFnon-crushed) were performed in 186 elderly with hypertension, from which CBF and ATT maps were calculated. Standard flow territory maps were subdivided into proximal, intermediate and distal flow territories, based on the measured ATT. The coefficient of variation (CV) and physiological correlations with age and gender were compared between the three perfusion parameters. RESULTS: There was no difference in CV between CBFcrushed and CBFnon-crushed (15-24%, p>0.4) but the CV of ATT (4-9%) was much smaller. The total gray matter correlations with age and gender were most significant with ATT (p = .016 and p<.001 respectively), in between for CBFcrushed (p = .206 and p = .019) and least significant for CBFnon-crushed (p = .236 and p = .100). CONCLUSION: These data show the feasibility and added value of combined measurements of both crushed CBF and ATT for group analyses in elderly with hypertension. The obtained flow territories provide knowledge on vascular anatomy of elderly with hypertension and can be used in future studies to investigate regional vascular effects. PMID- 26241898 TI - Tumor Progression Locus 2 Promotes Induction of IFNlambda, Interferon Stimulated Genes and Antigen-Specific CD8+ T Cell Responses and Protects against Influenza Virus. AB - Mitogen-activated protein kinase (MAP) cascades are important in antiviral immunity through their regulation of interferon (IFN) production as well as virus replication. Although the serine-threonine MAP kinase tumor progression locus 2 (Tpl2/MAP3K8) has been implicated as a key regulator of Type I (IFNalpha/beta) and Type II (IFNgamma) IFNs, remarkably little is known about how Tpl2 might contribute to host defense against viruses. Herein, we investigated the role of Tpl2 in antiviral immune responses against influenza virus. We demonstrate that Tpl2 is an integral component of multiple virus sensing pathways, differentially regulating the induction of IFNalpha/beta and IFNlambda in a cell-type specific manner. Although Tpl2 is important in the regulation of both IFNalpha/beta and IFNlambda, only IFNlambda required Tpl2 for its induction during influenza virus infection both in vitro and in vivo. Further studies revealed an unanticipated function for Tpl2 in transducing Type I IFN signals and promoting expression of interferon-stimulated genes (ISGs). Importantly, Tpl2 signaling in nonhematopoietic cells is necessary to limit early virus replication. In addition to early innate alterations, impaired expansion of virus-specific CD8+ T cells accompanied delayed viral clearance in Tpl2-/- mice at late time points. Consistent with its critical role in facilitating both innate and adaptive antiviral responses, Tpl2 is required for restricting morbidity and mortality associated with influenza virus infection. Collectively, these findings establish an essential role for Tpl2 in antiviral host defense mechanisms. PMID- 26241899 TI - Finasteride Has Regionally Different Effects on Brain Oxidative Stress and Acetylcholinesterase Activity in Acute Thioacetamide-Induced Hepatic Encephalopathy in Rats. AB - Finasteride (FIN) inhibits neurosteroid synthesis and potentially improves the course of hepatic encephalopathy (HE). This study aimed to investigate the effects of FIN on brain oxidative stress and acetylcholinesterase (AchE) activity in acute thioacetamide-induced HE in rats. Male Wistar rats were divided into groups: 1. control; 2. thioacetamide-treated group (TAA; 900 mg/kg); 3. finasteride-treated group (FIN; 150 mg/kg); 4. group treated with FIN and TAA (FIN+TAA). Daily doses of FIN (50 mg/kg) and TAA (300 mg/kg) were administered intraperitoneally during three days and in FIN+TAA group FIN was administered 2h before every dose of TAA. FIN pretreatment prevented TAA-induced rise in malondialdehyde level in the cortex due to restoration of catalase activity and increased expression of superoxide dismutase 1 (SOD1) and induced an increase in malondialdehyde level in the thalamus due to reduction of glutathione peroxidase (GPx) and glutathione reductase (GR) activity. Although FIN pretreatment did not affect malondialdehyde level in hippocampus and caudate nucleus, hippocampal SOD1 expression was higher (p<0.05) and GR activity lower in FIN+TAA vs. TAA group (p<0.05). GPx activity was lower in caudate nucleus in FIN+TAA vs. TAA group (p<0.01). FIN pretreatment prevented TAA-induced rise in AchE activity in the thalamus and caudate nucleus and AchE activity correlates inversely in the thalamus (p<0.05) and positively in caudate nucleus (p<0.01) with malondialdehyde level. FIN has regionally selective effects on oxidative stress and AchE activity in the brain in acute TAA-induced HE in rats. The prooxidant role of FIN in the thalamus may be causally linked with inhibition of AchE. PMID- 26241900 TI - A Comparison of the Number of Men Who Have Sex with Men among Rural-To-Urban Migrants with Non-Migrant Rural and Urban Residents in Wuhan, China: A GIS/GPS Assisted Random Sample Survey Study. AB - BACKGROUND: Mobile populations and men who have sex with men (MSM) play an increasing role in the current HIV epidemic in China and across the globe. While considerable research has addressed both of these at-risk populations, more effective HIV control requires accurate data on the number of MSM at the population level, particularly MSM among migrant populations. METHODS: Survey data from a random sample of male rural-to-urban migrants (aged 18-45, n=572) in Wuhan, China were analyzed and compared with those of randomly selected non migrant urban (n=566) and rural counterparts (580). The GIS/GPS technologies were used for sampling and the survey estimation method was used for data analysis. RESULTS: HIV-related risk behaviors among rural-to-urban migrants were similar to those among the two comparison groups. The estimated proportion of MSM among migrants [95% CI] was 5.8% [4.7, 6.8], higher than 2.8% [1.2, 4.5] for rural residents and 1.0% [0.0, 2.4] for urban residents, respectively. Among these migrants, the MSM were more likely than non-MSM to be older in age, married, and migrated to more cities. They were also more likely to co-habit with others in rental properties located in new town and neighborhoods with fewer old acquaintances and more entertainment establishments. In addition, they were more likely to engage in commercial sex and less likely to consistently use condoms. CONCLUSION: Findings of this study indicate that compared to rural and urban populations, the migrant population in Wuhan consists of a higher proportion of MSM who also exhibit higher levels of HIV-related risk behaviors. More effective interventions should target this population with a focus on neighborhood factors, social capital and collective efficacy for risk reduction. PMID- 26241901 TI - Identification of a new mutant allele, Grm6(nob7), for complete congenital stationary night blindness. AB - Electroretinogram (ERG) studies identified a new mouse line with a normal a-wave but lacking the b-wave component. The ERG phenotype of this new allele, nob7, matched closely that of mouse mutants for Grm6, Lrit3, Trpm1, and Nyx, which encode for proteins expressed in depolarizing bipolar cells (DBCs). To identify the underlying mutation, we first crossed nob7 mice with Grm6 nob3 mutants and measured the ERGs in offspring. All the offspring lacked the b-wave, indicating that nob7 is a new allele for Grm6: Grm6 nob7 . Sequence analyses of Grm6 nob7 cDNAs identified a 28 base pair insertion between exons 8 and 9, which would result in a frameshift mutation in the open reading frame that encodes the metabotropic glutamate receptor 6 (Grm6). Sequencing both the cDNA and genomic DNA from exon 8 and intron 8, respectively, from the Grm6 nob7 mouse revealed a G to A transition at the last position in exon 8. This mutation disrupts splicing and the normal exon 8 is extended by 28 base pairs, because splicing occurs 28 base pairs downstream at a cryptic splice donor. Consistent with the impact of the resulting frameshift mutation, there is a loss of mGluR6 protein (encoded by Grm6) from the dendritic tips of DBCs in the Grm6 nob7 retina. These results indicate that Grm6 nob7 is a new model of the complete form of congenital stationary night blindness, a human condition that has been linked to mutations of GRM6. PMID- 26241902 TI - Vitamin D Status in Rheumatoid Arthritis: Inflammation, Arterial Stiffness and Circulating Progenitor Cell Number. AB - BACKGROUND AND AIMS: Suboptimal vitamin D status was recently acknowledged as an independent predictor of cardiovascular diseases and all-cause mortality in several clinical settings, and its serum levels are commonly reduced in Rheumatoid Arthritis (RA). Patients affected by RA present accelerated atherosclerosis and increased cardiovascular morbidity and mortality with respect to the general population. In RA, it has been reported an impairment of the number and the activity of circulating proangiogenic haematopoietic cells (PHCs), including CD34+, that may play a role in endothelial homeostasis. The purpose of the study is to investigate the association between vitamin D levels and PHCs, inflammatory markers, and arterial stiffening in patients with RA. METHODS AND RESULTS: CD34+ cells were isolated from 27 RA patients and 41 controls. Vitamin D levels, C-reactive protein (CRP), fibrinogen, pulse wave velocity (PWV), and carotid intima-media thickness (cIMT) were also evaluated. CD34+ count and vitamin D levels were lower in RA patients as compared to controls, while fibrinogen, CRP, PWV and cIMT were higher in RA patients. CD34+ cell number appeared to be associated with vitamin D levels, and negatively correlated to fibrinogen and early atherosclerosis markers (PWV and cIMT); vitamin D levels appear also to be inversely associated to fibrinogen. CONCLUSIONS: RA patients with moderate disease activity presented with low vitamin D levels, low CD34+ cell count, increased PWV and cIMT; we found that vitamin D deficiency is associated to CD34+ cell reduction in peripheral blood, and with fibrinogen levels. This suggests that vitamin D might contribute to endothelial homeostasis in patients with RA. PMID- 26241904 TI - Aquaporins in Coffea arabica L.: Identification, expression, and impacts on plant water relations and hydraulics. AB - Plant aquaporins (AQPs) are involved in the transport of water and other small solutes across cell membranes, and thus play major roles in the regulation of plant water balance, as well as in growth regulation and response to abiotic stress factors. Limited information is currently available about the presence and role of AQPs in Coffea arabica L., despite the economic importance of the species and its vulnerability to drought stress. We identified candidate AQP genes by screening a proprietary C. arabica transcriptome database, resulting in the identification of nine putative aquaporins. A phylogenetic analysis based on previously characterized AQPs from Arabidopsis thaliana and Solanum tuberosum allowed to assign the putative coffee AQP sequences to the Tonoplast (TIP) and Plasma membrane (PIP) subfamilies. The possible functional role of coffee AQPs was explored by measuring hydraulic conductance and aquaporin gene expression on leaf and root tissues of two-year-old plants (C. arabica cv. Pacamara) subjected to different experimental conditions. In a first experiment, we tested plants for root and leaf hydraulic conductance both before dawn and at mid-day, to check the eventual impact of light on AQP activity and plant hydraulics. In a second experiment, we measured plant hydraulic responses to different water stress levels as eventually affected by changes in AQPs expression levels. Our results shed light on the possible roles of AQPs in the regulation of C. arabica hydraulics and water balance, opening promising research lines to improve the sustainability of coffee cultivation under global climate change scenarios. PMID- 26241903 TI - Glycated Hemoglobin, Fasting Insulin and the Metabolic Syndrome in Males. Cross Sectional Analyses of the Aragon Workers' Health Study Baseline. AB - BACKGROUND AND AIMS: Glycated hemoglobin (HbA1c) is currently used to diagnose diabetes mellitus, while insulin has been relegated to research. Both, however, may help understanding the metabolic syndrome and profiling patients. We examined the association of HbA1c and fasting insulin with clustering of metabolic syndrome criteria and insulin resistance as two essential characteristics of the metabolic syndrome. METHODS: We used baseline data from 3200 non-diabetic male participants in the Aragon Workers' Health Study. We conducted analysis to estimate age-adjusted odds ratios (ORs) across tertiles of HbA1c and insulin. Fasting glucose and Homeostatic model assessment - Insulin Resistance were used as reference. Here we report the uppermost-to-lowest tertile ORs (95%CI). RESULTS: Mean age (SD) was 48.5 (8.8) years and 23% of participants had metabolic syndrome. The ORs for metabolic syndrome criteria tended to be higher across HbA1c than across glucose, except for high blood pressure. Insulin was associated with the criteria more strongly than HbA1c and similarly to Homeostatic model assessment - Insulin Resistance (HOMA-IR). For metabolic syndrome, the OR of HbA1c was 2.68, of insulin, 11.36, of glucose, 7.03, and of HOMA-IR, 14.40. For the clustering of 2 or more non-glycemic criteria, the OR of HbA1c was 2.10, of insulin, 8.94, of glucose, 1.73, and of HOMA-IR, 7.83. All ORs were statistically significant. The areas under the receiver operating characteristics curves for metabolic syndrome were 0.670 (across HbA1c values) and 0.770 (across insulin values), and, for insulin resistance, 0.647 (HbA1c) and 0.995 (insulin). Among non-metabolic syndrome patients, a small insulin elevation identified risk factor clustering. CONCLUSIONS: HbA1c and specially insulin levels were associated with metabolic syndrome criteria, their clustering, and insulin resistance. Insulin could provide early information in subjects prone to develop metabolic syndrome. PMID- 26241905 TI - Specificity of brain reactions to second-order visual stimuli. AB - The second-order visual mechanisms perform the operation of integrating the spatially distributed local visual information. Their organization is traditionally considered within the framework of the filter-rectify-filter model. These are the second-order filters that provide the ability to detect texture gradients. However, the question of the mechanisms' selectivity to the modulation dimension remains open. The aim of this investigation is to answer the above question by using visual evoked potentials (VEPs). Stimuli were textures consisting of staggered Gabor patches. The base texture was nonmodulated (NM). Three other textures represented the base texture which was sinusoidally modulated in different dimensions: contrast, orientation, or spatial frequency. EEG was recorded with 20 electrodes. VEPs of 500 ms duration were obtained for each of the four textures. After that, VEP to the NM texture was subtracted from VEP to each modulated texture. As a result, three different waves (d-waves) were obtained for each electrode site. Each d-wave was then averaged across all the 48 observers. The revealed d-waves have a latency of about 200 ms and, in our opinion, reflect the second-order filters reactivation through the feedback connection. The d-waves for different modulation dimensions were compared with each other in time, amplitude, topography, and localization of the sources of activity that causes the d-wave (with sLORETA). We proceeded from the assumption that the d-wave (its first component) represents functioning of the second-order visual mechanisms and activity changes at the following processing stages. It was found that the d-waves for different modulation dimensions significantly differ in all parameters. The obtained results indicate that the spatial modulations of different texture parameters caused specific changes in the brain activity, which could be evidence supporting the specificity of the second-order visual mechanisms to modulation dimension. PMID- 26241906 TI - Buccal Versus Lingual Mucosa Graft in Anterior Urethroplasty: A Prospective Comparison of Surgical Outcome and Donor Site Morbidity. AB - PURPOSE: We prospectively compared buccal mucosa graft and lingual mucosa graft urethroplasty with respect to donor site morbidity and urethroplasty outcome. MATERIALS AND METHODS: Patients treated with buccal mucosa graft (29) or lingual mucosa graft (29) urethroplasty were included in the study. Oral pain and morbidity were assessed using the numeric rating scale (scale 0 to 10) as well as an in-home questionnaire administered 3 days, 2 weeks and 6 months postoperatively. RESULTS: After a mean (+/- SD) followup of 30 (+/- 13) months successful urethroplasty was achieved in 24 (82.8%) and 26 (89.7%) patients treated with buccal mucosa graft and lingual mucosa graft, respectively (p = 0.306). Median numeric rating scale after 3 days, 2 weeks and 6 months was 4, 2 and 0 for buccal mucosa graft and 6, 3 and 0 for lingual mucosa graft, respectively, with no statistical differences between the groups. At day 3 significantly more patients in the lingual mucosa graft group had severe difficulties with eating and drinking (62.1% vs 24.1%, p = 0.004) and speaking (93.1% vs 55.2%, p = 0.001), and had dysgeusia (48.3% vs 13.8%, p = 0.01). Two weeks postoperatively speech impairment was still more frequent with lingual mucosa graft (55.2% vs 13.8%, p = 0.002), whereas oral tightness was more frequent with buccal mucosa graft (41.4% vs 6.9%, p = 0.005). After 6 months 44.8% and 31% of patients treated with buccal mucosa graft and lingual mucosa graft, respectively, still reported sensitivity disorders (p = 0.279). CONCLUSIONS: The success of urethroplasty with lingual and buccal mucosa grafts was similar. Oral pain was not different after both grafts. In the early postoperative period there were differences in oral morbidity between buccal and lingual mucosa grafts. Long-term oral morbidity was not infrequent with both grafts. PMID- 26241907 TI - Forecasting Seizures Using Intracranial EEG Measures and SVM in Naturally Occurring Canine Epilepsy. AB - Management of drug resistant focal epilepsy would be greatly assisted by a reliable warning system capable of alerting patients prior to seizures to allow the patient to adjust activities or medication. Such a system requires successful identification of a preictal, or seizure-prone state. Identification of preictal states in continuous long- duration intracranial electroencephalographic (iEEG) recordings of dogs with naturally occurring epilepsy was investigated using a support vector machine (SVM) algorithm. The dogs studied were implanted with a 16 channel ambulatory iEEG recording device with average channel reference for a mean (st. dev.) of 380.4 (+87.5) days producing 220.2 (+104.1) days of intracranial EEG recorded at 400 Hz for analysis. The iEEG records had 51.6 (+52.8) seizures identified, of which 35.8 (+30.4) seizures were preceded by more than 4 hours of seizure-free data. Recorded iEEG data were stratified into 11 contiguous, non-overlapping frequency bands and binned into one-minute synchrony features for analysis. Performance of the SVM classifier was assessed using a 5 fold cross validation approach, where preictal training data were taken from 90 minute windows with a 5 minute pre-seizure offset. Analysis of the optimal preictal training time was performed by repeating the cross validation over a range of preictal windows and comparing results. We show that the optimization of feature selection varies for each subject, i.e. algorithms are subject specific, but achieve prediction performance significantly better than a time-matched Poisson random predictor (p<0.05) in 5/5 dogs analyzed. PMID- 26241908 TI - CholesteroNitrones for Stroke. AB - This study describes CholesteroNitrone 2 as an antioxidant and neuroprotective agent against ischemic injury. Neuroprotection was assessed using in vitro and in vivo experimental ischemia models. The compound significantly increased cell viability, induced neuroprotection following ischemic reperfusion, and decreased neurological deficit scores in treated animals, supporting the next preclinical studies as a potential agent for the treatment of stroke. PMID- 26241909 TI - [How Useful is a Geriatric Assessment Prior or Urological Surgery with Regard to Cognitive Changes?]. AB - OBJECTIVE: Detection of changes in cognition after transurethral resection (TURP) or 180-Watt green-light XPS laser treatment (GLL) of the prostate is required by the German "Krankenhausbedarfsplan" which demands an interdisciplinary dialogue including special aspects of the operating discipline. This has as yet not been investigated in Germany or in Europe. METHODS: Assessments of the cognitive capacity were made by application of the "Mini Mental State Examination" and the "Uhrentest" preoperatively and on postoperative day 2 in addition to documentation of clinical parameters such as patient age, prostate size, duration of surgery, comorbidities, co-medication, changes in haemoglobin and sodium. RESULTS: Patients treated with transurethral resection (n=88) or GLL (n=114) were comparable regarding age, prostate size and operative time. Baseline characteristics of the patients who would be treated with laser showed an increased potential for postoperative cognitive changes: they had an average of 3.8 comorbidities (TURP: 3.11, p=0.005) and were to a greater extent using multiple medications 6.79 (TURP: 5.24, p<0.001). However neither the MMSE nor Uhrentest demonstrated a decrease in the average postoperative score (difference post-preop. MMSE+0.6+/-1.6 for the GLL and+0.6+/-1.6 for TURP, p=0.944; difference post- and preoperative Uhrentest+0.43+/-1.44 for the GLL and 0.13+/ 1.17 for the TURP, p=0.097). Neither the postoperative haemoglobin nor the postoperative sodium, as safety-relevant parameters, demonstrated clinically relevant changes. The differences between the surgical procedures were not statistically significant. 28.6% of the patients with a preoperatively impaired cognition measured by an MMSE-score of<=23.7 incurred a further decline of their cognitive capability in comparison with patients without preoperative cognitive impairment with a further decline in 19.2%. CONCLUSIONS: Neither the GLL nor transurethral prostate resection demonstrated changes in cognition by comparing the preoperative Mini Mental State Examination or the Uhrentest. In this study, the baseline characteristics of lasered patients showed a higher number of comorbidities and a higher use of medication, in particular, with anticholinergic potency. Patients with a preoperatively impaired cognition had an increased risk of further worsening of their cognitive capabilities and should be treated carefully. PMID- 26241910 TI - [Low capacity bladder: dugs and/or toilet training]. AB - BACKGROUND: Behavioral interventions are part of the standard therapy for the overactive bladder syndrome although its impact still is unclear. METHODS: A systematic review according to the key words "overactive bladder" and "behavioral therapy" was undertaken. Original studies dealing with adults and with an English abstract were taken into consideration. RESULTS: Due to these requirements, only 6 studies were found. They use behavioral interventions as single therapy or compare a behavioral intervention with a standard drug therapy. On the one hand this was a direct comparison to a therapy with antimuscarinics, on the other hand drug therapy was augmented by behavioral interventions if the primary therapy failed. Inclusion criteria, patient characteristics, methods of behavioral intervention, the kind of media used and the results were inconsistent. As a result behavioral interventions are considered to be effective in controlling symptoms of an overactive bladder; in some studies an additive effect to drug therapy is seen if behavioral interventions are performed as supplementary measure; other studies could not confirm such an effect. CONCLUSION: Although experimental studies about micturition control in the CNS make a positive effect of behavioral interventions in overactive bladder more than likely, the literature reports on this topic remain inhomogeneous. PMID- 26241911 TI - Expression of human GLUD1 and GLUD2 glutamate dehydrogenases in steroid producing tissues. AB - Besides the housekeeping glutamate dehydrogenase1 (hGDH1), humans have acquired, via a recent duplication event, a hGDH2 isoenzyme with distinct functional properties and tissue expression profile. GDH catalyzes the reversible deamination of glutamate to alpha-ketoglutarate while reducing NAD(P) to NAD(P)H. As the generated NADPH can be used in bio-synthetic pathways, we studied here the expression of hGDH1 and hGDH2 in human steroidogenic tissues using specific antibodies. Results revealed high levels of hGDH1 and hGDH2 expression in steroid producing cells in all tissues studied. While the cellular expression pattern of the two proteins was similar for the adrenal cortex, it was distinct for testis, ovaries and placenta. Functional analyses revealed that steroid hormones interacted differentially with the two isoenzymes. As synthesis of steroid hormones requires NADPH, expression of hGDH1 and hGDH2 in steroidogenic cells may serve their particular metabolic needs. PMID- 26241912 TI - Multilevel Nonlinear Mixed-Effect Crown Ratio Models for Individual Trees of Mongolian Oak (Quercus mongolica) in Northeast China. AB - In this study, an individual tree crown ratio (CR) model was developed with a data set from a total of 3134 Mongolian oak (Quercus mongolica) trees within 112 sample plots allocated in Wangqing Forest Bureau of northeast China. Because of high correlation among the observations taken from the same sampling plots, the random effects at levels of both blocks defined as stands that have different site conditions and plots were taken into account to develop a nested two-level nonlinear mixed-effect model. Various stand and tree characteristics were assessed to explore their contributions to improvement of model prediction. Diameter at breast height, plot dominant tree height and plot dominant tree diameter were found to be significant predictors. Exponential model with plot dominant tree height as a predictor had a stronger ability to account for the heteroskedasticity. When random effects were modeled at block level alone, the correlations among the residuals remained significant. These correlations were successfully reduced when random effects were modeled at both block and plot levels. The random effects from the interaction of blocks and sample plots on tree CR were substantially large. The model that took into account both the block effect and the interaction of blocks and sample plots had higher prediction accuracy than the one with the block effect and population average considered alone. Introducing stand density into the model through dummy variables could further improve its prediction. This implied that the developed method for developing tree CR models of Mongolian oak is promising and can be applied to similar studies for other tree species. PMID- 26241913 TI - Self-assembly of biogenic gold nanoparticles and their use to enhance drug delivery into cells. AB - Integration of the principles of green chemistry into nanotechnology is one of the key issues in nanobio-science research. There is a growing need for development of a synthesis method for producing environmentally harmless nanoparticles in order to avoid adverse effects in medical applications. Here, we report the use of a simple and rapid in vivo biosynthesis method for the preparation of gold nanoparticles (AuNPs) using heavy metal binding proteins (HMBPs) in recombinant Escherichia coli. The HMBPs were found to act as reducing, stabilizing, and capping agents to form the spherical nanoparticles with 5-20 nm in diameter. The size and the shape of AuNPs were modulated by varying the concentration ratio of recombinant proteins in the medium. Only 20 min was required to form AuNPs at room temperature, suggesting that the reaction rate of the proposed method is faster than that of the chemical methods commonly used for nanoparticle synthesis. The AuNPs could be applied as drug carriers in therapeutic applications to improve drug delivery, since they exhibit higher biocompatibility and less toxic effects than chemically synthesized materials. To achieve high cytotoxicity for cancer chemotherapy, doxorubicin (Dox) was released from AuNPs, which can be a more efficient anti-cancer agent than free Dox. PMID- 26241914 TI - Synthesis of PEG-PCL-based polyurethane nanoparticles by miniemulsion polymerization. AB - In this work biocompatible polyurethane nanoparticles for future application as noninvasive polymeric nanocarriers using propellant-based inhalers in the treatment of respiratory diseases were prepared by miniemulsion interfacial polymerization derived from isophorone diisocyanate, poly(epsilon-caprolactone), and poly(ethylene glycol). The effects of the surfactant type, nonionic Tween 80 and Brij 35, anionic sodium dodecyl sulfate, and cationic cetyltrimethyl ammonium bromide, and poly(ethylene glycol) molar mass on the stability, size and morphology of nanoparticles were evaluated. In addition, the ability of cells to proliferate in contact with polyurethane nanoparticles was assessed by MTS ([(3 (4,5-dimethylthiazole-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfo-phenyl)-2H tetrazolium, inner salt]) assay using human lung adenocarcinoma A549 cells, an in vitro model of Type II alveolar epithelium. PMID- 26241915 TI - Enhancement of in vivo human skin penetration of resveratrol by chitosan-coated lipid microparticles. AB - In this study, lipid microparticles (LMs) uncoated or coated with chitosan, and containing the antioxidant polyphenol, resveratrol were developed in order to enhance its in vivo skin permeation. The LMs loaded with resveratrol were prepared by melt emulsification and sonication, using tristearin as lipidic material and hydrogenated phosphatidylcholine as the surfactant. Two different methods were examined for the coating of the LMs: chitosan addition during LM preparation or treatment of already formed LMs with a chitosan solution. The latter method achieved a better modulation of the in vitro release of resveratrol and hence was used for subsequent studies. The resveratrol loading and mean diameter of the LMs were 4.1 +/- 0.3% (w/w) and 5.7 MUm and 3.8 +/- 0.2 % (w/w) and 6.1 MUm for the uncoated and the chitosan-coated LMs, respectively. Chitosan coating changed the LM surface charge, from a negative zeta potential value ( 17.8 +/- 4.8 mV) for the uncoated particles, to a higher positive values (+64.2 +/- 4.4 mV) for the chitosan-coated ones. Creams containing resveratrol free, encapsulated in the uncoated or chitosan-coated LMs were applied to the forearm of human volunteers and the penetration of the polyphenol in the stratum corneum was investigated in vivo by the tape stripping technique. Uncoated LMs did not produce any significant increase in the fraction of the applied resveratrol dose diffused in the stratum corneum (32.8 +/- 8.9 %) compared to the control cream containing the non-encapsulated polyphenol (26.2 +/- 5.6 % of the applied dose). On the other hand, application of the cream containing the chitosan-coated LMs produced a significant enhancement in the in vivo permeation of resveratrol to 49.3 +/- 5.9% of the applied dose, the effect being more marked in the upper region of the horny layer. The observed improvement in the human stratum corneum penetration of resveratrol achieved by the LMs coated with chitosan should favour the efficiency of its topical application. PMID- 26241916 TI - In-vitro assessment of cytotoxicity of halloysite nanotubes against HepG2, HCT116 and human peripheral blood lymphocytes. AB - Halloysite is a clay mineral with chemical similarity to kaolin, a pharmaceutical ingredient. It consists of mainly aluminosilicate nanotubular particles in the size range of ~ 200-1000 nm. Many studies have tried to empirically explore this novel clay for its potential in drug delivery systems but no work has yet studied its cytotoxicity from the perspective of oral drug delivery system. In this study, the halloysite nanotubes (HNTs) were subjected to size distribution analyses, which reveal more than 50% of nanotubes in the size range of 500 nm and rest mainly in the sub micrometer range. HNTs were then evaluated for in-vitro cytotoxicity against HCT116 (colorectal carcinoma) and HepG2 (hepatocellular carcinoma) cells which represent the earliest entry point and the first accumulating organ, respectively, for nanoparticles en-route to systemic circulation after oral delivery. Moreover, HNTs were tested for their cytogenetic toxicity against human peripheral blood lymphocytes. Both these results collectively indicated that HNTs are generally safe at practical concentrations of excipients for oral dosage forms. PMID- 26241917 TI - Strategies of polymeric nanoparticles for enhanced internalization in cancer therapy. AB - In order to achieve long circulation time and high drug accumulation in the tumor sites via the EPR effects, anticancer drugs have to be protected by non-fouling polymers such as poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), dextran, and poly(acrylic acid) (PAA). However, the dense layer of stealth polymer also prohibits efficient uptake of anticancer drugs by target cancer cells. For cancer therapy, it is often more desirable to accomplish rapid cellular uptake after anticancer drugs arriving at the pathological site, which could on one hand maximize the therapeutic efficacy and on the other hand reduce probability of drug resistance in cells. In this review, special attention will be focused on the recent potential strategies that can enable drug-loaded polymeric nanoparticles to rapidly recognize cancer cells, leading to enhanced internalization. PMID- 26241918 TI - The influence of small intestinal mucus structure on particle transport ex vivo. AB - Mucus provides a barrier to bacteria and toxins while allowing nutrient absorption and waste transport. Unlike colonic mucus, small intestinal mucus structure is poorly understood. This study aimed to provide evidence for a continuous, structured mucus layer and assess the diffusion of different sized particles through it. Mucus structure was assessed by histology and immunohistochemistry. Ultra-structure was assessed by scanning electron microscopy. Tracking of 100 nm and 500 nm latex beads was conducted using ex vivo porcine mucus. The porcine jejunum and ileum were filled with mucus. Layered MUC2 staining was visible throughout the small intestine, covering villus tips. Scanning electron microscopy showed net-like mucin sheets covering villi (211 +/- 7 nm pore diameter). Particle tracking of 100 nm latex beads, showed no inhibition of diffusion through mucus while 500 nm beads displayed limited diffusion. These results suggest a continuous mucus layer exists throughout the small intestine, which is highly stratified adjacent to the epithelium. The network observed is consistent with previous observations and correlates with stratified MUC2 staining. Mucin pore size is consistent with free diffusion of 100 nm and limited diffusion of 500 nm particles. Small Intestinal mucus structure has important implications for drug delivery systems and prevention and treatment of conditions like mucositis and inflammatory bowel disease. PMID- 26241919 TI - Microsphere-based selective laser sintering for building macroporous bone scaffolds with controlled microstructure and excellent biocompatibility. AB - Fabrication of bulk biomaterials with controlled structures and excellent properties is increasingly important in tissue engineering, but remains a major challenge in the current stage. Herein we used selective laser sintering (SLS) to construct a series of three-dimensional (3D) bone scaffolds with uniform multi scaled porosity, moderate mechanical properties as well as good biocompatibility. As starting architectural units for SLS, the pure microspheres of polycaprolactone (PCL) and the composite microspheres of PCL and hydroxyapatite (HA) were firstly synthesized via a modified solvent evaporation method, respectively. Our findings showed that the as-prepared microspheres exhibited the uniform size and monodispersity. Moreover, the microsphere-based 3D scaffolds generated by SLS technique showed a multi-scaled porous structure, and adequate mechanical features. Both in vitro and in vivo evaluations further demonstrated that the resultant SLS-derived scaffolds can not only manipulate multiple stem cell behaviors including promoting cell adhesion, supporting cell proliferation and inducing cell differentiation in vitro, but also showed an excellent histocompatibility and induced the vascularization of newly formed tissue in vivo. Consequently, our current study suggests a feasible and effective protocol for fabricating new biomimetic bone biomaterials via SLS technique, also paves a new way for other bulk biomaterials. PMID- 26241920 TI - Size controlled protein nanoemulsions for active targeting of folate receptor positive cells. AB - Bovine serum albumin (BSA) nanoemulsions were produced by high pressure homogenization with a tri-block copolymer (Poloxamer 407), which presents a central hydrophobic chain of polyoxypropylene (PPO) and two identical lateral hydrophilic chains of polyethylene glycol (PEG). We observed a linear correlation between tri-block copolymer concentration and size - the use of 5mg/mL of Poloxamer 407 yields nanoemulsions smaller than 100nm. Molecular dynamics and fluorescent tagging of the tri-block copolymer highlight their mechanistic role on the size of emulsions. This novel method enables the fabrication of highly stable albumin emulsions in the nano-size range, highly desirable for controlled drug delivery. Folic Acid (FA)-tagged protein nanoemulsions were shown to promote specific folate receptor (FR)-mediated targeting in FR positive cells. The novel strategy presented here enables the construction of size controlled, functionalized protein-based nanoemulsions with excellent characteristics for active targeting in cancer therapy. PMID- 26241921 TI - A rational approach towards the design of chitosan-based nanoparticles obtained by ionotropic gelation. AB - Chitosan is a linear aminopolysaccharide that has been widely used for the formation of chitosan-based nanoparticles by ionic gelation with sodium tripolyphosphate (TPP). Often, the experimental design used to obtain these systems does not take into consideration important variables, such as the degree of acetylation (DA) and the molecular weight (Mw) of chitosan. In this work, we studied the formation of chitosan-TPP nanoparticles with chitosan samples of varying DA and Mw (DA0 ~ 0-47% and Mw ~ 2.5-282 kDa). We addressed the influence the degree of space occupancy and the degree of crosslinking on the physical properties of chitosan-TPP nanoparticles. Nanoparticles that comprised chitosan of DA ~ 0-21.7% behaved differently than those made of chitosan of DA ~ 34.7-47%. We attributed these differences to the polymer conformation and chain flexibility of the distinct chitosans in solution. Moreover, chitosan of high Mw were found to have a stronger preference for incorporating into the formed nanoparticles than do low-Mw ones, as determined by SEC-HPLC. These results open new perspectives to understand the formation of chitosan nanoparticles by the ionic gelation technique. PMID- 26241922 TI - Liposomes loaded with hydrophilic magnetite nanoparticles: Preparation and application as contrast agents for magnetic resonance imaging. AB - Magnetic fluid-loaded liposomes (MFLs) were fabricated using magnetite nanoparticles (MNPs) and natural phospholipids via the thin film hydration method followed by extrusion. The size distribution and composition of MFLs were studied using dynamic light scattering and spectrophotometry. The effective ranges of magnetite concentration in MNPs hydrosol and MFLs for contrasting at both T2 and T1 relaxation were determined. On T2 weighted images, the MFLs effectively increased the contrast if compared with MNPs hydrosol, while on T1 weighted images, MNPs hydrosol contrasting was more efficient than that of MFLs. In vivo magnetic resonance imaging (MRI) contrasting properties of MFLs and their effects on tumor and normal tissues morphology, were investigated in rats with transplanted renal cell carcinoma upon intratumoral administration of MFLs. No significant morphological changes in rat internal organs upon intratumoral injection of MFLs were detected, suggesting that the liposomes are relatively safe and can be used as the potential contrasting agents for MRI. PMID- 26241923 TI - Polycaprolactone multicore-matrix particle for the simultaneous encapsulation of hydrophilic and hydrophobic compounds produced by membrane emulsification and solvent diffusion processes. AB - Co-encapsulation of drugs in the same carrier, as well as the development of microencapsulation processes for biomolecules using mild operating conditions, and the production of particles with tailored size and uniformity are major challenges for encapsulation technologies. In the present work, a suitable method consisting of the combination of membrane emulsification with solvent diffusion is reported for the production of multi-core matrix particles with tailored size and potential application in multi-therapies. In the emulsification step, the production of a W/O/W emulsion was carried out using a batch Dispersion Cell for formulation testing and subsequently a continuous azimuthally oscillating membrane emulsification system for the scaling-up of the process to higher capacities. In both cases precise and gentle control of droplet size and uniformity of the W/O/W emulsion was achieved, preserving the encapsulation of the drug model within the droplet. Multi-core matrix particles were produced in a post emulsification step using solvent diffusion. The compartmentalized structure of the multicore-matrix particle combined with the different chemical properties of polycaprolactone (matrix material) and fish gelatin (core material) was tested for the simultaneous encapsulation of hydrophilic (copper ions) and hydrophobic (alpha-tocopherol) test components. The best operating conditions for the solidification of the particles to achieve the highest encapsulation efficiency of copper ions and alpha-tocopherol of 99 (+/- 4)% and 93(+/- 6)% respectively were found. The multi-core matrix particle produced in this work demonstrates good potential as a co-loaded delivery system. PMID- 26241924 TI - Synthesis, nanoprecipitation and pH sensitivity of amphiphilic linear-dendritic hybrid polymers and hyperbranched-polydendrons containing tertiary amine functional dendrons. AB - The combination of linear polymers with dendritic chain-ends has led to numerous studies of linear-dendritic polymer hybrid materials. Interchain branching within the linear segment of these materials has recently extended this concept to the formation of soluble hyperbranched-polydendrons. Here, the introduction of amphiphilicity into hyperbranched-polydendrons has been achieved for the first time through the use of tertiary amine functional dendritic chain-ends and branched hydrophobic polymer segments. The synthesis and aqueous nanoprecipitation of these branched materials is compared with their linear dendritic polymer analogues, showing that chain-end chemistry/generation, precipitation medium pH and polymer architecture are all capable of influencing the ability to generate nanoparticles, the resulting nanoparticle diameter and dispersity, and subsequent response to changes in pH. PMID- 26241925 TI - Experimental investigation and oral bioavailability enhancement of nano-sized curcumin by using supercritical anti-solvent process. AB - The biomedical applications of curcumin (CUR) are limited due to its poor oral bioavailability. In this work, CUR nanoparticles were successfully prepared by combining the supercritical anti-solvent (SAS) process with Tween 80 as a solubilizing agent and permeation enhancer. Different processing parameters that can govern the mean particle size and size distribution of nanoparticles were well investigated by manipulating the types of solvents, mixing vessel pressure, mixing vessel temperature, CO2 flow rate, solution flow rate and solution concentration. Solid state characterization was done by Fourier Transform infrared spectroscopy, differential scanning calorimetry, dynamic light scattering, scanning electron microscopy, and powder X-ray diffraction study. Solubility and dissolution profile of SAS-processed CUR were found to be significantly increased in comparison with native CUR. Further, a validated ultra performance liquid chromatographic method with quadrupole-time of flight-mass spectrometry was developed to investigate the pharmacokinetic parameters after a single oral dose (100mg/kg) administration of CUR (before/after SAS-processed) in male Wistar rats. From the plasma concentration vs. time profile graph, oral bioavailability of SAS-processed CUR was found to be increased approximately 11.6 fold (p<0.001) as compared to native CUR. PMID- 26241926 TI - Contribution of Lumbar Spine BMD to Fracture Risk in Individuals With T-Score Discordance. AB - Fracture risk estimates are usually based on femoral neck (FN) BMD. It is unclear how to address T-score discordance, where lumbar spine (LS) T-score is lower than FN T-score. The objective of this work was to examine the impact of LS BMD on fracture risk, in individuals with lower LS T-score than FN T-score. Participants aged 60+ years from the Dubbo Osteoporosis Epidemiology Study with LS and FN BMD measured at first visit, and were followed from 1989 to 2014. Five-hundred and seventy-three (573) of 2270 women and 131 of 1373 men had lower LS than FN T score by >= 0.6 standard deviation (SD) (low-LS group based on least significant change). In low-LS women, each 1 SD lower LS T-score than FN was associated with a 30% increase in fracture risk (hazard ratio [HR] 1.30; 95% CI, 1.11 to 1.45). For low-LS men there was a 20% nonsignificant increase in fracture risk for each 1 SD lower LS than FN T-score (HR 1.20; 95% CI, 0.10 to 1.67). Low-LS women had greater absolute fracture risks than the rest of the women. This increased risk was more apparent for lower levels of FN T-score and in older age groups. At an FN T-score of -2, low-LS women had a 3%, 10%, and 23% higher 5-year absolute fracture risk than non-low LS women in the 60 to 69 year, 70 to 79 year, and 80+ years age-groups, respectively. Furthermore, an osteoporotic LS T-score increased 5-year absolute fracture risk for women with normal or osteopenic FN T-score by 10% to 13%. Men in the low-LS group had very few fractures; therefore, a meaningful analyses of fracture risk could not be conducted. This study shows the significant contribution of lower LS BMD to fracture risk over and above FN BMD in women. A LS BMD lower than FN BMD should be incorporated into fracture risk calculators at least for women in older age-groups. PMID- 26241927 TI - Using Drosophila models of Huntington's disease as a translatable tool. AB - The Huntingtin (Htt) protein is essential for a wealth of intracellular signaling cascades and when mutated, causes multifactorial dysregulation of basic cellular processes. Understanding the contribution to each of these intracellular pathways is essential for the elucidation of mechanisms that drive pathophysiology. Using appropriate models of Huntington's disease (HD) is key to finding the molecular mechanisms that contribute to neurodegeneration. While mouse models and cell lines expressing mutant Htt have been instrumental to HD research, there has been a significant contribution to our understating of the disease from studies utilizing Drosophila melanogaster. Flies have an Htt protein, so the endogenous pathways with which it interacts are likely conserved. Transgenic flies engineered to overexpress the human mutant HTT gene display protein aggregation, neurodegeneration, behavioral deficits and a reduced lifespan. The short life span of flies, low cost of maintaining stocks and genetic tools available for in vivo manipulation make them ideal for the discovery of new genes that are involved in HD pathology. It is possible to do rapid genome wide screens for enhancers or suppressors of the mutant Htt-mediated phenotype, expressed in specific tissues or neuronal subtypes. However, there likely remain many yet unknown genes that modify disease progression, which could be found through additional screening approaches using the fly. Importantly, there have been instances where genes discovered in Drosophila have been translated to HD mouse models. PMID- 26241929 TI - Thermal treatment of medical waste in a rotary kiln. AB - This paper presents the results of a study of an experimental system with thermal treatment (incineration) of medical waste conducted at a large complex of hospital facilities. The studies were conducted for a period of one month. The processing system was analysed in terms of the energy, environmental and economic aspects. A rotary combustion chamber was designed and built with the strictly assumed length to inner diameter ratio of 4:1. In terms of energy, the temperature distribution was tested in the rotary kiln, secondary combustion (afterburner) chamber and heat recovery system. Calorific value of medical waste was 25.0 MJ/kg and the thermal efficiency of the entire system equalled 66.8%. Next, measurements of the pollutant emissions into the atmosphere were performed. Due to the nature of the disposed waste, particular attention was paid to the one minute average values of carbon oxide and volatile organic compounds as well as hydrochloride, hydrogen fluoride, sulphur dioxide and total dust. Maximum content of non-oxidized organic compounds in slag and bottom ash were also verified during the analyses. The best rotary speed for the combustion chamber was selected to obtain proper afterburning of the bottom slag. Total organic carbon content was 2.9%. The test results were used to determine the basic economic indicators of the test system for evaluating the profitability of its construction. Simple payback time (SPB) for capital expenditures on the implementation of the project was 4 years. PMID- 26241928 TI - piRNAs Are Associated with Diverse Transgenerational Effects on Gene and Transposon Expression in a Hybrid Dysgenic Syndrome of D. virilis. AB - Sexual reproduction allows transposable elements (TEs) to proliferate, leading to rapid divergence between populations and species. A significant outcome of divergence in the TE landscape is evident in hybrid dysgenic syndromes, a strong form of genomic incompatibility that can arise when (TE) family abundance differs between two parents. When TEs inherited from the father are absent in the mother's genome, TEs can become activated in the progeny, causing germline damage and sterility. Studies in Drosophila indicate that dysgenesis can occur when TEs inherited paternally are not matched with a pool of corresponding TE silencing PIWI-interacting RNAs (piRNAs) provisioned by the female germline. Using the D. virilis syndrome of hybrid dysgenesis as a model, we characterize the effects that divergence in TE profile between parents has on offspring. Overall, we show that divergence in the TE landscape is associated with persisting differences in germline TE expression when comparing genetically identical females of reciprocal crosses and these differences are transmitted to the next generation. Moreover, chronic and persisting TE expression coincides with increased levels of genic piRNAs associated with reduced gene expression. Combined with these effects, we further demonstrate that gene expression is idiosyncratically influenced by differences in the genic piRNA profile of the parents that arise though polymorphic TE insertions. Overall, these results support a model in which early germline events in dysgenesis establish a chronic, stable state of both TE and gene expression in the germline that is maintained through adulthood and transmitted to the next generation. This work demonstrates that divergence in the TE profile is associated with diverse piRNA-mediated transgenerational effects on gene expression within populations. PMID- 26241930 TI - Automated negotiation in environmental resource management: Review and assessment. AB - Negotiation is an integral part of our daily life and plays an important role in resolving conflicts and facilitating human interactions. Automated negotiation, which aims at capturing the human negotiation process using artificial intelligence and machine learning techniques, is well-established in e-commerce, but its application in environmental resource management remains limited. This is due to the inherent uncertainties and complexity of environmental issues, along with the diversity of stakeholders' perspectives when dealing with these issues. The objective of this paper is to describe the main components of automated negotiation, review and compare machine learning techniques in automated negotiation, and provide a guideline for the selection of suitable methods in the particular context of stakeholders' negotiation over environmental resource issues. We advocate that automated negotiation can facilitate the involvement of stakeholders in the exploration of a plurality of solutions in order to reach a mutually satisfying agreement and contribute to informed decisions in environmental management along with the need for further studies to consolidate the potential of this modeling approach. PMID- 26241931 TI - Building green supply chains in eco-industrial parks towards a green economy: Barriers and strategies. AB - As suggested by UNEP, the key to sustainable development is to create a "green economy" which should encapsulate all three sectors: the industry, the people, and the government. Therefore, there is an urgent need to develop and implement the green technologies into the existing facilities, especially in the developing countries. In this study, the role of green supply chains in eco-industrial parks (EIPs) towards a green economy was investigated. The strategies and effective evaluation procedures of the green economy were proposed by assessing the barriers from the perspective of institution, regulation, technology, and finance. In addition, three case studies from iron and steel-making, paper mill and pulping, and petrochemical industries were presented and illustrated for building the green supply chains. For example, in the case of Lin-Hai Industrial Park, a total of 15 efficient green supply chains using waste-to-resources technologies were established by 2012, resulting in an economic benefit of USD 100 million per year. It suggests that the green supply chains should be established to achieve both economic growth and environmental protection. With these successful experiences, building a green supply chain within industrial park should be extensively promoted to make traditional industries around the world being environmentally bearable, economic viable, and social equitable. PMID- 26241932 TI - Hydraulic performance of compacted clay liners under simulated daily thermal cycles. AB - Compacted clay liners (CCLs) are commonly used as hydraulic barriers in several landfill applications to isolate contaminants from the surrounding environment and minimize the escape of leachate from the landfill. Prior to waste placement in landfills, CCLs are often exposed to temperature fluctuations which can affect the hydraulic performance of the liner. Experimental research was carried out to evaluate the effects of daily thermal cycles on the hydraulic performance of CCLs under simulated landfill conditions. Hydraulic conductivity tests were conducted on different soil specimens after being exposed to various thermal and dehydration cycles. An increase in the CCL hydraulic conductivity of up to one order of magnitude was recorded after 30 thermal cycles for soils with low plasticity index (PI = 9.5%). However, medium (PI = 25%) and high (PI = 37.2%) plasticity soils did not show significant hydraulic deviation due to their self healing potential. Overlaying the CCL with a cover layer minimized the effects of daily thermal cycles, and maintained stable hydraulic performance in the CCLs even after exposure to 60 thermal cycles. Wet-dry cycles had a significant impact on the hydraulic aspect of low plasticity CCLs. However, medium and high plasticity CCLs maintained constant hydraulic performance throughout the test intervals. The study underscores the importance of protecting the CCL from exposure to atmosphere through covering it by a layer of geomembrane or an interim soil layer. PMID- 26241933 TI - Adapting livestock management to spatio-temporal heterogeneity in semi-arid rangelands. AB - Management strategies in rotational grazing systems differ in their level of complexity and adaptivity. Different components of such grazing strategies are expected to allow for adaptation to environmental heterogeneities in space and time. However, most models investigating general principles of rangeland management strategies neglect spatio-temporal system properties including seasonality and spatial heterogeneity of environmental variables. We developed an ecological-economic rangeland model that combines a spatially explicit farm structure with intra-annual time steps. This allows investigating different management components in rotational grazing systems (including stocking and rotation rules) and evaluating their effect on the ecological and economic states of semi-arid grazing systems. Our results show that adaptive stocking is less sensitive to overstocking compared to a constant stocking strategy. Furthermore, the rotation rule becomes important only at stocking numbers that maximize expected income. Altogether, the best of the tested strategies is adaptive stocking combined with a rotation that adapts to both spatial forage availability and seasonality. This management strategy maximises mean income and at the same time maintains the rangeland in a viable condition. However, we could also show that inappropriate adaptation that neglects seasonality even leads to deterioration. Rangelands characterised by higher inter-annual climate variability show a higher risk of income losses under a non-adaptive stocking rule, and non-adaptive rotation is least able to buffer increasing climate variability. Overall, all important system properties including seasonality and spatial heterogeneity of available resources need to be considered when designing an appropriate rangeland management system. Resulting adaptive rotational grazing strategies can be valuable for improving management and mitigating income risks. PMID- 26241934 TI - A safe, efficient and cost effective process for removing petroleum hydrocarbons from a highly heterogeneous and relatively inaccessible shoreline. AB - A rocky, intractable and highly heterogeneous, intertidal zone, was contaminated from a diesel fuel spill that occurred during refuelling of a grader used in road construction, on an operational mine's shiploading facility. A practical, cost effective, and safer (to personnel by avoiding drilling and earthworks), and non invasive sampling and remediation strategy was designed and implemented since the location and nature of the impacted geology (rock fill) and sediment, precluded conventional ex-situ and any in-situ treatment where drilling would be required. Enhanced biostimulation with surfactant, available N & P (which were highly constrained), and increased aeration, increased the degradation rate from no discernable change for 2 years post-spill, to 170 mg/kg/day; the maximum degradation rate after intervention. While natural attenuation was ineffective in this application, the low-cost, biostimulation intervention proved successful, allowing the site owner to meet their regulatory obligations. Petroleum hydrocarbons (aliphatic fraction) decreased from ~20,000 mg/kg to <200 mg/kg at the completion of 180 weeks of treatment. PMID- 26241935 TI - Novel tradable instruments in the conservation of coral reefs, based on the coral gardening concept for reef restoration. AB - Nearly all coral reefs bordering nations have experienced net losses in reef biodiversity, goods and services, even without considering the ever-developing global change impacts. In response, this overview wishes to reveal through prospects of active reef-restoration, the currently non-marketed or poorly marketed reef services, focusing on a single coral species (Stylophora pistillata). It is implied that the integration of equity capitals and other commodification with reef-restoration practices will improve total reef services. Two tiers of market-related activities are defined, the traditional first-tier instruments (valuating costs/gains for extracting tradable goods and services) and novel second-tier instruments (new/expanded monetary tools developed as by products of reef restoration measures). The emerging new suite of economic mechanisms based on restoration methodologies could be served as an incentive for ecosystem conservation, enhancing the sum values of all services generated by coral reefs, where the same stocks of farmed/transplanted coral colonies will be used as market instruments. I found that active restoration measures disclose 12 classes of second-tier goods and services, which may partly/wholly finance restoration acts, bringing to light reef capitalizations that allow the expansion of markets with products that have not been considered before. The degree to which the second tier of market-related services could buffer coral-reef degradation is still unclear and would vary with different reef types and in various reef restoration scenarios; however, reducing the uncertainty associated with restoration. It is expected that the expansion of markets with the new products and the enhancement of those already existing will be materialized even if reef ecosystems will recover into different statuses. PMID- 26241936 TI - Correlation between mesopore volume of carbon supports and the immobilization of laccase from Trametes versicolor for the decolorization of Acid Orange 7. AB - Immobilization of laccase from Trametes versicolor was carried out using carbon supports prepared from different lignocellulosic wastes. Enzymes were immobilized by physical adsorption. Taguchi methodology was selected for the design of experiments regarding the preparation of the carbon materials, which included the use of activating agents for the promotion of mesoporosity. A good correlation between the mesopore volumes of the carbon supports and the corresponding laccase loadings attained was observed. Specifically, the chemical activation of pecan nut shell with FeCl3 led to a highly mesoporous material that also behaved as the most efficient support for the immobilization of laccase. This particular laccase/carbon support system was used as biocatalyst for the decolorization of aqueous solutions containing Acid Orange 7. Mass spectrometry coupled to a liquid chromatograph allowed us to identify the products of the dye degradation. PMID- 26241937 TI - High-density lipoprotein deficiency in genetically modified mice deeply affects skin morphology: A structural and ultrastructural study. AB - Cutaneous lipids, endogenously synthetized and transported by lipoproteins, play a pivotal role in maintaining skin barrier. An impairment of extracutaneous lipid trafficking leads to the development of xanthomas, mostly arising in hyperlipidemic patients, but also in subjects with high-density lipoprotein (HDL) deficiency. The aim of this work was to evaluate, in a genetically modified mouse model, lacking two protein components of HDL particles, apolipoprotein(apo)E and apoA-I, the effect of HDL deficiency on skin morphology. Control mice (C57BL/6), apoE deficient mice (EKO), apoA-I deficient mice (A-IKO) and apoA-I/apoE double knockout mice (A-IKO/EKO) were maintained on a low-fat/low-cholesterol diet up to 30 weeks of age. At sacrifice, skin biopsies were processed for light (LM) and transmission electron microscopy (TEM). Whereas the skin of EKO, A-IKO, and C57BL/6 mice was comparable, LM analysis in A-IKO/EKO mice showed an increase in dermal thickness and the presence of foam cells and T lymphocytes in reticular dermis. TEM analysis revealed the accumulation of cholesterol clefts in the papillary dermis and of cholesterol crystals within foam cells. In conclusion, A IKO/EKO mice represent an experimental model for investigating the cutaneous phenotype of human HDL deficiency, thus mimicking a condition in which human xanthomatous lesions can develop. PMID- 26241938 TI - Breast cancer: rational use of regional nodal irradiation needed. PMID- 26241939 TI - Clinical overview of metronomic chemotherapy in breast cancer. AB - Over 15 years ago, low-dose metronomic chemotherapy was shown to induce disease control in patients with advanced-stage breast cancer with a lower incidence of adverse events compared with conventional maximum tolerated dose chemotherapy. Good response rates have been seen in heavily pre-treated patients for whom limited treatment options are available. Most patients prefer oral therapy and metronomic chemotherapy is a convenient alternative in patients with advanced stage disease in which minimal toxicity and good tumour control are the overall aims of treatment. The addition of metronomic protocols to standard neoadjuvant chemotherapy regimens has produced promising pathological complete response rates. Ongoing trials including the SYSUCC-001 trial in patients with triple negative breast cancer and the IBCSG 22-00 trial that is assessing a cyclophosphamide-methotrexate maintenance regimen after standard adjuvant therapy in hormone receptor-negative disease, will clarify the value of adding this approach to conventional therapies. The low cost associated with metronomic chemotherapy represents an opportunity for the utilization of this treatment option, especially in developing countries, and poses a challenge for the launch of large trials sponsored by industry. Using breast cancer as the principal example, we discuss the key clinical advances in this area, including new trial design, appropriate patient and end point selection, as well as the evolving rationale for metronomic chemotherapy combinations. PMID- 26241940 TI - MKL1 is an epigenetic modulator of TGF-beta induced fibrogenesis. AB - Transforming growth factor (TGF-beta) induced activation of portal fibroblast cells serves as a primary cause for liver fibrosis following cholestatic injury. The underlying epigenetic mechanism is not clear. We studied the role of a transcriptional modulator, megakaryoblastic leukemia 1 (MKL1) in this process. We report here that MKL1 deficiency ameliorated BDL-induced liver fibrosis in mice as assessed by histological stainings and expression levels of pro-fibrogenic genes. MKL1 silencing by small interfering RNA (siRNA) abrogated TGF-beta induced transactivation of pro-fibrogenic genes in portal fibroblast cells. TGF-beta stimulated the binding of MKL1 on the promoters of pro-fibrogenic genes and promoted the interaction between MKL1 and SMAD3. While SMAD3 was necessary for MKL1 occupancy on the gene promoters, MKL1 depletion impaired SMAD3 binding reciprocally. TGF-beta treatment induced the accumulation of trimethylated histone H3K4 on the gene promoters by recruiting a methyltransferase complex. Knockdown of individual members of this complex significantly weakened the binding of SMAD3 and down-regulated the activation of portal fibroblast cells. In conclusion, we have identified an epigenetic pathway that dictates TGF-beta induced pro-fibrogenic transcription in portal fibroblast thereby providing novel insights for the development of therapeutic solutions to treat liver fibrosis. PMID- 26241941 TI - The NO stimulator, Catestatin, improves the Frank-Starling response in normotensive and hypertensive rat hearts. AB - The myocardial response to mechanical stretch (Frank-Starling law) is an important physiological cardiac determinant. Modulated by many endogenous substances, it is impaired in the presence of cardiovascular pathologies and during senescence. Catestatin (CST:hCgA352-372), a 21-amino-acid derivate of Chromogranin A (CgA), displays hypotensive/vasodilatory properties and counteracts excessive systemic and/or intra-cardiac excitatory stimuli (e.g., catecholamines and endothelin-1). CST, produced also by the myocardium, affects the heart by modulating inotropy, lusitropy and the coronary tone through a Nitric Oxide (NO)-dependent mechanism. This study evaluated the putative influence elicited by CST on the Frank-Starling response of normotensive Wistar Kyoto (WKY) and hypertensive (SHR) hearts by using isolated and Langendorff perfused cardiac preparations. Functional changes were evaluated on aged (18 month-old) WKY rats and SHR which mimic human chronic heart failure (HF). Comparison to WKY rats, SHR showed a reduced Frank-Starling response. In both rat strains, CST administration improved myocardial mechanical response to increased end-diastolic pressures. This effect was mediated by EE/IP3K/NOS/NO/cGMP/PKG, as revealed by specific inhibitors. CST-dependent positive Frank-Starling response is paralleled by an increment in protein S-Nitrosylation. Our data suggested CST as a NO-dependent physiological modulator of the stretch-induced intrinsic regulation of the heart. This may be of particular importance in the aged hypertrophic heart, whose function is impaired because of a reduced systolic performance accompanied by delayed relaxation and increased diastolic stiffness. PMID- 26241942 TI - 3D Simulation Modeling of the Tooth Wear Process. AB - Severe tooth wear is the most common non-caries dental disease, and it can seriously affect oral health. Studying the tooth wear process is time-consuming and difficult, and technological tools are frequently lacking. This paper presents a novel method of digital simulation modeling that represents a new way to study tooth wear. First, a feature extraction algorithm is used to obtain anatomical feature points of the tooth without attrition. Second, after the alignment of non-attrition areas, the initial homogeneous surface is generated by means of the RBF (Radial Basic Function) implicit surface and then deformed to the final homogeneous by the contraction and bounding algorithm. Finally, the method of bilinear interpolation based on Laplacian coordinates between tooth with attrition and without attrition is used to inversely reconstruct the sequence of changes of the 3D tooth morphology during gradual tooth wear process. This method can also be used to generate a process simulation of nonlinear tooth wear by means of fitting an attrition curve to the statistical data of attrition index in a certain region. The effectiveness and efficiency of the attrition simulation algorithm are verified through experimental simulation. PMID- 26241943 TI - Agricultural Activities of a Meadow Eliminated Plant Litter from the Periphery of a Farmland in Inner Mongolia, China. AB - The purpose of our investigation was to clarify the effects of agriculture on the process of loss of litter at the periphery of a farmland. This study revealed the generation process of an ecologically unusual phenomenon that is observed around cropland in semi-arid regions. We hypothesized that the vegetation around a farmland cannot supply plant litter to the ground surface because the ecological structure has been changed by agricultural activities. The study was conducted at Xilingol steppe, Xilingol League, Inner Mongolia Autonomous Region, China. Four study lines were established from the edge of an arable field to the surrounding meadow and parallel to the wind direction during the strong wind season. Key measurement for each line was set at the border between the farmland and steppe. Four study sites were set at intervals along each line. Plant litter, soil particle size distribution, plant species composition, plant volume, and species diversity were investigated. Despite using the same mowing method at the meadows of all study sites, the litter at the only periphery of the farmland completely disappeared. Soil particle size distribution in steppe, which was adjacent to the farmland, was similar to that of the farmland. Plant community structure at the periphery of the farmland was different from that of the far side from the farmland. This implies that soil scattered from the farmland affected the species composition of the steppe. Consequently, the change in plant community structure induced litter loss because of mowing. We concluded that plant litter was lost near the farmland because of the combined effects of farming and mowing. The results support our hypothesis that the vegetation around a farmland cannot supply plant litter because the ecological structure has been changed by agricultural activities. PMID- 26241944 TI - Two Mitochondrial Barcodes for one Biological Species: The Case of European Kuhl's Pipistrelles (Chiroptera). AB - The Kuhl's pipistrelle (Pipistrellus kuhlii) is a Western Palaearctic species of bat that exhibits several deeply divergent mitochondrial lineages across its range. These lineages could represent cryptic species or merely ancient polymorphism, but no nuclear markers have been studied so far to properly assess the taxonomic status of these lineages. We examined here two lineages occurring in Western Europe, and used both mitochondrial and nuclear markers to measure degrees of genetic isolation between bats carrying them. The sampling focused on an area of strict lineage sympatry in Switzerland but also included bats from further south, in North Africa. All individuals were barcoded for the COI gene to identify their mitochondrial lineages and five highly polymorphic microsatellite loci were used to cluster them according to their nuclear genotypes. Despite this low number of nuclear markers, all North African nuclear genotypes were grouped in a highly distinct subpopulation when compared with European samples sharing the same mitochondrial barcodes. The reverse situation prevailed in Switzerland where bats carrying distinct barcodes had similar nuclear genotypes. There was a weak east/west nuclear structure of populations, but this was independent of mitochondrial lineages as bats carrying either variant were completely admixed. Thus, the divergent mitochondrial barcodes present in Western Europe do not represent cryptic species, but are part of a single biological species. We argue that these distinct barcodes evolved in allopatry and came recently into secondary contact in an area of admixture north of the Alps. Historical records from this area and molecular dating support such a recent bipolar spatial expansion. These results also highlight the need for using appropriate markers before claiming the existence of cryptic species based on highly divergent barcodes. PMID- 26241945 TI - Evolution of animal models in cancer vaccine development. AB - Advances in cancer vaccine development are facilitated by animal models reflecting key features of human cancer and its interface with host immunity. Several series of transplantable preneoplastic and neoplastic mouse mammary lesions have been used to delineate mechanisms of anti-tumor immunity. Mimicking immune tolerance to tumor-associated antigens (TAA) such as HER2/neu, transgenic mice developing spontaneous mammary tumors are strong model systems for pre clinical vaccine testing. In these models, HER2 DNA vaccines are easily administered, well-tolerated, and induce both humoral and cellular immunity. Although engineered mouse strains have advanced cancer immunotherapy, basic shortcomings remain. For example, multiple mouse strains have to be tested to recapitulate genetic regulation of immune tolerance in humans. Outbred domestic felines more closely parallel humans in the natural development of HER2 positive breast cancer and their varying genetic background. Electrovaccination with heterologous HER2 DNA induces robust adaptive immune responses in cats. Importantly, homologous feline HER2 DNA with a single amino acid substitution elicits unique antibodies to feline mammary tumor cells, unlocking a new vaccine principle. As an alternative approach to targeted vaccination, non-surgical tumor ablation such as cryoablation induces anti-tumor immunity via in situ immunization, particularly when combined with toll-like receptor (TLR) agonist. As strategies for vaccination advance, non-invasive monitoring of host response becomes imperative. As an example, magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning following administration of tryptophan metabolism tracer [11C]-alpha-methyl-tryptophan (AMT) provides non-invasive imaging of both tumor growth and metabolic activities. Because AMT is a substrate of indoleamine-pyrrole 2,3-dioxygenase (IDO), an enzyme that produces the immune regulatory molecule kynurenine, AMT imaging can provide novel insight of host response. In conclusion, new feline models improve the predictive power of cancer immunotherapy and real-time PET imaging enables mechanistic monitoring of host immunity. Strategic utilization of these new tools will expedite cancer vaccine development. PMID- 26241946 TI - Development of oral CTL vaccine using a CTP-integrated Sabin 1 poliovirus-based vector system. AB - We developed a CTL vaccine vector by modification of the RPS-Vax system, a mucosal vaccine vector derived from a poliovirus Sabin 1 strain, and generated an oral CTL vaccine against HIV-1. A DNA fragment encoding a cytoplasmic transduction peptide (CTP) was integrated into the RPS-Vax system to generate RPS CTP, a CTL vaccine vector. An HIV-1 p24 cDNA fragment was introduced into the RPS CTP vector system and a recombinant poliovirus (rec-PV) named vRPS-CTP/p24 was produced. vRPS-CTP/p24 was genetically stable and efficiently induced Th1 immunity and p24-specific CTLs in immunized poliovirus receptor-transgenic (PVR Tg) mice. In challenge experiments, PVR-Tg mice that were pre-immunized orally with vRPS-CTP/p24 were resistant to challenge with a lethal dose of p24 expressing recombinant vaccinia virus (rMVA-p24). These results suggested that the RPS-CTP vector system had potential for developing oral CTL vaccines against infectious diseases. PMID- 26241947 TI - Vaccinia virus strain LC16m8 defective in the B5R gene keeps strong protection comparable to its parental strain Lister in immunodeficient mice. AB - BACKGROUND: Attenuated vaccinia virus strain, LC16m8, defective in the B5R envelope protein gene, is used as a stockpile smallpox vaccine strain in Japan against bioterrorism: the defect in the B5R gene mainly contributes to its highly attenuated properties. METHODS: The protective activity of LC16m8 vaccine against challenge with a lethal dose of vaccinia Western Reserve strain was assessed in wild-type and immunodeficient mice lacking CD4, MHC class I, MHC class II or MHC class I and II antigens. RESULTS: The immunization with LC16m8 induced strong protective activity comparable to that of its parent strain, Lister (Elstree) strain, in wild-type mice from 2 days to 1 year after vaccination, as well as in immunodeficient mice at 2 or 3 weeks after vaccination. These results implicated that the defect in the B5R gene hardly affected the potential activity of LC16m8 to induce innate, cell-mediated and humoral immunity, and that LC16m8 could be effective in immunodeficient patients. CONCLUSION: LC16m8 with truncated B5 protein has an activity to induce immunity, such as innate immunity and subsequent cell-mediated and humoral immunity almost completely comparable to the activity of its parental strain Lister. PMID- 26241948 TI - Peru-15 (Choleragarde((r))), a live attenuated oral cholera vaccine, is safe and immunogenic in human immunodeficiency virus (HIV)-seropositive adults in Thailand. AB - BACKGROUND: Many areas with endemic and epidemic cholera report significant levels of HIV transmission. According to the World Health Organization (WHO), over 95% of reported cholera cases occur in Africa, which also accounts for nearly 70% of people living with HIV/AIDS globally. Peru-15, a promising single dose live attenuated oral cholera vaccine (LA-OCV), was previously found to be safe and immunogenic in cholera endemic areas. However, no data on the vaccine's safety among HIV-seropositive adults had been collected. METHODS: This study was a double-blinded, individually randomized, placebo-controlled trial enrolling HIV seropositive adults, 18-45 years of age, conducted in Bangkok, Thailand, to assess the safety of Peru-15 in a HIV-seropositive cohort. RESULTS: 32 HIV infected subjects were randomized to receive either a single oral dose of the Peru-15 vaccine with a buffer or a placebo (buffer only). No serious adverse events were reported during the follow-up period in either group. The geometric mean fold (GMF) rise in V. cholerae O1 El Tor specific antibody titers between baseline and 7 days after dosing was 32.0 (p<0.001) in the vaccine group compared to 1.6 (p<0.14) in the placebo group. Among the 16 vaccinees,14 vaccinees (87.5%) had seroconversion compared to 1 of 16 placebo recipients (6.3%). V. cholerae was isolated from the stool of one vaccinee, and found to be genetically identical to the Peru-15 vaccine strain. There were no significant changes in HIV viral load or CD4 T-cell counts between vaccine and placebo groups. CONCLUSION: Peru-15 was shown to be safe and immunogenic in HIV-seropositive Thai adults. PMID- 26241949 TI - Profiling the host immune response to tuberculosis vaccines. AB - There is an urgent need for improved vaccines for protection against tuberculosis (TB) disease and an immune correlate of protection would aid in the design, development and testing of a new TB vaccine candidates. The immune response to TB is likely to be multi-factorial and transcriptional profiling is a potentially useful tool for the simultaneous measurement of multiple immune processes. Although there are 16 candidate TB vaccines in clinical development the only published transcriptomics studies are from the MVA85A trials. With the publication of transcriptional signatures from the South African adolescent cohort study and the GC6 consortium also expected in 2015 the next year could see an increase of interest in the use of transcriptomics in TB vaccine development. PMID- 26241950 TI - Safety, immunogenicity and shedding of LAIV4 in HIV-infected and uninfected children. AB - OBJECTIVES: HIV-infected children have poor responses to inactivated influenza vaccines. Live vaccines (LAIVs) are highly efficacious in children, but they are not used in HIV-infected children du e to limited information. We investigated the safety, immunogenicity and viral shedding of LAIV4 in HIV-infected compared with uninfected children. DESIGN: Forty-six HIV-infected and 56 uninfected children 2 to 25 years old, who had been previously vaccinated against influenza, consented to receive a single dose of LAIV4. All grade adverse events (AEs) were recorded in the first month post-vaccination and serious AEs (SAEs) throughout the influenza season. Nasopharyngeal swabs for influenza PCR and IgA ELISA and blood for hemagglutination inhibition antibody (HAI) measurements were collected at entry, 2-5, 7-10 and 21-28 days post-vaccination. RESULTS: The HIV-infected subjects had median CD4+ cells of 649 cells/MUL and plasma HIV RNA of 20 copies/mL. AEs were similar in the two groups. There were no vaccine-related SAEs. Shedding of >=1 vaccine virus was detected in 67% HIV-infected and 50% uninfected participants (p=0.14). HAI titers did not appreciably change, but mucosal IgA antibodies significantly increased post-vaccination in both groups. High baseline HAI and IgA antibody concentrations were associated with decreased viral shedding in controls, but not in HIV-infected subjects. Similar proportions of HIV-infected vaccinees and controls reported influenza-like illnesses (12% and 6%) throughout the season. CONCLUSIONS: LAIV4 was equally safe and immunogenic and caused similar viral shedding in HIV-infected and uninfected children. A correlate of protection against vaccine viral shedding was not identified in HIV infected participants, although both circulating and mucosal antibodies correlated with protection in controls. PMID- 26241952 TI - Recombinant invasive Lactococcus lactis can transfer DNA vaccines either directly to dendritic cells or across an epithelial cell monolayer. AB - Lactococcus lactis (L. lactis), a generally regarded as safe (GRAS) bacterium has recently been investigated as a mucosal delivery vehicle for DNA vaccines. Because of its GRAS status, L. lactis represents an attractive alternative to attenuated pathogens. Previous studies showed that eukaryotic expression plasmids could be delivered into intestinal epithelial cells (IECs) by L. lactis, or recombinant invasive strains of L. lactis, leading to heterologous protein expression. Although expression of antigens in IECs might lead to vaccine responses, it would be of interest to know whether uptake of L. lactis DNA vaccines by dendritic cells (DCs) could lead to antigen expression as they are unique in their ability to induce antigen-specific T cell responses. To test this, we incubated mouse bone marrow-derived DCs (BMDCs) with invasive L. lactis strains expressing either Staphylococcus aureus Fibronectin Binding Protein A (LL FnBPA+), or Listeria monocytogenes mutated Internalin A (LL-mInlA+), both strains carrying a plasmid DNA vaccine (pValac) encoding for the cow milk allergen beta lactoglobulin (BLG). We demonstrated that they can transfect BMDCs, inducing the secretion of the pro-inflammatory cytokine IL-12. We also measured the capacity of strains to invade a polarized monolayer of IECs, mimicking the situation encountered in the gastrointestinal tract. Gentamycin survival assay in these cells showed that LL-mInlA+ is 100 times more invasive than L. lactis. The cross talk between differentiated IECs, BMDCs and bacteria was also evaluated using an in vitro transwell co-culture model. Co-incubation of strains in this model showed that DCs incubated with LL-mInlA+ containing pValac:BLG could express significant levels of BLG. These results suggest that DCs could sample bacteria containing the DNA vaccine across the epithelial barrier and express the antigen. PMID- 26241951 TI - A multi-trimeric fusion of CD40L and gp100 tumor antigen activates dendritic cells and enhances survival in a B16-F10 melanoma DNA vaccine model. AB - Vaccination with tumor-associated antigens can induce cancer-specific CD8+ T cells. A recent improvement has been the targeting of antigen to dendritic cells (DC) using antibodies that bind DC surface molecules. This study explored the use of multi-trimers of CD40L to target the gp100 melanoma tumor antigen to DC. The spontaneously-multimerizing gene Surfactant Protein D (SPD) was used to fuse gp100 tumor antigen and CD40L, creating the recombinant protein SPD-gp100-CD40L. This "third generation" DC-targeting vaccine was designed to both target antigen to DC and optimally activate dendritic cells by aggregating CD40 trimers on the DC membrane surface. SPD-gp100-CD40L expressed as a 110kDa protein. Analytical light scattering analysis gave elution data corresponding to 4-trimer and multi trimer SPD-gp100-CD40L oligomers. The protein was biologically active on dendritic cells and induced CD40-mediated NF-kappaB signaling. DNA vaccination with SPD-gp100-CD40L plasmid, together with plasmids encoding IL-12p70 and GM CSF, significantly enhanced survival and inhibited tumor growth in a B16-F10 melanoma model. Expression of gp100 and SPD-CD40L as separate molecules did not enhance survival, highlighting the requirement to encode gp100 within SPD-CD40L for optimal vaccine activity. These data support a model where DNA vaccination with SPD-gp100-CD40L targets gp100 to DC in situ, induces activation of these DC, and generates a protective anti-tumor response when given in combination with IL 12p70 and GM-CSF plasmids. PMID- 26241953 TI - Activity-Dependent Bidirectional Regulation of GAD Expression in a Homeostatic Fashion Is Mediated by BDNF-Dependent and Independent Pathways. AB - Homeostatic synaptic plasticity, or synaptic scaling, is a mechanism that tunes neuronal transmission to compensate for prolonged, excessive changes in neuronal activity. Both excitatory and inhibitory neurons undergo homeostatic changes based on synaptic transmission strength, which could effectively contribute to a fine-tuning of circuit activity. However, gene regulation that underlies homeostatic synaptic plasticity in GABAergic (GABA, gamma aminobutyric) neurons is still poorly understood. The present study demonstrated activity-dependent dynamic scaling in which NMDA-R (N-methyl-D-aspartic acid receptor) activity regulated the expression of GABA synthetic enzymes: glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67). Results revealed that activity-regulated BDNF (brain derived neurotrophic factor) release is necessary, but not sufficient, for activity-dependent up-scaling of these GAD isoforms. Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF independent pathways, both triggered by NMDA-R activity. Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF. In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion. Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses. PMID- 26241954 TI - Antipsychotic Maintenance Treatment: Time to Rethink? AB - Joanna Moncrieff looks at the lack of long-term evidence for antipsychotic medication and considers what is needed to ensure we have the knowledge to maximize benefits and minimize harms. PMID- 26241955 TI - Wheat Grain Filling Is Limited by Grain Filling Capacity rather than the Duration of Flag Leaf Photosynthesis: A Case Study Using NAM RNAi Plants. AB - It has been proposed that delayed leaf senescence can extend grain filling duration and thus increase yields in cereal crops. We found that wheat (Triticum aestivum) NAM RNAi plants with delayed senescence carried out 40% more flag leaf photosynthesis after anthesis than control plants, but had the same rate and duration of starch accumulation during grain filling and the same final grain weight. The additional photosynthate available in NAM RNAi plants was in part stored as fructans in the stems, whereas stem fructans were remobilised during grain filling in control plants. In both genotypes, activity of starch synthase was limiting for starch synthesis in the later stages of grain filling. We suggest that in order to realise the potential yield gains offered by delayed leaf senescence, this trait should be combined with increased grain filling capacity. PMID- 26241957 TI - The medial parietal occipital areas in the macaque monkey. AB - The number, location, extent, and functional properties of the cortical areas that occupy the medial parieto-occipital cortex (mPOC) have been, and still is, a matter of scientific debate. The mPOC is a convoluted region of the brain that presents a high level of individual variability, and the fact that many areas of mPOC are located within very deep sulci further limits the possibility to investigate their anatomo-functional properties. In the present review, we summarize the location and extent of mPOC areas in the macaque brain as obtained by architectural, connectional, and functional data. The different approaches lead to a subdivision of mPOC that includes areas V2, V3, V6, V6Av, and V6Ad. Extrastriate areas V2 and V3 occupy the posterior wall of the parieto-occipital sulcus (POs). The fundus of POs and the ventralmost part of the anterior wall of the sulcus are occupied by a retinotopically organized visual area, called V6, which represents the contralateral part of the visual field and emphasizes its periphery. The remaining part of the anterior wall of POs is occupied by two areas, V6Av and V6Ad, which contain visual as well as arm reaching neurons. Our analyses suggest that areas V6 and V6Av, together, occupy the cortical territory previously described as area PO. Functionally, area V6 is a motion area particularly sensitive to the real motion of objects in the animal's field of view, while V6Av and V6Ad are visuomotor areas likely involved in the visual guidance of arm movement and object prehension. PMID- 26241956 TI - Association between Paraoxonase 1 (PON1) Polymorphisms and the Risk of Acute Coronary Syndrome in a North African Population. AB - The purpose of the present study was to investigate the distribution of PON1 Q192R and L55M polymorphisms and activities in a North African population and to determine their association with cardiovascular complications. The prevalence of the QQ, QR, RR, LL, LM, and MM genotypes in the study population was 55.4%, 34.09%, 9.83%, 41.97%, 48.20%, and 9.83% respectively. The Q, R, L, and M alleles had a gene frequency of 0.755, 0.245, 0.67, and 0.33, respectively. The PON1 192 RR genotype was significantly more prevalent among ACS patients than among healthy subjects. There was a 4.33-fold increase in the risk of ACS in subjects presenting the PON1 192 RR genotype compared to those with the QQ genotype (OR=4.33; 95% CI=1.27-17.7). There was a significantly different distribution of PON1 L55M in the ACS patient groups (UA, STEMI, NSTEMI). Moreover, individuals presenting the PON1 55MM genotype present a higher risk for ACS than those with LL genotype (OR=3.69; 95% CI=1.61-11.80). Paraoxonase activities were significantly lower in coronary patients than in healthy subjects. The decrease in PON1 activity was inversely correlated with the number of concomitant risk factors for CVD (r=0.57, p<0.0001). The results of the present study suggested that the PON1 R and M alleles may play a role in the pathogenesis of cardiac ischemia in our North African population and that a decrease in PON1 activity may be a valuable marker for monitoring the development of the atherosclerosis process and the associated cardiovascular complications. PMID- 26241958 TI - Decoding the Traumatic Memory among Women with PTSD: Implications for Neurocircuitry Models of PTSD and Real-Time fMRI Neurofeedback. AB - Posttraumatic Stress Disorder (PTSD) is characterized by intrusive recall of the traumatic memory. While numerous studies have investigated the neural processing mechanisms engaged during trauma memory recall in PTSD, these analyses have only focused on group-level contrasts that reveal little about the predictive validity of the identified brain regions. By contrast, a multivariate pattern analysis (MVPA) approach towards identifying the neural mechanisms engaged during trauma memory recall would entail testing whether a multivariate set of brain regions is reliably predictive of (i.e., discriminates) whether an individual is engaging in trauma or non-trauma memory recall. Here, we use a MVPA approach to test 1) whether trauma memory vs neutral memory recall can be predicted reliably using a multivariate set of brain regions among women with PTSD related to assaultive violence exposure (N=16), 2) the methodological parameters (e.g., spatial smoothing, number of memory recall repetitions, etc.) that optimize classification accuracy and reproducibility of the feature weight spatial maps, and 3) the correspondence between brain regions that discriminate trauma memory recall and the brain regions predicted by neurocircuitry models of PTSD. Cross validation classification accuracy was significantly above chance for all methodological permutations tested; mean accuracy across participants was 76% for the methodological parameters selected as optimal for both efficiency and accuracy. Classification accuracy was significantly better for a voxel-wise approach relative to voxels within restricted regions-of-interest (ROIs); classification accuracy did not differ when using PTSD-related ROIs compared to randomly generated ROIs. ROI-based analyses suggested the reliable involvement of the left hippocampus in discriminating memory recall across participants and that the contribution of the left amygdala to the decision function was dependent upon PTSD symptom severity. These results have methodological implications for real time fMRI neurofeedback of the trauma memory in PTSD and conceptual implications for neurocircuitry models of PTSD that attempt to explain core neural processing mechanisms mediating PTSD. PMID- 26241959 TI - Deconvolution of Complex 1D NMR Spectra Using Objective Model Selection. AB - Fluorine (19F) NMR has emerged as a useful tool for characterization of slow dynamics in 19F-labeled proteins. One-dimensional (1D) 19F NMR spectra of proteins can be broad, irregular and complex, due to exchange of probe nuclei between distinct electrostatic environments; and therefore cannot be deconvoluted and analyzed in an objective way using currently available software. We have developed a Python-based deconvolution program, decon1d, which uses Bayesian information criteria (BIC) to objectively determine which model (number of peaks) would most likely produce the experimentally obtained data. The method also allows for fitting of intermediate exchange spectra, which is not supported by current software in the absence of a specific kinetic model. In current methods, determination of the deconvolution model best supported by the data is done manually through comparison of residual error values, which can be time consuming and requires model selection by the user. In contrast, the BIC method used by decond1d provides a quantitative method for model comparison that penalizes for model complexity helping to prevent over-fitting of the data and allows identification of the most parsimonious model. The decon1d program is freely available as a downloadable Python script at the project website (https://github.com/hughests/decon1d/). PMID- 26241960 TI - Double-Edge Sword of Sustained ROCK Activation in Prion Diseases through Neuritogenesis Defects and Prion Accumulation. AB - In prion diseases, synapse dysfunction, axon retraction and loss of neuronal polarity precede neuronal death. The mechanisms driving such polarization defects, however, remain unclear. Here, we examined the contribution of RhoA associated coiled-coil containing kinases (ROCK), key players in neuritogenesis, to prion diseases. We found that overactivation of ROCK signaling occurred in neuronal stem cells infected by pathogenic prions (PrPSc) and impaired the sprouting of neurites. In reconstructed networks of mature neurons, PrPSc-induced ROCK overactivation provoked synapse disconnection and dendrite/axon degeneration. This overactivation of ROCK also disturbed overall neurotransmitter associated functions. Importantly, we demonstrated that beyond its impact on neuronal polarity ROCK overactivity favored the production of PrPSc through a ROCK-dependent control of 3-phosphoinositide-dependent kinase 1 (PDK1) activity. In non-infectious conditions, ROCK and PDK1 associated within a complex and ROCK phosphorylated PDK1, conferring basal activity to PDK1. In prion-infected neurons, exacerbated ROCK activity increased the pool of PDK1 molecules physically interacting with and phosphorylated by ROCK. ROCK-induced PDK1 overstimulation then canceled the neuroprotective alpha-cleavage of normal cellular prion protein PrPC by TACE alpha-secretase, which physiologically precludes PrPSc production. In prion-infected cells, inhibition of ROCK rescued neurite sprouting, preserved neuronal architecture, restored neuronal functions and reduced the amount of PrPSc. In mice challenged with prions, inhibition of ROCK also lowered brain PrPSc accumulation, reduced motor impairment and extended survival. We conclude that ROCK overactivation exerts a double detrimental effect in prion diseases by altering neuronal polarity and triggering PrPSc accumulation. Eventually ROCK emerges as therapeutic target to combat prion diseases. PMID- 26241961 TI - Increased Eotaxin and MCP-1 Levels in Serum from Individuals with Periodontitis and in Human Gingival Fibroblasts Exposed to Pro-Inflammatory Cytokines. AB - Periodontitis is a chronic inflammatory disease of tooth supporting tissues resulting in periodontal tissue destruction, which may ultimately lead to tooth loss. The disease is characterized by continuous leukocyte infiltration, likely mediated by local chemokine production but the pathogenic mechanisms are not fully elucidated. There are no reliable serologic biomarkers for the diagnosis of periodontitis, which is today based solely on the degree of local tissue destruction, and there is no available biological treatment tool. Prompted by the increasing interest in periodontitis and systemic inflammatory mediators we mapped serum cytokine and chemokine levels from periodontitis subjects and healthy controls. We used multivariate partial least squares (PLS) modeling and identified monocyte chemoattractant protein-1 (MCP-1) and eotaxin as clearly associated with periodontitis along with C-reactive protein (CRP), years of smoking and age, whereas the number of remaining teeth was associated with being healthy. Moreover, body mass index correlated significantly with serum MCP-1 and CRP, but not with eotaxin. We detected higher MCP-1 protein levels in inflamed gingival connective tissue compared to healthy but the eotaxin levels were undetectable. Primary human gingival fibroblasts displayed strongly increased expression of MCP-1 and eotaxin mRNA and protein when challenged with tumor necrosis factor-alpha (TNF-alpha and interleukin-1beta (IL-1beta), key mediators of periodontal inflammation. We also demonstrated that the upregulated chemokine expression was dependent on the NF-kappaBeta pathway. In summary, we identify higher levels of CRP, eotaxin and MCP-1 in serum of periodontitis patients. This, together with our finding that both CRP and MCP-1 correlates with BMI points towards an increased systemic inflammatory load in patients with periodontitis and high BMI. Targeting eotaxin and MCP-1 in periodontitis may result in reduced leukocyte infiltration and inflammation in periodontitis and maybe prevent tooth loss. PMID- 26241962 TI - Are Tree Species Diversity and Genotypic Diversity Effects on Insect Herbivores Mediated by Ants? AB - Plant diversity can influence predators and omnivores and such effects may in turn influence herbivores and plants. However, evidence for these ecological feedbacks is rare. We evaluated if the effects of tree species (SD) and genotypic diversity (GD) on the abundance of different guilds of insect herbivores associated with big-leaf mahogany (Swietenia macrophylla) were contingent upon the protective effects of ants tending extra-floral nectaries of this species. This study was conducted within a larger experiment consisting of mahogany monocultures and species polycultures of four species and -within each of these two plot types- mahogany was represented by either one or four maternal families. We selected 24 plots spanning these treatment combinations, 10 mahogany plants/plot, and within each plot experimentally reduced ant abundance on half of the selected plants, and surveyed ant and herbivore abundance. There were positive effects of SD on generalist leaf-chewers and sap-feeders, but for the latter group this effect depended on the ant reduction treatment: SD positively influenced sap-feeders under ambient ant abundance but had no effect when ant abundance was reduced; at the same time, ants had negative effects on sap feeders in monoculture but no effect in polyculture. In contrast, SD did not influence specialist stem-borers or leaf-miners and this effect was not contingent upon ant reduction. Finally, GD did not influence any of the herbivore guilds studied, and such effects did not depend on the ant treatment. Overall, we show that tree species diversity influenced interactions between a focal plant species (mahogany) and ants, and that such effects in turn mediated plant diversity effects on some (sap-feeders) but not all the herbivores guilds studied. Our results suggest that the observed patterns are dependent on the combined effects of herbivore identity, diet breadth, and the source of plant diversity. PMID- 26241965 TI - Dysfunction of Neurovascular/Metabolic Coupling in Chronic Focal Epilepsy. AB - GOAL: We aim to evaluate the mechanisms underlying the neurovascular/metabolic coupling in the epileptogenic cortices of rats with chronic focal epilepsy. METHODS: We performed and analyzed intracranial recordings obtained from the seizure-onset zones during ictal periods on epileptic rats, and then, used these data to fit a metabolically coupled balloon model. Normal rats undergoing forepaw stimulation were used as control. RESULTS: We found a significant higher contribution from high local field potential frequency bands to the cerebral blood flow (CBF) responses in the epileptogenic cortices during ictal neuronal activities. The hemodynamic responses associated with ictal activities were distance-dependent with regard to the seizure focus, though varied in profiles from those obtained from acute seizure models. Parameters linking the CBF and relative concentration of deoxyhemoglobin to neuronal activity in the biophysical model were significantly different between epileptic and normal rats. CONCLUSION: We found that the coefficient associated with the strength of the functional hyperemic response was significantly larger in the epileptogenic cortices, and changes in hemoglobin concentration associated with ictal activity reflected the existence of a significantly higher baseline for oxygen metabolism in the epileptogenic cortices. SIGNIFICANCE: Introducing methods to estimate these physiological parameters would enhance our understanding of the neurovascular/metabolic coupling in epileptic brains and improve the localization accuracy on irritative zones and seizure-onset zones through neuroimaging techniques. PMID- 26241963 TI - Differential Levels of Alpha-2-Macroglobulin, Haptoglobin and Sero-Transferrin as Adjunct Markers for TB Diagnosis and Disease Progression in the Malnourished Tribal Population of Melghat, India. AB - Lack of diagnostic capacity has been a crucial barrier preventing an effective response to the challenges of malnutrition and tuberculosis (TB). Point-of-care diagnostic tests for TB in immuno-incompetent, malnourished population are thus needed to ensure rapid and accurate detection. The aim of the study was to identify potential biomarkers specific for TB infection and progression to overt disease in the malnourished population of Melghat. A prospective cohort study was conducted in the year 2009 through 2011 in six villages of the Melghat region. 275 participants consisting of malnourished cases with a) active TB (n = 32), b) latent TB infection (n = 90), c) with no clinical or bacteriological signs of active or latent TB (n = 130) and healthy control subjects (n = 23) were recruited for the study. The proteome changes of the host serum in response to Mycobacterium tuberculosis (M.tb) infection were investigated using one dimensional electrophoresis in combination with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Three most differentially expressed proteins; alpha-2-macroglobulin (A-2-M), sero transferrin and haptoglobin were identified by MALDI-TOF MS analysis, which were up-regulated in the malnourished patients with active TB and down-regulated in the malnourished patients compared with the healthy controls. Additionally, follow-up studies indicated that the expression of these proteins increased to nearly two folds in patients who developed active disease from latent state. Our preliminary results suggest that A-2-M, sero-transferrin and haptoglobin may be clinically relevant host biomarkers for TB diagnosis and disease progression in the malnourished population. This study provides preliminary framework for an in depth analysis of the biomarkers in larger well-characterized cohorts. Evaluation of these biomarkers in follow-up cases may further aid in improving TB diagnosis. PMID- 26241964 TI - Structure and Function in Homodimeric Enzymes: Simulations of Cooperative and Independent Functional Motions. AB - Large-scale conformational change is a common feature in the catalytic cycles of enzymes. Many enzymes function as homodimers with active sites that contain elements from both chains. Symmetric and anti-symmetric cooperative motions in homodimers can potentially lead to correlated active site opening and/or closure, likely to be important for ligand binding and release. Here, we examine such motions in two different domain-swapped homodimeric enzymes: the DcpS scavenger decapping enzyme and citrate synthase. We use and compare two types of all-atom simulations: conventional molecular dynamics simulations to identify physically meaningful conformational ensembles, and rapid geometric simulations of flexible motion, biased along normal mode directions, to identify relevant motions encoded in the protein structure. The results indicate that the opening/closure motions are intrinsic features of both unliganded enzymes. In DcpS, conformational change is dominated by an anti-symmetric cooperative motion, causing one active site to close as the other opens; however a symmetric motion is also significant. In CS, we identify that both symmetric (suggested by crystallography) and asymmetric motions are features of the protein structure, and as a result the behaviour in solution is largely non-cooperative. The agreement between two modelling approaches using very different levels of theory indicates that the behaviours are indeed intrinsic to the protein structures. Geometric simulations correctly identify and explore large amplitudes of motion, while molecular dynamics simulations indicate the ranges of motion that are energetically feasible. Together, the simulation approaches are able to reveal unexpected functionally relevant motions, and highlight differences between enzymes. PMID- 26241966 TI - A Filtering Approach for Image-Guided Surgery With a Highly Articulated Surgical Snake Robot. AB - GOAL: The objective of this paper is to introduce a probabilistic filtering approach to estimate the pose and internal shape of a highly flexible surgical snake robot during minimally invasive surgery. METHODS: Our approach renders a depiction of the robot that is registered to preoperatively reconstructed organ models to produce a 3-D visualization that can be used for surgical feedback. Our filtering method estimates the robot shape using an extended Kalman filter that fuses magnetic tracker data with kinematic models that define the motion of the robot. Using Lie derivative analysis, we show that this estimation problem is observable, and thus, the shape and configuration of the robot can be successfully recovered with a sufficient number of magnetic tracker measurements. RESULTS: We validate this study with benchtop and in-vivo image-guidance experiments in which the surgical robot was driven along the epicardial surface of a porcine heart. CONCLUSION: This paper introduces a filtering approach for shape estimation that can be used for image guidance during minimally invasive surgery. SIGNIFICANCE: The methods being introduced in this paper enable informative image guidance for highly articulated surgical robots, which benefits the advancement of robotic surgery. PMID- 26241967 TI - Study of Estimation Method for Unsteady Inflow Velocity in Two-Dimensional Ultrasonic-Measurement-Integrated Blood Flow Simulation. AB - Information on hemodynamics is essential for elucidation of mechanisms and development of novel diagnostic methods for circulatory diseases. Two-dimensional ultrasonic-measurement-integrated (2D-UMI) simulation can correctly reproduce an intravascular blood flow field and hemodynamics by feeding back an ultrasonic measurement to the numerical blood flow simulation. In this method, it is critically important to give the correct cross-sectional average inflow velocity (inflow velocity) as the boundary condition. However, systematic study has not been done on the relative validity and effectiveness of existing inflow velocity estimation methods for various target flow fields. The aim of this study was to examine the existing methods systematically and to establish a method to accurately estimate inflow velocities for various vessel geometries and flow conditions in 2D-UMI simulations. A numerical experiment was performed for 2D-UMI simulation of blood flow models in a straight vessel with inflow velocity profiles symmetric and asymmetric to the vessel axis using existing evaluation functions based on Doppler velocity error for the inflow velocity estimation. As a result, it was clarified that a significantly large estimation error occurs in the asymmetric flow due to a nonfeedback domain near the downstream end of the calculation domain. Hence, a new inflow velocity estimation method of 2D-UMI simulation is proposed in which the feedback and evaluation domains are extended to the downstream end. Further numerical experiments of 2D-UMI simulation for two realistic vessel geometries of a healthy blood vessel and a stenosed one confirmed the effectiveness of the proposed method. PMID- 26241968 TI - A Simple and Robust Event-Detection Algorithm for Single-Cell Impedance Cytometry. AB - Microfluidic impedance cytometry is emerging as a powerful label-free technique for the characterization of single biological cells. In order to increase the sensitivity and the specificity of the technique, suited digital signal processing methods are required to extract meaningful information from measured impedance data. In this study, a simple and robust event-detection algorithm for impedance cytometry is presented. Since a differential measuring scheme is generally adopted, the signal recorded when a cell passes through the sensing region of the device exhibits a typical odd-symmetric pattern. This feature is exploited twice by the proposed algorithm: first, a preliminary segmentation, based on the correlation of the data stream with the simplest odd-symmetric template, is performed; then, the quality of detected events is established by evaluating their E2O index, that is, a measure of the ratio between their even and odd parts. A thorough performance analysis is reported, showing the robustness of the algorithm with respect to parameter choice and noise level. In terms of sensitivity and positive predictive value, an overall performance of 94.9% and 98.5%, respectively, was achieved on two datasets relevant to microfluidic chips with very different characteristics, considering three noise levels. The present algorithm can foster the role of impedance cytometry in single-cell analysis, which is the new frontier in "Omics." PMID- 26241969 TI - Fabric-Based Wearable Dry Electrodes for Body Surface Biopotential Recording. AB - A flexible and conformable dry electrode design on nonwoven fabrics is examined as a sensing platform for biopotential measurements. Due to limitations of commercial wet electrodes (e.g., shelf life, skin irritation), dry electrodes are investigated as the potential candidates for long-term monitoring of ECG signals. Multilayered dry electrodes are fabricated by screen printing of Ag/AgCl conductive inks on flexible nonwoven fabrics. This study focuses on the investigation of skin-electrode interface, form factor design, electrode body placement of printed dry electrodes for a wearable sensing platform. ECG signals obtained with dry and wet electrodes are comparatively studied as a function of body posture and movement. Experimental results show that skin-electrode impedance is influenced by printed electrode area, skin-electrode interface material, and applied pressure. The printed electrode yields comparable ECG signals to wet electrodes, and the QRS peak amplitude of ECG signal is dependent on printed electrode area and electrode on body spacing. Overall, fabric-based printed dry electrodes present an inexpensive health monitoring platform solution for mobile wearable electronics applications by fulfilling user comfort and wearability. PMID- 26241970 TI - Estimating CT Image From MRI Data Using Structured Random Forest and Auto-Context Model. AB - Computed tomography (CT) imaging is an essential tool in various clinical diagnoses and radiotherapy treatment planning. Since CT image intensities are directly related to positron emission tomography (PET) attenuation coefficients, they are indispensable for attenuation correction (AC) of the PET images. However, due to the relatively high dose of radiation exposure in CT scan, it is advised to limit the acquisition of CT images. In addition, in the new PET and magnetic resonance (MR) imaging scanner, only MR images are available, which are unfortunately not directly applicable to AC. These issues greatly motivate the development of methods for reliable estimate of CT image from its corresponding MR image of the same subject. In this paper, we propose a learning-based method to tackle this challenging problem. Specifically, we first partition a given MR image into a set of patches. Then, for each patch, we use the structured random forest to directly predict a CT patch as a structured output, where a new ensemble model is also used to ensure the robust prediction. Image features are innovatively crafted to achieve multi-level sensitivity, with spatial information integrated through only rigid-body alignment to help avoiding the error-prone inter-subject deformable registration. Moreover, we use an auto-context model to iteratively refine the prediction. Finally, we combine all of the predicted CT patches to obtain the final prediction for the given MR image. We demonstrate the efficacy of our method on two datasets: human brain and prostate images. Experimental results show that our method can accurately predict CT images in various scenarios, even for the images undergoing large shape variation, and also outperforms two state-of-the-art methods. PMID- 26241971 TI - Deblurring Saturated Night Image With Function-Form Kernel. AB - Deblurring saturated night images are a challenging problem because such images have low contrast combined with heavy noise and saturated regions. Unlike the deblurring schemes that discard saturated regions when estimating blur kernels, this paper proposes a novel scheme to deduce blur kernels from saturated regions via a novel kernel representation and advanced algorithms. Our key technical contribution is the proposed function-form representation of blur kernels, which regularizes existing matrix-form kernels using three functional components: 1) trajectory; 2) intensity; and 3) expansion. From automatically detected saturated regions, their skeleton, brightness, and width are fitted into the corresponding three functional components of blur kernels. Such regularization significantly improves the quality of kernels deduced from saturated regions. Second, we propose an energy minimizing algorithm to select and assign the deduced function form kernels to partitioned image regions as the initialization for non-uniform deblurring. Finally, we convert the assigned function-form kernels into matrix form for more detailed estimation in a multi-scale deconvolution. Experimental results show that our scheme outperforms existing schemes on challenging real examples. PMID- 26241972 TI - Missing Modality Transfer Learning via Latent Low-Rank Constraint. AB - Transfer learning is usually exploited to leverage previously well-learned source domain for evaluating the unknown target domain; however, it may fail if no target data are available in the training stage. This problem arises when the data are multi-modal. For example, the target domain is in one modality, while the source domain is in another. To overcome this, we first borrow an auxiliary database with complete modalities, then consider knowledge transfer across databases and across modalities within databases simultaneously in a unified framework. The contributions are threefold: 1) a latent factor is introduced to uncover the underlying structure of the missing modality from the known data; 2) transfer learning in two directions allows the data alignment between both modalities and databases, giving rise to a very promising recovery; and 3) an efficient solution with theoretical guarantees to the proposed latent low-rank transfer learning algorithm. Comprehensive experiments on multi-modal knowledge transfer with missing target modality verify that our method can successfully inherit knowledge from both auxiliary database and source modality, and therefore significantly improve the recognition performance even when test modality is inaccessible in the training stage. PMID- 26241973 TI - Transfer Function Model of Physiological Mechanisms Underlying Temporal Visual Discomfort Experienced When Viewing Stereoscopic 3D Images. AB - When viewing 3D images, a sense of visual comfort (or lack of) is developed in the brain over time as a function of binocular disparity and other 3D factors. We have developed a unique temporal visual discomfort model (TVDM) that we use to automatically predict the degree of discomfort felt when viewing stereoscopic 3D (S3D) images. This model is based on physiological mechanisms. In particular, TVDM is defined as a second-order system capturing relevant neuronal elements of the visual pathway from the eyes and through the brain. The experimental results demonstrate that the TVDM transfer function model produces predictions that correlate highly with the subjective visual discomfort scores contained in the large public databases. The transfer function analysis also yields insights into the perceptual processes that yield a stable S3D image. PMID- 26241974 TI - A Surface Approximation Method for Image and Video Correspondences. AB - Although finding correspondences between similar images is an important problem in image processing, the existing algorithms cannot find accurate and dense correspondences in images with significant changes in lighting/transformation or with the non-rigid objects. This paper proposes a novel method for finding accurate and dense correspondences between images even in these difficult situations. Starting with the non-rigid dense correspondence algorithm [1] to generate an initial correspondence map, we propose a new geometric filter that uses cubic B-Spline surfaces to approximate the correspondence mapping functions for shared objects in both images, thereby eliminating outliers and noise. We then propose an iterative algorithm which enlarges the region containing valid correspondences. Compared with the existing methods, our method is more robust to significant changes in lighting, color, or viewpoint. Furthermore, we demonstrate how to extend our surface approximation method to video editing by first generating a reliable correspondence map between a given source frame and each frame of a video. The user can then edit the source frame, and the changes are automatically propagated through the entire video using the correspondence map. To evaluate our approach, we examine applications of unsupervised image recognition and video texture editing, and show that our algorithm produces better results than those from state-of-the-art approaches. PMID- 26241975 TI - An Efficient Adaptive Binary Arithmetic Coder Based on Logarithmic Domain. AB - This paper proposes an efficient adaptive binary arithmetic coder based on a logarithmic domain (LBAC) and a probability estimation based on the LBAC (P LBAC). Both the LBAC and the P-LBAC achieve a high data-compression ratio with low complexity and a hardware-efficient structure. They introduce a mapping mechanism between the logarithmic domain and the original domain for both the coding process and the probability estimation. The proposed schemes have high accuracy and constitute an efficient BAC. The proposed LBAC and P-LBAC do not use either multiplication and division operations or lookup tables, and only addition and shifting operations are required. The proposed LBAC is designed to favor the coding of multiple symbols and has high throughput. The proposed P-LBAC achieves a good tradeoff between accuracy and speed in probability estimation through a single parameter. When the proposed algorithms are implemented on H.265/HEVC platforms, and they achieve a compression efficiency equivalent to that of CABAC. PMID- 26241976 TI - Image Location Estimation by Salient Region Matching. AB - Nowadays, locations of images have been widely used in many application scenarios for large geo-tagged image corpora. As to images which are not geographically tagged, we estimate their locations with the help of the large geo-tagged image set by content-based image retrieval. In this paper, we exploit spatial information of useful visual words to improve image location estimation (or content-based image retrieval performances). We proposed to generate visual word groups by mean-shift clustering. To improve the retrieval performance, spatial constraint is utilized to code the relative position of visual words. We proposed to generate a position descriptor for each visual word and build fast indexing structure for visual word groups. Experiments show the effectiveness of our proposed approach. PMID- 26241977 TI - One-Pass Mode and Motion Decision for Multilayer Quality Scalable Video Coding. AB - This paper presents a novel low-complexity motion estimation and mode decision algorithm for encoding multiple quality layers following the H.264/scalable video coding standard, considering both coarse grain scalability (CGS) and medium grain scalability (MGS). The proposed algorithm conducts motion estimation and mode decision only at the base layer (BL) and enforces the higher layers to inherit the motion and mode decisions of the BL. In order for the decision made at the BL to be nearly optimal for all layers, we use the highest layer reconstructed frame as the reference frame for motion estimation and set the Lagrangian multipliers according to the quantization parameter of the current and higher layers. We also propose a simple early skip/direct decision to further boost the encoding speed. Mode decision and motion estimation is conducted at a higher layer only if the layer below it uses the skip/direct mode for a block. Significant complexity reduction can be achieved because the mode and motion estimation is performed at most once for each macroblock. Because the mode and motion information only needs to be transmitted once, we also achieve a slightly better rate-distortion (R-D) performance for typical videos. Experiments have shown more than 2* (up to 5*) speedup for a three-layer encoder against the conventional R-D optimized reference software JSVM on both CIF and HD sequences, and for both CGS and MGS, with the tradeoff of the coding efficiency measured by the Bjontegaard delta rate. PMID- 26241978 TI - Constrained Clustering With Nonnegative Matrix Factorization. AB - Nonnegative matrix factorization (NMF) and symmetric NMF (SymNMF) have been shown to be effective for clustering linearly separable data and nonlinearly separable data, respectively. Nevertheless, many practical applications demand constrained algorithms in which a small number of constraints in the form of must-link and cannot-link are available. In this paper, we propose an NMF-based constrained clustering framework in which the similarity between two points on a must-link is enforced to approximate 1 and the similarity between two points on a cannot-link is enforced to approximate 0. We then formulate the framework using NMF and SymNMF to deal with clustering of linearly separable data and nonlinearly separable data, respectively. Furthermore, we present multiplicative update rules to solve them and show the correctness and convergence. Experimental results on various text data sets, University of California, Irvine (UCI) data sets, and gene expression data sets demonstrate the superiority of our algorithms over existing constrained clustering algorithms. PMID- 26241979 TI - An Emerging Era in the Management of Parkinson's Disease: Wearable Technologies and the Internet of Things. AB - Current challenges demand a profound restructuration of the global healthcare system. A more efficient system is required to cope with the growing world population and increased life expectancy, which is associated with a marked prevalence of chronic neurological disorders such as Parkinson's disease (PD). One possible approach to meet this demand is a laterally distributed platform such as the Internet of Things (IoT). Real-time motion metrics in PD could be obtained virtually in any scenario by placing lightweight wearable sensors in the patient's clothes and connecting them to a medical database through mobile devices such as cell phones or tablets. Technologies exist to collect huge amounts of patient data not only during regular medical visits but also at home during activities of daily life. These data could be fed into intelligent algorithms to first discriminate relevant threatening conditions, adjust medications based on online obtained physical deficits, and facilitate strategies to modify disease progression. A major impact of this approach lies in its efficiency, by maximizing resources and drastically improving the patient experience. The patient participates actively in disease management via combined objective device- and self-assessment and by sharing information within both medical and peer groups. Here, we review and discuss the existing wearable technologies and the Internet-of-Things concept applied to PD, with an emphasis on how this technological platform may lead to a shift in paradigm in terms of diagnostics and treatment. PMID- 26241980 TI - Fusing Heterogeneous Features From Stacked Sparse Autoencoder for Histopathological Image Analysis. AB - In the analysis of histopathological images, both holistic (e.g., architecture features) and local appearance features demonstrate excellent performance, while their accuracy may vary dramatically when providing different inputs. This motivates us to investigate how to fuse results from these features to enhance the accuracy. Particularly, we employ content-based image retrieval approaches to discover morphologically relevant images for image-guided diagnosis, using holistic and local features, both of which are generated from the cell detection results by a stacked sparse autoencoder. Because of the dramatically different characteristics and representations of these heterogeneous features (i.e., holistic and local), their results may not agree with each other, causing difficulties for traditional fusion methods. In this paper, we employ a graph based query-specific fusion approach where multiple retrieval results (i.e., rank lists) are integrated and reordered based on a fused graph. The proposed method is capable of combining the strengths of local or holistic features adaptively for different inputs. We evaluate our method on a challenging clinical problem, i.e., histopathological image-guided diagnosis of intraductal breast lesions, and it achieves 91.67% classification accuracy on 120 breast tissue images from 40 patients. PMID- 26241981 TI - Automated Detection of Tonic-Clonic Seizures Using 3-D Accelerometry and Surface Electromyography in Pediatric Patients. AB - Epileptic seizure detection is traditionally done using video/electroencephalography monitoring, which is not applicable for long-term home monitoring. In recent years, attempts have been made to detect the seizures using other modalities. In this study, we investigated the application of four accelerometers (ACM) attached to the limbs and surface electromyography (sEMG) electrodes attached to upper arms for the detection of tonic-clonic seizures. sEMG can identify the tension during the tonic phase of tonic-clonic seizure, while ACM is able to detect rhythmic patterns of the clonic phase of tonic-clonic seizures. Machine learning techniques, including feature selection and least squares support vector machine classification, were employed for detection of tonic-clonic seizures from ACM and sEMG signals. In addition, the outputs of ACM and sEMG-based classifiers were combined using a late integration approach. The algorithms were evaluated on 1998.3 h of data recorded nocturnally in 56 patients of which seven had 22 tonic-clonic seizures. A multimodal approach resulted in a more robust detection of short and nonstereotypical seizures (91%), while the number of false alarms increased significantly compared with the use of single sEMG modality (0.28-0.5/12h). This study also showed that the choice of the recording system should be made depending on the prevailing pediatric patient specific seizure characteristics and nonepileptic behavior. PMID- 26241982 TI - First Trimester Noninvasive Prenatal Diagnosis: A Computational Intelligence Approach. AB - The objective of this study is to examine the potential value of using machine learning techniques such as artificial neural network (ANN) schemes for the noninvasive estimation, at 11-13 weeks of gestation, the risk for euploidy, trisomy 21 (T21), and other chromosomal aneuploidies (O.C.A.), from suitable sonographic, biochemical markers, and other relevant data. A database(1) (1)The dataset can become available for academic purposes by communicating directly with the authors. PMID- 26241983 TI - Robust Consensus of Nonlinear Multiagent Systems With Switching Topology and Bounded Noises. AB - Consensus of multiagent systems (MASs) is an intriguing topic in recent years due to its widely used application in robotics, biology, computer, and social science. In the real world, the evolution of MAS is inevitably involved in dynamical environments and the recent development of MAS calls for novel tools for the analysis of MAS with dynamic topology. In addition, the interactions between agents are generally nonlinear and environmental noises are ubiquitous in the communication channels between agents. However, the existing investigation on MAS places little attention on nonlinear models and the inner relationship between external disturbance and consensus is still unclear. Facing these problems, this paper considers an MAS in which the interactions between agents are nonlinear and the communication between agents are infected by environmental noises. By using a novel method of nonsmooth Lyapunov candidate, it has been demonstrated that such an MAS can realize robust consensus under the conditions of jointly (sequentially) connected topology and bounded noises. Finally, simulation results validate the effectiveness of these criteria. PMID- 26241984 TI - High-Speed General Purpose Genetic Algorithm Processor. AB - In this paper, an ultrafast steady-state genetic algorithm processor (GAP) is presented. Due to the heavy computational load of genetic algorithms (GAs), they usually take a long time to find optimum solutions. Hardware implementation is a significant approach to overcome the problem by speeding up the GAs procedure. Hence, we designed a digital CMOS implementation of GA in [Formula: see text] process. The proposed processor is not bounded to a specific application. Indeed, it is a general-purpose processor, which is capable of performing optimization in any possible application. Utilizing speed-boosting techniques, such as pipeline scheme, parallel coarse-grained processing, parallel fitness computation, parallel selection of parents, dual-population scheme, and support for pipelined fitness computation, the proposed processor significantly reduces the processing time. Furthermore, by relying on a built-in discard operator the proposed hardware may be used in constrained problems that are very common in control applications. In the proposed design, a large search space is achievable through the bit string length extension of individuals in the genetic population by connecting the 32-bit GAPs. In addition, the proposed processor supports parallel processing, in which the GAs procedure can be run on several connected processors simultaneously. PMID- 26241985 TI - Reaching Synchronization in Networked Harmonic Oscillators With Outdated Position Data. AB - This paper studies the synchronization problem for a network of coupled harmonic oscillators by proposing a distributed control algorithm based only on delayed position states, i.e., outdated position states stored in memory. The coupling strength of the network is conveniently designed according to the absolute values and the principal arguments of the nonzero eigenvalues of the network Laplacian matrix. By analyzing a finite number of stability switches of the network with respect to the variation in the time delay, some necessary and sufficient conditions are derived for reaching synchronization in networked harmonic oscillators with positive and negative coupling strengths, respectively, and it is shown that the time delay should be taken from a set of intervals bounded by some critical values. Simulation examples are given to illustrate the effectiveness of the theoretical analysis. PMID- 26241986 TI - Synchronization of a Group of Mobile Agents With Variable Speeds Over Proximity Nets. AB - This paper focuses on the synchronization analysis of a class of multiagent systems, where both speed and heading of each agent depend on the states of its local neighbors. The neighbors are defined through the distance between agents and all agents are interconnected via proximity nets. In the variable speed model, the speed of each agent depends on the polarization order of its neighbors in a power-law manner, and the heading is updated according to the average heading of its neighbors. Therefore, the speeds, headings, and positions of all agents are strongly coupled together. For the uniformly and independently distributed initial states, we provide sufficient conditions, imposed only on model parameters, to guarantee synchronization of the variable speed model in the following two cases: 1) the maximum speed and the neighborhood radius are fixed constants and 2) the maximum speed and the neighborhood radius are changing with the population size. Our results reveal that the permitted maximum speed in the variable speed model can be larger than that in the relevant constant speed model. PMID- 26241987 TI - F -Discrepancy for Efficient Sampling in Approximate Dynamic Programming. AB - In this paper, we address the problem of generating efficient state sample points for the solution of continuous-state finite-horizon Markovian decision problems through approximate dynamic programming. It is known that the selection of sampling points at which the value function is observed is a key factor when such function is approximated by a model based on a finite number of evaluations. A standard approach consists in generating these points through a random or deterministic procedure, aiming at a balanced covering of the state space. Yet, this solution may not be efficient if the state trajectories are not uniformly distributed. Here, we propose to exploit F -discrepancy, a quantity that measures how closely a set of random points represents a probability distribution, and introduce an example of an algorithm based on such concept to automatically select point sets that are efficient with respect to the underlying Markovian process. An error analysis of the approximate solution is provided, showing how the proposed algorithm enables convergence under suitable regularity hypotheses. Then, simulation results are provided concerning an inventory forecasting test problem. The tests confirm in general the important role of F -discrepancy, and show how the proposed algorithm is able to yield better results than uniform sampling, using sets even 50 times smaller. PMID- 26241988 TI - Learning Hierarchical Spectral-Spatial Features for Hyperspectral Image Classification. AB - This paper proposes a spectral-spatial feature learning (SSFL) method to obtain robust features of hyperspectral images (HSIs). It combines the spectral feature learning and spatial feature learning in a hierarchical fashion. Stacking a set of SSFL units, a deep hierarchical model called the spectral-spatial networks (SSN) is further proposed for HSI classification. SSN can exploit both discriminative spectral and spatial information simultaneously. Specifically, SSN learns useful high-level features by alternating between spectral and spatial feature learning operations. Then, kernel-based extreme learning machine (KELM), a shallow neural network, is embedded in SSN to classify image pixels. Extensive experiments are performed on two benchmark HSI datasets to verify the effectiveness of SSN. Compared with state-of-the-art methods, SSN with a deep hierarchical architecture obtains higher classification accuracy in terms of the overall accuracy, average accuracy, and kappa ( kappa ) coefficient of agreement, especially when the number of the training samples is small. PMID- 26241989 TI - Identification-Based Closed-Loop NMES Limb Tracking With Amplitude-Modulated Control Input. AB - An upper motor neuron lesion (UMNL) can be caused by various neurological disorders or trauma and leads to disabilities. Neuromuscular electrical stimulation (NMES) is a technique that is widely used for rehabilitation and restoration of motor function for people suffering from UMNL. Typically, stability analysis for closed-loop NMES ignores the modulated implementation of NMES. However, electrical stimulation must be applied to muscle as a modulated series of pulses. In this paper, a muscle activation model with an amplitude modulated control input is developed to capture the discontinuous nature of muscle activation, and an identification-based closed-loop NMES controller is designed and analyzed for the uncertain amplitude modulated muscle activation model. Semi-global uniformly ultimately bounded tracking is guaranteed. The stability of the closed-loop system is analyzed with Lyapunov-based methods, and a pulse frequency related gain condition is obtained. Experiments are performed with five able-bodied subjects to demonstrate the interplay between the control gains and the pulse frequency, and results are provided which indicate that control gains should be increased to maintain stability if the stimulation pulse frequency is decreased to mitigate muscle fatigue. For the first time, this paper brings together an analysis of the controller and modulation scheme. PMID- 26241991 TI - [Update on Current Care Guideline: Glaucoma]. AB - The up-date of the Finnish Current Care Guideline for glaucoma is based primarily on systematic reviews searched up by March 2014. The recommendations are presented in nine tables, which are based on 95 graded statements with evidence summaries. The online availability (www.kaypahoito.fi) of the English translation of guideline and evidence summaries enables the verification of the evidence and recommendations. Ten external stakeholders gave a mean value of 1.8 (range of 1 = completely agree to 4 = completely disagree) for the structured questions (e.g. definitions, goals, questions, target users) and judged the evidence and the recommendations. PMID- 26241992 TI - Fifth Circuit Upholds the Enforcement of Two Abortion Provisions of a Texas Act- Whole Woman's Health v. Lakey. PMID- 26241990 TI - Road Traffic and Railway Noise Exposures and Adiposity in Adults: A Cross Sectional Analysis of the Danish Diet, Cancer, and Health Cohort. AB - BACKGROUND: Traffic noise has been associated with cardiovascular and metabolic disorders. Potential modes of action are through stress and sleep disturbance, which may lead to endocrine dysregulation and overweight. OBJECTIVES: We aimed to investigate the relationship between residential traffic and railway noise and adiposity. METHODS: In this cross-sectional study of 57,053 middle-aged people, height, weight, waist circumference, and bioelectrical impedance were measured at enrollment (1993-1997). Body mass index (BMI), body fat mass index (BFMI), and lean body mass index (LBMI) were calculated. Residential exposure to road and railway traffic noise exposure was calculated using the Nordic prediction method. Associations between traffic noise and anthropometric measures at enrollment were analyzed using general linear models and logistic regression adjusted for demographic and lifestyle factors. RESULTS: Linear regression models adjusted for age, sex, and socioeconomic factors showed that 5-year mean road traffic noise exposure preceding enrollment was associated with a 0.35-cm wider waist circumference (95% CI: 0.21, 0.50) and a 0.18-point higher BMI (95% CI: 0.12, 0.23) per 10 dB. Small, significant increases were also found for BFMI and LBMI. All associations followed linear exposure-response relationships. Exposure to railway noise was not linearly associated with adiposity measures. However, exposure > 60 dB was associated with a 0.71-cm wider waist circumference (95% CI: 0.23, 1.19) and a 0.19-point higher BMI (95% CI: 0.0072, 0.37) compared with unexposed participants (0-20 dB). CONCLUSIONS: The present study finds positive associations between residential exposure to road traffic and railway noise and adiposity. PMID- 26241993 TI - The profit margin: Education Department's new rule affects for-profit veterinary technology programs. PMID- 26241994 TI - National Veterinary Stockpile at the ready. PMID- 26241995 TI - Idexx develops test for new dog flu, USDA shares isolate toward vaccine. PMID- 26241996 TI - Antimicrobial sales outpace meat production: regulators, industry caution that sales may differ from use. PMID- 26241997 TI - See your veterinarian, not the Internet, for pet health concerns. PMID- 26241998 TI - Findings of research misconduct. PMID- 26241999 TI - Medical Devices; Immunology and Microbiology Devices; Classification of Trichomonas Vaginalis Nucleic Acid Assay. Final order. AB - The Food and Drug Administration (FDA) is classifying a Trichomonas vaginalis nucleic acid assay into class II (special controls). The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 26242000 TI - Medical Devices; Ear, Nose, and Throat Devices; Classification of the External Upper Esophageal Sphincter Compression Device. Final order. AB - The Food and Drug Administration (FDA) is classifying the external upper esophageal sphincter (UES) compression device into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified language for the external UES compression device's classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 26242001 TI - Vet Centers. Interim final rule. AB - The Department of Veterans Affairs (VA) is amending its medical regulation that governs Vet Center services. The National Defense Authorization Act for Fiscal Year 2013 (the 2013 Act) requires Vet Centers to provide readjustment counseling services to broader groups of veterans, members of the Armed Forces, including a member of a reserve component of the Armed Forces, and family members of such veterans and members. This interim final rule amends regulatory criteria to conform to the 2013 Act, to include new and revised definitions. PMID- 26242003 TI - [Central nervous system tumor: glioma]. PMID- 26242002 TI - Medicare Program; Prospective Payment System and Consolidated Billing for Skilled Nursing Facilities (SNFs) for FY 2016, SNF Value-Based Purchasing Program, SNF Quality Reporting Program, and Staffing Data Collection. Final Rule. AB - This final rule updates the payment rates used under the prospective payment system (PPS) for skilled nursing facilities (SNFs) for fiscal year (FY) 2016. In addition, it specifies a SNF all-cause all-condition hospital readmission measure, as well as adopts that measure for a new SNF Value-Based Purchasing (VBP) Program, and includes a discussion of SNF VBP Program policies we are considering for future rulemaking to promote higher quality and more efficient health care for Medicare beneficiaries. Additionally, this final rule will implement a new quality reporting program for SNFs as specified in the Improving Medicare Post-Acute Care Transformation Act of 2014 (IMPACT Act). It also amends the requirements that a long-term care (LTC) facility must meet to qualify to participate as a skilled nursing facility (SNF) in the Medicare program, or a nursing facility (NF) in the Medicaid program, by establishing requirements that implement the provision in the Affordable Care Act regarding the submission of staffing information based on payroll data. PMID- 26242004 TI - [I. Photodynamic therapy for glioblastoma]. PMID- 26242005 TI - [II. Autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma]. PMID- 26242006 TI - [III. Peptide vaccination therapy against brain tumors]. PMID- 26242007 TI - [IV. Oncolytic virus therapy for brain tumors and cancer]. PMID- 26242008 TI - In Reply. PMID- 26242009 TI - Full Mouth Implant-supported Rehabilitation of a Patient with Ectodermal Dysplasia: Clinical Report and Literature Review. AB - OBJECTIVE: The purpose of this case report is to present the clinical course of full mouth rehabilitation in an 1 8-year-old female patient with ectodermal dysplasia who was treated with implant-supported fixed partial dentures for the mandible and the maxilla. CASE REPORT: Fourteen dental implants (8 in the maxilla and 6 in the mandible) were placed simultaneously after full mouth extraction and alveoloplasty surgery. After 6 months of healing, prosthetic rehabilitation was started for screw-retained fixed partial dentures. The patient was followed for one year and a peri-implant maintenance regime established for six-month recalls. The patient was satisfied with the prosthesis both esthetically and functionally. Furthermore, the patient reported significant improvements in oral function and psychosocial activities. CONCLUSION: The use of dental implants to support full mouth prosthetic rehabilitation for adolescents with ectodermal dysplasia may provide a considerable improvement in function and esthetic compared to conventional removable prosthetic options. This has the potential to enhance the quality of life for these patients. PMID- 26242011 TI - Subgingival Microbial and Inflammatory Cell Morphotypes Associated with Chronic Periodontitis Progression in Treated Adults. AB - OBJECTIVE: In a secondary data analysis, this pilot study evaluated the relationship between subgingival biofilm morphotypes and chronic periodontitis progression in treated adults. METHODS: Periodontal parameters in 47 adults with chronic periodontitis were assessed by a calibrated examiner at baseline and a mean 4.5 years after a non-surgical periodontal therapy regimen. Microbial and inflammatory cell morphotypes in subgingival biofilm specimens from each patient were evaluated with phase-contrast microscopy at baseline, and at post-treatment intervals. Chronic periodontitis progression in patients was defined as >= 2 teeth exhibiting >= 3 mm interproximal clinical periodontal attachment loss from baseline evaluations. Bivariate and odds ratio analysis assessed baseline and post-treatment variables relative to chronic periodontitis progression. RESULTS: Eight (17%) patients had chronic periodontitis progression. No baseline clinical, radiographic or microbiological variables, and no post-treatment clinical variables demonstrated statistically significant relationships with chronic periodontitis progression. Elevated post-treatment counts of subgingival spirochetes, medium to large-sized motile rods, and crevicular leukocytes, both alone and concurrently, appeared more frequently in patients experiencing chronic periodontitis progression. A post-treatment occurrence of high concurrent counts of subgingival spirochetes and crevicular leukocytes exhibited the strongest association with chronic periodontitis progression (odds ratio = 10.1; 95% Cl = 2.2, 45.4; p = 0.004), which was greater than with either morphotype alone. CONCLUSIONS: Joint morphotype analysis of subgingival spirochetes and crevicular leukocytes, as simplified biomarkers of pathogenic biofilm infection and host inflammatory responses in periodontal pockets, may be diagnostically useful in assessing risk of progressive disease in treated chronic periodontitis patients. PMID- 26242012 TI - A Simplified Technique to Measure Plaque on the Intaglio Surfaces of Complete Dentures. AB - OBJECTIVE: The main aim of this study was to develop a simplified quantitative denture plaque index that could help dentists to motivate denture patients to maintain optimal oral hygiene. The secondary aim was to assess specific areas of dentures more prone to accumulate plaque and subjects' oral hygiene habits related to their dentures. METHODS: One hundred subjects who wore maxillary and/or mandibular complete dentures for at least one year were included in the study as a powered sample. Fifteen females and 85 males, age range 45-75 years, were recruited. The study was carried out at King Saud University (KSU), College of Dentistry. A plaque disclosing solution was used to assess the plaque covered areas of denture. A quantitative percentage (10 x 10%) score index was developed by assessing plaque scores from digital images of intaglio surfaces of the dentures. The weighted kappa method was used to assess inter-examiner agreement in the main study. RESULTS: The new denture plaque index was identified as ASKD DPI (Almas, Salameh, Kutkut, and Doubali-Denture Plaque Index). It ranged from 0 100%, and reflected the percentage of the intaglio surfaces of maxillary and mandibular complete dentures that contained plaque. It also classified quantitative percentages: 30 subjects ranged from 0 - 30% (low DPI), 50 subjects ranged from 31 - 70% (moderate DPI), and 20 subjects ranged from 71 - 100% (high DPI) denture plaque score. CONCLUSIONS: A simplified denture plaque index (ASKD DPI) technique was developed and tested in this study. ASKD-DPI may be used for evaluating denture plaque scores, monitoring denture hygiene, and measuring compliance of patients regarding plaque control for complete dentures. PMID- 26242010 TI - Efficacy of Subgingivally Delivered Satranidazole in the Treatment of Type 2 Diabetes Subjects with Chronic Periodontitis: A Randomized Controlled Clinical Trial. AB - BACKGROUND: The present clinical trial was designed to investigate the effectiveness of subgingivally delivered satranidazole (SZ) gel as an adjunct to scaling and root planing (SRP) in the treatment of chronic periodontitis. METHODS: Sixty-four subjects with probing depth (PD) >= 5 mm and who were diagnosed with type 2 diabetes were selected. Thirty-two subjects each were randomly assigned to SRP + placebo (Group 1) and SRP + SZ (Group 2). The clinical outcomes evaluated were plaque index (PI), gingival index (GI), clinical attachment level (CAL) and PD at baseline, 1 month, 3-months and 6 months. RESULTS: At 6 months, Group 2 had greater mean reduction (4.73 mm) in PD as compared to Group 1 (2.09 mm; p < 0.05) and also a greater mean CAL gain (3.92 mm versus 1.64 mm; p < 0.05). CONCLUSION: The use of 3% SZ gel, when used as an adjunct to non-surgical periodontal therapy in subjects with periodontitis, achieves significantly better clinical results than initial periodontal treatment alone. PMID- 26242013 TI - And then my stethoscope fell into the commode.... PMID- 26242014 TI - HAIR SALON? PMID- 26242015 TI - Frontiers in Therapy of Treatment-Resistant-Depression: A Future Role of Ketamine? AB - Many patients treated for major depression in mental health and primary care settings fail to respond to adequate trials of available evidence-based treatments. Antidepressants, psychotherapy, and brain stimulation therapies have had some success, but many individuals do not respond to these treatments. Ketamine, a dissociative general anesthetic agent, is emerging as an unexpected possible future treatment to help individuals who suffer from refractory major depression. PMID- 26242016 TI - Assessment of Translational and Interdisciplinary Clinical Research at an Oklahoma Health Sciences Center. AB - PURPOSE: In response to National Institutes of Health initiatives to improve translation of basic science discoveries we surveyed faculty to assess patterns of and barriers to translational research in Oklahoma. METHODS: An online survey was administered to University of Oklahoma Health Sciences Center, College of Medicine faculty, which included demographic and research questions. Results: Responses were received from 126 faculty members (24%). Two-thirds spent >= 20%time on research; among these, 90% conduct clinical and translational research. Identifying funding; recruiting research staff and participants; preparing reports and agreements; and protecting research time were commonly perceived as at least moderate barriers to conducting research. While respondents largely collaborated within their discipline, clinical investigators were more likely than basic science investigators to engage in interdisciplinary research. CONCLUSION: While engagement in translational research is common, specific barriers impact the research process. This could be improved through an expanded interdisciplinary collaboration and research support structure. PMID- 26242017 TI - The Heart of Man. New research shows how simple moves can boost men's cardiac health. PMID- 26242018 TI - The Incredible, Surprising, Controversial New Way to Make a Baby. PMID- 26242019 TI - CAN DRUGMAKERS LIVE WITHOUT MERGERS? PMID- 26242020 TI - OUR FOOD, OURSELVES. PMID- 26242021 TI - DANONE GOES WITH THE GUT. PMID- 26242022 TI - "Are You Having Fun Yet"? PMID- 26242023 TI - Celebrating Mutual Success! PMID- 26242024 TI - [Accountable Care Organization]. PMID- 26242025 TI - Criminal Drug Abusers Are Allowed to Sue Their Doctors. PMID- 26242026 TI - New Mother Gets 15-Year Sentence for Using Drugs During Pregnancy. PMID- 26242027 TI - Redo Heller Myotomy for Achalasia in a Patient with Down Syndrome: a Case Report. AB - Up to 77% of Down syndrome (DS) patients have associated structural or functional gastrointestinal abnormalities. Functional disturbances, such as processes affecting the enteric nervous system, can often affect the outcome of corrective surgical procedures. Recently, an association between DS and achalasia has been reported. In this report we present a 28-year-old male patient with a history of Down syndrome and achalasia, who presented with recurrent dysphagia, gastroesophageal reflux, and recurrent aspirations. The patient had previously undergone a laparoscopic Heller myotomy with Dor fundoplication. Unfortunately, despite this surgery, he continued to require multiple esophageal dilations, and intraesophageal administration of Botox therapy. Additionally, there were numerous subsequent hospital admissions for recurrent aspiration pneumonia. Evaluation revealed an incomplete myotomy and a revision long Heller myotomy was successfully performed intraabdominally and he is now symptom and aspiration free. PMID- 26242028 TI - Obesity, Hypertension and Metabolic Syndrome in Children in West Virginia. PMID- 26242029 TI - Recognizing Guttate Psoriasis and Initiating Appropriate Treatment. AB - Guttate psoriasis is a less common form of psoriasis. It manifests with numerous small, teardrop shaped, scaly plaques on the trunk and extremities. The etiology includes both environmental and genetic factors. It commonly arises 3-4 weeks following a beta hemolytic streptococcal infection. In some cases, it may be misdiagnosed as an allergy to the antibiotics being used to treat the streptococcal infection. The treatment of guttate psoriasis can vary by severity, but the mainstay treatment includes photo therapy and topical steroids. This case report presents the etiology, clinical findings and current treatment options of guttate psoriasis. It also discusses importance of differentiating guttate psoriasis from an antibiotic allergy. The confusion between the two can often delay and make treatment more difficult. PMID- 26242030 TI - Differences in Health-related Behaviors and Attitudes between Urban, Rural, and Isolated Households in Western West Virginia. AB - This study uses data from a 2013 survey of 275 randomly sampled households across nine counties in western West Virginia to examine the significant differences between the health behaviors and attitudes of rural and isolated populations. The results show that age, education, and income are significant factors in explaining differences in health-related behaviors and attitudes for all urban, rural and isolated respondents. However, after controlling for socio-demographic differences, isolation is found to have only a few significant effects, and some of the effects run counter to stereotypes of isolated populations. Rural respondents are significantly more likely than isolated respondents to be obese and to have ever been diagnosed with hypertension. Rural Respondents are significantly less likely than isolated respondents to have annual dental or medical checkups, to engage in physical activity during the spring months, and to raise their own chickens and cattle for food. PMID- 26242031 TI - Radiation-Induced Supratentorial Primitive Neuroectodermal Tumor after Treatment for Non-Hodgkin's Lymphoma. AB - Secondary, radiation-induced, supratentorial primitive neuroectodermal tumors (PNETs) are extremely rare entities which may present in survivors of childhood cancers after central nervous system radiation. These lesions have been described after a number of pediatric cancers and demonstrate unique treatment problems and an accelerated clinical course compared to primary PNETs. We present a case of a sixteen year old male with a history of non-Hodgkin's lymphoma who presented with a radiation-induced PNET, and describe our treatment for this lesion. These secondary, radiation-induced tumors increase in significance as the survival of childhood malignancy increases in West Virginia. PMID- 26242032 TI - Pediatric Patients Need Your Help. PMID- 26242033 TI - WVSOM and UC Physician Assistant Program Establish Working Collaboration with Their First Interprofessional Education Day. PMID- 26242034 TI - Dieter's Dilemma. Science weighs in on which popular weight-loss plans truly work. PMID- 26242035 TI - [Updated treatment of erectile dysfunction after prostatectomy]. AB - The incidence rate of erectile dysfunction (ED) is reportedly as high as 30-90% after radical prostatectomy for prostate cancer, which seriously affects the patients' quality of life. Penile rehabilitation is defined as the use of any drug or device at or after radical prostatectomy to maximize erectile function recovery. A variety of treatment options are available for post-prostatectomy ED patients, including oral phosphodiesterase 5 inhibitors (PDE5I) , intracorporal injections, vacuum erection device, and penile prosthesis. This article presents an overview of the currently used methods for the drug treatment and penile rehabilitation of the ED patients after radical prostatectomy. It seems proper to recommend daily use of a vacuum erection device plus oral PDE5I in the early postoperative period. For those who fail to respond to this therapy, intraurethral alprostadil, intracorporal injections, or a penile prosthesis could be considered. PMID- 26242036 TI - [Effects of stromal cells derived from the normal prostate on the glycolysis of prostate cancer cells]. AB - OBJECTIVE: To investigate the effects of prostate stromal cells from different zones of normal prostate tissue on the growth of prostate cancer cells and their action mechanisms. METHODS: We extracted stromal cells in the fresh normal prostatic tissue derived from the peripheral zone (PZ) or transitional zone (TZ), amplified them in vitro, and used the supernatants of the cells as conditioned media to culture hormone-resistant prostate cancer DU145 cells. We measured the growth curve of the tumor cells using the CCK8 method, determined the number and viability of the cells by trypan blue staining, evaluated their invasiveness by scratch test, and detected the effects of the stromal cells on the key enzymes in the glycolysis of the tumor cells by Western blot. RESULTS: The conditioned medium with the PZ-derived stromal cells promoted, while that with the TZ-derived stromal cells inhibited the growth of the tumor cells. The former significantly increased, while the latter markedly decreased the expressions of the key enzymes hexokinase 2 (HK-2), pyruvate kinase 2 (PKM-2), lactate dehydrogenase (LDHA), and pyruvate dehydrogenase (PDH) in the glycolysis of the tumor cells. CONCLUSION: Prostate stromal cells from different zones exert different influences on the growth of tumor cells, which may be associated with their different effects on the glycolysis of tumor cells. PMID- 26242037 TI - [Basic fibroblast growth factor promotes the differentiation of rat bone marrow mesenchymal stem cells into Leydig cells]. AB - OBJECTIVE: To explore the role of the basic fibroblast growth factor (bFGF) in the directional differentiation of bone marrow mesenchymal stem cells (BMSCs) into Leydig cells. METHODS: After purification and identification, we inoculated the third-generation BMSCs of SD rats onto a six-orifice board and then randomly divided them into groups A (normal saline control), B (human chorionic gonadotropin [hCG] + platelet-derived growth factor [PDGF] induction), C (hCG + PDGF + 5.0 ng/ml bFGF induction), D (hCG + PDGF + 10.0 ng/ml bFGF induction), and E (hCG + PDGF + 20.0 ng/ml bFGF induction). On the 7th, 14th and 21st day of induction, we observed the morphological changes of the cells and measured the level of testosterone (T) and expression of 3 beta hydroxy steroid dehydrogenase (3beta-HSD) in the supernatant by immunofluorescence staining. RESULTS: After induction, the BMSCs of groups B, C, D, and E exhibited microscopic features of enlarged size, inter-connection, long-shuttle or irregular shape, adherent growth, and large round nuclei, all characteristic of Leydig cells. With the prolonging of time and enhanced concentration of bFGF, gradual increases were observed in the T level and the count of 3beta-HSD-positive BMSCs in the four induction groups, with statistically significant differences between group B and groups C, D, and E (P < 0.05), as well as between group C and groups D and E (P < 0.05), but not between D and E (P > 0.05). CONCLUSION: The bFGF has an obvious promoting effect in the in vitro induced differentiation of rat BMSCs into Leydig cells. PMID- 26242038 TI - [miRNA-101 inhibits the expression of the enhancer of zeste homolog 2 in androgen independent prostate cancer LNCaP cell line]. AB - OBJECTIVE: To investigate the effect of miRNA-101 on the expression of the enhancer of zeste homolog 2 (EXH2) in human androgen-independent prostated cancer LNCaP cells. METHODS: We divided LNCaP cells into a blank control, a negative control, and a miRNA-l01 transfection group, constructed the vector by transfecting synthetic miRNA-101 mimics into the LNCaP cells, and evaluated the efficiency of transfection by fluorescence microscopy. Then we determined the expression level of EZH2 mRNA by qRT-PCR in the three groups of cells and that of the EZH2 protein in the negative control and transfection groups by Western blot. RESULTS: Green fluorescence signals were observed in over 70% of the LNCaP cells in the transfection group after 24 hours of transfection. At 72 hours, the expression of miRNA-101 was significantly upregulated in the transfected cells (P < 0.01), that of EZH2 mRNA was remarkably lower in the transfection group (0.01 +/- 0.10) than in the blank control (0.95 +/- 0.40) and negative control (0.86 +/ 0.30) groups (both P < 0.01), and that of the EZH2 protein was increased in the negative control but decreased in the transfection group with the extension of culture time. CONCLUSION: miRNA-101, with its inhibitory effect on the expression of EZH2 in LNCaP cells, is a potential biotherapeutic for prostate cancer. PMID- 26242039 TI - [Dynamic infusion cavernosometry and cavernosography for the diagnosis and classification of venous erectile dysfunction]. AB - OBJECTIVE: To explore the procedures of dynamic infusion cavernosometry and cavernosography (DICC) and their application in the diagnosis and classification of venous erectile dysfunction (VED). METHODS: This study included 103 ED patients, aged 20 to 43 years, highly suspected of VED, with disease courses of 4 months to 6 years. DICC was performed and analyses were made on the results, especially the parameters of flow-to-maintain (FTM) and pressure decay (PD) in the corpus cavernosum. RESULTS: Based on the parameters of FTM and PD, 21 of the patients were normal, 5 were suspected of VED, 39 had mild VED, 25 had moderate VED, and 13 had severe VED. Penile subcutaneous hematoma was found in 4 of the patients, all recovered after 3 to 5 days, with no other complications. CONCLUSION: DICC is a reliable, safe and minimally invasive method for the diagnosis and classification of VED. PMID- 26242040 TI - [Expression of ZEB1 in the prepuce of hypospadias children and its implication]. AB - OBJECTIVE: To investigate the expression of zinc finger E-box binding homebox 1 (ZEB1) in the prepuce of hypospadias children and its relationship to the incidence of hypospadias. METHODS: Prepuce tissues were collected from 37 children aged 6-15 months undergoing hypospadias repair and 11 age-matched controls receiving circumcision. Based on the position of the urethral meatus, the hypospadias cases were classified as severe (n = 13) and mild-moderate (n = 24). The mRNA and protein expressions of ZEB1 were determined by immunohistochemistry and RT-PCR. RESULTS: The expression of the ZEB1 protein was remarkably higher in the severe (100% [13/13]) and mild-moderate hypospadias patients (75.0% [18/24]) than in the controls (9.1% [1/11]), with statistically significant differences between any two groups (P < 0.05). RT-PCR showed the integrated density value (IDV) of the ZEB1 mRNA expression to be (0.67 +/- 0.21), (0.81 +/- 0.24), and (1.55 +/- 0.29) in the control, mild-moderate, and severe hypospadias patients, respectively, significantly higher in the severe hypospadias than in the control and mild-moderate hypospadias groups (P < 0.05), but with no significant difference between the latter two (P = 0.64). CONCLUSION: The expression of ZEB1 is significantly increased in hypospadias patients, and its upregulation is positively correlated with the severity of hypospadias, which suggests that the overexpression of ZEB1 may contribute to the development of hypospadias. PMID- 26242041 TI - [Impact of mobile phone radiation on the quality and DNA methylation of human sperm in vitro]. AB - OBJECTIVE: To investigate the influences of mobile phone radiation on the quality and DNA methylation of human sperm in vitro. METHODS: According to the fifth edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, we randomly selected 97 male volunteers with normal semen parameters and divided each semen sample from the subjects into two equal parts, one exposed to mobile phone radiation at 1950 M Hz, SAR3. 0 W/kg for 3 hours while the other left untreated as the control. We obtained routine semen parameters as well as the acrosomal reaction ability, apoptosis and DNA methylation of sperm, and compared them between the two groups. RESULTS: Compared with the control, the radiation group showed significantly decreased progressive sperm motility ([36.64 +/- 16.93] vs [27.56 +/- 16.92]%, P < 0.01) and sperm viability ([63.72 +/- 16.35] vs [54.31 +/- 17.35]%, P < 0.01) and increased sperm head defects ([69.92 +/- 4.46] vs [71.17 +/- 4.89]%, P < 0.05), but no significant differences in sperm acrosomal reaction ([66.20 +/- 6.75] vs [64.50 +/- 3.47]%, P > 0.05). The early apoptosis rate of sperm cells was remarkably higher in the radiation group ([6.89 +/- 9.84]%) than in the control ([4.44 +/- 5.89]%) (P < 0.05). However, no statistically significant differences were found between the control and radiation groups in the DNA methylation patterns of the paternal imprinting gene H19 ICR ([0.60 +/- 0.02] vs [1.40 +/- 0.03]%, P > 0.05) or the maternal imprinting gene KvDMR1 ([0.00 +/- 0.00] vs [1.80 +/- 0.031%, P > 0.05). CONCLUSION: Mobile phone radiation reduces the progressive motility and viability of human sperm and increases sperm head defects and early apoptosis of sperm cells. PMID- 26242042 TI - [Protective effect of lycopene on human spermatozoa during cryopreservation and its mechanism]. AB - OBJECTIVE: To investigate the protective effect of lycopene against cryopreservation injury of post-thawing human sperm and its mechanism. METHODS: Semen samples were collected from 25 volunteers, each sample equally divided into four parts to be cryopreserved with cryoprotectant only (Ly0 control) or cryoprotectant + lycopene at the concentrations of 2 (Ly2), 5 (Ly5), and 10 umol/L (Ly10), respectively. Before and after thawing, the semen samples were subjected to computer-assisted semen analysis ( CASA) for sperm kinematics, flow cytometry for sperm apoptosis, thiobarbituric acid assay for malondialdehyde (MDA) concentration, and JC-1 fluorescent staining for the sperm mitochondrial membrane potential (MMP). RESULTS: After cryopreservation, sperm motility was markedly decreased in all the groups (P < 0.01). The rate of sperm apoptosis was significantly lower in the Ly5 group than in the Ly0 control ([25.68 +/- 4.36]% vs [33.26 +/- 4.78]%, P < 0.05), while sperm MMP remarkably higher in the former than in the latter ([66.18 +/- 14.23]% vs [55.24 +/- 12.31]%, P < 0.05). The Ly2, Ly5 and Ly10 groups showed no statistically significance differences in the MDA level from the Ly0 control (P > 0.05). CONCLUSION: Addition of lycopene at a proper concentration to cryoprotectant may reduce oxidative damage to sperm mitochondria in the freezing-thawing process, attenuate oxidative stress injury induced by reactive oxygen species to sperm plasma membrane, and improve the anti apoptosis ability of sperm. PMID- 26242043 TI - [Influence of male age on the pregnancy outcomes of IVF-ET]. AB - OBJECTIVE: To investigate the influence of male age on the pregnancy outcomes of in vitro fertilization-embryo transfer (IVF-ET). METHODS: We retrospectively analyzed 7,533 cycles of IVF-ET performed between January 1, 2009 and October 31, 2013. We divided the samples into three groups according to the female age (< 30, 30-34, and 35-38 yr), each again subdivided into six groups based on the male age (< 30, 30-32, 33-35, 36-38, 39-41, and >= 42 yr). We compared the rates of implantation, pregnancy, miscarriage, and live birth among different age groups. RESULTS: There were no statistically significant differences in basal E2, FSH, endometrium thickness on the day of hCG administration, number of oocytes retrieved, and days of embryo transfer among different male age groups (P > 0.05). The implantation rate showed an age-dependent decrease in the < 30, 30-32, 33-35, 36-38, 39-41, and >= 42 yr male groups, 41.1, 42.0, 39.5, 31.3, 40.7, and 48.6% among the women aged < 30 years (P < 0.05), 40.3, 36.4, 35.1, 35.3, 29.4, and 37.3% among the women aged 30-34 years (P < 0.05), and 48.2, 17.8, 25.3, 23.5, 22.1, and 23.8% among the women aged 35-38 years (P < 0.05). The miscarriage rate was significantly higher in the >= 39 yr than in the 30-32 and 33-35 yr male age groups among the women aged 30-34 years (P < 0.05), but showed no remarkable differences among the other male age groups in the women aged < 30 and 35-38 years (P > 0.05). No statistically significant differences were observed in the rates of pregnancy and live birth among different male age groups (P > 0.05). CONCLUSION: Male age has some influence on the rates of implantation and miscarriage but not on the rates of pregnancy and live birth in IVF-ET. PMID- 26242044 TI - [Time interval from the end of sperm processing to artificial intrauterine in semination with husband's sperm correlates to the rate of clinical pregnancy]. AB - OBJECTIVE: To investigate the influence of the time interval from the end of semen processing to artificial intrauterine in semination with husband's sperm (AIH-IUI) on the rate of clinical pregnancy. METHODS: This study involved 191 AIH IUI cycles with the same ovulation induction protocol. After Percoll density gradient centrifugation, we divided the sperm into four groups based on the incubation time: 0-19, 20-39, 40-59, and 60-80 min, and again into another four groups according to the total progressively motile sperm count (TPMC): (0-9), (10 20), (21-30), and > 30 x 10(6). We analyzed the correlation of the clinical pregnancy rate with the time interval from the end of sperm processing to AIH-IUI and with other influencing factors, such as maternal age, infertility duration, and semen quality. RESULTS: The rate of clinical pregnancy was significantly higher in the 20-39 min group (18.3%) than in the 0-19, 40-59, and 60-80 min groups (12.7, 11.4 and 9.1%) (all P < 0.05). The (10-20) x 10(6) group achieved a remarkably higher pregnancy rate (16.7%) than the (0-9), (21-30), and > 30 x 10(6) groups (0, 11.4, and 8.3%) (all P < 0.05). Logistic multivariate analysis showed that the rate of clinical pregnancy was decreased with the increased age of the women (OR 0.89, 95% CI 0.83-0.94) but significantly elevated in the 20-39 min group (OR 2.11, 95% CI 1.34-3.13) and of (10-20) x 10(6) group (OR 2.06, 95% CI 1.32-3.46). CONCLUSION: The time interval from the end of sperm processing to AIH-IUI is a most significant factor influencing the rate of clinical pregnancy of AIH-IUI. PMID- 26242045 TI - [Association of serum testosterone with atherosclerosis in middle-aged and elderly men]. AB - OBJECTIVE: To investigate the association between the level of serum testosterone and atherosclerosis in middle-aged and elderly men. METHODS: We conducted a population-based study of 413 males aged 40-75 years in a community in Guangzhou. We obtained the sociodemographic characteristics, clinical data, physical measurements, and laboratory results of sex hormones, blood glucose, and blood lipid of the subjects. We also measured the carotid intima media thickness (CIMT) by color Doppler ultrasonography. RESULTS: The subjects were divided into a carotid atherosclerosis (CAS) group (CIMT >= 0.9 mm) and a non-CAS group (CIMT < 0.9 mm). The medians of free testosterone (FT) were 57.41 and 59.72 pmol/L in the CAS and non-CAS groups, respectively (P = 0.005), and no significant difference was found between the two groups in total testosterone (TT). The levels of serum FT and TT were negatively correlated to CIMT, with Spearman's rank correlation coefficients of -0.126 (P = 0.011) and -0.188 (P < 0.001), respectively. The incidence rates of CAS were 23.30, 13.46, 17.48, and 7.77% in the Q1, Q2, Q3, and Q4 groups, respectively according to the quartile of FT (P for trend = 0.008) and 17.48, 18.27, 16.50, and 9.71% respectively according to the quartile of TT (P for trend = 0.116). Based on the quartile of FT and after adjustment for age, waist circumference, systolic blood pressure, and HbAlc, the risk of CAS was significantly increased in the Q1 group as compared with Q4 (OR = 2.491, 95% CI 1.01-6.149), but no statistically significant differences were observed according to the quartile of TT. CONCLUSION: A low serum FT level may be a risk factor of atherosclerosis in Chinese men aged 40 years or older. PMID- 26242046 TI - [Modified circumcision with a disposable suture device]. AB - OBJECTIVE: To improve the methods and reduce the complications of circumcision with a disposable suture device. METHODS: This study included 325 male patients aged 14-65 (mean 28.9) years, treated for redundant prepuce or phimosis by modified (n = 201) or conventional circumcision with a disposable suture device (n = 124). We compared the incidence of complications and the patients' satisfaction between the two surgical methods. RESULTS: Compared with conventional circumcision, the modified method showed a significantly lower incidence of postoperative bleeding (14.52% vs 2.49% , P < 0.05) and a lower rate of second surgery for penile hematoma (4.03% vs 0.50%, P < 0.05). The patients' satisfaction was markedly higher with the modified method (91.94%) than with conventional circumcision (97.51%) (P < 0.05). CONCLUSION: Modified circumcision with the disposable suture device can significantly reduce the incidence of postoperative bleeding and penile hematoma and therefore deserves wide clinical application. PMID- 26242047 TI - [Shugan Jieyu Capsules combined with conventional therapy for type III B prostatitis complicated by sexual dysfunction]. AB - OBJECTIVE: To explore the clinical effect of Shugan Jieyu Capsules (SJC) on type III B prostatitis complicated by sexual dysfunction. METHODS: A total of 98 patients with type III B prostatitis complicated by sexual dysfunction were equally randomized to a control and a trial group, the former treated with the combination of biofeedback/electrical stimulation and the alpha-blocker Tamsulosin Hydrochloride, and the latter with oral SJC in addition, both for 8 weeks. Before and after treatment, the severity of the symptoms was determined with NIH-CPSI, the patients'sexual function evaluated with CIPE-5 and IIEF-5, and their anxiety, depression and other psychological problems assessed with Hamilton Anxiety Scale (HAMA) and Hamilton Depression Rating Scale ( HAMD). The results were subjected to statistical analysis and compared between the two groups. RESULTS: Statistically significant differences were found between the control and trial groups in the NIH-CPSI score (26.31 +/- 7.91 vs 18.84 +/- 6.63, P < 0.01), CIPE-5 premature ejaculation score (10. 41 +/- 3.03 vs 14.37 +/- 2.35, P < 0.05), IIEF-5 score (10.29 +/- 3.97 vs 14.69 +/- 4.19, P < 0.05), HAMA score (24.31 +/- 1.78 vs 13.41 +/- 4.21, P < 0.01), and HAMD score (25.24 +/- 2.83 vs 14.49 +/- 4.44, P < 0.01). CONCLUSION: SJC can effectively relieve anxiety, depression and other psychological problems in type III B prostatitis patients with sexual dysfunction and improve their clinical symptoms as well. PMID- 26242048 TI - [Qilin Pills combined with clomiphene for idiopathic oligoasthenozoospermia]. AB - OBJECTIVE: To observe the therapeutic effect of Qilin Pills combined with clomiphene on idiopathic oligoasthenospermia. METHODS: We randomly assigned 300 patients with idiopathic oligoasthenospermia to a trial (n = 156) and a control group (n = 144) to be treated with Qilin Pills (6 g, tid) combined with clomiphene (50 mg, qd) and clomiphene alone (50 mg, qd), respectively, both for a course of 12 weeks. Before and after 4, 8, and 12 weeks of medication, we determined sperm concentration, the percentages of grade a and grade a + b sperm, sperm motility, and the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T), followed by evaluation of the clinical efficacy of Qilin Pills with the pregnancy rate in the patients' spouses as the secondaty therapeutic indexes. RESULTS: Compared with the baseline, both groups of patients showed remarkably improved semen parameters and hormone levels after treatment (all P < 0.01). After 4, 8, and 12 weeks of medication, statistically significant differences were observed between the trial and control groups in sperm concentration ([17.06 +/- 2.24] vs [15.07 +/- 2.48], [22.10 +/- 2.65] vs [18.11 +/- 2.97], and [28.13 +/- 3.59] vs [21.21 +/- 3.60] x 10(6)/mL, P < 0.01), the percentage of grade a sperm ([15.03 +/- 2.39] vs [13.08 +/- 2.51], [21.08 +/- 3.16] vs [16.04 +/- 3.05], and [28.08 +/- 4.70] vs [20.14 +/- 4.74]%, P < 0.01), the percentage of grade a + b sperm ([30.10 +/- 5.07] vs [26.21 +/- 3.96], [38.08 +/- 5.64] vs [30.07 +/- 4.80], and [48.04 +/- 6.49] vs [35.28 +/- 4.77]%, P < 0.01), sperm motility ([42.04 +/- 4.86] vs [40.29 +/- 4.19], [52.05 +/- 5.58] vs [48.03 +/- 4.40], and [65.03 +/- 5.13] vs [56.67 +/- 4.99]%), the FSH level ([7.75 +/- 1.38] vs [7.20 +/- 1.17], [10.83 +/- 1.23] vs [9.10 +/- 1.32], and [14.22 +/- 0.84] vs [12.06 +/- 1.45] IU/L, P < 0.01), the LH level ([10.05 +/- 1.68] vs [9.18 +/- 1.54], [13.96 +/- 1.68] vs [11.99 +/- 1.71], and [19.01 +/- 2.42] vs [15.86 +/- 2.08] IU/L, P < 0.01) and the T level ([19.19 +/- 192] vs [18.34 +/- 1.79] [21.06 +/- 1.63] vs [20.06 +/- 1.56], and [24.63 +/- 1.06] vs [22.03 +/- 1.49] nmol/L, P < 0.01). The pregnancy rate in the patients' spouses was significantly higher in the trial than in the control group at 4, 8, and 12 weeks (1.92 vs 0.69, 4.81 vs 3.47, and 11.54 vs 8.33%, P < 0.01). There were no statistically significant differences in drug tolerance between the two groups (P > 0.05). No obvious adverse reactions were observed. CONCLUSION: Qilin Pills combined with clomiphene can evidently improve the seminal quality and hormone level of oligoasthenospermia patients with no obvious adverse events. However, its long-term efficacy and tolerance deserve further clinical investigation. PMID- 26242049 TI - [2014 Annual Meeting of the American Urological Association: early screening and molecular markers of prostate cancer]. AB - The 109th Annual Meeting of the American Urological Association was held in Orlando, Florida, USA in May 2014, which received more than 1,000 abstracts on prostate cancer (PCa), covering new epidemiological data about PCa, new theories of early screening, novel molecular markers, new surgical methods, new ideas of diagnosis and treatment of castration-resistant PCa, and progress in basic researches. This paper focuses on the new theories of early screening and novel molecular markers of PCa, including the risk factors of PCa, a revolutionary understanding of the relationship between testosterone and PCa, and new application of PSA, new imaging techniques and molecular markers in the early diagnosis of PCa. PMID- 26242050 TI - [Phosphodiesterase type 5 inhibitors for premature ejaculation: advances in studies]. AB - Premature ejaculation (PE) is a common male sexual disorder with an incidence rate of 20-30%. Recent clinical trials have demonstrated that phosphodiesterase type 5 inhibitors (PDE5i), as the first-line drug for erectile dysfunction (ED), can improve ejaculatory function probably by acting on the peripheral and central adrenergic nerves. The possible action mechanisms of PDE5i may involve lessening of the central sympathetic output, modulation of the contractile responses from the vas deferens, seminal vesicles, prostate and urethra, induction of peripheral analgesia, and prolonging of the total erectile duration, increasing the confidence of ejaculation control, and reducing the post-ejaculation refractory time. This review discusses the possible mechanisms and clinical application of PDE5i in the treatment of PE. PMID- 26242051 TI - [Eosin Y-water test for sperm function examination]. AB - Based on the principles of the in vitro staining technique, hypotonic swelling test, and water test, the Eosin Y-water test method was developed to simultaneously detect the integrity of the sperm head and tail and sperm membrane structure and function. As a widely used method in clinical laboratories in China, the Eosin Y-water test is methodologically characterized by three advantages. Firstly, both the sperm head and tail can be detected at the same time, which allows easy and comprehensive assessment of membrane damage in different parts of sperm. Secondly, distilled water is used instead of the usual formula solution to simplify and standardize the test by eliminating any potential effects on the water molecules through the sperm membrane due to different osmotic pressure or different sugar proportions and electrolyte solutions. Thirdly, the test takes less time and thus can be repeated before and after treatment. This article focuses on the fundamental principles and modification of the Eosin Y-water test and its application in sperm function examination and routine semen analysis for male infertility, assessment of the quality of sperm retrieved by testicular fine needle aspiration, semen cryopreservation program development, and evaluation of sperm membrane integrity after microwave radiation. PMID- 26242052 TI - HIV Still Needs our Focus. PMID- 26242053 TI - HIV from a Personal and Public Health Perspective: Early Diagnosis is the Key. PMID- 26242054 TI - Pre- and Post-Exposure Prophylaxis and the Changing Paradigm of HIV Prevention. PMID- 26242055 TI - Late Diagnoses of HIV Infection in Mississippi: Implications for Improved Testing Strategies and Treatment. AB - INTRODUCTION: According to the Centers for Disease Control and Prevention, more than 1.1 million people in the United States are living, with HIV infection, and approximately 1 in 6 (18%) are unaware of their infection. People living with undiagnosed HIV are more likely to progress to AIDS, transmit the virus to others, and have poorer overall health outcomes. In 2013, Mississippi had the 6th highest estimated AIDS diagnoses rate among adults and adolescents in the United States and when comparing persons living with AIDS, the Jackson, MS metropolitan area had the tenth highest rate among all MSAs. OBJECTIVE: The objective of this study is to describe people who are diagnosed with HIV late in their course of illness and to identify characteristics associated with late diagnoses. METHODS: Demographic data was obtained for all Mississippi residents who were diagnosed with HIV infection between Janary 1, 2004 and December 31,2014. Late diagnoses of HIV infection is defined as an AIDS diagnosis made within 12 months from an initial HIV diagnosis. Prevalence trends, demographics, and predictors of late diagnoses were measured. Results: Among 4,864 cases of -IV disease, 35% (1,682) were late diagnoses. Late diagnoses were more likely to occur among males, individuals over the age of 34, and individuals who were diagnosed outside of Mississippi State Department of Health clinics. CONCLUSION: A large proportion of individuals had late diagnoses of HIV infection and this proportion has slightly declined in recent years. Routine testing in medical settings and in areas with high morbidity may increase early HIV diagnosis. PMID- 26242056 TI - Antiretroviral Therapy. PMID- 26242057 TI - Miracles can Happen. We can Help. PMID- 26242058 TI - What is Better than "Curing" an HIV-Infected Child? PMID- 26242059 TI - Top Ten Facts You Need to Know about HIV. PMID- 26242060 TI - CODE with CONFIDENCE. Optimize your coding strategy for 2015. PMID- 26242061 TI - EFFECTIVE COLLECTION AGENCY USE: THE IMPORTANCE OF INTERNAL POLICIES. AB - Increasing patient accountability for the cost of healthcare means physician practices likely will need to improve their internal collection processes and consider contracting with an outside collection agency. But choosing a good collection agency is the second priority. The first is establishing well-thought out and specific internal procedures for collecting as much as possible before turning to an outside collection agency. PMID- 26242062 TI - Building better care teams with non-physician providers. PMID- 26242063 TI - The referral dilemma. Managing patients and liability concerns. PMID- 26242064 TI - THE EVALUATION AND MANAGEMENT CODES AUDITORS FOCUS ON. PMID- 26242065 TI - The fight for clinical control. PMID- 26242067 TI - When practicing medicine RUNS IN THE FAMILY. PMID- 26242066 TI - Lemons to lemonade. Why I remain in practice. PMID- 26242068 TI - RESTRICTIONS GROWING ON PHYSICIAN SPEECH IN EXAM ROOM. AB - An open relationship between physician and patient is crucial to good healthcare. But are there limits to what physicians can ask their patients? Laws restricting doctors' freedom to discuss certain topics with patients, enacted primarily to promote a particular political viewpoint, are nothing new. Still, physicians must be mindful of this troubling trend. PMID- 26242069 TI - STUDY: ACA DEMANDS MAY DETER FAMILY DOCS FROM TREATING KIDS. AB - The availability of primary care services for children is declining, as fewer family physicians are seeing children, according to a recent Annals of Family Medicine study. The study's authors say they are concerned that the Affordable Care Act policies that are increasing coverage for adults are spreading the services of current family physicians too thin. PMID- 26242071 TI - Primary care physicians seeing fewer patients. PMID- 26242072 TI - Financial progress stalls. Practices grapple with new pressures. PMID- 26242073 TI - Physicians wait for ACA's malpractice impact. PMID- 26242070 TI - The 86th Annual Physician Report. Administrative burdens keep physicians away from patients. PMID- 26242074 TI - CANCER CARES NEW PATH. PMID- 26242075 TI - 5 ways to improve patient flow . PMID- 26242076 TI - DON'T LET PEAK DEMAND SABOTAGE YOUR SCHEDULE. PMID- 26242077 TI - THE BATTLE OVER PATIENT DATA. How to secure your access. AB - Who owns patient data in an electronic health record (EHR)? It's a simple question with a complex answer. No longer confined to the shelves of a physician's office, patient data is now shared and used by a myriad of organizations across healthcare: Other physicians and health systems, the EHR vendor, payers, and researchers, not to mention patients themselves. While primary care physicians often originate the medical record, the resulting data are not theirs alone. PMID- 26242078 TI - The EHR switch. Why it may be the best change your practice ever makes. PMID- 26242079 TI - The future of interoperability. PMID- 26242080 TI - Meaningful Use 2. A work in progress for physicians. PMID- 26242081 TI - On the front lines of diabetes care. PMID- 26242082 TI - HOW TO AVOID MODIFIER 25 DENIALS. PMID- 26242083 TI - CREATING YOUR PRACTICE'S 'BRING YOUR OWN DEVICE' POLICY. PMID- 26242085 TI - EHR SCORECARD. Physician ratings on system usability. PMID- 26242084 TI - CMS LAUNCHES 'OPEN PAYMENTS' SITE DESPITE PHYSICIAN CONCERNS. PMID- 26242086 TI - SATISFACTION with EHR SYSTEMS GROWS AMONG PHYSICIANS. PMID- 26242087 TI - Top 50 EHRs. PMID- 26242088 TI - ONC's plan to solve the interoperability puzzle. PMID- 26242089 TI - EHR 2.0: 4 ways vendors are building better systems. PMID- 26242090 TI - Embracing the mobile health revolution. PMID- 26242091 TI - Technology opens new avenues for patient communication. PMID- 26242092 TI - Work smarter. Why your patient portal can boost practice efficiency. PMID- 26242094 TI - ACP issues recommendations on diagnosis of obstructive sleep apnea. PMID- 26242093 TI - STUDY: ONLINE COMMUNICATION ELUSIVE FOR PRIMARY CARE PHYSICIANS. PMID- 26242095 TI - Paying for the ACA: The Medicare and net-investment tax. PMID- 26242096 TI - Optimize your patient portal. PMID- 26242097 TI - Managing influenza season. PMID- 26242098 TI - COUNTING THE MINUTES: PROPER USE OF TIME-BASED CODING. PMID- 26242099 TI - Choosing Whom to Ask. PMID- 26242100 TI - The Nature of Offense. PMID- 26242101 TI - From the Desk of the Executive Director. PMID- 26242102 TI - What If My Practice Partner Becomes Incapacitated With a Short or Long-Term Disability? PMID- 26242103 TI - Five Things to Know About Regenerative Periodontal Therapies in Dental Medicine. PMID- 26242104 TI - Oral Pathology Quiz #87. Case Number 1. Ameloblastoma. PMID- 26242105 TI - Oral Pathology Quiz #87. Case Number 2. Irritation fibroma. PMID- 26242106 TI - Oral Pathology Quiz #87. Case Number 3. Lichenoid mucositis. PMID- 26242107 TI - Oral Pathology Quiz #87. Case Number 4. Peripheral ossifying fibroma. PMID- 26242108 TI - Community Water Fluoridation Put to the Test in Two New Jersey Towns. PMID- 26242109 TI - Dysplastic Papillary Lesions in the Immunosuppressed. A Clinically Relevant Dilemma. PMID- 26242110 TI - Comparison of Patient Satisfaction in the Fabrication of Conventional Dentures vs. DENTCA (CAD/CAM) Dentures: A Case Report. PMID- 26242111 TI - [Combination Sites of Chinese Medicine and Western Medicine in Clinical Laboratory Diagnostics]. PMID- 26242112 TI - [Treatment of Radical Resected NSCLC by Chinese Medicine Combined with Adjuvant Chemother- apy: a Clinical Study]. AB - OBJECTIVE: To evaluate the efficacy of Chinese medicine (CM) combined adjuvant chemotherapy in postponing relapse and metastasis of radical resected Ib-IIIa stage non-small cell lung cancer (NSCLC) patients, and to explore its effect in improving their quality of life (QOL) and clinical symptoms. METHODS: We designed a cohort study of 336 radical resected Ib-IIIa NSCLC patients by analyzing disease free survival (DFS) using Log-rank test. They were randomly assigned to the control group (155 cases, treated by adjuvant chemotherapy group) and the test group (181 cases, treated by adjuvant chemotherapy combined CM). By using controlled method, 60 radical resected NSCLC patients undergoing NP/NC program in 2012 (vinorelbine 25 mg/m2, combined with cisplatin 75 mg/m2 on day 1 and day 8/on day 1 or on day 1, 2, and 3; or carboplatin AUC = 5 on day 1) were assigned to the control group (29 cases) and the test group (31 cases). QOL scores (using EORTC QLQ-LC43 questionnaire) and TCM symptoms scores were compared between the two groups before chemotherapy, peri-chemotherapy (one day before the 2nd course of chemotherapy) , and after chemotherapy (20 days after ending the 4th course of chemotherapy). RESULTS: (1) The median DFS was longer in the test group than in the control group, but with no statistical difference between the two groups (42.73 months vs 35.57 months , P = 0.179). In the subgroup analysis, there was statistical difference in IIIa stage DFS. The median IIIa stage DFS of was longer in the test group than in the control group with statistical difference (27.87 months vs 19. 93 months, P = 0.047). (2) In the control study, repeated measured data indicated there was significant difference in physical functions between the two groups (P < 0.05). Total scores for health states decreased more in the test group than in the control group, but with no statistical difference (P > 0.05). Scores for constipation and CM syndrome scores were higher in the test group than in the control group (P < 0.05). CONCLUSIONS: CM had advantages in postponing DFS of radical resected NSCLC patients, especially in IIIa stage. CM could improve their QOL and clinical symptoms during adjuvant chemotherapy. PMID- 26242113 TI - [A Retrospective Study of Chinese Herbal Medicine Combined with Systemic Chemotherapy and/or Regional Arterial Perfusion for Pancreatic Cancer with Liver Metastases]. AB - OBJECTIVE: To evaluate the efficacy and safety of Chinese herbal medicine combined with systemic chemotherapy and/or regional arterial perfusion for pancreatic cancer with liver metastases (PCLM). METHODS: We retrospectively selected 292 patients with PCLM who were treated by Chinese herbal medicine combined with systemic chemotherapy and/or regional arterial perfusion at Tianjin Medical University Cancer Hospital from January 2001 to December 2010. All patients were assigned to the Western medicine treatment group (157 cases) and the integrative medicine treatment group (135 cases). Patients in the Western medicine treatment group were treated with gemcitabine (GEM)-based chemotherapy, and partial of them received regional arterial perfusion. Those in the integrative medicine treatment group additionally took Chinese herbs of clearing heat and eliminating mass for at least 4 weeks. The median survival time (MST) , adverse reactions and the incidence of complications were observed. RESULTS: There was no statistical significance in general data between the two groups (P > 0.05). There was statistical difference in MST between the two groups (4.8 months vs 5.5 months, P < 0.05). No death occurred during chemotherapy or regional arterial perfusion. All toxic or adverse reactions were tolerable. CONCLUSION: Chinese herbal medicine combined with systemic chemotherapy and/or regional arterial perfusion was effective and safe, and it could be optimally selected as palliative therapy for PCLM. PMID- 26242114 TI - [Metabolomics Study on Non-Small Cell Lung Cancer Patients with Different Chinese Medical Syndromes]. AB - OBJECTIVE: To study the relationship between Chinese medical syndrome types and metabolomics of non-small cell lung cancer (NSCLC) patients. METHODS: Totally 120 NSCLC patients were assigned to asthenia syndrome group and sthenia syndrome group, 60 in each group. Meanwhile, 60 cases of benign pulmonary nodules in physical examinations were recruited as the control group. Tumor tissues or benign pulmonary nodules tissues were obtained by thoracoscope. Changes of their metabolites were observed using gas chromatography-mass spectrometry (GC-MS). Their differences were studied using principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA). ROC curve analysis was performed in different metabolic compounds of sthenia and asthenia syndromes groups. The area under the curve (AUC) was calculated to evaluate the sensitivity of diagnosing syndrome types. RESULTS: Compared with the control group, difference existed in 16 compounds. Of them , contents of citric acid, pyruvic acid, alanine, choline phosphate, glycerol phosphate choline, linoleic acid, oleic acid, lactic acid, inositol were more in the two tumors group than in the control group. Difference existed in 10 compounds between the sthenia syndrome group and the asthenia syndrome group. Of them, citric acid, pyruvic acid, alanine, choline phosphate, glycerol phosphate choline, lactic acid, and inositol were more in the asthenia syndrome group than in the sthenia syndrome group. Contents of valine, glucose, and glutamine were more in the sthenia syndrome group than in the asthenia syndrome group. ROC curve analyses of different compounds indicated that AUC of lactic acid and glucose was more than 0.8 (P < 0.01); AUC of inositol, choline phosphate, and glycerol phosphate choline was more than 0.7 (P < 0.01); AUC of valine, citric acid, glutamine, alanine, and pyruvic acid was more than 0.6 (P < 0.05). CONCLUSIONS: There existed certain correlation between CM syndrome types and metabolomics of lung cancer. Lactic acid, glucose, inositol, choline phosphate, glycerol phosphate choline, valine, citric acid, glutamine, alanine, pyruvic acid were sensitive diagnostic compounds, and the first four kinds were most sensitive compounds. PMID- 26242115 TI - [Relation between Chinese Medical Constitutions and Chemotherapy-induced Leucopenia in Breast Cancer Patients: a Clinical Study]. AB - OBJECTIVE: To analyze the relationship between Chinese medical constitutions and chemotherapy-induced leucopenia (CIL) of primary breast cancer patients. METHODS: Totally 306 breast cancer patients undergoing adjunctive chemotherapy for the 1st time, and effective 291 breast cancer patients were recruited in this study.Nine Basic Constitutional Scale was used before first chemotherapy. Chinese medical constitutions were classified and quantitatively scored. The highest grading for any item of adverse reactions in each case during the whole chemotherapy course was recorded after chemotherapy. Data were statistically analyzed using SPSS16.0. RESULTS: There was no significant difference in CIL between different chemotherapy regimens and various Chinese medical constitutions of breast cancer patients (P > 0.05). Yang deficiency constitution is one risk factor for CIL. The higher the score of yang deficiency constitution, the more severe the CIL. CONCLUSIONS: Yang deficiency constitution was correlated with the degree of CIL. The higher the score of yang deficiency constitution, the greater the risk of III IV grade CIL in breast cancer patients. PMID- 26242116 TI - [Effect of Lappaconitine on Postoperative Pain and Serum Complement 3 and 4 Levels of Cancer Patients Undergoing Rectum Surgery]. AB - OBJECTIVE: To explore the effect of lappaconitine on patient-controlled intravenous analgesia (PCIA) and serum complement 3 and 4 (C3 and C4) levels of cancer patients undergoing rectum surgery. METHODS: Totally 60 patients, who were scheduled for rectum carcinoma surgery, were recruited to the study and assigned in 3 groups, the blank control group, the tramadol group, and the lappaconitine group, 20 in each group. Lappaconitine (8 mg) was intravenously dripped to patients in the lappaconitine group 30 min before ending the operation. PCIA started as soon as the end of the surgery and the total dose of lappaconitine was 36 mg. Patients of the tramadol group were treated with tramadol (100 mg) intravenously within 30 min before ending the operation. The dripping was completed within 30 min. PCIA was started as soon as the end of the surgery and the total dose of lappaconitine was 36 mg. Tramadol (100 mg) was intravenously dripped to patients in the tramadol group 30 min before ending the operation. PICA was started as soon as the end of the surgery and the total dose of tramadol was 900 mg. Pethidine (50 mg) and droperidol (2. 5 mg) was intramuscularly injected to patients in the blank control group for pain relief according to their complaints. Pain degrees were assessed by visual analog scale (VAS) 12 h before surgery, 12, 24, 48, and 72 h after surgery. Blood samples were withdrawn at the same time point. Contents of serum C3 and C4 were determined by immunoturbidimetry. RESULTS: VAS scores of the blank control group were significantly higher after surgery than before surgery (P <0. 01). There was no statistical difference in VAS scores between before surgery and after surgery in the tramadol group and the lappaconitine group (P >0. 05). VAS scores were significantly lower at each post-surgery time point in the tramadol group and the lappaconitine group than in the blank control group with statistical difference (P < 0.01). There was no statistical difference in VAS scores at each post surgery time point between the tramadol group and the lappaconitine group (P >0. 05). Compared with before surgery, contents of serum C3 and C4 significantly decreased in all of the three groups at 12, 24, and 48 h after surgery (P < 0.05, P < 0.01). They recovered to the pre-surgery level till 72 h after surgery (P > 0.05). Serum C3 and C4 contents at 48 h after surgery were higher in the tramadol group than in the blank control group (P < 0.05). Serum C3 and C4 contents at 24 and 48 h after surgery were higher in the lappaconitine group than in the blank control group (P < 0.05). There was no statistical difference in serum C3 and C4 contents at each time point between the tramadol group and the lappaconitine group (P > 0.05). VAS scores were obviously negatively correlated with serum contents of C3 and C4 (r = -0.622, r = -0.649, P < 0.01). CONCLUSIONS: Lappaconitine (used at the dose in this study) showed better pain relief effect after surgery. Besides, it could inhibit the surgic wound and pain, and elevate serum contents of C3 and C4. PMID- 26242117 TI - [Efficacy and Safety Evaluation of Bushen Shuji Granule in Treating Ankylosing Spondylitis Patients: a Clinical Study]. AB - OBJECTIVE: To evaluate the short-term efficacy and safety of Bushen Shuji Granule (BSG) in treating ankylosing spondylitis (AS) patients. METHODS: A prospective randomized controlled clinical trial was carried out in 62 active stage AS patients with Shen deficiency Du-channel cold syndrome (SDDCS), who were randomly assigned to the BSG group (treated with BSG) and the control group (treated with Celecoxib Capsule). Twelve weeks consisted of one therapeutic course. Therapeutic effects were evaluated by ASAS20 and ASAS40 (set by Assessments in Ankylosing Spondylitis working group) , BASDA150, Chinese medical (CM) syndrome efficacy evaluation standards. BASDAI, the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath AS Metrology Index (BASMI), scores for spine pain, scores for pain at night, patient global assessment (PGA) , erythrocyte sedimentation rate (ESR) , and C reactive protein (CRP) were observed before and after treatment. RESULTS: After three-month treatment by BSG, ASAS20 standard rate was 63. 33% (19/30 cases) in the BSG group and 66.67% (20/30 cases) in the control group with no significant difference between the two groups (chi2 = 0.073, P > 0.05). The efficacy for CM syndromes was 70.00% (21/30 cases) in the BSG group, higher than that in the control group [40.00% (12/30 cases), chi2 = 5.455, P < 0.05]. Scores for CM syndromes, BASDAI, night pain index, spinal pain index, PGA, CRP were improved in the BSG group (P < 0.05, P < 0.01). The incidence of adverse events in the BSG group was lower than that of the control group. CONCLUSION: BSG based on Shen supplementing, Du-channel strengthening, blood activating, and channels dredging method had good short-term clinical efficacy and safety in treating AS. PMID- 26242118 TI - [Treatment of Knee Osteoarthritis by Tendons of Minimally Invasive Therapy Combined Drug Ther- apy: a Clinical Observation of Sixty Cases]. AB - OBJECTIVE: To assess the efficacy of tendons of minimally invasive therapy (TMIT) combined drug therapy by comparing it with treatment by drug therapy alone on patients with knee osteoarthritis (KOA). METHODS: Totally 60 KOA patients were assigned to the treatment group and the control group according to random digit table, 30 in each group. Patients in the control group took Hydrochloric Acid Glucosamine Capsule and Celecoxib Capsule. Patients in the treatment group additionally received TMIT. The treatment course for all was 4 weeks. Scores for visual analogue scale (VAS) and the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index were observed and recorded at week 1 and 4 after treatment by acupotomology mirror. RESULTS: Compared with before treatment, improvement was shown in VAS score, pain and stiffness degrees, activities and functions, and WOMAC scores at week 1 and 4 after treatment in all patients with statistical difference (P < 0.05). Besides, better effect was shown in the treatment group (P < 0.05). CONCLUSIONS: TMIT combined drug therapy could relieve KOA patients' pain, stiffness and joint activities, elevate the overall efficacy. TMIT was easily operated with less injury. PMID- 26242119 TI - [Effects of Tansvaginal Aspiration of Hydrosalpinx Combined Auricular Point Sticking on IVF-ET Outcomes]. AB - OBJECTIVE: To explore effective pretreated methods for hydrosalpinx before frozen embryo transfer (FET). METHODS: A randomized controlled study was performed on 229 FET cycles of hydrosalpinx patients. They were assigned to two groups by random digit table, Group A (94 cases), Group B (89 cases), and Group C (46 cases). Patients in Group A received transvaginal aspiration of hydrosalpinx combined with auricular point sticking. Those in Group B received transvaginal aspiration of hydrosalpinx group. Those in Group C received no transvaginal aspiration of hydrosalpinx. Pregnancy outcomes of FET, endometrial and subendometrial blood flow distribution on the embryo transfer day were compared among the three groups. RESULTS: There was no statistical difference in the endometrial thickness on FET day, the number of transfer embryos, the number of transferred good quality embryos among the three groups (P > 0.05). The clinical pregnancy rate and the embryo implantation rate were significantly higher in Group A than in Group C (P < 0.05), and the clinical pregnancy rate was significantly higher in Group A than in Group B (P < 0.05). The early abortion rate and the transfer cycle cancel rate were significantly lower in Group A than in Group C (P < 0.05). Type A endometrial and subendometrial blood flow distribution was dominant in Group A, which was significantly higher in Group A than the rest two groups (P < 0.05). Type A distribution rate was also significantly higher in Group B than in Group C (P < 0.05). CONCLUSION: Transvaginal aspiration of hydrosalpinx combined with auricular point sticking before FET could improve the endometrial receptivity and improve outcomes of IVF. PMID- 26242120 TI - [Relevant Research on ACE Gene Single Nucleotide Polymorphisms and Premature Coronary Heart Disease Patients with Blood Stasis Syndrome]. AB - OBJECTIVE: To explore the relationship between angiotensin converting enzyme (ACE) gene single nucleotide polymorphisms (SNP) and premature coronary heart disease (PCHD) patients with blood stasis syndrome (BSS). METHODS: rs4343, rs4293, and rs4267385 were selected at SNP from ACE gene. Allele and genotype were detected. Frequencies of allele and genotype were compared by using time-of flight mass spectrometry technique (TOF-MS). RESULTS: Compared with the healthy control group, genotype of rs4293 and rs4267385 in ACE gene were similar, but there was statistical difference in polymorphisms and allele frequencies of rs4343 in the I and II group (P < 0.05, P < 0.01). The frequency of G allele was higher in the 3 groups than in the healthy control group (P < 0.05, P < 0.01). The relative risk analysis showed that the risk for PCHD occurrence in G allele carriers at rs4343 (GG +AG) was 3. 6 times the risk in non-G allele carriers (95% CI: 1.224-10.585, P = 0.02). There was also statistical difference in sex, age, TC, and TG after adjusted Logistic regression analysis (OR = 3.994, 95% CI: 1.230 12.974, P = 0.021). CONCLUSION: The polymorphism at rs4343 (G2350A) might be one of risk factors for PCHD occurrence, but not a predisposing factor for PCHD patients of BSS. PMID- 26242121 TI - [Relation between Chinese Medical Constitutions of Female Patients with Late onset Acne: an Epidemiological Investigation]. AB - OBJECTIVE: To explore the correlation between syndrome types of late-onset acne female patients and constitutions of Chinese medicine (CM). METHODS: A questionnaire was performed in 365 late-onset acne female patients and 135 healthy subjects (as the control) using Professor WANG Qi's. methods and Standards for Chinese Medical Constitutions Classification. RESULTS: Their CM constitutions were sequenced as damp-heat constitution, yin-deficiency constitution, balanced constitution, yang-deficiency constitution, blood-stasis constitution, qi-stagnation constitution, qi-deficiency constitution, phlegm-damp constitution, inherited special constitution, with statistical difference when compared with those of the control group ( chi2 = 85.206, P < 0.01). In the 365 female late-onset acne patients, 114 (31.23%) were with Chongren imbalance syndrome, 108 (29.59%) were with blood stasis or coagulated phlegm syndrome, 83 (22.74%) were with dampness heat syndrome, and 60 (16.44%) were with wind heat syndrome. There was statistical difference in CM constitution distributions among different CM syndrome types (chi2 = 105.671, P < 0.01). The distribution of CM medical constitutions was different between the two groups. Biased constitutions were often seen in the patient group, while balanced constitution was often seen in the control group. Binary Logistic regression analysis indicated that influencing factors covered sweet food, light diet, roasted food, coffee, stress, work pressure, and family pressure. Of them light diet was one protective factor, while the rest were adverse factors. CONCLUSION: The etiology and syndrome types of female late-onset acne female patients were associated with CM constitution. PMID- 26242122 TI - [Effect of Compound Qingre Granule on the Expression of Peripheral Blood Lymphocyte Subsets of Acute Virus Infection Patients]. AB - OBJECTIVE: To observe interventional effects of anti-viral therapy and Compound Qin-gre Granule (CQG) on host cellular immune functions of acute virus infection patients. METHODS: Thirty acute virus infection patients were recruited to detect peripheral lymphocyte subsets. They were randomly assigned to two groups, the Western medicine treatment group (treated with anti-virus Western medicine) and the integrative medicine treatment group (treated with anti-virus Western medicine plus CQG). T-cell subsets were re-examined 7 days later. Changes between before and after treatment were observed. Effect on host cellular immune functions and efficacy were compared between the Western medicine treatment and the integrative medicine treatment. RESULTS: Compared with the normal control group, the percentage of peripheral T cells increased, and the percentage of B/NK cells decreased in acute virus infection patients (P < 0.01). Meanwhile, in T cell subsets, the percentage of CD8+ T cells and CD8+ CD38+ T cells increased (P < 0.05, P < 0.01); and percentages of CD4+ T cells, CD4+ CD28 + T cells, and CD8+ CD28+ T cells decreased (P < 0.05, P < 0.01). After one-week treatment, percentages of CD4+ T cells, CD4+ CD28+ T cells, and CD8+ CD28+ T cells increased (P < 0.05, P < 0.01), while the percentage of CD8+ CD38+ T cells decreased (P < 0.01). More significantly, these changes were greater in the integrative medicine treatment group than in the Western medicine treatment group (P < 0.05). CONCLUSIONS: Disarranged cellular immune functions existed in acute virus infection patients. CQG could significantly improve viral infection induced immunologic derangement and immunologic injury. PMID- 26242123 TI - [The Radiosensitizing Effect of Resveratrol on Hopypharyngeal Carcinoma Cell Line FADU and its Effect on the Cell Cycle]. AB - OBJECTIVE: To study the radiosensitizing effect of resveratrol on hypopharyngeal carcinoma cell line FADU in vitro. METHODS: Hypopharyngeal carcinoma cell line FADU was cultured in in vitro DMEM. Its inhibition on cell proliferation was detected using cytotoxicity test (MTT assay). The cell survival curve was drawn using clone formation to obtain sensitive enhancement ratio (SER). Changes of the cell cycle and cell apoptosis were analyzed using flow cytometry (FCM). RESULTS: Results of MTT showed the inhibition of resveratrol on FADU cells increased along with its concentrations (P < 0.05). Results of clone formation indicated the surviving fraction at 2 Gy (SF2) was 0.717 +/- 0.062 in the irradiation group, and 0.426 +/- 0.035 in the resveratrol plus irradiation group (with SER ranged 1.684 +/- 0.178) with statistical difference (P = 0.007). Results of FCM showed that after radiation of 4 Gy radiation, cells at G2/M phase arrest increased, but cells at G1 decreased. After radiation of resveratrol for 24 h, cells at G1 decreased, but cells at G2/M phase and S phase arrest increased. When 4 Gy radiation combined resveratrol was used, cells at G2/M phase arrest significantly increased, but cells at G1 significantly decreased. The apoptosis rate was 1.94% +/- 1.65% in the control group, 4.56% +/- 0.92% in the irradiation group, 2.03% +/- 1.46% in the resveratrol group, and 23.11% +/- 7.22% in the resveratrol plus irradiation group. There was statistical difference between the resveratrol plus irradiation group and the rest 3 groups (P < 0.05). CONCLUSION: Resveratrol could enhance the radiosensitivity of hypopharyngeal carcinoma FADU cells in vitro possibly by inducing cell apoptosis and causing changes in the cell cycle distribution. PMID- 26242124 TI - [Effect of Zhixin Formula on Gliocyte Protein Expressions, TLRs and NF-kappaB in Bone Cancer Pain Model Rats]. AB - OBJECTIVE: To explore the analgesic effect of Zhixin Formula (ZF) and its effects on spinal glial fibrillary acidic protein (glial fibillary acidic protein, GFAP, a marker of astrocyte) , CD11b (a maker of microglia), Toll like receptors (TLR2 and TLR4) and nuclear factor kappaB (NF-kappaB) in bone cancer pain model rats. METHODS: Totally 20 male SD rats were randomly divided into the blank control group and the bone cancer pain group, 10 in each group. The bone cancer pain model was induced by injecting ascites tumor fluid containing 3 x 10(3) Walker256 cell line from the left tibia. Ethological tests, X-ray test, and HE staining were performed to confirm a successful modeling. After model was successfully established, 70 male SD rats were randomly divided into seven groups, 10 in each group: the blank control group, the bone cancer pain group (as the model group), the Western medicine (WM) group (Tramadol Hydrochloride), the high dose ZF group, the middle dose ZF group, the low dose ZF group, and the Chinese medicine (CM) group (Wulin Zhitong Capsule). Fourteen days after modeling, rats in the high, middle, and low dose ZF groups were administrated by gastrogavage with 9, 4.5, and 2.25 g/kg ZF water condensed preparation respectively, once a day for seven consecutive days. On day 21 MS typical protein expressions including GFAP, CD11b, TLR (2,4) and NF-kappaB from cornu dorsal medullae spindis L4-L5 were detected by immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. RESULTS: Compare with the blank control group, increased weight in the model group was slow and showed a decreasing trend (P < 0.01), spontaneous ambulatory pain score (SAPS) obviously increased (P < 0.01), paw withdrawal threshold (PWT) obviously decreased in the model group (P < 0.05, P < 0.01). Results of lateral tibial X-ray and HE staining showed obvious changes and damage occurred in bone structures of rats in the model group. Immunohistochemistry showed that GFAP expression significantly increased in the model group (P < 0.05). Protein levels of NF-kappaB also significantly increased in the model group (P < 0.05). Compared with the model group, CD11b expressions obviously decreased in the middle and high dose ZF groups (P < 0.01). Meanwhile, protein expressions of TLR2 and TLR4, as well as NF-kappaB also obviously decreased (P < 0.05). CONCLUSION: ZF had analgesic effect, which might be probably related to inhibiting proliferation and activation of gliocytes, as well as activation of TLRs and NF-kappaB. PMID- 26242125 TI - [Effect of Guanmaitong Tablet on ERK and p38 Protein of TLR2 Pathway Expression in Cerebral Ischemia/Reperfusion Rats: an Experimental Study]. AB - OBJECTIVE: To explore the inflammatory cascade mechanism through Toll like receptor 2 (TLR2) pathway after cerebral ischemia/reperfusion, and to study molecular mechanisms of Guanmaitong (GMT) Tablet for protecting brain damage. METHODS: We used bolt-line method to block/release the middle cerebral artery, causing cerebral ischemia/reperfusion (I/R) injury model. GMT Tablet was given by gastrogavage. Rats were then divided into the high dose GMT group (1200 mg/kg), the middle dose GMT group (600 mg/kg), the low dose GMT group (300 mg/kg), the positive control group (Tanakan, 20 mg/kg). Their right brain tissues were fixed in 10% neutral formalin. TLR2 expressions were detected by immunofluorescence staining. The total protein was extracted from right brain tissues by ultrasonica tion. Expression levels of extracellular regulated protein kinases (ERK), phospho-extracellular regulated protein kinases (p-ERK), p38-mitogen activated protein kinases (p-ERK), phospho-p38-mitogen activated protein kinases [p-p38 MAPKs(p-p38)] were assessed by Western blot. Abdominal aortic blood was withdrawn. IL-6 and IL-1beta levels were detected by ELISA in brain tissues and serum. RESULTS: Compared with the sham-oepration group, expression levels of TLR2, ERK, p-ERK, p38, p-p38 protein were up-regulated (P < 0.05, P < 0.01), and contents of IL-6 and IL-1beta in brain tissues and serum were increased in the model group (P < 0.01). Expression levels of TLR2, ERK, p-ERK, p38, p-p38 were down-regulated (P < 0.05, P < 0.01), and contents of IL-6 and IL-1beta were reduced in brain tissues and serum in middle and high dose GMT groups (P < 0.05, P < 0.01). CONCLUSIONS: TLR2 pathway was involved in cerebral I/R injury. GMT protected neurons by down-regulating protein expressions of TLR2, ERK, p-ERK, p38, p-p38 and contents of IL-1beta and IL-6. PMID- 26242126 TI - [Effects of Bushen Wenyang Huayu Recipe on TRPV1 and Sensitization Factor NGF in Experimental Endometriosis]. AB - OBJECTIVE: To study the effect of Bushen Wenyang Huayu Recipe (BSWYHYR) on nerve growth factor (NGF) and transient receptor potential vanilloid receptor I (TRPV1) in experimental endometriosis (EMT), and to explore its mechanism for treating EMT-induced pain. METHODS: Totally in-bred line BALB/c 75 female mice were divided into five groups, i.e., the sham-operation group, the model group, the high dose BSWYHYR group, the low dose BSWYHYR group, the gestrinone group, 15 in each group. Writhing response was observed in each group. Serum contents of NGF were detected using ELISA. Expression levels of NGF and TRPV1 in uterus and ectopic foci were detected using immunohistochemical staining SP and Western blot. mRNA expression levels of NGF and TRPV1 in uterus and ectopic foci were detected by Real-time PCR. RESULTS: The serum NGF content in the model group was higher than that in the sham-operation group (P < 0.01), and there was positive correlation between NGF and the writhing frequency (r = 0.574, P < 0.01). Compared with the model group, serum levels of NGF significantly decreased in the 3 treatment groups (P < 0.05). Compared with the sham-operation group, mRNA and protein expression levels of NGF and TRPV1 increased significantly in the model group (P < 0.01). Protein expression levels of NGF and TRPV1 decreased significantly in the 3 treatment groups, when compared with the model group (P < 0.01). mRNA expression levels of NGF and TRPV1 decreased most in the high dose BSWYHYR group (P < 0.01). NGF in uterus and ectopic foci was positively correlated with protein and mRNA expression levels of TRPV1 (P < 0.01). CONCLUSIONS: NGF and TRPV1 participated in the occurrence of pain in EMS. BSWYHYR played an important role in inhibiting EMT-induced pain through reducing the up regulation of NGF on TRPV1. PMID- 26242127 TI - [Effect of Combination Therapy of Tetramethylpyrazine with Methotrexate on Inflammatory Reac- tions and Hemorheology in Collagen-induced Arthritis Rats]. AB - OBJECTIVE: To explore the effect of combination therapy of tetramethylpyrazine (TMP) with methotrexate (MTX) on collagen induced arthritis (CIA) rats. METHODS: Totally 55 male SD rats were stratified by body weight. Nine of them were randomly recruited as the normal control group. The rest 46 were immunized with type II bovine collagen (C II) for establishing rheumatoid arthritis (RA) model. Forty successfully modeled rats were randomly divided into 4 groups according to swollen toe degree, i.e., the CIA group, the TMP group, the MTX group, and the TMP plus MTX group, 10 in each group. Rats in the MTX group were administered with MTX (1. 2 mg/kg) , once per week for 4 continuous weeks. Those in the TMP group were administered with 40 mg/kg TMP, once per day for 10 continuous days, and then discontinued for 7 successive days, and continued for another 10 successive days. Rats in the TMP plus MTX group were administered with a mixture of equal dose MTX and TMP, and when MTX was discontinue, TMP was administered according to the way in the TMP group. Equal volume of saline solution was given to rats in the normal control group and the CIA group. Clinical parameters including ankle width (mediolateral diameter) and hindpaw swelling were measured at day 0, 4, 11, 18, and 26 after treatment. Rats were sacrificed 28 days after treatment, their knee joints and ankle joints were collected for pathological analyses. Serum levels of IL-1beta, IL-6, and IL-17A were detected by ELISA. Changes of fibrinogen (FIB) and platelet aggregation rate (PAg) were detected. RESULTS: Compared with the normal control group, the ankle width and hindpaw swelling increased significantly (P < 0.01), contents of FIB and PAg increased obviously (P < 0.05, P < 0.01), serum levels of IL-1beta, IL-6, and IL-17 increased remarkably (P <0. 01) in the CIA group. Obvious cell proliferation, inflammatory cell infiltration, hyperemia and edema of synovial tissues could be seen. Pannus formed and immerged in cartilages, resulting in necrosis. Compared with the model group, changes of ankle width and hindpaw swelling were all alleviated in each medicated group (P <0. 05, P <0. 01). Of them, the effect was superior in the MTX group to that of the TMP group and the MTX plus TMP group (P < 0.05, P < 0.01). Contents of FIB, serum levels of IL-1beta and IL-6 decreased significantly in the MTX group (P < 0.05). Contents of FIB, serum levels of IL 1beta and IL-6 decreased significantly in the TMP group and the MTX plus TMP group (P < 0.05). Besides, serum levels of FIB and IL-6 were obviously lower in the MTX plus TMP group than in the TMP group and the MTX group (P < 0.01). Levels of PAg and IL-17A were more significantly lowered in the TMP group than in the MTX plus TMP group and the MTX group. Pathological changes could be alleviated in each medicated group, with the optimal effect obtained in the MTX plus TMP group. CONCLUSION: Combination of TMP with MTX could significantly ameliorate inflammatory reactions and FIB contents of CIA rats. PMID- 26242128 TI - [Effects of Rhodiola on the Expression of iNOS mRNA in Severe Acute Pancreatitis Associated Re- nal Injury Rats]. AB - OBJECTIVE: To explore the effect of Rhodiola on the expression of iNOS mRNA in severe acute pancreatitis (SAP) associated renal injury rats. METHODS: A total of 72 healthy rats were randomly divided into the sham-operated group (S), the SAP associated renal injury group (M), and the Rhodiola-treated group (RHO), 24 in each group. Rats in S and M groups were peritoneally injected with 10 mL/kg saline 3h before modeling, while rats in the RHO group were peritoneally injected with 10 mL/kg Rhodiola Injection 3 h before modeling. The peripheral ligament of pancreas was bluntly dissociated in rats of M and RHO groups. The head of pancreas was occlused by nontraumatic blood vessel forceps 3 h later to establish the model. Eight rats were randomly selected from each group at 12, 24, and 36 h after modeling to detect levels of serum amylase, creatinine, and blood urea nitrogen. Serum levels of interleukin 1beta (IL-1beta) and interleukin 10 (IL-10) were detected by enzyme-linked immunosorbent assay (ELISA). Pathological changes of the left kidney were observed under light microscope. The expression of inducible nitric oxide synthase (iNOS) mRNA in the right kidney was detected with real time polymerase chain reaction (RT-PCR). RESULTS: Compared with the S group, serum levels of amylase, creatinine (Cr), blood urea nitrogen (BUN), IL-1beta, IL 10, and iNOS mRNA expression significantly increased in the M group (P < 0.01). The function of kidney and pancreas were obviously improved in the RHO group than in the M group. Levels of IL-1beta and iNOS significantly decreased, but IL-10 levels significantly increased in the RHO group with statistical difference (P < 0.05). CONCLUSION: Rhodiola had better protective effect on SAP associated renal injury, which might be achieved through inhibiting the expression of IL-1beta, stimulating the expression of IL-10, down-regulating iNOS mRNA expression, reducing the generation of oxygen free radicals and NO damage to cells, and improving hypoxia tolerance capabilities of the kidney. PMID- 26242129 TI - [Effect of Bushen Huoxue Compound on Retinal Muller Cells in High Glucose or AGEs Conditions]. AB - OBJECTIVE: To explore the effect of Bushen Huoxue Compound (BHC) on lactate dehydrogenase (LDH) leakage, expressions of vascular endothelial growth factor (VEGF) and VEGF mRNA in retinal Muller cells under high glucose condition or advanced glycosylation end products (AGEs) condition by using serum pharmacological method. METHODS: The retinal Muller cells of 5-7 days post-natal Sprague Dawley (SD) rats were cultured with modified enzyme-digestion method. Purified retinal Muller cells were cultured in normal conditions, high glucose condition (50 mmol/L) or AGEs (50 mg/L and 100 mg/L) conditions, and BHC containing serum was added to culture medium. The LDH leakage and VEGF expressions were measured by enzyme-linked immunosorbent assay (ELISA). In addition, the relative expression of VEGF mRNA was tested by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Compared with the normal control group, expressions of VEGF and VEGF mRNA were significantly increased in the high glucose group, the low dose AGEs group and the high dose AGEs group (all P < 0.01). The LDH leakage was obviously increased in the high dose AGEs group, when compared with the normal control group and the high glucose group (P < 0.01). The LDH leakage, expressions of VEGF and VEGF mRNA were obviously decreased by BHC-containing serum both in high glucose and AGEs conditions (P < 0.05, P < 0.01). BHC-containing serum had no significant effect on the LDH leakage and expressions of VEGF and VEGF mRNA in normal conditions (P > 0.05). CONCLUSIONS: AGEs intervention could obviously lower the stability of Muller cell membrane. Up-regulated expressions of VEGF and VEGF mRNA in cultured Muller cells could be induced by AGEs or high glucose. BHC-containing serum could stabilize the stability of Muller cell membrane, inhibit the transcription of VEGF mRNA and decrease the protein expression of VEGF, which might be one of important mechanisms for preventing and treating diabetic retinopathy. PMID- 26242130 TI - [Effects of Different Compatibilities of Ramulus Cinnamomi and Peony in Guizhi Decoction on Diabetic Cardiac Autonomic Neuropathy]. AB - OBJECTIVE: To observe the preventive effect different compatibilities of Ramulus Cinnamomi (RC) and peony in Guizhi Decoction (GD) on diabetic cardiac autonomic neuropathy (DCAN). METHODS: Totally 60 male rats were randomly divided into 5 groups, i.e., the blank control DM group, the model group, the methycobal group, the 1:1 (RC/peony) Guishao group, the 2:1 Guishao group, and the 1:2 Guishao group, 10 in each group. Rats were pretreated with corresponding drugs for 1 week, and then induced diabetes by intraperitoneal injection of STZ. Drugs were administrated by gastrogavage for 4 more weeks after STZ-injection. Enzyme-linked immunosorbent assay (ELISA) was employed to detect levels of tyrosine hydroxylase (TH), choline acetyltransferase (CHAT), nerve growth factor. (NGF), and ciliary neurotrophic factor (CNTF) in myocardial homogenates. RESULTS: After 4-week modeling, body weight (BW) was obviously lower, but blood glucose (BG) was higher in STZ rats than in rats of the blank control DM group. There was no statistical difference in BW or BG among the 5 groups (P >0.05). Compared with the blank control group, TH, TH/CHAT, and NGF in left ventricle and ventricular septum increased, CHAT and CNTF increased in the model group (P < 0.05, P < 0.01). Compared with the model group, TH and TH/CHAT in left ventricle decreased (P < 0.05, P < 0.01), CNTF in left ventricle increased (P < 0.05), CHAT in left ventricle and ventricular septum increased (P < 0.05, P < 0.01) in the methycobal group. TH and TH/CHAT in left ventricle and ventricular septum decreased, CNTF in left ventricle and ventricular septum increased (P < 0.05, P < 0.01), CHAT in left ventricle and ventricular septum increased (P < 0.01), NGF in ventricular septum decreased (P < 0.01) in the 1:1 Guishao group. TH/CHAT in left ventricle decreased (P < 0.01), CHAT and CNTF in left ventricle and ventricular septum increased (P < 0.05, P < 0.01) in the 1:2 Guishao group. Compared with the methycobal group, CHAT in left ventricle decreased, TH and TH/CHAT in left ventricle increased in the 2:1 Guishao group (P < 0.05, P < 0.01). TH and TH/CHAT in ventricular septum decreased (P < 0.05), CHAT and CNTF in left ventricle and ventricular septum increased (P < 0.05, P < 0.01) in the 1:1 Guishao group. Compared with the 1:2 Guishao group and the 2:1 Guishao group, CHAT in left ventricle increased, TH/CHAT in left ventricle decreased, TH and TH/CHAT in ventricular septum decreased, CHAT in ventricular septum increased, CNTF in left ventricle and ventricular septum also increased in the 1:1 Guishao group (all P < 0.01). CONCLUSIONS: STZ model rats had autonomic neural injury, manifested as lowered vagal nerve activity and hyperactive sympathetic nerves. GD could effectively suppress hyperactive cardiac sympathetic nerves and protect the vagus. Besides, GD (1:1) showed the optimal effect in regulating the balance of cardiac autonomic nerves and could be used in early prevention of DCAN. PMID- 26242131 TI - [The New Idea about Early Intervention for Type 2 Diabetes Based on Gan Disease Transferring to Pi in Metabolic Diseases]. AB - Excess energy has become a main reason for increasingly serious human health hazards. Excess energy, mainly ectopically deposits in the liver, pancreas and other organs in the form of triglycerides, and produces chronic oxidative, nitrosative stress (ONS) , and fat toxicity, resulting in insulin resistance and impaired insulin secretion, and further impaired glucose regulation (Pidan). By combining Chinese medical pathogeneses and symptoms analyses, authors found this process has features of Gan disease transferring to Pi. Based on a number of related guidelines and clinical practice, we demonstrated treating sputum and stasis by the same method was one treatment method for intervening liver disease transferring to spleen in metabolic diseases. This idea helps to organic integrating prevention and treatment of major metabolic diseases including non alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus, which can improve clinical effectiveness and efficiency of Chinese medicine. PMID- 26242132 TI - [Probing into Second Pathological Factors of Sjogren's Syndrome]. AB - Sjogren's syndrome is a chronic autoimmune disease with unclear etiology. From the point of etiology, Chinese medicine (CM) theory holds that pathological products like dry toxin, blood stasis are produced in the pathological process. They are both pathologic results and pathogenic factors for its further development. So pathological products are also named as second pathogenic factors. In this article, the concept of second pathogenic factors was sorted and defined. Main second pathogenic factors of Sjogren's syndrome were pinpointed, and their modern medical bases were analyzed. Authors came to a conclusion that clearing away second pathogenic factors is a key point in treating Sjogren's syndrome. PMID- 26242133 TI - [Research Design for Brain-Gut Axis Based Functional Dyspepsia Patients with Gan Stagnation Pi Deficiency Syndrome]. PMID- 26242134 TI - [Treatment of Masturbation Syndrome by Nourishing Yin Lowering Fire Method: a Case Report in One Child]. PMID- 26242135 TI - [Haplopappus gracillis Resources of Elemene in China: a Review]. PMID- 26242136 TI - The Trillion-Dollar Medicine Cabinet. PMID- 26242137 TI - WE NEED MORE ANTIBIOTICS. PMID- 26242138 TI - On-the-Road Care. PMID- 26242139 TI - CAN BIOGEN BEAT THE MEMORY THIEF? PMID- 26242140 TI - [CRYOSURGERY IN ONCOLOGY]. AB - Cryodestruction remains one of the effective methods of treatment. There is collected the sufficient experience of its application in oncology and described the positive changes in the immune status of patients after cryodestruction. The technology of minimally invasive percutaneous puncture cryotherapy expands treatment options but requires training and implementing new equipment of domestic production into practice. PMID- 26242141 TI - [PROSPECTIVE SYNTHETIC MATRICES FOR THE RECONSTRUCTION OF TRACHEAL DEFECTS IN CANCER PATIENTS]. AB - A replacement of major defects of the trachea remains a challenge despite numerous attempts to use for this purpose various options of autologous and allogeneic implants as well as synthetic matrixes. The most prospective direction is to create tracheal matrixes based on biocompatible porous or fibrous materials that mimic native tissues and provide the proliferation of multipotent cells. This review summarizes current data regarding the development of experimental research and clinical testing of biocompatible tracheal matrixes, which were created using innovative technologies. PMID- 26242142 TI - [CURRENT STATE OF COMBINED TREATMENT FOR LOCALLY ADVANCED GASTRIC CANCER. ACHIEVEMENTS AND FAILURES: BASIC TRENDS IN CLINICAL ONCOLOGY]. AB - Despite the modern achievements of different methods of treatment, primarily surgical, with recognized need of standardization of lymphadenectomy D2, gastric cancer still remains one of the most difficult malignant tumors characterized by high rates of one-year mortality and low rates of survival that are far from satisfactory. According to experts such unsatisfactory results are determined by a combination of factors: the characteristics of ill people, their functional status, age characteristics, the prevalence of the disease at diagnosis with the presence of systemic micrometastases, resistance to treatment, etc. Moreover, a factor of resistance to treatment i.e. to existing schemes and methods is mostly a key one that determines low levels of long-term survival. PMID- 26242143 TI - [CURRENT STATE OF ADJUVANT TREATMENT FOR GASTRIC CANCER AFTER RADICAL SURGERY WITH EXTENDED LYMPH NODE DISSECTION]. AB - There are presented results of recently published large multicenter randomized trials on the effectiveness of different adjuvant therapy regimens after gastrectomy D2 in patients with gastric cancer. It is shown that adjuvant chemotherapy as monotherapy by drug S-1 and polychemotherapy by XELOX improves long-term outcomes of patients with stages 2-3. At the same time the intensification of therapy--additional administration of paclitaxel, the combination FOLFIRI scheme with docetaxel and cisplatin--have not led to a significant increase in survival rate. In regard of the advisability of combination of adjuvant chemotherapy and radiotherapy. The data obtained do not allow to make a define conclusion up to date. Promising areas of research is the use of targeted drugs in adjuvant regimen as well as the search for biomarkers to identify patients at high risk of recurrence and to predict the effectiveness of adjuvant therapy. PMID- 26242144 TI - [MODERN APPROACHES TO THE SURGICAL TREATMENT FOR EARLY-STAGE ENDOMETRIAL CANCER]. AB - The article is devoted to one of the most controversial issues of modern oncogynecology--the volume of surgery for endometrial cancer of early stages. There are discussed the indications for lymphadenectomy and its volume as well as how correlate performing lymphadenectomy and conducting postoperative radiotherapy. PMID- 26242145 TI - [LAPAROSCOPIC AND OPEN RADICAL CYSTECTOMY FOR BLADDER CANCER]. AB - Radical cystectomy is the standard method for treatment of muscle-invasive and locally advanced bladder cancer. Several less invasive approaches have been suggested recently, including totally laparoscopic radical cystectomy and robotic cystectomy. However despite significant improvements in surgical techniques the overall occurrence of perioperative complications is still high. Analysis of the literature data and comparison of these data with the results of our study was performed with respect to perioperative complications after radical cystectomy and oncological outcomes. In most of the studies, operating time during laparoscopic cystectomy was longer than that of open approach. Despite that, there was no influence of type of surgery on intraoperative complications. Major complication rates were similar between all groups. However laparoscopic cystectomy had lower rate of minor complications compared to open cystectomy. Laparoscopic cystectomy is safe and associated with lower blood loss, decreased postoperative ileus and lower length of stay compared with open radical cystectomy. Laparoscopic surgery for bladder cancer decreased minor complications (mainly due to lower bleeding and gastrointestinal complication rate) and had no impact on major complications. Moreover, if performed following the oncologic principles of open surgery, our results and literature data suggest that LRC is safe and determines non-inferior long-term cancer control compared with open surgery. PMID- 26242146 TI - [RESULTS OF LAPAROSCOPIC SURGERY FOR ENDOMETRIAL CANCER: EXPERIENCE OF THE N. N. PETROV RESEARCH INSTITUTE OF ONCOLOGY]. AB - For the period from September 2010 to September 2014 there were operated 513 patients with endometrial cancer using laparoscopic installation the Karl Storz company. 304 patients (59.2%) underwent hysterectomy with appendages, 209 (40.8%) -hysterectomy with appendages and pelvic lymphadenectomy, including 11 patients (2.2%) with the addition of omentectomy in serous and serous-papillary forms of endometrial cancer. The average age of patients was 58.4 years (44-75 years). Body mass index over 25.0 was determined in 456 patients (88.9%), of whom 183 patients (35.6%) had an excess of body weight, in 159 (31.0%)--obesity of I degree, in 79 (15.5%)--obesity of II degree and in 35 patients (6.8%)--obesity of III degree. There were no reported complications during surgery. The postoperative period in the majority of patients was characterized by the minimal complications and absence of contraindications for adjuvant radiotherapy. During follow-up period there were registered 4 relapses: in 1 patient with serous- papillary form of endometrial cancer during the first year after surgery--in the form of dissemination of tumor in the abdomen and pelvis; in 3 patients--in the form of a cytological detection of glandular cancer cells in vaginal stump. As a result, regardless of age and comorbidities, laparoscopy allows performing to endometrial cancer patients the entire volume of planned radical surgery with minimum damage and with minimal risk of intra- and postoperative complications, favorable and accelerated rehabilitation period. PMID- 26242147 TI - [LAPAROSCOPIC SURGERY FOR EARLY OVARIAN CANCER: EXPERIENCE AT THE P. A. HERZEN ONCOLOGY RESEARCH INSTITUTE]. AB - For the period from 2003 to 2014 at the Oncogynecology Department laparoscopic surgery for ovarian cancer was performed in 49 patients aged 19 to 76 years. During the surgical interventions special attention was paid to the principles of oncological radicalism and ablastics, the volume of surgery depended on the extent of tumor process, morphological characteristics of tumor, a patient's age and the desire to preserve reproductive function. In 42 (85.7%) cases laparoscopic procedures were conducted to restaging (after non-radical operations in gynecological hospitals). In all 49 patients a histological form of ovarian tumor corresponded to adenocarcinoma. Mean operative time was 140 +/- 10,5 minutes, the average blood loss--80,2 +/- 14,3 ml. Postoperative complications (bleeding from the omentum) were recorded in 1 (2%) patient, the need for conversion was occurred in 4 (8.2%) cases due to the adhesive process or signs of dissemination. As a result of laparoscopic surgery an increase in staging of disease was fixed in 14 cases (28.6%). Follow-up median was 45 months, relapses occurred in 5 (10.2%) patients. Of 49 patients 2 (4.1%) died from disease progression. Disease-free and overall survival rates were 89.8% and 95.9%, respectively. Thus, data of world literature and our own experience indicate the potential equivalent of laparoscopic and laparotomy approaches in treatment for early ovarian cancer. PMID- 26242148 TI - [MINIMALLY INVASIVE ESOPHAGECTOMY]. AB - During the period from April 2012 to December 2014 54 patients aged 29-76 years, 36 (66.6%) males and 18 (33.4%) females, with esophageal cancer underwent minimally invasive esophagectomy as final phase of treatment. Squamous cell carcinoma was diagnosed in 50 patients and adenocarcinoma identified in 4 patients. The disease was staged as follows: IA--5 (9.3%) patients, IB--11 (20.4%) patients, IIA-- (16,.%) cases, III -- (3,.%) cases, IIII --8 (33,.%), IIII -- (14,8%), III -- (1,.%). 37 (68,.%) patients had surgery after induction chemoradiation therapy. Of 54 surgical interventions there were 20 hybrid and 34 minimally invasive operations. 19 (35,.%) patients developed complications, postoperative mortality was 2 (3,.)%. Minimally invasive esophagectomy meets basic oncological principles and leads to tolerable short-term results. PMID- 26242150 TI - [COMPARATIVE EVALUATION OF SURGICAL APPROACHES TO TREATMENT OF PATIENTS WITH SKIN MELANOMA]. AB - In recent years there has been rapid growth in the incidence of melanoma. Due to the large number of patients with various pigmented lesions, suspicious for melanoma, requiring differential diagnosis there is an actual problem of excisional biopsy in this group of patients. This review extensively covered approaches to radical surgical treatment of patients with skin melanoma. There are described in detail results of the studies of foreign experts regarding the influence of excisional and incisional biopsy on overall and disease-free survival rates of patients. On a large representative material (1126 patients) there are widely reflected the results of our studies to assess the effect of different surgical approaches to treatment of patients with skin melanoma. At present the authors can not recommend to perform excisional biopsy of patients with primary skin melanoma in oncological practice. Obviously for a final resolution of this problem it is necessary to conduct a multicenter randomized trial. PMID- 26242149 TI - [BREAST-CONSERVING SURGERY AFTER NEOADJUVANT THERAPY FOR BREAST CANCER]. AB - In the randomized phase 2 study there was evaluated the efficacy of neoadjuvant endocrine treatment (anastrozole, exemestane) in comparison with chemotherapy (doxorubicin plus paclitaxel). Preoperative endocrine therapy was well tolerated. There was a trend towards higher overall rates of objective response and breast conserving surgery (BCS) among patients with tumors expressing high levels of ER (luminal A) in endocrine therapy group compared with chemotherapy group (43% vs 24%; p = 0,054). In HER2-positive breast cancer patients the addition of trastuzumab to neoadjuvant chemotherapy improved the overall and pathological complete response. Trastuzumab made possible an increasing number of breast conserving surgery (23% vs 13%; p = 0,022). No patient treated with trastuzumab and with chemotherapy had a local recurrence after BCS. PMID- 26242151 TI - [LAPAROSCOPIC NERVE-SPARING RADICAL HYSTERECTOMY IN CERVICAL CANCER]. AB - Cervical cancer is the most common cancer of the female reproductive system up to 20% of malignant tumors of the female genital organs. Surgery is the main method in treatment for local cervical cancer but postoperative complications often are associated with dysfunction of the pelvic organs. Some researchers focus their attention on the preservation of the pelvic innervation without loss of surgery's radicalism, which is represented in this survey. The paper presents the results of comparative analysis of 54 cases of surgical treatment for invasive cervical cancer. PMID- 26242152 TI - [MULTIMODAL APPROACH IN THE TREATMENT OF PATIENTS WITH MALIGNANT PLEURAL LESIONS]. AB - The study includes data on 54 patients with pleural malignant lesions (39 with metastatic pleural malignant tumors and 15 with pleural malignant mesothelioma) received treatment using a multimodal approach: maximum cytoreduction, intraoperative photodynamic therapy and hyperthermic chemoperfusion of pleural cavity. A control group of patients with malignant pleural mesothelioma consisted of 21 patients who had undergone only conservative treatment. It was found out that the use two-thoracotomy surgical approach had advantages over standard thoracotomy across IV intercostal space. The use of multimodal treatment was accompanied by relatively low (1.85%) postoperative mortality on the background of a relatively high number (79.6%) of postoperative complications, easily cured in the early postoperative period. The use of multimodal therapy in treatment for metastatic pleural malignant lesions was accompanied by a median of disease-free survival of 11 months and a median of overall survival of 23 months. The proposed multimodal treatment compared with conservative methods of therapy improved disease-free (12 months vs. 7.5 months) and overall (18.8 months vs. 10.2 months) survival. Thus the use of a multimodal approach in treatment for pleural malignant lesions is relatively safe but requires further study. PMID- 26242153 TI - [ENDOSCOPIC MUCOSAL RESECTION AND ENDOSCOPIC DISSECTION IN THE SUBMUCOSAL LAYER FOR EARLY GASTRIC CANCER]. AB - The development of endoscopic techniques of surgery of patients with early gastric cancer (high and moderately differentiated adenocarcinoma) by endoscopic mucosal resection and endoscopic submucosal dissection with regard to their minimally invasion, high efficiency and quality of life after treatment allowed seriously establishing itself and be accepted for use in worldwide. PMID- 26242154 TI - [THORACOSCOPIC LOBECTOMY WITH MEDIASTINAL LYMPH NODE DISSECTION--THE STANDARD IN SURGICAL TREATMENT OF PATIENTS WITH T1-2N0M0 NON-SMALL CELL LUNG CANCER]. AB - In recent years a large number of thoracic clinics in the world recommend the performance of minimally invasive surgical procedures in the early stages of lung cancer arguing that this technique reduces a number of postoperative complications, shortens the period of social rehabilitation of patients and does not significantly affect the long-term results of treatment. This work is devoted to the study of immediate and long-term results of surgical treatment of patients who have had surgery in the volume of thoracoscopic lobectomy at the early stages of non-small cell lung cancer. PMID- 26242155 TI - [METHODOLOGIC PROBLEMS OF SENTINEL LYMPH NODE BIOPSY IN PATIENTS WITH BREAST CANCER]. AB - The study included data on 168 patients with breast cancer, surgical treatment of whom was supplemented by axillary dissection (133 patients or 79.2%) or biopsy of sentinel lymph nodes (35 patients or 20.8%). The examination included ultrasound, planar scintigraphy of the breast and zones of regional lymph drainage. In 122 patients with primary breast cancer stage cT1-2N0M0 retrospective analysis of radionuclide imaging sentinel lymph node was performed. In 89 patients the introduction of colloidal radiopharmaceutical was carried out using a particle diameter of not more than 80-100 nm, in 33 patients study was conducted after administration of radiocolloid with a particle diameter of 200 to 1000 nm. Based on the data obtained by scintigraphy and ultrasonography of zones of regional lymph drainage there were offered two diagnostics models: the first, in which the presence of metastatic axillary lymph nodes was established when there were changes according to at least one of the diagnostic methods--scintigraphy or ultrasound; the second, in which the defeat of lymph nodes was determined only in the case of simultaneous detection of ultrasound and scintigraphic evidence of axillary lymph nodes. Sensitivity, specificity, and overall accuracy of the combination of ultrasound and planar scintigraphy axillary lymph nodes using the first model accounted for 82.7%, 67.7% and 74.4%, respectively. In the second model, the specificity was 94.6%, sensitivity--56%. Rapid transport of radiopharmaceuticals from the injection site, a high gradient of radiopharmaceuticals accumulation in sentinel lymph nodes, effective their visualization, approaching to 100%, were undoubted advantages of radiocolloids having a particle diameter up to 100 nm. PMID- 26242156 TI - [LAPAROSCOPIC SURGERY FOR ENDOMETRIAL CANCER IN PATIENTS OVER 70 YEARS OF AGE]. AB - Surgery is the main method in treatment for endometrial cancer. The complexity of treatment of endometrial cancer patients in elderly age is a result of a large number of comorbidities and, as a consequence, the potential possibility of a large number of intra--and postoperative complications. The article presents the international data and the analysis of own results of a use of laparoscopy in surgical treatment of these patients. A comparison with a group of operations performed by laparotomy is carried out as well as it is evaluated the main intra- and perioperative parameters and also complications, and immediate outcomes of patients treated at the Oncogynecology Department of the N.N.Petrov Research Institute of Oncology. PMID- 26242157 TI - [PHOTODYNAMIC THERAPY FOR INTRADERMAL METASTASES OF BREAST CANCER USING THE MATRIX LIGHT-EMITTING DIODES APPARATUS LATUS]. AB - There are presented results of photodynamic therapy (PDT) for patients with chemo and radioresistant intradermal metastases of breast cancer using the matrix light-emitting diodes apparatus. To all patients prior to irradiation there was performed fluorescence diagnostics to assess the accumulation of the photosensitizer of chlorine series and photobleaching during PDT. The size of the irradiation area was 400 sm, the total dose of irradiation was 250J/cm2. PDT was accompanied by mild pain, which was stopped by administration of non-narcotic analgesics. Complete regression of intradermal lesions was registered in 2 of 4 cases, partial response was observed in 1 patient and the progression of the process in 1 case. PMID- 26242158 TI - [NOMOGRAM AS A PROGNOSTIC TOOL FOR LYMPH NODE METASTASIS IN PATIENTS WITH BREAST CANCER]. AB - It was retrospectively analyzed clinicopathological features of 529 breast cancer patients treated at the Ulyanovsk Oncology Center. Of 529 patients 235 (44.4%) had at least one positive axillary lymph node. Tumor size (p = 0,0005), histological grade (p = 0004), lymphovascular invasion (p < 0,0001), HER2-status (p = 0,014) and total score of malignancy (p < 0,0001) were significant independent predictors for lymph nodes metastases. By univariate and multivariate regression analysis it was created the graphic variant of nomogram which could predict the risk of lymph nodes metastases in breast cancer patients. An area under ROC-curve in our nomogram reached 0,737 that demonstrated high prediction level of accuracy of the developed model. Thus new nomogram is a useful tool in planning axillary surgery in breast cancer patients. PMID- 26242159 TI - [HEMIHEPATECTOMY FOR RESECTABLE HEPATIC METASTASIS FROM COLORECTAL CANCER WITH POOR PROGNOSIS]. AB - The current study aimed at improvement of treatment effects for patients with resectable metastases of colorectal cancer in the liver with a poor prognosis. Overall 437 patients were enrolled with metastatic colorectal cancer in the liver exhibiting at least one adverse factor of long-term prognosis: multiple metastases, bilobar liver metastases, large metastases, the presence of extrahepatic metastases, etc. Combined treatment was performed for 339 (78%) patients: combined treatment with adjuvant systemic chemotherapy (163 patients), combined treatment with perioperative systemic chemotherapy (54 patients), or combined treatment of perioperative regional chemotherapy (122 patients). Surgical treatment was performed in 66 (15%) patients. The remaining group of 32 (7%) patients with resectable metastases who received only systemic chemotherapy was considered separately. All liver resections were extensive due to the widespread metastases. The complication rate stood at 56%. Mortality among operated patients was 4%. Postoperative mortality and complications as well as the intraoperative blood loss were not statistically different in two groups. Adding bevacizumab to preoperative chemotherapy did not increase blood loss. After combined treatment with adjuvant chemotherapy a 5-year survival was 26 +/- 4% that significantly outperforming a 5-year survival rate after surgery (17 +/- 5%), after just drug treatment a 5-year survival has not been reached, and also after combined treatment with perioperative systemic chemotherapy (13 +/- 5%) and not statistically significant exceeded a 5-year survival after combined treatment with perioperative regional chemotherapy (20 +/-5%). Thus our study demonstrates the benefits of combined treatment with adjuvant systemic chemotherapy for resectable metastases of colorectal cancer in the liver with a poor prognosis. For initially unresectable metastases with extrahepatic manifestations of the disease treatment should be begun with systemic chemotherapy. To liver resection in the latter cases there are resorted only after the transfer of patients in operable condition. PMID- 26242160 TI - [OUTCOME OF PELVIC EXENTERATION FOR LOCALLY ADVANCED CANCER OF THE PELVIC ORGANS]. AB - We analyzed the outcomes of pelvic exenteration in patients with locally advanced cancer of the pelvic organs. During the period from 2006 to 2013 at the Leningrad Regional Oncology Dispensary there were carried out 218 exenterations of the pelvis. Postoperative complications occurred in 68 patients (31.2%), 17 patients died, mortality was 7.8%. The average surgery time was 186 minutes. The average blood loss was 860 ml. In assessing the oncological effectiveness of surgical interventions it was revealed that a 5-year survival rate ranged from 32% in bladder cancer, up to 50% in cervical cancer. Careful selection of patients, multidisciplinary approach to the problem has paramount importance to achieve satisfactory outcomes. PMID- 26242161 TI - [SURGERY FOR SARCOMA OF THE PULMONARY ARTERY]. AB - Sarcoma of the pulmonary artery is a rare tumor. At present the literature describes single cases. However the number of publications increases in recent time due to improved diagnostics. There are appeared papers, which provide a series of observations of surgical treatment for this kind of tumor exceeded more than 10 cases. It can be assumed that today the number of these cases in the literature contains several hundreds. Thus despite the rarity of this tumor there is a certain understanding of the clinical picture of this disease and treatment that we tried to do in this paper being studied the available literature and bringing four of our observation. PMID- 26242162 TI - [AUTOLOGOUS TRANSPLANTATION OF ADIPOSE TISSUE IN RECONSTRUCTIVE AND PLASTIC SURGERY. NEW POSSIBILITIES OF "OLD" MATERIAL]. AB - The work is devoted to the methods of application of own adipose tissue as a plastic material and presents the summary of the currently known data on the use of transplantation of adipose tissue in order to correct various defects of the body in plastic and reconstructive surgery. There are analyzed theoretical basis for the use of adipose tissue, provided the methods of administration depending on the area of the use, the severity of the defect and its localization. Data on new methods of the use of adipose tissue and own observations are presented. As an example of the effective use there is provided a detailed analysis of the use of adipose tissue transplantation in breast cancer patients who have different area defects after reconstructive surgery. PMID- 26242163 TI - [EPIDURAL ANESTHESIA AND ANALGESIA IN ONCOLOGIC SURGERY ON ABDOMINAL ORGANS]. AB - The use of epidural anesthesia (EA) in 75 patients during abdominal surgery has revealed a number of advantages of EA over endotracheal anesthesia. EA reduces the consumption of analgesics and myorelaxants and the time of postoperative artificial ventilation of lungs as well as offers more qualitative analgesia. PMID- 26242164 TI - [INDOCYANINE GREEN (ICG) IN THE DETECTION OF SENTINEL LYMPH NODES IN ENDOMETRIAL AND CERVIX CANCER]. AB - We analyzed the international and our own experience of using different dyes in the identification of sentinel lymph nodes in oncogynecological practice. We evaluated the possibility of using indocyanine green (ICG) in the detection of sentinel lymph nodes in patients with endometrial and cervical cancer. The first results of the use of ICG at the Oncogynecology Department of the N.N.Petrov Research Institute of Oncology are presented. PMID- 26242165 TI - [CHEMOPERFUSION TECHNOLOGIES IN TREATMENT FOR MALIGNANT TUMORS]. AB - The data of literature on possibility of the use of perfusion technologies in combined treatment for malignant tumors of different sites are presented. Possible complications during hyperthermic chemoperfusion are discussed and the effectiveness of this method is analyzed. PMID- 26242166 TI - [PERSONALIZATION OF TREATMENT FOR CERVICAL CANCER DURING PREGNANCY]. AB - The paper presents a clinical case of a patient of 29 years old with a diagnosis of cervical cancer sIIA1 stage with the modern therapeutic approach: as a diagnostic and treatment phase there was performed videoendoscopic pelvic lymph node dissection at a 16-week pregnancy, excluded lymphogenous spread of tumor and on the basis of which it was decided to prolong pregnancy, given the strong desire of the patient to keep the baby. At a 19-week and a 23-week pregnancy there were two courses of neoadjuvant chemotherapy and at a 34-week--Cesarean delivery with simultaneous radical hysterectomy and ovarian transposition followed by a course of adjuvant distant radiotherapy. The final diagnosis was as pT2aN0M0. The observation was during 7 months: the patient is alive without recurrence, the child develops without physical and psychomotor abnormalities. PMID- 26242167 TI - [CYTOREDUCTIVE NEPHRECTOMY IN METASTATIC RENAL CELL CANCER]. AB - The role of cytoreductive nephrectomy in the current era of targeted therapy remains unknown. Two prospective randomized phase III trials (CARMENA and SURTIME) are now opened to evaluate the efficacy of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma. So far it is not well known who will and who will not benefit from such surgery. PMID- 26242168 TI - [MODERN APPROACHES TO PERIOPERATIVE THERAPY FOR LUNG CANCER: "PRO" AND "CONTRA" FROM THE PERSPECTIVE OF EVIDENCE-BASED MEDICINE]. AB - Patients with resectable non-small cell lung cancer have a chance to reach a 5 year survival rates ranging from 70% or more for stage IA and 20% for stage IIIA. These figures have remained stable for the past 20 years. Moreover, the inability to improve long-term outcomes is generally determined by a fatal disease progression due to the emergence of distant metastases or local recurrence often in combination with systemic progression process. Thus the use of chemotherapy both in neoadjuvant and adjuvant regimens has stimulated for a long time the search for the optimal scheme and treatment options. This article presents a critical analysis of the current state of the problem of neoadjuvant and adjuvant chemotherapy as well as chemoradiotherapy in order to optimize the tactics of combined treatment of these groups of patients. PMID- 26242169 TI - [PERFUSION TECHNOLOGIES IN TREATMENT OF PATIENTS WITH SKIN MELANOMA AND SOFT TISSUE SARCOMAS OF EXTREMITIES]. AB - A steady increase of incidence of skin melanoma and soft tissue sarcomas of the extremities currently continues to be observed. Taking into account the high probability of developing of locally disseminated forms of skin melanoma and soft tissue sarcomas of extremities, the need to use combined methods in their treatment is quite high. In the 21st century the possibility of a use of isolated regional chemoperfusion provides a high objective response of tumor to chemotherapy without their systemic impact and improves the quality of life through preservation of the limb. This review describes the currently used drugs, and the results of ongoing clinical research in the world, as well as the results of our own study. PMID- 26242170 TI - Size- and type-specific exposure assessment of an asbestos products factory in China. AB - This study describes fibre size and type-specific airborne asbestos exposures in an asbestos product factory. Forty-four membrane filter samples were analysed by scanning electron microscopy to determine the size distribution of asbestos fibres, by workshop. Fibre frequencies of bivariate (length by width) categories were calculated and differences between workshops were tested by analysis of variance. Data were recorded for 13,435 chrysotile and 1075 tremolite fibres. The proportions between size metrics traditionally measured and potentially biologically important size metrics were found to vary in this study from proportions reported in other cohort studies. One, common size distribution was generated for each asbestos type over the entire factory because statistically significant differences in frequency between workshops were not detected. This study provides new information on asbestos fibre size and type distributions in an asbestos factory. The extent to which biologically relevant fibre size indices were captured or overlooked between studies can potentially reconcile currently unexplained differences in asbestos-related disease (ARD) risk between cohorts. The fibre distributions presented here, when combined with similar data from other sites, will contribute to the development of quantitative models for predicting risk and our understanding of the effects of fibre characteristics in the development of ARD. PMID- 26242171 TI - A scoping review to explore the suitability of interactive voice response to conduct automated performance measurement of the patient's experience in primary care. AB - INTRODUCTION: Practice-based performance measurement is fundamental for improvement and accountability in primary care. Traditional performance measurement of the patient's experience is often too costly and cumbersome for most practices. OBJECTIVE/METHODS: This scoping review explores the literature on the use of interactive voice response (IVR) telephone surveys to identify lessons for its use for collecting data on patient-reported outcome measures at the primary care practice level. RESULTS: The literature suggests IVR could potentially increase the capacity to reach more representative patient samples and those traditionally most difficult to engage. There is potential for long term cost effectiveness and significant decrease of the burden on practices involved in collecting patient survey data. Challenges such as low response rates, mode effects, high initial set-up costs and maintenance fees, are also reported and require careful attention. CONCLUSION: This review suggests IVR may be a feasible alternative to traditional patient data collection methods, which should be further explored. PMID- 26242172 TI - Deferoxamine Preconditioning of Neural-Like Cells Derived from Human Wharton's Jelly Mesenchymal Stem Cells as a Strategy to Promote Their Tolerance and Therapeutic Potential: An In Vitro Study. AB - Transplantation of neural-like cells is considered as a promising therapeutic strategy developed for neurodegenerative disease in particular for ischemic stroke. Since cell survival is a major concern following cell implantation, a number of studies have underlined the protective effects of preconditioning with hypoxia or hypoxia mimetic pharmacological agents such as deferoxamine (DFO), induced by activation of hypoxia inducible factor-1 (HIF-1) and its target genes. The present study has investigated the effects of DFO preconditioning on some factors involved in cell survival, angiogenesis, and neurogenesis of neural-like cells derived from human Wharton's jelly mesenchymal stem cells (HWJ-MSCs) in presence of hydrogen peroxide (H2O2). HWJ-MSCs were differentiated toward neural like cells for 14 days and neural cell markers were identified using immunocytochemistry. HWJ-MSC-derived neural-like cells were then treated with 100 uM DFO, as a known hypoxia mimetic agent for 48 h. mRNA and protein expression of HIF-1 target genes including brain-derived neurotrophic factors (BDNF) and vascular endothelial growth factor (VEGF) significantly increased using RT-PCR and Western blotting which were reversed by HIF-1alpha inhibitor, while, gene expression of Akt-1, Bcl-2, and Bax did not change significantly but pAkt-1 was up-regulated as compared to poor DFO group. However, addition of H2O2 to DFO treated cells resulted in higher resistance to H2O2-induced cell death. Western blotting analysis also showed significant up-regulation of HIF-1alpha, BDNF, VEGF, and pAkt-1, and decrease of Bax/Bcl-2 ratio as compared to poor DFO. These results may suggest that DFO preconditioning of HWJ-MSC-derived neural-like cells improves their tolerance and therapeutic potential and might be considered as a valuable strategy to improve cell therapy. PMID- 26242173 TI - A New Role Discovered for IGTP: The Protective Effect of IGTP in ICH-Induced Neuronal Apoptosis. AB - Interferon gamma-induced GTPase (IGTP), which is also named Irgm3, has been widely described in regulating host resistance against intracellular pathogens. Previous researches have demonstrated that IGTP exerts beneficial function during coxsackievirus B3 (CVB3) infection. However, little information is available regarding the role of IGTP in central nervous system. Here, our study revealed that IGTP may have an essential role during ICH-induced neuronal apoptosis. We found the expression level of IGTP adjacent to hematoma was strongly increased after ICH, accompanied with the up-regulation of proliferating cell nuclear antigen (PCNA), active-caspase-3, p-GSK-3beta, and Bax. IGTP was also observed to be co-localized with PCNA in astrocytes and active-caspase-3 in neurons, indicating its association with astrocyte proliferation and neuronal apoptosis after ICH. Finally, in vitro study, knocking down IGTP with IGTP-specific siRNA promoted active-caspase-3, p-GSK-3beta, and Bax expression, and led to more severe neuronal apoptosis after ICH. All these results above suggested that IGTP might play a critical role in protecting neurons from apoptosis after ICH. PMID- 26242174 TI - In vitro decidualisation of canine uterine stromal cells. AB - BACKGROUND: The uterine response to the presence of embryos is poorly understood in the domestic dog (Canis familiaris). The intimate embryo-maternal cross-talk, which begins following the hatching of blastocysts and embryo attachment leads to strong structural and functional remodelling of the uterus. A part of this process is decidualisation, comprising morphological and biochemical changes that result in formation of maternal stroma-derived decidual cells. These are an integral part of the canine placenta materna, which together with the maternal vascular endothelium are the only cells of the canine endotheliochorial placenta able to resist trophoblast invasion. These cells are also the only ones within the canine placenta expressing the progesterone receptor (PGR). Understanding the decidualisation process thus appears essential for understanding canine reproductive physiology. METHODS: Here, we investigated the capability of canine uterine stromal cells to decidualise in vitro, thereby serving as a canine model of decidualisation. A dbcAMP-mediated approach was chosen during a time course of 24 - 72 h. Tissue material from six (n = 6) healthy, dioestric bitches was used (approximately 2 weeks after ovulation). Cells were characterized by differential staining, nearly 100 % of which were vimentin-positive. Scanning and transmission electron microscope analyses were applied, and morphological changes were recorded with a live cell imaging microscope. Expression of several decidualisation markers was investigated. RESULTS: The in vitro cultured stromal cells acquired characteristics of decidual cells when incubated with 0.5 mM dbcAMP for 72 h. Their shape changed from elongated to rounded, while ultrastructural analysis revealed higher numbers of mitochondria and secretory follicles, and an increased proliferation rate. Elevated expression levels of IGF1, IGF2, PRLR and ERalpha were observed in decidualised cells; PRL and ERbeta remained mostly below the detection limit, while PGR remained unaffected. The expression of smooth muscle alpha actin (alphaSMA), another decidualisation marker, was strongly induced. Among prostaglandin system members, levels of COX2 (PTGS2) and of PGE2-synthase (PTGES) were upregulated. Expression of the PGE2 receptors, PTGER2 and PTGER4, was clearly detectable. CONCLUSION: An in vitro decidualisation model with canine uterine stromal cells was successfully established, allowing future, more detailed studies to be undertaken on the underlying molecular and endocrine mechanisms of canine decidualisation. PMID- 26242175 TI - Comparison and evaluation of two exome capture kits and sequencing platforms for variant calling. AB - BACKGROUND: To promote the clinical application of next-generation sequencing, it is important to obtain accurate and consistent variants of target genomic regions at low cost. Ion Proton, the latest updated semiconductor-based sequencing instrument from Life Technologies, is designed to provide investigators with an inexpensive platform for human whole exome sequencing that achieves a rapid turnaround time. However, few studies have comprehensively compared and evaluated the accuracy of variant calling between Ion Proton and Illumina sequencing platforms such as HiSeq 2000, which is the most popular sequencing platform for the human genome. The Ion Proton sequencer combined with the Ion TargetSeq Exome Enrichment Kit together make up TargetSeq-Proton, whereas SureSelect-Hiseq is based on the Agilent SureSelect Human All Exon v4 Kit and the HiSeq 2000 sequencer. RESULTS: Here, we sequenced exonic DNA from four human blood samples using both TargetSeq-Proton and SureSelect-HiSeq. We then called variants in the exonic regions that overlapped between the two exome capture kits (33.6 Mb). The rates of shared variant loci called by two sequencing platforms were from 68.0 to 75.3% in four samples, whereas the concordance of co-detected variant loci reached 99%. Sanger sequencing validation revealed that the validated rate of concordant single nucleotide polymorphisms (SNPs) (91.5%) was higher than the SNPs specific to TargetSeq-Proton (60.0%) or specific to SureSelect-HiSeq (88.3%). With regard to 1-bp small insertions and deletions (InDels), the Sanger sequencing validated rates of concordant variants (100.0%) and SureSelect-HiSeq specific (89.6%) were higher than those of TargetSeq-Proton-specific (15.8%). CONCLUSIONS: In the sequencing of exonic regions, a combination of using of two sequencing strategies (SureSelect-HiSeq and TargetSeq-Proton) increased the variant calling specificity for concordant variant loci and the sensitivity for variant loci called by any one platform. However, for the sequencing of platform specific variants, the accuracy of variant calling by HiSeq 2000 was higher than that of Ion Proton, specifically for the InDel detection. Moreover, the variant calling software also influences the detection of SNPs and, specifically, InDels in Ion Proton exome sequencing. PMID- 26242176 TI - Leptin, its receptor and aromatase expression in deep infiltrating endometriosis. AB - BACKGROUND: The aim of this study was to evaluate the leptin levels in the serum and peritoneal fluid (PF) and the protein expression in three different peritoneal ectopic implants in patients who underwent surgery for deep infiltrating endometriosis. METHODS: All patients had been treated at the Department of Gynecology of the Pedro Ernesto University Hospital, Rio de Janeiro. The study group consisted of 15 patients who underwent surgery for adnexal masses and infertility, while the control group consisted of ten women who underwent surgery for tubal ligation. Peritoneal fluid and samples tissues were collected during surgery. Serum samples were obtained before anesthesia. In this study, the leptin levels in the serum and peritoneal fluid (PF) were evaluated by ELISA. The protein expression of leptin and its receptors (ObR) and aromatase enzyme were evaluated by Western blot analysis of the intestine, uterosacral ligament and vaginal septum in the ectopic implants. The t-test and one-way ANOVA with Holm-Sidak post-test were used, and p < 0.05 was considered to be statistically significant. RESULTS: Compared to the controls, the serum leptin levels (control = 14.7 ng/mL +/- 2.63, endometriosis = 19.2 ng/mL +/- 1.84, p < 0.0001) were increased, while in PF, there was no difference (control = 6.68 ng/mL +/- 0.43, endometriosis = 7.71 ng/mL +/- 0.59, p = 0.18). Comparing women with and without ovarian implants, the leptin levels in both the serum and PF were significantly higher in women without ovarian implants (serum: with ovarian implant = 15.85 +/- 1.99; without ovarian implant = 23.14 +/- 2.60; ng/mL, p = 0.04; PF: with ovarian implant = 4.28 +/- 1.30; without ovarian implant = 11.18 +/- 2.98;ng/mL, p = 0.048). The leptin, ObR and aromatase protein expression levels were increased in lesions in the vaginal septum and were decreased in the intestine lesions. CONCLUSION: This study reports several interesting associations between the leptin levels in serum, peritoneal fluid, and tissue samples and the localization of the ectopic endometrium. Although this study does not provide a clear picture of the role of leptin in the development and progression of peritoneal implants, it contributed new data that might be useful to elucidating the enigma that is the role of leptin in endometriosis disease. PMID- 26242178 TI - An enhanced surface passivation effect in InGaN/GaN disk-in-nanowire light emitting diodes for mitigating Shockley-Read-Hall recombination. AB - We present a detailed study of the effects of dangling bond passivation and the comparison of different sulfide passivation processes on the properties of InGaN/GaN quantum-disk (Qdisk)-in-nanowire based light emitting diodes (NW-LEDs). Our results demonstrated the first organic sulfide passivation process for nitride nanowires (NWs). The results from Raman spectroscopy, photoluminescence (PL) measurements, and X-ray photoelectron spectroscopy (XPS) showed that octadecylthiol (ODT) effectively passivated the surface states, and altered the surface dynamic charge, and thereby recovered the band-edge emission. The effectiveness of the process with passivation duration was also studied. Moreover, we also compared the electro-optical performance of NW-LEDs emitting at green wavelength before and after ODT passivation. We have shown that the Shockley-Read-Hall (SRH) non-radiative recombination of NW-LEDs can be greatly reduced after passivation by ODT, which led to a much faster increasing trend of quantum efficiency and higher peak efficiency. Our results highlighted the possibility of employing this technique to further design and produce high performance NW-LEDs and NW-lasers. PMID- 26242177 TI - The effect of on-demand vs deep neuromuscular relaxation on rating of surgical and anaesthesiologic conditions in patients undergoing thoracolaparoscopic esophagectomy (DEPTH trial): study protocol for a randomized controlled trial. AB - BACKGROUND: Deep muscle relaxation has been shown to facilitate operating conditions during laparoscopic surgery. Minimally invasive esophageal surgery is a high-risk procedure in which the use of deep neuromuscular block (NMB) may improve conditions in the thoracic phase as well. Neuromuscular antagonists can be given on demand or by continuous infusion (deep NMB). However, the positioning of the patient often hampers train-of-four (TOF) monitoring. A continuous infusion thus may result in a deep NMB at the end of surgery. The use of neostigmine not only is insufficient for reversing deep NMB but also may be contraindicated for this procedure because of its cholinergic effects. Sugammadex is an effective alternative but is rather expensive. This study aims to evaluate the use of deep versus on-demand NMB on operating, anaesthesiologic conditions, and costs in patients undergoing a two- or three-phase thoracolaparoscopic esophageal resection. METHODS/DESIGN: We will conduct a single-center randomized controlled double-blinded intervention study. Sixty-six patients undergoing a thoracolaparoscopic esophageal resection will be included. Patients will receive either continuous infusion of rocuronium 0.6 mg/kg per hour (group 1) or continuous infusion of NaCl 0.9 % 0.06 ml/kg per hour (group 2). In both groups, on-demand boluses of rocuronium can be given (open-label design). The primary aim of this study is to compare the surgical rating scale (SRS) during the abdominal phase. Main secondary aims are to evaluate SRS during the thoracic phase, to evaluate anesthesiologic conditions, and to compare costs (in euros) associated with use of rocuronium, sugammadex, and duration of surgery. DISCUSSION: This study is the first to evaluate the benefits of deep neuromuscular relaxation on surgical and anaesthesiologic conditions during thoracolaparoscopic esophageal surgery. This surgical procedure is unique because it consists of both an abdominal phase and a thoracic phase taking place in different order depending on the subtype of surgery (a two- or three-stage transthoracic esophagectomy). In addition, possible benefits associated with deep NMB, such as decrease in operating time, will be weighed against costs. TRIAL REGISTRATION: European Clinical Trials Database (EudraCT) number: 2014-002147-18 (obtained 19 May 2014) ClinicalTrials.gov: NCT02320734 (obtained 18 Dec. 2014). PMID- 26242179 TI - Poxvirus-encoded TNF decoy receptors inhibit the biological activity of transmembrane TNF. AB - Poxviruses encode up to four different soluble TNF receptors, named cytokine response modifier B (CrmB), CrmC, CrmD and CrmE. These proteins mimic the extracellular domain of the cellular TNF receptors to bind and inhibit the activity of TNF and, in some cases, other TNF superfamily ligands. Most of these ligands are released after the enzymic cleavage of a membrane precursor. However, transmembrane TNF (tmTNF) is not only a precursor of soluble TNF but also exerts specific pro-inflammatory and immunological activities. Here, we report that viral TNF receptors bound and inhibited tmTNF and describe some interesting differences in their activity against the soluble cytokine. Thus, CrmE, which does not inhibit mouse soluble TNF, could block murine tmTNF-induced cytotoxicity. We propose that this anti-tmTNF effect should be taken into consideration when assessing the role of viral TNF decoy receptors in the pathogenesis of poxvirus. PMID- 26242180 TI - Influence of surgical approach on component positioning in primary total hip arthroplasty. AB - BACKGROUND: Minimal invasive surgery (MIS) has gained growing popularity in total hip arthroplasty (THA) but concerns exist regarding component malpositioning. The aim of the present study was to evaluate femoral and acetabular component positioning in primary cementless THA comparing a lateral to a MIS anterolateral approach. METHODS: We evaluated 6 week postoperative radiographs of 52 hips with a minimal invasive anterolateral approach compared to 54 hips with a standard lateral approach. All hips had received the same type of implant for primary cementless unilateral THA and had a healthy hip contralaterally. RESULTS: Hip offset was equally restored comparing both approaches. No influence of the approach was observed with regard to reconstruction of acetabular offset, femoral offset, vertical placement of the center of rotation, stem alignment and leg length discrepancy. However, with the MIS approach, a significantly higher percentage of cups (38.5 %) was malpositioned compared to the standard approach (16.7 %) (p = 0.022). CONCLUSIONS: The MIS anterolateral approach allows for comparable reconstruction of stem position, offset and center of rotation compared to the lateral approach. However, surgeons must be aware of a higher risk of cup malpositioning for inclination and anteversion using the MIS anterolateral approach. PMID- 26242181 TI - Tumor-associated macrophages in oral premalignant lesions coexpress CD163 and STAT1 in a Th1-dominated microenvironment. AB - BACKGROUND: Tumor-associated macrophages (TAMs) are implicated in the growth, invasion and metastasis of various solid tumors. However, the phenotype of TAMs in premalignant lesions of solid tumors has not been clarified. In the present study, we identify the phenotype of TAMs in leukoplakia, an oral premalignant lesion, by immunohistochemical analysis and investigate the involvement of infiltrated T cells that participate in the polarization of TAMs. METHODS: The subjects included 30 patients with oral leukoplakia and 10 individuals with normal mucosa. Hematoxylin and eosin slides were examined for the histological grades, and immunohistochemical analysis was carried out using antibodies against CD68 (pan-MPhi), CD80 (M1 MPhi), CD163 (M2 MPhi), CD4 (helper T cells: Th), CD8 (cytotoxic T cells), CXCR3, CCR5 (Th1), CCR4 (Th2), signal transducer and activator of transcription (STAT1), phosphorylated STAT1 (pSTAT1) and chemokine CXCL9. The differences in the numbers of positively stained cells among the different histological grades were tested for statistical significance using the Kruskal-Wallis test. Correlations between different types of immune cells were determined using Spearman's rank analysis. RESULTS: An increase in the rate of CD163(+) TAM infiltration was observed in mild and moderate epithelial dysplasia, which positively correlated with the rate of intraepithelial CD4(+) Th cell infiltration. Although CCR4(+) cells rarely infiltrated, CXCR3(+) and CCR5(+) cells were observed in these lesions. Cells positive for STAT1 and chemokine CXCL9, interferon- (IFN)-induced gene products, and pSTAT1 were also observed in the same lesions. Double immunofluorescence staining demonstrated that the cells that were positive for CD163 were also positive for STAT1. CONCLUSIONS: CD163(+) TAMs in oral premalignant lesions coexpress CD163 and STAT1, suggesting that the TAMs in oral premalignant lesions possess an M1 phenotype in a Th1-dominated micromilieu. PMID- 26242182 TI - Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PMID- 26242183 TI - Plk1 regulates MEK1/2 and proliferation in airway smooth muscle cells. AB - BACKGROUND: Polo-like kinase 1 (Plk1) is a serine/threonine protein kinase that has been implicated in the regulation of mitosis. In addition, the activation of mitogen-activated protein kinase (MAPK) is a key event in the early stage of the growth factor response. The role of Plk1 in MAPK phosphorylation in cells has not been investigated. METHODS: Immunoblot analysis was used to evaluate Plk1 and MAPK phosphorylation in cells upon stimulation with platelet-derived growth factor (PDGF). We also generated stable Plk1 knockdown (KD) cells to assess the role of Plk1 in MAPK activation and cell proliferation. Furthermore, we used a non-phosphorylatable Plk1 mutant to determine the function of Plk1 phosphorylation in these processes. RESULTS: Treatment with PDGF increased Plk1 phosphorylation at Thr-210 (an indication of Plk1 activation) in human airway smooth muscle cells. Plk1 KD attenuated the PDGF-induced phosphorylation of MEK1/2 and ERK1/2 as well as cell proliferation. However, phosphorylation of Raf 1 and AKT upon stimulation with PDGF was not reduced in Plk1 KD cells. Furthermore, the expression of T210A Plk1 (alanine substitution at Thr-210) inhibited the PDGF-stimulated MEK1/2 phosphorylation, ERK1/2 phosphorylation and cell proliferation. CONCLUSIONS: Together, these findings suggest that Plk1 is activated upon growth factor stimulation, which may control the activation of MEK1/2 and ERK1/2, and smooth muscle cell proliferation. PMID- 26242187 TI - Vascular Calcification Revisited: A New Perspective for Phosphate Transport. AB - Elevated serum phosphorus has emerged as a key risk factorfor pathologic calcification of cardiovascular structures, or vascular calcification (VC). To prevent the formation of calciumphosphate deposits (CPD), the body uses adenosine 5'-triphosphate (ATP) to synthesize inhibitors of calcification, including proteins and inhibitors of low molecular weight. Extracellular pyrophosphate (PPi) is a potent inhibitor of VC,which is produced during extracellular hydrolysis of ATP. Loss of function in the enzymes and transporters that are involved in the cycle of extracellular ATP, including Pi transporters, leads to excessive deposition of calcium-phosphate salts. Treatment of hyperphosphatemia with Pi-binders and Injection of exogenous PPi are the effective treatments to prevent CPD in the aortic wall. The role of sodium phosphate cotransporters in ectopic calcification is contradictory and not well defined, but their important role in the control of intracellular Pi levels and the synthesis of ATP make them an important target to study. PMID- 26242186 TI - Indoor use of attractive toxic sugar bait (ATSB) to effectively control malaria vectors in Mali, West Africa. AB - BACKGROUND: Attractive toxic sugar bait (ATSB) solutions containing any gut toxins can be either sprayed on plants or used in simple bait stations to attract and kill sugar-feeding female and male mosquitoes. This field study in Mali demonstrates the effect of ATSB bait stations inside houses as a vector control method that targets and kills endophilic African malaria vectors. METHODS: The studies were conducted in five villages located near the River Niger, Mali. Baseline village-wide assessments of densities for female and male Anopheles gambiae sensu lato were performed by pyrethrum spray collections (PSC) in ten houses in each of five villages. To determine the rate of mosquito feeding on bait stations, one bait station per house containing attractive sugar bait (ASB) (without toxin) plus a food dye marker, was set up in ten houses in each of the five villages. PSC collections were conducted on the following day and the percentage of female and male mosquitoes that had fed was determined by visual inspection for the dye marker. Then, a 50-day field trial was done. In an experimental village, one bait station containing ATSB (1% boric acid active ingredient) was placed per bedroom (58 bedrooms), and indoor densities of female and male An. gambiae s.l. were subsequently determined by PSC, and female mosquitoes were age graded. RESULTS: In the five villages, the percentages of An. gambiae s.l. feeding inside houses on the non-toxic bait stations ranged from 28.3 to 53.1% for females and 36.9 to 78.3% for males. Following ATSB indoor bait station presentation, there was a significant reduction, 90% in female and 93% in male populations, of An. gambiae s.l. at the experimental village. A 3.8-fold decrease in the proportion of females that had undergone four or more gonotrophic cycles was recorded at the experimental village, compared to a 1.2-fold increase at the control village. CONCLUSION: The field trial demonstrates that An. gambiae s.l. feed readily from ATSB bait stations situated indoors, leading to a substantial reduction in the proportion of older female mosquitoes. This study demonstrates that ATSB inside houses can achieve impressive malaria vector control in Africa. PMID- 26242188 TI - Left Atrial Appendage Closure -The WATCHMAN Device. AB - Atrial fibrillation (AF) is one of the most common arrhythmias seen in clinical cardiology practice. Patients with non-valvular AF have an approximately 5-fold increase in the risk of stroke, with an exponential increase with advancing age. Cardioembolic strokes carry a high mortality risk. Although the potential of warfarin to reduce systemic embolization in AF patients is well established, its use is difficult due to narrow therapeutic windows and additional complications (e.g. increased risk of bleeding), especially for aging patients. Therefore, alternative means of treatment to reduce stroke risk in these patients are needed. The left atrial appendage is the major source of thrombus formation in patients with non-valvular AF. The WATCHMAN device (Boston Scientific, MA) is a percutaneous left atrial appendage closure device which has been tested prospectively in multiple randomized trials. It offers a new stroke risk reduction option for high-risk patients with non-valvular atrial fibrillation who are seeking an alternative to long-term warfarin therapy. Based on the robust WATCHMAN clinical program which consists of numerous studies, with more than 2,400 patients and nearly 6,000 patient-years of follow-up, the WATCHMAN LAAC Device is approved by FDA. In this article we reviewed the preclinical studies and clinical trials, as well as the next generation of the device. PMID- 26242185 TI - Trichomonas vaginalis: a review of epidemiologic, clinical and treatment issues. AB - Trichomonas vaginalis (TV) is likely the most common non-viral sexually transmitted infection (STI) in the world. It is as an important source of reproductive morbidity, a facilitator of HIV transmission and acquisition, and thus it is an important public health problem. Despite its importance in human reproductive health and HIV transmission, it is not a reportable disease and surveillance is not generally done. This is problematic since most persons infected with TV are asymptomatic. Metronidazole (MTZ) has been the treatment of choice for women for decades, and single dose has been considered the first line of therapy. However, high rates of retest positive are found among TV infected persons after single dose MTZ treatment. This has not been explained by drug resistance since in vitro resistance is only 2-5 %. Treatment failure can range from 7-10 % and even higher among HIV+ women. Treatment efficacy may be influenced by vaginal ecology. The origins of repeat positives need further explanation and better treatment options are needed. PMID- 26242184 TI - Markers of beta-Cell Failure Predict Poor Glycemic Response to GLP-1 Receptor Agonist Therapy in Type 2 Diabetes. AB - OBJECTIVE: To assess whether clinical characteristics and simple biomarkers of beta-cell failure are associated with individual variation in glycemic response to GLP-1 receptor agonist (GLP-1RA) therapy in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We prospectively studied 620 participants with type 2 diabetes and HbA1c >=58 mmol/mol (7.5%) commencing GLP-1RA therapy as part of their usual diabetes care and assessed response to therapy over 6 months. We assessed the association between baseline clinical measurements associated with beta-cell failure and glycemic response (primary outcome HbA1c change 0-6 months) with change in weight (0-6 months) as a secondary outcome using linear regression and ANOVA with adjustment for baseline HbA1c and cotreatment change. RESULTS: Reduced glycemic response to GLP-1RAs was associated with longer duration of diabetes, insulin cotreatment, lower fasting C-peptide, lower postmeal urine C peptide-to-creatinine ratio, and positive GAD or IA2 islet autoantibodies (P <= 0.01 for all). Participants with positive autoantibodies or severe insulin deficiency (fasting C-peptide <=0.25 nmol/L) had markedly reduced glycemic response to GLP-1RA therapy (autoantibodies, mean HbA1c change -5.2 vs. -15.2 mmol/mol [-0.5 vs. -1.4%], P = 0.005; C-peptide <0.25 nmol/L, mean change -2.1 vs. -15.3 mmol/mol [-0.2 vs. -1.4%], P = 0.002). These markers were predominantly present in insulin-treated participants and were not associated with weight change. CONCLUSIONS: Clinical markers of low beta-cell function are associated with reduced glycemic response to GLP-1RA therapy. C-peptide and islet autoantibodies represent potential biomarkers for the stratification of GLP-1RA therapy in insulin-treated diabetes. PMID- 26242189 TI - Converting 3D rigid metal-organic frameworks (MOFs) to 2D flexible networks via ligand exchange for enhanced CO2/N2 and CH4/N2 separation. AB - We report a synthetic strategy for constructing a novel flexible MOF from a rigid parent structure by ligand exchange. This is the first reported study on introducing flexible heterogeneity into a rigid structure via substantial structural rearrangement. The daughter material exhibits enhanced gas separation selectivity compared with the parent. PMID- 26242190 TI - Democrats block vote on bill to deny federal funds to Planned Parenthood. PMID- 26242191 TI - Left adrenal tumor extending into the renal vein: surgical management with ipsilateral kidney preservation. AB - If single adrenal metastasis surgery is well admitted, no recommendation exists about the management of a renal vein tumor thrombus, even though the actual consensual attitude consists in a nephrectomy associated to an adrenalectomy. We report, here, the case of a 74-year-old man with a suspected adrenal metastasis of a lung carcinoma associated with a left adrenal and renal vein tumor thrombus treated by adrenalectomy and renal vein thrombectomy and ipsilateral kidney sparing. The postoperative computed tomography scan showed no thrombus in the left renal vein. Doppler ultrasound performed 1 month after adrenalectomy proved a good left renal vein flux. At 36 months of follow-up, the patient is alive without signs of recurrence. PMID- 26242192 TI - Epigenetic Regulation of Chondrocyte Catabolism and Anabolism in Osteoarthritis. AB - Osteoarthritis (OA) is one of the most prevalent forms of joint disorder, associated with a tremendous socioeconomic burden worldwide. Various non-genetic and lifestyle-related factors such as aging and obesity have been recognized as major risk factors for OA, underscoring the potential role for epigenetic regulation in the pathogenesis of the disease. OA-associated epigenetic aberrations have been noted at the level of DNA methylation and histone modification in chondrocytes. These epigenetic regulations are implicated in driving an imbalance between the expression of catabolic and anabolic factors, leading eventually to osteoarthritic cartilage destruction. Cellular senescence and metabolic abnormalities driven by OA-associated risk factors appear to accompany epigenetic drifts in chondrocytes. Notably, molecular events associated with metabolic disorders influence epigenetic regulation in chondrocytes, supporting the notion that OA is a metabolic disease. Here, we review accumulating evidence supporting a role for epigenetics in the regulation of cartilage homeostasis and OA pathogenesis. PMID- 26242193 TI - Identification and Clinical Implications of Novel MYO15A Mutations in a Non consanguineous Korean Family by Targeted Exome Sequencing. AB - Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies. Here, we found two novel MYO15A mutations, c.3871C>T (p.L1291F) and c.5835T>G (p.Y1945X) in an affected individual carrying congenital profound sensorineural hearing loss (SNHL) through targeted resequencing of 134 known deafness genes. The variant, p.L1291F and p.Y1945X, resided in the myosin motor and IQ2 domains, respectively. The p.L1291F variant was predicted to affect the structure of the actin-binding site from three-dimensional protein modeling, thereby interfering with the correct interaction between actin and myosin. From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene. Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies. This genotype-phenotype correlation suggests that preservation of residual hearing during auditory rehabilitation like cochlear implantation should be intended for those who carry mutations in the N-terminal domain and that individuals with mutations elsewhere in MYO15A require early cochlear implantation to timely initiate speech development. PMID- 26242194 TI - Tricyclic Antidepressants Amitriptyline and Desipramine Induced Neurotoxicity Associated with Parkinson's Disease. AB - Recent studies report that a history of antidepressant use is strongly correlated with the occurrence of Parkinson's disease (PD). However, it remains unclear whether antidepressant use can be a causative factor for PD. In the present study, we examined whether tricyclic antidepressants amitriptyline and desipramine can induce dopaminergic cell damage, both in vitro and in vivo. We found that amitriptyline and desipramine induced mitochondria-mediated neurotoxicity and oxidative stress in SH-SY5Y cells. When injected into mice on a subchronic schedule, amitriptyline induced movement deficits in the pole test, which is known to detect nigrostriatal dysfunction. In addition, the number of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta was reduced in amitriptyline-injected mice. Our results suggest that amitriptyline and desipramine may induce PD-associated neurotoxicity. PMID- 26242196 TI - Erratum to: Anion Transport or Nucleotide Binding by Ucp2 Is Indispensable for Ucp2-Mediated Efferocytosis. PMID- 26242195 TI - The Actin-Related Protein BAF53 Is Essential for Chromosomal Subdomain Integrity. AB - A chromosome territory is composed of chromosomal subdomains. The internal structure of chromosomal subdomains provides a structural framework for many genomic activities such as replication and DNA repair, and thus is key to determining the basis of their mechanisms. However, the internal structure and regulating proteins of a chromosomal subdomain remains elusive. Previously, we showed that the chromosome territory expanded after BAF53 knockdown. Because the integrity of chromosomal subdomains is a deciding factor of the volume of a chromosome territory, we examined here the effect of BAF53 knockdown on chromosomal subdomains. We found that BAF53 knockdown led to the disintegration of histone H2B-GFP-visualized chromosomal subdomains and BrdU-labeled replication foci. In addition, the size of DNA loops measured by the maximum fluorescent halo technique increased and became irregular after BAF53 knockdown, indicating DNA loops were released from the residual nuclear structure. These data can be accounted for by the model that BAF53 is prerequisite for maintaining the structural integrity of chromosomal subdomains. PMID- 26242197 TI - Underutilization of warfarin for stroke prophylaxis in patients with atrial fibrillation or atrial flutter in Korea. AB - OBJECTIVE: Anticoagulation therapy with warfarin is recommended for stroke prevention in patients with atrial fibrillation (AF) or atrial flutter (AFL) whose risks for stroke are high. However, previous studies suggest that warfarin is markedly underused. This study aims to investigate the incidence and risk factors of warfarin underutilization in patients with high risk of stroke in Korea. METHODS: This was a cross-sectional study using the data of 2009 from National Patients Sample compiled by the Health Insurance Review and Assessment Service. Patients with high risk of thromboembolism were identified with congestive heart failure, hypertension, age >=75 years, diabetes, and prior stroke (CHADS2) score >=2. High-risk patients of bleeding were excluded using Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) score >4. Warfarin and antithrombotic therapy underutilization were defined and estimated in high-risk patients. Any demographic and clinical factors associated with warfarin and antithrombotic therapy underutilization were explored using a logistic regression model. RESULTS: Of the national patient sample, 15,885 patients were identified with AF or AFL. Among them, a total of 8475 patients who had an admission history, CHADS2 >=2, and ATRIA score <=4 were included in the analysis. From the study sample, warfarin underutilization and antithrombotic therapy underutilization were estimated to be 64.0% and 20.4%, respectively. Predictors of warfarin underutilization include female sex, age >=80 years, lower CHADS2 score, and insurance type (Medical Aid program). CONCLUSIONS: A high portion of AF/AFL patients with CHADS2 score >=2 were undertreated with warfarin. As ischemic stroke is one of the leading causes of death in Korea, a more aggressive approach to prevent stroke in patients with AF/AFL is required. PMID- 26242198 TI - Navigator Approach to Improve Quality of Care for Vulnerable Populations in Mexico. AB - For nearly 30 years, Programa Companeros Inc (Companeros) has worked in Ciudad Juarez, Chihuahua, Mexico, to ensure that vulnerable populations can exercise their rights to receive HIV and substance abuse prevention and treatment services. Companeros staff has worked to ameliorate the negative results that limit access to care to the most vulnerable individuals: those who are poor, homeless, sex workers, addicted, and others whose life context put them at greater risk for being infected with HIV. With support from the MAC AIDS Foundation, Companeros has expanded its capacity to deliver services to persons living with HIV/AIDS (PLWHA) and to HIV-vulnerable populations. This short communication describes findings from an internal evaluation conducted to investigate the effectiveness of the MAC AIDS-funded navigator-based program implemented at Companeros. PMID- 26242199 TI - The English proficiency and academic language skills of Australian bilingual children during the primary school years. AB - PURPOSE: Evidence suggests that early proficiency in the language of school instruction is an important predictor of academic success for bilingual children. This study investigated whether English-proficiency at 4-5 years of age predicts academic language and literacy skills among Australian bilingual children at 10 11 years of age, as part of the Longitudinal Study of Australian Children ( LSAC, 2012 ). METHOD: The LSAC comprises a nationally representative clustered cross sequential sample of Australian children. Data were analysed from a sub-sample of 129 bilingual children from the LSAC Kindergarten cohort (n = 4983), for whom teachers completed the Australian Early Development Index (AEDI) checklist (a population measure of early childhood development) and the Academic Rating Scale (ARS) language and literacy subscale. RESULT: Linear regression analyses revealed that bilingual children who commenced school with stronger English proficiency had higher academic language and literacy scores at the end of primary school (beta = 0.45). English proficiency remained a significant predictor, even when accounting for gender and socio-economic disadvantage (beta = 0.38). CONCLUSION: The findings indicate that bilingual children who begin school without English proficiency are at risk of difficulties with academic language and literacy, even after 6 years of schooling. Risk factors need to be identified so early support can be targeted towards the most vulnerable children. PMID- 26242201 TI - Best Practices for Reporting on Energy Storage. PMID- 26242200 TI - Prediction of acute encephalopathy with biphasic seizures and late reduced diffusion in patients with febrile status epilepticus. AB - INTRODUCTION: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common subtype of acute encephalopathy among children in Japan. The pathogenesis of AESD is mostly delayed cerebral edema caused by excitotoxic injury. It is difficult to discriminate AESD and complex febrile seizure in the early phase. Many cases have neurologic sequelae because early intervention is difficult. METHODS: To establish an early diagnostic method, we assessed 213 hospitalized cases of febrile status epilepticus (FSE) between January 2004 and August 2014. We categorized FSE cases into an AESD group and a non-AESD group and compared their clinical courses, laboratory data and cranial computed tomography (CT) findings. RESULTS: Of 213 hospitalized FSE cases, 19 (9%) were AESD. Univariate analysis showed that the AESD group took a significantly longer time to wake after FSE, had a higher degree of respiratory acidemia, and higher levels of serum AST, ALT, LD, hyperglycemia and hyperammonemia than the non-AESD group. We developed a scoring model that predicts AESD based on multivariate analysis. Using cut-off points of 4 and more with this scoring model, we could identify the AESD cases with 93% sensitivity and 91% specificity. These scores also had a positive correlation with prognosis. DISCUSSION: Our scoring model enables early diagnosis of AESD. Patients with high scores should be observed carefully and early intervention should be considered. PMID- 26242203 TI - Morphological characterization of Class III phosphoinositide 3-kinase during mouse brain development. AB - The mammalian Class III phosphoinositide 3-kinase (PIK3C3, also known as mammalian vacuolar protein sorting 34 homologue, Vps34) is a regulator of vesicular trafficking, autophagy, and nutrient sensing. In this study, we generated a specific antibody against PIK3C3, and carried out expression and morphological analyses of PIK3C3 during mouse brain development. In Western blotting, PIK3C3 was detected throughout the developmental process with higher expression in the early embryonic stage. In immunohistochemical analyses with embryonic day 16 mouse brain, PIK3C3 was detected strongly in the axon of cortical neurons. While PIK3C3 was distributed at the soma, nucleus, axon, and dendrites in primary cultured mouse hippocampal neurons at 3 days in vitro (div), it was also found in a punctate distribution with partial colocalization with synaptic marker, synaptophysin, at 21 div. The obtained results indicate that PIK3C3 is expressed and may have a physiological role in central nervous system during corticogenesis. PMID- 26242202 TI - Endothelial glucocorticoid receptor promoter methylation according to dexamethasone sensitivity. AB - We have previously shown that in vitro sensitivity to dexamethasone (DEX) stimulation in human endothelial cells is positively regulated by the glucocorticoid receptor (NR3C1, GR). The present study determined the role of differential GR transcriptional regulation in glucocorticoid sensitivity. We studied 25 human umbilical vein endothelial cells (HUVECs) that had been previously characterized as DEX-sensitive (n=15), or resistant (n=10). Real-time PCR analysis of GR 5'UTR mRNA isoforms showed that all HUVECs expressed isoforms 1B, 1C, 1D, 1F, and 1H, and isoforms 1B and 1C were predominantly expressed. DEX resistant cells expressed higher basal levels of the 5'UTR mRNA isoforms 1C and 1D, but lower levels of the 5'UTR mRNA isoform 1F than DEX-sensitive cells. DEX treatment significantly decreased GRalpha and GR-1C mRNA isoform expression in DEX-resistant cells only. Reporter luciferase assays indicated that differential GR mRNA isoform expression was not due to differential promoter usage between DEX sensitive and DEX-resistant cells. Analysis of promoter methylation, however, showed that DEX-sensitive cells have higher methylation levels of promoter 1D and lower methylation levels of promoter 1F than DEX-resistant cells. Treatment with 5-aza-2-deoxycytidine abolished the differential 5'UTR mRNA isoform expression between DEX-sensitive and DEX-resistant cells. Finally, both GRalpha overexpression and 5-aza-2-deoxycytidine treatment eliminated the differences between sensitivity groups to DEX-mediated downregulation of endothelial nitric oxide synthase (NOS3), and upregulation of plasminogen activator inhibitor 1 (SERPINE1). In sum, human endothelial GR 5'UTR mRNA expression is regulated by promoter methylation with DEX-sensitive and DEX-resistant cells having different GR promoter methylation patterns. PMID- 26242204 TI - CD7 aberrant expression led to a lineage switch at relapsed childhood acute pre-B lymphoblastic leukemia. AB - Immunophenotypic changes and lineage switch between diagnosis and relapse in acute lymphoblastic leukemia are uncommon and accompanied by poor outcomes. In this report, a 12-year-old boy with diagnosis of pre-B ALL with an aberrant expression of CD 7 is described. Patient was treated with the ALL-BFM 2000 protocol and suffered an episode of relapse with a lineage switch from pre-B ALL to T cell ALL. This report concludes that presence of aberrant expression of CD7 at diagnosis of pre-B ALL can have prognostic value of lineage switch to T cell ALL at relapse. PMID- 26242205 TI - [Nurses' perception, experience and knowledge of palliative care in intensive care units]. AB - BACKGROUND: Adequate provision of palliative care by nursing in intensive care units is essential to facilitate a "good death" to critically ill patients. OBJECTIVE: To determine the perceptions, experiences and knowledge of intensive care nurses in caring for terminal patients. METHODOLOGY: A literature review was conducted on the bases of Pubmed, Cinahl and PsicINFO data using as search terms: cuidados paliativos, UCI, percepciones, experiencias, conocimientos y enfermeria and their alternatives in English (palliative care, ICU, perceptions, experiences, knowledge and nursing), and combined with AND and OR Boolean. Also, 3 journals in intensive care were reviewed. RESULTS: Twenty seven articles for review were selected, most of them qualitative studies (n=16). After analysis of the literature it has been identified that even though nurses perceive the need to respect the dignity of the patient, to provide care aimed to comfort and to encourage the inclusion of the family in patient care, there is a lack of knowledge of the end of life care in intensive care units' nurses. CONCLUSION: This review reveals that to achieve quality care at the end of life, is necessary to encourage the training of nurses in palliative care and foster their emotional support, to conduct an effective multidisciplinary work and the inclusion of nurses in decision making. PMID- 26242207 TI - In reference to "Managing superutilizers--staying patient centered is the solution". PMID- 26242208 TI - A phase 1 clinical trial of sequential pralatrexate followed by a 48-hour infusion of 5-fluorouracil given every other week in adult patients with solid tumors. AB - BACKGROUND: Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5 FU). METHODS: Twenty-seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m(2) on day 1 followed 24 hours later by 5-FU at a dose of 3000 mg/m(2) /48 hours every 2 weeks with folic acid and vitamin B12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase. RESULTS: Mucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6%), dehydration (33.3%), fatigue (25.9%), and diarrhea (22.2%). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities The median progression-free survival (PFS) was 112 days (range, 28-588 days). Seven patients (26%) had a PFS of >180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non-small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity. CONCLUSIONS: The recommended dose of PDX was 148 mg/m(2) . A subset of heavily pretreated patients had PFS durations of >=6 months with this regimen. PMID- 26242209 TI - Calciphylaxis associated with acute renal failure in multicentric Castleman's disease. PMID- 26242210 TI - Marketplace Analysis of Conjugated Estrogens: Determining the Consistently Present Steroidal Content with LC-MS. AB - Conjugated estrogens purified from pregnant mares urine has been used as estrogen hormone replacement therapy since 1942. Previously, methods were proposed to identify and quantify the components of this complex mixture but ultimately were withdrawn due to incomplete characterization of the product and difficulties in transferring the method between laboratories. The aim of the current study is to develop a LC method that can reliably detect multiple steroidal components in conjugated estrogen tablets and measure their relative amount. The method developed was optimized for UHPLC columns, and the elution profile was analyzed using high-resolution mass spectrometry. A total of 60 steroidal components were identified using their exact m/z, product ion spectra of known, and predicted conjugated estrogen structures. These components were consistently present in 23 lots of Premarin tablets spanning two production years. The ten conjugated estrogens identified in the USP monograph and other additional estrogens reported elsewhere are among the 60 steroidal components reported here. The LC-MS method was tested in different laboratories using multiple samples, and the obtained results were reproducible among laboratories. PMID- 26242211 TI - Alcohol and the Heart: A Proteomics Analysis of Pericardium and Myocardium in a Swine Model of Myocardial Ischemia. AB - BACKGROUND: Previous studies have demonstrated that moderate alcohol consumption is cardioprotective and reduces postoperative pericardial adhesions; however, the mechanism is not fully understood. Using proteomic analysis, we sought to objectively investigate the effects of daily moderate alcohol consumption in the pericardium and myocardium in a swine model of chronic myocardial ischemia. METHODS: Fourteen swine underwent placement of an ameroid constrictor to induce chronic myocardial ischemia. Animals were supplemented with 90 mL of ethanol daily (ETOH) or 80 g of sucrose of equal caloric value (SUC). After 7 weeks, the ischemic myocardium and pericardium were harvested for proteomics analysis. RESULTS: Pericardial proteomics analysis yielded 397 proteins, of which 23 were unique to SUC and 52 were unique to ETOH. Of the 322 common proteins, 71 were statistically significant and 23 were characterized (p < 0.05). Alcohol supplementation increased structural proteins, and decreased immune protease inhibitors and coagulation proteins in the pericardium (p < 0.01). Myocardial proteomics analysis yielded 576 proteins, of which 32 were unique to SUC and 21 were unique to ETOH. Of the 523 common proteins, 85 were significant, and 32 were characterized (p < 0.05). Alcohol supplementation decreased cardiac remodeling proteins, cell death proteins and motor proteins, and increased metabolic proteins (p < 0.05). CONCLUSIONS: The results suggest that daily moderate alcohol consumption affects numerous pathways that contribute to cardioprotection, including cardiac remodeling, metabolism, and cell death. Our findings reveal the biosignature of myocardial and pericardial protein expression in the setting of chronic myocardial ischemia and daily moderate alcohol consumption. PMID- 26242212 TI - Clinical Analysis of Percutaneous Computed Tomography-Guided Hook Wire Localization of 168 Small Pulmonary Nodules. AB - BACKGROUND: The aim of this study was to evaluate the correlation of clinical and radiologic characteristics and pathologic features in small pulmonary nodules and to evaluate the success rate and safety of a computed tomography (CT)-guided hook wire system. METHODS: One hundred sixty-eight pulmonary nodules that were 20 mm or less in diameter in 161 patients were percutaneously localized by a CT-guided hook wire system, followed by pulmonary resection. The general clinical data, computed tomographic characteristics, and pathologic findings were evaluated, and the major side effects during the localization procedure were reviewed. RESULTS: Of the targeted nodules, 71 (42.3%) nodules were pure ground-glass opacities (GGOs), 59 (35.1%) nodules were partially solid GGOs, and 38 (22.6%) nodules were solid lesions. Pathologically, 49.3% of the pure GGOs were atypical adenomatous hyperplasia (AAH), 54.2% of the partially solid GGOs were lung cancer, and 65.8% of the solid nodules were benign lesions. Lung cancer tended to develop in older patients with larger nodule diameters. Subsolid nodules greater than 10 mm showed a statistically significant correlation with malignancy (p < 0.001). The hook wires were successfully placed in 164 (97.6%) nodules, and no serious complications occurred. CONCLUSIONS: In resected specimens with a CT-guided hook wire, pulmonary subsolid nodules tend to be AAH or lung cancer, whereas small solid nodules tend to be benign lesions. Pulmonary subsolid nodules larger than 10 mm are more frequently malignant. Preoperative localization of small pulmonary nodules with a hook wire system has a high success rate and acceptable utility. PMID- 26242213 TI - Outcomes in Nonagenarians Undergoing Transcatheter Aortic Valve Replacement in the PARTNER-I Trial. AB - BACKGROUND: This study describes short-term and mid-term outcomes of nonagenarian patients undergoing transfemoral or transapical transcatheter aortic valve replacement (TAVR) in the Placement of Aortic Transcatheter Valve (PARTNER)-I trial. METHODS: From April 2007 to February 2012, 531 nonagenarians, mean age 93 +/- 2.1 years, underwent TAVR with a balloon-expandable prosthesis in the PARTNER I trial: 329 through transfemoral (TF-TAVR) and 202 transapical (TA-TAVR) access. Clinical events were adjudicated and echocardiographic results analyzed in a core laboratory. Quality of life (QoL) data were obtained up to 1 year post-TAVR. Time varying all-cause mortality was referenced to that of an age-sex-race-matched US population. RESULTS: For TF-TAVR, post-procedure 30-day stroke risk was 3.6%; major adverse events occurred in 35% of patients; 30-day paravalvular leak was greater than moderate in 1.4%; median post-procedure length of stay (LOS) was 5 days. Thirty-day mortality was 4.0% and 3-year mortality 48% (44% for the matched population). By 6 months, most QoL measures had stabilized at a level considerably better than baseline, with Kansas City Cardiomyopathy Questionnaire (KCCQ) 72 +/- 21. For TA-TAVR, post-procedure 30-day stroke risk was 2.0%; major adverse events 32%; 30-day paravalvular leak was greater than moderate in 0.61%; and median post-procedure LOS was 8 days. Thirty-day mortality was 12% and 3-year mortality 54% (42% for the matched population); KCCQ was 73 +/- 23. CONCLUSIONS: A TAVR can be performed in nonagenarians with acceptable short- and mid-term outcomes. Although TF- and TA-TAVR outcomes are not directly comparable, TA-TAVR appears to carry a higher risk of early death without a difference in intermediate-term mortality. Age alone should not preclude referral for TAVR in nonagenarians. PMID- 26242214 TI - Ebola, Bats and Evidence-Based Policy : Informing Ebola Policy. PMID- 26242215 TI - Streptococcus pyogenes Infection in a Free-Living European Hedgehog (Erinaceus europaeus). AB - Streptococcus pyogenes, a common pathogen of humans, was isolated from the carcass of a free-living European hedgehog (Erinaceus europaeus) found in northern England in June 2014. The animal had abscessation of the deep right cervical lymph node, mesenteric lymph nodes and liver. The S. pyogenes strain isolated from the lesions, peritoneal and pleural cavities was characterised as emm 28, which can be associated with invasive disease in humans. This is the first known report of S. pyogenes in a hedgehog and in any free-living wild animal that has been confirmed by gene sequencing. As close associations between wild hedgehogs and people in England are common, we hypothesise that this case might have resulted from anthroponotic infection. PMID- 26242216 TI - The prognostic significance of anti-angiogenesis therapy in ovarian cancer: a meta-analysis. AB - OBJECTIVE: The prognostic value of anti-angiogenesis therapy in ovarian cancer patients is currently under debate. In this study, we assessed the effects of anti-angiogenesis therapy on the progression free survival (PFS) and overall survival (OS) of ovarian cancer patients. MATERIALS AND METHODS: PubMed was searched to identify relevant studies that evaluated the therapeutic value of anti-angiogenic agents in ovarian cancer (the final search was current to Dec. 13th 2014). Reviews of each study were conducted, and the data were extracted. The primary outcomes that were analysed were progression free survival (PFS) and overall survival (OS). The pooled hazard ratio (HR) and 95 % confidence intervals (CIs) were calculated using the random and fixed-effects models, and subgroup and sensitivity analyses were subsequently performed. RESULTS: A total of 12 studies were included in the meta-analysis. The overall analysis revealed that the incorporation of anti-angiogenesis therapy was significantly associated with a longer PFS (HR, 0.66; 95% CI, 0.58-0.75; P < 0.01) and a longer OS (HR, 0.89; 95% CI, 0.82-0.97; P = 0.01) in the total population, and these findings were confirmed by one-way sensitivity analyses. Further subgroup analyses demonstrated that the administrations of each of the agents were associated with improved PFSs. The prognostic value of anti-angiogenesis therapy for the OS was significant in the trebananib subgroup (HR, 0.81; 95% CI, 0.67-0.99; P = 0.04). The bevacizumab subgroup exhibited a similar trend that did not reach statistical significance (HR, 0.90; 95% CI, 0.80-1.01; P = 0.08). CONCLUSIONS: The present meta-analysis indicated that anti-angiogenesis therapy in ovarian cancer patients was associated with a better clinical outcome. Further studies are warranted to identify the specific subgroup of patients who are most likely to benefit from anti-angiogenesis therapy. PMID- 26242217 TI - A transcriptomal analysis of bovine oviductal epithelial cells collected during the follicular phase versus the luteal phase of the estrous cycle. AB - BACKGROUND: Reproductive success depends on a functional oviduct for gamete storage, maturation, fertilization, and early embryonic development. The ovarian derived steroids estrogen and progesterone are key regulators of oviductal function. The objective of this study was to investigate luteal and follicular phase-specific oviductal epithelial cell function by using microarray-based transcriptional profiling, to increase our understanding of mRNAs regulating epithelial cell processes, and to identify novel genes and biochemical pathways that may be found to affect fertility in the future. METHODS: Six normally cycling Angus heifers were assigned to either luteal phase (LP, n = 3) or follicular phase (FP, n = 3) treatment groups. Heifers in the LP group were killed between day 11 and 12 after estrus. Heifers in the FP group were treated with 25 mg PGF2alpha (Lutalyse, Pfizer, NY) at 8 pm on day 6 after estrus and killed 36 h later. Transcriptional profiling by microarray and confirmation of selected mRNAs by real-time RT-PCR analyses was performed using total RNA from epithelial cells isolated from sections of the ampulla and isthmus collected from LP and FP treatment groups. Differentially expressed genes were subjected to gene ontology classification and bioinformatic pathway analyses. RESULTS: Statistical one-way ANOVA using Benjamini-hochberg multiple testing correction for false discovery rate (FDR) and pairwise comparison of epithelial cells in the ampulla of FP versus LP groups revealed 972 and 597 transcripts up- and down-regulated, respectively (P < 0.05). Within epithelial cells of the isthmus in FP versus LP groups, 946 and 817 transcripts were up- and down-regulated, respectively (P < 0.05). Up-regulated genes from both ampulla and isthmus were found to be largely involved in cholesterol biosynthesis and cell cycle pathways, while down regulated genes were found in numerous inflammatory response pathways. CONCLUSIONS: Microarray-based transcriptional profiling revealed phase of the cycle-dependent changes in the expression of mRNA within the epithelium of the oviducts' ampulla and isthmus. PMID- 26242218 TI - 'On Your Feet to Earn Your Seat': update to randomised controlled trial protocol. AB - BACKGROUND: This update describes changes to procedures for our randomised controlled trial of 'On Your Feet to Earn Your Seat', a habit-based intervention to reduce sedentary behaviour in older adults. Some of the amendments have arisen from the addition of new sites, each offering different possibilities and constraints for study procedures. Others have been made in response to problems encountered in administering intended recruitment procedures at the London sites described in our original protocol. All changes have received ethics and governance clearance, and were made before or during data collection and prior to analyses. METHODS/DESIGN: Five non-London UK NHS-based sites (three general practices, one hospital, one NHS Foundation Trust) have been added to the study, each employing locally-tailored variations of recruitment and data collection procedures followed at the London sites. In contrast to the London sites, accelerometry data are not being collected nor are shopping vouchers being given to participants at the new sites. Data collection was delayed at the London sites because of technical difficulties in contacting participants. Subsequently, a below-target sample size was achieved at the London sites (n = 23), and recruitment rates cannot be estimated. Additionally, the physical inactivity inclusion criterion (i.e., <30 consecutive minutes of leisure time activity) has been removed from all sites, because we found that participants at the London sites meeting this criterion at consent subsequently reported activity above this threshold at the baseline assessment. CONCLUSION: This is primarily a feasibility trial. The addition of new sites, each employing different study procedures, offers the opportunity to assess the feasibility of alternative recruitment and data collection methods, so enriching the informational value of our analyses of primary outcomes. Recruitment has finished, and the coincidence of a small sample at the London sites with addition of new sites has ensured a final sample size similar to our original target. TRIAL REGISTRATION: Current Controlled Trials ISRCTN47901994 (registration date: 16th January 2014). PMID- 26242219 TI - Specialty Training's Organizational Readiness for curriculum Change (STORC): development of a questionnaire in a Delphi study. AB - BACKGROUND: In postgraduate medical education (PGME), programs have been restructured according to competency-based frameworks. The scale and implications of these adjustments justify a comprehensive implementation plan. Organizational Readiness for Change (ORC) is seen as a critical precursor for a successful implementation of change initiatives. Though, ORC in health care settings is mostly assessed in small scale settings and in relation to new policies and practices rather than educational change. Therefore our aim with this work was to develop an instrument to asses Specialty Training's Organizational Readiness for curriculum Change (STORC). METHODS: A Delphi procedure was conducted to examine the applicability of a preliminary questionnaire in PGME, which was based on existing instruments designed for business and health care organizations. The 41 panellists (19 trainees and 22 supervisors from 6 specialties) from four different countries who were confronted with an apparent curriculum change, or would be in the near future, were asked to rate the relevance of a 89-item web based questionnaire with regard to changes in specialty training on a 5-point Likert scale. Furthermore, they were invited to make qualitative comments on the items. RESULTS: In two rounds the 89-item preliminary questionnaire was reduced to 44 items. Items were either removed, kept, adapted or added based on individual item scores and qualitative comments. In the absence of a gold standard, this Delphi procedure was considered complete when the overall questionnaire rating exceeded 4.0 (scale 0-5). The overall item score reached 4.1 in the second round, meeting our criteria for completion of this Delphi procedure. CONCLUSIONS: This Delphi study describes the initial validating step in the development of an instrument to asses Specialty Training's Organisational Readiness for curriculum Change (STORC). Since ORC is measured on various subscales and presented as such, its strength lies in analysing these subscales. The latter makes it possible for educational leaders to identify and anticipate on hurdles in the implementation process and subsequently optimize efforts for successful curriculum change. PMID- 26242220 TI - Olaparib tablet formulation: effect of food on the pharmacokinetics after oral dosing in patients with advanced solid tumours. AB - BACKGROUND: The oral PARP inhibitor olaparib has shown efficacy in patients with BRCA-mutated cancer. This Phase I, open-label, three-part study (Parts A-C) in patients with advanced solid tumours evaluated the effect of food on the pharmacokinetics (PK) of olaparib when administered in tablet formulation. METHODS: PK data were obtained in Part A using a two-treatment period crossover design; single-dose olaparib 300 mg (two 150 mg tablets) was administered in two prandial states: fasted and fed. In Part B, patients received olaparib tablets (300 mg bid) for 5 days under fasting conditions; in Part C, patients were allowed continued access to olaparib. Safety was assessed throughout, with data reported for Parts A and B. RESULTS: A total of 60 and 56 patients were evaluable for safety and PK analyses, respectively; 57 patients entered Part B. Rate of olaparib absorption was slower in the presence of food (t max delayed by 2.5 h), resulting in a statistically significant ~21 % decrease in peak plasma exposure (C max) [ratio of geometric means (90 % CI), 0.79 (0.72, 0.86)] but only a marginal increase in olaparib absorption (AUC0-infinity) [ratio of geometric means (90 % CI), 1.08 (1.01, 1.16)]. The point estimate and 90 % CI for the AUC0 infinity treatment ratio were within pre-defined bioequivalence limits (0.80 1.25). Adverse event data were consistent with the known safety profile of olaparib. CONCLUSIONS: Results of this study showed that a high-fat meal decreases the rate of absorption and peak exposure to olaparib 300 mg tablets, although in the absence of an effect on the extent of olaparib absorption. PMID- 26242221 TI - Phase II study of first-line biweekly docetaxel and cisplatin combination chemotherapy in advanced gastric cancer. AB - PURPOSE: Previous studies have shown that docetaxel and cisplatin, as single agents, are effective and relatively well tolerated in patients with advanced gastric cancer. The aim of this study was to assess efficacy and toxicity of a biweekly regimen of docetaxel plus cisplatin in patients with advanced gastric cancer. PATIENTS/METHODS: Fifty-five patients with histologically proven advanced gastric cancer with at least 1 measurable lesion and ECOG PS <= 2 were enrolled. Patients received docetaxel 50 mg/m(2) and cisplatin 50 mg/m(2) every 2 weeks until progression disease, unbearable toxicity or a maximum of 12 cycles. RESULTS: In total, 426 cycles were administered (median 8.5 cycles) to 52 evaluable patients. One patient (1.9 %) showed a complete response, while 21 (40.4 %) had partial responses. The objective response rate was 42.3 % (95 % CI 28.9-55.7), the median time to progression was 5.5 months (95 % CI 4.0-7.0), and the median overall survival was 8.9 months (95 % CI 6.0-11.9). The most common grade 3-4 toxicities per cycle were haematological [neutropenia (5.9 %)]. CONCLUSIONS: Biweekly administration of docetaxel and cisplatin in advanced gastric cancer has a manageable toxicity profile and shows a promising antitumour activity as a first-line therapy. PMID- 26242222 TI - Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations. AB - PURPOSE: To describe concentration versus time profiles of capecitabine and its metabolites 5'-DFUR, 5'-DFCR and 5-FU, depending on tablet formulation and on frequent and/or relevant genetic polymorphisms of cytidine deaminase, dihydropyrimidine dehydrogenase, thymidylate synthase and methylenetetrahydrofolate reductase (MTHFR). METHODS: In 46 cancer patients on chronic capecitabine treatment, who voluntarily participated in the study, individual therapeutic doses were replaced on four consecutive mornings by the study medication. The appropriate number of 500 mg test (T) or reference (R) capecitabine tablets was given in randomly allocated sequences TRTR or RTRT (replicate design). Average bioavailability was assessed by ANOVA. RESULTS: Thirty female and 16 male patients suffering from gastrointestinal or breast cancer (mean age 53.4 years; mean dose 1739 mg) were included. The T/R ratios for AUC0-t(last) and C max were 96.7 % (98 % CI 90.7-103.2 %) and 87.2 % (98 % CI 74.9-101.5 %), respectively. Within-subject variability for AUC0-t(last) and C max (coefficient of variation for R) was 16.5 and 30.2 %, respectively. Similar results were seen for all metabolites. No serious adverse events occurred. For the MTHFR C677T (rs1801133) genotype, an increasing number of 677C alleles showed borderline correlation with an increasing elimination half-life of capecitabine (p = 0.043). CONCLUSIONS: The extent of absorption was similar for T and R, but the rate of absorption was slightly lower for T. While such differences are not considered as clinically relevant, formal bioequivalence criteria were missed. A possible, probably indirect role of the MTHFR genotype in pharmacokinetics of capecitabine and/or 5-FU should be investigated in further studies. PMID- 26242223 TI - Candida albicans is able to use M cells as a portal of entry across the intestinal barrier in vitro. AB - Candida albicans is the most frequent yeast responsible for systemic infections in humans. These infections mainly originate from the gastrointestinal tract where C. albicans can invade the gut epithelial barrier to gain access to the bloodstream. Along the gut, pathogens can use Microfold (M) cells as a portal of entry to cross the epithelial barrier. M cells are specialized cells mainly located in the follicule-associated epithelium of Peyer patches. In this study, we used scanning electron and fluorescence microscopy, adhesion and invasion assays and fungal mutants to investigate the interactions of C. albicans with M cells obtained in an established in vitro model whereby enterocyte-like Caco-2 cells co-cultured with the Raji B cell line undergo a phenotypic switch to morphologically and functionally resembling M cells. Our data demonstrate that C. albicans co-localizes with and invades preferentially M cells, providing evidence that the fungus can use M cells as a portal of entry into the intestinal barrier. In addition to active penetration, F-actin dependent endocytosis contributes to internalization of the fungus into M cells through a mechanism involving hypha associated invasins including Ssa1 and Als3. PMID- 26242224 TI - Letter to the Editor. PMID- 26242225 TI - The Economic Impact of Smoking and of Reducing Smoking Prevalence: Review of Evidence. AB - BACKGROUND: Tobacco smoking is the cause of many preventable diseases and premature deaths in the UK and around the world. It poses enormous health- and non-health-related costs to the affected individuals, employers, and the society at large. The World Health Organization (WHO) estimates that, globally, smoking causes over US$500 billion in economic damage each year. OBJECTIVES: This paper examines global and UK evidence on the economic impact of smoking prevalence and evaluates the effectiveness and cost effectiveness of smoking cessation measures. STUDY SELECTION: SEARCH METHODS We used two major health care/economic research databases, namely PubMed and the National Institute for Health Research (NIHR) database that contains the British National Health Service (NHS) Economic Evaluation Database; Cochrane Library of systematic reviews in health care and health policy; and other health-care-related bibliographic sources. We also performed hand searching of relevant articles, health reports, and white papers issued by government bodies, international health organizations, and health intervention campaign agencies. SELECTION CRITERIA The paper includes cost effectiveness studies from medical journals, health reports, and white papers published between 1992 and July 2014, but included only eight relevant studies before 1992. Most of the papers reviewed reported outcomes on smoking prevalence, as well as the direct and indirect costs of smoking and the costs and benefits of smoking cessation interventions. We excluded papers that merely described the effectiveness of an intervention without including economic or cost considerations. We also excluded papers that combine smoking cessation with the reduction in the risk of other diseases. DATA COLLECTION AND ANALYSIS The included studies were assessed against criteria indicated in the Cochrane Reviewers Handbook version 5.0.0. OUTCOMES ASSESSED IN THE REVIEWPrimary outcomes of the selected studies are smoking prevalence, direct and indirect costs of smoking, and the costs and benefits of smoking cessation interventions (eg, "cost per quitter", "cost per life year saved", "cost per quality-adjusted life year gained," "present value" or "net benefits" from smoking cessation, and "cost savings" from personal health care expenditure). MAIN RESULTS: The main findings of this study are as follows: The costs of smoking can be classified into direct, indirect, and intangible costs. About 15% of the aggregate health care expenditure in high-income countries can be attributed to smoking. In the US, the proportion of health care expenditure attributable to smoking ranges between 6% and 18% across different states. In the UK, the direct costs of smoking to the NHS have been estimated at between L2.7 billion and L5.2 billion, which is equivalent to around 5% of the total NHS budget each year. The economic burden of smoking estimated in terms of GDP reveals that smoking accounts for approximately 0.7% of China's GDP and approximately 1% of US GDP. As part of the indirect (non health-related) costs of smoking, the total productivity losses caused by smoking each year in the US have been estimated at US$151 billion.The costs of smoking notwithstanding, it produces some potential economic benefits. The economic activities generated from the production and consumption of tobacco provides economic stimulus. It also produces huge tax revenues for most governments, especially in high-income countries, as well as employment in the tobacco industry. Income from the tobacco industry accounts for up to 7.4% of centrally collected government revenue in China. Smoking also yields cost savings in pension payments from the premature death of smokers.Smoking cessation measures could range from pharmacological treatment interventions to policy-based measures, community-based interventions, telecoms, media, and technology (TMT) based interventions, school-based interventions, and workplace interventions.The cost per life year saved from the use of pharmacological treatment interventions ranged between US$128 and US$1,450 and up to US$4,400 per quality-adjusted life years (QALYs) saved. The use of pharmacotherapies such as varenicline, NRT, and Bupropion, when combined with GP counseling or other behavioral treatment interventions (such as proactive telephone counseling and Web-based delivery), is both clinically effective and cost effective to primary health care providers.Price-based policy measures such as increase in tobacco taxes are unarguably the most effective means of reducing the consumption of tobacco. A 10% tax-induced cigarette price increase anywhere in the world reduces smoking prevalence by between 4% and 8%. Net public benefits from tobacco tax, however, remain positive only when tax rates are between 42.9% and 91.1%. The cost effectiveness ratio of implementing non-price-based smoking cessation legislations (such as smoking restrictions in work places, public places, bans on tobacco advertisement, and raising the legal age of smokers) range from US$2 to US$112 per life year gained (LYG) while reducing smoking prevalence by up to 30% 82% in the long term (over a 50-year period).Smoking cessation classes are known to be most effective among community-based measures, as they could lead to a quit rate of up to 35%, but they usually incur higher costs than other measures such as self-help quit-smoking kits. On average, community pharmacist-based smoking cessation programs yield cost savings to the health system of between US$500 and US$614 per LYG.Advertising media, telecommunications, and other technology-based interventions (such as TV, radio, print, telephone, the Internet, PC, and other electronic media) usually have positive synergistic effects in reducing smoking prevalence especially when combined to deliver smoking cessation messages and counseling support. However, the outcomes on the cost effectiveness of TMT-based measures have been inconsistent, and this made it difficult to attribute results to specific media. The differences in reported cost effectiveness may be partly attributed to varying methodological approaches including varying parametric inputs, differences in national contexts, differences in advertising campaigns tested on different media, and disparate levels of resourcing between campaigns. Due to its universal reach and low implementation costs, online campaign appears to be substantially more cost effective than other media, though it may not be as effective in reducing smoking prevalence.School-based smoking prevalence programs tend to reduce short-term smoking prevalence by between 30% and 70%. Total intervention costs could range from US$16,400 to US$580,000 depending on the scale and scope of intervention. The cost effectiveness of school-based programs show that one could expect a saving of approximately between US$2,000 and US$20,000 per QALY saved due to averted smoking after 2-4 years of follow up.Workplace-based interventions could represent a sound economic investment to both employers and the society at large, achieving a benefit-cost ratio of up to 8.75 and generating 12-month employer cost savings of between $150 and $540 per nonsmoking employee. Implementing smoke-free workplaces would also produce myriads of new quitters and reduce the amount of cigarette consumption, leading to cost savings in direct medical costs to primary health care providers. Workplace interventions are, however, likely to yield far greater economic benefits over the long term, as reduced prevalence will lead to a healthier and more productive workforce. CONCLUSIONS: We conclude that the direct costs and externalities to society of smoking far outweigh any benefits that might be accruable at least when considered from the perspective of socially desirable outcomes (ie, in terms of a healthy population and a productive workforce). There are enormous differences in the application and economic measurement of smoking cessation measures across various types of interventions, methodologies, countries, economic settings, and health care systems, and these may have affected the comparability of the results of the studies reviewed. However, on the balance of probabilities, most of the cessation measures reviewed have not only proved effective but also cost effective in delivering the much desired cost savings and net gains to individuals and primary health care providers. PMID- 26242226 TI - The evolution in registration of clinical trials: a chronicle of the historical calls and current initiatives promoting transparency. AB - PURPOSE: Quality of care is strongly influenced by evidence-based medicine, a large part of which is based on results obtained from clinical trials. If trials are conducted in secret, patient safety is at risk. Several mandates-legal, editorial, financial, and ethical-have tried to influence the disclosure of clinical trials, first by encouraging registration in publicly accessible registers and, second, by calling for the publication of results. Not all these initiatives have reached high rates of compliance, but the succession of national and international events over a few years gave an important boost to information disclosure. This article provides a chronicle of the succession of the events, from the historical calls to the recent EMA policy and WHO statement, and public consultations requested by the NIH, and the HHS, which will inevitably change the international panorama. The path of these new policies is moving towards more supervised clinical research. Individual scientific institutions can also contribute, at the local level, to such an ethical endeavor as is improving research transparency, by disclosing information on the trials coordinated by their own researchers. RESULTS: The way is long and complex, but, if everyone contributes there could be a prompt, worldwide diffusion of the findings of clinical trials, and therefore a more possible evidenced-based medicine. PMID- 26242228 TI - The Dermatological Manifestations of Postural Tachycardia Syndrome: A Review with Illustrated Cases. AB - Postural tachycardia syndrome (POTS) is a syndrome of excessive tachycardia with orthostatic challenge, and relief of such symptoms with recumbence. There are several proposed subtypes of the syndrome, each with unique pathophysiology. Numerous symptoms such as excessive tachycardia, lightheadedness, blurry vision, weakness, fatigue, palpitations, chest pain, and tremulousness are associated with orthostatic intolerance. Other co-morbid conditions associated with POTS are not clearly attributable to orthostatic intolerance. These include chronic headache, fibromyalgia, functional gastrointestinal or bladder disorders, cognitive impairment, and sleep disturbances. Dermatological manifestations of POTS are also common and wide ranging, from livedo reticularis to Raynaud's phenomenon, from cutaneous flushing to erythromelalgia. Here, we provide three illustrative cases of POTS with dermatological manifestations. We discuss the potential pathophysiology underlying such dermatological manifestations, and how such mechanisms could in turn help guide development of management. PMID- 26242227 TI - Acute vasodilator response to vardenafil and clinical outcome in patients with pulmonary hypertension. AB - PURPOSE: Acute vasodilator testing is recommended in patients with pulmonary arterial hypertension to identify individuals who may benefit from long-term treatment with oral calcium channel blockers. The aim of this study was to investigate the use of vardenafil in acute vasoreactivity testing compared to adenosine. METHODS: A total of 20 patients eligible for right heart catheterisation were enrolled. Acute vasoreactivity testing was carried out with intravenous (iv) adenosine (n = 18) followed by oral vardenafil (n = 20). Haemodynamic responses were recorded at baseline and after 60 min (vardenafil). Responders were defined according to consensus guideline criteria. RESULTS: Both vardenafil and adenosine significantly decreased mean pulmonary arterial pressure (mPAP, p < 0.001 and p = 0.026, respectively) and pulmonary vascular resistance (p < 0.001 and p > 0.001, respectively), and significantly increased cardiac output (p = 0.001 and p = 0.005, respectively). Vardenafil reduced mPAP more than adenosine (p = 0.044), while adenosine resulted in higher responses of cardiac index (p = 0.009) and pulmonary arterial oxygen saturation (p = 0.042). Acute adverse reactions were common with adenosine, while no side effects were observed after a single oral dose vardenafil. Vardenafil identified five responders (out of 20), while adenosine identified three responders (out of 18). During a 7-year follow-up, vardenafil responders had significantly lower NT-proBNP levels compared to non-responders. CONCLUSIONS: Vardenafil may be safely used for acute vasoreactivity testing in patients with PH. A single oral dose of vardenafil is better tolerated than iv adenosine and may identify additional responders who could benefit from long-term vasodilator treatment. PMID- 26242229 TI - Investigation of the Association of the Second-to-Fourth Digit Ratio with Skin Sebum Levels in Females with Acne Vulgaris. AB - BACKGROUND: A relationship between acne vulgaris (AV) and the masculinized (lower) second-to-fourth digit (2D:4D) ratio in females was demonstrated in our previous study. Development of the digits and the sebaceous glands both occur during the same gestational period; therefore, the association between the 2D:4D ratios and AV may result from the effects of the prenatal endocrine environment on the sebaceous glands. OBJECTIVE: The aim of this study was to evaluate the relationship between the 2D:4D ratio and sebum levels in the skin of females with AV. METHODS: In total, 215 female AV patients and 92 healthy controls, aged 18-35 years, were enrolled in this study. Finger-length measurements were made using a digital Vernier caliper, and the sebum levels of five facial areas were measured using a Sebumeter SM 815. Acne severity was assessed using the International Consensus Conference on Acne Classification System. RESULTS: The 2D:4D ratios of the AV patients were significantly lower than those of the controls, for both hands. The mean sebum levels in the T-zone, U-zone and whole face were significantly higher for AV patients compared with controls. The 2D:4D ratio in the left hand showed significant negative correlations with the sebum levels in the U-zone; however, no association was found between the 2D:4D ratios and sebum levels in the T-zone and whole face. While acne severity was positively correlated with skin sebum levels, no correlation between acne severity and 2D:4D ratios was observed. CONCLUSION: This study provides preliminary evidence regarding the association between lower 2D:4D ratios and higher rates of sebum secretion in the U-zone for females with AV. The 2D:4D ratio might be a predictor of sebum levels, as well as acne development, in females. PMID- 26242230 TI - Granular Parakeratosis: A Comprehensive Review and a Critical Reappraisal. AB - Granular parakeratosis (GP) is a rare, idiopathic, and benign skin condition that presents classically as erythematous to brown hyperkeratotic papules that can coalesce into plaques. Axillary GP was initially observed by Northcutt and colleagues and has since been described in various other areas of the body including other intertriginous and non-intertriginous sites. The term "granular parakeratosis" is now used to describe not only the skin condition, but also a distinctive histological reactive pattern on biopsy specimens that are either regarded as the disease itself, or merely as an incidental finding. Upon review of the current findings, opinions, and associations of this entity, we propose the reappraisal of GP as a reactive pattern, rather than a distinct entity. PMID- 26242231 TI - Adolescent idiopathic scoliosis without limb weakness: a differential diagnosis of core myopathy? AB - BACKGROUND: Core myopathies are a clinically and genetically heterogeneous group of congenital myopathies with the common defined histopathological feature of focally reduced oxidative activity on muscle biopsy. It has a low incidence, however, recent articles show broad clinical spectrum, suggesting that the real incidence should be considerably larger than previously described. Due to the important association between scoliosis and paravertebral muscle imbalance, numerous authors study, by biopsy of the spinal rotator muscles, potential changes that may elucidate the etiology of adolescent idiopathic scoliosis. CASE PRESENTATION: Two patients have been followed at Spine Group of Department of Orthopedics at Federal University of Sao Paulo, with an initial diagnosis of idiopathic scoliosis. Both patients had clinical and radiological findings compatible with it. The patients authorized, through the Term of Consent, intraoperative biopsy of muscle multifidus from the apex of the thoracic curve on concave and convex sides. After muscle biopsy was performed a histopathological analysis. As regard to the histopathological features: in both patients were identified, the presence of core structures in extensive areas with reduced oxidative activity running along the muscle fiber. CONCLUSIONS: All patients with 'idiopathic' scoliosis deserve a careful neurological evaluation, even if they have minimal muscle symptoms in the extremities. The frequent occurrence of scoliosis in patients with CORE Myopathies, supports the thesis that the change in the paravertebral muscle fiber must be the underlying pathogenic factor in scoliosis and may help us understand the onset and progression of curves in patients previously diagnosed with idiopathic scoliosis. PMID- 26242232 TI - Trajectories of length, weight, and bone mineral density among preterm infants during the first 12 months of corrected age in China. AB - BACKGROUND: Limited evidence has been provided on the trajectories of length, weight, and bone mineral density (BMD) among preterm infants in early life in Asian countries. METHODS: We conducted a longitudinal study, which included 652 late preterm (gestational age: 34-36.9 weeks), 486 moderate preterm (32-33.9), 291 very preterm (28-31.9), 149 extremely preterm infants (<= 28.9) and 1434 full term peers (>= 37) during the first 12 months of corrected age in Wuhan, China. Weight and length were measured at birth, once randomly before term, and every month thereafter. BMD was examined at 3, 6, 9 and 12 months using dual-energy X ray absorptiometry. RESULTS: From birth to 12 months of corrected age, growth peaks in length and weight were observed at 1-3 months among preterm infants. No catch-up growth in length, weight, and BMD was observed among preterm infants. However, accelerated growth in length, weight, and BMD was found. Among extremely preterm infants, relative to full-term infants, length was -6.77 cm (95% CI: 7.14, -6.40; P for trend < 0.001) lower during the first 12 months; weight was 1.23 kg (-1.33, -1.13; P for trend < 0.001) lower; and BMD was -0.070 g/cm(2)( 0.087, -0.053; P for trend < 0.001) lower; however, average growth rates of these measures were higher (Ps < 0.05). Small gestational age and low birth weight were independently associated with lower length, weight, and BMD. CONCLUSION: Growth peaks in length and weight among preterm infants were observed at 1-3 months. No catch-up growth in length, weight, and BMD was observed, however, there was accelerated growth in length, weight, and BMD. PMID- 26242233 TI - Accuracy of pleth variability index to predict fluid responsiveness in mechanically ventilated patients: a systematic review and meta-analysis. AB - To systemically evaluate the accuracy of pleth variability index to predict fluid responsiveness in mechanically ventilated patients. A literature search of PUBMED, OVID, CBM, CNKI and Wanfang Data for clinical studies in which the accuracy of pleth variability index to predict fluid responsiveness was performed (last update 5 April 2015). Related journals were also searched manually. Two reviewers independently assessed trial quality according to the modified QUADAS items. Heterogeneous studies and meta-analysis were conducted by Meta-Disc 1.4 software. A subgroup analysis in the operating room (OR) and in intensive care unit (ICU) was also performed. Differences between subgroups were analyzed using the interaction test. A total of 18 studies involving 665 subjects were included. The pooled area under the receiver operating characteristic curve (AUC) to predict fluid responsiveness in mechanically ventilated patients was 0.88 [95 % confidence interval (CI) 0.84-0.91]. The pooled sensitivity and specificity were 0.73 (95 % CI 0.68-0.78) and 0.82 (95 % CI 0.77-0.86), respectively. No heterogeneity was found within studies nor between studies. And there was no significant heterogeneity within each subgroup. No statistical differences were found between OR subgroup and ICU subgroup in the AUC [0.89 (95 % CI 0.85-0.92) versus 0.90 (95 % CI 0.82-0.94); P = 0.97], and in the specificity [0.84 (95 % CI 0.75-0.86) vs. 0.84 (95 % CI 0.75-0.91); P = 1.00]. Sensitivity was higher in the OR subgroup than the ICU subgroup [0.84 (95 % CI 0.78-0.88) vs. 0.56 (95 % CI 0.47-0.64); P = 0.00004]. The pleth variability index has a reasonable ability to predict fluid responsiveness. PMID- 26242234 TI - Helping Callers to the National Suicide Prevention Lifeline Who Are at Imminent Risk of Suicide: Evaluation of Caller Risk Profiles and Interventions Implemented. AB - Crisis lines are settings where identifying individuals at imminent risk of suicidal behavior and intervening to keep them safe are critical activities. We examined clinical characteristics of crisis callers assessed by telephone crisis helpers as being at imminent risk of suicide, and the interventions implemented with these callers. Data were derived from 491 call reports completed by 132 helpers at eight crisis centers in the National Suicide Prevention Lifeline network. Helpers actively engaged the callers in collaborating to keep themselves safe on 76.4% of calls and sent emergency services without the callers' collaboration on 24.6% of calls. Four different profiles of imminent risk calls emerged. Caller profiles and some helper characteristics were associated with intervention type. Our findings provide a first step toward an empirical formulation of imminent risk warning signs and recommended interventions. PMID- 26242236 TI - The interacting effects of food, spring temperature, and global climate cycles on population dynamics of a migratory songbird. AB - Although long-distance migratory songbirds are widely believed to be at risk from warming temperature trends, species capable of attempting more than one brood in a breeding season could benefit from extended breeding seasons in warmer springs. To evaluate local and global factors affecting population dynamics of the black throated blue warbler (Setophaga caerulescens), a double-brooded long-distance migrant, we used Pradel models to analyze 25 years of mark-recapture data collected in New Hampshire, USA. We assessed the effects of spring temperature (local weather) and the El Nino Southern Oscillation index (a global climate cycle), as well as predator abundance, insect biomass, and local conspecific density on population growth in the subsequent year. Local and global climatic conditions affected warbler populations in different ways. We found that warbler population growth was lower following El Nino years (which have been linked to poor survival in the wintering grounds and low fledging weights in the breeding grounds) than La Nina years. At a local scale, populations increased following years with warm springs and abundant late-season food, but were unaffected by spring temperature following years when food was scarce. These results indicate that the warming temperature trends might have a positive effect on recruitment and population growth of black-throated blue warblers if food abundance is sustained in breeding areas. In contrast, potential intensification of future El Nino events could negatively impact vital rates and populations of this species. PMID- 26242237 TI - Canine DNA Profiling in Forensic Casework: The Tail Wagging the Dog. AB - The popularity of dogs as faithful human companions instigates forensically relevant issues on a regular basis. Domestic dogs take an active role as the causes of accidents and as perpetrators of attacks; even more frequently, dogs act as links between victims and suspects in crime cases due to the fact that dog owners/keepers live in an environment rich with canine material. Mitochondrial and nuclear DNA analyses of canine cells have been applied successfully in individual cases. However, a review of published casework amply demonstrates great interlaboratory variability not only in methodological but also in general terms. We screened the literature for application of canine DNA analysis in the forensic context and found 12 publications presented by 10 different laboratories. In almost no case did employed DNA markers widely overlap between these studies. Even worse is the situation with respect to allele nomenclature, where a plethora of variants has been reported by the different groups. Despite great technological achievements in the recent past, it seems that in forensic canine DNA analysis the cart was put before the horse. The canine forensic field faces the urgent need for general standardization and harmonization activities such as those that have taken place in the human forensic field in the past years. In particular, the nature and selection of DNA markers to be tested, the implementation of a generally compatible allele nomenclature, and a settlement on standardized statistical calculation methods adopted for the specific genetic peculiarities of dog populations need thorough consideration. PMID- 26242238 TI - Forensic Botany: Evidence and Analysis. AB - Forensic botany is the use of plant evidence in matters of law. While plant fragments are often collected as trace evidence, they are only occasionally identified using microscopy and are still more rarely assessed using molecular biology techniques for individualization and sourcing of a sample. There are many different methods useful for DNA typing of plants; this review focuses on those techniques (DNA sequencing, STR, AFLP, RAPD) most relevant to the forensic science community and on those methods currently in practice. Plant evidence is commonly associated with homicides, with clandestine graves, as trace pollen on clothing, vehicles, or packaging, or in the transport of illicit drugs. DNA can be especially useful for the identification of minute quantity of samples, for differentiation of plants that lack distinguishing morphological features, and for generating a unique identifier for associative forensic evidence. PMID- 26242235 TI - MuRF2 regulates PPARgamma1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet. AB - BACKGROUND: In diabetes mellitus the morbidity and mortality of cardiovascular disease is increased and represents an important independent mechanism by which heart disease is exacerbated. The pathogenesis of diabetic cardiomyopathy involves the enhanced activation of PPAR transcription factors, including PPARalpha, and to a lesser degree PPARbeta and PPARgamma1. How these transcription factors are regulated in the heart is largely unknown. Recent studies have described post-translational ubiquitination of PPARs as ways in which PPAR activity is inhibited in cancer. However, specific mechanisms in the heart have not previously been described. Recent studies have implicated the muscle-specific ubiquitin ligase muscle ring finger-2 (MuRF2) in inhibiting the nuclear transcription factor SRF. Initial studies of MuRF2-/- hearts revealed enhanced PPAR activity, leading to the hypothesis that MuRF2 regulates PPAR activity by post-translational ubiquitination. METHODS: MuRF2-/- mice were challenged with a 26-week 60% fat diet designed to simulate obesity-mediated insulin resistance and diabetic cardiomyopathy. Mice were followed by conscious echocardiography, blood glucose, tissue triglyceride, glycogen levels, immunoblot analysis of intracellular signaling, heart and skeletal muscle morphometrics, and PPARalpha, PPARbeta, and PPARgamma1-regulated mRNA expression. RESULTS: MuRF2 protein levels increase ~20% during the development of diabetic cardiomyopathy induced by high fat diet. Compared to littermate wildtype hearts, MuRF2-/- hearts exhibit an exaggerated diabetic cardiomyopathy, characterized by an early onset systolic dysfunction, larger left ventricular mass, and higher heart weight. MuRF2-/- hearts had significantly increased PPARalpha- and PPARgamma1-regulated gene expression by RT-qPCR, consistent with MuRF2's regulation of these transcription factors in vivo. Mechanistically, MuRF2 mono-ubiquitinated PPARalpha and PPARgamma1 in vitro, consistent with its non-degradatory role in diabetic cardiomyopathy. However, increasing MuRF2:PPARgamma1 (>5:1) beyond physiological levels drove poly-ubiquitin-mediated degradation of PPARgamma1 in vitro, indicating large MuRF2 increases may lead to PPAR degradation if found in other disease states. CONCLUSIONS: Mutations in MuRF2 have been described to contribute to the severity of familial hypertrophic cardiomyopathy. The present study suggests that the lack of MuRF2, as found in these patients, can result in an exaggerated diabetic cardiomyopathy. These studies also identify MuRF2 as the first ubiquitin ligase to regulate cardiac PPARalpha and PPARgamma1 activities in vivo via post-translational modification without degradation. PMID- 26242239 TI - Mass Spectrometry in Microbial Forensics. AB - Mass spectrometry (MS) has become a powerful tool to identify microbial biomarkers. Rapid and reliable identification of microorganisms by MS without extensive sample pretreatment is now possible. An effective microbial forensics program requires accurate characterization of pathogens to indicate their presence. MS methods provide such capabilities for forensic analysis. MS methods currently utilized for microbial analyses are reviewed. Techniques including capillary electrophoresis, liquid chromatography, gas chromatography, and pyrolysis that are coupled to MS analysis are described. A brief introduction to the two advanced ionization techniques, electrospray ionization and matrix assisted laser desorption/ionization, for MS is provided in this review. Methods based on characterization of biomarkers including proteins, DNA molecules, lipids, and other small molecules are reviewed. PMID- 26242240 TI - Clinical and microbiological characteristics of purulent and non-purulent cellulitis in hospitalized Taiwanese adults in the era of community-associated methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: The risk factors, microbial etiology, differentiation, and clinical features of purulent and non-purulent cellulitis are not well defined in Taiwan. METHODS: We conducted a retrospective cohort study of hospitalized adults with cellulitis in Taiwan in 2013. The demographic characteristics, underlying diseases, clinical manifestations, laboratory and microbiological findings, treatments, and outcomes were compared for patients with purulent and non purulent cellulitis. RESULTS: Of the 465 patients, 369 had non-purulent cellulitis and 96 had purulent cellulitis. The non-purulent group was significantly older (p = 0.001) and was more likely to have lower limb involvement (p < 0.001), tinea pedis (p = 0.003), stasis dermatitis (p = 0.025), a higher Charlson comorbidity score (p = 0.03), and recurrence at 6 months post infection (p = 0.001) than the purulent group. The purulent group was more likely to have a wound (p < 0.001) and a longer hospital stay (p = 0.001) and duration of antimicrobial therapy (p = 0.003) than the non-purulent group. The etiological agent was identified in 35.5 % of the non-purulent cases, with beta-hemolytic streptococci the most frequent cause (70.2 %). The etiological agent was identified in 83.3 % of the purulent cases, with Staphylococcus aureus the predominant pathogen (60 %): 50 % of these were methicillin-resistant S. aureus (MRSA). In multivariable analysis, purulent group (odds ratio (OR), 5.188; 95 % confidence interval (CI), 1.995-13.493; p = 0.001) was a positive predictor of MRSA. The prescribed antimicrobial agents were significantly different between the purulent and non-purulent groups, with penicillin the most frequently used antimicrobial agent in the non-purulent group (35.2 %), and oxacillin the most frequent in the purulent group (39.6 %). The appropriate antimicrobial agent was more frequently prescribed in the non-purulent group than in the purulent group (83.2 % vs. 53.8 %, p < 0.001). CONCLUSIONS: The epidemiology, clinical features, and microbiology of purulent and non-purulent cellulitis were significantly different in hospitalized Taiwanese adults. Purulence was a positive predictor of MRSA as the causal agent of cellulitis. These findings provide added support for the adoption of the IDSA guidelines for empirical antimicrobial therapy of cellulitis in Taiwan. PMID- 26242241 TI - Synthesis, biological evaluation and molecular modeling of new tetrahydroacridine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease. AB - A novel series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with 4 dimethylaminobenzoic acid moiety was synthesized and tested towards inhibition of cholinesterases and amyloid beta aggregation. Target compounds were designed as dual binding site cholinesterase inhibitors able to bind to both the catalytic and the peripheral site of the enzyme and therefore potentially endowed with other properties. The obtained derivatives were very potent inhibitors of both cholinesterases (EeAChE, EqBChE) with IC50 values ranging from sub-nanomolar to nanomolar range, and the inhibitory potency of the most promising agents was higher than that of the reference drugs (rivastigmine and tacrine). The kinetic studies of the most active compound 3a revealed competitive type of AChE inhibition. Moreover, all target compounds were more potent inhibitors of human AChE than tacrine with the most active compound 3b (IC50 = 19 nM). Compound 3a was also tested and displayed inhibitory potency against AChE-induced Abeta 1-42 aggregation (80.6% and 91.3% at 50 MUM and 100 MUM screening concentration, respectively). Moreover, cytotoxicity assay performed on A549 cells did not indicate toxicity of this agent. Compound 3a is a promising candidate for further development of novel multi-functional agents in the therapy of AD. PMID- 26242242 TI - Optimization of N-aryl-6-methoxy-1,2,3,4-tetrahydroquinolines as tubulin polymerization inhibitors. AB - Thirteen new N-aryl 1,2,3,4-tetrahydroquinoline compounds (4a-f, 6a-c, and 8a-d) were synthesized and evaluated for antitumor activity and drug-like properties. Compound 4a exhibited high inhibitory potency with low nanomolar GI50 values of 16-20 nM in cellular assays, including excellent activity against the P glycoprotein overexpressing cell line KBvin. Compound 4a inhibited colchicine binding to tubulin and tubulin assembly with an IC50 value of 0.85 MUM, superior to the reference compound CA4 (1.2 MUM) in the same assay. In addition, 4a also exhibited highly improved water solubility (75 MUg/mL) and a suitable logP value (3.43) at pH 7.4. With a good balance between antitumor potency and drug-like properties, compound 4a could be a new potential drug candidate for further development. Current results on SAR studies and molecular modeling provided more insight about this class of compounds as tubulin polymerization inhibitors targeting the colchicine site. PMID- 26242243 TI - Submicroscopic carriage of Plasmodium falciparum and Plasmodium vivax in a low endemic area in Ethiopia where no parasitaemia was detected by microscopy or rapid diagnostic test. AB - BACKGROUND: Motivated by the success in malaria control that was documented over the last decade Ethiopia is aiming at malaria elimination by 2020 in selected districts. It is currently unknown if asymptomatic, submicroscopic malaria parasite carriage may form a hurdle to achieve elimination. The elimination effort may further be complicated by possible glucose-6 phosphate dehydrogenase (G6PD) deficiency which would hinder the use of 8-aminoquinolines in the elimination efforts. METHOD: In February 2014 a community-based cross-sectional survey was conducted in Malo, southwest Ethiopia. Finger-prick blood samples (n = 555) were tested for presence of Plasmodium falciparum and Plasmodium vivax with microscopy, rapid diagnostic test (RDT), and nested polymerase chain reaction (nPCR). Multiplicity of P. falciparum infections was determined based on genotyping the polymorphic merozoite surface protein-2 (MSP-2) gene. Individuals were also genotyped for mutations in the gene that produces G6PD. RESULTS: All study participants were malaria infection negative by microscopy and RDT. Nested PCR revealed P. falciparum mono-infection in 5.2% (29/555), P. vivax mono infection in 4.3% (24/555) and mixed infection in 0.2% (1/555) of individuals. All parasitemic individuals were afebrile (axillary temperature <37.5 degrees C). None of the study participants carried mutations for the G6PD African A-(202GA) and Mediterranean (563CT) variants. All infections, except one, were single-clone infection by MSP-2 genotyping. CONCLUSION: The detection of a substantial number of subpatent malaria infections in an apparently asymptomatic population without evidence for malaria transmission by conventional diagnostics raises questions about the path to malaria elimination. It is currently unknown how important these infections are for sustaining malaria transmission in the study sites. The absence of G6PD deficiency indicates that 8-aminoquinolines may be safely deployed to accelerate elimination initiatives. PMID- 26242244 TI - Association of chromosome 5q21.3 polymorphisms with the exploratory eye movement dysfunction in schizophrenia. AB - Schizophrenia patients show abnormalities in many eye movement tasks. Among them, exploratory eye movements (EEM) dysfunction seems to be specific to schizophrenia. However the mechanism of EEM disturbances in schizophrenia patients remains elusive. We investigate the relationship between EEM and single nucleotide polymorphisms (SNPs) or genes to identify susceptibility loci for EEM in schizophrenia. We firstly performed EEM test, then performed a genome-wide association study (GWAS) and gene-based association study of EEM in 128 individuals with schizophrenia and 143 healthy control subjects. Comparing to healthy controls, schizophrenia patients show significant decrease in NEF (22.99 +/- 3.96 vs. 26.02 +/- 5.72, P <0.001), TESL (368.78 +/- 123.57 vs. 603.12 +/- 178.63, P <0.001), MESL (16.86 +/- 5.27 vs. 24.42 +/- 6.46, P <0.001), RSS (8.22 +/- 1.56 vs. 10.92 +/- 1.09, P <0.001), and CSS (5.06 +/- 0.97 vs. 6.64 +/- 0.87, P <0.001). Five SNPs of the MAN2A1, at 5q21.3, were associated with EEM abnormalities (deceased CSS) and satisfied the criteria of GWAS significance threshold. One is localized near 5'-UTR (rs17450784) and four are in intron (rs1438663, rs17162094, rs6877440 and rs10067856) of the gene. Our findings suggest that the identified loci may control the schizophrenia-related quantitative EEM trait. And the identified gene, associated with the EEM phenotype, may lead to new insights into the etiology of schizophrenia. PMID- 26242245 TI - Rutin inhibits amylin-induced neurocytotoxicity and oxidative stress. AB - Recent evidence showed that amylin deposition is not only found in the pancreas in type 2 diabetes mellitus (T2DM) patients, but also in other peripheral organs, such as kidneys, heart and brain. Circulating amylin oligomers that cross the blood-brain barrier and accumulate in the brain may be an important contributor to diabetic cerebral injury and neurodegeneration. Moreover, increasing epidemiological studies indicate that there is a significant association between T2DM and Alzheimer's disease (AD). Amylin and beta-amyloid (Abeta) may share common pathophysiology and show strikingly similar neurotoxicity profiles in the brain. To explore the potential effects of rutin on AD, we here investigated the effect of rutin on amylin aggregation by thioflavin T dyeing, evaluated the effect of rutin on amylin-induced neurocytotoxicity by the MTT assay, and assessed oxidative stress, as well as the generation of nitric oxide (NO) and pro inflammatory cytokines in neuronal cells. Our results showed that the flavonoid antioxidant rutin inhibited amylin-induced neurocytotoxicity, decreased the production of reactive oxygen species (ROS), NO, glutathione disulfide (GSSG), malondialdehyde (MDA) and pro-inflammatory cytokines TNF-alpha and IL-1beta, attenuated mitochondrial damage and increased the GSH/GSSG ratio. These protective effects of rutin may have resulted from its ability to inhibit amylin aggregation, enhance the antioxidant enzyme activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and reduce inducible nitric oxide synthase (iNOS) activity. These in vitro results indicate that rutin is a promising natural product for protecting neuronal cells from amylin-induced neurotoxicity and oxidative stress, and rutin administration could be a feasible therapeutic strategy for preventing AD development and protecting the aging brain or slowing neurodegenerative processes. PMID- 26242246 TI - Social Eavesdropping in Zebrafish: Tuning of Attention to Social Interactions. AB - Group living animals may eavesdrop on signalling interactions between conspecifics in order to collect adaptively relevant information obtained from others, without incurring in the costs of first-hand information acquisition. This ability (aka social eavesdropping) is expected to impact Darwinian fitness, and hence predicts the evolution of cognitive processes that enable social animals to use public information available in the environment. These adaptive specializations in cognition may have evolved both at the level of learning and memory mechanisms, and at the level of input mechanisms, such as attention, which select the information that is available for learning. Here we used zebrafish to test if attention in a social species is tuned to the exchange of information between conspecifics. Our results show that zebrafish are more attentive towards interacting (i.e. fighting) than towards non-interacting pairs of conspecifics, with the exposure to fighting not increasing activity or stress levels. Moreover, using video playbacks to manipulate form features of the fighting fish, we show that during the assessment phase of the fight, bystanders' attention is more driven by form features of the interacting opponents; whereas during the post resolution phase, it is driven by biological movement features of the dominant fish chasing the subordinate fish. PMID- 26242247 TI - DNA-Microarray-based Genotyping of Clostridium difficile. AB - BACKGROUND: Clostridium difficile can cause antibiotic-associated diarrhea and a possibility of outbreaks in hospital settings warrants molecular typing. A microarray was designed that included toxin genes (tcdA/B, cdtA/B), genes related to antimicrobial resistance, the slpA gene and additional variable genes. RESULTS: DNA of six reference strains and 234 clinical isolates from South Western and Eastern Germany was subjected to linear amplification and labeling with dUTP-linked biotin. Amplicons were hybridized to microarrays providing information on the presence of target genes and on their alleles. Tested isolates were assigned to 37 distinct profiles that clustered mainly according to MLST defined clades. Three additional profiles were predicted from published genome sequences, although they were not found experimentally. CONCLUSIONS: The microarray based assay allows rapid and high-throughput genotyping of clinical C. difficile isolates including toxin gene detection and strain assignment. Overall hybridization profiles correlated with MLST-derived clades. PMID- 26242248 TI - Screening and Identification of Inhibitors of Trypanosoma brucei Cathepsin L with Antitrypanosomal Activity. AB - Current treatment options for human African trypanosomiasis (HAT) are ineffective, and they have several well-known clinical limitations. In our continued efforts to identify chemotypes that can be developed into clinically useful drugs, we screened a targeted compound library against the major cathepsin L (rhodesain) in T. brucei. We report the antirhodesain activity and antitrypanosomal activity of the compounds in this letter. The identified compounds can serve as starting points for structure- and/or phenotype-based lead optimization strategy against Trypanosoma brucei. PMID- 26242249 TI - An EQ-5D-5L value set based on Uruguayan population preferences. AB - PURPOSE: To derive a value set from Uruguayan general population using the EQ-5D 5L questionnaire and report population norms. METHODS: General population individuals were randomly assigned to value 10 health states using composite time trade off and 7 pairs of health states through discrete choice experiments. A stratified sampling with quotas by location, gender, age and socio-economic status was used to respect the Uruguayan population structure. Trained interviewers conducted face-to-face interviews. The EuroQol valuation technology was used to administer the protocol as well as to collect the data. OLS and maximum likelihood robust regression models with or without interactions were tested. RESULTS: We included 794 respondents between 20 and 83 years. Their characteristics were broadly similar to the Uruguayan population. The main effects robust model was chosen to derive social values. Values ranged from 0.264 to 1. States with a misery index = 6 had a mean predicted value of 0.965. When comparing the Uruguayan population with the Argentinian EQ-5D-5L crosswalk value set, the prediction for states which differed from full health only in having one of the dimensions at level 2 were about 0.05 higher in Uruguay. The mean index value, using the selected Uruguayan EQ-5D-5L value set, for the general population in Uruguay was 0.895. In general, older people had worse values and males had slightly better values than females. CONCLUSION: We derived the EQ-5D-5L Uruguayan value set, the first in Latin America. These results will help inform decision-making using economic evaluations for resource allocation decisions. PMID- 26242250 TI - The definition and role of quality of life in Germany's early assessment of drug benefit: a qualitative approach. AB - PURPOSE: In 2011, Germany introduced a new form of drug benefit assessment, linking reimbursement prices to drug benefit and making quality of life (QoL) one of the main benefit criteria. Thus, QoL outcomes co-determine drug prices in Germany. QoL has, however, not been defined in the regulations. This study analyzed the definition and role of QoL in Germany's drug benefit assessment. It serves as a case study on the complexity of QoL as a parameter of health technology and drug assessments, which have become mandatory in almost all industrialized countries. METHODS: In a qualitative analysis, the publicly available dossiers (summaries), dossier evaluations, protocols of the oral hearings, the final resolutions of the Federal Joint Committee (G-BA) and its rationale of all benefit assessments completed by 2013 (n = 66) were processed. Additionally, quantitative data on the decision outcomes were collected. RESULTS: Only two decisions drew on QoL outcomes as "main justifications" for additional benefit. It was due to a lack of valid and statistically significant QoL results, a deficient presentation of QoL data, or differing understandings of QoL, that QoL benefit was not demonstrated in more than two cases. While manufacturers applied wider definitions of QoL, the assessment institutions questioned evidence if it was not reported with the help of validated QoL questionnaires or deviated from their definition of QoL. CONCLUSIONS: The German experience with QoL as a drug benefit criterion highlights the importance of a clear QoL definition and according methodological regulations. PMID- 26242251 TI - Dielectrophoretic manipulation of the mixture of isotropic and nematic liquid. AB - In various applications involving liquid crystals, the manipulation of the nanoscale molecular assembly and microscale director alignment is highly useful. Here we show that a nematic-isotropic mixture, a unique bi-liquid system, has potential for the fabrication of microstructures having an ordered phase within a disordered phase, or vice versa. The volume expansion and shrinkage, migration, splitting, mergence and elongation of one phase within the other are easily accomplished via thermal treatment and dielectrophoretic manipulation. This is particularly achievable when one phase is suspended in the middle. In that case, a highly biased ordered-phase preference of surfaces, that is, the nematic-philic nature of a polyimide layer and the nematic-phobic nature of a self-assembled monolayer of chlorosilane derivatives, is used. Further, by combining this approach with photopolymerization, the patterned microstructure is solidified as a patterned polymer film having both isotropic and anisotropic molecular arrangements simultaneously, or as a template with a morphological variation. PMID- 26242252 TI - Health-related quality of life and mental distress in patients with partial deafness: preliminary findings. AB - The aim of the study was to evaluate mental distress and health-related quality of life in patients with bilateral partial deafness (high-frequency sensorineural hearing loss) before cochlear implantation, with respect to their audiological performance and time of onset of the hearing impairment. Thirty-one patients and 31 normal-hearing individuals were administered the Beck Depression Inventory (BDI), the State-Trait-Anxiety-Inventory (STAI) and the World Health Organization Quality of Life-BREF questionnaire (WHOQOL-BREF). Patients also completed the Nijmegen-Cochlear-Implant-Questionnaire (NCIQ), a tool for evaluation of quality of life related to hearing loss. Patients revealed increased depressive and anxiety symptoms, as well as decreased health-related quality of life (psychological health, physical health), in comparison with their healthy counterparts (t tests, p < 0.05). Furthermore, a General Linear Model demonstrated in patients with a prelingual onset of hearing loss enhanced self evaluated social interactions and activity (NCIQ), when their outcomes were contrasted with those obtained in individuals with postlingual partial deafness (p < 0.05). The study failed to show any effect of collateral tinnitus. Patients not using hearing aids had better audiological performance and, therefore, better sound perception and speech production, as measured with NCIQ. There was no effect of hearing aid use with respect to mental distress. Additional statistically significant correlations seen in patients included those between a steeper slope hearing loss configuration (averaged pure-tone thresholds at 1 and 2 kHz with subtracted threshold at 0.5 kHz) and better audiometric speech detection, between audiometric thresholds and the subjectively rated sound perception (NCIQ), as well as left-ear audiometric word recognition scores and the subjectively perceived ability to recognize advanced sounds (NCIQ). In addition, a longer duration of postlingual deafness, as well as a younger age at the onset were both related to worse speech detection thresholds. The results of the study provide evidence that successful rehabilitation in patients with partial deafness might have to go beyond the standard speech therapy. Enhancement of the regular diagnostic assessment with additional psychological tools is highly recommended. Further investigation is required as to the role of functional residual hearing, hearing aid use and tinnitus, in relation to future outcomes of cochlear implantation. PMID- 26242253 TI - Redesign and treatment planning orbital floor reconstruction using computer analysis anatomical landmarks. AB - Orbital floor fractures are one of the most commonly encountered maxillofacial fractures due to their weak anatomical structure. Restoration of the orbital floor following a traumatic injury or a tumor surgery is often difficult due to inadequate visibility and lack of knowledge on its anatomical details. The aim of this study is to investigate the locations of the inferior orbital fissure (IOF), infraorbital groove (G), and infraorbital foramen (Fo) and their relationship with the orbital floor using a software. Measurements from the inferior orbital rim (IOR) using the Fo, the IOF, G, and the optic canal (OC) were calculated in 268 orbits as reference points. The surgical landmarks from the G and the OC, the G and the IOF, the G and the intersection point were measured as 31.6 +/- 6, 12.9 +/- 4, and 12 +/- 5 mm, respectively. The mean distances between the G and the IOR, the Fo and the IOF, and the Fo and the OC were found as 8.3 +/- 2.1, 28.7 +/ 3.5, and 53.6 +/- 5.9 mm, respectively. The mean angles were calculated as OC IOF-G 68.1 degrees +/- 16.4 degrees ; intersection-G-IOF as 61.4 degrees +/- 15.8 degrees ; IOF-OC-G as 19 degrees +/- 5.5 degrees ; OC-G-intersection as 31.5 degrees +/- 11.9 degrees , G-intersection-OC as 129.5 degrees , IOF intersection-G as 50.5 degrees . Furthermore, variable bony changes on the orbital floor which may lead to the differences at intersection point of the G and Fo were determined. In 28 specimens (20.9 %), unilateral accessory Fo (AcFo) was present. In 27 specimens, AcFo was situated supermaedially (96.4 %) on the main aperture. In one specimen, two intraorbital canals and Fo emerged from different points and coursed into different apertures. The measured mean distances of the AcFo-IOR and the AcFo-Fo were as 7 +/- 2 and 7.3 +/- 3.2 mm, respectively. The primary principle in the oculoplastic treatment of orbital floor reconstructions must be repositioning the herniated orbital aperture by maintaining the infraorbital artery and the nerve in the orbital floor. The IOF and the G were recommended as the more reliable oculoplastic surgical landmarks for identifying the orbital floor. To avoid pinching of the orbital floor structures, the triangle (IS-G-IOF) should be equilateral with an exigence of a 70 degrees angle within it. Among each distance of the intersection-IOF, IOF-G, G-intersection should be equal. With the help of certain software, this study made possible to investigate the variability of the orbital floor structures, observe the variety in measurements and calculate the parameters which are crucial in implementing personalized reconstruction and implanting support. PMID- 26242254 TI - FNAC and frozen section correlations with definitive histology in thyroid diseases. AB - The ability to diagnose thyroid cancers pre-op or intra-operatively by fine needle aspiration cytology (FNAC) or frozen section (FS) leads to the delivery of appropriate one-stage surgical management. We aim to study the concordance and discordance of FNAC and FS with final histology in thyroid pathologies. All thyroid procedures from 2007 to 2011(n = 423), involving FNAC and or frozen section in their management pathway were included. FNAC (n = 159) were classified in a five-tier system (Nondiagnostic, Benign, Atypical, Suspicious or Malignant). FS (n = 128) were classified as inconclusive, benign, suspicious or malignant. FNAC and FS were correlated with final histopathology. 159 out of 423 patients had FNAC (PPV 85.1 %), 26 inadequate specimens noted, benign cytology 57, atypical (n = 23), follicular neoplasm (n = 27), suspicious for malignancy (n = 16) and malignant 11. 13 out of 27 follicular neoplasm and 6 of atypical FNAC cases showed malignancy in their final histopathology. Frozen sections; total of 126 patients had intra-operative frozen section biopsies performed. Overall 105 out of 126 FS biopsies were benign; 21 malignancies detected intraoperatively. Three FS were inconclusive and reported benign in final histopathology. Overall, FNAC demonstrated a PPV of 66.6 % and NPV of 84.6 %. FS demonstrated PPV and NPV of 76.1 and 85.7%, respectively. In conclusion, FNAC is considered as the best modality to triage the thyroid nodule pre-operatively. Atypical and follicular neoplasm cytology categories warrant further clinical assessment and close follow ups when appear benign. The intra-operative frozen sections are helpful to perform a one-stage operation for suspicious thyroid lesion. This study also highlights the recognised limitation of intra-operative frozen section analysis of thyroid neoplasia. PMID- 26242255 TI - [Psychosomatic Care Needs to be Increased in Transplantation Medicine]. PMID- 26242256 TI - Why Anticancer Nanomedicine Needs Sugars? AB - Nowadays, nanomedicine brings new opportunities for diagnosis and treatment through innovative combinations of materials structured at the nanoscale, biomolecules and physicochemical processes. If the intrinsic properties of nanomaterials appear of major importance in this new discipline, the functionalization of these nanotools with biomolecules improves both their biocompatibility and efficacy. This is the case of carbohydrate derivatives, natural or synthetic, which are increasingly being used in nanostructures for medical purposes. As in current medicine, sugars are used to mimic their physiological roles. Indeed, carbohydrates enhance the solubility and reduce the clearance of drugs. They are used to mask immunogenic components of nano-objects and escape the body defenses and finally facilitate the delivery to the target tissue. All these properties explain the growing importance of sugars in nanomedicine. PMID- 26242257 TI - Flavonoids and Related Compounds in Non-Alcoholic Fatty Liver Disease Therapy. AB - Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, is one of the most common chronic liver diseases, which may progress to fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD is characterized by the accumulation of lipids in the liver arising from multiple factors: increased fatty acid uptake, increased de novo lipogenesis, reduced fatty acid oxidation and very low density lipoproteins (VLDL) secretion. Most therapeutic approaches for this disease are often directed at reducing body mass index and improving insulin resistance through lifestyle modifications, bariatric surgery and pharmacological treatments. Nevertheless, there is increasing evidence that the use of natural compounds, as polyphenols, exert multiple benefits on the disorders associated with NAFLD. These molecules seem to be able to regulate the expression of genes mainly involved in de novo lipogenesis and fatty acid oxidation, which contributes to their lipid-lowering effect in the liver. Their antioxidant, anti-inflammatory, antifibrogenic and antilipogenic properties seem to confer on them a great potential as strategy for preventing NAFLD progression. In this review, we summarized the effects of these compounds, especially flavonoids, and their mechanisms of action, that have been reported in several studies carried out in in vitro and in vivo models of NAFLD. PMID- 26242258 TI - PET and SPECT Radiotracers for Alzheimer's Disease. AB - The two main pathological hallmarks of Alzheimer's disease (AD) in the brain are senile plaques (SPs) composed of beta-amyloid (Abeta) peptides and neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein. These hallmarks are associated with a cholinergic deficit. While the process leading to the development of AD is complex and multifactorial, and the etiology of AD is not completely known, it is nowadays clear that AD is a multifaceted illness requiring the combination of synergetic treatment strategies. Because definite diagnosis is achieved by postmortem examination of the brain, new noninvasive diagnostic imaging modalities for AD are in high demand, both to detect and monitor the evolution of this sickness, and evaluate the efficacy of treatments. Positron Emission Tomography (PET) is a nuclear molecular imaging technique that uses radiopharmaceuticals labeled with a positron-emitting isotope (carbon-11, fluorine-18, copper-64, gallium- 68...), to visualize in vivo cellular metabolism with high-spatial resolution and unique sensitivity, while Single-Photon Emission Computed Tomography (SPECT) using radioisotopes such as technetium-99m or iodine 123. Besides being a powerful tool for diagnosis (mostly in oncology with [(18)F] FDG), PET experiments can provide information about biochemical mechanisms in living tissues or interactions between neurotransmitter and brain receptors. For the past two decades, numerous radiopharmaceuticals have been developed for imaging the lesions observed in AD patients. Tau aggregates and Abeta plaques can also be visualized and quantified by mean of specific radioligands. The latter has been the focus of intense research efforts lately, leading to new FDA approved radiopharmaceuticals. This paper aimed at summarizing the recent advances in PET and SPECT imaging of AD pathophysiology. PMID- 26242259 TI - MALAT1-miR-124-RBG2 axis is involved in growth and invasion of HR-HPV-positive cervical cancer cells. AB - Metastasis-associated lung adenocarcinoma transcript 1 (MALAT 1) is a large, infrequently spliced non-coding RNA aberrantly expressed in cervical cancer. But the molecular mechanisms of its oncogenic role are still not quite clear. The present study explored whether there is a competing endogenous RNAs (ceRNAs) mechanism involved in the oncogenic effect of MALAT1. MALAT1 expression was firstly verified in high-risk human papillomavirus (HR-HPV)-positive tumor tissues and cell lines. Its regulation over miR-124 and the downstream target of miR-124 in regulation of growth, invasion, and apoptosis of the cancer cells are also studied. Findings of this study confirmed higher MALAT1 expression in HR-HPV (+) cervical cancer. Knockdown of endogenous MALAT1 significantly reduced cell growth rate and invasion and increased cell apoptosis of Hela and siHa cells. Besides, knockdown of MALAT1 increased the expression of miRNA-124, while ectopic expression of miR-124 decreased MALAT1 expression. In addition, we also verified a direct interaction between miR-124 and 3'UTR of GRB2. MALAT1 can indirectly modulate GRB2 expression via competing miR-124. Knockdown of GRB2 reduced cell invasion and increased cell apoptosis. In conclusion, MALAT1 can promote HR-HPV (+) cancer cell growth and invasion at least partially through the MALAT1-miR-124 RBG2 axis. This finding might provide some useful evidence about the lncRNA interaction regulatory network in tumorigenesis cervical cancer. PMID- 26242260 TI - Approach for chemosensitization of cisplatin-resistant ovarian cancer by cucurbitacin B. AB - Ovarian cancer is the most deadly gynecological cancer. The first line in treatment is platinum-based drugs. However, most patients suffer from tumor recurrence, characterized by resistance to cisplatin. A plausible approach to address the tumor resistance is to co-administer the chemotherapeutic agents along with natural products to offer a synergistic effect and optimize the dosage regimen. Cucurbitacin B is a natural product and displays antitumor activity against a wide array of cancer cell lines. The aim of this work is to determine the antitumor activity against ovarian cancer cell line (A2780) and possible sensitization activity on cisplatin-resistant cell line (A2780CP) in 2D and 3D culture model. 3D spheroids were generated from A2780CP cell line. A2780, A2780CP, and the spheroids were treated with cucurbitacin B, cisplatin alone, or pretreated with cucurbitacin B followed by cisplatin. The viability, cell cycle, and apoptosis were analyzed. Level of ROS and total glutathione was measured. In this study, cucurbitacin B showed cytotoxicity against the ovarian cancer cell lines, and pretreatment of A2780CP cells leads to a significant increase in the cytotoxicity of cisplatin. The mechanism behind the sensitization effect was dependent in part on the depletion of the total glutathione, an increase in ROS through a decrease in the level of dual-specificity tyrosine-regulated kinase (Dyrk1B), decrease in pERK1/2 and pSTAT3 level. The viability of spheroids treated with a combination of cisplatin and cucurbitacin B were significantly decreased. The resulting data shows that cucurbitacin B is a promising chemosensitizer for the cisplatin-resistant ovarian cancer. PMID- 26242261 TI - Survivin mRNA-circulating tumor cells are associated with prostate cancer metastasis. AB - Detection of circulating tumor cells (CTCs) has been made to develop reliable assays for early diagnosis of various cancers. Overexpression of survivin in cancer cells is strongly associated with tumor progression. Although upregulation of survivin is observed in various tumors, its expression profile in the peripheral blood of prostate cancer (PCa) patients has not yet been investigated. In this study, we validated the application of survivin as the tumor marker to detect CTC and assessed its utility for diagnosis of PCa distant metastasis. Immunohistochemistry and quantitative real-time PCR (QRT-PCR) were performed to confirm the levels of surviving expression in PCa tissues. In addition, CTC values in 3 mL of peripheral blood from PCa patients, benign prostate hyperplasia (BPH) patients, and normal controls were also measured by the survivin-targeted PCR. Our results showed that surviving was overexpressed in PCa tissues. The median levels of blood surviving mRNA of PCa patients, BPH patients, and normal controls were 5.67 (range from 0 to 12.46), 2.24 (range from 0 to 6.55), and 1.85 (range from 0 to 3.82), respectively. The levels of survivin are positively associated with PCa distant metastasis. Our results concluded that quantitation of CTCs through survivin-PCR could be a promising marker for diagnosis of PCa metastasis. PMID- 26242262 TI - MiR-200 suppresses metastases of colorectal cancer through ZEB1. AB - Poor prognosis of some colorectal cancer (CRC) cases largely results from early metastases of CRC to the distal organs. Thus, suppression of the invasion of CRC appears to be crucial therapy. Since microRNAs (miRNAs) play critical roles in the regulation of cancer metastases, identification of the involved miRNAs may provide novel therapeutic targets for CRC treatment. Here, we showed that the levels of miR-200 were significantly decreased and the levels of ZEB1 were significantly increased in the CRC specimens from patients, compared to the paired non-tumor tissue. Moreover, the levels of miR-200 and ZEB1 are inversely correlated. Bioinformatics analyses showed that miR-200 targeted the 3'-UTR of ZEB1 mRNA to inhibit its translation, which was confirmed by luciferase reporter assay. Moreover, miR-200 overexpression inhibited ZEB1-mediated cell invasiveness, while miR-200 depletion increased ZEB1-mediated cell invasiveness in CRC cells. Together, our data suggest that miR-200 suppression in CRC cells may promote ZEB1-mediated cancer metastasis. Our work thus highlights a novel molecular regulatory machinery that regulates metastases of CRC. PMID- 26242263 TI - CCL18 promotes the invasion and migration of gastric cancer cells via ERK1/2/NF kappaB signaling pathway. AB - CCL18 is a member of CCL chemokines and is frequently overexpressed in cancer. Elevated CCL18 expression has been reported to be associated with poor prognosis of gastric cancer. However, the molecular mechanisms of CCL18 in gastric cancer cells remain elusive. In our study, we found that CCL18 was highly expressed in different gastric cancer cells. CCL18 stimulation dose-dependently enhanced the invasion and migration of MGC-803 cells. Knockdown of endogenous CCL18 inhibited the invasion and migration of MGC-803 cells, whereas overexpression of CCL18 promoted the invasion and migration of MKN28 cells. We further found that CCL18 increased the expressions of MMP-3 and Slug and decreased the expression of E cadherin in MGC-803 cells. In addition, CCL18 time-dependently induced activation of ERK1/2, IkappaBalpha, and NF-kappaB. These effects of CCL18 were prevented by ERK1/2 selective inhibitor U0126 as well as NF-kappaB selective inhibitor BAY117082. Taken together, our findings establish a signaling role for CCL18 in gastric cancer cells and identify that the CCL18/ERK1/2/NF-kappaB signaling pathway is essential for tumor invasiveness in gastric cancer cells. Thus, our data may provide knowledge for using CCL18 as a novel target for effective diagnosis and treatment of gastric cancer. PMID- 26242264 TI - Upregulation of KPNbeta1 in gastric cancer cell promotes tumor cell proliferation and predicts poor prognosis. AB - KPNbeta1, also known as importin beta, P97, is reported as one of soluble transport factors that mediates transportion of proteins and RNAs between the nucleus and cytoplasm in cellular process. Recent studies show that KPNbeta1 is a tumor gene which is highly expressed in several malignant tumors such as ovarian cancer, cervical tumor, neck cancer, and lung cancer via promoting cell proliferation or inhibiting cell apoptotic pathways. However, the the role of KPNbeta1 in gastric cancer remains unclear. In this study, Western blot and immunohistochemistrical analyses showed that KPNbeta1 was significantly upregulated in clinical gastric cancer specimens compared with adjacent noncancerous tissues. KPNbeta1 was positively correlated with tumor grade, Ki-67, and predicted poor prognosis of gastric cancer. More importantly, through starvation-refeeding model, CCK8 assay, flow cytometry, colony formation assays, the vitro studies demonstrated that KPNbeta1 promoted proliferation of gastric cancer cells, while KPNbeta1 knockdown led to decreased cell proliferation and arrested cell cycle at G1 phase. Furthermore, our results also indicated that KPNbeta1 expression could result in docetaxel resistance. And, KPNbeta1 could interact with Stat1, contributed to its nucleus import in gastric cancer cells. These findings provided a novel promising therapeutic targets for clinical treatment against human gastric cancer. PMID- 26242265 TI - Inhibition of autophagy by bafilomycin A1 promotes chemosensitivity of gastric cancer cells. AB - Autophagy is an intracellular degradation pathway that delivers organelles or protein to the lysosome and has been recently implicated in the resistance of gastric cancer to chemotherapy. This study aimed to investigate whether blocking autophagy is a new approach for the treatment of chemoresistant gastric cancer. SGC-7901 gastric cancer cell line was treated with 5-fluorouracil (5-FU) or/and autophagy inhibitor bafilomycin A1. Cell viability and growth were evaluated by 3 [4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and clonogenic assay. Apoptosis was evaluated by flow cytometry. Cell migratory and invasive ability were evaluated by migration and invasion assays. Autophagy was evaluated by scanning electron microscopic, acridine orange staining, and Western blot analysis. We observed that 5-FU induced autophagy in SGC-7901 cells. Bafilomycin A1 decreased the viability and clone formation, inhibited the invasive and migratory ability, and increased the apoptosis of SGC-7901 cells. Taken together, our data suggest that chemotherapy-induced autophagy contributes to gastric cancer chemoresistance, and the inhibition of autophagy is a promising strategy for gastric cancer therapy. PMID- 26242266 TI - Long noncoding RNA NEAT1 promotes glioma pathogenesis by regulating miR-449b-5p/c Met axis. AB - Growing evidence demonstrates that long noncoding RNAs (lncRNAs) are involved in the progression of various cancers including glioma. Nuclear enriched abundant transcript 1 (NEAT1), an essential lncRNA for the formation of nuclear body paraspeckles, was not fully explored in glioma. We aimed to determine the expression, roles, and functional mechanisms of NEAT1 in the progression of glioma. By real-time PCR, we suggested that NEAT1 was upregulated in glioma tissues than noncancerous brain tissues. Knockdown of NEAT1 reduced glioma cell proliferation, invasion, and migration. RNA immunoprecipitation assay combined with luciferase reporter assay confirmed miR-449b-5p-specific binding to NEAT1. Furthermore, we verified that c-Met was a directly target of miR-449b-5p. Rescue assays demonstrated NEAT1 functions a molecular sponge for miR-449b-5p and leads to the upregulation of c-Met. This regulation menchaism promotes glioma pathogenesis and may provide a potential target for the prognosis and treatment of glioma. PMID- 26242267 TI - Downregulation of HMGA2 inhibits cellular proliferation and invasion, improves cellular apoptosis in prostate cancer. AB - Prostate cancer is the most commonly diagnosed cancer among men and is the second leading cause of cancer-associated deaths among men in the world. Unfortunately, treatment failures are common due to the metastasis and chemoresistance, but the underlying molecular mechanism remains unclear. Accumulating evidence has indicated that the deregulation of DNA-binding protein High Mobility Group A2 (HMGA2) is associated with the development and progression of cancer. This study aimed to explore the expression of HMGA2 in prostate cancer tissues and its correlation to the clinical pathology of prostate cancer, and to discuss the role of HMGA2 in the development of prostate cancer. The results showed that the expression of HMGA2 messenger RNA (mRNA) in the prostate cancer tissues and cells was significantly higher than that in normal prostate tissues and cells (p < 0.05), and the positive expression rate of HMGA2 mRNA in the prostate cancer tissues from patients with positive lymph node metastasis or with high Gleason grade was significantly higher than that from patients with negative lymph node metastasis or with low Gleason grade (p < 0.05). In order to explore the role of HMGA2 in prostate cancer, the expression of HMGA2 in the human prostate cancer PC3 cell line was downregulated by RNA interference. Then, the changes in proliferation, apoptosis, invasion, and migration of PC3 cells were examined by MTT test, PI staining, Annexin V-FITC staining, and Transwell chamber assay. Results showed that the abilities of proliferation, invasion, and migration were suppressed in HMGA2 knockdown PC3 cells, and the abilities of apoptosis were enhanced in HMGA2 knockdown PC3 cells. The expression of cyclin A and vimentin was downregulated in HMGA2 knockdown PC3 cells, and the expression of caspase 3 and E-cadherin was upregulated in HMGA2 knockdown PC3 cells. Taken together, the overexpression of HMGA2 in prostate cancer might be related to the tumorigenesis, invasion, and metastasis of prostate cancer, the downregulation of HMGA2 could inhibit cellular proliferation, invasion, and metastasis, and improve cellular apoptosis in prostate cancer, which might be a potential target for the treatment of prostate cancer. PMID- 26242268 TI - Question about Liu Y et al. entitled "Effect of c-erbB2 overexpression on prognosis in osteosarcoma: evidence from eight studies". AB - We read with great interest on the recent paper by Liu Y et al. "Effect of c erbB2 overexpression on prognosis in osteosarcoma: evidence from eight studies" published online in Tumor Biology (Tumor Biol 5(9):8939-43, 2014). The investigators (Liu Y et al.) performed a meta-analysis to study the relationship between c-erbB2 expression and prognostic impact in patients with osteosarcoma. They conducted a comprehensive and detailed meta-analysis to reveal the prognostic role of c-erbB2 for osteosarcoma. As a result, eight studies with 411 osteosarcoma patients were involved to estimate the relationship. Positive expressions of c-erbB2 predicted poorer survival in osteosarcoma patients with the pooled RR of 1.53 (95 % CI 1.20-1.94, P = 0.0006). Finally, they concluded that c-erbB2 overexpression is related to poor prognostic of osteosarcoma and can be a useful clinical prognostic factor for those patients. Nevertheless, we have several queries which we would like to communicate with them. PMID- 26242269 TI - Introducing differential expression of human heat shock protein 27 in hepatocellular carcinoma: moving toward identification of cancer biomarker. AB - Previously, it has to be acknowledged that overexpressed heat shock protein B27 (HSPB27) have been implicated in the etiology of wide range of human cancers. However, the molecular mechanism leading to the disease initiation to progression in liver cancer is still unknown. Present work was undertaken to investigate the differentially expressed HSPB27 in association with those damages that lead to liver cancer development. For the identification of liver cancer biomarker, samples were subjected to comparative proteomic analysis using two-dimensional gel electrophoresis (2-DE) and were further validated by Western blot and immunohistochemical analysis. After validation, in silico studies were applied to demonstrate the significantly induced phosphorylated and S-nitrosylated signals. The later included the interacting partner of HSPB27, i.e., mitogen-activated protein kinase-3 and 5 (MAPK3 and 5), ubiquitin C (UBC), v-akt murine thymoma viral oncogene homolog 1 (AKT1), mitogen-activated protein kinase 14 (MAPK14), and tumor protein p53 (TP53), which bestowed with critical capabilities, namely, apoptosis, cell cycling, stress activation, tumor suppression, cell survival, angiogenesis, proliferation, and stress resistance. Taking together, these results shed new light on the potential biomarker HSPB27 that overexpression of HSPB27 did lead to upregulation of their interacting partner that together demonstrate their possible role as a novel tumor progressive agent for the treatment of metastasis in liver cancer. HSPB27 is a promising diagnostic marker for liver cancer although further large-scale studies are required. Also, molecular profiling may help pave the road to the discovery of new therapies. PMID- 26242270 TI - Histological mixed-type as an independent risk factor for nodal metastasis in submucosal gastric cancer. AB - Recent studies reported that the histological mixed-type, which consists of differentiated and undifferentiated components, was related to the aggressive clinical features of gastric cancer as well as its poor outcomes. This study was designed to investigate the influences of the mixed-type on lymph node metastasis in patients with submucosal gastric cancer. We analyzed a total of 239 consecutive patients who underwent curative gastrectomy for submucosal gastric cancer between 2004 and 2012 from their hospital records. The overall prevalence of histological mixed-type in submucosal gastric cancer was 46.9 % (112/239). The histological mixed-type correlated more strongly with lymph node metastasis (P = 0.0016; 25.0 % (28/112)) than the undifferentiated type in the Japanese classification of gastric carcinoma (JCGC) (P = 0.2779; 20.5 % (17/83)) and 7th tumor-node-metastasis (TNM) (P = 0.0476; 20.7 % (31/150)) classifications. Univariate and multivariate logistic regression analyses identified a tumor size of 25 mm or greater (P = 0.0003, OR 4.51 (95 % CI 1.95-11.9)) and the histological mixed-type (P = 0.0316, OR 4.02 (95 % CI 1.12-19.2)) as independent risk factors for lymph node metastasis. The incidence of lymph node metastasis was high in patients with both these factors (33.8 % (23/68)) and low in patients without both factors (3.0 % (2/67)). These results suggest that the histological mixed-type correlated more strongly with lymph node metastasis than the undifferentiated type in the JCGC and TNM classifications and highlight its usefulness as a risk factor for lymph node metastasis in submucosal gastric cancer. PMID- 26242273 TI - A Guide to Searching PubMed (and Other Free Databases) for Health Facilities Design Research. PMID- 26242274 TI - Syntheses, structure solutions, and catalytic performance of two novel layered silicates. AB - Two novel layered silicates, PKU-13 and PKU-13a, were hydrothermally synthesized by using trimethylpropylammonium hydroxide as the structure directing agent (SDA). Their structures were solved by using powder X-ray diffraction data in combination with electron diffraction technique and NMR spectroscopy. These two silicates are built from the same r52 layer in different stacking modes: the adjacent r52 layers in PKU-13a have a 0.5b + 0.68c shift compared with those in PKU-13. The difference is due to the SDA cations located between the layers. The SDA cations exist as a monolayer in the structure of PKU-13, and link the adjacent layers by Coulomb actions in combination with strong hydrogen bonds. In PKU-13a, the SDA cations present in the bi-layer expend the distance between layers and destroy the inter-layer hydrogen bonds. PKU-13a can transform to PKU 13 after treatment with acetic acid solution. The co-existence of intra-layer hydrogen bonds in PKU-13 interfere in its condensation to an ordered crystalline microporous framework. Both PKU-13 and PKU-13a exhibit good catalytic activities as base catalysts in the Knoevenagel condensation reaction. PMID- 26242271 TI - Genetic susceptibility to cervical cancer: role of common polymorphisms in apoptosis-related genes. AB - Cervical cancer is a common malignancy which poses a significant health burden among women, especially those living in the developing countries. Although human papillomavirus (HPV) infection has been unequivocally implicated in the etiopathogenesis of the cancer, it alone is not adequate to contribute to the malignant transformation of cervical cells. Most HPV infections regress spontaneously, and only a small proportion of women have persistent infections which eventually lead to malignancy. This suggests that interplays between HPV infection and other cofactors certainly exist during the process of cervical carcinogenesis, which synergistically contribute to the differential susceptibility of an individual to the malignancy. Undoubtedly, host genetic factors represent a major element involved in such a synergistic interaction, and accumulating evidence suggests that polymorphisms in apoptosis-related genes play an important role in the genetic susceptibility to cervical cancer. This review consolidates the recent literatures on the role of common polymorphisms in apoptosis-related genes in genetic susceptibility to cervical cancer. PMID- 26242277 TI - Optimised production and spray drying of ACE-inhibitory enzyme-modified cheese. AB - The proteolytic stage of the digestion process of white cheese curd was optimised to maximise the angiotensin I-converting enzyme (ACE)-inhibitory activity of the final enzyme-modified cheese (EMC) paste. It was found that bioactive peptides generation in EMC paste was of multi-variable dependent nature and could be optimised by targeted selection of specific component variables. Maximum ACE inhibitory was obtained by proteolysis at 48 degrees C for 25 h with 1 g Flavourzyme/kg cheese curd. This bioactive EMC paste was subsequently spray dried. The drying conditions were optimised to obtain a highly soluble powder to warrant quick and complete hydration, with the lowest water activity to maximise long term storage. The higher the inlet drying air temperature, the greater was the solubility of resultant EMC powder. Differential scanning calorimetry analysis revealed that the highest drying air temperature (200 degrees C) resulted in a lower glass transition temperature for the potentially bioactive EMC powder. PMID- 26242276 TI - Pilot study to determine whether transient receptor potential melastatin type 8 (TRPM8) antibodies are detected in scleroderma. AB - OBJECTIVES: A key mediator in cold-sensation is the protein transient receptor potential melastatin 8 (TRPM8), which is expressed on sensory nerves and cutaneous blood vessels. These receptors are activated by cold temperatures and play a key role in body thermoregulation. Cold sensitivity and Raynaud's phenomenon are frequent clinical features in scleroderma, and are thought to be secondary to a local defect in cutaneous thermoregulation. We investigated whether autoantibodies targeting TRPM8 were present in the sera of patients with scleroderma as evidence for a possible mechanism for an acquired immune mediated defect in thermoregulation. METHODS: Sera from 50 well-characterised scleroderma patients with Raynaud's phenomenon were studied. TRPM8 autoantibodies were assayed as follows: 1. immunoprecipitation with 35S-methionine-labelled TRPM8 generated by in vitro transcription and translation, 2. immunoblotting lysates made from cells transiently transfected with TRPM8 cDNA, 3. Immunoprecipitation of TRPM8 transfected lysates with detection by blotting and 4. flow cytometry. RESULTS: Fifty scleroderma patients with Raynaud's phenomenon (41 female, 39 Caucasian, 23 with limited scleroderma, and 20 with history of cancer) were studied. Four different methods to assay for TRPM8 antibodies were set up, optimised and validated using commercial antibodies. All 50 scleroderma patients' sera were assayed using each of the above methods, and all were negative for TRPM8 autoantibodies. CONCLUSIONS: Antibodies against TRPM8 are not found in scleroderma patient sera, suggesting that the abnormal cold sensitivity and associated abnormal vascular reactivity in scleroderma patients is not the result of an immune process targeting TRPM8. PMID- 26242279 TI - T-cell immune responses to Bordetella pertussis infection and vaccination. AB - The recent immunological investigations, stemming from the studies performed in the nineties within the clinical trials of the acellular pertussis vaccines, have highlighted the important role played by T-cell immunity to pertussis in humans. These studies largely confirmed earlier investigations in the murine respiratory infection models that humoral immunity alone is not sufficient to confer protection against Bordetella pertussis infection and that T-cell immunity is required. Over the last years, knowledge of T-cell immune response to B. pertussis has expanded broadly, taking advantage of the general progress in the understanding of anti-bacterial immunity and of refinements in methods to approach immunological investigations. In particular, experimental models of B. pertussis infection highlighted the cooperative role played by T-helper (Th)1 and Th17 cells for protection. Furthermore, the new baboon experimental model suggested a plausible explanation for the differences observed in the strength and persistence of protective immunity induced by the acellular or whole-cell pertussis vaccines and natural infection in humans, contributing to explain the upsurge of recent pertussis outbreaks. Despite the progress, open questions remain, the answer to them will possibly provide better tools to fight one of the hardest-to-control vaccine preventable disease. PMID- 26242278 TI - The role of Staphylococcal carotenogenesis in resistance to host defense peptides and in vivo virulence in experimental endocarditis model. AB - The defining hallmark of the newly described species, Staphylococcus argenteus, in comparison to its sister species, S. aureus and S. schweitzeri, is the absence of production of the carotenoid pigment, staphyloxanthin. Staphylococcus argenteus lacks the responsible genetic locus crtOPQMN. We examined the impact of carotenoid synthesis in two non-pigmented S. argenteus strains, MSHR1132 and SCC1165. Following complementation with a plasmid containing the carotenoid operon (pTX-crtOPQMN), compared to wild type, both complemented strains showed substantial carotenoid production, with a resultant increase in cell membrane rigidity. Surprisingly, both crtOPQMN-complemented strains exhibited increased susceptibility to the host defense peptides, LL-37 and hNP-1 in vitro, and reduced virulence in an experimental rabbit endocarditis model. PMID- 26242280 TI - Bordetella pertussis, B. parapertussis, vaccines and cycles of whooping cough. AB - Whooping cough is a vaccine-preventable disease due to Bordetella pertussis and B. parapertussis. This highly contagious respiratory disease occurs through epidemic cycles every 3-5 years and vaccination did not change this frequency. Models suggest that the cyclic increase of susceptibles is linked to demographic differences and different vaccine coverage. However, differences in surveillance of the disease as well as adaptation of the agents of the disease to their human hosts and to vaccine pressure might also play an important role. These parameters are discussed in this review. PMID- 26242281 TI - Spinal Cord Injury After Extremity Surgery in Children With Thoracic Kyphosis. AB - BACKGROUND: Spinal cord injury is a rare complication after lower extremity surgery in children with skeletal dysplasia and thoracic kyphosis. We encountered two patients who had this complication, from among 51 (39 from Nemours/Alfred I. duPont Hospital for Children and 12 from Seattle Children's Hospital) who underwent lower extremity surgery during an 8.5-year period (June 2004 to December 2012). Because spinal cord injury is a devastating complication likely not known to most physicians treating patients with skeletal dysplasias, we sought to examine factors that may contribute to this rare complication. CASE DESCRIPTION: We performed a retrospective review of two patients with skeletal dysplasia who had paraplegia develop after extremity surgery. Outcome measures included operative time, vital signs, and postsurgery recovery of neurologic deficit. MR images were reviewed. Two patients were found-an 8.5-year-old boy with spondyloepiphyseal dysplasia congenita with a 76 degrees -thoracic kyphosis apex at T4 and a 6.5-year-old boy with mucopolysaccharidosis type 1-H with an 80 degrees -thoracic kyphosis apex at T2. Bilateral proximal femoral osteotomies or bilateral innominate and proximal femoral osteotomies had been performed. The spinal cord injuries occurred at the apex of the kyphosis as determined by clinical examination and MRI assessment. In both patients, the mean arterial blood pressure decreased below 50 mm Hg and might be a factor in the etiology of the paralysis. The first patient recovered motor function in 5 months; the second had no recovery. LITERATURE REVIEW: Paraplegia is extremely rare after nonspine operations. Many factors contribute to the risk for a spinal cord event: low mean arterial pressure, duration of the surgery, position on the operating table, the kyphotic spine deformity, or unappreciated vascular disease. Motor-evoked potentials and somatosensory-evoked potentials together potentially provide high sensitivity and specificity for predicting a postoperative neurologic deficit. CLINICAL RELEVANCE: Based on our two patients with skeletal dysplasia and a literature review of patients with hyperkyphosis undergoing extremity surgery, the surgeon must be aware of the risk of spinal cord injury. Careful preoperative assessment possibly including MRI of the spine is recommended. Mean arterial pressure should be maintained at a safe level; neuromonitoring should be considered. PMID- 26242282 TI - Does Race Affect Outcomes in Total Joint Arthroplasty? AB - BACKGROUND: Several studies suggest worse surgical outcomes among racial/ethnic minorities. There is a paucity of research on preoperative and postoperative pain, general health, and disease-specific measures in which race is the main subject of investigation; furthermore, the results are not conclusive. QUESTIONS/PURPOSES: (1) Do black patients have more severe or more frequent preoperative pain, well-being, general health, and disease-specific scores when compared with white patients? (2) Are there differences between black patients and white patients after hip or knee arthroplasty on those same measures? METHODS: In this retrospective study, we used an institutional arthroplasty registry to analyze data on 2010 primary arthroplasties (1446 knees and 564 hips) performed by one surgeon at a single institution. Cases from patients self identifying as black (n = 105) and white (n = 1905) were compared (controlling for confounders, including age and ethnicity) on the following preoperative and postoperative patient-oriented outcomes: pain intensity/frequency as measured by a visual analog scale (VAS), Quality of Well-Being (QWB-7), SF-36, and WOMAC scores. T-tests, chi square, and multivariate analysis of covariance were used. Alpha was set at 0.05. Postoperative analysis was performed only on those cases that had a minimum followup of 1 year (mean, 3.5 years; range, 1-9 years). Of the 2010 arthroplasties, 37% (39 of 105) of those cases performed in black patients and 64% (1219 of 1905) of those performed in white patients were included in the final postoperative model (multivariate analysis of covariance). RESULTS: Black patients had more severe preoperative pain intensity (VAS: 8 +/- 1.8 versus 8 +/- 2.0, mean difference = 0.76 [95% confidence interval {CI}, 0.34-1.1], p < 0.001). Black patients also had worse well-being scores (QWB-7: 0.527 +/- 0.04 versus 0.532 +/- 0.05, mean difference = -0.01 [CI, -0.02 to 0.00], p = 0.037). Postoperatively, pain intensity (VAS: 1 +/- 3.1 versus 1 +/- 1.8, mean difference= 0.8 [CI, 0.19-1.4], p= 0.010) and (QWB-7: 0.579 +/- 0.09 versus 0.607 +/- 0.11, mean difference= -0.049 [CI, -0.08 to -0.01], p = 0.008) were different but without clinical significance. CONCLUSIONS: Black patients underwent surgery earlier in life and with different preoperative diagnoses when compared with white patients. Black patients had worse preoperative baseline pain, well-being, general health, and disease-specific scores as well as worse postoperative scores. However, these differences were very narrow and without clinical significance. Notwithstanding, the relations of race with outcomes remain complex. Further investigations to recognize disparities and minimize or address them are warranted. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 26242283 TI - Posterior glenoid wear in total shoulder arthroplasty: eccentric anterior reaming is superior to posterior augment. AB - BACKGROUND: Uncorrected glenoid retroversion during total shoulder arthroplasty may lead to an increased likelihood of glenoid prosthetic loosening. Augmented glenoid components seek to correct retroversion to address posterior glenoid bone loss, but few biomechanical studies have evaluated their performance. QUESTIONS/PURPOSES: We compared the use of augmented glenoid components with eccentric reaming with standard glenoid components in a posterior glenoid wear model. The primary outcome for biomechanical stability in this model was assessed by (1) implant edge displacement in superior and inferior edge loading at intervals up to 100,000 cycles, with secondary outcomes including (2) implant edge load during superior and inferior translation at intervals up to 100,000 cycles, and (3) incidence of glenoid fracture during implant preparation and after cyclic loading. METHODS: A 12 degrees -posterior glenoid defect was created in 12 composite scapulae, and the specimens were divided in two equal groups. In the posterior augment group, glenoid version was corrected to 8 degrees and an 8 degrees -augmented polyethylene glenoid component was placed. In the eccentric reaming group, anterior glenoid reaming was performed to neutral version and a standard polyethylene glenoid component was placed. Specimens were cyclically loaded in the superoinferior direction to 100,000 cycles. Superior and inferior glenoid edge displacements were recorded. RESULTS: Surviving specimens in the posterior augment group showed greater displacement than the eccentric reaming group of superior (1.01 +/- 0.02 [95% CI, 0.89-1.13] versus 0.83 +/- 0.10 [95% CI, 0.72-0.94 mm]; mean difference, 0.18 mm; p = 0.025) and inferior markers (1.36 +/- 0.05 [95% CI, 1.24-1.48] versus 1.20 +/- 0.09 [95% CI, 1.09-1.32 mm]; mean difference, 0.16 mm; p = 0.038) during superior edge loading and greater displacement of the superior marker during inferior edge loading (1.44 +/- 0.06 [95% CI, 1.28-1.59] versus 1.16 +/- 0.11 [95% CI, 1.02-1.30 mm]; mean difference, 0.28 mm; p = 0.009) at 100,000 cycles. No difference was seen with the inferior marker during inferior edge loading (0.93 +/- 0.15 [95% CI, 0.56-1.29] versus 0.78 +/- 0.06 [95% CI, 0.70-0.85 mm]; mean difference, 0.15 mm; p = 0.079). No differences in implant edge load were seen during superior and inferior loading. There were no instances of glenoid vault fracture in either group during implant preparation; however, a greater number of specimens in the eccentric reaming group were able to achieve the final 100,000 time without catastrophic fracture than those in the posterior augment group. CONCLUSIONS: When addressing posterior glenoid wear in surrogate scapula models, use of angle-backed augmented glenoid components results in accelerated implant loosening compared with neutral-version glenoid after eccentric reaming, as shown by increased implant edge displacement at analogous times. CLINICAL RELEVANCE: Angle-backed components may introduce shear stress and potentially compromise stability. Additional in vitro and comparative long-term clinical followup studies are needed to further evaluate this component design. PMID- 26242284 TI - CORR Insights((r)): High Rates of Interest in Sex in Patients With Hip Arthritis. PMID- 26242285 TI - Correlation of microbiologic culture and fine-needle aspiration cytology: A 14 year experience at a single institution. AB - BACKGROUND: Fine-needle aspiration (FNA) is an important tool for the diagnosis of infectious disease. FNA material should be appropriately submitted for cultures when indicated by preliminary findings. Correlation of cytologic diagnoses with culture results are important quality assurance tools. The current study reviewed 14 years of FNA-culture correlation. METHODS: FNA cytology-culture correlation records from the years 1996 through 2007 and 2010 through 2011 were retrieved from electronic databases compiled for histology and culture correlation. Correlation was limited to those cases for which material was submitted for culture from the FNA sample. Culture results were retrieved from the laboratory or hospital information system. RESULTS: Correlative data included 770 cases. Cytology, culture, or both were positive for microbes in 416 of 770 samples (54%), excluding cultured bacterial skin contaminants. Among the 204 bacteria cases, 93 (46%) were identified by cytology and culture, 92 (45%) were identified by culture only, and 19 (9%) were identified by cytology only. Among the 16 cases of Actinomycetales, 8 (50%) were identified by cytology and culture, 5 (31%) were identified by culture only, and 3 (19%) were identified by cytology only. Of the 129 cases of mycobacteria, 63 (49%) were identified by cytology and culture, 44 (34%) were identified by culture only, and 22 (17%) were identified by cytology only. Among the 67 cases of fungi, 34 (51%) were identified by cytology only, with 15 of these 34 cases being fungal hyphae; 25 cases (37%) were identified by cytology and culture, with a 100% concordance between the cytology diagnosis and culture result; and 8 cases (12%) were identified by culture only. CONCLUSIONS: FNA cytology-culture correlation is a valuable tool with which to assess the efficacy and limitations of the direct diagnosis of infectious agents, and to identify types of infections that may be negative on culture but positive on cytology diagnosis. PMID- 26242286 TI - Transition Metal Complexes of Phosphinous Acids Featuring a Quasichelating Unit: Synthesis, Characterization, and Hetero-bimetallic Complexes. AB - Diorganophosphane oxides were employed as preligands for the synthesis of catalytically active transition metal complexes of the phosphinous acids (CF3)2POH and (C2F5)2POH. Their reactions with solid PtCl2 and PdCl2 led to the formation of mononuclear phosphinous acid complexes [Cl2M{P(R(f))2OH}2] (M = Pd, Pt; R(f) = C2F5, CF3), which can be crystallized, for example, as its pyridinium salts, 2[HPy](+)[Cl2Pd{P(CF3)2O}2](2-). In vacuo HCl is liberated from the neutral palladium complexes affording mixtures of di- and polynuclear complexes. Moreover, (C2F5)2POH was reacted with several beta-diketonato complexes of palladium, platinum, and nickel yielding air- and moisture-stable complexes [(acac)M{[P(R(f))2O]2H}], featuring a quasichelating phosphinous acid phosphinito unit {P(R(f))2O...H...O(R(f))2P}(-). Treatment of [Ni(Cp)2] (Cp = cyclopentadienyl) and [(cod)RhCl]2 (cod = 1,5-cyclooctadiene) with (C2F5)2POH leads to the substitution of one Cp or chloro ligand by a quasichelating unit. The novel coordination compounds were characterized by NMR and IR spectroscopies, mass spectrometry, and X-ray diffraction analysis. The platinum complex [(acac)Pt{[P(C2F5)2O]2H}] (acac = acetylacetonato) was used for the construction of hetero-bimetallic complexes by the treatment with [(cod)RhCl]2 and [Ni(Cp)2]. The trinuclear bimetallic complex [{(acac)Pt[P(C2F5)2O]2}2Ni] is the first structurally characterized hetero-bimetallic species containing a bis(perfluoroalkyl)phosphinito bridge. PMID- 26242287 TI - Acupressure at BL60 and K3 Points Before Heel Lancing in Preterm Infants. AB - CONTEXT: Acupressure is an ancient Chinese healing art. In this pain-relieving method, the fingers are used to press key acupuncture points on the skin surface that stimulates the body's regulatory processes. OBJECTIVE: The aim of this study was to investigate the effect of acupressure at Kun Lun (UB60) and Taixi (K3) points for pain management in preterm infants prior to heel lancing for blood collection. DESIGN: This was a prospective, randomized controlled study. SETTING: The study setting was the neonatal intensive care unit at Baskent University Hospital in Turkey. PATIENTS: A total of 32 preterm infants between 28 and 36 weeks' gestational age were randomly assigned to one of two groups: an acupressure group (n = 16) or a control group (n = 16). INTERVENTION: In the acupressure group, immediately before the heel prick, acupressure was applied for three minutes at UB60 and K3 points. MAIN OUTCOME MEASURES: A behavioral pain score was determined using the Premature Infant Pain Profile (PIPP) scale. RESULTS: There were no significant differences between the groups with respect to gestational age, birth weight, sex, mode of delivery, age at time of procedure, weight at time of procedure, or PIPP score. Mean duration of procedure and mean duration of crying were both shorter in the acupressure group (both P = .001). CONCLUSIONS: Applying acupressure at the BL60 and K3 points before heel lancing was associated with shorter procedural time and shorter duration of crying in preterm infants. PMID- 26242288 TI - Psychophysical and Vasomotor Responses of the Oral Tissues: A Nicotine Dose Response and Menthol Interaction Study. AB - INTRODUCTION: This study implemented an intra-oral test-platform to assess the sensory, psychophysical, and vasomotor responses to nicotine and menthol, alone or in combination. METHODS: Two double-blinded, placebo-controlled, randomized, cross-over studies, including healthy nonsmoking participants were performed. Study I: A dose-response relationship (N = 20) between 0, 2, and 4 mg nicotine gum. Study II: An interaction response (N = 22) to 30 mg menthol and 4 mg nicotine alone or in combination. Heart rate, blood pressure, tactile and thermosensory thresholds, intra-oral blood flow and temperature, pain/irritation intensities/locations, McGill Pain Questionnaire, and taste experience were assessed before, during or after the completion of a standardized chewing regime. RESULTS: A dose-response elevation in heart rate was attenuated when nicotine was combined with menthol. Blood flow, temperature, and warm-detection thresholds, as assessed on the tongue, similarly increased for all gums. Pain intensity and taste experiences were similar between nicotine doses. Nicotine attenuated the sweet, cooling, and freshening sensation of menthol. Within the first 4 minutes, menthol reduced the intensity but not the area of nicotine-induced pain and irritation. The 4-mg nicotine dose led to a continued increase in the intensity and area of irritation in the throat post-chewing. Moreover, one-half of participants responded to menthol as an irritant, and these individuals demonstrated larger areas of nicotine-induced irritation in the throat post chewing. CONCLUSIONS: The intra-oral test platform provides a basis to optimize the assessment of nicotine-related taste and sensory experiences and can be used in future studies for profiling nicotine gum. PMID- 26242289 TI - Low Carbohydrate and Moderately Fat-Reduced Diets Similarly Affected Early Weight Gain in Varenicline-Treated Overweight or Obese Smokers. AB - INTRODUCTION: Weight gain is common when stopping smoking. This study compared the effect of advising smokers to follow a diet low in carbohydrates versus a usual fat-reduced diet on weight gain and nicotine withdrawal. METHODS: In a randomized clinical trial, 122 men and women smokers with body mass index 25 40kg/m(2) were assigned low-carbohydrate versus moderately fat-reduced diets. Within a week thereafter all participants started treatment with a 12-week course of varenicline 10 days prior to the target quit date. Brief dietary and motivational counseling was given at all visits. Self-reported abstinence was validated. RESULTS: Protein intake in the low-carbohydrate versus fat-reduced diets was 26.4% of total energy versus 20.0%, fat 38.2% versus 30.1%, and carbohydrates 29.0% versus 41.7% (all P < .001). Mean weight changes for the low carbohydrate versus fat-reduced groups were -1.2 (SD 2.2) versus -0.5 (SD 2.0) kg, -0.2 (SD 3.3) versus 0.5 (SD 2.6) kg, and 2.2 (SD 4.5) versus 2.1 (SD 3.9) kg at 4, 12, and 24 weeks after the target quit date, respectively (not statistically significant). Smoking abstinence rates did not differ between diets. In the combined groups, point prevalence abstinence rates were 71.0% at 12 weeks and 46.3% at 24 weeks. The Minnesota Nicotine Withdrawal Symptoms score was lower in the fat-reduced group compared with the low-carbohydrate group at weeks 4 and 12. CONCLUSIONS: In overweight or obese smokers using varenicline a low carbohydrate diet was no better than a fat-reduced diet in reducing weight gain but may result in more severe nicotine withdrawal symptoms. Compared to previous studies, cessation rates with varenicline were not impaired by dietary counseling. IMPLICATIONS: The study implies that a popular low-carbohydrate diet does not result in greater weight loss than a moderately fat-reduced diet in overweight and obese smokers who are attempting to quit smoking with the aid of varenicline. Dietary counseling combined with varenicline treatment did not appear to unfavorably influence quit rates compared to previous studies in smokers not selected for overweight or obesity. Notably, the withdrawal symptoms score was lower in the fat-reduced dietary group than the low-carbohydrate group, suggesting a venue for further study. PMID- 26242290 TI - Implementing a template for major incident reporting: experiences from the first year. AB - Major incidents are resource-demanding situations that require urgent and effective medical management. The possibility to extract learning from them is therefore important. Comparative analysis of information based on uniform data collection from previous incidents may facilitate learning. The Major Incident Reporting Collaborators have developed a template for reporting of the medical pre-hospital response to major incidents. The template is accompanied by an open access webpage ( www.majorincidentreporting.org ) for online reporting and access to published reports. This commentary presents the experiences from the first year of implementing the template including a presentation of the five published reports. PMID- 26242291 TI - Bacterial Contamination During Diagnostic and Interventional Neuroangiography is a Frequent Finding: But Does It Matter? An Observational Study. AB - INTRODUCTION: Bacterial contamination during angiographic procedures is a potential source of bacteremia. It is largely unknown whether it is clinically relevant. Our aim was to evaluate the incidence of contamination of liquids during catheter-based neuroangiographic examinations, the spectrum of microorganisms, a comparison of two different trolley-settings, and a follow-up of all patients with regard to clinical and lab signs of infection. METHODS: A total of 170 patients underwent either diagnostic angiography (n = 111) or arterial neuroendovascular procedures (n = 59). To study the impact of airborne contamination of sterile liquids, we randomly assigned equal numbers of procedures to two distinct setups. Group A with standard open-surface bowls and group B with repetitive coverage of liquids throughout the procedure. Patient preparation was performed with utmost care. After each procedure, samples of the liquids were sent for microbiological evaluation. Patients were followed for signs of infection (fever, white blood cell count, C-reactive-protein). RESULTS: Of all samples, 25.3 % were contaminated. Contamination consisted of resident skin microbiota only and was more common with procedures (28.8 %) than with diagnostic angiography (23.4 %) and less common in uncovered (23.5 %) than in covered bowls (27.1 %). However, these differences were insignificant. None of the patients developed clinical or lab signs of infection. CONCLUSION: Contamination during diagnostic and interventional angiography does occur and cannot be avoided by intermittent coverage. Despite a surprisingly high incidence, our findings support the common strategy that antibiotic coverage is unnecessary in most patients undergoing arterial angiography as it lacks clinical impact. Airborne contamination does not appear to play a role. PMID- 26242293 TI - Levetiracetam Pharmacokinetics in a Patient Receiving Continuous Venovenous Hemofiltration and Venoarterial Extracorporeal Membrane Oxygenation. AB - Levetiracetam is a first-line therapy for seizures in critically ill patients because of its clinical efficacy, minimal drug interactions, and wide therapeutic window. The primary mechanism of levetiracetam clearance is renal, and the drug has a low molecular weight. It is hydrophilic and exhibits minimal protein binding. Thus it is expected that levetiracetam will be removed by continuous venovenous hemofiltration (CVVH), with limited clearance by venoarterial extracorporeal membrane oxygenation (ECMO). We describe the case of a 67-year-old man who was admitted to the cardiovascular surgery intensive care unit after cardiac arrest and initiation of venoarterial ECMO. His course was complicated by multiorgan dysfunction including acute renal failure requiring CVVH. On hospital day 6, intravenous levetiracetam, at a loading dose of 2000 mg followed by a maintenance dose of 1000 mg every 12 hours, was initiated for new-onset seizures. The volume of distribution was 0.65 L/kg, and clearance was measured with peak (ranging from 26.5-39.8 MUg/ml) and trough (ranging from 13.9-18.2 MUg/ml) concentrations. Elimination half-life ranged from 8.7-10.1 hours. Renal dysfunction reduces levetiracetam clearance, and dosage reductions are recommended to prevent accumulation. Current CVVH dosing recommendations are based on predicted removal without clinical data. The volume of distribution and clearance in this case were similar to those of a normal healthy patient. Based on these results, we recommend considering an initial levetiracetam dose of 1000 mg every 12 hours for patients receiving CVVH, with dosage adjustments based on therapeutic drug monitoring. PMID- 26242294 TI - First example of a modular porphyrinoid assembly capable of stabilizing different metal ions in a single molecular scaffold. AB - We report the synthesis and characterization of porphyrin-corrole-porphyrin (Por Cor-Por) hybrids directly linked at the meso-meso positions for the first time. The stability and solubility of the trimer are carefully balanced by adding electron-withdrawing substituents to the corrole ring and sterically bulky groups on the porphyrins. The new hybrids are capable of stabilizing more than one metal ion in a single molecular scaffold. The versatility of the triad has been demonstrated by successfully stabilizing homo- (Ni) and heterotrinuclear (Ni-Cu Ni) coordination motifs. The solid-state structure of the NiPor-CuCor-PorNi hybrid was revealed by single-crystal X-ray diffraction studies. The Ni(II) porphyrins are significantly ruffled and tilted by 83 degrees from the plane of corrole. The robustness of the synthesized hybrids was reflected in the electrochemical investigations and the redox behaviour of the hybrids show that the oxidation processes are mostly corrole-centred. In particular it is worth noting that the Por-Cor-Por hybrid can further be manipulated due to the presence of substituent-free meso-positions on both the terminals. PMID- 26242296 TI - Exploring chiropractic students' experiences of the educational environment in healthcare professional training: a qualitative study. AB - BACKGROUND: The educational environment has a significant impact on students' behavior, sense of well-being, and academic advancement. While various research methodologies have been used to explore the educational environment, there is a paucity of studies employing qualitative research methods. This study engages in an in-depth exploration of chiropractic students' experiences of the meaning of the educational environment. METHODS: A qualitative approach was employed by interviewing 26 students in four focus group interviews at two different points in time. A conventional manifest and latent content analysis was chosen to investigate and interpret the experiences of the educational environment in an undergraduate chiropractic training institution in Sweden. RESULTS: The analysis resulted in five overarching themes: Personal growth; Being part of a community; A place of meaningfulness; Trust in a regulated system; and Scaffolding relationships. Early in the training, the meaning of the educational environment was experienced as part of a vocational community and the scaffolding of intra institutional relationships. In later stages, the environment was experienced in terms of personal growth - balancing academic pressures and progress within the professional community - thus laying the foundations for autonomy and motivation. During the clinical training, the environment was experienced as where learning happens, thus creating a place of meaningfulness. Throughout the training, the formal and clinical environments were experienced as isolating, with little bridging between the two. A regulated system - conveying an operative organization with clear communication regarding what to expect - was experienced as important for an apt educational environment. CONCLUSIONS: We found that experiences of an educational environment are dynamic and change over time. When restructuring or evaluating curriculums, educational managers can consider the emerged themes as constituting facets relating to the educational environment, and thus possible learning conditions. Likewise, researchers can consider these aspects of the educational environment when: interpreting results from quantitative and qualitative inquiries, constructing and refining instruments, or conceptualizing and framing the educational environment phenomenon. PMID- 26242295 TI - The link between obesity and vitamin D in bariatric patients with omega-loop gastric bypass surgery - a vitamin D supplementation trial to compare the efficacy of postoperative cholecalciferol loading (LOAD): study protocol for a randomized controlled trial. AB - BACKGROUND: Beyond its classical role in calcium homoeostasis and bone metabolism, vitamin D deficiency has been found to be associated with several diseases, including diabetes, non-alcoholic fatty liver disease, and even obesity itself. Importantly, there are limited data on therapeutic strategies for vitamin D deficiency in bariatric patients, and the procedure-specific guidelines may not be sufficient. To improve long-term outcomes, nutritional screening and appropriate supplementation to prevent nutrient deficiencies are urgently needed. Therefore, the aim of this study is to examine effects and safety of a forced dosing regimen of vitamin D versus conventional dose supplementation on vitamin D levels and other parameters in bariatric patients. METHODS/DESIGN: The study includes loading plus repeat dosing compared with repeated administration of vitamin D without a loading dose, according to guidelines, in a prospective, double-blind, randomized controlled trial. Up to a triple oral loading dose is given on day 1, then 2 and 4 weeks after surgery (100,000 IU dose each time), followed by an oral maintenance dose (3420 IU/day). The control group (n = 25) will receive placebo, followed by administration of a standard dose (3420 IU/day). We hypothesize that a significant increase in vitamin D levels will occur in patients in the treatment group (n = 25) by 24 weeks after surgery. Further measurements are aimed at evaluating changes in inflammation, bone turnover, insulin resistance, blood pressure, liver, mental health, and gut microbiota of patients undergoing omega-loop gastric bypass surgery. Furthermore, possible associations between concentrations of vitamin D, the involved enzymes, or vitamin D receptor in adipose and/or liver tissues will be determined. DISCUSSION: To our knowledge, this trial is the first of its kind with this type of vitamin D supplementation in bariatric patients. Its major strength is the design and implementation of evaluation of influencing factors such as liver function, bone health, inflammation, insulin resistance, blood pressure, symptoms of depression, or microbiota. This alternative vitamin D dosing regimen has the potential to be a safe, fast, evidence-based treatment of vitamin D deficiency in bariatric patients. Owing to the increasing number of bariatric patients, it is also of interest to elucidate the link between obesity and vitamin D. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02092376 . Registered on 17 March 2014. PMID- 26242297 TI - Prevalence and socio-demographic correlates of cooking skills in UK adults: cross sectional analysis of data from the UK National Diet and Nutrition Survey. AB - BACKGROUND: Poor cooking skills may be a barrier to healthy eating and a contributor to overweight and obesity. Little population-representative data on adult cooking skills has been published. We explored prevalence and socio demographic correlates of cooking skills among adult respondents to wave 1 of the UK National Diet and Nutrition Survey (2008-9). METHODS: Socio-demographic variables of interest were sex, age group, occupational socio-economic group and whether or not respondents had the main responsibility for food in their households. Cooking skills were assessed as self-reported confidence in using eight cooking techniques, confidence in cooking ten foods, and ability to prepare four types of dish (convenience foods, a complete meal from ready-made ingredients, a main meal from basic ingredients, and cake or biscuits from basic ingredients). Frequency of preparation of main meals was also reported. RESULTS: Of 509 respondents, almost two-thirds reported cooking a main meal at least five times per week. Around 90 % reported being able to cook convenience foods, a complete meal from ready-made ingredient, and a main dish from basic ingredients without help. Socio-demographic differences in all markers of cooking skills were scattered and inconsistent. Where these were found, women and main food providers were most likely to report confidence with foods, techniques or dishes, and respondents in the youngest age (19-34 years) and lowest socio-economic group least likely. CONCLUSIONS: This is the only exploration of the prevalence and socio-demographic correlates of adult cooking skills using recent and population representative UK data and adds to the international literature on cooking skills in developed countries. Reported confidence with using most cooking techniques and preparing most foods was high. There were few socio-demographic differences in reported cooking skills. Adult cooking skills interventions are unlikely to have a large population impact, but may have important individual effects if clearly targeted at: men, younger adults, and those in the least affluent social groups. PMID- 26242298 TI - Characterization of acinar airspace involvement in asthmatic patients by using inert gas washout and hyperpolarized (3)helium magnetic resonance. AB - BACKGROUND: The multiple-breath inert gas washout parameter acinar ventilation heterogeneity (Sacin) is thought to be a marker of acinar airway involvement but has not been validated by using quantitative imaging techniques in asthmatic patients. OBJECTIVE: We aimed to use hyperpolarized (3)He diffusion magnetic resonance at multiple diffusion timescales and quantitative computed tomographic (CT) densitometry to determine the nature of acinar airway involvement in asthmatic patients. METHODS: Thirty-seven patients with asthma and 17 age-matched healthy control subjects underwent spirometry, body plethysmography, multiple breath inert gas washout (with the tracer gas sulfur hexafluoride), and hyperpolarized (3)He diffusion magnetic resonance. A subset of asthmatic patients (n = 27) underwent quantitative CT densitometry. RESULTS: Ninety-four percent (16/17) of patients with an increased Sacin had Global Initiative for Asthma treatment step 4 to 5 asthma, and 13 of 17 had refractory disease. The apparent diffusion coefficient (ADC) of (3)He at 1 second was significantly higher in patients with Sacin-high asthma compared with that in healthy control subjects (0.024 vs 0.017, P < .05). Sacin correlated strongly with ADCs at 1 second (R = 0.65, P < .001) but weakly with ADCs at 13 ms (R = 0.38, P < .05). ADCs at both 13 ms and 1 second correlated strongly with the mean lung density expiratory/inspiratory ratio, a CT marker of expiratory air trapping (R = 0.77, P < .0001 for ADCs at 13 ms; R = 0.72, P < .001 for ADCs at 1 second). CONCLUSION: Sacin is associated with alterations in long-range diffusion within the acinar airways and gas trapping. The precise anatomic nature and mechanistic role in patients with severe asthma requires further evaluation. PMID- 26242299 TI - Estrogen and progesterone decrease let-7f microRNA expression and increase IL 23/IL-23 receptor signaling and IL-17A production in patients with severe asthma. AB - BACKGROUND: Women have an increased prevalence of severe asthma compared with men. IL-17A is associated with severe asthma and requires IL-23 receptor (IL-23R) signaling, which is negatively regulated by let-7f microRNA. OBJECTIVE: We sought to Determine the mechanism by which 17beta-estradiol (E2) and progesterone (P4) increase IL-17A production. METHODS: IL-17A production was determined by using flow cytometry in TH17 cells from women (n = 14) and men (n = 15) with severe asthma. Cytokine levels were measured by using ELISA, and IL-23R and let-7f expression was measured by using quantitative PCR in TH17-differentiated cells from healthy women (n = 13) and men (n = 14). In sham-operated or ovariectomized female mice, 17beta-E2, P4, 17beta-E2+P4, or vehicle pellets were administered for 3 weeks before ex vivo TH17 cell differentiation. Airway neutrophil infiltration and CXCL1 (KC) expression were also determined in ovalbumin (OVA) challenged wild-type female recipient mice with an adoptive transfer of OVA specific TH17 cells from female and male mice. RESULTS: In patients with severe asthma and healthy control subjects, IL-17A production was increased in TH17 cells from women compared with men. IL-23R expression was increased and let-7f expression was decreased in TH17-differentiated cells from women compared with men. In ovariectomized mice IL-17A and IL-23R expression was increased and Let-7f expression was decreased in TH17 cells from mice administered 17beta-E2+P4 compared with those administered vehicle. Furthermore, transfer of female OVA specific TH17 cells increased acute neutrophil infiltration in the lungs of OVA challenged recipient mice compared with transfer of male OVA-specific TH17 cells. CONCLUSIONS: 17beta-E2+P4 increased IL-17A production from TH17 cells, providing a potential mechanism for the increased prevalence of severe asthma in women compared with men. PMID- 26242301 TI - Extrapulmonary tuberculosis mimicking Mendelian susceptibility to mycobacterial disease in a patient with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation. PMID- 26242302 TI - Reliability, validity, sensitivity and internal consistency of the ICF based Basic Mobility Scale for measuring the mobility of patients with musculoskeletal problems in the acute hospital setting: a prospective study. AB - BACKGROUND: The assessment of mobility is important in the acute care setting. Existing tests suffer from limitations. The aim of the study was to examine the inter-rater reliability, the validity, the sensitivity to change, and the internal consistency of an ICF based scale. METHODS: In a prospective study inpatients in the acute care setting with restricted mobility aged above 50 years assigned to rehabilitative treatment were included. Assessment of subscales of the Functional Independence Measure (FIM) and the ICF based Basic Mobility Scale (BMS) were performed at admission and before discharge. Furthermore pain, length of stay in hospital, and post-discharge residential status were recorded. Inter rater reliability, criterion-concurrent validity, sensitivity to change, and internal consistency were calculated. Furthermore, floor and ceiling effects were determined. RESULTS: One hundred twenty-five patients (79 women/46 men) were included. The BMS showed an excellent inter-rater reliability for the total BMS (ICC BMS: 0.85 (95 % CI: 0.81-0.88). The criterion-concurrent validity was high to excellent (Spearman correlation coefficient: -0.91 in correlation to FIM) and the internal consistency was good (Cronbach's alpha 0.88). The BMS proved to be sensitive to improvements in mobility (Wilcoxon's signed rank test: p < 0.0001; The effect size for the BMS was 1.075 and the standardized response mean 1.10. At admission, the BMS was less vulnerable to floor effects. CONCLUSIONS: The BMS may be used as a reliable and valid tool for the assessment of mobility in the acute care setting. It is easy to apply, sensitive to change during the hospital stay and not vulnerable to floor and ceiling effects. PMID- 26242303 TI - Molecular mobility on graphene nanoroads. AB - We study molecular mobility on a graphene nanoroad (GNRD), a pristine graphene strip embedded in between two hydrogenated graphene domains serving as a nanoscale pathway for transporting admolecules. Our molecular dynamics simulations using a prototype physisorbed C60 admolecule demonstrate that the proposed GNRD is able to confine the diffusive motion of the admolecule within the nanoroad up to a certain temperature, depending on its width and edge type. Within the confinement regime, the width and edge-type of the GNRD also play an important role in the molecular motion. Specifically, when the GNRD width is narrower than the admolecule diameter, the admolecule performs one-dimensional hopping motion along the nanoroad. When the GNRD width is larger than the admolecule diameter, the admolecule moves only along one of its edges at low temperatures, and shuffle between two edges at high temperatures. We further show the admolecule motion on the zigzag-edged GRND is faster than that on the armchair-edged GRND with the same width and at the same temperature. These results can be well explained by analysing the potential energy surfaces of the systems. Since such hydrogenated graphene nanostructures have been experimentally realized, our results provide a valuable reference for constructing molecular conveyor circuits. PMID- 26242300 TI - Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)(+) TH2/TH1 cell imbalance, whereas adults acquire CLA(+) TH22/TC22 cell subsets. AB - BACKGROUND: Identifying differences and similarities between cutaneous lymphocyte antigen (CLA)(+) polarized T-cell subsets in children versus adults with atopic dermatitis (AD) is critical for directing new treatments toward children. OBJECTIVE: We sought to compare activation markers and frequencies of skin-homing (CLA(+)) versus systemic (CLA(-)) "polar" CD4 and CD8 T-cell subsets in patients with early pediatric AD, adults with AD, and control subjects. METHODS: Flow cytometry was used to measure CD69/inducible costimulator/HLA-DR frequency in memory cell subsets, as well as IFN-gamma, IL-13, IL-9, IL-17, and IL-22 cytokines, defining TH1/cytotoxic T (TC) 1, TH2/TC2, TH9/TC9, TH17/TC17, and TH22/TC22 populations in CD4 and CD8 cells, respectively. We compared peripheral blood from 19 children less than 5 years old and 42 adults with well characterized moderate-to-severe AD, as well as age-matched control subjects (17 children and 25 adults). RESULTS: Selective inducible costimulator activation (P < .001) was seen in children. CLA(+) TH2 T cells were markedly expanded in both children and adults with AD compared with those in control subjects, but decreases in CLA(+) TH1 T-cell numbers were greater in children with AD (17% vs 7.4%, P = .007). Unlike in adults, no imbalances were detected in CLA(-) T cells from pediatric patients with AD nor were there altered frequencies of TH22 T cells within the CLA(+) or CLA(-) compartments. Adults with AD had increased frequencies of IL-22-producing CD4 and CD8 T cells within the skin-homing population, compared with controls (9.5% vs 4.5% and 8.6% vs 2.4%, respectively; P < .001), as well as increased HLA-DR activation (P < .01). CONCLUSIONS: These data suggest that TH2 activation within skin-homing T cells might drive AD in children and that reduced counterregulation by TH1 T cells might contribute to excess TH2 activation. TH22 "spreading" of AD is not seen in young children and might be influenced by immune development, disease chronicity, or recurrent skin infections. PMID- 26242304 TI - Clinical Outcomes in Dialysis Patients: Prospects for Improvement with Aldosterone Receptor Antagonists. AB - Patients with advanced chronic kidney disease (CKD), particularly those who have end-stage renal disease (ESRD) and require therapy with dialysis, suffer disproportionately from cardiovascular illnesses. Therapy with mineralocorticoid receptor antagonists (MRAs) effectively reduces cardiac risk in discrete populations. Blockade of the mineralocorticoid receptor carries the potential to reduce blood pressure and to promote favorable remodeling of cardiac structure. Preliminary observations suggest that MRAs can improve survival in patients with ESRD though their widespread adoption is tempered by concerns about effectiveness in patients who have reduced kidney function and the risks of hyperkalemia. This generates a particular conundrum, as sudden cardiac arrest is the predominant cause of death in patients with advanced CKD. In this review, we highlight the potential cardiovascular benefits and review the evident risks of MRAs in patients with ESRD. PMID- 26242305 TI - Replacement of grass and maize silages with lucerne silage: effects on performance, milk fatty acid profile and digestibility in Holstein-Friesian dairy cows. AB - In total, 20 multiparous Holstein-Friesian dairy cows received one of four diets in each of four periods of 28-day duration in a Latin square design to test the hypothesis that the inclusion of lucerne in the ration of high-yielding dairy cows would improve animal performance and milk fatty acid (FA) composition. All dietary treatments contained 0.55 : 0.45 forage to concentrates (dry matter (DM) basis), and within the forage component the proportion of lucerne (Medicago sativa), grass (Lolium perenne) and maize silage (Zea mays) was varied (DM basis): control (C)=0.4 : 0.6 grass : maize silage; L20=0.2 : 0.2 : 0.6 lucerne : grass : maize silage; L40=0.4 : 0.6 lucerne : maize silage; and L60=0.6 : 0.4 lucerne : maize silage. Diets were formulated to contain a similar CP and metabolisable protein content, with the reduction of soya bean meal and feed grade urea with increasing content of lucerne. Intake averaged 24.3 kg DM/day and was lowest in cows when fed L60 (P0.05) by dietary treatment. Digestibility of DM, organic matter, CP and fibre decreased (P<0.01) with increasing content of lucerne in the diet, although fibre digestibility was similar in L40 and L60. It is concluded that first cut grass silage can be replaced with first cut lucerne silage without any detrimental effect on performance and an improvement in the milk FA profile, although intake and digestibility was lowest and plasma urea concentrations highest in cows when fed the highest level of inclusion of lucerne. PMID- 26242306 TI - Parent/caregiver health literacy among children with special health care needs: a systematic review of the literature. AB - BACKGROUND: Children with special health care needs (CSHCN) are children with medical or behavioral diagnoses that require services beyond those generally needed by pediatric populations. They account for a significant portion of pediatric health care expenditures and often have complicated treatment regiments. Health literacy has recently been recognized as a key indicator of quality chronic disease self-management and parental/caregiver health literacy of CSHCN is an understudied area. The purpose of this systematic review was to assess the available evidence of studies investigating parent/caregiver health literacy of CSHCN. METHODS: Databases were searched to retrieve relevant articles for inclusion (dating from 1998 to 2014). Only studies that assessed the relationship between parent/caregiver health literacy on outcomes pertinent to CSHCN were included. Because of the limited number of studies, there were no restrictions placed on type of outcome. RESULTS: Thirteen studies were included in the final review with a range of health literacy assessments and outcome ascertainment. The majority of studies; (1) focused on the relationship between parental/caregiver health literacy and asthma outcomes, (2) were cross-sectional study designs, and (3) included samples recruited from pediatric clinics in academic medical settings. CONCLUSIONS: There were several gaps in the literature where future research is needed including; (1) direct assessment of child/adolescent health literacy, (2) inclusion of children with co-morbid conditions, (3) further assessment of the relationship between health literacy and health care utilization and cost, and (4) assessment of parental/caregiver health literacy in the inpatient care setting. PMID- 26242307 TI - Plasmodium falciparum merozoite surface protein 1 block 2 gene polymorphism in field isolates along the slope of mount Cameroon: a cross - sectional study. AB - BACKGROUND: Malaria remains a major global health burden despite the intensification of control efforts, due partly to the lack of an effective vaccine. Information on genetic diversity in natural parasite populations constitutes a major impediment to vaccine development efforts and is limited in some endemic settings. The present study characterized diversity by investigating msp1 block 2 polymorphisms and the relationship between the allele families with ethnodemographic indices and clinical phenotype. METHOD: Individuals with asymptomatic parasitaemia (AP) or uncomplicated malaria (UM) were enrolled from rural, semi-rural and semi-urban localities at varying altitudes along the slope of mount Cameroon. P. falciparum malaria parasitaemic blood screened by light microscopy was depleted of leucocytes using CF11 cellulose columns and the parasite DNA genotyped by nested PCR. RESULTS: Length polymorphism was assessed in 151 field isolates revealing 64 (5) and 274 (22) distinct recombinant and major msp1 allelic fragments (genotypes) respectively. All family specific allelic types (K1, MAD20 and RO33) as well as MR were observed in the different locations, with K1 being most abundant. Eighty seven (60 %) of individuals harbored more than one parasite clone, with a significant proportion (p = 0.009) in rural compared to other settings. AP individuals had higher (p = 0.007) K1 allele frequencies but lower (p = 0.003) mean multiplicity of genotypes per infection (2.00 +/- 0.98 vs. 2.56 +/- 1.17) compared to UM patients. CONCLUSIONS: These results indicate enormous diversity of P. falciparum in the area and suggests that allele specificity and complexity may be relevant for the progression to symptomatic disease. PMID- 26242309 TI - Reflective oxygen saturation monitoring at hypothenar and its validation by human hypoxia experiment. AB - BACKGROUND: Pulse oxygen saturation (SpO2) is an important parameter for healthcare, and wearable sensors and systems for SpO2 monitoring have become increasingly popular. The aim of this paper is to develop a novel SpO2 monitoring system, which detects photoplethysmographic (PPG) signals at hypothenar with a reflection-mode sensor embedded into a glove. METHODS: A special photo-detector section was designed with two photodiodes arranged symmetrically to the red and infrared light-emitting diodes (LED) to enhance the signal quality. The reflective sensor was placed in a soft silicon substrate sewn in a glove to fit the surface of the hypothenar. To lower the power consumption, the LED driving current was reduced and energy-efficient electronic components were applied. The performance for PPG signal detection and SpO2 monitoring was evaluated by human hypoxia experiments. Accelerometer-based adaptive noise cancellation (ANC) methods applying the least mean squares (LMS) and recursive least squares (RLS) algorithms were studied to suppress motion artifact. RESULTS: A total of 20 subjects participated in the hypoxia experiment. The degree of comfort for wearing this system was accepted by them. The PPG signals were detected effectively at SpO2 levels from about 100-70%. The experiment validated the accuracy of the system was 2.34%, compared to the invasive measurements. Both the LMS and RLS algorithms improved the performance during motion. The total current consumed by the system was only 8 mA. CONCLUSIONS: It is feasible to detect PPG signal and monitor SpO2 at the location of hypothenar. This novel system can achieve reliable SpO2 measurements at different SpO2 levels and on different individuals. The system is light-weighted, easy to wear and power-saving. It has the potential to be a solution for wearable monitoring, although more work should be conducted to improve the motion-resistant performance significantly. PMID- 26242308 TI - Coronary microvascular function is independently associated with left ventricular filling pressure in patients with type 2 diabetes mellitus. AB - BACKGROUND: Left ventricular (LV) diastolic dysfunction is known as an early marker of myocardial alterations in patients with diabetes. Because microvascular disease has been regarded as an important cause of heart failure or diastolic dysfunction in diabetic patients, we tested the hypothesis that coronary flow reserve (CFR), which reflects coronary microvascular function, is associated with LV diastolic dysfunction in patients with type 2 diabetes. METHODS: We studied asymptomatic patients with type 2 diabetes but without overt heart failure. Transthoracic Doppler echocardiography was performed that included pulsed tissue Doppler of the mitral annulus and CFR of the left anterior descending artery (induced by adenosine 0.14 mg/kg/min). The ratio of mitral velocity to early diastolic velocity of the mitral annulus (E/e') was used as a surrogate marker of diastolic function. We also evaluated renal function, lipid profile, parameters of glycemic control and other clinical characteristics to determine their association with E/e'. Patients with LV ejection fraction <50%, atrial fibrillation, valvular disease, regional wall motion abnormality, renal failure (serum creatinine >2.0 mg/dl) or type 1 diabetes were excluded. Patients with a CFR <2.0 were also excluded based on the suspicion of significant coronary artery stenosis. RESULTS: We included 67 asymptomatic patients with type 2 diabetes and 14 non-diabetic controls in the final study population. In univariate analysis, age, presence of hypertension, LV mass index, estimated glomerular filtration rate and CFR were significantly associated with E/e'. Multivariate analysis indicated that both LV mass index and CFR were independently associated with E/e'. In contrast, there were no significant associations between parameters of glycemic control and E/e'. CONCLUSIONS: CFR was associated with LV filling pressure in patients with type 2 diabetes. This result suggests a possible link between coronary microvascular disease and LV diastolic function in these subjects. PMID- 26242310 TI - Identifying alkali metal inhibitors of crystal growth: a selection criterion based on ion pair hydration energy. AB - We show that alkali metals function as effective modifiers of calcium oxalate monohydrate (COM) crystallization wherein alkali-oxalate ion parings reduce the rate of crystal growth by as much as 60%. Our findings reveal a distinct trend in alkali metal efficacy that cannot be explained by colloidal theories or simple descriptors, such as ion size, but is consistent with a theoretical model that accounts for the ion pair's affinity for water. PMID- 26242313 TI - Evaluation of circulating betatrophin levels in gestational diabetes mellitus. AB - Experimental data indicate that betatrophin plays a significant role in the regulation of lipid metabolism and glucose homeostasis. In recent years, considerable attention has focused on the relationship between betatrophin and diabetes mellitus in humans. This case-control study included 45 women diagnosed with gestational diabetes mellitus (GDM) and 45 pregnant healthy controls. The groups were matched for maternal and gestational age and body mass index. Serum betatrophin levels were significantly higher in women with GDM (median = 635.8 ng/L; range: 290-1841.6 ng/L) compared to control subjects (median = 320.1 ng/L; range: 94.6-936.8 ng/L; p = 0.001). No significant correlations were observed between serum betatrophin levels and clinical or biochemical parameters in the control group. However, in the GDM group, serum betatrophin levels were positively correlated with weight gain during pregnancy (r = 0.304, p = 0.042), systolic blood pressure (r = 0.394, p = 0.007), fasting insulin level (r = 0.348, p = 0.019), and homeostatic model assessment insulin resistance (HOMA-IR; r = 0.311, p = 0.038). Multivariate stepwise linear regression analysis revealed that fasting insulin levels (beta = 0.342, p = 0.022) and HOMA-IR (beta = 0.312, p = 0.037) were independently associated with serum betatrophin levels. PMID- 26242311 TI - Characteristics and survival for HIV-associated multicentric Castleman disease in Malawi. AB - INTRODUCTION: Clinical reports of multicentric Castleman disease (MCD) from sub Saharan Africa (SSA) are scarce despite high prevalence of HIV and Kaposi sarcoma associated herpesvirus (KSHV). Our objective is to describe characteristics and survival for HIV-associated MCD patients in Malawi. To our knowledge, this is the first HIV-associated MCD case series from the region. METHODS: We describe HIV positive patients with MCD in Lilongwe, and compare them to HIV-associated lymph node Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) patients treated at our centre. All patients were enrolled into a prospective longitudinal cohort study at a national teaching hospital and cancer referral centre serving half of Malawi's 16 million people. We included adult patients>=18 years of age with HIV associated MCD (n=6), lymph node KS (n=5) or NHL (n=31) enrolled between 1 June 2013 and 31 January 2015. RESULTS AND DISCUSSION: MCD patients had a median age of 42.4 years (range 37.2-51.8). All had diffuse lymphadenopathy and five had hepatosplenomegaly. Concurrent KS was present for one MCD patient, and four had performance status >=3. MCD patients had lower median haemoglobin (6.4 g/dL, range 3.6-9.3) than KS (11.0 g/dL, range 9.1-12.0, p=0.011) or NHL (11.2 g/dL, range 4.5-15.1, p=0.0007). Median serum albumin was also lower for MCD (2.1 g/dL, range 1.7-3.2) than KS (3.7 g/dL, range 3.2-3.9, p=0.013) or NHL (3.4 g/dL, range 1.8-4.8, p=0.003). All six MCD patients were on antiretroviral therapy (ART) with median CD4 count 208 cells/uL (range 108-1146), and all with HIV RNA <400 copies/mL. Most KS and NHL patients were also on ART, although ART duration was longer for MCD (56.4 months, range 18.2-105.3) than KS (14.2 months, range 6.8 21.9, p=0.039) or NHL (13.8 months, range 0.2-98.8, p=0.017). Survival was poorer for MCD patients than lymph node KS or NHL. CONCLUSIONS: HIV-associated MCD occurs in Malawi, is diagnosed late and is associated with high mortality. Improvements in awareness, diagnostic facilities, treatment and supportive care are needed to address this likely under-recognized public health problem in SSA. PMID- 26242312 TI - Development of a heptaplex PCR assay for identification of Staphylococcus aureus and CoNS with simultaneous detection of virulence and antibiotic resistance genes. AB - BACKGROUND: Staphylococcal toxicity and antibiotic resistance (STAAR) have been menacing public health. Although vancomycin-resistant Staphylococcus aureus (VRSA) is currently not as widespread as methicillin-resistant S. aureus (MRSA), genome evolution of MRSA into VRSA, including strains engineered within the same patient under anti-staphylococcal therapy, may build up to future public health concern. To further complicate diagnosis, infection control and anti-microbial chemotherapy, non-sterile sites such as the nares and the skin could contain both S. aureus and coagulase-negative staphylococci (CoNS), either of which could harbour mecA the gene driving staphylococcal methicillin-resistance and required for MRSA-VRSA evolution. RESULTS: A new heptaplex PCR assay has been developed which simultaneously detects seven markers for: i) eubacteria (16S rRNA), ii) Staphylococcus genus (tuf), iii) Staphylococcus aureus (spa), iv) CoNS (cns), v) Panton-Valentine leukocidin (pvl), vi) methicillin resistance (mecA), and vii) vancomycin resistance (vanA). Following successful validation using 255 reference bacterial strains, applicability to analyse clinical samples was evaluated by direct amplification in spiked blood cultures (n = 89) which returned 100 % specificity, negative and positive predictive values. The new assay has LoD of 1.0x10(3) CFU/mL for the 16S rRNA marker and 1.0x10(4) CFU/mL for six other markers and completes cycling in less than one hour. CONCLUSION: The speed, sensitivity (100 %), NPV (100 %) and PPV (100 %) suggest the new heptaplex PCR assay could be easily integrated into a routine diagnostic microbiology workflow. Detection of the cns marker allows for unique identification of CoNS in mono microbial and in poly-microbial samples containing mixtures of CoNS and S. aureus without recourse to the conventional elimination approach which is ambiguous. In addition to the SA-CoNS differential diagnostic essence of the new assay, inclusion of vanA primers will allow microbiology laboratories to stay ahead of the emerging MRSA-VRSA evolution. To the best of our knowledge, the new heptaplex PCR assay is the most multiplexed among similar PCR-based assays for simultaneous detection of STAAR. PMID- 26242314 TI - The adjuvant effect of metformin and N-acetylcysteine to clomiphene citrate in induction of ovulation in patients with Polycystic Ovary Syndrome. AB - OBJECTIVES: To assess the adjuvant effect of metformin and N-acetylcysteine (NAC) to clomiphene citrate (CC) in induction of ovulation in Polycystic Ovary Syndrome (PCOS) patients. STUDY DESIGN: 120 women with PCOS were randomly divided into three equal groups: group I received CC only, group II received CC plus NAC and group III received CC plus metformin. RESULTS: There was a significant difference between group II and other two groups regarding average number of ovulatory follicles >18 mm (2.25 versus 1.75 and 1.89, respectively), but no significant difference between the three study groups regarding number of intermediate follicles 14-18 mm (4, 10 and 4, respectively). There was no significant difference between the three study groups regarding occurrence and laterality of ovulation, pregnancy rate per cycle but a significant difference between group II and other two groups regarding pregnancy rate per patient (20% versus 10% and 10%, respectively, p value 0.05). There was a highly statistically significant difference between group II and other two groups regarding peak endometrial thickness (7.3 +/- 1.1 versus 5.4 +/- 0.6 and 5.3 +/- 0.6, respectively). CONCLUSIONS: NAC as an adjuvant to CC for induction of ovulation improves ovulation and pregnancy rates in PCOS patients with beneficial impacts on endometrial thickness. PMID- 26242315 TI - Model of End-Stage Liver Disease Score and Derived Variants Lack Prognostic Ability after Liver Transplantation. AB - BACKGROUND The model of end-stage liver disease (MELD) score is currently used for donor liver allocation in many regions. The objective of this retrospective study was to assess the MELD score and its diverse variants as prognostic models for mortality after liver transplantation. MATERIAL AND METHODS An analysis of 454 consecutive adult liver transplants since the introduction of MELD-based donor liver allocation was conducted. Eight different MELD score variants were investigated. Receiver operating characteristic (ROC) curve analysis was performed to calculate the sensitivity, specificity, and overall model correctness of the investigated scores as a predictive model. The Brier score was used for the prediction of model accuracy and calculated as described before. Study endpoints were 90-day mortality and long-term patient mortality. RESULTS A 90-day mortality of 15.4% (n=69) and long-term mortality of 25% (n=112) were observed. All investigated models fail to reach relevant areas under the ROC curve greater than 0.700 for the prediction of mortality after liver transplantation. All calculated Brier scores were greater than 0.25, indicating a significant lack of model discrimination and calibration of the investigated scores. CONCLUSIONS A prognostic model for the prediction of outcome after transplantation still needs to be identified and should allow weighing urgency against utility in liver transplantation. PMID- 26242316 TI - Benign emptying of the post-pneumonectomy space: recognizing this rare complication retrospectively. AB - Patients presenting with a sudden drop in the pleural fluid level after a pneumonectomy in the absence of a recognizable bronchopleural fistula (BPF) have been classified as cases of benign emptying of the post-pneumonectomy space (BEPS). A retrospective study of 1378 pneumonectomies identified 4 cases of BEPS (0.29%). The patients were men; median age 64 years and all had undergone a right pneumonectomy. The median time at diagnosis was 31 days postoperatively and the median follow-up time was 31 months. None of the patients experienced a documented BPF or empyema. Although BEPS is an extremely rare complication, early recognition and close patient monitoring will prevent unnecessary interventional strategies. PMID- 26242317 TI - Elevated inflammatory parameters and inflammation scores are associated with poor prognosis in patients undergoing pulmonary metastasectomy for colorectal cancer. AB - OBJECTIVES: Pulmonary metastasectomy (PM) has evolved to become a standard treatment for colorectal cancer lung metastases. However, biomarkers to estimate the prognosis after PM are currently missing. We therefore investigated the prognostic impact of inflammatory-related biomarkers and scores in patients undergoing curative PM for colorectal cancer. METHODS: We analysed prospectively collected datasets of 52 patients treated in our institution between April 2009 and June 2014. Fibrinogen (cut-off 325 mg/dl), C-reactive protein (CRP, cut-off 0.5 mg/dl), the modified Glasgow prognostic score (mGPS) and the neutrophil-to lymphocyte ratio (NLR) at the time of PM were tested for their prognostic power, and correlated to time to recurrence (TTR), time to lung-specific recurrence (TTLR) and overall survival (OS). RESULTS: Median OS after PM of all patients (n = 52, 21 females, 31 males, mean age +/- standard deviation: 62.65 +/- 11.41 years) was 36 months [95% confidence interval (CI) 24.7-47.3 months, number of events: n = 20/38.5%]. In univariable survival analyses, high fibrinogen [hazard ratio (HR) 5.51, 95% CI 1.21-25.17], elevated CRP (HR 2.81, 95% CI 1.08-7.28), mGPS >0 (HR 2.81, 95% CI 1.08-7.28) and an NLR of 4 or higher (HR 3.05, 95% CI 1.02-9.13) was associated with poor OS. Median TTR was 15 months for all patients (number of events: n = 35/67.3%). Fibrinogen (HR 3.79, 95% CI 1.32-10.94) and NLR (HR 2.99, 95% CI 1.20-7.46) but not CRP (P = 0.102) and mGPS (P = 0.102) were found to indicate TTR. With regard to TTLR (number of events: n = 26/50%), only NLR predicted early lung recurrence (HR 3.02, 95% CI 1.06-8.564). After multivariable analyses, fibrinogen was the only significant OS predictor. However, all investigated inflammatory biomarkers and scores were prognostic for TTR in multivariable analyses. Finally, we divided the study population into an inflammatory phenotype (one or more inflammatory marker/score-elevated) and a non inflammatory phenotype group. The inflammatory phenotype was prognostic in uni- and multivariable analyses for all three outcome parameters (OS, TTR and TTLR). CONCLUSIONS: Inflammatory markers provided promising prognostic information in this cohort of curative PM patients after colorectal cancer. Further validation is needed to verify the prognostic role of these markers and establish them in clinical routine. PMID- 26242318 TI - A novel bioabsorbable pericardial membrane substitute to reduce postoperative pericardial adhesions in a rabbit model. AB - OBJECTIVES: In paediatric cardiac surgery, reoperations remain challenging since the injury and the formation of dense adhesions before reoperations can be life threatening to the heart, bypass conduits or great vessels. To prevent the formation of dense adhesions, a variety of different types of pericardial membrane substitute have been employed. However, due to peel formation, calcification and infection, the routine application of these pericardial membrane substitute has not been achieved clinically. A novel bioabsorbable membrane has been developed from polylactic acid (PLA) to overcome these drawbacks. The purpose of this study was to assess the biosafety and the effectiveness of PLA membrane as a new bioabsorbable pericardial membrane substitute after pericardium replacement in a rabbit model. METHODS: A total of 33 rabbits underwent abrasion on the surface of the heart through right thoracotomy and were divided into a PLA membrane group (n = 17) and a control group (n = 16). Biosafety was assessed by comparing pre- and postoperative liver/kidney function and C-reactive protein levels. Subsequently, at 4 and 12 weeks postoperatively, the degree of reabsorption of the membrane and the intensity of adhesions were macroscopically assessed, followed by a microscopic evaluation for histological changes. Samples of the regenerated fibrous membranes that were harvested 12 weeks after implantation were used to perform immunostaining for cytokeratin and human bone marrow endothelial cell-1 (HBME-1). RESULTS: The PLA membrane group exhibited a little inflammatory response (P > 0.05) and liver/kidney dysfunction (P > 0.05). The PLA membrane was mostly absorbed by 12 weeks with the replacement of loosely adherent tissue. Moderate adhesions were found between the pericardial membrane substitute and the epicardium at the 4-week postoperative inspection. After 12 weeks postoperatively, the adhesions were found to have resolved completely. The composite score, which combined the histological findings of inflammation and the tightness of adhesions, was graded on a scale of 0 to 3. Significant differences between the PLA and control groups were detected at 4 weeks (1.2 +/- 0.4, 2.1 +/- 0.6; P = 0.007, respectively) and 12 weeks (0.5 +/- 0.5, 2.5 +/- 0.7; P = 0.001, respectively). Twelve weeks after the replacement of the pericardium with the PLA membrane, as shown by the cells positively immunostained for cytokeratin and HBME 1, the regenerated membrane consisted of a bilayer structure mimicking the native pericardium. CONCLUSIONS: To prevent the formation of adhesions after cardiac surgery, the bioabsorbable PLA membrane might serve as a promising substitute for the pericardium, which proved to be safe and efficacious in our study. PMID- 26242319 TI - Comprehensive analysis of metastatic N1 lymph nodes in completely resected non small-cell lung cancer. AB - OBJECTIVES: The aim of this study was to comprehensively analyse metastatic lymph nodes as prognostic factors after complete resection in N1 non-small-cell lung cancer (NSCLC). METHODS: We enrolled 195 patients with pathological N1 NSCLC after complete resection. The number of metastatic lymph nodes and metastatic stations, locations of metastatic lymph nodes, total number of dissected LNs, number of dissected N1 and N2 nodes and the ratio of the number of metastatic N1 nodes to the total number of dissected LNs were evaluated. Univariate analysis by the log-rank test and multivariate analysis by a Cox proportional hazards model were performed to identify prognostic factors of metastatic N1 lymph nodes. RESULTS: The median follow-up duration was 44.2 (6-135) months, recurrence occurred in 76 (39%) and 66 (34%) died. The 3- and 5-year disease-free survival rates and overall survival rates were 65 and 58%, and 89 and 72%, respectively. Univariate analysis identified being a never smoker, adenocarcinoma, pathological stage, hilar node metastasis, multistation metastasis, having four or more metastatic LNs and the lymph node ratio as factors predicting recurrence. Multivariate analysis revealed that adenocarcinoma, pathological stage III and multiple stations of metastatic lymph node were independent risk factors of recurrence. CONCLUSIONS: Besides adenocarcinoma and pathological stage III, multistation metastasis was the single prognostic factor among various characteristics of metastatic N1 lymph nodes. PMID- 26242320 TI - TRUE Test(r) and baseline series. PMID- 26242321 TI - Phototoxicity of B-RAF inhibitors: Exclusively due to UVA radiation and rapidly regressive. AB - BACKGROUND: New targeted melanoma therapies such as B-RAF inhibitors have shown high and promising clinical benefit but have cutaneous side-effects, including photosensitivity, which is triggered in the UVA radiation spectrum. However, visible spectrum implication has not yet been investigated. We conducted a study to determine whether visible light also contributes to the phototoxicity action spectrum of vemurafenib. The secondary end points were to determine the time to complete regression of the phototoxicity post-vemurafenib discontinuation and whether there was a significant difference between the UVA radiation immediate reactivity cut-offs, in patients treated with vemurafenib vs. those treated with dabrafenib. METHOD: This prospective, observational study included patients with B-RAF mutant metastatic melanoma: 34 patients treated with vemurafenib and 9 with dabrafenib. RESULTS: The visible-light phototest results in patients treated with vemurafenib were all negative before and after 2 months of treatment. The UVA radiation phototests conducted 1 or 2 weeks post-vemurafenib discontinuation in 4 patients showed a normalised UVA-radiation reactivity cut-off. UVA radiation phototests after 2 months of treatment were conducted for all patients. The UVA radiation reactivity cut-off had been lowered for 30 patients (88%) on vemurafenib and 3 patients (33%) on dabrafenib. The median UVA radiation reactivity cut-off was 12 J/cm(2) for the patients on vemurafenib and 20 J/cm(2) for the patients on dabrafenib. CONCLUSION: B-RAF inhibitor phototoxicity is exclusively triggered by UVA radiation and resolves rapidly post-treatment discontinuation. A significant difference between the UVA immediate reactivity cut-offs, vemurafenib vs. dabrafenib, explains the difference in the clinical photosensitivity rates reported in the clinical trials. PMID- 26242323 TI - Drosophila germ granules are structured and contain homotypic mRNA clusters. AB - Germ granules, specialized ribonucleoprotein particles, are a hallmark of all germ cells. In Drosophila, an estimated 200 mRNAs are enriched in the germ plasm, and some of these have important, often conserved roles in germ cell formation, specification, survival and migration. How mRNAs are spatially distributed within a germ granule and whether their position defines functional properties is unclear. Here we show, using single-molecule FISH and structured illumination microscopy, a super-resolution approach, that mRNAs are spatially organized within the granule whereas core germ plasm proteins are distributed evenly throughout the granule. Multiple copies of single mRNAs organize into 'homotypic clusters' that occupy defined positions within the center or periphery of the granule. This organization, which is maintained during embryogenesis and independent of the translational or degradation activity of mRNAs, reveals new regulatory mechanisms for germ plasm mRNAs that may be applicable to other mRNA granules. PMID- 26242324 TI - Mass Spectra and Cross-Contribution of Ion Intensity Between Drug Analytes and Their Isotopically Labelled Analogs - Benzodiazepines and Their Derivatives. AB - With GC-MS as the preferred method and isotopically labeled analogs (ILAs) of the analytes as the internal standards (ISs) of choice for quantitative determination of drugs/metabolites in biological specimens, one important aspect associated with chemical derivatization (CD) is that the CD products derived from the analyte and the selected IS must generate ions suitable for designating the analyte and the IS. These ions must not have significant cross-contribution (CC), i.e., ISs' contribution to the intensities of the ions designating the analytes, and vice versa. With this in mind, the authors have reviewed literature and information provided by manufacturers, searching for suitable CD reagents, CD methods, and ILAs of the analytes related to the following 18 benzodiazepines: oxazepam, diazepam, nordiazepam, nitrazepam, temazepam, clonazepam, 7 aminoclonazepam, prazepam, lorazepam, flunitrazepam, 7-aminoflunitrazepam, N desalkylflurazepam, N-desmethylflunitrazepam, 2-hydroxyethylflurazepam, estazolam, alprazolam, alpha-hydroxyalprazolam, and alpha-hydroxytriazolam. These analytes and ILAs were derivatized with various derivatization groups, followed by GC-MS analysis. The resulting mass spectrometric data are systematically presented in two forms: (a) full-scan mass spectra; and (b) CC data of ion-pairs with potential for designating the analytes and their respective ILAs (candidates of ISs in quantitative analytical protocols). Many of these full-scan mass spectra are not yet available in the literature and should be of reference value to laboratories engaged in the analysis of these drugs/metabolites. Full-scan MS data were further used to select ion-pairs with potential for designating the analytes and ISs in quantitative analysis protocols. The CC data of these ion pairs were evaluated using data collected in selected ion monitoring mode and systematically tabulated, making the data readily available for analysts searching for this important analytical parameter. PMID- 26242322 TI - RNA-seq reveals the critical role of OtpR in regulating Brucella melitensis metabolism and virulence under acidic stress. AB - The response regulator OtpR is critical for the growth, morphology and virulence of Brucella melitensis. Compared to its wild type strain 16 M, B. melitensis 16 MDeltaotpR mutant has decreased tolerance to acid stress. To analyze the genes regulated by OtpR under acid stress, we performed RNA-seq whole transcriptome analysis of 16 MDeltaotpR and 16 M. In total, 501 differentially expressed genes were identified, including 390 down-regulated and 111 up-regulated genes. Among these genes, 209 were associated with bacterial metabolism, including 54 genes involving carbohydrate metabolism, 13 genes associated with nitrogen metabolism, and seven genes associated with iron metabolism. The 16 MDeltaotpR also decreased capacity to utilize different carbon sources and to tolerate iron limitation in culture experiments. Notably, OtpR regulated many Brucella virulence factors essential for B. melitensis intracellular survival. For instance, the virB operon encoding type IV secretion system was significantly down-regulated, and 36 known transcriptional regulators (e.g., vjbR and blxR) were differentially expressed in 16 MDeltaotpR. Selected RNA-seq results were experimentally confirmed by RT-PCR and RT-qPCR. Overall, these results deciphered differential phenomena associated with virulence, environmental stresses and cell morphology in 16 MDeltaotpR and 16 M, which provided important information for understanding the detailed OtpR regulated interaction networks and Brucella pathogenesis. PMID- 26242325 TI - Management of Postoperative Spondylodiscitis with and without Internal Fixation. AB - Postoperative spondylodiscitis is relatively uncommon. This complication is associated with increased cost, and long-term of inability to work, and even morbidity. Although the majority of postoperative spondylodiscitis cases can be well managed by conservative treatment, postoperative spondylodiscitis after internal fixation and those cases that are unresponsive to the conservative treatment present challenges to the surgeon. Here, a review was done to analyze the treatment of postoperative spondylodiscitis with/without internal fixation. This review article suggested that majority of postoperative spondylodiscitis without internal fixation could be cured by conservative treatment. Either posterior or anterior debridement can be used to treat postoperative spondylodiscitis without internal fixation when conservative treatment fails. In addition, minimally invasive debridement and drainage may also be an alternative treatment. In case of postoperative spondylodiscitis after internal fixation, surgical treatment was required. In the cervical spine, it can be well managed by anterior debridement, removal of internal fixation, and reconstruction of the spinal stability by using bone grafting/cage/anterior plate. Postoperative spondylodiscitis after internal fixation is successfully managed by combined anterior debridement, fusion with posterior approach and removal of pedicle screw or extension of pedicle screw beyond the lesion site, in the thoracic and lumbar spine. PMID- 26242326 TI - Preventive Role of Hilar Parasympathetic Ganglia on Pulmonary Artery Vasospasm in Subarachnoid Hemorrhage: An Experimental Study. AB - AIM: Pulmonary arteries are mainly innervated by sympathetic vasoconstrictor and parasympathetic vasodilatory fibers. We examined whether there is a relationship between the neuron densities of hilar parasympathetic ganglia and pulmonary vasospasm in subarachnoid hemorrhage (SAH). MATERIAL AND METHODS: Twenty-four rabbits were divided into two groups: control (n=8) and SAH (n=16). The animals were observed for 20 days following experimental SAH. The number of hilar parasympathetic ganglia and their neuron densities were determined. Proportion of pulmonary artery ring surface to lumen surface values was accepted as vasospasm index (VSI). Neuron densities of the hilar ganglia and VSI values were compared statistically. RESULTS: Animals in the SAH group experienced either mild (n=6) or severe (n=10) pulmonary artery vasospasm. In the control group, the mean VSI of pulmonary arteries was 0.777+/-0.048 and the hilar ganglion neuron density was estimated as 12.100+/-2.010/mm < sup > 3 < /sup > . In SAH animals with mild vasospasm, VSI=1.148+/-0.090 and neuron density was estimated as 10.110+/ 1.430/mm < sup > 3 < /sup > ; in animals with severe vasospasm, VSI=1.500+/-0.120 and neuron density was estimated as 7.340+/-990/mm < sup > 3 < /sup > . CONCLUSION: There was an inverse correlation between quantity and neuron density of hilar ganglia and vasospasm index value. The low numbers and low density of hilar parasympathetic ganglia may be responsible for the more severe artery vasospasm in SAH. PMID- 26242327 TI - Endovascular Management of Superior Cerebellar Artery Aneurysms: Mid and Long Term Results. AB - AIM: Superior cerebellar artery (SCA) aneurysms are uncommon vascular lesions, thus data about their presentation and clinical management are limited. Our aim was to determine clinical presentation, angiographic findings and mid and long term clinical and imaging results of endovascular treatment of 49 patients with SCA aneurysm. MATERIAL AND METHODS: Forty-nine patients with SCA aneurysms underwent endovascular treatment (25 female, 24 male; mean age 46.7 years; range, 21-79 years) in our institution. Both aneurysms arising at the origin of SCA and peripheral SCA aneurysms were included to our retrospective study. 73.5% of the patients were presented with subarachnoid hemorrhage. Forty-two of 49 (85.7%) aneurysms were located in the origin of SCA. Mean aneurysm size was 6.5 mm (range 2-16 mm). RESULTS: Forty-seven (95.9%) of the aneurysms were coiled with detachable coils. In two peripheral aneurysms, liquid embolic agent was used. Overall control angiographic occlusion rates were as follows: 87.5% (34/40) total occlusion and 12.5% (6/40) dog-ear remnant. All peripheral SCA aneurysms were occluded with the parent artery. Procedure related mortality was seen in one patient (2%) due to the rupture of another aneurysm. There was no procedure related permanent morbidity. CONCLUSION: Endovascular treatment is an effective and safe option in both peripheral and proximal SCA aneurysms. PMID- 26242328 TI - The Comparison of Pullout Strengths of Various Pedicle Screw Designs on Synthetic Foams and Ovine Vertebrae. AB - AIM: One of the most common problems with transpedicular screws is screw pullout. This study was conducted to measure the pullout strengths of newly designed transpedicular screws. MATERIAL AND METHODS: The design of the three group screws were conical cored standard pedicle screw (Type A), dual threaded pedicle screw (Type B), dual core and dual threaded pedicle screw (Type C), respectively. Polyurethane (PU) blocks in 25 mm and 50 mm thickness were used to investigate the effect of just the pedicle on pullout strength and both distal (vertebral body) and proximal (pedicle) parts of the screw. The screws were also tested in ovine lumbar vertebrae. RESULTS: Type C screw exhibited 5.9% and 12.9% higher pullout strength than Type A and Type B, and 15.4% and 8.6% higher pullout strength than Type A and Type B, respectively on 25 mm and 50 mm thick PU foam block. Type C also exhibited 74.5% and 22.5% higher pullout strength than Type A and Type B, respectively on the ovine vertebrae. CONCLUSION: Transpedicular screws redesigned with modified helical angles exhibit higher pullout strength compared to the classical transpedicular screws and can be inserted more rapidly with the same number of screwing rounds result with doubled insertion depth. PMID- 26242329 TI - Microsurgical Anatomy of the Labyrinthine Artery and Clinical Relevance. AB - AIM: To describe the origin, the course, and relationships of the labyrinthine artery (LA). MATERIAL AND METHODS: Thanks to a colored silicone mix preparation, ten cranial bases were examined using x3 to x40 magnification under surgical microscope. RESULTS: The LA often arose from the meatal loop of the anterior inferior cerebellar artery (AICA) (90%), or basilar artery (10%). The loop was extra-meatal of the internal auditory meatus (IAM) in 30%, at the opening of the internal auditory meatus in 20%, or intra-meatal in 35%. The AICA coursed in closed relationship to the VII and VIII cranial nerves. It coursed between VII and VIII cranial nerve roots in 85%, or passed over the ventral side of both VII and VIII cranial nerve. The average diameter of the LA was 0.2 +/- 0.05 mm. LA was single trunk in 60%, and bi-arterial in 40%. CONCLUSION: The implication of these anatomic findings for cerebello-pontine angle tumors surgery and neurovascular pathology such as infarction, aneurysm of the LA or the AICA are reviewed and discussed. PMID- 26242330 TI - Effects of Intensive Blood Pressure Lowering on Intracerebral Hemorrhage Outcomes: A Meta-Analysis of Randomized Controlled Trials. AB - AIM: Elevation of blood pressure (BP) is common after intracerebral hemorrhage (ICH). Early BP treatment may be beneficial after ICH, but the effect of intensive BP lowering on ICH outcomes is not known and no systematic review or meta-analysis was published regarding this issue. MATERIAL AND METHODS: We conducted a meta-analysis to compare the effect of more versus less intensive BP targets on clinical outcomes in patients with ICH. Mortality, unfavorable outcome and adverse events were analyzed. Meta-analysis was performed in terms of the odds ratio (OR) and 95% confidence interval (CI). RESULTS: Five eligible studies were included and analyzed, involving 3243 patients to use systolic BP (SBP) < 140 mmHg as target BP and 142 patients to use other BP target in intensive BP target group. The pooled OR of mortality and unfavorable outcome after ICH in intensive BP control group comparing with less intensive BP targets group were 0.99 (95% CI 0.81 to 1.23) and 0.90 (95% CI 0.78 to 1.03) respectively. The pooled OR were 0.97 (95% CI 0.80 to 1.18) for neurological deterioration and 0.83 (95% CI 0.61 to 1.11) for hematoma expansion. There is no difference in other adverse events between two groups. CONCLUSION: Acute lowering of SBP to 140 mmHg is probably beneficial for functional outcome in patients with ICH, but the evidence is still insufficient. Further large multicenter studies are required to enhance the evidence to guide the BP lowering target following ICH. PMID- 26242331 TI - Neuroprotective Effects of Erythropoietin in Patients with Severe Closed Brain Injury. AB - AIM: Our research was focused on the neuroprotective function of erythropoietin (Epo) in patients with severe closed traumatic brain injury (TBI). MATERIAL AND METHODS: Our model examined the influence of the outcome and neurological recovery in 42 adults with TBI who were admitted to ICU within 6 hours of their injury and were recruited into a randomized controlled study of two groups; only the patients of the intervention group received 10,000 i.u. of Epo for 7 consecutive days. A prognostic model based on CRASH II injury model and outcome was measured by survival and Glasgow Outcome Scale-Extended version (GOS-E) score at 6 months post-injury. RESULTS: Six patients (18.7%) died during the first two weeks; 4 of the control group and 2 of the intervention group. A mortality rate of 22.2% and 8.3% for the control and intervention group respectively was observed. A lower rate of good outcome (GOS-E score > 4) at 6 months was mentioned among patients of the control group. CONCLUSION: The study provides evidence of lower mortality and better neurological outcome for the patients who received Epo increasing the possibility that Epo therapy could be used in clinical practice, limiting neuronal damage induced by TBI. PMID- 26242332 TI - Feasibility of Screw Placement in the Occipital Condyle of Chinese Patients for Occipitocervical Arthrodesis: A Cadaveric Study. AB - AIM: The feasibility of computed tomography (CT) and two-dimensional (2D) reconstruction-guided screw placement in the occipital condyle (OC) of Chinese patients was investigated. MATERIAL AND METHODS: Twenty (40 OCs) fresh cadaveric specimens with intact superior cervical spine and occipital bones were placed in the prone position. Simulated screw placement was achieved by placing 4.0 mm diameter virtual screws with the help of the 2D reconstruction CT scan image technology. Maximal screw length, angulation in the sagittal and transverse planes, and medial and cranial base OC entry points were determined and recorded. Actual screw placement was achieved by similar placement; actual position and angulation were determined by postoperative CT scanning. RESULTS: Screws were successfully inserted in 36 of 40 (90%) OCs. Four ruptures of the medial OC wall were on the left side. Actual screw placement did not damage the hypoglossal canal, and no screws pierced the medial or lateral OC walls. Females displayed significantly smaller left and right maximum screw lengths than males (p < 0.05); no other significant gender differences were noted. CONCLUSION: The results can feasibly accommodate 4-mm OC screws for OA treatment. As in other populations, OC shape and size is smaller in females and varies in Chinese individuals, necessitating individualized imaging for good outcomes. PMID- 26242333 TI - Morphometric Analysis of the Sacral Canal and Hiatus Using Multidetector Computed Tomography for Interventional Procedures. AB - AIM: The sacral canal has been frequently used as "a passage" for minimally invasive diagnostic and therapeutic procedures for spinal diseases. The aim of the present study was to investigate morphometric analyses of the sacral canal, hiatus, and surrounding structures according to different age groups and gender by using the "multidetector computed tomography" method. MATERIAL AND METHODS: Multiplanar-reconstructed images from 300 adult (150 females and 150 males, between 20 and 80 years old) were divided into three groups according to age and retrospectively examined. Various anatomic measurements of the sacral hiatus, surrounding structures, and sacral canal were performed. Sacral curvature angle and lumbosacral lordotic angle were noted. RESULTS: Bony anatomic abnormalities such as absent hiatus (0.3%), complete agenesis (1%), and bony septum (2.6%) were detected in some cases. The anteroposterior (AP) diameter of the hiatus was less than 2 mm in 5% of cases. In all groups, the mean values of the hiatus AP diameter and area, and the shortest distance of the sacral canal AP diameter were shorter in the 60-80 years age group when compared with those in 20-39 years age group (p=0.01). The shortest sacral canal AP diameter was commonly located at the S2 and S3 levels in 59.2% and 33.9% of cases, respectively. The levels of maximum curvature were at S3 and S2 in 63.3% and 26.7% of cases, respectively. Median sacral curvature angles and lumbosacral lordotic angles were measured as 164 degrees and 134 degrees , respectively. CONCLUSION: Sacral structures have morphometric variations. Understanding of the detailed anatomy may improve the reliability of interventional procedures. PMID- 26242334 TI - Expression of Stem Cell Marker Nestin and MicroRNA-21 in Meningiomas. AB - AIM: Meningiomas are one of the most common benign intracranial tumors, making up nearly one third of all primary intracranial tumors. The majority of meningiomas have benign histological features and total resection is associated with favourable prognosis. Atypical and malignant meningiomas are associated with increased risk of recurrence. In the present study we set out to investigate the role of nestin mRNA levels and miR-21 in meningiomas. MATERIAL AND METHODS: We studied 17 patients with meningiomas that were treated surgically in our institute. Clinical variables that were analyzed were age, sex and histology. The expression of stem cell marker nestin mRNA levels and miR-21 was investigated in tissue samples by qRT-PCR. RESULTS: Considerable levels of both miR-21 and nestin mRNA were found. Atypical and anaplastic meningiomas had higher expression of both miR-21 and nestin compared to benign tumors. Furthermore, a trend towards a positive correlation between miR-21 and nestin mRNA levels was also found. CONCLUSION: Increased miR-21 and nestin mRNA levels were found in anaplastic meningiomas, in which recurrence is common, and the role of miR-21 and Nestin in meningiomas therefore warrants further investigation. PMID- 26242335 TI - Effect of Posterior Dynamic Instrumentation on High-Intensity Zone in Lumbar Degenerative Disc Disease. AB - AIM: To investigate high-intensity zone (HIZ) changes after lumbar posterior dynamic instrumentation. MATERIAL AND METHODS: Our study included 53 patients: 27 patients in group 1, 26 patients in group 2. All patients had one or two levels of degenerative disc disease with an HIZ confirmed by magnetic resonance imaging (MRI). Group 1 underwent one- or two-level dynamic lumbar posterior instrumentation. Group 2 was treated conservatively with an exercise program. Patients were evaluated using MRI, a numerical visual analog pain scale (VAS), and the Oswestry Disability Index (ODI) at baseline, at 1 year after surgery, and at final follow-up evaluation. RESULTS: The mean duration of follow-up was 49.3 months in group 1 and 47.19 months in group 2. The baseline VAS and ODI scores were similar for both groups. The mean VAS score of group 1 was significantly improved at 1 year after surgery and at final follow-up. The mean ODI value was lower in group 1 than in group 2 at 1 year and at final follow-up. Pfirrmann grades in group 1 significantly differed at 1 year and at final follow-up but did not change in group 2. The number of HIZs significantly decreased in from baseline to 1 year and from baseline to final follow-up in group 1 but did not differ in group 2. CONCLUSION: Dynamic lumbar stabilization systems are promising. Observations such as Pfirrmann grade improvements and disappearance of HIZs are concordant with improvements in VAS and ODI scores demonstrate that dynamic stabilization systems may provide an environment for regeneration. PMID- 26242336 TI - Anatomical Variability in the Termination of the Basilar Artery in the Human Cadaveric Brain. AB - AIM: The basilar artery (BA) is the prominent median vessel of the vertebrobasilar circulation and usually terminates into two posterior cerebral arteries forming the posterior angle of the Circle of Willis (CW). To tackle different variations of CW, basilar artery acts as a guideline for neuroradiologists and neurosurgeons. Basilar termination is the most frequent site of aneurysm. Abnormalities at the site of termination may compress the oculomotor nerve. Variations at the termination may complicate surgeries at the base of brain. The present study aims to add to the knowledge regarding the termination pattern of the BA. MATERIAL AND METHODS: 170 BA terminations were studied. Morphological variations in the termination pattern were noted. Frequency of variations in termination patterns was recorded. Dimensions of BA were measured. Data were analyzed. RESULTS: Morphological variations in termination were seen in 17.64%. Bifurcation, Trifurcation, Quadrifurcation, Pentafurcation and Nonfurcation of BA was seen in 82.35%, 5.29%, 5.88%, 3.52% and 2.94% respectively. BA associated with aneurysm and Fenestration was seen in 3.52% and 1.17% respectively. Mean length and diameter of BA was 30.27 mm and 4.8 mm respectively. CONCLUSION: Awareness of these anatomical variations in termination patterns of BA is important in neurovascular procedures. PMID- 26242337 TI - Laminoplasty using the Posterior Midline Approach in the Treatment of C1-2 Spinal Tumors. AB - AIM: This study aimed to investigate the method and efficacy of vertebral reconstruction using the posterior midline approach (PMA) in the treatment of C1 2 spinal tumors. MATERIAL AND METHODS: Twenty-seven patients with C1-2 spinal tumors from the Affiliated Hospital of Luzhou Medical College, who underwent microsurgical tumor resection through an occipitocervical PMA and spinal reset reconstruction from January 2007 to December 2013, were enrolled in the study. The clinical data and results of these patients were analyzed and summarized. RESULTS: All patients underwent a successful complete tumor resection, with no operative deaths. The postoperative pathological diagnoses were schwannoma, neurofibroma, and meningioma in 21, 1, and 5 cases, respectively. The follow-up period was 4-48 months. Postoperatively, 1 patient was independent in daily activities, and 26 patients were able to live and work normally. No significant change was found between preoperative and postoperative MRI sequences of the cervical spine, and no cervical instability and tumor recurrence had occurred. CONCLUSION: PMA is suitable as the preferred approach for resection of C1-2 spinal tumors, and the vertebral reconstruction maintains spinal stability. PMID- 26242338 TI - A Haptic Guided Robotic System for Endoscope Positioning and Holding. AB - AIM: To determine the feasibility, advantages, and disadvantages of using a robot for holding and maneuvering the endoscope in transnasal transsphenoidal surgery. MATERIAL AND METHODS: The system used in this study was a Stewart Platform based robotic system that was developed by Kocaeli University Department of Mechatronics Engineering for positioning and holding of endoscope. After the first use on an artificial head model, the system was used on six fresh postmortem bodies that were provided by the Morgue Specialization Department of the Forensic Medicine Institute (Istanbul, Turkey). RESULTS: The setup required for robotic system was easy, the time for registration procedure and setup of the robot takes 15 minutes. The resistance was felt on haptic arm in case of contact or friction with adjacent tissues. The adaptation process was shorter with the mouse to manipulate the endoscope. The endoscopic transsphenoidal approach was achieved with the robotic system. The endoscope was guided to the sphenoid ostium with the help of the robotic arm. CONCLUSION: This robotic system can be used in endoscopic transsphenoidal surgery as an endoscope positioner and holder. The robot is able to change the position easily with the help of an assistant and prevents tremor, and provides a better field of vision for work. PMID- 26242339 TI - Angiographic Morphometry of Internal Carotid Artery Circulation in Turkish Children. AB - AIM: Knowledge of cerebrovascular morphology is integral in planning neuroendovascular interventions, especially for procedures involving placement of stents, flow diverters or stentrievers. There is insufficient data on angiographic normative values of cerebral circulation in the pediatric age group since angiograms are uncommonly performed in children except for arteriovenous malformations in which arterial dimensions are larger than normal. We aimed to measure the diameters of internal carotid circulation (ICC) arteries on digital subtraction angiograms of pediatric patients and determine the growth trends. MATERIAL AND METHODS: This is a retrospective cross-sectional study measurements of ICC arteries of 64 pediatric patients (4-122 months) with retinoblastoma undergoing intra-arterial chemotherapy. RESULTS: Petrous, cavernous, supraclinoid and choroidal segments of internal carotid artery (ICA) and anterior cerebral artery (ACA) diameters had significant correlation with age. Most of the growth was noted in the first 36-48 months of life. Middle cerebral artery (MCA) diameter did not show significant correlation with age. 87% of the adult diameter of the MCA was attained in the first 6 months of life. ICC arteries reached 81% to 99% of adult sizes in the first 48 months of life. On the contrary, the main iliac artery was only 59% of the adult diameter at this age group. CONCLUSION: Use of current intracranial stents in children appears tolerable due to the growth pattern of ICC arteries. Based on this data, the current armamentarium of intracranial stents or stent-like devices is sufficient to cover the need in the pediatric population. PMID- 26242340 TI - Paclitaxel Inhibits Expression of Neuronal Nitric Oxide Synthase and Prevents Mitochondrial Dysfunction in Spinal Ventral Horn in Rats After C7 Spinal Root Avulsion. AB - AIM: This study evaluated the neuroprotective effect of intrathecally infused paclitaxel in the prevention of motoneuron death and mitochondrial dysfunction following brachial plexus avulsion injury. MATERIAL AND METHODS: Brachial root avulsion injury was induced in Sprague-Dawley rats. The Paclitaxel treatment group (n = 32) received a 5-d intrathecal infusion of paclitaxel (256 ng/d) via a micro infusion pump, whereas the Control group (n = 32) received normal saline. The cervical cord was harvested at survival times of 1, 2, 4, and 6 wk (n = 8 each). The number of surviving and nNOS-positive motoneurons at the injury level in the ventral horn was determined with NADPH-d histochemistry. Mitochondrial function at this location was measured with CcO histochemistry and densitometry. An independent t-test was applied to detect differences between the study groups at specific survival times. RESULTS: The Paclitaxel treatment group showed a significant relative reduction in nNOS expression at 2, 4, and 6 wk, and significantly improved mitochondrial function at 4 and 6 wk. Motoneuron survival was significantly increased at 2, 4, and 6 wk. CONCLUSION: Paclitaxel has a significant neuroprotective effect against spinal motoneuron degeneration following brachial plexus avulsion injury, which involves inhibition of nNOS expression and prevention of mitochondrial dysfunction. PMID- 26242341 TI - Intraspinal Transplantation of Autologous Neurogenically-Induced Bone Marrow Derived Mesenchymal Stem Cells in the Treatment of Paraplegic Dogs without Deep Pain Perception Secondary to Intervertebral Disk Disease. AB - AIM: To investigate the effects of neurogenically-induced autologous bone marrow derived mesenchymal stem cells (NIBM-MSCs) in paraplegic dogs without deep pain perception (DPP) secondary to intervertebral disk disease (IVDD). MATERIAL AND METHODS: Seven dogs which could not be improved neurologically with conventional treatment modalities were included in the study. All dogs were diagnosed by magnetic resonance imaging and surgically treated. Each dog received two times a suspension of autologous 5.0x106 NIBM-MSCs, which were positive to CNPase and MAP 2, as well as to GFAP and beta III tubulin into the spinal cord through the hemilaminectomy defect percutaneously, with a 21-day interval. RESULTS: Two months after cell transplantation, there were no changes except for 1 gait score improvement for 1 of the cases. At the 4th month, gait score had improved 1 score in 5 cases, and one score progress was recorded in proprioception and nociception in 1 case. In eight months-followed up 4 cases were evaluated by the same parameter; gait score had improved in 3 cases, and propriception improved in 2 cases, and nociception improved in 3 cases. CONCLUSION: Our findings suggest that utility of autologous NIBM-MSCs for cases with poor prognosis after IVDD can be a promising approach. PMID- 26242342 TI - Emergency Superficial Temporal Artery to Middle Cerebral Artery Bypass After Intravenous Administration of Tissue Plasminogen Activator for Stroke. AB - Intravenous tissue plasminogen activator (IVtPA) is effective for the treatment of acute stroke. Although IVtPA is easily administered and is effective in many cases, the clinical condition of some patients can worsen after the initiation of thrombolytic therapy due to sustained cerebrovascular insufficiency. In such cases, several additional treatment options to re-establish cerebral perfusion are available, including superficial temporal artery to middle cerebral artery bypass. However, it is recommended that invasive procedures should be avoided soon after IVtPA administration because tPA is believed to exert prolonged fibrinolytic effects may continue for more than 24 hours. We described three cases of emergency superficial temporal artery to middle cerebral artery bypass performed within 24 hours of IVtPA administration, and discussed the safety of such procedures. We believe that superficial temporal artery to middle cerebral artery bypass can be safely performed even within 24 hours after IVtPA administration. PMID- 26242343 TI - Surgical Resection of a Complex Multiple Scalp Avf without Preoperative Embolization: A Case Report. AB - Complex multiple arteriovenous fistula (AVF) of the scalp is an extremely rare disease and the traditional treatment is either endovascular embolization or surgical resection with preoperative endovascular embolization. Here, a 34-year old male with pulsating mass and multiple tortuous vessels in front of the left tragus and scalp who was diagnosed as complex multiple arteriovenous fistula of the scalp is presented. Nearly total surgical resection of the lesion without preoperative intervention was performed. The deformity appearance and the buzzing sound in the patient's left ear were eradicated after operation. Therefore, surgical resection without preoperative embolization is still a promising method to treat complex multiple scalp AVF. PMID- 26242344 TI - Rapid Clinical Course of Multiple Metastatic Cerebral Angiosarcoma. AB - Central nervous system (CNS) angiosarcoma, both primary and secondary, is an exceptionally rare malignant tumor. The behaviour of angiosarcoma is one of rapid progression with early metastatic spread but as with all sarcomas, the primary site may not clinically evident by the time metastases develop. Identification of the primary site of origin is masked by the carpet-like growth pattern that may occur in the left atrium, the most frequently encountered primary site for angiosarcoma. This rare tumor presents many diagnostic challenges. We describe the clinical and neuropathologic features of two patients with angiosarcoma of the brain and review the previously published cases described to date. PMID- 26242345 TI - Gradual Growth of Spontaneous Dissecting Aneurysm of the Extracranial Internal Carotid Artery After Aneurysmal Subarachnoid Hemorrhage. AB - Spontaneous dissecting aneurysm of the extracranial internal carotid artery is uncommon, and simultaneous onset of multiple dissecting aneurysms is rare in patients without congenital or traumatic risk factors. A few reports suggest that extracranial internal carotid artery dissecting aneurysms can grow after SAH due to another intracranial dissecting aneurysm. The present report describes two cases in which gradual growth of unruptured dissecting aneurysm of extracranial internal carotid artery occurred after SAH due to ruptured dissecting aneurysm of the vertebral artery and in which carotid artery stenting was subsequently performed. A 42-year-old man was admitted to our hospital with SAH due to ruptured left vertebral artery dissecting aneurysm and was managed surgically. Dissecting aneurysm of the right extracranial internal carotid artery was found and showed gradual growth. The aneurysm was treated with a stent at 7 weeks after onset. In another case, a 47-year-old woman presented with SAH due to ruptured right vertebral artery dissecting aneurysm and was managed surgically. Concomitant left extracranial internal carotid artery dissecting aneurysm was found and showed gradual growth. The aneurysm was treated with stent and coils. These are rare cases of multiple dissecting aneurysms that originated from different arteries simultaneously and that showed growth after SAH. PMID- 26242346 TI - Remote Multiple Intraparenchymal Hemorrhages Following Aneurysmal Clipping of the Anterior Communicating Artery: A Case Report and Literature Review. AB - Remote intraparenchymal hemorrhage after clipping of a ruptured aneurysm is rare. The pathogenesis is variable, and the therapeutic strategies remain controversial, because the natural history is unclear. Here we report a woman with subarachnoid hemorrhage (SAH), who had an aneurysm of the anterior communicating artery identified by computed tomography angiography (CTA). A 51 year-old women, who was in a good preoperative condition without movement disorders before operation, went on to exhibit left hemiparesis after aneurysmal clipping as she recovered from anesthesia in the operating room. CT images performed immediately after surgery showed that two intraparenchymal hemorrhages were present contralateral to the site of the operation. After conservative treatment, the patient recovered, but still displayed a movement disorder in the left limb. SAH induced-vasospasm, defective vascular autoregulation, excessive drainage of the cerebrospinal fluid, a change in the intracranial pressure after craniotomy, and brain shift may contribute to the pathogenesis of remote hemorrhage after surgery. PMID- 26242347 TI - Spontaneous Regression of Lumbar Disc Herniation After Weight Loss: Case Report. AB - Diagnosis, treatment, and surgery for lumbar disc herniations have existed for over a century. However, during the last three decades, there have been many new developments in imaging techniques, surgical procedures, physical medicine, and rehabilitation. In light of this, the most effective and appropriate treatment is controversial. Spontaneous regression of sequestrated, extruded, or protruded disc herniation has often been reported in the literature, although it is still a rare phenomenon. After a thorough review of the literature, we did not find any case report about this phenomenon after weight loss. In this report, though, we present a recent case about spontaneous regression of extruded disc herniation following weight loss. PMID- 26242348 TI - Clinical and Angiographical Delayed Cerebral Vasospasms After Uncomplicated Surgical Clipping of Unruptured Intracranial Aneurysms: Illustrated Review and Two Case Reports. AB - From January 2007 to April 2012, we performed 2427 surgical clippings for unruptured intracranial aneurysms (UIAs). Among these patients, two cases showed symptomatic and angiographic cerebral vasospasm in the delayed post-operative period without a complicated event. Additionally, we reviewed four cases of delayed cerebral vasospasms following uncomplicated operations that were consistent with our inclusion criteria in the previous literature. The pathogenesis and characteristics of these rare occurrences are reviewed from our two cases and previous literature. For clipping of UIAs, it should be kept mind that neurological symptoms are caused by delayed cerebral vasospasm, and careful observation with proper conservative treatment are necessary to ensure favorable outcomes. PMID- 26242349 TI - Surgical Position, Cause of Extracranial Internal Carotid Artery Dissection, Presenting as Pourfour Du Petit Syndrome: Case Report and Literature Review. AB - Dissection of the internal carotid artery is a rare cause of stroke overall, but causes 22% of strokes in younger patients. A common clinical presentation is as Claude Bernard Horner syndrome. We report a craniotomy with 30 degrees rotation of the neck (standard position) in a patient with no major risk factors for carotid dissection, who showed a Pourfour du Petit syndrome due to a dissection of the internal carotid artery. To the best of our knowledge, this is the first reported case in which a common surgical position causes an internal carotid artery dissection in a patient without relevant risk factors. The presentation with Pourfour du Petit syndrome is extremely unusual. PMID- 26242350 TI - Spontaneous Shrinkage of a Suprasellar Arachnoid Cyst Diagnosed with Prenatal Sonography and Fetal Magnetic Resonance Imaging: Case Report and Review of the Literature. AB - Arachnoid cysts (AC's) are congenital anomalies that occur within the cerebrospinal fluid (CSF) cisterns and major cerebral fissures. Suprasellar AC's comprise 5-12.5% of all the lesions. Despite being commonly reported, their etiology and pathogenesis still remain unclear. In this report, we presented an unusual case of spontaneous shrinkage of a suprasellar AC that had been incidentally diagnosed during a routine prenatal sonographic examination. To our knowledge, only three cases of spontaneous shrinkage of suprasellar AC have been reported in the literature. In detail of the manuscript, fetal and postnatal radiological images were presented and the possible mechanisms were discussed with a review of the literature. PMID- 26242351 TI - Intraoperative Neurophysiological Evidence of Hydrogen Peroxide-Induced Stroke in Insular Tumor Surgery. AB - Hydrogen peroxide (H2O2) is commonly used as a haemostatic agent in all type of surgeries. Some adverse effects have been described related to its use. However, only very few cases are published in the literature of a stroke associated with the application of this agent directly to the brain. We present the case of a patient operated on for a right insular tumor with the assistance of intraoperative neurophysiological monitoring who developed a postoperative severe hemiparesis caused by a stroke in left middle cerebral artery territory due to the irrigation with H2O2. Based on this case, we recommend avoiding the H2O2 irrigation for hemostasis in surgery for brain tumors when vascular structures are exposed. PMID- 26242352 TI - Is it Safe to Evaluate Pedicle Screw Position with Postoperative Tomography? PMID- 26242353 TI - Authors' Reply to "Pituitary Atypical Adenoma or Carcinoma Sensitive to Temozolomide Combined with Radiation Therapy: A Case Report of Early Identification and Management". PMID- 26242354 TI - Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells. PMID- 26242355 TI - "Ferritin Out" a Cause of Acute Hepatitis. PMID- 26242356 TI - Effective W-state fusion strategies for electronic and photonic qubits via the quantum-dot-microcavity coupled system. AB - We propose effective fusion schemes for stationary electronic W state and flying photonic W state, respectively, by using the quantum-dot-microcavity coupled system. The present schemes can fuse a n-qubit W state and a m-qubit W state to a (m + n - 1)-qubit W state, that is, these schemes can be used to not only create large W state with small ones, but also to prepare 3-qubit W states with Bell states. The schemes are based on the optical selection rules and the transmission and reflection rules of the cavity and can be achieved with high probability. We evaluate the effect of experimental imperfections and the feasibility of the schemes, which shows that the present schemes can be realized with high fidelity in both the weak coupling and the strong coupling regimes. These schemes may be meaningful for the large-scale solid-state-based quantum computation and the photon-qubit-based quantum communication. PMID- 26242357 TI - Preliminary report on the cost effectiveness of ventricular assist devices. AB - The aim of the present study was to perform a cost-effectiveness analysis (CEA) of ventricular assist devices (VAD) implantation surgery in the Japanese medical reimbursement system. The study group consisted of thirty-seven patients who had undergone VAD implantation surgery for dilated cardiomyopathy (n = 25; 67.6 %) or hypertrophic cardiomyopathy (n = 4; 10.8 %), and others (n = 8; 21.6 %). Quality adjusted life years (QALYs) were calculated using the utility score and years of life. Medical reimbursement bills were chosen as cost indices. The observation period was the 12-month period after surgery. Then, the incremental cost effectiveness ratio was calculated according to the VAD type. In addition, the prognosis after 36 months was estimated on the basis of the results obtained using the Markov chain model. The mean preoperative INTERMACS profile score was 2.35 +/- 0.77. Our results showed that the utility score, which indicates the effectiveness of VAD implantation surgery, improved by 0.279 +/- 0.188 (DeltaQALY, p < 0.05). The cost of VAD implantation surgery was 313,282 +/- 25,275 (DeltaUS$/year) on the basis of medical reimbursement bills associated with therapeutic interventions. The calculated result of CEA was 364,501 +/- 190,599 (DeltaUS$/QALY). The improvement in the utility score was greater for implantable versus extracorporeal VADs (0.233 +/- 0.534 vs. 0.371 +/- 0.238) and ICER was 303,104 (DeltaUS$/DeltaQALY). Furthermore, when we estimated CEA for 36 months, the expected baseline value was 102,712 (US$/QALY). Therefore, VAD implantation surgery was cost effective considering the disease specificities. PMID- 26242358 TI - [Relevance of preoperative anxiety for postoperative outcome in urological surgery patients: A prospective observational study]. AB - BACKGROUND: Preoperative anxiety is not systematically assessed during premedication appointments, although it may influence the postoperative course and outcome. OBJECTIVES: The aim of this study was to assess preoperative anxiety in a sample of patients before major urological surgery and to characterize the impact on postoperative pain. An additional aim was to analyze the agreement between patients' self-ratings and physicians' anxiety ratings. PATIENTS AND METHODS: In all, 127 male and 27 female patients participated in a prospective observational study. Preoperative anxiety was assessed with two validated instruments - the APAIS (Amsterdam Preoperative Anxiety and Information Scale) and the State Scale of the STOA questionnaire (State-Trait Operation Anxiety) - during the premedication appointment. Physicians provided their subjective ratings on patients' anxiety and need for information using the APAIS. The predictive value of preoperative anxiety for postoperative pain was evaluated. RESULTS: Nearly four out of ten patients were identified as "anxiety cases"; thereof women were more afraid than men were. Preoperative anxiety was not correctly assessed by physicians, who overestimated patients' anxiety. In female patients, preoperative anxiety was predictive of increased postoperative pain scores. CONCLUSION: Preoperative anxiety is a frequent concern and often not correctly assessed by physicians. The use of scoring systems to detect preoperative anxiety is useful in clinical routine and helps to decide on therapeutic interventions. PMID- 26242359 TI - [Non-opioid pain medication in the elderly]. AB - Non-opioid analgesics are frequently used to control chronic pain in elderly patients; however some of these drugs show high rates of adverse drug reactions. Among these are significant clinical problems which impede an effective and safe pain control. This review provides recent data concerning non-steroidal anti inflammatory drugs (NSAID), acetaminophen, metamizol and flupirtin. Due to their risk profile NSAIDs are less appropriate due to high incidence rates and drug related risk patterns. Acetaminophen, metamizol and flupirtin may be recommended instead; however a shortcoming of acetaminophen in comparison to NSAIDs is its weaker action to control pain. Metamizol is still banned in some countries due to rare but potentially severe hematological side effects and flupirtin frequently causes unfavorable sedation. PMID- 26242360 TI - Robust set-point regulation for ecological models with multiple management goals. AB - Population managers will often have to deal with problems of meeting multiple goals, for example, keeping at specific levels both the total population and population abundances in given stage-classes of a stratified population. In control engineering, such set-point regulation problems are commonly tackled using multi-input, multi-output proportional and integral (PI) feedback controllers. Building on our recent results for population management with single goals, we develop a PI control approach in a context of multi-objective population management. We show that robust set-point regulation is achieved by using a modified PI controller with saturation and anti-windup elements, both described in the paper, and illustrate the theory with examples. Our results apply more generally to linear control systems with positive state variables, including a class of infinite-dimensional systems, and thus have broader appeal. PMID- 26242361 TI - Susceptibility-weighted imaging in stroke-like migraine attacks after radiation therapy syndrome. AB - INTRODUCTION: Stroke-like migraine attacks after radiation therapy (SMART) syndrome has a characteristic clinical presentation and postcontrast T1WI MRI appearance. Susceptibility-weighted imaging (SWI) may help distinguish SMART from other disorders that may have a similar postcontrast MRI appearance. METHODS: The MRI examinations of four patients with SMART syndrome are described herein, each of which included SWI, FLAIR, DWI, and postcontrast T1WI on the presenting and follow-up MRI examinations. RESULTS: In each, the initial SWI MRI demonstrated numerous susceptibility hypointensities <5 mm in size throughout the cerebrum, particularly within the periventricular white matter (PVWM), presumably related to radiation-induced cavernous hemangiomas (RICHs). By follow-up MRI, each postcontrast examination had demonstrated resolution of the gyriform enhancement on T1WI, without susceptibility hypointensities on SWI within those previously enhancing regions. CONCLUSION: These preliminary findings suggest that SWI may help identify SMART syndrome or at least help discriminate it from other disorders, by the findings of numerous susceptibility hypointensities on SWI likely representing RICHs, gyriform enhancement on T1WI, and postsurgical findings or appropriate clinical history. PMID- 26242362 TI - Usefulness of Magnetic Resonance Sialography for the Evaluation of Radioactive Iodine-Induced Sialadenitis. AB - PURPOSE: Radioactive iodine (RAI) ablation therapy after thyroidectomy commonly leads to obstructive sialadenitis. Magnetic resonance (MR) sialography is an emerging imaging modality that enables morphological and functional changes to be evaluated. This study was conducted to investigate the usefulness of MR sialography for the evaluation of RAI sialadenitis. In addition, the authors evaluated the correlation of MR sialographic grading with symptom severity using a symptom questionnaire (SQ), and salivary gland (SG) functions as determined by salivary flow rates (SFRs) and salivary scintigraphy (SSG) parameters. METHODS: Eighteen patients with RAI sialadenitis who underwent MR sialography imaging were retrospectively enrolled. Subjective symptom scores were assessed and objective SG functions were evaluated. MR sialographic characteristics were analyzed and correlations between MR sialographic findings and clinicopathologic data, SQ, SFRs, and SSG parameters were investigated. RESULTS: MR sialography demonstrated diagnostic findings of ductal stenosis and sialectasis, non-visualized ducts, and glandular atrophy mainly involving parotid glands. A significant correlation was found between obstructive symptom scores and ductal stenosis and sialectasis grades (both p < 0.05). Degrees of ductal stenosis and sialectasis were significantly correlated with SSG excretory variables [time from stimulation to minimum count (t min) and maximum secretion; all p < 0.05]. Significant linear correlations were found between duct nonvisualization and uptake variables [uptake ratio (UR) and maximum accumulation (MA); both p < 0.05]. Glandular volumes were also significantly correlated with UR and MA (both p < 0.05). CONCLUSIONS: MR sialography images are useful for evaluating RAI sialadenitis, and its findings are in accordance with disease severity. An MR sialographic grading system is suggested to describe the severity of obstructive sialadenitis and SG dysfunction. PMID- 26242363 TI - Overall Survival, Disease-Free Survival, Local Recurrence, and Nipple-Areolar Recurrence in the Setting of Nipple-Sparing Mastectomy: A Meta-Analysis and Systematic Review. AB - BACKGROUND: Nipple-sparing mastectomy (NSM) is an increasingly common procedure; however, concerns exist regarding its oncological safety due to the potential for residual breast tissue to harbor occult malignancy or future cancer. METHODS: A systematic literature review was performed. Studies with internal comparison arms evaluating therapeutic NSM versus skin-sparing mastectomy (SSM) and/or modified radical mastectomy (MRM) were included in a meta-analysis of overall survival (OS), disease-free survival (DFS), and local recurrence (LR). Studies lacking comparison arms were only included in the systematic review to evaluate mean OS, DFS, LR, and nipple-areolar recurrence (NAR). RESULTS: The search yielded 851 articles. Twenty studies with 5594 patients met selection criteria. The meta analysis included eight studies with comparison arms. Seven studies that compared OS found a 3.4% risk difference between NSM and MRM/SSM, five studies that compared DFS found a 9.6% risk difference between NSM and MRM/SSM, and eight studies that compared LR found a 0.4% risk difference between NSM and MRM/SSM. Risk differences for all outcomes were not statistically significant. The systematic review included all 20 studies and evaluated OS, DFS, LR, and NAR. Studies with follow-up intervals of <3 years, 3-5 years, and >5 years had mean OS of 97.2, 97.9, and 86.8%; DFS of 93.1, 92.3, and 76.1%; LR of 5.4, 1.4, and 11.4%; and NAR of 2.1, 1.0, and 3.4%, respectively. CONCLUSIONS: This study did not detect adverse oncologic outcomes of NSM in carefully selected women with early-stage breast cancer. Use of prospective data registries, notably the Nipple Sparing Mastectomy Registry, will add clarity to this important clinical question. PMID- 26242364 TI - Breast Cancer Risk and Follow-up Recommendations for Young Women Diagnosed with Atypical Hyperplasia and Lobular Carcinoma In Situ (LCIS). AB - BACKGROUND: The risk of breast cancer in young women diagnosed with atypical hyperplasia and (LCIS) is not well defined. The objectives were to evaluate outcomes and to help determine guidelines for follow-up in this population. METHODS: A retrospective review of women under age 35 diagnosed with ADH, ALH, LCIS, and severe ADH from 1987 to 2010 was performed. Patient characteristics, pathology and follow-up were determined from chart review. RESULTS: We identified 58 young women with atypical breast lesions. Median age at diagnosis was 31 years (range 19-34). 34 patients had ADH, 11 had ALH, 8 had LCIS, and 5 had severe ADH. 7 (12%) patients developed breast cancer. The median follow-up was 86 months (range 1-298). Median time to cancer diagnosis was 90 months (range 37-231). 4 cancers were on the same side, 3 were contralateral. 4 were IDC, 1 was ILC, and 2 were DCIS. Cancer was detected by screening mammogram in 4 patients, 2 by clinical exam, and 1 unknown. In the entire cohort, 26 (45%) patients had screening mammograms as part of their follow up, 12 patients had only clinical follow up, and 20 had no additional follow up. 13 patients required subsequent biopsies. CONCLUSION: Young women with atypical breast lesions are at a markedly increased risk for developing breast cancer and should be followed closely. Based on our findings, we recommend close clinical follow-up, MRI starting at age 25 through age 29, and screening mammograms for those over 30 in this high-risk group of patients. PMID- 26242365 TI - Breast Surgery in 2015: Advances in Recent Years. PMID- 26242366 TI - A Review of Anatomy, Physiology, and Benign Pathology of the Nipple. AB - The nipple and areola are pigmented areas of modified skin that connect with the underlying gland of the breast via ducts. The fairly common congenital anomalies of the nipple include inversion, clefts, and supernumerary nipples. The anatomy of the nipple areolar complex is discussed as a foundation to review anatomical variants, and the physiologic development of the nipple, including changes in puberty and pregnancy, as well as the basis of normal physiologic discharge, are addressed. Skin conditions affecting the nipple include eczema, which, while similar to eczema occurring elsewhere on the body, poses unique aspects in terms of diagnosis and treatment. This article concludes with discussion on the benign abnormalities that develop within the nipple, including intraductal papilloma and nipple adenoma. PMID- 26242367 TI - Radiographic Sarcopenia and Self-reported Exhaustion Independently Predict NSQIP Serious Complications After Pancreaticoduodenectomy in Older Adults. AB - INTRODUCTION: Sarcopenia is linked to poor outcomes after abdominal surgery. We hypothesized that radiographic sarcopenia metrics enhance prediction of complications after pancreaticoduodenectomy (PD) when combined with clinical and frailty data. METHODS: Preoperative geriatric assessments and CT scans of patients undergoing PD were reviewed. Sarcopenia was assessed at L3 using total psoas area index (TPAI) and weighted average Hounsfield units (HU), i.e., estimates of psoas muscle volume and density. Outcomes included 30-day American College of Surgeons National Surgical Quality Improvement Program (NSQIP) serious complications, Clavien-Dindo complications, unplanned intensive care unit (ICU) admission, hospital length of stay (LOS), non-home facility (NHF) discharge, and readmission rates. RESULTS: Low HU score correlated with NSQIP serious complications (r = -0.31, p = 0.0098), Clavien-Dindo complication grade (r = 0.29, p = 0.0183), unplanned ICU admission (r = -0.28, p = 0.0239), and NHF discharge (r = -0.25, p = 0.0426). Controlling for a "base model" of age, body mass index, American Society of Anesthesiologists score, and comorbidity burden, Fried's exhaustion (odds ratio [OR] 4.72 [1.23-17.71], p = 0.021), and HU (OR 0.88 [0.79-0.98], p = 0.024) predicted NSQIP serious complications. Area under the receiver-operator characteristic (AUC) curves demonstrated that the combination of the base model, exhaustion, and HU trended towards improving the prediction of NSQIP serious complications compared with the base model alone (AUC = 0.81 vs. 0.70; p = 0.09). Additionally, when controlling for the base model, TPAI (beta-coefficient = 0.55 [0.10-1.01], p = 0.018) and exhaustion (beta coefficient = 2.47 [0.75-4.20], p = 0.005) predicted LOS and exhaustion (OR 4.14 [1.48-11.6], p = 0.007) predicted readmissions. CONCLUSIONS: When combined with clinical and frailty assessments, radiographic sarcopenia metrics enhance prediction of post-PD outcomes. PMID- 26242368 TI - Beyond "Age": Frailty Assessment Strategies Improve Care of Older Patients with Cancer. PMID- 26242369 TI - Is Hepatic Resection for Non-colorectal, Non-neuroendocrine Liver Metastases Justified? AB - BACKGROUND: Discussions about the benefit of liver resection (LRx) for non colorectal, non-neuroendocrine metastases are controversial. This study aimed to analyze the outcome of LRx for these patients and validate a previously published prognostic risk model. METHODS: The study analyzed 150 patients who underwent LRx for non-colorectal non-neuroendocrine (NCNN) metastases. Patients' demographics, tumor characteristics, treatment options, and postoperative outcome were investigated. The Kaplan-Meier method and Cox regression models were used to assess survival and prognostic variables. RESULTS: After a median follow-up period of 61 months, 39 % of the patients were alive. The 30-day mortality rate was 0.7 %. The overall, disease-free, and intrahepatic recurrence-free survival rates were respectively 42, 29, and 51 % at 5 years and 28, 23, and 47 % at 10 years. The negative prognostic factors identified in the multivariate analysis were melanoma (p = 0.04), squamous tumors (p = 0.01), and a primary tumor liver metastasis, with an interval shorter than 2 years (p = 0.02), whereas the predictive prognostic factors identified were breast cancer (p = 0.04), stromal tumors (p = 0.03), and major LRx (p = 0.04). The prognostic risk score stratified patients into low risk (0-3 points: n = 50; 5-year overall survival [OS] 58 %), medium risk (4-6 points: n = 91; 5-year OS 35 %), and high risk (>=7 points: n = 9; 5-year OS, 33 %) groups (p = 0.01). CONCLUSION: Liver resection for patients with NCNN metastases is a safe treatment option. More than 25 % of patients can achieve a long-term survival of 10 years when the histology of the primary tumor and the surrogates for the individual biologic tumor behavior are taken into account. Exclusion of patients with NCNN liver metastases from surgical therapy is no longer justified. PMID- 26242370 TI - Electrochemotherapy in the Treatment of Cutaneous Metastases from Breast Cancer: A Multicenter Cohort Analysis. AB - BACKGROUND: The management of breast cancer (BC) skin metastases represents a therapeutic challenge. Electrochemotherapy (ECT) combines the administration of bleomycin with temporary permeabilization induced by locally administered electric pulses. Preliminary experience with ECT in BC patients is encouraging. METHODS: A total of 125 patients with BC skin metastases who underwent ECT between 2010 and 2013 were enrolled onto a multicenter retrospective cohort study. The treatment was administered following the European Standard Operative Procedures of Electrochemotherapy. Tumor response was clinically assessed adapting the Response Evaluation Criteria in Solid Tumors, and toxicity was evaluated according to Common Terminology Criteria for Adverse Events 4.0. Cox regression analysis was used to identify predictive factors. RESULTS: Response was evaluable in 113 patients for 214 tumors (median 1 per patient, range 1-3). The overall response rate after 2 months was 90.2 %, while the complete response (CR) rate was 58.4 %. In multivariate analysis, small tumor size (P < 0.001), absence of visceral metastases (P = 0.001), estrogen receptor positivity (P = 0.016), and low Ki-67 index (P = 0.024) were significantly associated with CR. In the first 48 h, 10.4 % of patients reported severe skin pain. Dermatologic toxicity included grade 3 skin ulceration (8.0 %) and grade 2 skin hyperpigmentation (8.8 %). Tumor 1-year local progression-free survival was 86.2 % (95 % confidence interval 79.3-93.8) and 96.4 % (95 % confidence interval 91.6 100) in the subgroup of those with CR. CONCLUSIONS: In this study, small tumor size, absence of visceral metastases, estrogen receptor positivity, and low Ki-67 index were predictors of CR after ECT. Patients who experienced CR had durable local control. ECT represents a valuable skin-directed therapy for selected patients with BC. PMID- 26242371 TI - The Prognostic Significance of Inflammation-Associated Blood Cell Markers in Patients with Upper Tract Urothelial Carcinoma. AB - BACKGROUND: Inflammation-related parameters based on blood cells, including white blood cell (WBC) count, neutrophil-lymphocyte ratio, platelet count, and red cell distribution width (RDW), have been shown to be associated with prognosis in many cancers. However, no previous study evaluated these inflammation-associated markers simultaneously in upper tract urothelial carcinoma (UTUC). METHODS: A total of 195 patients with UTUC who received radical nephroureterectomy between 2005 and 2010 were included retrospectively as the derivation cohort to investigate the impact of inflammation markers on overall survival (OS) and cancer-specific survival (CSS). In turn, another independent set of 225 patients were used for validation. Finally, we performed survival analysis in the combined cohort consisting of 420 UTUC patients. RESULTS: The predictive value of RDW and WBC count on outcome was replicable in different cohorts. Multivariate analysis showed high RDW was independently associated with poor OS (P < 0.001), and WBC count was a significant prognosticator for both OS and CSS (both P < 0.001). In subgroup analysis, we found the prognostic significance of RDW for OS was limited in organ-confined disease (<=pT2 without pN+). More importantly, a clear survival difference can be demonstrated by combining RDW and WBC count with other known prognostic factors in the risk stratification model. CONCLUSIONS: RDW and WBC count have the advantage of their common accessibility and are useful markers to predict outcome of UTUC in the preoperative setting. RDW and WBC count could provide additional prognostic value and help physicians identify patients at high risk for mortality and formulate individualized treatment strategy. PMID- 26242372 TI - Poorly Differentiated Carcinoma Component in Submucosal Layer Should be Considered as an Additional Criterion for Curative Endoscopic Resection of Early Gastric Cancer. AB - BACKGROUND: Some studies have reported lymph node metastasis (LNM) in early gastric cancer (EGC) cases meeting the expanded criteria for endoscopic resection. Therefore, we investigated whether a minor poorly differentiated carcinoma (PDC) component in the submucosal (SM) layer affects LNM in differentiated EGC. METHODS: We performed surgery in 1096 patients with differentiated SM gastric cancer and compared the clinicopathologic features of node-positive (n = 194) and node-negative (n = 902) differentiated SM cancer, with special reference to the portion of PDC component in the SM layer. RESULTS: When we categorized patients by the proportion of PDC component in the SM layer, we found 840 patients had <5 % and 256 patients had >=5 % PDC components in the SM layer. The >=5 % group was significantly associated with younger age, female sex, moderate differentiation, deep SM invasion, lymphovascular invasion (LVI), perineural invasion, and LNM. In multivariate analysis, middle third location, moderate differentiation, SM2 invasion, size >2 cm, LVI, and PDC components in the SM layer were independent risk factors for LNM. When we limited the depth of invasion to SM1, the incidence of LNM was significantly higher in the >=5 % group. On multivariate analysis, tumor size >2 cm, moderate differentiation, LVI positivity, and >=5 % PDC components in the SM1 layer were independent risk factors for LNM in SM1 cancer. CONCLUSIONS: The PDC component in the SM layer of differentiated EGC was an independent risk factor of LNM, which might constitute a supplementary criterion in the expanded indications for endoscopic resection in differentiated EGC. PMID- 26242373 TI - Efficient red luminescence from organic-soluble Au25 clusters by ligand structure modification. AB - An efficient method to enhance visible luminescence in a visibly non-luminescent organic-soluble 4-(tert butyl)benzyl mercaptan (SBB)-stabilized Au25 cluster has been developed. This method relies mainly on enhancing the surface charge density on the cluster by creating an additional shell of thiolate on the cluster surface, which enhances visible luminescence. The viability of this method has been demonstrated by imparting red luminescence to various ligand-protected quantum clusters (QCs), observable to the naked eye. The bright red luminescent material derived from Au25SBB18 clusters was characterized using UV-vis and luminescence spectroscopy, TEM, SEM/EDS, XPS, TG, ESI and MALDI mass spectrometry, which collectively proposed an uncommon molecular formula of Au29SBB24S, suggested to be due to different stapler motifs protecting the Au25 core. The critical role of temperature on the emergence of luminescence in QCs has been studied. The restoration of the surface ligand shell on the Au25 cluster and subsequent physicochemical modification to the cluster were probed by various mass spectral and spectroscopic techniques. Our results provide fundamental insights into the ligand characteristics determining luminescence in QCs. PMID- 26242374 TI - Enhanced production of reactive oxygen species by gadolinium oxide nanoparticles under core-inner-shell excitation by proton or monochromatic X-ray irradiation: implication of the contribution from the interatomic de-excitation-mediated nanoradiator effect to dose enhancement. AB - Core-inner-valence ionization of high-Z nanoparticle atomic clusters can de excite electrons through various interatomic de-excitation processes, thereby leading to the ionization of both directly exposed atoms and adjacent neutral atoms within the nanoparticles, and to an enhancement in photon-electron emission, which is termed the nanoradiator effect. To investigate the nanoradiator-mediated dose enhancement in the radio-sensitizing of high-Z nanoparticles, the production of reactive oxygen species (ROS) was measured in a gadolinium oxide nanoparticle (Gd-oxide NP) solution under core-inner-valence excitation of Gd with either 50 keV monochromatic synchrotron X-rays or 45 MeV protons. This measurement was compared with either a radiation-only control or a gadolinium-chelate magnetic resonance imaging contrast agent solution containing equal amounts of gadolinium as the separate atomic species in which Gd-Gd interatomic de-excitations are absent. Ionization excitations followed by ROS measurements were performed on nanoparticle-loaded cells or aqueous solutions. Both photoexcitation and proton impact produced a dose-dependent enhancement in the production of ROS by a range of factors from 1.6 to 1.94 compared with the radiation-only control. Enhanced production of ROS, by a factor of 1.83, was observed from Gd-oxide NP atomic clusters compared with the Gd-chelate molecule, with a Gd concentration of 48 MUg/mL in the core-level photon excitation, or by a factor of 1.82 under a Gd concentration of 12 MUg/mL for the proton impact at 10 Gy (p < 0.02). The enhanced production of ROS in the irradiated nanoparticles suggests the potential for additional therapeutic dose enhancements in radiation treatment via the potent Gd-Gd interatomic de-excitation-driven nanoradiator effect. PMID- 26242375 TI - Phosphodiesterase type 5 inhibitors and kidney disease. AB - Chronic kidney disease (CKD) represents a worldwide health problem. Traditionally, the nephroprotective treatment for CKD aims to slow progression to end-stage renal disease and includes dietary protein restriction, correction of metabolic acidosis, and renin-angiotensin system blockers. However, current standard therapeutic options may not be enough for preventing CKD progression in a subset of patients making necessary to develop novel therapeutic options to further slow renal function loss. Phosphodiesterase type 5 (PDE5) inhibitors represent a class of drugs traditionally used to treat erectile dysfunction and pulmonary hypertension. However, recent evidence suggests that PDE5 inhibitors may have additional therapeutic effects, such as cardioprotection and cerebrovascular protection. In the current review, we summarize PDE5 inhibitors' utility in disease states and clinical conditions related to kidney disease such as systemic hypertension and acute and chronic kidney injury and discuss the mechanisms explaining possible kidney protective roles of PDE5 inhibitors. A recently completed phase 2 trials demonstrated that the long-acting PDE5 inhibitor PF-00489791 decreased albuminuria in patients with overt diabetic nephropathy when added on top of renin-angiotensin system blockade. PMID- 26242376 TI - Identification and genomic analysis of a novel member of Microviridae, IME-16, through high-throughput sequencing. PMID- 26242377 TI - Identification of a novel strain of influenza A (H9N2) virus in chicken. PMID- 26242378 TI - Sensitive detection of DNA methyltransferase activity by transcription-mediated duplex-specific nuclease-assisted cyclic signal amplification. AB - We develop a sensitive fluorescence method for DNA methyltransferase (MTase) assay based on T7 RNA polymerase-mediated transcription amplification and duplex specific nuclease (DSN)-assisted cyclic signal amplification. This method exhibits excellent specificity and high sensitivity with a detection limit of 0.015 U mL(-1), and it may be further applied for the screening of antimicrobial drugs. PMID- 26242379 TI - Clinical Pharmacokinetic and Pharmacodynamic Profile of Idelalisib. AB - Idelalisib is a potent and selective phosphatidylinositol 3-kinase-delta inhibitor, which is a first-in-class agent to be approved for the treatment of relapsed chronic lymphocytic leukaemia, follicular B cell non-Hodgkin's lymphoma and small lymphocytic lymphoma. In dose-ranging studies, idelalisib exposure increased in a less than dose-proportional manner, likely because of solubility limited absorption. The approved starting dose of 150 mg twice daily was supported by extensive exposure-response evaluations, with dose reduction to 100 mg twice daily being allowed for specific toxicities. Idelalisib may be administered without regard to food on the basis of the absence of clinically relevant food effects, and was accordingly dosed in primary efficacy/safety studies. Idelalisib is metabolized primarily via aldehyde oxidase (AO) and, to a lesser extent, via cytochrome P450 (CYP) 3A. Coadministration with the strong CYP3A inhibitor ketoconazole 400 mg once daily resulted in a ~79 % increase in the idelalisib area under the plasma concentration-time curve (AUC). Administration with the potent inducer rifampin resulted in a 75 % decrease in idelalisib exposure (AUC) and, as such, coadministration with strong inducers should be avoided. GS-563117 is an inactive primary circulating metabolite of idelalisib formed mainly via AO. Unlike idelalisib, GS-563117 is a mechanism based inhibitor of CYP3A. Accordingly, idelalisib 150 mg twice-daily dosing increases the midazolam AUC 5.4-fold. Clinically, idelalisib is not an inhibitor of the transporters P-glycoprotein, breast cancer resistance protein, organic anion-transporting polypeptide (OATP) 1B1 or OAPT1B3. In a population pharmacokinetic model, no meaningful impact on idelalisib pharmacokinetics was noted for any of the covariates tested. Idelalisib exposure was ~60 % higher with moderate/severe hepatic impairment; no relevant changes were observed with severe renal impairment. This article reviews a comprehensive pharmacology programme, including drug-drug interaction studies and mechanistic and special population studies, which has allowed a thorough understanding of idelalisib clinical pharmacokinetics and their impact on clinical safety and efficacy. PMID- 26242380 TI - Blockade of the High-Affinity Interleukin-2 Receptors with Daclizumab High-Yield Process: Pharmacokinetic/Pharmacodynamic Analysis of Single- and Multiple-Dose Phase I Trials. AB - BACKGROUND AND OBJECTIVE: Daclizumab high-yield process (DAC HYP) is a humanized monoclonal antibody that selectively blocks the alpha-subunit (CD25) of the high affinity interleukin-2 receptors, and has shown robust efficacy as a treatment for multiple sclerosis (MS). This work quantitatively characterized the relationship between DAC HYP serum concentrations and saturation of CD25 expressed on antigen-rich target T cells in blood. METHODS: Serial pharmacokinetic and 968 CD25 measurements from three double-blind, randomized, placebo-controlled, phase I studies of DAC HYP (50-300 mg subcutaneous and 200 400 mg intravenous doses or placebo) in healthy volunteers (n = 95) were analyzed using nonlinear mixed-effects modeling. CD25 occupancy was determined using flow cytometry and a fluorescently-labeled DAC HYP-competing antibody. RESULTS: CD25 occupancy was described using a direct inhibitory sigmoidal maximum effect (E max) model (where DAC HYP fully inhibited CD25 labeling with competing antibody). Two IC50 (serum concentration corresponding to 50 % of maximal inhibition) parameters were used to describe rapid CD25 saturation at initiation of dosing and apparently slower desaturation during DAC HYP washout. Parameter estimates (95 % bootstrap confidence intervals) were: baseline CD25 labeling, 47 % (45-48); DAC HYP IC50(saturation), 0.023 ug/mL (0.005-0.073); IC50(desaturation) 0.86 ug/mL (0.74-0.98); Hill coefficient 5.6 (4.3-6.8). CONCLUSIONS: Based on the developed model, the 150 mg monthly subcutaneous regimen of DAC HYP in subjects with MS is predicted to saturate CD25 on target effector T cells within a few hours of dosing and maintain CD25 saturation during the entire dosing interval. Free CD25 levels return to baseline within 4-6 months of the last DAC HYP dose. PMID- 26242381 TI - To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non Linear Pharmacokinetics. AB - Microdosing studies allow clinical investigation of pharmacokinetics earlier in drug development, before all high-dose safety concerns have been sorted out. Furthermore, microdosing allows inclusion of target groups that are inadmissible in high-dose phase I trials. A potential concern when considering a microdosing study is that a particular drug candidate may display non-linear pharmacokinetics. Saturation of, for example, membrane transport or metabolism at exposure levels between the microdose and therapeutic dose may limit the predictivity of high-dose pharmacokinetics from microdose observations. Guidance on the likelihood of appreciable non-linear pharmacokinetics based on preclinical information can be helpful in staging the clinical phase and the place of microdosing in it. We present a decision tree that evaluates concerns about non linearities raised in the preclinical phase and their potential impact on the proportionality between microdose and intended therapeutic dose as predicted from preclinical information. The expected maximum concentrations at relevant sites are estimated by non-compartmental methods. These are compared with dissolution, Michaelis constants for active or enzymatic processes, and binding protein concentrations to assess the potential saturation of the processes below therapeutic doses. The decision tree was applied to ten published cases comparing microdose and therapeutic dose pharmacokinetics, for which concerns about non linear pharmacokinetics were raised a priori. The decision tree was able to discriminate cases showing substantial non-linearities from cases displaying dose proportional pharmacokinetics. The recommendations described in this paper may be useful in deciding whether a microdosing study is a sensible option to gain early insight in clinical pharmacokinetics of drug candidates. PMID- 26242382 TI - Pharmacokinetics and Safety of Single Intravenous Doses of JNJ-54452840, an Anti beta1-Adrenergic Receptor Antibody Cyclopeptide, in Healthy Male Japanese and Caucasian Participants. AB - AIM: To evaluate the pharmacokinetics and safety of single intravenous doses of JNJ-54452840 infused over 1 minute in healthy male Japanese and Caucasian participants. JNJ-54452840 is a novel peptide for the treatment of chronic heart failure, with a proposed mechanism of action of binding interference and decreased production of anti-beta1-adrenergic receptor (anti-beta1-AR) antibodies, which stimulate the cardiac beta1-AR. METHODS: In this randomized, single-centre, double-blind, placebo-controlled, four-way crossover study, 32 male Japanese and Caucasian participants (16 in each group) received single intravenous doses of JNJ-54452840 20, 80 and 240 mg, and placebo, each separated by a >=7-day washout period. Pharmacokinetics and safety were assessed predose and at specified timepoints for 24 h. Anti-beta1-AR antibodies were monitored. RESULTS: The mean JNJ-54452840 maximum observed plasma concentration (C max) and area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase (AUCinf) values increased linearly with dose, with rapid elimination in both groups. Dose proportionality criteria were not met between the 20 and 240 mg doses for both study cohorts. The median time to reach C max (T max) ranged from 1 to 5 minutes. The mean total systemic clearance after intravenous administration (CL), volume of distribution at steady state (V ss), mean residence time (MRT) and terminal half-life (T 1/2) values were similar for both groups. The mean T 1/2 values ranged from 5.9 to 26.1 min in a dose dependent manner. The overall prevalence of antibodies was 9.4 % at baseline; antibodies not present at baseline developed in five Caucasians (15.6 %) but not in Japanese participants. One participant in each group experienced a serious thromboembolic event (pulmonary embolism, ischaemic stroke). CONCLUSION: JNJ 54452840 demonstrated similar pharmacokinetics in both groups. JNJ-54452840 was possibly immunogenic, and two participants reported thromboembolic serious adverse events. The relationship between these events and antibody formation is not known. PMID- 26242383 TI - Does trans-10, cis-12 conjugated linoleic acid affect the intermediary glucose and energy expenditure of dairy cows due to repartitioning of milk component synthesis? AB - The overall goal of this study was to evaluate if intermediary energy metabolism of cows fed with trans-10, cis-12 conjugated linoleic acid (CLA) was modified such that milk-energy compounds were produced with less intermediary energy expenditure as compared to control cows. Published data on supplemented CLA were assembled. The extent was calculated to which the trans-10, cis-12 CLA isomer has an impact on glucose and energy conversion in the mammary gland by modifying glucose equivalent supply and energy required for fatty acid (FA) and fat synthesis, and if this will eventually lead to an improved glucose and energy status of CLA-supplemented high-yielding dairy cows. A possible relationship between CLA supplementation level and milk energy yield response was also studied. Calculations were conducted separately for orally and abomasally administered CLA and based on energy required for supply of glucose equivalents, i.e. lactose, glycerol and NADPH2. Further, modifications of milk FA profile due to CLA supplementation were considered when energy expenditures for FA and fat synthesis were quantified. Differences in yields between control and CLA groups were transformed into glucose energy equivalents. Only abomasal infusion (r(2) = 0.31) but not oral CLA administration (r(2) = 0.11) supplementation to dairy cow diets resulted in less glucose equivalent energy. Modifications of milk FA profiles also saved energy but the relationship with CLA supplementation was weaker for abomasal infusion (r(2) = 0.06) than oral administration (r(2) = 0.38). On average, 10 g/d of abomasally infused trans-10, cis-12 CLA saved 1.1 to 2.3 MJ net energy expressed as glucose equivalents, whereas both positive and negative values were observed when the trans-10, cis-12 CLA was fed to the cows. This study revealed a weak to moderate dose-dependent relationship between the amount of trans-10, cis-12 CLA administered and the amount of energy in glucose equivalents and energy for the synthesis of milk fat conserved from milk ingredient synthesis. Because abomasal infusion of the trans-10, cis-12 CLA more consistently conserved energy in glucose equivalents compared with oral CLA intake, rumen protection of the fed CLA products appears incomplete. Milk fat synthesis showed an energy saving with a weak dose-dependent relationship when CLA was supplemented orally or by abomasal infusion. PMID- 26242384 TI - Enzymatic transformation of stevioside using a beta-galactosidase from Sulfolobus sp. AB - Enzymatic hydrolysis and transgalactosylation of stevioside (St) were investigated using a beta-galactosidase from Sulfolobus sp. The hydrolysis yielded steviol as the main final product. Under the optimal transgalactosylation conditions, the highest conversion of stevioside was 87.3% with lactose as a donor, several galactosylated products (St-Gals) were obtained. Metal ions such as Na(+), K(2+), Ca(2+), Ba(2+), Mn(2+) and Mg(2+) (2 mM) did not affect the transgalactosylation activity, while Fe(2+), Fe(3+) and Cu(2+) reduced the transgalactosylation activity of beta-galactosidase to 64%, 33% and 18%, respectively. PMID- 26242385 TI - Gold nanoparticle decorated graphene sheet-polypyrrole based nanocomposite: its synthesis, characterization and genosensing application. AB - We report herein the synthesis of gold nanoparticle (GNP) decorated-graphene sheets (GO-GNPs) using the template of graphene oxide (GO) by a one-pot solution based method. A polypyrrole-GO decorated GNP nanocomposite (GO-GNP/PPY) has been electropolymerized using a potentiodynamic method on an indium tin oxide (ITO) coated glass substrate. The as-synthesized nanocomposites are characterized by transmission electron microscopy, energy dispersive X-ray spectroscopy, scanning electron microscopy, thermogravimetric analysis, Fourier transform infrared and Raman spectroscopy. It has been found that GNPs of ca. 13 nm are uniformly dispersed on the surface of GO, and have a high electrochemically active surface area. The surface morphology studies show that PPY structure changes from nanoflowers to nanostars and then to nanosheets with an increase in the scan rate (20-200 mV s(-1)). The prepared GO-GNP/PPY/ITO electrode was further used as a genosensor, where the electrochemical response was measured using methylene blue (MB) as a redox indicator. The genosensor shows a response time of 60 s with high sensitivity (1 * 10(-15) M) and linearity (1 * 10(-15)-1 * 10(-6) M) with the correlation coefficient of 0.9975. PMID- 26242386 TI - A Novel Member of GH16 Family Derived from Sugarcane Soil Metagenome. AB - Glycoside hydrolases (GHs) are enzymes found in all living kingdoms that are involved in multiple physiological functions. Due to their multiple enzymatic activities, GHs are broadly applied in bioethanol, food, and paper industry. In order to increase the productivity of these industrial processes, a constant search for novel and efficient enzymes has been proved to be necessary. In this context, metagenomics is a powerful approach to achieve this demand. In the current study, we describe the discovery and characterization of a novel member of GH16 family derived from the sugarcane soil metagenome. The enzyme, named SCLam, has 286 amino acid residues and displays sequence homology and activity properties that resemble known laminarases. SCLam is active against barley beta glucan, laminarin, and lichenan (72, 33, and 10 U mg(-1), respectively). The optimal reaction conditions were identified as 40 degrees C and pH 6.5. The low resolution structure was determined using the small-angle X-ray scattering technique, revealing that SCLam is a monomer in solution with a radius of gyration equal to 19.6 A. To the best of our knowledge, SCLam is the first nonspecific (1,3/1,3:1,4)-beta-D-glucan endohydrolase (EC 3.2.1.6) recovered by metagenomic approach to be characterized. PMID- 26242387 TI - Study of Biological Degradation of New Poly(Ether-Urethane-Urea)s Containing Cyclopeptide Moiety and PEG by Bacillus amyloliquefaciens Isolated from Soil. AB - The present work for the first time investigates the effect of Bacillus amyloliquefaciens, M3, on a new poly(ether-urethane-urea) (PEUU). PEUU was synthesized via reaction of 4,4'-methylenebis(4-phenylisocyanate) (MDI), L leucine anhydride cyclopeptide (LACP) as a degradable monomer and polyethylene glycol with molecular weight of 1000 (PEG-1000). Biodegradation of the synthesized PEUU as the only source for carbon and nitrogen for M3 was studied. The co-metabolism biodegradation of the polymer by this organism was also investigated by adding mannitol or nutrient broth to the basic media. Biodegradation of the synthesized polymer was followed by SEM, FT-IR, TGA, and XRD techniques. It was shown that incubation of PEUU with M3 resulted in a 30-44 % reduction in polymer's weight after 1 month. This study indicates that the chemical structure of PEUU significantly changes after exposure to M3 due to hydrolytic and enzymatic degradation of polymer chains. The results of this work supports the idea that this poly(ether-urethane) is used as a sole carbon source by M3 and this bacterium has a good capability for degradation of poly(ether urethane)s. PMID- 26242388 TI - Quantum Hall conductance of graphene combined with charge-trap memory operation. AB - The combination of quantum Hall conductance and charge-trap memory operation was qualitatively examined using a graphene field-effect transistor. The characteristics of two terminal quantum Hall conductance appeared clearly on the background of a huge conductance hysteresis during a gate-voltage sweep for a device using monolayer graphene as a channel,hexagonal boron-nitride flakes as a tunneling dielectric and defective silicon oxide as the charge storage node. Even though there was a giant shift of the charge neutrality point, the deviation of quantized resistance value at the state of filling factor 2 was less than 1.6% from half of the von Klitzing constant. At high Landau level indices, the behaviors of quantum conductance oscillation between the increasing and the decreasing electron densities were identical in spite ofa huge memory window exceeding 100 V. Our results indicate that the two physical phenomena, two terminal quantum Hall conductance and charge-trap memory operation, can be integrated into one device without affecting each other. PMID- 26242389 TI - Tumoral calcinosis of the spine in the course of systemic sclerosis: report of a new case and review of the literature. AB - We report here a case of a 62-year-old Caucasian woman, suffering from diffuse cutaneous systemic sclerosis (SSc), who developed a tumoural calcinosis (TC) localised in the left side of the neck around the cervical spine that caused severe pain and motion impairment, without involvement of regional neurological structures. A review of the literature on this issue (based on PubMed database) allowed us to identify 35 previously described cases of TC in para-vertebral area in the course of SSc. The main characteristics of these patients have been summarised. PMID- 26242391 TI - [Recruitment for multicenter surgical studies in Germany: ongoing studies]. PMID- 26242392 TI - Editorial: Uveitis: Pathology, Molecular Mechanisms and Therapy. PMID- 26242393 TI - Perioperative chemotherapy more of a benefit for overall survival than adjuvant chemotherapy for operable gastric cancer: an updated Meta-analysis. AB - To clarify the effect of neoadjuvant chemotherapy (NAC) on the survival outcomes of operable gastric cancers, we searched PubMed, Embase, and Cochrane Library for randomized clinical trials published until June 2014 that compared NAC-containing strategies with NAC-free strategies in patients with adenocarcinoma of the stomach or the esophagogastric junction, who had undergone potentially curative resection. The adjusted pooled hazard ratio (HR) for overall survival (OS) was insignificant when comparing the NAC-containing arm with the NAC-free arm. Subgroup analysis showed that the OS of the treatment arm that involved both adjuvant chemotherapy (AC) and NAC was significantly improved over the control arm (AC only) (HR = 0.48, 95% CI: 0.35-0.67; P < 0.001). While NAC alone plus surgery did not show any survival benefit over surgery alone. Perioperative chemotherapy (PC) also showed a significant increase in PFS and a significant reduction in distant metastasis compared to surgery alone. Therefore, in patients with resectable gastric cancer, NAC alone is not enough and AC alone is not good enough to definitely improve their OS. Collectively, PC combined with surgery could maximize the survival benefit for patients with resectable gastric cancer. PMID- 26242394 TI - Injury pattern, outcome and characteristics of severely injured pedestrian. AB - BACKGROUND: Pedestrians who are involved in motor vehicle collisions present with a unique trauma situation. The aim of this study was to demonstrate the specific clinical characteristics of this patient population in comparison to injured motor vehicle occupants in the medical emergency setting. METHODS: A total of 4435 pedestrian traffic collision victims admitted to hospitals participating at TraumaRegister DGU(r) between 2002 and 2012 (primary admission, Injury Severity Score, ISS >= 9; age >= 2 years) was assessed and compared to 16,042 severely injured motor vehicle occupants. Analyses included features such as demographic distribution, injury patterns, treatment course, subsequent complications and overall clinical outcome. RESULTS: Severely injured pedestrians more commonly were female (42 % vs. 34 % of motor vehicle occupants) and children below 16 years (12 % vs. 2 %) or seniors above 60 years of age (39 % vs. 17 %). Pedestrians were injured more severely (ISS: 26 vs. 25; NISS 32 vs. 30) with higher rates of head injuries (64 % vs. 47 %), pelvic injuries (32 % vs. 23 %) and lower extremity injuries (52 % vs. 43 %). Accordingly, pedestrians more commonly presented with Glasgow Coma Scale <9 (36 % vs. 28 %) and a systolic blood pressure below 90 mmHg (18 % vs. 13 %) accumulating in a worse prognosis (RISC-Score 24 % vs. 15 %) despite of a shorter on-scene treatment time (26 min vs. 38 min) and a shorter period from the collision until hospital admission (61 min vs. 78 min). Finally, pedestrians showed a higher mortality (22 % vs. 12 %). CONCLUSION: Severely injured pedestrians represent a challenging patient population with unique injury patterns and high subsequent mortality. Emergency team members should be sensitized to the trigger term "pedestrian" in order to improve the initial emergency management and thus the overall clinical outcome. PMID- 26242397 TI - Phone Consultation for Behavioral Health-Related Referrals in Integrated Primary Care. AB - Behavioral health (BH) providers add value to primary care teams. This descriptive study illustrates one such role that the BH provider can serve. The on-site BH provider responded to patient phone inquiries regarding BH topics for pediatricians over the course of 15 months. The majority of these calls were for children 10 years and younger and related to externalizing problems. Phone calls were relatively brief (i.e., 11-15 minutes). More than half of these phone calls resulted in families scheduling an appointment with nearly 75% showing up for the initial session. Providing this type of adjunctive service may result in earlier access to care and efficiently assigning responsibilities to the appropriate team member. PMID- 26242396 TI - Fetal sex differences in human chorionic gonadotropin fluctuate by maternal race, age, weight and by gestational age. AB - Circulating levels of the placental glycoprotein hormone human chorionic gonadotropin (hCG) are higher in women carrying female v. male fetuses; yet, the significance of this difference with respect to maternal factors, environmental exposures and neonatal outcomes is unknown. As a first step in evaluating the biologic and clinical significance of sex differences in hCG, we conducted a population-level analysis to assess its stability across subgroups. Subjects were women carrying singleton pregnancies who participated in prenatal and newborn screening programs in CA from 2009 to 2012 (1.1 million serum samples). hCG was measured in the first and second trimesters and fetal sex was determined from the neonatal record. Multivariate linear models were used to estimate hCG means in women carrying female and male fetuses. We report fluctuations in the ratios of female to male hCG by maternal factors and by gestational age. hCG was higher in the case of a female fetus by 11 and 8% in the first and second trimesters, respectively (P<0.0001). There were small (1-5%) fluctuations in the sex difference by maternal race, weight and age. The female-to-male ratio in hCG decreased from 17 to 2% in the first trimester, and then increased from 2 to 19% in the second trimester (P<0.0001). We demonstrate within a well enumerated, diverse US population that the sex difference in hCG overall is stable. Small fluctuations within population subgroups may be relevant to environmental and physiologic effects on the placenta and can be probed further using these types of data. PMID- 26242398 TI - HSP27 modulates survival signaling in endosulfan-exposed human peripheral blood mononuclear cells treated with curcumin. AB - Endosulfan, a well-known organochlorine pesticide, induces apoptosis and depletion of reduced glutathione (GSH) in human peripheral blood mononuclear cells (PBMC). Thus, for the amelioration of its effect, antioxidant and antiapoptotic potential of curcumin was evaluated. For ascertaining the attenuating effect of curcumin, various biochemical indices of cell damage such as cytotoxicity, oxidative stress, apoptosis (phosphatidylserine externalization, DNA fragmentation, and cytochrome c) in human PBMC was evaluated following endosulfan exposure (0-100 uM). To assess the role of HSP27 on endosulfan-induced apoptosis, the expression of HSP27 was examined. Curcumin (25 uM) increased cell viability significantly. As evident from the restoration of GSH, antiapoptotic potential was directly proportional to their antioxidant nature of curcumin. The present study indicates that the beneficial effect of curcumin on endosulfan induced cytotoxicity is related to the induced synthesis of HSP27, emphasizing its antioxidant and therapeutic potential as well as underscoring the mechanism of pesticide-induced toxicity at cellular level. Taken together, these findings suggest that curcumin protects against endosulfan-induced immunotoxicity in human PBMC by attenuating apoptosis. PMID- 26242395 TI - Consumption of spicy foods and total and cause specific mortality: population based cohort study. AB - OBJECTIVE: To examine the associations between the regular consumption of spicy foods and total and cause specific mortality. DESIGN: Population based prospective cohort study. SETTING: China Kadoorie Biobank in which participants from 10 geographically diverse areas across China were enrolled between 2004 and 2008. PARTICIPANTS: 199,293 men and 288,082 women aged 30 to 79 years at baseline after excluding participants with cancer, heart disease, and stroke at baseline. MAIN EXPOSURE MEASURES: Consumption frequency of spicy foods, self reported once at baseline. MAIN OUTCOME MEASURES: Total and cause specific mortality. RESULTS: During 3,500,004 person years of follow-up between 2004 and 2013 (median 7.2 years), a total of 11,820 men and 8404 women died. Absolute mortality rates according to spicy food consumption categories were 6.1, 4.4, 4.3, and 5.8 deaths per 1000 person years for participants who ate spicy foods less than once a week, 1 or 2, 3 to 5, and 6 or 7 days a week, respectively. Spicy food consumption showed highly consistent inverse associations with total mortality among both men and women after adjustment for other known or potential risk factors. In the whole cohort, compared with those who ate spicy foods less than once a week, the adjusted hazard ratios for death were 0.90 (95% confidence interval 0.84 to 0.96), 0.86 (0.80 to 0.92), and 0.86 (0.82 to 0.90) for those who ate spicy food 1 or 2, 3 to 5, and 6 or 7 days a week, respectively. Compared with those who ate spicy foods less than once a week, those who consumed spicy foods 6 or 7 days a week showed a 14% relative risk reduction in total mortality. The inverse association between spicy food consumption and total mortality was stronger in those who did not consume alcohol than those who did (P=0.033 for interaction). Inverse associations were also observed for deaths due to cancer, ischemic heart diseases, and respiratory diseases. CONCLUSION: In this large prospective study, the habitual consumption of spicy foods was inversely associated with total and certain cause specific mortality, independent of other risk factors of death. PMID- 26242399 TI - Which family physician should I choose? The analytic hierarchy process approach for ranking of criteria in the selection of a family physician. AB - BACKGROUND: Choosing the most appropriate family physician (FP) for the individual, plays a fundamental role in primary care. The aim of this study is to determine the selection criteria for the patients in choosing their family doctors and priority ranking of these criteria by using the multi-criteria decision-making method of the Analytic Hierarchy Process (AHP) model. METHODS: The study was planned and conducted in two phases. In the first phase, factors affecting the patients' decisions were revealed with a qualitative research. In the next phase, the priorities of FP selection criteria were determined by using AHP model. Criteria were compared in pairs. 96 patient were asked to fill the information forms which contains comparison scores in the Family Health Centres. RESULTS: According to the analysis of focus group discussions FP selection criteria were congregated in to five groups: Individual Characteristics, Patient Doctor relationship, Professional characteristics, the Setting, and Ethical Characteristics. For each of the 96 participants, comparison matrixes were formed based on the scores of their information forms. Of these, models of only 5 (5.2 %) of the participants were consistent, in other words, they have been able to score consistent ranking. The consistency ratios (CR) were found to be smaller than 0.10. Therefore the comparison matrix of this new model, which was formed based on the medians of scores only given by these 5 participants, was consistent (CR = 0.06 < 0.10). According to comparison results; with a 0.467 value-weight, the most important criterion for choosing a family physician is his/her 'Professional characteristics'. CONCLUSIONS: Selection criteria for choosing a FP were put in a priority order by using AHP model. These criteria can be used as measures for selecting alternative FPs in further researches. PMID- 26242400 TI - Living With and Within the Rules of Domestic Violence Shelters: A Qualitative Exploration of Residents' Experiences. AB - As emergency domestic violence (DV) shelters have proliferated, there has been an increase in rules that shelter residents must follow. This qualitative descriptive study explores intimate partner violence (IPV) survivors' experiences living with DV shelter rules. Five thematic clusters emerged from interviews with 11 survivors: (1) shelter environment/staff approach, (2) making sense of the rules, (3) staff enforcement of the rules, (4) short-term impact of the rules, and (5) coping. Results suggest that residents benefit from more flexible boundaries between staff and residents, less restrictive rules, and collaborative, transparent rule enforcement. Recommendations are made for shelter practice and future research. PMID- 26242401 TI - Virtual restorative environment therapy as an adjunct to pain control during burn dressing changes: study protocol for a randomised controlled trial. AB - BACKGROUND: The pain of a severe burn injury is often characterised by intense background pain, coupled with severe exacerbations associated with essential procedures such as dressing changes. The experience of pain is affected by patients' psychological state and can be enhanced by the anxiety, fear and distress caused by environmental and visual inputs. Virtual Reality (VR) distraction has been used with success in areas such as burns, paediatrics and oncology. The underlying principle of VR is that attention is diverted from the painful stimulus by the use of engaging, dynamic 3D visual content and associated auditory stimuli. Functional magnetic resonance imaging (fMRI) studies undertaken during VR distraction from experimental pain have demonstrated enhancement of the descending cortical pain-control system. METHODS/DESIGN: The present study will evaluate the feasibility of introducing a novel VR system to the Burns Unit at the Queen Elizabeth Hospital Birmingham for dressing changes: virtual restorative environment therapy (VRET). The study will also explore the system's impact on pain during and after the dressing changes compared to conventional analgesia for ward-based burn dressing changes. A within-subject crossover design will be used to compare the following three conditions: 1. Interactive VRET plus conventional analgesics. 2. Passive VRET with conventional analgesics. 3. Conventional analgesics alone. Using the Monte Carlo method, and on the basis of previous local audit data, a sample size of 25 will detect a clinically significant 33 % reduction in worst pain scores experienced during dressing changes. DISCUSSION: The study accrual rate is currently slower than predicted by previous audits of admission data. A review of the screening log has found that recruitment has been limited by the nature of burn care, the ability of burn inpatients to provide informed consent and the ability of patients to use the VR equipment. Prior to the introduction of novel interactive technologies for patient use, the characteristics and capabilities of the target population needs to be evaluated, to ensure that the interface devices and simulations are usable. TRIAL REGISTRATION: Current Controlled Trials ISRCTN23330756 . Date of Registration 25 February 2014. PMID- 26242402 TI - Essential metals at the host-pathogen interface: nutritional immunity and micronutrient assimilation by human fungal pathogens. AB - The ability of pathogenic microorganisms to assimilate sufficient nutrients for growth within their hosts is a fundamental requirement for pathogenicity. However, certain trace nutrients, including iron, zinc and manganese, are actively withheld from invading pathogens in a process called nutritional immunity. Therefore, successful pathogenic species must have evolved specialized mechanisms in order to adapt to the nutritionally restrictive environment of the host and cause disease. In this review, we discuss recent advances which have been made in our understanding of fungal iron and zinc acquisition strategies and nutritional immunity against fungal infections, and explore the mechanisms of micronutrient uptake by human pathogenic fungi. PMID- 26242403 TI - A novel placental like alkaline phosphatase promoter driven transcriptional silencing combined with single chain variable fragment antibody based virosomal delivery for neoplastic cell targeting [corrected]. AB - BACKGROUND: Placental like alkaline phosphatase (PLAP), an oncofetal antigen, is highly expressed in germ cell, cervical, ovarian and several other tumour types but minimally in normal tissues [corrected]. The expression of a PLAP promoter based transcriptional unit following antigen mediated cell specific delivery is a possible approach for tumour targeting. METHODS: PLAP promoter alone or in combination with NFkappaB DNA response elements was used for expressing shRNA targeting the long control region (LCR) of human papillomavirus (HPV)-16 oncogenes E6 and E7 via transcriptional gene silencing in PLAP expressing cervical cancer cell lines, SiHa and CaSki. This was packaged in a Sendai virus envelope incorporating a single chain variable fragment antibody (scFv) for antibody mediated targeting. Specificity and efficacy of the shRNA was assessed by studying the heterochromatization, down regulation of the HPV-16 E6/E7 genes and subsequent effects on their targets and cell growth properties. RESULTS: Reduction of HPV-16 E6 and E7 expression by TGS led to the activation of the previously suppressed target genes of p53 (PUMA and NOXA) and Rb (cyclins A2 and E). Cell death was seen only in PLAP expressing HPV-16 infected SiHa and CaSki cells but not in the HPV-18 integrated HeLa and non-PLAP CHO cells. There was reduction in the enhancer associated transcripts of the long control region (LCR) of HPV-16 E6/E7 genes. Also, an increase in the enrichment of dimethylated histone three lysine nine (H3K9Me2) and trimethylated histone three lysine twenty seven (H3K27Me3) was observed by ChIP assay, which decreased upon trichostatin A treatment, indicating a possible mechanism for the heterochromatization of the target LCR region. CONCLUSION: A combination of novel PLAP promoter and antibody based specificities has the potential for being developed as a possible therapeutic strategy for PLAP positive neoplasia. PMID- 26242404 TI - One-stage posterior-only approach in surgical treatment of single-segment thoracic spinal tuberculosis with neurological deficits in adults: a retrospective study of 34 cases. AB - BACKGROUND: There are quite a few controversies on the surgical management of single-segment thoracic spinal tuberculosis with neurological deficits (STSTND). In this study, the clinical efficacy and feasibility of one-stage posterior-only transpedicular debridement, interbody fusion, and posterior instrumentation for treating STSTND in adults were retrospectively evaluated. METHODS: Thirty-four cases with STSTND underwent one-stage posterior-only transpedicular debridement, interbody fusion and posterior instrumentation at the same institution from January 2003 to January 2013. Follow-up time was 34.4 +/- 10.2 months (range, 18 48 months), and kyphosis angle was 34.1 +/- 12.3 degrees . The American Spinal Injury Association (ASIA) classification of spinal cord injury was employed to evaluate neurological deficits, while visual analogue scale (VAS) was employed to assess the degree of pain. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were used to evaluate the activity of tuberculosis (TB). RESULTS: All 34 patients with spinal tuberculosis (ST) were completely cured, and there was no recurrence of TB. Postoperative kyphosis angle was 8.2 +/- 1.8 degrees , and there was no significant loss of correction during the final follow-up. Solid fusion was achieved and pain was relieved in all cases. Neurological condition in all patients improved after surgery. CONCLUSIONS: One-stage posterior-only transpedicular debridement, interbody fusion, and posterior fixation followed by chemotherapy seems to be adequate for obtaining satisfactory healing of single segment thoracic spinal tuberculosis with neurological deficits. Careful patient selection is critical to the successful outcome with this technique. PMID- 26242405 TI - Microscopic and molecular evidence of the presence of asymptomatic Plasmodium falciparum and Plasmodium vivax infections in an area with low, seasonal and unstable malaria transmission in Ethiopia. AB - BACKGROUND: The presence of asymptomatic infections has serious implications for malaria elimination campaigns. Since asymptomatic carriers do not seek treatment for their infection and may become gametocyte carriers, they undoubtedly contribute to the persistence of malaria transmission in a population. The presence of asymptomatic parasitemias was noted in areas with seasonal malaria transmission. In Ethiopia there is a paucity of data regarding the prevalence of asymptomatic malaria carriage. This study was undertaken to assess the presence and prevalence of asymptomatic Plasmodium falciparum and Plasmodium vivax infections in south-central Oromia, Ethiopia. METHODS: A total of 1094 apparently healthy individuals >= 2 years of age in south-central Oromia, Ethiopia, an area with seasonal and unstable malaria transmission, were screened for the presence of asymptomatic plasmodial infections. Finger-prick blood samples were taken from each participant for blood film preparation for microscopy and the rapid diagnostic test (RDT). Blood samples were also spotted on Whatman 3MM filter paper for parasite DNA extraction. RESULTS: The prevalence of asymptomatic Plasmodium carriage (P. falciparum, P. vivax and mixed species) was 5.0 % (55/1,094) as determined by microscopy, while the prevalence as determined using RDT was 8.2 % (90/1,094). PCR was done on 47 of 55 microscopy-confirmed and on 79 of 90 RDT-confirmed samples. PCR detected parasite DNA in 89.4 % (42/47) of the microscopy-positive samples and in 77.2 % (61/79) of the RDT-positive samples. No significant difference was observed in the prevalence of asymptomatic P. falciparum or P. vivax infections in the study area (P > 0.1). However, the prevalence of asymptomatic parasitaemia was significantly associated with gender (OR = 0.47, P = 0.015; being higher in males than females) and age (X(2) = 25, P < 0.001; being higher in younger than in older individuals). Age and parasite densities had an inverse relationship. CONCLUSIONS: This study confirms the presence of asymptomatic P. falciparum and P. vivax infections in south-central Oromia, an area with low, seasonal and unstable malaria transmission in Ethiopia. Of 55 microscopically confirmed asymptomatic infections, P. falciparum monoinfection accounted for 45.5 % and of 90 RDT positive asymptomatic infections, 66.7 % were P. falciparum. Although not statistically significant, P. falciparum accounted for a relatively large number of the asymptomatic infections as determined by both tests. The prevalence of asymptomatic parasitaemia was highest in the younger age group. HRP-2-based RDTs specific for P. falciparum showed high false positivity rate compared to Plasmodium lactate dehydrogenase (pLDH) specific to P. vivax. Although microscopy and RDT detected substantial numbers of asymptomatic infections in apparently healthy inhabitants, the use of a highly sensitive molecular diagnostics offers a more accurate assessment of the magnitude of asymptomatic infections. PMID- 26242406 TI - Broadly protective immunity against divergent influenza viruses by oral co administration of Lactococcus lactis expressing nucleoprotein adjuvanted with cholera toxin B subunit in mice. AB - BACKGROUND: Current influenza vaccines need to be annually reformulated to well match the predicated circulating strains. Thus, it is critical for developing a novel universal influenza vaccine that would be able to confer cross-protection against constantly emerging divergent influenza virus strains. Influenza virus A is a genus of the Orthomyxoviridae family of viruses. Influenza virus nucleoprotein (NP) is a structural protein which encapsidates the negative strand viral RNA, and anti-NP antibodies play role in cross-protective immunity. Lactococcus lactis (L. lactis) is an ideal vaccine delivery vehicle via oral administration route. However, L. lactis vectored vaccine exhibits poor immunogenicity without the use of mucosal adjuvant. To enhance the immunogenicity of L. lactis vectored vaccine, cholera toxin B (CTB) subunit, one of mucosal adjuvants, is a safe adjuvant for oral route, when combined with L. lactis vectored vaccine. In this study, we hypothesized that pNZ8008, a L. lactis expression plasmid, encoding NP antigen, would be able to elicit cross-protection with the use of CTB via oral administration route. RESULTS: To construct L. lactis vectored vaccine, nucleoprotein (NP) gene of A/California/04/2009(H1N1) was sub-cloned into a L. lactis expression plasmid, pNZ8008. The expression of recombinant L. lactis/pNZ8008-NP was confirmed by Western blot, immunofluorescence assay and flow cytometric analysis. Further, immunogenicity of L. lactis/pNZ8008-NP alone or adjuvanted with cholera toxin B (CTB) subunit was evaluated in a mouse model via oral administration route. Antibodies responses were detected by ELISA. The result indicated that oral administration of L. lactis/pNZ8008-NP adjuvanted with CTB could elicit significant humoral and mucosal immune responses, as well as cellular immune response, compared with L. lactis/pNZ8008-NP alone. To further assess the cross-protective immunity of L. lactis/pNZ8008-NP adjuvanted with CTB, we used L. lactis/pNZ8110-pgsA-HA1 alone or adjuvanted with CTB as controls. Mice that received L. lactis/pNZ8008-NP adjuvanted with CTB were completely protected from homologous H1N1 virus and showed 80% protection against heterologous H3N2 or H5N1 virus, respectively. By contrast, L. lactis/pNZ8110-pgsA-HA1 adjuvanted with CTB also conferred 100% protection against H5N1 virus infection, but indicated no cross-protection against H1N1 or H5N1 virus challenge. As controls, mice vaccinated orally with L. lactis/pNZ8008-NP alone or L. lactis/pNZ8110-pgsA-HA1 alone could not survive. CONCLUSION: This study is the first to report the construction of recombinant L. lactis/pNZ8008-NP and investigate its immunogenicity with the use of CTB. Compared with L. lactis/pNZ8110-pgsA-HA1 adjuvanted with CTB, our data support 5 * 10(11) CFU of L. lactis/pNZ8008-NP adjuvanted with 1 ug of CTB is a better combination for universal influenza vaccines development that would provide cross protective immunity against divergent influenza A viruses. PMID- 26242408 TI - Disadvantaged children at greater relative risk of thinness (as well as obesity): a secondary data analysis of the England National Child Measurement Programme and the UK Millennium Cohort Study. AB - INTRODUCTION: Young children living in more disadvantaged socio-economic circumstances (SECs) are at an increased risk of overweight and obesity. However, there is scant research examining the prevalence and social distribution of thinness in early childhood, despite potential negative consequences for health and development across the life-course. METHODS: We examined the social gradient in thinness (and overweight and obesity for comparison) for 2,620,422 four-to five year olds attending state maintained primary schools from 2007/8 to 2011/12, in the England National Child Measurement Programme (NCMP), and 16,715 children from the UK Millennium Cohort Study (MCS), born in 2000-2002, and measured at ages of three, five and seven. Children were classified as being thin, healthy weight (and, for completeness, overweight or obese) using international age and sex adjusted cut-offs for body mass index (BMI). Prevalences (and 95% confidence intervals (CIs)) were estimated, overall, and according to SECs: area deprivation (NCMP, MCS); household income, and maternal social class and education (MCS only). Relative Risk Ratios (RRRs) and CIs for thinness, overweight and obesity were estimated in multinomial models by SECs (baseline healthy weight). In the MCS, standard errors were estimated using clustered sandwich estimators to account for repeated measures, and, for thinness, RRRs by SECs were also estimated adjusting for a range of early life characteristics. RESULTS: In 2007/8 to 2011/12, 5.20% of four-to-five year old girls (n = 66,584) and 5.88% of boys (78,934) in the NCMP were thin. In the MCS, the prevalence of thinness was 4.59% (693) at three, 4.21% (702) at five, and 5.84% (804) at seven years. In both studies, and for all measures of SECs, children from the most disadvantaged groups were more likely to be thin than those from the most advantaged groups. For example, MCS children whose mothers had no educational qualifications were fifty percent more likely to be thin (RRR 1.5 (CI: 1.24, 1.8)) than those whose mothers had a degree. These patterns were attenuated but remained after adjusting for early life characteristics. CONCLUSIONS: Children from more disadvantaged backgrounds are at elevated relative risk of thinness as well as obesity. Researchers and policymakers should consider environmental influences on thinness in addition to overweight and obesity. PMID- 26242407 TI - The New Zealand 1986 very low birth weight cohort as young adults: mapping the road ahead. AB - BACKGROUND: Very low birth weight (less than 1500 g) is associated with increased morbidity and costs of health care in childhood. Emerging evidence suggests these infants face a range of health and social problems as young adults. We studied all New Zealand very low birth weight infants born in 1986 (when 58% were exposed to antenatal corticosteroids) in infancy, with later follow-up at 7 to 8 years and 23 to 24 years. We now aim to assess the cohort at 26-28 years compared with controls. METHODS/DESIGN: The case sample will comprise a minimum of 250 members of the 1986 New Zealand national very low birth weight cohort (77% of survivors). Outcomes will be compared with a control group of 100 young adults born at term in 1986. Following written informed consent, participants will travel to Christchurch for 2 days of assessments undertaken by experienced staff. Medical assessments include growth measures, vision, respiratory function, blood pressure and echocardiogram, renal function, dental examination and blood tests. Cognitive and neuropsychological functioning will be assessed with standard tests, and mental health and social functioning by participant interview. A telephone interview will be conducted with a parent or significant other person nominated by the respondent to gain a further perspective on the young person's health and functioning. All those born at less than 28 weeks' gestation, plus a random subset of the cohort to a total of 150 cases and 50 controls, will be offered cranial magnetic-resonance imaging. Statistical analysis will examine comparison with controls and long-term trajectories for the very low birth weight cohort. DISCUSSION: The research will provide crucial New Zealand data on the young adult outcomes for very low birth weight infants and address gaps in the international literature, particularly regarding cardiovascular, respiratory, visual and neurocognitive outcomes. These data will inform future neonatal care, provide evidence-based guidelines for care of preterm graduates transitioning to adult care, and help shape health education and social policies for this high risk group. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000995875 . Registered 1 October 2012. PMID- 26242409 TI - Fratricide activity of MafB protein of N. meningitidis strain B16B6. AB - BACKGROUND: Neisseria meningitidis is an inhabitant of the mucosal surfaces of the human nasopharynx. We recently demonstrated that the secreted meningococcal Two-partner secretion protein A (TpsA) is involved in interbacterial competition. The C-terminal end of the large TpsA protein contains a small toxic domain that inhibits the growth of target bacteria. The producing cells are protected from this toxic activity by a small immunity protein that is encoded by the gene immediately downstream of the tpsA gene. Further downstream on the chromosome, a repertoire of toxic modules, designated tpsC cassettes, is encoded that could replace the toxic module of TpsA by recombination. Each tpsC cassette is associated with a gene encoding a cognate immunity protein. RESULTS: Blast searchers using the toxic domains of TpsA and TpsC proteins as queries identified homologies with the C-terminal part of neisserial MafB proteins, which, for the rest, showed no sequence similarity to TpsA proteins. On the chromosome, mafB genes are part of genomic islands, which include cassettes for additional toxic modules as well as genes putatively encoding immunity proteins. We demonstrate that a MafB protein of strain B16B6 inhibits the growth of a strain that does not produce the corresponding immunity protein. Assays in E. coli confirmed that the C-terminal region of MafB is responsible for toxicity, which is inhibited by the cognate immunity protein. Pull-down assays revealed direct interaction between MafB toxic domains and the cognate immunity proteins. CONCLUSIONS: The meningococcal MafB proteins are novel toxic proteins involved in interbacterial competition. PMID- 26242410 TI - The usefulness of the three-dimensional enhanced T1 high-resolution isotropic volume excitation MR in the evaluation of shoulder pathology: comparison with two dimensional enhanced T1 fat saturation MR. AB - OBJECTIVE: To evaluate the diagnostic accuracy of three-dimensional (3D) enhanced T1 high-resolution isotropic volume excitation (eTHRIVE) shoulder MR for variable shoulder pathology such as rotator cuff tear, labral injury and synovial pathology in comparison with two-dimensional enhanced fast spin echo T1 fat saturation (2D T1 FS) sequences MR. METHODS: This retrospective study included 86 patients who underwent MRI of the shoulder using eTHRIVE technique. Two radiologists evaluated anatomic identification of the supraspinatus, glenoid labrum and acromioclavicular joint (AC joint) on routine MRI sequences (2D T1 FS) and compared them with the reformatted eTHRIVE images. Subjective scoring of the images was performed with a four-point scale that rated the degree of discrimination of the shape of the supraspinatus, glenoid labrum and AC joint. The diagnostic accuracy of eTHRIVE compared with routine MR images was evaluated in terms of rotator cuff pathology, labral pathology and synovial pathology. RESULTS: Anatomic identification scores of the supraspinatus tendon and labrum were significantly lower for eTHRIVE than for 2D T1 FS. There were no significant differences between eTHRIVE and 2D T1 FS in anatomic identification of the AC joint. There were no significant differences between eTHRIVE and 2D T1 FS in diagnosing the three disease categories. CONCLUSION: eTHRIVE had comparable diagnostic accuracy to 2D T1 FS imaging in the evaluation of rotator cuff tears, labral injury and synovial pathology, but anatomic identification was inferior to that of 2D T1 FS. ADVANCES IN KNOWLEDGE: The accuracy of 3D eTHRIVE imaging is comparable to that of 2D T1 FS for the diagnosis of rotator cuff tears, labral injury and synovial pathology. PMID- 26242411 TI - Enhanced hepatitis B virus (HBV) pre-genomic RNA levels and higher transcription efficiency of defective HBV genomes. AB - Defective hepatitis B virus (dHBV) particles contain genomes corresponding to singly spliced HBV RNA. A limited number of studies show that dHBV is present in all chronically HBV-infected patients. Clinical studies have linked dHBV and dHBV gene products to high virus loads and liver damage. The replication characteristics of dHBV genomes remain poorly understood. We found that the splice donor/acceptor sites critical for the formation of dHBV genomes are conserved across HBV genotypes. We report a novel method to create dHBV constructs from corresponding wild-type (WT) HBV constructs. We assessed the transcriptional characteristics of the dHBV constructs with those of the corresponding WT construct using a cell culture model. Interestingly, dHBV constructs had higher pre-genomic RNA levels, transcription efficiency, HBV e antigen levels and intracellular HBV core antigen levels compared with the corresponding WT HBV constructs. Our findings highlight previously unrecognized fundamental molecular characteristics of dHBV genomes and their potential role in the pathogenesis of HBV infection. PMID- 26242413 TI - Queer diagnoses revisited: The past and future of homosexuality and gender diagnoses in DSM and ICD. AB - The American Psychiatric Association (APA) recently completed a several year process of revising the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). During that time, there were objections raised to retaining DSM's gender identity disorder diagnoses and calls to remove them, just as homosexuality had been removed from DSM-II in 1973. At the conclusion of the DSM-5 revision process, the gender diagnoses were retained, albeit in altered form and bearing the new name of 'gender dysphoria'. The author of this paper was a member of the DSM-5 Workgroup on Sexual and Gender Identity Disorders and presently serves on the WHO Working Group on Sexual Disorders and Sexual Health. Both groups faced similar tasks: reconciling patients' needs for access to care with the stigma of being given a psychiatric diagnosis. The differing nature of the two diagnostic manuals led to two different outcomes. As background, this paper updates the history of homosexuality and the gender diagnoses in the DSM and in the International Statistical Classification of Diseases and Related Health Problems (ICD) as well as what is expected to happen to the homosexuality and gender diagnoses following the current ICD-11 revision process. PMID- 26242414 TI - Clinical cure rates in subjects treated with azithromycin for community-acquired respiratory tract infections caused by azithromycin-susceptible or azithromycin resistant Streptococcus pneumoniae: analysis of Phase 3 clinical trial data authors' response. PMID- 26242412 TI - IGF1 Receptor Targeted Theranostic Nanoparticles for Targeted and Image-Guided Therapy of Pancreatic Cancer. AB - Overcoming resistance to chemotherapy is a major and unmet medical challenge in the treatment of pancreatic cancer. Poor drug delivery due to stromal barriers in the tumor microenvironment and aggressive tumor biology are additional impediments toward a more successful treatment of pancreatic cancer. In attempts to address these challenges, we developed IGF1 receptor (IGF1R)-directed, multifunctional theranostic nanoparticles for targeted delivery of therapeutic agents into IGF1R-expressing drug-resistant tumor cells and tumor-associated stromal cells. These nanoparticles were prepared by conjugating recombinant human IGF1 to magnetic iron oxide nanoparticles (IONPs) carrying the anthracycline doxorubicin (Dox) as the chemotherapeutic payload. Intravenously administered IGF1-IONPs exhibited excellent tumor targeting and penetration in an orthotopic patient-derived xenograft (PDX) model of pancreatic cancer featuring enriched tumor stroma and heterogeneous cancer cells. IGF1R-targeted therapy using the theranostic IGF1-IONP-Dox significantly inhibited the growth of pancreatic PDX tumors. The effects of the intratumoral nanoparticle delivery and therapeutic responses in the orthotopic pancreatic PDX tumors could be detected by magnetic resonance imaging (MRI) with IONP-induced contrasts. Histological analysis showed that IGF1R-targeted delivery of Dox significantly inhibited cell proliferation and induced apoptotic cell death of pancreatic cancer cells. Therefore, further development of IGF1R-targeted theranostic IONPs and MRI-guided cancer therapy as a precision nanomedicine may provide the basis for more effective treatment of pancreatic cancer. PMID- 26242415 TI - [Good prognosis after myocardial infarct - also the general practitioner is necessary]. PMID- 26242416 TI - [CME. Stable coronary heart disease: non-invasive diagnostic methods]. PMID- 26242418 TI - [Follow-up care of patients after heart attack]. AB - Survivors of a myocardial infarction are at increased risk for future cardiac events, including recurrent infarction, heart failure, arrhythmia, stroke, and sudden cardiac death. The primary care physician needs to be aware of the potential risks and complications facing these patients. Secondary preventive measures after myocardial infarction include an optimal medical therapy (dual antiplatelet therapy, Statin, ACE-inhibitor, and in most cases a beta-blocker) and life style modifications (quit smoking, regular physical activity, Mediterranean-style diet). Patients should be informed about how to recognize and react to cardiac symptoms. PMID- 26242419 TI - [Emergencies in ophthalmology]. AB - Acute vision loss, a painful eye, or a red/pink eye are typical symptoms of an ophthalmic emergency. Ascertain a thorough medical history concerning type, duration, and location of visual loss to point out the etiology of the disease. With simple diagnostic tools the differential diagnosis can be narrowed down even by non-ophthalmologists. This first differential diagnosis shows how urgent the patient has to be referred to an ophthalmologist. PMID- 26242420 TI - [Functional gastrointestinal disorders]. AB - Functional gastrointestinal complaints are very common in daily clinic practice. Functional gastrointestinal disorders are characterized in disturbances of motility patterns and/or of visceral hypersensitivity. The main functional gastrointestinal disorders are functional dyspepsia and irritable bowel syndrome. There is no causative therapy, but we have many medication and also non medication therapeutic options which all can be tried on an indivual basis. PMID- 26242421 TI - [Pros and cons of antipsychotics in children and adolescents]. AB - In the last decade the indication of antipsychotics has been expanded from the treatment of psychoses to the treatment of impulsive-aggressive behaviors in mentally retarded children and adolescents with conduct disorder or autism spectrum disorders. As a consequence the use of antipsychotics in children and adolescents has increased worldwide. This increase of prescriptions is under critical discussion. In this paper the indication and the potential side-effects of antipsychotics in children and adolescents are described. The risks of antipsychotic medication are contrasted with the potential benefits to arrive at rational treatment recommendations. PMID- 26242422 TI - [Use of non-steroidal antirheumatic drugs in acute gout]. PMID- 26242423 TI - [Broad-spectrum sunscreen prevents the development of melanocytic nevi in fair skinned children]. PMID- 26242424 TI - [Lipophilic beta blockers cause an increase in depression in primary care patients]. PMID- 26242426 TI - [CME-ORL 16. Supraglottic space-occupying lesion with dysphagia. Lipoma]. PMID- 26242428 TI - Verruciform xanthoma developing in eroded skin of recessive dystrophic epidermolysis bullosa. PMID- 26242429 TI - Exceptional river gorge formation from unexceptional floods. AB - An understanding of rates and mechanisms of incision and knickpoint retreat in bedrock rivers is fundamental to perceptions of landscape response to external drivers, yet only sparse field data are available. Here we present eye witness accounts and quantitative surveys of rapid, amphitheatre-headed gorge formation in unweathered granite from the overtopping of a rock-cut dam spillway by small moderate floods (~100-1,500 m(3) s(-1)). The amount of erosion demonstrates no relationship with flood magnitude or bedload availability. Instead, structural pattern of the bedrock through faults and joints appears to be the primary control on landscape change. These discontinuities facilitate rapid erosion (>270 m headward retreat; ~100 m incision; and ~160 m widening over 6 years) principally through fluvial plucking and block topple. The example demonstrates the potential for extremely rapid transient bedrock erosion even when rocks are mechanically strong and flood discharges are moderate. These observations are relevant to perceived models of gorge formation and knickpoint retreat. PMID- 26242430 TI - [A Review of Taiwan's Community Mental Health Policies: Current Developments and Future Prospect]. AB - Community mental health is an important area of public health. This study initially elaborates from the perspective of community psychology the concept and basis of the practice of community mental health work, including the importance of prevention over treatment, of valuing personal advantages and capabilities, and of adopting an ecological perspective, a respect for diversity, empowerment, and scientific cooperation and integration. Subsequently, this paper reviews the history of the development of community mental health work in Taiwan and of the operations, developmental issues, and difficulties currently faced by community mental health centers. Finally, this paper addresses the future prospects for community mental health work in Taiwan in hopes that the government will attach greater importance to related policies and implementation plans, optimize the service and delivery systems of community mental health organizations, reinforce community mental health education, develop effective community mental health promotion strategies, provide accessible and continuous direct services, integrate community mental health resources, and support the families of mental health patients in order to consolidate and better promote community-based mental health work. PMID- 26242431 TI - [The Discursive Analysis of Mental Health Promotion Efforts Targeting Community Dwelling Young Adults at High Risk of Mental Illness]. AB - The mental health of adolescents and young adults is an issue of concern worldwide due to the increase in violent incidents that have been perpetrated by members of this age group. Young people at high-risk of mental disability are easily ignored. Therefore, social tensions in society have increased due to safety issues arising from the problems that are associated with mental disabilities in this population. This paper discusses the importance of early identification and early prevention of mental disabilities in high-risk young people, defines high-risk mental illness, and identifies the various subcategories of mental diseases. Based on our review of the literature, the present paper suggests targeting young people in high-risk categories with health promotion that addresses the following six health-promotion lifestyle habits: engaging in regular exercise, eating a balanced diet, managing stress, engaging in social relationships, taking responsibility for personal health, and fulfilling self-actualization. This discursive analysis discusses these strategies as safe and sustained interventions for adolescents and young adults that may improve self-awareness and thus maintain health and enhance opportunities to promote an ideal health status. PMID- 26242432 TI - [A Community-Based Experience Model of Mental-Social Health Promotion for Older People in Taichung City]. AB - Active ageing is one of the most important issues taken up by the WHO in regard to ageing societies. "Prolonging Healthy Life Expectance" and "Decreasing the Depression Rate Among Older People" are critical indicators for "2020 Healthy People in Taiwan". This paper conducts a trial run of the program planning and evaluation of mental-social health promotion using focus group research that surveys 29 administrative districts and a depression survey that randomly samples older individuals in Taichung City. We also introduce how we apply local characteristics to develop the 3-level and innovative-action plans to meet the needs of self-identity and social participation for older people. For example, the "Learning Mobile Classroom" program promotes health promotion using activities that are tailored to the lifestyle and culture characteristics of target individuals. Another example is the "Seniors Show", which uses community groups and annual active-ageing shows to promote a positive concept of aging and to promote social participation for older people. Finally, the "Navigator APP of Active Ageing", created using a geographic information system, addresses the resource information needs of older people. This experience in Taichung City uniquely empowers older people, allowing them to take the initiative to make a difference not only for mental-social wellness but also for the hope of life and for graceful ageing. PMID- 26242433 TI - [A Long Way Home: The Current State of Care Provided by Family Caregivers and Public Health Nurses to Persons With Mental Illness in the Community]. AB - According to Taiwan's Health and Welfare Ministry statistics, Taiwan had a total of 122,538 people who were officially registered as mentally disabled at the end of December 2013. Worldwide, schizophrenia ranks as the sixth most burdensome disease in terms of total expenditures. The present paper uses the two actual care stories of the families of mental illness patients and compares and contrasts these with the community mental illness care models used in other countries. The hospital-based psychiatric and community-based mental illness care that is practiced in Taiwan presents dilemmas and has long focused on "disease orientated care" rather than holistic care. The gap between institutional and community mental rehabilitation services in Taiwan are examined. We recommend that policy makers create an open space for mental illness family caregivers and public health nurses to engage in dialogue in order to effectively integrate the care resources available to community mental illness patients and to break down the care barriers that currently separate community mental illness patients, family caregivers, and public health nurses. PMID- 26242434 TI - [Mental Health Promotion Among the Chronic Disabled Population in the Community]. AB - Societal ageing and the rising prevalence of chronic disease are important causes that underlie the growth in the number of disabled individuals. The disease induced psychological distress experienced by this population not only decreases quality of life but also increases demand for healthcare. The healthcare policy for the disabled population currently focuses on community healthcare. Therefore, developing appropriate programs to promote mental health among the disabled population in community settings is a critical issue. The present paper reviews current mental health promotion initiatives that target the disabled population in the community and addresses mental healthcare issues that are prevalent among the chronically disabled; strategies of mental health promotion that use music therapy, reminiscence therapy, and horticultural therapy; and the roles and responsibilities of community professionals in mental healthcare. We offer these perspectives as a reference to promote mental health and to establish holistic community healthcare for chronically disabled individuals. PMID- 26242435 TI - [The Impact of Late Umbilical Cord Clamping on Neonatal Jaundice and Postpartum Hemorrhage: A Randomized Controlled Trail]. AB - BACKGROUND: The current evidence supports the clinical benefits of late umbilical cord clamping. These benefits include increased blood volume and total body iron. Furthermore, delayed cord clamping facilitates the transplantation of stem cells, which helps the development of infant bodily systems. However, due to concerns related to postpartum hemorrhaging and neonate jaundice, most maternity units still clamp the cord immediately after a child is born. PURPOSE: This study investigates the impact of delaying cord clamping on neonatal jaundice and postpartum hemorrhage. METHODS: A randomized, controlled trial was conducted at a regional teaching hospital in northern Taiwan. One hundred and five healthy nulliparous women at 36 weeks of pregnancy were included and allocated randomly to the experiment group (n=44) and the control group (n=61). Participants in the experiment group received delayed cord clamping (DCC) at 3 minutes after delivery. Participants in the control group received early cord clamping (ECC) at around 1 minute after delivery. Clinical measures of the outcomes were measured by the infant transcutaneous bilirubin levels (TcB) and postpartum hemorrhage at birth. A structured questionnaire and biophysical measures were used to collect data on participant demographics, obstetrical information, maternal blood loss at birth, neonate weight and TcB level at hospitalization, and whether or not the infant received phototherapy at 4-7 days postpartum. RESULTS: Overall, there was no significant difference between the two groups in terms of neonatal jaundice, maternal hemorrhage at birth, and phototherapy rates at time of hospitalization and at 4-7 days postpartum. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The findings of the present study support that late umbilical cord clamping does not increase the risk of maternal postpartum hemorrhaging or neonate jaundice. Thus, we suggest that clinicians inform clients during prenatal classes of the benefits of delayed cord clamping and also use current, evidence-based knowledge to dispel client worries regarding the dangers to maternal-neonate health of delayed cord clamping. PMID- 26242436 TI - [A Survey of the Perception of Nurses Toward the Practice Environment at a Regional Teaching Hospital in Central Taiwan]. AB - BACKGROUND: The nursing practice environment has been shown to wield significant influence on nursing retention and nursing quality of care. Because a large percentage of Taiwan nurses currently work at regional teaching hospitals, exploring the perception toward the practice environment of nurses working at this type of hospital is important. PURPOSE: This study explored the perception of nurses working at a regional teaching hospital in central Taiwan toward their practice environment. METHODS: A cross-sectional research design with a sample of 474 nurses from a regional hospital in central Taiwan was conducted. Instruments including the demographic data and the Chinese-version Practice Environment Scale Nursing Work Index (CPES-NWI) were anonymously self-administered. RESULTS: Overall, participants were moderately satisfied with their practice environment, with the greatest dissatisfaction focused on staffing and resource adequacy. Work unit and nursing level, respectively, had significant impacts on perceptions regarding the practice environment. Furthermore, discriminant analysis identified two new compound variables: 1) adequate staffing resources and partnership in the workplace and 2) supportive administrative management environment. Participants who worked in medical and surgical units were significantly more dissatisfied with the adequacy of staffing resources and partnership in the workplace than participants who worked in acute/intensive and special units. Participants at the N2 level were significantly more dissatisfied with the supportive nature of the administrative management environment. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: These findings support that the nursing practice environment of regional hospitals may be improved using several measures, including: modifying the staffing and resource adequacy of nurses, fostering collaborative nurse-physician relationships, and further involving nurses in administrative management and decision-making. PMID- 26242437 TI - [Applying the Modified Delphi Technique to Develop the Role of HIV Case Managers and Essential Nursing Competencies in HIV Care]. AB - BACKGROUND: Since 2005, the Taiwan Centers for Disease Control (Taiwan CDC) initiated an HIV case management program in AIDS-designated hospitals to provide integrative services and risk-reduction counseling for HIV-infected individuals. In light of the increasingly complex and highly specialized nature of clinical care, expanding and improving competency-based professional education is important to enhance the quality of HIV/AIDS care. PURPOSE: The aim of this study was to develop the essential competency framework for HIV care for HIV case managers in Taiwan. METHODS: We reviewed essential competencies of HIV care from Canada, the United Kingdom, and several African countries and devised descriptions of the roles of case managers and of the associated core competencies for HIV care in Taiwan. The modified Delphi technique was used to evaluate the draft framework of these roles and core competencies. A total of 15 HIV care experts were invited to join the expert panel to review and rank the draft framework. RESULTS: The final framework consisted of 7 roles and 27 competencies for HIV case managers. In Round 1, only 3 items did not receive consensus approval from the experts. After modification based on opinions of the experts, 7 roles and 27 competencies received 97.06% consensus approval in Round 2 and were organized into the final framework for HIV case managers. These roles and associated core competencies were: HIV Care Expert (9 competencies), Communicator (1 competency), Collaborator (4 competencies), Navigator (2 competencies), Manager (4 competencies), Advocate (2 competencies), and Professional (5 competencies). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The authors developed an essential competency framework for HIV care using the consensus of a multidisciplinary expert panel. Curriculum developers and advanced nurses and practitioners may use this framework to support developments and to ensure a high quality of HIV care. PMID- 26242438 TI - [Self-Reflection From Group Dialogue: The Lived Experience of Psychiatric/Mental Health Nurses]. AB - BACKGROUND: Self-reflection is an essential element of reflective practice for group facilitators. However, this element typically exists largely at the personal level and is not addressed in group dialogues of nurses. PURPOSE: The purpose of this study was to explore the self-reflection of psychiatric nurses in a supervision group. METHODS: A phenomenological approach was used to investigate the dialogues across 12 sessions in terms of discussion content and the reflective journals of the psychiatric nurse participants. RESULTS: The findings showed that two forms of self-reflection included: Embodied self-reflection derived from the physical sensibility and discursive self-reflection derived from the group dialogues. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The embodied and discursive self-reflections promote self-awareness in nurses. The embodiment and initiation in the group facilitates the process of self-becoming through the group dialogue, which promotes self-examination and self-direction in healthcare professionals. PMID- 26242439 TI - [Major Burn Trauma Management and Nursing Care]. AB - Major burn injury is one of the most serious and often life-threatening forms of trauma. Burn patients not only suffer from the physical, psychological, social and spiritual impacts of their injury but also experience considerable changes in health-related quality of life. This paper presents a review of the literature on the implications of previous research and clinical care guidelines related to major burn injuries in order to help clinical practice nurses use evidence-based care guidelines to respond to initial injury assessments, better manage the complex systemic response to these injuries, and provide specialist wound care, emotional support, and rehabilitation services. PMID- 26242440 TI - [A Concept Analysis for Mind-Body Interaction]. AB - Mind-body interaction (MBI) refers the holistic association and interactive process between wisdom, thinking, belief, and physiological reaction, which critically affects health. The main goal of nursing is to maintain mind and body in a healthy state of well being. Few reports in the literatures have addressed the evaluation and application of MBI. Thus, a conceptual analysis of this subject is worth exploring in depth. This paper analyzes the MBI concept step by step based on the procedures of Walker and Avant. The result defines the characteristics of MBI as (1) being aware of psychosomatic effects, (2) interacting between psychology, neurology, immunology and others, and (3) turning out a bio-psycho-social status. Antecedents include geography, culture, race, gender, age, education, profession, values, personality, experience, and health status. Consequences of MBI include well-being, illness, and death. This paper provides new information on MBI that clarifies its meaning, provides comprehensive cognition, and suggests useful applications. PMID- 26242441 TI - [Transference in the Nurse-Patient Relationship: A Case Report on a Prostate Cancer Patient]. AB - This article explores the dilemma posed with regard to a prostate cancer patient suffering from transference syndrome. Transference is generally recognized as an unconscious and inevitable part of relationships. Both nurse and patient "transfer" their past emotional and psychological needs into present situations and react accordingly. Consequently, the emotions and behaviors of nurses influence the reactions of their patients. Nurses must better understand their contributions to the nurse-patient relationship in order to better detect patient thoughts and feelings. Furthermore, nurses must recognize the needs of their patients and maintain a neutral and uncritical attitude. We developed a case management model to provide a consultation corner for cancer patients. Additionally, in an attempt to improve the quality of life of cancer patients, the developed model encouraged medical personnel to discuss sexual, belonging, and love problems with patients and to hold attitudes of professionalism, composure, caring, and solemnity. Belonging and love are basic human needs. However, for patients with prostate cancer, this basic need cannot be satisfied. Even professionally trained medical personnel have difficulty directly addressing this problem. This paper describes the meaning of transference and the importance of this concept in the therapeutic nurse-patient relationship. Finally, developing better insights into the nurse-patient relationship will help nurses use these insights to improve the quality of patient interactions and of care. PMID- 26242442 TI - Assessment and determinants of aesthetic discomfort in hand osteoarthritis. PMID- 26242443 TI - Effect of continuous versus on-demand treatment of ankylosing spondylitis with diclofenac over 2 years on radiographic progression of the spine: results from a randomised multicentre trial (ENRADAS). AB - BACKGROUND: To date, only a single controlled trial provided evidence that non steroidal anti-inflammatory drugs (NSAIDs) given continuously reduce radiographic progression compared with an on-demand therapy over 2 years in patients with ankylosing spondylitis (AS). In the current study, we tested whether such an effect of NSAIDs could be confirmed in another randomised trial. METHODS: Patients with AS were randomised for treatment with either continuous (150 mg/day) or on-demand diclofenac for 2 years. Tumour necrosis factor-blocker treatment was not allowed during the entire study period. The primary outcome was the difference in radiographic progression in the spine as measured by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) scored by two readers blinded to treatment arm and time point. RESULTS: 62 of 85 patients enrolled in the continuous arm and 60 of 82 enrolled in the on-demand arm completed the study. The mSASSS progression was numerically higher in the continuous group (1.28 (0.7 to 1.9) vs 0.79 (0.2 to 1.4)) (p=0.39). If only patients were analysed who were either C reactive protein positive or had syndesmophytes at baseline, there was again a higher radiographic progression in the continuous versus the on demand group: 1.68 (0.7 to 2.6) vs 0.96 (0.0 to 1.9) and 2.11 (1.1 to 3.1) vs 0.95 (0.0 to 1.9), respectively. There was no difference between the two treatment groups regarding adverse events. CONCLUSIONS: In our study, continuous treatment with diclofenac over 2 years did not reduce radiographic progression compared with on-demand treatment in AS. TRIAL REGISTRATION NUMBERS: EudraCt-no 2007-007637-39; ClinicalTrials.gov NCT00715091. PMID- 26242445 TI - Can I Author Myself? The Limits of Transformation. AB - Narrative medicine is predicated on the importance of narrative to human life. Although that in itself is not controversial, an extension of this principle that has sprung up in narrative psychiatry--namely, that by coming to imagine a different life story one can become a different person--ought to be. One reason one cannot remake one's life in the image of a story is that life is not to be mistaken for a story in the first place. The seminal study of psychotherapy, Persuasion and Healing, although recommending that the demoralized absorb more uplifting stories about themselves, appears to recognize some limit to the possibility of modeling life on story. The same study likens therapeutic stories to placebos, but as it happens, placebos themselves have their limits, alleviating symptoms but not curing or "healing." In order for someone to become a different person through the agency of the placebo effect, it would have to be more robust than it is. The argument that life follows narrative is an ironic one for a discipline devoted to narrative to make, given the salience in the tradition of the novel, from Don Quixote forward, of works that explore the fallacies of that presumption. In keeping with its attention to narrative, this article challenges the use of a short story by Chitra Divakaruni as an illustration of the principles of narrative psychiatry. PMID- 26242444 TI - Increased Expression of Tissue/Salivary Transgelin mRNA Predicts Poor Prognosis in Patients with Oral Squamous Cell Carcinoma (OSCC). AB - BACKGROUND: Transgelin is supposed to be a tumor suppression gene and it is down regulated in a variety of human cancers. However, the role of transgelin in different cancers is still very controversial. In addition, currently little information is available the relationship between transgelin and Oral Squamous Cell Carcinoma (OSCC). MATERIAL AND METHODS: Western Blotting was performed to test the transgelin protein expression level in OSCC tissues and adjacent normal tissues. Real-time PCR was used to examine the expression level of transgelin mRNA in tissue, serum and saliva of OSCC patients and negative controls. The correlation between tissue and salivary transgelin mRNA expression level with a variety of clinical parameters was further studied. RESULTS: Transgelin protein expression was increased in OSCC patients compared with healthy individuals. Similarly, the expression level of both tissue and salivary transgelin mRNA were increased significantly in patients with OSCC in comparison with normal controls. However, little difference of serum transgelin mRNA expression was found between the OSCC patients and healthy controls. In addition, overexpression of tissue or salivary transgelin was closely associated with various clinical parameters including poorer overall survival. Furthermore, our results showed that tissue and salivary transgelin mRNA were independent prognosis factors for OSCC. CONCLUSIONS: The expressions level of tissue mRNA and protein were increased in OSCC patients. Both tissue and salivary transgelin mRNA were closely correlated with various important clinicopathological parameters and were independent prognosis factors for OSCC, indicating they might serve promising biomarkers for OSCC. PMID- 26242446 TI - Medicine, Morality, and Mortality: The Challenges of Moral Diversity. AB - This issue of The Journal of Medicine and Philosophy assesses the deep and abiding tensions that exist among the competing epistemic perspectives that bear on medicine and morality. Concepts of health and disease, as well as the theoretical framing of medical ethics and health care policy, intersect with an overlapping set of culturally situated communities (scientific, political, moral, and religious), striving to understand and manipulate the world in ways that each finds explanatory, appropriate, or otherwise befitting. The articles explore the complexities of framing public health care policy to guide bioethical decision making in the face of the plurality of ethical viewpoints and moral rationalities -including health enhancing supplements, continuous sedation until death, medical futility, the protection of vulnerable populations, and competing professional obligations. PMID- 26242447 TI - Contesting the Equivalency of Continuous Sedation until Death and Physician assisted Suicide/Euthanasia: A Commentary on LiPuma. AB - Patients who are imminently dying sometimes experience symptoms refractory to traditional palliative interventions, and in rare cases, continuous sedation is offered. Samuel H. LiPuma, in a recent article in this Journal, argues that continuous sedation until death is equivalent to physician-assisted suicide/euthanasia based on a higher brain neocortical definition of death. We contest his position that continuous sedation involves killing and offer four objections to the equivalency thesis. First, sedation practices are proportional in a way that physician-assisted suicide/euthanasia is not. Second, continuous sedation may not entirely abolish consciousness. Third, LiPuma's particular version of higher brain neocortical death relies on an implausibly weak construal of irreversibility--a position that is especially problematic in the case of continuous sedation. Finally, we explain why continuous sedation until death is not functionally equivalent to neocortical death and, hence, physician-assisted suicide/euthanasia. Concluding remarks review the differences between these two end-of-life practices. PMID- 26242451 TI - Challenges of Drug-Facilitated Sexual Assault. AB - This article provides the reader with an understanding of the numerous challenges of drug-facilitated sexual assaults (DFSA). The challenges are categorized as follows: the drugs, reporting the crime, evidence collection, and laboratory analysis of specimens. The challenges associated with the drugs used to commit DFSA emphasizes the pharmacological effects of strong central nervous system depressants and how the pharmacokinetics and pharmacodynamics of these drugs create difficulties in an investigation. For example, while sexual assaults are generally considered to be a significantly underreported crime, the drug effects further complicate victims' reporting to law enforcement. Any delay in reporting decreases the ability of a laboratory to detect the presence of drugs or metabolites in useful evidentiary specimens such as blood and urine. Finally, differences in instrumentation and mission from one laboratory to the next will impact the ability to provide consistent identification of DFSA drugs or metabolites in these cases. Although the true prevalence of DFSAs will never be fully known, acknowledgment of the many challenges that come with these cases provides insight as to how to improve chances of successfully investigating DFSA allegations. PMID- 26242449 TI - Sp-miR396a-5p acts as a stress-responsive genes regulator by conferring tolerance to abiotic stresses and susceptibility to Phytophthora nicotianae infection in transgenic tobacco. AB - KEY MESSAGE: Overexpression of Sp-miR396a-5p in tobacco increased tolerance to salt, drought, cold stress and susceptibility to Phytophthora nicotianae infection. MicroRNA396 (miR396) is one of the conserved microRNA families in plants, and it targeted growth-regulating factors (GRFs) family. The GRF transcription factors are associated with growth and stress responses. However, the molecular mechanisms of miR396 responding to environmental stresses are elusive. The purpose of this study was to explore the function of tomato miR396a 5p (Sp-miR396a-5p) in Solanaceae responses to abiotic and biotic stresses. We showed that Sp-miR396a-5p transcript levels were up-regulated under salt and drought stresses and down-regulated after Phytophthora infestans (P. infestans) infection. Consistently, overexpression of Sp-miR396a-5p in tobacco enhanced its tolerance to salt, drought and cold stresses. Additionally, the expression of Sp miR396a-5p was found to be down-regulated under pathogen-related biotic stress. Tobacco plants overexpressing Sp-miR396a-5p showed increased susceptibility to Phytophthora nicotianae (P. nicotianae) infection. Physiological analysis indicated that Sp-miR396a-5p overexpression enhanced osmoregulation and decreased production of reactive oxygen species (ROS). Furthermore, four Sp-miR396a-5p target genes, NtGRF1, NtGRF3, NtGRF7 and NtGRF8, were down-regulated in these plants. Our results suggested that Sp-miR396a-5p plays critical roles in both abiotic stresses through targeting NtGRF7-regulated expression of osmotic stress responsive genes and pathogen infection via the regulatory networks of NtGRF1 and NtGRF3. PMID- 26242450 TI - Lab-score is a valuable predictor of serious bacterial infection in infants admitted to hospital. AB - Parents frequently bring their children to the Emergency Department (ED) because of the fever without apparent source (FWAS). To avoid possible complications, it is important to recognize serious bacterial infection (SBI) as early as possible. Various tests, including different clinical scores and scales, are used in the laboratory evaluation of patients. However, it is still impossible to predict the presence of SBI with complete certainty. Galetto-Lacour et al. developed and validated a risk index score, named Lab-score. Lab-score is based on the three predictive variables independently associated with SBI: procalcitonin (PCT), C reactive protein (CRP), and urinary dipstick. The objective of this study was to assess the performance of the Lab-score in predicting SBI in well-appearing infants <= 180 days of age with FWAS, who presented to ED and were hospitalized with suspicion of having SBI. Based on this study findings, white blood cells count (WBC), CRP, PCT, and lab-score >= 3 were confirmed as useful biomarkers for differentiation between SBI and non-SBI. Also, receiver operating characteristic curve (ROC) analysis confirmed that all of them were useful for differentiation between SBI and non-SBI patients with the highest area under curve (AUC) calculated for the Lab-score. The results of this research confirmed its value, with calculated sensitivity of 67.7% and specificity of 98.6% in prediction of SBI in infants aged <= 180 days. Its value was even better in infants aged <= 90 days with sensitivity of 75% and specificity of 97.7%. In conclusion, we demonstrated the high value of lab-score in detecting SBI in infants under 6 months of age with FWAS. PMID- 26242452 TI - The Frequency of Drug-Facilitated Sexual Assault Investigations. AB - While there is a general belief throughout parts of the world that drug facilitated sexual assault (DFSA) cases have dramatically increased in recent times, the true prevalence of DFSA will never be fully realized. This is due to the general underreporting of sexual assaults, the pharmacodynamics of the drugs used to commit these crimes, the challenges that delayed reporting can impose on the charges associated with these cases, and the lack of a uniform system of defining and statistically capturing data on sexual assaults that are facilitated by drugs. Over the years, a number of studies have attempted to quantitate the frequency of DFSA in various countries throughout the world. Unfortunately, no two studies have taken the same approach in their assessment of DFSA; therefore, it is difficult to combine their results to allow for a realistic evaluation of how prevalent DFSA really is. This manuscript reviews the studies that have attempted such an assessment of DFSA prevalence to compare and contrast their results. PMID- 26242453 TI - The Use of Alcohol to Facilitate Sexual Assault. AB - The presence of alcohol (ethanol) is a common toxicological finding in alleged cases of drug-facilitated sexual assault (DFSA). Alcohol was identified as the most frequently encountered drug in DFSAs more than a decade ago, and epidemiological studies to date confirm this initial finding. There is no single substance that is uniquely associated with DFSA. Alcohol has been used by humans for thousands of years and its effect on sexual behavior is well established. Despite the fact that alcohol has been the subject of scientific investigation for several hundred years, DFSA casework involving alcohol remains complex and poses numerous challenges. The prevalence of alcohol in DFSAs is reviewed within the context of toxicological findings and blood alcohol concentration (BAC). Pharmacological aspects are briefly presented, including pharmacokinetics and retrograde extrapolation. The effects of alcohol are discussed within the context of the pharmacodynamics of alcohol and the mechanistic issues associated with alcohol's disruption of memory. The amnesic effects of alcohol are reviewed, with particular focus on the two distinct types of alcohol-induced blackout: fragmentary and en bloc. The prevalence of and the BACs associated with this type of alcohol-mediated memory loss are described. Finally, biological specimens (blood, serum, and urine) are reviewed from a toxicological standpoint, and the associated methodology for quantitative alcohol determination is presented. PMID- 26242454 TI - The Use of Benzodiazepines to Facilitate Sexual Assault. AB - Benzodiazepines are one of the classes of drugs most commonly associated with drug-facilitated sexual assault. As a widely prescribed class of medications and abused drugs, benzodiazepines are extensively available. Their sedating and amnesic effects make them effective candidates for use in drug-facilitated assaults. Detection methods for benzodiazepines and their metabolites in biological fluids are plentiful, but methods must be tailored to the low concentrations of drugs and metabolites expected to be encountered in these cases. PMID- 26242455 TI - The Use of GHB to Facilitate Sexual Assault. AB - gamma-Hydroxybutyric acid (GHB) and its metabolic precursors, gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), may be among the most favored drugs used to commit drug-facilitated sexual assault (DFSA). In fact, federal legislation was enacted in the form of the Hillory J. Farias and Samantha Reid Date-Rape Drug Prohibition Act of 2000 to control and penalize use and distribution of GHB, GBL, and 1,4-BD. Unfortunately, solid proof of their use in many cases is difficult to obtain because GHB, GBL, and 1,4-BD have strong sedative and memory-impairing effects and are rapidly eliminated after ingestion. To further complicate the matter, GHB is a metabolite of gamma-aminobutyric acid (GABA), a naturally occurring neurotransmitter in humans. This review focuses on the chemistry and pharmacology of these drugs and their use in DFSA. An overview of analytical techniques used to identify their presence is provided, as well as guidance on the toxicological interpretation of findings of GHB in biological specimens. PMID- 26242456 TI - The Use of Z-Drugs to Facilitate Sexual Assault. AB - Zolpidem, zopiclone, and zaleplon are commonly referred to as the "Z-drugs." The Z-drugs are nonbenzodiazepine hypnotics indicated for the short-term treatment of insomnia. Since becoming widely prescribed as sleep aids in the United States, they are increasingly being detected in a variety of forensic specimens. We present a comprehensive overview of the basic chemistry, pharmacodynamics, and pharmacokinetics of zolpidem, zopiclone, and zaleplon, including their interaction with other prescription drugs and ethanol, findings in drug facilitated sexual assault (DFSA) casework, and methods of analysis. PMID- 26242457 TI - The Use of Over-The-Counter Medications to Facilitate Sexual Assault. AB - Over-the-counter drugs are medications that are available without the requirement of a prescription. They are considered relatively safe and well-tolerated when taken in accordance with the dosing instructions on the package label. However, when taken alone or in combination with other drugs, they possess pharmacological properties that have the potential to facilitate sexual assault. This chapter reviews the chemistry and pharmacology of these drugs. Additionally, a brief overview of analytical methodology is presented. PMID- 26242458 TI - The Use of Miscellaneous Prescription Medications to Facilitate Sexual Assault. AB - Drugs used to facilitate sexual assaults are typically those that rapidly render the potential victim unconscious or sedated, and produce memory loss or amnesia. Many of these drugs are difficult to detect due to a delay in biological specimen collection. Detection is further hampered as the drugs are often administered in single low doses and are rapidly and extensively metabolized, resulting in low concentrations in biological specimens. Miscellaneous prescription drugs such as the barbiturates, antipsychotics, opioids, tricyclic antidepressants, ketamine, and chloral hydrate have the potential to produce varying degrees of sedation; however, they are not frequently detected in drug-facilitated sexual assault cases. A review of the literature shows that these drugs are often knowingly taken by the victim before or subsequent to the assault, and therefore may contribute to the sedation or unconsciousness experienced by the victim when ethanol or other central nervous system drugs are co-administered. Most barbiturates, opioids, and tricyclic antidepressants are routinely screened for in hospitals and forensic toxicology laboratories, and may be detectable in a urine specimen for several days. Antipsychotics, particularly the atypical class, ketamine, and chloral hydrate, generally require more targeted analyses. This review provides an overview of the pharmacodynamics, pharmacokinetics, and common analytical methods for the barbiturates, antipsychotics, opioids, tricyclic antidepressants, ketamine, and chloral hydrate. PMID- 26242459 TI - Laboratory Management of Drug-Facilitated Sexual Assault Cases. AB - Over the past two decades, cases of drug-facilitated sexual assaults (DFSA) have increased in forensic laboratories in many parts of the world. Investigators of DFSA allegations know of the many challenges associated with these cases, but forensic toxicologists find that delays in the reporting of such crimes to law enforcement and subsequent lags in specimen collection are particularly important concerns. These delays are usually a result of the traumatic experience of sexual assaults, as well as the amnesic effect of the drugs typically used to commit DFSA. Unfortunately, such a delay in specimen collection may be the difference between detecting traces of a drug (or metabolite) and reporting a negative result. Therefore, it is imperative for toxicology laboratories to properly prepare for DFSA cases by developing forms, policies, and procedures to ensure that truly meaningful analyses are performed. This article provides guidance in the steps laboratories may take to best prepare themselves to analyze evidentiary specimens from DFSA investigations. PMID- 26242460 TI - Effect of xylan oligosaccharides generated from corncobs on food acceptability, growth performance, haematology and immunological parameters of Dicentrarchus labrax fingerlings. AB - The objective of this study was to determine the effect of two levels of inclusion of xylan oligosaccharides (XOS) extracted from corncob on growth, feed utilization, immune status and disease resistance of Mediterranean sea bass (Dicentrarchus labrax) fingerlings. Specimens of 4.75 +/- 0.69 g at initial density of 2.7 +/- 0.13 kg/m(3) were fed during 12 weeks at 0 g kg(-1) diet, 5 g kg(-1) diet and 10 g kg(-1) diet, dietary XOS level of inclusion in a commercial sea bass diet. Feeding the fish at both XOS dietary inclusion levels significantly increased weight gain, protein efficiency ratio and feed conversion ratio. Feeding of supplemented diets to fish led to reducing mortalities after challenging with A. hydrophila. The haematological and immunological parameters were assayed in both pre-challenged and post-challenged groups. There was an increased trend in red blood corpuscles, white blood corpuscles, pack cell volume, haemoglobin (Hb %) and serum protein content in treated groups over the control as time elapsed with the feeding trials. The serum immunoglobulin level and lysozyme activity showed an increased trend in the fed groups. Histological features of the liver showed lower lipid vacuolization and regular-shaped morphology of hepatocytes around the sinusoidal spaces denoting a better utilization of dietary nutrients supported with the morphometric data. In conclusion, XOS added at a designated dose (5 g kg(-1) diet) in the diet improves growth and stimulates the immunity and makes D. labrax fingerlings more resistant to infection by A. hydrophila. PMID- 26242461 TI - Radioimmunotherapy in relapsed/refractory mantle cell lymphoma patients: final results of a European MCL Network Phase II Trial. PMID- 26242462 TI - A unique aptamer-drug conjugate for targeted therapy of multiple myeloma. PMID- 26242463 TI - Specificity of JAK-kinase inhibition determines impact on human and murine T-cell function. PMID- 26242464 TI - The effect of SUV discretization in quantitative FDG-PET Radiomics: the need for standardized methodology in tumor texture analysis. AB - FDG-PET-derived textural features describing intra-tumor heterogeneity are increasingly investigated as imaging biomarkers. As part of the process of quantifying heterogeneity, image intensities (SUVs) are typically resampled into a reduced number of discrete bins. We focused on the implications of the manner in which this discretization is implemented. Two methods were evaluated: (1) R(D), dividing the SUV range into D equally spaced bins, where the intensity resolution (i.e. bin size) varies per image; and (2) R(B), maintaining a constant intensity resolution B. Clinical feasibility was assessed on 35 lung cancer patients, imaged before and in the second week of radiotherapy. Forty-four textural features were determined for different D and B for both imaging time points. Feature values depended on the intensity resolution and out of both assessed methods, R(B) was shown to allow for a meaningful inter- and intra patient comparison of feature values. Overall, patients ranked differently according to feature values-which was used as a surrogate for textural feature interpretation-between both discretization methods. Our study shows that the manner of SUV discretization has a crucial effect on the resulting textural features and the interpretation thereof, emphasizing the importance of standardized methodology in tumor texture analysis. PMID- 26242465 TI - Minimally invasive versus standard percutaneous nephrolithotomy: a meta-analysis. AB - The aim of the study was to objectively analyze the outcomes for minimally invasive percutaneous nephrolithotomy (MPCNL) vs standard percutaneous nephrolithotomy (PCNL) by systematic review and meta-analysis of published data. A systematic literature review was performed in November 2014 using the PUBMED, EMBASE and Cochrane Library databases to identify relevant studies. Only comparative studies investigating MPCNL vs PCNL were included. Effect sizes were estimated by pooled odds ratio (ORs) and mean differences (MDs). The analyzed outcomes were stone-free rate (SFR), blood loss, pain assessment, operative time, hospital stay and complications. We identified 8 trials with a total 749 patients. 353 patients were treated with MPCNL and 396 with PCNL. Meta-analysis of the data showed that there was no difference in SFR between MPCNL and PCNL (OR 1.06, 95% CI 0.71-1.58). Patients in the MPCNL group experienced less drop in hemoglobin (MD: -4.67 g/L, 95% CI -7.29 to -2.04), a lower incidence of blood transfusion (OR 0.18, 95% CI 0.06-0.54), less pain (visual analog score) (MD: 0.53, 95% CI -0.94 to -0.13) and shorter hospitalization (MD: -1.32 days, 95% CI 2.15 to -0.50). Operative time was longer in the MPCNL group (MD: 15.54 min, 95% CI 4.25-26.83). Postoperative fever and pyelocalyceal perforation did not differ between the groups (p = 0.38 and 0.44, respectively). Current evidence suggested that MPCNL was a safe and effective procedure with an SFR comparable to that of PCNL. MPCNL resulted in less bleeding, fewer transfusion, less pain and shorter hospitalization. Well-designed multicentric/international randomized, controlled trials are still needed. PMID- 26242467 TI - Genetic Counseling Supervisors' Self-Efficacy for Select Clinical Supervision Competencies. AB - Supervision is a primary instructional vehicle for genetic counseling student clinical training. Approximately two-thirds of genetic counselors report teaching and education roles, which include supervisory roles. Recently, Eubanks Higgins and colleagues published the first comprehensive list of empirically-derived genetic counseling supervisor competencies. Studies have yet to evaluate whether supervisors possess these competencies and whether their competencies differ as a function of experience. This study investigated three research questions: (1) What are genetic counselor supervisors' perceptions of their capabilities (self efficacy) for a select group of supervisor competencies?, (2) Are there differences in self-efficacy as a function of their supervision experience or their genetic counseling experience, and 3) What training methods do they use and prefer to develop supervision skills? One-hundred thirty-one genetic counselor supervisors completed an anonymous online survey assessing demographics, self efficacy (self-perceived capability) for 12 goal setting and 16 feedback competencies (Scale: 0-100), competencies that are personally challenging, and supervision training experiences and preferences (open-ended). A MANOVA revealed significant positive effects of supervision experience but not genetic counseling experience on participants' self-efficacy. Although mean self-efficacy ratings were high (>83.7), participant comments revealed several challenging competencies (e.g., incorporating student's report of feedback from previous supervisors into goal setting, and providing feedback about student behavior rather than personal traits). Commonly preferred supervision training methods included consultation with colleagues, peer discussion, and workshops/seminars. PMID- 26242466 TI - Decreased urinary glycosaminoglycan excretion following alfuzosin treatment on ureteral stent-related symptoms: a prospective, randomized, placebo-controlled study. AB - The objectives of the study were to evaluate changes in ureteral stent-related symptoms and urinary glycosaminoglycan (GAG) excretion after alfuzosin treatment, and to further investigate the relationship between stent-related symptoms and loss of urinary GAGs. Seventy consecutive patients scheduled for unilateral retrograde ureteroscopy with stent placement were recruited. Patients were randomly assigned to treatment with alfuzosin 10 mg/day or placebo for 3 weeks starting on the third postoperative day. The ureteral stent was removed when treatment stopped. International Prostate Symptom Score (IPSS), visual analog scale (VAS) score, and urinary GAG excretion were determined before treatment at 1, 2, and 3 weeks after treatment, and at 3 weeks after stent removal. Fifty-nine patients completed the study. IPSS, VAS score, and urinary GAG excretion were significantly lower in the alfuzosin group, compared with the placebo group, at 1, 2, and 3 weeks after treatment (P < 0.01). In both groups, IPSS, VAS score, and urinary GAG excretion were significantly lower at 3 weeks after stent removal compared with those before stent removal. No significant differences in IPSS, VAS score, or urinary GAG excretion were observed between the two groups at baseline and 3 weeks after stent removal (P > 0.05). Positive correlations were found between urinary GAG excretion (R(2) = 0.65, P < 0.001) and IPSS and between urinary GAG excretion and VAS score (R(2) = 0.33, P < 0.001). Stent placement contributes to loss of urinary GAGs. However, alfuzosin effectively reduces such loss and improves ureteral stent-related symptoms. Loss of urinary GAGs plays a role in these symptoms. PMID- 26242468 TI - Genomic Testing: a Genetic Counselor's Personal Reflection on Three Years of Consenting and Testing. AB - Whole exome sequencing (WES) is increasingly used in research and clinical genetics as the cost of sequencing decreases and the interpretation improves. Genetic counselors need to be prepared to counsel a diverse patient population for this complex test. This commentary is a reflection of one genetic counselor's experiences in counseling, consenting, and returning results for clinical and research WES for over 120 participants and patients. She reflects on how she overcame the initial challenges and concerns of counseling for WES and how her counseling evolved from a teaching based counseling model to an interactive patient-center counseling model. Her insights are offered to prepare other genetic counselors for the growing use of genomic testing. PMID- 26242469 TI - Topical diclofenac therapy for osteoarthritis: a meta-analysis of randomized controlled trials. AB - The objective of this study was to evaluate the efficacy and safety of topical diclofenac therapy for osteoarthritis (OA). A meta-analysis of randomized controlled trials was conducted. A comprehensive literature search, covering the databases of Medline, the Cochrane Central Register of Controlled Trials, and EMBASE, was conducted in September 2014 to identify the randomized controlled trials which adopted the topical diclofenac therapy for OA. A total of nine papers were included in this meta-analysis. Topical diclofenac appears to be effective in both pain relief (standard mean differences (SMD) = 0.40; 95 % confidence interval (CI) 0.19 to 0.62; P = 0.0003) and function improvement (SMD = 0.23; 95 % CI 0.03 to 0.43; P = 0.03) when compared with the control group. The sensitivity analysis and subgroup analysis showed that the result of pain intensity was stable and reliable, while the result of physical function improvement was vague. With respect to safety, topical diclofenac demonstrated a higher incidence of adverse events such as dry skin, rash, dermatitis, neck pain, and withdrawal. Topical diclofenac is effective in pain relief as a treatment of OA. It may also have a potential effect in function improvement, which needs further studies to be explored. Although, some adverse effects were observed in the application of topical diclofenac, none of them was serious. PMID- 26242471 TI - Post-chikungunya chronic arthralgia: a first retrospective follow-up study of 39 cases in Colombia. PMID- 26242470 TI - Subcutaneous nodules are associated with cardiovascular events in patients with rheumatoid arthritis: results from a large US registry. AB - Subcutaneous nodules are the most common conspicuous extra-articular manifestation of rheumatoid arthritis (RA). Cardiovascular disease (CVD) is the leading cause of death in patients with RA. The objective of this study is to examine the possibility of a relationship between subcutaneous nodules and "first ever" cardiovascular disease event, i.e., myocardial infarction (MI), stroke, or cardiovascular death in a large registry-cohort of patients with RA. Patient information was collected from the CORRONA registry from October 2001 to September 2011. A total of 26,042 patients with RA were studied for the presence or absence of subcutaneous nodules. Cox proportional hazards regression models were constructed to estimate the hazard ratios (HR) for CVD events in relation to subcutaneous nodules at baseline. Three statistical models were used to examine the association between subcutaneous nodules and CVD: Model A adjusted for age and sex associated risk, model B adjusted for traditional CV risk factors, and model C adjusted for factors in models A and B plus underlying RA-specific measures. The definition of primary exposure was "subcutaneous nodules at baseline." A total of 3908 patients had subcutaneous nodules at baseline. Of the 566 total composite CVD events, 138 occurred in the group that had SCN at baseline. Incidence rate-ratio values (patients with subcutaneous nodules at baseline vs. no subcutaneous nodules at baseline) for composite CVD events, MI, stroke, and cardiovascular death were 1.55, 1.65, 1.37, and 1.68, respectively. Adjusted HR values (95 % CI) for composite CVD events based on "subcutaneous nodules-status at baseline" (primary exposure) were as follows: 1.35 (1.11-1.63) for model A, 1.25 (1.03-1.52) for model B, and 1.03 (0.831-1.277) for model C. Subcutaneous nodules were associated with increased CVD events in RA. This association persisted after adjusting for age, sex, and traditional CV risk factors. PMID- 26242472 TI - Efficient photocatalytic water oxidation catalyzed by polyoxometalate [Fe11(H2O)14(OH)2(W3O10)2(alpha-SbW9O33)6](27-) based on abundant metals. AB - An eleven iron-containing nanoscale inorganic polyanionic oxide cluster was reported as the first example for exceptional photocatalytic water oxidation. Under optimal conditions, a remarkable turn-over number (TON) of 1815 +/- 50 and a turn-over frequency (TOF(initial)) of 6.3 s(-1) over were achieved for water oxidation. PMID- 26242473 TI - ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function. AB - Neural vascular barrier is essential for the life of multicellular organisms, and its impairment by tissue hypoxia is known to be a central of pathophysiology accelerating the progression of various intractable neural diseases. Therefore, the molecules involved in hypoxia-induced impairment of vascular barrier can be the targets to establish new therapies for intractable diseases. Here, we demonstrate that a disintegrin and metalloproteinases (ADAMs) 12 and 17 expressed in endothelial cells are the molecules responsible for the impairment of neural vascular barrier by hypoxia. Brain microvascular endothelial cells in vitro lost their barrier properties immediately after hypoxic stimulation through diminished localization of claudin-5, a tight junction molecule, on cell membranes. Hypoxic disappearance of claudin-5 from cell membranes and the consequent loss of barrier properties were completely suppressed by inhibition of the metalloproteinase activity which was found to be attributed to ADAM12 and ADAM17. Inhibition of either ADAM12 or ADAM17 was sufficient to rescue the in vivo neural vasculature under hypoxia from the loss of barrier function. This is the first report to specify the molecules which are responsible for hypoxia-induced impairment of neural vascular barrier and furthermore can be the targets of new therapeutic strategies for intractable neural diseases. PMID- 26242474 TI - Novel insights into a major DNA oxidative lesion: its effects on Z-DNA stabilization. AB - Here, we have provided novel insights into the effects of 8-oxodG substitutions on B-Z transitions of CpG dinucleotide DNAs. A combination of different techniques including a CD study, a PAGE analysis, DFT calculations and molecular modeling has been collectively used. PMID- 26242475 TI - Novel risk stratification score for predicting early distant brain failure and salvage whole-brain radiotherapy after stereotactic radiosurgery for brain metastases. AB - BACKGROUND: The purpose of this study was to evaluate predictors of early distant brain failure (DBF) and salvage whole-brain radiotherapy (WBRT) after treatment with stereotactic radiosurgery (SRS) for brain metastases and create a clinically relevant risk score to stratify patients' risk for these events. METHODS: The records of 270 patients with brain metastases who were treated with SRS between 2003 and 2012 were reviewed. Pretreatment patient and tumor characteristics were analyzed with univariate and multivariate analyses. The cumulative incidences of first DBF and salvage WBRT were calculated. Significant factors were used to create a score for stratifying early (6-month) DBF risk. RESULTS: No prior WBRT, a total lesion volume < 1.3 cm(3), primary breast cancer or malignant melanoma histology, and multiple metastases (>=2) were found to be significant predictors of early DBF. Each factor was ascribed 1 point because of similar hazard ratios. Scores of 0 to 1, 2, and 3 to 4 were considered to indicate low, intermediate, and high risk, respectively. This correlated with 6-month cumulative incidences of DBF of 16.6%, 28.8%, and 54.4%, respectively (P < .001). For patients without prior WBRT, the 6-month cumulative incidence of salvage WBRT was 2%, 17.7%, and 25.7%, respectively (P < .001). CONCLUSIONS: Early DBF after SRS requiring salvage WBRT remains a significant clinical problem. Patient stratification for early DBF can better inform the decision for the initial treatment strategy for brain metastases. The provided risk score may help to predict early DBF and subsequent salvage WBRT if SRS is initially used. External validation is needed before clinical implementation. PMID- 26242476 TI - On computer-intensive simulation and estimation methods for rare-event analysis in epidemic models. AB - This article focuses, in the context of epidemic models, on rare events that may possibly correspond to crisis situations from the perspective of public health. In general, no close analytic form for their occurrence probabilities is available, and crude Monte Carlo procedures fail. We show how recent intensive computer simulation techniques, such as interacting branching particle methods, can be used for estimation purposes, as well as for generating model paths that correspond to realizations of such events. Applications of these simulation-based methods to several epidemic models fitted from real datasets are also considered and discussed thoroughly. PMID- 26242479 TI - In situ studies of lithium-ion diffusion in a lithium-rich thin film cathode by scanning probe microscopy techniques. AB - This paper presents in situ characterization of lithium-ion diffusion at nano- to micro-meter scales in a Li-rich layered oxide thin film cathode under external bias by using Electrochemical Strain Microscopy (ESM) and Atomic Force Microscopy (AFM) techniques. The local variations of the diffusion coefficient are calculated and visualized from the ESM images. The results indicate that the Li ion movement is closely correlated with the changes in the surface topography when the Li-rich cathode is subjected to an external bias. Furthermore, bias induced Li-ion redistribution is partially reversible. Topography evolution due to Li-ion diffusion and relaxation behaviour are observed. The results from this in situ study provide the insight into the Li-ion diffusion mechanism in the cathode material and pave the way for studying the details of the diffusion related phenomenon in Li-ion battery materials. PMID- 26242477 TI - The therapeutic potential of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists for the treatment of the cognitive deficits associated with schizophrenia. AB - Homomeric alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) have implications in the regulation of cognitive processes such as memory and attention, and have shown promise as a therapeutic target for the treatment of the cognitive deficits associated with schizophrenia. Multiple alpha7 nAChR agonists have entered human trials; however, unfavorable side effects and pharmacokinetic issues have hindered the development of a clinical alpha7 nAChR agonist. Currently, EVP-6124 is in phase III clinical trials, and several other alpha7 nAChR agonists (GTS-21 and AQW051) are in earlier stages of development. This review will summarize the recent advances and failures of alpha7 nAChR agonists in clinical trials for the treatment of the aforementioned pathology. PMID- 26242478 TI - Antipsychotic drug use and the risk of seizures: follow-up study with a nested case-control analysis. AB - OBJECTIVE: To investigate the association between antipsychotic drug use and the development of first-time seizures in patients with schizophrenia, affective disorders, or dementia. METHODS: We used data from the UK-based Clinical Practice Research Datalink database to conduct a follow-up study with a nested case control analysis between 1998 and 2013. We identified patients with schizophrenia, affective disorders, or dementia, and estimated incidence rates of seizures among users of four antipsychotic drug subclasses, defined according to existing hypotheses on their seizure-inducing potential (1, olanzapine or quetiapine; 2, amisulpride, aripiprazole, risperidone, or sulpiride; 3, low-to medium potency first-generation antipsychotic drugs [chlorpromazine, zuclopenthixol, flupenthixol, pericyazine, promazine, thioridazine]; 4, medium-to high potency first-generation antipsychotic drugs [haloperidol, prochlorperazine, trifluoperazine]), and among those who did not use antipsychotic drugs. To adjust for confounding, we estimated odds ratios for seizures separately among patients with affective disorders or dementia, stratified by antipsychotic drug use and timing of use. RESULTS: In the total cohort of 60,121 patients (who had schizophrenia, affective disorders, or dementia), the incidence rate of seizures per 10,000 person-years was 32.6 (95 % confidence interval [CI] 22.6-42.6) in users of olanzapine or quetiapine, 24.1 (95 % CI 13.2-34.9) in users of amisulpride, aripiprazole, risperidone, or sulpiride, 49.4 (95 % CI 27.7-71.0) in users of low-to-medium potency antipsychotic drugs, 59.1 (95 % CI 40.1-78.2) in users of medium-to-high potency antipsychotic drugs, and 11.7 (95 % CI 10.0-13.4) in non-users of antipsychotic drugs. Patients with dementia had significantly higher incidence rates of first-time seizures compared with patients with affective disorders, irrespective of antipsychotic drug use. In patients with affective disorders, current use of medium-to-high potency first-generation antipsychotic drugs was associated with an increased risk of seizures (adjusted odds ratio 2.51 [95 % CI 1.51-4.18]) compared with non-use, while use of other antipsychotic drugs was not associated with seizures. In patients with dementia, current use of olanzapine or quetiapine (adjusted odds ratio 2.37 [95 % CI 1.35 4.15]), low-to-medium potency first-generation antipsychotic drugs (adjusted odds ratio 3.08 [95 % CI 1.34-7.08]), and medium-to-high potency first-generation antipsychotic drugs (adjusted odds ratio 2.24 [95 % CI 1.05-4.81]) was associated with an increased risk of seizures compared with non-use, but current use of amisulpride, aripiprazole, risperidone, or sulpiride (adjusted odds ratio 0.92 [95 % CI 0.48-1.75]) was not. Use of antipsychotic drugs in patients with schizophrenia could not be investigated because of small numbers. CONCLUSIONS: Current use of medium-to-high potency first-generation antipsychotic drugs was associated with a 2.5-fold increased risk of seizures compared with non-use of antipsychotic drugs in patients with affective disorders. In these patients, current use of all other antipsychotic drug subclasses was not associated with seizures. In patients with dementia, current and past use of all antipsychotic drug subclasses, except amisulpride, aripiprazole, risperidone, or sulpiride, was associated with an increased risk of seizures. PMID- 26242481 TI - Hybrid [5]Radialenes with Bispyrroloheteroles: New Electron-Donating Units. AB - Bispyrroloheteroles have been synthesized to address their intrinsic structural, optical, and electrochemical properties. The X-ray crystal structures and calculated natural bond orbital (NBO) bond orders unambiguously demonstrated the existence of a two pyrrole-fused five-membered ring with short exocyclic C-C double bonds and long endocyclic C-C single bonds, supporting that the bispyrroloheteroles are rare examples of structurally characterized hybrid [5]radialenes. The bispyrroloheteroles were found to act as an electron-donating unit, which would be fascinating for the rational design of new charge transporting and donor-acceptor photovoltaic materials as well as versatile charge-transfer complexes. PMID- 26242480 TI - Predicting Response to Therapy for Autoimmune and Inflammatory Diseases Using a Folate Receptor-Targeted Near-Infrared Fluorescent Imaging Agent. AB - PURPOSE: Although current therapies for many inflammatory/autoimmune diseases are effective, a significant number of patients still exhibit only partial or negligible responses to therapeutic intervention. Since prolonged use of an inadequate therapy can result in both progressive tissue damage and unnecessary expense, methods to identify nonresponding patients are necessary. PROCEDURES: Four murine models of inflammatory disease (rheumatoid arthritis, ulcerative colitis, pulmonary fibrosis, and atherosclerosis) were induced, treated with anti inflammatory agents, and evaluated for inflammatory response. The mice were also injected intraperitoneally with OTL0038, a folate receptor-targeted near-infrared dye that accumulates in activated macrophages at sites of inflammation. Uptake of OTL0038 in inflamed lesions was then correlated with clinical measurements of disease severity. RESULTS: OTL0038 accumulated at sites of inflammation in all four animal models. More importantly, changes in lesion-associated OTL0038 preceded changes in clinical symptoms in mice treated with all anti-inflammatory drugs examined. CONCLUSION: OTL0038 has the ability to predict responses to multiple therapies in four murine models of inflammation. PMID- 26242482 TI - Transfer printing of CVD graphene FETs on patterned substrates. AB - We describe a simple and scalable method for the transfer of CVD graphene for the fabrication of field effect transistors. This is a dry process that uses a modified RCA-cleaning step to improve the surface quality. In contrast to conventional fabrication routes where lithographic steps are performed after the transfer, here graphene is transferred to a pre-patterned substrate. The resulting FET devices display nearly zero Dirac voltage, and the contact resistance between the graphene and metal contacts is on the order of 910 +/- 340 Omega MUm. This approach enables formation of conducting graphene channel lengths up to one millimeter. The resist-free transfer process provides a clean graphene surface that is promising for use in high sensitivity graphene FET biosensors. PMID- 26242483 TI - Natural Antioxidants Against Arsenic-Induced Genotoxicity. AB - Arsenic is present in water, soil, and air in organic as well as in inorganic forms. However, inorganic arsenic is more toxic than organic and can cause many diseases including cancers in humans. Its genotoxic effect is considered as one of its carcinogenic actions. Arsenic can cause DNA strand breaks, deletion mutations, micronuclei formation, DNA-protein cross-linking, sister chromatid exchange, and DNA repair inhibition. Evidences indicate that arsenic causes DNA damage by generation of reactive free radicals. Nutritional supplementation of antioxidants has been proven highly beneficial against arsenic genotoxicity in experimental animals. Recent studies suggest that antioxidants protect mainly by reducing excess free radicals via restoring the activities of cellular enzymatic as well as non-enzymatic antioxidants and decreasing the oxidation processes such as lipid peroxidation and protein oxidation. The purpose of this review is to summarize the recent literature on arsenic-induced genotoxicity and its mitigation by naturally derived antioxidants in various biological systems. PMID- 26242484 TI - TAPP1 inhibits the differentiation of oligodendrocyte precursor cells via suppressing the Mek/Erk pathway. AB - Oligodendrocytes (OLs) are glial cells that form myelin sheaths around axons in the central nervous system (CNS). Loss of the myelin sheath in demyelinating and neurodegenerative diseases can lead to severe impairment of movement. Understanding the extracellular signals and intracellular factors that regulate OL differentiation and myelination during development can help to develop novel strategies for enhancing myelin repair in neurological disorders. Here, we report that TAPP1 was selectively expressed in differentiating OL precursor cells (OPCs). TAPP1 knockdown promoted OL differentiation and myelin gene expression in culture. Conversely, over-expression of TAPP1 in immature OPCs suppressed their differentiation. Moreover, TAPP1 inhibition in OPCs altered the expression of Erk1/2 but not AKT. Taken together, our results identify TAPP1 as an important negative regulator of OPC differentiation through the Mek/Erk signaling pathway. PMID- 26242486 TI - A novel formula from mulberry leaf ameliorates diabetic nephropathy in rats via inhibiting the TGF-beta1 pathway. AB - INTRODUCTION: Based on the hypoglycemia and hypolipidemia of mulberry leaf and its extracts, we investigated the effect of a novel formula, Sang Tong Jian (STJ), from mulberry leaf on rats with diabetic nephropathy (DN). METHODS: The DN rats were induced by a long-term high-fat diet and a single streptozotocin injection. STJ was introduced for 12 weeks from the presence of hyperglycemia. The fasting blood glucose of DN rats was determined at weeks 5, 7, 9, and 11 respectively. The serum GSP, GHb and lipid profiles were analyzed by using a colorimetric method and ELISA kits. The kidney function of DN rats was demonstrated through the analysis of urine creatinine, urine albumin, serum urea nitrogen, serum creatinine and the creatinine clearance rate. The H-E (haematoxylin and eosin) and PAS (Periodic Acid-Schiff) staining were adopted to exhibit the morphology of the kidney. The TGF-beta1 and p-smad2/3, smad2/3, collagen IV, connexin 43 and E-cadherin were assayed via immunohistochemistry and western blot. RESULTS: STJ significantly decreased the fasting blood glucose (p < 0.01) and the glycation end product (p < 0.05), and regulated dyslipidemia. Inhibition of the thickening of the glomerular basement membrane and amelioration of the kidney function were shown in STJ-treated DN rats. Moreover, STJ decreased the levels of TGF-beta1, collagen IV, connexin 43 and activation of smad2/3 (p < 0.01), and enhanced E-cadherin (p < 0.01) in the kidney of DN rats. CONCLUSION: 12 week administration of STJ improved the metabolic parameters associated with blood glucose and lipid and inhibited the TGF-beta1 signaling pathway, which positively contributed to the amelioration of chronic diabetic kidney disease. PMID- 26242485 TI - Evaluation of an automated spike-and-wave complex detection algorithm in the EEG from a rat model of absence epilepsy. AB - The aim of this prospective blinded study was to evaluate an automated algorithm for spike-and-wave discharge (SWD) detection applied to EEGs from genetic absence epilepsy rats from Strasbourg (GAERS). Five GAERS underwent four sessions of 20 min EEG recording. Each EEG was manually analyzed for SWDs longer than one second by two investigators and automatically using an algorithm developed in MATLAB(r). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the manual (reference) versus the automatic (test) methods. The results showed that the algorithm had specificity, sensitivity, PPV and NPV >94%, comparable to published methods that are based on analyzing EEG changes in the frequency domain. This provides a good alternative as a method designed to mimic human manual marking in the time domain. PMID- 26242487 TI - PET of EGFR with (64) Cu-cetuximab-F(ab')2 in mice with head and neck squamous cell carcinoma xenografts. AB - Overexpression of the epidermal growth factor receptor (EGFR) is linked to an adverse outcome in various solid tumors. Cetuximab is an EGFR inhibitor, which in combination with radiotherapy improves locoregional control and survival in a subgroup of patients with head and neck squamous cell carcinomas (HNSCCs). The aim of this study was to develop and characterize an EGFR-directed PET tracer, (64) Cu-cetuximab-F(ab')2, to determine the systemic accessibility of EGFR. Mice with HNSCC xenografts, UT-SCC-8 (n = 6) or UT-SCC-45 (n = 6), were imaged 24 h post injection with (64) Cu-NODAGA-cetuximab-F(ab')2 using PET/CT. One mouse for each tumor model was co-injected with excess unlabeled cetuximab 3 days before radiotracer injection to determine non-EGFR-mediated uptake. Ex vivo biodistribution of the tracer was determined and tumors were analyzed by autoradiography and immunohistochemistry. The SUVmax of UT-SCC-8 tumors was higher than that of UT-SCC-45: 1.5 +/- 1.0 and 0.8 +/- 0.2 (p < 0.05), respectively. SUVmax after in vivo blocking of EGFR with cetuximab was 0.4. Immunohistochemistry showed that UT-SCC-8 had a significantly higher EGFR expression than UT-SCC-45: 0.50 +/- 0.19 versus 0.12 +/- 0.08 (p < 0.005), respectively. Autoradiography indicated that (64) Cu-cetuximab-F(ab')2 uptake correlated with EGFR expression in both tumors: r = 0.86 +/- 0.06 (UT-SCC-8) and 0.90 +/- 0.06 (UT-SCC-45). (64) Cu-cetuximab-F(ab')2 is a promising PET tracer to determine expression of EGFR in vivo. Clinically, this tracer has the potential to be used to determine cetuximab targeting of tumors and possibly to non invasively monitor the response to EGFR-inhibitor treatment. PMID- 26242488 TI - pH value manipulated phase transition, microstructure evolution and tunable upconversion luminescence in Yb(3+)-Er(3+) codoped LiYF4/YF3 nanoparticles. AB - The pH value plays an important role in controlling the crystallization process and microstructure of the final products in the synthesis of nanocrystals with a solvothermal method. This work reported the effect of the mother solution pH value on the precipitation of LiYF4 and YF3 nanoparticles, as well as the microstructure evaluation of YF3 from a bowknot-like to spindle-like shape. Spectroscopy study suggests that there is strong correlation between the upconversion emission properties of the Yb(3+)-Er(3+) couple and the phase and the microstructure of the host. The strongest emissions and lowest red-to-green ratio are observed in the bowknot-like YF3 nanocrystals with the largest open ends. Further spectral investigation indicates that the phase and microstructure dependent upconversion properties are associated with the upconversion efficiency. The present study is of great importance in the design and synthesis of rare earth ion doped nanocrystals with tunable upconversion properties. PMID- 26242489 TI - Response to letter regarding the publication "Evaluation of the retinal, choroidal and nerve fiber layer thickness changes in patients with toxic anterior segment syndrome". PMID- 26242490 TI - Human activities and climate variability drive fast-paced change across the world's estuarine-coastal ecosystems. AB - Time series of environmental measurements are essential for detecting, measuring and understanding changes in the Earth system and its biological communities. Observational series have accumulated over the past 2-5 decades from measurements across the world's estuaries, bays, lagoons, inland seas and shelf waters influenced by runoff. We synthesize information contained in these time series to develop a global view of changes occurring in marine systems influenced by connectivity to land. Our review is organized around four themes: (i) human activities as drivers of change; (ii) variability of the climate system as a driver of change; (iii) successes, disappointments and challenges of managing change at the sea-land interface; and (iv) discoveries made from observations over time. Multidecadal time series reveal that many of the world's estuarine coastal ecosystems are in a continuing state of change, and the pace of change is faster than we could have imagined a decade ago. Some have been transformed into novel ecosystems with habitats, biogeochemistry and biological communities outside the natural range of variability. Change takes many forms including linear and nonlinear trends, abrupt state changes and oscillations. The challenge of managing change is daunting in the coastal zone where diverse human pressures are concentrated and intersect with different responses to climate variability over land and over ocean basins. The pace of change in estuarine-coastal ecosystems will likely accelerate as the human population and economies continue to grow and as global climate change accelerates. Wise stewardship of the resources upon which we depend is critically dependent upon a continuing flow of information from observations to measure, understand and anticipate future changes along the world's coastlines. PMID- 26242492 TI - Donor-Acceptor Polymers. PMID- 26242491 TI - A new way to measure milk yield persistency: a genetic point of view with application to Gyr (Bos indicus) cattle. AB - The objective of this work was to estimate genetic parameters for a measure of persistency of milk yield and to evaluate its association with 305-d cumulative milk yield and lactation length. 12 346 records from 8202 dairy Gyr cows including lactations up to fifth calving were used. The measure of persistency was obtained from one of the parameters of a quadratic model that describes the cumulative yield across lactation as a function of days in milk. A three-trait multivariate analysis was done. Heritability and repeatability for persistency were 0.08 and 0.21, respectively. Deviance Information Criterion provided evidence that the additive genetic covariance between the measure of persistency studied and 305-d cumulative yield is zero. Genetic correlations between persistency and lactation length were 0.50 and 0.27 for first or all lactations, respectively. Milk yield persistency as measured in this study has low heritability. Selection for persistency can increase lactation length. The measure of milk yield persistency studied here is genetically independent of total milk yield and can be included in routine genetic evaluations of dairy cattle. PMID- 26242494 TI - Correlation of p16 immunohistochemistry in FNA biopsies with corresponding tissue specimens in HPV-related squamous cell carcinomas of the oropharynx. AB - BACKGROUND: Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC) is a unique form of carcinoma that is important to identify for prognosis and treatment. Immunohistochemistry (IHC) for p16 (also known as cyclin dependent kinase inhibitor 2A, multiple tumor suppressor 1) is used as a surrogate marker for transcriptionally active, high-risk HPV. The primary objective of this study was to correlate p16 IHC of cell blocks from fine-needle aspirations (FNAs) with surgical pathology specimens of HPV-related oropharyngeal SCC. METHODS: In total, 48 patients who had a diagnosis of oropharyngeal or nonoropharyngeal SCC and also had an FNA that demonstrated metastatic SCC with available cell block material were identified. IHC for p16 was evaluated on both FNA cell blocks and surgical pathology specimens. In situ hybridization for high risk HPV messenger RNA was performed on 31 of the FNA cell blocks. RESULTS: Although partial p16 staining was observed in the majority of cell blocks, there was concordance in 47 of 48 FNAs (98%) with surgical pathology specimens when strong positive p16 staining of at least 15% of tumor cells in FNA cell block material was present. In addition, high-risk HPV RNA in situ hybridization demonstrated a high correlation with p16 staining in surgical pathology specimens (96%) and FNAs (93%). CONCLUSIONS: There was excellent correlation between p16 IHC of FNA cell blocks and surgical pathology specimens using a cutoff of at least 15% positive staining in cell blocks. The recommended threshold (70% positive staining) for surgical pathology specimens may yield a high rate of false-negative results if applied to FNA cell blocks. PMID- 26242495 TI - Severe Quetiapine Withdrawal Syndrome with Nausea and Vomiting in a 65-year-old Patient with Psychotic Depression. AB - A 65-year old patient suffering from severe psychotic depression obtained quetiapine for roughly one year. Several attempts to discontinue quetiapine by tapering the dose provoked severe withdrawal symptoms with nausea and vomitus. Pretreatment with domperidone largely prevented withdrawal so that he finally could successfully discontinue quetiapine administration. PMID- 26242496 TI - [Impact of Geriatric Drug Guidelines on the Quality Requirement of Elderly Patients]. AB - OBJECTIVE: Elderly with several pathologies are usually treated with many drugs, and are exposed to a majored risk of drug-induced adverse effects. A network of local nursing homes (EHPAD) in the south Seine-Saint-Denis area (France) created a geriatric drug guidelines to improve the quality of the drugs prescriptions. This study assesses the conformity of prescriptions in elderly patients prior and after the distribution of the booklet. METHODS: This before and after design study focused on the drug prescriptions for patients in eight EHPAD followed for two randomly given days in 2012 (n = 503) and 2013 (n = 334). The geriatric drug guidelines included a list of medicines suitable for the elderly (conformity list) and recommendations for prescription and monitoring. Data collection was conducted from medical records and interviews with coordinators doctors and nursing staff in nursing homes. A 6 items-quality score was calculated, ranging from 0 (lowest quality) to 6 (highest quality). RESULTS: Median age, weight and creatinine level were respectively 88 years, 61.0 kg, and 74.9 MUmol/L (prior) and 88 years, 59.6 kg, and 77.0 MUmol/L (after). Median times of latest serum creatinine dosage were 112 days (prior) and 108 days (after). The median number of prescribed drugs was 8 per resident during the two period of study. The conformity rate of prescription was better prior the distribution of the guidelines, respectively 87.5% and 80.0% (p<10-3). The average formal quality score was better after the distribution of the booklet increasing form 4.23 to 4.40 points (p<10-4). For high risk inducing drugs, monitoring was prescribed in 34.2% (prior) and 32.4% (after). CONCLUSIONS: This study shows that the drug geriatric guidelines does not improve prescription conformity and monitoring for high risk drugs, but it does significantly improve the median formal quality score. PMID- 26242497 TI - Contribution of Therapeutic Monitoring in the Assessment of Toxic Adverse Effects of Mitotane: a Case Report. AB - Mitotane provided serious side effects and low doses seemed to be tolerated. Determination of mitotane concentration in plasma is recommended. We report the case of toxic plasma levels with low doses of mitotane in a 47-year-old man with adrenocortical cancer. PMID- 26242499 TI - [Abuse Liability of Quetiapine (Xeroquel(r))]. AB - OBJECTIVE: In recent years, there have been several reports in the literature concerning the misuse and abuse of quetiapine. The aim of this study was to review the data reported to the French Network of the Addictovigilance Centers as well as the published data. METHODS: Epidemiological data from the studies of French network addictovigilance centers (spontaneous notifications, suspicious presciptions suggesting possible abuse [ ordonnances suspectes indicateur d'abus possibles, OSIAP], observatory of illegal psychotropic substances or delivered substances diverted from their medicinal use survey [observation des produits psychotropes illicites ou detournees de leur utilisation medicamenteuse, OPPIDUM], deaths related to medication and substance abuse survey [deces en relation avec l'abus de medicaments et de substances, DRAMES]) were analyzed between 2011 and 2014. All cases of abuse and dependence with quetiapine in PubMed were reviewed using the MeSH terms "quetiapine," "substances abuse," and "dependence", until October 2014. RESULTS: The analysis of the literature has identified 21 cases of abuse related to quetiapine, mainly in men (85.7%), with a history of substance abuse (76%). The main route of administration was oral but other routes were also reported (intravenous, intranasal). The main reason for abuse was sedation and anxiolytic. Other characteristics of quetiapine abuse include amplification or even simulation of psychotic symptoms to obtain quetiapine, an increased dose and the existence of street names. The French addictovigilance network reported few cases of abuse with quetiapine. DISCUSSION CONCLUSION: The pharmacological mechanism of abuse of quetiapine is not fully understood. However, several arguments are in favor of the abuse liability of quetiapine. Despite the recent availability of quetiapine in France, there have been some isolated signals of abuse. Therefore, it seems important to inform prescribers on the risk of misuse of quetiapine and also of some other antipsychotics. PMID- 26242498 TI - [Proton Pump Inhibitor and High-dose Methotrexate: Two Cases Reports]. AB - Methotrexate (MTX) is a cytotoxic agent prescribed at high dose in treatment of malignancy. Association of MTX to proton pump inhibitor (PPI) is not recommended if doses are more than 20 mg per weeks and only to take into account for smaller doses. Review relate some cases of delayed elimination of methotrexate in patients taking PPI, which increase risk of toxic event. However, currently there is no status quo on interaction between PPI and MTX according to available data. We report two clinical cases illustrating one more time a toxic event to MTX in presence of PPI. In absence of risk/benefit ratio set correctly, an assessment of appropriateness of PPI prescription before MTX therapy can limit an iatrogenic risk. PMID- 26242500 TI - Thrombocytopenic Purpura Associated with Dietary Supplements Containing Citrus Flavonoids. AB - We report a case of thrombocytopenic purpura associated with the intake of two dietary supplements containing mainly citrus flavonoids. This is the first case to be notified to the French Agency for Food, Environmental and Occupational Health Safety (ANSES). It addresses the importance of an accurate medication history interview for each patient. PMID- 26242501 TI - Validation study of predictive value of capillaroscopic skin ulcer risk index (CSURI) in scleroderma patients treated with bosentan. PMID- 26242503 TI - Bias voltage control of magnetic phase transitions in graphene nanojunctions. AB - The magnetic state of a spintronic device is usually controlled by magnetic contacts or a transverse electric field generated by side gates. In this work, we consider a graphene nanojunction in the presence of a bias voltage that leads to magnetic phase transitions in the system. Combining the non-equilibrium Green's function with the Hubbard model, our self consistent calculation reveals that an increasing bias voltage induces consecutive transitions among antiferromagnetic and ferromagnetic states. It is further shown that the graphene nanojunction is turned off in the antiferromagnetic state when the bias voltage is low and can then be switched on to the ferromagnetic state by a high bias voltage. We therefore demonstrate that the magnetic state of the graphene system can be controlled by the bias voltage without resorting to any transverse gates. PMID- 26242502 TI - Reduced Expression of Argonaute 1, Argonaute 2, and TRBP Changes Levels and Intracellular Distribution of RNAi Factors. AB - Until recently, Argonaute 2 (AGO2) and other RNA factors were believed to be restricted to the cytoplasm of mammalian somatic cells. It is now becoming appreciated that RNAi factors can also be found in cell nuclei, but much remains to be learned about their transport, molecular recognition, and function. We find that siRNA-mediated reduction of AGO1 or AGO2 increases the proportion of AGO1 or AGO2 in cell nuclei. Inhibition of AGO1 expression led to increased AGO2 levels, while knockdown of AGO2 led to increased levels of AGO1. Blocking AGO1, AGO2, or TRBP expression changed expression levels and nuclear distribution of RNAi factors Dicer, TNRC6A (GW182), and TRBP. These data reveal the expression of RNAi proteins is mutually dependent and that perturbation can affect subcellular distribution of those factors inside cells. PMID- 26242504 TI - Digitalis reappraised: Still here today, but gone tomorrow? AB - Digoxin is one of the oldest of drugs acting on the heart and still one of the most frequently used. While in atrial fibrillation digoxin continues to have a valid role in the control of ventricular rate when added to beta-blockers and calcium antagonists, digoxin for heart failure is no longer a supportable option in view of the negative recent meta-analysis. PMID- 26242505 TI - The unsuspected killer: Liquefied petroleum gas overexposure in South Africa. AB - A 21-year-old woman with no past medical history of note was found unconscious together with five of her family members after prolonged exposure to liquefied petroleum gas. She was admitted to the intensive care unit at Victoria Hospital, Wynberg, Cape Town, South Africa, following resuscitation for pulseless electrical activity. On examination the following was found: coma without focal neurology; shock requiring fluid resuscitation and adrenaline; probable pneumonitis or aspiration pneumonia; acute rhabdomyolysis with severe metabolic acidosis; and raised serum K+. A carboxyhaemoglobin test was unable to confirm or exclude carbon monoxide poisoning. PMID- 26242506 TI - The utility of urine sulphosalicylic acid testing in the detection of non-albumin proteinuria. AB - We report two cases of immunoglobulin light chain proteinuria (Bence Jones proteinuria) detected by simple side-room invest-igations: urine dipstick negative/1+, but with strong positive pre-cipitation on addition of an equal volume of sulphosalicylic acid (SSA) 3%. We highlight a significant limitation of urine dipstick testing, namely specificity for albumin, and the utility of SSA testing for the detection of urinary free light chain immunoglobulins. PMID- 26242507 TI - Digoxin therapy in the modern management of cardiovascular disease: An unusual but serious complication. PMID- 26242508 TI - Arthritis mutilans: A rare phenomenon. PMID- 26242509 TI - For external use only. PMID- 26242510 TI - Schistosomiasis misdiagnosed as abdominal tuberculosis. PMID- 26242511 TI - An additional X chromosome. PMID- 26242512 TI - Wernicke's encephalopathy as a complication of gastroparesis after emergency partial antrectomy. PMID- 26242513 TI - Fever, sore throat and myalgia. PMID- 26242515 TI - On getting published in the SAMJ. PMID- 26242517 TI - Implications of Cochrane Review on restricting or banning alcohol advertising in South Africa. PMID- 26242518 TI - Hands-on student training in private hospitals has arrived. PMID- 26242519 TI - Honing healthcare leaders' competence and attitudes equals facility-level delivery. PMID- 26242520 TI - Mannie Stein, 1920 - 2014. PMID- 26242521 TI - Recommendations pertaining to the use of influenza vaccines and influenza antiviral drugs: Influenza 2015. AB - Prevention of influenza is the most effective management strategy. Influenza vaccine is administered each year before the influenza season. Here we provide recommendations for the use of influenza vaccines in anticipation of the 2015 Southern Hemisphere influenza season. For a review of the 2014 influenza season, please refer to the website of the National Institute for Communicable Diseases of the National Health Laboratory Service, www.nicd.ac.za. PMID- 26242522 TI - Trauma quality improvement: The Pietermaritzburg Metropolitan Trauma Service experience with the development of a comprehensive structure to facilitate quality improvement in rural trauma and acute care in KwaZulu-Natal, South Africa. AB - Improving the delivery of efficient and effective surgical care in rural South Africa is a mammoth task bedevilled by conflict between the stakeholders, who include rural doctors, surgeons, ancillary staff, researchers, educators and administrators. Management training is not part of most medical school curricula, yet as they progress in their careers, many clinicians are required to manage a health system and find the shift from caring for individual patients to managing a complex system difficult. Conflict arises when management-type interventions are imposed in a top-down manner on surgical staff suspicious of an unfamiliar field of study. Another area of conflict concerns the place of surgical research. Researchers are often accused of not being sufficiently focused on or concerned about the tasks of service delivery. This article provides an overview of management theory and describes a comprehensive management structure that integrates a model for health systems with a strategic planning process, strategic planning tools and appropriate quality metrics, and shows how the Pietermaritzburg Metropolitan Trauma Service in KwaZulu-Natal Province, South Africa, successfully used this structure to facilitate and contextualise a diverse number of quality improvement programmes and research initiatives in the realm of rural acute surgery and trauma. We have found this structure to be useful, and hope that it may be applied to other acute healthcare systems. PMID- 26242523 TI - Must doctors disclose their fees before treatment? AB - The bioethical principles of patient autonomy, beneficence, non-maleficence and justice or fairness require doctors to disclose their fees before treating patients. The provisions regarding disclosures about fees in the Health Professions Act and National Health Act are in conflict. Those in the National Health Act are likely to be applied by the courts to impose a legal duty on healthcare practitioners to disclose their fees before treating patients. This is because the National Health Act is consistent with the access to healthcare provision in the Constitution, as the nature of the access is often determined by the patient's ability to afford the treatment. Given the unequal bargaining power between doctors and patients, very few patients may ask doctors what their fees are before being treated. It is feasible for doctors to provide such information, or an estimate, and ethically and legally they have a duty to do so. PMID- 26242524 TI - Evidence insufficient to confirm the value of population screening for diabetes and hypertension in low- and-middle-income settings. AB - To assess the evidence from systematic reviews on the effect on morbidity and mortality of blanket screening for hypertension or diabetes mellitus compared with targeted, opportunistic or no screening, we searched for relevant systematic reviews and conducted duplicate study selection, data extraction and quality appraisal. Results were summarised narratively. We included two completed reviews of moderate quality and one ongoing Cochrane review. In one completed review, general health checks had no effect on total morbidity or mortality or on healthcare services compared with no health checks. In the other, intensive hypertension screening methods were ineffective in increasing screening uptake or detecting new cases compared with less intensive methods. Both reviews included studies in high-income settings. There is insufficient evidence from currently available systematic reviews to confirm a beneficial effect of blanket screening for hypertension and/or diabetes compared with other types of screening methods in low- and middle-income settings. Scarce resources are being mobilised to implement mass screening intervention for diabetes and hypertension without adequate evidence of its effects. A systematic review is needed to assess clinical effectiveness, cost-effectiveness and overall impact on the health system of screening strategies, especially in low- and middle-income settings such as exist in South Africa. Robust evaluation of these outcomes would then be necessary to inform secondary prevention strategies. PMID- 26242525 TI - Why is cancer not a priority in South Africa? PMID- 26242526 TI - Morbidity and mortality of black HIV-positive patients with end-stage kidney disease receiving chronic haemodialysis in South Africa. PMID- 26242527 TI - South African National Cancer Registry: Effect of withheld data from private health systems on cancer incidence estimates. AB - BACKGROUND: The National Cancer Registry (NCR) was established as a pathology based cancer reporting system. From 2005 to 2007, private health laboratories withheld cancer reports owing to concerns regarding voluntary sharing of patient data. OBJECTIVES: To estimate the impact of under-reported cancer data from private health laboratories. METHODS: A linear regression analysis was conducted to project expected cancer cases for 2005-2007. Differences between actual and projected figures were calculated to estimate percentage under-reporting. RESULTS: The projected NCR case total varied from 53,407 (3.8% net increase from actual cases reported) in 2005 to 54,823 (3.7% net increase) in 2007. The projected number of reported cases from private laboratories in 2005 was 26,359 (19.7% net increase from actual cases reported), 27,012 (18.8% net increase) in 2006 and 27,666 (28.4% net increase) in 2007. CONCLUSION: While private healthcare reporting decreased by 28% from 2005 to 2007, this represented a minimal impact on overall cancer reporting (net decrease of <4%). PMID- 26242528 TI - Morbidity and mortality of black HIV-positive patients with end-stage kidney disease receiving chronic haemodialysis in South Africa. AB - INTRODUCTION: There are few published data from South Africa (SA) on the outcomes of black HIV-positive patients receiving chronic haemodialysis. METHODS: This retrospective study compared the incidences of vascular and infectious morbidity and mortality in black HIV-positive patients with those in a group of HIV negative patients matched for ethnicity, age and gender. All the patients were receiving chronic haemodialysis in the medically insured healthcare sector of SA. RESULTS: The incidence of tuberculosis and hospital admission rates for vascular access-related infections were significantly higher in the HIV-positive group than the HIV-negative group. The HIV-positive group had significantly lower albumin (p<0.05) and haemoglobin levels (p<0.01), but this did not impact on mortality. Survival in both groups was excellent. In the HIV-positive group, viral suppression rates were suboptimal with <50% of patients on antiretroviral therapy completely virally suppressed. CONCLUSION: This study has shown that black HIV-positive patients receiving chronic haemodialysis in a healthcare funded environment in SA have excellent overall survival in spite of higher hospital admission rates and higher infectious morbidity compared with HIV negative patients. PMID- 26242529 TI - The Vaccine and Cervical Cancer Screen (VACCS) project: Linking cervical cancer screening to HPV vaccination in the South-West District of Tshwane, Gauteng, South Africa. AB - BACKGROUND: Cervical cancer is preventable, but still highly prevalent in South Africa (SA). Screening strategies in the country have been ineffective, and new ways to prevent the disease are needed. OBJECTIVES: To investigate the feasibility of linking cervical cancer screening in adult women to human papillomavirus (HPV) vaccination in schoolgirls. METHODS: Ten primary schools in the South-West District of Tshwane, Gauteng Province, SA, took part in the study. Cervical cancer and HPV vaccine information was provided to schoolgirls and their parents. Consented schoolgirls were vaccinated and their female parents were invited to participate in self-screening. RESULTS: Among 1 654 girls invited for vaccination, the consented and invited uptake rates were 99.4% and 64.0%, respectively. Vaccine completion rates were higher in schools where the vaccination programme was completed in the same calendar year than in those where it was administered over two calendar years. Of 569 adult females invited, 253 (44.5%) returned screen tests; 169 (66.8%) tested negative and 75 (29.6%) positive for any high-risk HPV (hrHPV). There were no differences in level of education, employment status or access to healthcare between women with positive and those with negative screen results. CONCLUSIONS: Implementation of HPV vaccination in a primary school-based programme was successful, with high vaccine uptake and completion rates. Self-screening reached the ideal target group, and it is possible to link cervical cancer screening to the cervical cancer vaccine by giving women the opportunity of self-sampling for hrHPV testing. This is a novel and feasible approach that would require some adaptive strategies. PMID- 26242530 TI - Prevalence of gastrointestinal pathogenic bacteria in patients with diarrhoea attending Groote Schuur Hospital, Cape Town, South Africa. AB - BACKGROUND: Diarrhoea due to gastrointestinal infections is a significant problem facing the South African (SA) healthcare system. Infections can be acquired both from the community and from the hospital environment itself, the latter acting as a reservoir for potential pathogenic bacteria. OBJECTIVES: To examine the prevalence of a panel of potential diarrhoea-causing bacteria in patients attending a tertiary healthcare facility in Cape Town, SA. METHODS: Polymerase chain reaction (PCR) primers specific for Clostridium difficile, Shigella spp., Salmonella spp., Klebsiella oxytoca, enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC/EHEC), Staphylococcus aureus, enterotoxigenic Bacteroides fragilis and Campylobacter spp. were used to screen total bacterial genomic DNA extracted from stool samples provided by 156 patients with diarrhoea attending Groote Schuur Hospital, Cape Town, SA. RESULTS: C. difficile was the most frequently detected pathogen (16% of cases) in the 21-87-year-old patient range, but was not present in samples from the 16-20-year-old range. K. oxytoca (6%), EPEC/EHEC strains (9%) and S. aureus (6%) were also detected. The remaining pathogens were present at low frequencies (0-2.9%), and the occurrence of mixed infections was 5%. The majority of non-C. difficile-related diarrhoeas were community acquired. CONCLUSION: C. difficile was the main cause of infectious diarrhoea in the sampled patients, while K. oxytoca and EPEC/EHEC strains were present as relatively minor but potentially significant pathogens. PMID- 26242531 TI - Predictors of in-hospital mortality following non-cardiac surgery: Findings from an analysis of a South African hospital administrative database. AB - BACKGROUND: Predictors of in-hospital mortality (IHM) following non-cardiac surgery in South African (SA) patients are not well described. OBJECTIVE: To determine the association between patient comorbidity and IHM in a cohort of SA non-cardiac surgery patients. METHODS: Data related to comorbidity and IHM for 3,727 patients aged >=45 years were obtained from a large administrative database at a tertiary SA hospital. Logistic regression analysis was used to determine independent predictors of IHM. In addition, population-attributable fractions (PAFs) were calculated for all clinical factors identified as independent predictors of IHM. RESULTS: Renal dysfunction, congestive heart failure, cerebrovascular disease, male gender and high-risk surgical specialties were independently associated with IHM (odds ratios (95% confidence intervals) 7.585 (5.480-10.50); 2.604 (1.119-6.060); 2.645 (1.414-4.950); 1.433 (1.107-1.853); and 1.646 (1.213-2.233), respectively). Ischaemic heart disease, diabetes and hypertension were not identified as independent predictors of IHM in SA non cardiac surgery patients. Renal dysfunction had the largest contribution to IHM in this study (PAF 0.34), followed by high-risk surgical specialties (PAF 0.15), male gender (PAF 0.08), cerebrovascular disease (PAF 0.03) and congestive heart failure (PAF 0.03). CONCLUSION: Renal dysfunction, congestive heart failure, cerebrovascular disease, male gender and high-risk surgical specialties were major contributors to increased IHM in SA non-cardiac surgery patients. Prospectively designed research is required to determine whether ischaemic heart disease, diabetes and hypertension contribute to IHM in these patients. PMID- 26242532 TI - Human myiasis in rural South Africa is under-reported. AB - BACKGROUND: Myiasis is the infestation of live tissue of humans and other vertebrates by larvae of flies. Worldwide, myiasis of humans is seldom reported, although the trend is gradually changing in some countries. Reports of human myiasis in Africa are few. Several cases of myiasis were recently seen at the Mthatha Hospital Complex, Mthatha, Eastern Cape Province, South Africa (SA). OBJECTIVE: Because of a paucity of literature on myiasis from this region, surgeons and scientists from Walter Sisulu University, Mthatha, decided to document myiasis cases presenting either at Nelson Mandela Academic Hospital or Umtata General Hospital from May 2009 to April 2013. The objective was to determine the incidence, epidemiology, patient age group and gender, and fly species involved. The effect of season on incidence was also investigated. RESULTS: Twenty-five cases (14 men and 11 women) were recorded in the 4-year study period. The fly species involved were Lucilia sericata, L. cuprina, Chrysomya megacephala, C. chloropyga and Sarcophaga (Liosarcophaga) nodosa, the latter being confirmed as an agent for human myiasis for the first time. The patients were 3 - 78 years old (median 56). Cases were most numerous during spring and summer, and were associated with underlying pathologies typical of ageing. CONCLUSION: Myiasis is a more common medical condition than expected in the Mthatha region. The study shows that human myiasis is still frequently encountered in SA, and there is a need to understand its epidemiology better. PMID- 26242533 TI - Multimorbidity in non-communicable diseases in South African primary healthcare. AB - BACKGROUND: Multimorbidity in non-communicable diseases (NCDs) is a complex global healthcare challenge that is becoming increasingly prevalent. In Africa, comorbidity of communicable diseases and NCDs is also increasing. OBJECTIVES: To evaluate the extent of multimorbidity among patients with NCDs in South African (SA) primary healthcare (PHC). METHODS: A dataset obtained from a previous morbidity survey of SA ambulatory PHC was analysed. Data on conditions considered active and ongoing at consultations by PHC providers were obtained. RESULTS: Altogether 18 856 consultations were included in the dataset and generated 31 451 reasons for encounter and 24 561 diagnoses. Hypertension was the commonest NCD diagnosis encountered (13.1%), followed by type 2 diabetes (3.9%), osteoarthritis (2.2%), asthma (2.0%), epilepsy (1.9%) and chronic obstructive pulmonary disease (COPD) (0.6%). The majority of patients (66.9%) consulted a nurse and 33.1% a doctor. Overall 48.4% of patients had comorbidity and 14.4% multimorbidity. Multimorbidity (two or more conditions) was present in 36.4% of patients with COPD, 23.7% with osteoarthritis, 16.3% with diabetes, 15.3% with asthma, 12.0% with hypertension and 6.7% with epilepsy. Only 1.1% also had HIV, 1.0% TB, 0.4% depression and 0.04% anxiety disorders. CONCLUSION: About half of the patients with NCDs had comorbidity, and multimorbidity was common in patients with COPD and osteoarthritis. However, levels of multimorbidity were substantially lower than reported in higher-income countries. Future clinical guidelines, training of PHC nurses and involvement of doctors in the continuum of care should address the complexity of patients with NCDs and multimorbidity. PMID- 26242534 TI - Prospective analysis of the medicine possession ratio of antidepressants in the private health sector of South Africa, 2006 - 2011. AB - BACKGROUND: Major depressive disorder (MDD) is a disabling mental illness with high morbidity and mortality rates. Inadequate treatment efficacy, unfavourable side-effect profiles and consequent shortfalls in compliance are major stumbling blocks in its treatment. Non-compliance data in low- to middle-income countries are lacking. OBJECTIVE: To investigate the prevalence of antidepressant (AD) non compliance in the private healthcare sector of South Africa (SA). METHODS: We conducted a prospective cohort study analysing AD medicine claims (N=35 175) for 14 135 patients, obtained from a nationally representative pharmaceutical benefit management company, over a 6-year study period (1 January 2006 - 31 December 2011). The medicine possession ratio (MPR) was used as a proxy to determine compliance with AD medication. Only patients >18 years of age whose treatment had been initiated by a psychiatrist following an appropriate International Classification of Diseases (10th edition) (ICD-10) diagnosis of a mood disorder were included. A patient was considered compliant if the MPR was between >=80% and <=110% over a >4-month treatment period. RESULTS: After the first 4 months, only 34% of patients were compliant. A statistically significant association was found between active ingredient consumed and compliance (p<0.0001). Only 26.2% of patients who received amitriptyline-containing products were compliant, compared with 38.8% and 38.7% for venlafaxine and duloxetine, respectively. CONCLUSION: Compliance data collected from pharmacy claims provide a workable estimate of the broader clinical scenario they represent. Although differences between classes of AD were evident, non-compliance was found to be high in the private healthcare environment of SA, comparable with global trends. PMID- 26242535 TI - Integrated positron emission tomography/computed tomography for evaluation of mediastinal lymph node staging of non-small-cell lung cancer in a tuberculosis endemic area: A 5-year prospective observational study. AB - BACKGROUND: Integrated positron emission tomography/computed tomography (PET-CT) is a well-validated modality for assessing mediastinal lymph node metastasis in non-small-cell lung cancer (NSCLC), which determines management and predicts survival. Tuberculosis (TB) is known to lead to false-positive PET-CT findings. OBJECTIVES: To assess the diagnostic accuracy of PET-CT in identifying mediastinal lymph node involvement of NSCLC in a high TB-endemic area. METHODS: Patients who underwent both PET-CT and lymph node tissue sampling for the investigation of suspected NSCLC were prospectively included in this observational study. Results were analysed per patient and per lymph node stage. A post-hoc analysis was performed to test the validity of a maximum standardised uptake value (SUV-max) cut-off for lymph node positivity. RESULTS: PET-CT had a sensitivity of 92.6%, specificity of 48.6%, positive predictive value of 56.8% and negative predictive value (NPV) of 90.0% in the per-patient analysis. Diagnostic accuracy was 67.2%. Similar values were obtained in the per-lymph node stage analysis. TB was responsible for 21.1% of false-positive results. A SUVmax cut-off of 4.5 yielded an improvement in diagnostic accuracy from 64.0% to 84.7% compared with a cut-off of 2.5, but at the cost of decreasing the NPV from 90.6% to 83.5%. CONCLUSION: In a high TB-endemic area, PET-CT remains a valuable method for excluding mediastinal lymph node involvement in NSCLC. Patients with a negative PET-CT may proceed to definitive management without further invasive procedures. However, PET-CT-positive lymph nodes require pathological confirmation, and the possibility of TB must be considered. PMID- 26242537 TI - Helpful hints for writing SI units. PMID- 26242538 TI - Full circle. PMID- 26242539 TI - HMPG secures top-drawer CEO. PMID- 26242541 TI - The medical case report. PMID- 26242542 TI - A tale of two viruses. PMID- 26242544 TI - Retraction Note to: Contrast-enhanced ultrasound appearances of enhancement patterns of intrahepatic cholangiocarcinoma: correlation with pathological findings. PMID- 26242545 TI - [Bootcamp: longitudinal gender-based surgical and clinical skills training]. AB - BACKGROUND: Sex parity of medical students has increased to the degree that approximately 50 % of medical students are women. Orthopedic and trauma surgery, however, has not managed to keep up with this trend and women are still grossly underrepresented. OBJECTIVES: Description of an innovative longitudinal gender based surgical and clinical skills training course. METHODS: An elective 5-day modular skills course is offered for third to fifth year medical students. Module 1 aims at teaching basic surgical and communication skills involving local and regional anesthesia, initial experience with arthroscopy, fracture fixation, emergency measures as well as communication skills training using standardized patients. The subsequent modules cover surgical knowledge and skills of increasing complexity. The main goals are to increase the interest in orthopedic trauma surgery and to reduce concerns regarding discrimination and gender-related issues. Learning outcomes are assessed using a 6-item multiple choice questionnaire (MCQ) and a 3-stage objective structured clinical examination (OSCE) regarding induction of anesthesia, arthroscopy simulation and communication skills. RESULTS: A total of 52 second year medical students (39 females, 13 males) completed module I. There were no differences between men and women with regard to the MCQ and anesthesia and communication skills; however, male students scored significantly higher in the arthroscopy test. All students rated the course as being highly effective in terms of acquisition of knowledge and skills. Almost all participants would recommend the course to fellow students and 70 % of participants stated they would participate in the advanced courses. Female participants in particular reported a marked increase in interest in orthopedic trauma surgery and less concerns regarding discrimination and gender related issues. CONCLUSION: The effectiveness of the approach will have to be proven by further evaluation, especially with respect to assessment of career development and application rates of participants. Adaptation of environmental and working conditions to suit women's needs seem to play an important role in promoting new surgery residents. PMID- 26242546 TI - [Augmentation techniques on the proximal femur]. AB - BACKGROUND: Due to the demographic change fractures of the proximal femur are an increasing major healthcare problem and are associated with the highest mortality among frailty fractures. OBJECTIVES: These mainly osteoporosis-associated fractures of the hip often represent a surgical challenge and the outcome has a decisive influence on the preservation of function and independency of orthogeriatric patients. Augmentation techniques could improve the stability of osteosynthesis in proximal femoral fractures. METHODS: Cement augmentation of proximal femoral nailing (PFNA) for the treatment of pertrochanteric femoral fractures is the most commonly used and standardized method of augmentation for these fractures by which a safer condition for immediate full weight bearing and mobilization can be achieved. RESULTS: In biomechanical and clinical studies good fracture healing was shown and there was no evidence of cement-associated complications in augmented PFNA nailing. In the majority of patients the mobility level prior to trauma could be achieved. CONCLUSION: In addition to the optimal surgical treatment, secondary prevention such as osteoporosis management to avoid further fractures is crucial in the treatment of these patients. This article is based on the current literature and provides an overview of the possible applications of cement augmentation for the treatment of proximal femoral fractures. In addition the surgical approach as well as previous scientific data on an established osteosynthesis using cement-augmented PFNA for the treatment of pertrochanteric frailty fractures are presented. PMID- 26242547 TI - [In Process Citation]. PMID- 26242549 TI - Evidence of hospital failures was not disclosed at surgeon's manslaughter trial. PMID- 26242548 TI - Congenital generalized hypertrichosis: the skin as a clue to complex malformation syndromes. AB - Hypertrichosis is defined as an excessive growth in body hair beyond the normal variation compared with individuals of the same age, race and sex and affecting areas not predominantly androgen-dependent. The term hirsutism is usually referred to patients, mainly women, who show excessive hair growth with male pattern distribution.Hypertrichosis is classified according to age of onset (congenital or acquired), extent of distribution (generalized or circumscribed), site involved, and to whether the disorder is isolated or associated with other anomalies. Congenital hypertrichosis is rare and may be an isolated condition of the skin or a component feature of other disorders. Acquired hypertrichosis is more frequent and is secondary to a variety of causes including drug side effects, metabolic and endocrine disorders, cutaneous auto-inflammatory or infectious diseases, malnutrition and anorexia nervosa, and ovarian and adrenal neoplasms. In most cases, hypertrichosis is not an isolated symptom but is associated with other clinical signs including intellective delay, epilepsy or complex body malformations.A review of congenital generalized hypertrichosis is reported with particular attention given to the disorders where excessive diffuse body hair is a sign indicating the presence of complex malformation syndromes. The clinical course of a patient, previously described, with a 20-year follow-up is reported. PMID- 26242550 TI - Streptococcus panodentis sp. nov. from the oral cavities of chimpanzees. AB - Three strains TKU9, TKU49 and TKU50(T) , were isolated from the oral cavities of chimpanzees (Pan troglodytes). The isolates were all gram-positive, facultative anaerobic cocci that lacked catalase activity. Analysis of partial 16S rRNA gene sequences showed that the most closely related species was Streptococcus infantis (96.7%). The next most closely related species to the isolates were S. rubneri, S. mitis, S. peroris and S. australis (96.6 to 96.4%). Based on the rpoB and gyrB gene sequences, TKU50(T) was clustered with other member of the mitis group. Enzyme activity and sugar fermentation patterns differentiated this novel bacterium from other members of the mitis group streptococci. The DNA G + C content of strain TKU50(T) was 46.7 mol%, which is the highest reported value for members of the mitis group (40-46 mol%). On the basis of the phenotypic characterization, partial 16S rRNA gene and sequences data for two housekeeping gene (gyrB and rpoB), we propose a novel taxa, S. panodentis for TKU 50(T) (type strain = CM 30579(T) = DSM 29921(T) ), for these newly described isolates. PMID- 26242551 TI - Sexual health behaviors of Deaf American Sign Language (ASL) users. AB - BACKGROUND: Little is known about the sexual health behaviors of Deaf American Sign Language (ASL) users. OBJECTIVE: We sought to characterize the self-reported sexual behaviors of Deaf individuals. METHODS: Responses from 282 Deaf participants aged 18-64 from the greater Rochester, NY area who participated in the 2008 Deaf Health were analyzed. These data were compared with weighted data from a general population comparison group (N = 1890). We looked at four sexual health-related outcomes: abstinence within the past year; number of sexual partners within the last year; condom use at last intercourse; and ever tested for HIV. We performed descriptive analyses, including stratification by gender, age, income, marital status, and educational level. RESULTS: Deaf respondents were more likely than the general population respondents to self-report two or more sexual partners in the past year (30.9% vs 10.1%) but self-reported higher condom use at last intercourse (28.0% vs 19.8%). HIV testing rates were similar between groups (47.5% vs 49.4%) but lower for certain Deaf groups: Deaf women (46.0% vs 58.1%), lower-income Deaf (44.4% vs 69.7%) and among less educated Deaf (31.3% vs 57.7%) than among respondents from corresponding general population groups. CONCLUSION: Deaf respondents self-reported higher numbers of sexual partners over the past year compared to the general population. Condom use was higher among Deaf participants. HIV was similar between groups, though HIV testing was significantly lower among lower income, less well-educated, and female Deaf respondents. Deaf individuals have a sexual health risk profile that is distinct from that of the general population. PMID- 26242552 TI - Dopamine dysregulation syndrome and punding in levodopa-carbidopa intestinal gel (LCIG) infusion: A serious but preventable complication. PMID- 26242553 TI - Antibiotic resistance: An ethical challenge. AB - In this paper, we argue that antibiotic resistance (ABR) raises a number of ethical problems that have not yet been sufficiently addressed. We outline four areas in which ethical issues that arise in relation to ABR are particularly pressing. First, the emergence of multidrug-resistant and extensively drug resistant infections exacerbates traditional ethical challenges of infectious disease control, such as the restriction of individual liberty for the protection of the public's health. Second, ABR raises issues of global distributive justice, both with regard to the overuse and lack of access to antibiotics. Third, the use of antibiotics in veterinary medicine raises serious concerns for animal welfare and sustainable farming practices. Finally, the diminishing effectiveness of antibiotics leads to questions about intergenerational justice and our responsibility for the wellbeing of future generations. We suggest that current policy discussions should take ethical conflicts into account and engage openly with the challenges that we outline in this paper. PMID- 26242555 TI - Modification of the argon stripping target of the tandem accelerator. AB - The tandem accelerator with vacuum insulation has been proposed and developed in Budker Institute of Nuclear Physics. Negative hydrogen ions are accelerated by the positive 1MV potential of the high-voltage electrode, converted into protons in the gas stripping target inside the electrode, and then protons are accelerated again by the same potential. A stationary proton beam with 2 MeV energy, 1.6 mA current, 0.1% energy monochromaticity, and 0.5% current stability is obtained now. To conduct Boron Neutron Capture Therapy it is planned to increase the proton beam current to at least 3 mA. The paper presents the results of experimental studies clarifying the reasons for limiting the current, and gives suggestions for modifying the gas stripping target in order to increase the proton beam current along with the stability of the accelerator. PMID- 26242556 TI - PGNAA system preliminary design and measurement of In-Hospital Neutron Irradiator for boron concentration measurement. AB - A prompt gamma neutron activation analysis (PGNAA) system has been recently developed at the 30-kW research reactor In-Hospital Neutron Irradiator (IHNI) in Beijing. Neutrons from the specially designed thermal neutron beam were used. The thermal flux of this beam is 3.08*10(6) cm(-2) s(-1) at a full reactor power of 30 kW. The PGNAA system consists of an n-type high-purity germanium (HPGe) detector of 40% efficiency, a digital spectrometer, and a shielding part. For both the detector shielding part and the neutron beam shielding part, the inner layer is composed of (6)Li2CO3 powder and the outer layer lead. The boron-10 sensitivity of the PGNAA system is approximately 2.5 cps/ppm. Two calibration curves were produced for the 1-10 ppm and 10-50 ppm samples. The measurement results of the control samples were in accordance with the inductively coupled plasma atomic emission spectroscopy (ICP-AES) results. PMID- 26242557 TI - Neutron intensity monitor with activation foil for p-Li neutron source for BNCT- Feasibility test of the concept. AB - Proton-lithium (p-Li) reaction is being examined worldwide as a candidate nuclear production reaction for accelerator based neutron source (ABNS) for BNCT. In this reaction, the emitted neutron energy is not so high, below 1 MeV, and especially in backward angles the energy is as low as about 100 keV. The intensity measurement was thus known to be difficult so far. In the present study, a simple method was investigated to monitor the absolute neutron intensity of the p-Li neutron source by employing the foil activation method based on isomer production reactions in order to cover around several hundreds keV. As a result of numerical examination, it was found that (107)Ag, (115)In and (189)Os would be feasible. Their features found out are summarized as follows: (107)Ag: The most convenient foil, since the half life is short. (115)In: The accuracy is the best at 0 degrees , though it cannot be used for backward angles. And (189)Os: Suitable nuclide which can be used in backward angles, though the gamma-ray energy is a little too low. These would be used for p-Li source monitoring depending on measuring purposes in real BNCT scenes. PMID- 26242558 TI - Boron analysis for neutron capture therapy using particle-induced gamma-ray emission. AB - The neutron source of BNCT is currently changing from reactor to accelerator, but peripheral facilities such as a dose-planning system and blood boron analysis have still not been established. To evaluate the potential application of particle-induced gamma-ray emission (PIGE) for boron measurement in clinical boron neutron capture therapy, boronophenylalanine dissolved within a cell culture medium was measured using PIGE. PIGE detected 18 MUgB/mL f-BPA in the culture medium, and all measurements of any given sample were taken within 20 min. Two hours of f-BPA exposure was required to create a boron distribution image. However, even though boron remained in the cells, the boron on the cell membrane could not be distinguished from the boron in the cytoplasm. PMID- 26242559 TI - Boron containing magnetic nanoparticles for neutron capture therapy--an innovative approach for specifically targeting tumors. AB - The selective delivery of (10)B into the tumor tissue remains to be further improved for successful and reliable Boron Neutron Capture Therapy applications. Magnetic Drug Targeting using intraarterially administered superparamagnetic nanoparticles and external magnetic fields already exhibited convincing results in terms of highly efficient and selective drug deposition. Using the same technique for the targeted (10)B delivery is a promising new approach. Here, systematic irradiation experiments of phantom cubes containing different concentrations of boron and nanoparticles as well as varying three-dimensional arrangements have been performed. PMID- 26242560 TI - Additive effect of BPA and Gd-DTPA for application in accelerator-based neutron source. AB - Because of its fast metabolism gadolinium as a commercial drug was not considered to be suitable for neutron capture therapy. We studied additive effect of gadolinium and boron co-administration using colony forming assay. As a result, the survival of tumor cells with additional 5 ppm of Gd-DTPA decreased to 1/10 compared to the cells with boron only. Using gadolinium to increase the effect of BNCT instead of additional X-ray irradiation might be beneficial, as such combination complies with the short-time irradiation regimen at the accelerator based neutron source. PMID- 26242561 TI - Testing and linearity calibration of films of phenol compounds exposed to thermal neutron field for EPR dosimetry. AB - This paper reports the preliminary results obtained by Electron Paramagnetic Resonance (EPR) measurements on films of IRGANOX(r) 1076 phenols with and without low content (5% by weight) of gadolinium oxide (Gd2O3) exposed in the thermal column of the Triga Mark II reactor of LENA (Laboratorio Energia Nucleare Applicata) of Pavia (Italy). Thanks to their size, the phenolic films here presented are good devices for the dosimetry of beams with high dose gradient and which require accurate knowledge of the precise dose delivered. The dependence of EPR signal as function of neutron dose was investigated in the fluence range between 10(11) cm(-2) and 10(14) cm(-2). Linearity of EPR response was found and the signal was compared with that of commercial alanine films. Our analysis showed that gadolinium oxide (5% by weight) can enhance the thermal neutron sensitivity more than 18 times. Irradiated dosimetric films of phenolic compound exhibited EPR signal fading of about 4% after 10 days from irradiation. PMID- 26242562 TI - Coumarin: A Privileged Scaffold for the Design and Development of Antineurodegenerative Agents. AB - Drug development for neurodegenerative diseases (NDs) is foremost task for the medicinal chemists in the 21st century. Coumarins are exemplary of an assorted and aptitudinally useful set of drugs. Coumarins play a momentous role in several pharmacological and medicinal aspects. Its analogues are anticipated to play a significant role in the development of new therapeutic leads for NDs. Their promising applications in the field of ND medication are exemplified by clinical candidates such as nodakenin that have been potent for demoting memory impairment. Apart from ND, clinically used anticoagulant warfarin, anticoagulant dicoumarol, and antibiotic coumermycin, novobiocin and chartesium grab the interest of researchers in coumarins. It would be worthwhile to look at the different biological processes that could cause neurodegeneration, thereby establishing a link with distinct coumarin derivatives to serve the purpose of medication. This review undertakes estimation of the wide spectrum of studies focusing coumarin to the domain of drug research for ND. Herein, we search for multitarget coumarin-based inhibitors and their scope for NDs. Future challenges in coumarin-based drug development have been discussed, and emphases have been laid on the future perspectives of coumarins as possible drugs in the future for the treatment of NDs. PMID- 26242563 TI - Short-term outcomes in patients with acute coronary syndrome treated with direct bioresorbable scaffold deployment. AB - BACKGROUND: Direct coronary stenting is a validated therapeutic option for coronary lesions. We studied the feasibility of direct deployment with a bioresorbable vascular scaffold (BVS) in acute coronary syndrome (ACS). METHODS: Demographic, procedural, and survival data were obtained for patients who had direct scaffold deployment with BVS from 1 May 2013 to 1 April 2014. RESULTS: We performed a retrospective review of nine patients which included eight patients having ST-elevation myocardial infarction. There were no cases of worsening coronary flow, scaffold thrombosis, target lesion revascularization or death up to 30 days post intervention. CONCLUSION: Direct BVS deployment in ACS appears safe and feasible. PMID- 26242564 TI - Inappropriate drug use in elderly patients is associated with prolonged hospital stay and increased postoperative mortality after colorectal cancer surgery: a population-based study. AB - AIM: The study aimed to investigate whether continuing potentially inappropriate medication (PIM) is associated with length of hospital stay (LOS) and postoperative mortality in elderly people undergoing colorectal cancer surgery. METHOD: The Swedish National Colorectal Cancer Register and the Swedish Prescribed Drug Register provided matched data on 7279 patients aged 75 years or more who had undergone bowel resection for colorectal cancer between 2007 and 2010. Patients were divided into two groups depending on whether or not they were taking PIM at the time of surgery. The primary efficacy variables were the LOS and 30-day postoperative mortality. RESULTS: Of the 7279 patients, 22.5% (1641) of the patients were exposed to at least one PIM and the total number of drugs taken in this group was six, compared with three in the non-PIM group (P < 0.001). Postoperative mortality was higher in the PIM group (7.1% vs 4.5%, P < 0.001), and LOS was longer (10 days vs 9, P = 0.001). When adjusted for independent predictors, the differences in LOS (odds ratio 1.14; 95% confidence interval 1.00-1.29, P = 0.046) and postoperative mortality (odds ratio 1.43; 95% confidence interval 1.11-1.85, P = 0.006) remained significant. CONCLUSION: The use of PIM prior to surgery is associated with increased postoperative mortality and prolonged hospital stay. Although no causal relationship is proved, the results add a further aspect to preoperative optimization of elderly patients about to have major colorectal surgery. PMID- 26242565 TI - Enacting corporate governance of healthcare safety and quality: a dramaturgy of hospital boards in England. AB - The governance of patient safety is a challenging concern for all health systems. Yet, while the role of executive boards receives increased scrutiny, the area remains theoretically and methodologically underdeveloped. Specifically, we lack a detailed understanding of the performative aspects at play: what board members say and do to discharge their accountabilities for patient safety. This article draws on qualitative data from overt non-participant observation of four NHS hospital Foundation Trust boards in England. Applying a dramaturgical framework to explore scripting, setting, staging and performance, we found important differences between case study sites in the performative dimensions of processing and interpretation of infection control data. We detail the practices associated with these differences--the legitimation of current performance, the querying of data classification, and the naming and shaming of executives--to consider their implications. PMID- 26242566 TI - Stimulatory effect of luteinizing hormone, insulin-like growth factor-1, and epidermal growth factor on vascular endothelial growth factor production in cultured bubaline luteal cells. AB - The purpose of this study was to evaluate the temporal (24, 48, and 72 hours) and dose-dependent (0, 5, 10, and 100 ng/mL of LH, insulin-like growth factor 1 [IGF 1], and EGF) in vitro expression and secretion patterns of vascular endothelial growth factor (VEGF) in luteal cell culture during different stages of estrous cycle in water buffaloes. Corpus luteum samples from ovaries of early luteal phase (ELP; Days 1-4), midluteal phase (Days 5-10), and late luteal phase (Days 11-16) were collected from a local slaughterhouse. The samples were then processed and cultured in (serum containing) appropriate cell culture medium and incubated separately with three factors (LH, IGF-1, or EGF) at the previously mentioned three dose-duration combinations. At the end of the respective incubation periods, VEGF was assayed in the spent culture medium by ELISA, whereas the cultured cells were used for VEGF mRNA expression by quantitative real-time polymerase chain reaction. The results of the present study disclosed dose- and time-dependent stimulatory effects of LH, IGF-1, and EGF on VEGF production in bubaline luteal cells. The VEGF expression and secretion from the cultured luteal cells were highest during the ELP, intermediate in the midluteal phase, and lowest in the late luteal phase of the estrous cycle for all the three tested factors. Comparison of the results of the three treatments depicted EGF as the most potent stimulating factor followed by IGF-1 and LH. Immunocytochemistry findings in luteal cell culture of ELP agreed with the VEGF expression and secretion. In conclusion, mRNA expression, protein secretion, and immunolocalization of VEGF data clearly indicated for the first time that LH, IGF 1, and EGF play an important role in stimulating luteal angiogenesis in buffalo CL. The highest expression and secretion of VEGF in the ELP might be associated with the development of blood vessels in early growth of CL, which in turn gets augmented by the aforementioned factors emphasizing their regulatory role in luteal angiogenesis. Further studies are however necessary to divulge more information on other factors which regulate VEGF secretion in bubaline CL and the synergistic effects existing among such growth factors. PMID- 26242568 TI - Prevalence of adverse reactions following a passed oral food challenge and factors affecting successful re-introduction of foods. A retrospective study of a cohort of 199 children. AB - BACKGROUND: After a passed oral food challenge (OFC), regular and normal food consumption is attended. The main objective of this study is to assess the safety of tested food dietary re-introduction after a passed OFC. PATIENTS AND METHODS: In 2014, a telephone survey was submitted to patients who passed OFC and those who failed it only presenting with contact urticaria (we consider these OFC as passed), between 2009 and 2013. Questionnaire items included demographic data, food allergy details, food consumption after the OFC was performed, recurring symptoms and life style changes. RESULTS: 249 OFC questionnaires were collected from 199 children, 228 OFC were passed, 21 were failed exclusively due to contact urticaria. The most tested food was cows' milk. In 71% of cases target food was re-introduced in patients diet in normal amounts. We found children >2 years introduced less frequently tested food than infants. In 2% of cases adverse reactions to offending food were reported, but severe reactions never occurred. DISCUSSION: The majority of children of this study ate target food regularly and their family's quality of life improved. In our study, adverse reactions frequency in patients who passed OFC was very low and never serious. We highlight the importance of re-assessing proper food consumption in every patient who passed OFC. PMID- 26242567 TI - Quality of life in caregivers of children with asthma: Validity and reliability of the IFABI-R questionnaire. AB - BACKGROUND: Parents'/caregivers' quality of life is an important aspect to consider when handling paediatric asthma, but there is a paucity of valid and reliable instruments to measure it. The Family Impact of Childhood Bronchial Asthma (IFABI-R) is a recently developed questionnaire to facilitate the assessment of asthma-related parents'/caregivers' quality of life. This study researches the psychometric properties of IFABI-R. METHODS: Parents/main caregivers of 462 children between 4 and 14 years of age with active asthma were included in the sample. IFABI-R was administered on two different occasions and a number of other variables related to the parents'/caregivers' quality of life were measured: child's asthma control, family functioning, and parents'/caregivers' perception of asthma symptoms in the child. IFABI-R evaluative and discriminative properties were analysed, and the minimal important change in the IFABI-R score was identified. RESULTS: IFABI-R showed high internal consistency (Cronbach's alpha=0.941), cross-sectional construct validity (correlation with the degree of child's asthma control, family functioning and parent/caregiver perception of the child's asthma symptoms), longitudinal construct validity (correlation of changes in the IFABI-R with changes in asthma control and changes in the perception of symptoms), sensitivity to change and test-retest reliability. An absolute change of 0.3 units in IFABI-R related to a minimal significant change in the parents'/caregivers' quality of life. CONCLUSIONS: IFABI-R is a reliable and valid instrument to study the quality of life of parents/caregivers of children with asthma. PMID- 26242569 TI - Induction of nasal polyps using house dust mite and Staphylococcal enterotoxin B in C57BL/6 mice. AB - BACKGROUND: The murine polyp model was developed previously using ovalbumin and Staphylococcus aureus enterotoxin B (SEB). Here, we established a model mimicking key aspects of chronic eosinophilic rhinosinusitis with nasal polyps using the house dust mite (HDM), a clinically relevant aeroallergen, co-administered with SEB. We assessed the inflammatory response and formation of nasal polypoid lesions in an experimental murine model using intranasal delivery of HDM and ovalbumin. METHODS: After induction of HDM-induced allergic rhinosinusitis in C57BL/6 mice, SEB (10ng) was instilled into the nasal cavity of mice for eight weeks. Phosphate-buffered saline-challenged mice served as control. Histopathological changes were evaluated using haematoxylin and eosin for overall inflammation, Sirius red for eosinophils, and periodic acid-Schiff stain for goblet cells. The distribution of mast cells in mouse nasal tissue was determined by immunohistochemistry. Serum total IgE was measured using enzyme-linked immunosorbent assay. RESULTS: Compared to mice treated with HDM only, the HDM+SEB treated mice demonstrated nasal polypoid lesion formation and a significant increase in the number of secretory cells and eosinophilic infiltration. Moreover, mice challenged intranasally with HDM showed highly abundant mast cells in the nasal mucosa. In contrast, OVA+SEB-challenged mice showed a significantly lower degree of mast cell infiltration. CONCLUSION: We established an in vivo model of chronic allergic rhinosinusitis with nasal polypoid lesions using HDM aeroallergen. This study demonstrated that the HDM+SEB-induced murine polyp model could be utilised as a suitable model for nasal polyps, especially with both eosinophil and mast cell infiltration. PMID- 26242570 TI - Histamine, histamine intoxication and intolerance. AB - Excessive accumulation of histamine in the body leads to miscellaneous symptoms mediated by its bond to corresponding receptors (H1-H4). Increased concentration of histamine in blood can occur in healthy individuals after ingestion of foods with high contents of histamine, leading to histamine intoxication. In individuals with histamine intolerance (HIT) ingestion of food with normal contents of histamine causes histamine-mediated symptoms. HIT is a pathological process, in which the enzymatic activity of histamine-degrading enzymes is decreased or inhibited and they are insufficient to inactivate histamine from food and to prevent its passage to blood-stream. Diagnosis of HIT is difficult. Multi-faced, non-specific clinical symptoms provoked by certain kinds of foods, beverages and drugs are often attributed to different diseases, such as allergy and food intolerance, mastocytosis, psychosomatic diseases, anorexia nervosa or adverse drug reactions. Correct diagnosis of HIT followed by therapy based on histamine-free diet and supplementation of diamine oxidase can improve patient's quality of life. PMID- 26242571 TI - Nerve Ultrasound and Electrophysiology for Therapy Monitoring in Chronic Inflammatory Demyelinating Polyneuropathy. AB - BACKGROUND AND PURPOSE: We evaluated prospectively nerve ultrasound and electrophysiology as monitoring methods of intravenous immunoglobulin (IVIG) therapy in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Overall 15 healthy subjects and 11 CIDP patients undergoing IVIG therapy were recruited in the study. All patients underwent clinical, ultrasound, and electrophysiological evaluation at the time point of first onset of symptoms (<6 weeks of symptoms) and 4, 8, and 12 months after onset. RESULTS: The intranerve cross-sectional area (CSA) variability of each nerve, but not the CSA alone, correlated with the MRC Scale score during 12-month follow-up. On the other hand, none of the electrophysiological parameters correlated with the MRC Scale Score in each of the peripheral nerves. Interestingly, in 3/4 of the CIDP patients, the resolution of the conduction block correlated with the improvement in the MRC Sum score. CONCLUSIONS: Nerve ultrasound and in particular the intranerve CSA variability seems to be a useful method in monitoring CIDP patients. Although the sample size is small, the intranerve CSA variability seems to be more promising than neurophysiology. PMID- 26242572 TI - Ovarian lesion volumes as a screening tool for malignancy in adolescent ovarian tumors. AB - BACKGROUND: Preoperative evaluation of ovarian tumors for malignancy is essential to determine appropriate treatment. Our study assessed the utility of ovarian lesion volumes to screen for malignancy in adolescent ovarian lesions. METHODS: A retrospective chart review of adolescent patients (8-18years) who underwent an ovarian operation from January 2008 to December 2012. Data included demographics, ultrasonographic volume measurements, and tumor markers. Volumes were calculated using the prolate ellipsoid formula. Data are presented as medians. RESULTS: One hundred twenty-three females were included at a median age of 13.7years (IQR 12.5 16). Eight patients had malignancies. The median benign lesion volume was significantly smaller than malignant [152cm3 (IQR 57-592)vs. 1548cm(3) (IQR 627 2105), p=0.001]. A receiver operating characteristic (ROC) curve analysis (AUC 0.84, p=0.001) revealed a threshold ovarian lesion volume of <184cm(3) (100% sensitivity, 54% specificity, NPV 100%, PPV 13%) to accurately screen for malignancy. This held true when applied to our dataset as none of the 62 girls with volumes <184cm(3) had malignant pathology. CONCLUSIONS: This is the first documented use of ovarian lesion volumes as a screening tool in adolescent ovarian lesions. This should be used in conjunction with tumor markers and other imaging features to better screen for malignancy. PMID- 26242573 TI - Breaking traditions of practice: workforce challenges in implementing disability service standards within purpose-built accommodation for younger adults. AB - Inadequate community housing and support for adults under 65 years with complex health needs often leads to residential aged care placement. In 2006, Australian government authorities funded a range of supported housing alternatives for younger adults requiring access to 24-hour support including the Integrated Living Model (ILM). The ILM provided purpose-built accommodation for 10-20 people and represented a change in practice from traditional 24/7 nursing care toward a more holistic, individualised approach. AIM: Examine workforce challenges in implementing disability service standards (DSS) within an ILM. METHOD: Thematic Analysis of workforce practices was conducted by coding staff interviews (n = 20) against the prevailing DSS. RESULTS: Emerging challenges identified against each standard were: expectation management; coordination; client expertise; blurred boundaries; role confusion; valued status beyond client; unclear practice boundaries; multilayered communication; reflective practices; and mixed service model responses. CONCLUSION: This ILM setting requires workforce development in rights-based practice, personalisation and effective communication. Key paradigm shifts are also recommended. PMID- 26242574 TI - Experience of using mHealth to link village doctors with physicians: lessons from Chakaria, Bangladesh. AB - BACKGROUND: Bangladesh is facing serious shortage of trained health professionals. In the pluralistic healthcare system of Bangladesh, formal health care providers constitute only 5 % of the total workforce; the rest are informal health care providers. Information Communication Technologies (ICTs) are increasingly seen as a powerful tool for linking the community with formal healthcare providers. Our study assesses an intervention that linked village doctors (a cadre of informal health care providers practising modern medicine) to formal doctors through call centres from the perspective of the village doctors who participated in the intervention. METHODS: The study was conducted in Chakaria, a remote rural area in south-eastern Bangladesh during April-May 2013. Twelve village doctors were selected purposively from a pool of 55 village doctors who participated in the mobile health (mHealth) intervention. In depth interviews were conducted to collect data. The data were manually analysed using themes that emerged. RESULT: The village doctors talked about both business benefits (access to formal doctors, getting support for decision making, and being entitled to call trained doctors) and personal benefits (both financial and non-financial). Some of the major barriers mentioned were technical problems related to accessing the call centre, charging consultation fees, and unfamiliarity with the call centre physicians. CONCLUSION: Village doctors saw many benefits to having a business relationship with the trained doctors that the mHealth intervention provided. mHealth through call centres has the potential to ensure consultation services to populations through existing informal healthcare providers in settings with a shortage of qualified healthcare providers. PMID- 26242575 TI - Pannexin 1 channels regulate leukocyte emigration through the venous endothelium during acute inflammation. AB - Inflammatory cell recruitment to local sites of tissue injury and/or infection is controlled by a plethora of signalling processes influencing cell-to-cell interactions between the vascular endothelial cells (ECs) in post-capillary venules and circulating leukocytes. Recently, ATP-sensitive P2Y purinergic receptors have emerged as downstream regulators of EC activation in vascular inflammation. However, the mechanism(s) regulating cellular ATP release in this response remains elusive. Here we report that the ATP-release channel Pannexin1 (Panx1) opens downstream of EC activation by TNF-alpha. This process involves activation of type-1 TNF receptors, recruitment of Src family kinases (SFK) and SFK-dependent phosphorylation of Panx1. Using an inducible, EC-specific Panx1 knockout mouse line, we report a previously unidentified role for Panx1 channels in promoting leukocyte adhesion and emigration through the venous wall during acute systemic inflammation, placing Panx1 channels at the centre of cytokine crosstalk with purinergic signalling in the endothelium. PMID- 26242576 TI - Trauma/hemorrhagic shock instigates aberrant metabolic flux through glycolytic pathways, as revealed by preliminary (13)C-glucose labeling metabolomics. AB - BACKGROUND: Metabolic derangement is a key hallmark of major traumatic injury. The recent introduction of mass spectrometry-based metabolomics technologies in the field of trauma shed new light on metabolic aberrations in plasma that are triggered by trauma and hemorrhagic shock. Alteration in metabolites associated with catabolism, acidosis and hyperglycemia have been identified. However, the mechanisms underlying fluxes driving such metabolic adaptations remain elusive. METHODS: A bolus of U-(13)C-glucose was injected in Sprague-Dawley rats at different time points. Plasma extracts were analyzed via ultra-high performance liquid chromatography-mass spectrometry to detect quantitative fluctuations in metabolite levels as well as to trace the distribution of heavy labeled carbon isotopologues. RESULTS: Rats experiencing trauma did not show major plasma metabolic aberrations. However, trauma/hemorrhagic shock triggered severe metabolic derangement, resulting in increased glucose levels, lactate and carboxylic acid accumulation. Isotopologue distributions in late Krebs cycle metabolites (especially succinate) suggested a blockade at complex I and II of the electron transport chain, likely due to mitochondrial uncoupling. Urate increased after trauma and hemorrhage. Increased levels of unlabeled mannitol and citramalate, metabolites of potential bacterial origin, were also observed in trauma/hemorrhagic shock rats, but not trauma alone or controls. CONCLUSIONS: These preliminary results are consistent with observations we have recently obtained in humans, and expand upon our early results on rodent models of trauma and hemorrhagic shock by providing the kinetics of glucose fluxes after trauma and hemorrhage. Despite the preliminary nature of this study, owing to the limited number of biological replicates, results highlight a role for shock, rather than trauma alone, in eliciting systemic metabolic aberrations. This study provides the foundation for tracing experiments in rat models of trauma. The goal is to improve our understanding of substrate specific metabolic derangements in trauma/hemorrhagic shock, so as to design resuscitative strategies tailored toward metabolic alterations and the severity of trauma. PMID- 26242577 TI - Psychometric evaluation of the Major Depression Inventory (MDI) as depression severity scale using the LEAD (Longitudinal Expert Assessment of All Data) as index of validity. AB - BACKGROUND: The Major Depression Inventory (MDI) was developed to cover the universe of depressive symptoms in DSM-IV major depression as well as in ICD-10 mild, moderate, and severe depression. The objective of this study was to evaluate the standardization of the MDI as a depression severity scale using the Visual Analogue Scale (VAS) as index of external validity in accordance with the LEAD approach (Longitudinal Expert Assessment of All Data). METHODS: We used data from two previously published studies in which the patients had a MINI Neuropsychiatric Interview verified diagnosis of DSM-IV major depression. The conventional VAS scores for no, mild, moderate, and severe depression were used for the standardization of the MDI. RESULTS: The inter-correlation for the MDI with the clinician ratings (VAS, MES, HAM-D17 and HAM-D6) increased over the rating weeks in terms of Pearson coefficients. After nine weeks of therapy the coefficient ranged from 0.74 to 0.83. Using the clinician-rated VAS depression severity scale, the conventional MDI cut-off scores for no or doubtful depression, and for mild, moderate and severe depression were confirmed. CONCLUSIONS: Using the VAS as index of external, clinical validity, the standardization of the MDI as a measure of depression severity was accepted, with an MDI cut-off score of 21 for mild depression, 26 for moderate depression severity, and 31 for severe depression. TRIAL REGISTRATION: Martiny et al. Acta Psychiatr Scand 112:117-25, 2005: None - due to trial commencement date. Straaso et al. Acta Neuropsychiatr 26:272-9; 2014: ClinicalTrials.gov ID NCT01353092 . PMID- 26242579 TI - High-dose therapy and autologous hematopoietic cell transplantation as front-line consolidation in chronic lymphocytic leukemia: a systematic review. PMID- 26242580 TI - A qualitative study of pain experiences in patients requiring hip and knee arthroplasty. AB - The aim of this study was to conduct an in-depth investigation of experiences with pain before knee and hip replacement surgery. A total of 20 patients were interviewed, and interpretative phenomenological analysis was used to identify themes. These were as follows: living with pain, pain conceptualised, pain treatments and healthcare system. Pre-surgical pain is very disabling and is viewed as biological. There was an associated loss of independence. Pharmaceutical management is used by all but not entirely effective, psychological therapies are underutilised. Patients were frustrated, angry, and confused about qualifying for surgery. Many areas of care could be improved to help these pre-surgical patients. PMID- 26242578 TI - Metformin and sitAgliptin in patients with impAired glucose tolerance and a recent TIA or minor ischemic Stroke (MAAS): study protocol for a randomized controlled trial. AB - BACKGROUND: Impaired glucose tolerance is present in one third of patients with a TIA or ischemic stroke and is associated with a two-fold risk of recurrent stroke. Metformin improves glucose tolerance, but often leads to side effects. The aim of this study is to explore the feasibility, safety, and effects on glucose metabolism of metformin and sitagliptin in patients with TIA or minor ischemic stroke and impaired glucose tolerance. We will also assess whether a slow increase in metformin dose and better support and information on this treatment will reduce the incidence of side effects in these patients. METHODS/DESIGN: The Metformin and sitAgliptin in patients with impAired glucose tolerance and a recent TIA or minor ischemic Stroke trial (MAAS trial) is a phase II, multicenter, randomized, controlled, open-label trial with blinded outcome assessment. Non-diabetic patients (n = 100) with a recent (<6 months) TIA, amaurosis fugax or minor ischemic stroke (modified Rankin scale <= 3) and impaired glucose tolerance, defined as 2-hour post-load glucose levels between 7.8 and 11.0 mmol/L after repeated standard oral glucose tolerance test, will be included. Patients with renal or liver impairment, heart failure, chronic hypoxic lung disease stage III-IV, history of lactate acidosis or diabetic ketoacidosis, pregnancy or breastfeeding, pancreatitis and use of digoxin will be excluded. The patients will be randomly assigned in a 1:1:2 ratio to metformin, sitagliptin or "no treatment." Patients allocated to metformin will start with 500 mg twice daily, which will be slowly increased during a 6-week period to a twice daily dose of 1000 mg. Patients allocated to sitagliptin will be treated with a daily fixed dose of 100 mg. The study has been registered as NTR 3196 in The Netherlands Trial Register. Primary outcomes include percentage still on treatment, percentage of (serious) adverse events, and the baseline adjusted difference in 2-hour post-load glucose levels at 6 months. DISCUSSION: This study will give more information about the feasibility and safety of metformin and sitagliptin as well as the effect on 2-hour post-load glucose levels at 6 months in patients with TIA or ischemic stroke and impaired glucose tolerance. TRIAL REGISTRATION NUMBER: NTR3196 , Date of registration: 15 December 2011. PMID- 26242581 TI - Congenital Ichthyosis in 14 Great Dane Puppies With a New Presentation. AB - The present study describes a generalized congenital skin condition in 14 Great Dane puppies. Macroscopically, all dogs showed generalized gray to yellow scaling and skin wrinkles on the head and all 4 extremities. Skin sections were histologically examined using hematoxylin and eosin, Heidenhain's Azan, and Sudan red III staining methods and by conducting the alcian blue/periodic acid Schiff (AB/PAS) reaction technique on sections. Furthermore, incubation with hyaluronidase was performed. Skin samples were ultrastructurally analyzed using transmission electron microscopy. All affected Great Dane puppies had epidermal and follicular orthokeratotic hyperkeratosis, enlarged keratohyaline granules, vacuolated keratinocytes, and accumulations of an eosinophilic and alcianophilic, lipid-rich material within dilated hair follicular lumina and the cytoplasm of sebocytes. The macroscopic, histopathologic, and ultrastructural skin changes in all 14 Great Dane puppies indicate a new variant of a primary disorder of cornification with congenital, non-epidermolytic, lamellar ichthyosiform appearance. PMID- 26242582 TI - Microcredit participation and women's health: results from a cross-sectional study in Peru. AB - INTRODUCTION: Social and economic conditions are powerful determinants of women's health status. Microcredit, which involves the provision of small loans to low income women in the hopes of improving their living conditions, is an increasingly popular intervention to improve women's socioeconomic status. Studies examining the health effects of microcredit programs have had mixed results. METHODS: We conduct a cross-sectional study among female clients of a non-profit microcredit program in Peru (N = 1,593). The predictor variable is length of microcredit participation. We conduct bivariate and multivariate linear regressions to examine the associations between length of microcredit participation and a variety of measures of women's health. We control for participants' sociodemographic characteristics. RESULTS: We find that longer participation is associated with decreased depressive symptoms, increased social support, and increased perceived control, but these differences are attenuated with the inclusion of covariates. We find no association between length of participation and contraception use, cancer screening, or self-reported days sick. CONCLUSIONS: These results demonstrate a positive association between length of microcredit participation and measures of women's psychological health, but not physical health. These findings contribute to the discussion on the potential of microcredit programs to address the socioeconomic determinants of health, and suggest that addressing socioeconomic status may be a key way to improve women's health worldwide. PMID- 26242583 TI - Differentiation of early gastric cancer with ulceration and resectable advanced gastric cancer using multiphasic dynamic multidetector CT. AB - OBJECTIVES: Early gastric cancer with ulceration (EGC-U) mimics advanced gastric cancer (AGC), as EGC-Us and ACGs often have similar endoscopic appearance to ulceration. The purpose of this retrospective study was to determine whether multiphasic dynamic multidetector CT (MDCT) can help differentiate EGC-Us from AGCs. METHODS: Patients with EGC-Us with ulcer stages Ul-III or IV and AGCs with tumour stages T2 to T4a were enrolled. MDCT images were obtained 40 s (arterial phase), 70 s (portal phase) and 240 s (delayed phase) after injection of non ionic contrast material. Two readers independently measured the attenuation values of the lesions by placing regions of interest. We compared the EGC-Us and AGCs using the mean attenuation values in each phase and peak enhancement phase. We analysed the diagnostic performance of CT for differentiating EGC-Us from AGCs. RESULTS: Forty cases (16 EGC-Us and 24 AGCs) were analysed. The mean attenuation values of the EGC-Us were significantly lower than those of the AGCs in both the arterial and portal phases (all p < 0.0001 for each reader). The peak enhancement was significantly different between the EGC-Us and AGCs for both readers (Reader 1, p = 0.0131; Reader 2, p = 0.0006). CONCLUSION: Multiphasic dynamic contrast-enhanced MDCT can help differentiate EGC-Us from AGCs. KEY POINTS: * Early gastric cancer with ulceration and advanced gastric cancer have similar endoscopic appearances. * EGC-U shows significantly lower attenuation values in both arterial and portal phases. * Multiphasic dynamic contrast enhanced MDCT differentiates EGC-U from AGC. PMID- 26242585 TI - Intravenous fenoldopam for acute kidney injury. PMID- 26242584 TI - Elevated body swing test after focal cerebral ischemia in rodents: methodological considerations. AB - BACKGROUND: The elevated body swing test (EBST) is a behavioral test used to evaluate experimental stroke in rodents. The basic idea is that when the animal is suspended vertically by the tail, it will swing its head laterally to the left or right depending on lesion side. In a previous study from our lab using the EBST after middle cerebral artery occlusion (MCAo), rats swung contralateral to the infarct day 1 post-MCAo, but ipsilateral day 3 post-MCAo. This shift was unexpected and prompted us to perform the present study. First, the literature was systematically reviewed to elucidate whether a similar shift had been noticed before, and if consensus existed regarding swing direction. Secondly, an experiment was conducted to systematically investigate the suggested behavior. Eighty-three adult male and female Sprague-Dawley rats were subjected to MCAo or sham surgery and the EBST was performed up to 7 days after the lesion. RESULTS: Both experimentally and through systematic literature review, the present study shows that the direction of biased swing activity in the EBST for rodents after cerebral ischemia can differ and even shift over time in some situations. The EBST curve for females was significantly different from that of males after the same occlusion time (p = 0.023). CONCLUSIONS: This study highlights the importance of adequate reporting of behavioral tests for lateralization and it is concluded that the EBST cannot be recommended as a test for motor asymmetry after MCAo in rats. PMID- 26242587 TI - Strengthening tactical planning and operational frameworks for vector control: the roadmap for malaria elimination in Namibia. AB - BACKGROUND: Namibia has made tremendous gains in malaria control and the epidemiological trend of the disease has changed significantly over the past years. In 2010, the country reoriented from the objective of reducing disease morbidity and mortality to the goal of achieving malaria elimination by 2020. This manuscript outlines the processes undertaken in strengthening tactical planning and operational frameworks for vector control to facilitate expeditious malaria elimination in Namibia. CASE DESCRIPTION: The information sources for this study included all available data and accessible archived documentary records on malaria vector control in Namibia. A methodical assessment of published and unpublished documents was conducted via a literature search of online electronic databases, Google Scholar, PubMed and WHO, using a combination of search terms. DISCUSSION AND EVALUATION: To attain the goal of elimination in Namibia, systems are being strengthened to identify and clear all infections, and significantly reduce human-mosquito contact. Particularly, consolidating vector control for reducing transmission at the identified malaria foci will be critical for accelerated malaria elimination. Thus, guarding against potential challenges and the need for evidence-based and sustainable vector control instigated the strengthening of strategic frameworks by: adopting the integrated vector management (IVM) strategy; initiating implementation of the global plan for insecticide resistance management (GPIRM); intensifying malaria vector surveillance; improving data collection and reporting systems on DDT; updating the indoor residual spraying (IRS) data collection and reporting tool; and, improving geographical reconnaissance using geographical information system-based satellite imagery. CONCLUSIONS: Universal coverage with IRS and long-lasting insecticidal nets, supplemented by larval source management in the context of IVM and guided by vector surveillance coupled with rational operationalization of the GPIRM, will enable expeditious attainment of elimination in Namibia. However, national capacity to plan, implement, monitor and evaluate interventions will require adequate and sustained support for technical, physical infrastructure, and human and financial resources for entomology and vector control operations. PMID- 26242588 TI - An alkaline follicular fluid fraction induces capacitation and limited release of oviduct epithelium-bound stallion sperm. AB - Induction of hyperactivated motility is considered essential for triggering the release of oviduct-bound mammalian spermatozoa in preparation for fertilization. In this study, oviduct-bound stallion spermatozoa were exposed for 2 h to: i) pre ovulatory and ii) post-ovulatory oviductal fluid; iii) 100% and iv) 10% follicular fluid (FF); v) cumulus cells, vi) mature equine oocytes, vii) capacitating and viii) non-capacitating medium. None of these triggered sperm release or hyperactivated motility. Interestingly, native FF was detrimental to sperm viability, an effect that was negated by heat inactivation, charcoal treatment and 30 kDa filtration alone or in combination. Moreover, sperm suspensions exposed to treated FF at pH 7.9 but not pH 7.4 showed Ca(2+) dependent hypermotility. Fluo-4 AM staining of sperm showed elevated cytoplasmic Ca(2+) in hyperactivated stallion spermatozoa exposed to treated FF at pH 7.9 compared to a modest response in defined capacitating conditions at pH 7.9 and no response in treated FF at pH 7.4. Moreover, 1 h incubation in alkaline, treated FF induced protein tyrosine phosphorylation in 20% of spermatozoa. None of the conditions tested induced widespread release of sperm pre-bound to oviduct epithelium. However, the hyperactivating conditions did induce release of 70-120 spermatozoa per oviduct explant, of which 48% showed protein tyrosine phosphorylation and all were acrosome-intact, but capable of acrosomal exocytosis in response to calcium ionophore. We conclude that, in the presence of elevated pH and extracellular Ca(2+), a heat-resistant, hydrophilic, <30 kDa component of FF can trigger protein tyrosine phosphorylation, elevated cytoplasmic Ca(2+) and hyperactivated motility in stallion sperm, but infrequent release of sperm pre bound to oviduct epithelium. PMID- 26242589 TI - Automated prostate cancer detection via comprehensive multi-parametric magnetic resonance imaging texture feature models. AB - BACKGROUND: Prostate cancer is the most common form of cancer and the second leading cause of cancer death in North America. Auto-detection of prostate cancer can play a major role in early detection of prostate cancer, which has a significant impact on patient survival rates. While multi-parametric magnetic resonance imaging (MP-MRI) has shown promise in diagnosis of prostate cancer, the existing auto-detection algorithms do not take advantage of abundance of data available in MP-MRI to improve detection accuracy. The goal of this research was to design a radiomics-based auto-detection method for prostate cancer via utilizing MP-MRI data. METHODS: In this work, we present new MP-MRI texture feature models for radiomics-driven detection of prostate cancer. In addition to commonly used non-invasive imaging sequences in conventional MP-MRI, namely T2 weighted MRI (T2w) and diffusion-weighted imaging (DWI), our proposed MP-MRI texture feature models incorporate computed high-b DWI (CHB-DWI) and a new diffusion imaging modality called correlated diffusion imaging (CDI). Moreover, the proposed texture feature models incorporate features from individual b-value images. A comprehensive set of texture features was calculated for both the conventional MP-MRI and new MP-MRI texture feature models. We performed feature selection analysis for each individual modality and then combined best features from each modality to construct the optimized texture feature models. RESULTS: The performance of the proposed MP-MRI texture feature models was evaluated via leave-one-patient-out cross-validation using a support vector machine (SVM) classifier trained on 40,975 cancerous and healthy tissue samples obtained from real clinical MP-MRI datasets. The proposed MP-MRI texture feature models outperformed the conventional model (i.e., T2w+DWI) with regard to cancer detection accuracy. CONCLUSIONS: Comprehensive texture feature models were developed for improved radiomics-driven detection of prostate cancer using MP MRI. Using a comprehensive set of texture features and a feature selection method, optimal texture feature models were constructed that improved the prostate cancer auto-detection significantly compared to conventional MP-MRI texture feature models. PMID- 26242590 TI - Stochastic resource allocation in emergency departments with a multi-objective simulation optimization algorithm. AB - The number of emergency cases or emergency room visits rapidly increases annually, thus leading to an imbalance in supply and demand and to the long-term overcrowding of hospital emergency departments (EDs). However, current solutions to increase medical resources and improve the handling of patient needs are either impractical or infeasible in the Taiwanese environment. Therefore, EDs must optimize resource allocation given limited medical resources to minimize the average length of stay of patients and medical resource waste costs. This study constructs a multi-objective mathematical model for medical resource allocation in EDs in accordance with emergency flow or procedure. The proposed mathematical model is complex and difficult to solve because its performance value is stochastic; furthermore, the model considers both objectives simultaneously. Thus, this study develops a multi-objective simulation optimization algorithm by integrating a non-dominated sorting genetic algorithm II (NSGA II) with multi objective computing budget allocation (MOCBA) to address the challenges of multi objective medical resource allocation. NSGA II is used to investigate plausible solutions for medical resource allocation, and MOCBA identifies effective sets of feasible Pareto (non-dominated) medical resource allocation solutions in addition to effectively allocating simulation or computation budgets. The discrete event simulation model of ED flow is inspired by a Taiwan hospital case and is constructed to estimate the expected performance values of each medical allocation solution as obtained through NSGA II. Finally, computational experiments are performed to verify the effectiveness and performance of the integrated NSGA II and MOCBA method, as well as to derive non-dominated medical resource allocation solutions from the algorithms. PMID- 26242591 TI - Forensic DNA Evidence at a Crime Scene: An Investigator's Commentary. AB - The purpose of this article is twofold. The first is to present a law enforcement perspective of the importance of a crime scene, the value of probative evidence, and how to properly recognize, document, and collect evidence. The second purpose is to provide forensic scientists who primarily work in laboratories with the ability to gain insight on how law enforcement personnel process a crime scene. With all the technological advances in the various disciplines associated with forensic science, none have been more spectacular than those in the field of DNA. The development of sophisticated and sensitive instrumentation has led forensic scientists to be able to detect DNA profiles from minute samples of evidence in a much timelier manner. In forensic laboratories, safeguards and protocols associated with ASCLD/LAB International, Forensic Quality Services, and or ISO/IEC 17020:1998 accreditation have been established and implemented to ensure proper case analysis. But no scientist, no instrumentation, and no laboratory could come to a successful conclusion about evidence if that evidence had been compromised or simply missed at a crime scene. Evidence collectors must be trained thoroughly to process a scene and to be able to distinguish between probative evidence and non probative evidence. I am a firm believer of the phrase "garbage in is garbage out." One of the evidence collector's main goals is not only to recover enough DNA so that an eligible CODIS profile can be generated to identify an offender but also, more importantly, to recover sufficient DNA to exonerate the innocent. PMID- 26242592 TI - Optimizing Storage and Handling of DNA Extracts. AB - Nucleic acid sample storage is of paramount importance in forensic science as well as in epidemiological, clinical, and genetic laboratories. Millions of biological samples, including cells, viruses, and DNA/RNA, are stored every year for diagnostics, research, and forensic science. PCR has permitted the analysis of minute sample quantities. Samples such as bone, teeth, touch samples, and some sexual assault evidence may yield only low-quality and low-quantity DNA/RNA. Efficient storage of the extracted DNA/RNA is needed to ensure the stability of the sample over time for retesting of the CODIS STRs, mtDNA, YSTRs, mRNA, and other future marker-typing systems. Amplification of some or all of these markers may fail because the biological material has been highly degraded, contains inhibitors, is too low in quantity, or is contaminated with contemporary DNA. Reduction in recovery has been observed with refrigerated liquid DNA extracts and also those exposed to multiple freeze-thaw cycles. Therefore, the development of optimal storage and amplification methods is critical for successful recovery of profiles from these types of samples since, in many cases, retesting is necessary. This review is divided into three sections. The Introduction and Background covers forensic DNA storage, factors that influence DNA stability, and a brief review of molecular strategies to type non-optimal DNA. Section I covers the importance of DNA extract storage in forensic and non-forensic DNA databanks and the mechanisms responsible for loss during storage. Finally, Section II covers strategies and technologies being utilized to store DNA. PMID- 26242593 TI - RNA Profiling for the Identification of the Tissue Origin of Dried Stains in Forensic Biology. AB - Examination of crime scene items for biological evidence typically begins with a preliminary screening for the presence of biological fluids in order to identify possible sources of DNA. Conventional biochemical and immunological assays employed for this screening require multiple tests to be performed in a serial manner, can consume a significant amount of valuable evidentiary material, and can require a significant amount of time and labor for completion. Moreover, the presence of several biological fluids, such as saliva, vaginal secretions, and menstrual blood, cannot be conclusively identified using current methods. Due to the disadvantages of conventional body fluid testing, some operational crime laboratories have chosen to bypass the body fluid identification process and proceed directly to DNA analysis. However, while reducing the time spent on each case, this "shortcut" could result in a failure to provide important probative information regarding the nature of the crime as well as result in increased cost to crime laboratories if unnecessary DNA testing is performed. In the past several years, a number of forensic researchers have attempted to develop molecular-based approaches to body fluid identification that would provide operational crime laboratories with significantly improved specificity. This has resulted in an increased interest in the use of RNA profiling strategies for the identification of forensically relevant biological fluids. This review provides an overview of studies carried out on the use of both messenger RNA and small (micro) RNA profiling. The results of these studies are encouraging and presage the routine identification the tissue source(s) of forensic evidence using molecular-based approaches. PMID- 26242594 TI - Extraction of DNA from Forensic Biological Samples for Genotyping. AB - Biological forensic samples constitute evidence with probative organic matter. Evidence believed to contain DNA is typically processed for extraction and purification of its nucleic acid content. Forensic DNA samples are composed of two things, a tissue and the substrate it resides on. Compositionally, a sample may contain almost anything and for each, the type, integrity, and content of both tissue and substrate will vary, as will the contaminant levels. This fact makes the success of extraction one of the most unpredictable steps in genotypic analysis. The development of robust genotyping systems and analysis platforms for short tandem repeat (STR) and mitochondrial DNA sequencing and the acceptance of results generated by these methods in the court system, resulted in a high demand for DNA testing. The increasing variety of sample submissions created a need to isolate DNA from forensic samples that may be compromised or contain low levels of biological material. In the past decade, several robust chemistries and isolation methods have been developed to safely and reliably recover DNA from a wide array of sample types in high yield and free of PCR inhibitors. In addition, high-throughput automated workflows have been developed to meet the demand for processing increasing numbers of samples. This review summarizes a number of the most widely adopted methods and the best practices for DNA isolation from forensic biological samples, including manual, semiautomated, and fully automated platforms. PMID- 26242595 TI - Extraction of DNA from Human Remains. AB - Improvements to analytical methods have made it possible for highly discriminative genotypic information to be gleaned from smaller and smaller amounts of sample material. This fact makes it practical to genotype samples or remains consisting of bone and tooth-samples that likely would not have yielded interpretable genotypic results a short time ago. In parallel, there have been improvements to protocols specifically designed to recover DNA from very old calcified tissues, i.e., ancient or compromised nature. This review discusses the current best practices for isolating and purifying DNA from bones and teeth with a focus on the processes of lysis and DNA purification linked together to yield DNA from these challenging samples. The mitochondrial and genomic DNA recovered from more recently developed techniques for isolation from skeletal remains and teeth, even very old samples, is surprisingly amenable to genotypic analysis. PMID- 26242596 TI - DNA Extraction on Microfluidic Devices. AB - Purification of DNA is a critical step of the genetic analysis process, particularly when the interrogation of forensic samples, often contaminated by exogenous and endogenous inhibitors, is considered. Recently, examples of microfluidic DNA purification strategies are becoming more prolific, with successful extraction of DNA from a variety of forensically relevant targets demonstrated using these microscale techniques and systems. From silica-based purification strategies that mimic their macroscale counterparts, to novel functionally derivatized systems, these purification tools represent the newest schemes for rapid, automated, closed-system sample processing that can integrate seamlessly with downstream microscale analysis techniques. The work presented herein highlights the development of novel microscale purification systems for extraction of DNA, their potential application in forensic analysis, and their potential for future incorporation in micro total analysis systems (uTAS). PMID- 26242597 TI - Assessment of DNA Extracted from Forensic Samples Prior to Genotyping. AB - Quantification of human DNA has been an integral part of forensic DNA analysis. Hybridizationbased methods such as Quantiblot(r) kits were used extensively in the 1990s. These methods fulfilled the need at the time, since their sensitivity range was similar to the genotyping methods in use, such as restricted fragment length polymorphism. Later, the development of robust and more sensitive megaplex genotyping systems such as short tandem repeat profiling, mitochondrial DNA sequencing, and single nucleotide polymorphism typing, created the need not only for quantification of DNA at the picogram level but also for assessment of the quality of the DNA extract to make informed decisions to ensure the success of downstream analysis. Real-time PCR-based quantification methods fulfilled this need. The different real-time PCR methods developed range from singleplex reactions for quantification of human or mitochondrial DNA to multiplex systems that enable analysis of up to four targets for quantification of human DNA, human male DNA, mitochondrial DNA, detection of PCR inhibitors, or determination of the extent of DNA degradation. Incorporation of these assays into the workflow enables selection of appropriate genotyping systems and increases the first-pass success rate for obtaining a genotype using a minimal amount of evidence sample. The real-time PCR methods described here would also be useful as DNA assessment tools prior to other genotyping methods like copy number variation, insertion/deletion, and Alu dimorphism analysis as well as sequencing, etc., that are currently being investigated as additional informative tools for human identification purposes. PMID- 26242598 TI - CD11c(+) monocyte/macrophages promote chronic Helicobacter hepaticus-induced intestinal inflammation through the production of IL-23. AB - In inflammatory bowel diseases, a breakdown in host microbial interactions accompanies sustained activation of immune cells in the gut. Functional studies suggest a key role for interleukin-23 (IL-23) in orchestrating intestinal inflammation. IL-23 can be produced by various mononuclear phagocytes (MNPs) following acute microbial stimulation, but little is known about the key cellular sources of IL-23 that drive chronic intestinal inflammation. Here we have addressed this question using a physiological model of bacteria-driven colitis. By combining conditional gene ablation and gene expression profiling, we found that IL-23 production by CD11c(+) MNPs was essential to trigger intestinal immunopathology and identified MHCII(+) monocytes and macrophages as the major source of IL-23. Expression of IL-23 by monocytes was acquired during their differentiation in the intestine and correlated with the expression of major histocompatibility complex class II (MHCII) and CD64. In contrast, Batf3 dependent CD103(+) CD11b(-) dendritic cells were dispensable for bacteria-induced colitis in this model. These studies reinforce the pathogenic role of monocytes in dysregulated responses to intestinal bacteria and identify production of IL-23 as a key component of this response. Further understanding of the functional sources of IL-23 in diverse forms of intestinal inflammation may lead to novel therapeutic strategies aimed at interrupting IL-23-driven immune pathology. PMID- 26242600 TI - Annular ligament reconstruction by suture anchor for treatment of radial head dislocation in children. AB - BACKGROUND: We investigated the efficacy of annular ligament reconstruction by suture anchor in the treatment of radial head dislocation (RHD) in children. METHOD: A total of 20 RHD children nderwent annular ligament reconstruction surgery using suture anchor. Preoperative and postoperative elbow functions were evaluated according to Broberg and Morrey 100-point scale. Recovery of radial nerve function was assessed using the Chinese Medical Association of Hand Surgery Branch of Upper Limb Functional Assessment Standard. All statistical analyses were performed using SPSS version 17.0 software. RESULTS: All 20 RHD children who underwent the procedure were followed up for a median duration of 24 months. At the last follow-up, the average Broberg-Morrey score was 94.3, with 12 children (60.0%) showing excellent outcomes (score range, 95 to 100), 7 children (35.0%) showing good outcomes (score range, 80 to 94), 1 child (5.0%) displayed a fair outcome (score range, 60 to 79), and 0 (0%) poor outcome. A significant difference in the excellent-good rate was observed when the elbow function before surgery was compared to after surgery (chi(2) = 5.559, P = 0.018). The radial nerve function of the 13 RHD children with radial nerve injury also recovered to normal. Among these 13 RHD children, nine exhibited excellent outcomes, 3 showed good outcomes, 1 displayed a fair outcome, and no patient showed a poor outcome. A significant difference in the excellent-good rate of radial nerve function was also observed when before surgery was compared to after surgery in these RHD children (chi(2) = 4.887, P = 0.027). CONCLUSION: Our results strongly indicated that suture anchor is highly effective for reconstruction of the annular ligament and to promote full functional recovery in RHD children, demonstrating that the procedure is an excellent treatment choice in RHD children. PMID- 26242599 TI - The function and affinity maturation of HIV-1 gp120-specific monoclonal antibodies derived from colostral B cells. AB - Despite the risk of transmitting HIV-1, mothers in resource-poor areas are encouraged to breastfeed their infants because of beneficial immunologic and nutritional factors in milk. Interestingly, in the absence of antiretroviral prophylaxis, the overwhelming majority of HIV-1-exposed, breastfeeding infants are naturally protected from infection. To understand the role of HIV-1 envelope (Env)-specific antibodies in breast milk in natural protection against infant virus transmission, we produced 19 HIV-1 Env-specific monoclonal antibodies (mAbs) isolated from colostrum B cells of HIV-1-infected mothers and investigated their specificity, evolution, and anti-HIV-1 functions. Despite the previously reported genetic compartmentalization and gp120-specific bias of colostrum HIV Env-specific B cells, the colostrum Env-specific mAbs described here demonstrated a broad range of gp120 epitope specificities and functions, including inhibition of epithelial cell binding and dendritic cell-mediated virus transfer, neutralization, and antibody-dependent cellular cytotoxicity. We also identified divergent patterns of colostrum Env-specific B-cell lineage evolution with respect to crossreactivity to gastrointestinal commensal bacteria, indicating that commensal bacterial antigens play a role in shaping the local breast milk immunoglobulin G (IgG) repertoire. Maternal vaccine strategies to specifically target this breast milk B-cell population may be necessary to achieve safe breastfeeding for all HIV-1-exposed infants. PMID- 26242601 TI - A Model of Genome Size Evolution for Prokaryotes in Stable and Fluctuating Environments. AB - Temporal variability in ecosystems significantly impacts species diversity and ecosystem productivity and therefore the evolution of organisms. Different levels of environmental perturbations such as seasonal fluctuations, natural disasters, and global change have different impacts on organisms and therefore their ability to acclimatize and adapt. Thus, to understand how organisms evolve under different perturbations is a key for predicting how environmental change will impact species diversity and ecosystem productivity. Here, we developed a computer simulation utilizing the individual-based model approach to investigate genome size evolution of a haploid, clonal and free-living prokaryotic population across different levels of environmental perturbations. Our results show that a greater variability of the environment resulted in genomes with a larger number of genes. Environmental perturbations were more effectively buffered by populations of individuals with relatively large genomes. Unpredictable changes of the environment led to a series of population bottlenecks followed by adaptive radiations. Our model shows that the evolution of genome size is indirectly driven by the temporal variability of the environment. This complements the effects of natural selection directly acting on genome optimization. Furthermore, species that have evolved in relatively stable environments may face the greatest risk of extinction under global change as genome streamlining genetically constrains their ability to acclimatize to the new environmental conditions, unless mechanisms of genetic diversification such as horizontal gene transfer will enrich their gene pool and therefore their potential to adapt. PMID- 26242602 TI - Human toxoplasmosis: a comparative evaluation of the diagnostic potential of recombinant Toxoplasma gondii ROP5 and ROP18 antigens. AB - Toxoplasmosis is one of the most common parasitic diseases worldwide and it poses a serious challenge regarding prevention, diagnosis and therapy. The commonly used diagnostic methods are mostly based on the detection of specific antibodies in sera. Since they are not always accurate enough and do not allow precise definition of the phase of the Toxoplasma gondii infection, there is an urgent need to find specific molecular markers of acute or chronic infection stages. This study provides a comparative assessment of recombinant ROP5 and ROP18 T. gondii proteins in the serodiagnosis of human toxoplasmosis. We found that both ROP5 and ROP18 proteins allowed the detection of specific IgM and IgG antibodies with a relatively low sensitivity; however, ROP18 IgM ELISA proved to be more sensitive than the SAG1 assay. This study also points to a relatively weak potential of the corresponding native ROP5 and ROP18 kinases in the generation of a strong antibody response in humans. PMID- 26242604 TI - Spatial Analysis of Metal Profiles in Sediments in a Tropical Estuary: A Geostatistical Approach. AB - The spatial structure and distribution of heavy metals [cadmium (Cd), copper (Cu), iron (Fe), lead (Pb), and nickel (Ni)] in sediments were geostatistically analyzed along the estuarine ecosystem of Tigre River-San Andres Lagoon (Tamaulipas, Mexico). In most cases, heavy-metal concentrations exhibited a strong spatial autocorrelation along the estuary as indicated by variogram analysis. Heavy-metal concentrations were found to be higher in the middle estuary, close to the mouth of the Tigre River, and declined as distance from the mouth increased. Metal mean levels at the middle estuary were 2.41 mg/kg Cd, 4.80 mg/kg Cu, 172.36 mg/kg Fe, 5.22 mg/kg Pb, and 2.10 mg/kg Ni. The spatial distribution of heavy metals suggests the existence of a common heavy-metal source located in this area of the estuary. The importance of wastewater discharges and open dumping in the town of El Moron, adjacent to the mouth of the Tigre River, is highlighted; these are believed to be the anthropogenic sources for heavy metals in this estuarine ecosystem. PMID- 26242605 TI - Sketchbooks & Sutures: A Blog about Learning to Heal. PMID- 26242603 TI - Effects of the interaction between TiO2 with different percentages of exposed {001} facets and Cu(2+) on biotoxicity in Daphnia magna. AB - Anatase TiO2 nanosheets (NSs) with exposed {001} facets have been widely used because of their high activity and particular surface atomic configuration. However, investigations on their biotoxicity are rare. In this study, bioaccumulation of five different TiO2 (with 10%, 61%, 71%, 74% and 78% exposed {001} facets), as well as copper and enzyme activities in Daphnia magna, are systematically investigated and rationalized. The results indicated that the addition of Cu(2+) enhanced agglomeration-sedimentation of TiO2, resulting in the reduction of TiO2 bioaccumulation by 10% to 26%. TiO2 nanoparticles (NPs) increased copper bioaccumulation by 9.8%, whereas the other four TiO2 nanosheets (NSs) decreased it by 43% to 53%, which depended on TiO2 variant adsorption and free Cu(2+) concentrations in the supernatant. The levels of superoxide dismutase (SOD) enzyme and Na(+)/K(+)-ATPase activities suggested that oxidative stress, instead of membrane damage, was the main toxicity in D. magna. Meanwhile, the SOD enzyme activities increased with decreasing Cu accumulation and increasing Ti accumulation because of the different functions of Cu and Ti in organisms. This research highlighted the important role of the percentage of exposed {001} facets in nanostructured TiO2 on bioaccumulation and biotoxicity of TiO2 and Cu(2+) in Daphnia magna. PMID- 26242606 TI - Neurodharma Self-Help: Personalized Science Communication as Brain Management. AB - Over the past ten to fifteen years, medical interventions, therapeutic approaches and scientific studies involving mindfulness meditation have gained traction in areas such as clinical psychology, psychotherapy, and neuroscience. Simultaneously, mindfulness has had a very strong public appeal. This article examines some of the ways in which the medical and scientific meaning of mindfulness is communicated in public and to the public. In particular, it shows how experts in the field of mindfulness neuroscience seek to communicate to the public at large the imperative of brain fitness for the promotion of health, wellbeing and happiness. The study identifies claims being made in popular outlets that, by and large, bypass traditional mass media, such as self-help books, websites and online videos. By treating this material as a form of personalized science communication, this article contributes to the body of literature that understands science communication as a continuum and the boundary between science and popularized science as the outcome of human negotiations. The study finds that processes of personalization help to build bridges between scientific findings and their supposed application, that they infuse science with subjective meaning, and turn expert communication with the public into a moral vocation. PMID- 26242607 TI - Adolescent Daughters and Ritual Abjection: Narrative Analysis of Self-injury in Four US Films. AB - Media representations of illnesses, particularly those associated with stigma such as non-suicidal self-injury (NSSI), not only define health conditions for mass audiences, but generally do so in ways that are consistent with dominant ideologies. This article examines the construction of non-suicidal self-injury as practiced by female adolescents and young adults in four US films: Girl, Interrupted, Painful Secrets, Prozac Nation, and Thirteen. The methodology used to examine the films' narrative structure is Kenneth Burke's dramatism, while Julia Kristeva's concept of abjection informs the analysis. On one hand, a paradigmatic reading suggests that the films frame self-injury as resistance to repressive maternal domination of female adolescents. On the other hand, syntagmatic analysis reveals a privileged response to NSSI in the form of pacification administered by psychotherapists functioning as the return of the phallic-mother fantasy. PMID- 26242608 TI - Stimulus probability effects on temporal bisection performance of mice (Mus musculus). AB - In the temporal bisection task, participants classify experienced stimulus durations as short or long based on their temporal similarity to previously learned reference durations. Temporal decision making in this task should be influenced by the experienced probabilities of the reference durations for adaptiveness. In this study, we tested the temporal bisection performance of mice (Mus musculus) under different short and long reference duration probability conditions implemented across two experimental phases. In Phase 1, the proportion of reference durations (compared to probe durations) was 0.5, whereas in Phase 2 it was increased to 0.8 to further examine the adjustment of choice behavior with more frequent reference duration presentations (under higher reinforcement rate). Our findings suggest that mice developed adaptive biases in their choice behaviors. These adjustments in choice behavior were nearly optimal as the mice maximized their gain to a great extent which required them to monitor stimulus probabilities as well as the level of variability in their temporal judgments. We further found that short but not long categorization response times were sensitive to stimulus probability manipulations, which in turn suggests an asymmetry between short and long categorizations. Finally, we investigated the latent decision processes underlying the bias manifested in subjects' choice behavior within the diffusion model framework. Our results revealed that probabilistic information influenced the starting point and the rate of evidence accumulation process. Overall, the stimulus probability effects on choice behavior were modulated by the reinforcement rate. Our findings illustrate that mice can adapt their temporal behaviors with respect to the probabilistic contingencies in the environment. PMID- 26242609 TI - Caching in the presence of competitors: Are Cape ground squirrels (Xerus inauris) sensitive to audience attentiveness? AB - When social animals cache food close to their burrow, the potential for an audience member to observe the event is significantly increased. As a consequence, in order to reduce theft it may be advantageous for animals to be sensitive to certain audience cues, such as whether they are attentive or not to the cache event. In this study, observations were made on three groups of Cape ground squirrels (Xerus inauris) in their natural habitat when they cached provisioned food items. When individuals cached within 10 m of conspecifics, we recorded the attentiveness (i.e. whether any audience members were orientated towards the cacher, had direct line of site and were not engaged in other activities) and identity of audience members. Overall, there was a preference to cache when audience members were inattentive rather than attentive. Additionally, we found rank effects related to cache avoidance whereby high-ranked individuals showed less avoidance to cache when audience members were attentive compared to medium- and low-ranked individuals. We suggest this audience sensitivity may have evolved in response to the difference in competitive ability amongst the ranks in how successful individuals are at winning foraging competitions. This study demonstrates that Cape ground squirrels have the ability to not only monitor the presence or absence of conspecifics but also discriminate individuals on the basis of their attentive state. PMID- 26242610 TI - Mismatched changes of the photoluminescence and crystalline structure of a mechanochromic gold(I) isocyanide complex. AB - The mechanochromic compound 1 forms green-emitting crystals (1g) and blue emitting crystals (1b) that exhibit two intriguing responses to mechanical stimulation. Upon mechanical stimulation, the emission color of 1g does not change but its crystalline structure does. Conversely, 1b shows a clear emission shift, but it retains its molecular arrangement upon grinding. PMID- 26242611 TI - CRISPR/Cas9-based generation of knockdown mice by intronic insertion of artificial microRNA using longer single-stranded DNA. AB - Knockdown mouse models, where gene dosages can be modulated, provide valuable insights into gene function. Typically, such models are generated by embryonic stem (ES) cell-based targeted insertion, or pronuclear injection, of the knockdown expression cassette. However, these methods are associated with laborious and time-consuming steps, such as the generation of large constructs with elements needed for expression of a functional RNAi-cassette, ES-cell handling, or screening for mice with the desired knockdown effect. Here, we demonstrate that reliable knockdown models can be generated by targeted insertion of artificial microRNA (amiRNA) sequences into a specific locus in the genome [such as intronic regions of endogenous eukaryotic translation elongation factor 2 (eEF-2) gene] using the Clustered Regularly Interspaced Short Palindromic Repeats/Crispr associated 9 (CRISPR/Cas9) system. We used in vitro synthesized single-stranded DNAs (about 0.5-kb long) that code for amiRNA sequences as repair templates in CRISPR/Cas9 mutagenesis. Using this approach we demonstrate that amiRNA cassettes against exogenous (eGFP) or endogenous [orthodenticle homeobox 2 (Otx2)] genes can be efficiently targeted to a predetermined locus in the genome and result in knockdown of gene expression. We also provide a strategy to establish conditional knockdown models with this method. PMID- 26242612 TI - Migration, Multiple Sexual Partnerships, and Sexual Concurrency in the Garifuna Population of Honduras. AB - The Garifuna, an ethnic minority group in Honduras, have been disproportionately affected by HIV. Previous research suggests that migration and high rates of multiple sexual partnerships are major drivers of the epidemic. Using data from a 2012 population-based survey, we assessed whether temporary migration was associated with (1) multiple sexual partnerships and (2) sexual concurrency among Garifuna men and women in Honduras. Among both men and women, temporary migration in the last year was associated with an increased likelihood of multiple sexual partnerships and with concurrency, though only the association between migration and multiple sexual partnerships among men was statistically significant (Adjusted Prevalence Ratio 1.7, 95 % CI 1.2-2.4). Migration may contribute to HIV/STI vulnerability among Garifuna men and women via increases in these sexual risk behaviors. Research conducted among men and women at elevated risk of HIV should continue to incorporate measures of mobility, including history of internal migration. PMID- 26242614 TI - Attitude towards technology, social media usage and grade-point average as predictors of global citizenship identification in Filipino University Students. AB - We examine the influence of a positive attitude towards technology, number of social media network memberships and grade-point average (GPA) on global citizenship identification antecedents and outcomes. Students (N = 3628) at a university in the Philippines completed a survey assessing the above constructs. The results showed that attitude towards technology, number of social network site memberships and GPA-predicted global citizenship identification, and subsequent prosocial outcomes (e.g. intergroup helping, responsibility to act for the betterment of the world), through the perception that valued others prescribe a global citizen identity (normative environment) and perceived knowledge of the world and felt interconnectedness with others (global awareness). The results highlight the associations between technology and academic performance with a global identity and associated values. PMID- 26242613 TI - Parameter estimation in Cox models with missing failure indicators and the OPPERA study. AB - In a prospective cohort study, examining all participants for incidence of the condition of interest may be prohibitively expensive. For example, the "gold standard" for diagnosing temporomandibular disorder (TMD) is a physical examination by a trained clinician. In large studies, examining all participants in this manner is infeasible. Instead, it is common to use questionnaires to screen for incidence of TMD and perform the "gold standard" examination only on participants who screen positively. Unfortunately, some participants may leave the study before receiving the "gold standard" examination. Within the framework of survival analysis, this results in missing failure indicators. Motivated by the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study, a large cohort study of TMD, we propose a method for parameter estimation in survival models with missing failure indicators. We estimate the probability of being an incident case for those lacking a "gold standard" examination using logistic regression. These estimated probabilities are used to generate multiple imputations of case status for each missing examination that are combined with observed data in appropriate regression models. The variance introduced by the procedure is estimated using multiple imputation. The method can be used to estimate both regression coefficients in Cox proportional hazard models as well as incidence rates using Poisson regression. We simulate data with missing failure indicators and show that our method performs as well as or better than competing methods. Finally, we apply the proposed method to data from the OPPERA study. PMID- 26242615 TI - Safety of Perflutren Ultrasound Contrast Agents: A Disproportionality Analysis of the US FAERS Database. AB - INTRODUCTION: Perflutren microbubble/microsphere ultrasound contrast agents have a black-box warning based on case reports of serious cardiopulmonary events. There have been several subsequent observational safety studies. Large spontaneous reporting databases may help detect/refine signals of rare adverse events that elude other data sources/study designs. OBJECTIVE: The objective of this study was to supplement existing knowledge of the reported safety of perflutren using statistical analysis of spontaneous reports. METHODS: We analyzed information from the US Food and Drug Administration Adverse Event Reporting System using a disproportionality analysis. Analysis of overall reporting for perflutren was supplemented by subset (age, indication) analysis. A signal of disproportionate reporting (SDR) was defined as EB05 >2. RESULTS: Overall, 18/380 Preferred Terms and 1/83 Standardized Medical Queries had SDRs. Most were small (EB05 = 2-4). Back pain and flank pain were the largest SDRs followed by events compatible with signs/symptoms of hypersensitivity. The general pattern of SDRs in the subset analysis was consistent with the overall analysis. Almost all events with SDRs were literally or conceptually labeled. Except for chest pain (higher in the age <65 years subgroup) and back pain (higher in the age >=65 years subgroup), there were no statistically significant differences between age subsets. Except for the Preferred Terms Pruritus and Urticaria and the narrow Standardized Medical Queries Ventricular tachyarrhythmia, Angioedema, Oropharyngeal allergic conditions, and Hypersensitivity (higher in the stress test subgroup), there were no statistically significant reporting differences between indication subsets. There were no SDRs associated with the major cardiovascular events of death, myocardial infarction/ischemia, angina, arrhythmias, or convulsions in any analysis. CONCLUSIONS: Our combined signal detection/evaluation analysis did not identify SDRs of novel adverse events or major cardiovascular events associated with perflutren ultrasound contrast agents. The negative results for major cardiovascular events extend previous signal evaluation exercises supporting the relative cardiovascular safety of these agents. PMID- 26242616 TI - Evaluating Social Media Networks in Medicines Safety Surveillance: Two Case Studies. AB - INTRODUCTION: There is growing interest in whether social media can capture patient-generated information relevant for medicines safety surveillance that cannot be found in traditional sources. OBJECTIVE: The aim of this study was to evaluate the potential contribution of mining social media networks for medicines safety surveillance using the following associations as case studies: (1) rosiglitazone and cardiovascular events (i.e. stroke and myocardial infarction); and (2) human papilloma virus (HPV) vaccine and infertility. METHODS: We collected publicly accessible, English-language posts on Facebook, Google+, and Twitter until September 2014. Data were queried for co-occurrence of keywords related to the drug/vaccine and event of interest within a post. Messages were analysed with respect to geographical distribution, context, linking to other web content, and author's assertion regarding the supposed association. RESULTS: A total of 2537 posts related to rosiglitazone/cardiovascular events and 2236 posts related to HPV vaccine/infertility were retrieved, with the majority of posts representing data from Twitter (98 and 85%, respectively) and originating from users in the US. Approximately 21% of rosiglitazone-related posts and 84% of HPV vaccine-related posts referenced other web pages, mostly news items, law firms' websites, or blogs. Assertion analysis predominantly showed affirmation of the association of rosiglitazone/cardiovascular events (72%; n = 1821) and of HPV vaccine/infertility (79%; n = 1758). Only ten posts described personal accounts of rosiglitazone/cardiovascular adverse event experiences, and nine posts described HPV vaccine problems related to infertility. CONCLUSIONS: Publicly available data from the considered social media networks were sparse and largely untrackable for the purpose of providing early clues of safety concerns regarding the prespecified case studies. Further research investigating other case studies and exploring other social media platforms are necessary to further characterise the usefulness of social media for safety surveillance. PMID- 26242617 TI - Comment on: "Adverse Drug Reactions and Clinical Outcomes in Patients Initiated on Antiretroviral Therapy: A Prospective Cohort Study from Ethiopia". PMID- 26242618 TI - Authors' Reply to Cotton and Nicol's Comment on "Adverse Drug Reactions and Clinical Outcomes in Patients Initiated on Antiretroviral Therapy: A Prospective Cohort Study from Ethiopia". PMID- 26242619 TI - Unusual Mn coordination and redox chemistry in the high capacity borate cathode Li7Mn(BO3)3. AB - The recently discovered lithium-rich cathode material Li7Mn(BO3)3 has a high theoretical capacity and an unusual tetrahedral Mn(2+) coordination. Atomistic simulation and density functional theory (DFT) techniques are employed to provide insights into the defect and redox chemistry, the structural changes upon lithium extraction and the mechanisms of lithium ion diffusion. The most favourable intrinsic defects are Li/Mn anti-site pairs, where Li and Mn ions occupy interchanged positions, and Li Frenkel defects. DFT calculations reproduce the experimental cell voltage and confirm the presence of the unusually high Mn(V) redox state, which corresponds to a theoretical capacity of nearly 288 mA h g( 1). The ability to reach the high manganese oxidation state is related to both the initial tetrahedral coordination of Mn and the observed distortion/tilting of the BO3 units to accommodate the contraction of the Mn-O bonds upon oxidation. Molecular dynamics (MD) simulations indicate fast three-dimensional lithium diffusion in line with the good rate performance observed. PMID- 26242620 TI - Overcoming acquired drug resistance in colorectal cancer cells by targeted delivery of 5-FU with EGF grafted hollow mesoporous silica nanoparticles. AB - Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The effect and mechanism of 5-FU loaded EGF grafted HMSNs (EGF-HMSNs-5-FU) in overcoming acquired drug resistance in SW480/ADR cells were studied. The EGF-HMSNs were demonstrated to be specifically internalized in EGFR overexpressed SW480/ADR cells via a receptor mediated endocytosis and can escape from endo-lysosomes. The EGF-HMSNs-5-FU exhibited much higher cytotoxicity on SW480/ADR cells than HMSNs-5-FU and free 5 FU while the plain HMSNs did not show significant cytotoxicity. The mechanism of EGF-HMSNs-5-FU in overcoming drug resistance in SW480/ADR cells could be attributed to the specific internalization of EGF-HMSNs-5-FU in EGFR overexpressed cells which can lead to high intracellular drug accumulation and cause cell death through S phase arrest. PMID- 26242622 TI - Formation of Foam-like Microstructural Carbon Material by Carbonization of Porous Coordination Polymers through a Ligand-Assisted Foaming Process. AB - Porous carbon material with a foam-like microstructure has been synthesized by direct carbonization of porous coordination polymer (PCP). In situ generation of foaming agents by chemical reactions of ligands in PCP during carbonization provides a simple way to create lightweight carbon material with a foam-like microstructure. Among several substituents investigated, the nitro group has been shown to be the key to obtain the unique foam-like microstructure, which is due to the fast kinetics of gas evolution during carbonization. Foam-like microstructural carbon materials showed higher pore volume and specific capacitance compared to a microporous carbon. PMID- 26242621 TI - Role of (68)Ga-DOTATATE PET/CT in patients with multiple endocrine neoplasia type 1 (MEN1). AB - Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome predisposing to many endocrine and neuroendocrine tumors (NET). Conventional imaging (CI) cannot provide satisfactory results for all the different types of MEN1-related tumors. Objective of this prospective observational study was to evaluate the role of (68)Ga-DOTATATE PET/CT in MEN1 compared to CI. Diagnostic performance of (68)Ga-DOTATATE PET/CT for the detection of NET was evaluated as well as the prognostic role of SUVmax. Eighteen patients with genetically confirmed MEN1 were evaluated by (68)Ga-DOTATATE PET/CT, endoscopic ultrasounds, multidetector-row computed tomography, magnetic resonance imaging, and hormone/markers serum measurements. Four MEN1-related tumor sites (pancreas, pituitary, parathyroids, adrenals) were considered. Sensitivity and specificity of (68)Ga-DOTATATE PET/CT for the detection of NET were calculated. There was (68)Ga-DOTATATE PET/CT uptake in 11/11 patients with pancreatic lesions, in 9/12 with pituitary adenoma, in 5/15 with parathyroid enlargements, and in 5/7 with adrenal lesions. (68)Ga DOTATATE PET/CT showed sensitivity and specificity of 100 and 100 % in pancreas, 75 and 83 % in pituitary, 28 and 100 % in parathyroids, and 62.5 and 100 % in adrenals, respectively. Compared with CI, no significant difference in sensitivity for pancreas, pituitary, and adrenals was found, while CI had a better sensitivity for parathyroids (p = 0.002). On the ROC analysis, progression of pancreatic lesions was significantly associated to SUVmax <12.3 (p < 0.05). (68)Ga-DOTATATE PET/CT is greatly helpful in the work-up of MEN1 providing a panoramic view of MEN1-related lesions. There is also a prognostic role of (68)Ga PET in patients with MEN1-pancreatic lesions. PMID- 26242623 TI - Salts of highly fluorinated weakly coordinating anions as versatile precursors towards hydrogen storage materials. AB - We report the most recent results related to application of a metathetic pathway towards mixed-metal borohydrides. The synthetic protocol utilizes highly fluorinated weakly coordinating anion salts as precursors. We discuss the technicalities related to the use of fluorine-rich anions as well as the improvements which are still needed to deliver high-purity materials with potential applications for hydrogen storage. The applicability of the method is expanded beyond the previously described complex borohydrides of alkali metal Zn or Y, towards the systems containing Mg(II), Sc(III), Mn(II), or Eu(III). We have prepared for the first time [Ph4P]2[Mn(BH4)4] and [Me4N]2[Mg(BH4)4], solved their crystal structures from powder x-ray diffraction, and used selected organic metal borohydride derivatives as precursors towards mixed-metal borohydrides (K2Mn(BH4)4, Rb3Mg(BH4)5, etc.). We have also prepared [Ph4P][Eu(BH4)4], which is the first derivative of Eu(III) in the homoleptic environment of borohydride anions. PMID- 26242624 TI - Suppressive effects of saponin-enriched extracts from quinoa on 3T3-L1 adipocyte differentiation. AB - This study was performed to investigate the effect of quinoa saponins (QS) on the differentiation of 3T3-L1 preadipocytes. QS inhibited triglyceride (TG) accumulation in the mature adipocytes, evidenced by oil-red O staining and intracellular quantification. Real time-PCR analysis and western blot analysis showed that QS significantly down-regulated the mRNA and protein expression of key adipogenic transcription factors, peroxisome proliferator-activated receptor gamma (PPARgamma), and CCAAT/enhancer-binding protein alpha (C/EBPalpha), however, they had no significant effect on CCAAT/enhancer-binding protein beta (C/EBPbeta) and CCAAT/enhancer-binding protein delta (C/EBPdelta) which are the upstream regulators for adipogenesis compared with mature adipocytes. QS also reduced mRNA and protein expression of sterol regulatory element-binding protein 1c (SREBP-1c) related to the late stage of adipogenesis. Furthermore, lipoprotein lipase (LPL), adipocyte protein 2 (aP2) and glucose transporter 4 (Glut4), as adipocyte specific genes, were decreased in mature adipocytes by QS treatment. These findings indicate that QS are capable of suppressing adipogenesis and therefore they seem to be natural bioactive factors effective in adipose tissue mass modulation. PMID- 26242625 TI - Successional Trajectories of Rhizosphere Bacterial Communities over Consecutive Seasons. AB - It is well known that rhizosphere microbiomes differ from those of surrounding soil, and yet we know little about how these root-associated microbial communities change through the growing season and between seasons. We analyzed the response of soil bacteria to roots of the common annual grass Avena fatua over two growing seasons using high-throughput sequencing of 16S rRNA genes. Over the two periods of growth, the rhizosphere bacterial communities followed consistent successional patterns as plants grew, although the starting communities were distinct. Succession in the rhizosphere was characterized by a significant decrease in both taxonomic and phylogenetic diversity relative to background soil communities, driven by reductions in both richness and evenness of the bacterial communities. Plant roots selectively stimulated the relative abundance of Alphaproteobacteria, Betaproteobacteria, and Bacteroidetes but reduced the abundance of Acidobacteria, Actinobacteria, and Firmicutes. Taxa that increased in relative abundance in the rhizosphere soil displayed phylogenetic clustering, suggesting some conservation and an evolutionary basis for the response of complex soil bacterial communities to the presence of plant roots. The reproducibility of rhizosphere succession and the apparent phylogenetic conservation of rhizosphere competence traits suggest adaptation of the indigenous bacterial community to this common grass over the many decades of its presence. IMPORTANCE: We document the successional patterns of rhizosphere bacterial communities associated with a "wild" annual grass, Avena fatua, which is commonly a dominant plant in Mediterranean-type annual grasslands around the world; the plant was grown in its grassland soil. Most studies documenting rhizosphere microbiomes address "domesticated" plants growing in soils to which they are introduced. Rhizosphere bacterial communities exhibited a pattern of temporal succession that was consistent and repeatable over two growing seasons. There are few studies assessing the reproducibility over multiple seasons. Through the growing season, the rhizosphere community became progressively less diverse, likely reflecting root homogenization of soil microniches. Phylogenetic clustering of the rhizosphere dynamic taxa suggests evolutionary adaptation to Avena roots. The reproducibility of rhizosphere succession and the apparent phylogenetic conservation of rhizosphere competence traits suggest adaptation of the indigenous bacterial community to this common grass over the many decades of its presence. PMID- 26242626 TI - Vibrio cholerae CsrA Regulates ToxR Levels in Response to Amino Acids and Is Essential for Virulence. AB - ToxR is a major virulence gene regulator in Vibrio cholerae. Although constitutively expressed under many laboratory conditions, our previous work demonstrated that the level of ToxR increases significantly when cells are grown in the presence of the 4 amino acids asparagine, arginine, glutamate, and serine (NRES). We show here that the increase in ToxR production in response to NRES requires the Var/Csr global regulatory circuit. The VarS/VarA two-component system controls the amount of active CsrA, a small RNA-binding protein involved in the regulation of a wide range of cellular processes. Our data show that a varA mutant, which is expected to overproduce active CsrA, had elevated levels of ToxR in the absence of the NRES stimulus. Conversely, specific amino acid substitutions in CsrA were associated with defects in ToxR production in response to NRES. These data indicate that CsrA is a positive regulator of ToxR levels. Unlike previously described effects of CsrA on virulence gene regulation, the effects of CsrA on ToxR were not mediated through quorum sensing and HapR. CsrA is likely essential in V. cholerae, since a complete deletion of csrA was not possible; however, point mutations in CsrA were tolerated well. The CsrA Arg6His mutant had wild-type growth in vitro but was severely attenuated in the infant mouse model of V. cholerae infection, showing that CsrA is critical for pathogenesis. This study has broad implications for our understanding of how V. cholerae integrates its response to environmental cues with the regulation of important virulence genes. IMPORTANCE: In order to colonize the human host, Vibrio cholerae must sense and respond to environmental signals to ensure appropriate expression of genes required for pathogenesis. Uncovering how V. cholerae senses its environment and activates its virulence gene repertoire is critical for our understanding of how V. cholerae transitions from its natural aquatic habitat to the human host. Here we demonstrate a previously unknown link between the global regulator CsrA and the major V. cholerae virulence gene regulator ToxR. The role of CsrA in the cell is to receive input from the environment and coordinate an appropriate cellular response. By linking environmental sensing to the ToxR regulon, CsrA effectively acts as a switch that controls pathogenesis in response to specific signals. We demonstrate that CsrA is critical for virulence in the infant mouse model of V. cholerae infection, consistent with its role as an in vivo regulator of virulence gene expression. PMID- 26242627 TI - Identification of Restriction Factors by Human Genome-Wide RNA Interference Screening of Viral Host Range Mutants Exemplified by Discovery of SAMD9 and WDR6 as Inhibitors of the Vaccinia Virus K1L-C7L- Mutant. AB - RNA interference (RNAi) screens intended to identify host factors that restrict virus replication may fail if the virus already counteracts host defense mechanisms. To overcome this limitation, we are investigating the use of viral host range mutants that exhibit impaired replication in nonpermissive cells. A vaccinia virus (VACV) mutant with a deletion of both the C7L and K1L genes, K1L( )C7L(-), which abrogates replication in human cells at a step prior to late gene expression, was chosen for this strategy. We carried out a human genome-wide small interfering RNA (siRNA) screen in HeLa cells infected with a VACV K1L( )C7L(-) mutant that expresses the green fluorescent protein regulated by a late promoter. This positive-selection screen had remarkably low background levels and resulted in the identification of a few cellular genes, notably SAMD9 and WDR6, from approximately 20,000 tested that dramatically enhanced green fluorescent protein expression. Replication of the mutant virus was enabled by multiple siRNAs to SAMD9 or WDR6. Moreover, SAMD9 and WDR6 clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 knockout HeLa cell lines were permissive for replication of the K1L(-)C7L(-) mutant, in agreement with the siRNA data. Expression of exogenous SAMD9 or interferon regulatory factor 1 restricted replication of the K1L(-)C7L(-) mutant in the SAMD9(-/-) cells. Independent interactions of SAMD9 with the K1 and C7 proteins were suggested by immunoprecipitation. Knockout of WDR6 did not reduce the levels of SAMD9 and interactions of WDR6 with SAMD9, C7, and K1 proteins were not detected, suggesting that these restriction factors act independently but possibly in the same innate defense pathway. IMPORTANCE: The coevolution of microbial pathogens with cells has led to an arms race in which the invader and host continuously struggle to gain the advantage. For this reason, traditional siRNA screens may fail to uncover important immune mechanisms if the pathogens have already developed effective responses. However, host-restricted viral mutants have lost one or more defense genes needed for their replication in nonpermissive cells. By screening human genome libraries of short RNAs that inhibit the expression of individual host genes in nonpermissive cells, we identified SAMD9 and WDR6 as major restriction factors that prevented replication of a vaccinia virus mutant and suggest that host range screening can be generally useful for the investigation of host-pathogen interactions. PMID- 26242628 TI - Achieving Speaker Gender Equity at the American Society for Microbiology General Meeting. AB - In 2015, the American Society for Microbiology (ASM) General Meeting essentially achieved gender equity, with 48.5% of the oral presentations being given by women. The mechanisms associated with increased female participation were (i) making the Program Committee aware of gender statistics, (ii) increasing female representation among session convener teams, and (iii) direct instruction to try to avoid all-male sessions. The experience with the ASM General Meeting shows that it is possible to increase the participation of female speakers in a relatively short time and suggests concrete steps that may be taken to achieve this at other meetings. IMPORTANCE: Public speaking is very important for academic advancement in science. Historically women have been underrepresented as speakers in many scientific meetings. This article describes concrete steps that were associated with achieving gender equity at a major meeting. PMID- 26242629 TI - A Simple Flow-Cytometric Method Measuring B Cell Surface Immunoglobulin Avidity Enables Characterization of Affinity Maturation to Influenza A Virus. AB - Antibody (Ab) affinity maturation enables an individual to maintain immunity to an increasing number of pathogens within the limits of a total Ig production threshold. A better understanding of this process is critical for designing vaccines that generate optimal Ab responses to pathogens. Our study describes a simple flow-cytometric method that enumerates virus-specific germinal center (GC) B cells as well as their AC50, a measure of Ab avidity, defined as the antigen concentration required to detect 50% of specific B cells. Using a model of mouse Ab responses to the influenza A virus hemagglutinin (IAV HA), we obtained data indicating that AC50 decreases with time postinfection in an affinity maturation dependent process. As proof of principle of the utility of the method, our data clearly show that relative to intranasal IAV infection, intramuscular immunization against inactivated IAV in adjuvant results in a diminished GC HA B cell response, with increased AC50 correlating with an increased serum Ab off rate. Enabling simultaneous interrogation of both GC HA B cell quantity and quality, this technique should facilitate study of affinity maturation and rational vaccine design. IMPORTANCE: Though it was first described 50 years ago, little is known about how antibody affinity maturation contributes to immunity. This question is particularly relevant to developing more effective vaccines for influenza A virus (IAV) and other viruses that are difficult vaccine targets. Limitations in methods for characterizing antigen-specific B cells have impeded progress in characterizing the quality of immune responses to vaccine and natural immunogens. In this work, we describe a simple flow cytometry-based approach that measures both the number and affinity of IAV-binding germinal center B cells specific for the IAV HA, the major target of IAV-neutralizing antibodies. Using this method, we showed that the route and form of immunization significantly impacts the quality and quantity of B cell antibody responses. This method provides a relatively simple yet powerful tool for better understanding the contribution of affinity maturation to viral immunity. PMID- 26242631 TI - William Campbell Little, M.D. In Memoriam. PMID- 26242630 TI - Deficient Natural Killer Dendritic Cell Responses Underlay the Induction of Theiler's Virus-Induced Autoimmunity. AB - The initiating events in autoimmune disease remain to be completely understood, but it is thought that genetic predisposition synergizes with "environmental" factors, including viral infection, leading to disease. One elegant animal model used to study the pathogenesis of multiple sclerosis that perfectly blends genetics and environmental components in the context of virus-induced autoimmunity is Theiler's murine encephalitis virus-induced demyelinating disease (TMEV-IDD). TMEV-infected disease-susceptible SJL/J mice develop a persistent central nervous system (CNS) infection and later develop autoimmune demyelination, while disease-resistant C57BL/6 (B6) mice rapidly clear the infection and develop no autoimmune pathology. Mice of the (B6 * SJL/J)F1 cross between these two mouse strains are classified as intermediately susceptible. We employed this model to investigate if rapid virus clearance in B6 versus SJL/J mice was perhaps related to differences in the innate immune response in the CNS of the two strains in the first few days following intracerebral virus inoculation. Here we show that SJL/J mice lack, in addition to NK cells, a novel innate immune subset known as natural killer dendritic cells (NKDCs), which express phenotypic markers (CD11c(int) NK1.1(+)) and functional activity of both NK cells and DCs. These NKDCs are activated in the periphery and migrate into the infected CNS in a very late antigen 4 (VLA-4)-dependent fashion. Most significantly, NKDCs are critical for CNS clearance of TMEV, as transfer of NKDCs purified from B6 mice into TMEV-IDD-susceptible (B6 * SJL/J)F1 mice promotes viral clearance. Together the findings of this work show for the first time a link between NKDCs, viral infection, and CNS autoimmunity. IMPORTANCE: Viral infection is an important cofactor, along with genetic susceptibility, in the initiation of a variety of organ-specific autoimmune diseases. Thus, in-depth understanding of how virus infections trigger autoimmunity may lead to novel ways to prevent or treat these diseases. Theiler's murine encephalitis virus-induced demyelinating disease (TMEV-IDD) serves as an important model for the human T cell-mediated autoimmune demyelinating disease multiple sclerosis. Induction of TMEV-IDD is genetically controlled as SJL/J mice develop persistent central nervous system (CNS) infection leading to chronic autoimmune demyelination, while C57BL/6 mice rapidly clear virus and are disease resistant. We determined that, as opposed to resistant B6 mice, disease-susceptible SJL/J mice lacked a unique innate immune population, the natural killer dendritic cell (NKDC), which was shown to play a critical role in early CNS virus clearance via its ability to both present virus antigen to T cells and to lyse target cells. PMID- 26242632 TI - Reductions in finger blood flow induced by 125-Hz vibration: effect of location of contact with vibration. AB - PURPOSE: This study investigated whether the reductions in finger blood flow induced by 125-Hz vibration applied to different locations on the hand depend on thresholds for perceiving vibration at these locations. METHODS: Subjects attended three sessions during which vibration was applied to the right index finger, the right thenar eminence, or the left thenar eminence. Absolute thresholds for perceiving vibration at these locations were determined. Finger blood flow in the middle finger of both hands was then measured at 30-s intervals during five successive 5-min periods: (i) pre-exposure, (ii) pre-exposure with 2 N force, (iii) 2-N force with vibration, (iv) post-exposure with 2-N force, (v) recovery. During period (iii), vibration was applied at 15 dB above the absolute threshold for perceiving vibration at the right thenar eminence. RESULTS: Vibration at all three locations reduced finger blood flow on the exposed and unexposed hand, with greater reductions when vibrating the finger. Vibration induced vasoconstriction was greatest for individuals with low thresholds and locations of excitation with low thresholds. CONCLUSIONS: Differences in vasoconstriction between subjects and between locations are consistent with the Pacinian channel mediating both absolute thresholds and vibration-induced vasoconstriction. PMID- 26242633 TI - The Covalent Functionalization of Graphene on Substrates. AB - The utilization of grown or deposited graphene on solid substrates offers key benefits for functionalization processes, but especially to attain structures with a high level of control for electronics and "smart" materials. In this review, we will initially focus on the nature and properties of graphene on substrates, based on the method of preparation. We will then analyze the most relevant literature on the functionalization of graphene on substrates. In particular, we will comparatively discuss radical reactions, cycloadditions, halogenations, hydrogenations, and oxidations. We will especially address the question of how the reactivity of graphene is affected by its morphology (i.e., number of layers, defects, substrate, curvature, etc.). PMID- 26242634 TI - Phleboliths as a marker of slow-flow venous malformation. PMID- 26242635 TI - An abnormal thumbnail. PMID- 26242636 TI - X-ray microtomography study of otic capsule deficiencies: three-dimensional modelling of the fissula ante fenestram. AB - BACKGROUND: The postulated sites of perilymph fistulae involve otic capsule deficiencies, in particular, at the fissula ante fenestram. Histological studies have revealed this to be a channel extending from the middle ear, and becoming continuous with the inner ear medial to the anterior limit of the oval window. The relationship between a patent fissula and symptoms of perilymph fistula is contentious. OBJECTIVE: The understanding of the anatomy of the fissula ante fenestram is incomplete. Histopathology is inherently destructive to the delicate ultrastructure of the middle and inner ear. Conversely, X-ray microtomography allows non-destructive examination of the otic capsule. In this study, we used X ray microtomography to characterise the fissula ante fenestram. MATERIALS AND METHODS: We imaged cadaveric temporal bones with X-ray microtomography. We used the Avizo Fire (Visualization Science Group, Merignac Cedex, France) software to perform post-processing and image analysis. RESULTS: Three-dimensional modelling of the fissula ante fenestram allowed stratification into four forms: rudimentary pit; partial fissula; complete occluded fissula; and complete patent fissula. CONCLUSION: X-ray microtomography showed that the fissula ante fenestram is present in various forms from rudimentary pit to complete deficiency of the otic capsule. This understanding may have implications for otologic surgery and clinical diagnosis of perilymph fistula. PMID- 26242637 TI - Anti-Glycation Effects of Pomegranate (Punica granatum L.) Fruit Extract and Its Components in Vivo and in Vitro. AB - Accumulation of advanced glycation end products (AGEs) leads to various diseases such as diabetic complications and arteriosclerosis. In this study, we examined the effect of pomegranate fruit extract (PFE) and its constituent polyphenols on AGE formation in vivo and in vitro. PFE, fed with a high-fat and high-sucrose (HFS) diet to KK-A(y) mice, significantly reduced glycation products such as glycoalbumin (22.0 +/- 2.4%), hemoglobin A1c (5.84 +/- 0.23%), and serum AGEs (8.22 +/- 0.17 MUg/mL), as compared to a control HFS group (30.6 +/- 2.6%, 7.45 +/- 0.12%, and 9.55 +/- 0.17 MUg/mL, respectively, P < 0.05). In antiglycation assays, PFE, punicalin, punicalagin, ellagic acid, and gallic acid suppressed the formation of AGEs from bovine serum albumin and sugars. In this study, we discuss the mechanism of the antiglycation effects of PFE and its components in vivo and in vitro. PMID- 26242638 TI - Significance of what is not sampled: Characteristics of thyroid nonmicrocarcinomas (>1.0 cm) that were not targeted. AB - BACKGROUND: Although most unsuspected thyroid carcinomas qualify as microcarcinomas (<=1 cm), larger, nontargeted carcinomas may be found also. This study evaluated the significance of these nonmicrocarcinomas (>1 cm) in the setting of a large-volume thyroid practice. METHODS: Thyroid resection specimens from May 2007 to December 2012 were reviewed. For these cases, the pathologic characteristics of nontargeted carcinomas larger than 1.0 cm were evaluated. Those interpreted as intrathyroidal metastases were not included in this study. Specifically, the histologic classification, size, and molecular features were documented. RESULTS: From a total of 4815 thyroid resections and 9279 thyroid fine-needle aspiration procedures that were performed during the study period, 27 nontargeted nonmicrocarcinomas were identified (0.6% of resection cases) in 26 patients. The histologic classifications were as follows: follicular variant of papillary carcinoma (n = 19), classic papillary carcinoma (n = 3), papillary carcinoma with oncocytic features (n = 1), tall-cell variant of papillary carcinoma (n = 2), and follicular carcinoma (n = 2). The size parameters were as follows: mean, 1.9 cm; median, 1.4 cm; and range, 1.1 to 7.0 cm. RAS and BRAF mutations were identified in 8 and 7 cases, respectively (71% of the cases tested with a 7-gene panel), whereas 6 cases showed no mutation. Molecular information was not available for 6 cases. CONCLUSIONS: In the authors' experience, nontargeted thyroid nonmicrocarcinomas (>1 cm) are rare (0.6%), and the majority are low-grade carcinomas. The likelihood of finding one of the common mutations (71%) is comparable to the likelihood for thyroid carcinomas in general (~70%). PMID- 26242639 TI - Subgroups of fibromyalgia patients using the 1990 American College of Rheumatology criteria and the modified 2010 preliminary diagnostic criteria: the al-Andalus project. AB - OBJECTIVES: We aimed to investigate the symptom profiles in subsets of fibromyalgia patients according to the subgroups created from the satisfaction of the 1990 American College of Rheumatology (ACR) diagnostic criteria (1990c) and/or the modified 2010 ACR preliminary diagnostic criteria (m-2010c). METHODS: A total of 913 (84 men) participants took part in this cross-sectional study. Participants were grouped as follows: i) 285 who did not fulfil any ACR diagnostic criteria (non-fibromyalgia); ii) 73 who fulfilled the 1990c only; iii) 96 who fulfilled the m-2010c only; iv) 459 who fulfilled both ACR diagnostic criteria. Experimental and clinical pain, chronic pain self-efficacy, pain catastrophising, fibromyalgia severity, fatigue, health-related quality of life, depression, state anxiety and physical fitness were assessed by means of several questionnaires and tests. RESULTS: Overall, the differences were consistent across all study outcomes (all, overall p<0.001), showing that the subgroup fulfilling both diagnostic criteria had the worst profile of all the subgroups, whereas those fulfilling any diagnostic criteria (non-fibromyalgia participants) had the most favourable results. Furthermore, the subgroup fulfilling the m-2010c only had a worse profile than the subgroup fulfilling the 1990c only, and presented similar but slightly better results than those fulfilling both diagnostic criteria. CONCLUSIONS: Our results reinforce the understanding of fibromyalgia as a heterogeneous condition. Subgrouping of fibromyalgia patients is highly recommendable, since these subgroups show diverse clinical pictures and therefore treatment options should be individually tailored to their specific profile. The combination of 1990c and the m-2010c is potentially useful to identify subgroups of fibromyalgia patients. PMID- 26242640 TI - The benefits of treating undetectable tumors. AB - Cancer prevention is predicted to result in more positive therapeutic outcomes than post-diagnostic interventions, and so may be a viable option for future personalized medicine. PMID- 26242642 TI - A facile patterning of silver nanowires using a magnetic printing method. AB - Patterning of metal nanowires (NWs) is vital for the fabrication of NW-based, high-performance devices such as sensors, transparent conducting electrodes, and optoelectronics. However, the majority of existing patterning methods require complex and expensive technologies. For this reason, we report for the first time a facile and quick patterning method of silver (Ag) NWs using a magnetic printing method. We successfully demonstrated a patterned AgNW grid structure ona flexible substrate as transparent electrodes. The flexible AgNW grid electrode exhibited optical and electrical properties comparable to those of commercial transparent conducting electrodes.We believe our work will be broadly applicable to other NW based devices such as sensors,energy storage devices, meta devices, nanoscale electronics, and optoelectronics. PMID- 26242641 TI - An optimised direct lysis method for gene expression studies on low cell numbers. AB - There is increasing interest in gene expression analysis of either single cells or limited numbers of cells. One such application is the analysis of harvested circulating tumour cells (CTCs), which are often present in very low numbers. A highly efficient protocol for RNA extraction, which involves a minimal number of steps to avoid RNA loss, is essential for low input cell numbers. We compared several lysis solutions that enable reverse transcription (RT) to be performed directly on the cell lysate, offering a simple rapid approach to minimise RNA loss for RT. The lysis solutions were assessed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in low cell numbers isolated from four breast cancer cell lines. We found that a lysis solution containing both the non-ionic detergent (IGEPAL CA-630, chemically equivalent to Nonidet P 40 or NP-40) and bovine serum albumin (BSA) gave the best RT-qPCR yield. This direct lysis to reverse transcription protocol outperformed a column-based extraction method using a commercial kit. This study demonstrates a simple, reliable, time- and cost-effective method that can be widely used in any situation where RNA needs to be prepared from low to very low cell numbers. PMID- 26242643 TI - Possible association of anti-tumor necrosis factor-alpha antibody therapy with the development of scleroderma-like changes with lichen planus. PMID- 26242644 TI - Feasibility, acceptability and uptake rates of gestational diabetes mellitus screening in primary care vs secondary care: findings from a randomised controlled mixed methods trial. AB - AIMS/HYPOTHESIS: It is postulated that uptake rates for gestational diabetes mellitus (GDM) screening would be improved if offered in a setting more accessible to the patient. The aim of this study was to evaluate the proportion of uptake of GDM screening in the primary vs secondary care setting, and to qualitatively explore the providers' experiences of primary care screening provision. METHODS: This mixed methods study was composed of a quantitative unblinded parallel group randomised controlled trial and qualitative interview trial. The primary outcome was the proportion of uptake of screening in both the primary and secondary care settings. All pregnant women aged 18 years or over, with sufficient English and without a diagnosis or diabetes or GDM, who attended for their first antenatal appointment at one of three hospital sites along the Irish Atlantic seaboard were eligible for inclusion in this study. Seven hundred and eighty-one pregnant women were randomised using random permutated blocks to receive a 2 h 75 g OGTT in either a primary (n = 391) or secondary care (n = 390) setting. Semi-structured interviews were conducted with 13 primary care providers. Primary care providers who provided care to the population covered by the three hospital sites involved were eligible for inclusion. RESULTS: Statistically significant differences were found between the primary care (n = 391) and secondary care (n = 390) arms for uptake (52.7% vs 89.2%, respectively; effect size 36.5 percentage points, 95% CI 30.7, 42.4; p < 0.001), crossover (32.5% vs 2.3%, respectively; p < 0.001) and non-uptake (14.8% vs 8.5%, respectively; p = 0.005). There were no significant differences in uptake based on the presence of a practice nurse or the presence of multiple general practitioners in the primary care setting. There was evidence of significant relationship between probability of uptake of screening and age (p < 0.001). Primary care providers reported difficulties with the conduct of GDM screening, despite recognising that the community was the most appropriate location for screening. CONCLUSIONS/INTERPRETATION: Currently, provision of GDM screening in primary care in Ireland, despite its acknowledged benefits, is unfeasible due to poor uptake rates, poor rates of primary care provider engagement and primary care provider concerns. TRIAL REGISTRATION: http://isrctn.org ISRCTN02232125 FUNDING: This study was funded by the Health Research Board (ICE2011/03). PMID- 26242645 TI - Paediatric chemoprophylaxis for child contacts of drug-resistant tuberculosis cases: Are current guidelines effective in preventing disease? PMID- 26242647 TI - The World Health Organization Global Action Plan for antimicrobial resistance. PMID- 26242648 TI - Practical solutions to the antibiotic resistance crisis. PMID- 26242650 TI - Better menstrual management options for adolescents needed in South Africa: What about the menstrual cup? PMID- 26242652 TI - Masterly inactivity: A forgotten precept. PMID- 26242651 TI - Outcomes in treatment with darunavir/ritonavir in ART-experienced paediatric patients. PMID- 26242653 TI - Tracking antenatal HIV prevalence in South Africa. PMID- 26242654 TI - Tygerberg Hospital keeps more hearts beating with pioneering service. PMID- 26242655 TI - Little-used medical technology could help thousands see, hear and feel better. PMID- 26242656 TI - SAMA pitches in to help victims of medical negligence. PMID- 26242657 TI - Lifesaving water quality solution 'ignored'. PMID- 26242658 TI - Philippe Emile Agnes Schuermans (1943 - 2014). PMID- 26242659 TI - Updated recommendations for the management of upper respiratory tract infections in South Africa. AB - BACKGROUND: Inappropriate use of antibiotics for non-severe upper respiratory tract infections (URTIs), most of which are viral, significantly adds to the burden of antibiotic resistance. Since the introduction of pneumococcal conjugate vaccines in 2009 in South Africa, the relative frequency of the major bacterial pathogens causing acute otitis media (AOM) and acute bacterial rhinosinusitis (ABRS) has changed. RECOMMENDATIONS: Since URTIs are mostly viral in aetiology and bacterial AOM and ABRS frequently resolve spontaneously, the guideline includes diagnostic criteria to separate viral from bacterial causes and hence, those patients not requiring antibiotics. Penicillin remains the drug of choice for tonsillopharyngitis. Amoxicillin remains the drug of choice for both AOM and ABRS. A dose of 90 mg/kg/day is recommended for children, which should be effective for pneumococci with high-level penicillin resistance and will also cover most infections with H. influenzae. Amoxicillin-clavulanate (in high-dose amoxicillin formulations available for both children and adults) should be considered initial treatment of choice in patients with recent antibiotic therapy with amoxicillin (previous 30 days) and with resistant H.influenzae infections pending the results of studies of local epidemiology (beta-lactamase production >=15%). The macrolide/azalide class of antibiotics are not recommended routinely for URTIs and are reserved for beta-lactam allergic patients. CONCLUSION: The guideline should facilitate rational antibiotic prescribing for URTIs as a component of antibiotic stewardship. However, it requires updating when new information becomes available particularly from randomised controlled trials and surveillance studies of local etiology and antibiotic susceptibility patterns. PMID- 26242660 TI - The simple bread tag - a menace to society? AB - Foreign bodies are potentially life-threatening when inhaled by a child, depending on where they lodge. Symptoms can range from acute upper airway obstruction to mild, vague respiratory complaints. Between 80% and 90% of inhaled foreign bodies occlude the bronchi, while the larynx is a less common site. The commonest inhaled paediatric foreign bodies are organic, e.g. seeds or nuts. Plastic foreign bodies are less common and more difficult to diagnose. They are generally radiolucent on lateral neck radiographs and are often clear and thin. We report three cases of an unusual plastic laryngeal foreign body, the bread tag. Plastic bread tags were first reported in the medical literature as an ingested gastrointestinal foreign body in 1975. Since then, over 20 cases of gastrointestinal complications have been described. We report what is to our knowledge the first paediatric case of an inhaled bread tag, and also the first case series, briefly discuss the symptoms and options for removal of laryngeal foreign bodies, and highlight the dangers of the apparently harmless bread tag. Images of the bread tags in situ and after their removal are included. PMID- 26242661 TI - Key to antimicrobial stewardship success: Surveillance by diagnostic microbiology laboratories. PMID- 26242662 TI - Rheumatic fever and rheumatic heart disease in Africa. PMID- 26242663 TI - Description of an internal medicine outreach consultant appointment in Western KwaZulu-Natal, South Africa, 2007 to mid-2014. AB - BACKGROUND: . This study is a description of an Internal Medicine outreach appointment in western KwaZulu-Natal (KZN) from 2007 to mid-2014, facilitated by the transport services of the Red Cross Air Mercy Service (AMS) and funded by the KZN-Department of Health (KZN-DOH). The hospital visits represented 'multifaceted' as opposed to 'simple' outreach. METHODS: The AMS database of outreach visits was analysed according to frequencies of visits, number of patient contacts and number of contacts with medical personnel. A brief history and nature of the outreach visits is described. RESULTS: From January 2007 to end June 2014, the outreach physician undertook 481 hospital visits and visited seven hospitals (out of 21) more than 40 times each. A total of 3340 medical personnel contacts were made, and 5239 patients were seen. Other Internal Medicine specialists undertook an additional 199 visits, during which they made 1157 personnel contacts and saw 2020 patients. The combined total was thus 680 visits undertaken, 4497 medical personnel contacts made, and 7259 patients seen. CONCLUSION: This study showed that the appointment of a dedicated outreach consultant for a particular discipline together with a reliable air and road transport system was successful in providing access to specialist care in rural settings. This strategy could be recommended throughout South Africa. Further studies would be required in order to assess outcomes. PMID- 26242664 TI - Community- versus healthcare-acquired bloodstream infections at Groote Schuur Hospital, Cape Town, South Africa. AB - BACKGROUND: Bloodstream infections (BSIs) cause considerable morbidity and mortality. The epidemiology of bacterial infections differs in community and hospital settings. Regular surveillance and reporting of pathogens and antimicrobial susceptibility can assist in appropriate management of BSIs. OBJECTIVES: To describe the distribution of organisms and of antibiotic susceptibility among isolates from blood cultures at a tertiary academic hospital during a 1-year period, stratifying by place of infection acquisition. METHODS: This was a retrospective descriptive study of bloodstream isolates from cultures from adults (>13 years of age) routinely submitted between 1 October 2011 and 30 September 2012 to the clinical laboratory at Groote Schuur Hospital, Cape Town, South Africa. Community-acquired infections were compared with healthcare acquired infections, defined as infections developing at least 48 hours after admission or within 3 months of admission to a healthcare facility. Frequencies and proportions of infecting organisms are presented, along with susceptibility results for selected pathogens. The hospital-acquired isolates were stratified by ward (emergency, general medical or general surgical ward or intensive care unit (ICU)) to determine organism frequency and susceptibility patterns by hospital ward. RESULTS: Among adults, 740 non-duplicate pathogens were isolated from BSIs. Nearly three-quarters of infections were healthcare acquired. Enterobacteriaceae and non-fermentative Gram-negative bacilli were predominant among healthcare acquired pathogens (39.2% and 28.5%, respectively), while Enterobacteriaceae and Gram-positive organisms were the most common among community-acquired pathogens (39.2% and 54.3%, respectively). The majority of community-acquired Enterobacteriaceae were highly susceptible to antibiotics (gentamicin 95.6%, ceftriaxone 96.1% and ciprofloxacin 92.2%), whereas 64.6% of healthcare associated isolates were susceptible to gentamicin, 58.5% to ceftriaxone and 70% to ciprofloxacin. All community-acquired Staphylococcus aureus isolates v. 52.4% of healthcare-acquired isolates were susceptible to cloxacillin. The susceptibility of healthcare-acquired Pseudomonas aeruginosa and Acinetobacter baumanii complex isolates was <80% to all antibiotics with the exception of colistin. Klebsiella spp., S. aureus and Escherichia coli were the commonest causes of healthcare-acquired infections in all areas outside of the ICUs, whereas Acinetobacter was common in the ICUs and rare in all other areas. CONCLUSION: The distinction between community- and healthcare-acquired infections is critical in antibiotic selection because narrow-spectrum agents can be utilised for community-acquired infections. The considerable antibiotic resistance of healthcare-acquired pathogens highlights the importance of infection prevention and control. This type of surveillance could be incorporated into routine laboratory practice. PMID- 26242665 TI - Validation of a severity-of-illness score in patients with tuberculosis requiring intensive care unit admission. AB - BACKGROUND: There is a paucity of data on the determinants of mortality due to tuberculosis (TB) in the intensive care unit (ICU). OBJECTIVE: To develop a simple severity-of-illness score for use in patients with TB admitted to an ICU. METHODS: A scoring system was generated by retrospectively identifying the four most significant and clinically unrelated predictors of mortality from an existing prospectively collected dataset (January 2012 - May 2013), and combining these with known predictors of poor outcome. RESULTS: Of 83 patients admitted with TB, 38 (45.8%) died in the ICU. The four parameters identified from the retrospective analysis were: (i) HIV co-infection with a CD4cell count <200/uL; (ii) a raised creatinine level: (iii) a chest radiograph showing diffuse parenchymal infiltrates/miliary pattern; and (iv) absence of TB treatment on admission. These were combined with septic shock and a low arterial partial pressure of oxygen/fractional inspired oxygen (P:F) ratio to generate a six-point severity-of-illness score (one point for each parameter). The scores for survivors were significantly lower than those for non-survivors (mean (standard deviation) 2.27 (1.47) v. 3.58 (1.08); p<0.01). A score of >=2 was associated with significantly higher mortality than a score of <2 (7.1% v. 46.4%; odds ratio (OR) 15.03; 95% confidence interval (CI) 1.86 - 121.32; p<0.01), whereas a score of >=3 was associated with a significantly higher mortality than a score of <3 (64.6% v. 20.0%; OR 7.29; 95% CI 2.64 - 20.18; p<0.01). CONCLUSION: The proposed scoring system identified patients at increased risk of dying from TB in the ICU. Further prospective studies are indicated to validate its use. PMID- 26242666 TI - Self-monitoring of blood glucose measurements and glycaemic control in a managed care paediatric type 1 diabetes practice. AB - BACKGROUND: Intensive diabetes management requires intensive insulin treatment and self-monitoring of blood glucose (SMBG) measurements to obtain immediate information on the status of the blood glucose level and to obtain data for pattern analysis on which meal planning, insulin and lifestyle adjustments can be made. The value and optimal frequency of SMBGs are often questioned. OBJECTIVES: To document the relationship between SMBG frequency and glycaemic control in a managed care paediatric type 1 diabetes practice. METHODS: A retrospective analysis was performed on 141 managed care paediatric and adolescent patients over a 1-year period from 1 February 2010 to 30 January 2011. The patients were stratified according to their insulin regimen, frequency of SMBG was analysed, and glycaemic control was measured by glycated haemoglobin (HbA1c). RESULTS: The records of 141 paediatric and adolescent children aged 2 - 18 years were examined. A highly significant decrease (p<0.0001) in HbA1c was found when moving from two injections per day to three- and five-injection regimens. The average HbA1c and its variability reduced as the diabetes regimen became more intensive. A highly significant decrease (p<0.001) in HbA1c levels was detected as the frequency of SMBG increased, with an average decrease of 0.19% in HbA1c per unit increase in the number of SMBG measurements performed per day. The modal frequency of five SMBG measurements per day was required to achieve the American Diabetes Association and International Society for Pediatric and Adolescent Diabetes guideline recommended target HbA1c of <7.5% for a paediatric population. CONCLUSION: A beneficial relationship exists between frequency of SMBG and lower HbA1c in paediatric patients with type 1 diabetes. PMID- 26242667 TI - Outcomes of TB/HIV co-infected patients presenting with antituberculosis drug induced liver injury. AB - BACKGROUND: South Africa has a significant burden of tuberculosis (TB). Anti-TB drug-induced liver injury (TB DILI) is one of the most serious adverse events that can arise from TB treatment (TBT). There are limited data on TB DILI among HIV-infected patients and those on antiretroviral therapy (ART). OBJECTIVE: To describe characteristics of HIV-infected patients presenting with TB DILI and the proportion reintroduced on standard or modified TBT after DILI. METHODS: This was a retrospective study of TB/HIV co-infected patients with DILI between 1 July 2009 and 30 September 2012. The primary focus of interest was HIV-infected patients with TB DILI on ART (ART/TB DILI) v. not on ART (TB DILI). RESULTS: A total of 94 patients were included, 41 with TB DILI and 53 with ART/TB DILI. Compared with patients with TB DILI, patients with ART/TB DILI were more likely to present with symptomatic DILI (71.2% v. 51.2%; p=0.03) and had a lower median alanine aminotransferase level at diagnosis (89 IU/L v. 118 IU/L; p=0.008), a lower rate of ALT decline (-23 IU/L v. -76 IU/L; p=0.047) and longer duration of TBT at DILI diagnosis (53 days v. 11 days; p<0.001). In 71.8% of patients, standard TBT was reintroduced. More patients with ART/TB DILI than TB DILI required modified TBT (37.2% v.17.1%; p=0.05; crude odds ratio 2.17; 95% confidence interval 0.95 - 4.96). The rate of death/loss to follow-up was higher in the ART/TB DILI group (18.9% v. 14.5%). CONCLUSION: A significant number of TB/HIV co-infected patients were not able to tolerate standard TBT. Furthermore, ART appears to complicate TBT, with relatively few patients reintroduced on standard TBT. PMID- 26242668 TI - Ocular surface squamous neoplasia among HIV-infected patients in Botswana. AB - BACKGROUND: Ocular surface squamous neoplasia (OSSN) is a group of ocular tumours that has been rising in incidence among HIV-infected individuals in sub-Saharan Africa. Surgical excision is the mainstay of treatment for OSSN in this region. METHODS: This retrospective cohort study examined the clinical characteristics and treatment modalities used for 468 patients with OSSN from a large tertiary referral center in Gaborone, Botswana, over a 10-year period from 1998 to 2008. RESULTS: The estimated annual incidence of OSSN in Botswana reached a peak of 7.0 cases per 100 000 persons per year in 2004. The mean age of the patients in the study was 38 years (interquartile range 30 - 44), and 53.9% were women. Of the patients, 48.5% were known to be HIV-infected, 1.5% were HIV-uninfected, and 50.0% had unknown HIV status. Among HIV-infected patients with CD4 counts, the median CD4 count was 192 cells/uL. As initial OSSN treatment, 20.7% of patients received simple surgical excision, 70.9% received surgical excision with adjunctive beta radiation, 0.9% received evisceration, 1.3% received enucleation, and 6.2% underwent surgical removal of unknown type. The overall rate of known recurrence was 7.1%; however, among those with at least 6 months of follow-up, the recurrence rate was 24.2%. Rates of known recurrence after simple surgical excision and surgical excision with adjunctive beta-radiation were 10.3% and 5.4%, respectively. CONCLUSION: This study confirms the high incidence of OSSN among young individuals in Botswana. Further investigation is warranted to determine the most effective treatment modalities to prevent recurrence of OSSN among patients in sub-Saharan Africa. PMID- 26242669 TI - Kaposi's sarcoma, a South African perspective: Demographic and pathological features. AB - BACKGROUND: The incidence of Kaposi's sarcoma (KS) has increased dramatically since the onset of the AIDS epidemic. Of the estimated 66 200 cases of KS worldwide, 58 800 are considered to have occurred in sub-Saharan Africa. OBJECTIVES: To describe the epidemiology and pathological characteristics of KS at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa. METHODS: A retrospective cross-sectional study design was used. Nine hundred and thirty eight histopathology reports of KS diagnosed in 901 patients at CHBAH between 2005 and 2009 were reviewed. Age, gender, topographic site, CD4 count, HIV status, KS histological stage, findings of human herpesvirus 8 latency-associated nuclear antigen 1 immunohistochemistry and concomitant pathological findings were recorded. RESULTS: The male/female ratio was 1.2:1, the mean age 37 years and the median CD4 count 128 cells/uL. Lower limb skin biopsies accounted for 49.6% of cases. Paediatric, visceral and endemic KS accounted for only limited proportions (1.4%, 1.4% and 1.3% of biopsies, respectively). There were concomitant pathological findings in 4.6% of biopsy specimens, infections and inflammatory dermatoses being the most frequent. CONCLUSION: The findings of this study highlight the need for allocation of diagnostic and treatment resources for KS. Documentation of the various demographic aspects of KS will prove to be of historical, clinical and histopathological interest as the long-term outcomes of antiretroviral therapy begin to emerge. PMID- 26242670 TI - The poor children of the poor: Coping with diabetes control in a resource-poor setting. AB - BACKGROUND: Coping with diabetes control is difficult for newly diagnosed and experienced patients alike. Children with diabetes face severe challenges, as they may not yet have attained the necessary cognitive, fine motor or psychosocial skills required for performance of the tasks required from the diabetic patient. Most therefore require some adult assistance. OBJECTIVES: To establish whether paediatric diabetic patients are adequately supported by their families in terms of giving insulin injections and doing home blood glucose monitoring (HBGM), and whether insulin and the necessary equipment are appropriately stored in their homes. METHODS: Patients attending a paediatric diabetes clinic were interviewed. The data collected included demographic variables, type of insulin, measurement of insulin doses, administration of insulin, and blood glucose monitoring tests. RESULTS: Twenty-five subjects were interviewed: 18 measured the insulin themselves, five mothers and one aunt did so, and in one case the mother and patient did so together. The four children aged <=10 years had their insulin measured by their mothers, but one had to administer the injection himself. Eight of the nine children aged 11 - 15 years measured and administered the insulin themselves; in four cases the doses were checked by an adult. The mothers of four children did the fingerpricks, and eight children were helped with measuring the results. Only two children aged 11 - 15 years had their doses checked by an adult. CONCLUSION: Adult assistance with regard to both insulin injections and HBGM is rarely forthcoming. The children seem not to be sufficiently supported by their families. PMID- 26242671 TI - A prospective observational study of bacteraemia in adults admitted to an urban Mozambican hospital. AB - BACKGROUND: Bacteraemia is a common cause of fever among patients presenting to hospitals in sub-Saharan Africa. The worldwide rise of antibiotic resistance makes empirical therapy increasingly difficult, especially in resource-limited settings. OBJECTIVES: To describe the incidence of bacteraemia in febrile adults presenting to Maputo Central Hospital (MCH), an urban referral hospital in the capital of Mozambique, and characterise the causative organisms and antibiotic susceptibilities. We aimed to describe the antibiotic prescribing habits of local doctors, to identify areas for quality improvement. METHODS: Inclusion criteria were: (i) >=18 years of age; (ii) axillary temperature >=38 degrees C or <=35 degrees C; (iii) admission to MCH medical wards in the past 24 hours; and (iv) no receipt of antibiotics as an inpatient. Blood cultures were drawn from enrolled patients and incubated using the BacT/Alert automated system (bioMerieux, France). Antibiotic susceptibilities were tested using the Kirby-Bauer disc diffusion method. RESULTS: Of the 841 patients enrolled, 63 (7.5%) had a bloodstream infection. The most common isolates were Staphylococcus aureus, Escherichia coli, and non-typhoidal Salmonella. Antibiotic resistance was common, with 20/59 (33.9%) of all bacterial isolates showing resistance to ceftriaxone, the broadest-spectrum antibiotic commonly available at MCH. Receipt of insufficiently broad empirical antibiotics was associated with poor in-hospital outcomes (odds ratio 8.05; 95% confidence interval 1.62 - 39.91; p=0.04). CONCLUSION: This study highlights several opportunities for quality improvement, including educating doctors to have a higher index of suspicion for bacteraemia, improving local antibiotic guidelines, improving communication between laboratory and doctors, and increasing the supply of some key antibiotics. PMID- 26242672 TI - The success of various management techniques used in South African children with type 1 diabetes mellitus. AB - BACKGROUND: Despite the availability of international guidelines for the treatment of type 1 diabetes mellitus in children, important aspects of treatment are not accessible to all young patients in South Africa (SA). OBJECTIVE: To investigate factors in diabetes management strategies that are associated with poor glycaemic control and decreased quality of life (QoL) in SA children with type 1 diabetes mellitus (T1DM). METHODS: Eighty children (mean (standard deviation) age 12.9 (2.7) years) with T1DM were asked to answer standardised questionnaires on demographics, management techniques used and perceptions of diabetes. The height and weight of each child was recorded and glycosylated haemoglobin (HbA1c) measured. Informed consent and assent for each participant was obtained before enrolment. RESULTS: A total of 51.4% of the participants had poor metabolic control, with an HbA1c level >10.0% (86 mmol/mol). Factors in clinical practice found to have a significant association with decreased HbA1c and/or QoL were healthcare system (p<0.001), insulin administration (p=0.001), correction dose (p=0.002), carbohydrate counting (p<0.001) and number of severe hyperglycaemic events (p=0.048). Regular exercise did not show any association with HbA1c classification or QoL. Children from single-parent households were prone to unsuccessful diabetes management regardless of treatment techniques used (p=0.002). CONCLUSIONS: The use of premixed insulin without access to rapid acting insulin, absence of correction doses for hyperglycaemia and lack of carbohydrate counting showed significant association with poor diabetes management. Some recommendations regarding the adoption of more effective diabetes management strategies in the public healthcare system are suggested. PMID- 26242673 TI - Role of splenectomy for immune thrombocytopenic purpura (ITP) in the era of new second-line therapies and in the setting of a high prevalence of HIV-associated ITP. AB - BACKGROUND: New agents are being used as second-line treatment for immune thrombocytopenia (ITP) and have brought into question the relevance of splenectomy for steroid-resistant ITP. METHODS: We retrospectively analysed 73 patients who underwent splenectomy for ITP at our institution over an 11-year period. The median follow-up period was 25 months; patients with follow-up of <1 month were excluded. The outcomes of splenectomy were compared in HIV-positive v. HIV-negative patients. RESULTS: The rate of complete response was 83%, and response was sustained for at least 1 year or until latest follow-up in 80% of patients. Twelve patients were HIV-positive. Splenectomy was laparoscopic in 43 patients (62%) with an overall 16% complication rate. The 90-day mortality rate was 1.38%. There was no statistically significant difference in response or complication rate in the HIV-positive patients. There was a statistically significant (p=0.003) poorer response to splenectomy in the patients with steroid resistant ITP. CONCLUSION: Splenectomy is effective and safe irrespective of HIV status and remains an appropriate second-line treatment for ITP. Further research is needed to corroborate our finding of lower response in patients who are steroid-resistant, as this might be a subgroup of patients who may benefit from thrombopoietin agonists as second line therapy. PMID- 26242674 TI - Role of antibiotic stewardship in extending the age of modern medicine. AB - Antibiotic resistance is threatening modern medicine. Overuse and misuse of antibiotics is driving resistance to such an extent that we have entered the post antibiotic era, where some multidrug- and pandrug-resistant bacterial infections are no longer treatable. If the situation is not reversed,10 million people will die annually of drug-resistant infections by 2050. More than just a question of mortality, such infections are causing the closure of wards, cancellation of operations, and interference with other common medical procedures that rely on antibiotics for their success. The response to this crisis requires co-ordinated international action with increased surveillance of bacterial resistance, infection prevention, and antibiotic stewardship, i.e. access to affordable, quality-assured antibiotics prescribed appropriately. This review describes antibiotic stewardship at the individual patient and programmatic level, which must be adopted by every prescriber if we are to preserve modern medicine for future generations. PMID- 26242679 TI - Role of infection control in combating antibiotic resistance. AB - Infection control has been identified as one of the key interventions in controlling the threat of antibiotic resistance. Reducing thetransmission of multidrug-resistant organisms (MDROs) reduces the need for broad-spectrum antibiotics in particular, while interventionsthat decrease the risk of infection have an impact on the use of any antibiotic. Hand hygiene remains the cornerstone of decreasing thetransmission of MDROs. Alcohol-based hand rubs are a cheap, effective and convenient means of performing hand hygiene. Patientscolonised or infected with MDROs should be placed on contact precautions, although implementation remains challenging in resourcelimitedenvironments. Screening for certain MDROs may play a role in curbing transmission of these organisms. If implemented, screeningmust be part of a comprehensive infection control strategy. In resource-limited settings, the costs and potential benefits of screeningprogrammes need to be carefully weighed up. Care bundles have been shown to reduce the incidence of common healthcare-associatedinfections, including catheter-associated urinary tract infection, ventilator-associated pneumonia, central line-associated bloodstreaminfection and surgical site infection. These bundles are relatively inexpensive, and can play an important role in reducing antibiotic use andimproving clinical outcomes. PMID- 26242680 TI - A lady with a broken heart: Apical ballooning syndrome. AB - Severe chest pain afteran emotional argumentresulted in the admissionof a healthy 72-year-oldwoman. She was haemodynamicallycompromised, with anelectrocardiogram (ECG) demonstratinganterior ST-depression and T-wave inversions(Fig. 1). Her 6 hour troponin T levelwas 132 ng/L. Cardiac catheterisationrevealed unobstructed coronary arteriesand a reduced left ventricular ejectionfraction (LVEF) of <35%, with basalhyperkinesia and apical segment ballooning(Figs 2 - 5). She was discharged home after3 days of supportive therapy. At 3 monthsshe was asymptomatic, with an equilibriumradionuclide angiography scan revealing anormal heart with an LVEF of 73%. PMID- 26242681 TI - Government inability to harness high-tech radiology blurs NHI vision. PMID- 26242684 TI - Rheumatic fever and rheumatic heart disease among children presenting to two referral hospitals in Harare, Zimbabwe. AB - BACKGROUND: Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) remain significant causes of morbidity and mortality in resource-limited settings. In Zimbabwe ARF/RHD characteristics have not been systematically documented. OBJECTIVES: To document cases of ARF/RHD among children presenting at referral hospitals in Harare, Zimbabwe, determine their clinical and echocardiographic characteristics, and identify opportunities for improving care. METHODS: A cross sectional survey was carried out in which consecutive children aged 1 - 12 years presenting with ARF/RHD according to the 2002/3 World Health Organization modified Jones criteria were enrolled. RESULTS: Out of 2 601 admissions and 1 026 outpatient visits over 10 months, 50 children were recruited, including 31 inpatients with ARF/RHD and 19 outpatients with chronic RHD. Among inpatients, 9 had ARF only, 7 recurrent ARF with RHD, and 15 RHD only. The commonest valve lesions were mitral regurgitation (26/31) and aortic regurgitation (11/31). The commonest reason for admission was cardiac failure (22/31). The proportion of ARF/RHD cases among inpatients aged 1 - 12 years was 11.9/1 000. Of the 22 with RHD, 14 (63.6%) presented de novo and 1 had bacterial endocarditis. Among the outpatients, 15 had cardiac failure while echocardiographic findings included mitral regurgitation (18/19) and aortic regurgitation (5/19). At presentation, 18/26 known cases were on oral penicillin prophylaxis and 7 on injectable penicillin. Of those on secondary prophylaxis, 68.0% reported taking it regularly. CONCLUSION: ARF/RHD remains a major problem and cause of hospital admissions in Harare, Zimbabwe. Children often present late with established RHD and cardiac failure. With the majority on oral penicillin, secondary prophylaxis was suboptimal in a resource-limited setting unable to offer valve replacement surgery. PMID- 26242685 TI - VIM-2 carbapenemase-producing Pseudomonas aeruginosa in a patient from Port Elizabeth, South Africa. PMID- 26242688 TI - Adult bronchiolitis--a clinical and pathological interpretative classification. AB - INTRODUCTION: Bronchiolitis is a heterogeneous group of diseases of an inflammatory nature, centered on small conducting airways and often associated with other pulmonary disorders. No single classification scheme for bronchiolar diseases has been widely accepted. In this retrospective study, it was decided to apply a new clinical and pathological interpretative classification. OBJECTIVES: To propose a new clinical and pathological interpretative classification for adult bronchiolitis, based on statistical analysis of a population of 193 patients with histopathological diagnosis of bronchiolitis. MATERIALS AND METHODS: A retrospective study analyzed the epidemiological characteristics, co morbidities and radiological findings present in a group of patients with histopathological diagnosis of bronchiolitis. RESULTS: This trial involved 193 cases collected over a period of eleven years; 48 (24.9%) patients had simultaneous pulmonary disease; non-pulmonary diseases, such as cardiovascular diseases, type II Diabetes mellitus and dyslipidemia were present in 57 cases. The image study was extremely important in order to integrate clinical and pathological aspects. In this study respiratory bronchiolitis related to smoking dominated. The radiological findings confirmed the secondary nature of the histopathological features, with prevalence of ground-glass patterns, pneumothorax and patterns of interstitial involvement, as described in the literature. It was also verified that clinical behavior of different forms of bronchiolitis was important to distinguish the various types, since they could progress without typical anatomopathological aspects. CONCLUSION: This trial showed that the vast majority of diagnosis obtained corresponded to bronchiolitis as secondary to pulmonary pathology. In most cases, morphological findings had to be complemented with clinical and radiological characteristics, in order to obtain the final diagnosis. PMID- 26242686 TI - The effect of a tertiary bile acid, taurocholic acid, on the morphology and physical characteristics of microencapsulated probucol: potential applications in diabetes: a characterization study. AB - In recent studies, we designed multi-compartmental microcapsules as a platform for the targeted oral delivery of lipophilic drugs in an animal model of type 2 diabetes (T2D). Probucol (PB) is a highly lipophilic, antihyperlipidemic drug with potential antidiabetic effects. PB has low bioavailability and high inter individual variations in absorption, which limits its clinical applications. In a new study, the bile acid, taurocholic acid (TCA), exerted permeation enhancing effects in vivo. Accordingly, this study aimed to design and characterize TCA based PB microcapsules and examine the effects of TCA on the microcapsules' morphology, stability, and release profiles. Microcapsules were prepared using the polymer sodium alginate (SA). Two types of microcapsules were produced, one without TCA (PB-SA, control) and one with TCA (PB-TCA-SA, test). Microcapsules were studied in terms of morphology, surface structure and composition, size, drug contents, cross-sectional imaging (using microtomography (Micro-CT) analysis), Zeta potential, thermal and chemical profiles, rheological parameters, swelling, mechanical strength, and release studies at various temperature and pH values. The production yield and the encapsulation efficiency were also studied together with in vitro efficacy testing of cell viability at various glucose concentrations and insulin and TNF-alpha production using clonal-mouse pancreatic beta-cells. PB-TCA-SA microcapsules showed uniform structure and even distribution of TCA within the microcapsules. Drug contents, Zeta potential, size, rheological parameters, production yield, and the microencapsulation efficiency remained similar after TCA addition. In vitro testing showed PB-TCA-SA microcapsules improved beta-cell survival under hyperglycemic states and reduced the pro-inflammatory cytokine TNF-alpha while increasing insulin secretions compared with PB-SA microcapsules. PB-TCA-SA microcapsules also showed good stability, better mechanical (p < 0.01) and swelling (p < 0.01) characteristics, and optimized controlled release at pH 7.8 (p < 0.01) compared with control, suggesting desirable targeted release properties and potential applications in the oral delivery of PB in T2D. PMID- 26242689 TI - Alterations of the blood-spinal cord barrier in sporadic amyotrophic lateral sclerosis. AB - The blood-spinal cord barrier (BSCB) of the spinal cord capillary consists of non fenestrated endothelial cells with tight junctions, basal laminae, pericytes and astrocyte feet processes, referred to as a "neurovascular unit." The primary function of the BSCB is the maintenance and control of homeostasis of the spinal cord parenchyma by the selective transport of molecules and cells from the systemic compartment. Dysfunction of the BSCB shows important function in the etiology or progression of several pathological conditions of the spinal cord, including amyotrophic lateral sclerosis (ALS). However, the role of BSCB in the pathogenesis of ALS is still unclear. Here the changes of BSCB in sporadic ALS patients were studied by electron microscopy to determine whether the BSCB is disrupted and involved in the pathogenesis of motor neuron degeneration. A total of 358 and 366 cross-sectioned capillaries were quantitatively examined in controls and ALS patients, respectively. The frequency of degenerated endothelia and pericytes, vacuolar changes of the cytoplasm in the endothelia and pericytes, and the replication of basement membranes was significantly higher in ALS patients than in the controls (P = 0.0175). The areas of the capillaries with diameters of <= 5 um in the ALS patients were significantly smaller than those in the controls (P = 0.0124). The frequency of collagen fiber content of more than a moderate degree around the perivascular space was significantly higher in the ALS patients compared to the controls (P = 0.048), although there was no significant difference in the mild degree of accumulation of collagen fibers. Thus, the BSCB may be disrupted in sporadic ALS patients due to increased permeability and reduced microcirculation, leading to motor neuron degeneration and to the progression of the disease. PMID- 26242687 TI - Inkjet printing of insulin microneedles for transdermal delivery. AB - Inkjet printing technology was used to apply insulin polymeric layers on metal microneedles for transdermal delivery. A range of various polymers such as gelatin (GLN), polyvinyl caprolactame-polyvinyl acetate-polyethylene glycol (SOL), poly(2-ethyl-2-oxazoline) (POX) and trehalose (THL) were assessed for their capacity to form thin uniform and homogeneous layers that preserve insulin intact. Atomic force microscopy (AFM) showed homogeneous insulin-polymer layers without any phase separation while SOL demonstrated the best performance. Circular discroism (CD) analysis of rehydrated films showed that insulin's alpha helices and beta-sheet were well preserved for THL and SOL. In contrast, GLN and POX insulin layers revealed small band shifts indicating possible conformational changes. Insulin release in Franz diffusion cells from MNs inserted into porcine skin showed rapid release rates for POX and GLN within the first 20 min. Inkjet printing was proved an effective approach for transdermal delivery of insulin in solid state. PMID- 26242690 TI - Comparative cytogenetics of six Indo-Pacific moray eels (Anguilliformes: Muraenidae) by chromosomal banding and fluorescence in situ hybridization. AB - A comparative cytogenetic analysis, using both conventional staining techniques and fluorescence in situ hybridization, of six Indo-Pacific moray eels from three different genera (Gymnothorax fimbriatus, Gymnothorax flavimarginatus, Gymnothorax javanicus, Gymnothorax undulatus, Echidna nebulosa and Gymnomuraena zebra), was carried out to investigate the chromosomal differentiation in the family Muraenidae. Four species displayed a diploid chromosome number 2n = 42, which is common among the Muraenidae. Two other species, G. javanicus and G. flavimarginatus, were characterized by different chromosome numbers (2n = 40 and 2n = 36). For most species, a large amount of constitutive heterochromatin was detected in the chromosomes, with species-specific C-banding patterns that enabled pairing of the homologous chromosomes. In all species, the major ribosomal genes were localized in the guanine-cytosine-rich region of one chromosome pair, but in different chromosomal locations. The (TTAGGG)n telomeric sequences were mapped onto chromosomal ends in all muraenid species studied. The comparison of the results derived from this study with those available in the literature confirms a substantial conservation of the diploid chromosome number in the Muraenidae and supports the hypothesis that rearrangements have occurred that have diversified their karyotypes. Furthermore, the finding of two species with different diploid chromosome numbers suggests that additional chromosomal rearrangements, such as Robertsonian fusions, have occurred in the karyotype evolution of the Muraenidae. PMID- 26242692 TI - The only certain measure of the effectiveness of multiple sclerosis therapy is cerebrospinal neurofilament level-NO. PMID- 26242691 TI - Relevance of dietary glycerophospholipids and sphingolipids to human health. AB - Glycerophospholipids and sphingolipids participate in a variety of indispensable metabolic, neurological, and intracellular signaling processes. In this didactic paper we review the biological roles of phospholipids and try to unravel the precise nature of their putative healthful activities. We conclude that the biological actions of phospholipids activities potentially be nutraceutically exploited in the adjunct therapy of widely diffused pathologies such as neurodegeneration or the metabolic syndrome. As phospholipids can be recovered from inexpensive sources such as food processing by-products, ad-hoc investigation is warranted. PMID- 26242693 TI - The only certain measure of the effectiveness of multiple sclerosis therapy is cerebrospinal neurofilament level: Commentary. PMID- 26242694 TI - Symbiotic effectiveness and phylogeny of rhizobia isolated from faba bean (Vicia faba L.) in Sichuan hilly areas, China. AB - A total of 54 rhizobial strains were isolated from faba bean root nodules in 21 counties of Sichuan hilly areas in China, and their symbiotic effectiveness, genetic diversity and phylogeny were assessed. Only six strains increased the shoot dry mass of the host plant significantly (P <= 0.05). Based on the cluster analysis of combined 16S rDNA and intergenic spacer region (IGS) PCR-RFLP, the strains were divided into 31 genotypes in 11 groups, indicating a high degree of genetic diversity among the strains. The sequence analysis of three housekeeping genes (atpD, glnII and recA) and 16S rDNA indicated that the strains represented two R. leguminosarum, two Rhizobium spp., R. mesosinicum, Agrobacterium sp. and A. tumefaciens. The strains representing four Rhizobium species were divided into two distinct nodC and nifH genotypes. However, the phylogeny of housekeeping genes and symbiotic genes was not congruent, implying that the strains had been shaped by vertical evolution of the housekeeping genes and lateral evolution of the symbiotic genes. PMID- 26242696 TI - UK academic general practice and primary care. PMID- 26242695 TI - Site-directed Mutagenesis of Key Residues Unveiled a Novel Allosteric Site on Human Adenosine Kinase for Pyrrolobenzoxa(thia)zepinone Non-Nucleoside Inhibitors. AB - Most nucleoside kinases, besides the catalytic domain, feature an allosteric domain which modulates their activity. Generally, non-substrate analogs, interacting with allosteric sites, represent a major opportunity for developing more selective and safer therapeutics. We recently developed a series of non nucleoside non-competitive inhibitors of human adenosine kinase (hAK), based on a pyrrolobenzoxa(thia)zepinone scaffold. Based on computational analysis, we hypothesized the existence of a novel allosteric site on hAK, topographically distinct from the catalytic site. In this study, we have adopted a multidisciplinary approach including molecular modeling, biochemical studies, and site-directed mutagenesis to validate our hypothesis. Based on a three dimensional model of interaction between hAK and our molecules, we designed, cloned, and expressed specific, single and double point mutants of hAK (Q74A, Q78A, H107A, K341A, F338A, and Q74A-F338A). Kinetic characterization of recombinant enzymes indicated that these mutations did not affect enzyme functioning; conversely, mutated enzymes are endowed of reduced susceptibility to our non-nucleoside inhibitors, while maintaining comparable affinity for nucleoside inhibitors to the wild-type enzyme. This study represents the first characterization and validation of a novel allosteric site in hAK and may pave the way to the development of novel selective and potent non-nucleoside inhibitors of hAK endowed with therapeutic potential. PMID- 26242697 TI - A bar-retained overdenture as an external fixator device in a three-dimensional CAD/CAM-based surgical reconstruction of the mandible. AB - Large defects of the human face often cause esthetic as well as functional disorders. We present a new technique for reconstruction of the mandible with prosthodontic rehabilitation in a single surgery, using the implant-supported, bar-retained overdenture as an external fixator. A 58-year-old patient presented with a near total defect of the mandible after cancer resection. For rehabilitation, the mandibular condyles were virtually positioned in the centre of the fossae, and four dental implants were planned. The position of the fibula segments as well as their angulation and lengths were adapted to the implant position. To transfer this plan into surgery, a combined cutting/implant drilling guide was computer-aided printed. To provide the correct angulation of the fibula segments, a CAD/CAM dental arch-bar was made from titanium, fulfilling three functions: to bear the provisional prosthesis; to stabilize the molded fibula as an external fixator; and to position the complete fibula with the prosthesis in a correct relation to the upper jaw and occlusion, as indicated by the prosthesis. This innovative approach of combined prosthodontic and reconstructive rehabilitation could shorten the total reconstruction/rehabilitation time and avoid the need for additional extended surgeries. PMID- 26242698 TI - Primary and secondary reconstruction of complex craniofacial defects using polyetheretherketone custom-made implants. AB - PURPOSE: The aim of this study was to evaluate the surgical outcomes using polyetheretherketone (PEEK) patient-specific prostheses produced by computer aided design and manufacturing for primary and secondary reconstruction in patients with craniofacial defects. MATERIAL AND METHODS: The study included 13 patients who underwent reconstruction for craniofacial defects using PEEK patient specific implants (PSI). Eight patients underwent single-step primary reconstruction using individual custom-made surgical guides and custom-made prostheses during the same surgery; five patients underwent delayed reconstruction. The material used to manufacture the implants was PEEK in 13 cases. All patients underwent esthetic examination, ophthalmological examination, and radiological evaluation during the preoperative and follow-up periods. The operation duration and short- and long-term complications were recorded. RESULTS: The shape and global position of the implants were satisfactory in each case. Fitting of the implant during surgery required extensive adaptation in 1 case and minor in 11 cases. Of 13 implants, 11 adequately restored a morphological complex area with satisfactory cosmetic results. No complications related to the implants were reported. CONCLUSION: Reconstruction for cranio-facial defects using PEEK computer-aided designed and manufactured implants is a promising new technique that allows for accurate restoration of the complex 3D anatomy of the craniofacial region. PMID- 26242699 TI - Vitamin D in Allergy and Chronic Airway Inflammation. PMID- 26242700 TI - Does Vitamin D Deficiency Epidemic Parallel with Allergy and Asthma Epidemic? AB - Vitamin D (VD) deficiency has re-emerged, after more than hundred years, as a public health problem worldwide. Asthma and allergic disorders constitute another major public health problem with studies having recorded increasing prevalences worldwide since the decade of the 60s. Most of the available experimental and epidemiologic evidence point towards a causal association between low levels of VD and the development of asthma and allergic disorders, and imply a role of VD deficiency on the currently high prevalences of asthma and allergic diseases. The proposed, but still largely hypothetical, underlying mechanism is that VD affects the programming of the fetus and it also has a central modulating role in immune functions involved in asthma and allergic disorders. However, the evidence is not yet clear, since there are studies which support that VD supplementation during pregnancy may promote the development of asthma and allergic disorders. More researches, and especially randomized clinical trials, are required in order to draw safe conclusions and define the role of VD in the prevention or even therapy of asthma and allergic disorders. PMID- 26242701 TI - Vitamin D and Cystic Fibrosis Lung Disease. AB - Vitamin D has been increasingly recognized as being involved in a wide spectrum of biological actions, including significant immunomodulatory effects. The cystic fibrosis (CF) airways are characterized by dysregulated and disproportionately increased, in relation to the underlying bacterial stimuli, inflammatory responses. Vitamin D downregulates pro-inflammatory cytokines and chemokines that promote tissue destruction, and which are abundant in CF lungs. However, despite mounting evidence for a pathophysiological role of Vitamin D in CF airways inflammation, there are only a few clinical reports supporting a relevance of Vitamin D insufficiency with CF airways damage, and so it is early to assign an indisputable causal role to Vitamin D. The present review will examine the current literature regarding the association of Vitamin D status with CF lung disease, and comment on the therapeutic implications accruing from these relations. PMID- 26242702 TI - Vitamin D, Breastfeeding and Food Allergy. AB - In as much as many infants develop allergic symptoms early in infancy, and exposure to allergens may be important in the development of food allergies, there is great interest in maternal dietary strategies during pregnancy and lactation that may prevent food allergies, and thus reduce the burden of disease. Vitamin D levels are known to be associated with atopic disease development in early infancy; however, existing data are controversial. The aim of this review was to investigate any possible effect of vitamin D on the onset of neonatal allergy via breast feeding. PMID- 26242704 TI - Combined and independent cytotoxicity of sodium hypochlorite, ethylenediaminetetraacetic acid and chlorhexidine. AB - AIM: To evaluate the capacity of commonly used root canal irrigants to induce cytotoxic effects, when applied singly or in combination. The hypothesis tested was that the irrigants were less cytotoxic when applied in combination than independently. METHODOLOGY: MRC5 cells were grown as monolayer cultures at 37 degrees C in an atmosphere containing 5% CO2 in air and 100% relative humidity. Cells were exposed to sodium hypochlorite (NaOCl), ethylenediaminetetraacetic acid (EDTA), chlorhexidine (CHX) and their combinations (NaOCl/EDTA, NaOCl/CHX, EDTA/CHX) in serial dilutions. Growth medium was Dulbecco's modified Eagle's medium supplemented with 10% foetal bovine serum and antibiotics and was used as control. The effect on cell survival was estimated after 6 and 24 h of exposure by means of the sulforhodamine B assay, in reference to controls. Dose-response curves were plotted, and 50% inhibitory doses (IC50 ) were subjected to statistical analysis (anova and post hoc comparison test; P < 0.05). Analysis of cell survival and interaction of the irrigants was performed using CalcuSyn dose effect analyzer software to calculate a combination index (CI). RESULTS: The tested irrigants were cytotoxic in dose- and time-dependent manner. CHX was the most cytotoxic irrigant tested, followed by NaOCl, whilst EDTA was the least cytotoxic irrigant tested. The difference between CHX and NaOCl was significant (P < 0.05) as well as between NaOCl and EDTA (P < 0.05). Based on CalcuSyn modelling, a mainly antagonistic effect was recorded with NaOCl/CHX and NaOCl/EDTA combinations. The combination EDTA/CHX had an additive to antagonistic effect. CONCLUSIONS: CHX was significantly more cytotoxic than NaOCl and EDTA. NaOCl was significantly more cytotoxic than EDTA. The combined action of irrigants did not produce a significant increase in their cytotoxicity. PMID- 26242703 TI - Anti-infective immunoadhesins from plants. AB - Immunoadhesins are recombinant proteins that combine the ligand-binding region of a receptor or adhesion molecule with immunoglobulin constant domains. All FDA approved immunoadhesins are designed to modulate the interaction of a human receptor with its normal ligand, such as Etanercept (Enbrel((r)) ), which interferes with the binding of tumour necrosis factor (TNF) to the TNF-alpha receptor and is used to treat inflammatory diseases such as rheumatoid arthritis. Like antibodies, immunoadhesins have long circulating half-lives, are readily purified by affinity-based methods and have the avidity advantages conferred by bivalency. Immunoadhesins that incorporate normal cellular receptors for viruses or bacterial toxins hold great, but as yet unrealized, potential for treating infectious disease. As decoy receptors, immunoadhesins have potential advantages over pathogen-targeted monoclonal antibodies. Planet Biotechnology has specialized in developing anti-infective immunoadhesins using plant expression systems. An immunoadhesin incorporating the cellular receptor for anthrax toxin, CMG2, potently blocks toxin activity in vitro and protects animals against inhalational anthrax. An immunoadhesin based on the receptor for human rhinovirus, ICAM-1, potently blocks infection of human cells by one of the major causes of the common cold. An immunoadhesin targeting the MERS coronavirus is in an early stage of development. We describe here the unique challenges involved in designing and developing immunoadhesins targeting infectious diseases in the hope of inspiring further research into this promising class of drugs. PMID- 26242705 TI - Loss of functional connectivity is greater outside the default mode network in nonfamilial early-onset Alzheimer's disease variants. AB - The common and specific involvement of brain networks in clinical variants of Alzheimer's disease (AD) is not well understood. We performed task-free ("resting state") functional imaging in 60 nonfamilial AD patients, including 20 early onset AD (age at onset <65 years, amnestic/dysexecutive deficits), 24 logopenic aphasia (language deficits), and 16 posterior cortical atrophy patients (visual deficits), as well as 60 healthy controls. Seed-based connectivity analyses were conducted to assess differences between groups in 3 default mode network (DMN) components (anterior, posterior, and ventral) and 4 additional non-DMN networks: left and right executive-control, language, and higher visual networks. Significant decreases in connectivity were found across AD variants compared with controls in the non-DMN networks. Within the DMN components, patients showed higher connectivity in the anterior DMN, in particular in logopenic aphasia. No significant differences were found for the posterior and ventral DMN. Our findings suggest that loss of functional connectivity is greatest in networks outside the DMN in early-onset and nonamnestic AD variants and may thus be a better biomarker in these patients. PMID- 26242706 TI - Therapeutic potentials of human adipose-derived stem cells on the mouse model of Parkinson's disease. AB - The treatment of Parkinson's disease (PD) using stem cells has long been the focus of many researchers, but the ideal therapeutic strategy has not yet been developed. The consistency and high reliability of the experimental results confirmed by animal models are considered to be a critical factor in the stability of stem cell transplantation for PD. Therefore, the aim of this study was to investigate the preventive and therapeutic potential of human adipose derived stem cells (hASC) for PD and was to identify the related factors to this therapeutic effect. The hASC were intravenously injected into the tail vein of a PD mouse model induced by 6-hydroxydopamine. Consequently, the behavioral performances were significantly improved at 3 weeks after the injection of hASC. Additionally, dopaminergic neurons were rescued, the number of structure-modified mitochondria was decreased, and mitochondrial complex I activity was restored in the brains of the hASC-injected PD mouse model. Overall, this study underscores that intravenously transplanted hASC may have therapeutic potential for PD by recovering mitochondrial functions. PMID- 26242707 TI - Association of plasma beta-amyloid with MRI markers of structural brain aging the 3-City Dijon study. AB - Cerebral beta-amyloid (Abeta) deposition and atrophy are central features of Alzheimer disease. Studies of Alzheimer disease biomarkers have largely focused on Abeta in cerebrospinal fluid (CSF), and there is uncertainty as to what plasma Abeta may be a marker. We examined the association of Abeta levels in the plasma with magnetic resonance imaging (MRI)-markers of brain aging, including longitudinal changes in global and regional brain volumes, in dementia-free persons. We studied 1530 participants of the Three-City-Dijon cohort, aged 65-80 years. Plasma Abeta measurement and magnetic resonance imaging were performed at baseline and after a 4-year follow up. Total brain, gray matter, and hippocampal volume were estimated using voxel-based morphometry, and annualized change in brain volumes was calculated. Increased plasma Abeta1-40 was associated with lower baseline hippocampal volume. Although baseline plasma Abeta levels were not associated with longitudinal change in brain volumes, consistently high plasma Abeta1-40 levels were associated with faster total brain atrophy and consistently low plasma Abeta1-42/Abeta1-40 ratio, with increased total brain atrophy and gray matter atrophy. In dementia-free older adults, high plasma Abeta1-40 and low plasma Abeta1-42/Abeta1-40 ratio were associated with smaller hippocampal volume and accelerated global and regional brain atrophy respectively. PMID- 26242708 TI - What is the role of hydrogen peroxide in plant peroxisomes? AB - Plant peroxisomes are unusual subcellular compartments with an apparent simple morphology but with complex metabolic activity. The presence of signal molecules, such as hydrogen peroxide (H(2)O(2)) and nitric oxide inside plant peroxisomes have added new functions in the cross-talk events among organelles and cells under physiological and stress conditions. Moreover, recent advances in proteomic analyses of plant peroxisomes have identified new protein candidates involved in several novel metabolic pathways. With all these new data, the present concise manuscript will focus on the relevance of the peroxisomal H(2)O(2) and its two main antioxidant enzymes, catalase and membrane-bound ascorbate peroxidase, which regulate its level and consequently its potential functions. PMID- 26242709 TI - Patient-specific estimates of vascular and placental properties in growth restricted fetuses based on a model of the fetal circulation. AB - INTRODUCTION: Intrauterine growth restriction (IUGR) due to placental insufficiency is associated with blood-flow redistribution in order to maintain perfusion to the brain. However, some hemodynamic parameters that might be more directly related to staging of the disease cannot be measured non-invasively in clinical practice. For this, we developed a patient-specific model of the fetal circulation to estimate vascular properties of each individual. METHODS: A lumped model of the fetal circulation was developed and personalized using measured echographic data from 37 normal and IUGR fetuses to automatically estimate model based parameters. A multivariate regression analysis was performed to evaluate the association between the Doppler pulsatility indices (PI) and the model-based parameters. The correlation between model-based parameters and the placental lesions was analyzed in a set of 13 IUGR placentas. A logistic regression analysis was done to assess the added value of the model-based parameters relative to Doppler indices, for the detection of fetuses with adverse perinatal outcome. RESULTS: The estimated model-based placental and brain resistances were respectively increased and reduced in IUGR fetuses while placental compliance was increased in IUGR fetus. Umbilical and middle cerebral arteries PIs were most associated with both placental resistance and compliance, while uterine artery PI was more associated with the placental compliance. The logistic regression analysis showed that the model added significant information to the traditional analysis of Doppler waveforms for predicting adverse outcome in IUGR. DISCUSSION: The proposed patient-specific computational model seems to be a good approach to assess hemodynamic parameters than cannot be measured clinically. PMID- 26242710 TI - Effect of oleic acid supplementation on prostaglandin production in maternal endometrial and fetal allantochorion cells isolated from late gestation ewes. AB - INTRODUCTION: Elevated circulating non-esterified fatty acids including oleic acid (OA) are associated with many pregnancy related complications. Prostaglandins (PGs) play crucial roles during parturition. We investigated the effect of OA supplementation on PG production using an in vitro model of ovine placenta. METHODS: Maternal endometrium (ME) and fetal allantochorion (FC) were collected in late pregnancy (day 135). Confluent cells were cultured in serum free medium supplemented with 0, 20 or 100 MUM OA and challenged with control medium, oxytocin (OT, 250 nM), lipopolysaccharide (LPS, 0.1 MUg/ml) or dexamethasone (DEX, 5 MUM). Spent medium was harvested at 2 and 24 h after challenge for quantifying PGs. RESULTS: In ME cells OA increased PGE2 production moderately but attenuated PGF2alpha production leading to a doubling of the PGE2:PGF2alpha ratio (E:F) (P < 0.01). Without OA, both OT and LPS stimulated PG production for about 3-fold (P < 0.01) without changing the E:F ratio. In the ME cells challenged with OT, OA decreased both PGE2 and PGF2alpha production by up to 70% (P < 0.01) whereas in LPS treated cells OA increased the E:F ratio. In FC cells PGE2 production at 2 h was stimulated by 100 MUM OA (P < 0.05). In these cells LPS caused a 3-fold increase in PGE2 (P < 0.01), an effect which was completely inhibited by DEX. DISCUSSION: OA supplementation favours basal PGE2 production in both ME and FC. In ME OA increased E:F ratios and antagonized the stimulatory effect of OT on PG production. This suggests that raised circulating OA may affect both the initiation and progression of parturition. PMID- 26242711 TI - The role of metabolic syndrome in heart failure. AB - Metabolic syndrome (MS) is a highly prevalent condition in patients affected by heart failure (HF); however, it is still unclear whether, in the setting of cardiac dysfunction, it represents an adverse risk factor for the occurrence of cardiac events. The epidemiologic implications of MS in HF have been studied intensely, as many of its components contribute to the incidence and severity of HF. In particular, insulin resistance, diabetes mellitus, and lipid abnormalities represent the main components that negatively influence disease progression and evolution. Yet, other components of the MS, i.e. overweight/obesity and high blood pressure, are favourably associated with outcome in HF patients. The aim of this review was to report epidemiology and prognostic role of MS in HF and to investigate current clinical implications and future research needs. PMID- 26242712 TI - Syncope clinical management in the emergency department: a consensus from the first international workshop on syncope risk stratification in the emergency department. PMID- 26242713 TI - Optical coherence tomography imaging during percutaneous coronary intervention impacts physician decision-making: ILUMIEN I study. AB - AIMS: ILUMIEN I is the largest prospective, non-randomized, observational study of percutaneous coronary intervention (PCI) procedural practice in patients undergoing intra-procedural pre- and post-PCI fractional flow reserve (FFR) and optical coherence tomography (OCT). We report on the impact of OCT on physician decision-making and the association with post-PCI FFR values and early clinical events. METHODS AND RESULTS: Optical coherence tomography and documentary FFR were performed pre- and post-PCI in 418 patients (with 467 stenoses) with stable or unstable angina or NSTEMI. Based on pre-PCI OCT, the procedure was altered in 55% of patients (57% of all stenoses) by selecting different stent lengths (shorter in 25%, longer in 43%). After clinically satisfactory stent implantation using angiographic guidance, post-PCI FFR and OCT were repeated. Optical coherence tomography abnormalities deemed unsatisfactory by the implanting physician were identified: 14.5% malapposition, 7.6% under-expansion, 2.7% edge dissection and prompted further stent optimization based on OCT in 25% of patients (27% of all stenoses) using additional in-stent post-dilatation (81%, 101/124) or placement of 20 new stents (12%). Optimization subgroups were identified post hoc: stent placement without reaction to OCT findings (n = 137), change in PCI planning by pre-PCI OCT (n = 165), post-PCI optimization based on post-PCI OCT (n = 41), change in PCI planning, and post-PCI optimization based on OCT (n = 65). Post-PCI FFR values were significantly different (P = 0.003) between optimization groups (lower in cases with pre- and post-PCI reaction to OCT) but no longer different after post-PCI stent optimization. MACE events at 30 days were low: death 0.25%, MI 7.7%, repeat PCI 1.7%, and stent thrombosis 0.25%. CONCLUSION: Physician decision-making was affected by OCT imaging prior to PCI in 57% and post-PCI in 27% of all cases. CLINICALTRIALS. GOV IDENTIFIER: NCT01663896, Observational Study of Optical Coherence Tomography (OCT) in Patients Undergoing Fractional Flow Reserve (FFR) and Percutaneous Coronary Intervention (ILUMIEN I). PMID- 26242714 TI - Cholesterol, not just cardiovascular risk, is important in deciding who should receive statin treatment. AB - AIMS: Guidelines for primary prevention of cardiovascular disease (CVD) with statins, including the most recent, fail to make the best use of the evidence from clinical trials by concentrating on absolute CVD risk as a statin indication and not also considering that a major determinant of therapeutic benefit is the magnitude of the low-density lipoprotein (LDL) (or non-HDL) cholesterol reduction achieved. This decrease is proportional to the pretreatment concentration. We set out to apply this knowledge to the calculation of the number needed to treat to prevent one event (NNT) and to assess critically how current guidelines performed at different degrees of CVD risk across a range of LDL (or non-HDL) cholesterol concentrations. METHODS AND RESULTS: Number needed to treat to prevent one event revealed exclusion from the treatment of some people with higher cholesterol levels, who may benefit more than others needlessly exposed to statins with no realistic prospect of benefit. Furthermore, abandonment of cholesterol therapeutic goals disadvantaged people with higher levels. CONCLUSION: These problems can be overcome by basing the decision to treat on the NNT calculated both from absolute CVD risk and also on the LDL (or non-HDL) cholesterol reduction achievable with statin treatment. This need not adds an additional layer of complexity for the clinician, because computer programmes already used to estimate CVD risk could be easily amended, thus permitting more effective deployment of statins in the population. PMID- 26242715 TI - Cardiovascular risk in relation to body mass index and use of evidence-based preventive medications in patients with or at risk of atherothrombosis. AB - AIM: Explore the relation between body mass index (BMI) and cardiovascular disease, and the influence of optimal medical therapy (OMT) on this relationship. METHODS AND RESULTS: Patients from the REACH cohort, an international, prospective cohort of patients with or at high risk of atherosclerosis with documentation of potential confounders, including treatments and risk factors, were followed up to 4 years (n = 54 285). Patients were categorized according to baseline BMI (ranging from underweight to Grade III obesity). Optimal medical therapy was defined as the use of the four cardioprotective medication classes (statins, ACE inhibitors/angiotensin II receptor blockers, beta-blockers, and antiplatelet agents). The main outcomes were all-cause mortality, cardiovascular (CV) mortality, and CV events. In primary and secondary prevention, a reverse J shaped curve best described the relationship between BMI categories and the incidence of the various outcomes. In secondary prevention, the highest adjusted risks were observed for underweight patients (1.97, P < 0.01, and 1.29, P = 0.03, for CV mortality and CV events) and the lowest HRs were observed, respectively, in Grade II and Grade III obese patients (0.73, P < 0.01 and 0.80, P < 0.01). The proportion of patients on OMT increased with BMI from 10.1 to 36% (P < 0.001). The apparent CV protection conferred by obesity persisted in patients receiving OMT. CONCLUSION: An obesity paradox was observed in both primary and secondary CV prevention patients. The intensity of use of evidence-based preventive medications does not account for the paradoxical CV protection associated with obesity. At extremes of BMI, further interventions beyond OMT may be needed to reduce CV risk. PMID- 26242717 TI - Reply to Carsten Stephan, Henning Cammann, and Klaus Jung's Letter to the Editor re: Scott A. Tomlins, John R. Day, Robert J. Lonigro, et al. Urine TMPRSS2:ERG Plus PCA3 for Individualized Prostate Cancer Risk Assessment. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2015.04.039. PMID- 26242716 TI - DOSIMETRIC CONSEQUENCES OF USING CONTRAST-ENHANCED COMPUTED TOMOGRAPHIC IMAGES FOR INTENSITY-MODULATED STEREOTACTIC BODY RADIOTHERAPY PLANNING. AB - Potential benefits of planning radiation therapy on a contrast-enhanced computed tomography scan (ceCT) should be weighed against the possibility that this practice may be associated with an inadvertent risk of overdosing nearby normal tissues. This study investigated the influence of ceCT on intensity-modulated stereotactic body radiotherapy (IM-SBRT) planning. Dogs with head and neck, pelvic, or appendicular tumors were included in this retrospective cross sectional study. All IM-SBRT plans were constructed on a pre- or ceCT. Contours for tumor and organs at risk (OAR) were manually constructed and copied onto both CT's; IM-SBRT plans were calculated on each CT in a manner that resulted in equal radiation fluence. The maximum and mean doses for OAR, and minimum, maximum, and mean doses for targets were compared. Data were collected from 40 dogs per anatomic site (head and neck, pelvis, and limbs). The average dose difference between minimum, maximum, and mean doses as calculated on pre- and ceCT plans for the gross tumor volume was less than 1% for all anatomic sites. Similarly, the differences between mean and maximum doses for OAR were less than 1%. The difference in dose distribution between plans made on CTs with and without contrast enhancement was tolerable at all treatment sites. Therefore, although caution would be recommended when planning IM-SBRT for tumors near "reservoirs" for contrast media (such as the heart and urinary bladder), findings supported the use of ceCT with this dose calculation algorithm for both target delineation and IM-SBRT treatment planning. PMID- 26242718 TI - Lethal leukoencephalopathy secondary to Tegafur, a 5-fluorouracil prodrug. PMID- 26242719 TI - The analysis of mitochondrial DNA haplogroups and variants for in vitro fertilization failure in a Han Chinese population. AB - In this study, we aimed to investigate the associations of mitochondrial DNA (mtDNA) haplogroups and variants with in vitro fertilization (IVF) failure. A retrospective, comparative study of 260 fresh IVF cycles in a Han Chinese population was performed from July 2011 to April 2014. Seventy-three couples had low fertilization rates (<=30%) or total fertilization failure, and 187 controls with normal fertilization were included. Human sperm mtDNA haplogroups and variants were determined by polymerase chain reaction (PCR), nested PCR and direct sequencing. One unreported point variant, A15397G, and two novel deletions at positions 8270-8278 and 8276-8284 were found in this study. A homozygous variant, G9053A in MT-ATP6, was detected in 4 of the 73 cases with fertilization failure, whereas this substitution was not detected in the control group (p < 0.01). The frequency of the point 10397 homozygous variant in MT-ND3 in the IVF failure group was markedly lower than that in the control group (p < 0.05). Furthermore, this study showed that the frequencies of point 8701 and 8943 heterozygous variants in MT-ATP6 in the IVF failure group were also markedly lower than those in the control group (p < 0.05). In addition, the frequency of haplogroup Z was markedly higher in the IVF failure group than in the control group (p < 0.05). Our results suggested that MT-ATP6 variants might be possible causes of IVF failure, but the 10397 homozygous variant in MT-ND3 might help decrease the risk of developing IVF failure. Furthermore, this study indicated that men with haplogroup Z might inherit a higher risk of IVF failure in the Han Chinese population. PMID- 26242720 TI - Complete mitogenomes of Armitage angelfish (Apolemichthys armitagei) and Griffisi angelfish (Apolemichthys griffisi) (Teleostei: Pomacanthidae). AB - In this study, we used the next-generation sequencing method to deduce complete mitogenomes of Armitage angelfish (Apolemichthys armitagei) and Griffisi angelfish (A. griffisi) for the first time. The assembled mitogenomes, consists 16,551 bp (A. armitagei) and 16,528 bp (A. griffisi) in length, shows 92% identity each other. Both mitogenomes follow the typical vertebrate arrangement, including 13 protein coding genes, 22 transfer RNAs, two ribosomal RNAs genes, and a non-coding control region of D-loop. D-loop contains a length of 828 bp in A. armitagei and 849 bp in A. griffisi and locates between tRNA-Pro and tRNA-Phe. Complete mitogenomes of Armitage angelfish and Griffisi angelfish deduced in this study provide essential and important DNA molecular data for further phylogenetic and evolutionary analysis for marine angelfish. PMID- 26242721 TI - The complete mitochondrial genome of Coptotermes testaceus (Isoptera: Rhinotermitidae). AB - The complete circular mitochondrial genome (mitogenome) of Coptotermes testaceus is 15 752bp in size, containing 37 typical genes and one non-coding AT-rich region. The AT content of the AT-rich region is 68.3%. All protein coding genes (PCGs) start with standard ATN initiation codons and end with complete termination codons TAA or TAG except for cox2, atp8, and nad5 genes using an incomplete stop codon T. tRNA genes are predicted with a characteristic cloverleaf secondary structure except for trnS1(()(AGN)()), whose dihydrouridine (DHU) arm is replaced by a simple loop. The size of the large and small ribosomal RNA genes are 1315 and 818 bp, respectively. Phylogenetic analysis found that (i) the C. testaceus clade formed the sister group with another clade containing Coptotermes lacteus and Coptotermes formosanus; and (ii) Coptotermes lacteus had a close relationship with Coptotermes clade, but with lower credibility than other clades, the bootstrap value was 97%. PMID- 26242722 TI - Yauk gyar mann yin (Be a man!): masculinity and betel quid chewing among men in Mandalay, Myanmar. AB - Betel quid chewing is associated with various oral cancers and other health concerns, including reproductive health issues. Nevertheless, the practice is widespread in Myanmar, especially among men. This qualitative study elucidates the gendered aspects of betel quid chewing by examining how it links with masculine ideology among male betel quid chewers in Mandalay, Myanmar. Data were collected through in-depth interviews, focus-group discussions, key-informant interviews and participant observation. The thematic content analysis was guided by Connell's concept of hegemonic masculinity and Butler's notion of gender performativity. The findings indicated that young Mandalay men were drawn to betel quid chewing by the value they gave to satisfying their curiosity, power competition, risk-taking and a display of manliness. Thus, the practice of betel quid chewing, as defined by our participants, was perceived as manly, trendy, stylish and sexually attractive. For adult men, betel quid chewing was a social lubricant that assisted them in talking with clients and co-workers, thus enhancing their economic opportunities with other men. It also helped working class men to work harder. Betel quid chewing harm-reduction programmes therefore need to be mindful of masculinity issues as well as the economic aspects of betel quid chewing. PMID- 26242723 TI - Assessing the contribution of interferon antagonism to the virulence of West African Ebola viruses. AB - The current Ebola virus (EBOV) outbreak in West Africa is unprecedented in terms of both its size and duration, and there has been speculation and concern regarding the potential for EBOV to increase in virulence as a result of its prolonged circulation in humans. Here we investigate the relative potency of the interferon (IFN) inhibitors encoded by EBOVs from West Africa, since an important EBOV virulence factor is inhibition of the antiviral IFN response. Based on this work we show that, in terms of IFN antagonism, the West African viruses display no discernible differences from the prototype Mayinga isolate, which corroborates epidemiological data suggesting these viruses show no increased virulence compared with those from previous outbreaks. This finding has important implications for public health decisions, since it does not provide experimental support for theoretical claims that EBOV might gain increased virulence due to the extensive human-to-human transmission in the on-going outbreak. PMID- 26242724 TI - Comparison of nutrient intakes from two selected diet plans considered healthful versus the cutoff points for green lights as defined by the UK's multiple traffic light scheme. AB - This study compared nutrient intakes from 7-day menus for the US MyPlate and DASH Eating Plan versus the cutoff points for green lights defined by the UK's multiple traffic light (MTL) scheme. For both diets, the foods achieved green lights for saturated fat and salt, and for beverages for total fat, saturated fat and salt. The other nutrients achieved amber lights but were within the range of the two diets. By contrast, the MTL threshold for salt in beverages was outside the range of the diets. The values for salt in beverages in the MyPlate and Dash diet plans were 0.06+/-0.07 and 0.19+/-0.01 (s.d.) g/100 ml, which are both considerably lower compared with the cutoff of 0.3 g/100 ml for an MTL green light. Adjusting the green MTL threshold values to the median values for a healthful diet could help make MTL labelling a more valid way of helping consumers choose a healthful diet. PMID- 26242726 TI - Implementing cognitive therapies into routine psychosis care: organisational foundations. AB - BACKGROUND: Treatment outcomes for people diagnosed with psychosis remain suboptimal due in part to the limited systematic application of evidence based practice (Adm Policy Ment Health, 36: 1-7, 2009) [1]. The Implementation science literature identifies a number of factors organisationally that need to be considered when planning to introduce a particular EBP. Profiling these organisational characteristics at baseline, prior to commencement of service reform can determine the focus of a subsequent implementation plan. This study examined the organisational baseline factors existing in two services promoting the routine use of cognitive interventions for psychosis. One of the services studied has since undertaken organisational structural reform to facilitate the greater uptake of Evidence Based Practice (EBP). The results of this study were used to design an implementation strategy to make cognitive therapies a part of routine psychosis care. METHODS: One hundred-and-six mental health staff from two metropolitan mental health services in Australia was surveyed to ascertain their attitudes, competencies and interest in Cognitive Behavioural Therapy for psychosis (CBTp) and Cognitive Remediation Therapy (CRT). In addition perceptions of organisational values were profiled using the Organisational Culture Profile (OCP). Fifty five participants were excluded because they completed less than 50% of the survey. The final sample consisted of 51 participants. RESULTS: 48.1% of surveys were completed. Over 50% of staff were interested in CBTp and CRT approaches to psychosis. Staff were aware of existing CBTp and CRT programs but these were not uniformly available throughout the services. Fourteen percent of staff identified as CBT therapist and 35% were trained CRT facilitators. Only 12% of staff were receiving therapy specific supervision. The Organisational Culture Profile (OCP) at baseline revealed highest scores amongst leadership, planning, and humanistic workplace domains, with communication receiving the lowest rating indicative of organisational weakness. CONCLUSION: Profiling the factors associated with successful implementation of service reform informed the implementation planning and the efficient deployment of resources in a mental health service introducing cognitive therapies for psychosis into routine clinical care. The majority of staff had positive attitudes to the evidence based cognitive therapies allowing a focus on training and supervision and the development of supporting organisational elements. PMID- 26242725 TI - Body composition during fetal development and infancy through the age of 5 years. AB - Fetal body composition is an important determinant of body composition at birth, and it is likely to be an important determinant at later stages in life. The purpose of this work is to provide a comprehensive overview by presenting data from previously published studies that report on body composition during fetal development in newborns and the infant/child through 5 years of age. Understanding the changes in body composition that occur both in utero and during infancy and childhood, and how they may be related, may help inform evidence based practice during pregnancy and childhood. We describe body composition measurement techniques from the in utero period to 5 years of age, and identify gaps in knowledge to direct future research efforts. Available literature on chemical and cadaver analyses of fetal studies during gestation is presented to show the timing and accretion rates of adipose and lean tissues. Quantitative and qualitative aspects of fetal lean and fat mass accretion could be especially useful in the clinical setting for diagnostic purposes. The practicality of different pediatric body composition measurement methods in the clinical setting is discussed by presenting the assumptions and limitations associated with each method that may assist the clinician in characterizing the health and nutritional status of the fetus, infant and child. It is our hope that this review will help guide future research efforts directed at increasing the understanding of how body composition in early development may be associated with chronic diseases in later life. PMID- 26242727 TI - Is there a place for virtual reality simulators in assessment of competency in percutaneous renal access? AB - OBJECTIVE: To assess competency of urology post-graduate trainees (PGTs) in percutaneous renal access (PCA). METHODS: Upon obtaining ethics approval and informed consents, PGTs between post-graduate years (PGY-3 to PGY-5) from all four urology programs in Quebec were recruited. PCA competency of each participant was assessed objectively by performing task 4 on the PERC MentorTM simulator, where they had to correctly access and pop 7 balloons in 7 different renal calyces and subjectively by the validated Percutaneous Nephrolithotomy Global Rating Scale (PCNL-GRS). RESULTS: A total of 26 PGTs with a mean age of 29.2 +/- 0.7 years participated in this study. When compared with the 21 PGTs without practice, all 5 PGTs who had practiced on the simulator were competent (p = 0.03), performed the task with significantly shorter operative time (13.9 +/- 0.7 vs. 4.4 +/- 0.4 min; p < 0.001) and fluoroscopy time (9.3 +/- 0.6 vs. 3.4 +/- 0.4 min; p < 0.001), and had significantly higher PCNL-GRS scores (13 +/- 0.6 vs. 20.6 +/- 1; p < 0.001) and successful attempts to access renal calyces (23 +/- 5 vs. 68.7 +/- 11; p = 0.001). According to a pass score of 13/25, thirteen PGTs were competent. Competent PGTs performed the task with significantly shorter fluoroscopy time (9.8 vs. 6.5 min; p = 0.01) and higher percentage of successful attempts to access renal calyces (p < 0.001), higher PCNL-GRS scores (p < 0.001), and lower complications (p = 0.01). CONCLUSION: The PCNL-GRS in combination with the PERC MentorTM simulator was able to differentiate between competent and non competent PGTs. PMID- 26242728 TI - Stereoscopic (3D) versus monoscopic (2D) laparoscopy: comparative study of performance using advanced HD optical systems in a surgical simulator model. AB - PURPOSE: To compare task performances of novices and experts using advanced high definition 3D versus 2D optical systems in a surgical simulator model. METHODS: Fifty medical students (novices in laparoscopy) were randomly assigned to perform five standardized tasks adopted from the Fundamentals of Laparoscopic Surgery (FLS) curriculum in either a 2D or 3D laparoscopy simulator system. In addition, eight experts performed the same tasks. Task performances were evaluated using a validated scoring system of the SAGES/FLS program. Participants were asked to rate 16 items in a questionnaire. RESULTS: Overall task performance of novices was significantly better using stereoscopic visualization. Superiority of performances in 3D reached a level of significance for tasks peg transfer and precision cutting. No significant differences were noted in performances of experts when using either 2D or 3D. Overall performances of experts compared to novices were better in both 2D and 3D. Scorings in the questionnaires showed a tendency toward lower scores in the group of novices using 3D. CONCLUSIONS: Stereoscopic imaging significantly improves performance of laparoscopic phantom tasks of novices. The current study confirms earlier data based on a large number of participants and a standardized task and scoring system. Participants felt more confident and comfortable when using a 3D laparoscopic system. However, the question remains open whether these findings translate into faster and safer operations in a clinical setting. PMID- 26242730 TI - Diuretics vs. placebo for postpartum blood pressure control in preeclampsia (DIUPRE): a randomized clinical trial. AB - BACKGROUND: Hypertension affects about 10% of pregnancies and is responsible for both maternal and neonatal devastating complications such as eclampsia, HELLP syndrome, prematurity and maternal and neonatal death. The resolution of the disease occurs in the first twelve weeks postpartum. The behavior of blood pressure and occurrence of very high blood pressure episodes among women with severe preeclampsia is related to remodeling of the dynamics of body fluids with consequent increase in intravascular volume. The persistence of hypertension in critical levels results in increased puerperal morbidity. OBJECTIVES: To evaluate the effectiveness of furosemide in accelerating blood pressure recovery among women with severe preeclampsia. METHODS/DESIGN: A triple-masked placebo controlled clinical trial, will be conducted including 120 postpartum women with severe preeclampsia, after eclampsia prophylaxis with magnesium sulfate and with adequate diuresis. Women with chronic hypertension and users of diuretics will be deleted. Informed consent will be obtained from all participants. Patients will be randomized to receive furosemide (40 mg orally every twenty four hours) or placebo. The variables are systolic and diastolic blood pressure, frequency of hypertensive crises, need for maintenance of antihypertensive therapy, number of antihypertensive agents used to control blood pressure, urine output, length of hospital stay, adverse effects and maternal complications. This study was approved by the Research Ethics Committee in humans of our institution. All participants will be duly informed about the aims of the project and will be included only if they agree to participate voluntarily, signing the informed consent. TRIAL REGISTRATION: This study was registered on Clinical Trials.gov under the number NCT02163655. ( http://clinicaltrials.gov/show/NCT02163655). PMID- 26242729 TI - The first morphometric and phylogenetic perspective on molecular epidemiology of Echinococcus granulosus sensu lato in stray dogs in a hyperendemic Middle East focus, northwestern Iran. AB - BACKGROUND: Hydatidosis is considered to be a neglected cyclo-zoonotic disease in Middle East countries particularly northwestern Iran which is caused by metacestode of tapeworm Echinococcus granulosus sensu lato. Human hydatidosis is a high public health priority in the area, however there is little known from a morphometric and phylogenetic perspective on molecular epidemiology of adult Echinococcus spp. in Iranian stray dogs. METHODS: 80 dogs (38 males and 42 females) were collected during June 2013 to April 2014 in northwestern Iran. The isolated parasites from each dog were distinguished by morphometric keys including small, large hook length and blade length. Subsequently, isolates were confirmed by sequencing of mitochondrial cytochrome oxidase subunit 1 gene. RESULTS: 16 (8 males and 8 females) (Prevalence 20%) out of 80 dogs were infected to genus Echinococcus. With regard to demographic factors, the frequency of parasitism in both male, female adults and their age groups showed no difference (P > 0.05). The phylogenetic analyses of cox1 sequences firmly revealed the 13 sheep strains (G1), one buffalo strain (G3), one camel strain (G6) and one mixed infection. The findings of rostellar hook morphology show an intraspecies variation range among G1 isolates. However, hook measurements in Echinococcus derived from G1 (sheep strain) were not a significant difference from those G6 and G3 strains. Six unique haplotypes were identified containing a high range of diversity (Haplotype diversity 0.873 vs. Nucleotide diversity 0.02). CONCLUSIONS: First presence of camel strain (G6) in this region seems to indicate that potential intermediate hosts play a secondary role in the maintenance of camel dog biology. Current findings have heightened our knowledge about determination of Echinococcus prevalence, strains of taxonomy and genotypic trait of parasite in Iranian stray dogs which will also help in the development of strategies for monitoring and control of infected stray dogs in the area. PMID- 26242731 TI - Use of intraoperative fluoroscopy for the safe placement of C2 laminar screws: technical note. AB - INTRODUCTION: Rigid fixation of the atlantoaxial joint can be quite challenging due to complex anatomic variants. Numerous techniques have evolved over time, improving the surgeon's adaptability. The recent advent of C2 laminar screws adds to the surgeon's armamentarium, but is not without its own set of limitations. Risk of ventral laminar breach with possible spinal cord injury, CSF leak, or poor bony fixation have led some to recommend prefabricated models or expensive intraoperative spinal navigation to aid screw placement. The purpose of this report is to detail how the use of intraoperative fluoroscopy can be used to aid in the safe placement of C2 laminar screws. METHODS: One patient with rheumatoid arthritis and progressive cervical myelopathy from C1-2 instability underwent C1 2 fixation using C2 laminar screws. Intraoperative fluoroscopy was used to guide and confirm safe laminar screw placement. RESULTS: Immediate and 6-month postoperative imaging demonstrated excellent placement of C2 laminar screws without ventral breach. At 6 months, the patient noted significant improvement of her preoperative symptoms. CONCLUSION: Use of intraoperative fluoroscopy is an easy and safe method for the placement of C2 laminar screws. Given its use of readily available equipment, this method can be implemented without significant pre-planning, or as an impromptu salvage maneuver. PMID- 26242732 TI - L-type Calcium Channel Cav1.2 Is Required for Maintenance of Auditory Brainstem Nuclei. AB - Cav1.2 and Cav1.3 are the major L-type voltage-gated Ca(2+) channels in the CNS. Yet, their individual in vivo functions are largely unknown. Both channel subunits are expressed in the auditory brainstem, where Cav1.3 is essential for proper maturation. Here, we investigated the role of Cav1.2 by targeted deletion in the mouse embryonic auditory brainstem. Similar to Cav1.3, loss of Cav1.2 resulted in a significant decrease in the volume and cell number of auditory nuclei. Contrary to the deletion of Cav1.3, the action potentials of lateral superior olive (LSO) neurons were narrower compared with controls, whereas the firing behavior and neurotransmission appeared unchanged. Furthermore, auditory brainstem responses were nearly normal in mice lacking Cav1.2. Perineuronal nets were also unaffected. The medial nucleus of the trapezoid body underwent a rapid cell loss between postnatal days P0 and P4, shortly after circuit formation. Phosphorylated cAMP response element-binding protein (CREB), nuclear NFATc4, and the expression levels of p75NTR, Fas, and FasL did not correlate with cell death. These data demonstrate for the first time that both Cav1.2 and Cav1.3 are necessary for neuronal survival but are differentially required for the biophysical properties of neurons. Thus, they perform common as well as distinct functions in the same tissue. PMID- 26242733 TI - Structural Insight into Specificity of Interactions between Nonconventional Three finger Weak Toxin from Naja kaouthia (WTX) and Muscarinic Acetylcholine Receptors. AB - Weak toxin from Naja kaouthia (WTX) belongs to the group of nonconventional "three-finger" snake neurotoxins. It irreversibly inhibits nicotinic acetylcholine receptors and allosterically interacts with muscarinic acetylcholine receptors (mAChRs). Using site-directed mutagenesis, NMR spectroscopy, and computer modeling, we investigated the recombinant mutant WTX analogue (rWTX) which, compared with the native toxin, has an additional N terminal methionine residue. In comparison with the wild-type toxin, rWTX demonstrated an altered pharmacological profile, decreased binding of orthosteric antagonist N-methylscopolamine to human M1- and M2-mAChRs, and increased antagonist binding to M3-mAChR. Positively charged arginine residues located in the flexible loop II were found to be crucial for rWTX interactions with all types of mAChR. Computer modeling suggested that the rWTX loop II protrudes to the M1-mAChR allosteric ligand-binding site blocking the entrance to the orthosteric site. In contrast, toxin interacts with M3-mAChR by loop II without penetration into the allosteric site. Data obtained provide new structural insight into the target-specific allosteric regulation of mAChRs by "three finger" snake neurotoxins. PMID- 26242734 TI - Functional Analysis of the Bacteriophage T4 Rad50 Homolog (gp46) Coiled-coil Domain. AB - Rad50 and Mre11 form a complex involved in the detection and processing of DNA double strand breaks. Rad50 contains an anti-parallel coiled-coil with two absolutely conserved cysteine residues at its apex. These cysteine residues serve as a dimerization domain and bind a Zn(2+) cation in a tetrathiolate coordination complex known as the zinc-hook. Mutation of the zinc-hook in bacteriophage T4 is lethal, indicating the ability to bind Zn(2+) is critical for the functioning of the MR complex. In vitro, we found that complex formation between Rad50 and a peptide corresponding to the C-terminal domain of Mre11 enhances the ATPase activity of Rad50, supporting the hypothesis that the coiled-coil is a major conduit for communication between Mre11 and Rad50. We constructed mutations to perturb this domain in the bacteriophage T4 Rad50 homolog. Deletion of the Rad50 coiled-coil and zinc-hook eliminates Mre11 binding and ATPase activation but does not affect its basal activity. Mutation of the zinc-hook or disruption of the coiled-coil does not affect Mre11 or DNA binding, but their activation of Rad50 ATPase activity is abolished. Although these mutants excise a single nucleotide at a normal rate, they lack processivity and have reduced repetitive exonuclease rates. Restricting the mobility of the coiled-coil eliminates ATPase activation and repetitive exonuclease activity, but the ability to support single nucleotide excision is retained. These results suggest that the coiled-coiled domain adopts at least two conformations throughout the ATPase/nuclease cycle, with one conformation supporting enhanced ATPase activity and processivity and the other supporting nucleotide excision. PMID- 26242735 TI - Peroxisome Proliferator-activated Receptor-D (PPARD) Coordinates Mouse Spermatogenesis by Modulating Extracellular Signal-regulated Kinase (ERK) dependent Signaling. AB - Ppard(-/-) mice exhibit smaller litter size compared with Ppard(+/+) mice. To determine whether peroxisome proliferator-activated receptor-D (PPARD) could possibly influence this phenotype, the role of PPARD in testicular biology was examined. Atrophic testes and testicular degeneration were observed in Ppard(-/-) mice compared with Ppard(+/+) mice, indicating that PPARD modulates spermatogenesis. Higher expression of p27 and decreased expression of proliferating cellular nuclear antigen in Sertoli cells were observed in Ppard(+/+) mice as compared with Ppard(-/-) mice, and these were associated with decreased Sertoli cell number in Ppard(+/+) mice. Cyclin D1 and cyclin D2 expression was lower in Ppard(+/+) as compared with Ppard(-/-) mice. Ligand activation of PPARD inhibited proliferation of a mouse Sertoli cell line, TM4, and an inverse agonist of PPARD (DG172) rescued this effect. Temporal inhibition of extracellular signal-regulated kinase (ERK) activation by PPARD in the testis was observed in Ppard(+/+) mice and was associated with decreased serum follicle stimulating hormone and higher claudin-11 expression along the blood-testis barrier. PPARD-dependent ERK activation also altered expression of claudin-11, p27, cyclin D1, and cyclin D2 in TM4 cells, causing inhibition of cell proliferation, maturation, and formation of tight junctions in Sertoli cells, thus confirming a requirement for PPARD in accurate Sertoli cell function. Combined, these results reveal for the first time that PPARD regulates spermatogenesis by modulating the function of Sertoli cells during early testis development. PMID- 26242736 TI - Single and Compound Knock-outs of MicroRNA (miRNA)-155 and Its Angiogenic Gene Target CCN1 in Mice Alter Vascular and Neovascular Growth in the Retina via Resident Microglia. AB - The response of the retina to ischemic insult typically leads to aberrant retinal neovascularization, a major cause of blindness. The epigenetic regulation of angiogenic gene expression by miRNAs provides new prospects for their therapeutic utility in retinal neovascularization. Here, we focus on miR-155, a microRNA functionally important in inflammation, which is of paramount importance in the pathogenesis of retinal neovascularization. Whereas constitutive miR-155 deficiency in mice results in mild vascular defects, forced expression of miR-155 causes endothelial hyperplasia and increases microglia count and activation. The mouse model of oxygen-induced retinopathy, which recapitulates ischemia-induced aberrant neovessel growth, is characterized by increased expression of miR-155 and localized areas of microglia activation. Interestingly, miR-155 deficiency in mice reduces microglial activation, curtails abnormal vessel growth, and allows for rapid normalization of the retinal vasculature following ischemic insult. miR 155 binds to the 3'-UTR and represses the expression of the CCN1 gene, which encodes an extracellular matrix-associated integrin-binding protein that both promotes physiological angiogenesis and harnesses growth factor-induced abnormal angiogenic responses. Single CCN1 deficiency or double CCN1 and miR-155 knock-out in mice causes retinal vascular malformations typical of faulty maturation, mimicking the vascular alterations of miR-155 gain of function. During development, the miR-155/CCN1 regulatory axis balances the proangiogenic and proinflammatory activities of microglia to allow for their function as guideposts for sprout fusion and anastomosis. Under ischemic conditions, dysregulated miR 155 and CCN1 expression increases the inflammatory load and microglial activation, prompting aberrant angiogenic responses. Thus, miR-155 functions in tandem with CCN1 to modulate inflammation-induced vascular homeostasis and repair. PMID- 26242737 TI - Dihydrofolate Reductase and Thymidylate Synthase Transgenes Resistant to Methotrexate Interact to Permit Novel Transgene Regulation. AB - Methotrexate (MTX) is an anti-folate that inhibits de novo purine and thymidine nucleotide synthesis. MTX induces death in rapidly replicating cells and is used in the treatment of multiple cancers. MTX inhibits thymidine synthesis by targeting dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS). The use of MTX to treat cancer also causes bone marrow suppression and inhibits the immune system. This has led to the development of an MTX-resistant DHFR, DHFR L22F, F31S (DHFR(FS)), to rescue healthy cells. 5-Fluorouracil-resistant TYMS T51S, G52S (TYMS(SS)) is resistant to MTX and improves MTX resistance of DHFR(FS) in primary T cells. Here we find that a known mechanism of MTX-induced increase in DHFR expression persists with DHFR(FS) and cis-expressed transgenes. We also find that TYMS(SS) expression of cis-expressed transgenes is similarly decreased in an MTX-inducible manner. MTX-inducible changes in DHFR(FS) and TYMS(SS) expression changes are lost when both genes are expressed together. In fact, expression of the DHFR(FS) and TYMS(SS) cis-expressed transgenes becomes correlated. These findings provide the basis for an unrecognized post transcriptional mechanism that functionally links expression of DHFR and TYMS. These findings were made in genetically modified primary human T cells and have a clear potential for use in clinical applications where gene expression needs to be regulated by drug or maintained at a specific expression level. We demonstrate a potential application of this system in the controlled expression of systemically toxic cytokine IL-12. PMID- 26242740 TI - The Effect of Medical Treatment of Attention Deficit Hyperactivity Disorder (ADHD) on Foster Care Caseloads: Evidence from Danish Registry Data. AB - Since the early 2000s, foster care caseloads have decreased in many wealthy democracies, yet the causes of these declines remain, for the most part, a mystery. This article uses administrative data on all Danish municipalities (N = 277) and a 10% randomly drawn sample of all Danish children (N = 157,938) in the period from 1998 to 2010 to show that increasing medical treatment of attention deficit hyperactivity disorder (ADHD) accounts for a substantial share of the decrease in foster care caseloads. According to our estimates, the decline in foster care caseloads during this period would have been 45% smaller absent increases in medical treatment of ADHD. These findings are especially provocative in light of recent research showing ambiguous effects of medical treatment of ADHD. Future research should be attentive to how medical treatment aimed at addressing children's acute behavioral problems could also have a powerful effect on foster care caseloads. PMID- 26242741 TI - The Effect of Assertiveness Training on the Mobbing That Nurses Experience. AB - This research was designed to determine the impact of assertiveness training on the mobbing experience of nurses. This study was conducted in two phases. In the first phase, 218 nurses completed the mobbing scale; the education group consisted of 38 nurses who received a score at or above 204 points. A total of 180 nurses were excluded from the education group because they received less than 204 points. The study was conducted with 30 nurses because 8 nurses did not agree to participate in the study. The 30 nurses received the assertiveness training program. Six months after training, the nurses completed the mobbing scale and Rathus Assertiveness Inventory (RAI) again. The assertiveness training positively affected the assertiveness and mobbing scores (p = .000). After the training, the assertiveness scores increased and the mobbing condition score decreased (p < .01). Assertiveness training is an effective method for decreasing mobbing. In line with these results, training programs, which support nurses' personal development by providing counseling and support to nurse victims of mobbing, are recommended. PMID- 26242739 TI - Endocrine disruptors alter social behaviors and indirectly influence social hierarchies via changes in body weight. AB - BACKGROUND: In humans, the causal link between socioeconomic status (SES) and body weight (BW) is bidirectional, as chronic stress associated with low SES may increase risk of obesity and excess weight may worsen career opportunities resulting in lower SES. We hypothesize that environmental factors affecting BW and/or social stress might reprogram physiological and social trajectories of individuals. OBJECTIVES: To analyze interactions between BW and social behaviors in mice perinatally exposed to one of several environmental endocrine disruptors. METHODS: CD-1 mice were fed 0.2 mg/kg BW/day tetrabromobisphenol-A (TBBPA), 2,2,4,4-tetrabromodiphenyl ether (BDE-47), bisphenol S (BPS), or oil (vehicle) from pregnancy day 8 through postpartum day 21. Three male offspring (triad) from each litter were housed together until week 15 and subjected to a Sociability Test and Tube Tests. Cages were then rearranged so that animals of the same social rank from the four exposure groups were housed together in tetrads. Social hierarchy in tetrads was again analyzed by Tube Tests. RESULTS: In Sociability Tests, the mean velocity of all exposed animals increased when they encountered a stranger mouse and less time was spent with conspecifics. BW and social dominance of animals in triads and tetrads were inversely associated. BDE-47 and BPS caused transient decreases in BW. CONCLUSIONS: Developmental exposure to environmental xenobiotics shifted behavior towards increased anxiety and decreased interest in social interactions. Our mouse model reproduces negative associations between social hierarchy status and BW. These results suggest that manipulation of BW by endocrine disruptors may affect social ranking. PMID- 26242742 TI - N-Acetyl Cysteine improves the diabetic cardiac function: possible role of fibrosis inhibition. AB - BACKGROUND: Diabetic cardiomyopathy is one of the leading causes of death in diabetes mellitus (DM) patients. This study aimed to explore the therapeutic implication of N-acetyl-L-cysteine (NAC, an antioxidant and glutathione precursor) and the possible underlying mechanism. METHODS: Thirty five 12-week old male C57BL/6 mice were included. Twenty-five diabetic mice were induced by intraperitoneal injection of streptozocin (STZ, 150 mg/kg, Sigma-Aldrich) dissolved in a mix of citrate buffer after overnight fast. Mice with a blood glucose level above 13.5 mmol/L were considered diabetic. As a non-DM (diabetic) control, mice were injected with equal volume of citrate buffer. The 25 diabetic mice were divided into 5 groups with 5 animals in each group: including DM (diabetes without NAC treatment), and 4 different NAC treatment groups, namely NAC1, NAC3, NAC5 and NAC7, with the number defining the start time point of NAC treatment. In the 10 non-DM mice, mice were either untreated (Ctrl) or treated with NAC for 5 weeks (NAC only). Echocardiography was performed 12 weeks after STZ injection. Heart tissue were collected after echocardiography for Hematoxylin Eosin (HE) and Trichrome staining and ROS staining. Cardiac fibroblast cells were isolated, cultured and treated with high glucose plus NAC or the vehicle. qPCR analysis and CCK-8 assay were performed to observe fibrotic gene expression and cell proliferation. RESULTS: We found that both cardiac systolic function and diastolic function were impaired, coupled with excessive reactive oxygen stress and cardiac fibrosis 12 weeks after STZ induction. NAC significantly reduced ROS generation and fibrosis, together with improved cardiac systolic function and diastolic function. Strikingly, NAC1 treatment, which had the earlier and longer treatment, produced significant improvement of cardiac function and less fibrosis. In the cardiac fibroblasts, NAC blocked cardiac fibroblast proliferation and collagen synthesis induced by hyperglycemia. CONCLUSIONS: Our study indicates that NAC treatment in diabetes effectively protects from diabetic cardiomyopathy, possibly through inhibiting the ROS production and fibrosis, which warrants further clarification. PMID- 26242744 TI - What Does It Mean to be Central? A Botanical Geography of Paris 1830-1848. AB - This paper focuses on the geography of the botanical community in Paris, under the July Monarchy (1830-1848). At that time, the Museum d'Histoire naturelle (MHN) was at its institutional acme and, under the impulse of Francois Guizot, its budget was increasing dramatically. However, closer attention to manuscript sources (correspondence, travel diaries) reveals that the botanists of the time favoured other private institutions, located both on the Right and Left Banks of the Seine. The MHN was prestigious for its collections and professors but it was relatively remote from the centre of Paris, and its plant samples were sometimes difficult to access. Several other first-class private herbaria granted liberal access to botanists: those of Jacques Gay, Phillip Barker Webb, and Benjamin Delessert. Thanks to their wealth, these plant amateurs had ownership of historical herbaria consisting of species types alongside rich botanical libraries. Botanists visiting Paris from foreign countries or other provinces of France also spent some time studying less general plant collections, like those of Count Jaubert, or specialized collections, like Montagne's or Leveille's on cryptogams. Other botanists also enjoyed renown at the time, although they published little, if anything (like Maire). Living in crammed apartments, literally in the middle of their plant samples, these botanists were key nodes in botanical networks, although they had no relation with the prestigious MHN. PMID- 26242745 TI - The Bacterial Cell Wall in the Antibiotic Era: An Ontology in Transit Between Morphology and Metabolism, 1940s-1960s. AB - This essay details a historical crossroad in biochemistry and microbiology in which penicillin was a co-agent. I narrate the trajectory of the bacterial cell wall as the precise target for antibiotic action. As a strategic object of research, the bacterial cell wall remained at the core of experimental practices, scientific narratives and research funding appeals throughout the antibiotic era. The research laboratory was dedicated to the search for new antibiotics while remaining the site at which the mode of action of this new substance was investigated. This combination of circumstances made the bacterial wall an ontology in transit. As invisible as the bacterial wall was for clinical purposes, in the biological laboratory, cellular meaning in regard to the action of penicillin made the bacterial wall visible within both microbiology and biochemistry. As a border to be crossed, some components of the bacterial cell wall and the biochemical destruction produced by penicillin became known during the 1950s and 1960s. The cell wall was constructed piece by piece in a transatlantic circulation of methods, names, and images of the shape of the wall itself. From 1955 onwards, microbiologists and biochemists mobilized new names and associated conceptual meanings. The composition of this thin and rigid layer would account for its shape, growth and destruction. This paper presents a history of biochemical morphology: a chemistry of shape - the shape of bacteria, as provided by its wall - that accounted for biology, for life itself. While penicillin was being established as an industrially-manufactured object, it remained a scientific tool within the research laboratory, contributing to the circulation of further scientific objects. PMID- 26242743 TI - Clinical review: intensive care unit acquired weakness. AB - A substantial number of patients admitted to the ICU because of an acute illness, complicated surgery, severe trauma, or burn injury will develop a de novo form of muscle weakness during the ICU stay that is referred to as "intensive care unit acquired weakness" (ICUAW). This ICUAW evoked by critical illness can be due to axonal neuropathy, primary myopathy, or both. Underlying pathophysiological mechanisms comprise microvascular, electrical, metabolic, and bioenergetic alterations, interacting in a complex way and culminating in loss of muscle strength and/or muscle atrophy. ICUAW is typically symmetrical and affects predominantly proximal limb muscles and respiratory muscles, whereas facial and ocular muscles are often spared. The main risk factors for ICUAW include high severity of illness upon admission, sepsis, multiple organ failure, prolonged immobilization, and hyperglycemia, and also older patients have a higher risk. The role of corticosteroids and neuromuscular blocking agents remains unclear. ICUAW is diagnosed in awake and cooperative patients by bedside manual testing of muscle strength and the severity is scored by the Medical Research Council sum score. In cases of atypical clinical presentation or evolution, additional electrophysiological testing may be required for differential diagnosis. The cornerstones of prevention are aggressive treatment of sepsis, early mobilization, preventing hyperglycemia with insulin, and avoiding the use parenteral nutrition during the first week of critical illness. Weak patients clearly have worse acute outcomes and consume more healthcare resources. Recovery usually occurs within weeks or months, although it may be incomplete with weakness persisting up to 2 years after ICU discharge. Prognosis appears compromised when the cause of ICUAW involves critical illness polyneuropathy, whereas isolated critical illness myopathy may have a better prognosis. In addition, ICUAW has shown to contribute to the risk of 1-year mortality. Future research should focus on new preventive and/or therapeutic strategies for this detrimental complication of critical illness and on clarifying how ICUAW contributes to poor longer-term prognosis. PMID- 26242746 TI - CD163 interacts with TWEAK to regulate tissue regeneration after ischaemic injury. AB - Macrophages are an essential component of the immune response to ischaemic injury and play an important role in promoting inflammation and its resolution, which is necessary for tissue repair. The type I transmembrane glycoprotein CD163 is exclusively expressed on macrophages, where it acts as a receptor for haemoglobin:haptoglobin complexes. An extracellular portion of CD163 circulates in the blood as a soluble protein, for which no physiological function has so far been described. Here we show that during ischaemia, soluble CD163 functions as a decoy receptor for TWEAK, a secreted pro-inflammatory cytokine of the tumour necrosis factor family, to regulate TWEAK-induced activation of canonical nuclear factor-kappaB (NF-kappaB) and Notch signalling necessary for myogenic progenitor cell proliferation. Mice with deletion of CD163 have transiently elevated levels of TWEAK, which stimulate muscle satellite cell proliferation and tissue regeneration in their ischaemic and non-ischaemic limbs. These results reveal a role for soluble CD163 in regulating muscle regeneration after ischaemic injury. PMID- 26242747 TI - Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of seventh biannual meeting (March 2015). AB - The Malaria Policy Advisory Committee to the World Health Organization held its seventh meeting in Geneva, Switzerland from 5 to 7 March 2015. This article provides a summary of the discussions, conclusions and meeting recommendations. Meeting sessions included: an update on the Greater Mekong Subregion elimination strategy; an update on the RTS,S vaccine; G6PD testing to support the safe use of anti-relapse therapy for Plasmodium vivax; update from the Vector Control Advisory Group; newly proposed evidence reviews or consultations on malaria terminology, malaria in pregnancy, and the feasibility of eradication; as well as updates from the World Health Organization Global Malaria Programme regarding their strategy update and policy setting processes. Policy statements, position statements, and guidelines that arise from the Malaria Policy Advisory Committee meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme. PMID- 26242748 TI - A Secure User Anonymity and Authentication Scheme Using AVISPA for Telecare Medical Information Systems. AB - Telecare medicine information systems (TMIS) have been known as an effective mechanism to increase quality and security of healthcare services. In other to the protection of patient privacy, several authentication schemes have been proposed in TMIS, however, most of them have a security problems. Recently, Das proposed a secure and robust password-based remote user authentication scheme for the integrated EPR information system. However, in this paper, we show that his scheme have some security flaws. Then, we shall propose a secure authentication scheme to overcome their weaknesses. We prove the proposed scheme with random oracle and also use the BAN logic to prove the correctness of the proposed scheme. Furthermore, we simulate our scheme for the formal security analysis using the AVISPA (Automated Validation of Internet Security Protocols and Applications) tool. PMID- 26242749 TI - Data-Centric Routing for Intra Wireless Body Sensor Networks. AB - A significant proportion of the worldwide population is of the elderly people living with chronic diseases that result in high health-care cost. To provide continuous health monitoring with minimal health-care cost, Wireless Body Sensor Networks (WBSNs) has been recently emerged as a promising technology. Depending on nature of sensory data, WBSNs might require a high level of Quality of Service (QoS) both in terms of delay and reliability during data reporting phase. In this paper, we propose a data-centric routing for intra WBSNs that adapts the routing strategy in accordance with the nature of data, temperature rise issue of the implanted bio-medical sensors due to electromagnetic wave absorption, and high and dynamic path loss caused by postural movement of human body and in-body wireless communication. We consider the network models both with and without relay nodes in our simulations. Due to the multi-facet routing strategy, the proposed data-centric routing achieves better performance in terms of delay, reliability, temperature rise, and energy consumption when compared with other state-of-the-art. PMID- 26242750 TI - The Association between eHealth Capabilities and the Quality and Safety of Health Care in the Netherlands: Comparison of HIMSS Analytics EMRAM data with Elsevier's 'The Best Hospitals' data. AB - OBJECTIVE: To test the hypothesis that advanced electronic medical record (EMR) capabilities are associated with better quality and safety of hospital care. METHODS AND FINDINGS: We used data from the HIMSS Analytics EMR Adoption Model (EMRAM(SM)) to measure the adoption and use of information technology in Dutch hospitals. To measure the quality and safety of healthcare in Dutch Hospitals we used select data from the publicly available basic set and the safety set of the Health Care Inspectorate (IGZ) and the Dutch Health Care Transparency Program 'Zichtbare Zorg' (ZIZO) program. The quality and safety measures selected reflect the measures used to score Dutch hospitals as presented in Elsevier's annual 'The Best Hospitals' publication. The scores of this publication are based upon 542 of the 1516 available indicators from this basic set and safety set. Almost all indicators from the hospital-wide indicator sets are included in the selection, as are a large portion of indicators for acute care delivered by all hospitals. Of the 84 non-academic hospitals in the Netherlands, 67 (80 %) were included in this study. RESULTS: There is no statistically significant association found between a hospital's EMRAM score and their overall quality/safety performance in the Elsevier hospital scoring model. CONCLUSION: There is no evidence found to support the research hypothesis at this point in time. This outcome maybe the result of a multiplicity of factors to include the (limited) use of the methodologies used in this study, the fact that no fully digitalized hospital (EMRAM stage 7) is yet present in the NL, and/or the organizational competency of the NL hospitals in fully leveraging the EMR to facilitate patient care. Further research is needed to explore these findings. PMID- 26242751 TI - Manipulating the banana rhizosphere microbiome for biological control of Panama disease. AB - Panama disease caused by Fusarium oxysporum f. sp. cubense infection on banana is devastating banana plantations worldwide. Biological control has been proposed to suppress Panama disease, though the stability and survival of bio-control microorganisms in field setting is largely unknown. In order to develop a bio control strategy for this disease, 16S rRNA gene sequencing was used to assess the microbial community of a disease-suppressive soil. Bacillus was identified as the dominant bacterial group in the suppressive soil. For this reason, B. amyloliquefaciens NJN-6 isolated from the suppressive soil was selected as a potential bio-control agent. A bioorganic fertilizer (BIO), formulated by combining this isolate with compost, was applied in nursery pots to assess the bio-control of Panama disease. Results showed that BIO significantly decreased disease incidence by 68.5%, resulting in a doubled yield. Moreover, bacterial community structure was significantly correlated to disease incidence and yield and Bacillus colonization was negatively correlated with pathogen abundance and disease incidence, but positively correlated to yield. In total, the application of BIO altered the rhizo-bacterial community by establishing beneficial strains that dominated the microbial community and decreased pathogen colonization in the banana rhizosphere, which plays an important role in the management of Panama disease. PMID- 26242752 TI - Intra-Colonial Functional Differentiation-Related Modulation of the Cellular Membrane in a Pocilloporid Coral Seriatopora caliendrum. AB - Scleractinian corals have displayed phenotypic gradients of polyps within a single genotypic colony, and this has profound implications for their biology. The intrinsic polymorphism of membrane lipids and the molecular interactions involved allow cells to dynamically organize their membranes to have physicochemical properties appropriate for their physiological requirements. To gain insight into the accommodation of the cellular membrane during ontogenetic shifts, intra-colony differences in the glycerophosphocholine profiling of a pocilloporid coral, Seriatopora caliendrum, were characterized using a previously validated method. Specifically, several major polyunsaturated phosphatidylcholines showed higher levels in the distal tissue of coral branches. In contrast, the corresponding molecules with 1-2-degree less unsaturation and plasmanylcholines were expressed more highly in the proximal tissue. The lipid profiles of these two colonial positions also contrasted sharply with regard to the saturated, monounsaturated, and lyso-glycerophosphocholine ratios. Based on the biochemical and biophysical properties of these lipids, the associated modulation of cellular membrane properties could be related to the physiological requirements, including coral growth and aging, of the functionally differentiated polyps. In this study, the metabolic regulation of membrane lipids involved in the functional differentiation of polyps within a S. caliendrum colony was identified. PMID- 26242753 TI - Induced All-Female Autotriploidy in the Allotetraploids of Carassius auratus red var. (?) * Megalobrama amblycephala (?). AB - Following activation by UV-irradiated BSB sperm, the fertilized eggs of tetraploid hybrids (abbreviated as 4nF1) (4n = 148, AABB) of Carassius auratus red var. (abbreviated as RCC) (2n = 100, AA) (?) * Megalobrama amblycephala (abbreviated as BSB) (2n = 48, BB) (?) developed into normal live gynogenetic offspring without chromosome doubling treatment. Some of these were autotriploids with three sets of red crucian carp chromosomes (abbreviated as G1) (3n = 150, AAA). G1 were all-females, and can produce unreduced (3n) eggs at age 1 year. After activation by UV-irradiated BSB sperm, the fertilized eggs of G1 developed into a second generation of autotriploid gynogenetic offspring (abbreviated as G2) (3n = 150) without chromosome doubling treatment. G1 were obviously different from both 4nF1 and RCC in their morphological traits and showed a significantly higher growth rate than RCC. In aquaculture, the autotriploid fish could provide an important source of gametes for the production of all-female triploid fish and for the establishment of autotriploid gynogenetic lines. PMID- 26242754 TI - Transcriptomic Analyses Reveal Novel Genes with Sexually Dimorphic Expression in Yellow Catfish (Pelteobagrus fulvidraco) Brain. AB - Yellow catfish (Pelteobagrus fulvidraco) is a pivotal freshwater aquaculture species in China. It shows sexual size dimorphism favoring male in growth. Whole transcriptome approach is required to get the overview of genetic toolkit for understanding the sex determination mechanism aiming at devising its monosex production. Beside gonads, the brain is also considered as a major organ for vertebrate reproduction. Transcriptomic analyses on the brain and of different developmental stages will provide the dynamic view necessary for better understanding its sex determination. In this regard, we have performed a de novo assembly of yellow catfish brain transcriptome by high throughput Illumina sequencing. A total number of 154,507 contigs were obtained with the lengths ranging from 201 to 27,822 bp and N50 of 2,101 bp, as well as 20,699 unigenes were identified. Of these unigenes, 13 and 54 unigenes were detected to be XY specifically expressed genes (SEGs) for one and 2-year-old yellow catfish, while the corresponding numbers of XX-SEGs for those two stages were 19 and 13, respectively. Our work identifies a set of annotated genes that are candidate factors affecting sexual dimorphism as well as simple sequence repeat (SSR) and single nucleotide variation (SNV) in yellow catfish. To validate the expression patterns of the sex-related genes, we performed quantitative real-time PCR (qRT PCR) indicating the reliability and accuracy of our analysis. The results in our study may enhance our understanding of yellow catfish sex determination and potentially help to improve the production of all-male yellow catfish for aquaculture. PMID- 26242756 TI - Solid electrolyte interphase in semi-solid flow batteries: a wolf in sheep's clothing. AB - The formation of the alkyl carbonate-derived solid electrolyte interphase (SEI) enables the use of active materials operating at very cathodic potentials in Li ion batteries. However, the SEI in semi-solid flow batteries results in a hindered electron transfer between a fluid electrode and the current collector restricting the operating potentials to ca. 0.8 V vs. Li/Li(+) for EC-based electrolytes. PMID- 26242755 TI - Electrical Retrieval of Living Microorganisms from Cryopreserved Marine Sponges Using a Potential-Controlled Electrode. AB - The purpose of this study was to develop a novel electrical retrieval method (ER method) for living sponge-associated microorganisms from marine sponges frozen at -80 degrees C. A -0.3-V vs. Ag/AgCl constant potential applied for 2 h at 9 degrees C induced the attachment of the sponge-associated microorganisms to an indium tin oxide/glass (ITO) or a gallium-doped zinc oxide/glass (GZO) working electrode. The electrically attached microorganisms from homogenized Spirastrella insignis tissues had intact cell membranes and showed intracellular dehydrogenase activity. Dead microorganisms were not attracted to the electrode when the homogenized tissues were autoclaved for 15 min at 121 degrees C before use. The electrically attached microorganisms included cultivable microorganisms retrieved after detachment from the electrode by application of a 9-MHz sine-wave potential. Using the ER method, we obtained 32 phyla and 72 classes of bacteria and 3 archaea of Crenarchaeota thermoprotei, Marine Group I, and Thaumarchaeota incertae sedis from marine sponges S. insignis and Callyspongia confoederata. Employment of the ER method for extraction and purification of the living microorganisms holds potential of single-cell cultivation for genome, transcriptome, proteome, and metabolome analyses of bioactive compounds producing sponge-associated microorganisms. PMID- 26242757 TI - Auxiliary KCNE subunits modulate both homotetrameric Kv2.1 and heterotetrameric Kv2.1/Kv6.4 channels. AB - The diversity of the voltage-gated K(+) (Kv) channel subfamily Kv2 is increased by interactions with auxiliary beta-subunits and by assembly with members of the modulatory so-called silent Kv subfamilies (Kv5-Kv6 and Kv8-Kv9). However, it has not yet been investigated whether these two types of modulating subunits can associate within and modify a single channel complex simultaneously. Here, we demonstrate that the transmembrane beta-subunit KCNE5 modifies the Kv2.1/Kv6.4 current extensively, whereas KCNE2 and KCNE4 only exert minor effects. Co expression of KCNE5 with Kv2.1 and Kv6.4 did not alter the Kv2.1/Kv6.4 current density but modulated the biophysical properties significantly; KCNE5 accelerated the activation, slowed the deactivation and steepened the slope of the voltage dependence of the Kv2.1/Kv6.4 inactivation by accelerating recovery of the closed state inactivation. In contrast, KCNE5 reduced the current density ~2-fold without affecting the biophysical properties of Kv2.1 homotetramers. Co localization of Kv2.1, Kv6.4 and KCNE5 was demonstrated with immunocytochemistry and formation of Kv2.1/Kv6.4/KCNE5 and Kv2.1/KCNE5 complexes was confirmed by Fluorescence Resonance Energy Transfer experiments performed in HEK293 cells. These results suggest that a triple complex consisting of Kv2.1, Kv6.4 and KCNE5 subunits can be formed. In vivo, formation of such tripartite Kv2.1/Kv6.4/KCNE5 channel complexes might contribute to tissue-specific fine-tuning of excitability. PMID- 26242758 TI - Magnitude and concurrence of anxiety and depression among attendees with multiple sclerosis at a tertiary care Hospital in Oman. AB - BACKGROUND: Anxiety, depression and functional impairments are commonly reported by persons with multiple sclerosis (PwMS) but no data, to our knowledge, has emerged from an Arab Islamic population. The study aims to investigate the prevalence of anxiety, depression and related disabilities among PwMS attending tertiary care in Sultan Qaboos University Hospital (SQUH), one of the urban hospitals in Oman. METHODS: Consecutive and consenting PwMS (n = 57) and healthy subjects (n = 53) completed the following measures: Hospital Anxiety and Depression Scale (HADS) which was used to measure anxiety (cut-point >7) and depression (>7); and Expanded Disability Status Scale (EDSS) to measure the level of disability (>=5). Characteristics such as socio-demographic and clinical variables were also explored. RESULTS: Fifty seven subjects with multiple sclerosis (MS) met the inclusion criteria. The majority of them were females who were 40 years old or younger and the majority were employed and unmarried. Approximately 86 % of the participants were using beta interferon, 96 % scored >=5 in EDSS. MS of the Relapsing-Remitting type constituted the majority of the cohort (94 %). Approximately 35 % and 51 % endorsed symptoms of anxiety and depression respectively. The MS group scored significantly higher than controls on HADS measurements of depression and anxiety. CONCLUSION: Disability and symptoms of anxiety and depression are common among the PwMS attendees of tertiary care hospital in Oman. Such psychosocial variables have been largely unreported emerging from non-western populations. As these variables are strong indicators of the burden of MS, resolute effort is needed to address such psychosocial dysfunctions in the algorithms of care for PwMS in the Arab Islamic part of the world. PMID- 26242759 TI - Recent synthetic additions to the visible light photoredox catalysis toolbox. AB - The boom in visible light photoredox catalysis (VLPC) research has demonstrated that this novel synthetic approach is here to stay. VLPC enables reactive radical intermediates to be catalytically generated at ambient temperature, a feat not generally allowed through traditional pyrolysis- or radical initiator-based methodologies. VLPC has vastly extended the range of substrates and reaction schemes that have been traditionally the domain of radical reactions. In this review the photophysics background of VLPC will be briefly discussed, followed by a report on recent inroads of VLPC into decarboxylative couplings and radical C-H functionalization of aromatic compounds. The bulk of the review will be dedicated to advances in synergistic catalysis involving VLPC, namely the combination of photoredox catalysis with organocatalysis, including beta-functionalization of carbonyl groups, functionalization of weak aliphatic C-H bonds, and anti Markovnikov hydrofunctionalization of alkenes; dual catalysis with gold or with nickel, photoredox catalysis as an oxidation promoter in transition metal catalysis, and acid-catalyzed enantioselective radical addition to pi systems. PMID- 26242761 TI - The 2015 AACR Joseph H. Burchenal Memorial Award for Outstanding Achievement in Clinical Cancer Research. PMID- 26242760 TI - Reflections on the Histopathology of Tumor-Infiltrating Lymphocytes in Melanoma and the Host Immune Response. AB - In the past five decades, the role for lymphocytes in host immune response to tumors has been shown, at least in some patients, to be a critical component in disease prognosis. Also, the heterogeneity of lymphocytes has been documented, including the existence of regulatory T cells that suppress the immune response. As the functions of lymphocytes have become better defined in terms of antitumor immunity, specific targets on lymphocytes have been uncovered. The appreciation of the role of immune checkpoints has also led to therapeutic approaches that illustrate the effectiveness of blocking negative regulators of the antitumor immune response. In this Masters of Immunology article, we trace the evolution of our understanding of tumor-infiltrating lymphocytes and discuss their role in melanoma prognosis from the very basic observation of their existence to the latest manipulation of their functions with the result of improvement of the host response against the tumor. PMID- 26242762 TI - The 2015 AACR Clowes Memorial Award for Outstanding Achievement in Basic Cancer Research. PMID- 26242763 TI - Factors associated with magnetic resonance imaging defined patellar tendinopathy in community-based middle-aged women: a prospective cohort study. AB - BACKGROUND: Patellar tendinopathy identified by imaging modalities has been reported in asymptomatic athletes and associated with tendon-related symptoms. However there is little data in community-based populations. The aim of this cohort study was to examine the prevalence of magnetic resonance imaging (MRI) defined patellar tendinopathy, the factors associated with this condition, and whether it was associated with knee pain in community-based middle-aged women. METHODS: One hundred seventy six women, aged 40-67 years, with no significant knee pain or injury underwent knee MRI. Patellar tendinopathy was defined on both T1- and T2-weighted fat-saturated MRIs. The cross-sectional area of vastus medialis was measured from MRI. Height and weight were measured to calculate body mass index (BMI). Physical activity was assessed using a questionnaire. Knee pain was assessed using the Western Ontario and McMaster University Osteoarthritis Index. RESULTS: The prevalence of MRI defined patellar tendinopathy was 30.1%. Higher levels of physical activity (odds ratio 1.65, 95% CI 1.09-2.51) and greater vastus medialis cross-sectional area (odds ratio 1.22, 95% CI 1.04-1.43) were associated with increased prevalence of patellar tendinopathy, independent of age and BMI. The persistence of patellar tendinopathy was associated with the worsening of knee pain over 2 years (odds ratio 10.65, 95% CI 1.14-99.77). CONCLUSION: In community-based middle-aged women MRI-diagnosed patellar tendinopathy is common, with higher levels of physical activity and greater vastus medialis size being risk factors suggesting a biomechanical effect. Persistent patellar tendinopathy is associated with worsening of knee pain. These findings suggest that further work is needed to determine the contribution of patellar tendinopathy on knee pain and function in older people. PMID- 26242764 TI - Unrelated donor hematopoietic stem cell transplantation for the treatment of non malignant genetic diseases: An alemtuzumab based regimen is associated with cure of clinical disease; earlier clearance of alemtuzumab may be associated with graft rejection. AB - Hematopoietic stem cell transplantation (HSCT) with matched unrelated donors (MUD), offers potentially curative therapy for patients with non-malignant genetic diseases. In this pilot study conducted from 2006 to 2014, we report the outcomes of 15 patients with non-malignant genetic diseases who received a myeloablative regimen with a reduced cyclophosphamide dose, adjunctive serotherapy and MUD HSCT [intravenous alemtuzumab (52 mg/m(2) ), busulfan (16 mg/kg), fludarabine (140mg/m(2) ), and cyclophosphamide (105 mg/kg)]. Graft versus-host-disease (GVHD) prophylaxis consisted of tacrolimus/cyclosporine and methylprednisolone. Median (range) time to neutrophil engraftment (>500 cells/uL) and platelet engraftment (>20,000/mm(3) ) were 15 (12-28) and 25 (17-30) days, respectively. At a median follow-up of 2 (0.2-5.4) years, the overall survival (OS) was 93.3% (95% CI: 0.61-0.99) and disease-free survival (DFS) was 73.3% (95% CI: 0.44-0.89). Among this small sample, earlier alemtuzumab clearance was significantly associated with graft rejection (P = 0.047), earlier PHA response (P = 0.009) and a trend toward earlier recovery of recent thymic emigrants (RTE) (P = 0.06). This regimen was associated with durable donor engraftment and relatively low rates of regimen related toxicity (RRT); future alemtuzumab pharmacokinetic studies may improve outcomes, by allowing targeted alemtuzumab clearance to reduce graft rejection and promote more rapid immune reconstitution. PMID- 26242765 TI - Use of Integrase Inhibitors in HIV-Infected Children and Adolescents. AB - Resistance to antiretroviral drugs is an increasingly prevalent challenge affecting both the adult and pediatric HIV-infected populations. Though data on the safety, pharmacokinetics, and efficacy of newer antiretroviral agents in children typically lags behind adult data, newer agents are becoming available for use in HIV-infected children who are failing to respond to or are experiencing toxicities with traditional antiretroviral regimens. Integrase strand transfer inhibitors are one such new class of antiretrovirals. Raltegravir has been US Food and Drug Administration (FDA) approved for use in patients over the age of 4 weeks. Elvitegravir is a second member of this class, and has the potential for use in children but does not yet have a Pediatric FDA indication. Dolutegravir, a second-generation integrase inhibitor, is approved for those older than 12 years. This review summarizes the use of integrase inhibitors in children and adolescents, and highlights the results of recent clinical trials. PMID- 26242766 TI - Diabetic Macular Edema: Options for Adjunct Therapy. AB - Diabetes mellitus (DM) is a chronic disease that affects 387 million people worldwide. Diabetic retinopathy (DR), a common complication of DM, is the main cause of blindness in the active population. Diabetic macular edema (DME) may occur at any stage of DR, and is characterized by vascular hyperpermeability accompanied by hard exudates within the macula. Medical and surgical therapies have dramatically reduced the progression of DR, and timely intervention can reduce the risk of severe vision loss by more than 90 %. In 2012, intravitreal ranibizumab became the first antivascular endothelial growth factor (anti-VEGF) agent approved for DME and, since then, many reports of the use of ranibizumab for DME have been promising. Randomized, prospective, multicenter clinical trials most notably, RESOLVE, READ-2, RISE/RIDE, RESTORE, DRCR.net protocol I, and RETAIN-reported improvements in best-corrected visual acuity and decreased central retinal thickness as measured with optical coherence tomography in patients with DME. Similar treatment benefits have also been noted in clinical trials evaluating intravitreal aflibercept and bevacizumab (DAVINCI, VISTA/VIVID, and BOLT) and more recently DRCR.net protocol T. Intravitreal steroids (dexamethasone intravitreal implant and fluocinolone acetonide), particularly in refractory cases, also play a significant role in the management of DME (MEAD/CHAMPLAIN and FAMOUS/FAME studies). In summary, over the last 5 years, blocking VEGF and inflammation has been shown to improve visual outcomes in patients with macular edema due to DM, revolutionizing the treatment of center involved DME and establishing a new standard of care. PMID- 26242767 TI - Insulin Degludec/Liraglutide: A Review in Type 2 Diabetes. AB - Insulin degludec/liraglutide (Xultophy((r))), a fixed-ratio combination of an ultra-long-acting insulin analogue and a glucagon-like protein-1 (GLP-1) receptor agonist, is available in the EU for the management of inadequately controlled type 2 diabetes. Once-daily subcutaneous insulin degludec/liraglutide as add-on therapy to oral antidiabetics was effective and generally well tolerated in adults with inadequately controlled type 2 diabetes in several well designed 26 week phase III trials. In insulin-naive patients, add-on insulin degludec/liraglutide provided significantly greater improvements in glycated haemoglobin (HbA1c) levels than add-on insulin degludec, liraglutide or placebo, or unchanged GLP-1 receptor agonists (i.e. liraglutide or exenatide). In the extension of one of these trials, the efficacy of add-on insulin degludec/liraglutide was maintained for a total of 52 weeks. In insulin experienced patients, add-on insulin degludec/liraglutide was significantly more effective with regard to improvements in HbA1c levels than add-on insulin degludec (at equivalent doses) or ongoing insulin glargine therapy. Add-on insulin degludec/liraglutide was associated with a lower incidence of confirmed hypoglycaemia than add-on insulin degludec in insulin-naive patients or ongoing insulin glargine in insulin-experienced patients, and a lower initial rate of nausea than add-on liraglutide. Thus, once-daily subcutaneous insulin degludec/liraglutide is a useful add-on therapy option for adult patients with inadequately controlled type 2 diabetes. PMID- 26242769 TI - A photoionization mass spectroscopic study on the formation of phosphanes in low temperature phosphine ices. AB - Isovalency rationalizes fundamental chemical properties of elements in the same group, but often fails to account for differences in the molecular structure due to the distinct atomic sizes and electron-pair repulsion of the isovalent atoms. With respect to main group V, saturated hydrides of nitrogen are limited to ammonia (NH3) and hydrazine (N2H4) along with ionic and/or metal-bound triazene (N3H5) and potentially tetrazene (N4H6). Here, we present a novel approach for synthesizing and detecting phosphanes formed via non-classical synthesis exploiting irradiation of phosphine ices with energetic electrons, subliming the newly formed phosphanes via fractionated sublimation, and detecting these species via reflectron time-of-flight mass spectrometry (ReTOF) coupled with vacuum ultraviolet (VUV) single photon ionization. This approach is able to synthesize, to separate, and to detect phosphanes as large as octaphosphane (P8H10), which far out-performs the traditional analytical tools of infrared spectroscopy and residual gas analysis via mass spectrometry coupled with electron impact ionization that could barely detect triphosphane (P3H5) thus providing an unconventional tool to prepare complex inorganic compounds such as a homologues series of phosphanes, which are difficult to synthesize via classical synthetic methods. PMID- 26242768 TI - 13-Valent Pneumococcal Conjugate Vaccine: A Review of Its Use in Adults. AB - The 13-valent pneumococcal conjugate vaccine (Prevenar 13((r)), Prevnar 13((r))) [PCV13] consists of 13 serotype-specific polysaccharides of Streptococcus pneumoniae (pneumococcus), each covalently conjugated to a non-toxic immunogenic carrier protein. PCV13 has a well established immunogenicity and tolerability profile in adults, particularly those >=50 years of age. Results of CAPiTA, a randomized, double-blind, placebo-controlled trial in >84,000 older adults aged >=65 years, showed that PCV13 was effective in preventing vaccine-type pneumococcal community-acquired pneumonia (CAP), vaccine-type pneumococcal nonbacteraemic (noninvasive) CAP and vaccine-type invasive pneumococcal disease (IPD). These findings, along with changes in pneumococcal serotype distribution and epidemiology of pneumococcal disease, prompted the US Advisory Committee on Immunization Practices (ACIP) to recommend PCV13 in series with 23-valent pneumococcal polysaccharide vaccine (PPVS23) for all adults aged >=65 years. PCV13 also has a role in preventing pneumococcal disease (pneumonia and IPD) in younger adults with immunocompromising conditions and potentially in those with other underlying medical conditions that increase the risk of pneumococcal disease. PMID- 26242770 TI - Inactivating effects of the lactoperoxidase system on bacterial lyases involved in oral malodour production. AB - The main components of oral malodour have been identified as volatile sulfur compounds (VSCs), including hydrogen sulfide (H(2)S) and methyl mercaptan (CH(3)SH). The lactoperoxidase (LPO) system (consisting of LPO, glucose oxidase, glucose and thiocyanate) was previously shown to exhibit antimicrobial activities against some oral bacteria in vitro and suppressive effects on VSCs in mouth air in a clinical trial. Here, we examined the in vitro effects of the LPO system on the activities of the bacterial lyases involved in the production of VSCs by oral anaerobes. The exposure of crude bacterial extracts of Fusobacterium nucleatum and Porphyromonas gingivalis or purified methionine gamma-lyase to the LPO system resulted in the inactivation of their lyase activities through l-cysteine and l methionine, which was linked to the production of H(2)S and CH(3)SH, respectively. The exposure of living F. nucleatum and P. gingivalis cells to the LPO system resulted in the suppression of cell numbers and lyase activities. The inactivation of the crude bacterial extracts of F. nucleatum and purified methionine gamma-lyase by the LPO system was partly recovered by the addition of DTT. Therefore, the LPO system may inactivate bacterial lyases including methionine gamma-lyase by reacting with the free cysteine residues of lyases. These results suggested that the LPO system suppresses the production of VSCs not only through its antimicrobial effects, but also by its inactivating effects on the bacterial lyases of F. nucleatum and P. gingivalis. PMID- 26242771 TI - Understanding the nanoscale local buckling behavior of vertically aligned MWCNT arrays with van der Waals interactions. AB - The local buckling behavior of vertically aligned carbon nanotubes (VACNTs) has been investigated and interpreted in the view of a collective nanotube response by taking van der Waals interactions into account. To the best of our knowledge, this is the first report on the case of collective VACNT behavior regarding van der Waals force among nanotubes as a lateral support effect during the buckling process. The local buckling propagation and development of VACNTs were experimentally observed and theoretically analyzed by employing finite element modeling with lateral support from van der Waals interactions among nanotubes. Both experimental and theoretical analyses show that VACNTs buckled in the bottom region with many short waves and almost identical wavelengths, indicating a high mode buckling. Furthermore, the propagation and development mechanism of buckling waves follow the wave damping effect. PMID- 26242772 TI - Phlebosclerotic colitis: case report and literature review focused on the radiologic findings in relation to the intake period of toxic material. AB - Phlebosclerotic colitis (PC) is a rare disease entity of intestinal ischemia characterized by calcification at the right hemicolon and is predominant in Asian populations. We present a 57-year-old Korean patient who was an Oriental medicine practitioner himself and had been taking herbal medicine for decades. We reviewed previous literature on similar cases and analyzed radiologic features of PC in relation to the intake period of toxic material and extent of disease. PMID- 26242773 TI - Getting published in Radiology: A Deputy Editor's perspective. AB - Radiology has been the official journal of the Radiological Society of North America since 1923. In 2014 it had an impact factor of 6.867, the highest for general radiology journals. The journal attracts a world-wide readership of approximately 54,000. Contributions from Japanese radiologists, radiographers, and radiological scientists are greatly welcomed. This article explains how we process the manuscripts submitted to the journal and describes the factors that can contribute to the decision to accept or reject. PMID- 26242775 TI - Scalloping of placenta-myometrium interface on ultrasound in case with myomectomy scar. PMID- 26242774 TI - Fatal laryngeal angioedema: a case report and a workup of angioedema in a forensic setting. AB - Angioedema is an episodic swelling of the deep dermis, subcutis, and/or submucosal tissue due to an increase in local vascular permeability. Swelling may involve skin, respiratory, and gastrointestinal tracts. The most commonly involved areas are the periorbital region and the lips. Here we report a case of a fatal laryngeal obstruction due to angioedema likely caused by an angiotensin converting-enzyme inhibitor. The decedent, a 58-year-old man, was witnessed developing sudden facial swelling and acute respiratory difficulties quickly followed by unresponsiveness. His past medical history suggested that this was his second episode of angioedema without urticaria. Postmortem examination revealed a complete laryngeal obstruction in the absence of infection, neoplasm, or autoimmune disease. Postmortem computed tomography of the head and neck showed a complete obstruction of the upper airway. Based on the current understanding of the pathophysiology of different types of angioedema, we will suggest a workup of angioedema without urticaria in the forensic setting and offer readers resources they can use in their practice. PMID- 26242776 TI - K3LaTe2O9: a new alkali-rare earth tellurate with face-sharing TeO6 octahedra. AB - A new quaternary alkali-lanthanide metal tellurate K3LaTe2O9 has been synthesized by a conventional high-temperature solid state method, and single crystals have been grown by spontaneous crystallization. K3LaTe2O9 crystallizes in the hexagonal space group P63/mmc, with a = b = 6.0589(9) A, c = 15.024(3) A, and Z = 2. In the structure, [Te2O9](6-) contains rare face-sharing TeO6 polyhedra, which are connected by LaO6 octahedra forming a three-dimensional framework structure. Furthermore, its properties are investigated by UV-vis-NIR diffuse reflectance spectroscopy, Raman and IR spectroscopy, thermal analysis, variable-temperature X ray powder diffraction, and first-principles calculations. PMID- 26242777 TI - Diet-induced obesity causes insulin resistance in mouse brown adipose tissue. AB - OBJECTIVE: Diet-induced obesity (DIO) causes several pathophysiological changes in adipose tissue. Increased inflammation reduces white adipose tissue (WAT) insulin sensitivity and contributes to the development of diabetes. However, little is known about how DIO alters the function of brown adipose tissue (BAT), an organ that consumes calories by beta3-adrenergic receptor (AR)-mediated thermogenesis and helps regulate energy balance. METHODS: To test the effects of DIO on BAT, we fed 6-week-old C57BL/6 mice either a normal chow diet (NCD) or a high-fat diet (HFD). After 16 additional weeks, we measured body fat, WAT, and BAT mRNA expression, glucose tolerance, and rates of glucose uptake in response to insulin and the beta3-AR agonist mirabegron. RESULTS: Compared with NCD, HFD increased body fat and impaired glucose tolerance. Both WAT and BAT had higher mRNA levels of markers of inflammation, including TNFalpha and F4/80. Insulin signaling in BAT and WAT was reduced, with decreased Akt phosphorylation. Diet normalized BAT glucose uptake rates were lower in response to mirabegron. CONCLUSIONS: These results support a model in which DIO leads to BAT inflammation and insulin resistance, leading to a broader impairment of BAT function. PMID- 26242778 TI - Predicting maximal aerobic speed through set distance time-trials. AB - PURPOSE: Knowledge of aerobic performance capacity allows for the optimisation of training programs in aerobically dominant sports. Maximal aerobic speed (MAS) is a measure of aerobic performance; however, the time and personnel demands of establishing MAS are considerable. This study aimed to determine whether time trials (TT), which are shorter and less onerous than traditional MAS protocols, may be used to predict MAS. METHODS: 28 Australian Rules football players completed a test of MAS, followed by TTs of six different distances in random order, each separated by at least 48 h. Half of the participants completed TT distances of 1200, 1600 and 2000 m, and the others completed distances of 1400, 1800 and 2200 m. RESULTS: Average speed for the 1200 and 1400 m TTs were greater than MAS (P < 0.01). Average speed for 1600, 1800, 2000 and 2200 m TTs were not different from MAS (P > 0.08). Average speed for all TT distances correlated with MAS (r = 0.69-0.84; P < 0.02), but there was a negative association between the difference in average TT speed and MAS with increasing TT distance (r = -0.79; P < 0.01). Average TT speed over the 2000 m distance exhibited the best agreement with MAS. CONCLUSIONS: MAS may be predicted from the average speed during a TT for any distance between 1200 and 2200 m, with 2000 m being optimal. Performance of a TT may provide a simple alternative to traditional MAS testing. PMID- 26242779 TI - Identification of a beta1/beta2-specific sulfonamide proteasome ligand by crystallographic screening. AB - The proteasome represents a validated drug target for the treatment of cancer, however, new types of inhibitors are required to tackle the development of resistant tumors. Current fluorescence-based screening methods suffer from low sensitivity and are limited to the detection of ligands with conventional binding profiles. In response to these drawbacks, a crystallographic screening procedure for the discovery of agents with a novel mode of action was utilized. The optimized workflow was applied to the screening of a focused set of compounds, resulting in the discovery of a beta1/beta2-specific sulfonamide derivative that noncovalently binds between subunits beta1 and beta2. The binding pocket displays significant differences in size and polarity between the immuno- and constitutive proteasome. The identified ligand thus provides valuable insights for the future structure-based design of subtype-specific proteasome inhibitors. PMID- 26242780 TI - Nutrition transition and chronic diseases in Nigeria. AB - Nutrition transition goes with industrialisation that fosters human development which is usually desirable, especially in developing nations. However, the health consequences of this development include high rates of preventable non communicable diseases which are usually undermined in the quest for industrialisation. The goal of the present paper is to provide evidence-based information that will promote healthy lifestyle including healthy consumption pattern among urban dwellers. Relevant local and international literature was accessed and reviewed to harvest evidence-based information through the use of validated review guide in addition to observation from the field experience. Industrialisation promotes creation of more job opportunities and this facilitates proliferation of fast-food eateries in the cities. However, it was also observed that many of the available workplaces in urban areas are not health promoting because employees have poor access to preventive health information and sensitisation to healthy lifestyle has been poorly considered. Ironically, weight gain among urban workers which may be linked with increased intake of high-energy foods and low participation in physical activities as a result of accessibility to many energy saving devices have been highlighted as some of the pull-pull factors that attract many people to the cities. Using the concept of health promoting workplace, the workforce in urban areas can be trained as agent of change in health-promoting lifestyle. Consumption of healthy indigenous foods through aggressive promotion of its health potentials should be seriously advocated through the use of existing structure of urban fast-food vendors who constitute a strong stakeholder in nutrition transition. PMID- 26242781 TI - Nucleophilic Addition of Thiols to Deoxynivalenol. AB - Conjugation of deoxynivalenol (DON) with sulfur compounds is recognized as a significant reaction pathway, and putative DON-glutathione (DON-GSH) conjugates have been reported in planta. To understand and control the reaction of trichothecenes with biologically important thiols, we studied the reaction of DON, T-2 tetraol, and de-epoxy-DON with a range of model thiols. Reaction conditions were optimized for DON with 2-mercaptoethanol. Major reaction products were identified using HRMS and NMR spectroscopy. The results indicate that thiols react reversibly with the double bond (Michael addition) and irreversibly with the epoxide group in trichothecenes. These reactions occurred at different rates, and multiple isomers were produced including diconjugated forms. LC-MS analyses indicated that glutathione and cysteine reacted with DON in a similar manner to the model thiols. In contrast to DON, none of the tested mercaptoethanol adducts displayed toxicity in human monocytes or induced pro-inflammatory cytokines in human macrophages. PMID- 26242782 TI - Challenges in Maintaining Quality of Pharmaceutical Products. PMID- 26242783 TI - Comment and Completion: Implementation of Parallelism Testing for Four-Parameter Logistic Model in Bioassays. AB - Parallelism testing between two four-parameter logistic curves has been widely discussed over the last decade. Current tests available in common statistical software used in laboratories have been shown to be highly flawed. In 2012, Yang et al. showed an easy way to implement an intersection union test based on confidence intervals on ratios of parameters of both curves. The method was automated using a fully good manufacturing practice-compliant software package. Although the rationale is correct and efficient, a small mistake appears in the computation of the confidence intervals in the paper and may lead to error when implementing the intersection union test in a software package. Because parallelism testing is both a prerequisite for the determination of relative potency of bioassays and a regulatory requirement, it is important to rectify this mistake. In this paper, we show the actual formulas to be used to compute confidence interval on ratios of parameters. PMID- 26242784 TI - Moving Forward towards Standardized Analytical Methods for Extractables and Leachables Profiling Studies. AB - This commentary considers the standardization of analytical methods used in extractables and leachables screening and proposes that method standardization is not the end goal but rather the necessary first step for enabling efficient, effective, robust, and consistent extractables and leachables profiling. Standardized methods are the platform upon which a knowledge set and a knowledge management process can be built, and it is the combination of the methods, the set, and the process that facilitates extractables and leachables profiling. PMID- 26242785 TI - Characterization of Propylene Glycol-Mitigated Freeze/Thaw Agglomeration of a Frozen Liquid nOMV Vaccine Formulation by Static Light Scattering and Micro-Flow Imaging. AB - The purpose of this work was to investigate the susceptibility of an aluminum adjuvant and an aluminum-adjuvanted native outer membrane vesicle (nOMV) vaccine formulation to freeze/thaw-induced agglomeration using static light scattering and micro-flow Imaging analysis; and to evaluate the use of propylene glycol as a vaccine formulation excipient by which freeze/thaw-induced agglomeration of a nOMV vaccine formulation could be mitigated. Our results indicate that including 7% v/v propylene glycol in an nOMV containing aluminum adjuvanted vaccine formulation, mitigates freeze/thaw-induced agglomeration. LAY ABSTRACT: We evaluated the effect of freeze-thawing on an aluminum adjuvant and an aluminum adjuvanted native outer membrane vesicle (nOMV) vaccine formulation. Specifically, we characterized the freeze/thaw-induced agglomeration through the use of static light scattering, micro-flow imaging, and cryo-electron microscopy analysis. Further, we evaluated the use of 0-9% v/v propylene glycol as an excipient which could be included in the formulation for the purpose of mitigating the agglomeration induced by freeze/thaw. The results indicate that using 7% v/v propylene glycol as a formulation excipient is effective at mitigating agglomeration of the nOMV vaccine formulation, otherwise induced by freeze-thawing. PMID- 26242786 TI - Quality Control Testing for Tracking Endotoxin-Producing Gram-Negative Bacteria during the Preparation of Polyvalent Snake Antivenom Immunoglobulin. AB - Snake bites represent a serious public health problem, particularly in rural areas worldwide. Antitoxic sera preparations are antibodies from immunized animals and are considered to be the only treatment option. The purification of antivenom antibodies should aim at obtaining products of consistent quality, safety, efficacy, and adherence to good manufacturing practice principles. Endotoxins are an integral component of the outer cell surface of Gram-negative bacteria. They are common contaminates of the raw materials and processing equipment used in the manufacturing of antivenoms. In this work, and as a part of quality control testing, we establish and examine an environmental monitoring program for identification of potential sources of endotoxin-producing Gram negative bacteria throughout the whole steps of antivenom preparation. In addition, we follow all the steps of preparation starting from crude plasma till finished product using a validated sterility and endotoxin testing.Samples from air, surface, and personnel were collected and examined through various stages of manufacturing for the potential presence of Gram-negative bacteria. A validated sterility and endotoxin test was carried out in parallel at the different production steps. The results showed that air contributed to the majority of bacterial isolates detected (48.43%), followed by surfaces (37.5%) and then personnel (14%). The most common bacterial isolates detected were Achromobacter xylosoxidans, Ochrobactrum anthropi, and Pseudomonas aeruginosa, which together with Burkholderia cepacia were both also detected in cleaning water and certain equipment parts. A heavy bacterial growth with no fungal contamination was observed in all stages of antivenom manufacturing excluding the formulation stage. All samples were positive for endotoxin including the finished product.Implementation and continued evaluation of quality assurance and quality improvement programs in aseptic preparation is essential in ensuring the safety and quality of these products. LAY ABSTRACT: Antitoxic sera preparations are the only treatment option for snake bites worldwide. They are prepared by immunizing animals, usually horses, with snake venom and collecting horse plasma, which is then subjected to several purification steps in order to finally prepare the purified immunoglobulins. Components of the bacterial cell wall known as endotoxins can constitute a potential hazardous contamination known as pyrogen in antisera, which can lead to fever and many other adverse reactions to the person subjected to it.In this work, we monitored the environment associated with the different steps of production and purification of snake antivenom prepared from immunized horses. We examined the air quality, surface, and personnel for possible sources of contamination, particularly the presence of Gram-negative bacteria, which is the major source of endotoxin presence. We also monitored all stages of preparation by sterility and endotoxin testing. Our results showed that air contributed to the majority of bacterial isolates. Sterility testing revealed the presence of bacterial contamination in all the intermediate steps, as only the final preparation after filtration was sterile. Endotoxin was present in all tested samples and the final product. Good manufacturing practice procedures are essential in any facility involved in antisera production. PMID- 26242787 TI - Kinetic Modeling of Methionine Oxidation in Monoclonal Antibodies from Hydrogen Peroxide Spiking Studies. AB - When isolator technology is applied to biotechnology drug product fill-finish process, hydrogen peroxide (H2O2) spiking studies for the determination of the sensitivity of protein to residual peroxide in the isolator can be useful for assessing a maximum vapor phase hydrogen peroxide (VPHP) level. When monoclonal antibody (mAb) drug products were spiked with H2O2, an increase in methionine (Met 252 and Met 428) oxidation in the Fc region of the mAbs with a decrease in H2O2 concentration was observed for various levels of spiked-in peroxide. The reaction between Fc-Met and H2O2 was stoichiometric (i.e., 1:1 molar ratio), and the reaction rate was dependent on the concentrations of mAb and H2O2. The consumption of H2O2 by Fc-Met oxidation in the mAb followed pseudo first-order kinetics, and the rate was proportional to mAb concentration. The extent of Met 428 oxidation was half of that of Met 252, supporting that Met 252 is twice as reactive as Met 428. Similar results were observed for free L-methionine when spiked with H2O2. However, mAb formulation excipients may affect the rate of H2O2 consumption. mAb formulations containing trehalose or sucrose had faster H2O2 consumption rates than formulations without the sugars, which could be the result of impurities (e.g., metal ions) present in the excipients that may act as catalysts. Based on the H2O2 spiking study results, we can predict the amount Fc Met oxidation for a given protein concentration and H2O2 level. Our kinetic modeling of the reaction between Fc-Met oxidation and H2O2 provides an outline to design a H2O2 spiking study to support the use of VPHP isolator for antibody drug product manufacture. LAY ABSTRACT: Isolator technology is increasing used in drug product manufacturing of biotherapeutics. In order to understand the impact of residual vapor phase hydrogen peroxide (VPHP) levels on protein product quality, hydrogen peroxide (H2O2) spiking studies may be performed to determine the sensitivity of monoclonal antibody (mAb) drug products to residual peroxide in the isolator. In this study, mAbs were spiked with H2O2; an increase in methionine (Met) oxidation of the mAbs with a decrease in H2O2 concentration was observed for various levels of spiked-in peroxide. The reaction between Met and H2O2 was 1:1, and its rate was dependent on mAb and H2O2 concentrations. Consumption of H2O2 by Met followed pseudo first-order kinetics; the rate was proportional to mAb concentration. Formulations containing trehalose or sucrose had faster consumption rates than formulations without the sugars, which could be due to excipient impurities. Based on H2O2 spiking study results, we can predict the amount of Met oxidation for a given mAb concentration and H2O2 level. Our modeling of the reaction between Fc-Met oxidation and H2O2 provides an outline to design a H2O2 spiking study that supports using VPHP isolators during manufacture of mAb products. PMID- 26242788 TI - Evaluation of PDA Technical Report No 33. Statistical Testing Recommendations for a Rapid Microbiological Method Case Study. AB - New recommendations for the validation of rapid microbiological methods have been included in the revised Technical Report 33 release from the PDA. The changes include a more comprehensive review of the statistical methods to be used to analyze data obtained during validation. This case study applies those statistical methods to accuracy, precision, ruggedness, and equivalence data obtained using a rapid microbiological methods system being evaluated for water bioburden testing. Results presented demonstrate that the statistical methods described in the PDA Technical Report 33 chapter can all be successfully applied to the rapid microbiological method data sets and gave the same interpretation for equivalence to the standard method. The rapid microbiological method was in general able to pass the requirements of PDA Technical Report 33, though the study shows that there can be occasional outlying results and that caution should be used when applying statistical methods to low average colony-forming unit values. LAY ABSTRACT: Prior to use in a quality-controlled environment, any new method or technology has to be shown to work as designed by the manufacturer for the purpose required. For new rapid microbiological methods that detect and enumerate contaminating microorganisms, additional recommendations have been provided in the revised PDA Technical Report No. 33. The changes include a more comprehensive review of the statistical methods to be used to analyze data obtained during validation. This paper applies those statistical methods to analyze accuracy, precision, ruggedness, and equivalence data obtained using a rapid microbiological method system being validated for water bioburden testing. The case study demonstrates that the statistical methods described in the PDA Technical Report No. 33 chapter can be successfully applied to rapid microbiological method data sets and give the same comparability results for similarity or difference as the standard method. PMID- 26242789 TI - Reciprocal Translocation Observed in End-of-Production Cells of a Commercial CHO Based Process. AB - During the validation of an additional working cell bank derived from a validated master cell bank to support the commercial production continuum of a recombinant protein, we observed an unexpected chromosomal location of the gene of interest in some end-of-production cells. This event-identified by fluorescence in situ hybridization and multicolour chromosome painting as a reciprocal translocation involving a chromosome region containing the gene of interest with its integral coding and flanking sequences-was unique, occurred probably during or prior to multicolour chromosome painting establishment, and was transmitted to the descending generations. Cells bearing the translocation had a transient and process-independent selective advantage, which did not affect process performance and product quality. However, this first report of a translocation affecting the gene of interest location in Chinese Hamster Ovary cells used for producing a biotherapeutic indicates the importance of the demonstration of the integrity of the gene of interest in end-of-production cells. LAY ABSTRACT: The expression of recombinant therapeutic proteins in mammalian cells depends on the establishment of a cell line with the gene of interest integrated in the host genome and stably expressed over time. Before being used for commercial production, cell lines are submitted to a qualification program in order to ensure their phenotypic and genotypic characteristics and the efficacy and safety of the product. During the production life cycle of a therapeutic protein, additional cells banks have to be validated after exhaustion of the current qualified cell bank in order to support the commercial production continuum of the recombinant protein. It is during the validation of an additional working cell bank derived from a validated master cell bank that we detected a different chromosome bearing the gene of interest in a portion of cells at the end of the upstream production phase. In our case, this event did not affect the process performance, the product quality, or its safety profile, but it highlights the need to characterize the integrity of the gene of interest in end-of-production cells when producing recombinant proteins for human use. PMID- 26242790 TI - A Review of the Aging Process and Facilities Topic. AB - Aging facilities have become a concern in the pharmaceutical and biopharmaceutical manufacturing industry, so much that task forces are formed by trade organizations to address the topic. Too often, examples of aging or obsolete equipment, unit operations, processes, or entire facilities have been encountered. Major contributors to this outcome are the failure to invest in new equipment, disregarding appropriate maintenance activities, and neglecting the implementation of modern technologies. In some cases, a production process is insufficiently modified to manufacture a new product in an existing process that was used to produce a phased-out product. In other instances, manufacturers expanded the facility or processes to fulfill increasing demand and the scaling occurred in a non-uniform manner, which led to non-optimal results. Regulatory hurdles of post-approval changes in the process may thwart companies' efforts to implement new technologies. As an example, some changes have required 4 years to gain global approval. This paper will address cases of aging processes and facilities aside from modernizing options. PMID- 26242791 TI - Drug Shortages, Today and Tomorrow-An Industry Perspective. PMID- 26242793 TI - Compounding Pharmacists, Skills and Knowledge, and the Role of Pharmacy Colleges. PMID- 26242792 TI - Quality Culture vs. Cost of Quality-Quality Culture Is Understanding the Value, not Just the Price, of Quality. PMID- 26242795 TI - Dynein arms are strain-dependent direction-switching force generators. AB - Dynein is a minus-end-directed motor that can generate (forward) force to move along the microtubule toward its minus end. In addition, axonemal dyneins were reported to oscillate in the generation of forward force, and cytoplasmic dynein is observed to generate bidirectional forces in response to defined chemical states. Both dyneins can also respond to mechanically applied force. To test whether axonemal dynein can switch direction of force generation, we measured force using an optical trap and UV-photolysis of caged ATP. We observed that isolated dynein could repeatedly generate force in both directions along the microtubule. Bidirectional force was also observed for dynein arms that are still attached on the doublet microtubules. Axonemal dynein generated force to move backward (~ 4 pN) as well as forward (5-6 pN) along microtubules. Furthermore, backward force could be stimulated by plus-end directed external force applied to axonemal dynein before ATP application. The results show that axonemal dynein is unique exhibiting multiple modes of force generation including backward and forward force, oscillatory force and slow, repetitive bidirectional force. The results also demonstrate that mechanical strain is important for switching the directionality of force generation in axonemal dyneins. PMID- 26242794 TI - The course of depression in late life as measured by the Montgomery and Asberg Depression Rating Scale in an observational study of hospitalized patients. AB - BACKGROUND: Depression and depressive symptoms are highly prevalent in old persons but are potentially reversible. Full recovery is the main goal in the treatment of depressive episodes. Compared to clinical trials, observational studies of patients with depression in late life (DLL) show poorer prognoses in terms of response and remission. However, observational studies on the course of DLL are scarce. The aims of this study were to examine the course of DLL in terms of response, remission and symptom-specific changes as measured by the Montgomery and Asberg Depression Rating Scale (MADRS), and to explore which clinical variables were associated with the response and remission. METHODS: This is an observational, multicenter and prospective study of patients aged 60 years and older who were referred to treatment of depression in the department of old-age psychiatry at specialist health care services in Norway. The patients were evaluated with the MADRS at admission to and discharge from hospital. The mean, median, minimum and maximum values for days stayed in hospital were 68, 53, 16 and 301, respectively. Effect size (ES) was calculated to determine which MADRS symptoms changed most during the treatment. To assess the predictors for change in the MADRS score (continuous variable) and for remission and response (both dichotomous variables), regression models adjusting for cluster effects within center were estimated. RESULTS: Of 145 inpatients, 99 (68.3 %) had a response to treatment (50 % or more improvement of the MADRS score). Remission (MADRS score <=9 at discharge) was experienced in 74 (51.0 %) of the patients. Of the individual MADRS items, "reported sadness" (ES =0.88) and "lassitude" (ES = 0.80) showed the greatest amount of improvement, and "concentration difficulties" (ES = 0.50) showed the least amount of improvement during treatment. Having a diagnosis of dementia was associated with a lower remission rate and less improvement in the MADRS score during the treatment. Poorer physical health was associated with a lower response rate. Having experienced previous episode(s) of depression was associated with a lower remission rate. CONCLUSIONS: Recurrent episodes of depression, poor somatic health and a diagnosis of dementia were found to be negative prognostic factors for the course of DLL. Clinicians should therefore pay close attention to these factors when evaluating treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01952366. PMID- 26242796 TI - Capillaroscopic patterns in systemic sclerosis: do we need a "stable" pattern? PMID- 26242797 TI - Internal stress drives slow glassy dynamics and quake-like behaviour in ionotropic pectin gels. AB - Frustrated, out-of-equilibrium materials have been of considerable interest for some time and continue to be some of the least understood materials. Recent measurements have shown that many gelled biopolymer materials display slow dynamics on timescales greater than one second, that are not accessible with typical methods, and are characteristic of glassy trapped systems. In this study we have controlled the fine structure of the anionic polysaccharide pectin in order to construct a series of ionotropic gels having differing binding energies between the constituent chains, in an attempt to further understand the slow dynamical processes occurring. Using multi-speckle light scattering techniques it is shown that the slow dynamics observed in these gelled systems are stress driven. As the binding lengths, and thus the binding energies, of the junction zones between the polymer chains in these networks increase the long-time dynamics initially slow, as might be expected, until a critical level of internal stress is reached upon which the dynamics increase significantly, with gentle creaking punctuated by localised stress-relieving quakes. PMID- 26242798 TI - Associations of prepregnancy body mass index and gestational weight gain with pregnancy outcomes in nulliparous women delivering single live babies. AB - The study was to assess the associations of prepregnancy body mass index (BMI) and gestational weight gain (GWG) with pregnancy outcomes. This was a retrospective analysis of 2973 nulliparous women who delivered single live babies. Prepregnancy BMI was categorized as underweight (<18.5 kg/m(2)), normal weight (18.5-24.9 kg/m(2)) or overweight/obese (>=25.0 kg/m(2)). GWG was categorized as inadequate, adequate or excessive. 567 (19.1%) women were overweight/obese, and 1600 (53.8%) exhibited excessive GWG. Compared with women of normal weight, overweight/obese women had a higher incidence of cesarean section (odds ratio, 95% confidence interval: 2.02, 1.59-2.56), postpartum hemorrhage (1.50, 1.05-2.14), preterm delivery (2.51, 1.83-3.45), preterm premature rupture of membranes (2.11, 1.32-3.38), gestational diabetes mellitus (2.04, 1.65-2.53), gestational hypertension (7.68, 4.21-14.00), preeclampsia (1.98, 1.18-3.33) and small for gestational age (2.81, 1.21-6.54). Compared with adequate GWG, excessive GWG increased the incidence of cesarean section (2.02, 1.59-2.56), preterm delivery (1.48, 1.05-2.71), preeclampsia (1.78, 1.34-4.27) and macrosomia (2.61, 1.61-4.25), and reduced the incidence of gestational diabetes mellitus (0.75, 0.62-0.92). High prepregnancy BMI and excessive GWG in nulliparous Chinese women are associated with adverse pregnancy outcomes. Weight control before and during pregnancy could reduce the complications of pregnancy. PMID- 26242799 TI - Nitrogen-enriched carbon sheets derived from egg white by using expanded perlite template and its high-performance supercapacitors. AB - Nitrogen-enriched carbon sheets were synthesized using egg white as a unique carbon source and expanded perlite as a novel template. The as-prepared material was further used as an electrode material for super capacitor applications, demonstrating excellent super capacitance with a maximum gravimetric specific capacitance of 302 F g(-1) at 0.5 A g(-1) in a 3-electrode setup for a sample carbonized at 850 degrees C and activated for 6 h. Moreover, the carbon sheet based capacitor with 2-symmetric electrodes showed an excellent cycle life (2% loss at 0.1 A g(-1) after 10 000 cycles). The excellent performance may be attributed to the combination of the 3D carbon structure and the highly concentrated doped nitrogen component from the natural egg source for superior pseudocapacitance. PMID- 26242800 TI - The health of immigrant children who live in areas with high immigrant concentration. AB - OBJECTIVES: Our objective is to contribute to the literature regarding the association between immigrant children's health, their ethnicity and their living in neighbourhoods with a high ethnic concentration of one's own ethnicity. Using data from families from five ethnic groups who all immigrated to Vancouver metropolitan region in Canada, our research question asks: How ethnicity, ethnic concentration and living in a neighbourhood with others of the same ethnic background contribute to the health of immigrant children? DESIGN: Two data sets are integrated in our study. The first is the New Canadian Children and Youth Study, which collected original data from five ethnic groups who immigrated to metropolitan Vancouver. The second data set, from which we derived neighbourhood data, is the Canadian census. The dependent variable is health status as reported by the parent. Independent variables are at both the individual and neighbourhood levels, including ethnicity, sex and the percentage of people living in the neighbourhood of the same ethnic background. Analysis was completed using hierarchical linear modelling. RESULTS: Children (n = 759) from 24 neighbourhoods were included in the analyses. Health status varied by ethnicity and ethnic concentration, indicating the heterogeneity of immigrant populations. CONCLUSION: With the lack of research on the health of immigrant children and youth living in ethnic concentrations, our findings make an important contribution to understanding the influences on the well-being of immigrant populations. PMID- 26242801 TI - The Effects of Web-Based Patient Access to Laboratory Results in British Columbia: A Patient Survey on Comprehension and Anxiety. AB - BACKGROUND: Web-based patient access to personal health information is limited but increasing in Canada and internationally. OBJECTIVE: This exploratory study aimed to increase understanding of how Web-based access to laboratory test results in British Columbia (Canada), which has been broadly available since 2010, affects patients' experiences. METHODS: In November 2013, we surveyed adults in British Columbia who had had a laboratory test in the previous 12 months. Using a retrospective cohort design, we compared reported wait-time for results, test result comprehension, and anxiety levels of "service users" who had Web-based access to their test results (n=2047) with those of a general population panel that did not have Web-based access (n=1245). RESULTS: The vast majority of service users (83.99%, 95% CI 82.31-85.67) said they received their results within "a few days", compared to just over a third of the comparison group (37.84%, 95% CI 34.96-40.73). Most in both groups said they understood their test results, but the rate was lower for service users than the comparison group (75.55%, 95% CI 73.58-77.49 vs 84.69%, 95% CI 82.59-86.81). There was no significant difference between groups in levels of reported anxiety after receiving test results. CONCLUSIONS: While most patients who received their laboratory test results online reported little anxiety after receiving their results and were satisfied with the service, there may be opportunities to improve comprehension of results. PMID- 26242802 TI - Effect of Phosphate Addition on Cadmium Precipitation and Adsorption in Contaminated Arable Soil with a Low Concentration of Cadmium. AB - The objectives of this study were to determine (1) the phosphorus (P) level required to induce cadmium (Cd) precipitation in a contaminated arable soil with low concentrations of Cd and (2) the primary mechanism of Cd immobilization at different P levels. Phosphorus was added at levels of 0 800, 1600, and 16,000 mg P kg(-1) to a soil containing 5.57 mg Cd kg(-1). The concentration of 1 M NH4OAc extractable Cd decreased significantly with P levels up to 1600 mg kg(-1) due to an increase in soil pH and negative charge of soil (p<0.001). A further decrease in 1 M NH4OAc extractable Cd concentration was noted when P was increased to 16,000 mg P kg(-1) and may have been the result of Cd precipitation. This study suggest that adding P at high levels may help in the formation of geochemically stable Cd minerals in soil containing low levels of this heavy metal. PMID- 26242803 TI - Pb and Cd Contents in Soil, Water, and Trees at an Afforestation Site, South China. AB - Pb and Cd contents in 13 plantation tree species (leaf and branch components), soil, water (groundwater and river water) at a young (3-5 year-old) seashore afforestation stand were investigated in Nansha district, Guangzhou city in southern China. The results showed that (1) soil, rather than water or trees, had the highest content of both Pb (averagely 48.79 mg/kg) and Cd (0.50 mg/kg), demonstrating that soil might function as a major reservoir for extraneously derived heavy metals; (2) Pb content was higher in branches than in leaves, but Cd content appeared similar in both components, implying possibly different accumulation mechanisms in trees; (3) Pb and Cd appeared to accumulate differently among some tree taxa, whereas almost no significant difference was detected between introduced and indigenous species. The study indicated that trees were potentially useful to remediate sites contaminated with Pb and Cd in the urbanized areas. PMID- 26242804 TI - Online Investigation of Aqueous-Phase Electrochemical Reactions by Desorption Electrospray Ionization Mass Spectrometry. AB - Electrochemistry (EC) combined with mass spectrometry (MS) is a powerful tool for elucidation of electrochemical reaction mechanisms. However, direct online analysis of electrochemical reaction in aqueous phase was rarely explored. This paper presents the online investigation of several electrochemical reactions with biological relevance in the aqueous phase, such as nitrosothiol reduction, carbohydrate oxidation, and carbamazepine oxidation using desorption electrospray ionization mass spectrometry (DESI-MS). It was found that electroreduction of nitrosothiols [e.g., nitrosylated insulin B (13-23)] leads to free thiols by loss of NO, as confirmed by online MS analysis for the first time. The characteristic mass shift of 29 Da and the reduced intensity provide a quick way to identify nitrosylated species. Equally importantly, upon collision-induced dissociation (CID), the reduced peptide ion produces more fragment ions than its nitrosylated precursor ion (presumably the backbone fragmentation cannot compete with the facile NO loss for the precursor ion), thus facilitating peptide sequencing. In the case of saccharide oxidation, it was found that glucose undergoes electro oxidation to produce gluconic acid at alkaline pH, but not at neutral and acidic pHs. Such a pH-dependent electrochemical behavior was also observed for disaccharides such as maltose and cellobiose. Upon electrochemical oxidation, carbamazepine was found to undergo ring contraction and amide bond cleavage, which parallels the oxidative metabolism observed for this drug in leucocytes. The mechanistic information of these redox reactions revealed by EC/DESI-MS would be of value in nitroso-proteome research and carbohydrate/drug metabolic studies. PMID- 26242805 TI - Numerical analysis of ion-funnel transmission efficiency in an API-MS system with a continuum/microscopic approach. AB - A multi-step numerical approach is used to analyze the efficiency of an ion funnel to transport ions over a wide range of m/z. A continuum approach based on the solution of the Navier-Stokes equations is applied to model the gas flow through a capillary connecting the atmospheric and subatmospheric sections of a mass spectrometer. A microscopic, fully kinetic approach based on the solution of the Boltzmann equation is used to examine the ion and gas transport through an ion-funnel kept at a 0.1-3 Torr pressure to the quadrupole section kept at a 0.01 Torr pressure. In addition to aerodynamic drag, the developed approach takes into account the combined effect of the DC field driving the ions downstream toward the funnel exit, the rf field confining the ions in radial direction, and the space charge causing ion repulsion. The sensitivity of the ion transmission to the gas pressure in the ion-funnel, the rf, and the total ion current injected to the funnel from capillary nozzle is shown. Graphical Abstract ?. PMID- 26242806 TI - A novel deletion mutation of the ATP2C1 gene in a family with Hailey-Hailey disease. PMID- 26242808 TI - Relationships between otolith size and fish length in some mesopelagic teleosts (Myctophidae, Paralepididae, Phosichthyidae and Stomiidae). AB - Length-mass relationships and linear regressions are given for otolith size (length and height) and standard length (LS ) of certain mesopelagic fishes (Myctophidae, Paralepididae, Phosichthyidae and Stomiidae) living in the central Mediterranean Sea. The length-mass relationship showed isometric growth in six species, whereas linear regressions of LS and otolith size fit the data well for all species. These equations represent a useful tool for dietary studies on Mediterranean marine predators. PMID- 26242809 TI - Next Accreditation System outcomes and Special Review as part of Graduate Medical Oversight of Internal Medicine Programs in the United States. PMID- 26242807 TI - Prognostic factors of recurrent disease in upper urinary tract urothelial cancer after radical nephroureterectomy: Subanalysis of the multi-institutional national database of the Japanese Urological Association. AB - OBJECTIVES: To explore predictive factors of disease recurrence after radical nephroureterectomy in patients with upper urinary tract urothelial cancer. METHODS: A multi-institutional national database promoted by the Japanese Urological Association including 293 institutions and 1172 patients was used for the present study. Patient with non-metastatic upper urinary tract urothelial cancer who underwent primary radical nephroureterectomy with curative intent were analyzed. Univariate analysis using the Kaplan-Meier method and multivariate Cox regression models with stepwise selection was used to evaluate time to recurrence after surgery. RESULTS: The median duration of follow up was 55.8 months, and disease recurred in 325 (27.7%) patients at a median of 11.4 months after radical nephroureterectomy. According to a Cox proportional hazards model, the Union International Contre le Cancer 2002 pathological stage of the primary tumor, lymph node status, presence of lymphatic and/or vascular invasion, infiltrative growth pattern, and age were independent predictors (P < 0.05) of recurrence-free survival. CONCLUSIONS: Despite several limitations, our analysis suggests that pathological tumor stage, lymph node status, lymphovascular invasion, infiltrative growth pattern and age represent important prognostic variables after radical nephroureterectomy in Japanese patients with upper urinary tract urothelial cancer. This information could be potentially used to select patients for adjuvant systemic therapy. PMID- 26242810 TI - The impact of pediatric-specific dose modulation curves on radiation dose and image quality in head computed tomography. AB - BACKGROUND: The volume of CT examinations has increased with resultant increases in collective dose values over the last decade. OBJECTIVE: To analyze the impact of the tube current and voltage modulation for dose values and image quality of pediatric head CT examinations. MATERIALS AND METHODS: Head CT examinations were performed on anthropomorphic phantoms and four pediatric age categories before and after the introduction of dedicated pediatric curves for tube voltage and current modulation. Local diagnostic reference levels were calculated. Visual grading characteristic image quality evaluation was performed by four pediatric neuroradiologists and image noise comparisons were performed. RESULTS: Pediatric specific modulation curves demonstrated a 49% decrease in mean radiation dose for phantom examinations. The local diagnostic reference levels (CTDIvol) for clinical examinations decreased by 52%, 41%, 46% and 40% for newborn, 5-, 10- and 15-year-old patients, respectively. Visual grading characteristic image quality was maintained for the majority of age categorizations (area under the curve = 0.5) and image noise measurements did not change (P = 0.693). CONCLUSION: Pediatric-specific dose modulation curves resulted in an overall mean dose reduction of 45% with no significant differences in subjective or objective image quality findings. PMID- 26242812 TI - Catastrophic pneumoperitoneum in a patient with perforated colorectal cancer with liver metastasis. PMID- 26242813 TI - Executive function in paediatric medulloblastoma: The role of cerebrocerebellar connections. AB - Executive functions (EFs) are involved in the attainment, maintenance, and integration of information; these functions may play a key role in cognitive and behavioural outcomes in children treated for medulloblastoma (MB). At present, it remains unclear which EFs are most sensitive to the treatment effects for MB and whether damage to cerebrocerebellar circuitry is associated with EF. We completed a comprehensive evaluation of EF in 24 children treated for MB and 20 age-matched healthy children (HC) and distilled these measures into components. Six components (C1-C6) were extracted from our model, reflecting dissociable constructs of EF: C1 = cognitive efficiency; C2 = planning/problem-solving; C3 = positive cognitive emotion regulation; C4 = working memory; C5 = negative cognitive emotion regulation; and C6 = mixed cognitive emotion regulation. Group differences were found for C1, C2, C3, and C4; the MB group showed poorer performance on EF tasks and made less use of positive cognitive emotion regulation strategies relative to HC. Compromise to cerebrocerebellar microstructure - cerebro-ponto-cerebellar and cerebello-thalamo-cerebral pathways - was evident in children treated for MB compared to HC. We found that cerebrocerebellar circuitry has a mediating effect on one component of EF following treatment for MB - working memory. PMID- 26242814 TI - How can air conducted sound be an otolithic stimulus and cause VEMPs? PMID- 26242815 TI - An improved electrical impedance myography (EIM) tongue array for use in clinical trials. AB - OBJECTIVES: Electrical impedance myography (EIM) measurements of the tongue could provide valuable information about bulbar dysfunction in amyotrophic lateral sclerosis (ALS). A prototype tongue depressor EIM array produced gag reflexes. The objectives of this study were to determine the reliability, mean phase values, and tolerability of tongue EIM measurements using a smaller electrode array. METHODS: Tongue EIM measurements were performed in a total of 31 healthy individuals and four neuromuscular patients with lingual abnormalities. Reliability was assessed by calculating the intraclass correlation coefficient (ICC) and percent difference in addition to performing Bland-Altman analyses. Standard descriptive statistics, including results of a Mann-Whitney test, were also determined. RESULTS: At the 50 kHz frequency, the ICCs for intra- and inter rater reliability were 0.76 with 5.17% difference and 0.78 with 5.34% difference respectively. The mean EIM phase values of healthy participants (11.61 degrees +/- 1.00 degrees ) and patients (9.87 degrees +/- 1.28 degrees ) were significantly different (p=0.0051). None of the participants experienced gag reflexes or discomfort. CONCLUSIONS: The small tongue array provided good inter- and intra-rater reliability, could preliminarily distinguish between healthy and diseased muscle, and was well-tolerated. SIGNIFICANCE: Biomarker information about tongue health could be more comfortably obtained with a smaller EIM array. PMID- 26242816 TI - The duration and course of opioid therapy in patients with chronic non-malignant pain. AB - BACKGROUND: Prescription databases provide the opportunity for investigating opioid treatment and co-medication within large populations. So far, few studies have investigated the duration of opioid therapy, and large differences in discontinuation rates have been reported. METHODS: Data from the Norwegian Prescription Database were used to follow the study population of all adult persistent opioid users with non-malignant pain in Norway in 2005 (n = 44,867) for 6 years. Persistent opioid use was defined as being dispensed >= 180 defined daily doses (DDD) or 4500 mg oral morphine equivalents (OMEQ) during a 365-day period. The study population was stratified according to previous opioid use into new persistent opioid users, without previous persistent opioid use, and previous low-dose or previous high-dose persistent opioid users, having earlier persistent opioid use and received less or more than 120 mg OMEQ/day in 2005, respectively. RESULTS: Twenty-seven percent of new, 59% of previous low-dose, and 55% of previous high-dose users met the criteria of persistent use of opioids each year. Exactly, 22%, 11%, and 3% increased their cumulative yearly opioid dose by 200% or more during the study period. With 80% still being regular users of either drugs, 6 years later, long-term persistent opioid users were more likely to continue concomitant use of benzodiazepines or z-hypnotics than other users, CONCLUSION: The findings confirm high discontinuation rates in patients receiving opioids for chronic non-malignant pain. However, a clinically significant number of patients increase their doses over 6 years and many patients combine long-term opioid treatment with benzodiazepines and z-hypnotics. PMID- 26242818 TI - Are all GMOs the same? Consumer acceptance of cisgenic rice in India. AB - India has more than 215 million food-insecure people, many of whom are farmers. Genetically modified (GM) crops have the potential to alleviate this problem by increasing food supplies and strengthening farmer livelihoods. For this to occur, two factors are critical: (i) a change in the regulatory status of GM crops, and (ii) consumer acceptance of GM foods. There are generally two classifications of GM crops based on how they are bred: cisgenically bred, containing only DNA sequences from sexually compatible organisms; and transgenically bred, including DNA sequences from sexually incompatible organisms. Consumers may view cisgenic foods as more natural than those produced via transgenesis, thus influencing consumer acceptance. This premise was the catalyst for our study--would Indian consumers accept cisgenically bred rice and if so, how would they value cisgenics compared to conventionally bred rice, GM-labelled rice and 'no fungicide' rice? In this willingness-to-pay study, respondents did not view cisgenic and GM rice differently. However, participants were willing-to-pay a premium for any aforementioned rice with a 'no fungicide' attribute, which cisgenics and GM could provide. Although not significantly different (P = 0.16), 76% and 73% of respondents stated a willingness-to-consume GM and cisgenic foods, respectively. PMID- 26242819 TI - [Heterotopic gastric mucosa in the rectum: Report of a case]. AB - BACKGROUND: Ectopic gastric mucosa has been described in different locations of the digestive tract, but that of the rectum is the least frequent. CLINICAL CASE: The case is described of a 48 year-old woman being investigated by the gastrointestinal department due to rectal bleeding and rectal tenesmus. Colonoscopy showed a diverticular cavity 3 cm, which was reported by histology as fundic-type heterotopic gastric mucosa. Barium enema and abdominopelvic CT showed a diverticular image at level of the right posterolateral wall of the rectal ampulla. Trans-rectal diverticulectomy was performed with primary closure of the resulting mucosal defect. The surgical specimen showed areas of gastric epithelium with no signs of atypia. CONCLUSIONS: It is not known whether the origin of heterotopic gastric mucosa occurs during foetal development or is the result of abnormal regeneration under inflammatory conditions. It is usually clinically asymptomatic or presents as haematochezia, especially in cases where gastric acid is being produced. In these cases there must be an initial treatment with proton pump inhibitors, although the definitive treatment is always surgical or endoscopic excision of the mucosa. PMID- 26242817 TI - Metabolomic profiling of hormone-dependent cancers: a bird's eye view. AB - Hormone-dependent cancers present a significant public health challenge, because they are among the most common cancers in the world. One factor associated with cancer development and progression is metabolic reprogramming. By understanding these alterations, we can identify potential markers and novel biochemical therapeutic targets. Metabolic profiling is an advanced technology that allows investigators to assess low-molecular-weight compounds that reflect physiological alterations. Current research in metabolomics on prostate (PCa) and breast cancer (BCa) have made great strides in uncovering specific metabolic pathways that are associated with cancer development, progression, and resistance. In this review, we highlight some of the major findings and potential therapeutic advances that have been reported utilizing this technology. PMID- 26242820 TI - [Splenic lymphangioma. A rare tumour. Presentation of 3 cases and a literature review]. AB - BACKGROUND: Lymphangiomas are benign tumours, considered to be congenital malformations of the lymphatic system that predominately affect children, with only a few cases reported in adults. The most common sites of these lesions are the neck (75%) and axillary region (20%), but rarely found in the spleen. OBJECTIVE: A description is presented of 3 cases of incidentally detected splenic lymphangioma, one in a child and in 2 adults, respectively, as well as a literature review. CLINICAL CASES: After a clinical and physical examination, all patients had an abdominal ultrasound, CT scan and a complete splenectomy, followed by a histopathological study on the removed spleen. Two patients were asymptomatic, and the paediatric patient referred to intermittent abdominal pain without other symptoms. The clinical and physical examinations related to the mass were negative. The final diagnosis was based on a combination of radiological and histopathological findings. Total splenectomy was undertaken in all cases without complications. CONCLUSIONS: Splenic lymphangioma is very rare, and more so in adults. This condition is often asymptomatic and is incidentally detected by imagenology due to any other differet cause. The final diagnosis should be based on a combination of clinical, radiological, and histopathological findings. Splenectomy is the treatment of choice and the prognosis is good. PMID- 26242821 TI - [Multiple recurrent eccrine porocarcinoma with inguinal metastasis. A case report]. AB - BACKGROUND: Eccrine porocarcinoma, first described in 1963, is a rare malignant lesion arising from the eccrine sweat glands. It is usually a primary tumour, or even more common, a malignant degeneration of an eccrine poroma. It usually affects older persons and is located most commonly on the lower extremities. About 20% of eccrine porocarcinoma will recur after treatment. The treatment is wide local excision of the primary lesion. This uncommon skin tumour has a locally aggressive behaviour and a high recurrence rate. CLINICAL CASE: An 82 year-old man presenting with multiple recurrent eccrine porocarcinoma with inguinal metastasis. The treatment was a radical excision and inguinal lymphadenectomy. There were no postoperative complications, but there was local recurrence after six months. CONCLUSION: Early diagnosis and wide excision is the best way to achieve a good prognosis, due to the aggressiveness of this tumour. PMID- 26242823 TI - [Pancreatic pseudoaneurysms: forms of presentation and therapeutic options]. PMID- 26242822 TI - [Drug related colonic perforation: Case report]. AB - BACKGROUND: Acute pseudo-obstruction of the colon is a disorder characterised by an increase in intra-luminal pressure that leads to ischaemia and necrosis of the intestinal wall. The mechanism that produces the lesion is unknown, although it has been associated with: trauma, anaesthesia, or drugs that alter the autonomic nervous system. The pathophysiology of medication induced colon toxicity can progress to a perforated colon and potentially death. OBJECTIVE: Present a case of a colonic pseudo-obstruction in a patient with polypharmacy as the only risk factor and to review the medical literature related to the treatment of this pathology. CLINICAL CASE: The case is presented of a 67 year old woman with colonic pseudo-obstruction who presented with diffuse abdominal pain and distension. The pain progressed and reached an intensity of 8/10, and was accompanied by fever and tachycardia. There was evidence of free intraperitoneal air in the radiological studies. The only risk factor was the use of multiple drugs. The colonic pseudo-obstruction progressed to intestinal perforation, requiring surgical treatment, which resolved the problem successfully. CONCLUSION: It is important to consider drug interaction in patients with multiple diseases, as it may develop complications that can be avoided if detected on time. PMID- 26242824 TI - [Acute posterior multifocal placoid pigment epitheliopathy. Case report]. AB - BACKGROUND: Acute posterior multifocal placoid pigment epitheliopathy is an unusual, self-limited, inflammatory disease that affects the choriocapillaris, and external retinal layers. CLINICAL CASE: A 26 year-old male patient complained of decreased visual acuity, as well as photopsia in both eyes for the past three days. Best corrected visual acuity was 20/200 in the right eye and 20/80 in the left eye. There was no anterior chamber inflammation or vitritis in either eye. There were plaque-like, cream-coloured sub-retinal lesions with ill-defined borders in the posterior pole of both eyes. Fluorescein angiography showed hypofluorescent lesions in early phases that corresponded to the lesions seen in the clinical examination. These lesions were hyperfluorescent in later phases of the angiography. Based on the clinical and angiographic findings, an acute posterior multifocal placoid pigment epitheliopathy diagnosis was made. CONCLUSIONS: Acute posterior multifocal placoid pigment epitheliopathy is an inflammatory condition of unknown origin that is part of the differential diagnosis of placoid retinal diseases. PMID- 26242825 TI - [Synchronous acute cholecystolithiasis and perforated acute appendicitis. Case report]. AB - BACKGROUND: Acute appendicitis and acute cholecystitis are among the most common diagnoses that general surgeons operate on. However, it is rarely described in its synchronous form. CLINICAL CASE: A 43 year-old woman attending the clinic for right upper quadrant pain of 11 days duration. The patient refers to intermittent radiating pain in the right side, with positive Murphy, tachycardia, and fever. The laboratory results showed white cells 16,200/mm(3), glucose 345 mg/dl, abnormal liver function tests. Acute cholecystitis was reported with ultrasound. A Masson-type incision was made, noting an enlarged pyogenic gallbladder with thickened walls, sub-hepatic abscess of approximately 300 ml, greenish-yellow colour, and foetid. An anterograde subtotal cholecystectomy is performed due to difficulty in identifying elements of Calot triangle due to the inflammatory process, opening it and extracting stones. The right iliac fossa is reviewed, finding a plastron and a sub-serous retrocaecal appendix perforated in its middle third with free fecalith and an abscess in the pelvic cavity. An anterograde appendectomy was performed and the patient progressed satisfactorily, later being discharged due to improvement. DISCUSSION: In this patient, with a history of recurrent episodes of gallbladder pain and disseminated acute abdominal pain without peritoneal irritation, clinical suspicion was exacerbated cholecystitis with probable empyema of the gallbladder. Open surgery approach for this patient allowed access to both the appendix and gallbladder in order to perform a complete exploration of the abdominal cavity. CONCLUSION: The synchronous presentation of cholecystolithiasis and complicated appendicitis has not been reported in the literature. PMID- 26242826 TI - [Minimally invasive treatment for traumatic chylopericardium. Paediatric case report]. AB - BACKGROUND: Chylopericardium is a rare occurrence in children. The most common causes are associated with cardiac surgery, malformations of the lymphatic system, idiopathic reasons, among others. OBJECTIVE: The case is presented of a patient with traumatic chylopericardium, the diagnostic methodology, and in particular, its successful resolution by surgical means. CLINICAL CASE: Male patient of 6 years old, previous accident of fall from patient's height. Chest x ray showed evidence of cardiomegaly. An echocardiogram with pericardial effusion was performed. Pericardial puncture was performed with drainage of milky material, confirming chylous liquid. Treatment included pericardial catheterisation, total parenteral nutrition, octreotide, and diet with medium chain triglycerides, with persistent increased pericardial fluid. Lymphatic abnormalities were ruled out by MRI. He underwent surgical treatment due to failure of prior treatment. A thoracoscopic approach was adopted with a favourable outcome. CONCLUSIONS: Chylopericardium occurs in children in most cases after cardiovascular surgery. The case presented here was classified as idiopathic. Patients with this condition may present with severe symptoms, such as tamponade, or can be asymptomatic as in the case presented. If medical treatment fails, it should be resolved by surgery; the best choice is minimally invasive treatment with its well-known advantages. PMID- 26242827 TI - [Acute pancreatitis secondary to partial multidrug resistance 3 p-glycoprotein deficit]. PMID- 26242828 TI - Frequency of ITPA gene polymorphisms in Iranian patients with acute lymphoblastic leukemia and prediction of its myelosuppressive effects. AB - 6-Mercaptopurine (6-MP) plays an important role in treatment of childhood acute lymphoblastic leukemia (ALL). Inosine triphosphate pyrophosphohydrolase (ITPA) is an enzyme involved in 6-MP metabolic pathway that convert the inosine triphosphate (ITP) to inosine monophosphate (IMP) and prevents the accumulation of the toxic metabolite ITP. Our objective was to evaluate the ITPA 94C>A, IVS2+21A>C polymorphisms in patients with ALL treated with 6-MP and prediction of its clinical outcomes. Our study population consisted of 70 patients diagnosed with ALL in the Division of Hematology-Oncology of Tehran Mofid Hospital. PCR was carried out to amplify exon 2, exon 3, intron 2, and intron 3 of ITPA gene then, all the amplified fragments were subjected to directional sequencing and then association between genotype and 6-MP toxicity was studied. In this study two exonic variants including 94C>A and 138G>A showed a prevalence of 8.5% and 36.4%, respectively. Two intronic variants, IVS2+21A>C and IVS3+101G>A were found in 13.5% and 7% of the samples, respectively. The rate of myelosuppression in the presence of mutant homozygote and heterozygous alleles (94C>A, 138G>A, IVS2+21A>C and IVS3+101G>A) was higher than that of wild type alleles during the use of 6 MP. Hepatotoxicity in patients with mutant homozygous and heterozygous 94C>A and IVS3+101G>A during the treatment 6-MP was higher than before treatment with 6-MP. Our results showed that patients with aberrant ITPase genotype (mutant homozygous or heterozygous), more likely to be myelosuppressed and show liver toxicity after treatment with 6-MP. Our results suggest that pre-therapeutic screening of patients for ITPA 94C>A, IVS2+21A>C and IVS3+101G>A can help in minimizing the adverse effects of 6-MP in ALL patients. PMID- 26242829 TI - DNMT3A intragenic hypomethylation is associated with adverse prognosis in acute myeloid leukemia. AB - DNA methyltransferase 3A (DNMT3A), a member of de novo methyltransferases, has been found with overexpression in several cancers including acute myeloid leukemia (AML). The present study was aimed to investigate the methylation status of DNMT3A intragenic differentially methylated region 2 (DMR2) using real-time quantitative methylation-specific PCR (RQ-MSP) and analyze its clinical significance in AML. Aberrant hypomethylation of DNMT3A gene was found in 55.3% (84/152) of AML cases, but the status of DNMT3A hypomethylation was not correlated with the expression of four DNMT3A isoforms as well as DNMT3A mutation. There was no significant difference in the rates of complete remission (CR) between patients with and without DNMT3A hypomethylation. However, the patients with DNMT3A hypomethylation had shorter overall survival (OS) time than those without DNMT3A hypomethylation (7 months vs. 11 months, P=0.034). Moreover, the patients with DNMT3A hypomethylation also showed significantly shorter OS than those without DNMT3A hypomethylation in cytogenetically normal AML (CN-AML) (7 months vs. 25 months, P=0.011). Multivariate analysis confirmed the independent adverse impact of DNMT3A hypomethylation in CN-AML. Our data suggest that DNMT3A DMR2 hypomethylation is a negative prognostic hallmark in CN-AML. PMID- 26242830 TI - Having it all? Where are we with "social" egg freezing today? PMID- 26242831 TI - Hydrocellular foam dressing increases the leptin level in wound fluid. AB - Hydrocellular foam dressing (HCF) absorbs excessive wound fluid, which contains various cytokines and growth factors, and ensures a moist environment to promote wound healing. However, the molecular mechanisms underlying the wound fluid component changes induced by HCF are poorly understood. In the present study, we examined the effect of HCF on wound healing and the associated regulatory mechanisms in relation to variations in cytokine levels in the wound fluid. We created full-thickness wounds on the dorsolateral skin of rats and collected the resulting wound fluid samples. HCF was immersed in a plate containing the wound fluids. HCF was then removed and the excess wound fluid remaining in the plate was examined by cytokine array and enzyme-linked immunosorbent assay. We also used a rat model and human dermal fibroblast cultures to examine the effect of wound fluid component changes during the wound healing process. Upon treatment with HCF, leptin levels were upregulated in the wound fluid. Fibroblast proliferation was enhanced and the effect was suppressed in the presence of leptin antagonist. In our in vivo model, HCF increased wound contraction compared with film dressings and this positive effect of HCF was suppressed by addition of leptin antagonist. Our results suggest that dermal fibroblast proliferation is upregulated by HCF due to increased leptin level at the wound surface, and these effects promote wound healing. We believe that the present study contributes to furthering the understanding of the mechanisms underlying the effects of HCF induced wound healing. PMID- 26242832 TI - Rashes in School: Can They Stay, or Should They Go? AB - School-aged children frequently present to the school nurse office due to a rash. School nurses need to be familiar with common childhood rashes and evidence-based treatment recommendations. Most importantly, school nurses must possess knowledge of whether rashes are contagious and whether the child should remain in school or at home until resolution of the rash. It is essential that school nurses are aware of interventions to reduce the risk of spreading a contagious skin infection throughout their school. PMID- 26242833 TI - Haemato-biochemical and oxidative status of buffaloes naturally infected with Trypanosoma evansi. AB - Blood samples were collected from 05 clinically healthy and 10 adult female water buffaloes naturally infected with Trypanosoma evansi. Confirmation of disease free and infected status of buffaloes was made on clinical signs, observation of T. evansi parasites in the blood smear and duplex PCR based assay. Blood samples were evaluated for levels of haemoglobin (Hb), packed cell volume (PCV), differential leucocytes count (DLC), lipid peroxidation (LPO), calcium, phosphorous, magnesium sodium and potassium and activities of superoxide dismutase (SOD), catalase (CAT), aspartate transaminase (AST), lactate dehydogenase (LDH) and alkaline phosphatase (ALP). The results of the study revealed substantial decrease in levels of Hb, PCV and increase in LPO, SOD, CAT and AST in infected animals compared to healthy animals. However other haematological and biochemical indices did not show significant variations in infected and healthy buffaloes. The enhanced erythrocytic oxidation and reduction of hematological indices, suggests that the enhanced oxidation of the erythrocytes may be a contributory factor in erythrocytic destruction and progression of the anaemia in T. evansi infection in water buffaloes. PMID- 26242834 TI - Flow patterns in externally stented saphenous vein grafts and development of intimal hyperplasia. AB - BACKGROUND: Low and oscillatory wall shear stress promotes endothelial dysfunction and vascular disease. The aim of the study was to investigate the impact of an external stent on hemodynamic flow parameters in saphenous vein grafts (SVGs) and their correlation with the development of intimal hyperplasia. METHODS: We performed post hoc computational fluid dynamics analysis of the randomized Venous External Support Trial, in which angiography and intravascular ultrasound data were available for 29 patients, 1 year after coronary artery bypass grafting. Each patient received 1 external stent, to either the right or left coronary territories; >= 1 patients with nonstented SVGs served as control(s). Diffuse flow patterns were assessed using mean values of various hemodynamic parameters, including time-averaged wall shear stress and oscillatory shear index (OSI). Focal flow disturbances were characterized using percentile analysis of each parameter. RESULTS: Angiography and intravascular ultrasound data were available for 53 and 43 SVGs, respectively. The stented versus nonstented SVG failure rates were significantly lower in the left territory (17.6% vs 27.5%; P = .02), and significantly higher in the right territory (46.2% vs 13.4%; P = .01). In both diffuse and focal flow-pattern analyses, OSI was significantly lower in the stented versus nonstented SVG group (P = .009 and P < .003, respectively), whereas no significant differences were observed in time averaged wall shear stress values. High OSI values were correlated with the development of intimal hyperplasia (P = .01). CONCLUSIONS: External stenting affects SVG's hemodynamics 1 year after coronary artery bypass grafting and may mitigate the progression of intimal hyperplasia by reducing oscillatory shear stress. PMID- 26242835 TI - Noninfectious aortitis and ascending aneurysms: The tip of the iceberg. PMID- 26242836 TI - Discussion. PMID- 26242837 TI - Historical perspectives of The American Association for Thoracic Surgery: Dr David B. Skinner (1935-2003)--a surgeon and something more. PMID- 26242838 TI - Comparison of in-hospital and longer-term outcomes of hybrid and Norwood stage 1 palliation of hypoplastic left heart syndrome. AB - OBJECTIVES: The hybrid approach for the initial management of hypoplastic left heart syndrome shifts the risks of major open surgery from the vulnerable neonatal period to an older age. This study determined differences between the hybrid and the standard Norwood procedures in postoperative in-hospital mortality, renal failure, and survival to at least 2 years of age. METHODS: Data from the Pediatric Health Information System, a detailed hospital discharge database of 43 freestanding children's hospitals, were analyzed. The Pediatric Health Information System includes demographic information, diagnosis, and procedure and clinical service data. Instrumental variable regression techniques were used to estimate the predicted probability of in-hospital mortality, renal failure, and survival to 24 months of age for infants with hypoplastic left heart syndrome who received a hybrid or Norwood procedure. The statistical models controlled for demographics and comorbid chromosomal anomalies. RESULTS: A total of 3654 infants with hypoplastic left heart syndrome underwent intervention from 1998 to 2012. Of these, 242 underwent the hybrid approach and the remainder underwent the Norwood procedure. Instrumental variable models showed significantly reduced odds of patients who underwent the hybrid approach being diagnosed with renal failure (adjusted risk ratio [ARR], 0.48; 95% confidence interval [CI], 0.26-0.89); increased odds of surviving initial hospitalization (ARR, 1.28; 95% CI, 1.06-1.55); increased odds of survival, indicated by readmissions more than 6 months after initial hospitalization (ARR, 1.53; 95% CI, 1.05-2.22); and a decrease in length of stay by 20 days for the initial surgical hospitalization (95% CI, -27.4 to -13.9). CONCLUSIONS: The short term hospital based outcomes and longer-term survival outcomes of the hybrid approach for hypoplastic left heart syndrome may be better than those of the Norwood procedure. PMID- 26242839 TI - An e-score is born. PMID- 26242840 TI - Compliance trumps oxygenation: Predicting quality with ex vivo lung perfusion. PMID- 26242841 TI - Spray congealing as a microencapsulation technique to develop modified-release ibuprofen solid lipid microparticles: the effect of matrix type, polymeric additives and drug-matrix miscibility. AB - This study aimed to achieve modified-release of ibuprofen (IBU) by encapsulation within lipid-based matrix materials [cetyl alcohol (CA), stearic acid (SA) and glyceryl dibehenate (GB)] using spray congealing to produce solid lipid microparticles (SLMs). Polymeric additives, polyvinyl-2-pyrrolidone-vinyl-acetate and ethylcellulose, were employed as release-modifying agents. Spray-congealed SLMs yield, scanning electron microscopy (SEM)-based morphology, particle size, drug content and entrapment efficiency were investigated. The influence of matrix type, additive type and concentration and drug-matrix miscibility on release of IBU was elucidated. Yields (81.4-96.4%) and drug encapsulation efficiencies (88.4 100%) of SLMs were high for all formulations. SLMs were generally discrete, spherical and dense. Increasing additives concentration led to not only larger median size SLMs but also faster drug release due to increased hydrophilicity conferred by the additives. Solid solution systems (SA-IBU, GB-IBU) sustained the release of IBU better than solid dispersion system (CA-IBU). CA- and GB-based SLMs closely adhered to the Weibull model of drug release, while SA counterparts followed the Korsmeyer-Peppas model. PMID- 26242842 TI - Formulation and evaluation of Itraconazole nanoemulsion for enhanced oral bioavailability. AB - Itraconazole (ITR), an antifungal agent has poor bioavailability due to low aqueous solubility. The present investigation aimed at development of ITR nanoemulsion to enhance its oral bioavailability. ITR nanoemulsion was prepared using Capmul MCM C8 as oil, Pluronic F68 as co-surfactant and Cremophore EL as surfactant using high speed stirring, followed by probe sonication. Nanoemulsion with average globule size of 100.9 nm and zeta potential of -35.9 +/- 1.2 mV was able to penetrate well into the intestinal membrane as confirmed by the laser confocal scanning microscopy and ex vivo intestinal permeability study. Antimycotic study confirmed the efficacy of ITR nanoemulsion. Significantly higher values of pharmacokinetic parameters the formulation than the plain drug and marketed formulation indicated an increase in the bioavailability of ITR. The prepared nanoemulsion was stable at both, refrigerated and room temperature conditions. Nanoemulsion of ITR seems to be a promising formulation for enhancement of its oral bioavailability. PMID- 26242843 TI - Cisgender male and transgender female sex workers in South Africa: gender variant identities and narratives of exclusion. AB - Sex workers are often perceived as possessing 'deviant' identities, contributing to their exclusion from health services. The literature on sex worker identities in relation to health has focused primarily on cisgender female sex workers as the 'carriers of disease', obscuring the experiences of cisgender male and transgender sex workers and the complexities their gender identities bring to understandings of stigma and exclusion. To address this gap, this study draws on 21 interviews with cisgender male and transgender female sex workers receiving services from the Sex Workers Education and Advocacy Taskforce in Cape Town, South Africa. Our findings suggest that the social identities imposed upon sex workers contribute to their exclusion from public, private, discursive and geographic spaces. While many transgender female sex workers described their identities using positive and empowered language, cisgender male sex workers frequently expressed shame and internalised stigma related to identities, which could be described as 'less than masculine'. While many of those interviewed felt empowered by positive identities as transgender women, sex workers and sex worker advocates, disempowerment and vulnerability were also linked to inappropriately masculinised and feminised identities. Understanding the links between gender identities and social exclusion is crucial to creating effective health interventions for both cisgender men and transgender women in sex work. PMID- 26242844 TI - Assessing the painful, uninflamed eye in primary care. PMID- 26242845 TI - Unusual sites for hemodialysis vascular access construction and catheter placement: A review. AB - As more end-stage renal disease patients require hemodialysis and live longer, many will fail to develop or maintain a functioning upper extremity vascular access. When a patient exhausts vascular access sites in the upper extremities, new fistulas and grafts can be constructed in the lower extremities, thorax, and abdomen as long as a pair of proximate artery and vein provide adequate blood inflow and outflow, respectively. When only a moderate size vein with adequate blood flow provides a conduit to either a patent superior or inferior vena cava, inserting a double-lumen venous hemodialysis catheter can provide temporary or permanent access. We review the literature and report the unusual sites for hemodialysis vascular access and catheter placement. PMID- 26242846 TI - Immunoadsorption and hemodialysis as a tandem procedure: a single-center experience of more than 60 procedures. AB - PURPOSE: We have designed a desensitization program that gives good results and is cost effective for kidney-transplant patients who have a potential living donor, who are ABO incompatible (ABOi), and who may or may not have donor specific alloantibodies (DSAs). METHODS: Desensitization at pretransplant is based on immunosuppressants (such as rituximab, tacrolimus, and mycophenolic acid) and apheresis to retrieve potentially detrimental isoagglutinins and DSAs from blood. In 2011, we implemented immunoadsorption (IA) instead of plasmapheresis in our center as part of the desensitization protocol. Because IA is very tedious and time-consuming, we decided to perform IA and hemodialysis (HD) in tandem instead of performing these methods sequentially. Herein, we report on more than 100 of these tandem procedures and compare the results to those obtained when IA was performed before a HD session. RESULTS: The tandem process resulted in nursing time being cut by half: from almost 10h30 min/patient to 6 h/patient. When IA was performed alone, body-weight gain was 1 kg (range 0 to 1.75) and the median volume of plasma treated per session was 6500 mL (range 4500 to 10 600). Conversely, during a tandem IA + HD session, the net median weight gain was -1.5 kg (range -4.1 to 0) and the median volume of plasma treated per session was 5000 mL (range 4000 to 8600). In addition, the tandem procedure was as well tolerated as that for IA followed by HD. CONCLUSIONS: Tandem IA plus HD is a safe and cost-effective procedure. PMID- 26242847 TI - LVAD inflow cannula covered with a titanium mesh induces neointimal tissue with neovessels. AB - BACKGROUND: Thrombus formation at the interfaces of inflow cannulas and left ventricular apexes is considered to be one of the predominant sources of thromboembolic complication. Use of a fine titanium mesh-covered inflow cannula is expected to prevent such thrombus formation by inducing neointimal tissue around the cannula. METHODS: Titanium pins (20 mm long, 3 mm diameter) covered with a fine titanium mesh (wire dia. 85 MUm; volumetric porosity 40-70%) were developed to mimic the inflow cannulas of left ventricular assist devices (LVADs). Smooth-surface pins of the same size were also designed. The pins were implanted into the left ventricular apexes of rabbits. The rabbits were bled without anticoagulation for between 1 week and 1 year. The tissues around the pins were evaluated histologically. RESULTS: 28 rabbits (mesh group, 15; smooth group, 13) were evaluated. The mesh-covered pins inhibited thrombus formation to a remarkable degree throughout the entire observation period. The tissues around the mesh-covered titanium pins appeared to be in the process of conversion from thrombus formation to granulation, resulting in the replacement of fibrotic tissue containing myofibroblasts with endothelialized and angiogenic tissue. On the surface of the mesh-covered pins, endothelial cells were arranged without platelet adhesion. The tissue formed around the smooth-surface pins was partially organized into a thrombus without angiogenesis. CONCLUSIONS: The titanium-mesh surface modification prevented thrombus formation with formation of neointimal tissue with endothelialization and angiogenesis. This surface modification could prevent wedge thrombus formation among patients supported by LVADs. PMID- 26242848 TI - Multi-objective optimization of pulsatile ventricular assist device hemocompatibility based on neural networks and a genetic algorithm. AB - PURPOSE: Given the benefit of pulsatile blood flow for perfusion of coronary arteries and end organs, pulsatile ventricular assist devices (VADs) are still widely used as paracorporeal mechanical circulatory support devices in clinical applications. However, poor hemocompatibility limits the service period of the VADs. Most previous improvements on VAD hemocompatibility were conducted by trial and-error CFD analysis, which does not easily arrive at the best solution. METHODS: In this paper, a multi-objective optimization method integrating neural networks and NSGA-II (Non-dominated Sorted Genetic Algorithm-II) based on FSI simulation was developed and applied to a pulsatile VAD to optimize its hemocompatibility. First, the VAD blood chamber was parameterized with the principal geometrical parameters. Three hemocompatibility indices including hemolysis, platelet activation, and platelet deposition were chosen as goal functions. The neural networks were built to fit the nonlinear relationship between goal functions and geometrical parameters. Next, a multi-objective optimization algorithm (NSGA-II) was used to search out the Pareto optimal solutions in the built neural networks. Finally, the best compromise solution was selected from the Pareto optimal solutions by a fuzzy membership approach and validated by FSI simulation. RESULTS: The best compromise solution simultaneously possesses an acceptable hemolysis index, platelet activation index, and platelet deposition index, and the corresponding relative errors between the indices predicted by optimization algorithm and the one calculated by FSI simulations are all less than 5%. CONCLUSIONS: The results suggest that the proposed multi objective optimization method has the potential for application in optimizing pulsatile VAD hemocompatibility, and may also be applied to other blood-wetted devices. PMID- 26242849 TI - Anticoagulation with citrate for hemodiafiltration in an acute bleeding trauma. PMID- 26242850 TI - [Reliable recognition of glaucoma by spectral domain optical coherence tomography?]. AB - BACKGROUND: The latest approach to diagnosing glaucoma by high resolution spectral domain optical coherence tomography (SD-OCT) is to assess the minimal rim width (MRW) of the retinal nerve fiber layer (RNFL) at the Bruch's membrane opening (BMO) in the optic disk margin. OBJECTIVE: This study was carried out to evaluate if this new parameter allows a more precise detection of glaucomatous damage to the RNFL. METHODS: This article presents clinical examples and differences in the measurement methods in glaucoma cases. RESULTS: The main advantage is the automated detection by software allowing precise landmark tracking and coherent follow-up investigations. There seem to be considerable differences between the funduscopically assumed margin and the detection of the margin by the new software. Likewise there is a difference between RNFL measurements taken at the BMO and the peripapillary scan by SD-OCT. DISCUSSION: Ongoing research should assess the potential of this new parameter for a more precise detection of nerve fiber defects and changes over time compared to other imaging techniques. PMID- 26242851 TI - [Thickening or hypoplasia of the fovea]. AB - A 64-year-old female patient complained of a bilateral reduction in vision. The foveal reflex was remarkable bilaterally and optical coherence tomography (OCT) demonstrated the absence of a foveal depression. After exclusion of possible diseases foveal hypoplasia was diagnosed. This rare alteration of the fovea should not be mistaken for foveal edema. A volume scan with a narrow grid is advisable to avoid a misinterpretation. PMID- 26242852 TI - [Retinal vein occlusion: Therapy of retinal vein occlusion]. AB - Treatment of retinal vein occlusion can be systemic or local. Therapeutic strategies include improved blood supply, treatment of the vision-reducing macular edema by intravitreal injection of inhibitors of vascular endothelial growth factors (VEGF) or corticosteroids and laser photocoagulation for neovascular complications. As long as head-to-head studies comparing steroids and VEGF inhibitors have not been published, none of the available intravitreally injected substances can be given priority. Well-known side effects of intravitreal steroids are cataract formation and ocular hypertension whereas VEGF inhibitors need to be frequently injected. Although therapy for retinal vein occlusion is protracted, initial long-term data indicate that treatment can be terminated in at least half of the patients . Finally, a treatment recommendation according to the current state of data is presented. PMID- 26242853 TI - Enriched autologous facial fat grafts in aesthetic surgery: 3D volumetric results. AB - BACKGROUND: Improved results with aesthetic fat augmentation of the face have been recently described by the concomitant use of autologous stem cells from the stromal vascular fraction (SVF). OBJECTIVE: There are no studies in the literature regarding facial fat augmentation results with the use of SVF using 3D computer volumetric analyses. This prospective study was thus undertaken to answer this question. METHODS: Fat was harvested by a standard liposuction technique for reinjection. A 50 cc aliquot of fat was also processed to obtain the SVF using a standard collagenase technique. A cell count was done using a cytometer, and the amount of injected fat and cells were recorded. The Vultus 3D photogrammetric scanning system was used to scan the face pre- and posttreatment and long-term, and volume changes were then calculated at the different time intervals. The data was then correlated to the variables. RESULTS: Ten subjects were included in the study, with an average follow-up of 12.6 months. The average amount of fat injected was 18.4 cc, of which 68% was retained. The average cell count of the SVF was 4.8 * 105. The amount of retained fat by volume was found to be positively correlated to the number of cells in the SVF. There was no correlation between the age and number of cells in the SVF. CONCLUSIONS: There is a correlation between the number of cells in the SVF and the amount of fat retained. LEVEL OF EVIDENCE: 3 Therapeutic. PMID- 26242854 TI - Effectiveness of Dimethylsulfoxide on the Survival and Volume Preservation of Autologous Fat Graft Tissue: A Preliminary Study. AB - BACKGROUND: The survival of autologous fat graft tissue is dependent on various factors, such as vascularization and inflammation. OBJECTIVE: This study aims to evaluate the possible beneficial effects of dimethylsulfoxide (DMSO) on fat graft volume and survival. METHODS: Eighteen male Wistar albino rats were divided randomly into three groups. An autologous fat graft obtained from the inguinal region of each rat was transferred to its back. DMSO was administered intraperitoneally (IP) in the DMSO-IP group and cutaneously (C) in the DMSO-C group once daily for 15 days after the surgical procedure. The control group underwent surgery but was not administered with DMSO. Two months after surgery, the grafted fatty tissues were harvested for histopathological and biochemical analyses. RESULTS: The results showed that 2 months postoperatively, fat grafts of the DMSO-C and DMSO-IP groups weighed significantly more than the grafts of the control group. Moreover, the vascularity of the grafts was higher in the DMSO C group than in the control group, and no significant difference was found between the two DMSO groups. The mean lipid peroxidation levels were the same in the three groups, but myeloperoxidation was significantly lower in the DMSO-C group than in the other two groups. CONCLUSIONS: The study results showed that cutaneous rather than intraperitoneal DMSO administration could preserve the quality and volume of transplanted fat tissue in rats by enhancing vascularity and decreasing inflammation. PMID- 26242855 TI - Commentary on: The 19th Century Origins of Facial Cosmetic Surgery and John H. Woodbury. PMID- 26242856 TI - Efficacy and safety of belimumab given for 12 months in primary Sjogren's syndrome: the BELISS open-label phase II study. AB - OBJECTIVE: To report the efficacy and safety of long-term treatment of SS with belimumab, targeting the B-cell-activating factor. METHODS: Patients with primary SS were included in the BELISS open-label phase II study, a 1-year open-label trial, if they were positive for anti-SSA or anti-SSB antibodies and had systemic complications or persistent salivary gland enlargement or early disease or biomarkers of B-cell activation. They received belimumab, 10 mg/kg i.v., at weeks 0, 2 and 4 and then every 4 weeks; if response was observed at week 28, or if the clinician and the patient agreed to continue the study in the absence of side effects, treatment was continued for 1 year. Efficacy and safety were analysed during the 1-year period of treatment. RESULTS: Among the 30 patients recruited, 28 were evaluated at week 28 as already reported. Nineteen terminated the 52-week study, 15 of them being responders and 4 non-responders at week 28. Thirteen of the 15 responders at week 28 also responded at week 52 (86.7%). The improvement in the EULAR Sjogren's Syndrome Disease Activity Index and EULAR Sjogren's Syndrome Patient Reported Index scores observed at week 28 showed a trend to further improvement at week 52, and the amelioration of peculiar EULAR Sjogren's Syndrome Disease Activity Index domains (glandular, lymphadenopathy, articular) appeared of particular relevance. The decrease in biomarkers of B-cell activation observed at week 28 persisted unchanged until week 52, with RF decreasing further. Salivary flow, Schirmer's test and the focus score of salivary biopsy did not change. Safety of treatment was good. CONCLUSION: Long-term treatment with belimumab may be beneficial in SS. Randomized, double-blind, controlled studies in larger populations are encouraged. PMID- 26242857 TI - Paradoxical psoriatic arthritis in a patient with psoriasis treated with ustekinumab. PMID- 26242858 TI - Can the publication of guidelines change the management of early rheumatoid arthritis? An interrupted time series analysis from the United Kingdom. AB - OBJECTIVE: To assess whether publication of national treatment guidelines improved the management of early RA in the UK. METHODS: Incident diagnoses of RA in persons aged over 18 years from 1995 to 2010 were identified from the Clinical Practice Research Datalink. Using a natural experimental study design, interrupted time series analysis was used to assess whether trends in the proportion of patients receiving DMARDs, within 3 and 12 months of diagnosis, changed following publication of British Society for Rheumatology guidelines in 2006. RESULTS: Between 1995 and 2010, 11 772 incident cases of RA were identified. There was a progressive increase in the proportion of patients prescribed any DMARD within 12 months from 43.3% in 1995 to 78.5% in 2010. After publication of the British Society for Rheumatology guidelines, the proportion of patients prescribed any DMARD within 12 months increased by 4.2% (P = 0.053). Prior to the guidance, prescribing was increasing by 1.64% per year, compared with 3.55% per year after publication (P < 0.001). CONCLUSION: Guidelines published by a national body can improve the proportion of patients receiving DMARD treatment in the first year after diagnosis of RA. PMID- 26242859 TI - Calprotectin more accurately discriminates the disease status of rheumatoid arthritis patients receiving tocilizumab than acute phase reactants. AB - OBJECTIVE: To compare the accuracy of serum calprotectin levels, CRP and ESR in stratifying disease activity in RA patients receiving tocilizumab (TCZ). METHODS: Cross-sectional study of 33 RA patients receiving TCZ. DAS28, Simplified Disease Activity Index, Clinical Disease Activity Index, joint counts and serum levels of CRP, ESR, calprotectin and TCZ were measured. Associations between calprotectin, ESR and CRP and articular indices were analysed by correlation and linear regression. The accuracy and discriminatory capacity of calprotectin was assessed by receiver operating characteristic curves (area under the curve). RESULTS: Calprotectin levels, but not CRP or ESR, were strongly correlated with all composite indices (all r coefficients over 0.50). Calprotectin, but not CRP or ESR, was significantly lower in patients in remission compared with those with low disease activity [1.57 MUg/ml (s.d. 1) vs 3.35 MUg/ml (s.d. 1), P = 0.001]. In a fully adjusted model (R(2) = 0.82), DAS28-ESR increased 0.48 units per MUg/ml calprotectin increase (P < 0.001). Using a DAS28 >3.2 as the reference variable, calprotectin showed an area under the curve of 0.922, and the best cut off was 5.19 MUg/ml (odds ratio 11.5). CRP levels, but not calprotectin, were dependent on detectable TCZ trough serum levels. CONCLUSION: Calprotectin serum levels seem to be an accurate biomarker for assessing disease activity in RA patients receiving TCZ. PMID- 26242860 TI - Primary synovial osteochondromatosis of the knee. PMID- 26242861 TI - Rapid destructive arthritis of the hip revisited. AB - Rapid destructive arthritis of the hip is a rare entity with unknown pathogenesis and outcome. First described by Forestier in 1957, it is characterized by a rapidly progressive hip disease resulting in rapid destruction of both the femoral and acetabular aspects of the hip joint, with almost complete disappearance of the femoral head within a few months. Since the original description, case reports and small series have been reported, and many names have been proposed to describe the rapid destruction of the femoral head and occasionally the acetabulum. Initial presentation includes acute hip pain with the lack of radiographic evidence of joint destruction, rapidly progressing to complete vanishing of the proximal femur within a few months. This article summarizes the related literature aiming to present the current concepts for the diagnosis and treatment of rapid destructive arthritis of the hip. PMID- 26242863 TI - Empowering patients through eHealth: a case report of a pan-European project. AB - BACKGROUND: This paper crystallises the experience developed by the pan-European PALANTE Consortium in dealing with the generation of relevant evidence from heterogeneous eHealth services for patient empowerment in nine European Regions. The European Commission (EC) recently funded a number of pan-European eHealth projects aimed at empowering European patients/citizens thus transforming the traditional patient/citizen role in the management of their health (e.g., PALANTE, SUSTAIN, CARRE, HeartCycle, Empower). However, the heterogeneity of the healthcare systems, of the implemented services and of the target patients, the use of ad-hoc definitions of the salient concepts and the development of small size experiences have prevented the dissemination of "global" results and the development of cumulative knowledge. The main challenge has been the generation of large-scale evidence from heterogeneous small-size experiences. DISCUSSION: Three lessons have been collectively learnt during the development of the PALANTE project, which involves 9 sites that have implemented different eHealth services for empowering different typologies of patients. These lessons have been refined progressively through project meetings, reviews with the EC Project Officer and Reviewers. The paper illustrates the ten steps followed to develop the three lessons. The first lesson learnt is about how EC-funded projects should develop cumulative knowledge by avoiding self-crafted measures of outcome and by adopting literature-grounded definitions and scales. The second lesson learnt is about how EC-funded projects should identify ambitious, cross-pilot policy and research questions that allow pooling of data from across heterogeneous experiences even if a multi-centre study design was not agreed before. The third lesson learnt is about how EC-funded projects should open their collections of data and make them freely-accessible to the scientific community shortly after the conclusion of the project in order to guarantee the replicability of results and conclusions. SUMMARY: The three lessons might provide original elements for fuelling the ongoing debate about the capability of the EC to develop evidence-based policies by pooling evidence from heterogeneous, local experiences. PMID- 26242864 TI - Multicohort analysis of the maternal age effect on recombination. AB - Several studies have reported that the number of crossovers increases with maternal age in humans, but others have found the opposite. Resolving the true effect has implications for understanding the maternal age effect on aneuploidies. Here, we revisit this question in the largest sample to date using single nucleotide polymorphism (SNP)-chip data, comprising over 6,000 meioses from nine cohorts. We develop and fit a hierarchical model to allow for differences between cohorts and between mothers. We estimate that over 10 years, the expected number of maternal crossovers increases by 2.1% (95% credible interval (0.98%, 3.3%)). Our results are not consistent with the larger positive and negative effects previously reported in smaller cohorts. We see heterogeneity between cohorts that is likely due to chance effects in smaller samples, or possibly to confounders, emphasizing that care should be taken when interpreting results from any specific cohort about the effect of maternal age on recombination. PMID- 26242865 TI - Functional Effects of WNT1-Inducible Signaling Pathway Protein-1 on Bronchial Smooth Muscle Cell Migration and Proliferation in OVA-Induced Airway Remodeling. AB - Upregulation of WISP1 has been demonstrated in lung remodeling. Moreover, it has been recently found that some signaling components of WNT pathway can activate GSK3beta signaling to mediate remodeling of airway smooth muscle (ASM) in asthma. Therefore, we hypothesized that WISP1, a signaling molecule downstream of the WNT signaling pathway, is involved in PI3K/GSK3beta signaling to mediate ASM remodeling in asthma. Our results showed that WISP1 depletion partly suppressed OVA-induced ASM hypertrophy in vivo. In vitro, WISP1 could induce hBSMC hypertrophy and proliferation, accompanied by upregulation of levels of PI3K, p Akt, p-GSK3beta, and its own expression. TGF-beta treatment could increase expression of PI3K, p-Akt, p-GSK3beta, and WISP1. SH-5 treatment could partly suppress TGF-beta-induced hypertrophy and proliferation of hBSMC, and depress expression of p-GSK3beta and WISP1. In conclusion, WISP1 may be a potential inducer of ASM proliferation and hypertrophy in asthma. The pro-remodeling effect of WISP1 is likely due to be involved in PI3K-GSK3beta-dependent noncanonical TGF beta signaling. PMID- 26242866 TI - Prior administration of a non-steroidal anti-androgen failed to prevent the flare up caused by a luteinizing hormone-releasing hormone agonist in a patient with metastatic prostate cancer. AB - BACKGROUND: 'Flare phenomenon' after initial luteinizing hormone-releasing hormone agonist administration is a widely approved concept in the treatment of prostate cancer. In most guidelines, concomitant therapy with anti-androgens is recommended to prevent this flare phenomenon. However, there are few reports describing serum prostate-specific antigen transitions after hormonal therapy. Here, we present a case of a man who experienced the biochemical and clinical flare phenomenon despite prior anti-androgen use and who has detailed data. CASE PRESENTATION: A 70-year-old Asian man with metastatic prostate cancer (multiple bone) was referred to our hospital. He was treated with prior anti-androgens and luteinizing hormone-releasing hormone agonist. Regardless of prior use of anti androgens, his low back pain caused by bone metastases was deteriorated and serum prostate-specific antigen level was raised from 974.8 ng/mL to 2,555.5 ng/mL within 3 weeks. Then, his serum prostate specific antigen level started to decrease along with the pain. The nadir reached 1.0 ng/mL and remained for 6 months. Because the serum level of prostate-specific antigen then began to increase again, anti-androgen was discontinued for anti-androgen withdrawal syndrome. Then the serum level decreased again to less than 0.1 ng/mL. Until now, his serum prostate-specific antigen level has been maintained at less than 0.1 ng/mL for more than 30 months without any clinical progressions. CONCLUSION: We present the case of a patient in whom a clinical flare caused by an leuteinizing hormone-releasing hormone agonist was not prevented by prior anti-androgen administration. In addition, the nadir level of prostate-specific antigen when he received leuteinizing hormone-releasing hormone monotherapy was ten times lower than when he received concomitant therapy, and period of anti-androgen withdrawal syndrome was longer than usual. In this case, anti-androgen was probably not effective from the initial administration. Awareness of the possibility of ineffectiveness of anti-androgens is important in the treatment of symptomatic metastatic prostate cancer. Leuteinizing hormone-releasing hormone antagonist and surgical castration is a more reliable clinical approach for the prostate cancer patients with symptomatic metastatic disease. PMID- 26242867 TI - Binding of the eukaryotic translation elongation factor 1A with the 5'UTR of HIV 1 genomic RNA is important for reverse transcription. AB - BACKGROUND: The cellular protein eukaryotic translation elongation factor 1A (eEF1A) binds to aminoacylated transfer RNAs and delivers them to the ribosome during translation. eEF1A also binds to RNA secondary structures present in genomes of several RNA viruses and plays important roles in their replication. As a RNA binding protein, whether eEF1A can bind with HIV-1 genomic RNA has not been investigated and was the aim of the study. METHODS: RNA-protein interaction was determined by reversible crosslink co-immunoprecipitation (RC-Co-IP) and biolayer Interferometry assay (BLI). eEF1A binding region within RNA was mapped by deletion and mutation analysis. Virus with genomic RNA mutations were examined for eEF1A-RT interaction by proximity ligation assay, for reverse transcription by qPCR and for replication by CAp24 ELISA in cells. RESULTS: The interaction of eEF1A with 5'UTR of HIV-1 genomic RNA was detected in cells and in vitro. Truncation and substitution mutations in the 5'UTR RNA demonstrated that a stem loop formed by nucleotides 142 to 170, which encompass a reported tRNA anticodon like-element, binds to eEF1A. Mutations that altered the stem-loop structure by changing two highly conserved sequence clusters in the stem-loop region result in reduction of the interaction with eEF1A in vitro. HIV-1 virus harbouring the same 5'UTR mutations significantly reduced the interaction of eEF1A with HIV-1 reverse transcription complex (RTC), reverse transcription and replication. CONCLUSION: eEF1A interacts with 5'UTR of HIV-1 genomic RNA and the interaction is important for late DNA synthesis in reverse transcription. PMID- 26242868 TI - Nucleoside Diphosphate Kinase from Psychrophilic Pseudoalteromonas sp. AS-131 Isolated from Antarctic Ocean. AB - Nucleoside diphosphate kinase isolated from psychrophilic Pseudoalteromonas sp. AS-131 (ASNDK) was expressed in Escherichia coli and purified to homogeneity. Comparing to mesophilic NDK isolated from Pseudomonas aeruginosa, ASNDK exhibited highly elevated thermolability: E. coli expression at 37 degrees C as a denatured insoluble form, 30 degrees C lower optimum temperature of enzymatic activity, and greatly reduced heat stability with 38 degrees C lower Tm value, fourfold higher Km and reduced Kcat/Km by 0.4-fold upon reaction temperature increase from 20 to 37 degrees C. The subunit structure of ASNDK was suggested to be dimer, as in NDKs isolated from moderate halophiles. PMID- 26242869 TI - Crystal Structure of Mg(2+) Containing Hemopexin-Fold Protein from Kabuli Chana (Chickpea-White, CW-25) at 2.45 A Resolution Reveals Its Metal Ion Transport Property. AB - Plant seeds contain a number of proteins which play important roles in the protection and the process of germination of seeds. We have isolated and purified a 25 kDa protein from Kabuli Chana (Cicer arietinum L., Chickpea-white, CW-25). The CW-25 protein was crystallized using 0.5 M magnesium acetate, 0.1 M sodium cacodylate and 20 % (w/v) polyethylene glycol 8000, pH 6.5. The crystals of CW-25 belonged to space group P3 with unit cell dimensions, a = b = 80.5 A, and c = 69.2 A. The structure of CW-25 was determined using molecular replacement method and refined to an R factor of 0.152. The buried surface area between two molecules was found to be approximately 653 A(2) indicating the formation of a weak homodimer. The polypeptide chain of CW-25 adopted a hemopexin-fold with four bladed beta-propellers. The structure formed a central tunnel-like architecture. A magnesium ion was observed in the centre of the tunnel. It was located at distances varying between 2.3 and 2.7 A from five oxygen atoms of which four were backbone oxygen atoms belonging to residues, Asn7, Asp65, Asp121 and Asp174 while the fifth oxygen atom, O(delta1) was from the side chain of Asn7. The approximate length of the tunnel was 30 A. Furthermore, a series of carbonyl oxygen atoms were present along the internal face of the tunnel. The diameter of the tunnel varied from 4.6 to 6.2 A. The diameter and chemical environment of the tunnel clearly indicated that it might be used for the transport of various metal ions across the molecule. PMID- 26242872 TI - C1-Benzyl and benzoyl isoquinoline synthesis through direct oxidative cross dehydrogenative coupling with methyl arenes. AB - An oxidative cross-dehydrogenative coupling (CDC) of isoquinolines with methyl arenes has been developed, allowing for the facile synthesis of a broad range of structurally diverse C1-benzyl and -benzoyl isoquinolines. The direct use of readily available methyl arenes as coupling partners avoids unproductive steps for preactivating the functional group installation, and is therefore attractive. The method exhibits excellent chemoselectivity, affording exclusive benzylated products in the presence of DTBP and a catalytic amount of Y(OTf)3, and yielding benzoylated ones with TBHP and a catalytic amount of MnO2. PMID- 26242870 TI - Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasis. AB - BACKGROUND: The dioxin (AhR) receptor can have oncogenic or tumor suppressor activities depending on the phenotype of the target cell. We have shown that AhR knockdown promotes melanoma primary tumorigenesis and lung metastasis in the mouse and that human metastatic melanomas had reduced AhR levels with respect to benign nevi. METHODS: Mouse melanoma B16F10 cells were engineered by retroviral transduction to stably downregulate AhR expression, Aldh1a1 expression or both. They were characterized for Aldh1a1 activity, stem cell markers and migration and invasion in vitro. Their tumorigenicity in vivo was analyzed using xenografts and lung metastasis assays as well as in vivo imaging. RESULTS: Depletion of aldehyde dehydrogenase 1a1 (Aldh1a1) impairs the pro-tumorigenic and pro-metastatic advantage of melanoma cells lacking AhR expression (sh-AhR). Thus, Aldh1a1 knockdown in sh-AhR cells (sh-AhR + sh-Aldh1a1) diminished their migration and invasion potentials and blocked tumor growth and metastasis to the lungs in immunocompetent AhR+/+ recipient mice. However, Aldh1a1 downmodulation in AhR expressing B16F10 cells did not significantly affect tumor growth in vivo. Aldh1a1 knockdown reduced the high levels of CD133(+)/CD29(+)/CD44(+) cells, melanosphere size and the expression of the pluripotency marker Sox2 in sh-AhR cells. Interestingly, Sox2 increased Aldh1a1 expression in sh-AhR but not in sh AhR + sh-Aldh1a1 cells, suggesting that Aldh1a1 and Sox2 may be co-regulated in melanoma cells. In vivo imaging revealed that mice inoculated with AhR + Aldh1a1 knockdown cells had reduced tumor burden and enhanced survival than those receiving Aldh1a1-expressing sh-AhR cells. CONCLUSIONS: Aldh1a1 overactivation in an AhR-deficient background enhances melanoma progression. Since AhR may antagonize the protumoral effects of Aldh1a1, the AhR(low)-Aldh1a1(high) phenotype could be indicative of bad outcome in melanoma. PMID- 26242871 TI - Inhibition of dipeptidyl peptidase 8/9 impairs preadipocyte differentiation. AB - Adipocytes are the primary cells in adipose tissue, and adipocyte dysfunction causes lipodystrophy, obesity and diabetes. The dipeptidyl peptidase (DPP) 4 family includes four enzymes, DPP4, DPP8, DPP9 and fibroblast activation protein (FAP). DPP4 family inhibitors have been used for the treatment of type 2 diabetes patients, but their role in adipocyte formation are poorly understood. Here we demonstrate that the DPP8/9 selective inhibitor 1G244 blocks adipogenesis in preadipocyte 3T3-L1 and 3T3-F422A, while DPP4 and FAP inhibitors have no effect. In addition, knockdown of DPP8 or DPP9 significantly impairs adipocyte differentiation in preadipocytes. We further uncovered that blocking the expression or activities of DPP8 and DPP9 attenuates PPARgamma2 induction during preadipocyte differentiation. Addition of PPARgamma agonist thiazolidinediones (TZDs), or ectopic expression of PPARgamma2, is able to rescue the adipogenic defect caused by DPP8/9 inhibition in preadipocytes. These results indicate the importance of DPP8 and DPP9 on adipogenesis. PMID- 26242873 TI - Theoretical analysis of headache recurrence in patients administered triptans for migraine based on receptor occupancy. AB - BACKGROUND: In this study, we retrospectively analyzed the relationship between headache recurrence and serotonin 5-HT1B/1D receptor occupancy (Phi1B and Phi1D). Triptans marketed in Japan (sumatriptan, zolmitriptan, eletriptan, rizatriptan, naratriptan) were investigated. METHODS: Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans. We examined the relationships between recurrence rate and elimination half-lives, and F1B and F1D, as calculated from the time-course of plasma drug concentration obtained from other studies. The time until F1B and F1D became 50% or less, 40% or less, and 30% or less was calculated as duration time to examine the relationship with recurrence rate. RESULTS: For F1B, eletriptan remained at a low level. For F1D, it was indicated that all triptans obtained an occupancy of 80% or higher at maximum. For all items, though recurrence tended to be lower along with longer half-life, no significant statistical correlation was found. For both F1B and F1D, the recurrence rate tended to be lower as the duration became longer. In addition, a significant correlation was observed for F1D (p < 0.05). For clarifying the F value and time period most closely correlated with recurrence rate, recurrence and F1B and F1D at 6, 12, and 18 h after administration were calculated. The most significant correlation was observed between recurrence rate and F1D at 12 h after administration (p < 0.01). CONCLUSIONS: As an index for evaluating headache recurrence following triptan administration, recurrence rate and F1D value at 12 h after administration were found to be most closely correlated and useful for analysis. Our results indicate that headache recurrence inhibition can be evaluated using these values. PMID- 26242874 TI - Glucose recovery from aqueous solutions by adsorption in metal-organic framework MIL-101: a molecular simulation study. AB - A molecular simulation study is reported on glucose recovery from aqueous solutions by adsorption in metal-organic framework MIL-101. The F atom of MIL-101 is identified to be the most favorable adsorption site. Among three MIL-101-X (X = H, NH2 or CH3), the parent MIL-101 exhibits the highest adsorption capacity and recovery efficacy. Upon functionalization by -NH2 or -CH3 group, the steric hindrance in MIL-101 increases; consequently, the interactions between glucose and framework become less attractive, thus reducing the capacity and mobility of glucose. The presence of ionic liquid, 1-ethyl-3-methyl-imidazolium acetate, as an impurity reduces the strength of hydrogen-bonding between glucose and MIL-101, and leads to lower capacity and mobility. Upon adding anti-solvent (ethanol or acetone), a similar adverse effect is observed. The simulation study provides useful structural and dynamic properties of glucose in MIL-101, and it suggests that MIL-101 might be a potential candidate for glucose recovery. PMID- 26242875 TI - A note on obtaining correct marginal predictions from a random intercepts model for binary outcomes. AB - BACKGROUND: Clustered data with binary outcomes are often analysed using random intercepts models or generalised estimating equations (GEE) resulting in cluster specific or 'population-average' inference, respectively. METHODS: When a random effects model is fitted to clustered data, predictions may be produced for a member of an existing cluster by using estimates of the fixed effects (regression coefficients) and the random effect for the cluster (conditional risk calculation), or for a member of a new cluster (marginal risk calculation). We focus on the second. Marginal risk calculation from a random effects model is obtained by integrating over the distribution of random effects. However, in practice marginal risks are often obtained, incorrectly, using only estimates of the fixed effects (i.e. by effectively setting the random effects to zero). We compare these two approaches to marginal risk calculation in terms of model calibration. RESULTS: In simulation studies, it has been seen that use of the incorrect marginal risk calculation from random effects models results in poorly calibrated overall marginal predictions (calibration slope <1 and calibration in the large ? 0) with mis-calibration becoming worse with higher degrees of clustering. We clarify that this was due to the incorrect calculation of marginal predictions from a random intercepts model and explain intuitively why this approach is incorrect. We show via simulation that the correct calculation of marginal risks from a random intercepts model results in predictions with excellent calibration. CONCLUSION: The logistic random intercepts model can be used to obtain valid marginal predictions by integrating over the distribution of random effects. PMID- 26242876 TI - Contralateral breast cancer can represent a metastatic spread of the first primary tumor: determination of clonal relationship between contralateral breast cancers using next-generation whole genome sequencing. AB - INTRODUCTION: By convention, a contralateral breast cancer (CBC) is treated as a new primary tumor, independent of the first cancer (BC1). Although there have been indications that the second tumor (BC2) sometimes may represent a metastatic spread of BC1, this has never been conclusively shown. We sought to apply next generation sequencing to determine a "genetic barcode" for each tumor and reveal the clonal relationship of CBCs. METHODS: Ten CBC patients with detailed clinical information and available fresh frozen tumor tissue were studied. Using low coverage whole genome DNA-sequencing data for each tumor, chromosomal rearrangements were enumerated and copy number profiles were generated. Comparisons between tumors provided an estimate of clonal relatedness for tumor pairs within individual patients. RESULTS: Between 15-256 rearrangements were detected in each tumor (median 87). For one patient, 76 % (68 out of 90) of the rearrangements were shared between BC1 and BC2, highly consistent with what has been seen for true primary-metastasis pairs (>50 %) and thus confirming a common clonal origin of the two tumors. For most of the remaining cases, BC1 and BC2 had similarly low overlap as unmatched randomized pairs of tumors from different individuals, suggesting the CBC to represent a new independent primary tumor. CONCLUSION: Using rearrangement fingerprinting, we show for the first time with certainty that a contralateral BC2 can represent a metastatic spread of BC1. Given the poor prognosis of a generalized disease compared to a new primary tumor, these women need to be identified at diagnosis of CBC for appropriate determination of treatment. Our approach generates a promising new method to assess clonal relationship between tumors. Additional studies are required to confirm the frequency of CBCs representing metastatic events. PMID- 26242877 TI - Correlates of Mood and RPE During Multi-Lap Off-Road Cycling. AB - This study examined the relationship between mood and rating of perceived exertion (RPE) during a simulated multiple-lap time trial (MLTT). Nineteen male cyclists performed a MLTT consisting of four 9.9 km laps, each lap with a gradient ranging from 0 to 10 %. Mood as measured by the Profile of Mood States Questionnaire (POMS) and perceived exertion as measured by the Borg CR100 scale (RPE) were obtained at the end of each lap. A categorical multiple regressive model, having median of POMS subscales as independent variables, was obtained to explain the variance in median RPE responses. Increases in POMS fatigue scores and decreases in POMS vigour scores were observed throughout the MLTT (P < 0.001). A linear increase in RPE during the MLTT was also observed (P < 0.001). POMS fatigue subscale scores accounted for 88 % of the variance in RPE during the MLTT (R(2) = 0.88, P = 0.002), and no other POMS subscale improved the final predictive model. With the exception of fatigue these results suggest that most aspects of mood do not have a discernable effect on RPE during a MLTT. The rate of increase in RPE can predict the MLTT endpoint. PMID- 26242879 TI - A new (68)Ga anionic concentration and purification method for automated synthesis of [(68)Ga]-DOTA or NODAGA conjugated peptides in high radiochemical purity. AB - The (68)Ge/(68)Ga generator is of increasing interest for clinical PET. For successful labelling, the eluate has to be purified. The aim of our approach is to improve the existing anionic methods which have a number of advantages compared to other methods but which use high concentrated HCl, and require an additional anionizing step. A new (68)Ga-eluate anionic purification method that enables rapid and high efficiency labelling of DOTA and NODAGA conjugated peptides in high radiochemical purity is described. The new method uses NaCl as an alternative Cl(-) source to the corrosive HCl and combines the three standard steps in a single step. The recovery yield was >=90%, and the (68)Ge breakthrough was in conformity with the European Pharmacopeia limit. An automated labelling of DOTA and NODAGA-conjugated peptides was performed with the new method, using acetate sodium buffer, with a total duration of 13 min and a radiochemical yield >85%. The labelled peptides have a radiochemical purity exceeding 99% and can be used directly without any further purification step and without the quality control by gas chromatography. Furthermore, the new method has an economic advantage: it offers the possibility to use generator until 20 months after the calibration date. PMID- 26242878 TI - The unique distribution of the Plasmodium vivax merozoite surface protein 1 in parasite isolates with short and long latent periods from the Republic of Korea. AB - BACKGROUND: Vivax malaria occurring in the Republic of Korea is occasionally characterized by a long latent infection induced by hypnozoites in the liver. So far, the mechanisms responsible for short and long latent infections of vivax malaria are not known. Therefore, the present study classified the parasite isolates according to the long and short latent periods and then analysed the genetic diversity of the Plasmodium vivax merozoite surface protein 1 (PvMSP-1). METHODS: Blood samples containing P. vivax isolates were collected from 465 patients from 2011 to 2013 at health centers in the Republic of Korea. PvMSP-1 gene sequences were analysed in groups classified by the collection year, and short or long latent periods. The samples in short and long latent periods were selected by the timing of vivax malaria occurrence, July-August and January-May, respectively. RESULTS: Three PvMSP-1 types (Sal-1, Belem, and recombinant) were observed in P. vivax isolates collected from 2011 to 2013. Interestingly, the recombinant and Sal-1 types were dominant in vivax malaria of the long and short latent periods, respectively. In addition, the S-b like subtype of the PvMSP-1 Sal-1 type was first identified in 2013. CONCLUSION: This study revealed that the genetic type of PvMSP-1 is likely related to the duration of its latent period. Moreover, trends of the genetic types of PvMSP-1 seem to be stable in recent years compared with those of previous years in which various new types were observed. PMID- 26242880 TI - Use of vitamin K antagonists for secondary stroke prevention depends on the treating healthcare provider in Germany - results from the German AFNET registry. AB - BACKGROUND: Anticoagulation using vitamin K antagonists (VKAs) significantly reduces the risk of recurrent stroke in stroke patients with atrial fibrillation (AF) and is recommended by guidelines. METHODS: The German Competence NETwork on Atrial Fibrillation established a nationwide prospective registry including 9,574 AF patients, providing the opportunity to analyse AF management according to German healthcare providers. RESULTS: On enrolment, 896 (9.4 %) patients reported a prior ischaemic stroke or transient ischaemic attack. Stroke patients were significantly older, more likely to be female, had a higher rate of cardiovascular risk factors, and more frequently received anticoagulation (almost exclusively VKA) than patients without prior stroke history. Following enrolment, 76.4 % of all stroke patients without VKA contraindications received anticoagulation, which inversely associated with age (OR 0.95 per year; 95 % CI 0.92-0.97). General practitioners/internists (OR 0.40; 95 % CI 0.21-0.77) and physicians working in regional hospitals (OR 0.47; 95 % CI 0.29-0.77) prescribed anticoagulation for secondary stroke prevention less frequently than physicians working at university hospitals (reference) and office-based cardiologists (OR 1.40; 95 % CI 0.76-2.60). The impact of the treating healthcare provider was less evident in registry patients without prior stroke. CONCLUSIONS: In the AFNET registry, anticoagulation for secondary stroke prevention was prescribed in roughly three-quarters of AF patients, a significantly higher rate than in primary prevention. We identified two factors associated with withholding oral anticoagulation in stroke survivors, namely higher age and-most prominently treatment by a general practitioner/internist or physicians working at regional hospitals. PMID- 26242881 TI - A blue-emitting Sc silicate phosphor for ultraviolet excited light-emitting diodes. AB - A blue-emitting phosphor BaSc2Si3O10:Eu(2+) was synthesized using the conventional solid-state reaction. The crystallographic occupancy of Eu(2+) in the BaSc2Si3O10 matrix was studied based on the Rietveld refinement results and the photoluminescence properties. BaSc2Si3O10 exhibits blue emission ascribed to (3)T2-(1)A1 and (3)T1-(1)A1 charge transfer of SiO4(4-) excited by 360 nm. All the phosphors of BaSc2Si3O10:Eu(2+) exhibit strong broad absorption bands in the near ultraviolet range, and give abnormal blue emission upon 330 nm excitation. The abnormal phenomenon was explored in detail through many pieces of experimental evidence. The concentration of Eu(2+) is optimized to be 3 mol% according to emission intensity and the quenching mechanism is verified to be a quadrupole-quadrupole interaction. The CIE coordinates of BaSc2Si3O10:0.03Eu(2+) are calculated to be (0.15, 0.05) and BaSc2Si3O10:0.03Eu(2+) shows similar thermal stability to commercial BaMgAl10O17:Eu(2+). PMID- 26242882 TI - Cost Effectiveness of Falls and Injury Prevention Strategies for Older Adults Living in Residential Aged Care Facilities. AB - OBJECTIVE: To evaluate the cost effectiveness of interventions designed to prevent falls and fall-related injuries among older people living in residential aged care facilities (RACFs) from an Australian health care perspective. METHODS: A decision analytic Markov model was developed that stratified individuals according to their risk of falling and accounted for the risk of injury following a fall. The effectiveness of the interventions was derived from two Cochrane reviews of randomized controlled trials for falls/fall-related injury prevention in RACFs. Interventions were considered effective if they reduced the risk of falling or reduced the risk of injury following a fall. The interventions that were modelled included vitamin D supplementation, annual medication review, multifactorial intervention (a combination of risk assessment, medication review, vision assessment and exercise) and hip protectors. The cost effectiveness was calculated as the incremental cost relative to the incremental benefit, in which the benefit was estimated using quality-adjusted life-years (QALYs). Uncertainty was explored using univariate and probabilistic sensitivity analysis. RESULTS: Vitamin D supplementation and medication review both dominated 'no intervention', as these interventions were both more effective and cost saving (because of healthcare costs avoided). Hip protectors are dominated (less effective and more costly) by vitamin D and medication review. The incremental cost-effectiveness ratio (ICER) for medication review relative to vitamin D supplementation is AU$2442 per QALY gained, and the ICER for multifactorial intervention relative to medication review is AU$1,112,500 per QALY gained. The model is most sensitive to the fear of falling and the cost of the interventions. CONCLUSION: The model suggests that vitamin D supplementation and medication review are cost-effective interventions that reduce falls, provide health benefits and reduce health care costs in older adults living in RACFs. PMID- 26242883 TI - Enhanced ultraviolet-visible light responses of phototransistors based on single and a few ZrS3 nanobelts. AB - Phototransistors based on single and three ZrS3 nanobelts were fabricated on SiO2/Si wafers by photolithography and the lift-off technique, respectively, and their light-induced electric properties were investigated in detail. Both the devices demonstrate a remarkable photoresponse from ultraviolet to near infrared light. The photoswitch current ratio (PCR) of the single-nanobelt phototransistor is 13 under the illumination of 405 nm light with an optical power of 10.5 mW cm( 2) at a bias of 5 V, while the PCR of the three-nanobelt device is 210 under the illumination of 405 nm light with an optical power of 5.57 mW cm(-2) at a bias of 1 V. On comparison of the photoresponses under the same conditions, the latter is found to be superior to the former, and both the devices show a much better photoresponse than the reported flexible ZrS3-nanobelt-film photodetector. PMID- 26242884 TI - Gangrenous Cholecystitis Related to Transcatheter Arterial Chemoembolization (TACE) Treatment for Hepatocellular Carcinoma. AB - A 69-year-old male with a history of hepatitis B-induced cirrhosis underwent segmental liver resection for hepatocellular carcinoma. At his 12-month follow up, local recurrence in segment VII was diagnosed, measuring 7.8 by 6.2 cm, with irregular margins and the presence of a tumor thrombus in the portal vein. After evaluation by the multidisciplinary liver team, the patient underwent transcatheter arterial chemoembolization with drug-eluting beads. Forty-eight hours after his discharge, the patient presented with gangrenous cholecystitis and he underwent an uneventful cholecystectomy. Cholecystitis is a well documented complication of transcatheter arterial chemoembolization due to inadvertent reflux of the embolic material into the cystic artery. However, super selective embolization significantly reduces the risk of cholecystitis. In most cases, management is conservative and only severe cases require further intervention. PMID- 26242885 TI - Symptom Relief After Laparoscopic Paraesophageal Hernia Repair Without Mesh. AB - BACKGROUND: Laparoscopic repair of paraesophageal hernia (LPEHR) is considered today the standard of care for this condition. While attention has been mostly focused on the incidence of postoperative radiologic recurrence of a hiatal hernia, few data are available about the effect of the operation on symptoms. AIMS: In this study, we aim to determine the effect of primary LPEHR on postoperative symptoms. PATIENTS AND METHODS: One hundred and sixty-two patients underwent LPEH repair in two academic tertiary care centers. Preoperative evaluation included barium swallow (100 %), endoscopy (80 %), manometry (81 %), and pH monitoring (25 %). Type III PEH was the most common (94 %), and it was associated with a gastric volvulus in 27 % of patients. RESULTS: A fundoplication was performed in all patients: Nissen in 57 %, Dor in 36 %, and Toupet in 6 %. A Collis gastroplasty was added in 6 % of patients. There were no perioperative deaths. The intraoperative complication rate was 7 %. The operation was completed laparoscopically in 98 % of patients. Postoperative complications occurred in four patients, and three needed a second operation. Average follow-up was 24 months. Heartburn, regurgitation, chest pain, dysphagia, respiratory symptoms, and hoarseness improved as a result of the operation. Anemia fully resolved in all patients. CONCLUSIONS: LPEH repair is safe and effective, and the need for reoperation is rare. Few patients experience postoperative symptoms, and these are easily controlled with acid-reducing medications. PMID- 26242886 TI - Association of Body Mass Index (BMI) with Patterns of Fundoplication Failure: Insights Gained. AB - BACKGROUND: Obesity has been implicated as an important risk factor for fundoplication failure. However, the mechanism of fundoplication in obese patients is not fully understood. Our objective is to evaluate the patterns of failure in relation to the body mass index (BMI) undergoing re-operative intervention after failed fundoplication. METHODS: After Institutional Review Board approval, the patients who underwent re-operative intervention for failed fundoplication between November 2008 and December 2013 were identified. Patients were classified into three groups: non-obese, obese, and morbidly obese (<30, 30 35, >35 BMI, respectively). Pre-operative assessment and operative procedure performed were compared between the groups. RESULTS: One hundred twenty-four patients satisfied study criteria. Non-obese patients (53.2 %) had significantly more dysphagia as an indication for re-operative procedure (obese 31.6 %, p < 0.05; morbidly 16.7 %, p < 0.05). Obese and morbidly obese patients had significantly higher incidence of recurrent hiatal hernia than non-obese patients (88.7 vs. 65.6 %, p < 0.05). Morbidly obese patients had significantly higher incidence of disrupted fundoplication than non-obese patients (41.7 vs. 19.4 %, p < 0.05). CONCLUSION: Similar anatomical failure patterns of state of fundoplication and recurrent hiatal hernia were noted between obese patients and morbidly obese patients and were distinct from non-obese patients. PMID- 26242887 TI - Diabetes in Pregnancy Adversely Affects the Expression of Glycogen Synthase Kinase-3beta in the Hippocampus of Rat Neonates. AB - Diabetes during pregnancy causes a wide range of neurodevelopmental and neurocognitive abnormalities in offspring. Glycogen synthase kinase-3 (GSK-3) is widely expressed during brain development and regulates multiple cellular processes, and its dysregulation is implicated in the pathogenesis of diverse neurodegenerative and psychological diseases. This study was designed to examine the effects of maternal diabetes on GSK-3beta messenger RNA (mRNA) expression and phosphorylation in the developing rat hippocampus. Female rats were maintained diabetic from a week before pregnancy through parturition, and male offspring was killed immediately after birth. We found a significant bilateral upregulation of GSK-3beta mRNA expression in the hippocampus of pups born to diabetic mothers at P0, compared to controls. Moreover, at the same time point, there was a marked bilateral increase in the phosphorylation level of GSK-3beta in the diabetic group. Unlike phosphorylation levels, there was a significant upregulation in hippocampal GSK-3beta mRNA expression in the insulin-treated group, when compared to controls. The present study revealed that diabetes during pregnancy strongly influences the regulation of GSK-3beta in the right/left developing hippocampi. These dysregulations may be part of the cascade of events through which diabetes during pregnancy affects the newborn's hippocampal structure and function. PMID- 26242889 TI - General cooperative effects of single atom ligands on a metal: a (195)Pt NMR chemical shift as a function of coordinated halido ligands' ionic radii overall sum. AB - An inverse linear relationship between the experimentally observed (195)Pt NMR signals and the overall sum of coordinated halido ligands' ionic radii was discovered in Pt(ii) and Pt(iv) complexes. The reduction of (195)Pt NMR frequencies parallels the increase of coordinated halido ligands' ionic radii sum. This suggests that each halido ligand may act as a conducting ring whose induced electric current shields the (195)Pt NMR signals proportionally to the ionic radius of the coordinated halido ligand. PMID- 26242888 TI - Agreements and disagreements in exercise therapy prescriptions after hip replacement among rehabilitation professionals: a multicenter survey. AB - BACKGROUND: Exercise therapy following total hip replacement (THR) is considered to be important during the initial postoperative care, but till date only a few evidence-based recommendations exist. The aim of this survey was to identify prescription standards among different rehabilitation professionals, for the exercise therapy management after THR in Germany. METHODS: The study was a cross sectional survey. Standardized questionnaires were sent to 38 eligible rehabilitation facilities in Germany. Participating surgeons, orthopaedic physicians, physiotherapists and exercise therapists rated the optimal early weight-bearing, resistance training, key components and dose of exercise therapy, and the hip loading during exercising. The returned questionnaires were then analyzed for level of agreement (>=80%) among respondents. RESULTS: 313 rehabilitation professionals from 28 clinics returned completed questionnaires and were considered eligible for analysis. Out of total respondents, 53.9% (cemented THR) and 18.2% (uncemented THR) recommended full weight-bearing within five days after surgery. Commencement of resistance training later than three weeks after surgery is recommended by 20.6% (36%) for cemented (uncemented) prosthesis. Feedback varied significantly amongst the professions. Regarding the overall objectives of rehabilitation after hip replacement, respondents agree in six out of eight requested items. Agreement concerning priorities of specific exercises was achieved in three out of twelve items. The recommended exercise therapy dose varied significantly with working experience (p = 0.02). CONCLUSION: Rehabilitation professionals mainly disagreed with the exercise therapy prescriptions following the total hip replacement during the initial postoperative care in Germany. PMID- 26242890 TI - Forming a Stress Management and Health Promotion Program for Women Undergoing Chemotherapy for Breast Cancer: A Pilot Randomized Controlled Trial. AB - OBJECTIVE: To assess the effects of an 8-week stress management and health promotion program on women undergoing breast cancer chemotherapy treatment. Patients and methods A total of 61 patients were recruited in 2 cancer centers and were randomly assigned to the intervention program (n = 30) or control group (n = 31). The intervention program consisted of different stress management techniques, which were combined with instructions for lifestyle modification. Assessments were carried out through questionnaires and measurement of body mass index (BMI) at baseline and at the end of the 8-week program. RESULTS: In all, 25 participants completed the intervention program, whereas 28 participants completed the observational control program. The intervention program resulted in a small effect size on internal dimension of Health Locus of Control (HLC) and a medium effect size on stress, depression, anxiety, night sleep duration, and chance dimension of HLC. A strong effect size was recorded for BMI and sleep onset latency. Self-rated health, spiritual well-being, and powerful others dimension of HLC were not significantly affected. Additionally, some of the participants reported a reduction in the side effects caused by chemotherapy. CONCLUSIONS: The intervention resulted in several benefits for the general health status of patients. Therefore, it should be considered as feasible and potentially beneficial for women undergoing breast cancer chemotherapy. However, it is necessary for this intervention to be tested through a randomized controlled trial in a larger sample of patients before adopting this program in standard cancer care. PMID- 26242891 TI - Eupolyphaga sinensis Walker Ethanol Extract Suppresses Cell Growth and Invasion in Human Breast Cancer Cells. AB - AIM OF THE STUDY: To examine the antiproliferation and anti-invasion of Eupolyphaga sinensis Walker 70% ethanol extract (ESWE) on breast cancer and elucidate the underlying signaling mechanisms. METHODS: MTT and colony formation assays were used to investigate the effect of ESWE on proliferation of breast cancer cells in vitro. The xenograft mouse tumor model was used to determine the effect of ESWE on breast cancer in vivo. To investigate the underlying molecular mechanisms, we used western blotting to analyze the expression of ERK1/2, CXCR4, matrix metalloproteinase 2 (MMP2), and MMP9 pretreated with ESWE. The stromal cell-derived factor (SDF)-1alpha-induced migration and invasion potential of breast cancer cells were examined by wound-healing assays and Matrigel invasion chamber assays. RESULTS: ESWE effectively inhibited the proliferation of MDA-MB 435s and MDA-MB-231 cells and exhibited antitumor effects in an MDA-MB-231 xenograft mice model. Furthermore, ESWE suppressed the activity of ERK1/2, a key molecule of MAPK signaling. We also observed that ESWE treatment led to downregulation of CXCR4 expression as well as greatly reduced MMP2 and MMP9. ESWE affected CXCR4 expression partially through the modulation of autocrine vascular endothelial growth factor. However, suppression of CXCR4 expression was the result of downregulation of mRNA expression. Inhibition of CXCR4 expression by ESWE further correlated with the suppression of SDF-1alpha-induced migration and invasion in breast cancer cells. CONCLUSION: ESWE exerted its antiproliferation and antiinvasion by regulating MAPK signaling and related metastasis factorsand thus could be a useful therapeutic candidate for breast cancer intervention. PMID- 26242892 TI - Prospective associations of eating behaviors with weight gain in infants. AB - OBJECTIVE: To examine whether maternal reports of infant eating behaviors are stable over time and whether eating behaviors are prospectively associated with weight gain. METHODS: In an ongoing study of infant growth, weight and length were measured at 2 weeks, 3 months, and 5 months of age. Food responsiveness (FR), satiety responsiveness (SR), enjoyment of feeding (EF), and slow eating (SE) were assessed with the Baby Eating Behavior Questionnaire. Repeated measures ANOVA was used to examine changes in eating behaviors from 2 weeks to 5 months. Simple Pearson correlations examined associations among eating behaviors across time and associations of eating behaviors with subsequent change in weight-for length z-scores. RESULTS: Among 31 infants studied from 2 weeks to 3 months, FR and SR remained consistent (P < 0.05), and among 21 infants studied from 3 to 5 months, FR, EF, and SE were consistent (P < 0.01). Infants ate more quickly (P < 0.01) and tended to have greater SR with age (P = 0.09). Only SE at 3 months was associated with subsequent gain in weight-for-length (P < 0.05). CONCLUSIONS: Consistent with previous research, SE was predictive of weight gain during infancy. Given that eating behaviors were largely consistent after 3 months of age, it may be important to encourage the development of healthy eating behaviors during early infancy. PMID- 26242893 TI - A Multicenter Randomized Trial of Ibandronate Compared With Single-Dose Radiotherapy for Localized Metastatic Bone Pain in Prostate Cancer. AB - BACKGROUND: The radiotherapy or ibandronate (RIB) trial was a randomized multicenter nonblind two-arm trial to compare intravenous ibandronate given as a single infusion with single-dose radiotherapy for metastatic bone pain. METHODS: Four hundred seventy prostate cancer patients with metastatic bone pain who were suitable for local radiotherapy were randomly assigned to radiotherapy (single dose, 8 Gy) or intravenous infusion of ibandronate (6mg) in a noninferiority trial. Pain was measured using the Brief Pain Inventory at baseline and four, eight, 12, 26, and 52 weeks. Pain response was assessed using World Health Organization (WHO) criteria and the Effective Analgesic Score (EAS); the maximum allowable difference was +/-15%. Patients failing to respond at four weeks were offered retreatment with the alternative treatment. Quality of life (QoL) was assessed at baseline and four and 12 weeks. Because the trial was designed with a 5% one-sided test, we provide 90% confidence intervals (two-sided) for differences in pain response. RESULTS: Overall, pain response was not statistically different at four or 12 weeks (WHO: -3.7%, 90% confidence interval [CI] = -12.4% to 5.0%; and 6.7%, 90% CI = -2.6 to 16.0%, respectively). Corresponding differences using the EAS were -7.5% and -3.5%. However, a more rapid initial response with radiotherapy was observed. There was no overall difference in toxicity, although each treatment had different side effects. QoL was similar at four and 12 weeks. Overall survival was similar between the two groups but was better among patients having retreatment than those who did not. CONCLUSIONS: A single infusion of ibandronate had outcomes similar to a single dose of radiotherapy for metastatic prostate bone pain. Ibandronate could be considered when radiotherapy is not available. PMID- 26242894 TI - Strategies to Prevent "Bad Luck" in Cancer. AB - It is impossible to predict exactly who will develop a cancer and who will not. We know that several "risk factors" may increase the chance of getting cancer and that risk increases with age. However, even with that in mind we seem to be able to explain only a certain number of cancers. Recently, Tomasetti and Vogelstein published a provocative article in Science stating that a large percentage of cancers may be due to "bad luck" (stochastic mutation events during DNA replication) and only a few to carcinogens, pathogens, or inherited genes and that this should impact public health policies. However, their intriguing analysis has numerous limitations, some of which have already been commented upon, including the likely biased subset of cancers and that finding a correlation does not signify a cause-effect mechanism. Here, we point out that there may also be an alternative explanation for the data, the cancer stem cell hypothesis, which postulates that cancers are derived from tissue stem cells and not from somatic differentiated cells. We also highlight the importance of the tissue microenvironment in the growth of transformed cells and outline a table of concurrent factors for several cancers. The message communicated to the public should not be one of helplessness in avoiding cancers, particularly given the now extensive knowledge of known risk factors and several agents/behaviors that can lower risk for specific cancers. While some tumors will still be due to chance, prevention should still be a primary goal for public health policies. PMID- 26242895 TI - Biofilm synthesis and presence of virulence factors among enterococci isolated from patients and water samples. AB - The goal of this study was to compare biofilm synthesis among enterococci recovered from clinical samples (infection or colonization) of patients as well as environmental samples in order to determine possible virulence factors and clonal relationship. During a two-year period, clinical samples (blood, catheter tips, bronchial secretions, wounds, peritoneal fluid, urine) and rectal swabs collected from hospitalized patients as well as environmental water samples were tested for the presence of Enterococcus faecalis and Enterococcus faecium. Antibiotic susceptibility testing was performed by the disc diffusion method and Etest. Strains were tested for the presence of vanA, vanB, esp, ace and asp genes by PCR. Clones were identified by PFGE (SmaI). From infected patients, 48 strains were identified: 24 Enterococcus faecium (10 vanA-positive, 14 vancomycin susceptible) and 24 Enterococcus faecalis (one vanA-positive, 23 vancomycin susceptible). Among 143 colonizing isolates, 134 were Enterococcus faecium (58 vanA-positive, 11 vanB-positive, 65 vancomycin-susceptible) and nine Enterococcus faecalis (three vanA-positive, two vanB-positive, four vancomycin-susceptible). Among 167 environmental water samples, 51 Enterococcus faecalis and 19 Enterococcus faecium isolates, all glycopeptide-susceptible, were recovered. In total, 64 strains produced biofilm, whereas 34 were esp-positive, 64 asp-positive and 54 ace-positive. Biofilm production was associated with the presence of esp (P < 0.001) and ace genes (P = 0.021), being higher in infecting (P < 0.001) and water (P 0.005) isolates as compared with colonizing ones. Clones of environmental water-strains were different than the patients' clones. The differences found in the incidence of antibiotic resistance, virulence factors and clones suggest that hospital and water enterococci are of different origin. PMID- 26242896 TI - Controlling molecular ordering in solution-state conjugated polymers. AB - Rationally encoding molecular interactions that can control the assembly structure and functional expression in a solution of conjugated polymers hold great potential for enabling optimal organic optoelectronic and sensory materials. In this work, we show that thermally-controlled and surfactant-guided assembly of water-soluble conjugated polymers in aqueous solution is a simple and effective strategy to generate optoelectronic materials with the desired molecular ordering. We have studied a conjugated polymer consisting of a hydrophobic thiophene backbone and hydrophilic, thermo-responsive ethylene oxide side groups, which shows a step-wise, multi-dimensional assembly in water. By incorporating the polymer into phase-segregated domains of an amphiphilic surfactant in solution, we demonstrate that both chain conformation and degree of molecular ordering of the conjugated polymer can be tuned in hexagonal, micellar and lamellar phases of the surfactant solution. The controlled molecular ordering in conjugated polymer assembly is demonstrated as a key factor determining the electronic interaction and optical function. PMID- 26242897 TI - Tridimensional titanium-printed custom-made prosthesis for sternocostal reconstruction. AB - A broad range of materials have been described for sternal reconstruction in order to guarantee not only the best preservation of respiratory mechanics, but also adequate mediastinal protection and acceptable cosmetic results. Today, titanium implants are preferred by many surgeons because of their optimal features. As a step forward, tridimensional (3D) laser sintering printing techniques allow us to virtually reproduce even more complex bony structures. Here, we present a case of sternocostal reconstruction by means of a 3D titanium printed custom-made prosthesis after extensive resection of a chest wall sarcoma. The use of an intraoperative template to precisely set resection margins, the novel prosthetic design as well as a new and safer rib fixation system may offer some advantages over other custom-made reconstructive techniques. PMID- 26242898 TI - Doing better in more complex patients: leading the way for QUIP. PMID- 26242899 TI - Structure and functioning of the Heart Team: primum non nocere. PMID- 26242900 TI - Application of chemical biology in target identification and drug discovery. AB - Drug discovery and development is vital to the well-being of mankind and sustainability of the pharmaceutical industry. Using chemical biology approaches to discover drug leads has become a widely accepted path partially because of the completion of the Human Genome Project. Chemical biology mainly solves biological problems through searching previously unknown targets for pharmacologically active small molecules or finding ligands for well-defined drug targets. It is a powerful tool to study how these small molecules interact with their respective targets, as well as their roles in signal transduction, molecular recognition and cell functions. There have been an increasing number of new therapeutic targets being identified and subsequently validated as a result of advances in functional genomics, which in turn led to the discovery of numerous active small molecules via a variety of high-throughput screening initiatives. In this review, we highlight some applications of chemical biology in the context of drug discovery. PMID- 26242901 TI - Mechanisms of a novel anticancer therapeutic strategy involving atmospheric pressure plasma-mediated apoptosis and DNA strand break formation. AB - Atmospheric pressure plasma has been developed for a variety of biomedical applications due to its chemically reactive components. Recently, the plasma has emerged as a promising novel cancer therapy based on its ability to selectively ablate cancer cells while leaving normal cells essentially unaffected. The therapeutic effect of plasma is attributed to intracellular generation of reactive oxygen/nitrogen species (ROS/RNS) leading to mitochondria-mediated apoptosis and to activation of the DNA damage checkpoint signaling pathway via severe DNA strand break formation. However, the biochemical mechanisms responsible for appropriate activation of these physiological events and which pathway is more crucial for plasma-mediated cytotoxicity have not been clarified. Understanding the molecular link between ROS/RNS-mediated apoptosis and DNA damage-involved chromosome instability is critical for the development of more efficacious therapeutic strategies for selective killing of diverse cancer cells. PMID- 26242902 TI - Gender-specific differences in therapy and laboratory parameters and validation of mortality predictors in severely injured patients--results of a German level 1 trauma center. AB - PURPOSE: Gender-specific differences in trauma patients have been reported in several studies. There is a lack of knowledge about differences in therapy and laboratory parameters. The objective of this study is to analyze differences between genders, confirming the therapy and laboratory parameters. Additionally, predictors for mortality were validated. METHODS: Patients on primary admission to the hospital between 2002 and 2012 with an Injury Severity Score (ISS) >= 16 were included. 1073 patients met the inclusion criteria. Comparisons and matched pair analyses between deceased and survived females, males, and between deceased females and males were conducted. RESULTS: The analyzed laboratory parameters differed between genders, especially the base excess, lactate, and coagulation parameters. In particular, females presented values that were normal or only slightly pathological. The prothrombin ratio was 75.3% in female and 63.2% in male (p = 0.027) and lactate 2.5 mmol/l in female and 3.8 mmol/l in male (p = 0.049). No differences between genders could be found in the initial treatment of severely injured patients. Only the infused volume differed between genders with 1178.2 ml in male and 793.6 ml in female (p = 0.02). The known predictors for mortality, lactate, and prothrombin ratio could not be validated in female trauma patients. CONCLUSIONS: No gender differences, except the infused volume, in the treatment of severely injured patients could be found. Differences in laboratory tests, especially base excess, lactate, and coagulation parameters were found. As these parameters are also used as predictors of mortality in trauma patients, gender-specific cut-offs of these laboratory tests might be necessary to avoid underestimating injured women. PMID- 26242903 TI - Enantioselective ortho-C-H cross-coupling of diarylmethylamines with organoborons. AB - The commonly used para-nitrobenzenesulfonyl (nosyl) protecting group is employed to direct the C?H activation of amines for the first time. An enantioselective ortho-C?H cross-coupling between nosyl-protected diarylmethylamines and arylboronic acid pinacol esters has been achieved utilizing chiral mono-N protected amino acid (MPAA) ligands as a promoter. PMID- 26242904 TI - Nutrition sensitivity of the 2014 budget statement of Republic of Ghana. AB - Ghana's Constitution and several international treaties she has ratified demonstrate support for fundamental human rights to nutrition and freedom from hunger. However, it is unknown how this support is being translated into investment in nutrition. National budgets are important vehicles through which governments communicate intent to address pertinent national challenges. The present paper assesses the nutrition sensitivity of Ghana's budget statement for the year ending 31 December 2014. We perused the budget in its entirety, examining allocations to various sectors with the goal of identifying support for direct nutrition interventions. We examined allocations to various sectors as per cent of gross domestic product (GDP). The review shows that the total revenue and grants for the 2014 fiscal year is Ghana Cedis (GHc) 26 001.9 million (25 % of GDP). The total expenditure for the same period is estimated at GHc34 956.8 million (33.1 % of GDP). The health sector is allocated GHc3 353 707 814 (3.8 % of GDP). As of 28 October 2014, the Bank of Ghana's Official Exchange Rate was US$1 = GHc3.20. It is one of the key sectors whose interventions directly or indirectly impact on nutrition. However, the proportion of the national budget that goes to direct nutrition interventions is not evident in the budget. Nutrition is embedded in other budget lines. Allocations to relevant nutrition sensitive sectors are very low (<0.5 % of GDP). We conclude that Ghana's 2014 budget statement pays scant attention to nutrition. By embedding nutrition in other budget lines, Ghana runs the risk of perpetually rolling out national spending actions insensitive to nutrition. PMID- 26242905 TI - Sterol Composition in Infant Formulas and Estimated Intake. AB - Sterol contents in infant formulas (IFs) from the European market were determined, and their intakes by infants between 0 and 6 months were evaluated. Total animal sterols (mg/100 mL) ranged from 1.71 to 5.46, cholesterol being the main animal sterol (1.46-5.1). In general, cholesterol and desmosterol were lower than the human milk (HM) values indicated by other authors. Total plant sterol (mg/100 mL) ranged from 3.1 to 5.0. beta-Sitosterol, the most abundant phytosterol, ranged from 1.82 to 3.01, followed by campesterol (0.72-1.15), stigmasterol (0.27-0.53), and brassicasterol (0.14-0.28). Cholesterol intake (mg/day) ranged from 9 to 51 and plant sterol intake (mg/day) from 19 to 50. The sterol profile of IFs is highly dependent on the type and quantity of fats used in their formula. The use of bovine milk fat and milk fat globule membrane in the IFs can approximate the profile of animal sterols to those found in HM, though cholesterol intakes in breastfed infants are still higher than in formula-fed infants. PMID- 26242906 TI - Planktonic and sedimentary bacterial diversity of Lake Sayram in summer. AB - Lake Sayram is an ancient cold water lake locating at a mountain basin in Xinjiang, China. The lake water is brackish, alkaline, unpolluted, and abundant in SO4(2-) and Mg(2+). The lacustrine ecosystem of Lake Sayram has been intensely investigated. However, profiles of the microbial communities in the lake remain largely unknown. In this study, taxonomic compositions of the planktonic and sedimentary bacterial communities in Lake Sayram were investigated using 16S rRNA metagenomics. The lacustrine bacterial communities were generally structured by environmental conditions, including the hydrological and physicochemical parameters. Proteobacteria was the dominating phylum. In the lake water, the genera Acinetobacter and Ilumatobacter held an absolute predominance, implying their metabolic significance. In the bottom sediment, biogeochemically significant bacteria and thermophilic or acidothermophilic extremophiles were recovered. In contrast to the planktonic bacteria, an appreciable portion of the sedimentary bacteria could not be classified into any known taxonomic unit, indicating the largely unknown bacteriosphere hiding in the bottom sediment of Lake Sayram. PMID- 26242908 TI - Predictive value of vascular disease biomarkers for digital ulcers in systemic sclerosis patients. AB - OBJECTIVES: To investigate the role of endothelial dysfunction and angiogenesis vascular biomarkers as risk factors and their predictive value for digital ulcers in systemic sclerosis patients. METHODS: Endothelin-1 (ET-1), asymmetric dimethylarginine (ADMA), vascular endothelial growth factor (VEGF), endostatin and endoglin were measured in an observational prospective cohort of 77 SSc patients. The primary outcome was the occurrence of one or more new ischaemic digital ulcers during a planned 3-year follow-up. RESULTS: After the 3-year follow-up, 40 patients developed new digital ulcers. Logistic regression confirmed VEGF (HR 1.128, 95% CI 1.010-1.260, p=0.033) and ADMA (HR 0.995, 95% CI 0.991-0.998, p=0.006) as independent predictors of new digital ulcers. Patients with serum levels of ET-1>11.9 pmol/ml (p<0.001) and VEGF<422.47 pg/ml (p=0.028) had significantly more DU in the 3-year follow-up. Although not significant, a trend towards increased serum levels of endoglin>4.215 ng/ml (p=0.053) was associated to a new DU episode. No predictive serum value was found for ADMA (p=0.075) and endostatin (p=0.130). CONCLUSIONS: Endothelial dysfunction and angiogenic vascular biomarkers have an important role in the underlying and in the progression of microvascular disease in systemic sclerosis. Increased serum levels of ET-1, ADMA and VEGF are strong predictors of severe microangiopathy complications, namely ischaemic digital ulcers. PMID- 26242909 TI - Neural signatures of response planning occur midway through an incoming question in conversation. AB - A striking puzzle about language use in everyday conversation is that turn-taking latencies are usually very short, whereas planning language production takes much longer. This implies overlap between language comprehension and production processes, but the nature and extent of such overlap has never been studied directly. Combining an interactive quiz paradigm with EEG measurements in an innovative way, we show that production planning processes start as soon as possible, that is, within half a second after the answer to a question can be retrieved (up to several seconds before the end of the question). Localization of ERP data shows early activation even of brain areas related to late stages of production planning (e.g., syllabification). Finally, oscillation results suggest an attention switch from comprehension to production around the same time frame. This perspective from interactive language use throws new light on the performance characteristics that language competence involves. PMID- 26242910 TI - Visible light photocatalytic H2-production activity of wide band gap ZnS nanoparticles based on the photosensitization of grapheme. AB - Visible light photocatalytic H(2) production from water splitting is considered an attractive way to solve the increasing global energy crisis in modern life. In this study, a series of zinc sulfide nanoparticles and graphene (GR) sheet composites were synthesized by a two-step hydrothermal method, which used zinc chloride, sodium sulfide, and graphite oxide (GO) as the starting materials. The as-prepared ZnS-GR showed highly efficient visible light photocatalytic activity in hydrogen generation. The morphology and structure of the composites obtained by transmission electron microscope and x-ray diffraction exhibited a small crystallite size and a good interfacial contact between the ZnS nanoparticles and the two-dimensional (2D) GR sheet,which were beneficial for the photocatalysis. When the content of the GR in the catalyst was 0.1%, the ZG0.1 sample exhibited the highest H(2)-production rate of 7.42 MUmol h(-1) g(-1), eight times more than the pure ZnS sample. This high visible-light photocatalytic H(2) production activity is attributed to the photosensitization of GR. Irradiated by visible light, the electrons photogenerated from GR transfer to the conduction band of ZnS to participate in the photocatalytic process. This study presents the visible light photocatalytic activity of wide bandgap ZnS and its application in H(2) evolution. PMID- 26242911 TI - Signaling Scaffold Protein IQGAP1 Interacts with Microtubule Plus-end Tracking Protein SKAP and Links Dynamic Microtubule Plus-end to Steer Cell Migration. AB - Cell migration is orchestrated by dynamic interaction of microtubules with the plasma membrane cortex. However, the regulatory mechanisms underlying the cortical actin cytoskeleton and microtubule dynamics are less characterized. Our earlier study showed that small GTPase-activating proteins, IQGAPs, regulate polarized secretion in epithelial cells (1). Here, we show that IQGAP1 links dynamic microtubules to steer cell migration via interacting with the plus-end tracking protein, SKAP. Biochemical characterizations revealed that IQGAP1 and SKAP form a cognate complex and that their binding interfaces map to the WWIQ motif and the C-terminal of SKAP, respectively. The WWIQ peptide disrupts the biochemical interaction between IQGAP1 and SKAP in vitro, and perturbation of the IQGAP1-SKAP interaction in vivo using a membrane-permeable TAT-WWIQ peptide results in inhibition of directional cell migration elicited by EGF. Mechanistically, the N-terminal of SKAP binds to EB1, and its C terminus binds to IQGAP1 in migrating cells. Thus, we reason that a novel IQGAP1 complex orchestrates directional cell migration via coupling dynamic microtubule plus ends to the cell cortex. PMID- 26242912 TI - Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways. AB - Bioactive phytochemicals can suppress the growth of malignant cells, and investigation of the mechanisms responsible can assist in the identification of novel therapeutic strategies for cancer therapy. Ginger has been reported to exhibit potent anti-cancer effects, although previous reports have often focused on a narrow range of specific compounds. Through a direct comparison of various ginger compounds, we determined that gingerenone A selectively kills cancer cells while exhibiting minimal toxicity toward normal cells. Kinase array screening revealed JAK2 and S6K1 as the molecular targets primarily responsible for gingerenone A-induced cancer cell death. The effect of gingerenone A was strongly associated with relative phosphorylation levels of JAK2 and S6K1, and administration of gingerenone A significantly suppressed tumor growth in vivo. More importantly, the combined inhibition of JAK2 and S6K1 by commercial inhibitors selectively induced apoptosis in cancer cells, whereas treatment with either agent alone did not. These findings provide rationale for dual targeting of JAK2 and S6K1 in cancer for a combinatorial therapeutic approach. PMID- 26242913 TI - Phosphorylation-induced Conformational Ensemble Switching in an Intrinsically Disordered Cancer/Testis Antigen. AB - Prostate-associated gene 4 (PAGE4) is an intrinsically disordered cancer/testis antigen that is up-regulated in the fetal and diseased human prostate. Knocking down PAGE4 expression results in cell death, whereas its overexpression leads to a growth advantage of prostate cancer cells (Zeng, Y., He, Y., Yang, F., Mooney, S. M., Getzenberg, R. H., Orban, J., and Kulkarni, P. (2011) The cancer/testis antigen prostate-associated gene 4 (PAGE4) is a highly intrinsically disordered protein. J. Biol. Chem. 286, 13985-13994). Phosphorylation of PAGE4 at Thr-51 is critical for potentiating c-Jun transactivation, an important factor in controlling cell growth, apoptosis, and stress response. Using NMR spectroscopy, we show that the PAGE4 polypeptide chain has local and long-range conformational preferences that are perturbed by site-specific phosphorylation at Thr-51. The population of transient turn-like structures increases upon phosphorylation in an ~20-residue acidic region centered on Thr-51. This central region therefore becomes more compact and more negatively charged, with increasing intramolecular contacts to basic sequence motifs near the N and C termini. Although flexibility is decreased in the central region of phospho-PAGE4, the polypeptide chain remains highly dynamic overall. PAGE4 utilizes a transient helical structure adjacent to the central acidic region to bind c-Jun with low affinity in vitro. The binding interaction is attenuated by phosphorylation at Thr-51, most likely because of masking the effects of the more compact phosphorylated state. Therefore, phosphorylation of PAGE4 leads to conformational shifts in the dynamic ensemble, with large functional consequences. The changes in the structural ensemble induced by posttranslational modifications are similar conceptually to the conformational switching events seen in some marginally stable ("metamorphic") folded proteins in response to mutation or environmental triggers. PMID- 26242914 TI - The effect of kisspeptin on the regulation of vascular tone. AB - Kisspeptin has been implicated in cardiovascular control. Eicosanoids play a crucial role in the activation of platelets and the regulation of vascular tone. In the present study, we investigated the effect of kisspeptins on eicosanoid synthesis in platelets and aorta in vitro. Platelets and aorta were isolated from Wistar-Kyoto rats. After preincubation with different doses of kisspeptin, samples were incubated with [1-(14)C]arachidonic acid (0.172 pmol/mL) in tissue culture Medium 199. The amount of labeled eicosanoids was measured with liquid scintillation, after separation with overpressure thin-layer chromatography. Kisspeptin-13 stimulated the thromboxane synthesis. The dose-response curve was bell-shaped and the most effective concentration was 2.5 * 10(-8) mol/L, inducing a 27% increase. Lipoxygenase products of platelets displayed a dose-dependent elevation up to the dose of 5 * 10(-8) mol/L. In the aorta, kisspeptin-13 induced a marked elevation in the production of 6-keto-prostaglandin F1alpha, the stable metabolite of prostacyclin, and lipoxygenase products. Different effects of kisspeptin on cyclooxygenase and lipoxygenase products indicate that beyond intracellular Ca(2+) mobilization, other signaling pathways might also contribute to its actions. Our data suggest that kisspeptin, through the alteration of eicosanoid synthesis in platelets and aorta, may play a physiologic and (or) pathologic role in the regulation of vascular tone. PMID- 26242917 TI - [Not Available]. PMID- 26242915 TI - Overview of systematic reviews on the health-related effects of government tobacco control policies. AB - BACKGROUND: Government interventions are critical to addressing the global tobacco epidemic, a major public health problem that continues to deepen. We systematically synthesize research evidence on the effectiveness of government tobacco control policies promoted by the Framework Convention on Tobacco Control (FCTC), supporting the implementation of this international treaty on the tenth anniversary of it entering into force. METHODS: An overview of systematic reviews was prepared through systematic searches of five electronic databases, published up to March 2014. Additional reviews were retrieved from monthly updates until August 2014, consultations with tobacco control experts and a targeted search for reviews on mass media interventions. Reviews were assessed according to predefined inclusion criteria, and ratings of methodological quality were either extracted from source databases or independently scored. RESULTS: Of 612 reviews retrieved, 45 reviews met the inclusion criteria and 14 more were identified from monthly updates, expert consultations and a targeted search, resulting in 59 included reviews summarizing over 1150 primary studies. The 38 strong and moderate quality reviews published since 2000 were prioritized in the qualitative synthesis. Protecting people from tobacco smoke was the most strongly supported government intervention, with smoke-free policies associated with decreased smoking behaviour, secondhand smoke exposure and adverse health outcomes. Raising taxes on tobacco products also consistently demonstrated reductions in smoking behaviour. Tobacco product packaging interventions and anti-tobacco mass media campaigns may decrease smoking behaviour, with the latter likely an important part of larger multicomponent programs. Financial interventions for smoking cessation are most effective when targeted at smokers to reduce the cost of cessation products, but incentivizing quitting may be effective as well. Although the findings for bans on tobacco advertising were inconclusive, other evidence suggests they remain an important intervention. CONCLUSION: When designing and implementing tobacco control programs, governments should prioritize smoking bans and price increases of tobacco products followed by other interventions. Additional studies are needed on the various factors that can influence a policy's effectiveness and feasibility such as cost, local context, political barriers and implementation strategies. PMID- 26242916 TI - The OnTrack Diabetes Web-Based Program for Type 2 Diabetes and Dysphoria Self Management: A Randomized Controlled Trial Protocol. AB - BACKGROUND: The prevalence of type 2 diabetes is rising with the majority of patients practicing inadequate disease self-management. Depression, anxiety, and diabetes-specific distress present motivational challenges to adequate self-care. Health systems globally struggle to deliver routine services that are accessible to the entire population, in particular in rural areas. Web-based diabetes self management interventions can provide frequent, accessible support regardless of time and location OBJECTIVE: This paper describes the protocol of an Australian national randomized controlled trial (RCT) of the OnTrack Diabetes program, an automated, interactive, self-guided Web program aimed to improve glycemic control, diabetes self-care, and dysphoria symptoms in type 2 diabetes patients. METHODS: A small pilot trial is conducted that primarily tests program functionality, efficacy, and user acceptability and satisfaction. This is followed by the main RCT, which compares 3 treatments: (1) delayed program access: usual diabetes care for 3 months postbaseline followed by access to the full OnTrack Diabetes program; (2) immediate program: full access to the self guided program from baseline onward; and (3) immediate program plus therapist support via Functional Imagery Training (FIT). Measures are administered at baseline and at 3, 6, and 12 months postbaseline. Primary outcomes are diabetes self-care behaviors (physical activity participation, diet, medication adherence, and blood glucose monitoring), glycated hemoglobin A1c (HbA1c) level, and diabetes-specific distress. Secondary outcomes are depression, anxiety, self efficacy and adherence, and quality of life. Exposure data in terms of program uptake, use, time on each page, and program completion, as well as implementation feasibility will be conducted. RESULTS: This trial is currently underway with funding support from the Wesley Research Institute in Brisbane, Australia. CONCLUSIONS: This is the first known trial of an automated, self-guided, Web based support program that uses a holistic approach in targeting both type 2 diabetes self-management and dysphoria. Findings will inform the feasibility of implementing such a program on an ongoing basis, including in rural and regional locations. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registration number: ACTRN12612000620820; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12612000620820 (Archived by WebCite at http://www.webcitation.org/6a3BeXC5m). PMID- 26242918 TI - Progressive multifocal leukoencephalopathy mimicking milliary CNS tuberculosis. PMID- 26242920 TI - Unlocking Potentials of Microwaves for Food Safety and Quality. AB - Microwave is an effective means to deliver energy to food through polymeric package materials, offering potential for developing short-time in-package sterilization and pasteurization processes. The complex physics related to microwave propagation and microwave heating require special attention to the design of process systems and development of thermal processes in compliance with regulatory requirements for food safety. This article describes the basic microwave properties relevant to heating uniformity and system design, and provides a historical overview on the development of microwave-assisted thermal sterilization (MATS) and pasteurization systems in research laboratories and used in food plants. It presents recent activities on the development of 915 MHz single-mode MATS technology, the procedures leading to regulatory acceptance, and sensory results of the processed products. The article discusses needs for further efforts to bridge remaining knowledge gaps and facilitate transfer of academic research to industrial implementation. PMID- 26242919 TI - Toll-like receptor 2 activators modulate oral tolerance in mice. AB - BACKGROUND: Toll-like receptor 2 (TLR2) is a widely expressed pattern recognition receptor critical for innate immunity. TLR2 is also a key regulator of mucosal immunity implicated in the development of allergic disease. TLR2 activators are found in many common foods, but the role of TLR2 in oral tolerance and allergic sensitization to foods is not well understood. OBJECTIVE: The purpose of this study was to evaluate the impacts of TLR2 expression and TLR2 activation on oral tolerance to food antigens in a murine model. METHODS: Mice were fed ovalbumin (OVA) or peanut butter with or without the addition of low doses of TLR2 activators Pam3 CSK4 or FSL-1. Oral tolerance was assessed by analysing antibody responses after a systemic antigen challenge. OVA-specific Tregs were assessed in the Peyer's patches, mesenteric lymph nodes, and spleen in wild-type and TLR2(-/ ) mice. Low-dose Pam3 CSK4 was also tested as an oral adjuvant. RESULTS: Oral tolerance was successfully induced in both wild-type and TLR2(-/-) recipient mice, with an associated regulatory T-cell response. Oral TLR2 activation, with low-dose Pam3 CSK4 or FSL-1, during oral antigen exposure was found to alter oral tolerance and was associated with the development of substantial IgE and IgA responses to foods upon systemic challenge. Low-dose oral Pam3 CSK4 treatment also selectively enhanced antigen-specific IgA responses to oral antigen exposure. CONCLUSIONS AND CLINICAL RELEVANCE: TLR2 is not necessary for oral tolerance induction, but oral TLR2 activation modulates humoral IgE and IgA responses during tolerance development. Low-dose Pam3 CSK4 is also an effective oral adjuvant that selectively enhances IgA production. These observations are pertinent to the optimization of oral allergen immunotherapy and oral vaccine development. PMID- 26242921 TI - Choline supplementation restores substrate balance and alleviates complications of Pcyt2 deficiency. AB - Choline plays a critical role in systemic lipid metabolism and hepatic function. Here we conducted a series of experiments to investigate the effect of choline supplementation on metabolically altered Pcyt2(+/-) mice. In Pcyt2(+/-) mice, the membrane phosphatidylethanolamine (PE) turnover is reduced and the formation of fatty acids (FA) and triglycerides (TAG) increased, resulting in hypertriglyceridemia, liver steatosis and obesity. One month of choline supplementation reduced the incorporation of FA into TAG and facilitated TAG degradation in Pcyt2(+/-) adipocytes, plasma and liver. Choline particularly stimulated adipocyte and liver TAG lipolysis by specific lipases (ATGL, LPL and HSL) and inhibited TAG formation by DGAT1 and DGAT2. Choline also activated the liver AMPK and mitochondrial FA oxidation gene PPARalpha and reduced the FA synthesis genes SREBP1, SCD1 and FAS. Liver (HPLC) and plasma (tandem mass spectroscopy and (1)H-NMR) metabolite profiling established that Pcyt2(+/-) mice have reduced membrane cholesterol/sphingomyelin ratio and the homocysteine/methionine cycle that were improved by choline supplementation. These data suggest that supplementary choline is beneficial for restoring FA and TAG homeostasis under conditions of obesity caused by impaired PE synthesis. PMID- 26242922 TI - Occupational protein contact dermatitis. AB - Occupational contact dermatitis is generally caused by haptens but can also be induced by proteins causing mainly immunological contact urticaria (ICU); chronic hand eczema in the context of protein contact dermatitis (PCD). In a monocentric retrospective study, from our database, only 31 (0.41%) of patients with contact dermatitis had positive skin tests with proteins: 22 had occupational PCD, 3 had non-occupational PCD, 5 occupational ICU and 1 cook had a neutrophilic fixed food eruption (NFFE) due to fish. From these results and analysis of literature, the characteristics of PCD can be summarized as follows. It is a chronic eczematous dermatitis, possibly exacerbated by work, suggestive if associated with inflammatory perionyxix and immediate erythema with pruritis, to be investigated when the patient resumes work after a period of interruption. Prick tests with the suspected protein-containing material are essential, as patch tests have negative results. In case of multisensitisation revealed by prick tests, it is advisable to analyse IgE against recombinant allergens. A history of atopy, found in 56 to 68% of the patients, has to be checked for. Most of the cases are observed among food-handlers but PCD can also be due to non-edible plants, latex, hydrolysed proteins or animal proteins. Occupational exposure to proteins can thus lead to the development of ICU. Reflecting hypersensitivity to very low concentrations of allergens, investigating ICU therefore requires caution and prick tests should be performed with a diluted form of the causative protein containing product. Causes are food, especially fruit peel, non-edible plants, cosmetic products, latex, animals. PMID- 26242923 TI - Inpatient Treatment after Multi-Dose Racemic Epinephrine for Croup in the Emergency Department. AB - BACKGROUND: Emergency department (ED) discharge is safe when croup-related stridor has resolved after corticosteroids and a single dose of racemic epinephrine (RE). Little evidence supports the traditional practice of hospital admission after >= 2 doses of RE. OBJECTIVE: Our aim was to describe the frequency and timing of clinically important inpatient interventions after >= 2 ED RE doses. METHODS: We identified patients hospitalized for croup after ED treatment with corticosteroids and >=2 doses of RE. We compared asymptomatic (admitted solely on the number of RE doses) and symptomatic (admitted due to disease severity) groups with regard to inpatient RE administration, supplemental oxygen, helium-oxygen mixture (heliox) therapy, intubation, or transfer to a higher level of care, time to hospital discharge, and revisit and readmission rates within 48 h of discharge. RESULTS: Of 200 subjects admitted after >= 2 ED RE doses, 72 (36%) received clinically important inpatient interventions: RE (n = 68 [34%]), heliox (n = 9 [5%]), and supplemental oxygen (n = 4 [2%]). Of patients who received inpatient RE, 53% received only 1 dose. No patients underwent intubation or transfer to higher level of care. The 112 asymptomatic patients had fewer interventions (14% vs. 63%; p < 0.001) and shorter hospital durations (14.5 vs. 22 h; p < 0.001). Only 14% of the asymptomatic group received RE, with 75% receiving a single dose. There were no differences in revisit and readmission rates. CONCLUSIONS: Inpatient interventions after >= 2 ED doses of RE for croup were infrequent, most commonly RE administration. Most patients asymptomatic upon admission require 0-1 inpatient RE doses and may be candidates for outpatient management. PMID- 26242924 TI - Phlegmasia Cerulea Dolens in the Pediatric Population: A Life-threatening Condition. AB - BACKGROUND: Phlegmasia cerulea dolens is a rare complication of deep venous thromboembolism that can have life-threatening consequences. It is more commonly reported in the adult population, and rarely in the pediatric population, especially in a healthy child. CASE REPORT: We report a case of a healthy 7-year old girl who presented with right leg pain and fever, found to have a thrombus involving her inferior vena cava and right lower extremity. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case illustrates the importance of early recognition and a multimodal approach to treatment of phlegmasia cerulea dolens. PMID- 26242925 TI - Predictors of a Top Performer During Emergency Medicine Residency. AB - BACKGROUND: Emergency Medicine (EM) residency program directors and faculty spend significant time and effort creating a residency rank list. To date, however, there have been few studies to assist program directors in determining which pre residency variables best predict performance during EM residency. OBJECTIVE: To evaluate which pre-residency variables best correlated with an applicant's performance during residency. METHODS: This was a retrospective multicenter sample of all residents in the three most recent graduating classes from nine participating EM residency programs. The outcome measure of top residency performance was defined as placement in the top third of a resident's graduating class based on performance on the final semi-annual evaluation. RESULTS: A total of 277 residents from nine institutions were evaluated. Eight of the predictors analyzed had a significant correlation with the outcome of resident performance. Applicants' grade during home and away EM rotations, designation as Alpha Omega Alpha (AOA), U.S. Medical Licensing Examination (USMLE) Step 1 score, interview scores, "global rating" and "competitiveness" on nonprogram leadership standardized letter of recommendation (SLOR), and having five or more publications or presentations showed a significant association with residency performance. CONCLUSION: We identified several predictors of top performers in EM residency: an honors grade for an EM rotation, USMLE Step 1 score, AOA designation, interview score, high SLOR rankings from nonprogram leadership, and completion of five or more presentations and publications. EM program directors may consider utilizing these variables during the match process to choose applicants who have the highest chance of top performance during residency. PMID- 26242926 TI - Partial androgen insensitivity syndrome with persistent mullerian remnants. A case report. PMID- 26242927 TI - Pegvisomant: Balance after 10 years. PMID- 26242929 TI - The adipokine preadipocyte factor-1 is downregulated in preeclampsia and expressed in placenta. AB - BACKGROUND: Adipokines contribute to the development of preeclampsia (PE), a severe pregnancy complication which increases the future risk for cardiovascular and metabolic disease in both mother and newborn. Pre-adipocyte factor-1 (Pref-1) was recently introduced as a novel antiangiogenic and antiadipogenic adipokine. MATERIAL AND METHODS: Pref-1 was quantified in patients with PE (n=51) and healthy pregnant controls (n=51) during pregnancy, as well as 6 months after delivery (study population 1). Furthermore, Pref-1 was investigated in the immediate peripartal period and the placenta in 40 healthy pregnant women undergoing elective cesarean section (study population 2). RESULTS: In study population 1, median Pref-1 serum concentrations during pregnancy were significantly lower in women with PE (0.5 MUg/l) as compared to healthy pregnant controls (0.7 MUg/l) (p<0.001). Furthermore, Pref-1 serum concentrations were independently predicted by PE, leptin levels, and gestational age in this population. In both study populations, Pref-1 serum levels significantly decreased after delivery as compared to prepartal levels. Moreover, significant expression of Pref-1 was detected in placental tissue. CONCLUSION: Maternal Pref 1 serum concentrations are significantly decreased in PE. The pathophysiological significance of this regulation needs to be studied in more detail in future experiments. PMID- 26242930 TI - Self-assertiveness interfacing incivility in student nurses: Possible outcomes. PMID- 26242928 TI - Making many from few: IL-12p40 as a model for the combinatorial assembly of heterodimeric cytokines. AB - How dendritic cells (DCs) gather information from the local milieu at a site of infection or injury and communicate this to influence adaptive immunity is not well understood. We and others have reported that soon after microbial encounter, DCs secrete the p40 subunit of IL-12, by itself, in a monomeric form. Based on recent data that this p40 monomer subsequently associates with p35 released from other cells to generate functional IL-12, we proposed that p40 can function as a DC-derived probe which samples the composition of the local milieu by looking for other binding partners. In this opinion, we discuss how such a sampling function might generate an elaborate combinatorial "code" of heterodimeric cytokines, capable of conveying location-specific information to cells downstream of DC activation, including NK and T cells. PMID- 26242931 TI - Suitable clinical learning environments: Still a global issue for nursing students. PMID- 26242934 TI - Brain-stem microRNAs implicated in hypertension. PMID- 26242935 TI - Young children use pedagogical cues to modulate the strength of normative inferences. AB - Young children understand pedagogical demonstrations as conveying generic, kind relevant information. But, in some contexts, they also see almost any confident, intentional action on a novel artefact as normative and thus generic, regardless of whether this action was pedagogically demonstrated for them. Thus, although pedagogy may not be necessary for inferences to the generic, it may nevertheless be sufficient to produce inductive inferences on which the child relies more strongly. This study addresses this tension by bridging the literature on normative reasoning with that on social learning and inductive inference. Three year-old children learned about a novel artefact from either a pedagogical or non pedagogical demonstration, and then, a series of new actors acted on that artefact in novel ways. Although children protested normatively in both conditions (e.g., 'No, not like that'), they persisted longer in enforcing the learned norms in the face of repeated non-conformity by the new actors. This finding suggests that not all generic, normative inferences are created equal, but rather they depend - at least for their strength - on the nature of the acquisition process. PMID- 26242933 TI - Role of the Na+/H+ exchanger 3 in angiotensin II-induced hypertension. AB - The renal mechanisms responsible for angiotensin II (ANG II)-induced hypertension remain incompletely understood. The present study tested the hypothesis that the Na(+)/H(+) exchanger 3 (NHE3) is required for ANG II-induced hypertension in mice. Five groups of wild-type (Nhe3(+/+)) and Nhe3(-/-) mice were treated with vehicle or high pressor doses of ANG II (1.5 mg/kg/day ip, via minipump for 2 wk, or 10 pmol/min iv for 30 min). Under basal conditions, Nhe3(-/-) mice had significantly lower systolic blood pressure (SBP) and mean intra-arterial pressure (MAP) (P < 0.01), 24 h urine (P < 0.05), urinary Na(+) (P < 0.01) and urinary K(+) excretion (P < 0.01). In response to ANG II, SBP and MAP markedly increased in Nhe3(+/+) mice in a time-dependent manner, as expected (P < 0.01). However, these acute and chronic pressor responses to ANG II were significantly attenuated in Nhe3(-/-) mice (P < 0.01). Losartan blocked ANG II-induced hypertension in Nhe3(+/+) mice but induced marked mortality in Nhe3(-/-) mice. The attenuated pressor responses to ANG II in Nhe3(-/-) mice were associated with marked compensatory humoral and renal responses to genetic loss of intestinal and renal NHE3. These include elevated basal plasma ANG II and aldosterone and kidney ANG II levels, salt wasting from the intestines, increased renal AQP1, Na(+)/HCO3 (-), and Na(+)/K(+)-ATPase expression, and increased PKCalpha, mitogen-activated protein kinases ERK1/2, and glycogen synthase kinase 3alphabeta signaling proteins in the proximal tubules (P < 0.01). We concluded that NHE3 in proximal tubules of the kidney, along with NHE3 in intestines, is required for maintaining basal blood pressure as well as the full development of ANG II-induced hypertension. PMID- 26242936 TI - INTRODUCTION: Intersections in Reproduction: Perspectives on Abortion and Assisted Reproductive Technologies. PMID- 26242937 TI - The Bad Mother: Stigma, Abortion and Surrogacy. AB - Stigma taints individuals with a spoiled identity and loss of status or discrimination. This article is the first to examine the stigma attached to abortion and surrogacy and consider how law may stigmatize women for failing to conform to social expectations about maternal roles. Courts should consider evidence of stigma when evaluating laws regulating abortion or surrogacy to determine whether these laws are based on impermissible gender stereotyping. PMID- 26242938 TI - Legal Change and Stigma in Surrogacy and Abortion. AB - Stigma marks both surrogacy and abortion. Legal change lessens stigma but may not remove it altogether. Post-legalization regulation may reinstall stigma by surrounding a legalized practice with barriers that make exercise of that right more difficult. As a result, law may reenact stigma even as it purports to take it away. PMID- 26242939 TI - Selective Reduction: "A Soft Cover for Hard Choices" or Another Name for Abortion? AB - Selective reduction and abortion both involve the termination of fetal life, but they are classified by different designations to underscore the notion that they are regarded as fundamentally different medical procedures: the two are performed using distinct techniques by different types of physicians, upon women under very different circumstances, in order to further dramatically different objectives. Hence, the two procedures appear to call for a distinct moral calculus, and they have traditionally evoked contradictory reactions from society. This essay posits that despite their different appellations, selective reduction and abortion are essentially equivalent. PMID- 26242940 TI - When Is an Abortion Not an Abortion? AB - Discussion about the similarities and differences between abortion and multi fetal pregnancy reduction, including the tug-of-war over naming, highlights ongoing contestation about the relationship between the law, ethics, and women's bodies. Ultimately, the law must root itself in the realities of pregnancy including the physical and social consequences that any pregnancy creates for the woman who carries it. PMID- 26242941 TI - Selection against Disability: Abortion, ART, and Access. AB - This essay re-examines the disability critique of prenatal and pre-implantation screening in light of evidence about the larger context in which fertility and reproductive healthcare is rendered in the U.S. It argues that efforts to identify acceptable criteria for trait-based selection or otherwise impose reasons-based limitations on reproductive choice should be avoided because such limitations tend to perpetuate the discrimination encountered by adults with disabilities seeking fertility and reproductive health services. PMID- 26242942 TI - Normalizing Disability in Families. AB - This comment shifts Ouellette's frame of reference in linking prenatal selection against disability, laws prohibiting prenatal sex selection, and fertility specialists' discrimination against disabled adults. Viewing decisions about who can reproduce and what children will be born as fundamentally decisions about family suggests ways to promote acceptance of people with disabilities as valued family members - without limiting reproductive liberties. PMID- 26242943 TI - Non-Invasive Testing, Non-Invasive Counseling. AB - This article describes a new prenatal genetic test that is painless, early, and increasingly available. State legislatures have reacted by prohibiting abortion for reason of fetal sex or of fetal diagnosis and managing genetic counseling. This article explores these legislative responses and considers how physicians and genetic counselors currently communicate post-testing options. The article then examines the challenges ahead for genetic counseling, particularly in light of the troubling grip of abortion politics on conversations about prenatal diagnosis. PMID- 26242944 TI - Reproductive Information and Reproductive Decision-Making. AB - Opponents of reproductive choice are attempting to limit reproductive decisions based on certain underlying reasons. This commentary explores the rationales for these limitations and the objections to them. It concludes that reasoned-based limitations are unsupportable and unenforceable. PMID- 26242945 TI - Disclosure Two Ways. AB - This article is an initial attempt to compare the pre-abortion disclosure mandates that have proliferated in the two decades since the Court decided Planned Parenthood v. Casey with laws that, in the context of assisted reproduction and reproductive health, require specific disclosures beyond a state's baseline informed consent requirements. While some scholars have characterized pre-abortion disclosure laws as sui generis, they share some important common features with disclosure mandates in the context of oocyte donation and other reproductive health procedures. This article suggests that in critiquing pre-abortion disclosure mandates, scholars and advocates should be careful to differentiate the use of disclosure laws in general from uses where the government interest conveys a moral preference against a particular procedure. PMID- 26242946 TI - Distinctions in Disclosure: Mandated Informed Consent in Abortion and ART. AB - Enactment of mandated pre-procedure disclosures in abortion and assisted reproductive technology (ART) services has swelled in recent years. Calls to equally regard these mandates as neutral tools in furtherance of patient protection fail to acknowledge key substantive and structural differences in these reproduction-affecting mandates. While ART mandates permit physicians to use their medical judgment to protect presumptively vulnerable egg donors and gestational carriers, abortion disclosures impart scientifically suspect messaging aimed at dissuading women from pursuing pregnancy termination. These and other distinctions counsel in favor of regarding and analyzing abortion and ART mandated disclosures as separate and distinguishable informed consent tools. PMID- 26242947 TI - Eggs and Abortion: "Women-Protective" Language Used by Opponents in Legislative Debates over Reproductive Health. AB - In this paper we undertake an examination of the presence of similar "women protective" discourses in policy debates occurring over two bills on reproductive related topics considered during the 2013 California legislature session. The first bill (AB154), now signed into law, allows nurse practitioners, certified nurse midwives, and physician assistants to perform first-trimester aspiration abortions. The second bill (AB926), had it passed, would remove the prohibition on paying women for providing eggs to be used for research purposes. Using frame analysis we find evidence of similar protective arguments by opponents of both bills, although these advocates do not share ideological positions on abortion rights or women's autonomy. In the case of AB154, anti-abortion advocates use language and frames that call for protecting the health of women against the imputed interests of the "abortion industry." In the case of AB926, feminists and pro-choice advocates evoke similar frameworks for the protection of women against the interests of the "medical research industry." Both sides argue for the "protection of women," from opposing positions on the rights and autonomy of women in relationship to reproductive freedom. PMID- 26242948 TI - False Framings: The Co-opting of Sex-Selection by the Anti-Abortion Movement. AB - Jesudason and Weitz's article examines two public policy debates in California, where both sides of the debate used similar language that had the potential to be detrimental to women. Specifically, they show how anti-abortion crusaders in California used similar language to describe why women's rights should be curtailed as pro-choice advocates use when fighting for more choice and privacy for women's reproductive decisions. This commentary builds upon their article by demonstrating the harm that such co-opting causes to women's rights using the example of sex selective abortion. By examining the legislative history of state and national bills to ban sex-selective abortion, this commentary demonstrates how the anti-abortion lobby has adopted the language of pro-choice advocates quite effectively. Although the framing of this issue as being "woman-protective" is strategic and insincere, such political framing is powerful, as Jesudason and Weitz have noted. Anti-abortion activists have convinced lawmakers in many states that sex-selective abortion is a dire issue in their state and that they must restrict it in order to protect women. In fact, there is no evidence that sex selective abortion is a problem in the United States, yet these frames have been very effective in weakening women's privacy rights. Whenever woman-protective framings are invoked for self-serving purposes, women's rights advocates must work hard to uncover the truth behind these discourses to prevent successful legislative efforts that curtail women's reproductive freedom. PMID- 26242949 TI - The Triple System for Regulating Women's Reproduction. AB - Analysis of ART and abortion must include the experiences of women at the emerging center of American life, as well as those at the top and bottom of the socioeconomic scale. Our contribution explores the triple system of fertility regulation, analyzing the intersections between fertility and class and using the experiences of women in the middle to add depth to our understanding of women's exercises of autonomy. PMID- 26242950 TI - The Invisible Classes in High Stakes Reproduction. AB - This essay argues that what separates poor mothers from their middle class counterparts are many factors - not simply couples' ability to plan, the power of their choices, and agency. For example, power, social clout, and access to health care (and health information) influence status and parenting. Historically, for white women choice has been about abortion; for many women of color, choice is about being able to be a mother. This essay begs the question whether real parallels can be drawn on questions of contraception, abortion, and ART simply by examining class and to what extent race and sexual orientation matter in research on parenting. PMID- 26242951 TI - Conceiving of Products and the Products of Conception: Reflections on Commodification, Consumption, ART, and Abortion. AB - Assisted reproductive technologies and abortion prompt serious questions about how we should understand the complex relationship between money, markets, choice, and the care relationship. This essay defines "patient" and "consumer," and then describes how they are less important than their attributes. Then it describes theories of commodification and consumption in reproductive contexts and their consequences, from compliance and coercion to resistance and creativity. It also examines whether ART and abortion are "markets." Finally, this essay explores how the attributes which comprise the patient/consumer roles can be incorporated into health care reform, and the implications of health care reform models on ART and abortion. PMID- 26242952 TI - Complexifying Commodification, Consumption, ART, and Abortion. AB - This commentary on Madeira's paper complicates the relationships between commodification, consumption, abortion, and assisted reproductive technologies (ARTs) she draws in two ways. First, I examine under what conditions the commodification of ARTs, gametes, and surrogacy lead to patients becoming consumers. Second, I show that there are some stark difference between applying commodification critiques to ART versus abortion. PMID- 26242953 TI - The Doctor's Dilemma: Paternalisms in the Medicolegal History of Assisted Reproduction and Abortion. AB - This article analyzes the comparative history of the law and practice of abortion and assisted reproduction in the United States to consider the interplay between medical paternalism and legal paternalism. It supplements existing critiques of paternalism as harmful to women's equality with the medical perspective, as revealed through the writings of Alan F. Guttmacher, to consider when legal regulation might be warranted. PMID- 26242954 TI - How to Escape the Doctor's Dilemma? De-Medicalize Reproductive Technologies. AB - Kara Swanson details the professional evolution of Alan Guttmacher, and the quandary he faced when the law interfered with prerogatives he wished to exercise in his practice of reproductive medicine. This response focuses on how decoupling reproductive technologies from a regime requiring medical licensure could lead to more complete reproductive autonomy for women. PMID- 26242955 TI - Expectant Fathers, Abortion, and Embryos. AB - One thread of abortion criticism, arguing that gender equality requires that men be allowed to terminate legal parental status and obligations, has reinforced the stereotype of men as uninterested in fatherhood. As courts facing disputes over stored pre-embryos weigh the equities of allowing implantation of the pre embryos, this same gender stereotype has been increasingly incorporated into a legal balancing test, leading to troubling implications for ART and family law. PMID- 26242956 TI - Respecting Intent and Dispelling Stereotypes by Reducing Unintended Pregnancy. AB - In "Expectant Fathers, Abortion, and Embryos," Dara Purvis evaluates the concepts of intent and gender stereotypes in connection with "expectational fathers" in the related contexts of abortion and assisted reproductive technologies. This comment seeks to build upon Purvis's own analysis to obviate her concern that abortion discourse promotes harmful stereotypes of men as disinterested fathers. To the contrary, for men - no less than for women - a desire to avoid or terminate pregnancy is fully consistent with loving and shared parenthood of existing or future children. The same individuals who choose to become parents at other times in their long reproductive lives will use contraception and have abortions. In fact, most women who have abortions already have children. Policies that empower men and women to avoid unintended pregnancy are the sensible, win win, front-line approach to avoid disputes over abortion. PMID- 26242957 TI - The State's Interest in Potential Life. AB - Courts have resolved a range of controversies by casual appeal to the state's interest in "potential life" that Roe held capable of overriding even fundamental rights. My analysis of this potential-life interest reveals its use to mean not one but four species of concern. I call these prenatal welfare, postnatal welfare, social values, and social effects and demonstrate how they operate under different conditions and with varying levels of strength. PMID- 26242958 TI - Membership Has Its Privileges? Life, Personhood, and Potential in Discussions about Reproductive Choice. AB - As Professor Dov Fox points out in his essay, reference to "potential life" in American abortion jurisprudence is both indeterminate and underspecified. This commentary highlights that use of the phrase "potential life" by courts also obscures the fact that a position has been taken that biological life is not the equivalent of legal personhood. Worse, the position has been imposed on those who do not share it without offering reasons to justify its imposition in terms that those who oppose it can reasonably be expected to endorse. PMID- 26242959 TI - What Will It Take to Address the Global Threat of Antibiotic Resistance? AB - In March 2015, the Dag Hammarskjold Foundation convened a workshop in Uppsala, Sweden to address questions about antibiotic resistance, in partnership with the Global Strategy Lab, the Journal of Law, Medicine & Ethics (JLME), the Norwegian Institute of Public Health, and ReAct - Action on Antibiotic Resistance. Eleven concise articles were commissioned to explore whether ABR depended on global collective action, and if so, what tools could help states and non-state actors to achieve it. This article introduces that collection, which is found in an online-only symposium at aslme.org. PMID- 26242960 TI - Organ Donation, Brain Death and the Family: Valid Informed Consent. AB - I argue that valid informed consent is ethically required for organ donation from individuals declared dead using neurological criteria. Current policies in the U.S. do not require this and, not surprisingly, current practices inhibit the possibility of informed consent. Relevant information is withheld, opportunities to ensure understanding and appreciation are extremely limited, and the ability to make and communicate a free and voluntary decision is hindered by incomplete disclosure and other practices. Current practices should be revised to facilitate valid informed consent for organ donation. PMID- 26242961 TI - Institutional Oversight of Faculty-Industry Consulting Relationships in U.S. Medical Schools: A Delphi Study. AB - The conflicts of interest that may arise in relationships between academic researchers and industry continue to prompt controversy. The bulk of attention has focused on financial aspects of these relationships, but conflicts may also arise in the legal obligations that faculty acquire through consulting contracts. However, oversight of faculty members' consulting agreements is far less vigorous than for financial conflicts, creating the potential for faculty to knowingly or unwittingly contract away important rights and freedoms. Increased regulation could prevent this, but it is unclear what forms of oversight universities view as feasible and effective. In this article, we report on a Delphi study to evaluate several approaches for oversight of consulting agreements by medical schools. The panel was comprised of 11 senior administrators with responsibility for oversight of faculty consulting relationships. We found broad agreement among panelists regarding the importance of institutional oversight to protect universities' interests. There was strong support for two specific approaches: providing educational resources to faculty and submitting consulting agreements for institutional review. Notwithstanding the complexities of asserting authority to regulate private consulting agreements between faculty members and companies, medical school administrators reached consensus that several approaches to improving institutional oversight are feasible and useful. PMID- 26242962 TI - Stakeholders' Views of Alternatives to Prospective Informed Consent for Minimal Risk Pragmatic Comparative Effectiveness Trials. AB - As interest in comparative effectiveness research grows, questions have emerged regarding whether it is ever acceptable to alter informed consent requirements for research when patients are randomly assigned to widely-used therapies. This paper reports on interviews with Institutional Review Board members and researchers and on focus groups with patients from Geisinger and Johns Hopkins health systems. The objective was to elicit participants' views of the acceptability of four different disclosure and authorization models for low-risk pragmatic comparative effectiveness trials of widely-used therapies. Results suggest that although participants valued autonomous choice, many also believed that it was acceptable to streamline information disclosure and to use an opt-out process for eligible individuals who would prefer not to participate. This provides some preliminary evidence that relevant stakeholders find alternatives to traditional informed consent acceptable for low-risk pragmatic comparative effectiveness trials of widely-used therapies as long as a sufficient amount of choice is preserved. PMID- 26242963 TI - Conflicts of Interest and Effective Oversight of Assisted Reproduction Using Donated Oocytes. AB - Oocyte donation raises conflicts of interest and commitment for physicians but little attention has been paid to how to reduce these conflicts in practice. Yet the growing popularity of assisted reproduction has increased the stakes of maintaining an adequate oocyte supply and (where appropriate) minimizing conflicts. A growing body of professional guidelines, legal challenges to professional self-regulation, and empirical research on the practice of oocyte donation all call for renewed attention to the issue. As empirical findings better inform existing conflicts and their potential harms, we can better attempt to reduce these conflicts. To that end, the article first describes the nature of conflicts in oocyte donation and relevant regulations and professional guidelines. We then describe studies on conflicts at four phases of oocyte donation: recruitment, screening, stimulation, and post-stimulation monitoring. Next we consider three models for conflict reduction in medicine generally: improved professional self-regulation, outright restriction like Stark anti referral laws, or the use of conflict mediators, like in living organ donation. We ultimately conclude that improved professional self-regulation is a reasonable starting place for oocyte donation. PMID- 26242964 TI - Ethical Issues in Big Data Health Research: Currents in Contemporary Bioethics. PMID- 26242967 TI - Production characterization and working characteristics in DICI engine of Pongamia biodiesel. AB - Renewable energy plays a predominant role in solving the current energy requirement problems and biodiesel is a promising alternative fuel to tide over the energy crisis and conserve fossil fuels. The present work investigates an eco friendly substitute for the replacement of fossil fuels and the experiments are designed to determine the effects of a catalyst in the biodiesel production processes. Pongamia pinnata oil was utilized to produce the biodiesel by using catalysts namely KOH and NaOH and the properties of the fuel were found by using Carbon Hydrogen Nitrogen Sulfur (CHNS) elemental analysis, Fourier Transform Infrared (FTIR) Spectroscopy, Gas Chromatography & Mass Spectrometry (GC-MS), and Proton Nuclear Magnetic Resonance ((1)H NMR) Spectroscopy and the thermophysical properties were compared with those of neat diesel. In continuation, the working characteristics of the biodiesel and biodiesel-water emulsions were accomplished in a four stroke compression ignition engine and the results were compared to those of neat diesel. It was found that the exhaust emission characteristics like brake specific carbon monoxide (BSCO), brake specific hydrocarbons (BSHC) and smoke opacity were better for neat biodiesel (except brake specific nitric oxide BSNO) than those of neat diesel. PMID- 26242966 TI - Redundant synthesis of a conidial polyketide by two distinct secondary metabolite clusters in Aspergillus fumigatus. AB - Filamentous fungi are renowned for the production of bioactive secondary metabolites. Typically, one distinct metabolite is generated from a specific secondary metabolite cluster. Here, we characterize the newly described trypacidin (tpc) cluster in the opportunistic human pathogen Aspergillus fumigatus. We find that this cluster as well as the previously characterized endocrocin (enc) cluster both contribute to the production of the spore metabolite endocrocin. Whereas trypacidin is eliminated when only tpc cluster genes are deleted, endocrocin production is only eliminated when both the tpc and enc non-reducing polyketide synthase-encoding genes, tpcC and encA, respectively, are deleted. EncC, an anthrone oxidase, converts the product released from EncA to endocrocin as a final product. In contrast, endocrocin synthesis by the tpc cluster likely results from incomplete catalysis by TpcK (a putative decarboxylase), as its deletion results in a nearly 10-fold increase in endocrocin production. We suggest endocrocin is likely a shunt product in all related non-reducing polyketide synthase clusters containing homologues of TpcK and TpcL (a putative anthrone oxidase), e.g. geodin and monodictyphenone. This finding represents an unusual example of two physically discrete secondary metabolite clusters generating the same natural product in one fungal species by distinct routes. PMID- 26242968 TI - Emergency department use and hospitalizations among homeless adults with substance dependence and mental disorders. AB - BACKGROUND: Homelessness, substance use, and mental disorders each have been associated with higher rates of emergency department (ED) use and hospitalization. We sought to understand the correlation between ED use, hospital admission, and substance dependence among homeless individuals with concurrent mental illness who participated in a 'Housing First' (HF) intervention trial. METHODS: The Vancouver At Home study consisted of two randomized controlled trials addressing homeless individuals with mental disorders who have "high" or "moderate" levels of need. Substance dependence was determined at baseline prior to randomization, using the Mini International Neuropsychiatric Interview diagnostic tool, version 6.0. To assess health service use, we reviewed the number of ED visits and the number of hospital admissions based on administrative data for six urban hospitals. Negative binomial regression modeling was used to test the independent association between substance dependence and health service use (ED use and hospitalization), adjusting for HF intervention, age, gender, ethnicity, education, duration of lifetime homelessness, mental disorders, chronic health conditions, and other variables that were selected a priori to be potentially associated with use of ED services and hospital admission. RESULTS: Of the 497 homeless adults with mental disorders who were recruited, we included 381 participants in our analyses who had at least 1 year of follow-up and had a personal health number that could be linked to administrative health data. Of this group, 59% (n = 223) met criteria for substance dependence. We found no independent association between substance dependence and ED visits or hospital admissions [rate ratio (RR) = 0.85; 95% CI 0.62-1.17 and RR = 1.21; 95% CI 0.83 1.77, respectively]. The most responsible diagnoses (defined as the diagnosis that accounts for the length of stay) for hospital admissions were schizo affective disorder, schizophrenia-related disorder, or bipolar affective disorder; collectively reported in 48% (n = 263) of admissions. Fifteen percent (n = 84) of hospital admissions listed substance dependence as the most responsible diagnosis. CONCLUSIONS: Substance dependence was not independently associated with ED use or hospital admission among homeless adults with mental disorders participating in an HF trial. Hospital admissions among this cohort were primarily associated with severe mental disorders. TRIAL REGISTRATION: ISRCTN57595077 and ISRCTN66721740. PMID- 26242969 TI - TEK, local perceptions of risk, and diversity of management practices of Agave inaequidens in Michoacan, Mexico. AB - BACKGROUND: Mescal production is the main economic activity associated to agaves in Mexico, which involves 53 species mostly harvested from forests. The increasing mescal demand has influenced risk in both agave populations and mescal production, but other social and ecological factors also intervene. We hypothesized that the greater the risk the greater the complexity of management responses; otherwise, the greater the probability of populations' depletion. We analysed this hypothesis by examining the diversity of risk conditions and management practices of Agave inaequidens in the state of Michoacan, in central western Mexico. METHODS: We studied five communities of Michoacan, documenting through 41 semi-structured interviews the use forms, risk perception, number of agaves annually extracted, and the management practices. Using a matrix with social-ecological and technological data analyzed by PCA, we evaluated similarities of management contexts. A data matrix with information on risk of agave populations, and other about management practices were analysed also through CCA and PCA. The scores of the first principal components were considered as indexes of risk and management complexity, respectively. A regression analysis of these indexes evaluated their relation. RESULTS: We recorded 34 different uses of A. inaequidens, the most important being mescal production (mentioned by 76.1 % of people interviewed). Nearly 12.5 % of people practice only gathering, but others mentioned the following practices: Selective let standing of agaves for seed production (20 %); in situ transplanting of saplings; seed propagation in nurseries and saplings transplanting to forest (10 %); suckers transplanting (7.5 %); seed dispersal in forests; banning (5 %); enhancing of agave growth by removing tree canopies (2.5 %); transplanting from the wild to live fences (45 %); intensive plantations (35 %). The highest vulnerability of agave populations was identified in communities where risk is not counteracted by management. In two communities we identified the highest risk (annual extraction from 4,353 to 6,557 agaves), but different actions counteracting such risk. CONCLUSIONS: Interchange of knowledge and management experiences developed by handlers is crucial for the regional conservation, recovering, and sustainable management of A. inaequidens populations. PMID- 26242970 TI - Consumption of hot spicy foods and mortality--is chilli good for your health? PMID- 26242971 TI - Predation mechanisms of Rapana venosa (Gastropoda: Muricidae) in different biotopes along the Black Sea coast. AB - Mechanisms of feeding by the invasive gastropod Rapana venosa from different biotopes of 11 sites along the Black Sea coast are discussed. Two methods--edge drilling and suffocation--are used, but the prevailing method in a particular biotope depends on the type of bivalve prey. Drill signs were present on almost all shells of Chamelea gallina, captured by rapa whelks in field conditions, while in a field experiment, only 11% of all empty Mytilus galloprovincialis had drilling signatures. The degree of radula abrasion was also dependent on the available bivalves: it was the highest in biotopes with C. gallina and juvenile mussels, and the lowest in biotopes with large mussels. Intermediate degrees of abrasion were observed in biotopes with mixed prey: C. gallina and Anadara kagoshimensis, C. gallina and mussels, or small and large mussels. Since we observed only initial signs of drilling, simultaneous application of boring and suffocation could take place. PMID- 26242972 TI - Method and application of ocean environmental awareness measurement: Lessons learnt from university students of China. AB - Different studies have proved that enhancing public Ocean Environmental Awareness (OEA) will lead to increased public support for ocean environmental protection. Our study develops a questionnaire to investigate current levels of students' OEA from three aspects including ocean environmental concerns, ocean environment knowledge and willingness to participate in ocean related activities. This questionnaire was applied to students from Xiamen University to understand the OEA of university students in China, of which there are few studies. Using data gathered from a random purposive sample, the OEA level of students in Xiamen University was investigated and then the influencing factors (education, geographical situation, age and gender etc.) were further analyzed. Findings suggest that most students are concerned about the ocean environment but their knowledge is not enough that makes the willingness to participate in ocean related actions limited as well. The results show there is an urgent need to improve students' OEA. PMID- 26242973 TI - Novel genetic advances in schizophrenia: an interview with Michael O'Donovan. AB - In this podcast, we talk to Professor Michael O'Donovan about the latest genetic advances in schizophrenia based on research data from the Schizophrenia Working Group of the Psychiatric Genomics Consortium. Functional and prediction studies from the identified genetic loci are described together with future directions in psychiatric genetics and its interplay with the environment.The podcast for this interview is available at http://media.biomedcentral.com/content/movies/supplementary/s12916-015-0417-1 s1.mp3. PMID- 26242975 TI - Dependence of the bystander effect for micronucleus formation on dose of heavy ion radiation in normal human fibroblasts. AB - Ionising radiation-induced bystander effects are well recognised, but its dependence on dose or linear energy transfer (LET) is still a matter of debate. To test this, 49 sites in confluent cultures of AG01522D normal human fibroblasts were targeted with microbeams of carbon (103 keV um(-1)), neon (375 keV um(-1)) and argon ions (1260 keV um(-1)) and evaluated for the bystander-induced formation of micronucleus that is a kind of a chromosome aberration. Targeted exposure to neon and argon ions significantly increased the micronucleus frequency in bystander cells to the similar extent irrespective of the particle numbers per site of 1-6. In contrast, the bystander micronucleus frequency increased with increasing the number of carbon-ion particles in a range between 1 and 3 particles per site and was similar in a range between 3 and 8 particles per site. These results suggest that the bystander effect of heavy ions for micronucleus formation depends on dose. PMID- 26242974 TI - Transiently responsive protein-polymer conjugates via a 'grafting-from' RAFT approach for intracellular co-delivery of proteins and immune-modulators. AB - We report on transiently responsive protein-polymer conjugates that temporarily change their protein conformation from the soluble to the particle-like state. 'Grafting-from' RAFT polymerization of a dioxolane-containing acrylamide with a protein macroCTA is used to design polymer-protein conjugates that self-assemble into nanoparticles at physiological temperature and pH. Acid triggered hydrolysis of the dioxolane units into diol moeities rendered the conjugates fully water soluble irrespective of temperature. PMID- 26242976 TI - A method to perform multi-scale Monte Carlo simulations in the clinical setting. AB - In order to model the track structure of clinical mega-voltage photon beams in a reasonable time, it is necessary to use a multi-scale approach incorporating a track-structure algorithm for the regions of interest and a condensed history algorithm for the rest of the geometry. This paper introduces a multi-scale Monte Carlo system, which is used to hand off particle trajectory information between the two algorithms. Since condensed history algorithms ignore electrons with energy below a fixed threshold and those electrons are important to the track structure on the micrometre scale, it is necessary to hand over all charged particles to the track-structure algorithm only in a volume that extends beyond the scoring volume. Additionally, the system is validated against experimental results for radio-isotope gamma spectra. PMID- 26242977 TI - Long-lasting insecticidal nets no longer effectively kill the highly resistant Anopheles funestus of southern Mozambique. AB - BACKGROUND: Chemical insecticides are crucial to malaria control and elimination programmes. The frontline vector control interventions depend mainly on pyrethroids; all long-lasting insecticidal nets (LLINs) and more than 80% of indoor residual spraying (IRS) campaigns use chemicals from this class. This extensive use of pyrethroids imposes a strong selection pressure for resistance in mosquito populations, and so continuous resistance monitoring and evaluation are important. As pyrethroids have also been used for many years in the Manhica District, an area in southern Mozambique with perennial malaria transmission, an assessment of their efficacy against the local malaria vectors was conducted. METHODS: Female offspring of wild-caught Anopheles funestus s.s. females were exposed to deltamethrin, lambda-cyhalothrin and permethrin using the World Health Organization (WHO) insecticide-resistance monitoring protocols. The 3-min WHO cone bioassay was used to evaluate the effectiveness of the bed nets distributed or available for purchase in the area (Olyset, permethrin LLIN; PermaNet 2.0, deltamethrin LLIN) against An. funestus. Mosquitoes were also exposed to PermaNet 2.0 for up to 8 h in time-exposure assays. RESULTS: Resistance to pyrethroids in An. funestus s.s. was extremely high, much higher than reported in 2002 and 2009. No exposure killed more than 25.8% of the mosquitoes tested (average mortality, deltamethrin: 6.4%; lambda-cyhalothrin: 5.1%; permethrin: 19.1%). There was no significant difference in the mortality generated by 3-min exposure to any net (Olyset: 9.3% mortality, PermaNet 2.0: 6.0%, untreated: 2.0%; p = 0.2). Six hours of exposure were required to kill 50% of the An. funestus s.s. on PermaNet 2.0. CONCLUSIONS: Anopheles funestus s.s. in Manhica is extremely resistant to pyrethroids, and this area is clearly a pyrethroid-resistance hotspot. This could severely undermine vector control in this district if no appropriate countermeasures are undertaken. The National Malaria Control Programme (NMCP) of Mozambique is currently improving its resistance monitoring programme, to design and scale up new management strategies. These actions are urgently needed, as the goal of the NMCP and its partners is to reach elimination in southern Mozambique by 2020. PMID- 26242978 TI - Prevention and treatment effect of total flavonoids in Stellera chamaejasme L. on nonalcoholic fatty liver in rats. AB - BACKGROUND: The incidence of nonalcoholic fatty liver disease (NAFLD) has been increasing worldwide in parallel with the obesity epidemic. This study aims to investigate the effects of the total flavonoids in Stellera chamaejasme L. (TFSC) on the experimental NAFLD in high fat diet fed (HFD) rats. METHODS: NAFLD model was induced in male Wistar rats by high-fat diet, and the rats in NAFLD group were randomized into NAFLD group (n = 20) and TFSC-treated group (n = 60). Both groups were given high-fat diet, and the normal group (n = 20) was given normal diet. In addition, the TFSC treated group was administered TFSC orally once a day at a low dose of 100 mg/kg (n = 20), medium dose of 200 mg/kg (n = 20), and high dose of 400 mg/kg (n = 20) for 6 weeks. Subsequently, the rats were sacrificed and body weight changes, lipid profiles in plasma and liver pathology were examined. The relative levels of fatty acid synthesis and beta-oxidation gene expression in hepatic tissues were measured by quantitative real-time polymerase chain reaction (RT-PCR). RESULTS: After the HFD administration for 4 weeks, the body weight,serum TC and TG levels in the rat of model group were significantly higher than in normal group (P < 0.05), and which Showed that the experimental NAFLD model was successfully established. While continual feeding with HFD deteriorated NAFLD and hyperlipidemia, and treatment with the different doses of TFSC effectively improved serum and liver lipid metabolism and liver function. A linear relationship between the dose of TFSC and blood lipid level was observed. The mRNA expression of hepatic acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), Leptin (LEP) and sterol regulatory element binding protein (SREBP)-1c as well as peroxisome proliferator-activated receptor (PPAR) -gamma were significantly lower in high-dose group compared to the positive control group (P < 0.05). The hepatic mRNA expression of Cholesterol 7alpha-hydroxylase1 (CYP7A1), Carnitine palmitoyltransferase-1 (CPT1) and peroxisome proliferator-activated receptor (PPAR) -alpha were significantly higher in the high-dose group compared to the positive control group (P < 0.05). However, no difference was detected in the middle-dose group or the low-dose group compared to the positive control group (P > 0.05). CONCLUSION: TFSC treatment effectively improved NAFLD-related hyperlipidemia and inhibited liver steatosis in rats, and accompanied by modulating the expression of genes for regulating lipid metabolism. PMID- 26242979 TI - Analysis of a child who developed abnormal neuropsychiatric symptoms after administration of oseltamivir: a case report. AB - BACKGROUND: Neuropsychiatric side effects of oseltamivir occur occasionally, especially in infants and young patients, but nothing is known about possible contributory factors. CASE PRESENTATION: We report a case of a 15-year-old Japanese female with influenza infection who developed abnormal psychiatric symptoms after administration of standard doses of oseltamivir. She had no history of neurological illness, had never previously taken oseltamivir, and had not developed psychiatric reactions during previous influenza infection. Her delirium-like symptoms, including insomnia, visual hallucinations, and a long term memory deficit, disappeared after cessation of oseltamivir and administration of benzodiazepine. Detailed assessment was performed, including neurological examination (electroencephalogram, brain magnetic resonance imaging, single photon emission computed tomography with 99mTc-ethyl cysteinate dimer and with (123)I-iomazenil, cerebrospinal fluid analysis and glutamate receptor autoantibodies), drug level determination and simulation, and genetic assessment (OAT1, OAT3, CES1, Neu2). CONCLUSIONS: Abnormal slowing in the electroencephalogram, which is characteristic of influenza-associated encephalopathy, was not observed in repeated recordings. The serum level determination of active metabolite Ro 64-0802 determined at 154 h after final dosing of oseltamivir was higher than the expected value, suggesting delayed elimination of Ro 64-0802. Thus, abnormal exposure to Ro 64-0802 might have contributed, at least in part, to the development of neuropsychiatric symptoms in this patient. The score on Naranjo's adverse drug reaction probability scale was 6. Mutation of c.122G > A (R41Q) in the sialidase Neu2 gene, increased CSF glutamate receptor autoantibodies, and limbic GABAergic dysfunction indicated by SPECT with (123)I-iomazenil were found as possible contributory factors to the CNS side effects. PMID- 26242980 TI - Fractional flow reserve, maximum hyperemia, adenosine, and regadenoson. PMID- 26242981 TI - Pooled comparison of regadenoson versus adenosine for measuring fractional flow reserve and coronary flow in the catheterization laboratory. AB - BACKGROUND: Adenosine is the gold standard for augmenting coronary flow during fractional flow reserve (FFR) testing of intermediate coronary stenoses. However, intravenous infusion is time-consuming and intracoronary injection is subject to variability. Regadenoson is a newer adenosine alternative administered as a single intravenous bolus during nuclear stress testing, but its efficacy and safety during FFR testing have been evaluated only in small, single-center studies. METHODS: We pooled data from 5 academic hospitals, in which patients undergoing clinically-indicated FFR prospectively underwent comparison of intravenous adenosine infusion (140-175mcg/kg/min) versus regadenoson bolus (400mcg). Hemodynamics and symptoms with adenosine were recorded until maximal hyperemia occurred, and after returning to baseline hemodynamics, regadenoson was administered and monitoring was repeated. In a subset of patients with coronary flow data, average peak velocity (APV) at the distal flow sensor was recorded. RESULTS: Of 149 patients enrolled, mean age was 59+/-9years, 76% were male, and 54% underwent testing of the left anterior descending artery. Mean adenosine-FFR and regadenoson-FFR were identical (0.82+/-0.10) with excellent correlation of individual values (r=0.96, p<0.001) and no difference in patient-reported symptoms. Four patients (2.6%) had discrepancies between the 2 drugs for the clinical decision-making cutoff of FFR<=0.80. Coronary flow responses to adenosine and regadenoson were similar (APV at maximal hyperemia 36cm/s for both, p=0.81). CONCLUSIONS: Regadenoson single-bolus administration has comparable FFR, symptoms, and coronary flow augmentation when compared with standard intravenous adenosine infusion. With its greater ease of administration, regadenoson may be a more "user-friendly" option for invasive ischemic testing. PMID- 26242982 TI - Virtual 5-French intra-aortic pumping using a Glidesheath Slender and 6-French intra-aortic balloon catheter. AB - OBJECTIVES: The aim of this study was to evaluate the feasibility and safety of the 6-Fr Glidesheath Slender, which has equivalent outer size to the conventional 5-Fr sheath, for use with the 6-Fr intra-aortic balloon pump (IABP) catheter. METHODS: Between May 2014 and March 2015, 24 patients with acute coronary syndrome underwent percutaneous coronary intervention using a 6-Fr IABP catheter through a 6-Fr Glidesheath Slender for support. The adverse events, including access site complications, kinking of the sheath during the procedure, and any evidence of balloon pump failure, were retrospectively investigated. RESULTS: Insertion of the IABP catheter through either the femoral or brachial artery was successful in all patients. The mean support time was 32.4+/-22.0h. No major hemorrhagic event or severe limb ischemia was observed. Kinking of the shaft occurred during insertion in one patient; however, the subsequent balloon pumping was well maintained and did not require exchange of the sheath or IABP catheter. No kind of IABP failure was observed. CONCLUSION: Although this sheath was originally designed to allow radial access, our results suggest that the use of the Glidesheath Slender is feasible for insertion of the 6-Fr IABP catheter through the brachial and femoral arteries, and may reduce vascular complications in patients who undergo percutaneous coronary intervention. PMID- 26242983 TI - Cardiac rehabilitation improves the ischemic burden in patients with ischemic heart disease who are not suitable for revascularization. AB - BACKGROUND: Ischemic heart diseases including stable angina & acute events, represent a huge burden on both the individual & the society and represent an important source of disability. AIM: We aimed to identify the effect of cardiac rehabilitation program (CRP) on the ischemic burden in patients with ischemic heart disease (IHD) unsuitable for coronary revascularization. METHODS: The study included 40 patients with IHD who were not suitable for coronary revascularization either by PCI or CABG (due to unsuitable coronary anatomy, co morbidities, high surgical/procedural risk or patient preference). All patients were subjected to sophisticated CRP protocols, including patient education, nutritional, medical, psychological and sexual counseling and group smoking cessation. All patients participated in low intensity exercise program twice weekly. The patient's symptoms, vitals and medications were evaluated at each visit and clinical and laboratory data, echocardiography and stress myocardial perfusion imaging (SPECT) were evaluated before and 3months after the end of the study. RESULTS: The mean age was 56.8+/-3.1years and only 2 patients (5%) were females. 22 (55%) patients were diabetic, 21 (53%) were hypertensive and 30 (75%) were smokers. It was found that 3months after completion of CRP, there was a significant decrease in BMI (30.3+/-2.9 vs. 31.2+/-1.9, p<0.001), and mean blood pressure (93.4+/-11 vs. 105+/-10.6mmHg, p<0.001). There was also a favorable effect on lipid profile and a significant improvement of the functional capacity in terms of NYHA functional class (2.1+/-0.62 vs. 1.4+/-0.6, p<0.001). Despite that wall motion score index did not significantly change after CRP, there was a strong trend toward a better ejection fraction (53.7+/-7.8 vs. 54.5+/-6.3 %, p=0.06) and significant improvement of Canadian cardiovascular class (1.42+/-0.6 vs. 1.95+/-0.5, p<0.001) post CRP. Importantly, the difference between the SPECT derived summed segmental scores at peak stress and at rest (SDS) was significantly lower after CRP (4.4+/-3 vs. 7.2+/-3, p<0.001). CONCLUSION: Participation in cardiac rehabilitation program improves ischemic burden in patients with IHD who are unfit or not suitable for conventional cardiac revascularization. In addition the decreased ischemic burden, functional capacity, hemodynamic and metabolic profiles also improve for this group of patients and thus, cardiac rehabilitation should be implemented for routine management of those patients. PMID- 26242984 TI - Role of near-infrared spectroscopy in intravascular coronary imaging. AB - Near-infrared spectroscopy is an intracoronary imaging modality that has been validated in preclinical and clinical studies to help quantify the lipid content of the coronary plaque and provide information regarding its vulnerability. It has the potential to develop into a valuable tool for the risk stratification of a vulnerable plaque and, furthermore, a vulnerable patient. In addition, in the future this technology may help in the development of novel therapies that impact vascular biology. PMID- 26242985 TI - May osteoarticular infections be influenced by vitamin D status? An observational study on selected patients. AB - BACKGROUND: Vitamin D deficiency has been associated with a high number of health outcomes, and its role on the immune system has been deeply investigated in recent years, although poor data are still available on vitamin D status in orthopedic infections including those of prosthetic implants. METHODS: We focused on preoperative values of 25(OH)D in selected groups of patients with septic (Group A) or aseptic (Group B) prosthetic loosening, infective bone disease such as septic arthritis and osteomyelitis (Group C) and other orthopedic pathologies (Group D) to evaluate differences in the vitamin D status. RESULTS: A high prevalence of vitamin D deficiency was recorded among the study population (16.5 +/- 5.4 ng/mL, mean +/- SD). Interestingly, all patients with an infection presented a higher 25(OH)D concentration (17.7 +/- 5.3 ng/mL) in respect to uninfected ones (15.1 +/- 5.6 ng/mL). Significantly higher levels of 25(OH)D were observed in patients with prosthetic joint infection (18.5 +/- 6.5 ng/mL), when compared with those presenting an aseptic loosening (13.6 +/- 9.4 ng/mL). CONCLUSIONS: Deficiency in vitamin D levels have been found in orthopaedic patients. Prosthetic joint infections seems to be associated to higher values of vitamin D in respect to other bone infections or to other orthopaedic conditions requiring surgery. More studies are needed to improve the knowledge on vitamin D status in these patients and to better clarify the role of vitamin D in relation to osteoarticular infections. PMID- 26242986 TI - The challenges of trying to increase preventive healthcare for children in general practice: results of a feasibility study. AB - BACKGROUND: In Australia, general practice, the linchpin for delivery of preventive health care to large segments of the population, provides child immunisation and preventive health alongside government services. Despite this, less than half of eligible children complete a Healthy Kids Check (HKC), a preschool preventative health assessment available since 2008. Using a rigorous theoretical process, the barriers that affected delivery and reduced general practitioner and practice nurse motivation to provide HKCs, were addressed. The resulting multifaceted intervention, aimed at increasing the proportion of children receiving evidence informed HKCs from general practice, was piloted to inform a future randomised controlled trial. METHODS: The intervention was piloted in a before and after study at three sites located southeast of Melbourne, between February and October 2014. The HKC-intervention involved: 1) Delivery of training modules that motivated reception and clinical staff by delivering key messages about local prevalence rates and the "Core Story of Child Development" 2) Practical advice to prepare clinics for specific HKC-examinations 3) Workflow advice regarding systems that included all staff in the HKC process, and 4) Provision of a "Community Resources Folder" that enabled decision making and referrals. A major component of the intervention incorporated the promotion of structured developmental screening by the practice team using Parents' Evaluation of Developmental Status. RESULTS: Twenty of 22 practitioners and practice managers agreed to join the study. Post-training questionnaires showed participants had developed their skills working with young children as a result of the training and all respondents believed they had successfully implemented standardised HKC services. Post intervention proportions of children completing HKCs significantly increased in two of the practices and quality improvements in HKC-processes were recorded across all three sites. CONCLUSION: This pilot study confirmed the feasibility of delivering a multi-faceted intervention to increase HKCs from general practice and demonstrated that significant quality improvements could be made. Future studies need to extend the intervention to other states and research the health outcomes of HKCs. PMID- 26242988 TI - The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome. AB - The RASopathies, which include Noonan syndrome (NS) and Cardiofaciocutaneous syndrome (CFC), are autosomal dominant disorders with genetic heterogeneity associated with germline mutations of genes in the Ras/mitogen-activated protein kinase (MAPK; RAS-MAP kinase) pathway. The conditions overlap and are characterised by facial dysmorphism, short stature and congenital heart disease. NS and CFC, in particular, are known to be associated with lymphatic problems, but this has not been well characterised to date. We describe 11 patients with Noonan or CFC syndrome with significant, persistent and progressive lymphatic dysplasia. The lymphatic disorders in Noonan and CFC syndrome are rare, but have a characteristic pattern with bilateral lower limb lymphoedema, genital swelling with chylous reflux and frequent systemic involvement, including intestinal lymphangiectasia and chylothoraces, which may be progressive. Lymphoscintigraphy demonstrates reflux and/or rerouting of lymphatic drainage associated with incompetent veins on the venous duplex scans. PMID- 26242987 TI - Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence. AB - INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies. RESULTS: In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations. CONCLUSION: There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways. PMID- 26242989 TI - Clinical utility gene card for: DPAGT1 defective congenital disorder of glycosylation. PMID- 26242990 TI - No significant impact of IFN-gamma pathway gene variants on tuberculosis susceptibility in a West African population. AB - The concept of interferon-gamma (IFN-gamma) having a central role in cell mediated immune defence to Mycobacterium tuberculosis has long been proposed. Observations made through early candidate gene studies of constituents of the IFN gamma pathway have identified moderately associated variants associated with resistance or susceptibility to tuberculosis (TB). By analysing 20 major genes whose proteins contribute to IFN-gamma signalling we have assessed a large fraction of the variability in genes that might contribute to susceptibility to TB. Genetic variants were identified by sequencing the promoter regions and all exons of IFNG, IFNGR1, IFNGR2, IRF1, IL12A, IL12B, IL12RB1, IL12RB2, IL23A, IL23R, IL27, EBI3, IL27RA, IL6ST, SOCS1, STAT1, STAT4, JAK2, TYK2 and TBX21 in 69 DNA samples from Ghana. In addition, we screened all exons of IFNGR1 in a Ghanaian study group comprising 1999 TB cases and 2589 controls by high resolution melting point analysis. The fine-mapping approach allows for a detailed screening of all variants, common and rare. Statistical comparisons of cases and controls, however, did not yield significant results after correction for multiple testing with any of the 246 variants selected for genotyping in this investigation. Gene-wise haplotype tests and analysis of rare variants did not reveal any significant association with susceptibility to TB in our investigation as well. Although this analysis was applied on a plausible set of IFN-gamma pathway genes in the largest African TB cohort available so far, the lack of significant results challenges the view that genetic marker of the IFN-gamma pathway have an important impact on susceptibility to TB. PMID- 26242991 TI - Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. AB - Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes. PMID- 26242992 TI - Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry. AB - X-linked congenital cerebellar ataxia is a heterogeneous nonprogressive neurodevelopmental disorder with onset in early childhood. We searched for a genetic cause of this condition, previously reported in a Buryat pedigree of Mongolian ancestry from southeastern Russia. Using whole-genome sequencing on Illumina HiSeq 2000 platform, we found a missense mutation in the ABCB7 (ABC binding cassette transporter B7) gene, encoding a mitochondrial transporter, involved in heme synthesis and previously associated with sideroblastic anemia and ataxia. The mutation resulting in a substitution of a highly conserved glycine to serine in position 682 is apparently a major causative factor of the cerebellar hypoplasia/atrophy found in affected individuals of a Buryat family who had no evidence of sideroblastic anemia. Moreover, in these affected men we also found the genetic defects in two other genes closely linked to ABCB7 on chromosome X: a deletion of a genomic region harboring the second exon of copper transporter gene (ATP7A) and a complete deletion of PGAM4 (phosphoglycerate mutase family member 4) retrogene located in the intronic region of the ATP7A gene. Despite the deletion, eliminating the first of six metal-binding domains in ATP7A, no signs for Menkes disease or occipital horn syndrome associated with ATP7A mutations were found in male carriers. The role of the PGAM4 gene has been previously implicated in human reproduction, but our data indicate that its complete loss does not disrupt male fertility. Our finding links cerebellar pathology to the genetic defect in ABCB7 and ATP7A structural variant inherited as X-linked trait, and further reveals the genetic heterogeneity of X-linked cerebellar disorders. PMID- 26242993 TI - Indirect Effects of the Fast Track Intervention on Conduct Disorder Symptoms and Callous-Unemotional Traits: Distinct Pathways Involving Discipline and Warmth. AB - Little is known about intervening processes that explain how prevention programs improve particular youth antisocial outcomes. We examined whether parental harsh discipline and warmth in childhood differentially account for Fast Track intervention effects on conduct disorder (CD) symptoms and callous-unemotional (CU) traits in early adolescence. Participants included 891 high-risk kindergarteners (69% male; 51% African American) from urban and rural United States communities who were randomized into either the Fast Track intervention (n = 445) or non-intervention control (n = 446) groups. The 10-year intervention included parent management training and other services (e.g., social skills training, universal classroom curriculum) targeting various risk factors for the development of conduct problems. Harsh discipline (Grades 1 to 3) and warmth (Grades 1 and 2) were measured using parent responses to vignettes and direct observations of parent-child interaction, respectively. Parents reported on children's CD symptoms in Grade 6 and CU traits in Grade 7. Results demonstrated indirect effects of the Fast Track intervention on reducing risk for youth antisocial outcomes. That is, Fast Track was associated with lower scores on harsh discipline, which in turn predicted decreased levels of CD symptoms. In addition, Fast Track was associated with higher scores on warmth, which in turn predicted reduced levels of CU traits. Our findings inform developmental and intervention models of youth antisocial behavior by providing evidence for the differential role of harsh discipline and warmth in accounting for indirect effects of Fast Track on CD symptoms versus CU traits, respectively. PMID- 26242995 TI - Minority Participation and Well-Being in Majority Catholic Nations: What Does it Mean to be a Religious Minority? AB - This paper examines the effect of religious majority size on religious minority well-being. Religious minorities face a number of challenges ranging from deliberate discrimination to inadequate worship space and accommodations. Yet for many of the members of religious minority groups, religion remains an important part of community organizing and individual well-being. Given this paradox, it is important to consider the ways that minority status is experienced in different contexts and by different groups. Using data on non-Catholics in majority Catholic nations, this paper demonstrates that the personal benefits of participation in a minority religion are dependent on the size of the Catholic majority. Although religious minorities generally experience health and wellness gains via their engagement with religious communities, the non-Catholic residents of some Catholic nations score higher on self-reports of mental and physical health when they are not actively engaged with their religious tradition. Explanations for this conditional relationship are considered in the discussion of the results. PMID- 26242994 TI - Role of the culture medium in porin expression and piperacillin-tazobactam susceptibility in Escherichia coli. AB - The continuing emergence of the multidrug resistance phenotype in Gram-negative bacteria makes the development of rapid susceptibility tests mandatory. To achieve this goal, proprietary specific media for bacterial growth can be used but may have some adverse effects. In this study, we dissected the role of media on porin, efflux pump and beta-lactamase expression. Depending on the medium used, we observed a change in piperacillin-tazobactam susceptibility for some isolates, such as increases in MIC values. No significant alteration in efflux activity or in beta-lactamase production was detected after changing the incubation medium. The ratio of piperacillinase:nitrocefinase showed no specific alteration, indicating that the various media did not affect significantly the relative enzymic affinity for the substrates. In contrast, osmotic variation was able to modulate both porin expression and OmpC : OmpF balance, thus modulating the antibiotic uptake. This study suggests that porin expression may be impacted by a susceptibility testing medium, which may modify the antibiotic diffusion into the bacteria, thus affecting MIC results. PMID- 26242996 TI - Everyday places, heterosexist spaces and risk in contemporary Sweden. AB - Subjective feelings of risk are a central feature of everyday life, and evidence shows that people who do not conform to contemporary normative notions are often more exposed to everyday risks than others. Despite this, normative notions are rarely acknowledged as risk objects. By drawing on the theory of 'doing' and 'undoing' risk, which combines intersectional and risk theory, this study contributes new perspectives on the everyday risks in contemporary society that face people who many would label as being 'at risk' - lesbian, gay, bisexual and transgender people. The study consists of five focus group interviews with lesbian, gay, bisexual and transgender people of different ages in Sweden. Findings pinpoint risks and how these are done and un-done in different spheres of interviewees' lives: the emotional risks prevailing in their private lives; the risk of discrimination at work and in relations with other institutions; and the risk of violence and harassment in public places. These risks are all related to the heteronormative order in which the mere fact of being lesbian, gay, bisexual and transgender is perceived as a risk. PMID- 26242997 TI - Erratum to: Genetic Population Structure of Thunnus albacares in the Central Pacific Ocean Based on mtDNA COI Gene Sequences. PMID- 26242999 TI - Nanoengineering: Super symmetry in cell division. PMID- 26243001 TI - Correction. PMID- 26243000 TI - Biological machines: Molecular motor teamwork. PMID- 26243002 TI - Correction. PMID- 26243003 TI - Self-assembly gets physical. PMID- 26243004 TI - High-rate aluminium yolk-shell nanoparticle anode for Li-ion battery with long cycle life and ultrahigh capacity. AB - Alloy-type anodes such as silicon and tin are gaining popularity in rechargeable Li-ion batteries, but their rate/cycling capabilities should be improved. Here by making yolk-shell nanocomposite of aluminium core (30 nm in diameter) and TiO2 shell (~3 nm in thickness), with a tunable interspace, we achieve 10 C charge/discharge rate with reversible capacity exceeding 650 mAh g(-1) after 500 cycles, with a 3 mg cm(-2) loading. At 1 C, the capacity is approximately 1,200 mAh g(-1) after 500 cycles. Our one-pot synthesis route is simple and industrially scalable. This result may reverse the lagging status of aluminium among high-theoretical-capacity anodes. PMID- 26243005 TI - Evolution of a UK endoscopic anterior skull base pituitary service - the first one hundred and twenty-three patients: Our Experience. PMID- 26243006 TI - Cholinesterase Research Outreach Project (CROP): measuring cholinesterase activity and pesticide use in an agricultural community. AB - BACKGROUND: Australian farmers and their workers are exposed to a wide variety of pesticides. Organophosphate (OP) insecticides are a widely used class of pesticide used for animal husbandry practices (Naphthalophos for sheep dipping, jetting and drench), crop production for pest control (Dimethoate) and in public health (Maldison for head lice). Acute poisonings with this class of insecticide are reported among agricultural workers and children around the globe, due to the inhibition of acetylcholinesterase (AChE). Less is known about chronic exposures. Regular monitoring of erythrocyte AChE will enable farmers to identify potential exposure to organophosphate insecticides and take action to reduce exposures and improve their health and safety practices. This study aims to assess and improve the integration of AChE monitoring into routine point of care health clinics, and provide farming and non-farming people with a link between their AChE activity and their household chemical and agrichemical use. METHODS/DESIGN: The research will target individuals who work on mixed farming enterprises and routinely using OPs (n = 50) and non-farmers (n = 30). Baseline data are collected regarding demographic, health conditions and behaviours, Kessler 10 (K10) scores, chemical use and personal protection. Baseline anthropometric measures include height, weight, hip and waist circumference, body fat analysis and, biochemical analysis of fasted total serum cholesterol, triglycerides, low-density cholesterol (LDL), high-density cholesterol (HDL) and blood glucose. Analysis of erythrocyte cholinesterase (EAChE) activity is also conducted using a finger prick test. Testing of EAChE is then repeated in all participants every 3 weeks for a maximum of three times over a period 10 weeks. Participants are provided with full feedback and counselling about their EAChE activity after each reading and a detailed summary provided to all participants at the completion of the study. Data will be analysed using repeated measures within a general linear model. DISCUSSION: This work will provide an evidence base and recommendations for the integration of EAChE monitoring into Australian rural health clinics, leading to research which will further quantify pesticide exposure both on the farm and in the home, highlighting the importance of sustaining and providing a safe work and home environment for farming communities. TRIAL REGISTRATION: ACTRN12613001256763. PMID- 26243008 TI - Management of post-operative pain after craniotomy. PMID- 26243007 TI - Structure mediation in substrate binding and post-translational processing of penicillin acylases: Information from mutant structures of Kluyvera citrophila penicillin G acylase. AB - Penicillin acylases are industrially important enzymes for the production of 6 APA, which is used extensively in the synthesis of secondary antibiotics. The enzyme translates into an inactive single chain precursor that subsequently gets processed by the removal of a spacer peptide connecting the chains of the mature active heterodimer. We have cloned the penicillin G acylase from Kluyvera citrophila (KcPGA) and prepared two mutants by site-directed mutagenesis. Replacement of N-terminal serine of the beta-subunit with cysteine (Serbeta1Cys) resulted in a fully processed but inactive enzyme. The second mutant in which this serine is replaced by glycine (Serbeta1Gly) remained in the unprocessed and inactive form. The crystals of both mutants belonged to space group P1 with four molecules in the asymmetric unit. The three-dimensional structures of these mutants were refined at resolutions 2.8 and 2.5 A, respectively. Comparison of these structures with similar structures of Escherichia coli PGA (EcPGA) revealed various conformational changes that lead to autocatalytic processing and consequent removal of the spacer peptide. The large displacements of residues such as Arg168 and Arg477 toward the N-terminal cleavage site of the spacer peptide or the conformational changes of Arg145 and Phe146 near the active site in these structures suggested probable steps in the processing dynamics. A comparison between the structures of the processed Serbeta1Cys mutant and that of the processed form of EcPGA showed conformational differences in residues Argalpha145, Phealpha146, and Phebeta24 at the substrate binding pocket. Three conformational transitions of Argalpha145 and Phealpha146 residues were seen when processed and unprocessed forms of KcPGA were compared with the substrate bound structure of EcPGA. Structure mediation in activity difference between KcPGA and EcPGA toward acyl homoserine lactone (AHL) is elucidated. PMID- 26243009 TI - One-pot synthesis of GABA amides via the nucleophilic addition of amines to 3,3 disubstituted cyclopropenes. AB - A one-pot synthesis of various GABA amides has been demostrated, employing the nucleophilic addition of primary and secondary amines across the double bond of cyclopropene-3-carboxamides, followed by ring-opening of the resulting donor acceptor cyclopropanes and subsequent in situ reduction of enamine (imine) intermediates. PMID- 26243010 TI - Capsule Commentary on Weng et al., Assessing the Quality of Osteoporosis Care in Practice. PMID- 26243011 TI - Geometrical aspects of patient-specific modelling of the intervertebral disc: collagen fibre orientation and residual stress distribution. AB - Patient-specific modelling of the spine is a powerful tool to explore the prevention and the treatment of injuries and pathologies. Albeit several methods have been proposed for the discretization of the bony structures, the efficient representation of the intervertebral disc anisotropy remains a challenge, especially with complex geometries. Furthermore, the swelling of the disc's nucleus pulposus is normally added to the model after geometry definition, at the cost of changes of the material properties and an unrealistic description of the prestressed state. The aim of this study was to develop techniques, which preserve the patient-specific geometry of the disc and allow the representation of the system anisotropy and residual stresses, independent of the system discretization. Depending on the modelling features, the developed approaches resulted in a response of patient-specific models that was in good agreement with the physiological response observed in corresponding experiments. The proposed methods represent a first step towards the development of patient-specific models of the disc which respect both the geometry and the mechanical properties of the specific disc. PMID- 26243012 TI - ETV1 mRNA is specifically expressed in gastrointestinal stromal tumors. AB - Gastrointestinal stromal tumors (GISTs) develop from interstitial cells of Cajal (ICCs) mainly by activating mutations in the KIT or PDGFRA genes. Immunohistochemical analysis for KIT, DOG1, and PKC-theta is used for the diagnosis of GIST. Recently, ETV1 has been shown to be a lineage survival factor for ICCs and required for tumorigenesis of GIST. We investigated the diagnostic value of ETV1expression in GIST. On fresh-frozen tissue samples, RT-PCR analysis showed that ETV1 as well as KIT, DOG1, and PKC-theta are highly expressed in GISTs. On tissue microarrays containing 407 GISTs and 120 non-GIST mesenchymal tumors of GI tract, we performed RNA in situ hybridization (ISH) for ETV1 together with immunohistochemical analysis for KIT, DOG1, PKC-theta, CD133, and CD44. Overall, 387 (95 %) of GISTs were positive for ETV1, while KIT and DOG1 were positive in 381 (94 %) and 392 (96 %) cases, respectively, showing nearly identical overall sensitivity of ETV1, KIT, and DOG1 for GISTs. In addition, ETV1 expression was positively correlated with that of KIT. Notably, ETV1 was positive in 15 of 26 (58 %) KIT-negative GISTs and even positive in 2 cases of GIST negative for KIT and DOG1, whereas only 6 (5 %) non-GIST mesenchymal GI tumors expressed ETV1. We conclude that ETV1 is specifically expressed in the majority of GISTs, even in some KIT-negative cases, suggesting that ETV1 may be useful as ancillary marker in diagnostically difficult select cases of GIST. PMID- 26243013 TI - The Influence of the Chain Length of Polycations on their Complexation with Anionic Liposomes. AB - A series of strong polycations is synthesized through the anionic polymerization of 2-vinylpyridine, followed by subsequent quaternization of the resulting polymer. Polycations based on quaternized 2-vinylpyridine (PVPQs) with degrees of polymerization (DP) from 20 to 440 are adsorbed on the surface of small anionic liposomes. Liposome/PVPQ complexes are characterized by using a number of physicochemical methods. All PVPQs are totally adsorbed onto the liposome surface up to a certain concentration at which saturation is reached (which is specific for each PVPQ). The integrity of the adsorbed liposomes remains intact. Short PVPQs interact with anionic lipids localized on the outer membrane leaflet, whereas long PVPQs extract anionic lipids from the inner to outer leaflet. Complexes tend to aggregate, and the largest aggregates are formed when the initial charge of the liposomes is fully neutralized by the charge of the PVPQ. PVPQs with intermediate DPs demonstrate behavioral features of both short and long PVPQs. These results are important for the interpretation of the biological effects of cationic polymers and the selection of cationic polymers for biomedical applications. PMID- 26243015 TI - Systematic Review on Concussion Recovery Time Lacks Comprehensiveness. PMID- 26243014 TI - Effectiveness of High-Intensity Interval Training (HIT) and Continuous Endurance Training for VO2max Improvements: A Systematic Review and Meta-Analysis of Controlled Trials. AB - BACKGROUND: Enhancing cardiovascular fitness can lead to substantial health benefits. High-intensity interval training (HIT) is an efficient way to develop cardiovascular fitness, yet comparisons between this type of training and traditional endurance training are equivocal. OBJECTIVE: Our objective was to meta-analyse the effects of endurance training and HIT on the maximal oxygen consumption (VO2max) of healthy, young to middle-aged adults. METHODS: Six electronic databases were searched (MEDLINE, PubMed, SPORTDiscus, Web of Science, CINAHL and Google Scholar) for original research articles. A search was conducted and search terms included 'high intensity', 'HIT', 'sprint interval training', 'endurance training', 'peak oxygen uptake', and 'VO2max'. Inclusion criteria were controlled trials, healthy adults aged 18-45 years, training duration >=2 weeks, VO2max assessed pre- and post-training. Twenty-eight studies met the inclusion criteria and were included in the meta-analysis. This resulted in 723 participants with a mean +/- standard deviation (SD) age and initial fitness of 25.1 +/- 5 years and 40.8 +/- 7.9 mL.kg(-1).min(-1), respectively. We made probabilistic magnitude-based inferences for meta-analysed effects based on standardised thresholds for small, moderate and large changes (0.2, 0.6 and 1.2, respectively) derived from between-subject SDs for baseline VO2max. RESULTS: The meta-analysed effect of endurance training on VO2max was a possibly large beneficial effect (4.9 mL.kg(-1).min(-1); 95 % confidence limits +/-1.4 mL.kg( 1).min(-1)), when compared with no-exercise controls. A possibly moderate additional increase was observed for typically younger subjects (2.4 mL.kg( 1).min(-1); +/-2.1 mL.kg(-1).min(-1)) and interventions of longer duration (2.2 mL.kg(-1).min(-1); +/-3.0 mL.kg(-1).min(-1)), and a small additional improvement for subjects with lower baseline fitness (1.4 mL.kg(-1).min(-1); +/-2.0 mL.kg( 1).min(-1)). When compared with no-exercise controls, there was likely a large beneficial effect of HIT (5.5 mL.kg(-1).min(-1); +/-1.2 mL.kg(-1).min(-1)), with a likely moderate greater additional increase for subjects with lower baseline fitness (3.2 mL.kg(-1).min(-1); +/-1.9 mL.kg(-1).min(-1)) and interventions of longer duration (3.0 mL.kg(-1).min(-1); +/-1.9 mL.kg(-1).min(-1)), and a small lesser effect for typically longer HIT repetitions (-1.8 mL.kg(-1).min(-1); +/ 2.7 mL.kg(-1).min(-1)). The modifying effects of age (0.8 mL.kg(-1).min(-1); +/ 2.1 mL.kg(-1).min(-1)) and work/rest ratio (0.5 mL.kg(-1).min(-1); +/-1.6 mL.kg( 1).min(-1)) were unclear. When compared with endurance training, there was a possibly small beneficial effect for HIT (1.2 mL.kg(-1).min(-1); +/-0.9 mL.kg( 1).min(-1)) with small additional improvements for typically longer HIT repetitions (2.2 mL.kg(-1).min(-1); +/-2.1 mL.kg(-1).min(-1)), older subjects (1.8 mL.kg(-1).min(-1); +/-1.7 mL.kg(-1).min(-1)), interventions of longer duration (1.7 mL.kg(-1).min(-1); +/-1.7 mL.kg(-1).min(-1)), greater work/rest ratio (1.6 mL.kg(-1).min(-1); +/-1.5 mL.kg(-1).min(-1)) and lower baseline fitness (0.8 mL.kg(-1).min(-1); +/-1.3 mL.kg(-1).min(-1)). CONCLUSION: Endurance training and HIT both elicit large improvements in the VO2max of healthy, young to middle-aged adults, with the gains in VO2max being greater following HIT when compared with endurance training. PMID- 26243017 TI - NAM: association studies in multiple populations. AB - MOTIVATION: Mixed linear models provide important techniques for performing genome-wide association studies. However, current models have pitfalls associated with their strong assumptions. Here, we propose a new implementation designed to overcome some of these pitfalls using an empirical Bayes algorithm. RESULTS: Here we introduce NAM, an R package that allows user to take into account prior information regarding population stratification to relax the linkage phase assumption of current methods. It allows markers to be treated as a random effect to increase the resolution, and uses a sliding-window strategy to increase power and avoid double fitting markers into the model. AVAILABILITY AND IMPLEMENTATION: NAM is an R package available in the CRAN repository. It can be installed in R by typing install.packages ('NAM'). CONTACT: krainey@purdue.edu. SUPPLEMENTARY INFORMATION: Supplementary date are available at Bioinformatics online. PMID- 26243018 TI - Correcting systematic bias and instrument measurement drift with mzRefinery. AB - MOTIVATION: Systematic bias in mass measurement adversely affects data quality and negates the advantages of high precision instruments. RESULTS: We introduce the mzRefinery tool for calibration of mass spectrometry data files. Using confident peptide spectrum matches, three different calibration methods are explored and the optimal transform function is chosen. After calibration, systematic bias is removed and the mass measurement errors are centered at 0 ppm. Because it is part of the ProteoWizard package, mzRefinery can read and write a wide variety of file formats. AVAILABILITY AND IMPLEMENTATION: The mzRefinery tool is part of msConvert, available with the ProteoWizard open source package at http://proteowizard.sourceforge.net/ CONTACT: samuel.payne@pnnl.gov. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26243016 TI - A Review of Factors Influencing Athletes' Food Choices. AB - Athletes make food choices on a daily basis that can affect both health and performance. A well planned nutrition strategy that includes the careful timing and selection of appropriate foods and fluids helps to maximize training adaptations and, thus, should be an integral part of the athlete's training programme. Factors that motivate food selection include taste, convenience, nutrition knowledge and beliefs. Food choice is also influenced by physiological, social, psychological and economic factors and varies both within and between individuals and populations. This review highlights the multidimensional nature of food choice and the depth of previous research investigating eating behaviours. Despite numerous studies with general populations, little exploration has been carried out with athletes, yet the energy demands of sport typically require individuals to make more frequent and/or appropriate food choices. While factors that are important to general populations also apply to athletes, it seems likely, given the competitive demands of sport, that performance would be an important factor influencing food choice. It is unclear if athletes place the same degree of importance on these factors or how food choice is influenced by involvement in sport. There is a clear need for further research exploring the food choice motives of athletes, preferably in conjunction with research investigating dietary intake to establish if intent translates into practice. PMID- 26243019 TI - ERC analysis: web-based inference of gene function via evolutionary rate covariation. AB - The recent explosion of comparative genomics data presents an unprecedented opportunity to construct gene networks via the evolutionary rate covariation (ERC) signature. ERC is used to identify genes that experienced similar evolutionary histories, and thereby draws functional associations between them. The ERC Analysis website allows researchers to exploit genome-wide datasets to infer novel genes in any biological function and to explore deep evolutionary connections between distinct pathways and complexes. The website provides five analytical methods, graphical output, statistical support and access to an increasing number of taxonomic groups. AVAILABILITY AND IMPLEMENTATION: Analyses and data at http://csb.pitt.edu/erc_analysis/ CONTACT: nclark@pitt.edu. PMID- 26243020 TI - Antiseptic effect of vicenin-2 and scolymoside from Cyclopia subternata (honeybush) in response to HMGB1 as a late sepsis mediator in vitro and in vivo. AB - Cyclopia subternata is a medicinal plant commonly used in traditional medicine to relieve pain. In this study, we investigated the antiseptic effects and underlying mechanisms of vicenin-2 and scolymoside, which are 2 active compounds from C. subternata that act against high mobility group box 1 (HMGB1)-mediated septic responses in human umbilical vein endothelial cells (HUVECs) and mice. The antiseptic activities of vicenin-2 and scolymoside were determined by measuring permeability, neutrophil adhesion and migration, and activation of proinflammatory proteins in HMGB1-activated HUVECs and mice. According to the results, vicenin-2 and scolymoside effectively inhibited lipopolysaccharide induced release of HMGB1, and suppressed HMGB1-mediated septic responses such as hyperpermeability, the adhesion and migration of leukocytes, and the expression of cell adhesion molecules. In addition, vicenin-2 and scolymoside suppressed the production of tumor necrosis factor-alpha and interleukin 6, and activation of nuclear factor-kappaB and extracellular regulated kinases 1/2 by HMGB1. Collectively, these results indicate that vicenin-2 and scolymoside could be a potential therapeutic agents for the treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway. PMID- 26243021 TI - The role of the peripheral cannabinoid system in the pathogenesis of detrusor overactivity evoked by increased intravesical osmolarity in rats. AB - The cannabinoid receptors CB1 and CB2 are localized in the urinary bladder and play a role in the regulation of its function. We investigated the pathomechanisms through which hyperosmolarity induces detrusor overactivity (DO). We compared urinary bladder activity in response to blockade of CB1 and CB2 receptors using AM281 and AM630, respectively, in normal rats and after hyperosmolar stimulation. Experiments were performed on 44 rats. DO was induced by intravesical instillation of hyperosmolar saline. Surgical procedures and cystometry were performed under urethane anaesthesia. The measurements represent the average of 5 bladder micturition cycles. We analysed basal, threshold, and micturition voiding pressure; intercontraction interval; compliance; functional bladder capacity; motility index; and detrusor overactivity index. The blockage of CB1 and CB2 receptors diminished the severity of hyperosmolar-induced DO. In comparison with naive animals the increased frequency of voiding with no significant effect on intravesical voiding pressure profile was observed as a result of the blockage of CB1 and CB2 receptors. These results demonstrate that hyperosmolar-induced DO is mediated by CB1 and CB2 receptors. Therefore, the cannabinoid pathway could potentially be a target for the treatment of urinary bladder dysfunction. PMID- 26243022 TI - Resveratrol ameliorates cisplatin-induced oxidative injury in New Zealand rabbits. AB - This study investigated the preventive role of resveratrol in cisplatin-induced nephrotoxicity. The study used groups of New Zealand rabbits that were treated as follows: group C (cisplatin treated), group R (resveratrol treated), group R+C (resveratrol + cisplatin treatment), and group E (control group). Kidney levels of glutathione were significantly lower in group C than in groups E and R, whereas glutathione levels in group R+C were found to be similar to the control values. Malondialdehyde levels in group C were significantly higher than in groups E and R. However, malondialdehyde levels in group R+C were similar to group E. Kidney levels of nitric oxide were significantly higher in the cisplatin group than in the control, whereas nitric oxide levels were at basal values in group R+C. Cisplatin treatment significantly reduced kidney levels of glutathione peroxidase, superoxide dismutase, and catalase activity compared with those of group E, whereas resveratrol treatment significantly increased levels of glutathione peroxidase, superoxide dismutase, and catalase activity in group R+C. However, cisplatin injection did not affect mRNA levels of glutathione peroxidase, superoxide dismutase, or catalase enzymes. Histopathological and immunohistochemical analyses indicated that cisplatin caused kidney damage, which was mostly prevented by resveratrol treatment. In conclusion, resveratrol ameliorates cisplatin-induced oxidative injury in the kidney of rabbit. PMID- 26243023 TI - Measuring arbitrary diffusion coefficient distributions of nano-objects by taylor dispersion analysis. AB - Taylor dispersion analysis is an absolute and straightforward characterization method that allows determining the diffusion coefficient, or equivalently the hydrodynamic radius, from angstroms to submicron size range. In this work, we investigated the use of the Constrained Regularized Linear Inversion approach as a new data processing method to extract the probability density functions of the diffusion coefficient (or hydrodynamic radius) from experimental taylorgrams. This new approach can be applied to arbitrary polydisperse samples and gives access to the whole diffusion coefficient distributions, thereby significantly enhancing the potentiality of Taylor dispersion analysis. The method was successfully applied to both simulated and real experimental data for solutions of moderately polydisperse polymers and their binary and ternary mixtures. Distributions of diffusion coefficients obtained by this method were favorably compared with those derived from size exclusion chromatography. The influence of the noise of the simulated taylorgrams on the data processing is discussed. Finally, we discuss the ability of the method to correctly resolve bimodal distributions as a function of the relative separation between the two constituent species. PMID- 26243024 TI - Rising Residency Applications: How High Will It Go? AB - Otolaryngology is viewed as a competitive residency program, and as a result, a high number of applications are submitted by each applicant. A look at the data quantifies the cost and the challenges. PMID- 26243025 TI - Perception of Shame in Otolaryngology-Head and Neck Surgery Training. AB - OBJECTIVE: This survey was developed to assess the prevalence and effects of the perception of shame in otolaryngology-head and neck surgery residency training in the United States. STUDY DESIGN: Survey. SETTING: US otolaryngology training programs. SUBJECTS: Faculty and trainees in US otolaryngology training programs. METHODS: A 14-item survey to assess the prevalence of the experience of shame and the attitudes toward use of shame in otolaryngology residency training was sent to all otolaryngology-head and neck surgery program directors for distribution among their respective faculty and resident cohorts. RESULTS: A total of 267 responses were received (women, 24.7%; men, 75.3%): 42.7% of respondents were trainees; 7.0% of trainees thought that shame was a necessary/effective tool, compared with 11.4% of faculty; 50% of respondents felt that they had been personally shamed during residency; and 69.9% of respondents had witnessed another trainee being shamed during residency training. Trainees were most commonly shamed in the operating room (78.4%). Otolaryngology faculty members did the shaming 95.1% of the time. Although shaming prompted internal reflection/self improvement in 57.4% of trainees, it also caused loss of self-confidence in 52.5%. Trainees who had been shamed were more likely to view shame as an appropriate educational tool (P < .05). CONCLUSION: Half of respondents have felt shamed during their residency training, and a majority has witnessed a colleague being shamed. Understanding the negative impact that shaming behaviors have on the learning environment and on the performance of the individual within it is an important first step in creating an environment maximally conducive to learning, professional development, and patient safety. PMID- 26243026 TI - Isolated Langerhans Cell Histiocytosis Bone Lesion in Pediatric Patients: Systematic Review and Treatment Algorithm. AB - OBJECTIVE: The present study reviewed all cases reported of isolated Langerhans cell histiocytosis bone lesions in the head and neck of pediatric patients. The objective was to create a treatment algorithm to facilitate the diagnosis and management of these lesions. DATA SOURCES: Eligible articles were identified through a comprehensive search of the following electronic databases: PubMed, Ovid Medline, Embase, and Cochrane Library. REVIEW METHODS: Two authors independently reviewed the titles and abstracts retrieved by the electronic search concordant with the criteria for study eligibility. The lists of articles from each author were jointly reviewed and a common list created. All relevant articles were reviewed in hard copies and as full texts to justify inclusion. RESULTS: A total of 201 patients (67% male, mean age: 8.1 +/- 4.3 years) were included from 45 studies. Clinical presentations included swelling (64%), pain (9%), or both (18%). The skull (61%) and the orbit (24%) were the most common location for isolated bone lesions in the head and neck. The most frequently documented management option was resection, followed by observation, chemotherapy, and intralesional steroid injection. CONCLUSIONS: Due to its rarity and variability in presentation and severity, treatment of these lesions has yet to be standardized. Based on the review, a diagnosis and treatment algorithm was created for head and neck surgeons when encountering these types of lesions. PMID- 26243027 TI - Transverse Retropalatal Collapsibility Is Associated with Obstructive Sleep Apnea Severity and Outcome of Relocation Pharyngoplasty. AB - OBJECTIVE: The aim of this study was to investigate whether the retropalatal airway shape and collapsibility defined by awake nasopharyngoscopy with Muller's maneuver were associated with apnea-hypopnea index (AHI), positional dependency, and surgical outcome of relocation pharyngoplasty in patients with obstructive sleep apnea. STUDY DESIGN: Case series with planned data collection. SETTING: Tertiary referral center. SUBJECTS AND METHODS: A total of 45 obstructive sleep apnea patients were included who underwent conservative treatment (n = 13) or relocation pharyngoplasty (n = 32), and their baseline and postoperative polysomnographies and awake nasopharyngoscopies with Muller's maneuver were reviewed. Shape ratio (transverse diameter [TD] / longitudinal diameter [LD]) in the stationary and Muller's phases and collapsibility (ColTD and ColLD) of the airway at the level of the uvular base were measured with a picture archiving and communication system. Intra- and interrater reliabilities were assessed. Associations among nasopharyngoscopic measurements, AHI, positional dependency, and surgical success (defined as a reduction of AHI >=50% and a postoperative AHI <=20/h) were statistically analyzed. RESULTS: Reliability tests indicated substantial agreements of all nasopharyngoscopic measurements between raters and within raters. A higher baseline ColTD was significantly associated with an elevated AHI (r = 0.49, P = .001), whereas a lower postoperative ColTD was significantly related to surgical success (r = -0.38, P = .034). Nasopharyngoscopic findings were not statistically significantly correlated with positional dependency. CONCLUSION: Transverse retropalatal collapsibility measured by awake nasopharyngoscopy with Muller's maneuver helps to predict individuals with moderate to severe sleep apnea and surgical outcome. PMID- 26243028 TI - Ameliorating effects of Inonotus obliquus on high fat diet-induced obese rats. PMID- 26243029 TI - Outcomes in children with advanced heart failure in Japan: importance of mechanical circulatory support. AB - The Japanese organ transplant law was revised in July 2010 in order to enable children aged <15 years to donate organs. However, the waiting time for orthotopic heart transplantation (HTx) is as long as 636 days in children due to a shortage of organ donors. Ventricular assist devices (VADs) have been widely used as a bridge to transplantation in Western countries, whereas experience with VADs is limited in Japan due to a lack of device availability for small children. This study aimed to clarify the clinical profiles and outcomes of children with advanced heart failure in Japan and to investigate the importance of mechanical circulatory support (MCS), VADs, and extracorporeal membrane oxygenation (ECMO) in children. A retrospective chart review of patients with advanced heart failure who were eligible for HTx between January 2006 and May 2015 was performed at the Department of Pediatric Cardiology, Tokyo Woman's Medical University, Japan. Patients were divided into two groups based on need for MCS. Clinical data pre- and post-revision of the Japanese organ transplant law were compared. Preoperative clinical conditions were evaluated based on Interagency Registry for Mechanically Circulatory Support (INTERMACS) profiles. Twenty-two patients were included in the study, 12 of whom required MCS. VADs were implanted in nine patients and ECMO was needed in seven patients. Of the MCS group, 5 deaths occurred in patients with a preoperative INTERMACS profile-1. High total bilirubin was found to be associated with mortality by multivariate logistic regression analysis (OR 7.8, p = 0.02). Wait list mortality was 32 % and no difference in clinical profiles pre- and post-revision of the Japanese organ transplant law was observed. Approximately 55 % of pediatric patients with advanced heart failure required MCS support. Preoperative conditions such as INTERMACS profile-1 and high total bilirubin were associated with poor outcomes. The Japanese organ transplant law revision had no significant influence on patient profiles or outcomes. PMID- 26243030 TI - Complementary mass spectrometric techniques for the quantification of the protein corona: a case study on gold nanoparticles and human serum proteins. AB - Once nanoparticles enter a biological system, it is known that their surface is instantly covered by the biomolecules present with preference to proteins. This protein corona has been a subject of numerous studies in order to reveal its composition. Besides that, growing interest exists in its quantitative determination in order to gain a deeper insight into the nature of these nanoparticle-protein bioconjugates. Only a few analytical methods are available nowadays, so the aim of this study is to provide a reliable and alternative methodology for the quantification of the protein corona. The suggested approach is based on the assumption that the total protein content within the corona can be correlated to its sulfur concentration due to the presence of cysteine and methionine as sulfur-containing amino acids. Once the most abundant proteins had been identified with the use of gel electrophoresis with subsequent peptide analysis by electrospray ionization-tandem mass spectrometry (ESI-MS/MS), the isolated nanoparticle-protein conjugates were subjected to total analysis of sulfur and the corresponding metal being present in the nanoparticles by inductively coupled plasma-mass spectrometry (ICP-MS). The concept is exemplarily demonstrated on citrate-stabilized gold nanoparticles (GNPs) incubated with human serum. Two different purification procedures were tested in order to isolate the sought bioconjugates. 26 most abundant proteins could be identified and an average of approximately 40 S atoms per protein was calculated and used for further studies. ICP-MS analyses of S/Au ratios served for the quantification of the protein corona revealing an absolute number of proteins bound to the incubated GNPs. Two main results could be obtained for this specific system under the chosen experimental conditions: the number of proteins per GNP decreased with their size from 10 nm to 60 nm and the obtained values suggested that the protein corona in this specific case was theoretically formed either as a monolayer (60 nm GNPs) or as a multilayer (5-7 protein layers per 10 nm GNP). Studies with bovine serum albumin (BSA) as the model protein showed similar results. PMID- 26243032 TI - Referral bias in female functional hyperandrogenism and polycystic ovary syndrome. AB - OBJECTIVE: Women with polycystic ovary syndrome (PCOS) seeking health care in the United States may be more obese and hyperandrogenic than those present in the general population. We aimed to assess the impact of referral bias on European women with functional androgen excess disorders. DESIGN: Cross-sectional study. METHODS: We studied two groups of patients: i) 368 consecutive patients referred to our clinic for the study of functional hyperandrogenism (FH) (referral patients); ii) 57 consecutive premenopausal patients identified by screening during blood donation (unselected patients). We compared the anthropometric data from the groups of patients with those of two control populations: iii) a group of unselected premenopausal healthy female blood donors (unselected controls); and iv) data available from the local general premenopausal female population. RESULTS: Referral patients with FH were more hirsute, had a higher percentage of hyperandrogenemia, and fulfilled PCOS criteria more frequently than unselected patients. The prevalence of obesity in unselected controls was similar to that observed in the general population, whereas referral patients and unselected patients were more frequently obese. The prevalence of obesity was also higher among referral patients compared to unselected patients. CONCLUSION: Referral bias influences the phenotype of patients with FH. Patients studied at the clinical setting may show more severe hyperandrogenic and obese phenotypes than patients from the general population, even though PCOS appears to be associated with weight excess also in the general European population. This fact should be considered when establishing reference values and control populations for clinical and research purposes. PMID- 26243033 TI - Pegvisomant in combination with long-acting somatostatin analogues in acromegaly: the role of the GH receptor deletion of exon 3. AB - BACKGROUND: Doses of the GH receptor (GHR) antagonist pegvisomant (PEGV) that normalize insulin-like growth factor 1 (IGF1) levels vary widely among acromegaly patients. Predictors for PEGV response are baseline IGF1 levels, sex, body weight and previous radiotherapy. A GHR polymorphism lacking exon 3 (d3-GHR) is frequent in the general population. The influence of d3-GHR on PEGV responsiveness in acromegaly is unclear. OBJECTIVE: To assess the influence of d3-GHR on IGF1 levels and PEGV responsiveness in acromegaly patients using combined PEGV and long-acting somatostatin receptor ligand (LA-SRIF) treatment. DESIGN: Data were collected at the Rotterdam Pituitary Centre between 2004 and 2013. Patients with elevated IGF1 levels (>1.2 upper limit of normal; n=112) and over 6 months of high-dose LA-SRIF treatment were co-treated with PEGV. GHR genotype was assessed using genomic DNA in 104 patients. RESULTS: D3-GHR was observed in 51 (49.0%) of the patients (7.7% homozygous, 41.3% heterozygous) and was in Hardy-Weinberg equilibrium (P=0.859). Baseline characteristics were similar in d3-GHR and full length (fl)-GHR genotypes. During PEGV/LA-SRIF treatment IGF1 levels were not different between d3-carriers and non-carriers. Similarly, no difference in PEGV dose required to normalize IGF1 (P=0.337) or PEGV serum levels (P=0.433) was observed between the two groups. However, adenoma size decreased significantly (>20% of largest diameter) in 25.6% of the fl-GHR genotype but only in 7.5% of d3 carriers (P=0.034, OR: 4.6 (CI: 1.1-18.9)). CONCLUSIONS: GHR genotype does not predict the IGF1 normalizing dose of PEGV in acromegaly patients using combination PEGV/LA-SRIF treatment. However, fewer d3-carriers showed significant reductions in adenoma size. PMID- 26243034 TI - Dissipative Continuous Spontaneous Localization (CSL) model. AB - Collapse models explain the absence of quantum superpositions at the macroscopic scale, while giving practically the same predictions as quantum mechanics for microscopic systems. The Continuous Spontaneous Localization (CSL) model is the most refined and studied among collapse models. A well-known problem of this model, and of similar ones, is the steady and unlimited increase of the energy induced by the collapse noise. Here we present the dissipative version of the CSL model, which guarantees a finite energy during the entire system's evolution, thus making a crucial step toward a realistic energy-conserving collapse model. This is achieved by introducing a non-linear stochastic modification of the Schrodinger equation, which represents the action of a dissipative finite temperature collapse noise. The possibility to introduce dissipation within collapse models in a consistent way will have relevant impact on the experimental investigations of the CSL model, and therefore also on the testability of the quantum superposition principle. PMID- 26243035 TI - Microbubble embedded with upconversion nanoparticles as a bimodal contrast agent for fluorescence and ultrasound imaging. AB - Bimodal imaging offers additional imaging signal thus finds wide spread application in clinical diagnostic imaging. Fluorescence/ultrasound bimodal imaging contrast agent using fluorescent dyes or quantum dots for fluorescence signal has emerged as a promising method, which however requires visible light or UV irradiation resulting in photobleaching, photo blinking,auto-fluorescence and limited tissue penetration depth. To surmount these problems, we developed a novel bimodal contrast agent using layer-by-layer assembly of up conversion nanoparticles onto the surface of microbubbles. The resulting microbubbles with average size of 2 MUm provide enhanced ultrasound echo for ultrasound imaging and upconversion emission upon near infrared irradiation for fluorescence imaging. The developed bimodal contrast agent holds great potential to be applied in ultrasound target technique for targeted diseases diagnostics and therapy. PMID- 26243037 TI - Authenticity of rice (Oryza sativa L.) geographical origin based on analysis of C, N, O and S stable isotope ratios: a preliminary case report in Korea, China and Philippine. AB - BACKGROUND: Although rice (Oryza sativa L.) is the third largest food crop, relatively fewer studies have been reported on rice geographical origin based on light element isotope ratios in comparison with other foods such as wine, beef, juice, oil and milk. Therefore this study tries to discriminate the geographical origin of the same rice cultivars grown in different Asian countries using the analysis of C, N, O and S stable isotope ratios and chemometrics. RESULTS: The delta(15) NAIR , delta(18) OVSMOW and delta(34) SVCDT values of brown rice were more markedly influenced by geographical origin than was the delta(13) CVPDB value. In particular, the combination of delta(18) OVSMOW and delta(34) SVCDT more efficiently discriminated rice geographical origin than did the remaining combinations. Principal component analysis (PCA) revealed a clear discrimination between different rice geographical origins but not between rice genotypes. In particular, the first components of PCA discriminated rice cultivated in the Philippines from rice cultivated in China and Korea. CONCLUSION: The present findings suggest that analysis of the light element isotope composition combined with chemometrics can be potentially applicable to discriminate rice geographical origin and also may provide a valuable insight into the control of improper or fraudulent labeling regarding the geographical origin of rice worldwide. (c) 2015 Society of Chemical Industry. PMID- 26243038 TI - DFT studies of the bonding mechanism of 8-hydroxyquinoline and derivatives on the (111) aluminum surface. AB - The 8-hydroxyquinoline (8-HQ) molecule is an efficient corrosion inhibitor for aluminum and is also used in organic electronic devices. In this paper, the adsorption modes of 8-HQ and its derivatives (tautomer, dehydrogenated and hydrogenated species) on the Al(111) surface are characterized using dispersion corrected density functional theory calculations. The 8-HQ molecule is physisorbed and is chemisorbed on the aluminum surface with similar adsorption energy (-0.86 eV to -1.11 eV) and these adsorption modes are stabilized by vdW interactions. The binding of the dehydrogenated species is the strongest one (adsorption energy of -3.27 eV to -3.45 eV), followed by the tautomer molecule ( 2.16 eV to -2.39 eV) and the hydrogenated molecule (-1.71 eV) that bind weaker. In all the chemisorbed configurations there is a strong electronic transfer from the Al substrate to the adsorbate (0.72 e to 2.16 e). The adsorbate is strongly distorted and its deformation energy is high (0.55 eV to 2.77 eV). The analysis of the projected density of states onto the orbitals of the molecule and the electronic density variation upon adsorption (Deltarho) between the molecule and the surface account for covalent bonding. PMID- 26243039 TI - Regional gray matter volume mediates the relationship between family socioeconomic status and depression-related trait in a young healthy sample. AB - Socioeconomic status (SES) is a complex phenomenon that is predicted by a broad spectrum of variables and is often conceptualized as a combination of financial, occupational, and educational influences. SES is associated with symptoms of depression and depression-related personality traits. Many studies have focused on the relationship between SES and depression symptoms in clinical subjects; however, there are few studies of the neural basis of the relationship between SES and depression-related personality traits in nonclinical subjects. Thus, in the present study, we studied the neural basis of the relationship between SES and depression-related traits. The first step was to use voxel-based morphometry (VBM) to investigate the neuroanatomical basis underlying family SES in a large sample of healthy subjects. We found a significant negative correlation between family SES and the medial prefrontal cortex (mPFC) that extending to the anterior cingulate cortex (ACC). Then, the mediation analysis revealed that the correlation between family SES, especially family income, and depression-related traits were mediated by the region of the mPFC that extending to the ACC volume. These findings suggest that the family income may play more important role in driving depression-related traits than that of parental education. They also suggest that the mPFC extension to the ACC may play an important role in the correlation between familial SES, especially with respect to family income and the depression-related traits. PMID- 26243040 TI - Pre-eclampsia and first-onset postpartum psychiatric episodes: a Danish population-based cohort study. AB - BACKGROUND: Recent evidence suggests that postpartum psychiatric episodes may share similar etiological mechanisms with immune-related disorders. Pre-eclampsia is one of the most prevalent immune-related disorders of pregnancy. Multiple clinical features are shared between pre-eclampsia and postpartum psychiatric disorders, most prominently a strong link to first pregnancies. Therefore, we aimed to study if pre-eclampsia is a risk factor for first-onset postpartum psychiatric episodes. METHOD: We conducted a cohort study using the Danish population registry, with a total of 400 717 primiparous women with a singleton delivery between 1995 and 2011. First-lifetime childbirth was the main exposure variable and the outcome of interest was first-onset postpartum psychiatric episodes. The main outcome measures were monthly incidence rate ratios (IRRs), with the period 11-12 months after birth as the reference category. Adjustments were made for age, calendar period, reproductive history, and perinatal maternal health including somatic and obstetric co-morbidity. RESULTS: Primiparous women were at particularly high risk of first-onset psychiatric episodes during the first month postpartum [IRR 2.93, 95% confidence interval (CI) 2.53-3.40] and pre eclampsia added to that risk (IRR 4.21, 95% CI 2.89-6.13). Having both pre eclampsia and a somatic co-morbidity resulted in the highest risk of psychiatric episodes during the 3-month period after childbirth (IRR 4.81, 95% CI 2.72-8.50). CONCLUSIONS: We confirmed an association between pre-eclampsia and postpartum psychiatric episodes. The possible explanations for this association, which are not mutually exclusive, include the psychological impact of a serious medical condition such as pre-eclampsia and the neurobiological impact of pre-eclampsia related vascular pathology and inflammation. PMID- 26243041 TI - Disease duration and Medsger's severity score are associated with significant liver fibrosis in patients with systemic sclerosis. AB - OBJECTIVES: We investigated the prevalence and predictors of significant liver fibrosis in patients with systemic sclerosis (SSc) who had no evidences of liver diseases due to viral infection, drug, and heavy alcohol consumption. METHODS: A total of 44 SSc patients were recruited. In addition to the clinical and laboratory data, the 2013 College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria score, modified Rodnan skin score (mRSS), and Medsger's severity score (MSS) were analysed. Liver stiffness (LS) was measured using transient elastography to assess the degree of liver fibrosis and 7.4 kPa was adopted as the cut-off value for significant liver fibrosis. RESULTS: The median age of patients (38 women) was 54 years and the median disease duration was 41.0 months. The median LS value was 4.6 kPa. The median mRSS and MSS were 7.0 and 5.0, respectively. Six (13.6%) patients had significant liver fibrosis. Disease duration (standardised beta=0.375, p=0.018) and MSS (standardised beta=0.398, p=0.047) significantly correlated with LS values. In multivariate analysis, disease duration>=63 months (odds ratio (OR) 19.166, 95% confidence interval 1.090, 336.962, p=0.043) and MSS>=7 (OR 19.796, 95% confidence interval 1.439, 272.252, p=0.026) independently predicted the presence of significant liver fibrosis. CONCLUSIONS: The prevalence of significant liver fibrosis was relatively high (13.6%) and its independent predictors were disease duration and MSS. PMID- 26243042 TI - HPLC/Q-TOF-MS-Based Identification of Absorbed Constituents and Their Metabolites in Rat Serum and Urine after Oral Administration of Cistanche deserticola Extract. AB - As a famous health food in China, Cistanche deserticola (C. deserticola) suggested an estrogenic activity according to our previous study. However, no one clarifies its active material basis to date. To find more potentially active constituents and elucidate metabolic pathways of metabolites, a method to simultaneously analyze multiple absorbed constituents and metabolites from C. deserticola in rat serum and urine was established using high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (HPLC/Q-TOF-MS). Based on HPLC/Q-TOF-MS method, a total of 24 components, involving 9 prototype constituents and 15 metabolites in rat serum and urine samples, were tentatively identified based on retention time, ultraviolet spectrum, MS data, compound fragmentation laws, published literatures, and reference substances. Most of the compounds existed in the form of metabolites. The proposed metabolic pathways of main metabolites were discussed, including methylation, demethylation, hydrolysis, hydroxylation, acetoxylation, glucuronidation, dehydrogenation, sulfation, esterification, and so on. Phenylethanoid glycosides were extensively metabolized and mutually transformed in vivo. This investigation provided valuable information for further study of the active ingredients and action mechanism of C. deserticola. PMID- 26243043 TI - Clinicopathological features of breast angiosarcoma. AB - BACKGROUND: Breast angiosarcomas are rare neoplasm. Due to its rarity, our therapeutic strategy is extremely limited. Therefore, we investigated the clinicopathologic features and examined the treatment for angiosarcoma compared with some literatures. METHODS: We conducted a retrospective chart and slide review of all patients in our division seen from 1997 to 2012 with a diagnosis of primary or secondary breast angiosarcoma at the National Cancer Center Hospital (Tokyo, Japan). RESULTS: Nine patients were diagnosed with breast angiosarcoma (six primary and three secondary cases). The median age of patients with primary angiosarcoma was 39 years (range 27-65 years). The median tumor size was 6.78 cm (range 3.0-8.8 cm). In the primary tumor, 4 patients had total mastectomy and 2 had a breast conserving surgery. 3- and 5-year disease-free survival (DFS) of the patients with primary angiosarcoma was 20 and 0 %. 5-year surviving rate of primary angiosarcoma was 50 %. In all patients with secondary angiosarcoma, recurrence was observed in all cases. But one case obtained long-term survival in local control therapy. CONCLUSIONS: Our study demonstrates breast angiosarcoma exhibits high recurrence rates. Tumor size and surgical margin may be important factor to obtain long-term survival. In this point of view, total mastectomy with adequate tumor margin with early detection is desired. In case of recurrence, if it is local, surgery may be potentially curative. PMID- 26243044 TI - Glyphosate-based herbicides reduce the activity and reproduction of earthworms and lead to increased soil nutrient concentrations. AB - Herbicide use is increasing worldwide both in agriculture and private gardens. However, our knowledge of potential side-effects on non-target soil organisms, even on such eminent ones as earthworms, is still very scarce. In a greenhouse experiment, we assessed the impact of the most widely used glyphosate-based herbicide Roundup on two earthworm species with different feeding strategies. We demonstrate, that the surface casting activity of vertically burrowing earthworms (Lumbricus terrestris) almost ceased three weeks after herbicide application, while the activity of soil dwelling earthworms (Aporrectodea caliginosa) was not affected. Reproduction of the soil dwellers was reduced by 56% within three months after herbicide application. Herbicide application led to increased soil concentrations of nitrate by 1592% and phosphate by 127%, pointing to potential risks for nutrient leaching into streams, lakes, or groundwater aquifers. These sizeable herbicide-induced impacts on agroecosystems are particularly worrisome because these herbicides have been globally used for decades. PMID- 26243045 TI - Clinical, anthropometric and laboratory nutritional markers of pancreatic exocrine insufficiency: Prevalence and diagnostic use. AB - Pancreatic exocrine insufficiency (PEI) frequently occurs secondary to exocrine pancreatic disease (e.g. chronic pancreatitis, cystic fibrosis, cancer) or pancreatic/gastrointestinal surgery, resulting in the maldigestion of nutrients and consequently malnutrition. Pancreatic enzyme replacement therapy (PERT) is the cornerstone of PEI management. Despite its clinical relevance, the diagnosis of PEI in clinical practice is challenging, as the current gold standard test is cumbersome, and alternatives have limited availability or accuracy. There is a need for accurate and easily applicable diagnostic modalities. We review the prevalence of clinical symptoms and changes in anthropometric measurements and laboratory nutritional markers indicative of malnutrition in patients with PEI, and the relevance of these findings in diagnosing PEI and monitoring PERT efficacy. Based on limited available evidence, assessment of clinical symptoms, body weight, body mass index and other anthropometric parameters are not sensitive methods for PEI diagnosis, owing to high variability and multiple confounding factors, but appear useful in monitoring PERT efficacy. Limited evidence precludes strong recommendations but suggests that serum levels of vitamin E, magnesium, and plasma proteins, notably retinol binding protein, albumin, and prealbumin, may have diagnostic utility in PEI. Studies show that assessment of changes in these and other nutritional parameters is helpful in monitoring PERT efficacy. Further research is needed to confirm the diagnostic accuracy of these parameters for PEI. Until such data are available, a nutritional evaluation including circulating vitamin E, magnesium, retinol binding protein, albumin, and prealbumin may be used to evaluate the probability of PEI in clinical practice when reliable pancreatic function tests are not available. PMID- 26243046 TI - Systemic embolization with coronary artery obstruction from a left ventricular thrombus. PMID- 26243047 TI - Hybrid graphene nematic liquid crystal light scattering device. AB - A hybrid graphene nematic liquid crystal (LC) light scattering device is presented. This device exploits the inherent poly-crystallinity of chemical vapour deposited (CVD) graphene films to induce directional anchoring and formation of LC multi-domains. This thereby enables efficient light scattering without the need for crossed polarisers or separate alignment layers/additives. The hybrid LC device exhibits switching thresholds at very low electric fields (< 1 V MUm(-1)) and repeatable, hysteresis free characteristics. This exploitation of LC alignment effects on CVD graphene films enables a new generation of highly efficient nematic LC scattering displays as well as many other possible applications. PMID- 26243048 TI - Targeted percutaneous microwave ablation at the pulmonary lesion combined with mediastinal radiotherapy with or without concurrent chemotherapy in locally advanced non-small cell lung cancer evaluation in a randomized comparison study. AB - Concurrent chemoradiotherapy is the standard treatment for patients with locally advanced lung cancer. The most common dose-limiting adverse effect of thoracic radiotherapy (RT) is radiation pneumonia (RP). A randomized comparison study was designed to investigate targeted percutaneous microwave ablation at pulmonary lesion combined with mediastinal RT with or without chemotherapy (ablation group) in comparison with RT (target volume includes pulmonary tumor and mediastinal node) with or without chemotherapy (RT group) for the treatment of locally advanced non-small cell lung cancers (NSCLCs). From 2009 to 2012, patients with stage IIIA or IIIB NSCLCs who refused to undergo surgery or were not suitable for surgery were enrolled. Patients were randomly assigned to the RT group (n = 47) or ablation group (n = 51). Primary outcomes were the incidence of RP and curative effectiveness (complete response, partial response, and stable disease); secondary outcome was the 2-year overall survival (OS). Fifteen patients (31.9%) in the RT and two (3.9%) in the ablation group experienced RP (P < 0.001). The ratio of effective cases was 85.1 versus 80.4% for mediastinal lymph node (P = 0.843) and 83.0 versus 100% for pulmonary tumors (P = 0.503), respectively, for the RT and ablation groups. Kaplan-Meier analysis demonstrated 2-year OS rate of NSCLC patients in ablation group was higher than RT group, but no statistical difference (log-rank test, P = 0.297). Percutaneous microwave ablation followed by RT for inoperable stage III NSCLCs may result in a lower rate of RP and better local control than radical RT treatments. PMID- 26243049 TI - Long noncoding RNA-LET, which is repressed by EZH2, inhibits cell proliferation and induces apoptosis of nasopharyngeal carcinoma cell. AB - Recent studies have reported that long noncoding RNAs (lncRNAs) play critical roles in carcinogenesis and progression. LncRNA-LET, a recently identified lncRNA, has been shown to be a tumor suppressor in hepatocellular carcinoma. However, the expression and functional of lncRNA-LET in other type of cancers remain largely unknown. In this study, we found that lncRNA-LET was significantly downregulated in nasopharyngeal carcinoma (NPC) tissues compared with corresponding normal tissues. Decreased LET expression is significantly correlated with advanced clinical stage, larger tumor size, increased lymph node tumor burden, and poor survival of NPC patients. Gain- and loss-of-function experiments demonstrated that enhanced LET expression inhibited NPC cells proliferation and induced cell apoptosis. By contrast, the knockdown of LET promoted NPC cells proliferation and inhibited cell apoptosis. Importantly, we found lncRNA-LET is transcriptional repressed by EZH2-mediated H3K27 histone methylation on the LET promoter. The expressions of EZH2 and lncRNA-LET are significantly inversely correlated in NPC tissues. Collectively, these findings indicate a pivotal role for lncRNA-LET in NPC cell proliferation and apoptosis, and reveal an epigenetic mechanism for lncRNA-LET dysregulation. PMID- 26243051 TI - The application of SRF vs. RDF classification and specifications to the material flows of two mechanical-biological treatment plants of Rome: Comparison and implications. AB - This work assessed the quality in terms of solid recovered fuel (SRF) definitions of the dry light flow (until now indicated as refuse derived fuel, RDF), heavy rejects and stabilisation rejects, produced by two mechanical biological treatment plants of Rome (Italy). SRF classification and specifications were evaluated first on the basis of RDF historical characterisation methods and data and then applying the sampling and analytical methods laid down by the recently issued SRF standards. The results showed that the dry light flow presented a worst SRF class in terms of net calorific value applying the new methods compared to that obtained from RDF historical data (4 instead of 3). This lead to incompliance with end of waste criteria established by Italian legislation for SRF use as co-fuel in cement kilns and power plants. Furthermore, the metal contents of the dry light flow obtained applying SRF current methods proved to be considerably higher (although still meeting SRF specifications) compared to those resulting from historical data retrieved with RDF standard methods. These differences were not related to a decrease in the quality of the dry light flow produced in the mechanical-biological treatment plants but rather to the different sampling procedures set by the former RDF and current SRF standards. In particular, the shredding of the sample before quartering established by the latter methods ensures that also the finest waste fractions, characterised by higher moisture and metal contents, are included in the sample to be analysed, therefore affecting the composition and net calorific value of the waste. As for the reject flows, on the basis of their SRF classification and specification parameters, it was found that combined with the dry light flow they may present similar if not the same class codes as the latter alone, thus indicating that these material flows could be also treated in combustion plants instead of landfilled. In conclusion, the introduction of SRF definitions, classification and specification procedures, while not necessarily leading to an upgrade of the waste as co-fuel in cement kilns and power plants, may anyhow provide new possibilities for energy recovery from waste by increasing the types of mechanically treated waste flows that may be thermally treated. PMID- 26243050 TI - A permutation approach for selecting the penalty parameter in penalized model selection. AB - We describe a simple, computationally efficient, permutation-based procedure for selecting the penalty parameter in LASSO-penalized regression. The procedure, permutation selection, is intended for applications where variable selection is the primary focus, and can be applied in a variety of structural settings, including that of generalized linear models. We briefly discuss connections between permutation selection and existing theory for the LASSO. In addition, we present a simulation study and an analysis of real biomedical data sets in which permutation selection is compared with selection based on the following: cross validation (CV), the Bayesian information criterion (BIC), scaled sparse linear regression, and a selection method based on recently developed testing procedures for the LASSO. PMID- 26243052 TI - A room-temperature sodium rechargeable battery using an SO2-based nonflammable inorganic liquid catholyte. AB - Sodium rechargeable batteries can be excellent alternatives to replace lithium rechargeable ones because of the high abundance and low cost of sodium; however, there is a need to further improve the battery performance, cost-effectiveness, and safety for practical use. Here we demonstrate a new type of room-temperature and high-energy density sodium rechargeable battery using an SO2-based inorganic molten complex catholyte, which showed a discharge capacity of 153 mAh g(-1) based on the mass of catholyte and carbon electrode with an operating voltage of 3 V, good rate capability and excellent cycle performance over 300 cycles. In particular, non-flammability and intrinsic self-regeneration mechanism of the inorganic liquid electrolyte presented here can accelerate the realization of commercialized Na rechargeable battery system with outstanding reliability. Given that high performance and unique properties of Na-SO2 rechargeable battery, it can be another promising candidate for next generation energy storage system. PMID- 26243054 TI - WetA and VosA are distinct regulators of conidiation capacity, conidial quality, and biological control potential of a fungal insect pathogen. AB - Many filamentous fungi produce only conidia for dispersal and survival in vitro or in vivo. Here, we show that the developmental regulator WetA and the velvet protein VosA are not only required for conidial maturation but indispensable for conidiation in Beauveria bassiana, a filamentous entomopathogen. Deletion of wetA or vosA resulted in more than 90 % transcriptional depression of brlA and abaA, two activator genes in the central developmental pathway, during the critical period of conidiophore development and conidiation. Consequently, DeltawetA and DeltavosA strains lost 98 % in and 88 % of their conidiation capacities under optimal culture conditions, respectively. The conidia of DeltawetA showed more defective features than those of DeltavosA, including smaller size, lesser density, lower hydrophobicity, and impaired cell walls although intracellular trehalose content decreased more in the aging culture of DeltavosA than of DeltawetA. As a result, conidial sensitivity to cell wall perturbation was elevated in DeltawetA but unaffected in DeltavosA, which produced conidia more sensitive to the oxidant menadione and the wet-heat stress at 45 degrees C. Both deletion mutants showed similar defects in conidial tolerance to high osmolarity or UV-B irradiation but no change in conidial sensitivity to the other oxidant H2O2 or the fungicide carbendazim. Moreover, DeltawetA lost more virulence to Galleria mellonella larvae than DeltavosA. All these phenotypical changes were restored by either wetA or vosA complementation. Taken together, WetA and VosA are indispensable for asexual development and contribute differentially to conidial quality and hence the biological control potential of B. bassiana against insect pests. PMID- 26243053 TI - Tributyltin differentially promotes development of a phenotypically distinct adipocyte. AB - OBJECTIVE: Environmental endocrine disrupting chemicals (EDCs) are increasingly implicated in the pathogenesis of obesity. Evidence implicates various EDCs as being proadipogenic, including tributyltin (TBT), which activates the peroxisome proliferator activated receptor-gamma (PPARgamma). However, the conditions required for TBT-induced adipogenesis and its functional consequences are incompletely known. METHODS: The costimulatory conditions necessary for preadipocyte-to-adipocyte differentiation were compared between TBT and the pharmacological PPARgamma agonist troglitazone (Trog) in the 3T3-L1 cell line; basal and insulin-stimulated glucose uptake were assessed using radiolabeled 2 deoxyglucose. RESULTS: TBT enhanced expression of the adipocyte marker C/EBPalpha with coexposure to either isobutylmethylxanthine or insulin in the absence of other adipogenic stimuli. Examination of several adipocyte-specific proteins revealed that TBT and Trog differentially affected protein expression despite comparable PPARgamma stimulation. In particular, TBT reduced adiponectin expression upon maximal adipogenic stimulation. Under submaximal stimulation, TBT and Trog differentially promoted adipocyte-specific gene expression despite similar lipid accumulation. Moreover, TBT attenuated Trog-induced adipocyte gene expression under conditions of cotreatment. Finally, TBT-induced adipocytes exhibited altered glucose metabolism, with increased basal glucose uptake. CONCLUSIONS: TBT-induced adipocytes are functionally distinct from those generated by a pharmacological PPARgamma agonist, suggesting that obesogen induced adipogenesis may generate dysfunctional adipocytes with the capacity to deleteriously affect global energy homeostasis. PMID- 26243055 TI - Chemodiversity in the genus Aspergillus. AB - Isolates of Aspergillus species are able to produce a large number of secondary metabolites. The profiles of biosynthetic families of secondary metabolites are species specific, whereas individual secondary metabolite families can occur in other species, even those phylogenetically and ecologically unrelated to Aspergillus. Furthermore, there is a high degree of chemo-consistency from isolate to isolate in a species even though certain metabolite gene clusters are silenced in some isolates. Genome sequencing projects have shown that the diversity of secondary metabolites is much larger in each species than previously thought. The potential of finding even further new bioactive drug candidates in Aspergillus is evident, despite the fact that many secondary metabolites have already been structure elucidated and chemotaxonomic studies have shown that many new secondary metabolites have yet to be characterized. The genus Aspergillus is cladistically holophyletic but phenotypically polythetic and very diverse and is associated to quite different sexual states. Following the one fungus one name system, the genus Aspergillus is restricted to a holophyletic clade that include the morphologically different genera Aspergillus, Dichotomomyces, Phialosimplex, Polypaecilum and Cristaspora. Secondary metabolites common between the subgenera and sections of Aspergillus are surprisingly few, but many metabolites are common to a majority of species within the sections. We call small molecule extrolites in the same biosynthetic family isoextrolites. However, it appears that secondary metabolites from one Aspergillus section have analogous metabolites in other sections (here also called heteroisoextrolites). In this review, we give a genus wide overview of secondary metabolite production in Aspergillus species. Extrolites appear to have evolved because of ecological challenges rather than being inherited from ancestral species, at least when comparing the species in the different sections of Aspergillus. Within the Aspergillus sections, secondary metabolite pathways seem to inherit from ancestral species, but the profiles of these secondary metabolites are shaped by the biotic and abiotic environment. We hypothesize that many new and unique section-specific small molecule extrolites in each of the Aspergillus will be discovered. PMID- 26243056 TI - Antibacterial properties of L-amino acid oxidase: mechanisms of action and perspectives for therapeutic applications. AB - Venom, the mucus layer covering the body surface, ink glands, mammary glands, milk, and various animal secretory functions as both a physical and chemical defense barrier against bacteria and virus infections. Previously, several studies reported that L-amino acid oxidases (LAAOs) present in animal secretary fluids have strong antimicrobial activities and selective cytotoxic activities against Gram-positive and Gram-negative bacteria, various pathogenic bacteria, viruses, and parasite species. These LAAOs catalyze oxidative deamination of an L amino acid substrate with the generation of hydrogen peroxide. The antibacterial activity of LAAOs is completely inhibited by catalase; thus, LAAOs kill bacteria by the hydrogen peroxide generated from the oxidation of L-amino acid substrates. This review focuses on the selective, specific, and local antibacterial actions of various LAAOs that may be used as novel therapeutic agents against infectious diseases. LAAOs that are suitable leads for combating multidrug-resistant bacterial infections are also studied. PMID- 26243057 TI - Use of a Risk-Stratification Tool in Identification of Potential Adrenal Suppression Preceding Steroid Injection Therapy in Chronic Pain Patients. AB - BACKGROUND: Patients who present for steroid injections are not routinely screened for potential hypothalamic-pituitary-adrenal (HPA) axis suppression from previous steroid exposure. Patients often receive various steroid therapies that are not reported by the patient or recorded in available medical records. Yet, HPA axis suppression has been reported with a single intra-articular injection. METHODS: An IRB-approved quality improvement questionnaire was implemented to comprehensively screen patients for risk of HPA axis suppression secondary to prior and/or concurrent corticosteroid use. This questionnaire was given to adult patients seen in a University Pain Management Clinic, who were being considered for a steroid injection, to define the extent of exposure to corticosteroids either by mouth, topically, inhaled, or systemic/local injection within the past 6 months. RESULTS: Two hundred patients completed the questionnaire. Eighty-nine patients (44.5%) screened positive for significant steroid exposure with a screen score of three or above. The average score for the screen positive group was 6.31 +/- 3.47 (range 3-22). Women were 1.9 times more likely to screen positive than men (53.4% vs 27.5%, P < 0.0004). Otherwise, the screen positive and screen negative groups were similar in demographic characteristics (age, BMI, and diabetes status). CONCLUSIONS: Our results suggest that patients receive steroids from many sources and may be at risk for HPA axis suppression. Further testing is necessary to determine if these patients indeed have biochemical evidence of adrenal suppression. Utilization of a screening questionnaire might help identify patients who should be considered for HPA axis testing prior to steroid injections. PMID- 26243058 TI - Allergen extract vs. component sensitization and airway inflammation, responsiveness and new-onset respiratory disease. AB - BACKGROUND: The absence of IgE sensitization to allergen components in the presence of sensitization to the corresponding extract has been reported, but its clinical importance has not been studied. OBJECTIVE: To evaluate the clinical significance of IgE sensitization to three aeroallergen extracts and the corresponding components in relation to the development of respiratory disease. METHODS: A total of 467 adults participated in the European Community Respiratory Health Survey (ECRHS) II and 302 in ECRHS III, 12 years later. IgE sensitization to allergen extract and components, exhaled nitric oxide (FeNO) and bronchial responsiveness to methacholine were measured in ECRHS II. Rhinitis and asthma symptoms were questionnaire-assessed in both ECRHS II and III. RESULTS: A good overall correlation was found between IgE sensitization to extract and components for cat (r = 0.83), timothy (r = 0.96) and birch (r = 0.95). However, a substantial proportion of subjects tested IgE positive for cat and timothy allergen extracts but negative for the corresponding components (48% and 21%, respectively). Subjects sensitized to both cat extract and components had higher FeNO (P = 0.008) and more bronchial responsiveness (P = 0.002) than subjects sensitized only to the extract. Further, subjects sensitized to cat components were more likely to develop asthma (P = 0.005) and rhinitis (P = 0.007) than subjects sensitized only to cat extract. CONCLUSION: Measurement of IgE sensitization to cat allergen components would seem to have a higher clinical value than extract-based measurement, as it related better to airway inflammation and responsiveness and had a higher prognostic value for the development of asthma and rhinitis over a 12-year period. PMID- 26243059 TI - Knowledge and preferences regarding cardiopulmonary resuscitation: A survey among older patients. AB - OBJECTIVE: Survival rates following cardiopulmonary resuscitation (CPR) are low for older people, and are associated with a high risk of neurological damage. This study investigated the relationship between the preferences, knowledge of survival chances, and characteristics among older people regarding CPR. METHODS: A cross-sectional, self-administrated survey was distributed by researchers to 600 patients aged at least 50 years. The 14-question survey tool was used to collect basic demographic data, knowledge about CPR, and preference for CPR. We performed binary logistic regression analysis to predict whether patients wanted to receive CPR or not. RESULTS: The response rate was 48%. Most respondents (84%) predicted the estimated survival rate to be higher than the actual rate. Patients were significantly less likely to want to receive CPR if they correctly estimated the survival rate, had ever contemplated CPR, were older, or female. Discussing CPR with a doctor had no influence on patient preference for CPR. CONCLUSION: Older patients choose to receive CPR based on incorrect knowledge. PRACTICE IMPLICATIONS: Doctors should be aware of the impact of knowing the true chances of survival on patient preference for CPR. Knowledge and skills need to be updated to provide this information to patients. PMID- 26243060 TI - Topical tretinoin in the treatment of vulvar lichen sclerosus: an advisable option? AB - OBJECTIVE: To assess the effectiveness and safety of a 24-week application of tretinoin 0.025% cream, with an alternate-day regimen, in achieving control of VLS signs and symptoms. METHODS: 17 patients affected with VLS were included. The main efficacy parameters were the response rate, as defined by protocol parameters, the rate of patients achieving an improvement from baseline of >=75% in the subjective and objective scores, and the mean reduction in subjective and objective scores throughout the treatment. The safety of the treatment was also assessed. RESULTS: By the end of the 24-week treatment, 12 patients (70.6%) experienced a response; 35.3% and 17.6% of patients achieved an improvement of at least 75% in subjective and objective scores, respectively. Mean scores of itching, leukoderma (pallor) and hyperkeratosis decreased significantly in the study patients, and none presented itching-related excoriations. Erythema increased compared with baseline. Six patients (35.29%) experienced some side effects related to tretinoin, mainly mild erythema and burning. None of the subjects discontinued the treatment because of side effects. CONCLUSIONS: Tretinoin 0.025% cream applied for 24 weeks may represent a useful alternative option to corticosteroids in the treatment of active VLS, acting particularly on hyperkeratosis and pallor. PMID- 26243061 TI - Indicators of oral nutritional supplements prescription in nursing home residents: A cross-sectional study. AB - BACKGROUND & AIMS: Identifying factors associated with oral nutritional supplement (ONS) prescription in nursing homes (NH) may help to treat malnutrition in this very old and vulnerable population. OBJECTIVES: The aim of the study was to investigate if resident-related and NH-related characteristics were associated with ONS prescription. DESIGN: Cross-sectional study using medical and demographic data from 6275 NH residents and data on the structure and organization (e.g., presence of a dietitian, organization of the meal) of 175 NHs in southwestern France. The main outcome measure was ONS prescription (dichotomous variable: yes/no). RESULTS: ONS were prescribed for 7.8% (n = 489) of NH residents. In a multivariate binary logistic regression, resident-related factors associated with the prescription of ONS were age, clinical markers of undernutrition (body mass index and weight loss), disability in activities of daily living, pain, pressure sores, and hospitalization in the last 12 months. NH related factors associated with ONS prescription were: presence of a dietitian (Odds Ratio (OR): 1.46, 95% Confidence Interval: 1.18-1.88), NH coordinating physician with specific training in geriatrics (OR: 2.58, 95% CI: 1.48-4.49), organization of evening snack (OR: 1.63, 95% CI: 1.28-2.07), number of general practitioners per NH bed (OR: 0.49, 95% CI: 0.38-0.64 intermediate tertile; OR:0.77, 95% CI:0.59-1.06 highest tertile. Reference category: lowest tertile) and number of drug prescriptions (OR: 0.97, 95% CI: 0.94-0.99). CONCLUSIONS: Both resident's characteristics and NH characteristics were associated with ONS prescription independently of each other. Our results showed that NH organizational aspects are associated with ONS prescribing, suggesting that modifiable aspects may contribute to achieve optimal nutritional status in the NH setting. PMID- 26243062 TI - Alteration in serum klotho levels in anorexia nervosa patients. AB - BACKGROUND & AIMS: Klotho is a trans-membrane protein which can be shed to act as a hormone; its blood levels may be regulated by the GH/IGF-1 axis. Klotho deficient mice exhibit short lifespan and characteristics of aging and malnutrition, including decreased fat and muscle mass, osteopenia, and impaired fertility. As anorexia nervosa (AN) is characterized by malnutrition and GH resistance, we hypothesized klotho levels would be altered in AN, and aimed to assess klotho levels in undernourished AN patients and changes in klotho following weight rehabilitation. PARTICIPANTS AND METHODS: 19 adolescent female AN inpatients (aged 16.1 +/- 1.8 years) admitted to an inpatient service for eating disorders in a tertiary center were recruited. Blood samples were obtained on admission and after weight restoration (interval 4.0 +/- 2.3 months) and analyzed for klotho, IGF-1, calcium, phosphorus, and alkaline phosphatase. RESULTS: Klotho levels on admission were lower than expected for age, and correlated with lumbar spine BMD Z-score (r = -0.81, p < 0.001) and alkaline phosphatase levels (r = 0.66, p = 0.003) but not with age, height-SDS, weight SDS, BMI-SDS, or serum calcium, phosphorus and IGF-1 levels. Both IGF-1 and klotho levels increased significantly during hospitalization (IGF-1: 44 +/- 17 nmol/l to 53 +/- 11 nmol/l, p = 0.008; klotho: 1061 +/- 421 pg/ml to 1519 +/- 781 pg/ml, p = 0.008). CONCLUSIONS: Klotho levels are low in the acute stage of AN and increase with nutritional rehabilitation. Low klotho on admission may be secondary to low IGF-1 levels and may contribute to the clinical manifestations of AN. The role of klotho in the pathophysiology of AN and as a novel marker of disease severity should be further explored. PMID- 26243064 TI - Coexisting KRAS and NRAS mutations in colon cancer. PMID- 26243063 TI - Facing the enigma of the vascular network in hepatocellular carcinomas in cirrhotic and non-cirrhotic livers. AB - AIMS: In this paper we aimed to analyse the typology and the phenotype of the different vascular modifications in human hepatocellular carcinomas (HCCs) with a new immunomorphological and gene expression approach. We also attempted to correlate these modifications with the histological parameters of tumour aggressiveness and the surrounding liver parenchyma. METHODS: Ninety-six HCCs (from 80 patients) were retrospectively enrolled, 46 occurring in non-cirrhotic livers, and 50 in livers transplanted for cirrhosis. Histopathological analysis, immunohistochemistry for CD34, Nestin and WT1 and RT-PCR for Nestin, transforming growth factor-beta1 (TGFbeta1) and insulin-like growth factor 1 (IGF1R) mRNA were performed in all nodules. RESULTS: By correlating the CD34 and Nestin immunoreactivity in HCC vasculature with the tumorous architecture, we identified four vascular patterns (named from 'a' to 'd'). Each of them was characterised by different expressions of TGFbeta1 and IGF1R mRNA. Pattern a showed CD34 positive/Nestin-negative sinusoids, and was prevalent in microtrabecular lesions. Pattern b showed similar morphology and architecture as pattern a, but with Nestin-positive sinusoids and a significant 'boost' in IGF1R and TGFbeta1 mRNAs. In patterns c and d a progressive sinusoid loss and a gain of newly formed arterioles were seen. Notably, HCCs with pattern a arose more frequently in cirrhosis (p=0.024), and showed lower incidence of microvascular invasion (p=0.002) and infiltration (p=0.005) compared with HCCs with other patterns. CONCLUSIONS: Although future studies are surely required, the identification of different vascular profiles in HCCs from cirrhotic and non-cirrhotic livers may help clarify the relationship between HCC progression and aggressiveness. PMID- 26243065 TI - INTRODUCTION: Teaching Public Health Law: Time for a Status Upgrade. PMID- 26243066 TI - Introducing Law Students to Public Health Law through a Bed Bug Scenario. AB - As the scientific evidence emerges, individuals and institutions faced with bed bug infestations find themselves without the legal protections that are available against legally recognized nuisances and threats to the public's health, such as rats or mosquitos. As a result, they are a good example of how individuals, institutions and municipalities struggle to use the patchwork of public and private legal remedies that are often inadequate to face an emerging threat. This unit is designed to help students gain an awareness that often no one statute or case can be invoked as a complete solution to a legal problem, as well as the inherent limits of legal solutions in addressing public health problems that stem from poverty and powerlessness. PMID- 26243067 TI - Personal Beliefs Exemption from Mandatory Immunization of Children for School Entry. AB - Requiring immunization for school attendance greatly reduced morbidity and mortality in children over the past seven decades but is now highly controversial. This two-part exercise on the implementation of a "personal belief" exemption allows students to examine constitutional questions as well as legislation and regulations as they affect public health and school officials. PMID- 26243068 TI - Including Public Health Content in a Bioethics and Law Course: Vaccine Exemptions, Tort Liability, and Public Health. AB - Incorporating public health content in a bioethics and law course can prompt rich discussions. This set of materials on mandatory vaccinations, nonmedical exemptions, and potential tort liability for nonvaccination explores the roles of public health law and tort law in advancing social goals and protecting individual rights and interests. PMID- 26243069 TI - Improving Regulatory Enforcement in the Face of Inadequate Resources. AB - This exercise is designed to focus students' attention on the challenges of regulatory enforcement. The case example is drawn from Oregon's regulation of in home care agencies (IHCA). Students are asked to formulate suggestions for enhancing compliance with IHCA regulations in the absence of additional funding. The author includes her own suggestions, which she developed during her fellowship. PMID- 26243070 TI - Disaster Relief: Restricting and Regulating Public Health Interventions. AB - The information contained in this teaching module and the accompanying PowerPoint slides is appropriate for use in a survey public health law course or seminar. The purpose of this lesson is two-fold. The first objective is to provide law students with an overview of the authority public health agencies have to set and enforce policies necessary to keep the population healthy. The second objective is to inform law students about the legal constraints courts have placed upon the actions of those agencies. The module ends with a project designed to give law students the opportunity to apply the law to a "real world" situation. PMID- 26243071 TI - Public Health Control Measures in Response to Global Pandemics and Drug Resistance. AB - These teaching materials provide problem-based exercises exploring the specific powers of governments to implement control measures in response to communicable disease. Topics include global pandemic disease and, in the United States, legal issues in tuberculosis control. PMID- 26243072 TI - The Quest to Develop New Medicines to Treat Alzheimer's Disease: Present Trends and Future Prospects. PMID- 26243073 TI - Global Trends in Alzheimer Disease Clinical Development: Increasing the Probability of Success. AB - PURPOSE: Alzheimer disease (AD) is a growing global health and economic issue as elderly populations increase dramatically across the world. Despite the many clinical trials conducted, currently no approved disease-modifying treatment exists. In this commentary, the present status of AD drug development and the grounds for collaborations between government, academia, and industry to accelerate the development of disease-modifying AD therapies are discussed. METHODS: Official government documents, literature, and news releases were surveyed by MEDLINE and website research. FINDINGS: Currently approved anti-AD drugs provide only short-lived symptomatic improvements, which have no effect on the underlying pathogenic mechanisms or progression of the disease. The failure to approve a disease-modifying drug for AD may be because the progression of AD in the patient populations enrolled in clinical studies was too advanced for drugs to demonstrate cognitive and functional improvements. The US Food and Drug Administration and the European Medicines Agency recently published draft guidance for industry which discusses approaches for conducting clinical studies with patients in early AD stages. For successful clinical trials in early-stage AD, however, it will be necessary to identify biomarkers highly correlated with the clinical onset and the longitudinal progress of AD. In addition, because of the high cost and length of clinical AD studies, support in the form of global initiatives and collaborations between government, industry, and academia is needed. IMPLICATIONS: In response to this situation, national guidance and international collaborations have been established. Global initiatives are focusing on 2025 as a goal to provide new treatment options, and early signs of success in biomarker and drug development are already emerging. PMID- 26243074 TI - Patterns of Innovation in Alzheimer's Disease Drug Development: A Strategic Assessment Based on Technological Maturity. AB - PURPOSE: This article examines the current status of translational science for Alzheimer's disease (AD) drug discovery by using an analytical model of technology maturation. Previous studies using this model have demonstrated that nascent scientific insights and inventions generate few successful leads or new products until achieving a requisite level of maturity. This article assessed whether recent failures and successes in AD research follow patterns of innovation observed in other sectors. METHODS: The bibliometric-based Technology Innovation Maturation Evaluation model was used to quantify the characteristic S curve of growth for AD-related technologies, including acetylcholinesterase, N methyl-d-aspartate (NMDA) receptors, B-amyloid, amyloid precursor protein, presenilin, amyloid precursor protein secretases, apolipoprotein E4, and transactive response DNA binding protein 43 kDa (TDP-43). This model quantifies the accumulation of knowledge as a metric for technological maturity, and it identifies the point of initiation of an exponential growth stage and the point at which growth slows as the technology is established. FINDINGS: In contrast to the long-established acetylcholinesterase and NMDA receptor technologies, we found that amyloid-related technologies reached the established point only after 2000, and that the more recent technologies (eg, TDP-43) have not yet approached this point. The first approvals for new molecular entities targeting acetylcholinesterase and the NMDA receptor occurred an average of 22 years after the respective technologies were established, with only memantine (which was phenotypically discovered) entering clinical trials before this point. In contrast, the 6 lead compounds targeting the formation of amyloid plaques that failed in Phase III trials between 2009 and 2014 all entered clinical trials before the respective target technologies were established. IMPLICATIONS: This analysis suggests that AD drug discovery has followed a predictable pattern of innovation in which technological maturity is an important determinant of success in development. Quantitative analysis indicates that the lag in emergence of new products, and the much-heralded clinical failures of recent years, should be viewed in the context of the ongoing maturation of AD-related technologies. Although these technologies were not sufficiently mature to generate successful products a decade ago, they may be now. Analytical models of translational science can inform basic and clinical research results as well as strategic development of new therapeutic products. PMID- 26243075 TI - Enzyme Replacement Therapies and Immunogenicity in Lysosomal Storage Diseases: Is There a Pattern? AB - Lysosomal storage diseases arise because of genetic mutations that result in nonfunctioning or dysfunctional lysosomal enzymes responsible for breaking down molecules such as glycosaminoglycans or glycogen. Many of these storage diseases, such as the mucopolysaccharidosis (MPS) disorders and Pompe disease, can now be treated with infusion therapies to replace the dysfunctional protein with active enzyme. Although these therapies are effective, in at least one condition, infantile-onset Pompe disease, antibodies that develop against the drug significantly reduce its efficacy. However, this influence on efficacy does not appear to manifest across all enzyme replacement therapies. An example is MPS IVA, or Morquio A syndrome, in which the glycosaminoglycans keratan sulfate and chondroitin-6-sulfate accumulate in tissues as a result of N-acetylgalactosamine 6-sulfatase deficiency. The current approved treatment for MPS IVA is elosulfase alfa, a recombinant human enzyme replacement therapy. Although all patients receiving elosulfase alfa treatment develop antidrug antibodies and most develop neutralizing antibodies, clinical data to date show no effect on drug efficacy or safety. Overall, the relevance of antidrug antibodies specific to enzyme replacement therapies for the lysosomal storage diseases remains a mixed picture that will require time and continued clinical follow-up to resolve for each specific condition and treatment. PMID- 26243076 TI - Cost-effectiveness of Tofacitinib in the Treatment of Moderate to Severe Rheumatoid Arthritis in South Korea. AB - PURPOSE: This study evaluated the cost-effectiveness of introducing tofacitinib, an oral Janus kinase inhibitor, to the treatment of Korean patients with rheumatoid arthritis (RA) and an inadequate response to conventional disease modifying antirheumatic drugs. METHODS: In this cost-utility analysis model, patients transitioned through treatment sequences based on Korean guidelines for RA patients with inadequate response to conventional disease-modifying antirheumatic drugs. Lifetime health-related quality of life and costs were evaluated. Characteristics of the model cohort were based on those reported by the Oral Rheumatoid Arthritis phase 3 triaL (ORAL) Standard randomized Controlled trial of tofacitinib or adalimumab versus placebo. Efficacy was assessed using American College of Rheumatology response rates, converted to the changes in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, based on tofacitinib clinical trials data. Published clinical trial data on discontinuation rates of the indicated drugs were incorporated in the model. The HAQ-DI scores were mapped onto utility values to calculate outcomes in terms of quality-adjusted life-years (QALYs); HAQ-DI-to-utility (EuroQoL 5D) mapping was based on data from 5 tofacitinib clinical trials. Costs were analyzed from a societal perspective, with values expressed in 2013 Korean won (KRW). Cost effectiveness is presented in terms of incremental cost-effectiveness ratios (ICERs). One-way sensitivity analyses were performed to assess the robustness of the model. FINDINGS: First-line tofacitinib used before the standard of care (base-case analysis) increased both treatment costs and QALYs gained versus the standard-of-care treatment sequence, resulting in an ICER of KRW 13,228,910 per QALY. Tofacitinib also increased costs and QALYs gained when incorporated as a second-, third-, or fourth-line therapy. The inclusion of first-line tofacitinib increased the duration of active immunomodulatory therapy from 9.4 to 13.2 years. Tofacitinib-associated increases in costs were attributable to the increased lifetime drug costs. In sensitivity analyses, variations in input parameters and assumptions yielded ICERs in the range of KRW 6,995,719 per QALY to KRW 37,450,109 per QALY. IMPLICATIONS: From a societal perspective, the inclusion of tofacitinib as a treatment strategy for moderate to severe RA is cost-effective; this conclusion was considered robust based on multiple sensitivity analyses. The study was limited by the lack of clinical data on follow-up therapy after tofacitinib administration and a lack of long-term data on discontinuation of drug use. PMID- 26243077 TI - Spirochaeta sinaica sp. nov., a halophilic spirochaete isolated from a cyanobacterial mat. AB - A strain of free-living obligately anaerobic, halophilic spirochaete, SLT, was isolated from a sample of a cyanobacterial mat of the hypersaline Solar Lake, Sinai shore. The strain had motile helical cells, 0.35-0.40 * 6-10 MUm. Strain SLT exhibited high resistance to NaCl among known halophilic spirochaetes growing at NaCl concentrations from 2 to 12% (optimum growth at 7%). The strain grew at temperatures from 10 to 32 degrees C (optimum at 28 degrees C) and pH from 6 to 8.5 (optimum at pH 7.0-7.5). Carbohydrates, but not alcohols, organic acids or nitrogenous compounds (peptone, yeast extract and amino acids), were used as energy substrates for growth. Ethanol, acetate, lactate, H2 and CO2 were the products of glucose fermentation. Sulfide was produced in the presence of S0 or thiosulfate in the medium. The DNA G+C content was 44.7 mol%. Based on 16S rRNA gene sequence analysis, strain SLT clustered within the genus Spirochaeta, exhibiting 94.2 and 93.7% similarity with its closest relatives, Spirochaeta bajacaliforniensis DSM 160554T and Spirochaeta smaragdinae DSM 11293T, respectively; similarity with other species did not exceed 86%. The phenotypic and chemotaxonomic characteristics of the strain, as well as the results of phylogenetic analysis support the classification of strain SLT as representing a novel species of the genus Spirochaeta, for which the name Spirochaeta sinaica sp. nov. is proposed. The type strain is SLT ( = DSM 14994 = NIQEM U 783). PMID- 26243078 TI - Add your voice to end of life care consultation. PMID- 26243079 TI - Facing up to the Mount Cavell Challenge. PMID- 26243080 TI - NICE issues draft guidance for care of people entering final days of life. PMID- 26243081 TI - Holiday incentive could cause more staffing gaps. PMID- 26243083 TI - NMC to widen its revalidation publicity campaign across smaller employers. PMID- 26243082 TI - NICE leaves work for safe staffing guide on the shelf. PMID- 26243084 TI - 40,000 viewers for nurse's NHS video. PMID- 26243085 TI - Link between nurse numbers and patient outcomes under scrutiny. PMID- 26243086 TI - Report on infection-prevention nursing calls for career clarity. PMID- 26243087 TI - NHS strategy for learning disability. PMID- 26243090 TI - Nurses will join forces with safety bodies in bid to reduce violence. PMID- 26243089 TI - Staff urged to improve inpatient stays by giving wards a little TLC. PMID- 26243091 TI - Pinpointing the risks and benefits of shift patterns. PMID- 26243097 TI - Health in the workplace. PMID- 26243098 TI - Carter bows out with his head held high. PMID- 26243099 TI - A fresh take on prevention. PMID- 26243100 TI - How over-recruiting saves cash. PMID- 26243110 TI - The Breastfeeding Network. PMID- 26243112 TI - Headache Pro. PMID- 26243113 TI - Equipment alarms make sleep on wards impossible. PMID- 26243114 TI - Hunt's plan for NHS will take 25 more years to untangle. PMID- 26243115 TI - Balloting on industrial action would demonstrate power of the profession. PMID- 26243116 TI - Using the right to strike is fighting for our patients. PMID- 26243118 TI - NMC's timing is off with its change to re-registration. PMID- 26243121 TI - Coeliac disease in children. AB - Coeliac disease is an immune-mediated systemic disorder caused by ingestion of gluten. The condition presents classically with gastrointestinal signs including diarrhoea, bloating, weight loss and abdominal pain, but presentations can include extra-intestinal symptoms such as iron-deficiency anaemia, faltering growth, delayed puberty and mouth ulcers. Some children are at higher risk of developing coeliac disease, for example those with a strong family history, certain genetic disorders and other autoimmune conditions. If coeliac disease is suspected, serological screening with anti-tissue transglutaminase titres should be performed and the diagnosis may be confirmed by small bowel biopsy while the child remains on a normal (gluten-containing) diet. Modified European guidelines recommend that symptomatic children with anti-tissue transglutaminase titres more than ten times the upper limit of normal, and positive human leucocyte antigen (HLA)-DQ2 or HLA-DQ8 status, do not require small bowel biopsy for diagnosis of coeliac disease. Management of the disease involves strict adherence to a lifelong gluten-free diet, which should lead to resolution of symptoms and prevention of long-term complications. Healthcare professionals should be aware of the varied presentations of coeliac disease to ensure timely screening and early initiation of a gluten-free diet. PMID- 26243122 TI - Ethical issues in caring for patients with dementia. AB - This article discusses issues that might count as 'ethical' in the care of people with dementia and some of the dilemmas that occur. Ethical theories, such as virtue ethics, deontology and consequentialism are discussed, and ethical approaches that can be useful are outlined. Thinking about matters case-by-case is another approach, one that forms the first component of the Nuffield Council's ethical framework for dementia care, which is described. Case examples are provided, raising issues of autonomy, diagnosis, restraint and withholding treatment. The notion of personhood and the need to understand the person with dementia as broadly as possible are emphasised. Recommendations for nursing practice are included. PMID- 26243123 TI - Effective communication and teamwork promotes patient safety. AB - Teamwork requires co-operation, co-ordination and communication between members of a team to achieve desired outcomes. In industries with a high degree of risk, such as health care, effective teamwork has been shown to achieve team goals successfully and efficiently, with fewer errors. This article introduces behaviours that support communication, co-operation and co-ordination in teams. The central role of communication in enabling co-operation and co-ordination is explored. A human factors perspective is used to examine tools to improve communication and identify barriers to effective team communication in health care. PMID- 26243124 TI - Patient confidentiality. PMID- 26243125 TI - Faith in the system. PMID- 26243127 TI - Taking theory into real life. PMID- 26243129 TI - University challenge. PMID- 26243130 TI - Direct Plasmon-Driven Photoelectrocatalysis. AB - Harnessing the energy from hot charge carriers is an emerging research area with the potential to improve energy conversion technologies.1-3 Here we present a novel plasmonic photoelectrode architecture carefully designed to drive photocatalytic reactions by efficient, nonradiative plasmon decay into hot carriers. In contrast to past work, our architecture does not utilize a Schottky junction, the commonly used building block to collect hot carriers. Instead, we observed large photocurrents from a Schottky-free junction due to direct hot electron injection from plasmonic gold nanoparticles into the reactant species upon plasmon decay. The key ingredients of our approach are (i) an architecture for increased light absorption inspired by optical impedance matching concepts,4 (ii) carrier separation by a selective transport layer, and (iii) efficient hot carrier generation and injection from small plasmonic Au nanoparticles to adsorbed water molecules. We also investigated the quantum efficiency of hot electron injection for different particle diameters to elucidate potential quantum effects while keeping the plasmon resonance frequency unchanged. Interestingly, our studies did not reveal differences in the hot-electron generation and injection efficiencies for the investigated particle dimensions and plasmon resonances. PMID- 26243133 TI - Mesoporous TiO2/Zn2Ti3O8 hybrid films synthesized by polymeric micelle assembly. AB - A hybrid mesoporous TiO2/Zn2Ti3O8 film with a pore size of around 40 nm is successfully synthesized by the polymeric micelle assembly approach. The chemically distinct units of polymeric micelles of the poly(styrene-2 vinylpyridine-ethylene oxide) triblock copolymer simultaneously contribute to the formation of mesoporous TiO2/Zn2Ti3O8 films with enhanced photocatalytic activity during H2 evolution reaction. PMID- 26243132 TI - Building a bonfire that remains stoked: sustainment of a contingency management intervention developed through collaborative design. AB - BACKGROUND: Community dissemination of empirically-supported behavior therapies is fostered by collaborative design, a joint process pooling expertise of purveyors and treatment personnel to contextualize a therapy for sustainable use. The adaptability of contingency management renders it an exemplary therapy to model this collaborative design process. METHODS: At conclusion of an implementation/effectiveness hybrid trial conducted at an opiate treatment program, a group elicitation interview was conducted with the setting's five managerial staff to cull qualitative impressions of a collaboratively-designed contingency management intervention after 90 days of provisional implementation in the setting. Two independent raters reviewed the audio-recording and conducted a phenomenological narrative analysis, extracting themes and selecting excerpts to correspond with innovation attributes (i.e., relative advantage, compatibility, complexity, trialability, observability) of a well-known implementation science framework. RESULTS: This qualitative analysis suggested the intervention was regarded as: (1) cost-effective and clinically useful relative to prior practices, (2) a strong fit with existing service structure and staffing resources, (3) procedurally uncomplicated, with staff consistently implementing it as intended, (4) providing site-specific data to sufficiently inform decisions about its sustainment, and (5) offering palpable benefits to staff-patient interactions. CONCLUSIONS: The current work complements prior reports of positive implementation outcomes and intervention effectiveness for the parent trial, mapping qualitative managerial accounts of this contingency management intervention to a set of attributes thought to influence the speed and effectiveness with which an innovative practice is disseminated. Findings support the incorporation of collaborative design processes in future efforts to transport contingency management to the addiction treatment community. PMID- 26243134 TI - Number of dengue cases in Delhi is highest for five years. PMID- 26243131 TI - Whole-genome sequencing targets drug-resistant bacterial infections. AB - During the past two decades, the technological progress of whole-genome sequencing (WGS) had changed the fields of Environmental Microbiology and Biotechnology, and, currently, is changing the underlying principles, approaches, and fundamentals of Public Health, Epidemiology, Health Economics, and national productivity. Today's WGS technologies are able to compete with conventional techniques in cost, speed, accuracy, and resolution for day-to-day control of infectious diseases and outbreaks in clinical laboratories and in long-term epidemiological investigations. WGS gives rise to an exciting future direction for personalized Genomic Epidemiology. One of the most vital and growing public health problems is the emerging and re-emerging of multidrug-resistant (MDR) bacterial infections in the communities and healthcare settings, reinforced by a decline in antimicrobial drug discovery. In recent years, retrospective analysis provided by WGS has had a great impact on the identification and tracking of MDR microorganisms in hospitals and communities. The obtained genomic data are also important for developing novel easy-to-use diagnostic assays for clinics, as well as for antibiotic and therapeutic development at both the personal and population levels. At present, this technology has been successfully applied as an addendum to the real-time diagnostic methods currently used in clinical laboratories. However, the significance of WGS for public health may increase if: (a) unified and user-friendly bioinformatics toolsets for easy data interpretation and management are established, and (b) standards for data validation and verification are developed. Herein, we review the current and future impact of this technology on diagnosis, prevention, treatment, and control of MDR infectious bacteria in clinics and on the global scale. PMID- 26243135 TI - Iterative development and the scope for plasticity: contrasts among trait categories in an adaptive radiation. AB - Phenotypic plasticity can influence evolutionary change in a lineage, ranging from facilitation of population persistence in a novel environment to directing the patterns of evolutionary change. As the specific nature of plasticity can impact evolutionary consequences, it is essential to consider how plasticity is manifested if we are to understand the contribution of plasticity to phenotypic evolution. Most morphological traits are developmentally plastic, irreversible, and generally considered to be costly, at least when the resultant phenotype is mis-matched to the environment. At the other extreme, behavioral phenotypes are typically activational (modifiable on very short time scales), and not immediately costly as they are produced by constitutive neural networks. Although patterns of morphological and behavioral plasticity are often compared, patterns of plasticity of life history phenotypes are rarely considered. Here we review patterns of plasticity in these trait categories within and among populations, comprising the adaptive radiation of the threespine stickleback fish Gasterosteus aculeatus. We immediately found it necessary to consider the possibility of iterated development, the concept that behavioral and life history trajectories can be repeatedly reset on activational (usually behavior) or developmental (usually life history) time frames, offering fine tuning of the response to environmental context. Morphology in stickleback is primarily reset only in that developmental trajectories can be altered as environments change over the course of development. As anticipated, the boundaries between the trait categories are not clear and are likely to be linked by shared, underlying physiological and genetic systems. PMID- 26243136 TI - Fine-scale landscape genetics of the American badger (Taxidea taxus): disentangling landscape effects and sampling artifacts in a poorly understood species. AB - Landscape genetics is a powerful tool for conservation because it identifies landscape features that are important for maintaining genetic connectivity between populations within heterogeneous landscapes. However, using landscape genetics in poorly understood species presents a number of challenges, namely, limited life history information for the focal population and spatially biased sampling. Both obstacles can reduce power in statistics, particularly in individual-based studies. In this study, we genotyped 233 American badgers in Wisconsin at 12 microsatellite loci to identify alternative statistical approaches that can be applied to poorly understood species in an individual based framework. Badgers are protected in Wisconsin owing to an overall lack in life history information, so our study utilized partial redundancy analysis (RDA) and spatially lagged regressions to quantify how three landscape factors (Wisconsin River, Ecoregions and land cover) impacted gene flow. We also performed simulations to quantify errors created by spatially biased sampling. Statistical analyses first found that geographic distance was an important influence on gene flow, mainly driven by fine-scale positive spatial autocorrelations. After controlling for geographic distance, both RDA and regressions found that Wisconsin River and Agriculture were correlated with genetic differentiation. However, only Agriculture had an acceptable type I error rate (3-5%) to be considered biologically relevant. Collectively, this study highlights the benefits of combining robust statistics and error assessment via simulations and provides a method for hypothesis testing in individual-based landscape genetics. PMID- 26243137 TI - Genomic diversity and differentiation of a managed island wild boar population. AB - The evolution of island populations in natural systems is driven by local adaptation and genetic drift. However, evolutionary pathways may be altered by humans in several ways. The wild boar (WB) (Sus scrofa) is an iconic game species occurring in several islands, where it has been strongly managed since prehistoric times. We examined genomic diversity at 49 803 single-nucleotide polymorphisms in 99 Sardinian WBs and compared them with 196 wild specimens from mainland Europe and 105 domestic pigs (DP; 11 breeds). High levels of genetic variation were observed in Sardinia (80.9% of the total number of polymorphisms), which can be only in part associated to recent genetic introgression. Both Principal Component Analysis and Bayesian clustering approach revealed that the Sardinian WB population is highly differentiated from the other European populations (FST=0.126-0.138), and from DP (FST=0.169). Such evidences were mostly unaffected by an uneven sample size, although clustering results in reference populations changed when the number of individuals was standardized. Runs of homozygosity (ROHs) pattern and distribution in Sardinian WB are consistent with a past expansion following a bottleneck (small ROHs) and recent population substructuring (highly homozygous individuals). The observed effect of a non-random selection of Sardinian individuals on diversity, FST and ROH estimates, stressed the importance of sampling design in the study of structured or introgressed populations. Our results support the heterogeneity and distinctiveness of the Sardinian population and prompt further investigations on its origins and conservation status. PMID- 26243138 TI - Comorbid Social Anxiety Disorder in Adults with Autism Spectrum Disorder. AB - Social anxiety symptoms are common among cognitively unimpaired youth with autism spectrum disorder (ASD). Few studies have investigated the co-occurrence of social anxiety disorder (SAD) in adults with ASD, although identification may aid access to effective treatments and inform our scientific efforts to parse heterogeneity. In this preliminary study, we examined the clinical presentation of SAD in adults with ASD (n = 28), relative to SAD uncomplicated by ASD (n = 26). A large subset (50 %) of the adults with ASD met diagnostic criteria for SAD. The adults with ASD plus SAD differed from those with ASD without SAD on several characteristics. Findings demonstrate that many adults with ASD are aware of their social difficulties and experience impairing social anxiety. PMID- 26243139 TI - Why Are Half of Women Interested in Participating in Group Prenatal Care? AB - OBJECTIVE: To determine the likelihood of participating in group prenatal care (GPC) and associated factors among low-risk women receiving traditional prenatal care from obstetricians, family physicians or midwives, and to determine factors associated with likelihood of participating. METHODS: Prior to completing a self administered questionnaire, a 2-min compiled video of GPC was shown to pregnant women receiving traditional prenatal care. Data were collected on opinions of current prenatal care, GPC, and demographics. Biologically plausible variables with a p value <=0.20 were entered in the multivariable logistic regression model and those with a p value <0.05 were retained. RESULTS: Of 477 respondents, 234 [49.2%, 95% confidence interval (CI) 44.6-53.6%] reported being "definitely" or "probably likely" to participate in GPC. Women were more likely to participate in GPC if they had at least postsecondary education [adjusted odds ratio (aOR) 1.84, 95% CI 1.05-3.24], had not discussed labour with their care provider (aOR 1.67, 95% CI 1.12-2.44), and valued woman-centeredness ("fairly important" aOR 2.81, 95% CI 1.77-4.49; "very important" aOR 4.10, 95% CI 2.45-6.88). Women placed high importance on learning components of GPC. The majority would prefer to be with similar women, especially in age. About two-thirds would prefer to have support persons attend GPC and over half would be comfortable with male partners. CONCLUSION: Approximately half of women receiving traditional prenatal care were interested in participating in GPC. Our findings will hopefully assist providers interested in optimizing satisfaction with traditional prenatal care and GPC by identifying important elements of each, and thus help engage women to consider GPC. PMID- 26243140 TI - Lipid changes within the epidermis of living skin equivalents observed across a time-course by MALDI-MS imaging and profiling. AB - BACKGROUND: Mass spectrometry imaging (MSI) is a powerful tool for the study of intact tissue sections. Here, its application to the study of the distribution of lipids in sections of reconstructed living skin equivalents during their development and maturation is described. METHODS: Living skin equivalent (LSE) samples were obtained at 14 days development, re-suspended in maintenance medium and incubated for 24 h after delivery. The medium was then changed, the LSE re incubated and samples taken at 4, 6 and 24 h time points. Mass spectra and mass spectral images were recorded from 12 MUm sections of the LSE taken at each time point for comparison using matrix assisted laser desorption ionisation mass spectrometry. RESULTS: A large number of lipid species were identified in the LSE via accurate mass-measurement MS and MSMS experiments carried out directly on the tissue sections. MS images acquired at a spatial resolution of 50 MUm * 50 MUm showed the distribution of identified lipids within the developing LSE and changes in their distribution with time. In particular development of an epidermal layer was observable as a compaction of the distribution of phosphatidylcholine species. CONCLUSIONS: MSI can be used to study changes in lipid composition in LSE. Determination of the changes in lipid distribution during the maturation of the LSE will assist in the identification of treatment responses in future investigations. PMID- 26243141 TI - Household survey of availability of long-lasting insecticide-treated nets and its determinants in rural Mozambique. AB - BACKGROUND: Mosquito nets treated with long-lasting insecticide offer highly effective personal protection against malaria transmission. In Mozambique, nets are distributed freely in antenatal care visits since 2006 and through mass distribution campaigns since 2009, but the country has not yet been able to report a consistent decline in malaria incidence. Routine data show that Changara District, Tete Province, shows an increase in malaria cases, although it has a reasonable theoretical coverage of nets. This study evaluated household availability of nets and its determinants in Changara district. METHODOLOGY: Quantitative household survey at the end of 2013, in a representative sample of 450 households in 30 villages of Changara district, using the sampling method of randomly selected households in clusters selected with probability proportional to size. Data were analysed with Epi-Info version 7.1.2.0. The significance level was 0. 05. RESULTS: Of 450 households, 62.5% (95% CI 57.5-66.7) had at least one long-lasting insecticide-treated net. Availability of nets showed a positive association with socioeconomic status and the existence of at least one pregnant woman or child under 5 years in the household, but a negative association with distance between health facility and residence. Most of the observed nets were not in good condition, only 19.2% (95% CI 15.7-23.2) of households had at least one net in good condition. The condition of the nets reduced with increasing number of washes. CONCLUSIONS: The household availability of long-lasting insecticide-treated nets in Changara district has not yet reached levels that may have an impact on the incidence of malaria, despite distribution through campaign and antenatal care. The habit of washing nets frequently reduces their lifespan. It is recommended to strengthen education on good practices of net conservation, in addition to their distribution. PMID- 26243142 TI - Emission and control of N2O and composition of ash derived from cattle manure combustion using a pilot-scale fluidized bed incinerator. AB - This study investigates the emission of nitrous oxide (N2O) and discusses the reduction of N2O emissions during the 24-h combustion of cattle manure using a pilot-scale fluidized bed incinerator under various experimental conditions. The results of these experiments were then validated against previously reported data. In addition, the characteristics of cattle manure incineration ash and their changes under different combustion conditions were estimated. In incineration experiments with composted cattle manure, N2O concentrations using multi-stage combustion were 75% lower than the concentrations resulting from normal combustion without additional auxiliary fuel, since N2O could be decomposed in the high-temperature zone formed by the inlet of the secondary combustion air. The N2O emission factor under normal combustion conditions (800 degrees C) was 6.0% g-N2O-N/g-N. This result is similar to the values found in previous studies at the same temperature. The N2O emission factor was decreased to 1.6% g-N2O-N/g-N using a multi-stage combustion procedure. The current Japanese N2O emission factor of 0.1% g-N2O-N/g-N is an underestimate for some conditions and should be uniquely specified for each condition. Finally, cattle manure ash contains ample fertilizer elements, little Fe, Al and Zn, but abundant Cl. Therefore if Cl could be removed by some kind of pretreatment, cattle manure ash could be used as a favourable fertilizer. PMID- 26243143 TI - Signature of microRNA expression during osteogenic differentiation of bone marrow MSCs reveals a putative role of miR-335-5p in osteoarthritis. AB - BACKGROUND: The aim of this study was to evaluate, the existence of a signature of differentially expressed microRNAs (miRNAs) during osteogenic differentiation of bone marrow MSCs from OA and healthy donors and to describe their possible implication in joint regeneration through modulation of molecular mechanisms involved in homeostatic control in OA pathophysiology. METHODS: Following phenotypic assessment of BM-MSCs obtained from OA diagnosed patients (n = 10) and non-OA (n = 10), total small RNA was isolated after osteogenic induction for 1, 10 and 21 days, miRNA profiles were generated using a commercial expression array of 754 well-characterized miRNAs. MiRNAs, with consistent differential expression were selected for further validation by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis. RESULTS: A total of 246 miRNAs were differentially expressed (fold change >= +/- 2, P <=0.05) between OA and non-OA BM-MSC samples; these miRNAs showed variable interactions depending on the cell and differentiation status. Two miRNAs, hsa-miR-210 and hsa-miR-335-5p out of 21 used for validation showed a significant downregulated expression during induced osteogenesis. In particular hsa-miR-335-5p, a critical regulator in bone homeostasis, was further studied. hsa-miR-335-5p downregulation in OA-MSCs, as well as their host coding gene, MEST, were also assessed. CONCLUSIONS: To our knowledge, this study represents the most comprehensive assessment to date of miRNA expression profiling in BM-MSCs from OA patients and their role during osteogenic differentiation. We describe the existence of a correlation between miR-335-5p expression and OA indicating the putative role of this miRNA in OA features. These findings, may contribute to our understanding of the molecular mechanisms involved in MSCs mediated homeostatic control in OA pathophysiology that could be applicable in future therapeutic approaches. PMID- 26243144 TI - A randomised trial assessing the acceptability and effectiveness of providing generic versus tailored feedback about health risks for a high need primary care sample. AB - BACKGROUND: Tailored feedback has been shown to be effective for modifying health risk behaviours and may aid the provision of preventive care by general practitioners (GPs). However, provision of tailored patient feedback for vulnerable or socially disadvantaged groups is not well explored. The aims of this study were to examine the acceptability and effectiveness of providing generic compared to tailored feedback on self-reported health risk behaviours among a high need sample of people attending an Aboriginal Community Controlled Health Service (ACCHS). METHODS: Participants attending two ACCHSs in regional New South Wales completed a touch screen health risk survey and received either generic or tailored health risk feedback. Participants were asked to complete an exit survey after their appointment. The exit survey asked about feedback acceptability and effectiveness. Self-reported ease of understanding, relevance and whether the generic versus tailored feedback helped patients talk to their GP was compared using Chi-square analysis; The mean number of survey health risks talked about or for which additional actions were undertaken (such as provision of lifestyle advice or referral) was compared using t-tests. RESULTS: Eighty seven participants (36 % consent rate) completed the exit survey. Tailored feedback was rated as more relevant and was more likely to be shown to the participant's GP than generic feedback. There was no difference in the mean number of health risk topics discussed or number of additional actions taken by the GP by type of feedback. CONCLUSIONS: Tailored and generic feedback showed no difference in effectiveness, and little difference in acceptability, among this socially disadvantaged population. Completing a health risk survey and receiving any type of feedback may have overwhelmed more subtle differences in outcomes between the generic and the tailored feedback. Future work to rigorously evaluate the longer-term effectiveness of the provision of tailored health risk feedback for Aboriginal Australians, as well as other high need groups, is still needed. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ANZCTRN12614001205628. Registered 11 November 2014. PMID- 26243145 TI - Human breast cancer cells educate macrophages toward the M2 activation status. AB - INTRODUCTION: The immune system plays a major role in cancer progression. In solid tumors, 5-40 % of the tumor mass consists of tumor-associated macrophages (TAMs) and there is usually a correlation between the number of TAMs and poor prognosis, depending on the tumor type. TAMs usually resemble M2 macrophages. Unlike M1-macrophages which have pro-inflammatory and anti-cancer functions, M2 macrophages are immunosuppressive, contribute to the matrix-remodeling, and hence favor tumor growth. The role of TAMs is not fully understood in breast cancer progression. METHODS: Macrophage infiltration (CD68) and activation status (HLA DRIIalpha, CD163) were evaluated in a large cohort of human primary breast tumors (562 tissue microarray samples), by immunohistochemistry and scored by automated image analysis algorithms. Survival between groups was compared using the Kaplan Meier life-table method and a Cox multivariate proportional hazards model. Macrophage education by breast cancer cells was assessed by ex vivo differentiation of peripheral blood mononuclear cells (PBMCs) in the presence or absence of breast cancer cell conditioned media (MDA-MB231, MCF-7 or T47D cell lines) and M1 or M2 inducing cytokines (respectively IFN-gamma, IL-4 and IL-10). Obtained macrophages were analyzed by flow cytometry (CD14, CD16, CD64, CD86, CD200R and CD163), ELISA (IL-6, IL-8, IL-10, monocyte colony stimulating factor M CSF) and zymography (matrix metalloproteinase 9, MMP-9). RESULTS: Clinically, we found that high numbers of CD163(+) M2-macrophages were strongly associated with fast proliferation, poor differentiation, estrogen receptor negativity and histological ductal type (p<0.001) in the studied cohort of human primary breast tumors. We demonstrated ex vivo that breast cancer cell-secreted factors modulate macrophage differentiation toward the M2 phenotype. Furthermore, the more aggressive mesenchymal-like cell line MDA-MB231, which secretes high levels of M CSF, skews macrophages toward the more immunosuppressive M2c subtype. CONCLUSIONS: This study demonstrates that human breast cancer cells influence macrophage differentiation and that TAM differentiation status correlates with recurrence free survival, thus further emphasizing that TAMs can similarly affect therapy efficacy and patient outcome. PMID- 26243146 TI - An epigenetic regulator emerges as microtubule minus-end binding and stabilizing factor in mitosis. AB - The evolutionary conserved NSL complex is a prominent epigenetic regulator controlling expression of thousands of genes. Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. Moreover, we identify KANSL3 as a microtubule minus-end-binding protein, revealing a new class of mitosis-specific microtubule minus-end regulators. By adopting distinct functions in interphase and mitosis, KANSL proteins provide a link to coordinate the tasks of faithful expression and inheritance of the genome during different phases of the cell cycle. PMID- 26243147 TI - A Novel Approach to Measuring Efficiency of Scientific Research Projects: Data Envelopment Analysis. AB - PURPOSE: Measuring the efficiency of resource allocation for the conduct of scientific projects in medical research is difficult due to, among other factors, the heterogeneity of resources supplied (e.g., dollars or FTEs) and outcomes expected (e.g., grants, publications). While this is an issue in medical science, it has been approached successfully in other fields by using data envelopment analysis (DEA). DEA has a number of advantages over other techniques as it simultaneously uses multiple heterogeneous inputs and outputs to determine which projects are performing most efficiently, referred to as being at the efficiency frontier, when compared to others in the data set. METHOD: This research uses DEA for the evaluation of supported translational science projects by the Oregon Clinical and Translational Research Institute (OCTRI), a NCATS Clinical & Translational Science Award (CTSA) recipient. RESULTS: These results suggest that the primary determinate of overall project efficiency at OCTRI is the amount of funding, with smaller amounts of funding providing more efficiency than larger funding amounts. CONCLUSION: These results, and the use of DEA, highlight both the success of using this technique in helping determine medical research efficiency and those factors to consider when distributing funds for new projects at CTSAs. PMID- 26243148 TI - Frequent topoisomerase IV mutations associated with fluoroquinolone resistance in Ureaplasma species. AB - This study aimed to investigate the role of quinolone resistance-determining regions (QRDRs) of DNA gyrase (encoded by gyrA and gyrB) and topoisomerase IV (encoded by parC and parE) associated with fluoroquinolone resistance. A total of 114 Ureaplasma spp. strains, isolated from clinical female patients with symptomatic infection, were tested for species distribution and susceptibility to four fluoroquinolones. Moreover, we analysed the QRDRs and compared these with 14 ATCC reference strains of Ureaplasma spp. serovars to identify mutations that caused antimicrobial resistance. Our study indicated that moxifloxacin was the most effective fluoroquinolone against Ureaplasma spp. (MIC range: 0.125-32 MUg ml-1). However, extremely high MICs were estimated for ciprofloxacin (MIC range: 1-256 MUg ml-1) and ofloxacin (MIC range: 0.5-128 MUg ml-1), followed by levofloxacin (MIC range: 0.5-64 MUg ml-1). Seven amino acid substitutions were discovered in GyrB, ParC and ParE, but not in GyrA. Ser-83 -> Leu/Trp (C248T/G) in ParC and Arg-448 -> Lys (G1343A) in ParE, which were potentially responsible for fluoroquinolone resistance, were observed in 89 (77.2 %) and three (2.6 %) strains, respectively. Pro-462 -> Ser (C1384T), Asn-481 -> Ser (A1442G) and Ala 493 -> Val (C1478T) in GyrB and Met-105 -> Ile (G315T) in ParC seemed to be neutral polymorphisms, and were observed and occurred along with the amino acid change of Ser-83 -> Leu (C248T) in ParC. Interestingly, two novel mutations of ParC and ParE were independently found in four strains. These observations suggest that amino acid mutation in topoisomerase IV appears to be the leading cause of fluoroquinolone resistance, especially the mutation of Ser-83 -> Leu (C248T) in ParC. Moxifloxacin had the best activity against strains with Ser-83 > Leu mutation. PMID- 26243150 TI - Pigment compositions are linked to the habitat types in dinoflagellates. AB - Compared to planktonic species, there is little known about the ecology, physiology, and existence of benthic dinoflagellates living in sandy beach or seafloor environments. In a previous study, we discovered 13(2),17(3) cyclopheophorbide a enol (cPPB-aE) from sand-dwelling benthic dinoflagellates. This enol had never been detected in phytoplankton despite the fact that it is a chlorophyll a catabolite. We speculated from this discovery that habitat selection might be linked to pigment compositions in dinoflagellates. To test the hypothesis of habitat selection linking to pigment compositions, we conducted extensive analysis of pigments with high performance liquid chromatography (HPLC) for 40 species using 45 strains of dinoflagellates including three habitat types; sand-dwelling benthic forms, tidal pool inhabitants and planktonic species. The 40 dinoflagellates are also able to be distinguished into two types based on their chloroplast origins; red alga-derived secondary chloroplasts and diatom derived tertiary ones. By plotting the pigments profiles onto three habitats, we noticed that twelve pigments including cPPB-aE were found to occur only in benthic sand-dwelling species of red alga-derived type. The similar tendency was also observed in dinoflagellates with diatom-derived chloroplasts, i.e. additional sixteen pigments including chl c 3 were found only in sand-dwelling forms. This is the first report of the occurrence of chl c 3 in dinoflagellates with diatom-derived chloroplasts. These results clarify that far greater diversity of pigments are produced by the dinoflagellates living in sand regardless of chloroplast types relative to those of planktonic and tidal pool forms. Dinoflagellates seem to produce a part of their pigments in response to their habitats. PMID- 26243151 TI - Determinants of attitudes towards professional mental health care, informal help and self-reliance in people with subclinical depression. AB - BACKGROUND: Although little is known about which people with subclinical depression should receive care to prevent the onset of depression, it is clear that remediating symptoms of depression is important. However, depending on the beliefs people hold about help, some people will seek professional help, while others seek informal help or solve problems on their own. AIMS: This study examined associations between attitudes about help and socio-demographic variables, mastery, severity of depressive symptoms, accessibility to care, and health care utilization at baseline and 4-year follow-up. METHODS: Data were derived from a large cohort study, the Netherlands Study of Depression and Anxiety (NESDA). A total of 235 respondents with subclinical depression completed questionnaires at baseline and follow-up. Attitude was assessed using a short version of the 'Trust in mental health care' questionnaire. RESULTS: Positive attitude towards professional care was associated with being male, younger age, higher mastery and easy accessibility to care. Positive attitude towards informal help was associated with higher mastery and unemployment. Older age, less accessibility to care and lower mastery were associated with positive attitude towards self-reliance. A change in care utilization was associated with positive attitudes towards professional care at follow-up. CONCLUSIONS: People differ in the way they cope with symptoms which may influence their preferred care. Higher levels of mastery were positively associated with professional and informal care, but negatively associated with self-reliance. Both age and mastery showed relatively large effect sizes. PMID- 26243152 TI - Fabrication and Properties of High-Efficiency Perovskite/PCBM Organic Solar Cells. AB - This work presents a CH3NH3PbI3/PCBM organic solar cell. Organic PCBM film and CH3NH3PbI3 perovskite film are deposited on the PEDOT: PSS/ITO glass substrate by the spin coating method. The performance of the organic solar cells was observed by changing the thickness of CH3NH3PbI3 perovskite. The thickness of a perovskite film can affect the carrier diffusion length in a device that strongly absorbs light in the red spectral region. The short-circuit current density and the power conversion efficiency were 21.9 mA/cm(2) and 11.99 %, respectively, for the sample with 210-nm-thick CH3NH3PbI3 perovskite active layer. PMID- 26243153 TI - Application of the pi-accepting ability parameter of N-heterocyclic carbene ligands in iridium complexes for signal amplification by reversible exchange (SABRE). AB - The new pi-accepting ability parameter (PAAP) appears to be the best tool to analyse the electronic properties of NHC ligands in [Ir(H)2(NHC)(Py)3](+) complexes for SABRE. Together with the buried volume, the efficiency of hyperpolarisation transfer in SABRE, depending on the exchange rate of pyridine, can be described. PMID- 26243155 TI - ESP Abstracts 2015. PMID- 26243154 TI - Identifying binge drinkers based on parenting dimensions and alcohol-specific parenting practices: building classifiers on adolescent-parent paired data. AB - BACKGROUND: Most Dutch adolescents aged 16 to 18 engage in binge drinking. Previous studies have investigated how parenting dimensions and alcohol-specific parenting practices are related to adolescent alcohol consumption. Mixed results have been obtained on both dimensions and practices, highlighting the complexity of untangling alcohol-related factors. The aim of this study was to investigate (1) whether parents' reports of parenting dimensions and alcohol-specific parenting practices, adolescents' perceptions of these dimensions and practices, or a combination are most informative to identify binge drinkers, and (2) which of these parenting dimensions and alcohol-specific parenting practices are most informative to identify binge drinkers. METHODS: Survey data of 499 adolescent parent dyads were collected. The computational technique of data mining was used to allow for a data driven exploration of nonlinear relationships. Specifically, a binary classification task, using an alternating decision tree, was conducted and measures regarding the performance of the classifiers are reported after a 10 fold cross-validation. RESULTS: Depending on the parenting dimension or practice, parents' reports correctly identified the drinking behaviour of 55.8% (using psychological control) up to 70.2% (using rules) of adolescents. Adolescents' perceptions were best at identifying binge drinkers whereas parents' perceptions were best at identifying non-binge drinkers. CONCLUSIONS: Of the parenting dimensions and practices, rules are particularly informative in understanding drinking behaviour. Adolescents' perceptions and parents' reports are complementary as they can help identifying binge drinkers and non-binge drinkers respectively, indicating that surveying specific aspects of adolescent-parent dynamics can improve our understanding of complex addictive behaviours. PMID- 26243157 TI - Muscle metabolism and whole blood amino acid profile in patients with liver disease. AB - OBJECTIVE: Branched-chain amino acids (BCAA) are used in liver cirrhosis to promote protein synthesis, support ammonia detoxification, and treat hepatic encephalopathy. Cirrhosis leads to subnormal BCAA plasma concentrations and studies indicate that levels are decreased due to their role in muscle ammonia removal. Muscle contribution has not been fully elucidated. We studied muscle amino acid metabolism in six healthy subjects, 13 cirrhosis patients and six patients with an episode of alcoholic hepatitis. METHODS: Subjects had catheters inserted into the femoral artery and vein to obtain arterial (A) and venous (V) concentrations of amino acids (MUmol/L blood). RESULTS: BCAA concentrations were lower in patients with cirrhosis compared to healthy subjects (p < 0.05) with no difference between patients with alcoholic hepatitis and the other groups. Muscle BCAA uptake was variable and on average higher in patients with alcoholic hepatitis and patients with stable cirrhosis compared to healthy subjects (mean A V difference 0.5 and 32 vs. - 12 MUmol/L blood) (p = 0.22). The release of aromatic amino acids (AAA) was comparable in the three groups (P > 0.30). The BCAA/AAA (Fischer's ratio) was lower in patients with cirrhosis and patients with alcoholic hepatitis compared to healthy subjects (mean 1.65, 1.17 and 2.73, both p < 0.05) and it was negatively correlated to the Child-Pugh score (p < 0.05). CONCLUSIONS: Patients with liver disease have lower BCAA and higher AAA blood concentrations compared to healthy subjects. The trend towards an increased muscle uptake of BCAA may have contributed but this was not significant. PMID- 26243156 TI - Functional and Structural Impact of ATP-Binding Cassette Transporter A1 R219K and I883M Gene Polymorphisms in Obese Children and Adolescents. AB - INTRODUCTION: Obesity is a serious medical condition that affects children and adolescents. ATP-binding cassette transporter A1 (ABCA1) protein is known to mediate the transport of intracellular cholesterol and phospholipids across the cell membranes. Thus, we aimed to investigate the association between ABCA1 gene polymorphisms and overweight/obesity risk, and to evaluate their relation to the lipid profile. MATERIALS AND METHODS: The study included in silico analysis of ABCA1 gene and protein. Two genetic variants in ABCA1 gene-R219K (rs2230806; G/A) and I883M (rs2066714; A/G)-were genotyped in 128 normal weight and 128 overweight/obese subjects using polymerase chain reaction-restriction fragment length polymorphism technology. Anthropometric and biochemical assessments were performed. RESULTS: Our findings suggest that the heterozygote GA genotype of R219K polymorphism increased susceptibility to obesity under the heterozygous model (odds ratio 2.75, 95 % CI 1.01-6.12; p = 0.014) compared with the control group. This susceptibility could be gender-specific, with higher risk among females. In addition, the A variant was associated with a higher degree of obesity (p < 0.001). On the other hand, individuals with the G variant of I883M polymorphism showed lower susceptibility to obesity under all genetic models (allelic, homozygote, heterozygote, dominant, and recessive models; p < 0.05), with no observed association with body mass index or degree of obesity. However, both single nucleotide polymorphisms (SNPs) showed significant differences in lipid levels among patients with different genotypes. CONCLUSIONS: The study results suggest that R219K and I883M SNPs of the ABCA1 gene may play a role in susceptibility to obesity in our Egyptian population; the former increases susceptibility and phenotype severity, and the latter is protective. Larger epidemiological studies are needed for validation of the results. PMID- 26243158 TI - Energy Equivalence of Information in the Mitochondrion and the Thermodynamic Efficiency of ATP Synthase. AB - Half a century ago, Johnson and Knudsen resolved the puzzle of the apparent low efficiency of the kidney (~ 0.5%) compared to most other bodily organs (~ 40%) by taking into account the entropic cost of ion sorting, the principal function of this organ. Similarly, it is shown that the efficiency of energy transduction of the chemiosmotic proton-motive force by ATP synthase is closer to 90% instead of the oft-quoted textbook value of only 60% when information theoretic considerations are applied to the mitochondrion. This high efficiency is consistent with the mechanical energy transduction of ATP synthase known to be close to the 100% thermodynamic limit. It would have been wasteful for evolution to maximize the mechanical energy transduction to 100% while wasting 40% of the chemiosmotic free energy in the conversion of the proton-motive force into mechanical work before being captured as chemical energy in adenosine 5' triphosphate. PMID- 26243159 TI - Intraoperative ultrasound in pediatric brain tumors: does the surgeon get it right? AB - PURPOSE: Intraoperative ultrasound (iUS) is a valuable tool-inexpensive, adds minimal surgical time, and involves minimal risk. The diagnostic predictive value of iUS is not fully characterized in Pediatric Neurosurgery. Our objective is to determine if surgeon-completed iUS has good concordance with post-operative MRI in estimating extent of surgical resection (EOR) of pediatric brain tumors. METHODS: We reviewed charts of all pediatric brain tumor resections (single institution 2006-2013). Those with iUS and postoperative imaging (<1 week) were included. The surgeon's estimation of the EOR based on iUS and the post-operative neuroimaging results (gold standard) were collected, as well as information about the patients/tumors. RESULTS: Two hundred two resections were reviewed and 58 cases were included. Twenty-six of the excluded cases utilized iUS but did not have EOR indicated. The concordance of interpretation between iUS and post operative MRI was 98.3%. Of 43 cases where iUS suggested gross total resection, 42 were confirmed on MRI (negative predictive value (NPV), 98%). All 15 cases where iUS suggested subtotal resection were confirmed on MRI (positive predictive value (PPV), 100 %). Agreement between iUS and post-operative imaging had an overall Kappa score of 0.956, signifying almost perfect agreement. CONCLUSION: The results from this study suggest that iUS is reliable with both residual tumor (PPV-100%) and when it suggests no residual (NPV-98%) in tumors that are easily identifiable on iUS. However, tumors that were difficult to visualize on iUS were potentially excluded, and therefore, these results should not be extrapolated for all brain tumor types. PMID- 26243160 TI - Factors associated with delayed recovery in athletes with concussion treated at a pediatric neurology concussion clinic. AB - PURPOSE: With the increase in knowledge and management of sport-related concussion over the last 15 years, there has been a shift from a grading scale approach to an individualized management approach. As a result, there is an increased need to better understand the factors involved in delayed recovery of concussion. The purpose of this retrospective study was to examine factors that may be associated with recovery from sport-related concussion in student athletes aged 11 to 18 years old. METHODS: Of the 366 patients who met the inclusion criteria, 361 were included in our analysis. The primary dependent variable included days until athlete was able to return to play (RTP). Independent variables of interest included age, gender, academic performance, comorbid factors, sports, on-field markers, days until initial neurological evaluation, Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT(r)) scores, acute headache rescue medications, chronic headache medication, sleep medication, and referral to concussion rehabilitation program. RESULTS: Variables associated with longer median RTP were being female (35 days), having a referral to concussion rehabilitation program (53 days), being prescribed acute headache rescue therapy (34 days), and having chronic headache treatment (53 days) (all p < 0.05). Variables associated with shorter RTP were on-field marker of headache (23 days) and evaluation within 1 week of concussion by a concussion specialist (16 days) (Both p < 0.05). CONCLUSION: This study supports the need for a concussed athlete to have access to a provider trained in concussion management in a timely fashion in order to prevent delayed recovery and return to play. PMID- 26243161 TI - John Hunter (1728-1793) and his legacy to science. PMID- 26243162 TI - Karl Ewald Konstantin Hering (1834-1918), Heinrich Ewald Hering (1866-1948), and the namesake for the Hering-Breuer reflex. PMID- 26243163 TI - Synthesis and controllable oxidation of monodisperse cobalt-doped wustite nanoparticles and their core-shell stability and exchange-bias stabilization. AB - Cobalt-doped wustite (CWT), Co0.33Fe0.67O, nanoparticles were prepared via the thermal decomposition of CoFe2-oleate complexes in organic solvents. A controllable oxidation process was then performed to obtain Co0.33Fe0.67O/CoFe2O4 core-shell structures with different core-to-shell volume ratios and exchange bias properties. The oxidized core-shell samples with a ~4 nm CoFe2O4 shell showed good resistance to oxygen transmission. Thus, it is inferred that the cobalt ferrite shell provides a better oxidation barrier performance than magnetite in the un-doped case. The hysteresis loops of the oxidized 19 nm samples exhibited a high exchange bias field (H(E)), an enhanced coercivity field (H(C)), and a pronounced vertical shift, thus indicating the presence of a strong exchange bias coupling effect. More importantly, the onset temperature of H(E) was found to be higher than 200 K, which suggests that cobalt doping increases the Neel temperature (T(N)) of the CWT core. In general, the results show that the homogeneous dispersion of Co in iron precursors improves the stability of the final CWT nanoparticles. Moreover, the CoFe2O4 shells formed following oxidation increase the oxidation resistance of the CWT cores and enhance their anisotropy energy. PMID- 26243166 TI - Growth of highly textured PbTiO3 films on conductive substrate under hydrothermal conditions. AB - Perovskite structure (ABO(3)) thin films have wide applications in electronic devices due to their unique properties, including high dielectric permittivity, ferroelectricity and piezoelectric coupling. Here, we report an approach to grow highly textured thick lead titanate (PbTiO(3)) filmson conductive substrates by a two-step hydrothermal reaction. Initially, vertically aligned TiO(2) nanowire arrays are grown on fluorine-doped tin oxide (FTO) coated glass, which act as template crystals for conversion to the perovskite structure. The PbTiO(3) films are then converted from TiO(2) NW arrays by diffusing Pb(2+) ions into the template through a second hydrothermal reaction. The dielectric permittivity and piezoelectric coupling coefficient (d(33)) of the PbTiO(3) films are as high as 795 at 1 kHz and 52 pm V-1, respectively. The reported process can also potentially be expanded for the assembly of other complex perovskite ATiO(3) (A = Ba, Ca, Cd,etc) films by using the highly aligned TiO(2) NW arrays as templates. Therefore, the approach introduced here opens up a new door to synthesize ferroelectric thin films on conductivesubstrates for application in sensors, actuators, and ultrasonic transducers that are important in various industrial and scientific areas. PMID- 26243167 TI - Uncertainties in diagnosis, treatment and prevention of trichinellosis. AB - This review summarizes expert opinion and evidence on the diagnosis, treatment and prevention of trichinellosis. Laboratory test results are not sufficiently sensitive for the diagnosis of individual patients when outbreaks are suspected. A likely diagnosis depends on identifying a potential common source of exposure supported by detection of antibodies to Trichinella antigens in a higher than expected proportion of exposed patients. Expert opinion is discordant, but for patients with symptomatic disease, there are theoretical reasons to recommend treatment with albendazole (rather than mebendazole) taken with fatty meals and prednisone. Education of the public is probably not a reliable way to prevent trichinellosis and when feasible should be augmented with mandatory testing of all potentially infected meat. PMID- 26243165 TI - Barnidipine or Lercanidipine on Echocardiographic Parameters in Hypertensive, Type 2 Diabetics with Left Ventricular Hypertrophy: A Randomized Clinical Trial. AB - The aim of this study was to evaluate the effects of lercanidipine or barnidipine on echocardiographic parameters, in hypertensive, type 2 diabetics with left ventricular hypertrophy. One hundred and forty-four patients were randomized to lercanidipine, 20 mg/day, or barnidipine, 20 mg/day, in addition to losartan, 100 mg/day, for 6 months. We evaluated: blood pressure, fasting plasma glucose (FPG), glycated hemoglobin (HbA(1c)), lipid profile, creatinine, estimated glomerular filtration rate (eGFR), sodium, potassium, and acid uric. Echocardiography was performed at baseline and after 6 months. Both lercanidipine and barnidipine decreased blood pressure. Left ventricular mass index was reduced to a greater extent with barnidipine + losartan. Interventricular septal thickness in diastole was reduced by barnidipine + losartan. Posterior wall thickness in diastole was decreased by both treatments, even if barnidipine + losartan were more effective. Ratio of peak early diastolic filling velocity to peak filling velocity at atrial contraction was increased by barnidipine + losartan, but not by lercanidipine + losartan. Finally, isovolumetric relaxation and time and left atrial volume index were reduced by barnidipine + losartan, while lercanidipine + losartan did not affect them. In conclusion, barnidipine + losartan provided a greater improvement of echocardiographic parameters compared to lercanidipine + losartan. PMID- 26243168 TI - Performance evaluation of Puritan(r) universal transport system (UniTranz-RTTM) for preservation and transport of clinical viruses. AB - The ability of a non-propagating microbial transport medium to maintain the viability of clinically relevant viruses was compared to a similar commercial medium to establish performance equivalence. Two dilutions of stock of test viruses, namely adenovirus (AdV), cytomegalovirus (CMV), echovirus Type 30 (EV), herpes simplex virus (HSV) types 1 and 2, influenza A, parainfluenza 3 (PIV), respiratory syncytial virus (RSV), and varicella zoster virus (VZV), were spiked into Puritan(r) Medical Products Company Universal Transport System (UniTranz RTTM) and BD(TM) Universal Viral Transport System (UVT) and incubated at 4 degrees C and room temperature (RT) for up to 72 hr. Post incubation assessment of recovery of AdV, EV, HSV-2, PIV, and VZV from UniTranz-RTTM and UVT using shell vial assays followed by immunofluorescence staining demonstrated statistically significant differences between both transport media. In general, significantly higher recoveries of AdV, EV, and VZV were found from UniTranz-RTTM than UVT whereas HSV-2 and PIV were recovered better from UVT than UniTranz-RTTM, under specific test conditions. The recovery of HSV-1, influenza A, PIV, and RSV showed no significant differences between transport media. Sulforhodamine B-based assay analysis of UniTranz-RTTM lots prior to and at expiration exhibited no cytotoxicity. The overall results of the study validate the full performance of UniTranz-RTTM as a viral transport medium and establish its effectiveness on par with the UVT. PMID- 26243170 TI - Pituitary Infarct Masquerading as a Pituitary Abscess. PMID- 26243171 TI - Quantifying the origin of inter-adsorbate interactions on reactive surfaces for catalyst screening and design. AB - The adsorption energy of reactant molecules and reaction intermediates is one of the key descriptors of catalytic activity of surfaces and is commonly used as a metric in screening materials for design of heterogeneous catalysts. The efficacy of such screening schemes depends on the accuracy of calculated adsorption energies under reaction conditions. These adsorption energies can depend strongly on interactions between adsorbed molecules in the adlayer. However, these interactions are typically not accounted for in screening procedures that use DFT based zero-coverage adsorption energies. Identifying the physical mechanisms behind these interactions is essential to model realistic catalyst surfaces under reaction conditions and to understand the dependence of adsorption energies on reaction parameters like surface strain and composition. This article describes a method to quantitatively resolve the observed inter-adsorbate interactions into various direct adsorbate-adsorbate interactions (i.e. Coulombic and steric) and surface-mediated interactions (i.e. adsorbate-induced surface relaxation and change in electronic structure) by combining density functional theory and cluster-expansion calculations of coverage-dependent adsorption energies. The approach is implemented on a model catalyst surface of FeS2(100) reacting with H2S molecules. We find that the adsorption energy of H2S molecules can be affected by over 0.55 eV by the repulsive inter-adsorbate interactions caused primarily by the adsorbate-induced changes to the electronic structure of the FeS2 surface. These interactions also show a strong monotonic dependence on surface strain, being three times stronger on compressively strained surfaces than on surfaces under tensile strain. The large magnitude of inter-adsorbate interactions as well as their strong dependence on lattice strain demonstrate the need for using coverage-dependent adsorption energies for more accurate screening, for example for strained catalytic systems like core-shell and overlayer structures. PMID- 26243172 TI - Identifying a set that contains the best dynamic treatment regimes. AB - A dynamic treatment regime (DTR) is a treatment design that seeks to accommodate patient heterogeneity in response to treatment. DTRs can be operationalized by a sequence of decision rules that map patient information to treatment options at specific decision points. The sequential, multiple assignment, randomized trial (SMART) is a trial design that was developed specifically for the purpose of obtaining data that informs the construction of good (i.e. efficacious) decision rules. One of the scientific questions motivating a SMART concerns the comparison of multiple DTRs that are embedded in the design. Typical approaches for identifying the best DTRs involve all possible comparisons between DTRs that are embedded in a SMART, at the cost of greatly reduced power to the extent that the number of embedded DTRs (EDTRs) increase. Here, we propose a method that will enable investigators to use SMART study data more efficiently to identify the set that contains the most efficacious EDTRs. Our method ensures that the true best EDTRs are included in this set with at least a given probability. Simulation results are presented to evaluate the proposed method, and the Extending Treatment Effectiveness of Naltrexone SMART study data are analyzed to illustrate its application. PMID- 26243173 TI - Production of a modified peptide clavanin in Pichia pastoris: cloning, expression, purification and in vitro activities. AB - Antimicrobial peptides are one of the most promising peptide-based drugs due to their enormous potential as novel biopharmaceuticals in both human and animal industries. In order to develop strategies to over produce such molecules, heterologous production of a modified version of clavanin A, here named clavanin MO (clavMO), was successfully achieved in the methylothopic yeast Pichia pastoris. ClavMO was fused to thioredoxin as a carrier protein and the construction was tested using two promoters, PAOX1 and PGAP, based on either induced or constitutive expression systems, respectively. After growth in 5 L Bioreactor, clavMO-thio was recovered and purified through size exclusion chromatography. Our findings show that both constitutive and inducible expression systems produce active clavMO fused to thioredoxin against both Gram-negative Klebsiella pneumoniae and Gram-positive Staphylococcus aureus microorganisms. PMID- 26243174 TI - Systemic sclerosis: a critical digest of the recent literature. AB - Systemic sclerosis is a complex chronic disease characterised by chronic multisystem involvement of skin and internal organs. We reviewed all the articles published during the last 12 months on systemic sclerosis and in this article we provide a critical analysis of the most relevant studies regarding the pathogenesis, classification and management of the disease. PMID- 26243175 TI - Impact of silicone prosthesis on hand function, grip power and grip-force tracking ability after finger amputation. AB - BACKGROUND: Literature mostly describes the cosmetic role of prostheses for finger amputation. The impact on hand function has not been systematically explored. OBJECTIVES: Our aim was to describe the impact of silicone finger prostheses on hand function and gripping ability. STUDY DESIGN: Prospective descriptive cross-sectional study. METHODS: We included 42 adult patients with partial or complete single- or multiple-digit amputation of one hand. We evaluated hand function of the injured hand without and with the prosthesis with the Southampton Hand Assessment Procedure, and grip power and tracking ability with a grip-force tracking system. RESULTS: Southampton Hand Assessment Procedure grip index scores were slightly higher when using the prosthesis as compared to not using it (though not reaching the minimum real difference reported in the literature), except for lateral grip. Grip power was not significantly affected by prosthesis use for power grip and lateral grip and slightly diminished for tip grip. Tracking errors only differed with respect to the signal type but not with respect to using the prosthesis. CONCLUSION: A minimum improvement of hand function can be expected at best with silicone prostheses for finger amputation, accompanied by a slight decrease in tip grip power. CLINICAL RELEVANCE: Based on our results, an evidence-based explanation can be given to patients after finger amputation regarding the functional benefits that can be expected from a silicone prosthesis. PMID- 26243176 TI - A new theory of essential hypertension based on analysis of the association between a polymorphism of the alpha2-adrenoceptor at the 10q24-q26 locus and hypertension in African-Americans. AB - Some key historical observations about essential hypertension (HTN) are reviewed, analyzed logically, and used to construct a new theory of hypertension. The historical observations are as follows: Lockette reported a statistical association between HTN in African-Americans and the 6.3-kb allele of a restriction fragment-length polymorphism of the gene for the alpha2-adrenoceptor, which is found on platelets. Individuals carrying at least one copy of the 6.3-kb allele had increased in vitro epinephrine-induced platelet aggregation. Systemic or blood-wide platelet activation (SPA) induced by epinephrine has been shown to be an in vivo feature of HTN, and serotonin and thromboxane A2, two vasoconstrictors released by activated platelets, synergize in vitro with angiotensin II. Esler showed that there is increased noradrenergic drive in the heart and kidney in HTN, although renin levels are usually normal. Mulvany's group showed that small arteries controlling vascular resistance undergo remodeling in HTN. Putting together these observations leads to the following theory. Essential HTN is a disease in which the brainstem set point for blood pressure (BP) is reset, which causes the autonomic nervous system to release increased norepinephrine in the heart and kidney and increased epinephrine from the adrenal medulla. Epinephrine release causes SPA. In the first stage of the disease, when renin is high, serotonin and thromboxane A2 released by activated platelets synergize with high angiotensin II to raise BP. Rising BP causes vascular remodeling, a structural attempt at autoregulation of blood flow which maintains normal flow artery-by-artery but has the side-effect of increasing total peripheral resistance (TPR), even beyond that caused by high renin. The presence of ever rising TPR and, therefore, ever rising BP, gradually overcomes the effect of noradrenergic drive in the kidney and leads to suppression of renin release by the juxtaglomerular apparatus. Renin levels fall pari passu with rising TPR caused by vascular remodeling. In the second stage of the disease, when renin has fallen back to normal (or low), increased TPR caused by vascular remodeling persists as a factor raising BP. PMID- 26243177 TI - Management and visual outcome of SCH in vitrectomized eye. AB - Suprachoroidal hemorrhage is a rare complication of all types of intraocular surgery and is always associated with poor visual outcome or even eye enucleation. Better understanding of SCH during various types of intraocular surgery can help surgeons to avoid this devastating complication and to optimally treat patients. We encountered three cases of SCH in vitrectomized eyes and found that there were some common characteristics compared to SCH developed in other intraocular surgeries. We hypothesized that SCH in vitrectomized eye might be localized, not severe and ended up comparably good without surgical intervention. Then we analyzed the risk factors and incidence, characteristics and severity, management and prognosis of SCH in vitrectomized eye to evaluate the hypothesis. PMID- 26243178 TI - HPLC-MS(n) Identification of Betalain Profile of Different Beetroot (Beta vulgaris L. ssp. vulgaris) Parts and Cultivars. AB - The distribution of betalains in peel, flesh, and petioles of yellow and red beetroot cultivars has been investigated using an High-performance liquid chromatography (HPLC) system with electrospray mass spectrometry. Differences in the levels of betacyanins and betaxanthins between different colored cultivars were individually determined for 3 plant parts. The content of almost all analyzed compounds decreased in the following order: peel > flesh > petiole. Betanin/isobetanin pigments comprised a major portion of the relative peak area measured in red beetroot peel. Isobetanin relative peak areas were also high in leaf petioles (68.94% to 74.16%) of red colored cultivars. However, betacyanins were completely absent from the extracts of all analyzed parts of yellow beet. Glutamine-bx represented a very high relative peak area (59.54% to 64.18%) in flesh of red-colored cultivars analyzed in the study. Our results indicate that red beet cultivars can be utilized as a potential source of red and yellow natural colorants. However, differences in pigment composition among different beetroot parts must be considered and in order to maximize the pigment yields petioles can also be used as a source rich in specific betalain compounds. PMID- 26243179 TI - The effects of 18-h fasting with low-carbohydrate diet preparation on suppressed physiological myocardial (18)F-fluorodeoxyglucose (FDG) uptake and possible minimal effects of unfractionated heparin use in patients with suspected cardiac involvement sarcoidosis. AB - BACKGROUND: (18)F-fluorodeoxyglucose (FDG) PET plays an important role in the detection of cardiac involvement sarcoidosis (CS). However, diffuse left ventricle (LV) wall uptake sometimes makes it difficult to distinguish between positive uptake and physiological uptake. The aims of this study were to evaluate the effects of 18-h fasting with low-carbohydrate diet (LCD) vs a minimum of 6-h fasting preparations on diffuse LV FDG uptake and free fatty acid (FFA) levels in patients with suspected CS. METHODS: Eighty-two patients with suspected CS were divided into 2 preparation protocols: one with a minimum 6-h fast without LCD preparation (group A, n = 58) and the other with a minimum 18-h fast with LCD preparation (group B, n = 24). All patients also received intravenous unfractionated heparin (UFH; 50 IU/kg) before the injection of FDG. RESULTS: Group A showed a higher percentage of diffuse LV uptake than did group B (27.6 vs 0.0%, P = .0041). Group B showed higher FFA levels (1159.1 +/- 393.0, 650.5 +/ 310.9 MUEq/L, P < .0001) than did group A. Patients with diffuse LV uptake (n = 16) showed lower FFA levels than did other patients (n = 66) (432.1 +/- 296.1, 888.4 +/- 381.4 MUEq/L, P < .0001). UFH administration significantly increased FFAs in both groups, even in the patients with diffuse LV FDG uptake. CONCLUSIONS: The 18-h fast with LCD preparation significantly reduced diffuse LV uptake and increased FFA levels. In particular, the FFA level was significantly lower in patients with LV diffuse uptake than in patients without LV diffuse uptake. Acutely increasing plasma FFA through the use of UFH may not have a significant role in reducing physiological LV FDG uptake. PMID- 26243180 TI - Bifunctional Mesoporous Carbon Nitride: Highly Efficient Enzyme-like Catalyst for One-pot Deacetalization-Knoevenagel Reaction. AB - Recently, mesoporous carbon nitride (MCN) has aroused extensive interest for its potential applications in organocatalysis, photo- and electrochemistry and CO2 capture. However, further surface functionalization of MCN for advanced nanomaterials and catalysis still remains very challenging. Here we show that acidic carboxyl groups can be smoothly introduced onto the surface of well ordered MCN without annihilation between the introduced acid groups and MCN's inherent basic groups through a facile UV light oxidation method. The functionalization generates a novel bifunctional nanocatalyst which offers an enzyme-like catalytic performance in the one-pot deacetalization-Knoevenagel reaction of benzaldehyde dimethylacetal and malononitrile with 100% conversion and more than 99% selectivity due to the cooperative catalysis between the acid and base groups separated on the surface of the catalyst. The results provide a general method to create multifunctional nanomaterials and open new opportunities for the development of high efficient catalyst for green organic synthesis. PMID- 26243181 TI - Assessment of urethral vascularity using 2D colour Doppler high-frequency endovaginal ultrasonography in women treated for symptomatic stress urinary incontinence: 1-year prospective follow-up study. AB - INTRODUCTION: Urethral vascularity is responsible for organ perfusion. It is also believed to contribute to maintaining the normal tension in the urethral mucosa and contributes to approximately one third of urethral closure pressure. We hypothesised that in women undergoing treatment for stress urinary incontinence (SUI), there is no change in blood flow intensity. METHODS: In this pilot study we recruited women attending the urogynaecology clinics between July and October 2009. Exclusion criteria included symptoms of pelvic organ prolapse or urinary tract infection. Colour Doppler ultrasound was performed at the level of the mid urethra using a high-frequency (9-12 MHz) endovaginal ultrasonography (EVUS) focusing on the following vascular parameters: flow velocity (V), area of the vessels (A), intensity of perfusion (I), Tissue Pulsatility Index (TPI) and Tissue Resistance Index (TRI). Vascular assessments were repeated at 1 year. RESULTS: We examined 67 women with symptoms of SUI (17 women had surgery and 50 conservative management, i.e., pelvic floor muscle exercises). The mean (+/- SD) age in the conservative and surgical groups was 46 (+/-11) and 40 (+/-9) years respectively and median (range) parity was 2 (0-8) in both groups. Compared to baseline, no statistically significant differences were observed within each group (p > 0.05) or between the values of vascular parameters (V, A, I, TRI and TPI) at 1 year. There was also no difference in vascular parameters between the two groups. CONCLUSION: At 12 months there is no change in vascularity parameters in women who opt for conservative or surgical treatment of SUI. PMID- 26243182 TI - Vaginal adhesions after transvaginal pelvic reconstructive surgeries: prevalence and clinical implications. AB - INTRODUCTION AND HYPOTHESIS: Our aim was to assess the prevalence of vaginal adhesions after transvaginal pelvic reconstructive surgeries and evaluate relevant risk factors and impact on surgical outcome and sexual function. METHODS: This was a retrospective study examining medical records of all patients undergoing transvaginal pelvic reconstructive surgeries for pelvic organ prolapse (POP) at our institution between January 2006 and December 2007. RESULTS: One hundred and ninety -nine women were included in the study, of whom 165 had a comprehensive pre- and postoperative follow-up assessment and were available for final analysis. Vaginal adhesions were reported in 18 (10.9%) women during the first follow-up visit 36 +/- 34 days postoperatively. Adhesions were reported to be successfully separated manually in all cases during pelvic examination. Patients with or without vaginal adhesions showed no statistically significant differences in demographic, obstetric, or clinical characteristics or in severity of prolapse. No statistically significant correlation was found between any specific surgical procedure and the risk of developing vaginal adhesions. Rates of prolapse recurrence, postoperative vaginal narrowing and dyspareunia were not significantly different between groups. CONCLUSIONS: Vaginal adhesion formation is a relatively common complication after transvaginal pelvic reconstructive surgeries unrelated to preoperative degree of prolapse or to the type of surgery. If adhesions are separated manually at an early stage, surgical outcome and sexual function do not seem to be adversely affected. PMID- 26243183 TI - Highly sensitive and fast phototransistor based on large size CVD-grown SnS2 nanosheets. AB - A facile and fruitful CVD method is reported for the first time, to synthesize high-quality hexagonal SnS2 nanosheets on carbon cloth via in situ sulfurization of SnO2. Moreover, highly sensitive phototransistors based on SnS2 with an on/off ratio surpassing 10(6) under ambient conditions and a rising time as short as 22 ms under vacuum are fabricated, which are superior than most phototransistors based on LMDs. Electrical transport measurements at varied temperatures together with theoretical calculations verify that sulfur vacancies generated by the growth process would induce a defect level near the bottom of the conduction band, which significantly affects the performance of the SnS2 device. These findings may open up a new pathway for the synthesis of LMDs, shed light on the effects of defects on devices and expand the building blocks for high performance optoelectronic devices. PMID- 26243184 TI - An Updated and Comprehensive Meta-Analysis of Association Between Seven Hot Loci Polymorphisms from Eight GWAS and Glioma Risk. AB - Eight genome-wide association studies (GWASs) found that seven loci (rs2736100, rs4295627, rs4977756, rs498872, rs11979158, rs2252586, rs6010620) polymorphisms could elevate the risk of glioma, one of the most common types of primary brain cancer in adults. However, the replication studies about these seven loci obtained inconsistent results. In order to derive a more accurate estimation about the relationship between the selected single-nucleotide polymorphism (SNP) and susceptibility to glioma, we conducted a meta-analysis containing all eligible published case control studies to evaluate the association. An overall literature search was conducted using the database of PubMed, Science Direct, China national knowledge infrastructure (CNKI), and Embase. Seventeen articles with 25 studies were included in the meta-analysis. Glioma risk (odds ratio, OR; 95 % confidential interval, 95 %CI) was estimated with the random-effect model or the fixed-effects model. STATA 12.0 was applied to analyze all statistical data. Results showed that seven hot loci were all associated with increased risk of glioma (rs2736100, OR = 1.28, 95 %CI = 1.23-1.32; rs4295627, OR = 1.34, 95 %CI = 1.21-1.47; rs4977756, OR = 1.24, 95 %CI = 1.20-1.28; rs498872, OR = 1.24, 95 %CI = 1.15-1.33; rs6010620, OR = 1.29, 95 %CI = 1.24-1.35; rs11979158: OR = 1.18, 95 %CI = 1.10-1.25; rs2252586: OR = 1.18, 95 %CI = 1.10-1.25). Additionally, subgroup analysis by stages of glioma found that variation of rs11979158 had stronger relationship with high-grade (OR = 1.32, 95 %CI = 1.19-1.45) than low grade glioma (OR = 1.12, 95 % CI = 1.03-1.21). Similarly, stratified analysis of rs2252586 by stages revealed the similar trend, with OR of 1.26 (95 %CI = 1.17 1.35) in high-grade glioma and OR of 1.15 (95 %CI = 1.08-1.22) in low-grade glioma. In summary, the present study showed that mutations of the seven loci could elevate the risk of glioma significantly. However, more other factors that could be related with glioma should be considered in further studies. PMID- 26243187 TI - Discussion of "Deductive derivation and turing-computerization of semiparametric efficient estimation" by Frangakis et al. PMID- 26243185 TI - Thyroid Hormone Potentially Benefits Multiple Sclerosis via Facilitating Remyelination. AB - Myelin destruction due to inflammatory damage of oligodendrocytes (OLs) in conjunction with axonal degeneration is one of the major histopathological hallmarks of multiple sclerosis (MS), a common autoimmune disorder affecting the central nervous system (CNS). Therapies over the last 20 years mainly focus on the immune system and, more specifically, on the modulation of immune cell behavior. It seems to be effective in MS with relapse, while it is of little benefit to progressive MS in which neurodegeneration following demyelination outweighs inflammation. Otherwise, remyelination, as a result of oligodendrocyte production from oligodendrocyte precursor cells (OPCs), is considered to be a potential target for the treatment of progressive MS. In this review, positive effects of remyelination on MS will be discussed in view of the critical role played by thyroid hormone (TH), focusing on the following points: (1) promising treatment of TH on MS that potentially targets to remyelination; (2) the active role of TH that is able to promote remyelination; (3) the regulative role of TH that works on endogenous stem and precursor cells; (4) the effect of TH on gene transcription; and (5) a working hypothesis which is developed that TH can alleviate MS by promoting remyelination, and the mechanism of which is its regulative role in gene transcription of OPCs. PMID- 26243186 TI - Cocaine-Mediated Autophagy in Astrocytes Involves Sigma 1 Receptor, PI3K, mTOR, Atg5/7, Beclin-1 and Induces Type II Programed Cell Death. AB - Cocaine, a commonly used drug of abuse, has been shown to cause neuropathological dysfunction and damage in the human brain. However, the role of autophagy in this process is not defined. Autophagy, generally protective in nature, can also be destructive leading to autophagic cell death. This study was designed to investigate whether cocaine induces autophagy in the cells of CNS origin. We employed astrocyte, the most abundant cell in the CNS, to define the effects of cocaine on autophagy. We measured levels of the autophagic marker protein LC3II in SVGA astrocytes after exposure with cocaine. The results showed that cocaine caused an increase in LC3II level in a dose- and time-dependent manner, with the peak observed at 1 mM cocaine after 6-h exposure. This result was also confirmed by detecting LC3II in SVGA astrocytes using confocal microscopy and transmission electron microscopy. Next, we sought to explore the mechanism by which cocaine induces the autophagic response. We found that cocaine-induced autophagy was mediated by sigma 1 receptor, and autophagy signaling proteins p-mTOR, Atg5, Atg7, and p-Bcl-2/Beclin-1 were also involved, and this was confirmed by using selective inhibitors and small interfering RNAs (siRNAs). In addition, we found that chronic treatment with cocaine resulted in cell death, which is caspase-3 independent and can be ameliorated by autophagy inhibitor. Therefore, this study demonstrated that cocaine induces autophagy in astrocytes and is associated with autophagic cell death. PMID- 26243188 TI - Latitude, sun exposure and vitamin D supplementation: associations with quality of life and disease outcomes in a large international cohort of people with multiple sclerosis. AB - BACKGROUND: A growing evidence base implicates vitamin D, sun exposure and latitude in the aetiology of multiple sclerosis (MS), however there are less data on the associations of these variables with disease outcomes. METHODS: We undertook a cross-sectional survey of over 2000 people with MS recruited through internet platforms, seeking self-reported data on geographical location, intentional sun exposure for health, and supplementation with vitamin D, among other lifestyle variables. We also requested data on health-related quality of life (MSQOL-54), self-reported doctor-diagnosed relapse rate, and disability (Patient Determined Disease Steps). Bivariate and multivariate analyses were used for comparisons, including multiple linear regression modeling. RESULTS: Of 2301 participants, 82.3 % were female, median age was 45 years (IQR 38-53 years), with a median time since diagnosis of 6 years (IQR 3-12 years), the majority (61.6 %) having relapsing-remitting MS. Nearly two-thirds (64.6 %) lived in the Northern hemisphere, mostly in developed countries. Most (66.8 %) reported deliberate sun exposure to raise their vitamin D level, and the vast majority (81.8 %) took vitamin D supplements, mostly 2000-5000 IU a day on average. Unadjusted regression modeling incorporating deliberate sun exposure, latitude and vitamin D supplementation showed strong associations of sun exposure with HRQOL which disappeared when controlling for gender, age, disability, physical activity, and fish consumption. In contrast, associations between vitamin D supplementation and HRQOL were maintained adjusting for these variables, with a dose-response effect. Only latitude had significant adjusted associations with disability, with an increase of latitude by one degree (further from the equator) predicting increased odds of moderate disability (OR 1.02 (95 % CI 1.01-1.04)) or high disability (OR 1.03 (95 % CI 1.01-1.05)) compared to no/mild disability. Similarly, latitude was related to relapse rate, with increase in latitude of 1 degree associated with increased odds of having more relapses over the previous year (1.01 (1.00-1.02)). CONCLUSIONS: We detected significant associations between latitude, deliberate sun exposure and vitamin D supplementation and health outcomes of this large group of people with MS. Vitamin D is likely to have a key role in these associations and its role in the health outcomes of people with MS urgently requires further study. PMID- 26243189 TI - Plant receptor complexes. AB - In this issue of Science Signaling, Somssich and co-workers use fluorescence techniques to show the dynamics that occur during the activation of two different receptor complexes in living plant cells. PMID- 26243190 TI - Real-time dynamics of peptide ligand-dependent receptor complex formation in planta. AB - The CLAVATA (CLV) and flagellin (flg) signaling pathways act through peptide ligands and closely related plasma membrane-localized receptor-like kinases (RLKs). The plant peptide CLV3 regulates stem cell homeostasis, whereas the bacterial flg22 peptide elicits defense responses. We applied multiparameter fluorescence imaging spectroscopy (MFIS) to characterize the dynamics of RLK complexes in the presence of ligand in living plant cells expressing receptor proteins fused to fluorescent proteins. We found that the CLV and flg pathways represent two different principles of signal transduction: flg22 first triggered RLK heterodimerization and later assembly into larger complexes through homomerization. In contrast, CLV receptor complexes were preformed, and ligand binding stimulated their clustering. This different behavior likely reflects the nature of these signaling pathways. Pathogen-triggered flg signaling impedes plant growth and development; therefore, receptor complexes are formed only in the presence of ligand. In contrast, CLV3-dependent stem cell homeostasis continuously requires active signaling, and preformation of receptor complexes may facilitate this task. PMID- 26243192 TI - The ASK family kinases differentially mediate induction of type I interferon and apoptosis during the antiviral response. AB - Viral infection activates host defense mechanisms, including the production of type I interferon (IFN) and the apoptosis of infected cells. We investigated whether these two antiviral responses were differentially regulated in infected cells. We showed that the mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK) apoptosis signal-regulating kinase 1 (ASK1) was activated in cells by the synthetic double-stranded RNA analog polyinosinic:polycytidylic acid [poly(I:C)] and by RNA viruses, and that ASK1 played an essential role in both the induction of the gene encoding IFN-beta (IFNB) and apoptotic cell death. In contrast, we found that the MAPKKK ASK2, a modulator of ASK1 signaling, was essential for ASK1-dependent apoptosis, but not for inducing IFNB expression. Furthermore, genetic deletion of either ASK1 or ASK2 in mice promoted the replication of influenza A virus in the lung. These results indicated that ASK1 and ASK2 are components of the antiviral defense mechanism and suggested that ASK2 acts as a key modulator that promotes apoptosis rather than the type I IFN response. Because ASK2 is selectively present in epithelium-rich tissues, such as the lung, ASK2-dependent apoptosis may contribute to an antiviral defense in tissues with a rapid repair rate in which cells could be readily replaced. PMID- 26243193 TI - Prognosis, stage and oestrogen receptor status of contralateral breast cancer in relation to characteristics of the first tumour, prior endocrine treatment and radiotherapy. AB - AIM: A contralateral breast cancer (CBC) is today treated as an independent primary tumour, although recent data suggest risk and prognosis of CBC to be influenced by characteristics of and treatment given for the first tumour (BC1). We hereby investigate phenotypical and prognostic features of the second tumour (BC2) in relation to prior endocrine treatment and radiotherapy. METHODS: From a well-defined population-based cohort of CBC-patients, we have constructed a unique tissue-microarray including 600 pairs of primary tumours and CBCs. Breast cancer mortality was primary end-point for prognosis. RESULTS: Both oestrogen receptor (ER) status and stage was strongly correlated between BC1 and BC2 within CBC-pairs. Although BC2 had the highest prognostic impact, BC1 continued to influence prognosis after diagnosis of CBC. Patients diagnosed with two high stage tumours within a short time-interval had a particularly bad prognosis. Prior endocrine therapy and radiotherapy both correlated to ER-negativity of BC2. An ER-negative BC2 was associated with an inferior prognosis compared to an ER positive BC2 regardless of ER-status of BC1 or prior endocrine therapy. CONCLUSIONS: Our results suggest that both the residual prognostic impact of BC1, the possibility of contralateral metastasis, as well as prior treatment given, need to be considered when determining appropriate diagnostic work-up and treatment of CBC. In addition, radiation to the contralateral breast and risk of inducing CBC with an aggressive ER-negative phenotype should be considered when establishing new radiation treatment techniques. This study indicates loss of ER expression as an important 'endocrine treatment escape mechanism', although further studies are warranted. PMID- 26243191 TI - Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer. AB - Most patients with pancreatic ductal adenocarcinoma (PDA) present with metastatic disease at the time of diagnosis or will recur with metastases after surgical treatment. Semaphorin-plexin signaling mediates the migration of neuronal axons during development and of blood vessels during angiogenesis. The expression of the gene encoding semaphorin 3D (Sema3D) is increased in PDA tumors, and the presence of antibodies against the pleiotropic protein annexin A2 (AnxA2) in the sera of some patients after surgical resection of PDA is associated with longer recurrence-free survival. By knocking out AnxA2 in a transgenic mouse model of PDA (KPC) that recapitulates the progression of human PDA from premalignancy to metastatic disease, we found that AnxA2 promoted metastases in vivo. The expression of AnxA2 promoted the secretion of Sema3D from PDA cells, which coimmunoprecipitated with the co-receptor plexin D1 (PlxnD1) on PDA cells. Mouse PDA cells in which SEMA3D was knocked down or ANXA2-null PDA cells exhibited decreased invasive and metastatic potential in culture and in mice. However, restoring Sema3D in AnxA2-null cells did not entirely rescue metastatic behavior in culture and in vivo, suggesting that AnxA2 mediates additional prometastatic mechanisms. Patients with primary PDA tumors that have abundant Sema3D have widely metastatic disease and decreased survival compared to patients with tumors that have relatively low Sema3D abundance. Thus, AnxA2 and Sema3D may be new therapeutic targets and prognostic markers of metastatic PDA. PMID- 26243194 TI - An "oxhorn"-shaped V-Y advancement flap unilaterally pedicled on a nasal superficial musculoaponeurotic system for nasal reconstruction. AB - BACKGROUND: Laterally based nasalis myocutaneous flaps pedicled on the superior nasal superficial musculoaponeurotic system (SMAS), which contains the bilateral dorsal nasal arteries, have not been utilized for the reconstruction of nasal defects. METHODS: According to the location and size of the nasal defects, a V-Y advancement nasalis myocutaneous flap was designed along the proximal alar groove and nasolabial fold. The flap was superficially elevated from the perichondrium, and the nasal SMAS above the flap was dissected as the unilateral pedicle. After the flap was rotated and advanced to the defect, the secondary defect was primarily closed. RESULTS: A total of 20 cases of nasal defects, including six cases of nasal dorsum, five cases of nasal tip, four cases of nasal tip-alar junctions and five cases of nasal tip-dorsum junctions, were reconstructed using this method. The defect size ranged from 0.8 * 0.8 cm to 2 * 1.8 cm. All of the flaps survived with satisfactory aesthetics and function. All of the patients were postoperatively followed up for 6-12 months. CONCLUSION: Application of the V-Y advancement nasalis myocutaneous flaps pedicled on a nasal SMAS is appropriate for the reconstruction of small to medium sized nasal tips and peri tip defects, and it can achieve satisfactory results due to its simple design, convenient transfer, reliable blood supply and concealed incision. PMID- 26243195 TI - Reconstruction of skin defects in the medial cheek using lateral cheek rotation flap combined with Z-plasties. AB - BACKGROUND: Cervicofacial flaps are commonly used in the reconstruction of skin defects in regions such as the medial cheek and lower eyelid. However, their drawbacks include long flap incision, extensive undermining, and a high possibility of postoperative complications including distal flap necrosis and lower eyelid ectropion. METHODS: Nine cases of reconstruction of skin defects in the medial cheek and adjacent areas were performed using a lateral cheek rotation flap in combination with Z-plasties between October 2009 and August 2014. In the surgery, the defect was trimmed into a downward-pointing triangle, with the flap incision line starting from the bottom edge of the defect and extending outward in the lateral orbital direction in an arc until before the sideburn. After the flap was undermined, double or quadruple Z-plasties were performed along the lateral orbital incision line to elongate the flap. RESULTS: All flaps survived without the occurrence of complications such as hematoma, wound infection, distal flap necrosis, and lower eyelid ectropion. During the follow-up period, the flaps exhibited good color and texture. A natural looking cheek was restored without obvious scars. CONCLUSIONS: A lateral cheek rotation flap in combination with Z plasty is an optimal method for reconstruction of skin defects in the medial cheek and lower eyelid region. Compared to conventional cervicofacial flaps, the lateral cheek rotation flap was shown to have a variety of advantages, including a simpler operation, shorter flap incision, minimal undermining, and effective prevention of complications such as lower eyelid ectropion and distal flap necrosis. PMID- 26243196 TI - Functional lower lip reconstruction with the modified Bernard-Webster flap. AB - BACKGROUND: Lower lip defects after squamous cell carcinoma (SCC) excisions have been repaired by several surgical techniques. However, the functional reconstruction of full-thickness defects of the lower lip remains a therapeutic challenge. We therefore evaluated functional results of the modified Bernard Webster flap for the reconstruction of full-thickness lower lip defects after SCC excisions. METHODS: A prospective study was performed on all patients with lower lip full-thickness defects after SCC excisions greater than 1/3 of the lip, reconstructed with the modified Bernard-Webster flap in 2011-2013. Functional (sphincter, motor, and sensory functions) postoperative results were evaluated according to criteria previously adopted. RESULTS: Twelve lower lip defects were reconstructed without complications, except for two (16.7%) wound dehiscence successfully managed. Ten (83.3%) patients presented transient and permanent functional abnormalities in the recent and late postoperative assessments. Ten (83.3%) patients classified the late functional results as satisfactory. CONCLUSIONS: The modified Bernard-Webster flap proved to be an excellent alternative to repair full-thickness lower lip defects with more than 1/3 of the lower lip length, as it allowed the use of similar neighboring tissues, could be performed in one stage, and was functionally effective. PMID- 26243197 TI - Associations between individual socioeconomic position, neighbourhood disadvantage and transport mode: baseline results from the HABITAT multilevel study. AB - BACKGROUND: Understanding how different socioeconomic indicators are associated with transport modes provide insight into which interventions might contribute to reducing socioeconomic inequalities in health. The purpose of this study was to examine associations between neighbourhood-level socioeconomic disadvantage, individual-level socioeconomic position (SEP), and usual transport mode. METHODS: This investigation included 11,036 residents from 200 neighbourhoods in Brisbane, Australia. Respondents self-reported their usual transport mode (car or motorbike, public transport, walking or cycling). Indicators for individual-level SEP were education, occupation and household income; and neighbourhood disadvantage was measured using a census-derived index. Data were analysed using multilevel multinomial logistic regression. High SEP respondents and residents of the most advantaged neighbourhoods who used a private motor vehicle as their usual form of transport was the reference category. RESULTS: Compared with driving a motor vehicle, the odds of using public transport were higher for white collar employees (OR 1.68, 95% CrI 1.41-2.01), members of lower income households (OR 1.71 95% CrI 1.25-2.30) and residents of more disadvantaged neighbourhoods (OR 1.93, 95% CrI 1.46-2.54); and lower for respondents with a certificate-level education (OR 0.60, 95% CrI 0.49-0.74) and blue collar workers (OR 0.63, 95% CrI 0.50-0.81). The odds of walking for transport were higher for the least educated (OR 1.58, 95% CrI 1.18-2.11), those not in the labour force (OR 1.94, 95% CrI 1.38-2.72), members of lower income households (OR 2.10, 95% CrI 1.23-3.64) and residents of more disadvantaged neighbourhoods (OR 2.73, 95% CrI 1.46-5.24). The odds of cycling were lower among less educated groups (OR 0.31, 95% CrI 0.19 0.48). CONCLUSIONS: The relationships between socioeconomic characteristics and transport modes are complex, and provide challenges for those attempting to encourage active forms of transportation. Further work is required exploring the individual-level and neighbourhood-level mechanisms behind choice of transport mode, and what factors might influence individuals from different socioeconomic backgrounds to change to more active transport modes. PMID- 26243200 TI - Mammography Screening Still Brings Mixed Advice. PMID- 26243198 TI - miRegulome: a knowledge-base of miRNA regulomics and analysis. AB - miRNAs regulate post transcriptional gene expression by targeting multiple mRNAs and hence can modulate multiple signalling pathways, biological processes, and patho-physiologies. Therefore, understanding of miRNA regulatory networks is essential in order to modulate the functions of a miRNA. The focus of several existing databases is to provide information on specific aspects of miRNA regulation. However, an integrated resource on the miRNA regulome is currently not available to facilitate the exploration and understanding of miRNA regulomics. miRegulome attempts to bridge this gap. The current version of miRegulome v1.0 provides details on the entire regulatory modules of miRNAs altered in response to chemical treatments and transcription factors, based on validated data manually curated from published literature. Modules of miRegulome (upstream regulators, downstream targets, miRNA regulated pathways, functions, diseases, etc) are hyperlinked to an appropriate external resource and are displayed visually to provide a comprehensive understanding. Four analysis tools are incorporated to identify relationships among different modules based on user specified datasets. miRegulome and its tools are helpful in understanding the biology of miRNAs and will also facilitate the discovery of biomarkers and therapeutics. With added features in upcoming releases, miRegulome will be an essential resource to the scientific community. AVAILABILITY: http://bnet.egr.vcu.edu/miRegulome. PMID- 26243201 TI - Using Sound To Separate Circulating Tumor Cells. PMID- 26243199 TI - Amniotic fluid exerts a neurotrophic influence on fetal neurodevelopment via the ERK/GSK-3 pathway. AB - BACKGROUND: The fetus is surrounded by the amniotic fluid (AF) contained by the amniotic sac of the pregnant female. The AF is directly conveyed to the fetus during pregnancy. Although AF has recently been reported as an untapped resource containing various substances, it remains unclear whether the AF could influence fetal neurodevelopment. RESULTS: We used AF that was extracted from embryos at 16 days in pregnant SD rat and exposed the AF to the neural cells derived from the embryos of same rat. We found that the treatment of AF to cortical neurons increased the phosphorylation in ERK1/2 that is necessary for fetal neurodevelopment, which was inhibited by the treatment of MEK inhibitors. Moreover, we found the subsequent inhibition of glycogen synthase kinase-3 (GSK 3), which is an important determinant of cell fate in neural cells. Indeed, AF increased the neural clustering of cortical neurons, which revealed that the clustered cells were proliferating neural progenitor cells. Accordingly, we confirmed the ability of AF to increase the neural progenitor cells through neurosphere formation. Furthermore, we showed that the ERK/GSK-3 pathway was involved in AF-mediated neurosphere enlargement. CONCLUSIONS: Although the placenta mainly supplies oxygenated blood, nutrient substances for fetal development, these findings further suggest that circulating-AF into the fetus could affect fetal neurodevelopment via MAP kinases-derived GSK-3 pathway during pregnancy. Moreover, we suggest that AF could be utilized as a valuable resource in the field of regenerative medicine. PMID- 26243202 TI - American Association of Cancer Research Showcases Immunotherapy Advances. PMID- 26243205 TI - Nitric Oxide Inhibitors Hit Target for Triple-Negative Breast Cancer. PMID- 26243207 TI - Evaluation of the Zenith low-profile abdominal aortic aneurysm stent graft. AB - BACKGROUND: Low-profile (LP) stent grafts are now commercially available in Europe for endovascular aortic aneurysm repair (EVAR). In this study the midterm outcomes and characteristics of patients treated with this last generation of stent grafts were compared with a cohort of patients treated with "standard profile" (SP) stent grafts. METHODS: The current study enrolled all patients treated for elective EVAR by the SP Zenith Flex stent graft (Cook Medical, Bloomington, Ind) between March 2010 and November 2011 and patients treated for elective EVAR by the Zenith LP stent graft (Cook Medical) between November 2011 and March 2013. All patients had a follow-up >18 months. Preoperative computed tomography angiograms were analyzed on a dedicated three-dimensional workstation. All data were prospectively collected in an electronic database and retrospectively analyzed. A comparative study was conducted. RESULTS: The present study included 208 patients (107 SP and 101 LP). Patients' physiologic characteristics were similar in both groups. The iliac anatomy was considered "more challenging" in LP patients: respectively, 7% and 22% (P = .002) of SP and LP patients had bilateral external iliac diameter <7 mm; and 16% and 34% (P = .005) had a combination of an external iliac diameter <7 mm and an iliac tortuosity ratio index >1.5. No 30-day deaths were documented. The 24-month freedom from reintervention and overall survival rates after SP and LP were, respectively, 88% and 91% (P = .450) and 92% and 96% (P = .153). The 24-month rates for freedom from sac expansion and from limb occlusion were 96.4% and 98.7% (P = .320) and 92% and 95% (P = .293), respectively. One patient in each group presented with a type I endoleak during follow-up, and two LP patients presented with a type III endoleak (P = .235). CONCLUSIONS: This study demonstrates that the last-generation LP stent grafts have favorable midterm outcomes similar to SP stent grafts despite being used to treat more patients with unfavorable iliac anatomy. PMID- 26243206 TI - One-year outcomes from the international multicenter study of the Zenith Alpha Thoracic Endovascular Graft for thoracic endovascular repair. AB - OBJECTIVE: This study evaluated the safety and effectiveness of the Zenith Alpha Thoracic Endovascular Graft (Cook Medical, Bloomington, Ind) for the treatment of descending thoracic aortic aneurysms and large ulcers. METHODS: The Zenith Alpha Thoracic Endovascular Graft, with a 16F to 20F delivery system, was developed to address vascular access issues associated with larger-profile devices and to increase conformability in tortuous anatomy. This prospective, nonrandomized, multicenter study was conducted in Europe, Japan, and the United States. The main anatomical inclusion criteria included proximal neck seal zone of >=20 mm, aortic arch radius of >=20 mm, and a neck diameter of 15 to 42 mm. Patients were evaluated preprocedure, predischarge, and postdischarge 1, 6, and 12 months and yearly thereafter through 5 years. RESULTS: Between March 2010 and January 2013, 110 patients (64 men and 46 women; mean age, 72 +/- 10 years) were enrolled in the study for the treatment of descending thoracic aortic aneurysms (n = 90) or ulcers (n = 20). Access was percutaneous in 36% (40 of 110) of patients. The study device was successfully implanted in all but two patients (both due to inability to gain access or advance to the target treatment site). There was no 30-day mortality. Five deaths occurred <=1 year (only one was aneurysm-related by independent adjudication), resulting in a 95% freedom from all-cause mortality and a 99% freedom from thoracic aortic aneurysm-related mortality. At one or more time points <=1 year, type I endoleak (all distal) was observed in 4 patients, type III endoleak in 2, and aneurysm growth in 4. Five patients experienced stroke <=1 year (2 procedure-related). No aortic rupture, paraplegia, paralysis, or permanent spinal cord injury was observed <=1 year. CONCLUSIONS: Early outcomes after Zenith Alpha implantation appear promising and suggest expanded thoracic endovascular aortic repair applicability in patients with smaller access vessels. Longer-term follow-up is ongoing. PMID- 26243208 TI - Revascularization of acute mesenteric ischemia after creation of a dedicated multidisciplinary center. AB - OBJECTIVE: Arterial acute mesenteric ischemia (AAMI) is a vascular and gastroenterologic emergency, most often surgical, still associated with a poor prognosis and frequent short bowel syndrome in survivors. We report the results of revascularization in AAMI patients after the creation of an intestinal stroke center. METHODS: Since July 2009, we developed a multimodal and multidisciplinary management for AMI, focusing on intestinal viability and involving gastroenterologists, vascular and abdominal surgeons, radiologists, and intensive care specialists. This management was the first step to the creation of an intestinal stroke center, based on the stroke unit model. All patients received: (1) a specific medical protocol; (2) endovascular and/or open surgical revascularization whenever possible; and/or (3) resection of non-viable small bowel. We aimed to study survival, morbidity, type of revascularization, and bowel resection in patients who benefited from arterial revascularization in our intestinal stroke center. RESULTS: Eighty-three patients with AMI were prospectively enrolled in the intestinal stroke center. Among them, 29 patients with AAMI underwent revascularization. The mean age was 50.2 +/- 12 years, with 41% of male gender. The mean follow-up was 22.7 +/- 19 months. Overall 2-year survival was 89.2%, and 30-day operative mortality was 6.9%. Surgical revascularization included bypass grafting (65%), endarterectomy with patch angioplasty (21%) +/- retrograde open mesenteric stenting of the superior mesenteric artery (7%), and endovascular revascularization as first stage procedure (38%). The 2-year primary patency rate of open revascularization was 88%. The rate and the median length of bowel resected were 24% and 43 cm (range, 36-49 cm), respectively. CONCLUSIONS: In our experience, revascularization of AAMI patients as part of a multidisciplinary and multimodal management leads to encouraging results. Vascular surgeons have a central role in a dedicated intestinal stroke center. PMID- 26243209 TI - Loss of function mutations in the rice chromomethylase OsCMT3a cause a burst of transposition. AB - Methylation patterns of plants are unique as, in addition to the methylation at CG dinucleotides that occurs in mammals, methylation also occurs at non-CG sites. Genes are methylated at CG sites, but transposable elements (TEs) are methylated at both CG and non-CG sites. The role of non-CG methylation in transcriptional silencing of TEs is being extensively studied at this time, but only very rare transpositions have been reported when non-CG methylation machineries have been compromised. To understand the role of non-CG methylation in TE suppression and in plant development, we characterized rice mutants with changes in the chromomethylase gene, OsCMT3a. oscmt3a mutants exhibited a dramatic decrease in CHG methylation, changes in the expression of some genes and TEs, and pleiotropic developmental abnormalities. Genome resequencing identified eight TE families mobilized in oscmt3a during normal propagation. These TEs included tissue culture activated copia retrotransposons Tos17 and Tos19 (Lullaby), a pericentromeric clustered high-copy-number non-autonomous gypsy retrotransposon Dasheng, two copia retrotransposons Osr4 and Osr13, a hAT-tip100 transposon DaiZ, a MITE transposon mPing, and a LINE element LINE1-6_OS. We confirmed the transposition of these TEs by polymerase chain reaction (PCR) and/or Southern blot analysis, and showed that transposition was dependent on the oscmt3a mutation. These results demonstrated that OsCMT3a-mediated non-CG DNA methylation plays a critical role in development and in the suppression of a wide spectrum of TEs. These in planta mobile TEs are important for studying the interaction between TEs and the host genome, and for rice functional genomics. PMID- 26243211 TI - Halocynthiibacter arcticus sp. nov., isolated from Arctic marine sediment. AB - A Gram-staining-negative, oxidase- and catalase-positive, non-motile, aerobic and rod-shaped bacterium producing white colonies, PAMC 20958T, was isolated from a marine sediment of the Arctic. PAMC 20958T grew at 10-27 degrees C (optimally at 21 degrees C), at pH 5.5-9.5 (optimally at pH 7.0-7.5) and in the presence of 0.5-7.5 % (w/v) (optimally at 2.0 %) NaCl. PAMC 20958T showed 97.5 % 16S rRNA gene sequence similarity with Halocynthiibacter namhaensis KCTC 32362T and formed a robust phylogenetic clade with this species. The average nucleotide identity value between strain PAMC 20958T and H. namhaensis KCTC 32362T was 79.7 % and the genome-to-genome distance was 13.0 % on average. The genomic DNA G+C content calculated from the genome sequence was 53.2 mol%. The major fatty acids were C18 : 1omega7c and/or C18 : 1omega6c. The major respiratory isoprenoid quinone was ubiquinone-10 (Q-10) and major polar lipids were phosphatidylcholine, phosphatidylglycerol, an unidentified aminolipid and two unidentified lipids. On the basis of phylogenetic analysis and genotypic and phenotypic data obtained in this study, it is concluded that strain PAMC 20958T ( = KCTC 42129T = JCM 30530T) represents the type strain of a novel species of the genus Halocynthiibacter, for which the name Halocynthiibacter arcticus sp. nov. is proposed. PMID- 26243210 TI - A Protein Rotaxane Controls the Translocation of Proteins Across a ClyA Nanopore. AB - Rotaxanes, pseudorotaxanes, and catenanes are supramolecular complexes with potential use in nanomachinery, molecular computing, and single-molecule studies. Here we constructed a protein rotaxane in which a polypeptide thread is encircled by a Cytolysin A (ClyA) nanopore and capped by two protein stoppers. The rotaxane could be switched between two states. At low negative applied potentials (<-50 mV) one of the protein stoppers resided inside the nanopore indefinitely. Under this configuration the rotaxane prevents the diffusion of protein molecules across the lipid bilayer and provides a useful platform for single-molecule analysis. High negative applied potentials (-100 mV) dismantled the interlocked rotaxane system by the forceful translocation of the protein stopper, allowing new proteins to be trapped inside or transported across the nanopore. The observed voltage threshold for the translocation of the protein stopper through the nanopore related well to the biphasic voltage dependence of the residence time measured for the freely diffusing protein stopper. We propose a model in which molecules translocate through a nanopore when the average dwell time decreases with the applied potential. PMID- 26243212 TI - Elevated hepcidin serum level in response to inflammatory and iron signals in exercising athletes is independent of moderate supplementation with vitamin C and E. AB - Iron deficiency among endurance athletes is of major concern for coaches, physicians, and nutritionists. Recently, it has been observed that hepcidin, the master regulator of iron metabolism, was upregulated after exercise and was found to be related to interleukin-6 (IL-6) elevation. In this study performed on noniron deficient and well-trained runners, we observed that hepcidin concentrations remain elevated in response to inflammatory and iron signals despite a 28-days supplementation period with vitamins C (500 mg/day) and E (400 IU/day). PMID- 26243213 TI - Heat stress increases insulin sensitivity in pigs. AB - Proper insulin homeostasis appears critical for adapting to and surviving a heat load. Further, heat stress (HS) induces phenotypic changes in livestock that suggest an increase in insulin action. The current study objective was to evaluate the effects of HS on whole-body insulin sensitivity. Female pigs (57 +/- 4 kg body weight) were subjected to two experimental periods. During period 1, all pigs remained in thermoneutral conditions (TN; 21 degrees C) and were fed ad libitum. During period 2, pigs were exposed to: (i) constant HS conditions (32 degrees C) and fed ad libitum (n = 6), or (ii) TN conditions and pair-fed (PFTN; n = 6) to eliminate the confounding effects of dissimilar feed intake. A hyperinsulinemic euglycemic clamp (HEC) was conducted on d3 of both periods; and skeletal muscle and adipose tissue biopsies were collected prior to and after an insulin tolerance test (ITT) on d5 of period 2. During the HEC, insulin infusion increased circulating insulin and decreased plasma C-peptide and nonesterified fatty acids, similarly between treatments. From period 1 to 2, the rate of glucose infusion in response to the HEC remained similar in HS pigs while it decreased (36%) in PFTN controls. Prior to the ITT, HS increased (41%) skeletal muscle insulin receptor substrate-1 protein abundance, but did not affect protein kinase B or their phosphorylated forms. In adipose tissue, HS did not alter any of the basal or stimulated measured insulin signaling markers. In summary, HS increases whole-body insulin-stimulated glucose uptake. PMID- 26243214 TI - A new method to measure muscle protein synthesis in humans by endogenously introduced d9-leucine and using blood for precursor enrichment determination. AB - Enrichment from the easily accessible blood amino acid pool is commonly used as precursor enrichment to calculate rates of muscle protein fractional synthesis in relevant human studies in lieu of the less accessible muscle fluid amino acid pool. However, the accuracy of this approach depends largely on the extent to which there is low discrepancy in free amino acid enrichment between blood and muscle. Steady-state gradient (i.e., ratio) of amino acid enrichment between blood and muscle fluid in the basal state and in response to amino acid infusion were determined in five healthy subjects, and in association with two separate tracers: d9-leucine, introduced endogenously by the metabolism of d10-leucine (i.e., l-[2,3,3,4,5,5,5,6,6,6-(2)H10]leucine) infused in blood, and (13)C6 phenylalanine introduced/infused in blood. The blood-to-muscle fluid amino acid enrichment ratio was lower (P < 0.05) for d9-leucine compared to (13)C6 phenylalanine both before (1.5 +/- 0.1 vs. 2.5 +/- 0.1) and during (1.1 +/- 0.1 vs. 1.2 +/- 0.1) amino acid infusion. Importantly, the decrease in this ratio in association with the amino acid infusion was considerably less for the d9-leucine than the (13)C6-phenylalanine (-0.38 +/- 0.03 vs. -1.29 +/- 0.07; P < 0.05). In conclusion, blood d9-leucine enrichment introduced endogenously by intravenous infusion of d10-leucine provides a closer estimate of the muscle fluid amino acid enrichment, and its associated changes, than blood phenylalanine enrichment to calculate rates of muscle protein synthesis in humans. PMID- 26243215 TI - Thick airway surface liquid volume and weak mucin expression in pendrin-deficient human airway epithelia. AB - Pendrin is an anion exchanger whose mutations are known to cause hearing loss. However, recent data support the linkage between pendrin expression and airway diseases, such as asthma. To evaluate the role of pendrin in the regulation of the airway surface liquid (ASL) volume and mucin expression, we investigated the function and expression of pendrin and ion channels and anion exchangers. Human nasal epithelial cells were cultured from 16 deaf patients carrying pendrin mutations (DFNB4) and 17 controls. The cells were treated with IL-13 to induce mucus hypersecretion. Airway surface liquid thickness was measured and real-time polymerase chain reaction was performed targeting various transporters and MUC5AC. Anion exchanger activity was measured using a pH-sensitive fluorescent probe. Periodic acid-Schiff staining was performed on the cultured cells and inferior turbinate tissues. The ASL layer of the nasal epithelia from DFNB4 subjects was thicker than the controls, and the difference became more prominent following IL-13 stimulation. There was no difference in anion exchange activity after IL-13 treatment in the cells from DFNB4 patients, while it increased in the controls. Goblet cell metaplasia induced by IL-13 treatment seen in the controls was not observed in the DFNB4 cells. Furthermore, the periodic acid-Schiff staining-positive area was lesser in the inferior turbinate tissues from DFNB4 patients that those from controls. Pendrin plays a critical role in ASL volume regulation and mucin expression as pendrin-deficient airway epithelial cells are refractory to stimulation with IL-13. Specific blockers targeting pendrin in the airways may therefore have therapeutic potential in the treatment of allergic airway diseases. PMID- 26243216 TI - The Geropathology Research Network: An Interdisciplinary Approach for Integrating Pathology Into Research on Aging. AB - Geropathology is the study of aging and age-related lesions and diseases in the form of whole necropsies/autopsies, surgical biopsies, histology, and molecular biomarkers. It encompasses multiple subspecialties of geriatrics, anatomic pathology, molecular pathology, clinical pathology, and gerontology. In order to increase the consistency and scope of communication in the histologic and molecular pathology assessment of tissues from preclinical and clinical aging studies, a Geropathology Research Network has been established consisting of pathologists and scientists with expertise in the comparative pathology of aging, the design of aging research studies, biostatistical methods for analysis of aging data, and bioinformatics for compiling and annotating large sets of data generated from aging studies. The network provides an environment to promote learning and exchange of scientific information and ideas for the aging research community through a series of symposia, the development of uniform ways of integrating pathology into aging studies, and the statistical analysis of pathology data. The efforts of the network are ultimately expected to lead to a refined set of sentinel biomarkers of molecular and anatomic pathology that could be incorporated into preclinical and clinical aging intervention studies to increase the relevance and productivity of these types of investigations. PMID- 26243217 TI - Seven day NHS is possible only with more resources, say surgeons. PMID- 26243218 TI - De novo assembly and transcriptome analysis of Plasmodium gallinaceum identifies the Rh5 interacting protein (ripr), and reveals a lack of EBL and RH gene family diversification. AB - BACKGROUND: Malaria parasites that infect birds can have narrow or broad host tropisms. These differences in host specificity make avian malaria a useful model for studying the evolution and transmission of parasite assemblages across geographic ranges. The molecular mechanisms involved in host-specificity and the biology of avian malaria parasites in general are important aspects of malaria pathogenesis that warrant further examination. Here, the transcriptome of the malaria parasite Plasmodium gallinaceum was characterized to investigate the biology and the conservation of genes across various malaria parasite species. METHODS: The P. gallinaceum transcriptome was annotated and KEGG pathway mapping was performed. The ripr gene and orthologous genes that play critical roles in the purine salvage pathway were identified and characterized using bioinformatics and phylogenetic methods. RESULTS: Analysis of the transcriptome sequence database identified essential genes of the purine salvage pathway in P. gallinaceum that shared high sequence similarity to Plasmodium falciparum when compared to other mammalian Plasmodium spp. However, based on the current sequence data, there was a lack of orthologous genes that belonged to the erythrocyte-binding-like (EBL) and reticulocyte-binding-like homologue (RH) family in P. gallinaceum. In addition, an orthologue of the Rh5 interacting protein (ripr) was identified. CONCLUSIONS: These findings suggest that the pathways involved in parasite red blood cell invasion are significantly different in avian Plasmodium parasites, but critical metabolic pathways are conserved throughout divergent Plasmodium taxa. PMID- 26243219 TI - Palliative Care: A Core Competency for Stroke Neurologists. PMID- 26243220 TI - Rate of Contrast Extravasation on Computed Tomographic Angiography Predicts Hematoma Expansion and Mortality in Primary Intracerebral Hemorrhage. AB - BACKGROUND AND PURPOSE: In primary intracerebral hemorrhage, the presence of contrast extravasation after computed tomographic angiography (CTA), termed the spot sign, predicts hematoma expansion and mortality. Because the biological underpinnings of the spot sign are not fully understood, we investigated whether the rate of contrast extravasation, which may reflect the rate of bleeding, predicts expansion and mortality beyond the simple presence of the spot sign. METHODS: Consecutive intracerebral hemorrhage patients with first-pass CTA followed by a 90-second delayed postcontrast CT (delayed CTA) were included. CTAs were reviewed for spot sign presence by 2 blinded readers. Spot sign volumes on first-pass and delayed CTA and intracerebral hemorrhage volumes were measured using semiautomated software. Extravasation rates were calculated and tested for association with hematoma expansion and mortality using uni- and multivariable logistic regressions. RESULTS: One hundred and sixty-two patients were included, 48 (30%) of whom had >=1 spot sign. Median spot sign volume was 0.04 mL on first pass CTA and 0.4 mL on delayed CTA. Median extravasation rate was 0.23 mL/min overall and 0.30 mL/min among expanders versus 0.07 mL/min in nonexpanders. Extravasation rates were also significantly higher in patients who died in hospital: 0.27 mL/min versus 0.04 mL/min. In multivariable analysis, the extravasation rate was independently associated with in-hospital mortality (odds ratio, 1.09 [95% confidence interval, 1.04-1.18], P=0.004), 90-day mortality (odds ratio, 1.15 [95% confidence interval, 1.08-1.27]; P=0.0004), and hematoma expansion (odds ratio, 1.03 [95% confidence interval, 1.01-1.08]; P=0.047). CONCLUSIONS: Contrast extravasation rate, or spot sign growth, further refines the ability to predict hematoma expansion and mortality. Our results support the hypothesis that the spot sign directly measures active bleeding in acute intracerebral hemorrhage. PMID- 26243221 TI - Effects of Postconditioning on Neurogenesis and Angiogenesis During the Recovery Phase After Focal Cerebral Ischemia. AB - BACKGROUND AND PURPOSE: Postconditioning may be a clinically feasible way to protect the brain after a stroke. However, its effects during the recovery phase post stroke remain to be fully elucidated. Here, we examine the hypothesis that ischemic postconditioning amplifies neurogenesis and angiogenesis during stroke recovery. METHODS: Male Sprague-Dawley rats were subjected to 100-minute transient middle cerebral artery occlusion (MCAO) or postconditioning (100-minute middle cerebral artery occlusion plus 10-minute reperfusion plus 10-minute reocclusion). After 2 weeks, infarct volumes, behavioral outcomes, and immunohistochemical markers of neurogenesis and angiogenesis were quantified. RESULTS: Postconditioning significantly reduced infarction and improved neurological outcomes. Concomitantly, brains subjected to postconditioning showed an increase in doublecortin/BrdU and collagen-IV/Ki67-positive cells. CONCLUSIONS: These results suggest that therapeutic effects of postconditioning may involve the promotion of neurogenesis and angiogenic remodeling during the recovery phase after focal cerebral ischemia. PMID- 26243223 TI - Treatment Concepts for Wake-Up Stroke and Stroke With Unknown Time of Symptom Onset. PMID- 26243222 TI - Neurorestorative Therapy of Stroke in Type 2 Diabetes Mellitus Rats Treated With Human Umbilical Cord Blood Cells. AB - BACKGROUND AND PURPOSE: Diabetes mellitus is a high-risk factor for ischemic stroke. Diabetic stroke patients suffer worse outcomes, poor long-term recovery, risk of recurrent strokes, and extensive vascular damage. We investigated the neurorestorative effects and the underlying mechanisms of stroke treatment with human umbilical cord blood cells (HUCBCs) in type 2 diabetes mellitus (T2DM) rats. METHODS: Adult male T2DM rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo). Three days after MCAo, rats were treated via tail-vein injection with (1) PBS and (2) HUCBCs (5*10(6)), n=10 per group. RESULTS: HUCBC stroke treatment initiated 3 days after MCAo in T2DM rats did not significantly decrease blood-brain barrier leakage (P=0.1) and lesion volume (P=0.078), but significantly improved long-term functional outcome and decreased brain hemorrhage (P<0.05) when compared with the PBS-treated T2DM MCAo control group. HUCBC treatment significantly promoted white matter remodeling as indicated by increased expression of Bielschowsky silver (axons marker), Luxol fast blue (myelin marker), SMI-31 (neurofilament), and Synaptophysin in the ischemic border zone. HUCBC promoted vascular remodeling and significantly increased arterial and vascular density. HUCBC treatment of stroke in T2DM rats significantly increased M2 macrophage polarization (increased M2 macrophage, CD163and CD 206; decreased M1 macrophage, ED1 and inducible nitric oxide synthase expression) in the ischemic brain compared with PBS-treated T2DM MCAo controls (P<0.05). HUCBC also significantly decreased proinflammatory factors, that is, matrix metalloproteinase 9, receptor for advanced glycation end products and toll-like receptor 4 expression in the ischemic brain. CONCLUSIONS: HUCBC treatment initiated 3 days after stroke significantly increased white matter and vascular remodeling in the ischemic brain as well as decreased neuroinflammatory factor expression in the ischemic brain in T2DM rats and promoted M2 macrophage polarization. HUCBC reduction of neuroinflammation and increased vascular and white matter axonal remodeling may contribute to the HUCBC-induced beneficial effects in T2DM stroke rats. PMID- 26243224 TI - High-Resolution Intracranial Pressure Burden and Outcome in Subarachnoid Hemorrhage. AB - BACKGROUND AND PURPOSE: Intracranial pressure (ICP) control is a therapeutic target in patients with aneurysmal subarachnoid hemorrhage, although only a limited number of studies assessed its course and effect on outcome. Pressure time dose (PTDICP) is a method to quantify the burden and the time spent above a defined threshold of ICP. PTDICP or its relationship with outcome has never been evaluated in aneurysmal subarachnoid hemorrhage. METHODS: Analysis of data prospectively collected from aneurysmal subarachnoid hemorrhage patients admitted to Neurointensive Care Unit. Monitored data, including intraparenchymal ICP, were digitally recorded minute-by-minute in the first 7 days. PTDICP (mm Hg h) was computed using 4 predefined thresholds (15, 20, 25, and 30 mm Hg). Outcome was assessed through Extended Glasgow Outcome Scale at hospital discharge and at 6 months. RESULTS: Fifty-five patients were enrolled. Forty-two patients (76%) presented with a poor clinical grade. Overall, mortality was 17% at hospital discharge and 34% at 6 months. Half of patients required extensive therapy to control high ICP during day 1. Median ICP was 10 mm Hg (4-75), whereas median PTDICP15, PTDICP20, PTDICP25, PTDICP30 were, respectively, 13, 4, 2, and 1 mm Hg h. We observed an association between mortality at hospital discharge and higher level of PTDICP using 20, 25, and 30 mm Hg as thresholds and between exposure to a moderate-level PTDICP30 and unfavorable long-term outcome. CONCLUSIONS: PTDICP may better define one of the insults that the brain suffers after aneurysmal rupture, and exposure to moderate PTDICP30 was significant prognostic factor of 6 month unfavorable outcome. PMID- 26243226 TI - Prognostic Significance of Short-Term Blood Pressure Variability in Acute Stroke: Systematic Review. AB - BACKGROUND AND PURPOSE: Blood pressure variability (BPV) may be an important prognostic factor acutely after stroke. This review investigated the existing evidence for the effect of BPV on outcome after stroke, also considering BPV measurement techniques and definitions. METHODS: A literature search was performed according to a prespecified study protocol. Two reviewers independently assessed study eligibility and quality. Where appropriate, meta-analyses were performed to assess the effect of BPV on poor functional outcome. RESULTS: Eighteen studies from 1359 identified citations were included. Seven studies were included in a meta-analysis for the effect of BPV on functional outcome (death or disability). Systolic BPV was significantly associated with poor functional outcome: pooled odds ratio per 10-mm Hg increment, 1.2; confidence interval (1.1 1.3). A descriptive review of included studies also supports these findings, and in addition, it suggests that systolic BPV may be associated with increased risk of intracranial hemorrhage in those treated with thrombolytic therapy. CONCLUSIONS: This systematic review and meta-analysis suggest that greater systolic BPV, measured early from ischemic stroke or intracerebral hemorrhage onset, is associated with poor longer-term functional outcome. Future prospective studies should investigate how best to measure and define BPV in acute stroke, as well as to determine its prognostic significance. PMID- 26243225 TI - Rosiglitazone Promotes White Matter Integrity and Long-Term Functional Recovery After Focal Cerebral Ischemia. AB - BACKGROUND AND PURPOSE: Oligodendrogenesis is essential for white matter repair after stroke. Although agonists of peroxisome proliferator-activated receptors gamma confer neuroprotection in models of cerebral ischemia, it is not known whether this effect extends to white matter protection. This study tested the hypothesis that the peroxisome proliferator-activated receptors gamma agonist rosiglitazone enhances oligodendrogenesis and improves long-term white matter integrity after ischemia/reperfusion. METHODS: Male adult C57/BL6 mice (25-30 g) were subjected to 60-minute middle cerebral artery occlusion and reperfusion. Rosiglitazone (3 mg/kg) was injected intraperitoneally once daily for 14 days beginning 2 hours after reperfusion. Sensorimotor and cognitive functions were evaluated <=21 days after middle cerebral artery occlusion. Immunostaining was used to assess infarct volume, myelin loss, and microglial activation. Bromodeoxyuridine (BrdU) was injected for measurements of proliferating NG2(+) oligodendrocyte precursor cells (OPCs) and newly generated adenomatous polyposis coli(+) oligodendrocytes. Mixed glial cultures were used to confirm the effect of rosiglitazone on oligodendrocyte differentiation and microglial polarization. RESULTS: Rosiglitazone significantly reduced brain tissue loss, ameliorated white matter injury, and improved sensorimotor and cognitive functions for at least 21 days after middle cerebral artery occlusion. Rosiglitazone enhanced OPC proliferation and increased the numbers of newly generated mature oligodendrocytes after middle cerebral artery occlusion. Rosiglitazone treatment also reduced the numbers of Iba1(+)/CD16(+) M1 microglia and increased the numbers of Iba1(+)/CD206(+) M2 microglia after stroke. Glial culture experiments confirmed that rosiglitazone promoted oligodendrocyte differentiation, perhaps by promoting microglial M2 polarization. CONCLUSIONS: Rosiglitazone treatment improves long-term white matter integrity after cerebral ischemia, at least, in part, by promoting oligodendrogenesis and facilitating microglial polarization toward the beneficial M2 phenotype. PMID- 26243228 TI - Outcome Following Decompressive Hemicraniectomy for Malignant Cerebral Infarction: Ethical Considerations. PMID- 26243227 TI - Accuracy of the ABC/2 Score for Intracerebral Hemorrhage: Systematic Review and Analysis of MISTIE, CLEAR-IVH, and CLEAR III. AB - BACKGROUND AND PURPOSE: The ABC/2 score estimates intracerebral hemorrhage (ICH) volume, yet validations have been limited by small samples and inappropriate outcome measures. We determined accuracy of the ABC/2 score calculated at a specialized reading center (RC-ABC) or local site (site-ABC) versus the reference standard computed tomography-based planimetry (CTP). METHODS: In Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for Intracerebral Hemorrhage Evacuation-II (MISTIE-II), Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) and CLEAR-III trials. ICH volume was prospectively calculated by CTP, RC-ABC, and site-ABC. Agreement between CTP and ABC/2 was defined as an absolute difference up to 5 mL and relative difference within 20%. Determinants of ABC/2 accuracy were assessed by logistic regression. RESULTS: In 4369 scans from 507 patients, CTP was more strongly correlated with RC-ABC (r(2)=0.93) than with site-ABC (r(2)=0.87). Although RC-ABC overestimated CTP-based volume on average (RC-ABC, 15.2 cm(3); CTP, 12.7 cm3), agreement was reasonable when categorized into mild, moderate, and severe ICH (kappa=0.75; P<0.001). This was consistent with overestimation of ICH volume in 6 of 8 previous studies. Agreement with CTP was greater for RC-ABC (84% within 5 mL; 48% of scans within 20%) than for site-ABC (81% within 5 mL; 41% within 20%). RC-ABC had moderate accuracy for detecting >=5 mL change in CTP volume between consecutive scans (sensitivity, 0.76; specificity, 0.86) and was more accurate with smaller ICH, thalamic hemorrhage, and homogeneous clots. CONCLUSIONS: ABC/2 scores at local or central sites are sufficiently accurate to categorize ICH volume and assess eligibility for the CLEAR-III and MISTIE III studies and moderately accurate for change in ICH volume. However, accuracy decreases with large, irregular, or lobar clots. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: MISTIE-II NCT00224770; CLEAR-III NCT00784134. PMID- 26243229 TI - Genetic Architecture of Lacunar Stroke. AB - BACKGROUND AND PURPOSE: Lacunar strokes comprise ~20% of all strokes. Despite this frequency, their pathogenesis is poorly understood. Previous genome-wide association studies in lacunar stroke have been disappointing, which may be because of phenotypic heterogeneity. Pathological and radiological studies suggest that there may be different pathologies underlying lacunar strokes. This has led to the suggestion of 2 subtypes: isolated lacunar infarcts and multiple lacunar infarcts and leukoaraiosis. METHODS: We performed genome-wide analyses in a magnetic resonance imaging-verified cohort of 1012 younger onset lacunar stroke cases and 964 controls. Using these data, we first estimated the heritability of lacunar stroke and its 2 hypothesized subtypes, and secondly, we determined whether this is enriched for regulatory regions in the genome, as defined by data from Encyclopedia of DNA Elements (ENCODE) and other sources. Finally, we determine the evidence for a polygenic contribution from rare variation to lacunar stroke and its subtypes. RESULTS: Our results indicate a substantial heritable component to magnetic resonance imaging-verified lacunar stroke (20% 25%) and its 2 subtypes (isolated lacunar infarct, 15%-18%; multiple lacunar infarcts/leukoaraiosis, 23%-28%). This heritable component is significantly enriched for sites affecting expression of genes. In addition, we show that the risk of the 2 subtypes of lacunar stroke in isolation, but not in combination, is associated with rare variation in the genome. CONCLUSIONS: Lacunar stroke, when defined on magnetic resonance imaging, is a highly heritable complex disease. Much of this heritability arises from regions of the genome affecting gene regulation. Rare variation affects 2 subtypes of lacunar in isolation, suggesting that they may have distinct genetic susceptibility factors. PMID- 26243230 TI - Occurrence and Predictors of Falls in People With Stroke: Six-Year Prospective Study. AB - BACKGROUND AND PURPOSE: The purpose was to investigate the occurrence of self reported falls in people with stroke at 3, 6, and 12 months and 6 years post stroke and predictors for falls during 6 years. METHODS: A prospective study involving 121 people with stroke. Data were obtained through structured interviews and assessments. Generalized estimating equation modeling using proportional odds was used to explore the predictive value of fall history, functioning/disability, and personal factors during 6 years. RESULTS: The proportion of fallers constituted of 35%, 26%, 33%, and 35% of the sample at 3, 6, and 12 months and 6 years of follow-up, respectively. Higher perceived effect of stroke on activities of daily living (odds ratio, 1.37; 95% confidence interval, 1.04-1.80), falls at 3 months (odds ratio, 1.0; 95% confidence interval, 1.01-3.94), and no gait/balance disability at baseline (odds ratio, 7.29; 95% confidence interval, 1.99-26.73) were predictors for future falls. During the 6 years, the odds for a fall decreased for participants with gait/balance disability at baseline but increased for those with no gait/balance disability. CONCLUSIONS: Results highlight the importance of performing fall risk evaluations over time among people with stroke, even when gait and balance functioning initially post stroke is good. PMID- 26243231 TI - Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke-Full Dose Regimen Stroke Trial. AB - BACKGROUND AND PURPOSE: The Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator (r-tPA; CLEAR) in Acute Ischemic Stroke (AIS) and CLEAR-Enhanced Regimen (CLEAR-ER) trials demonstrated safety of reduced dose r-tPA plus the glycoprotein 2b/3a inhibitor, eptifibatide, in AIS compared with r-tPA alone. The objective of the CLEAR-Full Dose Regimen (CLEAR FDR) trial was to estimate the rate of symptomatic intracerebral hemorrhage (sICH) in AIS patients treated with the combination of full-dose r-tPA plus eptifibatide. METHODS: CLEAR-FDR was a single-arm, prospective, open-label, multisite study. Patients aged 18 to 85 years treated with 0.9 mg/kg IV r-tPA within 3 hours of symptom onset were enrolled. After obtaining consent, eptifibatide (135 MUg/kg bolus and 2-hour infusion at 0.75 MUg/kg per minute) was administered. The primary end point was the proportion of patients who experienced sICH within 36 hours. An independent clinical monitor adjudicated if an sICH had occurred and an independent neuroradiologist reviewed all images. The stopping rule was 3 sICHs within the first 19 patients or 4 sICHs within 29 patients. RESULTS: From October 2013 to December 2014, 27 patients with AIS were enrolled. Median age was 73 years (range, 34-85; interquartile range, 65-80) and median National Institute of Health stroke scale score was 12 (range, 6-26; interquartile range, 9-16). One sICH (3.7%; 95% confidence interval, 0.7%-18%) was observed. CONCLUSIONS: These results demonstrate comparable safety of full dose r-tPA plus eptifibatide with historical rates of sICH with r-tPA alone and support proceeding with a phase 3 trial evaluating full-dose r-tPA combined with eptifibatide to improve outcomes after AIS. PMID- 26243233 TI - Remission of an epidermodysplasia verruciformis-like eruption in an HIV-positive man long after immune restoration. PMID- 26243234 TI - Interproximal biofilm removal by intervallic use of a sonic toothbrush compared to an oral irrigation system. AB - BACKGROUND: The purpose of this in-vitro study was to investigate the potential of biofilm removal in interproximal tooth regions using intervallic cleaning with an oral irrigator or a sonic toothbrush. METHODS: Three-species biofilms (Streptococcus mutans (OMZ 918), Streptococcus oralis SK 248 (OMZ 60), Actinomyces naeslundii (OMZ 745)) were grown on hydroxyapatite discs for 3 days in culture media. Every 24 h, specimens were incubated for 15 min in resazurin solution (i.e., culture medium and 10 % v/v alamarBlue(r)) to measure the metabolic activity with a fluorescence spectrophotometer in relative fluorescence units (rfu) at baseline. Then, specimens were fixed in interproximal holding devices and underwent treatment with an oral irrigator (WF; Waterpik(r) Sensonic WP-100E), an active sonic toothbrush (WPa), or an inactive sonic toothbrush (WPi; Waterpik(r) Sensonic SR-3000E) for 10 s (n = 18/group). Untreated biofilms served as controls (CO). After treatment, bacterial activity was re-measured, and specimens were re-grown in fresh medium for 24 h until next cleaning procedure. Altogether, cleaning was repeated in intervals of three treatment days (d1, d2, d3). After d3, SEM images were taken (n = 8) and CFU was measured (n = 3). Metabolic activity was analyzed for each disc separately, rfu values were averaged for d1 to compare initial biofilm stability, and ratios of baseline and post-treatment values were compared. Results were analyzed using ANOVA with the post-hoc Scheffe test, or Kruskal-Wallis with post-hoc Mann-Whitney test. RESULTS: Median baseline rfu-values of d1 resulted in 7821.8 rfu (interquartile range = 5114.5). Highest reduction in metabolic activity was recorded significantly for the oral irrigator used for 10 s (residual activity per day d1: WF 17.9 %, WPa 58.8 %, WPi 82.5 %, CO 89.6 %; d2: WF 36.8 %, WPa 85.2 %, WPi 82.5 %, CO 90.0 %; d3: WF 17.2.%, WPa 79.6 %, WPi 96.3 %, CO 116.3 %). SEM images of untreated specimens (CO) and specimens treated with the sonic toothbrush (WPa and WPi) showed huge amounts of biofilm, while oral irrigator-treated specimens (WF) revealed barely any bacteria. CFU data confirmed the graduations between the groups. CONCLUSIONS: Cleaning of interproximal regions achieved better success with an oral irrigator as compared to the use of a sonic toothbrush. (350/350 words). PMID- 26243232 TI - Low-Versus Standard-Dose Alteplase for Ischemic Strokes Within 4.5 Hours: A Comparative Effectiveness and Safety Study. AB - BACKGROUND AND PURPOSE: The low-dose (0.6 mg/kg) alteplase strategy to treat acute ischemic stroke patients became widespread in East Asian countries, without rigorous testing against standard-dose (0.9 mg/kg) alteplase treatment. Our aim was to investigate the comparative effectiveness and safety of the low-dose versus standard-dose intravenous alteplase strategy. METHODS: A total of 1526 acute ischemic stroke patients who qualified for intravenous alteplase and treated within 4.5 hours were identified from a prospective, multicenter, and nationwide stroke registry database. Primary outcomes were a modified Rankin scale score of 0 to 1 at 3 months after stroke and occurrence of symptomatic hemorrhagic transformation. Inverse probability of low-dose alteplase weighting by propensity scores was used to remove baseline imbalances between the 2 groups, and variation among centers were also accounted using generalized linear mixed models with a random intercept. RESULTS: Low-dose intravenous alteplase was given to 450 patients (29.5%) and standard-dose intravenous alteplase to 1076 patients (70.5%). Low-dose alteplase treatment was comparable to standard-dose therapy according to the following adjusted outcomes and odds ratios (95% confidence intervals): modified Rankin scale score 0 to 1 at 3 months and 0.95 (0.68-1.32); modified Rankin scale 0 to 2 at 3 months and 0.84 (0.62-1.15); symptomatic hemorrhagic transformation and 1.05 (0.65-1.70); and 3-month mortality and 0.54 (0.35-0.83). The associations were unchanged when the analysis was limited to those without endovascular recanalization. CONCLUSIONS: The low-dose alteplase strategy was comparable to the standard-dose treatment in terms of the effectiveness and safety. PMID- 26243236 TI - INTRODUCTION: What Will It Take to Address the Global Threat of Antibiotic Resistance? PMID- 26243235 TI - The formation of titan cells in Cryptococcus neoformans depends on the mouse strain and correlates with induction of Th2-type responses. AB - Cryptococcus neoformans is a pathogenic yeast that can form titan cells in the lungs, which are fungal cells of abnormal enlarged size. Little is known about the factors that trigger titan cells. In particular, it is not known how the host environment influences this transition. In this work, we describe the formation of titan cells in two mouse strains, CD1 and C57BL/6J. We found that the proportion of C. neoformans titan cells was significantly higher in C57BL/6J mice than in CD1. This higher proportion of titan cells was associated with a higher dissemination of the yeasts to the brain. Histology sections demonstrated eosinophilia in infected animals, although it was significantly lower in the CD1 mice which presented infiltration of lymphocytes. Both mouse strains presented infiltration of granulocytes, but the amount of eosinophils was higher in C57BL/6J. CD1 mice showed a significant accumulation of IFN-gamma, TNF-alpha and IL17, while C57BL/BL mice had an increase in the anti-inflammatory cytokine IL-4. IgM antibodies to the polysaccharide capsule and total IgE were more abundant in the sera from C57BL/6J, confirming that these animals present a Th2-type response. We conclude that titan cell formation in C. neoformans depends, not only on microbe factors, but also on the host environment. PMID- 26243237 TI - Antibiotic Resistance Spreads Internationally Across Borders. AB - Antibiotic-resistant (ABR) bacteria develop when bacteria are exposed to antibiotics either during treatments in humans or animals or through environmental sources contaminated with antibiotic residues. Resistant bacteria selected by medical, agricultural, and industrial use spread globally through international travel, the export of animals and retail products, and the environment. It is essential that nations work together to identify how to reduce emergence and amplification of resistant bacteria through sensible antibiotic treatment guidelines and restrictions, concerted efforts for surveillance, and infection control. PMID- 26243238 TI - Universal Access to Effective Antibiotics is Essential for Tackling Antibiotic Resistance. AB - Universal access to effective antimicrobials is essential to the realization of the right to health. At present, 5.7 million people die from treatable infections each year because they lack this access. Yet, community-based diagnosis and appropriate treatment for many of the leading causes of avoidable infectious deaths has been shown to be feasible and effective, demonstrating that strategies to reach the under-served need to receive high priority. This is a necessary part of a broad strategy to assure the long-term benefits of antimicrobials and to combat antimicrobial resistance, both because the lack of systematic and rigorous efforts to assure effective coverage increases the likelihood of antimicrobial resistance, and because global efforts aimed at antimicrobial stewardship and innovation cannot succeed without explicitly addressing the needs of the under served. Elements of this strategy will include clear evidence-based treatment protocols, a robust international framework and locally tailored regulations, active engagement with communities and local health providers, strong attention to program management and cost considerations, a focus on the end user, and robust surveillance and response to emerging resistance patterns. Only by balancing the needs of universal access with stewardship and innovation, and assuring that they are mutually reinforcing can a global strategy hope to effectively address antimicrobial resistance. PMID- 26243239 TI - The Global Innovation Model for Antibiotics Needs Reinvention. AB - The dangers presented by antibiotic resistance (ABR) have now established themselves as a global health security issue. From an international policy perspective, three key pillars have been established - responsible access, conservation, and innovation. These pillars are intrinsically linked, meaning that any attempt to address one, must take into account the implications for the other two. This article attempts to address all three of these pillars. PMID- 26243240 TI - History Teaches Us That Confronting Antibiotic Resistance Requires Stronger Global Collective Action. AB - Antibiotic development and usage, and antibiotic resistance in particular, are today considered global concerns, simultaneously mandating local and global perspectives and actions. Yet such global considerations have not always been part of antibiotic policy formation, and those who attempt to formulate a globally coordinated response to antibiotic resistance will need to confront a history of heterogeneous, often uncoordinated, and at times conflicting reform efforts, whose legacies remain apparent today. Historical analysis permits us to highlight such entrenched trends and processes, helping to frame contemporary efforts to improve access, conservation and innovation. PMID- 26243241 TI - Antibiotic Resistance Is a Tragedy of the Commons That Necessitates Global Cooperation. AB - Antibiotics may be thought of as a common pool resource that can be depleted over time; the economics of this problem are relatively well known. The importance of antibiotics to human health means that limiting access through privatization is undesirable. Therefore, other solutions to prevent overuse are essential - stewardship programs, and for non-human use, taxation, all within the context of an international agreement. To solve problems of access while offering adequate rewards for innovation, a key tool is delinking prices from payment to innovators. PMID- 26243242 TI - An Integrated Systems Approach is Needed to Ensure the Sustainability of Antibiotic Effectiveness for Both Humans and Animals. AB - The growing demand for animal products and the widespread use of antibiotics in bringing food animals to market have heightened concerns over cross-species transmission of drug resistance. Both the biology and emerging epidemiology strongly support the need for global coordination in stemming the generation and propagation of resistance, and the patchwork of global and country-level regulations still leaves significant gaps. More importantly, discussing such a framework opens the door to taking modular steps towards solving these challenges - for example, beginning among targeted parties rather than all countries, tying accountability to financial and technical support, or taxing antibiotic use in animals to deter low-value usage of these drugs. An international agreement would allow integrating surveillance data collection, monitoring and enforcement, research into antibiotic alternatives and more sustainable approaches to agriculture, technical assistance and capacity building, and financing under the umbrella of a One Health approach. PMID- 26243243 TI - Much Can Be Learned about Addressing Antibiotic Resistance from Multilateral Environmental Agreements. AB - Antibiotic resistance (ABR) is a common-pool resource challenge. This means that efforts to address ABR can learn from similar collective action problems faced within the environmental sector. Multilateral environmental agreements are the backbone of global environmental governance. Their ability to effectively solve environmental problems depends on the problem structure and the regime's problem solving capacity. The success or failure of environmental agreements is mainly determined by the problem structure, including the degree of political consensus and scientific certainty. But agreements' institutional design also matter because they can change the problem structure and problem-solving capacity. Based on experiences with environmental agreements, an international ABR agreement should contain robust reporting/verification procedures, sanctions for non compliance, assistance for implementation, majority vote decision-making rules, a strong secretariat, an independent scientific panel, and specific commitments. More research on global strategies for achieving collective action is needed to help inform future institutional designs that are both effective and politically feasible. PMID- 26243244 TI - Addressing Antibiotic Resistance Requires Robust International Accountability Mechanisms. AB - A proposed international agreement on antibiotic resistance will depend on robust accountability mechanisms for real-world impact. This article examines the central aspects of accountability relationships in international agreements and lays out ways to strengthen them. We provide a menu of accountability mechanisms that facilitate transparency, oversight, complaint, and enforcement, describe how these mechanisms can promote compliance, and identify key considerations for a proposed international agreement on antibiotic resistance. These insights can be useful for bringing about the revolutionary changes that new international agreements aspire to achieve. PMID- 26243245 TI - International Law Has a Role to Play in Addressing Antibiotic Resistance. AB - If an international legal agreement is needed for any of today's global health challenges, it would be antibiotic resistance (ABR). This challenge is transnational, its solution justifies coercion, tangible benefits are likely to be achieved, and other commitment mechanisms have thus far not been successful. Since addressing ABR depends on near-universal and interdependent collective action across sectors, states should utilize an international legal agreement - which formally represents the strongest commitment mechanism available to them. PMID- 26243246 TI - Some Global Policies for Antibiotic Resistance Depend on Legally Binding and Enforceable Commitments. AB - To address the challenge of antibiotic resistance (ABR), the international community must ensure access, conservation and innovation of antibiotics. These goals can be significantly advanced through ten global policies that have been recommended to form part of an international legal agreement. Policies that could be central to this agreement include the establishment of standards, responsible antibiotic use regulations, and strengthening global surveillance systems. Funding for access, mobilizing resources for infrastructure, strengthening infection control practices, and regulating antibiotic marketing could also be helpful if included in a legal agreement. Incentives for innovation could also be included to mobilize support for its implementation. The inclusion of these policies in an international legal agreement could effectively support global collective action towards several ABR policy goals, some of which may depend on it for their achievement. PMID- 26243247 TI - Effective Global Action on Antibiotic Resistance Requires Careful Consideration of Convening Forums. AB - Global collective action is needed to address the growing transnational threat of antibiotic resistance (ABR). Some commentators have recommended an international legal agreement as the most promising mechanism for coordinating such action. While much has been said about what must be done to address ABR, far less work has analyzed how or where such collective action should be facilitated - even though the success of any international agreement depends greatly on where it is negotiated and implemented. This article evaluates four different forums that states may use to develop an international legal agreement for antibiotic resistance: (1) a self-organized venue; (2) the World Health Organization; (3) the World Trade Organization; and (4) the United Nations General Assembly. The need for a multisectoral approach and the diverse institutional landscape suggest that an effective response may best be coordinated through linked action pursued through multiple forums. PMID- 26243248 TI - Listening to food workers: Factors that impact proper health and hygiene practice in food service. AB - BACKGROUND: Foodborne disease is a significant problem worldwide. Research exploring sources of outbreaks indicates a pronounced role for food workers' improper health and hygiene practice. OBJECTIVE: To investigate food workers' perceptions of factors that impact proper food safety practice. METHOD: Interviews with food service workers in Baltimore, MD, USA discussing food safety practices and factors that impact implementation in the workplace. A social ecological model organizes multiple levels of influence on health and hygiene behavior. RESULTS: Issues raised by interviewees include factors across the five levels of the social ecological model, and confirm findings from previous work. Interviews also reveal many factors not highlighted in prior work, including issues with food service policies and procedures, working conditions (e.g., pay and benefits), community resources, and state and federal policies. CONCLUSION: Food safety interventions should adopt an ecological orientation that accounts for factors at multiple levels, including workers' social and structural context, that impact food safety practice. PMID- 26243249 TI - Single Intradiscal Administration of the Tumor Necrosis Factor-Alpha Inhibitor, Etanercept, for Patients with Discogenic Low Back Pain. AB - OBJECTIVE: To examine the analgesic effect of intradiscal administration of a tumor necrosis factor-alphaalpha (TNF-alpha) inhibitor in patients with discogenic low back pain (LBP). DESIGN: Prospective, randomized study. SETTING: Department of Orthopaedic Surgery, Chiba (Japan) University Hospital. SUBJECTS: Seventy-seven patients diagnosed with discogenic LBP. METHODS: Discogenic LBP patients were randomly assigned to the etanercept (n = 38; bupivacaine [2 mL] with etanercept [10 mg]) or control (n = 39; bupivacaine [2 mL]) groups. Patients received a single intradiscal injection. Numerical rating scale (NRS) scores for LBP at baseline, 1 day, and 1, 2, 4, and 8 weeks after the injection were recorded. The Oswestry disability index (ODI) scores at baseline and at 4 and 8 weeks after injection were evaluated. Postinjection complications were recorded and evaluated. RESULTS: In the etanercept group, the NRS scores were significantly lower than in the control group at every time point after the injection for 8 weeks (P < 0.05). Similarly, 4 weeks after the injection, the ODI score was lower in the etanercept group than in the control group (P < 0.05). However, the ODI scores were not significantly different at 8 weeks. Complications were not observed. CONCLUSIONS: Single intradiscal administration of a TNF-alpha inhibitor can alleviate intractable discogenic LBP for up to 8 weeks. TNF-alpha may be involved in discogenic pain pathogenesis. This procedure is a novel potential treatment; longer-term effectiveness trials are required in the future. PMID- 26243250 TI - [Update of treatment in chronic heart failure]. PMID- 26243251 TI - [Meningeal lymphomatosis as late relapse of Waldenstrom's macroglobulinemia]. PMID- 26243252 TI - [Need for changes in hospitals: 10 recommendations to improve efficiency, quality and effectiveness]. PMID- 26243253 TI - [Neonatal lupus]. PMID- 26243254 TI - [A strange shadow in a small bowel series]. PMID- 26243255 TI - [Fast diagnosis of type 1 neurofibromatosis]. PMID- 26243256 TI - [Ibuprofen-induced recurrent aseptic meningitis with good response to corticosteroids]. PMID- 26243257 TI - OrthoFinder: solving fundamental biases in whole genome comparisons dramatically improves orthogroup inference accuracy. AB - Identifying homology relationships between sequences is fundamental to biological research. Here we provide a novel orthogroup inference algorithm called OrthoFinder that solves a previously undetected gene length bias in orthogroup inference, resulting in significant improvements in accuracy. Using real benchmark datasets we demonstrate that OrthoFinder is more accurate than other orthogroup inference methods by between 8 % and 33 %. Furthermore, we demonstrate the utility of OrthoFinder by providing a complete classification of transcription factor gene families in plants revealing 6.9 million previously unobserved relationships. PMID- 26243258 TI - Serotype distribution and antibiotic resistance of Streptococcus pneumoniae isolates collected at a Chinese hospital from 2011 to 2013. AB - BACKGROUND: Streptococcus pneumoniae infections are a major cause of global morbidity and mortality, and the emergence of antibiotic-resistant Streptococcus pneumoniae strains has been increasingly reported. This study provides up-to-date information on bacterial serotype distribution and drug resistance from S. pneumoniae clinical isolates that could guide prevention and treatment strategies for pneumococcal disease in China. METHODS: A total of 94 S. pneumoniae isolates were collected from outpatients and inpatients at one Chinese hospital from 2011 2013. Drug susceptibility and resistance was determined by minimum inhibitory concentrations (MICs). Capsular serotypes were identified by the quellung reaction test and multiplex polymerase chain reaction. RESULTS: Fifteen serotypes were identified among the 94 S. pneumoniae clinical isolates that were collected. Prevalent serotypes were 19F (42.6 %), 19A (8.5 %), 3 (8.5 %), and 6B (7.4 %). Potential immunization coverage rates for the 7-, 10- and 13-valent pneumococcal polysaccharide conjugate vaccines were 59.6, 62.6, and 79.6 %, respectively. Resistance rates to tetracycline, erythromycin, and trimethoprim/sulfamethoxazole were 91.2, 80.2 and 63.8 %, respectively. Resistance rates to penicillin, amoxicillin, ceftriaxone, and cefotaxime were 47.3, 34.1, 19.8, and 18.7 %, respectively. In almost all cases, antimicrobial resistance of the S. pneumoniae isolates in patients five years or younger was higher than isolates collected from patients aged 51 years or older. CONCLUSION: Prevalent serotypes among the 94 S. pneumoniae clinical isolates were 19F, 19A, 3, and 6B. The 13-valent pneumococcal polysaccharide conjugate vaccine covered the majority of the serotypes identified in this sample. Drug resistance varied among different serotypes and age groups. Clinical precautions should be taken to avoid the development of multidrug resistance in this potential human pathogen. PMID- 26243259 TI - The efficacy of negative pressure wound therapy in treating sacroiliac joint tuberculosis with a chronic sinus tract: a case series. AB - OBJECTIVE: Tuberculous sacroiliitis with abscess accounts for approximately 50 % of all sacroiliac joint tuberculosis cases. Tuberculous abscesses spread into the sacroiliac joint capsule, subcutaneous tissue, and the skin, and finally becomes a skin sinus. As there are no previous reports about sacroiliac joint tuberculosis with a chronic sinus, we evaluated its clinical characteristics and management by negative pressure wound therapy. METHODS: A retrospective analysis of 12 patients with sacroiliac joint tuberculosis with chronic sinuses treated between January 2005 and January 2010 was conducted. Patients were treated with negative pressure wound therapy (NPWT). Treatment was divided into three phases: control phase, standard dressing changes daily for 4 weeks; interphase washout period, dressing changes every 3 days for 1 week; and intervention phase, no dressing changes until minimal sinus tract drainage (<5 ml per 24 h). Outcomes including the sinus healing time and the drainage volume were evaluated. RESULTS: The mean follow-up was 37.1 months. Sinus healing was observed at an average of 25.25 +/- 7.23 (range, 20-42) days after initial treatment. The mean volume of drainage did not change during the control phase, but decreased from 29.17 +/- 16.63 to 0.25 +/- 0.87 ml in the intervention phase. The mean daily reduction of wound volume, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) in the intervention phase was greater than in the control phase (P < 0.05). Anti tubercular therapy was administered an average of 14.00 +/- 2.95 (range, 12-18) months. ESR and CRP returned to normal within 3 months after the sinus closure. Bony fusion was observed in 5 (41.7 %) patients, and fibrous ankylosis in the other patients at last follow-up. All patients healed uneventfully. CONCLUSIONS: Early diagnosis of sacroiliac joint tuberculosis with a chronic sinus can be difficult. NPWT provides better healing of sacroiliac joint tuberculosis with a chronic sinus than standard dressing changes. PMID- 26243260 TI - Acute exacerbations of chronic obstructive pulmonary disease are associated with decreased CD4+ & CD8+ T cells and increased growth & differentiation factor-15 (GDF-15) in peripheral blood. AB - BACKGROUND: Although T cells, especially CD8+, have been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, their role during acute exacerbations (AE-COPD) is uncertain. METHODS: We recruited subjects with COPD and a history of previous AE-COPD and studied them quarterly to collect blood and spontaneously expectorated sputum while stable. During exacerbations (defined by a change in symptoms plus physician diagnosis and altered medications), we collected blood and sputum before administering antibiotics or steroids. We used flow cytometry to identify leukocytes in peripheral blood, plus Luminex(r) analysis or ELISA to determine levels of inflammatory biomarkers in serum and sputum supernatants. RESULTS: Of 33 enrolled subjects, 13 participated in multiple stable visits and had >=1 AE-COPD visit, yielding 18 events with paired data. Flow cytometric analyses of peripheral blood demonstrated decreased CD4+ and CD8+ T cells during AE-COPD (both absolute and as a percentage of all leukocytes) and significantly increased granulocytes, all of which correlated significantly with serum C-reactive protein (CRP) concentrations. No change was observed in other leukocyte populations during AE-COPD, although the percentage of BDCA-1+ dendritic cells expressing the activation markers CD40 and CD86 increased. During AE-COPD, sICAM-1, sVCAM-1, IL-10, IL-15 and GDF-15 increased in serum, while in sputum supernatants, CRP and TIMP-2 increased and TIMP-1 decreased. CONCLUSIONS: The decrease in CD4+ and CD8+ T cells (but not other lymphocyte subsets) in peripheral blood during AE-COPD may indicate T cell extravasation into inflammatory sites or organized lymphoid tissues. GDF-15, a sensitive marker of cardiopulmonary stress that in other settings independently predicts reduced long-term survival, is acutely increased in AE-COPD. These results extend the concept that AE-COPD are systemic inflammatory events to which adaptive immune mechanisms contribute. TRIAL REGISTRATION: NCT00281216 , ClinicalTrials.gov. PMID- 26243261 TI - Frontiers: Integration of a Research Participant Registry with Medical Clinic Registration and Electronic Health Records. PMID- 26243262 TI - Assessment of toxicity and biodegradability on activated sludge of priority and emerging pollutants. AB - Several methods for evaluating the toxicity and biodegradability of hazardous pollutants (chlorinated compounds, chemical additives and pharmaceuticals) have been studied in this work. Different bioassays using representative bacteria of marine and terrestrial ecosystems such as Vibrio fischeri and Pseudomonas putida have been used to assess the ecotoxicity. Activated sludge was used to analyse the effect of those pollutants in a biological reactor of a sewage treatment plant (STP). The results demonstrate that none of the compounds is toxic to activated sludge, except ofloxacin to P. putida. The additives tested can be considered moderately toxic according to the more sensitive V. fischeri assays, whereas the EC50 values of the pharmaceuticals depend on the specific microorganism used in each test. Regarding the biodegradability, respirometric measurements were carried out for fast biodegradability assessment and the Zahn Wellens test for inherent biodegradability. The evolution of the specific oxygen uptake rate (SOUR) showed that only diethyl phthalate was easily biodegradable and acetylsalicylic acid was partially biodegradable (98% and 65% degradation, respectively). The persistence of dichloromethane, ofloxacin and hidrochlorothiazide was confirmed along the 28 days of the Zahn-Wellens test whereas 1,1,1-trichloroethane showed inherent biodegradability (74% removal). Most of the chlorinated compounds, pharmaceuticals, bisphenol A and ethylenediaminetetraacetic acid were partially degraded in 28 d with total organic carbon (TOC) reduction ranging from 21% to 51%. Sulphamethoxazole showed certain biodegradation (50% removal) with TOC decrease around 31%, which indicates the formation of non-biodegradable by-products. PMID- 26243263 TI - The bactericidal activity of beta-lactam antibiotics is increased by metabolizable sugar species. AB - Here, the influence of metabolizable sugars on the susceptibility of Escherichia coli to beta-lactam antibiotics was investigated. Notably, monitoring growth and survival of mono- and combination-treated planktonic cultures showed a 1000- to 10 000-fold higher antibacterial efficacy of carbenicillin and cefuroxime in the presence of certain sugars, whereas other metabolites had no effect on beta lactam sensitivity. This effect was unrelated to changes in growth rate. Light microscopy and flow cytometry profiling revealed that bacterial filaments, formed due to beta-lactam-mediated inhibition of cell division, rapidly appeared upon beta-lactam mono-treatment and remained stable for up to 18 h. The presence of metabolizable sugars in the medium did not change the rate of filamentation, but led to lysis of the filaments within a few hours. No lysis occurred in E. coli mutants unable to metabolize the sugars, thus establishing sugar metabolism as an important factor influencing the bactericidal outcome of beta-lactam treatment. Interestingly, the effect of sugar on beta-lactam susceptibility was suppressed in a strain unable to synthesize the nutrient stress alarmone (p)ppGpp. Here, to the best of our knowledge, we demonstrate for the first time a specific and significant increase in beta-lactam sensitivity due to sugar metabolism in planktonic, exponentially growing bacteria, unrelated to general nutrient availability or growth rate. Understanding the mechanisms underlying the nutritional influences on antibiotic sensitivity is likely to reveal new proteins or pathways that can be targeted by novel compounds, adding to the list of pharmacodynamic adjuvants that increase the efficiency and lifespan of conventional antibiotics. PMID- 26243264 TI - Locoregional tumour evaluation of squamous cell carcinoma in the head and neck area: a comparison between MRI, PET/CT and integrated PET/MRI. AB - PURPOSE: To evaluate the accuracy of integrated (18)F-FDG PET/MR imaging for locoregional tumour evaluation compared to (18)F-FDG PET/CT and MR imaging in initial tumour and recurrence diagnosis in histopathologically confirmed head and neck squamous cell carcinoma (HNSCC). METHODS: (18)F-FDG PET/CT and integrated (18)F-FDG PET/MR imaging were performed for initial tumour staging or recurrence diagnosis in 25 patients with HNSCC. MR, fused (18)F-FDG PET/CT and fused (18)F FDG PET/MR images were analysed by two independent readers in separate sessions in random order. In initial tumour staging, T and N staging was performed while individual lesions were analysed in patients with suspected cancer recurrence. In T and N staging, histopathological results after tumour resection served as the reference standard while histopathological sampling as well as cross-sectional and clinical follow-up were accepted in cancer recurrence diagnosis. The diagnostic accuracy of each modality was calculated separately for T and N staging as well as for tumour recurrence, and compared using McNemar's test. Values of p <0.017 were considered statistically significant after Bonferroni correction. RESULTS: In 12 patients undergoing (18)F-FDG PET/CT and (18)F-FDG PET/MR for initial tumour staging, T staging was accurate in 50 % with MRI, in 59 % with PET/CT and in 75 % with PET/MR while N staging was accurate in 75 % with MRI, in 77 % with PET/CT and in 71 % with PET/MR in relation to the reference standard. No significant differences were observed in T and N staging among the three modalities (p > 0.017). In 13 patients undergoing hybrid imaging for cancer recurrence diagnosis, diagnostic accuracy was 57 % with MRI and in 72 % with (18)F-FDG PET/CT and (18)F-FDG PET/MR, respectively. Again, no significant differences were found among the three modalities (p > 0.017). CONCLUSION: In this initial study, no significant differences were found among (18)F-FDG PET/MR, (18)F-FDG PET/CT and MRI in local tumour staging and cancer recurrence diagnosis. PMID- 26243265 TI - New frontiers for cardiac PET: looking beyond mean transmural myocardial quantification. PMID- 26243266 TI - Association among house infestation index, dengue incidence, and sociodemographic indicators: surveillance using geographic information system. AB - BACKGROUND: We identified dengue transmission areas by using the Geographic Information Systems located at local surveillance units of the Itaborai municipality in state of Rio de Janeiro. We considered the association among the house infestation index, the disease incidence, and sociodemographic indicators during a prominent dengue outbreak in 2007 and 2008. METHODS: In this ecological study, the Local Surveillance Units (UVLs) of the municipality were used as spatial pattern units. For the house analysis, we used the period of higher vector density that occurred previous to the larger magnitude epidemic range of dengue cases. The average dengue incidence rates calculated in this epidemic range were smoothed using the Bayesian method. The associations among the House Infestation Index (HI), the Bayesian rate of the average dengue incidence, and the sociodemographic indicators were evaluated using a Pearson's correlation coefficient. The areas that were at a higher risk of dengue occurrence were detected using a kernel density estimation with the kernel quartic function. RESULTS: The dengue transmission pattern in Itaborai showed that the increase in the vector density preceded the increase in incidence. The HI was positively correlated to the Bayesian dengue incidence rate (r = 0.641; p = 0.01). The higher risk areas were those that were close to the main highways. In the Kernel density estimation analysis, we observed that the regions that were at a higher risk of dengue were those that were located in the UVLs and had the highest population densities; these locations were typically located along major highways. Four nuclei were identified as epicenters of high risk. CONCLUSIONS: The spatial analysis units used in this research, i.e., UVLs, served as a methodological resource for examining the compatibility of different information sources concerning the disease, the vector indices, and the municipal sociodemographic aspects and were arranged in distinct cartographic bases. Dengue is a multi-scale geographic phenomenon, and using the UVLs as analysis units made it possible to differentiate the dengue occurrence throughout the municipality. The methodological approach used in this research helped improve the Itaborai municipality monitoring activities and the local territorial monitoring in other municipalities that are affected by this public health issue. PMID- 26243267 TI - Bridging the qualitative-quantitative divide: Experiences from conducting a mixed methods evaluation in the RUCAS programme. AB - Quantitative and qualitative approaches to planning and evaluation in education for sustainable development have often been treated by practitioners from a single research paradigm. This paper discusses the utility of mixed method evaluation designs which integrate qualitative and quantitative data through a sequential transformative process. Sequential mixed method data collection strategies involve collecting data in an iterative process whereby data collected in one phase contribute to data collected in the next. This is done through examples from a programme addressing the 'Reorientation of University Curricula to Address Sustainability (RUCAS): A European Commission Tempus-funded Programme'. It is argued that the two approaches are complementary and that there are significant gains from combining both. Using methods from both research paradigms does not, however, mean that the inherent differences among epistemologies and methodologies should be neglected. Based on this experience, it is recommended that using a sequential transformative mixed method evaluation can produce more robust results than could be accomplished using a single approach in programme planning and evaluation focussed on education for sustainable development. PMID- 26243268 TI - Versatile strategy for the divergent synthesis of linear oligosaccharide domain variants of Quillaja saponin vaccine adjuvants. AB - We describe a new, versatile synthetic approach to Quillaja saponin variants based on the natural product immunoadjuvant QS-21. This modular, divergent strategy provides efficient access to linear oligosaccharide domain variants with modified sugars and regiochemistries. This new synthetic approach opens the door to the rapid generation of diverse analogues to identify novel saponin adjuvants with improved synthetic accessibility. PMID- 26243269 TI - IDH1 mutation is prognostic for diffuse astrocytoma but not low-grade oligodendrogliomas in patients not treated with early radiotherapy. AB - Despite accumulating knowledge regarding molecular backgrounds, the optimal management strategy for low-grade gliomas remains controversial. One reason is the marked heterogeneity in the clinical course. To establish an accurate subclassification of low-grade gliomas, we retrospectively evaluated isocitrate dehydrogenase-1 (IDH1) mutation in clinical specimens of diffuse astrocytomas (DA) and oligodendroglial tumors separately. No patients were treated with early radiotherapy, and modified PCV chemotherapy was used for postoperative residual tumors or recurrence in oligodendroglial tumors. Immunohistochemical evaluation of IDH status, p53 status, O(6)-methylguanine methyltransferase expression, and the MIB-1 index were performed. The 1p and 19q status was analyzed with fluorescence in situ hybridization. Ninety-four patients were followed for a median period of 8.5 years. For DAs, p53 was prognostic for progression- free survival (PFS) and IDH1 was significant for overall survival (OS) with multivariate analysis. In contrast, for oligodendroglial tumors, none of the parameters was significant for PFS or OS. Thus, the significance of IDH1 mutation is not clear in oligodendroglial tumors that are homogeneously indolent and chemosensitive. In contrast, DAs are heterogeneous tumors including some potentially malignant tumors that can be predicted by examining the IDH1 mutation status. PMID- 26243270 TI - Reciprocal Inhibitory Interactions Between the Reward-Related Effects of Leptin and Cocaine. AB - Cocaine is habit-forming because of its ability to enhance dopaminergic neurotransmission in the forebrain. In addition to neuronal inputs, forebrain dopamine circuits are modulated by hormonal influences; one of these is leptin, an adipose-derived hormone that attenuates the rewarding effects of food- and hunger-associated brain stimulation reward. Here we report reciprocal inhibition between the reward-related effects of leptin and the reward-related effects of cocaine in rats. First, we report that cocaine and the expectancy of cocaine each depresses plasma leptin levels. Second, we report that exogenous leptin, given systemically or directly into the ventral tegmental area, attenuates the ability of cocaine to elevate dopamine levels in the nucleus accumbens, the ability of cocaine to establish a conditioned place preference, and the ability of cocaine predictive stimuli to prolong responding in extinction of cocaine-seeking. Thus, whereas leptin represents an endogenous antagonist of the habit-forming and habit sustaining effects of cocaine, this antagonism is attenuated by cocaine and comes to be attenuated by the expectancy of cocaine. PMID- 26243272 TI - Targeted Proteomics to Assess the Response to Anti-Angiogenic Treatment in Human Glioblastoma (GBM). AB - Glioblastoma (GBM) is a highly aggressive primary brain tumor with dismal outcome for affected patients. Because of the significant neo-angiogenesis exhibited by GBMs, anti-angiogenic therapies have been intensively evaluated during the past years. Recent clinical studies were however disappointing, although a subpopulation of patients may benefit from such treatment. We have previously shown that anti-angiogenic targeting in GBM increases hypoxia and leads to a metabolic adaptation toward glycolysis, suggesting that combination treatments also targeting the glycolytic phenotype may be effective in GBM patients. The aim of this study was to identify marker proteins that are altered by treatment and may serve as a short term readout of anti-angiogenic therapy. Ultimately such proteins could be tested as markers of efficacy able to identify patient subpopulations responsive to the treatment. We applied a proteomics approach based on selected reaction monitoring (SRM) to precisely quantify targeted protein candidates, selected from pathways related to metabolism, apoptosis and angiogenesis. The workflow was developed in the context of patient-derived intracranial GBM xenografts developed in rodents and ensured the specific identification of human tumor versus rodent stroma-derived proteins. Quality control experiments were applied to assess sample heterogeneity and reproducibility of SRM assays at different levels. The data demonstrate that tumor specific proteins can be precisely quantified within complex biological samples, reliably identifying small concentration differences induced by the treatment. In line with previous work, we identified decreased levels of TCA cycle enzymes, including isocitrate dehydrogenase, whereas malectin, calnexin, and lactate dehydrogenase A were augmented after treatment. We propose the most responsive proteins of our subset as potential novel biomarkers to assess treatment response after anti-angiogenic therapy that warrant future analysis in clinical GBM samples. PMID- 26243273 TI - Extracting ligands from receptors by reversed targeted molecular dynamics. AB - Short targeted MD trajectories are used to expel ligands from binding sites. The expulsion is governed by a linear increase of the target RMSD value, growing from zero to an arbitrary chosen final RMSD that forces the ligand to a selected distance outside of the receptor. The RMSD lag (i.e., the difference between the imposed and the actual RMSD) can be used to follow barriers encountered by the ligand during its way out of the receptor. The force constant used for the targeted MD can transform the RMSD lag into a strain energy. Integration of the (time-dependent) strain energy over time yields a value with the dimensions of "action" (i.e, energy multiplied by time) and can serve as a measure for the overall effort required to extract the ligand from its binding site. Possibilities to compare (numerically and graphically) the randomly detected exit pathways are discussed. As an example, the method is tested on the exit of bisphenol A from the human estrogen-related receptor [Formula: see text] and of GW0072 from the peroxysome proliferator activated receptor. PMID- 26243274 TI - Paracoccus laeviglucosivorans sp. nov., an l-glucose-utilizing bacterium isolated from soil. AB - Strain 43PT was isolated as an l-glucose-utilizing bacterium from soil in Japan. Cells of the strain were Gram-stain-negative, aerobic and non-motile cocci. The 16S rRNA gene sequence of the strain showed high similarity to that of Paracoccus limosus (98.5 %). Phylogenetic analyses based on 16S rRNA gene sequences revealed that this strain belongs to the genus Paracoccus. Strain 43PT contained Q-10 as the sole isoprenoid quinone. The major cellular fatty acids were C18: 1omega7c or C18: 1omega6c and C16: 0, and C18: 0, C18: 1omega9c, C10: 0 3-OH and summed feature 2 were detected as minor components. The DNA G+C content of strain 43PT was 64.1 mol%. Strain 43PT contained the major polar lipids phosphatidylcholine, phosphatidylglycerol, diphosphatidylglycerol, an unknown aminolipid and two unknown glycolipids. The DNA-DNA relatedness between strain 43PT and the six related type strains of the genus Paracoccus, including P. limosus, was below 23 %. Based on the chemotaxonomic and physiological data and the values of DNA-DNA relatedness, especially the ability to assimilate l-glucose, this strain should be classified as a representative of a novel species of the genus Paracoccus, for which the name Paracoccus laeviglucosivorans sp. nov. (type strain 43PT = JCM 30587T = DSM 100094T) is proposed. PMID- 26243277 TI - Ex vivo simulation of cardiopulmonary bypass with human blood for hemocompatibility testing. AB - OBJECT: Experimental circuits for biomaterial surface testing are frequently limited by the tested blood volume, composition of the circuit, flow conditions and the use of animal blood. This report describes an ex vivo set-up for simulated cardiopulmonary bypass with human blood perfusion. We investigated the clinical generalizability of the observed effects on hematological and metabolic parameters and the hemocompatibility of the system. METHODS: The simulated cardiopulmonary bypass circuit consisted of a heparin-coated tubing system connected to an oxygenator and a venous reservoir. Normothermic flow of blood obtained from healthy donors was maintained at 2.4 L/min/m(2) by a roller pump. Heparin was dosed to obtain a target activated clotting time (ACT) ?500 s. Blood was drawn at baseline and 0, 10, 60 and 120 minutes following the initiation of blood flow to determine hematological and metabolic parameters and the hemocompatibility of the extracorporeal system. Data were analyzed using repeated measures ANOVA. RESULTS: Two hours of blood perfusion resulted in a small, but clinically unimportant reduction in hematocrit, whereas hemoglobin levels and red blood cell, platelet and leukocyte counts remained stable. There was a significant increase in ACT throughout the experiment. While pO2 levels and the pH remained unaltered during the experiment, pCO2 values decreased from 51 +/- 6 mmHg at T0 to 41 +/- 3 mmHg at T120 (p<0.001). Simulated cardiopulmonary bypass induced a two-fold increase in C3a (p=0.001) while tissue factor was decreased from 44 +/- 14 pg/mL at T0 to 38 +/- 13 pg/mL at T120 (p=0.009). Levels of CD40L, prothrombin fragment 1+2, beta-thromboglobulin and factor VIIa remained stable over time. CONCLUSION: The ex vivo set-up for simulated cardiopulmonary bypass mimicked the clinical cardiosurgical setting. Exposure of fresh donor blood to the extracorporeal circuit showed a good hemocompatibility, indicated by maintained hematological parameters and a mild immune response. PMID- 26243275 TI - Immigrants from conflict-zone countries: an observational comparison study of obstetric outcomes in a low-risk maternity ward in Norway. AB - BACKGROUND: Immigrants have higher risks for some adverse obstetric outcomes. Furthermore, refugees are reported to be the most vulnerable group. This study compared obstetric outcomes between immigrant women originating from conflict zone countries and ethnic Norwegians who gave birth in a low-risk setting. METHODS: This was a population-based study linking the Medical Birth Registry of Norway to Statistics Norway. The study included the first registered birth during the study period of women from Somalia (n = 278), Iraq (n = 166), Afghanistan (n = 71), and Kosovo (n = 67) and ethnic Norwegians (n = 6826) at Baerum Hospital from 2006-2010. Background characteristics and obstetric outcomes of each immigrant group were compared with ethnic Norwegians with respect to proportions and risks calculated by logistic regression models. RESULTS: In total, 7408 women and their births were analyzed. Women from Somalia were most at risk for adverse obstetric outcomes. Compared with ethnic Norwegians, they had increased odds ratios (OR) for emergency cesarean section (OR 1.81, CI 1.17-2.80), postterm birth (OR 1.93, CI 1.29-2.90), meconium-stained liquor (OR 2.39, CI 1.76-3.25), and having a small-for-gestational-age infant (OR 3.97, CI 2.73-5.77). They had a reduced OR for having epidural analgesia (OR 0.40, CI 0.28-0.56) and a large-for gestational-age infant (OR 0.32, CI 0.16-0.64). Women from Iraq and Afghanistan had increased risk of having a small-for-gestational-age infant with OR of 2.21 (CI 1.36-3.60) and 2.77 (CI 1.42-5.39), respectively. Iraqi women also had reduced odds ratio of having a large-for-gestational-age infant (OR 0.35, CI 0.15 0.83). Women from Kosovo did not differ from ethnic Norwegians in any of the outcomes we tested. CONCLUSIONS: Even in our low-risk maternity ward, women originating from Somalia were at the greatest risk for adverse obstetric outcomes in the compared groups. We could not find the same risk among the other immigrant women, also originating from conflict-zone countries. Several factors may influence these findings, and this study suggests that immigrant women from Somalia need more targeted care during pregnancy and childbirth. PMID- 26243278 TI - Streptococcus pyogenes strains in Sao Paulo, Brazil: molecular characterization as a basis for StreptInCor coverage capacity analysis. AB - BACKGROUND: Several human diseases are caused by Streptococcus pyogenes, ranging from common infections to autoimmunity. Characterization of the most prevalent strains worldwide is a useful tool for evaluating the coverage capacity of vaccines under development. In this study, a collection of S. pyogenes strains from Sao Paulo, Brazil, was analyzed to describe the diversity of strains and assess the vaccine coverage capacity of StreptInCor. METHODS: Molecular epidemiology of S. pyogenes strains was performed by emm-genotyping the 229 isolates from different clinical sites, and PCR was used for superantigen profile analysis. The emm-pattern and tissue tropism for these M types were also predicted and compared based on the emm-cluster classification. RESULTS: The strains were fit into 12 different emm-clusters, revealing a diverse phylogenetic origin and, consequently, different mechanisms of infection and escape of the host immune system. Forty-eight emm-types were distinguished in 229 samples, and the 10 most frequently observed types accounted for 69 % of all isolates, indicating a diverse profile of circulating strains comparable to other countries under development. A similar proportion of E and A-C emm-patterns were observed, whereas pattern D was less frequent, indicating that the strains of this collection primarily had a tissue tropism for the throat. In silico analysis of the coverage capacity of StreptInCor, an M protein-conserved regionally based vaccine candidate developed by our group, had a range of 94.5 % to 59.7 %, with a mean of 71.0 % identity between the vaccine antigen and the predicted amino acid sequence of the emm-types included here. CONCLUSIONS: This is the first report of S. pyogenes strain characterization in Sao Paulo, one of the largest cities in the world; thus, the strain panel described here is a representative sample for vaccine coverage capacity analysis. Our results enabled evaluation of StreptInCor candidate vaccine coverage capacity against diverse M-types, indicating that the vaccine candidate likely would induce protection against the diverse strains worldwide. PMID- 26243279 TI - Elevated H3K18 acetylation in airway epithelial cells of asthmatic subjects. AB - BACKGROUND: Epigenetic adjustments of the chromatin architecture through histone modifications are reactive to the environment and can establish chromatin states which are permissive or repressive to gene expression. Epigenetic regulation of gene expression is cell specific and therefore, it is important to understand its contribution to individual cellular responses in tissues like the airway epithelium which forms the mucosal barrier to the inhaled environment within the lung. The airway epithelium of asthmatics is abnormal with dysregulation of genes such as epidermal growth factor receptor (EGFR), the DeltaN isoform of the transcription factor p63 (DeltaNp63), and signal transducer and activator of transcription 6 (STAT6), integral to differentiation, proliferation, and inflammation. It is important to establish in diseases like asthma how histone modifications affect tissue responses such as proliferation and differentiation. OBJECTIVES: To characterize the global histone acetylation and methylation status in the epithelium of asthmatic compared to healthy subjects and to identify the impact of these variations on genes involved in epithelial functions. METHODS: Whole lungs were obtained from healthy and asthmatic subjects (n = 6) from which airway epithelial cells (AECs) were isolated and airway sections were taken for analysis of histone lysine acetylation and methylation by immunohistochemistry. AECs were subjected to chromatin immunoprecipitation (ChIP) using anti-H3K18ac and anti-H3K4me2 antibodies followed by RT-PCR targeting DeltaNp63, EGFR, and STAT6. AECs were also treated with TSA and changes in DeltaNp63, EGFR, and STAT6 expression were determined. RESULTS: We identified an increase in the acetylation of lysine 18 on histone 3 (H3K18ac) and trimethylation of lysine 9 on histone 3 (H3K9me3) in the airway epithelium of asthmatic compared to healthy subjects. We found increased association of H3K18ac around the transcription start site of DeltaNp63, EGFR, and STAT6 in AECs of asthmatics. However, we were unable to modify the expression of these genes with the use of the HDAC inhibitor TSA in healthy subjects. DISCUSSION: The airway epithelium from asthmatic subjects displays increased acetylation of H3K18 and association of this mark around the transcription start site of DeltaNp63, EGFR, and STAT6. These findings suggest a complex interaction between histone modifications and gene regulation in asthma. PMID- 26243280 TI - Improvement of culture conditions for long-term in vitro culture of Plasmodium vivax. AB - BACKGROUND: The study of the biology, transmission and pathogenesis of Plasmodium vivax is hindered due to the lack of a robustly propagating, continuous culture of this parasite. The current culture system for P. vivax parasites still suffered from consistency and difficulties in long-term maintenance of parasites in culture and for providing sufficient biological materials for studying parasite biology. Therefore, further improvement of culture conditions for P. vivax is needed. METHODS: Clinical samples were collected from patients diagnosed with P. vivax in western Thailand. Leukocyte-depleted P. vivax infected blood samples were cultured in a modified McCoy's 5A medium at 5% haematocrit under hypoxic condition (5% O2, 5% CO2, and 90% N2). Reticulocytes purified from adult peripheral blood were added daily to maintain 4% reticulocytes. Parasites were detected by microscopic examination of Giemsa-stained smears and molecular methods. RESULTS: The effects of culture variables were first analysed in order to improve the culture conditions for P. vivax. Through analysis of the sources of host reticulocytes and nutrients of culture medium, the culture conditions better supporting in vitro growth and maturation of the parasites were identified. Using this system, three of 30 isolates could be maintained in vitro for over 26 months albeit parasite density is low. CONCLUSIONS: Based on the analysis of different culture variables, an improved and feasible protocol for continuous culture of P. vivax was developed. PMID- 26243282 TI - Molecular epidemiology of coxsackievirus type B1. AB - Coxsackievirus type B1 (CVB1) has emerged globally as the predominant enterovirus serotype and is associated with epidemics of meningitis and chronic diseases. In this report, the phylogeny of CVB1 was studied based on the VP1 sequences of 11 North African isolates and 81 published sequences. All CVB1 isolates segregated into four distinct genogroups and 10 genotypes. Most of the identified genotypes of circulating CVB1 strains appear to have a strict geographical specificity. The North African strains were of a single genotype and probably evolved distinctly. Using a relaxed molecular clock model and three different population models (constant population, exponential growth and Bayesian skyline demographic models) in coalescent analysis using the BEAST program, the substitution rate in CVB1 varied between 6.95 * 10(-3) and 7.37 * 10(-3) substitutions/site/year in the VP1 region. This study permits better identification of circulating CVB1, which has become one of the most predominant enterovirus serotypes in humans. PMID- 26243281 TI - Regulation of PLCbeta2 by the electrostatic and mechanical properties of lipid bilayers. AB - Phosphoinositide-specific phospholipase C (PLC) is an important family of enzymes constituting a junction between phosphoinositide lipid signaling and the trans membrane signal transduction processes that are crucial to many living cells. However, the regulatory mechanism of PLC is not yet understood in detail. To address this issue, activity studies were carried out using lipid vesicles in a model system that was specifically designed to study protein-protein and lipid protein interactions in concert. Evidence was found for a direct interaction between PLC and the GTPases that mediate phospholipase activation. Furthermore, for the first time, the relationships between PLC activity and substrate presentation in lipid vesicles of various sizes, as well as lipid composition and membrane mechanical properties, were analyzed. PLC activity was found to depend upon the electrostatic potential and the stored curvature elastic stress of the lipid membranes. PMID- 26243283 TI - Early maternal age and multiparity are associated to poor physical performance in middle-aged women from Northeast Brazil: a cross-sectional community based study. AB - BACKGROUND: Adolescent childbirth and elevated parity are relatively common in middle and low-income countries and they may be related to the higher prevalence and earlier onset of physical decline documented in these settings, especially in women. The aim of this paper is to investigate whether reproductive history is associated with physical function in middle-aged women from Northeast Brazil. METHODS: The relationship between poor physical performance (grip strength, gait speed and chair stand), early maternal age at first birth (<18 years old), and multiparity (>= 3 children) was evaluated in a community sample of 473 women living in Parnamirim (Northeast Brazil). Linear regression models were used to examine the relationship of interest; in addition, mediation analyses were employed to assess indirect effects of obesity and family income. RESULTS: Women who gave birth at less than 18 years of age took approximately 0.50 s longer to complete the chair stand test compared to women who gave birth at 18 years or older. Moreover, women who gave birth to < 3 children completed the chair stand test 0.42 s faster compared to those who had >= 3 children. The relation between reproductive history and physical performance was mediated by BMI. Reproductive history was not associated with performance in gait speed. CONCLUSIONS: This study provides evidence that adolescent childbirth and multiparity are related to worse physical performance in middle-aged women from a low income setting. Reproductive history may partially account for earlier physical decline and greater disability in women from lower income settings. PMID- 26243271 TI - CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease. AB - The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (P(meta)=5.0 * 10(-4)) and rs800292 (P(meta)=1.3 * 10(-5)) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16 795 controls). Rs1061170 (P=2.5 * 10(-3)) and rs800292 (P=4.7 * 10(-4)) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and Abeta levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress. PMID- 26243284 TI - Incremental health expenditure and lost days of normal activity for individuals with mental disorders: results from the Sao Paulo Megacity Study. AB - BACKGROUND: With the recent increase in the prevalence of mental disorders in developing countries, there is a growing interest in the study of its consequences. We examined the association of depression, anxiety and any mental disorders with incremental health expenditure, i.e. the linear increase in health expenditure associated with mental disorders, and lost days of normal activity. METHODS: We analyzed the results from a representative sample survey of residents of the Metropolitan Region of Sao Paulo (n = 2,920; Sao Paulo Megacity Mental Health Survey), part of the World Mental Health (WMH) Survey Initiative, coordinated by the World Health Organization and performed in 28 countries. The instrument used for obtaining the individual results, including the assessment of mental disorders, was the WMH version of the Composite International Diagnostic Interview 3.0 (WMH-CIDI 3.0) that generates psychiatric diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Statistical analyses were performed by multilevel generalized least squares (GLS) regression models. Sociodemographic determinants such as income, age, education and marital status were included as controls. RESULTS: Depression, anxiety and any mental disorders were consistently associated with both incremental health expenditure and missing days of normal activity. Depression was associated with an incremental annual expenditure of R$308.28 (95% CI: R$194.05-R$422.50), or US$252.48 in terms of purchasing power parity (PPP). Anxiety and any mental disorders were associated with a lower, but also statistically significant, incremental annual expenditure (R$177.82, 95% CI: 79.68-275.97; and R$180.52, 95% CI: 91.13-269.92, or US$145.64 and US$147.85 in terms of PPP, respectively). Most of the incremental health costs associated with mental disorders came from medications. Depression was independently associated with higher incremental health expenditure than the two most prevalent chronic diseases found by the study (hypertension and diabetes). CONCLUSIONS: The fact that individuals with mental disorders had a consistent higher health expenditure is notable given the fact that Brazil has a universal free-of-charge healthcare and medication system. The results highlight the growing importance of mental disorders as a public health issue for developing countries. PMID- 26243285 TI - Ulnar nerve stability-based surgery for cubital tunnel syndrome via a small incision: a comparison with classic anterior nerve transposition. AB - OBJECTIVE: The purpose of this study was to compare the clinical outcomes of ulnar nerve stability-based surgery via a small incision with those of classic anterior transposition of the ulnar nerve for cubital tunnel syndrome. METHODS: From March 2008 to December 2013, 107 patients with cubital tunnel syndrome underwent simple decompression or anterior transposition via a small incision, according to an ulnar nerve stability-based decision based on an assessment of intraoperative ulnar nerve stability (group A, n = 51), or anterior transposition via a classic incision (group B, n = 56). Clinical outcome was assessed using grip and pinch strength, two-point discrimination, the mean of the disabilities of arm, shoulder, and hand (DASH) survey, and the modified Bishop scale. RESULTS: At the final follow-up, all outcome measures improved significantly in both groups and there were no significant differences between the two groups. However, there were fewer operation-related complications in group A (one revision surgery) than in group B (one superficial infection, two painful scars, and five cases of numbness at the medial elbow). CONCLUSIONS: Outcomes after the ulnar nerve stability-based approach and anterior transposition were similar, although more patients experienced operation-related complications after anterior transposition via a classic incision. Making an ulnar nerve stability-based decision to perform either simple decompression or anterior transposition via a small incision seems to be a better strategy for patients with cubital tunnel syndrome. PMID- 26243286 TI - Metabarcoding analysis of home composts reveals distinctive fungal communities with a high number of unassigned sequences. AB - Home composting has been strongly advocated in the UK, Europe and North America to divert organic waste away from conventional waste processing. Despite this, little attention has been given to microbial communities and their diversity in these systems. In this study, we examined the diversity of fungal species in 10 different domestic composts by 454 tag-encoded pyrosequencing. We report the recovery of 478 different molecular operational taxonomic units (MOTUs) from the 10 composts with a mean of 176.7 +/- 19.6 MOTUs per compost and a mean of 12.9 +/ 3.8 unique MOTUs per sample. Microascales (17.21 %), Hypocreales (16.76 %), Sordariales (14.89 %), Eurotiales (11.25 %) and Mortierellales (7.38 %) were the dominant orders in the community, with Pseudallescheria (9.52 %), Penicillium (8.43 %), Mortierella (3.60 %) and Fusarium (3.31 %) being the most abundant genera. Fungal communities in home composts were substantially different to large scale commercial composts, with thermophilic and thermotolerant fungi present in much lower numbers. Significantly, 46.2 % of all sequences were identified as uncultured fungi or could not be assigned above the family level, suggesting there are a high number of new genera and species in these environments still to be described. PMID- 26243288 TI - Fitness Inference from Short-Read Data: Within-Host Evolution of a Reassortant H5N1 Influenza Virus. AB - We present a method to infer the role of selection acting during the within-host evolution of the influenza virus from short-read genome sequence data. Linkage disequilibrium between loci is accounted for by treating short-read sequences as noisy multilocus emissions from an underlying model of haplotype evolution. A hierarchical model-selection procedure is used to infer the underlying fitness landscape of the virus insofar as that landscape is explored by the viral population. In a first application of our method, we analyze data from an evolutionary experiment describing the growth of a reassortant H5N1 virus in ferrets. Across two sets of replica experiments we infer multiple alleles to be under selection, including variants associated with receptor binding specificity, glycosylation, and with the increased transmissibility of the virus. We identify epistasis as an important component of the within-host fitness landscape, and show that adaptation can proceed through multiple genetic pathways. PMID- 26243289 TI - Quantitation of circulating wild-type alpha-1-antitrypsin in heterozygous carriers of the S and Z deficiency alleles. AB - BACKGROUND: Alpha-1-antitrypsin (A1AT) deficiency disease results from mutations in the A1AT gene. Controversy exists in regards to treatment of heterozygous carriers of the S and Z deficiency alleles. Quantitation of allelic expression has not been possible with standard laboratory methods. Here we show that the recently described method for liquid chromatography tandem mass spectrometry (LC MS/MS) analysis of A1AT tryptic peptides can differentiate between mutated (S and Z) and wild-type (non-S and non-Z) proteins allowing for quantitation of circulating allelic expression in heterozygous patients. METHODS: Serum (244 M/M, 61 M/Z, and 63 M/S) was combined with isotopically labeled peptide standards, digested with trypsin, and quantitated by LC-MS/MS. Total and allele-specific A1AT quantitation was performed by comparison of peptide peak height ratios to a standard curve for each peptide. Linear regression was used to compare results and central 95(th) percentile intervals were calculated using parametric analysis. RESULTS: Quantitation of circulating wild-type A1AT based on the proteotypic and allelic (non-S and non-Z) peptides was validated in M/M patients. Proteotypic peptide concentrations correlated linearly with quantitation by non-Z and non-S peptides [slopes (Spearman correlation coefficient) of 1.09 (0.89) and 0.98 (0.80), respectively]. Allele-specific quantitation showed significant differences in wild-type protein expression in M/Z and M/S patients. Although average total A1AT concentration was lower for M/Z patients, the percentage of wild-type protein in M/Z patients was significantly higher at 82 % (55- > 95 %) compared to 63 % (43-83 %) for M/S heterozygotes. In a cohort of M/Z patients with sufficient total A1AT (>=80 mg/dL), half had insufficient wild-type protein that could have clinical implications for pulmonary dysfunction. CONCLUSIONS: For the first time, a method to quantitate A1AT allele protein expression is described. Given the wide range of circulating wild-type protein observed in heterozygous patients, this method has the potential to reveal correlations between allele concentration and development and/or severity of clinical symptoms. PMID- 26243290 TI - Trajectory optimization based on the signal-to-noise ratio for spatial encoding with nonlinear encoding fields. AB - PURPOSE: Multiple nonlinear gradient fields offer many potential benefits for spatial encoding including reduced acquisition time, fewer artefacts and region specific imaging, although designing a suitable trajectory for such a setup is difficult. This work aims to optimize encoding trajectories for multiple nonlinear gradient fields based on the image signal-to-noise ratio. THEORY AND METHODS: Image signal-to-noise ratio is directly linked to the covariance of the reconstructed pixels, which can be calculated recursively for each projection of the trajectory under a Bayesian formulation. An evolutionary algorithm is used to find the higher-dimensional projections that minimize the pixel covariance, incorporating receive coil profiles, intravoxel dephasing, and reconstruction regularization. The resulting trajectories are tested through simulations and experiments. RESULTS: The optimized trajectories produce images with higher resolution and fewer artefacts compared with traditional approaches, particularly for high undersampling. However, higher-dimensional projection experiments strongly depend on accurate hardware and calibration. CONCLUSION: Computer-based optimization provides an efficient means to explore the large trajectory space created by the use of multiple nonlinear encoding fields. The optimization framework, as presented here, is necessary to fully exploit the advantages of nonlinear fields. Magn Reson Med 76:104-117, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26243291 TI - Empiric therapy for hospital-acquired, Gram-negative complicated intra-abdominal infection and complicated urinary tract infections: a systematic literature review of current and emerging treatment options. AB - BACKGROUND: Empiric therapy for healthcare-associated infections remains challenging, especially with the continued development of Gram-negative organisms producing extended-spectrum beta-lactamases (ESBLs) and the threat of multi-drug resistant organisms. Current treatment options for resistant Gram-negative infections include carbapenems, tigecycline, piperacillin-tazobactam, cefepime, ceftazidime, and two recently approved therapies, ceftolozane-tazobactam and ceftazidime-avibactam. METHODS: This systematic literature review surveys the published clinical trial evidence available since 2000 in support of both current and emerging treatment options in the settings of complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI). When available, clinical cure rates for patients with infections from ESBL-producing strains are provided, as is information about efficacy against Pseudomonas aeruginosa. RESULTS: Clinical trial evidence to guide selection of empiric antibiotic therapy in patients with complicated, hospital-acquired, Gram-negative IAIs and UTIs is limited. Though most of the clinical trials explored in this overview enrolled patients with complicated infections, often patients with severe infections and multiple comorbidities were excluded. CONCLUSIONS: Practitioners in the clinical setting who are treating patients with complicated, hospital-acquired, Gram negative IAIs and UTIs need to consider the possibility of polymicrobial infections, antibiotic-resistant organisms, and/or severely ill patients with multiple comorbidities. There is a severe shortage of evidence-based research to guide the selection of empiric antibiotic therapy for many patients in this setting. New therapies recently approved or in late-stage development promise to expand the number of options available for empiric therapy of these hospital acquired, Gram-negative infections. PMID- 26243292 TI - The Words Children Hear: Picture Books and the Statistics for Language Learning. AB - Young children learn language from the speech they hear. Previous work suggests that greater statistical diversity of words and of linguistic contexts is associated with better language outcomes. One potential source of lexical diversity is the text of picture books that caregivers read aloud to children. Many parents begin reading to their children shortly after birth, so this is potentially an important source of linguistic input for many children. We constructed a corpus of 100 children's picture books and compared word type and token counts in that sample and a matched sample of child-directed speech. Overall, the picture books contained more unique word types than the child directed speech. Further, individual picture books generally contained more unique word types than length-matched, child-directed conversations. The text of picture books may be an important source of vocabulary for young children, and these findings suggest a mechanism that underlies the language benefits associated with reading to children. PMID- 26243293 TI - [Anesthesiologists are the guarantors of security and quality in endoscopy rooms]. PMID- 26243294 TI - Potential predictors for health-related quality of life in stroke patients undergoing inpatient rehabilitation. AB - BACKGROUND: Improving HRQOL is the desired outcome for patients with stroke undergoing inpatient rehabilitation services. This study aimed to comprehensively identify the potential health-related quality of life (HRQOL) predictors in patients with stroke undergoing inpatient rehabilitation within the first year after stroke; thus far, such an investigation has not been conducted. METHODS: We enrolled 119 patients (88 males, 31 females) with stroke, and examined 12 potential predictors: age, sex, stroke type, stroke side, duration after onset, cognition (Mini-Mental State Examination; MMSE), depression (Beck Depression Inventory-II), stroke severity (National Institutes of Health Stroke Scale; NIHSS), upper- and lower-extremity motor function scores of the Fugl-Meyer Assessment (FMA) scale, balance (Berg Balance Scale; BBS), and functional status (Functional Independence Measure). HRQOL was measured using Stroke Impact Scale (SIS) 3.0. RESULTS: NIHSS score predicted the strength domain and total SIS score (41.5% and 41.7% of the variances, respectively). BBS score was a major predictor of mobility and participation/role domains (48.6% and 10% of the variances, respectively). MMSE score predicted the memory and communication domains (22.5% and 36.3% of the variances, respectively). Upper extremity score of the FMA scale predicted the daily living/instrumental activities of daily life and hand function domains (40.3% and 20.6% of the variances, respectively). Stroke side predicted the emotion domain (11.6% of the variance). CONCLUSIONS: NIHSS, MMSE, BBS, FMA, and stroke side predicted most HRQOL domains. These findings suggest that different factors predicted various HRQOL domains in patients with stroke. PMID- 26243296 TI - New QOF targets focus on physical health of patients with mental health problems. PMID- 26243295 TI - Seasonal and temporal trends in all-cause and malaria mortality in rural Burkina Faso, 1998-2007. AB - BACKGROUND: High mortality levels in sub-Saharan Africa are still a major public health problem. Children are the most affected group with malaria as one of the major causes of death in this region. To plan health interventions, reliable empirical information on cause-specific mortality patterns is essential, yet such data are often not available in developing countries. Health and Demographic Surveillance Systems (HDSS) implementing the verbal autopsy (VA) method provide such data on a longitudinal basis. Physician Coded VA is usually used to determine cause of death, but recently a computerized method, Interpreting VA (InterVA) was alternatively introduced. This study investigates the effect of season on all-cause and malaria mortality analysing cause of death data from 1998 to 2007 obtained by the Nouna HDSS in rural Burkina Faso and derived by InterVA. METHODS: Monthly mortality rates were calculated for different age groups (infants, children, adolescents, adults, elderly). Seasonal and temporal trends were modelled with parametric Poisson regression adjusted for sex, area of residence and year of death. RESULTS: Overall, 7,378 deaths occurred corresponding to a mortality rate of 11.9/1,000 with highest rates in infants (56.8/1,000) and children (22.0/1,000). Young children were most affected by malaria. Malaria mortality patterns in children showed significantly higher rates during the rainy season and a stagnant long-term trend. The seasonal trend is well described parametrically with a sinusoidal function. InterVA assigned about half as many deaths to malaria than physicians. CONCLUSIONS: Malaria mortality remains highly seasonal in rural Burkina Faso. The InterVA method appears to determine reasonably well seasonal mortality patterns, which should be considered for the planning of health resources and activities. PMID- 26243297 TI - A membrane computing simulator of trans-hierarchical antibiotic resistance evolution dynamics in nested ecological compartments (ARES). AB - BACKGROUND: Antibiotic resistance is a major biomedical problem upon which public health systems demand solutions to construe the dynamics and epidemiological risk of resistant bacteria in anthropogenically-altered environments. The implementation of computable models with reciprocity within and between levels of biological organization (i.e. essential nesting) is central for studying antibiotic resistances. Antibiotic resistance is not just the result of antibiotic-driven selection but more properly the consequence of a complex hierarchy of processes shaping the ecology and evolution of the distinct subcellular, cellular and supra-cellular vehicles involved in the dissemination of resistance genes. Such a complex background motivated us to explore the P system standards of membrane computing an innovative natural computing formalism that abstracts the notion of movement across membranes to simulate antibiotic resistance evolution processes across nested levels of micro- and macro environmental organization in a given ecosystem. RESULTS: In this article, we introduce ARES (Antibiotic Resistance Evolution Simulator) a software device that simulates P-system model scenarios with five types of nested computing membranes oriented to emulate a hierarchy of eco-biological compartments, i.e. a) peripheral ecosystem; b) local environment; c) reservoir of supplies; d) animal host; and e) host's associated bacterial organisms (microbiome). Computational objects emulating molecular entities such as plasmids, antibiotic resistance genes, antimicrobials, and/or other substances can be introduced into this framework and may interact and evolve together with the membranes, according to a set of pre-established rules and specifications. ARES has been implemented as an online server and offers additional tools for storage and model editing and downstream analysis. CONCLUSIONS: The stochastic nature of the P-system model implemented in ARES explicitly links within and between host dynamics into a simulation, with feedback reciprocity among the different units of selection influenced by antibiotic exposure at various ecological levels. ARES offers the possibility of modeling predictive multilevel scenarios of antibiotic resistance evolution that can be interrogated, edited and re-simulated if necessary, with different parameters, until a correct model description of the process in the real world is convincingly approached. ARES can be accessed at http://gydb.org/ares. PMID- 26243298 TI - Neglect of skin wounds and the risk of becoming a Staphylococcus aureus nasal carrier: a cohort study. AB - BACKGROUND: Nasal carriers of Staphylococcus aureus have an increased risk of acquiring skin and soft tissue infections, which could manifest as outbreaks, especially in crowded settings. Current prevention programs are ineffective, antibiotic resistance is rising and risk factors for becoming a carrier are incompletely understood. We aimed to examine whether a behavior, the neglect of skin wounds, is a risk factor for becoming a Staphylococcus aureus carrier during training. METHODS: We conducted a field-based cohort study among male infantry trainees in three seasons in Israel during 2011-12. Participants underwent anterior nares cultures and answered structured questionnaires on potential risk factors on two occasions: before and 3 weeks after start of training (N = 542). Attitudes and practices toward neglect of skin wounds were defined as perseverance in training at all costs, despite having a wound. Samples were processed within 18 hours for identification of Staphylococcus aureus. Univariable and multivariable logistic regression analyses were performed to assess risk factors for becoming a carrier. RESULTS: Carriage prevalence increased by 43.3% during training, from 33.2% to 47.6% (p < 0.01). One-fourth (25.4%) of those with a negative culture before training became carriers. None of the socio-demographic characteristics was a risk factor for becoming a carrier while the risk was lower in the winter (Odds ratio [OR] = 0.42; 95% confidence interval [CI]: 0.23-0.78, p < 0.01) and spring (OR = 0.46; 0.26-0.81, p < 0.01) seasons compared to the summer season. Neglect of skin wounds in practice and attitude was a risk factor for becoming a carrier (OR = 2.40; 1.13-5.12, p = 0.02), as well as neglect in practice or attitude (OR = 1.86; 1.04-3.34, p = 0.04) compared to no neglect when controlled for season. The preventable fraction in the population attributed to neglect of skin wounds was 33%. CONCLUSIONS: Neglect of skin wounds is an independent, common and strong risk factor for becoming a Staphylococcus aureus carrier during training. This preventable behavior should not be ignored and should be addressed in public health programs during training and in other settings. Further research on behavioral determinants of Staphylococcus aureus carriage and infection is warranted. PMID- 26243299 TI - microRNA-93 promotes cell proliferation via targeting of PTEN in Osteosarcoma cells. AB - BACKGROUND: Aberrant microRNA (miRNA) expression plays an essential role in osteosarcoma (OS) pathogenesis. Recent studies have shown that dysregulation of miRNA expression is associated with increased tumorigenesis and poor prognosis in several types of cancers, including OS. The aim of this study was to investigate the relevant microRNAs involved in the development of OS. METHODS: To explore possible oncogenic factors in OS, we used a microarray-based approach to profile changes in the expression of miRNAs and their target mRNAs in five OS cell lines and human mesenchymal stem cells (hMSCs). An miRNA, miR-93, was significantly up regulated, whereas phosphatase and tensin homologue (PTEN) expression was significantly down-regulated in all tested OS cells, when compared with hMSCs. RESULTS: When anti-miR-93 was transfected into OS cell lines, PTEN expression was greatly increased, suggesting that PTEN might be a target of miR-93 in ES cells. The expression of phosphorylated Akt protein, which is known to be inversely correlated with that of PTEN, was significantly down-regulated in anti-miR-93 transfected cells. Furthermore, transfection of anti-miR-93 inhibited the proliferation and cell cycle progression of ES cells. In addition, the down regulation of miR-93 in these cells significantly suppressed tumor growth in vivo. CONCLUSION: Ectopic expression of miR-93 decreased PTEN protein levels. Furthermore, miR-93 increased proliferation and decreased apoptosis in OS cells, whereas its silencing in these cells inhibited such carcinogenic processes. Taking these observations together, miR-93 can be seen to play a critical role in carcinogenesis through suppression of PTEN, and may serve as a therapeutic target for the treatment of OS. PMID- 26243300 TI - Contributions of mindful eating, intuitive eating, and restraint to BMI, disordered eating, and meal consumption in college students. AB - PURPOSE: Mindful eating and intuitive eating are promoted as means to circumvent potentially maladaptive dietary restraint while maintaining a healthy weight. Although theoretically related, no studies have examined the correlations between intuitive eating, mindful eating, and restraint in the same sample. This study sought to examine these constructs and their correlations with body mass index (BMI), eating-disordered behaviors, and meal consumption in a college sample. METHODS: Participants (N = 125) completed a laboratory taste-test meal and measures of each eating-related construct using the EDDS, IES, MEQ, and TFEQ Restraint Subscale. RESULTS: Mindful eating, intuitive eating, and restraint were not strongly correlated. Hierarchical multiple regression analyses indicated that restraint and intuitive eating accounted for significant variance in disordered eating and BMI. Elevated restraint was associated with increased BMI and disordered eating; elevated intuitive eating was associated with decreased BMI and disordered eating. Mindful eating did not correlate with any outcome variables. Follow-up analyses suggested that specific intuitive eating subscales accounted for unique variance in the relation between intuitive eating and disordered eating. Intuitive eating was the only construct that was significantly associated with meal consumption. CONCLUSIONS: Intuitive eating and restraint appear to be only weakly correlated, and each is differentially associated with meal consumption. Mindful eating does not appear to relate to outcome variables. PMID- 26243301 TI - Potentiostatic current and galvanostatic potential oscillations during electrodeposition of cadmium. AB - Cathodic current and potential oscillations were observed during electrodeposition of cadmium from a cyanide electrolyte on a vertical platinum electrode, in potentiostatic and galvanostatic experiments. Electrochemical impedance spectroscopy experiments revealed a region of negative real impedance in a range of non-zero frequencies, in the second descending branch with a positive slope of the N-shape current-potential curve. This kind of dynamical behaviour is characteristic of the HN-NDR oscillators (oscillators with the N Shape current-potential curve and hidden negative differential resistance). The oscillations could be mainly attributed to the changes in the real active cathodic area, due to the adsorption of hydrogen molecules and their detachment from the surface. The instabilities of the electrochemical processes were characterized by time series, Fast Fourier Transforms and 2-D phase portraits showing quasi-periodic oscillations. PMID- 26243302 TI - Corynebacterium tapiri sp. nov. and Corynebacterium nasicanis sp. nov., isolated from a tapir and a dog, respectively. AB - Two Gram-stain-positive bacterial isolates, strain 2385/12T and strain 2673/12T were isolated from a tapir and a dog's nose, respectively. The two strains were rod to coccoid-shaped, catalase-positive and oxidase-negative. The highest 16S rRNA gene sequence similarity identified Corynebacterium singulare CCUG 37330T (96.3% similarity) as the nearest relative of strain 2385/12T and suggested the isolate represented a novel species. Corynebacterium humireducens DSM 45392T (98.7% 16S rRNA gene sequence similarity) was identified as the nearest relative of strain 2673/12T. Results from DNA-DNA hybridization with the type strain of C. humireducens demonstrated that strain 2673/12T also represented a novel species. Strain 2385/12T showed a quinone system consisting predominantly of menaquinones MK-8(H2) and MK-9(H2) whereas strain 2673/12T contained only MK-8(H2) as predominant quinone. The polar lipid profiles of the two strains showed the major compounds phosphatidylglycerol, diphosphatidylglycerol and an unidentified glycolipid. Phosphatidylinositol was identified as another major lipid in 2673/12T whereas it was only found in moderate amounts in strain 2385/12T. Furthermore, moderate to minor amounts of phosphatidylinositol-mannoside, beta gentiobiosyl diacylglycerol and variable counts of several unidentified lipids were detected in the two strains. Both strains contained corynemycolic acids. The polyamine patterns were characterized by the major compound putrescine in strain 2385/12T and spermidine in strain 2673/12T. In the fatty acid profiles, predominantly C18:1omega9c and C16:0 were detected. The two strains are distinguishable from each other and the nearest related established species of the genus Corynebacterium phylogenetically and phenotypically. In conclusion, two novel species of the genus Corynebacterium are proposed, namely Corynebacterium tapiri sp. nov. (type strain, 2385/12T = CCUG 65456T = LMG 28165T) and Corynebacterium nasicanis sp. nov. (type strain, 2673/12T = CCUG 65455T = LMG 28166T). PMID- 26243303 TI - Texture analysis on MR images helps predicting non-response to NAC in breast cancer. AB - BACKGROUND: To assess the performance of a predictive model of non-response to neoadjuvant chemotherapy (NAC) in patients with breast cancer based on texture, kinetic, and BI-RADS parameters measured from dynamic MRI. METHODS: Sixty-nine patients with invasive ductal carcinoma of the breast who underwent pre-treatment MRI were studied. Morphological parameters and biological markers were measured. Pathological complete response was defined as the absence of invasive and in situ cancer in breast and nodes. Pathological non-responders, partial and complete responders were identified. Dynamic imaging was performed at 1.5 T with a 3D axial T1W GRE fat-suppressed sequence. Visual texture, kinetic and BI-RADS parameters were measured in each lesion. ROC analysis and leave-one-out cross validation were used to assess the performance of individual parameters, then the performance of multi-parametric models in predicting non-response to NAC. RESULTS: A model based on four pre-NAC parameters (inverse difference moment, GLN, LRHGE, wash-in) and k-means clustering as statistical classifier identified non-responders with 84 % sensitivity. BI-RADS mass/non-mass enhancement, biological markers and histological grade did not contribute significantly to the prediction. CONCLUSION: Pre-NAC texture and kinetic parameters help predicting non-benefit to NAC. Further testing including larger groups of patients with different tumor subtypes is needed to improve the generalization properties and validate the performance of the predictive model. PMID- 26243304 TI - Motor Cortex Activity During Functional Motor Skills: An fNIRS Study. AB - Assessments of brain activity during motor task performance have been limited to fine motor movements due to technological constraints presented by traditional neuroimaging techniques, such as functional magnetic resonance imaging. Functional near-infrared spectroscopy (fNIRS) offers a promising method by which to overcome these constraints and investigate motor performance of functional motor tasks. The current study used fNIRS to quantify hemodynamic responses within the primary motor cortex in twelve healthy adults as they performed unimanual right, unimanual left, and bimanual reaching, and stepping in place. Results revealed that during both unimanual reaching tasks, the contralateral hemisphere showed significant activation in channels located approximately 3 cm medial to the C3 (for right-hand reach) and C4 (for left-hand reach) landmarks. Bimanual reaching and stepping showed activation in similar channels, which were located bilaterally across the primary motor cortex. The medial channels, surrounding Cz, showed significantly higher activations during stepping when compared to bimanual reaching. Our results extend the viability of fNIRS to study motor function and build a foundation for future investigation of motor development in infants during nascent functional behaviors and monitor how they may change with age or practice. PMID- 26243306 TI - Electro-optic Coefficient Enhancement of Al(x)Ga(1-x)N via Multiple Field Modulations. AB - AlGaN has attracted growing interest for applications in electro-optic devices that generate and process optical signals. To enhance the electric-optic effect with polarity, we designed and grew GaN/AlxGa1-xN quantum structures with x of about 0.5 by metal-organic vapor-phase epitaxy. Spectroscopic ellipsometry measurement and ab initio calculation demonstrated that the stronger polarization fields induced by higher Al contents in the barrier result in larger electro optic effects. By applying external biases directly on both sides of these quantum structures, a high intensity of external field was achieved, and extraordinary and ordinary refractive indices were characterized by fitting the variable-angle spectroscopic ellipsometry. The values of deduced electric-optic coefficients were significantly enhanced by combining the resonance effect with the internal and external fields. Given the comparable electric-optic coefficients with conventional electro-optic crystals, AlGaN is an attractive candidate for nonlinear optical material, which provides a basis for large-scale integrations of ultraviolet electro-optic devices based on nitride semiconductors. PMID- 26243305 TI - Arum Palaestinum with isovanillin, linolenic acid and beta-sitosterol inhibits prostate cancer spheroids and reduces the growth rate of prostate tumors in mice. AB - BACKGROUND: Arum palaestinum is a plant commonly found in the Middle East that is ingested as an herbal remedy to fight cancer. However, no studies have examined the direct effect of the plant/plant extract on tumor growth in an animal model. METHODS: Verified prostate cancer cells were plated as 3D spheroids to determine the effect of extract from boiled Arum Palaestinum Boiss roots. In addition, male NU/NU mice (8 weeks old) with xenograft tumors derived from the prostate cancer cell line were treated daily with 1000 mg/kg body weight gavage of the suspension GZ17. The tumor growth was measured repeatedly with calipers and the excised tumors were weighed at the termination of the 3 week study. Control mice (10 mice in each group) received vehicle in the same manner and volume. RESULTS: The number of live prostate cancer cells declined in a dose/dependent manner with a 24 h exposure to the extract at doses of 0.015 to 6.25 mg/mL. A fortified version of the extract (referred to as GZ17) that contained higher levels of isovanillin, linolenic acid and beta-sitosterol had a stronger effect on the cell death rate, shifting the percentage of dead cells from 30 % to 55 % at the highest dose while the vehicle control had no effect on cell numbers. When GZ17 was applied to non cancer tissue, in this case, human islets, there was no cell death at doses that were toxic to treated cancer cells. Preliminary toxicity studies were conducted on rats using an up-down design, with no signs of toxic effect at the highest dose. NU/NU mice with xenograft prostate tumors treated with GZ17 had a dramatic inhibition of tumor progression, while tumors in the control group grew steadily through the 3 weeks. The rate of tumor volume increase was 73 mm(3)/day for the vehicle group and 24 mm(3)/day for the GZ17 treated mice. While there was a trend towards lower excised tumor weight at study termination in the GZ17 treatment group, there was no statistical difference. CONCLUSIONS: Fortified Arum palaestinum Boiss caused a reduction in live cells within prostate cancer spheroids and blocked tumor growth in xenografted prostate tumors in mice without signs of toxicity. PMID- 26243307 TI - Role of sphingomyelinases in neurological disorders. AB - INTRODUCTION: Sphingomyelinases, which catalyze the hydrolysis of sphingomyelin to ceramide and phosphorylcholine, are abundant in the brain. These enzymes are a major, rapid source of ceramide production not only during physiological responses to receptor stimulation, but also in neurological disorders. AREAS COVERED: We covered an introduction to sphingomyelinases and its enzymatic product ceramide, in membrane domains or lipid rafts and the nucleus; followed by crosstalk between sphingomyelinase and cytosolic phospholipase A2 (cPLA2) catalysed products including arachidonic acid, functions of acid sphingomyelinase (aSMase) and neutral sphingomyelinase (N-SMase) in neurons, neuronal progenitor cells, glial cells, and brain endothelial cells; alterations in acid and N-SMases in Niemann Pick Disease Type A, major depression, Alzheimer's disease, cerebral ischemia, and pain; and recent developments in identification of inhibitors to sphingomyelinases. As literature search methodology, we did key word searches using Pubmed. EXPERT OPINION: More research needs to be carried out to develop pharmacological agents that act on sphingomyelinases, for the prevention or treatment of neurological disorders. PMID- 26243308 TI - Childhood-onset psoriatic onycho-pachydermo-periostitis treated successfully with infliximab. PMID- 26243309 TI - Aschantin targeting on the kinase domain of mammalian target of rapamycin suppresses epidermal growth factor-induced neoplastic cell transformation. AB - Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, forms two different complexes, complex 1 and 2, and plays a key role in the regulation of Akt signaling-mediated cell proliferation and transformation. This study reveals aschantin, a natural compound abundantly found in Magnolia flos, as a novel mTOR kinase inhibitor. Aschantin directly targeted the active pocket of mTOR kinase domain by competing with adenosine triphosphate (ATP), but not PI3K and PDK1. Aschantin inhibited epidermal growth factor (EGF)-induced full activation of Akt by phosphorylation at Ser473/Thr308, resulting in inhibition of the mTORC2/Akt and Akt/mTORC1/p70S6K signaling pathways and activation of GSK3beta by abrogation of Akt-mediated GSK3beta phosphorylation at Ser9. The activated GSK3beta inhibited cell proliferation by c-Jun phosphorylation at Ser243, which facilitated destabilization and degradation of c-Jun through the ubiquitination-mediated proteasomal degradation pathway. Notably, aschantin treatment decreased c-Jun stability through inhibition of the mTORC2-Akt signaling pathway, which suppressed EGF-induced anchorage-independent cell transformation in non-malignant JB6 Cl41 and HaCaT cells and colony growth of LNCaP and MIAPaCa-2 cancer cells in soft agar. Altogether, the results show that aschantin targets mTOR kinase and destabilizes c-Jun, which implicate aschantin as a potential chemopreventive or therapeutic agent. PMID- 26243310 TI - DNA repair by MGMT, but not AAG, causes a threshold in alkylation-induced colorectal carcinogenesis. AB - Epidemiological studies indicate that N-nitroso compounds (NOC) are causally linked to colorectal cancer (CRC). NOC induce DNA alkylations, including O (6) methylguanine (O (6)-MeG) and N-methylated purines, which are repaired by O (6) MeG-DNA methyltransferase (MGMT) and N-alkyladenine-DNA glycosylase (AAG) initiated base excision repair, respectively. In view of recent evidence of nonlinear mutagenicity for NOC-like compounds, the question arises as to the existence of threshold doses in CRC formation. Here, we set out to determine the impact of DNA repair on the dose-response of alkylation-induced CRC. DNA repair proficient (WT) and deficient (Mgmt (-/-), Aag (-/-) and Mgmt (-/-)/Aag (-/-)) mice were treated with azoxymethane (AOM) and dextran sodium sulfate to trigger CRC. Tumors were quantified by non-invasive mini-endoscopy. A non-linear increase in CRC formation was observed in WT and Aag (-/-) mice. In contrast, a linear dose-dependent increase in tumor frequency was found in Mgmt (-/-) and Mgmt (-/ )/Aag (-/-) mice. The data were corroborated by hockey stick modeling, yielding similar carcinogenic thresholds for WT and Aag (-/-) and no threshold for MGMT lacking mice. O (6)-MeG levels and depletion of MGMT correlated well with the observed dose-response in CRC formation. AOM induced dose-dependently DNA double strand breaks in colon crypts including Lgr5-positive colon stem cells, which coincided with ATR-Chk1-p53 signaling. Intriguingly, Mgmt (-/-) mice displayed significantly enhanced levels of gamma-H2AX, suggesting the usefulness of gamma H2AX as an early genotoxicity marker in the colorectum. This study demonstrates for the first time a non-linear dose-response for alkylation-induced colorectal carcinogenesis and reveals DNA repair by MGMT, but not AAG, as a key node in determining a carcinogenic threshold. PMID- 26243312 TI - Kinin-B1 and B2 receptors and neural differentiation of pluripotent or multipotent stem cells. PMID- 26243311 TI - Patterns of somatic uniparental disomy identify novel tumor suppressor genes in colorectal cancer. AB - Colorectal cancer (CRC) is characterized by specific patterns of copy number alterations (CNAs), which helped with the identification of driver oncogenes and tumor suppressor genes (TSGs). More recently, the usage of single nucleotide polymorphism arrays provided information of copy number neutral loss of heterozygosity, thus suggesting the occurrence of somatic uniparental disomy (UPD) and uniparental polysomy (UPP) events. The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs and CNAs in sporadic CRC. Our results indicate that regions showing high frequencies of UPD/UPP mostly coincide with regions typically involved in genomic losses. Among them, chromosome arms 3p, 5q, 9q, 10q, 14q, 17p, 17q, 20p, 21q and 22q preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. Several regions affected by recurrent UPDs/UPPs contain well-known TSGs, as well as novel candidates such as ARID1A, DLC1, TCF7L2 and DMBT1. In addition, VCAN, FLT4, SFRP1 and GAS7 were also frequently involved in regions of UPD/UPP and displayed high levels of methylation. Finally, sequencing and fluorescence in situ hybridization analysis of the gene APC underlined that a somatic UPD event might represent the second hit to achieve biallelic inactivation of this TSG in colorectal tumors. In summary, our data define a profile of somatic UPDs/UPPs in sporadic CRC and highlights the importance of these events as a mechanism to achieve the inactivation of TSGs. PMID- 26243313 TI - Quantitative Variation in Responses to Root Spatial Constraint within Arabidopsis thaliana. AB - Among the myriad of environmental stimuli that plants utilize to regulate growth and development to optimize fitness are signals obtained from various sources in the rhizosphere that give an indication of the nutrient status and volume of media available. These signals include chemical signals from other plants, nutrient signals, and thigmotropic interactions that reveal the presence of obstacles to growth. Little is known about the genetics underlying the response of plants to physical constraints present within the rhizosphere. In this study, we show that there is natural variation among Arabidopsis thaliana accessions in their growth response to physical rhizosphere constraints and competition. We mapped growth quantitative trait loci that regulate a positive response of foliar growth to short physical constraints surrounding the root. This is a highly polygenic trait and, using quantitative validation studies, we showed that natural variation in EARLY FLOWERING3 (ELF3) controls the link between root constraint and altered shoot growth. This provides an entry point to study how root and shoot growth are integrated to respond to environmental stimuli. PMID- 26243315 TI - Serum Samples From Middle-aged Adults Vaccinated Annually with Seasonal Influenza Vaccines Cross-neutralize Some Potential Pandemic Influenza Viruses. AB - We examined serum samples from adults ages 48-64 who received multiple seasonal influenza vaccines from 2004 to 2009 for cross-neutralizing antibodies to potential pandemic strains. Using pseudoviruses bearing various hemagglutinins (HA-pseudoviruses), we found serum neutralization titers (>=160) in 100% against A/Japan/305/1957 (H2N2), 53% against A/Hong Kong/1073/99 (H9N2), 56% against the H3N2 variant A/Indiana/08/11 (H3N2v), 11% against A/Hong Kong/G9/97 (H9N2), and 36% A/chicken/Hong Kong/SF4/01 (H6N1). None had titers >160 to A/Shanghai/2/13 (H7N9) or A/Netherlands/219/03 (H7N7). Thirty-six percent to 0% had neutralization titers to various H5N1 strains. Titers to H9, H6, and H5 HA pseudoviruses correlated with each other, but not with H3N2v, suggesting group specific cross-neutralization. PMID- 26243316 TI - Influenza A Virus Diversity and Transmission in Exhibition Swine. PMID- 26243314 TI - Brassinosteroids Are Master Regulators of Gibberellin Biosynthesis in Arabidopsis. AB - Plant growth and development are highly regulated processes that are coordinated by hormones including the brassinosteroids (BRs), a group of steroids with structural similarity to steroid hormones of mammals. Although it is well understood how BRs are produced and how their signals are transduced, BR targets, which directly confer the hormone's growth-promoting effects, have remained largely elusive. Here, we show that BRs regulate the biosynthesis of gibberellins (GAs), another class of growth-promoting hormones, in Arabidopsis thaliana. We reveal that Arabidopsis mutants deficient in BR signaling are severely impaired in the production of bioactive GA, which is correlated with defective GA biosynthetic gene expression. Expression of the key GA biosynthesis gene GA20ox1 in the BR signaling mutant bri1-301 rescues many of its developmental defects. We provide evidence that supports a model in which the BR-regulated transcription factor BES1 binds to a regulatory element in promoters of GA biosynthesis genes in a BR-induced manner to control their expression. In summary, our study underscores a role of BRs as master regulators of GA biosynthesis and shows that this function is of major relevance for the growth and development of vascular plants. PMID- 26243317 TI - Evolutionary Dynamics of Influenza A Viruses in US Exhibition Swine. AB - The role of exhibition swine in influenza A virus transmission was recently demonstrated by >300 infections with influenza A(H3N2) variant viruses among individuals who attended agricultural fairs. Through active influenza A virus surveillance in US exhibition swine and whole-genome sequencing of 380 isolates, we demonstrate that exhibition swine are actively involved in the evolution of influenza A viruses, including zoonotic strains. First, frequent introduction of influenza A viruses from commercial swine populations provides new genetic diversity in exhibition pigs each year locally. Second, genomic reassortment between viruses cocirculating in exhibition swine increases viral diversity. Third, viral migration between exhibition swine in neighboring states demonstrates that movements of exhibition pigs contributes to the spread of genetic diversity. The unexpected frequency of viral exchange between commercial and exhibition swine raises questions about the understudied interface between these populations. Overall, the complexity of viral evolution in exhibition swine indicates that novel viruses are likely to continually reemerge, presenting threats to humans. PMID- 26243318 TI - The Management of Cubital Tunnel Syndrome. AB - Symptomatic cubital tunnel syndrome is a condition that frequently prompts patients to seek hand surgical care. Although cubital tunnel syndrome is readily diagnosed, achieving complete symptom resolution remains challenging. This article reviews related anatomy, clinical presentation, and current management options for cubital tunnel syndrome with an emphasis on contemporary outcomes research. PMID- 26243319 TI - Lifelong Learning for the Hand Surgeon. AB - Hand surgeons are faced with the impossible task of mastering a rapidly expanding pool of knowledge and surgical techniques. Dedication to lifelong learning is, therefore, an essential component of delivering the best, most up-to-date care for patients. Board certification, participation in continuing medical education and maintenance of certification activities, and attendance at national meetings are essential mechanisms by which hand surgeons may foster the acquisition of essential knowledge and clinical skills, This article highlights the history, current status, and emerging needs in continuing medical education for the hand surgeon. PMID- 26243320 TI - Defining Features of the Upper Extremity in Holt-Oram Syndrome. AB - PURPOSE: To investigate the distinguishing morphological characteristics of children with radial longitudinal deficiency (RLD) in Holt-Oram syndrome (HOS). METHODS: One hundred fourteen involved extremities in 62 patients with a diagnosis of HOS were identified at 3 institutions. Medical records and radiographs were evaluated. Radial longitudinal deficiency and thumb hypoplasia were classified according to the modified Bayne and Klug classification and Blauth classifications, respectively, when possible. Other unusual or distinguishing characteristics were catalogued. RESULTS: There was bilateral involvement in 84% of patients. The forearm was involved in 81% of the extremities and a shortened distal radius (Bayne and Klug type I RLD) was the most commonly identified forearm anomaly (40%). Radioulnar synostosis was present in 15% of the extremities, all in the proximal forearms with reduced radial heads. Thumb aplasia (Blauth type V hypoplastic thumb) was the most common type of classifiable thumb abnormality and occurred in 35% of involved thumbs. Twenty seven percent of abnormal thumbs affected were not classifiable according to the Blauth classification, and 19% of involved thumbs (hypoplastic or absent) had first-web syndactyly. CONCLUSIONS: The upper extremity in HOS differs from the typical presentation of RLD. The forearm is more often involved and may demonstrate radioulnar synostosis. The thumb is frequently unclassifiable by the Blauth classification and has first-web syndactyly. The presence of radioulnar synostosis and syndactyly of the radial 2 digits in RLD should prompt the hand surgeon to obtain a cardiac evaluation and consider genetic testing for HOS. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III. PMID- 26243321 TI - Scapholunate Advanced Collapse: Nomenclature and Differential Diagnosis. PMID- 26243322 TI - Management of Severely Comminuted Distal Radius Fractures. AB - Distal radius fractures are among the most common fractures of the upper extremity. Indications for operative and nonsurgical management have evolved over time, as have fixation techniques. Volar locking plates are commonly used in the treatment of selected distal radius fractures such as low-energy or relatively uncomplicated fractures. They have limitations, however, in the management of highly comminuted fracture patterns and in polytrauma patients. In these patients, other methods ranging from spanning fixation to fragment-specific fixation have emerged as useful alternatives in the surgeon's armamentarium for treatment of these challenging fractures. PMID- 26243323 TI - Dissemination, Implementation, and Improvement Science Research in Population Health: Opportunities for Public Health and CTSAs. AB - IMPORTANCE: The complex, dynamic nature of health systems requires dissemination, implementation, and improvement (DII) sciences to effectively translate emerging knowledge into practice. Although they hold great promise for informing multisector policies and system-level changes, these methods are often not strategically used by public health. OBJECTIVES AND METHODS: More than 120 stakeholders from Southern California, including the community, federal and local government, university, and health services were convened to identify key priorities and opportunities for public health departments and Clinical and Translational Science Awards programs (CTSAs) to advance DII sciences in population health. MAIN OUTCOMES: Participants identified challenges (mismatch of practice realities with narrowly focused research questions; lack of iterative learning) and solutions (using methods that fit the dynamic nature of the real world; aligning theories of change across sectors) for applying DII science research to public health problems. Pragmatic steps that public health and CTSAs can take to facilitate DII science research include: employing appropriate study designs; training scientists and practicing professionals in these methods; securing resources to advance this work; and supporting team science to solve complex-systems issues. CONCLUSIONS: Public health and CTSAs represent a unique model of practice for advancing DII research in population health. The partnership can inform policy and program development in local communities. PMID- 26243324 TI - Can Self-Enhancement Values Predict Retirement Behavior? An Analysis Combining Survey and Register Data From Norway. AB - This analysis investigates to what extent the self-enhancement values in the Schwartz taxonomy-achievement, power, and hedonism-can predict retirement behavior. Self-enhancement values were measured using the Norwegian Life Course, Generations and Gender Study beginning in 2007. Register data were merged with the survey data to identify those collecting a pension by the end of 2010; these persons were defined as being retired. Statistical analysis was performed using discrete time proportional odds (logistic regression) duration models for each birthday. The results show that two self-enhancement values, achievement and hedonism, discourage disability retirement but do not affect nondisability retirement. These results are largely consistent across statistical models controlling or not controlling for other known predictors of retirement behavior, including education and income, occupational group (class), and health. The hedonism effect is partially associated with the fact that individuals holding hedonistic values are in good health. PMID- 26243325 TI - Marriage Squeeze and Intergenerational Support in Contemporary Rural China: Evidence from X County of Anhui Province. AB - With China's gender imbalance and increasingly severe male marriage squeeze, patterns of intergenerational support in rural areas are likely to undergo significant change. Using data from a survey of four towns from X county in Anhui province carried out in 2008, this article analyzes the effects of sons' marital status on intergenerational support. Random-effect regression analysis shows that son's marital status has strong effects on financial support to and coresidence with parents. Compared with married sons, older unmarried sons (so-called forced bachelors) tend to provide less financial support to their parents and are more likely to live with their parents. Parents' support of sons, as well as the parents' own needs and sons' capabilities all affect the support provided by sons. These results show that both theories of exchange and altruism are simultaneously relevant in the context of the marriage squeeze of contemporary rural China. PMID- 26243326 TI - Advertising Representations of Older People in the United Kingdom and Taiwan: A Comparative Analysis. AB - Cross-cultural studies of advertising representations of older people are relatively scarce. This article aims to fill in this gap via a comparison between Taiwan and the United Kingdom, employing a combination of quantitative content analysis and the qualitative grounded theory method. The content-analysis phase reveals underrepresentation of older people in both countries' advertising contexts, as well as representational differences between Taiwan and the United Kingdom in terms of older characters' role salience, the products, physical settings, and social networks they are associated with. The grounded-theory phase yields nine prototypes of older people along with subcategories to conceptualize the qualities of older people as they appear in TV ads in these countries. The findings are discussed in relation to the stereotyping of older people and transformed into hypothetical statements to be modified in future research. In conclusion, the Confucian tradition of filial piety is still found to be important in explaining the observed cross-cultural differences, but the emergence of new norms about aging in Taiwanese advertising also suggests that this tradition may be in decline. PMID- 26243327 TI - Have I Ever Done Anything Like This Before? Older Adults Solving Ill-Defined Problems in Intensive Volunteering. AB - This study examined the ways in which individuals over 50 years old solved problems while volunteering in intensive humanitarian and disaster relief service. Thirty-seven men and women in the sample were sponsored by three religious organizations well known for providing humanitarian and disaster relief service. Semistructured interviews yielded data that were analyzed qualitatively, using McCracken's five-step process for analysis. We found that volunteers used three different abilities to solve problems: drawing upon experience to create strategies, maintaining emotional stability in the midst of trying circumstances, and applying strategies in a context-sensitive manner. These findings illustrate that these factors, which are comparable to those used in solving everyday problems, are unique in the way they are applied to intensive volunteering. The volunteers' sharing of knowledge, experience, and support with each other were also noticeable in their accounts of their service. This sharing contributed strongly to their sense of emotional stability and effectiveness in solving problems. PMID- 26243328 TI - Clinical significance of high intramedullary signal on T2-weighted cervical flexion-extension magnetic resonance imaging in cervical myelopathy. AB - BACKGROUND: In cervical myelopathy, significant findings are seen in flexion extension MRI due to the increased likelihood of cord compression during neck extension. In addition, a high intramedullary signal on T2-weighted MR images has been reported to be a prognostic factor in this condition. However, the relationship between Japanese Orthopaedic Association (JOA) scores and the signal intensity in preoperative cervical flexion-extension T2-weighted images has not been evaluated. The purpose of this study was to evaluate whether preoperative flexion-extension MRI may be used to predict surgical outcomes in patients with cervical myelopathy. METHODS: A total of 121 patients who underwent surgery for cervical myelopathy were included. All patients underwent preoperative cervical flexion-extension MRI followed by cervical decompression surgery, with or without spinal fusion, and postoperative follow-up for at least 2 years. Pre- and postoperative (2 years after surgery) JOA scores were recorded, and the degree of postoperative improvement was calculated. The relationship between intramedullary signal intensity on preoperative cervical dynamic MRI findings and degree of clinical recovery was examined. RESULTS: Patients with a high intramedullary signal on the extension MRI had significantly better neurological recovery than those with a high signal on the flexion MRI (p < 0.000005). There was no significant difference in neurological recovery between patients with and without a high intramedullary signal on extension MRI. CONCLUSIONS: A preoperative high intramedullary signal on flexion MRI was associated with a poor surgical outcome, while no such association was seen with extension MRI. PMID- 26243329 TI - Response of Sugarcane and Sugarcane Stalk Borers Sesamia spp. (Lepidoptera: Noctuidae) to Calcium Silicate Fertilization. AB - Sugarcane is grown extensively throughout the world including more than 100,000 ha in Khuzestan province, Iran. The pink stalk borers Sesamia are key pests of sugarcane in this region, while other stalk borers will occur in sugarcane worldwide. Application of silicon as a soil amendment has provided plant mitigation to both biotic and abiotic stresses. Silicon has been shown to enhance resistance of sugarcane against stalk borers. Field trials were conducted to determine the effects of calcium silicate against infestations of stalk borers Sesamia spp. and on yield quality. Experiments were conducted with three sugarcane varieties CP69-1062, IRC99-01, and SP70-1143 and two rates of calcium silicate (400 and 800 kg/ha). Percentage of stalk damaged, percentage of bored internodes, length of borer tunnel (mm), number of larvae + pupae per 100 stalks, number of exit holes, and cane yield quality were determined. We demonstrate significant reduction on borer population and damage under silicon treatment, but greater reduction in the percentages of stalk damage, bored internodes, moth exit holes, and length of borer tunnel and number of larvae and pupae per 100 stalks were observed in the susceptible variety CP69-1062. Silicon treatment positively affected cane and sugarcane juice quality of for the variety CP69-1062, but not for SP70-1143. We conclude that the benefits of silicon to sugarcane quality and sugarcane resistance to stalk borers are dependent on the sugarcane variety. PMID- 26243330 TI - Population Dynamic of Blastopsylla occidentalis Taylor (Hemiptera: Psyllidae), a Psyllid Pest of Eucalypts. AB - Eucalypts host a variety of insect pests among which the psyllid Blastopsylla occcidentalis Taylor is responsible for the degeneration of eucalypt seedlings. This psyllid is present in Cameroon, but no record has been published on the study of its population dynamics and the main factors that regulate its population. Our study aimed to describe the numerical variation of psyllid population and to correlate these variations to the abiotic and biotic factors that may naturally regulate the population of this pest. This study was carried out in Yaounde (Cameroon) from August 2009 to July 2011. The survey took place once a week on 1-year-old 111 eucalypts. During the 2 years of study, a total of 52,341 males and 64,725 females were collected. The population of B. occidentalis showed three periods of psyllid outbreaks each year. Six and five psyllid generations were observed during the first and the second years, respectively. Among the climatic factors, the increase of relative humidity and rainfall led to a decrease of the number of psyllids on the host plant. The number of new buds on host plants was positively correlated with the number of psyllids infesting. Psyllid parasitoids and predators were identified. These results constitute an important step for the elaboration of an integrated pest management against the eucalypt psyllid in Cameroon. PMID- 26243331 TI - Influence of Pools and Riffles on Chironomidae Diversity in Headwater Streams of the Atlantic Forest. AB - Studies on mesohabitat scale have been used to shed light on the ecology and distribution of chironomid larvae in small streams. Thus, the objective of the present study was to examine the diversity and distribution of the Chironomidae assemblage on the mesohabitat scale in three streams located in different preserved areas of southeastern Brazil. In each stream, litter samples were obtained in the dry season of 2010 in ten pools and ten riffles with a Surber sampler (area 0.04 m(2); mesh size 0.21 mm). The abundance was similar among streams and between mesohabitats, while the estimated richness was highest in riffles. There was a difference in the composition of the Chironomidae assemblages between the mesohabitats, although the litter composition was similar between them, indicating the importance of current speed on the distribution of the taxa. The dispersion of the sample units (beta-diversity) of riffles and pools was similar, although it was different among the three streams. The results of this study provide further evidence of the importance of habitat heterogeneity within streams as a generator of diversity for Chironomidae in tropical lotic systems. PMID- 26243332 TI - Redescription of the Monotypic Neotropical Genus Crepititermes Emerson (Termitidae: Termitinae). AB - Based on a reexamination of specimens of Crepititermes Emerson deposited in the Museu de Zoologia da Universidade de Sao Paulo, Sao Paulo, Brasil (MZUSP), we characterize the morphology and coiling in situ of the digestive tube of workers of Crepititermes verruculosus Emerson for the first time. We provide additional notes on the imago and soldier and present digital images and illustrations for all castes. We also update the currently known geographical distribution of C. verruculosus, adding some biological remarks. PMID- 26243333 TI - Temporal Variation in Immune Components of the White Grub Phyllophaga polyphylla (Bates) (Coleoptera: Melolonthidae). AB - Ecological immunology assumes that the host immune efficiency is correlated with its survival after pathogen challenge. To test this hypothesis, we challenged Phyllophaga polyphylla (Bates) larvae with the naturally occurring fungus Metarhizium pingshaense on two consecutive years (2011 and 2012). In each year, we injected the blastospores of M. pingshaense and then used levels of prophenoloxidase (proPO), phenoloxidase (PO) and total haemolymph serum protein as indicators of immune efficiency. Larvae were injected with (1) phosphate buffered saline (PBS) + Tween and viable blastospores of M. pingshaense, (2) PBS + Tween and non-viable blastospores of M. pingshaense, (3) PBS + Tween, or (4) non-manipulated. Overall, levels of PO, proPO and total haemolymph serum protein in larvae after 12 h were similar amongst treatments within each year of collection. However, larvae collected in 2011 showed higher PO and proPO activity but lower total haemolymph serum protein compared with larvae collected in 2012. A survival study injecting viable blastospores showed that larvae collected in both years died within 48 h; however, when non-viable blastospores were injected, which were still toxic to larvae, mortality was greater in larvae collected in 2011 compared with larvae collected in 2012. Altogether, these results indicate that PO, proPO and total haemolymph serum protein do not predict immune strength of P. polyphylla against blastospores of M. pingshaense, but higher values of PO and proPO were correlated with higher survival rates against non-infective but toxic agents. The possible role of some abiotic factors over the differences observed for immune components of P. polyphylla in different years of collection is discussed. PMID- 26243334 TI - Depressive Symptoms, Transitions to Widowhood, and Informal Support From Adult Children Among Older Women and Men in Japan. AB - This study examines the relationships among depressive symptoms, transitions to widowhood, worsening health, and family support in Japan over 10 years. The analyses focus on availability and receipt as the two primary dimensions of intergenerational support relationships. We used growth curve models to analyze data from the Nihon University Japanese Longitudinal Study of Aging, finding that (1) becoming widowed correlated with increased depressive symptoms and this relationship was weaker among women than men, (2) continuous widowhood was associated with fewer depressive symptoms over time, (3) transitions to coresidence with sons and daughters among the widowed was correlated with reduced depressive symptoms, (4) self-reported health and difficulty with activities of daily living were predictors of depressive symptoms over time. The findings suggest the importance of new research on household transitions, availability and proximity of family caregivers, and social embeddedness as protections against depressive symptoms. PMID- 26243336 TI - Carboxylic acid derivatives via catalytic carboxylation of unsaturated hydrocarbons: whether the nature of a reductant may determine the mechanism of CO2 incorporation? AB - Application of CO2 as a renewable feedstock and C1 building block for production of commodity and fine chemicals is a highly challenging but obvious industry relevant task. Of particular interest is the catalytic coupling of CO2 with inexpensive unsaturated hydrocarbons (olefins, dienes, styrenes, alkynes), providing direct access to carboxylic acids and their derivatives. Although not brand new for the scientific community, it is still a complete challenge, as no truly effective catalytic system has been reported to date. In this Perspective, we discuss the available experimental, theoretical and mechanistic data for such homogeneously catalyzed carboxylation processes. A special focus is placed on the understanding of the key elementary steps and of some thermodynamic and kinetic constraints. PMID- 26243335 TI - Critical role of sphingosine-1-phosphate receptor-2 in the disruption of cerebrovascular integrity in experimental stroke. AB - The use and effectiveness of current stroke reperfusion therapies are limited by the complications of reperfusion injury, which include increased cerebrovascular permeability and haemorrhagic transformation. Sphingosine-1-phosphate (S1P) is emerging as a potent modulator of vascular integrity via its receptors (S1PR). By using genetic approaches and a S1PR2 antagonist (JTE013), here we show that S1PR2 plays a critical role in the induction of cerebrovascular permeability, development of intracerebral haemorrhage and neurovascular injury in experimental stroke. In addition, inhibition of S1PR2 results in decreased matrix metalloproteinase (MMP)-9 activity in vivo and lower gelatinase activity in cerebral microvessels. S1PR2 immunopositivity is detected only in the ischemic microvessels of wild-type mice and in the cerebrovascular endothelium of human brain autopsy samples. In vitro, S1PR2 potently regulates the responses of the brain endothelium to ischaemic and inflammatory injury. Therapeutic targeting of this novel pathway could have important translational relevance to stroke patients. PMID- 26243337 TI - Natural acquired inhibitory antibodies to Plasmodium vivax Duffy binding protein (PvDBP-II) equally block erythrocyte binding of homologous and heterologous expressed PvDBP-II on the surface of COS-7 cells. AB - The binding domain of Plasmodium vivax Duffy binding protein (PvDBP-II) is a promising blood-stage vaccine candidate for vivax malaria. For the development of a successful vivax malaria vaccine based on DBP-II, the antigenic diversity and also naturally occurring functional antibodies to different PvDBP-II variant types in the various populations must be determined. However, similar to other blood-stage antigens, allelic variation within the PvDBP-II is a fundamental challenge for the development of a broadly efficient vaccine. The present study was performed to define whether the polymorphisms in PvDBP-II influence the nature of functional inhibitory activity of naturally acquired or induced anti DBP-II antibodies in mice. In this investigation, five genetically distinct variants of PvDBP-II were transiently expressed on the COS-7 cell surface. Erythrocyte-binding inhibition assay (EBIA) was performed using human sera infected with corresponding and non-corresponding P. vivax variants as well as by the use of mice sera immunized with different expressed recombinant PvDBP-IIs. EBIA results showed that the inhibitory percentage varied between 50 and 63 % by using sera from infected individuals, and in case of mouse antisera, inhibition was in the range of 76-86 %. Interestingly, no significant difference was detected in red blood cell binding inhibition when different PvDBP-II variants on the COS-7 cell surfaces were incubated with heterologous and homologous sera infected with PvDBP-II variants. This suggests that the detected polymorphisms in all five forms of PvDBP-II may not affect functional activity of anti-DBP-II antibodies. In conclusion, our results revealed that there are functional cross reactive antibody responses to heterologous PvDBP-II variants that might provide a broader inhibitory response against all, or at least the majority of strains compared to single allele of this protein that should be considered in development of PvDBP-II-based vaccine. PMID- 26243338 TI - Large intracranial meningioma masquerading as Parkinson's disease. PMID- 26243339 TI - A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK. AB - BACKGROUND: Hereditary transthyretin amyloidosis (ATTR) is usually characterised by a progressive peripheral and autonomic neuropathy often with associated cardiac failure and is due to dominantly inherited transthyretin mutations causing accelerated amyloid deposition. The UK population is unique in that the majority of patients have the T60A missense mutation in ATTR where tyrosine is replaced by adenine at position 60. This has been traced to a single founder mutation from north-west Ireland. The neuropathy phenotype is less well described than the cardiac manifestations in this group. METHODS: We present the findings from an observational cohort study of patients with ATTR attending the National Hospital Inherited Neuropathy Clinic between 2009 and 2013. Detailed clinical neurological and electrophysiological data were collected on all patients alongside correlating autonomic and cardiac assessments. Follow-up data were available on a subset. RESULTS: Forty-four patients with genetically confirmed ATTR were assessed; 37 were symptomatic; mean age at onset=62 years, range=38-75 years; 75.7% male. T60A was the most common mutation (17/37), followed by V30M (5/37). A severe, rapidly progressive, predominantly length dependent axonal sensorimotor neuropathy was the predominant phenotype. T60A patients were distinguished by earlier and more frequent association with carpal tunnel syndrome; a predominance of negative sensory symptoms at onset; significant vibration deficits; and a non-length dependent progression of motor deficit. Progression of the neuropathy was observed over a relatively short follow-up period (2 years) in 20 patients with evidence of clinically measurable annual change in Medical Research Council (MRC) sum score (-1.5 points per year) and Charcot Marie Tooth Neuropathy Score (CMTNS:2.7 points per year), and a congruent trend in the electrophysiological measures used. CONCLUSION: The description of the ATTR neuropathy phenotype, especially in the T60A patients, should aid early diagnosis as well as contribute to the understanding of its natural history. PMID- 26243340 TI - Atlantic hurricane activity during the last millennium. AB - Hurricanes are a persistent socio-economic hazard for countries situated in and around the Main Development Region (MDR) of Atlantic tropical cyclones. Climate model simulations have attributed their interdecadal variability to changes in solar and volcanic activity, Saharan dust flux, anthropogenic greenhouse gas and aerosol emissions and heat transport within the global ocean conveyor belt. However, the attribution of hurricane activity to specific forcing factors is hampered by the short observational record of Atlantic storms. Here, we present the Extended Hurricane Activity (EHA) index, the first empirical reconstruction of Atlantic tropical cyclone activity for the last millennium, derived from a high-resolution lake sediment geochemical record from Jamaica. The EHA correlates significantly with decadal changes in tropical Atlantic sea surface temperatures (SSTs; r = 0.68; 1854-2008), the Accumulated Cyclone Energy index (ACE; r = 0.90; 1851-2010), and two annually-resolved coral-based SST reconstructions (1773-2008) from within the MDR. Our results corroborate evidence for the increasing trend of hurricane activity during the Industrial Era; however, we show that contemporary activity has not exceeded the range of natural climate variability exhibited during the last millennium. PMID- 26243342 TI - Use of neoadjuvant therapy in patients 75 years of age and older with pancreatic cancer. AB - BACKGROUND: Treatment sequencing in older patients is difficult because of concomitant comorbidities and often decreasing performance status. The present study sought to examine the effect of neoadjuvant therapy and pancreatic surgery in older patients with resectable or borderline-resectable (BLR pancreatic cancer (PC). METHODS: Patients with resectable or BLR PC treated with neoadjuvant therapy were classified as older (>= 75 years) or younger (<75 years). RESULTS: Neoadjuvant therapy was initiated in 246 patients; 210 (85%) younger than 75 years and 36 (15%) older. Older patients had a greater median Charlson comorbidity index (CCI): 6 vs 4 (P < .01). Completion of all intended therapy (neoadjuvant therapy and surgery) occurred in 177 (72%) of the 246 patients; 153 (73%) of the 210 younger and 24 (67%) of the 36 older patients (P = .43). Failure to complete all therapy was associated with BLR clinical stage (odds ratio [OR] 0.26, P = .001), increased posttreatment/preoperative serum levels of CA19-9 (OR 0.27, 95% confidence interval 0.14-0.53), and CCI >= 6 (OR 0.44, 95% confidence interval 0.22-0.86). Median overall survival for all study patients was 26.1 and 19.7 months (P = .13) for younger and older patients, respectively. Of the 177 patients who completed all therapy, the difference in survival between younger and older patients was not statistically significant (36.5 months vs 27.2 months, P = .47). CONCLUSION: Failure to complete neoadjuvant therapy and eventual pancreatic resection is associated with BLR stage, increased posttreatment/preoperative CA19-9, and CCI >= 6, but not older age. Older patients who completed neoadjuvant therapy and underwent resection experienced a survival benefit compared with those who did not complete all intended therapy. Balancing the toxicity of sequential therapies with their cumulative effect on tolerance and risk for pancreatic surgery will be the key to developing optimal treatment sequencing in older patients with PC. PMID- 26243343 TI - Frequency of diagnosis of cancer or high-risk lesion at operation for pathologic nipple discharge. AB - BACKGROUND: Pathologic nipple discharge is managed customarily with diagnostic subareolar duct excision. We evaluated for features predictive of malignancy to identify cases where operation might be avoided. METHODS: We studied 311 consecutive subareolar duct excisions for pathologic nipple discharge from January 2008 to July 2014. chi(2) tests were used to test for associations with final pathology. RESULTS: In 27 cases, cancer was diagnosed preoperatively. Among the remaining 284, 26 (9%) were diagnosed with cancer and 8 (3%) with atypia at operation. At greatest risk of upstage to cancer were patients with prior ipsilateral breast cancer (3/8; 38%), BRCA mutation (2/3; 67%) or atypia on core needle biopsy (CNB; 3/8 [38%]). Excluding these patients lowered cancer and atypia upstages (7% [18/265] and 3% [7/265]), with bloody (versus serous) discharge (P = .001), and focal imaging abnormality (P = .02), the strongest risk factors. Serous discharge and either normal imaging or a benign CNB had a 1.3% cancer upstage rate. CONCLUSION: Despite contemporary imaging, pathologic nipple discharge upstage rates to malignancy and atypia remain high, especially with prior ipsilateral breast cancer, BRCA mutation, or atypia on CNB. Absent these risk factors, patients with serous discharge and a benign CNB or normal imaging (cancer risk <2%) may be considered for nonoperative management. PMID- 26243345 TI - The incidence of hiatal hernia and technical feasibility of repair during bariatric surgery. AB - PURPOSE: To evaluate the incidence and outcomes of hiatal hernias (HH) that are repaired concomitantly during bariatric surgery. METHODS: We identified patients who had concomitant HH repair during bariatric surgery from 2010 to 2014. Data collected included baseline demographics, perioperative parameters, type of HH repair, and postoperative outcomes. RESULTS: A total of 83 underwent concomitant HH during study period. The male-to-female ratio was 1:8, mean age was 57.2 +/- 10.0 years, and mean body mass index was 44.5 +/- 7.9 kg/m(2). A total of 61 patients had laparoscopic Roux-en-Y gastric bypass, and 22 had laparoscopic sleeve gastrectomy. HH was diagnosed before bariatric surgery in 32 (39%) subjects, whereas 51 (61%) were diagnosed intraoperatively. Primary hernia repair was performed with anterior reconstruction in 45 (54%) patients, posterior in 21 (25%), and additional mesh placement in 7 (8%). A total of 24 early minor postoperative symptoms were reported. At 12 month follow-up, mean body mass index improved to 30.0 +/- 6.2 kg/m(2), and anti-reflux medication was decreased from 84% preoperatively to 52%. Late postoperative complications were observed in 3 patients. A comparative analysis with a matched 1:1 control group displayed no significant differences in operative time (P = .07), duration of stay (P = .9), intraoperative complications, or early (P = .09) and late post-operative symptoms (P = .3). In addition, no differences were noted in terms of weight-loss outcomes. CONCLUSION: The true incidence of HH may be underestimated before bariatric surgery. Combined repair of HH during bariatric surgery appears safe and feasible. PMID- 26243346 TI - Current management of gastrointestinal stromal tumors: Surgery, current biomarkers, mutations, and therapy. AB - In the past decade, the addition of molecular diagnosis of mutations and use of tyrosine kinase inhibitors (TKIs), either as neoadjuvant/adjuvant therapy with surgery or as primary therapy in nonresectable gastrointestinal stromal tumors (GIST), has improved patient outcomes markedly. Additional therapeutics also are on the horizon. The goal of this review is to identify the current incidence, diagnostic modalities, and trends in personalizing the medical and operative management for patients with GIST. Medline, PubMed, and Google scholar were queried for recently published literature regarding new molecular mechanisms, targeted therapies, and clinical trials investigating the treatment of GIST. The objective of this review is to highlight the biomarkers under development, newly discovered mutations, and newer therapies targeting specific mutational phenotypes which are continually improving the outlook for patients with this disease. PMID- 26243347 TI - "Right place at the right time" impacts outcomes for acute intestinal obstruction. AB - BACKGROUND: The purpose of this study was to measure how the duration of nonoperative intervention for intestinal obstruction impacted patient outcomes and whether hospital characteristics influenced the timing of operative intervention. METHODS: The State Inpatient Database (Florida) of the Health Care Utilization Project and the Annual Survey database of the American Hospital Association were linked from 2006 to 2011. Included were patients >=18 years of age with a primary diagnosis of intestinal obstruction. Patient factors included age, sex, socioeconomic factors, and comorbid conditions. RESULTS: A total of 116,195 patients met our inclusion criteria, and 43,079 underwent operative intervention (37.1%). Patients who required operative correction of the intestinal obstruction after the fifth day of hospitalization, compared with patients who underwent an operation on the day of admission, had increases in mortality (6.1% vs 1.8%, P < .001), complication rates (15.4% vs 4.0%, P < .001), and postoperative hospital stay (9 vs 5 days, P < .001). Patients cared for at a large teaching facility (with surgery residents) had increased odds of early operative intervention by 23% (odds ratio 1.23, [1.20-1.28]), whereas patients at low-volume hospitals had decreased odds of early intervention (odds ratio 0.88, [0.73-0.91]). CONCLUSION: Initial nonoperative treatment in patients with uncomplicated intestinal obstruction is an important strategy, but the odds of having an adverse event increase as intestinal obstruction is delayed. Importantly, the presence of surgery residents and increasing bed size are hospital characteristics associated with earlier operative intervention, suggesting a quality benefit for care at large teaching hospitals. PMID- 26243349 TI - Youth Early-intervention Study (YES) - group interventions targeting social participation and physical well-being as an adjunct to treatment as usual: study protocol for a randomized controlled trial. AB - BACKGROUND: It is increasingly acknowledged that clinical interventions for young persons with mental disorders need to optimize social, vocational and physical functioning, and take into account developmental needs, rather than focusing only on the traditional target of psychiatric symptom change. However, few interventions for youth presenting to mental health services offer a coherent rationale for multi-faceted approaches that efficiently address all these targets. This trial uses two facilitated group therapy modules (social and physical activity) as a vehicle for promoting clinical, cognitive, social and vocational change. The modules are an adjunct to usual treatments offered to youth attending mental health services in Sydney, Australia. METHODS/DESIGN: The design is a 2-arm, parallel group cross-over, randomized clinical trial (RCT) that examines the efficacy of this adjunctive youth early intervention program (called "YES") for improving social, vocational, mental and physical health functioning in a trans-diagnostic sample of 120 young persons aged 14-25 years who are currently receiving a range of "usual treatments" for clinically diagnosed anxiety, affective and/or psychotic disorders. Individuals who provide written informed consent are offered 2 group therapy modules (each comprising 4 hours per week for 8 weeks) with a 3-week "pause" between modules. Randomization determines whether individuals commence with module A or module B. The sample will be assessed pre-randomization, and at week 1 and week 8 (after completion of the first module), and at week 11 (commencement of second module) and week 19 (completion of second module). Final follow-up is 1-year post trial entry. DISCUSSION: If the findings of this exploratory trial demonstrate benefits in the target domains, then it will be important to extend the research by undertaking: (a) a comparison of the YES program to a control intervention in a randomized controlled trial, (b) an explanatory study of putative mediators of change, and (c) a multi-center trial with a number of trained therapists offering the group modules combined with a longer follow-up period. TRIAL REGISTRATION: Australian New Zealand Controlled Trial Registration: ACTRN1262400175673 , Date: 16 July 2015. PMID- 26243350 TI - Current Evidence on Platelet P2Y12 Receptor Inhibitors: Is There Still a Role for Clopidogrel in 2015? AB - Antiplatelets play a significant role in the management of patients with coronary disease. Novel inhibitors of the platelet P2Y12 receptor have more rapid, potent, and consistent inhibitory effect on platelets compared with clopidogrel. Evidence from large clinical studies have defined populations in which novel agents are superior to clopidogrel. Ticagrelor or prasugrel in addition to aspirin should be used preferentially for patients with ST-elevation myocardial infarction because of significant anti-ischemic benefits. In patients with non-ST segment elevation acute coronary syndromes, ticagrelor has proven superiority over clopidogrel whether or not an invasive strategy is adopted, and prasugrel has been shown to be beneficial when started at the time of percutaneous coronary intervention. Of note, neither prasugrel nor ticagrelor have been studied in patients who underwent percutaneous coronary intervention for stable coronary disease or those who required 'triple therapy.' In these situations, clopidogrel should remain the default until further data are available. Prolonged use of clopidogrel in patients with drug-eluting stents beyond 12 months is emerging as a novel indication for the agent. PMID- 26243351 TI - Relationship Between Insulin-Like Growth Factor Binding Protein-2 and Left Ventricular Stroke Volume in Patients With Aortic Stenosis. AB - BACKGROUND: Lower plasma insulin-like growth factor binding protein (IGFBP)-2 levels have been associated with altered metabolism linked to visceral obesity. These abnormalities have been linked with worsening of left ventricle (LV) remodelling and dysfunction in patients with aortic stenosis (AS). Whether IGFBP 2 is involved in these relationships is currently unknown. The objective of this study was to examine the relationship between circulating IGFBP-2 and LV pump function measured according to stroke volume index in AS patients with preserved LV ejection fraction. METHODS: Two hundred eight patients with mild to moderate AS were prospectively recruited in the Metabolic Determinants of the Progression of Aortic Stenosis (PROGRESSA) study and underwent Doppler-echocardiography. Stroke volume index (SVi) was calculated using Doppler in the LV outflow tract and was indexed to body surface area. Plasma circulating IGFBP-2 levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Patients with lower IGFBP-2 levels were younger (P < 0.0001), had a higher body mass index (P = 0.0003), larger waist circumference (P = 0.01), higher homeostatic assessment model index (P = 0.0005), and lower high-density lipoprotein cholesterol (P = 0.01). Moreover, SVi was decreased in patients with low IGFBP-2 (P = 0.009). After multivariable adjustment for age, sex, LV mass index, aortic valve area, and LV ejection fraction, a lower plasma IGFBP-2 level was independently related with lower SVi (P < 0.001). After further adjustment for other traditional cardiometabolic risk factors, plasma IGFBP-2 remained independently associated with SVi (all P < 0.05). CONCLUSIONS: In this study, we documented that lower IGFBP-2 levels are independently associated with lower SVi, a powerful predictor of worse outcomes in the mild to moderate AS population. PMID- 26243352 TI - Out-of-Hospital Cardiac Arrest and Acute Coronary Syndromes: Reviewing Post Resuscitation Care Strategies. AB - Out-of-hospital cardiac arrest (OHCA) carries an enormous global burden of mortality and morbidity. The post-cardiac arrest syndrome consists of complex pathophysiological changes that result in hypoxic brain injury, myocardial and peripheral organ dysfunction, and the systemic ischemia-reperfusion response. We review common cardiac arrest cases to highlight key management issues and recommendations in post-resuscitation care, including therapeutic hypothermia, coronary angiography and revascularization, and circulatory support. Guidelines still suggest mild therapeutic hypothermia be administered for OHCA over targeted temperature management preventing pyrexia. Similarly, early invasive coronary angiography is particularly beneficial when there is ST-elevation on the post resuscitation electrocardiogram, but might be considered in the absence of ST elevation if there is no noncardiac cause to explain the OHCA. However, there remain a large number of unanswered questions that require ongoing research. PMID- 26243353 TI - Anaphylaxis in an urban Belgian emergency department: epidemiology and aetiology. AB - OBJECTIVES: Anaphylaxis is an emergency condition of which reliable epidemiological data are lacking. This study focusses on epidemiology and aetiology of anaphylactic reactions in an urban Belgian emergency department (ED). METHODS: Patient data were collected from 04/2009 to 04/2013.During this period, emergency doctors completed a questionnaire for adult patients (>15 years) with anaphylaxis presenting at the ED. Inclusion criteria were based on the Sampson criteria of anaphylaxis. Data were analysed using a Microsoft Excel database. RESULTS: Anaphylaxis accounted for 0.04% of all emergency visits in this 4-year period. In both women and men, dyspnoea and urticaria were noted most frequently. 51.7% of cases were possibly elicited by foods, 46.1% by drugs and 3.4% by hymenoptera stings. Women more often reported allergic diseases in their personal history. 55.7% of patients, who had a history of allergy, reported a suspected food-related allergy, 24.6% a drug-related allergy and 8.2% a hymenoptera venom-related allergy. In 76.5% of patients who reported a history of food allergy, food was the presumed elicitor of anaphylaxis. For patients with history of drug allergy, 88.2% had a presumed drug anaphylaxis at the time of presentation at the ED. 81% of cases presented with grade 4 or 5 anaphylaxis. With increasing age, the severity of anaphylaxis increased. Higher tryptase levels correlated with a higher grade of anaphylaxis. CONCLUSION: In this Belgian urban population, foods and drugs were by far the most common suspected elicitors of anaphylaxis. Personal history of allergic diseases was present in more than half of the cases. PMID- 26243354 TI - Structural defect-dependent resistive switching in Cu-O/Si studied by Kelvin probe force microscopy and conductive atomic force microscopy. AB - In this study, we show structural defect-dependent presence or absence of resistive switching in Cu-O films. We use Kelvin probe force microscopy and conductive atomic force microscopy to show the presence of resistive switching. In addition, local current mapping provides direct evidence on the formation of nanoscale filament. These findings match well with the existing theoretical model on resistive switching. In particular, understanding the role of structural defects in resistive switching can be considered as critically important to take a step forward for designing advanced nanoscale memory devices. PMID- 26243355 TI - Impact of smoking on outcome of resected lung adenocarcinoma. AB - OBJECTIVE: Smoking is a well-known causative factor of lung cancer and the association of smoking with adenocarcinoma is considered to be the weakest. We investigated the influence of smoking on postoperative prognosis in patients with lung adenocarcinoma. METHODS: One hundred and eighty-one consecutive patients of resected lung adenocarcinoma were studied retrospectively. The histologic subtype was subdivided into 2 groups: lepidic dominant histologic subtype, including adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant invasive adenocarcinoma versus other subtypes. RESULTS: The 5-year survival of ever smokers was significantly unfavorable than that of never smokers. Similarly, there was also a relationship between the patients' survival and Brinkman index (BI), with unfavorable survival found in patients with greater smoking histories. Based on a multivariable analysis, pN status and BI were significant factors affecting the postoperative prognosis of patients undergoing surgery. However, gender, serum carcinoembryonic antigen (CEA) level, lepidic dominant histologic subtype and pure/mixed ground-glass opacity (GGO) were not prognostic factors although previous reports showed prognostic significance. These factors that we failed to find the prognostic significance were significantly associated with smoking. CONCLUSION: The smoking was significantly predictive of an unfavorable prognosis after surgery for lung adenocarcinoma. It is suggested that smoking is associated with serum CEA level, histologic subtype and GGO, resulting in unfavorable outcome. PMID- 26243356 TI - The mortality and direct medical costs of osteoporotic fractures among postmenopausal women in Taiwan. AB - This study estimated the fracture-related mortality and direct medical costs among postmenopausal women in Taiwan by fracture types and age groups by utilizing a nationwide population-based database. Results demonstrated that hip fractures constituted the most severe and expensive complication of osteoporosis across fracture sites. INTRODUCTION: The aims of the study were to evaluate the risk of death and direct medical costs associated with osteoporotic fractures by fracture types and age groups among postmenopausal women in Taiwan. METHODS: This nationwide, population-based study was based on data from the National Health Insurance Research Database in Taiwan. Female patients aged 50 years and older in the fracture case cohort were matched in 1:1 ratio with randomly selected subjects in the reference control cohort by age, income-related insurance amount, urbanization level, and the Charlson comorbidity index. There were two main outcome measures of the study: age-differentiated mortality and direct medical costs in the first and subsequent years after osteoporotic fracture events among postmenopausal women. The bootstrap method by resampling with replacement was conducted to generate descriptive statistics of mortality and direct medical costs of the case and control cohorts. Student's t tests were then performed to compare mortality and costs between the two cohorts. RESULTS: A total of 155,466 postmenopausal women in the database met the inclusion criteria for the fracture case cohort, including 22,791 hip fractures, 72,292 vertebral fractures, 15,621 upper end humerus (closed) fractures, 36,774 wrist fractures, and 7,988 multiple fractures. Analytical results demonstrated that patients experiencing osteoporotic fractures were at considerable excess risk of death and incurred substantially higher treatment costs, notably for hip fractures. Furthermore, results also revealed that the risk of mortality increased with advancing age across the spectrum of fracture sites. CONCLUSIONS: The present study confirmed an excess mortality and higher direct medical costs associated with osteoporotic fractures. Moreover, hip fractures constituted the most severe and expensive complication of osteoporosis among fracture types. PMID- 26243357 TI - Relationship of sarcopenia and body composition with osteoporosis. AB - The purpose of the study is to investigate the relationship between sarcopenia and body composition and osteoporosis in cohorts of three different races with a total of 17,891 subjects. Lean mass and grip strength were positively associated with bone mineral densities (BMDs). Subjects with sarcopenia were two times more likely to have osteoporosis compared with normal subjects. INTRODUCTION: The relationship between sarcopenia and osteoporosis is not totally clear. First, the present study assessed this relationship by using two different definitions for sarcopenia. Second, we examined the associations of body composition (including muscle mass as a major and important component) and muscle strength on regional and whole-body BMDs. METHODS: In total, 17,891 subjects of African American, Caucasian, and Chinese ethnicities were analyzed. Sarcopenia was defined by relative appendicular skeletal muscle mass (RASM) cut points and also by the definition of the European Working Group on Sarcopenia in Older People (low RASM plus low muscle function). Multiple regression analyses were conducted to examine the association of fat mass, lean mass (including muscle mass), and grip strength with regional and whole-body BMDs. Multivariate logistic regression analysis was performed to explore the association between sarcopenia and osteopenia/osteoporosis. RESULTS: BMDs were positively associated with lean mass and negatively associated with fat mass, after controlling for potential confounders. Grip strength was significantly associated with higher BMDs. Each standard deviation (SD) increase in RASM resulted in a ~37 % reduction in risk of osteopenia/osteoporosis (odds ratio (OR) = 0.63; 95 % confidence interval (CI) = 0.59, 0.66). Subjects with sarcopenia defined by RASM were two times more likely to have osteopenia/osteoporosis compared with the normal subjects (OR = 2.04; 95 % CI = 1.61, 2.60). Similarly, subjects with sarcopenia (low muscle mass and low grip strength) were ~1.8 times more likely to have osteopenia/osteoporosis than normal subjects (OR = 1.87; 95 % CI = 1.09, 3.20). CONCLUSIONS: High lean mass and muscle strength were positively associated with BMDs. Sarcopenia is associated with low BMD and osteoporosis. PMID- 26243358 TI - Potential blindness in children of patients with hereditary bone disease. AB - Mono- and bi-allelic mutations in the low-density lipoprotein receptor related protein 5 (LRP5) may cause osteopetrosis, autosomal dominant and recessive exudative vitreoretinopathy, juvenile osteoporosis, or persistent hyperplastic primary vitreous (PHPV). We report on a child affected with PHPV and carrying compound mutations. The father carried the splice mutation and suffered from severe bone fragility since childhood. The mother carried the missense mutation without any clinical manifestations. The genetic diagnosis of their child allowed for appropriate treatment in the father and for the detection of osteopenia in the mother. Mono- and bi-allelic mutations in LRP5 may cause osteopetrosis, autosomal dominant and recessive exudative vitreoretinopathy, juvenile osteoporosis, or PHPV. PHPV is a component of persistent fetal vasculature of the eye, characterized by highly variable expressivity and resulting in a wide spectrum of anterior and/or posterior congenital developmental defects, which may lead to blindness. We evaluated a family diagnosed with PHPV in their only child. The child presented photophobia during the first 3 weeks of life, followed by leukocoria at 2 months of age. Molecular resequencing of NDP, FZD4, and LRP5 was performed in the child and segregation of the observed mutations in the parents. At presentation, fundus examination of the child showed a retrolental mass in the right eye. Ultrasonography revealed retinal detachment in both eyes. Thorough familial analysis revealed that the father suffered from many fractures since childhood without specific fragility bone diagnosis, treatment, or management. The mother was asymptomatic. Molecular analysis in the proband identified two mutations: a c.[2091+2T>C] splice mutation and c.[1682C>T] missense mutation. We report the case of a child affected with PHPV and carrying compound heterozygous LRP5 mutations. This genetic diagnosis allowed the clinical diagnosis of the bone problem to be made in the father, resulting in better management of the family. It also enabled preventive treatment to be prescribed for the mother and accurate genetic counseling to be provided. PMID- 26243359 TI - Serum chitotriosidase in postmenopausal women with severe osteoporosis. AB - Human chitotriosidase (Chit) increases during the osteoclast differentiation and their activity. We demonstrated that serum Chit was significantly higher in osteoporotic subjects than in healthy control ones and revealed a negative correlation between Chit and bone mineral density (BMD). This is the first study showing a correlation between Chit and severe postmenopausal osteoporosis. INTRODUCTION: Mammalian chitinases exert important biological roles in the monocyte lineage and chronic inflammatory diseases. In particular, Chit seems to promote bone resorption in vitro. No in vivo studies have been performed to confirm this finding. We aim to evaluate Chit activity in postmenopausal women affected by severe osteoporosis. METHODS: In this cross-sectional study, 91 postmenopausal women affected by osteoporosis and 61 with either osteopenia or normal BMD were screened. All subjects were assessed by dual-energy X-ray absorptiometry (DXA) and X-ray vertebral morphometry. Osteoporotic subjects were considered eligible if they were affected by at least one vertebral osteoporotic fracture (group A = 57 subjects). Osteopenic or healthy subjects were free from osteoporotic fractures (group B = 51 subjects). Enzymatic Chit and serum beta CrossLaps (CTX) were measured in the whole population. RESULTS: Group A showed higher serum levels of beta-CTX compared to group B (0.40 +/- 0.26 ng/mL vs 0.29 +/- 0.2 ng/mL, p = 0.022). Chit was significantly higher in group A than in group B (1042 +/- 613 nmol/mL/h vs 472 +/- 313 nmol/mL/h, p < 0.001, respectively) even after adjustment for age (p < 0.001). Spearman correlation test revealed a negative correlation between Chit and BMD at each site (lumbar spine: r = -0.38, p = 0.001, femoral neck: r = -0.35, p = 0.001, total femur: r = -0.39, p < 0.001). Furthermore, a positive correlation between Chit and PTH was observed (r = 0.26, p = 0.013). No significant correlation was found between Chit and beta CTX (r = 0.12, p = 0.229). After a multivariate analysis, a positive correlation between severe osteoporosis and Chit (p < 0.001), beta-CTX (p = 0.013), and age (p < 0.001) was observed. CONCLUSION: This is the first clinical study showing a correlation between Chit and severe postmenopausal osteoporosis. Larger and prospective studies are needed to evaluate if Chit may be a promising clinical biomarker and/or therapeutic monitor in subjects with osteoporosis. PMID- 26243360 TI - Periarticular osteoporosis of the forearm correlated with joint destruction and functional impairment in patients with rheumatoid arthritis. AB - The relationship between periarticular osteoporosis in the distal forearm and joint destruction or functional impairment in patients with rheumatoid arthritis (RA) is not sufficiently elucidated. From a single institutional cohort study, we found a strong correlation between periarticular forearm bone mineral density (BMD) and joint destruction or functional impairment. INTRODUCTION: This study was conducted to investigate (1) the difference between various periarticular regions of interest (ROIs) of BMD of the forearm, (2) the correlation between periarticular forearm BMD and joint destruction and physical function, (3) the independent variables for predicting BMD of the forearm, and (4) the forearm BMD of different ROIs in the early stage of RA. METHODS: We conducted a cross sectional study in an RA cohort. Measurements included BMD of the distal forearm, joint destruction of the hands assessed by modified total Sharp score (mTSS), functional impairment assessed by a health assessment questionnaire (HAQ), and other clinical data. Variables affecting the forearm BMD values were analyzed by correlation and stepwise regression analyses. RESULTS: Of the 405 patients enrolled in the present study, 370 (average age; 62.9 years) were identified as having definite RA with a complete set of data. BMD in the distal end of the forearm (BMDud) was significantly reduced compared with that in the distal third of the forearm (BMD1/3). In a stepwise regression analysis, the mTSS in BMD1/3 was an independent predicting variable, while age and partial HAQ scores associated with the upper extremity were common independent variables in BMDud and BMD1/3. BMDud was significantly less than BMD1/3, even in patients with a short duration of the disease. BMD1/3 was significantly less in non-remission group compared with that in remission group in patients with a short duration of the disease. CONCLUSION: Periarticular BMD in the distal forearm is closely correlated with joint destruction and functional impairment in RA. Periarticular BMD in the distal forearm may be already reduced at the clinical manifestation of the disease. PMID- 26243361 TI - Bone histomorphometry in diabetes mellitus. PMID- 26243362 TI - Fracture prediction from repeat BMD measurements in clinical practice. AB - We investigated whether repeat BMD measurements in clinical populations are useful for fracture risk assessment. We report that repeat BMD measurements are a robust predictor of fracture in clinical populations; this is not affected by preceding BMD change or recent osteoporosis therapy. INTRODUCTION: In clinical practice, many patients selectively undergo repeat bone mineral density (BMD) measurements. We investigated whether repeat BMD measurements in clinical populations are useful for fracture risk assessment and whether this is affected by preceding change in BMD or recent osteoporosis therapy. METHODS: We identified women and men aged >= 50 years who had a BMD measurement during 1990-2009 from a large clinical BMD database for Manitoba, Canada (n = 50,215). Patient subgroups aged >= 50 years at baseline with repeat BMD measures were identified. Data were linked to an administrative data repository, from which osteoporosis therapy, fracture outcomes, and covariates were extracted. Using Cox proportional hazards models, we assessed covariate-adjusted risk for major osteoporotic fracture (MOF) and hip fracture according to BMD (total hip, lumbar spine, femoral neck) at different time points. RESULTS: Prevalence of osteoporosis therapy increased from 18 % at baseline to 55 % by the fourth measurement. Total hip BMD was predictive of MOF at each time point. In the patient subgroup with two repeat BMD measurements (n = 13,481), MOF prediction with the first and second measurements was similar: adjusted-hazard ratio (HR) per SD 1.45 (95 % CI 1.34-1.56) vs. 1.64 (95 % CI 1.48-1.81), respectively. No differences were seen when the second measurement results were stratified by preceding change in BMD or osteoporosis therapy (both p-interactions >0.2). Similar results were seen for hip fracture prediction and when spine and femoral neck BMD were analyzed. CONCLUSION: Repeat BMD measurements are a robust predictor of fracture in clinical populations; this is not affected by preceding BMD change or recent osteoporosis therapy. PMID- 26243363 TI - Heavy resistance training is safe and improves bone, function, and stature in postmenopausal women with low to very low bone mass: novel early findings from the LIFTMOR trial. AB - The aim of the LIFTMOR (Lifting Intervention For Training Muscle and Osteoporosis Rehabilitation) trial is to determine the safety and efficacy of brief, bone targeted, high-intensity progressive resistance training (HiPRT) with impact loading for postmenopausal women with low bone mass. Preliminary findings indicate the LIFTMOR program is safe and effective. INTRODUCTION: Despite a lack of notable efficacy, exercise guidelines for osteoporosis typically recommend moderate-intensity exercises, owing to a perceived risk of fracture from high intensity loading. Indeed, safety concerns alone have prevented the well recognised preferential response of bone tissue to high-intensity loads from being applied to those who stand to benefit the most. To progress from this therapeutic stalemate, a challenge to conventional wisdom was required. Our goal was to examine the safety and efficacy of HiPRT and impact loading for risk factors of osteoporotic fracture in postmenopausal women with low to very low bone mass. METHODS: Participants have been randomised to either 8 months of twice weekly 30-min supervised HiPRT and impact loading or a low-intensity home-based exercise program of the same duration and dose. Testing at baseline and follow-up has included anthropometry; bone, muscle, and fat mass; and functional performance. RESULTS: Twenty-eight women (66.1 +/- 4.8 years, mean lumbar spine T score -2.15 +/- 0.72) have completed the study. HiPRT and impact loading (n = 12) improved height (0.4 +/- 0.2 cm vs -0.3 +/- 0.1 cm, p = 0.003), femoral neck bone mineral density (0.3 +/- 0.5 % vs -2.5 +/- 0.8 %, p = 0.016), lumbar spine bone mineral density (1.6 +/- 0.9 % vs -1.7 +/- 0.6 %, p = 0.005), and functional performance (p < 0.05), compared to controls (n = 16). Compliance has been >87 %. There have been no injuries. CONCLUSIONS: Brief supervised HiPRT with impact loading is a safe and effective exercise therapy for postmenopausal women with low to very low bone mass. PMID- 26243364 TI - Low bone mineral density for age/osteoporosis in triple A syndrome-an overlooked symptom of unexplained etiology. AB - Triple A syndrome (alacrima, achalasia, adrenal failure, progressive neurodegenerative disease) is caused by mutations in the AAAS gene which encodes the protein alacrima achalasia adrenal insufficiency neurologic disorder (ALADIN). Our investigation suggests that low bone mineral density (BMD) for age/osteoporosis could be a common but overlooked symptom of unexplained etiology in this rare multisystemic disease. INTRODUCTION: The purpose of this study is to evaluate incidence and etiology of BMD for age/osteoporosis, a possibly overlooked symptom in triple A syndrome. METHODS: Dual-energy X-ray absorptiometry (DXA) of the femoral neck, total hip, lumbar spine, and radius, bone turnover markers, minerals, total alkaline phosphatase (ALP), 25-hydroxy vitamin D (25-OHD), 1,25-dihydroxy vitamin D (1,25-OH2D), intact parathyroid hormone (PTH), and adrenal androgens (dehydroepiandrosterone sulfate (DHEAS) and androstenedione) were measured in five male and four female patients. RESULTS: At time of diagnosis, low BMD for age was suspected on X-ray in seven of nine patients aged 2-11 years (not performed in two patients); normal levels of minerals and ALP were found in nine patients and low levels of adrenal androgens in eight patients (not measured in one patient). Reevaluation 5-35 years after introduction of 12 mg/m(2)/day hydrocortisone showed low BMD for age in two children, osteopenia in one, and osteoporosis in six adults. Normal levels of minerals, ALP, PTH, 1,25-OH2D, procollagen type 1, crosslaps, and osteocalcin were found in all patients. Low levels of adrenal androgens were found in all and 25OHD deficiency in six patients. Body mass index was <25 % for age and sex in eight of nine patients. CONCLUSION: Low BMD for age/osteoporosis in our patients probably is not a result of glucocorticoid therapy but could be the consequence of low level of adrenal androgens, neurological impairment causing physical inactivity, inadequate sun exposure, and protein malnutrition secondary to achalasia. Considering ubiquitous ALADIN expression, low BMD/osteoporosis may be a primary phenotypic feature of the disease. Besides optimizing glucocorticoid dose, physical activity, adequate sun exposure, appropriate nutrition, and vitamin D supplementation, therapy with DHEA should be considered. PMID- 26243365 TI - Prospective study of predictive factors of changes in pain and hip function after hip fracture among the elderly. AB - Our study identified pre-fracture variables, such as home status or function, that are directly or indirectly associated with frailty status before fracture. The prevention in the deterioration of those variables would improve the prognosis of those hip fractured, being this an important issue for the societies with increasingly aging population. INTRODUCTION: This study was designed to identify predictors of pain and declines in function among elderly patients following a fall-related hip fracture. METHODS: Patients aged 65 or older with a fall-related hip fracture retrospectively completed pre-fracture status questionnaires (T0; n = 740) and were then prospectively followed for 6 months (T1; n = 546). Of these, 474 were randomly selected to complete an additional 18 months of follow-up (T2; n = 356). Primary outcome measures were changes in the pain and function dimensions of the Western Ontario and McMaster Universities Osteoarthritis Index questionnaire's short form (WOMAC-SF). Potential predictors included sociodemographic variables, in-hospital and clinical pre- and post fracture data, and activities of daily living at baseline and follow-up. Multivariate logistic regression was used for analysis. RESULTS: Predictors of worsening pain at T1 and/or T2 included living in a home care situation or nursing home before the fracture (OR at T1, 1.515; OR at T2, 2.749), and low pre fracture pain (OR at T1, 1.028; OR at T2, 1.027). Predictors of deterioration in function at T1 and/or T2 included age >=85 years (OR at T1, 2.714; OR at T2, 4.762), lower income (OR at T1, 1.755), high pre-fracture hip function (OR at T1, 1.029; OR at T2, 1.028), referral to rehabilitation upon discharge (OR at T1, 2.378; OR at T2, 2.881), and longer delay between fall and surgery (OR at T1, 1.133; OR at T2, 1.124). CONCLUSIONS: Frailty before hip fracture is a predictor of greater post-fracture pain and deterioration in function. Given that exercise programs help prevent frailty, promoting exercise in elderly may improve the prognosis of hip fracture. PMID- 26243366 TI - Management of imported cutaneous larva migrans: A case series and mini-review. AB - BACKGROUND: Cutaneous larva migrans (CLM), a zoonotic helminthiasis imported to Canada by travelers to the tropics, causes morbidity due to severe, intractable pruritus. Treatment in Canada is only available through the Special Access Program (SAP) of Health Canada, thus, many patients are prescribed ineffective courses of non-targeted therapy. OBJECTIVE: We analyzed patients with CLM referred to our specialized Tropical Disease Unit (TDU) having failed non targeted therapy prior to referral, and characterized demographic and travel related correlates of CLM. METHODS: Patients with CLM evaluated between June 2012 and December 2014 were identified through our SAP application log, and charts were reviewed for demographic, clinical, and travel-related data following IRB approval. RESULTS: 25 patients with CLM were identified: 12 women, and 13 men. Median age was 35 years (range 4-58 years). Patients had primarily acquired their CLM in the Caribbean (80%), with Jamaica being the most well represented source destination (N = 10, 40%). Reported symptoms included intense, function-limiting pruritus (N = 25, 100%) and loss of sleep (N = 3, 12%). Twelve patients (48%) with CLM had received at least 1 course of non-targeted therapy prior to referral. Non-targeted therapies included topical steroids (N = 7), cryotherapy (N = 3), oral antibiotics (N = 2), and oral mebendazole (N = 11). Median duration of symptoms was 34 days (range 5-226 days). Of 25 patients with CLM, 23 (92%) were prescribed a single 3-day course of albendazole and responded appropriately, and 2 (8%) required a second 3-day course of albendazole. CONCLUSIONS: Although CLM is non-communicable and of little public health relevance in Canada, it causes significant morbidity. A substantial proportion of patients with CLM referred to our specialized TDU had a prolonged course of illness and were prescribed ineffective and non-targeted therapies. Oral albendazole or ivermectin, or topical thiabendazole, are the drugs of choice for CLM, and should be prescribed as first-line therapy. PMID- 26243367 TI - Synthesis, antibacterial and QSAR evaluation of 5-oxo and 5-thio derivatives of 1,4-disubstituted tetrazoles. AB - A series of 1,4-disubstituted tetrazol-5-ones 3a, 5, 7, 12, 13 and 1,4 disubstituted tetrazol-5-thiones 3b, 9, 10 was synthesized and fully characterized by IR, MS, (1)H NMR and (13)C NMR. The series was evaluated for in vitro antibacterial activity against four Gram negative (Escherichia coli, Proteus mirabilis, Klebsiella pneumonia, and Pseudomonas aeruginosa) and three Gram positive (Staphylococcus aureus, Enterococcus faecalis, and Bacillus subtilis) bacteria. The zone of inhibition was measured using the well-diffusion assay, and in vitro minimum inhibitory concentration (MIC) was determined by microbroth dilution assay. MIC values indicate that compounds exhibited a varied range (0.2-37 MUg/mL) of antibacterial activity against the tested bacterial strains. Statistically significant QSAR models were developed by the simple linear regression analysis for the correlation of MIC with computed descriptors. The concluded cross validated regression factors are 0.953 and 0.986 for E. coli, and S. aureus, respectively. PMID- 26243368 TI - Synthesis and validation of novel cholesterol-based fluorescent lipids designed to observe the cellular trafficking of cationic liposomes. AB - Cholesterol-based fluorescent lipids with ether linker were synthesized using NBD (Chol-E-NBD) or Rhodamine B (Chol-E-Rh), and the usefulnesses as fluorescent probes for tracing cholesterol-based liposomes were validated. The fluorescent intensities of liposomes containing these modified lipids were measured and observed under a microscope. Neither compound interfered with the expression of GFP plasmid, and live cell images were obtained without interferences. Changes in the fluorescent intensity of liposomes containing Chol-E-NBD were followed by flow cytometry for up to 24h. These fluorescent lipids could be useful probes for trafficking of cationic liposome-mediated gene delivery. PMID- 26243369 TI - Antiviral activity and interaction mechanisms study of novel glucopyranoside derivatives. AB - Novel glucopyranoside derivatives were synthesized and evaluated for their antiviral activities against tobacco mosaic virus (TMV). Bioassay results indicated that some of the target compounds exhibited good in vivo antiviral activities against TMV. Among the title compounds, f6 showed appreciable inactivation effect against TMV, with the 50% effective concentration value (EC50) of 52.9 MUg/mL, which was better than that of ribavirin (145.1 MUg/mL). In addition, interaction between f6 and TMV-CP was characterized by fluorescence spectroscopy, isothermal titration calorimetry (ITC), and microscale thermophoresis (MST). Results showed that f6 bound to TMV-CP with micromole affinity, and thermodynamic parameters suggested that this interaction was typically endothermic and spontaneous, with 1:1.53 ratio of TMV-CP to f6. Thus, the synthesized glucopyranoside derivatives containing 1,4-pentadien-3-one moiety could be promising antiviral agents. PMID- 26243370 TI - Design, synthesis and RON receptor tyrosine kinase inhibitory activity of new head groups analogs of LCRF-0004. AB - New heteroarylcarboxamide head groups substituted with two aromatic rings analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Potent inhibitors of RON tyrosine kinase with various level of selectivity for c-Met RTK were obtained. PMID- 26243372 TI - Synthesis and molecular docking studies of oxochromenyl xanthenone and indolyl xanthenone derivatives as anti-HIV-1 RT inhibitors. AB - A series of novel oxochromenyl xanthenone and indolyl xanthenone derivatives were obtained by one-pot reaction of substituted salicylaldehyde, 4-hydroxy coumarin/indole and dimedone at ambient temperature condition using eco-friendly reusable ionic liquid [Hmim]HSO4 in ethanol solvent. Excellent yields, mild reaction condition, and simple experimental work-up procedure are some of the advantages of this method. The obtained derivatives were studied for their molecular docking as an anti-HIV-1 RT. All synthesized compounds from indolyl xanthenone and chromenyl xanthenone series were be docked into the non-nucleoside inhibitor binding pocket (NNIBP) of HIV-1 RT. Compounds 4r, 4j and 4k was found to be good around -12.487, -12.457, -12.256, respectively, with respective to native ligand TMC278, was found to be -13.413 which confirms that these compounds might have potent RT inhibition activity. PMID- 26243371 TI - N-Aryl benzenesulfonamide inhibitors of [3H]-thymidine incorporation and beta catenin signaling in human hepatocyte-derived Huh-7 carcinoma cells. AB - Structure-activity relationships (SAR) in 2,5-dichloro-N-(2-methyl-4 nitrophenyl)benzenesulfonamide (FH535) were examined as part of a program to identify agents that inhibit the Wnt/beta-catenin signaling pathway that is frequently upregulated in hepatocellular carcinoma (HCC). FH535 was reported as an inhibitor of both beta-catenin in the Wnt signaling pathway and the peroxisome proliferator-activated receptor (PPAR). A beta-catenin/T-cell factor (TCF)/Lymphoid-enhancer factor (LEF)-dependent assay (i.e., luciferase-based TOPFlash assay) as well as a [(3)H]-thymidine incorporation assay were used to explore SAR modifications of FH535. Although replacing the 2,5 dichlorophenylsulfonyl substituent in FH535 with a 2,6-dihalogenation pattern generally produced more biologically active analogs than FH535, other SAR modifications led only to FH535 analogs with comparable or slightly improved activity in these two assays. The absence of a clear SAR pattern in activity suggested a multiplicity of target effectors for N-aryl benzenesulfonamides. PMID- 26243373 TI - Preventive use of a hepatoprotectant against anti-tuberculosis drug-induced liver injury: A randomized controlled trial. AB - BACKGROUND AND AIM: Hepatoprotectants are routinely prescribed in China to prevent anti-tuberculosis drug-induced liver injury (ATLI). However, their biological mechanisms have not yet been clearly demonstrated. This study aims to evaluate the preventive effects of Silybum marianum against drug-induced liver injury among tuberculosis patients and to provide clinical guidelines for tuberculosis management in China. METHODS: A randomized controlled trial was performed in Jiangsu, China. Tuberculosis patients were randomly allocated to the experimental group (anti-tuberculosis therapy plus S. marianum capsule) or the control group (anti-tuberculosis therapy plus vitamin C tablet). The primary outcomes were the occurrence of probable and possible ATLI, the peak aspartate aminotransferase/alanine aminotransferase ratio and the maximum altered alkaline phosphatase or gamma-glutamyl transferase. RESULTS: The final analysis comprised 183 cases in the experiment group and 187 cases in the control group. The risk of developing probable ATLI was not significantly different between the two groups. During the follow-up period, 43.72% of cases in the experiment group and 35.83% of cases in the control group were determined to have possible ATLI (relative risk = 1.23, 95% confidence interval: 0.94-1.54). When using a more strict definition of possible ATLI, the adjusted relative risk (95% confidence interval) was 1.76 (1.14-2.56). The risks of adverse drug reactions, prolonged treatment length, taking second-line tuberculosis drugs, and the clearance of tuberculosis bacteria were similar between the two groups. CONCLUSIONS: No significant preventive effect of silymarin was found for either lowering the risk of liver injury or boosting the positive outcomes. Worse, we even found a potential risk of liver damage caused by the hepatoprotectant. PMID- 26243374 TI - Lack of specific association between panicogenic properties of caffeine and HPA axis activation. A placebo-controlled study of caffeine challenge in patients with panic disorder. AB - A subgroup of patients with Panic Disorder (PD) exhibits increased sensitivity to caffeine administration. However, the association between caffeine-induced panic attacks and post-caffeine hypothalamic-pituitary-adrenal (HPA)-axis activation in PD patients remains unclear. In a randomized, double-blind, cross-over experiment, 19 PD patients underwent a 400-mg caffeine-challenge and a placebo challenge, both administered in the form of instant coffee. Plasma levels of adrenocorticotropic hormone (ACTH), cortisol and dehydroepiandrosterone sulfate (DHEAS) were assessed at both baseline and post-challenge. No patient panicked after placebo-challenge, while nine patients (47.3%) panicked after caffeine challenge. Placebo administration did not result in any significant change in hormones' plasma levels. Overall, sample's patients demonstrated significant increases in ACTH, cortisol, and DHEAS plasma levels after caffeine administration. However, post-caffeine panickers and non-panickers did not differ with respect to the magnitude of the increases. Our results indicate that in PD patients, caffeine-induced panic attacks are not specifically associated with HPA axis activation, as this is reflected in post-caffeine increases in ACTH, cortisol and DHEAS plasma levels, suggesting that caffeine-induced panic attacks in PD patients are not specifically mediated by the biological processes underlying fear or stress. More generally, our results add to the evidence that HPA-axis activation is not a specific characteristic of panic. PMID- 26243375 TI - Semaphorin and plexin gene expression is altered in the prefrontal cortex of schizophrenia patients with and without auditory hallucinations. AB - Auditory hallucinations (AH) are clinical hallmarks of schizophrenia, however little is known about molecular genetics of these symptoms. In this study, gene expression profiling of postmortem brain samples from prefrontal cortex of schizophrenic patients without AH (SNA), patients with AH (SA) and control subjects were compared. Genome-wide expression analysis was conducted using samples of three individuals of each group and the Affymetrix GeneChip Human-Gene 1.0 ST-Array. This analysis identified the Axon Guidance pathway as one of the most differentially expressed network among SNA, SA and CNT. To confirm the transcriptome results, mRNA level quantification of seventeen genes involved in this pathway was performed in a larger sample. PLXNB1, SEMA3A, SEMA4D and SEM6C were upregulated in SNA or SA patients compared to controls. PLXNA1 and SEMA3D showed down-regulation in their expression in the patient's samples, but differences remained statistically significant between the SNA patients and controls. Differences between SNA and SA were found in PLXNB1 expression which is decreased in SA patients. This study strengthens the contribution of brain plasticity in pathophysiology of schizophrenia and shows that non-hallucinatory patients present more alterations in frontal regions than patients with hallucinations concerning neural plasticity. PMID- 26243376 TI - Aryl hydrocarbon receptor deletion in cerebellar granule neuron precursors impairs neurogenesis. AB - The aryl hydrocarbon receptor (AhR) is a ligand-activated member of the basic helix-loop-helix/PER-ARNT-SIM(PAS) transcription factor superfamily that also mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increasing evidence suggests that AhR influences the development of many tissues, including the central nervous system. Our previous studies suggest that sustained AhR activation by TCDD and/or AhR deletion disrupts cerebellar granule neuron precursor (GNP) development. In the current study, to determine whether endogenous AhR controls GNP development in a cell-autonomous manner, we created a GNP-specific AhR deletion mouse, AhR(fx/fx) /Math1(CRE/+) (AhR CKO). Selective AhR deletion in GNPs produced abnormalities in proliferation and differentiation. Specifically, fewer GNPs were engaged in S-phase, as demonstrated by ~25% reductions in thymidine (in vitro) and Bromodeoxyuridine (in vivo) incorporation. Furthermore, total granule neuron numbers in the internal granule layer at PND21 and PND60 were diminished in AhR conditional knockout (CKO) mice compared with controls. Conversely, differentiation was enhanced, including ~40% increase in neurite outgrowth and 50% increase in GABARalpha6 receptor expression in deletion mutants. Our results suggest that AhR activity plays a role in regulating granule neuron number and differentiation, possibly by coordinating this GNP developmental transition. These studies provide novel insights for understanding the normal roles of AhR signaling during cerebellar granule cell neurogenesis and may have important implications for the effects of environmental factors in cerebellar dysgenesis. PMID- 26243377 TI - Conserved features in TamA enable interaction with TamB to drive the activity of the translocation and assembly module. AB - The biogenesis of membranes from constituent proteins and lipids is a fundamental aspect of cell biology. In the case of proteins assembled into bacterial outer membranes, an overarching question concerns how the energy required for protein insertion and folding is accessed at this remote location of the cell. The translocation and assembly module (TAM) is a nanomachine that functions in outer membrane biogenesis and virulence in diverse bacterial pathogens. Here we demonstrate the interactions through which TamA and TamB subunits dock to bridge the periplasm, and unite the outer membrane aspects to the inner membrane of the bacterial cell. We show that specific functional features in TamA have been conserved through evolution, including residues surrounding the lateral gate and an extensive surface of the POTRA domains. Analysis by nuclear magnetic resonance spectroscopy and small angle X-ray scattering document the characteristic structural features of these POTRA domains and demonstrate rigidity in solution. Quartz crystal microbalance measurements pinpoint which POTRA domain specifically docks the TamB subunit of the nanomachine. We speculate that the POTRA domain of TamA functions as a lever arm in order to drive the activity of the TAM, assembling proteins into bacterial outer membranes. PMID- 26243378 TI - Managing the challenging pediatric airway: Continuing Professional Development. AB - PURPOSE: This module will give the anesthesia provider the information needed to identify, prepare for, and clinically manage a difficult airway in children. PRINCIPAL FINDINGS: Although the incidence of difficult intubation is lower in children than in adults, the anesthesiologist who even occasionally cares for children must be prepared to manage the pediatric patient with a known or suspected difficult airway. Many of the predictors of a difficult intubation that are useful in adults do not apply to children. Predictably, many children with a challenging airway also have a syndrome or diagnosis known to be associated with difficult intubation. Due to the unique emotional, physiological, and anatomical characteristics of small children, the approach to airway management is different from that in adults. Awake intubation is almost never an option, and recently, there has been a trend towards using cuffed tracheal tubes and apneic intubation. The flexible fibrescope has seen less action as the sole intubating device with the recent introduction of the various video laryngoscopes designed for pediatric use. Supraglottic airways are now being used in children with a difficult airway, not only as a rescue device in the event of failed intubation but also as a first choice airway device and as a conduit for tracheal intubation. CONCLUSION: Although direct laryngoscopy can still be used to manage the care of the majority of children with a known or suspected challenging airway, there is now a noticeable trend towards the use of a supraglottic airway and apneic intubation using fibreoptic and video laryngoscopic equipment. PMID- 26243379 TI - Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence. AB - Emerging evidence from epidemiological studies supports the notion that maternal folate status regulated by dietary and genetic factors early in pregnancy may influence the risk of autism spectrum disorders (ASD). In this review, we provide an overview of what is known about the role of folate in the aetiology of neurodevelopmental disorders; summarise relevant biological, genetic and epigenetic mechanisms; and synthesise the evidence from human observational studies and randomised controlled trials that have examined the relationship between maternal folate and ASD or related traits. Much of the existing literature on this topic is subject to limitations such as potential confounding by healthy behaviours and other dietary factors, and exposure assessed within limited exposure windows. As the existing evidence is inconclusive, further research remains to be conducted in order to verify this hypothesis. Complete assessment of maternal functional folate status through the pre- and peri conceptional periods requires biological measurement of folate, vitamin B12 and homocysteine and genetic variants involved in one-carbon metabolism and epigenetic mechanisms. In addition to more complete assessment of maternal functional folate status, careful consideration of potential confounding is warranted. PMID- 26243380 TI - Navigating the System: How Transgender Individuals Engage in Health Care Services. AB - PURPOSE: Transgender individuals (TIs) experience a number of healthcare disparities that result in compromised access to health care, placing them at high risk for poor health outcomes. Despite their unique health concerns, there is little known about how they engage in health care. The purpose of this grounded theory study was to construct a theoretical framework that depicts the process by which transgender individuals engage in health care. METHODS: In this grounded theory study, data from interviews with 25 individuals who self identified as transgender were used to develop a theoretical framework that depicts the process by which TIs engage in health care. Data analysis included open coding, category formation, and theoretical coding. Constant comparative analysis was used to facilitate theory generation. CONCLUSIONS: The central phenomenon of how TIs engage in health care was the core process of navigating the system. The core process involves four subprocesses: needing to move forward, doing due diligence, finding loopholes, and making it work. CLINICAL RELEVANCE: The theoretical framework of navigating the system can provide healthcare providers with a way to understand how TIs engage in health care as they move through the subprocesses of moving forward, doing due diligence, finding loopholes, and making it work in order to get their healthcare needs met. With a better understanding of the healthcare journeys of TIs, healthcare providers can provide better care for this population and advocate for change in policies that contribute to the health disparities TIs experience. PMID- 26243381 TI - Application of X-ray microcomputed tomography in the characterization of irradiated nuclear fuel and material specimens. AB - X-ray microcomputed tomography (MUCT) was applied in characterizing the internal structures of a number of irradiated materials, including carbon-carbon fibre composites, nuclear-grade graphite and tristructural isotropic-coated fuel particles. Local cracks in carbon-carbon fibre composites associated with their synthesis process were observed with MUCT without any destructive sample preparation. Pore analysis of graphite samples was performed quantitatively, and qualitative analysis of pore distribution was accomplished. It was also shown that high-resolution MUCT can be used to probe internal layer defects of tristructural isotropic-coated fuel particles to elucidate the resulting high release of radioisotopes. Layer defects of sizes ranging from 1 to 5 MUm and up could be isolated by tomography. As an added advantage, MUCT could also be used to identify regions with high densities of radioisotopes to determine the proper plane and orientation of particle mounting for further analytical characterization, such as materialographic sectioning followed by optical and electron microscopy. In fully ceramic matrix fuel forms, despite the highly absorbing matrix, characterization of tristructural isotropic-coated particles embedded in a silicon carbide matrix was accomplished using MUCT and related advanced image analysis techniques. PMID- 26243383 TI - Extensive oral mucosal hyperkeratosis caused by over-the-counter long lasting snoring relief agent. PMID- 26243385 TI - Modified free pectoral skin flaps in rats. AB - Various types of murine free flaps have been developed for microsurgical training and research. We present a new modification of the free pectoral skin flap in Sprague-Dawley rats. Twelve free pectoral skin flaps were raised according to the standard protocol except that we deviated from it by transecting the common thoracic vessels at the origin of the axillary vessels and anastomosing them end to-side to the femoral vessels in the groin. This reduced operating time and complications as well as postoperative morbidity and mortality. Overall, it simplified the procedure considerably and therefore made the model more attractive to beginners in microvascular surgery. PMID- 26243384 TI - Skeletal stability in orthognathic surgery: evaluation of methods of rigid internal fixation after counterclockwise rotation in patients with class II deformities. AB - Our aim was to assess the influence of internal fixation in skeletal stability on patients who had had counterclockwise rotation of the maxillomandibular complex and mandibular advancement procedures. We studied 60 records of 20 patients (14 female, 6 male), mean (range) age at operation 29 (16-50) years. The mean (range) postoperative follow-up was 15 (8-24) months. Sixty standard lateral cephalometric radiographs were randomly traced and digitised by one senior radiologist to estimate surgical and postoperative changes. Patients were divided into two groups, the first group (n=10) of which had fixation with only 2.0 system plates (2 plates with monocortical screws alone) and the second (n=10) of which had hybrid fixation (1 plate with monocortical screws and 2 or 3 bicortical bone screws). During operation the change in the mean occlusal plane with counterclockwise rotation was 9.4 degrees (range -17.3 to -2.5mm). The maxilla moved forward and upward. All the anterior mandibular measurements had advanced horizontally, the mean (range) being 17 (6.4 to 9.9) mm for the pogonion, and 17.6 (6.0 to 30.7) mm for the menton. At the longest follow-up period, there were significant long-term changes, but these were clinically acceptable (<2mm). There was no significant difference between the two groups in postoperative stability or in the magnitude of the advancement and stability. PMID- 26243386 TI - Silicone wafers at the Royal Surrey County Hospital: 3-year review. AB - Accurate orthognathic wafers manufactured in the laboratory are essential for the transfer of preoperative prescribed movements to theatre, and most are made of poly(methyl methacrylate) (PMMA). At the Royal Surrey County Hospital we used 416 silicone wafers in 292 patients from January 2011 to December 2013. We report how a revised design has improved self-retention and intraoperative visualisation. PMID- 26243387 TI - The impact of leukapheresis on immune-cell number and function in patients with advanced cancer. AB - BACKGROUND: Leukapheresis is often performed in cancer patients to harvest stem cells, manufacture therapeutic vaccines, or follow immunologic response to therapy. We have recently described the minimal impact of leukapheresis on normal donors. Here we provide additional immunologic data from patients with advanced cancer who underwent leukapheresis. METHODS: Using data from cancer patients on clinical trials who had leukapheresis (n = 64) or peripheral blood draws only (n = 90) as controls for immune analysis, we evaluated the impact of leukapheresis on number and function of lymphocytes. RESULTS: In the leukapheresis group, median age was 63.5 (range 38-82); 87.5 % were male. Comparing pre- and post leukapheresis values within the groups, with each patient as its own control, there was no significant difference in enzyme-linked immunosorbent spot (ELISPOT), antivector humoral response, absolute lymphocyte count (ALC), or T cell number. Twelve patients completed three leukaphereses with subsequent ELISPOT analysis; seven had increased responses to flu (1.1- to 2.3-fold) with an even distribution around no change. Nineteen patients had matched ALC values after completing three leukaphereses with no significant change from baseline. CONCLUSIONS: These data provide evidence that leukapheresis has no detectable effects on a cancer patient's immune system in terms of number or function. These results contribute to a growing body of evidence refuting the hypothesis that a patient's immune competence is meaningfully affected by the procedure. Limitations include a restriction to 2-L leukapheresis procedure and small sample size. PMID- 26243388 TI - Heterotaxy and intestinal rotation anomalies: 20 years experience at a UK regional paediatric surgery centre. AB - BACKGROUND: The association of heterotaxy with intestinal rotation anomalies is well described. However debate exists with regard optimal management notably should 'asymptomatic' bowel rotation anomalies undergo operation? The present study therefore sought to determine: (1) the risk(s) of volvulus in patients diagnosed with heterotaxy and (2) define morbidity associated with operation for 'asymptomatic' anomalies in a fragile patient cohort with co-existent congenital heart disease. METHODS: Medical case record reviews of ALL heterotaxy patients born during January 1993-December 2013 and attending a UK paediatric centre were analyzed. RESULTS: Of a total of 92 patients, 16 (17.4%) cases underwent foregut imaging studies. Three examinations were performed in 'symptomatic' patients. Twelve studies reported 'abnormal anatomy' with only five patients undergoing surgical correction. No complication(s) were recorded after Ladd's operation to correct defects. A single fatality occurred within 30 days postoperatively from cardiac failure. In 87 patients in whom Ladd's operation was not undertaken, no single patient developed intestinal volvulus (median length of follow-up 27.2 months, total 446.1 person years). CONCLUSION: This study strongly supports a 'watchful waiting' policy for heterotaxy patients. Many children who ultimately die from heart disease may avoid unnecessary abdominal surgery. PMID- 26243389 TI - Variation in the use of primary care services for diabetes management according to country of birth and geography among older Australians. AB - AIMS: To investigate variation according to country of birth and geography in the use of primary care services funded through Medicare Australia-Australian universal health insurance-for diabetes annual cycle of care among older overseas born Australians with type-2 diabetes. METHODS: Records of Medicare claims for medical services were linked to self-administered questionnaire data for people with type-2 diabetes enrolled in the 45 and Up Study, including 840 participants born in Italy, Greece, Vietnam, Lebanon, China, India, or the Philippines and 12,444 participants born in Australia, living in 195 statistical local areas (SLAs) in New South Wales, Australia. Study outcomes included >=6 claims for general practitioner (GP) visits, at least one claim for specialist, optometrist, Practice Incentive Payment for completion of diabetes annual cycle of care (PIP), GP Management Plan or Team Care Arrangement (GPMP/TCA), allied health, blood tests for glycosylated haemoglobin (HbA1c) and cholesterol, and urine test for micro-albumin. Multivariable multilevel logistic regression was performed, controlling for personal socio-demographic and health characteristics and geographical area remoteness and socio-economic status. RESULTS: Compared with Australia-born participants, people born in Vietnam and China had significantly lower rates of claims for allied health services (odds ratio [OR] 0.14, 95% confidence interval [CI] 0.05-0.43, and OR 0.40, 95%CI 0.18-0.87, respectively), those born in Italy had lower rates of PIP claims (OR 0.60, 95%CI 0.39-0.92) and micro-albuminuria testings (OR 0.65, 95%CI 0.47-0.89), and those born in the Philippines had lower claims for specialist services (OR 0.59, 95%CI 0.38-0.91). Participants born in Greece and China (GP visits), Vietnam (optometrist services), and India (micro-albuminuria tests) were more likely to claims for these services than Australia-born people. Significant geographic variation was observed for all study outcomes, with the greatest variations in claims for allied health services (variation 9.3%, median odds ratio [MOR] 1.74, 95% credible interval [CrI] 1.60-2.01), PIP (7.8%, MOR 1.65, 95%CrI 1.55-1.83), and GPMP/TCA items (6.6%, MOR 1.58, 95%CrI 1.49-1.73). CONCLUSIONS: Different approach among geographical areas and intervention programs for identified cultural groups and their providers are warranted to improve disparities in diabetes care. PMID- 26243390 TI - Reduction of L-phenylalanine in protein hydrolysates using L-phenylalanine ammonia-lyase from Rhodosporidium toruloides. AB - L-Phenylalanine ammonia-lyase (PAL, EC 4.3.1.25) from Rhodosporidium toruloides was utilized to remove L-phenylalanine (L-Phe) from different commercial protein hydrolysates. A casein acid hydrolysate (CAH, L-Phe ~2.28 %) was employed as a model substrate. t-Cinnamic acid resulting from deamination of L-Phe was extracted, analyzed at lambda = 290 nm, and used for PAL activity determination. Optimum reaction conditions, optimized using successive Doehlert design, were 35 mg mL(-1) of CAH and 800 mU mL(-1) of PAL, while temperature and pH were 42 degrees C and 8.7, respectively. Reaction kinetics of PAL with CAH was determined under optimized conditions. Then, removal of L-Phe from CAH was tested. Results showed that more than 92 % of initial L-Phe was eliminated. Similar results were obtained with other protein hydrolysates. These findings demonstrate that PAL is a useful biocatalyst for L-Phe removal from protein hydrolysates, which can be evaluated as potential ingredients in foodstuffs for PKU patients. PMID- 26243391 TI - MEK-independent ERK activation in human neutrophils and its impact on functional responses. AB - Neutrophils influence innate and adaptative immunity, notably through the generation of numerous cytokines and chemokines and through the modulation of their constitutive apoptosis. Several signaling cascades are known to control neutrophil responses, including the MEK pathway, which is normally coupled to ERK. However, we show here that in human neutrophils stimulated with cytokines or TLR ligands, MEK and ERK are activated independently of each other. Pharmacological blockade of MEK had no effect on the induction of ERK kinase activity and vice versa. In autologous PBMC exposed to the same stimuli or in neutrophils exposed to chemoattractants, this uncoupling of MEK and ERK was not observed. Whereas we had shown before that MEK inhibition impairs cytokine generation translationally in LPS- or TNF-stimulated neutrophils, ERK inhibition affected this response transcriptionally and translationally. Transcriptional targets or ERK include the mitogen- and stress-activated protein kinase 1 (MSK-1) and its substrates, C/EBPbeta and CREB, whereas translational targets include the S6 kinase and its substrate, the S6 ribosomal protein. In addition to affecting cytokine production, ERK inhibition interfered with how LPS or TNF promotes neutrophil survival and levels of the myeloid cell leukemia 1 (Mcl-1) antiapoptotic protein. Whereas the ERK-activating kinase was not identified, we found that the MAP3K, TGF-beta-activated kinase 1 (TAK1), acts upstream of ERK and MEK in neutrophils. Our results document a functional uncoupling of the MEK/ERK module under certain stimulatory conditions and suggest that therapeutic strategies based on MEK inhibition might benefit from being complemented by ERK inhibition, particularly in chronic inflammatory conditions featuring a strong neutrophilic component. PMID- 26243392 TI - High pretreatment neutrophil-lymphocyte ratio predicts recurrence and poor prognosis for combined small cell lung cancer. AB - BACKGROUNDS: Compared to pure small cell lung cancer (SCLC), combined small cell lung cancer (C-SCLC) has its own characteristics. High neutrophil to lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have been shown to be related to poor prognosis in several types of tumors. The aim of this study was to explore the prognosis value of NLR and PLR in patients with C-SCLC. METHODS: A total of 112 patients diagnosed with C-SCLC between January 2000 and March 2009 were enrolled in the study. The clinicopathological parameters, laboratory analyses, and survival time were collected and analyzed. The correlation between NLR, PLR, and clinicopathological characters was analyzed. Univariate and multivariate analyses were performed to investigate the prognostic significance of these parameters for C-SCLC. RESULTS: The pretreatment NLR was elevated in 37.5 % patients (NLR >= 4.15; n = 42; H-NLR). NLR was significantly related to disease stage (p = 0.033) and tumor recurrence (p = 0.014). The median overall survival (OS) and progression-free survival (PFS) were significantly worse in the H-NLR group (OS: 22.0 months vs 11.7 months, p = 0.001; PFS: 11.1 vs 6.0 months, p < 0.001). However, PLR at diagnosis was not associated with OS or PFS. Multivariate analyses indicated elevated NLR (HR = 1.6; p = 0.001), disease stage (HR = 1.6; p = 0.001), and performance status (HR = 1.8; p = 0.015) as independent prognostic factors. CONCLUSIONS: High pretreatment NLR (>=4.15) is a potential useful indicator for C-SCLC recurrence and predicts a poor long-term prognosis for C SCLC, which should be considered in defining the prognosis with other well-known prognosticators in C-SCLC patients. PMID- 26243393 TI - Early evaluation of targeted therapy effectiveness in non-small cell lung cancer by dynamic contrast-enhanced CT. AB - PURPOSE: To study the feasibility and clinical value of dynamic contrast-enhanced (DCE) computed tomography (CT) for early evaluation of targeted therapy efficacy in non-small cell lung cancer (NSCLC). METHODS: We measured tumor diameter, peak height (PH), time to peak (TP), tumor mass-aortic peak height ratio (M/A), and blood perfusion (BP) in 20 patients with advanced NSCLC using DCE-CT before and 7 days after treatment. Therapy efficacy was assessed with conventional CT 4-6 weeks post-treatment. RESULTS: Patients were grouped into those with partial response (PR), stable disease (SD), and progressive disease (PD) according to the therapy efficacy assessment at 4-6 weeks post-treatment. The PR group primary tumor diameter (P = 0.0007) and BP (P = 0.0225) were reduced at 7 days post treatment; the SD group DCE-CT value changes were not significant. The PD group M/A (P = 0.0443) and BP (P = 0.0268) were increased 7 days post-treatment. The BP decrease group had significantly longer progression-free survival than the BP increase group (median, 54 vs. 6 weeks). CONCLUSION: DCE-CT can evaluate targeted therapy efficacy at 7 days post-treatment. Decreased primary tumor diameter and BP indicate tumor sensitivity to therapy; increased BP with unchanged tumor diameter suggests the tumor is not sensitive to therapy. Reduced BP suggests treatment effectiveness. PMID- 26243394 TI - Erratum to: Expression of serum miR-200a, miR-200b and miR-200c as candidate biomarkers in epithelial ovarian cancer and their association with clinicopathological features. PMID- 26243395 TI - Expression and clinical significance of cortactin protein in ovarian neoplasms. AB - OBJECTIVE: To examine the expression of cortactin in epithelial ovarian cancer, and discuss the relationship between the expression of cortactin and the clinical pathology characteristics in epithelial ovarian cancer, as well as clinical significance. METHODS: The expression of cortactin was detected using real-time fluorescence quantitative PCR and immunohistochemical SP method in epithelial ovarian cancer. RESULTS: (1) The relative content of cortactin mRNA in epithelial ovarian cancer tissue was higher than that in benign control tissue, and expression was related to histological classification and FIGO stage. (2) Cortactin protein was localized in the cytoplasm and membrane of tumor cells. The positive rate of cortactin was 73.3 % in epithelial ovarian cancer, and the rate of cortactin expression was related to histological classification. (3) The average survival period of epithelial ovarian cancer patients with positive expression of cortactin was 19.5 +/- 1.2 months (95 % CI 14.6-21.4 months), compared with 34.5 +/- 4.3 months in the negative expression group (95 % CI 22.1 25.9 months). Univariate survival analysis showed that: negative expression of cortactin had a significant survival advantage (chi (2) = 5.739, P = 0.017). A cox regression model for multivariate analysis revealed that cortactin was an independent prognostic factor for epithelial ovarian cancer (P = 0.001; RR = 6.452, 95 % CI 2.289-7.112). CONCLUSIONS: Negative expression of cortactin was an independent prognostic factor and had a survival advantage. This suggested that cells with poor differentiation showed increasing motility. Cortactin is closely related to poor prognosis. PMID- 26243396 TI - Stereotactic body radiotherapy (SBRT) for the treatment of inoperable stage I non small cell lung cancer patients. AB - INTRODUCTION: Lung cancer is the most frequent neoplasm in humans. Surgery is considered the best therapeutic approach for stage I non-small lung cell cancer (NSCLC). However, a remarkable amount of patients are considered as inoperable. Stereotactic body radiotherapy (SBRT) has risen as an option for those patients, rendering excellent results in quality of life and survival. MATERIALS AND METHODS: We analyzed clinical studies published between 2002 and 2015 which included SBRT as a treatment modality. Our own clinical series was analyzed as well. The patterns of failure following SBRT were investigated, together with the outcomes and the toxicity observed. RESULTS: SBRT has proven to maintain an excellent local control. The analysis showed the tumor size and the histology as determinant factors for the response to treatment. CONCLUSION: According to the published evidence as well as our own experience, SBRT is a safe and feasible approach for early NSCLC. Its results may be comparable with surgery treatment. PMID- 26243397 TI - The expression and function of Frizzled-7 in human renal cell carcinoma. AB - PURPOSE: Wnt/beta-catenin has emerged as an important signal pathway in renal cell carcinoma (RCC) pathogenesis. Frizzled 7 (Fzd7) is a member of Frizzled (Fzd) receptor family which binds with Wnt ligands and transduces canonical and non-canonical pathways. However, the expression of Fzd7 in human RCC is poorly investigated. METHODS: 53 RCC tissues and peri-tumor tissues were collected from the patients treated with radical nephrectomy. The expression of Fzd7 was investigated by immunohistochemical staining. Three RCC cells were transfected with Fzd7shRNA and GFPshRNA to investigate the function of Fzd7 in RCC cells. RESULTS: The immunohistochemical analysis showed that Fzd7 protein expression level was significantly increased in RCC tissues when compared with peri-tumor tissues, which suggested that Fzd7 might be involved in the formation of tumors. However, the Fzd7 expression was not correlated with clinicopathological parameters. Three RCC cell lines: 786-O, Caki-1, and OS-RC-2 also expressed Fzd7. With Fzd7 expression being interfered by shRNA, the RCC cell proliferation was mildly decreased. Wnt3a could stimulate the RCC cells proliferation, but the stimulation was decreased when Fzd7 expression was interfered. Restoring the Fzd7 expression led to the proliferation stimulation effect of Wnt3a being restored. CONCLUSIONS: This paper suggests that Fzd7 may act as one of the molecules that take part in the course of RCC formation. Fzd7 can be activated by Wnt3a to stimulate cell proliferation. PMID- 26243398 TI - Overexpression of CIP2A promotes bladder cancer progression by regulating EMT. AB - BACKGROUND: Bladder cancer is the second most common urological malignancy worldwide. CIP2A is a newly identified inhibitor of PP2A. Recent studies have highlighted a potential role for CIP2A in promoting the proliferation of several cancer cells. However, the role of CIP2A in bladder cancer still remains unclear. METHODS: The expression of CIP2A was detected by quantitative real-time polymerase chain reaction and IHC in bladder cancer tissues and bladder cancer cell lines. In addition, silencing of CIP2A with siRNA was performed in T24 cells, and the impact on proliferation, and apoptosis of T24 cells was analyzed. RESULTS: Our results found that CIP2A expression levels were higher in bladder cancer tissues and cell lines. Furthermore, CIP2A siRNA significantly reduced the proliferation rate of T24 cells, induced a significant population of early and late apoptosis, and could reverse EMT in T24 cells, indicates that CIP2A expression is increased in bladder cancer and implies a role of the protein in bladder cancer progression. CONCLUSIONS: These results suggest that CIP2A is involved in tumor progression, and thus CIP2A could represent selective targets for the targeted treatments of bladder cancer. PMID- 26243399 TI - Prognostic factors affecting survival in metastatic soft tissue sarcoma: an analysis of 110 patients. AB - BACKGROUND: Data on treatment outcome and prognostic factors in patients with metastatic soft tissue sarcoma (STS) are limited in the literature. METHODS: A total of 119 patients with metastatic STS treated between June 2003 and December 2012 were analyzed for treatment outcome and prognostic factors. RESULTS: Median age was 37 years (range 2-72 years) with a male to female ratio of 1.5:1. Most common histologic subtypes were synovial sarcoma (36 %) and leiomyosarcoma (16 %). Median tumor size was 12 cm (range 1.6-30 cm). Twenty-four (20 %) patients were treated with multimodality therapy and 80 % patients received systemic chemotherapy alone. At a median follow-up of 10 months (range 1-66 months), the 2 year EFS and OS were 10 and 19 %, respectively, with a median EFS and OS of 6 and 10 months, respectively. Univariate analysis identified albumin <=4 g/dl (p = 0.001), histologic subtypes other than synovial sarcoma (p = 0.02), non-extremity tumors (p = 0.03) and single modality treatment (p = 0.03) as factors predicting poor EFS; however, for OS, hemoglobin <=10 g/dl (p = 0.02), tumor size >10 cm (p = 0.01) and single modality treatment (p = 0.04) were identified as poor prognostic factors. Multivariate analysis identified only serum albumin <=4 g/dl (p = 0.002, HR 0.47, 95 % CI 0.29-0.75) associated with poor EFS; however, for OS, hemoglobin <=10 g/dl (p = 0.009, HR 0.49, 95 % CI 0.29-0.83), tumor size >10 cm (p = 0.003, HR 2.11, 95 % CI 1.28-3.47) and single modality treatment (p = 0.01, HR 0.47, 95 % CI 0.25-0.86) emerged as poor prognostic factors. CONCLUSIONS: Serum albumin, tumor size, hemoglobin and treatment modality affect survival in metastatic STS. PMID- 26243401 TI - Quantifying change in pulmonary function as a prognostic marker in systemic sclerosis-related interstitial lung disease. AB - OBJECTIVES: Clinically meaningful change in systemic sclerosis (SSc) related interstitial lung (SSc-ILD) disease is unknown. The aim of this study was to quantify change in pulmonary function as a predictor of outcome in SSc-ILD. METHODS: All patients had SSc-ILD defined by HRCT chest. All PFTs during follow up, including FVC (L), DLCO (ml/min/mmHg) and KCO (DLCO/alveolar volume ratio; DLCO/VA) (ml/min/mmHg/L) were retrieved. The rate of change over the first four years, and percentage change in the first year of follow-up were used in ROC curve analysis to determine the best cut-off points to predict adverse outcome (home oxygen, lung transplantation, or death). RESULTS: Among 264 patients, there were 49 events (38 deaths, 10 supplemental oxygen, one lung transplant) over a mean (+/-SD) follow-up of 3.0 (+/-1.7) years. The rates of decline over time and percentage change over one year in each of FVC, DLCO and KCO were predictive of adverse outcome. Stable PFTs over four years gave the optimal negative predictive values (NPVs) of 88-96%. The best sensitivity-specificity trade-off was a decline in FVC of 10% and in DLCO and KCO of 15% with NPVs of 92-93%. CONCLUSIONS: The course that SSc-ILD takes is evident within the first 1-4 years of follow up. Patients who have no decline in PFTs over 4 years have better outcomes. A decline within one year in DLCO or KCO of 15% or more is a poor prognostic factor, and identifies patients who should be monitored more closely and considered for therapy. PMID- 26243400 TI - Central nervous system niche involvement in the leukemia. AB - Central nervous system (CNS) impairment is commonly involved in leukemia, as it can be observed upon onset or relapse of the disease. It is associated with poor prognosis and is a challenging clinical problem. The objective of this paper was to provide a characterization of the CNS niche in leukemia, to elucidate the culprits of CNS involvement, including diagnostic micro RNAs (miRs) and early leukemia prognosis. CNS niche is a proper location for homing of leukemic stem cells, thus representing a candidate target in the treatment of leukemia. Recent advances in the study of leukemia hallmarks have enlightened miRs as novel biomarkers for diagnosis and detection of CNS involvement in leukemia, thus providing the opportunity to develop novel therapeutic approaches. Given the importance of prognosis and early diagnosis of CNS involvement in leukemias as well as the severe side effects of current treatments, diagnostic and therapeutic approaches should focus on identification and inhibition of the factors contributing to CNS involvement, including CXCR3, P-selectin glycoprotein ligand 1 and MCP1. MiRs such as miR-221 and miR-222 are emerging as potential tools for an innovative non-invasive therapy of CNS in leukemia affected patients. PMID- 26243402 TI - Evaluation extracellular matrix-chitosan composite films for wound healing application. AB - The present study describes the preparation of extracellular matrix (ECM; from porcine omentum) based chitosan composite films for wound dressing applications. The films were prepared by varying the ECM content, whereas, the amount of chitosan was kept constant. The interactions amongst the components of the films were analyzed by FTIR and XRD studies. The films were thoroughly characterized for surface hydrophilicity, moisture retention capability, water vapor permeability, mechanical and biocompatibility. FTIR study indicated that both chitosan and ECM were present in their native form and did not lose their activity. XRD analysis suggested composition dependent change in the crystallinity of the films. The mechanical properties suggested that the composite films had sufficient properties to be used for wound dressing applications. An increase in the ECM content resulted in better hydrophilicity of the films and hence better the moisture retention capacity and retardant water vapor transmission rate property of the composite films. The films were found to be biocompatible to both blood and adipose tissue derived stem cells. In gist, the prepared films may be explored as wound dressing materials. PMID- 26243404 TI - WRKY40 and WRKY6 act downstream of the green leaf volatile E-2-hexenal in Arabidopsis. AB - Plants are known to be responsive to volatiles, but knowledge about the molecular players involved in transducing their perception remains scarce. We study the response of Arabidopsis thaliana to E-2-hexenal, one of the green leaf volatiles (GLV) that is produced upon wounding, herbivory or infection with pathogens. We have taken a transcriptomics approach to identify genes that are induced by E-2 hexenal, but not by defence hormones or other GLVs. Furthermore, by studying the promoters of early E-2-hexenal-induced genes we determined that the only statistically enriched cis-element was the W-box motif. Since members of the plant-specific family of WRKY transcription factors act in trans on this cis element, we focused on WRKY6, 40 and 53 that were most strongly induced by E-2 hexenal. Root elongation of Arabidopsis seedlings of the wrky40 wrky6 double mutant was much less inhibited than in wt plants, similar to the E-2-hexenal responsive mutant her1, which is perturbed in gamma-amino butyric acid (GABA) metabolism. The induction of several of the E-2-hexenal-specific genes was much higher in the wrky40, wrky6 or wrky40 wrky6 mutants, including GAD4, a glutamate decarboxylase that catalyzes the formation of GABA from glutamate. In conclusion, WRKY6 and 40 seem to act as important players transducing E-2-hexenal perception. PMID- 26243406 TI - Innate detection of hepatitis B and C virus and viral inhibition of the response. AB - Viral hepatitis caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infections poses a significant burden to the public health system. Although HBV and HCV differ in structure and life cycles, they share unique characteristics, such as tropism to infect hepatocytes and association with hepatic and extrahepatic disorders that are of innate immunity nature. In response to HBV and HCV infection, the liver innate immune cells eradicate pathogens by recognizing specific molecules expressed by pathogens via distinct cellular pattern recognition receptors whose triggering activates intracellular signalling pathways inducing cytokines, interferons and anti-viral response genes that collectively function to clear infections. However, HBV and HCV evolve strategies to inactivate innate signalling factors and as such establish persistent infections without being recognized by the innate immunity. We review recent insights into how HBV and HCV are sensed and how they evade innate immunity to establish chronicity. Understanding the mechanisms of viral hepatitis is mandatory to develop effective and safe therapies for eradication of viral hepatitis. PMID- 26243405 TI - Hand-Schuler-Christian disease presenting with recurrent, bilateral, symmetrical mandibular lesions in an 8-year-old boy: report of a case. AB - INTRODUCTION: Hand-Schuller-Christian disease (HSC) is the unisystem multifocal form of Langerhans Cell Histiocytosis (LCH) and is primarily seen in infants and children. CASE REPORT: An 8-year-old boy was referred for acute mandibular pain. His medical history included otic LCH and diabetes insipidus at age of 11 months. Intraorally, a pressure sensitive swelling, and radiographically, extensive bone loss were revealed on the area of lower second primary molars. The primary molars were extracted and histological examination confirmed the final diagnosis of HSC. The patient was treated with chemotherapy and the lesions decreased considerably. Two years later, a new swelling was recorded in the same area bilaterally. Biopsy confirmed recurrent HSC disease and the patient entered an alternative chemotherapy protocol. Six months later, improvement of the lesions was revealed. CONCLUSIONS: Dentists can contribute to a timely and valid identification of HSC disease by correctly differentially diagnosing lesions of head and neck. PMID- 26243407 TI - Structure and spectroscopic properties of the dimeric copper(I) N-heterocyclic carbene complex [Cu2(CNC(t-Bu))2](PF6)2. AB - In recent years, the use of copper N-heterocyclic carbene (NHC) complexes has expanded to fields besides catalysis, namely medicinal chemistry and luminescence applications. In the latter case, multinuclear copper NHC compounds have attracted interest, however, the number of these complexes in the literature is still quite limited. Bis[MU-1,3-bis(3-tert-butylimidazolin-2-yliden-1 yl)pyridine]-1kappa(4)C(2),N:N,C(2');2kappa(4)C(2),N:N,C(2')-dicopper(I) bis(hexafluoridophosphate), [Cu2(C19H25N5)2](PF6)2, is a dimeric copper(I) complex bridged by two CNC, i.e. bis(N-heterocyclic carbene)pyridine, ligands. Each Cu(I) atom is almost linearly coordinated by two NHC ligands and interactions are observed between the pyridine N atoms and the metal centres, while no cuprophilic interactions were observed. Very strong absorption bands are evident in the UV-Vis spectrum at 236 and 274 nm, and an emission band is observed at 450 nm. The reported complex is a new example of a multinuclear copper NHC complex and a member of a compound class which has only rarely been reported. PMID- 26243408 TI - Weak C-H...O and C-H...pi hydrogen bonds and pi-pi stacking interactions in a series of four N'-[(E)-(aryl)methylidene]-N-methyl-2-oxo-1,3-oxazolidine-4 carbohydrazides. AB - Oxazolidin-2-ones are widely used as protective groups for 1,2-amino alcohols and chiral derivatives are employed as chiral auxiliaries. The crystal structures of four differently substituted oxazolidinecarbohydrazides, namely N'-[(E) benzylidene]-N-methyl-2-oxo-1,3-oxazolidine-4-carbohydrazide, C12H12N3O3, (I), N' [(E)-2-chlorobenzylidene]-N-methyl-2-oxo-1,3-oxazolidine-4-carbohydrazide, C12H12ClN3O3, (II), (4S)-N'-[(E)-4-chlorobenzylidene]-N-methyl-2-oxo-1,3 oxazolidine-4-carbohydrazide, C12H12ClN3O3, (III), and (4S)-N'-[(E)-2,6 dichlorobenzylidene]-N,3-dimethyl-2-oxo-1,3-oxazolidine-4-carbohydrazide, C13H13Cl2N3O3, (IV), show that an unexpected mild-condition racemization from the chiral starting materials has occurred in (I) and (II). In the extended structures, the centrosymmetric phases, which each crystallize with two molecules (A and B) in the asymmetric unit, form A+B dimers linked by pairs of N-H...O hydrogen bonds, albeit with different O-atom acceptors. One dimer is composed of one molecule with an S configuration for its stereogenic centre and the other with an R configuration, and possesses approximate local inversion symmetry. The other dimer consists of either R,R or S,S pairs and possesses approximate local twofold symmetry. In the chiral structure, N-H...O hydrogen bonds link the molecules into C(5) chains, with adjacent molecules related by a 21 screw axis. A wide variety of weak interactions, including C-H...O, C-H...Cl, C-H...pi and pi pi stacking interactions, occur in these structures, but there is little conformity between them. PMID- 26243409 TI - N-(6-Methylpyridin-2-yl)mesitylenesulfonamide and acetic acid--a salt, a cocrystal or both? AB - In the solid obtained from N-(6-methylpyridin-2-yl)mesitylenesulfonamide and acetic acid, the constituents interact via two N-H...O hydrogen bonds. The H atom situated in one of these short contacts is disordered over two positions: one of these positions is formally associated with an adduct of the neutral sulfonamide molecule and the neutral acetic acid molecule, and corresponds to a cocrystal, while the alternative site is associated with salt formation between a protonated sulfonamide molecule and deprotonated acetic acid molecule. Site-occupancy refinements and electron densities from difference Fourier maps suggest a trend with temperature, albeit of limited significance; the cocrystal is more relevant at 100 K, whereas the intensity data collected at room temperature match the description as cocrystal and salt equally well. PMID- 26243410 TI - Multiple N-H...NC, C-H...NC and nitrile...pi interactions in 4,4'-bipyridine-1,1' diium bis(1,1,3,3-tetracyano-2-ethoxypropenide): structure determination and DFT calculations of anion...pi cation interaction energies. AB - Polynitrile anions are important in both coordination chemistry and molecular materials chemistry, and are interesting for their extensive electronic delocalization. The title compound crystallizes with two symmetry-independent half 4,4'-bipyridine-1,1'-diium (bpyH2(2+)) cations and two symmetry-independent 1,1,3,3-tetracyano-2-ethoxypropenide (tcnoet(-)) anions in the asymmetric unit. One of the bpyH2(2+) ions is located on a crystallographic twofold rotation axis (canted pyridine rings) and the other is located on a crystallographic inversion center (coplanar pyridine rings). The ethyl group of one of the tcnoet(-) anions is disordered over two sites with equal populations. The extended structure exhibits two separate N-H...NC hydrogen-bonding motifs, which result in a sheet structure parallel to (010), and weak C-H...NC hydrogen bonds form joined rings. Two types of multicenter CN...pi interactions are observed between the bpyH2(2+) rings and tcnoet(-) anions. An additonal CN...pi interaction between adjacent tcnoet(-) anions is observed. Using density functional theory, the calculated attractive energy between cation and anion pairs in the tcnoet( )...pi(bipyridinediium) interactions were found to be 557 and 612 kJ mol(-1) for coplanar and canted bpyH2(2+) cations, respectively. PMID- 26243411 TI - Anisole at 100 K: the first crystal structure determination. AB - The simplest alkyl aryl ether, anisole (methoxybenzene), C7H8O, is a feedstock chemical and is widely used in the pharmaceutical industry. The structure of anisole at 100 K, as determined by single-crystal X-ray analysis, is reported. A crystal (m.p. 236 K) suitable for X-ray diffraction was obtained from the melt. The title compound crystallizes in the centrosymmetric space group P2(1)/c with two molecules in the asymmetric unit (Z' = 2). Both crystallographically distinct molecules adopt a virtually flat (Cs-symmetric) conformation. The arrangement of the molecules in the solid state appears to be governed by close packing. No face to-face pi-pi stacking of the molecules is observed, but rather edge-to-face interactions result in a herringbone packing motif. PMID- 26243412 TI - Two novel ferrocenyl dipeptide-like compounds generated via the Ugi four component reaction. AB - The Ugi four-component reaction, a powerful method for the synthesis of diverse dipeptide-like derivatives in combinatorial chemistry, was used to synthesize (S) 1'-{N-[1-(anthracen-9-yl)-2-(tert-butylamino)-2-oxoethyl]-N-(4 methoxyphenyl)carbamoyl}ferrocene-1-carboxylic acid dichloromethane disolvate, [Fe(C6H5O2)(C33H31N2O3)].2CH2Cl2, (I), and (S)-2-(anthracen-9-yl)-N-tert-butyl-2 [N-(4-methylphenyl)ferrocenylformamido]acetamide, [Fe(C5H5)(C33H31N2O2)], (II). They adopt broadly similar molecular conformations, with near-eclipsed cyclopentadienyl rings and near-perpendicular amide planes in their dipeptide like chains, one of which is almost coplanar with its attached cyclopentadienyl ring but perpendicular to the aromatic ring bound to the N atom. In the supramolecular structure of (I), a two-dimensional network is constructed based on molecular dimers and a combination of intermolecular O-H...O, N-H...O and C H...O hydrogen bonds, forming R2(2)(11), R2(2)(16), R2(2)(22) and C(9) motifs. These two-dimensional networks are connected by C-H...O and C-H...Cl contacts to create a three-dimensional framework, where one dichloromethane solvent molecule acts as a bridge between two neighbouring networks. In the packing of (II), classical hydrogen bonds are absent and an infinite one-dimensional chain is generated via a combination of C-H...O hydrogen bonds and C-H...pi interactions, producing a C(7) motif. This work describes a simple synthesis and the supramolecuar structures of ferrocenyl dipeptide-like compounds and is significant in the development of redox-active receptors. PMID- 26243413 TI - Synthesis and crystal structures of two coordination polymers and a binuclear cadmium(II) complex containing 3- and 4-aminobenzoate ligands. AB - Due to their wide range of coordination modes and versatile conformations when binding to metal atoms, multicarboxylate ligands are of interest in the design of metal-organic frameworks (MOFs). Three Cd(II) complexes, namely catena poly[diammonium [[chloridocadmium(II)]-di-MU-chlorido-[chloridocadmium(II)] bis(MU-3-aminobenzoato)-kappa(3)N:O,O';kappa(3)O,O':N]], {(NH4)[CdCl2(C7H6NO2)]}n, (I), catena-poly[[[aquacadmium(II)]-bis(MU-4 aminobenzoato)-kappa(3)N:O,O';kappa(3)O,O':N] monohydrate], {[Cd(C7H6NO2)2(H2O)].H2O}n, (II), and di-MU-acetato-kappa(4)O:O'-bis[(4 aminobenzoato-kappa(2)O,O')(2,2'-bipyridine-kappa(2)N,N')cadmium(II)], [Cd2(CH3COO)2(C7H6NO2)2(C10H8N2)2], (III), with different stuctural forms are reported. Complex (I) has a one-dimensional ladder structure, with strong N-H...O and weak N-H...Cl hydrogen bonds linking the cations and anions in the three dimensional supramolecular structure. Complex (II) has a one-dimensional chain structure. Extensive O-H...O and N-H...O hydrogen bonds between the anionic ligands and the solvent water molecules and pi-pi stacking interactions between the centroids of the benzene rings lead to the three-dimensional supramolecular structure. Complex (III) is a binuclear molecule which is extended into a three dimensional supramolecular structure via strong N-H...O and weak C-H...O hydrogen bonds. PMID- 26243414 TI - A new linear bismuth coordination polymer based on 1,10-phenanthroline-2,9 dicarboxylic acid: ionothermal synthesis, crystal structure and fluorescence properties. AB - A new linear bismuth(III) coordination polymer, catena poly[[chloridobismuth(III)]-MU3-1,10-phenanthroline-2,9-dicarboxylato kappa(6)O(2):O(2),N(1),N(10),O(9):O(9)], [Bi(C14H6N2O4)Cl]n, has been obtained by an ionothermal method and characterized by elemental analysis, energy-dispersive X-ray spectroscopy, IR spectroscopy, thermal stability studies and single-crystal X-ray diffraction. The structure is constructed by Bi(C14H6N2O4)Cl fragments in which each Bi(III) centre is seven-coordinated by one Cl atom, four O atoms and two N atoms. The coordination geometry of the Bi(III) cation is distorted pentagonal-bipyramidal (BiO4N2Cl), with one bridging carboxylate O atom and one Cl atom located in the axial positions. The Bi(C14H6N2O4)Cl fragments are further extended into a one-dimensional linear polymeric structure via subsequent but different centres of symmetry (bridging carboxylate O atoms). Neighbouring linear chains are assembled via weak C-H...O and C-H...Cl hydrogen bonds, forming a three-dimensional supramolecular architecture. Intermolecular pi-pi stacking interactions are observed, with centroid-to-centroid distances of 3.678 (4) A, which further stabilize the structure. In addition, the solid-state fluorescence properties of the title coordination polymer were investigated. PMID- 26243415 TI - Syntheses and structures of one CuI-containing coordination polymer and two macrocyclic supramolecular complexes based on flexible 1,3,4-oxadiazole containing ligands. AB - Three coordination complexes with Cu(I) centres have been prepared using the symmetrical flexible organic ligands 1,3-bis{[5-(quinolin-2-yl)-1,3,4-oxadiazol-2 yl]sulfanyl}propane (L1) and 1,4-bis{[5-(quinolin-2-yl)-1,3,4-oxadiazol-2 yl]sulfanyl}butane (L2). Crystallization of L1 with Cu(SO3CF3)2 and of L2 with Cu(BF4)2 and Cu(ClO4)2 in a CH2Cl2/CH3OH mixed-solvent system at room temperature afforded the coordination complexes catena-poly[[copper(I)-MU-1,3-bis{[5 (quinolin-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}propane] methanesulfonate dichloromethane 0.6-solvate], {[Cu(C25H18N6O2S2)](CF3SO3).0.6CH2Cl2}n, (I), bis(MU-1,4-bis{[5-(quinolin-2-yl)-1,3,4-oxadiazol-2 yl]sulfanyl}butane)dicopper(I) bis(tetrafluoridoborate)-dichloromethane-methanol (1/1.5/1), [Cu2(C26H20N6O2S2)2](BF4)2.1.5CH2Cl2.CH3OH, (II), and bis(MU-1,4 bis{[5-(quinolin-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}butane)dicopper(I) bis(perchlorate)-dichloromethane-methanol (1/2/1), [Cu2(C26H20N6O2S2)2](ClO4)2.2CH2Cl2.CH3OH, (III). Under the control of the dumbbell-shaped CF3SO3(-) anion, complex (I) forms a one-dimensional chain and neighbouring chains form a spiral double chain. Under the control of the regular tetrahedron-shaped BF4(-) and ClO4(-) anions, complexes (II) and (III) have been obtained as bimetallic rings, which further interact via pi-pi interactions to form two-dimensional networks. The anions play a decisive role in determining the arrangement of these discrete molecular complexes in the solid state. PMID- 26243416 TI - Monoreduced 1,2-dihydrocorannulene versus the parent corannulene. AB - The monoanion of dihydrogenated corannulene isolated in the form of its potassium salt, namely tris(diglyme-kappa(3)O,O',O'')potassium hexacyclo[11.5.2.0(4,17).0(7,16).0(10,15).0(14,18)]icosa 1,3,5,7(16),8,10(15),11,13,17-nonaenide, [K(C6H14O3)3](C20H12), has been structurally characterized for the first time. The X-ray study confirms the previous NMR spectroscopic prediction that the two H atoms are attached to the same six-membered ring to form 1,2-dihydrocorannulene, thus destroying the aromaticity of only one arene ring of the corannulene core. The direct comparison of (C20H12)(-) with the parent corannulene anion, (C20H10)(-), is provided to illustrate the geometry perturbations caused by rim hydrogenation. PMID- 26243417 TI - Polymorphism of dinitro[tris(2-aminoethyl)amine]cobalt(III) chloride. AB - Three polymorphs of bis(nitrito-kappaN)[tris(2-aminoethyl)amine kappa(4)N,N',N'',N''']cobalt(III) chloride, [Co(NO2)2(C6H18N4)]Cl, have been structurally characterized in the 100-300 K temperature range. Two orthorhombic polymorphs are related by a solid-state enantiotropic order-disorder k2 phase transition at ca 152 K. The third, monoclinic, polymorph crystallizes as a nonmerohedral twin. In the structure of the high-temperature (300 K) orthorhombic polymorph, the Co(III) complex cation resides on a crystallographic mirror plane, whereas the Cl(-) anion occupies a crystallographic twofold axis. In the unit cell of the monoclinic polymorph, the cationic Co(III) complex is in a general position, whose charge is balanced by two halves of two Cl(-) anions, each residing on a crystallographic twofold axis. PMID- 26243418 TI - A new two-dimensional ZnII coordination polymer constructed by a multidentate N heterocyclic ligand and 5-carboxybenzene-1,3-dicarboxylate. AB - In the coordination polymer, poly[[{MU-1-[(1H-benzimidazol-2-yl)methyl]-1H imidazole-kappa(2)N:N'}(MU-5-carboxybenzene-1,3-dicarboxylato kappa(2)O(1):O(3))zinc(II)] dimethylformamide monosolvate pentahydrate], {[Zn(C9H4O6)(C11H10N4)].C3H7NO.5H2O}n, the Zn(II) ion is coordinated by two N atoms from two symmetry-related 1-[(1H-benzimidazol-2-yl)methyl]-1H-imidazole (bmi) ligands and two O atoms from two symmetry-related 5-carboxybenzene-1,3 dicarboxylate (Hbtc(2-)) ligands in a slightly distorted tetrahedral geometry. The Zn(II) ions are bridged by Hbtc(2-) and bmi ligands, leading to a 4-connected two-dimensional network with the topological notation (4(4).6(2)). Adjacent layers are further connected by 12 kinds of hydrogen bonds and also by pi-pi interactions, resulting in a three-dimensional supramolecular architecture in the solid state. PMID- 26243419 TI - Diamondoid framework solid with Sn(OCH3)2-tetrapyridylporphyrin linkers, CuI nodes and [CuICl2]- counter-ions. AB - We report on the synthesis of a new metal-organic framework (MOF) composed of Sn(OCH3)2-tetrakis(pyridin-4-yl)porphyrin linkers, Cu(+) connecting nodes and [CuCl2](-) counter-ions, namely poly[[bis(methanolato-kappaO)[MU5-5,10,15,20 tetrakis(pyridin-4-yl)porphyrin kappa(8)1kappaN(5):1'kappaN(10):1''kappaN(15):1'''kappaN(20):2kappa(4)N(21),N(22) N(23),N(24)]copper(I)tin(II)] dichloridocuprate(I)], [CuSn(C40H24N8)(CH3O)2][CuCl2]. Its crystal structure consists of a single framework coordination polymer of the organic ligand and the Cu(I) ions. The latter are characterized by a tetrahedral coordination geometry [with CN (coordination number) = 4], linking to the pyridyl N-atom sites of four different ligands and imparting to the positively charged polymeric assembly a diamondoid PtS-type topology. Correspondingly, every porphyrin unit is coordinated to four different Cu(I) connectors. The [CuCl2](-) anions occupy the intra-lattice voids, along with disordered molecules of the water crystallization solvent. The asymmetric unit of this structure consists of two halves of the porphyrin scaffold, located on centres of crystallographic inversion, and the Cu(+) and [CuCl2](-) ions. This report provides unique structural evidence for the formation of tetrapyridylporphyrin-based three-dimensional MOFs with a diamondoid architecture that have been observed earlier only on rare occasions. PMID- 26243420 TI - A linear bridging angle in the pyrovanadate group within the crystal structure of Hg2V2Te2O11. AB - The title compound, dimercury(II) divanadium(V) ditellurium(IV) undecaoxide, Hg2V2Te2O11, is a new representative within the family of divalent oxovanadato(V)tellurates(IV). The anionic framework is made up of disphenoidal [TeO4] polyhedra that are linked by corner-sharing to two neighbouring pyrovanadate units, resulting in chains of six-membered rings propagating parallel to [1-10]. The bridging O atom of the pyrovanadate unit is located on an inversion centre, leading to a staggered conformation and a linear V-O-V angle between the two [VO4] tetrahedra. The anionic chains are connected by interjacent six-coordinate Hg(2+) cations into a three-dimensional framework. The 5s(2) lone electron pair of the Te(IV) atom is stereochemically active and protrudes into the free space of the chain links. PMID- 26243421 TI - A two-dimensional anionic CdII polymer constructed through dicyanamide coordination bridges. AB - In the search for potential ferroelectric materials, molecular-based one-, two- and three-dimensional cadmium(II) organic-inorganic compounds have been of interest as they often display solid-solid phase transitions induced by a variation in temperature. A new cadmium dicyanamide complex, poly[4-dimethylamino 1-ethylpyridin-1-ium [tri-MU-dicyanamido-kappa(6)N(1):N(5)-cadmium(II)]], {(C9H15N2)[Cd(C2N3)3]}n, was synthesized by the reaction of 4-dimethylamino-1 ethylpyridin-1-ium bromide, cadmium nitrate tetrahydrate and sodium dicyanamide in aqueous solution. In the crystal structure, each Cd(II) cation is octahedrally coordinated by six terminal N atoms from six anionic dicyanamide (dca) ligands. Neighbouring Cd(II) cations are linked together by dicyanamide bridges to form a two-dimensional coordination polymer. The organic cations are not involved in the formation of the supramolecular network. PMID- 26243422 TI - Three structures of dispirooxindole derivatives generated in situ through a three component one-pot strategy with complete regio- and stereoselectivity. AB - The challenging molecular architecture of spirooxindoles is appealing to chemists because it evokes novel synthetic strategies that address configurational demands and provides platforms for further reaction development. The [3+2] cycloaddition of the carbonyl ylide with arylideneoxindole via a five-membered cyclic transition state gave a novel class of dispirooxindole derivatives, namely tert butyl 4'-(4-bromophenyl)-1''-methyl-2,2''-dioxo-5'-phenyl-4',5' dihydrodispiro[indoline-3,2'-furan-3',3''-indoline]-1-carboxylate, C36H31BrN2O, (Ia), 5'-(4-bromophenyl)-1,1''-dimethyl-4'-phenyl-4',5'-dihydrodispiro[indoline 3,2'-furan-3',3''-indoline]-2,2''-dione, C32H25BrN2O3, (Ib), and tert-butyl 1'' methyl-2,2''-dioxo-4'-phenyl-5'-(p-tolyl)-4',5'-dihydrodispiro[indoline-3,2' furan-3',3''-indoline]-1-carboxylate, C37H34N2O5, (Ic). Crystal structure analyses of these dispirooxindoles revealed the formation of two diastereoisomers selectively and confirmed their relative stereochemistry (SSSR and RRRS). In all three structures, intramolecular C-H...O and pi-pi interactions between oxindole and dihydrofuran rings are the key factors governing the regio- and stereoselectivity, and in the absence of conventional hydrogen bonds, their crystal packings are strengthened by intermolecular C-H...pi interactions. PMID- 26243423 TI - Isostructural organic-inorganic hybrid compounds: triethylcholine tribromidocadmate and triethylcholine tribromidomercurate. AB - In order to search for new anionic architectures and develop useful organic inorganic hybrid materials in halometallate systems, two new crystalline organic inorganic hybrid compounds have been prepared, i.e. catena-poly[triethyl(2 hydroxyethyl)azanium [[bromidocadmate(II)]-di-MU-bromido]], {(C8H20NO)[CdBr3]}n, (1), and catena-poly[triethyl(2-hydroxyethyl)azanium [[bromidomercurate(II)]-di MU-bromido]], {(C8H20NO)[HgBr3]}n, (2), and the structures determined by X-ray diffraction analysis. The compounds are isostructural, crystallizing in the space group P21/n. The metal centres are five-coordinated by bromide anions, giving a slightly distorted trigonal-bipyramidal geometry. The crystal structures consist of one-dimensional edge-sharing chains of MBr5 trigonal bipyramids, between which triethylcholine counter-cations are intercalated. O-H...Br hydrogen-bonding interactions are present between the cations and anions. PMID- 26243424 TI - Unusual hydrogen bonding in L-cysteine hydrogen fluoride. AB - L-Cysteine hydrogen fluoride, or bis(L-cysteinium) difluoride-L-cysteine-hydrogen fluoride (1/1/1), 2C3H8NO2S(+).2F(-).C3H7NO2S.HF or L-Cys(+)(L-Cys...L-Cys(+))F( )(F(-)...H-F), provides the first example of a structure with cations of the 'triglycine sulfate' type, i.e. A(+)(A...A(+)) (where A and A(+) are the zwitterionic and cationic states of an amino acid, respectively), without a doubly charged counter-ion. The salt crystallizes in the monoclinic system with the space group P2(1). The dimeric (L-Cys...L-Cys(+)) cation and the dimeric (F( )...H-F) anion are formed via strong O-H...O or F-H...F hydrogen bonds, respectively, with very short O...O [2.4438 (19) A] and F...F distances [2.2676 (17) A]. The F...F distance is significantly shorter than in solid hydrogen fluoride. Additionally, there is another very short hydrogen bond, of O-H...F type, formed by a L-cysteinium cation and a fluoride ion. The corresponding O...F distance of 2.3412 (19) A seems to be the shortest among O-H...F and F-H...O hydrogen bonds known to date. The single-crystal X-ray diffraction study was complemented by IR spectroscopy. Of special interest was the spectral region of vibrations related to the above-mentioned hydrogen bonds. PMID- 26243425 TI - Dihydrooxazolones and dihydroimidazolones derived from acylglycines: syntheses, molecular structures and supramolecular assembly. AB - Syntheses and structures are described for some alkylidene-substituted dihydrooxazolones and dihydroimidazoles derived from simple acylglycines. A second, triclinic, polymorph of 4-benzylidene-2-(4-methylphenyl)-1,3-oxazol-5(4H) one, C17H13NO2, (I), has been identified and the structure of 2-methyl-4 [(thiophen-2-yl)methylidene]-1,3-oxazol-5(4H)-one, C9H7NO2S, (II), has been rerefined taking into account the orientational disorder of the thienyl group in each of the two independent molecules. The reactions of phenylhydrazine with 2 phenyl-4-[(thiophen-2-yl)methylidene]-1,3-oxazol-5(4H)-one or 2-(4-methylphenyl) 4-[(thiophen-2-yl)methylidene]-1,3-oxazol-5(4H)-one yield, respectively, 3 anilino-2-phenyl-5-[(thiophen-2-yl)methylidene]-3,5-dihydro-4H-imidazol-4-one, C10H15N3OS, (III), and 3-anilino-2-(4-methylphenyl)-5-[(thiophen-2 yl)methylidene]-3,5-dihydro-4H-imidazol-4-one, C21H17N3OS, (IV), which both exhibit orientational disorder in their thienyl groups. The reactions of 2-phenyl 4-[(thiophen-2-yl)methylidene]-1,3-oxazol-5(4H)-one with hydrazine hydrate or with water yield, respectively, N-[3-hydrazinyl-3-oxo-1-(thiophen-2-yl)prop-1-en 2-yl]benzamide and 2-(benzoylamino)-3-(thiophen-2-yl)prop-2-enoic acid, which in turn react, respectively, with thiophene-2-carbaldehyde to form 2-phenyl-5 [(thiophen-2-yl)methylidene]-3-{[(E)-(thiophen-2-yl)methylidene]amino}-3,5 dihydro-4H-imidazol-4-one, C19H13N3OS2, (V), which exhibits orientational disorder in only one of its thienyl groups, and with methanol to give methyl (2Z) 2-(benzoylamino)-3-(thiophen-2-yl)prop-2-enoate, C15H13NO3S, (VI). There are no direction-specific intermolecular interactions in the crystal structure of the triclinic polymorph of (I), but the molecules of (II) are linked by two independent C-H...O hydrogen bonds to form C2(2)(14) chains. Compounds (III) and (IV) both form centrosymmetric R2(2)(10) dimers built from N-H...O hydrogen bonds, while compound (V) forms a centrosymmetric R2(2)(10) dimer built from C H...O hydrogen bonds. In the structure of compound (VI), a combination of N-H...O and C-H...pi(arene) hydrogen bonds links the molecules into sheets. Comparisons are made with some similar compounds. PMID- 26243426 TI - Liver resection for ovarian cancer liver metastases as part of cytoreductive surgery is safe and may bring survival benefit. AB - BACKGROUND: The aim of this study was to evaluate whether hepatic resections of ovarian cancer liver metastases provide a benefit in terms of survival as part of primary, secondary, tertiary, and even quaternary cytoreductive surgery. METHODS: Data of patients submitted to surgery for ovarian cancer liver metastases at Fundeni Clinical Institute between January 2002 and April 2014 were retrospectively reviewed. Liver lesions were classified according to their origin in parenchymal and peritoneal lesions. RESULTS: A total of 31 patients were identified: 11 of them underwent liver resection as part of primary cytoreduction, 15 at secondary cytoreduction, 3 at tertiary cytoreduction, and 2 at the time of quaternary cytoreduction. The survival of patients with primary cytoreduction including liver resection was significantly higher compared with that of patients with secondary cytoreductive surgery including liver resection (15.63 versus 6.63 months, log-rank p=0.057, 90% CI). The median survival of patients with hepatectomy for liver metastases from peritoneal seeding was higher than that of patients with hepatectomy for liver metastases from hematogenous origin (16.08 versus 12.66 months, log-rank p=0.523). CONCLUSIONS: Hepatectomy in ovarian cancer liver metastases is a safe and effective procedure; however, a benefit in terms of survival in favor of peritoneal seeding has been systematically observed. PMID- 26243427 TI - Structural and functional insights into the conductive pili of Geobacter sulfurreducens revealed in molecular dynamics simulations. AB - Geobacter sulfurreducens (GS) electronically connects with extracellular electron acceptors using conductive protein filaments or pili. To gain insights into their role as biological nanowires, we investigated the structural dynamics of the GS pilus in solution via molecular dynamics simulations. In the model, all of the pilin's aromatics clustered as a right-handed helical band along the pilus, maintaining inter-aromatic distances and dimer configurations optimal for multistep hopping. The aromatics were interspersed within the regions of highest negative potential, which influenced the type and configuration of the aromatic contacts and the rates of electron transfer. Small foci of positive potential were also present but were neutralized within uncharged regions, thus minimizing charge trapping. Consistent with the model predictions, mutant strains with reduced aromatic contacts or negative potentials had defects in pili functions such as the reduction of Fe(III) oxides and electrodes. The results therefore support the notion of a pilus fiber evolved to function as an electronic conduit between the cell and extracellular electron acceptors. PMID- 26243428 TI - Driving the Hypoxia-Inducible Pathway in Human Pericytes Promotes Vascular Density in an Exosome-Dependent Manner. AB - OBJECTIVES: The mechanisms involved in activating pericytes, cells that ensheath capillaries, to engage in the formation of new capillaries, angiogenesis, remain unknown. In this study, the hypothesis was tested that pericytes could be stimulated to promote angiogenesis by driving the HIF pathway. METHODS: Pericytes were stimulated with CoCl2 to activate the HIF pathway. Stimulated pericytes were cocultured with endothelial cells in a wound healing assay and in a 3D collagen matrix assay of angiogenesis. A culture system of spinal cord tissue was used to assess microvascular outcomes after treatment with stimulated pericytes. Pharmaceutical inhibition of exosome production was also performed. RESULTS: Treatment with stimulated pericytes resulted in faster wound healing (1.92 +/- 0.18 fold increase, p < 0.05), greater endothelial cord formation (2.9 +/- 0.14 fold increase, p < 0.05) in cell culture assays, and greater vascular density (1.78 +/- 0.23 fold increase, p < 0.05) in spinal cord tissue. Exosome secretion and the physical presence of stimulated pericytes were necessary in the promotion of angiogenic outcomes. CONCLUSIONS: These results elucidate a mechanism that may be exploited to enhance features of angiogenesis in the CNS. PMID- 26243429 TI - CARD9 mediates necrotic smooth muscle cell-induced inflammation in macrophages contributing to neointima formation of vein grafts. AB - AIMS: Inflammation plays an important role in the neointima formation of grafted veins. However, the initiation of inflammation in grafted veins is still unclear. Here, we investigated the role and underlying mechanism of an innate immunity signalling protein, caspase-associated recruitment domain 9 (CARD9) in vein grafts in mice. METHODS AND RESULTS: In early murine vein grafts, we observed robust death of smooth muscle cells (SMCs), which was accompanied by infiltration of macrophages and expression of pro-inflammatory cytokines. Meanwhile, SMC necrosis was associated with the expression of pro-inflammatory cytokines in macrophages in vitro. To explore the mediators of necrotic SMC-induced inflammation in grafted veins from mice, we examined the expression of CARD family proteins and found CARD9 highly expressed in infiltrated macrophages of grafted veins. CARD9-knockout (KO) inhibited necrotic SMC-induced pro inflammatory cytokine expression and NF-kappaB activation. Furthermore, CARD9-KO suppressed necrotic SMC-induced expression of VEGF in macrophages. Finally, CARD9 KO decreased neointima formation of grafted veins in mice. CONCLUSION: The innate immune protein CARD9 in macrophages may mediate necrotic SMC-induced inflammation by activating NF-kappaB and contributed to neointima formation in the vein grafts. PMID- 26243430 TI - Pitx2 impairs calcium handling in a dose-dependent manner by modulating Wnt signalling. AB - AIMS: Atrial fibrillation (AF) is the most common type of arrhythmia in humans, yet the genetic cause of AF remains elusive. Genome-wide association studies (GWASs) have reported risk variants in four distinct genetic loci, and more recently, a meta-GWAS has further implicated six new loci in AF. However, the functional role of these AF GWAS-related genes in AF and their inter-relationship remain elusive. METHODS AND RESULTS: To get further insights into the molecular mechanisms driven by Pitx2, calcium handling and novel AF GWAS-associated gene expression were analysed in two distinct Pitx2 loss-of-function models with distinct basal electrophysiological defects; a novel Pitx2 conditional mouse line, Sox2CrePitx2, and our previously reported atrial-specific NppaCrePitx2 line. Molecular analyses of the left atrial appendage in NppaCrePitx2(+/-) and NppaCrePitx2(-/-) adult mice demonstrate that AF GWAS-associated genes such as Zfhx3, Kcnn3, and Wnt8a are severely impaired but not Cav1, Synpo2l, nor Prrx1. In addition, multiple calcium-handling genes such as Atp2a2, Casq2, and Plb are severely altered in atrial-specific NppaCrePitx2 mice in a dose-dependent manner. Functional assessment of calcium homeostasis further underscores these findings. In addition, multiple AF-related microRNAs are also impaired. In vitro over expression of Wnt8, but not Zfhx3, impairs calcium handling and modulates microRNA expression signature identified in Pitx2 loss-of-function models. CONCLUSION: Our data demonstrate a dose-dependent relation between Pitx2 expression and the expression of AF susceptibility genes, calcium handling, and microRNAs and identify a complex regulatory network orchestrated by Pitx2 with large impact on atrial arrhythmogenesis susceptibility. PMID- 26243432 TI - Erratum: Electroporation enables the efficient mRNA delivery into the mouse zygotes and facilitates CRISPR/Cas9-based genome editing. PMID- 26243431 TI - Diagnostic accuracy of the Thessaly test, standardised clinical history and other clinical examination tests (Apley's, McMurray's and joint line tenderness) for meniscal tears in comparison with magnetic resonance imaging diagnosis. AB - BACKGROUND: Reliable non-invasive diagnosis of meniscal tears is difficult. Magnetic resonance imaging (MRI) is often used but is expensive and incidental findings are problematic. There are a number of physical examination tests for the diagnosis of meniscal tears that are simple, cheap and non-invasive. OBJECTIVES: To determine the diagnostic accuracy of the Thessaly test and to determine if the Thessaly test (alone or in combination with other physical tests) can obviate the need for further investigation by MRI or arthroscopy for patients with a suspected meniscal tear. DESIGN: Single-centre prospective diagnostic accuracy study. SETTING: Although the study was performed in a secondary care setting, it was designed to replicate the results that would have been achieved in a primary care setting. PARTICIPANTS: Two cohorts of patients were recruited: patients with knee pathology (n = 292) and a control cohort with no knee pathology (n = 75). MAIN OUTCOME MEASURES: Sensitivity, specificity and diagnostic accuracy of the Thessaly test in determining the presence of meniscal tears. METHODS: Participants were assessed by both a primary care clinician and a musculoskeletal clinician. Both clinicians performed the Thessaly test, McMurray's test, Apley's test, joint line tenderness test and took a standardised clinical history from the patient. RESULTS: The Thessaly test had a sensitivity of 0.66, a specificity of 0.39 and a diagnostic accuracy of 54% when utilised by primary care clinicians. This compared with a sensitivity of 0.62, a specificity of 0.55 and diagnostic accuracy of 59% when used by musculoskeletal clinicians. The diagnostics accuracy of the other tests when used by primary care clinicians was 54% for McMurray's test, 53% for Apley's test, 54% for the joint line tenderness test and 55% for clinical history. For primary care clinicians, age and past history of osteoarthritis were both significant predictors of MRI diagnosis of meniscal tears. For musculoskeletal clinicians age and a positive diagnosis of meniscal tears on clinical history taking were significant predictors of MRI diagnosis. No physical tests were significant predictors of MRI diagnosis in our multivariate models. The specificity of MRI diagnosis was tested in subgroup of patients who went on to have a knee arthroscopy and was found to be low [0.53 (95% confidence interval 0.28 to 0.77)], although the sensitivity was 1.0. CONCLUSIONS: The Thessaly test was no better at diagnosing meniscal tears than other established physical tests. The sensitivity, specificity and diagnostic accuracy of all physical tests was too low to be of routine clinical value as an alternative to MRI. Caution needs to be exercised in the indiscriminate use of MRI scanning in the identification of meniscal tears in the diagnosis of the painful knee, due to the low specificity seen in the presence of concomitant knee pathology. Further research is required to determine the true diagnostic accuracy and cost-effectiveness of MRI for the detection of meniscal tears. TRIAL REGISTRATION: Current Controlled Trial ISRCTN43527822. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 26243433 TI - Neurofibromatosis type 1 (NF1) with transient paraplegia after a surgical procedure in the prone position. PMID- 26243434 TI - "Sundowning" as a biological phenomenon: current understandings and future directions: an update. AB - The clinical phenomenon of early evening disruptive behavior also called "Sundowning" in elderly patients has been largely reported in the medical literature without a consistent diagnosis and criteria to define this phenomenon. The current understandings of sundowning are incomplete and current treatment strategies have relied heavily on use of antipsychotic medications, despite side effects and limited evidence to justify their use. A comprehensive understanding of the biogenesis of this phenomenon and mechanistic changes from oxidative pathways may provide novel information on completing the sundowning puzzle. Future studies could examine the utility of natural factors in reviving neuronal energy loss and altering the oxidative pathways might be safe and additional options in development of treatment models for this behavioral disorder. PMID- 26243435 TI - Present and future of ribonucleic acid interference. PMID- 26243436 TI - Optic neuropathy secondary to a sphenoid-ethmoidal mucocele: Case report. AB - CASE REPORT: The case is presented of a 51-year old male patient with a history of blunt trauma in the frontal region and a one-year history of vision loss, proptosis and paresis of the lateral rectus muscle of the right eye. A right ethmoid and bilateral sphenoid mucocele was diagnosed. Drainage was performed using an external and endoscopic approach with improvement in symptoms without recurrence at 10 months. DISCUSSION: Sphenoid mucoceles represent 1% of all mucoceles and may present with different clinical manifestations. Surgical excision is the treatment of choice, and early intervention is indicated to prevent complications. PMID- 26243437 TI - Ligandless Palladium-Catalyzed Regioselective Direct C-H Arylation of Imidazo[1,2 a]imidazole Derivatives. AB - Herein a novel access to functionalizable 6-substituted imidazo[1,2-a]imidazole scaffolds is described. The reactivity of this heterobicyclic unit toward direct C-H arylation was studied, and conditions allowing regioselective arylation at position 3 were successfully developed. The practicability of this method is manifested by the ligandless conditions and low catalyst loading. The strategy is functional group tolerant and provides rapid access to a large variety of 3,6 di(hetero)arylated imidazo[1,2-a]imidazole derivatives. A second arylation at position 2 was then carried out, and a library of diversified 2,3,6 tri(hetero)arylated imidazo[1,2-a]imidazoles was generated in good yields. A one pot, two-step procedure was finally developed. PMID- 26243438 TI - Clinical spectrum of Hashimoto encephalopathy: report of 5 cases. PMID- 26243439 TI - Studying Human Brain Inflammation in Leptomeningeal and Choroid Plexus Explant Cultures. AB - The meninges (dura, pia and arachnoid) are critical membranes encasing and protecting the brain within the skull. The leptomeninges, which comprise the arachnoid and pia, have many functions beyond brain protection including roles in neurogenesis, fibrotic scar formation and brain inflammation. Similarly, the choroid plexus plays important roles in normal brain function but is also involved in brain inflammation. We have begun studying the role of human leptomeninges and choroid plexus in brain inflammation and leptomeninges in fibrotic scar formation, using human brain derived explant cultures. To study the composition of the cells generated in these explants we undertook immunocytochemical characterisation. Cells, mainly pericytes and meningeal macrophages, emerge from leptomeningeal explants (LME's) and respond to inflammatory mediators by producing inflammatory molecules. LME-derived cells also respond to mechanical injury and cytokines, providing an in vitro human brain model of fibrotic scar formation. Choroid plexus explants (CPE's) generate epithelial cells, pericytes and microglia/macrophages. CPE-derived cells also respond to inflammatory mediators. LME and CPE explants survive and generate cells for many months in vitro and provide a remarkable opportunity to study basic mechanisms of human brain inflammation and fibrosis and to test human active anti-inflammatory and anti-scarring treatments. PMID- 26243440 TI - Implementation of fuzzy-sliding mode based control of a grid connected photovoltaic system. AB - The present work describes an optimal operation of a small scale photovoltaic system connected to a micro-grid, based on both sliding mode and fuzzy logic control. Real time implementation is done through a dSPACE 1104 single board, controlling a boost chopper on the PV array side and a voltage source inverter (VSI) on the grid side. The sliding mode controller tracks permanently the maximum power of the PV array regardless of atmospheric condition variations, while The fuzzy logic controller (FLC) regulates the DC-link voltage, and ensures via current control of the VSI a quasi-total transit of the extracted PV power to the grid under a unity power factor operation. Simulation results, carried out via Matlab-Simulink package were approved through experiment, showing the effectiveness of the proposed control techniques. PMID- 26243441 TI - Neoadjuvant clinical trial designs: Challenges of the genomic era. AB - The modern era has brought huge changes in the way we approach breast cancer clinical trials. The neoadjuvant, or preoperative, approach is increasingly popular because of several advantages over traditional adjuvant trials in terms of size, speed, capacity for embedded correlative science, and design flexibility. True neoadjuvant trials test the administration of a new drug or regimen preoperatively, with clinical or pathologic evaluation post-therapy at the time of surgery serving as the primary endpoint. The most commonly used and validated neoadjuvant endpoint is pathologic complete response, or pCR, which is itself not clinically meaningful but has been amply demonstrated to be prognostic of both disease-free and overall survival. However, it has also become clear that the association of pCR to outcome is not clean and that we lack a formula for pCR augmentation that will translate into significant improvements in clinically meaningful endpoints such as survival. Breast cancer is well recognized to be comprised of multiple biologically distinct molecular subsets, which has driven the move to more economical approaches such as neoadjuvant clinical trials, but also produces considerable confounding since we lack clinical assays that accurately reflect underlying biology. In this sense, the challenge for the clinical research community is multifaceted; we need to delineate the breast cancer biologic entities that we want to target, develop and validate the assays to identify those entities, and test the targeted drugs in the appropriate setting. PMID- 26243442 TI - Segmented golden ratio radial reordering with variable temporal resolution for dynamic cardiac MRI. AB - PURPOSE: Golden ratio (GR) radial reordering allows for retrospective choice of temporal resolution by providing a near-uniform k-space sampling within any reconstruction window. However, when applying GR to electrocardiogram (ECG)-gated cardiac imaging, the k-space coverage may not be as uniform because a single reconstruction window is broken into several temporally isolated ones. The goal of this study was to investigate the image artifacts caused by applying GR to ECG gated cardiac imaging and to propose a segmented GR method to address this issue. METHODS: Computer simulation and phantom experiments were used to evaluate the image artifacts resulting from three k-space sampling patterns (ie, uniform radial, conventional GR, and segmented GR). Two- and three-dimensional cardiac cine images were acquired in seven healthy subjects. Imaging artifacts due to k space sampling nonuniformity were graded on a 5-point scale by an experienced cardiac imaging reader. RESULTS: Segmented GR provides more uniform k-space sampling that is independent of heart-rate variation than conventional GR. Cardiac cine images using segmented GR have significantly higher and more reliable image quality than conventional GR. CONCLUSION: Segmented GR successfully addresses the nonuniform sampling that occurs with combining conventional GR with ECG gating. This technique can potentially be applied to any ECG-gated cardiac imaging application to allow for retrospective selection of a reconstruction window. Magn Reson Med 76:94-103, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26243443 TI - Levonorgestrel-releasing intrauterine system and the risk of breast cancer: A nationwide cohort study. AB - BACKGROUND: Prolonged steroid hormone therapy increases the risk of breast cancer, especially the risk of lobular cancer, but the effect of the levonorgestrel-releasing intrauterine system (LNG-IUS) use is controversial. In this study we aimed to test the hypothesis that risk for lobular breast cancer is elevated among LNG-IUS users. MATERIAL AND METHODS: We identified from the national Medical Reimbursement Registry of Finland the women aged 30-49 who had used LNG-IUS for the treatment or prevention of menorrhagia in 1994-2007, and from the Finnish Cancer Registry breast cancers diagnosed before the age of 55 and by the end of 2012. RESULTS: A total of 2015 women had breast cancer diagnosed in a cohort of 93 843 LNG-IUS users during follow-up consisting of 1 032 767 women-years. The LNG-IUS users had an increased risk for both ductal breast cancer [standardized incidence ratio (SIR) 1.20, 95% confidence interval (CI) 1.14-1.25] and for lobular breast cancer (SIR 1.33, 95% CI 1.20-1.46), as compared with the general female population. The highest risk was found in LNG IUS users who purchased the device at least twice, whose SIR for lobular cancer was 1.73 (95% CI 1.37-2.15). CONCLUSIONS: The results imply that intrauterine administration of levonorgestrel is not only related to an excess risk of lobular breast cancer but also, in contrary to previous assumptions, to an excess risk of ductal breast cancer. PMID- 26243444 TI - A new phenyldilactone from Lespedeza cuneata. AB - A new phenyldilactone, maysedilactone B (1), together with twenty known compounds, were isolated from the aerial parts of Lespedeza cuneata. The structural elucidation of the isolated compounds was primarily based on HR-ESI MS, IR and 1D and 2D NMR analyses. Compounds 1-8 and 15-21 were tested for cytotoxicity against four human tumor cell lines (A549, HCT116, SKOV3, and HepG2) using MTT method in vitro, while no significant activities were observed for the evaluated compounds. PMID- 26243445 TI - Detoxification of selenite to form selenocyanate in mammalian cells. AB - When human hepatoma HepG2 cells were exposed to sodium selenite, an unknown selenium metabolite was detected in the cytosolic fraction by HPLC-inductively coupled plasma mass spectrometry (ICP-MS). The unknown selenium metabolite was also detected in the mixture of HepG2 homogenate and sodium selenite in the presence of exogenous glutathione (GSH). The unknown selenium metabolite was identified as selenocyanate by electrospray ionization mass spectrometry (ESI-MS) and ESI quadrupole time-of-flight mass spectrometry (ESI-Q-TOF-MS). Because exogenous cyanide increased the amount of selenocyanate in the mixture, selenocyanate seemed to be formed by the reaction between selenide or its equivalent, the product of the reduction of selenite, and endogenous cyanide. Rhodanase, an enzyme involved in thiocyanate synthesis, was not required for the formation of selenocyanate. Selenocyanate was less toxic to HepG2 cells than selenite or cyanide, suggesting that it was formed to reduce the toxicity of selenite. However, selenocyanate could be assimilated into selenoproteins and selenometabolites in rats in the same manner as selenite. Consequently, selenite was metabolized to selenocyanate to temporarily ameliorate its toxicity, and selenocyanate acted as an intrinsic selenium pool in cultured cells exposed to surplus selenite. PMID- 26243446 TI - Ag(+)-induced reverse vesicle to helical fiber transformation in a self-assembly by adjusting the keto-enol equilibrium of a chiral salicylideneaniline. AB - A new chiral amphiphilic salicylideneaniline bearing a terminal pyridine was synthesized. It formed reverse vesicles in toluene. The addition of Ag(+), however, reversibly transforms these reverse vesicles into left-handed nanohelices accompanied by spontaneous gel formation at room temperature. PMID- 26243448 TI - Proceedings of the RAMI Section of Ophthalmology Meetings2005-2015. PMID- 26243447 TI - Racial/ethnic differences in lifestyle-related factors and prostate cancer risk: the Multiethnic Cohort Study. AB - PURPOSE: Older age, African ancestry, and family history of prostate cancer are well-established risk factors for prostate cancer, and all are non-modifiable. Various lifestyle factors have been examined in relation to prostate cancer risk, including diet, obesity, and physical activity; however, none of them has been consistently related to risk. In the Multiethnic Cohort Study, we investigated whether lifestyle-related factors are associated with prostate cancer risk and whether such factors explain the racial/ethnic differences in risk. METHODS: During a mean follow-up of 13.9 years, 7,115 incident cases were identified among 75,216 white, African-American, Native Hawaiian, Japanese American, and Latino men. Cox proportional hazards models were used to calculate relative risks (RRs) and 95 % confidence intervals (95 % CIs) for prostate cancer. RESULTS: Among selected lifestyle-related factors including body mass index, height, education, physical activity, and intakes of alcohol, calcium, legumes, lycopene, and selenium, only smoking (RR for current (>=20 cigarettes/day) vs. never smoking = 0.72; 95 % CI 0.63-0.83) and history of diabetes (RR for yes vs. no = 0.78; 95 % CI 0.72-0.85) were significantly associated with prostate cancer risk. Compared to whites, the risk of incident prostate cancer was twofold higher in African Americans and 16 % higher in Latinos. Additional adjustment for a history of PSA testing did not change the results. CONCLUSIONS: The findings suggest that racial/ethnic differences in prostate cancer risk are not explained by the lifestyle factors examined and that underlying genetic factors may be involved. PMID- 26243449 TI - Regulatory Considerations in the Design and Manufacturing of Implantable 3D Printed Medical Devices. AB - Three-dimensional (3D) printing, or additive manufacturing, technology has rapidly penetrated the medical device industry over the past several years, and innovative groups have harnessed it to create devices with unique composition, structure, and customizability. These distinctive capabilities afforded by 3D printing have introduced new regulatory challenges. The customizability of 3D printed devices introduces new complexities when drafting a design control model for FDA consideration of market approval. The customizability and unique build processes of 3D-printed medical devices pose unique challenges in meeting regulatory standards related to the manufacturing quality assurance. Consistent material powder properties and optimal printing parameters such as build orientation and laser power must be addressed and communicated to the FDA to ensure a quality build. Postprinting considerations unique to 3D-printed devices, such as cleaning, finishing and sterilization are also discussed. In this manuscript we illustrate how such regulatory hurdles can be navigated by discussing our experience with our group's 3D-printed bioresorbable implantable device. PMID- 26243450 TI - Shelter crowding and increased incidence of acute respiratory infection in evacuees following the Great Eastern Japan Earthquake and tsunami. AB - Although outbreaks of acute respiratory infection (ARI) at shelters are hypothesized to be associated with shelter crowding, no studies have examined this relationship. We conducted a retrospective study by reviewing medical records of evacuees presenting to one of the 37 clinics at the shelters in Ishinomaki city, Japan, during the 3-week period after the Great Eastern Japan Earthquake and tsunami in 2011. On the basis of a locally weighted scatter-plot smoothing technique, we categorized 37 shelters into crowded (mean space <5.5 m2/per person) and non-crowded (?5.5 m2) shelters. Outcomes of interest were the cumulative and daily incidence rate of ARI/10 000 evacuees at each shelter. We found that the crowded shelters had a higher median cumulative incidence rate of ARI [5.4/10 000 person-days, interquartile range (IQR) 0-24.6, P = 0.04] compared to the non-crowded shelters (3.5/10 000 person-days, IQR 0-8.7) using Mann Whitney U test. Similarly, the crowded shelters had an increased daily incidence rate of ARI of 19.1/10 000 person-days (95% confidence interval 5.9-32.4, P < 0.01) compared to the non-crowded shelters using quasi-least squares method. In sum, shelter crowding was associated with an increased incidence rate of ARI after the natural disaster. PMID- 26243451 TI - Late surgery for acetabular fractures in a Chinese level I trauma centre: surgical experience and outcomes. AB - PURPOSE: Delayed surgical management of acetabular fractures, often necessary due to life-threatening concomitant injuries, is a great challenge because delays may potentially increase complications and decrease outcomes. We report clinical outcomes of 61 acetabular fractures treated by delayed open reduction and internal fixation (ORIF) with an injury-to-surgery interval (ISI) of 22-399 days. METHODS: Operations were performed between April 2001 and December 2008. There were 61 cases (42 men 19 women), with an average age of 38 years. All patients were followed for an average of 82 months. Demographic data, fracture pattern, ISI, concomitant injuries, surgical approach, complications and clinical outcomes were recorded and analysed. There were 16 simple fractures (26.2%) and 45 associated fractures (73.8%). Matta criteria were used to evaluate reduction quality. The Merle d'Aubigne and Postel scoring system was employed to assess post-operative functionality. RESULTS: Anatomical reduction was achieved in 45 cases (73.8%). The clinical result was excellent in 38 cases, good in 13, fair in six and poor in four. Osteonecrosis of the femoral head was observed in three cases, and heterotopic ossification was found in 28 cases. Four patients had transient palsy of the sciatic nerve. CONCLUSIONS: ORIF for fresh acetabular fractures might yield a better prognosis; however, for delayed acetabular fractures, clinical outcomes are also predictable when sophisticated surgical techniques are employed. Our results indicate that delayed ORIF could yield satisfactory clinical outcomes in the majority of patients with acetabular fractures. PMID- 26243453 TI - A chronobiological perspective on ketamine's antidepressant efficacy. PMID- 26243454 TI - Erratum to: a subanesthetic dose of ketamine in the Rhesus monkey reduces the occurrence of anticipatory saccades. PMID- 26243452 TI - Novel mechanism of gene transfection by low-energy shock wave. AB - Extracorporeal shock wave (SW) therapy has been studied in the transfection of naked nucleic acids into various cell lines through the process of sonoporation, a process that affects the permeation of cell membranes, which can be an effect of cavitation. In this study, siRNAs were efficiently transfected into primary cultured cells and mouse tumor tissue via SW treatment. Furthermore SW-induced siRNA transfection was not mediated by SW-induced sonoporation, but by microparticles (MPs) secreted from the cells. Interestingly, the transfection effect of the siRNAs was transferable through the secreted MPs from human umbilical vein endothelial cell (HUVEC) culture medium after treatment with SW, into HUVECs in another culture plate without SW treatment. In this study, we suggest for the first time a mechanism of gene transfection induced by low-energy SW through secreted MPs, and show that it is an efficient physical gene transfection method in vitro and represents a safe therapeutic strategy for site specific gene delivery in vivo. PMID- 26243455 TI - Patient reporting pain intensity immediately after surgery can be associated with underlying depression in women with breast cancer. AB - OBJECTIVE: The aims of this study were to determine the prevalence of severe, definite depression symptoms, as measured using the Center for Epidemiological Studies Depression Scale (CES-D), and the association between high CES-D scores (i.e., >=25) and sociodemographic and perioperative factors during perioperative period. METHODS: Among 1690 consecutive breast cancer patients who were admitted for definitive breast surgery during the study period, 1499 patients were included in this study. Patients with a past medical history of psychiatric medication or support, a plan for elective surgery due to locoregional recurrence, or any metastatic disease were excluded. The CES-D score was checked 1 day before definitive surgeries. The sociodemographic data and perioperative data were analyzed. RESULTS: The mean CES-D score was 18.5, with 24.1% (362/1499) and 56.7% (850/1499) having high CES-D scores of >=25 and >=16, respectively. Multivariate analysis revealed that the number of family members with any malignancy (>=2 vs. 0), sedative medication (yes vs. no), and postoperative numeric rating scale scores (persistent, severe pain vs. stably mild pain) were significantly associated factors for severe, definite depression symptoms [CES-D score of >=25: adjusted odds ratio (OR) = 1.56, 95% confidence interval (CI) = 1.10-2.21, p = 0.013; adjusted OR = 1.65, 95% CI = 1.00-2.71, p = 0.048; and adjusted OR = 2.14, 95% CI = 1.15-3.95, p = 0.016, respectively]. CONCLUSION: Depression may increase the intensity of postoperative acute pain. Self-reporting of persistent postoperative pain intensity is potentially useful in detecting hidden depression symptoms in breast cancer patients during the perioperative period. PMID- 26243456 TI - Influence of mechanical compression on human periodontal ligament fibroblasts and osteoblasts. AB - OBJECTIVES: The aim of this study was to investigate and compare the changes in human periodontal ligament fibroblasts (HPdLFs) and osteoblasts (HOBs) after the application of compressive force (CF) at two different strengths in vitro. MATERIALS AND METHODS: HPdLF and HOB were exposed to CF with various strengths (5 and 10 %) using a Flexercell Compression Unit for 12 h in vitro. Viability was detected via 3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide (MTT) and apoptosis rate by transferase dUTP nick end labeling (TUNEL) assay. The gene expression of alkaline phosphatase (ALP), osteocalcin (OCN), osteoprotegerin (OPG), and receptor activator of NF-kappaB ligand (RANKL) was analyzed using reverse transcriptase polymerase chain reaction (RT-PCR). Osteopontin (OPN), matrix metalloproteinase-8 (MMP-8), and tissue inhibition of metalloproteinase-1 (TIMP-1) were quantified by an ELISA. RESULTS: Ten percent CF decreased viability, particularly in HOBs, but did not induce increased apoptosis. ALP gene expression increased the most after 5 % CF in HPdLFs and after 10 % CF in HOB. OCN was not affected by CF in either cell line. The highest RANKL/OPG ratio was measured after 5 % CF in both cell lines. OPN was upregulated in HOB by 5 %. HPdLFs showed an upregulation of MMP-8-synthesis and an increased MMP-8/TIMP-1 ratio. CONCLUSIONS: HOBs have a greater effect on bone remodeling through the upregulation of OPN, whereas HPdLFs facilitate orthodontic tooth movement by influencing the extracellular matrix via the MMP-8/TIMP-1 ratio. CLINICAL RELEVANCE: High CF in orthodontics should be avoided to prevent tissue damage, whereas moderate CF enables active tissue remodeling and tooth movement. PMID- 26243457 TI - A temporary filling material during endodontic treatment may cause tooth fractures in two-surface class II cavities in vitro. AB - OBJECTIVES: To investigate the effect of a zinc oxide/zinc sulphate-based cement as a temporary filling material during root canal treatment on the occurrence of cracks within the filling material or the tooth. MATERIALS AND METHODS: Root canals of 122 extracted human molars were prepared using ProTaper instruments. Standardized occlusal-distal cavities were prepared. After placing calcium hydroxide into the root canals, the teeth were divided randomly into four groups containing 33 specimens each. In the Coltosol group, the cavity was completely filled with Coltosol(r) F. In the Coltosol-Clearfil group, a 2-mm layer of Coltosol(r) F was placed into the apical part of the pulp chamber, and in the Clearfil group, a foam pellet was placed into the coronal pulp chamber. The remaining cavities were filled with ClearfilTM. In the control group, the cavities were not restored. The teeth were stored at 37 degrees C for 14 days and examined every 24 h under a stereomicroscope. RESULTS: Fractures of the filling and/or the tooth were only observed in the Coltosol group. All Coltosol(r) F restorations had cracks after 24 h. Tooth fractures were found in 25 (76 %) teeth. Among these teeth, 21 (84 %) had crown fractures, four (16 %) had root-crown fractures. All root-crown fractures were vertical. CONCLUSION: Coltosol(r) F when used alone led to tooth fractures in two-surface class II cavities in teeth undergoing root canal treatment. CLINICAL RELEVANCE: Coltosol(r) F solely used as restorative material may lead to tooth fractures in two-surface class II cavities. PMID- 26243459 TI - Heterobimetallic complexes with highly flexible 1,1' bis(phospholanoalkyl)ferrocene ligands. AB - The two highly flexible ligands 1,1'-bis(4-phospholanobutyl)ferrocene (5a) and 1,1'-bis(5-phospholanopentyl)ferrocene (5b) reacted with [PtCl2(cod)] (cod = 1,5 cyclooctadiene), [AuCl(tht)] (tht = tetrahydrothiophene) and [{RhCl(CO)2}2] to give the respective chelate complexes cis-[PtCl2(5a,b-kappa(2)P,P')] (7a,b), [AuCl(5a,b-kappa(2)P,P')] (8a,b) and trans-[RhCl(CO)(5b-kappa(2)P,P')] (9b). Treatment of 5a,b with selenium gave the corresponding selenides 6a,b. All compounds have been fully characterised by NMR ((1)H, (13)C, (31)P) and IR spectroscopy and mass spectrometry. In addition, crystal structures of 6a, 7b, 8a,b and 9b were determined by X-ray crystallography. Furthermore, the rhodium catalysed hydroformylation of 1-octene has been studied with ligand 5b. PMID- 26243458 TI - CITED4 gene silencing in colorectal cancer cells modulates adherens/tight junction gene expression and reduces cell proliferation. AB - PURPOSE: CITED4 is one member of a family of transcriptional cofactors, several of which are deregulated in a variety of tumors, including colorectal cancer (CRC). We modulated CITED4 expression, in vitro, and analyzed the associated phenotypic and gene expression changes. METHODS: CITED4-overexpressing and shRNA mediated knockdown cell lines and control cell lines were established in the CRC cell line SW480. The cells were analyzed for changes in proliferation, apoptosis/cell cycle, migration, invasion, colony formation and adhesion. mRNA expression changes were determined by microarray and pathway analysis, and several deregulated genes were validated by qRT-PCR and Western blotting. Based on results obtained from these studies, the status of the actin cytoskeleton was evaluated by phalloidin/vinculin staining. RESULTS: Phenotypically, the CITED4 overexpressing cell line showed only moderate changes in adhesion. Microarray analysis identified several deregulated genes, including several G protein coupled receptors. Phenotypic analysis of the CITED4 shRNA knockdown cell line demonstrated decreased cell proliferation and G2 cell cycle blockage. Microarray analysis identified many deregulated genes, and pathway analysis discovered genes linked to actin-associated adherens junctions/tight junctions (claudin-4, claudin 7, ezrin, MET, beta-catenin). Phenotypically, no morphological changes of the actin cytoskeleton were seen. CONCLUSIONS: Upregulation of CITED4 in SW480 resulted in no obvious phenotype. CITED4 shRNA-mediated knockdown led to decreased cellular proliferation and modulation of a large number of genes, including the c-MET tyrosine kinase and several actin-associated adherens junctions/tight junction genes. PMID- 26243460 TI - Kinin-B1 and B2 receptor activity in proliferation and neural phenotype determination of mouse embryonic stem cells. AB - The kinins bradykinin and des-arg(9) -bradykinin cleaved from kininogen precursors by kallikreins exert their biological actions by stimulating kinin-B2 and B1 receptors, respectively. In vitro models of neural differentiation such as P19 embryonal carcinoma cells and neural progenitor cells have suggested the involvement of B2 receptors in neural differentiation and phenotype determination; however, the involvement of B1 receptors in these processes has not been established. Here, we show that B1 and B2 receptors are differentially expressed in mouse embryonic E14Tg2A stem cells undergoing neural differentiation. Proliferation and differentiation assays, performed in the presence of receptor subtype-selective agonists and antagonists, revealed that B1 receptor activity is required for the proliferation of embryonic and differentiating cells as well as for neuronal maturation at later stages of differentiation, while the B2 receptor acts on neural phenotype choice, promoting neurogenesis over gliogenesis. Besides the elucidation of bradykinin functions in an in vitro model reflecting early embryogenesis and neurogenesis, this study contributes to the understanding of B1 receptor functions in this process. PMID- 26243461 TI - Child poisonings with methadone in France: A 6-year prospective national survey since the availability of capsules in 2008. AB - BACKGROUND: Methadone for opiate substitution was available only in syrup formulation prior to 2008. In 2007, the French Health Authorities made solid forms available. A national survey was performed in order to evaluate the modification of child poisonings induced by such a new pharmaceutical formulation. METHODS: A prospective study was set up (April 15, 2008 to April 15, 2014) with the analysis of cases of unintentional ingestion of methadone by patients under 18 years old and managed by the 10 French poison control centers at the national level. As soon as a new pediatric exposure was recorded in the informatics data bank of the Poison Centers, a telephone survey was performed by the Marseilles' Poison Center to obtain the evolution and all the necessary details. RESULTS: 87 cases of child poisonings with the 2 forms were reviewed (syrup, 56 patients; capsules, 31 patients). Comparison shows that patients were similar for both formulations (no significant difference concerning age [median 2 years], sex ratio [M/F 0.85], previous history, and ingested quantities of methadone). There was a similar severity profile with both formulations proving that methadone can lead to lethal child intoxications (1 death with capsules and 4 with syrup). The relative risk of pediatric accidents is also the same with 2 formulations, leading the health authorities, in collaboration with laboratories, to design and distribute flyers. The aim was to inform patients who are also parents about the high danger risk of their treatment for children, whatever the formulation of methadone present in the house. DISCUSSION: The results of this survey were similar to those of another national study by the French Poison Centers concerning adult suicide attempts with methadone. Both prospective studies led to the conclusion that methadone must be considered as a dangerous molecule for patients and their families. The recent availability of a solid formulation in France did not change the profile of poisonings with this opiate substitute treatment. PMID- 26243462 TI - Alberta's Caring for Diabetes Project: Engaged Scholarship Informing Quality Improvement. PMID- 26243463 TI - The Alberta's Caring for Diabetes (ABCD) Study: Rationale, Design and Baseline Characteristics of a Prospective Cohort of Adults with Type 2 Diabetes. AB - OBJECTIVE: To better understand the factors that affect care and outcomes in patients with type 2 diabetes, we developed the prospective Alberta's Caring for Diabetes (ABCD) cohort to collect, monitor and analyze data concerning several sociodemographic, behavioural, psychosocial, clinical and physiological factors that might influence diabetes care and outcomes. METHODS: We recruited 2040 individuals with type 2 diabetes through primary care networks, diabetes clinics and public advertisements. Data are being collected through self-administered surveys, including standardized measures of health status and self-care behaviours, and will eventually be linked to laboratory and administrative healthcare data and other novel databases. RESULTS: The average age of respondents was 64.4 years (SD=10.7); 45% were female, and 91% were white, with average duration of diabetes of 12 years (SD=10.0). The majority (76%) were physically inactive, and 10% were smokers. Most (88%) reported 2 or more chronic conditions in addition to diabetes, and 18% screened positively for depressive symptoms. The majority (92%) consented to future linkage with administrative data. Based on the literature and comparison with other surveys, the cohort appeared to fairly represent the general Alberta population with diabetes. CONCLUSIONS: The ABCD cohort will serve as the basis for explorations of the multidimensional and dynamic nature of diabetes care and complications. These data will contribute to broader scientific literature and will also help to identify local benchmarks and targets for intervention strategies, helping to guide policies and resource allocation related to the care and management of patients with type 2 diabetes in Alberta, Canada. PMID- 26243464 TI - Diabetic Foot Disease, Self-Care and Clinical Monitoring in Adults with Type 2 Diabetes: The Alberta's Caring for Diabetes (ABCD) Cohort Study. AB - OBJECTIVE: To examine the prevalence and predictors of foot disease, self-care and clinical monitoring in adults with type 2 diabetes in Alberta, Canada. METHOD: Baseline data from a prospective cohort of adults with type 2 diabetes were used. Assessment of foot disease included self-reported peripheral neuropathy, peripheral vasculopathy, foot or leg ulcer/infection or gangrene/amputation. Foot self-care was assessed using the Summary of Diabetes Self-Care Activities, and clinical monitoring using patients' reports of having feet checked for lesions or sensory loss. RESULTS: The mean age of respondents (N=2040) was 64 (SD 10.7) years; 45% were female, and 91% were Caucasian. Peripheral neuropathy was reported by 18% of the respondents, peripheral vasculopathy by 28%, ulcer/infection by 6% and gangrene/amputation by 1.4%. Only 14% of respondents performed foot self-care behaviours >=6 days per week, and only 41% and 34% had their feet clinically checked for lesions or sensory loss, respectively. Predictors of foot disease included longer duration of diabetes, smoking, depressive symptoms, low self-efficacy and a history of cardiovascular diseases. Predictors of good self-care included older age, female sex, longer duration of diabetes and no report of hyperlipidemia. Predictors of clinical monitoring included female sex, current smoking, residing in urban areas, longer duration of diabetes, and histories of heart disease or hyperlipidemia. CONCLUSIONS: Peripheral neuropathy and vasculopathy were the most common reported foot problems in this population. Foot self-care is generally infrequent, and clinical monitoring is performed for less than half of these patients, with significant variations by patient demographics and clinical presentation. PMID- 26243465 TI - Reduction in sodium intake is independently associated with improved blood pressure control in people with chronic kidney disease in primary care. AB - Decreasing sodium intake has been associated with improvements in blood pressure (BP) and proteinuria, two important risk factors for CVD and chronic kidney disease (CKD) progression. We aimed to investigate the role of sodium intake by examining the effect of changes in sodium intake over 1 year on BP and proteinuria in people with early stage CKD. From thirty-two general practices, 1607 patients with previous estimated glomerular filtration rate of 59-30 ml/min per 1.73 m2 and mean age of 72.9 (sd 9.0) years were recruited. Clinical assessment, urine and serum biochemistry testing were performed at baseline and after 1 year. Sodium intake was estimated from early morning urine specimens using an equation validated for this study population. We found that compared with people who increased their sodium intake from <= 100 to >100 mmol/d over 1 year, people who decreased their intake from >100 to <= 100 mmol/d evidenced a greater decrease in all BP variables (Deltamean arterial pressure (DeltaMAP) = 7.44 (SD 10.1) v. -0.23 (SD 10.4) mmHg; P<0.001) as well as in pulse wave velocity (DeltaPWV = -0.47 (SD 1.3) v. 0.08 (SD 1.88) m/s; P<0.05). Albuminuria improved only in albuminuric patients who decreased their sodium intake. BP improved in people who maintained low sodium intake at both times and in those with persistent high intake, but the number of anti-hypertensive increased only in the higher sodium intake group, and PWV improved only in participants with lower sodium intake. Decreasing sodium intake was an independent determinant of DeltaMAP. Although more evidence is needed, our results support the benefits of reducing and maintaining sodium intake below 100 mmol/d (2.3-2.4 g/d) in people with early stages of CKD. PMID- 26243466 TI - Selective enhancement of insulin sensitivity in the mature adipocyte is sufficient for systemic metabolic improvements. AB - Dysfunctional adipose tissue represents a hallmark of type 2 diabetes and systemic insulin resistance, characterized by fibrotic deposition of collagens and increased immune cell infiltration within the depots. Here we generate an inducible model of loss of function of the protein phosphatase and tensin homologue (PTEN), a phosphatase critically involved in turning off the insulin signal transduction cascade, to assess the role of enhanced insulin signalling specifically in mature adipocytes. These mice gain more weight on chow diet and short-term as well as long-term high-fat diet exposure. Despite the increase in weight, they retain enhanced insulin sensitivity, show improvements in oral glucose tolerance tests, display reduced adipose tissue inflammation and maintain elevated adiponectin levels. These improvements also lead to reduced hepatic steatosis and enhanced hepatic insulin sensitivity. Prolonging insulin action selectively in the mature adipocyte is therefore sufficient to maintain normal systemic metabolic homeostasis. PMID- 26243467 TI - Management of adenomas within the area of rectal cancer that develop complete pathological response. PMID- 26243468 TI - Diffuse cavernous hemangioma of the rectum: case report and literature review. PMID- 26243469 TI - Type D personality is associated with delaying patients to medical assessment and poor quality of life among rectal cancer survivors. AB - OBJECTIVE: The aim of this research was to explore quality of life (QoL), mental health status, type D personality, symptom duration, and emergency admissions of Chinese rectal cancer patients as well as the relationship between these factors. METHODS: Type D personality was measured with the 14-item Type D Personality Scale (DS14). Mental health status was measured with the Hospital Anxiety and Depression Scale (HADS). The QoL outcomes were assessed longitudinally using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires at the baseline and 6 months after diagnosis. RESULTS: Of the 852 survivors who responded (94 %), 187 (22 %) had a type D personality. The proportion of patients with duration of symptoms >1 month and being diagnosed after emergency admissions in type D group is significantly higher than that in non-type D group. At both of the time points, type D patients reported statistically significant lower scores on most of the functional scales, global health status/QoL scales, and worse symptom scores compared to patients without a type D personality. At the 6-month time point, a higher percentage of patients in the type D group demonstrated QoL deterioration. Clinically elevated levels of anxiety and depression were more prevalent in type D than in non-type D survivors. CONCLUSIONS: Type D personality was associated with poor QoL and mental health status among survivors of rectal cancer, even after adjustment for confounding background variables. Type D personality might be a general vulnerability factor to screen for subgroups at risk for longer symptom duration and emergency admissions in clinical practice. PMID- 26243470 TI - Colorectal endoscopic submucosal dissection (ESD) performed by experienced endoscopists with limited experience in gastric ESD. AB - PURPOSE: Since colorectal endoscopic submucosal dissection (ESD) requires higher level skills than endoscopic mucosal resection (EMR), it is recommended to acquire sufficient experience in gastric ESD prior to attempting colorectal ESD. We evaluated the ability of experienced endoscopists with limited experience in gastric ESD to perform colorectal ESD. METHODS: We retrospectively reviewed 120 colorectal ESDs performed by two endoscopists who had expertise in colonoscopy and colorectal EMR but experience of fewer than five gastric ESDs. Main outcomes were the en bloc resection rate with tumor-free margins (R0 resection rate) and adverse events rate. Using only clinical characteristics prior to ESD, we also identified factors affecting outcomes. RESULTS: A total of 113 patients (94.2 %) received en bloc resection, and the R0 resection rate was 80.0 % (96/120). Perforation and postoperative hemorrhage occurred in eight (6.7 %) and two (1.7 %) patients, respectively. Dividing the 120 cases into three learning phases, R0 resection and perforation rates improved from 77.5 % (31/40) and 12.5 % (5/40) in phase 1 to 85.0 % (34/40) and 2.5 % (1/40) in phase 3, respectively. Multivariate analysis revealed that lesions at junctions (dentate line, sigmoid-descending junction, splenic flexure, hepatic flexure, ileocecal valve) and lesions with factors reflecting fibrosis in the submucosal layer (based on endoscopic findings before ESD) were significantly correlated with R0 resection failure, with adjusted odds ratios of 10.5 (95 % CI 2.1-67.6) and 10.4 (2.7-48.6), respectively. CONCLUSIONS: Colorectal ESD is feasible for experienced endoscopists with limited experience in gastric ESD. Novices should avoid lesions at junctions or those with factors reflecting fibrosis. PMID- 26243471 TI - Incidence and risk factors of postoperative delirium in elderly patients who underwent laparoscopic surgery for colorectal cancer. AB - BACKGROUND: The reported incidence of postoperative delirium (POD) in elderly patients ranges from 6 to 53 %. Several preoperative and operative factors have been reported as risk factors of POD. AIM: The aim of this study was to determine the incidence of and risk factors for POD in patients with colorectal cancer who had undergone laparoscopic colorectal resection. METHODS: A total of 311 consecutive patients aged 75 years and older who underwent laparoscopic surgery for colorectal cancer at our department from January 2008 to December 2013 were classified as delirious group (n = 44) and nondelirious group (n = 267). Short term outcomes and risk factors for POD were analyzed. RESULTS: POD was diagnosed in 14.1 % of elderly patients with colorectal cancer. Univariate analysis showed that older age, high American Society of Anesthesiology (ASA) score, performance status >2, low prognostic nutrition index (PNI), past history of delirium or dementia, operative approach, Organ/Space SSI, and cardiac or pulmonary disease were significantly associated with POD. Multivariate logistic regression analysis identified older age, past history of delirium or dementia, operative approach, and Organ/Space SSI as four independent risk factors for POD. CONCLUSIONS: Our results suggest that the risk of POD is associated with older age, past history of delirium or dementia, operative approach, Organ/Space SSI. PMID- 26243472 TI - Association of dialysis with adverse postoperative outcomes in colorectal cancer an analysis of ACS-NSQIP. AB - PURPOSE: Dialysis is an important factor in predicting the risk associated with cardiovascular and general abdominal surgery. The association between cancer patients and dialysis was also studied, and in particular, the effects of dialysis on the postoperative outcomes of colorectal cancer which has not been widely reported in the literature. METHODS: This is a retrospective, multi institutional study of the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database, investigating preoperative dialysis status and its association with postoperative mortality and morbidity. RESULTS: Among 42,403 colorectal cancer patients, 265 patients (0.6 %) were receiving dialysis. Patients undergoing dialysis had a higher risk of re-intubation (6.8 %, p < 0.001), on ventilator-support more than 48 h (7.2 %, p < 0.001), and sepsis (7.2 %, p < 0.05). Deep surgical site infection (adjusted odds ratio = 2.09), pneumonia (adjusted odds ratio = 1.86), and septic shock (adjusted odds ratio = 1.9) were significantly associated with dialysis status. The postoperative mortality rate of dialysis patients was 8.3 % (p < 0.001) and had significant association in a multivariate Cox proportional hazard model (hazard ratio = 1.63, p = 0.026). Total length of hospital stay (coefficient = 3.5, p < 0.001) and overall complication (coefficient = 0.134, p < 0.001) were prominent in the dialysis groups. The rate of laparoscopic surgery in dialysis and non-dialysis patients was 33 and 42 %, respectively (odds ratio = 0.693, p = 0.005). CONCLUSIONS: In colorectal cancer, dialysis status significantly contributes to postoperative morbidity, length of total hospital stay, and mortality. In addition, the rates of preventable infection and pulmonary complications were shown to require more careful attention in the hospital setting, and particularly in dialysis patients. Preoperative dialysis patients are less likely than non dialysis patients to undergo a minimally invasive approach. PMID- 26243473 TI - Formation of highly toxic hydrogen cyanide upon ruby laser irradiation of the tattoo pigment phthalocyanine blue. AB - Since laser treatment of tattoos is the favored method for the removing of no longer wanted permanent skin paintings, analytical, biokinetics and toxicological data on the fragmentation pattern of commonly used pigments are urgently required for health safety reasons. Applying dynamic headspace-gas chromatography with mass spectrometric detection (DHS-GC/MS) and comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GCxGC-ToF-MS), we identified 1,2-benzene dicarbonitrile, benzonitrile, benzene, and the poisonous gas hydrogen cyanide (HCN) as main fragmentation products emerging dose dependently upon ruby laser irradiation of the popular blue pigment copper phthalocyanine in suspension. Skin cell viability was found to be significantly compromised at cyanide levels of >=1 mM liberated during ruby laser irradiation of >1.5 mg/ml phthalocyanine blue. Further, for the first time we introduce pyrolysis-GC/MS as method suitable to simulate pigment fragmentation that may occur spontaneously or during laser removal of organic pigments in the living skin of tattooed people. According to the literature such regular tattoos hold up to 9 mg pigment/cm(2) skin. PMID- 26243474 TI - Volume regulation and shape bifurcation in the cell nucleus. AB - Alterations in nuclear morphology are closely associated with essential cell functions, such as cell motility and polarization, and correlate with a wide range of human diseases, including cancer, muscular dystrophy, dilated cardiomyopathy and progeria. However, the mechanics and forces that shape the nucleus are not well understood. Here, we demonstrate that when an adherent cell is detached from its substratum, the nucleus undergoes a large volumetric reduction accompanied by a morphological transition from an almost smooth to a heavily folded surface. We develop a mathematical model that systematically analyzes the evolution of nuclear shape and volume. The analysis suggests that the pressure difference across the nuclear envelope, which is influenced by changes in cell volume and regulated by microtubules and actin filaments, is a major factor determining nuclear morphology. Our results show that physical and chemical properties of the extracellular microenvironment directly influence nuclear morphology and suggest that there is a direct link between the environment and gene regulation. PMID- 26243475 TI - Validation of a semiconductor next-generation sequencing-based protocol for preimplantation genetic diagnosis of reciprocal translocations. AB - OBJECTIVE: We aim to validate a semiconductor next-generation sequencing (NGS) based method to detect unbalanced chromosome translocation in preimplantation embryos. METHODS: The study consisted of a blinded retrospective evaluation with NGS of 145 whole-genome amplification products obtained from biopsy of cleavage stage embryos or blastocysts, derived from 33 couples carrying different balanced translocations. Consistency of NGS-based copy number assignments was evaluated and compared with the results obtained by array-comparative genomic hybridization. RESULTS: Reliably identified with the NGS-based protocol were 162 segmental imbalances derived from 33 different chromosomal translocations, with the smallest detectable chromosomal segment being 5 Mb in size. Of the 145 embryos analysed, 20 (13.8%) were balanced, 43 (29.6%) were unbalanced, 53 (36.5%) were unbalanced and aneuploid, and 29 (20%) were balanced but aneuploid. NGS sensitivity for unbalanced/aneuploid chromosomal call (consistency of chromosome copy number assignment) was 99.75% (402/403), with a specificity of 100% (3077/3077). NGS specificity and sensitivity for unbalanced/aneuploid embryo call were 100%. CONCLUSIONS: Next-generation sequencing can detect chromosome imbalances in embryos with the added benefit of simultaneous comprehensive aneuploidy screening. Given the high level of consistency with array-comparative genomic hybridization, NGS has been demonstrated to be a robust high-throughput technique ready for clinical application in preimplantation genetic diagnosis for chromosomal translocations, with potential advantages of automation, increased throughput and reduced cost. PMID- 26243476 TI - Data concurrency is required for estimating urban heat island intensity. AB - Urban heat island (UHI) can generate profound impacts on socioeconomics, human life, and the environment. Most previous studies have estimated UHI intensity using outdated urban extent maps to define urban and its surrounding areas, and the impacts of urban boundary expansion have never been quantified. Here, we assess the possible biases in UHI intensity estimates induced by outdated urban boundary maps using MODIS Land surface temperature (LST) data from 2009 to 2011 for China's 32 major cities, in combination with the urban boundaries generated from urban extent maps of the years 2000, 2005 and 2010. Our results suggest that it is critical to use concurrent urban extent and LST maps to estimate UHI at the city and national levels. Specific definition of UHI matters for the direction and magnitude of potential biases in estimating UHI intensity using outdated urban extent maps. PMID- 26243477 TI - Urban planning with respect to environmental quality and human well-being. AB - The cities of today present requirements that are dissimilar to those of the past. There are cities where the industrial and service sectors are in decline, and there are other cities that are just beginning their journey into the technological and industrial sectors. In general, the political and social realms have been restructured in terms of economics, which has resulted in an entirely different shape to the primitive structures of civilization. As people begin to understand the dynamic nature of landscapes, they stop seeing landscapes as a static scene. Sustainable cities must be simultaneously economically viable, socially just, politically well managed and ecologically sustainable to maximize human comfort. The present research suggests a multi-disciplinary approach for attaining a holistic understanding of urban environmental quality and human well being in relation to sustainable urban development. PMID- 26243478 TI - Association of maternal menarcheal age with anthropometric dimensions and blood pressure in children from Greater Bilbao. AB - BACKGROUND: Earlier menarche has been related to shorter height and greater obesity-related anthropometric dimensions and blood pressure in women. Boys and girls with earlier maternal menarcheal age (MMA) have shown greater height and body mass index (BMI) in childhood. AIM: To analyse associations of menarcheal age with their own and their children's anthropometric dimensions and blood pressure. SUBJECTS AND METHODS: The sample consisted of 493 women and their children (aged 2-19 years) from Greater Bilbao (Basque Country, Spain). For both generations there is information on 19 anthropometric dimensions, blood pressure and socio-demographic characteristics. Linear regressions adjusted for different covariates were used to analyse the associations. RESULTS: Menarcheal age in women showed the greatest positive associations with iliospinal height and ectomorphy and negative associations with BMI, sum of six skin-folds, endomorphy and mesomorphy. Boys with earlier MMA had greater body heights and breadths, particularly iliospinal height and biacromial breadth (0.10 z-score/year; p < 0.05). In girls, earlier MMA predicted greater sitting height, biepicondylar humerus breadth, weight and sum of four circumferences (0.07-0.09 z-score/year; p < 0.05). However, there was some evidence that MMA was positively associated with body heights, ectomorphy and blood pressure in girls aged >=12. CONCLUSION: Children with earlier MMA tend to have greater anthropometric dimensions. Adolescent growth spurt might affect these relationships, at least in girls. PMID- 26243480 TI - Rapid Recovery After Hip and Knee Arthroplasty--A Transatlantic Gap? PMID- 26243481 TI - Reply to Letter by Uslu et al Entitled "The Assessment of Platelet-Lymphocyte Ratio Based on EDTA-Dependent Pseudothrombocytopenia". PMID- 26243482 TI - Effects of Renin-Angiotensin-Aldosterone System Blockers and Renoprotective Regimens on Contrast-Induced Nephropathy. PMID- 26243483 TI - Preprocedural Albumin Levels and Risk of In-Stent Restenosis After Coronary Stenting With Bare-Metal Stent. AB - In-stent restenosis (ISR) remains a significant clinical problem in patients with coronary artery disease treated with percutaneous coronary intervention. Decreased serum albumin (SA) level is related to an increased risk of cardiovascular events. The aim of the present study was to assess whether SA levels at admission are an independent predictor of ISR in patients undergoing bare-metal stent (BMS) implantation. A total of 341 patients (aged 61 +/- 11, 65.4% men) with a history of BMS implantation and a further control coronary angiography due to stable angina pectoris (SAP) were included. The study population was classified into 2 groups: patients with and without ISR. The ISR was observed in 140 (41.1%) patients. We found significantly lower SA levels in patients who developed ISR than in those who did not (3.69 +/- 0.41 vs 4.07 +/- 0.35 mg/dL,P< .001). Multivariate analysis revealed that SA level (odds ratio 0.109, 95% confidence interval 0.017-0.700,P= .020), stent diameter, reason for stent implantation, and body mass index were independent risk factors for the development of ISR. The SA level at admission is inversely associated with ISR in patients with SAP. PMID- 26243485 TI - New developments in tobacco control. PMID- 26243486 TI - The national and international regulatory environment in tobacco control. AB - Despite their lethality, cigarettes are subject to little regulation that directly restricts their contents or their legality. This may change in the near future with the Framework Convention on Tobacco Control (FCTC), the world's first global health treaty, now in force, as well as developments in a few individual countries. Cigarettes are subject to a substantial number of country-specific regulations regarding their conditions of sale: their price (mostly through taxation), the places where they can be consumed (clean indoor air laws), who can smoke them (prohibitions on their use by or sales to minors), how they can be advertised or promoted (if at all), and how they must be packaged (minimum pack sizes, warning labels, plain packaging). Such policies constitute the core of successful tobacco control. The FCTC has been ratified by 180 countries representing 90% of the world's population. The FCTC requires compliance with numerous provisions relating to the kinds of regulations noted above. The treaty also mandates explicit attention to direct product regulation. Several countries have such authority, at least in limited forms. In the US, for example, the Food and Drug Administration (FDA) now has the legal authority to regulate tobacco products, including their contents. The possibility exists that, in the foreseeable future, a country will mandate product standards that will substantially reduce the appeal of cigarettes and other combusted tobacco products, which are by far the leading sources of the death and disease associated with tobacco. PMID- 26243484 TI - Protective associations of HDL with blood-brain barrier injury in multiple sclerosis patients. AB - The purpose of this work was to investigate the associations of serum cholesterol and apolipoproteins with measures of blood-brain barrier (BBB) permeability and CNS inflammation following the first clinical demyelinating event. This study included 154 patients [67% female; age, 29.5 +/- 8.2 years (mean +/- SD)] enrolled in a multi-center study of interferon beta1-a treatment following the first demyelinating event. Blood and cerebrospinal fluid (CSF) were obtained at screening prior to treatment. A comprehensive serum lipid profile and multiple surrogate markers of BBB breakdown and CNS immune activity were obtained. Higher levels of serum HDL cholesterol (HDL-C) and ApoA-I were associated with lower CSF total protein level, CSF albumin level, albumin quotient, and CSF IgG level (all P <= 0.001 for HDL-C and all P < 0.01 for ApoA-I). HDL-C was also associated with CSF CD80+ (P < 0.001) and with CSF CD80+CD19+ (P = 0.007) cell frequencies. Higher serum HDL is associated with lower levels of BBB injury and decreased CD80+ and CD80+CD19+ cell extravasation into the CSF. HDL may potentially inhibit the initiation and/or maintenance of pathogenic BBB injury following the first demyelinating event. PMID- 26243487 TI - Lifting the burden: a coordinated approach to action on Aboriginal tobacco resistance and control in NSW. AB - Smoking prevalence continues to be significantly higher among Aboriginal people than non-Aboriginal people, resulting in a range of serious health consequences and inequities. The Aboriginal Health and Medical Research Council of New South Wales (AHandMRC) and the New South Wales (NSW) Ministry of Health (the Ministry) have worked in partnership to develop The ATRAC Framework: A Strategic Framework for Aboriginal Tobacco Resistance and Control in NSW, in collaboration with Aboriginal communities and a range of stakeholders. The goal of the ATRAC Framework is to reduce smoking prevalence and the harmful impacts of tobacco use among Aboriginal people and communities in NSW. The framework includes reviews of relevant evidence and recommended actions, organised under six areas: leadership, partnerships and coordination; community action, awareness and engagement; workforce development; supportive environments; quitting support; and evidence, evaluation and research. The framework stresses that, to be successful, Aboriginal tobacco resistance and control programs and activities need to be evidence based, coordinated, integrated and involve Aboriginal people and Aboriginal community controlled health organisations in all aspects, from development through to implementation and evaluation. Consultations and evidence reviews highlight the importance of workforce support and development, including the ongoing need for more workers specialising in Aboriginal tobacco resistance and control, as well as ongoing training for all staff involved in delivering care to Aboriginal people. Other key strategies identified in the framework include improving access to nicotine replacement therapy and other medications to support quitting; supporting, strengthening and building on existing innovative community-based programs; and further developing the evidence base. The AHandMRC and the Ministry will continue to work in partnership to drive the use of the ATRAC Framework by all people involved in Aboriginal tobacco resistance and control in NSW for resource allocation, planning, implementation and evaluation of existing and future activities. PMID- 26243488 TI - Tobacco retail regulation: the next frontier in tobacco control? AB - Australia has experienced significant reductions in smoking rates in recent decades, and public health scrutiny is turning to how further gains will be made. Regulatory controls, such as licensing to reduce retailer density or limit tobacco proximity to schools or licensed premises, have been suggested by some public health advocates as appropriate next steps. This paper summarises best practice evidence in relation to tobacco retailer regulation, noting measures undertaken in New South Wales (NSW). Research on controlling the display of tobacco products and supply of tobacco to minors is well established. The evidence shows that a combination of licensing, enforcement, education, promotion restrictions at the point of sale and a well-funded compliance program to prevent sales to minors is a best-practice approach to tobacco retail regulation. The evidence for other measures - such as restricting the number of retail outlets, and restricting how and where tobacco is sold - is far less developed. There is insufficient evidence to determine if a positive licensing system and controls on the density and location of tobacco outlets would be effective in the Australian context. More evidence is required from jurisdictions that have implemented a positive licensing scheme to evaluate the effect of such schemes on smoking rates, the potential cost benefits and any unintended consequences. PMID- 26243489 TI - Smoking-attributable cancer mortality in NSW, Australia, 1972-2008. AB - AIM: To estimate the impact of smoking-attributable cancer mortality on trends in cancer mortality in New South Wales (NSW), Australia, between 1972 and 2008. STUDY TYPE: The study is a retrospective analysis of cancer mortality in NSW using NSW Central Cancer Registry data. METHODS: Smoking-attributable cancer deaths were estimated using the smoking impact ratio method, which provides an indirect estimate of exposure to tobacco in the NSW population using lung cancer mortality. Trends in age-standardised cancer mortality rates by cancer type and the number of years of life lost due to smoking-attributable cancer deaths were estimated. RESULTS: In NSW, the cancer mortality rate decreased in males by 26% and females by 19% between 1989 and 2008. Nearly half (44%) of the decrease for males was a result of the decline in smoking-attributable cancer deaths. Despite a decline in the female all-cancer mortality rate, the smoking-attributable cancer mortality rate increased from 20.3 per 100 000 to 26.8 per 100 000 between 1989 and 2008. Smoking-attributable cancer deaths in women increased from around 150 per year in the early 1970s to 1186 in 2008; for men, the number remained stable at just over 2000 deaths per year since the 1980s. Although the lung cancer mortality rate declined in men, lung cancer remains the largest cause of cancer death. Lung cancer has overtaken breast cancer to be the largest cause of cancer death among women, with 17.1% (n = 998) of cancer deaths due to lung cancer in 2008. CONCLUSIONS: Despite declining all-cancer mortality in NSW, around 3330 cancer deaths in 2008 were due to the accumulated hazard of smoking in current and ex-smokers. This highlights the importance of tobacco control as part of a comprehensive cancer control plan. PMID- 26243490 TI - Applications of system dynamics modelling to support health policy. AB - INTRODUCTION: The value of systems science modelling methods in the health sector is increasingly being recognised. Of particular promise is the potential of these methods to improve operational aspects of healthcare capacity and delivery, analyse policy options for health system reform and guide investments to address complex public health problems. Because it lends itself to a participatory approach, system dynamics modelling has been a particularly appealing method that aims to align stakeholder understanding of the underlying causes of a problem and achieve consensus for action. The aim of this review is to determine the effectiveness of system dynamics modelling for health policy, and explore the range and nature of its application. METHOD: A systematic search was conducted to identify articles published up to April 2015 from the PubMed, Web of Knowledge, Embase, ScienceDirect and Google Scholar databases. The grey literature was also searched. Papers eligible for inclusion were those that described applications of system dynamics modelling to support health policy at any level of government. RESULTS AND DISCUSSION: Six papers were identified, comprising eight case studies of the application of system dynamics modelling to support health policy. No analytic studies were found that examined the effectiveness of this type of modelling. Only three examples engaged multidisciplinary stakeholders in collective model building. Stakeholder participation in model building reportedly facilitated development of a common 'mental map' of the health problem, resulting in consensus about optimal policy strategy and garnering support for collaborative action. The paucity of relevant papers indicates that, although the volume of descriptive literature advocating the value of system dynamics modelling is considerable, its practical application to inform health policy making is yet to be routinely applied and rigorously evaluated. CONCLUSION: Advances in software are allowing the participatory model building approach to be extended to more sophisticated multimethod modelling that provides policy makers with more powerful tools to support the design of targeted, effective and equitable policy responses for complex health problems. Building capacity and investing in communication to promote these modelling methods, as well as documenting and evaluating their applications, will be vital to supporting uptake by policy makers. PMID- 26243491 TI - Categorising major cardiovascular disease hospitalisations from routinely collected data. AB - Objectives and importance of the study: Routine hospital administrative data provide an important source of information about cardiovascular disease (CVD) for health statistics reporting, health services and research. How such conditions are classified and grouped has implications for the use and interpretation of these data. International Classification of Diseases (ICD) diagnosis codes from hospital data collections are often used to classify CVD, but there is little published evidence on the most appropriate ways to use these codes to categorise CVD in a way that maximises the usefulness of hospital data for reporting and research. In particular, ICD codes under 'Diseases of the circulatory system' (I00-I99) are often grouped together into a general CVD category. However, this category is heterogeneous and combines common severe atherosclerotic and thrombotic CVDs (such as myocardial infarction and pulmonary embolism) with common, less severe and pathologically dissimilar conditions (such as varicose veins and haemorrhoids). In addition, hospital data collections contain a range of data fields, including those relating to primary and additional diagnoses and those relating to procedures. All of these have the potential to contribute valuable information on CVD. This paper proposes a pragmatic approach to using ICD diagnosis codes and procedure codes to capture major atherosclerotic and arteriovenous thromboembolic and related CVD. METHODS: We reviewed the ICD diagnosis codes and procedure codes and developed an algorithm for classifying and categorising major CVD diagnoses. This approach was then applied to linked hospitalisation data from individuals participating in the 45 and Up Study, a cohort study of 267 153 New South Wales residents aged 45 and over, to investigate the implications of the proposed approach for quantifying CVD. RESULTS: Large differences were observed in the numbers of events in grouped CVD outcomes, depending on the methods used. CONCLUSIONS: In cases where the reporting and research interest relates to incident disease, it may be appropriate to prioritise specific disease categories and pathological homogeneity. PMID- 26243492 TI - Managing nicotine dependence in NSW hospitals under the Smoke-free Health Care Policy. AB - Under the new NSW Health Smoke-free Health Care Policy, the smoke-free status of public hospital campuses has been reaffirmed and all clinical staff are required to provide routine brief interventions for all smoking patients. The policy creates a unique opportunity to assist smokers to quit permanently in a supportive environment when motivation to quit is high. Smoking remains the leading cause of preventable death and disability in New South Wales (NSW). Counselling beginning in hospital and continuing for at least 1 month after discharge significantly increases quit rates. Smoking can be addressed using the 5As model, which includes asking about smoking, assessing readiness to change and nicotine dependence, advising all smokers to quit, assisting smokers to quit and arranging follow-up. Postdischarge support is a vital ingredient for long-term success and should be arranged during the hospital stay. Nicotine replacement therapy (NRT) should be offered to all nicotine-dependent smokers soon after admission. NRT helps manage cravings and nicotine withdrawal symptoms and significantly increases quit rates. Most smokers commence NRT on a nicotine patch, with an oral form of NRT added as required. It is important to give patients detailed instructions on the correct use of NRT and to ensure an adequate dose is taken to relieve symptoms. NRT is well tolerated and can be used perioperatively, during pregnancy and in patients with cardiovascular disease. Blood levels of certain drugs rise within several days after smoking cessation, so dose reductions may be required. Drugs with a narrow therapeutic index such as clozapine, olanzapine, warfarin and theophylline are of special importance. PMID- 26243493 TI - Who has Australia's most-followed Twitter accounts in health and medicine? AB - Twitter is a social media platform that can be used by people working in health and medicine to distribute information, advocate, debate and network with large numbers of other users. We set out to determine the top 10 Australian Twitter accounts in four categories, ranked by number of Twitter followers. We extracted names with high follower volumes from 'lists' of health and medical Twitter accounts, and then 'crowdsourced' on Twitter for names that were not included on those lists. Individuals tweeting on single-issue topics (especially sugar, nutrition and fitness), health institutions, and people working in the media had higher Twitter followings and lower tweet-to-follower ratios than those tweeting on mixed health topics. Tweeting pictures was nominated by several as a way of attracting retweets. Highly followed Twitter users expressed a variety of benefits of using Twitter. PMID- 26243494 TI - Making the cycling environment safer: an investigation based on hospital admissions. PMID- 26243495 TI - Aboriginal quit project gets results. PMID- 26243496 TI - Smoke-free outdoor dining begins in NSW. PMID- 26243497 TI - NSW bans e-cig sales to minors. PMID- 26243498 TI - Midwives' experiences of transfer in labour from a Western Australian birth centre to a tertiary maternity hospital. AB - BACKGROUND: When transfer in labour takes place from a woman-centred, midwifery led centre to a tertiary maternity hospital it is accepted that women are negatively affected, however the midwife's role is unevaluated, there is no published literature exploring their experience. This study aimed to describe these experiences. METHODS: Giorgi's descriptive phenomenological method of analysis was used to explore the 'lived' experiences of the midwives. Seventeen interviews of transferring midwives took place and data saturation was achieved. FINDINGS: The overall findings suggest that midwives find transfer in labour challenging, both emotionally and practically. Five main themes emerged: (1) 'The midwife's internal conversation' with subtheme: 'Feeling under pressure', (2) 'Challenged to find a role in changing circumstances' with subtheme: 'Varying degrees of support', (3) 'Feeling out of place' with subtheme: 'Caught in the middle of different models of care, (4) 'A constant support for the parents across the labour and birth process' with subthemes: 'Acknowledging the parents' loss of their desired birth' and (5) 'The midwives' need for debrief'. CONCLUSION: Midwives acknowledged the challenge of finding the balance between fulfilling parents' birth plan wishes with hospital protocol and maintaining safety. Transfer for fetal or maternal compromise caused anxiety and concern. The benefits of providing continuity of care were acknowledged by the midwife's knowledge of the woman and her history but these were not always recognised by the receiving team. Discussing the transfer story afterwards helped midwives review their practice. Effective communication between all stakeholders is essential throughout the transfer process. PMID- 26243500 TI - Evaluation of a short dynamic 18F-fluoride PET/CT scanning method to assess bone metabolic activity in spinal orthopedics. AB - OBJECTIVE: A complication after spinal fusion surgery is pseudarthrosis, but its radiological diagnosis is of limited value. (18)F-fluoride PET with its ability to assess bone metabolism activity could be of value. The goal of this study was to assess the clinical feasibility of calculating the static standardized uptake value (SUV) from a short dynamic scan without the use of blood sampling, thereby obtaining all dynamic and static parameters in a scan of only 30 min. This approach was tested on a retrospective patient population with persisting pain after spinal fusion surgery. METHODS: In 16 patients, SUVs (SUV max, SUV mean) and kinetic parameters (K 1, k 2, k 3, v b, K i,NLR, K 1/k 2, k 3/(k 2 + k 3), K i,patlak) were derived from static and dynamic PET/CT scans of operated and control regions of the spine, after intravenous administration of 156-214 MBq (18)F-fluoride. Parameter differences between control and operated regions, as well as between pseudarthrosis and fused segments were evaluated. SUVmean at 30 and 60 min was calculated from kinetic parameters obtained from the dynamic data set (SUV mean,2TCM). Agreement between measured and calculated SUVs was evaluated through Bland-Altman plots. RESULTS: Overall, statistically significant differences between control and operated regions were observed for SUV max, SUV mean, K i,NLR, K i,patlak, K 1/k 2 and k 3/(k 2 + k 3). Diagnostic CT showed pseudarthrosis in 6/16 patients, while in 10/16 patients, segments were fused. Of all parameters, only those regarding the incorporation of bone [K i,NLR, K i,patlak, k 3/(k 2 + k 3)] differed statistically significant in the intervertebral disc space between the pseudarthrosis and fused patients group. The mean values of the patient-specific blood clearance rate [Formula: see text] differed statistically significant between the pseudarthrosis and the fusion group, with a p value of 0.011. This may correspond with the lack of statistical significance of the SUV values between pseudarthrosis and fused patients. Bland Altman plots show that calculated SUV mean,2TCM values corresponded well with the measured SUV mean values. CONCLUSION: This study shows the feasibility of a 30 min dynamic (18)F-fluoride PET/CT scanning and this may provide dynamic parameters clinically relevant to the diagnosis of pseudarthrosis. PMID- 26243501 TI - Biodistribution and estimation of radiation-absorbed doses in humans for 13N ammonia PET. AB - OBJECTIVE: To evaluate the biodistribution of radiation-absorbed doses of (13)N ammonia in healthy people. METHODS: Five healthy human subjects underwent whole body PET and CT scans after injection of 555-740 MBq of (13)N-ammonia. Five serial dynamic emission scans in each healthy volunteer were acquired. Regions of interest were drawn on the CT image and transferred to the corresponding transverse PET slice. Estimates of the radiation-absorbed doses were calculated using the medical internal radiation dosimetry method. RESULTS: The highest concentrations of (13)N-ammonia were found in the heart and liver, followed by pancreas, brain, spleen and stomach. The highest absorbed organ doses were to the heart wall (7.14E-03 +/- 3.63E-03 mGy/MBq) and kidneys (6.02E-03 +/- 3.53E-03 mGy/MBq). The effective dose (ED) was 6.58E-03 +/- 1.23E-03 mSv/MBq. CONCLUSIONS: With these new estimates for (13)N-ammonia dosimetry, the results for Chinese people were not appreciably different from those of the previous study performed with old devices. As one of the most important myocardial perfusion PET tracers, the whole-body (13)N-ammonia PET appears to be safe for humans, yielding a relatively modest radiation burden that would allow multiple PET studies on the same subject per year. PMID- 26243502 TI - Tinnitus and hyperacusis in autism spectrum disorders with emphasis on high functioning individuals diagnosed with Asperger's Syndrome. AB - OBJECTIVES: To evaluate the prevalence of tinnitus and hyperacusis in individuals with Asperger's Syndrome (AS). METHODS: A home-developed case-history survey and three item-weighted questionnaires: Tinnitus Reaction Questionnaire (TRQ), Tinnitus Handicap Inventory (THI), and the Hyperacusis Questionnaire (HQ) were employed. These tools categorize the subjective response to tinnitus and hyperacusis. The research tools were mailed to a mailing list of individuals with Asperger's Syndrome. RESULTS: A total of 55 subjects diagnosed with AS were included in the analysis (15.5% response rate). Sixty-nine percent of all respondents (38/55) reported hyperacusis with an average HQ score of 20.7. Furthermore, 35% (19/55) reported perceiving tinnitus with average scores of 27 for the TRQ and 23 for the THI. Thirty-one percent (17/55) reported both hyperacusis and tinnitus. The prevalence of hyperacusis in the AS respondents remained relatively constant across age groups. CONCLUSIONS: Hyperacusis and tinnitus are more prevalent in the ASD population subgroup diagnosed with AS under DSM-IV criteria than in the general public. Hyperacusis also appears to be more prevalent in the AS population than in the ASD population at large. Future research is warranted to provide insight into the possible correlation between tinnitus and hyperacusis symptoms and the abnormal social interactions observed in this group. PMID- 26243503 TI - First records of tool-set use for ant-dipping by Eastern chimpanzees (Pan troglodytes schweinfurthii) in the Kalinzu Forest Reserve, Uganda. AB - Chimpanzees at numerous study sites are known to prey on army ants by using a single wand to dip into the ant nest or column. However, in Goualougo (Republic of Congo) in Central Africa, chimpanzees use a different technique, use of a woody sapling to perforate the ant nest, then use of a herb stem as dipping tool to harvest the army ants. Use of a tool set has also been found in Guinea, West Africa: at Seringbara in the Nimba Mountains and at nearby Bossou. There are, however, no reports for chimpanzees in East Africa. We observed use of such a tool set in Kalinzu, Uganda, for the first time by Eastern chimpanzees. This behavior was observed among one group of chimpanzees at Kalinzu (S-group) but not among the adjacent group (M-group) with partly overlapping ranging areas despite the fact that the latter group has been under intensive observation since 1997. In Uganda, ant-dipping has not been observed in the northern three sites (Budongo, Semliki, and Kibale) but has been observed or seems to occur in the southern sites (Kalinzu and Bwindi), which suggests that ant-dipping was invented by and spread from the southern region after the northern and southern forest blocks became separated. Use of a tool-set by only one group at Kalinzu further suggests that this behavior was recently invented and has not yet spread to the other group via migrating females. PMID- 26243504 TI - Discovery of an island population of dwarf lemurs (Cheirogaleidae: Cheirogaleus) on Nosy Hara, far northern Madagascar. AB - The species-level diversity of Madagascar's lemurs has increased hugely over the last two decades, growing from 32 species in 1994 to 102 species in 2014. This growth is primarily due to the application of molecular phylogenetic analyses and the phylogenetic species concept to known populations, and few previously unknown lemur populations have been discovered during this time. We report on a new population of dwarf lemurs (Cheirogaleus sp.) from Nosy Hara, a 312-ha island in far northern Madagascar, which constitutes the northernmost distribution record for the genus. The dwarf lemurs appeared to show two characteristics of island populations-insular dwarfism and predator naivete-that suggest a long isolation, and may thus represent an undescribed taxon. If this is the case, the dwarf lemurs of Nosy Hara are probably one of the rarest primate taxa on Earth. PMID- 26243505 TI - Serum Amyloid-Beta Levels are Increased in Patients with Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is associated with cognitive decline, but the molecular link between COPD and dementia or Alzheimer's disease (AD) remains unclear. This study was aimed to investigate whether serum Abeta levels are correlated with COPD. 77 cognitively normal COPD patients and 45 age- and gender-matched normal controls were admitted to the study. Serum Abeta40 and Abeta42 levels were measured using ELISA kits. Serum C-reactive protein (CRP), interleukin 6 (IL-6), and procalcitonin (PCT) measurements were done using standard laboratory methods. Pulmonary function tests were performed to assess the pulmonary function and determine the degree of lung damage. Significantly increased levels of serum Abeta40, Abeta42, and total Abeta levels were found in patients with COPD in comparison with normal controls. In COPD patients, serum Abeta levels were higher in subjects with serum CRP, IL-6, and PCT upper the limit of normal. Moreover, serum Abeta levels were dramatically higher in COPD patients with worse pulmonary function. Our study suggests that cognitively normal COPD patients may undergo AD-related pathological changes, and COPD might facilitate AD-type pathogenesis. PMID- 26243506 TI - Benzodiazepine use as an independent risk factor for HIV infection in a Canadian setting. AB - BACKGROUND: Although the harms of prescription drug diversion are of growing international concern, the potential impact of prescription drug use on HIV infection has not been well assessed. We evaluated whether benzodiazepine use was associated with HIV seroconversion among a cohort of persons who inject drugs (PWID) in a Canadian setting. METHODS: Between May, 1996 and November, 2013, data were derived through a prospective cohort study of PWID in Vancouver, Canada. A total of 1682 baseline HIV negative participants were followed for a median of 79.5 months (interquartile range: 32.1-119.1), among whom 501 (29.8%) reported benzodiazepine use at baseline, and 176 seroconverted during follow-up, equal to an incidence density of 1.5 (95% Confidence Interval [CI]: 1.3-1.7) cases per 100 person-years. Poisson regression with time-dependent variables was used to assess whether benzodiazepine use was associated with the time to HIV seroconversion. RESULTS: After adjustment for potential confounders, benzodiazepine use (Adjusted Rate Ratio: 1.50; 95% CI: 1.01-2.24) was independently associated with a higher rate of HIV seroconversion. CONCLUSIONS: Benzodiazepine use was an independent risk factor for HIV seroconversion among PWID in this setting. Greater recognition of the safety concerns related to benzodiazepine medications including diversion are needed. PMID- 26243507 TI - Differential profiles of drug-addicted patients according to gender and the perpetration of intimate partner violence. AB - BACKGROUND: This study explored the differential profiles of drug-addicted patients according to gender and the perpetration of intimate partner violence (IPV). METHODS: The study assessed a sample of 127 drug-addicted patients (84 male and 43 female) who sought treatment. Information about socio-demographic and consumption characteristics, IPV, psychopathological symptoms, personality characteristics and maladjustment variables was obtained. Four groups were created according to gender and the presence or absence of the perpetration of IPV: (a) men with IPV (n=41), (b) women with IPV (n=29), (c) men without IPV (n=43), and (d) women without IPV (n=14). The four groups were compared in terms of all of studied variables. RESULTS: There were significant differences between the groups in the severity of the addiction and personality characteristics. In general, the drug-addicted patients with associated IPV perpetration exhibited greater scores for nearly all of the studied variables, independent of gender. Moreover, the differences among groups were more strongly related to perpetration of IPV than to the gender of the patients. CONCLUSIONS: According to the results obtained, treatment programs for drug addiction are a suitable context for identifying the presence of IPV, but IPV is typically unnoticed in addiction treatment programs. The implications of these results for future research and clinical practice are discussed. PMID- 26243508 TI - Salivary but not plasma cortisone tracks the plasma cortisol response to exercise: effect of time of day. AB - INTRODUCTION: The cortisol, cortisone, corticosterone, and CBG responses to exercise in the AM and PM have not been described. This study examined the response of these glucocorticoids and CBG to intense exercise in 12 endurance trained men in plasma (Pl) and saliva (Sa). METHODS: Each subject completed treadmill exercise in the morning and evening. Paired blood and Sa samples were obtained at rest before and after exercise. RESULTS: Significant time effect existed for Pl-cortisol and Sa-cortisol from baseline in the AM and PM (p < 0.01). Pl-cortisone and CBG significantly increased in the PM (p < 0.01). Pl corticosterone increased in the AM and PM (p < 0.01). Unlike Pl-cortisone, Sa cortisone was significantly higher in the AM compared to the PM, increasing in the AM and PM (All p < 0.01). Strong associations were found between Pl-cortisol and Sa-cortisol (r = 0.81, p < 0.0001), Pl-cortisol and Sa-cortisone (r = 0.81, p < 0.0001). CONCLUSIONS: (1) Intense EX induces a similar increase in Pl-cortisone (~90 %) and corticosterone (~200 %) in the AM and PM, whereas exercise increases CBG in the PM, but not in the AM; (2) vigorous exercise increases Sa-cortisone; (3) Sa-cortisone and cortisol are equally strongly correlated to Pl-cortisol, suggesting a significant role for Sa-cortisone as a novel marker of free cortisol during exercise. PMID- 26243509 TI - Development of mucous membrane pemphigoid with antibodies to the beta3 subunit of laminin 332 and bronchiolitis obliterans in a patient with chronic graft-versus host disease. PMID- 26243510 TI - Atomically-thin molecular layers for electrode modification of organic transistors. AB - Atomically-thin molecular layers of aryl-functionalized graphene oxides (GOs) were used to modify the surface characteristics of source-drain electrodes to improve the performances of organic field-effect transistor (OFET) devices. The GOs were functionalized with various aryl diazonium salts, including 4 nitroaniline, 4-fluoroaniline, or 4-methoxyaniline, to produce several types of GOs with different surface functional groups (NO2-Ph-GO, F-Ph-GO, or CH3O-Ph-GO, respectively). The deposition of aryl-functionalized GOs or their reduced derivatives onto metal electrode surfaces dramatically enhanced the electrical performances of both p-type and n-type OFETs relative to the performances of OFETs prepared without the GO modification layer. Among the functionalized rGOs, CH3O-Ph-rGO yielded the highest hole mobility of 0.55 cm(2) V(-1) s(-1) and electron mobility of 0.17 cm(2) V(-1) s(-1) in p-type and n-type FETs, respectively. Two governing factors: (1) the work function of the modified electrodes and (2) the crystalline microstructures of the benchmark semiconductors grown on the modified electrode surface were systematically investigated to reveal the origin of the performance improvements. Our simple, inexpensive, and scalable electrode modification technique provides a significant step toward optimizing the device performance by engineering the semiconductor electrode interfaces in OFETs. PMID- 26243511 TI - Efficacy and safety of canakinumab in cryopyrin-associated periodic syndromes: results from a Spanish cohort. AB - OBJECTIVES: Cryopyrin-associated periodic syndromes (CAPS) are dominantly inherited autoinflammatory diseases. The uncontrolled IL-1beta overproduction observed in these patients is the rational basis to treat them with anti-IL-1 drugs. The objective of this study was to evaluate the efficacy and safety of treatment with the long-lasting fully humanised anti-IL-1beta monoclonal antibody canakinumab in a Spanish cohort of patients with CAPS. METHODS: Clinical and laboratory data of CAPS patients carrying a heterozygous germline NLRP3 mutation were obtained. The initial treatment scheme with canakinumab was 150 mg/8 weeks administered subcutaneously in adult patients and 2 mg/kg/8 weeks in paediatric patients. RESULTS: Eight unrelated patients were enrolled. Canakinumab was the first anti-IL-1 drug used in three of them; five were already receiving anakinra. The clinical response to the initial canakinumab scheme was positive in all patients, and was quickly observed in the first 24-72 hours. Four required increasing the frequency and/or dose of canakinumab. A limited or no efficacy in those symptoms related to consequence of the deforming arthropathy and neurosensorial deafness was observed. The adverse side effects were restricted to infectious complications in a small percentage of patients. The treatment was well tolerated by all patients, with no reactions at drug site injections. CONCLUSIONS: Canakinumab caused fast and sustained remissions in most clinical and biochemical manifestations in all enrolled patients, with a limited efficacy in the structural lesions. Dose adjustments seem to be necessary for children and/or for patients with the most severe CAPS phenotypes. Treatment was well tolerated with a low incidence of adverse effects. PMID- 26243512 TI - Structure of the alpha-crystallin domain from the redox-sensitive chaperone, HSPB1. PMID- 26243513 TI - From nerve to blood vessel: a new role of Olfm2 in smooth muscle differentiation from human embryonic stem cell-derived mesenchymal cells. PMID- 26243515 TI - Statistical analysis for genome-wide association study. AB - In the past few years, genome-wide association study (GWAS) has made great successes in identifying genetic susceptibility loci underlying many complex diseases and traits. The findings provide important genetic insights into understanding pathogenesis of diseases. In this paper, we present an overview of widely used approaches and strategies for analysis of GWAS, offered a general consideration to deal with GWAS data. The issues regarding data quality control, population structure, association analysis, multiple comparison and visual presentation of GWAS results are discussed; other advanced topics including the issue of missing heritability, meta-analysis, set-based association analysis, copy number variation analysis and GWAS cohort analysis are also briefly introduced. PMID- 26243514 TI - Translating transitions - how to decipher peripheral human B cell development. AB - During the last two decades our understanding of human B cell differentiation has developed considerably. Our understanding of the human B cell compartment has advanced from a point where essentially all assays were based on the presence or not of class-switched antibodies to a level where a substantial diversity is appreciated among the cells involved. Several consecutive transitional stages that newly formed IgM expressing B cells go through after they leave the bone marrow, but before they are fully mature, have been described, and a significant complexity is also acknowledged within the IgM expressing and class-switched memory B cell compartments. It is possible to isolate plasma blasts in blood to follow the formation of plasma cells during immune responses, and the importance and uniqueness of the mucosal IgA system is now much more appreciated. Current data suggest the presence of at least one lineage of human innate-like B cells akin to B1 and/or marginal zone B cells in mice. In addition, regulatory B cells with the ability to produce IL-10 have been identified. Clinically, B cell depletion therapy is used for a broad range of conditions. The ability to define different human B cell subtypes using flow cytometry has therefore started to come into clinical use, but as our understanding of human B cell development further progresses, B cell subtype analysis will be of increasing importance in diagnosis, to measure the effect of immune therapy and to understand the underlying causes for diseases. In this review the diversity of human B cells will be discussed, with special focus on current data regarding their phenotypes and functions. PMID- 26243516 TI - Comparison of dimension reduction-based logistic regression models for case control genome-wide association study: principal components analysis vs. partial least squares. AB - With recent advances in biotechnology, genome-wide association study (GWAS) has been widely used to identify genetic variants that underlie human complex diseases and traits. In case-control GWAS, typical statistical strategy is traditional logistical regression (LR) based on single-locus analysis. However, such a single-locus analysis leads to the well-known multiplicity problem, with a risk of inflating type I error and reducing power. Dimension reduction-based techniques, such as principal component-based logistic regression (PC-LR), partial least squares-based logistic regression (PLS-LR), have recently gained much attention in the analysis of high dimensional genomic data. However, the performance of these methods is still not clear, especially in GWAS. We conducted simulations and real data application to compare the type I error and power of PC LR, PLS-LR and LR applicable to GWAS within a defined single nucleotide polymorphism (SNP) set region. We found that PC-LR and PLS can reasonably control type I error under null hypothesis. On contrast, LR, which is corrected by Bonferroni method, was more conserved in all simulation settings. In particular, we found that PC-LR and PLS-LR had comparable power and they both outperformed LR, especially when the causal SNP was in high linkage disequilibrium with genotyped ones and with a small effective size in simulation. Based on SNP set analysis, we applied all three methods to analyze non-small cell lung cancer GWAS data. PMID- 26243517 TI - Class II transactivator (CIITA) mediates transcriptional repression of pdk4 gene by interacting with hypermethylated in cancer 1 (HIC1). AB - Increased accumulation and/or impaired utilization of fatty acid in extra-adipose tissues are implicated in the pathogenesis of insulin resistance and type 2 diabetes. Pyruvate dehydrogenase kinase 4 (Pdk4) is a key enzyme involved in fatty oxidation and energy expenditure, and its expression can be repressed by pro-inflammatory stimuli. Previously, we have shown that class II transactivator (CIITA) mediates the adverse effect of interferon gamma (IFN-gamma) in skeletal muscle cells by cooperating with hypermethylated in cancer 1 (HIC1) to repress silent information regulator 1 (SIRT1) transcription. Building upon this finding, we report here that CIITA interacted with HIC1 via the GTP-binding domain (GBD) while HIC1 interacted with CIITA via the BTB/POZ domain. The GBD domain was required for CIITA to repress SIRT1 transcription probably acting as a bridge for CIITA to bind to HIC1 and consequently to bind to the SIRT1 promoter. IFN-gamma stimulation, CIITA over-expression, or HIC1 over-expression repressed Pdk4 promoter activity while silencing either CIITA or HIC1 normalized Pdk4 expression in the presence of IFN-gamma. An increase in SIRT1 expression or activity partially rescued Pdk4 expression in the presence of CIITA, but SIRT1 inhibition abrogated Pdk4 normalization even in the absence of CIITA. Taken together, our data have identified a HIC1-CIITA-SIRT1 axis that regulates Pdk4 transcription in response to IFN-gamma stimulation. PMID- 26243518 TI - Co-firing of levator palpebrae and masseter muscles links the masticatory and oculomotor system in humans. AB - Simultaneous co-firing of the levator palpebrae (LP) and pterygoid muscles were recorded in Marcus Gann Syndrome (MGS) patients in early clinical studies. "Release hypothesis" proposed an intrinsic masticatory oculomotor neural circuit and this kind circuit, which, however, has been observed only in amphibian. On the other hand, congenital miswiring hypothesis has overwhelmed other interpretations. However, the same phenomenon visualized in MGS cases was unveiled in human subjects without any sign of congenital oculomotor disorder. To further study co-firing of the upper eyelid and jaw muscles, we applied non invasive EMG recording of the upper eyelid and ipsilateral masseter muscle belly in nine healthy volunteers. LP activity was determined initially by looking upward and active retraction of upper eyelid with head fixed. Then, dual channel inputs from upper eyelid and masseter muscle was recorded during tooth occlusion motivated by isometric masseter muscle contraction without jaw and face moving. The EMG recorded from upper eyelid when the subjects retracted eyelid with head fixed exhibited the same pattern as that collected during tooth occlusion, but the pattern was completely different from EMG of active eye closure. This reflects tooth occlusion evoked LP activity. Then, simultaneous co-firing of the LP and masseter muscle was recorded simultaneously during tooth occlusion without jaw movement. Finally, the aforementioned co-firing was recorded when the subjects conducted rhythmic occlusion and synchronous EMG from both muscles was acquired. In conclusions, humans may also have an intrinsic masticatory oculomotor circuit and release hypothesis may apply, at least, to some cases of MGS. PMID- 26243519 TI - Impact of crosslinking/riboflavin-UVA-photodynamic inactivation on viability, apoptosis and activation of human keratocytes in vitro. AB - Riboflavin-UVA photodynamic inactivation is a potential treatment alternative in therapy resistant infectious keratitis. The purpose of our study was to determine the impact of riboflavin-UVA photodynamic inactivation on viability, apoptosis and activation of human keratocytes in vitro. Primary human keratocytes were isolated from human corneal buttons and cultured in DMEM/Ham's F12 medium supplemented with 10% fetal calf serum. Keratocytes underwent UVA light illumination (375 nm) for 4.10 minutes (2 J/cm2) during exposure to different concentrations of riboflavin. Twenty-four hours after treatment, cell viability was evaluated photometrically, whereas apoptosis, CD34 and alpha-smooth muscle actin (alpha-SMA) expression were assessed using flow cytometry. We did not detect significant changes in cell viability, apoptosis, CD34 and alpha-SMA expression in groups only treated with riboflavin or UVA light. In the group treated with riboflavin-UVA-photodynamic inactivation, viability of keratocytes decreased significantly at 0.1% riboflavin (P<0.01) while the percentage of CD34 (P<0.01 for both 0.05% and 0.1% riboflavin) and alpha-SMA positive keratocytes (P<0.01 and P<0.05 for 0.05% and 0.1% riboflavin, respectively) increased significantly compared to the controls. There was no significant change in the percentage of apoptotic keratocytes compared to controls at any of the used riboflavin concentrations (P=0.09 and P=0.13). We concluded that riboflavin-UVA photodynamic-inactivation decreases viability of myofibroblastic transformation and multipotent haematopoietic stem cell transformation; however, it does not have an impact on apoptosis of human keratocytes in vitro. PMID- 26243520 TI - Delorme's operation plus sphincteroplasty for complete rectal prolapse associated with traumatic fecal incontinence. AB - Rectal prolapse associated with traumatic fecal incontinence is a rare clinical combination. This study was designed to assess Delorme's operation with sphincteroplasty as a surgical management of this combination in terms of recurrence and improvement of fecal incontinence. In this prospective study, we enrolled patients suffering from short, full-thickness rectal prolapse associated with traumatic fecal incontinence who had been admitted to Alexandria Main University Hospital during the period of May 2010-January 2013. Preoperative data including cause of trauma, duration of symptoms, results of anal manometry, and degree of fecal incontinence using Wexner score were collected from all patients. Delorme's procedure with overlap sphincteroplasty was done in all patients. Recurrence of prolapse and improvement of fecal incontinence were assessed after 1, 3, 6 and 12 months. The study included 13 patients aged (32+/-8.7) years, 9 females and 4 males. Cause of sphincteric injury included previous anal surgery in 7 patients and normal labor in 6 patients. Duration between sphincteric injury and operation was (8.08+/-2.47) months. Preoperative Wexner's mean score was 16.07+/-3.4. Early postoperative complications included superficial wound infection (69.2%), minor wound dehiscence (61.5%), and postoperative bleeding (7.6%). Recurrence was detected in 1 patient at 6 month follow-up. Wexner's score showed significant improvement for all patients after 6 months (4.00+/-2.04). In conclusion, combination of Delorme's procedure and sphincteroplasty for treatment of patients with short complete rectal prolapse associated with traumatic fecal incontinence is a safe, effective surgical management with satisfactory results regarding anatomical and functional outcomes. PMID- 26243521 TI - Distraction osteogenesis for correction of post ankylosis mandibular deformities. AB - Temporomandibular joint ankylosis, a debilitating disease mainly affecting children, is characterized by progressive restriction of mouth opening and maxilla-mandibular developmental deformities. Craniofacial distraction osteogenesis has been developed as a standard surgical strategy for rectification of craniofacial deformities. The purpose of this study was to assess mono-planar distraction devices for the correction of various mandibular asymmetries in patients with unilateral temporomandibular joint ankylosis who developed restricted mouth opening and mandibular retrognathia. All patients were treated using one-stage distraction osteogenesis followed by temporalis fascia interpositional arthroplasty under general anesthesia. A significant increase in mandibular ramus and base length was observed. Although an increase in anterior lower facial height was observed, it was not significant statistically. A decrease in posterior lower facial height and corpus was observed. Oblique distraction with angular osteotomy allowed lengthening of both the ramus and corpus, yielding satisfactory results and hence eliminating the need of secondary surgery. In conclusion, univector internal distractors are effective for correction of multi-planar mandibular deficiencies by optimizing its placement through meticulous planning. PMID- 26243522 TI - TYMS gene 5'- and 3'-untranslated region polymorphisms and risk of non-syndromic cleft lip and palate in an Indian population. PMID- 26243523 TI - Fine-Needle Aspiration Cytology in Breast Cancer Diagnosis Still Dependable; Higher Yield With Triple Assessment Test. PMID- 26243524 TI - Retrospective review of tibial plateau fractures treated by two methods without staging. AB - INTRODUCTION: Management of complex tibial plateau fractures can be challenging for orthopaedic surgeons. Wide disagreement still remains about the best surgical technique to use in these fractures. The purpose of this study was to compare the results of complex tibial plateau fractures treated by an open reduction and internal fixation (ORIF) versus hybrid external fixation (EF) in term of clinical and functional outcomes. MATERIALS AND METHODS: We retrospectively examined a series of 79 patients affected by tibial plateau fractures admitted at our Department between January 2006 and November 2011. Forty-one patients were treated using a hybrid EF; in 38 cases, ORIF technique was used. Clinical evaluation was performed using the method of Rasmussen; functional assessment was made using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire. Residual pain was detected using a Numeric Rating Scale (NRS). RESULTS: The average time to union in the plate group was 17.2 weeks (9.1-45 weeks), while in the EF one 15.9 (7.5-32). The mean overall hospital stay was 14.2 days for the ORIF group and 7.8 for the EF group. At the last follow-up, the mean Rasmussen score was 24.9 (good) in the patients treated with ORIF and 25 (good) in those who received EF. The WOMAC index disclosed a relatively higher score in the EF group (80.5 ORIF-84.2 EF). Pain evaluation revealed no differences between the groups. In terms of complications, deep infection occurred in four (10.5%) patients belonging to the ORIF group and 2 (4.9%) to EF one. Signs of osteoarthritis (OA) were observed in 4 (10.5%) knees that had open reduction and in 11 (26.9%) that had a hybrid external fixator. CONCLUSIONS: Either ORIF or hybrid EF represents a valid treatment option in complex tibial plateau fractures. However, hybrid external fixation has shown relative better functional outcome results, relative lower rate of infection and decreased hospital stays. These aspects make of EF our best choice in case of high-energy complex tibial fractures. PMID- 26243525 TI - Paediatric distal fibula reconstruction using a pedicled composite second metatarsal flap: a technical note. AB - The case of a 4-year-old boy in whom a pedicled second metatarsal flap was used for lateral malleolar reconstruction after lawnmower injury is presented. Leg initial assessment demonstrated a 5cm bone loss at the distal fibula combined with severe soft tissue damage. Immediate healing was achieved with split thickness skin graft but secondary reconstruction was necessary to obtain bone replacement with soft tissue coverage to allow bone growth and shoe donning. To avoid microsurgical fibular epiphyseal transplant morbidity and complications, we used a pedicled second metatarsal flap based on the dorsalis pedis vessels including the second metatarsal bone, the skin of the second toe and the brevis pedis muscle. Repair of the donor side was performed with direct suture and no post-operative course complication was noted. At seven-year follow-up, transferred bone had excellent growth and the patient had adequate ankle function and stable ride. The case provides technique descriptions, considerations in the paediatric population, an overview of other techniques and a seven-year follow up. It suggests that vascularized chimeric second metatarsal flap may be a useful option in paediatric distal fibula reconstruction. PMID- 26243527 TI - Coevolution can explain defensive secondary metabolite diversity in plants. AB - Many plant species produce defensive compounds that are often highly diverse within and between populations. The genetic and cellular mechanisms by which metabolite diversity is produced are increasingly understood, but the evolutionary explanations for persistent diversification in plant secondary metabolites have received less attention. Here we consider the role of plant herbivore coevolution in the maintenance and characteristics of diversity in plant secondary metabolites. We present a simple model in which plants can evolve to invest in a range of defensive toxins, and herbivores can evolve resistance to these toxins. We allow either single-species evolution or reciprocal coevolution. Our model shows that coevolution maintains toxin diversity within populations. Furthermore, there is a fundamental coevolutionary asymmetry between plants and their herbivores, because herbivores must resist all plant toxins, whereas plants need to challenge and nullify only one resistance trait. As a consequence, average plant fitness increases and insect fitness decreases as number of toxins increases. When costs apply, the model showed both arms race escalation and strong coevolutionary fluctuation in toxin concentrations across time. We discuss the results in the context of other evolutionary explanations for secondary metabolite diversification. PMID- 26243528 TI - The effect of impurities in ultra-thin hydrogenated silicene and germanene: a first principles study. AB - Spin polarized density functional theory within the GGA-PBE and HSE06 approach for the exchange correlation term has been used to investigate the stability and electronic properties of nitrogen and boron impurities in single layers of silicane and germanane. We have observed that these impurities have lower formation energies in silicane and germanane when compared to their counterparts in graphane. We have also noticed that the adsorption of H atoms in the vicinity of defects stabilizes the system. In addition, we have shown that the electronic properties of silicane and germanane can be tuned when N and B are incorporated in the Si and Ge network. N-doping and B-doping give rise to n-type and p-type semiconductor properties. However, the adsorption of H atoms quenches the doping effects. PMID- 26243526 TI - Noisy neighbourhoods: quorum sensing in fungal-polymicrobial infections. AB - Quorum sensing was once considered a way in which a species was able to sense its cell density and regulate gene expression accordingly. However, it is now becoming apparent that multiple microbes can sense particular quorum-sensing molecules, enabling them to sense and respond to other microbes in their neighbourhood. Such interactions are significant within the context of polymicrobial disease, in which the competition or cooperation of microbes can alter disease progression. Fungi comprise a small but important component of the human microbiome and are in constant contact with bacteria and viruses. The discovery of quorum-sensing pathways in fungi has led to the characterization of a number of interkingdom quorum-sensing interactions. Here, we review the recent developments in quorum sensing in medically important fungi, and the implications these interactions have on the host's innate immune response. PMID- 26243529 TI - Medication histories by pharmacy technicians and physicians in an emergency department. AB - BACKGROUND: Medication histories (MHs) obtained at the time of patients' admission to hospital are often incomplete, and lack of information about patients' actual medicine use can potentially lead to prescribing failures and serious adverse events. Uses of clinical pharmacists in obtaining MHs are beneficial, but due to limited economic resources clinical pharmacists cannot be present in every hospital ward, and therefore pharmacy technicians (PTs) could probably be trained in obtaining MHs. OBJECTIVE: To compare discrepancies in MHs obtained by physicians and PTs in an emergency department. Second to evaluate, whether PTs could assist and/or replace physicians in obtaining MHs. METHODS: The study was conducted in the emergency department at Svendborg Hospital, Denmark and patients treated with a minimum of three prescribed medicines were included. On patients' admission to hospital, physicians recorded the primary MHs, and within 48 h the secondary MHs were made by PTs. All MHs were conducted using standard guidelines. A clinical pharmacist reviewed the MHs, and based on these reviews, a final medication list was defined, and the MHs were compared to this. The discrepancies were registered with respect to type and therapeutic group (medicines). RESULTS: A total of 113 patients were included in this study, and data for 106 patients were analysed. On average, three discrepancies were detected for each patient in the primary MHs, and less than one discrepancy per patient in the secondary MHs. A total of 1075 prescriptions were registered, and for the physicians, 287 discrepancies (27 % of total prescriptions) were found, and for PTs the number was 28 (2 % of total prescriptions). The commonly detected discrepancy was "drug missing in the electronic patient record". The largest number of discrepancies was found for nervous system medications (ATC group N), medicines from ATC group A (alimentary tract and metabolism) and respiratory medicine (ATC group R). CONCLUSION: Fewer discrepancies in the MHs obtained by PTs than physicians were detected compared to standard medicine lists made by an experienced clinical pharmacist. PMID- 26243530 TI - Therapy-related acute myeloid leukemia in autoimmune diseases: caveats and pitfalls. PMID- 26243532 TI - Anxiety-related threat bias in recognition memory: the moderating effect of list composition and semantic-similarity effects. AB - Individuals with high anxiety show bias for threatening information, but it is unclear whether this bias affects memory. Recognition memory studies have shown biases for recognising and rejecting threatening items in anxiety, prompting the need to identify moderating factors of this effect. This study focuses on the role of semantic similarity: the use of many semantically related threatening words could increase familiarity for those items and obscure anxiety-related differences in memory. To test this, two recognition memory experiments varied the proportion of threatening words in lists to manipulate the semantic similarity effects. When similarity effects were reduced, participants with high trait anxiety were biased to respond "new" to threatening words, whereas when similarity effects were strong there was no effect of anxiety on memory bias. Analysis of the data with the drift diffusion model showed that the bias was due to differences in processing of the threatening stimuli rather than a simple response bias. These data suggest that the semantic similarity of the threatening words significantly affects the presence or absence of anxiety-related threat bias in recognition memory. The results indicate that trait anxiety is associated with a bias to decide that threatening stimuli were not previously studied, but only when semantic-similarity effects are controlled. Implications for theories of anxiety and future studies in this domain are discussed. PMID- 26243531 TI - Trends in antithrombotic drug use and adherence to non-vitamin K oral anticoagulants in the Netherlands. AB - BACKGROUND: Non-vitamin K oral anticoagulants (NOACs) became available in the Netherlands in 2008, providing another antithrombotic treatment besides vitamin K antagonists (VKAs) and antiplatelet agents (APAs). OBJECTIVE: To describe the patterns of antithrombotic drug use between 2008 and 2013 by examination of dispensing data form community pharmacies in the Netherlands; to determine the concomitant use of NOACs with VKAs and APAs and switching between the drug classes; and to compare adherence to NOACs with adherence to APAs. SETTING: An observational retrospective study was conducted using routinely collected dispensing data from Dutch community pharmacies. METHODS: For each calendar year, the numbers of NOAC, VKA, and APA users were calculated. Adherence was determined for NOACs and APAs by the percentage of days covered by medication (PDC). Information on the prescribed daily dose of VKAs was unavailable. MAIN OUTCOME MEASURES: Comparison of age, sex, and co-medications of users of the three drug classes; concomitant use of different antithrombotic drug classes and switching between these in each year; and mean PDC and percentages of all users with a PDC above 80 %. RESULTS: NOAC use increased during the study period to 29,687 users in 2013. In that year there were 484,024 VKA users and 1313,032 APA users. Compared with users of VKAs, NOAC users were slightly younger and more frequently used antiarrhythmic drugs and beta blockers as co-medications. Substantial numbers of patients were dispensed potentially harmful combinations in 2013: 820 subjects were dispensed NOACs together with VKAs, and 684 subjects were dispensed NOACs, VKAs, and APAs concomitantly. Mean adherence to NOACs was 84.2 % compared with 87.3 % to APA. One in four NOAC users had a PDC lower than 80 % compared with one in five APA users. CONCLUSION: Our findings show increasing use of NOACs by outpatients. The number of patients taking potentially harmful combinations of antithrombotic drugs was substantial. Adherence to NOACs in daily practice may be suboptimal to prevent thrombotic events. PMID- 26243533 TI - N-Acetylglycine Cation Tautomerization Enabled by the Peptide Bond. AB - We present a combined experimental and theoretical study of the ionization of N acetylglycine molecules by 48 keV O(6+) ions. We focus on the single ionization channel of this interaction. In addition to the prompt fragmentation of the N acetylglycine cation, we also observe the formation of metastable parent ions with lifetimes in the microsecond range. On the basis of density functional theory calculations, we assign these metastable ions to the diol tautomer of N acetylglycine. In comparison with the simple amino acids, the tautomerization rate is higher because of the presence of the peptide bond. The study of a simple biologically relevant molecule containing a peptide bond allows us to demonstrate how increasing the complexity of the structure influences the behavior of the ionized molecule. PMID- 26243534 TI - Additive prognostic value of coronary artery calcium score and renal function in patients with acute chest pain without known coronary artery disease: up to 5 year follow-up. AB - Long-term incremental prognostic value of renal function over coronary artery calcium score (CACS) in symptomatic patients without known coronary artery disease (CAD) is unclear. The objective of this study was to examine additive prognostic value of renal function over CACS in patients with acute chest pain suspected of CAD. Renal function and CACS were assessed in patients without known CAD who presented to the emergency department with chest pain from 2005 to 2008. Renal function was assessed using estimated glomerular filtration rate (eGFR), and chronic kidney disease (CKD) was defined as eGFR < 60 mL/min/1.73 m(2). A total of 949 patients (804 non-CKD and 145 CKD, age 54 +/- 13 years) were included. During the follow-up period of up to 5.3 years, major adverse cardiac events (MACE) occurred in 5.7% of patients (19 cardiac deaths, 6 myocardial infarction and 29 late coronary revascularization). Annualized MACE rate was higher in patients in higher CACS categories with and without CKD (p = 0.011 and p < 0.001 respectively). In multivariate logistic regression analysis, CACS categories (CACS 1-100: HR 3.17, p = 0.005; CACS 101-400: HR 7.68, p < 0.001; CACS > 400: HR 8.88, p < 0.001) and CKD (HR 10.18, p < 0.001) were independent predictors for MACE. Both adding renal function and CACS significantly improved the overall predictive performance (p < 0.001 for global Chi square increase) from Framingham risk categories or thrombolysis in myocardial infarction (TIMI) risk score. Both CACS and renal function were independent predictors for future cardiac events and provided additive prognostic value to each other and over either Framingham risk categories or TIMI risk score. PMID- 26243535 TI - Dual processing theory and experts' reasoning: exploring thinking on national multiple-choice questions. AB - BACKGROUND: An ongoing debate exists in the medical education literature regarding the potential benefits of pattern recognition (non-analytic reasoning), actively comparing and contrasting diagnostic options (analytic reasoning) or using a combination approach. Studies have not, however, explicitly explored faculty's thought processes while tackling clinical problems through the lens of dual process theory to inform this debate. Further, these thought processes have not been studied in relation to the difficulty of the task or other potential mediating influences such as personal factors and fatigue, which could also be influenced by personal factors such as sleep deprivation. We therefore sought to determine which reasoning process(es) were used with answering clinically oriented multiple-choice questions (MCQs) and if these processes differed based on the dual process theory characteristics: accuracy, reading time and answering time as well as psychometrically determined item difficulty and sleep deprivation. METHODS: We performed a think-aloud procedure to explore faculty's thought processes while taking these MCQs, coding think-aloud data based on reasoning process (analytic, nonanalytic, guessing or combination of processes) as well as word count, number of stated concepts, reading time, answering time, and accuracy. We also included questions regarding amount of work in the recent past. We then conducted statistical analyses to examine the associations between these measures such as correlations between frequencies of reasoning processes and item accuracy and difficulty. We also observed the total frequencies of different reasoning processes in the situations of getting answers correctly and incorrectly. RESULTS: Regardless of whether the questions were classified as 'hard' or 'easy', non-analytical reasoning led to the correct answer more often than to an incorrect answer. Significant correlations were found between self reported recent number of hours worked with think-aloud word count and number of concepts used in the reasoning but not item accuracy. When all MCQs were included, 19 % of the variance of correctness could be explained by the frequency of expression of these three think-aloud processes (analytic, nonanalytic, or combined). DISCUSSION: We found evidence to support the notion that the difficulty of an item in a test is not a systematic feature of the item itself but is always a result of the interaction between the item and the candidate. Use of analytic reasoning did not appear to improve accuracy. Our data suggest that individuals do not apply either System 1 or System 2 but instead fall along a continuum with some individuals falling at one end of the spectrum. PMID- 26243536 TI - Soft yellowish papules on the neck: a clinicopathological challenge. PMID- 26243537 TI - Long-term trends in cardiovascular disease mortality and association with respiratory disease. AB - The recent decline in cardiovascular disease mortality in Western countries has been linked with changes in life style and treatment. This study considers periods of decline before effective medical interventions or knowledge about risk factors. Trends in annual age-standardized death rates from cerebrovascular disease, heart disease and circulatory disease, and all cardiovascular disease are reviewed for three phases, 1881-1916, 1920-1939, and 1940-2000. There was a consistent decline in the cerebrovascular disease death rate between 1891 and 2000, apart from brief increases after the two world wars. The heart disease and circulatory disease death rate was declining between 1891 and 1910 before cigarette smoking became prevalent. The early peak in cardiovascular mortality in 1891 coincided with an influenza pandemic and a peak in the death rate from bronchitis, pneumonia and influenza. There is also correspondence between short term fluctuations in the death rates from these respiratory diseases and cardiovascular disease. This evidence of ecological association is consistent with the findings of many studies that seasonal influenza can trigger acute myocardial infarction and episodes of respiratory infection are followed by increased risk of cardiovascular events. Vaccination studies could provide more definitive evidence of the role in cardiovascular disease and mortality of influenza, other viruses, and common bacterial agents of respiratory infection. PMID- 26243539 TI - ortho-(Methyltosylaminoethynyl)benzyl glycosides as new glycosyl donors for latent-active glycosylation. AB - A new glycosylation protocol employing ortho-(methyltosylaminoethynyl)benzyl glycosides as glycosyl donors and TMSOTf as the catalyst is disclosed. These donors can be readily prepared from the corresponding 'latent' ortho-iodobenzyl glycosides via a Sonogashira coupling, thus providing a new approach for the 'latent-active' synthesis of glycans. PMID- 26243538 TI - Unexpected co-linearity of Hox gene expression in an aculiferan mollusk. AB - BACKGROUND: Mollusca is an extremely diverse animal phylum that includes the aculiferans (worm-like aplacophorans and eight-shelled polyplacophorans) and their sister group, the conchiferans, comprising monoplacophorans, bivalves (clams, mussels), gastropods (snails, slugs), scaphopods (tusk shells) and cephalopods (squids, octopuses). Studies on mollusks have revealed an overall number of 11 Hox genes in seven out of eight molluscan "class"-level taxa, but expression data of key developmental regulators such as homeotic genes are only available for three gastropod and two cephalopod species. These show that Hox genes are involved in the formation of specific features including shell, foot, funnel or tentacles and not in antero-posterior body plan patterning as in most other bilaterian animals. The role of Hox genes in non-conchiferan (i.e., aculiferan) mollusks remains entirely unknown. RESULTS: Here we present the first data on the expression of seven Hox genes in apolyplacophoran mollusk, Acanthochitona crinita. In A. crinita the Hox genes Acr-Hox1-5, Hox7 and Post2 are expressed in a co-linear pattern along the antero-posterior axis, but not in molluscan-specific features such as the shell or the foot. The expression pattern is restricted to the post-trochal region and the transcripts are present in ecto , endo- and mesodermal cell layers. Contrary to the situation in gastropods and cephalopods, we did neither find Hox gene expression in distinct neural subsets of A. crinita, nor in its developing shell plates. CONCLUSIONS: Our analysis and comparison with other lophotrochozoans indicate that the basal role of Hox genes is in antero-posterior axis patterning in mollusks, similar to the vast majority of bilaterian animals, and that this role has been conserved in polyplacophorans, while co-option into patterning of evolutionary novelties emerged either at the base of Conchifera or independently in gastropods and cephalopods. These morphological innovations most likely contributed to the evolutionary success of its representatives, as exemplified by, e.g., the wide ecological range and species richness of gastropods. PMID- 26243540 TI - Early acute ischaemic stroke in two patients with acute type B aortic dissection: an unusual complication. AB - Aortic thoracic dissection (AD) is a serious cardiovascular disease. According to the Stanford classification; type A involves the ascending aorta and type B the descending distal to the left subclavian artery. Neurological complications secondary to AD are devastating. Ischaemic stroke and hypoxic encephalopathy are early-recognised complications of type A as the arch vessels can be involved AD. Although, late ischaemic stroke had been reported in 1.4-5% of patients with type B dissection, early stroke is very unusual as it cannot be simply explained by AD anatomical pathogenesis. We report two patients who presented with type B AD complicated by early ischaemic strokes. Work-up revealed significant cardiomyopathies in both patients but with left ventricle thrombus in one. In both patients the strokes were felt to be of cardioembolic origin. PMID- 26243541 TI - Laparoscopic 'sleeve' caecectomy for idiopathic solitary caecal ulcer mimicking appendicitis. AB - Idiopathic ulcer of the caecum is a rare condition of unknown aetiology. Its clinical presentation may mimic various pathologies, including appendicitis, inflammatory bowel disease and caecal malignancy. A definitive diagnosis is rarely established preoperatively, and is usually only confirmed histologically following surgical resection. We report a case of a young patient with caecal ulceration presenting with symptoms and signs of appendicitis, in whom laparoscopic anterior 'sleeve' caecectomy was performed to excise an inflammatory looking mass involving the caecum. Histological examination demonstrated a deep mucosal ulcer and subsequent colonoscopy did not reveal any further pathology. PMID- 26243542 TI - Determination of the Cytosolic NADPH/NADP Ratio in Saccharomyces cerevisiae using Shikimate Dehydrogenase as Sensor Reaction. AB - Eukaryotic metabolism is organised in complex networks of enzyme catalysed reactions which are distributed over different organelles. To quantify the compartmentalised reactions, quantitative measurements of relevant physiological variables in different compartments are needed, especially of cofactors. NADP(H) are critical components in cellular redox metabolism. Currently, available metabolite measurement methods allow whole cell measurements. Here a metabolite sensor based on a fast equilibrium reaction is introduced to monitor the cytosolic NADPH/NADP ratio in Saccharomyces cerevisiae: NADP + shikimate ? NADPH + H(+) + dehydroshikimate. The cytosolic NADPH/NADP ratio was determined by measuring the shikimate and dehydroshikimate concentrations (by GC-MS/MS). The cytosolic NADPH/NADP ratio was determined under batch and chemostat (aerobic, glucose-limited, D = 0.1 h(-1)) conditions, to be 22.0 +/- 2.6 and 15.6 +/- 0.6, respectively. These ratios were much higher than the whole cell NADPH/NADP ratio (1.05 +/- 0.08). In response to a glucose pulse, the cytosolic NADPH/NADP ratio first increased very rapidly and restored the steady state ratio after 3 minutes. In contrast to this dynamic observation, the whole cell NADPH/NADP ratio remained nearly constant. The novel cytosol NADPH/NADP measurements provide new insights into the thermodynamic driving forces for NADP(H)-dependent reactions, like amino acid synthesis, product pathways like fatty acid production or the mevalonate pathway. PMID- 26243543 TI - Negative Effects of SRD5A1 on Nuclear Activity of Progesterone Receptor Isoform B in JEG3 Cells. AB - Progesterone withdrawal signals labor in mammals. Elevated intracellular metabolism contributes to progesterone functional withdrawal through unknown mechanism, which is thought to act via progesterone receptor (PR). This study aims to investigate molecular mechanisms underlying progesterone withdrawal during pregnancy and labor. We investigated the role of 5alpha-reductase type I (SRD5A1) in enzymatic catalysis of progesterone and loss of PR function in a human trophoblast choriocarcinoma cell line JEG3. The PR isoform B (PR-B) was robustly expressed in JEG3 cells. The SRD5A1 small-interfering RNA knockdown led to significant increase in PR-B nuclear import, ectopic, whereas SRD5A1 overexpression resulted in remarkable inhibition of nuclear PR-B in P4-treated cells. Repression of SRD5A1 activated PR-B responsive gene, whereas overexpression of SRD5A1 possessed an inhibitory effect. JEG3 cell line is a valuable tool to study mechanisms responsible for loss of PR function and screening of drugs for preterm birth treatment. Our study aims to investigate the molecular mechanisms underlying progesterone withdrawal during pregnancy and labor. PMID- 26243544 TI - Sex-Specific Changes in Renal Angiotensin-Converting Enzyme and Angiotensin Converting Enzyme 2 Gene Expression and Enzyme Activity at Birth and Over the First Year of Life. AB - OBJECTIVE: Angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) are key enzymes of the renin-angiotensin system. We investigated developmental changes in renal ACE and ACE2 gene expression and activity in both male and female sheep. METHODS: Three groups of sheep (fetus, newborn, and adult) were used. Renal ACE and ACE2 activities, messenger RNA (mRNA), and protein expression were studied. RESULTS: Renal ACE and ACE2 activities increased at 1 year in males, while there were no changes throughout development in females. Renal ACE and ACE2 mRNA and protein showed no sex differences but increased by 1 year of age. CONCLUSION: There are sex-related differences in the development of renal-converting enzyme activities that may have functional implications in terms of the regulation of blood pressure and renal function in men and women. The difference in the patterns of gene expression and enzyme activity indicates that changes in gene expression may not accurately reflect changes in activity. PMID- 26243545 TI - Agonist-Dependent Downregulation of Progesterone Receptors in Human Cervical Stromal Fibroblasts. AB - Progesterone (P(4)) maintains uterine quiescence during the majority of pregnancy, whereas diminished progesterone receptor (PR) expression and/or activity (ie, functional P(4) withdrawal) promotes parturition. To investigate the regulation of PR expression in cervical stroma, fibroblasts from premenopausal hysterectomy specimens were prepared. Greater than 99% of the cultures were vimentin positive (mesenchymal cell marker) with only occasional cytokeratin-8 positivity (epithelial cell marker) and no evidence of CD31 positive (endothelial cell marker) cells. Cells were immunolabeled with antibodies directed against PRs (PR-A and PR-B), estrogen receptor alpha (ER alpha), and glucocorticoid receptor-alpha/beta (GR-alpha/beta). All cells were uniformly immunopositive for ER-alpha and GR-alpha/beta but did not express PRs. Incubation of cells with 10(-8) mol/L 17beta-estradiol induced a time-dependent increase in PR-A and PR-B messenger RNAs (mRNAs) by quantitative real-time polymerase chain reactions and proteins by immunoblotting and immunofluorescence. Incubation of cervical fibroblasts with PR ligands (medroxyprogesterone acetate or Org-2058) downregulated PR-A and PR-B levels. Coincubation of cells with PR ligands plus RU-486, a PR antagonist, partially abrogated agonist-induced receptor downregulation. Dexamethasone, a pure glucocorticoid, had no inhibitory effect on PR expression. These results indicate that progestins and estrogens regulate PR expression in cervical fibroblasts. We postulate that hormonal regulation of PR expression in the cervical stroma may contribute to functional P(4) withdrawal in preparation for parturition. PMID- 26243546 TI - Maternal Obesity, Cage Density, and Age Contribute to Prostate Hyperplasia in Mice. AB - Identification of modifiable risk factors is gravely needed to prevent adverse prostate health outcomes. We previously developed a murine precancer model in which exposure to maternal obesity stimulated prostate hyperplasia in offspring. Here, we used generalized linear modeling to evaluate the influence of additional environmental covariates on prostate hyperplasia. As expected from our previous work, the model revealed that aging and maternal diet-induced obesity (DIO) each correlated with prostate hyperplasia. However, prostate hyperplasia was not correlated with the length of maternal DIO. Cage density positively associated with both prostate hyperplasia and offspring body weight. Expression of the glucocorticoid receptor in prostates also positively correlated with cage density and negatively correlated with age of the animal. Together, these findings suggest that prostate tissue was adversely patterned during early life by maternal overnutrition and was susceptible to alteration by environmental factors such as cage density. Additionally, prostate hyperplasia may be acutely influenced by exposure to DIO, rather than occurring as a response to worsening obesity and comorbidities experienced by the mother. Finally, cage density correlated with both corticosteroid receptor abundance and prostate hyperplasia, suggesting that overcrowding influenced offspring prostate hyperplasia. These results emphasize the need for multivariate regression models to evaluate the influence of coordinated variables in complicated animal systems. PMID- 26243547 TI - Fertilization competence of the egg-coating envelope is regulated by direct interaction of dicalcin and gp41, the Xenopus laevis ZP3. AB - Fertilization begins with species-restricted interaction of sperm and the egg coating envelope, which includes a three-dimensional meshwork of filaments composed of glycoproteins (called ZP proteins). Growing evidence has unveiled the molecular nature of ZP proteins; however, the structural property conferring fertilization competence to the egg-coating envelope remains unknown. Here, we show the molecular mechanism that mediates direct interaction between dicalcin, a novel fertilization-suppressive ZP protein-associated protein, and gp41, a Xenopus laevis ortholog of mammalian ZP3, and subsequently demonstrate the structural basis of the envelope for fertilization competence. The interactive regions between dicalcin and gp41 comprised five and nine amino acid residues within dicalcin and twenty-three within gp41 [corrected]. Synthetic peptides corresponding to these regions dramatically affected fertilization: treatment with dicalcin- or gp41-derived peptides decreased or increased fertilization rates, respectively. Prior application of these peptides caused distinct alterations in the in vivo lectin-staining pattern of the envelope as well. Transmission electron microscopy analysis revealed that the dicalcin-derived peptide induced the formation of a well-organized meshwork, whereas the gp41 derived peptide caused the formation of a significantly disorganized meshwork. These findings indicated that the fertilization competence of the egg-coating envelope is crucially regulated by the direct interaction between dicalcin and gp41. PMID- 26243548 TI - Assessing the family dynamics of childhood maltreatment history with the Childhood Attachment and Relational Trauma Screen (CARTS). AB - BACKGROUND: Existing survey measures of childhood trauma history generally fail to take into account the relational-socioecological environment in which childhood maltreatment occurs. Variables such as the relationship between the perpetrator and the victim, the emotional availability of caregivers, witnessing the abuse of others, and the respondent's own thoughts, feelings, and actions in response to maltreatment are rarely assessed by current measures. METHODS: To address these concerns, the current study further investigated the family dynamics of childhood maltreatment using the Childhood Attachment and Relational Trauma Screen (CARTS) in 1,782 persons assessed online. RESULTS: Paired differences in means between item-rated descriptiveness of self, mothers, and fathers suggested that respondents' relationship with their biological fathers was less positive and secure than their relationship with their biological mothers, and that biological fathers were more often the perpetrator of emotional, physical, and sexual abuse than biological mothers. However, results further suggested that ratings between self, mothers, and fathers were positively correlated such that, for example, reports of a mother's or a respondent's own abusive behavior were more likely in the presence of reports of a father's abusive behavior. In addition, analyses evaluating witnessing violence demonstrated that fathers were rated as more often violent toward mothers than the reverse, although intimate partner violence was also frequently bidirectional. Analyses of sibling ratings further demonstrated that older brothers were either as or more frequently abusive when compared with parents. Finally, results suggested that childhood emotional, physical, and sexual abuse were much more often perpetrated by family members than extra-familial and non family members. CONCLUSIONS: In so far as these findings are consistent with the prior childhood trauma and attachment literature, the current study further supports the utility of the CARTS as a means of assessing the family dynamics of childhood attachment and maltreatment within a relational-socioecological framework. PMID- 26243549 TI - Reliability of muscle strength assessment in chronic post-stroke hemiparesis: a systematic review and meta-analysis. AB - BACKGROUND: Muscle weakness is the main cause of motor impairment among stroke survivors and is associated with reduced peak muscle torque. OBJECTIVE: To systematically investigate and organize the evidence of the reliability of muscle strength evaluation measures in post-stroke survivors with chronic hemiparesis. DATA SOURCES: Two assessors independently searched four electronic databases in January 2014 (Medline, Scielo, CINAHL, Embase). STUDY SELECTION: Inclusion criteria comprised studies on reliability on muscle strength assessment in adult post-stroke patients with chronic hemiparesis. DATA EXTRACTION: We extracted outcomes from included studies about reliability data, measured by intraclass correlation coefficient (ICC) and/or similar. The meta-analyses were conducted only with isokinetic data. RESULTS: Of 450 articles, eight articles were included for this review. After quality analysis, two studies were considered of high quality. Five different joints were analyzed within the included studies (knee, hip, ankle, shoulder, and elbow). Their reliability results varying from low to very high reliability (ICCs from 0.48 to 0.99). Results of meta-analysis for knee extension varying from high to very high reliability (pooled ICCs from 0.89 to 0.97), for knee flexion varying from high to very high reliability (pooled ICCs from 0.84 to 0.91) and for ankle plantar flexion showed high reliability (pooled ICC = 0.85). CONCLUSION: Objective muscle strength assessment can be reliably used in lower and upper extremities in post-stroke patients with chronic hemiparesis. PMID- 26243550 TI - Correction. PMID- 26243551 TI - Correction. PMID- 26243552 TI - Glycated haemoglobin A1c is associated with low-grade albuminuria in Chinese adults. AB - BACKGROUND AND OBJECTIVE: Diabetes is a strong risk factor for cardiovascular diseases, whereas few studies have investigated simultaneously the associations of glycated haemoglobin A1c (HbA1c), fasting blood glucose (fasting plasma glucose (FPG)) and 2 h postload blood glucose (2 h PG) with low-grade albuminuria, which is an earlier marker of cardiovascular diseases in the general population. Our study aimed to investigate and compare associations of HbA1c, FPG, and 2 h PG levels with risks of low-grade albuminuria in the middle-aged and elderly Chinese. DESIGN AND METHODS: This was a cross-sectional study involving 9188 participants aged 40 years or older. All participants underwent a standard 75 g oral glucose tolerance test. Low-grade albuminuria was defined as the highest quartile of urinary albumin-to-creatinine ratio (ACR) (>6.10 mg/g in males and >8.76 mg/g in females) in respondents without microalbuminuria or macroalbuminuria. RESULTS: HbA1c, FPG and 2 h PG were all significantly correlated with urinary ACR after adjustment for confounders (all p values <0.0001). After adjustment for HbA1c, the relationships of FPG and 2 h PG with ACR reduced to null. HbA1c levels were still significantly associated with ACR after further adjustment for FPG and 2 h PG. Multiple logistic regression showed that risks of low-grade albuminuria were positively associated with HbA1c levels in a dose-response manner. Compared with participants with HbA1c <= 37 mmol/mol (5.5%), ORs (95% CIs) for low-grade albuminuria were 1.05 (0.94 to 1.18), 1.25 (1.04 to 1.50), 1.40 (1.04 to 1.90) and 2.21 (1.61 to 3.03) for HbA1c categories of 38-42 mmol/mol (5.6-6.0%), 43-48 mmol/mol (6.1-6.5%), 49-53 mmol/mol (6.6 7.0%), and >53 mmol/mol (7.0%), respectively (p for trend <0.0001). CONCLUSIONS: HbA1c, but not FPG or 2 h PG, was independently associated with an increased risk of low-grade albuminuria in the middle-aged and elderly Chinese. PMID- 26243554 TI - A case-control study of occupational contact levels in the childhood leukaemia cluster at Seascale, Cumbria, UK. AB - OBJECTIVES: To investigate adult occupational contact levels and risk of childhood leukaemia and non-Hodgkin's lymphoma (LNHL) in Seascale, an association found in other situations of rural population mixing (PM). DESIGN: Matched case control study. SETTING: Seascale, Cumbria, UK. PARTICIPANTS: For each case of LNHL recorded in patients under age 25 years during 1950-2006, up to 20 matched controls were chosen and parental occupational details obtained; an exception was a single working young adult, whose own occupation (and that of controls) was used. PRIMARY OUTCOME MEASURES: Contact levels of occupations were categorised as: low/medium (reference group), high or very high contact levels, as in previous studies, with provision for certain unusual occupations. In particular, specialist policemen responsible for security and access at the nearby Sellafield nuclear complex were allocated to the highest contact category, and those Sellafield employees who worked in controlled areas to the middle (high) category. Since of possible bias, unusual contact aspects noted in the main research and development (R&D) building were reserved for a supplementary analysis. ORs were calculated for the occupational contact levels. RESULTS: Compared to the reference group, the social class adjusted ORs for the high and very high contact categories were 8.18 (95% CI 0.95 to 70.33) and 14.90 (1.20 to 184.90), respectively, with a significant trend across the categories (p value=0.024). In the supplementary analysis with R&D workers moved to the very high contact category, the OR for the latter became 29.68 (2.12 to 415.79), and the p value for trend, 0.011. CONCLUSIONS: The Seascale LNHL excess was most marked among those young people linked with high occupational contact levels; it is therefore not an exception to the pattern of family infection shown by other PM-related excesses. The findings have implications for the choice of controls in certain types of virus study. PMID- 26243553 TI - Impact of family medicine clerkships in undergraduate medical education: a systematic review. AB - OBJECTIVE: Synthesise evidence about the impact of family medicine/general practice (FM) clerkships on undergraduate medical students, teaching general/family practitioners (FPs) and/or their patients. DATA SOURCES: Medline, ERIC, PsycINFO, EMBASE and Web of Knowledge searched from 21 November to 17 December 2013. Primary, empirical, quantitative or qualitative studies, since 1990, with abstracts included. No country restrictions. Full text languages: English, French, Spanish, German, Dutch or Italian. REVIEW METHODS: Independent selection and data extraction by two authors using predefined data extraction fields, including Kirkpatrick's levels for educational intervention outcomes, study quality indicators and Best Evidence Medical Education (BEME) strength of findings' grades. Descriptive narrative synthesis applied. RESULTS: Sixty-four included articles: impact on students (48), teaching FPs (12) and patients (8). Sample sizes: 16-1095 students, 3-146 FPs and 94-2550 patients. Twenty-six studies evaluated at Kirkpatrick level 1, 26 at level 2 and 6 at level 3. Only one study achieved BEME's grade 5. The majority was assessed as grade 4 (27) and 3 (33). Students reported satisfaction with content and process of teaching as well as learning in FM clerkships. They enhanced previous learning, and provided unique learning on dealing with common acute and chronic conditions, health maintenance, disease prevention, communication and problem-solving skills. Students' attitudes towards FM were improved, but new or enhanced interest in FM careers did not persist without change after graduation. Teaching FPs reported increased job satisfaction and stimulation for professional development, but also increased workload and less productivity, depending on the setting. Overall, student's presence and participation did not have a negative impact on patients. CONCLUSIONS: Research quality on the impact of FM clerkships is still limited, yet across different settings and countries, positive impact is reported on students, FPs and patients. Future studies should involve different stakeholders, medical schools and countries, and use standardised and validated evaluation tools. PMID- 26243556 TI - Penicyrones A and B, an epimeric pair of alpha-pyrone-type polyketides produced by the marine-derived Penicillium sp. AB - Two polyketides containing an alpha-pyrone unit, named penicyrones A (1) and B (2), were isolated from a culture broth of the marine-derived Penicillium sp. TPU1271 together with nine known compounds: verrucosidin (3), fructigenine A (4), verrucofortine (5), cyclo-(L-Trp-L-Phe) (6), cyclopenol (7), cyclopenin (8), penipratynolene (9), aspterric acid (10) and viridicatol (11). The structures of 1 and 2 were elucidated by analyzing the spectroscopic data of 1, 2 and their O acetyl derivatives (1a and 2a). Compounds 1 and 2 were epimers of each other at the C-9 position. The absolute configurations of 1 and 2 were assigned on the basis of NOESY data for 1, 2, 1a and 2a, a conformational analysis and the identity of the biogenetic pathway with verrucosidin (3). The planar structure of penicyrones was found in the SciFinder as a compound in the commercial chemical libraries; however, the stereostructure and spectroscopic data were not available. Therefore, this is the first study on the isolation and structure elucidation, including the absolute configurations, of penicyrones A (1) and B (2) as fungal metabolites. Compound 3 exhibited growth inhibitory activity against Mycobacterium smegmatis at 40 MUg per disc (inhibition zone of 11 mm). This is the first study to demonstrate that verrucosidin (3) exhibited anti mycobacterial activity. PMID- 26243555 TI - 'HeART of Stroke (HoS)', a community-based Arts for Health group intervention to support self-confidence and psychological well-being following a stroke: protocol for a randomised controlled feasibility study. AB - INTRODUCTION: Over 152,000 people in the UK have strokes annually and a third experience residual disability. Low mood also affects a third of stroke survivors; yet psychological support is poor. While Arts for Health interventions have been shown to improve well-being in people with mild-to-moderate depression post-stroke, their role in helping people regain sense of self, well-being and confidence has yet to be evaluated. The main aim of this study is to explore the feasibility of conducting a pragmatic multicentre randomised controlled trial to assess the effectiveness and cost-effectiveness of an Arts for Health group intervention ('HeART of Stroke' (HoS)) for stroke survivors. HoS is a 10-session artist-facilitated group intervention held in the community over 14 weeks. It offers a non-judgemental, supportive environment for people to explore sense of self, potentially enhancing well-being and confidence. METHODS AND ANALYSIS: Sixty-four people, up to 2 years post-stroke, recruited via secondary care research staff or community stroke/rehabilitation teams in two UK centres will be randomised to either HoS plus usual care or usual care only. Self-reported outcomes, measured at baseline and approximately 5 months postrandomisation, will include stroke-related, well-being, mood, self-esteem, quality of life and process measures. Analyses will focus on estimating key feasibility parameters (eg, rates of recruitment, retention, intervention attendance). We will develop outcome and resource use data collection methods to inform an effectiveness and cost-effectiveness analysis in the future trial. Interviews, with a sample of participants, will explore the acceptability of the intervention and study processes, as well as experiences of the HoS group. ETHICS AND DISSEMINATION: National Health Service (NHS), Research and Development and University ethical approvals have been obtained. Two peer-reviewed journal publications are planned plus one service user led publication. Findings will be disseminated at key national conferences, local stakeholder events and via institutional websites. TRIAL REGISTRATION NUMBER: ISRCTN99728983. PMID- 26243557 TI - Actinoplanes bogoriensis sp. nov., a novel actinomycete isolated from leaf litter. AB - A novel actinomycete, designated LIPI11-2-Ac043(T), was isolated from leaf litter collected in Indonesia. According to phylogenetic analysis based on the 16S rRNA gene sequence comparisons, strain LIPI11-2-Ac043(T) was closely related to Actinoplanes abujensis A4029(T) (99.3%) and Actinoplanes brasiliensis DSM 43805(T) (98.8%). Spores of strain LIPI11-2-Ac043(T) were motile and the sporangia were spherical. The predominant menaquinone was MK-9(H6) and the principal polar lipids were phosphatidylinositol, phosphatidylethanolamine, phosphatidylglycerol and diphospatidylglycerol. The whole-cell sugars were galactose, glucose and mannose; rhibose, arabinose and xylose were also detected as minor components. The major fatty acids were anteiso-C15:0, iso-C16:0, iso C15:0 and anteiso-C17:0. These data supported the affiliation of strain LIPI11-2 Ac043(T) to the genus Actinoplanes. Meanwhile, the results of DNA-DNA hybridization and physiological and biochemical tests indicated that strain LIPI11-2-Ac043(T) can be distinguished from its closest related species. Therefore, strain LIPI11-2-Ac043(T) represents a novel species of the genus Actinoplanes, for which the name Actinoplanes bogoriensis sp. nov. is proposed. The type strain is LIPI11-2-Ac043(T) (=InaCC A522(T)=NBRC 110975(T)). PMID- 26243558 TI - Well-defined palladium(ii) complexes for ligand-enabled C(sp(3))-alkynylation. AB - The first example of ligand-enabled C(sp(3))-alkynylation of 8-methylquinoline is reported. The reaction is catalysed by well-defined Pd(ii) complexes. The present C(sp(3))-alkynylation has a broad substrate scope as well as functional group tolerance and proceeds efficiently under mild conditions. PMID- 26243559 TI - Clinical Outcomes of Carotid Endarterectomy in Symptomatic and Asymptomatic Patients with Ipsilateral Intracranial Stenosis. AB - BACKGROUND AND PURPOSE: The risk of perioperative stroke and the benefits of carotid endarterectomy (CEA) remain uncertain in the case of an ipsilateral intracranial stenosis. The aim of this observational study was to analyze the early and late outcomes of CEA in patients with a carotid tandem lesion (CTL), defined as a severe stenosis at the bifurcation with any concomitant lesion >=50 % involving the intracranial portion of the ipsilateral internal carotid artery or the main trunk of the anterior or middle cerebral artery. METHODS: From 2000 to 2009, 1143 patients underwent CEA for symptomatic or asymptomatic extracranial carotid stenosis according to the NASCET and ACAS recommendations, respectively. CTLs were diagnosed in 219 patients (19.2 %) by extracranial and transcranial color-coded Doppler sonography combined with noninvasive brain imaging studies. The primary endpoints of the study were perioperative (30-day) stroke and death, and any ipsilateral ischemic adverse events during the follow-up, which ranged from 0.1 to 10 years (mean 4.9 +/- 3.3 years). The rates of the primary endpoints were compared between patients with (group I) and without CTL (group II). RESULTS: Overall, 219 CEAs were performed in group I and 924 in group II. Nearly two in three of the carotid lesions (777 of 1143, 68 %) were symptomatic at presentation (62.1 % in group I vs 69.4 % in group II; p = 0.03), with a 23.8 % rate of stroke (21.9 % in group I vs 24.2 % in group II; p = 0.85). There were 2 (0.9 %) perioperative ipsilateral strokes in group I and 5 (0.5 %) in group II (p = 0.62), and no deaths. The 5-year ipsilateral stroke-free, any stroke-free, and overall survival rates did not differ significantly between patients with and without CTL. CONCLUSIONS: This study has shown that patients with and without CTL who underwent CEA had a similar occurrence of perioperative adverse events (probably due to the extremely low incidence of perioperative complications) and comparable late outcomes, suggesting that the presence of CTL does not justify refusing CEA for patients who could benefit from it. PMID- 26243560 TI - Is There Justification for Total Thyroidectomy in Low-Risk Papillary Thyroid Carcinoma? A Decision-Analysis Model. AB - BACKGROUND: Low-risk papillary thyroid carcinoma is commonly treated surgically. However, uncertainties exist in regard to the optimal extent of surgery. We approached this question using a decision-analysis model. METHODS: A Markov model was used to compare outcome between patients with small (1-2 cm) low-risk PTC treated by hemithyroidectomy or total thyroidectomy. Probabilities and utilities were derived from the literature. The model was evaluated with Monte Carlo simulation. Sensitivity analysis was used to determine which variables most affected the model. RESULTS: Hemithyroidectomy was associated with a minor increase in mortality risk. After incorporation of mortality risk, complications, and quality-of-life measures, hemithyroidectomy was found to be superior to total thyroidectomy, with an increasing benefit over time. Quality-of-life measures, especially disutility of disease recurrence and undergoing surgery, had the greatest effect on the incremental benefit of hemithyroidectomy. CONCLUSION: Based on our decision-analysis model, hemithyroidectomy is the preferred option in low-risk PTC. PMID- 26243561 TI - Barriers to Essential Surgical Care in Low- and Middle-Income Countries: A Pilot Study of a Comprehensive Assessment Tool in Ghana. AB - BACKGROUND: Beyond resource deficiencies, other barriers to care prevent patients from receiving surgery in low- and middle-income countries (LMICs). This study aimed to develop and pilot a comprehensive, generalizable tool for assessing the barriers to surgical care. METHODS: Sociodemographic, clinical and 38 questions regarding potential barriers to surgical care were asked during a surgical outreach to two district and one regional hospital in Upper East Region, Ghana. Sites were selected to capture individuals with prolonged unmet surgical needs and represent geographic, socioeconomic, and healthcare development differences. Results were indexed into three dimensions of barriers to care (i.e., 'acceptability,' 'affordability,' and 'accessibility') so that communities could be compared and targeted interventions developed. RESULTS: The tool was administered to 148 participants (98 % response rate): Bolgatanga 54 (37 %); Amiah 16 (11 %); and Sandema 78 (52 %). Amiah had the fewest barriers to surgical care (median index 8.3; IQR 7.6-9.3), followed by Sandema (8.2; IQR 5.3-9.2) and Bolgatanga (6.7; IQR 3.9-9.5). Individual dimension scores (i.e., acceptability, affordability, accessibility) ranged from 10.8 to 18 out of 18 possible points. Main factors contributing to low dimension scores were different between communities: Bolgatanga-cost and healthcare navigation; Amiah-social marginalization and poor medical understanding; Sandema-distance to surgically capable facility. CONCLUSION: This study identified a number of significant barriers, as well as successes for patients' ability and willingness to access surgical care that differed between communities. The tool itself was well accepted, easy to administer and provided valuable data from which targeted interventions can be developed. PMID- 26243562 TI - The Significance of BRAF V600e Mutation and Preoperative Ultrasound for Central Compartment Lymph Node Metastasis in Papillary Thyroid Microcarcinoma. PMID- 26243563 TI - A Novel Approach to Major Surgery: Tracking Its Pathophysiologic Footprints. AB - BACKGROUND: To study the 'metabolic profile' of different surgical procedures and correlate it with pertinent surgical details and postoperative complications. METHODS: We conducted a prospective pilot study of 70 patients, ten for each of the seven following groups: (1) laparoscopic cholecystectomy, (2) incisional hernia repair, (3) laparoscopic and (4) open colon surgery, (5) upper gastrointestinal, (6) hepatic, and (7) pancreatic resections. Biochemical assessment included white blood cell count (WBC), C-reactive protein (CRP), glucose, triglycerides (TG), albumin (Alb), and pre-albumin (Pre-Alb), from the day before surgery until 5 days thereafter. Biological markers were compared for major versus minor surgery groups, which were defined on a clinical basis. Univariable analysis was used to identify risk factors for postoperative complications and p < 0.05 was the significance threshold. RESULTS: Common findings in all surgery groups were the acute inflammatory response (?: WBC, CRP, ?: TG, Alb, pre-Alb). Using cut-off values of 240 min operative (OR) time and 300 ml estimated blood loss (EBL), laparoscopic cholecystectomy, incisional hernia repair, and laparoscopic colectomy could be distinguished from open colectomy, upper gastrointestinal, liver, and pancreas resections. In a biochemical level, increased CRP and reduced postoperative Alb levels were highly discriminative of all types of 'major surgery.' Significant risk factors for postoperative complications were age, male gender, malignancy, longer OR time, higher blood loss, high CRP, and low Alb levels. CONCLUSIONS: Biochemically, CRP and Alb levels can help quantify the magnitude of the surgical trauma, which is correlated with adverse outcomes. PMID- 26243564 TI - Revisiting Low-Risk Thyroid Papillary Microcarcinomas Resected Without Observation: Was Immediate Surgery Necessary? AB - INTRODUCTION: Low-risk thyroid papillary microcarcinomas (PMCs) without evidence of metastasis grow slowly if at all. However, we recommended surgery for tumors touching the trachea (TR) or located in the course of the recurrent laryngeal nerve (RN). Here we compared the cases of low-risk PMC patients who underwent immediate surgery to cases of TR- and RN-involved PMCs. MATERIALS AND METHODS: We enrolled 1143 low-risk PMC patients who underwent immediate surgery in the years 2006-2014. The PMCs of 437 patients touched the TR on imaging studies: 270, 104, and 63 were graded as low, intermediate, and high risk, respectively, for TR invasion based on the angles between the tumor and the TR surface. The tumor was in the course of the RN in 144 patients, with 35 graded low risk and 109 high risk for RN invasion based on the normal rim of the thyroid in the direction of the RN. RESULTS: Invasion of the TR cartilage was observed only in high-risk patients. Peritracheal connective tissue was resected in 21, 15, and 6 of the high-, intermediate- and low-risk patients, respectively. Significant invasion of the RN requiring complete resection was observed in only nine patients at high risk for RN invasion. The incidence of TR invasion in high- and intermediate patients and the incidence of RN invasion in the high-risk patients were significantly higher than those of the low-risk patients. Tumors <7 mm did not show TR or RN invasion. CONCLUSION: Among PMCs that touched the TR or were located in the course of the RN, observation could be the first choice for tumors < 7 mm and those >= 7 mm judged as low risk for TR or RN invasion. However, for PMCs with high-risk features, immediate surgery after cytological diagnosis by a needle aspiration biopsy is recommended. PMID- 26243565 TI - Idiopathic Granulomatous Mastitis: Do We Really Regard it as a Surgical Disease Anymore? PMID- 26243566 TI - In vivo demonstration of ultrasound power delivery to charge implanted medical devices via acute and survival porcine studies. AB - Animal studies are an important step in proving the utility and safety of an ultrasound based implanted battery recharging system. To this end an Ultrasound Electrical Recharging System (USERTM) was developed and tested. Experiments in vitro demonstrated power deliveries at the battery of up to 600 mW through 10-15 mm of tissue, 50 mW of power available at tissue depths of up to 50 mm, and the feasibility of using transducers bonded to titanium as used in medical implants. Acute in vivo studies in a porcine model were used to test reliability of power delivery, temperature excursions, and cooling techniques. The culminating five week survival study involved repeated battery charging, a total of 10.5h of ultrasound exposure of the intervening living tissue, with an average RF input to electrical charging efficiency of 20%. This study was potentially the first long term cumulative living-tissue exposure using transcutaneous ultrasound power transmission to an implanted receiver in situ. Histology of the exposed tissue showed changes attributable primarily due to surgical implantation of the prototype device, and no damage due to the ultrasound exposure. The in vivo results are indicative of the potential safe delivery of ultrasound energy for a defined set of source conditions for charging batteries within implants. PMID- 26243567 TI - Imaging flow cytometry as a sensitive tool to detect low-dose-induced DNA damage by analyzing 53BP1 and gammaH2AX foci in human lymphocytes. AB - Ionizing radiation induced foci (IRIF) are considered the most sensitive indicator for DNA double-strand break (DSB) detection. Monitoring DSB induction by low doses of ionizing radiation is important due to the increasing exposure in the general population. gammaH2AX and 53BP1 are commonly used molecular markers for in situ IRIF assessment. Imaging flow cytometry (IFC) via ImageStream system provides a new opportunity in this field. We analyzed the formation of 53BP1, gammaH2AX foci and their co-localization induced by gamma-rays (2, 5, 10, 50, 200 cGy) in human lymphocytes using ImageStream and the automated microscopic system Metafer. We observed very similar sensitivity of both systems for the detection of endogenous and low-dose-induced IRIF. Statistically significant induction of gammaH2AX foci was found at doses of 2 and 10 cGy using ImageStream and Metafer, respectively. Statistically significant induction of 53BP1 foci was evident at doses >= 5 cGy when analyzed by IFC. Analysis of the co-localizing foci by ImageStream and Metafer showed statistical significance at doses >= 2 cGy, suggesting that foci co-localization is a sensitive parameter for DSB quantification. Assessment of gammaH2AX, 53BP1 foci and their co-localization by Metafer and ImageStream showed similar linear dose responses in the low-dose range up to 10 cGy, although IFC showed slightly better resolution for IRIF in this dose range. At higher doses, IFC underestimated IRIF numbers. Using the imaging ability of ImageStream, we introduced an optimized assay by gating gammaH2AX foci positive (with 1 or more gammaH2AX foci) and negative (cells without foci) cells. This assay resulted in statistically significant IRIF induction at doses >= 5cGy and a linear dose response up to 50 cGy. In conclusion, we provide evidence for the use of IFC as an accurate high throughput assay for the prompt detection and enumeration of endogenous and low-dose induced IRIF. PMID- 26243568 TI - Neural coding: Speed awareness. PMID- 26243570 TI - NaV1.9: a sodium channel linked to human pain. AB - The voltage-gated sodium channel Na(V)1.9 is preferentially expressed in nociceptors and has been shown in rodent models to have a major role in inflammatory and neuropathic pain. These studies suggest that by selectively targeting Na(V)1.9, it might be possible to ameliorate pain without inducing adverse CNS side effects such as sedation, confusion and addictive potential. Three recent studies in humans--two genetic and functional studies in rare genetic disorders, and a third study showing a role for Na(V)1.9 in painful peripheral neuropathy--have demonstrated that Na(V)1.9 plays an important part both in regulating sensory neuron excitability and in pain signalling. With this human validation, attention is turning to this channel as a potential therapeutic target for pain. PMID- 26243571 TI - Simultaneous fingerprint and high-wavenumber fiber-optic Raman spectroscopy improves in vivo diagnosis of esophageal squamous cell carcinoma at endoscopy. AB - This work aims to evaluate clinical value of a fiber-optic Raman spectroscopy technique developed for in vivo diagnosis of esophageal squamous cell carcinoma (ESCC) during clinical endoscopy. We have developed a rapid fiber-optic Raman endoscopic system capable of simultaneously acquiring both fingerprint (FP)(800 1800 cm(-1)) and high-wavenumber (HW)(2800-3600 cm(-1)) Raman spectra from esophageal tissue in vivo. A total of 1172 in vivo FP/HW Raman spectra were acquired from 48 esophageal patients undergoing endoscopic examination. The total Raman dataset was split into two parts: 80% for training; while 20% for testing. Partial least squares-discriminant analysis (PLS-DA) and leave-one patient-out, cross validation (LOPCV) were implemented on training dataset to develop diagnostic algorithms for tissue classification. PLS-DA-LOPCV shows that simultaneous FP/HW Raman spectroscopy on training dataset provides a diagnostic sensitivity of 97.0% and specificity of 97.4% for ESCC classification. Further, the diagnostic algorithm applied to the independent testing dataset based on simultaneous FP/HW Raman technique gives a predictive diagnostic sensitivity of 92.7% and specificity of 93.6% for ESCC identification, which is superior to either FP or HW Raman technique alone. This work demonstrates that the simultaneous FP/HW fiber-optic Raman spectroscopy technique improves real-time in vivo diagnosis of esophageal neoplasia at endoscopy. PMID- 26243572 TI - Evaluation of the MGL method to detect Paragonimus eggs and its improvement. AB - Dog feces containing 500 Paragonimus westermani eggs per gram were examined by the Medical General Laboratory (MGL), the simple sedimentation (SS), and the Army Medical School III (AMS III) methods. The number of eggs per gram of feces (EPG) obtained by the MGL method was 17.2 and was significantly lower than those obtained by the SS method (324.0) and the AMS III method (505.6). When isolated P. westermani eggs were processed by the MGL method and four layers (ether, ether fecal, formalin layers, and sediment) of the final centrifugation product were separately examined, almost 100% of eggs were found at the ether-fecal layer. Similarly, when fecal samples containing P. westermani, Paragonimus skrjabini miyazakii, Paragonimus ohirai, or Paragonimus harinasutai eggs were processed by the MGL method, more than 95% of the eggs were found in the supernatant layers. The formalin-ethyl acetate (FEA) method showed a similar tendency as the MGL method and over 90% of eggs remained in the supernatant layers. Contrary to Paragonimus eggs, 63 and 96% of Clonorchis and Metagonimus eggs were found in the sediment in the MGL method, respectively. When surfactant (Tween 80) was added to fecal solution, most of Paragonimus eggs spun down in the sediment in the MGL and FEA methods, suggesting that Paragonimus eggs have hydrophobic components on their surface. It is suggested that surfactant addition to the fecal solution should be considered when the MGL method is used for detection of Paragonimus eggs. PMID- 26243569 TI - A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. AB - Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP)--an Alzheimer disease risk factor- although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population. PMID- 26243573 TI - Sarcocystis heydorni, n. sp. (Apicomplexa: Sarcocystidae) with cattle (Bos taurus) and human (Homo sapiens) cycle. AB - Cattle (Bos taurus) are intermediate hosts for four species of Sarcocystis, namely Sarcocystis cruzi, Sarcocystis hirsuta, Sarcocystis hominis, and Sarcocystis rommeli. Of these four species, mature sarcocysts of S. cruzi are thin-walled (<1 MUm), whereas S. hirsuta, S. hominis, and S. rommeli have thick walls (4 MUm or more). Here, we describe a new species of Sarcocystis with thin walled sarcocysts in cattle. Two newborn calves were fed with sporocysts from the feces of a human volunteer who had ingested raw beef. The calves were killed 111 and 222 days later. In addition to thick-walled sarcocysts of S. hominis, both calves were coinfected with a Sarcocystis species that had a thin-walled sarcocysts, distinct from S. cruzi. The sarcocysts were mature, microscopic, up to 80 MUm wide, and up to 1060 MUm long. By light microscopy, the sarcocyst wall was thin (<1 MUm thick) and had minute protrusions. By transmission electron microscopy, the sarcocyst wall had short, conical villar protrusions (vp) that were up to 0.5 MUm long and up to 0.5 MUm wide, similar to type 29. The vp on the sarcocyst wall lacked microtubules but had six or more disc-shaped plaques. The ground substance layer was smooth, approximately 0.5 MUm thick, and without microtubules. The bradyzoites were 8-11 MUm long. The structure of the sarcocyst wall was distinct from any species of Sarcocystis reported from livestock. This unique species is named in honor of Dr. Alfred Otto Heydorn who provided the sporocysts. PMID- 26243574 TI - A long-lasting protective immunity against chronic toxoplasmosis in mice induced by recombinant rhoptry proteins encapsulated in poly (lactide-co-glycolide) microparticles. AB - Toxoplasma gondii infection in humans and animals is a worldwide zoonosis. Prevention and control of toxoplasmosis based on vaccination is one of the promising strategies. In the present study, recombinant T. gondii rhoptry proteins 38 and 18 (TgROP38 and TgROP18) were encapsulated into poly (lactide-co glycolide) (PLG) (1:1), respectively, to obtain the stable water-in-oil-in-water double emulsion. Female Kunming mice were then immunized with the protein vaccines twice at a 2-week interval. Eight weeks after the second immunization, 10 mice from each group were challenged with T. gondii PRU strain (genotype II). The entrapment rates of PLG-rROP38 and PLG-rROP18 ranged from 65.5 to 77.7% and 58.1 to 72.3%, respectively. Immunization of mice with rROP38 and rROP18 proteins encapsulated into PLG microparticles elicited strongly humoral and cell-mediated responses against T. gondii, associated with relatively high levels of total IgG, IgG2a isotype, and IFN-gamma, as well as the mixed Th1/Th2 immunity responses. Immunization with various protein vaccines induced significant reduction of the brain cysts after chronic infection with the T. gondii PRU strain, and the most effective protection was achieved in the PLG-rROP38-rROP18-immunized mice, with a cyst reduction of 81.3%. The findings of the present study indicated that recombinant rhoptry antigens encapsulated in PLG could maintain the protein immunogenicity in an extended period and elicit effective protection against chronic T. gondii infection, which has implications for the development of long lasting vaccines against chronic toxoplasmosis in animals. PMID- 26243575 TI - Stem-cell-based therapy in the field of urology: a review of stem cell basic science, clinical applications and future directions in the treatment of various sexual and urinary conditions. AB - INTRODUCTION: Stem cell (SC) research plays a key role in the increasingly promising area of regenerative medicine, with the potential to treat, prevent and cure disease. The following article provides an overview of the basic science and brief summary of major preclinical animal studies and clinical studies pertaining to SC-based research in the field of urology. AREAS COVERED: A literature review was conducted based on MEDLINE/PubMed searches for English articles using a combination of the following keywords: SC, SC-based therapy (SCT), urology, erectile dysfunction, Peyronie's disease (PD), bladder dysfunction, urinary incontinence, regeneration technology, tissue engineering, prostate disease and urinary bladder. EXPERT OPINION: While current evidence is accruing to suggest that SCT showed great promise in animal studies such as in erectile dysfunction, PD and urothelial tissue engineering, and is likely to be effective and has minimal adverse effects as observed in stress urinary incontinence and bladder dysfunction, there are still significant challenges to overcome before wide spread human application. Important issues, such as reliable outcomes, safety risks with genomic or epigenetic changes in the longer term, as well as potential immune reactions and infection risks, need to be identified in more stringent clinical trials. PMID- 26243576 TI - Stress: the good, the bad and the ugly? PMID- 26243577 TI - Impact of Combined C-Reactive Protein and High-Density Lipoprotein Cholesterol Levels on Long-Term Outcomes in Patients With Coronary Artery Disease After a First Percutaneous Coronary Intervention. AB - Cardiovascular risk persists despite intensive low-density lipoprotein cholesterol (LDL-C) reduction using statins. High-density lipoprotein (HDL-C) is inversely associated with coronary artery disease (CAD) that is independent of LDL-C levels. C-reactive protein (CRP) is an established marker of inflammation that can impair the protective function of HDL-C: however, the impact of inflammation on the association between HDL-C and long-term outcomes in patients with CAD under statin therapy remains uncertain. We prospectively enrolled 3,507 consecutive patients with CAD who underwent a first percutaneous coronary intervention (PCI) from 1997 to 2011 at our institution. We stratified 1,682 patients (48%) who had been treated with statin at the time of PCI into 4 groups according to HDL-C levels (cutoffs of 40 and 50 mg/dl for men and women, respectively) and a CRP cutoff of 2 mg/dl: (1) high HDL-C/low CRP, (2) high HDL C/high CRP, (3) low HDL-C/low CRP, and (4) low HDL-C/high CRP comparing the rates of all-cause death among them. The median follow-up period was 1,985 days (interquartile range 916 to 3,183 days). During this period, 197 patients (11.7%) died because of cardiac death (n = 58), carcinoma (n = 61), stroke (n = 10), and other causes (n = 69). The rates of all-cause death significantly differed among the groups (log-rank test, p <0.0001). In multivariate Cox hazard regression analyses, low HDL-C with high CRP levels remained significantly associated with a higher rate of all-cause death even after adjustment for other co-variates (hazard ratio 2.38, 1.59 to 3.61, p <0.0001). Low HDL-C together with elevated CRP levels is significantly associated with long-term outcomes in patients who received statin therapy after PCI. PMID- 26243578 TI - Fracture of Bioresorbable Vascular Scaffold After Side-Branch Balloon Dilation in Bifurcation Coronary Narrowings. AB - The possibility of strut fractures after bioresorbable vascular scaffold (BVS) treatment is a new problem associated with the use of this novel technology. There is little in vivo information regarding the effects of lateral dilation on BVS. The present study aimed to evaluate the effects of lateral balloon dilation after bioresorbable vascular scaffold implantation in the treatment of bifurcation lesions. From January 2012 to February 2015, 49 patients with bifurcation lesions who had been treated with BVS required balloon dilation of the side branch (SB). Optical coherence tomographic studies were performed in each of these patients. In 3 patients (6%), the optical coherence tomographic results met the criteria for rupture. Prolonged inflation using a noncompliant balloon with a diameter within the expansion limits of the device resolved the complication in all patients. The clinical course was favorable in all patients, and there were no inhospital deaths or myocardial infarctions. At 14 +/- 8 months of follow-up, 2 patients with integrity of the BVS presented target lesion revascularization (4%). Another patient (2%) suffered a probable stent thrombosis 11 months after the procedure (myocardial infarction and death at home). The patients with the BVS rupture at the index procedure had a favorable clinical outcome, and the 6-month computed tomographic scan revealed maintenance of the initial good results. In conclusion, minor BVS rupture after 2.5-mm lateral balloon dilation may occur but is infrequent (6%). Prolonged balloon inflation of the main vessel may partially restore the geometry of the BVS. PMID- 26243579 TI - Procedural Predictors of Angiographic Restenosis After Bifurcation Coronary Stenting (from the Choice of Optimal Strategy for Bifurcation Lesions With Normal Side Branch and Optimal Stenting Strategy for True Bifurcation Lesions Studies). AB - Most subordinate techniques accompanying bifurcation stenting have not been supported by relevant clinical trials. The aim of this study was to investigate the impact of technical specifications involved in bifurcation stenting on angiographic outcomes. We analyzed patients enrolled in a cohort consisting of the patients in 2 randomized studies: one comparing routine final kissing inflation (FKI) versus leave-alone strategy after the 1-stent technique for bifurcations without side branch (SB) stenosis (<50%) and the other comparing crush versus the 1-stent technique for lesions with SB stenosis (>=50%). The effects of subordinate techniques and devices on 8-month angiographic restenosis were studied using multivariate models. Of 514 patients whose 8-month angiograms were available, 58 (11.3%) were found to have restenosis involving, in total, 35 main branches (MBs) and 27 SBs. Using multivariate models, we identified FKI as the only independent predictor of MB restenosis in the technically modifiable variables. The effect of FKI was significantly different across subgroups defined by bifurcation lesion type and stenting technique (test for homogeneity, p = 0.003): FKI was unrelated to MB restenosis in the 1-stent for diseased SB (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.10 to 1.72; p = 0.22) and the 2 stent groups (OR 0.14, 95% CI 0.01 to 1.36; p = 0.09) but predictive of MB restenosis in the 1-stent for normal SB group (OR 4.90, 95% CI 1.58 to 15.16; p = 0.006). PMID- 26243580 TI - Consistent Efficacy of Wendan Decoction for the Treatment of Digestive Reflux Disorders. AB - Gastroesophageal reflux disease (GERD) and bile reflux gastritis (BRG) are common gastrointestinal (GI) disorders with unmet medical needs. Traditional Chinese medicine has long been used for the treatment of GERD and BRG whereas the ginger containing formula Wendan decoction (WDD) targets homeostatic disturbances characterized by "reflux" and "gut-juice exposure" problems. Here we used WDD as a therapeutic tool to unravel the common pathogenesis of GI reflux disorders. Control clinical trials reporting the WDD-treated patients with GERD and BRG were included in this systematic review and meta-analysis. Outcome measurements were clinical efficacy defined by symptom relief with normal GI endoscopy, radiology, and pathology. Eventually, 33 studies involved 3253 participants (1351 vs. 1035 of the BRG in 20 publications, 449 vs. 418 of the GERD in 13 studies, and 194 vs. 159 of relapse rate in 6 trials). Pooled data showed a consistent therapeutic efficacy of WDD on BRG (OR = 6.00, 95%C = 4.68-7.69) and GERD (OR = 4.39, 95%CI = 2.72-7.07). The relapse rate was 12.4% for WDD, significantly lower than 44.0% for conventional therapies (OR = 0.14, 95%CI = 0.08-0.26). The consistent therapeutic efficacy of the single TCM formula on GERD and BRD indirectly indicates reflux as a common pathogenesis in reflux-associated GI disorders. PMID- 26243581 TI - Chemical Constituents, Quality Control, and Bioactivity of Epimedii Folium (Yinyanghuo). AB - Epimedii Folium (Yinyanghuo in Chinese) is one of the most commonly used traditional Chinese medicines. Its main active components are flavonoids, which exhibit multiple biological activities, such as promotion of bone formation and sexual function, protection of the nervous system, and prevention of cardiovascular diseases. Flavonoids also show anti-inflammatory and anticancer effects. Various effective methods, including genetic and chemical approaches, have been developed for the quality control of Yinyanghuo. In this review, the studies conducted in the last decade about the chemical constituents, quality control, and bioactivity of Yinyanghuo are summarized and discussed. PMID- 26243582 TI - Cnidium monnieri: A Review of Traditional Uses, Phytochemical and Ethnopharmacological Properties. AB - Cnidium monnieri (L.) Cuss., an annual plant of the Umbelliferae species is one of the most widely used traditional herbal medicines and its fruits have been used to treat a variety of diseases in China, Vietnam, and Japan. The aim of this review is to provide an up-to-date and comprehensive analysis of the botany, traditional uses, phytochemistry, pharmacology, toxicity and contraindication of Cnidium monnieri (L.) Cuss. and to provide future directions of research on this plant. To date, 350 compounds have been isolated and identified from Cnidium monnieri (L.) Cuss., including the main active constituent, coumarins. In vitro and in vivo studies suggest that osthole and other coumarin compounds possess wide range of pharmacological properties for the treatment of female genitals, male impotence, frigidity, skin-related diseases, and exhibit strong antipruritic, anti-allergic, antidermatophytic, antibacterial, antifungal, anti osteoporotic effects. Although coumarins have been identified as the main active constituents responsible for the observed pharmacological effects, the molecular mechanisms of their actions are still unknown. Therefore, further studies are still required to reveal the structure-activity relationship of these active constituents. In addition, toxicological and clinical studies are also required to provide further data for pharmaceutical use. PMID- 26243584 TI - Improving Care of Patients With CKD: The 2015 National Kidney Foundation Presidential Address. PMID- 26243583 TI - Turning terminally differentiated skeletal muscle cells into regenerative progenitors. AB - The ability to repeatedly regenerate limbs during the entire lifespan of an animal is restricted to certain salamander species among vertebrates. This ability involves dedifferentiation of post-mitotic cells into progenitors that in turn form new structures. A long-term enigma has been how injury leads to dedifferentiation. Here we show that skeletal muscle dedifferentiation during newt limb regeneration depends on a programmed cell death response by myofibres. We find that programmed cell death-induced muscle fragmentation produces a population of 'undead' intermediate cells, which have the capacity to resume proliferation and contribute to muscle regeneration. We demonstrate the derivation of proliferating progeny from differentiated, multinucleated muscle cells by first inducing and subsequently intercepting a programmed cell death response. We conclude that cell survival may be manifested by the production of a dedifferentiated cell with broader potential and that the diversion of a programmed cell death response is an instrument to achieve dedifferentiation. PMID- 26243585 TI - The Effectiveness of Clinically Indicated Replacement of Peripheral Intravenous Catheters: An Evidence Review With Implications for Clinical Practice. AB - BACKGROUND: Current clinical guidelines from the Centers for Disease Control and Prevention (CDC; 2011) state that peripheral intravenous catheters are to be replaced every 72-96 hr to prevent infection and phlebitis in the adult patient. It is unclear whether this practice reduces the incidence of phlebitis or other infections. AIM: The aim of this study was to examine levels I and II evidence to determine if replacing peripheral intravenous catheters only when clinically indicated compared to every 72-96 hr increases the adult patient's risk for infection or phlebitis. METHODS: The following patient or population, intervention, comparison, outcome question was used to search the literature databases PubMed, ClinicalKey, ProQuest, Ovid SP, and CINAHL: In the adult patient requiring a peripheral vascular catheter (P), does replacing the catheter only when clinically indicated (I) compared to replacing the catheter every 72-96 hr (C) increase the occurrence of phlebitis and infection (O)? A set of specific search criteria along with critical appraisal tools was used to identify relative studies. RESULTS: Four level II randomized controlled trials with no less than 155 subjects, and two level I meta-analyses reviewing a total of 13 research studies indicated that the replacement of peripheral intravenous catheters only when clinically indicated does not increase patient risk of phlebitis or infection when compared to the current practice of routine replacement between 72 and 96 hr in the adult patient population. LINKING EVIDENCE TO ACTION: The current practice of replacing peripheral intravenous catheters every 72-96 hr does not decrease the incidence of phlebitis or infection when compared to replacing catheters when clinically indicated in the adult population. By translating this research into current practice, healthcare costs and nursing care time will decrease, and unnecessary invasive procedures would be eliminated thereby increasing patient safety and satisfaction. PMID- 26243587 TI - Prolonged use of tenofovir and entecavir in hepatitis B virus-related cirrhosis. AB - BACKGROUND AND AIMS: Limited data is available from India on outcome and efficacy of tenofovir and entecavir in hepatitis B virus (HBV)-related cirrhosis when used for prolonged time. We report the long-term efficacy and outcome of these antiviral drugs in patients with chronic HBV infection, with compensated or decompensated cirrhosis. METHODS: We retrospectively analyzed laboratory and clinical data of 400 HBV-related cirrhotic patients without access to liver transplantation, who were treated with tenofovir/entecavir therapy, from January 2007 to January 2014. Two hundred and ten (52.5 %) patients had at least one of the components of decompensation at baseline. Two hundred and twenty (55 %) and 180 (45 %) patients were initiated tenofovir and entecavir, respectively. Follow up period was 45 (12-68) months for tenofovir and 36 (11-60) months for entecavir. RESULTS: At the end of 1 year, levels of HBV DNA <20 IU/mL were achieved in 91.8 % and 88.8 % of patients, and alanine aminotransferase normalized in 54.5 % and 55.5 % of patients who received tenofovir and entecavir, respectively. At the last visit, Child-Turcotte-Pugh scores improved among 29.5 % of patients who received tenofovir, 25 % of those who received entecavir, and remained stable in 61.9 % and 65 % patients, respectively, in both groups. The 5 year cumulative rate of liver decompensation, hepatocellular carcinoma, and cirrhosis-related complications were 3.1 %, 1.9 %, and 2.1 % with an annual incidence of 0.8 %, 0.3 %, and 0.5 % per person-year, respectively. CONCLUSION: Tenofovir and entecavir were effective and potent drugs for prolonged treatment of HBV cirrhosis and improved the overall clinical course. PMID- 26243588 TI - Diversion proctocolitis and response to treatment with short-chain fatty acids--a clinicopathological study in children. AB - OBJECTIVE: Diversion proctocolitis (DPC) frequently develops in the colorectum after diversion of the fecal stream characterized by bleeding from the inflamed mucosa. Short-chain fatty acids (SCFA) are responsible for growth and differentiation of enterocytes. Adult series have reported variable response of DPC to luminal SCFA. There is dearth of studies in children. We aimed to study incidence, clinical, endoscopic, and histopathological characteristics of DPC and effect of SCFA in children. METHODS: Prospectively clinical, endoscopic, and histopathological evaluation was done for DPC in children undergoing fecal diversion. Patient characteristics, type and duration of stoma, symptoms, endoscopy and biopsy findings, duration of treatment and response to SCFA, time of closure of stoma, and any associated gut anomaly were recorded. RESULTS: Fifteen children completed the study. Anorectal malformation was the commonest indication for stoma. Sixty percent were symptomatic within 2-9 months, excessive mucous discharge being the commonest symptom. All had at least one positive endoscopic finding; erythema, edema, and exudates being the commonest findings. All DPCs improved clinically and endoscopically following SCFA. Histological resolution was seen in 78 %, while 22 % had persistent disease. Closure of stoma showed complete resolution of DPC. CONCLUSION: DPC was common (87 %) following stoma formation in children with strong male preponderance (6.5:1). The commonest indication for stoma was anorectal malformation (67 %). Clinical, endoscopic, and histopathological changes appeared within 2-9 months with symptomatic DPC in 60 %. All patients (100 %) had at least one positive endoscopic finding, histopathological examination confirmed the diagnosis. SCFA led to symptomatic, endoscopic, and histopathological resolution of DPCs. Closure of stoma cured all the persistent DPCs. PMID- 26243589 TI - Massive parallel sequencing applied to the molecular autopsy in sudden cardiac death in the young. AB - Sudden cardiac death in the young is a very traumatic event that occurs often in apparently healthy individuals without an explainable cause of death after a comprehensive medico-legal investigation. Knowledge about the pathologies with a risk of sudden death is increasingly showing a greater underlying genetic heterogeneity, which provides one of the main handicaps for molecular autopsy. On the other hand the enormous technological advances in sequencing technologies, allow us to analyse as many genes as we want at a cost increasingly reduced. The sum of these two factors (increased knowledge of genetics and available technologies) allow us to make an individualized study of the causes of sudden cardiac death in young adults, through massive sequencing of all potential genes involved in the process. We define this approach as massive genomic autopsy, and with this review we will try to explain the possible scenarios and methods available for its implementation. PMID- 26243590 TI - FGF8 signaling sustains progenitor status and multipotency of cranial neural crest-derived mesenchymal cells in vivo and in vitro. AB - The cranial neural crest (CNC) cells play a vital role in craniofacial development and regeneration. They are multi-potent progenitors, being able to differentiate into various types of tissues. Both pre-migratory and post migratory CNC cells are plastic, taking on diverse fates by responding to different inductive signals. However, what sustains the multipotency of CNC cells and derivatives remains largely unknown. In this study, we present evidence that FGF8 signaling is able to sustain progenitor status and multipotency of CNC derived mesenchymal cells both in vivo and in vitro. We show that augmented FGF8 signaling in pre-migratory CNC cells prevents cell differentiation and organogenesis in the craniofacial region by maintaining their progenitor status. CNC-derived mesenchymal cells with Fgf8 overexpression or control cells in the presence of exogenous FGF8 exhibit prolonged survival, proliferation, and multi potent differentiation capability in cell cultures. Remarkably, exogenous FGF8 also sustains the capability of CNC-derived mesenchymal cells to participate in organogenesis such as odontogenesis. Furthermore, FGF8-mediated signaling strongly promotes adipogenesis but inhibits osteogenesis of CNC-derived mesenchymal cells in vitro. Our results reveal a specific role for FGF8 in the maintenance of progenitor status and in fate determination of CNC cells, implicating a potential application in expansion and fate manipulation of CNC derived cells in stem cell-based craniofacial regeneration. PMID- 26243591 TI - The Role of Negative Charge in the Delivery of Quantum Dots to Neurons. AB - Despite our extensive knowledge of the structure of negatively charged cell surface proteoglycans and sialoglycoconjugates in the brain, we have little understanding of how their negative charge contributes to brain function. We have previously shown that intensely photoluminescent 9-nm diameter quantum dots (QDs) with a CdSe core, a ZnS shell, and a negatively charged compact molecular ligand coating (CL4) selectively target neurons rather than glia. We now provide an explanation for this selective neuronal delivery. In this study, we compared three zwitterionic QD coatings differing only in their regions of positive or negative charge, as well as a positively charged (NH2) polyethylene glycol (PEG) coat, for their ability to deliver the cell-membrane-penetrating chaperone lipopeptide JB577 (WG(Palmitoyl)VKIKKP9G2H6) to individual cells in neonatal rat hippocampal slices. We confirm both that preferential uptake in neurons, and the lack of uptake in glia, is strongly associated with having a region of greater negative charge on the QD coating. In addition, the role of negatively charged chondroitin sulfate of the extracellular matrix (ECM) in restricting uptake was further suggested by digesting neonatal rat hippocampal slices with chondroitinase ABC and showing increased uptake of QDs by oligodendrocytes. Treatment still did not affect uptake in astrocytes or microglia. Finally, the future potential of using QDs as vehicles for trafficking proteins into cells continues to show promise, as we show that by administering a histidine-tagged green fluorescent protein (eGFP-His6) to hippocampal slices, we can observe neuronal uptake of GFP. PMID- 26243592 TI - Nrf2 and HSF-1 Pathway Activation via Hydroquinone-Based Proelectrophilic Small Molecules is Regulated by Electrochemical Oxidation Potential. AB - Activation of the Kelch-like ECH-associated protein 1/nuclear factor (erythroid derived 2)-like 2 and heat-shock protein 90/heat-shock factor-1 signal transduction pathways plays a central role in combatting cellular oxidative damage and related endoplasmic reticulum stress. Electrophilic compounds have been shown to be activators of these transcription-mediated responses through S alkylation of specific regulatory proteins. Previously, we reported that a prototype compound (D1, a small molecule representing a proelectrophilic, para hydroquinone species) exhibited neuroprotective action by activating both of these pathways. We hypothesized that the para-hydroquinone moiety was critical for this activation because it enhanced transcription of these neuroprotective pathways to a greater degree than that of the corresponding ortho-hydroquinone isomer. This notion was based on the differential oxidation potentials of the isomers for the transformation of the hydroquinone to the active, electrophilic quinone species. Here, to further test this hypothesis, we synthesized a pair of para- and ortho-hydroquinone-based proelectrophilic compounds and measured their redox potentials using analytical cyclic voltammetry. The redox potential was then compared with functional biological activity, and the para-hydroquinones demonstrated a superior neuroprotective profile. PMID- 26243593 TI - Cell-mediated and humoral acute vascular rejection and graft loss: A registry study. AB - AIMS: Rejection of renal allografts following transplantation continues to be a major impediment to long-term graft survival. Although acute vascular rejection (AVR) is associated with a high risk of graft loss, it remains unclear whether AVR with accompanied cellular or acute humoral rejection (AHR) have dissimilar outcomes. The aim of this registry study was to examine the association between subtypes of AVR and graft loss. METHODS: Using Australia and New Zealand Dialysis and Transplant registry, primary kidney transplant recipients between 2005 and 2012 whose first rejection episode was AVR were included and categorized into AVR none (AVR without other rejections), AVR-CG (AVR with cellular and/or glomerular rejections), and AVR-AHR (AVR with AHR). Association between AVR groups and graft loss was examined using logistic and Cox regression models. RESULTS: Of the 274 recipients, 61 (22.3%) experienced AVR-none, 79 (28.8%) AVR-AHR and 134 (48.9%) AVR-CG. Compared with AVR-none and AVR-CG, AVR-AHR was associated with the highest incidence of overall graft loss at 3 months (12%, 10% and 27%, respectively, chi(2) = 11.88, P = 0.003). AVR-AHR was associated with almost a threefold greater risk of death-censored graft loss compared with AVR-none (adjusted hazard ratio 2.84, 95% confidence interval 1.22-2.62, P < 0.01). CONCLUSION: AVR-AHR is associated with the poorest outcome with over 25% of grafts being lost 3 months after transplantation. Future studies evaluating factors that predict graft loss in AVR-AHR may help determine prognosis and inform treatment practices. PMID- 26243595 TI - Stress and pain response after oligofructose induced-lameness in dairy heifers. AB - Lameness is one of the most painful conditions that affects dairy cattle. This study was conducted to evaluate clinical signs and plasma concentration of several pain and stress biomarkers after oligofructose-induced lameness in dairy heifers. Lameness was induced using an oligofructose overload model in 12 non pregnant heifers. Clinical parameters and blood samples were obtained at 48 and 24 h and at 6, 12, 24, 36 and 48 h after induction of lameness. Clinical parameters included heart rate, respiratory rate, ruminal frequency and lameness score. Plasma biomarkers included cortisol, haptoglobin, norepinephrine, beta endorphin and substance P. Differences were observed in all parameters between control and treated heifers. The plasma concentration of biomarkers increased significantly in treated animals starting 6 h after induction of lameness, reaching maximum levels at 24 h for cortisol, 48 h for haptoglobin, 6 h for norepinephrine, 12 h for substance P and at 24 h for beta-endorphin. Overall, our results confirm that lameness associated pain induced using the oligofructose model induced changes in clinical parameters and plasma biomarkers of pain and stress in dairy heifers. PMID- 26243598 TI - Anti-adipogenic effect of Artemisia annua in diet-induced-obesity mice model. AB - Obesity has increased continuously in western countries during the last several decades and recently become a problem in developing countries. Currently, anti obesity drugs originating from natural products are being investigated for their potential to overcome adverse effects associated with chemical drugs. Artemisinic acid, which was isolated from the well-known anti-malaria herb Artemisia annua (AA) L., was recently shown to possess anti-adipogenic effects in vitro. However, the anti-adipogenic effects of AA in animal models have not yet been investigated. Therefore, we conducted daily oral administration with AA water extract in a diet-induced obesity animal model and treated 3T3-L1 cells with AA to confirm the anti-adipogenic effects in the related protein expressions. We then evaluated the physiology, adipose tissue histology and mRNA expressions of many related genes. Inhibition of adipogenesis by the AA water extract was observed in vitro. In the animal model, weight gain was significantly lower in the AA treated group, but there were no changes in food intake volume or calories. Reductions in lipid droplet size and mRNA expression associated with adipogenesis were also observed in animal epididymal fat. This study is the first to report that AA has an anti-obese effects in vivo. PMID- 26243597 TI - Serum IGFBP4 concentration decreased in dairy heifers towards day 18 of pregnancy. AB - This study was conducted to determine if the main components of the somatotropic axis change during the early phase of pregnancy in the maternal blood system and whether differences exist on day 18 after pregnancy recognition by the maternal organism. Blood samples of pregnant heifers (Holstein Friesian; n = 10 after embryo transfer) were obtained on the day of ovulation (day 0), as well as on days 7, 14, 16 and 18 and during pregnant, non-pregnant and negative control cycles. The concentrations of progesterone (P4), oestrogen, growth hormone (GH), insulin-like growth factor-1 and -2 (IGF1, -2) and IGF-binding protein-2, -3 and 4 (IGFBP2, -3, -4) were measured. The mRNA expressions of growth hormone receptor 1A, IGF1, IGF2, IGFBP2, IGFBP3 and IGFBP4 were detected using RT-qPCR in liver biopsy specimens (day 18). In all groups, total serum IGF1 decreased from day 0 to 16. Notably, IGFBP4 maternal blood concentrations were lower during pregnancy than during non-pregnant cycles and synchronized control cycles. It can be speculated that the lower IGFBP4 in maternal blood may result in an increase of free IGF1 for local action. Further studies regarding IGFBP4 concentration and healthy early pregnancy are warranted. PMID- 26243599 TI - Downregulation of cellular prion protein inhibited the proliferation and invasion and induced apoptosis of Marek's disease virus-transformed avian T cells. AB - Cellular prion protein (PrP(C)) is ubiquitously expressed in the cytomembrane of a considerable number of eukaryotic cells. Although several studies have investigated the functions of PrP(C) in cell proliferation, cell apoptosis, and tumorigenesis of mammals, the correlated functions of chicken PrP(C) (chPrP(C)) remain unknown. In this study, stable chPrP(C)-downregulated Marek's disease (MD) virus-transformed avian T cells (MSB1-SiRNA-3) were established by introducing short interfering RNA (SiRNA) targeting chicken prion protein genes. We found that downregulation of chPrP(C) inhibits proliferation, invasion, and migration, and induces G1 cell cycle phase arrest and apoptosis of MSB1-SiRNA-3 cells compared with Marek's disease virus-transformed avian T cells (MSB1) and negative control cells. To the best of our knowledge, the present study provides the first evidence supporting the positive correlation between the expression level of chPrP(C) and the proliferation, migration, and invasion ability of MSB1 cells, but appears to protect MSB1 cells from apoptosis, which suggests it functions in the formation and development of MD tumors. This evidence may contribute to future research into the specific molecular mechanisms of chPrP(C) in the formation and development of MD tumors. PMID- 26243601 TI - Experimental infection and pathology of clade 2.2 H5N1 virus in gulls. AB - During 2006, H5N1 HPAI caused an epizootic in wild birds, resulting in a die-off of Laridae in the Novosibirsk region at Chany Lake. In the present study, we infected common gulls (Larus canus) with a high dose of the H5N1 HPAI virus isolated from a common gull to determine if severe disease could be induced over the 28 day experimental period. Moderate clinical signs including diarrhea, conjunctivitis, respiratory distress and neurological signs were observed in virus-inoculated birds, and 50% died. The most common microscopic lesions observed were necrosis of the pancreas, mild encephalitis, mild myocarditis, liver parenchymal hemorrhages, lymphocytic hepatitis, parabronchi lumen hemorrhages and interstitial pneumonia. High viral titers were shed from the oropharyngeal route and virus was still detected in one bird at 25 days after infection. In the cloaca, the virus was detected sporadically in lower titers. The virus was transmitted to direct contact gulls. Thus, infected gulls can pose a significant risk of H5N1 HPAIV transmission to other wild migratory waterfowl and pose a risk to more susceptible poultry species. These findings have important implications regarding the mode of transmission and potential risks of H5N1 HPAI spread by gulls. PMID- 26243606 TI - Effects of aluminum on the reduction of neural stem cells, proliferating cells, and differentiating neuroblasts in the dentate gyrus of D-galactose-treated mice via increasing oxidative stress. AB - Aluminum (Al) accumulation increases with aging, and long-term exposure to Al is regarded as a risk factor for Alzheimer's disease. In this study, we investigated the effects of Al and/or D-galactose on neural stem cells, proliferating cells, differentiating neuroblasts, and mature neurons in the hippocampal dentate gyrus. AlCl3 (40 mg/kg/day) was intraperitoneally administered to C57BL/6J mice for 4 weeks. In addition, vehicle (physiological saline) or D-galactose (100 mg/kg) was subcutaneously injected to these mice immediately after AlCl3 treatment. Neural stem cells, proliferating cells, differentiating neuroblasts, and mature neurons were detected using the relevant marker for each cell type, including nestin, Ki67, doublecortin, and NeuN, respectively, via immunohistochemistry. Subchronic (4 weeks) exposure to Al in mice reduced neural stem cells, proliferating cells, and differentiating neuroblasts without causing any changes to mature neurons. This Al-induced reduction effect was exacerbated in D-galactose-treated mice compared to vehicle-treated adult mice. Moreover, exposure to Al enhanced lipid peroxidation in the hippocampus and expression of antioxidants such as Cu, Zn- and Mn-superoxide dismutase in D-galactose-treated mice. These results suggest that Al accelerates the reduction of neural stem cells, proliferating cells, and differentiating neuroblasts in D-galactose-treated mice via oxidative stress, without inducing loss in mature neurons. PMID- 26243611 TI - Correction. PMID- 26243608 TI - Improved development of somatic cell cloned bovine embryos by a mammary gland epithelia cells in vitro model. AB - Previous studies have established a bovine mammary gland epithelia cells in vitro model by the adenovirus-mediated telomerase (hTERT-bMGEs). The present study was conducted to confirm whether hTERT-bMGEs were effective target cells to improve the efficiency of transgenic expression and somatic cell nuclear transfer (SCNT). To accomplish this, a mammary-specific vector encoding human lysozyme and green fluorescent protein was used to verify the transgenic efficiency of hTERT-bMGEs, and untreated bovine mammary gland epithelial cells (bMGEs) were used as a control group. The results showed that the hTERT-bMGEs group had much higher transgenic efficiency and protein expression than the bMGEs group. Furthermore, the nontransgenic and transgenic hTERT-bMGEs were used as donor cells to evaluate the efficiency of SCNT. There were no significant differences in rates of cleavage or blastocysts or hatched blastocysts of cloned embryos from nontransgenic hTERT-bMGEs at passage 18 and 28 groups (82.8% vs. 81.9%, 28.6% vs. 24.8%, 58.6% vs. 55.3%, respectively) and the transgenic group (80.8%, 26.5% and 53.4%); however, they were significantly higher than the bMGEs group (71.2%, 12.8% and 14.8%), (p < 0.05). We confirmed that hTERT-bMGEs could serve as effective target cells for improving development of somatic cell cloned cattle embryos. PMID- 26243614 TI - An Ancestral Role for CONSTITUTIVE TRIPLE RESPONSE1 Proteins in Both Ethylene and Abscisic Acid Signaling. AB - Land plants have evolved adaptive regulatory mechanisms enabling the survival of environmental stresses associated with terrestrial life. Here, we focus on the evolution of the regulatory CONSTITUTIVE TRIPLE RESPONSE1 (CTR1) component of the ethylene signaling pathway that modulates stress-related changes in plant growth and development. First, we compare CTR1-like proteins from a bryophyte, Physcomitrella patens (representative of early divergent land plants), with those of more recently diverged lycophyte and angiosperm species (including Arabidopsis [Arabidopsis thaliana]) and identify a monophyletic CTR1 family. The fully sequenced P. patens genome encodes only a single member of this family (PpCTR1L). Next, we compare the functions of PpCTR1L with that of related angiosperm proteins. We show that, like angiosperm CTR1 proteins (e.g. AtCTR1 of Arabidopsis), PpCTR1L modulates downstream ethylene signaling via direct interaction with ethylene receptors. These functions, therefore, likely predate the divergence of the bryophytes from the land-plant lineage. However, we also show that PpCTR1L unexpectedly has dual functions and additionally modulates abscisic acid (ABA) signaling. In contrast, while AtCTR1 lacks detectable ABA signaling functions, Arabidopsis has during evolution acquired another homolog that is functionally distinct from AtCTR1. In conclusion, the roles of CTR1 related proteins appear to have functionally diversified during land-plant evolution, and angiosperm CTR1-related proteins appear to have lost an ancestral ABA signaling function. Our study provides new insights into how molecular events such as gene duplication and functional differentiation may have contributed to the adaptive evolution of regulatory mechanisms in plants. PMID- 26243615 TI - SHORT VEGETATIVE PHASE Up-Regulates TEMPRANILLO2 Floral Repressor at Low Ambient Temperatures. AB - Plants integrate day length and ambient temperature to determine the optimal timing for developmental transitions. In Arabidopsis (Arabidopsis thaliana), the floral integrator FLOWERING LOCUS T (FT) and its closest homolog TWIN SISTER OF FT promote flowering in response to their activator CONSTANS under long-day inductive conditions. Low ambient temperature (16 degrees C) delays flowering, even under inductive photoperiods, through repression of FT, revealing the importance of floral repressors acting at low temperatures. Previously, we have reported that the floral repressors TEMPRANILLO (TEM; TEM1 and TEM2) control flowering time through direct regulation of FT at 22 degrees C. Here, we show that tem mutants are less sensitive than the wild type to changes in ambient growth temperature, indicating that TEM genes may play a role in floral repression at 16 degrees C. Moreover, we have found that TEM2 directly represses the expression of FT and TWIN SISTER OF FT at 16 degrees C. In addition, the floral repressor SHORT VEGETATIVE PHASE (SVP) directly regulates TEM2 but not TEM1 expression at 16 degrees C. Flowering time analyses of svp tem mutants indicate that TEM may act in the same genetic pathway as SVP to repress flowering at 22 degrees C but that SVP and TEM are partially independent at 16 degrees C. Thus, TEM2 partially mediates the temperature-dependent function of SVP at low temperatures. Taken together, our results indicate that TEM genes are also able to repress flowering at low ambient temperatures under inductive long-day conditions. PMID- 26243616 TI - Rice TUTOU1 Encodes a Suppressor of cAMP Receptor-Like Protein That Is Important for Actin Organization and Panicle Development. AB - Panicle development, a key event in rice (Oryza sativa) reproduction and a critical determinant of grain yield, forms a branched structure containing multiple spikelets. Genetic and environmental factors can perturb panicle development, causing panicles to degenerate and producing characteristic whitish, small spikelets with severely reduced fertility and yield; however, little is known about the molecular basis of the formation of degenerating panicles in rice. Here, we report the identification and characterization of the rice panicle degenerative mutant tutou1 (tut1), which shows severe defects in panicle development. The tut1 also shows a pleiotropic phenotype, characterized by short roots, reduced plant height, and abnormal development of anthers and pollen grains. Molecular genetic studies revealed that TUT1 encodes a suppressor of cAMP receptor/Wiskott-Aldrich syndrome protein family verprolin-homologous (SCAR/WAVE) like protein. We found that TUT1 contains conserved functional domains found in eukaryotic SCAR/WAVE proteins, and was able to activate Actin-related protein2/3 to promote actin nucleation and polymerization in vitro. Consistently, tut1 mutants show defects in the arrangement of actin filaments in trichome. These results indicate that TUT1 is a functional SCAR/WAVE protein and plays an important role in panicle development. PMID- 26243617 TI - On the Extent of Tyrosine Phosphorylation in Chloroplasts. PMID- 26243618 TI - Salt-Related MYB1 Coordinates Abscisic Acid Biosynthesis and Signaling during Salt Stress in Arabidopsis. AB - Abiotic stresses, such as salinity, cause global yield loss of all major crop plants. Factors and mechanisms that can aid in plant breeding for salt stress tolerance are therefore of great importance for food and feed production. Here, we identified a MYB-like transcription factor, Salt-Related MYB1 (SRM1), that negatively affects Arabidopsis (Arabidopsis thaliana) seed germination under saline conditions by regulating the levels of the stress hormone abscisic acid (ABA). Accordingly, several ABA biosynthesis and signaling genes act directly downstream of SRM1, including SALT TOLERANT1/NINE-CIS-EPOXYCAROTENOID DIOXYGENASE3, RESPONSIVE TO DESICCATION26, and Arabidopsis NAC DOMAIN CONTAINING PROTEIN19. Furthermore, SRM1 impacts vegetative growth and leaf shape. We show that SRM1 is an important transcriptional regulator that directly targets ABA biosynthesis and signaling-related genes and therefore may be regarded as an important regulator of ABA-mediated salt stress tolerance. PMID- 26243619 TI - EARLY SENESCENCE1 Encodes a SCAR-LIKE PROTEIN2 That Affects Water Loss in Rice. AB - The global problem of drought threatens agricultural production and constrains the development of sustainable agricultural practices. In plants, excessive water loss causes drought stress and induces early senescence. In this study, we isolated a rice (Oryza sativa) mutant, designated as early senescence1 (es1), which exhibits early leaf senescence. The es1-1 leaves undergo water loss at the seedling stage (as reflected by whitening of the leaf margin and wilting) and display early senescence at the three-leaf stage. We used map-based cloning to identify ES1, which encodes a SCAR-LIKE PROTEIN2, a component of the suppressor of cAMP receptor/Wiskott-Aldrich syndrome protein family verprolin-homologous complex involved in actin polymerization and function. The es1-1 mutants exhibited significantly higher stomatal density. This resulted in excessive water loss and accelerated water flow in es1-1, also enhancing the water absorption capacity of the roots and the water transport capacity of the stems as well as promoting the in vivo enrichment of metal ions cotransported with water. The expression of ES1 is higher in the leaves and leaf sheaths than in other tissues, consistent with its role in controlling water loss from leaves. GREEN FLUORESCENT PROTEIN-ES1 fusion proteins were ubiquitously distributed in the cytoplasm of plant cells. Collectively, our data suggest that ES1 is important for regulating water loss in rice. PMID- 26243621 TI - Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice. AB - Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step in the metabolism of tryptophan along the kynurenine pathway. In tumors, increased IDO activity inhibits proliferation and induces apoptosis of T cells and natural killer cells. We investigated the therapeutic potential of IDO inhibitor 1-methyl D-tryptophan (D-1MT) with cyclophosphamide (CY) in a mouse model of lymphoma. To examine the effect of D-1MT, mice were killed on day 28. Serum concentrations of L-kynurenine and L-tryptophan were measured by high-performance liquid chromatography. Regulatory T cells (Tregs) were counted by flow cytometry, and mRNA expressions of IDO1, Foxp3, IFN-gamma, and COX-2 were examined by quantitative real-time reverse transcription-polymerase chain reaction. D-1MT+CY combination treatment significantly inhibited tumor growth as compared to either treatment alone. There were no significant differences in the serum L kynurenine/L-tryptophan ratio or the IDO1 expression level in the tumors among the treatment groups. The expression levels of IFN-gamma and COX-2 mRNA in tumor draining lymph nodes (TDLNs) were found to be significantly up-regulated in the CY and D-1MT+CY groups. The number of Tregs in TDLNs in the D-1MT+CY group was significantly lower than that in CY groups on day 17. These results suggest that D-1MT in combination with CY is an effective treatment for lymphoma in a mouse model. PMID- 26243620 TI - Distinct Cellular Locations of Carbonic Anhydrases Mediate Carbon Dioxide Control of Stomatal Movements. AB - Elevated carbon dioxide (CO2) in leaves closes stomatal apertures. Research has shown key functions of the beta-carbonic anhydrases (betaCA1 and betaCA4) in rapid CO2-induced stomatal movements by catalytic transmission of the CO2 signal in guard cells. However, the underlying mechanisms remain unclear, because initial studies indicate that these Arabidopsis (Arabidopsis thaliana) betaCAs are targeted to distinct intracellular compartments upon expression in tobacco (Nicotiana benthamiana) cells. Which cellular location of these enzymes plays a key role in native guard cells in CO2-regulated stomatal movements remains unknown. Here, we express fluorescently tagged CAs in guard cells of ca1ca4 double-mutant plants and show that the specific locations of betaCA4 at the plasma membrane and betaCA1 in native guard cell chloroplasts each can mediate rapid CO2 control of stomatal movements. Localization and complementation analyses using a mammalian alphaCAII-yellow fluorescent protein in guard cells further show that cytoplasmic localization is also sufficient to restore CO2 regulation of stomatal conductance. Mathematical modeling of cellular CO2 catalysis suggests that the dynamics of the intracellular HCO3 (-) concentration change in guard cells can be driven by plasma membrane and cytoplasmic localizations of CAs but not as clearly by chloroplast targeting. Moreover, modeling supports the notion that the intracellular HCO3 (-) concentration dynamics in guard cells are a key mechanism in mediating CO2-regulated stomatal movements but that an additional chloroplast role of CAs exists that has yet to be identified. PMID- 26243622 TI - Evaluation of a novel multiplex RT-qPCR assay for the quantification of leukemia associated BCR-ABL1 translocation. AB - Although monitoring of BCR-ABL1 translocation has become an established practice in the management of chronic myeloid leukemia (CML), the detection limit of the BCR-ABL1 transcripts needs more standardization. The aim of the present study was to evaluate the clinical performances of a novel assay for the quantification of BCR-ABL1 fusion transcripts (e13a2 and e14a2) and ABL1 in a single reaction. This assay is based on the real-time reverse transcription polymerase chain reaction (RT-qPCR) in multiplex format. In a retrospective comparative clinical study performed in a reference laboratory, RNA was extracted from 48 CML patient blood samples with various BCR-ABL1/ABL1 ratios and RT-qPCR was performed using either MAScIR assay or the RT-qPCR simplex reference assay used in routine clinical testing. The comparative clinical results showed high qualitative and quantitative concordance (correlation coefficient >0.95) between MAScIR and the reference assays. The present study illustrates the utility of MAScIR assay as a sensitive, rapid, and cost-effective quantitative device to monitor the BCR-ABL1 ratios by RT-qPCR on whole blood of diagnosed Philadelphia chromosome-positive (Ph+) leukemia patients. This test could be used as an aid in the assessment of molecular response to available treatments. PMID- 26243623 TI - Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) after treatment for Hodgkin's lymphoma. AB - Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare central nervous system (CNS) disorder with distinct radiological features. However, CLIPPERS may mimic CNS lymphoma, and several cases in which CLIPPERS occurred premonitory to CNS lymphoma have been reported. We report a 31-year-old man presenting with progressive gait ataxia and the characteristic MRI features of CLIPPERS. He was diagnosed with stage II Hodgkin's lymphoma at the age of 15, and we considered the possibility of newly emerged CNS lymphoma occurring in the immunosuppressive condition after the treatment of Hodgkin's lymphoma. Histological findings showed no evidence of CNS lymphoma and the neurological symptoms were resolved by steroids. Although CLIPPERS developed in the reverse order in this case, CLIPPERS should be considered in different diagnosis for CNS lymphoma. PMID- 26243624 TI - Serum BAFF and APRIL levels in patients with autoimmune hemolytic anemia and their clinical significance. AB - B cell-activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) play crucial roles in B cell development, survival, and antibody production. Autoimmune hemolytic anemia (AIHA) is an acquired autoimmune disease that occurs when antibodies target autologous red blood cells. Here, we analyzed the serum levels of BAFF and APRIL and their respective clinical associations in patients with AIHA. Serum BAFF and APRIL levels in patients with AIHA were significantly higher (P < 0.01) than in healthy individuals. Serum BAFF and APRIL levels were significantly augmented in patients with lower hemoglobin levels (hemoglobin was <8 g/dL) and higher LDH activity (LDH > 480 IU/mL). Glucocorticoid treatment dramatically reduced serum levels of BAFF and APRIL. Thus, serum BAFF and APRIL levels may reflect the clinical activity of this disease. Our results indicate that analysis of serum concentrations of BAFF and APRIL potentially represents a useful tool for the assessment of AIHA disease activity and progression. PMID- 26243625 TI - Trough level monitoring of intravenous busulfan to estimate the area under the plasma drug concentration-time curve in pediatric hematopoietic stem cell transplant recipients. AB - Optimizing systemic busulfan exposure, the area under the concentration-time curve (AUC), improves the outcomes for hematopoietic stem cell transplantation (HSCT). The AUC is conventionally calculated using six plasma concentrations (AUC(0-infinity)) drawn after the first of 16 intravenous busulfan doses given as a 2-h infusion every 6 h. The aim of the present study was to develop limited sampling strategies using three or fewer busulfan concentrations to reliably calculate AUC(0-infinity) in patients undergoing HSCT. We investigated the pharmacokinetics of busulfan 46 times in 29 pediatric patients receiving intravenous busulfan. Limited sampling strategies using one, two, or three plasma busulfan concentrations were developed by multiple linear regression that showed excellent agreement with AUC(0-infinity). In single-point sampling strategies, the AUC(0-infinity) predicted based on C(6) (trough level: busulfan plasma concentration 6 h after the start of the infusion) was significantly correlated with, and not statistically different from, actual values as follows: AUC(0 infinity) = 2556.5 C6 + 320.9 (r(2) = 0.929, P < 0.0001, mean bias 0.282 %, precision 7.91 %). In contrast, the predicted AUCs derived from the other sampling single points did not meet the criteria. The trough level well correlated with actual AUC(0-infinity), suggesting that this time-point is acceptable for busulfan monitoring. PMID- 26243626 TI - Understanding rice adaptation to varying agro-ecosystems: trait interactions and quantitative trait loci. AB - BACKGROUND: Interaction and genetic control for traits influencing the adaptation of the rice crop to varying environments was studied in a mapping population derived from parents (Moroberekan and Swarna) contrasting for drought tolerance, yield potential, lodging resistance, and adaptation to dry direct seeding. A BC2F3-derived mapping population for traits related to these four trait groups was phenotyped to understand the interactions among traits and to map and align QTLs using composite interval mapping (CIM). The study also aimed to identify QTLs for the four trait groups as composite traits using multivariate least square interval mapping (MLSIM) to further understand the genetic control of these traits. RESULTS: Significant correlations between drought- and yield related traits at seedling and reproductive stages respectively with traits for adaptation to dry direct-seeded conditions were observed. CIM and MLSIM methods were applied to identify QTLs for univariate and composite traits. QTL clusters showing alignment of QTLs for several traits within and across trait groups were detected at chromosomes 3, 4, and 7 through CIM. The largest number of QTLs related to traits belonging to all four trait groups were identified on chromosome 3 close to the qDTY 3.2 locus. These included QTLs for traits such as bleeding rate, shoot biomass, stem strength, and spikelet fertility. Multivariate QTLs were identified at loci supported by univariate QTLs such as on chromosomes 3 and 4 as well as at distinctly different loci on chromosome 8 which were undetected through CIM. CONCLUSION: Rice requires better adaptation across a wide range of environments and cultivation practices to adjust to climate change. Understanding the genetics and trade-offs related to each of these environments and cultivation practices thus becomes highly important to develop varieties with stability of yield across them. This study provides a wider picture of the genetics and physiology of adaptation of rice to wide range of environments. With a complete understanding of the processes and relationships between traits and trait groups, marker-assisted breeding can be used more efficiently to develop plant types that can combine all or most of the beneficial traits and show high stability across environments, ecosystems, and cultivation practices. PMID- 26243628 TI - Highly Efficient Genome Editing via CRISPR/Cas9 to Create Clock Gene Knockout Cells. AB - Targeted genome editing using CRISPR/Cas9 is a relatively new, revolutionary technology allowing for efficient and directed alterations of the genome. It has been widely used for loss-of-function studies in animals and cell lines but has not yet been used to study circadian rhythms. Here, we describe the application of CRISPR/Cas9 genome editing for the generation of an F-box and leucine-rich repeat protein 3 (Fbxl3) knockout in a human cell line. Genomic alterations at the Fbxl3 locus occurred with very high efficiency (70%-100%) and specificity at both alleles, resulting in insertions and deletions that led to premature stop codons and hence FBXL3 knockout. Fbxl3 knockout cells displayed low amplitude and long period oscillations of Bmal1-luciferase reporter activity as well as increased CRY1 protein stability in line with previously published phenotypes for Fbxl3 knockout in mice. Thus, CRISPR/Cas9 genome editing should be highly valuable for studying circadian rhythms not only in human cells but also in classic model systems as well as nonmodel organisms. PMID- 26243627 TI - Comparing the Morningness-Eveningness Questionnaire and Munich ChronoType Questionnaire to the Dim Light Melatonin Onset. AB - The dim light melatonin onset (DLMO) is the most reliable measure of central circadian timing in humans. However, it is not always possible to measure the DLMO because sample collection has to occur in the hours before usual sleep onset, it requires staff support and considerable participant effort, and it is relatively expensive. Questionnaires that ask people about the timing of their behavior, such as their sleep, may provide an easier and less expensive estimate of circadian timing. The objective of this analysis was to compare the MEQ score derived from the Morningness-Eveningness Questionnaire (MEQ) and the MSFsc derived from the Munich ChronoType Questionnaire (MCTQ) to the DLMO in the largest sample to date (N = 60). Our hypothesis was that MSFsc would correlate more highly with the DLMO than MEQ score. Our sample of 36 healthy controls and 24 patients with delayed sleep phase disorder ranged in age from 18 to 62 years. All participants slept at times of their own choosing for a week before the assessment of their DLMO. The DLMO correlated significantly with both the MEQ score (r = -0.70, p < 0.001) and MSFsc (r = 0.68, p < 0.001). A linear regression using MEQ, MSFsc, and age to predict the DLMO explained 60% of the DLMO variance. The strongest predictor of the DLMO was MSFsc (beta = 0.51, p = 0.001), followed by MEQ (beta = -0.41, p = 0.004), and age (beta = 0.26, p = 0.013). The beta values for MSFsc and MEQ score were not statistically different from each other. Nonetheless, around a 4-h range in the DLMO was observed at a given MEQ score and a given MSFsc, indicating that neither questionnaire should be exclusively used to time light or exogenous melatonin treatment, as this could result in the mistiming of these treatments relative to the DLMO, thereby potentially worsening circadian misalignment. PMID- 26243629 TI - A Gelatin-Thrombin Matrix Topical Hemostatic Agent (Floseal) in Combination With Harmonic Scalpel Is Effective in Patients Undergoing Total Thyroidectomy: A Prospective, Multicenter, Single-Blind, Randomized Controlled Trial. AB - BACKGROUND: Hemostasis during thyroidectomy is essential; however, the safest, most efficient, and most cost-effective way to achieve this is unclear. This randomized, multicenter, single-blind, prospective study evaluated the efficacy and safety of using different hemostatic approaches in patients undergoing total thyroidectomy. METHODS: Patients aged >=18 to 70 years were randomized to Floseal + a harmonic scalpel (HS), Floseal alone, HS alone, or standard total thyroidectomy. Primary endpoint was 24-hour drain output. Secondary endpoints included surgery duration and complications. RESULTS: Two hundred and six patients were randomized to Floseal + HS (n = 52), Floseal alone (n = 54), HS alone (n = 50), and standard total thyroidectomy (n = 50). The 24-hour drain output was lower in the Floseal + HS group compared with standard thyroidectomy. Floseal + HS also had a shorter surgery time (P < .0001) versus the other 3 treatments. CONCLUSION: Floseal + HS can be effective at reducing postsurgical drain output and provides a complementary hemostatic approach in patients undergoing total thyroidectomy. PMID- 26243632 TI - [Position Paper: Perioperative Management of Adult Patients with Obstructive Sleep Apnea in ENT Surgery]. AB - Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder with an increasing prevalence. Affected individuals suffer from a repetitive partial or complete occlusion of the pharyngeal airway despite continued respiratory efforts leading to sleep fragmentation, abnormal gas exchange and significant cardiovascular and metabolic morbidity. Surgical patients with OSA, which in the majority of cases has not been diagnosed prior to surgery, have an increased risk of developing a variety of pulmonary, cardiovascular and other complications throughout the perioperative period. Certain actions may contribute to increase the safety of patients with OSA during this time. Among them are preoperatively, a timely recognition and assessment of OSA and potentially co-existing diseases, intraoperatively, the selection of an appropriate anaesthesia and monitoring technique, and postoperatively, the continuation of monitoring for an adequate period of time with the option of intensive care treatment. The actual clinical approach should follow the risk profile of the individual patient which is determined by OSA severity, invasiveness of the surgical procedure and requirement for postoperative opioids as well as the incidence of critical events in the early postoperative period. Initiated and mandated by the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery, and conceived on the basis of the available literature and existing guidelines, the following paper provides recommendations for the perioperative management of adult patients with OSA in ENT surgery. PMID- 26243633 TI - [Hearing aids: it must not necessarily be the most economical ones]. PMID- 26243630 TI - A chemical genetic strategy identify the PHOSTIN, a synthetic molecule that triggers phosphate starvation responses in Arabidopsis thaliana. AB - Plants display numerous strategies to cope with phosphate (Pi)-deficiency. Despite multiple genetic studies, the molecular mechanisms of low-Pi-signalling remain unknown. To validate the interest of chemical genetics to investigate this pathway we discovered and analysed the effects of PHOSTIN (PSN), a drug mimicking Pi-starvation in Arabidopsis. We assessed the effects of PSN and structural analogues on the induction of Pi-deficiency responses in mutants and wild-type and followed their accumulation in plants organs by high pressure liquid chromotography (HPLC) or mass-spectrophotometry. We show that PSN is cleaved in the growth medium, releasing its active motif (PSN11), which accumulates in plants roots. Despite the overaccumulation of Pi in the roots of treated plants, PSN11 elicits both local and systemic Pi-starvation effects. Nevertheless, albeit that the transcriptional activation of low-Pi genes by PSN11 is lost in the phr1;phl1 double mutant, neither PHO1 nor PHO2 are required for PSN11 effects. The range of local and systemic responses to Pi-starvation elicited, and their dependence on the PHR1/PHL1 function suggests that PSN11 affects an important and early step of Pi-starvation signalling. Its independence from PHO1 and PHO2 suggest the existence of unknown pathway(s), showing the usefulness of PSN and chemical genetics to bring new elements to this field. PMID- 26243634 TI - [Meniere's Disease]. AB - Meniere's disease is one of the most common inner ear and vestibular disorders. It is defined as the idiopathic syndrome of endolymphatic hydrops (ELH). Despite the development of several different animal models of ELH, its etiology and pathogenesis is still unresolved. In humans, endolymphatic hydrops may occur spontaneously or as a consequence of specific disorders with distinct inner ear pathologies, e. g., infectious labyrinthitis, noise induced hearing loss or vestibular schwannoma. Recent imaging studies using MRI have shown that hydropic ear disease is associated not only with the full triad of vertigo, hearing, loss and tinnitus/aural pressure, but also with inner ear symptoms that do not fulfill the clinical criteria of definite Meniere's disease as set forth by the AAO-HNS. Therefore, terms like "atypical" or "cochlear"/"vestibular" Meniere's disease or "forme fruste" should be avoided and the term "Meniere's disease" should universally be applied according only to these guidelines. Besides that, the recent possibility of visualizing endolymphatic hydrops on MRI and thereby ascertaining the diagnosis in difficult cases and new audiovestibular function tests for the indirect detection of endolymphatic hydrops show promising results. Evidenced based reviews of currently available therapeutic options still reveal many uncertainties with regard to efficacy, with the exception of the ablative therapies, e. g., intratympanic gentamicin application. PMID- 26243635 TI - [Dural defect (cerebrospinal fluid leak)]. PMID- 26243636 TI - Epidermolysis bullosa acquisita in a patient with psoriasis vulgaris. PMID- 26243637 TI - The 10 Hounsfield units unenhanced computed tomography attenuation threshold does not apply to cortisol secreting adrenocortical adenomas. AB - CONTEXT: Computed tomography (CT) unenhanced attenuation value of <10 Hounsfield units (HU) has an excellent specificity (98%) to diagnose lipid-rich adrenocortical adenomas (ACAs) with a weaker sensitivity (71%). OBJECTIVE: To determine from a routine clinical perspective if unenhanced attenuation value is influenced by cortisol secretion in ACAs. DESIGN: This was a retrospective study of cases collected between 2009 and 2012. SETTING: This study was conducted in a tertiary-care university hospital. PATIENTS: Seventy-two patients operated on for an ACA (Weiss score <= 2) were analysed. Thirty-four patients had an ACA oversecreting cortisol (Cush-ACA). Thirty-eight patients had an ACA without cortisol oversecretion (Non Hyper-ACA). MAIN OUTCOME MEASURE: CT unenhanced attenuation value was correlated with the functional status. The Weiss score items were analysed. RESULTS: Among the 34 patients with a Cush-ACA a minority (n = 7) had an unenhanced attenuation value under 10 HU. Among the high precontrast density (> 10 HU) Cush-ACAs, washout analysis after contrast administration was consistent with the benign nature of the tumor in ~ 60% of the cases. Less than 25% clear cells (lipid-rich cells), a Weiss score item, was present in 50% of the Cush-ACAs in favour of a lipid-poor content. CONCLUSIONS: Unenhanced attenuation value has a poor sensitivity to diagnose an ACA in case of cortisol oversecretion due to poor lipid content. Nevertheless, the accuracy of washout analysis was preserved in the group of Cush-ACAs. PMID- 26243638 TI - Management of endocrine disease: Diabetes and osteoporosis: cause for concern? AB - Diabetes and osteoporosis are both frequent conditions, and they may thus occur simultaneously by chance. However, a growing body of evidence suggests that hyperglycemia may impair bone matrix formation and biochemical competence. Decreased biomechanical competence may be present even in a setting of increased bone mineral density, as assessed by traditional dual energy X-ray absorptiometry or normal structural parameters by quantitative computed tomography. Also, the absence of endogenous insulin secretion in type 1 diabetes (T1D) and insulin resistance or, in some cases, frank hyperinsulinemia in T2D may play a role. PMID- 26243639 TI - Visualizing Non-abrupt Transition of Quantum Well States at Stepped Silver Surfaces. AB - We use scanning tunneling spectroscopy (STS) experiments and first-principles density functional theory (DFT) calculations to address a fundamental question of how quantum well (QW) states for electrons in a metal evolve spatially in the lateral direction when there is a surface step that changes the vertical confinement thickness. This study reveals a clear spatially dependent, nearly continuous trend in the energetic shifts of quantum well (QW) states of thin Ag(111) film grown on Cu(111) substrate, showing the strongest change near the step edge. A large energetic shift equaling up to ~200 meV with a lateral extension of the QW states of the order of ~20 A is found, even though the step edge is atomically sharp as evidenced by a line scan. The observed lateral extension and the nearly smooth transition of QW states are understood within the context of step-induced charge oscillation, and Smoluchowski-type charge spreading and smoothing. PMID- 26243640 TI - Enhanced water vapor separation by temperature-controlled aligned-multiwalled carbon nanotube membranes. AB - Here we present a new strategy of selectively rejecting water vapor while allowing fast transport of dry gases using temperature-controlled aligned multiwalled carbon nanotubes (aligned-MWNTs). The mechanism is based on the water vapor condensation at the entry region of nanotubes followed by removing aggregated water droplets at the tip of the superhydrophobic aligned-MWNTs. The first condensation step could be dramatically enhanced by decreasing the nanotube temperature. The permeate-side relative humidity was as low as ~17% and the helium-water vapor separation factor was as high as 4.62 when a helium-water vapor mixture with a relative humidity of 100% was supplied to the aligned-MWNTs. The flow through the interstitial space of the aligned-MWNTs allowed the permeability of single dry gases an order of magnitude higher than the Knudsen prediction regardless of membrane temperature. The water vapor separation performance of hydrophobic polytetrafluoroethylene membranes could also be significantly enhanced at low temperatures. This work combines the membrane-based separation technology with temperature control to enhance water vapor separation performance. PMID- 26243643 TI - Mechanisms and dynamics of protonation and lithiation of ferrocene. AB - By elucidating the mechanism of the simplest electrophilic substitution reaction of ferrocene, it was found that the verification of the protonation reaction has been a difficulty. In the work reported here, ab initio chemical dynamics simulations were performed at B3LYP/DZVP level of theory to understand the atomic level mechanisms of protonation and lithiation of ferrocene. Protonation of ferrocene resulted in the agostic and metal-protonated forms. Trajectory calculations revealed that protonation of ferrocene occurs by exo and endo mechanisms, with exo being the major path. H(+) was found to be mobile and hopped from the Cp ring to the metal center and vice versa after the initial attack on ferrocene, with the metal-complex having a shorter lifetime. These results remove the ambiguity surrounding the mechanism, as proposed in earlier experimental and computational studies. Lithiation of ferrocene resulted in the formation of cation-pi and metal-lithiated complexes. Similar to protonation, trajectory results revealed that both exo and endo paths were followed, with the exo path being the major one. In addition, lithiated-ferrocene exhibited planetary motion. The major path (exo) followed in the protonation and lithiation of ferrocene is consistent with the observations in earlier experimental studies for other hard electrophiles. PMID- 26243641 TI - Social-cognitive factors mediating intervention effects on handwashing: a longitudinal study. AB - Handwashing with soap effectively prevents diarrhoea, a leading cause of death in infants. Theory-based interventions are expected to promote handwashing more successfully than standard approaches. The present article investigates the underlying change processes of theory-based handwashing interventions. A nonrandomised field study compared a standard approach to two theory-based interventions that were tailored to the target population, the inhabitants of four villages in southern Ethiopia (N = 408). Data were collected before and after interventions by structured interviews and analysed by mediation analysis. In comparison to the standard approach (i.e., education only), education with public commitment and reminder was slightly more effective in changing social cognitive factors and handwashing. Education with an infrastructure promotion and reminder was most effective in promoting handwashing through enhancing social cognitive factors. The results confirm the relevance of testing interventions' underlying change processes. PMID- 26243642 TI - Spirituality is associated with better prostate cancer treatment decision making experiences. AB - This study examined whether spiritual beliefs are associated with greater decision-making satisfaction, lower decisional conflict and decision-making difficulty with the decision-making process in newly diagnosed men with prostate cancer. Participants were 1114 men diagnosed with localized prostate cancer who had recently made their treatment decision, but had not yet been treated. We used multivariable linear regression to analyze relationships between spirituality and decision-making satisfaction, decisional conflict, and decision-making difficulty, controlling for optimism and resilience, and clinical and sociodemographic factors. Results indicated that greater spirituality was associated with greater decision-making satisfaction (B = 0.02; p < 0.001), less decisional conflict (B = -0.42; p < 0.001), and less decision-making difficulty (B = -0.08; p < 0.001). These results confirm that spiritual beliefs may be a coping resource during the treatment decision-making process. Providing opportunities for patients to integrate their spiritual beliefs and their perceptions of their cancer diagnosis and trajectory could help reduce patient uncertainty and stress during this important phase of cancer care continuum. PMID- 26243644 TI - Cortical inhibition within motor and frontal regions in alcohol dependence post detoxification: A pilot TMS-EEG study. AB - OBJECTIVES: Preclinical studies suggest that cortical alterations within the prefrontal cortex (PFC) are critical to the pathophysiology of alcohol dependence. Combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) allows direct assessment of cortical excitability and inhibition within the PFC of human subjects. We report the first application of TMS-EEG to measure these indices within the PFC of alcohol-dependent (ALD) patients post-detoxification. METHODS: Cortical inhibition was assessed in 12 ALD patients and 14 healthy controls through single and paired-pulse TMS paradigms. Long-interval cortical inhibition indexed cortical inhibition in the PFC. In the motor cortex (MC), short- interval intracortical inhibition and cortical silent period determined inhibition, while intracortical facilitation measured facilitation, resting and active motor threshold indexed cortical excitability. RESULTS: ALD patients demonstrated altered cortical inhibition across the bilateral frontal cortices relative to controls. There was evidence of altered cortical excitability in ALD patients; however, no significant differences in MC inhibition. CONCLUSIONS: Our study provides first direct evidence of reduced cortical inhibition in the PFC of ALD patients post-detoxification. Altered cortical excitability in the MC may reflect hyper-excitability within the cortex associated with chronic alcohol consumption. These findings provide initial neurophysiological evidence of disrupted cortical excitability within the PFC of ALD patients. PMID- 26243646 TI - Five algorithms that calculate cardiac output from the arterial waveform: a comparison with Doppler ultrasound. AB - BACKGROUND: Different mathematical approaches are used to calculate arterial pulse pressure wave analysis (PPWA) cardiac output. The CardioQ-Combi is a research oesophageal Doppler (COODM) monitor that includes these five fundamental PPWA algorithms. We compared these PPWA cardiac output readings to COODM and suprasternal USCOM Doppler (COUS) over a range of cardiac output values induced by dopamine infusion in patients undergoing major surgery. USCOM acted as a control. METHODS: Serial sets of cardiac output data were recorded at regular intervals as cardiac output increased. Formulae included: cardiac output calculated form systemic vascular resistance (COMAP), pulse pressure (COPP), Liljestrand-Zander formula (COLZ), alternating current power (COAC) and systolic area with Kouchoukos correction (COSA). The reference method for comparisons was COODM. Statistical methods included: Scatter plots (correlation), Bland-Altman (agreement) and concordance (trending) and polar (trending). RESULTS: From 20 patients 255 sets of cardiac output comparative data were collected. Mean cardiac output for each method ranged between 5.0 and 5.5 litre min(-1). For comparisons between COUS and the five PPWA algorithms with COODM: Correlation was best with COUS (R(2)=0.81) followed by COLZ (R(2)=0.72). Bias ranged between 0.1 and 0.5 litre min(-1). Percentage error was lowest with COUS (26.4%) followed by COLZ (35.2%), others (40.7 to 56.3%). Concordance was best with COUS (92%), followed by COLZ (71%), others (64 to 66%). Polar analysis (mean(standard deviation)) were best with COUS (-2.7 (21.1)), followed by COLZ (+4.7 (26.6). CONCLUSIONS: The Liljestrand-Zander PPWA formula was most reliable compared with oesophageal Doppler in major surgical patients under general anaesthesia, but not better than USCOM. PMID- 26243647 TI - Tracheal intubation by trainees does not alter the incidence or duration of postoperative sore throat and hoarseness: a teaching hospital-based propensity score analysis. AB - BACKGROUND: Postoperative throat complications, such as sore throat and hoarseness, are frequent complications of tracheal intubation. To assess whether severity of throat complications is related to the experience of physicians performing tracheal intubation, we compared the incidence and duration of postoperative sore throat and hoarseness and patient satisfaction between tracheal intubation performed by trainees and experienced consultant anaesthetists. METHODS: This is a retrospective review of an institutional registry containing records of 21 606 patients undergoing general anaesthesia and was conducted with ethics board approval. All tracheal intubations by trainees were performed under the supervision of consultant anaesthetists. To avoid channel bias, the propensity score analysis was used to generate a set of matched cases (intubations by trainees) and controls (intubations by anaesthetists), yielding 3465 (sore throat) and 3267 (hoarseness) matched patient pairs. The incidence and sustained rate of symptoms were compared as primary outcomes. We also compared patient satisfaction with perioperative care. RESULTS: After propensity score matching, there was no difference between tracheal intubation by trainees and tracheal intubation by consultant anaesthetists in the incidences of sore throat (32.9 vs 32.6%, P=0.84) or hoarseness (35.8 vs 35.2%, P=0.60). Odds ratios and 95% confidence intervals for tracheal intubation by trainees were 1.01 (0.91-1.12) for sore throat and 1.03 (0.93-1.14) for hoarseness. The rates of sustained sore throat and hoarseness over the course were low (P=0.85 and P=0.67, respectively). Hazard ratios and 95% confidence intervals for tracheal intubation by trainees were 0.99 (0.94-1.05) for sustained sore throat and 0.99 (0.93-1.05) for sustained hoarseness. Patient satisfaction did not differ between matched groups (P=0.66 and P=0.83). CONCLUSIONS: Tracheal intubation by trainees under the supervision of consultant anaesthetists did not worsen the postoperative airway outcomes, such as sore throat and hoarseness. PMID- 26243645 TI - ADHD and Emotion Dysregulation Among Children and Adolescents. AB - Individuals with attention-deficit/hyperactivity disorder (ADHD) experience impairments in a number of functional domains. Although current evidence-based treatments for ADHD reduce symptoms and improve academic and behavioral functioning, they have minimal impact on social functioning or on risky behaviors (see Evans et al. in J Clin Child Adolesc Psychol, 43:527-551, 2014 for review). Preliminary evidence indicates that emotion dysregulation (ED) is associated with impairments across the developmental spectrum, such as social impairment and risky behaviors, and that its relative absence/presence is differentially associated with treatment response. It thus stands to reason that by incorporating a focus on ED in interventions targeting social impairment and risky behaviors, we may be able to increase the number of youth who respond to such interventions and decrease the prevalence or degree of these impairments and behaviors among youth and adults with ADHD. However, a number of questions remain unaddressed about the association between ADHD and ED, such as the portion of individuals with ADHD who experience ED, the extent to which ED is associated with the above impairments and behaviors, and whether or not ED is malleable. To begin addressing these questions, we summarize and critically evaluate the literature on the association between ADHD and ED and make recommendations for future basic, translational, and treatment outcome research. PMID- 26243648 TI - Adding Bevacizumab to the Treatment of Patients With Non-Small-Cell Lung Cancer: Caveat Emptor. PMID- 26243650 TI - Understanding Oral Chemotherapy Prescribing Patterns at the End of Life at a Comprehensive Cancer Center: Analysis of a Massachusetts Payer Claims Database. AB - PURPOSE: Receipt of chemotherapy in the last 14 days of life is a measure of potential overuse of care. Specific measures defining appropriate end-of-life use of oral agents have not yet been described, and little is known about prescribing patterns. METHODS: We conducted an exploratory analysis of 371 patients at Dana Farber Cancer Institute who were covered by the Blue Cross Blue Shield of Massachusetts pharmacy benefit and died during 2012 to 2013. We analyzed processed claims as a surrogate for chemotherapy administration. We compared oral with parenteral chemotherapy claims in the last 6 months of life. RESULTS: In the last 6 months of life, 294 patients (79%) had chemotherapy claims, including 81 (22%) prescribed an oral agent; 20 patients had claims for oral chemotherapy in the last 30 days of life. For eight patients (40%), this was the initial start of that oral agent. In the last 14 days of life, only 23 patients had chemotherapy claims, including six patients prescribed an oral agent. CONCLUSION: The collection of oral chemotherapy use data through insurance claims was feasible. Processed claims for chemotherapy, including oral, sharply declined during the last 30 days of life, consistent with a shift to palliative management. These results highlight the need for a more comprehensive analysis of oral chemotherapy prescribing patterns and development of specific measures to define the appropriate use of oral chemotherapy at the end of life. PMID- 26243649 TI - HIV Testing in Patients With Cancer at the Initiation of Therapy at a Large US Comprehensive Cancer Center. AB - PURPOSE: To determine the rates of HIV testing and infection among patients with cancer at initiation of systemic cancer therapy. METHODS: We conducted a retrospective cohort study of adults with cancer who registered at a comprehensive cancer center from January 2004 through April 2011 and received systemic cancer therapy. We determined rates of HIV-1/2 and/or Western blot testing and HIV positivity at initiation of systemic cancer therapy. Multivariable logistic regression was used to determine predictors of HIV testing. RESULTS: Of 18,874 patients with cancer who received systemic cancer therapy during the study period, 3,514 (18.6%) were tested for HIV at initiation of cancer therapy. The prevalence of positive HIV test results was 1.2% (41 of 3,514), and the prevalence of newly diagnosed HIV was 0.3% (12 of 3,514). The HIV testing rate was lower in black than in white patients (13.7% v 19.2%), but the prevalence of positive test results was higher in black patients (4.5%) than in any other racial/ethnic group. Among patients with AIDS-defining cancers (eg, non Hodgkin lymphoma and cervical cancer), predictors of HIV testing were history of non-Hodgkin lymphoma, younger age, and registration after 2006. Among patients with non-AIDS-defining cancers, predictors of HIV testing were younger age, registration after 2006, male sex, history of illicit drug use or sexually transmitted disease, having a hematologic malignancy, and black race. CONCLUSION: The prevalence of HIV infection among patients with cancer was 1.2%, higher than the 0.1% prevalence threshold above which national guidelines recommend routine opt-out testing; however, the overall HIV testing rate was low. PMID- 26243651 TI - Breast Cancer Experience of the Molecular Tumor Board at the University of California, San Diego Moores Cancer Center. AB - PURPOSE: Multiplex genomic tests are enabling oncologists to interrogate the DNA of their patients. However, few oncologists are proficient with respect to the implications of complex molecular diagnostics. We initiated a Molecular Tumor Board that focused on individual patients with advanced cancer whose tumors underwent genomic profiling, and here report our experience with breast cancer. METHODS: A multidisciplinary team that included physicians, scientists, geneticists, and bioinformatics/pathway specialists attended. All molecular tests were performed in a Clinical Laboratory Improvement Amendments environment (next generation sequencing, 182 or 236 genes). RESULTS: Forty of 43 patients (93%; mean age, 59 years) had at least one theoretically actionable aberration (mean, 4.79 anomalies/patient). Median time from ordering to report was 27 days (median of approximately 11 days for specimen acquisition and approximately 14 days for diagnostic processing). Even if we considered distinct abnormalities in a gene as the same, there were only two patients with an identical molecular profile. Seventy-three genes (206 abnormalities; 119 distinct) were aberrant. Seventeen of the 43 patients (40%; median, seven previous therapies in the metastatic setting) were treated in a manner consistent with Molecular Tumor Board discussions; seven (16% of 43, or 41% of 17) achieved stable disease for 6 or more months (n = 2) or partial remission (n = 5). Lack of access to targeted medication was the most common reason that patients could not be treated. CONCLUSION: Multidisciplinary molecular tumor boards may help to optimize the management of patients with advanced, heavily pretreated breast cancer who have undergone genomic testing. Facilitating availability of appropriately targeted drugs and clinical trials is needed. PMID- 26243653 TI - Raman Spectroscopic Observations of the Ion Association between Mg(2+) and SO4(2 ) in MgSO4-Saturated Droplets at Temperatures of <=380 degrees C. AB - Liquid-liquid phase separation was observed in aqueous MgSO4 solutions with excess H2SO4 at elevated temperatures; the aqueous MgSO4/H2SO4 solutions separated into MgSO4-rich droplets (fluid F1) and a MgSO4-poor phase (fluid F2) during heating. The phase separation temperature increases with SO4(2-)/Mg2+ ratio at a constant MgSO4 concentration. At a MgSO4/H2SO4 ratio of 5, the liquid liquid phase separation temperature decreases with an increase in MgSO4 concentration up to ~1.0 mol/kg and then increases at higher concentrations, showing a typical macroscale property of polymer solutions with a lower critical solution temperature (LCST) of ~271.4 degrees C. In situ Raman spectroscopic analyses show that the MgSO4 concentration in fluid F1 increases with an increase in temperature, whereas that in fluid F2 decreases with an increase in temperature. In addition, HSO4(-), which does not readily form complexes with Mg(2+), tends to accumulate in fluid F2. Analyses of the v1(SO4(2-)) bands confirmed the presence of four-sulfate species of unassociated SO4(2-) (~980 cm( 1)), contact ion pairs (CIPs; ~995 cm(-1)), and triple ion pairs (TIPs; ~1005 cm( 1)) in aqueous solution, and more complex ion pair chain structure (~1020 cm(-1)) in fluid F1. Comparison of the sulfate species in fluids F1 and F2 at 280 degrees C suggests that SO4(2-) in fluid F2 is less associated with Mg(2+). On the basis of in situ visual and Raman spectroscopic observations, we suggest that the formation of the complex Mg(2+)-SO4(2-) ion association might be responsible for the liquid-liquid phase separation. In addition, Raman spectroscopic analyses of the OH stretching bands indicate that the hydrogen bonding in fluid F1 is stronger than that in fluid F2, which might be ascribed to the increasing probability of collision of H2O with Mg(2+) and SO4(2-) in fluid F1. PMID- 26243652 TI - An observational cohort study of patients with newly diagnosed digital ulcer disease secondary to systemic sclerosis registered in the EUSTAR database. AB - OBJECTIVES: This study describes clinical characteristics, prognostic factors, and quality of life in patients with newly diagnosed (incident) digital ulcers (DU). METHODS: Observational cohort study of 189 consecutive SSc patients with incident DU diagnosis identified from the EUSTAR database (22 centres in 10 countries). Data were collected from medical charts and during one prospective visit between 01/2004 and 09/2010. RESULTS: Median age at DU diagnosis was 51 years, majority of patients were female (88%), and limited cutaneous SSc was the most common subtype (61%). At incident DU diagnosis, 41% of patients had one DU and 59% had >=2 DU; at the prospective visit 52% had DU. Pulmonary arterial hypertension (PAH) and multiple DU at diagnosis were associated with presence of any DU at the prospective visit (odds ratios: 4.34 and 1.32). During the observation period (median follow-up was 2 years) 127 patients had >=1 hospitalisation. The event rate of new DU per person-year was 0.66, of DU associated complications was 0.10, and of surgical or diagnostic procedures was 0.12. At the prospective visit, patients with >=1 DU reported impairment in daily activities by 57%, those with 0 DU by 37%. The mean difference between patients with or without DU in the SF-36 physical component was 2.2, and in the mental component 1.4. DU patients were not routinely prescribed endothelin receptor antagonists or prostanoids. CONCLUSIONS: This real world cohort demonstrates that DU require hospital admission, and impair daily activity. PAH and multiple DU at diagnosis were associated with future occurrence of DU. PMID- 26243654 TI - When Injury Clouds Understanding of Others: Theory of Mind after Mild TBI in Preschool Children. AB - There is evidence to suggest that social skills, such as the ability to understand the perspective of others (theory of mind), may be affected by childhood traumatic brain injuries; however, studies to date have only considered moderate and severe traumatic brain injury (TBI). This study aimed to assess theory of mind after early, mild TBI (mTBI). Fifty-one children who sustained mTBI between 18 and 60 months were evaluated 6 months post-injury on emotion and desires reasoning and false-belief understanding tasks. Their results were compared to that of 50 typically developing children. The two groups did not differ on baseline characteristics, except for pre- and post-injury externalizing behavior. The mTBI group obtained poorer scores relative to controls on both the emotion and desires task and the false-belief understanding task, even after controlling for pre-injury externalizing behavior. No correlations were found between TBI injury characteristics and theory of mind. This is the first evidence that mTBI in preschool children is associated with theory of mind difficulties. Reduced perspective taking abilities could be linked with the social impairments that have been shown to arise following TBI. PMID- 26243656 TI - Pharmacotherapeutic considerations for using colchicine to treat idiopathic pericarditis in the USA. AB - The clinical significance of colchicine in the treatment of acute idiopathic (viral) pericarditis (IP) was only elucidated less than a decade ago. Multiple trials have shown the benefit of colchicine in decreasing the rate of recurrence, primarily in the European population. However, the colchicine formulation used in these trials is not available in Western countries such as the USA. In the USA, two formulations are available: the 0.6 mg capsule and the 0.6 mg tablet. As a result, higher doses than administered in the European trials must be utilized to treat IP. However, the use of these dosage forms has never been studied in the treatment of IP. Pharmacokinetic and pharmacodynamic knowledge of colchicine germane to clinicians such as drug disposition and drug-drug or drug-disease interactions have not been extensively reviewed in recent years. Furthermore, the safety of colchicine in the treatment of IP has not been extensively studied, and literature regarding adverse drug events originates from data in patients treated for familial Mediterranean fever and gout. This review will help the clinician understand pharmacotherapeutic considerations and thereby optimize therapy and ensure patient safety when using colchicine to treat IP. PMID- 26243655 TI - Validated prediction of pro-invasive growth factors using a transcriptome-wide invasion signature derived from a complex 3D invasion assay. AB - The invasion of activated fibroblasts represents a key pathomechanism in fibrotic diseases, carcinogenesis and metastasis. Invading fibroblasts contribute to fibrotic extracellular matrix (ECM) formation and the initiation, progression, or resistance of cancer. To construct transcriptome-wide signatures of fibroblast invasion, we used a multiplex phenotypic 3D invasion assay using lung fibroblasts. Microarray-based gene expression profiles of invading and non invading fibroblasts demonstrated that 1,049 genes were differentially regulated (>1.5-fold). Unbiased pathway analysis (Ingenuity) identified significant enrichment for the functional clusters 'invasion of cells', 'idiopathic pulmonary fibrosis', and 'metastasis'. Matrix metalloprotease 13 (MMP13), transforming growth factor (TGF)-beta1, Caveolin (Cav) 1, Phosphatase and Tensin Homolog (Pten), and secreted frizzled-related protein (Sfrp) 1 were among the highest regulated genes, confirmed by qRT-PCR and Western Blotting. We next performed in silico analysis (Ingenuity Pathway Analysis) to predict mediators that induced fibroblast invasion. Of these, TGFbeta1, epidermal growth factor (EGF), fibroblast growth factor (FGF) 2, and platelet-derived growth factor (PDGF)-BB were tested in our 3D invasion assay and found to significantly induce invasion, thus validating the transcriptome profile. Accordingly, our transcriptomic invasion signature describes the invading fibroblast phenotype in unprecedented detail and provides a tool for future functional studies of cell invasion and therapeutic modulation thereof using complex phenotypic assays. PMID- 26243657 TI - MCM2 binding to histones H3-H4 and ASF1 supports a tetramer-to-dimer model for histone inheritance at the replication fork. PMID- 26243658 TI - Corrigendum: The zinc-finger domains of PARP1 cooperate to recognize DNA strand breaks. PMID- 26243659 TI - How does relativity affect magnetically induced currents? AB - Magnetically induced probability currents in molecules are studied in relativistic theory. Spin-orbit coupling (SOC) enhances the curvature and gives rise to a previously unobserved current cusp in AuH or small bulge-like distortions in HgH2 at the proton positions. The origin of this curvature is magnetically induced spin-density arising from SOC in the relativistic description. PMID- 26243660 TI - A Broadly Cross-protective Vaccine Presenting the Neighboring Epitopes within the VP1 GH Loop and VP2 EF Loop of Enterovirus 71. AB - Human enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the major etiological agents of hand, foot and mouth disease (HFMD) and are often associated with neurological complications. Currently, several vaccine types are being developed for EV71 and CA16. In this study, we constructed a bivalent chimeric virus-like particle (VLP) presenting the VP1 (aa208-222) and VP2 (aa141 155) epitopes of EV71 using hepatitis B virus core protein (HBc) as a carrier, designated HBc-E1/2. Immunization with the chimeric VLPs HBc-E1/2 induced higher IgG titers and neutralization titers against EV71 and CA16 in vitro than immunization with only one epitope incorporated into HBc. Importantly, passive immunization with the recombinant HBc-E2 particles protected neonatal mice against lethal EV71 and CA16 infections. We demonstrate that anti-VP2 (aa141-155) sera bound authentic CA16 viral particles, whereas anti-VP1 (aa208-222) sera could not. Moreover, the anti-VP2 (aa141-155) antibodies inhibited the binding of human serum to virions, which demonstrated that the VP2 epitope is immunodominant between EV71 and CA16. These results illustrated that the chimeric VLP HBc-E1/2 is a promising candidate for a broad-spectrum HFMD vaccine, and also reveals mechanisms of protection by the neighboring linear epitopes of the VP1 GH and VP2 EF loops. PMID- 26243661 TI - Functional restoration and risk of non-union of the first metatarsocuneiform arthrodesis for hallux valgus: A finite element approach. AB - First metatarsocuneiform arthrodesis is one of the surgical interventions to correct hallux valgus, especially those with hypermobile first ray. There is lacking of biomechanical investigations to assess this operation. The objective of this study was to explore the functional restoration and the risk of non-union after the surgery via finite element analysis. A three-dimensional foot model was constructed from a female aged 28 via magnetic resonance imaging. Thirty bones and encapsulated bulk tissue were modeled. Walking stance was simulated by the gait analysis data of the same participant. Parts of the first metatarsal and cuneiform were resected and the bone graft was assigned with the same stiffness as adjacent bones to resemble the surgery of first metatarsocuneiform arthrodesis. The third principal stress of the first metatarsal at midstance (25% stance) and push off (60% stance) was increased by 76% and 139% respectively after the operation, while that of the second metatarsal was decreased by 14% and 66%. The operation reduced the medial deviation of the first metatarsal head by about 3.5mm during initial push off (60% stance). Besides, the bone graft could experience tensile stress inferiorly (26.51MPa). In conclusion, the increase of stress on the first metatarsal and the reduced medial excursion of the first metatarsal head after the simulated operation reflected that metatarsocuneiform arthrodesis could restore the load-bearing function of the first ray. However, inter-fragmentary compression could not be guaranteed. The appropriate course of hardware and non-weight-bearing protocol should be noted and further investigated. PMID- 26243662 TI - Development of SSR markers and genetic diversity analysis in enset (Ensete ventricosum (Welw.) Cheesman), an orphan food security crop from Southern Ethiopia. AB - BACKGROUND: Enset (Ensete ventricosum (Welw.) Cheesman; Musaceae) is a multipurpose drought-tolerant food security crop with high conservation and improvement concern in Ethiopia, where it supplements the human calorie requirements of around 20 million people. The crop also has an enormous potential in other regions of Sub-Saharan Africa, where it is known only as a wild plant. Despite its potential, genetic and genomic studies supporting breeding programs and conservation efforts are very limited. Molecular methods would substantially improve current conventional approaches. Here we report the development of the first set of SSR markers from enset, their cross-transferability to Musa spp., and their application in genetic diversity, relationship and structure assessments in wild and cultivated enset germplasm. RESULTS: SSR markers specific to E. ventricosum were developed through pyrosequencing of an enriched genomic library. Primer pairs were designed for 217 microsatellites with a repeat size > 20 bp from 900 candidates. Primers were validated in parallel by in silico and in vitro PCR approaches. A total of 67 primer pairs successfully amplified specific loci and 59 showed polymorphism. A subset of 34 polymorphic SSR markers were used to study 70 both wild and cultivated enset accessions. A large number of alleles were detected along with a moderate to high level of genetic diversity. AMOVA revealed that intra-population allelic variations contributed more to genetic diversity than inter-population variations. UPGMA based phylogenetic analysis and Discriminant Analysis of Principal Components show that wild enset is clearly separated from cultivated enset and is more closely related to the out-group Musa spp. No cluster pattern associated with the geographical regions, where this crop is grown, was observed for enset landraces. Our results reaffirm the long tradition of extensive seed-sucker exchange between enset cultivating communities in Southern Ethiopia. CONCLUSION: The first set of genomic SSR markers were developed in enset. A large proportion of these markers were polymorphic and some were also transferable to related species of the genus Musa. This study demonstrated the usefulness of the markers in assessing genetic diversity and structure in enset germplasm, and provides potentially useful information for developing conservation and breeding strategies in enset. PMID- 26243663 TI - Controllable Synthesis of Functional Hollow Carbon Nanostructures with Dopamine As Precursor for Supercapacitors. AB - N-doped hollow carbon spheres (N-HCSs) are promising candidates as electrode material for supercapacitor application. In this work, we report a facile one step synthesis of discrete and highly dispersible N-HCSs with dopamine (DA) as a carbon precursor and TEOS as a structure-assistant agent in a mixture containing water, ethanol, and ammonia. The architectures of resultant N-HCSs, including yolk-shell hollow carbon spheres (YS-HCSs), single-shell hollow carbon spheres (SS-HCSs), and double-shells hollow carbon spheres (DS-HCSs), can be efficiently controlled through the adjustment of the amount of ammonia. To explain the relation and formation mechanism of these hollow carbon structures, the samples during the different synthetic steps, including polymer/silica spheres, carbon/silica spheres and silica spheres by combustion in air, were characterized by TEM. Electrochemical measurements performed on YS-HCSs, SS-HCSs, and DS-HCSs showed high capacitance with 215, 280, and 381 F g(-1), respectively. Moreover, all the nitrogen-doped hollow carbon nanospheres showed a good cycling stability 97.0% capacitive retention after 3000 cycles. Notably, the highest capacitance of DS-HCSs up to 381 F g(-1) is higher than the capacitance reported so far for many carbon-based materials, which may be attributed to the high surface area, hollow structure, nitrogen functionalization, and double-shell architecture. These kinds of N-doped hollow-structured carbon spheres may show promising prospects as advanced energy storage materials and catalyst supports. PMID- 26243664 TI - Growth Impairment Caused by Raw Linseed Consumption: Can Trypsin Inhibitors Be Harmful for Health? AB - Linseed (Linun usitatissimum L.) is an important oilseed whose nutritional value can be impaired due to presence of antinutritional factors and low protein digestibility. Protein fractions from raw linseed meal were extracted, isolated and analyzed in vitro and in vivo. Globulins, the major protein fraction of linseed, showed low in vitro susceptibility to trypsin and chymotrypsin, but its in vivo digestibility was 93.2 %. Albumin fraction had high trypsin inhibition activity (5250 Inhibition Units g(-1)) and presented low molecular mass protein bands, similar to known trypsin inhibitors. Raw linseed consumption caused negative effects on rat growth and reduction of intestinal villi. Results indicate that raw linseed meal must not be used as an exclusive source of protein regardless of the major proteins have high digestibility; digestive enzymes inhibitors in raw linseed probably reduces the protein utilization. PMID- 26243665 TI - Jatropha curcas Protein Concentrate Stimulates Insulin Signaling, Lipogenesis, Protein Synthesis and the PKCalpha Pathway in Rat Liver. AB - Jatropha curcas is an oil seed plant that belongs to the Euphorbiaceae family. Nontoxic genotypes have been reported in Mexico. The purpose of the present work was to evaluate the effect of a Mexican variety of J. curcas protein concentrate (JCP) on weight gain, biochemical parameters, and the expression of genes and proteins involved in insulin signaling, lipogenesis, cholesterol and protein synthesis in rats. The results demonstrated that short-term consumption of JCP increased serum glucose, insulin, triglycerides and cholesterol levels as well as the expression of transcription factors involved in lipogenesis and cholesterol synthesis (SREBP-1 and LXRalpha). Moreover, there was an increase in insulin signaling mediated by Akt phosphorylation and mTOR. JCP also increased PKCalpha protein abundance and the activation of downstream signaling pathway targets such as the AP1 and NF-kappaB transcription factors typically activated by phorbol esters. These results suggested that phorbol esters are present in JCP, and that they could be involved in the activation of PKC which may be responsible for the high insulin secretion and consequently the activation of insulin-dependent pathways. Our data suggest that this Mexican Jatropha variety contains toxic compounds that produce negative metabolic effects which require caution when using in the applications of Jatropha-based products in medicine and nutrition. PMID- 26243666 TI - Phenolic Profiles, Phytchemicals and Mineral Content of Decoction and Infusion of Opuntia ficus-indica Flowers. AB - Opuntia flowers are a natural source of biologically active compounds and they have been used as medicinal plant for a long time. Despite the various uses reported for the decoction and infusion of these flowers, their characterization has been discarded. In this study, the decoction and infusion prepared from Opuntia ficus-indica were analyzed with respect to their content in minerals and phytochemicals in order to evaluate its nutritional characteristics. The obtained data proved that these preparations are a rich source of minerals mainly K and Ca. Moreover, the phytochemical analysis revealed that they have important polyphenols, flavonoids and tannins contents with the infusion that presented the highest polyphenol levels. LC-MS analyses of decoction and infusion allowed the characterization of 20 phenolic compounds. It is mainly identified by the presence of flavonols glycosides. PMID- 26243667 TI - Septic cardiomyopathy in rat LPS-induced endotoxemia: relative contribution of cellular diastolic Ca(2+) removal pathways, myofibrillar biomechanics properties and action of the cardiotonic drug levosimendan. AB - Cardiac dysfunction is a common complication in sepsis and is characterized by forward pump failure. Hallmarks of septic cardiomyopathy are decreased myofibrillar contractility and reduced Ca(2+) sensitivity but it is still not clear whether reduced pump efficiency is predominantly a diastolic impairment. Moreover, a comprehensive picture of upstream Ca(2+) handling mechanisms and downstream myosin biomechanical parameters is still missing. Ca(2+)-sensitizing agents in sepsis may be promising but mechanistic insights for drugs like levosimendan are scarce. Here, we used an endotoxemic LPS rat model to study mechanisms of sepsis on in vivo hemodynamics, multicellular myofibrillar Ca(2+) sensitivity, in vitro cellular Ca(2+) homeostasis and subcellular actomyosin interaction with intracardiac catheters, force transducers, confocal Fluo-4 Ca(2+) recordings in paced cardiomyocytes, and in vitro motility assay, respectively. Left ventricular ejection fraction and myofibrillar Ca(2+) sensitivity were depressed in LPS animals but restored by levosimendan. Diastolic Ca(2+) transient kinetics was slowed down by LPS but ameliorated by levosimendan. Selectively blocking intracellular and sarcolemmal Ca(2+) extrusion pathways revealed minor contribution of sarcoplasmic reticulum Ca(2+) ATPase (SERCA) to Ca(2+) transient diastole in LPS-evoked sepsis but rather depressed Na(+)/Ca(2+) exchanger and plasmalemmal Ca(2+) ATPase. This was mostly compensated by levosimendan. Actin sliding velocities were depressed in myosin heart extracts from LPS rats. We conclude that endotoxemia specifically impairs sarcolemmal diastolic Ca(2+) extrusion pathways resulting in intracellular diastolic Ca(2+) overload. Levosimendan, apart from stabilizing Ca(2+)-troponin C complexes, potently improves cellular Ca(2+) extrusion in the septic heart. PMID- 26243668 TI - Mto2 multisite phosphorylation inactivates non-spindle microtubule nucleation complexes during mitosis. AB - Microtubule nucleation is highly regulated during the eukaryotic cell cycle, but the underlying molecular mechanisms are largely unknown. During mitosis in fission yeast Schizosaccharomyces pombe, cytoplasmic microtubule nucleation ceases simultaneously with intranuclear mitotic spindle assembly. Cytoplasmic nucleation depends on the Mto1/2 complex, which binds and activates the gamma tubulin complex and also recruits the gamma-tubulin complex to both centrosomal (spindle pole body) and non-centrosomal sites. Here we show that the Mto1/2 complex disassembles during mitosis, coincident with hyperphosphorylation of Mto2 protein. By mapping and mutating multiple Mto2 phosphorylation sites, we generate mto2-phosphomutant strains with enhanced Mto1/2 complex stability, interaction with the gamma-tubulin complex and microtubule nucleation activity. A mutant with 24 phosphorylation sites mutated to alanine, mto2[24A], retains interphase-like behaviour even in mitotic cells. This provides a molecular-level understanding of how phosphorylation 'switches off' microtubule nucleation complexes during the cell cycle and, more broadly, illuminates mechanisms regulating non-centrosomal microtubule nucleation. PMID- 26243669 TI - Anti-inflammatory activity of polyphenolics from acai (Euterpe oleracea Martius) in intestinal myofibroblasts CCD-18Co cells. AB - The demand for tropical fruits high in polyphenolics including acai (Euterpe oleracea Mart.) has been increasing based on ascribed health benefits and antioxidant properties. This study evaluated the anti-inflammatory activities of acai polyphenolics in human colon myofibroblastic CCD-18Co cells to investigate the suppression of reactive oxygen species (ROS), and mRNA and protein expression of inflammatory proteins. Non-cytotoxic concentrations of acai extract, 1-5 mg gallic acid equivalent L(-1), were selected. The generation of ROS was induced by lipopolysaccharide (LPS) and acai extract partially reversed this effect to 0.53 fold of the LPS-control. Acai extract (5 mg GAE L(-1)) down-regulated LPS-induced mRNA-expression of tumor necrosis factor alpha, TNF-alpha (to 0.42-fold), cyclooxygenase 2, COX-2 (to 0.61-fold), toll-like receptor-4, TLR-4 (to 0.52 fold), TNF receptor-associated factor 6, TRAF-6 (to 0.64-fold), nuclear factor kappa-B, NF-kappaB (to 0.76-fold), vascular cell adhesion molecule 1, VCAM-1 (to 0.71-fold) and intercellular adhesion molecule 1, ICAM-1 (to 0.68-fold). The protein levels of COX-2, TLR-4, p-NF-kappaB and ICAM-1 were induced by LPS and the acai extract partially reversed this effect in a dose-dependent manner. These results suggest the anti-inflammatory effect of acai polyphenolic extract in intestinal cells are at least in part mediated through the inhibition of ROS and the expression of TLR-4 and NF-kappaB. Results indicate the potential for acai polyphenolics in the prevention of intestinal inflammation. PMID- 26243670 TI - Mouse Models of Frailty: an Emerging Field. AB - Frailty is highly prevalent in the elderly, increasing the risk of poor outcomes that include falls, incident disability, hospitalization, and mortality. Thus, a great need exists to characterize the underlying mechanisms and ultimately identify strategies that prevent, delay, and even reverse frailty. Mouse models can provide insight into molecular mechanisms of frailty by reducing variability in lifestyle and genetic factors that can complicate interpretation of human clinical data. Frailty, generally recognized as a syndrome involving reduced homeostatic reserve in response to physiologic challenges and increasing susceptibility to poor health outcomes, is predominantly assessed using two independent strategies, integrated phenotype and deficit accumulation. The integrated phenotype defines frailty by the presentation of factors affecting functional capacity such as weight loss, exhaustion, low activity levels, slow gait, and grip strength. The deficit accumulation paradigm draws parameters from a greater range of physiological systems, such as the ability to perform daily activities, coordination and gait, mental components, physiological problems, and history and presence of medical morbidities. This strategic division also applies within the emerging field of mouse frailty models, with both methodologies showing usefulness in providing insight into physiologic mechanisms and testing interventions. Our review will explore the strategies used, caveats in methodology, and future directions in the application of animal models for the study of the frailty syndrome. PMID- 26243671 TI - Are clear cell carcinomas of the ovary and endometrium phenotypically identical? A proteomic analysis. AB - Phenotypic differences between otherwise similar tumors arising from different gynecologic locations may be highly significant in understanding the underlying driver molecular events at each site and may potentially offer insights into differential responses to treatment. In this study, the authors sought to identify and quantify phenotypic differences between ovarian clear cell carcinoma (OCCC) and endometrial clear cell carcinoma (ECCC) using a proteomic approach. Tissue microarrays were constructed from tumor samples of 108 patients (54 ECCCs and 54 OCCCs). Formalin-fixed samples on microarray slides were analyzed by matrix-assisted laser desorption/ionization mass spectrometry, and 730 spectral peaks were generated from the combined data set. A linear mixed-effect model with random intercept was used to generate 93 (12.7%) peaks that were significantly different between OCCCs and ECCCs at the fold cutoffs of 1.5 and 0.667 and an adjusted P value cutoff of 1.0 * 10(-10). Liquid chromatography-tandem mass spectrometry was performed on selected cores from each group, and peptides identified therefrom were compared with lists of statistically significant peaks from the aforementioned linear mixed-effects model to find matches within 0.2 Da. A total of 53 candidate proteins were thus identified as being differentially expressed in OCCCs and ECCCs, 45 (85%) of which were expressed at higher levels in ECCCs than OCCCs. These proteins were functionally diverse and did not highlight a clearly dominant cellular theme or molecular pathway. Although ECCCs and OCCCs are very similar, some phenotypic differences are demonstrable. Additional studies of these differentially expressed proteins may ultimately clarify the significance of these differences. PMID- 26243672 TI - Acute graft-versus-host disease is more prevalent and severe in the lower than the upper gastrointestinal tract. AB - It is unclear whether acute gastrointestinal (GI) graft-versus-host disease (GVHD) affects all segments of the GI tract equally. Up to 45% patients reported showed discrepancy in involvement between upper GI (UGI) and lower GI (LGI) tract. We compared the prevalence and the severity of acute GVHD in UGI and LGI tract on histologic examination. A cohort of 110 cases of simultaneous UGI and LGI biopsies from 105 allogeneic hematopoietic stem cell transplantation recipients with clinically confirmed GI GVHD were reviewed retrospectively. The chi(2) test and 1-way analysis of variance test were used for statistical analysis. Most (75%) of the cases had GVHD involvement in both UGI and LGI tracts, whereas UGI-only GVHD was found in 6% and LGI-only GVHD in 19%. GVHD prevalence was the lowest in stomach (61%) and significantly increased toward duodenum/jejunum (81%; P = .0019). The LGI tract showed similar GVHD prevalence (P = .3648); the highest was in the sigmoid colon (97%). The histologic grade was lowest in the stomach (mean +/- SD, 1.6 +/- 0.8) and was similar across all UGI segments (P = .0883). The histologic grade in LGI significantly increased (P = .0265) from the terminal ileum (2.0 +/- 1.3) to the rectum (2.9 +/- 1.0). Overall, both the prevalence and the histologic grade of GVHD in LGI were significantly higher than those of UGI (P < .0001 for both). Our results show that acute GVHD had a higher prevalence and was more severe in the LGI than in UGI tract. A small subset of patients had only UGI involvement. PMID- 26243673 TI - FloReMi: Flow density survival regression using minimal feature redundancy. AB - Advances in flow cytometry bioinformatics have resulted in a wide variety of clustering, classification and visualization techniques. To objectively evaluate the performance of such methods, common benchmarks such as the FlowCAP initiative have proven to be of great value. In this work, we report on a novel method, FloReMi, which was developed to tackle the most recent FlowCAP IV challenge. This challenge was formulated as a survival modeling problem, where participants were expected to design a model to predict the time until progression to AIDS for HIV patients. It is known that variability in progression rate cannot be fully predicted by simple CD4(+) T cell counts. However, it is hypothesized that the immunopathogenesis established early in HIV already indicates the course of future disease. Adequately estimating the progression rate of HIV patients is crucial in their treatment. Using an automated pipeline to preprocess the data, and subsequently identify and select informative cell subsets, a survival regression method based on random survival forests was built, which obtained the best results of all submitted approaches to the FlowCAP IV challenge. PMID- 26243674 TI - Symptoms of PTSD Associated With Painful and Nonpainful Vicarious Reactivity Following Amputation. AB - Although the experience of vicarious sensations when observing another in pain have been described postamputation, the underlying mechanisms are unknown. We investigated whether vicarious sensations are related to posttraumatic stress disorder (PTSD) symptoms and chronic pain. In Study 1, 236 amputees completed questionnaires about phantom limb phenomena and vicarious sensations to both innocuous and painful sensory experiences of others. There was a 10.2% incidence of vicarious sensations, which was significantly more prevalent in amputees reporting PTSD-like experiences, particularly increased arousal and reexperiencing the event that led to amputation (phi = .16). In Study 2, 63 amputees completed the Empathy for Pain Scale and PTSD Checklist-Civilian Version. Cluster analyses revealed 3 groups: 1 group did not experience vicarious pain or PTSD symptoms, and 2 groups were vicarious pain responders, but only 1 had increased PTSD symptoms. Only the latter group showed increased chronic pain severity compared with the nonresponder group (p = .025) with a moderate effect size (r = .35). The findings from both studies implicated an overlap, but also divergence, between PTSD symptoms and vicarious pain reactivity postamputation. Maladaptive mechanisms implicated in severe chronic pain and physical reactivity posttrauma may increase the incidence of vicarious reactivity to the pain of others. PMID- 26243675 TI - Clinical signs in the foot that are predictors of ligamentous laxity in the adult population. AB - OBJECTIVES: This study evaluates the influence of ligamentous laxity on the foot from observation of clinical signs and quantification of certain joint ranges. METHODS: The sample consisted of 400 subjects - 200 in the non-lax control group (ages 32.49 +/- 11.06 years) and 200 in the lax group (ages 29.82 +/- 9.41 years). The Beighton criteria were applied to each subject to diagnose laxity or non-laxity after noting their gender, age, and 2 joint ranges and 2 clinical signs for both feet. This was an observational analytical study of cases and controls, in which a multivariate binary logistic regression model was applied. RESULTS: Extension of the first metatarsophalangeal joint (MTPJ) >=95 degrees , extension of the 1st toe's interphalangeal joint (IPJ) >=14 degrees , and the signs 1st "in the plantar footprint, marked and narrowly confined support under metatarsal heads" and 2nd "in the plantar footprint, continuity of the 1st toe to the 1st metatarsal" presented significant differences between the lax and the non lax groups. These are usable as parameters with which to detect laxity. The Beighton criteria were confirmed as being the most appropriate for diagnosis. CONCLUSIONS: We propose the use of 2 clinical signs that can be evaluated in plantar footprints ("1st" and "2nd") and 2 exploratory manoeuvres (extension of the first MTPJ >=95 degrees and extension of the 1st toe's IPJ >=14 degrees ) as factors present in the foot which allow the detection of ligamentous laxity in the adult population, for subsequent confirmation by applying the Beighton criteria. PMID- 26243676 TI - Clinical use of semiliquid dermal substitute: A case report. AB - Nowadays IntegraTM is an integral part of the "reconstructive ladder", recently the new IntegraTM Flowable Dermal Regeneration has appeared on the market. This is a semiliquid compound, malleable and those characteristics widen the indication for its use. In this report we describe two cases in which we used this product to repair undermined and tunnelled wounds. We believe that this product can be useful for treatment of tunnelled wounds of small dimensions reducing the need for major procedures. PMID- 26243677 TI - Surrogate endpoints for overall survival in combined chemotherapy and radiotherapy trials in nasopharyngeal carcinoma: Meta-analysis of randomised controlled trials. AB - BACKGROUND AND PURPOSE: We used a literature-based meta-analysis to assess whether failure-free survival (FFS) or progression-free survival (PFS) could be reliable surrogate endpoints for overall survival (OS) in trials of combined chemotherapy and radiotherapy for nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: We identified randomised trials that evaluated combined chemoradiotherapy strategies, and reported FFS or PFS and OS in NPC. We analysed the treatment effects on FFS or PFS, and OS. We used the coefficient of determination (R(2)), and the surrogate threshold effect (STE) to assess the trial-level correlation. RESULTS: Twenty-one trials (5212 patients), with sixteen treatment-control comparisons for FFS, and nine for PFS, were analysed. FFS was strongly correlated with OS (R(2)=0.88, STE=0.84), as was PFS (R(2)=0.90, STE=0.88). Moreover, FFS and PFS at 3 years were still strongly correlated with 5 year OS (R(2)=0.80, STE=0.83; R(2)=0.85, STE=0.84). CONCLUSIONS: Both FFS and PFS could be valid surrogate endpoints for OS in trials of combined chemotherapy and radiotherapy for NPC; PFS may be a more acceptable surrogate endpoint compared with FFS. PMID- 26243678 TI - Neoadjuvant chemoradiotherapy with cisplatin plus vinorelbine versus cisplatin plus fluorouracil for esophageal squamous cell carcinoma: A matched case-control study. AB - BACKGROUND: To compare the clinical outcomes of neoadjuvant chemoradiotherapy (CRT) with cisplatin/vinorelbine versus cisplatin/fluorouracil in patients with locally advanced esophageal cancer. METHODS: Between 2000 and 2012, 279 patients with thoracic esophageal squamous cell carcinoma (SCC) undergoing neoadjuvant CRT followed by surgery were reviewed. Through a matched case-control study, 57 patients treated with cisplatin/vinorelbine were matched 1:1 to patients who received cisplatin/fluorouracil according to age, sex, performance status, tumor location, tumor length, and pretreatment TNM stage. RESULTS: Patient and disease related characteristics were comparable between the two groups. The pathologic complete response (pCR) rate was 47.4% for the cisplatin/vinorelbine group and 28.1% for the cisplatin/fluorouracil group (P=0.034). Median overall survival (OS) in the cisplatin/vinorelbine group was significantly better compared with the cisplatin/fluorouracil group (52.8 vs. 25.2 months), with 3-year OS rates of 64.3% vs. 31.3%, respectively (P=0.001). However, cisplatin/vinorelbine was associated with a significantly higher rate of grade 3-4 leukopenia than cisplatin/fluorouracil (P=0.03). Multivariate analysis showed that being female, age ?55 years, pCR after CRT, and chemotherapy with cisplatin/vinorelbine were independent positive prognostic factors for survival. CONCLUSIONS: Cisplatin/vinorelbine might lead to a higher pCR rate and better survival outcomes than cisplatin/fluorouracil in esophageal SCC. The incidence of hematologic toxicity is increased with cisplatin/vinorelbine, but is tolerable and manageable. Prospective controlled studies are required to confirm the efficacy of this regimen. PMID- 26243679 TI - The effect of travel distance on radiotherapy utilization in NSW and ACT. AB - BACKGROUND: It has been estimated that half of all cancer patients should receive radiotherapy during the course of the disease. Actual Radiotherapy Utilization (RTU) rates are usually lower than the optimal rates. METHODS: Data were collected from all radiotherapy departments (RTD) in New South Wales (NSW) and the Australian Capital Territory (ACT) for the period 2004-06 and were linked to Central Cancer Registries. Geographic Information System (GIS) software was used to calculate road distance between patient residence and the closest RTD. Patients were excluded from the study if their nearest RTD was outside NSW. RESULTS: The overall RTU rate was 26%. The RTU rates decreased with increasing travel distance from patient residence to the nearest RTD (p<0.0001). Multivariate logistic regression shows that male gender, younger age and shorter travel distance were significantly associated with receiving radiotherapy. Patients were 10% less likely to receive radiotherapy for each additional 100 km distance from the nearest RTD (p<0.001). CONCLUSIONS: There was a statistically significant reduction in radiotherapy access with longer road distance between patient residence and radiotherapy department. PMID- 26243680 TI - A tumor control probability model for anal squamous cell carcinoma. AB - BACKGROUND AND PURPOSE: A recent update of the RTOG 9811, reported differing relapse rates for early and late anal squamous cell carcinoma following chemoradiotherapy (CRT). There may be a role for dose-individualization, however the dose-response relationship for anal cancer is not currently known. Intensity modulated radiotherapy (IMRT) has been widely adopted with multiple series published. The aim is to fit a tumor control probability (TCP) model to the published IMRT data. MATERIALS AND METHODS: We performed a systematic review of PubMed and Embase databases to identify thirteen appropriate papers, including 625 patients. Predefined data fields were collected. A standard linear quadratic TCP model, which included repopulation, was fit by least squares minimization. RESULTS: The fitted TCP curve demonstrated a dose-response relationship with alpha=0.196 Gy(-1). The curve suggests: in early stage tumours, a dose reduction from 50 Gy to 45 Gy reduces 2 year local control from 98% to 95%; in late stage tumours, a dose escalation from 50 Gy to 55 Gy improves the 2 year local control rate from approximately 50% to 80%. CONCLUSIONS: The published data are broadly consistent with a linear quadratic dose-response model. Dose-individualization in anal cancer should be further investigated in the context of clinical trials. PMID- 26243681 TI - Use of proton therapy for re-irradiation in pediatric intracranial ependymoma. AB - BACKGROUND AND PURPOSE: To report disease control, survival and treatment associated toxicity with the use of proton therapy (PRT) for re-irradiation of intracranial ependymoma. MATERIALS AND METHODS: Twenty patients underwent 33 PRT re-irradiation courses for recurrent or metastatic lesions between June 2004 and February 2015 at Massachusetts General Hospital. RESULTS: The majority of patients were female (60%), with infratentorial tumors (90%), anaplastic histology (55%), and initially received 55.8 GyRBE (52.2-59.4) involved field (IF) PRT. First failure was local (55%), distant (30%) or both (15%) at a median time of 23.9 months (9.9-98.5) from first treatment. Salvage therapy included re resection (75%), chemotherapy (60%) and IFPRT (70%) to a median dose 50.4 GyRBE (35-55.8) in the majority of patients. The median follow-up was 37.8 months (5.5 138.0). Three year OS and PFS are 78.6% (95% CI 67.6-89.6) and 28.1% (95% CI 15.6 40.6), respectively. Longer OS was significantly associated with surgical resection of recurrent disease (HR 9.19, 95% CI 1.27-66.44, p=0.028). The pattern of second failure after re-irradiation was directly related to the pattern of first failure (p<0.01). Three of 14 patients (21.4%) locally re-treated experienced grade 2 radiation-associated treatment change. CONCLUSIONS: Proton therapy appears safe and efficacious for the re-treatment of recurrent intracranial ependymoma. PMID- 26243682 TI - Leaflet Augmentation for Treating Tricuspid Valve Regurgitation: Indications and the Patch Size. PMID- 26243683 TI - Mechanisms linking depression co-morbid with obesity: An approach for serotonergic type 3 receptor antagonist as novel therapeutic intervention. AB - Despite of the enormous research, therapeutic treatment for depression has always been a serious issue. Even though depression and obesity are individual abnormal health conditions, each act as a triggering factor for the other. Obese individuals are twice prone to develop depression than that of non-obese persons. The exact mechanism how obesity increases the risk for depression still remains an area of interest for research in neuropsychopharmacology. Depression and obesity share some common pathological pathways such as hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis, dysregulation of oxidant/antioxidant system balance, higher level of inflammatory cytokines, leptin resistance, altered plasma glucose, insulin resistance, reduced neuronal brain derived neurotrophic factor (BDNF) and decreased serotonergic neurotransmission in various regions of brain. The antidepressant-like effect of 5-HT3 receptor antagonists through allosteric modulation of serotonergic pathways is well evident from several research investigations belonging to our and some in other laboratories. Furthermore, serotonin regulates diet intake, leptin, corticosterone, inflammatory mechanisms, altered plasma glucose, insulin resistance and BDNF concentration in brain. The present review deals with various biological mechanisms involved in depression co-morbid with obesity and 5-HT3 receptor antagonists by modulation of serotonergic system as a therapeutic target for such co-morbid disorder. PMID- 26243684 TI - Familial erosive pustular dermatosis of the scalp and legs successfully treated with ciclosporin. PMID- 26243685 TI - TELEMEDICINE VERSUS IN-PERSON DELIVERY OF COGNITIVE PROCESSING THERAPY FOR WOMEN WITH POSTTRAUMATIC STRESS DISORDER: A RANDOMIZED NONINFERIORITY TRIAL. AB - BACKGROUND: This study examined the effectiveness of telemedicine to provide psychotherapy to women with posttraumatic stress disorder (PTSD) who might be unable to access treatment. Objectives were to compare clinical and process outcomes of PTSD treatment delivered via videoteleconferencing (VTC) and in person (NP) in an ethnically diverse sample of veteran and civilian women with PTSD. METHODS: A randomized controlled trial of Cognitive Processing Therapy, an evidence-based intervention for PTSD, was conducted through a noninferiority design to compare delivery modalities on difference in posttreatment PTSD symptoms. Women with PTSD, including 21 veterans and 105 civilians, were assigned to receive psychotherapy delivered via VTC or NP. Primary treatment outcomes were changes in PTSD symptoms in the completer sample. RESULTS: Improvements in PTSD symptoms in the VTC condition (n = 63) were noninferior to outcomes in the NP condition (n = 63). Clinical outcomes obtained when both conditions were pooled together (N = 126) demonstrated that PTSD symptoms declined substantially posttreatment (mean = -20.5, 95% CI -29.6 to -11.4) and gains were maintained at 3- (mean = -20.8, 95% CI -30.1 to -11.5) and 6-month followup (mean = -22.0, 95% CI -33.1 to -10.9. Veterans demonstrated smaller symptom reductions posttreatment (mean = -9.4, 95% CI -22.5 to 3.7) than civilian women (mean = -22.7, 95% CI 29.9 to -15.5. CONCLUSIONS: Providing psychotherapy to women with PTSD via VTC produced outcomes comparable to NP treatment. VTC can increase access to specialty mental health care for women in rural or remote areas. PMID- 26243686 TI - Implications of critical PPARgamma2, ADIPOQ and FTO gene polymorphisms in type 2 diabetes and obesity-mediated susceptibility to type 2 diabetes in an Indian population. AB - Peroxisome proliferator-activated receptors (PPARgamma), adiponectin (ADIPOQ) and fat mass and obesity-associated gene (FTO) have been reported as a key candidate genes for obesity, type 2 diabetes (T2D) susceptibility and insulin resistance, and we hypothesize that in the background of obesity, the effect of PPARgamma2 (rs1801282), ADIPOQ (rs16861194) and FTO (rs9939609) variant could potentially influence T2D susceptibility. To decipher a more accurate estimation toward its population-specific impact of these variants toward susceptibility to T2D, a case control study, systematic review and a meta-analysis was performed in a South Asian population. A case-control analysis of 518 T2D cases and 518 controls of Karnataka origin were performed to analyze the association of PPARgamma2 (rs1801282), ADIPOQ (rs16861194) and FTO (rs9939609) on the risk of T2D. In addition, a systematic review and meta-analysis for PPARgamma2 (rs1801282) and FTO (rs9939609) was elucidated from Asian population. Our investigation showed that PPARgamma2 (rs1801282) and FTO (rs9939609) are associated with T2D susceptibility. When T2D cohort was further stratified according to the obesity status, PPARgamma2 (rs1801282) and FTO (rs9939609) showed association with T2D only in the obese diabetic group and ADIPOQ (rs16861194) showed no difference in risk of susceptibility to the disease. The meta-analysis of PPARgamma2 (rs1801282) showed population-specific association for T2D susceptibility as opposed to FTO (rs9939609) which showed no difference in population effect toward T2D susceptibility. In conclusion, our study showed that PPARgamma2 (rs1801282) and FTO (rs9939609) variants are associated with T2D susceptibility when associated with adiposity in Indian population. PMID- 26243687 TI - Discovery of microRNAs and transcript targets related to witches' broom disease in Paulownia fortunei by high-throughput sequencing and degradome approach. AB - Paulownia witches' broom (PaWB) caused by the phytoplasma is a devastating disease of Paulownia trees. It has caused heavy yield losses to Paulownia production worldwide. However, knowledge of the transcriptional and post transcriptional regulation of gene expression by microRNAs (miRNAs), especially miRNAs responsive to PaWB disease stress, is still rudimentary. In this study, to identify miRNAs and their transcript targets that are responsive to PaWB disease stress, six sequencing libraries were constructed from healthy (PF), PaWB infected (PFI), and PaWB-infected, 20 mg L(-1) methyl methane sulfonate-treated (PFI20) P. fortunei seedlings. As a result, 95 conserved miRNAs belonging to 18 miRNA families, as well as 122 potential novel miRNAs, were identified. Most of them were found to be a response to PaWB disease-induced stress, and the expression levels of these miRNAs were validated by quantitative real-time PCR analysis. The study simultaneously identified 109 target genes from the P. fortunei for 14 conserved miRNA families and 24 novel miRNAs by degradome sequencing. Furthermore, the functions of the miRNA targets were annotated based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. The results presented here provide the groundwork for further analysis of miRNAs and target genes responsive to the PaWB disease stress, and could be also useful for addressing new questions to better understand the mechanisms of plant infection by phytoplasma in the future. PMID- 26243688 TI - Prevalence, risk factors and sequelae of Staphylococcus aureus carriage in diabetes: the Fremantle Diabetes Study Phase II. AB - AIMS: To determine the prevalence and associates of Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) carriage in community-based diabetes, and their relationship to hospitalization with S. aureus infection. METHODS: A cross sectional subset of 660 Fremantle Diabetes Study Phase II patients (mean+/-SD age 65.1+/-11.5years, 53.1% males) had nasal/axillary swabs as part of biennial review. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured in 358 patients. Those with positive swabs were invited back for a repeat swab. Hospitalizations with S. aureus infections were ascertained from validated data linkage. Multiple logistic regression was used to identify associates of carriage, and Cox proportional hazards modelling was used to determine predictors of subsequent hospitalization. RESULTS: 258 patients (39.1%) were positive for S. aureus and eight (3.1%) carried MRSA. S. aureus carriage was independently associated with being married/in a de facto relationship and inversely with older age and being born overseas (P<=0.043). Repeat swabs in 137 patients (53.1% of those with an initially positive swab) grew S. aureus in 113 (82.5%). Five of eight MRSA-positive patients were re-swabbed, and four were MRSA-positive. Independent predictors of hospitalization with staphylococcal infection after the initial swab were S. aureus carriage (hazard ratio (95% CI) 5.42 (1.49-19.79)), prior hospitalization with S. aureus (4.84 (1.19-19.63)) and Aboriginality (7.20 (1.91-27.17) (P<=0.027). Serum 25(OH)D was not associated with S. aureus carriage or subsequent hospitalization. CONCLUSIONS: S. aureus and MRSA carriage in our patients was consistent with previous general population studies. There were no diabetes-specific risk factors. Persistent colonization may underlie the increased risk of hospitalization with S. aureus. PMID- 26243690 TI - Seven Countries Study cohort in Crete, Greece: gluteal adipose-tissue fatty-acid profiles of survivors, at 2010. AB - OBJECTIVE: To analyse the gluteal adipose-tissue fatty-acid profiles from Cretan cohort survivors of the Seven Countries Study (SCS) at 2010 and to compare them with those of survivors assessed in 2000, as well as with literature data on male Cretans at 1965. DESIGN: We analysed data concerning the gluteal adipose-tissue fatty acids (analysed by GC) from three studies. SETTING: The island of Crete (rural areas and the city of Heraklion). SUBJECTS: Twenty-two of the 2010 SCS survivors aged 90 years and over; seventy-eight men aged 80 years of the 2000 SCS survivors; and 280 men assessed in 1965. RESULTS: In comparison to 1965 and 2000, the SCS survivors in 2010 had a higher amount of 18:1n-9 (P<0.05) in their gluteal adipose tissue and a lower amount of PUFA (P<0.05). On the other hand, a constant decrease in adipose-tissue 14:1n-5 and 16:1n-7 was recorded between 1965 and 2010 (P<0.001), and between 2000 and 2010 (P<0.05), while 18:2n-6 appeared to decrease between the 1965 and 2010 assessments (P<0.001). CONCLUSIONS: Comparison with a 1965 representative Cretan sample and 2000 SCS survivors indicated an increased concentration of oleic acid (known for its protective role against mortality) and a decreased concentration of PUFA (known for their susceptibility to oxidation) in our surviving sample at 2010. These changes may reflect internal physiological processes due to diet change within these years and/or ageing. PMID- 26243691 TI - Modulation of cell surface transport and lipid raft localization by the cytoplasmic tail of the influenza virus hemagglutinin. AB - Viral glycoproteins are highly variable in their primary structure, but on the other hand feature a high functional conservation to fulfil their versatile tasks during the pathogenic life cycle. Typically, all protein domains are optimized in that indispensable functions can be assigned to small conserved motifs or even individual amino acids. The cytoplasmic tail of many viral spike proteins, although of particular relevance for the virus biology, is often only insufficiently characterized. Hemagglutinin (HA), the receptor-binding protein of the influenza virus comprises a short cytoplasmic tail of 13 amino acids that exhibits three highly conserved palmitoylation sites. However, the particular importance of these modifications and the tail in general for intracellular trafficking and lateral membrane organization remains elusive. In this study, we generated HA core proteins consisting of transmembrane domain, cytoplasmic tail and a minor part of the ectodomain, tagged with a yellow fluorescent protein. Different mutation and truncation variants of these chimeric proteins were investigated using confocal microscopy, to characterize the role of cytoplasmic tail and palmitoylation for the intracellular trafficking to plasma membrane and Golgi apparatus. In addition, we assessed raft partitioning of the variants by Foerster resonance energy transfer with an established raft marker. We revealed a substantial influence of the cytoplasmic tail length on the intracellular distribution and surface exposure of the proteins. A complete removal of the tail hampers a physiological trafficking of the protein, whereas a partial truncation can be compensated by cytoplasmic palmitoylations. Plasma membrane raft partitioning on the other hand was found to imperatively require palmitoylations, and the cysteine at position 551 turned out to be of most relevance. Our data shed further light on the tight interconnection between cytoplasmic elements and intracellular trafficking and suggest a function of HA palmitoylations in both lateral sorting and anterograde trafficking of the glycoprotein. PMID- 26243692 TI - Effects of testing on subsequent re-encoding and long-term forgetting of action relevant materials: On the influence of recall type. AB - Testing one's memory of previously studied information reduces the rate of forgetting, compared to restudy. However, little is known about how this direct testing effect applies to action phrases (e.g., "wash the car") - a learning material relevant to everyday memory. As action phrases consist of two different components, a verb (e.g., "wash") and a noun (e.g., "car"), testing can either be implemented as noun-cued recall of verbs or verb-cued recall of nouns, which may differently affect later memory performance. In the present study, we investigated the effect of testing for these two recall types, using verbally encoded action phrases as learning materials. Results showed that repeated study test practice, compared to repeated study-restudy practice, decreased the forgetting rate across 1 week to a similar degree for both noun-cued and verb cued recall types. However, noun-cued recall of verbs initiated more new subsequent learning during the first restudy, compared to verb-cued recall of nouns. The study provides evidence that testing has benefits on both subsequent restudy and long-term retention of action-relevant materials, but that these benefits are differently expressed with testing via noun-cued versus verb-cued recall. PMID- 26243694 TI - Enhanced photovoltaic performance of inverted pyramid-based nanostructured black silicon solar cells passivated by an atomic-layer-deposited Al2O3 layer. AB - Inverted pyramid-based nanostructured black-silicon (BS) solar cells with an Al2O3 passivation layer grown by atomic layer deposition (ALD) have been demonstrated. A multi-scale textured BS surface combining silicon nanowires (SiNWs) and inverted pyramids was obtained for the first time by lithography and metal catalyzed wet etching. The reflectance of the as-prepared BS surface was about 2% lower than that of the more commonly reported upright pyramid-based SiNW BS surface over the whole of the visible light spectrum, which led to a 1.7 mA cm(-2) increase in short circuit current density. Moreover, the as-prepared solar cells were further passivated by an ALD-Al2O3 layer. The effect of annealing temperature on the photovoltaic performance of the solar cells was investigated. It was found that the values of all solar cell parameters including short circuit current, open circuit voltage, and fill factor exhibit a further increase under an optimized annealing temperature. Minority carrier lifetime measurements indicate that the enhanced cell performance is due to the improved passivation quality of the Al2O3 layer after thermal annealing treatments. By combining these two refinements, the optimized SiNW BS solar cells achieved a maximum conversion efficiency enhancement of 7.6% compared to the cells with an upright pyramid based SiNWs surface and conventional SiNx passivation. PMID- 26243693 TI - Characteristics and surgical outcomes of consecutive exotropia of different etiologies. AB - PURPOSE: To investigate the surgical results for consecutive exotropia with or without insertion abnormalities on the basis of the position of the lateral rectus muscle at surgery. METHODS: Patients with consecutive exotropia who had undergone medial rectus recession as a primary procedure or advancement of previously recessed medial rectus muscles from 2002 to 2012 were included in the study. The characteristics, postoperative courses, and final results were compared among 3 patient groups. The patients' characteristics including sex, refractive error, and age at the initial surgery were compared. The main outcome measures were the angles of deviation in the primary position and the average divergent drift per month after the exotropia surgery. RESULTS: Twenty-four eyes of 23 patients were investigated. The patients were divided into 3 groups according to insertion status: with normal muscle insertion (4 men, 4 women), slipped muscles (9 women), and stretched scars (2 men, 4 women). The preoperative angles of deviation at near differed significantly between the slipped muscle group and the normal muscle insertion group (P = 0.02). Only patients with normal insertions had significantly greater hyperopia in the nondominant eye (0.95 D) than in the dominant eye (0.53 D). The postoperative divergent shift per month was similar among the groups (0.3, 0.1, and 0.2 prism diopters per month in the slipped muscle, stretched scar, and normal muscle insertion groups, respectively; P = 0.70). CONCLUSIONS: Hyperopic anisometropia is an important factor in the natural course of outward drift. The postoperative course of advancement of the medial rectus muscle was equally stable in all 3 patient groups. PMID- 26243695 TI - Molecular characterization of rotavirus isolated from alpaca (Vicugna pacos) crias with diarrhea in the Andean Region of Cusco, Peru. AB - Alpacas (Vicugna pacos), a species of South American camelids (SAC), suffer high morbidity and mortality from infectious diseases. Diarrhea is one of the leading causes of alpaca cria mortality in Peru and elsewhere. In order to develop appropriate control and/or treatment, it is necessary to identify infectious pathogens that cause diarrhea in crias. Rotavirus was isolated in cell culture from feces collected from crias with acute diarrhea that tested positive to rotaviral antigen by rapid immunochromatographic methods in an earlier study. The isolates were identified as rotaviruses by RT-PCR run with specific primers for human rotavirus VP7 coding sequences using total RNA extracted from cells displaying cytopathic effects as template. These alpaca isolates were further identified as group A rotaviruses by means of a VP6-specific PCR and were designated as ALRVA-K'ayra/Peru/3368-10 and ALRVA-K'ayra/Peru/3386-10. Molecular G and P typing, placed the former as G3/P11 and the latter as G3/P?. Sequence analysis of two genome segments (coding for VP4 and VP7) from the alpaca isolates revealed partial homologies to swine and human rotaviruses, respectively. These results demonstrate that rotaviruses are associated with a proportion of cases of diarrhea in crias, although prevalence and impact remain to be determined. The isolation of rotaviruses from alpaca crias with diarrhea will contribute positively to further understand the pathogen and its role in the diarrhea complex. PMID- 26243696 TI - Anatomical distribution of Mycobacterium bovis genotypes in experimentally infected white-tailed deer. AB - Mycobacterium bovis (M. bovis) causes tuberculosis in white-tailed deer (WTD). Natural infection of WTD with M. bovis is most closely mimicked by instilling inoculum into palatine tonsillar crypts. One hundred fifty days after intratonsillar inoculation, M. bovis was cultured from 30 tissues originating from 14 deer. Whole-genome sequencing (WGS) was performed on the original inoculum, single colonies subcultured from the original inoculum, and M. bovis isolated from each culture positive tissue. Single nucleotide polymorphisms (SNP) were identified by comparing the derived sequences to the reference strain AF2122/97. Results indicate that the majority of the SNPs that were identified were homogeneous between the inoculum and the isolates from the tissues. The majority of individual tissues had different WGS genotypes from each other, suggesting that dissemination of M. bovis beyond the initial site of infection may require few mycobacteria representing a bottleneck. PMID- 26243697 TI - A gold-catalyzed 1,2-acyloxy migration/intramolecular cyclopropanation/ring enlargement cascade: syntheses of medium-sized heterocycles. AB - The synthesis of medium-sized heterocycles possessing a trans double bond is still a challenge. Herein, gold(I)-catalyzed 1,2-acyloxy migration/intramolecular cyclopropanation/ring enlargement cascade reaction of furans has been developed, providing highly efficient access to ten- and eleven-membered heterocycles with a broad substrate scope under mild reaction conditions. The reaction outcome features high chemoselectivity at the C5-position of furan. Moreover, a trans double bond was embodied in the medium ring system. PMID- 26243698 TI - Current prescription pattern of maintenance treatments for bipolar patients in Korea: A focus on the transition from acute treatments. AB - AIMS: We examined prescription patterns in maintenance treatment for recovered bipolar patients and compared these with acute treatments. METHODS: Using retrospective methods, the bipolar patients in clinical recovery (Clinical Global Impression Bipolar Version score <= 2 for 6 months) after acute episode were selected. We reviewed differences between prescription patterns at remission and after a maintenance period of at least 6 months. RESULTS: A total of 340 bipolar disorder patients were selected. During the maintenance period, more than half of the patients (192, 56.5%) took a mood stabilizer (MS) + antipsychotic (AP) combination. Among the MS, valproate (149, 43.8%) was most prescribed, and lithium (98, 28.8%) was second, but as patients moved into maintenance treatment, lithium use decreased, and the use of lamotrigine (86, 25.3%) increased. Preferred AP were quetiapine (125, 36.8%), aripiprazole (67, 19.7%), risperidone (48, 14.1%), and olanzapine (39, 11.5%). The use of olanzapine in maintenance was greatly decreased compared with that during acute treatment (67, 19.7%). Most patients did not take an antidepressant (AD), but the proportion using one or more AD was increased during maintenance (17.9% to 30.3%), and bupropion (28, 8.2%) was the preferred AD. Doses were decreased in all drugs, but lamotrigine was maintained at a dose of 133.2 +/- 68.5 mg/day. CONCLUSIONS: The most common prescription combination for bipolar maintenance treatment was MS + AP. The use of AP was decreased, whereas the use of AD in combination with MS and/or AP was increased. The doses of MS and AP were generally decreased during the maintenance periods, with the exception of lamotrigine. PMID- 26243700 TI - Erythema induratum of Bazin in a patient with scrofuloderma. PMID- 26243699 TI - Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol alleviates elastase-induced emphysema in a mouse model. AB - Chronic obstructive pulmonary disease (COPD) is a sustained blockage of the airways due to lung inflammation occurring with chronic bronchitis and/or emphysema. Progression of emphysema may be slowed by vascular endothelial growth factor A (VEGFA), which reduces apoptotic tissue depletion. Previously, authors of the present report demonstrated that cis-resveratrol (c-RSV)-induced heat shock protein 70 (HSP70) promoter-regulated VEGFA expression promoted neovascularization of genetically modified mesenchymal stem cells (HSP-VEGFA-MSC) in a mouse model of ischemic disease. Here, this same stem cell line was evaluated for its protective capacity to alleviate elastase-induced pulmonary emphysema in mice. Results of this study showed that c-RSV-treatment of HSP-VEGFA MSC exhibited synergy between HSP70 transcription activity and induced expression of anti-oxidant-related genes when challenged by cigarette smoke extracts. Eight weeks after jugular vein injection of HSP-VEGFA-MSC into mice with elastase induced pulmonary emphysema followed by c-RSV treatment to induce transgene expression, significant improvement was observed in respiratory functions. Expression of VEGFA, endogenous nuclear factor erythroid 2-related factor (Nrf 2), and manganese superoxide dismutase (MnSOD) was significantly increased in the lung tissues of the c-RSV-treated mice. Histopathologic examination of treated mice revealed gradual but significant abatement of emphysema and restoration of airspace volume. In conclusion, the present investigation demonstrates that c-RSV regulated VEGFA expression in HSP-VEGFA-MSC significantly improved the therapeutic effects on the treatment of COPD in the mouse, possibly avoiding side effects associated with constitutive VEGFA expression. PMID- 26243701 TI - Risk Stratification for Cardiovascular Disease in Women in the Primary Care Setting. AB - BACKGROUND: Traditional risk assessment tools classify the majority of middle aged women at low risk despite cardiovascular (CV) disease's affecting >50% of women and remaining the leading cause of death. Ultrasound-determined carotid intima-media thickness (CIMT) and/or computed tomographic coronary artery calcium score (CACS) quantify subclinical atherosclerosis and add incremental prognostic value. The aim of this study was to assess the utility of CIMT and CACS to detect subclinical atherosclerosis in younger women. METHODS: Asymptomatic women aged 50 to 65 years with at least one CV risk factor and low Framingham risk scores were identified prospectively at primary care and cardiology clinics. Mean intimal thickness, plaque on CIMT, and Agatston calcium score for CACS were obtained. RESULTS: Of 86 women (mean age, 58 +/- 4.6 years; mean Framingham risk score, 1.9 +/- 1.2; mean low-density lipoprotein cholesterol level, 138.9 +/- 37.0 mg/dL), 53 (62%) had high-risk CIMT (51% plaque, 11% CIMT > 75th percentile). In contrast, three women (3.5%) had CACS > 100, all of whom had plaque by CIMT. Of the 58 women with CACS of 0, 32 (55%) had high-risk CIMT (48% plaque, 7% CIMT > 75th percentile). CONCLUSIONS: In patients referred by their physicians for assessment of CV risk, CIMT in asymptomatic middle-aged women with at least one CV risk factor and low risk by the Framingham risk score identified a large number with advanced subclinical atherosclerosis despite low CACS. Our results suggest that CIMT may be a more sensitive method for CV risk assessment than CACS or traditional risk tools in this population. Further studies are needed to determine if earlier detection would be of clinical benefit. PMID- 26243702 TI - Polycystic ovary syndrome: not just a fertility problem. PMID- 26243703 TI - Simultaneous determination of polyvinylchloride plasticizers di(2-ethylhexyl) phthalate and tri(2-ethylhexyl) trimellitate and its degradation products in blood by liquid chromatography-tandem mass spectrometry. AB - Di(2-ethylhexyl) phthalate (DEHP) and tri(2-ethylhexyl) trimellitate (TEHTM or TOTM) are common plasticizers that are also largely used for PVC medical devices, e.g. bags and tubing for blood transfusions and infusions. The leachability of medical devices is a well-known situation of increasing toxicological concern. To assess the migration of plasticizers from PVC medical devices into human blood we developed and validated an analytical method for the determination of DEHP and TOTM in combination with the determination of their primary degradation products mono(2-ethylhexyl) phthalate (MEHP), 1,2-di(2-ethylhexyl) trimellitate (1,2 DEHTM) and 2-mono(2-ethylhexyl) trimellitate (2-MEHTM). The presented method involves liquid-liquid extraction of the analytes from the blood followed by the subsequent analytical separation and detection using LC-MS/MS analysis. The validation of the procedure showed a good precision in the range of 1.8 to 5.3%. Mean accuracy ranged from 86% for 1,2-DEHTM to 109% for MEHP. LOQ was found to be 2 to 5MUg/L for each of the analytes. Additionally, the method is characterised by its wide linear range up to 2mg/L each for the degradation products of TOTM to 100mg/L for the parent plasticizer DEHP. The presented method promises to be of major advantage for further studies as it allows for the first time the simultaneous determination of DEHP and TOTM in human blood in combination with the analysis of their degradation products that render possible to investigate the leachability of a broad range of PVC medical devices in human blood using only one analytical method. PMID- 26243704 TI - Development of a standard gas generating vial comprised of a silicon oil polystyrene/divinylbenzene composite sorbent. AB - In this work, a highly reproducible standard gas generating vial is proposed. The vial is comprised of a silicon diffusion pump oil spiked with an appropriate calibration compound, such as modified McReynolds probes (benzene, 2-pentanone, pyridine, 1-nitropropane, 1-pentanol, and n-octane), and then mixed with polystyrene/divinylbenzene (PS/DVB) particles. The concentrations of these compounds in gaseous headspace were found to substantially decrease in comparison to previously developed hydrocarbon pump oil based vials; hence, the amount of standard loaded onto SPME fibers was at most, half that of the previous vial design. Depletion for all compounds after 208 successive extractions was shown to be less than 3.5%. Smaller quantities of standards being used resulted in a vial that depleted slower while remaining statistically repeatable over a wider number of runs. Indeed, it was found that depletion could be largely predicted by using a mass balance theoretical model. This behavior allowed a further increase in the number of loadings that could be performed repeatedly. At a 95% level of confidence, the ANOVA test demonstrated that the prepared vials were statistically identical, with no significant intra- or inter-batch differences. In addition, it was found that vials stored under different conditions (e.g. under light exposure, room temperature, and within a refrigerator) were stable over 10 weeks. Silicon based vials proved to be ideal for performing instrument quality control and loading of internal standards onto fibers, both of which are of great importance when performing on-site analysis using portable GC-MS instrumentation and high throughput determinations in laboratory. PMID- 26243705 TI - A rapid method for the chromatographic analysis of volatile organic compounds in exhaled breath of tobacco cigarette and electronic cigarette smokers. AB - A method for the rapid analysis of volatile organic compounds (VOCs) in smoke from tobacco and electronic cigarettes and in exhaled breath of users of these smoking systems has been developed. Both disposable and rechargeable e-cigarettes were considered. Smoke or breath were collected in Bio-VOCs. VOCs were then desorbed in Tenax cartridges which were subsequently analyzed by thermal desorption coupled to gas chromatography-mass spectrometry. The method provides consistent results when comparing the VOC compositions from cigarette smoke and the equivalent exhaled breath of the smokers. The differences in composition of these two sample types are useful to ascertain which compounds are retained in the respiratory system after tobacco cigarette or e-cigarette smoking. Strong differences were observed in the VOC composition of tobacco cigarette smoke and exhaled breath when comparing with those of e-cigarette smoking. The former involved transfers of a much larger burden of organic compounds into smokers, including benzene, toluene, naphthalene and other pollutants of general concern. e-Cigarettes led to strong absorptions of propylene glycol and glycerin in the users of these systems. Tobacco cigarettes were also those showing highest concentration differences between nicotine concentrations in smoke and exhaled breath. The results from disposable e-cigarettes were very similar to those from rechargeable e-cigarettes. PMID- 26243706 TI - Response surface methodology for the enantioseparation of dinotefuran and its chiral metabolite in bee products and environmental samples by supercritical fluid chromatography/tandem mass spectrometry. AB - Tracing the enantiomers of dinotefuran and its metabolite in bee products and relevant environmental matrices is vital because of the high toxicity of their racemates to bees. In this study, a statistical optimization strategy using three dimensional response surface methodology for the enantioseparation of dinotefuran and its metabolite UF was developed by a novel supercritical fluid chromatography/tandem mass spectrometry (SFC-MS/MS) technique. After direct evaluation of the chromatographic variables - co-solvent content, mobile phase flow rate, automated backpressure regulator pressure (ABPR), and column temperature - involved in the separation mechanism and assessment of the interactions among these variables, the optimal SFC-MS/MS working conditions were selected as a CO2/2% formic acid-methanol mobile phase, 1.9mL/min flow rate, 2009.8psi ABPR, and 26.0 degrees C column temperature using an amylose tris-(3,5 dimethylphenylcarbamate) chiral stationary phase under electrospray ionization positive mode. Baseline resolution, favorable retention, and high sensitivity of the two pairs of enantiomers were achieved in pollen, honey, water, and soil matrices within 4.5min. Additionally, the parameters affecting the dispersive solid-phase extraction procedure, such as the type and content of extractant or purification sorbents, were systematically screened to obtain better extraction yields of the enantiomers. Mean recoveries were between 78.3% and 100.2% with relative standard deviations lower than 8.0% in all matrices. The limits of quantification ranged from 1.0MUg/kg to 12.5MUg/kg for the dinotefuran and UF enantiomers. Furthermore, the developed method was effectively applied to authentic samples from a market, an irrigation canal, and a trial field, and the enantioselective dissipation of dinotefuran and UF in soil was demonstrated. PMID- 26243707 TI - Comparative assessment of parametric neuroreceptor mapping approaches based on the simplified reference tissue model using [11C]ABP688 PET. AB - In recent years, several linearized model approaches for fast and reliable parametric neuroreceptor mapping based on dynamic nuclear imaging have been developed from the simplified reference tissue model (SRTM) equation. All the methods share the basic SRTM assumptions, but use different schemes to alleviate the effect of noise in dynamic-image voxels. Thus, this study aimed to compare those approaches in terms of their performance in parametric image generation. We used the basis function method and MRTM2 (multilinear reference tissue model with two parameters), which require a division process to obtain the distribution volume ratio (DVR). In addition, a linear model with the DVR as a model parameter (multilinear SRTM) was used in two forms: one based on linear least squares and the other based on extension of total least squares (TLS). Assessment using simulated and actual dynamic [(11)C]ABP688 positron emission tomography data revealed their equivalence with the SRTM, except for different noise susceptibilities. In the DVR image production, the two multilinear SRTM approaches achieved better image quality and regional compatibility with the SRTM than the others, with slightly better performance in the TLS-based method. PMID- 26243708 TI - Micro-heterogeneity of flow in a mouse model of chronic cerebral hypoperfusion revealed by longitudinal Doppler optical coherence tomography and angiography. AB - Although microvascular dysfunction accompanies cognitive decline in aging, vascular dementia, and Alzheimer's disease, tools to study microvasculature longitudinally in vivo are lacking. Here, we use Doppler optical coherence tomography (OCT) and angiography for noninvasive, longitudinal imaging of mice with chronic cerebral hypoperfusion for up to 1 month. In particular, we optimized the OCT angiography method to selectively image red blood cell (RBC) perfused capillaries, leading to a novel way of assessing capillary supply heterogeneity in vivo. After bilateral common carotid artery stenosis (BCAS), cortical blood flow measured by Doppler OCT dropped to half of baseline throughout the imaged tissue acutely. Microscopic imaging of the capillary bed with OCT angiography further revealed local heterogeneities in cortical flow supply during hypoperfusion. The number of RBC-perfused capillaries decreased, leading to increased oxygen diffusion distances in the days immediately after BCAS. Linear regression showed that RBC-perfused capillary density declined by 0.3% for a drop in flow of 1 mL/100 g per minute, and decreases in RBC-perfused capillary density as high as 25% were observed. Taken together, these results demonstrate the existence of local supply heterogeneity at the capillary level even at nonischemic global flow levels, and demonstrate a novel imaging method to assess this heterogeneity. PMID- 26243709 TI - Noninvasive cerebral oximetry during endovascular therapy for acute ischemic stroke: an observational study. AB - Implementing endovascular stroke care often impedes neurologic assessment in patients who need sedation or general anesthesia. Cerebral near-infrared spectroscopy (NIRS) may help physicians monitor cerebral tissue viability, but data in hyperacute stroke patients receiving endovascular treatment are sparse. In this observational study, the NIRS index regional oxygen saturation (rSO2) was measured noninvasively before, during, and after endovascular therapy via bilateral forehead NIRS optodes. During the study period, 63 patients were monitored with NIRS; 43 qualified for analysis. Before recanalization, 10 distinct rSO2 decreases occurred in 11 patients with respect to time to intubation. During recanalization, two kinds of unilateral rSO2 changes occurred in the affected hemisphere: small peaks throughout the treatment (n=14, 32.6%) and sustained increases immediately after recanalization (n=2, 4.7%). Lower area under the curve 10% below baseline was associated with better reperfusion status (thrombolysis in cerebral infarction >= 2b, P=0.009). At the end of the intervention, lower interhemispheric rSO2 difference predicted death within 90 days (P=0.037). After the intervention, higher rSO2 variability predicted poor outcome (modified Rankin scale > 3, P=0.032). Our findings suggest that bi channel rSO2-NIRS has potential for guiding neuroanesthesia and predicting outcome. To better monitor local revascularization, an improved stroke-specific set-up in future studies is necessary. PMID- 26243710 TI - Adapting an evidence-based intervention for autism spectrum disorder for scaling up in resource-constrained settings: the development of the PASS intervention in South Asia. AB - BACKGROUND: Evidence-based interventions for autism spectrum disorders evaluated in high-income countries typically require highly specialised manpower, which is a scarce resource in most low- and middle-income settings. This resource limitation results in most children not having access to evidence-based interventions. OBJECTIVE: This paper reports on the systematic adaptation of an evidence-based intervention, the Preschool Autism Communication Therapy (PACT) evaluated in a large trial in the United Kingdom for delivery in a low-resource setting through the process of task-shifting. DESIGN: The adaptation process used the Medical Research Council framework for the development and adaptation of complex interventions, focusing on qualitative methods and case series and was conducted simultaneously in India and Pakistan. RESULTS: The original intervention delivered by speech and language therapists in a high-resource setting required adaptation in some aspects of its content and delivery to enhance contextual acceptability and to enable the intervention to be delivered by non-specialists. CONCLUSIONS: The resulting intervention, the Parent-mediated intervention for Autism Spectrum Disorder in South Asia (PASS), shares the core theoretical foundations of the original PACT but is adapted in several respects to enhance its acceptability, feasibility, and scalability in low-resource settings. PMID- 26243711 TI - The authors reply "Managing superutilizers--staying patient centered is the solution". PMID- 26243712 TI - Mechanism of Dimercaptosuccinic Acid Coated Superparamagnetic Iron Oxide Nanoparticles with Human Serum Albumin. AB - To research the mechanism of dimercaptosuccinic acid coated-superparamagnetic iron oxide nanoparticles (SPION) with human serum albumin (HSA), the methods of spectroscopy, molecular modeling calculation, and calorimetry were used in this paper. The inner filter effect of the fluorescence intensity was corrected to obtain the accurate results. Ultraviolet-visible absorption and circular dichroism spectra reflect that SPION changed the secondary structure with a loss of alpha-helix and loosened the protein skeleton of HSA; the activity of the protein was also affected by the increasing exposure of SPION. Fluorescence lifetime measurement indicates that the quenching mechanism type of this system was static quenching. The isothermal titration calorimetry measurement and molecular docking calculations prove that the predominant force of this system was the combination of Van der Waals' force and hydrogen bonds. PMID- 26243713 TI - Peptide delta-Turn: Literature Survey and Recent Progress. AB - Among the various types of alpha-peptide folding motifs, delta-turn, which requires a central cis-amide disposition, has been one of the least extensively investigated. In particular, this main-chain reversal topology has been studied in-depth neither in linear/cyclic peptides nor in proteins. This Minireview article assembles and critically analyzes relevant data from a literature survey on the delta-turn conformation in those compounds. Unpublished results from recent conformational energy calculations and a preliminary solution-state analysis on a small model peptide, currently ongoing in our laboratories, are also briefly outlined. PMID- 26243714 TI - Update on prolactinomas. Part 2: Treatment and management strategies. AB - The authors present an update on the various treatment modalities and discuss management strategies for prolactinomas. Prolactinomas are the most common type of functional pituitary tumor. Effective hyperprolactinemia treatment is of great importance, due to its potential deleterious effects including infertility, gonadal dysfunction and osteoporosis. Dopamine agonist therapy is the first line of treatment for prolactinomas because of its effectiveness in normalizing serum prolactin levels and shrinking tumor size. Though withdrawal of dopamine agonist treatment is safe and may be implemented following certain recommendations, recurrence of disease after cessation of the drug occurs in a substantial proportion of patients. Concerns regarding the safety of dopamine agonists have been raised, but its safety profile remains high, allowing its use during pregnancy. Surgery is typically indicated for patients who are resistant to medical therapy or intolerant of its adverse side effects, or are experiencing progressive tumor growth. Surgical resection can also be considered as a primary treatment for those with smaller focal tumors where a biochemical cure can be expected as an alternative to lifelong dopamine agonist treatment. Stereotactic radiosurgery also serves as an option for those refractory to medical and surgical therapy. PMID- 26243715 TI - Cardiovascular Health of Filipinos in the United States: A Review of the Literature. AB - PURPOSE: Filipino Americans (FAs) are at high risk for cardiovascular disease. The purpose of this literature review is to enhance understanding of cardiovascular health among FAs. DESIGN: Databases searched: MEDLINE (via PubMed), Google Scholar, Journals@OVID, and EBSCO databases including CINAHL Complete. Health Source: Nursing/Academic Edition, Academic Search Complete, and Biological Abstracts 1969-Present. Key terms used: FAs and cardiovascular disease. Criteria for inclusion: peer-reviewed empirical articles published in English. FINDINGS/RESULTS: A total of 51 studies were identified and 27 were selected for the review based on relevance to nursing care for FAs. Three main themes emerged from the literature reviewed: risk factors and disease prevalence, health promotion, and health beliefs/practices. DISCUSSION/CONCLUSIONS: The literature review identified that FAs were at high risk for cardiovascular disease, hypertension, type 2 diabetes, and metabolic syndrome at lower BMI levels. IMPLICATIONS FOR PRACTICE: Health care providers should implement prevention strategies and interventions for the FA population to ensure the best outcomes. PMID- 26243716 TI - Exploring Health Beliefs and Practices of Caribbean Immigrants in Ontario to Prevent Type 2 Diabetes. AB - This qualitative study explored the beliefs held by adult Caribbean immigrants regarding type 2 diabetes (T2D) and their practices in preventing it. A purposive sample of 15 immigrants living in Ontario, Canada participated in the study. Semistructured interviews were used to collect data from participants. Four themes emerged from the data: beliefs that protect participants from developing T2D, cultural practices to stay healthy, preserving culture through preparation of meals, and cultural practices determine number of servings of fruit and vegetables per day. Findings indicate how beliefs and cultural practices influence prevention of T2D and the need to design culturally tailored interventions for ethnic groups. Future research should explore health beliefs and cultural practices of other high-risk groups and use their findings to design and evaluate culturally tailored interventions to prevent T2D. PMID- 26243717 TI - Macrophages recognize the Helicobacter pylori type IV secretion system in the absence of toll-like receptor signalling. AB - Helicobacter pylori strains carrying the cag pathogenicity island (cagPAI) provoke an increased inflammatory response, conferring an increased risk of ulcer formation and carcinogenesis. How the immune system recognizes the presence of cagPAI positive strains is yet unclear. By comparing the transcriptional response of wild type and MyD88/Trif(-/-) bone marrow macrophages to infection with H. pylori, we found that the majority of regulated genes were dependent on toll-like receptor (TLR) signalling. To determine the role of TLR-independent responses, we analysed the transcriptome of MyD88/Trif(-/-) bone marrow macrophages at different time points after infection with cagPAI positive versus negative strains. We identified a group of genes that exhibited different kinetic behaviour depending on whether cagPAI was present. Analysis of their gene expression kinetics demonstrated that this responsiveness to cagPAI was observed only in MyD88/Trif(-/-) macrophages. This group of cagPAI-sensing genes was enriched for AU-rich element containing early response genes involved in immune regulation, including interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha). Recognition of cagPAI positive strains was found to be mediated by the type IV secretion system (cagT4SS), rather than its effector protein CagA. We hypothesize that anergic macrophages of the gastric mucosa initiate an innate immune response following detection of the T4SS of H. pylori. PMID- 26243719 TI - Precursor T-lymphoblastic lymphoma: Speedy diagnosis in FNA and effusion cytology by morphology, immunochemistry, and flow cytometry. AB - BACKGROUND: Precursor T-lymphoblastic lymphoma (T-LBL) is a rare lymphoma presenting clinically in children and adolescents with a rapidly enlarging mediastinal mass, dyspnea, and cervical lymphadenopathy requiring quick diagnosis. The objective of the current study was to report on the spectrum of cytomorphology and flow cytometric immunophenotyping (FCI). METHODS: The clinical profile, cytomorphological features, FCI, and cell block immunocytochemistry (CB ICC) of all cases of T-LBL diagnosed from 2011 through 2013 were reviewed. RESULTS: Fifteen cases of precursor T-LBL (10 fine-needle aspiration samples and 5 pleural/pericardial fluid samples) were evaluated. Smears demonstrated dispersed lymphoblasts, with a high nuclear:cytoplasmic ratio and scanty basophilic cytoplasm. Nuclei demonstrated notches, clefts, and indentations. The chromatin was condensed in small and intermediate-sized blasts and dispersed in larger blasts. Nucleoli were present only in the larger blasts. Hand mirror shaped cells and mitoses were variable. With regard to immunophenotyping, flow cytometry demonstrated positivity for CD2 (15 of 15 cases), surface CD3 (14 of 15 cases), cytoplasmic CD3 (15 of 15 cases), terminal deoxynucleotidyl transferase (TdT) (8 of 15 cases), CD5 (13 of 15 cases), CD10 (7 of 15 cases), and human leukocyte antigen-D related (HLA-DR) (1 of 15 cases). Dual CD4/CD8 positivity was observed in all cases forming a tight cluster, which is consistent with the cortical T-LBL subtype. CB-ICC demonstrated a uniform CD3-positive/TdT positive/CD20-negative phenotype. In 7 cases in which TdT was negative by flow cytometry, CB-ICC was positive. CONCLUSIONS: Combining cytomorphology and FCI enables the accurate and rapid diagnosis of T-LBL on fine-needle aspiration and effusion cytology specimens, thereby obviating the need for a biopsy. PMID- 26243720 TI - Open Calcaneus Fractures and Associated Injuries. AB - Open calcaneus fractures are usually the result of high-energy mechanisms and are associated with other orthopedic and whole body system injures. Understanding the difference between open versus closed fractures is essential for the provider, and they must be vigilant for the associated injuries that present with this condition. We performed a retrospective medical record review of 62 patients (64 calcaneus fractures) with open calcaneus fractures from January 2003 to January 2013 presenting at a level 1 trauma center. Sex, age, laterality, mechanism of injury, wound appearance, initial management, and associated injures were recorded. The most common mechanisms were motor vehicle accidents (35 [56.4%]) and falls from >6 ft (15 [24.1%]). Four (6.4%) patients had a posterior tibial artery transection. Eight (12.9%) patients had a femoral shaft fracture, 14 (22.5%) an ipsilateral ankle fracture, 16 (25.8%) a metatarsal fracture, and 11 (17.7%) had associated midfoot fractures. Of the midfoot fractures, 12 (19.3%) patients had a talus fracture and 5 (8.0%) a cuboid fracture. Spinal fractures were present in 9 (14.5%) of the patients, with lumbar fractures occurring in 6 (9.6%) patients. Fifteen (24.1%) patients had associated upper extremity fractures. Thirteen (20.9%) patients had an associated pulmonary injury, including 8 pneumothoraces. Ten (16.1%) patients had a closed head injury and 6 (9.6%) had an abdominal injury. Fifteen (23.4%) patients were treated with percutaneous wire fixation and 7 (10.9%) with open reduction internal fixation. A total of 44 (68.7%) fractures were treated without internal fixation. Overall, 5 (8.0%) patients with an open calcaneus fracture eventually underwent a below-the knee amputation. Open calcaneus fractures are severe, high-energy injuries with the potential for considerable morbidity to the patient, given the high rate of concomitant orthopedic and whole body system injuries. Type III open injuries have an increased risk of requiring subsequent amputation. The management of these injuries should include intravenous antibiotics, tetanus prophylaxis, and urgent debridement and irrigation. PMID- 26243721 TI - Irreducible Ankle Fracture Dislocation Due to Tibialis Posterior Tendon Interposition: A Case Report. AB - Traumatic ankle fractures and dislocations that fail closed reduction present a challenging set of circumstances that can potentially lead to unnecessary complications and require surgical intervention. Interposition of adjacent tendons occurs rarely and can obstruct the anatomic realignment. Because of the potential for neurovascular compromise and possible skin tension necrosis, an irreducible fracture dislocation must be addressed with open reduction and internal fixation. The present case details an unusual, low-energy, external rotation ankle fracture and dislocation that was incapable of skeletal traction relocation. The present report also details the intraoperative finding of a complex injury pattern. PMID- 26243722 TI - Music and communication in the operating theatre. AB - AIMS: To observe the extent and the detail with which playing music can impact on communication in the operating theatre. BACKGROUND: According to the cited sources, music is played in 53-72% of surgical operations performed. Noise levels in the operating theatre already exceed World Health Organisation recommendations. There is currently a divide in opinions on the playing of music in operating theatres, with few studies conducted and no policies or guidance provided. DESIGN: An ethnographic observational study of teamwork in operating theatres through video recordings. Quantitative and qualitative data analysis approaches were used. METHODS: This study was conducted between 2012-2013 in the UK. Video recordings of 20 operations over six months in two operating theatres were captured. The recordings were divided into music and non-music playing cases. Each case was logged using a request/response sequence identified through interactional analysis. Statistical analysis, using a chi(2) , explored the difference between the proportion of request repetitions and whether music was playing or not. Further interactional analysis was conducted for each request repetition. RESULTS: Request/response observations (N = 5203) were documented. A chi-square test revealed that repeated requests were five times more likely to occur in cases that played music than those that did not. A repeated request can add 4-68 seconds each to operation time and increased tensions due to frustration at ineffective communication. CONCLUSIONS: Music played in the operating theatre can interfere with team communication, yet is seldom recognized as a potential safety hazard. Decisions around whether music is played and around the choice of music and its volume, are determined largely by surgeons. Frank discussions between clinicians, managers, patients and governing bodies should be encouraged for recommendations and guidance to be developed. PMID- 26243723 TI - Fungal-bacterial interactions and their relevance in health. AB - Cross-kingdom interactions between bacteria and fungi are a common occurrence in the environment. Recent studies have identified various types of interactions that either can take the form of a synergistic relationship or can result in an antagonistic interplay with the subsequent destruction or inhibition of growth of bacteria, fungi or both. This cross-kingdom communication is of particular significance in human health and disease, as bacteria and fungi commonly colonize various human surfaces and their interactions can at times alter the outcome of invasive infections. Moreover, mixed infections from both bacteria and fungi are relatively common among critically ill patients and individuals with weak immune responses. The purpose of this review is to summarize our knowledge on the type of interactions between bacteria and fungi and their relevance in human infections. PMID- 26243724 TI - Conservation threats and the phylogenetic utility of IUCN Red List rankings in Incilius toads. AB - Phylogenetic analysis of extinction threat is an emerging tool in the field of conservation. However, there are problems with the methods and data as commonly used. Phylogenetic sampling usually extends to the level of family or genus, but International Union for Conservation of Nature (IUCN) rankings are available only for individual species, and, although different species within a taxonomic group may have the same IUCN rank, the species may have been ranked as such for different reasons. Therefore, IUCN rank may not reflect evolutionary history and thus may not be appropriate for use in a phylogenetic context. To be used appropriately, threat-risk data should reflect the cause of extinction threat rather than the IUCN threat ranking. In a case study of the toad genus Incilius, with phylogenetic sampling at the species level (so that the resolution of the phylogeny matches character data from the IUCN Red List), we analyzed causes of decline and IUCN threat rankings by calculating metrics of phylogenetic signal (such as Fritz and Purvis' D). We also analyzed the extent to which cause of decline and threat ranking overlap by calculating phylogenetic correlation between these 2 types of character data. Incilius species varied greatly in both threat ranking and cause of decline; this variability would be lost at a coarser taxonomic resolution. We found far more phylogenetic signal, likely correlated with evolutionary history, for causes of decline than for IUCN threat ranking. Individual causes of decline and IUCN threat rankings were largely uncorrelated on the phylogeny. Our results demonstrate the importance of character selection and taxonomic resolution when extinction threat is analyzed in a phylogenetic context. PMID- 26243725 TI - NF-kappaB signaling regulates the generation of intermediate progenitors in the developing neocortex. AB - In addition to its well-established role during immune system function, NF-kappaB regulates cell survival and synaptic plasticity in the mature nervous system. Here, we show that during mouse brain development, NF-kappaB activity is present in the neocortical ventricular and subventricular zones (VZ and SVZ), where it regulates proliferative pool maintenance. Activation of NF-kappaB signaling, by expression of p65 or an activated form of the IkappaB kinase complex subunit IKK2, inhibited neuronal differentiation and promoted retention of progenitors in the VZ and SVZ. In contrast, blockade of the pathway with dominant negative forms of IKK2 and IkappaBalpha promoted neuronal differentiation both in vivo and in vitro. Furthermore, by modulating both the NF-kappaB and Notch pathways, we show that in the absence of canonical Notch activity, after knockdown of the pathway effector CBF1, NF-kappaB signaling promoted Tbr2 expression and intermediate neural progenitor fate. Interestingly, however, activation of NF-kappaB in vivo, with canonical Notch signaling intact, promoted expression of the radial glial marker Pax6. This work identifies NF-kappaB signaling as a regulator of neocortical neurogenesis and suggests that the pathway plays roles in both the VZ and SVZ. PMID- 26243726 TI - Thoracic endometriosis: clinicopathologic updates and issues about 18 cases from a tertiary referring center. AB - Thoracic endometriosis is defined as the ectopic presence of endometrial glands and stroma in lung or pleura and constitutes an uncommon cause of spontaneous pneumothorax in nonsmoker women in childbearing age. From 2000 to 2014, 18 (7.3%) women of 246 had a histologically proven endometriosis-related pneumothorax. The examination of thoracic samples was performed on formalin-fixed, paraffin embedded hematoxylin and eosin-stained slides. Immunohistochemistry was carried out on all samples. The pathologic findings included endometriosis foci appearing as a triad of endometrial glands, stroma, and hemosiderin-laden macrophages in 8 patients. In the remaining 10 patients, minute nests of endometrial stroma were recognized at histologic examination and immunohistochemistry. One patient displayed diaphragmatic endometriosis and pulmonary lymphangioleiomyomatosis. Thoracic endometriosis is an uncommon cause of recurrent pneumothorax necessitating histologic confirmation. The histologic diagnosis of endometriosis may be challenging on small pleural or lung biopsies because endometriosis mostly appears as minute nests of endometrial stromal cells. Here, we present our experience on thoracic endometriosis: considering frequent interpretation difficulties of biopsy samples, we propose a multidisciplinary diagnostic algorithm. PMID- 26243727 TI - A moving view: subcellular trafficking processes in pattern recognition receptor triggered plant immunity. AB - A significant challenge for plants is to induce localized defense responses at sites of pathogen attack. Therefore, host subcellular trafficking processes enable accumulation and exchange of defense compounds, which contributes to the plant on-site defenses in response to pathogen perception. This review summarizes our current understanding of the transport processes that facilitate immunity, the significance of which is highlighted by pathogens reprogramming membrane trafficking through host cell translocated effectors. Prominent immune-related cargos of plant trafficking pathways are the pattern recognition receptors (PRRs), which must be present at the plasma membrane to sense microbes in the apoplast. We focus on the dynamic localization of the FLS2 receptor and discuss the pathways that regulate receptor transport within the cell and their link to FLS2-mediated immunity. One emerging theme is that ligand-induced late endocytic trafficking is conserved across different PRR protein families as well as across different plant species. PMID- 26243728 TI - Roots shaping their microbiome: global hotspots for microbial activity. AB - Land plants interact with microbes primarily at roots. Despite the importance of root microbial communities for health and nutrient uptake, the current understanding of the complex plant-microbe interactions in the rhizosphere is still in its infancy. Roots provide different microhabitats at the soil-root interface: rhizosphere soil, rhizoplane, and endorhizosphere. We discuss technical aspects of their differentiation that are relevant for the functional analysis of their different microbiomes, and we assess PCR (polymerase chain reaction)-based methods to analyze plant-associated bacterial communities. Development of novel primers will allow a less biased and more quantitative view of these global hotspots of microbial activity. Based on comparison of microbiome data for the different root-soil compartments and on knowledge of bacterial functions, a three-step enrichment model for shifts in community structure from bulk soil toward roots is presented. To unravel how plants shape their microbiome, a major research field is likely to be the coupling of reductionist and molecular ecological approaches, particularly for specific plant genotypes and mutants, to clarify causal relationships in complex root communities. PMID- 26243729 TI - Grapevine leafroll disease and associated viruses: a unique pathosystem. AB - Grapevine leafroll is the most complex and intriguing viral disease of grapevine (Vitis spp.). Several monopartite closteroviruses (family Closteroviridae) from grapevines have been molecularly characterized, yet their role in disease etiology is not completely resolved. Hence, these viruses are currently designated under the umbrella term of Grapevine leafroll-associated viruses (GLRaVs). This review examines our current understanding of the genetically divergent GLRaVs and highlights the emerging picture of several unique aspects of the leafroll disease pathosystem. A systems biology approach using contemporary technologies in molecular biology, -omics, and cell biology aids in exploring the comparative molecular biology of GLRaVs and deciphering the complex network of host-virus-vector interactions to bridge the gap between genomics and phenomics of leafroll disease. In addition, grapevine-infecting closteroviruses have a great potential as designer viruses to pursue functional genomics and for the rational design of novel disease intervention strategies in this agriculturally important perennial fruit crop. PMID- 26243731 TI - Label-Free Kinetics: Exploiting Functional Hemi-Equilibrium to Derive Rate Constants for Muscarinic Receptor Antagonists. AB - Drug receptor kinetics is as a key component in drug discovery, development, and efficacy; however, determining kinetic parameters has historically required direct radiolabeling or competition with a labeled tracer. Here we present a simple approach to determining the kinetics of competitive antagonists of G protein-coupled receptors by exploiting the phenomenon of hemi-equilibrium, the state of partial re-equilibration of agonist, antagonist, and receptor in some functional assays. Using functional [Ca(2+)]i-flux and extracellular kinases 1 and 2 phosphorylation assays that have short incubation times and therefore are prone to hemi-equilibrium "behaviors," we investigated a wide range of structurally and physicochemically distinct muscarinic acetylcholine receptor antagonists. Using a combined operational and hemi-equilibrium model of antagonism to both simulate and analyze data, we derived estimates of association and dissociation rates for the test set of antagonists, identifying both rapidly dissociating (4-DAMP, himbacine) and slowly dissociating (tiotropium, glycopyrrolate) ligands. The results demonstrate the importance of assay incubation time and the degree of receptor reserve in applying the analytical model. There was an excellent correlation between estimates of antagonist pK(B), k(on), and k(off) from functional assays and those determined by competition kinetics using whole-cell [(3)H]N-methylscopolamine binding, validating this approach as a rapid and simple method to functionally profile receptor kinetics of competitive antagonists in the absence of a labeled tracer. PMID- 26243732 TI - Suppression of Cytochrome P450 3A4 Function by UDP-Glucuronosyltransferase 2B7 through a Protein-Protein Interaction: Cooperative Roles of the Cytosolic Carboxyl-Terminal Domain and the Luminal Anchoring Region. AB - There is a large discrepancy between the interindividual difference in the hepatic expression level of cytochrome P450 3A4 (CYP3A4) and that of drug clearance mediated by this enzyme. However, the reason for this discrepancy remains largely unknown. Because CYP3A4 interacts with UDP glucuronosyltransferase 2B7 (UGT2B7) to alter its function, the reverse regulation is expected to modulate CYP3A4-catalyzed activity. To address this issue, we investigated whether protein-protein interaction between CYP3A4 and UGT2B7 modulates CYP3A4 function. For this purpose, we coexpressed CYP3A4, NADPH cytochrome P450 reductase, and UGT2B7 using a baculovirus-insect cell system. The activity of CYP3A4 was significantly suppressed by coexpressing UGT2B7, and this suppressive effect was lost when UGT2B7 was replaced with calnexin (CNX). These results strongly suggest that UGT2B7 negatively regulates CYP3A4 activity through a protein-protein interaction. To identify the UGT2B7 domain associated with CYP3A4 suppression we generated 12 mutants including chimeras with CNX. Mutations introduced into the UGT2B7 carboxyl-terminal transmembrane helix caused a loss of the suppressive effect on CYP3A4. Thus, this hydrophobic region is necessary for the suppression of CYP3A4 activity. Replacement of the hydrophilic end of UGT2B7 with that of CNX produced a similar suppressive effect as the native enzyme. The data using chimeric protein demonstrated that the internal membrane-anchoring region of UGT2B7 is also needed for the association with CYP3A4. These data suggest that 1) UGT2B7 suppresses CYP3A4 function, and 2) both hydrophobic domains located near the C terminus and within UGT2B7 are needed for interaction with CYP3A4. PMID- 26243730 TI - Human dendritic cell subsets and function in health and disease. AB - The method of choice for the development of new vaccines is to target distinct dendritic cell subsets with antigen in vivo and to harness their function in situ to enhance cell-mediated immunity or induce tolerance to specific antigens. The innate functions of dendritic cells themselves may also be targeted by inhibitors or activators that would target a specific function such as interferon production, potentially important in autoimmune disease and chronic viral infections. Importantly targeting dendritic cells requires detailed knowledge of both the surface phenotype and function of each dendritic cell subset, including how they may respond to different types of vaccine adjuvants, their ability to produce soluble mediators and to process and present antigens and induce priming of naive T cells. This review summarizes our knowledge of the functional attributes of the human dendritic cell subsets in the steady state and upon activation and their roles in human disease. PMID- 26243733 TI - Brief Intervention in the Emergency Department Among Mexican-Origin Young Adults at the US-Mexico Border: Outcomes of a Randomized Controlled Clinical Trial Using Promotores. AB - AIMS: A randomized controlled trial of brief intervention (BI), for drinking and related problems, using peer health promotion advocates (promotores), was conducted among at-risk and alcohol-dependent Mexican-origin young adult emergency department (ED) patients, aged 18-30. METHODS: Six hundred and ninety eight patients were randomized to: screened only (n = 78), assessed (n = 310) and intervention (n = 310). Primary outcomes were at-risk drinking and Rapid Alcohol Problems Screen (RAPS4) scores. Secondary outcomes were drinking days per week, drinks per drinking day, maximum drinks in a day and negative consequences of drinking. RESULTS: At 3- and 12-month follow-up the intervention condition showed significantly lower values or trends on all outcome variables compared to the assessed condition, with the exception of the RAPS4 score; e.g. at-risk drinking days dropped from 2.9 to 1.7 at 3 months for the assessed condition and from 3.2 to 1.2 for the intervention condition. Using random effects modeling controlling for demographics and baseline values, the intervention condition showed significantly greater improvement in all consumption measures at 12 months, but not in the RAPS4 or negative consequences of drinking. Improvements in outcomes were significantly more evident for non-injured patients, those reporting drinking prior to the event, and those lower on risk taking disposition. CONCLUSIONS: At 12-month follow-up this study demonstrated significantly improved drinking outcomes for Mexican-origin young adults in the ED who received a BI delivered by promotores compared to those who did not. TRIAL REGISTER: ClinicalTrials.gov. CLINICAL TRIAL REGISTRATION NUMBER: NCT02056535. PMID- 26243734 TI - Smoking, Smoking Cessation, and Risk of Tooth Loss: The EPIC-Potsdam Study. AB - The aim of this study was to investigate the association between cigarette smoking and smoking cessation and the prevalence and incidence of tooth loss in a large cohort study in Germany. We analyzed data of 23,376 participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study recruited between 1994 and 1998 from the general population in Potsdam and other parts of Brandenburg, Germany, who had complete data on cigarette smoking, tooth loss, and covariates. Negative binomial regression and tooth-specific logistic regression models were fit to evaluate the association between smoking and the baseline prevalence and incidence of tooth loss during follow-up, respectively. Cigarette smoking was associated with higher prevalence of tooth loss at baseline as well as higher incidence of tooth loss during follow-up. The association between smoking and the incidence of tooth loss was stronger in men than women and stronger in younger versus older individuals. Heavy smoking (>=15 cigarettes/d) was associated with >3 times higher risk of tooth loss in men (odds ratio, 3.6; 95% confidence interval, 3.0, 4.4) and more than twice the risk of tooth loss in women (odds ratio, 2.5; 95% confidence interval, 2.1, 2.9) younger than 50 y when compared with never smokers. Smoking cessation was consistently associated with a reduction in tooth loss risk, with the risk of tooth loss approaching that of never smokers after approximately 10 to 20 y of cessation. PMID- 26243735 TI - Apremilast for the treatment of psoriasis. AB - INTRODUCTION: Psoriasis is a chronic inflammatory skin disease characterized by dysregulation of the immune system and release of pro-inflammatory mediators. Drugs available for psoriasis show some limits as tolerability and route of administration. Apremilast , Otezla(r), is an oral small molecule recently approved for the treatment of patients with moderate-to-severe plaque psoriasis. Compared to biologics that target a single cytokine, apremilast, degrading phosphodiesterase 4 (PDE4), interferes with cyclic anti-microbial peptides, which is involved in the transduction of intracellular signals, controlling the balance of pro-inflammatory and anti-inflammatory signals. AREAS COVERED: This review reported the latest data available from Phase I, II and III trials on apremilast for the treatment of plaque psoriasis. A focus on the clinical management of apremilast, safety and clinical efficacy based on two pivotal clinical trials (ESTEEM 1 and ESTEEM 2) currently ongoing was described. A systematic search was conducted using the PubMed Medline database for primary articles. EXPERT OPINION: Apremilast treatment was demonstrated effective and well tolerated in Phase II and III clinical trials. Several drug peculiarities, such as the low frequency of adverse events and the oral route of administration, make apremilast an innovative treatment for moderate-to-severe psoriasis. PMID- 26243737 TI - Trauma, comorbidity, and mortality following diagnoses of severe stress and adjustment disorders: a nationwide cohort study. AB - Longitudinal outcomes following stress or trauma diagnoses are receiving attention, yet population-based studies are few. The aims of the present cohort study were to examine the cumulative incidence of traumatic events and psychiatric diagnoses following diagnoses of severe stress and adjustment disorders categorized using International Classification of Diseases, Tenth Revision, codes and to examine associations of these diagnoses with all-cause mortality and suicide. Data came from a longitudinal cohort of all Danes who received a diagnosis of reaction to severe stress or adjustment disorders (International Classification of Diseases, Tenth Revision, code F43.x) between 1995 and 2011, and they were compared with data from a general-population cohort. Cumulative incidence curves were plotted to examine traumatic experiences and psychiatric diagnoses during the study period. A Cox proportional hazards regression model was used to examine the associations of the disorders with mortality and suicide. Participants with stress diagnoses had a higher incidence of traumatic events and psychiatric diagnoses than did the comparison group. Each disorder was associated with a higher rate of all-cause mortality than that seen in the comparison cohort, and strong associations with suicide were found after adjustment. This study provides a comprehensive assessment of the associations of stress disorders with a variety of outcomes, and we found that stress diagnoses may have long-lasting and potentially severe consequences. PMID- 26243736 TI - Associations of body mass index, smoking, and alcohol consumption with prostate cancer mortality in the Asia Cohort Consortium. AB - Many potentially modifiable risk factors for prostate cancer are also associated with prostate cancer screening, which may induce a bias in epidemiologic studies. We investigated the associations of body mass index (weight (kg)/height (m)(2)), smoking, and alcohol consumption with risk of fatal prostate cancer in Asian countries where prostate cancer screening is not widely utilized. Analysis included 18 prospective cohort studies conducted during 1963-2006 across 6 countries in southern and eastern Asia that are part of the Asia Cohort Consortium. Body mass index, smoking, and alcohol intake were determined by questionnaire at baseline, and cause of death was ascertained through death certificates. Analysis included 522,736 men aged 54 years, on average, at baseline. During 4.8 million person-years of follow-up, there were 634 prostate cancer deaths (367 prostate cancer deaths across the 11 cohorts with alcohol data). In Cox proportional hazards analyses of all cohorts in the Asia Cohort Consortium, prostate cancer mortality was not significantly associated with obesity (body mass index >25: hazard ratio (HR) = 1.08, 95% confidence interval (CI): 0.85, 1.36), ever smoking (HR = 1.00, 95% CI: 0.84, 1.21), or heavy alcohol intake (HR = 1.00, 95% CI: 0.74, 1.35). Differences in prostate cancer screening and detection probably contribute to differences in the association of obesity, smoking, or alcohol intake with prostate cancer risk and mortality between Asian and Western populations and thus require further investigation. PMID- 26243738 TI - Invited commentary: screening and the elusive etiology of prostate cancer. AB - The role of lifestyle risk factors in prostate cancer risk remains elusive despite a large number of epidemiologic studies. In a pooled analysis of data from South and East Asian countries published in this issue, Fowke et al. (Am J Epidemiol. 2015;182(5):381-389) found no evidence for an association between prostate cancer mortality and obesity, alcohol, or smoking. Prostate cancer screening is very uncommon in these countries, and previous evidence for associations with lifestyle factors comes primarily from studies carried out in North America, where screening is very common. Fowke et al. concluded that screening biases are likely to explain the differences in study results. In this commentary, we discuss the potential influence of population-based cancer screening programs in estimates of association from epidemiologic studies. This highlights the importance of carefully considering the impact of screening in the analysis and interpretation of results, in order to advance our understanding of the etiology of cancers that can be detected by screening. PMID- 26243739 TI - Biodistribution and Efficacy of Targeted Pulmonary Delivery of a Protein Kinase C delta Inhibitory Peptide: Impact on Indirect Lung Injury. AB - Sepsis and sepsis-induced lung injury remain a leading cause of death in intensive care units. We identified protein kinase C-delta (PKCdelta) as a critical regulator of the acute inflammatory response and demonstrated that PKCdelta inhibition was lung-protective in a rodent sepsis model, suggesting that targeting PKCdelta is a potential strategy for preserving pulmonary function in the setting of indirect lung injury. In this study, whole-body organ biodistribution and pulmonary cellular distribution of a transactivator of transcription (TAT)-conjugated PKCdelta inhibitory peptide (PKCdelta-TAT) was determined following intratracheal (IT) delivery in control and septic [cecal ligation and puncture (CLP)] rats to ascertain the impact of disease pathology on biodistribution and efficacy. There was negligible lung uptake of radiolabeled peptide upon intravenous delivery [<1% initial dose (ID)], whereas IT administration resulted in lung retention of >65% ID with minimal uptake in liver or kidney (<2% ID). IT delivery of a fluorescent-tagged (tetramethylrhodamine PKCdelta-TAT) peptide demonstrated uniform spatial distribution and cellular uptake throughout the peripheral lung. IT delivery of PKCdelta-TAT at the time of CLP surgery significantly reduced PKCdelta activation (tyrosine phosphorylation, nuclear translocation and cleavage) and acute lung inflammation, resulting in improved lung function and gas exchange. Importantly, peptide efficacy was similar when delivered at 4 hours post-CLP, demonstrating therapeutic relevance. Conversely, spatial lung distribution and efficacy were significantly impaired at 8 hours post-CLP, which corresponded to marked histopathological progression of lung injury. These studies establish a functional connection between peptide spatial distribution, inflammatory histopathology in the lung, and efficacy of this anti-inflammatory peptide. PMID- 26243741 TI - Select injury-related variables are affected by stride length and foot strike style during running. AB - BACKGROUND: Some frontal plane and transverse plane variables have been associated with running injury, but it is not known if they differ with foot strike style or as stride length is shortened. PURPOSE: To identify if step width, iliotibial band strain and strain rate, positive and negative free moment, pelvic drop, hip adduction, knee internal rotation, and rearfoot eversion differ between habitual rearfoot and habitual mid-/forefoot strikers when running with both a rearfoot strike (RFS) and a mid-/forefoot strike (FFS) at 3 stride lengths. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 42 healthy runners (21 habitual rearfoot, 21 habitual mid-/forefoot) ran overground at 3.35 m/s with both a RFS and a FFS at their preferred stride lengths and 5% and 10% shorter. RESULTS: Variables did not differ between habitual groups. Step width was 1.5 cm narrower for FFS, widening to 0.8 cm as stride length shortened. Iliotibial band strain and strain rate did not differ between foot strikes but decreased as stride length shortened (0.3% and 1.8%/s, respectively). Pelvic drop was reduced 0.7 degrees for FFS compared with RFS, and both pelvic drop and hip adduction decreased as stride length shortened (0.8 degrees and 1.5 degrees , respectively). Peak knee internal rotation was not affected by foot strike or stride length. Peak rearfoot eversion was not different between foot strikes but decreased 0.6 degrees as stride length shortened. Peak positive free moment (normalized to body weight [BW] and height [h]) was not affected by foot strike or stride length. Peak negative free moment was -0.0038 BW.m/h greater for FFS and decreased -0.0004 BW.m/h as stride length shortened. CONCLUSION: The small decreases in most variables as stride length shortened were likely associated with the concomitant wider step width. RFS had slightly greater pelvic drop, while FFS had slightly narrower step width and greater negative free moment. CLINICAL RELEVANCE: Shortening one's stride length may decrease or at least not increase propensity for running injuries based on the variables that we measured. One foot strike style does not appear universally better than the other; rather, different foot strike styles may predispose runners to different types of injuries. PMID- 26243740 TI - Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels. AB - Sphingosine 1-phosphate (S1P) levels are significantly higher in blood and lymph than in tissues. This S1P concentration difference is necessary for proper lymphocyte egress from secondary lymphoid tissue and to maintain endothelial barrier integrity. Studies with mice lacking either sphingosine kinase (SphK) type 1 and 2 indicate that these enzymes are the sole biosynthetic source of S1P, but they play different roles in setting S1P blood levels. We have developed a set of drug-like SphK inhibitors, with differing selectivity for the two isoforms of this enzyme. Although all SphK inhibitors tested decrease S1P when applied to cultured U937 cells, only those inhibitors with a bias for SphK2 drove a substantial increase in blood S1P in mice and this rise was detectable within minutes of administration of the inhibitor. Blood S1P also increased in response to SphK2 inhibitors in rats. Mass-labeled S1P was cleared more slowly after intravenous injection into SphK2 inhibitor-treated mice or mice lacking a functional SphK2 gene; thus, the increased accumulation of S1P in the blood appears to result from the decreased clearance of S1P from the blood. Therefore, SphK2 appears to have a function independent of generating S1P in cells. Our results suggest that differential SphK inhibition with a drug might afford a method to manipulate blood S1P levels in either direction while lowering tissue S1P levels. PMID- 26243742 TI - Evaluation of four human cell lines with distinct biotransformation properties for genotoxic screening. AB - In a previous study, we validated an in vitro genotoxicity assay based on gammaH2AX quantification using the In-Cell Western (ICW) method in HepG2 cells. The assay demonstrated high sensitivity and specificity but failed to detect genotoxicity for few compounds that require specific metabolic bioactivation not sufficiently covered by HepG2 cells. The aim of the present study was to assess gammaH2AX ICW sensitivity using a broader range of genotoxic molecules with HepG2 cells and three additional human cell lines with distinct biotransformation properties: two cell lines expressing some phase I and II bioactivation capabilities (LS-174T and Hep3B), and one with poor general bioactivation properties (ACHN). We evaluated the four cell lines by testing 24 compounds recommended by European Centre for the Validation of Alternative Methods and a set of 24 additional chemicals with different mode of genotoxic action (MOA) (aneugenicity, DNA adducts formation, induction of oxidative stress), including some known to require specific cytochrome P450 metabolic bioactivation. Results for the 48 compounds tested showed that the gammaH2AX ICW assay was more sensitive with LS-174T and HepG2 cells than with Hep3B or ACHN cell lines. Among the 38 compounds tested with positive or equivocal carcinogenicity data, 36 (95%) showed a positive genotoxic response with the gammaH2AX ICW assay compared to only 27 (71%) using the Ames assay. We confirm that the gammaH2AX ICW assay on HepG2 cells, without an exogenous metabolic activation system, may be a suitable test to predict the in vivo genotoxicity of chemicals with different genotoxic MOA. Moreover, the use of the ACHN cell line in combination with LS-174T and HepG2 cells may permit in many cases to discriminate direct from bioactivated genotoxins. Overall, our results confirm the high sensitivity of the gammaH2AX ICW assay which, in turn, should reduce the number of animals used for genotoxicity assessment. PMID- 26243744 TI - Treatment of juvenile hallux valgus interphalangeus with a double compression headless bone screw. AB - A 14-year-old girl presented with idiopathic valgus deformity of her left great toe at the interphalangeal joint (IPJ). The deformity, which had been present but asymptomatic for the past 4 years, began to enlarge and cause discomfort. The measured IPJ angle on anteroposterior standing X-ray was 26 degrees . We treated the toe by medial closing wedge osteotomy and fixation with a double compression headless bone screw (DCHBS). Postoperative hallux valgus interphalangeus (HVI) angle was 14 degrees . PMID- 26243745 TI - Post-strabismus surgery aqueous misdirection syndrome. AB - A 24-year-old man was referred to the glaucoma clinic of our tertiary eye care centre in view of uncontrolled intraocular pressure (IOP) in the left eye despite maximal medication. The patient had undergone left eye cosmetic squint surgery 1 month before (medial rectus resection 9 mm and lateral rectus recession 12 mm) for congenital third nerve palsy. Post-squint surgery, the patient developed pain and was being managed symptomatically. However, 1 week later, he developed diffuse corneal oedema and severe pain, and was readmitted for management in the same hospital. He presented to our centre with an IOP of 16 mm Hg in the right eye and 58 mm Hg in the left eye. We made a diagnosis of left eye post-strabismus surgery aqueous misdirection syndrome, and performed left eye core vitrectomy with 360 degrees goniosynechialysis and ultimately a trabeculectomy to reduce IOP. PMID- 26243743 TI - Identification of genotoxic compounds using isogenic DNA repair deficient DT40 cell lines on a quantitative high throughput screening platform. AB - DNA repair pathways play a critical role in maintaining cellular homeostasis by repairing DNA damage induced by endogenous processes and xenobiotics, including environmental chemicals. Induction of DNA damage may lead to genomic instability, disruption of cellular homeostasis and potentially tumours. Isogenic chicken DT40 B-lymphocyte cell lines deficient in DNA repair pathways can be used to identify genotoxic compounds and aid in characterising the nature of the induced DNA damage. As part of the US Tox21 program, we previously optimised several different DT40 isogenic clones on a high-throughput screening platform and confirmed the utility of this approach for detecting genotoxicants by measuring differential cytotoxicity in wild-type and DNA repair-deficient clones following chemical exposure. In the study reported here, we screened the Tox21 10K compound library against two isogenic DNA repair-deficient DT40 cell lines (KU70 (-/-) /RAD54 (-/-) and REV3 (-/-) ) and the wild-type cell line using a cell viability assay that measures intracellular adenosine triphosphate levels. KU70 and RAD54 are genes associated with DNA double-strand break repair processes, and REV3 is associated with translesion DNA synthesis pathways. Active compounds identified in the primary screening included many well-known genotoxicants (e.g. adriamycin, melphalan) and several compounds previously untested for genotoxicity. A subset of compounds was further evaluated by assessing their ability to induce micronuclei and phosphorylated H2AX. Using this comprehensive approach, three compounds with previously undefined genotoxicity-2-oxiranemethanamine, AD-67 and tetraphenylolethane glycidyl ether-were identified as genotoxic. These results demonstrate the utility of this approach for identifying and prioritising compounds that may damage DNA. PMID- 26243746 TI - An unusual presentation of herpes simplex encephalitis with negative PCR. AB - A 74-year-old man presented with acute right-sided hemiparesis and epilepsia partialis continua in association with fever and confusion. Initial workup revealed possible cerebritis in the left medial frontal lobe without involvement of the temporal lobes. Cerebrospinal fluid (CSF) analysis revealed minimal lymphocytic pleocytosis but negative real-time herpes simplex virus (HSV) PCR. Acyclovir was discontinued on day 5 due to a negative infectious workup and clinical improvement. On day 9 his condition deteriorated and he was transferred to a higher level of acuity for advanced supportive care. Worsening encephalopathy and refractory status epilepticus ensued despite medical care. Repeat CSF analysis showed mild lymphocytic pleocytosis with negative real-time HSV PCR. Brain MRI revealed progression of cortical enhancement. Immunosuppressive therapy and plasma exchange were attempted without clinical response. On day 24, another lumbar puncture showed only mild lymphocytic pleocytosis. Brain MRI showed involvement of the right medial temporal lobe. Subsequently, acyclovir was resumed. The HSV-1 PCR result was positive on day 30. Unfortunately, the patient expired. PMID- 26243747 TI - Photopsia revealing a retinocytoma. PMID- 26243748 TI - Hand ischaemia after radial artery cannulation. AB - Arterial cannulation for haemodynamic monitoring has become a routine procedure in the clinical management of critically ill adults. Thrombosis is the most common complication of this procedure. We report the case of a patient with multiple traumatic injuries in which radial artery cannulation was associated with compartment syndrome of the forearm and hand. PMID- 26243749 TI - Mesothelial derived adenomatoid tumour in a location devoid of mesothelium: adrenal adenomatoid tumour. AB - This is a case report of a 40-year-old man with an adrenal mass that was found incidentally on routine check-up examination. MRI showed a 30 * 51 * 57 mm cystic semisolid heterogeneous mass; hormonal functions were within normal limits. Operative removal was planned because of the large size of the mass. Histopathological and immunohistochemical findings were consistent with adenomatoid tumour. The patient was disease-free at 1 year follow-up. We present this case with its radiological and histological characteristics under the review of the literature. PMID- 26243750 TI - Pheochromocytoma: clinical review based on a rare case in adolescence. AB - Pheochromocytomas are rare tumours originating in chromaffin cells, representing 0.1-1% of all secondary hypertension (HT) cases. The majority are benign and unilateral, characterised by the production of catecholamines and other neuropeptides. Mainly located in the adrenal gland, they are more frequent between the 3rd and 5th decades of life; however, 10-25% can be associated with genetic familial syndromes (multiple endocrine neoplasia type 2 (MEN 2), type 1 neurofibromatosis and Von-Hippel-Landau disease in younger ages. The authors present a rare case of secondary HT due to a pheochromocytoma in a 15-year-old patient, whose metanephrine assay confirmed the diagnosis, and abdominal ultrasound and CT localised the tumour in the adrenal gland. HT was controlled with alpha and beta blockers, with posterior retroperitoneal laparoscopic surgical intervention and subsequent resolution of HT. Age and concomitant hyperparathyroidism compelled genetic testing for the exclusion of MEN 2, which was negative. PMID- 26243751 TI - Intracerebral haemorrhage and hemiplegia with heterotopic ossification of the affected hip. AB - We present the case of a 72-year-old woman who developed right hemiparesis following a left frontal intraparenchymal haemorrhage. Three months following initial presentation, the patient noted poorly localised right lower quadrant pain. Following extensive investigations, a diagnosis of heterotopic ossification of the hip was made. We discuss the aetiology and pathogenesis of this uncommon entity, and discuss its relationship to ipsilateral neurological injury. The link with neurological injury can result in a delayed and atypical presentation. Early recognition and treatment are important for those caring for patients with acquired neurological deficits, and permit improved patient outcomes. PMID- 26243752 TI - Successful treatment of a radial artery pseudoaneurysm in an octogenarian. AB - The transradial approach for coronary catheterisation has gained rising popularity owing to its fewer access site complications compared with the transfemoral approach. A rare but recognisable complication of the procedure is radial artery pseudoaneurysm (PSA). We report a case of radial PSA occurring 2 h following percutaneous coronary intervention in an 85-year-old woman, which was successfully treated by ultrasound-guided thrombin injection. This non-surgical technique has recently gained rising popularity as a relatively novel modality of managing radial PSA. PMID- 26243753 TI - In-hospital Breastfeeding and Intention to Return to Work Influence Mothers' Breastfeeding Intentions. AB - BACKGROUND: Research continues to demonstrate that formula feeding is associated with numerous long-term negative outcomes for a mother and her infant. However, many women cease breastfeeding sooner than intended and recommended. Breastfeeding has been found to be related to demographics, maternal mood, and returning to work outside the home. OBJECTIVES: This study aimed to shed light on the woman's perception of the effect of working on intended breastfeeding duration. This study used intentions to return to work and in-hospital breastfeeding to predict breastfeeding intentions. METHODS: Women (N = 160) were surveyed during the first 48 hours postdelivery of healthy, full-term infants. Survey instruments included demographics (socioeconomic status, maternal age, education, and marital status), depression, fetal attachment, current exclusive breastfeeding status, as well as breastfeeding and return-to-work intentions for the next year. A path analysis was used to explore relationships and predictors of breastfeeding intentions. RESULTS: The model had a good fit and breastfeeding intentions were predicted by exclusive breastfeeding in the hospital (beta = 0.21, P < .01) and negatively predicted by return to work (beta = -0.18, P < .05). CONCLUSION: Exclusive breastfeeding in the hospital within the first 48 hours postpartum and intention to return to work influence how long a mother intends to breastfeed. Attention to these areas can be provided immediately postpartum to support exclusive breastfeeding and provide informational support on continuing to breastfeed/express milk upon return to work if the mother intends to return to work. PMID- 26243754 TI - Reliability of Lactation Assessment Tools Applied to Overweight and Obese Women. AB - BACKGROUND: The interrater reliability of lactation assessment tools has not been evaluated in overweight/obese women. OBJECTIVE: This study aimed to compare the interrater reliability of 4 lactation assessment tools in this population. METHODS: A convenience sample of 45 women (body mass index > 27.0) was videotaped while breastfeeding (twice daily on days 2, 4, and 7 postpartum). Three International Board Certified Lactation Consultants independently rated each videotaped session using 4 tools (Infant Breastfeeding Assessment Tool [IBFAT], modified LATCH [mLATCH], modified Via Christi [mVC], and Riordan's Tool [RT]). For each day and tool, we evaluated interrater reliability with 1-way repeated measures analyses of variance, intraclass correlation coefficients (ICCs), and percentage absolute agreement between raters. RESULTS: Analyses of variance showed significant differences between raters' scores on day 2 (all scales) and day 7 (RT). Intraclass correlation coefficient values reflected good (mLATCH) to excellent reliability (IBFAT, mVC, and RT) on days 2 and 7. All day 4 ICCs reflected good reliability. The ICC for mLATCH was significantly lower than all others on day 2 and was significantly lower than IBFAT (day 7). Percentage absolute interrater agreement for scale components ranged from 31% (day 2: observable swallowing, RT) to 92% (day 7: IBFAT, fixing; and mVC, latch time). Swallowing scores on all scales had the lowest levels of interrater agreement (31%-64%). CONCLUSION: We demonstrated differences in the interrater reliability of 4 lactation assessment tools when applied to overweight/obese women, with the lowest values observed on day 4. Swallowing assessment was particularly unreliable. Researchers and clinicians using these scales should be aware of the differences in their psychometric behavior. PMID- 26243755 TI - Role of Maternal Allergy on Immune Markers in Colostrum and Secretory Immunoglobulin A in Stools of Breastfed Infants. AB - BACKGROUND: Although protection against infectious diseases has been observed among breastfed infants as compared to formula-fed infants, possible benefits of breastfeeding by allergic mothers for allergy prevention remain controversial. OBJECTIVES: The aims of this study were to determine whether maternal allergy would influence immune markers (secretory immunoglobulin A [sIgA], interleukin-8 [IL-8], soluble CD14 [sCD14]) in colostrum and the associations between maternal allergy and fecal sIgA levels in breastfed infants. METHODS: Study subjects were enrolled from the Prediction of Allergies in Taiwanese Children (PATCH) birth cohort study. Colostrum samples were obtained from 98 lactating mothers. Stool samples were collected from 108 infants within 5 days after birth and at 2 and 4 months of age. We compared concentrations of sIgA, IL-8, and sCD14 in colostrum between mothers with and without a history of allergic disease and allergic sensitization. We also compared fecal sIgA levels between breastfed and formula fed infants and between infants with allergic and nonallergic mothers. RESULTS: The sIgA concentrations were significantly higher in colostrum from allergic mothers than from nonallergic mothers (P = .01) and from allergic mothers who were immunoglobulin E (IgE) sensitized compared to nonallergic mothers who were not IgE sensitized (P = .023). Breastfed infants had significantly higher fecal sIgA levels as compared to formula-fed infants, regardless of whether their lactating mothers had an allergy (P < .05). CONCLUSION: We found that breastfeeding is associated with increased infants' fecal sIgA levels and may have potential protective effects to the infants during the first 4 months of life, regardless of whether their lactating mothers have allergies. PMID- 26243756 TI - Implementation of a Donor Milk Program Is Associated with Greater Consumption of Mothers' Own Milk among VLBW Infants in a US, Level 3 NICU. AB - BACKGROUND: It is unclear whether use of donor milk (DM) changes the provision of mothers' own milk (MOM) to very low birth weight (VLBW) infants in the neonatal intensive care unit (NICU). OBJECTIVES: To determine whether (1) the rates of any MOM and human milk consumption at feeding initiation and discharge and (2) the proportion of VLBW infants who stopped consuming any MOM and human milk during hospitalization changed in the 2 years after versus before implementation of a DM program in a US, inner-city, level 3 NICU. METHODS: We studied VLBW infants admitted to Boston Medical Center in the 2 years before (n = 74) and after (n = 80) implementation of a DM program (June 2011). We used multivariable logistic regression to compare milk consumption at feeding initiation and discharge and Cox proportional hazards to compare the proportion of infants that stopped consuming milk during the hospitalization pre and post our DM program. RESULTS: After adjustment for maternal race, age, insurance, delivery type, gestational age, and birth weight, we found a 6.0-fold increased odds (95% CI, 2.0-17.7) of consuming MOM at discharge and a 49% reduction in the cessation of MOM consumption during hospitalization (hazard ratio [HR], 0.51; 95% CI, 0.28-0.93) in the 2 years after versus before our DM program. CONCLUSION: Implementation of a DM program was associated with greater consumption of MOM throughout hospitalization and at discharge among VLBW infants. Implementation of DM programs may augment support of mothers to provide breast milk in level 3 NICUs. PMID- 26243757 TI - Serum levels of pentraxin-3 and other inflammatory biomarkers in migraine: Association with migraine characteristics. AB - BACKGROUND: Several studies have been conducted on the inflammatory aspects of migraine. Pentraxins are a novel and important part of innate immunity as a superfamily of acute phase proteins. In our study, we aimed to demonstrate the relationship between migraine and the serum levels of pentraxin-3 (PTX-3), C reactive protein (CRP), fibrinogen and D-dimer. METHODS: We recruited 30 migraine patients (in both the attack and interictal period) and 30 healthy controls. Serum samples were obtained from all participants, and a brain MRI performed in the last six months was assessed regarding the presence of deep white matter lesions. Comparisons between the attack, interictal and control groups regarding the serum levels of PTX-3, CRP, fibrinogen and D-dimer were performed. The association between serum PTX-3 levels and migraine characteristics (disease duration, headache frequency, MRI findings, aura, family history, attack duration, and MIDAS score) was also assessed. RESULTS: We found higher serum levels of fibrinogen and PTX-3 in migraine attack patients compared with the interictal and control groups (p = 0.03 and p < 0.001, respectively). Subgroup analysis also showed that patients with a disease duration of more than five years and with an attack duration of more than 12 hours have lower serum levels of PTX-3 than patients who have a relatively new diagnosis and have relatively short-lasting migraine attacks (p = 0.042 and p = 0.038, respectively). CONCLUSIONS: PTX-3 and fibrinogen exhibit different serum levels in patients undergoing a migraine attack compared with the interictal group and the controls. Participants with longer attacks and disease durations have lower serum levels of PTX-3, suggesting that inflammatory processes change along with disease progression. PMID- 26243758 TI - Epidemiological and clinical features of migraine in the pediatric population of Northern Italy. AB - AIM: The aim of this article is to analyze the epidemiological and clinical features of migraine in a pediatric headache center. METHODS: A retrospective study was performed over six years. Hospital record databases were screened for the diagnosis of migraine with aura (MA) or without aura (MO), based on the ICHD II criteria. STATISTICAL ANALYSIS: Fisher's test or Mann-Whitney U test, significance at p < 0.05. RESULTS: Migraine was diagnosed in 495 children (29.7% MA, 70.3% MO). The majority of diagnoses were made between ages 9 and 14 years. After stratification for age into five groups, we observed an increase of diagnoses in females, with a peak after the age of 15 years, and an increase of MA. In both groups, the attacks were usually severe, infrequent (<1-3/month) lasting <2 hours, and associated with nausea/vomiting, photophobia, phonophobia (more frequent in MO). Osmophobia was reported in 24.7% of the patients with MO. Dizziness was more frequent in patients with MA. Visual auras were the most common occurrence (87.1%). Confusional state was observed in 10.88% of the patients. A positive family history of headache was observed in >88% of the patients. CONCLUSION: We describe the characteristics of pediatric migraine based on the ICHD-II criteria, showing a likely significant loss of diagnoses using the ICHD-III beta. The incidence of migraine increases with age. MO occurs more commonly and shows more frequent attacks and a higher prevalence of associated symptoms, in particular osmophobia. Although males are prevalent in the entire sample, the proportion of females is higher among patients with MA in all of the age groups. Phenotype and sexual prevalence of migraine acquire adult characteristics and become more frequent in females from the onset of puberty. PMID- 26243759 TI - Are DSM and logic not on good terms? AB - We would like to draw attention to the fact that the recently published DSM-5 (and also its predecessor, DSM-IV) contains annoying errors that are mainly logical in nature. These mistakes are undoubtedly a result of inadvertence, rather than either conceptual (professional) disagreements between authors/editors or shortage of scientific data for appropriate circumscription of diagnostic categories. The good news is that since these errors are mainly logical ones, they can be recognised and repaired. PMID- 26243760 TI - Duration of psychotherapy has little association with outcome. AB - Does more psychotherapy deliver better outcomes? The answer to this question has important implications for patients' lives and costs to society. This issue of the BJPsych contains an analysis of data from a large clinical cohort receiving courses of talking therapy of up to 40 sessions in length. Duration of therapy was inversely correlated with outcome. Should we be surprised? PMID- 26243763 TI - Romantic suicide - in 100 words. PMID- 26243766 TI - Did you add the same study twice in the meta-analysis? PMID- 26243761 TI - Interventions to improve therapeutic communications between Black and minority ethnic patients and professionals in psychiatric services: systematic review. AB - BACKGROUND: Communication may be an influential determinant of inequality of access to, engagement with and benefit from psychiatric services. AIMS: To review the evidence on interventions designed to improve therapeutic communications between Black and minority ethnic patients and clinicians who provide care in psychiatric services. METHOD: Systematic review and evidence synthesis (PROSPERO registration: CRD42011001661). Data sources included the published and the 'grey' literature. A survey of experts and a consultation with patients and carers all contributed to the evidence synthesis, interpretation and recommendations. RESULTS: Twenty-one studies were included in our analysis. The trials showed benefits mainly for depressive symptoms, experiences of care, knowledge, stigma, adherence to prescribed medication, insight and alliance. The effect sizes were smaller for better-quality trials (range of d 0.18-0.75) than for moderate- or lower-quality studies (range of d 0.18-4.3). The review found only two studies offering weak economic evidence. CONCLUSIONS: Culturally adapted psychotherapies, and ethnographic and motivational assessment leading to psychotherapies were effective and favoured by patients and carers. Further trials are needed from outside of the UK and USA, as are economic evaluations and studies of routine psychiatric care practices. PMID- 26243762 TI - Systematic synthesis of barriers and facilitators to service user-led care planning. AB - BACKGROUND: Service user (patient) involvement in care planning is a principle enshrined by mental health policy yet often attracts criticism from patients and carers in practice. AIMS: To examine how user-involved care planning is operationalised within mental health services and to establish where, how and why challenges to service user involvement occur. METHOD: Systematic evidence synthesis. RESULTS: Synthesis of data from 117 studies suggests that service user involvement fails because the patients' frame of reference diverges from that of providers. Service users and carers attributed highest value to the relational aspects of care planning. Health professionals inconsistently acknowledged the quality of the care planning process, tending instead to define service user involvement in terms of quantifiable service-led outcomes. CONCLUSIONS: Service user-involved care planning is typically operationalised as a series of practice based activities compliant with auditor standards. Meaningful involvement demands new patient-centred definitions of care planning quality. New organisational initiatives should validate time spent with service users and display more tangible and flexible commitments to meeting their needs. PMID- 26243767 TI - Authors' reply. PMID- 26243768 TI - Schizophrenia and mixed-handedness. PMID- 26243769 TI - Kaleidoscope. PMID- 26243772 TI - Innovative methods and techniques for frontiers of life science. PMID- 26243773 TI - Time Delay of CGM Sensors: Relevance, Causes, and Countermeasures. AB - BACKGROUND: Continuous glucose monitoring (CGM) is a powerful tool to support the optimization of glucose control of patients with diabetes. However, CGM systems measure glucose in interstitial fluid but not in blood. Rapid changes in one compartment are not accompanied by similar changes in the other, but follow with some delay. Such time delays hamper detection of, for example, hypoglycemic events. Our aim is to discuss the causes and extent of time delays and approaches to compensate for these. METHODS: CGM data were obtained in a clinical study with 37 patients with a prototype glucose sensor. The study was divided into 5 phases over 2 years. In all, 8 patients participated in 2 phases separated by 8 months. A total number of 108 CGM data sets including raw signals were used for data analysis and were processed by statistical methods to obtain estimates of the time delay. RESULTS: Overall mean (SD) time delay of the raw signals with respect to blood glucose was 9.5 (3.7) min, median was 9 min (interquartile range 4 min). Analysis of time delays observed in the same patients separated by 8 months suggests a patient dependent delay. No significant correlation was observed between delay and anamnestic or anthropometric data. The use of a prediction algorithm reduced the delay by 4 minutes on average. CONCLUSIONS: Prediction algorithms should be used to provide real-time CGM readings more consistent with simultaneous measurements by SMBG. Patient specificity may play an important role in improving prediction quality. PMID- 26243774 TI - The interaction of omega2 with the RNA polymerase beta' subunit functions as an activation to repression switch. AB - The omega gene is encoded in broad-host range and low-copy plasmids. It is genetically linked to antibiotic resistance genes of the major human pathogens of phylum Firmicutes. The homodimeric forms of omega (omega2) coordinate the plasmid copy number control, faithful partition (omega2 and delta2) and better-than random segregation (zetaepsilon2zeta) systems. The promoter (P) of the omegaepsilonzeta operon (Pomega) transiently interacts with omega2. Adding delta2 facilitates the formation of stable omega2.Pomega complexes. Here we show that limiting omega2 interacts with the N-terminal domain of the beta' subunit of the Bacillus subtilis RNA polymerase (RNAP-sigma(A)) vegetative holoenzyme. In this way omega2 recruits RNAP-sigma(A) onto Pomega DNA. Partial Pomega occupancy by omega2 increases the rate at which RNAP-sigma(A) complex shifts from its closed (RPC) to open (RPO) form. This shift increases transcription activation. Adding delta2 further increases the rate of Pomega transcription initiation, perhaps by stabilizing the omega2.Pomega complex. In contrast, full operator occupancy by omega2 facilitates RPC formation, but it blocks RPO isomerization and represses Pomega utilization. The stimulation and inhibition of RPO formation is the mechanism whereby omega2 mediates copy number fluctuation and stable plasmid segregation. By this mechanism, omega2 also indirectly influences the acquisition of antibiotic resistance genes. PMID- 26243775 TI - Mechanism of CRISPR-RNA guided recognition of DNA targets in Escherichia coli. AB - In bacteria and archaea, short fragments of foreign DNA are integrated into Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) loci, providing a molecular memory of previous encounters with foreign genetic elements. In Escherichia coli, short CRISPR-derived RNAs are incorporated into a multi-subunit surveillance complex called Cascade (CRISPR-associated complex for antiviral defense). Recent structures of Cascade capture snapshots of this seahorse-shaped RNA-guided surveillance complex before and after binding to a DNA target. Here we determine a 3.2 A x-ray crystal structure of Cascade in a new crystal form that provides insight into the mechanism of double-stranded DNA binding. Molecular dynamic simulations performed using available structures reveal functional roles for residues in the tail, backbone and belly subunits of Cascade that are critical for binding double-stranded DNA. Structural comparisons are used to make functional predictions and these predictions are tested in vivo and in vitro. Collectively, the results in this study reveal underlying mechanisms involved in target-induced conformational changes and highlight residues important in DNA binding and protospacer adjacent motif recognition. PMID- 26243776 TI - Origin-of-transfer sequences facilitate mobilisation of non-conjugative antimicrobial-resistance plasmids in Staphylococcus aureus. AB - Staphylococcus aureus is a common cause of hospital, community and livestock associated infections and is increasingly resistant to multiple antimicrobials. A significant proportion of antimicrobial-resistance genes are plasmid-borne, but only a minority of S. aureus plasmids encode proteins required for conjugative transfer or Mob relaxase proteins required for mobilisation. The pWBG749 family of S. aureus conjugative plasmids can facilitate the horizontal transfer of diverse antimicrobial-resistance plasmids that lack Mob genes. Here we reveal that these mobilisable plasmids carry copies of the pWBG749 origin-of-transfer (oriT) sequence and that these oriT sequences facilitate mobilisation by pWBG749. Sequences resembling the pWBG749 oriT were identified on half of all sequenced S. aureus plasmids, including the most prevalent large antimicrobial resistance/virulence-gene plasmids, pIB485, pMW2 and pUSA300HOUMR. oriT sequences formed five subfamilies with distinct inverted-repeat-2 (IR2) sequences. pWBG749 family plasmids encoding each IR2 were identified and pWBG749 mobilisation was found to be specific for plasmids carrying matching IR2 sequences. Specificity of mobilisation was conferred by a putative ribbon-helix-helix-protein gene smpO. Several plasmids carried 2-3 oriT variants and pWBG749-mediated recombination occurred between distinct oriT sites during mobilisation. These observations suggest this relaxase-in trans mechanism of mobilisation by pWBG749-family plasmids is a common mechanism of plasmid dissemination in S. aureus. PMID- 26243777 TI - A novel mechanism for NETosis provides antimicrobial defense at the oral mucosa. AB - Neutrophils are essential for host defense at the oral mucosa and neutropenia or functional neutrophil defects lead to disordered oral homeostasis. We found that neutrophils from the oral mucosa harvested from morning saliva had released neutrophil extracellular traps (undergone NETosis) in vivo. The NETosis was mediated through intracellular signals elicited by binding of sialyl Lewis(X) present on salival mucins to l-selectin on neutrophils. This led to rapid loss of nuclear membrane and intracellular release of granule proteins with subsequent neutrophil extracellular trap (NET) release independent of elastase and reduced NAD phosphate-oxidase activation. The saliva-induced NETs were more DNase resistant and had higher capacity to bind and kill bacteria than NETs induced by bacteria or by phorbol-myristate acetate. Furthermore, saliva/sialyl Lewis(X) mediated signaling enhanced intracellular killing of bacteria by neutrophils. Saliva from patients with aphthous ulcers and Behcet disease prone to oral ulcers failed to induce NETosis, but for different reasons it demonstrated that disordered homeostasis in the oral cavity may result in deficient saliva-mediated NETosis. PMID- 26243778 TI - Clinical and prognostic significance of 3q26.2 and other chromosome 3 abnormalities in CML in the era of tyrosine kinase inhibitors. AB - Chromosome 3q26.2 abnormalities in acute myeloid leukemia, including inv(3)/t(3;3) and t(3;21), have been studied and are associated with a poor prognosis. Their prevalence, response to tyrosine kinase inhibitor (TKI) treatment, and prognostic significance in chronic myelogenous leukemia (CML) are largely unknown. In this study, we explored these aspects using a cohort of 2013 patients with CML diagnosed in the era of TKI therapy. Chromosome 3 abnormalities were observed in 116 (5.8%) of 2013 cases. These cases were divided into 5 distinct groups: A, inv(3)(q21q26.2)/t(3;3)(q21;q26.2), 26%; B, t(3;21)(q26.2;q22), 17%; C, other 3q26.2 rearrangements, 7%; D, rearrangements involving chromosome 3 other than 3q26.2 locus, 32%; and E, gain or loss of partial or whole chromosome 3, 18%. In all, 3q26.2 rearrangements were the most common chromosome 3 abnormalities (50%, groups A-C). 3q26.2 rearrangements emerged at different leukemic phases. For cases with 3q26.2 rearrangements that initially emerged in chronic or accelerated phase, they had a high rate of transformation to blast phase. Patients with 3q26.2 abnormalities showed a marginal response to TKI treatment, and no patients achieved a long-term sustainable response at a cytogenetic or molecular level. Compared with other chromosomal abnormalities in CML, patients with 3q26.2 rearrangements had poorer overall survival. The presence or absence of other concurrent chromosomal abnormalities did not affect survival in these patients, reflecting the predominant role of 3q26.2 rearrangements in determining prognosis. Interestingly, although heterogeneous, chromosome 3 abnormalities involving non 3q26.2 loci (groups D, E) also conferred a worse prognosis compared with changes involving other chromosomes in this cohort. PMID- 26243782 TI - Trends in haemoglobin, erythropoietin-stimulating agents and iron use in Swedish chronic kidney disease patients between 2008 and 2013. AB - BACKGROUND: The guidelines for anaemia management in chronic kidney disease (CKD) patients have changed substantially during the past 10 years. We here evaluate whether these changes are followed by subsequent modifications in physicians' anaemia management in Sweden. METHODS: We included patients incident to the Swedish Renal Registry for CKD non-dialysis (CKD-ND, referred patients with an estimated glomerular filtration rate <45 mL/min/1.73 m(2)) and haemodialysis (HD) between 2008 and 2013. Time trends in anaemia management were investigated in relation to prescribed medication, laboratory measures and other relevant clinical characteristics. Linear and binominal regression models were used to describe trends across three predefined time periods (2008-09, 2010-11 and 2012 13). RESULTS: Erythropoiesis-stimulating agents (ESAs) use decreased over time among both CKD-ND and HD patients [risk ratio (RR) 2012-13 compared with 2008-09 for CKD-ND 0.88, 95% confidence interval (CI) 0.81-0.96; RR for HD 0.95, 95% CI 0.93-0.97]. Mean ESA dose decreased significantly among HD patients (7% in 2010 11 compared with 2008-09 and another 3% during 2012-13). Over the time periods studied, ESA doses increased slightly in the CKD-ND population. Mean haemoglobin (Hb) levels decreased in CKD-ND patients, among both ESA users and non-users, whereas it decreased to a lesser degree, albeit significantly, among HD ESA users. The risk of having an Hb >120 g/L decreased, especially between 2008-09 and 2010-11. Iron use increased over time, mainly in the HD population, but also among CKD-ND ESA non-users. CONCLUSIONS: Changes in guidelines have influenced the clinical anaemia practice of Swedish nephrology care, resulting in lower ESA use and lower Hb levels. PMID- 26243783 TI - Novel Poxvirus Infection in an Immune Suppressed Patient. AB - BACKGROUND: Human and animal poxvirus infections are being reported with increasing frequency. We describe a challenging case history and treatment of a previously unknown poxvirus rash illness in a renal transplant patient. METHODS: A combination of classical microbiology techniques, including viral culture and electron microscopy, were used to provide initial clinical diagnosis. Subsequent standard polymerase chain reaction assays available in 2001 were noncontributory. Next generation sequencing was used to provide definitive diagnosis. RESULTS: Retrospectively, next generation sequencing methods were used to ultimately provide the definitive diagnosis of a novel poxvirus infection initially identified by electron microscopy. The closest relative of this poxvirus, identified in North America, is a poxvirus collected from a mosquito pool from Central Africa in 1972. CONCLUSIONS: This diagnostic quandary was ultimately solved using next generation DNA sequencing. This article describes the use of classical and next generation diagnostic strategies to identify etiologic agents of emerging infectious diseases and once again demonstrates the susceptibility of immunossupressed patients to novel pathogens. The virus identified is closely related to Yoka virus; these viruses appear to have independently diverged from a common ancestor of all known orthopoxviruses. PMID- 26243784 TI - Rise in US autism cases is mostly due to changes in diagnosis, study claims. PMID- 26243785 TI - Allergic Inflammation Is Associated With Coronary Instability and a Worse Clinical Outcome After Acute Myocardial Infarction. AB - BACKGROUND: The role of allergic inflammation in acute coronary syndromes (ACS) has not been clearly defined to date. Aim of this study was to assess eosinophil and basophil activation in ACS and the prognostic role of eosinophil cationic protein in ST-segment-elevation myocardial infarction. METHODS AND RESULTS: In a cross-sectional study, we prospectively enrolled 51 patients undergoing percutaneous coronary intervention (60.8% patients with ACS and 39.2% with stable angina). Flow cytometry analysis assessed CD66b, CD69, and CD203c median fluorescence intensity expression. In a follow-up study, 181 patients presenting with ST-segment-elevation myocardial infarction, undergoing primary percutaneous coronary intervention, were prospectively enrolled with a follow-up of 24 months. Eosinophil activation (CD66b) was similar in patients with ACS and stable angina (6.61 [4.91-7.72] versus 6.62 [5.27-8.73], P=0.63), whereas eosinophil degranulation (CD69) and basophil activation (CD203c) were higher in ACS patients compared with stable angina patients (1.38 [1.16-1.52] versus 1.17 [1-1.31], P=0.01); 0.97 [0.89-1.11] versus 0.92 [0.87-0.95], P=0.03, respectively). Eosinophil cationic protein serum levels were significantly higher in ST-segment elevation myocardial infarction patients with major adverse cardiac events as compared with those without (21.1 [10.37-25.65] versus 7.83 [3.37-12.8] MUg/L, P=0.01) and in patients with thrombus score >3 compared with those with thrombus score <=3 (15.0 [9.8-24.7] versus 5.2 [3.5-22.9] MUg/L, P=0.006). Eosinophil cationic protein serum levels predicted major adverse cardiac events during follow-up (odds ratio =1.041, 95% confidence interval 1.012-1.071, P=0.005). C reactive protein serum levels showed a borderline statistical significance (odds ratio =0.904, 95% confidence interval 0.806-1.014, P=0.085). CONCLUSIONS: These findings are the first demonstration of in vivo eosinophil degranulation and basophil activation during ACS and of the prognostic role of eosinophil cationic protein in ST-segment-elevation myocardial infarction. PMID- 26243786 TI - Lack of information on "fit notes" renders them useless, says study. PMID- 26243787 TI - Colchicine for postoperative pericardial effusions: not the magic bullet for all kind of pericardial diseases! PMID- 26243788 TI - Left ventricular hypertrophy after hypertensive pregnancy disorders. AB - OBJECTIVE: Cardiac changes of hypertensive pregnancy include left ventricular hypertrophy (LVH) and diastolic dysfunction. These are thought to regress postpartum. We hypothesised that women with a history of hypertensive pregnancy would have altered LV geometry and function when compared with women with only normotensive pregnancies. METHODS: In this cohort study, we analysed echocardiograms of 2637 women who participated in the Family Blood Pressure Program. We compared LV mass and function in women with hypertensive pregnancies with those with normotensive pregnancies. RESULTS: Women were evaluated at a mean age of 56 years: 427 (16%) had at least one hypertensive pregnancy; 2210 (84%) had normotensive pregnancies. Compared with women with normotensive pregnancies, women with hypertensive pregnancy had a greater risk of LVH (OR: 1.42; 95% CI 1.01 to 1.99, p=0.05), after adjusting for age, race, research network of the Family Blood Pressure Program, education, parity, BMI, hypertension and diabetes. When duration of hypertension was taken into account, this relationship was no longer significant (OR: 1.19; CI 0.08 to 1.78, p=0.38). Women with hypertensive pregnancies also had greater left atrial size and lower mitral E/A ratio after adjusting for demographic variables. The prevalence of systolic dysfunction was similar between the groups. CONCLUSIONS: A history of hypertensive pregnancy is associated with LVH after adjusting for risk factors; this might be explained by longer duration of hypertension. This finding supports current guidelines recommending surveillance of women following a hypertensive pregnancy, and sets the stage for longitudinal echocardiographic studies to further elucidate progression of LV geometry and function after pregnancy. CLINICAL TRIAL REGISTRATIONS: GENOA- NCT00005269; HyperGEN- NCT00005267; Sapphire- NCT00005270; GenNet- NCT00005268. PMID- 26243789 TI - Acute kidney injury in patients with acute coronary syndromes. AB - Acute kidney injury (AKI) is increasingly being seen in patients with acute coronary syndromes (ACSs). This condition has a complex pathogenesis, an incidence that can reach 30% and it is associated with higher short-term and long term morbidity and mortality. Nevertheless, AKI is still characterised by lack of a single accepted definition, unclear pathophysiology understanding and insensitive diagnostic tools that make its detection difficult, particularly in the setting of ACS. Recent data suggested that patients with AKI during ACS, even those in whom renal function seems to fully recover, face an increased, persisting risk of future AKI and may develop chronic kidney disease. Thus, in these patients, nephrology follow-up, after hospital discharge, and secondary preventive measures should possibly be implemented. In this review, we aim at providing a framework of knowledge to increase cardiologists' awareness of AKI, with the goal of improving the outcome of patients with ACS. PMID- 26243790 TI - Clinical benefit from resection of recurrent glioblastomas: results of a multicenter study including 503 patients with recurrent glioblastomas undergoing surgical resection. AB - BACKGROUND: While standards for the treatment of newly diagnosed glioblastomas exist, therapeutic regimens for tumor recurrence remain mostly individualized. The role of a surgical resection of recurrent glioblastomas remains largely unclear at present. This study aimed to assess the effect of repeated resection of recurrent glioblastomas on patient survival. METHODS: In a multicenter retrospective-design study, patients with primary glioblastomas undergoing repeat resections for recurrent tumors were evaluated for factors affecting survival. Age, Karnofsky performance status (KPS), extent of resection (EOR), tumor location, and complications were assessed. RESULTS: Five hundred and three patients (initially diagnosed between 2006 and 2010) undergoing resections for recurrent glioblastoma at 20 institutions were included in the study. The patients' median overall survival after initial diagnosis was 25.0 months and 11.9 months after first re-resection. The following parameters were found to influence survival significantly after first re-resection: preoperative and postoperative KPS, EOR of first re-resection, and chemotherapy after first re resection. The rate of permanent new deficits after first re-resection was 8%. CONCLUSION: The present study supports the view that surgical resections of recurrent glioblastomas may help to prolong patient survival at an acceptable complication rate. PMID- 26243793 TI - Healthcare for Syrian refugees. PMID- 26243791 TI - Performance of 18F-FET versus 18F-FDG-PET for the diagnosis and grading of brain tumors: systematic review and meta-analysis. AB - BACKGROUND: For the past decade (18)F-fluoro-ethyl-l-tyrosine (FET) and (18)F fluoro-deoxy-glucose (FDG) positron emission tomography (PET) have been used for the assessment of patients with brain tumor. However, direct comparison studies reported only limited numbers of patients. Our purpose was to compare the diagnostic performance of FET and FDG-PET. METHODS: We examined studies published between January 1995 and January 2015 in the PubMed database. To be included the study should: (i) use FET and FDG-PET for the assessment of patients with isolated brain lesion and (ii) use histology as the gold standard. Analysis was performed on a per patient basis. Study quality was assessed with STARD and QUADAS criteria. RESULTS: Five studies (119 patients) were included. For the diagnosis of brain tumor, FET-PET demonstrated a pooled sensitivity of 0.94 (95% CI: 0.79-0.98) and pooled specificity of 0.88 (95% CI: 0.37-0.99), with an area under the curve of 0.96 (95% CI: 0.94-0.97), a positive likelihood ratio (LR+) of 8.1 (95% CI: 0.8-80.6), and a negative likelihood ratio (LR-) of 0.07 (95% CI: 0.02-0.30), while FDG-PET demonstrated a sensitivity of 0.38 (95% CI: 0.27-0.50) and specificity of 0.86 (95% CI: 0.31-0.99), with an area under the curve of 0.40 (95% CI: 0.36-0.44), an LR+ of 2.7 (95% CI: 0.3-27.8), and an LR- of 0.72 (95% CI: 0.47-1.11). Target-to-background ratios of either FDG or FET, however, allow distinction between low- and high-grade gliomas (P > .11). CONCLUSIONS: For brain tumor diagnosis, FET-PET performed much better than FDG and should be preferred when assessing a new isolated brain tumor. For glioma grading, however, both tracers showed similar performances. PMID- 26243792 TI - Differentiation of high-grade and low-grade diffuse gliomas by intravoxel incoherent motion MR imaging. AB - BACKGROUND: Our aim was to assess the diagnostic performance of intravoxel incoherent motion (IVIM) MR imaging for differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs). METHODS: Forty-five patients with diffuse glioma (age 50.9 +/- 20.4 y; 26 males, 19 females) were assessed with IVIM imaging using 13 b-values (0-1000 s/mm(2)) at 3T. The perfusion fraction (f), true diffusion coefficient (D), and pseudo-diffusion coefficient (D*) were calculated by fitting the bi-exponential model. The apparent diffusion coefficient (ADC) was obtained with 2 b-values (0 and 1000 s/mm(2)). Relative cerebral blood volume was measured by the dynamic susceptibility contrast method. Two observers independently measured D, ADC, D*, and f, and these measurements were compared between the LGG group (n = 16) and the HGG group (n = 29). RESULTS: Both D (1.26 +/- 0.37 mm(2)/s in LGG, 0.94 +/- 0.19 mm(2)/s in HGG; P < .001) and ADC (1.28 +/- 0.35 mm(2)/s in LGG, 1.03 +/- 0.19 mm(2)/s in HGG; P < .01) were lower in the HGG group. D was lower than ADC in the LGG (P < .05) and HGG groups (P < .0001). D* was not different between the groups. The f-values were significantly larger in HGG (17.5 +/- 6.3%) than in LGG (5.8 +/- 3.8%; P < .0001) and correlated with relative cerebral blood volume (r = 0.85; P < .0001). Receiver operating characteristic analyses showed areas under curve of 0.95 with f, 0.78 with D, 0.73 with ADC, and 0.60 with D*. CONCLUSION: IVIM imaging is useful in differentiating HGGs from LGGs. PMID- 26243794 TI - Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS. AB - Recent advances in techniques for manipulating genomes have allowed the generation of transgenic animals other than mice. These new models enable cross mammalian comparison of neurological disease from core cellular pathophysiology to circuit and behavioural endophenotypes. Moreover they will enable us to directly test whether common cellular dysfunction or behavioural outcomes of a genetic mutation are more conserved across species. Using a new rat model of Fragile X Syndrome, we report that Fmr1 knockout (KO) rats exhibit elevated basal protein synthesis and an increase in mGluR-dependent long-term depression in CA1 of the hippocampus that is independent of new protein synthesis. These defects in plasticity are accompanied by an increase in dendritic spine density selectively in apical dendrites and subtle changes in dendritic spine morphology of CA1 pyramidal neurons. Behaviourally, Fmr1 KO rats show deficits in hippocampal dependent, but not hippocampal-independent, forms of associative recognition memory indicating that the loss of fragile X mental retardation protein (FMRP) causes defects in episodic-like memory. In contrast to previous reports from mice, Fmr1 KO rats show no deficits in spatial reference memory reversal learning. One-trial spatial learning in a delayed matching to place water maze task was also not affected by the loss of FMRP in rats. This is the first evidence for conservation across mammalian species of cellular and physiological hippocampal phenotypes associated with the loss of FMRP. Furthermore, while key cellular phenotypes are conserved they manifest in distinct behavioural dysfunction. Finally, our data reveal novel information about the selective role of FMRP in hippocampus-dependent associative memory. PMID- 26243795 TI - Association Between Use of Statins and Mortality in Patients With Heart Failure and Ejection Fraction of >=50. AB - BACKGROUND: The pathophysiology of heart failure with preserved ejection fraction is poorly understood, but may involve a systemic proinflammatory state. Therefore, statins might improve outcomes in patients with heart failure with preserved ejection fraction defined as >=50%. METHODS AND RESULTS: Of 46 959 unique patients in the prospective Swedish Heart Failure Registry, 9140 patients had heart failure and ejection fraction >=50% (age 77+/-11 years, 54.0% women), and of these, 3427 (37.5%) were treated with statins. Propensity scores for statin treatment were derived from 40 baseline variables. The association between statin use and primary (all-cause mortality) and secondary (separately, cardiovascular mortality, and combined all-cause mortality or cardiovascular hospitalization) end points was assessed with Cox regressions in a population matched 1:1 based on age and propensity score. In the matched population, 1-year survival was 85.1% for statin-treated versus 80.9% for untreated patients (hazard ratio, 0.80; 95% confidence interval, 0.72-0.89; P<0.001). Statins were also associated with reduced cardiovascular death (hazard ratio, 0.86; 95% confidence interval, 0.75-0.98; P=0.026) and composite all-cause mortality or cardiovascular hospitalization (hazard ratio, 0.89; 95% confidence interval, 0.82-0.96; P=0.003). CONCLUSIONS: In heart failure with ejection fraction >=50%, the use of statins was associated with improved outcomes. The mechanisms should be evaluated and the effects tested in a randomized trial. PMID- 26243796 TI - Prognostic Significance of Resting Heart Rate and Use of beta-Blockers in Atrial Fibrillation and Sinus Rhythm in Patients With Heart Failure and Reduced Ejection Fraction: Findings From the Swedish Heart Failure Registry. AB - BACKGROUND: In heart failure and reduced ejection fraction, the prognostic role of heart rate (HR) in atrial fibrillation (AF) is unknown and the effectiveness of beta-blockers has recently been questioned in AF. METHODS AND RESULTS: A total of 18 858 patients with heart failure and reduced ejection fraction registered with Swedish Heart Failure Registry were included in this study: patients with sinus rhythm (SR; n=11 466) and patients with AF (n=7392). The outcome measure was all-cause mortality. Compared with HR <=60 beats per minute, the adjusted hazard ratios for mortality in SR were 1.26 for HR=61 to 70 beats per minute, 1.37 for HR=71 to 80 beats per minute, 1.52 for HR=81 to 90 beats per minute, 1.63 for HR=91 to 100 beats per minute, and 2.69 for HR >100 beats per minute. However, in AF, the hazard ratio increased only for HR >100 beats per minute (1.30; P=0.001). beta-blocker use was associated with reduced mortality in SR (hazard ratio, 0.77; P=0.011) and in AF (hazard ratio, 0.71; P<0.001). For beta blocker use in SR, the hazard ratio gradually increased with HR increment, whereas in AF, the hazard ratio significantly increased only for HR >100 beats per minute (1.29; P=0.003) compared with HR <=60 beats per minute. CONCLUSIONS: In patients with heart failure and reduced ejection fraction, a higher HR was associated with increased mortality in SR, but in AF, this is true only for HR >100 beats per minute. beta-blocker use was associated with reduced mortality both in SR and in AF. PMID- 26243797 TI - Non-Research-Related Physician-Industry Relationships of Radiologists in the United States. AB - PURPOSE: To evaluate non-research-related, physician-industry financial relationships in the United States, in 2013, as reported pursuant to the Physician Payments Sunshine Act (a provision of the Affordable Care Act). METHODS: In September 2014, CMS released the first five months (August 2013 to December 2013) of data disclosing physician-industry financial relationships. The frequency and value of non-research-related transfers in radiology were calculated and compared with those for 19 other specialties. Subanalyses of the frequency and value of such transfers in radiology were performed, based on state of licensure, radiologic subspecialty, nature of payment, manufacturer identity, and drug or device involved. RESULTS: A total of 7.4% (2,654 of 35,768) of radiologists from the United States had reportable non-research-related financial relationship(s) with industry during the 5-month period, the second-lowest level among the medical specialties evaluated. The average value of non-research related transfers of value to radiologists, excluding royalties and licenses, was low ($438.71; SD: $2,912.15; median: $43.85), with <4% of radiologists receiving >$10 per month. Of all categories, that of food and beverage had the most transfers of value (86.0%; 5,655 of 6,577); royalties and licensure were associated with the greatest average value ($27,072.34; SD: $67,524.92). Although high-value relationships were rare, 57.8% (26 of 45) of radiologists who received a value >$1,000 per month held leadership positions in imaging enterprises. CONCLUSIONS: Less than 4% of radiologists have non-research-related financial relationships with industry that are valued at >$10 per month, suggesting that meaningful, deleterious effects of such relationships on radiology practice, if present, are infrequent. PMID- 26243798 TI - Monitor tells NHS providers to "look again" at year's financial plans. PMID- 26243800 TI - Cardiac Hypertrophy Is Inhibited by a Local Pool of cAMP Regulated by Phosphodiesterase 2. AB - RATIONALE: Chronic elevation of 3'-5'-cyclic adenosine monophosphate (cAMP) levels has been associated with cardiac remodeling and cardiac hypertrophy. However, enhancement of particular aspects of cAMP/protein kinase A signaling seems to be beneficial for the failing heart. cAMP is a pleiotropic second messenger with the ability to generate multiple functional outcomes in response to different extracellular stimuli with strict fidelity, a feature that relies on the spatial segregation of the cAMP pathway components in signaling microdomains. OBJECTIVE: How individual cAMP microdomains affect cardiac pathophysiology remains largely to be established. The cAMP-degrading enzymes phosphodiesterases (PDEs) play a key role in shaping local changes in cAMP. Here we investigated the effect of specific inhibition of selected PDEs on cardiac myocyte hypertrophic growth. METHODS AND RESULTS: Using pharmacological and genetic manipulation of PDE activity, we found that the rise in cAMP resulting from inhibition of PDE3 and PDE4 induces hypertrophy, whereas increasing cAMP levels via PDE2 inhibition is antihypertrophic. By real-time imaging of cAMP levels in intact myocytes and selective displacement of protein kinase A isoforms, we demonstrate that the antihypertrophic effect of PDE2 inhibition involves the generation of a local pool of cAMP and activation of a protein kinase A type II subset, leading to phosphorylation of the nuclear factor of activated T cells. CONCLUSIONS: Different cAMP pools have opposing effects on cardiac myocyte cell size. PDE2 emerges as a novel key regulator of cardiac hypertrophy in vitro and in vivo, and its inhibition may have therapeutic applications. PMID- 26243801 TI - Toxicology findings in cases of hanging in the City and County of San Francisco over the 3-year period from 2011 to 2013. AB - In postmortem cases where the cause of death is hanging, toxicological analyses may be considered unnecessary by some medical examiners, toxicologists, and other persons involved in medico-legal investigations because the cause of death seems "obvious." To ascertain if toxicological analyses are necessary when the cause of death is hanging, all 102 hanging cases (25 females; 77 males) from 2011 to 2013 that came under the jurisdiction of the San Francisco Office of the Chief Medical Examiner were examined from a total of 3912 sudden, unexpected, or violent death cases in the same period. Suicide was the manner of death in 99 of these cases, with two accidental and one undetermined death. The average age of decedents was 43.9 years (median 41), the youngest was an 11-year old male and the oldest was an 86-year old female. Of the 102 cases, 33 had negative toxicology while 69 cases had at least one positive toxicology result. Females were equally likely to have negative or positive results (12 and 13 cases respectively), but males were 37.5% more likely to have positive toxicology (n=56) rather than negative toxicology (n=21). For females, alcohol, mirtazapine, venlafaxine, and trazodone were the top psychoactive substances in peripheral blood while THC, cocaine, hydrocodone, bupropion, olanzapine, doxylamine, quetiapine and dextromethorphan were also reported. For males, alcohol, THC, cocaine, amphetamine, methamphetamine, bupropion, and diphenhydramine were the top psychoactive substances in blood, but several other drugs were also found in individual cases. Our study of hanging cases over a 3-year period support the idea that complete postmortem toxicology investigation of hangings should be performed, even when the "obvious" cause of death is asphyxia due to hanging. Many of these cases involved psychoactive substances (most often alcohol and cannabis), and having such knowledge provides a better understanding of the circumstances surrounding the decedent's death, their possible state of impairment, including the possibility of a staged suicide if the decedent was too impaired to perform a self-hanging. PMID- 26243802 TI - Enteric fever in a British soldier from Sierra Leone. AB - Enteric fever (typhoid and paratyphoid) remains a threat to British troops overseas and causes significant morbidity and mortality. We report the case of a soldier who developed typhoid despite appropriate vaccination and field hygiene measures, which began 23 days after returning from a deployment in Sierra Leone. The incubation period was longer than average, symptoms started 2 days after stopping doxycycline for malaria chemoprophylaxis and initial blood cultures were negative. The Salmonella enterica serovar Typhi eventually isolated was resistant to amoxicillin, co-amoxiclav, co-trimoxazole and nalidixic acid and had reduced susceptibility to ciprofloxacin. He was successfully treated with ceftriaxone followed by azithromycin, but 1 month later he remained fatigued and unable to work. The clinical and laboratory features of enteric fever are non-specific and the diagnosis should be considered in troops returning from an endemic area with a febrile illness. Multiple blood cultures and referral to a specialist unit may be required. PMID- 26243803 TI - A century of British military neurosurgery. AB - At the time of the Boer War in 1899 penetrating head injuries, which formed a large proportion of the battlefield casualties, resulted in almost 100% mortality. Since that time up to the present day, significant improvements in technique, equipment and organisation have reduced the mortality to about 10%. PMID- 26243804 TI - Infective endocarditis in the military patient. AB - Infective endocarditis (IE) is a potentially fatal cardiac infection associated with an inhospital mortality rate of up to 22%. Fifty per cent of IE cases develop in patients with no known history of valve disease. It is therefore important to remain vigilant to the possibility of the diagnosis in patients with a febrile illness and unknown source. From a military perspective, our patients are unique due to the breadth of pathogens they are exposed to, and blood-culture negative IE is a risk. In particular, there should be awareness of Coxiella burnetii as a possible causative pathogen. In this review we incorporate the latest consensus from systematic reviews and publications identified by a literature search through Medline. We describe the diagnosis and management of IE with particular reference to the military population. PMID- 26243805 TI - Managing palpitations in the military patient. AB - 'Palpitations' include a broad range of symptoms relating to the perception of abnormal activity of the heart. They may reflect an underlying arrhythmia or a hyperawareness of normal cardiac activity caused by stress or anxiety. The challenge to a clinician assessing patients with palpitations is to assess the likely cause of symptoms, to stratify the individual patient risk and to choose the correct management strategy delivered with appropriate urgency. The young military population, subject to increased exposure to environmental stress, is at an increased risk of palpitations. Due to the distracting nature of this symptom and the frequently sudden and unheralded onset, a common consequence is medical downgrading. This article will provide a guide to assessing the heterogeneous group presenting with palpitations and how to both establish the cause and identify the correct treatment for each patient in a timely manner. PMID- 26243799 TI - Genetics of primary ovarian insufficiency: new developments and opportunities. AB - BACKGROUND: Primary ovarian insufficiency (POI) is characterized by marked heterogeneity, but with a significant genetic contribution. Identifying exact causative genes has been challenging, with many discoveries not replicated. It is timely to take stock of the field, outlining the progress made, framing the controversies and anticipating future directions in elucidating the genetics of POI. METHODS: A search for original articles published up to May 2015 was performed using PubMed and Google Scholar, identifying studies on the genetic etiology of POI. Studies were included if chromosomal analysis, candidate gene screening and a genome-wide study were conducted. Articles identified were restricted to English language full-text papers. RESULTS: Chromosomal abnormalities have long been recognized as a frequent cause of POI, with a currently estimated prevalence of 10-13%. Using the traditional karyotype methodology, monosomy X, mosaicism, X chromosome deletions and rearrangements, X autosome translocations, and isochromosomes have been detected. Based on candidate gene studies, single gene perturbations unequivocally having a deleterious effect in at least one population include Bone morphogenetic protein 15 (BMP15), Progesterone receptor membrane component 1 (PGRMC1), and Fragile X mental retardation 1 (FMR1) premutation on the X chromosome; Growth differentiation factor 9 (GDF9), Folliculogenesis specific bHLH transcription factor (FIGLA), Newborn ovary homeobox gene (NOBOX), Nuclear receptor subfamily 5, group A, member 1 (NR5A1) and Nanos homolog 3 (NANOS3) seem likely as well, but mostly being found in no more than 1-2% of a single population studied. Whole genome approaches have utilized genome-wide association studies (GWAS) to reveal loci not predicted on the basis of a candidate gene, but it remains difficult to locate causative genes and susceptible loci were not always replicated. Cytogenomic methods (array CGH) have identified other regions of interest but studies have not shown consistent results, the resolution of arrays has varied and replication is uncommon. Whole-exome sequencing in non-syndromic POI kindreds has only recently begun, revealing mutations in the Stromal antigen 3 (STAG3), Synaptonemal complex central element 1 (SYCE1), minichromosome maintenance complex component 8 and 9 (MCM8, MCM9) and ATP-dependent DNA helicase homolog (HFM1) genes. Given the slow progress in candidate-gene analysis and relatively small sample sizes available for GWAS, family-based whole exome and whole genome sequencing appear to be the most promising approaches for detecting potential genes responsible for POI. CONCLUSION: Taken together, the cytogenetic, cytogenomic (array CGH) and exome sequencing approaches have revealed a genetic causation in ~20-25% of POI cases. Uncovering the remainder of the causative genes will be facilitated not only by whole genome approaches involving larger cohorts in multiple populations but also incorporating environmental exposures and exploring signaling pathways in intragenic and intergenic regions that point to perturbations in regulatory genes and networks. PMID- 26243806 TI - Thoracic aortopathies in the military patient. AB - Thoracic aortic disease is an important contributor to arterial disease and therefore, mortality in the UK. It has close associations with hypertension, atherosclerosis and genetic conditions such as Marfan syndrome. The cardiovascular consequences of acute aortic dissection or the rupture of a thoracic aneurysm are life threatening with a 1% increase in mortality per hour with a type A aortic dissection and a high 30-day mortality rate. The clinical diagnosis can be difficult for the general physician as the symptoms can mimic more common conditions such as acute coronary syndrome, pulmonary embolism or acute abdomen. The investigations that carry the highest sensitivity and specificity, CT, transoesophageal echocardiography and MRI are not usually first line investigations in most patients so a high index of clinical suspicion is key. The management of acute aortic syndromes involves good initial resuscitation and early discussion with the cardiothoracic surgeons. Given the serious consequences of acute aortic syndromes, it is important for all military doctors to be aware of these presentations and to appreciate the difficulties that can be encountered when trying to accurately diagnose them. Routine medicals, particularly entrance medicals, present a unique clinical opportunity to recognise the clinical features that would warrant further investigation and specialist advice. PMID- 26243807 TI - Maintaining surgical skills for military general surgery: the potential role for multivisceral organ retrieval in military general surgery training and practice. AB - The closure of the Medical Treatment facility in Camp BASTION and the return to contingency operations presents a new challenge in training and maintaining the skills of military surgeons. Multivisceral organ retrieval presents a unique opportunity to practice some of the more unusual techniques required in military surgery in the National Health Service. This article details the experience that organ retrieval offers and matches this to the needs of military surgeons. National Organ Retrieval Service teams need skilled surgeons, and a mutually beneficial partnership is in prospect. PMID- 26243808 TI - The Hearts of Heroes: the epidemiology of cardiac disease in the UK Armed Forces. AB - When the general public look from the outside at the armed services, their impression is often one of earnest young men and women who are the pinnacle of physical fitness and health, and put their lives on the line for their country. There is usually sadness and respect for those killed on active operations, having put themselves in harm's way. Therefore, when the public discover that more than 1 in 10 deaths in the UK Armed Forces are due to cardiovascular disease, the air of sadness is invariably replaced with surprise and disbelief. These figures, while lower than those due to deaths in accidents, are approaching the numbers of those due to suicide in the armed services; yet deaths from cardiac disease are barely recognised by society, in spite of many of them being avoidable. This article reviews the epidemiology of cardiac disease in the UK Armed Forces, both in terms of morbidity and mortality. It outlines current understanding and gaps in the knowledge regarding the burden of cardiovascular disease in the military population. The particular demographics of the Armed Forces and its influence on cardiac disease burden are discussed. The role of inherited and congenital diseases in younger servicemen and women is highlighted, as is the trend that with increasing age, the burden of disease shifts to ischaemic heart disease, which becomes the dominant cause of both death and disability. PMID- 26243809 TI - The influence of menthol, e-cigarettes and other tobacco products on young adults' self-reported changes in past year smoking. AB - OBJECTIVE: Progression to regular smoking often occurs during young adulthood. This study examines self-reported changes in past year smoking among young adults and the potential influence of tobacco products on these trajectories. METHODS: Respondents to the 2011 National Young Adult Health Survey who smoked 100 cigarettes in their lifetime (n=909) described smoking behaviour at the time of the survey and 1 year prior. Cigarette smoking trajectories were categorised as: no change, quit, decreased smoking or increased smoking. Participants were also asked about current use of menthol cigarettes and other tobacco products (ie, cigars, smokeless tobacco, hookah) and ever use of e-cigarettes. RESULTS: Most young adults (73.1%) reported stable cigarette smoking behaviours, while 8.2% reported having quit, 5.8% reported that they smoke on fewer days, 5% progressed from someday to daily smoking and 8% increased from not at all to current smoking. The youngest smokers (18-20) had significantly higher odds (adjusted OR (AOR) =2.6) of increasing cigarette use over the past year compared to those aged 30-34, as did blacks versus whites (AOR=2.35). Menthol cigarette use nearly doubled (AOR=1.87) the odds of increased smoking behaviour. E-cigarette and other tobacco product (OTP) use were not associated with increasing smoking but OTP use was negatively associated with remaining quit from cigarettes. CONCLUSIONS: Young adulthood is a critical period for smoking interventions, particularly among those most vulnerable to increasing smoking behaviours (ie, black and younger young adults). Policy efforts to restrict menthol cigarettes may reduce young adult smoking progression. PMID- 26243810 TI - "Gone are the days of mass-media marketing plans and short term customer relationships": tobacco industry direct mail and database marketing strategies. AB - BACKGROUND: As limitations on traditional marketing tactics and scrutiny by tobacco control have increased, the tobacco industry has benefited from direct mail marketing which transmits marketing messages directly to carefully targeted consumers utilising extensive custom consumer databases. However, research in these areas has been limited. This is the first study to examine the development, purposes and extent of direct mail and customer databases. METHODS: We examined direct mail and database marketing by RJ Reynolds and Philip Morris utilising internal tobacco industry documents from the Legacy Tobacco Document Library employing standard document research techniques. RESULTS: Direct mail marketing utilising industry databases began in the 1970s and grew from the need for a promotional strategy to deal with declining smoking rates, growing numbers of products and a cluttered media landscape. Both RJ Reynolds and Philip Morris started with existing commercial consumer mailing lists, but subsequently decided to build their own databases of smokers' names, addresses, brand preferences, purchase patterns, interests and activities. By the mid-1990s both RJ Reynolds and Philip Morris databases contained at least 30 million smokers' names each. These companies valued direct mail/database marketing's flexibility, efficiency and unique ability to deliver specific messages to particular groups as well as direct mail's limited visibility to tobacco control, public health and regulators. CONCLUSIONS: Database marketing is an important and increasingly sophisticated tobacco marketing strategy. Additional research is needed on the prevalence of receipt and exposure to direct mail items and their influence on receivers' perceptions and smoking behaviours. PMID- 26243811 TI - State-ownership of tobacco industry: a 'fundamental conflict of interest' or a 'tremendous opportunity' for tobacco control? AB - Despite state-owned tobacco companies (SOTCs) accounting for over 40% of global production, the significance of state-ownership for tobacco control strategies has received limited academic and policy attention. The complex interests associated with SOTCs present diverse challenges for tobacco control policy, particularly in implementing Article 5.3 of WHO's Framework Convention on Tobacco Control (FCTC). Based on a review of existing literature, this paper examines current challenges and potential opportunities presented by governmental participation in the tobacco industry, identifying three contrasting perspectives from academic and policy sources. The first two perspectives centre on recognising that economic interests inherent in an SOTC are in tension with a government's public health responsibilities. This conflict can be perceived as either fundamental and fixed ('intrinsic conflict') or as amenable to either exacerbation or amelioration via organisational mechanisms ('institutionally mediated conflict')-as suggested by the contrasting examples of China and Thailand. A third, less prominent perspective (which we refer to as 'interest alignment') suggests that it may be possible to radically alter the objectives and behaviour of SOTCs in order to advance tobacco control. Finally, we draw on this analysis to consider policy options for advancing tobacco control in countries with SOTCs. Guidance on implementation of Article 5.3 demonstrates strategic ambiguity by including elements of all three perspectives described above. We argue that legislative separation of tobacco control from SOTC oversight provides a desirable alternative to industry privatisation, and that radically realigning the goals of SOTCs to reduce tobacco consumption could make an important contribution to endgame strategies. PMID- 26243813 TI - LSD: a new treatment emerging from the past. PMID- 26243814 TI - Private cannabis clinics offer clients access. PMID- 26243812 TI - Attenuation of Nitrogen Mustard-Induced Pulmonary Injury and Fibrosis by Anti Tumor Necrosis Factor-alpha Antibody. AB - Nitrogen mustard (NM) is a bifunctional alkylating agent that causes acute injury to the lung that progresses to fibrosis. This is accompanied by a prominent infiltration of macrophages into the lung and upregulation of proinflammatory/profibrotic cytokines including tumor necrosis factor (TNF)alpha. In these studies, we analyzed the ability of anti-TNFalpha antibody to mitigate NM-induced lung injury, inflammation, and fibrosis. Treatment of rats with anti TNFalpha antibody (15 mg/kg, iv, every 9 days) beginning 30 min after intratracheal administration of NM (0.125 mg/kg) reduced progressive histopathologic alterations in the lung including perivascular and peribronchial edema, macrophage/monocyte infiltration, interstitial thickening, bronchiolization of alveolar walls, fibrin deposition, emphysema, and fibrosis. NM-induced damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage (BAL) protein and cell content, was also reduced by anti-TNFalpha antibody, along with expression of the oxidative stress marker, heme oxygenase-1. Whereas the accumulation of proinflammatory/cytotoxic M1 macrophages in the lung in response to NM was suppressed by anti-TNFalpha antibody, anti inflammatory/profibrotic M2 macrophages were increased or unchanged. Treatment of rats with anti-TNFalpha antibody also reduced NM-induced increases in expression of the profibrotic mediator, transforming growth factor-beta. This was associated with a reduction in NM-induced collagen deposition in the lung. These data suggest that inhibiting TNFalpha may represent an efficacious approach to mitigating lung injury induced by mustards. PMID- 26243815 TI - Misplaced advocacy: What does better hepatitis C treatment really mean? PMID- 26243816 TI - A 65-year-old HIV-positive man with acute diarrhea. PMID- 26243817 TI - Advocacy needed for borderline personality disorder. PMID- 26243818 TI - Podcast: 10 questions with Dr. Peter Piot. PMID- 26243820 TI - Health Canada e-cigarette response delayed. PMID- 26243821 TI - A new online tool to improve physician billing. PMID- 26243819 TI - Diagnosis and management of acute ischemic stroke: speed is critical. PMID- 26243822 TI - Cystoid macular edema associated with chemotherapy. PMID- 26243823 TI - Sunscreens. PMID- 26243824 TI - Guest Editorial. PMID- 26243825 TI - Protein interaction network constructing based on text mining and reinforcement learning with application to prostate cancer. AB - Constructing interaction network from biomedical texts is a very important and interesting work. The authors take advantage of text mining and reinforcement learning approaches to establish protein interaction network. Considering the high computational efficiency of co-occurrence-based interaction extraction approaches and high precision of linguistic patterns approaches, the authors propose an interaction extracting algorithm where they utilise frequently used linguistic patterns to extract the interactions from texts and then find out interactions from extended unprocessed texts under the basic idea of co occurrence approach, meanwhile they discount the interaction extracted from extended texts. They put forward a reinforcement learning-based algorithm to establish a protein interaction network, where nodes represent proteins and edges denote interactions. During the evolutionary process, a node selects another node and the attained reward determines which predicted interaction should be reinforced. The topology of the network is updated by the agent until an optimal network is formed. They used texts downloaded from PubMed to construct a prostate cancer protein interaction network by the proposed methods. The results show that their method brought out pretty good matching rate. Network topology analysis results also demonstrate that the curves of node degree distribution, node degree probability and probability distribution of constructed network accord with those of the scale-free network well. PMID- 26243826 TI - Revisiting topological properties and models of protein-protein interaction networks from the perspective of dataset evolution. AB - Protein-protein interaction (PPI) networks are crucial for organisms. Many research efforts have thus been devoted to the study on the topological properties and models of PPI networks. However, existing studies did not always report consistent results on the topological properties of PPI networks. Although a number of PPI network models have been introduced, yet in the literature there is no convincing conclusion on which model is best for describing PPI networks. This situation is primarily caused by the incompleteness of current PPI datasets. To solve this problem, in this study, the authors propose to revisit the topological properties and models of PPI networks from the perspective of PPI dataset evolution. Concretely, they used 12 PPI datasets of Arabidopsis thaliana and 10 PPI datasets of Saccharomyces cerevisiae from different Biological General Repository for Interaction Datasets (BioGRID) database versions, and compared the topological properties of these datasets and the fitting capabilities of five typical PPI network models over these datasets. PMID- 26243827 TI - Graphics processing unit-based alignment of protein interaction networks. AB - Network alignment is an important bridge to understanding human protein-protein interactions (PPIs) and functions through model organisms. However, the underlying subgraph isomorphism problem complicates and increases the time required to align protein interaction networks (PINs). Parallel computing technology is an effective solution to the challenge of aligning large-scale networks via sequential computing. In this study, the typical Hungarian-Greedy Algorithm (HGA) is used as an example for PIN alignment. The authors propose a HGA with 2-nearest neighbours (HGA-2N) and implement its graphics processing unit (GPU) acceleration. Numerical experiments demonstrate that HGA-2N can find alignments that are close to those found by HGA while dramatically reducing computing time. The GPU implementation of HGA-2N optimises the parallel pattern, computing mode and storage mode and it improves the computing time ratio between the CPU and GPU compared with HGA when large-scale networks are considered. By using HGA-2N in GPUs, conserved PPIs can be observed, and potential PPIs can be predicted. Among the predictions based on 25 common Gene Ontology terms, 42.8% can be found in the Human Protein Reference Database. Furthermore, a new method of reconstructing phylogenetic trees is introduced, which shows the same relationships among five herpes viruses that are obtained using other methods. PMID- 26243828 TI - Identification of cancer-related genes and motifs in the human gene regulatory network. AB - The authors investigated the regulatory network motifs and corresponding motif positions of cancer-related genes. First, they mapped disease-related genes to a transcription factor regulatory network. Next, they calculated statistically significant motifs and subsequently identified positions within these motifs that were enriched in cancer-related genes. Potential mechanisms of these motifs and positions are discussed. These results could be used to identify other disease- and cancer-related genes and could also suggest mechanisms for how these genes relate to co-occurring diseases. PMID- 26243829 TI - Identify asthma genes across three phases based on protein-protein interaction network. AB - Asthma is a common inflammatory disease that is generally caused by genetic mutations or environmental factors. Recently, the emerging of omics data provides an alternative way to understand asthma. In this study, the authors present a new framework to detect asthma disease genes based on protein-protein interaction network (PPIN) and gene expression. Specifically, they construct PPINs for different stages of asthma, and detect those interactions occurred in the specific stages. By investigating the proteins in these stage-specific interactions, they find they are more likely related to asthma, and the functional enrichment analysis indicate that the pathways enriched in the differential interactions are related to the progress of asthma. Moreover, some proteins in the differential interactions have been previously reported to be related to asthma in the literature, implying the usefulness of the proposed approach. PMID- 26243830 TI - Understanding the aristolochic acid toxicities in rat kidneys with regulatory networks. AB - The natural products containing aristolochic acid (AA) have been widely used for acne, gastritis and so on. Recently, it is becoming accepted that AA may be responsible for acute and chronic renal failures as the side effects of Chinese herbs. However, it is unclear what happens in the cells after the AA treatment. In this study, the authors built a gene regulatory network as well as a microRNA gene regulatory network to investigate the molecular dynamics induced by AA from a systematic perspective. With the regulatory networks, they detected some important pathways and biological processes that were affected by AA treatment, which can help explain the nephrotoxicity and carcinogenicity of AA. They found some important regulators and genes responding to AA treatment, and these genes have been reported to be related to the kidney functions, indicating their important roles in the toxicity of AA. PMID- 26243831 TI - Mining gene link information for survival pathway hunting. AB - This study proposes a gene link-based method for survival time-related pathway hunting. In this method, the authors incorporate gene link information to estimate how a pathway is associated with cancer patient's survival time. Specifically, a gene link-based Cox proportional hazard model (Link-Cox) is established, in which two linked genes are considered together to represent a link variable and the association of the link with survival time is assessed using Cox proportional hazard model. On the basis of the Link-Cox model, the authors formulate a new statistic for measuring the association of a pathway with survival time of cancer patients, referred to as pathway survival score (PSS), by summarising survival significance over all the gene links in the pathway, and devise a permutation test to test the significance of an observed PSS. To evaluate the proposed method, the authors applied it to simulation data and two publicly available real-world gene expression data sets. Extensive comparisons with previous methods show the effectiveness and efficiency of the proposed method for survival pathway hunting. PMID- 26243832 TI - Prediction of human disease-associated phosphorylation sites with combined feature selection approach and support vector machine. AB - Phosphorylation is a crucial post-translational modification, which regulates almost all cellular processes in life. It has long been recognised that protein phosphorylation has close relationship with diseases, and therefore many researches are undertaken to predict phosphorylation sites for disease treatment and drug design. However, despite the success achieved by these approaches, no method focuses on disease-associated phosphorylation sites prediction. Herein, for the first time the authors propose a novel approach that is specially designed to identify associations between phosphorylation sites and human diseases. To take full advantage of local sequence information, a combined feature selection method-based support vector machine (CFS-SVM) that incorporates minimum-redundancy-maximum-relevance filtering process and forward feature selection process is developed. Performance evaluation shows that CFS-SVM is significantly better than the widely used classifiers including Bayesian decision theory, k nearest neighbour and random forest. With the extremely high specificity of 99%, CFS-SVM can still achieve a high sensitivity. Besides, tests on extra data confirm the effectiveness and general applicability of CFS-SVM approach on a variety of diseases. Finally, the analysis of selected features and corresponding kinases also help the understanding of the potential mechanism of disease-phosphorylation relationships and guide further experimental validations. PMID- 26243833 TI - Systematic functional genomics resource and annotation for poplar. AB - Poplar, as a model species for forestry research, has many excellent characteristics. Studies on functional genes have provided the foundation, at the molecular level, for improving genetic traits and cultivating elite lines. Although studies on functional genes have been performed for many years, large amounts of experimental data remain scattered across various reports and have not been unified via comprehensive statistical analysis. This problem can be addressed by employing bioinformatic methodology and technology to gather and organise data to construct a Poplar Functional Gene Database, containing data on 207 poplar functional genes. As an example, the authors investigated genes of Populus euphratica involved in the response to salt stress. Four small cDNA libraries were constructed and treated with 300 mM NaCl or pure water for 6 and 24 h. Using high-throughput sequencing, they identified conserved and novel miRNAs that were differentially expressed. Target genes were next predicted and detailed functional information derived using the Gene Ontology database and Kyoto Encyclopedia of Genes and Genomes pathway analysis. This information provides a primary visual schema allowing us to understand the dynamics of the regulatory gene network responding to salt stress in Populus. PMID- 26243834 TI - Positive selection on D-lactate dehydrogenases of Lactobacillus delbrueckii subspecies bulgaricus. AB - Lactobacillus delbrueckii has been widely used for yogurt fermentation. It has genes encoding both D- and L-type lactate dehydrogenases (LDHs) that catalyse the production of L(+) or D(-) stereoisomer of lactic acid. D-lactic acid is the primary lactate product by L. delbrueckii, yet it cannot be metabolised by human intestine. Since it has been domesticated for long time, an interesting question arises regarding to whether the selection pressure has affected the evolution of both L-LDH and D-LDH genes in the genome. To answer this question, in this study the authors first investigated the evolution of these two genes by constructing phylogenetic trees. They found that D-LDH-based phylogenetic tree could better represent the phylogenetic relationship in the acidophilus complex than L-LDH based tree. They next investigated the evolutions of LDH genes of L. delbrueckii at amino acid level, and found that D-LDH gene in L. delbrueckii is positively selected, possibly a consequence of long-term domestication. They further identified four amino acids that are under positive selection. One of them, V261, is located at the centre of three catalytic active sites, indicating likely functional effects on the enzyme activity. The selection from the domestication process thus provides direction for future engineering of D-LDH. PMID- 26243835 TI - Hepatic resection versus transarterial chemoembolization for the initial treatment of hepatocellular carcinoma: A systematic review and meta-analysis. AB - BACKGROUND & AIMS: According to the Barcelona Clinic Liver Cancer (BCLC) staging system, hepatic resection and transarterial chemoembolization (TACE) should be recommended in patients with hepatocellular carcinoma (HCC) within and beyond the BCLC stage A, respectively. We conducted a systematic review and meta-analysis to compare the overall survival between HCC patients undergoing hepatic resection and TACE. METHODS: PubMed, EMBASE, and Cochrane library databases were searched. All relevant studies were considered, if they reported the survival data in HCC patients undergoing hepatic resection and TACE. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for the comparison of cumulative overall survival. Odds ratios (ORs) with 95%CIs were calculated for the comparison of 1-, 3-, and 5-year survival rates. Subgroup analyses were performed according to the BCLC stages and portal vein tumor thrombus (PVTT). Sensitivity analyses were performed in moderate- and high-quality studies and in studies published after 2005. RESULTS: Fifty of 2029 retrieved papers were included. One, 15, and 34 studies were of high-, moderate-, and low-quality, respectively. The overall meta-analysis demonstrated a statistically significantly higher overall survival in hepatic resection group than in TACE group (HR=0.60, 95%CI=0.55 0.66). Additionally, 1-, 3-, and 5-year survival rates were statistically significantly higher in hepatic resection group than in TACE group (OR=1.82, 95%CI=1.56-2.14; OR=3.09, 95%CI=2.60-3.67; OR=3.48, 95%CI=2.83-4.27). The subgroup meta-analyses confirmed the statistical significance in HCC within the BCLC stage A (HR=0.72, 95%CI=0.64-0.80), in HCC beyond the BCLC stage A (HR=0.60, 95%CI=0.51-0.69), in HCC within the BCLC stage B alone (HR=0.48, 95%CI=0.25 0.90), and in HCC with PVTT (HR=0.78, 95%CI=0.68-0.91). The statistical significance was also confirmed by sensitivity analyses in moderate- and high quality studies (HR=0.62, 95%CI=0.53-0.71) and in studies published after 2005 (HR=0.59, 95%CI=0.53-0.66). CONCLUSIONS: Based on a systematic review and meta analysis, hepatic resection may be considered in HCC beyond the BCLC stage A. However, given the limitations of study quality, more well-designed randomized controlled trials should be warranted to confirm these findings. PMID- 26243836 TI - Genetic determinants of FOXM1 overexpression in epithelial ovarian cancer and functional contribution to cell cycle progression. AB - The FOXM1 transcription factor network is frequently activated in high-grade serous ovarian cancer (HGSOC), the most common and lethal subtype of epithelial ovarian cancer (EOC). We used primary human EOC tissues, HGSOC cell lines, mouse and human ovarian surface epithelial (OSE) cells, and a murine transgenic ovarian cancer model to investigate genetic determinants of FOXM1 overexpression in EOC, and to begin to define its functional contribution to disease pathology. The Cancer Genome Atlas (TCGA) data indicated that the FOXM1 locus is amplified in ~12% of HGSOC, greater than any other tumor type examined, and that FOXM1 amplification correlates with increased expression and poor survival. In an independent set of primary EOC tissues, FOXM1 expression correlated with advanced stage and grade. Of the three known FOXM1 isoforms, FOXM1c showed highest expression in EOC. In murine OSE cells, combined knockout of Rb1 and Trp53 synergistically induced FOXM1. Consistently, human OSE cells immortalized with SV40 Large T antigen (IOSE-SV) had significantly higher FOXM1 expression than OSE immortalized with hTERT (IOSE-T). FOXM1 was overexpressed in murine ovarian tumors driven by combined Rb1/Trp53 disruption. FOXM1 induction in IOSE-SV cells was partially dependent on E2F1, and FOXM1 expression correlated with E2F1 expression in human EOC tissues. Finally, FOXM1 functionally contributed to cell cycle progression and relevant target gene expression in human OSE and HGSOC cell models. In summary, gene amplification, p53 and Rb disruption, and E2F1 activation drive FOXM1 expression in EOC, and FOXM1 promotes cell cycle progression in EOC cell models. PMID- 26243837 TI - A Systemic Review and Experts' Consensus for Long-acting Injectable Antipsychotics in Bipolar Disorder. AB - Bipolar disorder (BD) is a major psychiatric disorder that is easily misdiagnosed. Patient adherence to a treatment regimen is of utmost importance for successful outcomes in BD. Several trials of antipsychotics suggested that depot antipsychotics, including long-acting first- and second-generation agents, are effective in preventing non-adherence, partial adherence, and in reducing relapse in BD. Various long-acting injectable (LAI) antipsychotics are available, including fluphenazine decanoate, haloperidol decanoate, olanzapine pamoate, risperidone microspheres, paliperidone palmitate, and aripiprazole monohydrate. Due to the increasing number of BD patients receiving LAI antipsychotics, treatment guidelines have been developed. However, the clinical applicability of LAI antipsychotics remains a global cause for concern, particularly in Asian countries. Expert physicians from Taiwan participated in a consensus meeting, which was held to review key areas based on both current literature and clinical practice. The purpose of this meeting was to generate a practical and implementable set of recommendations for LAI antipsychotic use to treat BD; target patient groups, dosage, administration, and adverse effects were considered. Experts recommended using LAI antipsychotics in patients with schizophrenia, rapid cycling BD, BD I, and bipolar-type schizoaffective disorder. LAI antipsychotic use was recommended in BD patients with the following characteristics: multiple episodes and low adherence; seldom yet serious episodes; low adherence potential per a physician's clinical judgment; preference for injectable agents over oral agents; and multiple oral agent users still experiencing residual symptoms. PMID- 26243839 TI - Holistic Consideration of Patients with Schizophrenia to Improve Medication Adherence and Outcomes. AB - Although several algorithms have been applied to treat patients with schizophrenia, their clinical use remains still limited, because most emphasize the prescription of antipsychotics. A new algorithm with a more holistic approach to treating patients with schizophrenia, to be used before applying traditional prescribing guidelines, was thus proposed by an expert team of Taiwanese psychiatrists. In this algorithm, several important treatment tasks/modalities are proposed, including long-acting injection antipsychotics, shared decision making, a case management system, compulsory treatment by law, community rehabilitation programs, the patients' feeling about their health care professionals (patients' behaviors) and their attitude/knowledge of their conditions/ illness. This study proposes that evaluating the medication adherence of patients can be determined by two key domains, namely patients' behaviors and attitudes. Based on different levels of their behaviors (X-axis) and attitude/knowledge (Y-axis), it is possible to categorize patients with schizophrenia into six subgroups, for which various different interventions, including the use of antipsychotics, could be applied and integrated. Further research is needed to assess the applicability of this treatment algorithm in clinical settings. PMID- 26243840 TI - Efficacy and Tolerability of Generic Mirtazapine (Mirtax) for Major Depressive Disorder: Multicenter, Open-label, Uncontrolled, Prospective Study. AB - OBJECTIVE: Mirtax is a generic mirtazapine widely used since 2003. We conducted an open-label, uncontrolled 6-week study to evaluate the efficacy and safety of Mirtax for major depressive disorder (MDD). METHODS: Ninety three MDD patients with the diagnosis of MDD and 17-item Hamilton Depression Rating Scale (HDRS) score >=14 were recruited. The HDRS, Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions-Severity Scale (CGI-S) were administered at baseline, 1, 2, 4 and 6 weeks. Response (>=50% decrease in the HDRS or MADRS score), remission (absolute HDRS score <=7 or MADRS score <=10) and CGI-I score <=2 were also calculated. Adverse event (AE) frequency and severity, weight, blood pressure, and pulse rate were checked to assess safety. RESULTS: The starting dosage was 11.5+/-6.4 mg/day, and the maintenance dosage was 23.1+/ 9.4 mg/day. During 6 weeks, HDRS, MADRS and CGI-S scores decreased from 25.1+/ 5.6 to 11.9+/-8.6 (mean change -13.1+/-8.3, p<0.001), from 30.2+/-6.3 to 13.73+/ 10.40 (mean change -16.5+/-9.8, p<0.001), and from 5.0+/-0.8 to 2.5+/-1.3 (mean change -2.5+/-1.3, p<0.001), respectively. The percentages of responders, remitters by HDRS and patients with a CGI-I score <=2 were 64.6%, 35.4% and 52.7%, respectively. Significant decreases in HDRS, MADRS and CGI-S scores were confirmed at week 1. The total rate of AEs was 32.3%; the most frequently reported AEs were sedation (4.3%) and constipation (4.3%). Weight was increased from 58.8+/-10.6 to 60.3+/-9.3 kg (mean change 0.7+/-1.7 kg, p=0.004). CONCLUSION: This study, as the first clinical trial of generic mirtazapine, demonstrated the efficacy and tolerability of Mirtax for MDD using a single treatment design. PMID- 26243838 TI - Omega-3 Polyunsaturated Fatty Acids in Prevention of Mood and Anxiety Disorders. AB - Psychiatric disorders in general, and major depression and anxiety disorders in particular, account for a large burden of disability, morbidity and premature mortality worldwide. Omega-3 polyunsaturated fatty acids (PUFAs) have a range of neurobiological activities in modulation of neurotransmitters, anti-inflammation, anti-oxidation and neuroplasticity, which could contribute to psychotropic effects. Here we reviewed recent research on the benefits of omega-3 PUFA supplements in prevention against major depression, bipolar disorders, interferon alpha-induced depression patients with chronic hepatitis C viral infection, and posttraumatic stress disorder. The biological mechanisms underlying omega-3 PUFAs'psychotropic effects are proposed and reviewed. Nutrition is a modifiable environmental factor that might be important in prevention medicine, which have been applied for many years in the secondary prevention of heart disease with omega-3 PUFAs. This review extends the notion that nutrition in psychiatry is a modifiable environmental factor and calls for more researches on prospective clinical studies to justify the preventive application of omega-3 PUFAs in daily practice. PMID- 26243841 TI - Improved Antidepressant Remission in Major Depression via a Pharmacokinetic Pathway Polygene Pharmacogenetic Report. AB - OBJECTIVE: Major depressive disorder (MDD) is projected to be a leading cause of disability globally by 2030. Only a minority of patients remit with antidepressants. If assay of polymorphisms influencing central nervous system (CNS) bioavailability could guide prescribers to more effectively dose patients, remission rates may improve and the burden of disease from MDD reduce. Hepatic and blood brain barrier (BBB) polymorphisms appear to influence antidepressant CNS bioavailability. METHODS: A 12-week prospective double blind randomized genetically guided versus unguided trial of antidepressant dosing in Caucasian adults with MDD (n=148) was conducted. RESULTS: Subjects receiving genetically guided prescribing had a 2.52-fold greater chance of remission (95% confidence interval [CI]=1.71-3.73, z=4.66, p<0.0001). The number needed to genotype (NNG)=3 (95% CI=1.7-3.5) to produce an additional remission. CONCLUSION: These data suggest that a pharmacogenetic dosing report (CNSDose((r))) improves antidepressant efficacy. The effect size was sufficient that translation to clinical care may arise if results are independently replicated. PMID- 26243842 TI - Effect of Adenine on Clozapine-induced Neutropenia in Patients with Schizophrenia: A Preliminary Study. AB - OBJECTIVE: This study examined the utility of adenine for preventing clozapine induced neutropenia. METHODS: This retrospective study examined the effect of adenine on clozapine-induced neutropenia in patients with treatment- resistant schizophrenia and was conducted at Okehazama Hospital in Japan from July 2010 to June 2013. Adenine was available for use from June 2011 onwards. Twenty-one patients started receiving clozapine treatment from July 2010 to April 2011 (the pre-adenine adoption group), and 47 patients started receiving it from May 2011 to June 2013 (the post-adenine adoption group). The effects of adenine were assessed based on changes in the patients' leukocyte counts and the frequency of treatment discontinuation due to clozapine-induced neutropenia. RESULTS: Sixty eight patients were treated with clozapine from July 2010 to June 2013. Of the 21 patients in the pre-adenine adoption group, 4 discontinued treatment due to clozapine-induced neutropenia, whereas only 2 of the 47 patients in the post adenine adoption group discontinued treatment. The frequency of treatment discontinuation due to clozapine-induced neutropenia was significantly lower in post-adenine adoption group than in the pre-adenine adoption group (p=0.047). CONCLUSION: Adenine decreased the frequency of treatment discontinuation due to clozapine-induced neutropenia. Our data suggest that combined treatment with clozapine and adenine is a safe and effective strategy against treatment resistant schizophrenia. PMID- 26243843 TI - Association between Abacus Training and Improvement in Response Inhibition: A Case-control Study. AB - OBJECTIVE: The abacus, first used in Asian countries more than 800 years ago, enables efficient arithmetic calculation via visuospatial configuration. We investigated whether abacus-trained children performed better on cognitive tasks and demonstrated higher levels of arithmetic abilities compared to those without such training. METHODS: We recruited 75 elementary school children (43 abacus trained and 32 not so trained). Attention, memory, and arithmetic abilities were measured, and we compared the abacus with the control group. RESULTS: Children who had learned to use an abacus committed fewer commission errors and showed better arithmetic ability than did controls. We found no significant differences between children with and without abacus training in other areas of attention. CONCLUSION: We speculate that abacus training improves response inhibition via neuroanatomical alterations of the areas that regulate such functions. Further studies are needed to confirm the association between abacus training and better response inhibition. PMID- 26243844 TI - The Effect of Choline Acetyltransferase Genotype on Donepezil Treatment Response in Patients with Alzheimer's Disease. AB - OBJECTIVE: We examined the difference in responses to donepezil between carriers and non-carriers of the A allele at the +4 position of the choline acetyltransferase (ChAT) gene in Koreans. METHODS: Patients who met the criteria for probable Alzheimer's disease (AD) (n=199) were recruited. Among these, 145 completed the 12-week follow-up evaluation and 135 completed the 26-week scheduled course. Differences and changes in the Korean version of the mini mental state examination (MMSE-KC) score, Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery (CERAD-K[N]) wordlist subtest score (WSS), CERAD-K(N) total score (TS), and the Korean version of geriatric depression scale (GDS-K) score between baseline and 12 weeks or 26 weeks were assessed by the Student's t-test. RESULTS: At 12 weeks, the changes in the MMSE-KC score, CERAD-K(N) WSS, and CERAD-K(N) TS from baseline were not significant between ChAT A allele carriers and non carriers; however, at 26 weeks, these changes were significantly larger in ChAT A allele carriers than in non-carriers (p=0.02 for MMSE-KC and p=0.03 for CERAD K(N) WSS respectively). CONCLUSION: Our findings in this study suggested that presence of the A allele at the +4 position of ChAT might positively influence the treatment effect of donepezil in the early stages of AD in Koreans. PMID- 26243845 TI - Comparison of the Effects of a Brand-name Drug and Its Generic Drug on the Quality of Life of Alzheimer's Disease Patients. AB - OBJECTIVE: The pharmacological effects of generic (GE) donepezil are the same as Aricept, its brand-name counterpart. However, little is known as to whether these two drugs provide the same quality of life (QOL). The study subjects were patients with Alzheimer's disease who were taking donepezil hydrochloride tablets, and were selected by visiting either the local pharmacies or the patients' homes. We chose the brand-name drug Aricept and its GE form donepezil to investigate, from a long-term caregiver's perspective, the influence of both drugs on the patients' QOL. METHODS: An EuroQol-5 Dimension (EQ-5D) was used to assess the QOL of patients with Alzheimer's disease, before and after various Aricept and/or donepezil regimens. Patients were divided into four groups: first time users of Aricept (n=43), first time users of GE donepezil (n=45), users refilling previous prescriptions of Aricept (n=51), and users switching from Aricept to GE donepezil (n=51). RESULTS: The average change in the EQ-5D utility indices rose significantly in the patients starting a new regimen of Aricept and its GE drug. The patients continuing an existing regimen of Aricept showed no significant differences, even after Aricept was switched to a GE drug. CONCLUSION: The QOL of patients starting a new regimen of Aricept and its GE drug improved. The QOL was maintained upon switching to the GE drug form. PMID- 26243846 TI - Quantitative Electroencephalography Reflects Inattention, Visual Error Responses, and Reaction Times in Male Patients with Attention Deficit Hyperactivity Disorder. AB - OBJECTIVE: Quantitative electroencephalography (qEEG) has been increasingly used to evaluate patients with attention deficit hyperactivity disorder (ADHD). The aim of this study was to assess the correlation between qEEG data and symptom severity in patients with ADHD. METHODS: Fifteen patients with ADHD and 20 healthy controls (HCs) were recruited. Electroencephalography was assessed in the resting-state, and qEEG data were obtained in the eyes-closed state. The Korean version of the ADHD Rating Scale (K-ARS) and continuous performance tests (CPTs) were used to assess all participants. RESULTS: Theta-band (4-7 Hz) power across the brain was significantly positively correlated with inattention scores on the K-ARS, reaction times and commission errors on the CPTs in ADHD patients. Gamma band (31-50 Hz) power was significantly positively correlated with the results of the auditory CPTs in ADHD patients. The theta/alpha (8-12 Hz) and theta/beta (13 30 Hz) ratios were significantly negatively correlated with commission and omission errors on auditory CPTs in ADHD patients. No significant correlations between qEEG relative power and K-ARS and CPT scores were observed in HCs. CONCLUSION: Our results suggest that qEEG may be a useful adjunctive tool in patients with ADHD. PMID- 26243847 TI - A Randomized, Placebo-controlled Trial of Digestive Enzymes in Children with Autism Spectrum Disorders. AB - OBJECTIVE: There is growing evidence for a gut-brain connection associated with autism spectrum disorders (ASDs). This suggests a potential benefit from introduced digestive enzymes for children with ASD. METHODS: We performed a double-blind, randomized clinical trial on 101 children with ASD (82 boys and 19 girls) aged from 3 to 9 years. ASD patients were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition, text revision (DSM-IV-TR) diagnostic criteria. Structured interviews of at least one hour each both with the parents and the child were performed. Later on, another two hours session was conducted applying the Childhood Autism Rating Scale (CARS). ASD patients were randomized to receive digestive enzymes or placebo. RESULTS: The ASD group receiving digestive enzyme therapy for 3 months had significant improvement in emotional response, general impression autistic score, general behavior and gastrointestinal symptoms. Our study demonstrated the usefulness of digestive enzyme in our population of ASD patients. CONCLUSION: Digestive enzymes are inexpensive, readily available, have an excellent safety profile, and have mildly beneficial effects in ASD patients. Depending on the parameter measured in our study, we propose digestive enzymes for managing symptoms of ASD. Digestive enzyme therapy may be a possible option in treatment protocols for ASD in the future. PMID- 26243848 TI - The Relationship between Quality of Life and Cognitive Functions, Anxiety and Depression among Hospitalized Elderly Patients. AB - OBJECTIVE: Older people seek not only a longer life, but also a better quality of life (QOL). Our aim was to find out the relationship between QOL and socio demographic factors, social activities, cognitive status, depression and anxiety symptoms among medically ill and hospitalized elderly people in Turkey. METHODS: Two hundred forty three patients age 65 years or older were examined. The Socio demographic Data Survey, the Mini Mental State Examination (MMSE), the Geriatric Depression Scale-short form (GDS-15), the Beck Anxiety Inventory (BAI) and the World Health Organization Quality of Life Instrument-Older Adults Module (WHOQOL OLD) were applied to participants. The independent samples t-test and analysis of variance (ANOVA) were used to analyze quantitative data. Pearson's correlation and linear regression analysis were performed. RESULTS: The total score for QOL was significantly higher for those who saw their family members and relatives frequently rather than rarely (p=0.002), who were always busy with social activities rather than rarely or never (p<0.001), who had more years of education (p=0.003), and who were frequently exercising (p=0.023). According to linear regression analysis, the WHOQOL-OLD total score increased by 0.295 and -0.936 units, while MMSE and GDS-15 scale scores increased one unit respectively (beta=0.295, t=1.979, p=0.04; beta=-0.936, t=-4.881, p<0.001). CONCLUSION: Cognitive disabilities, depression, and other psychiatric problems along with medical disease negatively affect the QOL of elderly patients. While performing medical assessment regarding elders, detecting and treating cognitive disabilities and depression is very valuable in improving the QOL of elderly patients. PMID- 26243850 TI - Psychiatric Symptoms in a Patient with Influenza A (H1N1) Treated with Oseltamivir (Tamiflu): A Case Report. AB - Oseltamivir is the most common antiviral drug used to treat and prevent influenza. Epidemiological studies performed in Japan, the United States, and the United Kingdom indicate that oseltamivir may cause psychiatric symptoms; however, the underlying mechanism has not been elucidated. In South Korea, interest in oseltamivir has increased with the spread of the new influenza virus; however, no case report or investigation of psychiatric symptoms associated with the drug has been reported to date. Here, we report a case of a 22-year-old male who complained of mood swings, suicidal feelings, auditory hallucinations, memory deterioration, and insomnia after taking oseltamivir. PMID- 26243849 TI - The Relationship between Chronotype and Sleep Quality in Korean Firefighters. AB - OBJECTIVE: We examined the relationship between chronotype and sleep disturbance, and assessed various factors that might be associated with sleep disturbance in Korean firefighters. METHODS: Self-administered questionnaires assessing chronotype, depression, alcohol use, posttraumatic stress disorder (PTSD), stress response and sleep quality were examined in 515 firefighters. RESULTS: Evening type firefighters more reported depression, alcohol use, PTSD, stress response and sleep disturbance. Also evening chronotype was the most significant risk factor for poor sleep quality (odds ratio [OR], 4.812; 95% confidence interval [CI], 2.448-9.459), even after controlling for all other variables (OR, 3.996; 95% CI, 1.806-8.841). CONCLUSION: Chronotype was the factor most strongly associated with sleep disturbance, and therefore should be considered an important variable in sleep quality, particularly in occupations involving stressful activities, such as firefighting. PMID- 26243851 TI - Overactive Bladder Successfully Treated with Duloxetine in a Female Adolescent. AB - Overactive bladder (OAB) is defined as urgency, usually with frequency and nocturia, and with or without urge incontinence. Duloxetine, an antidepressant that inhibits reuptake of serotonin and norepinephrine, is indicated for the treatment of stress urinary incontinence in Europe. In this paper, we present a case of a 17-year-old female patient with OAB and depressive symptoms who was successfully treated with duloxetine. This case suggests duloxetine can be an option for patient with OAB, and it also highlights the need for further studies of duloxetine's use in the treatment of OAB. PMID- 26243852 TI - Multimodal Hallucination (Audio-visual, Kinaesthetic and Scenic) Associated with the Use of Zolpidem. AB - We are reporting a case of zolpidem induced multimodal hallucinations in a 22 year old female without any history of psychiatric disorders. Zolpidem, by acting on gamma-amino butyric acid type A receptor has a potential to cause a paradoxical reaction and there also exists a possibility of an induced delirium with its use. This case reports evaluates its potential to cause multimodal hallucinations. Zolpidem needs to be prescribed judiciously with the caution of potential side effects particularly in females. PMID- 26243853 TI - Recurrent Idiopathic Catatonia: Implications beyond the Diagnostic and Statistical Manual of Mental Disorders 5th Edition. AB - We describe a case of recurrent, life-threatening, catatonic stupor, without evidence of any associated medical, toxic or mental disorder. This case provides support for the inclusion of a separate category of "unspecified catatonia" in the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) to be used to classify idiopathic cases, which appears to be consistent with Kahlbaum's concept of catatonia as a distinct disease state. But beyond the limited, cross-sectional, syndromal approach adopted in DSM-5, this case more importantly illustrates the prognostic and therapeutic significance of the longitudinal course of illness in differentiating cases of catatonia, which is better defined in the Wernicke-Kleist-Leonhard classification system. The importance of differentiating cases of catatonia is further supported by the efficacy of antipsychotics in treatment of this case, contrary to conventional guidelines. PMID- 26243854 TI - Mirtazapine in Paroxetine Induced Hyper-prolactinemic Galactorrhoea. PMID- 26243855 TI - Erratum: Figure Correction. AB - [This corrects the article on p. 68 in vol. 13, PMID: 25912540.]. PMID- 26243858 TI - By the numbers: global oncology drug spending, 2010-2014. AB - Global spending on oncology drugs hit $100 billion in 2014, an increase of 10.3% over 2013. The United States accounts for 42.2% of total spending. PMID- 26243860 TI - Clonal evolution: multiregion sequencing of esophageal adenocarcinoma before and after chemotherapy. AB - It is possible to decipher the clonal architecture of a tumor and the sequence in which cancer clones acquire genomic alterations through multiregion sequencing (M seq). Serial evaluation of tumor specimens through M-seq can provide valuable information on the molecular basis of resistance to therapy. PMID- 26243861 TI - ERBB2 emerges as a new target for colorectal cancer. AB - ERBB2 mutations and amplifications are present in 7% of colorectal cancers. The presence of these alterations may be a marker of resistance to anti-EGFR therapy and, more importantly, could help identify patients who would benefit from ERBB2 directed therapy. PMID- 26243862 TI - MET receptor juxtamembrane exon 14 alternative spliced variant: novel cancer genomic predictive biomarker. AB - Clinical studies on MET-targeting cancer therapeutics have yielded mixed results in recent years, and MET-relevant predictive biomarkers remain elusive. New studies now reveal METex14 alternative splicing aberrations to represent potential predictive cancer genomic biomarker, hence renewing optimism and directions in the quest for optimized MET-targeting personalized cancer therapy. PMID- 26243863 TI - HER2 activating mutations are targets for colorectal cancer treatment. AB - The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutants are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors neratinib and afatinib. HER2 gene sequencing of 48 cetuximab-resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) wild-type (WT) colorectal cancer patient-derived xenografts (PDX) identified 4 PDXs with HER2 mutations. HER2-targeted therapies were tested on two PDXs. Treatment with a single HER2-targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2-mutated PDXs. SIGNIFICANCE: HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines, and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy. These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer. PMID- 26243864 TI - The histone demethylase KDM1A is essential for the maintenance and differentiation of spermatogonial stem cells and progenitors. AB - Little is known of the fundamental processes governed by epigenetic mechanisms in the supplier cells of spermatogenesis, the spermatogonial stem cells (SSCs). The histone H3 lysine demethylase KDM1A is expressed in spermatogonia. We hypothesized that KDM1A serves in transcriptional regulation of SSCs and fertility. Using a conditional deletion of Kdm1a [conditional knockout (cKO)] in mouse spermatogonia, we determined that Kdm1a is essential for spermatogenesis as adult cKO males completely lack germ cells. Analysis of postnatal testis development revealed that undifferentiated and differentiating spermatogonial populations form in Kdm1a-cKO animals, yet the majority fail to enter meiosis. Loss of germ cells in the cKO was rapid with none remaining by postnatal day (PND) 21. To gain insight into the mechanistic implications of Kdm1a ablation, we isolated PND 6 spermatogonia enriched for SSCs and analyzed their transcriptome by RNA sequencing. Loss of Kdm1a was associated with altered transcription of 1206 genes. Importantly, differentially expressed genes between control and Kdm1a cKO animals included those that are essential for SSC and progenitor maintenance and spermatogonial differentiation. The complete loss of fertility and failure to establish spermatogenesis indicate that Kdm1a is a master controller of gene transcription in spermatogonia and is required for SSC and progenitor maintenance and differentiation. PMID- 26243865 TI - Microgram amounts of abscisic acid in fruit extracts improve glucose tolerance and reduce insulinemia in rats and in humans. AB - 2-Cis,4-trans-abscisic acid (ABA) is a plant hormone that is present also in animals. Several lines of evidence suggest that ABA contributes to the regulation of glycemia in mammals: nanomolar ABA stimulates insulin release from beta pancreatic cells and glucose transporter-4-mediated glucose uptake by myoblasts and adipocytes in vitro; plasma ABA increases in normal human subjects, but not in diabetic patients, after a glucose load for an oral glucose tolerance test (OGTT). The presence of ABA in fruits prompted an exploration of the bioavailability of dietary ABA and the effect of ABA-rich fruit extracts on glucose tolerance. Rats underwent an OGTT, with or without 1 ug/kg ABA, either synthetic or present in a fruit extract. Human volunteers underwent an OGTT or a standard breakfast and lunch, with or without a fruit extract, yielding an ABA dose of 0.85 or 0.5 ug/kg, respectively. Plasma glucose, insulin, and ABA were measured at different time points. Oral ABA at 0.5-1 ug/kg significantly lowered glycemia and insulinemia in rats and in humans. Thus, the glycemia-lowering effect of low-dose ABA in vivo does not depend on an increased insulin release. Low-dose ABA intake may be proposed as an aid to improving glucose tolerance in patients with diabetes who are deficient in or resistant to insulin. PMID- 26243866 TI - An interview with Lewis Wolpert. AB - Lewis Wolpert is a retired developmental biologist who, over his long career, has made many important contributions to the field, from his French Flag model and the concept of positional information to the famous quote that it is "not birth, marriage or death, but gastrulation which is truly the most important time in your life." In addition to his scientific contributions, Lewis is also a prolific writer, from the textbook 'Developmental Biology' to books about popular science, religion and his battle with depression. Although born in South Africa, it was in the United Kingdom that Lewis spent most of his scientific career. We met Lewis at the Spring Meeting of the British Society for Developmental Biology, where he was awarded the Waddington Medal. PMID- 26243867 TI - Transcriptional and epigenetic insights from stem cells and developing tissues. AB - In March 2015, over 200 scientists gathered in Steamboat Springs, Colorado, USA, for the Keystone Symposium 'Transcriptional and Epigenetic Influences on Stem Cell States' to discuss the molecular mechanisms of pluripotency, cell differentiation, cell reprogramming and transdifferentiation, among other topics. In this meeting, translational research on stem cells for disease modeling and therapy was also presented. This Meeting Review describes key themes and selected findings, providing a timely update on this fast-moving area of research. PMID- 26243869 TI - Perilipin+ embryonic preadipocytes actively proliferate along growing vasculatures for adipose expansion. AB - Despite the growing interest in adipose tissue as a therapeutic target of metabolic diseases, the identity of adipocyte precursor cells (preadipocytes) and the formation of adipose tissue during embryonic development are still poorly understood. Here, we clarified the identity and dynamic processes of preadipocytes in mouse white adipose tissue during embryogenesis through direct examination, lineage tracing and culture systems. Surprisingly, we found that lipid-lacking but perilipin(+) or adiponectin(+) proliferating preadipocytes started to emerge at embryonic day 16.5, and these cells underwent active proliferation until birth. Moreover, these preadipocytes resided as clusters and were distributed along growing adipose vasculatures. Importantly, the embryonic preadipocytes exhibited considerable coexpression of stem cell markers, such as CD24, CD29 and PDGFRalpha, and a small portion of preadipocytes were derived from PDGFRbeta(+) mural cells, in contrast to the adult preadipocytes present in the stromal vascular fraction. Further analyses with in vitro and ex vivo culture systems revealed a stepwise but dynamic regulation of preadipocyte formation and differentiation during prenatal adipogenesis. To conclude, we unraveled the identity and characteristics of embryonic preadipocytes, which are crucial for the formation and expansion of adipose tissue during embryogenesis. PMID- 26243868 TI - The developmental origins of the mammalian ovarian reserve. AB - The adult mammalian ovary is devoid of definitive germline stem cells. As such, female reproductive senescence largely results from the depletion of a finite ovarian follicle pool that is produced during embryonic development. Remarkably, the crucial nature and regulation of follicle assembly and survival during embryogenesis is just coming into focus. This developmental pathway involves the coordination of meiotic progression and the breakdown of germ cell cysts into individual oocytes housed within primordial follicles. Recent evidence also indicates that genetic and environmental factors can specifically perturb primordial follicle assembly. Here, we review the cellular and molecular mechanisms by which the mammalian ovarian reserve is established, highlighting the presence of a crucial checkpoint that allows survival of only the highest quality oocytes. PMID- 26243870 TI - Yap and Taz are required for Ret-dependent urinary tract morphogenesis. AB - Despite the high occurrence of congenital abnormalities of the lower urinary tract in humans, the molecular, cellular and morphological aspects of their development are still poorly understood. Here, we use a conditional knockout approach to inactivate within the nephric duct (ND) lineage the two effectors of the Hippo pathway, Yap and Taz. Deletion of Yap leads to hydronephrotic kidneys with blind-ending megaureters at birth. In Yap mutants, the ND successfully migrates towards, and contacts, the cloaca. However, close analysis reveals that the tip of the Yap(-/-) ND forms an aberrant connection with the cloaca and does not properly insert into the cloaca, leading to later detachment of the ND from the cloaca. Taz deletion from the ND does not cause any defect, but analysis of Yap(-/-);Taz(-/-) NDs indicates that both genes play partially redundant roles in ureterovesical junction formation. Aspects of the Yap(-/-) phenotype resemble hypersensitivity to RET signaling, including excess budding of the ND, increased phospho-ERK and increased expression of Crlf1, Sprouty1, Etv4 and Etv5. Importantly, the Yap(ND) (-/-) ND phenotype can be largely rescued by reducing Ret gene dosage. Taken together, these results suggest that disrupting Yap/Taz activities enhances Ret pathway activity and contributes to pathogenesis of lower urinary tract defects in human infants. PMID- 26243871 TI - Single-cell resolution of morphological changes in hemogenic endothelium. AB - Endothelial-to-hematopoietic transition (EHT) occurs within a population of hemogenic endothelial cells during embryogenesis, and leads to the formation of the adult hematopoietic system. Currently, the prospective identification of specific endothelial cells that will undergo EHT, and the cellular events enabling this transition, are not known. We set out to define precisely the morphological events of EHT, and to correlate cellular morphology with the expression of the transcription factors RUNX1 and SOX17. A novel strategy was developed to allow for correlation of immunofluorescence data with the ultrastructural resolution of scanning electron microscopy. The approach can identify single endothelial cells undergoing EHT, as identified by the ratio of RUNX1 to SOX17 immunofluorescence levels, and the morphological changes associated with the transition. Furthermore, this work details a new technical resource that is widely applicable for correlative analyses of single cells in their native tissue environments. PMID- 26243872 TI - Alfred J. Lotka and the origins of theoretical population ecology. PMID- 26243873 TI - Opinion: Celebrating R and D expenditures badly misses the point. PMID- 26243875 TI - IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions. AB - The barrier surfaces of the skin, lung, and intestine are constantly exposed to environmental stimuli that can result in inflammation and tissue damage. Interleukin (IL)-33-dependent group 2 innate lymphoid cells (ILC2s) are enriched at barrier surfaces and have been implicated in promoting inflammation; however, the mechanisms underlying the tissue-protective roles of IL-33 or ILC2s at surfaces such as the intestine remain poorly defined. Here we demonstrate that, following activation with IL-33, expression of the growth factor amphiregulin (AREG) is a dominant functional signature of gut-associated ILC2s. In the context of a murine model of intestinal damage and inflammation, the frequency and number of AREG-expressing ILC2s increases following intestinal injury and genetic disruption of the endogenous AREG-epidermal growth factor receptor (EGFR) pathway exacerbated disease. Administration of exogenous AREG limited intestinal inflammation and decreased disease severity in both lymphocyte-sufficient and lymphocyte-deficient mice, revealing a previously unrecognized innate immune mechanism of intestinal tissue protection. Furthermore, treatment with IL-33 or transfer of ILC2s ameliorated intestinal disease severity in an AREG-dependent manner. Collectively, these data reveal a critical feedback loop in which cytokine cues from damaged epithelia activate innate immune cells to express growth factors essential for ILC-dependent restoration of epithelial barrier function and maintenance of tissue homeostasis. PMID- 26243876 TI - The search engine manipulation effect (SEME) and its possible impact on the outcomes of elections. AB - Internet search rankings have a significant impact on consumer choices, mainly because users trust and choose higher-ranked results more than lower-ranked results. Given the apparent power of search rankings, we asked whether they could be manipulated to alter the preferences of undecided voters in democratic elections. Here we report the results of five relevant double-blind, randomized controlled experiments, using a total of 4,556 undecided voters representing diverse demographic characteristics of the voting populations of the United States and India. The fifth experiment is especially notable in that it was conducted with eligible voters throughout India in the midst of India's 2014 Lok Sabha elections just before the final votes were cast. The results of these experiments demonstrate that (i) biased search rankings can shift the voting preferences of undecided voters by 20% or more, (ii) the shift can be much higher in some demographic groups, and (iii) search ranking bias can be masked so that people show no awareness of the manipulation. We call this type of influence, which might be applicable to a variety of attitudes and beliefs, the search engine manipulation effect. Given that many elections are won by small margins, our results suggest that a search engine company has the power to influence the results of a substantial number of elections with impunity. The impact of such manipulations would be especially large in countries dominated by a single search engine company. PMID- 26243877 TI - Heterochrony underpins natural variation in Cardamine hirsuta leaf form. AB - A key problem in biology is whether the same processes underlie morphological variation between and within species. Here, by using plant leaves as an example, we show that the causes of diversity at these two evolutionary scales can be divergent. Some species like the model plant Arabidopsis thaliana have simple leaves, whereas others like the A. thaliana relative Cardamine hirsuta bear complex leaves comprising leaflets. Previous work has shown that these interspecific differences result mostly from variation in local tissue growth and patterning. Now, by cloning and characterizing a quantitative trait locus (QTL) for C. hirsuta leaf shape, we find that a different process, age-dependent progression of leaf form, underlies variation in this trait within species. This QTL effect is caused by cis-regulatory variation in the floral repressor ChFLC, such that genotypes with low-expressing ChFLC alleles show both early flowering and accelerated age-dependent changes in leaf form, including faster leaflet production. We provide evidence that this mechanism coordinates leaf development with reproductive timing and may help to optimize resource allocation to the next generation. PMID- 26243879 TI - Expressing our internal states and understanding those of others. AB - Vitality form is a term that describes the style with which motor actions are performed (e.g., rude, gentle, etc.). They represent one characterizing element of conscious and unconscious bodily communication. Despite their importance in interpersonal behavior, vitality forms have been, until now, virtually neglected in neuroscience. Here, using the functional MRI (fMRI) technique, we investigated the neural correlates of vitality forms in three different tasks: action observation, imagination, and execution. Conjunction analysis showed that, in all three tasks, there is a common, consistent activation of the dorsocentral sector of the insula. In addition, a common activation of the parietofrontal network, typically active during arm movements production, planning, and observation, was also found. We conclude that the dorsocentral part of the insula is a key element of the system that modulates the cortical motor activity, allowing individuals to express their internal states through action vitality forms. Recent monkey anatomical data show that the dorsocentral sector of the insula is, indeed, connected with the cortical circuit involved in the control of arm movements. PMID- 26243878 TI - Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer. AB - During chronic inflammation, neutrophil-secreted hypochlorous acid can damage nearby cells inducing the genomic accumulation of 5-chlorocytosine (5ClC), a known inflammation biomarker. Although 5ClC has been shown to promote epigenetic changes, it has been unknown heretofore if 5ClC directly perpetrates a mutagenic outcome within the cell. The present work shows that 5ClC is intrinsically mutagenic, both in vitro and, at a level of a single molecule per cell, in vivo. Using biochemical and genetic approaches, we have quantified the mutagenic and toxic properties of 5ClC, showing that this lesion caused C->T transitions at frequencies ranging from 3-9% depending on the polymerase traversing the lesion. X-ray crystallographic studies provided a molecular basis for the mutagenicity of 5ClC; a snapshot of human polymerase beta replicating across a primed 5ClC containing template uncovered 5ClC engaged in a nascent base pair with an incoming dATP analog. Accommodation of the chlorine substituent in the template major groove enabled a unique interaction between 5ClC and the incoming dATP, which would facilitate mutagenic lesion bypass. The type of mutation induced by 5ClC, the C->T transition, has been previously shown to occur in substantial amounts both in tissues under inflammatory stress and in the genomes of many inflammation-associated cancers. In fact, many sequence-specific mutational signatures uncovered in sequenced cancer genomes feature C->T mutations. Therefore, the mutagenic ability of 5ClC documented in the present study may constitute a direct functional link between chronic inflammation and the genetic changes that enable and promote malignant transformation. PMID- 26243881 TI - Influenza follicles in the posterior pharyngeal wall. PMID- 26243880 TI - Nuclear receptor RORalpha regulates pathologic retinal angiogenesis by modulating SOCS3-dependent inflammation. AB - Pathologic ocular angiogenesis is a leading cause of blindness, influenced by both dysregulated lipid metabolism and inflammation. Retinoic-acid-receptor related orphan receptor alpha (RORalpha) is a lipid-sensing nuclear receptor with diverse biologic function including regulation of lipid metabolism and inflammation; however, its role in pathologic retinal angiogenesis remains poorly understood. Using a mouse model of oxygen-induced proliferative retinopathy, we showed that RORalpha expression was significantly increased and genetic deficiency of RORalpha substantially suppressed pathologic retinal neovascularization. Loss of RORalpha led to decreased levels of proinflammatory cytokines and increased levels of antiinflammatory cytokines in retinopathy. RORalpha directly suppressed the gene transcription of suppressors of cytokine signaling 3 (SOCS3), a critical negative regulator of inflammation. Inhibition of SOCS3 abolished the antiinflammatory and vasoprotective effects of RORalpha deficiency in vitro and in vivo. Moreover, treatment with a RORalpha inverse agonist SR1001 effectively protected against pathologic neovascularization in both oxygen-induced retinopathy and another angiogenic model of very-low-density lipoprotein receptor (Vldlr)-deficient (Vldlr (-/-) ) mice with spontaneous subretinal neovascularization, whereas a RORalpha agonist worsened oxygen-induced retinopathy. Our data demonstrate that RORalpha is a novel regulator of pathologic retinal neovascularization, and RORalpha inhibition may represent a new way to treat ocular neovascularization. PMID- 26243882 TI - Pancreatic cancer: current management and treatment strategies. AB - The 5-year survival of patients with pancreatic cancer is poor and, despite oncological advances over the past two decades, has not significantly improved. However, there have been several surgical and oncological advances which have improved morbidity and mortality in surgery and more efficacious chemotherapy regimens, resulting in a better patient experience and an increase in survival by a number of months. Most patients have a tumour at the head of the pancreas and those with resectable disease undergo a pancreaticoduodenectomy, which can be performed laparoscopically. Those who have a pancreatic resection have an increased survival in comparison with those receiving oncological treatment only; however, only a quarter of patients have resectable disease at diagnosis. Some centres are now performing venous resections and/or arterial resections in order to increase the number of patients eligible for curative surgery. Innovative techniques using ablation technologies to downstage tumours for resection are also being investigated. After surgery, all patients should be offered adjuvant gemcitabine-based chemotherapy. Those with locally advanced tumours not suitable for surgery should be offered FOLFIRINOX chemotherapy, after which the tumour may be suitable for surgical resection. The use of radiotherapy in this group of patients is controversial but offered by a few centres. Patients with metastatic disease at diagnosis should also be offered FOLFIRINOX chemotherapy, which can improve survival by a few months. As our knowledge of the tumour biology of pancreatic cancer progresses, a number of new agents targeting specific genes and proteins are under investigation and there is hope that median survival will continue to improve over the next decade. PMID- 26243883 TI - Calcium modulation of exocytosis-linked plasma membrane potential oscillations in INS-1 832/13 cells. AB - In the presence of high glucose or pyruvate, INS-1 832/13 insulinoma cells undergo stochastic oscillations in plasma membrane potential (Deltapsip) leading to associated fluctuations in cytosolic free Ca(2+) concentration ([Ca(2+)]c). Oscillations are not driven by upstream metabolic fluctuations, but rather by autonomous ionic mechanisms, the details of which are unclear. We have investigated the nature of the oscillator, with simultaneous fluorescence monitoring of Deltapsip, [Ca(2+)]c and exocytosis at single-cell resolution, combined with analysis of the occurrence, frequency and amplitude of Deltapsip oscillations. Oscillations were closely coupled to exocytosis, indicated by coincident synaptopHluorin fluorescence enhancement. L-type Ca(2+) channel inhibitors enhanced Deltapsip and [Ca(2+)]c oscillation frequency in the presence of pyruvate, but abolished the sustained [Ca(2+)]c response following KCl depolarization. The L-type Ca(2+) channel inhibitor isradipine did not inhibit oscillation-linked exocytosis. The T-type Ca(2+) channel inhibitor NNC 55-0396 inhibited Deltapsip and [Ca(2+)]c oscillations, implying that T-type Ca(2+) channels trigger oscillations and consequent exocytosis. Since distinct ion channels operate in oscillating and non-oscillating cells, quantitative analysis of Deltapsip and [Ca(2+)]c oscillations in a beta-cell population may help to improve our understanding of the link between metabolism and insulin secretion. PMID- 26243884 TI - Polypeptide modification: an improved proglycinin design to stabilise oil-in water emulsions. AB - beta-Conglycinin and glycinin are soybean major seed storage proteins. Previous studies have shown that adding the extension region of beta-conglycinin alpha subunit improves the emulsifying properties of proglycinin and confers more favourable characteristics than fusing the extension region of beta-conglycinin alpha' subunit or the hypervariable regions (A4IV) of glycinin A1aB1b subunit. To evaluate the polypeptide properties, we designed mutants of A1aB1b subunits fused with truncated versions of A4IV (A4IVcut), alpha (alphacut) or alpha' (alpha'cut) extension regions lacking the C-terminus 25 or 31 residues (A4IVC25, alphaC25 or alpha'C31), and also A4IVcut and alpha'cut with alphaC25 residues added (A4IVcut alphaC25 and alpha'cut-alphaC25). All the modified proteins displayed conformations similar to the wild type. With good solubilities, the emulsion properties of the modified proteins were much better at ionic strength MU = 0.08 than at MU = 0.5. The modified A1aB1balphacut and A1aB1balpha'cut showed poorer emulsion properties than those of A1aB1balpha and A1aB1balpha'. Replacing the hydrophobic A4IVC25 region of A1aB1bA4IV with hydrophilic alphaC25 created A1aB1bA4IVcut-alphaC25, which had the best emulsion stability among these proglycinin mutants. We found that addition of alphaC25 improves the emulsifying properties of two C-terminally truncated proglycinin variants, thereby illustrating its potential general utility. Our investigation showed that in order to improve the emulsifying ability and emulsion stability of a globular protein, the introduced polypeptide should (i) be highly hydrophilic, (ii) consist of multiple hydrophobic-strong hydrophilic regions comprising at least two alpha helixes, (iii) harbour a terminal alpha-helix at the end of the C terminus and (iv) have properties similar to those of alphaC25. PMID- 26243885 TI - An efficient protocol towards site-specifically clickable nanobodies in high yield: cytoplasmic expression in Escherichia coli combined with intein-mediated protein ligation. AB - In this study, several expression strategies were investigated in order to develop a generic, highly productive and efficient protocol to produce nanobodies modified with a clickable alkyne function at their C-terminus via the intein mediated protein ligation (IPL) technique. Hereto, the nanobody targeting the vascular cell adhesion molecule 1 (NbVCAM1) was used as a workhorse. The highlights of the protocol can be ascribed to a cytoplasmic expression of the nanobody-intein-chitin-binding domain fusion protein in the Escherichia coli SHuffle((r)) T7 cells with a C-terminal extension, i.e. LEY, EFLEY or His6 spacer peptide, in the commonly used Luria-Bertani medium. The combination of these factors led to a high yield (up to 22 mg/l of culture) and nearly complete alkynation efficiency of the C-terminally modified nanobody via IPL. This yield can even be improved to ~45 mg/l in the EnPresso((r)) growth system but this method is more expensive and time-consuming. The resulting alkynated nanobodies retained excellent binding capacity towards the recombinant human VCAM1. The presented protocol benefits from time- and cost-effectiveness, which allows a feasible production up-scaling of generic alkynated nanobodies. The production of high quantities of site-specifically modified nanobodies paves the way to new biosurface applications that demand for a homogeneously oriented nanobody coupling. Prospectively, the alkynated nanobodies can be covalently coupled to a multitude of azide-containing counterparts, e.g. contrast labeling agents, particles or surfaces for numerous innovative applications. PMID- 26243886 TI - On the predictability of the orientation of protein domains joined by a spanning alpha-helical linker. AB - Connecting proteins together in prescribed geometric arrangements is an important element in new areas of biomolecular design. In this study, we characterize the degree of three-dimensional orientational control that can be achieved when two protein domains that have alpha-helical termini are joined using an alpha-helical linker. A fusion between naturally oligomeric protein domains was designed in this fashion with the intent of creating a self-assembling 12-subunit tetrahedral protein cage. While the designed fusion protein failed to assemble into a tetrahedral cage in high yield, a series of crystal structures showed that the two fused components were indeed bridged by an intact alpha helix, although the fusion protein was distorted from the intended ideal configuration by bending of the helix, ranging from 7 to 35 degrees . That range of deviation in orientation creates challenges for designing large, perfectly symmetric protein assemblies, although it should offer useful outcomes for other less geometrically demanding applications in synthetic biology. PMID- 26243887 TI - Sulfhydryl-specific PEGylation of phosphotriesterase cysteine mutants for organophosphate detoxification. AB - The catalytic bioscavenger phosphotriesterase (PTE) is experimentally an effective antidote for organophosphate poisoning. We are interested in the molecular engineering of this enzyme to confer additional functionality, such as improved in vivo longevity. To this aim, we developed PTE cysteine mutants with free sulfhydryls to allow macromolecular attachments to the protein. A library of PTE cysteine mutants were assessed for efficiency in hydrolysing the toxic pesticide metabolite paraoxon, and screened for attachment with a sulfhydryl reactive small molecule, fluorescein 5-maleimide (F5M), to examine cysteine availability. We established that the newly incorporated cysteines were readily available for labelling, with R90C, E116C and S291C displaying the highest affinity for binding with F5M. Next, we screened for efficiency in attaching a large macromolecule, a 30 000 Da polyethylene glycol (PEG) molecule. Using a solid-phase PEGylation strategy, we found the E116C mutant to be the best single mutant candidate for attachment with PEG30. Kinetic activity of PEGylated E116C, with paraoxon as substrate, displayed activity approaching that of the unPEGylated wild-type. Our findings demonstrate, for the first time, an efficient cysteine mutation and subsequent method for sulfhydryl-specific macromolecule attachment to PTE. PMID- 26243888 TI - Test result communication in primary care: a survey of current practice. AB - BACKGROUND: The number of blood tests ordered in primary care continues to increase and the timely and appropriate communication of results remains essential. However, the testing and result communication process includes a number of participants in a variety of settings and is both complicated to manage and vulnerable to human error. In the UK, guidelines for the process are absent and research in this area is surprisingly scarce; so before we can begin to address potential areas of weakness there is a need to more precisely understand the strengths and weaknesses of current systems used by general practices and testing facilities. METHODS: We conducted a telephone survey of practices across England to determine the methods of managing the testing and result communication process. In order to gain insight into the perspectives from staff at a large hospital laboratory we conducted paired interviews with senior managers, which we used to inform a service blueprint demonstrating the interaction between practices and laboratories and identifying potential sources of delay and failure. RESULTS: Staff at 80% of practices reported that the default method for communicating normal results required patients to telephone the practice and 40% of practices required that patients also call for abnormal results. Over 80% had no fail-safe system for ensuring that results had been returned to the practice from laboratories; practices would otherwise only be aware that results were missing or delayed when patients requested results. Persistent sources of missing results were identified by laboratory staff and included sample handling, misidentification of samples and the inefficient system for collating and resending misdirected results. CONCLUSIONS: The success of the current system relies on patients both to retrieve results and in so doing alert staff to missing and delayed results. Practices appear slow to adopt available technological solutions despite their potential for reducing the impact of recurring errors in the handling of samples and the reporting of results. Our findings will inform our continuing work with patients and staff to develop, implement and evaluate improvements to existing systems of managing the testing and result communication process. PMID- 26243889 TI - Microbial pigments as natural color sources: current trends and future perspectives. AB - Synthetic colors have been widely used in various industries including food, textile, cosmetic and pharmaceuticals. However toxicity problems caused by synthetic pigments have triggered intense research in natural colors and dyes. Among the natural Sources, pigment producing microorganisms hold a promising potential to meet present day challenges. Furthermore natural colors not only improve the marketability of the product but also add extra features like anti oxidant, anti cancer properties etc. In this review, we present various sources of microbial pigments and to explore their biological and clinical properties like antimicrobial, antioxidant, anticancer and anti inflammatory. The study also emphasizes upon key parameters to improve the bioactivity and production of microbial pigments for their commercial use in pharmacological and medical fields. PMID- 26243890 TI - Technology and potential applications of probiotic encapsulation in fermented milk products. AB - Fermented milk products containing probiotics and prebiotics can be used in management, prevention and treatment of some important diseases (e.g., intestinal and immune-associated diseases). Microencapsulation has been used as an efficient method for improving the viability of probiotics in fermented milks and gastrointestinal tract. Microencapsulation of probiotic bacterial cells provides shelter against adverse conditions during processing, storage and gastrointestinal passage. Important challenges in the field include survival of probiotics during microencapsulation, stability of microencapsulated probiotics in fermented milks, sensory quality of fermented milks with microencapsulated probiotics, and efficacy of microencapsulation to deliver probiotics and their controlled or targeted release in the gastrointestinal tract. This study reviews the current knowledge, and the future prospects and challenges of microencapsulation of probiotics used in fermented milk products. In addition, the influence of microencapsulation on probiotics viability and survival is reviewed. PMID- 26243891 TI - Quantity of selected probiotic cultures in semi-hard cheese with low-cooking curd during the maturation process. AB - The work studies the survival of added selected probiotic bacteria Lactobacillus acidophilus (S1), Lactobacillus casei (S2), and Lactobacillus plantarum96 (S3) in semi-hard cheese with low-cooking curd during the maturation process. Cheeses were made according to the standard procedure (Polyfood SI 050 device). Probiotic lactobacilli strains Lactobacillus acidophilus (S1), Lactobacillus casei (S2), and Lactobacillus plantarum96 (S3) used in this study were added into the milk before the renneting process. The manufactured cheeses were matured for 6 months at the temperature of 10 degrees C. Cheese samples were taken for pH and titratable acidity measurements, lactobacilli enumeration, and chemical analysis at 30, 60, 90, 120, 150 and 180 days of maturation. At the end of the experiment (180 days) the cheese samples were analyzed also for the amount of lactic acid and protein contents. Initial numbers of lactobacilli inoculated into the milk (10(8) CFU mL(-1)) decreased during the first 2 weeks of maturation and reached from 2.15 10(7) CFU g(-1) in S1 cheese to 4.32 10(7) CFU g(-1) in S3 cheese. The number of Lactobacillus acidophilus strain bacteria at the beginning of the maturation period was 2.47.10(7) CFU g(-1) and declined until day 120 of maturation to the number of 0.45 10(6) CFU g(-1). In the last month of the experiment day 180 the viable cell numbers started to rise up to the final number of 0.41 10(7) CFU g(-1). The numbers of Lactobacillus plantarum96 varied around 10(8) CFU g(-1) during the whole period of the experiment. According to our results it was detected that in all experimental cheeses, the used probiotic lactobacilli reached the values above 10(6) CFU g(-1). Thus the legislated and therapeutic minimum limits set for the products containing probiotic bacteria for human diet were fulfilled. PMID- 26243892 TI - Marine Collagen: An Emerging Player in Biomedical applications. AB - Mammalian collagen is a multifactorial biomaterial that is widely used for beneficial purposes in the advanced biomedical technologies. Generally, biomedical applicable collagen is extracted from the mammalian body, but it can also be derived from marine species. Recently, mammalian tissues collagen proteins are considered a great pathological risk for transmitted diseases, because purification of such protein is very challenging and needs efficient tool to avoid structure alteration. Thus, difficult extraction process and high cost decreased mammalian collagen demands for beneficial effects compared to marine collagen. In contrast, marine collagen is safe and easy to extract, however this potential source of collagen is hindered by low denaturing temperature, which is considered a main hurdle in the beneficial effects of marine collagen. Characterization and biomedical applications of marine collagen are in transition state and yet to be discovered. Therefore, an attempt was made to summarize the recent knowledge regarding different aspects of marine collagen applications in the biomedical engineering field. PMID- 26243893 TI - Antibiotic susceptibility and heterogeneity in technological traits of lactobacilli isolated from Algerian goat's milk. AB - The objective of this study was to identify and study the heterogeneity of technological traits of lactobacilli from goat's milk of Algeria and to evaluate in vitro their safety aspect. Using API50 CHL system and 16S rDNA sequencing, 51 % of strains were assigned as Lactobacillus plantarum, 34 % as L. pentosus, 7 % as L. rhamnosus and 8 % as L. fermentum. A large variability was noted for the acidifying capacity in skim milk after 6, 12 and 24 h of incubation. All strains expressed aminopeptidase activity against alanine-rho-NA and leucine-rho-NA at different levels. All strains were resistant to vancomycin and most of strains showed more susceptibility to beta-lactam antibiotic. High susceptibility toward the inhibitors of protein synthesis was also observed. Minimum inhibitory concentrations data obtained revealed that isolates were susceptible to penicillin and chloramphenicol, and resistant to gentamicin and vancomycin. Minimum inhibitory concentrations distribution of other antibiotics showed variability. The analysis of graphical representation of principal component analysis of technological properties of L. plantarum and L. pentosus strains showed diversity among the isolates. Finally, eight L. plantarum (LAM1, LAM3, LAM21, LAM25, LAM35, LF15, LAM34, and LAM35), four L. pentosus (LAM38, LAM39, LF9 and LF16) and two L. rhamnosus (LF3 and LF10) strains, could be good candidates as adjunct culture in dairy product in Algeria. PMID- 26243894 TI - Influence of selenium supplementation on fatty acids profile and biological activity of four edible amaranth sprouts as new kind of functional food. AB - Suitability assessment of amaranth sprouts as a new functional food was carried out. The optimisation of sprouting process and the influence of selenium supplementation, in doses 10, 15, and 30 mg/l of selenium as sodium selenite, on amaranth growth and fatty acid profile were examined. Methods such as FRAP, DPPH, polyphenols content and GPX activity were applied to characterize antioxidant potential of seeds and sprouts of four different edible amaranth genera. E. coli, S. aureus, C. albicans were used to evaluate amaranth sprouts antimicrobial properties. Interaction between amaranth sprouts and biological systems was assessed by analysing antibacterial and antifungal properties with a disc diffusion test. The studies proved amaranth sprouts to be potentially attractive as functional food. As confirmed by all the data amaranth sprouts are suitable as a moderate selenium accumulator and are rich in essential fatty acids, especially linoleic and alpha-linolenic acids, which are precursors of long chain polyunsaturated fatty acids. Thus, it opens dietary opportunities for amaranth sprouts. They can also serve as a moderate source of antioxidant compounds. Nevertheless, the experiments revealed neither antibacterial, nor antifungal properties of sprouts. In general, amaranth sprouts biological activity under evaluation has failed to prove to be significantly impacted by selenium fertilization. PMID- 26243896 TI - Effects of microwave - fluidized bed drying on quality, energy consumption and drying kinetics of soybean kernels. AB - Moisture content of soybean kernel at harvest time is too high for storage, and needs to be reduced. In this research, drying characteristics, quality and energy requirement for microwave-fluidized bed drying of soybean kernels were studied. The results showed that air temperature (80-140 degrees C), velocity (1.8-4.5 m/s) and microwave power (200-500 W) significantly influenced drying time, moisture diffusivity, rehydration capacity, cracking, and specific energy consumption (P <= 0.05). Among the applied models, Page's model has the best performance to estimate the microwave-fluidized bed drying behavior of the soybean kernels. Moisture diffusivity values increased (6.25 * 10(-10) to 42.14 * 10(-10) m(2)/s) as the air velocity decreased and air temperature and microwave power increased. Activation energy was foundto be between 3.33 and 17.70 kJ/mol. Minimum cracking percentage of soybean kernels (12.96 %) was obtained at 80 degrees C, 1.8 m/s and 200 W treatments. The increase in microwave power and decrease in air velocity level decreased the rehydration capacity. Specific energy consumption varied from 50.94 to 338.76 MJ/kg water and the lowest specific energy consumption were obtained at 80 degrees C, 4.5 m/s and 500 W. PMID- 26243895 TI - Antibacterial activity and mode of action of selected glucosinolate hydrolysis products against bacterial pathogens. AB - Plants contain numerous components that are important sources of new bioactive molecules with antimicrobial properties. Isothiocyanates (ITCs) are plant secondary metabolites found in cruciferous vegetables that are arising as promising antimicrobial agents in food industry. The aim of this study was to assess the antibacterial activity of two isothiocyanates (ITCs), allylisothiocyanate (AITC) and 2-phenylethylisothiocyanate (PEITC) against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Listeria monocytogenes. The antibacterial mode of action was also characterized by the assessment of different physiological indices: membrane integrity, intracellular potassium release, physicochemical surface properties and surface charge. The minimum inhibitory concentration (MIC) of AITC and PEITC was 100 MUg/mL for all bacteria. The minimum bactericidal concentration (MBC) of the ITCs was at least 10 times higher than the MIC. Both AITC and PEITC changed the membrane properties of the bacteria decreasing their surface charge and compromising the integrity of the cytoplasmatic membrane with consequent potassium leakage and propidium iodide uptake. The surface hydrophobicity was also non-specifically altered (E. coli and L. monocytogenes become less hydrophilic; P. aeruginosa and S. aureus become more hydrophilic). This study shows that AITC and PEITC have strong antimicrobial potential against the bacteria tested, through the disruption of the bacterial cell membranes. Moreover, phytochemicals are highlighted as a valuable sustainable source of new bioactive products. PMID- 26243897 TI - Enhancing arabic bread quality and shelf life stability using bread improvers. AB - Arabic breads is produced mainly from hard red winter wheat (HRWW) and have relatively little crumb, dense texture, form pocket and are often round with golden brown crust color. The objectives of this research were to investigate the effect of different bread improvers combinations addition in enhancing the quality parameters of Arabic bread. Therefore, the ability of Arabic bread for rolling, folding and overall quality were evaluated during the Arabic bread storage period for 2 days. It was found that there was significant effect of bread improvers combinations (Arabic gum "AG" * Mongglycerides "MG" *alpha amylase) addition on the ability of Arabic bread for rolling and folding on the second day (P <= 0.1). The highest white Arabic bread quality was obtained significantly from addition of low AG, high of MG and high alpha-amylase combination and high AG, low of MG and high alpha-amylase combination. While, low of AG, high of MG and low alpha-amylase combination and high of AG, high of MG and low alpha-amylase combination significantly exhibited the highest overall quality for the Arabic bread made from whole flour. PMID- 26243898 TI - Physical properties of cobia (Rachycentron canadum) surimi: effect of washing cycle at different salt concentrations. AB - This study aimed to determine the effects of 2-5 wash cycles and the addition of tetrasodium pyrophosphate (TSPP) (0 %, 0.05 Surimi% and 0.1 % w/w)-with or without the addition of 0.4 % calcium chloride (CaCl2)-on the physical properties such as texture, colour, expressible moisture and microstructure of Cobia (Rachycentron canadum) surimi gel. The highest breaking force (484.85 g) was obtained with the addition 0.1 % TSPP alone on the fifth wash. However, a combination of 0.1 and 0.4 % CaCl2 in surimi gels at wash cycle 5 resulted in the highest degree of whiteness (86.8 %), as well as total expressible moisture (2.785 %) and deformation (17.11 mm). The highest surimi gel strength (6,923 g.mm) was obtained after three wash cycles with the addition of 0.1 % TSPP +0.4 % CaCl2. The physical properties of Cobia fish surimi gels were affected by the number of wash cycles and treatments with TSPP and CaCl2. PMID- 26243899 TI - Gamma radiation and magnetic field mediated delay in effect of accelerated ageing of soybean. AB - Soybean seeds were exposed to gamma radiation (0.5, 1, 3 and 5 kGy), static magnetic field (50, 100 and 200 mT) and a combination of gamma radiation and magnetic energy (0.5 kGy + 200 mT and 5 kGy + 50 mT) and stored at room temperature for six months. These seeds were later subjected to accelerated ageing treatment at 42 degrees C temperature and 95-100 % relative humidity and were compared for various physical and biochemical characteristics between the untreated and the energized treatments. Energy treatment protected the quality of stored seeds in terms of its protein and oil content . Accelerated aging conditions, however, affected the oil and protein quantity and quality of seed negatively. Antioxidant enzymes exhibited a decline in their activity during aging while the LOX activity, which reflects the rate of lipid peroxidation, in general, increased during the aging. Gamma irradiated (3 and 5 kGy) and magnetic field treated seeds (100 and 200 mT) maintained a higher catalase and ascorbate peroxidase activity which may help in efficient scavenging of deleterious free radical produced during the aging. Aging caused peroxidative changes to lipids, which could be contributed to the loss of oil quality. Among the electromagnetic energy treatments, a dose of 1-5 kGy of gamma and 100 mT, 200 mT magnetic field effectively slowed the rate of biochemical degradation and loss of cellular integrity in seeds stored under conditions of accelerated aging and thus, protected the deterioration of seed quality. Energy combination treatments did not yield any additional protection advantage. PMID- 26243900 TI - Physicochemical, thermal and rheological properties of starches isolated from malting barley varieties. AB - The aim of this work was to characterize physicochemical, thermal and rheological properties of starches isolated from malting barley varieties. The analyzed starches contained 19.6-25.2 g of amylose, 42.47-70.67 mg of phosphorus, 0.50 1.26 g of protein and 0.10-0.61 g of fat per 100 g of starch dry mass. The clarity of the 1 % (w/w) starch pastes ranged from 5.4 to 9.8 %. Values of the characteristic gelatinization temperatures were in the ranges of 56.5-58.5 degrees C, 61.2-63.0 degrees C and 66.7-68.7 degrees C, respectively for TO, TP and TE, whereas values of gelatinization enthalpy were from 6.49 to 9.61 J/g. The barley starches showed various tendency to retrogradation, from 24.52 to 44.22 %, measured as R = ?HR/?HG value. The pasting curves showed differences in pasting characteristics of the barley starches, where values of peak (PV) and final (FV) viscosities were 133-230 mPa.s and 224-411 mPa.s, respectively. The barley starch pastes exhibited non-Newtonian, shear thinning flow behaviour and thixotropy phenomenon. After cooling the starch gels showed different viscoelastic properties, however, most of them behaved like weak gels (tan delta = G"/G' > 0.1). Significant linear correlations between the parameters of pasting characteristic and some rheological parameters were found. PMID- 26243901 TI - Changes on physico-chemical properties, lipid oxidation and volatile compounds during the manufacture of celta dry-cured loin. AB - The present study deals with the changes on the main technological characteristics and volatile compounds profile of a traditional Spanish dry ripened loin from Celta pig breed. The evolution of physicochemical properties, colour, texture, free fatty acid profile and volatile compounds were assessed throughout the process seasoning, post-seasoning and after 30 and 60 days of dry ripening. As it was expected, pH, moisture and activity water were significantly (P < 0.001) influenced by ripening time. Statistical analysis also displayed that colour parameters (lightness, L*; redness, a*; yellowness, b*) decreased significantly (P < 0.001) during the manufacturing process. On the other hand, lipid oxidation reached the highest levels at the end of process with mean values of 0.34 mg MDA/kg. Regarding total FFA, a significant (P < 0.001) increase was observed during the manufacturing process, being MUFA the most abundant at the end of process. Finally, sixty seven volatile compounds were identified during the manufacture of Celta dry-cured loin. At the end of process, volatile compounds from microbial activity were the most abundant followed by volatile compounds from lipid oxidation. PMID- 26243902 TI - Batch uniformity and energy efficiency improvements on a cabinet dryer suitable for smallholder farmers. AB - Drying can add value, facilitate transport and extend the storage life of agro products; therefore, in developing countries with poorly established cool-chains, drying is particularly effective. Furthermore, drying within small-scale village based enterprises contributes to rural development. However, most equipment suitable to such operations yields a product of non-uniform quality and shows low levels of energy efficiency. The aim of this research was to improve the batch uniformity and the energy efficiency of a cabinet dryer suitable for smallholder farmers. Experiments were carried out with the cooperation of a dryer manufacturer and a group of users. On each trial 144.5 kg of peeled and deseeded litchis were placed at the dryer's 17 trays, that were stacked atop each other. Moisture content (wet basis) was reduced from 87 to 23 % in about 15.5 h. It was found that a low-cost modification to the dryer chamber's air inlet was able to improve heat distribution and increase the uniformity of the fruit's moisture content. In the original design, at the end of the drying process, moisture content of the fruits on the top tray was 38 % while at the bottom tray was 12 %. The modification to the dryer reduced this disparity and the final moisture content of the fruits placed at the top tray was 25 % while at the bottom tray was 21 %. In addition, the modification reduced the dryer's air mass flow from 0.3 to 0.1 kg s(-1) without jeopardizing drying forces, consequently the dryer energy efficiency increased from 33 to 42 %. PMID- 26243903 TI - Developing consumer acceptable biscuits enriched with Psyllium fibre. AB - Consumer's demand for functional food is a trend of the last decades. Nowadays, the attention is focused on the development of products with health claims on the label, which can result in value-added products for the producers companies. Cookies are popular staple foods in the human diet in many countries and are generally well accepted by consumers due to their sensory attributes, long shelf life and convenience. The incorporation of solid components on the biscuit dough, such as dietary fibre, could have serious implications on its structure and perceived texture which explains the technological limitations for the fibre incorporation. The aim of this work is to develop an enriched functional biscuit with Psyllium fibre and understand the impact of the new ingredient on physicochemical and sensorial properties of the dough and biscuits. The optimum biscuit's formulation was determined using the response surface methodology (RSM). Effects of wheat flour (48-52 %) and Psyllium (3-9 %) contents on the dimensional features (spread ratio, expansion factor), water activity, colour parameters (L*, a*, b*), texture characteristics (firmness, adhesiveness, cohesiveness, springiness) and sensory properties (colour, flavour, texture, overall acceptability) of dough and biscuits were investigated. The most representative parameters evaluated were used to develop biscuits with similar features to commercial references. An optimum formulation was obtained by incorporating 6 % Psyllium and 50 % flour. This biscuit has the enough amount of Psyllium soluble fibre recommended by Food and Drug Administration (FDA) to prevent the risk of coronary heart disease and to bear a health claim on the label. PMID- 26243904 TI - Optimization of thermophysical properties of Pacific white shrimp (Litopenaeus vannamei) previously treated with freezing-point regulators using response surface methodology. AB - Three freezing-point regulators (glycine, sodium chloride and D-sorbitol) were employed to optimize thermophysical properties of Pacific white shrimp (Litopenaeus vannamei) using response surface methodology (RSM). The independent variables were glycine content (0.250-1.250 %), sodium chloride content (0.500 2.500 %) and D-sorbitol content (0.125-0.625 %) and analysis of variance showed that the effects of glycine, sodium chloride and D-sorbitol on the thermophysical properties were statistically significant (P < 0.05). The coefficient of determination, R (2) values for initial freezing point (T i ), unfreezable water mass fraction (W u ), apparent specific heat (C app ) and Enthalpy (H) were 0.896 ~ 0.999. The combined effects of these independent variables on T i , W u , C app and H were investigated. The results indicated that T i , C app and H varied curvilinearly with increasing of glycine, sodium chloride and D-sorbitol content whereas W u increased nearly linearly. Based on response plots and desirability functions, the optimum combination of process variables for Pacific white shrimp previously treated with freezing-point regulators were 0.876 % for glycine content, 2.298 % for sodium chloride content and 0.589 % for D-sorbitol content, correspondently the optimized thermophysical properties were T i , - 5.086 degrees C; W u , 17.222 %; C app , 41.038 J/g degrees C and H, 155.942 J/g, respectively. Briefly, the application of freezing-point regulators depressed T i and obtained the optimum W u , C app and H, which would be obviously beneficial for the exploitation of various thermal processing and food storage. PMID- 26243905 TI - Rheological and sensory behaviour of rice flour dough: effect of selected additives in relation to dough flattening. AB - The handling of rice flour doughs in terms of sheeting, flattening and rolling is difficult due to the absence of gluten forming proteins; scope exists to improve these characteristics by incorporating appropriate additives during the preparation of rice doughs. Different levels of additives such as whey protein concentrate (WPC) (0-10 %), xanthan gum (0-5 %), sucrose (0-20 %) and salt (0-2 %) have been incorporated, and the rheological (small-deformation oscillation) as well as sensory characteristics have been determined, in addition to microstructural observations and finding inter-relationships. The second order polynomial can adequately explain the rheological parameters like storage modulus, loss modulus and complex viscosity (R = 0.863-0.889, p <= 0.01) while it is poor for phase angle (R = 0.659, p <= 0.01). Among these additives, xanthan gum imparts the strongest effect (significant at p <= 0.01) followed by whey protein concentrate. The effects of these additives are predominantly linear though quadratic effects are also significant in several cases. A cohesive microstructure with improved binding occurs with a high level (7.5 %) of WPC. It is concluded that a judicious selection of additives in appropriate levels can develop rice doughs that possess the desirable handling properties leading to preparation of products. PMID- 26243906 TI - Storage behaviour and cooking quality of Indian potato varieties. AB - Tubers of forty four indigenous potato varieties were assessed for storage behaviour at room temperature, tuber dry matter content and cooking quality during 2010, 2011 and 2012. The maximum, minimum temperatures and relative humidity during storage period ranged between 26 to 40 degrees C, 17-28 degrees C and 18 to 82 %, respectively. The lowest total weight loss was recorded in variety Kufri Pushkar (7.7 %) followed by Kufri Lalima (7.9 %), Kufri Surya (8.3 %), Kufri Red (9.2 %), Kufri Dewa, Kufri Sheetman (9.3 %), Kufri Chandramukhi, Kufri Jyoti (9.5 %), Kufri Sindhuri (9.6 %), Kufri Kuber (9.7 %), Kufri Chipsona 1 (9.8 %), Kufri Kundan (9.9 %) and Kufri Chamatkar (10.0 %). Highest tuber dry matter content (%) was observed in Variety Kufri Kundan (24.2) followed by Kufri Himsona (23.7), Kufri Frysona (23.6), Kufri Kuber (22.7), Kufri Chipsona-2 (22.3). Kufri Khasigaro (22.0), Kufri Sheetman (21.9), Kufri Chipsona-3 (21.7) and lowest in Variety Kufri Khyati and Kufri Pukhraj (16.1 %). Of the total varieties, 14 were adjudged as floury, 15 mealy, 14 waxy and one (Kufri Ashoka) as soggy. The total weight loss had highly significant and positive correlation with sprout weight/Kg tubers (r = 0.76**), physiological weight loss (r = 0.97**). Based on the results potato varieties namely, Kufri Chamatkar, Kufri Chipsona-1, Kufri Chandramukhi, Kufri Dewa, Kufri Jyoti, Kufri Kuber, Kufri Kundan, Kufri Lalima, Kufri Lauvkar, Kufri Pushkar, Kufri Red, Kufri Safed, Kufri Sheetman, Kufri Sindhuri possessed excellent keeping quality with medium to long tuber dormancy, low storage losses, medium to high tuber dry matter and good flavour. The information generated in this study can be utilized in the breeding programme. This can also help the farmer to choose and cultivate the potato varieties as per demand of the consumers. PMID- 26243907 TI - A constitutive model for mechanical response characterization of pumpkin peel and flesh tissues under tensile and compressive loadings. AB - Enhancing quality of food products and reducing volume of waste during mechanical operations of food industry requires a comprehensive knowledge of material response under loadings. While research has focused on mechanical response of food material, the volume of waste after harvesting and during processing stages is still considerably high in both developing and developed countries. This research aims to develop and evaluate a constitutive model of mechanical response of tough skinned vegetables under postharvest and processing operations. The model focuses on both tensile and compressive properties of pumpkin flesh and peel tissues where the behaviours of these tissues vary depending on various factors such as rheological response and cellular structure. Both elastic and plastic response of tissue were considered in the modelling process and finite elasticity combined with pseudo elasticity theory was applied to generate the model. The outcomes were then validated using the published results of experimental work on pumpkin flesh and peel under uniaxial tensile and compression. The constitutive coefficients for peel under tensile test was alpha = 25.66 and beta = -18.48 Mpa and for flesh alpha = -5.29 and beta = 5.27 Mpa. under compression the constitutive coefficients were alpha = 4.74 and beta = 1.71 Mpa for peel and alpha = 0.76 and beta = -1.86 Mpa for flesh samples. Constitutive curves predicted the values of force precisely and close to the experimental values. The curves were fit for whole stress versus strain curve as well as a section of curve up to bio yield point. The modelling outputs had presented good agreement with the empirical values and the constructive curves exhibited a very similar pattern to the experimental curves. The presented constitutive model can be applied next to other agricultural materials under loading in future. PMID- 26243908 TI - Development of a novel cup cake with unique properties of essential oil of betel leaf (Piper betle L.) for sustainable entrepreneurship. AB - Betel vine (Piper betle L.) is a root climber with deep green heart shaped leaves. It belongs to the Piperaceae family. There is a huge wastage of the leaves during glut season and it can be reduced by various means including extraction of medicinal essential oil which can be considered as GRAS (generally recognized as safe) materials. Therefore, attempts were made to develop a novel cup cake by incorporating essential oil of betel leaf. The textural properties of the cakes were measured by texture analyzer instrument; whereas the organoleptic properties were adjudged by human preferences using sensory tables containing 9 point hedonic scale. Price estimation was done considering all costs and charges. Finally, all parameters of the developed cake were compared with different cup cakes available in the market for ascertaining consumer acceptability of the newly developed product in terms of quality and market price. Results revealed that the Novel cup cake developed with 0.005 % (v/w) essential oil of betel leaf occupied the 1st place among the four developed novel cup cakes. However, it occupied 4th place among the nine cup cakes in the overall preference list prepared based on the textural and organoleptic qualities, though its market price was calculated to be comparable to all the leading cupcakes available in the market. This indicates that manufacturing of novel cup cake with essential oil of betel leaf would be a profitable and self-sustaining entrepreneurship. PMID- 26243909 TI - Drying of chilli in a combined infrared and hot air rotary dryer. AB - The investigation of an economical and efficient drying method for chilli is beneficial because it could provide a means of overcoming the drawbacks of traditional drying methods: high operating power and long drying time, which result in a decrease in the quality of the chilli. This study involved the design and development of a combined infrared and hot air laboratory-scale rotary dryer, which consists of three operating modes: hot air, infrared, and combined infrared and hot air. Drying experiments were conducted at five different temperatures (50, 55, 60, 65, and 70 degrees C). The drying behavior produced with the three operating modes was evaluated. The best mode was determined based on the parameters for evaluating the quality of chilli, the power consumption, and the retention time. The results indicate that the optimal overall drying performance for chilli was achieved at 70, 65, 50 degrees C drying temperatures in hot air, combined, and IR mode, respectively. A positive correlation was observed between retention time and power consumption with the hot air and the combined modes, while a negative correlation was identified in the IR mode. PMID- 26243910 TI - Lipase catalyzed interesterification of rice bran oil with hydrogenated cottonseed oil to produce trans free fat. AB - Lipase catalyzed interesterification of rice bran oil (RBO) with hydrogenated cottonseed oil (HCSO) was carried out for producing a low trans free fat. The interesterification reaction was performed by varying parameters such as weight proportions of RBO and HCSO, reaction temperatures, time period and lipase concentration. Both non specific and specific lipases namely Novozym 435 and Lipozyme TL IM were employed for this study. Based on the data generated, the optimum reaction conditions were found to be: weight proportion of RBO and HCSO, 80:20; lipase concentration, 5 % (w/w) of substrates; reaction temperature, 60 degrees C; reaction time, 4 h for Lipozyme TL IM and 5 h for Novozym 435. The degree of interesterification, calculated based on the results of solid fat characteristics was used for comparing the catalytic activity of Novozym 435 and Lipozyme TL IM. It was observed that the degree of interesterification (DI) reached a near 100 % at the 4th hour for reaction employing Lipozyme TL IM with a rate constant of 0.191 h(-1) while Novozym 435 catalyzed reaction reached a near 100 % degree of interesterification at the 5th hour with a rate constant of 0.187 h(-1), suggesting that Lipozyme TL IM has a faster catalytic activity. PMID- 26243911 TI - Physicochemical and micro-structural properties of flours, starch and proteins from two varieties of legumes: bambara groundnut (Vigna subterranea). AB - This work is part of a large study aimed to evaluate the potential of bambara groundnut (Vigna subterranea) flour as starting raw material for the preparation of a widely cherished legume-based food product known as koki. Towards this objective, the flours from two varieties of bambara groundnut along with their respective starch and protein isolates were analyzed for some physicochemical and microstructural properties. It was observed that bambara flour contained appreciable amount of proteins (24.0-25.5 g/100 g), carbohydrates (57.9-61.7 g/100 g), fiber (3.45-3.68 g/100 g) and ash (3.65-3.85 g/100 g) with marginal differences between both varieties. The properties of starch and proteins isolated from the flours were different from one variety to another. In particular the starch granules of the white variety were larger (size range 10-35 MUm) and polygonal while those from the black variety were smaller (size range 6 15 MUm) and spherical in shape. In addition, the peak of gelatinization temperature was higher for white variety (81.7 degrees C) than for black variety (77.5 degrees C). The gelatinization temperature and the enthalpy of gelatinization of starch in the flours were systematically lower than for the starch isolates, suggesting an interaction of starch with other components on the gelatinization process. PMID- 26243912 TI - Microwave-assisted extraction and purification of chlorogenic acid from by products of Eucommia Ulmoides Oliver and its potential anti-tumor activity. AB - An efficient method for the rapid extraction, separation and purification of chlorogenic acid (CGA) from by-products of Eucommia Ulmoides Oliver (E. ulmoides) by microwave-assisted extraction (MAE) coupled with high-speed counter-current chromatography (HSCCC) was developed. The optimal MAE parameters were evaluated by response surface methodology (RSM), and they were extraction time of 12 min, microwave power of 420 W, ethanol concentration of 75 %, solvent/sample ratio of 30:1 (mL/g), yield of CGA reached 3.59 %. The crude extract was separated and purified directly by HSCCC using ethyl acetate-butyl alcohol-water (3:1:4, v/v) as the two-phase solvent system. The 14.5 mg of CGA with the purity of 98.7 % was obtained in one-step separation from 400 mg of crude extract. The chemical structure of CGA was verified with IR, ESI-MS analysis. Meanwhile, the purified CGA extract was evaluated by MTT assay and results indicate that CGA extract exhibited potential anti-tumor activity for AGS gastric cancer cell. PMID- 26243913 TI - Application of response surface methodology in optimization of lactic acid fermentation of radish: effect of addition of salt, additives and growth stimulators. AB - Lactic acid fermentation of radish was conducted using various additive and growth stimulators such as salt (2 %-3 %), lactose, MgSO4 + MnSO4 and Mustard (1 %, 1.5 % and 2 %) to optimize the process. Response surface methodology (Design expert, Trial version 8.0.5.2) was applied to the experimental data for the optimization of process variables in lactic acid fermentation of radish. Out of various treatments studied, only the treatments having ground mustard had an appreciable effect on lactic acid fermentation. Both linear and quadratic terms of the variables studied had a significant effect on the responses studied. The interactions between the variables were found to contribute to the response at a significant level. The best results were obtained in the treatment with 2.5 % salt, 1.5 % lactose, 1.5 % (MgSO4 + MnSO4) and 1.5 % mustard. These optimized concentrations increased titrable acidity and LAB count, but lowered pH. The second-order polynomial regression model determined that the highest titrable acidity (1.69), lowest pH (2.49) and maximum LAB count (10 * 10(8) cfu/ml) would be obtained at these concentrations of additives. Among 30 runs conducted, run 2 has got the optimum concentration of salt- 2.5 %, lactose- 1.5 %, MgSO4 + MnSO4- 1.5 % and mustard- 1.5 % for lactic acid fermentation of radish. The values for different additives and growth stimulators optimized in this study could successfully be employed for the lactic acid fermentation of radish as a postharvest reduction tool and for product development. PMID- 26243914 TI - Use of eugenol-lean clove extract as a flavoring agent and natural antioxidant in mayonnaise: product characterization and storage study. AB - Eugenol-lean fraction (98 % lower eugenol content than eugenol-rich fraction) having appreciable phytochemical properties was selectively isolated from clove buds (Syzygium aromaticum Linn) using supercritical carbon dioxide extraction at 40 degrees C and pressure of 25 MPa with static and dynamic time of 120 and 30 min respectively using ground clove powder which was previously subjected to steam distillation. The extract was used as a flavor ingredient (replacing mustard in classical formulation) and also as a source of natural antioxidant in formulating a new mayonnaise product to improve its nutraceutical value and shelf life. This product was found to be comparable to the mustard formulated sample (experimental control) organoleptically. The sample did not have typical pungency of clove and had improved physical properties such as increased color tonality with higher chroma values, lower thermal and non-thermal creaming, homogenous and compact microstructure and higher consistency index vis-a-vis the control and standard market samples, even at the end of the storage period of 6 months. Mayonnaise formulated with eugenol-lean clove extract had significantly higher antioxidant activity (IC50 = 10.85 mg/mL), phenolic content (1.89 mg gallic acid equivalent/g mayonnaise) and reducing power (11.29 mg BHT equivalent/g mayonnaise) than mustard-formulated mayonnaise and the market sample. While, the antioxidant activity and phytochemical properties tend to decrease after 30 days for the reference market sample and after 90 days for the experimental control sample, the mayonnaise formulated with eugenol-lean clove extract was found to be stable beyond 6 months. PMID- 26243915 TI - Drying characteristics of ultrasound assisted hot air drying of Flos Lonicerae. AB - Ultrasound assisted hot air drying of Flos Lonicerae was investigated in this study. The effects of drying parameters such as ultrasonic radiation distance, ultrasonic power and drying temperature on drying characteristics were discussed. The results showed that ultrasound application has positive and significant effects on hot air drying. Shortening ultrasonic radiation distance is beneficial to improve both ultrasonic energy efficiency and drying rate. Higher ultrasonic power had more positive and significant effects on drying rate. The influence of ultrasound power on drying rate decreased along with the decrease of moisture content during drying process, especially at low ultrasound powers. The increase of drying temperature significantly caused the reduction of drying time. D eff values ranged from 5.05 * 10(-11) to 20.33 * 10(-11) m(2)/s in ultrasound assisted hot air drying of Flos Lonicerae, and increased with the increase in drying temperature and ultrasonic power. The corresponding activation energy values ranged from 28.90 to 36.05 kJ/mol, and decreased with the increase in applied ultrasonic power. Therefore, ultrasound assistance is a helpful and promising method to enhance hot air drying process. PMID- 26243916 TI - Drying kinetics of syrup of Parinari curatellifolia fruit and cereal based product, zvambwa. AB - Drying properties of syrup prepared from Parinari curatellifolia fruit and cereal based product, zvambwa prepared from the syrup and finger millet (Eleusine coracana) meal were studied using a convective tray drier at temperatures ranging from 30 to 80 degrees C and air velocity of 0.72 m/s. Nine mathematical models namely Henderson and Pabis, Lewis, Midilli et al., Modified Page, Page, Two Term, Weibull, Modified Page Equation (II) and Wang and Singh were fitted to data for thin layer drying of the products using non-linear regression analysis. Thin layer drying processes for the syrup and zvambwa were best described by the Modified Page model. Effective moisture diffusivities for drying of syrup were higher than those for drying of zvambwa. The activation energies for drying of syrup and zvambwa were 21.0 +/- 2.0 kJ/mol and19.0 +/- 2.0 kJ/mol respectively. PMID- 26243917 TI - Feasibility study of date (Phoenix dactylifera L.) fruit syrup-based natural jelly using central composite design. AB - A feasibility study of natural fruit jelly from three Algerian raw materials, namely date (Phoenix dactylifera l.) fruit syrup and suspension of orange albedo powder (OAP) in lemon juice (LJ) was performed by response surface methodology (RSM) based on central composite design (CCD). The textural properties of the final jelly were investigated through two dependent variables: hardness and stickiness. The cooking temperature (X1), corresponding to that of thermo stated oil bath, and cooking time (X 2), taken for heating the initial fruit mixture in the oil bath (from ambient temperature without fixing however, the final temperature), were found to be the most influent factors, compared to degrees Brix of date syrup (X3) and temperature (X4) of the cooling stage following the cooking process. Results have also shown that the second-degree polynomial models correctly fit experimental data (R(2), adjusted R(2) (R(2) adj) and cross validation (Q(2)) ~ 1). Considering textural properties of commercial jellies as a reference, it was found that the cooking temperature of 155 degrees C for 10 min gave a jelly with suitable textural properties. On the other hand, FT-IR spectra revealed that the structure of such jelly was partially close to that of pectin molecules. Finally, the color analysis in the CIELab system of the fruit mixture over the cooking process showed that both lightness (L(*)) and a*/b* ratio were not affected by the experienced temperature range (80-155 degrees C). PMID- 26243918 TI - The effect of long-term storage on the quality of sterilized processed cheese. AB - The aim of this work is to evaluate the effect three different storage temperatures (6, 23 and 40 degrees C) on the sterilized processed cheese quality during 24-month storage. Sterilized processed cheese (SPC) is a product with extended shelf life (up to 2 years). The samples of SPC were subjected to basic chemical analyses, i.e. pH-values, dry matter, fat, crude protein and ammonia content, and microbiological analyses, i.e. total number of microorganisms, number of coliforms, colony forming units of yeasts and/or moulds and spore forming microorganisms. Furthermore, amino acid content (ion-exchange chromatography), protein profile (SDS-PAGE) and fat globules size (image analysis of microscopic technique) were monitored and sensory analysis (scale test and pair comparative test) was implemented, too. Increasing storage temperature and length evoked decrease of total amino acid content and protein nutrition value, increase of ammonia amount, protein changes, enlargement of fat globule size and deterioration of sensory properties of SPC. All the changes grew expressive with increasing storage temperature and time. PMID- 26243919 TI - Characterization of major betalain pigments -gomphrenin, betanin and isobetanin from Basella rubra L. fruit and evaluation of efficacy as a natural colourant in product (ice cream) development. AB - Basella rubra L. (Basellaceae) commonly known as Malabar spinach is a leafy vegetable which accumulates pigments in its fruits. To find out the feasibility of utilizing pigment rich extracts of its fruit as natural food colourant, fruits at different stages were analysed for pigment profiling, carbohydrate content, physical dimensions and weight. Total betalains content increased rapidly from early (green) through intermediate (half-done red-violet) to matured stage (red violet). Maximum pigment content was observed in ripened fruits (143.76 mg/100 g fresh weight). The major betalain pigment characterized was gomphrenin I in ripened fruits (26.06 mg), followed by intermediate fruits (2.15 mg) and least in early fruits (0.23 mg) in 100 g of fresh deseeded fruits. Total carbohydrates content and the chroma values (redness) were also increased during ontogeny of B. rubra fruits. The textural characters of developing fruits showed the smoothness of green fruits with lower rupture force (0.16 N/s) than ripe ones (0.38 N/s). The pigment-rich fruit extract was used as natural colourant in ice-cream, to evaluate its effect on physicochemical properties and acceptability of the product. After six months of storage at -20 degrees C, 86.63 % colour was retained in ice-cream. The ice-cream had good overall sensorial quality and was liked by consumers indicating that addition of B. rubra fruit extract did not alter the sensory quality of the product. The colour values also indicate that there was no significant decrease of this pigment-rich extracts of fruits for its incorporation in food products. PMID- 26243920 TI - Predictive modelling for shelf life determination of nutricereal based fermented baby food. AB - A shelf life model based on storage temperatures was developed for a nutricereal based fermented baby food formulation. The formulated baby food samples were packaged and stored at 10, 25, 37 and 45 degrees C for a test storage period of 180 days. A shelf life study was conducted using consumer and semi-trained panels, along with chemical analysis (moisture and acidity). The chemical parameters (moisture and titratable acidity) were found inadequate in determining the shelf life of the formulated product. Weibull hazard analysis was used to determine the shelf life of the product based on sensory evaluation. Considering 25 and 50 % rejection probability, the shelf life of the baby food formulation was predicted to be 98 and 322 days, 84 and 271 days, 71 and 221 days and 58 and 171 days for the samples stored at 10, 25, 37 and 45 degrees C, respectively. A shelf life equation was proposed using the rejection times obtained from the consumer study. Finally, the formulated baby food samples were subjected to microbial analysis for the predicted shelf life period and were found microbiologically safe for consumption during the storage period of 360 days. PMID- 26243921 TI - Subcritical water extraction of antioxidant phenolic compounds from XiLan olive fruit dreg. AB - Olive fruit dreg (OFD), waste from olive softdrink processing, has caused disposal problems. Nevertheless, OFD is a good source of functional ingredients, such as phenolic compounds. This study investigated the extraction conditions of phenolic compounds from OFD by using subcritical water (SCW) extraction method, antioxidant activity of SCW extracts, and components of phenolic compounds by LC MS. SCW extraction experiments were performed in a batch stainless steel reactor at temperatures ranging from 100 to 180 degrees C at residence time of 5 to 60 min, and at solid-to-liquid ratio of 1:20 to 1:60. Higher recoveries of phenolic compounds [37.52 +/- 0.87 mg gallic acid equivalents (GAE)/g, dry weight (DW)] were obtained at 160 degrees C, solid-to-liquid ratio of 1:50, and extract time of 30 min than at 2 h extraction with methanol (1.21 +/- 0.16 mg GAE/g DW), ethanol (0.24 +/- 0.07 mg GAE/g DW), and acetone (0.34 +/- 0.01 mg GAE/g DW). The antioxidant activities of the SCW extracts were significantly stronger than those in methanol extracts at the same concentration of total phenolic contents. LC-MS analysis results indicated that SCW extracts contained higher amounts of phenolic compounds, such as chlorogenic acid, homovanillic acid, gallic acid, hydroxytyrosol, quercetin, and syringic acid. SCW at 160 degrees C, 30 min, and solid-to-liquid ratio of 1:50 may be a good substitute of organic solvents, such as methanol, ethanol, and acetone to recover phenolic compounds from OFD. PMID- 26243922 TI - Incorporation of Lactobacillus adjuncts culture to improve the quality of Feta type cheese made using buffalo milk. AB - Feta-type cheese was made from buffalo milk using commercial adjunct culture of Lactobacillus helveticus and Lactobacillus casei along with standard mesophillic cheese cultures. The sensory, biochemical and texture characteristics of the experimental cheeses were studied during ripening. Expert panellists observed, significant differences (P < 0.01) between the control and the experimental cheeses. The pH, titratable acidity, soluble protein and free fatty acid content of the experimental cheeses were found to be significantly (P < 0.01) higher than those of the control. The texture parameter values of the experimental cheeses were found to be significantly (P < 0.01) lower than values of the control. PMID- 26243923 TI - Making soy sauce from defatted soybean meal without the mejus process by submerged cultivation using thermophilic bacteria. AB - The diversity of thermophilic bacteria was not significantly altered while growing in a defatted soybean meal (DFSM) slurry at 60 degrees C for 10, 20, and 30 days. Five species of thermophilic bacteria, which belong to the genera Aeribacillus (temperature gradient gel electrophoresis [TGGE] band no. 1), Saccharococcus (TGGE band no. 2), Geobacillus (TGGE band no. 3), Bacillus (TGGE band no. 4), and Anoxybacillus (TGGE band no. 5), were detected in the fermenting DFSM slurry. The cell-free culture fluid obtained from the fermenting DFSM slurry on day 14 hydrolyzed starch and soy protein at 60 degrees C but not at 30 degrees C. Soy sauce (test soy sauce) was prepared from the fermented DFSM slurry after a 30 day cultivation at 60 degrees C and a 60 day ripening at 45 degrees C. Free amino acid (AA) and organic acid contents in the soy sauce increased in proportion to the fermentation period, whereas ammonium decreased proportionally. Mg and Ca contained in the soy sauce decreased proportionally during fermentation and were lower than those in the non-fermented DFSM extract (control). Spectral absorbance of soy sauce prepared from the fermented DFSM slurry was maximal at 430 nm and increased slightly in proportion to the fermentation period. The aroma and flavor of the test soy sauce were significantly different from those of traditional Korean soy sauce. Conclusively, soy sauce may be prepared directly from the fermented DFSM slurry without meju-preparing process and fermentation period may be a factor for control of soy sauce quality. PMID- 26243924 TI - Gelling ability of kefiran in the presence of sucrose and fructose and physicochemical characterization of the resulting cryogels. AB - In this work, the influence of sucrose and fructose on the gel-forming capacity of kefiran was investigated as well as the physicochemical characteristics of the resulting gels. The addition of sugar to gel-forming solutions did not alter the pseudoplastic flow properties of kefiran solutions and after one freeze-thaw cycle translucent gels with high water-holding capability were obtained. A highly porous matrix was revealed by microscopy whose pore size varied with sugar concentration. Sucrose and fructose had different effects on the rheological characteristics of sugar-kefiran gels. An increment in the strength of the gels with progressive concentrations of sucrose was evidenced by an increase in the elastic modulus (G'), indicating that sucrose reinforces the binding interactions between the polymer molecules (p <= 0.05). A drastic reduction in elastic modulus occurred, however, when 50.0 % w/w sucrose was added to kefiran gels, resulting in less elasticity. In contrast, when fructose was added to kefiran gels, elastic modulus decreased slightly with progressive sugar concentrations up to 10 %, thereafter increasing up to 50 % (p <= 0.05). Supplementation with up to 30 % sugar contributed to water retention and increased the viscous modulus. The relative increment in the elastic and viscous moduli elevated the loss tangent (tandelta) depending on the type and concentration of sugar. Sugars (sucrose, fructose) present in the matrix of the polysaccharide networks modified water polymer and polymer-polymer interactions and consequently changed the gels' physicochemical characteristics, thus allowing the possibility of selecting the appropriate formulation through tailor-made kefiran cryogels. PMID- 26243925 TI - RSM based optimized enzyme-assisted extraction of antioxidant phenolics from underutilized watermelon (Citrullus lanatus Thunb.) rind. AB - Enzyme assisted solvent extraction (EASE) of phenolic compounds from watermelon (C. lanatus) rind (WMR) was optimized using Response Surface Methodology (RSM) with Rotatable Central Composite Design (RCCD). Four variables each at five levels i.e. enzyme concentration (EC) 0.5-6.5 %, pH 6-9, temperature (T) 25-75 degrees C and treatment time (t) 30-90 min, were augmented to get optimal yield of polyphenols with maximum retained antioxidant potential. The polyphenol extracts obtained under optimum conditions were evaluated for their in-vitro antioxidant activities and characterized for individual phenolic profile by RP HPLC-DAD. The results obtained indicated that optimized EASE enhanced the liberation of antioxidant phenolics up to 3 folds on fresh weight basis (FW) as compared to conventional solvent extraction (CSE), with substantial level of total phenolics (173.70 mg GAE/g FW), TEAC 279.96 mg TE/g FW and DPPH radical scavenging ability (IC50) 112.27 mg/mL. Chlorogenic acid (115.60-1611.04), Vanillic acid (26.13-2317.01) and Sinapic acid (113.01-241.12 MUg/g) were major phenolic acid found in EASEx of WMR. Overall, it was concluded that EASE might be efficient and green technique to revalorize under-utilized WMR into potent antioxidant phenolic for their further application in food and nutraceutical industries. PMID- 26243926 TI - Effects of pectinase clarification treatment on phenolic compounds of pummelo (Citrus grandis l. Osbeck) fruit juice. AB - The purpose of this study is to investigate the changes occured on phenolic compounds between two Malaysian varieties of pummelo fruit juice: Ledang (PO55) and Tambun (PO52) post-enzymatic clarification. The changes in polyphenols composition were monitored using High Performance Liquid Chromatography Diode Array Detection and Folin Ciocalteu's method. Clarification treatment of pummelo fruit juice with a commercial pectinase was optimized based on incubation temperature, time and enzyme concentration. Both varieties of pummelo fruit juice were treated with different optimized variables which produced the highest clarities with the least effect to the juice physical quality. Tambun variety was found to have significantly more total phenolic compounds (p <0.05) in comparison to Ledang variety, possibly due to the amount of naringin. Three types of hydroxycinnamic acids (chlorogenic, caffeic and coumaric acid) and three compounds of flavanones (naringin, hesperidin and narirutin) were found in both fruit juices, where naringin and chlorogenic acid were the major contributor to the total phenolic content. Naringin, which gave out bitter aftertaste to the juice, was found to decrease, 1.6 and 0.59 % reduction in Ledang and Tambun respectively, post-enzymatic treatment. The decrease in naringin, albeit nominal, could be a potential benefit to the juice production in reducing the bitterness of the juice. Post-enzymatic analysis furthermore resulted in no significance differences (p <0.05) on the total phenolic compounds of both varieties. This study in summary provides a compositional database for Malaysian pummelo fruit juice of various phenolic compounds, which can provide useful information for evaluating the authenticity and the health benefits from the juice. PMID- 26243927 TI - Use of UV-C postharvest treatment for extending fresh whole tomato (Solanum lycopersicum, cv. Zinac) shelf-life. AB - The effect of UV-C treatments (0.32, 0.97, 2.56, 4.16 and 4.83 kJ.m(-2) at 254 nm) on the physical-chemical properties [colour, texture, total phenolic content (TPC), weight loss (WL)], and mesophylic counts of whole tomato, was evaluated during 15 days at 10 degrees C. During storage, the Ctr samples acquired faster red colour than all UV-C samples (higher a* and lower degrees h values). Comparing texture of Ctr and UV-C samples at 15(th) storage day, an increase of 9 and 8 % on firmness of treated samples at low UV-C intensities (0.32 and 0.97 kJ.m(-2), respectively) was observed. At the end of the storage, Ctr samples showed ca. 4 Log10 of mesophylic load, and the samples treated at 0.97 and 4.83 kJ.m(-2) revealed the lowest microbial load (1.9 and 3.2 Log10, respectively). These results indicate that UV-C radiation, at an appropriate dose, combined with low storage temperature (10 degrees C) are an effective method to preserve the postharvest life of tomato, without adversely affecting quality parameters. PMID- 26243928 TI - Development of flaxseed fortified rice - corn flour blend based extruded product by response surface methodology. AB - Flaxseed imparted the evidence of health benefits in human being. Response surface methodology (RSM) was employed to develop flaxseed fortified rice - corn flour blend based extruded product using twin screw extruder. The effect of roasted flaxseed flour (RFF) fortification (15-25 %), moisture content of feed (12-16 %, wb), extruder barrel temperature (120-140 degrees C) and screw speed (300-330 RPM) on expansion ratio (ER), breaking strength (BS), bulk density (BD) and overall acceptability (OAA) score of extrudates were investigated using central composite rotatable design (CCRD). Increased RFF level decreased the ER and OAA score significantly while increased BS and BD of extrudates (p < 0.01). Moisture content of extruder feed was positively related to ER (p < 0.01) and OAA (p < 0.05) and negatively related to BD (p < 0.01). Extruder barrel temperature was found to be negatively related to ER and OAA (p < 0.05) and positively related to BD (p < 0.1). Quadratic effect of screw speed was significantly positively related to ER (p < 0.01), BS (p < 0.05) and negatively related to BD (p < 0.01). 15 % RFF fortification with rice flour, 16 % moisture content (wb) of extruder feed, 120 degrees C extruder barrel temperature and 330 RPM of screw speed gave an optimized product of high desirability with corresponding responses as 3.08 ER, 0.53 kgf BS, 0.106 g.cm(-3) BD and 7.86 OAA. PMID- 26243929 TI - Cereal bars enriched with antioxidant substances and rich in fiber, prepared with flours of acerola residues. AB - In the processing for obtaining acerola juice, a large amount of residues, which is usually discharged, is generated (seeds and bagasse). Adding value to these by products is of great interest, since their use can enrich human food as a good source of nutrients and dietary fiber. In this study, acerola seed flours (ASF) and acerola bagasse flours (ABF) were used to develop cereal bars (CB) in different combinations with brown oats: CB 1: control - with the addition of 25% brown oats, CB 2: with the addition of 12.5% ASF and 12.5% ABF, CB 3: with the addition of 6.25% ASF and 18.75% ABF, CB 4: with the addition of 12.5% ASF and 12.5% brown oats and CB 5: with the addition of 12.5% ABF and 12.5% brown oats. These bars were sensorially evaluated and CB 1, CB 4 and CB 5 received the highest scores. We conclude that CB 4 and CB 5 can be considered as products with enhanced nutritional value, containing iron with a low energetic value and high levels of dietary fibre, besides being enriched with antioxidants. PMID- 26243930 TI - Development of functional canned and pouched tuna products added inulin for commercial production. AB - Four formulas of canned tuna in spring water and tuna in mayonnaise and pouched tuna in salad cream and tuna in thousand island cream with added inulin were developed for commercial production. The effects of the addition of a prebiotic (inulin, Orafti(r)-HP) on the color and sensory properties of these products were studied. For inulin concentrations studied (3, 5, 7 and 10 %, w/w) caused more intensed yellow and red colors. Hedonic sensory values of tuna packed in spring water and in mayonnaise showed no significant differences (p > 0.05) among products with different inulin addition levels (3, 5, 7 and 10 %, w/w) in terms of color, flavor, sweetness and overall characteristics. However, when packed in thousand island cream, significant differences (p < 0.05) in color and overall characteristics were found when inulin was added higher than 7 %. Tuna in salad cream showed significant differences (p < 0.05) in color, flavor, sweetness and overall characteristics at higher than 7 % inulin. The panelists showed acceptable overall liking scores at upto 7 % inulin of all tuna products. The thermal sterilization process resulted in approximately 20 % decrease in final inulin content. The calculated residual fructans of finished products at shelf life of 3 years were 3.01, 2.78, 2.90 and 2.84 % for tuna in spring water, tuna in mayonnaise, tuna in thousand island and tuna in salad cream, respectively. Considering formula cost in a commercial production and the recommended daily intake (RDI) of inulin in the finished product at end of shelf life (>=3 g/d), an addition of 5 % inulin for tuna in spring water and 7 % inulin for tuna in mayonnaise, tuna in thousand island and tuna in salad cream are recommended. PMID- 26243931 TI - Effect of coated and uncoated ground flaxseed addition on rheological, physical and sensory properties of Taftoon bread. AB - Flaxseed is used to fortify bread. In order to reduce cyanogenic glycosides compounds of flaxseed, ground flaxseed was incubated at 30 degrees C and heated in a kitchen microwave oven. The cyanogenic compounds of flaxseed were reduced to 13.4 %. Treated ground flaxseed was coated with Arabic gum solution containing ascorbic acid and hydrogenated fat and was stored at 25 degrees C for 80 days in order to prevent oxidation of flaxseed oil. Results showed that oxidation in coated samples was lower than that in control samples and that there was a significant difference between them (p < 0.01). Coated and uncoated ground flaxseed was added to wheat flour in 5, 15 and 25 % levels in order to produce fortified Taftoon bread. Rheological, physical and organoleptic tests were carried out in order to evaluate dough and bread properties. Results showed that with increasing coated and uncoated ground flaxseed percentages, a decrease in water absorption and an increase in stability, dough development and relaxation time of dough occurred. The lowest water absorption was observed by adding 25 % coated ground flaxseed with hydrogenated fat. The highest dough development and dough stability time were observed by adding 25 % coated ground flaxseed with Arabic gum. Results indicated that coated and uncoated ground flaxseed has a good effect on decreasing the staling rate compared to the control bread. Results of organoleptic test showed that bread with 5 and 15 % coated and uncoated ground flaxseed had better acceptability. PMID- 26243932 TI - Effect of grilling and baking on physicochemical and textural properties of tilapia (Oreochromis niloticus) fish burger. AB - The influence of two common cooking methods, grilling and baking, on chemical composition, water retention, fat retention, cooking yield, diameter reduction, expressible water, color and mechanical texture of tilapia (Oreochromis niloticus) fish burgers was investigated. Texture analyses were performed using a Warner-Bratzler test. The fish burger had a softer texture with a lower shear force than other meat products reported in the literature. There were no significant differences in proximate composition, diameter reduction, fat retention and expressible water between the grilled and oven-baked fish burgers. Cooking methods did not affect the cooking times and cooking rates. Warner Bratzler parameters and color were significantly influenced by the cooking method. Grilling contributed to a shear force and work of shearing increase due to the lower cooking yield and water retention. Raw burgers had the highest L* (69.13 +/- 0.96) and lowest b* (17.50 +/- 0.75) values. Results indicated that baking yielded a product with better cooking characteristics, such as a desired softer texture with lower shear values (4.01 +/- 0.54) and increased water retention (95.82 +/- 0.77). Additionally, the baked fish burgers were lighter (higher L*) and less red (lower a*) than the grilled ones. PMID- 26243933 TI - Enhanced oxidative stability of fish oil by encapsulating in culled banana resistant starch-soy protein isolate based microcapsules in functional bakery products. AB - Oil in water emulsions were produced by the mixture of culled banana resistant starch (CBRS) & soy protein isolate (SPI), mixture of Hylon VII & SPI and SPI with 7.5 and 5 % (w/w) Menhaden fish oil. The emulsions were further freeze- dried obtaining 33 and 50 % oil load microcapsules. The range of particles diameter was 4.11 to 7.25 MUm and viscosity was 34.6 to 146.48 cP of the emulsions. Compressibility index (CI), Hasner ratio (HR) and angle of repose (AR) was significantly (p < 0.01) lower of the microcapsules made with starch and protein (CBRS & SPI and Hylon VII & SPI) than that made with protein (SPI) only. Microcapsules composed of CBRS & SPI with 33 % oil load had maximum microencapsulation efficiency (82.49 %) and highest oxidative stability. Muffin made with emulsions containing mixture of CBRS & SPI exhibited less fishy flavour than that containing mixture of Hylon VII & SPI. PMID- 26243934 TI - Evaluation of nutritional, textural and particle size characteristics of dough and biscuits made from composite flours containing sprouted and malted ingredients. AB - Composite flours (CF) using cereals, legumes, millets, soy-protein isolate, dairy ingredient and fruit without refined flour were used for preparing multi-nutrient biscuits. Dough and biscuits were evaluated for physical, nutritional and textural properties, particle size, colour and sensory evaluation and compared against refined-flour biscuits (C). Effect of malting and sprouting on biscuit quality were also analyzed. The highest volume of particles for CF was 140 MUm higher than C flour. CF biscuits had significantly (p <= 0.05) lower spread ratio and % weight loss compared to C. The hardness, stickiness and cohesiveness values of CF doughs were significantly (p <= 0.05) lower than C resulting in lower cutting strength and increased hardness of CF biscuits. Sprouting further decreased hardness of CF dough. Nutrient content of CF biscuits (sprouted and unsprouted) were significantly (p <= 0.05) higher than C biscuits. Sensory evaluation showed CF biscuits especially with sprouted flour had higher acceptability and were superior to C. PMID- 26243935 TI - Nutraceutical enriched Indian traditional chikki. AB - Chikki or peanut brittle, a traditional sweet snack was chosen as vehicle for enrichment with added natural nutraceuticals through herbs. The formulation and process for preparation of chikki with added herbs like ashwagandha (Withania somenifera), tulasi (Ocimumsanctum L.) and ajwain (Trachyspermum ammi S.) were standardized. The polyphenol content of chikki with added herbs ranged 0.29-0.46 g/100 g. Among the herbs, ajwain showed more potent antioxidant activity followed by tulasi, whereas ashwagandha and product prepared with it showed the least activity. Total carotenoid contents of chikki with added herbs ranged between 1.5 and 4.3 mg/100 g. Storage studies showed that chikki prepared with tulasi and ajwain were sensorily acceptable up to 90 days, while rancid notes were observed in control and chikki with added ashwagandha at the end of 30 days. Thus chikki with added herbs in addition to containing natural nutraceuticals like polyphenols and carotenoids had improved storage stability compared to control. PMID- 26243936 TI - Comparative study on nutritional and sensory quality of barnyard and foxtail millet food products with traditional rice products. AB - Millets have the potential to contribute to food security and nutrition, but still these are underutilized crops. The present study was undertaken with a view to analyse the physico-chemical, functional and nutritional composition of foxtail millet, barnyard millet and rice and to compare the sensory quality and nutritive value of food products from foxtail and barnyard millet with rice. Analysis of physico- chemical and functional characteristics revealed that the thousand kernel weight of foxtail millet, barnyard millet and rice was 2.5, 3.0 and 18.3 g, respectively and thousand kernel volume was 1.6, 13 2.0 and 7.1 ml, respectively. The water absorption capacity of foxtail millet, barnyard millet and rice was 1.90, 1.96 and 1.98 ml/g, respectively and water solubility index was 2.8, 1.2 and 1.0 %, respectively. Viscosity was measured for foxtail millet (1650.6 cps), barnyard millet (1581 cps) and rice (1668.3 cps). Analysis of nutritional composition showed that the moisture content of foxtail millet, barnyard millet and rice was 9.35, 11.93 and 11.91 %, respectively. The total ash, crude protein, crude fat, crude fibre and carbohydrate of foxtail millet were 3.10, 10.29, 3.06, 4.25 and 69.95 %, respectively, for barnyard millet were 4.27, 6.93, 2.02, 2.98 and 71.87 %, respectively and the corresponding values for rice were 0.59, 6.19, 0.53, 0.21 and 80.58 %, respectively. The energy value for foxtail millet, barnyard millet and rice was 349, 407 and 352 Kcal, respectively. The foxtail millet contained 30.10 mg/100 g calcium and 3.73 mg/100 g iron whereas barnyard millet contained 23.16 mg/100 g calcium and 6.91 mg/100 g iron. Values of 10 mg/100 g calcium and 0.10 mg/100 g iron were observed for rice. The formulated products viz. laddu, halwa and biryani from foxtail millet, barnyard millet and rice (control) were analysed for their sensory qualities. Among the products prepared, there was non significant difference with regard to the colour, flavor, texture, appearance and overall acceptability of foxtail and barnyard millet laddu and halwa when compared to control. Foxtail millet biryani was most acceptable compared to barnyard millet and control biryani. Nutritive value of formulated products was calculated and it was compared with the rice. The protein, fat and fibre content of the formulated products from foxtail and barnyard millet were higher than the rice products. Thus from the present study it was concluded that the foxtail millet and barnyard millet are superior in nutritive value to rice and have potential for use in traditional food products. PMID- 26243937 TI - Hydrothermal treatment of rough rice: effect of processing conditions on product attributes. AB - A method involving hydration, tempering and heating steps is presented to process rough rice as alternative to traditional parboiling with pressure steam. The effects of temperature (66-84 degrees C), tempering time (60-420 min) and heating time (30-180 min) on gelatinization degree and milling yield were analyzed by response surface method (RSM). A maximum value of gelatinization degree (37.0 %) and milling yield of 67.7 % were reached with a process temperature of 84 degrees C using tempering and heating times of 178 and 104 min respectively. A slight reduction of crystallinity (14 %) and a significant improvement of nutritional value with increments of 150 and 60 % in riboflavin and calcium contents were obtained in comparison with control (untreated rice). Hardness and adhesiveness of processed rice were intermediate between those of control and completely gelatinized rice. The proposed method, with lower temperature requirements than traditional parboiling, is presented to obtain an alternative product, expanding consumer choices. PMID- 26243938 TI - DNA extraction techniques compared for accurate detection of genetically modified organisms (GMOs) in maize food and feed products. AB - In this paper, DNA extraction methods have been evaluated to detect the presence of genetically modified organisms (GMOs) in maize food and feed products commercialised in Turkey. All the extraction methods tested performed well for the majority of maize foods and feed products analysed. However, the highest DNA content was achieved by the Wizard, Genespin or the CTAB method, all of which produced optimal DNA yield and purity for different maize food and feed products. The samples were then screened for the presence of GM elements, along with certified reference materials. Of the food and feed samples, 8 % tested positive for the presence of one GM element (NOS terminator), of which half (4 % of the total) also contained a second element (the Cauliflower Mosaic Virus 35S promoter). The results obtained herein clearly demonstrate the presence of GM maize in the Turkish market, and that the Foodproof GMO Screening Kit provides reliable screening of maize food and feed products. PMID- 26243939 TI - Comparative analysis of improved soy-mozzarella cheeses made of ultrafiltrated and partly skimmed soy blends with other mozzarella types. AB - The objective of this study was to improve the physicochemical properties and functional qualities of soy based mozzarella cheeses by ultrafiltration (UF) of soy milk blends, adding skim milk instead of cow's milk or increasing the soy milk proportions in cheese milk. Eight types of mozzarella cheeses made using soy milk and analyzed for nutritional, structural, and functional characteristics for 4 weeks at 4 degrees C. Cheeses made with cow milk, 10, 20, and 30 % soy milk in cow milk, skim milk, 10 % soy milk in skim milk, and ultrafiltrated 10 % soy milk in cow milk for first and second volume concentrations. Refrigerated storage of the soy-mozzarella led to a decrease in total solid, mineral, protein, fat, and lactose contents and rheological characteristics after 2 weeks. The nutritive quality of the mozzarella tended to increase proportionally to soy milk content, but the physical and functional qualities decreased. The UF-fortified soy mozzarella showed more improved qualities among the other soy cheeses like long shelf life, improved nutritional, structural and functional qualities. Blends of 10-20 % soy milk and UF soy milk blends can be used to achieve good quality, nutritive mozzarella cheese, even with skim milk instead of cow milk in a milk shortage. PMID- 26243940 TI - Antioxidant activity of raspberry (Rubus fruticosus) leaves extract and its effect on oxidative stability of sunflower oil. AB - Efficacy of R. fruticosus leaves extract in stabilizing sunflower oil during accelerated storage has been studied. Extracts of R. fruticosus were prepared in different solvents which methanolic extract yield with 15.43 % was higher than water and acetone ones (11.87 and 6.62 %, respectively). Methanolic extract was chosen to evaluate its thermal stability at 70 degrees C in sunflower oil, due to the highest yield, antioxidant and antiradical potential and also high content of phenolic compounds campared to other solvents. So, different concentrations of methanolic extract (200, 400, 600, 800 and 1,000 ppm) were added to sunflower oil. BHA and BHT at 200 ppm served as standards besides the control. Peroxide value (PV) and thiobarbituric acid (TBA) were taken as parameters for evaluation of effectiveness of R. fruticosus leaves extract in stabilization of sunflower oil. Moreover, antioxidant activity index (AAI) of the extract at 120 degrees C at rancimat were conducted. Results from different parameters were in agreement with each other, suggesting the highest efficiency of 1,000 ppm of the extract followed by BHT, BHA and other concentrations of the extract. Results reveal the R. fruticosus leaves extract to be a potent antioxidant for stabilization of sunflower oil. PMID- 26243941 TI - In vitro antioxidant assay of medium chain fatty acid rich rice bran oil in comparison to native rice bran oil. AB - The study aimed to evaluate the in vitro antioxidant activity of medium chain fatty acid (MCFA) rich-rice bran oils in comparison with native rice bran oil. Different in vitro methods were used to evaluate the free radical scavenging activity, metal chelation activity, reducing acitivity, ABTS radical scavenging activity, thiobarbituric acid (TBA) value and so on at different concentrations of the oils such as 10-100 MUg/mL. Inhibition of lipid peroxidation was evaluated measuring thiobarbituric acid responsive substance (TBARS) and conjugated diene formation. All the oils showed potent antioxidant activity at 100 MUg/mL concentration. TBARS formation and conjugated diene formation was lower with MCFA rich oils i.e. the inhibition of lipid peroxidation was more in MCFA rich oils than original rice bran oil. Caprylic acid rich rice bran oil showed maximum antioxidant activity in comparison to capric- and lauric acid rich rice bran oils. Overall the MCFA rich rice bran oils showed to be more potent antioxidant than rice bran oil due to their lower unsaturated fatty acid content. PMID- 26243942 TI - Physico-chemical characteristics and stability aspects of coconut water and kernel at different stages of maturity. AB - Coconut water and kernel are the edible portions of the coconut. A study was carried out to evaluate the physico-chemical characteristics, phytonutrients and stability of coconut water (CW), kernel (CK) at different stages of maturity and commercial coconut products (CCP). The moisture content of CW, CK and CCP were in the range of 95-97 g 100 g(-1), 50-85 g 100 g(-1) and 0.4-3 g 100 g(-1) respectively. Fat content in CW was low (4-115 mg 100 g(-1)) whereas in kernel it was high (37-56 g 100 g(-1)). The CW was acidic in nature (pH 4.5-5.2). Ash content of CK decreased with maturity (1.0-1.5 %) whereas that of CW remained steady (0.3-0.4 g 100 g(-1)) with maturity. The total sugar content (3.9-4.6 g 100 g(-1)) and acidity (0.3-0.4 g 100 g(-1)) of CW did not change with maturity. The phenolics content increased in water (1.4-4.3 mg 100 g(-1)) and kernel with maturity (18.5-24.8 mg 100 g(-1)). The fatty acid composition of the oil extracted from the CK had increased saturated fatty acids (C12:0) (38-48 g 100 g( 1)) and decreased monounsaturated fatty acid (C18:1) (13-5 g 100 g(-1)) with maturity. The percentage of medium chain fatty acids increased with different stages of maturity (47-78 g 100 g(-1)). The CW and CK contained higher amount of phenolics (1.4-4.3 mg 100 g(-1) and 18.5-24.8 mg 100 g(-1) respectively) and total tocopherols of CK (0.14-0.59 mg 100 g(-1)) when compared to CCP. This study indicated that CW and CK could serve as valuable raw materials for the preparation of functional food supplement. PMID- 26243943 TI - Quality assessment of rainbow trout (Oncorhynchus mykiss) fillets during super chilling and chilled storage. AB - In order to evaluate the effect of super chilling (-3 degrees C) and chilled (3 degrees C) storage on the quality of rainbow trout fillets, total volatile base nitrogen (TVB-N), drip loss, pH, electric conductivity (EC), total aerobic count (TAC), K and related values, adenosine triphosphate (ATP) and related compounds, color and sensory score were determined and correlation between these indicators were analyzed. According to the comprehensive evaluation of TAC, K value and sensory score, the limit for acceptability of rainbow trout fillets was 5 days at 3 degrees C and 11 days at -3 degrees C. Additionally, the correlation coefficients between TVB-N and other freshness indicators (TAC, K value, sensory score) were relatively low. TVB-N may be inadequate for evaluating freshness changes of rainbow trout fillets compared with other indicators. Among the K and related values, H value was a better freshness indicator in rainbow trout fillets during chilled and super chilling storage for its better correlation coefficients with other freshness indicators. Super chilling storage could extend the shelf life of rainbow trout fillets by 6 days compared to chilled storage. PMID- 26243944 TI - Development of menaquinone-7 enriched nutraceutical: inside into medium engineering and process modeling. AB - Menaquinone 7 (MK-7) is nutritionally important metabolite found by fermentation mainly using B. subtilis species. In this study, soybean medium was modified to improve the MK-7 production using Bacillus subtilis NCIM 2708 under solid state fermentation. The objective of this study was to produce large amount of MK-7 within a short period of time. Nine nutritional components viz. glycerol, mannitol, dextrose, sucrose, yeast extract, malt extract, K2HPO4, MgSO4.7H2O and CaCl2 were investigated to obtain the maximum MK-7 concentration. The highest MK 7 concentration 39.039 MUg/g was obtained after 24 h of fermentation in the following optimised medium components: soybean 20 g, glycerol 40 ml/kg, mannitol 60 g/kg, yeast extract 4 g/kg, malt extract 8 g/kg and calcium chloride 4 g/kg. The maximum production of MK-7 56.757 MUg/g was predicted by point prediction tool of Design Expert 7.1 software (Statease Inc. USA). This data shows 68.78 % validity of the predicted model. PMID- 26243945 TI - Modeling of extraction process of crude polysaccharides from Basil seeds (Ocimum basilicum l.) as affected by process variables. AB - Basil seed (Ocimum basilicum L.) has practical amounts of gum with good functional properties. In this work, extraction of gum from Basil seed was studied. Effect of pH, temperature and water/seed ratio on the kinetic and thermodynamic parameters; entropy, enthalpy and free energy of extraction were investigated. The maximum gum yield was 17.95 % at 50 degrees C for pH=7 and water/seed ratio 30:1. In this study, the experimental data were fitted to a mathematical model of mass transfer and equations constants were obtained. The kinetic of Basil seed gum extraction was found to be a first order mass transfer model. Statistical results indicated that the model used in this study will be able to predict the gum extraction from Basil seed adequately. It also found that DeltaH and DeltaS were positive and DeltaG was negative indicating that the extraction process was spontaneous, irreversible and endothermic. The DeltaH, DeltaS and DeltaG values were 0.26-7.87 kJ/mol, 8.12-33.2 J/mol K and 1.62-4.42 kJ/mol, respectively. PMID- 26243946 TI - Simultaneous separation and determination of organic acids in blueberry juices by capillary electrophoresis- electrospray ionization mass spectrometry. AB - A sensitive and expeditious capillary electrophoresis-electrospray ionization mass spectrometry(CE-ESIMS) method for the separation, identification and determination of succinic, citric, salicylic, malic, benzoic, sorbic, ascorbic, and tartaric acid in blueberry juices has been developed. In order to obtain the analytical separation, CE-MS interface parameters(e.g., buffer pH and composition, sheath liquid and gas flow rates, sheath liquid composition, electrospray voltage, etc.) were carefully optimized. Eight organic acids were baseline separated in 8 min under optimum experimental conditions. The precisions for eight replicate separations of a standard mixture solution were 2.54-4.12 % for peak area and 0.85-2.12 % for migration time respectively. The linear ranges were 10.0-1000.0, 8.0-1000.0, 13.0-1000.0, 6.0-1000.0, 9.0-1000.0, 3.2-600.0, 6.0 1000.0 and 18.0-1000.0 MUg/L for succinic, citric, salicylic, malic, benzoic, sorbic, ascorbic, and tartaric acid with detection limits of 2.5, 2.0, 3.4, 1.5, 2.2, 0.8, 1.5, 4.5 MUg/L, respectively. The average recoveries of the eight components were between 86.8 and 99.8 % with RSDs of 1.8-5.3 %. The proposed method was applied to the simultaneous analysis of eight analytes in Blueberry Juice samples with satisfactory results. PMID- 26243948 TI - Changes in chemical and physical properties of Latin American wheat flour based tortillas substituted with different levels of distillers dried grains with solubles (DDGS). AB - Tortilla is the most popular type of bread both in South and Central America. Since the demand for this bread among different classes of society is significant, improving its nutrient content could be important. Distillers dried grains with solubles is good source of fiber and protein, and can be used in the fortification of tortilla. In this study, three levels of DDGS (0, 10 and 20 %) were substituted for wheat flour and the physical and chemical properties of the resulting products were evaluated. Results showed that for the 20 % DDGS level, minimum force was required to rupture the tortilla. The color of the tortillas substituted with 10 and 20 % DDGS were darker, being 64.11 and 59.99, respectively (P < 0.05). As for chemical properties, the samples fortified with 10 and 20 % DDGS had higher protein (9.35 and 10.78 % dried basis), fiber (2.21 and 2.33 % dried basis) and fat (23.60 and 24.65 % dried basis) values at P < 0.05. Thus, it appeared that using DDGS in wheat tortillas can improve some of the nutritional values such as protein and fiber as well as the textural properties of these breads. Further work should examine consumer acceptability of these products. PMID- 26243947 TI - Fermentation profile of Saccharomyces cerevisiae and Candida tropicalis as starter cultures on barley malt medium. AB - Saccharomyces cerevisiae C8-5 and Candida tropicalis F0-5 isolated from traditional sorghum beer were tested for kinetic parameters on barley malt extract, YPD (863 medium) and for alcohol production. The results showed that C. tropicalis has the highest maximum growth rate and the lowest doubling time. Values were 0.22 and 0.32 h(-1) for maximum growth rate, 3 h 09 min and 2 h 09 min for doubling time respectively on barley malt extract and YPD. On contrary, glucose consumption was the fastest with S. cerevisiae (-0.36 and -0.722 g/l/h respectively on barley malt extract and YPD). When these two yeasts were used as starters in pure culture and co-culture at proportion of 1:1 and 2:1 (cell/cell) for barley malt extract fermentation, we noticed that maltose content increased first from 12.12 g/l to 13.62-16.46 g/l and then decreased. The highest increase was obtained with starter C. tropicalis + S. cerevisiae 2:1. On contrary, glucose content decreased throughout all the fermentation process. For all the starters used, the major part of the ethanol was produced at 16 h of fermentation. Values obtained in the final beers were 11.4, 11.6, 10.4 and 10.9 g/l for fermentation conducted with S. cerevisiae, C. tropicalis, C. tropicalis + S. cerevisiae 1:1 and C. tropicalis + S. cerevisiae 2:1. Cell viability measurement during the fermentation by using flow cytometry revealed that the lowest mean channel fluorescence for FL3 (yeast rate of death) was obtained with C. tropicalis + S. cerevisiae 2:1 after 48 h of fermentation. PMID- 26243949 TI - Determination of lipolytic and proteolytic activities of mycoflora isolated from dry-cured teruel ham. AB - Fungi play a key role in dry-cured ham production because of their lipolytic and proteolytic activities. In the present study, 74 fungal strains from dry-cured Teruel hams and air chambers were tested for proteolytic and lipolytic activities, with a view to their possible use as starter cultures. Lipolytic activity of fungi was studied against lauric, palmitic, stearic and oleic acids, whereas proteolytic activity was studied against casein and myosin. Of the 74 fungal strains tested, most of them demonstrated lipolytic activity (94.59 %). Lipolytic activity against lauric and oleic acids was stronger than against palmitic and stearic acids. 39 strains (52.70 %) demonstrated proteolytic activity against casein and the 6 highest proteolytic strains were also tested for pork myosin proteolysis. Some strains belonging to Penicillium commune, Penicillium chrysogenum, Penicillium nalgiovense and Cladosporium cladosporioides were selected because of their significant proteolytic and lipolytic activities and could be suitable to use as starters in dry-cured ham. PMID- 26243950 TI - Effect of germination and fermentation on the proximate composition and functional properties of full-fat and defatted cucumeropsis mannii seed flours. AB - Germinated, fermented and raw Cucumeropsis mannii (melon) seeds were processed into flours. A portion of the flours were defatted using n-hexane; both the full fat and defatted flours were evaluated for proximate composition and functional properties. The proximate compositions of the full fat and defatted C. mannii seed flours were: moisture, 4.97-5.67 % and 6.17-8.13 %; total ash, 1.95-3.24 % and 4.38-7.19 %; crude protein, 36.62-39.91 % and 71.91-77.05 %; crude fat, 45.06 49.57 % and 1.56-2.57 %; crude fibre, 2.71-3.63 % and 4.34-4.59 %; carbohydrate, 3.78-4.07 % and 4.45-6.54 %, respectively. The functional properties of the flour from full-fat and defatted seed were: water absorption capacity, 116.67-183.33 % and 216.67-267.67 %; oil absorption capacity, 252.33-274.00 % and 292.00-345.00 %; foaming capacity 17.36-30.34 % and 34.78-44.69 %; foaming stability, 5.17 11.54 % and 11.41-14.55 %; least gelation concentration, 24.67-28.00 and 13.33 18.67 %; emulsion capacity, 49.73-79.28 mL/g and 40.34-65.61 mL/g; bulk density 0.65-0.81 g/mL and 0.36-0.39 g/mL; protein solubility 4.00-5.89 % and 5.21-7.11 %, respectively. Germination enhanced the water absorption capacity, foaming capacity and protein solubility while fermentation increased the emulsion capacity. Defatting improved the water and oil absorption capacities, foaming capacity and protein solubility. The flour from germinated seeds may find use as ingredients in food emulsion and salad dressing, while those from fermented seeds may be used as food thickeners. PMID- 26243951 TI - Rheological, physico-sensory, nutritional and storage characteristics of bread enriched with roller milled fractions of black gram (Phaseolus mungo L.). AB - Black gram grains were fractionated using roller flour mill. Effect of combination of additives (CA) namely dry gluten powder, sodium stearoyl-2 lactylate, fungal alpha-amylase on the rheological and bread making characteristics of wheat flour partly replaced with roller milled fractions of black gram was studied. With increase in the addition of straight run flour (SRF), protein rich fraction (PRF), protein and fiber rich fraction (P&FRF) from 0 to 20 %, fiber rich fraction, FRF (0-15 %), the farinograph water absorption increased and dough stability decreased; amylograph pasting temperature increased and peak viscosity decreased; bread volume decreased and crumb firmness value increased indicating adverse effect of these fractions on the rheological and bread making characteristics of wheat flour. Sensory evaluation showed that breads were acceptable only up to the level of 15 % for SRF, PRF & P&FRF and 10 % for FRF. However, when CA containing dry gluten powder, sodium stearoyl-2 lactylate and fungal alpha-amylase was incorporated the overall quality of the products improved. Use of these fractions increased the protein and fiber contents of bread by 1.24-1.66 and 1.48-3.79 times respectively. The results showed that possibility of utilising roller milled black gram fractions along with CA to improve the taste, texture and nutritional quality of bread. PMID- 26243952 TI - Formulation and pilot scale production of low-trans vanaspati with modified polyunsaturated fatty acids content. AB - Pilot scale production of low-trans vanaspati through a combination of techniques including non-selective hydrogenation of palmolein and physical blending of 3 vegetable oils, namely Canola, soybean and sunflower oils was investigated. Six formulations (A-F) of trans-free vanaspati were prepared. The fatty acid composition, peroxide value, acid value, iodine value, slip melting point (SMP), solid fat content (SFC) at 10-40 degrees C and oil/oxidative stability of the formulations were evaluated. The percentage of trans-fatty acids obtained for vanaspati formulations were within the value recommended by WHO (<4), except for B and D formulations (5.81 and 5.28, respectively). A and E formulations had the lowest trans-fatty acids content. The total saturated fatty acids (SFA) in the vanaspati formulations ranged from 22.96 to 30.11 %. Among the six formulations, A showed the significant percentage of SFA. The highest and the Lowest of linolenic acid contents were obtained for samples E (4.36 %) and F (0.28 %). Percentage of the monounsaturated fatty acids (MUFA) of the vanaspati formulations suggested an order from the highest to lowest as: A > C > E > F > D > B formulations. B formulation had the highest significant percentage of PUFA, followed by D, E, F, C, and A formulations. Only A vanaspati had the induction periods (IP) of higher than commercial low-trans vanaspati, while the lowest stability time belonged to sample B (10.20 h). SMP of all the vanaspati formulations was higher than the commercial low-trans vanaspati, but less than 40 degrees C. Although A and E formulations contained lower SFA than the commercial low-trans vanaspati, they indicated higher SFC at 20-40 degrees C. According to the above information, E and A formulations could be recommended as suitable formulations for further research in a larger scale. PMID- 26243953 TI - Ripening process of Cascaval cheese: compositional and textural aspects. AB - Two textural characteristics, elasticity modulus and firmness, were determined during the ripening process of Cascaval cheese, using both instrumental and sensorial techniques. Uniaxial compression was used to determine the textural characteristics and the results were compared with the ones obtained by sensorial analysis, revealing a good correlation. The chemical composition of cheese was also determined, including the nitrogen fractions (total nitrogen, water soluble nitrogen, non-protein nitrogen and phosphotungstic acid soluble nitrogen). The data thus obtained were statistically processed in order to find the differences between the samples, as well as to find the correlation between the techniques of analysis. The study showed that the ripening process of the Cascaval cheese is similar to the ripening of other pasta filata cheese. The moisture content decreases during maturation as a result of water evaporation. The concentration of nitrogen fractions increases during the ripening stage, and so do the firmness and elasticity modulus. The biochemical processes that occur during maturation largely influence the textural parameters and this is proved by both instrumental and sensorial analyses. PMID- 26243954 TI - Sensory aroma characteristics of alcalase hydrolyzed rice bran protein concentrate as affected by spray drying and sugar addition. AB - The sensory aroma characteristics of alcalase hydrolyzed rice bran protein concentrate as affected by spray drying and sugar addition were investigated. Rice bran protein concentrate (RBPC) was hydrolyzed by alcalase. Sucrose, glucose or fructose was added to the liquid rice bran protein hydrolysate (LRBPH) and subsequently spray dried. The sensory aroma intensities of the hydrolysates were evaluated. Results showed that after spray drying, the rice bran protein concentrate powder (RBPC-P) had higher sweet and cocoa-like aroma intensities than RBPC (p <= 0.05) and hydrolyzed rice bran protein powder (HRBPP) had higher milk powder-like aroma intensities than LRBPH (p <= 0.05). The sweet, cocoa-like and milk powder-like aroma intensities in hydrolyzed rice bran protein powder with fructose addition (HRBPP-F) were significantly higher (p <= 0.05) than those of hydrolyzed rice bran protein powder with sucrose or glucose addition (HRBPP-S or HRBPP-G). HRBPP-F had the highest overall aroma liking score. These results also indicate that spray drying and sugar addition could improve the sensory aroma characteristics of alcalase hydrolyzed RBPC. PMID- 26243955 TI - Purification and characterization of [Formula: see text]-mannanase from Bacillus pumilus (M27) and its applications in some fruit juices. AB - Thermo alkaline mannanase was purified from the bacteria of Bacillus pumilus (M27) using the techniques of ammonium sulphate precipitation, DEAE-Sephadex ion exchange chromatography and Sephacryl S200 gel filtration chromatography with 111 fold and 36 % yield. It was determined that the enzyme had 2 sub-units including 35 kDa and 55 kDa in gel filtration chromatography and SDS-PAGE electrophoresis systems. The optimum pH and temperature was determined as 8 and 60 degrees C, respectively. It was also noticed that the enzyme did not lose its activity at a wide interval such as pH 3-11 and at high temperatures such as 90 degrees C. Additionally, the effects of some metal ions on the mannanase enzyme activity. Moreover, the clarifying efficiency of purified mannanase enzyme with some fruit juices such as orange, apricot, grape and apple was also investigated. Enzymatic treatment was carried out with 1 mL L(-1) of purified mannanase for 1 h at 60 degrees C. It was determined that the highest pure enzyme was efficient upon clarifying the apple juice at 154 % rate. PMID- 26243956 TI - Quantification of minerals and trace elements in raw caprine milk using flame atomic absorption spectrophotometry and flame photometry. AB - This study reports minerals and trace elements quantification in raw caprine milk of Beetal breed, reared in Northern India and their feed, fodder & water using flame atomic absorption spectrophotometry and flame photometry. The mineral and trace elements' concentration in the milk was in the order: K > Ca > Na > Fe > Zn > Cu. The results showed that minerals concentration in caprine milk was lesser than reference values. But trace elements concentration (Fe and Zn) was higher than reference values. Multivariate statistical techniques, viz., Pearsons' correlation, Cluster analysis (CA) and Principal component analysis (PCA) were applied to analyze the interdependences within studied variables in caprine milk. Significantly positive correlations were observed between Fe - Zn, Zn - K, Ca - Na and Ca - pH. The results of correlation matrix were further supported by Cluster analysis and Principal component analysis as primary cluster pairs were found for Ca - pH, Ca - Na and Fe - Zn in the raw milk. No correlation was found between mineral & trace elements content of the milk and feed. PMID- 26243957 TI - A Non-destructive method to assess freshness of raw bovine milk using FT-NIR spectroscopy. AB - A non-destructive method to analyze the freshness of raw milk was developed using a FT-NIR spectrometer and a fiber optic probe. Diffuse transmittance spectra were acquired in the spectral range 833 ~ 2,500 nm from raw milk samples collected from Northwest A&F University Animal Husbandry Station. After each spectral acquisition, quality parameters such as acidity, pH, and lactose content were measured by traditional detection methods. For all milk samples, PLS (partial least square regression), MLR (multiple linear regression), and ANN (artificial neural networks) analyses were carried out in order to develop models to predict parameters that were indicative of freshness. Predictive models showed R(2) values up to 0.9647, 0.9876 and 0.8772 for acidity, pH, and lactose content, respectively (validation set validations). The similarity analysis and classification between raw milk freshness during storage was also conducted by means of hierarchical cluster analysis. Over an 8 day storage period, the highest heterogeneity was evident between days 1 and 2. PMID- 26243958 TI - Detection and quantitative determination of diethylene glycol in ethyl alcohol using gamma- ray spectroscopy. AB - Determination of the toxic diethylene glycol contamination in ethyl alcohol demands a rapid, accurate and reliable method. Diethylene glycol (DEG) ingestion, accidental or intentional, can lead to death. Clinical and analytical methods used to detect diethylene glycol in alcohol require several hours to days due to tedious instrument handling and measurements. Enzymatic assays face difficulty due to analytic problems. As an alternative method of data analysis, we have used gamma-ray spectroscopic method to estimate the diethylene glycol contamination in alcohol by monitoring the variation in the linear and mass attenuation coefficients. This method is simple, robust, portable and can provide reliable and quantitative information about the ethyl alcohol adulterated with diethylene glycol which is of broader interest to society. PMID- 26243959 TI - Evaluation of antibiofilm effect of benzalkonium chloride, iodophore and sodium hypochlorite against biofilm of Pseudomonas aeruginosa of dairy origin. AB - The present study was undertaken with objectives of; a) to investigate and compare Pseudomonas aeruginosa isolates from two dairies for biofilm formation potential and, b) to compares three common biocides for biofilm eradication efficiencies. Amongst the isolates from commercial dairy, 70 % were strong and/or moderate biofilm former in comparison to 40 % isolates from small scale dairy. All isolates, irrespective of source, exhibited higher susceptibility to biocides in planktonic stage than in biofilm. Antibiofilm efficiencies of three biocides i.e. benzalkonium chloride, sodium hypochlorite and iodophore were determined in terms of their microbial biofilms eradicating concentration (MBEC). Our findings show that the three biocides were ineffective against preformed biofilms at recommended in-use concentrations. Biofilms were the most resistant to benzalkonium chloride and least against iodophore. A trend of decreasing MBECs was observed with extended contact time. The findings of present study warrant for a systematic approach for selecting types and concentrations of biocide for application as antibiofilm agent in food industry. PMID- 26243960 TI - Toxinotyping and antimicrobial susceptibility of enterotoxigenic Clostridium perfringens isolates from mutton, beef and chicken meat. AB - A total of 300 meat samples comprising mutton, beef, and chicken meat (n = 100) collected from either local butcher shops or large meat outlets situated at various areas of Lahore City located in Punjab province of Pakistan were tested for the isolation of Clostridium perfringens. Prevalence of the organism was highest in the chicken (6 %) followed by mutton (5 %) and beef (1 %). Contamination level was high (10/150) in the samples collected from local butcher shops in comparison to the samples collected from large meat outlets (2/150). All of the raw meat samples were negative for the presence of alpha, beta and epsilon toxins of C. perfringens as detected through ELISA. Out of a total number of 12 isolates only half were capable of producing enterotoxins when cultured in trypticase glucose yeast (TGY) broth. Toxinotyping of the isolates showed that 3 were of type A while one each of the remaining three belonged to type B, C, and D. Antibiotic susceptibility testing of the toxin producing isolates revealed that C. perfringens were susceptible to chloramphenicol, ciprofloxacin, metronidazole, and ceftriaxone. All of the other drugs were relatively less effective with a least activity of amoxicillin against the isolates. PMID- 26243961 TI - Effect of starter cultures and packaging methods on amino acid profile and eating quality characteristics of pork ham. AB - Wet cured pork hams were inoculated with a mixed starter cultures comprising of Lactobacillus acidophilus and Micrococcus varians M483 at the dose level of 106 cfu/g and the un inoculated hams served as controls. The amino acid profile of hams of the treated and the control groups stored at 4oC under MAP and VP and evaluated on 60th day of storage revealed that treated hams liberated higher concentration of free amino acids except for proline and methionine which were found in higher concentration (P < 0.01) in the MAP control samples. The MAP control samples liberated glutamic acid (85.65 +/- 1.40 ppm), cystine (21.56 +/- 1.14 ppm) and tyrosine (16.63 +/- 1.94 ppm) whereas, the treated samples did not release these amino acids. The VP control samples too liberated cystine (6.98 +/- 1.36 ppm) and arginine (42.70 +/- 2.78 ppm) but the treated ham of the VP did not liberate these amino acids. The VP hams had higher concentration (P < 0.01) of free proline, glycine, alanine, valine, methionine, isoleucine, phenylalanine, lysine and histidine than the MAP samples. Colour analysis of ham using CIE Lab colour system revealed that the treated samples had significantly higher concentrations of L*, a* and b* components. The L* and a* values were higher in the MAP than under VP systems while the b* values were higher in the VP samples than the MAP samples. Neither the bacterial cultures nor the packaging system influenced the textural property of ham. Starter cultures inoculated hams were rated superior (P < 0.05) in terms of their sensory properties. Hams packaged under MAP were rated superior (P < 0.05) than those packaged under VP in terms of appearance, colour, taste, tenderness, flavour, juiciness and overall acceptability. PMID- 26243962 TI - Influence of resistant starches on chemical and functional properties of tarhana. AB - Two different commercial resistant starches (RSa and RSb) were used in tarhana formulation on the basis of its replacement with wheat flour at 15, 30 and 45 % levels. Color values, some chemical, functional and sensory properties of tarhana were determined. Tarhana containing 30-45 % RSa gave lower darkness and yellowness compared to other samples. Increasing levels of RSa/RSb in tarhana formulation decreased protein and Fe, K, Mg, P and Zn content of the final products. Development in acidity was negatively affected above 30 % RS addition level. Although long fermentation period of tarhana dough, RS content of the tarhana samples changed between 5.4 and 26.2 %. Control tarhana was found to have 0.9 % RS content. Cooked viscosity decreased in tarhana soup with RS addition from 1,454 cP (control) to 166 cP. RSb showed more remarkable effect on cooked viscosity than RSa. High levels of RSa improved foaming capacity, foam stability, water and oil absorption capacity of the tarhana samples. RSa successfully incorporated into tarhana formulation up to 30 % level with minimum adverse effect on chemical and sensory properties. PMID- 26243963 TI - Rheological and physical properties of yogurt enriched with phytosterol during storage. AB - Phytosterols enriched products are innovative types of functional foods, in which dairy products, like low fat yogurt are ideal vehicles for this functional component. In this study, phytosterol dispersions were prepared using an oil/water (O/W) emulsion. The emulsion was added to yogurt milk. pH, titratable acidity (TA), syneresis, firmness and apparent viscosity of enriched yogurt were determined during storage. Moreover, phytosterols distribution in different parts of enriched yogurt was studied. Results indicated that in enriched yogurt, apparent viscosity and syneresis were lower and firmness was higher compared to the control. Addition of phytosterol to the yogurt had significant effect on acidity. Distribution of phytosterols in different parts of one sample was not uniform. Sensory results showed that there was no significant difference between enriched and control on texture, appearance, flavor and overall acceptance. PMID- 26243964 TI - Study of the rapid detection of gamma-aminobutyric acid in rice wine based on chemometrics using near infrared spectroscopy. AB - Rice wine, in which gamma-aminobutyric acid is present, is beneficial to human health and is one of the three most well-known fermented wines in the world, and is very popular in China. The rapid detection of gamma-aminobutyric acid was studied in rice wine using near infrared spectroscopy with an optical fibre probe. Through the selection of detection conditions, including a waveband range of 12500-4000 cm(-1), a scanning duration of 16 scans and a resolution of 8 cm( 1), the near infrared spectrum of rice wine was acquired three times, for every wine sample, with an optical fibre probe. The resulting average value of the spectrum was obtained and the corresponding data were analysed via normalization. By adopting a multivariate calibration partial least squares method (PLS) and establishing a calibration model, the highest precision for gamma-aminobutyric acid in rice wine was predicted when the factor coefficient was 17. The overall results demonstrating the content of gamma-aminobutyric acid in rice wine was predicted to be between 157.6696-317.5813 mg/L, with a relative standard deviation of prediction between 0.01-5 %, as well as the fact that the single sample measuring time was less than 20 s, prove that near infrared spectroscopy is a rapid, accurate and effective method to adopt for detecting the content of gamma-aminobutyric acid in rice wine. PMID- 26243965 TI - Influence of maturity and storage period on physical and biochemical characteristics of pear during post cold storage at ambient conditions. AB - The fruits of semi-soft pear (Pyrus communis) cv. Punjab Beauty harvested at three different harvest dates were stored at 0-1(0) C temperature with 90-95 % Relative Humidity for 30, 45, 60 and 75 days to assess the physical and chemical changes during storage. After every storage interval, the fruits were removed and kept at room temperature for 3 and 6 days to study the shelf life of fruits. Immature fruits always had the highest values of flesh firmness; optimum-mature fruits had the next and over-mature fruits the lowest at each corresponding sampling period during storage. The fruits harvested at optimum stage of maturity exhibited significantly (p < 0.05) lower incidence of fruit softening and physiological loss in weight. These fruits retained excellent quality up to 60 days of storage in cool chamber with 3 days shelf life at ambient temperature. The fruits of first harvest date were incapable of developing acceptable flavor and quality upon ripening throughout the storage period. However, the fruits harvested at post-optimum stage recorded maximum physiological loss in weight and lesser firmness thus making them suitable for immediate consumption with no shelf life at ambient temperature storage. PMID- 26243966 TI - Analysis of modes of heat transfer in baking Indian rice pan cake (Dosa,) a breakfast food. AB - Heat transfer by individual modes is estimated during baking of rice (Oryza sativa) pan cake (Dosa), a traditional food. The mathematical expressions proposed could be used to modify the baking oven for controlling the individual modes of heat transfer to obtain the desired product texture, colour and flavour. Conduction from the rotating hot plate is found to be the most prominent mode of heat transfer and is critical for obtaining the desired product characteristics such as texture and flavour. Temperature profiles along the thickness of Dosa are obtained and compared with those obtained experimentally. Heat transfer parameters such as thermal conductivity and emissivity of Dosa are determined (0.42 W/m K and 0.31, respectively). The effect of material of construction of the hot plate such as alloy steel, teflon coated aluminum, cast iron and stainless steel on product texture was studied and stainless steel was found to give good surface finish to the product, which was confirmed by scanning electron microscope. Sensory evaluation was carried out to evaluate the product acceptability. The thermal efficiency of the baking oven was 51.5%. PMID- 26243967 TI - Coliform risk assessment through use of the clam Anomalocardia brasiliana as animal sentinel for shellfish harvesting areas in Brazil's northeast. AB - Outbreaks of food-borne diseases related to consumption of contaminated shellfish have been reported in many countries, but not in Brazil, possibly due to deficient reporting. Here we investigated the suitability of the clam Anomalocardia brasiliana as an animal sentinel for coliform monitoring in shellfish harvesting areas of Brazil's northeast. Samples of shellfish meats (40 clams per sample; n = 8 per collection) were collected at random from April 2009 through March 2010 in the bay area of Mangue Seco (state of Pernambuco). The numbers of thermotolerant coliforms were analyzed through the most probable number technique, and these contamination levels were tentatively correlated with the precipitation recorded on the day of sampling or 24 to 48 h beforehand. A. brasiliana shellfish meats from local retail shops (250 g per sample/ n = 3 per market) sold frozen were also investigated from August 2010 through June 2011. We found that the highest coliform contamination levels were correlated with recent rainfall events, limited to 24 h before sampling. However, irrespective of the rainfall level, the mean contamination above the Brazilian legal threshold of < 3 * 10(2) MPN/ 100 g for shellfish harvesting areas ranged from 18.7 to 93.7 % of samples analyzed monthly. Additionally, a large number of samples obtained from retail shops were also highly contaminated by coliforms during rainy periods, and therefore were not proper for human consumption. We conclude that A. brasiliana can be successfully used to monitor the contamination levels of coliforms in shellfish harvesting areas in Brazil's northeast coast. PMID- 26243968 TI - Influence of natural and synthetic antioxidants on the degradation of Soybean oil at frying temperature. AB - The effect of several natural and synthetic antioxidants to retard the formation of polar compounds and thermo-oxidation at prolonged frying temperatures was studied. Antioxidants, including butyl hydroxyl toluene (BHT), ter-butyl hydroxyquinone (TBHQ), alpha- and gamma-tocopherols, tocopherol mixture (alpha, beta, gamma and delta), sesamol, beta-sitosterol, beta-sitostanol, gamma oryzanol, curcumin, rosemary extract and sucrose acetate isobutyrate (SAIB) were tested in refined soybean oil without added any additives recovered from refinery. Rosemary extract and SAIB were showed a considerable effect on both polar compound formation and secondary oxidation. These compounds increased the oxidative stability of oil for more than 30 % compared to conventional synthetic antioxidants. Oils treated with SAIB showed higher color retention after 6 h heating compared to the oils added with BHT, TBHQ and tocopherols. Curcumin, sesamol and gamma-oryzanol showed higher antioxidant potential compared to other antioxidants. Preliminary results obtained from this study have clearly demonstrated that SAIB and rosemary extracts are more commercially viable antioxidants to increase the stability of frying oils. PMID- 26243969 TI - Ru-Catalyzed Isomerization Provides Access to Alternating Copolymers via Ring Opening Metathesis Polymerization. AB - We describe an isomerization-alternating ROMP protocol that gives linear copolymers with rigorous sequence alternation. Bicyclo[4.2.0]oct-7-ene-7 carboxamides of primary amines are isomerized in the presence of (3 BrPyr)2Cl2(H2IMes)Ru=CHPh to the corresponding bicyclo[4.2.0]oct-1(8)-ene-8 carboxamides in which the olefinic bond is tetrasubstituted. The isomerized amides undergo alternating ring-opening metathesis polymerization with cyclohexene to provide soluble and linear copolymers with molecular weights up to ~130 kDa. This process provides efficient entry to strictly alternating copolymers that can display diverse functional groups. PMID- 26243970 TI - A moral price for medicine. PMID- 26243971 TI - Alexander Fleming (1881-1955): Discoverer of penicillin. PMID- 26243972 TI - PILL Series. The 'problematic' asthma patient. AB - Asthma is a reversible chronic inflammatory disorder of the airways that can be effectively controlled without causing any lifestyle limitation or burden on the quality of life of the majority of asthma patients. However, persistently uncontrolled asthma can be frustrating for both the patient and the managing physician. Patients who fail to respond to high-intensity asthma treatment fall into the category of 'problematic' asthma, which is further subdivided into 'difficult' asthma and 'severe refractory' asthma. Establishing the correct diagnosis of asthma and addressing comorbidities, compliance, inhaler technique and environmental triggers are essential when dealing with 'problematic' asthma patients. A systemic approach is also crucial in managing such patients. This is pertinent for general practitioners, as the majority of asthma patients are diagnosed and managed at the primary care level. PMID- 26243973 TI - Clinics in diagnostic imaging (161). Cervical OPLL with cord compression. AB - A 53-year-old man presented with acute cervical myelopathy following a fall. Cervical radiography and computed tomography showed ossification of the posterior longitudinal ligament (OPLL) from C2 to C6 level, with severe cervical canal stenosis and cord compression. Magnetic resonance imaging further showed increased T2-weighted signal in the spinal cord at the level of greatest central spinal canal stenosis. OPLL is a significant cause of myelopathy in Asian populations and is found in up to 25% of patients presenting with cervical compression myelopathy. The clinical presentation, radiological evaluation and management of OPLL are discussed. PMID- 26243974 TI - Medication discrepancies and associated risk factors identified among elderly patients discharged from a tertiary hospital in Singapore. AB - INTRODUCTION: Medication discrepancies and poor documentation of medication changes (e.g. lack of justification for medication change) in physician discharge summaries can lead to preventable medication errors and adverse outcomes. This study aimed to identify and characterise discrepancies between preadmission and discharge medication lists, to identify associated risk factors, and in cases of intentional medication discrepancies, to determine the adequacy of the physician discharge summaries in documenting reasons for the changes. METHODS: A retrospective clinical record review of 150 consecutive elderly patients was done to estimate the number of medication discrepancies between preadmission and discharge medication lists. The two lists were compared for discrepancies (addition, omission or duplication of medications, and/or a change in dosage, frequency or formulation of medication). The patients' clinical records and physician discharge summaries were reviewed to determine whether the discrepancies found were intentional or unintentional. Physician discharge summaries were reviewed to determine if the physicians endorsed and documented reasons for all intentional medication changes. RESULTS: A total of 279 medication discrepancies were identified, of which 42 were unintentional medication discrepancies (35 were related to omission/addition of a medication and seven were related to a change in medication dosage/frequency) and 237 were documented intentional discrepancies. Omission of the baseline medication was the most common unintentional discrepancy. No reasons were provided in the physician discharge summaries for 54 (22.8%) of the intentional discrepancies. CONCLUSION: Unintentional medication discrepancies are a common occurrence at hospital discharge. Physician discharge summaries often do not have adequate information on the reasons for medication changes. PMID- 26243975 TI - Comprehensive psychological intervention to improve outcome in functional gastrointestinal disorder: a cohort study. AB - INTRODUCTION: Patients with functional gastrointestinal disorders (FGIDs) have a decreased quality of life (QoL). Psychological illnesses are strongly associated with FGIDs. This study examined the effect of a comprehensive psychological intervention programme designed for refractory FGID patients. METHODS: Refractory FGID patients at a tertiary gastroenterology unit were encouraged to participate in a psychological intervention programme, which included screening for anxiety and depression in patients, educating patients and physicians on FGIDs, and providing early access to psychiatric consultation for patients with significant psychological illnesses. The duration of follow-up was six months. Outcomes were measured using the Irritable Bowel Syndrome-QoL (IBS-QoL) instrument and the EuroQol five dimensions (EQ-5D) questionnaire. RESULTS: A total of 1,189 patients (68% female, 80% Chinese, mean age 48.6 years) participated in the programme. Among these participants, 51% had a significant psychological disorder (Hospital Anxiety and Depression Scale [HADS] anxiety or depression score > 7). These participants had a significantly poorer QoL (IBS-QoL and EQ-5D, both p < 0.0001), and were more likely to be single or English-speaking, as compared to the participants without psychological disorders. Participants who completed >= 3 months of follow-up (n = 906) showed significant and durable improvement. High baseline HADS anxiety score predicted improvement (p < 0.001), with participant IBS-QoL and EQ-5D scores decreasing over time. CONCLUSION: The intervention programme was associated with a clinically meaningful improvement in the QoL of patients with refractory FGIDs. High baseline anxiety was predictive of improvement. PMID- 26243976 TI - Prevalence of dysglycaemic events among inpatients with diabetes mellitus: a Singaporean perspective. AB - INTRODUCTION: As the effectiveness of intensive glycaemic control is unclear and recommended glycaemic targets are inconsistent, this study aimed to ascertain the prevalence of dysglycaemia among hospitalised patients with diabetes mellitus in an Asian population and evaluate the current standards of inpatient glycaemic control. METHODS: A retrospective observational study was conducted at a secondary hospital. Point-of-care blood glucose (BG) values, demographic data, medical history, glycaemic therapy and clinical characteristics were recorded. Dysglycaemia prevalence was calculated as proportions of BG-monitored days with at least one reading exceeding the cut points of 8, 10 and 15 mmol/L for hyperglycaemia, and below the cut point of 4 mmol/L for hypoglycaemia. RESULTS: Among the 288 patients recruited, hyperglycaemia was highly prevalent (90.3%, 81.3% and 47.6% for the respective cut points), while hypoglycaemia was the least prevalent (18.8%). Dysglycaemic patients were more likely than normoglycaemic patients to have poorer glycated haemoglobin (HbA1c) levels (8.4% +/- 2.6% vs. 7.3% +/- 1.9%; p = 0.002 for BG > 10 mmol/L) and longer lengths of stay (10.1 +/- 8.2 days vs. 6.8 +/- 4.7 days; p = 0.007 for BG < 4 mmol/L). Hyperglycaemia was more prevalent in patients on more intensive treatment regimens, such as basal bolus combination therapy and the use of both insulin and oral hypoglycaemic agents (100.0% and 96.0%, respectively; p < 0.001 for BG > 10 mmol/L). CONCLUSION: Inpatient glycaemic control is suboptimal. Factors (e.g. type of treatment regimen, discipline and baseline HbA1c) associated with greater prevalence of dysglycaemia should be given due consideration in patient management. PMID- 26243977 TI - Xiaokening stimulates endothelial nitric oxide release in diabetic rats. AB - INTRODUCTION: Diabetes mellitus induces microangiopathic changes that lead to endothelial dysfunction. This study investigated the effect of Xiaokening, a type of Chinese compound medicine, on the mesenteric arteriolar endothelial cell function of diabetic rats and its underlying mechanism. METHODS: Diabetes mellitus was induced in rat models via intraperitoneal injection of 60 mg/kg streptozotocin and observed over three weeks. Mesenteric arterioles, which were isolated in a cannulated and pressurised state, were incubated with intravascular injections of 1, 3 or 5 g/L Xiaokening for 24, 48 or 72 hours. The effects of Xiaokening on the release of nitric oxide (NO) on the mesenteric arterioles were detected under shear stress of 1, 10 and 20 dyn/cm(2). Biochemical methods were used to determine the activities of superoxide dismutase (SOD) and xanthine oxidase (XO). The expressions of endothelial NO synthase (eNOS), SOD and XO in the mesenteric arterioles were assessed using Western blot. RESULTS: Compared to normal rat arterioles, less NO was released in the mesenteric arterioles of diabetic rats. Xiaokening was found to have a concentration- and time-dependent effect on NO release; when the shear stress was increased, there was a gradual increase in the release of NO. Compared to normal arterioles, the expression of eNOS in the mesenteric arterioles of diabetic rats was lower. Incubation with Xiaokening increased SOD activity and expression, and decreased XO activity and expression in the mesenteric arterioles of the diabetic rats. CONCLUSION: Xiaokening was able to significantly increase NO release and improve the endothelial function of mesenteric arterioles through antioxidative mechanisms. PMID- 26243979 TI - Prolonged hepatitis and jaundice: a rare complication of paediatric Epstein-Barr virus infection. AB - We herein report the case of a 14-year-old girl with Epstein-Barr virus (EBV) infectious mononucleosis who developed prolonged hepatitis and jaundice. At presentation, she had tender hepatomegaly with a markedly deranged liver function test. Abdominal ultrasonography showed hepatomegaly and a thickened gallbladder wall. During the subsequent 11 weeks, her transaminases showed two further peaks, which corresponded with clinical deterioration. Her highest alanine transaminase level was 1,795 u/L and total bilirubin level was 154 umol/L. She recovered fully with conservative management. EBV-related liver involvement is typically mild and self-limiting. We believe that tender hepatomegaly and gallbladder thickening may be important predictors of significant liver involvement. Although multiple transaminase peaks may occur, we do not consider this an indication for antiviral or immunosuppressive therapy. In the absence of strong evidence supporting the use of any specific therapy, we recommend a conservative approach for an immunocompetent patient. PMID- 26243978 TI - Haematological abnormalities in mitochondrial disorders. AB - INTRODUCTION: This study aimed to assess the kind of haematological abnormalities that are present in patients with mitochondrial disorders (MIDs) and the frequency of their occurrence. METHODS: The blood cell counts of a cohort of patients with syndromic and non-syndromic MIDs were retrospectively reviewed. MIDs were classified as 'definite', 'probable' or 'possible' according to clinical presentation, instrumental findings, immunohistological findings on muscle biopsy, biochemical abnormalities of the respiratory chain and/or the results of genetic studies. Patients who had medical conditions other than MID that account for the haematological abnormalities were excluded. RESULTS: A total of 46 patients ('definite' = 5; 'probable' = 9; 'possible' = 32) had haematological abnormalities attributable to MIDs. The most frequent haematological abnormality in patients with MIDs was anaemia. 27 patients had anaemia as their sole haematological problem. Anaemia was associated with thrombopenia (n = 4), thrombocytosis (n = 2), leucopenia (n = 2), and eosinophilia (n = 1). Anaemia was hypochromic and normocytic in 27 patients, hypochromic and microcytic in six patients, hyperchromic and macrocytic in two patients, and normochromic and microcytic in one patient. Among the 46 patients with a mitochondrial haematological abnormality, 78.3% had anaemia, 13.0% had thrombopenia, 8.7% had leucopenia and 8.7% had eosinophilia, alone or in combination with other haematological abnormalities. CONCLUSION: MID should be considered if a patient's abnormal blood cell counts (particularly those associated with anaemia, thrombopenia, leucopenia or eosinophilia) cannot be explained by established causes. Abnormal blood cell counts may be the sole manifestation of MID or a collateral feature of a multisystem problem. PMID- 26243981 TI - Thoracic endometriosis with catamenial haemoptysis and pneumothorax: computed tomography findings and long-term follow-up after danazol treatment. AB - Thoracic endometriosis (TE) is an uncommon disorder affecting women of childbearing age. We herein report clinical and thin-section computed tomography (CT) findings of two cases, in which one woman presented with catamenial haemoptysis (CH) alone and another woman presented with bilateral catamenial pneumothoraces (CP) coinciding with CH, a rare manifestation of TE. The dynamic changes demonstrated on thin-section chest CT performed during and after menses led to accurate localisation and presumptive diagnosis of TE in both patients. Following danazol treatment, the patient with CH alone had a complete cure, while the patient with CP and CH had an incomplete cure and required long-term danazol treatment. We discuss the role of imaging studies in TE, with an emphasis on the appropriate timing and scanning technique of chest CT in women presenting with CH, potential mechanisms, treatment and patient outcomes. PMID- 26243980 TI - Herb-induced cardiotoxicity from accidental aconitine overdose. AB - Patients who overdose on aconite can present with life-threatening ventricular arrhythmia. Aconite must be prepared and used with caution to avoid cardiotoxic effects that can be fatal. We herein describe a case of a patient who had an accidental aconite overdose but survived with no lasting effects. The patient had prepared Chinese herbal medication to treat his pain, which resulted in an accidental overdose of aconite with cardiotoxic and neurotoxic effects. The patient had ventricular tachycardia, bidirectional ventricular tachycardia and ventricular fibrillation. Following treatment with anti-arrhythmic medications, defibrillation and cardiopulmonary resuscitation, he made an uneventful recovery, with no further cardiac arrhythmias reported. PMID- 26243982 TI - Secondary haemochromatosis in a haemodialysis patient. AB - A 39-year-old woman with end-stage renal disease, which was maintained on haemodialysis, developed secondary haemochromatosis after receiving blood transfusions and intravenous iron supplementation without sufficient serum ferritin concentration monitoring. The patient received intravenous deferoxamine three times a week, combined with high-dose recombinant human erythropoietin therapy and haemodialysis. After three months, improvements in biochemical indicators and iron overload were noted. PMID- 26243983 TI - The use of virtual reality-based therapy to augment poststroke upper limb recovery. AB - Stroke remains one of the major causes of disability worldwide. This case report illustrates the complementary use of biomechanical and kinematic in-game markers, in addition to standard clinical outcomes, to comprehensively assess and track a patient's disabilities. A 65-year-old patient was admitted for right-sided weakness and clinically diagnosed with acute ischaemic stroke. She participated in a short trial of standard stroke occupational therapy and physiotherapy with additional daily virtual reality (VR)-based therapy. Outcomes were tracked using kinematic data and conventional clinical assessments. Her Functional Independence Measure score improved from 87 to 113 and Fugl-Meyer motor score improved from 56 to 62, denoting clinically significant improvement. Corresponding kinematic analysis revealed improved hand path ratios and a decrease in velocity peaks. Further research is being undertaken to elucidate the optimal type, timing, setting and duration of VR-based therapy, as well as the use of neuropharmacological adjuncts. PMID- 26243984 TI - Intralipid Infusion is the Current Favorite of Gynecologists for Immunotherapy. PMID- 26243985 TI - Postpartum IUCD: Rediscovering a Languishing Innovation. AB - The National Family Planning Programme of India, since its inception in 1951, has been able to successfully achieve significant reductions in maternal mortality and fertility. Over the past decade, the need for contraception has changed dramatically in India. Couples no longer desire sterilization, but prefer modern reversible long-term methods of contraception. The ideal time to discuss contraception is in the antenatal period when there is a good rapport between the doctor and the patient. The window period when the patient is admitted in the hospital during delivery can be used effectively to offer postpartum contraception. It has been found that the highest chance of unwanted pregnancy is in the first year after delivery, when women do not report to the doctor if this window period is missed. Postpartum intrauterine contraceptive devices are ideal for a country like India and it can be used to cover the unmet need of contraception if inserted immediately after delivery. There are two types of insertion: post placental, within 10 min of delivery of placenta and postpartum, within 48 h of delivery. Although there is a greater chance of expulsion in the postpartum insertions, it can be significantly reduced with proper training and user experience. Postpartum IUCD should be routinely offered to all patients delivering in institutions to provide complete care to a parturient and to achieve safe motherhood. PMID- 26243986 TI - Safety and Efficacy of Oral Mifepristone in Pre-induction Cervical Ripening and Induction of Labour in Prolonged Pregnancy. AB - OBJECTIVES: To study the safety and efficacy of oral mifepristone in pre induction cervical ripening and induction of labour in prolonged pregnancy. METHODS: This is a single blind randomized control trial. 100 women with prolonged pregnancy beyond 40 weeks and Bishop score <6 were recruited, and randomly allocated into two groups. Women who received Tab. Mifepristone 200 mg orally were assigned in Study Group (n = 50) and who received placebo orally were assigned in Control Group (n = 50) At the end of 24 h, change in the Bishop's score was assessed and Tab. Misoprostol 25 MUg was administered intravaginally every 4 h, maximum 6 doses for induction/augmentation of labour. Analysis regarding safety and efficacy of the drug was done with regards to maternal and perinatal outcome. RESULTS: Among 100 subjects, 50 received mifepristone and 50 received placebo. Mean induction to delivery interval was 1,907 +/- 368.4 min for Study Group versus 2,079 +/- 231.6 min for Control Group. The improvement in mean Bishop score was 5.0408 +/- 1.90 for Study Group compared with 3.26 +/- 1.15 was for Control Group after 24 h. Mean dose of misoprostol in Study Group was 40 +/- 27.2, while the same in Control Group was 52 +/- 19.46. Eight (16 %) women in Study Group and two (4 %) women in Control Group delivered vaginally within 24 h without any need of augmentation. There were 6 (12 %) cesareans and 2 (4 %) instrumental deliveries in Study Group and 8 (16 %) cesareans and 5 (10 %) instrumental deliveries in the Control Group. There was no statistically significant difference in perinatal outcomes between two groups. CONCLUSIONS: Mifepristone had a modest effect on cervical ripening when given 24 h prior to labour induction and appearing to reduce need for misoprostol compared with placebo. PMID- 26243987 TI - Risk Factors for Macrosomia. AB - OBJECTIVE: To identify risk factors for macrosomic babies. METHODS: This cross sectional analytical study was carried out in the University Teaching Hospital and the Central Hospital of Yaounde (Cameroon) from October 1st, 2012 to March 31st, 2013. Women who gave birth to >=4,000 or 3,000-3,499 g babies were recruited. Variables recorded were fetal sex and birth weight, gestational age, maternal age, parity, mother's body mass index (BMI), weight gain during pregnancy, previous macrosomia, and father's BMI. Fisher exact test and student t test were used for comparison. Level of significance was P < 0.05. RESULTS: Main risk factors for macrosomia are delivery of a previous macrosomic baby (OR 13.1), maternal weight gain >=16 kg (OR 10.2), parity >=3 (OR 4.8), father's BMI >=30 (OR 3.7), male sex (OR 2.2), and post-term (OR 1.9). CONCLUSION: Father's obesity should be added among the known risk factors for macrosomia. PMID- 26243988 TI - An Observational Study on the Use of IV Iron Sucrose Among Anaemic Pregnant Women in Government Healthcare Facilities from Two States of India. AB - BACKGROUND/PURPOSE OF THE STUDY: In India oral iron tablets for anaemia have been distributed through the health system since many years, but there has been no significant change in the burden of anaemia. The objective of the present study was to capture the existing practices on the use of intravenous iron sucrose (an alternative treatment for anaemia) in the public health system in two states of India (Tamil Nadu and Uttar Pradesh). METHODS: An observational study in the form of a registry was maintained for 3 months at purposively chosen public health facilities in the above-mentioned states of India. Anaemic pregnant women (n = 764) who were given intravenous iron sucrose during the antenatal or post-partum period were included in the registry. Information was collected on severity of anaemia at which intravenous iron sucrose therapy was initiated, the dose and schedule given and any adverse events noted during and immediate post-infusion period. RESULTS: 99 % of the infusions were given as slow infusion over a mean duration of 30 min, diluted with 0.9 % sodium chloride. The mean haemoglobin level at the time of start of intravenous therapy was 8.3 gm/dl. In Uttar Pradesh, 46 % of women received only one dose of iron sucrose in contrast with 15 % in Tamil Nadu. CONCLUSIONS: Although intravenous iron sucrose is commonly used in pregnant anaemic women, standard protocols and guidelines for its usage are lacking. These need to be formulated before scaling it up across public health facilities in India. PMID- 26243989 TI - Study of the Risk Factors for Cesarean Delivery in Induced Labors at Term. AB - BACKGROUND: Induction of labor has become one of the most common interventions in obstetrics. Induction is indicated when the benefits to either mother or fetus outweigh those of continuing the pregnancy. Maternal complication rates that are increased in association with labor induction include cesarean delivery, chorioamnionitis, abruptio placentae, and uterine atony. So identifying those pregnancies that can be induced with low risk of cesarean delivery is important. The aim of this study was to identify those factors which influence the risk of emergency cesarean delivery in induced labors at term. METHODS: It is a case control study conducted at Tertiary care center and affiliated hospitals. In this study, odds ratio with 95 % confidence interval is taken as a measure of relative risk. Patients were evaluated for risk factors for cesarean section using logistic regression. Cases include all women who were induced at term and delivered by emergency cesarean section. Controls include all women who were induced at term and delivered vaginally. RESULTS: The risk factors for cesarean delivery are advanced maternal age at delivery (>=35 years), high early pregnancy body mass index (>=30 kg/m(2)), nulliparity, low preinduction Bishops score (<5), gestational diabetes mellitus, and intrauterine growth restriction. CONCLUSION: Women with multiple risk factors for cesarean can be taken up for elective cesarean section rather than inducing them at term. PMID- 26243990 TI - A New Maneuver for Prevention of Postpartum Haemorrhage. AB - BACKGROUND: Postpartum hemorrhage (PPH) is the leading cause of maternal mortality worldwide. Many methods have been developed to decrease its rate. The aim of this study was to evaluate the applicability of a new non-pharmacologic maneuver in decreasing its rate. METHODS: This case series study was conducted in one center in Cairo, Egypt, from January-2010 to June-2013. 400 pregnant women, aged 18 years or more and candidate for normal labor, were enrolled to this study. High risk subjects for PPH were excluded. After placental delivery, the new maneuver was done by sustained traction of the anterior and posterior lips of the cervix by two ovum forceps for duration of 90 s. The amount of blood loss was estimated by standardized visual estimation after removal of the forceps. All subjects were followed up for 6 h. RESULTS: The rate of PPH, defined as more than 500 ml, was eight cases (2 %) with 95 % CI (0.63-3.37 %). The rate of PPH was not affected by parity, gestational age, episiotomy, or the presence of tears. PPH is more in cases with anemia (p 0.032). It occurred in all cases with uterine atony (p < 0.001). The range of estimated blood loss was 550-600 ml in cases with PPH and 150-450 ml in cases without PPH. Severe PPH more than 1,000 ml did not occur. CONCLUSION: This pilot study introduced a novel maneuver that can be helpful in decreasing the rate of PPH and reducing the amount of postpartum blood loss. Further RCT is recommended to investigate it. PMID- 26243991 TI - Comparative Study of Misoprostol in First and Second Trimester Abortions by Oral, Sublingual, and Vaginal Routes. AB - OBJECTIVE: To identify an effective misoprostol-only regimen for termination of pregnancy between 12 and 20 weeks of gestation, a prospective randomized study comparing sublingual, vaginal, and oral routes of administration of misoprostol was done. METHODS: One hundred and fifty women (12-20 weeks gestation) were randomly divided into three groups and given 400 mcg misoprostol sublingually, vaginally, and orally every 4 h up to a maximum of four doses. Primary outcome was the success rate at 24 h. Secondary outcomes were failure rate, induction abortion interval, and need for surgical intervention. Various side effects and patients' subjective assessment of comfort with the route of administration were also studied. RESULTS: Success rate at 24 h of sublingual (86 %) group was higher compared to oral (64 %) group (P = 0.011). Complete abortion rate of sublingual (76 %) group was higher than that of oral (48 %) group (P = 0.004). There was no significant difference in the failure rate and need for surgical intervention in the three groups. Induction-abortion interval in sublingual (9.8 +/- 3.6 h) and vaginal (10.6 +/- 2.9 h) groups was shorter than that in oral group (14.3 +/- 3.3). Diarrhea occurred significantly more in the oral group (28 %) and sublingual (22 %) compared to vaginal group (6 %). Fever was significantly higher in vaginal (36 %) than that in the oral group (12 %). Oral route of administration was most comfortable. CONCLUSION: Sublingual route results in significantly higher abortion rate compared to oral route. Vaginal route has efficacy similar to sublingual route. PMID- 26243992 TI - Choosing the Route of Hysterectomy. AB - PURPOSE: To compare the clinical results of three techniques of hysterectomy- abdominal hysterectomy (AH), non-descent vaginal hysterectomy (NDVH), and laparoscopic-assisted vaginal hysterectomy (LAVH). METHODS: A simple prospective randomized study was performed in a tertiary care centre between June 2011 and Dec 2012, among 150 consecutive women indicated to undergo hysterectomy for benign and mobile uterine conditions. They were randomly assigned 50 each to three routes of hysterectomy; (abdominal, vaginal, and laparoscopic-assisted vaginal). Outcome measures including operating time, blood loss, rate of complications, consumption of analgesics, and length of hospital stay were assessed and compared between groups. RESULTS: As far as duration of operation, mean blood loss, analgesic requirement, length of hospital stay, P value was significant. Incidence of complications is least among VH group. CONCLUSION: Vaginal hysterectomy is the gold standard in the era of minimal access surgery. Some of the contraindications to VH can be overcome by assistance of laparoscope and a potential abdominal hysterectomy can be converted to a vaginal procedure. PMID- 26243993 TI - Uterine Adenomatoid Tumors: A Study of Five Cases Including Three Cases of the Rare Leiomyoadenomatoid Variant. AB - OBJECTIVE: Adenomatoid tumor is a benign neoplasm of mesothelial origin encountered most often in the male and female genital tracts. This tumor has a distinct morphology and is characterized by anastomosing and variably sized tubules lined by epithelioid and flattened cells. Only 4 cases of the extremely rare leiomyoadenomatoid variant are on record. We report 5 cases of adenomatoid tumor including 3 cases of leiomyoadenomatoid tumor of the uterus, which is an extremely rare variant of adenomatoid tumor, difficult to recognize on morphology. METHOD: A detailed histopathological review of all the uterine tumor diagnosed as fibroid and adenomatoid tumor over the period of 4 years was done. RESULTS: A total of 5 cases of adenomatoid tumor were documented including 3 cases of leiomyoadenomatoid variant. CONCLUSION: Leiomyoadenomatoid variant of adenomatoid tumor often missed both on imaging and histopathological examination and hence needs to be recognized as a distinct morphological entity. PMID- 26243994 TI - Value of MRI in Characterizing Adnexal Masses. AB - Magnetic resonance imaging (MRI) increases the specificity of imaging evaluation for adnexal masses, especially when they are indeterminate on ultrasound, very large or when further imaging is required to establish tissue characteristics. This article is a pictorial essay describing the value of MRI in characterizing adnexal masses. PMID- 26243995 TI - A Giant Vesical Stone Causing Impending Rupture of Bladder During Labor. PMID- 26243996 TI - Unbelievable, Yet True....Spontaneous Quintuplets! PMID- 26243997 TI - Uterine Tumors Resembling Ovarian Sex Cord Tumor in Postmenopausal Woman. PMID- 26243998 TI - A Case of Salmonella enterica Serovar Typhi Tubo Ovarian Abscess. PMID- 26243999 TI - Customized Silicone Vaginal Stent. PMID- 26244000 TI - Good Time to Adopt Ten-Group Robson Classification to Report LSCS Rates in India? PMID- 26244001 TI - Thiol-Based Selective Extraction Assay to Comparatively Assess Bioavailable Mercury in Sediments. AB - Bioaccumulation of methylmercury in the aquatic food web is governed in part by the methylation of inorganic divalent mercury (Hg(II)) by anaerobic microorganisms. In sulfidic settings, a small fraction of total Hg(II) is typically bioavailable to methylating microorganisms. Quantification of this fraction is difficult due to uncertainties in the speciation of Hg(II) and the mechanisms of uptake by methylating microbes. However, recent studies have shown that the bioavailable fraction is likely to include a portion of Hg(II) associated with solid phases, that is, nanostructured mercuric sulfides. Moreover, addition of thiols to suspensions of methylating cultures coincides with increased uptake into cells and methylmercury production. Here, we present a thiol-based selective extraction assay to provide information on the bioavailable Hg fraction in sediments. In the procedure, sediment samples were exposed to a nitrogen-purged solution of glutathione (GSH) for 30 min and the amount of GSH leachable mercury was quantified. In nine sediment samples from a marine location, the relative GSH-leachable mercury concentration was strongly correlated to the relative amount of methylmercury in the sediments (r2=0.91, p<0.0001) across an order of magnitude of methylmercury concentration values. The approach was further applied to anaerobic sediment slurry microcosm experiments in which sediments were cultured under the same microbial growth conditions but were amended with multiple forms of Hg with a known spectrum of bioavailability. GSH-leachable Hg concentrations increased with observed methylmercury concentrations in the microcosms, matching the trend of species bioavailability in our previous work. Results suggest that a thiol-based selective leaching approach is an improvement compared with other proposed methods to assess Hg bioavailability in sediment and that this approach could provide a basis for comparison of sites where Hg methylation is a concern. PMID- 26244002 TI - The Origin of Land Plants: A Phylogenomic Perspective. AB - Land plants are a natural group, and Charophyte algae are the closest lineages of land plants and have six morphologically diverged groups. The conjugating green algae (Zygnematales) are now suggested to be the extant sister group to land plants, providing the novel understanding for character evolution and early multicellular innovations in land plants. We review recent molecular phylogenetic work on the origin of land plants and discuss some future directions in phylogenomic analyses. PMID- 26244003 TI - Effective Population Size and Signatures of Selection Using Bovine 50K SNP Chips in Korean Native Cattle (Hanwoo). AB - Inferring the effective population size and the pattern of selection signatures is of interest both from an evolutionary perspective and to improve models for mapping of quantitative trait genes. We used DNA samples of 61 sires and 486 progeny of the Hanwoo, genotyped by the Illumina Bovine SNP50 BeadChip, to analyze the genetic structure. Our study showed a persistent decline in effective population size throughout the period considered, but suggested a marked decline at one distinctive time point (100th generation) and two sharp decline intervals (50th-25th generation and 25th-10th generation). This pattern can be explained by Hanwoo formation and the modern breeding program. Our results revealed 95 regions exhibiting the footprint of recent positive selection at a threshold level of 0.01. We found an overlap of the 11 core regions presenting top P-values and those that had previously been identified as harboring quantitative trait loci from other breeds. The information generated from this study can be used to better understand the mechanism of selection in Hanwoo breeding, and provide important implications for the design and application of association studies in the Hanwoo population. PMID- 26244004 TI - Using Nonlinear Stochastic Evolutionary Game Strategy to Model an Evolutionary Biological Network of Organ Carcinogenesis Under a Natural Selection Scheme. AB - Molecular biologists have long recognized carcinogenesis as an evolutionary process that involves natural selection. Cancer is driven by the somatic evolution of cell lineages. In this study, the evolution of somatic cancer cell lineages during carcinogenesis was modeled as an equilibrium point (ie, phenotype of attractor) shifting, the process of a nonlinear stochastic evolutionary biological network. This process is subject to intrinsic random fluctuations because of somatic genetic and epigenetic variations, as well as extrinsic disturbances because of carcinogens and stressors. In order to maintain the normal function (ie, phenotype) of an evolutionary biological network subjected to random intrinsic fluctuations and extrinsic disturbances, a network robustness scheme that incorporates natural selection needs to be developed. This can be accomplished by selecting certain genetic and epigenetic variations to modify the network structure to attenuate intrinsic fluctuations efficiently and to resist extrinsic disturbances in order to maintain the phenotype of the evolutionary biological network at an equilibrium point (attractor). However, during carcinogenesis, the remaining (or neutral) genetic and epigenetic variations accumulate, and the extrinsic disturbances become too large to maintain the normal phenotype at the desired equilibrium point for the nonlinear evolutionary biological network. Thus, the network is shifted to a cancer phenotype at a new equilibrium point that begins a new evolutionary process. In this study, the natural selection scheme of an evolutionary biological network of carcinogenesis was derived from a robust negative feedback scheme based on the nonlinear stochastic Nash game strategy. The evolvability and phenotypic robustness criteria of the evolutionary cancer network were also estimated by solving a Hamilton-Jacobi inequality - constrained optimization problem. The simulation revealed that the phenotypic shift of the lung cancer-associated cell network takes 54.5 years from a normal state to stage I cancer, 1.5 years from stage I to stage II cancer, and 2.5 years from stage II to stage III cancer, with a reasonable match for the statistical result of the average age of lung cancer. These results suggest that a robust negative feedback scheme, based on a stochastic evolutionary game strategy, plays a critical role in an evolutionary biological network of carcinogenesis under a natural selection scheme. PMID- 26244005 TI - De Novo Transcriptome Assembly and Development of Novel Microsatellite Markers for the Traditional Chinese Medicinal Herb, Veratrilla baillonii Franch (Gentianaceae). AB - Veratrilla baillonii Franch is an important Chinese medicinal herb for treating liver-related diseases, which has been over-collected in the recent decades. However, the effective conservation and related population genetic study has been hindered because of the lack of genome sequences and genetic markers in the natural population. We have conducted RNA-seq on V. baillonii. We performed de novo assembly of these data to characterize the V. baillonii transcriptome, resulting in 133,019 contigs with size >200 bp. These contigs were annotated using the NCBI nonredundant database and Gene Ontology (GO) terms. From these contigs, we developed novel microsatellite simple sequence repeat (SSR) markers, identifying a total of 40,885 SSRs. SSRs with repeat motifs of 1-4 bp (mono-, di , tri-, and tetranucleotides) accounted for 99.8% of all SSRs, with mononucleotide repeats most common, followed by dinucleotide (16.2%) and trinucleotide repeats (14.7%). We selected 151 SSRs for experimental validation, of which 74 were confirmed by polymerase chain reaction. Fourteen SSRs were determined to be polymorphic by screening 40 individuals from six distant populations. The number of alleles per locus ranged from two to four, and the expected heterozygosity varied from 0.2637 to 0.8571, suggesting that these SSR markers are highly polymorphic and effective for further genetic analysis in the nature population. In addition, we explored the genetic structure of V. baillonii using five SSRs in four geographic populations and found that the identified genotypes were clustered into two phylogenetic clades: the Mekong River clade and Jinsha River clade. This result indicates that these two regions may harbor highly divergent genetic lineages and enriched genetic diversity. The de novo transcriptome sequences and new SSR markers discovered by this study provide an initial step for understanding the population genetics of V. baillonii, and a valuable resource for effective conservation management. PMID- 26244006 TI - Identification of Genetic Mutations in Human Lung Cancer by Targeted Sequencing. AB - Lung cancer remains the most prevalent malignancy and the primary cause of cancer related deaths worldwide. Unique mutations patterns can be found in lung cancer subtypes, in individual cancers, or within a single tumor, and drugs that target these genetic mutations and signal transduction pathways are often beneficial to patients. In this study, we used the Ion Torrent AmpliSeq Cancer Panel to sequence 737 loci from 45 cancer-related genes and oncogenes to identify genetic mutations in 48 formalin-fixed, paraffin-embedded (FFPE) human lung cancer samples from Chinese patients. We found frequent mutations in EGFR, KRAS, PIK3CA, and TP53 genes. Moreover, we observed that a portion of the lung cancer samples harbored two or more mutations in these key genes. This study demonstrates the feasibility of using the Ion Torrent sequencing to efficiently identify genetic mutations in individual tumors for targeted lung cancer therapy. PMID- 26244007 TI - The Impact of Microenvironmental Heterogeneity on the Evolution of Drug Resistance in Cancer Cells. AB - Therapeutic resistance arises as a result of evolutionary processes driven by dynamic feedback between a heterogeneous cell population and environmental selective pressures. Previous studies have suggested that mutations conferring resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in non-small-cell lung cancer (NSCLC) cells lower the fitness of resistant cells relative to drug-sensitive cells in a drug-free environment. Here, we hypothesize that the local tumor microenvironment could influence the magnitude and directionality of the selective effect, both in the presence and absence of a drug. Using a combined experimental and computational approach, we developed a mathematical model of preexisting drug resistance describing multiple cellular compartments, each representing a specific tumor environmental niche. This model was parameterized using a novel experimental dataset derived from the HCC827 erlotinib-sensitive and -resistant NSCLC cell lines. We found that, in contrast to in the drug-free environment, resistant cells may hold a fitness advantage compared to parental cells in microenvironments deficient in oxygen and nutrients. We then utilized the model to predict the impact of drug and nutrient gradients on tumor composition and recurrence times, demonstrating that these endpoints are strongly dependent on the microenvironment. Our interdisciplinary approach provides a model system to quantitatively investigate the impact of microenvironmental effects on the evolutionary dynamics of tumor cells. PMID- 26244008 TI - Self-organized Kidney Rudiments: Prospects for Better in vitro Nephrotoxicity Assays. AB - Kidneys are essential to life but vulnerable to a range of toxicants, including therapeutic drugs and their metabolites. Indeed, nephrotoxicity is often a limiting factor in both drug use and drug development. Most toxicants damage kidneys by one of four mechanisms: damage to the membrane and its junctions, oxidative stress and free radical generation, activation of inflammatory processes, and interference with vascular regulation. Traditionally, animal models were used in preclinical screening for nephrotoxicity, but these can be poorly predictive of human reactions. Animal screens have been joined by simple single-cell-type in vitro assays using primary or immortalized human cells, particularly proximal tubule cells as these are especially vulnerable to toxicants. Recent research, aimed mainly at engineering new kidneys for transplant purposes, has resulted in a method for constructing anatomically realistic mini-kidneys from renogenic stem cells. So far, this has been done only using renogenic stem cells obtained directly from mouse embryos but, in principle, it should be possible to make them from renogenically directed human induced pluripotent cells. If this can be done, the resulting human-based mini kidneys would be a promising system for detecting some types of nephrotoxicity and for developing nephroprotective drugs. PMID- 26244009 TI - Basal Plasma Levels of Copeptin are Elevated in Inactive Inflammatory Bowel Disease after Bowel Resection. AB - Evidence of interactions between the enteric nervous system, neuropeptides, and the immune system is growing. The aim of this study was to examine basal plasma levels of a variety of peptide precursors in patients with inflammatory bowel disease (IBD). In two middle-aged cohorts, Malmo Preventive Medicine (n = 5,415) and Malmo Diet and Cost Study (n = 6,103), individuals with the diagnosis of IBD were identified. Medical records were scrutinized. Three controls were matched for each patient. Copeptin, midregional fragments of adrenomedullin, pro-atrial natriuretic peptide, and proenkephalin A, as well as N-terminal protachykinin A and proneurotensin were analyzed in the plasma. Sixty-two IBD patients were identified. The only difference between patients and controls was higher copeptin levels in the patients compared with controls (P = 0.006), with higher copeptin levels in resected than unresected patients (P = 0.020). There was no difference in any precursor levels between Crohn's disease and ulcerative colitis, between different distributions of disease lesions, or between different treatments. PMID- 26244010 TI - A prospective study on postoperative discomfort after 20-gauge pars plana vitrectomy. AB - PURPOSE: To evaluate postoperative pain and other irritation symptoms after 20 gauge (20G) pars plana vitrectomy. MATERIALS AND METHODS: A total of 110 consecutive patients were enrolled in our studies, and 87 patients who underwent the conventional 20G pars plana vitrectomy were included in the final analysis. All vitrectomies were performed using the same surgical technique by the same surgeon. Patients were examined before surgery and 1 day, 3 days, 7 days, 1 month, and 2 months postoperatively. The main outcome measures include patient age and sex, intraocular pressure (IOP), ocular pain, pain score, pain medication use, and other irritation symptoms comprising itching, foreign body sensation, burning, photophobia, and dryness. The pain was evaluated using the Numerical Rating Scale scored from 0 to 10. RESULTS: Postoperative pain was relatively common during the first day after surgery, as it was reported by 43 (49.4%) patients. Then, the prevalence gradually decreased to eleven (12.6%) patients at 2 months. Most patients reported mild or moderate pain, with a pain score of 1-5, but only four patients were given analgesics for ocular pain. A postoperative rise of IOP was noted in 25 patients at day 1. Most of these patients with high IOP reported moderate pain. Other ocular irritation symptoms were varied after surgery. There was still one-quarter of patients that had foreign body sensation and dryness symptoms at month 2 after surgery. CONCLUSION: Mild and moderate ocular pain were relatively common after 20G vitrectomy, which is more often associated with elevated IOP. Other irritation symptoms were also presented after surgery and could affect the life quality of patients. Therefore, the discomforts after 20G pars plana vitrectomy should be of concern, and timely management should be provided as part of routine postoperative care. PMID- 26244012 TI - Ultrasound effects on brain-targeting mannosylated liposomes: in vitro and blood brain barrier transport investigations. AB - Delivering drugs to intracerebral regions can be accomplished by improving the capacity of transport through blood-brain barrier. Using sertraline as model drug for brain targeting, the current study aimed at modifying its liposomal vesicles with mannopyranoside. Box-Behnken design was employed to statistically optimize the ultrasound parameters, namely ultrasound amplitude, time, and temperature, for maximum mannosylation capacity, sertraline entrapment, and surface charge while minimizing vesicular size. Moreover, in vitro blood-brain barrier transport model was established to assess the transendothelial capacity of the optimized mannosylated vesicles. Results showed a dependence of vesicular size, mannosylation capacity, and sertraline entrapment on cavitation and bubble implosion events that were related to ultrasound power amplitude, temperature. However, short ultrasound duration was required to achieve >90% mannosylation with nanosized vesicles (<200 nm) of narrow size distribution. Optimized ultrasound parameters of 65 degrees C, 27%, and 59 seconds for ultrasound temperature, amplitude, and time were elucidated to produce 81.1%, 46.6 nm, and 77.6% sertraline entrapment, vesicular size, and mannosylation capacity, respectively. Moreover, the transendothelial ability was significantly increased by 2.5-fold by mannosylation through binding with glucose transporters. Hence, mannosylated liposomes processed by ultrasound could be a promising approach for manufacturing and scale-up of brain-targeting liposomes. PMID- 26244011 TI - Albumin-bound paclitaxel in solid tumors: clinical development and future directions. AB - Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free formulation of paclitaxel that was initially developed more than a decade ago to overcome toxicities associated with the solvents used in the formulation of standard paclitaxel and to potentially improve efficacy. Nab-paclitaxel has demonstrated an advantage over solvent-based paclitaxel by being able to deliver a higher dose of paclitaxel to tumors and decrease the incidence of serious toxicities, including severe allergic reactions. To date, nab-paclitaxel has been indicated for the treatment of three solid tumors in the USA. It was first approved for the treatment of metastatic breast cancer in 2005, followed by locally advanced or metastatic non-small-cell lung cancer in 2012, and most recently for metastatic pancreatic cancer in 2013. Nab-paclitaxel is also under investigation for the treatment of a number of other solid tumors. This review highlights key clinical efficacy and safety outcomes of nab-paclitaxel in the solid tumors for which it is currently indicated, discusses ongoing trials that may provide new data for the expansion of nab-paclitaxel's indications into other solid tumors, and provides a clinical perspective on the use of nab-paclitaxel in practice. PMID- 26244013 TI - Perspectives of patients on factors relating to adherence to post-acute coronary syndrome medical regimens. AB - PURPOSE: Poor adherence to cardioprotective medications after acute coronary syndrome (ACS) hospitalization is associated with increased risk of rehospitalization and mortality. Clinical trials of multifaceted interventions have improved medication adherence with varying results. Patients' perspectives on interventions could help researchers interpret inconsistent outcomes. Identifying factors that patients believe would improve adherence might inform the design of future interventions and make them more parsimonious and sustainable. The objective of this study was to obtain patients' perspectives on adherence to medical regimens after experiencing an ACS event and their participation in a medication adherence randomized control trial following their hospitalization. PATIENTS AND METHODS: Sixty-four in-depth interviews were conducted with ACS patients who participated in an efficacious, multifaceted, medication adherence randomized control trial. Interview transcripts were analyzed using the constant comparative approach. RESULTS: Participants described their post-ACS event experiences and how they affected their adherence behaviors. Patients reported that adherence decisions were facilitated by mutually respectful and collaborative provider-patient treatment planning. Frequent interactions with providers and medication refill reminder calls supported improved adherence. Additional facilitators included having social support, adherence routines, and positive attitudes toward an ACS event. The majority of patients expressed that being active participants in health care decision-making contributed to their health. CONCLUSION: Our findings demonstrate that respectful collaborative communication can contribute to medication adherence after ACS hospitalization. These results suggest a potential role for training health-care providers, including pharmacists, social workers, registered nurses, etc, to elicit and acknowledge the patients' views regarding medication treatment in order to improve adherence. Future research is needed with providers to understand how they elicit and acknowledge patients' views, particularly in the face of nonadherence, and with patients to understand how to empower them to share their opinions with their providers. PMID- 26244014 TI - Prediction of O-glycosylation Sites Using Random Forest and GA-Tuned PSO Technique. AB - O-glycosylation is one of the main types of the mammalian protein glycosylation; it occurs on the particular site of serine (S) or threonine (T). Several O glycosylation site predictors have been developed. However, a need to get even better prediction tools remains. One challenge in training the classifiers is that the available datasets are highly imbalanced, which makes the classification accuracy for the minority class to become unsatisfactory. In our previous work, we have proposed a new classification approach, which is based on particle swarm optimization (PSO) and random forest (RF); this approach has considered the imbalanced dataset problem. The PSO parameters setting in the training process impacts the classification accuracy. Thus, in this paper, we perform parameters optimization for the PSO algorithm, based on genetic algorithm, in order to increase the classification accuracy. Our proposed genetic algorithm-based approach has shown better performance in terms of area under the receiver operating characteristic curve against existing predictors. In addition, we implemented a glycosylation predictor tool based on that approach, and we demonstrated that this tool could successfully identify candidate glycosylation sites in case study protein. PMID- 26244015 TI - High-Throughput miRNA Sequencing Reveals a Field Effect in Gastric Cancer and Suggests an Epigenetic Network Mechanism. AB - Field effect in cancer, also called "field cancerization", attempts to explain the development of multiple primary tumors and locally recurrent cancer. The concept of field effect in cancer has been reinforced, since molecular alterations were found in tumor-adjacent tissues with normal histopatho-logical appearances. With the aim of investigating field effects in gastric cancer (GC), we conducted a high-throughput sequencing of the miRnome of four GC samples and their respective tumor-adjacent tissues and compared them with the miRnome of a gastric antrum sample from patients without GC, assuming that tumor-adjacent tissues could not be considered as normal tissues. The global number of miRNAs and read counts was highest in tumor samples, followed by tumor-adjacent and normal samples. Analyzing the miRNA expression profile of tumor-adjacent miRNA, hsa-miR-3131, hsa-miR-664, hsa-miR-483, and hsa-miR-150 were significantly downregulated compared with the antrum without tumor tissue (P-value < 0.01; fold change <5). Additionally, hsa-miR-3131, hsa-miR-664, and hsa-miR-150 were downregulated (P-value < 0.001) in all paired samples of tumor and tumor-adjacent tissues, compared with antrum without tumor mucosa. The field effect was clearly demonstrated in gastric carcinogenesis by an epigenetics-based approach, and potential biomarkers of the GC field effect were identified. The elevated expression of miRNAs in adjacent tissues and tumors tissues may indicate that a cascade of events takes place during gastric carcinogenesis, reinforcing the notion of field effects. This phenomenon seems to be linked to DNA methylation patterns in cancer and suggests the involvement of an epigenetic network mechanism. PMID- 26244016 TI - A Simple Rank Product Approach for Analyzing Two Classes. AB - The rank product statistic has been widely used to detect differentially expressed genes in replicated microarrays and a one-class setting. The objective of this article is to apply a rank product statistic to approximate the P-value of differential expression in a two-class setting, such as in normal and cancer cells. For this purpose, we introduce a simple statistic that compares the P values of each class's rank product statistic. Its null distribution is straightforwardly derived using the change-of-variable technique. PMID- 26244018 TI - Low Serum Alpha-Antitrypsin Associated with Anti-PR-3 ANCA in Autistic Children with GI Disease. AB - AIM: To assess the possible relationship between serum alpha-1 antitrypsin (AAT) levels and anti-neutrophil cytoplasmic antibodies (ANCA) in autistic children with severe GI disease and to test the hypothesis that there is an association between low serum AAT levels, the presence of ANCA and inflammatory GI disease seen in some autistic children. SUBJECTS AND METHODS: Serum from 40 autistic children with chronic digestive disease (many with ileo-colonic lymphoid nodular hyperplasia (LNH) and inflammation of the colorectum, small bowel and/or stomach), and 41 controls (21 age matched autistic children with no GI disease and 20 age matched children without autism or GI disease) were tested using ELISAs designed to quantitate ANCA (anti-PR3), AAT and PR3 levels. RESULTS: We found that a significant number of autistic children with chronic digestive disease had anti-PR3 ANCA, high serum PR3 and high severity of disease when compared to controls. This same group of autistic children had low serum levels of AAT compared to controls, which also correlated with the presence of anti-PR3 ANCA, high serum PR3, as well as the severity of intestinal disease, particularly LNH and severe erythema. DISCUSSION: These results suggest a relationship between low AAT levels, ANCA and severity of GI disease seen in a subpopulation of ASD individuals. We suggest that low AAT levels may result in high levels of PR3, which may, in turn be associated with the presence of ANCA. PMID- 26244019 TI - Gene Expression Analysis of Four Radiation-resistant Bacteria. AB - To investigate the general radiation-resistant mechanisms of bacteria, bioinformatic method was employed to predict highly expressed genes for four radiation-resistant bacteria, i.e. Deinococcus geothermalis (D. geo), Deinococcus radiodurans (D. rad), Kineococcus radiotolerans (K. rad) and Rubrobacter xylanophilus (R. xyl). It is revealed that most of the three reference gene sets, i.e. ribosomal proteins, transcription factors and major chaperones, are generally highly expressed in the four bacteria. Recombinase A (recA), a key enzyme in recombinational repair, is predicted to be highly or marginally highly expressed in the four bacteria. However, most proteins associated with other repair systems show low expression levels. Some genes participating in 'information storage and processing,' 'cellular processes and signaling' and 'metabolism' are among the top twenty predicted highly expressed (PHX) genes in the four genomes. Many antioxidant enzymes and proteases are commonly highly expressed in the four bacteria, indicating that these enzymes play important roles in resisting irradiation. Finally, a number of 'hypothetical genes' are among the top twenty PHX genes in each genome, some of them might contribute vitally to resist irradiation. Some of the prediction results are supported by experimental evidence. All the above information not only helps to understand the radiation-resistant mechanisms but also provides clues for identifying new radiation-resistant genes from these bacteria. PMID- 26244017 TI - Positioning new pharmacotherapies for COPD. AB - COPD imposes considerable worldwide burden in terms of morbidity and mortality. In recognition of this, there is now extensive focus on early diagnosis, secondary prevention, and optimizing medical management of the disease. While established guidelines recognize different grades of disease severity and offer a structured basis for disease management based on symptoms and risk, it is becoming increasingly evident that COPD is a condition characterized by many phenotypes and its control in a single patient may require clinicians to have access to a broader spectrum of pharmacotherapies. This review summarizes recent developments in COPD management and compares established pharmacotherapy with new and emerging pharmacotherapies including long-acting muscarinic antagonists, long acting beta-2 sympathomimetic agonists, and fixed-dose combinations of long acting muscarinic antagonists and long-acting beta-2 sympathomimetic agonists as well as inhaled cortiocosteroids, phosphodiesterase inhibitors, and targeted anti inflammatory drugs. We also review the available oral medications and new agents with novel mechanisms of action in early stages of development. With several new pharmacological agents intended for the management of COPD, it is our goal to familiarize potential prescribers with evidence relating to the efficacy and safety of new medications and to suggest circumstances in which these therapies could be most useful. PMID- 26244020 TI - Follicular dendritic cell sarcoma: two rare cases and a brief review of the literature. AB - Follicular dendritic cell sarcoma (FDCS) is a rare malignant tumor recognized in recent years. It accounts for only 0.4% of soft-tissue sarcomas, and its underlying causes are largely unknown. A correct diagnosis can be difficult to make. Diagnosis of FDCS depends on the combined clinical examination, histopathologic features, electron microscopic examination and confirmation with immunohistochemical studies. Here, we report two rare cases of FDCS: one case involving multiple bones, and the other involving extensive abdominal and pelvic cavities. Clinical, histopathological, and immunohistochemical aspects, therapeutic options, and a related literature review of the two cases are discussed. As the prevalence of FDCS is increasing, the details of these rare cases may highlight the importance and facilitate treatment of similar diseases. PMID- 26244021 TI - Ganetespib: research and clinical development. AB - Under stressful conditions, the heat shock protein 90 (HSP90) molecular chaperone protects cellular proteins (client proteins) from degradation via the ubiquitin proteasome pathway. HSP90 expression is upregulated in cancers, and this contributes to the malignant phenotype of increased proliferation and decreased apoptosis and maintenance of metastatic potential via conservation of its client proteins, including human epidermal growth factor receptor 2, anaplastic lymphoma kinase, androgen receptor, estrogen receptor, Akt, Raf-1, cell cycle proteins, and B-cell lymphoma 2 among others. Hence, inhibition of HSP90 leads to the simultaneous degradation of its many clients, thereby disrupting multiple oncogenic signaling cascades. This has sparked tremendous interest in the development of HSP90 inhibitors as an innovative anticancer strategy. Based on the wealth of compelling data from preclinical studies, a number of HSP90 inhibitors have entered into clinical testing. However, despite enormous promise and anticancer activity reported to date, none of the HSP90 inhibitors in development has been approved for cancer therapy, and the full potential of this class of agents is yet to be realized. This article provides a review on ganetespib, a small molecule HSP90 inhibitor that is currently under evaluation in a broad range of cancer types in combination with other therapeutic agents with the hope of further enhancing its efficacy and overcoming drug resistance. Based on our current understanding of the complex HSP90 machinery combined with the emerging data from these key clinical trials, ganetespib has the potential to be the first-in-class HSP90 inhibitor to be approved as a new anticancer therapy. PMID- 26244022 TI - Quantitative assessment of pre-miR-218 rs11134527 polymorphism and cancer risk in Chinese population. AB - BACKGROUND: Accumulated studies have evaluated the association of pre-miR-218 rs11134527 polymorphism with cancer risk in Chinese population. However, the results remain controversial. METHODS: To derive a more precise and more comprehensive estimation of the relationship, six studies focused on Chinese population were included for the pooled analysis for pre-miR-218 rs11134527 polymorphism using odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Pre-miR-218 rs11134527 polymorphism was associated with cancer risk (G versus A, OR =0.93, 95% CI: 0.88-0.98; GG versus AG + AA, OR =0.88, 95% CI: 0.79 0.97; GG versus AA, OR =0.85, 95% CI: 0.76-0.96). In the stratified analysis by cancer type, the pre-miR-218 rs11134527 polymorphism was only associated with the risk of cervical cancer (G versus A, OR =0.90, 95% CI: 0.83-0.98; GG versus AG + AA, OR =0.80, 95% CI: 0.68-0.94; GG versus AA, OR =0.79, 95% CI: 0.66-0.94). CONCLUSION: These findings suggest that the pre-miR-218 rs11134527 genetic polymorphism may decrease the susceptibility to cervical cancer, which needs to be verified or linked with functional studies. PMID- 26244023 TI - p27(Kip1) and Ser10-phosphorylated p27(Kip1) in breast cancer: clinical significance and expression. AB - BACKGROUND: The protein p27 (p27(Kip1)) is a member of the cyclin-dependent kinase inhibitor family, which negatively regulates cell cycle progression, and the phosphorylation of p27 has been proven to affect its stability and nuclear export. Clinical studies on the relation between p27 and phosphorylated p27 (p p27Ser10) in breast invasive ductal carcinomas are still scarce. METHODS: We examined the expression of p27 and p-p27Ser10 using immunohistochemistry in 107 breast invasive ductal carcinomas and analyzed the relationship of these biomarkers and tumor characteristics. RESULTS: Of the 107 tumor samples, 38.3% (41 of 107) overexpressed p27 and 64.5% (69 of 107) overexpressed p-p27Ser10. Analysis of correlation with clinical characteristics showed that high expression level of p-p27Ser10 was linked to poor differentiation, advanced disease stage, and lymph node metastasis, whereas a contrary trend was observed for p27 (all P<0.05). In addition, the expression of p-p27Ser10 was significantly higher in malignant tumors than in adjacent tissues, while p27 showed the opposite trend. Also, there were different levels of p27 and p-p27Ser10 in different types of breast cancer. CONCLUSION: p27 and p-p27Ser10 are involved in the development of invasive ductal carcinoma and are potential indicators to judge the degree of malignancy as well as recurrence and metastasis. PMID- 26244024 TI - miR-20b overexpression is predictive of poor prognosis in gastric cancer. AB - BACKGROUND: miR-20b has been shown to be aberrantly expressed in several tumor types. However, the clinical significance of miR-20b in the prognosis of patients with gastric cancer (GC) is poorly understood, and the exact role of miR-20b in GC remains unclear. MATERIALS AND METHODS: The expression of miR-20b was detected in 102 patients with GC by a SYBR Green assay and was compared with the expression in matched adjacent normal tissue specimens. The aim of the present study was to investigate the association of the expression of miR-20b with the clinicopathological characteristics and the overall survival of patients with GC as analyzed by Kaplan-Meier analysis and Cox proportional hazards regression models. RESULTS: Our results showed that miR-20b expression was upregulated in GC tissue compared with normal mucosa (P=0.00). Furthermore, miR-20b expression was positively correlated with advanced lymph node metastasis (P=0.041), tumor node metastasis stage (P=0.000), and deeper and distant metastasis (P=0.031). The overall survival rate of patients with GC was significantly lower in those whose tumors expressed high levels of miR-20b mRNA compared with those whose tumors expressed low levels of miR-20b mRNA (P=0.019). CONCLUSION: miR-20b may serve as a potential molecular marker for the prognosis of GC. PMID- 26244025 TI - Investigation of brain tumors using (18)F-fluorobutyl ethacrynic amide and its metabolite with positron emission tomography. AB - To date, imaging of malignant glioma remains challenging. In positron emission tomography-related diagnostic imaging, differential tumor uptake of 3'-deoxy-3' [(18)F] fluorothymidine ([(18)F]FLT) has been shown to reflect the levels of cell proliferation and DNA synthesis. However, additional biomarkers for tumors are urgently required. Aberrant levels of glutathione transferase (GST) activity have been hypothesized to constitute such a novel diagnostic marker. Here, a C6 rat glioma tumor model was used to assess the ability of the positron emission tomography tracers, [(18)F]FLT and (18)F-fluorobutyl ethacrynic amide ([(18)F]FBuEA), to indicate reactive oxygen species-induced stress responses as well as detoxification-related processes in tumors. Using a GST activity assay, we were able to demonstrate that FBuEA is more readily catalyzed by GST-pi than by GST-alpha. Furthermore, we showed that FBuEA-GS, a metabolite of FBuEA, elicits greater cytotoxicity in tumor cells than in normal fibroblast cells. Finally, in vitro and in vivo investigation of radiotracer distribution of [(18)F]FBuEA and [(18)F] FBuEA-GS revealed preferential accumulation in C6 glioma tumor cells over normal fibroblast cells for [(18)F]FBuEA-GS but not for [(18)F]FBuEA. PMID- 26244027 TI - Profile and microbiological isolates of asymptomatic bacteriuria among pregnant women in Abakaliki, Nigeria. AB - BACKGROUND: Detecting and treating asymptomatic bacteriuria (ASB) prevents urinary tract infection and its consequences. The cost-effectiveness of routine screening for ASB in pregnancy is controversial. In populations with high prevalence, however, it is worthwhile and justifiable. AIM: To determine the profile, prevalence, microbiological isolates, and risk factors of ASB among booking antenatal clinic attendees in Abakaliki, Nigeria. MATERIALS AND METHODS: This was a cross-sectional study involving booking antenatal clinic attendees at the Federal Teaching Hospital, Abakaliki, who met the inclusion criteria. This study occurred between January and December, 2012. The midstream urine samples of these women were subjected to microscopy, culture, and sensitivity. RESULTS: A total of 300 randomly selected booking antenatal clinic attendees participated in the study; 74 of them had ASB, giving a prevalence of 24.7%. With the exception of rural residence, sociodemographic and obstetric characteristics did not influence the risk of ASB among the participants in this study. Staphylococcus aureus was the commonest organism isolated. The majority of the organisms were sensitive to ofloxacin and ceftriaxone. CONCLUSION: There is a high prevalence of ASB among pregnant women in Abakaliki. With the exception of rural dwelling, sociodemographic and obstetric characteristics did not significantly influence the risk of ASB among these pregnant women. Therefore, routine ASB screening of pregnant women is recommended in our environment. PMID- 26244026 TI - Vancomycin-resistant enterococcal infections: epidemiology, clinical manifestations, and optimal management. AB - Since its discovery in England and France in 1986, vancomycin-resistant Enterococcus has increasingly become a major nosocomial pathogen worldwide. Enterococci are prolific colonizers, with tremendous genome plasticity and a propensity for persistence in hospital environments, allowing for increased transmission and the dissemination of resistance elements. Infections typically present in immunosuppressed patients who have received multiple courses of antibiotics in the past. Virulence is variable, and typical clinical manifestations include bacteremia, endocarditis, intra-abdominal and pelvic infections, urinary tract infections, skin and skin structure infections, and, rarely, central nervous system infections. As enterococci are common colonizers, careful consideration is needed before initiating targeted therapy, and source control is first priority. Current treatment options including linezolid, daptomycin, quinupristin/dalfopristin, and tigecycline have shown favorable activity against various vancomycin-resistant Enterococcus infections, but there is a lack of randomized controlled trials assessing their efficacy. Clearer distinctions in preferred therapies can be made based on adverse effects, drug interactions, and pharmacokinetic profiles. Although combination therapies and newer agents such as tedizolid, telavancin, dalbavancin, and oritavancin hold promise for the future treatment of vancomycin-resistant Enterococcus infections, further studies are needed to assess their possible clinical impact, especially in the treatment of serious infections. PMID- 26244028 TI - Epidemiology and burden of alopecia areata: a systematic review. AB - BACKGROUND: Alopecia areata (AA) is an autoimmune disorder characterized by patches of non-scarring alopecia affecting scalp and body hair that can be psychologically devastating. AA is clinically heterogenous, and its natural history is unpredictable. There is no preventative therapy or cure. OBJECTIVE: The objective of this study is to provide an evidence-based systematic review on the epidemiology and the burden of AA. METHODS AND SELECTION CRITERIA: A search was conducted of the published, peer-reviewed literature via PubMed, Embase, and Web of Science. Studies published in English within the last 51 years that measured AA's incidence, prevalence, distribution, disability-adjusted life years (DALYs), quality of life, and associated psychiatric and medical comorbidities were included. Two authors assessed studies and extracted the data. RESULTS: The lifetime incidence of AA is approximately 2% worldwide. Both formal population studies found no sex predominance. First onset is most common in the third and fourth decades of life but may occur at any age. An earlier age of first onset corresponds with an increased lifetime risk of extensive disease. Global DALYs for AA were calculated at 1,332,800 in 2010. AA patients are at risk for depression and anxiety, atopy, vitiligo, thyroid disease, and other autoimmune conditions. CONCLUSION: AA is the most prevalent autoimmune disorder and the second most prevalent hair loss disorder after androgenetic alopecia, and the lifetime risk in the global population is approximately 2%. AA is associated with psychiatric and medical comorbidities including depression, anxiety, and several autoimmune disorders, and an increased global burden of disease. PMID- 26244029 TI - Effects of exendin-4, a glucagon like peptide-1 receptor agonist, on neutrophil count and inflammatory cytokines in a rat model of endotoxemia. AB - BACKGROUND: Sepsis remains a major cause of morbidity and mortality. A variety of strategies targeting modulation of the pro-inflammatory response associated with early sepsis have been reported without clinical success. GLP-1 enhances glucose stimulated insulin secretion. In addition, it was shown to have anti-inflammatory effects. We hypothesized that treatment with exendin-4, a GLP-1 receptor agonist, would attenuate inflammation and improve glucose control in a lipopolysaccharide (LPS) rat model of inflammation. METHODS: Two-month-old male Wistar rats were randomly assigned to one of the following four groups: 1) treatment: intraperitoneal (IP) injection of LPS 10 mg/kg followed by exendin-4, 30 MUg/kg, 10 minutes later; 2) control-1: IP injection of LPS 10 mg/kg, followed by normal saline (NS); 3) control-2: IP NS injection followed by exendin-4; 4) sham: IP injection of NS followed by another NS injection. Glucose concentration, total white blood count with absolute neutrophil count, and pro- and anti-inflammatory cytokine concentrations were measured at 0, 3, 6, and 10 hours following LPS injection. RESULTS: At 3 hours, rats injected with LPS developed neutropenia, elevated pro- and anti-inflammatory cytokines, and mild hypoglycemia. Treatment with exendin-4 significantly modulated neutropenia, and decreased pro inflammatory cytokine concentrations (IL-1alpha, IL-1beta, IL-6, TNFalpha, and IFNgamma). However, exendin-4 had no effect on IL-10 concentrations. LPS injection led to mild hypoglycemia, that was not observed in rats treated with exendin-4. Sham animals exhibited no significant change from baseline in all parameters. CONCLUSION: In this LPS model of acute early phase inflammation, treatment with exendin-4 decreased pro-inflammatory cytokine concentrations without changing IL-10 blood levels and improved neutropenia. Following LPS injection, rats developed a tendency toward hypoglycemia that improved with exendin-4. Overall our data suggest that exogenous exendin-4 mediates anti inflammatory effects early in this rat model of endotoxin-induced inflammation. PMID- 26244030 TI - Prefrontal Cortex in Learning to Overcome Generalized Fear. AB - Normal brain functioning relies critically on the ability to control appropriate behavioral responses to fearful stimuli. Overgeneralized fear is the major symptom of anxiety disorders including posttraumatic stress disorder. This review describes recent data demonstrating that the medial prefrontal cortex (mPFC) plays a critical role in the refining of cues that drive the acquisition of fear response. Recent studies on molecular mechanisms that underlie the role of mPFC in fear discrimination learning are discussed. These studies suggest that prefrontal N-methyl-D-aspartate receptors expressed in excitatory neurons govern fear discrimination learning via a mechanism involving cAMP response element binding protein-dependent engagement of acetyltransferase. PMID- 26244031 TI - Everolimus-eluting stent platforms in percutaneous coronary intervention: comparative effectiveness and outcomes. AB - Despite the remarkable benefits obtained following the introduction of the first generation drug-eluting stent (DES), concerns were raised over its long-term safety, particularly with regard to very late (beyond 1 year) stent thrombosis. Newer-generation DESs have been developed to overcome this limitation using novel stent platforms, new drugs, more biocompatible durable polymers, and bioabsorbable polymers or backbones. To date, new-generation DESs have virtually replaced the use of first-generation DESs worldwide. In this review article, we discuss in detail the design, pharmacology, and mechanism of action of the newer generation permanent and bioresorbable everolimus-eluting platforms. Furthermore, we present and evaluate the current evidence on the performance and safety of these devices compared to those of other available stent platforms. PMID- 26244032 TI - Effects of vitamin D and quercetin, alone and in combination, on cardiorespiratory fitness and muscle function in physically active male adults. AB - INTRODUCTION: Vitamin D and the antioxidant quercetin, are promising agents for improving physical performance because of their possible beneficial effects on muscular strength and cardiorespiratory fitness. PURPOSE: The purpose of this study was to determine the effects of increased intakes of vitamin D, quercetin, and their combination on antioxidant status, the steroid hormone regulators of muscle function, and measures of physical performance in apparently healthy male adults engaged in moderate-to-vigorous-intensity exercise training. METHODS: A total of 40 adult male participants were randomized to either 4,000 IU vitamin D/d, 1,000 mg/d quercetin, vitamin D plus quercetin, or placebo for 8 weeks. Measures of cardiorespiratory fitness and muscle function, blood markers for antioxidant and vitamin D status, and hormones 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and testosterone were measured pre- and postsupplementation. RESULTS: At enrollment, 88.6% of participants were vitamin D sufficient (serum 25 hydroxyvitamin D >50 nmol/L) and had normal serum testosterone levels. Supplementation with vitamin D significantly increased serum 25(OH)D concentration (by 87.3% in the vitamin D group, P<0.001) and was associated with an increasing trend of testosterone concentration. There were no changes in concentration of 1,25(OH)2D3 and markers of antioxidant status associated with vitamin D or quercetin supplementation. No improvements in physical performance measures associated with vitamin D and quercetin supplementation were found. CONCLUSION: The findings obtained demonstrate that long-term vitamin D and quercetin supplementation, alone or in combination, does not improve physical performance in male adults with adequate vitamin D, testosterone, and antioxidant status. PMID- 26244033 TI - Interleukin 1beta-A Potential Salivary Biomarker for Cancer Progression? AB - The relationship between cancer and inflammation is a complex but intimate one. Decades of work has shown to us that cancer progression is influenced by a multitude of factors, including genetic, environmental, and immunological factors. We often overlook that cancer progression is also a pathological consequence of a dysregulated inflammatory control in the body. A current emerging topic in cancer research is the role of inflammasomes in carcinogenesis. The inflammasome is a multicomplex protein platform that when activated results in the release of proinflammatory cytokines, such as interleukin (IL)-1beta. There is increasing evidence suggesting that IL-1beta plays a pivotal role in cancer progression. This short review proposes the possibility of using IL-1beta as a potential cancer progression biomarker and discusses the use of saliva as a model biological fluid for measuring physiological IL-1beta levels in the body. PMID- 26244034 TI - Echocardiographic Assessment of the Right Ventricle, from the Conventional Approach to Speckle Tracking and Three-Dimensional Imaging, and Insights into the "Right Way" to Explore the Forgotten Chamber. AB - BACKGROUND: The right ventricle (RV) has an essential function in cardiovascular physiology and pathology. Currently, it is gaining an increasing interest given its recognized role in many cardiovascular conditions. However, echocardiographic assessment of the RV in daily practice is frequently based on qualitative estimation, and it has been regarded as a neglected chamber. OBJECTIVE: We sought to review and discuss the appropriate approach and latest methods of assessment of the RV by echocardiography. METHODS: A MEDLINE/Pubmed search was performed, and 55 relevant articles were selected; articles addressing right ventricular assessment by echocardiography, along with the latest recommendations, have been reviewed and discussed. RESULTS: A RV diameter >42 mm at the base and >35 mm at the mid-cavitary level indicates right ventricular dilatation; a longitudinal myocardial velocity (S') <9.5 mm/s, a tricuspid annular plane systolic excursion <17 mm, and a fractional area change <35% are indices of right ventricular systolic dysfunction. A right ventricular ejection fraction of >45% and an absolute value of global longitudinal strain of >21% reflect normal systolic function. The significance of dp/dt, the right myocardial performance index and isovolumic myocardial acceleration, is also discussed along with the parameters of right ventricular diastolic function. The use of novel echocardiographic approaches, such as three-dimensional echo and speckle tracking imaging, allows practitioners to overcome the challenges encountered with conventional echocardiography. CONCLUSION: Accurate assessment of the RV by echocardiography yields early detection of cardiac diseases, enhances risk stratification, and allows timely initiation of appropriate therapy. PMID- 26244035 TI - End-systolic Pressure-Volume Relation, Ejection Fraction, and Heart Failure: Theoretical Aspect and Clinical Applications. AB - A mathematical formalism describing the nonlinear end-systolic pressure-volume relation (ESPVR) is used to derive new indexes that can be used to assess the performance of the heart left ventricle by using the areas under the ESPVR (units of energy), the ordinates of the ESPVR (units of pressure), or from slopes of the curvilinear ESPVR. New relations between the ejection fraction (EF) and the parameters describing the ESPVR give some insight into the problem of heart failure (HF) with normal or preserved ejection fraction. Relations between percentage occurrence of HF and indexes derived from the ESPVR are also discussed. When ratios of pressures are used, calculation can be done in a noninvasive way with the possibility of interesting applications in routine clinical work. Applications to five groups of clinical data are given and discussed (normal group, aortic stenosis, aortic valvular regurgitation, mitral valvular regurgitation, miscellaneous cardiomyopathies). No one index allows a perfect segregation between all clinical groups, it is shown that appropriate use of two indexes (bivariate analysis) can lead to better separation of different clinical groups. PMID- 26244036 TI - Infiltrative Cardiomyopathies. AB - Infiltrative cardiomyopathies can result from a wide spectrum of both inherited and acquired conditions with varying systemic manifestations. They portend an adverse prognosis, with only a few exceptions (ie, glycogen storage disease), where early diagnosis can result in potentially curative treatment. The extent of cardiac abnormalities varies based on the degree of infiltration and results in increased ventricular wall thickness, chamber dilatation, and disruption of the conduction system. These changes often lead to the development of heart failure, atrioventricular (AV) block, and ventricular arrhythmia. Because these diseases are relatively rare, a high degree of clinical suspicion is important for diagnosis. Electrocardiography and echocardiography are helpful, but advanced techniques including cardiac magnetic resonance (CMR) and nuclear imaging are increasingly preferred. Treatment is dependent on the etiology and extent of the disease and involves medications, device therapy, and, in some cases, organ transplantation. Cardiac amyloid is the archetype of the infiltrative cardiomyopathies and is discussed in great detail in this review. PMID- 26244037 TI - Frailty in Advanced Heart Failure: A Consequence of Aging or a Separate Entity? AB - There are over 5 million Americans with heart failure (HF), the majority of whom are over age 65. Frailty is a systemic syndrome associated with aging that produces subclinical dysfunction across multiple organ systems and leads to an increased risk for morbidity and mortality. The prevalence of frailty is about 10% in community-dwelling elderly and 20% in those with advanced HF, and increases in both cohorts with age. Yet the relationship between the primary frailty of aging and frailty secondary to HF remains poorly defined. Whether the frailty of these two populations share similar etiologies or exist as separate entities is unknown. Teasing apart potential molecular, cellular, and functional differences between the frailty of aging and that of advanced HF has implications for risk stratification, quality of life, and pharmacological and therapeutic interventions for advanced HF patients. PMID- 26244038 TI - Androgen Deficiency and Erectile Dysfunction in Patients with Type 2 Diabetes. AB - BACKGROUND: The association between type 2 diabetes mellitus (T2DM) and low total serum testosterone (LST) has been identified in several cross-sectional studies. OBJECTIVES: To assess the prevalence of androgen deficiency and erectile dysfunction (ED) and their relation to glycemic control within a sample of Egyptian men with T2DM. RESEARCH DESIGN AND METHODS: A cross-sectional study including 70 men having T2DM. Their ages ranged from 30 to 50 years. They were evaluated for symptoms of androgen deficiency and ED, using a validated Arabic translated Androgen Deficiency in Aging Males questionnaire and five-items version of the International Index of Erectile Function-5, respectively. Total testosterone (TT), glycated hemoglobin (HbA1c), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin were measured for all study subjects. Penile hemodynamics was assessed using penile duplex study for subjects who gave history of ED. RESULTS: LST was found in 40% of studied men, and 92.9% of them reported overt symptoms of androgen deficiency. ED was detected in 85.7% of those with LST, as opposed to 31.0% of those with normal TT (P < 0.000). TT was lower in diabetic men with ED compared to those without ED (12.04 +/- 5.36 vs 17.11 +/- 7.11 nmol/L, P < 0.001). Significant negative correlation was found between TT and age, body mass index, waist circumference, systolic and diastolic blood pressures, and HBA1c (P < 0.00). FSH, LH, and prolactin levels were within the normal reference range in all subjects. HbA1c was higher in patients who had LST with ED, compared to those with normal TT and without ED. However, multivariate logistic regression analysis did not reveal a significant association between HBA1c and LST levels. CONCLUSION: LST, symptoms of androgen deficiency, and ED are common in the studied sample of Egyptian men with T2DM. Inappropriately normal FSH and LH in face of LST may denote a state of hypogonadotropic hypogonadism. HBA1c was found to be more significantly associated with ED than with LST. PMID- 26244039 TI - Pachymic acid induces apoptosis via activating ROS-dependent JNK and ER stress pathways in lung cancer cells. AB - BACKGROUND: Pachymic acid (PA), a lanostane-type triterpenoid from Poria cocos, has been reported to possess anti-emetic, anti-inflammatory, and anti-cancer properties. Nonetheless, the anti-tumor effect of PA in lung cancer cells remains unclear. Herein, we report the chemotherapeutic effects and underlying mechanisms of PA against human lung cancer. METHODS: The anti-proliferative ability of PA on lung cancer cells was assessed by MTT, colony formation and EdU proliferation assays. Flow cytometric analysis was used to detect cell cycle changes. Apoptosis was determined by annexin V/PI double-staining and the DNA ladder formation assays. The expressions of the apoptosis-related proteins were analysed by western blot. The in vivo efficacy of PA was measured using a NCI-H23 xenograft model in nude mice. RESULTS: PA exhibited anti-tumor effects in vitro accompanied by induction of G2/M phase arrest and apoptosis in NCI-H23 and NCI-H460 lung cancer cells. Mechanistically, our data showed that PA induced reactive oxygen species (ROS) production, resulting in the activation of both c-Jun N-terminal kinase (JNK) and endoplasmic reticulum (ER) stress apoptotic pathways in lung cancer cells. Moreover, blockage of ROS production reversed PA-induced JNK and ER stress activation. Finally, PA inhibited the growth of NCI-H23 xenograft tumors without causing any host toxicity, and inhibited cell proliferation and induction of apoptosis of tumor cells in tumor xenograft tissues. CONCLUSIONS: In summary, our study demonstrates that PA induces apoptosis through activation of the JNK and ER stress pathways in human lung cancer cells. Our findings provide a rationale for the potential application of PA in lung cancer therapy. PMID- 26244040 TI - Escaping the trap of allergic rhinitis. AB - Rhinitis is often the first symptom of allergy but is frequently ignored and classified as a nuisance condition. Ironically it has the greatest socioeconomic burden worldwide caused by its impact on work and on daily life. However, patients appear reticent to seek professional advice, visiting their doctor only when symptoms become 'intolerable' and often when their usual therapy proves ineffective. Clearly, it's time for new and more effective allergic rhinitis treatments. MP29-02 (Dymista(r); Meda, Solna, Sweden) is a new class of medication for moderate to severe seasonal and perennial allergic rhinitis if monotherapy with either intranasal antihistamine or intranasal corticosteroids is not considered sufficient. MP29-02 is a novel formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP). It benefits not only from the incorporation of two active agents, but also from a novel formulation; its lower viscosity, smaller droplet size, larger volume (137 MUl) and wider spray angle ensure optimal coverage of, and retention on the nasal mucosa and contribute to its clinical efficacy. In clinical trials, patients treated with MP29-02 experienced twice the symptom relief as those treated with FP and AZE, who in turn exhibited significantly greater symptom relief than placebo-patients. Indeed, the advantage of MP29-02 over FP was approximately the same as that shown for FP over placebo. The advantage of MP29-02 was particularly evident in those patients for whom nasal congestion is predominant, with MP29-02 providing three times the nasal congestion relief of FP (p = 0.0018) and five times the relief of AZE (p = 0.0001). Moreover, patients treated with MP29-02 achieved each and every response up to a week faster than those treated with FP or AZE alone and in real life 1 in 2 patients reported the perception of well-controlled disease after only 3 days. MP29-02's superiority over FP was also apparent long-term in patients with perennial allergic rhinitis or non-allergic rhinitis, with statistical significance noted from the first day of treatment, with treatment difference maintained for a full year. Taken together, these data suggest that MP29-02 may improve the lives of many of our patients, enabling them to finally escape the allergic rhinitis trap. PMID- 26244041 TI - Validation of the UKPDS 82 risk equations within the Cardiff Diabetes Model. AB - BACKGROUND: For end-users of diabetes models that include UKPDS 82 risk equations, an important question is how well these new equations perform. Consequently, the principal objective of this study was to validate the UKPDS 82 risk equations, embedded within an established type 2 diabetes mellitus (T2DM) model, the Cardiff Diabetes Model, to contemporary T2DM outcomes studies. METHODS: A total of 100 validation endpoints were simulated across treatment arms of twelve pivotal T2DM outcomes studies, simulation cohorts representing each validation study's cohort profile were generated and intensive and conventional treatment arms were defined in the Cardiff Diabetes Model. RESULTS: Overall the validation coefficient of determination was similar between both sets of risk equations: UKPDS 68, R(2) = 0.851; UKPDS 82, R(2) = 0.870. Results stratified by internal and external validation studies produced MAPE of 43.77 and 37.82%, respectively, when using UKPDS 82, and MAPE of 40.49 and 53.92%, respectively when using UKPDS 68. Areas of lack of fit, as measured by MAPE were inconsistent between sets of equations with ACCORD demonstrating a noteworthy lack of fit with UKPPDS 68 (MAPE = 170.88%) and the ADDITION study for UKPDS 82 (MAPE = 89.90%). CONCLUSIONS: This study has demonstrated that the UKPDS 82 equations exhibit similar levels of external validity to the UKPDS 68 equations with the additional benefit of enabling more diabetes related endpoints to be modeled. PMID- 26244042 TI - Comparing the Accuracy of the Three Dehydration Scales in Children with Acute Diarrhea in a Developing Country of Kosovo. AB - BACKGROUND: Although diarrhea is a preventable disease, it remains the second leading cause of death (after pneumonia) among children aged under five years worldwide. The World Health Organization (WHO) scale, the Gorelick scale, and the Clinical Dehydration Scale (CDS) were created to estimate dehydration status using clinical signs. The purpose of this study is to determine whether these clinical scales can accurately assess dehydration status of children in a developing country of Kosovo. METHODOLOGY: Children aged 1 month to 5 years with a history of acute diarrhea were enrolled in the study. After recording the data about the patients historical features the treating physician recorded the physical examination findings consistent with each clinical score. Receiver operating characteristic (ROC) curves were constructed to evaluate the performance of the three scales, compared to the gold standard, percent weight change with rehydration. Sensitivity, specificity and likelihood ratios were calculated using the best cut-off points of the ROC curves. RESULTS: We enrolled 230 children, and 200 children met eligibility criteria. The WHO scale for predicting significant dehydration (>=5 percent weight change) had an area under the curve (AUC) of 0.71 (95% : CI= 0.65-0.77). The Gorelick scales 4- and 10 point for predicting significant dehydration, had an area under the curve of 0.71 (95% : CI=0.63- 0.78) and 0.74 (95% : CI= 0.68-0.81) respectively. Only the CDS for predicting the significant dehydration above >=6% percent weight change, did not have an area under the curve statistically different from the reference line with an AUC of 0.54 (95% CI = 0.45- 0.63). CONCLUSION: The WHO dehydration scale and Gorelick scales were fair predictors of dehydration in children with diarrhea. Only the Clinical Dehydration Scale was found not to be a helpful predictor of dehydration in our study cohort. PMID- 26244043 TI - Kosovo's Public Health Damage from Abusive Use of Antibiotics in Dairy Cattle. AB - INTRODUCTION: The aim of the study is to assess the state of the use of antibiotics in dairy cattle in Kosovo according to different diagnosis as directed by treatment protocol and to evaluate the methods of their application in dairy cattle. METHODS: We've visited over 80% of dairy farms throughout the territory of Kosovo in 2013. Assessment was carried out through a specific questionnaire, which identifies problems with medical treatment of cattle, the number of cattle treated and untreated, description of dose and type of drugs used, as well as the duration of drugs issuance. RESULTS: In Kosovo for the treatment of sick cows are mainly used beta lactams and sulfonamides. The drugs were not given only to sick cattle by their diagnosis, but they were given to healthy cattle too, as a preventative therapy, mainly through intramuscular route. CONCLUSION: We conclude that the dairy cattle were not treated correctly as directed by the treatment protocol. In Kosovo's general health system there are no rules and procedures on monitoring and recording the expenditures on antibiotics. PMID- 26244044 TI - Causes of Sterility in Bosnia-Herzegovina Population. AB - INTRODUCTION: Infertility or sterility or barrenness is defined as a state of inability to conceive after a year of unprotected intercourse. Ovulation problems, uterine tube problems, endometriosis, uterine etiology problems, chromosomal problems which are not so rare, spermatogenesis disorders and azoospermia are stated as the most common causes of infertility. OBJECTIVE: Main objective of this research is to present most common causes of marital infertility in Bosnia-Herzegovina population. MATERIAL AND METHODS: Retrospective, descriptive- epidemiological study has been published at Bahceci IVF center in Sarajevo (Bosnia and Herzegovina). The research covered a time period of two years. During the time-period in question, 826 marital couples from Bosnia and Herzegovina diagnosed with marital sterility approached the Center. RESULTS: Analysis of female patients as per age groups determined that the largest number of respondents belonged to the 36 - 39 age group with a total number of 293 patients, followed by 30 - 35 age group with a total number of 245 patients, and the third most frequent age group included those of >= 40 years of age with 179 patients in total, followed by 25-29 age group with 98 respondents. In 42% (n=350) of the couples diagnosed with marital infertility, female sterility was established as the reason, while in 36 % (n=294) of the couples, male sterility was the reason. Both marital spouses were infertile in 11% of the couples (n=92), while in remaining 11% of the couples, no diagnosis was determined and they belonged in the group of unexplainable sterility. The most common cause of sterility in women is diminished ovarian reserve (DOR), as was the case in 38.57% of respondents. This diagnosis is in direct correlation with the age of a woman. Among causes of sterility of organic and functional origin, the most common is ovarian tube problem - in 31.4% of the cases, then ovulatory problems - in 12.86% of the cases, and polycystic ovary syndrome in 6% of the cases. Other causes such as endometrioma, endometriosis and genetic factors are present in less than 2% of respondents. Regarding male sterility, problems with spermatogenesis are prevailing (decreased number and mobility of sperm cells and problems with morphology of sperm cells), oligoasthenoteratozoospermia in 81.61% of the patients. In 14.19% of the cases, azoospermia was present. CONCLUSION: All of this contributes to the negative demographic trend in Bosnia and Herzegovina. In 2008, European Parliament warned of importance of infertility treatment. In collaboration with ESHRE (European Society of Human Reproduction and Embryology), main guidelines to alleviate this problem were provided. PMID- 26244045 TI - Interference of Bilirubin in the Determination of Magnesium with Methyl Thymol Blue. AB - INTRODUCTION: Jaundice is a disease named for the yellow color of the skin. This color is the result of elevated levels of bilirubin in the blood serum. In Roma from Krusevac region in the last few years have seen the emergence of jaundice. MATERIAL AND METHODS: In 80 of them (40 suffering and 40 from control group) were performed tests of numerous parameters in the laboratories of the Health Center in Krusevac. Magnesium was determined by spectrophotometry with methyl thymol blue, titanium yellow and blue xylidene. Bilirubin was determined by Jandresek Grofov's method. RESULTS: The results were within the expectations, in addition to magnesium which was determined with methyl thymol blue. In all patients suffering from jaundice concentration of magnesium (0.67 +/-0.14 mmol/l) statistically was significantly lower than tested of the control group (0.91+/- 0.059 mmol/). There is no theoretical data to reduce the concentration of magnesium in serum as a result of jaundice. That's why we determined magnesium both in the control group and in sufferings with two methods as the titanium yellow, and xylidene blew. With these two methods we obtained results that were examined were within normal limits. CONCLUSION: This has led us to conclude that the determination of bilirubin interferes with magnesium methyl thymol blue. PMID- 26244046 TI - The Comparison of Learning and Memorization Rate of English Among Sari Male Students in Secondary Schools (2010-2011). AB - BACKGROUND: The aim of present study was to investigate the learning and memorization rate of English based on authentic and traditional assessment approaches in Sari secondary schools. METHODS: It was performed in semi- experimental method. The sample included 60 first year high school male students, selected randomly. Then it has been divided in two groups as experimental and control groups. Assessment devices used in this research included: academic achievement pre-test of English, academic achievement post-test revised questionnaire of attitude toward tests (SAAS-R), and English performance test Before carrying the authentic and traditional assessment approaches into execution, two groups had been taken the scholar academic achievement pre-test in order to assure not to be any significant differences between two groups. After the execution of above mentioned method (about 14 weeks), the academic achievement post-test, and performance test and attitude toward tests (SAAS-R) were performed. Moreover, 2 months after post-test, it was repeated to measure the rate of memorization. In order to analyze data the statistical method, the dependent and independent T- tests were used to determine mean differences of two groups and K2 test was applied to assign the differences of two groups' attitude toward tests. RESULTS: The results implied that: The rate of students' performance learning in authentic assessments is more than the traditional ones. CONCLUSION: There was no significant difference between two group's post-test scores. The rate of memorization in authentic methods is more than the traditional ones. The attitude toward tests in authentic methods is more positive than the traditional ones. PMID- 26244047 TI - Angiotensin-converting enzyme inhibitors of Bothrops jararaca snake venom affect the structure of mice seminiferous epithelium. AB - BACKGROUND: Considering the similarity between the testis-specific isoform of angiotensin-converting enzyme and the C-terminal catalytic domain of somatic ACE as well as the structural and functional variability of its natural inhibitors, known as bradykinin-potentiating peptides (BPPs), the effects of different synthetic peptides, BPP-10c ( 0.05) to the other methods used for such purposes, as block digestion, and offered a Ca, Mg and P method of quantification limit of 10.6, 12.4 and 14 mg/kg, respectively. The major advantages of the UAE method compared to other methods are the high treatment rate, low reagent usage in the extracts and, it does not generate toxic residues that might negatively affect human health and the environment, accompanied by good precision and accuracy. PMID- 26244096 TI - Procalcitonin-guided antibiotic therapy for septic patients in the surgical intensive care unit. AB - In critically ill patients, elucidating those patients with the systemic inflammatory response syndrome (SIRS) from an infectious source (sepsis), versus those who have SIRS without infection, can be challenging since the clinical features are the same. Even with strict monitoring and testing, 39-98 % of patients with SIRS will never have bacteriological confirmation of an infection, and 6-17 % of patients with a documented infection will not show signs of SIRS. Due to this overlap, an extensive amount of research has been performed to investigate ways of determining and separating SIRS from infection, compared to SIRS due to trauma, surgical stress, or other non-infectious causes. This review article will discuss the recommended and peer-approved use of procalcitonin in septic patients in the intensive care unit and its use as a guide to antibiotic initiation and termination. The article will focus on the prospective randomized trials (Level 1 evidence) that have been conducted, and lesser levels of evidence will be referenced as needed to substantiate a conclusion. The literature documents multiple benefits of using procalcitonin as a guide to cost savings and appropriate termination of antibiotics by its use as a new objective marker of bacteremia that was previously not available. This article will show that antibiotics should be terminated when the procalcitonin level falls below 0.5 ng/mL. PMID- 26244097 TI - Application of concrete surfaces as novel substrate for immobilization of TiO2 nano powder in photocatalytic treatment of phenolic water. AB - BACKGROUND: In this study, concrete application as a substrate for TiO2 nano powder immobilization in heterogeneous photocatalytic process was evaluated. TiO2 immobilization on the pervious concrete surface was done by different procedures containing slurry method (SM), cement mixed method (CMM) and different concrete sealer formulations. Irradiation of TiO2 was prepared by UV-A and UV-C lamps. Phenolic wastewater was selected as a pollutant and efficiency of the process was determined in various operation conditions including influent phenol concentration, pH, TiO2 concentration, immobilization method and UV lamp intensity. FINDINGS: The removal efficiency of photocatalytic process in 4 h irradiation time and phenol concentration ranges of 25-500 mg/L was more than 80 %. Intermediates were identified by GC/Mass and spectrophotometric analysis. CONCLUSIONS: According to the results, photocatalytic reactions followed the pseudo-first-order kinetics and can effectively treate phenol under optimal conditions. PMID- 26244098 TI - Association between patterns of leisure time physical activity and asthma control in adult patients. AB - BACKGROUND: Physical activity has been shown to have various health benefits in patients with asthma, especially in children. However, there are still limited data on the nature of the association between physical activity and asthma control in adults. OBJECTIVE: The objective of the current study was to determine the nature of the association between physical activity and asthma control, with particular emphasis on the intensity of the activity and seasonal variations. METHODS: 643 adult patients with objectively confirmed asthma (mean age (SD)=53 (15) years, 60% women) were interviewed by telephone. Patients completed the asthma control questionnaire (ACQ), the asthma quality of life questionnaire, and a 1-year physical activity recall questionnaire to assess leisure time physical activity (LTPA). RESULTS: Total LTPA was related to control (beta (95% CI)=-0.013 (-0.030 to 0.006)), with those doing recommended levels of LTPA being nearly 2.5 times more likely to have good control compared with inactive patients. Analysis of seasonal exercise habits found that winter LTPA (beta=-0.027 (-0.048 to 0.006)) was more strongly associated with ACQ scores than summer LTPA (beta= 0.019 (-0.037 to -0.001)). Adjustment for age, sex, season of assessment, inhaled corticosteroid (ICS) dose, body mass index, and current smoking status reduced the strength of the relationships. CONCLUSIONS: Data indicate that higher levels of LTPA are associated with better levels of asthma control in adult patients with asthma, and that this seems to be more pronounced among asthmatics who do the recommended levels of exercise. PMID- 26244099 TI - Low rate of and rapid attention to inappropriate ICD shocks with remote device and rhythm monitoring: a qualitative study. AB - OBJECTIVES: Inappropriate shocks are unpleasant and painful. We hypothesise that remote monitoring and careful attention to known and incident atrial fibrillation (AF) can reduce inappropriate shocks to a very low level in clinical praxis. METHODS: Altogether 259 patients with implantable cardioverter defibrillator implanted for secondary (S, n=113) and primary (P, n=146) prevention were followed via remote monitoring. At implant, 42S (37%) and 54P (37%) patients had known AF. RESULTS: Inappropriate shocks, all but five due to AF, occurred in 7S (6.2%) and 11P (7.5%), and there were only inappropriate shocks in 5/7S and in 8/11P. They occurred in four of 42S (9.5%) with and in three of 71S (4.2%) without known AF, and in seven of 54P (13%) with and in four of 92P (4.3%) without known AF. The median time from shock to action was 5 and 1 day, respectively. Actions were medication with amiodarone, beta blockers, beta blockers+amiodarone or beta blockers+digoxin (n=5), beta blockers+insertion of an atrial lead (n=1), replacement of a fractured lead (n=2), reprogramming in combination with beta blockers, digoxin or amiodarone (n=4), reprogramming (n=2) and none (n=4). After action, four further inappropriate shocks occurred during more than 2 years of follow-up, all due to AF. CONCLUSIONS: Inappropriate shocks occurred at a low rate and most often because of AF known at implant. Remote monitoring enabled rapid action, after which few inappropriate shocks occurred over more than 2 years. Attention to known and incident AF was the most important action to reduce inappropriate shocks. PMID- 26244100 TI - Therapeutic Applications of Extracellular Matrix. AB - Chronic and hard-to-heal wounds are a tremendous burden on our healthcare system and impair the quality of life for millions of people. An emerging focus of regenerative medicine is the development of natural biomaterials that can stimulate tissue formation or repair by recreating the functional and structural properties of proteins and polysaccharides found within the extracellular matrix (ECM). Promising new developments include the fabrication of novel ECM-based biologics to selectively deliver drugs or growth factors to wounds; new classes of bioactive tissue sealants, scaffolds, and hydrogels; as well as inductive wound dressings derived from decellularized tissues. The advances highlighted in this forum issue provide an exciting glimpse into the growing potential of ECM based wound therapeutics. PMID- 26244101 TI - Chronic Wound Dressings Based on Collagen-Mimetic Proteins. AB - Objective: Chronic wounds are projected to reach epidemic proportions due to the aging population and the increasing incidence of diabetes. There is a strong clinical need for an improved wound dressing that can balance wound moisture, promote cell migration and proliferation, and degrade at an appropriate rate to minimize the need for dressing changes. Approach: To this end, we have developed a bioactive, hydrogel microsphere wound dressing that incorporates a collagen mimetic protein, Scl2GFPGER, to promote active wound healing. A redesigned Scl2GFPGER, engineered collagen (eColGFPGER), was created to reduce steric hindrance of integrin-binding motifs and increase overall stability of the triple helical backbone, thereby resulting in increased cell adhesion to substrates. Results: This study demonstrates the successful modification of the Scl2GFPGER protein to eColGFPGER, which displayed enhanced stability and integrin interactions. Fabrication of hydrogel microspheres provided a matrix with adaptive moisture technology, and degradation rates have potential for use in human wounds. Innovation: This collagen-mimetic wound dressing was designed to permit controlled modulation of cellular interactions and degradation rate without impact on other physical properties. Its fabrication into uniform hydrogel microspheres provides a bioactive dressing that can readily conform to irregular wounds. Conclusion: Overall, this new eColGFPGER shows strong promise in the generation of bioactive hydrogels for wound healing as well as a variety of tissue scaffolds. PMID- 26244102 TI - Ciprofloxacin-Loaded Keratin Hydrogels Prevent Pseudomonas aeruginosa Infection and Support Healing in a Porcine Full-Thickness Excisional Wound. AB - Objective: Cutaneous wound infection can lead to impaired healing, multiple surgical procedures, and increased hospitalization time. We tested the effectiveness of keratin-based hydrogels (termed "keratose") loaded with ciprofloxacin to inhibit infection and support healing when topically administered to porcine excision wounds infected with Pseudomonas aeruginosa. Approach: Using a porcine excisional wound model, 10 mm full-thickness wounds were inoculated with 106 colony-forming units of P. aeruginosa and treated on days 1 and 3 postinoculation with ciprofloxacin-loaded keratose hydrogels. Bacteria enumeration and wound healing were assessed on days 3, 7, and 11 postinjury. Results: Ciprofloxacin-loaded keratose hydrogels reduced the amount of P. aeruginosa in the wound bed by 99.9% compared with untreated wounds on days 3, 7, and 11 postinjury. Ciprofloxacin-loaded keratose hydrogels displayed decreased wound contraction and reepithelialization at day 7 postinjury. By day 11, wounds treated with ciprofloxacin-keratose hydrogels contained collagen-rich granulation tissue and myofibroblasts. Wounds treated with ciprofloxacin-loaded keratose hydrogels exhibited a transient increase in macrophages in the wound bed at day 7 postinjury that subsided by day 11. Innovation: Current therapies for wound infection include systemic antibiotics, which could lead to antibiotic resistance, and topical antimicrobial treatments, which require multiple applications and can delay healing. Here, we show that ciprofloxacin-loaded keratose hydrogels inhibit cutaneous wound infection without interfering with key aspects of the healing process including granulation tissue deposition and remodeling. Conclusions: Ciprofloxacin-loaded keratose hydrogels have the potential to serve as a point-of-injury antibiotic therapy that prevents infection and supports healing following cutaneous injury. PMID- 26244103 TI - Fibronectin Interaction and Enhancement of Growth Factors: Importance for Wound Healing. AB - Significance: This critical review focuses on interactions between cells, fibronectin (FN), and growth factors (GF). Recent Advances: Initially, the extracellular matrix (ECM) was thought to serve simply as a reservoir for GFs that would be released as soluble ligands during proteolytic degradation of ECM. This view was rather quickly extended by the observation that ECM could concentrate GFs to the pericellular matrix for more efficient presentation to cell surface receptors. However, recent reports support much more complex interactions among GFs and ECM molecules, particularly FN, and the way these interactions can fine-tune cell responses to the microenvironment. Critical Issues: Wounds that are unable to synthesize and sustain a functional ECM cannot optimally benefit from endogenous or exogenous GFs. Therefore, GF treatments have recently focused on utilizing ECM molecules as delivery vehicles. Thus, ECM can influence GF stability and activity, and GFs can modulate the ECM activity. Hence, both individually and together, ECM and GFs modulate cells that in turn control the type and level of GFs and ECM in the pericellular environment that ultimately results in new tissue generation. Although many ECM components are important for optimal tissue regeneration and wound healing, FN stands out as absolutely critical not only for wound healing and tissue regeneration but also for embryogenesis and morphogenesis. Future Directions: Understanding ECM/GF interactions will greatly facilitate our understanding of normal wound repair and regeneration, the failure of wounds to heal, and how the latter can be salvaged with proper ECM/GF combinations. PMID- 26244104 TI - Extracellular Matrix-Inspired Growth Factor Delivery Systems for Skin Wound Healing. AB - Significance: Growth factors are very promising molecules for the treatment of skin wounds. However, their translation to clinical use has been seriously limited, facing issues related to safety and cost-effectiveness. These problems may derive from the fact that growth factors are used at vastly supra physiological levels without optimized delivery systems. Recent Advances: The extracellular matrix (ECM) plays a fundamental role in coordinating growth factor signaling. Therefore, understanding the mechanisms by which the ECM modulates growth factor activity is key for designing efficient growth factor-based therapies. Recently, several growth factor-binding domains have been discovered within various ECM proteins, and growth factor delivery systems integrating these ECM growth factor-binding domains showed promising results in animal models of skin wound healing. Moreover, a novel strategy consisting of engineering growth factors to target endogenous ECM could substantially enhance their efficacy, even when used at low doses. Critical Issues: Optimal delivery of growth factors often requires complex engineered biomaterial matrices, which can face regulatory issues for clinical translation. To simplify delivery systems and render strategies more applicable, growth factors can be engineered to optimally function with clinically approved biomaterials or with endogenous ECM present at the delivery site. Future Directions: Further development and clinical trials will reveal whether growth factor-based therapies can be used as main therapeutic approaches for skin wound healing. The future impact of these therapies will depend on our capacity to deliver growth factors more precisely, to improve efficacy, safety, and cost-effectiveness. PMID- 26244105 TI - The Use of Biologic Scaffolds in the Treatment of Chronic Nonhealing Wounds. AB - Significance: Injuries to the skin as a result of illness or injury, particularly chronic nonhealing wounds, present a major healthcare problem. Traditional wound care approaches attempt to control the underlying causes, such as infection and ischemia, while the application of wound dressings aims to modify a poorly healing wound environment into a microenvironment more closely resembling an acute wound allowing the body to heal the wound naturally. Recent Advances: Regenerative medicine approaches, such as the use of biologic scaffold materials comprising an intact extracellular matrix (ECM) or individual components of the ECM, are providing new therapeutic options that focus upon the provision of biochemical cues that alter the wound microenvironment to facilitate rapid restoration of normal skin architecture. Critical Issues: The incidence of chronic nonhealing wounds continues to increase. For example, between 15% and 20% of diabetics are likely to develop chronic, nonhealing foot wounds creating an increasing burden on healthcare systems worldwide. Future Directions: Developing a thorough understanding of wound microenvironment and the mechanisms by which biologic scaffolds work in vivo has the potential to markedly improve outcomes in the clinical translation for the treatment of chronic wounds. PMID- 26244106 TI - Utilizing Fibronectin Integrin-Binding Specificity to Control Cellular Responses. AB - Significance: Cells communicate with the extracellular matrix (ECM) protein fibronectin (Fn) through integrin receptors on the cell surface. Controlling integrin-Fn interactions offers a promising approach to directing cell behavior, such as adhesion, migration, and differentiation, as well as coordinated tissue behaviors such as morphogenesis and wound healing. Recent Advances: Several different groups have developed recombinant fragments of Fn that can control epithelial to mesenchymal transition, sequester growth factors, and promote bone and wound healing. It is thought that these physiological responses are, in part, due to specific integrin engagement. Furthermore, it has been postulated that the integrin-binding domain of Fn is a mechanically sensitive switch that drives binding of one integrin heterodimer over another. Critical Issues: Although computational simulations have predicted the mechano-switch hypothesis and recent evidence supports the existence of varying strain states of Fn in vivo, experimental evidence of the Fn integrin switch is still lacking. Future Directions: Evidence of the integrin mechano-switch will enable the development of new Fn-based peptides in tissue engineering and wound healing, as well as deepen our understanding of ECM pathologies, such as fibrosis. PMID- 26244107 TI - Conducting perception research over the internet: a tutorial review. AB - This article provides an overview of the recent literature on the use of internet based testing to address important questions in perception research. Our goal is to provide a starting point for the perception researcher who is keen on assessing this tool for their own research goals. Internet-based testing has several advantages over in-lab research, including the ability to reach a relatively broad set of participants and to quickly and inexpensively collect large amounts of empirical data, via services such as Amazon's Mechanical Turk or Prolific Academic. In many cases, the quality of online data appears to match that collected in lab research. Generally-speaking, online participants tend to be more representative of the population at large than those recruited for lab based research. There are, though, some important caveats, when it comes to collecting data online. It is obviously much more difficult to control the exact parameters of stimulus presentation (such as display characteristics) with online research. There are also some thorny ethical elements that need to be considered by experimenters. Strengths and weaknesses of the online approach, relative to others, are highlighted, and recommendations made for those researchers who might be thinking about conducting their own studies using this increasingly-popular approach to research in the psychological sciences. PMID- 26244108 TI - All that is gold does not glitter? Age, taxonomy, and ancient plant DNA quality. AB - More than 600 herbarium samples from four distantly related groups of flowering plants were used for DNA extraction and subsequent measurements of DNA purity and concentration. We did not find any significant relation between DNA purity and the age of the sample. However, DNA yields were different between plant groups studied. We believe that there there should be no reservations about "old" samples if the goal is to extract more DNA of better purity. We argue that the older herbarium samples are the mine for the future DNA studies, and have the value not less than the "fresh" specimens. PMID- 26244109 TI - A population genetic assessment of coral recovery on highly disturbed reefs of the Keppel Island archipelago in the southern Great Barrier Reef. AB - Coral reefs surrounding the islands lying close to the coast are unique to the Great Barrier Reef (GBR) in that they are frequently exposed to disturbance events including floods caused by cyclonic rainfall, strong winds and occasional periods of prolonged above-average temperatures during summer. In one such group of islands in the southern GBR, the Keppel Island archipelago, climate-driven disturbances frequently result in major coral mortality. Whilst these island reefs have clearly survived such dramatic disturbances in the past, the consequences of extreme mortality events may include the loss of genetic diversity, and hence adaptive potential, and a reduction in fitness due to inbreeding, especially if new recruitment from external sources is limited. Here we examined the level of isolation of the Keppel Island group as well as patterns of gene flow within the Keppel Islands using 10 microsatellite markers in nine populations of the coral, Acropora millepora. Bayesian cluster analysis and assignment tests indicated gene flow is restricted, but not absent, between the outer and inner Keppel Island groups, and that extensive gene flow exists within each of these island groups. Comparison of the Keppel Island data with results from a previous GBR-wide study that included a single Keppel Island population, confirmed that A. millepora in the Keppel Islands is genetically distinct from populations elsewhere on the GBR, with exception of the nearby inshore High Peak Reef just north of the Keppel Islands. We compared patterns of genetic diversity in the Keppel Island populations with those from other GBR populations and found them to be slightly, but significantly lower, consistent with the archipelago being geographically isolated, but there was no evidence for recent bottlenecks or deviation from mutation-drift equilibrium. A high incidence of private alleles in the Keppel Islands, particularly in the outer islands, supports their relative isolation and contributes to the conservation value of the archipelago. The lack of evidence for genetic erosion, in combination with our observation that the North Keppel Island population samples collected in 2002 and 2008, respectively, exhibited a pairwise genetic distance of zero, supports previous published work indicating that, following bleaching, Acropora corals in the Keppel Islands predominantly recover from regrowth of small amounts of remaining live tissue in apparently dead coral colonies. This is likely supplemented by recruitment of larvae from genetically similar, less disturbed populations at nearby reefs, particularly following extreme flood events. PMID- 26244110 TI - Early prediction of language and literacy problems: is 18 months too early? AB - There is a lack of stability in language difficulties across early childhood: most late talkers (LTs) resolve their difficulties by pre-school; and a significant number of children who were not LTs subsequently manifest language difficulties. Greater reliability in predicting individual outcomes is needed, which might be achieved by waiting until later in development when language is more stable. At 18 months, productive vocabulary scores on the Oxford Communicative Developmental Inventory were used to classify children as LTs or average talkers (ATs). Thirty matched-pairs of LTs and ATs were followed up at school-age (average age 7 years), when language and literacy outcomes were assessed. For 18 children, intermediate testing at age 4 had classified them as showing typical development (TD) or specific language impairment (SLI). After correcting for multiple comparisons, there were no significant differences between the LTs and ATs on any outcome measure, and the LTs were performing in the average range. However, there were large-sized effects on all outcomes when comparing the TD and SLI groups. LT status on its own is not determinative of language and literacy difficulties. It would therefore not be appropriate to use expressive vocabulary measures alone to screen for language difficulties at 18 months. However, children with language impairment at age 4 are at risk of enduring difficulties. PMID- 26244111 TI - Age, growth, and natural mortality of yellowfin grouper (Mycteroperca venenosa) from the southeastern United States. AB - Ages of yellowfin grouper (n = 306) from the southeastern United States coast from 1979-2014 were determined using sectioned sagittal otoliths. Opaque zones were annular, forming January-June (peaking in February-March). Yellowfin grouper ranged in age from 3 to 31 years; the largest fish measured 1,000 mm fork length (FL). Body size relationships for yellowfin grouper were: W = 1.22 * 10(-5) FL(3.03) (n = 229, r (2) = 0.92); TL = 1.06 FL - 14.53 (n = 60, r (2) = 0.99); and FL = 0.93 TL + 18.63 (n = 60, r (2) = 0.99), where W = whole weight in grams, FL in mm, and TL = total length in mm. The von Bertalanffy growth equation was: Lt = 958 (1 - e(-0.11(t+2.94))) (n = 306). The point estimate of natural mortality for yellowfin grouper was M = 0.14, while age-specific estimates of M ranged from 1.59 to 0.17 for ages 1-31. PMID- 26244112 TI - The majority are not performing home-exercises correctly two weeks after their initial instruction-an assessor-blinded study. AB - Introduction. Time-under-tension (TUT) reflects time under load during strength training and is a proxy of the total exercise dose during strength training. The purpose of this study was to investigate if young participants are able to reproduce TUT and exercise form after two weeks of unsupervised exercises. Material and Methods. The study was an assessor-blinded intervention study with 29 participants. After an initial instruction, all participants were instructed to perform two weeks of home-based unsupervised shoulder abduction exercises three times per week with an elastic exercise band. The participants were instructed in performing an exercise with a predefined TUT (3 s concentric; 2 s isometric; 3 s eccentric; 2 s break) corresponding to a total of 240 s of TUT during three sets of 10 repetitions. After completing two weeks of unsupervised home exercises, they returned for a follow-up assessment of TUT and exercise form while performing the shoulder abduction exercise. A stretch sensor attached to the elastic band was used to measure TUT at baseline and follow-up. A physiotherapist used a pre-defined clinical observation protocol to determine if participants used the correct exercise form. Results. Fourteen of the 29 participants trained with the instructed TUT at follow-up (predefined target: 240 s +/-8%). Thirteen of the 29 participants performed the shoulder abduction exercise with a correct exercise form. Seven of the 29 participants trained with the instructed TUT and exercise form at follow-up. Conclusion. The majority of participants did not use the instructed TUT and exercise form at follow-up after two weeks of unsupervised exercises. These findings emphasize the importance of clear and specific home exercise instructions if participants are to follow the given exercise prescription regarding TUT and exercise form as too many or too few exercise stimuli in relation to the initially prescribed amount of exercise most likely will provide a misinterpretation of the actual effect of any given specific home exercise intervention. PMID- 26244113 TI - Linear and nonlinear characteristics of the runoff response to regional climate factors in the Qira River basin, Xinjiang, Northwest China. AB - The inland river watersheds of arid Northwest China represent an example of how, in recent times, climatic warming has increased the complexity of Earth's hydrological processes. In the present study, the linear and nonlinear characteristics of the runoff response to temperature and precipitation were investigated in the Qira River basin, located on the northern slope of the Kunlun Mountains. The results showed that average temperature on annual and seasonal scales has displayed a significantly increasing trend, but this has not been reflected in accumulated precipitation and runoff. Using path analysis, a positive link between precipitation and runoff was found both annually and in the summer season. Conversely, it was found that the impact of temperature on runoff has been negative since the 1960s, attributable to higher evaporation and infiltration in the Qira River basin. Over the past 50 years, abrupt changes in annual temperature, precipitation and runoff occurred in 1997, 1987 and 1995, respectively. Combined with analysis using the correlation dimension method, it was found that the temperature, precipitation and runoff, both annually and seasonally, possessed chaotic dynamic characteristics, implying that complex hydro-climatic processes must be introduced into other variables within models to describe the dynamics. In addition, as determined via rescaled range analysis, a consistent annual and seasonal decreasing trend in runoff under increasing temperature and precipitation conditions in the future should be taken into account. This work may provide a theoretical perspective that can be applied to the proper use and management of oasis water resources in the lower reaches of river basins like that of the Qira River. PMID- 26244114 TI - From promise to practice: pairing non-invasive sampling with genomics in conservation. AB - Conservation genomics has become an increasingly popular term, yet it remains unclear whether the non-invasive sampling that is essential for many conservation related studies is compatible with the minimum requirements for harnessing next generation sequencing technologies. Here, we evaluated the feasibility of using genotyping-by-sequencing of non-invasively collected hair samples to simultaneously identify and genotype single nucleotide polymorphisms (SNPs) in a climate-sensitive mammal, the American pika (Ochotona princeps). We identified and genotyped 3,803 high-confidence SNPs across eight sites distributed along two elevational transects using starting DNA amounts as low as 1 ng. Fifty-five outlier loci were detected as candidate gene regions under divergent selection, constituting potential targets for future validation. Genome-wide estimates of gene diversity significantly and positively correlated with elevation across both transects, with all low elevation sites exhibiting significant heterozygote deficit likely due to inbreeding. More broadly, our results highlight a range of issues that must be considered when pairing genomic data collection with non invasive sampling, particularly related to field sampling protocols for minimizing exogenous DNA, data collection strategies and quality control steps for enhancing target organism yield, and analytical approaches for maximizing cost-effectiveness and information content of recovered genomic data. PMID- 26244115 TI - Indicators of distress in newly diagnosed breast cancer patients. AB - Background. The diagnosis, treatment, and long-term management of cancer can present individuals with a multitude of stressors at various points in that trajectory. Psychosocial distress may appear early in the diagnostic process and have negative effects on compliance with treatment and subsequent quality of life. Purpose. The aim of the study was to determine early-phase predictors of distress before any medical treatment. Method. Consistent with the goals of the study, 123 newly diagnosed breast cancer patients (20 to 74 years old) completed multiple indicators of knowledge about breast cancer management and treatment, attitudes toward cancer, social support, coping efficacy, and distress. Results. SEM analysis confirmed the hypothesized model. Age was negatively associated with the patient's knowledge (beta = - 0.22), which, in turn, was positively associated with both attitudes toward breast cancer (beta = 0.39) and coping self efficacy (beta = 0.36). Self-efficacy was then directly related to psychological distress (beta = - 0.68). Conclusions. These findings establish indicators of distress in patients early in the cancer trajectory. From a practical perspective, our results have implications for screening for distress and for the development of early interventions that may be followed by healthcare professionals to reduce psychological distress. PMID- 26244116 TI - Not all jellyfish are equal: isotopic evidence for inter- and intraspecific variation in jellyfish trophic ecology. AB - Jellyfish are highly topical within studies of pelagic food-webs and there is a growing realisation that their role is more complex than once thought. Efforts being made to include jellyfish within fisheries and ecosystem models are an important step forward, but our present understanding of their underlying trophic ecology can lead to their oversimplification in these models. Gelatinous zooplankton represent a polyphyletic assemblage spanning >2,000 species that inhabit coastal seas to the deep-ocean and employ a wide variety of foraging strategies. Despite this diversity, many contemporary modelling approaches include jellyfish as a single functional group feeding at one or two trophic levels at most. Recent reviews have drawn attention to this issue and highlighted the need for improved communication between biologists and theoreticians if this problem is to be overcome. We used stable isotopes to investigate the trophic ecology of three co-occurring scyphozoan jellyfish species (Aurelia aurita, Cyanea lamarckii and C. capillata) within a temperate, coastal food-web in the NE Atlantic. Using information on individual size, time of year and delta (13)C and delta (15)N stable isotope values, we examined: (1) whether all jellyfish could be considered as a single functional group, or showed distinct inter-specific differences in trophic ecology; (2) Were size-based shifts in trophic position, found previously in A. aurita, a common trait across species?; (3) When considered collectively, did the trophic position of three sympatric species remain constant over time? Differences in delta (15)N (trophic position) were evident between all three species, with size-based and temporal shifts in delta (15)N apparent in A. aurita and C. capillata. The isotopic niche width for all species combined increased throughout the season, reflecting temporal shifts in trophic position and seasonal succession in these gelatinous species. Taken together, these findings support previous assertions that jellyfish require more robust inclusion in marine fisheries or ecosystem models. PMID- 26244117 TI - Motor neurons in the escape response circuit of white shrimp (Litopenaeus setiferus). AB - Many decapod crustaceans perform escape tailflips with a neural circuit involving giant interneurons, a specialized fast flexor motor giant (MoG) neuron, populations of larger, less specialized fast flexor motor neurons, and fast extensor motor neurons. These escape-related neurons are well described in crayfish (Reptantia), but not in more basal decapod groups. To clarify the evolution of the escape circuit, I examined the fast flexor and fast extensor motor neurons of white shrimp (Litopenaeus setiferus; Dendrobranchiata) using backfilling. In crayfish, the MoGs in each abdominal ganglion are a bilateral pair of separate neurons. In L. setiferus, the MoGs have massive, possibly syncytial, cell bodies and fused axons. The non-MoG fast flexor motor neurons and fast extensor motor neurons are generally found in similar locations to where they are found in crayfish, but the number of motor neurons in both the flexor and extensor pools is smaller than in crayfish. The loss of fusion in the MoGs and increased number of fast motor neurons in reptantian decapods may be correlated with an increased reliance on non-giant mediated tailflipping. PMID- 26244118 TI - A comparison of observation-level random effect and Beta-Binomial models for modelling overdispersion in Binomial data in ecology & evolution. AB - Overdispersion is a common feature of models of biological data, but researchers often fail to model the excess variation driving the overdispersion, resulting in biased parameter estimates and standard errors. Quantifying and modeling overdispersion when it is present is therefore critical for robust biological inference. One means to account for overdispersion is to add an observation-level random effect (OLRE) to a model, where each data point receives a unique level of a random effect that can absorb the extra-parametric variation in the data. Although some studies have investigated the utility of OLRE to model overdispersion in Poisson count data, studies doing so for Binomial proportion data are scarce. Here I use a simulation approach to investigate the ability of both OLRE models and Beta-Binomial models to recover unbiased parameter estimates in mixed effects models of Binomial data under various degrees of overdispersion. In addition, as ecologists often fit random intercept terms to models when the random effect sample size is low (<5 levels), I investigate the performance of both model types under a range of random effect sample sizes when overdispersion is present. Simulation results revealed that the efficacy of OLRE depends on the process that generated the overdispersion; OLRE failed to cope with overdispersion generated from a Beta-Binomial mixture model, leading to biased slope and intercept estimates, but performed well for overdispersion generated by adding random noise to the linear predictor. Comparison of parameter estimates from an OLRE model with those from its corresponding Beta-Binomial model readily identified when OLRE were performing poorly due to disagreement between effect sizes, and this strategy should be employed whenever OLRE are used for Binomial data to assess their reliability. Beta-Binomial models performed well across all contexts, but showed a tendency to underestimate effect sizes when modelling non Beta-Binomial data. Finally, both OLRE and Beta-Binomial models performed poorly when models contained <5 levels of the random intercept term, especially for estimating variance components, and this effect appeared independent of total sample size. These results suggest that OLRE are a useful tool for modelling overdispersion in Binomial data, but that they do not perform well in all circumstances and researchers should take care to verify the robustness of parameter estimates of OLRE models. PMID- 26244119 TI - Recent Molecular Advances in Our Understanding of Glioma. AB - Our molecular understanding of glioma has undergone a sea change over the last decade. In this review, we discuss two recent articles that employed whole genome sequencing to subclassify gliomas vis-a-vis known molecular alterations. We further discuss the relevance of these findings vis-a-vis current treatment paradigms. PMID- 26244120 TI - Sinonasal NUT-Midline Carcinoma - A Multimodality Approach to Diagnosis, Staging and Post-Surgical Restaging. AB - Nuclear protein testis (NUT) midline carcinoma is a rare malignancy involving predominantly the midline structures of the body. It is characterized by its genotypic feature of BRD4-NUT translocation, which is in contrast with other malignant processes that are usually categorized based on their histologic/phenotypic features. As these tumors may vary in their histologic presentation, they can be misdiagnosed as poorly differentiated carcinomas. Moreover, they are often very aggressive and associated with high mortality. Therefore, it is extremely important to diagnose them early using computed tomography (CT) and magnetic resonance imaging (MRI) and perform staging and restaging using 18-fluorodeoxyglucose positron emission tomography/computed tomography (18-FDG PET/CT), in addition to accurately identifying them at a microscopic and molecular level. We report a unique case of a sinonasal NUT midline carcinoma that was diagnosed with CT, staged with PET/CT, and restaged using PET/CT and MRI. PMID- 26244121 TI - Congenital Acute Myeloid Leukemia with Unique Translocation t(11;19)(q23;p13.3). AB - Congenital leukemia is rarely encountered in clinical practice, even in tertiary children's hospitals. Leukemia may cause significant coagulopathy, putting the patient at risk of intracranial hemorrhage. In this case, the authors present a female infant with a unique mixed phenotypic congenital acute myeloid leukemia showing mixed-lineage leukemia (MLL) rearrangement and severe coagulopathy resulting in a large subdural hematoma. Despite the fatal outcome in this case, neurosurgical treatment of patients with acute myeloid leukemia should be considered if coagulopathy and the clinical scenario allow. PMID- 26244122 TI - The COL5A1 genotype is associated with range of motion. AB - PURPOSE: The aim of our study was to investigate the association between COL5A1 genotype and Range of Motion as measured by the passive straight leg raise (SLR) and whole body join laxity (WBJL) in Asian population. METHODS: One hundred and seventy seven participants including Korean and Japanese college students (male = 109, female = 68) participated in the study. Each subject performed the passive straight leg raise and whole body join laxity test. Genotyping for the COL5A1 (rs 12722) polymorphism was performed using the TaqMan approach. The COL5A1 genotype exhibited a Hardy-Weinberg equilibrium distribution in our population. RESULTS: The physical parameters including height, weight, and BMI were higher in < 90 degrees group than > 90 degrees group. The SLR exhibited significant difference among the COL5A1 group. However, the WBJL did not differ significantly among the COL5A1 genotype, but significant difference was seen in CC genotype when compared to CT (2.99 +/- 1.72) or TT (2.70 +/- 1.52) genotype. CONCLUSION: We concluded that COL5A1 gene polymorphism is associated with increased SLR ROM in Asian population. PMID- 26244123 TI - Effects of unaccustomed downhill running on muscle damage, oxidative stress, and leukocyte apoptosis. AB - PURPOSE: The purpose of this study was to investigate the effect of unaccustomed downhill running on muscle damage, oxidative stress, and leukocyte apoptosis. METHODS: Thirteen moderately trained male subjects performed three 40 min treadmill runs at ~70% VO2max on separate days: a level run (L) followed by two downhill runs (DH1 and DH2). Blood samples were taken at rest (PRE) and immediately (POST), 2 h, 24 h, and 48 h after each run. Data were analyzed using 2-way repeated measures ANOVA with post hoc Tukey tests. RESULTS: Creatine kinase (CK) activity and oxidative stress level were significantly elevated at 24 h and 48 h following DH1 (P < 0.05). The level of oxidative stress at the POST measurement following DH1 and DH2 was greater than PRE. The rate of leukocyte apoptosis was significantly increased at the POST measurement following all three runs, and remained elevated for up to 48 h following DH1 (P < 0.01). CONCLUSION: CK activity and oxidative stress were elevated following an acute bout of moderate intensity downhill running, resulting in a greater apoptotic response at 24 h and 48 h post-exercise in comparison with level grade running or a second downhill run. These elevations were blunted following DH2. Although the link between exercise-induced muscle damage and leukocyte apoptosis is currently unknown, the differential response to DH1 vs. L and DH2 indicates that it may be mediated by the elevation of oxidative stress. PMID- 26244124 TI - The effects of either resveratrol or exercise on macrophage infiltration and switching from M1 to M2 in high fat diet mice. AB - PURPOSE: The aim of this study was to compare the effectiveness of either resveratrol supplementation or exercise training on macrophage infiltration and switching from M1 to M2 kupffer cells in high fat diet mice. METHODS: C57BL/6 mice were separated into 5 groups: normal diet (ND; n = 6), high-fat diet (HD; n = 6), high-fat diet with resveratrol (HR; n = 6), high-fat diet with exercise (HE; n = 6) or high-fat diet with resveratrol and exercise (HRE; n = 6). Resveratrol supplementation mice were orally gavaged with resveratrol (25mg/kg of body weight) dissolved in 50% propylene glycol. Exercise mice ran on a treadmill at 12-20 m/min for 30-60 min/day, 5 times/week for 12 weeks. RESULTS: After 12 weeks of intervention, the liver was analyzed. F4/80 expression was evaluated by western blot while CD11c and CD163 mRNA expressions were evaluated by RT-PCR. The weights of the body and liver were significantly increased in the HD and HR group compared to the ND group (p < 0.01). However, the weights were most effectively reduced in the HE and HRE groups compared to the HD group (p < 0.05). The macrophage marker, F4/80 expression was significantly lower in the HE and HRE groups compared to the HD group (p < 0.05). mRNA expression of the M1 macrophage marker, CD11c, in the HD group was significantly increased compared to the ND group (p < 0.01). mRNA expression of the M2 macrophage specific marker, CD163, in the HE and HRE groups were significantly increased compared to the HD group (p < 0.05). The mRNA expressions of TLR4, ICAM-1 and VCAM-1, which induce pro inflammatory cytokine production, were strongly decreased in the HR, HE, and HRE groups compared to the HD group. CONCLUSION: These results suggest that moderate exercise training inhibits macrophage infiltration and up regulation of CD163 expression. However, resveratrol supplementation is not enough to ameliorate obesity-induced macrophage infiltration and switching. PMID- 26244125 TI - The effect of regular Taekwondo exercise on Brain-derived neurotrophic factor and Stroop test in undergraduate student. AB - PURPOSE: The purpose of this study was to investigate the effect of Taekwondo exercise on Brain-derived neurotrophic factor and the Stroop test in undergraduate students. METHODS: Fourteen male subjects participated in this study. They were separated into a Control group (N = 7) and an Exercise group (N = 7). Subjects participated in Taekwondo exercise training for 8 weeks. They underwent to Taekwondo exercise training for 85 minutes per day, 5 times a week at RPE of 11~15. The taekwondo exercise training comprised an aerobic exercise (20min) mode and a dynamic exercise (65min) mode. All data were analyzed by repeated measures two-way ANOVA. RESULTS: There were no significant differences in the physical characteristics of the subjects. Although weight and BMI showed a tendency to decreased in the exercise group (EG). Also, neurotrophic factors (BDNF, NGF, IGF-1) were not significantly different after 8 weeks in the two groups. However, BDNF and IGF-1 showed a tendency to increase in the exercise group (EG). Finally, the Stroop test (word, color) results were significantly different(p < .05) in the exercise group (EG). CONCLUSION: These finding suggest that 8 weeks of regular Taekwondo exercise training may increase cognitive functions (Stroop test). However the training did not statistically affect neurotrophic factors (BDNF, NGF, IGF-1) in undergraduate students. PMID- 26244126 TI - Effects of summer school participation and psychosocial outcomes on changes in body composition and physical fitness during summer break. AB - PURPOSE: Evidence suggests that adolescents gain more weight during the summer break than they do during the school year, and that participation in the summer school program is beneficial in maintaining their healthy lifestyle. It is known that obesity and physical fitness in adolescents can be affected by their socio economic and psychological status, especially during a long school break. The purpose of this study was to examine the effects of summer school participation and psychosocial outcomes on changes in body composition and physical fitness in underprivileged adolescents during the summer break. METHODS: Body composition and physical fitness in 138 underprivileged adolescents were measured at the beginning and end of the summer break. A survey on socio-economic and psychological status was conducted at the beginning of the summer break. Two-way repeated measures ANOVA and Tukey post hoc tests were used for data analysis. Pearson correlation analysis was performed to establish a relation between psychological outcomes and changes in body composition and physical fitness during the summer break. RESULTS: Significant increases in body weight (p = .003) and % body fat (p = .014) as well as a decrease in VO2max (p = .018) were found in summer school non-attendants during the summer whereas no significant changes were found in summer school attendants. Summer school non-attendants with lower psychosocial outcomes had a greater decline in physical fitness and weight gain; however, summer school attendants were not affected by psychosocial outcomes. The summer school program effectively prevented summer weight gain among underprivileged adolescents due to the structured environment, restricted food access, and scheduled time for exercise in addition to minimizing the effects of their psychosocial outcomes. CONCLUSION: Results indicated that summer school non attendants may require comprehensive intervention for psychosocial outcomes and nutritional education to maintain body weight and physical fitness levels during the summer break. PMID- 26244127 TI - The effect of exercise on expression of myokine and angiogenesis mRNA in skeletal muscle of high fat diet induced obese rat. AB - PURPOSE: The purpose of this study was to investigate the effect of regular treadmill exercise on the mRNA expressions of myokines and angiogenesis factors in the skeletal muscle of obese rats. METHODS: Thirty two male Sprague-Dawley rats (4weeks old) were divided into the CO (control) and HF (high fat diet) groups. Obesity was induced in the HF group by consumption of 45% high-fat diet for 15 weeks. These groups were further subdivided into training groups (COT and HFT); the training groups conducted moderate intensity treadmill training for 8 weeks. Soleus muscles were excised and analyzed by real-time quantitative PCR. RESULTS: mRNA expression of myokines, such as PGC-1alpha, IL-6, and IL-15, in the COT and HFT groups (which conducted regular exercise), were higher as compared with the CO and HF groups (p < 0.05). Also, the levels in the HF group were significantly lower when compared with CO group (p < 0.05). Expression of angiogenesis mRNA, namely mTOR, VEGF, and FLT1, were significantly lower in the HF group, as compared to the CO group (p < 0.05). In addition, COT group had a higher expression of mTORC1, mTORC2, VEGF and FLT mRNA, than the CO group (p < 0.05); the HFT group also had higher expressions of mTOR, VEGF and FLT1 mRNA than the HF group (p < 0.05). CONCLUSION: These results indicate that mRNA expression of myokines was increased through the activity of muscle contraction, and it also promoted the mRNA expression of angiogenesis due to activation of mTOR. Thus, we conclude that not only under normal health conditions, but in obesity and excess nutritional circumstances also, regular exercise seems to act positively on the glycemic control and insulin sensitivity through the angiogenesis signaling pathway. PMID- 26244128 TI - The effect of physical activity on serum IL-6 and vaspin levels in late elementary school children. AB - PURPOSE: This study investigates the effects of physical activity on serum IL-6 and vaspin in late elementary school children. METHODS: Those who (n = 220) completed the 7-day physical activity monitoring underwent a second round of measurements including body fat, serum glucose and insulin, and serum IL-6 and vaspin. One way ANOVAs followed by LSD post hoc tests were used to test for significant differences in dependent variables across incremental physical activity levels at p=0.05. Multivariate stepwise linear regression analyses were used to determine significant predictors for serum IL-6 and vaspin levels at p=0.05. RESULTS: The results showed significant inverse linear trends for body fat parameters across incremental physical activity levels (from low to high); the lower the body fat, the higher the physical activity levels. On the other hand, there were no significant linear trends for insulin resistance markers or dietary intake across incremental physical activity levels. Multiple stepwise linear regression analyses were used to determine significant predictors for individual variations in serum IL-6 and vaspin in the study population. We found that body mass index (p=0.002) and low- and moderate-intensity physical activities (p=0.002 and p=0.0045, respectively) were significant determinants of serum IL-6. In addition, low- and moderate-intensity physical activities (p=0.01 & p=0.022, respectively) were significant determinants of serum vaspin levels in this study population. CONCLUSION: In summary, the findings of the current study suggest that promotion of physical activity along with a healthy diet should be key components of lifestyle interventions to improve serum cytokine profiles associated with insulin resistance syndrome in late elementary school children. PMID- 26244129 TI - Change of gene expression on protein uptake composition and hindlimb-suspension in rat skeletal muscle. AB - PURPOSE: This study was to investigate changes in BCAT and BCKDH genes by Hindlimb-Suspension (HS) and protein intake composition (casein, Whey protein) in rats. METHODS: Following 5-day preliminary feeding, forty-eight male 5 weeks old Sprague Dawley albino rats (110g) divided into 17% protein intake group (24 rats) and 30% protein intake group (24 rats), and each group divided further into Hindlimb-Suspension group (HS; 12 rats) and control group(CON; 12 rats). Eventually, this study was performed with Whey protein intake group (HS; 6 rats, CON; 6 rats) and casein intake group (HS; 6 rats, CON; 6 rats). For analysis purposes, total RNA was extracted from isolated skeletal muscles, and mRNA expression was analyzed using Real Time PCR. Two-way ANOVA was performed to examine the difference in BCATm and BCKDH mRNA expression on protein uptake and myoatrophy. post-hoc test was perform on interaction if any, and significance level was set at p<0.05. RESULTS: In this study, BCATm and BCKDH gene analysis in rat skeletal muscles by hindlimb-suspension and protein intake composition resulted in significant higher BCATm expression in 30% dietary protein group and hindlimb-suspension group that control group. In addition, regarding BCKDH, BCKDH was significantly higher in hindlimb-suspended 30% protein intake group than control group. CONCLUSION: Overall, protein intake and myoatrophy demonstrated close relationship in skeletal muscles. Therefore, it is likely to affect effectively in prevention or recovery of exercise induced muscle disorder. This effect is considered to be applied to maintain and improve health of not only athletes but also the general public. Additionally it would be applied in convalescent rehabilitation due to skeletal muscle atrophy. PMID- 26244130 TI - Effects of hippotherapy on brain function, BDNF level, and physical fitness in children with ADHD. AB - PURPOSE: The purpose of this study was to examine the effects of hippotherapy on brain function and levels of blood-derived neurotrophic factor (BDNF) in children with attention deficit and/or hyperactivity disorder (ADHD). METHODS: The hippotherapy group (HRG) included twenty children with ADHD and the control group (CG) included 19 children. All participants' physical fitness, fMRI brain scans, and blood BDNF levels were measured at baseline and after 32 weeks of participating in hippotherapy. RESULTS: After 32 weeks of participating in hippotherapy, the body fat of the HRG was significantly decreased (-1.12 +/- 4.20%) and the body fat of the CG was increased (2.38 +/- 6.35%) (p=0.049). There was no significant difference of physical fitness in both groups (p>0.05). Although there was a higher decrease in the activated insular area in the HRG ( 1.59 +/- 0.99) than in the CG (-1.14 +/- 1.41), there was no significant difference between the two groups (p>0.05) Also, there was a higher increase in the activated cerebellum area in the HRG (1.97 +/- 1.45) than in the CG (1.92 +/- 1.81). However, there was no significant difference between the two groups (p>0.05). BDNF levels showed an increased tendency in the HRG (166.29 +/- 277.52pg) compared to the CG (21.13 +/- 686.33pg); otherwise, there was not any significant difference in these blood levels between the two groups (p>0.05). It can be assumed that big individual differences in the level of ADHD in the study participants might not cause any significant results, although there might be positive changes in the brain function of children with ADHD. CONCLUSION: Therefore, this study suggests that hippotherapy training would need to be modified and developed to increase the efficacy of hippotherapy in children with ADHD. PMID- 26244131 TI - The relationship of creatine kinase variability with body composition and muscle damage markers following eccentric muscle contractions. AB - PURPOSE: The purpose of the study was to investigate the relationship between CK variability and body composition and muscle damage markers following eccentric exercise. METHODS: Total 119 healthy male subjects were recruited to perform 50 eccentric contractions consisted of 2 sets of 25 contractions. Then, blood creatine kinase (CK) activity was analyzed to divide into three groups based on their CK activity levels. Maximum isometric strength (MIS), muscle soreness (SOR) and body composition data were obtained before and after exercise. RESULTS: The results showed that high CK responders had a significant decrease in MIS (p<0.001) and greater SOR (p<0.01) following eccentric exercise compared to low CK responders. Percent body fat was also higher in high responders compared to low responders (p=0.014). Peak CK activity was significantly correlated with MIS and SOR but no correlation with % body fat, muscle mass, and body mass index. CONCLUSION: CK variability following eccentric exercise is closely related to MIS and SOR and % body fat may be a potent factor for CK variability. PMID- 26244132 TI - Moderate exercise training is more effective than resveratrol supplementation for ameliorating lipid metabolic complication in skeletal muscle of high fat diet induced obese mice. AB - PURPOSE: The aim of this study was to compare the effectiveness of moderate exercise training or resveratrol supplementation with a low fat diet on lipid metabolism in the skeletal muscle of high fat diet-induced obese mice. METHODS: C57BL/6J mice (5 weeks old, n = 30) were fed a high fat diet (45% fat) for 8 weeks first to make them obese. Afterward, all the mice were fed a low fat diet during 8 weeks of intervention with moderate exercise training and resveratrol supplementation. Before the intervention, the mice were separated into 3 groups: low-fat diet control (HLC; n = 10), low fat diet with resveratrol (HLR; n = 10) or low fat diet with exercise (HLE n = 10). The exercise group (HLE) performed treadmill running for 30-60 min/day at 10-22 m/min, 0% grade, 5 times/week for 8 weeks, while the resveratrol group (HLR) received a daily dose of resveratrol (10 mg/kg of body weight), 5 days/week for 8 weeks. RESULTS: Body weight was significantly reduced in HLE. Further, the lipogenesis marker SREBP and the inflammatory cytokine TNF-alpha were significant reduced in HLE. However, there was no significant effect from resveratrol supplementation with a low fat diet. Taken together, exercise training with a low fat diet has the positive effect of ameliorating lipid disturbance in the skeletal muscle of high fat diet-induced obese mice. CONCLUSION: These findings suggest that exercise training with a low fat diet is most effective to improve lipid metabolism by reducing lipogenesis and inflammation in the skeletal muscle of high fat diet-induced obese mice. PMID- 26244133 TI - Effect of leucine uptake on hepatic and skeletal muscle gene expression in rats: a microarray analysis. AB - PURPOSE: This study was performed to explore the physiological functions of leucine by exploring genes with leucine-dependent variability using DNA microarray. METHODS: Sprague-Dawley rats (n = 20) were separated into a HPD (30% High Protein Diet, n = 10) group and a NPD (0% Non Protein Diet, n = 10) group and fed a protein diet for 2 weeks. At the end of the 2-week period, the rats were fasted for 12-16 hours, further separated into subgroups within the HPD (Saline, n = 5, Leucine, n = 5) and NPD (Saline, n = 5, Leucine, n = 5) groups and administered with a leucine solution. The liver and muscles were harvested after 2 hours for RNA extraction. RNA purification from the isolated muscles and target gene identification using DNA chip were performed. The target gene was determined based on the results of the DNA chip experiment, and mRNA expression of the target gene was analyzed using Real-Time PCR. RESULTS: In the skeletal muscle, 27 genes were upregulated while 52 genes were down regulated after leucine administration in the NPD group. In the liver, 160 genes were up regulated while 126 were down-regulated. The per2 gene was one of the genes with leucine-dependent induction in muscles and liver. CONCLUSION: This study was performed to explore the physiological functions of leucine, however, a large number of genes showed variability. Therefore, it was difficult to definitively identify the genes linked with a particular physiological function. Various nutritional effects of leucine were observed. High variability in cytokines, receptors, and various membrane proteins were observed, which suggests that leucine functions as more than a nutrient. The interpretation may depend on investigators' perspectives, therefore, discussion with relevant experts and the BCAA (Branched-Chain Amino Acids) society may be needed for effective utilization of this data. PMID- 26244134 TI - Effect of the different assays of HbA1c on diabetic patients monitoring. AB - BACKGROUND: HbA1c test is widely used for glycemic monitoring of diabetic patients. This study aimed to evaluate clinical performance of different assays for classification of patients into controlled and uncontrolled group base on ADA recommendations. METHOD: A total of 154 samples from patients with diabetes type 2 with HbA1c concentration covering the whole clinical range were analyzed by four commercially methods; D-10 Hb A1c (Bio-Rad Laboratories), Cobas Integra 400 (Roche Diagnostics), NycoCard Reader II (Axis-Shield) and DS5 (Drew Scientific). For each individual assay, patient's results were classified into controlled and uncontrolled groups (less or more than three decision levels; 6.5 %, 7 % and 8 %) compared to D10 results as reference method. The frequency of each group and also sensitivity, specificity, negative and positive predictive value were estimated. RESULTS: We found a significant correlation between assays (r: 0.937-0.945). Sensitivity, specificity, and positive and negative predictive values of the evaluated method to identify uncontrolled patients were as follows: 49.2-95.7 %, 86.5-100 %, 89.1-100 %, and 52.9-93.3 %; respectively. CONCLUSIONS: Results show that some HbA1c assays capability to classify diabetic patients according to HbA1c level is still unacceptable. PMID- 26244135 TI - A pooled analysis of stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small cell lung cancer: is failure to recruit patients into randomized trials also an answer to the research question? PMID- 26244136 TI - Improved survival with stereotactic ablative radiotherapy (SABR) over lobectomy for early stage non-small cell lung cancer (NSCLC): addressing the fallout of disruptive randomized data. AB - The gold-standard therapy for early stage non-small cell lung cancer (esNSCLC) has historically been lobectomy with mediastinal lymph node dissection. However, up to one-third of patients with esNSCLC are considered medically-inoperable due to factors such as advanced age and comorbid illnesses. The past decade has witnessed a dramatic increase in the use of high-dose conformal radiotherapy delivered over 1-5 fractions, synonymously termed stereotactic ablative radiotherapy (SABR) or stereotactic body radiation therapy (SBRT). High rates of tumor control and favorable toxicity profiles have led to the adoption of SABR as the treatment of choice for medically-inoperable patients. Limited but growing data exist using SABR for medically-operable patients who are also candidates for lobectomy. A recent pooled analysis of two multicenter prospective randomized trials, the STARS (NCT00840749) and ROSEL (NCT00687986) protocols, published by Chang and colleagues (PMID 25981812) reported improved overall survival (OS) and reduced toxicity with SABR over lobectomy for medically-operable patients with esNSCLC. In this article we review the outcomes of this analysis in the context of existing radiotherapy and surgical data for NSCLC. Further, we discuss the potential causes and implications of these provocative results, including the shifting balance between oncologic control and treatment-related mortality in comparisons of SABR and surgical resection, termed the Head Start Effect. PMID- 26244137 TI - Stereotactic ablative radiotherapy (SABR) in operable early stage non-small cell lung cancer (NSCLC) patients: challenge to claim being undisputed gold standard. PMID- 26244138 TI - Anastomosing hemangioma of the kidney: a literature review of a rare morphological variant of hemangioma. AB - BACKGROUND: Anastomosing hemangioma (AH) of the kidney is a recently described morphological variant of hemangioma. It poses a diagnostic dilemma for clinicians because of its rarity and the overlapping features it shares with other renal vascular tumors. The aim of this paper is to review all the cases of AH of the kidney in the literature. METHODS: The literature was extensively searched for case reports of AH of the kidney and the clinical and pathological characteristics of the tumor were extracted. RESULTS: A total of 45 cases were reviewed. The mean age of presentation was 50 years (range, 15-83 years) and male sex accounted for 68.8% of the cases reviewed. AH of the kidney was mostly unilateral with only 4 cases of bilateral involvement of the kidney. The average size of the tumor is 1.5 cm (range, 0.1-7 cm). Incidental finding of AH of the kidney accounted for 62% of the cases reviewed. The ultrasound findings demonstrated varying echogenicity and the tumor appeared as solid and well demarcated heterogeneous masses on CT. The average follow up of the patients in this review was 26 months (range, 1-156 months). CONCLUSIONS: AH of the kidney is a rare vascular tumor and a morphological variant of hemangioma. It has a characteristic sinusoidal architecture with a semblance of splenic sinusoids. It has overlapping clinical and imaging features with other vascular tumors of the kidney. Histological review and immunohistochemical studies are essential for accurate diagnosis. AH runs a benign course without evidence of disease recurrence during follow up. PMID- 26244139 TI - Venous thromboembolism and coffee: critical review and meta-analysis. AB - BACKGROUND: Among the various risk factors of venous thromboembolism (VTE), nutrients seem to play a significant role in the pathogenesis of this condition. This study aimed to clarify the relationship between coffee intake and venous thrombosis, and we performed a critical review of clinical studies that have been published so far. METHODS: An electronic search was carried out in Medline, Scopus and ISI Web of Science with the keywords "coffee" AND "venous thromboembolism" OR "deep vein thrombosis" OR "pulmonary embolism" in "Title/Abstract/Keywords", with no language and date restriction. RESULTS: According to our criteria, three studies (two prospective and one case-control) were finally selected (inter-study heterogeneity: 78%; P<0.001). Cumulative data suggests that a modest intake of coffee (i.e., 1-4 cups/day) may be associated with an 11% increased risk of VTE compared to abstainers, whereas a larger intake (i.e., >=5 coffee/day) may be associated with a 25% decreased risk. CONCLUSIONS: Our analysis of published data seemingly confirm the existence of a U-shape relationship between coffee intake and VTE, thus exhibiting a trend that overlaps with that previously reported for cardiovascular disease (CVD). PMID- 26244140 TI - Immunological aspects of endometriosis: a review. AB - Endometriosis is a common and serious illness affecting women in their reproductive years. Despite the ongoing interest and intensive research of this crippling disease, the cause remains unknown since its first description over 150 years ago. The origins and genesis of endometriosis, despite numerous hypotheses, are still unclear. One of the possible causes of the development of endometriosis might be the immune system, despite the fact that endometriosis is generally considered to be a steroid-sensitive disease. Numerous aspects of the immune system has been found changed, from the different number of activated macrophages to different subtypes of lymphocytes and their activities, suggesting involvement of immunity. On the other hand, it is possible that immunological changes around the endometriotic lesion are only secondary to the establishment of endometriosis. In this review, we will summarize the current knowledge of immunological reactions in endometriosis. PMID- 26244142 TI - Robotic thoracic surgery of the right lower anterior mediastinal mass. PMID- 26244141 TI - Management of diabetic renal disease. AB - Diabetic nephropathy is the leading cause of end stage renal failure (ESRF) worldwide, representing over 50% of patients on renal replacement therapy in some parts of the world. The condition is common in people with type 1 and type 2 diabetes, although the incidence appears to be declining, especially in type 1 diabetes. More than 1 in 3 people with type 2 diabetes have impaired kidney function. Advances in our understanding of the pathogenesis and natural history of the condition have enabled us to consider earlier therapy aimed at renal preservation and reduction in cardiovascular morbidity. Microalbuminuria is now established as the earliest risk marker for nephropathy in type 1 diabetes and cardiovascular disease in type 2 diabetes. This review examines the current concepts in the pathogenesis and management of diabetic nephropathy. PMID- 26244143 TI - Robotic thoracic surgery of total thymectomy. PMID- 26244145 TI - Violence against health-providers is disappointingly spiraling now in China. PMID- 26244144 TI - Double primary non-small cell lung cancer with synchronous small cell lung cancer N2 nodes: a case report. AB - Synchronous multiple primary lung cancer (SMPLC) is rare and very hard to distinguish from metastatic disease. Recent studies indicate the presence of this entity in the lung, with no mention to the involvement of the mediastinum. An extremely rare case of a 68-year-old male with double primary non-small cell lung cancer (NSCLC) in the left upper lobe and N2 positive nodes for small cell lung cancer (SCLC) is presented. Modern diagnostic criteria as well as aggressive curative strategies are encouraged, in order to achieve better survival rates for such patients. PMID- 26244146 TI - Targeted drug combinations: avant-garde oncology. PMID- 26244147 TI - Where is hidden the ghost in phantom sensations? AB - The term phantom sensations (PS) refers to sensations in a missing body part. They are almost universal in amputees and can be both painful and not painful. Although PS have been frequently described in limb amputees, they can also occur in other clinical conditions and several pathophysiological interpretations have been proposed, with a predominance of theories based on a central origin. Actually, different mechanisms are able to create a phantom sensation. After an amputation, PS are frequently generated by the genesis of ectopic action potentials in the interrupted nerve fibers but the PS generator can also be more proximal. Sometimes PS are not created by the stimulation of somatosensory fibers with a missing territory, but they can be the result of central sensitization or neuroplastic changes that allow for the convergence of impulses coming from different body parts (referred sensations), one of which is missing. In conclusion, PS can be generated by both neuropathic and non-neuropathic mechanisms developed in the amputated body part or in other parts of the nervous system. Since these mechanisms are not pathognomonic of amputation there are no hidden ghosts to look for in phantom sensations. The only interpretative rule is just to follow the pathophysiological principles. PMID- 26244148 TI - Treatment strategies for multiple sclerosis: When to start, when to change, when to stop? AB - Multiple sclerosis (MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acute demyelination shows as clinical relapses that may fully or partially resolve, while chronic demyelination and neuroaxonal injury lead to persistent and irreversible neurological symptoms, often progressing over time. Currently approved disease-modifying therapies are immunomodulatory or immunosuppressive drugs that significantly although variably reduce the frequency of attacks of the relapsing forms of the disease. However, they have limited efficacy in preventing the transition to the progressive phase of MS and are of no benefit after it has started. It is therefore likely that the potential advantage of a given treatment is condensed in a relatively limited window of opportunity for each patient, depending on individual characteristics and disease stage, most frequently but not necessarily in the early phase of the disease. In addition, a sizable proportion of patients with MS may have a very mild clinical course not requiring a disease-modifying therapy. Finally, individual response to existing therapies for MS varies significantly across subjects and the risk of serious adverse events remains an issue, particularly for the newest agents. The present review is aimed at critically describing current treatment strategies for MS with a particular focus on the decision of starting, switching and stopping commercially available immunomodulatory and immunosuppressive therapies. PMID- 26244149 TI - From variome to phenome: Pathogenesis, diagnosis and management of ectopic mineralization disorders. AB - Ectopic mineralization - inappropriate biomineralization in soft tissues - is a frequent finding in physiological aging processes and several common disorders, which can be associated with significant morbidity and mortality. Further, pathologic mineralization is seen in several rare genetic disorders, which often present life-threatening phenotypes. These disorders are classified based on the mechanisms through which the mineralization occurs: metastatic or dystrophic calcification or ectopic ossification. Underlying mechanisms have been extensively studied, which resulted in several hypotheses regarding the etiology of mineralization in the extracellular matrix of soft tissue. These hypotheses include intracellular and extracellular mechanisms, such as the formation of matrix vesicles, aberrant osteogenic and chondrogenic signaling, apoptosis and oxidative stress. Though coherence between the different findings is not always clear, current insights have led to improvement of the diagnosis and management of ectopic mineralization patients, thus translating pathogenetic knowledge (variome) to the phenotype (phenome). In this review, we will focus on the clinical presentation, pathogenesis and management of primary genetic soft tissue mineralization disorders. As examples of dystrophic calcification disorders Pseudoxanthoma elasticum, Generalized arterial calcification of infancy, Keutel syndrome, Idiopathic basal ganglia calcification and Arterial calcification due to CD73 (NT5E) deficiency will be discussed. Hyperphosphatemic familial tumoral calcinosis will be reviewed as an example of mineralization disorders caused by metastatic calcification. PMID- 26244151 TI - Epidemiology, management, and economic evaluation of screening of gallstone disease among type 2 diabetics: A systematic review. AB - The knowledge of gallstone disease (GSD) is crucial to manage this condition when organizing screening and preventive strategies and identifying the appropriated clinical therapies. Although cholecystectomy still be the gold standard treatment for patients with symptomatic GSD, expectant management could be viewed as a valid therapeutic method for this disorder. If early treatment of GSD decreases the morbidity or avoids further cholecystectomy, it may save clinical care costs in later disease periods sufficiently to offset the screening and early treatment costs. In addition, whether routine screening for GSD is worthwhile depends on whether patients are willing to pay the ultrasonography screening cost that would reduce the risk of cholecystectomy. In this review we discuss the epidemiology, management, and economic evaluation of screening of GSD among type 2 diabetics. PMID- 26244150 TI - Role of quorum sensing in bacterial infections. AB - Quorum sensing (QS) is cell communication that is widely used by bacterial pathogens to coordinate the expression of several collective traits, including the production of multiple virulence factors, biofilm formation, and swarming motility once a population threshold is reached. Several lines of evidence indicate that QS enhances virulence of bacterial pathogens in animal models as well as in human infections; however, its relative importance for bacterial pathogenesis is still incomplete. In this review, we discuss the present evidence from in vitro and in vivo experiments in animal models, as well as from clinical studies, that link QS systems with human infections. We focus on two major QS bacterial models, the opportunistic Gram negative bacteria Pseudomonas aeruginosa and the Gram positive Staphylococcus aureus, which are also two of the main agents responsible of nosocomial and wound infections. In addition, QS communication systems in other bacterial, eukaryotic pathogens, and even immune and cancer cells are also reviewed, and finally, the new approaches proposed to combat bacterial infections by the attenuation of their QS communication systems and virulence are also discussed. PMID- 26244152 TI - How to use magnetic resonance imaging following neoadjuvant chemotherapy in locally advanced breast cancer. AB - Magnetic resonance imaging (MRI) is highly sensitive in identifying residual breast cancer following neoadjuvant chemotherapy (NAC), and consequently is a commonly used imaging modality in locally advanced breast cancer patients. In these patients, tumor response is an important prognostic indicator. However, discrepancies between MRI findings and surgical pathology are well documented. Overestimation of residual disease by MRI may result in greater surgery than is actually required while underestimation may result in insufficient surgery. Thus, it is important to understand when MRI findings are reliable and when they are less accurate. MRI most accurately predicts pathology in triple negative, Her2 positive and hormone receptor negative tumors, especially if they are of a solid imaging phenotype. In these cases, post-NAC MRI is highly reliable for surgical planning. Hormone receptor positive cancers and those demonstrating non mass enhancement show lower concordance with surgical pathology, making surgical guidance more nebulous in these cases. Radiologists and surgeons must assess MRI response to NAC in the context of tumor subtype. Indiscriminate interpretations will prevent MRI from achieving its maximum potential in the pre-operative setting. PMID- 26244153 TI - Cervical cancer screening: A never-ending developing program. AB - With the term "oncological screening", we define the overall performances made to detect early onset of tumors. These tests are conducted on a population that does not have any signs or symptoms related to a neoplasm. The whole population above a certain age, only one sex, only subjects with a high risk of developing cancer due to genetic, professional, discretionary reasons may be involved. Screening campaigns should be associated, when risk factors that can be avoided are known, with campaigns for the prevention of cancer by means of suitable behavior. The goal of cancer screening cannot however be limited to the diagnosis of a greater number of neoplasms. Screening will be useful only if it leads to a reduction in overall mortality or at least in mortality related to the tumor. Screening should then allow the diagnosis of the disease at a stage when there is a possibility of healing, possibility that is instead difficult when the disease is diagnosed at the appearance of signs or symptoms. This is the reason why not all campaigns of cancer screening have the same effectiveness. In Italy, every year there are about 150000 deaths due to cancer. Some of these tumors can be cured with a very high percentage of success if diagnosed in time. Cervical cancer can be diagnosed with non-invasive tests. The screening test used all over the world is Papanicolaou (Pap) test. This test may be carried out over the entire healthy population potentially exposed to the risk of contracting cancer. Public health has begun the screening campaigns in the hope of saving many of the approximately 270000 new cases of cancer reported each year. Screening is done following protocols that guarantee quality at the national level: these protocols are subject to change over time to reflect new realities or to correct any errors in the system. A simplified sketch of a possible route of cancer screening is as follows: (1) after selecting the target population, for example all women between 25 and 64 years (in the case of monitoring of cervical cancer), an invitation letter with the date and time of the appointment, planned according to the acceptance capacity of the hospital, is sent to all individuals; (2) an examination, which depending on the individual and the type of cancer to be monitored, for example, can be a Pap smear, is performed and the patient can go home; (3) once available the results of examinations, if negative, they shall be communicated to the person concerned that will be notified by mail and will be recalled for a second test at a few years of distance, in the case of non negativity, instead, the patient is contacted by telephone and informed of the need to carry out further examinations: it is said that the patient is in the "phase two" of the screening pathway; (4) in phase two, reached by only a small portion of the interested parties (usually less than 3%-5%), more in-depth tests are carried out, which, depending on the individual and the type of cancer, can be: cytological and colposcopic examinations, the removal of a fragment of tissue (biopsy) and subsequent histological examination, additional tests such as ultrasound, radiography, or others such as computerized tomography, magnetic resonance imaging, positron emission tomography, etc., in case of negativity, the concerned person will be called for new control tests at a a few years of distance, in case of non-negativity, it will be proposed instead an oncologic therapeutic plan and/or surgery to treat the diagnosed tumor; and (5) once the treatment plan is completed, the individual enters the follow-up protocol, which is monitored over time to see if the tumor has been completely removed or if instead it is still developing. Cervical cancer is undoubtedly the most successful example of a cancer screening campaign. Paradoxically, its effectiveness is one of the strongest reasons to criticize the usefulness of vaccination against human papillomavirus (HPV) in countries where the screening service with Pap test is organized in an efficient manner. Cervical cancer screening protocols are directed to sexually active women aged 25-64 years: they provide the Pap test performed by examining under a microscope or by staining with a specific "thin prep" the material taken from the cervix with a small spatula and a brush. It is recommended to repeat the test every two or three years. It is important to emphasize that women vaccinated against HPV must continue the screening with Pap test. Although some screening programs (e.g., Pap smears) have had remarkable success in reducing mortality from a specific cancer, any kind of screening is free from inherent limitations. The screening methods are in fact applied to large parts of the apparently healthy population. In particular, the limits for certain cancers may be as obvious as to prohibit the introduction of an organized screening program. Potential limitations of organized screenings are basically of two types: organizational and medical. The limits of organizational type relate to the ability of a program to recruit the whole target population. Although well organized, a screening program will hardly be able to exceed a coverage of 70%-80% of the target population, and in fact the results of the current programs are often much smaller. The limits of medical type are represented by the possibility of reducing the overall mortality, or specific mortality, using a specific screening campaign. PMID- 26244154 TI - Bayesian methods in reporting and managing Australian clinical indicators. AB - Sustained clinical improvement is unlikely without appropriate measuring and reporting techniques. Clinical indicators are tools to help assess whether a standard of care is being met. They are used to evaluate the potential to improve the care provided by healthcare organisations (HCOs). The analysis and reporting of these indicators for the Australian Council on Healthcare Standards have used a methodology which estimates, for each of the 338 clinical indicators, the gains in the system that would result from shifting the mean proportion to the 20(th) centile. The results are used to provide a relative measure to help prioritise quality improvement activity within clinical areas, rather than simply focus on "poorer performing" HCOs. The method draws attention to clinical areas exhibiting larger between-HCO variation and affecting larger numbers of patients. HCOs report data in six-month periods, resulting in estimated clinical indicator proportions which may be affected by small samples and sampling variation. Failing to address such issues would result in HCOs exhibiting extremely small and large estimated proportions and inflated estimates of the potential gains in the system. This paper describes the 20(th) centile method of calculating potential gains for the healthcare system by using Bayesian hierarchical models and shrinkage estimators to correct for the effects of sampling variation, and provides an example case in Emergency Medicine as well as example expert commentary from colleges based upon the reports. The application of these Bayesian methods enables all collated data to be used, irrespective of an HCO's size, and facilitates more realistic estimates of potential system gains. PMID- 26244155 TI - Scourge of intra-partum foetal death in Sub-Saharan Africa. AB - Intra-partum foetal death has been variously defined. However, a definition adopted at a technical consultation in 2006 is employed in this review. The quality of intra-partum care is a crucial factor for pregnancy outcome for both mothers and new-borns. Intra-partum stillbirth is defined as late foetal death during labour, which clinically presents as fresh stillbirth. The largest proportion of the world's stillbirths occurs in the late preterm, term and intra partum periods. The Western Pacific region has the greatest reduction in stillbirth with a 3.8% annual decline between 1995 and 2009; however, the annual decline in the African region is less than 1%. Caesarean delivery is still uncommon, especially in rural areas: 1% of births in rural Sub-Saharan Africa and 5% in rural South Asia are by caesarean delivery; 62% of stillbirths occurred during the intra-partum period; 61.4% of stillbirths are attributable to obstetrical complications. Preventive measures aimed at reducing the incidence of intra-partum foetal death entail all measures aimed at improving quality antenatal care and preventing intra-partum asphyxia. This review discusses intra partum foetal deaths from a Sub-Saharan African perspective. It explores the contribution of research within the region to identifying its impact on new-born health and potential cost-effective policy interventions. PMID- 26244156 TI - In vitro differentiation of human umbilical cord Wharton's jelly mesenchymal stromal cells to insulin producing clusters. AB - AIM: To investigate the differentiation of human Wharton's jelly derived mesenchymal stromal cells (WJ-MSCs) to insulin producing clusters (IPC) this study was conducted. METHODS: The umbilical cords samples were collected from full term caesarian section mothers and the WJ-MSCS were cultured from tissue explants in High glucose-Dulbecco's Modified Eagle Medium (H-DMEM); H-DMEM supplemented with 10% fetal bovine serum (FBS) and antibiotics. The expression of CD90, CD44, CD105, CD34 and CD133 as well as osteogenic and adipogenic differentiation of cells in appropriate medium were also evaluated. The cells were differentiated toward IPC with changing the culture medium and adding the small molecules such as nicotinic acid, epidermal growth factor, and exendin-4 during 3 wk period. The gene expression of PDX1, NGN3, Glut2, insulin was monitored by reveres transcription polymerase chain reaction method. The differentiated clusters were stained with Dithizone (DTZ) which confirms the presence of insulin granules. The insulin challenge test (low and high glucose concentration in Krebs-Ringer HEPES buffer) was also used to evaluate the functional properties of differentiated clusters. RESULTS: WJ-MSCS were positive for mesenchymal surface markers (CD90, CD44, CD105), and negative for CD34 and CD133. The accumulation of lipid vacuoles and deposition of calcium mineral in cells were considered as adipogenic and osteogenic potential of WJ-MSCS. The cells also expressed the transcriptional factors such as Nanog and OCT4. During this three step differentiation, the WJ-MSCS morphology was gradually changed from spindle shaped cells in to epithelioid cells and eventually to three dimensional clusters. The clusters expressed PDX1, NGN3, Glut2, and insulin. The cells became bright red color when stained with DTZ and the insulin secretion was also confirmed. In glucose challenge test a significant increase in insulin secretion from 0.91 +/- 0.04 MUIu/mL (2.8 mmol/L glucose) to to 8.34 +/- 0.45 MUIu/mL (16.7 mmol/L glucose) was recorded (P < 0.05). The insulin secretion of undifferentiated WJ-MSCS was not changed in this challenge test. CONCLUSION: WJ MSCs have the ability to differentiate in to islet-like cells in vitro. However, this process needs further optimization in order to generate efficient and functional IPCs. PMID- 26244157 TI - Perifollicular granulomas with IgG4 plasmacytosis: A case report and review of literature. AB - Perifollicular granuloma is a unique histologic feature and whether it is associated with immunoglobulin G4 (IgG4)-related disease is controversial. We report a case of a 38-year-old man who presented with worsening left eye pain, proptosis, tearing, gritty sensation, blurred vision and multiple lymphadenopathy. An axillary lymph node resection showed reactive follicular and interfollicular lymph node hyperplasia, and increased eosinophils and plasma cells (at least 80% of IgG(+) plasma cells were positive for IgG4). A distinct feature was the presence of multifocal, perifollicular histiocytic granulomas, which formed a wreath around the entire follicles. The human herpes virus 8 was not detected by immunohistochemistry. In addition, an extensive panel of special stains, immunohistochemistry, and flow cytometry was negative for lymphoma, fungal, or mycobacterial infection. The findings were suggestive of IgG4-related sclerosing disease-associated lymphadenopathy. Further laboratory testing showed a significant increase of serum immunoglobulin E (> 23000 IU/mL) and slight increase of total IgG, but normal serum IgG4. Even though perifollicular granuloma is a nonspecific histopathologic feature and can be seen in other diseases, such as nodular lymphocyte predominant Hodgkin lymphoma, IgG4-related lymphadenopathy should be listed in the differential diagnoses of benign reactive lymph nodes, especially when perifollicular granuloma and plasmacytosis coexist. PMID- 26244158 TI - Reversible postural orthostatic tachycardia syndrome. AB - Postural orthostatic tachycardia syndrome (POTS) is a relatively rare syndrome recognised since 1940. It is a heterogenous condition with orthostatic intolerance due to dysautonomia and is characterised by rise in heart rate above 30 bpm from base line or to more than 120 bpm within 5-10 min of standing with or without change in blood pressure which returns to base line on resuming supine position. This condition present with various disabling symptoms such as light headedness, near syncope, fatigue, nausea, vomiting, tremor, palpitations and mental clouding, etc. However there are no identifiable signs on clinical examination and patients are often diagnosed to have anxiety disorder. The condition predominantly affects young female between the ages of 15-50 but is rarely described in older people. We describe an older patient who developed POTS which recovered over 12 mo. Recognising this condition is important as there are treatment options available to alleviate the disabling symptoms. PMID- 26244159 TI - Arteriovenous malformation of the vestibulocochlear nerve. AB - We describe a rare case of an arteriovenous malformation (AVM) embedded in the vestibulocochlear nerve presenting with subarachnoid hemorrhage (SAH) treated by microsurgical elimination of the main feeding artery and partial nidus volume reduction with no permanent deficits. This 70-year-old woman was incidentally diagnosed 4 years previously with two small unruptured tandem aneurysms (ANs) on the right anterior inferior cerebral artery feeding a small right cerebellopontine angle AVM. The patient was followed conservatively until she developed sudden headache, nausea and vomiting and presented to our outpatient clinic after several days. Magnetic resonance imaging demonstrated findings suggestive of early subacute SAH in the quadrigeminal cistern. A microsurgical flow reduction technique via clipping between the two ANs and partial electrocoagulation of the nidus buried within the eighth cranial nerve provided radiographical devascularization of the ANs with residual AVM shunt flow and no major deficits during the 2.5 year follow-up. This is only the second report of an auditory nerve AVM. In the event of recurrence, reoperation or application of alternative therapies may be considered. PMID- 26244160 TI - Conservative management of type 2 gallbladder perforation in a child. AB - Gallbladder perforation (GBP) is a rare but serious complication of cholecystitis and needs to be managed promptly. Acalculus cholecystitis leading to GBP is frequently associated with enteric fever and found in critically ill patients, and a surgical approach is not always feasible in such patients. Use of percutaneous tube cholecystostomy (PTC) in such patients is a known entity but it is usually followed by interval cholecystectomy. Here we report a case of perforated gallbladder in a child managed conservatively and successfully with PTC as the definitive treatment wherein cholecystectomy was avoided. The functionality of the gallbladder was confirmed by a Tc99m-HIDA scan. PMID- 26244161 TI - Would the combination of everolimus with endocrine-therapy help in FGFR2 positive serous endometrial cancer? PMID- 26244162 TI - Carcinoma in situ to invasive breast cancer. PMID- 26244163 TI - Targeting CD44 as a novel therapeutic approach for treating pancreatic cancer recurrence. AB - Pancreatic ductal adenocarcinoma (PDAC) is an extraordinarily lethal disease, which, despite a more or less efficient chemotherapeutic treatment, systematically displays a rapid and uncontrolled progression towards a fatal recurrence. Determining which cells give rise to such tumor recurrence is thus crucial before an improved therapeutics outcome can be envisaged for patients with PDAC. In this regard, we recently reported that following a standard chemotherapy for PDAC, a heterogeneous subpopulation of CD44+ cells proliferates and is responsible for tumor recurrence, as shown by almost all recurrent tumor cells becoming CD44+. We designed a strategy to eliminate these cells based on a weekly administration of an anti-CD44 monoclonal antibody to human PDAC-derived xenografts in mice. We demonstrate that xenografts, which were unresponsive to gemcitabine treatment, are however sensitive to this strategy. In conclusion, CD44 represents an efficient therapeutic target in patients with recurrent PDAC. PMID- 26244164 TI - Challenges and perspective of drug repurposing strategies in early phase clinical trials. AB - Despite significant investments in the development of new agents only 5% of cancer drugs entering Phase I clinical trials are ultimately approved for routine clinical cancer care. Drug repurposing strategies using novel combinations of previously tested anticancer agents could reduce the cost and improve treatment outcomes. At MD Anderson Cancer Center, early phase clinical trials with drug repurposing strategies demonstrated promising outcomes in patients with both rare and common treatment refractory advanced cancers. Despite clinical efficacy advancing drug repurposing strategies in the clinical trial trajectory beyond early phase studies has been challenging mainly due to lack of funding and interest from the pharmaceutical industry. In this review, we delineate our experience and challenges with drug repurposing strategies. PMID- 26244165 TI - Durable clinical benefit to trastuzumab and chemotherapy in a patient with metastatic colon adenocarcinoma harboring ERBB2 amplification. AB - Somatic ERBB2 amplification or activating mutations occur in approximately 2-5% of metastatic colorectal adenocarcinomas and are presumed to be oncogenic drivers, but limited evidence exists to suggest these lesions are sensitive to targeted monotherapy in patients. Here we present the case of a patient with advanced CRC with pulmonary metastases, who had progressed on both standard of care cytotoxic chemotherapy and anti-EGFR targeted therapy. Comprehensive genomic profiling (FoundationOne((r))) identified amplification of ERBB2 and a TP53 mutation in the metastatic lesion. Treatment with trastuzumab with a chemotherapy backbone elicited stable disease/minor response in the patient over a one year course of therapy, reducing tumor burden and significantly improving quality of life. This report demonstrates the application of personalized targeted therapy guided by comprehensive genomic profiling in metastatic colorectal adenocarcinoma. PMID- 26244166 TI - Peloruside A is a microtubule-stabilizing agent with exceptional anti-migratory properties in human endothelial cells. AB - Peloruside A is a novel antimitotic drug originally isolated from the marine sponge Mycale hentschieli. Previous studies showed that peloruside A stabilizes microtubules by binding to a site on tubulin distinct from paclitaxel, another microtubule stabilizing drug. Peloruside A blocks mitosis, but little is known about the effects on other cellular activities. Here we report that peloruside A is the most potent microtubule inhibitor yet tested for its ability to block endothelial cell migration. Quantitative analysis indicated that it inhibits microtubule dynamics and endothelial cell migration at 1/200(th) of the concentration needed to inhibit cell division (the cytotoxic concentration), indicating that it could potentially have a large margin of safety when used to specifically target angiogenesis. By comparison, paclitaxel, a well-known cancer therapeutic drug, suppresses cell migration at 1/13(th) of its cytotoxic concentration; and vinblastine suppresses cell migration at just slightly below its cytotoxic antimitotic concentration. Thus, different microtubule targeted drugs have varying relative potencies for inhibition of cell migration versus cell division. The results suggest that peloruside A may be an especially useful agent for anti-angiogenesis therapy and point to the likelihood that other antimitotic drugs might be found with an even larger potential margin of safety. PMID- 26244167 TI - High-content analysis of tumour cell invasion in three-dimensional spheroid assays. AB - Targeting infiltrating tumour cells is an attractive way of combating cancer invasion and metastasis. Here we describe a novel and reproducible method for high content analysis of invading cells using multicellular tumour spheroid assays in a high grade glioma model. Live cell imaging of spheroids generated from glioma cell lines, U87 and U251, gave insight into migration dynamics and cell morphology in response to anti-migratory drugs. Immunofluorescence imaging confirmed cytoskeletal rearrangements in the treated cells indicating a direct effect on cell morphology. Effect on migration was determined by a Migration Index (MI) from brightfield images which confirmed anti-migratory activity of the drugs. A marked effect on the core with treatment suggestive of disordered proliferation was also observed. A newly developed technique to prepare the spheroids and migratory cells for immunohistochemistry allowed an assessment of response to drug treatment with a selection of markers. A difference in protein expression was noted between cells maintained within the core and migratory cells indicative of the presence of cell subpopulations within the spheroid core. We conclude that this high content analysis allows researchers to perform screening of anti-tumour invasion compounds and study their effects on cellular dynamics, particularly in relation to protein expression, for the first time. PMID- 26244168 TI - Expression of the cancer testis antigen IGF2BP3 in colorectal cancers; IGF2BP3 holds promise as a specific immunotherapy target. AB - INTRODUCTION: IGF2BP3 (IMP3) is a mRNA binding protein that regulates IGF2 translation and function during embryogenesis. Because IGF2BP3 is undetectable in adult human tissues except the testis, and increased IGF2BP3 expression has been noted in several cancers, it is considered a cancer testis (CT) protein. IGF2BP3 mRNA expression in colorectal cancers (CRC) has not been well studied. This study's aim was to quantitatively assess IGF2BP3 mRNA expression in CRC and, thus, determine if IGF2BP3 has potential as a vaccine target. METHOD: Data were collected prospectively from CRC patients in an IRB-approved tissue and data bank. Total RNA was isolated and purified from tumor and normal colonic tissue samples and cDNA synthesized. IGF2BP3 expression was analyzed by quantitative PCR (QPCR). Expression levels of IGF2BP3 in tumors and testis were determined and compared. Tumors with levels greater than 0.1% or more of the testis levels were considered positive. Analysis of IGF2BP3 protein expression by immunohistochemistry (IHC) in tumor and normal tissues was also performed. RESULTS: A total of 84 paired tumor and normal tissue specimens were assessed from patients with Stage 2 and 3 CRC; 43% of tumors had IGF2BP3 mRNA expression levels greater than 0.1 % of that of testis and were considered positive. The median tumor expression level was higher in women (p=0.042). No correlation was found between IGF2BP3 mRNA expression and tumor stage or lymph node involvement. IHC was carried out on paired tumor and normal tissue sections from 46 patients; IGF2BP3 staining was noted in 50% of the tumor sections and in 5% of the normal tissue sections. DISCUSSION: IGF2BP3 mRNA was over expressed in 43% of the tumors whereas the protein was noted in 50% of samples. No correlation between mRNA expression and disease severity was noted. This protein holds promise as a vaccine target, however, a larger study that assesses a more diverse population of patients (Stage 1-4) as well as a study of preoperative serum samples for auto antibodies to IGF2BP3 are needed to pursue this concept. PMID- 26244169 TI - Detection and quantification of new psychoactive substances (NPSs) within the evolved "legal high" product, NRG-2, using high performance liquid chromatography amperometric detection (HPLC-AD). AB - The global increase in the production and abuse of cathinone-derived New Psychoactive Substances (NPSs) has developed the requirement for rapid, selective and sensitive protocols for their separation and detection. Electrochemical sensing of these compounds has been demonstrated to be an effective method for the in-field detection of these substances, either in their pure form or in the presence of common adulterants, however, the technique is limited in its ability to discriminate between structurally related cathinone-derivatives (for example: (+/-)-4'-methylmethcathinone (4-MMC, 2a) and (+/-)-4'-methyl-N-ethylmethcathinone (4-MEC, 2b) when they are both present in a mixture. In this paper we demonstrate, for the first time, the combination of HPLC-UV with amperometric detection (HPLC-AD) for the qualitative and quantitative analysis of 4-MMC and 4 MEC using either a commercially available impinging jet (LC-FC-A) or custom-made iCell channel (LC-FC-B) flow-cell system incorporating embedded graphite screen printed macroelectrodes. The protocol offers a cost-effective, reproducible and reliable sensor platform for the simultaneous HPLC-UV and amperometric detection of the target analytes. The two systems have similar limits of detection, in terms of amperometric detection [LC-FC-A: 14.66 MUg mL(-1) (2a) and 9.35 MUg mL( 1) (2b); LC-FC-B: 57.92 MUg mL(-1) (2a) and 26.91 MUg mL(-1) (2b)], to the previously reported oxidative electrochemical protocol [39.8 MUg mL(-1) (2a) and 84.2 MUg mL(-1) (2b)], for two synthetic cathinones, prevalent on the recreational drugs market. Though not as sensitive as standard HPLC-UV detection, both flow cells show a good agreement, between the quantitative electroanalytical data, thereby making them suitable for the detection and quantification of 4-MMC and 4-MEC, either in their pure form or within complex mixtures. Additionally, the simultaneous HPLC-UV and amperometric detection protocol detailed herein shows a marked improvement and advantage over previously reported electroanalytical methods, which were either unable to selectively discriminate between structurally related synthetic cathinones (e.g. 4-MMC and 4-MEC) or utilised harmful and restrictive materials in their design. PMID- 26244170 TI - Flow injection chemiluminescence immunoassay based on resin beads, enzymatic amplification and a novel monoclonal antibody for determination of Hg(2+). AB - In the present work, a simple and sensitive flow injection chemiluminescent competitive immunoassay was developed for the determination of mercury(II) ion (Hg(2+)) based on carboxylic resin beads, a novel specific monoclonal antibody (McAb) and HRP enzyme-amplification. Resin beads with carboxyl groups were creatively employed as supports for immobilizing more coating antigen through acylamide bonds. With a competitive-type assay mode, the Hg(2+) in solution competed with the immobilized coating antigen for the limited McAb. Then, the second antibody labeled with HRP was introduced, and an effectively increased CL was obtained, which was ascribed to the catalytic activity of HRP for the luminol PIP-H2O2 reaction. With increasing concentration of Hg(2+), the CL of this system decreases because less HRP is present in the CL reaction. At optimal conditions, the CL signal displayed a good linear relation toward Hg(2+) in the range of 0.05 200 ng mL(-1) with a detection limit (3sigma) of 0.015 ng mL(-1). The immunosensor possessed high specificity, acceptable accuracy and reproducibility, and was examined in real samples with favorable results. This immunoassay will have intriguing application prospects for the determination of other heavy metal ions and environmental contaminants. PMID- 26244172 TI - Bond-shift isomers: the co-existence of allenic and propargylic phenylnitrile imines. AB - We discovered a 1,3-dipolar species co-existing in two different structures. Photolysis of matrix-isolated 5-phenyltetrazole generates two forms of phenylnitrile imine: propargylic and allenic. They are not resonance structures but correspond to different energy minima, representing bond-shift isomers. These distinct species were characterized spectroscopically and confirmed by calculations up to the CASSCF(14,12) theory level. PMID- 26244171 TI - Systematic adjustment of charge densities and size of polyglycerol amines reduces cytotoxic effects and enhances cellular uptake. AB - Excessive cationic charge density of polyplexes during cellular uptake is still a major hurdle in the field of non-viral gene delivery. The most efficient cationic vectors such as polyethylene imine (PEI) or polyamidoamine (PAMAM) can be highly toxic and may induce strong side effects due to their high cationic charge densities. Alternatives like polyethylene glycol (PEG) are used to 'shield' these charges and thus to reduce the cytotoxic effects known for PEI/PEG-core-shell architectures. In this study, we compared the ability of hyperbranched polyglycerol amines (hPG amines) with different amine densities and molecular weights as non-viral cationic vectors for DNA delivery. By adjusting the hydroxyl to amine group ratio on varying molecular weights, we were able to perform a systematic study on the cytotoxic effects caused by the effective charge density in correlation to size. We could demonstrate that carriers with moderate charge density have a higher potential for effective DNA delivery as compared to high/low charged ones independent of their size, but the final efficiency can be optimized by the molecular weight. We analyzed the physicochemical properties and cellular uptake capacity as well as the cytotoxicity and transfection efficiency of these new vector systems. PMID- 26244173 TI - From a metal-organic framework to hierarchical high surface-area hollow octahedral carbon cages. AB - For the first time, high surface-area hierarchical hollow octahedral carbon cages have been successfully fabricated by carbonization of a metal-organic framework, MIL-100(Al), followed by subsequent controlled acid etching, which exhibit significant CO2 and H2 adsorption capacities. PMID- 26244174 TI - Author's Reply. PMID- 26244175 TI - Author reply to comment on subconjunctival limbus oblique incision for mature cataracts. PMID- 26244176 TI - Professor Gert-Horst Schumacher's 90th anniversary. PMID- 26244177 TI - Safeguarding children's right to the best form of nurture: an interview with Dr Patricia Ip. PMID- 26244178 TI - The pill rolling machine. PMID- 26244179 TI - Asking health and social care staff to go the extra QA mile. PMID- 26244180 TI - NGNA: Position Paper on essential gerontological nursing education in registered nursing and continuing education programs. PMID- 26244181 TI - Application of resources for non-pharmacological interventions to improve dementia care in nursing homes. PMID- 26244182 TI - Advanced practice nurses choosing wisely. PMID- 26244183 TI - Chest x-ray quiz. PMID- 26244184 TI - Being Picky about Pick's disease: Considerations in the care of residents with frontotemporal dementia (FTD). PMID- 26244185 TI - Updated Choosing Wisely(r) list from AGS highlights tests, treatments to consider carefully when caring for older patients. PMID- 26244186 TI - NICHE develops Patient + Family App. PMID- 26244187 TI - Supporting healthcare staff in their QA duties. PMID- 26244189 TI - RESPONSE: The Necessity of Social Media Literacy. PMID- 26244190 TI - A Survey of Knowledge and Perspectives of Ventricular Assist Device Therapy: Evaluating the Timing of Advanced Heart Failure Referral. AB - BACKGROUND: While advancements in ventricular assist device (VAD) therapy have improved survival and quality of life for select patients with advanced heart failure (HF), variations in provider knowledge and opinions may ultimately serve as barriers to therapy. METHODS AND RESULTS: A 12-item survey assessing experience, knowledge, and perspectives of VAD therapy was sent to 106 practicing cardiologists at three neighboring institutions. We received 34 responses for a total response rate of 32.1%. The majority of respondents elected to refer patients with refractory disease for VAD therapy, while only 29.4% elected to refer when standard medical therapy is withdrawn due to hypotension. CONCLUSIONS: While providers are well-informed on the fundamentals of advanced therapy, identifying patients with advanced HF who may benefit from referral remains an educational challenge. An automated referral program that identifies patients with advanced HF based on validated clinical parameters could increase appropriately timed referrals to HF specialists to further improve survival and quality of life outcomes with advanced therapy. PMID- 26244191 TI - Reduction of Cardiac Arrests: The Experience of a Novel Service Centric Medical Emergency Team. AB - OBJECTIVE: To determine whether a novel, service-centric, medical emergency team (MET) model can impact cardiac arrest (CA) rates. METHODS: A retrospective pre- vs. postintervention analysis was performed on patients >= 18 years who had a CA between 2007 and 2012. A service centric MET model was initially implemented on the inpatient cardiology service and expanded hospital wide during 2008-2009, maturing to 10 teams in 2010. Service centric is defined as a medical or surgical service-specific MET team based on the location of the patient. RESULTS: The rate of CA (per 1,000 hospital days) in the year 2007 prior to the initiation of MET was compared to rates during program maturation (2008/2009) and after full maturation to 10 teams (2010-2012). A total of 1,140,233 hospital-care days were analyzed between 2007 and 2012, with 745 CAs recorded (0.65 events per 1,000 hospital days). The overall CA rate was higher prior to MET initiation (0.84 in 2007) compared to postinitiation (0.59 in 2008/09) and maturation to 10 teams (0.64 in 2010-12) (P < 0.003 for both pre- vs postcomparisons). No differences in CA rates were detected between either post-MET initiation time frames (P = 0.342). Similar trends in CA rates were observed in the intensive care unit (ICU) (3.96 vs 2.14 vs 2.68 per 1,000 hospital days in 2007, 2008/2009, and 2010-2012 respectively, with P < 0.001 for both pre- vs postcomparisons). CONCLUSIONS: A service-centric MET program was associated with a reduction in the rate of CAs both hospital wide and in the ICU. These observations maybe explained by the earlier intervention in care of unstable patients by an expanded group of caregivers. PMID- 26244192 TI - Intraoral Infection and Oral Health in the Surgical Patient: Need for Concern During the Perioperative Period? AB - A patient's intraoral health condition is not typically a chief perioperative concern of surgical health care providers and preoperative dental evaluation/therapy is often left unattended prior to elective surgery. Consequently, patients for surgery may possess untreated dental caries, intraoral infection(s), and/or periodontal disease. Individuals who have not had a dental evaluation or examination for the previous several years may be harboring a quiescent and potent oral infection. Deleterious effects of an intraoral infection may not only compromise surgical outcome, but lead to an increased need for additional interventional therapy(s) along with associated expenses. This article will review known connection(s) between oral health, systemic disease, and treatment concerns for bacterial endocarditis. Some of the barriers that exist with improving oral health prior to surgical procedures will also be examined. Augmenting recognition of perioperative dental considerations may result in interventional measures that can minimize use of additional healthcare related resources and optimize patient care. PMID- 26244193 TI - An Unusual Morphology of a Pleomorphic Adenoma. AB - We present a case of a deep lobe parotid pleomorphic adenoma extending into the parapharyngeal space via an unusual morphology. This is a single patient case report of an unusual morphology with an associated review of the literature. The patient successfully underwent right parotidectomy during which it was seen that the tumor was extending above rather than through the stylomandibular tunnel, an unusual morphology for a pleomorphic adenoma. Despite the classic teaching that deep lobe parotid tumors reach the parapharyngeal space by traveling through, or below, the stylomandibular tunnel, it is possible for tumors to occur outside this tunnel. Recognition that this unusual growth path, although rare, can occur is important when designing an appropriate surgical resection. PMID- 26244194 TI - Incidental Finding of Synchronous, Benign, Metastasizing Leiomyoma with Distinct Cytogenetics in the Lung and Uterus. AB - This paper will present a case of benign metastasizing leiomyoma, incidentally found during the preoperative evaluation for acute cholecystitis. The preoperative chest X-ray revealed diffuse bilateral lung nodules suspicious for hematogenous metastasis and the densities measured 1-1.5 cm. A pelvis computed tomography (CT) scan showed in-homogeneous uterine mass with unusual vascular supply raising concern for leiomyosarcoma. Open lung biopsy revealed benign appearing smooth-muscle neoplasm suggestive of metastatic leiomyoma. The patient was then treated with total abdominal hysterectomy with bilateral salpingo oopherectomy which had identical pathology to the lung. As there were innumerable pulmonary metastases where complete resection was impossible, surgical castration appeared to be effective in reducing tumor size. The patient was also started on an aromatase inhibitor that subsequently improved her clinical outcome. Management strategies, cytogenetics, and histological diagnosis are discussed. PMID- 26244195 TI - Young Physicians' Leadership Curriculum: A Novel Approach to Creating Future Physician Leaders and Health Policy Advocates. PMID- 26244196 TI - 50 Years Ago From Connecticut Medicine January 1965. HARVEY AND CIRCULATION OF BLOOD. 1965. PMID- 26244197 TI - Let Us Find Out. 1965. PMID- 26244198 TI - The Lymphatic System: The Scalene Node Biopsy. 1965. PMID- 26244199 TI - A Fortunate Man. PMID- 26244200 TI - To Quarantine or Not to Quarantine. PMID- 26244201 TI - A Compassion That Drives Us Forward. PMID- 26244202 TI - The Focus Should Be On Patients. PMID- 26244203 TI - Connecticut Hospital Readmissions Related to Chest Pain and Heart Failure: Differences by Race, Ethnicity, and Payer. AB - BACKGROUND: Racial and ethnic disparities in hospital readmissions for several major illnesses and conditions are well-documented. However, due to the data typically used to assess readmission disparities little is known regarding the interplay between race/ethnicity and payer in fostering readmissions. This study used a statewide database of acute-care hospital admissions to examine 30-day readmission rates following hospitalization for chest pain and heart failure byrace/ethnicity and insurance status. METHODS: Connecticut hospital discharge data for patients admitted for Chest Pain-DRG 313 (n = 23,450) and Heart Failure and Shock-DRG 291 and 292 (n = 39,985) from 2008 - 2012 were analyzed using marginal logistic models for clustered data with generalized estimating equations. RESULTS: Results from logistic models indicated that Black patients were significantly more likely to be readmitted within 30 days of discharge following hospitalization for chest pain (OR = 1.19, CI = 1.04, 1.37) than were White patients. Hispanics, but not Blacks, were significantly more likely to be readmitted within 30 days of discharge following hospitalization for heart failure (OR = 1.30, CI = 1.15, 1.47). Rates of 30-day readmission across these conditions were between 50-100% higher among those covered by Medicaid compared to those covered by private payer. Controlling for patient socioeconomic status, patient comorbidities, and payer substantially reduced Black/White differences in the odds of readmission for chest pain but did not reduce Hispanic-White differences for heart failure. CONCLUSIONS: Racial and ethnic disparities were seen in hospital readmission rates for Chest Pain (DRG 313) and Heart Failure and Shock (DRG 291 and 292) when a statewide database that captures all acute care hospital admissions was analyzed. When controlling for patient socioeconomic status, comorbidities, and payer status, the difference in the odds of readmission for chest pain, but not heart failure, was reduced. PMID- 26244204 TI - When Rings Are Not Ringworms: Case Reports and Review of Literature. AB - Presented are two cases of subcorneal pustular dermatosis (SPD), one of which was initially confused with, and treated as, a fungal infection. Eventually both cases were successfully treated with dapsone. The exact etiology and pathophysiology of SPD remains unclear and so does its classification. Dapsone remains the treatment of choice but other valid therapeutic alternatives i.e., retinoids, phototherapy, or anti-TNF inhibitors also need to be explored because of the side effects associated with dapsone. PMID- 26244205 TI - Adult Onset Henoch-Schonlein Purpura: Case Report and Review of Literature. AB - Henoch-Schonlein purpura (HSP) is an IgA mediated small-vessel vasculitis, more common in children than adults. We present the case of a 37-year-old male who presented with complaints of nausea, vomiting, abdominal pain, purpuric rash over lower extremities, and migratory polyarthralgia five days after being treated with antibiotics for bronchitis. In addition to the abdominal pain, he developed diarrhea and colonic biopsy findings were suggestive of inflammatory bowel disease (IBD). Skin biopsy revealed leukocytoclastic vasculitis with direct immunofluorescence studies (DIF) staining of IgA deposition confirming the diagnosis of HSP. The clinical features of cutaneous eruption with abdominal complaints can be seen with either HSP or IBD; however the specific skin biopsy findings on DIF can distinguish between the two disease processes. Though HSP is primarily seen in the pediatric population, it is a disease process that must be considered in adults presenting with vasculitic skin rashes and abdominal complaints. PMID- 26244206 TI - Synovial Sarcoma-AV Malformation Collision in the Anterior Mediastinum. AB - Arteriovenous malformation (AVM) and synovial sarcomas are both rare lesions in the mediastinum. Rarer still is a collision tumor in that region. Herein we present a case of a collision tumor comprised of AVM and synovial sarcoma in a 76 year-old man, presenting with pneumonia. Imaging showed a vascular lesion that spontaneously ruptured, causing enlargement of the mass and hemothorax. The resected specimen revealed the malignant second component. This report is a discussion of the never-before reported lesion. PMID- 26244207 TI - Glomus Tumor of the Esophagus: A Case Report and Review of the Literature. AB - We report an extremely rare case of primary glomus tumor of the esophagus, and review the corresponding literature. A 66-year-old female underwent a follow-up upper-gastrointestinal endoscopy due to dysphagia and previous history of esophageal lump. Endoscopic ultrasonography revealed a mass involving the deep mucosa and submucosa (Layers 2 and 3). Endoscopic biopsy revealed a mesenchymal tumor composed of nest of epithelioid cells with associated small blood vessels proliferation. Immunohistochemically, the tumor cells were positive for alpha smooth muscle actin and vimentin, but negative for c-kit and the vascular stroma was highlighted by positivity with CD34. Pathological examination confirmed that the tumor was a glomus tumor of the esophagus. The patient remains healthy without any recurrence to date. PMID- 26244208 TI - Goal-Directed Therapy for Sepsis: Has the Beast Been Slain or Do Questions Remain? AB - The identification and early management of severe sepsis and septic shock has undergone a significant evolution over the past decade and a half. Recently two large multicentered trials were published contradicting the original Early-Goal Directed Therapy (EGDT) trial published in 2001. In this commentary we evaluate the current trials place in the historical context of negative and positive trial's on EGDT sepsis resuscitation. PMID- 26244209 TI - Cadillac Health Care Syndrome. PMID- 26244210 TI - Thoughts on Radiology Education in Medical School. PMID- 26244211 TI - Targeted Cancer Therapy: Class Related Toxicities. PMID- 26244212 TI - Mitral Valve Surgery. 1965. PMID- 26244213 TI - Peptic Ulcer Today. 1965. PMID- 26244214 TI - Medical Staff Unification/Disunification. PMID- 26244215 TI - Stop the Insanity. PMID- 26244216 TI - Some Days Are Better Than Others. PMID- 26244217 TI - Uniting Against Forces That Have Made Medical Practice Intolerable For Doctors. PMID- 26244218 TI - The Biomechanics of Cranial Forces During Figure Skating Spinning Elements. AB - Several facets of figure skating, such as the forces associated with jumping and landing, have been evaluated, but a comprehensive biomechanical understanding of the cranial forces associated with spinning has yet to be explored. The purpose of this case study was to quantify the cranial rotational acceleration forces generated during spinning elements. This case report was an observational, biomechanical analysis of a healthy, senior-level, female figure skating athlete who is part of an on-going study. A triaxial accelerometer recorded the gravitational forces (G) during seven different spinning elements. Our results found that the layback spin generated significant cranial force and these forces were greater than any of the other spin elements recorded. These forces led to physical findings of ruptured capillaries, dizziness, and headaches in our participant. PMID- 26244219 TI - Tibial Spine Avulsion Fractures: A Focus on Arthroscopic Treatment and Rehabilitation. PMID- 26244220 TI - Anterior Cruciate Ligament (ACL) Reconstruction in Skeletally Immature Athletes. PMID- 26244221 TI - Kinesiophobia and Return to Sports After Anterior Cruciate Ligament Reconstruction. AB - Anterior cruciate ligament (ACL) reconstruction is typically recommended for patients who wish to return to aggressive athletic activity. Unfortunately, reconstructive knee surgery is not a guarantee that all patients will return to their preinjury level of function. A recent meta-analysis including 48 studies showed that after a mean follow-up of 41 months, 82% of participants had returned to some kind of athletic activity but only 63% returned to their preinjury level of participation and a disappointing 44% returned to competitive sports. The reasons why some athletes have been unsuccessful in returning to previous levels of activity are vast and our understanding of these factors is limited. The importance of psychological factors has recently been emphasized. One such factor, kinesiophobia, or fear of reinjury, may play a significant role in some patients' inability to successfully return to their previous level of sports participation. In the meta-analysis, kinesiophobia was the most common reason cited for postoperative reduction in, or cessation of, sports participation. PMID- 26244222 TI - Plantar Fasciitis. PMID- 26244223 TI - Sleep Disturbances in Concussed Athletes: A Review of the Literature. AB - Adolescents and young adults recovering from a concussion may experience subjective changes in their normal sleeping patterns. These subjective sleep complaints may influence a patient's perceived concussion symptoms and negatively impact cognition and school function. Clinicians should be cognizant of these changes in normal sleeping patterns for adolescent and young adult concussion patient and familiarize themselves with available treatment options. PMID- 26244224 TI - The Use of Braces in Athletes for Injury Prevention. PMID- 26244225 TI - Athletic Trainers in Connecticut Schools a Must. PMID- 26244226 TI - Primary Lymphoma of Bone. PMID- 26244227 TI - 50 Years Ago From Connecticut Medicine. March 1965. HUNTER: SCIENTIFIC SURGERY BEGINS. 1965. PMID- 26244229 TI - A Neurosurgeon Remembers. PMID- 26244228 TI - Mutual Medical Dental Problems: Fluoridation of Water Supply. 1965. PMID- 26244230 TI - Active About Sports Medicine. PMID- 26244231 TI - Sports Medicine: The Safest Way. PMID- 26244232 TI - Chaos Following Fragmentation. PMID- 26244233 TI - Insurance Companies: We Are Not Taking it Anymore. PMID- 26244235 TI - Synthesis of Enantioenriched Alkylfluorides by the Fluorination of Boronate Complexes. AB - The enantiospecific conversion of chiral secondary boronic esters into alkylfluorides is reported. Boronate complexes derived from boronic esters and PhLi were used as nucleophiles, with Selectfluor II as the electrophilic fluorinating agent, to afford alkylfluorides in short reaction times. The addition of styrene as a radical trap was found to enhance enantiospecificity. A broad range of alkyl boronic esters were converted into alkylfluorides with almost complete enantiospecificity by this method. PMID- 26244236 TI - Delirium in the Intensive Care Unit: A Case for Improvement Science. PMID- 26244237 TI - BEGINNING YOUR PROFESSIONAL CAREER: ADVICE FROM A CHIEF NURSING OFFICER. PMID- 26244238 TI - Implementation of the ABCDE Bundle to Improve Patient Outcomes in the Intensive Care Unit in a Rural Community Hospital. AB - The ABCDE bundle is an evidence-based, multidisciplinary approach to optimizing patient outcomes in the adult intensive care unit (ICU). The ABCDE bundle incorporates awakening, breathing, coordination, delirium monitoring and management, and early mobility to minimize potentially deleterious effects of prolonged hospitalization, including the development of delirium. Health care organizations that implement the ABCDE bundle have improved patient outcomes such as decreased ICU and hospital lengths of stay, decreased duration of mechanical ventilation, decreased prevalence and duration of delirium, and decreased health care costs. The purpose of this evidence-based practice project was to implement the ABCDE bundle in a six-bed general adult ICU of a rural community hospital. Implementation of the bundle decreased average patient hospital length of stay by 1.8 days, reduced length of mechanical ventilation by an average of 1 day, and established a baseline delirium prevalence of 19% over a 3-month time period. The results of this project indicate that the ABCDE bundle can be implemented in rural, community-based hospitals and provides a safe, cost-effective method for enhancing ICU patient outcomes. PMID- 26244239 TI - Delirium and Dementia in the Intensive Care Unit: Increasing Awareness for Decreasing Risk, Improving Outcomes, and Family Engagement. AB - : Longer stays in the intensive care unit (ICU) can be an opportunistic battlefield where not only is the length of stay longer, but also there is increased time that lapses with the potential for a patient fall, nosocomial infection, urinary tract infection, and other untoward events (http://oig.hhs.gov/oei/reports/oei-06-09-00090.pdf; ASHRM Forum. 2014;Q3:10-14). As such, the push has become for shorter lengths of stay whenever possible. Delirium and dementia are 2 conditions that the ICU clinician must remain diligent in monitoring for status changes. Delirium poses the threat of longer term undesirable outcomes and is a potential inherent risk in the care delivered. It rises to the level of a medical emergency that can be deadly but, when caught early, can be treated and resolved (Science Daily, September 16, 2013). Setting expectations with families, providing adequate education, and involving them in a holistic view of patient-centered care can help toward the detection of differences that may occur from an ICU stay. Interventions the ICU clinician can take for increasing self, patient, and family awareness to decrease risk and improve outcomes and ways to deepen family engagement in these populations are explored with practical applications. PMID- 26244240 TI - Achieving and Sustaining Zero: Preventing Surgical Site Infections After Isolated Coronary Artery Bypass With Saphenous Vein Harvest Site Through Implementation of a Staff-Driven Quality Improvement Process. AB - BACKGROUND: Surgical site infections (SSI) increase morbidity and mortality, hospital costs, length of stay, readmissions, and risk of litigation and may impact a facility's reputation. METHODS: Through implementation of a Six Sigma, interdisciplinary team process and the Contextual Model for change engaged all stakeholders. A total of 44 perioperative processes were evaluated, with 15 processes ultimately altered. Revisions involved identifying inconsistent implementation of procedures and standardizing processes, as well as utilizing new suture techniques and products including disposable electrocardiogram leads and pacing wires, antibiotic-coated sutures, and silver-impregnated midsternal dressings. RESULTS: In isolated coronary artery bypass grafting with donor-site procedures, an incidence of 3.74 per 100 procedures was reduced to 0.7 and ultimately to 0. No patients who underwent coronary artery bypass grafting developed a deep sternal wound infection in over 30 months and 590 procedures, resulting in an estimated cost savings of more than $600 000, from May 2012 through December 2014. CONCLUSIONS: A significant reduction in deep sternal wound infections was achieved by working at all levels of the organization through a multidisciplinary approach to create sustained change. Using real-time observations for current practices, areas for improvement were identified. By engaging frontline staff in the process, ownership of the outcomes and adherence to practice change were promoted. The result was a dramatic, rapid, and sustainable improvement in the prevention of deep sternal wound infection. PMID- 26244242 TI - Implementation of an Intensive Care Unit Delirium Protocol: An Interdisciplinary Quality Improvement Project. AB - BACKGROUND: Delirium is a commonly observed problem for adult patients in the intensive care unit (ICU) that is associated with increased mortality, increased hospital length of stay, and long-term disability of ICU survivors. This makes prevention and prompt treatment of delirium imperative goals for critical-care providers. Bedside critical-care nurses are uniquely poised to champion efforts to prevent, detect, and treat delirium but oftentimes are not aware of the most recent evidence-based guidelines or the potential long-term implications for the ICU survivor. Nurses have reported higher levels of confidence in detecting delirium, increased knowledge of delirium, and enhancement of patient care skills after receiving formal didactic educational training. OBJECTIVES: The objectives of this quality improvement project were to develop, implement, and evaluate a nursing education program for critical-care nurses that presented a protocol for the prevention and management of delirium in adult ICU patient populations, as well as improve nurses' familiarity, comfort, and compliance with using a standardized evaluation method for delirium and intervention care bundle. DESIGN: A didactic training program for bedside critical-care nurses was developed and implemented. Upon completion of the educational sessions, a daily bedside delirium screening and care bundle protocol were implemented for all patients in ICUs throughout the facility. PARTICIPANTS: Bedside critical-care nurses were invited to participate in the formal teaching sessions. This included nursing staff from each of the 3 ICUs in this facility, as well as supplemental "float pool" staff. MEASUREMENTS: Pre-educational and posteducational nursing attitudes and self-perceived confidence levels regarding delirium care were measured using a 5-point Likert scale. Pre-educational and posteducational nursing knowledge was measured using raw scores obtained from a 15-item multiple choice test. Following the implementation of the delirium screening and care bundle protocol, nursing staff compliance with screening and care bundle items was measured, as well as overall incidence of positive delirium screenings among all screenings completed. RESULTS: A sample of 49 nurses participated in the formal educational teaching sessions. All 5 nursing attitude and perceived confidence statements measured before and after the educational sessions showed a significant increase in positive perceptions overall (P < .0001). Overall mean posteducation knowledge test raw scores showed a significant improvement from pre-educational scores (70% +/- 12.8% vs 95% +/- 6.9%; P < .0001). Once-daily ICU delirium screenings and care bundle interventions were initiated for all ICU patients; overall compliance during the measurement period was 56.3% (598 of 1061 possible delirium screenings and protocols completed). Of all daily patient screenings performed, 20.4% resulted positive for ICU delirium. All patients who received the care bundle interventions received the interventions uniformly, regardless of clinical delirium status. CONCLUSION: This quality improvement project demonstrates that a formal didactic training program for ICU nurses can result in increased awareness and knowledge of ICU delirium and adequately prepare them for how to properly screen and treat patients. Although overall compliance with implementing daily ICU delirium screenings and care bundle interventions was relatively low, those patients who did receive screening and interventions demonstrated that the incidence of positive delirium screenings at this facility is low compared with reported figures. In addition, patients who did receive the appropriate care bundle interventions did so in a uniform manner, regardless of the presence or absence of clinical delirium. PMID- 26244244 TI - Effect of Anxiety on Individuals and Caregivers After Coronary Artery Bypass Grafting Surgery: A Review of the Literature. AB - BACKGROUND: Coronary artery bypass graft surgery is the most frequently performed heart surgery on adults in the United States and often results in increased anxiety in patients and their caregivers as they attempt to cope with the process of open heart surgery. OBJECTIVE: This article is a comprehensive literature review examining the current information available to health care professionals about the relationship between preoperative anxiety and postoperative surgical outcomes in patients who underwent coronary artery bypass graft surgery. METHODS: Research articles from peer-reviewed sources from 2000 to present were retrieved from CINAHL Plus, EBSCOhost, and Internet search engine Google Scholar, as well as from the Centers for Disease Control and Prevention and the National Heart, Lung and Blood Institute databases. Articles dating back to 2000 were included because of specificity of the topic. RESULTS: Research related to this particular situation supports the relationship between preoperative anxiety and negative postoperative outcomes for patients and their caregivers. However, limitations were identified during the course of the review, and further research on this particular relationship is warranted. DISCUSSION: The review of literature identified that preoperative anxiety increased the risk of poor postoperative outcomes including atrial fibrillation, acute myocardial infarction, increased risk of readmission, increased morbidity and mortality, increased health care utilization, and increased anxiety in caregivers resulting in role strain and frustration. PMID- 26244245 TI - Effect of Compression Devices on Preventing Deep Vein Thrombosis Among Adult Trauma Patients: A Systematic Review. AB - BACKGROUND: Trauma is the leading cause of death in Americans up to 44 years old each year. Deep vein thrombosis (DVT) is a significant condition occurring in trauma, and prophylaxis is essential to the appropriate management of trauma patients. The incidence of DVT varies in trauma patients, depending on patients' risk factors, modality of prophylaxis, and methods of detection. However, compression devices and arteriovenous (A-V) foot pumps prophylaxis are recommended in trauma patients, but the efficacy and optimal use of it is not well documented in the literature. OBJECTIVES: The aim of this study was to review the literature on the effect of compression devices in preventing DVT among adult trauma patients. METHODS: We searched through PubMed, CINAHL, and Cochrane Central Register of Controlled Trials for eligible studies published from 1990 until June 2014. Reviewers identified all randomized controlled trials that satisfied the study criteria, and the quality of included studies was assessed by Cochrane risk of bias tool. RESULTS: Five randomized controlled trials were included with a total of 1072 patients. Sequential compression devices significantly reduced the incidence of DVT in trauma patients. Also, foot pumps were more effective in reducing incidence of DVT compared with sequential compression devices. DISCUSSION: Sequential compression devices and foot pumps reduced the incidence of DVT in trauma patients. However, the evidence is limited to a small sample size and did not take into account other confounding variables that may affect the incidence of DVT in trauma patients. Future randomized controlled trials with larger probability samples to investigate the optimal use of mechanical prophylaxis in trauma patients are needed. PMID- 26244246 TI - The Ventilated Patient's Experience. AB - BACKGROUND: Critically ill intensive care unit (ICU) patients often experience pain, anxiety, panic, fear, dyspnea, and distress related to mechanical ventilation. Patients' recollections vary from having little or no memory of actual events to having total recall. Few studies have examined family members' memories and congruence with patients' symptom report and nurse observation. OBJECTIVES: To describe the experience of the mechanically ventilated ICU patient. AIMS: (1) to explore patient and family memories of pain, anxiety, distress, and dyspnea following mechanical ventilation; (2) to determine if there is a correlation among nurse-documented pain assessment and patient- and family reported pain intensity; and (3) to determine the level of patient and family satisfaction with care while on the ventilator. METHODS: This was a descriptive study design. A convenience sample of ICU patients (n = 84) and family members (n = 77) was interviewed. Medical record data abstraction included patient demographics, medication administration, and nurse assessment of pain and sedation. RESULTS: Most patient and family members reported memories of pain, anxiety/panic, nightmares or distress, and trouble breathing. Patients' perception of anxiety, nightmares, and dyspnea were moderately correlated with their pain perception (P = .000). Family members' memories of pain were correlated with nurse pain assessment behavioral scale ratings, but patients' memories of pain were not. Patients and family reported high satisfaction scores. CONCLUSION: Further inquiry of the patient's experience with mechanical ventilation, the use of a ventilation sedation management protocol, and the evaluation of effective communication tools such as the use of bedside reporting or patient communication boards is warranted. PMID- 26244247 TI - Innovations for Funding Research. PMID- 26244248 TI - Sex-Partner Roles in Homoerotic Relations: An Attempt of Classification. AB - The attempt is made to initially arrange in the terms of methodology the area of the research on partner roles in homoerotic relations. These issues have been noticed very early in human history (e.g., different roles performed or bimodal polarization), but only recently has science become interested in this subject. It is suggested to cover all such roles by the term sex-partner roles (SPR) instead of various other terms used and to classify them according to the ethological evolutionary approach into the appetitive and consummatory SPR. Further details of the division are discussed, and the utility of such classification is marked. PMID- 26244249 TI - Genes and Environment as Predisposing Factors in Autoimmunity: Acceleration of Spontaneous Thyroiditis by Dietary Iodide in NOD.H2h4 Mice. AB - In the field of autoimmune thyroiditis, NOD.H2h4 mice have attracted significant and increasing attention since they not only develop spontaneous disease but they present thyroiditis with accelerated incidence and severity if they ingest iodide through their drinking water. This animal model highlights the interplay between genetic and dietary factors in the triggering of autoimmune disease and offers new opportunities to study immunoregulatory parameters influenced by both genes and environment. Here, we review experimental findings with this mouse model of thyroiditis. PMID- 26244250 TI - Toluene Valence and Rydberg Excitations as Studied by ab initio Calculations and Vacuum Ultraviolet (VUV) Synchrotron Radiation. AB - The electronic spectroscopy of isolated toluene in the gas phase has been investigated using high-resolution photoabsorption spectroscopy in the 4.0-10.8 eV energy range, with absolute cross-section measurements derived. We present the first set of ab initio calculations (vertical energies and oscillator strengths), which we use in the assignment of valence and Rydberg transitions of the toluene molecule. The spectrum reveals several new features not previously reported in the literature, with particular relevance to 7.989 and 8.958 eV, which are here tentatively assigned to the pi*(17a') <- sigma(15a') and 1pi*(10a") <- 1pi(14a') transitions, respectively. The measured absolute photoabsorption cross sections have been used to calculate the photolysis lifetime of toluene in the upper stratosphere (20-50 km). PMID- 26244251 TI - Nanoparticles: 3D imaging in liquids. PMID- 26244252 TI - Paper-based technologies: Biosensors and electronics. PMID- 26244253 TI - Skyrmions: Room temperature and beyond. PMID- 26244254 TI - Artificial membranes: Phospholipids grow non-stop. PMID- 26244255 TI - Computational Analysis of SAXS Data Acquisition. AB - Small-angle x-ray scattering (SAXS) is an experimental biophysical method used for gaining insight into the structure of large biomolecular complexes. Under appropriate chemical conditions, the information obtained from a SAXS experiment can be equated to the pair distribution function, which is the distribution of distances between every pair of points in the complex. Here we develop a mathematical model to calculate the pair distribution function for a structure of known density, and analyze the computational complexity of these calculations. Efficient recursive computation of this forward model is an important step in solving the inverse problem of recovering the three-dimensional density of biomolecular structures from their pair distribution functions. In particular, we show that integrals of products of three spherical-Bessel functions arise naturally in this context. We then develop an algorithm for the efficient recursive computation of these integrals. PMID- 26244256 TI - Addressing the "Global Health Tax" and "Wild Cards": Practical Challenges to Building Academic Careers in Global Health. AB - Among many possible benefits, global health efforts can expand the skills and experience of U.S. clinicians, improve health for communities in need, and generate innovations in care delivery with relevance everywhere. Yet, despite high rates of interest among students and medical trainees to include global health opportunities in their training, there is still no clear understanding of how this interest will translate into viable and sustained global health careers after graduation. Building on a growing conversation about how to support careers in academic global health, this Perspective describes the practical challenges faced by physicians pursuing these careers after they complete training. Writing from their perspective as junior faculty at one U.S. academic health center with a dedicated focus on global health training, the authors describe a number of practical issues they have found to be critical both for their own career development and for the advice they provide their mentees. With a particular emphasis on the financial, personal, professional, and logistical challenges that young "expat" global health physicians in academic institutions face, they underscore the importance of finding ways to support these career paths, and propose possible solutions. Such investments would not only respond to the rational and moral imperatives of global health work and advance the mission of improving human health but also help to fully leverage the potential of what is already an unprecedented movement within academic medicine. PMID- 26244257 TI - Separating Residents' Inpatient and Outpatient Responsibilities: Improving Patient Safety, Learning Environments, and Relationships With Continuity Patients. AB - PROBLEM: Current regulations for internal medicine residency programs require scheduling that minimizes conflict between inpatient and outpatient responsibilities. To meet these regulations, the internal medicine residency program at Beth Israel Deaconess Medical Center implemented a unique scheduling model--the Alternating Call and Elective Scheduling (ACES) model-in July 2009. APPROACH: Beginning in academic year 2009-2010, the authors restructured schedules for their 95 postgraduate year 2 and 3 internal medicine residents using the ACES model. They report pre- and postimplementation housestaff responses from end-of-year program evaluation and culture-of-safety surveys, as well as residents' pre- and postintervention schedule and patient visit data. OUTCOMES: Prior to the intervention, 13/83 (16%) residents agreed that the structure of residency training minimized conflict between inpatient and outpatient responsibilities; after the intervention, 82/84 (98%) agreed with this statement. Before the intervention, 23/83 (28%) residents felt that the schedule promoted inpatient safety, compared with 83/84 (99%) after the intervention. Agreement that the schedule promoted outpatient safety went from 28/83 (34%) preintervention to 73/84 (87%) postintervention. Before the intervention, 45/84 (54%) residents felt that the schedule promoted a continuous healing relationship with continuity patients, compared with 67/84 (80%) after the intervention. After implementation, residents' continuity visits with their own patients increased by 14%, and total annual patient visits increased by 16%. NEXT STEPS: Separating residents' inpatient and outpatient responsibilities may improve patient safety, the learning environment, and resident-patient relationships. Future innovations might focus on improving patient safety and decreasing stress in the outpatient environment. PMID- 26244258 TI - Attention-Deficit/Hyperactivity Disorder and Successful Completion of Anesthesia Residency: A Case Report. AB - Cognitive and physical disabilities among anesthesia residents are not well studied. Cognitive disabilities may often go undiagnosed among trainees, and these trainees may struggle during their graduate medical education. Attention deficit/hyperactivity disorder (ADHD) is an executive function disorder that may manifest as lack of vigilance, an inability to adapt to the rapid changes associated with anesthesia cases, distractibility, an inability to prioritize activities, and even periods of hyperfocusing, among other signs. Programs are encouraged to work closely with residents with such disabilities to develop an educational plan that includes accommodations for their unique learning practices while maintaining the critical aspects of the program. The authors present the management of a case of an anesthesia resident with a diagnosis of ADHD, the perspectives of the trainee, program director, clinical competency director, and the office of general counsel. This article also provides follow-up in the five years since completion of residency. PMID- 26244259 TI - A Plea to Reassess the Role of United States Medical Licensing Examination Step 1 Scores in Residency Selection. AB - The three-step United States Medical Licensing Examination (USMLE) was developed by the National Board of Medical Examiners and the Federation of State Medical Boards to provide medical licensing authorities a uniform evaluation system on which to base licensure. The test results appear to be a good measure of content knowledge and a reasonable predictor of performance on subsequent in-training and certification exams. Nonetheless, it is disconcerting that the test preoccupies so much of students' attention with attendant substantial costs (in time and money) and mental and emotional anguish. There is an increasingly pervasive practice of using the USMLE score, especially the Step 1 component, to screen applicants for residency. This is despite the fact that the test was not designed to be a primary determinant of the likelihood of success in residency. Further, relying on Step 1 scores to filter large numbers of applications has unintended consequences for students and undergraduate medical education curricula. There are many other factors likely to be equally or more predictable of performance during residency. The authors strongly recommend a move away from using test scores alone in the applicant screening process and toward a more holistic evaluation of the skills, attributes, and behaviors sought in future health care providers. They urge more rigorous study of the characteristics of students that predict success in residency, better assessment tools for competencies beyond those assessed by Step 1 that are relevant to success, and nationally comparable measures from those assessments that are easy to interpret and apply. PMID- 26244260 TI - Exploiting the Electrophilic and Nucleophilic Dual Role of Nitrile Imines: One Pot, Three-Component Synthesis of Furo[2,3-d]pyridazin-4(5H)-ones. AB - An expeditious multicomponent reaction to synthesize tetrasubstituted furo[2,3 d]pyridazin-4(5H)-ones is reported. In brief, hydrazonoyl chlorides react with isocyanoacetamides, in the presence of TEA, to give 1,3-oxazol-2-hydrazones which, without being isolated, can react with dimethylacetylene dicarboxylate to afford furo[2,3-d]pyridazin-4(5H)-ones with an unprecedented level of complexity in a triple domino Diels-Alder/retro-Diels-Alder/lactamization reaction sequence. PMID- 26244261 TI - Dihydropyrimidinase and beta-ureidopropionase gene variation and severe fluoropyrimidine-related toxicity. AB - AIMS: To assess the association of DPYS and UPB1 genetic variation, encoding the catabolic enzymes downstream of dihydropyrimidine dehydrogenase, with early-onset toxicity from fluoropyrimidine-based chemotherapy. PATIENTS & METHODS: The coding and exon-flanking regions of both genes were sequenced in a discovery subset (164 patients). Candidate variants were genotyped in the full cohort of 514 patients. RESULTS & CONCLUSIONS: Novel rare deleterious variants in DPYS (c.253C > T and c.1217G > A) were detected once each in toxicity cases and may explain the occurrence of severe toxicity in individual patients, and associations of common variants in DPYS (c.1-1T > C: p(adjusted) = 0.003; OR = 2.53; 95% CI: 1.39-4.62, and c.265-58T > C: p(adjusted) = 0.039; OR = 0.61; 95% CI: 0.38-0.97) with 5 fluorouracil toxicity were replicated. PMID- 26244262 TI - Understanding of Altitude Illness and Use of Pharmacotherapy Among Trekkers and Porters in the Annapurna Region of Nepal. AB - We surveyed Nepali porters and guides as well as English- and non-English speaking trekkers on their knowledge of altitude illness and its treatment during trekking expeditions to the Annapurna region of Nepal. From March 15 to April 15, 2014, Nepali porters and visiting trekkers were surveyed regarding their ability to recognize and treat altitude illness in Manang, Nepal (3540 m). Their personal use of medications and home remedies and presence of acute mountain sickness (AMS) symptoms were also assessed. 504 subjects were surveyed, including 108 Nepalis. Overall incidence of AMS symptoms was 16%, 5% among Nepalis, and 21% among trekkers. Subjects recognized that headache (88%) was one of the symptoms of AMS, however many reported not knowing the symptoms of high altitude pulmonary edema (40%) or high altitude cerebral edema (42%). 58% of subjects reported carrying and 16% reported taking acetazolamide, while only 2 (0.4%) respondents took dexamethasone. The majority of subjects reported that they would be able to recognize (67%) and treat (62%) altitude illness. Trekkers reported a higher incidence of AMS symptoms than Nepalis. Although most respondents recognized symptoms of AMS, both Nepalis and trekkers lacked knowledge regarding more serious presentations of altitude illness, thus both groups were overconfident in their ability to recognize and treat altitude illness. PMID- 26244263 TI - The Impact of a Customized Tray on In-Office Bleaching Tooth Sensitivity: A Randomized Clinical Trial. AB - OBJECTIVE: It was recently demonstrated that using a tray over a bleaching agent reduces its pulpal chamber penetration, which can reduce tooth sensitivity. This study evaluated the effect of the sealed technique on the presence and level of sensitivity reported by patients during and after the bleaching procedure performed in office. METHODS: Forty-six patients underwent a bleaching procedure with 35% hydrogen peroxide used in a single application of 45 minutes for two sessions with an interval of seven days. A customized tray was maintained over the bleaching agent during the entire procedure in half of the patients. The sensitivity level was evaluated during and immediately after the bleaching using verbal and visual analogue scales. The shade alteration was evaluated with a bleach guide scale. The peak sensitivity after 24 hours and the presence/level at 24 hours were also evaluated using a verbal rating scale. Relative risks were calculated for all time assessments. Data on the sensitivity level for both scales were subjected to Friedman and Mann-Whitney tests (alpha=0.05). Data on the shades were analyzed by two-way repeated-measures analysis of variance and Tukey's test (alpha=0.05). RESULTS: The use of a customized tray increased the relative risks to the tooth measured 24 hours after each bleaching session. The sealed technique also increased the level of tooth sensitivity only at 24 hours after the first session. No difference was observed between the bleaching techniques regarding the shade evaluation. CONCLUSION: Using a tray over the bleaching agent can increase the level and risk of tooth sensitivity for the first 24 hours after in-office bleaching. PMID- 26244264 TI - Effect of Selective Etch on the Bond Strength of Composite to Enamel Using a Silorane Adhesive. AB - An improvement in bond strength to enamel has been demonstrated with the use of phosphoric acid prior to bonding with self-etch methacrylate-based adhesive agents. No research has evaluated the effect of phosphoric-acid etching of enamel with a newer self-etch silorane adhesive. The purpose of this study was to evaluate the shear-bond strength of composite to enamel using the self-etch silorane adhesive compared to other self-etching methacrylate-based adhesives, with or without a separate application of phosphoric acid. Bovine incisors were sectioned using a diamond saw and mounted in plastic pipe. The bonding agents were applied to flattened enamel surfaces with or without the application of 35% phosphoric acid. The bonded tooth specimens were inserted beneath a mold, and composite was placed incrementally and light cured. The specimens were stored for 24 hours and six months in water and tested in shear. Data were analyzed with a three-way analysis of variance (ANOVA) to evaluate the effects of surface treatment, adhesive agent, or time on the bond strength of composite to bovine enamel (alpha=0.05). Significant differences were found between the groups based on surface treatment (p<0.01) or adhesive agent (p<0.01), but not on time (p=0.19), with no significant interactions (p>0.14). Phosphoric-acid etching of bovine enamel significantly increased the bond strength of the self-etch methacrylate and the silorane adhesives. The methacrylate-based adhesives had significantly greater bond strength to enamel than the silorane adhesive. PMID- 26244265 TI - Esthetic Challenges in Rehabilitating the Anterior Maxilla: A Case Report. AB - The rehabilitation of an unesthetic smile in the anterior maxilla is always a clinical challenge, especially when an improper shape and size, old restorations, and unesthetic shading are present. In addition, an irregular gingival zenith contour in the anterior maxilla can affect the smile's harmony. Thus, detailed treatment planning is needed to define a functional and esthetic prosthetic rehabilitation. This study describes a clinical case in which a 55-year-old woman was rehabilitated using Digital Smile Design planning and full ceramic crowns (metal free) in the anterior zone of the maxilla and mandible. To normalize the gingival zenith, a dynamic compression technique was performed using provisional restorations to condition the gingival tissues and harmonize the proportional length of the anterior upper teeth. PMID- 26244266 TI - Principles, Practice, and Evolution of Capillary Electrophoresis as a Tool for Forensic DNA Analysis. AB - Capillary electrophoresis (CE) is a versatile and widely used analysis platform with application in diverse areas such as analytical chemistry, chiral separations, clinical, forensics, molecular biology, natural products, organic chemistry, and the pharmaceutical industry. Forensic applications of CE include fragment analysis, DNA sequencing, SNP typing, and analysis of gunshot residues, explosive residues, and drugs. Fragment analysis is a widely used method for short tandem repeat (STR) profiling for human identification (HID) due to the single-base resolution capability of CE. This approach circumvents the tedious and expensive approach of DNA sequencing for STR typing. The high sizing precision, ability to detect fluorescence emitted from multiple dyes, automated electrophoretic runs, and data collection software are key factors in the worldwide adoption of CE as the preferred platform for forensic DNA analysis. The most common CE systems used in forensic DNA analysis include the ABI PRISM(r) 310, 3100, 3100 Avant, 3130, 3130xl, 3500, and 3500xL Genetic Analyzers (GAs). The 3500 series GAs are developed with features useful for forensic scientists, including a normalization feature for analysis of the data designed to reduce the variation in peak height from instrument to instrument and injection to injection. Other hardware and software features include improved temperature control, radio frequency identification (RFID) tags for monitoring instrument consumables, HID-focused software features, and security and maintenance. PMID- 26244267 TI - Forensic Mitochondrial DNA Analysis: Current Practice and Future Potential. AB - Current practices for performing forensic mitochondrial DNA (mtDNA) sequence analysis, as employed in public and private laboratories across the United States, have changed remarkably little over the past 20 years. Alternative approaches have been developed and proposed, and new technologies have emerged, but the core methods have remained relatively unchanged. Once DNA has been recovered from biological material (for example, from older skeletal remains and hair shafts), segments of the mtDNA control region are amplified using a variety of approaches, dictated by the quality of the sample being tested. The amplified mtDNA products are subjected to Sanger-based sequencing and data interpretation is performed using one of many available software packages. These relatively simple methods, at least in retrospect, have remained robust, and have stood the test of time. However, alternative methods for mtDNA analysis remain viable options (for example, linear array assays and dHPLC), and should be revisited as the desire to streamline the testing process, interpret heteroplasmy, and deconvolute mixed mtDNA profiles intensifies. Therefore, it is important to periodically reassess the alternative methods available to the mtDNA practitioner, and to evaluate newer technologies being put forth by the scientific community, for example, next-generation sequencing. Although the basic mitochondrial DNA protocols and practices of public and private laboratories are similar, an overview of the current practices of forensic mtDNA analysis is provided, helping to frame the path forward. PMID- 26244268 TI - Sample-to-Result STR Genotyping Systems: Potential and Status. AB - Forensic DNA analysis using short tandem repeats (STRs) has become the cornerstone for human identification, kinship analysis, paternity testing, and other applications. However, it is a lengthy, laborious process that requires specialized training and numerous instruments, and it is one of the factors that has contributed to the formation and expansion of a casework backlog in the United States of samples awaiting DNA processing. Although robotic platforms and advances in instrumentation have improved the throughput of samples, there still exists a significant potential to enhance sample-processing capabilities. The application of microfluidic technology to STR analysis for human identification offers numerous advantages, such as a completely closed system, reduced sample and reagent consumption, and portability, as well as the potential to reduce the processing time required for biological samples to less than 2 h. Development of microfluidic platforms not only for forensic use, but clinical and diagnostic use as well, has exponentially increased since the early 1990s. For a microfluidic system to be generally accepted in forensic laboratories, there are several factors that must be taken into consideration and the data generated with these systems must meet or exceed the same guidelines and standards that are applicable for the conventional methods. This review covers the current state of forensic microfluidic platforms starting with microchips for the individual DNA-processing steps of extraction, amplification, and electrophoresis. For fully integrated devices, challenges that come with microfluidic platforms are covered, including circumventing issues with surface chemistry, monitoring flow control, and proper allele calling. Finally, implementation and future implications of a microfluidic rapid DNA system are discussed. PMID- 26244269 TI - Training of Forensic DNA Scientists - A Commentary. AB - For the past two decades, forensic DNA analysis has rapidly expanded in both utility and value to criminal investigations. As the number of crime scene and convict/arrestee samples has continued to grow, many forensic DNA laboratories find themselves struggling to test samples in a timely fashion. Agencies employ various methods for calculating their sample intake and processing capacity, yet database and casework sample backlogs continue to present a major challenge. One issue many forensic laboratories face is limited availability of resources for training new analysts. High-quality training enables analysts to effectively perform various aspects of DNA profiling, and as such, it is essential to ensuring consistent, high-quality results. This is well documented in the guidelines established in the FBI's Quality Assurance Standards for Forensic DNA Testing Laboratories in the United States as well as internationally by agencies like INTERPOL. A facility dedicated to training analysts on both theoretical and practical aspects of automated sample processing accelerates the establishment and expansion of high-throughput forensic DNA laboratories. The present article will discuss various aspects of training and agencies that provide such training programs. PMID- 26244270 TI - Patient Satisfaction and Short-Term Outcome in Elective Cranial Neurosurgery. AB - BACKGROUND: Patient-reported experience is often used as a measure for quality of care, but no reports on patient satisfaction after cranial neurosurgery exist. OBJECTIVE: To study the association of overall patient satisfaction and surgical outcome and to evaluate the applicability of overall patient satisfaction as a proxy for quality of care in elective cranial neurosurgery. METHODS: We conducted an observational study on the relationship of overall patient satisfaction at 30 postoperative days with surgical and functional outcome (modified Rankin Scale [mRS] score) in a prospective, consecutive, and unselected cohort of 418 adult elective craniotomy patients enrolled between December 2011 and December 2012 at Helsinki University Hospital, Helsinki, Finland. RESULTS: Postoperative overall (subjective and objective) morbidity was present in 194 (46.4%) patients; yet almost 94% of all study patients reported high overall satisfaction. Low overall patient satisfaction at 30 days was not associated with postoperative major morbidity in elective cranial neurosurgery. Dependent functional status (mRS score >=3) at 30 days, minor infections, poor postoperative subjective overall health status, and patient-reported severe symptoms (double vision, poor balance) may contribute to unsatisfactory patient experience. CONCLUSION: Overall patient satisfaction with elective cranial neurosurgery is high. Even 9 of 10 patients with postoperative major morbidity rated high overall patient satisfaction at 30 days. Overall patient satisfaction may merely reflect patient experience and subjective postoperative health status, and therefore it is a poor proxy for quality of care in elective cranial neurosurgery. PMID- 26244271 TI - Sulfamate inhibitor S4 influences carbonic anhydrase IX ectodomain shedding in colorectal carcinoma cells. AB - Carbonic anhydrase IX (CAIX) is a pivotal pH regulator under hypoxia, which by its tumor-specific expression represents an attractive target for cancer therapy. Here, we report on effects of the sulfamate CAIX inhibitor S4 (4-(3'-(3",5" dimethylphenyl)ureido)phenyl sulfamate) in colorectal carcinoma cell lines. S4 was administered under experimental hypoxia or normoxia to HT29, KM20L2 and HCT116 cells. Effects on survival, proliferation, pH, lactate extrusion and CAIX protein expression were evaluated. S4 treatment resulted in attenuated hypoxia induced extracellular acidification and reduced clonogenic survival under hypoxia in HT29 cells. The pH effects were present only in a [Formula: see text]-free buffer system and were accompanied by decreased lactate extrusion. The main finding of this work was that S4 treatment caused alterations in CAIX ectodomain shedding. This merits further investigation to understand how sulfamates influence CAIX activity and how such drugs may be of use in cancer treatment. PMID- 26244272 TI - Association of an Endovascular-First Protocol for Ruptured Abdominal Aortic Aneurysms With Survival and Discharge Disposition. AB - IMPORTANCE: Mortality after an open surgical repair of a ruptured abdominal aortic aneurysm (rAAA) remains high. The role and clinical benefit of ruptured endovascular aneurysm repair (rEVAR) have yet to be fully elucidated. OBJECTIVE: To evaluate the effect of an endovascular-first protocol for patients with an rAAA on perioperative mortality and associated early clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of a consecutive series of patients presenting with an rAAA before (1997-2006) and after (2007-2014) implementation of an endovascular-first treatment strategy (ie, protocol) at an academic medical center. MAIN OUTCOMES AND MEASURES: Early mortality, perioperative morbidity, discharge disposition, and overall survival. RESULTS: A total of 88 patients with an rAAA were included in the analysis, including 46 patients in the preprotocol group (87.0% underwent an open repair and 13.0% underwent an rEVAR) and 42 patients in the intention-to-treat postprotocol group (33.3% underwent an open repair and 66.7% underwent an rEVAR; P = .001). Baseline demographics were similar between groups. Postprotocol patients died significantly less often at 30 days (14.3% vs 32.6%; P = .03), had a decreased incidence of major complications (45.0% vs 71.8%; P = .02), and had a greater likelihood of discharge to home (69.2% vs 42.1%; P = .04) after rAAA repair compared with preprotocol patients. Kaplan-Meier analysis demonstrated significantly greater long-term survival in the postprotocol period (log-rank P = .002). One-, 3-, and 5-year survival rates were 50.0%, 45.7%, and 39.1% for open repair, respectively, and 61.9%, 42.9%, and 23.8% for rEVAR, respectively. CONCLUSIONS AND RELEVANCE: Implementation of a contemporary endovascular-first protocol for the treatment of an rAAA is associated with decreased perioperative morbidity and mortality, a higher likelihood of discharge to home, and improved long-term survival. Patients with an rAAA and appropriate anatomy should be offered endovascular repair as first-line treatment at experienced vascular centers. PMID- 26244274 TI - Beyond the initial 140 ms, lexical decision and reading aloud are different tasks: An ERP study with topographic analysis. AB - Most of our knowledge on the time-course of the mechanisms involved in reading derived from electrophysiological studies is based on lexical decision tasks. By contrast, very few ERP studies investigated the processes involved in reading aloud. It has been suggested that the lexical decision task provides a good index of the processes occurring during reading aloud, with only late processing differences related to task response modalities. However, some behavioral studies reported different sensitivity to psycholinguistic factors between the two tasks, suggesting that print processing could differ at earlier processing stages. The aim of the present study was thus to carry out an ERP comparison between lexical decision and reading aloud in order to determine when print processing differs between these two tasks. Twenty native French speakers performed a lexical decision task and a reading aloud task with the same written stimuli. Results revealed different electrophysiological patterns on both waveform amplitudes and global topography between lexical decision and reading aloud from about 140 ms after stimulus presentation for both words and pseudowords, i.e., as early as the N170 component. These results suggest that only very early, low-level visual processes are common to the two tasks which differ in core processes. Taken together, our main finding questions the use of the lexical decision task as an appropriate paradigm to investigate reading processes and warns against generalizing its results to word reading. PMID- 26244275 TI - Striatal-cerebellar networks mediate consolidation in a motor sequence learning task: An fMRI study using dynamic causal modelling. AB - The fast and slow learning stages of motor sequence learning are suggested to be realized through plasticity in a distributed cortico-striato-cerebellar network. To better understand the causal interactions within this network in the different phases of motor sequence learning, we investigated the effective connectivity within this network during encoding (Day 1) and after consolidation (Day 2) of a serial reaction time task. Using Dynamic Causal Modelling of fMRI data, we found general changes in network connections reflected in altered input nodes and endogenous connections when comparing the early and fast learning session to the late and slow learning session. Whereas encoding of a motor memory early on modulated several connections in a distributed network, slow learning resulted in a pruned network. More specifically, we found a negative modulation of connections from left M1 to right cerebellum, right premotor cortex to left cerebellum, as well as backward connections from putamen to cerebellum bilaterally in the encoding session. While connections during pre-sleep were significantly modulated by learning per se (i.e., specifically modulated by performance on sequence conditions), the connections observed after sleep were rather modulated by general performance (i.e., modulated by performance on both sequence and random conditions). A forward connection from left cerebellum to right putamen was found to be consistent across participants for the sequence condition only during slow learning. Together these findings suggest that whereas encoding in the fast learning phase requires plasticity in several connections implementing both motor and perceptual learning components, slow learning is mediated through connectivity from left cerebellum to right putamen. PMID- 26244276 TI - Detecting tones in complex auditory scenes. AB - In everyday life, our auditory system is bombarded with many signals in complex auditory scenes. Limited processing capacities allow only a fraction of these signals to enter perceptual awareness. This magnetoencephalography (MEG) study used informational masking to identify the neural mechanisms that enable auditory awareness. On each trial, participants indicated whether they detected a pair of sequentially presented tones (i.e., the target) that were embedded within a multi tone background. We analysed MEG activity for 'hits' and 'misses', separately for the first and second tones within a target pair. Comparing physically identical stimuli that were detected or missed provided insights into the neural processes underlying auditory awareness. While the first tone within a target elicited a stronger early P50m on hit trials, only the second tone evoked a negativity at 150 ms, which may index segregation of the tone pair from the multi-tone background. Notably, a later sustained deflection peaking around 300 and 500 ms (P300m) was the only component that was significantly amplified for both tones, when they were detected pointing towards its key role in perceptual awareness. Additional Dynamic Causal Modelling analyses indicated that the negativity at 150 ms underlying auditory stream segregation is mediated predominantly via changes in intrinsic connectivity within auditory cortices. By contrast, the later P300m response as a signature of perceptual awareness relies on interactions between parietal and auditory cortices. In conclusion, our results suggest that successful detection and hence auditory awareness of a two-tone pair within complex auditory scenes relies on recurrent processing between auditory and higher-order parietal cortices. PMID- 26244277 TI - An Optimized PatchMatch for multi-scale and multi-feature label fusion. AB - Automatic segmentation methods are important tools for quantitative analysis of Magnetic Resonance Images (MRI). Recently, patch-based label fusion approaches have demonstrated state-of-the-art segmentation accuracy. In this paper, we introduce a new patch-based label fusion framework to perform segmentation of anatomical structures. The proposed approach uses an Optimized PAtchMatch Label fusion (OPAL) strategy that drastically reduces the computation time required for the search of similar patches. The reduced computation time of OPAL opens the way for new strategies and facilitates processing on large databases. In this paper, we investigate new perspectives offered by OPAL, by introducing a new multi-scale and multi-feature framework. During our validation on hippocampus segmentation we use two datasets: young adults in the ICBM cohort and elderly adults in the EADC ADNI dataset. For both, OPAL is compared to state-of-the-art methods. Results show that OPAL obtained the highest median Dice coefficient (89.9% for ICBM and 90.1% for EADC-ADNI). Moreover, in both cases, OPAL produced a segmentation accuracy similar to inter-expert variability. On the EADC-ADNI dataset, we compare the hippocampal volumes obtained by manual and automatic segmentation. The volumes appear to be highly correlated that enables to perform more accurate separation of pathological populations. PMID- 26244279 TI - Sexual Orientation and Indoor Tanning Device Use: A Population-Based Study. PMID- 26244278 TI - Effects of aging on value-directed modulation of semantic network activity during verbal learning. AB - While impairments in memory recall are apparent in aging, older adults show a remarkably preserved ability to selectively remember information deemed valuable. Here, we use fMRI to compare brain activation in healthy older and younger adults during encoding of high and low value words to determine whether there are differences in how older adults achieve value-directed memory selectivity. We find that memory selectivity in older adults is associated with value-related changes in activation during word presentation in left hemisphere regions that are involved in semantic processing, similar to young adults. However, highly selective young adults show a relatively greater increase in semantic network activity during encoding of high-value items, whereas highly selective older adults show relatively diminished activity during encoding of low-value items. Additionally, only younger adults showed value-related increases in activity in semantic and reward processing regions during presentation of the value cue preceding each to-be-remembered word. Young adults therefore respond to cue value more proactively than do older adults, yet the magnitude of value-related differences in cue period brain activity did not predict individual differences in memory selectivity. Thus, our data also show that age-related reductions in prestimulus activity do not always lead to inefficient performance. PMID- 26244280 TI - Crystal structure of E. coli endonuclease V, an essential enzyme for deamination repair. AB - Endonuclease V (EndoV) is a ubiquitous protein present in all three kingdoms of life, responsible for the specific cleavages at the second phosphodiester bond 3' to inosine. E. coli EndoV (EcEndoV) is the first member discovered in the EndoV family. It is a small protein with a compact gene organization, yet with a wide spectrum of substrate specificities. However, the structural basis of its substrate recognition is not well understood. In this study, we determined the 2.4 A crystal structure of EcEndoV. The enzyme preserves the general 'RNase H like motif' structure. Two subunits are almost fully resolved in the asymmetric unit, but they are not related by any 2-fold axes. Rather, they establish "head to-shoulder" contacts with loose interactions between each other. Mutational studies show that mutations that disrupt the association mode of the two subunits also decrease the cleavage efficiencies of the enzyme. Further biochemical studies suggest that EcEndoV is able to bind to single-stranded, undamaged DNA substrates without sequence specificity, and forms two types of complexes in a metal-independent manner, which may explain the wide spectrum of substrate specificities of EcEndoV. PMID- 26244282 TI - Suppression of spreading depolarization and stabilization of dendritic spines by GLYX-13, an NMDA receptor glycine-site functional partial agonist. AB - Cortical spreading depolarization (SD) is a slow self-propagating wave of mass cellular depolarization in brain tissue, thought to be the underlying cause of migraine scintillating scotoma and aura, and associated with stroke, traumatic brain injury, and termination of status epilepticus. The N-methyl-d-aspartate subtype of glutamate receptor (NMDAR), which gates influx of calcium and is an important trigger of long-term synaptic plasticity, is also a contributor to the initiation and propagation of SD. The current study tested the potential of pharmacological modulation of NMDAR activity through the obligatory co-agonist binding site, to suppress the initiation of SD, and modulate the effects of SD on dendritic spine morphology, in in vitro hippocampal slices. A novel NMDAR functional glycine site partial agonist, GLYX-13, sometimes completely prevented the induction of SD and consistently slowed its rate of propagation. The passage of SD through the hippocampal CA1 region produced a rapid retraction of dendritic spines which reversed after neuronal depolarization had recovered. GLYX-13 improved the rate and extent of return of dendritic spines to their original sizes and locations following SD, suggesting that NMDAR modulators can protect synaptic connections in the brain from structural alterations elicited by SD. These data indicate that NMDAR modulation to renormalize activity may be an effective new treatment strategy for suppression or amelioration of the contribution of SD to short and long-term symptoms of migraine attacks, as well as the effects of SD on tissue damaged by stroke or traumatic brain injury. PMID- 26244281 TI - Increasing levels of the endocannabinoid 2-AG is neuroprotective in the 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. AB - Parkinson's disease (PD) is a common chronic neurodegenerative disorder, usually of idiopathic origin. Symptoms including tremor, bradykinesia, rigidity and postural instability are caused by the progressive loss of dopaminergic neurons in the nigrostriatal region of the brain. Symptomatic therapies are available but no treatment slows or prevents the loss of neurons. Neuroinflammation has been implicated in its pathogenesis. To this end, the present study utilises the 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to reproduce the pattern of cell death evident in PD patients. Herein, the role of a potential regulator of an immune response, the endocannabinoid system (ECS), is investigated. The most prevalent endocannabinoid, 2-arachidonoylglycerol (2-AG) (3 and 5mg/kg), was added exogenously and its enzymatic degradation inhibited to provide protection against MPTP-induced cell death. Furthermore, the addition of DFU (25mg/kg), a selective inhibitor of inflammatory mediator cyclooxygenase-2 (COX-2), potentiated these effects. Levels of 2-AG were shown to be upregulated in a time- and region-specific manner following MPTP administration, indicating that the ECS represents a natural defence mechanism against inflammation, potentiation of which could provide therapeutic benefits. The results expand the current understanding of the role that this signalling system has and its potential influence in PD. PMID- 26244283 TI - Cosolubilization of Coumarin30 and Warfarin in Cationic, Anionic, and Nonionic Micelles: A Micelle-Water Interfacial Charge Dependent FRET. AB - Solubilization of structurally varied coumarins, viz., Warfarin (WF; a 4-hydroxy coumarin) and Coumarin30 (C30, a 7-amino coumarin) individually and in mixed states (cosolubilization) within the aqueous surfactant self-assemblies of varying architectures has been explored, exploiting steady-state, time-resolved fluorimetric, and spectrophotometric techniques. Cosolubilization studies within micelles, which have rarely been done in the literature, were specifically undertaken with the aim of understanding the effect of micelles on their photophysical phenomena when simultaneously present within these nanocarriers and assess their prospective use as an efficient FRET pair. WF solubilizes within CTAB micelles, whereas little or no solubilization is observed in Brij30 and SDS micelles. On the other hand, C30 solubilizes deep into the palisade layer of CTAB micelles, between negatively charged head groups in SDS micelles and between OE groups in Brij30 micelles. C30 and WF maintain their solubilization sites during cosolubilization. In SDS and Brij30 micelles, an increase in WF causes fluorescence quenching of C30 molecules, while in CTAB, an increase in WF causes an increase in fluorescence of C30 by excited WF molecules indicating FRET between the two molecules. PMID- 26244284 TI - Anomalous incident-angle and elliptical-polarization rotation of an elastically refracted P-wave. AB - We report a newly discovered anomalous incident-angle of an elastically refracted P-wave, arising from a P-wave impinging on an interface between two VTI media with strong anisotropy. This anomalous incident-angle is found to be located in the post-critical incident-angle region corresponding to a refracted P-wave. Invoking Snell's law for a refracted P-wave provides two distinctive solutions before and after the anomalous incident-angle. For an inhomogeneously refracted and elliptically polarized P-wave at the anomalous incident-angle, its rotational direction experiences an acute variation, from left-hand elliptical to right-hand elliptical polarization. The new findings provide us an enhanced understanding of acoustical-wave scattering and lead potentially to widespread and novel applications. PMID- 26244287 TI - Evidence Basis for Ultrasound-Guided Block Characteristics Onset, Quality, and Duration. AB - This systematic review summarizes existing evidence for superior onset, quality, and duration of block for ultrasound guidance versus other techniques for nerve localization. MEDLINE was systematically searched from 1966 to June 2013 for randomized controlled trials (RCTs) comparing ultrasound guidance to another technique for peripheral nerve blocks. Twenty-three RCTs were identified for upper-extremity peripheral nerve blocks and 17 for lower extremity. Jadad scores for quality of RCT ranged from 1 to 5 with a median of 3. For upper-extremity blocks, 11 (48%) of 23 RCTs reported faster onset of block, 9 (39%) of 23 reported better quality of block, and 1 (14%) of 7 reported longer duration of block with ultrasound. One RCT reported that ultrasound was inferior for onset of combined median and ulnar block. For lower-extremity blocks, 8 (80%) of 10 RCTs reported faster onset, 9 (56%) of 16 reported better quality, and 2 (33%) of 6 RCTs reported longer duration of blocks. One RCT reported that ultrasound was inferior for quality and duration for ankle block. There is level 1b evidence to make a grade A recommendation that ultrasound guidance provides a modest improvement in block onset and quality of peripheral nerve blocks, especially for lower extremity. Ultrasound is rarely inferior to other techniques. PMID- 26244289 TI - Enhancement in intramolecular interactions and in vitro biological activity of a tripodal tetradentate system upon complexation. AB - Novel biomimetic mononuclear complexes, [Fe()Cl2](+) () and [Cu()(H2O)](2+) () based on naphthalimide appended tripodal tetradentate ligand ( = 2,2',2'' (3,3',3''-(2,2',2''-nitrilotris(methylene)tris(1H-benzo[d]imidazole-2,1 diyl))tris(propane-3,1-diyl))tris(1H-benzo-[de]isoquinoline-1,3(2H)-dione)) have been synthesized and characterized by various analytical and spectral techniques. In addition, the structures of the ligand () and complex were established unambiguously through X-ray crystal structure analysis. Uniquely, the coordination with a metal ion modified the ligand scaffold to interact efficiently with ct-DNA (groove binding) as well as protein (hydrophobic and/or electrostatic interactions). We have determined the affinity of these complexes for DNA/protein and the values are found to be in the range, KDNA = 0.34-1.01 * 10(4) M(-1) and KBSA = 4.1-5.0 * 10(5) M(-1). Furthermore, the fluorescence quenching of BSA with complexes and occurs through a static mechanism and affects the conformation of BSA around the tryptophan residues. The in vitro biological studies of these systems employing HeLa cell lines indicated that both these complexes exhibited enhanced cytotoxicity (IC50 = 32 +/- 0.19 and 10 +/- 0.21 MUM for complexes and , respectively), when compared to the ligand () (IC50 = 150 MUM). Interestingly, both the complexes ( and ) were found to be non-toxic to normal H9C2 cell lines. The mechanism of in vitro biological activity of these complexes has been evaluated through a variety of techniques: acridine orange/ethidium bromide, DAPI staining studies, annexin V-FITC/PI and poly(ADP ribose)-polymerase (PARP) cleavage, which confirmed the apoptotic mediated cell death. Our results demonstrate the importance of complexation of the naphthalimide ligand () as well as the potential of these biomimetic metal complexes as cytotoxic and anticancer agents. PMID- 26244290 TI - Molecular Characterization of FZD4, LRP5, and TSPAN12 in Familial Exudative Vitreoretinopathy. AB - PURPOSE: Familial exudative vitreoretinopathy (FEVR) is a rare hereditary disorder characterized by the failure of peripheral retinal vascularization. The genes FZD4, LRP5, and TSPAN12 are known to be associated with the autosomal inheritance form of FEVR. In this study, we performed mutation screening for FZD4, LRP5, and TSPAN12 in patients with clinical diagnosis of FEVR. In patients with no mutation detected, sequencing analyses for ZNF408, a novel gene potentially related to FEVR, and two other genes related to retinal development, LGR4 and ATOH7, were performed. METHODS: Mutational studies were done in 51 unrelated patients with diagnosis of FEVR during 2008 to 2012 at the Seoul National University Hospital. These patients were screened previously for NDP gene and confirmed to be negative for mutations. Diagnosis of FEVR was established by ophthalmic examinations. Data collected from medical records included sex, age at diagnosis, clinical presentation, and angiographic findings. RESULTS: In this study, we identified 3 known mutations, 10 novel variants with high possibility of pathogenicity, and a whole gene deletion in a total of 18 unrelated patients of 51, resulting in 35.3% of patients being genetically confirmed as having FEVR. Among the patients with pathogenic mutations detected, FZD4 mutations accounted for the largest proportion of autosomal inheritance FEVR cases (13/18 patients, 72.2%), followed by LRP5 (4/18 patients, 22.2%) and TSPAN12 (1/18 patients, 5.6%). No pathogenic mutations were identified in ZNF408, LGR4, and ATOH7. A significant difference in FEVR stage and visual acuity was observed according to the gene involved, showing that patients with FZD4 mutations had milder phenotype. CONCLUSIONS: Mutations of FZD4 accounted for the largest proportion, which could be directly applied to the testing strategy to start with screening for FZD4 mutations. Panel sequencing consisting of related genes would be an alternative choice for the diagnosis of FEVR. Also, genotype phenotype correlation suggested in this study could be helpful in genetic counseling of the probands and their family members as well. PMID- 26244291 TI - Regulation of ADAM10 and ADAM17 by Sorafenib Inhibits Epithelial-to-Mesenchymal Transition in Epstein-Barr Virus-Infected Retinal Pigment Epithelial Cells. AB - PURPOSE: The a-disintegrin-and-metalloprotease (ADAM) family proteins are widely expressed in the different layers of the retina throughout development. The effect of ADAM proteins on the epithelial-to-mesenchymal transition (EMT) in proliferative vitreoretinopathy (PVR) or AMD is yet to be elucidated. In this study we used Epstein-Barr virus (EBV)-transformed adult retinal pigment epithelial (ARPE) cells to investigate how sorafenib, a multikinase inhibitor, modulates ADAM proteins to control EMT. METHODS: Epithelial to mesenchymal transition and related mechanisms in EBV-infected ARPE cells were determined by RT-PCR, Western blot, invasion assay, ELISA assay, and gene silencing with siRNA. RESULTS: Mesenchymal-like ARPE/EBV cells exhibited considerably increased cellular migration and invasion compared with ARPE cells and produced EMT-related cytokines. Sorafenib significantly inhibited production of TGF-beta1, VEGF, IL-6, IL-8, MCP-1, and TNF-alpha and blocked the activation of migration-related signaling molecules, such as HIF-1alpha, p-STAT3, MMP2, and Ang-1. The expression of mature ADAM10, ADAM17, and cleaved Notch 1 proteins in ARPE/EBV cells was downregulated after treatment with sorafenib through the regulatory activity of nardilysin (NRD-1). Gene silencing of NRD-1 in ARPE/EBV cells attenuated secretion of EMT-related cytokines and expression of ADAM10 and 17 and upregulated epithelial markers. CONCLUSIONS: Sorafenib controls the mesenchymal characteristics of EBV-infected ARPE cells. Nardilysin and ADAM family proteins might be new targets for the prevention or control of EMT in retinal diseases. PMID- 26244292 TI - Erratum. Latanoprost Stimulates Secretion of Matrix Metalloproteinases in Tenon Fibroblasts Both In Vitro and In Vivo. PMID- 26244293 TI - Topical TSG-6 Administration Protects the Ocular Surface in Two Mouse Models of Inflammation-Related Dry Eye. AB - PURPOSE: To investigate the therapeutic potential of TNF-alpha stimulated gene/protein (TSG)-6 in two mouse models of inflammation-mediated dry eye syndrome (DES). METHODS: We created inflammation-mediated DES in mice by injecting concanavalin A (ConA; 10 mg/mL) into intraorbital and extraorbital lacrimal glands. Recombinant TSG-6 (1 MUg in phosphate-buffered solution [PBS]) or the same volume of PBS was administered topically to eyes of the mice four times a day (QID) for 1 week. In parallel experiments, we topically applied TSG-6 (1 MUg) or PBS QID to eyes of 12-week-old NOD.B10.H2b mice, a model for primary Sjogren's syndrome. Seven days later, tear production was measured, and the corneal surface was observed for epithelial defects. The number of goblet cells was evaluated in the forniceal conjunctiva. The levels of proinflammatory cytokines were analyzed in the cornea, conjunctiva, and lacrimal glands. Also, in vitro experiments were performed using cultures of corneal epithelial cells (CECs) to test the effects of TSG-6 on cell proliferation and migration. RESULTS: Topical TSG-6 administration improved tear production and reduced corneal epithelial defects both in ConA-injected mice and NOD.B10.H2b mice. The conjunctival goblet cell density was higher in TSG-6-treated eyes than in PBS treated eyes. The expression of proinflammatory cytokines in the cornea, conjunctiva, and intraorbital gland was repressed by TSG-6, while the levels of proinflammatory cytokines in the extraorbital gland were not changed. In vitro experiments revealed that TSG-6 promoted the migration of CECs, but did not affect the proliferation. CONCLUSIONS: Topical TSG-6 protected the ocular surface by suppressing inflammation and promoting corneal epithelial wound healing. PMID- 26244294 TI - Visual Impairments Following Term Neonatal Encephalopathy: Do Retinal Impairments Also Play a Role? AB - PURPOSE: We investigated the effects of term neonatal encephalopathy on retinal function and structure. METHODS: A rat model of term neonatal hypoxic-ischemic (HI) encephalopathy (Vannucci model) was used. Hypoxia-ischemia was induced by a left common carotid ligation followed by a 2-hour period of hypoxia (8% oxygen) in Long-Evans rat pups at postnatal day 10 (P10). Sham operated rats served as controls.. Retinal function was assessed at P30 and P60 by electroretinograms (ERGs), after which retinal histology was performed. Retinocortical function was assessed with visual evoked potentials (VEPs) at P60 and subsequently brain histology was performed. RESULTS: The ERGs of the HI animals at P30 and P60 demonstrated a significant reduction in the scotopic and photopic b-wave amplitudes, but a preserved a-wave amplitude. The retinal histology of the HI animals confirmed that the photoreceptor layer remained intact, whereas the inner layers of the retina were damaged. The HI animals also showed reduced VEP P100 amplitudes, which correlated with reduced left cerebral hemisphere surfaces. There was no correlation between the severities of retinal versus cerebral injuries. CONCLUSIONS: Our findings suggest that term neonatal encephalopathy resulting from HI induces functional and structural damages to the inner retina, while relatively sparing the photoreceptors. These findings raise the possibility that retinal injuries may contribute to visual impairments with or without the presence of brain injury in term asphyxiated newborns and, thus, warrant further studies with humans and animals to better understand the disease process. PMID- 26244295 TI - Roles of Epithelial Cell-Derived Type 2-Initiating Cytokines in Experimental Allergic Conjunctivitis. AB - PURPOSE: To clarify the possible involvement of the type 2-initiating cytokines interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) in the pathophysiology of allergic conjunctivitis, we evaluated ragweed (RW)-induced experimental allergic conjunctivitis (EAC) models by using IL-25 knockout (KO), IL-33 KO, and TSLP receptor (TSLPR) KO mice. METHODS: Interleukin-25 KO, IL-33 KO, TSLPR KO, and BALB/c wild-type mice were sensitized twice with RW in alum and then challenged with RW in eye drops. Clinical scores and eosinophil infiltration were evaluated. Expression levels of serum immunoglobulin E (IgE) and cytokines in the conjunctival tissues were quantified and immunohistochemical analysis was carried out. RESULTS: Significant reductions in clinical scores and numbers of infiltrating eosinophils were observed in the RW-EAC model using IL-33 KO mice. There were no significant differences in clinical scores and numbers of infiltrating eosinophils among IL-25KO, TSLPR KO, and wild-type mice. Serum IgE concentration was upregulated after RW challenges, and there were no differences among the mouse genotypes. Expression levels of of il4, il5, il13, and ccl5 mRNA were diminished in the conjunctivae of the RW-EAC model using IL-33 KO mice compared to those in wild-type mice. Interleukin-33 expression was upregulated as early as 1 hour after RW eye-drop challenge. The number of infiltrating basophils in the conjunctivae of the RW-EAC model using IL-33 KO mice was diminished compared to that in wild-type mice. CONCLUSIONS: Among the type 2-initiating cytokines, IL-33 may play a major role in conjunctival inflammation in an RW-EAC model. PMID- 26244296 TI - Histopathological Evaluation of a Hydrophobic Terpolymer (PTFE-PVD-PP) as an Implant Material for Nonpenetrating Very Deep Sclerectomy. AB - PURPOSE: The purpose of the study was to assess the biocompatibility of porous terpolymer (polytetrafluoroethylene-co-polyvinylidene fluoride-co-polypropylene, PTFE-PVDF-PP) membranes as an implant material to be placed during nonpenetrating very deep sclerectomy (NPVDS). Another study objective was to determine whether the polymer membrane under investigation could be used to manufacture a new generation implant, which would actively delay the process of fistula closure and facilitate aqueous humor drainage. METHODS: Histological response and tissue tolerance of the implant material were assessed. The study was performed on 38 eyeballs of 19 New Zealand white rabbits (19 implanted, 19 control). Histological assessment was carried out between 2 and 52 weeks after surgery. We routinely assessed inflammatory infiltrate, neovascularization, hemorrhage, and stromal edema as well as connective tissue attachment to the implant and adjacent tissues. RESULTS: At 52 weeks of observation, a statistically significant difference was revealed between the study and control groups in terms of resorptive granulation, tissue, and the inflammatory infiltrate. No features of acute inflammatory response to the implant were observed, and there was an absence of histological features of acute inflammatory infiltrates and subsidence of chronic inflammatory infiltrates and resorptive granulation over time. CONCLUSIONS: Slight fibrotic response and insignificant changes in neighboring eye tissues all indicate good tolerance to bioimplant materials. This allows for some optimism regarding the use of hydrophobic terpolymer in the construction of new intrascleral implants. However, the ultimate decision regarding its usefulness and safety in the treatment of glaucoma requires further investigation. PMID- 26244297 TI - Slit2 Promotes Angiogenic Activity Via the Robo1-VEGFR2-ERK1/2 Pathway in Both In Vivo and In Vitro Studies. AB - PURPOSE: Recent research has provided novel but contrary insight into the function of Slit2-Robo signaling in angiogenesis. Although the role of Robo in choroidal neovascularization (CNV) has been studied, the effect of its ligand, Slit2, on CNV development is unclear. This study investigated the role of endogenous Slit2 in CNV and the possible mechanisms. METHODS: Laser-induced CNV in Slit2 transgenic and wild-type mice was used to study the effects of endogenous Slit2 on angiogenesis in vivo. Fluorescein angiography was performed to evaluate the leakage area of each lesion. Plasmid-based gene transfer technology was used to increase Slit2 expression and to study its effects on human umbilical vein endothelial cells (HUVECs) in vitro. Cell proliferation, migration, and tube formation were assessed. Quantitative real-time PCR and Western blot were used to measure expression in the extracellular signal-related kinase 1/2 (ERK1/2), protein kinase B (AKT), and p38 mitogen-activated protein kinase (p38 MAPK) molecular pathways. RESULTS: Laser treatment led to more CNV and vascular leakage in Slit2 transgenic mice compared with wild-type mice. Upregulation of Slit2, Robo1, VEGF receptor 2 (VEGFR2), and phosphorylated ERK1/2 (p-ERK1/2) were detected in retina and choroidal tissue of laser-treated transgenic mice. After transfection of HUVECs with a Slit2 overexpression plasmid, cell proliferation, migration, and tube formation capacities were promoted. Slit2, Robo1, VEGFR2, and p-ERK1/2 were elevated in transfected HUVECs. CONCLUSION: Slit2 overexpression promoted angiogenic effects in both a laser induced CNV mouse model and HUVECs and promoted the biological activity of endothelial cells. Slit2 may promote angiogenesis by upregulating Robo1 and activating the VEGFR2-ERK1/2 pathway. PMID- 26244299 TI - OCT Angiography Compared to Fluorescein and Indocyanine Green Angiography in Chronic Central Serous Chorioretinopathy. AB - PURPOSE: Abnormal choroidal blood flow is considered important in the pathogenesis of chronic central serous chorioretinopathy (CSC). Optical coherence tomography (OCT) angiography can image ocular blood cell flow and could thus provide novel insights in disease mechanisms of CSC. We evaluated depth-resolved flow in chronic CSC by OCT angiography compared to fluorescein angiography (FA) and indocyanine green angiography (ICGA). METHODS: Eighteen eyes with chronic CSC, and six healthy controls, were included. Two human observers annotated areas of staining, hypofluorescence, and hotspots on FA and ICGA, and areas of abnormal flow on OCT angiography. Interobserver agreement in annotating OCT angiography and FA/ICGA was measured by Jaccard indices (JIs). We assessed colocation of flow abnormalities and subretinal fluid visible on OCT, and the distance between hotspots on ICGA from flow abnormalities. RESULTS: Abnormal areas were most frequently annotated in late-phase ICGA and choriocapillary OCT angiography, with moderately high (median JI, 0.74) and moderate (median JI, 0.52) interobserver agreement, respectively. Abnormalities on late-phase ICGA and FA colocated with those on OCT angiography. Aberrant choriocapillary OCT angiography presented as foci of reduced flow surrounded by hyperperfused areas. Hotspots on ICGA were located near hypoperfused spots on OCT angiography (mean distance, 168 MUm). Areas with current or former subretinal fluid were colocated with flow abnormalities. CONCLUSIONS: On OCT angiography, chronic CSC showed irregular choriocapillary flow patterns, corresponding to ICGA abnormalities. These results suggest focal choriocapillary ischemia with surrounding hyperperfusion that may lead to subretinal fluid leakage. PMID- 26244298 TI - Role of Matrix Metalloproteinases 2 and 9 in Lacrimal Gland Disease in Animal Models of Sjogren's Syndrome. AB - PURPOSE: Chronic inflammation of the lacrimal gland results in changes in the composition of the extracellular matrix (ECM), which is believed to compromise tissue repair. We hypothesized that increased production/activity of matrix metalloproteinases (MMPs), especially MMP-2 and -9, in inflamed lacrimal glands modifies the ECM environment, therefore disrupting tissue repair. METHODS: The lacrimal glands from female MRL/lpr and male NOD mice along with their respective control strains were harvested and divided into three pieces and processed for histology, immunohistochemistry, zymography, Western blotting, and RNA analyses. In another study, MRL/lpr mice were treated for 5 weeks with a selective MMP2/9 inhibitor peptide or a control peptide. At the end of treatment, the lacrimal glands were excised and the tissue was processed as described above. RESULTS: There was a 2.5- and 2.7-fold increase in MMP2 gene expression levels in MRL/lpr and NOD mice, respectively. Matrix metalloproteinase 2 and 9 enzymatic activities and protein expression levels were significantly upregulated in the lacrimal glands of MRL/lpr and NOD mice compared to controls. Treatment with the MMP2/9 inhibitor resulted in decreased activity of MMP-2 and -9 both in vitro and in vivo. Importantly, MMP2/9 inhibitor treatment of MRL/lpr mice improved aqueous tear production and resulted in reduced number and size of lymphocytic foci in diseased lacrimal glands. CONCLUSIONS: We conclude that MMP2/9 expression and activity are elevated in lacrimal glands of two murine models of Sjogren's syndrome, suggesting that manipulation of MMP2/9 activity might be a potential therapeutic target in chronically inflamed lacrimal glands. PMID- 26244300 TI - Polarization-Sensitive Optical Coherence Tomography and Conventional Retinal Imaging Strategies in Assessing Foveal Integrity in Geographic Atrophy. AB - PURPOSE: To compare current imaging methods with respect to their ability to detect the condition of the fovea in patients with geographic atrophy (GA). METHODS: The retinas of 176 eyes with GA were imaged using two spectral-domain optical coherence tomography (SD-OCT) systems, Cirrus HD-OCT and Spectralis HRA+OCT, and fundus autofluorescence (FAF) and infrared imaging (IR) was used in the scanning laser ophthalmoscope (SLO) mode. Polarization-sensitive OCT (PS OCT), which selectively visualizes the RPE in addition to SD-OCT features, was used to image 95 eyes. Geographic atrophy lesions were categorized as fovea spared, involved, or not quantifiable (grades 0, 1, and 2). Morphologic gradings were subsequently correlated with best-corrected visual acuity (BCVA) measurements to independently identify the corresponding functional condition of the fovea. Cohen's kappa statistics with a bootstrap method was applied to compare retinal imaging methods. RESULTS: In PS-OCT, 84% of eyes with BCVA greater than or equal to 20/40 were detected, whereas in conventional retinal imaging the rate ranged from 27% in FAF to 45% in the SD-OCT segment. Cohen's kappa statistics revealed significant differences between the gradings of PS-OCT and conventional imaging with kappa = 0.488 and a global Hotelling's T2 statistic of 17.9 with a P value of P = 0.003. Statistical tests revealed no statistically significant differences between the conventional retinal imaging modalities. CONCLUSIONS: Polarization-sensitive OCT can better allow correct grading of the fovea in relation to BCVA and identify foveal sparing than other imaging modalities. The differences in imaging precision should be considered in diagnostic and therapeutic evaluations. PMID- 26244301 TI - Identification and Functional Characterization of a GSH Conjugate Efflux Pathway in the Rat Lens. AB - PURPOSE: To identify and functionally characterize transporters involved in the release of glutathione (GSH) conjugates from the rat lens. METHODS: Polymerase chain reaction and Western blotting were used to screen for the presence of multidrug resistance-associated protein (Mrp) and organic anion transporting polypeptide (Oatp) isoforms, and immunohistochemistry used to localize Mrp isoforms. To test for Mrp function, lenses were loaded with 5 chloromethylfluorescein diacetate and monochlorobimane to form the fluorescent GSH conjugates glutathione methylfluorescein (GS-MF) and glutathione bimane (GS B), respectively, and cultured in artificial aqueous humour (AAH) in the presence or absence of MK571, an Mrp-specific inhibitor, or benzbromarone, a nonspecific organic anion transporter inhibitor. Glutathione-MF and GS-B fluorescence were measured in the AAH media and lenses. RESULTS: Multidrug resistance-associated proteins 1, 4, 5, and Oatp1a4 were present at the transcript level, but only Mrp1, 4, and 5 were detected at the protein level. Multidrug resistance associated proteins 1 and 5 localized to the epithelium and peripheral fiber cells, whereas Mrp4 strongly labeled the nuclei. Glutathione-MF and GS-B efflux was significantly decreased and accumulation in the lens significantly increased in the presence of MK571, indicating that the Mrps are the predominant transporters involved in GSH conjugate release from the lens. Glutathione-B conjugate efflux was further inhibited in the presence of benzbromarone, suggesting that alternative organic anion pathways were involved in mediating GS B efflux. CONCLUSIONS: Multidrug resistance-associated proteins are present in the lens and may be used to remove endogenous and exogenous compounds from the lens via GSH conjugation. This may represent an important pathway of detoxification required to minimize oxidative stress and maintain lens homeostasis. PMID- 26244302 TI - Total Corneal Astigmatism Measurement. PMID- 26244303 TI - Severe Cavitary, Fistulating Mycobacterium avium-intracellulare Complex Disease in an Immunocompetent Host. PMID- 26244304 TI - Australian Health Care--The Challenge of Reform in a Fragmented System. PMID- 26244305 TI - Public Health in the Precision-Medicine Era. PMID- 26244307 TI - CLINICAL PRACTICE. Pregnancy Complicated by Venous Thrombosis. PMID- 26244308 TI - Electrolyte and Acid-Base Disturbances in Patients with Diabetes Mellitus. PMID- 26244309 TI - IMAGES IN CLINICAL MEDICINE. A Giant Aneurysm of the Anterior Communicating Artery. PMID- 26244310 TI - CLINICAL PROBLEM-SOLVING. A Surprising Cause of Chronic Cough. PMID- 26244311 TI - Reexcision--The Other Breast Cancer Epidemic. PMID- 26244306 TI - Tenofovir Gel for the Prevention of Herpes Simplex Virus Type 2 Infection. AB - BACKGROUND: Globally, herpes simplex virus type 2 (HSV-2) infection is the most common cause of genital ulcer disease. Effective prevention strategies for HSV-2 infection are needed to achieve the goals of the World Health Organization global strategy for the prevention and control of sexually transmitted infections. METHODS: We assessed the effectiveness of pericoital tenofovir gel, an antiviral microbicide, in preventing HSV-2 acquisition in a subgroup of 422 HSV-2-negative women enrolled in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 study, a double-blind, randomized, placebo-controlled trial. Incident HSV-2 cases were identified by evidence of seroconversion on an HSV-2 IgG enzyme-linked immunosorbent assay between study enrollment and exit. A confirmatory analysis was performed by Western blot testing. RESULTS: The HSV-2 incidence rate was 10.2 cases per 100 person-years (95% confidence interval [CI], 6.8 to 14.7) among 202 women assigned to tenofovir gel, as compared with 21.0 cases per 100 person-years (95% CI, 16.0 to 27.2) among 222 women assigned to placebo gel (incidence rate ratio, 0.49; 95% CI, 0.30 to 0.77; P=0.003). The HSV 2 incidence rate among the 25 women with vaginal tenofovir concentrations of 10,000 ng per milliliter or more was 5.7 cases per 100 person-years, as compared with 15.5 cases per 100 person-years among the 103 women with no detectable vaginal tenofovir (incidence rate ratio, 0.37; 95% CI, 0.04 to 1.51; P=0.14). As confirmed by Western blot testing, there were 16 HSV-2 seroconversions among women assigned to tenofovir gel as compared with 36 among those assigned to the placebo gel (incidence rate ratio, 0.45; 95% CI, 0.23 to 0.82; P=0.005). CONCLUSIONS: In this study in South Africa, pericoital application of tenofovir gel reduced HSV-2 acquisition in women. (Funded by the U.S. Agency for International Development and others; ClinicalTrials.gov number, NCT00441298.). PMID- 26244313 TI - Ondine Undone. PMID- 26244315 TI - Early, Goal-Directed Resuscitation for Septic Shock. PMID- 26244314 TI - Early, Goal-Directed Resuscitation for Septic Shock. PMID- 26244316 TI - Early, Goal-Directed Resuscitation for Septic Shock. PMID- 26244317 TI - Early, Goal-Directed Resuscitation for Septic Shock. PMID- 26244318 TI - Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer. PMID- 26244319 TI - Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer. PMID- 26244320 TI - Everolimus-Eluting Stents or Bypass Surgery for Coronary Disease. PMID- 26244321 TI - Everolimus-Eluting Stents or Bypass Surgery for Coronary Disease. PMID- 26244322 TI - Everolimus-Eluting Stents or Bypass Surgery for Coronary Disease. PMID- 26244323 TI - Everolimus-Eluting Stents or Bypass Surgery for Coronary Disease. PMID- 26244324 TI - PML in Patients Treated with Dimethyl Fumarate. PMID- 26244325 TI - PML in Patients Treated with Dimethyl Fumarate. PMID- 26244326 TI - PML in Patients Treated with Dimethyl Fumarate. PMID- 26244327 TI - MYD88 Mutations and Response to Ibrutinib in Waldenstrom's Macroglobulinemia. PMID- 26244328 TI - IMAGES IN CLINICAL MEDICINE. Band Acro-osteolysis. PMID- 26244329 TI - An Abnormal Intraoperative Cholangiogram. PMID- 26244330 TI - Dimensional and Structural Control of Silica Aerogel Membranes for Miniaturized Motionless Gas Pumps. AB - With growing public interest in portable electronics such as micro fuel cells, micro gas total analysis systems, and portable medical devices, the need for miniaturized air pumps with minimal electrical power consumption is on the rise. Thus, the development and downsizing of next-generation thermal transpiration gas pumps has been investigated intensively during the last decades. Such a system relies on a mesoporous membrane that generates a thermomolecular pressure gradient under the action of an applied temperature bias. However, the development of highly miniaturized active membrane materials with tailored porosity and optimized pumping performance remains a major challenge. Here we report a systematic study on the manufacturing of aerogel membranes using an optimized, minimal-shrinkage sol-gel process, leading to low thermal conductivity and high air conductance. This combination of properties results in superior performance for miniaturized thermomolecular air pump applications. The engineering of such aerogel membranes, which implies pore structure control and chemical surface modification, requires both chemical processing know-how and a detailed understanding of the influence of the material properties on the spatial flow rate density. Optimal pumping performance was found for devices with integrated membranes with a density of 0.062 g cm(-3) and an average pore size of 142.0 nm. Benchmarking of such low-density hydrophobic active aerogel membranes gave an air flow rate density of 3.85 sccm.cm(-2) at an operating temperature of 400 degrees C. Such a silica aerogel membrane based system has shown more than 50% higher pumping performance when compared to conventional transpiration pump membrane materials as well as the ability to withstand higher operating temperatures (up to 440 degrees C). This study highlights new perspectives for the development of miniaturized thermal transpiration air pumps while offering insights into the fundamentals of molecular pumping in three-dimensional open mesoporous materials. PMID- 26244331 TI - Erratum: An all-silicon single-photon source by unconventional photon blockade. PMID- 26244333 TI - Xist Exon 7 Contributes to the Stable Localization of Xist RNA on the Inactive X Chromosome. AB - To equalize X-linked gene dosage between the sexes in mammalian females, Xist RNA inactivates one of the two X-chromosomes. Here, we report the crucial function of Xist exon 7 in X-inactivation. Xist exon 7 is the second-largest exon with a well conserved repeat E in eutherian mammals, but its role is often overlooked in X inactivation. Although female ES cells with a targeted truncation of the Xist exon 7 showed no significant differences in their Xist expression levels and RNA stability from control cells expressing wild-type Xist, compromised localization of Xist RNA and incomplete silencing of X-linked genes on the inactive X chromosome (Xi) were observed in the exon 7-truncated mutant cells. Furthermore, the interaction between the mutant Xist RNA and hnRNP U required for localization of Xist RNA to the Xi was impaired in the Xist exon 7 truncation mutant cells. Our results suggest that exon 7 of Xist RNA plays an important role for stable Xist RNA localization and silencing of the X-linked genes on the Xi, possibly acting through an interaction with hnRNP U. PMID- 26244332 TI - Global, Regional, and National Consumption of Sugar-Sweetened Beverages, Fruit Juices, and Milk: A Systematic Assessment of Beverage Intake in 187 Countries. AB - BACKGROUND: Sugar-sweetened beverages (SSBs), fruit juice, and milk are components of diet of major public health interest. To-date, assessment of their global distributions and health impacts has been limited by insufficient comparable and reliable data by country, age, and sex. OBJECTIVE: To quantify global, regional, and national levels of SSB, fruit juice, and milk intake by age and sex in adults over age 20 in 2010. METHODS: We identified, obtained, and assessed data on intakes of these beverages in adults, by age and sex, from 193 nationally- or subnationally-representative diet surveys worldwide, representing over half the world's population. We also extracted data relevant to milk, fruit juice, and SSB availability for 187 countries from annual food balance information collected by the United Nations Food and Agriculture Organization. We developed a hierarchical Bayesian model to account for measurement incomparability, study representativeness, and sampling and modeling uncertainty, and to combine and harmonize nationally representative dietary survey data and food availability data. RESULTS: In 2010, global average intakes were 0.58 (95%UI: 0.37, 0.89) 8 oz servings/day for SSBs, 0.16 (0.10, 0.26) for fruit juice, and 0.57 (0.39, 0.83) for milk. There was significant heterogeneity in consumption of each beverage by region and age. Intakes of SSB were highest in the Caribbean (1.9 servings/day; 1.2, 3.0); fruit juice consumption was highest in Australia and New Zealand (0.66; 0.35, 1.13); and milk intake was highest in Central Latin America and parts of Europe (1.06; 0.68, 1.59). Intakes of all three beverages were lowest in East Asia and Oceania. Globally and within regions, SSB consumption was highest in younger adults; fruit juice consumption showed little relation with age; and milk intakes were highest in older adults. CONCLUSIONS: Our analysis highlights the enormous spectrum of beverage intakes worldwide, by country, age, and sex. These data are valuable for highlighting gaps in dietary surveillance, determining the impacts of these beverages on global health, and targeting dietary policy. PMID- 26244334 TI - Comparison of the Transcriptional Profiles of Melanocytes from Dark and Light Skinned Individuals under Basal Conditions and Following Ultraviolet-B Irradiation. AB - We analysed the whole-genome transcriptional profile of 6 cell lines of dark melanocytes (DM) and 6 of light melanocytes (LM) at basal conditions and after ultraviolet-B (UVB) radiation at different time points to investigate the mechanisms by which melanocytes protect human skin from the damaging effects of UVB. Further, we assessed the effect of different keratinocyte-conditioned media (KCM+ and KCM-) on melanocytes. Our results suggest that an interaction between ribosomal proteins and the P53 signaling pathway may occur in response to UVB in both DM and LM. We also observed that DM and LM show differentially expressed genes after irradiation, in particular at the first 6h after UVB. These are mainly associated with inflammatory reactions, cell survival or melanoma. Furthermore, the culture with KCM+ compared with KCM- had a noticeable effect on LM. This effect includes the activation of various signaling pathways such as the mTOR pathway, involved in the regulation of cell metabolism, growth, proliferation and survival. Finally, the comparison of the transcriptional profiles between LM and DM under basal conditions, and the application of natural selection tests in human populations allowed us to support the significant evolutionary role of MIF and ATP6V0B in the pigmentary phenotype. PMID- 26244335 TI - The Way Humans Behave Modulates the Emotional State of Piglets. AB - The emotional state can influence decision-making under ambiguity. Cognitive bias tests (CBT) proved to be a promising indicator of the affective valence of animals in a context of farm animal welfare. Although it is well-known that humans can influence the intensity of fear and reactions of animals, research on cognitive bias often focusses on housing and management conditions and neglects the role of humans on emotional states of animals. The present study aimed at investigating whether humans can modulate the emotional state of weaned piglets. Fifty-four piglets received a chronic experience with humans: gentle (GEN), rough (ROU) or minimal contact (MIN). Simultaneously, they were individually trained on a go/no-go task to discriminate a positive auditory cue, associated with food reward in a trough, from a negative one, associated with punishments (e.g. water spray). Independently of the treatment (P = 0.82), 59% of piglets completed the training. Successfully trained piglets were then subjected to CBT, including ambiguous cues in presence or absence of a human observer. As hypothesized, GEN piglets showed a positive judgement bias, as shown by their higher percentage of go responses following an ambiguous cue compared to ROU (P = 0.03) and MIN (P = 0.02) piglets, whereas ROU and MIN piglets did not differ (P > 0.10). The presence of an observer during CBT did not modulate the percentage of go responses following an ambiguous cue (P > 0.10). However, regardless of the treatment, piglets spent less time in contact with the trough following positive cues during CBT in which the observer was present than absent (P < 0.0001). This study originally demonstrates that the nature of a chronic experience with humans can induce a judgement bias indicating that the emotional state of farm animals such as piglets can be affected by the way humans interact with them. PMID- 26244336 TI - Time-Point Dependent Activation of Autophagy and the UPS in SOD1G93A Mice Skeletal Muscle. AB - Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by a selective loss of motor neurons together with a progressive muscle weakness. Albeit the pathophysiological mechanisms of the disease remain unknown, growing evidence suggests that skeletal muscle can be a target of ALS toxicity. In particular, the two main intracellular degradation mechanisms, autophagy and the ubiquitin-proteasome degradative system (UPS) have been poorly studied in this tissue. In this study we investigated the activation of autophagy and the UPS as well as apoptosis in the skeletal muscle from SOD1G93A mice along disease progression. Our results showed a significant upregulation of proteasome activity at early symptomatic stage, while the autophagy activation was found at presymptomatic and terminal stages. The mRNA upregulated levels of LC3, p62, Beclin1, Atg5 and E2f1 were only observed at symptomatic and terminal stages, which reinforced the time-point activation of autophagy. Furthermore, no apoptosis activation was observed along disease progression. The combined data provided clear evidence for the first time that there is a time-point dependent activation of autophagy and UPS in the skeletal muscle from SOD1G93A mice. PMID- 26244337 TI - Amblyomma maculatum Feeding Augments Rickettsia parkeri Infection in a Rhesus Macaque Model: A Pilot Study. AB - Rickettsia parkeri is an emerging eschar-causing human pathogen in the spotted fever group of Rickettsia and is transmitted by the Gulf coast tick, Amblyomma maculatum. Tick saliva has been shown to alter both the cellular and humoral components of the innate and adaptive immune systems. However, the effect of this immunomodulation on Rickettsia transmission and pathology in an immunocompetent vertebrate host has not been fully examined. We hypothesize that, by modifying the host immune response, tick feeding enhances infection and pathology of pathogenic spotted fever group Rickettsia sp. In order to assess this interaction in vivo, a pilot study was conducted using five rhesus macaques that were divided into three groups. One group was intradermally inoculated with low passage R. parkeri (Portsmouth strain) alone (n = 2) and another group was inoculated during infestation by adult, R. parkeri-free A. maculatum (n = 2). The final macaque was infested with ticks alone (tick feeding control group). Blood, lymph node and skin biopsies were collected at several time points post-inoculation/infestation to assess pathology and quantify rickettsial DNA. As opposed to the tick-only animal, all Rickettsia-inoculated macaques developed inflammatory leukograms, elevated C-reactive protein concentrations, and elevated TH1 (interferon-gamma, interleukin-15) and acute phase inflammatory cytokines (interleukin-6) post inoculation, with greater neutrophilia and interleukin-6 concentrations in the tick plus R. parkeri group. While eschars formed at all R. parkeri inoculation sites, larger and slower healing eschars were observed in the tick feeding plus R. parkeri group. Furthermore, dissemination of R. parkeri to draining lymph nodes early in infection and increased persistence at the inoculation site were observed in the tick plus R. parkeri group. This study indicates that rhesus macaques can be used to model R. parkeri rickettsiosis, and suggests that immunomodulatory factors introduced during tick feeding may enhance the pathogenicity of spotted fever group Rickettsia. PMID- 26244338 TI - A Pyranose-2-Phosphate Motif Is Responsible for Both Antibiotic Import and Quorum Sensing Regulation in Agrobacterium tumefaciens. AB - Periplasmic binding proteins (PBPs) in association with ABC transporters select and import a wide variety of ligands into bacterial cytoplasm. They can also take up toxic molecules, as observed in the case of the phytopathogen Agrobacterium tumefaciens strain C58. This organism contains a PBP called AccA that mediates the import of the antibiotic agrocin 84, as well as the opine agrocinopine A that acts as both a nutrient and a signalling molecule for the dissemination of virulence genes through quorum-sensing. Here, we characterized the binding mode of AccA using purified agrocin 84 and synthetic agrocinopine A by X-ray crystallography at very high resolution and performed affinity measurements. Structural and affinity analyses revealed that AccA recognizes an uncommon and specific motif, a pyranose-2-phosphate moiety which is present in both imported molecules via the L-arabinopyranose moiety in agrocinopine A and the D glucopyranose moiety in agrocin 84. We hypothesized that AccA is a gateway allowing the import of any compound possessing a pyranose-2-phosphate motif at one end. This was structurally and functionally confirmed by experiments using four synthetic compounds: agrocinopine 3'-O-benzoate, L-arabinose-2 isopropylphosphate, L-arabinose-2-phosphate and D-glucose-2-phosphate. By combining affinity measurements and in vivo assays, we demonstrated that both L arabinose-2-phosphate and D-glucose-2-phosphate, which are the AccF mediated degradation products of agrocinopine A and agrocin 84 respectively, interact with the master transcriptional regulator AccR and activate the quorum-sensing signal synthesis and Ti plasmid transfer in A. tumefaciens C58. Our findings shed light on the role of agrocinopine and antibiotic agrocin 84 on quorum-sensing regulation in A. tumefaciens and reveal how the PBP AccA acts as vehicle for the importation of both molecules by means of a key-recognition motif. It also opens future possibilities for the rational design of antibiotic and anti-virulence compounds against A. tumefaciens or other pathogens possessing similar PBPs. PMID- 26244339 TI - Problematic Internet Usage and Immune Function. AB - Problematic internet use has been associated with a variety of psychological comorbidities, but it relationship with physical illness has not received the same degree of investigation. The current study surveyed 505 participants online, and asked about their levels of problematic internet usage (Internet Addiction Test), depression and anxiety (Hospital Anxiety and Depression Scales), social isolation (UCLA Loneliness Questionnaire), sleep problems (Pittsburgh Sleep Quality Index), and their current health - General Health Questionnaire (GHQ-28), and the Immune Function Questionnaire. The results demonstrated that around 30% of the sample displayed mild or worse levels of internet addiction, as measured by the IAT. Although there were differences in the purposes for which males and females used the internet, there were no differences in terms of levels of problematic usage between genders. The internet problems were strongly related to all of the other psychological variables such as depression, anxiety, social isolation, and sleep problems. Internet addiction was also associated with reduced self-reported immune function, but not with the measure of general health (GHQ-28). This relationship between problematic internet use and reduced immune function was found to be independent of the impact of the co-morbidities. It is suggested that the negative relationship between level of problematic internet use and immune function may be mediated by levels of stress produced by such internet use, and subsequent sympathetic nervous activity, which related to immune-supressants, such as cortisol. PMID- 26244340 TI - Recommended Reference Genes for Quantitative PCR Analysis in Soybean Have Variable Stabilities during Diverse Biotic Stresses. AB - For real-time reverse transcription-PCR (qRT-PCR) in soybean, reference genes in different tissues, developmental stages, various cultivars, and under stress conditions have been suggested but their usefulness for research on soybean under various biotic stresses occurring in North-Central U.S. is not known. Here, we investigated the expression stabilities of ten previously recommended reference genes (ABCT, CYP, EF1A, FBOX, GPDH, RPL30, TUA4, TUB4, TUA5, and UNK2) in soybean under biotic stress from Bean pod mottle virus (BPMV), powdery mildew (PMD), soybean aphid (SBA), and two-spotted spider mite (TSSM). BPMV, PMD, SBA, and TSSM are amongst the most common pest problems on soybean in North-Central U.S. and other regions. Reference gene stability was determined using three software algorithms (geNorm, NormFinder, BestKeeper) and a web-based tool (RefFinder). Reference genes showed variability in their expression as well as stability across various stressors and the best reference genes were stress-dependent. ABCT and FBOX were found to be the most stable in soybean under both BPMV and SBA stress but these genes had only minimal to moderate stability during PMD and TSSM stress. Expression of TUA4 and CYP was found to be most stable during PMD stress; TUB4 and TUA4 were stable under TSSM stress. Under various biotic stresses on soybean analyzed, GPDH expression was found to be consistently unstable. For all biotic stressors on soybean, we obtained pairwise variation (V2/3) values less than 0.15 which suggested that combined use of the two most stable reference genes would be sufficient for normalization. Further, we demonstrated the utility of normalizing the qRT-PCR data for target genes using the most stable reference genes validated in current study. Following of the recommendations from our current study will enable an accurate and reliable normalization of qRT-PCR data in soybean under biotic stress. PMID- 26244341 TI - Beer, Wood, and Welfare--The Impact of Improved Stove Use Among Dolo-Beer Breweries. AB - Local beer breweries in Burkina Faso absorb a considerable amount of urban woodfuel demand. We assess the woodfuel savings caused by the adoption of improved brewing stoves by these micro-breweries and estimate the implied welfare effects through the woodfuel market on private households as well as the environmental effect. We find substantial wood savings among the breweries, 36% to 38% if they fully switch to an improved stove. In absolute amounts, they save about 0.176 kg of fuelwood per litre of dolo brewed. These savings imply huge reductions in CO2-emissions and reduce the overall demand for woodfuel, which is predominantly used by the poorer strata for cooking purposes. We provide estimates for the price decrease that might result from this and show that the urban poor are likely to benefit. Thus, the intervention under study is an example for a green growth intervention with pro-poor welfare gains--something green growth strategies should look for. PMID- 26244342 TI - Open-Source Photometric System for Enzymatic Nitrate Quantification. AB - Nitrate, the most oxidized form of nitrogen, is regulated to protect people and animals from harmful levels as there is a large over abundance due to anthropogenic factors. Widespread field testing for nitrate could begin to address the nitrate pollution problem, however, the Cadmium Reduction Method, the leading certified method to detect and quantify nitrate, demands the use of a toxic heavy metal. An alternative, the recently proposed Environmental Protection Agency Nitrate Reductase Nitrate-Nitrogen Analysis Method, eliminates this problem but requires an expensive proprietary spectrophotometer. The development of an inexpensive portable, handheld photometer will greatly expedite field nitrate analysis to combat pollution. To accomplish this goal, a methodology for the design, development, and technical validation of an improved open-source water testing platform capable of performing Nitrate Reductase Nitrate-Nitrogen Analysis Method. This approach is evaluated for its potential to i) eliminate the need for toxic chemicals in water testing for nitrate and nitrite, ii) reduce the cost of equipment to perform this method for measurement for water quality, and iii) make the method easier to carryout in the field. The device is able to perform as well as commercial proprietary systems for less than 15% of the cost for materials. This allows for greater access to the technology and the new, safer nitrate testing technique. PMID- 26244343 TI - Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometric (LC/ESI MS/MS) Study for the Identification and Characterization of In Vivo Metabolites of Cisplatin in Rat Kidney Cancer Tissues: Online Hydrogen/Deuterium (H/D) Exchange Study. AB - In vivo rat kidney tissue metabolites of an anticancer drug, cisplatin (cis diamminedichloroplatinum [II]) (CP) which is used for the treatment of testicular, ovarian, bladder, cervical, esophageal, small cell lung, head and neck cancers, have been identified and characterized by using liquid chromatography positive ion electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) in combination with on line hydrogen/deuterium exchange (HDX) experiments. To identify in vivo metabolites, kidney tissues were collected after intravenous administration of CP to adult male Sprague-Dawley rats (n = 3 per group). The tissue samples were homogenized and extracted using newly optimized metabolite extraction procedure which involves liquid extraction with phosphate buffer containing ethyl acetate and protein precipitation with mixed solvents of methanol-water-chloroform followed by solid-phase clean-up procedure on Oasis HLB 3cc cartridges and then subjected to LC/ESI-HRMS analysis. A total of thirty one unknown in vivo metabolites have been identified and the structures of metabolites were elucidated using LC-MS/MS experiments combined with accurate mass measurements. Online HDX experiments have been used to further support the structural characterization of metabolites. The results showed that CP undergoes a series of ligand exchange biotransformation reactions with water and other nucleophiles like thio groups of methionine, cysteine, acetylcysteine, glutathione and thioether. This is the first research approach focused on the structure elucidation of biotransformation products of CP in rats, and the identification of metabolites provides essential information for further pharmacological and clinical studies of CP, and may also be useful to develop various effective new anticancer agents. PMID- 26244344 TI - Similarities between the Binding Sites of SB-206553 at Serotonin Type 2 and Alpha7 Acetylcholine Nicotinic Receptors: Rationale for Its Polypharmacological Profile. AB - Evidence from systems biology indicates that promiscuous drugs, i.e. those that act simultaneously at various protein targets, are clinically better in terms of efficacy, than those that act in a more selective fashion. This has generated a new trend in drug development called polypharmacology. However, the rational design of promiscuous compounds is a difficult task, particularly when the drugs are aimed to act at receptors with diverse structure, function and endogenous ligand. In the present work, using docking and molecular dynamics methodologies, we established the most probable binding sites of SB-206553, a drug originally described as a competitive antagonist of serotonin type 2B/2C metabotropic receptors (5-HT2B/2CRs) and more recently as a positive allosteric modulator of the ionotropic alpha7 nicotinic acetylcholine receptor (nAChR). To this end, we employed the crystal structures of the 5-HT2BR and acetylcholine binding protein as templates to build homology models of the 5-HT2CR and alpha7 nAChR, respectively. Then, using a statistical algorithm, the similarity between these binding sites was determined. Our analysis showed that the most plausible binding sites for SB-206553 at 5-HT2Rs and alpha7 nAChR are remarkably similar, both in size and chemical nature of the amino acid residues lining these pockets, thus providing a rationale to explain its affinity towards both receptor types. Finally, using a computational tool for multiple binding site alignment, we determined a consensus binding site, which should be useful for the rational design of novel compounds acting simultaneously at these two types of highly different protein targets. PMID- 26244345 TI - Increased Primary Production from an Exotic Invader Does Not Subsidize Native Rodents. AB - Invasive plants have tremendous potential to enrich native food webs by subsidizing net primary productivity. Here, we explored how a potential food subsidy, seeds produced by the aggressive invader cheatgrass (Bromus tectorum), is utilized by an important guild of native consumers--granivorous small mammals- in the Great Basin Desert, USA. In a series of field experiments we examined 1) how cheatgrass invasion affects the density and biomass of seed rain at the ecosystem-level; 2) how seed resources from cheatgrass numerically affect granivorous small mammals; and 3) how the food preferences of native granivores might mediate the trophic integration of cheatgrass seeds. Relative to native productivity, cheatgrass invasion increased the density and biomass of seed rain by over 2000% (P < 0.01) and 3500% (P < 0.01), respectively. However, granivorous small mammals in native communities showed no positive response in abundance, richness, or diversity to experimental additions of cheatgrass seeds over one year. This lack of response correlated with a distinct preference for seeds from native grasses over seeds from cheatgrass. Our experiments demonstrate that increased primary productivity associated with exotic plant invasions may not necessarily subsidize consumers at higher trophic levels. In this context, cheatgrass invasion could disrupt native food webs by providing less-preferred resources that fail to enrich higher trophic levels. PMID- 26244346 TI - Microbial Community Response of an Organohalide Respiring Enrichment Culture to Permanganate Oxidation. AB - While in situ chemical oxidation is often used to remediate tetrachloroethene (PCE) contaminated locations, very little is known about its influence on microbial composition and organohalide respiration (OHR) activity. Here, we investigate the impact of oxidation with permanganate on OHR rates, the abundance of organohalide respiring bacteria (OHRB) and reductive dehalogenase (rdh) genes using quantitative PCR, and microbial community composition through sequencing of 16S rRNA genes. A PCE degrading enrichment was repeatedly treated with low (25 MUmol), medium (50 MUmol), or high (100 MUmol) permanganate doses, or no oxidant treatment (biotic control). Low and medium treatments led to higher OHR rates and enrichment of several OHRB and rdh genes, as compared to the biotic control. Improved degradation rates can be attributed to enrichment of (1) OHRB able to also utilize Mn oxides as a terminal electron acceptor and (2) non-dechlorinating community members of the Clostridiales and Deltaproteobacteria possibly supporting OHRB by providing essential co-factors. In contrast, high permanganate treatment disrupted dechlorination beyond cis-dichloroethene and caused at least a 2-4 orders of magnitude reduction in the abundance of all measured OHRB and rdh genes, as compared to the biotic control. High permanganate treatments resulted in a notably divergent microbial community, with increased abundances of organisms affiliated with Campylobacterales and Oceanospirillales capable of dissimilatory Mn reduction, and decreased abundance of presumed supporters of OHRB. Although OTUs classified within the OHR-supportive order Clostridiales and OHRB increased in abundance over the course of 213 days following the final 100 MUmol permanganate treatment, only limited regeneration of PCE dechlorination was observed in one of three microcosms, suggesting strong chemical oxidation treatments can irreversibly disrupt OHR. Overall, this detailed investigation into dose-dependent changes of microbial composition and activity due to permanganate treatment provides insight into the mechanisms of OHR stimulation or disruption upon chemical oxidation. PMID- 26244348 TI - Milestone Age Affects the Role of Health and Emotions in Life Satisfaction: A Preliminary Inquiry. AB - Jill turns 40. Should this change how she evaluates her life, and would a similar change occur when she turns 41? Milestone age (e.g., 30, 40, 50)--a naturally occurring feature in personal timelines--has received much attention is popular culture, but little attention in academic inquiry. This study examines whether milestone birthdays change the way people evaluate their life. We show that life outlook is impacted by this temporal landmark, which appears to punctuate people's mental maps of their life cycle. At these milestone junctures, people take stock of where they stand and have a more evaluative perspective towards their lives when making life satisfaction judgments. Correspondingly, they place less emphasis on daily emotional experiences. We find that milestone agers (vs. other individuals) place greater weight on health satisfaction and BMI and lesser weight on daily positive emotions in their overall life satisfaction judgments, whereas negative emotions remain influential. PMID- 26244350 TI - Treating acne during pregnancy and lactation. PMID- 26244347 TI - Myocardin Family Members Drive Formation of Caveolae. AB - Caveolae are membrane organelles that play roles in glucose and lipid metabolism and in vascular function. Formation of caveolae requires caveolins and cavins. The make-up of caveolae and their density is considered to reflect cell-specific transcriptional control mechanisms for caveolins and cavins, but knowledge regarding regulation of caveolae genes is incomplete. Myocardin (MYOCD) and its relative MRTF-A (MKL1) are transcriptional coactivators that control genes which promote smooth muscle differentiation. MRTF-A communicates changes in actin polymerization to nuclear gene transcription. Here we tested if myocardin family proteins control biogenesis of caveolae via activation of caveolin and cavin transcription. Using human coronary artery smooth muscle cells we found that jasplakinolide and latrunculin B (LatB), substances that promote and inhibit actin polymerization, increased and decreased protein levels of caveolins and cavins, respectively. The effect of LatB was associated with reduced mRNA levels for these genes and this was replicated by the MRTF inhibitor CCG-1423 which was non-additive with LatB. Overexpression of myocardin and MRTF-A caused 5-10-fold induction of caveolins whereas cavin-1 and cavin-2 were induced 2-3-fold. PACSIN2 also increased, establishing positive regulation of caveolae genes from three families. Full regulation of CAV1 was retained in its proximal promoter. Knock down of the serum response factor (SRF), which mediates many of the effects of myocardin, decreased cavin-1 but increased caveolin-1 and -2 mRNAs. Viral transduction of myocardin increased the density of caveolae 5-fold in vitro. A decrease of CAV1 was observed concomitant with a decrease of the smooth muscle marker calponin in aortic aneurysms from mice (C57Bl/6) infused with angiotensin II. Human expression data disclosed correlations of MYOCD with CAV1 in a majority of human tissues and in the heart, correlation with MKL2 (MRTF-B) was observed. The myocardin family of transcriptional coactivators therefore drives formation of caveolae and this effect is largely independent of SRF. PMID- 26244351 TI - Therapies to improve the cosmetic symptoms of rosacea. AB - Rosacea is a commonly encountered chronic inflammatory skin disease with a predilection for highly visible areas of the skin such as the face. The cosmetic symptoms of rosacea can be substantial and may greatly reduce a patient's quality of life. Although there is no definitive cure for rosacea, effective treatment of symptoms can mitigate the deleterious effects of this condition and improve quality of life. In this article, we review both existing and emerging cosmetic treatments for rosacea, including topical medications, systemic pharmacologic therapies, light-based modalities, and procedural interventions, and assess their ability to improve the cosmetic symptoms of rosacea. PMID- 26244349 TI - Evoked Potentials and Memory/Cognition Tests Validate Brain Atrophy as Measured by 3T MRI (NeuroQuant) in Cognitively Impaired Patients. AB - To our knowledge, this is the largest study evaluating relationships between 3T Magnetic Resonance Imaging (MRI) and P300 and memory/cognitive tests in the literature. The 3T MRI using NeuroQuant has an increased resolution 15 times that of 1.5T MRI. Utilizing NeuroQuant 3T MRI as a diagnostic tool in primary care, subjects (N=169; 19-90 years) displayed increased areas of anatomical atrophy: 34.62% hippocampal atrophy (N=54), 57.14% central atrophy (N=88), and 44.52% temporal atrophy (N=69). A majority of these patients exhibited overlap in measured areas of atrophy and were cognitively impaired. These results positively correlated with decreased P300 values and WMS-III (WMS-III) scores differentially across various brain loci. Delayed latency (p=0.0740) was marginally associated with temporal atrophy; reduced fractional anisotropy (FA) in frontal lobes correlated with aging, delayed P300 latency, and decreased visual and working memory (p=0.0115). Aging and delayed P300 latency correlated with lower FA. The correlation between working memory and reduced FA in frontal lobes is marginally significant (p=0.0787). In the centrum semiovale (CS), reduced FA correlated with visual memory (p=0.0622). Lower demyelination correlated with higher P300 amplitude (p=0.0002). Compared to males, females have higher demyelination (p=0.0064). Along these lines, the higher the P300 amplitude, the lower the bilateral atrophy (p=0.0165). Hippocampal atrophy correlated with increased auditory memory and gender, especially in males (p=0.0087). In considering temporal lobe atrophy correlations: delayed P300 latency and high temporal atrophy (p=0.0740); high auditory memory and low temporal atrophy (p=0.0417); and high working memory and low temporal atrophy (p=0.0166). Central atrophy correlated with aging and immediate memory (p=0.0294): the higher the immediate memory, the lower the central atrophy. Generally, the validation of brain atrophy by P300 and WMS-III could lead to cost-effective methods utilizable in primary care medicine following further confirmation. PMID- 26244352 TI - Isotretinoin treatment in patients with acne vulgaris: does it impact muscle strength, fatigue, and endurance? AB - The objective of this study was to evaluate the effects of isotretinoin on muscle strength, fatigue, and endurance in patients with acne vulgaris. The study included 27 patients with acne vulgaris who underwent treatment with isotretinoin as well as 26 control patients for comparison. Participants in the treatment group received oral isotretinoin 0.5 mg/kg once daily for 1 month followed by an increased dose of 1 mg/kg once daily for 2 months. Isokinetic measurements were obtained from the hamstrings and quadriceps on the nondominant side of the body at baseline and 3-month follow-up using an isokinetic dynamometer. Results indicated that systemic isotretinoin did not significantly alter muscle strength, fatigue, and endurance. PMID- 26244353 TI - Novel psoriasis therapies and patient outcomes, Part 3: Systemic medications. AB - The therapeutic armamentarium for patients with psoriasis and psoriatic arthritis (PsA) has been strengthened by research affording more individualized treatment regimens with new therapeutic targets. In this article, new systemic therapies for psoriasis are discussed, including a review of the relevant clinical trials for novel therapeutics and their respective mechanisms of action, patient outcomes, and safety profiles. This article is the final installment in a 3-part series on agents in the pipeline for the management of psoriasis and PsA including topical agents, biologic treatments, and systemic therapies in phase 2 through phase 4 clinical trials. These systemic agents offer patients more targeted treatment regimens with the prospect of enhanced therapeutic efficacy and more favorable side-effect profiles with better tolerability. PMID- 26244354 TI - A phase 3 randomized, double-blind, vehicle-controlled trial of azelaic acid foam 15% in the treatment of papulopustular rosacea. AB - Rosacea is a chronic relapsing skin disorder primarily affecting the face. Although its etiology is not well defined, rosacea is associated with immune dysregulation and inflammation potentiated by external factors. These manifestations lead to skin sensitivity and impaired quality of life. Azelaic acid (AzA) is approved for the treatment of rosacea in a 15% gel formulation. This phase 3 study evaluated the efficacy and safety of AzA in a 15% foam formulation for the treatment of papulopustular rosacea (PPR). Coprimary efficacy end points were treatment success according to investigator global assessment (IGA) and the nominal change in inflammatory lesion count (ILC) from baseline to the end of treatment (EoT). Adverse events (AEs) were evaluated as a measure of safety. The IGA success rate at EoT was significantly greater in the AzA foam group versus vehicle (P<.001; Cochran-Mantel-Haenszel test). Likewise, nominal ILC change at EoT in the AzA foam group showed a significantly greater decrease versus vehicle (P<.001; F test). Drug-related AEs were mainly mild to moderate, cutaneous, and local. Overall, the study results support the efficacy and safety of twice-daily AzA foam 15% in patients with PPR. PMID- 26244355 TI - What is your diagnosis? The diagnosis: Eosinophilic fasciitis. PMID- 26244356 TI - Rosai-Dorfman disease. PMID- 26244357 TI - Erythematous papules and plaques on the flank of a child. PMID- 26244358 TI - Cutaneous infection with Mycobacterium kansasii in a patient with myelodysplastic syndrome and Sweet syndrome. PMID- 26244359 TI - Levonorgestrel-releasing intrauterine system causes a lichenoid drug eruption. PMID- 26244360 TI - Clustered vesicles in a blaschkoid pattern. PMID- 26244361 TI - Repigmentation of gray hair in lesions of annular elastolytic giant cell granuloma. AB - Hair pigmentation is a complex phenomenon that involves many hormones, neurotransmitters, cytokines, growth factors, eicosanoids, cyclic nucleotides, nutrients, and a physicochemical milieu. We report a case of repigmentation of gray hairs in lesions of annular elastolytic giant cell granuloma (AEGCG) on the scalp of a 67-year-old man. PMID- 26244362 TI - Nephrogenic systemic fibrosis following gadolinium administration. PMID- 26244363 TI - Primary capsule-deficient cutaneous cryptococcosis in a sporotrichoid pattern in an immunocompetent host. AB - Cryptococcosis is an opportunistic yeast infection caused by Cryptococcus neoformans that remains the most common systemic fungal infection in immunosuppressed patients and often presents with signs of meningitis. Primary cutaneous cryptococcosis (PCC) is a more rare clinical identity that is characterized by skin lesions confined to 1 body region, often presenting as a whitlow or phlegmon with positive culture for C neoformans and no evidence of simultaneous dissemination. We report a rare case of PCC in a 73-year-old man with intact cell-mediated immunity. PMID- 26244364 TI - Allergic contact dermatitis for residents. AB - Allergic contact dermatitis (ACD) is a very common skin disease faced by dermatologists. As residents, it is essential that we learn to appropriately diagnose and manage ACD and utilize helpful resources early on in our training. PMID- 26244365 TI - Progressive cribriform and zosteriform hyperpigmentation. PMID- 26244366 TI - Nonblanchable violaceous macules of the periorbital skin. PMID- 26244367 TI - Intraductal Radiofrequency Ablation Followed by Locoregional Tumor Treatments for Treating Occluded Biliary Stents in Non-Resectable Malignant Biliary Obstruction: A Single-Institution Experience. AB - OBJECTIVES: To determine the safety and feasibility of intraductal radiofrequency ablation (RFA) followed by locoregional tumor treatments in patients with non resectable malignant biliary obstruction and stent re-occlusion. METHODS: Fourteen patients with malignant biliary obstruction and blocked metal stents were studied retrospectively. All had intraductal RFA followed by locoregional tumor treatments and were monitored clinically and radiologically. The practicality, safety, postoperative complications, jaundice remission, stent patency and survival time were analyzed. RESULTS: Combination treatment was successful for all patients. There were no severe complications during RFA or local treatments. All patients had stent patency restored, with a decline in serum bilirubin. Three patients had recurrent jaundice by 195, 237 and 357 days; two patients underwent repeat intraductal RFA; and one required an internal external biliary drain. The average stent patency time was 234 days (range 187 544 days). With a median follow-up of 384 days (range 187-544 days), six patients were alive, while eight had died. There was no mortality at 30 days. The 3, 6, 12 and 18 month survival rates were 100%, 100%, 64.3% and 42.9%, respectively. CONCLUSION: Intraductal RFA followed by locoregional tumor treatments for occluded metal stents is safe and practically feasible and potential increase stent patency and survival times. PMID- 26244368 TI - The Influence of Art Expertise and Training on Emotion and Preference Ratings for Representational and Abstract Artworks. AB - Across cultures and throughout recorded history, humans have produced visual art. This raises the question of why people report such an emotional response to artworks and find some works more beautiful or compelling than others. In the current study we investigated the interplay between art expertise, and emotional and preference judgments. Sixty participants (40 novices, 20 art experts) rated a set of 150 abstract artworks and portraits during two occasions: in a laboratory setting and in a museum. Before commencing their second session, half of the art novices received a brief training on stylistic and art historical aspects of abstract art and portraiture. Results showed that art experts rated the artworks higher than novices on aesthetic facets (beauty and wanting), but no group differences were observed on affective evaluations (valence and arousal). The training session made a small effect on ratings of preference compared to the non trained group of novices. Overall, these findings are consistent with the idea that affective components of art appreciation are less driven by expertise and largely consistent across observers, while more cognitive aspects of aesthetic viewing depend on viewer characteristics such as art expertise. PMID- 26244369 TI - alpha-Tocopherol Improves Microcirculatory Dysfunction on Fructose Fed Hamsters. AB - Fructose, an everyday component of western diet associated to chronic hyperglycemia and enhanced free radical production, impairs endothelial function and supplementation with antioxidants might improve it. In this study we investigated if vitamin E could reverse the microvascular damage elicited by fructose. Male Syrian golden hamsters drank either 10% fructose solution (F) or filtered water (C), combined with three concentrations of vitamin E in their chows [zero, normal (VE) or 5X (5XVE)] during 60 days. Microvascular reactivity in response to topical application of acetylcholine (Ach; endothelium-dependent vasodilator) or sodium nitroprusside (SNP; endothelium-independent vasodilator) and macromolecular permeability increase induced by either 30 min ischemia followed by reperfusion (I/R) or topical application of histamine (5 MUM) were assessed using the cheek pouch preparation. Compared to controls (drinking filtered water), fructose-drinking animals showed decreased vasodilatation to acetylcholine in all concentrations tested (-56.2% for 10-9M, -53.9% for 10-7M and -43.7% for 10-5M). On the other hand, vitamin E supplementation resulted in increased responses for both water and fructose drinking groups (177.4% for F vs. F/5XVE and 241.6% for C vs. C/5XVE for 10-5M Ach). Endothelial-independent vasodilatation explored by topical application of SNP was restored and even enhanced with the supplementation of 5X vitamin E in both groups (80.1% for F vs. F/5XVE; 144.2% for C vs. C/5XVE; 3.4% of difference for C/5XVE vs. F/5XVE on 10 5M SNP). The number of leaky sites after I/R and histamine stimuli in vitamin E supplemented animals decreased (-25.1% and -15.3% for F vs. F/5XVE; and -21.7% and -16% of leaky sites comparing C vs. C/5XVE, respectively for I/R and histamine stimuli) pointing to tightening of the endothelial barrier for macromolecular permeability. Our results strongly suggest that vitamin E could improve the endothelial function and permeability barrier and also reverse impairments elicited by sugar overload. PMID- 26244370 TI - Helicobacter pylori, HIV and Gastric Hypochlorhydria in the Malawian Population. AB - BACKGROUND: HIV and Helicobacter pylori are common chronic infections in sub Saharan Africa. Both conditions can predispose to gastric hypochlorhydria that may be a risk factor for enteric infections and reduced drug absorption. We have investigated to what extent HIV and H. pylori infections are associated with hypochlorhydria in a Malawian cohort of patients undergoing endoscopy. METHODS: 104 sequential symptomatic adults referred for gastroscopy at Queen Elizabeth Central Hospital, Blantyre, Malawi, had blood taken for rapid HIV testing and fasting serum gastrin analysis. Gastric fluid was aspirated for pH testing, and gastric biopsies were taken. RESULTS: After 9/104 HIV-infected patients who were already established on anti-retroviral therapy were excluded, 17/95 (25.0%) were seropositive for untreated HIV, and 68/95 (71.6%) patients were H. pylori positive by histology. Hypochlorhydria (fasting gastric pH>4.0) was present in 55.8% (53/95) of patients. H. pylori infection was significantly associated with hypochlorhydria (OR 2.91, [1.02-7.75], p=0.046). While single infection with HIV was not significantly independently associated with hypochlorhydria. H. pylori and HIV co-infection was more strongly associated with hypochlorhydria (OR 6.25, [1.33-29.43], p=0.020) than either infection alone, suggesting an additive effect of co-infection. HIV infection was associated with higher serum gastrin levels (91.3 pM vs. 53.1 pM, p=0.040), while H. pylori infection was not (63.1 pM vs. 55.1 pM, p=0.610). Irrespective of H. pylori and HIV status, most patients (>90%) exhibited pangastritis. Only three patients had histological evidence of gastric atrophy, of which only one was HIV-infected. CONCLUSION: H. pylori infection was associated with fasting hypochlorhydria, while HIV was not independently associated. HIV and H. pylori co-infection, however, was more strongly associated with hypochlorhydria than H. pylori infection alone. The mechanism of this apparent additive effect between HIV and H. pylori remains unclear, but appears to be related to chronic pangastritis rather than gastric atrophy, and associated with hypergastrinaemia in HIV-infected individuals. PMID- 26244371 TI - Sexual Niche Segregation and Gender-Specific Individual Specialisation in a Highly Dimorphic Marine Mammal. AB - While sexual segregation is expected in highly dimorphic species, the local environment is a major factor driving the degree of resource partitioning within a population. Sexual and individual niche segregation was investigated in the Australian fur seal (Arctocephalus pusillus doriferus), which is a benthic foraging species restricted to the shallow continental shelf region of south eastern Australia. Tracking data and the isotopic values of plasma, red blood cells and whiskers were combined to document spatial and dietary niche segregation throughout the year. Tracking data indicated that, in winter, males and females overlapped in their foraging habitat. All individuals stayed within central Bass Strait, relatively close (< 220 km) to the breeding colony. Accordingly, both genders exhibited similar plasma and red cell delta13C values. However, males exhibited greater delta13C intra-individual variation along the length of their whisker than females. This suggests that males exploited a greater diversity of foraging habitats throughout the year than their female counterparts, which are restricted in their foraging grounds by the need to regularly return to the breeding colony to suckle their pup. The degree of dietary sexual segregation was also surprisingly low, both sexes exhibiting a great overlap in their delta15N values. Yet, males displayed higher delta15N values than females, suggesting they fed upon a higher proportion of higher trophic level prey. Given that males and females exploit different resources (mainly foraging habitats), the degree of individual specialisation might differ between the sexes. Higher degrees of individual specialisation would be expected in males which exploit a greater range of resources. However, comparable levels of inter-individual variation in delta15N whisker values were found in the sampled males and females, and, surprisingly, all males exhibited similar seasonal and inter-annual variation in their delta13C whisker values, suggesting they all followed the same general dispersion pattern throughout the year. PMID- 26244372 TI - Facing the Design Challenges of Particle-Based Nanosensors for Metabolite Quantification in Living Cells. PMID- 26244373 TI - A Protocol to Fabricate Nanostructured New Phase: B31-Type MnS Synthesized under High Pressure. AB - Synthesis of nanomaterials with target crystal structures, especially those new structures that cannot be crystallized in their bulk counterparts, is of considerable interest owing to their strongly structure-dependent properties. Here, we have successfully synthesized and identified new-phase nanocrystals (NCs) associated with orthorhombic MnP-type (B31) MnS by utilizing an effective high-pressure technique. It is particularly worth noting that the generated new structured MnS NCs were captured as expected by quenching the high-pressure phase to the ambient conditions at room temperature. Likewise, the commercially available bulk rocksalt (RS) MnS material underwent unambiguously a reversible phase transition when the pressure was released completely. First-principles calculations further supported that the B31-MnS was more energetically preferable than the RS one under high pressure, which can be plausibly interpreted by the structural buckling with respect to zigzagged arrangements within B31 unit cell. Our findings represent a significant step forward in a deeper understanding of the high-pressure phase diagram of MnS and even provide a promising strategy to prepare desired nanomaterials with new structures that do not exist in their bulk counterparts, thus greatly increasing the choice of materials for a variety of applications. PMID- 26244375 TI - Modern Room Temperature Ionic Liquids, a Simple Guide to Understanding Their Structure and How It May Relate to Dynamics. AB - Modern room temperature ionic liquids are structurally defined by symmetries on different length scales. Polar-apolar alternation defines their nanoscale structural heterogeneity, whereas positive-negative charge alternation defines short length scale order. Much progress has been made in the past few years as it pertains to the theoretical interpretation of X-ray scattering experiments for these liquids. Our group has contributed to the development of theoretical interpretation guidelines for the analysis of their structure function. Perhaps less well developed is our understanding of how transport and dynamics in general couple to the very unique structure of ionic liquids which are often dynamically and structurally heterogeneous. This article attempts to present our most current understanding of ionic liquid structure in general and its coupling to transport and dynamics in minimally technical terms for the benefit of the broadest audience. PMID- 26244374 TI - Systems Biology Approach Reveals a Calcium-Dependent Mechanism for Basal Toxicity in Daphnia magna. AB - The expanding diversity and ever increasing amounts of man-made chemicals discharged to the environment pose largely unknown hazards to ecosystem and human health. The concept of adverse outcome pathways (AOPs) emerged as a comprehensive framework for risk assessment. However, the limited mechanistic information available for most chemicals and a lack of biological pathway annotation in many species represent significant challenges to effective implementation of this approach. Here, a systems level, multistep modeling strategy demonstrates how to integrate information on chemical structure with mechanistic insight from genomic studies, and phenotypic effects to define a putative adverse outcome pathway. Results indicated that transcriptional changes indicative of intracellular calcium mobilization were significantly overrepresented in Daphnia magna (DM) exposed to sublethal doses of presumed narcotic chemicals with log Kow >= 1.8. Treatment of DM with a calcium ATPase pump inhibitor substantially recapitulated the common transcriptional changes. We hypothesize that calcium mobilization is a potential key molecular initiating event in DM basal (narcosis) toxicity. Heart beat rate analysis and metabolome analysis indicated sublethal effects consistent with perturbations of calcium preceding overt acute toxicity. Together, the results indicate that altered calcium homeostasis may be a key early event in basal toxicity or narcosis induced by lipophilic compounds. PMID- 26244376 TI - Tetraphenylhexaazaanthracenes: 16pi Weakly Antiaromatic Species with Singlet Ground States. AB - Tetraphenylhexaazaanthracene, TPHA-1, is a fluorescent zwitterionic biscyanine with a closed-shell singlet ground state. TPHA-1 overcomes its weak 16pi antiaromaticity by partitioning its pi system into 6pi positive and 10pi negative cyanines. The synthesis of TPHA-1 is low yielding and accompanied by two analogous TPHA isomers: the deep red, non-charge-separated, quinoidal TPHA-2, and the deep green TPHA-3 that partitions into two equal but oppositely charged 8pi cyanines. The three TPHA isomers are compared. PMID- 26244377 TI - Full-Dimensional Quantum Dynamical Studies of the Cl + HOD -> HCl/DCl + OD/OH Reaction: Bond Selectivity and Isotopic Branching Ratio. AB - Full-dimensional quantum dynamical calculations are carried out to study the mode specificity, bond selectivity, and isotopic branching ratio of the Cl + HOD reaction on an accurate global potential energy surface. Total reaction cross sections have been computed for several low-lying vibrational states of HOD. Our results confirm the experimental observed vibrationally promoted bond cleavage, in which the breaking of the OH(OD) bond is strongly enhanced by the OH(OD) excitation. These results are rationalized by the recently proposed sudden vector projection model. In addition, the OH/OD branching ratio as a function of energy is investigated and rationalized by a reorientation effect. PMID- 26244378 TI - Chemistry, Nutrition, and Health-Promoting Properties of Hericium erinaceus (Lion's Mane) Mushroom Fruiting Bodies and Mycelia and Their Bioactive Compounds. AB - The culinary and medicinal mushroom Hericium erinaceus is widely consumed in Asian countries, but apparently not in the United States, for its nutritional and health benefits. To stimulate broader interest in the reported beneficial properties, this overview surveys and consolidates the widely scattered literature on the chemistry (isolation and structural characterization) of polysaccharides and secondary metabolites such as erinacines, hericerins, hericenones, resorcinols, steroids, mono- and diterpenes, and volatile aroma compounds, nutritional composition, food and industrial uses, and exceptional nutritional and health-promoting aspects of H. erinaceus. The reported health promoting properties of the mushroom fruit bodies, mycelia, and bioactive pure compounds include antibiotic, anticarcinogenic, antidiabetic, antifatigue, antihypertensive, antihyperlipodemic, antisenescence, cardioprotective, hepatoprotective, nephroprotective, and neuroprotective properties and improvement of anxiety, cognitive function, and depression. The described anti inflammatory, antioxidative, and immunostimulating properties in cells, animals, and humans seem to be responsible for the multiple health-promoting properties. A wide range of research advances and techniques are described and evaluated. The collated information and suggestion for further research might facilitate and guide further studies to optimize the use of the whole mushrooms and about 70 characterized actual and potential bioactive secondary metabolites to help prevent or treat human chronic, cognitive, and neurological diseases. PMID- 26244379 TI - Resolution and Determination of the Absolute Configuration of a Twisted Bis Lactam Analogue of Troger's Base: A Comparative Spectroscopic and Computational Study. AB - The first reported twisted bis-lactam, a racemic Troger's base (TB) analogue (2), was resolved into its enantiomers on a chiral stationary phase HPLC column. The absolute configuration of (+)-2 was determined to be (R,R)-2 by comparing experimental and calculated vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectra. The absolute configuration of (-)-2 was determined by comparing experimental and calculated electronic circular dichroism (ECD) spectra. The corresponding theoretical spectra were calculated using the lowest energy conformation of (R,R)-2 and (S,S)-2 at the B3LYP/6-31G(d,p) level of theory. The absolute configuration of (+)-2 was also determined to (R,R)-2 by anomalous X-ray diffraction (AXRD) in a chiral space group P212121 using Cu irradiation resulting in a very low Flack parameter of -0.06(3), despite the heaviest element being an oxygen atom, thus unambiguously confirming the results from the spectroscopic studies. We conclude that, for the Troger's base (TB) analogue (2), we may rank the reliability of the individual methods for AC determination as AXRD ? VCD > ECD, while the synergy of all three methods provides very strong confidence in the assigned ACs of (+)-(R,R)-2 and (-)-(S,S) 2. PMID- 26244380 TI - Intravenous in-line filters for preventing morbidity and mortality in neonates. AB - BACKGROUND: Venous access is an essential part of caring for the sick neonate. However, problems such as contamination of fluids with bacteria, endotoxins and particulates have been associated with intravenous infusion therapy. Intravenous in-line filters claim to be an effective strategy for the removal of bacteria, endotoxins and particulates associated with intravenous therapy in adults and are increasingly being recommended for use in neonates. OBJECTIVES: To determine the effect of intravenous in-line filters on morbidity and mortality in neonates. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. We searched the electronic databases MEDLINE (from 1966 to May, 2015), EMBASE (from 1980 to May, 2015), CINAHL (from 1982 to May 2015) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 5). We did not impose any language restrictions. Further searching included cross references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs that compared the use of intravenous in-line filters with placebo or nothing in neonates. DATA COLLECTION AND ANALYSIS: We followed the procedures of the Cochrane Neonatal Review Group throughout. We checked titles and abstracts identified from the search. We obtained the full text of all studies of possible relevance. We independently assessed the trials for their methodological quality and subsequent inclusion in the review. We contacted authors for further information as needed. Statistical analysis followed the procedures of the Cochrane Neonatal Review Group. MAIN RESULTS: There were four eligible studies that recruited a total of 704 neonates. This review of low to very low quality evidence found that the use of in-line filters compared with unfiltered fluids for intravenous infusion had no statistically significant difference in effectiveness on overall mortality (typical RR 0.87, 95% CI 0.52 to 1.47; typical RD -0.01, 95% CI -0.06 to 0.04; two studies, 530 infants), proven and suspect septicaemia (typical RR 0.86, 95% CI 0.59 to 1.27; typical RD -0.02, 95% CI -0.09 to 0.04; two studies, 530 infants), or other secondary outcomes (including local phlebitis and thrombus, necrotising enterocolitis, duration of cannula patency, length of stay in hospital, number of catheters inserted and financial costs). AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend the use of intravenous in-line filters to prevent morbidity and mortality in neonates. PMID- 26244381 TI - Medication Nonadherence, "Professional Subjects," and Apparent Placebo Responders: Overlapping Challenges for Medications Development. AB - Nonadherence is a major problem in clinical trials of new medications. To evaluate the extent of nonadherence, this study evaluated pharmacokinetic sampling from 1765 subjects receiving active therapy across 8 psychiatric trials conducted between 2001 and 2011. With nonadherence defined as greater than 50% of plasma samples below the limit of quantification for study drug, the percentage of nonadherent subjects ranged from 12.8% to 39.2%. There was a trend toward increased nonadherence in studies with greater numbers of subjects, but an association with nonadherence was not apparent for other study design parameters or subject characteristics. For 2 trials with multiple recruitment sites in geographical proximity, several subjects attempted to simultaneously enroll at separate site locations. The construct of "professional subjects," those who enroll in trials only for financial gain, is gaining attention, and we therefore modeled the impact of professional subjects on medication efficacy trials. The results indicate that enrollment of professional subjects who are destined to succeed (those who will appear to achieve treatment success regardless of study drug assignment) can substantially increase both the apparent placebo response rate and the sample size requirement for statistical power, while decreasing the observed effect size. The overlapping nature of nonadherence, professional subjects, and placebo response suggests that these issues should be considered and addressed together. Following this approach, we describe a novel clinical trial design to minimize the adverse effects of professional subjects on trial outcomes and discuss methods to monitor adherence. PMID- 26244382 TI - The Clinical Implications of Hyperprolactinemia in Geriatric Patients Taking Antipsychotics. PMID- 26244383 TI - Natural killer cell education does not affect the magnitude of granzyme B delivery to target cells by antibody-dependent cellular cytotoxicity. AB - OBJECTIVE: Interest in the role of antibody-dependent cellular cytotoxicity (ADCC) in protection from HIV infection has grown since analyses of the RV144 HIV vaccine trial results found ADCC correlated with protection. Natural killer (NK) cells are among the effector cells that mediate ADCC. The level of antibody induced NK cell activation depends on NK cell education through inhibitory NK cell receptor human leukocyte antigen (HLA) ligand interactions. Here, we investigated the impact of NK cell education on the delivery of Granzyme B (GzB) to target cells. DESIGN: Lymphocytes from 50 HIV-uninfected [30 Bw4 (Bw4) and 20 Bw4 (Bw6)] KIR3DL1 homozygote persons were used as effectors and cocultured with gp120-coated target cells in the presence of a single source of anti-HIV gp120 antibody to ascertain whether NK cell education status influenced the level of GzB delivered to target cells. METHODS: The GTL assay assessed the frequency of GzB-positive (%GzB) CEM.NKr.CCR5 target cells generated by effectors from each individual. The frequency of CD107a, interferon (IFN)-gamma and CCL4 NK cells was assessed as a measure of antibody-induced NK cell activation. RESULTS: KIR3DL1 NK cells from the Bw4 group were more functional than KIR3DL1 NK cells. Despite this, the %GzB target cells generated in the GTL assay did not differ according to the KIR3DL1-HLA-B genotype of the effector cells. The %GzB cells positively correlated with the frequency of CD16KIR3DL1 NK cells in the effector population. CONCLUSION: ADCC potency does not depend on NK cell education. PMID- 26244384 TI - Monocytes from HIV-infected individuals show impaired cholesterol efflux and increased foam cell formation after transendothelial migration. AB - DESIGN: HIV-infected (HIV+) individuals have an increased risk of atherosclerosis and cardiovascular disease which is independent of antiretroviral therapy and traditional risk factors. Monocytes play a central role in the development of atherosclerosis, and HIV-related chronic inflammation and monocyte activation may contribute to increased atherosclerosis, but the mechanisms are unknown. METHODS: Using an in-vitro model of atherosclerotic plaque formation, we measured the transendothelial migration of purified monocytes from age-matched HIV+ and uninfected donors and examined their differentiation into foam cells. Cholesterol efflux and the expression of cholesterol metabolism genes were also assessed. RESULTS: Monocytes from HIV+ individuals showed increased foam cell formation compared with controls (18.9 vs. 0%, respectively, P = 0.004) and serum from virologically suppressed HIV+ individuals potentiated foam cell formation by monocytes from both uninfected and HIV+ donors. Plasma tumour necrosis factor (TNF) levels were increased in HIV+ vs. control donors (5.9 vs. 3.5 pg/ml, P = 0.02) and foam cell formation was inhibited by blocking antibodies to TNF receptors, suggesting a direct effect on monocyte differentiation to foam cells. Monocytes from virologically suppressed HIV+ donors showed impaired cholesterol efflux and decreased expression of key genes regulating cholesterol metabolism, including the cholesterol transporter ABCA1 (P = 0.02). CONCLUSION: Monocytes from HIV+ individuals show impaired cholesterol efflux and are primed for foam cell formation following transendothelial migration. Factors present in HIV+ serum, including elevated TNF levels, further enhance foam cell formation. The proatherogenic phenotype of monocytes persists in virologically suppressed HIV+ individuals and may contribute mechanistically to increased atherosclerosis in this population. PMID- 26244385 TI - The R263K substitution in HIV-1 subtype C is more deleterious for integrase enzymatic function and viral replication than in subtype B. AB - OBJECTIVES: Dolutegravir is an integrase strand-transfer inhibitor that has shown unprecedented robustness against the emergence of HIV drug-resistant strains in treatment-naive individuals. The R263K substitution in integrase was identified through culture selection as a resistance-associated substitution for dolutegravir and was recently detected in two treatment-experienced participants in the SAILING clinical trial, who experienced dolutegravir-based treatment failure, one of whom was infected by a subtype C virus. The objective of this study was to characterize the R263K substitution in HIV-1 subtype C integrase. DESIGN AND METHODS: We used cell-free strand transfer assays and tissue culture experiments to characterize the R263K substitution in HIV-1 subtype C integrase in comparison with subtype B. RESULTS: Cell-free biochemical assays showed that the R263K substitution diminished subtype C integrase strand-transfer activity by decreasing the affinity of integrase for target DNA. Similarly, both viral infectiousness and replication capacity were reduced by the R263K substitution in tissue culture. Decrease in enzyme activity and viral infectiousness exceeded 35 and 50%, respectively - significantly more than in HIV-1 subtype B. R263K in HIV 1 subtype C also conferred low levels of resistance against dolutegravir and high levels of cross-resistance against elvitegravir, but not raltegravir. CONCLUSIONS: The R263K substitution is more deleterious to integrase strand transfer activity and viral infectiousness in HIV-1 subtype C than in subtype B. Our results suggest that cross-resistance may prevent treatment-experienced individuals who are experiencing treatment failure with dolutegravir from being subsequently treated with elvitegravir. PMID- 26244386 TI - Resistance detected by pyrosequencing following zidovudine monotherapy for prevention of HIV-1 mother-to-child-transmission. AB - To prevent mother-to-child-transmission of HIV-1, the 2010 WHO guidelines recommended prenatal zidovudine (ZDV) monotherapy (option A). To determine if ZDV monotherapy selects for HIV resistance in antiretroviral-naive women during pregnancy, specimens from 50 individuals were examined using pyrosequencing. ZDV resistance mutations were detected at delivery in seven women (14%, 95% confidence interval 6.6-26.5%). These data raise the question whether women administered ZDV monotherapy for prevention of mother-to-child-transmission could have higher risk of virologic failure when later started on combination antiretroviral therapy, as has been demonstrated following single-dose nevirapine prophylaxis. PMID- 26244388 TI - The role of chemokine C-C motif ligand 2 genotype and cerebrospinal fluid chemokine C-C motif ligand 2 in neurocognition among HIV-infected patients. AB - OBJECTIVES: We examined interrelationships between chemokine C-C motif ligand 2 (CCL2) genotype and expression of inflammatory markers in the cerebrospinal fluid (CSF), plasma viral load, CD4 cell count and neurocognitive functioning among HIV infected adults. We hypothesized that HIV-positive carriers of the 'risk' CCL2 2578G allele, caused by a single nucleotide polymorphism (SNP) at rs1024611, would have a higher concentration of CCL2 in CSF, and that CSF CCL2 would be associated with both higher concentrations of other proinflammatory markers in CSF and worse neurocognitive functioning. DESIGN: A cross-sectional study of 145 HIV-infected individuals enrolled in the National NeuroAIDS Tissue Consortium cohort for whom genotyping, CSF and neurocognitive data were available. METHODS: Genomic DNA was extracted from peripheral blood mononuclear cells and/or frozen tissue specimens. CSF levels of CCL2, interleukin (IL)-2, IL-6, tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), soluble tumor necrosis factor receptor 2, sIL-6Ralpha, sIL-2, sCD14 and B-cell activating factor were quantified. Neurocognitive functioning was measured using a comprehensive battery of neuropsychological tests. RESULTS: Carriers of the CCL2 -2578G allele had a significantly higher concentration of CCL2 in CSF. CSF CCL2 level was positively and significantly associated with other CSF neuroinflammatory markers and worse cognitive functioning. There was a significant association between genotype and plasma viral load, such that carriers of the CCL2 -2578G allele with high viral load expressed greater levels of CCL2 and had higher neurocognitive deficit scores than other genotype/viral load groups. CONCLUSION: Individuals with the CCL2 -2578G allele had higher levels of CCL2 in CSF, which was associated with increased pro-inflammatory markers in CSF and worse neurocognitive functioning. The results highlight the potential role of intermediate phenotypes in studies of genotype and cognition. PMID- 26244387 TI - Efficacy and safety of three second-line antiretroviral regimens in HIV-infected patients in Africa. AB - OBJECTIVE: WHO recommends ritonavir-boosted protease inhibitor with two nucleoside reverse transcriptase inhibitors in HIV-infected patients failing non nucleoside reverse transcriptase inhibitor-based first-line treatment. Here, we aimed to provide more evidence for the choice of nucleoside reverse transcriptase inhibitor and boosted protease inhibitor. DESIGN: ANRS 12169 is a 48-week, randomized, open-label, non-inferiority trial in three African cities, comparing efficacy and safety of three second-line regimens. METHODS: Patients failing non nucleoside reverse transcriptase inhibitor-based antiretroviral therapy with confirmed plasma HIV-1 viral load above 1000 copies/ml were randomly assigned to tenofovir/emtricitabine + lopinavir/ritonavir (control group as per WHO recommendations), abacavir + didanosine + lopinavir/ritonavir (ABC/ddI group) or tenofovir/emtricitabine + darunavir/ritonavir (DRV group) regimens. The primary endpoint was the proportion of patients with plasma vral load below 50 copies/ml at week 48 in the modified intention-to-treat population. Non-inferiority was pre specified with a 15% margin. RESULTS: Of the 454 randomized patients, 451 were included in the analysis. Globally, 294 (65.2%) and 375 (83.2%) patients had viral load below 50 and 200 copies/ml, respectively, at week 48. The primary endpoint was achieved in 105 (69.1%) control group patients versus 92 (63.4%) in the ABC/ddI (difference 5.6%, 95% confidence interval -5.1 to 16.4) and 97 (63.0%) in the DRV (difference 6.1%, 95% confidence interval -4.5 to 16.7) groups (non-inferiority not shown). Overall, less number of patients with baseline viral load at least 100 000 copies/ml (n = 122) had a viral load below 50 copies/ml at week 48 (37.7 versus 75.4%; P < 0.001). CONCLUSIONS: The three second-line regimens obtained similar and satisfactory virologic control and confirmed the WHO recommendation (TDF/FTC/LPVr) as a valid option. However, the suboptimal response for patients with high viral load warrants research for improved strategies. PMID- 26244390 TI - Impact of hepatitis C virus coinfection on T-cell dynamics in long-term HIV suppressors under combined antiretroviral therapy. AB - OBJECTIVE: The objective of this study is to evaluate the impact of hepatitis C virus (HCV) serostatus on the evolution of CD8 cells and CD4 : CD8 ratio in HIV infected patients on combined antiretroviral therapy (cART) who achieve sustained undetectable viral load (HIV-pVL). DESIGN AND METHODS: A longitudinal study performed in an outpatient HIV-unit following 1495 HIV-infected patients. Data of patients on cART achieving undetectable HIV-pVL for at least 3 years were collected retrospectively from our medical e-database NADIS from January 1997 to April 2005, a period defined in order to select patients who were naive of hepatitis treatment. T-cell counts were assessed every 6 months from HIV suppression over the study period. RESULTS: Two hundred and twenty-six HIV mono infected (group 1) and 130 HCV-coinfected patients (group 2; genotype prevalence: 42% HCV-G1, 26% HCV-G3, 11% HCV-G4 and 21% HCV-G2) fulfilled the selection criteria. cART regimens were comparable between the groups, as were CD4 and CD8 cell counts at the first undetectable HIV-pVL. After 3 years, both groups displayed similar CD4 cell reconstitution, although CD4 percentage was higher in group 1 (30.3 +/- 1.1 vs. 27 +/- 1.1%; P < 0.001). HIV suppression led to a significant drop of median CD8 cell counts in group 1 (P = 0.027), but not in group 2, which displayed higher CD8 cell counts all through the follow-up (mean diff. = 135.71 +/- 26.89 cells/MUl, P < 0.001). Moreover, the fraction of patients reaching CD4 : CD8 ratio >= 1 was lower in group 2 (14 vs. 27.7%; P < 0.05). CONCLUSION: Despite sustained HIV suppression under cART, HCV coinfection was found to hamper CD8 downregulation. Further studies will determine the impact of treatment with direct-acting antiviral agents on the CD8 pool, and the advantage of systematic HCV-targeted therapy for HIV/HCV-coinfected patients. PMID- 26244389 TI - Clinical value of ultradeep HIV-1 genotyping and tropism testing in late presenters with advanced disease. AB - OBJECTIVE: This article aims to investigate if the detection of preexisting drug resistant minority variant (DRMV) and/or X4 HIV-1 variants could improve the efficacy of first-line combined antiretroviral therapy (ART) in late presenters. DESIGN: Post-hoc, combined analysis of two open-label, prospective, randomized clinical trials comparing first-line ART with efavirenz (EFV) vs. ritonavir boosted protease inhibitor (PI/r)-based regimens in ART-naive, HIV-1-infected patients, with CD4 T-cell counts less than 100 cells/MUl and wild-type HIV-1 by bulk sequencing. METHODS: Pre-ART samples were reanalyzed for the presence of DRMVs and X4 HIV-1 using 454 sequencing. Kaplan-Meier curves and Cox regression were used to evaluate the association between X4 HIV and DRMVs and risk of virological failure. RESULTS: From 141 evaluable patients, 57 received EFV, and 84 received PI/r, including first-line ART. Median pre-ART CD4 T-cell counts and HIV-1 RNA levels were 39 cells/MUl and 257 424 copies/ml, respectively; 35.5% of patients had X4 HIV variants. Detection of DRMVs leading to an ART-specific cumulative HIVdb score of at least 10 increased the risk of virological failure in patients initiating EFV [log-rank P = 0.048, hazard ratio = 4.3 (95% confidence interval: 0.8, 25.0), P = 0.074], but not in those starting PI/r. Presence of X4 HIV did not affect virological outcomes, but was associated with impaired CD4 T-cell count recovery over 2 years (214 vs. 315 cells/MUl with X4 vs. R5 HIV-1 tropism, respectively, P = 0.017). CONCLUSION: Accounting for preexisting DRMVs may improve the outcomes of first-line nonnucleoside reverse transcriptase inhibitor-based ART in late presenters with advanced immune suppression. Presence of X4 HIV-1 at diagnosis predicts impaired immune restoration under ART. PMID- 26244391 TI - Missed opportunities for prevention of mother-to-child transmission in the United States. AB - OBJECTIVE: To describe system failures potentially contributing to perinatal HIV transmission in the state of Georgia, United States, between 2005 and 2012. DESIGN: A retrospective chart review of antenatal and postnatal records of HIV infected infants between 1 January 2005 and 31 December 2012. METHODS: Study participants included all HIV-infected infants referred for specialized management to the Ponce Family and Youth Clinic within Grady Health Systems in Atlanta. Main outcomes included identification of maternal, perinatal, and neonatal risk factors associated with vertical transmission. RESULTS: Twenty seven cases were identified; 89% of mothers were African-American between 16 and 30 years of age. Seventy-four percent of women knew their HIV status prior to pregnancy, 44% had no prenatal care, and 52% did not receive combination antiretroviral therapy during pregnancy or intrapartum zidovudine. HIV-1 RNA near the time of delivery was available in only 10 of 27 mothers, and of those, only three had an undetectable HIV-1 RNA level. Caesarean section was performed in 70% of women. Of the 27 children, the mean gestational age was 37 (SD: 2.9) weeks, with 33% requiring neonatal ICU admission. Fifty-nine percent were men, and only 67% received postnatal zidovudine prophylaxis. CONCLUSION: Mother-to-child transmission of HIV continues to occur in Georgia at unacceptable levels. Increased education with adherence to existing national guidelines, as well as coordinated efforts between healthcare and public health providers to improve linkage and retention in medical care are urgently needed to prevent further vertical transmission events in Georgia. PMID- 26244394 TI - Disentangling the impact of within-host evolution and transmission dynamics on the tempo of HIV-1 evolution. AB - OBJECTIVE: To determine how HIV-1 risk groups impact transmitted diversity and the tempo of viral evolution at a population scale. METHODS: We investigated a set of previously described transmission chains (n = 70) using a population genetic approach, and tested whether the expected differences in proportions of multivariant transmissions are reflected by varying proportions of transmitted diversity between men having sex with men (MSM) and heterosexual (HET) subpopulations - the largest contributors to HIV spread. To assess evolutionary rate differences among the different risk groups, we compiled risk group datasets for subtypes A1, B and CRF01_AE, and directly compared the absolute substitution rate and its synonymous and non-synonymous components. RESULTS: There was sufficient demographic signal to inform the transmission model in Bayesian evolutionary analysis by sampling trees using env data to compare the transmission bottleneck size between the MSM and HET risk groups. We found no indications for a different proportion of transmitted genetic diversity at the population level between these groups. In the direct rate comparisons between the risk groups, however, we consistently recovered a higher evolutionary rate in the male-dominated risk group compared to the HET datasets. CONCLUSION: We find that the risk group composition affects the viral evolutionary rate and therefore potentially also the adaptation rate. In particular, risk group-specific sex ratios, and the variation in within-host evolutionary rates between men and women, impose evolutionary rate differences at the epidemic level, but we cannot exclude a role of varying transmission rates. PMID- 26244395 TI - Cascade of HIV care and population viral suppression in a high-burden region of Kenya. AB - INTRODUCTION: Direct measurement of antiretroviral treatment (ART) program indicators essential for evidence-based planning and evaluation - especially HIV incidence, population viral load, and ART eligibility - is rare in sub-Saharan Africa. DESIGN/METHODS: To measure key indicators in rural western Kenya, an area with high HIV burden, we conducted a population survey in September to November 2012 via multistage cluster sampling, recruiting everyone aged 15-59 years living in 3330 randomly selected households. Consenting individuals were interviewed and tested for HIV at home. Participants testing positive were assessed for CD4 cell count and viral load, and their infections classified as either recent or long term based on Limiting Antigen Avidity assays. HIV-negative participants were tested by nucleic acid amplification to detect acute infections. RESULTS: Of 6833 household members eligible for the study, 6076 (94.7% of all women and 81.0% of men) agreed to participate. HIV prevalence and incidence were 24.1% [95% confidence interval [CI] 23.0-25.2] and 1.9 new cases/100 person-years (95% CI 1.1-2.7), respectively. Among HIV-positive participants, 59.4% (95% CI 56.8-61.9) were previously diagnosed, 53.1% (95% CI 50.5-55.7) were receiving care, and 39.7% (95% CI 37.1-42.4) had viral load less than 1000 copies/ml. Applying 2013 WHO recommendations for ART initiation increased the proportion of ART-eligible people from 60.0% (based on national guidelines in place during the survey; 95% CI 57.3-62.7) to 82.0% (95% CI 79.5-84.5). Among HIV-positive people not receiving ART, viral load increased with decreasing CD4 cell count (500-749 vs. >=750 cells/MUl, adjusted mean difference, 0.40 log10 copies/ml, 95% CI 0.20 0.60, P < 0.01). CONCLUSION: This study demonstrates how population-level data can help optimize HIV programs. Based on these results, new regional programs are prioritizing diagnosis and expanding ART eligibility, key steps to reach undetectable viral load. PMID- 26244392 TI - Determinants of durability of first-line antiretroviral therapy regimen and time from first-line failure to second-line antiretroviral therapy initiation. AB - BACKGROUND: We described reasons for switching to second-line antiretroviral treatment (ART) and time to switch in HIV-infected children failing first-line ART in West Africa. METHODS: We included all children aged 15 years or less, starting ART (at least three drugs) in the paediatric IeDEA clinical centres in five West-African countries. We estimated the incidence of switch (at least one a drug class change) within 24 months of ART and associated factors were identified in a multinomial logistic regression. Among children with clinical-immunological failure, we estimated the 24-month probability of switching to a second-line and associated factors, using competing risks. Children who switched to second-line ART following the withdrawal of nelfinavir in 2007 were excluded. RESULTS: Overall, 2820 children initiated ART at a median age of 5 years; 144 (5%) were on nelfinavir. At 24-month post-ART initiation, 188 (7%) had switched to second line. The most frequent reasons were drug stock outs (20%), toxicity (18%), treatment failure (16%) and poor adherence (8%). Over the 24-month follow-up period, 322 (12%) children failed first-line ART after a median time of 7 months. Of these children, 21 (7%) switched to second-line after a median time of 21 weeks in failure. This was associated with older age [subdistribution hazard ratio (sHR) 1.21, 95% confidence interval (95% CI) 1.10-1.33] and longer time on ART (sHR 1.16, 95% CI 1.07-1.25). CONCLUSION: Switches for clinical failure were rare and switches after an immunological failure were insufficient. These gaps reveal that it is crucial to advocate for both sustainable access to first-line and alternative regimens to provide adequate roll-out of paediatric ART programmes. PMID- 26244397 TI - Can we avoid treatment interruption studies in the search for an HIV cure? PMID- 26244398 TI - Tenofovir disoproxil treatment for a HIV-hepatitis B virus coinfected patient undergoing peritoneal dialysis: which dose do we need? PMID- 26244396 TI - Evaluation of postpartum HIV superinfection and mother-to-child transmission. AB - OBJECTIVE: This study examined HIV superinfection in HIV-infected women postpartum, and its association with mother-to-child transmission (MTCT). DESIGN: Plasma samples were obtained from HIV-infected women who transmitted HIV to their infants after 6 weeks of age (transmitters, n = 91) and HIV-infected women who did not transmit HIV to their infants (nontransmitters, n = 91). These women were originally enrolled in a randomized trial for prevention of MTCT of HIV in Malawi (Post-Exposure Prophylaxis of Infants trial in Malawi). METHODS: Two HIV genomic regions (p24 and gp41) were analyzed by next-generation sequencing for HIV superinfection. HIV superinfection was established if the follow-up sample contained a new, phylogenetically distinct viral population. HIV superinfection and transmission risk were examined by multiple logistic regression, adjusted for Post-Exposure Prophylaxis of Infants study arm, baseline viral load, baseline CD4 cell count, time to resumption of sex, and breastfeeding duration. RESULTS: Transmitters had lower baseline CD4 cell counts (P = 0.001) and higher viral loads (P < 0.0001) compared with nontransmitters. There were five cases of superinfection among transmitters (rate of superinfection = 4.7/100 person-years) compared with five cases among the nontransmitters (rate of superinfection = 4.4/100 person-years; P = 0.78). HIV superinfection was not associated with increased risk of postnatal MTCT of HIV after controlling for maternal age, baseline viral load, and CD4 cell count (adjusted odds ratio = 2.32, P = 0.30). Longer breastfeeding duration was independently associated with a lower risk of HIV superinfection after controlling for study arm and baseline viral load (P = 0.05). CONCLUSION: There was a significant level of HIV superinfection in women postpartum, but this was not associated with an increased risk of MTCT via breastfeeding. PMID- 26244399 TI - Transmission of a multidrug-resistant HIV-1 from an occupational exposure, in Sao Paulo, Brazil. PMID- 26244400 TI - VOICE reveals the need to improve adherence in PrEP trials. PMID- 26244401 TI - The Effect of Functional Hearing and Hearing Aid Usage on Verbal Reasoning in a Large Community-Dwelling Population. AB - OBJECTIVES: Verbal reasoning performance is an indicator of the ability to think constructively in everyday life and relies on both crystallized and fluid intelligence. This study aimed to determine the effect of functional hearing on verbal reasoning when controlling for age, gender, and education. In addition, the study investigated whether hearing aid usage mitigated the effect and examined different routes from hearing to verbal reasoning. DESIGN: Cross sectional data on 40- to 70-year-old community-dwelling participants from the UK Biobank resource were accessed. Data consisted of behavioral and subjective measures of functional hearing, assessments of numerical and linguistic verbal reasoning, measures of executive function, and demographic and lifestyle information. Data on 119,093 participants who had completed hearing and verbal reasoning tests were submitted to multiple regression analyses, and data on 61,688 of these participants, who had completed additional cognitive tests and provided relevant lifestyle information, were submitted to structural equation modeling. RESULTS: Poorer performance on the behavioral measure of functional hearing was significantly associated with poorer verbal reasoning in both the numerical and linguistic domains (p < 0.001). There was no association between the subjective measure of functional hearing and verbal reasoning. Functional hearing significantly interacted with education (p < 0.002), showing a trend for functional hearing to have a greater impact on verbal reasoning among those with a higher level of formal education. Among those with poor hearing, hearing aid usage had a significant positive, but not necessarily causal, effect on both numerical and linguistic verbal reasoning (p < 0.005). The estimated effect of hearing aid usage was less than the effect of poor functional hearing. Structural equation modeling analyses confirmed that controlling for education reduced the effect of functional hearing on verbal reasoning and showed that controlling for executive function eliminated the effect. However, when computer usage was controlled for, the eliminating effect of executive function was weakened. CONCLUSIONS: Poor functional hearing was associated with poor verbal reasoning in a 40- to 70-year-old community-dwelling population after controlling for age, gender, and education. The effect of functional hearing on verbal reasoning was significantly reduced among hearing aid users and completely overcome by good executive function skills, which may be enhanced by playing computer games. PMID- 26244402 TI - Quality and Safety in Health Care, Part II: Three Early Reports on Quality. AB - The 1990 Institute of Medicine report Medicare: A Strategy for Quality Assurance offered a definition of quality in health care and recommendations on how to achieve it. The forces for change would include different activities by the federal government, informed consumers, professionalism, and private initiatives. Eight years later, the National Roundtable report Statement on Quality of Care indicated that there were major problems of underuse, overuse, and misuse of health care services. In the same year, the President's Advisory Commission report Quality First: Better Health Care for All Americans discussed major problems with health care and proposed many initiatives to correct them, and also recommended a Bill of Rights and Responsibilities for the patients. PMID- 26244393 TI - Has the employment status of people living with HIV changed since the early 2000s? AB - OBJECTIVES: In a context marked by major changes in the field of HIV and in the general socioeconomic context, this study aimed at investigating changes in the employment situation of people living with HIV (PLWHIV) in France since the early 2000s. DESIGN: Repeated cross-sectional survey among two nationally representative samples of PLWHIV followed at hospital in France in 2003 (N = 2932) and 2011 (N = 3022). METHODS: Differences between 2003 and 2011 in (1) rates of employment, unemployment, and inactivity and (2) rates of work cessation and access to work following HIV diagnosis were measured using two-step multivariate Poisson regression models adjusted for individual sociodemographic determinants of position on the labor market, and then additionally for health status characteristics. RESULTS: Overall, among working-age PLWHIV 60.9% in 2003 and 59.6% in 2011 were employed; 12.6 and 15.8%, respectively, were unemployed; and 26.5 and 24.6%, respectively, were inactive. Adjusting for sociodemographic determinants of position on the labor market, while employment rate was not different in 2011 compared with 2003, inactivity rate significantly decreased (adjusted prevalence rate ratio: 0.83, 95% confidence interval: [0.72-0.96]) and unemployment rate significantly increased (1.28 [1.04-1.57]). After additional adjustment for health status characteristics, the difference was no longer significant for inactivity (0.89 [0.77-1.03]) but remained significant for unemployment (1.55 [1.24-1.93]). Compared with 2003, in 2011 transitions to unemployment following HIV diagnosis tended to be more frequent (1.58 [0.92 2.68]) and access to work was significantly less frequent (0.57 [0.33-0.99]). CONCLUSION: Improvements in HIV care have not translated into improvements in PLWHIV's situation regarding employment. PMID- 26244403 TI - Range of Motion in Segmental Versus Nonsegmental Ultrahigh Molecular Weight Polyethylene Sublaminar Wire Growth Guidance Type Constructs for Early-Onset Scoliosis Correction. AB - STUDY DESIGN: An in vitro biomechanical study in porcine thoracic spine segments comparing range of motion (ROM) in segmental versus multiple nonsegmental ultrahigh molecular weight polyethylene (UHMWPE) sublaminar wire constructs. OBJECTIVE: To determine the effect of varying instrumentation (wire) density in an UHMWPE sublaminar wire construct for patients with early-onset scoliosis (EOS) to find an optimal wire density, which allows maximum growth whereas still providing adequate correction and fixation. SUMMARY OF BACKGROUND DATA: UHMWPE sublaminar wires in a segmental construct did not negatively affect longitudinal spinal growth during a 24-week period in an ovine model; application in growth guidance system for EOS may therefore be feasible. To avoid ectopic bone formation as much as possible, a reduction of instrumented levels, without affecting spinal stabilization, is desirable. METHODS: ROM of 9 porcine thoracic spines (T6-T14) was determined in flexion/extension (FE), lateral bending (LB), and axial rotation up to +/- 4 Nm. Tests were performed for the uninstrumented spine in a segmental construct with UHMWPE sublaminar wires and dual pedicle screws at the most caudal level, and in four nonsegmental constructs that were attained by stepwise removal of the most caudal wire. RESULTS: Segmental instrumentation led to a decrease in total ROM by approximately 70% for both FE and LB. A stepwise increase in ROM with decreasing number of consecutively instrumented levels was most clearly observed in LB. However, consistent significant but also relevant substantial differences in ROM for both FE and LB were noted only when comparing two and one consecutively instrumented end levels (P < 0.05). CONCLUSION: A construct with two consecutive end levels instrumented with UHMWPE sublaminar wires seems to provide the best balance between spinal stabilization and minimizing the number of instrumented levels and thereby surgical exposure, which is crucial for allowing longitudinal growth. LEVEL OF EVIDENCE: N/A. PMID- 26244405 TI - Pedicle Morphometry of Lumbar Vertebrae: Male, Taller, and Heavier Specimens Have Bigger Pedicles. AB - STUDY DESIGN: An anatomic study of pedicle dimensions was performed for lumbar vertebrae from American subjects. OBJECTIVE: To quantify the dimensions of the lumbar pedicles and to better define the demographic factors that could ultimately govern the caliber selection of pedicle screws. SUMMARY OF BACKGROUND DATA: Transpedicular screw fixation allows for segmental instrumentation into multiple vertebrae across multilevel fusion area, offering considerable biomechanical advantage over the conventional hook and lateral mass fixation. Large variations in morphology from previous studies may be related to differences in demographics, sample size, and methodology. METHODS: For this study, L1-L5 vertebrae from 503 American human cadavers were directly measured with a digital caliper. Examiner measured each vertebra to determine medial lateral pedicle width (PW) and cranial-caudal pedicle height (PH). Demographic information regarding age, sex, and race, as well as body height and weight, was available for all 503 subjects. RESULTS: PH decreased in size caudally down the lumbar spine, but PW increased in size. The largest PH was at the L1 level with a mean of 15.75 mm. The widest PW was at the L5 level with a mean of 18.33 mm. Males have larger pedicles than females for all lumbar levels. The tallest and heaviest groups generally had larger pedicles than the shorter and lighter groups, respectively. Age and race did not consistently affect pedicle dimension in a statistically significant manner. CONCLUSION: Our large-scale study of American specimens characterized the relationship between pedicle dimensions and a variety of demographic factors such as age, sex, body height, and weight. With substantial statistical power, the current study showed that male, taller, and heavier individuals had larger lumbar pedicles. LEVEL OF EVIDENCE: 3. PMID- 26244404 TI - A Nondestructive Method to Distinguish the Internal Constituent Architecture of the Intervertebral Discs Using 9.4 Tesla Magnetic Resonance Imaging. AB - STUDY DESIGN: An in vitro study of the intervertebral disc (IVD) structure using 9.4T magnetic resonance imaging (MRI). OBJECTIVE: Investigate the potential of ultrahigh-field strength MRI for higher quality 3-dimensional (3D) volumetric MRI datasets of the IVD to better distinguish structural details. SUMMARY OF BACKGROUND DATA: MRI has the advantages of being nondestructive and 3D in comparison to most techniques used to obtain the structural details of biological tissues, however, its poor image quality at higher resolution is a limiting factor. Ultrahigh-field MRI could improve the imaging of biological tissues but the current understanding of its application for spinal tissue is limited. METHODS: 2 ovine spinal segments (C7-T1, T2-T3) containing the IVD were separately imaged using 2 sequences; 3D spin echo (multislice-multiecho) pulse sequence for the C7-T1 sample and 3D gradient echo (fast-low-angle-shot) pulse sequence for the T2-T3 sample. The C7-T1 sample was subsequently decalcified and imaged again using the same scanning parameters. Histological sections obtained from the decalcified sample were stained followed by digital scanning. Observations from corresponding MRI slices and histological sections were compared as a method of confirmation of morphology captured under MRI. The signal to-noise ratio (SNR), contrast-to-noise ratio (CNR) and relative-contrast values were calculated for quantitative evaluation of image quality. RESULTS: Measurements from histology sections and corresponding MRI slices matched well. Both sequences revealed finer details of the IVD structure. Under the spin echo sequence, the annulus lamellae architecture was distinguishable and the SNR and CNR values were higher. The relative contrast was considerably higher between high (nucleus) and low (bone) signal constituents, but between the nucleus and the annulus the relative contrast was low. Under the gradient echo sequence, although the relative contrasts between constituents were poor, the fiber orientation was clearly manifested. CONCLUSION: The obtained positive results demonstrate the potential of ultrahigh-field strength MRI to nondestructively capture the IVD structure. LEVEL OF EVIDENCE: N/A. PMID- 26244406 TI - Anomalous Cervical Spinous Process Leading to Myelopathy. AB - STUDY DESIGN: A case report and literature review. OBJECTIVE: To present a rare case of anomalous spinous process of sixth cervical vertebra invaginating within the spinal canal, causing myelopathy and being successfully managed with surgical excision. SUMMARY OF BACKGROUND DATA: Though anomalous development of posterior arch of atlas and axis have been documented to cause impingement on spinal cord, there has been no documented literature on impingement of anomalous free-floating spinous process of subaxial spine causing compressive myelopathy. METHODS: A 42 year old female patient presenting with features of cervical myelopathy was investigated and found to have anomalous free-floating spinous process of sixth cervical vertebra impinging onto the cord. RESULTS: Patient underwent surgical excision of the anomalous bone and had a satisfactory clinical outcome. CONCLUSION: Though hitherto unreported, this rare anomaly of anomalous spinous process needs to be borne in mind while evaluating a relatively young patient with myelopathy. Surgical excision of the free-floating anomalous spinous process yields satisfactory outcome. PMID- 26244407 TI - To the Editor. PMID- 26244408 TI - Life Satisfaction, Self-Esteem, and Loneliness Among LGB Adults and Heterosexual Adults in China. AB - Low levels of life satisfaction have been linked to low self-esteem and loneliness, but this association has never been tested directly in LGB (lesbian/gay/bisexual) populations. We compared 275 Chinese LGB adults to 275 demographic-matched Chinese heterosexual controls on life satisfaction, self esteem, and loneliness. LGB adults reported lower levels of self-esteem and higher levels of loneliness than heterosexuals, but similar levels of overall life satisfaction. Self-esteem partially mediated (but did not moderate) the relationship between loneliness and life satisfaction in both groups. Hierarchical regressions indicated that demographic variables, loneliness, and self-esteem can predict life satisfaction in both LGB and heterosexual adults, but explained more variance of life satisfaction in the LGB group. Thus self esteem and loneliness play a more important role in life satisfaction for LGB rather than heterosexual Chinese adults. PMID- 26244410 TI - Correction: Total synthesis of two potent anti-inflammatory macrolactones of the oxacyclododecindione type. PMID- 26244409 TI - Protective Polymer Coatings for High-Throughput, High-Purity Cellular Isolation. AB - Cell-based therapies are emerging as the next frontier of medicine, offering a plausible path forward in the treatment of many devastating diseases. Critically, current methods for antigen positive cell sorting lack a high throughput method for delivering ultrahigh purity populations, prohibiting the application of some cell-based therapies to widespread diseases. Here we show the first use of targeted, protective polymer coatings on cells for the high speed enrichment of cells. Individual, antigen-positive cells are coated with a biocompatible hydrogel which protects the cells from a surfactant solution, while uncoated cells are immediately lysed. After lysis, the polymer coating is removed through orthogonal photochemistry, and the isolate has >50% yield of viable cells and these cells proliferate at rates comparable to control cells. Minority cell populations are enriched from erythrocyte-depleted blood to >99% purity, whereas the entire batch process requires 1 h and <$2000 in equipment. Batch scale-up is only contingent on irradiation area for the coating photopolymerization, as surfactant-based lysis can be easily achieved on any scale. PMID- 26244411 TI - Impact of Peroderma cylindricum (Copepoda: Pennellidae) Infection on Fatty Acid Composition and Lipid Quality of Sardine (Sardina pilchardus). AB - The parasite Peroderma cylindricum uses its host Sardina pilchardus to meet its own needs. The parasite can have many harmful effects on its host. The present study aims at investigating the impact of the parasite on the composition of fatty acids and the quality of the lipids of the sardine. Peroderma cylindricum reduces the total lipid content of its host by about 25% and decreases the content of saturated fatty acid and polyunsaturated acid. However, it increases the amount of monounsaturated fatty acids. The parasite induced a selective diversion of some fatty acids, which are dominated by the docosahexaenoic acid. Consequently, lower n-3 fatty acid content and omega-3/omega-6 ratio were recorded in parasitized sardines. Furthermore, both atherogenic and thrombogenic indices were found to be higher than those of unparasitized specimens. Nevertheless, these alterations do not lead to an important reduction of the nutritional value of the fish. PMID- 26244412 TI - Primary Medical Treatment of Thyrotropin-Secreting Pituitary Adenomas by First Generation Somatostatin Analogs: A Case Study of Seven Patients. AB - BACKGROUND: The first-choice treatment of thyrotropin (TSH)-secreting pituitary adenomas is surgical adenomectomy, with 40-60% of patients cured after surgery. The presence of somatostatin receptors on the adenomatous cells suggests that first-generation somatostatin analogs (octreotide, lanreotide) could be used as an adjuvant treatment to surgery for TSH-secreting pituitary adenomas. The aim of this study is to describe the efficacy and safety of primary medical treatment with first-generation somatostatin analogs in patients with a TSH-secreting pituitary adenoma. METHODS: Retrospective study on 7 patients (5 women, 2 men) aged 57+/-14 years with pure TSH (n=4) or mixed TSH/GH (n=3) secreting pituitary adenomas primarily treated with first generation somatostatin analogs. Magnetic resonance imaging revealed a microadenoma in 3 patients and a macroadenoma in 4 patients. The follow-up period was 8.5+/-7.3 years. RESULTS: At initial diagnosis, the patients presented with thyrotoxicosis with elevated free thyroxine (26.5+/-6.5 pg/mL) and free triiodothyronine (7.3+/-0.9 pg/mL) levels and a mean TSH of 4.3+/-1.4 mU/L. During somatostatin analog treatment, free thyroid hormones and TSH levels normalized after 4.4+/-3.9 and 7.0+/-8.4 months, respectively. At the time of the last visit, 6 patients were biochemically controlled. Adenoma volume decreased in 6 patients and a decrease in adenoma volume persisted in 2 patients several years after initiation of somatostatin analog treatment. Safety of treatment was good and no patients discontinued somatostatin analogs due to side effects. CONCLUSION: This study confirms the efficacy of primary medical treatment with first-generation somatostatin analogs in terms of hormonal control and tumor volume reduction in patients with TSH secreting pituitary adenomas, and its good safety profile. First-generation somatostatin analogs may serve as a medical alternative to surgical treatment, especially in patients where surgery is contraindicated or in subjects presenting with invasive macroadenomas that render complete surgical resection difficult. PMID- 26244415 TI - Correction to: Thyroid 2015;25(3):292-299. PMID- 26244413 TI - Prevalence, Phenotype, and Psychosocial Well-Being in Euthyroid/Hypothyroid Thyroid-Associated Orbitopathy. AB - BACKGROUND: At the onset of thyroid-associated orbitopathy (TAO), most patients are hyperthyroid, while scarce data are available on euthyroid/hypothyroid TAO. The aim of this study was to assess the prevalence, phenotype, and psychosocial burden of patients with initially euthyroid/hypothyroid TAO. METHODS: The medical records of 461 consecutive and unselected patients with TAO followed at a specialized joint thyroid-eye clinic were analyzed within this retrospective cross-sectional study. Main outcome measures were the prevalence of initially eu- or hypothyroid TAO as well as ophthalmic signs and symptoms, disease-specific quality of life (QoL), work impairment, and rate of psychotherapy in initially eu /hypothyroid versus hyperthyroid TAO. RESULTS: The prevalences of eu-/hypothyroid and hyperthyroid TAO were 4.3% (n=20; [confidence interval, CI, 2.6-6.3]) and 95.7% (n=441; [9.37-9.74]), respectively. In 12 patients (2.6% [CI 1.3-4.3]), Hashimoto's thyroiditis was present and in 8 (1.7% [CI 0.7-3.0]) no thyroid disease was noted at the time of inclusion. One (0.05%) patient with eu /hypothyroid TAO and 172 (39%) with hyperthyroid TAO had clinically active TAO (p=0.001). In eu-/hypothyroid versus hyperthyroid patients, 14 (70%) versus 135 (30.6%) had a mild TAO, 6 (30%) versus 183 (64.2%) a moderate-to-severe TAO, and 0 versus 23 (5.4%) had a sight-threatening TAO (p<0.001). TAO was asymmetric in 4 (20%) eu-/hypothyroid and in 27 (6.1%) hyperthyroid patients (p=0.038). Only 5.3% versus 30.2% and 10.5% versus 44.1% of patients with eu-/hypothyroid and hyperthyroid TAO, respectively, were on sick leave (p=0.003) or work disabled (p=0.018). QoL was less impaired in eu-/hypothyroid versus hyperthyroid TAO (median visual functioning and appearance scores: 100 versus 75; p<0.001 and 81.25 versus 75; p=0.315). Of patients with eu-/hypothyroid and hyperthyroid TAO, 15% and 20.2% had psychotherapy respectively (p=0.409). Eu-/hypothyroid TAO was positively (odds ratio 7.05, p=0.060) and negatively (odds ratio: 0.09, p=0.026) associated with a unilateral involvement and thyrotropin-receptor autoantibodies respectively. CONCLUSIONS: Compared with hyperthyroid TAO, QoL and working ability are less impaired in eu-/hypothyroid TAO with an often asymmetric and less severe clinical phenotype. PMID- 26244416 TI - A Dynamic Programming Algorithm for Finding the Optimal Placement of a Secondary Structure Topology in Cryo-EM Data. AB - The determination of secondary structure topology is a critical step in deriving the atomic structures from the protein density maps obtained from electron cryomicroscopy technique. This step often relies on matching the secondary structure traces detected from the protein density map to the secondary structure sequence segments predicted from the amino acid sequence. Due to inaccuracies in both sources of information, a pool of possible secondary structure positions needs to be sampled. One way to approach the problem is to first derive a small number of possible topologies using existing matching algorithms, and then find the optimal placement for each possible topology. We present a dynamic programming method of Theta(Nq(2)h) to find the optimal placement for a secondary structure topology. We show that our algorithm requires significantly less computational time than the brute force method that is in the order of Theta(q(N) h). PMID- 26244417 TI - Cognitive Behavioral Therapy as an Adjunct Treatment to Light Therapy for Delayed Sleep Phase Disorder in Young Adults: A Randomized Controlled Feasibility Study. AB - Delayed sleep phase disorder (DSPD) is common among young people, but there is still no evidence-based treatment available. In the present study, the feasibility of cognitive behavioral therapy (CBT) was evaluated as an additive treatment to light therapy (LT) in DSPD. A randomized controlled trial with participants aged 16 to 26 years received LT for two weeks followed by either four weeks of CBT or no treatment (NT). LT advanced sleep-wake rhythm in both groups. Comparing LT+CBT with LT+NT, no significant group differences were observed in the primary endpoints. Although anxiety and depression scores were low at pretreatment, they decreased significantly more in LT+CBT compared to LT+NT. The results are discussed and some suggestions are given for further studies. PMID- 26244418 TI - What can we learn from the ongoing challenge to implement routine outcome measures? AB - Routine outcomes measurement is important for clinical care, quality improvement, and performance management. The nine papers in this special volume describe national and regional efforts at implementation of outcomes measures in nine different countries. They describe successes and challenges. This special collection of papers makes an important contribution towards improving the implementation of routine outcomes measurement globally. PMID- 26244419 TI - Effector T Cells and Ischemia-Induced Systemic Angiogenesis in the Lung. AB - Lymphocytes have been shown to modulate angiogenesis. Our previous work showed that T regulatory (Treg) cell depletion prevented angiogenesis. In the present study, we sought to examine T-cell populations during lung angiogenesis and subsequent angiostasis. In a mouse model of ischemia-induced systemic angiogenesis in the lung, we examined the time course (0-35 d) of neovascularization and T-cell phenotypes within the lung after left pulmonary artery ligation (LPAL). T cells increased and reached a maximum by 10 days after LPAL and then progressively decreased, suggestive of a modulatory role during the early phase of new vessel growth. Because others have shown IFN-gamma to be angiostatic in tumor models, we focused on this effector T-cell cytokine to control the magnitude of angiogenesis. Results showed that IFN-gamma protein is secreted at low levels after LPAL and that mice required Treg depletion to see the full effect of effector T cells. Using Foxp3(DTR) and diphtheria toxin to deplete T regulatory cells, increased numbers of effector T cells (CD8(+)) and/or increased capacity to secrete the prominent angiostatic cytokine IFN-gamma (CD4(+)) were seen. In vitro culture of mouse systemic and pulmonary microvascular endothelial cells with IFN-gamma showed increased endothelial cell apoptosis. CD8(-/-) mice and IFN-gammaR(-/-) mice showed enhanced angiogenesis compared with wild-type mice, confirming that, in this model, IFN-gamma limits the extent of systemic neovascularization in the lung. PMID- 26244422 TI - Basic research in otolaryngology. PMID- 26244421 TI - Evaluation of predictive CYP2C19 genotyping assays relative to measured phenotype in a South African cohort. AB - AIM: To align predicted and measured CYP2C19 phenotype in a South African cohort. MATERIALS & METHODS: Genotyping of CYP2C19*2, *3, *9, *15, *17, *27 and *28 was performed using PCR-RFLP, and an activity score (AS) system was used to predict phenotype. True phenotype was measured using plasma concentrations of omeprazole and its metabolite 5'-hydroxyomperazole. RESULTS: Partial genotype-phenotype discrepancies were reported, and an adapted AS system was developed, which showed a marked improvement in phenotype prediction. Results highlight the need for a more comprehensive CYP2C19 genotyping approach to improve prediction of omeprazole metabolism. CONCLUSION: Evidence for the utility of a CYP2C19 AS system is provided, for which the accuracy can be further improved by means of comprehensive genotyping and substrate-specific modification. PMID- 26244423 TI - An interventional airway delivery service for congenital high airway obstruction. AB - BACKGROUND: Congenital airway obstruction is rare but potentially fatal. We developed a complex airways interventional delivery team to manage such cases. Antenatal imaging detects airway compromise at an early stage and facilitates the planning of delivery procedures ('ex utero intrapartum treatment' and 'operation on placental support') which maintain feto-placental circulation whilst an airway is secured. METHOD: A retrospective review was performed of cases in which ENT input was required at birth for airway obstruction. RESULTS: Four neonates were delivered before implementation of the service: two were intubated and another two underwent tracheostomy but died in the peri-natal period. Seven neonates were delivered after implementation of the service: six were intubated and one underwent immediate tracheostomy. Five subsequently underwent tracheostomy (three have since been decannulated). One child with multiple congenital anomalies died due to respiratory failure. Airway obstruction was caused by lymphatic malformation, teratoma, costo-craniomandibular syndrome and choristoma. CONCLUSION: In the absence of other anomalies, interventional airway delivery led to reduced mortality and improved outcomes. PMID- 26244424 TI - Spontaneous resolution of cerebrospinal fluid otorrhoea in a patient with a Hyrtl's fissure. AB - OBJECTIVE: This paper reports a rare case of cerebrospinal fluid leak due to a Hyrtl's fissure and discusses the non-operative management of the case. Background and case report: Cerebrospinal fluid otorrhoea is a rare phenomenon arising from an abnormal communicating tract between the subarachnoid space and middle ear. Affected patients are at a higher risk of developing meningitis and other neuro-otological complications. There are four common congenital causes of cerebrospinal fluid otorrhoea in the region of a normal labyrinth. This paper describes a case of cerebrospinal fluid in the middle ear resulting from a Hyrtl's fissure, which resolved spontaneously. CONCLUSION: A literature search indicated this to be the first case with such a resolution without the need for any intervention. PMID- 26244425 TI - Corrigendum: Effects of weight loss via high fat vs. low fat alternate day fasting diets on free fatty acid profiles. PMID- 26244426 TI - Increased Quantum Dot Loading by pH Control Reduces Interfacial Recombination in Quantum-Dot-Sensitized Solar Cells. AB - The power conversion efficiency of quantum-dot-sensitized solar cells (QDSSCs) hinges on interfacial charge transfer. Increasing quantum dot (QD) loading on the TiO2 anode has been proposed as a means to block recombination of electrons in the TiO2 to the hole transport material; however, it is not known whether a corresponding increase in QD-mediated recombination processes might lead to an overall higher rate of recombination. In this work, a 3-fold increase in PbS QD loading was achieved by the addition of an aqueous base to negatively charge the TiO2 surface during Pb cation deposition. Increased QD loading improved QDSSC device efficiencies through both increased light absorption and an overall reduction in recombination. Unexpectedly, we also found increased QD size had the detrimental effect of increasing recombination. Kinetic modeling of the effect of QD size on interfacial charge transfer processes provided qualitative agreement with the observed variation in recombination lifetimes. These results demonstrate a robust method of improving QD loading, identify the specific mechanisms by which increased QD deposition impacts device performance, and provide a framework for future efforts optimizing the device architecture of QDSSCs. PMID- 26244427 TI - Sodium-driven energy conversion for flagellar rotation of the earliest divergent hyperthermophilic bacterium. AB - Aquifex aeolicus is a hyperthermophilic, hydrogen-oxidizing and carbon-fixing bacterium that can grow at temperatures up to 95 degrees C. A. aeolicus has an almost complete set of flagellar genes that are conserved in bacteria. Here we observed that A. aeolicus has polar flagellum and can swim with a speed of 90 MUm s(-1) at 85 degrees C. We expressed the A. aeolicus mot genes (motA and motB), which encode the torque generating stator proteins of the flagellar motor, in a corresponding mot nonmotile mutant of Escherichia coli. Its motility was slightly recovered by expression of A. aeolicus MotA and chimeric MotB whose periplasmic region was replaced with that of E. coli. A point mutation in the A. aeolicus MotA cytoplasmic region remarkably enhanced the motility. Using this system in E. coli, we demonstrate that the A. aeolicus motor is driven by Na(+). As motor proteins from hyperthermophilic bacteria represent the earliest motor proteins in evolution, this study strongly suggests that ancient bacteria used Na(+) for energy coupling of the flagellar motor. The Na(+)-driven flagellar genes might have been laterally transferred from early-branched bacteria into late-branched bacteria and the interaction surfaces of the stator and rotor seem not to change in evolution. PMID- 26244428 TI - Arteriovenous Blood Metabolomics: A Readout of Intra-Tissue Metabostasis. AB - The human circulatory system consists of arterial blood that delivers nutrients to tissues, and venous blood that removes the metabolic by-products. Although it is well established that arterial blood generally has higher concentrations of glucose and oxygen relative to venous blood, a comprehensive biochemical characterization of arteriovenous differences has not yet been reported. Here we apply cutting-edge, mass spectrometry-based metabolomic technologies to provide a global characterization of metabolites that vary in concentration between the arterial and venous blood of human patients. Global profiling of paired arterial and venous plasma from 20 healthy individuals, followed up by targeted analysis made it possible to measure subtle (<2 fold), yet highly statistically significant and physiologically important differences in water soluble human plasma metabolome. While we detected changes in lactic acid, alanine, glutamine, and glutamate as expected from skeletal muscle activity, a number of unanticipated metabolites were also determined to be significantly altered including Krebs cycle intermediates, amino acids that have not been previously implicated in transport, and a few oxidized fatty acids. This study provides the most comprehensive assessment of metabolic changes in the blood during circulation to date and suggests that such profiling approach may offer new insights into organ homeostasis and organ specific pathology. PMID- 26244429 TI - Bundles of Care for Patients With Ruptured Abdominal Aortic Aneurysms: Is Endovascular Repair the Solution? PMID- 26244430 TI - Perceived Oral Health and Care of Children with Juvenile Idiopathic Arthritis: A Qualitative Study. AB - AIMS: To increase knowledge about how children diagnosed with juvenile idiopathic arthritis (JIA) perceive their oral health and dental care. METHODS: Fifteen interviews with children diagnosed with JIA, aged 6 to 16 years, were analyzed according to classical grounded theory. RESULTS: The children's main concern about their oral health was identified as creating a positive identity after being diagnosed with JIA and learning to live with oral health problems. While attempting to cope with this concern, the children often endured in silence, the core category in the analysis. A variety of aspects were found of this core coping strategy, which were categorized as differentiating from the disease, working on personal caretaking and positive attitude, fighting fears and sadness, control of professional aid, and building supportive relationships. The results emphasize the importance for caregivers to show empathy and interest in the child as a person, to ask precise questions when taking case histories so the child does not remain silent, to provide psychosocial support and suggest positive coping strategies, to describe and administer treatments, and to give hope for the future. CONCLUSION: Awareness of the social interaction between a child diagnosed with JIA and health professionals as well as awareness of how to approach a child with longstanding illness are crucial for disclosing and treating the child's orofacial symptoms. PMID- 26244431 TI - Oral Health-Related Quality of Life in Patients with Temporomandibular Disorders. AB - AIMS: To measure the oral health-related quality of life (OHRQoL) in patients with temporomandibular disorders (TMD) compared to controls and analyze its association with various demographic and clinical parameters. METHODS: The survey included 187 TMD patients and 200 controls. OHRQoL was measured using the validated Hebrew version of the Oral Health Impact Profile-14 (OHIP-14). A self report questionnaire assessed personal details, smoking habits, history of trauma and orthodontic treatment, comorbid headaches, oral habits, and pain. TMD patients were divided into diagnostic categories according to the newly recommended diagnostic criteria for TMD (DC/TMD) Axis I protocol. Differences between groups were examined with a Pearson chi-square test for categorical variables and analysis of variance (ANOVA) for continuous variables. RESULTS: Among TMD patients, the diagnostic categories included: (1) masticatory muscle disorders (MMD; n = 38; 20.32%), (2) isolated disorders of the temporomandibular joint (TMJ; n = 46; 24.59%), (3) patients with both MMD and TMJ (TMP; n = 103; 55.08%). Compared to controls, TMD patients exhibited worse global OHIP-14 scores (12.50 +/- 8.14 vs 9.58 +/- 10.00; P = .002) and worse scores in the following domains: physical pain (P < .001), psychological discomfort (P = .005), physical disability (P = .004), and psychological disability (P = .013). Among TMD patients, those categorized as TMP exhibited the highest scores in the physical pain (P = .02) domain. Previous orthodontic treatment, comorbid headache and body pain, limitations in mouth opening and lateral movement, pain, and muscle tenderness scores were found to be strongly related to the OHIP-14. CONCLUSION: TMD patients suffered from impaired OHRQoL considerably more than controls. OHRQoL in TMD patients is a multidimensional phenomenon influenced by previous orthodontic treatment, comorbid symptoms, pain, functional limitations, and muscle tenderness scores. PMID- 26244432 TI - Temporomandibular Disorders in a Young Adolescent Brazilian Population: Epidemiologic Characterization and Associated Factors. AB - AIMS: To carry out an epidemiologic characterization of the most common subtypes of temporomandibular disorders (TMD) and to identify associated factors in a Brazilian sample of young adolescents. METHODS: From a population of public schoolchildren (12 to 14 years of age), 3,117 students were randomly invited to participate in this study. TMD was assessed according to the Research Diagnostic Criteria for TMD (RDC/TMD) Axis I, in addition to some questions of the Axis II history questionnaire. The associated factors, ie, difficulty with concentration/attention, anger, sadness, anxiety, headache complaints, oral parafunctions, diurnal jaw clenching, tooth grinding at night, and parents not living together, were assessed based on the responses of the adolescents and their parents to structured questions. For the statistical analyses, descriptive statistics, chi-square tests, odds ratio, and logistic regression models were used, adopting a 95% confidence interval and 5% level of significance. RESULTS: The sample consisted of 1,307 individuals (response rate of 41.9%), 56.8% (n = 742) girls. Overall, 397 (30.4%) adolescents presented with TMD, of whom 330 (25.2%) had painful TMD diagnoses. The majority of these had painful TMD of muscular origin (13.1%) and comprised chronic cases (14.9%). Girls presented higher frequencies of TMD overall, painful TMD, painful combined TMD, and chronic painful TMD diagnoses The final multivariate logistic regression model revealed that headache complaints (odds ratio 2.87; confidence intervals 2.21-3.72), oral parafunctions (2.08; 1.26-3.44), tooth grinding at night (2.05; 1.56-2.70), diurnal jaw clenching (1.96; 1.50-2.55), and parents not living together (1.38; 1.07-1.80) were the factors significantly associated with a TMD (overall) diagnosis. CONCLUSION: About 25% of the adolescents evaluated presented painful TMD, and the majority of these comprised muscular and chronic cases. Some factors, such as reports of headache complaints, oral parafunctions, tooth grinding at night, and parents not living together, were associated with this condition among young Brazilian adolescents. Special attention should be given to these factors among adolescents with TMD. PMID- 26244433 TI - Sense of Coherence and Toothache of Adolescents from Southern Brazil. AB - AIMS: To investigate the association in adolescents between toothache and sense of coherence (SOC), a psychosocial construct defined as a global orientation to life. METHODS: A school-based cross-sectional study was carried out in 36 municipalities comprising up to 50,000 residents in southern Brazil. The target population was adolescents from 15 to 19 years of age. The sample consisted of 1,150 adolescents chosen by systematic sampling; the final adjusted analysis by Poisson regression included 1,065 individuals. Data were collected using a questionnaire, SOC scale, and the Decayed Missing Filled Teeth (DMFT) index. RESULTS: Of the adolescents in the sample, 29.8% reported experiencing toothache in the previous 6 months. The prevalence of dental caries was 31.0%, and the DMFT index was 3.22. SOC was a significant protective factor for toothache; the prevalence ratio was 0.65 (95% confidence interval [CI] = 0.55-0.75). Girls presented 39% more toothaches than boys (95% CI = 1.15-1.68). Individuals who saw the dentist for reasons other than reviews or check-ups had a toothache prevalence that was 85% higher than their counterparts (95% CI = 1.47-2.34). Adolescents with tooth decay reported up to two times more toothache than those without tooth decay. CONCLUSION: The results of this study showed that a strong SOC protected against toothache. A health-promotion approach may lead to better patterns of oral health. PMID- 26244434 TI - Spatial and Temporal Effects of Capsaicin and Menthol on Intraoral Somatosensory Sensitivity. AB - AIMS: To assess the spatial and temporal sensory effects of the topical application of capsaicin and menthol on the gingiva of healthy volunteers. METHODS: Capsaicin, menthol, and saline (control) were applied topically on the gingiva in the maxillary premolar area of healthy volunteers for 15 minutes. Pain intensity was rated on a 0 to 10 visual analog scale (VAS). Before, immediately after, and 30 minutes after application, three mechanical stimuli were applied at 15 gingival sites: fixed-intensity stimuli were applied by 32 mN and 512 mN von Frey filaments, and stimuli of increasing intensity were applied by an electronic von Frey (EVF, 10 g/s). The EVF was used to test the pinprick pain threshold (PiPT). The perceived pain from filament stimulation was rated on a 0-50-100 numeric rating scale (NRS). Analysis of variance for repeated measures was used to analyze the NRS scores, PiPT values, the number of hypersensitive or hyposensitive test sites, and the coordinates of the center of gravity (COG) of somatosensory sensitivity. RESULTS: The mean +/- SEM VAS score of pain intensity produced by the application of capsaicin (4.6 +/- 0.5) was significantly higher than that produced by menthol (0.3 +/- 0.2) and saline (0.1 +/- 0.1) (P < .001). Capsaicin induced local desensitization to all stimuli (P < .047) , and at the application site, capsaicin induced significant desensitization to 512 mN stimuli (P = .003). Menthol did not induce significant somatosensory changes (P > .147), and saline induced slight desensitization in two sites surrounding the application site (P < .023). The COG coordinates did not shift significantly over time during any condition (P > .125). CONCLUSION: Capsaicin but not menthol induced mechanical desensitization in the application area but not in the surrounding areas. PMID- 26244435 TI - Validation of the Chinese Version of ID-Migraine in Medical Students and Systematic Review with Meta-Analysis Concerning Its Diagnostic Accuracy. AB - AIMS: To validate the Chinese version of Migraine Screener (ID-Migraine) in medical students in mainland China and to estimate the diagnostic accuracy of ID Migraine by means of a systematic review with meta-analysis. METHODS: A total of 555 medical university students participated in the clinical study. Of these, 190 volunteered to take part in a face-to-face consultation and 365 in a telephone interview to diagnose the presence of migraine according to the criteria of the International Classification of Headache Disorders. The correctness of the diagnosis made clinically and by telephone was assessed by Cohen's kappa statistics. Twenty-two studies were included in the meta-analysis. Sensitivity and specificity were calculated for the clinical study and the meta-analysis. RESULTS: The overall sensitivity and specificity of the Chinese version of ID Migraine was 84.0% (95% confidence intervals [CI]: 75.0%-90.0%) and 64.0% (95% CI: 59.0%-68.0%), respectively. The Cohen's kappa value of the diagnosis obtained by the face-to-face consultation and the telephone interview was 0.85 (95% CI: 0.69-1.00). A total of 8,682 participants from the 22 studies were included in the meta-analysis. The pooled sensitivity, specificity, and diagnostic odds ratio were 81.0% (95% CI: 80.0%-82.0%), 68.0% (95% CI: 66.0%-69.0%) and 17.03 (95% CI: 9.94-29.18), respectively. CONCLUSIONS: The accurate recognition of migraine by the medical students suggests that the Chinese ID-Migraine version is a valid screening tool. In addition the meta-analysis confirmed the high diagnostic accuracy of this screening tool. PMID- 26244436 TI - Association of Functional Polymorphisms in Matrix Metalloproteinase-9 and Glutathione S-Transferase T1 Genes with Temporomandibular Disorders. AB - AIMS: To investigate the potential role of polymorphisms in matrix metalloproteinase-9 (MMP-9), glutathione S-transferase M1 (GSTM1) and T1 (GSTT1), and methylenetetrahydrofolate reductase (MTHFR) genes as risk factors for development of temporomandibular disorders (TMD) in a Serbian population. METHODS: This case-control study included 282 subjects: 100 with TMD and 182 healthy controls. Genotyping was done by means of polymerase chain reaction (PCR)/restriction fragment length polymorphism (RFLP) for single nucleotide polymorphisms (SNPs) analysis (C-1562T MMP-9 and C677T MTHFR) or multiplex PCR and real-time PCR methods for deletion analysis (GSTM1, GSTT1) of DNA obtained from buccal swabs. The association of gene variants with TMD risk was determined by calculating odds ratios (OR) and their 95% confidence intervals (CI). RESULTS: A statistically significant difference in genotype and allele frequencies was found between the TMD group and controls for the MMP-9 SNP. Heterozygotes (CT) were significantly more frequent in the TMD group than in the control group and carriers of the T allele had an approximately twofold increase of TMD risk (OR = 2.13, 95% CI = 1.24-3.67, P = .005). The null GSTT1 genotype as well as the combined non-null GSTM1/ null GSTT1 were associated with lower risk of TMD (OR = 0.28, CI = 0.10-0.74, P = .004 and OR = 0.16, CI = 0.03-0.58, P < .001, respectively). GSTM1 alone and MTHFR polymorphisms did not show an association with TMD. CONCLUSION: The C-1562T SNP in the promoter region of the MMP-9 gene, the GSTT1 null, as well as the combined GSTM1 non-null and GSTT1 null genotypes are modulators of TMD risk in a Serbian population. PMID- 26244437 TI - Effect of a Novel, Orally Active Matrix Metalloproteinase-2 and -9 Inhibitor in Spinal and Trigeminal Rat Models of Neuropathic Pain. AB - AIMS: To study the effects of a novel matrix metalloproteinase-2 (MMP-2) and MMP 9 inhibitor, AQU-118, on mechanical allodynia in the spinal nerve ligation (SNL) model of neuropathic pain and the chronic constriction injury of the infraorbital nerve (CCI-IoN) model of neuropathic orofacial pain. METHODS: Five groups of SNL rats were given daily oral doses of AQU-118 (5, 10, 20 mg/kg), gabapentin (100 mg/kg), or vehicle (0.5% methylcellulose) and then paw withdrawal threshold was measured with von Frey filaments (VF). Three groups of CCI-IoN rats were given daily oral doses of either AQU-118 (40 mg/kg), gabapentin (100 mg/kg), or vehicle (0.5% methylcellulose) and then mechanical allodynia was measured with facial VF and non-reflex-based orofacial stimulation test (OFST) assay. Naive rats were also tested for the effect of AQU-118 (40 mg/kg) on basal sensitivity to mechanical stimulation/locomotive activity. RESULTS: Mechanical allodynia in SNL rats was attenuated by gabapentin (100 mg/kg) and AQU-118 (in a dose-dependent manner). Mechanical allodynia in CCI-IoN rats was also attenuated (in an equipotent manner) by both AQU-118 (40 mg/ kg) and gabapentin (100 mg/kg) as measured by both facial VF and OFST assay. Upon cessation of either AQU-118 or gabapentin, VF-related responses in both models and OFST assay times reverted to levels observed in vehicle-treated rats. No statistically significant change was observed in locomotive activity/paw withdrawal threshold by AQU-118 (40 mg/kg) in naive rats. CONCLUSION: The results demonstrated that oral AQU-118 attenuates mechanical allodynia in both neuropathic pain models and with efficacies that mirror gabapentin at the 40 mg/kg dose used in the CCI-IoN model but without effect on basal sensitivity to mechanical stimulation/locomotive activity. These findings support a possible role for MMP-2/-9 in the etiology of neuropathic pain and also suggest that inhibition strategies represent a viable treatment option. PMID- 26244438 TI - Effect of Estrogen and Food Hardness on Metabolism and Turnover of Condylar Cartilage. AB - AIMS: To clarify the effect of estrogen and food hardness on condylar cartilage and the cartilage-bone interface. METHODS: A total of 56 rats were divided into four groups: (1) ovariectomized rats fed a normal (pressed pellet) food, (2) ovariectomized rats fed a soft (powder) food, (3) control rats fed a normal (pressed pellet) food, and (4) control rats fed a soft (powder) food. Some rats (n = 29) were sacrificed at the age of 67 days and others (n = 27) at the age of 87 days, and then 5-MUm-thick sagittal paraffin sections were prepared from each temporomandibular joint (TMJ). Toluidine blue staining, in situ hybridization with type X collagen, terminal deoxynucleotidyl transferase and deoxyuridine triphosphate nick end labeling (TUNEL-assay), and tartrate-resistant acid phosphatase (TRAP) histochemistry were performed. Immunohistochemical analyses included cathepsin K, adiponectin, proliferating cell nuclear antigen (PCNA), and type X collagen staining. Analysis of variance and appropriate post-hoc tests were used in all analyses. RESULTS: Ovariectomy and normal food consistency increased the thickness of condylar cartilage (P < .001), PCNA expression (P < .001) and type X collagen expression (P < .001). Ovariectomy decreased the number (P < .05) and size of osteoclasts (P < .01). Soft food increased the number of cartilage cells stained positively against adiponectin (P < .01). CONCLUSION: Decreased estrogen level and normal food hardness increase the thickness of condylar cartilage by various mechanisms. PMID- 26244441 TI - Incorrect Information in Abstract and Table. AB - In the Original Article titled "Depression and Anxiety as Predictors of 2-Year Cardiac Events in Patients With Stable Coronary Artery Disease" published in the January 2008 issue of JAMA Psychiatry (then Archives of General Psychiatry) (2008;65[1]:62-71), incorrect unadjusted data appeared in the abstract and Table 3.The data that appeared in the abstract should have been as follows: "Of the 804 patients, 57 (7.1%)met the criteria for MDD [major depressive disorder] and 43 (5.3%) for GAD [generalized anxiety disorder] (11 [1.4%] had comorbidity);220(27.4%) had elevated BDI-II [Beck Depression Inventory II] scores (14), and 3 33(41.4%) had elevated HADS-A [Hospital Anxiety and Depression Scale] scores (8), with 21.1% overlap. Major depressive disorder (odds ratio [OR], 2.55;95%confidence interval [CI], 1.38-4.73),GAD(OR, 2.47; 95%CI, 1.23-4.97), elevated BDI-II (OR, 1.81; 95%CI, 1.20-2.73), elevated HADS-A score(OR, 1.66;95%CI, 1.12-2.47), and continuous standardized scores on the BDI-II (OR, 1.31; 95% CI, 1.05-1.62) and the HADS-A (OR, 1.43; 95% CI, 1.19-1.73) all predicted MACEs [major adverse cardiac events]." These ORs and 95% CIs should have also appeared in Table 3. Also, the covariate-adjusted ORs and 95% CIs in Table 3 should have been as follows: current MDD(OR, 2.34;95%CI, 1.18-4.63; P = .02); elevated depression symptoms (BDI-II score 14)(OR,1.63;95%CI,1.05-2.54;P = .03); continuous BDI-II score (OR, 1.19; 95%CI, 0.95-1.49; P = .14); GAD (OR, 2.46; 95% CI,1.14-5.30;P = .02); elevated anxiety symptoms(HADS-A score 8)(OR,1.54;95% CI, 1.00-2.38; P = .05); and continuous HADS-A score (OR, 1.42; 95% CI, 1.14-1.75;P = .001). This article was corrected online. PMID- 26244442 TI - Information Omitted From Analyses. AB - In the Original Article titled "Higher- Order Genetic and Environmental Structure of Prevalent Forms of Child and Adolescent Psychopathology" published in the February 2011 issue of JAMA Psychiatry (then Archives of General Psychiatry) (2011;68[2]:181-189), there were 2 errors. Although the article stated that the dimensions of psychopathology were measured using parent informants for inattention, hyperactivity-impulsivity, and oppositional defiant disorder, and a combination of parent and youth informants for conduct disorder, major depression, generalized anxiety disorder, separation anxiety disorder, social phobia, specific phobia, agoraphobia, and obsessive-compulsive disorder, all dimensional scores used in the reported analyses were actually based on parent reports of symptoms; youth reports were not used. In addition, whereas the article stated that each symptom dimension was residualized on age, sex, age squared, and age by sex, the dimensions actually were only residualized on age, sex, and age-squared. All analyses were repeated using parent informants for inattention, hyperactivity-impulsivity, and oppositional defiant disorder, and a combination of parent and youth informants for conduct disorder,major depression, generalized anxiety disorder, separation anxiety disorder, social phobia, specific phobia, agoraphobia, and obsessive-compulsive disorder; these dimensional scores were residualized on age, age-squared, sex, sex by age, and sex by age-squared. The results of the new analyses were qualitatively the same as those reported in the article, with no substantial changes in conclusions. The only notable small difference was that major depression and generalized anxiety disorder dimensions had small but significant loadings on the internalizing factor in addition to their substantial loadings on the general factor in the analyses of both genetic and non-shared covariances in the selected models in the new analyses. Corrections were made to the tables and figures to reflect these changes. This article was corrected online . PMID- 26244443 TI - Molluscum Contagiosum-Induced Erythema Annulare Centrifugum. PMID- 26244444 TI - Bioinspired Surfaces with Superwettability: New Insight on Theory, Design, and Applications. PMID- 26244445 TI - Are the Crystal Structures of Enantiopure and Racemic Mandelic Acids Determined by Kinetics or Thermodynamics? AB - Mandelic acids are prototypic chiral molecules where the sensitivity of crystallized forms (enantiopure/racemic compound/polymorphs) to both conditions and substituents provides a new insight into the factors that may allow chiral separation by crystallization. The determination of a significant number of single crystal structures allows the analysis of 13 enantiopure and 30 racemic crystal structures of 21 (F/Cl/Br/CH3/CH3O) substituted mandelic acid derivatives. There are some common phenyl packing motifs between some groups of racemic and enantiopure structures, although they show very different hydrogen bonding motifs. The computed crystal energy landscape of 3-chloromandelic acid, which has at least two enantiopure and three racemic crystal polymorphs, reveals that there are many more possible structures, some of which are predicted to be thermodynamically more favorable as well as slightly denser than the known forms. Simulations of mandelic acid dimers in isolation, water, and toluene do not differentiate between racemic and enantiopure dimers and also suggest that the phenyl ring interactions play a major role in the crystallization mechanism. The observed crystallization behavior of mandelic acids does not correspond to any simple "crystal engineering rules" as there is a range of thermodynamically feasible structures with no distinction between the enantiopure and racemic forms. Nucleation and crystallization appear to be determined by the kinetics of crystal growth with a statistical bias, but the diversity of the mandelic acid crystallization behavior demonstrates that the factors that influence the kinetics of crystal nucleation and growth are not yet adequately understood. PMID- 26244446 TI - Long-term Metabolic Effects of Laparoscopic Sleeve Gastrectomy. AB - IMPORTANCE: The prevalence of laparoscopic sleeve gastrectomy (LSG) is increasing, but data on its long-term effect on obesity-related comorbidities are scarce. Because the population of bariatric patients is young, long-term results of those comorbidities are highly relevant. OBJECTIVE: To investigate the long term effects of LSG on weight loss, diabetes mellitus, hypertension, dyslipidemia, and hyperuricemia. DESIGN, SETTING, AND PARTICIPANTS: Cohort study using a retrospective analysis of a prospective cohort at a university hospital. Data were collected from all patients undergoing LSGs performed by the same team between April 1, 2006, and February 28, 2013, including demographic details, weight follow-up, blood test results, and information on medications and comorbidities. MAIN OUTCOMES AND MEASURES: Excess weight loss, obesity-related comorbidities, and partial and complete remission at 1, 3, and 5 years of follow up. RESULTS: A total of 443 LSGs were performed. Complete data were available for 241 of the 443 patients (54.4%) at the 1-year follow-up, for 128 of 259 patients (49.4%) at the 3-year follow-up, and for 39 of 56 patients (69.6%) at the 5-year follow-up. The percentage of excess weight loss was 76.8%, 69.7%, and 56.1%, respectively. Complete remission of diabetes was maintained in 50.7%, 38.2%, and 20.0%, respectively, and remission of hypertension was maintained in 46.3%, 48.0%, and 45.5%, respectively. Changes in high-density lipoprotein cholesterol level (mean [SD] level preoperatively and at 1, 3, and 5 years, 46.7 [15.8], 52.8 [13.6], 56.8 [16.0], and 52.4 [13.8] mg/dL, respectively) and triglyceride level (mean [SD] level preoperatively and at 1, 3, and 5 years, 155.2 [86.1], 106.3 [45.3], 107.2 [53.4], and 126.4 [59.7] mg/dL, respectively) were significant compared with preoperative and postoperative measurements (P < .001). The decrease of low-density lipoprotein cholesterol level was significant only at 1 year (P = .04) and 3 years (P = .04) (mean [SD] level preoperatively and at 1, 3, and 5 years, 115.8 [33.2], 110.8 [32.0], 105.7 [25.9], and 110.6 [28.3] mg/dL, respectively). The changes in total cholesterol level did not reach statistical significance (mean [SD] level preoperatively and at 1, 3, and 5 years, 189.5 [38.2], 184.0 [35.4], 183.4 [31.2], and 188.1 [35.7] mg/dL, respectively). No changes in comorbidity status correlated with preoperative excess weight. Hypertriglyceridemia was the only comorbidity whose remission rates at 1 year of follow-up (partial/complete, 80.6%; complete, 72.2%) correlated with percentage of excess weight loss (76.8%) (P = .005). CONCLUSIONS AND RELEVANCE: Undergoing LSG induced efficient weight loss and a major improvement in obesity-related comorbidities, with mostly no correlation to percentage of excess weight loss. There was a significant weight regain and a decrease in remission rates of diabetes and, to a lesser extent, other comorbidities over time. PMID- 26244447 TI - Selective Photodissociation of Acetonitrile Ligands in Ruthenium Polypyridyl Complexes Studied by Density Functional Theory. AB - Metal complexes that release ligands upon photoexcitation are important tools for biological research and show great potential as highly specific therapeutics. Upon excitation with visible light, [Ru(TQA)(MeCN)2](2+) [TQA = tris(2 quinolinylmethyl)amine] exchanges one of the two acetonitriles (MeCNs), whereas [Ru(DPAbpy)MeCN](2+) [DPAbpy = N-(2,2'-bipyridin-6-yl)-N,N-bis(pyridin-2 ylmethyl)amine] does not release MeCN. Furthermore, [Ru(TQA)(MeCN)2](2+) is highly selective for release of the MeCN that is perpendicular to the plane of the two axial quinolines. Density functional theory calculations provide a clear explanation for the photodissociation behavior of these two complexes. Excitation by visible light and intersystem crossing leads to a six-coordinate (3)MLCT state. Dissociation of acetonitrile can occur after internal conversion to a dissociative (3)MC state, which has an occupied dsigma* orbital that interacts in an antibonding fashion with acetonitrile. For [Ru(TQA)(MeCN)2](2+), the dissociative (3)MC state is lower than the (3)MLCT state. In contrast, the (3)MC state of [Ru(DPAbpy)MeCN](2+) that releases acetonitrile has an energy higher than that of the (3)MLCT state, indicating dissociation is unfavorable. These results are consistent with the experimental observations that efficient photodissociation of acetonitrile occurs for [Ru(TQA)(MeCN)2](2+) but not for [Ru(DPAbpy)MeCN](2+). For the release of the MeCN ligand in [Ru(TQA)(MeCN)2](2+) that is perpendicular to the axial quinoline rings, the (3)MLCT state has an occupied quinoline pi* orbital that can interact with a dsigma* Ru-NCCH3 antibonding orbital as the Ru-NCCH3 bond is stretched and the quinolines bend toward the departing acetonitrile. This reduces the barrier for the formation of the dissociative (3)MC state, leading to the selective photodissociation of this acetonitrile. By contrast, when the acetonitrile is in the plane of the quinolines or bpy, no interaction occurs between the ligand pi* orbital and the dsigma* Ru-NCCH3 orbital, resulting in high barriers for conversion to the corresponding (3)MC structures and no release of acetonitrile. PMID- 26244448 TI - Corallite-like Magnetic Fe3O4@MnO2@Pt Nanocomposites as Multiple Signal Amplifiers for the Detection of Carcinoembryonic Antigen. AB - A nonenzymatic sandwich-type electrochemical immunosensor using corallite-like magnetic Fe3O4@MnO2@Pt nanocomposites was developed for the sensitive detection of carcinoembryonic antigen (CEA). First, aminated graphene (GS-NH2) sheets were synthesized from graphite oxide using the Hummers' method, which was used to immobilize the primary antibody via the active amino groups on the GS-NH2. Second, corallite-like Fe3O4@MnO2@Pt nanoparticles (NPs) were synthesized and characterized by transmission electron microscope (TEM), scanning electron microscope (SEM), and energy dispersive spectroscopy (EDS). They were used as labels to conjugate with a secondary antibody. The multiple amplification of Fe3O4@MnO2@Pt NPs and the promoted electron transfer of GS-NH2 lead to a broad linear range from 0.5 pg/mL to 20 ng/mL and a low detection limit with 0.16 pg/mL. In addition, the immunosensor performed with good selectivity and acceptable stability and reproducibility as well. The results are satisfactory when the proposed method has been applied to analyze human serum samples. Thus, there would be a promising future in the early diagnosis of cancer to detect CEA and other tumor markers. PMID- 26244449 TI - Actuating Water Droplets on Graphene via Surface Wettability Gradients. AB - A surface wettability gradient can break the equilibrium status of a liquid droplet and drives its unidirectional movement on the surface. We propose a conceptual design of the driving water droplet on a graphene surface and demonstrate that both speed and direction of the movement can be controlled via a continuous gradient of surface wettability using comprehensive molecular dynamics (MD) simulations. Controlling the water droplet toward linear and nonlinear arc paths is exemplified in one- and two-dimensional gradients of surface wettability, respectively. Unbalanced Young's equation is extended to understand the speed of the droplet movement, and the predications agree well with MD simulations. PMID- 26244450 TI - In the Bottlebrush Garden: The Structural Aspects of Coordination Polymer Phases formed in Lanthanide Extraction with Alkyl Phosphoric Acids. AB - Coordination polymers (CPs) of metal ions are central to a large variety of applications, such as catalysis and separations. These polymers frequently occur as amorphous solids that segregate from solution. The structural aspects of this segregation remain elusive due to the dearth of the spectroscopic techniques and computational approaches suitable for probing such systems. Therefore, there is a lacking of understanding of how the molecular building blocks give rise to the mesoscale architectures that characterize CP materials. In this study we revisit a CP phase formed in the extraction of trivalent lanthanide ions by diesters of the phosphoric acid, such as the bis(2-ethylhexyl)phosphoric acid (HDEHP). This is a well-known system with practical importance in strategic metals refining and nuclear fuel reprocessing. A CP phase, referred to as a "third phase", has been known to form in these systems for half a century, yet the structure of the amorphous solid is still a point of contention, illustrating the difficulties faced in characterizing such materials. In this study, we follow a deductive approach to solving the molecular structure of amorphous CP phases, using semiempirical calculations to set up an array of physically plausible models and then deploying a suite of experimental techniques, including optical, magnetic resonance, and X-ray spectroscopies, to consecutively eliminate all but one model. We demonstrate that the "third phase" consists of hexagonally packed linear chains in which the lanthanide ions are connected by three O-P-O bridges, with the modifying groups protruding outward, as in a bottlebrush. The tendency to yield linear polynuclear oligomers that is apparent in this system may also be present in other systems yielding the "third phase", demonstrating how molecular geometry directs polymeric assembly in hybrid materials. We show that the packing of bridging molecules is central to directing the structure of CP phases and that by manipulating the steric requirements of ancillary groups one can control the structure of the assembly. PMID- 26244451 TI - Probing the Relationship Between Large-Amplitude Motions in H5(+) and Proton Exchange Between H3(+) and H2. AB - Understanding the spectroscopy and dynamics of H5(+) is central in gaining insights into the H3(+) + H2 -> H5(+) -> H2 + H3(+) proton transfer reaction. This molecular ion exhibits large-amplitude vibrations, which allow for the transfer of a proton between H3(+) and H2 even in its ground vibrational state. With vibrational excitation, the number of open channels for permutations of protons increase. In this work, the minimized energy path variant of diffusion Monte Carlo is used to investigate how the energetically accessible proton permutations evolve as H5(+) is dissociated into H3(+) + H2. Two mechanisms for proton permutation are investigated. The first is the proton hop, which correlates to large-amplitude vibrations of the central proton in H5(+). The second is the exchange of a pair of hydrogen atoms between H3(+) and H2. This mechanism requires several proton hops along with a 120 degrees rotation of H3(+) within the H5(+) molecular ion. This analysis shows that while there is a narrow region of configuration space over which both isomerization processes are energetically accessible, full permutation of the five protons in H5(+) more likely occurs through a stepwise mechanism. Such full permutation of the protons becomes accessible when the shared proton stretch is excited to the vpt = 2 or 3 excited state. The effects of deuteration and rotational excitation of the H2 and H3(+) products are also investigated. Deuteration inhibits permutation of protons, while rotational excitation has only a small impact on these processes. PMID- 26244452 TI - Comparison between indigenous and Western postnatal care practices in Mopani District, Limpopo Province, South Africa. AB - BACKGROUND: Postnatal care begins immediately after the expulsion of the placenta and continues for six to eight weeks post-delivery. High standard of care is required during the postnatal period because mothers and babies are at risk and vulnerable to complications related to postpartum haemorrhage and infections. Midwives and traditional birth attendants are responsible for the provision of postnatal care in different settings, such as clinics and hospitals, and homes. METHODS: A qualitative, exploratory, descriptive and contextual research approach was followed in this study. Unstructured interviews were conducted with the traditional birth attendants. An integrated literature review was conducted to identify the Western postnatal care practices. Tesch's process was followed during data analysis. FINDINGS: The following main categories were identified: similarities between indigenous and Western postnatal care practices, and differences between indigenous and Western postnatal care practices. Based on these findings, training of midwives and traditional birth attendants was recommended in order to empower them with knowledge and skills regarding the indigenous and Western postnatal care practices. CONCLUSIONS: It is evident that some indigenous postnatal care practices have adverse effects on the health of postnatal women and their newborn infants, but these are unknown to the traditional birth attendants. The employment of indigenous postnatal care practices by the traditional birth attendants is also influenced by their cultural beliefs, norms, values and attitudes. Therefore, there is an urgent need to train midwives and traditional birth attendants regarding the indigenous and Western postnatal care to improve the health of postnatal women and their babies. PMID- 26244453 TI - Adherence to antiretroviral treatment by adults in a rural area of Botswana. AB - BACKGROUND: As antiretroviral therapy (ART) is becoming increasingly available to people in developing countries, ART adherence challenges assume ever greater significance. Often underlying treatment failure is the fact that suboptimal adherence to ART is the strongest predictor of failure to achieve viral suppression below the level of detection. OBJECTIVES: The study's main objective was to identify factors affecting ART adherence levels, as well as the impact on immunologic and virologic responses in adult patients in one rural district in Botswana. METHODS: A cross-sectional quantitative survey, was used. Structured interviews were conducted with 300 ART patients between November 2011 and February 2012. Data were analysed, then presented in charts, graphs and frequency tables. RESULTS: The prevalence of non-adherence to ART was 14.0%. Motivators of good adherence included disclosure of HIV-positive status to more than one person, frequent adherence counselling, self-efficacy for adherence to ART, positive interactions between patients and healthcare providers; and using adherence partners. Barriers to adherence were forgetfulness, transportation costs to and from the clinic, time away from work and side-effects. There was a strong positive correlation between adherence, CD4 counts and viral load. Adherence was closely tied to immunologic and virologic improvements. Respondents with poor adherence were likely to have unsuppressed viral loads (OR 12.98, 95% CI 4.9-34). CONCLUSION: Adherence to ART is closely tied to virologic, immunologic, and clinical outcomes. Increases in adherence levels resulted in significant improvements in these outcomes. Near perfect adherence, however, is required to maximise the likelihood of long-term clinical success, which could pose challenges to many ART patients, especially in resource-limited rural settings. PMID- 26244454 TI - Determining professional nurses' knowledge on the performance management and development system in Tshwane. AB - BACKGROUND: The implementation of the Performance Management and Development System (PMDS) is seen as being vital to the quality of care, resource management and inter-professional work. However, there is evidence that, at present, professional nurses lack the knowledge to implement such a system. OBJECTIVES: The aim of this study was to explore and describe professional nurses' knowledge regarding the implementation of the PMDS in selected primary healthcare clinics in Tshwane. METHOD: A quantitative, descriptive, exploratory design was used and convenience sampling was used to recruit respondents. A self-administered structured questionnaire was used to collect data from 39 professional nurses who were involved in managing the work performance of employees. The data were analysed quantitatively with Statistical Analysis System version 8.2 software. RESULTS: The respondents had limited knowledge about the implementation of the performance management and development system. CONCLUSION: There is a need for educational initiatives before, during and after the implementation of the PMDS, such as quarterly PMDS workshops and routine catch-up training. These would address the lack of knowledge of respondents as seen from the results. PMID- 26244455 TI - The views of the elderly on the impact that HIV and AIDS has on their lives in the Thulamela Municipality, Vhembe District, Limpopo province. AB - BACKGROUND: HIV and AIDS have a devastating impact on the lives of elderly people, particularly so because they are often expected to take care of their terminally ill children and assume the responsibility of looking after children orphaned by AIDS - in most cases with very little resources. OBJECTIVES: The study sought to achieve to describe the views of elderly people regarding the impact of HIV and AIDS on their lives, to determine the challenges that elderly people living with HIV or AIDS (EPLWHA) face in their daily lives, and to gain a sense of the coping strategies they use to overcome the obstacles they face in relation to HIV and AIDS. Ethical issues, such as permission to conduct the study, informed consent, confidentiality and anonymity, withdrawal of participation and measure to ensure trustworthiness, were ensured. DESIGN: This was a qualitative, explorative, descriptive study. Participants were interviewed using an interview guide. Information provided by the participants was captured on a tape recorder and analysed using open coding, and thereafter collated into themes, categories and sub-themes. RESULTS: The study findings revealed that HIV and AIDS have serious negative impacts on the lives of elderly people, particularly those living in poverty. The following key areas in relation to EPLWHA were established: psychological or emotional health, as well as household and socio-economic burdens. Considering the role that elderly people play in the community in so far as HIV and AIDS are concerned, primary health promotion and social welfare programmes should be directed at educating all elderly people and their service providers on how to cope with the health and social problems related to HIV and AIDS. PMID- 26244456 TI - Health information needs of professional nurses required at the point of care. AB - BACKGROUND: Professional nurses work in dynamic environments and need to keep up to date with relevant information for practice in nursing to render quality patient care. Keeping up to date with current information is often challenging because of heavy workload, diverse information needs and the accessibility of the required information at the point of care. OBJECTIVES: The aim of the study was to explore and describe the information needs of professional nurses at the point of care in order to make recommendations to stakeholders to develop a mobile library accessible by means of smart phones when needed. METHOD: The researcher utilised a quantitative, descriptive survey design to conduct this study. The target population comprised 757 professional nurses employed at a state hospital. Simple random sampling was used to select a sample of the wards, units and departments for inclusion in the study. A convenience sample of 250 participants was selected. Two hundred and fifty structured self-administered questionnaires were distributed amongst the participants. Descriptive statistics were used to analyse the data. RESULTS: A total of 136 completed questionnaires were returned. The findings highlighted the types and accessible sources of information. Information needs of professional nurses were identified such as: extremely drug resistant tuberculosis, multi-drug-resistant tuberculosis, HIV, antiretrovirals and all chronic lifestyle diseases. CONCLUSION: This study has enabled the researcher to identify the information needs required by professional nurses at the point of care to enhance the delivery of patient care. The research results were used to develop a mobile library that could be accessed by professional nurses. PMID- 26244457 TI - Why do women not return for CD4 count results at Embhuleni Hospital, Mpumalanga, South Africa? AB - BACKGROUND: According to the South African Policy and guidelines for the implementation of the PMTCT programme of 2008, all pregnant women who tested HIV positive also had to have their CD4 count measured in order to inform the option of Prevention of Mother-to-Child Treatment (PMTCT): to be put on lifelong treatment or to be placed on temporary PMTCT. They were required to return for the results within two weeks, but some did not return, implying that they did not benefit from the programme. This study was conducted to establish their reasons for not returning. OBJECTIVES: To explore the reasons given by women attending antenatal care for not returning for the results of their CD4 count done for PMTCT at Embhuleni Hospital and satellite clinics, Mpumalanga. METHODS: The study was a qualitative study using the free-attitude interview technique. Women who had not returned for their results were traced and interviewed on their reasons for not returning. Interviews were conducted in Siswati, audio-taped, transcribed verbatim and translated into English for analysis. Data saturation was reached by the eighth participant. A thematic analysis was conducted. RESULTS: The themes that emerged were: participants were not informed about the PMTCT process; poor service delivery from the healthcare practitioners; unprofessional healthcare practitioners' conduct; shortages of medication in the healthcare facilities; fear of social stigma; and poor patient socioeconomic conditions. CONCLUSION: The reasons for not returning were mainly based on participants' experiences during consultations at the healthcare centres and their perceptions of the healthcare practitioners. Healthcare practitioners should adhere to the tenets of professionalism in order to address this problem. PMID- 26244458 TI - Perceptions of newly-qualified nurses performing compulsory community service in KwaZulu-Natal. AB - BACKGROUND: Compulsory community service (CCS) for nurses commenced in South African January 2008 after it was legislated in the new Nursing Act (Act No. 33 of 2005). Nurses completing their registered nurse programme are registered as community nurse practitioners (CNPs) during the CCS period and make up the largest number of health professionals serving CCS. Whilst health institutions have welcomed CNPs as additional resources for the shortage of nursing staff, no structured guidelines have been provided at a regional level as to how these nurses should be utilised or managed during the CCS year. To date, no large-scale study has been conducted on nurses carrying out CCS in order to generalise the findings. OBJECTIVES: To establish the perceptions of newly-qualified nurses carrying out CCS in KwaZulu-Natal, South Africa. METHOD: A quantitative survey design was used to obtain data from a randomly selected sample of the 2012 cohort of nurses carrying out CCS in KwaZulu-Natal. RESULTS: CNPs have a positive attitude toward CCS and perceive themselves as being well prepared for the year of community service in terms of knowledge, skills and ability to administer nursing care. They identified positive benefits of the year of community service.The concerns raised were limited orientation and support; and a few CNPs experienced problems of acceptance by the nurses with whom they work. CONCLUSION: It is recommended that all health institutions who receive CNPs develop structured orientation and support for these nurses in order to promote their development, thereby enhancing their benefit to the communities they serve. PMID- 26244459 TI - The quality of doctoral nursing education in South Africa. AB - BACKGROUND: The number of doctoral programmes in nursing has multiplied rapidly throughout the world. This has led to widespread concern about nursing doctoral education, specifically with regard to the quality of curricula and faculty, as well as to the availability of appropriate institutional resources. In South Africa, no study of these issues has been conducted at a national level. OBJECTIVE: To explore and describe the quality of nursing doctoral education in South Africa from the perspectives of deans, faculty, doctoral graduates and students. METHOD: A cross-sectional survey design was used. All deans (N = 15; n = 12), faculty (N = 50; n = 26), doctoral graduates (N = 43; n = 26) and students (N = 106; n = 63) at South African nursing schools that offer a nursing doctoral programme (N = 16; n = 15) were invited to participate. Data were collected by means of structured email-mediated Quality of Nursing Doctoral Education surveys. RESULTS: Overall, the graduate participants scored their programme quality most positively of all the groups and faculty scored it most negatively. All of the groups rated the quality of their doctoral programmes as good, but certain problems related to the quality of resources, students and faculty were identified. CONCLUSION: These evaluations, by the people directly involved in the programmes, demonstrated significant differences amongst the groups and thus provide valuable baseline data for building strategies to improve the quality of doctoral nursing education in South Africa. PMID- 26244460 TI - Primary health care nurses' management practices of common mental health conditions in KwaZulu-Natal, South Africa. AB - BACKGROUND: Psychiatric conditions contribute to 13%of the global burden of diseases and account for one third of years lost because of disability (YLD). Despite the high prevalence of mental health problems, primary health care (PHC) services remain ineffective in managing patients with mental health conditions. OBJECTIVES: The aim of the study was to determine the practices of PHC nurses in the management of psychiatric patients in primary health care clinics in one of the rural districts in South Africa. METHOD: A survey was conducted amongst nurses working in several PHC clinics in KwaZulu-Natal (KZN) in order to determine their practices in the management of psychiatric patients. Mixed methods were used to determine the PHC nurses practices in the management of psychiatric patients. RESULTS: The findings revealed that in five sites (83.3%) treatments are not reviewed every six months, there were no local protocols on the administration of psychiatric emergency drugs, and none of the study sites provided psychiatric patients with education on their medication and its possible side effects. CONCLUSION: Based on the results of this study it is evident that psychiatric patients at PHC clinics in the district where the study was conducted do not receive quality treatment according to institutional mental health guidelines. PMID- 26244461 TI - Socioeconomic factors contributing to exclusion of women from maternal health benefit in Abuja, Nigeria. AB - BACKGROUND: An understanding of the predictive effect of socioeconomic characteristics (SECs) of women on maternal healthcare service utilisation is essential in order to maximise maternal health benefits and outcomes for the newborn. OBJECTIVES: To describe how SECs of women contribute to their exclusion from maternal health benefits in Abuja Municipal Areas Council (AMAC) in Abuja, Nigeria. METHOD: A non-experimental, facility-based cross-sectional survey was done. Data were collected from 384 respondents using a structured interviewer administered questionnaire. The participants were sampled randomly at antenatal care (ANC) clinics in the five district hospitals in AMAC. Data analysis included descriptive statistics, cross-tabulations and measures of inequality. Logistic regression analysis was used to test the relationship between SECs (predictors) and maternal healthcare service utilisation. RESULTS: There were differentials in the utilisation of maternal healthcare services (ANC, delivery care, post natal care [PNC] and contraceptive services) amongst women with different SECs; and the payment system for maternal healthcare services was regressive. There were inconsistencies in the predictive effect of the SECs of women included in this study (age,education, birth order, location of residence, income group and coverage by health insurance) on maternal healthcare service utilisation when considered independently (bivariate analysis) as opposed to when considered together (logistic regression), with the exception of birth order, which showed consistent effect. CONCLUSION: SECs of women were predictive factors of utilisation of maternal healthcare services. There is a need for targeted policy measures and programme actions toward multiple SECs of women in their natural co existing state in order to optimise maternal health benefits. PMID- 26244462 TI - Lessons learned about ageing and gerontological nursing in South Africa. AB - BACKGROUND: The unprecedented global growth in older adults merits high-quality gerontological nursing care. As gerontological nursing grows in visibility in developed and developing countries, nurses must possess a broader worldview of ageing with knowledge of physiological, psychosocial, and cultural issues. PURPOSE: The purpose of this article is to: (1) highlight lessons learned on differences and similarities in ageing and care of older adults in the United States of America (USA) and South Africa (SA); and (2) provide recommendations on how to advance gerontological nursing education in SA. METHODS: A two-week international service-learning project was undertaken by visiting SA and learning about their nursing system and care of older adults. Service-learning is an innovative teaching-learning-service method that provided reflective and hands-on experience of gerontological nursing. This article provides a personal reflection of lessons learned about ageing and gerontological nursing during the service learning project. FINDINGS: Care of older adults in SA is in many ways different from and similar to that in the USA. Consequently global nurses should recognise those differences and provide culturally appropriate care. This service-learning experience also demonstrated the need for gerontological nursing education in SA. Based on this, recommendations on how to infuse and advance gerontological nursing education in SA are provided. CONCLUSION: Caring for older adults in a global context requires knowledge and understanding of cultures and their values and practices. With a growing population of diverse older adults, there is a need for incorporation. PMID- 26244463 TI - Allopathic and traditional health practitioners' collaboration. AB - BACKGROUND: Professional collaboration between traditional and allopathic health practitioners in South Africa is proposed in the Traditional Health Practitioners Act and could benefit and complement healthcare delivery. OBJECTIVES: To explore and describe the collaborative relationship between allopathic and traditional health practitioners regarding the legalisation of traditional healing, and these health practitioners' views of their collaborative and professional relationship, as role-players in the healthcare delivery landscape in South Africa. METHODS: A qualitative design was followed. The research population comprised 28 participants representing three groups: allopathic health practitioners (n = 10), traditionalhealers (n = 14), and traditional healers who are also allopathic health practitioners (n = 4). Purposive and snowball sampling was used. Data collection involved unstructured interviews, a focus group interview and modified participant observation. RESULTS: Results indicate both allopathic and traditional health practitioners experienced negative attitudes towards each other. Mutual understanding (in the form of changing attitudes and communication) was considered crucial to effective collaboration between these two health systems. Participants made suggestions regarding capacity building. CONCLUSIONS: Considering realities of staff shortages and the disease burden in South Africa, facilitating collaboration between allopathic and traditional health practitioners is recommended. Recommendations could be used to develop strategies for facilitating professional collaboration between traditional and allopathic health practitioners in order to complement healthcare delivery. PMID- 26244465 TI - Utility of Nitrogen Extrusion of Azido Complexes for the Synthesis of Nitriles, Benzoxazoles, and Benzisoxazoles. AB - The utility of the nitrogen extrusion reaction of azido complexes, generated in situ from the corresponding aldehydes or ketones with TMSN3 in the presence of ZrCl4 or TfOH, has been described. These azido complexes could undergo three different pathways, depending on the substrates. First, azido methanolate complexes or imine diazonium ions could lead to benzisoxazole products via an intramolecular nucleophilic substitution. Second, imine diazonium ions could also undergo either the elimination of proton to provide nitrile products in good to excellent yields or an aryl migration, followed by an intramolecular nucleophilic addition, to give benzoxazole products in good yields. PMID- 26244466 TI - Correction to structural characterization of gangliosides and glycolipids via ultraviolet photodissociation mass spectrometry. PMID- 26244464 TI - Perceptions of nursing students regarding responsible use of social media in the Eastern Cape. AB - BACKGROUND: Social media have become a popular communication system that has transformed communication from the traditional to the Web-based model. Because social media use has no limitations to place and time, it is now used extensively at clinical facilities. Social media useis becoming a popular activity amongst students at Nursing Education Institutions (NEI) in South Africa. However, lack of accountability and unethical use of social media by nursing students in South Africa has been reported. OBJECTIVES: The aim of the study was to explore and describe the perceptions of nursing students regarding responsible use of social media. METHODS: A qualitative, descriptive, explorative and contextual research design was used to explore and describe the perceptions of nursing students regarding the responsible use of social media. Twelve nursing students registered for the undergraduate nursing degree were purposely selected and interviewed individually using a semi-structured interview method. RESULTS: The results of this research study demonstrate that nursing students use socialmedia irresponsibly. Nursing students experience blurred boundaries between personal and professional lines and lack accountability when using social media. CONCLUSION: The extensive use of social media in the clinical environment, by healthcare students, requires a joint effort by Nursing Education Institutions and healthcare facilities to ensure that social media are used in an ethically acceptable manner. The implementation of the recommendations of this research study could positively influence legally and ethically acceptable use of social media at healthcare facilities. PMID- 26244467 TI - The current place of nitrous oxide in clinical practice: An expert opinion-based task force consensus statement of the European Society of Anaesthesiology. PMID- 26244468 TI - Epinephrine, compared with arginine vasopressin, is associated with similar haemodynamic effects but significantly improved brain oxygenation in the early phase of anaphylactic shock in rats: An experimental study. AB - BACKGROUND: In contrast to other types of shock, anaphylactic shock decreases cerebral blood flow more than would be expected from severe arterial hypotension, thus potentially affecting survival through brain ischaemia/hypoxia. We hypothesised that epinephrine (EPI) used as a first-line treatment of anaphylactic shock and arginine vasopressin (AVP) proposed in case of EPI refractoriness may have different effects on brain oxygenation. OBJECTIVES: To compare the effect of EPI and AVP on brain oxygenation under similar macro haemodynamic target values in an anaphylactic shock model. DESIGN: Prospective laboratory study. SETTING: University laboratory. ANIMALS: Male brown Norway rats (n = 27). INTERVENTIONS: Twenty-seven rats were sensitised with ovalbumin (OVA). Twenty rats had anaphylactic shock induced with OVA and were resuscitated with either 0.9% saline (OVA group), EPI (EPI group) or AVP (AVP group). Sensitised control rats received only 0.9% saline and no OVA (CON group). MAIN OUTCOME MEASURES: Mean arterial pressure (MAP), carotid artery blood flow (CaBF), cerebral cortical blood flow (CBF) and hippocampal oxygen partial pressure (PtiO2) were recorded. RESULTS: All rats in the OVA group died within 15 min. EPI and AVP restored comparable levels of MAP, carotid artery blood flow and CBF, and extended survival time. EPI was associated with biologically relevant and significantly (P < 0.05) higher PtiO2 values (nadir values at 20 min: 25.0 +/- 2.2 mmHg) compared with the AVP group (14.9 +/- 2.0 mmHg). The slopes of the correlations of MAP vs. PtiO2 and CBF were significantly steeper with AVP (more pressure dependence) compared with EPI. By the end of the experiment, hippocampal PtiO2 values between the EPI (24.1 +/- 2.1 mmHg) and the AVP (20.8 +/- 2.0 mmHg) groups were similar. CONCLUSION: At early, but not at late time points, resuscitation of anaphylactic shock with EPI or AVP to similar MAP and CBF endpoints resulted in hippocampal PtiO2 being significantly higher after EPI. In addition, the PtiO2 after EPI always remained above the threshold for brain hypoxia, whereas PtiO2 after AVP was below the hypoxic threshold most of the time. Because of this early brain hypoxia, AVP may not be the drug of first choice for resuscitation of anaphylactic shock. PMID- 26244469 TI - Correlation of the Physician Assistant Education Association End of Rotation Examinations with the Physician Assistant National Certifying Exam. AB - PURPOSE: The purpose of this study was to determine whether student scores on the Physician Assistant Education Association (PAEA) End of RotationTM subject examinations had a statistically significant relationship with subsequent performance on the Physician Assistant National Certifying Exam (PANCE). The raw scores achieved by students from 3 participating programs were correlated with scores on the PANCE. METHODS: Seven 120-question End of Rotation examinations, developed by the PAEA, were administered to students from 3 PA programs (n=72). The examinations measured knowledge in the following disciplines: family medicine, internal medicine, behavioral medicine, emergency medicine, surgery, OB/GYN, and pediatrics. RESULTS: The mean PANCE score for all programs was 426 (SD=90) and mean End of Rotation examinations score was 68% (SD=8.3). The Pearson coefficient between the PANCE and End of Rotation examinations scores was 0.856 (P<.05). CONCLUSION: The results of this pilot study suggest that there is a statistically significant correlation between scores on the PAEA End of Rotation examinations and subsequent PANCE performance. PMID- 26244470 TI - Facilitating Research in Physician Assistant Programs: Creating a Student-Level Longitudinal Database. AB - As physician assistant (PA) roles expand and diversify in the United States and around the world, there is a pressing need for research that illuminates how PAs may best be selected, educated, and used in health systems to maximize their potential contributions to health. Physician assistant education programs are well positioned to advance this research by collecting and organizing data on applicants, students, and graduates. Our PA program is creating a permanent longitudinal education database for research that contains extensive student level data. This database will allow us to conduct research on all phases of PA education, from admission processes through the professional practice of our graduates. In this article, we describe our approach to constructing a longitudinal student-level research database and discuss the strengths and limitations of longitudinal databases for research on education and the practice of PAs. We hope to encourage other PA programs to initiate similar projects so that, in the future, data can be combined for use in multi-institutional research that can contribute to improved education for PA students across programs. PMID- 26244471 TI - Is Craniosynostosis Repair Keeping Up With the Times? Results From the Largest National Survey on Craniosynostosis. AB - BACKGROUND: Given the great variability in perioperative management of craniosynostosis, a large-scale national survey of current practice patterns was conducted. METHODS: Using scaphocephaly as a test diagnosis, 115 craniofacial surgeons at all levels of career experience across the United States were invited to participate in an anonymous survey. RESULTS: Fifty-three surgeons (46%) completed the survey. All respondents complete repair before 1 year of age with a majority operating between 4 and 8 months. Surgeons with greater than 10 years of experience were significantly more likely to perform open repair at extremes of age (<4 months and 8-12 months) (P = 0.03) and reported shorter operative times (P = 0.01) compared with their less experienced colleagues. More than two-thirds of surgeons (68.8%) obtain preoperative imaging for every case; 83% of these prefer computed tomography scans. More than one-fourth of respondents (28%) routinely prescribe an extended course (>24 hours) of antibiotics. Overall transfusion rates remain high, with nearly 2 (65.2%) in 3 transfusing in 76% to 100% of operations. The overwhelming majority of respondents (93.6%) routinely send patients to an intensive care unit postoperatively. CONCLUSIONS: We present the largest US survey of craniosynostosis surgical practice patterns to date. General consensus exists regarding safety and emergency preparedness standards. In addition, we identified several patterns that deviate from published evidence based guidelines. Specifically, these practices relate to the routine use of high dose radiation imaging, long-term antibiotics, blood transfusions, and intensive postoperative surveillance. For the first time, stratifying by surgeon experience revealed significant differences in clinical practice. PMID- 26244474 TI - RESPONSE TO CRITIQUE OF "CARING AS EMANCIPATORY NURSING PRAXIS: THE THEORY OF RELATIONAL CARING COMPLEXITY". PMID- 26244475 TI - (Re)theorizing Integrated Knowledge Translation: A Heuristic for Knowledge-As Action. AB - Approaches to knowledge translation (KT) have undergone substantial transformation in an effort to find more effective strategies to ensure the best available knowledge informs nursing practice. However, the fundamental epistemology underpinning KT itself has gone largely unquestioned. Of particular concern is the inadequacy of current representational models to depict the complex, social process of KT. To address the limitations of representational models we propose an inquiry heuristic that conceptualizes KT as a knowledge-as action process. Developed through a series of KT research projects, the heuristic is intended to guide the KT process and support effective navigation in the complexities of contemporary health care milieus. PMID- 26244476 TI - Translational Scholarship and a Palliative Approach: Enlisting the Knowledge-As Action Framework. AB - Based on a retheorized epistemology for knowledge translation (KT) that problematizes the "know-do gap" and conceptualizes the knower, knowledge, and action as inseparable, this paper describes the application of the Knowledge-As Action Framework. When applied as a heuristic device to support an inquiry process, the framework with the metaphor of a kite facilitates a responsiveness to the complexities that characterize KT. Examples from a KT demonstration project on the integration of a palliative approach at 3 clinical sites illustrate the interrelatedness of 6 dimensions-the local context, processes, people, knowledge, fluctuating realities, and values. PMID- 26244477 TI - Advancing Organizational Cultural Competency With Dissemination and Implementation Frameworks: Towards Translating Standards into Clinical Practice. AB - Substantial public health efforts have been activated to reduce health disparities and ensure health equity for patients through the provision of culturally and linguistically appropriate services; yet associated policies and standards are sluggishly translating into practice. Little attention and resources have been dedicated to translation of public health policies into practice settings. Dissemination and implementation is presented as an active, strategic approach to enhance uptake of public health standards; reviews dissemination and implementation concepts; poses a systematic model to adoption, implementation, and dissemination; and concludes with recommendations for hospital-based implementation teams and complementary interprofessional collaboration. PMID- 26244478 TI - Advancing the Interdisciplinary Collaborative Health Team Model: Applying Democratic Professionalism, Implementation Science, and Therapeutic Alliance to Enact Social Justice Practice. AB - This essay reframes the interdisciplinary collaborative health team model by proposing the application of 3 foundational pillars-democratic professionalism, implementation science, and therapeutic alliance to advance this practice. The aim was to address challenges to the model, enhance their functional capacity, and explicate and enact social justice practices to affect individual health outcomes while simultaneously addressing health inequities. The pillars are described and examples from the author's dissertation research illustrate how the pillars were used to bring about action. Related theories, models, and frameworks that have negotiation, capacity building, collaboration, and knowledge/task/power sharing as central concepts are presented under each of the pillars. PMID- 26244479 TI - Synthesizing Marketing, Community Engagement, and Systems Science Approaches for Advancing Translational Research. AB - The adoption and implementation of evidence-based interventions (EBIs) are the goals of translational research; however, potential end-users' perceptions of an EBI value have contributed to low rates of adoption. In this article, we describe our application of emerging dissemination and implementation science theoretical perspectives, community engagement, and systems science principles to develop a novel EBI dissemination approach. Using consumer-driven, graphics-rich simulation, the approach demonstrates predicted implementation effects on health and employment outcomes for socioeconomically disadvantaged women at the local level and is designed to increase adoption interest of county program managers accountable for improving these outcomes in their communities. PMID- 26244481 TI - Being the Mother of an Adolescent Suffering From a Spinal Cord Injury: Possibilities of a Personal Narrative in Phenomenology. AB - The single case can be a very fruitful source of knowledge. A mother's narratives of her experiences when her adolescent son suffered a spinal cord injury seemed very rich and informative. The challenge arises in the dissemination of this knowledge. With a phenomenological approach the narratives of a mother's experiences were analyzed. This revealed an experience characterized by (1) being emotionally overwhelmed due to the shock of the accident, (2) resisting imagination and acceptance of a disrupted life path for the adolescent, (3) balancing your assistance to provide the needed support maintaining the adolescent's dignity when helpless, (4) comforting and supporting the adolescent when in need for comfort and support yourself, and (5) reconciling parental assistance with the need for professional assistance. The discussion explores what the findings from the single case can tell us about being in a situation like this, and to what extent this knowledge can be disseminated to assist health professionals. PMID- 26244480 TI - Proposing a New Conceptual Model and an Exemplar Measure Using Health Information: Technology to Examine the Impact of Relational Nurse Continuity on Hospital-Acquired Pressure Ulcers. AB - The influence of the staffing variable relational nurse continuity on patient outcomes has been rarely studied and with inconclusive results. Multiple definitions and an absence of systematic methods for measuring the influence of continuity have resulted in its exclusion from nurse-staffing studies and conceptual models. We present a new conceptual model and an innovative use of health information technology to measure relational nurse continuity and to demonstrate the potential for bringing the results of big data science back to the bedside. Understanding the power of big data to address critical clinical issues may foster a new direction for nursing administration theory development. PMID- 26244482 TI - Nurse Middle Managers' Dispositions of Habitus: A Bourdieusian Analysis of Supporting Role Behaviors in Dutch and American Hospitals. AB - A Magnet-related program has been recently adopted in the Netherlands. Support for staff nurses from nurse middle managers (NMMs) is a key component of such a program. A Bourdieusian ethnographic organizational case study in 4 hospitals in the Netherlands and the United States (Magnet, Magnet-related, and non-Magnet) was conducted to explore NMMs' supporting role behavior. Bourdieus concepts of habitus, field, and capital guided the analysis. Eight dispositions constitute NMMs habitus. A caring, clinical, and scientific disposition enhances NMMs' capital in particular organizations-as-fields. Further research is necessary to link Magnet (-related) program characteristics to various configurations of dispositions of NMMs habitus. PMID- 26244483 TI - Pedobarometric evaluation of specific shoe wearing in patients with diabetic peripheral neuropathy. PMID- 26244484 TI - The Boy Scouts of America: Slowly Changing. AB - The Boy Scouts of America National Executive Board (BSA) recently changed its longstanding policy of excluding gay youth up to the age of 18. Gay participants of its coed Venturing program would be allowed to be members until the age of 21. However, lesbians and homosexuals are still not permitted to be troop leaders. This article discusses the evolution of the change in BSA's policy, discusses the timeline of other proposals in regard to BSA's acceptance of gay youth, and suggests that changes in public opinion and the reaction of BSAs stakeholders lead to changes in the BSA policy. The BSA made a change to become more compatible with the environment in which it operates. PMID- 26244485 TI - Sleep Quality Improvement During Cognitive Behavioral Therapy for Anxiety Disorders. AB - Despite the ubiquity of sleep complaints among individuals with anxiety disorders, few prior studies have examined whether sleep quality improves during anxiety treatment. The current study examined pre- to posttreatment sleep quality improvement during cognitive behavioral therapy (CBT) for panic disorder (PD; n = 26) or generalized anxiety disorder (GAD; n = 24). Among sleep quality indices, only global sleep quality and sleep latency improved significantly (but modestly) during CBT. Sleep quality improvement was greater for treatment responders, but did not vary by diagnosis. Additionally, poor baseline sleep quality was independently associated with worse anxiety treatment outcome, as measured by higher intolerance of uncertainty. Additional intervention targeting sleep prior to or during CBT for anxiety may be beneficial for poor sleepers. PMID- 26244486 TI - Each tissue becomes master of its sex steroid environment at menopause. PMID- 26244487 TI - Endoparasites of the Eastern Rock Sengi (Elephantulus myurus) from South Africa. AB - The endoparasite fauna of the eastern rock sengi ( Elephantulus myurus Thomas and Schwann) was studied for the first time for any sengi species from September 2007 until August 2008 in the Limpopo Province of South Africa. From the 121 sengis examined, we recovered 11 endoparasite taxa, including 9 nematodes, 1 cestode family (Hymenolepididae), and 1 pentastomid species (Armillifer armillatus (Wyman, 1834)). The overall endoparasite prevalence was high, at 100%, and largely attributable to the nematode Maupasina weissi Seurat, 1913 , with only a single individual being parasite free. Despite the high diversity, species richness was low (1.58 +/- 0.06) and only M. weissi and spiruroid larvae occurred at a prevalence exceeding 8%. The abundance of M. weissi varied significantly between seasons and was lowest in summer and autumn. In contrast, the abundance of spiruroid larvae remained relatively constant across seasons in males, but was significantly higher in spring and summer compared to winter in females. These patterns may be generated by an accumulation of M. weissi with age as well as sex specific seasonal shifts in diet. An updated list on the hosts and geographic range of parasites of sengis is provided. PMID- 26244488 TI - Electronic Prescribing Usability: Reduction of Mental Workload and Prescribing Errors Among Community Physicians. AB - BACKGROUND: Medical errors are common in hospitals, and research is always needed to find ways of reducing these. This study attempts to address three gaps in this field. First, the factors leading to the reduction of mental workload and its relationship with the reduction of prescribing errors by improving electronic prescribing (e-prescribing) usability have not been empirically examined before. Second, the past research in the field of e-prescribing usability lacks robust theoretical models. Third, there are no existing studies to examine the direct influences of user interface consistency and error prevention with the reduction of mental workload and prescribing errors. MATERIALS AND METHODS: A quantitative survey method was used to collect data from 188 community physicians. The partial least squares path modeling technique was applied to analyze the data. RESULTS: Prescribing errors were reduced by improving the information quality, user interface consistency, system ease of use, and mental workload reduction. Mental workload is reduced by ease of use, error prevention, and consistency. No significant relationships between prescribing error reduction with error prevention and also between information quality with mental workload reduction were found. CONCLUSIONS: The designers of e-prescribing should improve the error prevention and consistency of the system and make it easy to use if they wish for the system to reduce users' mental workload. They should also improve the system information quality, ease of use, and consistency if they claim that their system reduces physicians' prescribing errors. The system should also reduce users' mental workload to meet this objective. PMID- 26244489 TI - Tuning steric and electronic effects in transition-metal beta-diketiminate complexes. AB - beta-Diketiminates are widely used supporting ligands for building a range of metal complexes with different oxidation states, structures, and reactivities. This Perspective summarizes the steric and electronic influences of ligand substituents on these complexes, with an eye toward informing the design of new complexes with optimized properties. The backbone and N-aryl substituents can give significant steric effects on structure, reactivity and selectivity of reactions. The electron density on the metal can be tuned by installation of electron withdrawing or donating groups on the beta-diketiminate ligand as well. Examples are shown from throughout the transition metal series to demonstrate different types of effects attributable to systematic variation of beta diketiminate ligands. PMID- 26244490 TI - The Role of Bone Marrow Fat in Skeletal Health: Usefulness and Perspectives for Clinicians. AB - CONTEXT: There is growing interest in the relationship between bone marrow fat (BMF), bone mineral density (BMD), and fractures. Moreover, BMF might be influenced by metabolic diseases associated with bone loss and fractures, such as type 2 diabetes mellitus (T2DM), anorexia nervosa (AN), and obesity. METHODS: The primary-source literature for this review was acquired using a PubMed search for articles published between January 2000 and April 2015. Search terms included BMF, BMD, fractures, T2DM, AN, and obesity. The titles and abstracts of all articles were reviewed for relevant subjects. RESULTS: Magnetic resonance imaging, with or without spectroscopy, was used to noninvasively quantify BMF in humans. A negative relationship was found between BMD and BMF in both healthy and osteopenic/osteoporotic populations. Data are lacking on the relationship between BMF and fractures. Studies in populations of individuals with metabolic diseases such as T2DM, AN, and obesity have shown BMF abnormalities. CONCLUSIONS: We conclude that most human data demonstrate an inverse relationship between BMF and BMD, but data on the relationship with fractures are inconsistent and need further study. In daily practice, the usefulness for clinicians of assessing BMF using magnetic resonance imaging is still limited. However, the perspectives are exciting, particularly in terms of improving the diagnosis and management of osteoporosis. PMID- 26244491 TI - The Incidence of Cancer Among Acromegaly Patients: Results From the German Acromegaly Registry. AB - CONTEXT: Acromegaly is a rare disease characterized by high serum levels of GH and IGF-1. Animal studies have demonstrated links between these hormones and cancer, but data regarding cancer incidence among acromegaly patients are inconsistent. Moreover, therapy options have changed considerably since many of the aforementioned data were collected. OBJECTIVE: The objective was to determine whether the overall and site-specific incidence of cancer is comparable to that of the general population. DESIGN AND SETTING: Data from the German Acromegaly Registry for 446 patients (6656 person-years from diagnosis) treated in seven specialized endocrine centers were analyzed. MAIN OUTCOME MEASURE: Standard incidence ratios (SIRs) were calculated as compared to the general population. RESULTS: Overall cancer incidence was slightly but not significantly lower than in the general population (SIR, 0.75; 95% confidence interval, 0.55 to 1.00; P = .051) and was not significantly higher for colorectal, breast, thyroid, prostate, and lung cancers. The SIRs of those with GH in the ranges <1, 1-2.5, and >= 2.5 ng/mL were 0.75, 0.44, and 0.92, respectively (P = .94). There was not a significant dependence on normal vs elevated IGF-1 (P = .87), radiation therapy (P = .45), disease duration (P = .96), age at diagnosis (P = .15), or during a period of high GH and IGF-1 from 8 years before to 2 years after diagnosis of acromegaly (P = .41). CONCLUSIONS: Cancer screening strategies need to take incidence into account, which does not seem to be substantially higher in treated acromegaly patients than in the general population for any site of cancer. PMID- 26244492 TI - CORRIGENDUM. PMID- 26244494 TI - Blame the Patient, Blame the Doctor or Blame the System? A Meta-Synthesis of Qualitative Studies of Patient Safety in Primary Care. AB - OBJECTIVE: Studies of patient safety in health care have traditionally focused on hospital medicine. However, recent years have seen more research located in primary care settings which have different features compared to secondary care. This study set out to synthesize published qualitative research concerning patient safety in primary care in order to build a conceptual model. METHOD: Meta ethnography, an interpretive synthesis method whereby third order interpretations are produced that best describe the groups of findings contained in the reports of primary studies. RESULTS: Forty-eight studies were included as 5 discrete subsets where the findings were translated into one another: patients' perspectives of safety, staff perspectives of safety, medication safety, systems or organisational issues and the primary/secondary care interface. The studies were focused predominantly on issues seen to either improve or compromise patient safety. These issues related to the characteristics or behaviour of patients, staff or clinical systems and interactions between staff, patients and staff, or people and systems. Electronic health records, protocols and guidelines could be seen to both degrade and improve patient safety in different circumstances. A conceptual reading of the studies pointed to patient safety as a subjective feeling or judgement grounded in moral views and with potentially hidden psychological consequences affecting care processes and relationships. The main threats to safety appeared to derive from 'grand' systems issues, for example involving service accessibility, resources or working hours which may not be amenable to effective intervention by individual practices or health workers, especially in the context of a public health system. CONCLUSION: Overall, the findings underline the human elements in patient safety primary health care. The key to patient safety lies in effective face-to-face communication between patients and health care staff or between the different staff involved in the care of an individual patient. Electronic systems can compromise safety when they override the opportunities for face-to-face communication. The circumstances under which guidelines or protocols are seen to either compromise or improve patient safety needs further investigation. PMID- 26244495 TI - Functional Activation of the Flagellar Type III Secretion Export Apparatus. AB - Flagella are assembled sequentially from the inside-out with morphogenetic checkpoints that enforce the temporal order of subunit addition. Here we show that flagellar basal bodies fail to proceed to hook assembly at high frequency in the absence of the monotopic protein SwrB of Bacillus subtilis. Genetic suppressor analysis indicates that SwrB activates the flagellar type III secretion export apparatus by the membrane protein FliP. Furthermore, mutants defective in the flagellar C-ring phenocopy the absence of SwrB for reduced hook frequency and C-ring defects may be bypassed either by SwrB overexpression or by a gain-of-function allele in the polymerization domain of FliG. We conclude that SwrB enhances the probability that the flagellar basal body adopts a conformation proficient for secretion to ensure that rod and hook subunits are not secreted in the absence of a suitable platform on which to polymerize. PMID- 26244496 TI - An siRNA Screen Identifies the U2 snRNP Spliceosome as a Host Restriction Factor for Recombinant Adeno-associated Viruses. AB - Adeno-associated viruses (AAV) have evolved to exploit the dynamic reorganization of host cell machinery during co-infection by adenoviruses and other helper viruses. In the absence of helper viruses, host factors such as the proteasome and DNA damage response machinery have been shown to effectively inhibit AAV transduction by restricting processes ranging from nuclear entry to second-strand DNA synthesis. To identify host factors that might affect other key steps in AAV infection, we screened an siRNA library that revealed several candidate genes including the PHD finger-like domain protein 5A (PHF5A), a U2 snRNP-associated protein. Disruption of PHF5A expression selectively enhanced transgene expression from AAV by increasing transcript levels and appears to influence a step after second-strand synthesis in a serotype and cell type-independent manner. Genetic disruption of U2 snRNP and associated proteins, such as SF3B1 and U2AF1, also increased expression from AAV vector, suggesting the critical role of U2 snRNP spliceosome complex in this host-mediated restriction. Notably, adenoviral co infection and U2 snRNP inhibition appeared to target a common pathway in increasing expression from AAV vectors. Moreover, pharmacological inhibition of U2 snRNP by meayamycin B, a potent SF3B1 inhibitor, substantially enhanced AAV vector transduction of clinically relevant cell types. Further analysis suggested that U2 snRNP proteins suppress AAV vector transgene expression through direct recognition of intact AAV capsids. In summary, we identify U2 snRNP and associated splicing factors, which are known to be affected during adenoviral infection, as novel host restriction factors that effectively limit AAV transgene expression. Concurrently, we postulate that pharmacological/genetic manipulation of components of the spliceosomal machinery might enable more effective gene transfer modalities with recombinant AAV vectors. PMID- 26244497 TI - Complexity of Multi-Channel Electroencephalogram Signal Analysis in Childhood Absence Epilepsy. AB - Absence epilepsy is an important epileptic syndrome in children. Multiscale entropy (MSE), an entropy-based method to measure dynamic complexity at multiple temporal scales, is helpful to disclose the information of brain connectivity. This study investigated the complexity of electroencephalogram (EEG) signals using MSE in children with absence epilepsy. In this research, EEG signals from 19 channels of the entire brain in 21 children aged 5-12 years with absence epilepsy were analyzed. The EEG signals of pre-ictal (before seizure) and ictal states (during seizure) were analyzed by sample entropy (SamEn) and MSE methods. Variations of complexity index (CI), which was calculated from MSE, from the pre ictal to the ictal states were also analyzed. The entropy values in the pre-ictal state were significantly higher than those in the ictal state. The MSE revealed more differences in analysis compared to the SamEn. The occurrence of absence seizures decreased the CI in all channels. Changes in CI were also significantly greater in the frontal and central parts of the brain, indicating fronto-central cortical involvement of "cortico-thalamo-cortical network" in the occurrence of generalized spike and wave discharges during absence seizures. Moreover, higher sampling frequency was more sensitive in detecting functional changes in the ictal state. There was significantly higher correlation in ictal states in the same patient in different seizures but there were great differences in CI among different patients, indicating that CI changes were consistent in different absence seizures in the same patient but not from patient to patient. This implies that the brain stays in a homogeneous activation state during the absence seizures. In conclusion, MSE analysis is better than SamEn analysis to analyze complexity of EEG, and CI can be used to investigate the functional brain changes during absence seizures. PMID- 26244498 TI - Stimulation of Cell Elongation by Tetraploidy in Hypocotyls of Dark-Grown Arabidopsis Seedlings. AB - Plant size is largely determined by the size of individual cells. A number of studies showed a link between ploidy and cell size in land plants, but this link remains controversial. In this study, post-germination growth, which occurs entirely by cell elongation, was examined in diploid and autotetraploid hypocotyls of Arabidopsis thaliana (L.) Heynh. Final hypocotyl length was longer in tetraploid plants than in diploid plants, particularly when seedlings were grown in the dark. The longer hypocotyl in the tetraploid seedlings developed as a result of enhanced cell elongation rather than by an increase in cell number. DNA microarray analysis showed that genes involved in the transport of cuticle precursors were downregulated in a defined region of the tetraploid hypocotyl when compared to the diploid hypocotyl. Cuticle permeability, as assessed by toluidine-blue staining, and cuticular structure, as visualized by electron microscopy, were altered in tetraploid plants. Taken together, these data indicate that promotion of cell elongation is responsible for ploidy-dependent size determination in the Arabidopsis hypocotyl, and that this process is directly or indirectly related to cuticular function. PMID- 26244499 TI - Quantitative Influence of ABO Blood Groups on Factor VIII and Its Ratio to von Willebrand Factor, Novel Observations from an ARIC Study of 11,673 Subjects. AB - ABO blood groups are known to influence the plasma level of von Willebrand factor (VWF), but little is known about the relationship between ABO and coagulation factor VIII (FVIII). We analyzed the influence of ABO genotypes on VWF antigen, FVIII activity, and their quantitative relationship in 11,673 participants in the Atherosclerosis Risk in Communities (ARIC) study. VWF, FVIII, and FVIII/VWF levels varied significantly among O, A (A1 and A2), B and AB subjects, and the extent of which varied between Americans of European (EA) and African (AA) descent. We validated a strong influence of ABO blood type on VWF levels (15.2%), but also detected a direct ABO influence on FVIII activity (0.6%) and FVIII/VWF ratio (3.8%) after adjustment for VWF. We determined that FVIII activity changed 0.54% for every 1% change in VWF antigen level. This VWF-FVIII relationship differed between subjects with O and B blood types in EA, AA, and in male, but not female subjects. Variations in FVIII activity were primarily detected at low VWF levels. These new quantitative influences on VWF, FVIII and the FVIII/VWF ratio help understand how ABO genotypes differentially influence VWF, FVIII and their ratio, particularly in racial and gender specific manners. PMID- 26244500 TI - Two Novel De Novo GARS Mutations Cause Early-Onset Axonal Charcot-Marie-Tooth Disease. AB - BACKGROUND: Mutations in the GARS gene have been identified in a small number of patients with Charcot-Marie-Tooth disease (CMT) type 2D or distal spinal muscular atrophy type V, for whom disease onset typically occurs during adolescence or young adulthood, initially manifesting as weakness and atrophy of the hand muscles. The role of GARS mutations in patients with inherited neuropathies in Taiwan remains elusive. METHODOLOGY AND PRINCIPAL FINDINGS: Mutational analyses of the coding regions of GARS were performed using targeted sequencing of 54 patients with molecularly unassigned axonal CMT, who were selected from 340 unrelated CMT patients. Two heterozygous mutations in GARS, p.Asp146Tyr and p.Met238Arg, were identified; one in each patient. Both are novel de novo mutations. The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability. CONCLUSION: GARS mutations are an uncommon cause of CMT in Taiwan. The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT. These findings broaden the mutational spectrum of GARS and also highlight the importance of considering GARS mutations as a disease cause in patients with early-onset neuropathies. PMID- 26244501 TI - Avian Reovirus Protein p17 Functions as a Nucleoporin Tpr Suppressor Leading to Activation of p53, p21 and PTEN and Inactivation of PI3K/AKT/mTOR and ERK Signaling Pathways. AB - Avian reovirus (ARV) protein p17 has been shown to regulate cell cycle and autophagy by activation of p53/PTEN pathway; nevertheless, it is still unclear how p53 and PTEN are activated by p17. Here, we report for the first time that p17 functions as a nucleoporin Tpr suppressor that leads to p53 nuclear accumulation and consequently activates p53, p21, and PTEN. The nuclear localization signal (119IAAKRGRQLD128) of p17 has been identified for Tpr binding. This study has shown that Tpr suppression occurs by p17 interacting with Tpr and by reducing the transcription level of Tpr, which together inhibit Tpr function. In addition to upregulation of PTEN by activation of p53 pathway, this study also suggests that ARV protein p17 acts as a positive regulator of PTEN. ARV p17 stabilizes PTEN by stimulating phosphorylation of cytoplasmic PTEN and by elevating Rak-PTEN association to prevent it from E3 ligase NEDD4-1 targeting. To activate PTEN, p17 is able to promote beta-arrestin-mediated PTEN translocation from the cytoplasm to the plasma membrane via a Rock-1-dependent manner. The accumulation of p53 in the nucleus induces the PTEN- and p21-mediated downregulation of cyclin D1 and CDK4. Furthermore, Tpr and CDK4 knockdown increased virus production in contrast to depletion of p53, PTEN, and LC3 reducing virus yield. Taken together, our data suggest that p17-mediated Tpr suppression positively regulates p53, PTEN, and p21 and negatively regulates PI3K/AKT/mTOR and ERK signaling pathways, both of which are beneficial for virus replication. PMID- 26244502 TI - Transcriptomic Profiling of Virus-Host Cell Interactions following Chicken Anaemia Virus (CAV) Infection in an In Vivo Model. AB - Chicken Anaemia Virus (CAV) is an economically important virus that targets lymphoid and erythroblastoid progenitor cells leading to immunosuppression. This study aimed to investigate the interplay between viral infection and the host's immune response to better understand the pathways that lead to CAV-induced immunosuppression. To mimic vertical transmission of CAV in the absence of maternally-derived antibody, day-old chicks were infected and their responses measured at various time-points post-infection by qRT-PCR and gene expression microarrays. The kinetics of mRNA expression levels of signature cytokines of innate and adaptive immune responses were determined by qRT-PCR. The global gene expression profiles of mock-infected (control) and CAV-infected chickens at 14 dpi were also compared using a chicken immune-related 5K microarray. Although in the thymus there was evidence of induction of an innate immune response following CAV infection, this was limited in magnitude. There was little evidence of a Th1 adaptive immune response in any lymphoid tissue, as would normally be expected in response to viral infection. Most cytokines associated with Th1, Th2 or Treg subsets were down-regulated, except IL-2, IL-13, IL-10 and IFNgamma, which were all up-regulated in thymus and bone marrow. From the microarray studies, genes that exhibited significant (greater than 1.5-fold, false discovery rate <0.05) changes in expression in thymus and bone marrow on CAV infection were mainly associated with T-cell receptor signalling, immune response, transcriptional regulation, intracellular signalling and regulation of apoptosis. Expression levels of a number of adaptor proteins, such as src-like adaptor protein (SLA), a negative regulator of T-cell receptor signalling and the transcription factor Special AT-rich Binding Protein 1 (SATB1), were significantly down-regulated by CAV infection, suggesting potential roles for these genes as regulators of viral infection or cell defence. These results extend our understanding of CAV-induced immunosuppression and suggest a global immune dysregulation following CAV infection. PMID- 26244503 TI - Iron Stores, Hepcidin, and Aortic Stiffness in Individuals with Hypertension. AB - BACKGROUND & AIMS: Iron accumulation within the arterial wall has been hypothesized to promote atherosclerosis progression. Aim of this study was to evaluate whether the hormone hepcidin and iron stores are associated with arterial stiffness in subjects with essential hypertension. METHODS: Circulating hepcidin, ferritin, and mutations in the hemochromatosis gene were compared between subjects included in the first vs. third tertile (n=284 each) of carotid femoral pulse wave velocity (PWV) in an unselected cohort of patients with arterial hypertension. RESULTS: At univariate logistic regression analysis, high PWV was associated with higher ferritin levels (p=0.010), but lower hepcidin (p=0.045), and hepcidin ferritin/ratio (p<0.001). Hemochromatosis mutations predisposing to iron overload were associated with high PWV (p=0.025). At multivariate logistic regression analysis, high aortic stiffness was associated with older age, male sex, lower BMI, higher systolic blood pressure and heart rate, hyperferritinemia (OR 2.05, 95% c.i. 1.11-3.17 per log ng/ml; p=0.022), and lower circulating hepcidin concentration (OR 0.29, 95% c.i. 0.16-0.51 per log ng/ml; p<0.001). In subgroup analyses, high PWV was associated with indices of target organ damage, including micro-albuminuria (n=125, p=0.038), lower ejection fraction (n=175, p=0.031), cardiac diastolic dysfunction (p=0.004), and lower S wave peak systolic velocity (p<0.001). Ferritin was associated with cardiac diastolic dysfunction, independently of confounders (p=0.006). CONCLUSIONS: In conclusion, hyperferritinemia is associated with high aortic stiffness and cardiac diastolic dysfunction, while low circulating hepcidin with high aortic stiffness. PMID- 26244504 TI - Virulence Characterization of Salmonella enterica by a New Microarray: Detection and Evaluation of the Cytolethal Distending Toxin Gene Activity in the Unusual Host S. Typhimurium. AB - Salmonella enterica is a zoonotic foodborne pathogen that causes acute gastroenteritis in humans. We assessed the virulence potential of one-hundred and six Salmonella strains isolated from food animals and products. A high through put virulence genes microarray demonstrated Salmonella Pathogenicity Islands (SPI) and adherence genes were highly conserved, while prophages and virulence plasmid genes were variably present. Isolates were grouped by serotype, and virulence plasmids separated S. Typhimurium in two clusters. Atypical microarray results lead to whole genome sequencing (WGS) of S. Infantis Sal147, which identified deletion of thirty-eight SPI-1 genes. Sal147 was unable to invade HeLa cells and showed reduced mortality in Galleria mellonella infection model, in comparison to a SPI-1 harbouring S. Infantis. Microarray and WGS of S. Typhimurium Sal199, established for the first time in S. Typhimurium presence of cdtB and other Typhi-related genes. Characterization of Sal199 showed cdtB genes were upstream of transposase IS911, and co-expressed with other Typhi-related genes. Cell cycle arrest, cytoplasmic distension, and nuclear enlargement were detected in HeLa cells infected by Sal199, but not with S. Typhimurium LT2. Increased mortality of Galleria was detected on infection with Sal199 compared to LT2. Thus, Salmonella isolates were rapidly characterized using a high through put microarray; helping to identify unusual virulence features which were corroborated by further characterisation. This work demonstrates that the use of suitable screening methods for Salmonella virulence can help assess the potential risk associated with certain Salmonella to humans. Incorporation of such methodology into surveillance could help reduce the risk of emergence of epidemic Salmonella strains. PMID- 26244505 TI - The Association between Maternal 25-Hydroxyvitamin D Concentration during Gestation and Early Childhood Cardio-metabolic Outcomes: Is There Interaction with Pre-Pregnancy BMI? AB - Both maternal 25-hydroxyvitamin D (25OHD) status and pre-pregnancy BMI (pBMI) may influence offspring cardio-metabolic outcomes. Lower 25OHD concentrations have been observed in women with both low and high pBMIs, but the combined influence of pBMI and 25OHD on offspring cardio-metabolic outcomes is unknown. Therefore, this study investigated the role of pBMI in the association between maternal 25OHD concentration and cardio-metabolic outcomes in 5-6 year old children. Data were obtained from the ABCD cohort study and 1882 mother-child pairs were included. The offspring outcomes investigated were systolic and diastolic blood pressure, heart rate, BMI, body fat percentage (%BF), waist-to-height ratio, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, glucose, C peptide, and insulin resistance (HOMA2-IR). 62% of the C-peptide samples were below the detection limit and were thus imputed using survival analysis. Models were corrected for maternal and offspring covariates and tested for interaction with pBMI. Interaction with pBMI was observed in the associations with insulin resistance markers: in offspring of overweight mothers (>=25.0 kg/m2), a 10 nmol/L increase in maternal 25OHD was associated with a 0.007(99%CI:-0.01,-0.001) nmol/L decrease in C-peptide and a 0.02(99%CI:-0.03,-0.004) decrease in HOMA2-IR. When only non-imputed data were analyzed, there was a trend for interaction in the relationship but the results lost significance. Interaction with pBMI was not observed for the other outcomes. A 10 nmol/L increase in maternal 25OHD was significantly associated with a 0.13%(99%CI:-0.3,-0.003) decrease in %BF after correction for maternal and child covariates. Thus, intrauterine exposure to both low 25OHD and maternal overweight may be associated with increased insulin resistance in offspring, while exposure to low 25OHD in utero may be associated with increased offspring %BF with no interactive effects from pBMI. Due to the limitations of this study, these results are not conclusive, however the observations of this study pose important research questions for future studies to investigate. PMID- 26244507 TI - Correction: Morphological and Molecular Revision of the Genus Ozirhincus (Diptera: Cecidomyiidae)-Long-Snouted Seed-Feeding Gall Midges on Asteraceae. PMID- 26244506 TI - The Gonococcal Transcriptome during Infection of the Lower Genital Tract in Women. AB - Gonorrhea is a highly prevalent disease resulting in significant morbidity worldwide, with an estimated 106 cases reported annually. Neisseria gonorrhoeae, the causative agent of gonorrhea, colonizes and infects the human genital tract and often evades host immune mechanisms until successful antibiotic treatment is used. The alarming increase in antibiotic-resistant strains of N. gonorrhoeae, the often asymptomatic nature of this disease in women and the lack of a vaccine directed at crucial virulence determinants have prompted us to perform transcriptome analysis to understand gonococcal gene expression patterns during natural infection. We sequenced RNA extracted from cervico-vaginal lavage samples collected from women recently exposed to infected male partners and determined the complete N. gonorrhoeae transcriptome during infection of the lower genital tract in women. On average, 3.19% of total RNA isolated from female samples aligned to the N. gonorrhoeae NCCP11945 genome and 1750 gonococcal ORFs (65% of all protein-coding genes) were transcribed. High expression in vivo was observed in genes encoding antimicrobial efflux pumps, iron response, phage production, pilin structure, outer membrane structures and hypothetical proteins. A parallel analysis was performed using the same strains grown in vitro in a chemically defined media (CDM). A total of 140 genes were increased in expression during natural infection compared to growth in CDM, and 165 genes were decreased in expression. Large differences were found in gene expression profiles under each condition, particularly with genes involved in DNA and RNA processing, iron, transposase, pilin and lipoproteins. We specifically interrogated genes encoding DNA binding regulators and iron-scavenging proteins, and identified increased expression of several iron-regulated genes, including tbpAB and fbpAB, during infection in women as compared to growth in vitro, suggesting that during infection of the genital tract in women, the gonococcus is exposed to an iron deplete environment. Collectively, we demonstrate that a large portion of the gonococcal genome is expressed and regulated during mucosal infection including genes involved in regulatory functions and iron scavenging. PMID- 26244508 TI - Are the SSB-Interacting Proteins RecO, RecG, PriA and the DnaB-Interacting Protein Rep Bound to Progressing Replication Forks in Escherichia coli? AB - In all organisms several enzymes that are needed upon replication impediment are targeted to replication forks by interaction with a replication protein. In most cases these proteins interact with the polymerase clamp or with single-stranded DNA binding proteins (SSB). In Escherichia coli an accessory replicative helicase was also shown to interact with the DnaB replicative helicase. Here we have used cytological observation of Venus fluorescent fusion proteins expressed from their endogenous loci in live E. coli cells to determine whether DNA repair and replication restart proteins that interact with a replication protein travel with replication forks. A custom-made microscope that detects active replisome molecules provided that they are present in at least three copies was used. Neither the recombination proteins RecO and RecG, nor the replication accessory helicase Rep are detected specifically in replicating cells in our assay, indicating that either they are not present at progressing replication forks or they are present in less than three copies. The Venus-PriA fusion protein formed foci even in the absence of replication forks, which prevented us from reaching a conclusion. PMID- 26244509 TI - Prenatal Exposure to DEHP Affects Spermatogenesis and Sperm DNA Methylation in a Strain-Dependent Manner. AB - Di-(2-ethylhexyl)phtalate (DEHP) is a plasticizer with endocrine disrupting properties found ubiquitously in the environment and altering reproduction in rodents. Here we investigated the impact of prenatal exposure to DEHP on spermatogenesis and DNA sperm methylation in two distinct, selected, and sequenced mice strains. FVB/N and C57BL/6J mice were orally exposed to 300 mg/kg/day of DEHP from gestation day 9 to 19. Prenatal DEHP exposure significantly decreased spermatogenesis in C57BL/6J (fold-change = 0.6, p-value = 8.7*10-4), but not in FVB/N (fold-change = 1, p-value = 0.9). The number of differentially methylated regions (DMRs) by DEHP-exposure across the entire genome showed increased hyper- and decreased hypo-methylation in C57BL/6J compared to FVB/N. At the promoter level, three important subsets of genes were massively affected. Promoters of vomeronasal and olfactory receptors coding genes globally followed the same trend, more pronounced in the C57BL/6J strain, of being hyper-methylated in DEHP related conditions. In contrast, a large set of micro-RNAs were hypo-methylated, with a trend more pronounced in the FVB/N strain. We additionally analyze both the presence of functional genetic variations within genes that were associated with the detected DMRs and that could be involved in spermatogenesis, and DMRs related with the DEHP exposure that affected both strains in an opposite manner. The major finding in this study indicates that prenatal exposure to DEHP can decrease spermatogenesis in a strain dependent manner and affects sperm DNA methylation in promoters of large sets of genes putatively involved in both sperm chemotaxis and post-transcriptional regulatory mechanisms. PMID- 26244511 TI - Better to Be in Bad Company than to Be Alone? Aedes Vectors Respond Differently to Breeding Site Quality in the Presence of Others. AB - This study focuses on two competing species, Aedes aegypti and Aedes albopictus (Diptera: Culicidae), both invasive mosquitoes of the New World. Context-specific competition between immature forms inside containers seems to be an important determinant of the coexistence or displacement of each species in different regions of the world. Here, competition experiments developed at low density (one, two or three larvae) and receiving four different resource food concentration, were designed to test whether Ae. albopictus and Ae. aegypti respond differently to competition, and whether competition can be attributed to a simple division of resources. Three phenotypic traits - larval development, adult survival under starvation and wing length - were used as indicators of performance. Larvae of neither species were limited by resource concentration when they were alone, unlike when they developed with competitors. The presence of conspecifics affected Ae. aegypti and Ae. albopictus, inducing slower development, reduced survival and wing length. The response to resource limitation was different when developing with heterospecifics: Ae. aegypti developing with one heterospecific showed faster development, producing smaller adults with shorter lives, while in the presence of two competitors, development increased and adults lived longer. Aedes albopictus demonstrated a better performance when developing with heterospecifics, with no loss in their development period and improved adult survival. Overall, our results suggest that response to competition can not simply be attributed to the division of resources, and that larvae of both species presented large phenotypic plasticity in their response to the presence or absence of heterospecifics and conspecifics. PMID- 26244510 TI - A Snack Dietary Pattern Increases the Risk of Hypercholesterolemia in Northern Chinese Adults: A Prospective Cohort Study. AB - The evidence about the effect of dietary patterns on blood cholesterol from cohort studies was very scarce. The study was to identify the association of dietary patterns with lipid profile, especially cholesterol, in a cohort in north China. Using a 1-year food frequency questionnaire, we assessed the dietary intake of 4515 adults from the Harbin People's Health Study in 2008, aged 20-74 years. Principle component analysis was used to identify dietary patterns. The follow-up was completed in 2012. Fasting blood samples were collected for the determination of blood lipid concentrations. Logistic regression models were used to evaluate the association of dietary patterns with the incidence of hypercholesterolemia, hypertriglyceridemia, and low-HDL cholesterolemia. Five dietary patterns were identified ("staple food", "vegetable, fruit and milk", "potato, soybean and egg", "snack", and "meat"). The relative risk (RR) between the extreme tertiles of the snack dietary pattern scores was 1.72 (95% CI = 1.14, 2.59, P = 0.004) for hypercholesterolemia, 1.39 (1.13, 1.75, P = 0.036) for hypertriglyceridemia, after adjustment for age, sex, education, body mass index, smoking, alcohol consumption, energy intake, exercise and baseline lipid concentrations. There was a significant positive association between the snack dietary pattern scores and fasting serum total cholesterol (SRC (standardized regression coefficient) = 0.262, P = 0.025), LDL-c (SRC = 0.324, P = 0.002) and triglycerides (SRC = 0.253, P = 0.035), after adjustment for the multiple variables above. Moreover, the adjusted RR of hypertriglyceridemia between the extreme tertiles was 0.73 (0.56, 0.94, P = 0.025) for the vegetable, fruit and milk dietary pattern, and 1.86 (1.33, 2.41, P = 0.005) for the meat dietary pattern. The snack dietary pattern was a newly emerged dietary pattern in northern Chinese adults. It appears conceivable that the risk of hypercholesterolemia can be reduced by changing the snack dietary pattern. PMID- 26244513 TI - Correction: Didymosphenia geminata in the Upper Esopus Creek: Current Status, Variability, and Controlling Factors. PMID- 26244512 TI - The Burden and Determinants of Non Communicable Diseases Risk Factors in Nepal: Findings from a Nationwide STEPS Survey. AB - BACKGROUND: World Health Organization (WHO) estimates for deaths attributed to Non Communicable Diseases (NCDs) in Nepal have risen from 51% in 2010 to 60% in 2014. This study assessed the distribution and determinants of NCD risk factors among the Nepalese adult population. METHODS AND FINDINGS: A nationally representative cross-sectional survey was conducted from Jan to June 2013 on the prevalence of NCD risk factors using the WHO NCD STEPS instrument. A multistage cluster sampling method was used to randomly select the 4,200 respondents. The adjusted prevalence ratio (APR) was used to assess the determinants of NCD risk factors using a Poisson regression model. The prevalence of current smoking (last 30 days) was 19% (95%CI:16.6-20.6), and harmful alcohol consumption (>=60 g of pure alcohol for men and >=40 g of pure alcohol for women on an average day) was 2% (95%CI:1.4-2.9). Almost all (99%, 95%CI:98.3-99.3) of the respondents consumed less than five servings of fruits and vegetables combined on an average day and 3% (95%CI:2.7-4.3) had low physical activity. Around 21% (95%CI:19.3-23.7) were overweight or obese (BMI>=25). The prevalence of raised blood pressure (SBP>=140 mm of Hg or DBP>=90 mm of Hg) and raised blood glucose (fasting blood glucose >=126 mg/dl), including those on medication were 26% (95%CI:23.6-28.0) and 4% (95%CI:2.9-4.5) respectively. Almost one quarter of respondents, 23% (95%CI:20.5 24.9), had raised total cholesterol (total cholesterol >=190 mg/dl or under current medication for raised cholesterol). he study revealed a lower prevalence of smoking among women than men (APR:0.30; 95%CI:0.25-0.36), and in those who had higher education levels compared to those with no formal education (APR:0.39; 95%CI:0.26-0.58). Harmful alcohol use was also lower in women than men (APR:0.26; 95%CI:0.14-0.48), and in Terai residents compared to hill residents (APR:0.16; 95%CI:0.07-0.36). Physical inactivity was lower among women than men (APR:0.55; 95%CI:0.38-0.80), however women were significantly more overweight and obese (APR:1.19; 95%CI:1.02-1.39). Being overweight or obese was significantly less prevalent in mountain residents than in hill residents (APR:0.41; 95%CI:0.21 0.80), and in rural compared to urban residents (APR:1.39; 95%CI:1.15-1.67). Lower prevalence of raised blood pressure was observed among women than men (APR:0.69; 95%CI: 0.60-0.80). Higher prevalence of raised blood glucose was observed among urban residents compared to rural residents (APR:2.05; 95%CI:1.29 3.25). A higher prevalence of raised total cholesterol was observed among the respondents having higher education levels compared to those respondents having no formal education (APR:1.76; 95%CI:1.35-2.28). CONCLUSION: The prevalence of low fruit and vegetable consumption, overweight and obesity, raised blood pressure and raised total cholesterol is markedly high among the Nepalese population, with variation by demographic and ecological factors and urbanization. Prevention, treatment and control of NCDs and their risk factors in Nepal is an emerging public health problem in the country, and targeted interventions with a multi-sectoral approach need to be urgently implemented. PMID- 26244514 TI - The Majority of the Migrant Factory Workers of the Light Industry in Shenzhen, China May Be Physically Inactive. AB - Physical inactivity is a strong risk factor of non-communicable diseases (NCD). In China, there are 250 million migrant factory workers, who are susceptible to physical inactivity and hence NCD because of work nature and setting. With random stratified sampling, 807 such workers of the light industry were recruited in Shenzhen, China and completed a self-administered questionnaire with informed consent. The prevalence of inadequate physical activity (defined according to the World Health Organization's recommendation on level of moderate/vigorous physical activity) was 95.4%. Of all participants, 69.1% showed "a very low level of physical activity" (VLLPA), defined as <=30 minutes of weekly moderate/vigorous physical activity, which was significantly associated with female sex (Odds ratio [OR]=1.65), lower education level (OR=0.10 to 0.33, primary education as the reference group) and married status (OR=0.63, single status as the reference group). Adjusted for these factors, perceived social support (Adjusted OR=0.87) was negatively associated with VLLPA, while job stress due to workload, which was significant in the univariate analysis (OR=0.98), became non-significant (p=0.184). Significant interaction between perceived social support and perceived job stress onto VLLPA was found (p=0.044), implying that the negative association between job stress and VLLPA, which might reflect a potential response to cope with stress by performing exercises, was stronger among those with weaker social support. The extremely low level of physical activity rings an alarm, as it implies high risk of NCD, and as there are no existing programs promoting physical activity in this group. Interventions need to take into account social support, potential coping to job stress, and structural factors of the factory setting, while involving factories' management. PMID- 26244515 TI - DNA Sequence Variants in the Five Prime Untranslated Region of the Cyclooxygenase 2 Gene Are Commonly Found in Healthy Dogs and Gray Wolves. AB - The aim of this study was to investigate the frequency of regional DNA variants upstream to the translation initiation site of the canine Cyclooxygenase-2 (Cox 2) gene in healthy dogs. Cox-2 plays a role in various disease conditions such as acute and chronic inflammation, osteoarthritis and malignancy. A role for Cox-2 DNA variants in genetic predisposition to canine renal dysplasia has been proposed and dog breeders have been encouraged to select against these DNA variants. We sequenced 272-422 bases in 152 dogs unaffected by renal dysplasia and found 19 different haplotypes including 11 genetic variants which had not been described previously. We genotyped 7 gray wolves to ascertain the wildtype variant and found that the wolves we analyzed had predominantly the second most common DNA variant found in dogs. Our results demonstrate an elevated level of regional polymorphism that appears to be a feature of healthy domesticated dogs. PMID- 26244516 TI - Factors Influencing Antiretroviral Adherence and Virological Outcomes in People Living with HIV in the Highlands of Papua New Guinea. AB - Adherence to antiretroviral therapy (ART) is paramount for virological suppression and positive treatment outcomes. ART has been rapidly scaled up in Papua New Guinea (PNG) in recent years, however clinical monitoring of HIV+ individuals on ART is limited. A cross-sectional study was conducted at two major sexual health clinics in high HIV prevalence provinces in the Highlands Region of PNG to assess ART adherence, factors affecting adherence and the relationship between ART adherence and virological outcomes. Ninety-five HIV+ individuals were recruited and administered a questionnaire to gather demographic and ART adherence information whilst clinical data and pill counts were extracted from patient charts and blood was collected for viral load testing. Bivariate analysis was performed to identify independent predictors of ART adherence. Fourteen percent (n = 12) of participants showed evidence of virological failure. Although the majority of participants self-reported excellent ART adherence in the last seven days (78.9%, 75/91), pill count measurements indicated only 40% (34/84) with >95% adherence in the last month. Taking other medications while on ART (p = 0.01) and taking ART for >=1 year (p = 0.037) were positively associated with adherence by self-report and pill count, respectively. Participants who had never heard of drug resistance were more likely to show virological failure (p = 0.033). Misconception on routes of HIV transmission still persists in the studied population. These findings indicate that non-adherence to ART is high in this region of PNG and continued education and strategies to improve adherence are required to ensure the efficacy of ART and prevent HIV drug resistance. PMID- 26244517 TI - Structural lipid changes and Na(+)/K(+)-ATPase activity of gill cells' basolateral membranes during saltwater acclimation in sea lamprey (Petromyzon marinus, L.) juveniles. AB - Seawater acclimation is a critical period for anadromous species and a process yet to be understood in lampreys. Considering that changes in lipid composition of the gill cells' basolateral membranes may disrupt the major transporter Na(+)K(+)-ATPase, the goal of this study was to detect changes at this level during juvenile sea lamprey seawater acclimation. The results showed that saltwater acclimation has a direct effect on the fatty acid composition of gill cells basolateral membrane's phospholipids. When held in full-strength seawater, the fatty acid profile of basolateral membrane's phospholipids suffered a restructure by increasing either saturation or the ratio between oleic acid and eicosapentaenoic acid. Simultaneously, the activity of Na(+)K(+)-ATPase revealed a significant and positive correlation with basolateral membrane's cholesterol content in the presence of highest salinity. Our results pointed out for lipid adjustments involving the functional transporter present on the gill cell basolateral membranes to ensure the role played by branchial Na(+)K(+)-ATPase in ion transport during saltwater acclimation process. The responses observed contributed to the strategy adopted by gill cell's basolateral membranes to compensate for osmotic and ionic stressors, to ensure the success of the process of seawater acclimation associated with the downstream trophic migration of juvenile sea lamprey. PMID- 26244518 TI - Effect of temperature on oxidative stress, antioxidant levels and uncoupling protein expression in striped hamsters. AB - According to the rate of living-free radical hypothesis, higher metabolic rates should increase reactive oxygen species (ROS) production. However, the "uncoupling to survive" hypothesis postulates that uncoupling proteins (UCPs) can decrease ROS production by lowering the potential of the inner mitochondrial membrane, in which case the correlation between metabolic rate and ROS levels would be a negative rather than positive. In this study, we examined energy intake, oxidative stress levels, antioxidant activity and the expression of UCPs in brown adipose tissue (BAT), and in the liver, heart, skeletal muscle and brain, of striped hamsters (Cricetulus barabensis) acclimated to either 5 degrees C or 32.5 degrees C. The energy intake of hamsters acclimated to 5 degrees C increased by 70.7%, whereas the energy intake of hamsters acclimated to 32.5 degrees C decreased by 31.3%, relative to hamsters kept at room temperature (21 degrees C) (P<0.05). Malonadialdehyde (MDA) levels, total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-PX) activity in BAT significantly decreased in 5 degrees C group, but increased in 32.5 degrees C group, relative to the 21 degrees C group. Neither ROS levels (i.e. H2O2 levels), nor antioxidants in skeletal muscle, liver, heart or brain tissue, were affected by temperature. UCP1 expression in BAT was significantly up-regulated in 5 degrees C group, but down-regulated in 32.5 degrees C group, relative to the 21 degrees C group. UCP3 expression of skeletal muscle was also up-regulated significantly in hamsters acclimated to 5 degrees C. These results suggest that the relationship between ROS levels and metabolic rate was negative, rather than positive. UCP1 expression in BAT may have played a role in lowering ROS levels. PMID- 26244519 TI - Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice. AB - AMPK is considered to have a role in regulating skeletal muscle mass. However, there are no studies investigating the function of AMPK in modulating skeletal muscle mass during atrophic conditions. In the present study, we investigated the difference in unloading-associated muscle atrophy and molecular functions in response to 2-wk hindlimb suspension between transgenic mice overexpressing the dominant-negative mutant of AMPK (AMPK-DN) and their wild-type (WT) littermates. Male WT (n = 24) and AMPK-DN (n = 24) mice were randomly divided into two groups: an untreated preexperimental control group (n = 12 in each group) and an unloading (n = 12 in each group) group. The relative soleus muscle weight and fiber cross-sectional area to body weight were decreased by ~30% in WT mice by hindlimb unloading and by ~20% in AMPK-DN mice. There were no changes in puromycin-labeled protein or Akt/70-kDa ribosomal S6 kinase signaling, the indicators of protein synthesis. The expressions of ubiquitinated proteins and muscle RING finger 1 mRNA and protein, markers of the ubiquitin-proteasome system, were increased by hindlimb unloading in WT mice but not in AMPK-DN mice. The expressions of molecules related to the protein degradation system, phosphorylated forkhead box class O3a, inhibitor of kappaBalpha, microRNA (miR) 1, and miR-23a, were decreased only in WT mice in response to hindlimb unloading, and 72-kDa heat shock protein expression was higher in AMPK-DN mice than in WT mice. These results imply that AMPK partially regulates unloading-induced atrophy of slow-twitch muscle possibly through modulation of the protein degradation system, especially the ubiquitin-proteasome system. PMID- 26244520 TI - Use of drug therapy in the management of symptomatic ureteric stones in hospitalised adults: a multicentre, placebo-controlled, randomised controlled trial and cost-effectiveness analysis of a calcium channel blocker (nifedipine) and an alpha-blocker (tamsulosin) (the SUSPEND trial). AB - BACKGROUND: Ureteric colic, the term used to describe the pain felt when a stone passes down the ureter from the kidney to the bladder, is a frequent reason for people to seek emergency health care. Treatment with the muscle-relaxant drugs tamsulosin hydrochloride (Petyme, TEVA UK Ltd) and nifedipine (Coracten((r)), UCB Pharma Ltd) as medical expulsive therapy (MET) is increasingly being used to improve the likelihood of spontaneous stone passage and lessen the need for interventional procedures. However, there remains considerable uncertainty around the effectiveness of these drugs for routine use. OBJECTIVES: To determine whether or not treatment with either tamsulosin 400 ug or nifedipine 30 mg for up to 4 weeks increases the rate of spontaneous stone passage for people with ureteric colic compared with placebo, and whether or not it is cost-effective for the UK NHS. DESIGN: A pragmatic, randomised controlled trial comparing two active drugs, tamsulosin and nifedipine, against placebo. Participants, clinicians and trial staff were blinded to treatment allocation. A cost-utility analysis was performed using data gathered during trial participation. SETTING: Urology departments in 24 UK NHS hospitals. PARTICIPANTS: Adults aged between 18 and 65 years admitted as an emergency with a single ureteric stone measuring <= 10 mm, localised by computerised tomography, who were able to take trial medications and complete trial procedures. INTERVENTIONS: Eligible participants were randomised 1 : 1 : 1 to take tamsulosin 400 ug, nifedipine 30 mg or placebo once daily for up to 4 weeks to make the following comparisons: tamsulosin or nifedipine (MET) versus placebo and tamsulosin versus nifedipine. MAIN OUTCOME MEASURES: The primary effectiveness outcome was the proportion of participants who spontaneously passed their stone. This was defined as the lack of need for active intervention for ureteric stones at up to 4 weeks after randomisation. This was determined from 4- and 12-week case-report forms completed by research staff, and from the 4-week participant self-reported questionnaire. The primary economic outcome was the incremental cost per quality-adjusted life-year (QALY) gained over 12 weeks. We estimated costs from NHS sources and calculated QALYs from participant completion of the European Quality of Life-5 Dimensions health status questionnaire 3-level response (EQ-5D-3LTM) at baseline, 4 weeks and 12 weeks. RESULTS: Primary outcome analysis included 97% of the 1167 participants randomised (378/391 tamsulosin, 379/387 nifedipine and 379/399 placebo participants). The proportion of participants who spontaneously passed their stone did not differ between MET and placebo [odds ratio (OR) 1.04, 95% confidence interval (CI) 0.77 to 1.43; absolute difference 0.8%, 95% CI -4.1% to 5.7%] or between tamsulosin and nifedipine [OR 1.06, 95% CI 0.74 to 1.53; absolute difference 1%, 95% CI -4.6% to 6.6%]. There was no evidence of a difference in QALYs gained or in cost between the trial groups, which means that the use of MET would be very unlikely to be considered cost-effective. These findings were unchanged by extensive sensitivity analyses around predictors of stone passage, including sex, stone size and stone location. CONCLUSIONS: Tamsulosin and nifedipine did not increase the likelihood of stone passage over 4 weeks for people with ureteric colic, and use of these drugs is very unlikely to be cost-effective for the NHS. Further work is required to investigate the phenomenon of large, high-quality trials showing smaller effect size than meta analysis of several small, lower-quality studies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN69423238. European Clinical Trials Database (EudraCT) number 2010-019469-26. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 63. See the NIHR Journals Library website for further project information. PMID- 26244522 TI - Binding of the 5'-Triphosphate End of mRNA to the gamma-Subunit of Translation Initiation Factor 2 of the Crenarchaeon Sulfolobus solfataricus. AB - The heterotrimeric archaeal IF2 orthologue of eukaryotic translation initiation factor 2 consists of the alpha-subunit, beta-subunit and gamma-subunit. Previous studies showed that the gamma-subunit of aIF2, besides its central role in Met tRNAi binding, has an additional function: it binds to the 5'-triphosphorylated end of mRNA and protects its 5'-part from degradation. Competition studies with nucleotides and mRNA, as well as structural and kinetic analyses of aIF2gamma mutants, strongly implicate the canonical GTP/GDP-binding pocket in binding to the 5'-triphosphate end of mRNAs. The biological implication of these findings is being discussed. PMID- 26244523 TI - Localization of a bacterial group II intron-encoded protein in human cells. AB - Group II introns are mobile retroelements that self-splice from precursor RNAs to form ribonucleoparticles (RNP), which can invade new specific genomic DNA sites. This specificity can be reprogrammed, for insertion into any desired DNA site, making these introns useful tools for bacterial genetic engineering. However, previous studies have suggested that these elements may function inefficiently in eukaryotes. We investigated the subcellular distribution, in cultured human cells, of the protein encoded by the group II intron RmInt1 (IEP) and several mutants. We created fusions with yellow fluorescent protein (YFP) and with a FLAG epitope. We found that the IEP was localized in the nucleus and nucleolus of the cells. Remarkably, it also accumulated at the periphery of the nuclear matrix. We were also able to identify spliced lariat intron RNA, which co-immunoprecipitated with the IEP, suggesting that functional RmInt1 RNPs can be assembled in cultured human cells. PMID- 26244521 TI - Studying Cellular Signal Transduction with OMIC Technologies. AB - In the gulf between genotype and phenotype exists proteins and, in particular, protein signal transduction systems. These systems use a relatively limited parts list to respond to a much longer list of extracellular, environmental, and/or mechanical cues with rapidity and specificity. Most signaling networks function in a highly non-linear and often contextual manner. Furthermore, these processes occur dynamically across space and time. Because of these complexities, systems and "OMIC" approaches are essential for the study of signal transduction. One challenge in using OMIC-scale approaches to study signaling is that the "signal" can take different forms in different situations. Signals are encoded in diverse ways such as protein-protein interactions, enzyme activities, localizations, or post-translational modifications to proteins. Furthermore, in some cases, signals may be encoded only in the dynamics, duration, or rates of change of these features. Accordingly, systems-level analyses of signaling may need to integrate multiple experimental and/or computational approaches. As the field has progressed, the non-triviality of integrating experimental and computational analyses has become apparent. Successful use of OMIC methods to study signaling will require the "right" experiments and the "right" modeling approaches, and it is critical to consider both in the design phase of the project. In this review, we discuss common OMIC and modeling approaches for studying signaling, emphasizing the philosophical and practical considerations for effectively merging these two types of approaches to maximize the probability of obtaining reliable and novel insights into signaling biology. PMID- 26244524 TI - A New Approach to Delivering Important Publications From the American College of Obstetricians and Gynecologists. PMID- 26244526 TI - Not Your Grandfather's Prescription Pad. PMID- 26244528 TI - Abnormal Placentation: Placenta Previa, Vasa Previa, and Placenta Accreta. AB - Placental disorders such as placenta previa, placenta accreta, and vasa previa are all associated with vaginal bleeding in the second half of pregnancy. They are also important causes of serious fetal and maternal morbidity and even mortality. Moreover, the rates of previa and accreta are increasing, probably as a result of increasing rates of cesarean delivery, maternal age, and assisted reproductive technology. The routine use of obstetric ultrasonography as well as improving ultrasonographic technology allows for the antenatal diagnosis of these conditions. In turn, antenatal diagnosis facilitates optimal obstetric management. This review emphasizes an evidence-based approach to the clinical management of pregnancies with these conditions as well as highlights important knowledge gaps. PMID- 26244529 TI - Characteristics of Long-Term Survivors of Epithelial Ovarian Cancer. AB - OBJECTIVE: To identify characteristics associated with long-term survival for patients with epithelial ovarian cancer using the California Cancer Registry. METHODS: A descriptive analysis of survival of all California residents diagnosed with epithelial ovarian cancer between 1994 and 2001 was conducted using patients identified through the cancer registry with follow-up through 2011. Characteristics of the patients who survived more than 10 years (long-term survivors) were compared with three other cohorts: patients who survived less than 2 years, those who survived at least 2 but no more than 5 years, and those who survived at least 5 but no more than 10 years. RESULTS: A total of 3,582 out of 11,541 (31%, confidence interval 30.2-31.8%) of the patients survived more than 10 years. Younger age, early stage, low-grade, and nonserous histology were significant predictors of long-term survival, but long-term survivors also included women with high-risk cancer. CONCLUSION: Long-term survival is not unusual in patients with epithelial ovarian cancer, even in those with high-risk disease. Many of the prognostic factors are well known, but it remains to be determined why some patients with advanced-stage high-grade cancers survive longer than others with the same histology. These findings are important for patient counseling. LEVEL OF EVIDENCE: III. PMID- 26244530 TI - The Most Commonly Dispensed Prescription Medications Among Pregnant Women Enrolled in the U.S. Medicaid Program. AB - OBJECTIVE: To characterize the 20 most common prescription medications and the 10 most common prescription medications classified in the former U.S. Food and Drug Administration categories D or X dispensed to pregnant women enrolled in the U.S. Medicaid program. METHODS: We conducted a cohort study of 1,106,757 pregnant women with live births using 2000-2007 Medicaid Analytic eXtract data. We used outpatient pharmacy records to identify medication dispensings and reported the proportion of pregnancies that were dispensed at least one prescription medication. Maternal age and race and ethnicity-stratified estimates were compared using prevalence ratios and 95% confidence intervals (CIs). RESULTS: During pregnancy, 82.5% of the cohort had a dispensing for one or more prescription medication. The most commonly dispensed medications during pregnancy included nitrofurantoin (21.6%), metronidazole (19.4%), amoxicillin (18.0%), azithromycin (16.9%), and promethazine (13.5%). Proportions were highest among younger women for several medications; eg, nitrofurantoin (23.9% compared with 15.4%; prevalence ratio 1.55, CI 1.52-1.58), metronidazole (20.7% compared with 12.0%; prevalence ratio 1.73, CI 1.69-1.77), and azithromycin (21.1% compared with 11.0%; prevalence ratio 1.93, CI 1.89-1.97) were more common among women younger than 20 years than among women aged 35 years or older. Proportions were highest among white women with some exceptions; eg, compared with white women, metronidazole was more common among black women (29.8% compared with 14.4%; prevalence ratio 2.07, CI 2.05-2.09). Excluding fertility treatments, 42.0% had at least one dispensing for a D or X medication during pregnancy. Codeine (11.9%) and hydrocodone (10.2%) were the most common D medications. CONCLUSION: Medications used to treat infections were the most commonly dispensed prescription medications. Dispensing of commonly used prescription medications during pregnancy varied by maternal age and race-ethnicity. LEVEL OF EVIDENCE: II. PMID- 26244531 TI - Third-Trimester Prenatal Syphilis Screening: A Cost-Effectiveness Analysis. AB - OBJECTIVE: To estimate the cost to prevent one case of congenital syphilis or fetal or neonatal death with universal third-trimester syphilis rescreening in the United States and to estimate the incidence of syphilis seroconversion at which rescreening becomes cost-effective. METHODS: We created a decision model comparing universal third-trimester syphilis rescreening in women who screened negative in the first trimester with no rescreening. The assumed base case incidence of seroconversion was 0.012%. The primary outcome was the cost to prevent one case of congenital syphilis. Secondary outcomes included the cost to prevent one fetal or neonatal death and the number needed to rescreen to prevent one adverse outcome. A strategy was considered cost-effective if it cost less than $285,000 to prevent one case of congenital syphilis (the estimated long-term care cost). RESULTS: Under our assumptions, universal third-trimester rescreening would cost an additional $419,842 for each case of congenital syphilis prevented and $3,621,144 and $6,052,534, respectively, for each fetal and neonatal death prevented. Rescreening 4,000,000 women would prevent 60 cases of congenital syphilis and seven fetal and four neonatal deaths. Prevention of one case of congenital syphilis would require 65,790 women be rescreened. Seroconversion incidence of 0.017% would make third-trimester rescreening cost-effective. CONCLUSION: Universal third-trimester syphilis rescreening requires a large number of women be rescreened at a high health care cost to prevent one adverse outcome from maternal syphilis. Seroconversion incidence must be 19-fold higher than the national average of primary and secondary syphilis in women for universal third-trimester rescreening to be cost-effective. PMID- 26244532 TI - Characteristics and Management of Ovarian Torsion in Premenarchal Compared With Postmenarchal Patients. AB - OBJECTIVE: To compare the clinical, ultrasonographic, and operative characteristics of premenarchal and postmenarchal patients with surgically verified ovarian torsion. METHODS: A retrospective cohort study of all patients with surgically verified ovarian torsion operated on at a single university affiliated tertiary medical center during 1997-2013. Age at presentation, presenting symptoms, diagnostic studies, surgical procedure, and pathologic findings were analyzed. RESULTS: A total of 41 premenarchal and 208 postmenarchal patients were diagnosed with ovarian torsion during the study period. Median ages were 9 and 27 years, respectively. Median duration of symptoms before first presentation was longer among the premenarchal patients (24.0 compared with 8.0 hours, P<.001) as was the median interval from hospital admission to surgery (9.5 compared with 4.6 hours, P<.001). Premenarchal girls had a higher rate of restlessness, fever, and evidence of pelvic mass at presentation and a similar rate of ultrasonographic signs for torsion (78.5% compared with 73.1% P=.53). During surgery, a finding of a black-bluish ovary was more common in premenarchal girls (61.0% compared with 41.3%, P=.02). CONCLUSION: Ovarian torsion in premenarchal girls is associated with a longer interval from onset of symptoms and an increased rate of fever and pelvic mass at presentation compared with postmenarchal patients. These data may aid the physician in the evaluation of abdominal pain in premenarchal girls. LEVEL OF EVIDENCE: II. PMID- 26244533 TI - Association of Spouse Deployment on Pregnancy Outcomes in a U.S. Military Population. AB - OBJECTIVE: To evaluate the association of spousal deployment during the antenatal period on maternal and neonatal outcomes and to estimate whether group prenatal care may be beneficial in reducing adverse outcomes when spouses are deployed. METHODS: Primigravid women who delivered at Womack Army Medical Center, Fort Bragg, North Carolina, were prospectively enrolled and selected for participation on a random basis between January 2013 and January 2014. Women whose spouses were deployed to a combat zone during the entire pregnancy (deployed group) were compared with women whose spouses were not deployed during the pregnancy (nondeployed group). Pregnancy and neonatal outcomes were compared between groups. RESULTS: Three hundred ninety-seven women were enrolled with 183 (46.1%) in the deployed group and 214 (53.9%) in the nondeployed group. Spouse deployment was associated with increased risk of preterm delivery (38 [20.8%] compared with 16 [7.5%], P<.001) and postpartum depression (30 [16.4%] compared with 13 [6.1%], P=.001) when compared with women in the nondeployed group. There were no differences in the incidence of preterm delivery and postpartum depression for women in the deployed group who participated in group prenatal care when compared with women participating in traditional care (preterm delivery 6 [14.6%] compared with 32 [22.5%], P=.38; postpartum depression 4 [9.8%] compared with 26 [18.3%], P=.24). CONCLUSION: Women who have a spouse deployed during their pregnancy are at increased risk for preterm birth and postpartum depression. Larger studies are needed to evaluate whether spouse deployment during pregnancy has other perinatal effects and whether group prenatal care may have a positive effect on adverse perinatal outcomes in this population. LEVEL OF EVIDENCE: II. PMID- 26244534 TI - The North American Fetal Therapy Network Consensus Statement: Management of Complicated Monochorionic Gestations. AB - The North American Fetal Therapy Network is a consortium of 30 medical institutions in the United States and Canada with established expertise in fetal therapy and other forms of multidisciplinary care for complex fetal disorders. This publication is the third in a series of articles written by NAFTNet about monochorionic pregnancies. In this article, we provide the general obstetric practitioner with information regarding management options available for complications of monochorionic gestations. This information may be useful for a better understanding of the pathophysiology of the various conditions, for better patient counseling, for timely referral to a regional treatment center, and for ongoing comanagement after treatment. PMID- 26244535 TI - Evaluation of a Transcervical Foley Catheter as a Source of Infection: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To evaluate associations between Foley catheter use for cervical ripening and infectious morbidity. DATA SOURCES: We searched computerized databases, references in published studies and textbook chapters without language restriction. Searches were performed in MEDLINE, PubMed, ClinicalTrials.gov, Web of Science, and the Cochrane Library from inception through December 2014. MeSH headings used included the terms "Foley catheter," "Foley balloon," "prostaglandin," "labor induction," and "cervical ripening." METHODS OF STUDY SELECTION: We identified randomized controlled trials that compared Foley catheter with locally applied (vaginal or cervical) prostaglandin preparations for cervical ripening or labor induction. Selected studies evaluated maternal or neonatal infection with at least one of the following outcomes: chorioamnionitis, endometritis, pooled maternal infection, and neonatal infection. Excluded studies used double-balloon catheters, outpatient Foley management, extraamniotic saline infusions, pregnancy termination, and oral administration of medication in the prostaglandin arm. TABULATION, INTEGRATION, AND RESULTS: We identified 26 randomized trials including 5,563 women. Compared with prostaglandin preparations alone, patients who underwent cervical ripening with a Foley catheter had similar rates of chorioamnionitis (56/782 [7.2%] with Foley compared with 54/754 [7.2%] with prostaglandins; relative risk [RR] 0.96; 95% confidence interval [CI] 0.66 1.38), endometritis (40/1,042 [3.8%] compared with 35/991 [3.5%]; RR 1.03, 95% CI 0.66-1.6), pooled maternal infection (237/2,699 [8.8%] compared with 257/2,864 [9%]; RR 0.95, 95% CI 0.81-1.12), and neonatal infection (34/1,061 [3.2%] compared with 39/1,074 [3.6%]; RR 0.9, 95% CI 0.58-1.39). With subgroup analysis, excluding studies using preinsertion cervical cleansing or prophylactic antibiotics in the Foley arm, results were similar. CONCLUSION: Use of transcervical Foley catheters for cervical ripening and induction of labor is not associated with an increased risk of infectious morbidity. PMID- 26244536 TI - Obesity as a Risk Factor for Complications After Second-Trimester Abortion by Dilation and Evacuation. AB - OBJECTIVE: To evaluate the association between obesity (body mass index [BMI] 30 or higher) and dilation and evacuation (D&E) complications. METHODS: We conducted a retrospective cohort study of women who underwent D&E abortion from February 2009 to April 2013 at a hospital-based abortion practice in California. We evaluated the association between obesity and risk of complication after D&E using logistic regression. We defined complications a priori as cervical laceration, hemorrhage, uterine atony, anesthesia complications, uterine perforation, disseminated intravascular coagulation, and retained products of conception. We defined major complications as those requiring hospitalization, transfusion, or further surgical intervention. RESULTS: Complications occurred in 442 of 4,520 D&Es (9.8%), with equal proportions in obese and nonobese women (9.8%). Major complications occurred in 78 (1.7%) patients. After adjustment for age, ethnicity, prior vaginal delivery, prior cesarean delivery, and gestational duration, there was no association between BMI and D&E complications. Any individual complication was associated with each additional week of gestation (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.3-1.4), prior vaginal delivery (OR 1.5, 95% CI 1.2-1.9) and prior cesarean delivery (OR 1.8, 95% CI 1.4 2.3). Major complications were associated with each additional week of gestation (OR 1.3, 95% CI 1.1-1.4) and cesarean delivery (OR 1.8, 95% CI 1.1-3.1). CONCLUSION: We found no association between obesity and D&E complications. Our findings are consistent with previous studies demonstrating that later gestational duration is associated with an increased risk of complications. Obesity may not warrant referral to a high-risk abortion center, particularly because referral-associated delay might increase the risk of complications. LEVEL OF EVIDENCE: II. PMID- 26244537 TI - Preparedness of Obstetrics and Gynecology Residents for Fellowship Training. AB - OBJECTIVE: To evaluate the perceptions of fellowship program directors of incoming clinical fellows for subspecialty training. METHODS: A validated survey by the American College of Surgeons was modified and distributed to all fellowship program directors in four subspecialties within obstetrics and gynecology: female pelvic medicine and reconstructive surgery, gynecologic oncology, maternal-fetal medicine, and reproductive endocrinology-infertility. The 59-item survey explored five domains concerning preparedness for fellowship: professionalism, independent practice, psychomotor ability, clinical evaluation, and academic scholarship. A Likert scale with five responses was used and tailored to each subspecialty. Standard statistical methods were used to compare responses between subspecialties and to analyze data within each subspecialty individually. RESULTS: One hundred thirty directors completed the survey, for a response rate of 60%. In the domain of professionalism, more than 88% of participants stated that incoming fellows had appropriate interactions with faculty and staff. Scores in this domain were lower for gynecologic oncology respondents (P=.046). Responses concerning independent practice of surgical procedures (hysterectomy, pelvic reconstruction, and minimally invasive) were overwhelmingly negative. Only 20% of first-year fellows were able to independently perform a vaginal hysterectomy, 46% an abdominal hysterectomy, and 34% basic hysteroscopic procedures. Appropriate postoperative care (63%) and management of the critically ill patient (71%) were rated adequate for all subspecialties. CONCLUSION: Graduating residents may be underprepared for advanced subspecialty training, necessitating an evaluation of the current structure of resident and fellow curriculum. LEVEL OF EVIDENCE: III. PMID- 26244538 TI - Clinical, Ethical, and Legal Considerations in Pregnant Women With Opioid Abuse. AB - The rising prevalence of women with opioid addiction in pregnancy necessitates understanding of medical, ethical, and legal considerations on the part of obstetricians. In addition to briefly reviewing the medical care of opioid abuse in pregnancy, we offer a careful consideration of the stigmatization of addiction and resultant medicolegal sequelae. We advocate for improved access to opioid maintenance therapy and social services as a means of improving healthful pregnancy outcomes and decry recent trends in the criminalization of addiction nationwide. PMID- 26244539 TI - Maternal and Neonatal Morbidity After Attempted Operative Vaginal Delivery According to Fetal Head Station. AB - OBJECTIVE: To compare severe short-term maternal and neonatal morbidity associated with midpelvic and low pelvic attempted operative vaginal delivery. METHODS: Prospective study of 2,138 women with live singleton term fetuses in vertex presentation who underwent an attempted operative vaginal delivery in a tertiary care university hospital. We used multivariate logistic regression and propensity score methods to compare outcomes associated with midpelvic and low pelvic delivery. Severe maternal morbidity was defined as third- or fourth-degree perineal laceration, perineal hematoma, cervical laceration, extended uterine incision for cesarean delivery, postpartum hemorrhage greater than 1,500 mL, surgical hemostatic procedures, uterine artery embolization, blood transfusion, infection, thromboembolic events, admission to the intensive care unit, and maternal death; severe neonatal morbidity was defined as 5-minute Apgar score less than 7, umbilical artery pH less than 7.00, need for resuscitation or intubation, neonatal trauma, intraventricular hemorrhage greater than grade 2, neonatal intensive care unit admission for more than 24 hours, convulsions, sepsis, and neonatal death. RESULTS: From December 2008 through October 2013 there were 2,138 attempted operative vaginal deliveries; 18.3% (n=391) were midpelvic, 72.5% (n=1,550) low, and 9.2% (n=197) outlet. Severe maternal morbidity occurred in 10.2% (n=40) of midpelvic, 7.8% (n=121) of low, and 6.6% (n=13) of outlet attempts (P=.21); and severe neonatal morbidity in 15.1% (n=59), 10.2% (n=158), and 10.7% (n=21) (P=.02), respectively. Multivariable logistic regression analysis found no significant difference between midpelvic and low attempted operative vaginal delivery for either composite severe maternal (adjusted odds ratio [OR] 1.01, 95% confidence interval [CI] 0.66-1.55) or neonatal morbidity (adjusted OR 1.25, 95% CI 0.84-1.86). Similarly, propensity score matching found no significant difference between midpelvic and low operative vaginal delivery for either severe maternal (adjusted OR 0.69, 95% CI 0.39-1.22) or neonatal morbidity (adjusted OR 0.88, 95% CI 0.53-1.45). CONCLUSION: In singleton term pregnancies, midpelvic attempted operative vaginal delivery compared with low pelvic attempted operative vaginal delivery was not associated with an increase in severe short-term maternal or neonatal morbidity. LEVEL OF EVIDENCE: II. PMID- 26244540 TI - Overcoming Electronic Medical Record Challenges on the Obstetrics and Gynecology Clerkship. AB - This article, for the "To the Point" series prepared by the Association of Professors of Gynecology and Obstetrics Undergraduate Medical Education Committee, supplies educators with a review of best practices regarding incorporation of the electronic medical record (EMR) into undergraduate medical education. The unique circumstances of the obstetrics and gynecology clerkship require specific attention as it pertains to medical student use of the EMR. An outline of the regulatory requirements and authoritative body recommendations provides some guidance for implementation in the undergraduate medical education setting. A review of the basic framework for development of an EMR curriculum and examples of curricular innovations published in the literature offers solutions for obstacles that may be encountered by students and medical educators. PMID- 26244541 TI - Pregnancy-Related Mortality Resulting From Influenza in the United States During the 2009-2010 Pandemic. AB - OBJECTIVE: To estimate the burden of pregnancy-related mortality resulting from influenza A (H1N1)pdm09 virus infection during the 2009-2010 pandemic influenza season. METHODS: Data from the Centers for Disease Control and Prevention's Pregnancy Mortality Surveillance System were used to identify women whose death during or shortly after pregnancy was attributed or likely attributed to the influenza A (H1N1)pdm09 virus from April 15, 2009, through June 30, 2010. We report the characteristics of these women and enumerate cases resulting in death as the pandemic began, peaked, and resolved. RESULTS: During the pandemic season, we identified 915 pregnancy-related deaths and 4,911,297 live births. Seventy five (8.2%) women died as a result of confirmed influenza A (H1N1)pdm09 infection deaths and 34 (3.7%) women as a result of possible influenza A (H1N1)pdm09 infection deaths. The pregnancy-related mortality ratio for confirmed and possible (combined) influenza A (H1N1)pdm09 infection deaths was 2.2 per 100,000 live births. Most deaths occurred during the 2009 calendar year with the peak of the distribution of deaths over time occurring in October 2009. CONCLUSION: Twelve percent of pregnancy-related deaths were attributed to confirmed or possible influenza A (H1N1)pdm09 infection during the 2009-2010 pandemic season. Because prediction of pandemics is difficult, planning for prevention of influenza and care for those women affected are critical for preventing associated severe maternal morbidity and mortality. LEVEL OF EVIDENCE: III. PMID- 26244542 TI - No Rush to Judgment for Bariatric Surgery. PMID- 26244543 TI - Understanding Variation in 30-Day Surgical Readmission in the Era of Accountable Care: Effect of the Patient, Surgeon, and Surgical Subspecialties. AB - IMPORTANCE: Readmission is a target area of quality improvement in surgery. While variation in readmission is common, to our knowledge, no study has specifically examined the underlying etiology of this variation among a variety of surgical procedures performed in a large academic medical center. OBJECTIVE: To quantify the variability in 30-day readmission attributable to patient, surgeon, and surgical subspecialty levels in patients undergoing a major surgical procedure. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of administrative claims data of patients discharged following a major surgical procedure at a tertiary care center between January 1, 2009, and, December 31, 2013. A total of 22,559 patients were included in this study and underwent a major surgical procedure performed by 56 surgeons practicing in 8 surgical subspecialties. MAIN OUTCOMES AND MEASURES: In-hospital morbidity, 30-day readmission, and proportional variation in 30-day readmission at patient, surgeon, and surgical subspecialty levels. RESULTS: Among the 22,559 patients in this study, patient age, race/ethnicity, and payer type differed across surgical subspecialties. Preoperative comorbidity was common and noted in 65.1% of patients. Postoperative complications were noted in 21.6% of patients varying from 2.1% following breast, melanoma or endocrine surgery to 37.0% following cardiac surgery. The overall 30 day readmission was 13.2% (n = 2975). Readmission varied considerably across the 8 different surgical subspecialties, ranging from 24.8% following transplant surgery (n = 557) to 2.1% following breast, melanoma, or endocrine surgery (n = 32). After adjusting for patient- and surgeon-level variables, factors associated with readmission included African American race/ethnicity (odds ratio, 1.23; 95% CI, 1.11-1.36; P < .001), increasing comorbidity (Charlson Comorbidity Index score of 1: odds ratio, 1.16; 95% CI, 1.02-1.32; P = .02; and a Charlson Comorbidity Index score of >=2 : odds ratio, 1.38; 95% CI, 1.24-1.53; P < .001), postoperative complication (odds ratio, 1.19; 95% CI, 1.08-1.32; P = .001), and an extended length of stay (odds ratio, 1.78; 95% CI, 1.61-1.96; P < .001). The majority of the variation in readmission was attributable to patient-related factors (82.8%) while surgical subspecialty accounted for 14.5% of the variability, and individual surgeon-level factors accounted for 2.8%. CONCLUSIONS AND RELEVANCE: Readmission occurred in more than 1 in 10 patients, with considerable variation across surgical subspecialties. Variation in readmission was overwhelmingly owing to patient-level factors while only a minority of the variation was attributable to factors at the surgical subspecialty and individual surgeon levels. PMID- 26244544 TI - The Evolutionary Potential of Phenotypic Mutations. AB - Errors in protein synthesis, so-called phenotypic mutations, are orders-of magnitude more frequent than genetic mutations. Here, we provide direct evidence that alternative protein forms and phenotypic variability derived from translational errors paved the path to genetic, evolutionary adaptations via gene duplication. We explored the evolutionary origins of Saccharomyces cerevisiae IDP3 - an NADP-dependent isocitrate dehydrogenase mediating fatty acids beta oxidation in the peroxisome. Following the yeast whole genome duplication, IDP3 diverged from a cytosolic ancestral gene by acquisition of a C-terminal peroxisomal targeting signal. We discovered that the pre-duplicated cytosolic IDPs are partially localized to the peroxisome owing to +1 translational frameshifts that bypass the stop codon and unveil cryptic peroxisomal targeting signals within the 3'-UTR. Exploring putative cryptic signals in all 3'-UTRs of yeast genomes, we found that other enzymes related to NADPH production such as pyruvate carboxylase 1 (PYC1) might be prone to peroxisomal localization via cryptic signals. Using laboratory evolution we found that these translational frameshifts are rapidly imprinted via genetic single base deletions occurring within the very same gene location. Further, as exemplified here, the sequences that promote translational frameshifts are also more prone to genetic deletions. Thus, genotypes conferring higher phenotypic variability not only meet immediate challenges by unveiling cryptic 3'-UTR sequences, but also boost the potential for future genetic adaptations. PMID- 26244545 TI - miR-126-3p Inhibits Thyroid Cancer Cell Growth and Metastasis, and Is Associated with Aggressive Thyroid Cancer. AB - BACKGROUND: Previous studies have shown that microRNAs are dysregulated in thyroid cancer and play important roles in the post-transcriptional regulation of target oncogenes and/or tumor suppressor genes. METHODOLOGY/PRINCIPAL FINDINGS: We studied the function of miR-126-3p in thyroid cancer cells, and as a marker of disease aggressiveness. We found that miR-126-3p expression was significantly lower in larger tumors, in tumor samples with extrathyroidal invasion, and in higher risk group thyroid cancer in 496 papillary thyroid cancer samples from The Cancer Genome Atlas study cohort. In an independent sample set, lower miR-126-3p expression was observed in follicular thyroid cancers (which have capsular and angioinvasion) as compared to follicular adenomas. Mechanistically, ectopic overexpression of miR-126-3p significantly inhibited thyroid cancer cell proliferation, in vitro (p<0.01) and in vivo (p<0.01), colony formation (p<0.01), tumor spheroid formation (p<0.05), cellular migration (p<0.05), VEGF secretion and endothelial tube formation, and lung metastasis in vivo. We found 14 predicted target genes, which were significantly altered upon miR-126-3p transfection in thyroid cancer cells, and which are involved in cancer biology. Of these 14 genes, SLC7A5 and ADAM9 were confirmed to be inhibited by miR-126-3p overexpression and to be direct targets of miR-136-3p. CONCLUSIONS/SIGNIFICANCE: To our knowledge, this is the first study to demonstrate that miR-126-3p has a tumor-suppressive function in thyroid cancer cells, and is associated with aggressive disease phenotype. PMID- 26244546 TI - A Non-enveloped Virus Hijacks Host Disaggregation Machinery to Translocate across the Endoplasmic Reticulum Membrane. AB - Mammalian cytosolic Hsp110 family, in concert with the Hsc70:J-protein complex, functions as a disaggregation machinery to rectify protein misfolding problems. Here we uncover a novel role of this machinery in driving membrane translocation during viral entry. The non-enveloped virus SV40 penetrates the endoplasmic reticulum (ER) membrane to reach the cytosol, a critical infection step. Combining biochemical, cell-based, and imaging approaches, we find that the Hsp110 family member Hsp105 associates with the ER membrane J-protein B14. Here Hsp105 cooperates with Hsc70 and extracts the membrane-penetrating SV40 into the cytosol, potentially by disassembling the membrane-embedded virus. Hence the energy provided by the Hsc70-dependent Hsp105 disaggregation machinery can be harnessed to catalyze a membrane translocation event. PMID- 26244548 TI - Tree-Ring Dating of the Reshui-1 Tomb in Dulan County, Qinghai Province, North West China. AB - Tuyuhun and Tubo were two important states that thrived in north-western China during AD 311-900 in parallel with the Han Chinese dynasties of Sui and Tang periods. The Reshui Tomb Cluster located in Dulan County of the north-eastern Tibetan Plateau is an important cultural relic of the Tuyuhun-Tubo age. The official excavations of the Reshui tombs were regarded as top events in archaeology in the 1980s and 1990s in China. The Reshui-1 Tomb is the largest one among the tombs in the area. Since its excavation, there have been debates on whether the owner of the tomb belonged to the Tuyuhun or Tubo ethnicity. Therefore, accurately dating the Reshui-1 Tomb has a critical place in studying the Tubo and Tuyuhun histories. We collected 7 discs and 11 increment cores of Qilian juniper (Juniperus przewalskii Kom.) from the exposed and fallen beams of the roof of the Reshui-1Tomb. The lengths of the 16 tree-ring records are between 69 and 152 years. Based on a previously developed master dating chronology using Qilian juniper samples from the eastern Qaidam Basin, the calendar dates of the 16 specimens were determined by the COFECHA program and visual dating procedure. The average inter-series correlation among the dated sample series is 0.696, indicating good quality of cross-dating. The year of the outermost rings is AD 715 for the 7 discs and 4 out of the 9 increment cores. Moreover, the ring-width variations of the samples are consistent with the existing chronologies from the region. The presence of late-wood of AD 715 in the samples indicated that the Reshui-1 Tomb was completed in late AD 715 or early 716, which means that the Reshui-1 Tomb was finished in the Tubo age. This date provides direct evidence for archaeologists to determine the owner's ethnicity and identify of the Reshui 1 Tomb. PMID- 26244547 TI - Gastroprotective Mechanisms of the Monoterpene 1,8-Cineole (Eucalyptol). AB - Recently, our research group identified and reported 1,8-cineole (CIN), a monoterpene that naturally occur in many aromatic plants, as one of the major constituent of the essential oil from leaves of Hyptis martiusii (EOHM), as well as characterized the gastroprotective action of this oil. The aim of this study was to investigate the mechanisms of action involved in the antiulcer and healing activity of CIN, in order to confirm its correlation with the gastroprotective effect of EOHM. Wistar rats were exposed to different protocols (acute ulceration, gastrointestinal motility and antisecretory activity). In addition, were determinated the involvement of nitric oxide and sulphydryl groups; the levels of gastric mucus, lipid peroxidation, sulphydryl groups and myeloperoxidase activity. The healing ability was evaluated by acetic acid induced chronic ulcer and histological and immunohistochemical analysis (PCNA, Ki 67 and BrdU). The treatment with CIN inhibited ethanol-, ethanol/HCl- and indomethacin-induced gastric lesions. The highest doses of CIN inhibited gastric emptying, but did not affect intestinal transit. CIN (100 mg/kg) reduced the volume of basal but not stimulated acid secretion. CIN increased levels of mucus (89.3%), prevented depletion of -SH groups (62.6%) and reduced the level of lipid peroxidation (55.3%) and myeloperoxidase activity (59.4%) in the gastric mucosa. In chronic ulcer model, CIN reduced in 43.1% the gastric area lesion, promoted significant regeneration and restoration of the levels of mucus in glandular cells as confirmed by histological analysis; and promoted increase in cell proliferation as evidenced by reactivity for PCNA, Ki-67 and BrdU. This findings demonstrate the role of 1,8-cineole as an important ulcer healing agent and indicate the involvement of antioxidant and cytoprotective mechanisms in the gastroprotective effect of compound. This study also provides evidence that 1,8 cineole is related to the gastroprotective effect of the essential oil of Hyptis martiusii. PMID- 26244550 TI - Decrypting Financial Markets through E-Joint Attention Efforts: On-Line Adaptive Networks of Investors in Periods of Market Uncertainty. AB - This paper looks at 800,000 messages on the Unicredit stock, exchanged by 7,500 investors in the Finanzaonline.com forum, between 2005 and 2012 and measured collective interpretations of stock market trends. We examined the correlation patterns between market uncertainty, bad news and investors' network structure by measuring the investors' communication patterns. Our results showed that the investors' network reacted to market trends in different ways: While less turbulent market phases implied less communication, higher market volatility generated more complex communication patterns. While the information content of messages was less technical in situations of uncertainty, bad news caused more informative messages only when market volatility was lower. This meant that bad news had a different impact on network behaviour, depending on market uncertainty. By measuring the investors' expertise, we found that their behaviour could help predict changes in daily stock returns. We also found that expert investors were more influential in communication processes during high volatility market phases, whereas they had less influence on the real-time forum's reaction after bad news. Our findings confirm the crucial role of e-communication platforms. However, they also show the need to reconsider the fragility of these collective intelligence systems when under external shocks. PMID- 26244549 TI - Hippocampal Synaptic Expansion Induced by Spatial Experience in Rats Correlates with Improved Information Processing in the Hippocampus. AB - Spatial water maze (WM) overtraining induces hippocampal mossy fiber (MF) expansion, and it has been suggested that spatial pattern separation depends on the MF pathway. We hypothesized that WM experience inducing MF expansion in rats would improve spatial pattern separation in the hippocampal network. We first tested this by using the the delayed non-matching to place task (DNMP), in animals that had been previously trained on the water maze (WM) and found that these animals, as well as animals treated as swim controls (SC), performed better than home cage control animals the DNMP task. The "catFISH" imaging method provided neurophysiological evidence that hippocampal pattern separation improved in animals treated as SC, and this improvement was even clearer in animals that experienced the WM training. Moreover, these behavioral treatments also enhance network reliability and improve partial pattern separation in CA1 and pattern completion in CA3. By measuring the area occupied by synaptophysin staining in both the stratum oriens and the stratun lucidum of the distal CA3, we found evidence of structural synaptic plasticity that likely includes MF expansion. Finally, the measures of hippocampal network coding obtained with catFISH correlate significantly with the increased density of synaptophysin staining, strongly suggesting that structural synaptic plasticity in the hippocampus induced by the WM and SC experience is related to the improvement of spatial information processing in the hippocampus. PMID- 26244552 TI - H-Aggregates of an Indocyanine Cy5 Dye: Transition from Strong to Weak Molecular Coupling. AB - The aggregation behavior of an Indocyanine Cy5 dye (2-[5-[1,1-dimethyl-3-(4 sulfobutyl)-1,3-dihydro-benzo[e]indol-2-ylidene]-penta-1,3-dienyl]-1,1-dimethyl-3 (4-sulfobutyl)-1H-benzo[e]indolium hydroxide, inner salt, sodium salt) in aqueous solution is investigated using absorption and fluorescence spectroscopies, as well as cryogenic transmission electron microscopy (cryo-TEM). The dye concentration is varied within a broad range from ~1 MUM to ~10 mM. At moderate concentrations, typical H-aggregates are formed. After longer storage time, the absorption spectra of these solutions change dramatically. The characteristic blue-shifted absorption band at around 600 nm becomes replaced by a three-banded absorption spectrum, which spreads over a wide wavelength range of ~600 up to 800 nm. However, at the highest dye concentration and in the presence of ~(10 to 30) mM NaCl, the three-banded spectrum is observed directly after preparation. The spectroscopic features can be ascribed to a structural transformation of strongly to weakly coupled H-type aggregates. The transformation is promoted by an increase of the ionic strength. Cryo-TEM data reveal that the weakly coupled H' aggregates are organized in well-ordered, extended monolayer sheets, whereas the strongly coupled H-aggregates appear to consist of particles of only a few nanometers in size. PMID- 26244551 TI - alphavbeta5 Integrin/FAK/PGC-1alpha Pathway Confers Protective Effects on Retinal Pigment Epithelium. AB - PURPOSE: To elucidate the mechanism of the induction of peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha) by photoreceptor outer segments (POS) and its effects on retinal pigment epithelium (RPE). METHODS: PGC 1alpha upregulation by POS was confirmed in ARPE-19 cells and in RPE ex vivo. To elucidate the mechanism, siRNAs against beta5 integrin, CD36, Mer tyrosine kinase (MerTK), and Atg5, blocking antibodies against CD36 and MerTK, and a specific inhibitor for focal adhesion kinase (FAK) were used. We examined the effect of POS-induced PGC-1alpha upregulation on the levels of reactive oxygen species (ROS), mitochondrial biogenesis, senescence-associated beta-galactosidase (SA beta-gal) after H2O2 treatment, and lysosomal activity. Lysosomal activity was evaluated through transcriptional factor EB and its target genes, and the activity of cathepsin D. Lipid metabolism after POS treatment was assessed using Oil Red O and BODIPY C11. RPE phenotypes of PGC-1alpha-deficient mice were examined. RESULTS: POS-induced PGC-1alpha upregulation was suppressed by siRNA against beta5 integrin and a FAK inhibitor. siRNAs and blocking antibodies against CD36 and MerTK enhanced the effect of POS on PGC-1alpha. The upregulation of PGC-1alpha increased the levels of mRNA for antioxidant enzymes and stimulated mitochondrial biogenesis, decreased ROS levels, and reduced SA-beta-gal staining in H2O2-treated ARPE-19 cells. PGC-1alpha was critical for lysosomal activity and lipid metabolism after POS treatment. PGC-1alpha-deficient mice demonstrated an accumulation of type 2 lysosomes in RPE, thickening of Bruch's membrane, and poor choriocapillaris vasculature. CONCLUSIONS: The binding, but not the internalization of POS confers protective effects on RPE cells through the alphavbeta5 integrin/FAK/PGC-1alpha pathway. PMID- 26244553 TI - Spinophilin Is Indispensable for the alpha2B Adrenergic Receptor-Elicited Hypertensive Response. AB - The alpha2 adrenergic receptor (AR) subtypes are important for blood pressure control. When activated, the alpha2A subtype elicits a hypotensive response whereas the alpha2B subtype mediates a hypertensive effect that counteracts the hypotensive response by the alpha2A subtype. We have previously shown that spinophilin attenuates the alpha2AAR-dependent hypotensive response; in spinophilin null mice, this response is highly potentiated. In this study, we demonstrate that spinophilin impedes arrestin-dependent phosphorylation and desensitization of the alpha2BAR subtype by competing against arrestin binding to this receptor subtype. The Del301-303 alpha2BAR, a human variation that shows impaired phosphorylation and desensitization and is linked to hypertension in certain populations, exhibits preferential interaction with spinophilin over arrestin. Furthermore, Del301-303 alpha2BAR-induced ERK signaling is quickly desensitized in cells without spinophilin expression, showing a profile similar to that induced by the wild type receptor in these cells. Together, these data suggest a critical role of spinophilin in sustaining alpha2BAR signaling. Consistent with this notion, our in vivo study reveals that the alpha2BAR elicited hypertensive response is diminished in spinophilin deficient mice. In arrestin 3 deficient mice, where the receptor has a stronger binding to spinophilin, the same hypertensive response is enhanced. These data suggest that interaction with spinophilin is indispensable for the alpha2BAR to elicit the hypertensive response. This is opposite of the negative role of spinophilin in regulating alpha2AAR-mediated hypotensive response, suggesting that spinophilin regulation of these closely related receptor subtypes can result in distinct functional outcomes in vivo. Thus, spinophilin may represent a useful therapeutic target for treatment of hypertension. PMID- 26244554 TI - Comparison of Leaf Sheath Transcriptome Profiles with Physiological Traits of Bread Wheat Cultivars under Salinity Stress. AB - Salinity stress has significant negative effects on plant biomass production and crop yield. Salinity tolerance is controlled by complex systems of gene expression and ion transport. The relationship between specific features of mild salinity stress adaptation and gene expression was analyzed using four commercial varieties of bread wheat (Triticum aestivum) that have different levels of salinity tolerance. The high-throughput phenotyping system in The Plant Accelerator at the Australian Plant Phenomics Facility revealed variation in shoot relative growth rate and salinity tolerance among the four cultivars. Comparative analysis of gene expression in the leaf sheaths identified genes whose functions are potentially linked to shoot biomass development and salinity tolerance. Early responses to mild salinity stress through changes in gene expression have an influence on the acquisition of stress tolerance and improvement in biomass accumulation during the early "osmotic" phase of salinity stress. In addition, results revealed transcript profiles for the wheat cultivars that were different from those of usual stress-inducible genes, but were related to those of plant growth. These findings suggest that, in the process of breeding, selection of specific traits with various salinity stress-inducible genes in commercial bread wheat has led to adaptation to mild salinity conditions. PMID- 26244555 TI - Corrigendum: Worldwide variations in artificial skyglow. PMID- 26244556 TI - Stable Reference Gene Selection for RT-qPCR Analysis in Nonviruliferous and Viruliferous Frankliniella occidentalis. AB - Reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) is a reliable technique for measuring and evaluating gene expression during variable biological processes. To facilitate gene expression studies, normalization of genes of interest relative to stable reference genes is crucial. The western flower thrips Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae), the main vector of tomato spotted wilt virus (TSWV), is a destructive invasive species. In this study, the expression profiles of 11 candidate reference genes from nonviruliferous and viruliferous F. occidentalis were investigated. Five distinct algorithms, geNorm, NormFinder, BestKeeper, the DeltaCt method, and RefFinder, were used to determine the performance of these genes. geNorm, NormFinder, BestKeeper, and RefFinder identified heat shock protein 70 (HSP70), heat shock protein 60 (HSP60), elongation factor 1 alpha, and ribosomal protein l32 (RPL32) as the most stable reference genes, and the DeltaCt method identified HSP60, HSP70, RPL32, and heat shock protein 90 as the most stable reference genes. Additionally, two reference genes were sufficient for reliable normalization in nonviruliferous and viruliferous F. occidentalis. This work provides a foundation for investigating the molecular mechanisms of TSWV and F. occidentalis interactions. PMID- 26244557 TI - Identification and Mechanistic Analysis of a Novel Tick-Derived Inhibitor of Thrombin. AB - A group of peptides from the salivary gland of the tick Hyalomma marginatum rufipes, a vector of Crimean Congo hemorrhagic fever show weak similarity to the madanins, a group of thrombin-inhibitory peptides from a second tick species, Haemaphysalis longicornis. We have evaluated the anti-serine protease activity of one of these H. marginatum peptides that has been given the name hyalomin-1. Hyalomin-1 was found to be a selective inhibitor of thrombin, blocking coagulation of plasma and inhibiting S2238 hydrolysis in a competitive manner with an inhibition constant (Ki) of 12 nM at an ionic strength of 150 mM. It also blocks the thrombin-mediated activation of coagulation factor XI, thrombin mediated platelet aggregation, and the activation of coagulation factor V by thrombin. Hyalomin-1 is cleaved at a canonical thrombin cleavage site but the cleaved products do not inhibit coagulation. However, the C-terminal cleavage product showed non-competitive inhibition of S2238 hydrolysis. A peptide combining the N-terminal parts of the molecule with the cleavage region did not interact strongly with thrombin, but a 24-residue fragment containing the cleavage region and the C-terminal fragment inhibited the enzyme in a competitive manner and also inhibited coagulation of plasma. These results suggest that the peptide acts by binding to the active site as well as exosite I or the autolysis loop of thrombin. Injection of 2.5 mg/kg of hyalomin-1 increased arterial occlusion time in a mouse model of thrombosis, suggesting this peptide could be a candidate for clinical use as an antithrombotic. PMID- 26244558 TI - Effect of Substrates on the Photoelectrochemical Reduction of Water over Cathodically Electrodeposited p-Type Cu2O Thin Films. AB - In this study, we demonstrate development of p-Cu2O thin films through cathodic electrodeposition technique at constant current of 0.1 mA/cm(2) on Cu, Al, and indium tin oxide (ITO) substrates from basic CuSO4 solution containing Triton X 100 as the surfactant at 30-35 degrees C. The optical and morphological characterizations of the semiconductors have been carried out using UV-vis spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), and Raman spectroscopy. The band gap energy of ~2.1 eV is recorded, whereas SEM reveals that the surface morphology is covered with Cu2O semiconductors. XRD analyses confirm that with change in substrate, the size of Cu2O "cubic" crystallites decreases from ITO to Al to Cu substrates. Photoelectrochemical characterizations under dark and illuminated conditions have been carried out through linear sweep voltammetry, chronoamperometry and electrochemical impedance spectroscopic analysis. The photoelectrochemical reduction of water (H2O -> H2) in pH 4.9 aqueous solutions over the different substrates vary in the order of Cu > Al > ITO. The highest current of 4.6 mA/cm(2) has been recorded over the Cu substrate even at a low illumination of 35 mW/cm(2), which is significantly higher than the values (2.4 mA/cm(2) on Au coated FTO or 4.07 mA/cm(2) on Cu foil substrate at an illumination of 100 mW/cm(2)) reported in literature. PMID- 26244559 TI - Impaired Function of CD5+CD19+CD1dhi B10 Cells on IgE Secretion in an Atopic Dermatitis-Like Mouse Model. AB - Atopic dermatitis (AD) is a chronic inflammatory pruritic skin disease in which the pathogenic mechanism is complicated and not completely understood. Reports on the role of regulated cells in AD have recently evolved to regulate B cells, which may play a role in allergic inflammation as well. In the present study, we examined the frequency and regulatory function of CD5+CD19+CD1dhi B10 cells in an AD-like mouse model. Our results showed that the percentage of CD5+CD19+CD1dhi B10 cells increased while the frequency of IL-10-producing B cells in CD19+B cells decreased in the mice of AD group. Moreover, no difference in the percentage of B10pro + B10 cells was observed between the AD and control groups. Strikingly, B10 cells from control mice effectively inhibited IgE secretion, whereas the suppressive function of B10 cells from the AD mice was significantly decreased, which was similar to that observed in the group without B10. Altogether, these results suggest that the number of IL-10-producing B cells decreased in the AD group and these cells showed a defective regulatory function on IgE secretion. PMID- 26244560 TI - Expression of Opacity Proteins Interferes with the Transmigration of Neisseria gonorrhoeae across Polarized Epithelial Cells. AB - Neisseria gonorrhoeae (GC) establishes infection at the mucosal surface of the human genital tract, most of which is lined with polarized epithelial cells. GC can cause localized as well as disseminated infections, leading to various complications. GC constantly change their surface structures via phase and antigenic variation, which has been implicated as a means for GC to establish infection at various anatomic locations of male and female genital tracks. However, the exact contribution of each surface molecule to bacterial infectivity remains elusive due to their phase variation. Using a GC derivative that is genetically devoid of all opa genes (MS11?Opa), this study shows that Opa expression interferes with GC transmigration across polarized human epithelial cells. MS11?Opa transmigrates across polarized epithelial cells much faster and to a greater extent than MS11Opa+, while adhering at a similar level as MS11Opa+. When MS11Opa+, able to phase vary Opa expression, was inoculated, only those bacteria that turn off Opa expression transmigrate across the polarized epithelial monolayer. Similar to bacteria alone or co-cultured with non-polarized epithelial cells, MS11?Opa fails to form large microcolonies at the apical surface of polarized epithelial cells. Apical inoculation of MS11Opa+, but not MS11?Opa, induces the recruitment of the Opa host-cell receptor carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) to the apical junction and the vicinity of bacterial adherent sites. Our results suggest that Opa expression limits gonococcal ability to invade into subepithelial tissues by forming tight interactions with neighboring bacteria and by inducing CEACAM redistribution to cell junctions. PMID- 26244561 TI - Diversification of the Genus Anopheles and a Neotropical Clade from the Late Cretaceous. AB - The Anopheles genus is a member of the Culicidae family and consists of approximately 460 recognized species. The genus is composed of 7 subgenera with diverse geographical distributions. Despite its huge medical importance, a consensus has not been reached on the phylogenetic relationships among Anopheles subgenera. We assembled a comprehensive dataset comprising the COI, COII and 5.8S rRNA genes and used maximum likelihood and Bayesian inference to estimate the phylogeny and divergence times of six out of the seven Anopheles subgenera. Our analysis reveals a monophyletic group composed of the three exclusively Neotropical subgenera, Stethomyia, Kerteszia and Nyssorhynchus, which began to diversify in the Late Cretaceous, at approximately 90 Ma. The inferred age of the last common ancestor of the Anopheles genus was ca. 110 Ma. The monophyly of all Anopheles subgenera was supported, although we failed to recover a significant level of statistical support for the monophyly of the Anopheles genus. The ages of the last common ancestors of the Neotropical clade and the Anopheles and Cellia subgenera were inferred to be at the Late Cretaceous (ca. 90 Ma). Our analysis failed to statistically support the monophyly of the Anopheles genus because of an unresolved polytomy between Bironella and A. squamifemur. PMID- 26244562 TI - Analysis of Conformational B-Cell Epitopes in the Antibody-Antigen Complex Using the Depth Function and the Convex Hull. AB - The prediction of conformational b-cell epitopes plays an important role in immunoinformatics. Several computational methods are proposed on the basis of discrimination determined by the solvent-accessible surface between epitopes and non-epitopes, but the performance of existing methods is far from satisfying. In this paper, depth functions and the k-th surface convex hull are used to analyze epitopes and exposed non-epitopes. On each layer of the protein, we compute relative solvent accessibility and four different types of depth functions, i.e., Chakravarty depth, DPX, half-sphere exposure and half space depth, to analyze the location of epitopes on different layers of the proteins. We found that conformational b-cell epitopes are rich in charged residues Asp, Glu, Lys, Arg, His; aliphatic residues Gly, Pro; non-charged residues Asn, Gln; and aromatic residue Tyr. Conformational b-cell epitopes are rich in coils. Conservation of epitopes is not significantly lower than that of exposed non-epitopes. The average depths (obtained by four methods) for epitopes are significantly lower than that of non-epitopes on the surface using the Wilcoxon rank sum test. Epitopes are more likely to be located in the outer layer of the convex hull of a protein. On the benchmark dataset, the cumulate 10th convex hull covers 84.6% of exposed residues on the protein surface area, and nearly 95% of epitope sites. These findings may be helpful in building a predictor for epitopes. PMID- 26244563 TI - Efficacy of Intralesional Botulinum Toxin A for Treatment of Painful Cutaneous Leiomyomas: A Randomized Clinical Trial. AB - IMPORTANCE: Cutaneous leiomyomas can be associated with severe paroxysmal pain in which nerve conduction may have a key role. Medical management of painful cutaneous leiomyomas is generally unsatisfactory. OBJECTIVE: To assess the efficacy of intralesional botulinum toxin A in the management of pain associated with cutaneous leiomyomas. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double blind, placebo-controlled pilot study conducted from January 5, 2009, to March 27, 2014. The setting was a single-center study at the National Institutes of Health among participants 18 years or older with cutaneous leiomyomas characterized by pain at least once weekly and pain of at least 4 on a pain scale ranging from 0 to 10. INTERVENTIONS: Eighteen participants were randomized to receive intralesional botulinum toxin A (5 U per 1 cm2) or equivalent volumes of intralesional saline placebo. MAIN OUTCOMES AND MEASURES: The primary outcomes were the differences in average lesional pain assessed by the Brief Pain Inventory and visual analog scale before and after ice provocation over a 4-week period. RESULTS: No significant difference in average lesional pain was observed between the study arms. Decreased pain was reported in the botulinum toxin vs placebo arms by visual analog scale scores before ice provocation (median, 0.00; range, -3.30 to 0.70 for botulinum toxin and median, 0.40; range, -1.30 to 1.50 for placebo; P = .06); however, this finding was nonsignificant. No significant difference was observed in change in pain after ice provocation. A significant difference was seen between the arms in skin-related quality of life by total Dermatology Life Quality Index (median, -4.00; range, -8.00 to 2.00 for botulinum toxin and median, 0.00; range, -1.00 to 4.00 for placebo; P = .007) and with the specific skin pain-related question on the Dermatology Life Quality Index (median, -1.00; range, -2.00 to 1.00 for botulinum toxin and median, 0.00; range, -1.00 to 0.00 for placebo; P = .048). No significant difference was found in pain as ascertained by Patient Global Impression of Change at week 4. No serious adverse events related to botulinum toxin use were observed. CONCLUSIONS AND RELEVANCE: The use of botulinum toxin to treat painful cutaneous leiomyomas was associated with improved quality of life and with a trend toward improved pain at rest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00971620. PMID- 26244564 TI - Scandinavian Journal of Work, Environment & Health: 40 years of innovative research with societal impact in the field of occupational health. PMID- 26244565 TI - Corrigendum: Functional transformations of bile acid transporters induced by high affinity macromolecules. PMID- 26244566 TI - Aprotinin: is it time to reconsider? PMID- 26244567 TI - Equivalence of postoperative quadriceps strength during 1 or 0.5 mg ml(-1) levobupivacaine administration for continuous femoral nerve block following total knee arthroplasty: A double-blinded, randomised controlled trial. PMID- 26244568 TI - Substrate-Assisted Catalysis in the Reaction Catalyzed by Salicylic Acid Binding Protein 2 (SABP2), a Potential Mechanism of Substrate Discrimination for Some Promiscuous Enzymes. AB - Although one of an enzyme's hallmarks is the high specificity for their natural substrates, substrate promiscuity has been reported more frequently. It is known that promiscuous enzymes generally show different catalytic efficiencies to different substrates, but our understanding of the origin of such differences is still lacking. Here we report the results of quantum mechanical/molecular mechanical simulations and an experimental study of salicylic acid binding protein 2 (SABP2). SABP2 has promiscuous esterase activity toward a series of substrates but shows a high activity toward its natural substrate, methyl salicylate (MeSA). Our results demonstrate that this enzyme may use substrate assisted catalysis involving the hydroxyl group from MeSA to enhance the activity and achieve substrate discrimination. PMID- 26244569 TI - Coordination of Tri-Substituted Nona-Germanium Clusters to Cu(I) and Pd(0). AB - The recently developed approach for the rational functionalization of deltahedral nona-germanium clusters Ge9(4-) with three substituents to form Ge9R3(-) (R = Si(SiMe3)3) in large amounts has made the latter a convenient starting material for further reactivity studies. Reported here are the synthesis, structures, and solution studies of two compounds where Ge9R3(-) are used as ligands to transition metals, [(Ge9R3)Cu(I)(Ge9R3)Cu(I)PPh3] (1) and [(Ge9R3)Pd(0)(Ge9R3)](2 ) (2). The former adds to the families of anionic [(Ge9R3)M(I)(Ge9R3)](-) (M(I) = Cu, Ag, and Au) as a neutral member and of the neutral [(Ge9R3)M(II)(Ge9R3)] (M(II) = Zn, Cd, and Hg), while the latter represents the first compound involving a metal from group 10. PMID- 26244570 TI - Physician-Patient Concordance in Pharmacological Management of Patients with COPD. AB - A retrospective analysis of a cross-sectional, multicenter survey was conducted in United States (US) medical practices to evaluate the concordance between patients with COPD and their physicians on disease-specific characteristics. Associations between patient and disease-related characteristics with monotherapy, dual therapy, or triple therapy prescribed as COPD maintenance regimens were also examined. Eligible physicians completed patient record forms (PRFs) for up to 6 consecutive patients with COPD. Patients for whom a PRF was completed were invited to complete a patient self-completion (PSC) survey consisting of questions similar to those on the PRF, as well as several validated measures to assess the impact of COPD on patients' lives. A total of 469 patients completed a PSC that was matched with the PRF completed by their physician, forming the sample for the concordance analysis. Moderate agreement (kappa (kappa) = 0.41-0.60) was observed for 79% of measures, with the lowest concordance rating corresponding to hemoptysis (kappa = 0.22). There were few differences in demographic or clinical characteristics between patients prescribed monotherapy and dual therapy. Triple therapy rather than monotherapy or dual therapy was more often prescribed for patients with greater frequency of symptoms, negative impact of COPD on daily life and interpersonal relationships, and respiratory impairment based on the most recent FEV1. Diverse factors influence US physicians' perceptions of disease and treatment choices, including patient symptoms, quality of life, and disease impact. Our results highlight that concordance between physicians and patients regarding symptoms and physical function may contribute to optimal management of COPD. PMID- 26244571 TI - Dual Processing Model for Medical Decision-Making: An Extension to Diagnostic Testing. AB - Dual Processing Theories (DPT) assume that human cognition is governed by two distinct types of processes typically referred to as type 1 (intuitive) and type 2 (deliberative). Based on DPT we have derived a Dual Processing Model (DPM) to describe and explain therapeutic medical decision-making. The DPM model indicates that doctors decide to treat when treatment benefits outweigh its harms, which occurs when the probability of the disease is greater than the so called "threshold probability" at which treatment benefits are equal to treatment harms. Here we extend our work to include a wider class of decision problems that involve diagnostic testing. We illustrate applicability of the proposed model in a typical clinical scenario considering the management of a patient with prostate cancer. To that end, we calculate and compare two types of decision-thresholds: one that adheres to expected utility theory (EUT) and the second according to DPM. Our results showed that the decisions to administer a diagnostic test could be better explained using the DPM threshold. This is because such decisions depend on objective evidence of test/treatment benefits and harms as well as type 1 cognition of benefits and harms, which are not considered under EUT. Given that type 1 processes are unique to each decision-maker, this means that the DPM threshold will vary among different individuals. We also showed that when type 1 processes exclusively dominate decisions, ordering a diagnostic test does not affect a decision; the decision is based on the assessment of benefits and harms of treatment. These findings could explain variations in the treatment and diagnostic patterns documented in today's clinical practice. PMID- 26244573 TI - EquiFACS: The Equine Facial Action Coding System. AB - Although previous studies of horses have investigated their facial expressions in specific contexts, e.g. pain, until now there has been no methodology available that documents all the possible facial movements of the horse and provides a way to record all potential facial configurations. This is essential for an objective description of horse facial expressions across a range of contexts that reflect different emotional states. Facial Action Coding Systems (FACS) provide a systematic methodology of identifying and coding facial expressions on the basis of underlying facial musculature and muscle movement. FACS are anatomically based and document all possible facial movements rather than a configuration of movements associated with a particular situation. Consequently, FACS can be applied as a tool for a wide range of research questions. We developed FACS for the domestic horse (Equus caballus) through anatomical investigation of the underlying musculature and subsequent analysis of naturally occurring behaviour captured on high quality video. Discrete facial movements were identified and described in terms of the underlying muscle contractions, in correspondence with previous FACS systems. The reliability of others to be able to learn this system (EquiFACS) and consistently code behavioural sequences was high--and this included people with no previous experience of horses. A wide range of facial movements were identified, including many that are also seen in primates and other domestic animals (dogs and cats). EquiFACS provides a method that can now be used to document the facial movements associated with different social contexts and thus to address questions relevant to understanding social cognition and comparative psychology, as well as informing current veterinary and animal welfare practices. PMID- 26244572 TI - Enhanced B-Cell Receptor Recognition of the Autoantigen Transglutaminase 2 by Efficient Catalytic Self-Multimerization. AB - A hallmark of the gluten-driven enteropathy celiac disease is autoantibody production towards the enzyme transglutaminase 2 (TG2) that catalyzes the formation of covalent protein-protein cross-links. Activation of TG2-specific B cells likely involves gluten-specific CD4 T cells as production of the antibodies is dependent on disease-associated HLA-DQ allotypes and dietary intake of gluten. IgA plasma cells producing TG2 antibodies with few mutations are abundant in the celiac gut lesion. These plasma cells and serum antibodies to TG2 drop rapidly after initiation of a gluten-free diet, suggestive of extrafollicular responses or germinal center reactions of short duration. High antigen avidity is known to promote such responses, and is also important for breakage of self-tolerance. We here inquired whether TG2 avidity could be a feature relevant to celiac disease. Using recombinant enzyme we show by dynamic light scattering and gel electrophoresis that TG2 efficiently utilizes itself as a substrate due to conformation-dependent homotypic association, which involves the C-terminal domains of the enzyme. This leads to the formation of covalently linked TG2 multimers. The presence of exogenous substrate such as gluten peptide does not inhibit TG2 self-cross-linking, but rather results in formation of TG2-TG2-gluten complexes. The celiac disease autoantibody epitopes, clustered in the N-terminal part of TG2, are conserved in the TG2-multimers as determined by mass spectrometry and immunoprecipitation analysis. TG2 multimers are superior to TG2 monomer in activating A20 B cells transduced with TG2-specific B-cell receptor, and uptake of TG2-TG2-gluten multimers leads to efficient activation of gluten specific T cells. Efficient catalytic self-multimerization of TG2 and generation of multivalent TG2 antigen decorated with gluten peptides suggest a mechanism by which self-reactive B cells are activated to give abundant numbers of plasma cells in celiac disease. Importantly, high avidity of the antigen could explain why TG2-specific plasma cells show signs of an extrafollicular generation pathway. PMID- 26244574 TI - Association of ABCB1 and FLT3 Polymorphisms with Toxicities and Survival in Asian Patients Receiving Sunitinib for Renal Cell Carcinoma. AB - Sunitinib is a tyrosine kinase inhibitor used as first-line treatment for metastatic renal cell carcinoma (mRCC). Asian ethnicity has been previously associated with lower clearance and greater toxicities for sunitinib treatment, relative to Caucasian ethnicity. Research focusing on identifying corresponding biomarkers of efficacy and toxicity has been hitherto conducted in Caucasian populations, and few of the reported associations have been externally validated. Our work thus aims to investigate candidate biomarkers in Asian patients receiving sunitinib, comparing the observed genotype effects with those reported in Caucasian populations. Using data from 97 Asian mRCC patients treated with sunitinib, we correlated 7 polymorphisms in FLT3, ABCB1, VEGFR2, ABCG2 and BIM with patient toxicities, response, and survival. We observed a stronger association of FLT3 738T genotype with leucopenia in our Asian dataset than that previously reported in Caucasian mRCC patients (odds ratio [OR]=8.0; P=0.03). We observed significant associations of FLT3 738T (OR=2.7), ABCB1 1236T (OR=0.3), ABCB1 3435T (OR=0.1), ABCB1 2677T (OR=0.4), ABCG2 421A (OR=0.3) alleles and ABCB1 3435, 1236, 2677 TTT haplotype (OR=0.1) on neutropenia. Primary resistance (OR=0.1, P=0.004) and inferior survival (progression-free: hazard ratio [HR]=5.5, P=0.001; overall: HR=5.0, P=0.005) were associated with the ABCB1 3435, 1236, 2677 TTT haplotype. In conclusion, ABCB1 and FLT3 polymorphisms may be helpful in predicting sunitinib toxicities, response and survival benefit in Asian mRCC patients. We have also validated the association between FLT3 738T and sunitinib induced leucopenia previously reported in Caucasian populations, but have not validated other reported genetic associations. PMID- 26244575 TI - Structure and Function of p53-DNA Complexes with Inactivation and Rescue Mutations: A Molecular Dynamics Simulation Study. AB - The tumor suppressor protein p53 can lose its function upon DNA-contact mutations (R273C and R273H) in the core DNA-binding domain. The activity can be restored by second-site suppressor or rescue mutations (R273C_T284R, R273H_T284R, and R273H_S240R). In this paper, we elucidate the structural and functional consequence of p53 proteins upon DNA-contact mutations and rescue mutations and the underlying mechanisms at the atomic level by means of molecular dynamics simulations. Furthermore, we also apply the docking approach to investigate the binding phenomena between the p53 protein and DNA upon DNA-contact mutations and rescue mutations. This study clearly illustrates that, due to DNA-contact mutants, the p53 structure loses its stability and becomes more rigid than the native protein. This structural loss might affect the p53-DNA interaction and leads to inhibition of the cancer suppression. Rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) can restore the functional activity of the p53 protein upon DNA-contact mutations and show a good interaction between the p53 protein and a DNA molecule, which may lead to reactivate the cancer suppression function. Understanding the effects of p53 cancer and rescue mutations at the molecular level will be helpful for designing drugs for p53 associated cancer diseases. These drugs should be designed so that they can help to inhibit the abnormal function of the p53 protein and to reactivate the p53 function (cell apoptosis) to treat human cancer. PMID- 26244576 TI - Effect of Roadside Vegetation Cutting on Moose Browsing. AB - Moose (Alces americanus ) vehicle collisions (MVCs) are an issue throughout the distribution of moose. Many mitigation strategies have been tested and implemented to reduce the number of MVCs, but there have been few empirical analyses of the effectiveness of roadside vegetation cutting. The goal of this study was to determine if roadside vegetation cutting attracted moose into roadside areas to browse on the vegetation regrowth. We hypothesized that moose would be attracted to roadside areas with cut vegetation. Consequently, we predicted that there would be higher levels of browsing in cut areas compared to uncut areas. To determine if moose were browsing more in cut or uncut areas, we measured the number of plants browsed by moose in paired treatment (cut on or after 2008) and control (not cut since at least 2008) sites, along with a suite of potential environmental covariates. Using a model selection approach, we fit generalized linear mixed-effects models to determine the most parsimonious set of environmental variables to explain variation in the proportion of moose browse among sites. In contrast to our hypothesis, our results show that the proportion of moose browse in the uncut control areas was significantly higher than in the cut treatment areas. The results of this study suggest that recently cut roadside areas (7 years or less based on our work) may create a less attractive foraging habitat for moose. The majority of the variance in the proportion of moose browse among sites was explained by treatment type and nested plot number within site identification (34.16%), with additional variance explained by traffic region (5.00%) and moose density (4.35%). Based on our study, we recommend that vegetation cutting be continued in roadside areas in Newfoundland as recently cut areas may be less attractive browsing sites for moose. PMID- 26244578 TI - Gait synthesis for an anthropomorphic human model with articulated feet. PMID- 26244577 TI - Rescue of Fructose-Induced Metabolic Syndrome by Antibiotics or Faecal Transplantation in a Rat Model of Obesity. AB - A fructose-rich diet can induce metabolic syndrome, a combination of health disorders that increases the risk of diabetes and cardiovascular diseases. Diet is also known to alter the microbial composition of the gut, although it is not clear whether such alteration contributes to the development of metabolic syndrome. The aim of this work was to assess the possible link between the gut microbiota and the development of diet-induced metabolic syndrome in a rat model of obesity. Rats were fed either a standard or high-fructose diet. Groups of fructose-fed rats were treated with either antibiotics or faecal samples from control rats by oral gavage. Body composition, plasma metabolic parameters and markers of tissue oxidative stress were measured in all groups. A 16S DNA sequencing approach was used to evaluate the bacterial composition of the gut of animals under different diets. The fructose-rich diet induced markers of metabolic syndrome, inflammation and oxidative stress, that were all significantly reduced when the animals were treated with antibiotic or faecal samples. The number of members of two bacterial genera, Coprococcus and Ruminococcus, was increased by the fructose-rich diet and reduced by both antibiotic and faecal treatments, pointing to a correlation between their abundance and the development of the metabolic syndrome. Our data indicate that in rats fed a fructose-rich diet the development of metabolic syndrome is directly correlated with variations of the gut content of specific bacterial taxa. PMID- 26244579 TI - Anaesthetic induction and recovery characteristics of a diazepam-ketamine combination compared with propofol in dogs. AB - Induction of anaesthesia occasionally has been associated with undesirable behaviour in dogs. High quality of induction of anaesthesia with propofol has been well described while in contrast variable induction and recovery quality has been associated with diazepam-ketamine. In this study, anaesthetic induction and recovery characteristics of diazepam-ketamine combination with propofol alone were compared in dogs undergoing elective orchidectomy. Thirty-six healthy adult male dogs were used. After habitus scoring (simple descriptive scale [SDS]), the dogs were sedated with morphine and acepromazine. Forty minutes later a premedication score (SDS) was allocated and general anaesthesia was induced using a combination of diazepam-ketamine (Group D/K) or propofol (Group P) and maintained with isoflurane. Scores for the quality of induction, intubation and degree of myoclonus were allocated (SDS). Orchidectomy was performed after which recovery from anaesthesia was scored (SDS) and times to extubation and standing were recorded. Data were analysed using descriptive statistics and Kappa Reliability and Kendall Tau B tests. Both groups were associated with acceptable quality of induction and recovery from anaesthesia. Group P, however, was associated with a poorer quality of induction (p = 0.014), prolonged induction period (p = 0.0018) and more pronounced myoclonus (p = 0.003), but had better quality of recovery (p = 0.000002) and shorter recovery times (p = 0.035) compared with Group D/K. Diazepam-ketamine and propofol are associated with acceptable induction and recovery from anaesthesia. Propofol had inferior anaesthetic induction characteristics, but superior and quicker recovery from anaesthesia compared with diazepam-ketamine. PMID- 26244580 TI - Controlled breeding and reproductive management in water buffaloes (Bubalus bubalis) using Eazi Breed controlled internal drug release. AB - Buffalo reproduction is considerably affected by late maturity, poor oestrus symptoms and long postpartum periods. This study was undertaken to evaluate the efficiency of Eazi Breed controlled internal drug release (CIDR), an intravaginal progesterone-releasing device, in relation to oestrus and fertility. Five hundred true anoestrus buffalo cows, in the age group 4-6 years in 10 villages of Dharwad district in Karnataka state in India, were randomly selected and treated with CIDR for 9 days. Two mL of Cidirol (1 mg oestradiol benzoate) was administered intramuscularly to all animals on day 10. Forty-two buffaloes (8.4%) that failed to show oestrus signs (1.6%) or showed weak signs of oestrus (6.8%) after the first treatment were treated again 72 h after the Cidriol injection with a new device, and inseminated after the expression of oestrus. After the second treatment all the animals showed oestrus signs. The percentage of buffaloes showing intense oestrus was 67.40%, intermediate oestrus was shown by 25.80%, whilst 6.80% buffaloes showed weak oestrus even after the second treatment. The buffaloes showing oestrus signs were inseminated twice with an interval of 12 h, starting 12 h after the start of the oestrus signs. In 86 buffaloes showing prolonged oestrus signs a third insemination was done. The conception rates were 85.16%, 60.47% and 44.11% respectively in buffaloes showing intense, intermediate and weak oestrus. Transrectal palpation of the genital tract was performed 45-60 days post-insemination to diagnose pregnancy status, and in doubtful cases pregnancy was reconfirmed at 90 days after insemination. Out of 500 buffaloes treated in this way 380 animals became pregnant and the pregnancy rate was 76%. This study revealed the usefulness of Eazi Breed CIDR along with Cidirol treatment in buffaloes to improve their reproductive performance. PMID- 26244581 TI - Molecular characterisation of Mycoplasma species isolated from the genital tract of Dorper sheep in South Africa. AB - Biochemical and molecular analysis were conducted on 34 strains of Mycoplasma species isolated between 2003 and 2009 from the genital tract of clinically healthy Dorper sheep and sheep with ulcerative vulvitis and balanitis. Earlier publications identified the causative agent as Mycoplasma mycoides mycoides large colony (MmmLC) and Arcanobacterium pyogenes. The aims of the study were to characterise Mycoplasma species isolated from the genital tract of Dorper sheep with polymerase chain reaction assay, cloning and gene sequencing. Basic Local Alignment Search Tool (BLAST) results revealed six predominant Mycoplasma species: Mycoplasma arginini, Mycoplasma bovigenitalium, Arcanobacterium laidlawii, MmmLC, Mycoplasma sp. ovine/caprine serogroup II and M. canadense. Sequencing of the 34 isolates were analysed using phylogenetic methods, and 18 (50%) were identified as M. arginini with 99% - 100% similarity to M. arginini from England and Sweden. Six isolates showed 99% similarity to M. bovigenitalium strains from Turkey and Germany. Two isolates had 99% similarity to an M. sp. ovine/caprine sero group II from the United Kingdom. BLAST for two isolates revealed 99% similarity to Acholeplasma laidlawii from India, another two were 99% similar to MmmLC strain from Sweden, two showed 98% similarity to Mycoplasma sp. Usp 120 from Brazil, and two isolates have a 97% - 99% similarity to M. mm. Jcv1 strain from the United States of America. Finally, one isolate showed similarity of 99% to Mycoplasma canadense strain from Italy. The findings support the hypothesis that ulcerative vulvitis and balanitis of Dorper sheep in South Africa (SA) is a multifactorial disease with involvement of different Mycoplasma species. PMID- 26244582 TI - Distribution of endemic and introduced tick species in Free State Province, South Africa. AB - The distributions of endemic tick vector species as well as the presence of species not endemic to Free State Province, South Africa, were determined during surveys or opportunistic collections from livestock, wildlife and vegetation. Amongst endemic ticks, the presence of Rhipicephalus appendiculatus was confirmed in the north of the province, whilst Rhipicephalus decoloratus was collected at 31 localities mostly in the centre and east, and Ixodes rubicundus at 11 localities in the south, south-west and centre of the province. Amongst the non endemic species adult Amblyomma hebraeum were collected from white rhinoceroses (Ceratotherium simum) on four privately owned farms, whilst the adults of Rhipicephalus microplus were collected from cattle and a larva from vegetation at four localities in the east of the province. The collection of Rhipicephalus evertsi mimeticus from a sheep in the west of the province is the second record of its presence in the Free State, whereas the presence of Haemaphysalis silacea on helmeted guineafowl (Numida meleagris) and vegetation in the centre of the province represents a first record for this species in the Free State. The first collection of the argasid tick, Ornithodoros savignyi, in the Free State was made from a domestic cow and from soil in the west of the province. The localities at which the ticks were collected have been plotted and the ticks' role in the transmission or cause of disease in domestic livestock and wildlife is discussed. PMID- 26244583 TI - Bovine mastitis prevalence and associated risk factors in dairy cows in Nyagatare District, Rwanda. AB - In response to farmer requests after milk from their herds was rejected by processors due to poor quality, a study was carried out from April to October 2011 to determine the prevalence of sub clinical mastitis, associated risk factors and causative micro-organisms. Samples were collected from 195 dairy cows on 23 randomly selected dairy farms delivering milk to Isangano, Kirebe and Nyagatare milk collection centres in Nyagatare District, Rwanda. The Draminski Mastitis Detector was used to detect sub clinical mastitis in individual cows based on milk electrical conductivity changes. Risk factors for mastitis that were evaluated included teat-end condition, cow dirtiness, breed, parity, age and stage of lactation. Relationships of these factors with mastitis status were determined using Chi-square analysis, and relative importance as causes of mastitis was assessed using logistic regression. Samples from 16 sub clinical mastitis positive dairy cows were analysed to identify causative micro-organisms using Dairy Quality Control Inspection analytical kits. Sub clinical mastitis prevalence was 52% across the farms. It was higher with increases in, amongst other risk factors, teat-end damage severity, cow dirtiness, and level of pure dairy breed genetics. The risk factors considered accounted for 62% of mastitis prevalence; teat-end condition alone accounted for 30%. Most of the mastitis cases (87.5%) were caused by coliform bacteria. Considering that farmers are upgrading their local Ankole cows to cross-breed dairy cows that are more susceptible to mastitis, results from this study indicate the need to dip the teats of cows in sanitisers, improve cow hygiene, and introduce mastitis prevention and control programmes. PMID- 26244584 TI - Questing ixodid ticks on the vegetation of sable antelope and multi-herbivore enclosures in Thabazimbi. AB - This survey of ixodid ticks was the first to compare the species composition and population dynamics of free-living ticks in intensive, sable antelope breeding enclosures, now commonplace in commercial wildlife ranching in South Africa, with those of multi-herbivore enclosures. The species composition, abundance and seasonal abundance of questing ixodid ticks on the vegetation in intensive breeding enclosures for sable antelope (Hippotragus niger), on which strategic tick control is practised, were compared with those of ticks in a multi-species herbivore enclosure surrounding the breeding enclosures in which no tick control is practised. A total of eight ixodid tick species were collected by drag sampling the woodland and grassland habitats in each enclosure type monthly from July 2011 to July 2013. Rhipicephalus decoloratus, a potential vector of fatal tick-borne disease in sable antelopes, was the most abundant, accounting for 65.4% of the total number of ticks collected in the sable enclosures, whilst representing only 25.4% of number of ticks collected in the multi-species herbivore enclosure. Rhipicephalus decoloratus and R. evertsi evertsi were more abundant than R. appendiculatus (both p < 0.05) and Amblyomma hebraeum (p < 0.001 and p < 0.01, respectively). Rhipicephalus decoloratus larvae were collected throughout the year, with peak collections in November 2012 and October to December 2013 in the sable enclosures; and in April/May 2012 and February/April 2013 in the multi-species herbivore enclosure. More R. decoloratus were recovered in the second year than in the first year in the grassland habitat of the sable enclosures (V = 7.0, p < 0.05) possibly as a result of acaricide resistance. The apparent temporal over-abundance of R. decoloratus in sable antelope breeding enclosures, in the face of strategic tick control, is of concern and requires further investigation. PMID- 26244585 TI - Investigations of foreign bodies in the fore-stomach of cattle at Ngoma Slaughterhouse, Rwanda. AB - Ingestion of indigestible foreign bodies in cattle is a pathological condition of both economic and health importance. It is has mostly been reported in association with feed scarcity. The aim of this study was to investigate the occurrence and nature of indigestible foreign materials in abattoir fore-stomach specimens in Ngoma district, Rwanda. Each chamber was opened by incision, then given a thorough macroscopic examination by visual inspection and palpation for the presence of foreign materials. The results show that there is an overall occurrence of 17.4% foreign bodies in cattle. The highest occurrence (25.3%) was recorded in June (the driest month). Results further show that the majority of the foreign bodies were plastics (65.0%). More foreign bodies (29.5%) were found in older animals (5 years and above) than in younger and middle-aged animals (16.5 % and 6.0%, respectively). There was a higher prevalence of foreign bodies in female cattle (20.0%) than in males (15.7%). The presence of cassette tape, as observed in the study, has not been reported elsewhere. The high representation of plastics in animals (65.5%) in the light of a government plastic bag ban in supermarkets presents a major challenge to livestock production in Rwanda. What is disturbing is that it is not known if this problem is increasing or decreasing as there are no previous studies for comparison. However, the results will serve as a reference point for future studies to understand the true trend and true burden of plastic bags in livestock. PMID- 26244586 TI - Beyond traditional dairy veterinary services: 'It's not just about the cows!'. AB - It remains a challenge for the role of the dairy veterinarian to move beyond that traditionally held. In larger herds with a high reproductive workload, we are at great risk of becoming specialist technicians. Instead we seek greater involvement, to deliver comprehensive services and to be recognised for them, personally and financially. Given the frequency of our visits, knowledge and analytical skills we are in a unique position to provide inputs that complement advice given by other consultants. Failure to do so has economic consequences for both veterinarian and dairyman. The opportunity for and value of inputs will differ for every client, and we need to remain cognizant of their motivation. This review article shares perspectives, opportunities and tools that might enable moving beyond the traditional role. It starts with a review of available research describing the dynamic between dairyman and veterinarian and how this might impact an animal health production management programme. A description of the experiences of others follows, interspersed by the personal experiences of the author, working with large total mixed ration-fed herds in the United States of America. The following attributes and roles can be associated with a significant economic impact: gatekeeper; conduit; executor; verifier; monitor; facilitator and mediator; trainer, motivator and coach; applied nutritionist; technologist; champion of animal welfare, food safety and judicious antibiotic use; and confidant. Each is elucidated and described in context, revealing a need for continuing education. The nature of the relationship between veterinarian and client will determine the opportunity for and value of each. The veterinarian is in a unique position to become an integral part of the management team and to be fairly compensated as such. The onus rests on the veterinarian to broaden his/her knowledge and skills and to demonstrate their value. PMID- 26244587 TI - Serodetection of Ehrlichia canis amongst dogs in central Namibia. AB - Ehrlichia canis is a major pathogen in dogs throughout Africa, yet it has not been reported in Namibia. The aim of this study was to determine the seroprevalence of canine ehrlichiosis in central Namibia using the ImmunoComb assay (Biogal, Galed Laboratories). The study included 76 dogs that presented to the Rhino Park Veterinary Clinic in the north-western suburb of Khomasdal, Windhoek, Namibia, as well as 30 stray dogs from the Windhoek branch of the Society for the Prevention of Cruelty to Animals. Of the 106 dogs tested, 53.8% were seropositive at titres > 1:80. Dogs that presented with symptoms of E. canis infection had a significantly higher seroprevalence (86.6%) compared with apparently healthy dogs (41.6%) (P = 0.00). Location of habitation was significant (P < 0.017), with a high percentage of dogs exposed to E. canis living in the northern or north-western part of Windhoek. As the first study to serologically establish E. canis as a major pathogen in dogs in central Namibia, it is notable that the highest proportion of seropositive dogs came from low income areas. Further investigation is necessary to describe the ecology of this important tick-borne pathogen of companion animals in Namibia. PMID- 26244588 TI - Lesions in canine stifle joints due to trochleoplasties as treatment for medial patellar luxation. AB - Lesions in canine stifle joints after previous trochleoplasty surgery were documented. In four clinical cases arthrotomies were performed due to stifle pain after previous trochlear deepening procedures. A small area of hyaline cartilage remained in the groove of the stifles in cases where previous wedge trochleoplasties had been performed. All of the stifles had significant areas of eburnation on the axial aspect of the medial trochlear ridge. The stifle joints of a dog that was euthanased due to severe irreversible osteoarthritis were photographed. The dog had undergone previous surgery for patellar luxation and cranial cruciate ligament ruptures. The trochlear grooves in this dog had almost no visible articular cartilage left. PMID- 26244589 TI - Platycodon grandiflorum A. De Candolle Ethanolic Extract Inhibits Adipogenic Regulators in 3T3-L1 Cells and Induces Mitochondrial Biogenesis in Primary Brown Preadipocytes. AB - This study was designed to evaluate the effects of Platycodon grandiflorum A. DC. ethanolic extract (PG) on obesity in brown/white preadipocytes. The effect of PG on the differentiation and mitochondrial biogenesis of brown adipocytes is still not examined. An in vivo study showed that PG induced weight loss in mice with high-fat-diet-induced obesity. PG successfully suppressed the differentiation of 3T3-L1 cells by down-regulating cellular induction of the peroxisome proliferators activated receptor gamma (PPARgamma), CCAAT enhancer binding protein alpha (C/EBPalpha), lipin-1, and adiponectin but increasing expression of silent mating type information regulation 2 homologue 1 (SIRT1) and the phosphorylation of AMP-activated protein kinase alpha (AMPKalpha). The effect of PG on the adipogenic factors was compared with that of its bioactive compound platycodin D. In addition, PG increased expressions of mitochondria-related genes, including uncoupling protein 1 (UCP1), peroxisome proliferator activated receptor-coactivator 1 alpha (PGC1alpha), PR domain containing 16 (PRDM16), SIRT3, nuclear respiratory factor (NRF), and cytochrome C (CytC) in primary brown adipocytes. These results indicate that PG stimulates the differentiation of brown adipocytes through modulation of mitochondria-related genes and could offer clinical benefits as a supplement to treat obesity. PMID- 26244590 TI - Plutonium partitioning in water-granite and water-alpha-FeOOH systems: from a viewpoint of a three-phase system. AB - Traditional sorption experiments commonly treat the colloidal species of low solubility contaminants as immobile species when separated by centrifugation or ultrafiltration. This study shows that, from a viewpoint of a three-phase system, the mobile Pu species, especially the colloidal species, play an important role in Pu partitioning in water-granite and water-alpha-FeOOH systems. A new distribution coefficient term Ks/(d+c) was defined to take the mobile colloidal species into consideration, and it differs to the traditional distribution coefficient Ks/d by orders of magnitude in the water-granite and water-alpha FeOOH systems. This term, Ks/(d+c), can quantitatively describe Pu partitioning in the suspension, in particular the fraction of mobile species that dominate Pu migration in the environment. The effects of ionic strength (I) and pH on the Pu partitioning in water-granite and water-alpha-FeOOH systems are well interpreted with respect to the zeta potential change of granite grains, alpha-FeOOH colloid particles and polymeric Pu. It is concluded that the presence of the alpha-FeOOH colloid with a low concentration (<10 mg L(-1)) is favorable for the stability of colloidal Pu and leads to large proportion of mobile Pu, especially colloid associated Pu, which will migrate much faster than dissolved Pu in groundwater. PMID- 26244591 TI - Changes in Sleep With Auricular Point Acupressure for Chronic Low Back Pain. AB - The purpose of this study was to report sleep quality from 4 weeks of auricular point acupressure that was designed for chronic low back pain and determine the relationship between pain intensity and sleep quality. Participants were randomized into the APA group (n = 30) or the sham-APA group (n = 31). At baseline assessment, 87% of the participants reported poor sleep quality. Participants who received APA had decreased daytime disturbance and improved global Pittsburgh Sleep Quality Index scores at end of intervention (EOI) and 1 month follow up compared to participants in the sham-APA group. For the APA group, both the sleep duration and wake after sleep onset decreased gradually during the 4-week APA (0.56% and 0.23% daily change, respectively). PMID- 26244592 TI - Ninetieth Annual Business Meeting. PMID- 26244593 TI - Strategy for Enhancement of (13)C-Photo-CIDNP NMR Spectra by Exploiting Fractional (13)C-Labeling of Tryptophan. AB - The photo-CIDNP effect has proven to be useful to strongly enhance NMR signals of photochemically active proteins simply by irradiation with light. The evolving characteristic patterns of enhanced absorptive and emissive NMR lines can be exploited to elucidate the photochemistry and photophysics of light-driven protein reactions. In particular, by the assignment of (13)C NMR resonances, redox-active amino acids may be identified and thereby electron-transfer pathways unraveled, in favorable cases, even with (13)C at natural abundance. If signal enhancement is weak, uniform (13)C isotope labeling is traditionally applied to increase the signal strength of protein (13)C NMR. However, this typically leads to cross relaxation, which transfers light-induced nuclear-spin polarization to adjacent (13)C nuclei, thereby preventing an unambiguous analysis of the photo CIDNP effect. In this contribution, two isotope labeling strategies are presented; one leads to specific but ubiquitous (13)C labeling in tryptophan, and the other is based on fractional isotope labeling affording sets of isotopologs with low probability of next-neighbor isotope accumulation within individual tryptophan molecules. Consequently, cross relaxation is largely avoided while the signal enhancement by (13)C enrichment is preserved. This results in significantly simplified polarization patterns that are easier to analyze with respect to the generation of light-generated nuclear-spin polarization. PMID- 26244594 TI - Resuscitation and Prevalence of External Facial, Neck, and Chest Injuries in Infants. AB - Cardiopulmonary resuscitation can transmit external injuries to the face, neck, and chest regions of infants. The aim of this study was to compare and contrast observations made during infant autopsies to delineate differences in the external appearance of those who did and those who did not receive resuscitation. We investigated 344 infant deaths between mid 2007 and 2013 in Wayne County, Detroit, Michigan, and identified 38 infants (11%) who displayed abrasions and/or contusions, independent of the cause of death. Of those, 27 infants (71%) were administered resuscitated whereas 11 infants (29%) were not. In both groups, contusions were more common in homicide cases and abrasions in nonhomicide ones, thus having the injuries more reflective of the cause of death than resuscitation. In addition, abrasions were frequently seen in infants who had not received resuscitation. PMID- 26244595 TI - Building Zebrafish Neurobehavioral Phenomics: Effects of Common Environmental Factors on Anxiety and Locomotor Activity. AB - Zebrafish are emerging as an important model organism for neurobehavioral phenomics research. Given the likely variation of zebrafish behavioral phenotypes between and within laboratories, in this study, we examine the influence and variability of several common environmental modifiers on adult zebrafish anxiety and locomotor activity. Utilizing the novel tank paradigm, this study assessed the role of various laboratory factors, including experimenter/handling, testing time and days, batch, and the order of testing, on the behavior of a large population of experimentally naive control fish. Although time of the day, experimenter identity, and order of testing had little effect on zebrafish anxiety and locomotor activity levels, subtle differences were found for testing days and batches. Our study establishes how zebrafish behaviors are modulated by common environmental/laboratory factors and outlines several implications for zebrafish neurobehavioral phenomics research. PMID- 26244596 TI - Recyclable and Reusable [RuCl2(p-cymene)]2/Cu(OAc)2/PEG-400/H2O System for Oxidative C-H Bond Alkenylations: Green Synthesis of Phthalides. AB - [RuCl2(p-cymene)]2 in a mixture of poly(ethylene glycol) (PEG-400) and water is shown to be an extremely efficient catalyst for the cross-dehydrogenative C-H bond alkenylation reaction between benzoic acids and alkenes. The reaction could be conducted at 80 degrees C using Cu(OAc)2.H2O as oxidant, yielding a variety of phthalide derivatives in good to excellent yields. More importantly, both [RuCl2(p-cymene)]2 and Cu(OAc)2 in the PEG-400/H2O system could be easily recycled and reused six times without any loss of catalytic activity. PMID- 26244597 TI - Asymmetric Colloidal Janus Particle Formation Is Core-Size-Dependent. AB - Colloidal particles with asymmetric surface chemistry (Janus particles) have unique bifunctional properties. The size of these particles is an important determinant for their applications in diverse fields from drug delivery to chemical catalysis. The size of Janus particles, with a core surface coated with carboxylate and a partially encapsulating silica shell, depends upon several factors, including the core size and the concentration of carboxylate coating. The role of the carboxylate coating on the Janus particle size is well understood; however, the role of the core size is not well defined. The role of the carboxylated polystyrene (cPS) core size on the cPS-silica Janus particle morphology (its size and shape) was examined by testing two different silica sizes and five different cPS core sizes. Results from electron microscopy (EM) and dynamic light scattering (DLS) analysis indicate that the composite cPS silica particle acquires two distinct shapes: (i) when the size of the cPS core is much smaller than the non-cPS silica (b-SiO2) sphere, partially encapsulated Janus particles are formed, and (ii) when the cPS core is larger than or equal to the b-SiO2 sphere, a raspberry-like structure rather than a Janus particle is formed. The cPS-silica Janus particles of ~100-500 nm size were obtained when the size of the cPS core was much smaller than the non-cPS silica (b-SiO2) sphere. These scalable nanoscale Janus particles will have wide application in a multifunctional delivery platform and catalysis. PMID- 26244598 TI - MiR-210 inhibits NF-kappaB signaling pathway by targeting DR6 in osteoarthritis. AB - Osteoarthritis (OA) is characterized by degradation of articular cartilage and joint inflammation. MicroRNAs have been proved to play an important role in the regulation of chondrogenesis. Previous study showed that microRNA-210 (miR-210) was probably associated with osteoarthritis, while the function of miR-210 in osteoarthritis still remains unknown. The aim of the present study was to investigate the protective effect of miR-210 on osteoarthritis. In the in vitro study, miR-210 level in chondrocytes was decreased after treatment with lipopolysaccharide (LPS). Transfection with miR-210 mimic inhibited LPS-induced pro-inflammatory cytokines production, cell viability reduction and cell apoptosis. Results of luciferase activity assay showed that miR-210 targeted 3' UTR of death receptor 6 (DR6) to inhibit its expression. MiR-210 mimic and DR6 siRNA transfection inhibited the activation of NF-kappaB pathway and cell apoptosis of chondrocytes. For the in vivo study, OA model was established on rats by anterior cruciate ligament transection (ACLT). MiR-210 expression is reduced in OA rats. MiR-210 over-expressing lentivirus was injected into the OA rats. Cytokines production, and NF-kappaB and DR6 expression in OA rats was inhibited by miR-210 overexpression. The results demonstrated that miR-210 decreased inflammation in articular cavity in OA rats by targeting DR6 and inhibiting NF-kappaB signaling pathway. PMID- 26244599 TI - Differential acute effects of carbohydrate- and protein-rich drinks compared with water on cardiac output during rest and exercise in healthy young men. AB - The acute effects of drinks rich in protein (PRO) versus carbohydrate (CHO) on cardiovascular hemodynamics and reactivity are uncertain. A randomized crossover design was used to compare 400-mL isoenergetic (1.1 MJ) drinks containing whey protein (PRO; 44 g) or carbohydrate (CHO; 57 g) versus 400 mL of water in 14 healthy men. The primary and secondary outcomes were changes in cardiac output, blood pressure, systemic vascular resistance (SVR) and digital volume pulse measured prior to and 30 min following consumption at rest, during 12 min of multi-stage bicycle ergometry, and 15 min postexercise. The mean change (95% confidence interval (CI)) in resting cardiac output at 30 min was greater for CHO than for PRO or water: 0.7 (0.4 to 1.0), 0.1 (-0.2 to 0.40), and 0.0 (-0.3 to 0.3) L/min (P < 0.001), respectively; the higher cardiac output following CHO was accompanied by an increase in stroke volume and a lower SVR. The mean increments (95% CI) in cardiac output during exercise were CHO 4.7 (4.4 to 5.0), PRO 4.9 (4.6 to 5.2), and water 4.6 (4.3 to 4.9) L/min with the difference between PRO versus water being significant (P < 0.025). There were no other statistically significant differences. In summary, a CHO-rich drink increased cardiac output and lowered SVR in the resting state compared with a PRO-rich drink or water but the effect size of changes in these variables did not differ during or after exercise between CHO and PRO. Neither protein nor carbohydrate affected blood pressure reactivity to exercise. PMID- 26244600 TI - The effects of adding single-joint exercises to a multi-joint exercise resistance training program on upper body muscle strength and size in trained men. AB - The aim of this study was compare changes in upper body muscle strength and size in trained men performing resistance training (RT) programs involving multi-joint plus single-joint (MJ+SJ) or only multi-joint (MJ) exercises. Twenty young men with at least 2 years of experience in RT were randomized in 2 groups: MJ+SJ (n = 10; age, 27.7 +/- 6.6 years) and MJ (n = 10; age, 29.4 +/- 4.6 years). Both groups trained for 8 weeks following a linear periodization model. Measures of elbow flexors and extensors 1-repetition maximum (1RM), flexed arm circumference (FAC), and arm muscle circumference (AMC) were taken pre- and post-training period. Both groups significantly increased 1RM for elbow flexion (4.99% and 6.42% for MJ and MJ+SJ, respectively), extension (10.60% vs 9.79%, for MJ and MJ+SJ, respectively), FAC (1.72% vs 1.45%, for MJ and MJ+SJ, respectively), and AMC (1.33% vs 3.17% for MJ and MJ+SJ, respectively). Comparison between groups revealed no significant difference in any variable. In conclusion, 8 weeks of RT involving MJ or MJ+SJ resulted in similar alterations in muscle strength and size in trained participants. Therefore, the addition of SJ exercises to a RT program involving MJ exercises does not seem to promote additional benefits to trained men, suggesting MJ-only RT to be a time-efficient approach. PMID- 26244601 TI - Associations between added sugar (solid vs. liquid) intakes, diet quality, and adiposity indicators in Canadian children. AB - Little is known about the influence of different forms of added sugar intake on diet quality or their association with obesity among youth. Dietary intake was assessed by three 24-h recalls in 613 Canadian children (aged 8-10 years). Added sugars (mean of 3-day intakes) were categorized according to source (solid or liquid). Dietary intake and the Canadian Healthy Eating Index (" HEI-C ") were compared across tertiles of solid and liquid added sugars separately as were adiposity indicators (body mass index (BMI), fat mass (dual-energy X-ray absorptiometry), and waist circumference). Cross-sectional associations were examined in linear regression models adjusting for age, sex, energy intake, and physical activity (7-day accelerometer). Added sugar contributed 12% of total energy intake (204 kcal) on average, of which 78% was from solid sources. Higher consumption of added sugars from either solid or liquid source was associated with higher total energy, lower intake of micronutrients, vegetables and fruit, and lower HEI-C score. Additionally liquid sources were associated with lower intake of dairy products. A 10-g higher consumption of added sugars from liquid sources was associated with 0.4 serving/day lower of vegetables and fruit, 0.4 kg/m(2) higher BMI, a 0.5-kg higher fat mass, and a 0.9-cm higher waist circumference whereas the associations of added sugars from solid sources and adiposity indicators tended to be negative. In conclusion, higher consumption of added sugar from either solid or liquid sources was associated with lower overall diet quality. Adiposity indicators were only positively associated with added sugars from liquid sources. PMID- 26244602 TI - Cholesterol ester transfer protein polymorphism rs5882 is associated with triglyceride-lowering in response to plant sterol consumption. AB - Recent work suggests that plant sterol (PS) consumption may lower triglyceride (TG) concentrations; however, human clinical trial evidence is inconsistent. We associated SNP r5882 in cholesteryl ester transfer protein with changes in TG concentrations following PS consumption (2 g/day for 4 weeks) in a dual-centre, single-blind, randomized, crossover trial. TG concentrations were lowered in homozygotes for the minor G-allele of rs5882 (-0.46 +/- 0.13 mmol/L, p = 0.002, n = 10); there was no effect in the A-allele carriers. PMID- 26244603 TI - Discussion of "The effects of pre-exhaustion, exercise order, and rest intervals in a full-body resistance training intervention"--Pre-exhaustion exercise and neuromuscular adaptations: an inefficient method? PMID- 26244604 TI - Reply to "Discussion of 'The effects of pre-exhaustion, exercise order, and rest intervals in a full-body resistance training intervention'--Pre-exhaustion exercise and neuromuscular adaptations: an inefficient method?". PMID- 26244605 TI - The lingering effects of a busted myth--false time limits in stroke rehabilitation. AB - It was once falsely believed that neurological and functional recovery after stroke occurred only in the first 6 months after lesion. The perception of this "6-month myth" continues to negatively impact the attitudes of patients towards their rehabilitation and on the clinicians and therapists making optimal training plans. Here we briefly outline some evidence that debunked the 6-month myth, where the concept of this temporal limit may have originated, and the lingering misunderstanding that individuals with stroke reach a plateau of recovery after 6 months even with rehabilitation training. We present evidence that significant functional improvement can occur years after stroke when rehabilitation training is applied. We frame the concepts of active and passive neurological recovery and that active neurological recovery continues far beyond any temporal limit. Because the effects of this busted 6-month myth persist, we aim to remind active physicians, therapists, exercise professionals, and those with stroke to continuously seek opportunities for active rehabilitation training. Meanwhile, trained and certified exercise professionals can play critical roles in facilitating rehabilitative training for community-dwelling stroke survivors. PMID- 26244606 TI - Crystal Structure of Barrel-Shaped Chiral Au130(p-MBT)50 Nanocluster. AB - We report the structure determination of a large gold nanocluster formulated as Au130(p-MBT)50, where p-MBT is 4-methylbenzenethiolate. The nanocluster is constructed in a four-shell manner, with 55 gold atoms assembled into a two-shell Ino decahedron. The surface is protected exclusively by -S-Au-S- staple motifs, which self-organize into five ripple-like stripes on the surface of the barrel shaped Au105 kernel. The Au130(p-MBT)50 can be viewed as an elongated version of the Au102(SR)44. Comparison of the Au130(p-MBT)50 structure with the recently discovered icosahedral Au133(p-TBBT)52 nanocluster (where p-TBBT = 4-tert butylbenzenethiolate) reveals an interesting phenomenon that a subtle ligand effect in the para-position of benzenethiolate can significantly affect the gold atom packing structure, i.e. from the 5-fold twinned Au55 decahedron to 20-fold twinned Au55 icosahedron. PMID- 26244607 TI - Dual regulation of skin sensitizer-induced HMOX1 expression by Bach1 and Nrf2: Comparison to regulation of the AKR1C2-ARE element in the KeratinoSens cell line. AB - Heme oxygenase (decycling) 1 (HMOX1) is the most consistently found genetic marker induced by skin sensitizers. HMOX1 is often referred to as typical gene regulated by nuclear factor erythroid 2-related factor 2 (Nrf2), however, it is also regulated by other DNA-binding factors, including BTB and CNC homolog 1 (Bach1). The KeratinoSensTM assay is the first validated in vitro assay for sensitizers that measures gene induction. It is based on luciferase expression regulated by the antioxidant response element (ARE) of the aldoketoreductase 1C2 (AKR1C2) gene. Luciferase upregulation is dependent on Nrf2, while HMOX1 upregulation is only partially Nrf2-dependent. Thus, sensitizer-dependent activation of HMOX1 may integrate multiple signals thereby providing additional information. We constructed reporter cell lines containing the full HMOX1 regulatory region or the HMOX1-ARE sequence and compared them with the construct containing the AKR1C2-ARE sequence. Induction of the AKR1C2-ARE depends on Nrf2, but not on the repressor Bach1. Results obtained with HMOX1-ARE and the full HMOX1 promoter indicate that, within the HMOX1 promoter, the HMOX1-ARE is sufficient to explain the induction by sensitizers and that (i) inhibiting Bach1 leads to strong basal expression, (ii) fold-induction by sensitizers above this level is reduced in the absence of Bach1 and (iii) these constructs are less dependent on Nrf2 as compared to the AKR1C2-ARE. Nevertheless, congruent dose response curves for luciferase activity were obtained with all constructs. Thus, while sensitizer-induced HMOX1 activation is dependent on Nrf2 and Bach1, all constructs give identical information for the in vitro prediction of the sensitization potential. PMID- 26244608 TI - Amyloid beta-Protein Assembly: Differential Effects of the Protective A2T Mutation and Recessive A2V Familial Alzheimer's Disease Mutation. AB - Oligomeric states of the amyloid beta-protein (Abeta) appear to be causally related to Alzheimer's disease (AD). Recently, two familial mutations in the amyloid precursor protein gene have been described, both resulting in amino acid substitutions at Ala2 (A2) within Abeta. An A2V mutation causes autosomal recessive early onset AD. Interestingly, heterozygotes enjoy some protection against development of the disease. An A2T substitution protects against AD and age-related cognitive decline in non-AD patients. Here, we use ion mobility-mass spectrometry (IM-MS) to examine the effects of these mutations on Abeta assembly. These studies reveal different assembly pathways for early oligomer formation for each peptide. A2T Abeta42 formed dimers, tetramers, and hexamers, but dodecamer formation was inhibited. In contrast, no significant effects on Abeta40 assembly were observed. A2V Abeta42 also formed dimers, tetramers, and hexamers, but it did not form dodecamers. However, A2V Abeta42 formed trimers, unlike A2T or wild type (wt) Abeta42. In addition, the A2V substitution caused Abeta40 to oligomerize similar to that of wt Abeta42, as evidenced by the formation of dimers, tetramers, hexamers, and dodecamers. In contrast, wt Abeta40 formed only dimers and tetramers. These results provide a basis for understanding how these two mutations lead to, or protect against, AD. They also suggest that the Abeta N terminus, in addition to the oft discussed central hydrophobic cluster and C terminus, can play a key role in controlling disease susceptibility. PMID- 26244609 TI - Methanogenesis from wastewater stimulated by addition of elemental manganese. AB - This study presents a novel procedure for accelerating methanogenesis from wastewater by adding elemental manganese into the anaerobic digestion system. The results indicated that elemental manganese effectively enhanced both the methane yield and the production rate. Compared to the control test without elemental manganese, the total methane yield and production rate with 4 g/L manganese addition increased 3.4-fold (from 0.89 +/- 0.03 to 2.99 +/- 0.37 M/gVSS within 120 h) and 4.4-fold (from 6.2 +/- 0.1 to 27.2 +/- 2.2 mM/gVSS/h), respectively. Besides, more acetate consumption and less propionate generation were observed during the methanogenesis with manganese. Further studies demonstrated that the elemental manganese served as electron donors for the methanogenesis from carbon dioxide, and the final proportion of methane in the total generated gas with 4 g/L manganese addition reached 96.9%, which was 2.1-fold than that of the control (46.6%). PMID- 26244611 TI - Networks of semiconducting SWNTs: contribution of midgap electronic states to the electrical transport. AB - Single-walled carbon nanotube (SWNT) thin films provide a unique platform for the development of electronic and photonic devices because they combine the advantages of the outstanding physical properties of individual SWNTs with the capabilities of large area thin film manufacturing and patterning technologies. Flexible SWNT thin film based field-effect transistors, sensors, detectors, photovoltaic cells, and light emitting diodes have been already demonstrated, and SWNT thin film transparent, conductive coatings for large area displays and smart windows are under development. While chirally pure SWNTs are not yet commercially available, the marketing of semiconducting (SC) and metallic (MT) SWNTs has facilitated progress toward applications by making available materials of consistent electronic structure. Nevertheless the electrical transport properties of networks of separated SWNTs are inferior to those of individual SWNTs. In particular, for semiconducting SWNTs, which are the subject of this Account, the electrical transport drastically differs from the behavior of traditional semiconductors: for example, the bandgap of germanium (E = 0.66 eV) roughly matches that of individual SC-SWNTs of diameter 1.5 nm, but in the range 300-100 K, the intrinsic carrier concentration in Ge decreases by more than 10 orders of magnitude while the conductivity of a typical SC-SWNT network decreases by less than a factor of 4. Clearly this weak modulation of the conductivity hinders the application of SC-SWNT films as field effect transistors and photodetectors, and it is the purpose of this Account to analyze the mechanism of the electrical transport leading to the unusually weak temperature dependence of the electrical conductivity of such networks. Extrinsic factors such as the contribution of residual amounts of MT-SWNTs arising from incomplete separation and doping of SWNTs are evaluated. However, the observed temperature dependence of the conductivity indicates the presence of midgap electronic states in the semiconducting SWNTs, which provide a source of low-energy excitations, which can contribute to hopping conductance along the nanotubes following fluctuation induced tunneling across the internanotube junctions, which together dominate the low temperature transport and limit the resistivity of the films. At high temperatures, the intrinsic carriers thermally activated across the bandgap as in a traditional semiconductor became available for band transport. The midgap states pin the Fermi level to the middle of the bandgap, and their origin is ascribed to defects in the SWNT walls. The presence of such midgap states has been reported in connection with scanning tunneling spectroscopy experiments, Coulomb blockade observations in low temperature electrical measurements, selective electrochemical deposition imaging, tip-enhanced Raman spectroscopy, high resolution photocurrent spectroscopy, and the modeling of the electronic density of states associated with various defects. Midgap states are present in conventional semiconductors, but what is unusual in the present context is the extent of their contribution to the electrical transport in networks of semiconducting SWNTs. In this Account, we sharpen the focus on the midgap states in SC-SWNTs, their effect on the electronic properties of SC-SWNT networks, and the importance of these effects on efforts to develop electronic and photonic applications of SC-SWNTs. PMID- 26244610 TI - Natural killer cell and gamma delta T cell alterations in enthesitis related arthritis category of juvenile idiopathic arthritis. AB - Enthesitis related arthritis (ERA) is associated with increased frequency of Th17 cells and synovial fluid (SF) IL-17 levels. Natural killer (NK) and gamma delta T cells have been recently shown to produce IL-17, thus we studied the NK and gamma delta-T cells in peripheral blood (PB) of 50 ERA, 16 other JIA patients and 19 healthy controls. We have analyzed the frequency of NK (total, CD56dim, CD56bright) and gamma delta-T cells, perforin and KIR3DL1/2 expression on NK cells and IL-17 and IFN-gamma production by them using flow cytometry. ERA patients had more NK cells with reduced perforin expression and IFN-gamma production but increased KIR3DL1/2 expression and IL-17 production as compared to controls. Also IL-17 producing gamma delta-T were increased in PB of ERA patients. Paired SF samples had NK cells with reduced perforin and KIR3DL expression. Thus increased NK and gamma delta-T cells may contribute to the inflammation in ERA by producing IL-17. PMID- 26244612 TI - Measurement of Dielectric Properties and Microwave-Assisted Homogeneous Acid Catalyzed Transesterification in a Monomode Reactor. AB - Microwave heating technology is dependent on the dielectric properties of the materials being processed. The dielectric properties of H2SO4, H3PO4, ClSO3H, and H3CSO3H were investigated in this study using a vector network analyzer in an open-ended coaxial probe method at various temperatures. Phosphoric and sulfuric acids presented higher loss tangents in the frequency range 0.3-13 GHz, reflecting greater mobility of the ions and counterions. The acids were employed as catalysts in microwave-assisted homogeneous transesterification reactions for the production of methylic and ethylic biodiesel. The effects of catalyst concentration, alcohol to oil molar ratio, and irradiation time on biodiesel conversions were investigated. The results showed a significant reduction in the reaction time for microwave-assisted transesterification reactions as compared to times for conventional heating. Also, despite its higher loss tangent, it was observed that H3PO4 leads to lower conversion to biodiesel, which can be explained by its lower carbonyl protonation capacity. PMID- 26244614 TI - Silicon Surface Modification and Characterization for Emergent Photovoltaic Applications Based on Energy Transfer. PMID- 26244615 TI - Magnetic Resonance Imaging of the Hip. AB - Hip pain is common in all age groups, and osteoarthritis of this joint is an increasingly recognized problem particularly in aging populations. One of the primary goals in the diagnostic evaluation in patients with hip pain is to identify and correct pathologies that could progress to osteoarthritis. Magnetic resonance imaging (MRI) has become an important noninvasive method for characterizing hip anatomy and pathology in these patients. Improvements in MRI hardware and techniques have allowed high spatial and contrast resolution imaging to detect subtle abnormalities, such as acetabular labral and articular cartilage injuries, which often contribute to patient symptoms. Newer MRI techniques, such as delayed gadolinium-enhanced MRI of cartilage and T2 mapping, can give insight into the biochemical structure of tissues such as the articular cartilage. In turn, these can allow quantitative assessment and enable imagers to more directly compare the findings of patients at earlier stages of disease. It is important to understand the fundamental principles of various MRI techniques and their limitations to know when these techniques can best be applied. In addition, understanding of normal hip anatomy and common anatomic variants is useful for being able to accurately detect and localize areas of pathology and to prevent misinterpreting normal structures as diseased. The aims of this work were to briefly review normal hip anatomy and common anatomic variants seen on routine MRI examination, to discuss principles often used in high-resolution hip MRI and newer techniques for biochemical evaluation, and to examine several intra articular pathologic conditions of the hip joint that are of current clinical interest. PMID- 26244616 TI - The Role of Magnetic Resonance Imaging in Athletic Pubalgia and Core Muscle Injury. AB - Magnetic resonance imaging (MRI) has become the standard of care imaging modality for a difficult, often misunderstood spectrum of musculoskeletal injury termed athletic pubalgia or core muscle injury. Armed with a dedicated noncontrast athletic pubalgia protocol and a late model phased array receiver coil, the musculoskeletal imager can play a great role in effective diagnosis and treatment planning for lesions, including osteitis pubis, midline pubic plate lesions, and rectus abdominis/adductor aponeurosis injury. Beyond these established patterns of MRI findings, there are many confounders and contributing pathologies about the pelvis in patients with activity related groin pain, including internal and periarticular derangements of the hip. The MRI is ideally suited to delineate the extent of expected injury and to identify the unexpected visceral and musculoskeletal lesions. PMID- 26244617 TI - The Knee. AB - Sports injuries at the knee are very common, not only in contact sports such as football but also in sports with jumping and pivoting. In addition, overuse injuries can affect the tendons, ligaments, and bone with degeneration, friction, and stress response. Radiologists and sports medicine professionals should be familiar with the range of injury occurring at the knee and patterns of injury that can be used to predict other more subtle pathology. These topics and others will be discussed. PMID- 26244618 TI - Magnetic Resonance Imaging of Sports Injuries Involving the Ankle. AB - Understanding of ankle injuries has evolved for the past few decades, influenced by capability to visualize ligaments, tendons, and bone marrow on magnetic resonance imaging (MRI). Natural history of injury progression, complications, and healing has also been characterized using MRI. Stress injury is particularly common at the ankle in athletes and "weekend warriors" alike. This article will discuss manifestations of ankle injury on MRI as well as associated findings that should be addressed. PMID- 26244619 TI - Midfoot and Forefoot Injuries. AB - Sports injuries of the midfoot and forefoot encompass a spectrum of osseous and soft tissue trauma. Magnetic resonance imaging serves as a primary or important supplementary diagnostic modality in evaluation of various injuries, most important of which include Lisfranc complex injury, stress fractures, and injury to the first metatarsophalangeal joint, aka "turf toe." Current technical advances in magnetic resonance and improved knowledge of regional anatomy enable thorough evaluation of the complex anatomic structures of the foot and facilitate accurate diagnosis in the setting of trauma. PMID- 26244620 TI - Atomic Description of the Interface between Silica and Alumina in Aluminosilicates through Dynamic Nuclear Polarization Surface-Enhanced NMR Spectroscopy and First-Principles Calculations. AB - Despite the widespread use of amorphous aluminosilicates (ASA) in various industrial catalysts, the nature of the interface between silica and alumina and the atomic structure of the catalytically active sites are still subject to debate. Here, by the use of dynamic nuclear polarization surface enhanced NMR spectroscopy (DNP SENS) and density functional theory (DFT) calculations, we show that on silica and alumina surfaces, molecular aluminum and silicon precursors are, respectively, preferentially grafted on sites that enable the formation of Al(IV) and Si(IV) interfacial sites. We also link the genesis of Bronsted acidity to the surface coverage of aluminum and silicon on silica and alumina, respectively. PMID- 26244621 TI - Inhibitory impact of 3'-terminal 2'-O-methylated small silencing RNA on target primed polymerization and unbiased amplified quantification of the RNA in Arabidopsis thaliana. AB - 3'-terminal 2'-O-methylation has been found in several kinds of small silencing RNA, regarded as a protective mechanism against enzymatic 3' -> 5' degradation and 3'-end uridylation. The influence of this modification on enzymatic polymerization, however, remains unknown. Herein, a systematic investigation is performed to explore this issue. We found these methylated small RNAs exhibited a suppression behavior in target-primed polymerization, revealing biased result for the manipulation of these small RNAs by conventional polymerization-based methodology. The related potential mechanism is investigated and discussed, which is probably ascribed to the big size of modified group and its close location to 3'-OH. Furthermore, two novel solutions each utilizing base-stacking hybridization and three-way junction structure have been proposed to realize unbiased recognition of small RNAs. On the basis of phosphorothioate against nicking, a creative amplified strategy, phosphorothioate-protected polymerization/binicking amplification, has also been developed for the unbiased quantification of methylated small RNA in Arabidopsis thaliana, demonstrating its promising potential for real sample analysis. Collectively, our studies uncover the polymerization inhibition by 3'-terminal 2'-O-methylated small RNAs with mechanistic discussion, and propose novel unbiased solutions for amplified quantification of small RNAs in real sample. PMID- 26244622 TI - GDP Matters: Cost Effectiveness of Cochlear Implantation and Deaf Education in Sub-Saharan Africa. AB - HYPOTHESIS: Cochlear implantation and deaf education are cost effective in Sub Saharan Africa. BACKGROUND: Cost effectiveness of pediatric cochlear implantation has been well established in developed countries but is unknown in low resource settings, where access to the technology has traditionally been limited. With incidence of severe-to-profound congenital sensorineural hearing loss 5 to 6 times higher in low/middle-income countries than the United States and Europe, developing cost-effective management strategies in these settings is critical. METHODS: Costs were obtained from experts in Nigeria, South Africa, Kenya, Rwanda, Uganda, and Malawi using known costs and published data, with estimation when necessary. A disability adjusted life years (DALY) model was applied using 3% discounting and 10-year length of analysis. Sensitivity analysis was performed to evaluate the effect of device cost, professional salaries, annual number of implants, and probability of device failure. Cost effectiveness was determined using the WHO standard of cost-effectiveness ratio/gross domestic product per capita (CER/GDP) less than 3. RESULTS: Cochlear implantation was cost effective in South Africa and Nigeria, with CER/GDP of 1.03 and 2.05, respectively. Deaf education was cost effective in all countries investigated, with CER/GDP ranging from 0.55 to 1.56. The most influential factor in the sensitivity analysis was device cost, with the cost-effective threshold reached in all countries using discounted device costs that varied directly with GDP. CONCLUSION: Cochlear implantation and deaf education are equally cost effective in lower-middle and upper-middle income economies of Nigeria and South Africa. Device cost may have greater impact in the emerging economies of Kenya, Uganda, Rwanda, and Malawi. PMID- 26244623 TI - Optimal SBP targets for the prevention of progression of type 2 diabetic nephropathy: is home blood pressure monitoring the solution? PMID- 26244624 TI - Method of calibration of measurement of central aortic pressure and prediction of all-cause mortality in chronic kidney disease. PMID- 26244625 TI - 20-Hydroxyeicosatetraenoic acid, a far-reaching autacoid in chronic kidney disease: hypertension and beyond. PMID- 26244626 TI - Aortic stiffness and myocardial ischemia. PMID- 26244627 TI - Targeted blood pressure screening in children and adolescents: a justifiable option? PMID- 26244628 TI - It's all starting to come together. AB - Chemical, genetic and cell biology tools have been used to probe which RNA protein granules behave like liquids and which behave like solids. PMID- 26244630 TI - Finding a worm's internal compass. AB - A pair of neurons is required for nematodes to be able to navigate using the Earth's magnetic field. PMID- 26244629 TI - An extrafollicular pathway for the generation of effector CD8(+) T cells driven by the proinflammatory cytokine, IL-12. AB - The proinflammatory cytokine IL-12 drives the generation of terminally differentiated KLRG1(+) effector CD8(+) T cells. Using a Toxoplasma vaccination model, we delineate the sequence of events that naive CD8(+) T cells undergo to become terminal effectors and the differentiation steps controlled by IL-12. We demonstrate that direct IL-12 signaling on CD8(+) T cells is essential for the induction of KLRG1 and IFN-gamma, but the subsequent downregulation of CXCR3 is controlled by IL-12 indirectly through the actions of IFN-gamma and IFN-gamma inducible chemokines. Differentiation of nascent effectors occurs in an extrafollicular splenic compartment and is driven by late IL-12 production by DCs distinct from the classical CD8alpha(+) DC. Unexpectedly, we also found extensive proliferation of both KLRG1(-) and KLRG1(+) CD8(+) T cells in the marginal zone and red pulp, which ceases prior to the final KLRG1(Hi) CXCR3(Lo) stage. Our findings highlight the notion of an extrafollicular pathway for effector T cell generation. PMID- 26244631 TI - Social Context and Problem Factors among Youth with Juvenile Justice Involvement Histories. AB - Youth with juvenile justice histories often reside in poorly resourced communities and report high rates of depression, gang involved networks, and STI sexual related risk behaviors, compared to their counterparts. The primary aim of this study was to examine the relationship between social context (ie, a combined index score comprised of living in public housing, being a recipient of free school lunch, and witnessing community violence) and risk factors that are disproportionately worse for juvenile justice youth such as depression, gang involved networks and STI sexual risk behaviors. Data were collected from a sample of detained youth ages 14 to 16 (N = 489). Questions assessed demographics, social context, depression, gang-involved networks, and STI risk behaviors. Multiple logistic regression models, controlling for age, gender, race, school enrollment, and family social support, indicated that participants who reported poorer social context had double the odds of reporting being depressed; three times higher odds of being in a gang; three times higher odds of personally knowing a gang member; and double the odds of having engaged in STI risk behaviors. These results provide significant information that can help service providers target certain profiles of youth with juvenile justice histories for early intervention initiatives. PMID- 26244632 TI - Variation Reduction to Reduce Readmission: A Figment of Imagination or Reality of the Future? PMID- 26244633 TI - Fluctuations in flows near jamming. AB - Bubbles, droplets or particles in flowing complex media such as foams, emulsions or suspensions follow highly complex paths, with the relative motion of the constituents setting the energy dissipation rate. What is their dynamics, and how is this connected to the global rheology? To address these questions, we probe the statistics and spatio-temporal organization of the local particle motion and energy dissipation in a model for sheared disordered materials. We find that the fluctuations in the local dissipation vary from nearly Gaussian and homogeneous at low densities and fast flows, to strongly intermittent for large densities and slow flows. The higher order moments of the relative particle velocities reveal strong evidence for a qualitative difference between two distinct regimes which are nevertheless connected by a smooth crossover. In the critical regime, the higher order moments are related by novel multiscaling relations. In the plastic regime the relations between these moments take on a different form, with higher moments diverging rapidly when the flow rate vanishes. As these velocity differences govern the energy dissipation, we can distinguish two qualitatively different types of flow: an intermediate density, critical regime related to jamming, and a large density, plastic regime. PMID- 26244634 TI - A Source of False Findings in Published Research Studies: Adjusting for Covariates. PMID- 26244635 TI - Corrigendum: Structural and functional characterization of a novel scFv anti HSP60 of Strongyloides sp. PMID- 26244636 TI - Protective Enterotoxigenic Escherichia coli Antigens in a Murine Intranasal Challenge Model. AB - Enterotoxigenic Escherichia coli (ETEC) is an endemic health threat in underdeveloped nations. Despite the significant effort extended to vaccine trials using ETEC colonization factors, these approaches have generally not been especially effective in mediating cross-protective immunity. We used quantitative proteomics to identify 24 proteins that differed in abundance in membrane protein preparations derived from wild-type vs. a type II secretion system mutant of ETEC. We expressed and purified a subset of these proteins and identified nine antigens that generated significant immune responses in mice. Sera from mice immunized with either the MltA-interacting protein MipA, the periplasmic chaperone seventeen kilodalton protein, Skp, or a long-chain fatty acid outer membrane transporter, ETEC_2479, reduced the adherence of multiple ETEC strains differing in colonization factor expression to human intestinal epithelial cells. In intranasal challenge assays of mice, immunization with ETEC_2479 protected 88% of mice from an otherwise lethal challenge with ETEC H10407. Immunization with either Skp or MipA provided an intermediate degree of protection, 68 and 64%, respectively. Protection was significantly correlated with the induction of a secretory immunoglobulin A response. This study has identified several proteins that are conserved among heterologous ETEC strains and may thus potentially improve cross-protective efficacy if incorporated into future vaccine designs. PMID- 26244637 TI - Pulmonary Endogenous Fluorescence Allows the Distinction of Primary Lung Cancer from the Perilesional Lung Parenchyma. AB - BACKGROUND: Pre-therapeutic pathological diagnosis is a crucial step of the management of pulmonary nodules suspected of being non small cell lung cancer (NSCLC), especially in the frame of currently implemented lung cancer screening programs in high-risk patients. Based on a human ex vivo model, we hypothesized that an embedded device measuring endogenous fluorescence would be able to distinguish pulmonary malignant lesions from the perilesional lung tissue. METHODS: Consecutive patients who underwent surgical resection of pulmonary lesions were included in this prospective and observational study over an 8-month period. Measurements were performed back table on surgical specimens in the operative room, both on suspicious lesions and the perilesional healthy parenchyma. Endogenous fluorescence signal was characterized according to three criteria: maximal intensity (Imax), wavelength, and shape of the signal (missing, stable, instable, photobleaching). RESULTS: Ninety-six patients with 111 suspicious lesions were included. Final pathological diagnoses were: primary lung cancers (n = 60), lung metastases of extra-thoracic malignancies (n = 27) and non tumoral lesions (n = 24). Mean Imax was significantly higher in NSCLC targeted lesions when compared to the perilesional lung parenchyma (p<0,0001) or non tumoral lesions (p<0,0001). Similarly, photobleaching was more frequently found in NSCLC than in perilesional lung (p<0,0001), or in non-tumoral lesions (p<0,001). Respective associated wavelengths were not statistically different between perilesional lung and either primary lung cancers or non-tumoral lesions. Considering lung metastases, both mean Imax and wavelength of the targeted lesions were not different from those of the perilesional lung tissue. In contrast, photobleaching was significantly more frequently observed in the targeted lesions than in the perilesional lung (p<=0,01). CONCLUSION: Our results demonstrate that endogenous fluorescence applied to the diagnosis of lung nodules allows distinguishing NSCLC from the surrounding healthy parenchyma and from non tumoral lesions. Inconclusive results were found for lung metastases due to the heterogeneity of this population. PMID- 26244638 TI - Long-Term Extensive Ectopic Hair Growth on the Spinal Cord of Mice from Transplanted Whisker Follicles. AB - We have previously demonstrated that hair follicles contain nestin-expressing pluripotent stem cells that can effect nerve and spinal cord repair upon transplantation. In the present study, isolated whisker follicles from nestin driven green fluorescent protein (ND-GFP) mice were histocultured on Gelfoam for 3 weeks for the purpose of transplantation to the spinal cord to heal an induced injury. The hair shaft was cut off from Gelfoam-histocultured whisker follicles, and the remaining part of the whisker follicles containing GFP-nestin expressing pluripotent stem cells were transplanted into the injured spinal cord of nude mice, along with the Gelfoam. After 90 days, the mice were sacrificed and the spinal cord lesion was observed to have healed. ND-GFP expression was intense at the healed area of the spinal cord, as observed by fluorescence microscopy, demonstrating that the hair follicle stem cells were involved in healing the spinal cord. Unexpectedly, the transplanted whisker follicles sprouted out remarkably long hair shafts in the spinal cord during the 90 days after transplantation of Gelfoam whisker histocultures to the injured spine. The pigmented hair fibers, grown from the transplanted whisker histocultures, curved and enclosed the spinal cord. The unanticipated results demonstrate the great potential of hair growth after transplantation of Gelfoam hair follicle histocultures, even at an ectopic site. PMID- 26244640 TI - Nanofibers Fabricated Using Triaxial Electrospinning as Zero Order Drug Delivery Systems. AB - A new strategy for creating functional trilayer nanofibers through triaxial electrospinning is demonstrated. Ethyl cellulose (EC) was used as the filament forming matrix in the outer, middle, and inner working solutions and was combined with varied contents of the model active ingredient ketoprofen (KET) in the three fluids. Triaxial electrospinning was successfully carried out to generate medicated nanofibers. The resultant nanofibers had diameters of 0.74 +/- 0.06 MUm, linear morphologies, smooth surfaces, and clear trilayer nanostructures. The KET concentration in each layer gradually increased from the outer to the inner layer. In vitro dissolution tests demonstrated that the nanofibers could provide linear release of KET over 20 h. The protocol reported in this study thus provides a facile approach to creating functional nanofibers with sophisticated structural features. PMID- 26244639 TI - Modification of beta-Defensin-2 by Dicarbonyls Methylglyoxal and Glyoxal Inhibits Antibacterial and Chemotactic Function In Vitro. AB - BACKGROUND: Beta-defensins (hBDs) provide antimicrobial and chemotactic defense against bacterial, viral and fungal infections. Human beta-defensin-2 (hBD-2) acts against gram-negative bacteria and chemoattracts immature dendritic cells, thus regulating innate and adaptive immunity. Immunosuppression due to hyperglycemia underlies chronic infection in Type 2 diabetes. Hyperglycemia also elevates production of dicarbonyls methylgloxal (MGO) and glyoxal (GO). METHODS: The effect of dicarbonyl on defensin peptide structure was tested by exposing recombinant hBD-2 (rhBD-2) to MGO or GO with subsequent analysis by MALDI-TOF MS and LC/MS/MS. Antimicrobial function of untreated rhBD-2 vs. rhBD-2 exposed to dicarbonyl against strains of both gram-negative and gram-positive bacteria in culture was determined by radial diffusion assay. The effect of dicarbonyl on rhBD-2 chemotactic function was determined by chemotaxis assay in CEM-SS cells. RESULTS: MGO or GO in vitro irreversibly adducts to the rhBD-2 peptide, and significantly reduces antimicrobial and chemotactic functions. Adducts derive from two arginine residues, Arg22 and Arg23 near the C-terminus, and the N terminal glycine (Gly1). We show by radial diffusion testing on gram-negative E. coli and P. aeruginosa, and gram-positive S. aureus, and a chemotaxis assay for CEM-SS cells, that antimicrobial activity and chemotactic function of rhBD-2 are significantly reduced by MGO. CONCLUSIONS: Dicarbonyl modification of cationic antimicrobial peptides represents a potential link between hyperglycemia and the clinical manifestation of increased susceptibility to infection, protracted wound healing, and chronic inflammation in undiagnosed and uncontrolled Type 2 diabetes. PMID- 26244641 TI - Li(+)-Oligoglyme Association in the Presence of Ionic Liquid Studied by Molecular Dynamics and Explicit or Implicit Solvent Model. AB - Molecular dynamics simulations have been applied to study properties of ternary oligoglyme/ionic liquid/lithium salt electrolytes. Different types of lithium coordination and phase behavior have been observed depending on the liquid/salt anion: from full phase separation and Li(+) coordination exclusively to anions in systems with BF4(-) to rather homogeneous systems and prevailing Li(+)-hexaglyme coordination for FSI(-) or B(CN)4(-) anion. Observed structural properties have been successfully correlated to the binding energies of Li(+)-glyme complexes in solution calculated within an explicit solvent model. Conversely, an implicit solvent approach has failed to predict differences between electrolytes based on different ionic liquids. PMID- 26244642 TI - IFI6 Inhibits Apoptosis via Mitochondrial-Dependent Pathway in Dengue Virus 2 Infected Vascular Endothelial Cells. AB - Dengue hemorrhagic fever (DHF)/Dengue shock syndrome (DSS) is a fatal infectious disease that demands an effective treatment. Interferon (IFN)-stimulated genes (ISGs) induced by dengue virus (DENV) exert antiviral effects. Among ISGs, IFN alpha inducible gene 6 (IFI6) was increased in DENV infected human umbilical vascular endothelial cells (HUVECs) by microarray analysis in our previous study. However, its function is incompletely understood. In this study, we confirmed that IFI6 was markedly induced in DENV infection of both primary HUVECs and EA.hy926 cell lines. Recombinant EA.hy926 cell lines in which IFI6 was either over-expressed (IFI6+/+) or knocked-down (IFI6-/-) were generated. The activation of caspase-3 and intrinsic apoptosis-related protein caspase-9 were down regulated in IFI6+/+ but up-regulated in IFI6-/- cells at 24-48 hrs post infection. After incubation with DENV for 48 hrs, the mitochondrial membrane potential (Deltapsi(m)) was more stable in IFI6+/+ cells but reduced in IFI6-/- cells, as assayed by fluorescence staining with JC-1. We observed that Bcl-2 expression was increased in IFI6+/+ and decreased in IFI6-/- cells. By contrast, Bax expression was decreased in IFI6+/+ and increased in IFI6-/- cells. It is presumed that the anti-apoptotic function of IFI6 is expressed by regulating the rheostatic balance between bcl-2/bax expression and inhibition of Deltapsi(m) depolarization during DENV infection of vascular endothelial cells(VECs). In addition, the pro-apoptotic protein X-linked Inhibitor of Apoptosis (XIAP) Associated Factor 1(XAF1) expression had been reported to be up-regulated and led to the induction of apoptosis in DENV2-infected VECs,but the relationship between XAF1 and IFI6 dengue virus-induced apoptosis in VECs warrants further study. PMID- 26244643 TI - How Diverse Detrital Environments Influence Nutrient Stoichiometry between Males and Females of the Co-Occurring Container Mosquitoes Aedes albopictus, Ae. aegypti, and Culex quinquefasciatus. AB - Allocation patterns of carbon and nitrogen in animals are influenced by food quality and quantity, as well as by inherent metabolic and physiological constraints within organisms. Whole body stoichiometry also may vary between the sexes who differ in development rates and reproductive allocation patterns. In aquatic containers, such as tree holes and tires, detrital inputs, which vary in amounts of carbon and nitrogen, form the basis of the mosquito-dominated food web. Differences in development times and mass between male and female mosquitoes may be the result of different reproductive constraints, which could also influence patterns of nutrient allocation. We examined development time, survival, and adult mass for males and females of three co-occurring species, Aedes albopictus, Ae. aegypti, and Culex quinquefasciatus, across environments with different ratios of animal and leaf detritus. We quantified the contribution of detritus to biomass using stable isotope analysis and measured tissue carbon and nitrogen concentrations among species and between the sexes. Development times were shorter and adults were heavier for Aedes in animal versus leaf-only environments, whereas Culex development times were invariant across detritus types. Aedes displayed similar survival across detritus types whereas C. quinquefasciatus showed decreased survival with increasing leaf detritus. All species had lower values of 15N and 13C in leaf-only detritus compared to animal, however, Aedes generally had lower tissue nitrogen compared to C. quinquefasciatus. There were no differences in the C:N ratio between male and female Aedes, however, Aedes were different than C. quinquefasciatus adults, with male C. quinquefasciatus significantly higher than females. Culex quinquefasciatus was homeostatic across detrital environments. These results allow us to hypothesize an underlying stoichiometric explanation for the variation in performance of different container species under similar detrital environments, and if supported may assist in explaining the production of vector populations in nature. PMID- 26244644 TI - Using DNA Barcodes to Identify Road-Killed Animals in Two Atlantic Forest Nature Reserves, Brazil. AB - Road mortality is the leading source of biodiversity loss in the world, especially due to fragmentation of natural habitats and loss of wildlife. The survey of the main species victims of roadkill is of fundamental importance for the better understanding of the problem, being necessary, for this, the correct species identification. The aim of this study was to verify if DNA barcodes can be applied to identify road-killed samples that often cannot be determined morphologically. For this purpose, 222 vertebrate samples were collected in a stretch of the BR-101 highway that crosses two Discovery Coast Atlantic Forest Natural Reserves, the Sooretama Biological Reserve and the Vale Natural Reserve, in Espirito Santo, Brazil. The mitochondrial COI gene was amplified, sequenced and confronted with the BOLD database. It was possible to identify 62.16% of samples, totaling 62 different species, including Pyrrhura cruentata, Chaetomys subspinosus, Puma yagouaroundi and Leopardus wiedii considered Vulnerable in the National Official List of Species of Endangered Wildlife. The most commonly identified animals were a bat (Molossus molossus), an opossum (Didelphis aurita) and a frog (Trachycephalus mesophaeus) species. Only one reptile was identified using the technique, probably due to lack of reference sequences in BOLD. These data may contribute to a better understanding of the impact of roads on species biodiversity loss and to introduce the DNA barcode technique to road ecology scenarios. PMID- 26244646 TI - Prevention in dangerous industries: does safety certification prevent tree-faller injuries? AB - OBJECTIVES: The aim of this study was to evaluate if safety certification reduces the risk of work injury among experienced manual tree-fallers. METHODS: This study used a retrospective cohort study design. Experienced manual tree-fallers employed in the Canadian province of British Columbia (N=3251) between 2003-2008 were enumerated from a mandatory faller registry. Registry records with demographic and certification data were linked to workers' compensation claims for injury outcomes. Data were analyzed using discrete time survival analysis over a two-year period, centered on certification date with pre- and post certification demarcated into four three-month periods. Models were adjusted for demographic, occupation/industry, previous injury, and seasonal/temporal effects. RESULTS: The relative risk (RR) of work injury during the post certification periods were elevated in comparison to the pre-certification reference period, but the 95% confidence intervals included "1" for all estimates by the end of follow-up, suggesting no statistically significant increased risk of injury. Results were consistent across different outcome measures of acute injury (ie, fracture or amputations) (N=186), musculoskeletal injury (ie, back strain) (N=137), and serious injury claims (ie, long duration, high cost and/or fatal) (N=155). CONCLUSION: Certification did not reduce the risk of work injury among experienced tree-fallers in the province of British Columbia. Non-statistically significant increases in the observed risk of work injury in the months immediately following certification may be attributable to an intervention effect or a methodological limitation related to a lack of individual-level, time-at risk exposure data. PMID- 26244647 TI - Risk Factors for Rehospitalization Within 90 Days in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Care of patients with inflammatory bowel disease (IBD) poses a significant burden to the health-care system. Repeat hospitalization in subgroups of IBD patients seems to be a large part of this issue; however, there are limited data examining the characteristics of these patients. The aim of this study was to characterize admission patterns in patients with IBD at a tertiary care center and to identify preventable risk factors of 90-day readmission after an index IBD admission. METHODS: Retrospective analysis was performed extracting data from an electronic medical record over a 2-year period. RESULTS: Three hundred fifty-six patients were admitted at least once during the 2-year study period for an unplanned IBD-related reason. Of these, 48.9% were admitted once, 38.2% were admitted 2 to 4 times, and 12.9% were admitted 5 or more times during the study period. Patients with any admission within 90 days before index were excluded; n = 33. One hundred two patients had experienced a readmission by 90 days after index admission. Numerous demographic and medical factors were examined for association with readmission. The final Cox model included 3 variables: depression (HR = 1.99, 1.33-3.00), chronic pain (HR = 1.88, 1.14 3.10), and steroid use in the previous 6 months (HR = 1.33, 0.92-2.04). CONCLUSIONS: Our findings suggest that patients with depression and chronic pain are at greatest risk for a readmission within 90 days after an initial IBD admission. Disease activity, represented by steroid use in the previous 6 months, was not related to readmission. Addressing these problems in the outpatient setting may reduce future hospitalizations. PMID- 26244645 TI - Down but Not Out: The Role of MicroRNAs in Hibernating Bats. AB - MicroRNAs (miRNAs) regulate many physiological processes through post transcriptional control of gene expression and are a major part of the small noncoding RNAs (snRNA). As hibernators can survive at low body temperatures (Tb) for many months without suffering tissue damage, understanding the mechanisms that enable them to do so are of medical interest. Because the brain integrates peripheral physiology and white adipose tissue (WAT) is the primary energy source during hibernation, we hypothesized that both of these organs play a crucial role in hibernation, and thus, their activity would be relatively increased during hibernation. We carried out the first genomic analysis of small RNAs, specifically miRNAs, in the brain and WAT of a hibernating bat (Myotis ricketti) by comparing deeply torpid with euthermic individual bats using high-throughput sequencing (Solexa) and qPCR validation of expression levels. A total of 196 miRNAs (including 77 novel bat-specific miRNAs) were identified, and of these, 49 miRNAs showed significant differences in expression during hibernation, including 33 in the brain and 25 in WAT (P<=0.01 &?logFC?>=1). Stem-loop qPCR confirmed the miRNA expression patterns identified by Solexa sequencing. Moreover, 31 miRNAs showed tissue- or state-specific expression, and six miRNAs with counts >100 were specifically expressed in the brain. Putative target gene prediction combined with KEGG pathway and GO annotation showed that many essential processes of both organs are significantly correlated with differentially expressed miRNAs during bat hibernation. This is especially evident with down-regulated miRNAs, indicating that many physiological pathways are altered during hibernation. Thus, our novel findings of miRNAs and Interspersed Elements in a hibernating bat suggest that brain and WAT are active with respect to the miRNA expression activity during hibernation. PMID- 26244648 TI - Inflammatory Articular Disease in Patients with Inflammatory Bowel Disease: Result of the Swiss IBD Cohort Study. AB - BACKGROUND: Inflammatory bowel diseases (IBD) are systemic conditions that commonly display extraintestinal manifestations. Inflammatory articular disease (IAD: axial or peripheral) is the most common extraintestinal manifestation. The aim of this study was to evaluate the prevalence and the clinical characteristics associated with IAD in patients with IBD. METHODS: We analyzed patients enrolled in the Swiss IBD cohort study. IAD was defined as persistent or recurrent joint pain with an inflammatory pattern (night pain, progressive relief during the day, morning stiffness lasting at least 30 minutes) or the presence of arthritis as diagnosed by the physicians. A multivariate logistic regression was performed to analyze which disease characteristics were independently associated with the presence of IAD. RESULTS: A total of 2353 patients with IBD, 1359 with Crohn's disease, and 994 with ulcerative colitis (UC) were included. Forty-four percent of patients fulfilled the criteria for IAD, whereas 14.5% presented with other extraintestinal manifestations. IAD was associated with Crohn's disease, with female sex, with older age, and generally in patients with more active intestinal disease. Only in UC, IAD was further associated with tobacco smoking and with increasing body mass index. CONCLUSIONS: This population of patients with IBD displays a high prevalence of IAD. IAD was more strongly associated with Crohn's disease than UC. Other risk factors for IAD were female sex, advanced age, active digestive disease, and tobacco consumption in patients with UC, which is interesting given the established association between smoking and other inflammatory arthritides. PMID- 26244649 TI - Genetic Markers Associated with Clinical Outcomes in Patients with Inflammatory Bowel Disease. AB - Genetic factors play a significant role in determining inflammatory bowel disease (IBD) susceptibility. Epidemiologic data support genetic contribution to the pathogenesis of IBD, which include familial aggregation, twin studies, and racial and ethnic differences in disease prevalence. Recently, several new genes have been identified to be involved in the genetic susceptibility to IBD. The characterization of novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD. The development of genetic markers associated with clinical outcomes in patients with IBD will be very important in the future. The progress of molecular biology tools (microarrays, proteomics, and epigenetics) have progressed the field of the genetic markers discovery. The advances in bioinformatics coupled with cross-disciplinary collaborations have greatly enhanced our ability to retrieve, characterize, and analyze large amounts of data generated by the technological advances. The techniques available for markers development are genomics (single nucleotide polymorphism genotyping, pharmacogenetics, and gene expression analyses) and proteomics. This could be a potential great benefit in predicting the course of disease in individual patients and in guiding appropriate medical therapy. PMID- 26244650 TI - Immunoregulatory Role of Myeloid-derived Cells in Inflammatory Bowel Disease. AB - As the frontiers of immunological research expand, new insights into the pathogenesis of long poorly understood diseases, such as inflammatory bowel disease (IBD), are opening up new possible avenues for treatment. Myeloid-derived cells (i.e., monocytes, macrophages, neutrophils, and dendritic cells), long believed to be effector cells driving the initiation of inflammation, have been increasingly shown to have immunoregulatory effects previously underappreciated. Dysfunction in the immunoregulatory roles of these cells may play a part in the pathogenesis of a subset of patients with IBD. The role of myeloid-derived suppressor cells, initially described in cancer, have been shown to play an important role in the balancing of effector and regulatory T cells in inflammation as well, and their role in IBD is also explored. The potential for future cell-based therapies for IBD is enhanced by the advances being made in the understanding of the innate immune system in the intestine. PMID- 26244651 TI - Reply to Are Worries and Concerns Information Side Effects? PMID- 26244652 TI - Erratum: Plant growth improvement mediated by nitrate capture in co-composted biochar. PMID- 26244653 TI - Questions of Safety and Fairness Raised as Right-to-Try Movement Gains Steam. PMID- 26244654 TI - Celecoxib Nanoparticles for Therapeutic Angiogenesis. AB - Controllable induction of blood vessel formation (angiogenesis) presents an important therapeutic goal in ischemic diseases and is also beneficial in various normal physiological processes. In this study, we have shown that nanoparticles of celecoxib, a lipophilic nonsteroidal anti-inflammatory drug, effectively evoke therapeutic angiogenesis in animal models, in both normal and ischemic organs. Celecoxib is widely considered to inhibit angiogenesis, although a recent study suggests that it can instead promote blood vessel growth in cancer cell lines. The hydrophobic nature of this drug necessitates its administration in nanoparticulate form in order to elicit a perceivable pharmacological response. We developed a facile method for nanoparticle formation by solvent extraction from microemulsions in supercritical carbon dioxide. This method exploits a spontaneous formation of nanometric domains within the microemulsion system and their rapid conversion to nanoparticles by supercritical fluid. The resultant nanoparticles were administered subcutaneously to mice in a biocompatible hydrogel, and caused a 4-fold increase in blood vessel count in normally perfused skin compared with drug-free particles. They were at least as effective in inducing angiogenesis as nanoparticles of deferoxamine, a well-established neovascularization promoter. Next, we evaluated their effect on ischemic tissues in murine model of myocardial infarction. We found that celecoxib nanoparticles were able to induce a significant vascularization of ischemic myocardium and hamper the progression of heart failure, which points toward a new approach for treating ischemia. PMID- 26244655 TI - Land Use as a Driver of Patterns of Rodenticide Exposure in Modeled Kit Fox Populations. AB - Although rodenticides are increasingly regulated, they nonetheless cause poisonings in many non-target wildlife species. Second-generation anticoagulant rodenticide use is common in agricultural and residential landscapes. Here, we use an individual-based population model to assess potential population-wide effects of rodenticide exposures on the endangered San Joaquin kit fox (Vulpes macrotis mutica). We estimate likelihood of rodenticide exposure across the species range for each land cover type based on a database of reported pesticide use and literature. Using a spatially-explicit population model, we find that 36% of modeled kit foxes are likely exposed, resulting in a 7-18% decline in the range-wide modeled kit fox population that can be linked to rodenticide use. Exposures of kit foxes in low-density developed areas accounted for 70% of the population-wide exposures to rodenticides. We conclude that exposures of non target kit foxes could be greatly mitigated by reducing the use of second generation anticoagulant rodenticides in low-density developed areas near vulnerable populations. PMID- 26244656 TI - The Nucleus-Localized Epidermal Growth Factor Receptor Is SUMOylated. AB - The epidermal growth factor receptor (EGFR) plays important roles in normal and cancer cell growth. The EGFR has principally two different signaling pathways: the canonical kinase route induced at the plasma membrane resulting in an intracellular phosphorylation cascade via MAPKs and PI3K and the more recently discovered pathway by which the receptor functions as a transcriptional co activator inside the cell nucleus. Full length EGFR translocates to the inner nuclear membrane, via the endoplasmic reticulum, through association with the sec61beta translocon. The c-myc (MYC) and cyclin D1 (CNND1) genes represent two target genes for nuclear EGFR (nEGFR). Here we show that EGFR is SUMOylated and that the SUMO-1-modified receptors are almost unexceptionally nuclear. Co immunoprecipitation experiments suggest that EGFR is multi-SUMOylated. Using two mass spectrometry-based strategies (matrix-assisted laser desorption ionization time of flight and electrospray ionization liquid chromatography with tandem mass spectrometry), lysine 37 was identified as a SUMO-1-modified residue by both methods. A lysine 37 site mutant (K37R) was transfected into EGFR deficient cells. Total SUMOylation of EGFR was not altered in the K37R-transfected cells, confirming the presence of other SUMOylation sites. To gain preliminary insight into the possible functional role of EGFR SUMOylation, we compared the effect of expression of the wild-type EGFR with the K37R mutant on promoter activity and expression of CMYC and CNND1. Our results indicate that SUMO-1 modification may affect the transcriptional activity of EGFR, which might have additional impact on, e.g., cancer progression. PMID- 26244657 TI - Oxoiron(IV) Complex of the Ethylene-Bridged Dialkylcyclam Ligand Me2EBC. AB - We report herein the first example of an oxoiron(IV) complex of an ethylene bridged dialkylcyclam ligand, [Fe(IV)(O)(Me2EBC)(NCMe)](2+) (2; Me2EBC = 4,11 dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane). Complex 2 has been characterized by UV-vis, (1)H NMR, resonance Raman, Mossbauer, and X-ray absorption spectroscopy as well as electrospray ionization mass spectrometry, and its properties have been compared with those of the closely related [Fe(IV)(O)(TMC)(NCMe)](2+) (3; TMC = 1,4,8,11-tetramethyl-1,4,8,11 tetraazacyclotetradecane), the intensively studied prototypical oxoiron(IV) complex of the macrocyclic tetramethylcyclam ligand. Me2EBC has an N4 donor set nearly identical with that of TMC but possesses an ethylene bridge in place of the 1- and 8-methyl groups of TMC. As a consequence, Me2EBC is forced to deviate from the trans-I configuration typically found for Fe(IV)(O)(TMC) complexes and instead adopts a folded cis-V stereochemistry that requires the MeCN ligand to coordinate cis to the Fe(IV)?O unit in 2 rather than in the trans arrangement found in 3. However, switching from the trans geometry of 3 to the cis geometry of 2 did not significantly affect their ground-state electronic structures, although a decrease in nu(Fe?O) was observed for 2. Remarkably, despite having comparable Fe(IV/III) reduction potentials, 2 was found to be significantly more reactive than 3 in both oxygen-atom-transfer (OAT) and hydrogen-atom-transfer (HAT) reactions. A careful analysis of density functional theory calculations on the HAT reactivity of 2 and 3 revealed the root cause to be the higher oxyl character of 2, leading to a stronger O---H bond specifically in the quintet transition state. PMID- 26244658 TI - Improved Long-Term Imaging of Embryos with Genetically Encoded alpha Bungarotoxin. AB - Rapid advances in microscopy and genetic labeling strategies have created new opportunities for time-lapse imaging of embryonic development. However, methods for immobilizing embryos for long periods while maintaining normal development have changed little. In zebrafish, current immobilization techniques rely on the anesthetic tricaine. Unfortunately, prolonged tricaine treatment at concentrations high enough to immobilize the embryo produces undesirable side effects on development. We evaluate three alternative immobilization strategies: combinatorial soaking in tricaine and isoeugenol, injection of alpha-bungarotoxin protein, and injection of alpha-bungarotoxin mRNA. We find evidence for co operation between tricaine and isoeugenol to give immobility with improved health. However, even in combination these anesthetics negatively affect long term development. alpha-bungarotoxin is a small protein from snake venom that irreversibly binds and inactivates acetylcholine receptors. We find that alpha bungarotoxin either as purified protein from snakes or endogenously expressed in zebrafish from a codon-optimized synthetic gene can immobilize embryos for extended periods of time with few health effects or developmental delays. Using alpha-bungarotoxin mRNA injection we obtain complete movies of zebrafish embryogenesis from the 1-cell stage to 3 days post fertilization, with normal health and no twitching. These results demonstrate that endogenously expressed alpha-bungarotoxin provides unprecedented immobility and health for time-lapse microscopy. PMID- 26244659 TI - Spatiotemporal Effects of Supplementary Feeding of Wild Boar (Sus scrofa) on Artificial Ground Nest Depredation. AB - Supplementary feeding of ungulates, being widely used in game management, may have unwanted consequences. Its role in agricultural damage is well-studied, but few studies have considered the potential for the practice to attract ground nest predators. Our goal was to identify the factors influencing ground nest predation in the vicinity of year-round supplementary feeding sites for wild boar and to characterise their spatiotemporal scope. We conducted two separate artificial ground nest experiments in five different hunting districts in south-eastern Estonia. The quantity of food provided and distance of a nest from the feeding site were the most important factors determining predation risk. Larger quantities of food resulted in higher predation risk, while predation risk responded in a non-linear fashion to distance from the feeding site. Although predation risk eventually decreases if supplementary feeding is ceased for at least four years, recently abandoned feeding sites still pose a high predation risk. PMID- 26244660 TI - Trends in Outpatient Visits with Benzodiazepines among US Adults With and Without Bronchitis or Chronic Obstructive Pulmonary Disease from 1999 to 2010. AB - Little is known about trends in prescriptions for benzodiazepines among patients with chronic obstructive pulmonary disease (COPD). Our objective was to examine trends of office/outpatient department visits with a mention of a benzodiazepine made by patients aged >=40 years with COPD in the United States. We used data from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey from 1999-2010. From 1999 to 2010, the estimated numbers of office/outpatient department visits with a benzodiazepine mentioned increased from 20.7 million to 43.2 million among all patients, from 684,000 to 1.5 million among patients with COPD, and from 20.0 million to 41.7 million among patients without COPD. Using all 12-years of data, patients with COPD were more likely to have a visit with a mention of a benzodiazepine than patients without COPD (adjusted prevalence ratio = 1.48, 95% CI = 1.27-1.71).The unadjusted percentage of all office/outpatient department visits by patients with COPD with a mention of a benzodiazepine increased from 4.6% during 1999-2002 to 10.2% during 2007 2010 (P trend < 0.001). After adjustment for age, sex, and race, the adjusted prevalence ratio for 2007-2010 compared with 1999-2002 was 2.26 (95% confidence interval: 1.60-3.17). Since 1999, the number and percentage of office/outpatient department visits with a mention of a benzodiazepine by patients with COPD and all patients may have increased in the United States. PMID- 26244661 TI - Cilostazol Upregulates Autophagy via SIRT1 Activation: Reducing Amyloid-beta Peptide and APP-CTFbeta Levels in Neuronal Cells. AB - Autophagy is a vital pathway for the removal of beta-amyloid peptide (Abeta) and the aggregated proteins that cause Alzheimer's disease (AD). We previously found that cilostazol induced SIRT1 expression and its activity in neuronal cells, and thus, we hypothesized that cilostazol might stimulate clearances of Abeta and C terminal APP fragment beta subunit (APP-CTFbeta) by up-regulating autophagy.When N2a cells were exposed to soluble Abeta1-42, protein levels of beclin-1, autophagy-related protein5 (Atg5), and SIRT1 decreased significantly. Pretreatment with cilostazol (10-30 MUM) or resveratrol (20 MUM) prevented these Abeta1-42 evoked suppressions. LC3-II (a marker of mammalian autophagy) levels were significantly increased by cilostazol, and this increase was reduced by 3 methyladenine. To evoke endogenous Abeta overproduction, N2aSwe cells (N2a cells stably expressing human APP containing the Swedish mutation) were cultured in medium with or without tetracycline (Tet+ for 48 h and then placed in Tet- condition). Abeta and APP-CTFbeta expressions were increased after 12~24 h in Tet condition, and these increased expressions were significantly reduced by pretreating cilostazol. Cilostazol-induced reductions in the expressions of Abeta and APP-CTFbeta were blocked by bafilomycin A1 (a blocker of autophagosome to lysosome fusion). After knockdown of the SIRT1 gene (to ~40% in SIRT1 protein), cilostazol failed to elevate the expressions of beclin-1, Atg5, and LC3-II, indicating that cilostazol increases these expressions by up-regulating SIRT1. Further, decreased cell viability induced by Abeta was prevented by cilostazol, and this inhibition was reversed by 3-methyladenine, indicating that the protective effect of cilostazol against Abeta induced neurotoxicity is, in part, ascribable to the induction of autophagy. In conclusion, cilostazol modulates autophagy by increasing the activation of SIRT1, and thereby enhances Abeta clearance and increases cell viability. PMID- 26244662 TI - Topographic Evolution and Climate Aridification during Continental Collision: Insights from Computer Simulations. AB - How do the feedbacks between tectonics, sediment transport and climate work to shape the topographic evolution of the Earth? This question has been widely addressed via numerical models constrained with thermochronological and geomorphological data at scales ranging from local to orogenic. Here we present a novel numerical model that aims at reproducing the interaction between these processes at the continental scale. For this purpose, we combine in a single computer program: 1) a thin-sheet viscous model of continental deformation; 2) a stream-power surface-transport approach; 3) flexural isostasy allowing for the formation of large sedimentary foreland basins; and 4) an orographic precipitation model that reproduces basic climatic effects such as continentality and rain shadow. We quantify the feedbacks between these processes in a synthetic scenario inspired by the India-Asia collision and the growth of the Tibetan Plateau. We identify a feedback between erosion and crustal thickening leading locally to a <50% increase in deformation rates in places where orographic precipitation is concentrated. This climatically-enhanced deformation takes place preferentially at the upwind flank of the growing plateau, specially at the corners of the indenter (syntaxes). We hypothesize that this may provide clues for better understanding the mechanisms underlying the intriguing tectonic aneurisms documented in the Himalayas. At the continental scale, however, the overall distribution of topographic basins and ranges seems insensitive to climatic factors, despite these do have important, sometimes counterintuitive effects on the amount of sediments trapped within the continent. The dry climatic conditions that naturally develop in the interior of the continent, for example, trigger large intra-continental sediment trapping at basins similar to the Tarim Basin because they determine its endorheic/exorheic drainage. These complex climatic-drainage-tectonic interactions make the development of steady-state topography at the continental scale unlikely. PMID- 26244663 TI - Nuclear Receptor Expression and Function in Human Lung Cancer Pathogenesis. AB - Lung cancer is caused by combinations of diverse genetic mutations. Here, to understand the relevance of nuclear receptors (NRs) in the oncogene-associated lung cancer pathogenesis, we investigated the expression profile of the entire 48 NR members by using QPCR analysis in a panel of human bronchial epithelial cells (HBECs) that included precancerous and tumorigenic HBECs harboring oncogenic K rasV12 and/or p53 alterations. The analysis of the profile revealed that oncogenic alterations accompanied transcriptional changes in the expression of 19 NRs in precancerous HBECs and 15 NRs according to the malignant progression of HBECs. Amongst these, peroxisome proliferator-activated receptor gamma (PPARgamma), a NR chosen as a proof-of-principle study, showed increased expression in precancerous HBECs, which was surprisingly reversed when these HBECs acquired full in vivo tumorigenicity. Notably, PPARgamma activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs. In fully tumorigenic HBECs with inducible expression of PPARgamma, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARgamma-sumoylation dependent manner. Mechanistically, the sumoylation of liganded-PPARgamma decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression. This suggests that ligand-mediated sumoylation of PPARgamma plays an important role in lung cancer pathogenesis by modulating prostaglandin metabolism. PMID- 26244665 TI - A Thermal Equilibrium Analysis of Line Contact Hydrodynamic Lubrication Considering the Influences of Reynolds Number, Load and Temperature. AB - Thermal effects such as conduction, convection and viscous dissipation are important to lubrication performance, and they vary with the friction conditions. These variations have caused some inconsistencies in the conclusions of different researchers regarding the relative contributions of these thermal effects. To reveal the relationship between the contributions of the thermal effects and the friction conditions, a steady-state THD analysis model was presented. The results indicate that the contribution of each thermal effect sharply varies with the Reynolds number and temperature. Convective effect could be dominant under certain conditions. Additionally, the accuracy of some simplified methods of thermo-hydrodynamic analysis is further discussed. PMID- 26244664 TI - Diagnostic Accuracy of Natriuretic Peptides for Heart Failure in Patients with Pleural Effusion: A Systematic Review and Updated Meta-Analysis. AB - BACKGROUND: Previous studies have reported that natriuretic peptides in the blood and pleural fluid (PF) are effective diagnostic markers for heart failure (HF). These natriuretic peptides include N-terminal pro-brain natriuretic peptide (NT proBNP), brain natriuretic peptide (BNP), and midregion pro-atrial natriuretic peptide (MR-proANP). This systematic review and meta-analysis evaluates the diagnostic accuracy of blood and PF natriuretic peptides for HF in patients with pleural effusion. METHODS: PubMed and EMBASE databases were searched to identify articles published in English that investigated the diagnostic accuracy of BNP, NT-proBNP, and MR-proANP for HF. The last search was performed on 9 October 2014. The quality of the eligible studies was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies tool. The diagnostic performance characteristics (sensitivity, specificity, and other measures of accuracy) were pooled and examined using a bivariate model. RESULTS: In total, 14 studies were included in the meta-analysis, including 12 studies reporting the diagnostic accuracy of PF NT-proBNP and 4 studies evaluating blood NT-proBNP. The summary estimates of PF NT-proBNP for HF had a diagnostic sensitivity of 0.94 (95% confidence interval [CI]: 0.90-0.96), specificity of 0.91 (95% CI: 0.86-0.95), positive likelihood ratio of 10.9 (95% CI: 6.4-18.6), negative likelihood ratio of 0.07 (95% CI: 0.04-0.12), and diagnostic odds ratio of 157 (95% CI: 57-430). The overall sensitivity of blood NT-proBNP for diagnosis of HF was 0.92 (95% CI: 0.86-0.95), with a specificity of 0.88 (95% CI: 0.77-0.94), positive likelihood ratio of 7.8 (95% CI: 3.7-16.3), negative likelihood ratio of 0.10 (95% CI: 0.06 0.16), and diagnostic odds ratio of 81 (95% CI: 27-241). The diagnostic accuracy of PF MR-proANP and blood and PF BNP was not analyzed due to the small number of related studies. CONCLUSIONS: BNP, NT-proBNP, and MR-proANP, either in blood or PF, are effective tools for diagnosis of HF. Additional studies are needed to rigorously evaluate the diagnostic accuracy of PF and blood MR-proANP and BNP for the diagnosis of HF. PMID- 26244666 TI - Protease Activated Receptors 1 and 2 Correlate Differently with Breast Cancer Aggressiveness Depending on Tumor ER Status. AB - Experimental models implicate protease activated receptors (PARs) as important sensors of the proteolytic tumor microenvironment during breast cancer development. However, the role of the major PARs, PAR-1 and PAR-2, in human breast tumors remains to be elucidated. Here, we have investigated how PAR-1 and PAR-2 protein expression correlate with established clinicopathological variables and patient outcome in a well-characterized cohort of 221 breast cancer patients. Univariable and multivariable hazard ratios (HR) were estimated by the Cox proportional hazards model, distant disease-free survival (DDFS) and overall survival by the Kaplan-Meier method, and survival in different strata was determined by the log-rank test. Associations between PARs and clinicopathological variables were analyzed using Pearson's chi2-test. We find that PAR-2 associates with DDFS (HR = 3.1, P = 0.003), whereas no such association was found with PAR-1 (HR = 1.2, P = 0.6). Interestingly, the effect of PAR-2 was confined to the ER-positive sub-group (HR = 5.5, P = 0.003 vs. HR = 1.2 in ER-negative; P = 0.045 for differential effect), and PAR-2 was an independent prognostic factor specifically in ER-positive tumors (HR = 3.9, P = 0.045). On the contrary, PAR-1 correlated with worse prognosis specifically in the ER-negative group (HR = 2.6, P = 0.069 vs. HR = 0.5, P = 0.19 in ER-positive; P = 0.026 for differential effect). This study provides novel insight into the respective roles of PAR-1 and PAR-2 in human breast cancer and suggests a hitherto unknown association between PARs and ER signaling that warrants further investigation. PMID- 26244667 TI - Managing Conflict between Bats and Humans: The Response of Soprano Pipistrelles (Pipistrellus pygmaeus) to Exclusion from Roosts in Houses. AB - Conflict can arise when bats roost in human dwellings and householders are affected adversely by their presence. In the United Kingdom, the exclusion of bats from roosts can be licensed under exceptional circumstances to alleviate conflict, but the fate of excluded bats and the impact on their survival and reproduction is not well understood. Using radio-tracking, we investigated the effects of exclusion on the soprano pipistrelle Pipistrellus pygmaeus, a species that commonly roosts in buildings in Europe. Exclusions were performed under licence at five roosts in England in spring, when females were in the early stages of pregnancy. Following exclusion, all bats found alternative roosts and colonies congregated in nearby known roosts that had been used by radio-tagged bats prior to exclusion. We found no difference in roosting behaviour before and after exclusion. Both the frequency of roost switching and the type of roosts used by bats remained unchanged. We also found no change in foraging behaviour. Bats foraged in the same areas, travelled similar distances to reach foraging areas and showed similar patterns of habitat selection before and after exclusion. Population modelling suggested that any reduction in survival following exclusion could have a negative impact on population growth, whereas a reduction in productivity would have less effect. While the number of soprano pipistrelle exclusions currently licensed each year is likely to have little effect on local populations, the cumulative impacts of licensing the destruction of large numbers of roosts may be of concern. PMID- 26244668 TI - The Effectiveness of Cognitive Behavioural Treatment for Non-Specific Low Back Pain: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: To assess whether cognitive behavioural (CB) approaches improve disability, pain, quality of life and/or work disability for patients with low back pain (LBP) of any duration and of any age. METHODS: Nine databases were searched for randomised controlled trials (RCTs) from inception to November 2014. Two independent reviewers rated trial quality and extracted trial data. Standardised mean differences (SMD) and 95% confidence intervals were calculated for individual trials. Pooled effect sizes were calculated using a random-effects model for two contrasts: CB versus no treatment (including wait-list and usual care (WL/UC)), and CB versus other guideline-based active treatment (GAT). RESULTS: The review included 23 studies with a total of 3359 participants. Of these, the majority studied patients with persistent LBP (>6 weeks; n=20). At long term follow-up, the pooled SMD for the WL/UC comparison was -0.19 (-0.38, 0.01) for disability, and -0.23 (-0.43, -0.04) for pain, in favour of CB. For the GAT comparison, at long term the pooled SMD was -0.83 (-1.46, -0.19) for disability and -0.48 (-0.93, -0.04) for pain, in favour of CB. While trials varied considerably in methodological quality, and in intervention factors such as provider, mode of delivery, dose, duration, and pragmatism, there were several examples of lower intensity, low cost interventions that were effective. CONCLUSION: CB interventions yield long-term improvements in pain, disability and quality of life in comparison to no treatment and other guideline-based active treatments for patients with LBP of any duration and of any age. SYSTEMATIC REVIEW REGISTRATION: PROSPERO protocol registration number: CRD42014010536. PMID- 26244669 TI - Study of less lethal projectiles blunt impacts on the thorax by experiments on pig thoracic cages and numerical simulations. PMID- 26244670 TI - The prevalence of melanocortin-4 receptor gene mutations in Slovak obese children and adolescents. AB - Melanocortin-4 receptor (MC4R) deficiency is the most frequent monogenic form of obesity. The contribution of MC4R mutations to the Slovak population has not been investigated as yet. We screened the coding sequence of the MC4R gene in a cohort of 210 Slovak obese children and adolescents. We identified four different mutations in four patients, giving a mutation detection rate of 0.95%. Of these, three were missense mutations previously identified and characterized by other research groups (p.R7C, p.S127L and p. R305W, respectively). One was a novel nonsense mutation p.W174* detected in a severely obese 7-year-old boy. This mutation was further analyzed in family segregation analysis and exhibited variable penetrance. Two known amino acid polymorphisms (p.V103I and p.I251L) were also identified in seven subjects of our cohort group. We also performed multifactorial statistical analysis to determine the influence of genotypes on standard biochemical blood markers. No significant influence was observed in carriers of DNA variants on tested parameters. We conclude that rare heterozygous MC4R mutations contribute to the onset of obesity only in a few cases in the Slovak population. PMID- 26244671 TI - Thyrotropin-secreting pituitary adenoma in an 11-year-old boy with type 1 autoimmune polyglandular syndrome. AB - Thyrotropinomas (TSHomas) are rare pituitary adenomas, particularly in childhood. We present here the case of an 11-year-old boy with type 1 autoimmune polyglandular syndrome (APS1) and TSHoma which was diagnosed by elevated thyroid stimulating hormone and thyroid hormones levels without evident clinical signs of hyperthyroidism. He was underwent partial resection of the tumor via transsphenoidal approach and subsequently radiation therapy. Consequently, 1 year after radiotherapy, the patient developed growth hormone deficiency, three and half years after radiation became euthyroid, and five and half years after treatment - hypothyroid. This is the first case of the coexistence of these two rare endocrine diseases in one patient. PMID- 26244672 TI - Levothyroxine replacement in primary congenital hypothyroidism: the higher the initial dose the higher the rate of overtreatment. AB - BACKGROUND: Congenital hypothyroidism (CH) is the most frequent endocrine disorder during the neonatal period, and a delay in diagnosis and treatment leads to irreversible complications. A high L-thyroxine (LT4) dose is recommended for treatment, while the optimal starting dose is still a matter of debate. The objective of this study was to determine the effects of various starting doses of LT4 on serum thyroid stimulating hormone (TSH) and thyroxine (fT4) at the end of the first month of treatment. METHODS: A total of 71 patients (37 males, 52.1%) with CH were included in the study. The patients were designated into three sets of subgroups according to the following categorical variables: (i) initial LT4 doses: 6-9.9 MUg/kg/day, 10-11.9 MUg/kg/day and 12-17 MUg/kg/day; (ii) initial TSH levels: 6-9.99 MUIU/mL, 10-75 MUIU/mL and >75 MUIU/mL; and (iii) etiology: dyshormonogenesis and dysgenesis. A fT4 level >2.3 ng/dL+/-a TSH level <0.5 MUIU/mL were considered as overtreatment. RESULTS: The mean age of the study population was 22.3+/-13.2 days at diagnosis. At diagnosis, the mean fT4 was 0.84+/-0.32 ng/dL, and TSH was 39.3+/-30 MUIU/mL. The mean initial dose of LT4 was 10.9+/-2.9 MUg/kg/day. Overtreatment rates were significantly higher in the highest dose group (12-17 MUg/kg/day) compared with the lowest dose group (6-9.9 MUg/kg/day) (61.5% and 25%, respectively, p<0.05). None of the patients was undertreated. CONCLUSIONS: In this study, we found that the rate of overtreatment was significantly higher in patients who were given LT4 doses of 12-17 MUg/kg/day. Thus, monitoring thyroid functions earlier than one month of treatment is necessary. PMID- 26244673 TI - Effect of 6-months' vitamin D supplementation on residual beta cell function in children with type 1 diabetes: a case control interventional study. AB - BACKGROUND: The aim of this study was to evaluate the effect of short-term vitamin D supplementation on the decline of residual beta cell function (RBCF) in children with type 1 diabetes (T1D). METHODS: The study involved an intervention group (cholecalciferol 2000 IU/day and calcium 25 mg/kg/day for 6 months) comprising 15 children aged 6-12 years and within 1-2 years of diagnosis of T1D. Fifteen age-matched T1D patients were followed up as controls. Stimulated C peptide levels were estimated at baseline and 6 months. RESULTS: The mean decrease in stimulated C-peptide levels in the intervention group was lower ( 0.048+/-0.15 ng/mL) as compared with the controls (-0.107+/-0.23 ng/mL) but did not reach statistical significance (p=0.472). The percent decrease in stimulated C-peptide from baseline to endpoint (8.3% vs. 20.3%, p=0.357) and the monthly decrease (0.008 ng/mL vs. 0.017 ng/mL, p=0.22) were non-significantly lower in the intervention group compared with the control group. Three (20%) patients progressed to undetectable stimulated C-peptide (<=0.01 ng/mL) over the study period in the control group as compared with one (6%) in the intervention group (p-value 0.260). CONCLUSIONS: There was a trend towards lesser decline of RBCF with short term cholecalciferol supplementation in children with T1D. Further larger studies are urgently needed to explore the beneficial effects of the relatively inexpensive vitamin D supplementation on RBCF. PMID- 26244674 TI - An unusual case of hereditary nephrogenic diabetes insipidus (HNDI) affecting mother and daughter. AB - Hereditary nephrogenic diabetes iInsipidus (HNDI) is an uncommon disorder due to a resistance to anti-diuretic hormone leading to a reduced urinary concentrating ability. The X-linked form is fully expressed in hemizygous male patients, but diabetes insipidus may also present in heterozygous females where it must be distinguished from autosomal and other secondary causes. We report a mother and daughter in the same family with HNDI due to a heterozygous deletion in exon 1 of the AVPR2 gene, not previously described in the literature. A 5-year-old girl was referred for investigation of polyuria and polydipsia. The patient had a water deprivation test elsewhere at the age of 3 that was inconclusive. A degree of water restriction was imposed leading to headaches. The thyroid, cortisol, renal, and calcium profiles were normal. Her mother showed similar symptoms that had not been previously investigated. AQP2 (Aquaporin) and initial AVPR2 gene sequencing had not identified a mutation, but subsequent quantitative polymerase chain reaction analysis revealed a heterozygous large exon 1 deletion of the AVPR2 gene. The same deletion was also found in the child's mother. The patient's symptoms have significantly improved on appropriate treatment. Further analysis revealed skewed X inactivation in mother and daughter. PMID- 26244675 TI - Eyelid Opening with Trigeminal Proprioceptive Activation Regulates a Brainstem Arousal Mechanism. AB - Eyelid opening stretches mechanoreceptors in the supratarsal Muller muscle to activate the proprioceptive fiber supplied by the trigeminal mesencephalic nucleus. This proprioception induces reflex contractions of the slow-twitch fibers in the levator palpebrae superioris and frontalis muscles to sustain eyelid and eyebrow positions against gravity. The cell bodies of the trigeminal proprioceptive neurons in the mesencephalon potentially make gap-junctional connections with the locus coeruleus neurons. The locus coeruleus is implicated in arousal and autonomic function. Due to the relationship between arousal, ventromedial prefrontal cortex, and skin conductance, we assessed whether upgaze with trigeminal proprioceptive evocation activates sympathetically innervated sweat glands and the ventromedial prefrontal cortex. Specifically, we examined whether 60 degrees upgaze induces palmar sweating and hemodynamic changes in the prefrontal cortex in 16 subjects. Sweating was monitored using a thumb-mounted perspiration meter, and prefrontal cortex activity was measured with 45-channel, functional near-infrared spectroscopy (fNIRS) and 2-channel NIRS at Fp1 and Fp2. In 16 subjects, palmar sweating was induced by upgaze and decreased in response to downgaze. Upgaze activated the ventromedial prefrontal cortex with an accumulation of integrated concentration changes in deoxyhemoglobin, oxyhemoglobin, and total hemoglobin levels in 12 subjects. Upgaze phasically and degree-dependently increased deoxyhemoglobin level at Fp1 and Fp2, whereas downgaze phasically decreased it in 16 subjects. Unilateral anesthetization of mechanoreceptors in the supratarsal Muller muscle used to significantly reduce trigeminal proprioceptive evocation ipsilaterally impaired the increased deoxyhemoglobin level by 60 degrees upgaze at Fp1 or Fp2 in 6 subjects. We concluded that upgaze with strong trigeminal proprioceptive evocation was sufficient to phasically activate sympathetically innervated sweat glands and appeared to induce rapid oxygen consumption in the ventromedial prefrontal cortex and to rapidly produce deoxyhemoglobin to regulate physiological arousal. Thus, eyelid opening with trigeminal proprioceptive evocation may activate the ventromedial prefrontal cortex via the mesencephalic trigeminal nucleus and locus coeruleus. PMID- 26244677 TI - A postmortem study on indigestible foreign bodies in the rumen and reticulum of ruminants, eastern Ethiopia. AB - A cross-sectional study was conducted on ruminants (cattle, sheep and goats) slaughtered at Haramaya University and Haramaya municipal abattoirs from November 2013 to April 2014 in Haramaya, eastern Ethiopia. The objective of the study was to identify types and estimate the prevalence of foreign bodies in the rumen and reticulum of domestic ruminants in the area. From 810 randomly selected study animals, 422 (52.1%) were found to have foreign bodies. Of the 332 cattle, 193 sheep and 285 goats examined, 144 (43.4%), 109 (56.5%) and 169 (59.3%) respectively were found with various types of foreign bodies. The prevalence of foreign bodies was significantly (chi2 = 17.53, p < 0.05) higher in sheep (59.3%) and goats (56.7%) than in cattle (43.4%). Overall the prevalence of foreign bodies in study animals with poor body condition was significantly higher (chi2 = 38.57, p < 0.05) than in those with medium and good body condition. A higher percentage of foreign bodies occurred in the rumen alone (87.9%) than in the reticulum alone (5.0%), with the rest present in both. Significantly higher proportions of foreign bodies were observed in the rumen of cattle (chi2 = 332, p < 0.05), sheep (chi2 = 193, p < 0.05) and goats (chi2 = 285.0, p = 0.000) than in the reticulum. Plastic was the most commonly encountered (79.2%) foreign body, followed by cloth (15.3%) and rope (12.3%). In addition, metal (0.9%) and calcified material and/or stone (1.0%) were found in the reticulum of cattle. Lack of a plastic waste disposal system in the area as well as communal/free grazing of livestock in highly waste-polluted areas seemed to be major factors in the high occurrence of foreign bodies in ruminants. To change this, collaborative intervention schemes involving professionals, policy makers, livestock keepers and environmental activists are needed. PMID- 26244676 TI - Diurnal Patterns and Correlates of Older Adults' Sedentary Behavior. AB - INTRODUCTION: Insights into the diurnal patterns of sedentary behavior and the identification of subgroups that are at increased risk for engaging in high levels of sedentary behavior are needed to inform potential interventions for reducing older adults' sedentary time. Therefore, we examined the diurnal patterns and sociodemographic correlates of older adults' sedentary behavior(s). METHODS: Stratified cluster sampling was used to recruit 508 non institutionalized Belgian older adults (>= 65 years). Morning, afternoon, evening and total sedentary time was assessed objectively using accelerometers. Specific sedentary behaviors, total sitting time and sociodemographic attributes were assessed using an interviewer-administered questionnaire. RESULTS: Participants self-reported a median of 475 (Q1-Q3 = 383-599) minutes/day of total sitting time and they accumulated a mean of 580 +/- 98 minutes/day of accelerometer-derived sedentary time. Sedentary time was lowest during the morning and highest during the evening. Older participants were as sedentary as younger participants during the evening, but they were more sedentary during daytime. Compared to married participants, widowers were more sedentary during daytime. Younger participants (< 75 years), men and the higher educated were more likely to engage in (high levels of) sitting while driving a car and using the computer. Those with tertiary education viewed 29% and 22% minutes/day less television compared to those with primary or secondary education, respectively. Older participants accumulated 35 sedentary minutes/day more than did younger participants and men accumulated 32 sedentary minutes/day more than did women. CONCLUSION: These findings highlight diurnal variations and potential opportunities to tailor approaches to reducing sedentary time for subgroups of the older adult population. PMID- 26244678 TI - The occurrence of Culicoides species, the vectors of arboviruses, at selected trap sites in Zimbabwe. AB - A study of the distribution of Culicoides species was conducted by establishing 12 light trap sites over five rainy seasons between 1998 and 2003 covering all the geo-climatic natural regions of Zimbabwe. In total, 279 919 specimens of Culicoides were trapped over a total of 163 trapping nights. The highest median counts of Culicoides per trapping night were recorded in natural region III, which has climatic conditions conducive to the successful development of the larvae. Culicoides imicola, the major vector of bluetongue and African horse sickness viruses in Africa, was found to be the most abundant species (80.4%), followed by Culicoides enderleini (5.9%) and Culicoides milnei (5.2%). This study identified 10 species of Culicoides that had not been previously described in Zimbabwe, including Culicoides loxodontis and Culicoides miombo, which are members of the C. imicola complex. A total of 23 994 Culicoides midges were collected from five trap sites in Harare, Zimbabwe, with the dominant species, C. imicola, representing 91.6% of the total collection. Seventeen arboviruses were isolated from these midges, 15 of which were bluetongue virus. The predominant bluetongue virus serotype was serotype 11, followed by serotypes 1, 8, 12 and 15. Bluetongue virus serotypes 1, 2, 8, 10, 12, 15, 16 and 18, detected in this study, had not been previously reported in Zimbabwe. PMID- 26244679 TI - Safety and immunogenicity of Onderstepoort Biological Products' Rift Valley fever Clone 13 vaccine in sheep and goats under field conditions in Senegal. AB - This blinded field safety study was conducted in Senegal to assess safety and immunogenicity of administration of the registered dose of Rift Valley fever virus (RVFV) Clone 13 vaccine (Onderstepoort Biological Products) to sheep and goats of West African breeds under natural conditions. A total of 267 small ruminants (220 sheep, 47 goats) were included; half received RVFV Clone 13 vaccine at the recommended dose and half received the diluent (as placebo) only. The study was performed on three commercial farms in the northern and eastern region of Senegal in accordance with veterinary good clinical practices. The animals were observed daily for 3 days after vaccination, and then weekly for 1 year. In both sheep and goats vaccinated against RVFV seroconversion rates above 70% were recorded. No seroconversion related to RVFV was observed in placebo treated animals. No statistically significant differences were determined between placebo and vaccinated groups for mean rectal temperatures for the first 3 days after administration (p > 0.05). No abnormal clinical signs related to treatment were noted, and only one slight injection site reaction was observed in one vaccinated animal for 2 days after vaccination. Out of 176 births assessed over 1 year (93 from the vaccinated group, 83 from the placebo group), 9 were abnormal in the placebo group and 3 in the vaccinated group (p > 0.05). The frequency of adverse events was similar in the placebo and vaccinated groups. RVFV Clone 13 vaccine administered according to the manufacturer's instructions was safe and well tolerated in West African breeds of sheep and goats, including animals of approximately 6 months of age and pregnant females, under field conditions in Senegal. Antibody levels persisted up to 1 year after vaccination. PMID- 26244680 TI - Prevalence of salivary gland hypertrophy syndrome in laboratory colonies and wild flies of Glossina pallidipes in Ethiopia. AB - Glossina pallidipes salivary gland hyperplasia (GpSGH) syndrome caused by the salivary gland hyperplasia virus reduces the reproduction potential of tsetse flies, posing a serious threat for rearing of sufficient colonies for use of tsetse and trypanosome control using the sterile insect technique. This research was conducted in the Kaliti Tsetse Mass Rearing and Irradiation Centre in Ethiopia with the objective of studying the prevalence of GpSGH syndrome in laboratory colonies of G. pallidipes (Tororo and Arbaminch) reared for release in the implementation of the sterile insect technique and a field strain of G. pallidipes Arbaminch. Presence or absence of GpSGH was determined when pathological features of the salivary gland were revealed after dissection. The overall prevalence of GpSGH syndrome in laboratory colonies was 48.3% (747/1548) with a statistically significant (z = 17.30, p = 0.001) prevalence of 70.2% (544/775) in Arbaminch colonies and 26.26% (203/773) in Tororo colonies. The prevalence of GpSGH in laboratory flies fed according to the clean blood feeding protocol was 68.9% and 22.4% in Arbaminch and Tororo strains respectively. It was 70.5% and 27.2% respectively in laboratory colonies of Arbaminch and Tororo strains fed according to the standard membrane feeding protocol. The difference in prevalence of the disease between the two feeding protocols was not statistically significant in either Arbaminch (z = 0.361, p = 0.359) or Tororo (z = 1.22, p = 0.111) strains. The prevalence of SGH in wild G. pallidipes Arbaminch strain was 3% (15/500) and was significantly (z = 23.61, p < 0.001) lower than in the laboratory strain. The effect of age and density-related stress on the development of GpSGH was not statistically significant. The prevalence of GpSGH in the newly emerging (teneral) flies in the laboratory colonies was 66.7% and 20% in the Arbaminch and Tororo strains respectively. For all considered risk factors, the prevalence was much higher in G. pallidipes Arbaminch laboratory colonies. PMID- 26244681 TI - First molecular isolation of Mycoplasma ovis from small ruminants in North Africa. AB - Eperythrozoonosis is a small ruminant disease caused by the bacterium Mycoplasma ovis (formerly known as Eperythrozoon ovis). Whilst acute infection in sheep may result in an anaemia and ill thrift syndrome, most animals do not develop clinical signs. Molecular methods were used to compare and evaluate the prevalence of infection with M. ovis in sheep and goats in Tunisia. A total of 739 whole blood samples from 573 sheep and 166 goats were tested for the M. ovis 16S rRNA gene using PCR. The overall prevalence was 6.28% +/- 0.019 (36/573). Only sheep were infected with M. ovis (p < 0.001), and the prevalence was significantly higher in central Tunisia (29.2%) compared with other regions (p < 0.05). The prevalence revealed significant differences according to breed and bioclimatic zones (p < 0.001). Furthermore, the prevalence in young sheep (35/330; 10.6%) was higher than in adults (1/243; 0.41%) (p < 0.001). Only sheep of the Barbarine breed were infected, with a prevalence of 11.8% (p < 0.001). This is the first molecular study and genetic characterisation of M. ovis in North African sheep breeds. PMID- 26244682 TI - Occurrence of porcine cysticercosis in free-ranging pigs delivered to slaughter points in Arapai, Soroti district, Uganda. AB - Poverty, hunger and the need for production of pigs with meagre or zero inputs have made most farmers release their pigs to range freely, thus creating a pig human cycle that maintains Taenia solium, the pig tapeworm and cause of porcine cysticercosis, in the ecosystem. A preliminary study was designed to establish the prevalence of porcine cysticercosis by postmortem examination of the tongue and carcass of free-range pigs from February to April 2014 in Arapai subcounty, Soroti district, eastern Uganda. The tongue of each pig was extended and examined before deep incisions were made and the cut surfaces were examined. The rest of the carcasses were examined for cysts. Out of 178 pigs examined, 32 were qualitatively positive for porcine cysticercosis, representing a prevalence of 18.0%. This high prevalence represents a marked risk to the communities in the study area of neurocysticercosis, a debilitating parasitic zoonosis. Proper human waste disposal by use of pit latrines, confinement of free-range pigs and treatment with albendazole and oxfendazole are recommended. PMID- 26244683 TI - The effect of Rift Valley fever virus Clone 13 vaccine on semen quality in rams. AB - Rift Valley fever (RVF) is an arthropod-borne viral disease of importance in livestock and humans. Epidemics occur periodically in domestic ruminants. People in contact with infected livestock may develop disease that varies from mild flu like symptoms to fatal viraemia. Livestock vaccination may assist in disease control. Rift Valley fever virus (RVFV) Clone 13 is a relatively new vaccine against RVF, derived from an avirulent natural mutant strain of RVFV, and has been shown to confer protective immunity against experimental infection with RVFV. The hypothesis tested in the current trial was that rams vaccinated with RVFV Clone 13 vaccine would not experience a reduction in semen quality (measured by evaluating the percentage progressively motile and percentage morphologically normal spermatozoa in successive ejaculates) relative to unvaccinated control animals. Ram lambs were screened for antibodies to RVFV using a serum neutralisation test. Animals without detectable antibodies (n = 23) were randomly allocated to either a test group (n = 12) or a control group (n = 11). Animals in the test group were vaccinated with RVFV Clone 13 vaccine. Daily rectal temperature measurements and weekly semen and blood samples were taken from all animals. Seven animals were eliminated from the statistical analysis because of potential confounding factors. Logistic regression analysis was performed on data gathered from the remaining animals to determine whether an association existed between animal group, rectal temperature and semen quality parameters. No correlation existed between the treatment group and values obtained for the semen quality parameters measured. There was no statistically significant post vaccination decline in the percentage of live morphologically normal spermatozoa, or the percentage of progressively motile spermatozoa, either when assessed amongst all animals or when assessed within individual groups. A repeat study with a larger sample size and a more comprehensive pre-screening process may be indicated to avoid the inclusion of unsuitable animals. PMID- 26244684 TI - Thoracic limb morphology of the red panda (Ailurus fulgens) evidenced by osteology and radiography. AB - The red panda (Ailurus fulgens) is distributed primarily in the Himalayas and southern China. It is classified as a vulnerable species by the International Union for Conservation of Nature. The aim of this study was to describe the normal osteology and radiographic anatomy of the thoracic limb of the red panda. Radiography of the right thoracic limb was performed in seven captive adult red pandas. Radiographic findings were correlated with bone specimens from three adult animals. The scapula was wide craniocaudally and presented with a large area for the origin of the teres major muscle. The square-shaped major tubercle did not extend proximal to the head of the humerus. The medial epicondyle was prominent. A supracondylar foramen was present. The radial tuberosity and sesamoid bone for the abductor digiti I longus were prominent. The accessory carpal bone was directed palmarolaterally. Metacarpal bones were widely spread. The thoracic limb morphology of the red panda evidenced by osteology and radiography indicated flexibility of the thoracic limb joints and well-developed flexor and supinator muscles, which are important in arboreal quadrupedal locomotion. Knowledge gained during this study may prove useful in identifying skeletal material or remains and diagnosing musculoskeletal diseases and injuries of the thoracic limb. PMID- 26244685 TI - Serological survey of antibodies to Toxoplasma gondii and Coxiella burnetii in rodents in north-western African islands (Canary Islands and Cape Verde). AB - Coxiella burnetii and Toxoplasma gondii are intracellular parasites that cause important reproductive disorders in animals and humans worldwide, resulting in high economic losses. The aim of the present study was to analyse the possible role of peridomestic small mammals in the maintenance and transmission of C. burnetii and T. gondii in the north-western African archipelagos of the Canary Islands and Cape Verde, where these species are commonly found affecting humans and farm animals. Between 2009 and 2013, 108 black rats (Rattus rattus) and 77 mice (Mus musculus) were analysed for the presence of Coxiella and Toxoplasma antibodies by enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence (IFA), respectively. Our results showed a wide distribution of C. burnetii and T. gondii, except for T. gondii in Cape Verde, in both rodent species. The overall seroprevalence of C. burnetii antibodies was 12.4%; 21.1% for Cape Verde and 10.2% for the Canary Islands. With respect to T. gondii, seropositive rodents were only observed in the Canary Islands, with an overall seroprevalence of 15%. Considering the fact that both pathogens can infect a large range of hosts, including livestock and humans, the results are of public health and veterinary importance and could be used by governmental entities to manage risk factors and to prevent future cases of Q fever and toxoplasmosis. PMID- 26244686 TI - Sesamin Inhibits PDGF-Mediated Proliferation of Vascular Smooth Muscle Cells by Upregulating p21 and p27. AB - Sesamin, an active ingredient of Asiasarum heterotropoides, is known to exhibit many bioactive functions, but the effect thereof on vascular smooth muscle cell (VSMC) proliferation remains poorly understood. Hence, we explored the antiproliferative action of sesamin on VSMCs and the underlying mechanism thereof, focusing on possible effects of sesamin on cell cycle progression. Sesamin significantly inhibited platelet-derived growth factor (PDGF)-induced VSMC proliferation (inhibition percentage at 1, 5, and 10 MUM sesamin was 49.8 +/ 22.0%, 74.6 +/- 19.9%, and 87.8 +/- 13.0%, respectively) in the absence of cytotoxicity and apoptosis, and PDGF-induced DNA synthesis; and arrested cell cycle progression in the G0/G1-to-S phase. Sesamin potently inhibited cyclin D1 and CDK4 expression, pRb phosphorylation, and expression of the proliferating cell nuclear antigen (PCNA); and upregulated p27(KIP1), p21(CIP1), and p53. The results thus indicate that the antiproliferative effect of sesamin on PDGF stimulated VSMCs is attributable to arrest of the cell cycle in G0/G1 caused, in turn, by upregulation of p27(KIP1), p21(CIP1), and p53, and inhibition of cyclin E-CDK2 and cyclin D1-CDK4 expression. PMID- 26244687 TI - Changes in Differentiation-Relatedness During Psychoanalysis. AB - This study sought to determine (a) if the Differentiation-Relatedness Scale of Self and Object Representations (D-RS), a coding model used with the Object Relations Inventory (Blatt, Wein, Chevron, & Quinlan, 1979 ) could be reliably applied to transcripts of psychoanalyses, and (b) if levels of differentiation relatedness improve over the course of psychoanalysis. Participants were 4 creative writers who underwent psychoanalysis as part of a longitudinal research project focused on the processes and outcomes of psychoanalysis. Transcripts from the beginning and termination phases of psychoanalysis were coded by 2 independent raters for global, low, and high levels of self and other differentiation-relatedness and compared. There was good interrater agreement, suggesting that, like other forms of narrative material, psychoanalysis transcripts can be reliably rated for levels of object relations. Analysands showed an increase in global levels of differentiation-relatedness from a predominance of emergent ambivalent constancy (M = 6.2) at the beginning of analysis to consolidated, constant representations of self and other (M = 7.5) at the end of analysis. These preliminary findings contribute significantly to the empirical literature with regard to the measurement of self and object representations and change in these representations over the course of psychoanalysis. PMID- 26244691 TI - Complete mitochondrial genome of Vaginulus alte and Homoiodoris japonica. AB - The complete mitochondrial genome sequence of Vaginulus alte and Homoiodoris japonica are described first in the article. The mitogenomes (14 772 bp and 14 601 bp) contain 22 tRNA genes, two ribosomal RNA genes, and 13 protein-coding genes, and one putative control region (CR). CR is not well characterized due to the lack of discrete conserved sequence blocks. This characteristic is similar with CRs of other invertebrate mitochondrial genomes, which is the typical bivalvia mitochondrial gene composition. PMID- 26244692 TI - Inference by Exclusion in Goffin Cockatoos (Cacatua goffini). AB - Inference by exclusion, the ability to base choices on the systematic exclusion of alternatives, has been studied in many nonhuman species over the past decade. However, the majority of methodologies employed so far are hard to integrate into a comparative framework as they rarely use controls for the effect of neophilia. Here, we present an improved approach that takes neophilia into account, using an abstract two-choice task on a touch screen, which is equally feasible for a large variety of species. To test this approach we chose Goffin cockatoos (Cacatua goffini), a highly explorative Indonesian parrot species, which have recently been reported to have sophisticated cognitive skills in the technical domain. Our results indicate that Goffin cockatoos are able to solve such abstract two-choice tasks employing inference by exclusion but also highlight the importance of other response strategies. PMID- 26244693 TI - One Hundred and Fifth Annual Council Meeting. PMID- 26244696 TI - Cochrane Review Summary: Pelvic floor muscle training added to another active treatment versus the same active treatment alone for urinary incontinence in women. PMID- 26244697 TI - An Alternative Synthetic Approach to 3-Alkylated/Arylated 5-Nitropyridines. AB - An alternative method for the synthesis of 3-alkylated/arylated 5-nitropyridines was developed involving a three-component ring transformation of 3,5-dinitro-2 pyridone on treatment with aldehyde in the presence of ammonium acetate. This method facilitates the modification of the substituent at the 3-position by changing the precursor aldehyde. The use of solid ammonium acetate instead of ammonia as the nitrogen source renders the synthetic method more practical and user-friendly. PMID- 26244700 TI - Melatonin and selenium reduce plasma cytokine and brain oxidative stress levels in diabetic rats. AB - BACKGROUND: Hyperglycaemia-induced progression of brain and erythrocyte oxidative injuries might be modulated by melatonin and selenium as potent antioxidants. The present study was conducted to explore whether melatonin and selenium protect against diabetic brain and erythrocyte oxidative stress levels in streptozotocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Seventy rats were equally divided into seven groups. The first and second groups were used as untreated and placebo treated controls. The third group was treated with STZ to induce diabetes. The fourth and sixth groups received 10 mg kg-1 melatonin. The fifth and seventh groups were treated with 1.5 mg kg-1 selenium (sodium selenite). The sixth and seventh groups were treated with STZ administered with melatonin and selenium as described for the fourth and fifth groups. RESULTS: Brain and erythrocyte lipid peroxidation levels and plasma IL-1beta and IL-4 levels were high in the STZ group, although they were low in melatonin and selenium treatments. Decreased glutathione peroxidase, reduced glutathione, total antioxidant status, vitamins A and vitamin E values in brain and erythrocyte of STZ group were increased by melatonin and selenium treatments. DISCUSSION: Melatonin and selenium induced protective effects against diabetes-induced brain and erythrocyte oxidative injuries through regulation of the antioxidant level and cytokine production. PMID- 26244698 TI - A Novel Role of Numb as A Regulator of Pro-inflammatory Cytokine Production in Macrophages in Response to Toll-like Receptor 4. AB - Activation of macrophages triggers the release of pro-inflammatory cytokines leading to inflammation. Numb is a negative regulator of Notch signaling, but the role of Numb in macrophages is not fully understood. In this study, the role of Numb as a regulator of inflammatory responses in macrophages was investigated. Murine bone marrow-derived macrophages, in which expression of Numb was silenced, secreted significantly less TNFalpha, IL-6 and IL-12 and more IL-10 upon activation by lipopolysaccharide (LPS), a ligand for Toll-like receptor 4 (TLR4), despite increased Notch signaling. The Tnfalpha mRNA levels both in Numb deficient and wild-type macrophages were not significantly different, unlike those of Il6 and Il12-p40. In Numb-deficient macrophages, the Tnfalpha mRNAs were degraded at faster rate, compared to those in control macrophages. Activation of p38 MAPK and NF-kappaBeta p65 were compromised in activated Numb deficient macrophages. Numb was found to interact with the E3 ubiquitin ligase, Itch, which reportedly regulates p38 MAPK. In addition, blocking the Notch signaling pathway in activated, Numb-deficient macrophages did not further reduce TNFalpha levels, suggesting a Notch-independent role for Numb. A proteomics approach revealed a novel function for Numb in regulating complex signaling cascades downstream of TLRs, partially involving Akt/NF-kappaB p65/p38 MAPK in macrophages. PMID- 26244701 TI - Effects of local administration of allogenic adipose tissue-derived mesenchymal stem cells on functional recovery in experimental traumatic brain injury. AB - OBJECTIVE: Traumatic brain injury (TBI) is the leading cause of mortality and morbidity in paediatric patients after the first year of life. The aim of this study was to evaluate effects of locally administered allogeneic mesenchymal stem cells (MSC), in the acute period after a TBI. METHODOLOGY: MSC were isolated from peritoneal fat of healthy rats, expanded in vitro and labelled with the green fluorescent protein. Rats were placed in one of three experimental groups: (1) Control: TBI, (2) IP-Control: TBI + local saline and (3) IP-Treat: TBI + 2 * 105 MSC 24 hours after receiving a moderate, unilateral, controlled cortical impact. Motor and cognitive behavioural tests were performed to evaluate functional recovery. Histological examination and immunohistochemistry were used to identify cell distribution. MAIN RESULTS: Improved performance was found on motor tests in the MSC-treated group compared to control groups. MSC were found in the perilesional area and their number decreased with time after transplantation. MSC treatment increased the cell density in the hippocampus (CA3 pyramidal cells and granule cells in the dentate gyrus) and enhanced neurogenesis in this area. CONCLUSION: MSC cell therapy resulted in better recovery of motor function compared with the control group. This cellular therapy might be considered for patients suffering from TBI. PMID- 26244704 TI - Steroidal Surfactants: Detection of Premicellar Aggregation, Secondary Aggregation Changes in Micelles, and Hosting of a Highly Charged Negative Substance. AB - CHAPSO and CHAPS are zwitterionic surfactants derived from bile salts which are usually employed in protein purification and for the preparation of liposomes and bicelles. Despite their spread use, there are significant discrepancies on the critical concentrations that determine their aggregation behavior. In this work, we study the interaction between these surfactants with the negative fluorescent dye pyranine (HPTS) by absorbance, fluorescence, and infrared spectrometry to establish their concentration-dependent aggregation. For the studied surfactants, we detect three critical concentrations showing their concentration-dependent presence as a monomeric form, premicellar aggregates, micelles, and a second type of micelle in aqueous medium. The nature of the interaction of HPTS with the surfactants was studied using analogues of their tails and the negative bile salt taurocholate (TC) as reference for the sterol ring. The results indicate that the chemical groups involved are the hydroxyl groups of the polar face of the sterol ring and the sulfonate groups of the dye. This interaction causes not only the incorporation of the negative dye in CHAPSO and CHAPS micelles but also its association with their premicellar aggregates. Surprisingly, this hosting behavior for a negative charged molecule was also detected for the negative bile salt TC, bypassing, in this way, the electrostatic repulsion between the guest and the host. PMID- 26244699 TI - Characterization of membrane protein interactions in plasma membrane derived vesicles with quantitative imaging Forster resonance energy transfer. AB - Here we describe an experimental tool, termed quantitative imaging Forster resonance energy transfer (QI-FRET), that enables the quantitative characterization of membrane protein interactions. The QI-FRET methodology allows us to acquire binding curves and calculate association constants for complex membrane proteins in the native plasma membrane environment. The method utilizes FRET detection, and thus requires that the proteins of interest are labeled with florescent proteins, either FRET donors or FRET acceptors. Since plasma membranes of cells have complex topologies precluding the acquisition of two-dimensional binding curves, the FRET measurements are performed in plasma membrane derived vesicles that bud off cells as a result of chemical or osmotic stress. The results overviewed here are acquired in vesicles produced with an osmotic vesiculation buffer developed in our laboratory, which does not utilize harsh chemicals. The concentrations of the donor-labeled and the acceptor-labeled proteins are determined, along with the FRET efficiencies, in each vesicle. The experiments utilize transient transfection, such that a wide variety of concentrations is sampled. Then, data from hundreds of vesicles are combined to yield dimerization curves. Here we discuss recent findings about the dimerization of receptor tyrosine kinases (RTKs), membrane proteins that control cell growth and differentiation via lateral dimerization in the plasma membrane. We focus on the dimerization of fibroblast growth factor receptor 3 (FGFR3), a RTK that plays a critically important role in skeletal development. We study the role of different FGFR3 domains in FGFR3 dimerization in the absence of ligand, and we show that FGFR3 extracellular domains inhibit unliganded dimerization, while contacts between the juxtamembrane domains, which connect the transmembrane domains to the kinase domains, stabilize the unliganded FGFR3 dimers. Since FGFR3 has been documented to harbor many pathogenic single amino acid mutations that cause skeletal and cranial dysplasias, as well as cancer, we also study the effects of these mutations on dimerization. First, we show that the A391E mutation, linked to Crouzon syndrome with acanthosis nigricans and to bladder cancer, significantly enhances FGFR3 dimerization in the absence of ligand and thus induces aberrant receptor interactions. Second, we present results about the effect of three cysteine mutations that cause thanatophoric dysplasia, a lethal phenotype. Such cysteine mutations have been hypothesized previously to cause constitutive dimerization, but we find instead that they have a surprisingly modest effect on dimerization. Most of the studied pathogenic mutations also altered FGFR3 dimer structure, suggesting that both increases in dimerization propensities and changes in dimer structure contribute to the pathological phenotypes. The results acquired with the QI-FRET method further our understanding of the interactions between FGFR3 molecules and RTK molecules in general. Since RTK dimerization regulates RTK signaling, our findings advance our knowledge of RTK activity in health and disease. The utility of the QI-FRET method is not restricted to RTKs, and we thus hope that in the future the QI-FRET method will be applied to other classes of membrane proteins, such as channels and G protein-coupled receptors. PMID- 26244705 TI - The pursuit of balance: An overview of covariate-adaptive randomization techniques in clinical trials. AB - Randomization is fundamental to the design and conduct of clinical trials. Simple randomization ensures independence among subject treatment assignments and prevents potential selection biases, yet it does not guarantee balance in covariate distributions across treatment groups. Ensuring balance in important prognostic covariates across treatment groups is desirable for many reasons. A broad class of randomization methods for achieving balance are reviewed in this paper; these include block randomization, stratified randomization, minimization, and dynamic hierarchical randomization. Practical considerations arising from experience with using the techniques are described. A review of randomization methods used in practice in recent randomized clinical trials is also provided. PMID- 26244706 TI - Molecular Interactions in Organic Nanoparticles for Phototheranostic Applications. PMID- 26244707 TI - Selective Intermolecular Oxidative Cross-Coupling of Enolates. AB - Selective intermolecular oxidative cross-coupling of enolates, which is a bond forming reaction between carbanion equivalents, remains as an unsolved issue despite its potential utility for the direct synthesis of unsymmetrical 1,4 diones. The main difficulty derives from the unavoidable homo-coupling. Our strategy depends on the selective one-electron oxidation of one enolate to afford an electrophilic carbonyl alpha-radical species, followed by trapping with another enolate. The present study demonstrates the selective oxovanadium(V) induced cross-coupling between boron and silyl enolates. PMID- 26244708 TI - Predicting the Risk for Central Pain Using the Sensory Components of the International Standards for Neurological Classification of Spinal Cord Injury. AB - Central neuropathic pain (CP) after spinal cord injury (SCI) is excruciating and difficult to manage. Pre-emptive treatment could be initiated in patients at risk for CP providing that it can be predicted. A combination of psychophysical tests could predict CP, but the process necessitates sophisticated equipment and constant monitoring. A simple predictive tool for CP is required. The aim of this study was to test the predictability for CP of the sensory component of the International Standards for Neurological Classification of Spinal Cord Injury (SC ISNCSCI), routinely performed on all SCI patients. In an historical-prospective study, the SC-ISNCSCI and background variables were extracted from medical records of 115 SCI patients. In a prospective study, 20 SCI patients underwent the SC-ISNCSCI at admission and were followed-up for 12 months. In both studies, pinprick (PP) and light touch (LT) scores from the SC-ISNCSCI and the difference between them (LT-PP) were compared between those who eventually developed CP and those who did not. Heat-pain and touch thresholds were measured and correlated with the SC-ISNCSCI to test its validity. In both studies, patients who developed CP had, prior to CP, lower PP than LT scores, and lower PP scores than those who did not develop CP. At-level delta LT-PP score>1 best predicted CP; the odds of developing CP with LT-PP>1 was 24.4 times that of the reverse category (LT-PP<1). Heat-pain and touch thresholds significantly correlated with PP and LT. We conclude that the SC-ISNCSCI can be used as a clinical biomarker of CP with high probability. PMID- 26244710 TI - Mothers' Management of Adolescent Peer Relationships: Associations With Aggressive, Prosocial, and Playful Behavior. AB - The authors examined the relation between adolescents' reports of mothers' management of peer relationships and adolescents' reports of their own aggressive, prosocial, and playful behaviors. The sample comprised 92 adolescents (M age = 15.41 years, SD = 1.81 years) enrolled in a residential summer camp. Higher levels of consulting were related to lower levels of adolescents' relational aggression, physical aggression, playful teasing, and rough-and-tumble play. Higher levels of consulting were related to higher levels of prosocial behavior. Higher levels of guiding were related to higher levels of adolescents' relational aggression and social inclusion. Higher levels of granting access to peers were related to higher levels of adolescents' prosocial behavior and social inclusion. Moderate levels of granting access to peers were related higher levels of playful teasing. PMID- 26244711 TI - Observation of Superconductivity in Tetragonal FeS. AB - The possibility of superconductivity in tetragonal FeS has attracted considerable interest because of its similarities to the FeSe superconductor. However, all efforts made to pursue superconductivity in tetragonal FeS have failed so far, and it remains controversial whether tetragonal FeS is metallic or semiconducting. Here we report the observation of superconductivity at 5 K in tetragonal FeS that is synthesized by the hydrothermal reaction of iron powder with sulfide solution. The obtained samples are highly crystalline and less air sensitive, in contrast to those reported in the literature, which are meta-stable and air-sensitive. Magnetic and electrical properties measurements show that the samples behave as a paramagnetic metal in the normal state and exhibit superconductivity below 5 K. The high crystallinity and the stoichiometry of the samples play important roles in the observation of superconductivity. The present results demonstrate that tetragonal FeS is a promising new platform to realize high-temperature superconductors. PMID- 26244712 TI - Photosensitized production of functionalized and unsaturated organic compounds at the air-sea interface. AB - The sea-surface microlayer (SML) has different physical, chemical and biological properties compared to the subsurface water, with an enrichment of organic matter i.e., dissolved organic matter including UV absorbing humic substances, fatty acids and many others. Here we present experimental evidence that dissolved organic matter, such as humic acids, when exposed to sunlight, can photosensitize the chemical conversion of linear saturated fatty acids at the air-water interface into unsaturated functionalized gas phase products (i.e. saturated and unsaturated aldehydes and acids, alkenes and dienes,...) which are known precursors of secondary organic aerosols. These functionalized molecules have previously been thought to be of biological origin, but here we demonstrate that abiotic interfacial photochemistry has the potential to produce such molecules. As the ocean is widely covered by the SML, this new understanding will impact on our ability to describe atmospheric chemistry in the marine environment. PMID- 26244714 TI - Ratiometric electrochemical sensor for effective and reliable detection of ascorbic acid in living brains. AB - The in vivo detection of ascorbic acid (AA), one of the physiologically important cerebral neurochemicals, is critical to probe and understand brain functions. Electrochemical sensors are convenient for AA detection. However, conventional electrochemical sensors usually suffer from several challenges, such as sluggish electron transfer kinetics for AA oxidation and poor reproducibility. To address these challenges, here we report ratiometric electrochemical sensors for effective and reliable detection of AA in living brains. The sensors were constructed by immobilizing preassembled thionine/Ketjen black (KB) nanocomposites onto glassy carbon (GC) electrodes or carbon fiber microelectrodes (CFMEs). The KB in the rationally functionalized nanocomposites efficiently facilitated AA oxidation at a relatively negative potential (~-0.14 V) without particular physical or chemical pretreatment, forming the basis of selective measurement of AA. With a well-defined and reversible pair of redox wave at -0.22 V, the assembled thionine acted as an internal reference to substantially alleviate the lab-to-lab, person-to-person, and electrode-to-electrode variations. The in vitro experiments demonstrated that the sensors exhibited extremely high reproducibility and stability toward selective measurement of AA. More, with operational simplicity and robustness in analytical performance, the designed sensors were successfully applied to in vivo effectively, selectively, and reliably monitor the dynamic change of cerebral AA associated with pathological processes (i.e., salicylate-induced tinnitus as the model) in living rats' brains. This study not only offers a new strategy for construction of ratiometric electrochemical sensors but also opens a new way for selective and reliable detection of neurochemicals for probing brain functions. PMID- 26244715 TI - A possible case of acquired syphilis at the former Royal Hospital of All-Saints (RHAS) in Lisbon, Portugal (18th century): a comparative methodological approach to differential diagnosis. AB - Between the years of 1999 and 2001, during the excavation of the Praca da Figueira (Lisbon, Portugal), several human osteological remains from various chronological periods were discovered. Amongst them several skeletons are known to be related with the Hospital Real de Todos-os-Santos (Royal Hospital of All Saints - RHAS), which had an important role. The hospital history begun in 1492 and ended in 1755 largely as a consequence of the Lisbon earthquake. Of the skeletons exhumed, one in particular, the adult female Sk. 1310 showed significant pathological changes. The bone lesions characterized by new bone deposition, with a symmetric and disseminate pattern, were found in the upper limbs, distal end of femurs and in tibia and fibula diaphyses. A bowing deformity with "sabre shape" morphology was also observed in the tibiae. The most striking lesions, characterized by healed nodular cavitations and similar to those of caries sicca, were recorded on the frontal bone. Considering the value of a complete description, as well as the application of multiple lines of enquiry for a reliable differential diagnosis, three distinct techniques were applied and compared: visual examination, imagiology and histology. The results showed that the macroscopic analysis coupled with conventional X-ray analysis were fundamental to obtain a possible diagnosis of acquired syphilis. In contrast, the CT-scan and the histological analyses were less informative. The application of a new scoring system also supports a diagnosis of acquired syphilis. This case study constitutes the first evidence of syphilis associated with the RHAS, supporting historical data on the pivotal role that this hospital had on the treatment of several conditions, namely, syphilis. PMID- 26244713 TI - Micro/nanofabricated platforms for oral drug delivery. AB - The oral route of drug administration is most preferred due to its ease of use, low cost, and high patient compliance. However, the oral uptake of many small molecule drugs and biotherapeutics is limited by various physiological barriers, and, as a result, drugs suffer from issues with low solubility, low permeability, and degradation following oral administration. The flexibility of micro- and nanofabrication techniques has been used to create drug delivery platforms designed to address these barriers to oral drug uptake. Specifically, micro/nanofabricated devices have been designed with planar, asymmetric geometries to promote device adhesion and unidirectional drug release toward epithelial tissue, thereby prolonging drug exposure and increasing drug permeation. Furthermore, surface functionalization, nanotopography, responsive drug release, motion-based responses, and permeation enhancers have been incorporated into such platforms to further enhance drug uptake. This review will outline the application of micro/nanotechnology to specifically address the physiological barriers to oral drug delivery and highlight technologies that may be incorporated into these oral drug delivery systems to further enhance drug uptake. PMID- 26244717 TI - A Framework for Conducting Deceased Donor Research in the United States. AB - There are a number of regulatory barriers both perceived and real that have hampered widespread clinical research in the field of donation and transplantation. This article sets forth a framework clarifying the existing legal requirements and their application to the conduct of research on deceased donors and donor organs within the United States. Recommendations are focused on resolving some of the ambiguity surrounding deceased donor authorization for research, Health Insurance Portability and Accountability Act requirements and the role of institutional review board oversight. The successful conduct of clinical research in the field of donation and transplantation requires an understanding of these regulatory nuances as well as identification of important ethical principles to consider. Facilitation of these concepts will ultimately provide support for innovative research designed to increase the availability of organs for transplantation. Further work identifying the optimal infrastructure for overview of clinical research in the field should be given priority. PMID- 26244718 TI - Increased Plasma Levels of Asymmetric Dimethylarginine in Nonalcoholic Fatty Liver Disease: Relation With Insulin Resistance, Inflammation, and Liver Histology. AB - BACKGROUND AND AIM: Cardiovascular disease (CVD) is the most frequent cause of death in nonalcoholic fatty liver disease (NAFLD). Insulin resistance, hepatic dysfunction, and chronic inflammation are factors interacting in explaining the increased CVD incidence in NAFLD. We aimed to evaluate the effects of insulin resistance and inflammatory biomarkers on asymmetric dimethylarginine (ADMA) levels, a predictor of CVD. We also investigated relationship between these markers and histological findings in patients with NAFLD. PATIENTS AND METHODS: Plasma ADMA, high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and homeostasis model assessment of insulin resistance (HOMA-IR) were measured in 70 patients with histologically verified NAFLD (53 with nonalcoholic steatohepatitis [NASH], 17 with non-NASH) and 12 controls. RESULTS: The HOMA-IR (5.3 [3.9] vs 1.9 [1], P < 0.001), hs-CRP (5.6 [4.2] vs 2.2 [2.3] mg/L, P < 0.001), ADMA (0.81 [0.25] vs 0.48 [0.24] MUmol/L, P = 0.005), and IL-6 (4.1 [1.2] vs 1.0 [0.4] pg/mL, P < 0.001) levels were all found higher in the NAFLD group than the control group. The ADMA levels were significantly higher in patients with NAFLD independent from HOMA-IR and body composition (P = 0.02). The IL-6 and HOMA-IR levels of the NASH group were found significantly higher than those of the non-NASH group. The only determinant significantly correlated to ADMA was HOMA-IR. CONCLUSIONS: Our data suggested that although ADMA levels are independently higher in NAFLD, the only determinant correlated to ADMA is HOMA-IR and not inflammatory biomarkers (hs-CRP, IL-6) or presence/absence of NASH. PMID- 26244716 TI - A Rationale for Age-Adapted Immunosuppression in Organ Transplantation. AB - Demographic changes are associated with a steady increase of older patients with end-stage organ failure in need for transplantation. As a result, the majority of transplant recipients are currently older than 50 years, and organs from elderly donors are more frequently used. Nevertheless, the benefit of transplantation in older patients is well recognized, whereas the most frequent causes of death among older recipients are potentially linked to side effects of their immunosuppressants.Immunosenescence is a physiological part of aging linked to higher rates of diabetes, bacterial infections, and malignancies representing the major causes of death in older patients. These age-related changes impact older transplant candidates and may have significant implications for an age-adapted immunosuppression. For instance, immunosenescence is linked to lower rates of acute rejections in older recipients, whereas the engraftment of older organs has been associated with higher rejection rates. Moreover, new-onset diabetes mellitus after transplantation is more frequent in the elderly, potentially related to corticosteroids, calcineurin inhibitors, and mechanistic target of rapamycin inhibitors.This review presents current knowledge for an age-adapted immunosuppression based on both, experimental and clinical studies in and beyond transplantation. Recommendations of maintenance and induction therapy may help to improve graft function and to design future clinical trials in the elderly. PMID- 26244719 TI - The Truth Before and After: Brain Potentials Reveal Automatic Activation of Event Knowledge during Sentence Comprehension. AB - How does knowledge of real-world events shape our understanding of incoming language? Do temporal terms like "before" and "after" impact the online recruitment of real-world event knowledge? These questions were addressed in two ERP experiments, wherein participants read sentences that started with "before" or "after" and contained a critical word that rendered each sentence true or false (e.g., "Before/After the global economic crisis, securing a mortgage was easy/harder"). The critical words were matched on predictability, rated truth value, and semantic relatedness to the words in the sentence. Regardless of whether participants explicitly verified the sentences or not, false-after sentences elicited larger N400s than true-after-sentences, consistent with the well-established finding that semantic retrieval of concepts is facilitated when they are consistent with real-world knowledge. However, although the truth judgments did not differ between before- and after-sentences, no such sentence N400 truth value effect occurred in before-sentences, whereas false-before sentences elicited an enhanced subsequent positive ERPs. The temporal term "before" itself elicited more negative ERPs at central electrode channels than "after." These patterns of results show that, irrespective of ultimate sentence truth value judgments, semantic retrieval of concepts is momentarily facilitated when they are consistent with the known event outcome compared to when they are not. However, this inappropriate facilitation incurs later processing costs as reflected in the subsequent positive ERP deflections. The results suggest that automatic activation of event knowledge can impede the incremental semantic processes required to establish sentence truth value. PMID- 26244720 TI - Rapid Attentional Selection of Non-native Stimuli despite Perceptual Narrowing. AB - Visual experiences increase our ability to discriminate environmentally relevant stimuli (native stimuli, e.g., human faces) at the cost of a reduced sensitivity to irrelevant or infrequent stimuli (non-native stimuli, e.g., monkey/ape faces) a developmental progression known as perceptual narrowing. One possible source of the reduced sensitivity in distinguishing non-native stimuli (e.g., one ape face vs. another ape face) could be underspecified attentional search templates (i.e., working memory representations). To determine whether perceptual narrowing stems from underspecified attentional templates for non-native exemplars, this study used ERP (the N2pc component) and behavioral measures in a visual search task, where the target was either an exemplar (e.g., a specific ape face) or a category (e.g., any ape face). The N2pc component, an ERP marker of early attentional selection emerging at 200 msec poststimulus, is typically modulated by the specificity of the target and, therefore, by the attentional template-the N2pc is larger for specific items versus categories. In two experiments using both human and ape faces (i.e., native and non-native stimuli), we found that perceptual narrowing affects later response selection (i.e., manual RT and accuracy), but not early attentional selection relying on attentional templates (i.e., the N2pc component). Our ERP results show that adults deploy exemplar level attentional templates for non-native stimuli (as well as native stimuli), despite poor downstream behavioral performance. Our findings suggest that long-term previous experience with reduced exemplar level judgments (i.e., perceptual narrowing) does not appear to eliminate early attentional selection of non-native exemplars. PMID- 26244721 TI - Facial Action and Emotional Language: ERP Evidence that Blocking Facial Feedback Selectively Impairs Sentence Comprehension. AB - There is a lively and theoretically important debate about whether, how, and when embodiment contributes to language comprehension. This study addressed these questions by testing how interference with facial action impacts the brain's real time response to emotional language. Participants read sentences about positive and negative events (e.g., "She reached inside the pocket of her coat from last winter and found some (cash/bugs) inside it.") while ERPs were recorded. Facial action was manipulated within participants by asking participants to hold chopsticks in their mouths using a position that allowed or blocked smiling, as confirmed by EMG. Blocking smiling did not influence ERPs to the valenced words (e.g., cash, bugs) but did influence ERPs to final words of sentences describing positive events. Results show that affectively positive sentences can evoke smiles and that such facial action can facilitate the semantic processing indexed by the N400 component. Overall, this study offers causal evidence that embodiment impacts some aspects of high-level comprehension, presumably involving the construction of the situation model. PMID- 26244722 TI - Task-positive Functional Connectivity of the Default Mode Network Transcends Task Domain. AB - The default mode network (DMN) was first recognized as a set of brain regions demonstrating consistently greater activity during rest than during a multitude of tasks. Originally, this network was believed to interfere with goal-directed behavior based on its decreased activity during many such tasks. More recently, however, the role of the DMN during goal-directed behavior was established for internally oriented tasks, in which the DMN demonstrated increased activity. However, the well-documented hub position and information-bridging potential of midline DMN regions indicate that there is more to uncover regarding its functional contributions to goal-directed tasks, which may be based on its functional interactions rather than its level of activation. An investigation of task-related changes in DMN functional connectivity during a series of both internal and external tasks would provide the requisite investigation for examining the role of the DMN during goal-directed task performance. In this study, 20 participants underwent fMRI while performing six tasks spanning diverse internal and external domains in addition to a resting-state scan. We hypothesized that the DMN would demonstrate "task-positive" (i.e., positively contributing to task performance) changes in functional connectivity relative to rest regardless of the direction of task-related changes in activity. Indeed, our results demonstrate significant increases in DMN connectivity with task-promoting regions (e.g., anterior insula, inferior frontal gyrus, middle frontal gyrus) across all six tasks. Furthermore, canonical correlation analyses indicated that the observed task-related connectivity changes were significantly associated with individual differences in task performance. Our results indicate that the DMN may not only support a "default" mode but may play a greater role in both internal and external tasks through flexible coupling with task-relevant brain regions. PMID- 26244723 TI - Semantic Relations between Visual Objects Can Be Unconsciously Processed but Not Reported under Change Blindness. AB - Change blindness-the failure to detect changes in visual scenes-has often been interpreted as a result of impoverished visual information encoding or as a failure to compare the prechange and postchange scene. In the present electroencephalography study, we investigated whether semantic features of prechange and postchange information are processed unconsciously, even when observers are unaware that a change has occurred. We presented scenes composed of natural objects in which one object changed from one presentation to the next. Object changes were either semantically related (e.g., rail car changed to rail) or unrelated (e.g., rail car changed to sausage). Observers were first asked to detect whether any change had occurred and then to judge the semantic relation of the two objects involved in the change. We found a semantic mismatch ERP effect, that is, a more negative-going ERP for semantically unrelated compared to related changes, originating from a cortical network including the left middle temporal gyrus and occipital cortex and resembling the N400 effect, albeit at longer latencies. Importantly, this semantic mismatch effect persisted even when observers were unaware of the change and the semantic relationship of prechange and postchange object. This finding implies that change blindness does not preclude the encoding of the prechange and postchange objects' identities and possibly even the comparison of their semantic content. Thus, change blindness cannot be interpreted as resulting from impoverished or volatile visual representations or as a failure to process the prechange and postchange object. Instead, change detection appears to be limited at a later, postperceptual stage. PMID- 26244724 TI - The Neural Bases of the Semantic Interference of Spatial Frequency-based Information in Scenes. AB - Current models of visual perception suggest that during scene categorization, low spatial frequencies (LSF) are processed rapidly and activate plausible interpretations of visual input. This coarse analysis would then be used to guide subsequent processing of high spatial frequencies (HSF). The present fMRI study examined how processing of LSF may influence that of HSF by investigating the neural bases of the semantic interference effect. We used hybrid scenes as stimuli by combining LSF and HSF from two different scenes, and participants had to categorize the HSF scene. Categorization was impaired when LSF and HSF scenes were semantically dissimilar, suggesting that the LSF scene was processed automatically and interfered with categorization of the HSF scene. fMRI results revealed that this semantic interference effect was associated with increased activation in the inferior frontal gyrus, the superior parietal lobules, and the fusiform and parahippocampal gyri. Furthermore, a connectivity analysis (psychophysiological interaction) revealed that the semantic interference effect resulted in increasing connectivity between the right fusiform and the right inferior frontal gyri. Results support influential models suggesting that, during scene categorization, LSF information is processed rapidly in the pFC and activates plausible interpretations of the scene category. These coarse predictions would then initiate top-down influences on recognition-related areas of the inferotemporal cortex, and these could interfere with the categorization of HSF information in case of semantic dissimilarity to LSF. PMID- 26244725 TI - Grisel Syndrome: An Unusual and Often Unrecognized Cause of Torticollis. AB - Torticollis can be due to many different etiologies. Torticollis is not a diagnosis, but a symptom of many conditions. We present a case of persistent torticollis in a child that was misdiagnosed during multiple visits to the pediatrician, otolaryngologist, and 3 different emergency departments. Grisel syndrome must be included in the differential diagnosis of any patient with torticollis after a head and neck infection, upper respiratory infection, or postoperative from head and neck surgery. Early diagnosis allows for appropriate management and can prevent significant morbidity. PMID- 26244726 TI - Tension Hydrocele: An Unusual Cause of Acute Scrotal Pain. AB - The etiology of acute scrotal pain can vary from a benign process such as mild trauma, appendicular torsion, or epididymo-orchitis to an emergent process such as an incarcerated inguinal hernia, testicular torsion, or rupture. Furthermore, testicular insult often results in a reactive hydrocele that can both cloud the diagnosis and impair the physical examination. Traditionally, the acute scrotum was managed with immediate exploration, but emergency physicians and urologists have increasingly used Doppler ultrasonography to assess vascular flow, aide in the diagnosis, and ultimately guide triage of those patients who require urgent intervention. We describe the case of a 15-year-old boy who presented with 2 days of increasing testicular pain and swelling, confirmed to have a large hydrocele with compromised testicular perfusion, and was managed by emergent operative drainage and repair of a "tension hydrocele" with immediate return of testicular perfusion. To our knowledge, this is the first report of tension hydrocele causing intratesticular vascular compromise in a pediatric patient. PMID- 26244727 TI - Protein-Assisted DNA Looping: A Delicate Balance among Interactions, Mechanics, and Entropy. PMID- 26244728 TI - Molecular Simulations of Gram-Negative Bacterial Membranes: A Vignette of Some Recent Successes. AB - In the following review we use recent examples from the literature to discuss progress in the area of atomistic and coarse-grained molecular dynamics simulations of selected bacterial membranes and proteins, with a particular focus on Gram-negative bacteria. As structural biology continues to provide increasingly high-resolution data on the proteins that reside within these membranes, simulations have an important role to play in linking these data with the dynamical behavior and function of these proteins. In particular, in the last few years there has been significant progress in addressing the issue of biochemical complexity of bacterial membranes such that the heterogeneity of the lipid and protein components of these membranes are now being incorporated into molecular-level models. Thus, in future we can look forward to complementary data from structural biology and molecular simulations combining to provide key details of structure-dynamics-function relationships in bacterial membranes. PMID- 26244729 TI - Controlled One-on-One Encounters between Immune Cells and Microbes Reveal Mechanisms of Phagocytosis. AB - Among many challenges facing the battle against infectious disease, one quandary stands out. On the one hand, it is often unclear how well animal models and cell lines mimic human immune behavior. On the other hand, many core methods of cell and molecular biology cannot be applied to human subjects. For example, the profound susceptibility of neutropenic patients to infection marks neutrophils (the most abundant white blood cells in humans) as vital immune defenders. Yet because these cells cannot be cultured or genetically manipulated, there are gaps in our understanding of the behavior of human neutrophils. Here, we discuss an alternative, interdisciplinary strategy to dissect fundamental mechanisms of immune-cell interactions with bacteria and fungi. We show how biophysical analyses of single-live-cell/single-target encounters are revealing universal principles of immune-cell phagocytosis, while also dispelling misconceptions about the minimum required mechanistic determinants of this process. PMID- 26244730 TI - Design Parameters for Granzyme-Mediated Cytotoxic Lymphocyte Target-Cell Killing and Specificity. AB - Cytotoxic lymphocytes are key elements of the immune system that are primarily responsible for targeting cells infected with intracellular pathogens, or cells that have become malignantly transformed. Target cells are killed mainly via lymphocyte exocytosis of specialized lysosomes containing perforin, a pore forming protein, and granzymes, which are proteases that induce apoptosis. Due to its central role in lymphocyte biology, as well as its implication in a host of pathologies from cancer to autoimmunity, the granzyme-perforin pathway has been the subject of extensive investigation. Nevertheless, the details of exactly how granzyme and perforin cooperate to induce target-cell death remain controversial. To further investigate this system, we developed a biophysical model of the immunological synapse between a cytotoxic lymphocyte and a target cell using a spatial stochastic simulation algorithm. We used this model to calculate the spatiotemporal evolution of granzyme B and perforin from the time of their exocytosis to granzyme internalization by the target cell. We used a metric of granzyme internalization to delineate which biological processes were critical for successful target-cell lysis. We found that the high aspect ratio of the immunological synapse was insufficient in this regard, and that molecular crowding within the synapse is critical to preserve sufficient concentrations of perforin and granzyme for consistent pore formation and granzyme transfer to target cells. However, even when pore formation occurs in our model, a large amount of both granzyme and perforin still escape from the synapse. We argue that a tight seal between the cytotoxic lymphocyte and its target cell is not required to avoid bystander killing. Instead, we propose that the requirement for spatiotemporal colocalization of granzyme and perforin acts as an effective bimolecular filter to ensure target specificity. PMID- 26244731 TI - Dissecting Collective Cell Behavior in Polarization and Alignment on Micropatterned Substrates. AB - Pattern-dependent collective behaviors of cells have recently raised intensive attention. However, the underlying mechanisms that regulate these behaviors are largely elusive. Here, we report a quantitative study, combining experiment and modeling, on cell polarization and arrangement on a micropatterned substrate. We show that cells exhibit position-dependent collective behaviors that can be regulated by geometry and stiffness of the patterned substrate. We find that the driving force for these collective behaviors is the in-plane maximum shear stress in the cell layer that directs the arrangement of cells. The larger the shear stress, the more the cells preferentially align and polarize along the direction of the maximum principal stress. We also find that the aspect ratio of cell polarization shape and the degree to which cells preferentially align along the direction of maximum principal stress exhibit a biphasic dependence on substrate rigidity, corresponding to our quantitative predictions that the magnitude of the maximum shear stress is biphasically dependent on the stiffness of the substrate. As such, the driving force of these cell collective behaviors can be quantified using the maximum shear stress. PMID- 26244732 TI - A Disulfide Bond Is Required for the Transmission of Forces through SUN-KASH Complexes. AB - Numerous biological functions of a cell, including polarization, differentiation, division, and migration, rely on its ability to endure mechanical forces generated by the cytoskeleton on the nucleus. Coupling of the cytoskeleton and nucleoskeleton is ultimately mediated by LINC complexes that are formed via a strong interaction between SUN- and KASH-domain-containing proteins in the nuclear envelope. These complexes are mechanosensitive and essential for the transmission of forces between the cytoskeleton and nucleoskeleton, and the progression of cellular mechanotransduction. Herein, using molecular dynamics, we examine the effect of tension on the human SUN2-KASH2 complex and show that it is remarkably stable under physiologically relevant tensile forces and large strains. However, a covalent disulfide bond between two highly conserved cysteine residues of SUN2 and KASH2 is crucial for the stability of this interaction and the transmission of forces through the complex. PMID- 26244733 TI - Relative Cosolute Size Influences the Kinetics of Protein-Protein Interactions. AB - Protein signaling occurs in crowded intracellular environments, and while high concentrations of macromolecules are postulated to modulate protein-protein interactions, analysis of their impact at each step of the reaction pathway has not been systematically addressed. Potential cosolute-induced alterations in target association are particularly important for a signaling molecule like calmodulin (CaM), where competition among >300 targets governs which pathways are selectively activated. To explore how high concentrations of cosolutes influence CaM-target affinity and kinetics, we methodically investigated each step of the CaM-target binding mechanism under crowded or osmolyte-rich environments mimicked by ficoll-70, dextran-10, and sucrose. All cosolutes stabilized compact conformers of CaM and modulated association kinetics by affecting diffusion and rates of conformational change; however, the results showed that differently sized molecules had variable effects to enhance or impede unique steps of the association pathway. On- and off-rates were modulated by all cosolutes in a compensatory fashion, producing little change in steady-state affinity. From this work insights were gained on how high concentrations of inert crowding agents and osmolytes fit into a kinetic framework to describe protein-protein interactions relevant for cellular signaling. PMID- 26244734 TI - Cell-Size Homeostasis and the Incremental Rule in a Bacterial Pathogen. AB - How populations of growing cells achieve cell-size homeostasis remains a major question in cell biology. Recent studies in rod-shaped bacteria support the "incremental rule" where each cell adds a constant length before dividing. Although this rule explains narrow cell-size distributions, its mechanism is still unknown. We show that the opportunistic pathogen Pseudomonas aeruginosa obeys the incremental rule to achieve cell-length homeostasis during exponential growth but shortens its cells when entering the stationary phase. We identify a mutant, called frik, which has increased antibiotic sensitivity, cells that are on average longer, and a fraction of filamentous cells longer than 10 MUm. When growth slows due to entry in stationary phase, the distribution of frik cell sizes decreases and approaches wild-type length distribution. The rare filamentous cells have abnormally large nucleoids, suggesting that a deficiency in DNA segregation prevents cell division without slowing the exponential elongation rate. PMID- 26244735 TI - The Integrity of the TRP Domain Is Pivotal for Correct TRPV1 Channel Gating. AB - Transient receptor potential vanilloid subtype I (TRPV1) is a thermosensory ion channel that is also gated by chemical substances such as vanilloids. Adjacent to the channel gate, this polymodal thermoTRP channel displays a TRP domain, referred to as AD1, that plays a role in subunit association and channel gating. Previous studies have shown that swapping the AD1 in TRPV1 with the cognate from the TRPV2 channel (AD2) reduces protein expression and produces a nonfunctional chimeric channel (TRPV1-AD2). Here, we used a stepwise, sequential, cumulative site-directed mutagenesis approach, based on rebuilding the AD1 domain in the TRPV1-AD2 chimera, to unveil the minimum number of amino acids needed to restore protein expression and polymodal channel activity. Unexpectedly, we found that virtually full restitution of the AD1 sequence is required to reinstate channel expression and responses to capsaicin, temperature, and voltage. This strategy identified E692, R701, and T704 in the TRP domain as important for TRPV1 activity. Even conservative mutagenesis at these sites (E692D/R701K/T704S) impaired channel expression and abolished TRPV1 activity. However, the sole mutation of these positions in the TRPV1-AD2 chimera (D692E/K701R/S704T) was not sufficient to rescue channel gating, implying that other residues in the TRP domain are necessary to endow activity to TRPV1-AD2. A biophysical analysis of a functional chimera suggested that mutations in the TRP domain raised the energetics of channel gating by altering the coupling of stimuli sensing and pore opening. These findings indicate that inter- and/or intrasubunit interactions in the TRP domain are essential for correct TRPV1 gating. PMID- 26244736 TI - Protonation of Glu(135) Facilitates the Outward-to-Inward Structural Transition of Fucose Transporter. AB - Major facilitator superfamily (MFS) transporters typically need to alternatingly sample the outward-facing and inward-facing conformations, in order to transport the substrate across membrane. To understand the mechanism, in this work, we focused on one MFS member, the L-fucose/H(+) symporter (FucP), whose crystal structure exhibits an outward-open conformation. Previous experiments imply several residues critical to the substrate/proton binding and structural transition of FucP, among which Glu(135), located in the periplasm-accessible vestibule, is supposed as being involved in both proton translocation and conformational change of the protein. Here, the structural transition of FucP in presence of substrate was investigated using molecular-dynamics simulations. By combining the equilibrium and accelerated simulations as well as thermodynamic calculations, not only was the large-scale conformational change from the outward facing to inward-facing state directly observed, but also the free energy change during the structural transition was calculated. The simulations confirm the critical role of Glu(135), whose protonation facilitates the outward-to-inward structural transition both by energetically favoring the inward-facing conformation in thermodynamics and by reducing the free energy barrier along the reaction pathway in kinetics. Our results may help the mechanistic studies of both FucP and other MFS transporters. PMID- 26244737 TI - Membrane Interaction of the Glycosyltransferase WaaG. AB - The glycosyltransferase WaaG is involved in the synthesis of lipopolysaccharides that constitute the outer leaflet of the outer membrane in Gram-negative bacteria such as Escherichia coli. WaaG has been identified as a potential antibiotic target, and inhibitor scaffolds have previously been investigated. WaaG is located at the cytosolic side of the inner membrane, where the enzyme catalyzes the transfer of the first outer-core glucose to the inner core of nascent lipopolysaccharides. Here, we characterized the binding of WaaG to membrane models designed to mimic the inner membrane of E. coli. Based on the crystal structure, we identified an exposed and largely alpha-helical 30-residue sequence, with a net positive charge and several aromatic amino acids, as a putative membrane-interacting region of WaaG (MIR-WaaG). We studied the peptide corresponding to this sequence, along with its bilayer interactions, using circular dichroism, fluorescence quenching, fluorescence anisotropy, and NMR. In the presence of dodecylphosphocholine, MIR-WaaG was observed to adopt a three dimensional structure remarkably similar to the segment in the crystal structure. We found that the membrane interaction of WaaG is conferred at least in part by MIR-WaaG and that electrostatic interactions play a key role in binding. Moreover, we propose a mechanism of anchoring WaaG to the inner membrane of E. coli, where the central part of MIR-WaaG inserts into one leaflet of the bilayer. In this model, electrostatic interactions as well as surface-exposed Tyr residues bind WaaG to the membrane. PMID- 26244738 TI - A Model for Shaping Membrane Sheets by Protein Scaffolds. AB - Membranes of peripheral endoplasmic reticulum form intricate morphologies consisting of tubules and sheets as basic elements. The physical mechanism of endoplasmic-reticulum shaping has been suggested to originate from the elastic behavior of the sheet edges formed by linear arrays of oligomeric protein scaffolds. The heart of this mechanism, lying in the relationships between the structure of the protein scaffolds and the effective intrinsic shapes and elastic properties of the sheets' edges, has remained hypothetical. Here we provide a detailed computational analysis of these issues. By minimizing the elastic energy of membrane bending, we determine the effects of a rowlike array of semicircular arclike membrane scaffolds on generation of a membrane fold, which shapes the entire membrane surface into a flat double-membrane sheet. We show, quantitatively, that the sheet's edge line tends to adopt a positive or negative curvature depending on the scaffold's geometrical parameters. We compute the effective elastic properties of the sheet edge and analyze the dependence of the equilibrium distance between the scaffolds along the edge line on the scaffold geometry. PMID- 26244739 TI - A Practical Implicit Membrane Potential for NMR Structure Calculations of Membrane Proteins. AB - The highly anisotropic environment of the lipid bilayer membrane imposes significant constraints on the structures and functions of membrane proteins. However, NMR structure calculations typically use a simple repulsive potential that neglects the effects of solvation and electrostatics, because explicit atomic representation of the solvent and lipid molecules is computationally expensive and impractical for routine NMR-restrained calculations that start from completely extended polypeptide templates. Here, we describe the extension of a previously described implicit solvation potential, eefxPot, to include a membrane model for NMR-restrained calculations of membrane protein structures in XPLOR NIH. The key components of eefxPot are an energy term for solvation free energy that works together with other nonbonded energy functions, a dedicated force field for conformational and nonbonded protein interaction parameters, and a membrane function that modulates the solvation free energy and dielectric screening as a function of the atomic distance from the membrane center, relative to the membrane thickness. Initial results obtained for membrane proteins with structures determined experimentally in lipid bilayer membranes show that eefxPot affords significant improvements in structural quality, accuracy, and precision. Calculations with eefxPot are straightforward to implement and can be used to both fold and refine structures, as well as to run unrestrained molecular dynamics simulations. The potential is entirely compatible with the full range of experimental restraints measured by various techniques. Overall, it provides a useful and practical way to calculate membrane protein structures in a physically realistic environment. PMID- 26244740 TI - Structural Thermodynamics of myr-Src(2-19) Binding to Phospholipid Membranes. AB - Many proteins are anchored to lipid bilayer membranes through a combination of hydrophobic and electrostatic interactions. In the case of the membrane-bound nonreceptor tyrosine kinase Src from Rous sarcoma virus, these interactions are mediated by an N-terminal myristoyl chain and an adjacent cluster of six basic amino-acid residues, respectively. In contrast with the acyl modifications of other lipid-anchored proteins, the myristoyl chain of Src does not match the host lipid bilayer in terms of chain conformation and dynamics, which is attributed to a tradeoff between hydrophobic burial of the myristoyl chain and repulsion of the peptidic moiety from the phospholipid headgroup region. Here, we combine thermodynamic information obtained from isothermal titration calorimetry with structural data derived from (2)H, (13)C, and (31)P solid-state nuclear magnetic resonance spectroscopy to decipher the hydrophobic and electrostatic contributions governing the interactions of a myristoylated Src peptide with zwitterionic and anionic membranes made from lauroyl (C12:0) or myristoyl (C14:0) lipids. Although the latter are expected to enable better hydrophobic matching, the Src peptide partitions more avidly into the shorter-chain lipid analog because this does not require the myristoyl chain to stretch extensively to avoid unfavorable peptide/headgroup interactions. Moreover, we find that Coulombic and intrinsic contributions to membrane binding are not additive, because the presence of anionic lipids enhances membrane binding more strongly than would be expected on the basis of simple Coulombic attraction. PMID- 26244741 TI - The Signaling State of Orange Carotenoid Protein. AB - Orange carotenoid protein (OCP) is the photoactive protein that is responsible for high light tolerance in cyanobacteria. We studied the kinetics of the OCP photocycle by monitoring changes in its absorption spectrum, intrinsic fluorescence, and fluorescence of the Nile red dye bound to OCP. It was demonstrated that all of these three methods provide the same kinetic parameters of the photocycle, namely, the kinetics of OCP relaxation in darkness was biexponential with a ratio of two components equal to 2:1 independently of temperature. Whereas the changes of the absorption spectrum of OCP characterize the geometry and environment of its chromophore, the intrinsic fluorescence of OCP reveals changes in its tertiary structure, and the fluorescence properties of Nile red indicate the exposure of hydrophobic surface areas of OCP to the solvent following the photocycle. The results of molecular-dynamics studies indicated the presence of two metastable conformations of 3'-hydroxyechinenone, which is consistent with characteristic changes in the Raman spectra. We conclude that rotation of the beta-ionylidene ring in the C-terminal domain of OCP could be one of the first conformational rearrangements that occur during photoactivation. The obtained results suggest that the photoactivated form of OCP represents a molten globule-like state that is characterized by increased mobility of tertiary structure elements and solvent accessibility. PMID- 26244742 TI - Retinal Conformation Changes Rhodopsin's Dynamic Ensemble. AB - G protein-coupled receptors are vital membrane proteins that allosterically transduce biomolecular signals across the cell membrane. However, the process by which ligand binding induces protein conformation changes is not well understood biophysically. Rhodopsin, the mammalian dim-light receptor, is a unique test case for understanding these processes because of its switch-like activity; the ligand, retinal, is bound throughout the activation cycle, switching from inverse agonist to agonist after absorbing a photon. By contrast, the ligand-free opsin is outside the activation cycle and may behave differently. We find that retinal influences rhodopsin dynamics using an ensemble of all-atom molecular dynamics simulations that in aggregate contain 100 MUs of sampling. Active retinal destabilizes the inactive state of the receptor, whereas the active ensemble was more structurally homogenous. By contrast, simulations of an active-like receptor without retinal present were much more heterogeneous than those containing retinal. These results suggest allosteric processes are more complicated than a ligand inducing protein conformational changes or simply capturing a shifted ensemble as outlined in classic models of allostery. PMID- 26244743 TI - Interplay of Protein Binding Interactions, DNA Mechanics, and Entropy in DNA Looping Kinetics. AB - DNA looping plays a key role in many fundamental biological processes, including gene regulation, recombination, and chromosomal organization. The looping of DNA is often mediated by proteins whose structural features and physical interactions can alter the length scale at which the looping occurs. Looping and unlooping processes are controlled by thermodynamic contributions associated with mechanical deformation of the DNA strand and entropy arising from thermal fluctuations of the conformation. To determine how these confounding effects influence DNA looping and unlooping kinetics, we present a theoretical model that incorporates the role of the protein interactions, DNA mechanics, and conformational entropy. We show that for shorter DNA strands the interaction distance affects the transition state, resulting in a complex relationship between the looped and unlooped state lifetimes and the physical properties of the looped DNA. We explore the range of behaviors that arise with varying interaction distance and DNA length. These results demonstrate how DNA deformation and entropy dictate the scaling of the looping and unlooping kinetics versus the J-factor, establishing the connection between kinetic and equilibrium behaviors. Our results show how the twist-and-bend elasticity of the DNA chain modulates the kinetics and how the influence of the interaction distance fades away at intermediate to longer chain lengths, in agreement with previous scaling predictions. PMID- 26244744 TI - Nascent beta-Hairpin Formation of a Natively Unfolded Peptide Reveals the Role of Hydrophobic Contacts. AB - Despite the important role of the unfolded states in protein stability, folding, and aggregation, they remain poorly understood due to the lack of residue specific experimental data. Here, we explore features of the unfolded state of the NTL9 protein by applying all-atom replica-exchange simulations to the two fragment peptides NTL9(1-22) and NTL9(6-17). We found that while NTL9(6-17) is unstructured, NTL9(1-22) transiently folds as various beta-hairpins, a fraction of which contain a native beta-sheet. Interestingly, despite a large number of charged residues, the formation of backbone hydrogen bonds is concomitant with hydrophobic but not electrostatic contacts. Although the fragment peptides lack a proposed specific contact between Asp(8) and Lys(12), the individually weak, nonspecific interactions with lysines together stabilize the charged Asp(8), leading to a pKa shift of nearly 0.5 units, in agreement with the NMR data. Taken together, our data suggest that the unfolded state of NTL9 likely contains a beta hairpin in segment 1-22 with sequence-distant hydrophobic contacts, thus lending support to a long-standing hypothesis that the unfolded states of proteins exhibit native-like topology with hydrophobic clusters. PMID- 26244745 TI - Isocost Lines Describe the Cellular Economy of Genetic Circuits. AB - Genetic circuits in living cells share transcriptional and translational resources that are available in limited amounts. This leads to unexpected couplings among seemingly unconnected modules, which result in poorly predictable circuit behavior. In this study, we determine these interdependencies between products of different genes by characterizing the economy of how transcriptional and translational resources are allocated to the production of proteins in genetic circuits. We discover that, when expressed from the same plasmid, the combinations of attainable protein concentrations are constrained by a linear relationship, which can be interpreted as an isocost line, a concept used in microeconomics. We created a library of circuits with two reporter genes, one constitutive and the other inducible in the same plasmid, without a regulatory path between them. In agreement with the model predictions, experiments reveal that the isocost line rotates when changing the ribosome binding site strength of the inducible gene and shifts when modifying the plasmid copy number. These results demonstrate that isocost lines can be employed to predict how genetic circuits become coupled when sharing resources and provide design guidelines for minimizing the effects of such couplings. PMID- 26244747 TI - Author Appreciation. PMID- 26244746 TI - Mapping the Dynamics Landscape of Conformational Transitions in Enzyme: The Adenylate Kinase Case. AB - Conformational transition describes the essential dynamics and mechanism of enzymes in pursuing their various functions. The fundamental and practical challenge to researchers is to quantitatively describe the roles of large-scale dynamic transitions for regulating the catalytic processes. In this study, we tackled this challenge by exploring the pathways and free energy landscape of conformational changes in adenylate kinase (AdK), a key ubiquitous enzyme for cellular energy homeostasis. Using explicit long-timescale (up to microseconds) molecular dynamics and bias-exchange metadynamics simulations, we determined at the atomistic level the intermediate conformational states and mapped the transition pathways of AdK in the presence and absence of ligands. There is clearly chronological operation of the functional domains of AdK. Specifically in the ligand-free AdK, there is no significant energy barrier in the free energy landscape separating the open and closed states. Instead there are multiple intermediate conformational states, which facilitate the rapid transitions of AdK. In the ligand-bound AdK, the closed conformation is energetically most favored with a large energy barrier to open it up, and the conformational population prefers to shift to the closed form coupled with transitions. The results suggest a perspective for a hybrid of conformational selection and induced fit operations of ligand binding to AdK. These observations, depicted in the most comprehensive and quantitative way to date, to our knowledge, emphasize the underlying intrinsic dynamics of AdK and reveal the sophisticated conformational transitions of AdK in fulfilling its enzymatic functions. The developed methodology can also apply to other proteins and biomolecular systems. PMID- 26244748 TI - Alcohol Consumption Increases Post-Operative Infection but Not Mortality: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Alcohol consumption causes multiple comorbidities with potentially negative outcome after operations. The aims are to study the association between alcohol consumption and post-operative non-surgical site infections and mortality and to determine the impact of peri-operative interventions. METHODS: MEDLINE, Embase, and The Cochrane Library were searched systematically. Observational studies reporting patients with a defined amount of alcohol consumption and randomized controlled trials (RCTs) aimed at reducing outcomes were included. Meta-analyses were performed separately for observational studies and RCTs. RESULTS: Thirteen observational studies and five RCTs were identified. Meta analyses of observational studies showed more infections in those consuming more than two units of alcohol per day compared with drinking less in both unadjusted and adjusted data. No association between alcohol consumption and mortality was found. Meta-analyses of RCTs showed that interventions reduce infections but not mortality in patients with alcohol abuse. CONCLUSIONS: Consumption of more than two units of alcohol per day increases post-operative non-surgical site infections. Alcohol-refraining interventions in patients with high daily alcohol consumption appear to reduce infections. The impact in patients with lesser intake is unknown. Further studies are needed. PMID- 26244750 TI - Solving the Geriatric Mental Health Crisis in the 21st Century. PMID- 26244751 TI - Effect of Roux-en-Y Gastric Bypass Surgery: Converting 2 Alcoholic Drinks to 4. PMID- 26244752 TI - Si/Ti2O3/Reduced Graphene Oxide Nanocomposite Anodes for Lithium-Ion Batteries with Highly Enhanced Cyclic Stability. AB - Silicon (Si) has attracted tremendous attention as a high-capacity anode material for next generation Li-ion batteries (LIBs); unfortunately, it suffers from poor cyclic stability due to excessive volume expansion and reduced electrical conductivity after repeated cycles. To circumvent these issues, we propose that Si can be complexed with electrically conductive Ti2O3 to significantly enhance the reversible capacity and cyclic stability of Si-based anodes. We prepared a ternary nanocomposite of Si/Ti2O3/reduced graphene oxide (rGO) using mechanical blending and subsequent thermal reduction of the Si, TiO2 nanoparticles, and rGO nanosheets. As a result, the obtained ternary nanocomposite exhibited a specific capacity of 985 mAh/g and a Coulombic efficiency of 98.4% after 100 cycles at a current density of 100 mA/g. Furthermore, these ternary nanocomposite anodes exhibited outstanding rate capability characteristics, even with an increased current density of 10 A/g. This excellent electrochemical performance can be ascribed to the improved electron and ion transport provided by the Ti2O3 phase within the Si domains and the structurally reinforced conductive framework comprised of the rGO nanosheets. Therefore, it is expected that our approach can also be applied to other anode materials to enable large reversible capacity, excellent cyclic stability, and good rate capability for high-performance LIBs. PMID- 26244753 TI - Corrigendum: Identification of a novel selective agonist of PPARgamma with no promotion of adipogenesis and less inhibition of osteoblastogenesis. PMID- 26244754 TI - (15)N and (1)H Solid-State NMR Investigation of a Canonical Low-Barrier Hydrogen Bond Compound: 1,8-Bis(dimethylamino)naphthalene. AB - Strong or low-barrier hydrogen bonds have often been proposed in proteins to explain enzyme catalysis and proton-transfer reactions. So far (1)H chemical shifts and scalar couplings have been used as the main NMR spectroscopic signatures for strong H-bonds. In this work, we report simultaneous measurements of (15)N and (1)H chemical shifts and N-H bond lengths by solid-state NMR in (15)N-labeled 1,8-bis(dimethylamino)naphthalene (DMAN), which contains a well known strong NHN H-bond. We complexed DMAN with three different counteranions to examine the effects of the chemical environment on the H-bond lengths and chemical shifts. All three DMAN compounds exhibit significantly elongated N-H distances compared to the covalent bond length, and the (1)H(N) chemical shifts are larger than ~17 ppm, consistent with strong NHN H-bonds in the DMAN cation. However, the (15)N and (1)H chemical shifts and the precise N-H distances differ among the three compounds, and the (15)N chemical shifts show opposite dependences on the proton localization from the general trend in organic compounds, indicating the significant effects of the counteranions on the electronic structure of the H-bond. These data provide useful NMR benchmarks for strong H-bonds and caution against the sole reliance on chemical shifts for identifying strong H-bonds in proteins since neighboring side chains can exert influences on chemical shifts similar to those of the bulky organic anions in DMAN. Instead, N-H bond lengths should be measured, in conjunction with chemical shifts, as a more fundamental parameter of H-bond strength. PMID- 26244755 TI - Lower-limb amputation and body weight changes in men. AB - Little is known about the relationship between lower-limb amputation (LLA) and subsequent changes in body weight. We conducted a retrospective cohort study using clinical and administrative databases to identify and follow weight changes in 759 males with amputation (partial foot amputation [PFA], n = 396; transtibial amputation [TTA], n = 267; and transfemoral amputation [TFA], n = 96) and 3,790 nondisabled persons frequency-matched (5:1) on age, body mass index, diabetes, and calendar year from eight Department of Veterans Affairs medical care facilities in the Pacific Northwest. We estimated and compared longitudinal percent weight change from baseline during up to 39 mo of follow-up in participants with and without amputation. Weight gain in the 2 yr after amputation was significantly more in men with an amputation than without, and in men with a TTA or TFA (8%-9% increase) than in men with a PFA (3%-6% increase). Generally, percent weight gain peaked at 2 yr and was followed by some weight loss in the third year. These findings indicate that LLA is often followed by clinically important weight gain. Future studies are needed to better understand the reasons for weight gain and to identify intervention strategies to prevent excess weight gain and the deleterious consequences that may ensue. PMID- 26244756 TI - Pathological Risk Factors and Outcomes in Women With Stage IB2 Cervical Cancer Treated With Primary Radical Surgery Versus Chemoradiotherapy. AB - OBJECTIVE: Both radical hysterectomy with pelvic lymphadenectomy and primary chemoradiotherapy have been shown to be effective in the management of women with stage IB2 cervical cancer. This study aims to review the outcomes related to each treatment modality and the effects of pathological risk factors on overall survival (OS) and disease-free survival. METHODS: We performed a retrospective study of 92 women with stage IB2 cervical cancer who were treated at the Northern Gynecological Oncology Center (Gateshead, United Kingdom) across a 22-year period between January 1991 and July 2013. Women were divided into those undergoing primary surgery and those undergoing primary radiotherapy/chemoradiotherapy. The main outcome measures were OS and progression-free survival (PFS). Pathological risk factors of survival were assessed using multivariate analysis. RESULTS: Sixty-seven women (72.8%) underwent primary surgery, and 25 women (27.2%) had primary radiotherapy/chemoradiotherapy. Thirty-one of 67 women (46.3%) required adjuvant radiotherapy/chemoradiotherapy after surgery because of positive lymph nodes in 77.4% of cases. The median follow-up was 57.5 months (range, 3-137 months). Thirty-two women (34.8%) had disease recurrence: 6 women (16.7%) in the group undergoing surgery alone, 15 women (48.4%) in the group requiring adjuvant treatment after surgery, and 11 women (44%) in the group having primary radiotherapy/chemoradiotherapy. Overall survival and PFS were higher for women undergoing surgery alone (91.7% and 83.3%) compared with women requiring adjuvant treatment after surgery (54.8% and 51.4%) and those having primary radiotherapy/chemoradiotherapy (60% and 56%) (P = 0.0004 and P = 0.005, respectively). Lymph node metastasis was a significant pathological risk factor of OS and PFS in multivariate analysis. CONCLUSIONS: Most women require adjuvant treatment after surgery because of positive lymph nodes. Because survival outcomes for women requiring dual treatment are similar to those for women undergoing primary chemoradiotherapy, nodal assessment before definitive treatment should guide the management of these women and identify a low-risk group that can be treated with surgery alone. PMID- 26244757 TI - Fischer 344 Rat: A Preclinical Model for Epithelial Ovarian Cancer Folate Targeted Therapy. AB - OBJECTIVE: Ovarian cancer prognosis remains dire after primary therapy. Recurrence rates are disappointingly high as 60% of women with advanced epithelial ovarian cancer considered in remission will develop recurrent disease within 5 years. Special attention to undetected peritoneal metastasis and residual tumorous cells during surgery is necessary as they are the main predictive factors of recurrences. Folate receptor alpha (FRalpha) shows promising prospects in targeting ovarian cancerous cells. Our aim was to determine if the Fischer model described by Rose et al could be used to evaluate folate-targeted therapies in preclinical studies. METHODS: NuTu-19 epithelial ovarian cancer cell line was used to induce peritoneal carcinomatosis in female Fischer 344 rats. FRalpha expression by NuTu-19 cells was assessed in vitro by immunofluorescence using "Cytospin(r)" protocol. In vitro folate-targeted compound uptake by NuTu-19 cells was evaluated by incubation of FRalpha-positive ovarian cancer cell lines (NuTu-19/SKOV-3/OVCAR-3/IGROV-1) with or without (control) a folate-targeted photosensitizer. Intracellular incorporation was assessed by confocal microscopy. Determination of in vivo FRalpha tissue expression by several organs of the peritoneal cavity was studied by immunohistochemistry. RESULTS: NuTu-19 cells express FRalpha which allows intracellular incorporation of folate-targeted compound by endocytosis. FRalpha is expressed in tumor tissue, ovary, and liver. Peritoneum, colon, small intestine, and kidney do not express the receptor. CONCLUSIONS: Female Fischer 344 rat is an inexpensive reproducible and efficient preclinical model to study ovarian peritoneal carcinomatosis folate-targeted therapies. PMID- 26244758 TI - A Comparison of Outcomes Following Laparoscopic and Open Hysterectomy With or Without Lymphadenectomy for Presumed Early-Stage Endometrial Cancer: Results From the Medical Research Council ASTEC Trial. AB - OBJECTIVES: Laparoscopic hysterectomy (LH) is increasingly used for the management of endometrial malignancy. Its benefits may be particularly pronounced as these women are more likely to be older or obese. The aim of this study was to determine whether outcomes for LH are comparable to the open hysterectomy (OH). DESIGN: This was a prospective cohort study nested within the multicenter ASTEC (A Study in the Treatment of Endometrial Cancer) randomized controlled trial (1998-2005). POPULATION: Women with presumed early endometrial cancer were included. METHODS: Laparoscopic hysterectomy was compared with OH with or without systematic lymphadenectomy. MAIN OUTCOME MEASURES: Overall survival, time to first recurrence, complication rates, and surgical outcomes were the main outcome measures. RESULTS: Of 1408 women, 1309 (93%) received OH, and 99 (7%) had LH. LH was associated with longer operating time (median, LH 105 minutes [interquartile range (IQR), 60-150] vs OH 80 minutes [IQR, 60-95]; P < 0.001) but 50% shorter hospital stay (median, LH 4 days [IQR, 3-5] vs OH 6 days [IQR, 5-7]). The number of harvested lymph nodes was similar (median, LH 13 [IQR, 10-16] vs OH 12 [IQR, 11-13]; P = 0.67). LH had fewer intraoperative and postoperative adverse events (9% difference, LH 21% vs OH 30%; borderline significance; P = 0.07). The rate of conversion to laparotomy for the LH group was high (27%). The median follow-up was 37 months. After adjusting for significant prognostic factors, the hazard ratio for overall survival in those who underwent LH compared with those who underwent OH was 0.67 (95% confidence interval, 0.31-1.43) (P = 0.30). CONCLUSIONS: Laparoscopic hysterectomy for early endometrial cancer is safe. Although it requires longer operating time it is associated with shorter hospital stay and favorable morbidity profile. Further studies are required to assess the long-term safety. PMID- 26244759 TI - The Paradox of Pelvic Exenteration: The Interaction of Clinical and Psychological Variables. AB - OBJECTIVES: To text the feasibility of a psychological intervention package administered to 49 pelvic exenteration candidates, aimed at evaluating the preoperative prevalence of psychological distress and assessing the presence of any correlation between preoperative psychological distress and clinical variables such as pain and hospitalization length. METHODS: Patients were referred to the psychology unit from the very beginning of their clinical pathway and were administered the Psychological Distress Inventory (PDI) and the Mini Mental Adjustment to Cancer (Mini-MAC) questionnaire at prehospital admission. Patients presenting with a significant level of distress received nonstandardized psychological support. Statistical analyses were performed to detect the presence of any correlation between psychological variables at prehospital admission and clinical outcomes. RESULTS: The 40% of patients had significant levels of distress at prehospital admission (PDI >= 30). As regards Mini-MAC, the mean value of fighting spirit attitude and fatalism was higher in our sample than in the normative sample of the Mini-MAC validation study in the Italian cancer population. Their anxious preoccupation attitude was lower. There were no correlations between clinical and psychological variables: level of postsurgery pain was higher (3.7) in the subgroup of patients with presurgery PDI < 30 compared with those with PDI >= 30 (3.5). However, this difference was not statistically significant (P = 1.00). Considering hospitalization length, the above described trend was similar. CONCLUSIONS: Although highly distressed, pelvic exenteration candidates show an adaptive range of coping mechanisms. This calls for a greater effort in studying the complexity of their psychoemotional status to provide them with the best multidisciplinary care. Extensive study of the real effectiveness of psychological intervention is warranted: randomized clinical trials could help in detecting the presence of any correlation between clinical and psychological variables in a multidisciplinary approach. PMID- 26244760 TI - Transcription Profiling of Malaria-Naive and Semi-immune Colombian Volunteers in a Plasmodium vivax Sporozoite Challenge. AB - BACKGROUND: Continued exposure to malaria-causing parasites in endemic regions of malaria induces significant levels of acquired immunity in adult individuals. A better understanding of the transcriptional basis for this acquired immunological response may provide insight into how the immune system can be boosted during vaccination, and into why infected individuals differ in symptomology. METHODOLOGY/PRINCIPAL FINDINGS: Peripheral blood gene expression profiles of 9 semi-immune volunteers from a Plasmodium vivax malaria prevalent region (Buenaventura, Colombia) were compared to those of 7 naive individuals from a region with no reported transmission of malaria (Cali, Colombia) after a controlled infection mosquito bite challenge with P. vivax. A Fluidigm nanoscale quantitative RT-PCR array was used to survey altered expression of 96 blood informative transcripts at 7 timepoints after controlled infection, and RNASeq was used to contrast pre-infection and early parasitemia timepoints. There was no evidence for transcriptional changes prior to the appearance of blood stage parasites at day 12 or 13, at which time there was a strong interferon response and, unexpectedly, down-regulation of transcripts related to inflammation and innate immunity. This differential expression was confirmed with RNASeq, which also suggested perturbations of aspects of T cell function and erythropoiesis. Despite differences in clinical symptoms between the semi-immune and malaria naive individuals, only subtle differences in their transcriptomes were observed, although 175 genes showed significantly greater induction or repression in the naive volunteers from Cali. CONCLUSION/SIGNIFICANCE: Gene expression profiling of whole blood reveals the type and duration of the immune response to P. vivax infection, and highlights a subset of genes that may mediate adaptive immunity. PMID- 26244761 TI - Novel Histone Deacetylase Class IIa Selective Substrate Radiotracers for PET Imaging of Epigenetic Regulation in the Brain. AB - Histone deacetylases (HDAC's) became increasingly important targets for therapy of various diseases, resulting in a pressing need to develop HDAC class- and isoform-selective inhibitors. Class IIa deacetylases possess only minimal deacetylase activity against acetylated histones, but have several other client proteins as substrates through which they participate in epigenetic regulation. Herein, we report the radiosyntheses of the second generation of HDAC class IIa specific radiotracers: 6-(di-fluoroacetamido)-1-hexanoicanilide (DFAHA) and 6 (tri-fluoroacetamido)-1-hexanoicanilide ([18F]-TFAHA). The selectivity of these radiotracer substrates to HDAC class IIa enzymes was assessed in vitro, in a panel of recombinant HDACs, and in vivo using PET/CT imaging in rats. [18F]TFAHA showed significantly higher selectivity for HDAC class IIa enzymes, as compared to [18F]DFAHA and previously reported [18F]FAHA. PET imaging with [18F]TFAHA can be used to visualize and quantify spatial distribution and magnitude of HDAC class IIa expression-activity in different organs and tissues in vivo. Furthermore, PET imaging with [18F]TFAHA may advance the understanding of HDACs class IIa mediated epigenetic regulation of normal and pathophysiological processes, and facilitate the development of novel HDAC class IIa-specific inhibitors for therapy of different diseases. PMID- 26244762 TI - Response to Therapeutic Plasma Exchange as a Rescue Treatment in Clinically Isolated Syndromes and Acute Worsening of Multiple Sclerosis: A Retrospective Analysis of 90 Patients. AB - OBJECTIVES: Experience with therapeutic plasma exchange (TPE) for acute relapses in clinically isolated syndrome (CIS) or multiple sclerosis (MS) patients has been derived from small and inhomogeneous patient populations so far. In the present study, we retrospectively evaluated features associated with TPE response in a larger cohort of CIS and MS patients with acute worsening of disease. PARTICIPANTS: Ninety CIS and MS patients with acute relapses or acute worsening of symptoms were firstly treated with TPE. The population consisted of 62 women and 28 men with a median age of 38 years (range 18-69 years). OUTCOME MEASURES: Primary endpoint was the clinical response to TPE, focused on the functional improvement of the target neurologic deficit. Secondary endpoint was an improvement in expanded disability status scale (EDSS) scoring. RESULTS: A clinical response to TPE was observed in 65 out of 90 patients (72.2%), with marked improvement in 18 (20.0%) and moderate improvement in 47 out of 90 patients (52.2%). The median EDSS was reduced from 3.75 before to 3.0 after TPE (p = 0.001). Response to TPE was significantly more frequent in patients with relapsing courses of disease (CIS, RR-MS, p = 0.001), no disease modifying drugs (p = 0.017), gadolinium-positive (Gd+) MRI lesions (p = 0.001) and EDSS <= 5.0 before TPE (p = 0.014). In the multiple logistic regression analysis only the detection of Gd+ MRI lesions was significantly altered (p = 0.004). CONCLUSION: Clinical response to TPE was achieved in the majority of our patients. We identified clinical and diagnostic features in CIS and MS relapses that might be helpful to identify patients responding to TPE. Gd+ MRI lesions before treatment were the best predictor of the response to TPE in our cohort. PMID- 26244763 TI - Bourdieu's Cultural Capital in Relation to Food Choices: A Systematic Review of Cultural Capital Indicators and an Empirical Proof of Concept. AB - OBJECTIVE: Unhealthy food choices follow a socioeconomic gradient that may partly be explained by one's 'cultural capital', as defined by Bourdieu. We aim 1) to carry out a systematic review to identify existing quantitative measures of cultural capital, 2) to develop a questionnaire to measure cultural capital for food choices, and 3) to empirically test associations of socioeconomic position with cultural capital and food choices, and of cultural capital with food choices. DESIGN: We systematically searched large databases for the key-word 'cultural capital' in title or abstract. Indicators of objectivised cultural capital and family institutionalised cultural capital, as identified by the review, were translated to food choice relevant indicators. For incorporated cultural capital, we used existing questionnaires that measured the concepts underlying the variety of indicators as identified by the review, i.e. participation, skills, knowledge, values. The questionnaire was empirically tested in a postal survey completed by 2,953 adults participating in the GLOBE cohort study, The Netherlands, in 2011. RESULTS: The review yielded 113 studies that fulfilled our inclusion criteria. Several indicators of family institutionalised (e.g. parents' education completed) and objectivised cultural capital (e.g. possession of books, art) were consistently used. Incorporated cultural capital was measured with a large variety of indicators (e.g. cultural participation, skills). Based on this, we developed a questionnaire to measure cultural capital in relation to food choices. An empirical test of the questionnaire showed acceptable overall internal consistency (Cronbach's alpha of .654; 56 items), and positive associations between socioeconomic position and cultural capital, and between cultural capital and healthy food choices. CONCLUSIONS: Cultural capital may be a promising determinant for (socioeconomic inequalities in) food choices. PMID- 26244764 TI - Erratum: OsTCP19 influences developmental and abiotic stress signaling by modulating ABI4-mediated pathways. PMID- 26244765 TI - MagIC, a genetically encoded fluorescent indicator for monitoring cellular Mg2+ using a non-Forster resonance energy transfer ratiometric imaging approach. AB - Intracellular Mg(2+) roles are commensurate with its abundance in the cell cytoplasm. However, little is known about Mg(2+) subcellular dynamics, primarily due to the lack of suitable Mg(2+)-selective tools to monitor this ion in intracellular compartments. To cope with this lack, we developed a Mg(2+) sensitive indicator--MagIC (indicator for Magnesium Imaging in Cell)--composed of a functionalized yellow fluorescent protein (FP) variant fused to a red-emitting FP serving as a reference, thus allowing ratiometric imaging of Mg(2+) MagIC expressed in mammalian cells is homogeneously distributed between the cytosol and nucleus but its fusion with appropriate targeting sequences redirects it to mitochondria or the endoplasmic reticulum. MagIC shows little interference by intracellular Ca(2+) [Kd (Mg(2+)) = 5.1 mM; Kd (Ca(2+)) = 4.8 mM] and its kinetic properties (k(off) = 84 s(-1)) approach those of indicator dyes. With MagIC, as reported previously, we also observed a cytosolic Mg(2+) increase provoked by application of 50 mM MgCl2 in the medium. This effect is, however, mimicked by 75 mM KCl or 150 mM D-sorbitol addition, indicating that it is a response to the associated hyperosmotic shock and not to Mg(2+) itself. Our results confirm the functionality of MagIC as a useful tool for the long-awaited possibility of prolonged and organelle-specific monitoring of cellular Mg(2+). PMID- 26244766 TI - Correcting spherical aberrations in a biospecimen using a transmissive liquid crystal device in two-photon excitation laser scanning microscopy. AB - Two-photon excitation laser scanning microscopy has enabled the visualization of deep regions in a biospecimen. However, refractive-index mismatches in the optical path cause spherical aberrations that degrade spatial resolution and the fluorescence signal, especially during observation at deeper regions. Recently, we developed transmissive liquid-crystal devices for correcting spherical aberration without changing the basic design of the optical path in a conventional laser scanning microscope. In this study, the device was inserted in front of the objective lens and supplied with the appropriate voltage according to the observation depth. First, we evaluated the device by observing fluorescent beads in single- and two-photon excitation laser scanning microscopes. Using a 25* water-immersion objective lens with a numerical aperture of 1.1 and a sample with a refractive index of 1.38, the device recovered the spatial resolution and the fluorescence signal degraded within a depth of 0.6 mm. Finally, we implemented the device for observation of a mouse brain slice in a two-photon excitation laser scanning microscope. An optical clearing reagent with a refractive index of 1.42 rendered the fixed mouse brain transparent. The device improved the spatial resolution and the yellow fluorescent protein signal within a depth of 0-0.54 mm. PMID- 26244767 TI - Heterozygous Mapping Strategy (HetMappS) for High Resolution Genotyping-By Sequencing Markers: A Case Study in Grapevine. AB - Genotyping by sequencing (GBS) provides opportunities to generate high-resolution genetic maps at a low genotyping cost, but for highly heterozygous species, missing data and heterozygote undercalling complicate the creation of GBS genetic maps. To overcome these issues, we developed a publicly available, modular approach called HetMappS, which functions independently of parental genotypes and corrects for genotyping errors associated with heterozygosity. For linkage group formation, HetMappS includes both a reference-guided synteny pipeline and a reference-independent de novo pipeline. The de novo pipeline can be utilized for under-characterized or high diversity families that lack an appropriate reference. We applied both HetMappS pipelines in five half-sib F1 families involving genetically diverse Vitis spp. Starting with at least 116,466 putative SNPs per family, the HetMappS pipelines identified 10,440 to 17,267 phased pseudo testcross (Pt) markers and generated high-confidence maps. Pt marker density exceeded crossover resolution in all cases; up to 5,560 non-redundant markers were used to generate parental maps ranging from 1,047 cM to 1,696 cM. The number of markers used was strongly correlated with family size in both de novo and synteny maps (r = 0.92 and 0.91, respectively). Comparisons between allele and tag frequencies suggested that many markers were in tandem repeats and mapped as single loci, while markers in regions of more than two repeats were removed during map curation. Both pipelines generated similar genetic maps, and genetic order was strongly correlated with the reference genome physical order in all cases. Independently created genetic maps from shared parents exhibited nearly identical results. Flower sex was mapped in three families and correctly localized to the known sex locus in all cases. The HetMappS pipeline could have wide application for genetic mapping in highly heterozygous species, and its modularity provides opportunities to adapt portions of the pipeline to other family types, genotyping technologies or applications. PMID- 26244768 TI - Detection and Characterization of Clade 1 Reassortant H5N1 Viruses Isolated from Human Cases in Vietnam during 2013. AB - Highly pathogenic avian influenza (HPAI) H5N1 is endemic in Vietnamese poultry and has caused sporadic human infection in Vietnam since 2003. Human infections with HPAI H5N1 are of concern due to a high mortality rate and the potential for the emergence of pandemic viruses with sustained human-to-human transmission. Viruses isolated from humans in southern Vietnam have been classified as clade 1 with a single genome constellation (VN3) since their earliest detection in 2003. This is consistent with detection of this clade/genotype in poultry viruses endemic to the Mekong River Delta and surrounding regions. Comparison of H5N1 viruses detected in humans from southern Vietnamese provinces during 2012 and 2013 revealed the emergence of a 2013 reassortant virus with clade 1.1.2 hemagglutinin (HA) and neuraminidase (NA) surface protein genes but internal genes derived from clade 2.3.2.1a viruses (A/Hubei/1/2010-like; VN12). Closer analysis revealed mutations in multiple genes of this novel genotype (referred to as VN49) previously associated with increased virulence in animal models and other markers of adaptation to mammalian hosts. Despite the changes identified between the 2012 and 2013 genotypes analyzed, their virulence in a ferret model was similar. Antigenically, the 2013 viruses were less cross-reactive with ferret antiserum produced to the clade 1 progenitor virus, A/Vietnam/1203/2004, but reacted with antiserum produced against a new clade 1.1.2 WHO candidate vaccine virus (A/Cambodia/W0526301/2012) with comparable hemagglutination inhibition titers as the homologous antigen. Together, these results indicate changes to both surface and internal protein genes of H5N1 viruses circulating in southern Vietnam compared to 2012 and earlier viruses. PMID- 26244769 TI - Thuniopsis: A New Orchid Genus and Phylogeny of the Tribe Arethuseae (Orchidaceae). AB - An investigation of a questionable orchid led to the discovery of a new genus and species Thuniopsis cleistogama, endemic to Yunnan province, China. It is characterized by having a subglobose corm, a spike-like (racemose) inflorescence, half opened and spurless flowers, a collar-shaped stigma and subglobose capsules. Based on DNA sequence data from three gene regions (nuclear ribosomal ITS, chloroplast matK and trnL), we investigated its phylogenetic position within the tribe Arethuseae. Phylogenies using maximum likelihood and Bayesian inference support the recognition of Thuniopsis as a distinct genus, and suggest its close relationship to the genera Bletilla, Dilochia, and Thunia. The new genus is circumscribed and a description and illustrations of the new species are provided. The phylogenetic relationships among the genera in Arethuseae are accessed. Moreover, our phylogeny also shed light on the phylogenetic positions of several genera which, to date, remain uncertain. PMID- 26244771 TI - Role of GxxxG Motifs in Transmembrane Domain Interactions. AB - Transmembrane (TM) helices of integral membrane proteins can facilitate strong and specific noncovalent protein-protein interactions. Mutagenesis and structural analyses have revealed numerous examples in which the interaction between TM helices of single-pass membrane proteins is dependent on a GxxxG or (small)xxx(small) motif. It is therefore tempting to use the presence of these simple motifs as an indicator of TM helix interactions. In this Current Topic review, we point out that these motifs are quite common, with more than 50% of single-pass TM domains containing a (small)xxx(small) motif. However, the actual interaction strength of motif-containing helices depends strongly on sequence context and membrane properties. In addition, recent studies have revealed several GxxxG-containing TM domains that interact via alternative interfaces involving hydrophobic, polar, aromatic, or even ionizable residues that do not form recognizable motifs. In multipass membrane proteins, GxxxG motifs can be important for protein folding, and not just oligomerization. Our current knowledge thus suggests that the presence of a GxxxG motif alone is a weak predictor of protein dimerization in the membrane. PMID- 26244770 TI - An Origin of Cooperative Oxygen Binding of Human Adult Hemoglobin: Different Roles of the alpha and beta Subunits in the alpha2beta2 Tetramer. AB - Human hemoglobin (Hb), which is an alpha2beta2 tetramer and binds four O2 molecules, changes its O2-affinity from low to high as an increase of bound O2, that is characterized by 'cooperativity'. This property is indispensable for its function of O2 transfer from a lung to tissues and is accounted for in terms of T/R quaternary structure change, assuming the presence of a strain on the Fe histidine (His) bond in the T state caused by the formation of hydrogen bonds at the subunit interfaces. However, the difference between the alpha and beta subunits has been neglected. To investigate the different roles of the Fe-His(F8) bonds in the alpha and beta subunits, we investigated cavity mutant Hbs in which the Fe-His(F8) in either alpha or beta subunits was replaced by Fe-imidazole and F8-glycine. Thus, in cavity mutant Hbs, the movement of Fe upon O2-binding is detached from the movement of the F-helix, which is supposed to play a role of communication. Recombinant Hb (rHb)(alphaH87G), in which only the Fe-His in the alpha subunits is replaced by Fe-imidazole, showed a biphasic O2-binding with no cooperativity, indicating the coexistence of two independent hemes with different O2-affinities. In contrast, rHb(betaH92G), in which only the Fe-His in the beta subunits is replaced by Fe-imidazole, gave a simple high-affinity O2-binding curve with no cooperativity. Resonance Raman, 1H NMR, and near-UV circular dichroism measurements revealed that the quaternary structure change did not occur upon O2-binding to rHb(alphaH87G), but it did partially occur with O2 binding to rHb(betaH92G). The quaternary structure of rHb(alphaH87G) appears to be frozen in T while its tertiary structure is changeable. Thus, the absence of the Fe-His bond in the alpha subunit inhibits the T to R quaternary structure change upon O2-binding, but its absence in the beta subunit simply enhances the O2-affinity of alpha subunit. PMID- 26244772 TI - Solution, Solid, and Gas Phase Studies on a Nickel Dithiolene System: Spectator Metal and Reactor Ligand. AB - The syntheses of cationic nickel complexes using N,N'-dimethyl piperazine 2,3 dithione (Me2Dt(0)) and N,N'-diisopropyl piperazine 2,3-dithione ((i)Pr2Dt(0)) ligands are reported. These ligands were used in synthesizing bis and tris(dithione)Ni(II) complexes as tetrafluoroborate or hexafluorophosphate salts, i.e., [Ni((i)Pr2Dt(0))2][BF4]2 ([1a][BF4]2), [Ni((i)Pr2Dt(0))2][PF6]2 ([1a][PF6]2), [Ni(Me2Dt(0))2][BF4]2 ([1b][BF4]2), [Ni((i)Pr2Dt(0))3][BF4]2 ([2a][BF4]2), and [Ni((i)Pr2Dt(0))3][PF6]2 ([2a][PF6]2), respectively. Complex [2a][PF6]2 was isolated from a methanolic solution of [1a][PF6]2. Compound [1a][BF4]2 crystallizes in a trigonal crystal system (space group, P31/c) and exhibits unique packing features, whereas [2a][BF4]2 crystallizes in a monoclinic (P21/n) space group. Cyclic voltammograms of [1a][BF4]2 and [1b][BF4]2 are indicative of four reduction processes associated with stepwise single-electron reduction of the ligands. Spectroelectrochemical experiments on [1a][BF4]2 exhibit an intervalence charge transfer (IVCT) transition as a spectroscopic signature of the mixed-valence [Ni((i)Pr2Dt(0))((i)Pr2Dt(1-))](-) species. Analysis of this IVCT band suggests that this ligand based mixed valence complex, [Ni((i)Pr2Dt(0))((i)Pr2Dt(1-))](-), behaves more like a traditional class II/III metal based mixed-valence complex. The density functional theory (DFT) and time dependent DFT calculations provide a theoretical framework for understanding the electronic structures and the nature of excited states of the target compounds that are consistent with their spectroscopic and redox properties. Vibrational spectra of [1a](2+) and [2a](2+) were investigated as discrete species in the gas phase using infrared multiple photon dissociation (IRMPD) spectroscopy. PMID- 26244773 TI - Review of the 2012 Epizootic Hemorrhagic Disease Outbreak in Domestic Ruminants in the United States. AB - An unusually large number of cases of Epizootic hemorrhagic disease (EHD) were observed in United States cattle and white-tailed deer in the summer and fall of 2012. USDA APHIS Veterinary Services area offices were asked to report on foreign animal disease investigations and state diagnostic laboratory submissions which resulted in a diagnosis of EHD based on positive PCR results. EHD was reported in the following species: cattle (129 herds), captive white-tailed deer (65 herds), bison (8 herds), yak (6 herds), elk (1 herd), and sheep (1 flock). A majority of the cases in cattle and bison were found in Nebraska, South Dakota, and Iowa. The majority of cases in captive white-tailed deer were found in Ohio, Iowa, Michigan, and Missouri. The most common clinical sign observed in the cattle and bison herds was oral lesions. The major observation in captive white-tailed deer herds was death. Average within-herd morbidity was 7% in cattle and bison herds, and 46% in captive white-tailed deer herds. The average within-herd mortality in captive white-tailed deer herds was 42%. PMID- 26244774 TI - Socioeconomic Status, Sex, Age and Access to Medications for COPD in Ontario, Canada. AB - Disparities in COPD health outcomes have been found with older individuals, men and those of lower socioeconomic status doing worse. We sought to determine if this was due to differences in access to COPD medications. We conducted a retrospective cohort study using population health administrative data from Ontario, Canada, a province with universal prescription drug coverage for older adults. All individuals with COPD aged 67 years and older in 2008 who were not taking inhaled long-acting bronchodilators or inhaled corticosteroids were followed for 2 years. Poisson regression was used to determine the effects of age, sex, and socioeconomic status on the likelihood of initiating one of these medications, after adjusting for potential confounders. Over the study period, 54,050 of 185,698 (29.1%) older individuals with COPD not previously taking any inhaled long-acting bronchodilators or corticosteroids were initiated on one or more of these medications. After adjustment, individuals of low socioeconomic status, measured using neighborhood income level quintiles, were slightly more likely to initiate COPD medications than those of high socioeconomic status (relative risk (RR) 1.05; 95% confidence interval (95% CI) 1.02-1.08). While men received COPD medication at a consistent rate across all age groups, the likelihood that a woman received medication decreased with increasing age. With the exception of older women, there was minimal disparity in prescription for COPD medications. Disparity in health outcomes among Ontario COPD patients is not clearly explained by differences in medication access by socioeconomic status, sex or age. PMID- 26244775 TI - Correction: High Inter-Individual Diversity of Point Mutations, Insertions, and Deletions in Human Influenza Virus Nucleoprotein-Specific Memory B Cells. PMID- 26244776 TI - Men's Sexual Faithfulness Judgments May Contain a Kernel of Truth. AB - Mechanisms enabling men to identify women likely to engage in extra-pair copulations (EPCs) would be advantageous in avoiding cuckoldry. Men's judgments of female sexual faithfulness often show high consensus, but accuracy appears poor. We examined whether accuracy of these judgments made to images of women could be improved through i) employing a forced choice task, in which men were asked to select the more faithful of two women and/or ii) providing men with full person images. In Experiment 1, men rated 34 women, for whom we had self-reported EPC behavior, on faithfulness, trustworthiness or attractiveness from either face or full person photographs. They then completed a forced choice task, selecting the more faithful of two woman from 17 pairs of images, each containing one woman who had reported no EPCs and one who had reported two or more EPCs. Men were unable to rate faithfulness with any accuracy, replicating previous findings. However, when asked to choose the more faithful of two women, they performed significantly above chance, although the ability to judge faithfulness at above chance levels did not generalize to all pairs of women. Although there was no significant difference in accuracy for face and full person image pairs, only judgments from faces were significantly above chance. In Experiment 2, we showed that this accuracy for faces was repeatable in a new sample of men. We also showed that individual variation in accuracy was unrelated to variation in preferences for faithfulness in a long-term partner. Overall, these results show that men's judgments of faithfulness made from faces of unfamiliar women may contain a kernel of truth. PMID- 26244777 TI - Swelling Mechanisms of UO2 Lattices with Defect Ingrowths. AB - The swelling that occurs in uranium dioxide as a result of radiation-induced defect ingrowth is not fully understood. Experimental and theoretical groups have attempted to explain this phenomenon with various complex theories. In this study, experimental lattice expansion and lattice super saturation were accurately reproduced using a molecular dynamics simulation method. Based on their resemblance to experimental data, the simulation results presented here show that fission induces only oxygen Frenkel pairs while alpha particle irradiation results in both oxygen and uranium Frenkel pair defects. Moreover, in this work, defects are divided into two sub-groups, obstruction type defects and distortion type defects. It is shown that obstruction type Frenkel pairs are responsible for both fission- and alpha-particle-induced lattice swelling. Relative lattice expansion was found to vary linearly with the number of obstruction type uranium Frenkel defects. Additionally, at high concentrations, some of the obstruction type uranium Frenkel pairs formed diatomic and triatomic structures with oxygen ions in their octahedral cages, increasing the slope of the linear dependence. PMID- 26244778 TI - Cooperative Emissions Trading Game: International Permit Market Dominated by Buyers. AB - Rapid reduction of anthropogenic greenhouse gas emissions is required to mitigate disastrous impacts of climate change. The Kyoto Protocol introduced international emissions trading (IET) to accelerate the reduction of carbon dioxide (CO2) emissions. The IET controls CO2 emissions through the allocation of marketable emission permits to sovereign countries. The costs for acquiring additional permits provide buyers with an incentive to reduce their CO2 emissions. However, permit price has declined to a low level during the first commitment period (CP1). The downward trend in permit price is attributed to deficiencies of the Kyoto Protocol: weak compliance enforcement, the generous allocation of permits to transition economies (hot air), and the withdrawal of the US. These deficiencies created a buyer's market dominated by price-making buyers. In this paper, I develop a coalitional game of the IET, and demonstrate that permit buyers have dominant bargaining power. In my model, called cooperative emissions trading (CET) game, a buyer purchases permits from sellers only if the buyer forms a coalition with the sellers. Permit price is determined by bargaining among the coalition members. I evaluated the demand-side and supply-side bargaining power (DBP and SBP) using Shapley value, and obtained the following results: (1) Permit price is given by the product of the buyer's willingness-to pay and the SBP (= 1 - DBP). (2) The DBP is greater than or equal to the SBP. These results indicate that buyers can suppress permit price to low levels through bargaining. The deficiencies of the Kyoto Protocol enhance the DBP, and contribute to the demand-side dominance in the international permit market. PMID- 26244779 TI - I Like, I Cite? Do Facebook Likes Predict the Impact of Scientific Work? AB - Due to the increasing amount of scientific work and the typical delays in publication, promptly assessing the impact of scholarly work is a huge challenge. To meet this challenge, one solution may be to create and discover innovative indicators. The goal of this paper is to investigate whether Facebook likes for unpublished manuscripts that are uploaded to the Internet could be used as an early indicator of the future impact of the scientific work. To address our research question, we compared Facebook likes for manuscripts uploaded to the Harvard Business School website (Study 1) and the bioRxiv website (Study 2) with traditional impact indicators (journal article citations, Impact Factor, Immediacy Index) for those manuscripts that have been published as a journal article. Although based on our full sample of Study 1 (N = 170), Facebook likes do not predict traditional impact indicators, for manuscripts with one or more Facebook likes (n = 95), our results indicate that the more Facebook likes a manuscript receives, the more journal article citations the manuscript receives. In additional analyses (for which we categorized the manuscripts as psychological and non-psychological manuscripts), we found that the significant prediction of citations stems from the psychological and not the non-psychological manuscripts. In Study 2, we observed that Facebook likes (N = 270) and non-zero Facebook likes (n = 84) do not predict traditional impact indicators. Taken together, our findings indicate an interdisciplinary difference in the predictive value of Facebook likes, according to which Facebook likes only predict citations in the psychological area but not in the non-psychological area of business or in the field of life sciences. Our paper contributes to understanding the possibilities and limits of the use of social media indicators as potential early indicators of the impact of scientific work. PMID- 26244780 TI - Social-class indicators differentially predict engagement in prevention vs. detection behaviours. AB - OBJECTIVE: Few systematic studies have examined the contexts in which social class variables will predict engagement in health-relevant behaviours. The current research examined whether the impact of social-class on health behaviours depends upon how social-class is assessed and the category of health behaviour under consideration. METHOD: Our sample was drawn from the Health Information National Trends Survey in 2012 (N = 3959). Participants reported their income and education as well as their engagement in a variety of prevention and detection behaviours. RESULTS: Consistent with our hypothesised framework, we found that income predicted engagement in a variety of detection behaviours above and beyond education, whereas education predicted engagement in a variety of prevention behaviours above and beyond income. CONCLUSIONS: Our findings suggest that income and education operate on health behaviours via different pathways and have implications for public health policy and intervention. PMID- 26244781 TI - Neuronal Correlates of Cognitive Control during Gaming Revealed by Near-Infrared Spectroscopy. AB - In everyday life we quickly build and maintain associations between stimuli and behavioral responses. This is governed by rules of varying complexity and past studies have identified an underlying fronto-parietal network involved in cognitive control processes. However, there is only limited knowledge about the neuronal activations during more natural settings like game playing. We thus assessed whether near-infrared spectroscopy recordings can reflect different demands on cognitive control during a simple game playing task. Sixteen healthy participants had to catch falling objects by pressing computer keys. These objects either fell randomly (RANDOM task), according to a known stimulus response mapping applied by players (APPLY task) or according to a stimulus response mapping that had to be learned (LEARN task). We found an increased change of oxygenated and deoxygenated hemoglobin during LEARN covering broad areas over right frontal, central and parietal cortex. Opposed to this, hemoglobin changes were less pronounced for RANDOM and APPLY. Along with the findings that fewer objects were caught during LEARN but stimulus-response mappings were successfully identified, we attribute the higher activations to an increased cognitive load when extracting an unknown mapping. This study therefore demonstrates a neuronal marker of cognitive control during gaming revealed by near-infrared spectroscopy recordings. PMID- 26244782 TI - Wolbachia Infection in a Natural Parasitoid Wasp Population. AB - The maternally transmitted bacterium Wolbachia pipientis is well known for spreading and persisting in insect populations through manipulation of the fitness of its host. Here, we identify three new Wolbachia pipientis strains, wHho, wHho2 and wHho3, infecting Hyposoter horticola, a specialist wasp parasitoid of the Glanville fritillary butterfly. The wHho strain (ST435) infects about 50% of the individuals in the Aland islands in Finland, with a different infection rate in the two mitochondrial (COI) haplotypes of the wasp. The vertical transmission rate of Wolbachia is imperfect, and lower in the haplotype with lower infection rate, suggesting a fitness trade-off. We found no association of the wHho infection with fecundity, longevity or dispersal ability of the parasitoid host. However, preliminary results convey spatial associations between Wolbachia infection, host mitochondrial haplotype and parasitism of H. horticola by its hyperparasitoid, Mesochorus cf. stigmaticus. We discuss the possibility that Wolbachia infection protects H. horticola against hyperparasitism. PMID- 26244783 TI - Spatial and Temporal Control of Hyperthermia Using Real Time Ultrasonic Thermal Strain Imaging with Motion Compensation, Phantom Study. AB - Mild hyperthermia has been successfully employed to induce reversible physiological changes that can directly treat cancer and enhance local drug delivery. In this approach, temperature monitoring is essential to avoid undesirable biological effects that result from thermal damage. For thermal therapies, Magnetic Resonance Imaging (MRI) has been employed to control real time Focused Ultrasound (FUS) therapies. However, combined ultrasound imaging and therapy systems offer the benefits of simple, low-cost devices that can be broadly applied. To facilitate such technology, ultrasound thermometry has potential to reliably monitor temperature. Control of mild hyperthermia was previously achieved using a proportional-integral-derivative (PID) controller based on thermocouple measurements. Despite accurate temporal control of heating, this method is limited by the single position at which the temperature is measured. Ultrasound thermometry techniques based on exploiting the thermal dependence of acoustic parameters (such as longitudinal velocity) can be extended to create thermal maps and allow an accurate monitoring of temperature with good spatial resolution. However, in vivo applications of this technique have not been fully developed due to the high sensitivity to tissue motion. Here, we propose a motion compensation method based on the acquisition of multiple reference frames prior to treatment. The technique was tested in the presence of 2-D and 3-D physiological-scale motion and was found to provide effective real-time temperature monitoring. PID control of mild hyperthermia in presence of motion was then tested with ultrasound thermometry as feedback and temperature was maintained within 0.3 degrees C of the requested value. PMID- 26244784 TI - A New Late Miocene Odobenid (Mammalia: Carnivora) from Hokkaido, Japan Suggests Rapid Diversification of Basal Miocene Odobenids. AB - The modern walrus, Odobenus rosmarus, is specialized and only extant member of the family Odobenidae. They were much more diversified in the past, and at least 16 genera and 20 species of fossil walruses have been known. Although their diversity increased in the late Miocene and Pliocene (around 8-2 Million years ago), older records are poorly known. A new genus and species of archaic odobenid, Archaeodobenus akamatsui, gen. et sp. nov. from the late Miocene (ca. 10.0-9.5 Ma) top of the Ichibangawa Formation, Hokkaido, northern Japan, suggests rapid diversification of basal Miocene walruses. Archaeodobenus akamatsui is the contemporaneous Pseudotaria muramotoi from the same formation, but they are distinguishable from each other in size and shape of the occipital condyle, foramen magnum and mastoid process of the cranium, and other postcranial features. Based on our phylogenetic analysis, A. akamatsui might have split from P. muramotoi at the late Miocene in the western North Pacific. This rapid diversification of the archaic odobenids occurred with a combination of marine regression and transgression, which provided geological isolation among the common ancestors of extinct odobenids. PMID- 26244786 TI - Limited effects of care management for high utilizers on total healthcare costs. PMID- 26244785 TI - Comparative Metabolomic and Lipidomic Analysis of Phenotype Stratified Prostate Cells. AB - Prostate cancer (PCa) is the most prevalent cancer amongst men and the second most common cause of cancer related-deaths in the USA. Prostate cancer is a heterogeneous disease ranging from indolent asymptomatic cases to very aggressive life threatening forms. The goal of this study was to identify differentially expressed metabolites and lipids in prostate cells with different tumorigenic phenotypes. We have used mass spectrometry metabolomic profiling, lipidomic profiling, bioinformatic and statistical methods to identify, quantify and characterize differentially regulated molecules in five prostate derived cell lines. We have identified potentially interesting species of different lipid subclasses including phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), glycerophosphoinositols (PIs) and other metabolites that are significantly upregulated in prostate cancer cells derived from distant metastatic sites. Transcriptomic and biochemical analysis of key enzymes that are involved in lipid metabolism demonstrate the significant upregulation of choline kinase alpha in the metastatic cells compared to the non-malignant and non-metastatic cells. This suggests that different de novo lipogenesis and other specific signal transduction pathways are activated in aggressive metastatic cells as compared to normal and non-metastatic cells. PMID- 26244787 TI - Self-efficacy in insurance decision making among older adults. AB - OBJECTIVES: The aim was to understand older adults' self-efficacy with insurance decision making by examining their preferences for delegating insurance decisions to others. STUDY DESIGN: Cross-sectional analysis of data from an observational cohort study. METHODS: English- and Spanish-speaking adults aged >=60 years were recruited and interviewed in residential and senior center locations in New York City neighborhoods with median annual household incomes<$50,000. The analyses included the subset of individuals 65 years and older and without Medicaid. Self efficacy in insurance decision making was measured with a 7-item assessment of perceived understanding of Medicare, preferences for decision support, and decision-making anxiety. We used multivariable linear regression to examine the association of self-efficacy with subject characteristics, including sociodemographics, insurance coverage, and health and functional status. RESULTS: Among the 250 subjects, 55% were aged >=75 years, 29% were black, and 33% were Hispanic. Half (53%) reported difficulty understanding insurance information and concern (45%) about making wrong insurance choices, yet 89% preferred to make decisions themselves. In adjusted analysis, greater decision-making self-efficacy was associated with male gender (P=.02), higher educational attainment (P=.04), better health (P=.0003), greater Medicare knowledge (P=.0002), and lack of a spouse or partner (P=.04) or any person who they trust to assist with decision making (P<.0001). CONCLUSIONS: Most older adults preferred to make insurance decisions themselves while also wanting to receive advice, and those who preferred to delegate decisions had less Medicare knowledge. Programs that support insurance decisions among older adults should identify clients who prefer delegating decisions and have the right support available to them. PMID- 26244788 TI - Costs of venous thromboembolism associated with hospitalization for medical illness. AB - OBJECTIVES: To determine population-based estimates of medical costs attributable to venous thromboembolism (VTE) among patients currently or recently hospitalized for acute medical illness. STUDY DESIGN: Population-based cohort study conducted in Olmsted County, Minnesota. METHODS: Using Rochester Epidemiology Project (REP) resources, we identified all Olmsted County residents with objectively diagnosed incident VTE during or within 92 days of hospitalization for acute medical illness over the 18-year period of 1988 to 2005 (n=286). One Olmsted County resident hospitalized for medical illness without VTE was matched to each case for event date (+/-1 year), duration of prior medical history, and active cancer status. Subjects were followed forward in REP provider-linked billing data for standardized, inflation-adjusted direct medical costs (excluding outpatient pharmaceutical costs) from 1 year before their respective event or index date to the earliest of death, emigration from Olmsted County, or December 31, 2011 (study end date). We censored follow-up such that each case and matched control had similar periods of observation. We used generalized linear modeling (controlling for age, sex, preexisting conditions, and costs 1 year before index) to predict costs for cases and controls. RESULTS: Adjusted mean predicted costs were 2.5-fold higher for cases ($62,838) than for controls ($24,464) (P<.001) from index to up to 5 years post index. Cost differences between cases and controls were greatest within the first 3 months after the event date (mean difference=$16,897) but costs remained significantly higher for cases compared with controls for up to 3 years. CONCLUSIONS: VTE during or after recent hospitalization for medical illness contributes a substantial economic burden. PMID- 26244789 TI - Elderly veterans with dual eligibility for VA and Medicare services: where do they obtain a colonoscopy? AB - OBJECTIVES: To examine the receipt of colonoscopy through the Veterans Health Administration (VA) or through Medicare by older veterans who are dually enrolled. STUDY DESIGN: Retrospective cohort study. METHODS: The VA Outpatient Care Files and Medicare Enrollment Files were used to identify 1,060,523 patients 65 years and older in 15 of the 22 Veterans Integrated Service Networks nationally, who had 2 or more VA primary care visits in 2009 and who were simultaneously enrolled in Medicare. VA and Medicare files were used to identify the receipt of an outpatient colonoscopy. Patients were categorized as receiving care in community-based outpatient clinics (CBOCs) (n=601,337; 57%) or VA medical centers (n=459,186; 43%) based on where most patient-centered encounters occurred. Analyses used multinomial logistic regression to identify patient characteristics related to the odds of receiving a colonoscopy at the VA or through Medicare. RESULTS: Patients had a mean age of 76.9 (SD=7.0) years; 98% were male, 89% were white, and 21% resided in a rural location. Overall, 100,060 (9.4%) patients underwent outpatient colonoscopy either through the VA (n=33,600; 35.5%) or Medicare providers (n=65,716; 65.5%). The adjusted odds of receiving a colonoscopy from Medicare providers were higher (P<.001) for patients who were male, white, receiving primary care at CBOCs, and for residents of an urban location. The receipt of colonoscopy through the VA decreased dramatically by age; for example, the odds of colonoscopy by the VA in patients aged >85 years and 80 to 84 years, relative to patients aged 65 to 69 years, were 0.26 and 0.13, respectively. In contrast, the receipt of colonoscopy through Medicare did not decline as markedly with age. CONCLUSIONS: In a national analysis of the receipt of an outpatient colonoscopy by older veterans, more veterans received their colonoscopies through CMS than through the VA. The use of colonoscopy within the VA was found to be more concordant with age-related practice guidelines. PMID- 26244790 TI - Binary measures for associating medication adherence and healthcare spending. PMID- 26244791 TI - Observation encounters and subsequent nursing facility stays. AB - BACKGROUND: Medicare coverage of skilled nursing facility (SNF) care requires that beneficiaries have a 3-night inpatient stay in the prior 30 days to be eligible. Time spent by beneficiaries receiving hospital-based observation services does not count toward this requirement. OBJECTIVES: To examine the frequency of Medicare beneficiary discharge from hospital-based observation services to SNFs and its impact on Medicare coverage. STUDY DESIGN: Retrospective cohort study. RESULTS: In 2010, 195,068 community-dwelling beneficiaries received hospital-based observation services. Beneficiaries were overwhelmingly (96.5%) discharged back to the community without home health services. Only 1.2% (2319) were discharged to non-covered SNFs, while 0.6% (1196) were discharged to covered SNFs. Patients discharged to SNFs experienced longer lengths of stay (LOS) than those discharged back to the community (34.9 hours vs 25.5 hours; P<.01). Approximately one-fourth of beneficiaries discharged to SNFs had an observation LOS of 48 hours or more. CONCLUSIONS: While only a small minority of community dwelling Medicare beneficiaries who received hospital-based observation services in 2010 were discharged to an SNF not covered by Medicare, the implications for these patients and the associated costs deserve attention. These findings have important implications for Medicare's observation service and 2-midnight policies. PMID- 26244792 TI - Functional status and readmissions in unilateral hip fractures. AB - OBJECTIVES: To test whether functional status is a robust predictor of acute care readmission risk in patients who have been discharged to an inpatient rehabilitation facility (IRF) following a unilateral hip fracture. STUDY DESIGN: Retrospective database study using a large administrative data set. METHODS: A retrospective analysis of data from the Uniform Data System for Medical Rehabilitation from the years 2002 to 2011 was performed, examining patients with an impairment of unilateral hip fracture. A basic prediction model based on functional status was compared with competing models incorporating medical comorbidities. C statistics were compared to evaluate model performance. RESULTS: There were a total of 433,154 patients: 32,783 (7.87%) patients were transferred back to an acute hospital, including 7937 (1.91%) transferred within 3 days, 16,150 (3.88%) transferred within 7 days, and 32,607 (7.83%) transferred within 30 days after IRF admission. The C statistics for the Basic Model are 0.710, 0.674, and 0.667 at days 3, 7, and 30, respectively. Compared with the Basic Model, the best performing Basic-Plus model was the Basic+Elixhauser Model with C statistic differences of +0.013, +0.014, and +0.019, and the best performing Age Comorbidity Model was the Age+Elixhauser Model with C statistic differences of 0.110, -0.079, and -0.065 at days 3, 7, and 30, respectively. CONCLUSIONS: Functional status is a robust and potentially modifiable risk factor for patients admitted to IRFs following a unilateral hip fracture. PMID- 26244793 TI - Structural Characterization of Melanin Pigments from Commercial Preparations of the Edible Mushroom Auricularia auricula. AB - Many of the most widely consumed edible mushrooms are pigmented, and these have been associated with some beneficial health effects. Nevertheless, the majority of the reported compounds associated with these desirable properties are non pigmented. We have previously reported that melanin pigment from the edible mushroom Auricularia auricula can protect mice against ionizing radiation, although no physicochemical characterization was reported. Consequently, in this study we have characterized commercial A. auricula mushroom preparations for melanin content and carried out structural characterization of isolated insoluble melanin materials using a panel of sophisticated spectroscopic and physical/imaging techniques. Our results show that approximately 10% of the dry mass of A. auricula is melanin and that the pigment has physicochemical properties consistent with those of eumelanins, including hosting a stable free radical population. Electron microscopy studies show that melanin is associated with the mushroom cell wall in a manner similar to that of melanin from the model fungus C. neoformans. Elemental analysis of melanin indicated C, H, and N ratios consistent with 5,6-dihydroxyindole-2-carboxylic acid/5,6-dihydroxyindole and 1,8 dihydroxynaphthalene eumelanin. Validation of the identity of the isolated product as melanin was achieved by EPR analysis. A. auricula melanin manifested structural differences, relative to the C. neoformans melanin, with regard to the variable proportions of alkyl chains or oxygenated carbons. Given the necessity for new oral and inexpensive radioprotective materials coupled with the commercial availability of A. auricula mushrooms, this product may represent an excellent source of edible melanin. PMID- 26244794 TI - A fiber-optic sorbitol biosensor based on NADH fluorescence detection toward rapid diagnosis of diabetic complications. AB - Accumulation of sorbitol in the tissue is known to cause microvascular diabetic complications. In this paper, a fiber-optic biosensor for sorbitol which is used as a biomarker of diabetic complications was developed and tested. The biosensor used a sorbitol dehydrogenase from microorganisms of the genus Flavimonas with high substrate specificity and detected the fluorescence of reduced nicotinamide adenine dinucleotide (NADH) by the enzymatic reaction. An ultraviolet light emitting diode (UV-LED) was used as the excitation light source of NADH. The fluorescence of NADH was detected using a spectrometer or a photomultiplier tube (PMT). The UV-LED and the photodetector were coupled using a Y-shaped optical fiber. In the experiment, an optical fiber probe with a sorbitol dehydrogenase immobilized membrane was placed in a cuvette filled with a phosphate buffer containing the oxidized form of nicotinamide adenine dinucleotide (NAD(+)). The changes in NADH fluorescence intensity were measured after adding a standard sorbitol solution. According to the experimental assessment, the calibration range of the sorbitol biosensor systems using a spectrometer and a PMT was 5.0 1000 MUmol L(-1) and 1.0-1000 MUmol L(-1), respectively. The sorbitol biosensor system using the sorbitol dehydrogenase from microorganisms of the genus Flavimonas has high selectivity and sensitivity compared with that from sheep liver. The sorbitol biosensor allows for point-of-care testing applications or daily health care tests for diabetes patients. PMID- 26244795 TI - External Quality Assessment for the Detection of Measles Virus by Reverse Transcription-PCR Using Armored RNA. AB - In recent years, nucleic acid tests for detection of measles virus RNA have been widely applied in laboratories belonging to the measles surveillance system of China. An external quality assessment program was established by the National Center for Clinical Laboratories to evaluate the performance of nucleic acid tests for measles virus. The external quality assessment panel, which consisted of 10 specimens, was prepared using armored RNAs, complex of noninfectious MS2 bacteriophage coat proteins encapsulated RNA of measles virus, as measles virus surrogate controls. Conserved sequences amplified from a circulating measles virus strain or from a vaccine strain were encapsulated into these armored RNAs. Forty-one participating laboratories from 15 provinces, municipalities, or autonomous regions that currently conduct molecular detection of measles virus enrolled in the external quality assessment program, including 40 measles surveillance system laboratories and one diagnostic reagent manufacturer. Forty laboratories used commercial reverse transcription-quantitative PCR kits, with only one laboratory applying a conventional PCR method developed in-house. The results indicated that most of the participants (38/41, 92.7%) were able to accurately detect the panel with 100% sensitivity and 100% specificity. Although a wide range of commercially available kits for nucleic acid extraction and reverse transcription polymerase chain reaction were used by the participants, only two false-negative results and one false-positive result were generated; these were generated by three separate laboratories. Both false-negative results were obtained with tests performed on specimens with the lowest concentration (1.2 * 104 genomic equivalents/mL). In addition, all 18 participants from Beijing achieved 100% sensitivity and 100% specificity. Overall, we conclude that the majority of the laboratories evaluated have reliable diagnostic capacities for the detection of measles virus. PMID- 26244797 TI - Science and Engineering Ph.D. Students' Career Outcomes, by Gender. AB - We examine differences in the careers of men and women Ph.D.s from two major European universities. Having performed regression analysis, we find that women are more likely than men to be employed in public administration when the alternatives are either academia or industry. Between the latter two alternatives, women are more likely to be employed in academia. These gender differences persist after accounting for Ph.D.s' and their supervisors' characteristics. Gender gaps are smaller for Ph.D.s with large research outputs and for those who conducted applied research. Restricting the analysis to Ph.D.s who pursued postdoc training, women are less likely than men to be employed in highly ranked universities, even after controlling for their research outputs. Finally, we find gender differences in Ph.D.s' appointment to professorship, which are explained by the Ph.D.s' publication output and the quality of their postdoc training. PMID- 26244798 TI - [New realities engender thoughts on the departure of the co-editor of "Pflege"]. PMID- 26244796 TI - Genome-Wide Mapping and Interrogation of the Nmp4 Antianabolic Bone Axis. AB - PTH is an osteoanabolic for treating osteoporosis but its potency wanes. Disabling the transcription factor nuclear matrix protein 4 (Nmp4) in healthy, ovary-intact mice enhances bone response to PTH and bone morphogenetic protein 2 and protects from unloading-induced osteopenia. These Nmp4(-/-) mice exhibit expanded bone marrow populations of osteoprogenitors and supporting CD8(+) T cells. To determine whether the Nmp4(-/-) phenotype persists in an osteoporosis model we compared PTH response in ovariectomized (ovx) wild-type (WT) and Nmp4(-/ ) mice. To identify potential Nmp4 target genes, we performed bioinformatic/pathway profiling on Nmp4 chromatin immunoprecipitation sequencing (ChIP-seq) data. Mice (12 w) were ovx or sham operated 4 weeks before the initiation of PTH therapy. Skeletal phenotype analysis included microcomputed tomography, histomorphometry, serum profiles, fluorescence-activated cell sorting and the growth/mineralization of cultured WT and Nmp4(-/-) bone marrow mesenchymal stem progenitor cells (MSPCs). ChIP-seq data were derived using MC3T3 E1 preosteoblasts, murine embryonic stem cells, and 2 blood cell lines. Ovx Nmp4( /-) mice exhibited an improved response to PTH coupled with elevated numbers of osteoprogenitors and CD8(+) T cells, but were not protected from ovx-induced bone loss. Cultured Nmp4(-/-) MSPCs displayed enhanced proliferation and accelerated mineralization. ChIP-seq/gene ontology analyses identified target genes likely under Nmp4 control as enriched for negative regulators of biosynthetic processes. Interrogation of mRNA transcripts in nondifferentiating and osteogenic differentiating WT and Nmp4(-/-) MSPCs was performed on 90 Nmp4 target genes and differentiation markers. These data suggest that Nmp4 suppresses bone anabolism, in part, by regulating IGF-binding protein expression. Changes in Nmp4 status may lead to improvements in osteoprogenitor response to therapeutic cues. PMID- 26244799 TI - [Admission and discharge of people with dementia- Communication from the perspective of respite care experts]. AB - BACKGROUND: There is a lack of information regarding the structures and processes of communication between home and respite care at admission and discharge of people with dementia (PwD}. Considering the background,it was aimed to reconstruct information exchange between home and respite care of PwD and to identify factors which affect the quality of communication structure and processes. METHODS: Semi-structured guided telephone interviews with 16 experts out of 15 respite care facilities were conducted. A structured content analysis and a process-mapping were performed. RESULTS: Core procedures of admission and discharge of PwD were identified. There were differences and overlaps between the institutions. The differences were related to the point of time and the frequency of intake inter-"views, the checks of information completeness and the provision of information.The institutions had in common that no further coordinative steps were planned after discharge. Aneed for action was identified regarding the coordination of care and the performance of handover evaluations. CONCLUSION: A timely provision of information for respite care is crucial fo rPwD. The coordination of all stakeholders,the assignment of responsibilities in communication, and easing the burden of informal caregivers is a requirement for care continuation. Across sectorial case-management, a standard of care transition, and the evaluation of hand overs is recommended. PMID- 26244800 TI - [Attitudes towards assisted living inAustria-A qualitative study]. AB - BACKGROUND: Surveys in German speaking countries identified motives for choosing assisted living, but their importance in the context of decision making remains unclear. AIM: This study aimed to identify types of attitudes towards assisted living among older persons in Austria that result from the interplay of single motives. METHOD: A comparative qualitative study with semi-structured interviews was conduCted in the land Salzburg among residents of assisted living facilities and home dwelling older adults. Data were analysed by using qualitative content analysis according to Mayring and subsequent construction of types. RESULTS: Among residents types of attitudes were "proactive users" who expected more safety or comfort and persons who "moved m due to external circumstances" like taking the opportunity of available place or feeling forced by functional/imitations or be ing influenced by significant others. Types of attitudes among home dwelling older persons were "conditional acceptance';"rejection" and ;'indecisiveness':Vague ideas about assisted living often prevented an informed decision. CONCLUSION: Choice of assisted living only depends to some extent on specific expectations. Better information,advice by significant others and availability of a place may favour a decision to move in. PMID- 26244801 TI - [The scientific discourse about dementia in Germany-first results of the exemplary exercise of an integrative methodological approach]. AB - BACKGROUND: The analysis of the discourse in dealing with people with dementia within the nursing and healthcare research in Germany is previously missing.Aim: How are people with dementia described in the discourse of the German nursing and health care research community and what does that mean for the nursing and health research in Germany? METHOD: Using an integrative methodological approach, the first steps of an analysis of dementia discourse are developed and exemplarily tested in a selected limited context datjramework. RESULT: The scientific discourse is focused on the burden or the family aregivers of the person with dementia.They are identified as those who have to handle the burden with their spouse or siblings with dementia. CONCLUSIONS: A methodologiCal approach of integrative analysis was tested. According perspectives should be developed to incorporate the perspective of people with dementia in a stronger way. PMID- 26244802 TI - [Recovery Self Assessment: Translation and cultural adaption of a recovery oriented assessment instrument]. AB - BACKGROUND: The recovery approach is becoming increasingly important in mental health services and research. In English-speaking countries, its practical implementation as well as the scientific discussion is far more advanced. To support the approach, assessment instruments are required. A widespread and recognised tool is the Recovery Self Assessment Scale {RSA}. This includes four versions of a questionnaire, which cover the perspectives of users, providers, family members and management. AIM/METHOD: In this article, the development of the instrument and the system atictranslation process are presented. Two independent research groups applied different translation. METHODS: The Swiss research group {AGS} used the ISOPR principles, the German research group (AGN} the Guidelines of the European Social Survey Programme for survey translations TRAPD. The methods differ in the fact,that TRAPD uses focus groups. The results of both groups were combined by means of a consensus process. RESULTS: Within the translation and cultural adjustment of the RSA-D, the the oretical framework of the RSA as well as the transferability into the German speaking context has been ensured. CONCLUSION: Before the RSA-D c~n beused in practice and research, further studies towards psychometric testing should be conducted. PMID- 26244803 TI - [Promoting self care in patients with chronic obstructive lung disease in ambulatory care - an observational study]. PMID- 26244804 TI - [Transformation of the facility culture in long-term inpatient nursing - does the quality of care improve?]. PMID- 26244805 TI - [Obituary: Dr. Marjory Gordon (PhD, RN, FAAN)]. PMID- 26244810 TI - Large-Scale Identification of N-Glycan Glycoproteins Carrying Lewis x and Site Specific N-Glycan Alterations in Fut9 Knockout Mice. AB - The Lewis x (Le(x)) structure (Galbeta1-4(Fucalpha1-3)GlcNAc-R) is a carbohydrate epitope comprising the stage-specific embryonic antigen-1 (SSEA-1) and CD15, and it is synthesized by alpha1,3-fucosyltransferase 9 (Fut9). Fut9 is expressed specifically in the stomach, kidney, brain, and in leukocytes, suggesting a specific function in these tissues. In this study, the N-linked glycan mass spectrometry profile of wild-type mouse kidney glycoproteins revealed the presence of abundant terminal fucoses, which were lost following knockout of the Fut9 gene; the terminal fucose was therefore concluded to be Le(x). These results suggested that Le(x) presence is widespread rather than being limited to specific proteins. We endeavored to comprehensively identify the Le(x) carriers in the mouse kidney. Glycopeptides carrying fucosylated glycans were collected by Aleuria aurantia lectin (AAL) affinity chromatography from kidney homogenates of wild-type and Fut9 knockout mice. The site-specific N-glycomes on the glycopeptides were subsequently analyzed by adopting a new glycoproteomic technology composed of dissociation-independent assignment of glycopeptide signals and accurate mass-based prediction of the N-glycome on the glycopeptides. Our analyses demonstrated that 24/32 glycoproteins contained the Le(x) N-glycan structure in wild-type kidney; of these, Le(x) was lost from 21 in the knockout mice. This is the first report of large-scale identification of Le(x)-carrying glycoproteins from a native sample based on the site-specific glycome analysis. PMID- 26244811 TI - Factors Affecting the Effectiveness of Topical NSAIDs. PMID- 26244812 TI - LMP1 Increases Expression of NADPH Oxidase (NOX) and Its Regulatory Subunit p22 in NP69 Nasopharyngeal Cells and Makes Them Sensitive to a Treatment by a NOX Inhibitor. AB - Oxidative stress is thought to contribute to cancer development. Epstein-Barr virus (EBV) and its encoded oncoprotein, latent membrane protein 1 (LMP1), are closely associated with the transformation of nasopharyngeal carcinoma (NPC) and Burkitt's lymphoma (BL). In this study, we used LMP1-transformed NP cells and EBV related malignant cell lines to assess the effects of LMP1 on reactive oxygen species (ROS) accumulation and glycolytic activity. Using NPC tissue samples and a tissue array to address clinical implications, we report that LMP1 activates NAD(P)H oxidases to generate excessive amount of ROS in EBV-related malignant diseases. By evaluating NAD(P)H oxidase (NOX) subunit expression, we found that the expression of the NAD(P)H oxidase regulatory subunit p22phox was significantly upregulated upon LMP1-induced transformation. Furthermore, this upregulation was mediated by the c-Jun N-terminal kinase (JNK) pathway. In addition, LMP1 markedly stimulated anaerobic glycolytic activity through the PI3K/Akt pathway. Additionally, in both NPC cells and tissue samples, p22phox expression correlated with LMP1 expression. The NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI) also exerted a marked cytotoxic effect in LMP1 transformed and malignant cells, providing a novel strategy for anticancer therapy. PMID- 26244813 TI - Efficient Sorption and Removal of Perfluoroalkyl Acids (PFAAs) from Aqueous Solution by Metal Hydroxides Generated in Situ by Electrocoagulation. AB - Removal of environmentally persistent perfluoroalkyl acids (PFAAs), that is, perfluorooctanesulfonate (PFOS) and perfluorocarboxylic acids (PFCAs, C4 ~ C10) were investigated through sorption on four metal hydroxide flocs generated in situ by electrocoagulation in deionized water with 10 mM NaCl as supporting electrolyte. The results indicated that the zinc hydroxide flocs yielded the highest removal efficiency with a wide range concentration of PFOA/PFOS (1.5 MUM ~ 0.5 mM) at the zinc dosage <150 mg L(-1) with the energy consumption <0.18 Wh L(-1). The sorption kinetics indicated that the zinc hydroxide flocs had an equilibrium adsorbed amount (qe) up to 5.74/7.69 mmol g(-1) (Zn) for PFOA/PFOS at the initial concentration of 0.5 mM with an initial sorption rate (v0) of 1.01 * 10(3)/1.81 * 10(3) mmol g(-1) h(-1). The sorption of PFOA/PFOS reached equilibrium within <10 min. The sorption mechanisms of PFAAs on the zinc hydroxide flocs were proposed based on the investigation of various driving forces. The results indicated that the hydrophobic interaction was primarily responsible for the PFAAs sorption. The electrocoagulation process with zinc anode may have a great potential for removing PFAAs from industrial wastewater as well as contaminated environmental waterbody. PMID- 26244814 TI - Synthetic heme/copper assemblies: toward an understanding of cytochrome c oxidase interactions with dioxygen and nitrogen oxides. AB - Our long-time niche in synthetic biological inorganic chemistry has been to design ligands and generate coordination complexes of copper or iron ions or both, those reacting with dioxygen (O2) or nitrogen oxides (e.g., nitric oxide (NO(g)) and nitrite (NO2(-))) or both. As inspiration for this work, we turn to mitochondrial cytochrome c oxidase, which is responsible for dioxygen consumption and is also the predominant target for NO(g) and nitrite within mitochondria. In this Account, we highlight recent advances in studying synthetic heme/Cu complexes in two respects. First, there is the design, synthesis, and characterization of new O2 adducts whose further study will add insights into O2 reductive cleavage chemistry. Second, we describe how related heme/Cu constructs reduce nitrite ion to NO(g) or the reverse, oxidize NO(g) to nitrite. The reactions of nitrogen oxides occur as part of CcO's function, which is intimately tied to cellular O2 balance. We had first discovered that reduced heme/Cu compounds react with O2 giving MU-oxo heme-Fe(III)-O-Cu(II)(L) products; their properties are discussed. The O-atom is derived from dioxygen, and interrogations of these systems led to the construction and characterization of three distinctive classes of heme-peroxo complexes, two high-spin and one low-spin species. Recent investigations include a new approach to the synthesis of low spin heme-peroxo-Cu complexes, employing a "naked" synthon, where the copper ligand denticity and geometric types can be varied. The result is a collection of such complexes; spectroscopic and structural features (by DFT calculations) are described. Some of these compounds are reactive toward reductants/protons effecting subsequent O-O cleavage. This points to how subtle improvements in ligand environment lead to a desired local structure and resulting optimized reactivity, as known to occur at enzyme active sites. The other sector of research is focused on heme/Cu assemblies mediating the redox interplay between nitrite and NO(g). In the nitrite reductase chemistry, the cupric center serves as a Lewis acid, while the heme is the redox active center providing the electron. The orientation of nitrite in approaching the ferrous heme center and N atom binding are important. Also, detailed spectroscopic and kinetic studies of the NO(g) oxidase chemistry, in excellent agreement with theoretical calculations, reveal the intermediates and key mechanistic steps. Thus, we suggest that both chemical and biochemical heme/Cu-mediated nitrite reductase and NO(g) oxidase chemistry require N-atom binding to a ferrous heme along with cupric ion O-atom coordination, proceeding via a three-membered O-Fe-N chelate ring transition state. These important mechanistic features of heme/Cu systems interconverting NO(g) and nitrite are discussed for the first time. PMID- 26244815 TI - Synthesis of Nonspherical Microcapsules through Controlled Polyelectrolyte Coating of Hydrogel Templates. AB - We report a simple approach to fabricate custom-shape microcapsules using hydrogel templates synthesized by stop flow lithography. Cargo-containing microcapsules were made by coating hydrogel particles with a single layer of poly l-lysine followed by a one-step core degradation and capsule cross-linking procedure. We determined appropriate coating conditions by investigating the effect of pH, ionic strength, and prepolymer composition on the diffusion of polyelectrolytes into the oppositely charged hydrogel template. We also characterized the degradation of the templating core by tracking the diffusivity of nanoparticles embedded within the hydrogel. Unlike any other technique, this approach allows for easy fabrication of microcapsules with internal features (e.g., toroids) and selective surface modification of Janus particles using any polyelectrolyte. These soft, flexible capsules may be useful for therapeutic applications as well as fundamental studies of membrane mechanics. PMID- 26244816 TI - Morphological and community changes of turf algae in competition with corals. AB - The morphological plasticity and community responses of algae competing with corals have not been assessed. We evaluated eight morphological characters of four species of stoloniferous clonal filamentous turf algae (FTA), including Lophosiphonia cristata (Lc) and Polysiphonia scopulorum var. villum (Psv), and the composition and number of turf algae (TA) in competition for space with the coral Orbicella spp. under experimental and non-manipulated conditions. All FTA exhibited morphological responses, such as increasing the formation of new ramets (except for Psv when competing with O. faveolata). Opposite responses in the space between erect axes were found when Psv competed with O. faveolata and when Lc competed with O. annularis. The characters modified by each FTA species, and the number and composition of TA species growing next to coral tissue differed from that of the TA growing at >= 3 cm. The specific and community responses indicate that some species of TA can actively colonise coral tissue and that fundamental competitive interactions between the two types of organisms occur within the first millimetres of the coral-algal boundary. These findings suggest that the morphological plasticity, high number, and functional redundancy of stoloniferous TA species favour their colonisation of coral tissue and resistance against coral invasion. PMID- 26244817 TI - A 4-year observation in lupus nephritis patients treated with an intensified B lymphocyte depletion without immunosuppressive maintenance treatment-Clinical response compared to literature and immunological re-assessment. AB - BACKGROUND: B cells (BC) play a critical role in systemic lupus erythematosus (SLE). BC depletion therapy still remains an attractive option, despite the disappointing results of randomized controlled trials (RTCs). METHODS: Twelve patients with SLE [3 males, mean age 43.8 yrs (25-55)] with severe multiorgan involvement all including kidney (3 patients with Class IV, 4 with Class III/V and 5 with Class V, according to the International Society of Nephrology/Renal Pathology Society glomerulonephritis classification), skin lesions [10], severe polyarthralgias with arthritis [10], polyserositis [2], and lymphadenopathy [5] have been prospectively treated with an intensified B cell depletion therapy (IBCDT) protocol due to their resistance or intolerance to previous therapy (six cases) or as a front line immunosuppressive treatment in 6 women with unsatisfactory therapeutic compliance or as a specific request of a short-time immunosuppression for gestational perspectives. PROTOCOL: Rituximab (RTX) 375 mg/sm on days 1, 8, 15, 22, and 2 more doses after 1 and 2 months, associated with 2 IV administrations of 10mg/kg of cyclophosphamide and 3 methylprednisolone pulses (15mg/kg) followed by oral prednisone (0.8 mg/kg/day, rapidly tapered to 5mg/day by the end of the 3rd month after RTX). No further immunosuppressive maintenance therapy has been given. RESULTS: Patients had been followed-up for a mean of 44.5 (24-93)months. Significant decreases (p<0.05) were found in the levels of ESR (baseline mean value: 55.0mm; 3 months: 36; end of follow-up: 13), anti-dsDNA antibodies (baseline: 185 U; 3 months: 107; end of follow-up: 15), and proteinuria (baseline: 4.9 g/24h; 3 months: 0.97; end of follow-up: 0.22). C4 values (baseline 11 mg/dl) significantly increased (p<0.05) after 3 months (22 mg/dl) and at the end of the follow-up (20mg/dl). Of the 12 patients, 9 (75%) have remained well after one cycle of IBCDT, with no flare (mean 51.6 months [25 93]). Three patients relapsed after 36, 41, and 72 months, respectively. Following re-treatment, they again showed complete remission over 18-48 months of observation. CONCLUSIONS: A promising role of RTX in an intensified protocol of induction therapy can be envisaged in patients for whom avoiding immunosuppressive maintenance therapy and sparing steroids are particularly appealing. Moreover, our data confirm in one of the longest follow-up available, the opportunity to reconsider the regimens of BL depletion in the treatment of the most severe or refractory forms of SLE despite the disappointing results of RCTs. PMID- 26244819 TI - The Confusion of Fear and Surprise: A Developmental Study of the Perceptual Attentional Limitation Hypothesis Using Eye Movements. AB - The goal of the present study was to test the Perceptual-Attentional Limitation Hypothesis in children and adults by manipulating the distinctiveness between expressions and recording eye movements. Children 3-5 and 9-11 years old as well as adults were presented pairs of expressions and required to identify a target emotion. Children 3-5 years old were less accurate than those 9-11 years old and adults. All children viewed pictures longer than adults but did not spend more time attending to the relevant cues. For all participants, accuracy for the recognition of fear was lower than for surprise when the distinctive cue was in the brow only. They also took longer and spent more time in both the mouth and brow zones than when a cue was in the mouth or both areas. Adults and children 9 11 years old made more comparisons between the expressions when fear comprised a single distinctive cue in the brow than when the distinctive cue was in the mouth only or when both cues were present. Children 3-5 years old made more comparisons for brow only than both. The results of the present study extend on the Perceptual-Attentional Limitation Hypothesis showing an importance of both decoder and stimuli, and an interaction between decoder and stimuli characteristics. PMID- 26244820 TI - Constructing Hierarchical Interfaces: TiO2-Supported PtFe-FeO(x) Nanowires for Room Temperature CO Oxidation. AB - In this communication, we report a facile approach to constructing catalytic active hierarchical interfaces in one-dimensional (1D) nanostructure, exemplified by the synthesis of TiO2-supported PtFe-FeO(x) nanowires (NWs). The hierarchical interface, constituting atomic level interactions between PtFe and FeO(x) within each NW and the interactions between NWs and support (TiO2), enables CO oxidation with 100% conversion at room temperature. We identify the role of the two interfaces by probing the CO oxidation reaction with isotopic labeling experiments. Both the oxygen atoms (Os) in FeO(x) and TiO2 participate in the initial CO oxidation, facilitating the reaction through a redox pathway. Moreover, the intact 1D structure leads to the high stability of the catalyst. After 30 h in the reaction stream, the PtFe-FeO(x)/TiO2 catalyst exhibits no activity decay. Our results provide a general approach and new insights into the construction of hierarchical interfaces for advanced catalysis. PMID- 26244818 TI - Nanoparticle-mediated drug delivery for treating melanoma. AB - Melanoma originated from melanocytes is the most aggressive type of skin cancer with limited treatment options. New targeted therapeutic options with the discovery of BRAF and MEK inhibitors have shown significant survival benefits. Despite the recent progress, development of chemoresistance and systemic toxicity remains a challenge for treating metastatic melanoma. While the response from the first line of treatment against melanoma using dacarbazine remains only 5-10%, the prolonged use of targeted therapy against mutated oncogene BRAF develops chemoresistance. In this review, we will discuss the nanoparticle-based strategies for encapsulation and conjugation of drugs to the polymer for maximizing their tumor distribution through enhanced permeability and retention effect. We will also highlight photodynamic therapy and design of melanoma targeted nanoparticles. PMID- 26244821 TI - Tunneling Nanoelectromechanical Switches Based on Compressible Molecular Thin Films. AB - Abrupt switching behavior and near-zero leakage current of nanoelectromechanical (NEM) switches are advantageous properties through which NEMs can outperform conventional semiconductor electrical switches. To date, however, typical NEMs structures require high actuation voltages and can prematurely fail through permanent adhesion (defined as stiction) of device components. To overcome these challenges, in the present work we propose a NEM switch, termed a "squitch," which is designed to electromechanically modulate the tunneling current through a nanometer-scale gap defined by an organic molecular film sandwiched between two electrodes. When voltage is applied across the electrodes, the generated electrostatic force compresses the sandwiched molecular layer, thereby reducing the tunneling gap and causing an exponential increase in the current through the device. The presence of the molecular layer avoids direct contact of the electrodes during the switching process. Furthermore, as the layer is compressed, the increasing surface adhesion forces are balanced by the elastic restoring force of the deformed molecules which can promote zero net stiction and recoverable switching. Through numerical analysis, we demonstrate the potential of optimizing squitch design to enable large on-off ratios beyond 6 orders of magnitude with operation in the sub-1 V regime and with nanoseconds switching times. Our preliminary experimental results based on metal-molecule-graphene devices suggest the feasibility of the proposed tunneling switching mechanism. With optimization of device design and material engineering, squitches can give rise to a broad range of low-power electronic applications. PMID- 26244824 TI - Intraabdominal Herniation Caused by Metastatic Disease to the Diaphragm. PMID- 26244825 TI - Six new cassane diterpenes from the twigs and leaves of Tara (Caesalpinia spinosa Kuntze). AB - Six new cassane diterpenes, isoneocaesalpin H (1), caespinosin A (2), caespinosin B (3), a cassane diterpene with unique 6/6/7 carbon rings, and caespinosins C-E (4-6) were isolated from the twigs and leaves of Tara (Caesalpinia spinosa Kuntze). The absolute configuration of isoneocaesalpin H (1) was determined by single-crystal X-ray crystallographic analysis. Compound 3 represents a class of rare natural cassane diterpene bearing unique 6/6/7 carbon rings. Their structures were identified by 1D and 2D NMR spectral data. Cassane diterpenes were firstly reported from Tara. Compounds 1-5 were evaluated for their cytotoxicity on HL-60, SMMC-7721, A-549, MCF-7 and SW-480 human cancer cell lines, but they were inactive. PMID- 26244826 TI - Concurrent Validity of a Velocity Perception Scale to Monitor Back Squat Exercise Intensity in Young Skiers. AB - Execution velocity is among the main variables used to quantify resistance exercise intensity. The velocity at which a given load is displaced is one of the factors, which determine the training adaptations induced in the muscles. The purpose of this study was to assess the validity of the scale of perceived velocity (SPV) applied to the back squat. The study participants were 11 international level young elite skiers (8 men and 3 women) of mean age, height, weight, and estimated 1-repetition maximum/body weight ratio (1RMest/BW) 15.4 +/- 1.12 years, 166.8 +/- 8.83 cm, 63.6 +/- 11.56 kg, and 1.61 +/- 0.40, respectively. Participants performed a 2-stage protocol. In the first stage (familiarization), subjects were instructed on how to use the scale and performed an incremental load test to determine their 1RMest. In the second, or validation stage (72 hours later), exercises were executed at 6 relative intensities (20, 30, 40, 50, 60, and 70% of 1RMest) in random order in 2 sessions separated by 72 hours. Real velocity (Velreal) and perceived velocity (Velscale) values were linearly distributed showing excellent coefficients of determination (R(2) = 0.98 and R(2) = 0.99 for the 2-session trial). A 2-way repeated measures analysis of variance (scale [2] * session [2] * intensity [6]) revealed significant differences in the factor intensity and the interaction scale * intensity (no significant differences were detected in scale, session, scale * session, or scale * session * intensity). These data support the validity of SPV to monitor exercise intensity during lower-body strength training. PMID- 26244827 TI - Do Match-Related Contextual Variables Influence Training Load in Highly Trained Soccer Players? AB - This study analyzed training loads of youth soccer players and examined the influence of match-related contextual variables in internal training load and fatigue. A secondary aim was to investigate the variability of these parameters throughout the season. Thirteen highly trained under-19 players (18.6 +/- 0.5 years) were followed during one season. Training load (daily) and fatigue scores (weekly) were assessed using rate of perceived exertion and a short questionnaire, respectively. Higher weekly training loads were reported after a defeat or draw compared to a win (2,342 +/- 987 and 2,395 +/- 613 vs. 1,877 +/- 392 AU; p <= 0.05; d = 0.30-0.45). Weekly training loads were higher after playing an away match than after a home match (2,493 +/- 821 vs. 2,153 +/- 577 AU; p <= 0.05; d = 0.23). Within training sessions, the coefficients of variation for internal training load ranged from 5 to 72%. Throughout the season, the coefficients of variation for weekly training loads and fatigue scores ranged from 29 to 49% and 18 to 44%, respectively. Weekly training load decreased as the season progressed (p < 0.001); no changes were detected for the fatigue score. In conclusion, the large variation in internal training load within a session and its sensitivity to initial and subsequent match conditions underline the need for a more individualized approach. These findings and the stability of the fatigue scores throughout the season may indicate that highly trained players modulate their pace during training. PMID- 26244828 TI - Whole-Body Vibration Training and Its Application to Age-Related Performance Decrements: An Exploratory Analysis. AB - Middle age is associated with a pronounced decline in power and flexibility. Whilst whole-body vibration training (WBVT) improves performance in a range of populations, whether WBVT can improve muscle power and flexibility in a middle aged population is not known. The present study aimed to determine the influence of 5 weeks progressive WBVT in middle-aged (45-55 years) and younger (20-30 years) recreationally active females. Participants in each age group were randomly allocated to an intervention (WBVT) or control group. The WBVT groups trained for 5 weeks on a vibration platform, while the control groups performed identical exercises, with no vibration. Prior to, and after, the 5-week study vertical countermovement jump (VCMJ) and range of motion (ROM) performance were measured. WBVT significantly (p = 0.001) improved VCMJ performance when compared to the control groups. This improvement was significantly (p = 0.001) greater in the middle-aged compared with the younger WBVT group. WBVT significantly (p = 0.001) improved ROM irrespective of age. Taken together, these results suggest that WBVT can off-set age related performance decrements, which has therapeutic implications for musculoskeletal aging. Therefore, WBVT could be undertaken to minimise age-related performance deterioration in middle-aged female populations. PMID- 26244829 TI - Structure-based Mechanistic Insights into Terminal Amide Synthase in Nosiheptide Represented Thiopeptides Biosynthesis. AB - Nosiheptide is a parent compound of thiopeptide family that exhibit potent activities against various bacterial pathogens. Its C-terminal amide formation is catalyzed by NosA, which is an unusual strategy for maturating certain thiopeptides by processing their precursor peptides featuring a serine extension. We here report the crystal structure of truncated NosA1-111 variant, revealing three key elements, including basic lysine 49 (K49), acidic glutamic acid 101 (E101) and flexible C-terminal loop NosA112-151, are crucial to the catalytic terminal amide formation in nosiheptide biosynthesis. The side-chain of residue K49 and the C-terminal loop fasten the substrate through hydrogen bonds and hydrophobic interactions. The side-chain of residue E101 enhances nucleophilic attack of H2O to the methyl imine intermediate, leading to Calpha-N bond cleavage and nosiheptide maturation. The sequence alignment of NosA and its homologs NocA, PbtH, TpdK and BerI, and the enzymatic assay suggest that the mechanistic studies on NosA present an intriguing paradigm about how NosA family members function during thiopeptide biosynthesis. PMID- 26244830 TI - Genetic structure and admixture between Bayash Roma from northwestern Croatia and general Croatian population: evidence from Bayesian clustering analysis. AB - The European Roma represent a transnational mosaic of minority population groups with different migration histories and contrasting experiences in their interactions with majority populations across the European continent. Although historical genetic contributions of European lineages to the Roma pool were investigated before, the extent of contemporary genetic admixture between Bayash Roma and non-Romani majority population remains elusive. The aim of this study was to assess the genetic structure of the Bayash Roma population from northwestern Croatia and the general Croatian population and to investigate the extent of admixture between them. A set of genetic data from two original studies (100 Bayash Roma from northwestern Croatia and 195 individuals from the general Croatian population) was analyzed by Bayesian clustering implemented in STRUCTURE software. By re-analyzing published data we intended to focus for the first time on genetic differentiation and structure and in doing so we clearly pointed to the importance of considering social phenomena in understanding genetic structuring. Our results demonstrated that two population clusters best explain the genetic structure, which is consistent with social exclusion of Roma and the demographic history of Bayash Roma who have settled in NW Croatia only about 150 years ago and mostly applied rules of endogamy. The presence of admixture was revealed, while the percentage of non-Croatian individuals in general Croatian population was approximately twofold higher than the percentage of non-Romani individuals in Roma population corroborating the presence of ethnomimicry in Roma. PMID- 26244831 TI - Depletion of IL-2 receptor beta-positive cells protects from diabetes in non obese diabetic mice. AB - The destruction of beta-cells in type 1 diabetes (T1D) progresses silently until only a minor fraction of the beta-cells remain. A late acting therapy leading to the prevention of further beta-cell killing would therefore be desirable. CD122, the beta chain of the interleukin-2 receptor, is highly expressed on natural killer (NK) cells and on a subpopulation of CD8 T cells. In this study, we have treated non-obese diabetic (NOD) mice with a depleting antibody against CD122. The treatment protected from diabetes, even when initiated just before disease onset. The degree of leukocyte infiltration into islets was unaffected by the treatment, further supporting effectiveness late in the disease process. It effectively removed all NK cells from the spleen, pancreas and pancreatic lymph nodes and abolished NK cell activity. Interestingly, despite the lack of CD122 expression on CD8 T cells in the pancreas, the overall frequency of CD8 cells decreased in this organ, whereas it was unaffected in the spleen. T cells were also still capable to respond against a foreign antigen. Conclusively, targeting of CD122(+) cells could represent a novel treatment strategy against T1D. PMID- 26244833 TI - Hospitalizations and Deaths Because of Respiratory and Diarrheal Diseases Among Haitian Children Under Five Years of Age, 2011-2013. AB - BACKGROUND: Respiratory and diarrheal diseases are leading causes of morbidity and mortality among children younger than 5 years in developing countries. Data on the burden of these diseases in Haiti are scarce. METHODS: We conducted a retrospective review of hospital admission registries during January 1, 2011 December 31, 2013 for children younger than 5 years in 6 hospitals in Haiti. We recorded the number of all-cause, respiratory and diarrheal disease admissions and deaths by epidemiologic week and age. RESULTS: A total of 31,565 hospital admissions and 1763 deaths were recorded among children aged <5 years during the study period. Respiratory diseases accounted for 9183 (29%) hospitalizations and 301 (17%) deaths. Children aged 6-23 months had the highest percentage of hospitalizations attributable to respiratory diseases (38%), whereas children aged 36-47 months had the highest proportion of deaths attributable to respiratory diseases (37%). Respiratory disease hospitalizations followed a bimodal seasonal pattern, with peaks during May-June and October-December. Diarrheal diseases accounted for 8063 (26%) hospitalizations and 224 (13%) deaths. Children aged 6-11 months had the highest percentage of diarrhea associated hospitalizations (39%) and deaths (29%). Diarrheal disease admissions peaked in January-April before the rainy season. CONCLUSIONS: Respiratory and diarrheal diseases contributed to more than half of hospitalizations and almost a third of deaths in children younger than 5 years in Haiti. These data are essential to assess the impact of pneumococcal and rotavirus vaccines and other interventions in Haiti. PMID- 26244832 TI - Safety, Pharmacokinetics and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents: Forty-eight-week Results from IMPAACT P1093. AB - OBJECTIVE: To assess the pharmacokinetics (PK), safety and efficacy of dolutegravir plus optimized background regimen in HIV-infected treatment experienced adolescents. METHODS: Children older than 12 to younger than 18 years received dolutegravir weight-based fixed doses at approximately 1.0 mg/kg once daily in a phase I/II multicenter open label 48-week study. Intensive PK evaluation was done at steady state after dolutegravir was added to a failing regimen or started at the end of a treatment interruption. Safety and HIV RNA and CD4 cell count assessments were performed through week 48. RESULTS: Twenty-three adolescents were enrolled and 22 (96%) completed the 48-week study visit. Median age and weight were 15 years and 52 kg, respectively. Median [interquartile range (IQR)] baseline CD4+ cell count was 466 cells/MUL (297, 771). Median (IQR) baseline HIV-1 RNA log10 was 4.3 log10 copies/mL (3.9, 4.6). Dolutegravir geometric mean of the area under the plasma concentration-time curve from time of administration to 24 hours after dosing (AUC0-24) and 24 hour postdose concentration (C24) were 46.0 MUg hours/mL and 0.90 MUg/mL, respectively, which were within the study targets based on adult PK ranges. Virologic success with an HIV RNA <400 copies/mL was achieved in 74% [95% confidence interval (CI): 52-90%] at week 48. Additionally, 61% (95% CI: 39-80%) had an HIV RNA <50 copies/mL at week 48. Median (IQR) gain in CD4 cell count at week 48 was 84 cells/MUL (-81, 238). Dolutegravir was well tolerated, with no grade 4 adverse events, serious adverse events or discontinuations because of serious adverse events. CONCLUSIONS: Dolutegravir achieved target PK exposures in adolescents. Dolutegravir was safe and well tolerated, providing good virologic efficacy through week 48. PMID- 26244834 TI - Influenza C Virus and Human Metapneumovirus Infections in Hospitalized Children With Lower Respiratory Tract Illness. AB - A 6-month prospective study in a hospital setting detected influenza C virus and human metapneumovirus in 10.0% (29/289) and 16.6% (48/289), respectively, of children hospitalized with lower respiratory tract illness. Influenza C virus infection had a similar rate of pneumonia (53.3% vs. 57.1%), significantly lower frequency of wheezing (13.3% vs. 68.6%) and higher values of white blood cell and C-reactive protein than human metapneumovirus infection. PMID- 26244835 TI - Risk Factors for Health Care-Associated Sepsis in Critically Ill Neonates Stratified by Birth Weight. AB - BACKGROUND: Health care-associated bloodstream infection (HABSI) is a frequent complication in neonatal intensive care. Research on risk factors stratified by birth weight and adjusted for severity of illness and comorbidities is limited. Our objective is to describe independent risk factors for HABSI in critically ill neonates with emphasis on risk variation between birth weight groups. METHODS: We performed a single-center historical cohort study in a tertiary referral center. A neonatal intensive care-audit system was used to identify eligible neonates admitted for >=72 hours (2002-2011). HABSI is defined according to National Institute of Child Health and Human Development criteria. Risk factors for HABSI were assessed by univariate and logistic regression analysis for the total cohort and for birth weight subgroups, that is, neonates <=1500 g and >1500 g. RESULTS: A total of 342 neonates developed HABSI in 5134 admissions of >=72 hours (6.7%). Very low birth weight, total parenteral nutrition (TPN), mechanical ventilation, gastrointestinal disease, surgery (cardiac and other type), and renal insufficiency are independent risk factors for the total cohort. Gastrointestinal disease and cardiac surgery are independent risk factors in both birth weight groups; mechanical ventilation (odds ratio [OR]: 2.6; confidence interval [CI]: 1.6-4.0) and other type of surgery (OR: 4.3; CI: 2.1-8.8) are solely independent risk factors in the <=1500-g cohort; TPN is exclusively an independent risk factor (OR: 7.9; CI: 3.9-16.2) in the >1500-g cohort. CONCLUSIONS: In our neonatal intensive care unit, risk stratification by birth weight revealed some difference. Special attention concerning infection control practices is for neonates receiving TPN, mechanical ventilation, cardiac surgery, and with a gastrointestinal disease. PMID- 26244836 TI - Long-Term Intermittent Palliative Sedation for Refractory Symptoms at the End of Life in Two Cancer Patients. AB - BACKGROUND: Palliative sedation (PS) can be classified as either continuous or intermittent. Continuous PS is most commonly used in end-of-life care, while no specific indication for intermittent PS exists. CASE PRESENTATION: Here we describe two cases of refractory severe cancer pain with psychological anguish that were controlled successfully by intermittent IPS for the long time. One patient complained of refractory severe cancer pain and insomnia. The other patient had uncontrollable pain and delirium, whose sufferings were relieved by intermittent PS. Case Management and Outcome: Intermittent PS was offered to the cases every night-time with family member/patient's consent. After providing intermittent PS, cancer pain decreased to mild intensity and psychological symptoms were significant improved simultaneously with patients awake during day time. CONCLUSIONS: Palliative PS may stop vicious cycle of physical and psychological distress in terminal cancer patients. Furthermore, intermittent type of PS could keep patients consciousness alert during day time and may be performed repeatedly for the long time. PMID- 26244837 TI - Effect of Lavage with Gentamicin vs. Clindamycin vs. Physiologic Saline on Drainage Discharge of the Axillary Surgical Bed after Lymph Node Dissection. AB - BACKGROUND: To date, without placement of a drain, seroma formation cannot be avoided after axillary lymph node dissection (ALND). The purpose of this study was to evaluate the effect on drainage volume of pre-closure axillary lavage with physiologic saline, gentamicin solution, or clindamycin solution. METHODS: A randomized study was performed between January 2013 and October 2014. Inclusion criteria were a diagnosis of breast neoplasm and plans to undergo an elective ALND because of axillary metastases. The patients were randomized into three groups: Two lavages with 500 mL of physiologic saline (Group 1), lavage with 500 mL of saline followed by lavage with 500 mL of a 240-mg gentamicin solution (Group 2), and lavage with 500 mL of saline followed by lavage with 500 mL of a 600-mg clindamycin solution (Group 3). RESULTS: A total of 51 patients were included. The mean number of days with a drain in place was 7.1+/-3 in Group 1, 4.1+/-1.2 in Group 2, and 6.4+/-2.1 in Group 3 (p<0.001). Total drainage volume before tube removal was 435.3+/-220.1 mL in Group 1, 155.2+/-82.4 mL in Group 2, and 352.3+/-212.9 mL in Group 3 (p=0.03). In a pairwise analysis, irrigation with gentamicin solution achieved a lower drainage volume and a reduction in the number of days of drainage maintenance compared with the other two groups. CONCLUSION: The post-operative output of the axillary drain is substantially lower in patients undergoing lavage of the surgical bed with a gentamicin solution than in patients undergoing lavage with physiologic saline or clindamycin solution. PMID- 26244839 TI - Catalytic Mechanism of Eukaryotic Neutral Ceramidase. AB - Neutral ceramidases are key enzymes of sphingolipid metabolism that hydrolyze the fatty acyl/sphingosine amide linkage of ceramide at neutral pH. In this issue of Structure, Airola et al. (2015) present the first crystal structure of human nCDase and show how complexation with phosphate supports a new catalytic mechanism for Zn-dependent amidases while providing a structurally based explanation for ceramide specificity. PMID- 26244840 TI - Docking Peptides on Proteins: How to Open a Lock, in the Dark, with a Flexible Key. AB - In this issue of Structure, Schindler et al. (2015b) present us with pepATTRACT, a protocol embedded in the ATTRACT docking engine for fully blind flexible peptide docking on proteins that yields high quality models of complexes. PMID- 26244841 TI - Electron Detachment as a Probe of Intrinsic Nucleobase Dynamics in Dianion Nucleobase Clusters: Photoelectron Spectroscopy of the Platinum II Cyanide Dianion Bound to Uracil, Thymine, Cytosine, and Adenine. AB - We report the first low-temperature photoelectron spectra of isolated gas-phase complexes of the platinum II cyanide dianion bound to nucleobases. These systems are models for understanding platinum-complex photodynamic therapies, and a knowledge of the intrinsic photodetachment properties is crucial for characterizing their broader photophysical properties. Well-resolved, distinct peaks are observed in the spectra, consistent with complexes where the Pt(CN)4(2 ) moiety is largely intact. Adiabatic electron detachment energies for the dianion-nucleobase complexes are measured to be 2.39-2.46 eV. The magnitudes of the repulsive Coulomb barriers of the complexes are estimated to be between 1.9 and 2.1 eV, values that are lower than for the bare Pt(CN)4(2-) dianion as a result of charge solvation by the nucleobases. In addition to the resolved spectral features, broad featureless bands indicative of delayed electron detachment are observed in the 193 nm photoelectron spectra of the four dianion nucleobase complexes and also in the 266 nm spectra of the Pt(CN)4(2-).thymine and Pt(CN)4(2-).adenine complexes. The selective excitation of these features in the 266 nm spectra is attributed to one-photon excitation of [Pt(CN)4(2 ).thymine]* and [Pt(CN)4(2-).adenine]* long-lived excited states that can effectively couple to the electron detachment continuum, producing strong electron detachment signals. We attribute the delayed electron detachment bands observed here for Pt(CN)4(2-).thymine and Pt(CN)4(2-).adenine but not for Pt(CN)4(2-).uracil and Pt(CN)4(2-).cytosine to fundamental differences in the individual nucleobase photophysics following 266 nm excitation. This indicates that the Pt(CN)4(2-) dianion in the clusters can be viewed as a "dynamic tag" which has the propensity to emit electrons when the attached nucleobase displays a long-lived excited state. PMID- 26244842 TI - Francisella tularensis: No Evidence for Transovarial Transmission in the Tularemia Tick Vectors Dermacentor reticulatus and Ixodes ricinus. AB - BACKGROUND: Tularemia is a zoonosis caused by the Francisella tularensis, a highly infectious Gram-negative coccobacillus. Due to easy dissemination, multiple routes of infection, high environmental contamination and morbidity and mortality rates, Francisella is considered a potential bioterrorism threat and classified as a category A select agent by the CDC. Tick bites are among the most prevalent modes of transmission, and ticks have been indicated as a possible reservoir, although their reservoir competence has yet to be defined. Tick-borne transmission of F. tularensis was recognized in 1923, and transstadial transmission has been demonstrated in several tick species. Studies on transovarial transmission, however, have reported conflicting results. OBJECTIVE: The aim of this study was to evaluate the role of ticks as reservoirs for Francisella, assessing the transovarial transmission of F. tularensis subsp. holarctica in ticks, using experimentally-infected females of Dermacentor reticulatus and Ixodes ricinus. RESULTS: Transmission electron microscopy and fluorescence in situ hybridization showed F. tularensis within oocytes. However, cultures and bioassays of eggs and larvae were negative; in addition, microscopy techniques revealed bacterial degeneration/death in the oocytes. CONCLUSIONS: These results suggest that bacterial death might occur in oocytes, preventing the transovarial transmission of Francisella. We can speculate that Francisella does not have a defined reservoir, but that rather various biological niches (e.g. ticks, rodents), that allow the bacterium to persist in the environment. Our results, suggesting that ticks are not competent for the bacterium vertical transmission, are congruent with this view. PMID- 26244843 TI - Efficacy and Safety of Alfuzosin as Medical Expulsive Therapy for Ureteral Stones: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Alfuzosin has been widely used to treat benign prostatic hyperplasia and prostatitis, and is claimed to be a selective agent for the lower urinary tract with low incidence of adverse side-effects and hypotensive changes. Recently, several randomized controlled trials have reported using Alfuzosin as an expulsive therapy of ureteral stones. Tamsulosin, another alpha blocker, has also been used as an agent for the expulsive therapy for ureteral stones. It is unclear whether alfuzosin has similar efficacy as Tamsulosin in the management of ureteral stones. OBJECTIVE: To perform a systematic review and analysis of literatures comparing Alfuzosin with Tamsulosin or standard conservative therapy for the treatment of ureteral stones less than 10 mm in diameter. METHODS: A systematic literature review was performed in December 2014 using Pubmed, Embase, and the Cochrane library databases to identify relevant studies. All randomized and controlled trials were included. A subgroup analysis was performed comparing Alfuzosin with control therapy on the management of distal ureteral stones. RESULTS: Alfuzosin provided a significantly higher stone-free rate than the control treatments (RR: 1.85; 95% confidence interval [CI], 1.35-2.55; p<0.001), and a shorter stone expulsion time (Weighted mean difference [WMD]: -4.20 d, 95%CI, -6.19 to -2.21; p<0.001), but it has a higher complication rate (RR: 2.02; 95% CI, 1.30-3.15; p<0.01). When Alfuzosin was compared to Tamsulosin, there was no significant difference in terms of stone-free rate (RR: 0.90; 95% CI, 0.79 1.02; p = 0.09) as well as the stone expulsion time (WMD: 0.52 d, 95%CI, -1.61 to 2.64; p = 0.63). The adverse effects of Alfuzosin were similar to those of Tamsulosin (RR: 0.88; 95% CI, 0.61-1.26; p = 0.47). CONCLUSIONS: Alfuzosin is a safe and effective agent for the expulsive therapy of ureteral stones smaller than 10 mm in size. It is more effective than therapeutic regiment without alpha blocker. It is equivalent to Tamsulosin in its effectiveness and safety profile. Adverse effects should always be kept in mind when use this class of drugs. PMID- 26244844 TI - Prevalence and Correlates of HIV and Hepatitis C Virus Infections and Risk Behaviors among Malaysian Fishermen. AB - Fishermen in Southeast Asia have been found to be highly vulnerable to HIV, with research evidence highlighting the role of sexual risk behaviors. This study aims to estimate the rate of HIV as well as hepatitis C virus (HCV) infections among Malaysian fishermen, and the risky sexual and injection drug use behaviors that may contribute to these infections. The study also includes an assessment of socio-demographic, occupational and behavioral correlates of testing positive for HIV or HCV, and socio-demographic and occupational correlates of risk behaviors. The study had a cross-sectional design and recruited 406 fishermen through respondent-driven sampling (RDS). Participants self-completed a questionnaire and provided biological specimens for HIV and HCV testing. We conducted and compared results of analyses of both unweighted data and data weighted with the Respondent Driven Sampling Analysis Tool (RDSAT). Of the participating fishermen, 12.4% were HIV positive and 48.6% had HCV infection. Contrary to expectations and findings from previous research, most fishermen (77.1%) were not sexually active. More than a third had a history of injection drug use, which often occurred during fishing trips on commercial vessels and during longer stays at sea. Of the fishermen who injected drugs, 42.5% reported unsafe injection practices in the past month. Reporting a history of injection drug use increased the odds of testing HIV positive by more than 6 times (AOR = 6.22, 95% CIs [2.74, 14.13]). Most fishermen who injected drugs tested positive for HCV. HCV infection was significantly associated with injection drug use, being older than 25 years, working on a commercial vessel and spending four or more days at sea per fishing trip. There is an urgent need to strengthen current harm reduction and drug treatment programs for Malaysian fishermen who inject drugs, especially among fishermen who work on commercial vessels and engage in deep-sea fishing. PMID- 26244845 TI - Estimation of Life-Years Saved by Solid-Organ Transplant. PMID- 26244847 TI - Polyethylenimine (PEI) As an Effective Dopant To Conveniently Convert Ambipolar and p-Type Polymers into Unipolar n-Type Polymers. AB - In this study, we added a small amount of polyethylenimine (PEI) into several ambipolar and p-type polymer semiconductors and used these blends as channel materials in organic thin film transistors (OTFTs). It is found that PEI can effectively suppress hole transport characteristics while maintaining or promoting the electron transport performance. Unipolar n-channel OTFTs with electron-only transport behavior is achieved for all the polymer semiconductors chosen with 2-10 wt % PEI. The electron-rich nitrogen atoms in PEI are thought to fill the electron traps, raise the Fermi level and function as trapping sites for holes, leading to promotion of electron transport and suppression of hole transport. This work demonstrates a convenient general approach to transforming ambipolar and p-type polymer semiconductors into unipolar n-type polymer semiconductors that are useful for printed logic circuits and many other applications. PMID- 26244846 TI - Stress Tolerance Variations in Saccharomyces cerevisiae Strains from Diverse Ecological Sources and Geographical Locations. AB - The budding yeast Saccharomyces cerevisiae is a platform organism for bioethanol production from various feedstocks and robust strains are desirable for efficient fermentation because yeast cells inevitably encounter stressors during the process. Recently, diverse S. cerevisiae lineages were identified, which provided novel resources for understanding stress tolerance variations and related shaping factors in the yeast. This study characterized the tolerance of diverse S. cerevisiae strains to the stressors of high ethanol concentrations, temperature shocks, and osmotic stress. The results showed that the isolates from human associated environments overall presented a higher level of stress tolerance compared with those from forests spared anthropogenic influences. Statistical analyses indicated that the variations of stress tolerance were significantly correlated with both ecological sources and geographical locations of the strains. This study provides guidelines for selection of robust S. cerevisiae strains for bioethanol production from nature. PMID- 26244848 TI - Evidence for Bidirectional Noninnocent Behavior of a Formazanate Ligand in Ruthenium Complexes. AB - Redox series of the complexes [Ru(L)(L')2](n), L = 1,5-diphenyl-3-(4-tolyl) formazanate and L' = 2,4-pentanedionate (acac(-)), 2,2'-bipyridine (bpy), or 2 phenylazopyridine (pap), were studied by cyclic and differential pulse voltammetry and by TD-DFT-supported spectroelectrochemistry (UV-vis-NIR, EPR). The precursors [Ru(III)(L(-))(acac(-))2], [Ru(II)(L(-))(bpy)2]ClO4, and [Ru(II)(L(-))(pap)2]ClO4 were identified in their indicated oxidation states by X ray crystal structure determination. The six-membered formazanato-ruthenium chelate rings have an envelope conformation with puckering of the metal. DFT calculations indicate a pronounced sensitivity of the N-N bond lengths toward the ligand oxidation state. Several electrochemically accessible charge states were analyzed, and the derived oxidation numbers Ru(II), Ru(III), or Ru(IV), L' or (L')(*-), and L(-), L(*2-), or the new formazanyl ligand L(*) for the two-way noninnocent formazanate reflect the increasing acceptor effect of the ancillary ligands L' in the series acac(-) < bpy < pap. PMID- 26244850 TI - Grain Boundary Structures and Electronic Properties of Hexagonal Boron Nitride on Cu(111). AB - Grain boundaries (GBs) of hexagonal boron nitride (h-BN) grown on Cu(111) were investigated by scanning tunneling microscopy/spectroscopy (STM/STS). The first experimental evidence of the GBs composed of square-octagon pairs (4|8 GBs) was given, together with those containing pentagon-heptagon pairs (5|7 GBs). Two types of GBs were found to exhibit significantly different electronic properties, where the band gap of the 5|7 GB was dramatically decreased as compared with that of the 4|8 GB, consistent with our obtained result from density functional theory (DFT) calculations. Moreover, the present work may provide a possibility of tuning the inert electronic property of h-BN via grain boundary engineering. PMID- 26244849 TI - Potential Antileukemia Effect and Structural Analyses of SRPK Inhibition by N-(2 (Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)Isonicotinamide (SRPIN340). AB - Dysregulation of pre-mRNA splicing machinery activity has been related to the biogenesis of several diseases. The serine/arginine-rich protein kinase family (SRPKs) plays a critical role in regulating pre-mRNA splicing events through the extensive phosphorylation of splicing factors from the family of serine/arginine rich proteins (SR proteins). Previous investigations have described the overexpression of SRPK1 and SRPK2 in leukemia and other cancer types, suggesting that they would be useful targets for developing novel antitumor strategies. Herein, we evaluated the effect of selective pharmacological SRPK inhibition by N (2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) on the viability of lymphoid and myeloid leukemia cell lines. Along with significant cytotoxic activity, the effect of treatments in regulating the phosphorylation of the SR protein family and in altering the expression of MAP2K1, MAP2K2, VEGF and FAS genes were also assessed. Furthermore, we found that pharmacological inhibition of SRPKs can trigger early and late events of apoptosis. Finally, intrinsic tryptophan fluorescence emission, molecular docking and molecular dynamics were analyzed to gain structural information on the SRPK/SRPIN340 complex. These data suggest that SRPK pharmacological inhibition should be considered as an alternative therapeutic strategy for fighting leukemias. Moreover, the obtained SRPK-ligand interaction data provide useful structural information to guide further medicinal chemistry efforts towards the development of novel drug candidates. PMID- 26244851 TI - Climate Tolerances and Habitat Requirements Jointly Shape the Elevational Distribution of the American Pika (Ochotona princeps), with Implications for Climate Change Effects. AB - Some of the most compelling examples of ecological responses to climate change are elevational range shifts of individual species, which have been observed throughout the world. A growing body of evidence, however, suggests substantial mediation of simple range shifts due to climate change by other limiting factors. Understanding limiting factors for a species within different contexts, therefore, is critical for predicting responses to climate change. The American pika (Ochotona princeps) is an ideal species for investigating distributions in relation to climate because of their unusual and well-understood natural history as well as observed shifts to higher elevation in parts of their range. We tested three hypotheses for the climatic or habitat characteristics that may limit pika presence and abundance: summer heat, winter snowpack, and forage availability. We performed these tests using an index of pika abundance gathered in a region where environmental influences on pika distribution have not been well-characterized. We estimated relative pika abundance via scat surveys and quantified climatic and habitat characteristics across two North-Central Rocky Mountain Ranges, the Wind River and Bighorn ranges in Wyoming, USA. Pika scat density was highest at mid elevations and increased linearly with forage availability in both ranges. Scat density also increased with temperatures conducive to forage plant growth, and showed a unimodal relationship with the number of days below -5 degrees C, which is modulated by insulating snowpack. Our results provide support for both the forage availability and winter snowpack hypotheses. Especially in montane systems, considering the context-dependent nature of climate effects across regions and elevations as well as interactions between climatic and other critical habitat characteristics, will be essential for predicting future species distributions. PMID- 26244852 TI - Erratum: Moisture-responsive films of cellulose stearoyl esters showing reversible shape transitions. PMID- 26244853 TI - Quantitative phase imaging through scattering media by means of coherence controlled holographic microscope. AB - A coherence-controlled holographic microscope (CCHM) enables quantitative phase imaging with coherent as well as incoherent illumination. The low spatially coherent light induces a coherence gating effect, which makes observation of samples possible also through scattering media. The paper describes theoretically and simulates numerically imaging of a two-dimensional object through a static scattering layer by means of CCHM, with the main focus on the quantitative phase imaging quality. The authors have investigated both strongly and weakly scattering media characterized by different amounts of ballistic and diffuse light. It is demonstrated that the phase information can be revealed also for the case of the static, strongly scattering layer. The dependence of the quality of imaging process on the spatial light coherence is demonstrated. The theoretical calculations and numerical simulations are supported by experimental data gained with a model phase object, as well as living carcinoma cells treated in an optically turbid emulsion. PMID- 26244854 TI - Telephone-Delivered Cognitive Behavioral Therapy and Telephone-Delivered Nondirective Supportive Therapy for Rural Older Adults With Generalized Anxiety Disorder: A Randomized Clinical Trial. AB - IMPORTANCE: Generalized anxiety disorder (GAD) is common in older adults; however, access to treatment may be limited, particularly in rural areas. OBJECTIVE: To examine the effects of telephone-delivered cognitive behavioral therapy (CBT) compared with telephone-delivered nondirective supportive therapy (NST) in rural older adults with GAD. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial in the participants' homes of 141 adults aged 60 years and older with a principal or coprincipal diagnosis of GAD who were recruited between January 27, 2011, and October 22, 2013. INTERVENTIONS: Telephone delivered CBT consisted of as many as 11 sessions (9 were required) focused on recognition of anxiety symptoms, relaxation, cognitive restructuring, the use of coping statements, problem solving, worry control, behavioral activation, exposure therapy, and relapse prevention, with optional chapters on sleep and pain. Telephone-delivered NST consisted of 10 sessions focused on providing a supportive atmosphere in which participants could share and discuss their feelings and did not provide any direct suggestions for coping. MAIN OUTCOMES AND MEASURES: Primary outcomes included interviewer-rated anxiety severity (Hamilton Anxiety Rating Scale) and self-reported worry severity (Penn State Worry Questionnaire-Abbreviated) measured at baseline, 2 months' follow-up, and 4 months' follow-up. Mood-specific secondary outcomes included self-reported GAD symptoms (GAD Scale 7 Item) measured at baseline and 4 months' follow-up and depressive symptoms (Beck Depression Inventory) measured at baseline, 2 months' follow-up, and 4 months' follow-up. Among the 141 participants, 70 were randomized to receive CBT and 71 to receive NST. RESULTS: At 4 months' follow-up, there was a significantly greater decline in worry severity among participants in the telephone-delivered CBT group (difference in improvement, -4.07; 95% CI, 6.26 to -1.87; P = .004) but no significant differences in general anxiety symptoms (difference in improvement, -1.52; 95% CI, -4.07 to 1.03; P = .24). At 4 months' follow-up, there was a significantly greater decline in GAD symptoms (difference in improvement, -2.36; 95% CI, -4.00 to -0.72; P = .005) and depressive symptoms (difference in improvement, -3.23; 95% CI, -5.97 to -0.50; P = .02) among participants in the telephone-delivered CBT group. CONCLUSIONS AND RELEVANCE: In this trial, telephone-delivered CBT was superior to telephone delivered NST in reducing worry, GAD symptoms, and depressive symptoms in older adults with GAD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01259596. PMID- 26244855 TI - Factors Affecting Dental Implant Stability Measured Using the Ostell Mentor Device: A Systematic Review. AB - OBJECTIVES: The aim of this study was to review the literature on factors that may affect dental implant stability as measured with the Ostell mentor device. MATERIALS AND METHODS: A systematic search of the literature was performed in Pubmed, Scopus, and Cochrane databases using dental implants, stability, and resonance frequency analysis as key words. RESULTS: The most relevant randomized controlled trials and clinical trials (n = 39) were selected from among 264 articles. CONCLUSIONS: Many factors can affect dental implant stability as measured with the Ostell mentor device. This may be a useful instrument for deciding the timing of implant loading, but additional research is required to establish the reliability and predictability of resonance frequency analysis for the future osseointegration of dental implants, which remains controversial. PMID- 26244857 TI - 22q11.2 deletion syndrome: atypical antipsychotics and relapsing psychoses. AB - In their letter to the editor, Boot and colleagues comment on the results of treatment with atypical antipsychotics in patients with 22q11.2 deletion syndrome and relapsing psychoses. They identify 3 issues (i. e., description of study rationale and assessments, the importance of endocrine dysfunctions and possible effects of sample bias) and conclude that "until strong evidence to the contrary [is available], standard pharmacological management of psychotic illness in 22q11DS remains recommended." In our reply, we will illustrate the erroneous nature of their conjectures. PMID- 26244858 TI - Clozapine prescription and quality of life in Chinese patients with schizophrenia treated in primary care. AB - OBJECTIVE: Clozapine is frequently used to treat schizophrenia in China. Maintenance treatment for clinically stable patients with schizophrenia is usually provided by Chinese primary care physicians, but no study has investigated the frequency of its use prescribed by primary care physicians. This study described the frequency, demographic and clinical characteristics of clozapine treatment and its impact on insight and quality of life (QOL) of patients with schizophrenia treated in primary care in China. METHOD: A total of 623 patients with schizophrenia treated in 22 primary care services in Guangzhou, China in 2013 formed the study sample. Patients' socio-demographic and clinical characteristics including psychopathology, medication side effects and QOL were recorded using a standardized protocol and data collection. RESULTS: The frequency of clozapine prescription was 35.6% with a mean daily dose of 127.7+/ 88.2 mg. There were no significant differences between the patients with and without clozapine in either of the QOL domains after controlling the confounding factors. Multiple logistic regression analyses revealed that patients on clozapine had younger age of onset, more hospitalizations, more severe extrapyramidal side effects, but better insight and fewer prescriptions of first generation antipsychotics. CONCLUSIONS: Clozapine use was found to be common and associated with better insight in patients with schizophrenia treated in primary care in China. Further examination of the rationale and appropriateness of clozapine in primary care in China is warranted. PMID- 26244860 TI - Corrigendum: Development of biodegradable Zn-1X binary alloys with nutrient alloying elements Mg, Ca and Sr. PMID- 26244859 TI - CARD15 Gene Polymorphisms Are Associated with Tuberculosis Susceptibility in Chinese Holstein Cows. AB - Bovine tuberculosis (BTB) is a significant veterinary and financial problem in many parts of the world. Associations between specific host genes and susceptibility to mycobacterial infections, such as tuberculosis, have been reported in several species. The objective of this study was to identify and evaluate the relationship of single-nucleotide polymorphisms (SNPs) in the CARD15 gene with susceptibility to BTB in Chinese Holstein cows. DNA samples from 201 Chinese Holstein cows (103 cases and 98 controls) were collected from Kunming City, Yuxi City, and Dali City in China. SNPs in the CARD15 gene were assessed using polymerase chain reaction (PCR) and restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). Case-control association testing and statistical analysis identified six SNPs associated with susceptibility to BTB in Chinese Holstein cows. The frequency of genotypes C/T, A/G, A/G, A/G, C/T, and A/G in E4 (-37), 208, 1644, 1648, 1799, and E10 (+107), respectively, was significantly higher in cases than in controls, and also the alleles C, A, A, G, T, and A, respectively, were associated with a greater relative risk in cases than in controls. The distribution of two haplotypes, TGGACA and CAGACA, was significantly different between cases and controls. Overall, this case-control study suggested that E4 (-37)(C/T), 208(A/G), 1644(A/G), 1648(A/G), 1799(C/T), and E10 (+107)(A/G) in the CARD15 gene were significantly associated with susceptibility to BTB in Chinese Holstein cows and that haplotypes TGGACA and CAGACA could be used as genetic markers in marker assisted breeding programs for breeding cows with high resistance to BTB. PMID- 26244861 TI - Plasticity of Escape Responses: Prior Predator Experience Enhances Escape Performance in a Coral Reef Fish. AB - Teleost and amphibian prey undertake fast-start escape responses during a predatory attack in an attempt to avoid being captured. Although previously viewed as a reflex reaction controlled by the autonomic nervous system, the escape responses of individuals when repeatedly startled are highly variable in their characteristics, suggesting some behavioural mediation of the response. Previous studies have shown that fishes are able to learn from past experiences, but few studies have assessed how past experience with predators affect the fast start response. Here we determined whether prior experience with the smell or sight of a predator (the Dottyback, Pseudochromis fuscus) affected the escape response of juveniles of the Spiny Chromis (Acanthochromis polyacanthus). Results show that individuals exposed to any of the predator cues prior to being startled exhibited a stronger escape response (i.e., reduced latency, increased escape distance, mean response speed, maximum response speed and maximum acceleration) when compared with controls. This study demonstrates the plasticity of escape responses and highlights the potential for naive reef fish to take into account both visual and olfactory threat cues simultaneously to optimise the amplitude of their kinematic responses to perceived risk. PMID- 26244862 TI - Checklist and Scoring System for the Assessment of Soft Tissue Preservation in CT Examinations of Human Mummies. AB - The purpose of this study was to develop a checklist for standardized assessment of soft tissue preservation in human mummies based on whole-body computed tomography examinations, and to add a scoring system to facilitate quantitative comparison of mummies. Computed tomography examinations of 23 mummies from the Capuchin Catacombs of Palermo, Sicily (17 adults, 6 children; 17 anthropogenically and 6 naturally mummified) and 7 mummies from the crypt of the Dominican Church of the Holy Spirit of Vilnius, Lithuania (5 adults, 2 children; all naturally mummified) were used to develop the checklist following previously published guidelines. The scoring system was developed by assigning equal scores for checkpoints with equivalent quality. The checklist was evaluated by intra- and inter-observer reliability. The finalized checklist was applied to compare the groups of anthropogenically and naturally mummified bodies. The finalized checklist contains 97 checkpoints and was divided into two main categories, "A. Soft Tissues of Head and Musculoskeletal System" and "B. Organs and Organ Systems", each including various subcategories. The complete checklist had an intra-observer reliability of 98% and an inter-observer reliability of 93%. Statistical comparison revealed significantly higher values in anthropogenically compared to naturally mummified bodies for the total score and for three subcategories. In conclusion, the developed checklist allows for a standardized assessment and documentation of soft tissue preservation in whole-body computed tomography examinations of human mummies. The scoring system facilitates a quantitative comparison of the soft tissue preservation status between single mummies or mummy collections. PMID- 26244863 TI - A Three-Tiered Study of Differences in Murine Intrahost Immune Response to Multiple Pneumococcal Strains. AB - We apply a previously developed 4-variable ordinary differential equation model of in-host immune response to pneumococcal pneumonia to study the variability of the immune response of MF1 mice and to explore bacteria-driven differences in disease progression and outcome. In particular, we study the immune response to D39 strain of bacteria missing portions of the pneumolysin protein controlling either the hemolytic activity or complement-activating activity, the response to D39 bacteria deficient in either neuraminidase A or B, and the differences in the response to D39 (serotype 2), 0100993 (serotype 3), and TIGR4 (serotype 4) bacteria. The model accurately reproduces infection kinetics in all cases and provides information about which mechanisms in the immune response have the greatest effect in each case. Results suggest that differences in the ability of bacteria to defeat immune response are primarily due to the ability of the bacteria to elude nonspecific clearance in the lung tissue as well as the ability to create damage to the lung epithelium. PMID- 26244864 TI - Correction: Assessment of Competition between Fisheries and Steller Sea Lions in Alaska Based on Estimated Prey Biomass, Fisheries Removals and Predator Foraging Behaviour. PMID- 26244865 TI - Near Work Related Parameters and Myopia in Chinese Children: the Anyang Childhood Eye Study. AB - PURPOSE: To examine the associations of near work related parameters with spherical equivalent refraction and axial length in Chinese children. METHODS: A total of 1770 grade 7 students with mean age of 12.7 years were examined with cycloplegic autorefraction and axial length. Questions were asked regarding time spent in near work and outdoors per day, and near work related parameters. RESULTS: Multivariate models revealed the following associations with greater odds of myopia: continuous reading (> 45min), odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1-1.8; close television viewing distance (<= 3m), OR, 1.7; 95% CI, 1.2-2.3; head tilt when writing, OR, 1.3; 95% CI, 1.1-1.7, and desk lighting using fluorescent vs. incandescent lamp, OR, 1.5; 95% CI, 1.2-2.0. These factors, together with close reading distance and close nib-to-fingertip distance were significantly associated with greater myopia (P<0.01). Among near work activities, only reading more books for pleasure was significantly associated with greater myopia (P=0.03). Television viewing distance (<= 3 m), fluorescent desk light, close reading distance (<=20 cm) and close nib-to-fingertip distance (<= 2 cm) were significantly associated with longer axial length (P<0.01). Reading distance, desk light, and reading books for pleasure had significant interaction effects with parental myopia. CONCLUSIONS: Continuous reading, close distances of reading, television viewing and nib-to-fingertip, head tilt when writing, reading more books for pleasure and use of fluorescent desk light were significantly associated with myopia in 12-year-old Chinese children, which indicates that visual behaviors and environments may be important factors mediating the effects of near work on myopia. PMID- 26244869 TI - Are FSHR polymorphisms risk factors to premature ovarian insufficiency? AB - Premature ovarian insufficiency (POI) is an ovarian dysfunction characterized by increased FSH levels and amenorrhea before 40 years old. In recent years, the search for genetic causes of POI intensified and studies have been published relating the presence of mutations and polymorphisms in genes associated with development, recruitment and oocyte atresia. The aim of this study was to evaluate the presence of FSHR polymorphisms in our population and contribute with the elucidation of POI etiology. To achieve it, we have studied 100 patients with POI (G1), 60 patients with border line levels of FSH (G2) and 123 controls with regular menopause onset. Cytogenetic analysis of patients' samples and genotyping of Asn680Ser and Ala307Thr polymorphisms were performed in cases and controls. Cytogenetic analysis showed that 92% of G1 patients had normal karyotype, 4% presented polymorphic variants, 3% presented mosaic karyotype involving X chromosome. In G2, 91.6% had normal karyotype results, 3.2% displayed polymorphic variants, and 3.3% presented a mosaic karyotype involving X chromosome. Statistical comparison showed that the polymorphic allele of Ala307Thr polymorphism is more frequent in patients than in controls (G1: p < 0.001 and G2: p = 0.0259). This association has not been previously reported. We concluded that Ala307Thr polymorphism in FSHR can be potentially associated to POI development and can be considered as a screening marker in patients with ovarian failure signals. PMID- 26244868 TI - Likelihood of Null Effects of Large NHLBI Clinical Trials Has Increased over Time. AB - BACKGROUND: We explore whether the number of null results in large National Heart Lung, and Blood Institute (NHLBI) funded trials has increased over time. METHODS: We identified all large NHLBI supported RCTs between 1970 and 2012 evaluating drugs or dietary supplements for the treatment or prevention of cardiovascular disease. Trials were included if direct costs >$500,000/year, participants were adult humans, and the primary outcome was cardiovascular risk, disease or death. The 55 trials meeting these criteria were coded for whether they were published prior to or after the year 2000, whether they registered in clinicaltrials.gov prior to publication, used active or placebo comparator, and whether or not the trial had industry co-sponsorship. We tabulated whether the study reported a positive, negative, or null result on the primary outcome variable and for total mortality. RESULTS: 17 of 30 studies (57%) published prior to 2000 showed a significant benefit of intervention on the primary outcome in comparison to only 2 among the 25 (8%) trials published after 2000 (chi2=12.2,df= 1, p=0.0005). There has been no change in the proportion of trials that compared treatment to placebo versus active comparator. Industry co-sponsorship was unrelated to the probability of reporting a significant benefit. Pre-registration in clinical trials.gov was strongly associated with the trend toward null findings. CONCLUSIONS: The number NHLBI trials reporting positive results declined after the year 2000. Prospective declaration of outcomes in RCTs, and the adoption of transparent reporting standards, as required by clinicaltrials.gov, may have contributed to the trend toward null findings. PMID- 26244870 TI - Identification of Catechin, Syringic Acid, and Procyanidin B2 in Wine as Stimulants of Gastric Acid Secretion. AB - Organic acids of wine, in addition to ethanol, have been identified as stimulants of gastric acid secretion. This study characterized the influence of other wine compounds, particularly phenolic compounds, on proton secretion. Forty wine parameters were determined in four red wines and six white wines, including the contents of organic acids and phenolic compounds. The secretory activity of the wines was determined in a gastric cell culture model (HGT-1 cells) by means of a pH-sensitive fluorescent dye. Red wines stimulated proton secretion more than white wines. Lactic acid and the phenolic compounds syringic acid, catechin, and procyanidin B2 stimulated proton secretion and correlated with the pro-secretory effect of the wines. Addition of the phenolic compounds to the least active white wine sample enhanced its proton secretory effect by 65 +/- 21% (p < 0.05). These results indicate that not only malic and lactic acid but also bitter and astringent tasting phenolic compounds in wine contribute to its stimulatory effect on gastric acid secretion. PMID- 26244871 TI - CCL18-mediated down-regulation of miR98 and miR27b promotes breast cancer metastasis. AB - Our previous work has indicated that CCL18 secreted by tumor-associated macrophages (TAMs) promotes breast cancer metastasis, which is associated with poor patient prognosis. However, it remains unclear whether microRNAs (miRNAs), which may modulate multiple cellular pathways, are involved in the regulation of CCL18 signaling and the ensuing metastasis of breast cancer. In this study, we demonstrated that CCL18 reduces miR98 and miR27b expression via the N Ras/ERK/PI3K/NFkappaB/Lin28b signaling pathway, while down-regulation of these mRNAs feedbacks to increase N-Ras and Lin28b levels. This cascade of events forms a positive feedback loop that sustains the activation of CCL18 signaling. More importantly, reduction in miR98 and miR27b enhances the epithelial-mesenchymal transition (EMT) of breast cancer cells, and thus promotes breast cancer metastasis. These findings suggest that down-regulation of miR98 and miR27b promotes CCL18-mediated invasion and migration of breast cancer cells. PMID- 26244872 TI - Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma. AB - Aberrant activation of Janus kinase-3 (Jak3) and its key down-stream effectors, Signal Transducer and Activator of Transcription-3 (STAT3) and STAT5, is a key feature of malignant transformation in cutaneous T-cell lymphoma (CTCL). However, it remains only partially understood how Jak3/STAT activation promotes lymphomagenesis. Recently, non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of this malignancy. Here, we show that (i) malignant T cells display a decreased expression of a tumor suppressor miRNA, miR-22, when compared to non-malignant T cells, (ii) STAT5 binds the promoter of the miR-22 host gene, and (iii) inhibition of Jak3, STAT3, and STAT5 triggers increased expression of pri-miR-22 and miR-22. Curcumin, a nutrient with anti-Jak3 activity and histone deacetylase inhibitors (HDACi) also trigger increased expression of pri-miR-22 and miR-22. Transfection of malignant T cells with recombinant miR-22 inhibits the expression of validated miR-22 targets including NCoA1, a transcriptional co activator in others cancers, as well as HDAC6, MAX, MYCBP, PTEN, and CDK2, which have all been implicated in CTCL pathogenesis. In conclusion, we provide the first evidence that de-regulated Jak3/STAT3/STAT5 signalling in CTCL cells represses the expression of the gene encoding miR-22, a novel tumor suppressor miRNA. PMID- 26244874 TI - Building a Beetle: How Larval Environment Leads to Adult Performance in a Horned Beetle. AB - The link between the expression of the signals used by male animals in contests with the traits which determine success in those contests is poorly understood. This is particularly true in holometabolous insects such as horned beetles where signal expression is determined during metamorphosis and is fixed during adulthood, whereas performance is influenced by post-eclosion feeding. We used path analysis to investigate the relationships between larval and adult nutrition, horn and body size and fitness-related traits such as strength and testes mass in the horned beetle Euoniticellus intermedius. In males weight gain post-eclosion had a central role in determining both testes mass and strength. Weight gain was unaffected by adult nutrition but was strongly correlated with by horn length, itself determined by larval resource availability, indicating strong indirect effects of larval nutrition on the adult beetle's ability to assimilate food and grow tissues. Female strength was predicted by a simple path diagram where strength was determined by eclosion weight, itself determined by larval nutrition: weight gain post-eclosion was not a predictor of strength in this sex. Based on earlier findings we discuss the insulin-like signalling pathway as a possible mechanism by which larval nutrition could affect adult weight gain and thence traits such as strength. PMID- 26244873 TI - Physical Activity Is Linked to Greater Moment-To-Moment Variability in Spontaneous Brain Activity in Older Adults. AB - Higher cardiorespiratory fitness (CRF) and physical activity (PA) in old age are associated with greater brain structural and functional integrity, and higher cognitive functioning. However, it is not known how different aspects of lifestyle such as sedentariness, light PA (LI-PA), or moderate-to-vigorous physical activity (MV-PA) relate to neural activity in aging. In addition, it is not known whether the effects of PA on brain function differ or overlap with those of CRF. Here, we objectively measured CRF as oxygen consumption during a maximal exercise test and measured PA with an accelerometer worn for 7 days in 100 healthy but low active older adults (aged 60-80 years). We modeled the relationships between CRF, PA, and brain functional integrity using multivariate partial least squares analysis. As an index of functional brain integrity we used spontaneous moment-to-moment variability in the blood oxygenation level-dependent signal (SDBOLD), known to be associated with better cognitive functioning in aging. We found that older adults who engaged more in LI-PA and MV-PA had greater SDBOLD in brain regions that play a role in integrating segregated functional domains in the brain and benefit from greater CRF or PA, such as precuneus, hippocampus, medial and lateral prefrontal, and temporal cortices. Our results suggest that engaging in higher intensity PA may have protective effects on neural processing in aging. Finally, we demonstrated that older adults with greater overall WM microstructure were those showing more LI-PA and MV-PA and greater SDBOLD. We conclude that SDBOLD is a promising correlate of functional brain health in aging. Future analyses will evaluate whether SDBOLD is modifiable with interventions aimed to increase PA and CRF in older adults. PMID- 26244875 TI - T-lymphocyte subset dynamics in well-treated HIV-infected men during a bout of exhausting exercise. AB - In healthy individuals the substantial lymphocytosis during a bout of exhausting exercise constitutes primarily mature T cells from the peripheral lymphoid organs but naive T cells are also recruited. This study investigated whether the defective CD4 + T-lymphocyte count in peripheral blood during rest in human immunodeficiency virus (HIV)-infected patients would also be observed following a maximal output ergometer bicycle test. At rest, in 45 well-treated HIV-infected patients, mature and naive CD4 + T-lymphocyte counts were decreased whereas the less immune active CD8 + T lymphocytes were increased compared with 10 healthy control subjects. In response to exercise mature and naive CD4 + T lymphocytes increased less and mature and naive CD8 + T lymphocytes increased most in HIV infected patients. In conclusion, defective resting mature and naive CD4 + T lymphocytes in well-treated HIV-infected patients are also reflected in defective acutely mobilized active immune cells following exhausting exercise. The CD4 + T lymphocyte count is highly sensitive to physical activity. PMID- 26244878 TI - Creating a Global Health Risk Framework. PMID- 26244879 TI - Combating Emerging Threats--Accelerating the Availability of Medical Therapies. PMID- 26244877 TI - Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. AB - BACKGROUND: Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone. METHODS: We assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone. RESULTS: A total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%. CONCLUSIONS: Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00309985.). PMID- 26244881 TI - A Statistical Model for Regional Tornado Climate Studies. AB - Tornado reports are locally rare, often clustered, and of variable quality making it difficult to use them directly to describe regional tornado climatology. Here a statistical model is demonstrated that overcomes some of these difficulties and produces a smoothed regional-scale climatology of tornado occurrences. The model is applied to data aggregated at the level of counties. These data include annual population, annual tornado counts and an index of terrain roughness. The model has a term to capture the smoothed frequency relative to the state average. The model is used to examine whether terrain roughness is related to tornado frequency and whether there are differences in tornado activity by County Warning Area (CWA). A key finding is that tornado reports increase by 13% for a two-fold increase in population across Kansas after accounting for improvements in rating procedures. Independent of this relationship, tornadoes have been increasing at an annual rate of 1.9%. Another finding is the pattern of correlated residuals showing more Kansas tornadoes in a corridor of counties running roughly north to south across the west central part of the state consistent with the dryline climatology. The model is significantly improved by adding terrain roughness. The effect amounts to an 18% reduction in the number of tornadoes for every ten meter increase in elevation standard deviation. The model indicates that tornadoes are 51% more likely to occur in counties served by the CWAs of DDC and GID than elsewhere in the state. Flexibility of the model is illustrated by fitting it to data from Illinois, Mississippi, South Dakota, and Ohio. PMID- 26244880 TI - High Glucose Concentration Promotes Vancomycin-Enhanced Biofilm Formation of Vancomycin-Non-Susceptible Staphylococcus aureus in Diabetic Mice. AB - We previously demonstrated that vancomycin treatment increased acquisition of eDNA and enhanced biofilm formation of drug-resistant Staphylococcus aureus through a cidA-mediated autolysis mechanism. Recently we found that such enhancement became more significant under a higher glucose concentration in vitro. We propose that besides improper antibiotic treatment, increased glucose concentration environment in diabetic animals may further enhance biofilm formation of drug-resistant S. aureus. To address this question, the diabetic mouse model infected by vancomycin-resistant S. aureus (VRSA) was used under vancomycin treatment. The capacity to form biofilms was evaluated through a catheter-associated biofilm assay. A 10- and 1000-fold increase in biofilm-bound bacterial colony forming units was observed in samples from diabetic mice without and with vancomycin treatment, respectively, compared to healthy mice. By contrast, in the absence of glucose vancomycin reduced propensity to form biofilms in vitro through the increased production of proteases and DNases from VRSA. Our study highlights the potentially important role of increased glucose concentration in enhancing biofilm formation in vancomycin-treated diabetic mice infected by drug-resistant S. aureus. PMID- 26244882 TI - Association between TNF-alpha (-308 A/G, -238 A/G, -857 C/T) polymorphisms and responsiveness to TNF-alpha blockers in spondyloarthropathy, psoriasis and Crohn's disease: a meta-analysis. AB - AIM: The aim of this study is to investigate whether TNF-alpha polymorphisms are associated with the responsiveness to anti-TNF-alpha therapy in patients with spondyloarthropathy, psoriasis, and Crohn's disease. METHODS: We conducted a meta analysis on the association between the TNF-alpha polymorphisms and responsiveness of patients. RESULTS: The meta-analysis indicated an association between the TNF-alpha -308 G allele (OR = 2.005; 95% CI: 1.417-2.838; p = 8.6 * 10(-5)), TNF-alpha -238 G allele (OR = 2.196; 95% CI: 1161-4.154; p = 0.016), and TNF-alpha -857 C allele (OR = 1.779; 95% CI: 1.130-2.802; p = 0.013) and response to TNF-alpha blockers in Caucasians. CONCLUSION: Individuals carrying the TNF alpha -308 G, -238 G, or -857 C common alleles show better responses to TNF-alpha blockers than those with minor alleles in Caucasians. PMID- 26244883 TI - Cerebral Correlates of Abnormal Emotion Conflict Processing in Euthymic Bipolar Patients: A Functional MRI Study. AB - BACKGROUND: Patients with bipolar disorder experience cognitive and emotional impairment that may persist even during the euthymic state of the disease. These persistent symptoms in bipolar patients (BP) may be characterized by disturbances of emotion regulation and related fronto-limbic brain circuitry. The present study aims to investigate the modulation of fronto-limbic activity and connectivity in BP by the processing of emotional conflict. METHODS: Fourteen euthymic BP and 13 matched healthy subjects (HS) underwent functional magnetic resonance imaging (fMRI) while performing a word-face emotional Stroop task designed to dissociate the monitoring/generation of emotional conflict from its resolution. Functional connectivity was determined by means of psychophysiological interaction (PPI) approach. RESULTS: Relative to HS, BP were slower to process incongruent stimuli, reflecting higher amount of behavioral interference during emotional Stroop. Furthermore, BP showed decreased activation of the right dorsolateral prefrontal cortex (DLPFC) during the monitoring and a lack of bilateral amygdala deactivation during the resolution of the emotional conflict. In addition, during conflict monitoring, BP showed abnormal positive connectivity between the right DLPFC and several regions of the default mode network. CONCLUSIONS: Overall, our results highlighted dysfunctional processing of the emotion conflict in euthymic BP that may be subtended by abnormal activity and connectivity of the DLPFC during the conflict monitoring, which, in turn, leads to failure of amygdala deactivation during the resolution of the conflict. Emotional dysregulation in BP may be underpinned by a lack of top-down cognitive control and a difficulty to focus on the task due to persistent self-oriented attention. PMID- 26244884 TI - Metabolite Profiling and Classification of DNA-Authenticated Licorice Botanicals. AB - Raw licorice roots represent heterogeneous materials obtained from mainly three Glycyrrhiza species. G. glabra, G. uralensis, and G. inflata exhibit marked metabolite differences in terms of flavanones (Fs), chalcones (Cs), and other phenolic constituents. The principal objective of this work was to develop complementary chemometric models for the metabolite profiling, classification, and quality control of authenticated licorice. A total of 51 commercial and macroscopically verified samples were DNA authenticated. Principal component analysis and canonical discriminant analysis were performed on (1)H NMR spectra and area under the curve values obtained from UHPLC-UV chromatograms, respectively. The developed chemometric models enable the identification and classification of Glycyrrhiza species according to their composition in major Fs, Cs, and species specific phenolic compounds. Further key outcomes demonstrated that DNA authentication combined with chemometric analyses enabled the characterization of mixtures, hybrids, and species outliers. This study provides a new foundation for the botanical and chemical authentication, classification, and metabolomic characterization of crude licorice botanicals and derived materials. Collectively, the proposed methods offer a comprehensive approach for the quality control of licorice as one of the most widely used botanical dietary supplements. PMID- 26244886 TI - Glycoforms of Immunoglobulin G Based Biopharmaceuticals Are Differentially Cleaved by Trypsin Due to the Glycoform Influence on Higher-Order Structure. AB - It has been reported that glycosylation can influence the proteolytic cleavage of proteins. A thorough investigation of this phenomenon was conducted for the serine protease trypsin, which is essential in many proteomics workflows. Monoclonal and polyclonal immunoglobulin G biopharmaceuticals were employed as model substances, which are highly relevant for the bioanalytical applications. Relative quantitation of glycopeptides derived from the conserved Fc glycosylation site allowed resolution of biases on the level of individual glycan compositions. As a result, a strong preferential digestion of high mannose, hybrid, alpha2-3-sialylated and bisected glycoforms was observed over the most abundant neutral, fucosylated glycoforms. Interestingly, this bias was, to a large extent, dependent on the intact higher order structure of the antibodies and, consequently, was drastically reduced in denatured versus intact antibodies. In addition, a cleavage protocol with acidic denaturation was tested, which featured reduced hands-on time and toxicity while showing highly comparable results to a published denaturation, reduction, and alkylation based protocol. PMID- 26244885 TI - An Extended, Boolean Model of the Septation Initiation Network in S.Pombe Provides Insights into Its Regulation. AB - Cytokinesis in fission yeast is controlled by the Septation Initiation Network (SIN), a protein kinase signaling network using the spindle pole body as scaffold. In order to describe the qualitative behavior of the system and predict unknown mutant behaviors we decided to adopt a Boolean modeling approach. In this paper, we report the construction of an extended, Boolean model of the SIN, comprising most SIN components and regulators as individual, experimentally testable nodes. The model uses CDK activity levels as control nodes for the simulation of SIN related events in different stages of the cell cycle. The model was optimized using single knock-out experiments of known phenotypic effect as a training set, and was able to correctly predict a double knock-out test set. Moreover, the model has made in silico predictions that have been validated in vivo, providing new insights into the regulation and hierarchical organization of the SIN. PMID- 26244887 TI - Influence of Ventilation Strategies and Anesthetic Techniques on Regional Cerebral Oximetry in the Beach Chair Position: A Prospective Interventional Study with a Randomized Comparison of Two Anesthetics. AB - BACKGROUND: Beach chair positioning during general anesthesia is associated with cerebral oxygen desaturation. Changes in cerebral oxygenation resulting from the interaction of inspired oxygen fraction (FIO2), end-tidal carbon dioxide (PETCO2), and anesthetic choice have not been fully evaluated in anesthetized patients in the beach chair position. METHODS: This is a prospective interventional within-group study of patients undergoing shoulder surgery in the beach chair position that incorporated a randomized comparison between two anesthetics. Fifty-six patients were randomized to receive desflurane or total intravenous anesthesia with propofol. Following induction of anesthesia and positioning, FIO2 and minute ventilation were sequentially adjusted for all patients. Regional cerebral oxygenation (rSO2) was the primary outcome and was recorded at each of five set points. RESULTS: While maintaining FIO2 at 0.3 and PETCO2 at 30 mmHg, there was a decrease in rSO2 from 68% (SD, 12) to 61% (SD, 12) (P < 0.001) following beach chair positioning. The combined interventions of increasing FIO2 to 1.0 and increasing PETCO2 to 45 mmHg resulted in a 14% point improvement in rSO2 to 75% (SD, 12) (P <0.001) for patients anesthetized in the beach chair position. There was no significant interaction effect of the anesthetic at the study intervention points. CONCLUSIONS: Increasing FIO2 and PETCO2 resulted in a significant increase in rSO2 that overcomes desaturation in patients anesthetized in the beach chair position and that appears independent of anesthetic choice. PMID- 26244888 TI - Impaired Pain-evoked Analgesia after Nerve Injury in Rats Reflects Altered Glutamate Regulation in the Locus Coeruleus. AB - BACKGROUND: Patients with neuropathic pain show reduced endogenous analgesia induced by a conditioned noxious stimulus. Here, the authors tested whether peripheral nerve injury impairs descending noradrenergic inhibition from the locus coeruleus (LC) after L5-L6 spinal nerve ligation (SNL) in rats. METHODS: A subdermal injection of capsaicin was used to examine noxious stimulation-induced analgesia (NSIA), evoked LC glutamate and spinal noradrenaline release, and evoked LC neuronal activity in normal and SNL rats. The authors also examined the role of presynaptic metabotropic glutamate receptors or the astroglial glutamate transporter-1 (GLT-1). RESULTS: SNL increased basal extracellular glutamate concentration in the LC (170.1%; 95% CI, 44.7 to 295.5; n = 15) and basal spinal cord noradrenaline release (252.1%; 95% CI, 113.6 to 391.3; n = 15), which was associated with an increased tonic LC neuronal activity and a down-regulation of GLT-1 in the LC. SNL reduced NSIA (-77.6%; 95% CI, -116.4 to -38.8; n = 14) and capsaicin evoked release of glutamate in the LC (-36.2%; 95% CI, -49.3 to -23.2; n = 8) and noradrenaline in the spinal cord (-38.8%; 95% CI, -45.1 to -32.5; n = 8). Capsaicin-evoked LC neuronal activation was masked in SNL rats. Removing autoinhibition of glutamatergic terminals by metabotropic glutamate receptor blockade or increasing GLT-1 expression by histone deacetylase inhibition restored NSIA in SNL rats. SNL-induced impairment of NSIA was mimicked in normal rats by knockdown of GLT-1 in the LC. CONCLUSIONS: These results suggest that increased extracellular glutamate in the LC consequent to down-regulation of GLT 1 contributes to LC dysfunction and impaired pain-evoked endogenous analgesia after nerve injury. PMID- 26244889 TI - FROG - Fingerprinting Genomic Variation Ontology. AB - Genetic variations play a crucial role in differential phenotypic outcomes. Given the complexity in establishing this correlation and the enormous data available today, it is imperative to design machine-readable, efficient methods to store, label, search and analyze this data. A semantic approach, FROG: "FingeRprinting Ontology of Genomic variations" is implemented to label variation data, based on its location, function and interactions. FROG has six levels to describe the variation annotation, namely, chromosome, DNA, RNA, protein, variations and interactions. Each level is a conceptual aggregation of logically connected attributes each of which comprises of various properties for the variant. For example, in chromosome level, one of the attributes is location of variation and which has two properties, allosomes or autosomes. Another attribute is variation kind which has four properties, namely, indel, deletion, insertion, substitution. Likewise, there are 48 attributes and 278 properties to capture the variation annotation across six levels. Each property is then assigned a bit score which in turn leads to generation of a binary fingerprint based on the combination of these properties (mostly taken from existing variation ontologies). FROG is a novel and unique method designed for the purpose of labeling the entire variation data generated till date for efficient storage, search and analysis. A web-based platform is designed as a test case for users to navigate sample datasets and generate fingerprints. The platform is available at http://ab openlab.csir.res.in/frog. PMID- 26244891 TI - Components of Particle Emissions from Light-Duty Spark-Ignition Vehicles with Varying Aromatic Content and Octane Rating in Gasoline. AB - Typical gasoline consists of varying concentrations of aromatic hydrocarbons and octane ratings. However, their impacts on particulate matter (PM) such as black carbon (BC) and water-soluble and insoluble particle compositions are not well defined. This study tests seven 2012 model year vehicles, which include one port fuel injection (PFI) configured hybrid vehicle, one PFI vehicle, and six gasoline direct injection (GDI) vehicles. Each vehicle was driven on the Unified transient testing cycle (UC) using four different fuels. Three fuels had a constant octane rating of 87 with varied aromatic concentrations at 15%, 25%, and 35%. A fourth fuel with higher octane rating, 91, contained 35% aromatics. BC, PM mass, surface tension, and water-soluble organic mass (WSOM) fractions were measured. The water insoluble mass (WIM) fraction of the vehicle emissions was estimated. Increasing fuel aromatic content increases BC emission factors (EFs) of transient cycles. BC concentrations were higher for the GDI vehicles than the PFI and hybrid vehicles, suggesting a potential climate impact for increased GDI vehicle production. Vehicle steady-state testing showed that the hygroscopicity of PM emissions at high speeds (70 mph; kappa > 1) are much larger than emissions at low speeds (30 mph; kappa < 0.1). Iso-paraffin content in the fuels was correlated to the decrease in WSOM emissions. Both aromatic content and vehicle speed increase the amount of hygroscopic material found in particle emissions. PMID- 26244890 TI - Clade-Specific Quantitative Analysis of Photosynthetic Gene Expression in Prochlorococcus. AB - Newly designed primers targeting rbcL (CO2 fixation), psbA (photosystem II) and rnpB (reference) genes were used in qRT-PCR assays to assess the photosynthetic capability of natural communities of Prochlorococcus, the most abundant photosynthetic organism on Earth and a major contributor to primary production in oligotrophic oceans. After optimizing sample collection methodology, we analyzed a total of 62 stations from the Malaspina 2010 circumnavigation (including Atlantic, Pacific and Indian Oceans) at three different depths. Sequence and quantitative analyses of the corresponding amplicons showed the presence of high light (HL) and low-light (LL) Prochlorococcus clades in essentially all 182 samples, with a largely uniform stratification of LL and HL sequences. Synechococcus cross-amplifications were detected by the taxon-specific melting temperatures of the amplicons. Laboratory exposure of Prochlorococcus MED4 (HL) and MIT9313 (LL) strains to organic pollutants (PAHs and organochlorine compounds) showed a decrease of rbcL transcript abundances, and of the rbcL to psbA ratios for both strains. We propose this technique as a convenient assay to evaluate effects of environmental stressors, including pollution, on the oceanic Prochlorococcus photosynthetic function. PMID- 26244892 TI - A Genomic Approach to Unravel Host-Pathogen Interaction in Chelonians: The Example of Testudinid Herpesvirus 3. AB - We report the first de novo sequence assembly and analysis of the genome of Testudinid herpesvirus 3 (TeHV3), one of the most pathogenic chelonian herpesviruses. The genome of TeHV3 is at least 150,080 nucleotides long, is arranged in a type D configuration and comprises at least 102 open reading frames extensively co-linear with those of Human herpesvirus 1. Consistently, the phylogenetic analysis positions TeHV3 among the Alphaherpesvirinae, closely associated with Chelonid herpesvirus 5, a Scutavirus. To date, there has been limited genetic characterization of TeHVs and a resolution beyond the genotype was not feasible because of the lack of informative DNA sequences. To exemplify the potential benefits of the novel genomic information provided by this first whole genome analysis, we selected the glycoprotein B (gB) gene, for detailed comparison among different TeHV3 isolates. The rationale for selecting gB is that it encodes for a well-conserved protein among herpesviruses but is coupled with a relevant antigenicity and is consequently prone to accumulate single nucleotide polymorphisms. These features were considered critical for an ideal phylogenetic marker to investigate the potential existence of distinct TeHV3 genogroups and their associated pathology. Fifteen captive tortoises presumptively diagnosed to be infected with TeHVs or carrying compatible lesions on the basis of either the presence of intranuclear inclusions (presumptively infected) and/or diphtheronecrotic stomatitis-glossitis or pneumonia (compatible lesions) were selected for the study. Viral isolation, TeHV identification, phylogenetic analysis and pathological characterization of the associated lesions, were performed. Our results revealed 1) the existence of at least two distinct TeHV3 genogroups apparently associated with different pathologies in tortoises and 2) the first evidence for a putative homologous recombination event having occurred in a chelonian herpesvirus. This novel information is not only fundamental for the genetic characterization of this virus but is also critical to lay the groundwork for an improved understanding of host-pathogen interactions in chelonians and contribute to tortoise conservation. PMID- 26244893 TI - Dynamic Allostery of the Catabolite Activator Protein Revealed by Interatomic Forces. AB - The Catabolite Activator Protein (CAP) is a showcase example for entropic allostery. For full activation and DNA binding, the homodimeric protein requires the binding of two cyclic AMP (cAMP) molecules in an anti-cooperative manner, the source of which appears to be largely of entropic nature according to previous experimental studies. We here study at atomic detail the allosteric regulation of CAP with Molecular dynamics (MD) simulations. We recover the experimentally observed entropic penalty for the second cAMP binding event with our recently developed force covariance entropy estimator and reveal allosteric communication pathways with Force Distribution Analyses (FDA). Our observations show that CAP binding results in characteristic changes in the interaction pathways connecting the two cAMP allosteric binding sites with each other, as well as with the DNA binding domains. We identified crucial relays in the mostly symmetric allosteric activation network, and suggest point mutants to test this mechanism. Our study suggests inter-residue forces, as opposed to coordinates, as a highly sensitive measure for structural adaptations that, even though minute, can very effectively propagate allosteric signals. PMID- 26244894 TI - Macrocyclic metal complexes for metalloenzyme mimicry and sensor development. AB - Examples of proteins that incorporate one or more metal ions within their structure are found within a broad range of classes, including oxidases, oxidoreductases, reductases, proteases, proton transport proteins, electron transfer/transport proteins, storage proteins, lyases, rusticyanins, metallochaperones, sporulation proteins, hydrolases, endopeptidases, luminescent proteins, iron transport proteins, oxygen storage/transport proteins, calcium binding proteins, and monooxygenases. The metal coordination environment therein is often generated from residues inherent to the protein, small exogenous molecules (e.g., aqua ligands) and/or macrocyclic porphyrin units found, for example, in hemoglobin, myoglobin, cytochrome C, cytochrome C oxidase, and vitamin B12. Thus, there continues to be considerable interest in employing macrocyclic metal complexes to construct low-molecular weight models for metallobiosites that mirror essential features of the coordination environment of a bound metal ion without inclusion of the surrounding protein framework. Herein, we review and appraise our research exploring the application of the metal complexes formed by two macrocyclic ligands, 1,4,7-triazacyclononane (tacn) and 1,4,7,10-tetraazacyclododecane (cyclen), and their derivatives in biological inorganic chemistry. Taking advantage of the kinetic inertness and thermodynamic stability of their metal complexes, these macrocyclic scaffolds have been employed in the development of models that aid the understanding of metal ion binding natural systems, and complexes with potential applications in biomolecule sensing, diagnosis, and therapy. In particular, the focus has been on "coordinatively unsaturated" metal complexes that incorporate a kinetically inert and stable metal-ligand moiety, but which also contain one or more weakly bound ligands, allowing for the reversible binding of guest molecules via the formation and dissociation of coordinate bonds. With regards to mimicking metallobiosites, examples are presented from our work on tacn-based complexes developed as simplified structural models for multimetallic enzyme sites. In particular, structural comparisons are made between multinuclear copper(II) complexes formed by such ligands and multicopper enzymes featuring type-2 and type-3 copper centers, such as ascorbate oxidase (AO) and laccase (Lc). Likewise, with the aid of relevant examples, we highlight the importance of cooperativity between either multiple metal centers or a metal center and a proximal auxiliary unit appended to the macrocyclic ligand in achieving efficient phosphate ester cleavage. Finally, the critical importance of the Zn(II)-imido and Zn(II)-phosphate interactions in Zn-cyclen-based systems for delivering highly sensitive electrochemical and fluorescent chemosensors is also showcased. The Account additionally highlights some of the factors that limit the performance of these synthetic nucleases and the practical application of the biosensors, and then identifies some avenues for the development of more effective macrocyclic constructs in the future. PMID- 26244895 TI - Phenylalanine Oligomers and Fibrils: The Mechanism of Assembly and the Importance of Tetramers and Counterions. AB - Phenylalanine is the only amino acid known to self-assemble into toxic fibrillar aggregates. An elevated concentration of phenylalanine in the blood can result in Phenylketonuria, a progressive mental retardation. Ion-mobility mass spectrometry is employed to investigate the structure and distribution of phenylalanine oligomers formed in the early stage of the aggregation cascade. The experimental cross sections indicate that phenyl-alanine self-assembles at neutral pH into oligomers composed of multiple layers of four monomers. The monomers arrange themselves to create a hydrophilic core made of zwitterionic termini and expose hydrophobic aromatic side chains to the outside. At high pH, the interactions between the neutral amino and negatively charged carboxylate of phenylalanine allow a minor population of ladder-like oligomers to be formed and detected in ion-mobility experiments. However, counterions such as ammonium rearrange those structures into the same structures observed at neutral pH. The cytotoxicity of Phe oligomers and fibrils may be due to favorable interactions between the hydrophobic exterior and the cell membrane and strong interactions between the hydrophilic core of Phe oligomers and ions, resulting in ion leakage and cellular damage. PMID- 26244897 TI - Osteoarthritis among the prehispanic population from La Gomera and El Hierro (Canary Islands): a comparative study. AB - The pathogenesis of osteoarthritis is still unclear, and several factors may play a role in its development, including joint trauma or microtrauma (usually related to lifestyle), local inflammation, loading charge, and genetics. Assessment of osteoarthritis among ancient populations is important, since it may yield information relative to life habits. Therefore, we have performed the present study in order to assess the prevalence of osteoarthritis among the prehispanic populations from La Gomera and El Hierro, two islands of the Canary Archipelago with a similar size and altitude which were colonized by individuals of North African origin about 2000 - 2500 years ago. The economy of these people was based on goat herding, shellfishing, and agriculture together with consumption of some wild vegetal species. However, despite a similar geographic environment and a similar economic pattern, prevalence of osteoarthritis was by far higher among the population from La Gomera (78.57 % vs 15.85 %, p < 0.001), and that of eburnation, 11.65 % and 1.05 %, respectively (p = 0.016); in contrast, the population of El Hierro was markedly more robust than that of La Gomera. Globally, a trend to an inverse relationship was observed between epiphyseal robusticity index and the presence of osteoarthritis, which was statistically significant when only men were analysed. However, after performing a multivariate analysis, the only factor that was independently related to the presence of osteoarthritis was the variable "island" (i.e., population group), suggesting that - possibly - genetic factors played a major role in the differences observed. PMID- 26244896 TI - Functional Local Renin-Angiotensin System in Human and Rat Periodontal Tissue. AB - The initiation or progression of periodontitis might involve a local renin angiotensin system (RAS) in periodontal tissue. The aim of this study was to further characterize the local RAS in human and rat periodontal tissues between healthy and periodontally-affected tissue. Components of the RAS were investigated using in vitro, ex vivo and in vivo experiments involving both human and Wistar rat periodontium. Although not upregulated when challenged with P. gingivalis-lipopolysaccharide, human gingival and periodontal ligament fibroblasts expressed RAS components. Likewise, healthy and inflamed human gingiva expressed RAS components, some of which were shown to be functional, yet no differences in expression were found between healthy and diseased gingiva. However, in inflamed tissue the immunoreactivity was greater for the AT1R compared to AT2R in fibroblasts. When compared to healthy tissue, ACE activity was increased in human gingiva from volunteers with gingivitis. Human-gingiva homogenates generated Ang II, Ang 1-9 and Ang 1-7 when incubated with precursors. In gingiva homogenates, Ang II formation from Ang I was nearly abolished only when captopril and chymostatin were combined. Ang 1-7 formation was significantly greater when human gingiva homogenates were incubated with chymostatin alone compared to incubation without any inhibitor, only captopril, or captopril and chymostatin. In rat gingiva, RAS components were also found; their expression was not different between healthy and experimentally induced periodontitis (EP) groups. However, renin inhibition (aliskiren) and an AT1R antagonist (losartan) significantly blocked EP-alveolar-bone loss in rats. Collectively, these data are consistent with the hypothesis that a local RAS system is not only present but is also functional in both human and rat periodontal tissue. Furthermore, blocking AT1R and renin can significantly prevent periodontal bone loss induced by EP in rats. PMID- 26244898 TI - Postnatal Environmental Tobacco Smoke Exposure Related to Behavioral Problems in Children. AB - OBJECTIVE: The purpose of this study was to examine the association between pre and post environmental tobacco smoke (ETS) exposure and behavioral problems in schoolchildren. METHODS: In the cross-sectional 6 cities Study conducted in France, 5221 primary school children were investigated. Pre- and postnatal exposure to secondhand tobacco smoke at home was assessed using a parent questionnaire. Child's behavioral outcomes (emotional symptoms and conduct problems) were evaluated by the Strengths and Difficulties Questionnaire (SDQ) completed by the parents. RESULTS: ETS exposure during the postnatal period and during both pre- and postnatal periods was associated with behavioral problems in children. Abnormal emotional symptoms (internalizing problems) were related to ETS exposure in children who were exposed during the pre- and postnatal periods with an OR of 1.72 (95% Confidence Interval (CI)= 1.36-2.17), whereas the OR was estimated to be 1.38 (95% CI= 1.12-1.69) in the case of postnatal exposure only. Abnormal conduct problems (externalizing problems) were related to ETS exposure in children who were exposed during the pre- and postnatal periods with an OR of 1.94 (95% CI= 1.51-2.50), whereas the OR was estimated to be 1.47 (95% CI=1.17 1.84) in the case of postnatal exposure only. Effect estimates were adjusted for gender, study center, ethnic origin, child age, low parental education, current physician diagnosed asthma, siblings, preterm birth and single parenthood. CONCLUSION: Postnatal ETS exposure, alone or in association with prenatal exposure, increases the risk of behavioral problems in school-age children. PMID- 26244900 TI - The Additional Cost Burden of Preexisting Medical Conditions During Pregnancy and Childbirth. AB - OBJECTIVES: To identify the prevalence of comorbidities in pregnant women and examine the incremental costs of these conditions on the care for mothers and their newborns. METHODS: This was a retrospective comparative cohort study of women ages 15-49 years with a documented live-birth delivery using de-identified claims from the MarketScan Research Commercial Claims and Encounters database incurred between January 1, 2007, and December 31, 2011. Total health care costs from date of first pregnancy-related claim through 3 months postdelivery were reported; pregnancy-related comorbidities prior to the pregnancy diagnosis were identified and categorized in the 12 months prior to the pregnancy diagnosis, and costs associated with each condition were compiled. A subset of newborns was matched to their mothers using a unique family identifier and their costs were captured for the three months following birth. Comparisons of costs for both mothers and newborns were made using both unadjusted and multivariate analyses between mothers with and without each condition. RESULTS: A total of 322,141 women with live births were identified; 135,572 of these mothers were linked to their newborn(s). Prevalent conditions included back disorders (8.9%), mental disorders (6.5%), headache (5.5%), allergic rhinitis (5.5%), and osteoarthritis (4.8%). Diabetes (0.97%) and hypertension (1.9%) were associated with the highest adjusted incremental costs of care in both mothers ($6,211 [95% confidence interval 5,720-6,702] and $3,367 [95% CI 2,935-3,799] respectively) and newborns ($2,067 [95% CI 1,515-2618]; and $1,210 [95% CI 725-1,695] respectively). The two most common conditions, back disorders and mental disorders, were associated with unadjusted costs of $1,895/$978 (mothers/infants) and $2,097/$1,902 (mothers/infants) respectively. CONCLUSION: Preexisting conditions common in pregnant women may result in additional resource utilization and costs for both mothers and newborns. PMID- 26244901 TI - Baseline higher peritoneal transport had been associated with worse nutritional status of incident continuous ambulatory peritoneal dialysis patients in Southern China: a 1-year prospective study. AB - The aim of the present study was to investigate the relationship between baseline peritoneal transport types and nutritional status in Chinese continuous ambulatory peritoneal dialysis (CAPD) patients. In the present single-centre, prospective study, incident CAPD patients were included from 15 April 2010 to 31 December 2011 and were followed up for 12 months. According to the results of baseline peritoneal equilibration test, patients were divided into lower peritoneal transport group (lower transporters) and higher peritoneal transport group (higher transporters). Nutritional status was evaluated by both subjective global assessment (SGA) and protein-energy wasting (PEW) score. The body composition parameters were assessed by body impedance analysis. A total of 283 CAPD patients were included in the study, of which 171 (60.4 %) were males with a mean age of 47.0 (sd 14.9) years. Compared with lower transporters (n 92), higher transporters (n 181) had lower levels of serum albumin (37.1 (sd 4.3) v. 39.6 (sd 4.3) g/l, P< 0.001), serum pre-albumin (356 (sd 99) v. 384 (sd 90) mg/l, P= 0.035), phase angle (6.15 (sd 0.39) v. 6.27 (sd 0.47) degrees , P< 0.05) and higher rate of malnutrition defined by SGA (52.5 v. 25.0%, P< 0.001) and PEW score (37.0 v. 14.1 %, P< 0.001) at 1-year of follow-up. Baseline higher peritoneal transport, analysed by multivariate binary logistic regressions, was independently associated with malnutrition (SGA mild to moderate and severe malnutrition: OR 3.43, 95% CI 1.69, 6.96, P< 0.01; PEW: OR 2.40, 95% CI 1.08, 5.31, P= 0.03). It was concluded that baseline higher peritoneal transport was independently associated with worse nutritional status of CAPD patients in Southern China. PMID- 26244904 TI - Concentration Field Evolution during the Drying of a Thin Polymer Solution Film near the Contact Line. AB - An experimental study is performed for polymer concentration field measurements during the drying of an aqueous poly(vinyl alcohol) solution inside a shallow cavity near a vertical side wall. The measurements are based on optical techniques such as 3D confocal microscopy for laser-induced fluorescence analysis. The results reveal a significant concentration heterogeneity across the film near the meniscus during the drying process. The concentration at the solution-air interface remains higher compared to the bulk, and it increases toward the pinned contact line and also over time. A skin layer starts forming as the surface concentration reaches the glass-transition concentration, after which the evaporation rate starts decreasing. Regardless of the cavity depth and the initial polymer concentration, the drying film undergoes a similar concentration evolution during the evaporation process, although minor differences can be recognized. For instance, a low local capillary number at the surface is associated with a wavy surface concentration profile while at higher capillary numbers disturbances are damped and a much more uniform concentration profile is observed. PMID- 26244903 TI - Mobile Device-Based Applications for Childhood Anxiety Disorders. AB - OBJECTIVE: Given that childhood anxiety disorders are common and frequently undertreated, novel treatment platforms are needed. The current article explores the potential for mobile device-based (m-health) applications, to expand access to evidence-based treatment. METHODS: This article reviews the relevant literature regarding barriers to disseminating evidence-based treatment, the potential benefits of the m-health platform, standards for evaluating m-health interventions, and currently available applications. RESULTS: Although a large number of m-health applications for anxiety are available, the vast majority of them are inconsistent with therapy protocols supported by the child anxiety treatment literature. The relatively few m-health applications based on evidence based practice have not yet been examined empirically. CONCLUSIONS: Realizing the potential of m-health for child anxiety will require addressing the uncertainty around the necessary and sufficient components of cognitive-behavioral therapy (CBT), as well as the common challenges associated with delivering interventions via information and communication technology. Mayo Clinic Anxiety Coach is an m health application designed by the author and colleagues to be consistent with exposure-based CBT and principles for effective intervention delivery via information and communication technology. Recommendations for identifying, using, and developing m-health applications for childhood anxiety disorders are presented. PMID- 26244906 TI - Analysis of copy number variations by SNP50 BeadChip array in Chinese sheep. AB - The sheep (Ovis aries) plays a major socio-economic role in the world. Copy number variations (CNVs) are increasingly recognized as a key and potent source of genetic variation and phenotypic diversity, but little is known about the extent to which CNVs contribute to genetic variation in Chinese sheep breeds. Analyses of CNVs in the genomes of eight sheep breeds were performed using the sheep SNP50 BeadChip genotyping array. A total of 111 CNV regions (CNVRs) were obtained from 160 Chinese sheep breeds. These CNVRs covered 13.75Mb of the sheep genome sequence. A total of 22 Go terms and 17 candidate genes were obtained from the functional analysis. Ten CNVRs were selected for validation, of which 7 CNVRs were further experimentally confirmed by quantitative PCR. Four candidate genes were selected to confirm the results of the functional analysis. These results provide a resource for furthering understanding of ruminant biology, and for further improving the genetic quality of sheep breeds. PMID- 26244905 TI - Graphene-based nanomaterials: biological and medical applications and toxicity. AB - Graphene and its derivatives, due to a wide range of unique properties that they possess, can be used as starting material for the synthesis of useful nanocomplexes for innovative therapeutic strategies and biodiagnostics. Here, we summarize the latest progress in graphene and its derivatives and their potential applications for drug delivery, gene delivery, biosensor and tissue engineering. A simple comparison with carbon nanotubes uses in biomedicine is also presented. We also discuss their in vitro and in vivo toxicity and biocompatibility in three different life kingdoms (bacterial, mammalian and plant cells). All aspects of how graphene is internalized after in vivo administration or in vitro cell exposure were brought about, and explain how blood-brain barrier can be overlapped by graphene nanomaterials. PMID- 26244907 TI - Differences in properties and proteomes of the midribs contribute to the size of the leaf angle in two near-isogenic maize lines. AB - The midrib of maize leaves provides the primary support for the blade and is largely associated with leaf angle size. To elucidate the role of the midrib in leaf angle formation, the maize line Shen137 (larger leaf angle) and a near isogenic line (NIL, smaller leaf angle) were used in the present study. The results of the analysis showed that both the puncture forces and proximal collenchyma number of the midribs of the first and second leaves above the ear were higher in NIL than in Shen137. Comparative proteomic analysis was performed to reveal protein profile differences in the midribs of the 5th, 10th and 19th newly expanded leaves between Shen137 and NIL. Quantitative analysis of 24 identified midrib proteins indicated that the maximum changes in abundance of 22 proteins between Shen137 and NIL appeared at the 10th leaf stage, of which phosphoglycerate kinase, adenosine kinase, fructose-bisphosphate aldolase and adenylate kinase were implicated in glycometabolism. Thus, glycometabolism might be associated with leaf angle formation and the physical and mechanical properties of the midribs. These results provide insight into the mechanism underlying maize leaf angle formation. PMID- 26244909 TI - Estimation of Life-Years Saved by Solid-Organ Transplant--Reply. PMID- 26244908 TI - A proteomic perspective of the interplay of Staphylococcus aureus and human alveolar epithelial cells during infection. AB - Infectious diseases caused by pathogens such as Staphylococcus aureus are still a major threat for human health. Proteome analyses allow detailed monitoring of the molecular interplay between pathogen and host upon internalization. However, the investigation of the responses of both partners is complicated by the large excess of host cell proteins compared to bacterial proteins as well as by the fact that only a fraction of host cells are infected. In the present study we infected human alveolar epithelial A549 cells with S. aureus HG001 pMV158GFP and separated intact bacteria from host cell debris or infected from non-infected A549 cells by cell sorting to enable detailed proteome analysis. During the first 6.5h in the intracellular milieu S. aureus displayed reduced growth rate, induction of the stringent response, adaptation to microaerobic conditions as well as cell wall stress. Interestingly, both truly infected host cells and those not infected but exposed to secreted S. aureus proteins and host cell factors showed differences in the proteome pattern compared to A549 cells which had never been in contact with S. aureus. However, adaptation reactions were more pronounced in infected compared to non-infected A549 bystander cells. PMID- 26244910 TI - From Reef to Table: Social and Ecological Factors Affecting Coral Reef Fisheries, Artisanal Seafood Supply Chains, and Seafood Security. AB - Ocean and coastal ecosystems provide critical fisheries, coastal protection, and cultural benefits to communities worldwide, but these services are diminishing due to local and global threats. In response, place-based strategies involve communities and resource users in management have proliferated. Here, we present a transferable community-based approach to assess the social and ecological factors affecting resource sustainability and food security in a small-scale, coral reef fishery. Our results show that this small-scale fishery provides large scale benefits to communities, including 7,353 +/- 1547 kg yr(-1) (mean +/- SE) of seafood per year, equating to >30,000 meals with an economic value of $78,432. The vast majority of the catch is used for subsistence, contributing to community food security: 58% is kept, 33.5% is given away, and 8.5% is sold. Our spatial analysis assesses the geographic distribution of community beneficiaries from the fishery (the "food shed" for the fishery), and we document that 20% of seafood procured from the fishery is used for sociocultural events that are important for social cohesion. This approach provides a method for assessing social, economic, and cultural values provided by small-scale food systems, as well as important contributions to food security, with significant implications for conservation and management. This interdisciplinary effort aims to demonstrate a transferable participatory research approach useful for resource-dependent communities as they cope with socioeconomic, cultural, and environmental change. PMID- 26244911 TI - Mn(II) Binding and Subsequent Oxidation by the Multicopper Oxidase MnxG Investigated by Electron Paramagnetic Resonance Spectroscopy. AB - The dynamics of manganese solid formation (as MnOx) by the multicopper oxidase (MCO)-containing Mnx protein complex were examined by electron paramagnetic resonance (EPR) spectroscopy. Continuous-wave (CW) EPR spectra of samples of Mnx, prepared in atmosphere and then reacted with Mn(II) for times ranging from 7 to 600 s, indicate rapid oxidation of the substrate manganese (with two-phase pseudo first-order kinetics modeled using rate coefficients of: k(1obs) = 0.205 +/- 0.001 s(-1) and k(2obs) = 0.019 +/- 0.001 s(-1)). This process occurs on approximately the same time scale as in vitro solid MnOx formation when there is a large excess of Mn(II). We also found CW and pulse EPR spectroscopic evidence for at least three classes of Mn(II)-containing species in the reaction mixtures: (i) aqueous Mn(II), (ii) a specifically bound mononuclear Mn(II) ion coordinated to the Mnx complex by one nitrogenous ligand, and (iii) a weakly exchange-coupled dimeric Mn(II) species. These findings provide new insights into the molecular mechanism of manganese mineralization. PMID- 26244912 TI - Reverse Engineering: Strategy to Teach Evidence-Based Practice to Online RN-to BSN Students. AB - This article describes an innovative approach to introducing RN-to-BSN students to nursing research and evidence-based practice (EBP). Reverse engineering updates an existing EBP project to better emphasize the role of research and evidence to practicing RNs enrolled in an RN-to-BSN program. Reverse engineering of a nursing practice guideline offers a method for teaching an appreciation of research and supporting nursing practice with best evidence. PMID- 26244914 TI - Attachment's Links With Adolescents' Social Emotions: The Roles of Negative Emotionality and Emotion Regulation. AB - Recent research has attempted to explain the mechanisms through which parental attachment affects social and emotional outcomes (e.g., Burnette, Taylor, Worthington, & Forsyth, 2007 ; Panfile & Laible, 2012 ). The authors' goal was to examine negative emotionality and emotion regulation as mediators of the associations that attachment has with empathy, forgiveness, guilt, and jealousy. One hundred forty-eight adolescents reported their parental attachment security, general levels of negative emotionality and abilities to regulate emotional responses, and tendencies to feel empathy, forgiveness, guilt, and jealousy. Results revealed that attachment security was associated with higher levels of empathy, forgiveness, and guilt, but lower levels of jealousy. In addition, emotion regulation mediated the links attachment shared with both empathy and guilt, such that higher levels of attachment security were linked with greater levels of emotion regulation, which led to greater levels of empathy and guilt. Alternatively, negative emotionality mediated the links attachment shared with both forgiveness and jealousy, such that higher levels of attachment security were associated with lower levels of negative emotionality, which in turn was linked to lower levels of forgiveness and higher levels of jealousy. This study provides a general picture of how attachment security may play a role in shaping an individual's levels of social emotions. PMID- 26244913 TI - Probing differentiation in cancer cell lines by single-cell micro-Raman spectroscopy. AB - Single-cell micro-Raman spectroscopy has been applied to explore cell differentiation in single, live, and malignant cells from two tumor cell lines. The spectra of differentiated cells exhibit substantial enhancement primarily in the intensities of protein peaks with concomitant decrease in intensities of O-P O asymmetric stretching peaks in DNA/RNA. Principal component analyses show that the spectral score of differentiated cells tends to asymptotically approach that of spectra obtained from normal neural stem cells/progenitors. This lends credence to the notion that the observed spectral changes are specific to differentiation, since upon differentiation, malignant cells become less malignant and tend toward benignity. PMID- 26244915 TI - An Urgent Airway. PMID- 26244916 TI - Field-effect control of superconductivity and Rashba spin-orbit coupling in top gated LaAlO3/SrTiO3 devices. AB - The recent development in the fabrication of artificial oxide heterostructures opens new avenues in the field of quantum materials by enabling the manipulation of the charge, spin and orbital degrees of freedom. In this context, the discovery of two-dimensional electron gases (2-DEGs) at LaAlO3/SrTiO3 interfaces, which exhibit both superconductivity and strong Rashba spin-orbit coupling (SOC), represents a major breakthrough. Here, we report on the realisation of a field effect LaAlO3/SrTiO3 device, whose physical properties, including superconductivity and SOC, can be tuned over a wide range by a top-gate voltage. We derive a phase diagram, which emphasises a field-effect-induced superconductor to-insulator quantum phase transition. Magneto-transport measurements show that the Rashba coupling constant increases linearly with the interfacial electric field. Our results pave the way for the realisation of mesoscopic devices, where these two properties can be manipulated on a local scale by means of top-gates. PMID- 26244920 TI - Violaceous Eruption on the Head and Extremities. Lichen Planus Actinicus. PMID- 26244918 TI - A Natural Combination Extract of Viscum album L. Containing Both Triterpene Acids and Lectins Is Highly Effective against AML In Vivo. AB - Aqueous Viscum album L. extracts are widely used in complementary cancer medicine. Hydrophobic triterpene acids also possess anti-cancer properties, but due to their low solubility they do not occur in significant amounts in aqueous extracts. Using cyclodextrins we solubilised mistletoe triterpenes (mainly oleanolic acid) and investigated the effect of a mistletoe whole plant extract on human acute myeloid leukaemia cells in vitro, ex vivo and in vivo. Single Viscum album L. extracts containing only solubilised triterpene acids (TT) or lectins (viscum) inhibited cell proliferation and induced apoptosis in a dose-dependent manner in vitro and ex vivo. The combination of viscum and TT extracts (viscumTT) enhanced the induction of apoptosis synergistically. The experiments demonstrated that all three extracts are able to induce apoptosis via caspase-8 and -9 dependent pathways with down-regulation of members of the inhibitor of apoptosis and Bcl-2 families of proteins. Finally, the acute myeloid leukaemia mouse model experiment confirmed the therapeutic effectiveness of viscumTT-treatment resulting in significant tumour weight reduction, comparable to the effect in cytarabine-treated mice. These results suggest that the combination viscumTT may have a potential therapeutic value for the treatment AML. PMID- 26244921 TI - Highly reactive free radicals in electronic cigarette aerosols. AB - Electronic cigarette (EC) usage has increased exponentially, but limited data are available on its potential harmful effects. We tested for the presence of reactive, short-lived free radicals in EC aerosols by electron paramagnetic resonance spectroscopy (EPR) using the spin-trap phenyl-N-tert-butylnitrone (PBN). Radicals were detected in aerosols from all ECs and eliquids tested (2.5 * 10(13) to 10.3 * 10(13) radicals per puff at 3.3 V) and from eliquid solvents propylene glycol and glycerol and from "dry puffing". These results demonstrate, for the first time, the production of highly oxidizing free radicals from ECs which may present a potential toxicological risk to EC users. PMID- 26244922 TI - alpha-Klotho is unstable in human urine. AB - alpha-Klotho is an interesting new biomarker in kidney and cardiovascular disease. As alpha-Klotho is primarily expressed in renal epithelial tissue, various papers have reported alpha-Klotho concentrations in urine. As these studies did not address the reliability of urinary alpha-Klotho measurements and as urine is known to be a complex milieu, we investigated the stability of alpha Klotho in both fresh catheter and fresh voided urine. alpha-Klotho was measured in these fresh urine samples and in the same samples under several other conditions. Storage of fresh catheter urine for 3 h at 37 degrees C, comparable to storage in the bladder, led to a 82% decrease in alpha-Klotho concentrations. Compared with fresh voided urine, alpha-Klotho concentrations decreased on an average of 45 and 82% after storage at -80 degrees C and -20 degrees C, respectively. An additional freeze-thaw cycle further decreased alpha-Klotho concentrations. The addition of a protease inhibitor or 0.1% albumin partly prevented degradation in fresh voided urine. Thus, alpha-Klotho is highly unstable in urine. Future studies showing results of urinary alpha-Klotho should mention conservation conditions and prove the reliability of the alpha-Klotho measurements. PMID- 26244923 TI - Association of prescribed Chinese herbal medicine use with risk of end-stage renal disease in patients with chronic kidney disease. AB - The evidence on whether Chinese herbal medicines affect outcome in patients with chronic kidney disease (CKD) is limited. Here we retrospectively explored the association of prescribed Chinese herbal medicine use and the risk of end-stage renal disease (ESRD) in patients with CKD. Patients with newly diagnosed CKD in the Taiwan National Health Insurance Research Database from 2000 to 2005 were categorized into new use or nonuse of prescribed Chinese herbal medicine groups. These patients were followed until death, dialysis initiation, or till the end of 2008. Among the 24,971 study patients, 11,351 were new users of prescribed Chinese herbal medicine after CKD diagnosis. Overall, after adjustment for confounding variables, the use group exhibited a significant 60% reduced ESRD risk (cause-specific hazard ratio 0.41, 95% confidence interval 0.37-0.46) compared with the nonuse group. The change was significantly large among patients using wind dampness-dispelling formulas (0.63, 0.51-0.77) or harmonizing formulas (0.59, 0.46-0.74), suggesting an independent association between specific Chinese herbal medicines and reduced ESRD risk. The findings were confirmed using propensity score matching, stratified analyses, and three weighting methods. However, dampness-dispelling and purgative formulas were associated with increased ESRD risk. Thus, specific Chinese herbal medicines are associated with reduced or enhanced ESRD risk in patients with CKD. PMID- 26244924 TI - Prediction and validation of hemodialysis duration in acute methanol poisoning. AB - The duration of hemodialysis (HD) in methanol poisoning (MP) is dependent on the methanol concentration, the operational parameters used during HD, and the presence and severity of metabolic acidosis. However, methanol assays are not easily available, potentially leading to undue extension or premature termination of treatment. Here we provide a prediction model for the duration of high efficiency HD in MP. In a retrospective cohort study, we identified 71 episodes of MP in 55 individuals who were treated with alcohol dehydrogenase inhibition and HD. Four patients had residual visual abnormality at discharge and only one patient died. In 46 unique episodes of MP with high-efficiency HD the mean methanol elimination half-life (T1/2) during HD was 108 min in women, significantly different from the 129 min in men. In a training set of 28 patients with MP, using the 90th percentile of gender-specific elimination T1/2 (147 min in men and 141 min in women) and a target methanol concentration of 4 mmol/l allowed all cases to reach a safe methanol of under 6 mmol/l. The prediction model was confirmed in a validation set of 18 patients with MP. High-efficiency HD time in hours can be estimated using 3.390 * (Ln (MCi/4)) for women and 3.534 * (Ln (MCi/4)) for men, where MCi is the initial methanol concentration in mmol/l, provided that metabolic acidosis is corrected. PMID- 26244925 TI - Molecular Plasmonics. AB - Graphene supports surface plasmons that have been observed to be both electrically and geometrically tunable in the mid- to far-infrared spectral regions. In particular, it has been demonstrated that graphene plasmons can be tuned across a wide spectral range spanning from the mid-infrared to the terahertz. The identification of a general class of plasmonic excitations in systems containing only a few dozen atoms permits us to extend this versatility into the visible and ultraviolet. As appealing as this extension might be for active nanoscale manipulation of visible light, its realization constitutes a formidable technical challenge. We experimentally demonstrate the existence of molecular plasmon resonances in the visible for ionized polycyclic aromatic hydrocarbons (PAHs), which we reversibly switch by adding, then removing, a single electron from the molecule. The charged PAHs display intense absorption in the visible regime with electrical and geometrical tunability analogous to the plasmonic resonances of much larger nanographene systems. Finally, we also use the switchable molecular plasmon in anthracene to demonstrate a proof-of-concept low-voltage electrochromic device. PMID- 26244926 TI - The ART of Lowering Ceramides. AB - Ceramides are lipid metabolites implicated in the metabolic dysregulation that accompanies dyslipidaemia and obesity. Using a genetic mouse model to acutely degrade ceramides in adipose tissue or the liver (i.e., by conditionally expressing acid ceramidase), in this issue of Cell MetabolismXia et al. (2015) identify roles for these molecules in insulin resistance, steatohepatitis, and interorgan communication. PMID- 26244927 TI - Segregation of Clock and Non-Clock Regulatory Functions of REV-ERB. AB - The molecular clock is a master controller of circadian cellular processes that affect growth, metabolic homeostasis, and behavior. A report in Science by Zhang et al. (2015) redefines our understanding of how Rev-erba acts as an internal feedback inhibitor that modulates activity of the core clock while simultaneously regulating tissue-specific metabolic processes. PMID- 26244928 TI - A New Hydroxy Metabolite of 2-Oxoglutarate Regulates Metabolism in Hypoxia. AB - Two articles in this issue (Intlekofer et al., 2015; Oldham et al., 2015) show a new metabolic pathway regulated by hypoxia, but independently of HIF1 or HIF2. L 2-hydroxyglutarate, produced in hypoxia by malate dehydrogenases and LDHA, is a potent inhibitor of KDM4C, and through redox stress reduces glycolysis. PMID- 26244929 TI - NNMT: A Bad Actor in Fat Makes Good in Liver. AB - High adipose expression of NNMT, an enzyme that converts nicotinamide to 1-methyl nicotinamide, correlates with adiposity. Though murine NNMT knockdown in fat and liver prevents weight gain on high-fat diet, Hong et al. (2015) now show that high hepatic expression of NNMT improves lipid parameters via SIRT1 stabilization. PMID- 26244930 TI - Type 1 Diabetes and MicroRNA: It's Complicated. AB - Type 1 diabetes is an autoimmune disease that manifests as impaired insulin secretion, with compounding complications over time. Bhatt et al. (2015) investigate protective mechanisms in survivors of type 1 diabetes by using induced pluripotent stem cells as genetic models, uncovering novel interactions between microRNA and the DNA damage checkpoint pathway. PMID- 26244931 TI - Browning of Subcutaneous White Adipose Tissue in Humans after Severe Adrenergic Stress. AB - Since the presence of brown adipose tissue (BAT) was confirmed in adult humans, BAT has become a therapeutic target for obesity and insulin resistance. We examined whether human subcutaneous white adipose tissue (sWAT) can adopt a BAT like phenotype using a clinical model of prolonged and severe adrenergic stress. sWAT samples were collected from severely burned and healthy individuals. A subset of burn victims were prospectively followed during their acute hospitalization. Browning of sWAT was determined by the presence of multilocular adipocytes, uncoupling protein 1 (UCP1), and increased mitochondrial density and respiratory capacity. Multilocular UCP1-positive adipocytes were found in sWAT samples from burn patients. UCP1 mRNA, mitochondrial density, and leak respiratory capacity in sWAT increased after burn trauma. Our data demonstrate that human sWAT can transform from an energy-storing to an energy-dissipating tissue, which opens new research avenues in our quest to prevent and treat obesity and its metabolic complications. PMID- 26244932 TI - Roux-en-Y Gastric Bypass and Vertical Banded Gastroplasty Induce Long-Term Changes on the Human Gut Microbiome Contributing to Fat Mass Regulation. AB - Bariatric surgery is currently the most effective procedure for the treatment of obesity. Given the role of the gut microbiota in regulating host metabolism and adiposity, we investigated the long-term effects of bariatric surgery on the microbiome of patients randomized to Roux-en-Y gastric bypass or vertical banded gastroplasty and matched for weight and fat mass loss. The two surgical procedures induced similar and durable changes on the gut microbiome that were not dependent on body mass index and resulted in altered levels of fecal and circulating metabolites compared with obese controls. By colonizing germ-free mice with stools from the patients, we demonstrated that the surgically altered microbiota promoted reduced fat deposition in recipient mice. These mice also had a lower respiratory quotient, indicating decreased utilization of carbohydrates as fuel. Our results suggest that the gut microbiota may play a direct role in the reduction of adiposity observed after bariatric surgery. PMID- 26244933 TI - Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long Standing Type 1 Diabetes. AB - The mechanisms underlying the development of complications in type 1 diabetes (T1D) are poorly understood. Disease modeling of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D (disease duration >= 50 years) with severe (Medalist +C) or absent to mild complications (Medalist -C) revealed impaired growth, reprogramming, and differentiation in Medalist +C. Genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist -C. In silico analyses showed altered expression patterns of DNA damage checkpoint factors among the Medalist groups to be targets of miR200, whose expression was significantly elevated in Medalist +C serum. Notably, neurons differentiated from Medalist +C iPSCs exhibited enhanced susceptibility to genotoxic stress that worsened upon miR200 overexpression. Furthermore, knockdown of miR200 in Medalist +C fibroblasts and iPSCs rescued checkpoint protein expression and reduced DNA damage. We propose miR200-regulated DNA damage checkpoint pathway as a potential therapeutic target for treating complications of diabetes. PMID- 26244934 TI - Quantifying Diet-Induced Metabolic Changes of the Human Gut Microbiome. AB - The human gut microbiome is known to be associated with various human disorders, but a major challenge is to go beyond association studies and elucidate causalities. Mathematical modeling of the human gut microbiome at a genome scale is a useful tool to decipher microbe-microbe, diet-microbe and microbe-host interactions. Here, we describe the CASINO (Community And Systems-level INteractive Optimization) toolbox, a comprehensive computational platform for analysis of microbial communities through metabolic modeling. We first validated the toolbox by simulating and testing the performance of single bacteria and whole communities in vitro. Focusing on metabolic interactions between the diet, gut microbiota, and host metabolism, we demonstrated the predictive power of the toolbox in a diet-intervention study of 45 obese and overweight individuals and validated our predictions by fecal and blood metabolomics data. Thus, modeling could quantitatively describe altered fecal and serum amino acid levels in response to diet intervention. PMID- 26244936 TI - Giant paramagnetic Meissner effect in multiband superconductors. AB - Superconductors, ideally diamagnetic when in the Meissner state, can also exhibit paramagnetic behavior due to trapped magnetic flux. In the absence of pinning such paramagnetic response is weak, and ceases with increasing sample thickness. Here we show that in multiband superconductors paramagnetic response can be observed even in slab geometries, and can be far larger than any previous estimate - even multiply larger than the diamagnetic Meissner response for the same applied magnetic field. We link the appearance of this giant paramagnetic response to the broad crossover between conventional Type-I and Type-II superconductors, where Abrikosov vortices interact non-monotonically and multibody effects become important, causing unique flux configurations and their locking in the presence of surfaces. PMID- 26244935 TI - Organization of the Mammalian Metabolome according to Organ Function, Lineage Specialization, and Longevity. AB - Biological diversity among mammals is remarkable. Mammalian body weights range seven orders of magnitude and lifespans differ more than 100-fold among species. While genetic, dietary, and pharmacological interventions can be used to modulate these traits in model organisms, it is unknown how they are determined by natural selection. By profiling metabolites in brain, heart, kidney, and liver tissues of 26 mammalian species representing ten taxonomical orders, we report metabolite patterns characteristic of organs, lineages, and species longevity. Our data suggest different rates of metabolite divergence across organs and reveal patterns representing organ-specific functions and lineage-specific physiologies. We identified metabolites that correlated with species lifespan, some of which were previously implicated in longevity control. We also compared the results with metabolite changes in five long-lived mouse models and observed some similar patterns. Overall, this study describes adjustments of the mammalian metabolome according to lifespan, phylogeny, and organ and lineage specialization. PMID- 26244937 TI - Weak Interactions between Salmonella enterica FlhB and Other Flagellar Export Apparatus Proteins Govern Type III Secretion Dynamics. AB - The bacterial flagellum contains its own type III secretion apparatus that coordinates protein export with assembly at the distal end. While many interactions among export apparatus proteins have been reported, few have been examined with respect to the differential affinities and dynamic relationships that must govern the mechanism of export. FlhB, an integral membrane protein, plays critical roles in both export and the substrate specificity switching that occurs upon hook completion. Reported herein is the quantitative characterization of interactions between the cytoplasmic domain of FlhB (FlhBC) and other export apparatus proteins including FliK, FlhAC and FliI. FliK and FlhAC bound with micromolar affinity. KD for FliI binding in the absence of ATP was 84 nM. ATP induced oligomerization of FliI induced kinetic changes, stimulating fast-on, fast-off binding and lowering affinity. Full length FlhB purified under solubilizing, nondenaturing conditions formed a stable dimer via its transmembrane domain and stably bound FliH. Together, the present results support the previously hypothesized central role of FlhB and elucidate the dynamics of protein-protein interactions in type III secretion. PMID- 26244938 TI - Genotoxic Evaluation of Mexican Welders Occupationally Exposed to Welding-Fumes Using the Micronucleus Test on Exfoliated Oral Mucosa Cells: A Cross-Sectional, Case-Control Study. AB - BACKGROUND: An estimated 800,000 people worldwide are occupationally exposed to welding-fumes. Previous studies show that the exposure to such fumes is associated with damage to genetic material and increased cancer risk. In this study, we evaluate the genotoxic effect of welding-fumes using the Micronucleus Test on oral mucosa cells of Mexican welders. MATERIAL AND METHODS: We conducted a cross-sectional, matched case-control study of n = 66 (33 exposed welders, and 33 healthy controls). Buccal mucosa smears were collected and stained with acridine orange, observed under 100x optical amplification with a fluorescence lamp, and a single-blinded observer counted the number of micronuclei and other nuclear abnormalities per 2,000 observed cells. We compared the frequencies of micronuclei and other nuclear abnormalities, and fitted generalised linear models to investigate the interactions between nuclear abnormalities and the exposure to welding-fumes, while controlling for smoking and age. RESULTS: Binucleated cells and condensed-chromatin cells showed statistically significant differences between cases and controls. The frequency of micronuclei and the rest of nuclear abnormalities (lobed-nuclei, pyknosis, karyolysis, and karyorrhexis) did not differ significantly between the groups. After adjusting for smoking, the regression results showed that the occurrence of binucleated cells could be predicted by the exposure to welding-fumes plus the presence of tobacco consumption; for the condensed-chromatin cells, our model showed that the exposure to welding-fumes is the only reliable predictor. CONCLUSIONS: Our findings suggest that Mexican welders who are occupationally exposed to welding fumes have increased counts of binucleated and condensed-chromatin cells. Nevertheless, the frequencies of micronuclei and the rest of nuclear abnormalities did not differ between cases and controls. Further studies should shed more light on this subject. PMID- 26244939 TI - [S3 Guideline. Part 3: Non-Traumatic Avascular Necrosis in Adults - Surgical Treatment of Atraumatic Avascular Femoral Head Necrosis in Adults]. AB - The present article describes the guidelines for the surgical treatment of atraumatic avascular necrosis (aFKN). These include joint preserving and joint replacement procedures. As part of the targeted literature, 43 publications were included and evaluated to assess the surgical treatment. According to the GRADE and SIGN criteria level of evidence (LoE), grade of recommendation (EC) and expert consensus (EK) were listed for each statement and question. The analysed studies have shown that up to ARCO stage III, joint-preserving surgery can be performed. A particular joint-preserving surgery currently cannot be recommended as preferred method. The selection of the method depends on the extent of necrosis. Core decompression performed in stage ARCO I (reversible early stage) or stage ARCO II (irreversible early stage) with medial or central necrosis with an area of less than 30 % of the femoral head shows better results than conservative therapy. In ARCO stage III with infraction of the femoral head, the core decompression can be used for a short-term pain relief. For ARCO stage IIIC or stage IV core decompression should not be performed. In these cases, the indication for implantation of a total hip replacement should be checked. Additional therapeutic procedures (e.g., osteotomies) and innovative treatment options (advanced core decompression, autologous bone marrow, bone grafting, etc.) can be discussed in the individual case. In elective hip replacement complications and revision rates have been clearly declining for decades. In the case of an underlying aFKN, however, previous joint-preserving surgery (osteotomies and grafts in particular) can complicate the implantation of a THA significantly. However, the implant life seems to be dependent on the aetiology. Higher revision rates for avascular necrosis are particularly expected in sickle cell disease, Gaucher disease, or kidney transplantation patients. Furthermore, the relatively young age of the patient with avascular necrosis should be seen as the main risk factor for higher revision rate. The results after resurfacing (today with known restricted indications) and cemented as well as cementless THA in aFKN are comparable for the appropriate indication to those in coxarthrosis or other diagnoses. Regardless of the underlying disease endoprosthetic treatment in aFKN leads to good results. Both cemented and cementless fixation techniques can be recommended. PMID- 26244941 TI - Erratum: Modulation of Igbeta is essential for the B cell selection in germinal center. PMID- 26244940 TI - [S3 guideline. Part 2: Non-Traumatic Avascular Femoral Head Necrosis in Adults - Untreated Course and Conservative Treatment]. AB - BACKGROUND: In Germany there are 5000 to 7000 new cases of atraumatic avascular necrosis of the femoral head in adults per year. It occurs mostly in middle age. An increased frequency of idiopathic cases can be observed. Chemotherapy, corticoids and kidney transplants are frequently associated with the disease. In most cases the disease occurs on both sides. Early diagnosis is of particular importance, since in early stages it is most likely to avoid late damage with joint destruction. Whereas previously the temporary operational joint preservation and subsequent joint replacement were often the only option of treatment, conservative and joint-preserving measures today play an increasing role. MATERIAL AND METHODS: After the AWMF guidelines for S3 guideline clinical questions were formulated. Over the period from 01/01/1970 to 31/05/2013 a literature search was conducted. Systematic reviews, metaanalyses, original papers and clinical trials of all designs were evaluated. There were a total of 3715 references, of which 422 for the assessment regarding SIGN were eligible and finally 180 were in accord with the defined inclusion and exclusion criteria. For the untreated course and the assessment of conservative measures, a total of 42 references was suitable. In formulating the recommendations the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system was used, which distinguishes A "shall", B "should" and 0 "can". RESULTS AND CONCLUSION: If left untreated, the aFKN within 2 years leads to a subchondral fracture and subsequent collapse. After the diagnosis of femoral head necrosis, the risk of a disease of the opposite side is high within the next 2 years, then unlikely. The sole conservative treatment brings no benefit for the treatment of atraumatic avascular necrosis in the adult. Although it improves function, less pain can be obtained, and surgical intervention can be delayed, the progression is not stopped. Conservative treatment must therefore always be part of the overall treatment. In ARCO stage I to II Iloprost may be considered as a pharmacological approach to reduce the pain and the bone marrow oedema. This also applies to alendronate. Since this is an off-label use, and thus a therapeutic trial, an appropriate patient education must take place. For the use of anticoagulants and statins, there is no recommendation. Also the hyperbaric oxygen therapy, shock waves and pulsating electromagnetic fields or electrical stimulation cannot be recommended. PMID- 26244943 TI - Vaccination Saves Lives. PMID- 26244944 TI - Pediatric Cardiology in India: Onset of a New Era. AB - Pediatric cardiology is outgrowing from the shadows of adult cardiology and cardiac surgery departments in India. It promises to be an attractive and sought after subspeciality of Pediatrics, dealing with not only congenital cardiac diseases but also metabolic, rheumatic and host of other cardiac diseases. The new government policy shall provide more training avenues for the budding pediatric cardiologists, pediatric cardiac surgeons, pediatric anesthetists, pediatric cardiac intensivists, neonatologists and a host of supportive workforce. The proactive role of Indian Academy of Pediatrics and Pediatric Cardiac Society of India, towards creating a political will at the highest level for framing policies towards building infrastructure, training of workforce and subsidies for pediatric cardiac surgeries and procedures shall fuel the development of multiple tertiary cardiac centers in the country, making pediatric cardiology services accessible to the needy population. PMID- 26244942 TI - An Engineered N-Cadherin Substrate for Differentiation, Survival, and Selection of Pluripotent Stem Cell-Derived Neural Progenitors. AB - For stem cell-based treatment of neurodegenerative diseases a better understanding of key developmental signaling pathways and robust techniques for producing neurons with highest homogeneity are required. In this study, we demonstrate a method using N-cadherin-based biomimetic substrate to promote the differentiation of mouse embryonic stem cell (ESC)- and induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) without exogenous neuro inductive signals. We showed that substrate-dependent activation of N-cadherin reduces Rho/ROCK activation and beta-catenin expression, leading to the stimulation of neurite outgrowth and conversion into cells expressing neural/glial markers. Besides, plating dissociated cells on N-cadherin substrate can significantly increase the differentiation yield via suppression of dissociation-induced Rho/ROCK-mediated apoptosis. Because undifferentiated ESCs and iPSCs have low affinity to N-cadherin, plating dissociated cells on N cadherin-coated substrate increase the homogeneity of differentiation by purging ESCs and iPSCs (~30%) from a mixture of undifferentiated cells with NPCs. Using this label-free cell selection approach we enriched differentiated NPCs plated as monolayer without ROCK inhibitor. Therefore, N-cadherin biomimetic substrate provide a powerful tool for basic study of cell-material interaction in a spatially defined and substrate-dependent manner. Collectively, our approach is efficient, robust and cost effective to produce large quantities of differentiated cells with highest homogeneity and applicable to use with other types of cells. PMID- 26244945 TI - Paracetamol in Patent Ductus Arteriosus, "Flavour of the Month" or Here to Stay? PMID- 26244946 TI - Paracetamol for Closure of Patent Ductus Arteriosus. PMID- 26244947 TI - Snakebite and Acute Kidney Injury: We Must do Better! PMID- 26244948 TI - Snake Bite: A Neglected Tropical Condition. PMID- 26244949 TI - Enteral paracetamol or Intravenous Indomethacin for Closure of Patent Ductus Arteriosus in Preterm Neonates: A Randomized Controlled Trial. AB - OBJECTIVE: To compare the efficacy of enteral paracetamol and intravenous indomethacin for closure of patent ductus arteriosus (PDA) in preterm neonates. DESIGN: Randomized controlled trial. SETTING: Level III neonatal intensive care unit. PARTICIPANTS: 77 preterm neonates with birth weight ?1500 g and PDA size ?1.5 mm, with left to right ductal flow with left atrium to aortic root ratio >1.5:1; diagnosed by 2D-Echo within first 48 hours of life. INTERVENTION: Paracetamol drops through the infant feeding tube (15 mg/kg/dose 6 hourly for 7 days) or intravenous indomethacin (0.2 mg/kg/dose once daily for 3 days). OUTCOME MEASURES: Primary: PDA closure rate assessed by echocardiography. Secondary: need for surgical closure of PDA, renal impairment, gastrointestinal bleed, necrotising enterocolitis, hepatotoxicity, pulmonary hemorrhage, sepsis, hypothermia, retinopathy of prematurity, intraventricular hemorrhage, bronchopulmonary dysplasia and mortality. RESULTS: PDA closure rate was 100% (36/36) in enteral paracetamol group as compared to 94.6% (35/37) in intravenous indomethacin group (P=0.13). The secondary outcomes were also similar between the two groups. There was no occurrence of hepatotoxicity. CONCLUSIONS: Enteral paracetamol is safe but not superior to intravenous indomethacin in the treatment of PDA in preterm neonates. PMID- 26244950 TI - Postnatal Lactational Counseling and Neonatal Weight Pattern. AB - OBJECTIVE: To compare the impact of postnatal lactational counseling on the weight gain and frequency of mixed feeding in full term neonates. DESIGN: Observational study. SETTING: Mother-infant pairs were observed in the maternity section of a multispecialty general hospital in Mumbai during two time periods. PARTICIPANTS: 260 mothers who delivered a full term, healthy, appropriate for gestational age neonate with birth weight >2.2 kg. METHODS: Between 18 November, 2007 and 4 March, 2008, 126 mothers received unstructured verbal encouragement to maintain breastfeeding from the maternity staff. From 1 June, 2008 to 16 December, 2008, 134 mothers were counseled about breastfeeding by the pediatric residents and nurses with the help of charts, literature and verbal advice. They were supervised and helped during the first feed and subsequently until discharge. MAIN OUTCOME MEASURES: Weight gain (g/kg/day) of neonate at 28 days of life. RESULTS: The mean (SD) weight gain was significantly higher in the counseled group in comparison to historical control group [9.2 (4.5) g/kg/d vs. 7.9 (5.1) g/kg/d; P=0.03]. Mixed feeding occurred less frequently in [RR 0.36, 95% CI 0.13, 0.98; P=0.046] the counseled group (5/134) as compared to control group (13/126). CONCLUSIONS: Postnatal lactational counseling leads to higher weight gain, and lesser chances of mixed feeding in the neonatal period. PMID- 26244951 TI - Russells Viper Envenomation-associated Acute Kidney Injury in Children in Southern India. AB - OBJECTIVE: To determine the frequency and risk factors of acute kidney injury in children with Russells viper envenomation using Acute Kidney Injury Network definition and classification system. METHODS: A prospective observational study recruiting 61 subjects managed as per the National Snakebite Protocol. RESULTS: 45.9% of envenomed children had acute kidney injury. The median (IQR) of the maximum serum creatinine level during hospitalization was 2 (1.3-4.8) mg/dL. The distribution of stages 1, 2 and 3 of acute kidney injury was 32.1%, 17.9% and 50% respectively. Dialysis was required in 35.7% of the children with acute kidney injury. CONCLUSION: Acute kidney injury is common with Russells viper envenomation. Native treatments and bleeding manifestations were associated with acute kidney injury in our patient population. PMID- 26244952 TI - Nocturnal Enuresis among Nigerian Children and its Association with Sleep, Behavior and School Performance. AB - OBJECTIVE: To study the association of nocturnal enuresis with sleep, behavior and school performance. METHODS: Hospital-based, cross-sectional descriptive study of 216 children (?6-year-old) using structured questionnaire and behavioral tools. SETTING: Two hospitals at Lucknow in Northern India. RESULTS: Prevalence of enuresis was 37.0%. Nocturnal enuresis was significantly associated with abnormal behaviour (P=0.049) and poor sleep hygiene (P%0.05). School performance was not associated with enuresis. CONCLUSION: Children with nocturnal enuresis were at an increased risk of behavioral problems and poor sleep hygiene. PMID- 26244953 TI - Entrustable Professional Activities: Teaching and Assessing Clinical Competence. AB - Entrustable Professional Activities are gaining acceptance as tools to demonstrate acquisition of competencies in a competency-based curriculum. The main advantage of Entrustable Professional Activities are that they are observable activities (thus assessable), are related to day-to-day functioning as a health care provider (thus relevant), and are awarded once the learner can be trusted to perform the activity effectively and safely, without supervision, and by integrating across different competency domains. In this article, we describe how Entrustable Professional Activities can serve as a useful learning and assessment tool. We have described the steps in formulation, the pitfalls to avoid, and the possible role of the Medical Council of India and the Indian Academy of Pediatrics in encouraging the use of Entrustable Professional Activities for executing competency-based modules. PMID- 26244954 TI - Infantile Tremor Syndrome--A Tale of 50 Years. PMID- 26244955 TI - An Infant with Prolonged Fever. PMID- 26244956 TI - Endotracheal Suctioning for Nonvigorous Neonates Born Through Meconium Stained Amniotic Fluid. PMID- 26244957 TI - Unusual Foreign Bodies in the Respiratory Tract of Children. AB - BACKGROUND: Diagnosis of a foreign body without history of aspiration has always been a challenge to pediatricians. CASE CHARACTERISTICS: Four cases presented with non-relieving acute or chronic history of respiratory symptoms. OBSERVATIONS: All of them had unusual types of foreign bodies-plastic flower toy, button, sticker or stone in their respiratory tract. OUTCOME: All four patients improved after removal of the foreign body. MESSAGE: A differential diagnosis of foreign body should always be made in an acute or chronic presentation of respiratory cases. PMID- 26244959 TI - Morbidity Profile of Adolescents Admitted in a General Pediatric Ward. AB - We studied the morbidity pattern of inpatient adolescents over a period of 17 months. Of 32115 admissions in this period, 2742 were adolescents (39.7% females). 93.9% were partially immunized, 37.3% were malnourished, 2.8% were overweight and 56% were anemic. Dengue and dengue-like illness (528) were the most common illness. PMID- 26244958 TI - Sevelamer Hydrochloride for Tumor Lysis Syndrome-related Hyperphosphatemia. AB - BACKGROUND: Tumour lysis syndrome is associated with high levels of uric acid, phosphate and potassium along with low levels of calcium and abnormal renal function. Sevelamer, an oral phosphate-binder is used in the treatment of hyperphosphatemia in children and adults on hemodialysis. CASE CHARACTERISTICS: Two children with T-cell acute lymphoblastic leukemia who presented with a high tumour load and developed tumour lysis syndrome. OBSERVATION: Both children received Rasburicase and Sevelamer hydrochloride. The serum phosphate reduced to normal levels within 24-48 hrs of initiation of sevelamer hydrochloride. MESSAGE: Sevelamer appears to be an effective treatment for hyperphosphatemia associated with tumour lysis syndrome. PMID- 26244960 TI - Obesity and its Complications Among Suburban Schoolchildren. PMID- 26244961 TI - Hand Hygiene Compliance of Healthcare Workers in a Pediatric Intensive Care Unit. AB - We conducted an observational study over 11 months to assess the hand-hygiene compliance of health-care workers in a Pediatric intensive care unit. The overall compliance was 80.9%, which decreased with increase in workload (79.2% vs. 82.9%). Assessment of hand hygiene compliance helps understand the gaps in practices followed by healthcare workers, and plan effective protocols. PMID- 26244962 TI - Possible Benign Partial Epilepsy. PMID- 26244963 TI - Possible Benign Partial Epilepsy: Authors' Reply. PMID- 26244964 TI - Horizontal Gaze Palsy: Additional Issues. PMID- 26244965 TI - Evaluation of the Serum Uric Acid: Important Issues. PMID- 26244966 TI - Evaluation of Serum Uric Acid: Authors' Reply. PMID- 26244967 TI - Pulse Oximetry Screening of Critical Congenital Heart Disease. PMID- 26244968 TI - Influenza Deaths in India--Whether Enough is Being Done? PMID- 26244969 TI - Infantile Tremor Syndrome: Still A Mystery! PMID- 26244970 TI - Urticaria Multiforme. PMID- 26244971 TI - Adams Oliver Syndrome. PMID- 26244972 TI - Facial Angiofibromas. PMID- 26244974 TI - New Fossil Scorpion from the Chiapas Amber Lagerstatte. AB - A new species of scorpion is described based on a rare entire adult male preserved in a cloudy amber from Miocene rocks in the Chiapas Highlands, south of Mexico. The amber-bearing beds in Chiapas constitute a Conservation Lagerstatte with outstanding organic preservation inside plant resin. The new species is diagnosed as having putative characters that largely correspond with the genus Tityus Koch, 1836 (Scorpiones, Buthidae). Accordingly, it is now referred to as Tityus apozonalli sp. nov. Its previously unclear phylogenetic relationship among fossil taxa of the family Buthidae from both Dominican and Mexican amber is also examined herein. Preliminarily results indicate a basal condition of T. apozonalli regarding to Tityus geratus Santiago-Blay and Poinar, 1988, Tityus (Brazilotityus) hartkorni Lourenco, 2009, and Tityus azari Lourenco, 2013 from Dominican amber, as was Tityus (Brazilotityus) knodeli Lourenco, 2014 from Mexican amber. Its close relationships with extant Neotropic Tityus-like subclades such as 'Tityus clathratus' and the subgenus Tityus (Archaeotityus) are also discussed. This new taxon adds to the knowledge of New World scorpions from the Miocene that are rarely found trapped in amber. PMID- 26244973 TI - Retinal Thickening and Photoreceptor Loss in HIV Eyes without Retinitis. AB - PURPOSE: To determine the presence of structural changes in HIV retinae (i.e., photoreceptor density and retinal thickness in the macula) compared with age matched HIV-negative controls. METHODS: Cohort of patients with known HIV under CART (combination Antiretroviral Therapy) treatment were examined with a flood illuminated retinal AO camera to assess the cone photoreceptor mosaic and spectral-domain optical coherence tomography (SD-OCT) to assess retinal layers and retinal thickness. RESULTS: Twenty-four eyes of 12 patients (n = 6 HIV positive and 6 HIV-negative) were imaged with the adaptive optics camera. In each of the regions of interest studied (nasal, temporal, superior, inferior), the HIV group had significantly less mean cone photoreceptor density compared with age matched controls (difference range, 4,308-6,872 cones/mm2). A different subset of forty eyes of 20 patients (n = 10 HIV-positive and 10 HIV-negative) was included in the retinal thickness measurements and retinal layer segmentation with the SD OCT. We observed significant thickening in HIV positive eyes in the total retinal thickness at the foveal center, and in each of the three horizontal B-scans (through the macular center, superior, and inferior to the fovea). We also noted that the inner retina (combined thickness from ILM through RNFL to GCL layer) was also significantly thickened in all the different locations scanned compared with HIV-negative controls. CONCLUSION: Our present study shows that the cone photoreceptor density is significantly reduced in HIV retinae compared with age matched controls. HIV retinae also have increased macular retinal thickness that may be caused by inner retinal edema secondary to retinovascular disease in HIV. The interaction of photoreceptors with the aging RPE, as well as possible low grade ocular inflammation causing diffuse inner retinal edema, may be the key to the progressive vision changes in HIV-positive patients without overt retinitis. PMID- 26244976 TI - Correction: Correction: Regulation of Neuronal Morphogenesis and Positioning by Ubiquitin-Specific Proteases in the Cerebellum. PMID- 26244975 TI - Assessment of Cancer-Related Fatigue, Pain, and Quality of Life in Cancer Patients at Palliative Care Team Referral: A Multicenter Observational Study (JORTC PAL-09). AB - INTRODUCTION: Cancer-related fatigue greatly influences quality of life in cancer patients; however, no specific treatments have been established for cancer related fatigue, and at present, no medication has been approved in Japan. Systematic research using patient-reported outcome to examine symptoms, particularly fatigue, has not been conducted in palliative care settings in Japan. The objective was to evaluate fatigue, pain, and quality of life in cancer patients at the point of intervention by palliative care teams. MATERIALS AND METHODS: Patients who were referred to palliative care teams at three institutions and met the inclusion criteria were invited to complete the Brief Fatigue Inventory, Brief Pain Inventory, and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative. RESULTS: Of 183 patients recruited, the majority (85.8%) were diagnosed with recurrence or metastasis. The largest group (42.6%) comprised lung cancer patients, of whom 67.2% had an Eastern Cooperative Oncology Group Performance Status of 0-1. The mean value for global health status/quality of life was 41.4, and the highest mean European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative symptom item score was for pain (51.0). The mean global fatigue score was 4.1, and 9.8%, 30.6%, 38.7%, and 20.8% of patients' fatigue severity was classified as none (score 0), mild (1-3), moderate (4-6), and severe (7-10), respectively. DISCUSSION: Cancer-related fatigue, considered to occur more frequently in cancer patients, was successfully assessed using patient-reported outcomes with the Brief Fatigue Inventory for the first time in Japan. Results suggested that fatigue is potentially as problematic as pain, which is the main reason for palliative care. PMID- 26244977 TI - Obesity and Hepatic Steatosis Are Associated with Elevated Serum Amyloid Beta in Metabolically Stressed APPswe/PS1dE9 Mice. AB - Diabesity-associated metabolic stresses modulate the development of Alzheimer's disease (AD). For further insights into the underlying mechanisms, we examine whether the genetic background of APPswe/PS1dE9 at the prodromal stage of AD affects peripheral metabolism in the context of diabesity. We characterized APPswe/PS1dE9 transgenic mice treated with a combination of high-fat diet with streptozotocin (HFSTZ) in the early stage of AD. HFSTZ-treated APPswe/PS1dE9 transgenic mice exhibited worse metabolic stresses related to diabesity, while serum beta-amyloid levels were elevated and hepatic steatosis became apparent. Importantly, two-way analysis of variance shows a significant interaction between HFSTZ and genetic background of AD, indicating that APPswe/PS1dE9 transgenic mice are more vulnerable to HFSTZ treatment. In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum beta-amyloid, as validated by Pearson's correlation analysis. Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis. Alleviating metabolic stresses including dysglycemia, obesity, and hepatic steatosis could be critical to prevent peripheral beta-amyloid accumulation at the early stage of AD. PMID- 26244978 TI - A Multi-Center, Randomized, Controlled, Pivotal Study to Assess the Safety and Efficacy of a Selective Cytopheretic Device in Patients with Acute Kidney Injury. AB - OBJECTIVE: Acute kidney injury (AKI) is a highly morbid condition in critically ill patients that is associated with high mortality. Previous clinical studies have demonstrated the safety and efficacy of the Selective Cytopheretic Device (SCD) in the treatment of AKI requiring continuous renal replacement therapy in the intensive care unit (ICU). DESIGN, SETTING, PATIENTS: A randomized, controlled trial of 134 ICU patients with AKI, 69 received continuous renal replacement therapy (CRRT) alone and 65 received SCD therapy. RESULTS: No significant difference in 60-day mortality was observed between the treated (27/69; 39%) and control patients (21/59; 36%, with six patients lost to follow up) in the intention to treat (ITT) analysis. Of the 19 SCD subjects (CRRT+SCD) and 31 control subjects (CRRT alone) who maintained a post-filter ionized calcium (iCa) level in the protocol's recommended range (<= 0.4 mmol/L) for greater or equal to 90% of the therapy time, 60-day mortality was 16% (3/19) in the SCD group compared to 41% (11/27) in the CRRT alone group (p = 0.11). Dialysis dependency showed a borderline statistically significant difference between the SCD treated versus control CRRT alone patients maintained for >= 90% of the treatment in the protocol's recommended (r) iCa target range of <= 0.4 mmol/L with values of, 0% (0/16) and 25% (4/16), respectively (P = 0.10). When the riCa treated and control subgroups were compared for a composite index of 60 day mortality and dialysis dependency, the percentage of SCD treated subjects was 16% versus 58% in the control subjects (p<0.01). The incidence of serious adverse events did not differ between the treated (45/69; 65%) and control groups (40/65; 63%; p = 0.86). CONCLUSION: SCD therapy may improve mortality and reduce dialysis dependency in a tightly controlled regional hypocalcaemic environment in the perfusion circuit. TRIAL REGISTRATION: ClinicalTrials.gov NCT01400893 http://clinicaltrials.gov/ct2/show/NCT01400893. PMID- 26244979 TI - Transcriptome Analysis of the Emerald Ash Borer (EAB), Agrilus planipennis: De Novo Assembly, Functional Annotation and Comparative Analysis. AB - BACKGROUND: The Emerald ash borer (EAB), Agrilus planipennis, is an invasive phloem-feeding insect pest of ash trees. Since its initial discovery near the Detroit, US- Windsor, Canada area in 2002, the spread of EAB has had strong negative economic, social and environmental impacts in both countries. Several transcriptomes from specific tissues including midgut, fat body and antenna have recently been generated. However, the relatively low sequence depth, gene coverage and completeness limited the usefulness of these EAB databases. METHODOLOGY AND PRINCIPAL FINDINGS: High-throughput deep RNA-Sequencing (RNA-Seq) was used to obtain 473.9 million pairs of 100 bp length paired-end reads from various life stages and tissues. These reads were assembled into 88,907 contigs using the Trinity strategy and integrated into 38,160 unigenes after redundant sequences were removed. We annotated 11,229 unigenes by searching against the public nr, Swiss-Prot and COG. The EAB transcriptome assembly was compared with 13 other sequenced insect species, resulting in the prediction of 536 unigenes that are Coleoptera-specific. Differential gene expression revealed that 290 unigenes are expressed during larval molting and 3,911 unigenes during metamorphosis from larvae to pupae, respectively (FDR< 0.01 and log2 FC>2). In addition, 1,167 differentially expressed unigenes were identified from larval and adult midguts, 435 unigenes were up-regulated in larval midgut and 732 unigenes were up-regulated in adult midgut. Most of the genes involved in RNA interference (RNAi) pathways were identified, which implies the existence of a system RNAi in EAB. CONCLUSIONS AND SIGNIFICANCE: This study provides one of the most fundamental and comprehensive transcriptome resources available for EAB to date. Identification of the tissue- stage- or species- specific unigenes will benefit the further study of gene functions during growth and metamorphosis processes in EAB and other pest insects. PMID- 26244981 TI - Anti-Osteoarthritic Effects of the Litsea japonica Fruit in a Rat Model of Osteoarthritis Induced by Monosodium Iodoacetate. AB - Osteoarthritis (OA) is a degenerative chronic disease that affects various tissues surrounding the joints, such as the subchondral bone and articular cartilage. The onset of OA is associated with uncontrolled catabolic and anabolic remodeling processes of the joints, including the cartilage and subchondral bone, to adapt to local biological and biochemical signals. In this study, we determined whether 70% ethanolic (EtOH) extract of Litsea japonica fruit (LJFE) had beneficial effects on the articular cartilage, including structural changes in the tibial subchondral bone, matrix degradation, and inflammatory responses, in OA by using a rat model of monosodium iodoacetate-induced OA. Our results showed that administration of LJFE increased the bone volume and cross-section thickness, but the mean number of objects per slice in this group was lower than that in the OA control (OAC) group. In addition, the LJFE decreased the expression of inflammatory cytokines. Compared to the OAC group, the group treated with high doses of LJFE (100 and 200 mg/kg) showed a more than 80% inhibition of the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases. Our results suggest that LJFE can be used as a potential anti-osteoarthritic agent. PMID- 26244982 TI - eSIP: A Novel Solution-Based Sectioned Image Property Approach for Microscope Calibration. AB - Fluorescence confocal microscopy represents one of the central tools in modern sciences. Correspondingly, a growing amount of research relies on the development of novel microscopic methods. During the last decade numerous microscopic approaches were developed for the investigation of various scientific questions. Thereby, the former qualitative imaging methods became replaced by advanced quantitative methods to gain more and more information from a given sample. However, modern microscope systems being as complex as they are, require very precise and appropriate calibration routines, in particular when quantitative measurements should be compared over longer time scales or between different setups. Multispectral beads with sub-resolution size are often used to describe the point spread function and thus the optical properties of the microscope. More recently, a fluorescent layer was utilized to describe the axial profile for each pixel, which allows a spatially resolved characterization. However, fabrication of a thin fluorescent layer with matching refractive index is technically not solved yet. Therefore, we propose a novel type of calibration concept for sectioned image property (SIP) measurements which is based on fluorescent solution and makes the calibration concept available for a broader number of users. Compared to the previous approach, additional information can be obtained by application of this extended SIP chart approach, including penetration depth, detected number of photons, and illumination profile shape. Furthermore, due to the fit of the complete profile, our method is less susceptible to noise. Generally, the extended SIP approach represents a simple and highly reproducible method, allowing setup independent calibration and alignment procedures, which is mandatory for advanced quantitative microscopy. PMID- 26244983 TI - Description of the Microsporidian Parasite, Heterosporis sutherlandae n. sp., Infecting Fish in the Great Lakes Region, USA. AB - Heterosporosis is an increasingly important microsporidian disease worldwide, impacting wild and farmed raised fishes in both marine and freshwater environments. A previously undescribed species (Heterosporis sp.), with widespread distribution in the Great Lakes region, was the subject of this study. Three angler-caught fish were submitted to the Minnesota Veterinary Diagnostic Laboratory from 2009-2010 with lesions caused by intracellular proliferation of parasitic spores, resulting in destruction and eventual widespread necrosis of the host skeletal muscles. Mature ovoid (5.8 x 3.5 MUm) spores of a microsporidian parasite, consistent with the genus Heterosporis, were observed by light and electron microscopy. Molecular identification was performed using primer walking to obtain a near-complete rRNA gene sequence (~3,600 bp). A unique species of Heterosporis was identified, demonstrating less than 96% sequence identity to other published Heterosporis sp. on the basis of partial rRNA gene sequence analysis. Heterosporis sutherlandae n. sp. (formerly Heterosporis sp.) was identified in yellow perch (Perca flavescens), northern pike (Esox lucius) and walleye (Sander vitreus) from inland lakes in Minnesota and Wisconsin. Previous research suggests this species may be even more widespread in the Great Lakes region and should be reexamined using molecular techniques to better understand the distribution of this novel species. PMID- 26244980 TI - Temporal Dissection of Rate Limiting Transcriptional Events Using Pol II ChIP and RNA Analysis of Adrenergic Stress Gene Activation. AB - In mammals, increasing evidence supports mechanisms of co-transcriptional gene regulation and the generality of genetic control subsequent to RNA polymerase II (Pol II) recruitment. In this report, we use Pol II Chromatin Immunoprecipitation to investigate relationships between the mechanistic events controlling immediate early gene (IEG) activation following stimulation of the alpha1a-Adrenergic Receptor expressed in rat-1 fibroblasts. We validate our Pol II ChIP assay by comparison to major transcriptional events assessable by microarray and PCR analysis of precursor and mature mRNA. Temporal analysis of Pol II density suggests that reduced proximal pausing often enhances gene expression and was essential for Nr4a3 expression. Nevertheless, for Nr4a3 and several other genes, proximal pausing delayed the time required for initiation of productive elongation, consistent with a role in ensuring transcriptional fidelity. Arrival of Pol II at the 3' cleavage site usually correlated with increased polyadenylated mRNA; however, for Nfil3 and probably Gprc5a expression was delayed and accompanied by apparent pre-mRNA degradation. Intragenic pausing not associated with polyadenylation was also found to regulate and delay Gprc5a expression. Temporal analysis of Nr4a3, Dusp5 and Nfil3 shows that transcription of native IEG genes can proceed at velocities of 3.5 to 4 kilobases/min immediately after activation. Of note, all of the genes studied here also used increased Pol II recruitment as an important regulator of expression. Nevertheless, the generality of co-transcriptional regulation during IEG activation suggests temporal and integrated analysis will often be necessary to distinguish causative from potential rate limiting mechanisms. PMID- 26244984 TI - Evidence for a Shared Mechanism in the Formation of Urea-Induced Kinetic and Equilibrium Intermediates of Horse Apomyoglobin from Ultrarapid Mixing Experiments. AB - In this study, the equivalence of the kinetic mechanisms of the formation of urea induced kinetic folding intermediates and non-native equilibrium states was investigated in apomyoglobin. Despite having similar structural properties, equilibrium and kinetic intermediates accumulate under different conditions and via different mechanisms, and it remains unknown whether their formation involves shared or distinct kinetic mechanisms. To investigate the potential mechanisms of formation, the refolding and unfolding kinetics of horse apomyoglobin were measured by continuous- and stopped-flow fluorescence over a time range from approximately 100 MUs to 10 s, along with equilibrium unfolding transitions, as a function of urea concentration at pH 6.0 and 8 degrees C. The formation of a kinetic intermediate was observed over a wider range of urea concentrations (0 2.2 M) than the formation of the native state (0-1.6 M). Additionally, the kinetic intermediate remained populated as the predominant equilibrium state under conditions where the native and unfolded states were unstable (at ~0.7-2 M urea). A continuous shift from the kinetic to the equilibrium intermediate was observed as urea concentrations increased from 0 M to ~2 M, which indicates that these states share a common kinetic folding mechanism. This finding supports the conclusion that these intermediates are equivalent. Our results in turn suggest that the regions of the protein that resist denaturant perturbations form during the earlier stages of folding, which further supports the structural equivalence of transient and equilibrium intermediates. An additional folding intermediate accumulated within ~140 MUs of refolding and an unfolding intermediate accumulated in <1 ms of unfolding. Finally, by using quantitative modeling, we showed that a five-state sequential scheme appropriately describes the folding mechanism of horse apomyoglobin. PMID- 26244985 TI - Impact of Pre-Treatment Lactate Dehydrogenase Levels on Prognosis and Bevacizumab Efficacy in Patients with Metastatic Colorectal Cancer. AB - BACKGROUND: To investigate the impact of pre-treatment lactate dehydrogenase (LDH) levels on the outcome of patients with metastatic colorectal cancer treated with first-line chemotherapy with or without the anti-VEGF monoclonal antibody, bevacizumab, in a phase III prospective multicentre randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial. METHODS: Three hundred and seventy patients enrolled onto the ITACa first-line trial were considered for this study, 176 receiving chemotherapy (either FOLFIRI or FOLFOX) plus bevacizumab and 194 receiving chemotherapy only. Pre-treatment LDH levels were evaluated to identify a potential correlation with progression-free survival (PFS), overall survival (OS) and objective response rate. RESULTS: Information on pre-treatment LDH levels was available for 344 patients. High LDH levels were predictive of a lower median PFS (8.1 months vs. 9.2 months, p< 0.0001) and median OS (16.1 months vs. 25.2 months, p< 0.0001) in the overall population. In the chemotherapy plus bevacizumab group, median PFS was 9.1 and 9.8 months in patients with high LDH and low LDH, respectively (p= 0.073), whereas in the chemotherapy-only arm it was 6.9 and 9.1 months, respectively (p < 0.0001). In patients with high LDH, the addition of bevacizumab to chemotherapy led to a reduction in the rate of progressive disease (16.4 vs. 30.5%, p= 0.081) and to a prolonged PFS (p= 0.028). CONCLUSION: A high LDH value was confirmed as a marker of poor prognosis. Bevacizumab reduced the progressive disease rate and improved PFS in the high-LDH subgroup, making serum LDH a potentially effective an easily available and marker to select patients who benefit from bevacizumab. TRIAL REGISTRATION: NCT01878422 ClinicalTrials.gov. PMID- 26244986 TI - An Overrepresentation of High Frequencies in the Mouse Inferior Colliculus Supports the Processing of Ultrasonic Vocalizations. AB - Mice are of paramount importance in biomedical research and their vocalizations are a subject of interest for researchers across a wide range of health-related disciplines due to their increasingly important value as a phenotyping tool in models of neural, speech and language disorders. However, the mechanisms underlying the auditory processing of vocalizations in mice are not well understood. The mouse audiogram shows a peak in sensitivity at frequencies between 15-25 kHz, but weaker sensitivity for the higher ultrasonic frequencies at which they typically vocalize. To investigate the auditory processing of vocalizations in mice, we measured evoked potential, single-unit, and multi-unit responses to tones and vocalizations at three different stages along the auditory pathway: the auditory nerve and the cochlear nucleus in the periphery, and the inferior colliculus in the midbrain. Auditory brainstem response measurements suggested stronger responses in the midbrain relative to the periphery for frequencies higher than 32 kHz. This result was confirmed by single- and multi unit recordings showing that high ultrasonic frequency tones and vocalizations elicited responses from only a small fraction of cells in the periphery, while a much larger fraction of cells responded in the inferior colliculus. These results suggest that the processing of communication calls in mice is supported by a specialization of the auditory system for high frequencies that emerges at central stations of the auditory pathway. PMID- 26244987 TI - Identification and Characterization of MicroRNAs from Longitudinal Muscle and Respiratory Tree in Sea Cucumber (Apostichopus japonicus) Using High-Throughput Sequencing. AB - MicroRNAs (miRNAs), as a family of non-coding small RNAs, play important roles in the post-transcriptional regulation of gene expression. Sea cucumber (Apostichopus japonicus) is an important economic species which is widely cultured in East Asia. The longitudinal muscle (LTM) and respiratory tree (RPT) are two important tissues in sea cucumber, playing important roles such as respiration and movement. In this study, we identified and characterized miRNAs in the LTM and RPT of sea cucumber (Apostichopus japonicus) using Illumina HiSeq 2000 platform. A total of 314 and 221 conserved miRNAs were identified in LTM and RPT, respectively. In addition, 27 and 34 novel miRNAs were identified in the LTM and RPT, respectively. A set of 58 miRNAs were identified to be differentially expressed between LTM and RPT. Among them, 9 miRNAs (miR-31a-3p, miR-738, miR 1692, let-7a, miR-72a, miR-100b-5p, miR-31b-5p, miR-429-3p, and miR-2008) in RPT and 7 miRNAs (miR-127, miR-340, miR-381, miR-3543, miR-434-5p, miR-136-3p, and miR-300-3p) in LTM were differentially expressed with foldchange value being greater than 10. A total of 14,207 and 12,174 target genes of these miRNAs were predicted, respectively. Functional analysis of these target genes of miRNAs were performed by GO analysis and pathway analysis. This result provided in this work will be useful for understanding biological characteristics of the LTM and RPT of sea cucumber and assisting molecular breeding of sea cucumber for aquaculture. PMID- 26244991 TI - Thorium Mono- and Bis(imido) Complexes Made by Reprotonation of cyclo-Metalated Amides. AB - Molecules containing actinide-nitrogen multiple bonds are of current interest as simple models for new actinide nitride nuclear fuels, and for their potential for the catalytic activation of inert hydrocarbon C-H bonds. Complexes with up to three uranium-nitrogen double bonds are now being widely studied, yet those with one thorium-nitrogen double bond are rare, and those with two are unknown. A new, simple mono(imido) thorium complex and the first bis(imido) thorium complex, K[Th(?NAr)N"3] and K2[Th(?NAr)2N"2], are readily made from insertion reactions (Ar = aryl, N" = N(SiMe3)2) into the Th-C bond of the cyclometalated thorium amides [ThN"2(N(SiMe3)(SiMe2CH2))] and K[ThN"(N(SiMe3)(SiMe2CH2))2]. X-ray and computational structural analyses show a "transition-metal-like" cis-bis(imido) geometry and polarized Th?N bonds with twice the Wiberg bond order of the formally single Th-N bond in the same molecule. PMID- 26244989 TI - Early environmental therapy rescues brain development in a mouse model of Down syndrome. AB - Down syndrome (DS), the most common genetic disorder associated with intellectual disabilities, is an untreatable condition characterized by a number of developmental defects and permanent deficits in the adulthood. Ts65Dn mice, the major animal model for DS, display severe cognitive and synaptic plasticity defects closely resembling the human phenotype. Here, we employed a multidisciplinary approach to investigate, for the first time in developing Ts65Dn mice, the effects elicited by early environmental enrichment (EE) on brain maturation and function. We report that exposure to EE resulted in a robust increase in maternal care levels displayed by Ts65Dn mothers and led to a normalization of declarative memory abilities and hippocampal plasticity in trisomic offspring. The positive effects of EE on Ts65Dn phenotype were not limited to the cognitive domain, but also included a rescue of visual system maturation. The beneficial EE effects were accompanied by increased BDNF and correction of over-expression of the GABA vesicular transporter vGAT. These findings highlight the beneficial impact of early environmental stimuli and their potential for application in the treatment of major functional deficits in children with DS. PMID- 26244990 TI - Potential of aryl-urea-benzofuranylthiazoles hybrids as multitasking agents in Alzheimer's disease. AB - New benzofuranylthiazole derivatives containing the aryl-urea moiety were synthesized and evaluated in vitro as dual acetylcholinesterase (AChE) butyrylcholinesterase (BuChE) inhibitors. In addition, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the synthesized compounds were assayed. The result showed that all the synthesized compounds exhibited inhibitory activity on both AChE and BuChE with 1 (4-(5-bromobenzofuran-2-yl)thiazol-2-yl)-3-(2-fluorophenyl)urea (e25, IC50 value of 3.85 MUM) and 1-(4-iodophenyl)-3-(4-(5-nitrobenzofuran-2-yl)thiazol-2-yl)urea (e38, IC50 value of 2.03 MUM) as the strongest inhibitors against AChE and BuChE, respectively. Compound e38 was 8.5-fold more potent than galanthamine. The selectivity index of e25 and e38 was 2.40 and 0.37 against AChE and BuChE, respectively. Compound e2, e4 and e11 (IC50 = 0.2, 0.5 and 1.13 MUM, respectively) showed a better ABTS cation radical scavenging ability than the standard quercetin (IC50 = 1.18 MUM). Best poses of compounds e38 on BuChE and e25 on AChE indicate that the thiazole ring and the amidic moiety are important sites of interaction with both ChEs. In addition, the benzofuran ring and phenyl ring are anchored to the side chains of both enzymes by pi-pi(pi-pi) interactions. PMID- 26244988 TI - Let-7 Represses Carcinogenesis and a Stem Cell Phenotype in the Intestine via Regulation of Hmga2. AB - Let-7 miRNAs comprise one of the largest and most highly expressed family of miRNAs among vertebrates, and is critical for promoting differentiation, regulating metabolism, inhibiting cellular proliferation, and repressing carcinogenesis in a variety of tissues. The large size of the Let-7 family of miRNAs has complicated the development of mutant animal models. Here we describe the comprehensive repression of all Let-7 miRNAs in the intestinal epithelium via low-level tissue-specific expression of the Lin28b RNA-binding protein and a conditional knockout of the MirLet7c-2/Mirlet7b locus. This ablation of Let-7 triggers the development of intestinal adenocarcinomas concomitant with reduced survival. Analysis of both mouse and human intestinal cancer specimens reveals that stem cell markers were significantly associated with loss of Let-7 miRNA expression, and that a number of Let-7 targets were elevated, including Hmga1 and Hmga2. Functional studies in 3-D enteroids revealed that Hmga2 is necessary and sufficient to mediate many characteristics of Let-7 depletion, namely accelerating cell cycle progression and enhancing a stem cell phenotype. In addition, inactivation of a single Hmga2 allele in the mouse intestine epithelium significantly represses tumorigenesis driven by Lin28b. In aggregate, we conclude that Let-7 depletion drives a stem cell phenotype and the development of intestinal cancer, primarily via Hmga2. PMID- 26244993 TI - A Short Letter to CSMS President, Robert Russo, MD. PMID- 26244994 TI - Constructing quality health policy. PMID- 26244992 TI - G protein-coupled receptors Flop1 and Flop2 inhibit Wnt/beta-catenin signaling and are essential for head formation in Xenopus. AB - Patterning of the vertebrate anterior-posterior axis is regulated by the coordinated action of growth factors whose effects can be further modulated by upstream and downstream mediators and the cross-talk of different intracellular pathways. In particular, the inhibition of the Wnt/beta-catenin signaling pathway by various factors is critically required for anterior specification. Here, we report that Flop1 and Flop2 (Flop1/2), G protein-coupled receptors related to Gpr4, contribute to the regulation of head formation by inhibiting Wnt/beta catenin signaling in Xenopus embryos. Using whole-mount in situ hybridization, we showed that flop1 and flop2 mRNAs were expressed in the neural ectoderm during early gastrulation. Both the overexpression and knockdown of Flop1/2 resulted in altered embryonic head phenotypes, while the overexpression of either Flop1/2 or the small GTPase RhoA in the absence of bone morphogenetic protein (BMP) signaling resulted in ectopic head induction. Examination of the Flops' function in Xenopus embryo animal cap cells showed that they inhibited Wnt/beta-catenin signaling by promoting beta-catenin degradation through both RhoA-dependent and independent pathways in a cell-autonomous manner. These results suggest that Flop1 and Flop2 are essential regulators of Xenopus head formation that act as novel inhibitory components of the Wnt/beta-catenin signaling pathway. PMID- 26244995 TI - Travellers' diarrhea. PMID- 26244996 TI - Reply. PMID- 26244997 TI - Food allergies. PMID- 26244998 TI - Reply. PMID- 26244999 TI - Acrodermatitis enteropathica in an adult. PMID- 26245000 TI - Biologic Medicines Under the Microscope. PMID- 26245001 TI - Mind Full. Recent brain research offers intriguing insights into leadership and decision-making. PMID- 26245002 TI - DEATH, BUT IS IT MURDER? THE ROLE OF STEREOTYPES AND CULTURAL PERCEPTIONS IN THE WRONGFUL CONVICTIONS OF WOMEN. PMID- 26245003 TI - GENDER ROLE OF INCONGRUENCE AND THE ADJUDICATION OF CRIMINAL RESPONSIBILITY. PMID- 26245004 TI - Medical Devices; General and Plastic Surgery Devices; Classification of the Internal Tissue Marker. Final order. AB - The Food and Drug Administration (FDA) is classifying the internal tissue marker into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified language for the internal tissue marker's classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 26245005 TI - Medicare Program; Inpatient Psychiatric Facilities Prospective Payment System- Update for Fiscal Year Beginning October 1, 2015 (FY 2016). Final rule. AB - This final rule updates the prospective payment rates for Medicare inpatient hospital services provided by inpatient psychiatric facilities (IPFs) (which are freestanding IPFs and psychiatric units of an acute care hospital or critical access hospital). These changes are applicable to IPF discharges occurring during fiscal year (FY) 2016 (October 1, 2015 through September 30, 2016). This final rule also implements: a new 2012-based IPF market basket; an updated IPF labor related share; a transition to new Core Based Statistical Area (CBSA) designations in the FY 2016 IPF Prospective Payment System (PPS) wage index; a phase-out of the rural adjustment for IPF providers whose status changes from rural to urban as a result of the wage index CBSA changes; and new quality measures and reporting requirements under the IPF quality reporting program. This final rule also reminds IPFs of the October 1, 2015 implementation of the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM), and updates providers on the status of IPF PPS refinements. PMID- 26245006 TI - The Coral of Death. Kunst- und Wunderkammern between Temporality and Allegory. AB - The aim of this essay is to show the existence of a substantial discontinuity between the Kunst- und Wunderkammern phenomenon and the practice of both eclectic and specialised collecting in the 18th century. A more detailed examination of the cases of fossils and corals, particularly the way they wove in and out of the differing rationales of collecting in the 17th and 18th centuries, brings to light how elusive their relationship was with the history of the notion of temporality. Subsequently, Lamarck and Darwin were to provide a conclusion to the temporality debate when they completed the historisation of nature. PMID- 26245007 TI - The Radium Terrors. Science Fiction and Radioactivity before the Bomb. AB - At the beginning of the 20th century the collective imagination was fascinated and terrified by the discovery of radium. A scientific imagery sprang up around radioactivity and was disseminated by public lectures and newspaper articles discussing the ambiguous power of this strange substance. It was claimed that radium could be used to treat cholera, typhus and tuberculosis, but at the same time there were warnings that it could be used for military purposes. The media and the scientists themselves employed a rich vocabulary influenced by religion, alchemy and magic. The ambivalent power of radioactive elements exerted a great influence on science fiction novelists. This paper will examine some significant works published in Europe, America and Russia during the first decades of the 20th century and their role in the creation of the complex imagery of radioactivity that seized the public imagination long before the invention of the atomic bomb. PMID- 26245008 TI - Alchemy in Cambridge. An Annotated Catalogue of Alchemical Texts and Illustrations in Cambridge Repositories. AB - Alchemy in Cambridge captures the alchemical content of 56 manuscripts in Cambridge, in particular the libraries of Trinity College, Corpus Christi College and St John's College, the University Library and the Fitzwilliam Museum. As such, this catalogue makes visible a large number of previously unknown or obscured alchemica. While extant bibliographies, including those by M.R. James a century ago, were compiled by polymathic bibliographers for a wide audience of researchers, Alchemy in Cambridge benefits from the substantial developments in the history of alchemy, bibliography, and related scholarship in recent decades. Many texts are here identified for the first time. Another vital feature is the incorporation of information on alchemical illustrations in the manuscripts, intended to facilitate research on the visual culture of alchemy. The catalogue is aimed at historians of alchemy and science, and of high interest to manuscript scholars, historians of art and historians of college and university libraries. PMID- 26245009 TI - Living Outside Their Heads: Assessing the Efficacy of a Multicultural Course on the Attitudes of Graduate Students in Teacher Education. AB - Given the importance of multicultural education, its impact on students and the ensuing impact on society, it would appear that studies assessing the efficacy of how social justice issues are taught appear to be essential. However, most studies assessing the efficacy of multicultural teacher education coursework appears to be inconclusive. This paper poses the following questions: to what extent is it possible for students who are teachers and administrators in American schools to engage in a multicultural graduate course taught using a social reconstructionist approach to see outside the boundaries of their own perspectives; and to what extent might a multicultural education course have a lasting impact on their personal and professional lives. Additionally, the study asks whether the effects of a multicultural course may be long lasting and significant. PMID- 26245010 TI - Prevalence and Severity of Symptoms in a Sample of African Americans and White Participants. AB - According to the Centers for Disease Control and Prevention (2013), African Americans have a substantially greater prevalence of a range of health conditions when compared to other racial or ethnic groups. Many of these conditions have been attributed to the historical and contemporary social and economic disparities faced by the African American community. While many health conditions occur at a higher rate in African Americans, it is unclear whether there are specific symptom clusters that may also be more prevalent in African Americans as a result of these disparities. Potential differences in symptomology have not been thoroughly examined between African Americans and White populations. The current study compares the prevalence and pain severity of symptoms among a sample of African Americans and White participants. Significant differences in symptom prevalence were found in disturbed sleep and reproductive areas. African Americans also experience more pain due to symptoms related to orthostatic intolerance. Implications of this finding are discussed. PMID- 26245011 TI - Improving Ethnocultural Empathy in Healthcare Students through a Targeted Intervention. AB - Students in training to become future healthcare providers must be trained not only how to provide quality care but also how to effectively communicate with patients, regardless of the patient's cultural background. Poor communication between provider and patient when racial or ethnic backgrounds differ between patient and provider is a relevant factor in suboptimal healthcare services to ethnic minorities. This pilot study was conducted to examine changes in the scores on the Scale of Ethnocultural Empathy (SEE)for first year nursing (n = 40) and dental students (n = 42)following an intervention. Participants completed an anonymous online survey that included the SEE, a validated measure of empathy toward people with racial and ethnic backgrounds different from one's own prior to the intervention (baseline), immediately following the intervention workshop (post-test) and one month following the workshop (follow-up). Results showed statistically significant increases from baseline to post-intervention on the SEE (p < .05), and these gains were maintained at follow-up. This study is the first to examine whether an intervention specifically designed to improve students' understanding of racial groups discordant from their own actually improves empathy and communication. Results from this pilot study support that controlled trials are warranted. PMID- 26245012 TI - Cultural Health Practices of Migrant Seasonal Farmworkers. AB - This study explored culturally related health practices among Hispanic migrant seasonal farmworkers. In this cross-sectional qualitative study, six Hispanic migrant seasonal farmworkers from southeastern Michigan farms were interviewed. Four major themes emerged from the study. Financial and employment limitations, rather than folk health care practices, were more likely to influence use of professional care systems. There was limited use of folk healers and culturally related practices, primarily due to lack of access. Results may be used to identify needs and develop culturally appropriate programs and services to improve the health of Hispanic migrant seasonal farmworkers. PMID- 26245013 TI - Diagnostic Accuracy of MRI in Predicting Breast Tumor Size: Comparative Analysis of MRI vs Histopathological Assessed Breast Tumor Size. AB - BACKGROUND: Diagnostic accuracy of MRI in predicting breast tumor size: comparative analysis of breast tumor size byMRI vs histopathological assessment. PURPOSE: Tumor size is one of the most important factors in making a clinical and pathological assessment of breast cancer. The purpose of this study is to evaluate if MRI imaging is helpful for the surgeon in the preoperative accurate assessment of tumor size. METHODS: We retrospectively reviewed the charts of 124 patients who were diagnosed or managed at the Saint Francis /Mt. Sinai Regional Cancer Center. We then compared the preoperative MRI tumor size with the histopathological tumor size obtained at surgical resection. Tumors were divided into four histological groups: invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), ductal carcinomain situ (DCIS), and mixed tumors (including mucinous, papillary, tubular, and apocrine breast carcinoma). MRI measurement of tumor size was compared against the reference size obtained from the microscopic measurement of the largest diameter of tumors. Concordance was defined as a difference <= 0.5 cm between MRI and pathology. RESULTS: A total of 124 patients with 147 breast tumors were included in our study. The mean age was 59.8 +/- 12.72 years. Histologically, there were 81 IDC (55.10%), 35 DCIS (23.81%), 15 ILC (10.20%), and 16 mixed tumors (10.88%). Out of 147 tumors, 55.78% showed concordance of MRI and pathologic tumor size within 0.5 cm. MRI overestimated 31.97% and underestimated 12.24% of tumors. CONCLUSION: Breast MRI provides an additional tool for preoperative assessment of tumor size. In our study, we noted 56% concordance between MRI with pathological tumor size within 0.5 cm. Several factors, including grading of tumor, cancer type, and size, strongly affect the accuracy of MRI in the preoperative assessment of tumor size. High-grade tumor and DCIS are the two strongest negative factors resulting in overestimation of tumor size on MRI. PMID- 26245014 TI - Carbapenem-Resistant Enterobacteriaceae: A Case Series of Infections at Hartford Hospital. AB - Infections due to carbapenem-resistant Enterobacteriaceae (CRE) represent a growing problem nationally, are difficult to treat, and are associated with high mortality rates. Features of CRE infection within Connecticut, a nonendemic area, have not been described in the medical literature. We report a case series of five patients with CRE isolates who were treated at Hartford Hospital in Hartford, Connecticut from 2011-2013. CRE isolates included three Klebsiella pneumoniae, one Klebsiella oxytoca, and two E. coli. Three isolates were obtained from urine cultures, one from respiratory culture, and one from blood and wound cultures. Four patients survived the hospital course, including three patients who had a hospital stay of > 100 days. In this nonendemic hospital, CRE infections were identified mainly in patients with multiple comorbidities who underwent catheter placement and surgical procedures, had contact with the health care system in the preceding 90 days, and tended to have prolonged, complicated hospital courses. PMID- 26245016 TI - Late-Onset Bipolar Disorder: A Case Report. AB - Treating refractory late-onset bipolar disorder has not been sufficiently presented in the literature. In this case report, we present a 54-year-old male with late-onset bipolar disorder, who did notimprove despite multiple medication and dosage changes. This case outlines the challenges in treatment of these patients as well as identifies areas of further study regarding late-onset bipolar disorder management. PMID- 26245015 TI - Prevalence of Metabolic Syndrome in Patients with HIV in the Era of Highly Active Antiretroviral Therapy. AB - OBJECTIVES: Since the introduction of combination antiretroviral therapy (cART) as the standard of care for HIV disease, there has been a precipitous decline in the death rate due to HIV/ AIDS. The purpose of this study was to report the prevalence of metabolic syndrome in HIV infected patients. METHODS: Retrospective, cross-sectional, observational study of 259 patients with HIV infection treated with cART from an urban community hospital. Metabolic syndrome prevalence was defined using the International Diabetes Federation (IDF) and the U.S. National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria. Study patients were included regardless of the duration of cART. RESULTS: The prevalence of metabolic syndrome was 27% using IDF criteria and 26% using ATP III criteria. Logistic regression analysis found an association between treatment with the protease inhibitor darunavir and metabolic syndrome. (OR 3.32 with 95% confidence interval between 1.54 and 7.15). CONCLUSION: There is a high prevalence of metabolic syndrome and obesity in HIV patients treated with cART, especially those taking the protease inhibitor darunavir. PMID- 26245018 TI - Do Medical Students Choose Historical Role Models Who "Look Like Me"? PMID- 26245017 TI - Endometrial Ablation for Aplastic Anemia-Associated Menorrhagia. AB - Aplastic anemia is characterized by bone marrow failure and pancytopenia. In women, this can lead to menorrhagia secondary to thrombocytopenia which may require treatment depending on its severity. We report a patient with aplastic anemia-associated menorrhagia requiring emergency inpatient endometrial ablation due to transfusion dependence. A 42-year-old G3P3003 female presented with severe anemia, thrombocytopenia, and metrorrhagia. Her subsequent bone marrow biopsy revealed aplastic anemia. Her menometrorrhagia progressively worsened and she remained transfusion dependent. In the hospital, the patient underwent an uneventful endometrial ablation to control her vaginal bleeding. Patient reports only minor spotting after the procedure. Endometrial ablation is a safe and effective technique of treating acute menorrhagia in patients with aplastic anemia. It can reduce vaginal bleeding and decrease transfusion dependence. PMID- 26245019 TI - Biosimilars. PMID- 26245020 TI - 50 Years Ago. From Connecticut Medicine. May 1965. Common Denominators In Chronic Illness Care. 1965. PMID- 26245021 TI - "Why Do You Want To Be A Doctor"? PMID- 26245023 TI - Looking Foward: Post-SGR. PMID- 26245022 TI - SGR to MIPS. PMID- 26245024 TI - Hyperbaric Medicine. PMID- 26245025 TI - 50 Years Ago. Group portrait Dr. German's clinic. PMID- 26245027 TI - Differential proteomics approach to identify putative protective antigens of Mycobacterium tuberculosis presented during early stages of macrophage infection and their evaluation as DNA vaccines. AB - Unsatisfactory performance of the existing BCG vaccines, especially against the adult pulmonary disease, has urged the need for an effective vaccine against tuberculosis (TB). In this study, we employed differential proteomics to obtain a list of antigens as potential vaccine candidates. Bacterial epitopes being presented at early stages on MHC class I and class II molecules of macrophages infected with Mycobacterium tuberculosis (M. tb) were identified using iTRAQ labelling and reverse phase LC-MS/MS. The putative vaccine candidates, thus identified, were tested as plasmid DNA vaccines in mice to ascertain their protective efficacy against the aerosolized M. tb challenge, based on their ability to reduce the bacterial load in the lungs of infected mice. Here, we observed that 4 out of the 17 selected antigens imparted significant protection against the challenge of M. tb. The four shortlisted antigens were further assessed in a more stringent guinea pig model, where too, they demonstrated.significant protection. It concludes that combining a proteomics approach with the in vivo assessment of vaccine candidates in animal models can be valuable in identifying new potential candidates to expand the antigenic repertoire for novel vaccines against TB. PMID- 26245028 TI - Forced egg retention and oviposition behavior of malaria, dengue and filariasis vectors to a topical repellent diethyl-phenylacetamide. AB - Egg retention and oviposition behavior of four species of mosquito vectors viz., Anopheles stephensi, Aedes aegypti, Aedes albopictus, and Culex quinquefasciatus to a topical insect repellent diethyl-phenylacetamide (DEPA) at 0.1-1000 mg/L was investigated under laboratory conditions. Based on oviposition activity indices, DEPA demonstrated concentration dependent oviposition deterrent effect to A. stephensi (-0.18 to -0.97), A. aegypti (-0.18 to -0.91) and A. albopictus (-0.50 to -0.98) females. In contrast, positive oviposition response by C. quinquefasciatus (+0.39 and +0.70) was observed respectively at 0.1 and 1 ppm, while 10 ppm of DEPA on water received 50% lesser egg rafts than control. Gravid Culex females laid no egg rafts at 100 and 1000 ppm DEPA treated bowls effecting 100% oviposition deterrence. Test mosquito females deposited most of their eggs (> 90%) in the absence of repellent odour, while DEPA odour on water surface forced them to retain huge numbers of eggs. Females of A. aegypti, A. albopictus and A. stephensi retained 49, 67 and 50% of total eggs, respectively throughout the experiment. Egg retention by Culex females due to DEPA on the water surface was ca. 65%, equivalent to 4 egg rafts. Therefore, DEPA at lower concentrations could effectively disturb the oviposition by these vectors. Application of repellents in small water bodies would help in reducing the population build up of mosquitoes near human households and could be useful in the integrated management of mosquito vectors. PMID- 26245029 TI - Panchagavya Ghrita, an Ayurvedic formulation attenuates seizures, cognitive impairment and oxidative stress in pentylenetetrazole induced seizures in rats. AB - Panchagavya Ghrita (PG), according to Ayurvedic formulary of India (AFI), is used to treat epilepsy (apasmara), fever (jvara), mania (unmade) and jaundice (kamala). In the present study, we examined its effect on convulsions, oxidative stress and cognitive impairment in pentylenetetrazole (PTZ) induced seizures in rats. PG @ 250, 500, 1000, 2000 and 4000 mg/kg was administered orally for 7 days to male Wistar rats. On day 7, PTZ (60 mg/kg) was injected intraperitoneally 2 h after the last dose of PG. Sodium valproate (300 mg/kg) was used as positive control. Latency to myoclonic jerks, clonus and generalized tonic clonic seizures (GTCS) were recorded for seizure severity. Cognitive impairment was assessed using elevated plus maze and passive avoidance tests. Malondialdehyde and reduced glutathione levels were measured in rat brain. The results have shown that pretreatment with PG @ 500, 1000, 2000 and 4000 mg/kg exhibited 16.6, 33.3, 50 and 100% protection against occurrence of GTCS. The pretreatment with PG has significantly improved cognitive functions and the oxidative stress induced by seizures demonstrating its protective effect against PTZ induced seizures, and further, use of PG as an anticonvulsant in Ayurvedic system of medicine. PMID- 26245030 TI - Effects of alcoholic extract of Curcuma longa on Ascaridia infestation affecting chicken. AB - Ascaridia galli, the common intestinal nematode, remains a major cause of economic loss in the poultry industry in developing countries. Treatments using chemicals are not only expensive but also affect host health. Plant extracts as better alternative is gaining significance. Here, we have studied the effects of alcoholic extract of turmeric, Curcuma longa L. (Zingiberaceae) roots, against A. galli infection in chicken. Different concentrations of C. longa root extract were tested in vitro on 5 groups of adults A. galli worms and in vivo on 6 groups of chicks. The results showed that the turmeric root extract @ 60 mg mL(-1) in vitro significantly (P < 0.001) proved paralytic and fatal against worms (16.80 +/- 1.28 h). In vivo, chicken groups (G2-G6) were infected with an average of 300 +/- 12 embryonated eggs of A. galli. The G2 was not given any treatment while G3 was treated with piperazine (@ 200 mg kg(-1) body wt.); and Groups 4, 5 and 6 were given turmeric @ 200, 400 and 600 mg kg(-1) body wt., respectively. The mean number of worms extracted at the end of the trial in G2 (untreated) was 18.10 +/- 2.42, while the G3 treated with piperazine had no worms. Groups 4 and 5 did not show any significant difference compared to G2. However, G6 that had 3.20 +/- 1.33 worms was statistically significant. Higher concentrations of turmeric given to infected chickens significantly reduced the length and weight of worms. The study showed that the worm infestation damaged the intestinal villi, and.treatment with high concentration of C. longa had healing effects and restored the integrity of intestinal mucosa. The results have demonstrated the ameliorating effect of C. longa turmeric on A. galli infested chickens. PMID- 26245031 TI - Antioxidant potential of banana: Study using simulated gastrointestinal model and conventional extraction. AB - Most reports on fruit antioxidant capacities are based on extraction of antioxidants using polar solvents. In banana, little is known about the fate of bioactive compounds during the digestion process, particularly in the food matrix under the gastric and intestinal conditions. In the present study, an in vitro gastrointestinal digestion method was used to simulate physiological conditions of the stomach and small intestine to evaluate the actual antioxidant capacity of banana. The simulated gastrointestinal extracts showed significantly higher antioxidant properties. The total phenol content of the physiological enzymatic extract was higher by almost 150% than the methanolic extract. Similarly, the flavonoid and flavonol contents were higher in the physiological enzymatic extract by 330.6 and 141.7%, respectively as compared to methanolic extract. These differences were also noticed in the antioxidant capacity measurement parameters. From the results, it can be concluded that the conventional extracts underrate the antioxidant value of banana and that they may have much higher health significance, as an antioxidant in particular. PMID- 26245032 TI - An efficient regeneration and rapid micropropagation protocol for Almond using dormant axillary buds as explants. AB - An efficient in vitro protocol was standardized for Almond (Prunus dulcis) propagation using dormant axillary buds as explants. Explants were cultured on Murashige and Skoog (MS) and woody plant medium (WPM) supplemented with different concentration/combination(s) of phytohormones. MS basal medium showed lowest shoot induction and took longest duration for shoot initiation. Multiple shoots were induced in MS medium supplemented with the combination of BAP (0.5 mgL(-1)). Cultures showed poor response for rooting in all combinations of plant growth regulators (PGRs) and took 90 days for initiation. Rooting was higher in half strength of MS than in full-strength. The highest root induction (33.33%) was recorded in half MS medium supplemented with 0.1 mgL(-1) IBA (indole-3-butyric acid) followed by full strength of MS medium (20%) supplemented with IBA (0.1 mgL(-1)). alpha-Naphthalene acetic acid (NAA) was less effective for rooting than IBA. The highest root induction (25%) was found in half strength of MS medium supplemented with 0.1 mgL(-1) NAA followed by full strength of MS medium (20%). The protocol developed would be of use in mass propagation of almond and also support in vitro conservation. PMID- 26245033 TI - Intra-plant floral variation in Cleome viscosa L. and its possible significance in breeding system. AB - Cleome viscosa L., an annual rainy season weed, is cosmopolitan in distribution. Two naturally growing populations of C. viscosa from Jammu, J & K, India have been studied for floral variation at an intra-plant level and its possible role in its life cycle. Plants of both the populations bear flowers which exhibit tremendous intra-plant variation in size (large and small) and sex (hermaphrodite, staminate and pistillate). The average number of flowers per plant varied significantly and so did their structural and functional details. Greater propensity, however, was towards hermaphroditism at both plant and flower levels. The large and small sized flowers differed in their morphology and reproductive features; the former were significantly larger than the latter. Anthesis, anther dehiscence and stigma receptivity were coupled in all flower types. This functional aspect along with the structural proximity between stamens at two lengths and pistil further facilitated self-pollination. However, conspicuous floral display attracted diverse pollinator fauna (Apis dorsata, Halictus albescens, Nomia curvipes and N. elliotii) which in turn mediated cross pollination. Nevertheless, each floral type contributed towards plant's fitness in its own way. Hermaphrodite flowers exhibited both self and cross pollination and assured survival by setting fruits and seeds with the large sized counterparts more productive. All these floral variations seemed to impart flexibility to the pollination system and provide fitness over the short flowering season. PMID- 26245034 TI - Assessment of pollution of river Ganges by tannery effluents using genotoxicity biomarkers in murrel fish, Channa punctatus (Bloch). AB - River pollution due to rapid industrialization and anthropogenic activities adversely affects the aquatic organisms, especially fish. Here, we assessed the genotoxicity, mutagenicity and bioaccumulative aspects of tannery effluents in freshwater murrel, Channa punctatus, an inhabitant of river Ganges. Test specimens were collected from three different polluted sites of the river within and nearby Kanpur area during different seasons and blood samples of these specimens were processed for comet assay and micronucleus test as genotoxicity biomarkers. A significantly (P < 0.05) higher micronuclei induction, nuclear abnormalities and % tail DNA was observed in the specimens collected from the polluted sites. Bioaccumulation studies in the muscle (1.202 MUg/g) and gill tissues (< 0.300 MUg/g) of the specimens revealed the concentration of chromium (core component of tanning industry) above the maximum permissible limits as prescribed by World Health Organization (WHO). The findings of the present analysis indicated contamination of river Ganges with tannery effluents which induce genotoxicity in fish with seasonal variation. PMID- 26245035 TI - Overview of Alpha-blockers in Hypertension: Reappraisal of Perspectives. PMID- 26245036 TI - Clinical Pharmacology of Alpha-1 Blockers Improving Drug-profile through Novel Formulations. AB - Clinical pharmacology is an essential consideration in chronic therapies, and may play a significant role in modifying the pharmacological characteristics of drug formulations. Improvement in drug formulations may ensure their safe and effective use over a period of time. This has been particularly observed with alpha-1 adrenergic blockers in hypertension management. Advancements in formulations like prazosin GITS, have resulted in improvement in tolerability profile and smoother, more effective blood pressure control, which reasonably translate into improvement in patient compliance and better clinical outcomes. PMID- 26245037 TI - Alpha Blockers and Metabolic Syndrome. PMID- 26245038 TI - Resistant Hypertension. PMID- 26245039 TI - alpha Blockers in Resistant Hypertension: A Cardiology Perspective. PMID- 26245040 TI - Alpha Adrenergic Blockers in the Treatment of Hypertension--A Nephrologist's Perspective. PMID- 26245041 TI - Alpha-blockers in Renal Disease: Appraisal of Evidence. PMID- 26245042 TI - Role of Alpha Blockers in Hypertension with Benign Prostatic Hyperplasia. AB - Hypertension and benign prostatic hyperplasia (BPH) are common disorders of aging men. As the world population is aging these two diseases are becoming a significant public health problem worldwide. Approximately 30% of men treated for BPH have coexisting hypertension. The alpha-Adrenergic Blockers: Prazosin, Terazosin and Doxazosin are established agents in the therapy of hypertension, and are also effective drugs in the treatment of BPH. It is reasonable to use alpha-Adrenergic Blockers as the treatment of choice for men with hypertension and BPH. PMID- 26245043 TI - [Evidence-based cesarean section]. AB - Cesarean delivery is the most frequent major surgery in Finland: in 2013 over 16% of the deliveries were via cesarean route. 27% of the mothers are estimated to face complications. Optimal surgical techniques and other operation-related measures aim to reduce the incidence of complications. Recommendations favor preoperative antibiotics, vaginal preparation, transversal skin incision, non development of bladder flap, blunt cephalo-caudad uterine extension, spontaneous placental removal, late cord clamping, continuous sutures for uterine closure and subcutaneous skin sutures. Optimal measures will not only reduce complications in cesarean deliveries but bring cost savings and unify the clinical routines and training in specialization programs. PMID- 26245044 TI - [Disorders of water balance]. AB - Disorders of water balance are manifested as hyponatremia, polyuria or hypernatremia. While a diagnostic scheme is useful in the exploration of hyponatremia, the urgency of restoration of hyponatremia is essential in the treatment. Regardless of the therapeutic method, strong diuresis is predictive of too rapid restoration of hyponatremia. There are many causes for an increased need to pass urine. Polyuria is in question if the volume of urine collected over a 24-hour period has increased. After excluding diabetes and other common causes of polyuria, the osmolality of the first urine voided in the morning reflects the ability of the kidneys to concentrate urine. A water deprivation test is helpful in the differential diagnosis of the causes of polyuria. PMID- 26245045 TI - [Narcolepsy as an autoimmune disease]. AB - Narcolepsy is a sleep disorder of central origin. Hypocretin deficiency is the essential feature of type 1 narcolepsy. The biological background of type 2 narcolepsy (without cataplexy) is less clear. Infections or other external factors are thought to function as triggers of narcolepsy. After the H1N1 vaccination campaign, the incidence of narcolepsy increased clearly in countries where a vaccine boosted with the AS03 adjuvant was used. According to the current view, the increase of narcolepsy in connection with the pandemic vaccine especially in children and adolescents was associated with the virus component of the vaccine, but the adjuvant may also have boosted the development of autoimmune response. PMID- 26245046 TI - [Atopic eczema can be treated in a pre-emptive manner]. AB - The inflammation and itching associated with atopic eczema can rob the patient and even the whole family of their night's sleep. Cutaneous symptoms can be quickly alleviated with a glucocorticoid cream. Calcineurin inhibitors are an alternative to glucocorticoids. Regular washing of the skin must not be forgotten. In the treatment of moderate and severe atopic eczema, the frequency of applications of the medicinal cream is decreased only after the itching has ceased. Maintenance therapy does not seem to have more adverse effects than the conventional reactive mode of treatment, and can in fact be recommended especially for adults affected with moderate and severe atopic eczema. PMID- 26245047 TI - [Diagnosis of cervical spine injuries]. AB - The use of clinical exclusion criteria in cervical spine injuries has increased in the 2000's. By applying these criteria an injury can be excluded in as many as one fifth of the patients. CT scanning has become the primary method of diagnostic imaging for cervical spine injuries. It is highly reliable, and interpretation of the images is easier than in other methods of imaging. Radiography still remains a valid method and may during monitoring indirectly reveal ligament injuries remaining undetected in CT scanning. MRI is good in the assessment of the extent of ligament injuries, in the evaluation of intervertebral disk damages and especially nerve entrapment and spinal cord injuries. PMID- 26245048 TI - [Practices for hospital discharge of patients with pulmonary embolism in university and central hospital emergency call services]. AB - INTRODUCTION: The recommendation to discharge low-risk pulmonary embolism patients from or after a brief monitoring in the emergency department has not been widely adopted in Finland. METHODS: We explored the practices for examination and treatment of patients with pulmonary embolism in a university hospital and a central hospital. An assessment was made on how these practices followed the risk classifications. RESULTS: A very small proportion (3.9%) of the patients were discharged directly from the emergency department. According to the risk classifications, the proportion of patients suited for home care would have been between 30 and 60%. CONCLUSIONS: A significant proportion of patients with pulmonary embolism can be treated on the outpatient basis. PMID- 26245049 TI - [Parkinson's disease associated with a mutation in the PARK2 gene]. AB - The most common cause of monogenic hereditary Parkinson's disease is a mutation in the PARK2 gene. Early onset, slow progression, dystonia, and good response to levodopa are typical of the disease phenotype. Finnish PARK2 patients have not been described previously. We describe two patients, in whom pathogenic mutations in the PARK2 gene were the cause of parkinsonism. PMID- 26245050 TI - [Current Care Guideline: Eating disorders]. AB - Early diagnosis with intervention is linked to better outcome. In primary care patients in risk for eating disorder should be screened and actively asked about eating disorder symptoms. Treatment is mainly out-patient care and should first be focused on gaining a normal nutritional status. It is important to involve the patient's family in the treatment. A confidential relationship between health care professionals and the patient is important. The patient's own motivation and readiness for recuperation are essential. Different therapeutic and psychosocial approaches are central in the treatment, as the disorders are psychiatric. Medical treatment may bring additional help in treating binge-eating disorder or bulimia nervosa, but it is seldom of help in treating anorexia nervosa. PMID- 26245052 TI - [Adjuvant drug therapies for breast cancer]. AB - Most breast cancers are hormone receptor positive and exhibit a slow growth pattern. Based on biological properties, breast cancers are divided into four different biological subtypes. Furthermore, these subtypes are indicative of the risk of recurrence, which is also influenced by the size of the tumor and extension to lymph nodes. Postoperative adjuvant drug therapy is chosen on the basis of the biological type. Chemotherapy can be used in all subtypes. Hormonal therapies are used exclusively for the treatment of hormone receptor positive breast cancer. Trastuzumab antibody belongs to the treatment of the HER2 positive subtype. PMID- 26245053 TI - [Oral health among the elderly]. AB - A large proportion of our population is ageing with own teeth in the mouth. Good oral health and an adequate number of teeth improve the functional capacity of an elderly person. Oral diseases are, however, becoming more common among the elderly population with the accumulation of risk factors such as insufficient self-care, cariogenic diet, reduced salivation, smoking and systemic diseases. Dryness of the mouth due to the adverse effects of drugs or systemic diseases makes eating and cleaning of the mouth more difficult. Prevention of oral diseases with good self-care and regular dental examinations is essential. PMID- 26245054 TI - [CT imaging--towards patient- and indication-specific optimization]. AB - The same CT imaging program should not be applied to all patients, because the required image quality and dose of radiation vary according to the indications and regions. The programs should be optimized on the basis of indication, size of the patient and usage of intravenously administered iodine contrast agent. New technical options are available for reducing the radiation exposure. Additional means of optimization include proper definition of the region being imaged, avoidance of redundant series of images, selection of correct image quality, tube current and voltage, and new methods of calculating images. Patients' radiation exposure and clinical image quality should also be monitored. PMID- 26245055 TI - [How to stop hormone replacement therapy?]. AB - Hormone replacement therapy is indicated for the treatment of menopausal and urogenital symptoms. The therapy is recommended to be started at the lowest effective dose for a minimum period of time. Discontinuation of the therapy or at least reduction of the dose should be considered yearly. The treatment can be stopped immediately or gradually. The risk of recurrence of menopausal symptoms is equal for both techniques of cessation. Furthermore, the number of those having restarted the therapy does not differ between cessation techniques. A woman is thus able to choose her own cessation technique. Immediate cessation is often successful, whereby complicated instructions for drug reduction are avoided. PMID- 26245056 TI - [Ideal body weight of a young woman--sociocultural and health aspects]. AB - A common question made by a young person attending a practice concerns her/his ideal body weight. Culture and health may result in a conflicting definition of good weight. Discontent with one's own body can motivate for successful weight control, but may also lead to unnecessary dieting or disturbed eating. Too strict dieting and accentuating of weight control increase the risk of eating disorders, but on the other hand, adolescent overweight is a risk factor of obesity in adulthood as well. PMID- 26245057 TI - [Empathy is lifelong learning]. AB - Empathy is often understood as a native feature, even though it involves cognitive components that can be learned. The first, instinctive component is the physician's ability to understand the experience and emotional state of the patient, the second one is the transmission of this understanding to the patient, the third one being the utilization of the obtained information to treat the patient. Empathy is a tool for the physician and a promoter of employee well being. While understanding the emotional response of both the physician and the patient will help the former in her/his work for the good of the patient, this tool should be practiced deliberately. PMID- 26245058 TI - [The prognosis of lung cancer continues to be poor--treatment outcome within The Hospital District of Southwest Finland in 2004 to 2011]. AB - BACKGROUND: The survival of lung cancer patients is still poor; 10-15% are alive five years after diagnosis. MATERIAL AND METHODS: We evaluated 1 542 patients with new lung cancer diagnosis in 2004-2011. RESULTS: The one-, two- and five year survival rate was 37.3%, 23.3% and 10.5%, respectively. The prognosis of women was better. There were no changes over the 8 years in the number or age of patients, the share of women, the histology, the number of operated patients or survival. CONCLUSIONS: Compared with earlier Finnish studies the short-term prognosis seems to be little better. PMID- 26245059 TI - [Rumination in a young woman]. AB - Rumination refers to bringing up undigested or partially digested food mass from the stomach into the mouth to be rechewed and ingested. This manner of digestion is characteristic of e.g. cattle, but exceptional and likely to cause symptoms for humans. This rare malfunction can be traced on the basis of accurate patient history and confirmed at a test meal by manometry and impedance measurement. Regurgitation may in some patients be triggered by gastroesophageal reflux or air suction into the esophagus caused by an unconscious movement of the pancreas. After the condition has been recognized, behavioral therapy should be primarily considered. PMID- 26245062 TI - [Update on Current Care Guidelines: Ectopic pregnancy]. AB - Ectopic pregnancy should be suspected it a woman of fertile age has lower abdominal pain and irregular vaginal bleeding. Symptoms range from almost none to shock. The diagnosis is based on a quantitative serum pregnancy test (hCG) and transvaginal ultrasound. An acute situation requires emergency surgery, whereas patients with mild symptoms should be treated policlinically by follow-up or a single intramuscular dose (1 mg/kg) of methotrexate. No folic acid supplementation is needed. In later pregnancies their location should be verified by transvaginal ultrasound done by the seventh gestational week at the latest. PMID- 26245063 TI - [Update on Current Care Guideline: Low back pain]. AB - Classification to severe diseases, sciatic symptoms or non-specific back pain is recommended. Radiography in acute or subacute non-specific back pain is not recommended in the primary health care. In specialized care magnetic resonance imaging is the main imaging modality. Importance of patient information is emphasized. In acute non-specific pain avoidance of bed rest, advice and paracetamol are recommended. Indications for an emergency referral should be considered. In disabling pain for 6 weeks, multidisciplinary measures are needed. Pain over 3 months indicates intensive multidisciplinary rehabilitation, and also surgery may be considered. PMID- 26245064 TI - [Treatment of disseminated breast cancer]. AB - Although several effective drugs have in recent years been introduced for the treatment of disseminated breast cancer, it is still an incurable illness. Many patients live a fairly normal life with their illness for a long time, and some of them are able to continue working in spite of the therapies. Factors considered in tailoring the treatment include tumor subtype, extent of the disease, symptoms, previous treatments and the achieved treatment outcome, and adverse effects of the treatments. PMID- 26245065 TI - [Amnion in the treatment of ocular diseases]. AB - Amnion is the innermost membrane of the structural layers of the placenta. It has been utilized both as tissue transplant and biological wound dressing in the treatment of cutaneous and mucosal injuries already for more than a century. It can be attached onto various tissue and wound surfaces even without sutures, if necessary. The amnion can also be utilized in the treatment of ocular diseases; and it has been shown to promote healing of the cornea in various ways. In this review we discuss the use of amnion in ophthalmology and in the treatment of ocular diseases. PMID- 26245066 TI - [Mentalization as a factor protecting a human being]. AB - Mentalization refers to the ability of an individual to contemplate her/his own or another person's perspective and experience. Good mentalizing ability will help control one's own emotional states, stabilize interpersonal relationships and reduce conflict-induced stress. Mentalizing ability is associated with good interaction with a child, and with a favorable cognitive and emotional development. Although experiences of interaction during childhood are of crucial importance for the development of mentalization, the ability may also be strengthened through later good human relations and precisely targeted therapy. PMID- 26245067 TI - [Tourette's syndrome--diverse group of patients, individual need for treatment]. AB - Tourette's syndrome is a neuropsychiatric syndrome having its onset in childhood and presenting tics as the characteristic feature. In spite of clear diagnostic criteria the syndrome often remains unrecognized. Recognition and treatment of comorbidities are essential. Drug treatment and cognitive therapy may be used, if tics cause functional or social handicap. In very difficult situations, deep brain stimulation may be considered for adult patients. While the natural course of the syndrome is usually favorable, 10 to 20% of the patients continue to have disturbing symptoms in adulthood. PMID- 26245068 TI - [Isomerism]. AB - In persons afflicted with left or right atrial isomerism the intrathoracic and intra-abdominal organs are symmetrical. In left atrial isomerism the intrathoracic organs located on the right are similar to those on the left: lungs, for example, have two lobes and long bronchi. In right atrial isomerism there are three lobes of the lung and short bronchi also on the left side of the chest. Both malformation syndromes are associated with a complex structural anomaly of the heart. The prognosis continues to be poor. We describe an inherited gene defect found in five children in a Finnish family and causing right atrial isomerism. PMID- 26245069 TI - [Toe walking--follow or treat?]. AB - Idiopathic toe walking refers to continual or intermittent symmetrical gait pattern, in which the normal heel strike is lacking and the weight of the gait is on the ball of the foot. Many toe walkers are able to walk normally if they so wish. Diagnosis is established by excluding any neurological, neuromuscular, structural and orthopedic causes. Toe walkers often exhibit problems in sensory integration. Idiopathic toe walking is considered a benign phenomenon, usually self-limiting before school age, but upon becoming prolonged it may cause physical and social handicap for the child. PMID- 26245070 TI - [Anticoagulation for continuous renal replacement therapy in the intensive care unit: a comparison of dalteparin infusion with regional citrate anticoagulation]. AB - Continuous renal replacement therapy (CRRT) is used to treat severe acute kidney injury in intensive care units. The aim of this study was to compare two anticoagulation techniques in CRRT, the infusion of dalteparin and regional citrate-calcium anticoagulation, in terms of efficacy and safety. In a retrospective study, we analysed data on 77 dalteparin and 75 citrate-calcium treatment periods. The primary endpoint was the life span of the CRRT circuit. The use of regional anticoagulation with citrate and calcium resulted in a significantly longer CRRT circuit life span as compared to that achieved with dalteparin infusion. PMID- 26245071 TI - [Treatment of posterior cruciate ligament injury in skeletally immature patients]. AB - Posterior cruciate ligament tear is a rare injury in the pediatric and adolescent population. Primary diagnosis of posterior cruciate ligament injury is based on careful attention to specific physical examination, but MRI is the mainstay for assessing the extent of ligamentous and possible associated injuries. In general, most of the posterior cruciate ligament tears in children and adolescents can be treated non-operatively with good functional outcome. Surgical treatment for these injuries should however be cautiously considered also for skeletally immature patients with a complete, intrasubstance ligament tear or dislocated avulsion fracture. PMID- 26245072 TI - [Recognition and rehabilitation of impaired awareness of illness, i.e. anosognosia in a patient with cerebrovascular disease]. AB - The prevalence of anosognosia after stroke is approximately 30%. Anosognosia refers to the lack of awareness of illness or specific symptom of illness in patients with neurological diseases. Because stroke patients with anosognosia are not properly comprehending the nature of their medical situation, they may not seek treatment in time, which weakens patients' commitment to treatment and rehabilitation. Anosognosia also exposes patients to dangerous situations in daily life. Anosognosia is associated with poor functional outcome after stroke, which makes the early neuropsychological identification and treatment of anosognosia important. PMID- 26245073 TI - [Plant sterols, cholesterol precursors and oxysterols: small amounts, big effects]. AB - Noncholesterol sterols are present in the body in very low concentrations compared with cholesterol. Minor structural changes in sterols give them completely individual biological activities. Steroid hormones are the best known example of this. The knowledge of other relatives of cholesterol, particularly plant sterols, cholesterol precursors and oxysterols, their properties, physiological effects, significance in disease processes and diagnostic applications has recently undergone a rapid increase. PMID- 26245074 TI - [Curative treatment of Alzheimer's disease is still missing--is amyloid plaque hypothesis the wrong starting point?]. AB - For more than a quarter century, the research of and drug development for Alzheimer's diseases have been governed by the amyloid plaque hypothesis, whereby deranged metabolism of the amyloid precursor protein leads to the formation of extracellular amyloid plaques, which in turn causes the activation of microglial cells, destruction of neurons and a progressive memory disease. The ending of three extensive clinical trials in disappointment has raised the question whether the amyloid plaque hypothesis is the correct starting point in the development of curative treatment for Alzheimer's disease at all. Two commencing new trials with patients that are still symptomless will be the final challenge for the hypothesis. PMID- 26245075 TI - [Can we prevent pain becoming chronic?]. AB - Central aspects in the prevention of pain from becoming chronic are good management of acute pain, early recognition of risk factors and a multidisciplinary working approach. Postherpetic neuralgia can probably be prevented with a vaccine and medication. In the prevention of prolonged postoperative pains there is some evidence of the effect of local anesthetics and ketamine, but their clinical significance is unclear. Multidisciplinary therapeutic and rehabilitative actions can be taken to prevent prolongation and recurrence of lower back pain especially in patients having an increased risk of chronic pain. PMID- 26245076 TI - [Eclampsias have declined in Finland between 2006 and 2010]. AB - BACKGROUND: We surveyed the occurrence of eclampsia in Finland since the time when the use of magnesium sulfate became more common. MATERIALS AND METHODS: We found a total of 46 persons with eclampsia diagnosis from two registers between 2006 and 2010. RESULTS: The occurrence of eclampsia was 1.5/10 000 childbirths. None of the mothers died, but severe complications occurred in 76% of the cases. CONCLUSIONS: The decline in occurrence of eclampsia, recurrence of seizures and severe prolonged complications in Finland is likely to be partly associated with the increased use of magnesium sulfate. Some risk patients continue to remain undetected. PMID- 26245077 TI - [A posseting infant]. AB - Excessive regurgitation and suspected reflux disease are increasingly leading to referrals to hospital and pharmacologic therapies. Reflux (or regurgitation) as such is a physiological phenomenon in infants and does not require treatment, unless it is associated with other symptoms indicating a disease. The reflux symptoms in infants will nearly always improve spontaneously. Proton pump inhibitors have been found to be no more efficient than placebo in the treatment of reflux symptoms in infants. Breast milk should not be exchanged for a special infant formula due to reflux. The prognosis of reflux symptoms of a basically healthy infant is almost invariably excellent. PMID- 26245078 TI - [Licorice as the cause of elevated blood pressure and headache?]. AB - Physicians are familiar with the effect on potassium metabolism of glycyrrhizine acid contained in licorice and salmiac. Even so, glycyrrhizine acid as the cause of even severe symptoms may escape attention, especially in an emergency situation. We describe a patient, who sought medical advice from an endocrinologist for recurrent, severe and symptomatic hypertension. After the patient had stopped eating salmiac and licorice, the headache that had persisted for years disappeared, fluctuations in weight stabilized and occasional edemas of the lower limbs vanished. Since the cessation of using licorice products normalized the blood pressure, it is likely that the patient had licorice-induced hypertension. PMID- 26245079 TI - [Update on Current Care Guideline: Depression]. AB - Treatment of depression is based on comprehensive diagnostic, clinical and psychosocial evaluation. Brief psychotherapies (cognitive, interpersonal, psychodynamic or problem-solving) are effective in mild to moderate depression; antidepressants in mild to severe, and electroconvulsive therapy in severe or psychotic. Combining antidepressants and psychotherapy is more effective than either alone. After the acute phase, antidepressants should be continued for six months to prevent relapses, and maintenance treatment considered after three lifetime episodes. Primary care is responsible for treatment of mild to moderate depressions; developing psychiatric consultation services and use of nurse case managers are recommended. PMID- 26245080 TI - Relative Expression of Indicators for Wound Age Estimation in Forensic Pathology. AB - OBJECTIVE: In order to understand which kind of function genes play an important role for estimating wound age, the variation of difference genes' mRNA expression were compared after injury. METHODS: The mRNA expression levels of seven candidate genes (ICAM-1, NF-kappaB, MX2, MT1, MT2, sTnI, and Cox6c) were analyzed in contused rat skeletal muscle at different time points using real-time fluorescent quantitative PCR (RT-qPCR). The raw Ct values were normalized relative to that of RPL32 mRNA, and converted to standard Ct values. At each time point after injury, the standard deviations (SD) of the standard Ct values were calculated by SPSS. RESULTS: The expression trends of the seven genes were all found to be related to wound age, but there were lower variation coefficients and greater reliability of s TnI and Cox6c when compared with other genes. CONCLUSION: The genes encoding structural proteins or proteins that perform basic functions can be suitable for wound age estimation. PMID- 26245081 TI - [Expression of Zonula Occludens-1 in Cerebral Cortex Following Traumatic Brain Injury]. AB - OBJECTIVE: To observe the time-course expression of zonula occludens-1 (ZO-1) in cerebral cortex after traumatic brain injury (TBI). METHODS: The TBI model of mouse was established. The mice were divided in 1 h, 3 h, 6 h, 12 h, 24 h, 3 d, 7 d after TBI, sham and control groups. The permeability of the blood brain barrier was evaluated by measuring the extravasation of Evans blue (EB) dye. The expression of ZO-1 in cerebral cortex in the injured area was detected by Western blotting and immunohistochemistry. RESULTS: The extravasation of EB dye of injured cortex gradually increased from 1 h, peaked at 1-3 d and approximately decreased to normal at 7 d after TBI. Western blotting revealed that the expression of ZO-1 gradually decreased after 1 h, was at the lowest at 1-3 d, and then significantly increased after 7 d but was still lower than that of normal and sham groups. The result of immunohistochemistry showed that ZO-1 had strong expression in vessel of normal cortex, gradually decreased after TBI, and almost disappeared at 3 d after TBI and gradually recovered to normal level later. CONCLUSION: The expression of ZO-1 in the injured cortex after TBI initially decreases and then increases. The negative correlation between ZO-1 expression and EB extravasation after TBI could be used as a new indicator for wound age estimation. PMID- 26245082 TI - [Apoptosis in Lungs and Liver after Crush Injury of Hindlimbs in Rat]. AB - OBJECTIVE: To investigate the process of apoptosis in lungs and liver induced by crushing hindlimbs of rat, and study the mechanism of crush injury. METHODS: The rat experimental model of hindlimbs crush injury was established. The cell apoptosis in lungs and liver was detected by TUNEL assay, and the expression of Bax, Bcl-2 and caspase-3 apoptin was examined by immunohistochemistry. RESULTS: Compared with the control group, the partial muscle injury of rat's hindlimbs was more serious with more apoptosis observed in lungs and liver (P < 0.05). The expression of Bax was up-regulated and Bcl-2 was down-regulated, whereas caspase 3 expression was activated (P < 0.05). CONCLUSION: The cell apoptosis has increased significantly in lungs and liver after crush injury of hindlimbs in rat. The correlation factor released during tissue injury may mediate apoptosis process. PMID- 26245083 TI - [Expression of p35 and p25 after Focal Cerebral Contusion in Rat]. AB - OBJECTIVE: To study the expression of p35 and p25 in rat after focal cerebral contusion and to provide experimental data for estimating brain injury time. METHODS: Fifty adult male SD rats were randomly divided into 0 h, 6 h, 12 h, 24 h, 3 d, 5 d, 7 d, 10 d after focal cerebral contusion, control and sham-operated groups (5 rats each group). The focal cerebral contusion rat model was established. The expression of p35 and p25 protein of the damage peripheral zone in brain were detected by HE staining, immunohistochemistry and Western blotting at different injury time. RESULTS: A large number of p35 protein and a small amount of p25 protein were expressed in control group and sham-operated group. After focal cerebral contusion, p35 presented unimodal change with time and p25 presented bimodal changes with time. CONCLUSION: Expression of p35 and p25 showed different regularity with good time correlation, which could help to estimate the brain injury time. PMID- 26245085 TI - [Simulation and Observation of Vertical Cast-off Bloodstain Pattern]. AB - OBJECTIVE: To observe the characteristics of vertical cast-off bloodstain pattern by different hitting-tools. METHODS: The regular hitting tools, a kitchen knife, a dirk, a plane set-hammer and an iron pipe, were selected. At a distance of 30 cm away from the wall, the hitting tool with 5 mL fresh chicken blood made the cast-off bloodstain from top to bottom. Then the holistic distribution characteristics (length, width and density) of cast-off bloodstain and morphology characteristics (length, width and contact angle) of first single cast-off bloodstain were analyzed. RESULTS: The distribution length of cast-off bloodstain formed by dirk was minimum (P < 0.05). The distribution width of cast-off bloodstain formed by kitchen knife was minimum (P < 0.05). Except the pair of kitchen knife and plane set-hammer, the distribution density between each two tools had statistical differences (P < 0.05). The length of first single cast-off bloodstain formed by plane set-hammer was longest compared (P < 0.05). The width of first single cast-off bloodstain had statistical differences between kitchen knife and plane set-hammer, and between dirk and plane set-hammer (P < 0.05). CONCLUSION: The type of hitting tool could be inferred by the specific characteristics of cast-off bloodstain pattern formed by every specific type of hitting tool in crime scene. PMID- 26245084 TI - [Expression of EV71-VP1, PSGL-1 and SCARB2 in Tissues of Infants with Brain Stem Encephalitis]. AB - OBJECTIVE: To understand the correlation of enterovirus 71 (EV71), P-selectin glycoprotein ligand-1 (PSGL-1), and scavenger receptor B2 (SCARB2) and to explore the possible pathway and mechanism of EV71 infection by observing the expression of EV71, PSGL-1 and SCARB2 in tissues of infants with brain stem encephalitis. METHODS: The organs and tissues of infants with EV71-VP1 positivity in their brain stems were chosen. Expression and distribution of EV71-VP1, PSGL-1, and SCARB2 were detected and compared by immunohistochemistry. RESULTS: Strong staining of EV71 -VP1 was observed in the neuron, glial cells, the inflammatory cells of perivascular cuffing, parietal cells of the gastric fundus gland while alveolar macrophages, intestinal gland epithelium cells, mucosa lymphoid nodule and lymphocyte of palatine tonsil showed moderate staining and weak staining were displayed in mesenteric lymph nodes and lymphocyte of spleen. PSGL-1 expression was detected in parietal cells of the gastric fundus gland, tonsillar crypt squamous epithelium, alveolar macrophages and leukocytes in each tissue. SCARB2 expression was observed in all the above tissues except the intestines and spleen. CONCLUSION: The distribution of EV71 correlates with SCARB2 expression. SCARB2 plays an important role in virus infection and replication. Stomach may be an important site for EV71 replication. PMID- 26245086 TI - [Forensic Application of Microperimetry and Visual Evoked Potential in Macular Disease]. AB - OBJECTIV: e To find the correlation between real best corrected visual acuity (BCVA) and testing results of microperimetry and visual evoked potential (VEP) and to explore a new method in recording BCVA in macular disease. METHODS: Sixty two patients with macular disease (macular disease group, 62 eyes) and eighteen healthy volunteers (control group, 36 eyes) had BCVA, microperimetry and VEP recorded. RESULTS: (1) By microperimetry, the values of retinal mean sensitivity and fixation percentage in macular disease group were lower than that in control group. The bicurve ellipse area in macular disease group was higher than that in control group. By VEP, P100 amplitude under 0.5 cpd and 2 cpd in macular disease group were significantly higher than that in control group and the latency was prolonged (P < 0.05). (2) In macular disease group, BCVA had significant positive correlation with retinal mean sensitivity, bicurve ellipse area, macular central 2 degrees and 4 degrees fixation percentage, respectively (P < 0.05). There was a significant correlation between retinal mean sensitivity and P100 amplitude (P < 0.05). (3) Multiple linear regression equation was y = 0.053 x1+0.008 x3+3.897 (y was BCVA, while x1 was retinal mean sensitivity and x3 was P100 amplitude under 2 cpd). CONCLUSION: Combined use of microperimetry and VEP is useful in the assessment of BCVA in macular disease. PMID- 26245087 TI - [Mutations in a Large Pedigree with Y-STR Genetic Markers]. AB - OBJECTIVE: To explore the mutation of Y-STR loci in meiotic allelic transmission in a large pedigree. METHODS: The oral swabs of 163 male individuals were collected from a Lin pedigree. Twenty-two Y-STR genetic markers were typed with AGCU Y24 fluorescent detection kit (AGCU Y24 system), which also contained 16 Y STR markers included in Yfiler multiple amplification kit (Yfiler system). The genotyping results of Y-STR loci were compared between each two males in the pedigree. RESULTS: There were 20 and 30 kinds of haplotypes obtained with Yfiler and AGCU Y24 systems in 163 male individuals from the Lin pedigree, respectively. The rates referred to haplotype differences (RRHD) of these two typing systems between male pairs were 0.910 5 and 0.922 7, respectively. The average number of marker differences were 6.582 1 and 9.824 8, respectively. The RRHD increased along with the incidents of meiosis. CONCLUSION: Y-STR mutation leads to different Y-STR haplotypes among the male members in a paternal pedigree and the rate of difference increases along with the incidents of meiosis. PMID- 26245088 TI - Chlorpyrifos Determined in Human Blood by UPLC-MS/MS and Its Application in Poisoning Cases. AB - OBJECTIVE: To determine the chlorpyrifos in human blood by liquid chromatography tandem mass spectrometry and to validate its application in poisoning cases. METHODS: The samples were extracted by a simple one-step protein precipitation procedure. Chromatography was performed on a Capcell Pack C18 MGII column (250 mm x 2.0 mm, 5 MUm) using an isocratic elution of solvent A (0.1% formic acid-water with 2 mmol/L ammonium acetate) and solvent B (methanol with 2 mmol/L ammonium acetate) at 5:95 V:V). RESULTS: The linear ranged from 5 to 500 ng/mL (r = 0.998 7). The limit of detection (LOD) and the lower limit of quantification (LLOQ) were 2 ng/mL and 4 ng/mL, respectively. For this method, the precision and accuracy of intra-day and inter-day were < 10% and 97.44%-101.10%, respectively. The results in stability test of long-term frozen were satisfied. The matrix effect, recovery and process efficiency were 64.97%-86.81%, 76.70%-85.52%, and 55.57%-66.58%, respectively. CONCLUSION: This method can provide a rapid approach to chlorpyrifos extraction and determination in toxicological analysis of forensic and clinical treatment. PMID- 26245089 TI - [Normal Range of 33 Elements in Blood Samples from General Population in Hunan Province]. AB - OBJECTIVE: To determine the normal range of the 33 elements (Li, Be, B, Mg, Al, Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, As, Se, Rb, Sr, Zr, Mo, Ag, Cd, Sb, Cs, Ba Au, Hg, Tl, Pb, Th and U) in human whole blood of general population in Hunan province. METHODS: Blood samples were analyzed by inductively coupled plasma-mass spectrometry (ICP-MS) to determine the normal range. The influences of district, gender and age to the element content in blood samples were also observed. RESULTS: The normal range of 33 elements in blood samples from general population in Hunan province were obtained. Gender was shown to statistically influence the concentrations of B, Mg, Ca, Ti, Mn, Fe, Co, Cu, Zn, As, Se, Rb, Sr, Ag, Cd, Cs, Hg and Pb (P < 0.05), while age was shown to influence the concentrations of Co, Ni, Cs and Hg in women (P < 0.05) as well as Cu, Se and Hg in men (P < 0.05). CONCLUSION: Although there are variables in different districts, the normal ranges of trace element in blood of the four cities in Hunan province are established. PMID- 26245090 TI - [Injury Mechanism of Scaphoid Fracture: Forensic Analysis of 43 Cases]. AB - OBJECTIVE: To explore the key points of injury mechanism of scaphoid fracture in forensic expertise and to provide the references for forensic practices. METHODS: Forty-three cases of injury mechanism identification of scaphoid fracture were selected from 2007 to 2011 in Institute of Forensic Evidence, Chinese Criminal Police Academy. Following aspects were analyzed: missed diagnosis and misdiagnosis at first visit, fracture classifications, accompanying injuries and mechanism of injury. RESULTS: The rates of missed diagnosis and misdiagnosis were high in the cases of scaphoid fractures, most common in the fracture of the waist. The disagreement on mechanism of injury was whether it was due to direct impact or indirect effect by falling. CONCLUSION: Wrist hyperextension due to fall with palm impact on the ground was the main cause of scaphoid fracture. PMID- 26245091 TI - [Composition Analysis of Remaining Metal Particles on Ferrochrome Kitchen Knife]. AB - OBJECTIVE: To establish a feasible evaluation index and method to identify composition of remaining metal particles on ferrochrome kitchen knife. METHODS: The small samples of remaining metal particles were rubbed from the knives using filter paper. The composition of remaining metal particles was detected by scanning electron microscopy and energy dispersive X-ray spectrometer (SEM-EDX) and GSR particle analysis function, using mathematical methods to calculate the ratio (relative amount) of Fe and Cr in remaining metal particles. RESULTS: The ratio (relative amount) of Fe and Cr of remaining metal particles had significant differences among most ferrochrome kitchen knives (P < 0.05). CONCLUSION: Using GSR particle analysis function to quantitatively detect the ratio (relative amount) of Fe and Cr of remaining metal particles on ferrochrome kitchen knife, which can establish the feasible evaluation method to estimate such injury tool. PMID- 26245092 TI - Progress of DNA-based Methods for Species Identification. AB - Species identification of biological samples is widely used in such fields as forensic science and food industry. A variety of accurate and reliable methods have been developed in recent years. The current review shows common target genes and screening criteria suitable for species identification, and described various DNA-based molecular biology methods about species identification. Additionally, it discusses the future development of species identification combined with real time PCR and sequencing technologies. PMID- 26245093 TI - [Application of Finite Element Method in Thoracolumbar Spine Traumatology]. AB - The finite element method (FEM) is a mathematical technique using modern computer technology for stress analysis, and has been gradually used in simulating human body structures in the biomechanical field, especially more widely used in the research of thoracolumbar spine traumatology. This paper reviews the establishment of the thoracolumbar spine FEM, the verification of the FEM, and the thoracolumbar spine FEM research status in different fields, and discusses its prospects and values in forensic thoracolumbar traumatology. PMID- 26245094 TI - [Advances in Event-related Potential and Its Forensic Application Value]. AB - The event-related potential (ERP) is considered as one of the most effective methods to study and analyze objectively human mental activity based on nerve electrophysiology. At present, ERP is not only used in the study of lie detection, but also in the clinical medicine for the cognitive assessment on patients with cerebrovascular disease, dementia or traumatic brain injury and auxiliary diagnosis of mental illness. With the further development of ERP detection technology, it would have a wider application prospect in the field of forensic medicine. PMID- 26245095 TI - [The myocardial histo-hematic barrier as a morphological criterion to be used for forensic medical diagnostics of alcoholic cardiomyopathy]. AB - The author estimates the effectiveness of morphological diagnostics of alcoholic cardiomyopathy taking into consideration the general patterns of the structural and functional organization of the heart with special reference to myocardial histo-hematic barrier (HHB) the components of which are characterized by specific structural and functional properties and close relationships between them. It was shown that the morphological changes in the histo-hematic barrier reflect the range of variability of its morphological components and may be used as the indicators of its integrity and stability in the case of disorder. The study has demonstrated that the structural and functional degradation as well as decay of myocardial components may occur under the influence of both an ultrastrong acute impact and latent chronic intoxication or the diseases accompanied by rapid or slow persisting disintegration of the structural organization of the organ. The author maintains that the maximally high informative value of the assessment of the morphological criteria for alcoholic cardiomyopathy can be achieved with the use of special immunohistochemical methods allowing the concrete components of the biological structures to be identified and giving the exact location of the cellular and tissue components in the affected regions. Such an approach permits to detect the developing pathological changes at the molecular level with a high degree of accuracy and visualize the structural reorganization, if any, of each component of the myocardial histo-hematic barrier responsible for the lesions associated with alcoholic cardiomyopathy. PMID- 26245096 TI - [Pathology of the vagus nerve system as a morphological marker of sympathetic imbalance in the case of sudden cardiac death]. AB - The present study was designed to examine the vagus nerve system, atrioventricular ganglion, and changes in cardiomyocytes in 45 cases of the fatal outcome of the disease among 20 patients who suffered a craniovertebral injury and 25 ones presenting with acute coronary insufficiency. Special attention was given to the central and peripheral parts of the vagus nerve system. The study revealed lesions in the jugular ganglia and their association with the previous craniovertebral injuries accompanied by hemorrhage in these ganglia, nerve trunks, and soft tissues of the jugular foramina. The well apparent atrophic changes were found in the ganglia of the vagus nerve system in the patients who died from acute coronary insufficiency. In all the examined cases, hemosiderosis of the pial soft tissues of the medulla oblongata was observed. PMID- 26245097 TI - [The compensatory and adaptive e reactions of the respiratory system as the diagnostic criteria for histological studies in forensic medicine]. AB - The objective of the present study was to characterize the structural changes in the respiratory system equivalent to its compensatory and adaptive reactions in response to the action of various factors under the normal and extreme conditions for the assessment of the possibility of their further use for the purpose of diagnostics. The action of various factors on the tissues obtained from the human respiratory system for forensic medical examination was shown to cause combined histomorphological alterations that refelect a wide spectrum of protective, compensatory, and adaptive reactions. The range of potential morphological and functional changes in the respiratory system depends on the characteristics of endogenous and exogenous factors influencing the organism of the affected subjects. It is concluded that the use of the proposed approach to morphological diagnostics may be useful for the development of criteria for the evaluation of various variants of tanatogenesis with their objective confirmation by mathematical models. PMID- 26245098 TI - [Specific features of suicides committed in a state of alcoholic intoxication]. AB - The objective of the present work was to study the specific features of suicides committed in a state of alcoholic intoxication in 1985, 1995, and 2010 based on the materials collected by the Central Bureau of Forensic Medical Expertise, Ministry of Health of Republic Uzbekistan. It was shown that the blood alcohol content in the subjects committing suicide tended to decrease during the aforementioned periods which does not confirm the opinion that limitations on alcohol consumption reduces the frequency of suicide attempts. Most cases of completed suicide among the residents of Tashkent were recorded in a group of men of the medium and advanced age in the state of alcoholic intoxication. The immediate cause of death in the majority of such cases was mechanical asphyxia due to hanging. PMID- 26245099 TI - [The influence of alcohol consumption on the chronological patterns of sudden cardiac death]. AB - The objective of the present study was the retrospective analysis of the materials collected by the Republican Bureau of Forensic Medical Expertise, Ministry of Health and Social Development of Chuvash Republic, during the period from 1997 till 2002 for the elucidation of the chronological patterns of sudden cardiac death (SCD) associated with alcohol consumption depending on the sex and age of the victims, days of the week and months of the year as well as weather conditions. It was shown that the peak of mortality among men and women taking no alcohol fell on Monday. It was highest in May and decreased by February. The alcohol consumption significantly changes the chronological patterns of mortality from cardiovascular pathology. It was highest among the women abusing alcohol in August and October. The study has demonstrated a weak negative correlation between the frequency of sudden cardiac death among non-consumers of alcohol and dew-point temperature among the persons having alcohol in blood. PMID- 26245100 TI - [The morphological characteristic of the skin lesions inflicted by plastic knives with four cutting edges]. AB - The objective of the present work was to study the morphological features of the skin lesions inflicted by the blades of the Fgx Boot Blade I knives having four cutting edges. The study revealed the signs that can be used to distinguish between morphological characteristics of the stab and lacerated wounds having the primary and secondary incisions made by the four-edge blade. PMID- 26245101 TI - [The possibilities for determining the passenger position inside the car passenger compartment based on the injuries to the extremities estimated with the use of the sequential mathematical analysis]. AB - The objective of the present study was to determine the diagnostic coefficients (DC) of injuries to the upper and lower extremities of the passengers inside the car passenger compartment based on the analysis of 599 archival expert documents available from 45 regional state bureaus of forensic medical examination of the Russian federation for the period from 1995 till 2014. These materials included the data obtained by the examination of 200 corpses and 300 live persons involved in the traffic accidents. The statistical and mathematical treatment of these materials with the use the sequential analysis method based on the Byes and Wald formulas yielded the diagnostic coefficients that made it possible to identify the most important signs characterizing the risk of injuries for the passenger occupying the front seat of the vehicle. In the case of the lethal outcome, such injuries include fractures of the right femur (DC -8.9), bleeding (DC -7.1), wounds in the soft tissues of the right thigh (DC -5.0) with the injurious force applied to its anterior surface, bruises on the posterior surface of the right shoulder (DC -6.2), the right deltoid region (DC -5.9), and the posterior surface of the right forearm (DC -5.5), fractures of the right humerus (DC -5.), etc. When both the driver and the passengers survive, the most informative signs in the latter are bleeding and scratches (DC -14.5 and 11.5 respectively) in the soft tissues at the posterior surface of the right shoulder, fractures of the right humerus (DC -10.0), bruises on the anterior surface of the right thigh (DC 13.0), the posterior surface of the right forearm (DC -10.0) and the fontal region of the right lower leg (DC -10.0), bleeding in the posterior region of the right forearm (DC -9.0) and the anterior region of the left thigh (DC -8.6), fractures of the right femur (DG -8.1), etc. It is concluded that the knowledge of diagnostic coefficients helps to draw attention of the experts to the analysis of the above morphological signs for the objective determination of the passenger position inside the car passenger compartment during traffic accidents and thereby to improve the quality of expert conclusions and the results of forensic medical examination of the injuries inflicted in car crashes. PMID- 26245102 TI - [Diagnostics of the human sex from the somatometric features in the cases of large-scale catastrophes]. AB - The objective of the present study was to develop the models for sex diagnostics based on the results of measurement of the wrist and its separate parts. It was shown that the best results are obtained using the size of the palm and finger III (from 87.9 to 93% of correct results). The measurement of finger III makes it possible to correctly determine the sex in 90% of the cases. At the same time, the incorrect identification of the sequential number of this finger more frequently results in erroneous diagnostics. The measurement of finger V is of the lowest informative value (73.7% of the correct results). Therefore, the use of its measurements is of a tentative value. When the sequential number of fingers II or IV is uncertain, both models can be used on equal terms without an appreciable loss of accuracy of the classification. The verification of the above models by means of comparison of the data obtained with those from the control group has demonstrated the high accuracy of the classification similar with that of the theoretical model. PMID- 26245103 TI - [The application of cybernetic modeling methods for the forensic medical personality identification based on the voice and sounding speech characteristics]. AB - The objective of the present publication was to discuss the possibility of application of cybernetic modeling methods to overcome the apparent discrepancy between two kinds of the speech records, viz. initial ones (e.g. obtained in the course of special investigation activities) and the voice prints obtained from the persons subjected to the criminalistic examination. The paper is based on the literature sources and the materials of original criminalistics expertises performed by the authors. PMID- 26245104 TI - [Optimization of the conditions for the detection of psychoactive compounds of the cholinoblocker and antidepressant groups with the use of the microcolumn HPLC technique]. AB - The objective of the present study was to evaluate the possibility of using the BD-2003 database to separate the mixtures of various antidepressants by high performance liquid chromatography (HPLC) based on the MiLiChrome A-02 complex with an EcoNova UV detector. The parameters of identification are described. The possibility of modification of the standard conditions for the analysis is demonstrated as exemplified by the identification of certain cholinoblockers. The proposed approach to the separation of psychoactive preparations provides a basis for the development of methods for the determination of these substances in biological tissues and fluids. PMID- 26245105 TI - [The identification of the drawbacks in the provision of medical assistance based on the so-called biased data]. AB - The authors discuss a case of inadequate provision of emergency care encountered in expert practice. The analysis of the difficulties currently facing experts engaged in the verification of medical diagnoses is described as exemplified by the patient presenting with the obstetric and gynecological problems and the aggravated medical history. The case under consideration is characterized by the almost total absence of the relevant comprehensive medical documentation concerning a women pregnant with twins. The data are presented needed to perform the expert evaluation and formulate the objective and scientifically sound conclusions about the cause-and-effect relationships between the drawbacks in the provision of medical assistance and the unfavourable outcome of pathological conditions. PMID- 26245106 TI - [Vishnevsky's spots: the history of discovery and the modern theories of their development (the analytical review)]. AB - The objective of the present study was to analyse the modern pathogenetic theories of the mechanisms underlying the development of the lesions in the gastric mucosa (the so-called Vishnevsky's spots) under effect of overcooling. It is emphasized that none of the currently available theories comprehensively accounts for different forms and scenarios of the development of Vishnevsky's spots. PMID- 26245107 TI - [The analysis of publications in the journal "Sudebno-meditsinskaya ekspertiza (Forensic Medical Expertise)" for the period from 2000 till 2014]. AB - This paper presents the result of the analysis of the scientometric characteristics of the materials concerning the main aspects of research carried out in the framework of the speciality 14.03.05 (Forensic medicine published in the journal "Sudebno-meditsinskaya ekspertiza (Forensic Medical Expertise)" during a long period. The objective of the analysis was to establish the priorities in this field, reveal the lines of research of the highest interest for domestic and foreign authors, and estimate the value of the relevant scientific publications. It is concluded that the scientometric analysis of the scientific literature on the problems of forensic medical examination is indispensable for the further improvement of its quality. PMID- 26245108 TI - [Sergey Pavlovich Lovtsov, the editor-in-chief of the journal "Arkhiv sudebnoy mditsiny i obshchestvennoy gigieny (Archive of Forensic Medicine and Public Hygiene)"]. PMID- 26245109 TI - [Lidiya Sergeevna Fedorovtseva. On the occasion of her 100th birthday anniversary]. PMID- 26245110 TI - [Vladimir Aleksandrovich Klevno. On the occasion of his 60th birthday anniversary]. PMID- 26245111 TI - [In memory of Vitaliy Nikolaevch Kryukov]. PMID- 26245112 TI - [The 9th scientific and practical conference of young scientists and specialists of the Moscow Society of forensic medical experts under the heading "Forensic medical practice", Moscow, December 10, 2014]. PMID- 26245113 TI - [A case of Trichuris trichiura infection detected by colonoscopy]. PMID- 26245114 TI - [Cloning, Expression and Immunodiagnostic Evaluation of the Fasciola gigantica Thioredoxin Peroxidase]. AB - OBJECTIVE: To immunoscreen the gene encoding thioredoxin peroxidase (TPx) from a cDNA library made from adult Fasciola gigantica worms, clone and express the gene, and evaluate the immunodiagnostic value of TPx recombinant protein. METHODS: The A ZAP cDNA library was immunoscreened with pooled serum of fascioliasis gigantica patients. The obtained positive clones were sequenced and analyzed by multiple sequence alignment. The full-length (rFgTPx) and N-termianal truncated (rFgTPx_nt) sequence of FgTPx was subcloned into prokaryotic plasmid pET28a(+) with a non-fusion expression technique, respectively. The recombinant proteins of rFgTPx and rFgTPx_nt were purified by His-bind affinity column (Ni NTA). rFgTPx and rFgTPx_nt were used in indirect ELISA to test the antibody response of the serum samples. Sera of 27 fascioliasis gigantica patients, 15 patients with schistosomaisis japonica, 15 clonorchiasis sinensis patients, and 32 healthy donors were tested by using the recombinant protein based ELISA. RESULTS: The TPx recombinant proteins were obtained through expression, purification and renaturation, the relative molecular mass of rFgTPx and rFgTPx_nt were Mr 30,000 and Mr 26,000, respectively. The total diagnostic coincidence rate, sensitivity and specificity of rFgTPx_nt-based ELISA was 87.6% (78/89), 66.7% (18/27), and 96.8% (60/62), respectively. The cross reaction with Schistosoma japonicum and Clonorchis sinensis was 0 and 1/15 for rFgTPx_nt, respectively. Before and after treatment, A450 value of the serum samples from fascioliasis patients was 0.233 +/- 0.088 and 0.129 +/- 0.072, respectively (t = 4.27, P < 0.01). CONCLUSION: The gene encoding TPx is expressed in the prokaryotic expression system. The recombinant protein shows proper sensitivity and high specificity for the serodiagnosis of Fasciola gigantica infection. PMID- 26245115 TI - [Screening Radius of Active Case Detection and the Malaria Parasite Rate of Carriers in China-Myanmar Border]. AB - OBJECTIVE: To explore the effective screening radii of active case detection of the 1-3-7 surveillance and response strategy, and investigate the malaria parasite rate of carriers in China-Myanmar border. METHODS: Three villages with indigenous malaria cases in Yingjiang County of Yunan Province were selected as study sites. The persons lived around the indigenous cases (index case) within the radius of 100 m, 300 m, 500 m, and 1 km were screened by microscopy and nested PCR. Parasite rate of asymptomatic carriers at different radii were calculated. RESULTS: Among 278 blood samples, the parasite rate of asymptomatic carriers was 1.1% (3/278) and 2.2% (6/278) using microscopy and nested PCR, respectively. Based on the results of nested PCR, all the asymptomatic carriers could be detected within a 300 m radius around the index case, and with the highest proportion (66.7%) in the radius of 101-300 m. CONCLUSION: The asymptomatic carriers of malaria parasites in the China-Myanmar border area can be effectively detected within a 300 m screening radius of index case by using nested PCR. PMID- 26245116 TI - [Establishment and Application of Multiplex PCR System for Detecting Four Human Plasmodium Species]. AB - OBJECTIVE: To establish a multiplex PCR detection system for identifying 4 human Plasmodium species and evaluate its applicability. METHODS: The sequences of 18S rDNA gene of the 4 human Plasmodium species were compared using DNAman software, and 4 downstream primers were designed using Oligo 6.0 software, which targeted the region of variability between conserved regions 5 and 6 of the sequences. Using these primers, the specificity and sensitivity of the multiplex PCR system were evaluated, with plasmids containing the 18S rDNA gene sequence as a template. Further, a new nest PCR system (M-Nest) was established by combining the multiplex PCR system with the first-cycle genus-specific primer of the NP 1993 system. The sensitivities of the multiplex PCR system and the M-nest system were evaluated in serial dilutions of blood DNA samples from patients infected by P. falciparum and P. vivax. In addition, the NP-1993 and M-Nest systems were applied to screen the Plasmodium species in 307 blood samples from people returning to Guangxi from Ghana, a malaria epidemic area. And the NP-2002 and M Nest systems were applied to re-check Plasmodium species in 66 blood samples collected in Guangxi from 2014 January to May, which were identified by microscopy to be infected mainly by P. ovale. RESULTS: The sizes of multiplex PCR products for P. falciparum, P. vivax, P. ovale, and P. malariae were 268 bp, 323 bp, 394 bp, and 446 bp, respectively, located in-between 50-bp DNA ladders. However, their melting curves had similar Tm values, thus could not be used to identify the 4 species. The minimum detection limits of P. falciparum, P. malariae, P. ovale, and P. vivax 18S rDNA gene by the multiplex PCR system were 5.58x102, 1.56x103, 1.66x103, and 1.80 x 10(2) copies/[A. The minimum detection limit of blood DNA from falciparum malaria patients by the multiplex PCR system was 1.43 x 10(2)-8.84 x 10(3) copies/p.1 or 5.10 x 10-4.92 x 10(2) parasites/ul, higher than that of P. vivax (17.4-69.1 copies/L or 13.5-83.2 parasites/p). Compared with this multiples PCR system, The M-Nest system further reduced the minimum detection limit of Plasmodium by 10-100 folds. Further, the M-Nest and NP 1993 systems reached inconsistent detection results in 307 blood samples from people returned to from Ghana; the former detected 2 cases of P. ovale infection while the latter failed. In addition, the NP-2002 and M-Nest systems came to the same results in re-checking Plasmodium species in the 66 blood samples. CONCLUSION: The established multiplex PCR system can identify 4 human Plasmodium species simultaneously and has good applicability in practice. PMID- 26245117 TI - [Effect of Excretory-secretory Products of Clonorchis sinensis on Nitric Oxide Production and NF-kappaB Activation in RAW264.7 Mouse Macrophages]. AB - OBJECTIVE: To study the role of excretory-secretory products (ESPs) from Clonorchis sinensis in the production of nitric oxide (NO) and the activation of nuclear transcription factor kappa B (NF-kappaB) in the macrophages of RAW264.7 mouse. METHODS: 20 ug/ml of C. sinensis EPSs, the organic solvent extracts of EPSs (ESP-ex), and 0.1 ug/ml of lipopolysaccharide from Salmonella minnesota (LPS SM) were used as stimulators in co-culture with RAW264.7 mouse macrophages as experimental groups. The Hank's balanced salt solution (HBSS) served as control. At the same time the RAW264.7 macrophages were stimulated with EPSs, ESP-ex, and LPS-SM, and then added 0.3 mmol/L of SMT, a specific inhibitor of iNOS as the interference groups. After co-culture for 18 days, the concentrations of NO2- in the culture supernatants were detected with Griess regents, and the activation of NF-kappaB was determined by transfection with a NF-kappaB-inducible reporter plasmid, pNiFty2-SEAP. The activities of secreted embryonic alkaline phosphatase (SEAP) in culture supernatants were quantified by using HEK-BlueTM detection medium and expressed as the value of optical density at 620 nm (A620 value). The intercellular activities of SEAP were determined by microscopic observation. RESULTS: After stimulation with both ESPs-ex and LPS-SM, the concentrations of NO2- in culture supernatants were (14.30 +/- 1.62) and (14.10 +/- 2.17) umol/L, respectively, which were significantly higher than that of the control [(7.70 +/- 0.95) umol/L] (P < 0.05), and significantly decreased to (8.97 +/- 0.81) and (4.96 +/- 1.36) umol/L after adding SMT, respectively (P < 0.05). However, the concentration of NO2- in ESPs stimulation group [(4.06 +/- 0.62) umol/L] was lower than that of the control (P < 0.05), and almost unchanged [(3.99 +/- 0.87) umol/L] after adding SMT (P > 0.05). SEAP activity in ESP group (0.836 +/- 0.005) was significantly higher than that of the control [(0.097 +/- 0.009) umol/L] (P < 0.05). A strong blue color reaction was observed in cells of ESP group. SEAP activity of ESPs-ex and LPS groups [(0.112 +/- 0.004), (0.116 +/- 0.009) umol/L] was slightly higher than that of the control (P > 0.05), and blue color reaction was observed in some cells. CONCLUSION: ESPs from C. sinensis can stimulate NF kappaB activation in RAW264.7 cells. The water-soluble components of ESPs can inhibit the NO production, while ESPs-ex and LPS-SM can promote the NO production. PMID- 26245118 TI - [Plasma Metabolism and Protective Effect of Oral Administration of Niclosamide on Schistosoma japonicum Cercarial Invasion in Mice]. AB - OBJECTIVE: To study the metabolism of niclosamide in plasma, and the protective effect of its oral administration on Schistosoma japonicum cercarial invasion in mice. METHODS: Twenty-four female Kunming mice were randomly divided into 8 groups, each with 3 mice. Each mouse was treated orally with 120 mg niclosamide per kilogram of body weight (120 mg/kg). The plasma samples were collected at 0.25, 0.5, 1, 2, 4, 8, 16, and 24 h after treatment by retro-orbital blood sampling. The blood drug concentration was determined by HPLC. The pharmacokinetics parameters were calculated such as peak concentration (Cmax), peak time (Tmax), mean residence time (MRT), and elimination half life (T1/2). Thirty Kunming mice were randomly divided into 6 groups. Among them, 5 groups were treated orally with 40, 80, 120, 160, and 200 mg/kg niclosamide, respectively. The remaining untreated group served as control. One hour post treatment, each mouse was infected with 40 +/- 2 Schistosoma japonicum cercariae. Another 35 mice treated with 200 mg/kg niclosamide were randomly divided into 7 groups. Mice in each group were infected with 40 +/- 2 S. japonicum cercariae on 0.25, 1, 4, 8, 12, and 24 h after treatment, named as group A, B, C, D, E, and F. Five untreated mice served as control (group G). All mice were sacrificed 35 days post-infection. Mean worm burden and worm reduction were calculated. RESULTS: At a dose of 120 mg/kg niclosamide, the blood drug concentration was (0.40 +/- 0.28) ug/ml at 0.25 h post-treatment, reached a peak of (0.91 +/- 0.34) ug/ml at 1 h, and decreased to (0.49 +/- 0.38) ug/ml at 2 h, and got close to 0 at 16 h. The mean residence time (MRT) in mice was (6.78 +/- 1.47) h, and the elimination half time was (6.80 +/- 7.05) h. No significant difference was found in worm burden between different dose groups and control group (P > 0.05). The mean worm burden in group A was significantly lower than that of the control (P < 0.05) with a mean worm reduction of 79.1%. And there was no significant difference in worm burden between other groups and the control (P > 0.05). CONCLUSIONS: The blood drug concentration increases rapidly by gavage administration of 120 mg/kg niclosamide, reaching to the maximum concentration at 1 h post-treatment. It shows a certain potective effect of oral administration of 200 mg/kg niclosamide on Schistosoma japonicum cercarial invasion at 0.25 h after treatment. PMID- 26245119 TI - [A Duplex PCR Method for Detection of Babesia caballi and Theileria equi]. AB - OBJECTIVE: To develop a duplex PCR assay for detection of Babesia caballi and Theileria equi. METHODS: Two pairs of primers were designed according to the BC48 gene of B. caballi and 18 s rRNA gene of T. equi, and a duplex PCR assay was developed by the optimization of reaction conditions. The specificity, sensitivity and reliability of the method were tested. The horse blood samples of suspected cases were collected from Yili region, and detected by the duplex PCR, microspopy, conventional PCR, and fluorescence quantitative PCR, and the results were compared. RESULTS: Using the duplex PCR assay, the specific fragments of 155 bp and 280 bp were amplified from DNA samples of B. caballi and T. equi, respectively. No specific fragment was amplified from DNA samples of B. bigemina, Theilerdia annulata, Theilerdia sergenti, Toxoplasma gondii, Neospora caninum, and Trypanosoma evansi. The limit of detection was 4.85 x 10(5) copies/L for B. caballi DNA and 4.85 x 10(4) copies/ul for T. equi DNA, respectively. Among the 24 blood samples, 11 were found B. caballi-positive by the duplex PCR assay, and 18 were T. equi-positive. The coincidence rate of microscopy, conventional PCR, and fluorescence quantitative PCR with duplex PCR was 91.7% (22/24), 95.8% (23/24), and 95.8% (23/24), respectively. CONCLUSION: A duplex PCR assay for simultaneous detection of B. caballi and T. equi is established. PMID- 26245120 TI - [The Levels of IL-4, IL-9, and IgE in Patients Infected with Intestinal Helminths and their Clinical Values]. AB - OBJECTIVE: To investigate the serum levels of interleukin-4 (IL-4), interleukin-9 (IL-9), and immunoglobulin E (IgE) in the patients infected with intestinal helminths, and study their relationship to the clinical symptoms or species of the helminths. METHODS: This study was carried out in the Department of Paediatrics, Henan Provincial People's Hospital from January 2010 to July 2014. The blood samples were collected from 55 infected patients. Among the 55 cases, 18 cases (32.7%) were with ascaris infection, 8 cases (14.5%) of hookworm infection, 7 cases (12.7%) of whipworm infection, and 22 cases (40%) of pinworm infection. ELISA were used to measure the levels of IL-4, IL-9, and IgE in peripheral blood samples from the patients and 15 healthy volunteers. The relationship between the concentration of the cytokines and clinical symptoms or species of the parasites was analyzed. RESULTS: The serum levels of IL-4, IL-9, and IgE in infection group were (157.42 +/- 41) pg/ml, (59.9 +/- 21.7) pg/ml, and (316.6 +/- 129) IU/ml, respectively, which were higher than that of the healthy control[ IL-4 (39.01 +/- .5) pg/ml, IL-9 (21.3 +/- 12.5) pg/m, IgE (127.7 +/- 57.6) IU/ml] (P > 0.01). After treatment by albendazole in the infection group, the level of IL-4, IL-9, and IgE decreased to (98.1 +/- 41.7) pg/ml, (38.7 +/- 14.1) pg/ml, and (253.1 +/- 94.0) IU/ml, respectively, but still higher than that of the control (P < 0.05). IL-9 level in patients with upper gastrointestinal hemorrhage was (76.1 +/- 23.5) pg/ml, which was higher than that of those with abdominal discomfort or disruption to bowel habits [(54.3 +/- 22.1) g/ml] (P < 0.05), but lower than that of those with allergic dermatitis [(108.5 +/- 33.4) pg/ml] (P < 0.05). No significant difference was found in the levels of IL-4 and IgE among the above three groups. The level of IL-9 in patients infected with pinworms was (120.3 +/- 41.0) pg/ml, which was higher than that of ascaris infection group [(90.1 +/- 29.7) pg/ml], hookworm infection group [(77.3 +/- 18.3) pg/ml], and whipworm infection group [(62.5 +/- 24.3) pg/ml] (P < 0.01). There was no significant difference in the serum level of IL-9 between ascaris infection group and hookworm infection group (P > 0.05), whereas the IL-9 level in ascaris infection group and hookworm infection group was higher than that of whipworm infection group [(62.5 +/- 24.3) pg/ ml] (P < 0.01). There were no significant difference in the serum level of IL-4 and IgE among the patients infected with the species of different helminthes (P > 0.05). CONCLUSION: The levels of IL-4, IgE, and IL-9 are considerably related with intestinal helminth infection, while IL-9 level varied with different helminth species and clinical symptoms. PMID- 26245121 TI - [Effect of Echinococcus multilocularis Cyst Fluid on the Expression of Five MAPK pathway Genes of Rat Hepatic Stellate Cells]. AB - OBJECTIVE: To investigate the effect of Echinococcus multilocularis cyst fluid on five MAPK (mitogen-activated protein kinase)-pathway genes of rat hepatic stellate cell. METHODS: Rat hepatic stellate cell line, HSC-T6 cells were co cultured with different protein concentrations of E. multilocularis cyst fluid (0.01, 0.025, 0.05, 0.1, 0.2, 0.4, 0.9, 1.7, 3.4, 6.8, and 13.5 mg/ml) for 24 h. HSC-T6 cells cultured with complete medium served as control group. The morphological change of cells was observed under the microscope. The expression of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase(p38) in HSC-T6 cells was detected by real time fluorescent quantitative PCR. RESULTS: After co-cultured for 24 h, most HSC-T6 cells in 13.5 mg/ml group shrank as a precursor to slough off; In 6.8 mg/ml group, some HSC-T6 cells shrank and changed to long fusiform shape with many slender pseudopodia; In 3.4 mg/ml group, most HSC-T6 cells showed as adherent cells with an irregular polygon shape, formed a sheet with short pseudopodia. There was no difference in cell morphology between < 1.7 mg/ml groups and control group. When the protein concentration was above 1.7 mg/ml, the mRNA level of ERK1/2, JNK1/2, and P38 increased significantly increased. In 6.8 mg/ml cyst fluid group, the mRNA level of ERK1/2, JNK1/2, and P38 was higher than that of the control (P < 0.05). CONCLUSION: 6.8 mg/ml Echinococcus multilocularis cyst fluid can have a significant impact on mRNA levels of ERK1/2, JNK1/2 and p38 in rat hepatic stellate cells. PMID- 26245122 TI - [Study on the Resistance of Culex tritaeniorhynchus to DDT and Deltamethrin in Yunnan Province]. AB - OBJECTIVE: To investigate the resistance level of Culex tritaeniorhynchus to DDT and deltamethrin in Yunnan Province. METHODS: Adult Culex tritaeniorhynchus samples were collected in Zhaoyang District of Zhaotong City, Mangshi County of Dehong Prefecture, Yuanjiang County of Yuxi City, Jiangcheng and Menglian County of Puer City. The susceptibility of Cx. tritaeniorhynchus to DDT and deltamethrin were tested by bioassay method. The resistance level was judged by adjusted mortality. RESULTS: Culex tritaeniorhynchus collected from Zhaoyang, Mangshi, Jiangcheng, Menglian, and Yuanjiang, and exposed to DDT for 1 h, the mortality after 24 hours was 51.1%, 86.8%, 35.4%, 21.0%, and 4.6%, respectively; the resistant grade in Mangshi was maybe resistance(M), and the others 4 sites were resistance (R). The range of KT, to DDT was from 18.76 min to 395.65 min. The mortality of the mosquitoes from the five sites to deltamethrin was 36.9%, 59.2%, 43.1%, 34.1%, and 3.3%, respectively; the resistant grade was R in all sites, and the range of KT50 was 8.69-715.37 min. CONCLUSION: Culex tritaeniorhynchus in Yunnan Province shows simultaneously resistant to DDT and deltamethrin, and therefore the insecticiding strategy should be adjusted. PMID- 26245123 TI - [Assessment of Serum IgG and Its Subclasses in Cystic Echinococcosis Patients and Its Application for Diagnosis]. AB - OBJECTIVE: To assess the diagnostic performance of hydatid cyst fluid (HCF) in detecting the anti-HCF IgG and its subclasses IgG1, IgG2 and IgG4 in serum of cystic echinococcosis patients. METHODS: ELISA was used to measure IgG and its subclasses IgG1, IgG2, and IgG4 specific for Echinococcus granulosus HCF, in the sera of 37 cystic echinococcosis (CE) patients and 29 healthy subjects in Huan County, Gansu Province. The receiver operating characteristic (ROC) curves of the four antibodies were analyzed by MedCalc software, referenced with the gold standard B ultrasonic imaging. The diagnostic performances between the four antibodies were compared using paired z statistics based on the areas under the curve (AUC), and the best diagnostic threshold was determined for each. The sensitivity and specificity for detecting the four types of antibodies were compared using Chi-square test. RESULTS: The AUCs for IgG and its subclasses IgG1, IgG2, and IgG4 were 0.722, 0.919, 0.712, and 0.835, respectively; the AUC of IgG1 was significantly higher than those of IgG (z = 3.629, P < 0.05) and IgG2 (z = 3.292, P<0.05). The sensitivity for detecting IgG, IgGl, IgG2, and IgG4 was 54.1%, 91.9%, 67.6%, and 75.7%, respectively; the sensitivity for IgGl was significantly higher than that for IgG (chi2 = 3.84, P < 0.05), IgG2 (chi2 = 6.80, P < 0.05), and IgG4 (chi2 = 10.16, P < 0.05). The specificity for the four antibodies was 89.7%, 82.8%, 72.4%, and 89.7%, respectively, and no significant difference was found between them. In addition, the sensitivity for detecting IgG4 antibody was significantly higher in CE I-III than in CE IV-V patients. CONCLUSION: The IgG1 antibody shows the highest detection sensitivity by HCF, thus having potential value in diagnosis of cystic echinococcosis. PMID- 26245124 TI - [Diagnosis and Treatment for Four Cases of Sparganosis mansoni]. AB - The data of 4 sparganosis mansoni cases were collected from January 2010 to September 2014, and analyzed by descriptive epidemiological methods. Among the cases, 3 cases had a history of eating raw frogs, and 1 case had a history of eating half-cooked frogs and drinking unboiled water. All cased and 3 out of 7 persons eating raw frogs together with case 3 were positive for anti-Sparganum mansoni antibody. 2 patients were cured by operation removal and praziquantel+alhendazole treatment, and the other 2 cases were cured by drugs only. PMID- 26245125 TI - [Percentage of Th17 Cells in Spleen and IL-17 Level in Bronchoalveolar Lavage Fluid in Dermatophagoides farinae Allergic Asthma Mice]. AB - OBJECTIVE: To detect the percentage of Th17 cells in spleen and IL-17 level in bronchoalveolar lavage fluid in Dermatophagoides farinae allergic asthma mice. METHODS: Twenty BALB/c mice were randomly divided into control group (n=10) and asthma group (n=10). Mice in control group were treated with PBS plus 2 mg Al(OH)3 and those in asthma group were sensitized with 200 ul solution [50 ug Dermatophagoides farinae crude extracts plus 2 mg Al (OH)3] on day 0, 7 and 14. One week after the last sensitization, all mice were intranasally challenged with 50 ug Dermatophagoides farinae crude extracts daily for 7 days. Twenty-four hours after the last challenge, mice were sacrificed. The sera, bronchoalveolar lavage fluid (BALF) and spleens were collected. The serum levels of IgE and IgG1, and IL 17 level in BALF were determined by ELISA. The percentage of Th17 cells in spleen was tested by flow cytometry. RESULTS: The serum levels of IgG, and IgE in asthma group were (0.10 +/- 0.01) pg/ml and (1.15 +/- 0.10) pg/ml, respectively, which were higher than that of the control [(0.06 +/- 0.01) pg/ml and (0.04 +/- 0.01) pg/ml] (P < 0.05). IL-17 level in asthma group (85.13 +/- 2.36) pg/ml was higher than that of the control [(48.27 +/- 4.14) pg/ml] (P < 0.01). The percentage of Th17 cells in asthma group [(5.19 +/- 0.68)%] was also higher than that of the control [(0.95 +/- 0.19)%] (P < 0.01). Meanwhile, the percentage of Thl7 cells in spleen was positively correlated with IL-17 level in BALF (r = 0.851, P < 0.01). CONCLUSION: Compared with healthy mice, both the percentage of Th17 cells in spleen and IL-17 level in BALF have increased significantly in Dermatophagoides farinae allergic asthma mice. PMID- 26245126 TI - [Scanning Electron Microscopic Observation on Adult Gnathostoma doloresi Worms and the Phylogenetic Analysis of G. doloresi Based on ITS2 and COX1 Gene Sequences]. AB - OBJECTIVE: To observe the ultrastructure of adult Gnathostoma doloresi worms isolated from wild boar by using scanning electron microscope (SEM), and analyze its phylogenetic relationships based on ITS2 and COXI gene sequences. METHODS: Two adult G. doloresi worms were fixed by glutaraldehyde and osmium peroxide. Ultrastructural characters of those samples were observed under SEM. Amplification and sequencing of the ITS2 and COXI genes were performed following the extraction of total genomic DNA. Sequence analysis was performed based on multiple alignments and phylogenetic analysis was made by Neighbor-Joining method using MEGA 6.0. RESULTS: The bottle-shaped adult worm covered with numerous small spines. The cervical groove connected head bulb and body without spines. There was obvious distinction in body spines which surround cervical papillae and swollen area in the middle part of the body. The fragments of ITS2 (418 bp) and COXI (381 bp) gene were obtained by PCR combined with sequencing, and were registered to the GenBank database with the accession No. of JN408329 and JN408299, respectively. The BLAST results showed that, two sequences had 99% and 98% consistency with G. doloresi ITS2 (GenBank accession No. AB181156) and COX1 (No. AB180100) gene sequences, respectively. The phylogenetic tree indicated that the two G. doloresi worms were at the same clade with a bootstrap value at 100% and 85% based on the ITS2 and COXI sequences, respectively. G. doloresi and G. hispidum were also clustered together. CONCLUSION: The results provide adequate information for the SEM morphological data of adult G. doloresi worms, and its phylogenetic relationship. PMID- 26245127 TI - [Application of Nano Carbon-based Immunosensor in Pathogen Detection]. AB - The biosensors exhibit many advantages such as simple operation, rapid reaction and high sensitivity in pathogen detection. The sensitivity and specificity of the biosensors can be significantly enhanced by the combined use of carbon nano materials (such as carbon nanotubes and graphene) and bio-sensing devices. This paper reviews the characteristics of carbon nano-biosensors, its applications in pathogen detection and new development. PMID- 26245128 TI - [Progress on the Relationship between Clonorchis sinensis Infection and Cholangiocarcinoma]. AB - Currently, 12.49 million people are infected with Clonorchis sinensis in China. The incidence of bile duct carcinoma increased for recent years. More than a century ago, some scholars have put forward the idea about the relations between C. sinensis infection and cholangiocarcinoma, and committed to research the mechanism. However, the intrinsic mechanisms involved in these processes remain obscure. It is therefore important to pay more attention to the further investigation of the relevance between C. sinensis infection and bile duct carcinoma. This review summarizes the possible mechanism of cholangiocarcinoma caused by C. sinensis, which is displayed on mechanical damage, stimulation of the worms and their excretory-secretory products (ESP), abnormity of immunoreaction and molecular genetic lesions. PMID- 26245129 TI - [The Role of Dendritic Cells in Host Immunity against Helminth Infections]. AB - Dendritic cells are the strongest professional antigen-presenting cells. Helminth infection could promote maturation of immature dendritic cells, induce Th2-type immune responses, and inhibit the normal function of dendritic cells which is closely associated with the immune evasion. This paper reviews the role of dendritic cells in host immunity against helminth infections. PMID- 26245130 TI - [Analysis on Research Projects Supported by the National Natural Science Foundation of China at the National Institute of Parasitic Diseases during 2003 2013]. AB - The data of the National Natural Science Foundation (NSFC) projests obtained by the National Institute of Parasitic Diseases (NIPD), Chinese Center for Disease Control and Prevention (China CDC) during 2003-2013 were collected from internet based science information system of NSFC, and NSFC search tool of Dingxiang Garden (http://nsfc.biomart.cn/). The number of funded projects, their subject classification and approved amount were analyzed, and compared with the other institutes of China CDC. Furthermore, the rationalization proposals were given in order to enhance the level of foundation management in the future. PMID- 26245131 TI - [Toxoplasma gondi Antibody Profile in Patients with Leukemia or Lymphoma]. AB - Blood samples were collected from patients with leukemia (n = 150) or lymphoma (n = 150) in the Cancer Hospital from March to September 2014. The specific antibodies (IgG, IgM) to, and circulating antigens (CAg) of Toxoplasma gondii were determined by ELISA. A 529 bp specific sequence was amplified by PCR from the genomic DNA of T. gondii. T. gondii-specific IgG positive rate in patients with leukemia and lymphoma were 16.0% (24/150) and 20.0% (30/150), respectively, which were significantly higher than that of healthy persons (6.4%, 7/110) (P < 0.05). IgM positive rate of the leukemia patients, lymphoma patients, and healthy persons was 2.7% (4/150), 1.3% (2/150), and 0.9% (1/110) (P > 0.05), respectively. No significant difference was found in IgM and CAg positive rate among leukemia patients, lymphoma patients, and healthy persons (P > 0.05). No specific band (529 bp) was detected in all samples. PMID- 26245132 TI - [Tracing Investigation of One Vivax Malaria Case by Detecting the Gene Encoding Circumsporozoite Protein in Henan]. AB - A vivax malaria case in Henan Province was diagnosed as an indigenous case firstly in June 2013, and replased in April 2014. The clinical data of this case were collected and the epidemiological investigation was conducted. The blood samples were examined by Giemsa-stained blood smear, rapid diagnostic test strip (RDT) and nested PCR. This patient stayed at Myanmar for about one week in May 2013, had the symptoms of chills, fever and sweating in June, and was diagnosed as vivax malaria. After treated with artesunate, the symptoms disappeared. The CSP sequence was amplified from the blood samples of the first and second attack, and there was no difference in the central repeat domain of CSP gene. The identity of our two CSP gene sequences to that of Myanmar isolates (GenBank accessssion No. ABS95455, ABS95456) was 95.1% and 100%, while their nucleotide sequence was with 88.8% and 67.1% identity with that of Henan isolates (accessssion No. KP888996, KP889000), respectively. This patient is therefore confirmed as an imported relapse case of Plasmodium vivax infection. PMID- 26245133 TI - [Expression, Purification and Bioinformatics Analysis of beta-hexosaminidase of Dermatophagoides farinae]. AB - The DNA fragment encoding beta-hexosaminidase was synthesized, and cloned into pET-28a vector. The constructed plasmid pMD18-T-beta-hexosaminidase was transformed into E. coli Top 10 and followed by expression of the protein induced by IPTG. SDS-PAGE result showed that the relative molecular mass of the recombinant protein was about M, 55 000. The full length of beta-hexosaminidase gene was 1 410 bp. Bioinformatics analysis revealed that beta-hexosaminidase was composed with 469 amino acid residues with a calculated molecular weight of Mr 55,000, and its secondary structure was composed of strand (14.71%), helix (30.70%), and loop (54.58%). beta-hexosaminidase was a hydrophilic protein without signal peptide, and located in the extracellular space. PMID- 26245134 TI - Low temperature catalytic oxidative aging of LDPE films in response to heat excitation. AB - The waste treatment of polymer materials is often conducted using the photocatalytic technique; however, complete decomposition is frequently inhibited owing to several shortcomings such as low quantum yield and the requirement of ultraviolet irradiation. Herein, we report a strategy to implement moderate management of polymeric films via thermocatalytic oxidative route, which is responsive to heat stimulus. Diverse LDPE-matrix films together with as-prepared thermal catalysts (TCs) or initiators were synthesized to further investigate heat-dependent-catalytic degradation effects. After artificial ageing, structural textures of the as-synthesized films could be chemically deteriorated, followed by a huge increase in surface roughness values, and appreciable loss was also found in the average molecular weights and mechanical parameters. We found an emergent phenomenon in which crystallization closely resembled two-dimensional (2D) growth, which displayed rod-like or disc-type crystal shapes. New chemical groups generated on film surfaces were monitored, and led to a higher limiting oxygen index because of strong catalytic oxidation, thus demonstrating the success of catalytic oxidative ageing by heat actuation. The underlying mechanism responsible for thermocatalytic oxidative pattern is also discussed. Accordingly, these findings may have important implications for better understanding the development of polymeric-matrix waste disposal. PMID- 26245135 TI - Phylogenomic grouping of Listeria monocytogenes. AB - The precise delineation of lineages and clonal groups are a prerequisite to examine within-species genetic variations, particularly with respect to pathogenic potential. A whole-genome-based approach was used to subtype and subgroup isolates of Listeria monocytogenes. Core-genome typing was performed, employing 3 different approaches: total core genes (CG), high-scoring segment pairs (HSPs), and average nucleotide identity (ANI). Examination of 113 L. monocytogenes genomes available in-house and in public domains revealed 33 phylogenomic groups (PGs). Each PG could be differentiated into a number of genomic types (GTs), depending on the approach used: HSPs (n = 57 GTs), CG (n = 71 GTs), and ANI (n = 83 GTs). Demarcation of the PGs was concordant with the 4 known lineages and led to the identification of sublineages in the lineage groups I, II, and III. In addition, PG assignments had discriminatory power similar to multi-virulence-locus sequence typing types and clonal complexes of multilocus sequence typing. Clustering of genomically highly similar isolates from different countries, sources, and isolation dates using whole-genome-based PG suggested that dispersion of phylogenomic clones of L. monocytogenes preceded their subsequent evolution. Classification according to PG may act as a guideline for future epidemiological studies. PMID- 26245137 TI - Bipolar radiofrequency ablation for metastatic spinal tumors: an evolving paradigm in palliative care. PMID- 26245136 TI - Phase II trial of sunitinib as adjuvant therapy after stereotactic radiosurgery in patients with 1-3 newly diagnosed brain metastases. AB - Patients with 1-3 brain metastases (BM) often receive sterotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT). SRS without WBRT carries a high rate of relapse in the central nervous system (CNS). This trial used sunitinib as an alternative to WBRT for post-SRS adjuvant therapy. Eligible patients with 1-3 newly diagnosed BM, RTOG RPA class 1-2, received sunitinib after SRS. Patients with controlled systemic disease were allowed to continue chemotherapy for their primary disease according to a list of published regimens (therapy + sunitinib) included in the protocol. Patients received sunitinib 37.5 or 50 mg/days 1-28 every 42 days until CNS progression. Neuropsychological testing and MRIs were obtained every two cycles. The primary endpoint was the rate of CNS progression at 6 months (PFS6) after SRS. Fourteen patients with a median age of 59 years were enrolled. Primary cancers included lung 43 %, breast 21 %, melanoma 14 %. Toxicity included grade 3 or higher fatigue in five patients and neutropenia in two patients. The CNS PFS6 and PFS12 were 43 +/- 14 and 34 +/- 14 %, respectively. Of the ten patients who completed >1 neurocognitive assessment, none showed cognitive decline. Sunitinib after SRS for 1-3 BM was well tolerated with a PFS6 of 43 %. The prevention of progressive brain metastasis after SRS requires the incorporation of chemotherapy regimens to control the patient's primary disease. Future trials should continue to explore the paradigm of secondary chemoprevention of BM after definitive local therapy. PMID- 26245138 TI - Turing instabilities on Cartesian product networks. AB - The problem of Turing instabilities for a reaction-diffusion system defined on a complex Cartesian product network is considered. To this end we operate in the linear regime and expand the time dependent perturbation on a basis formed by the tensor product of the eigenvectors of the discrete Laplacian operators, associated to each of the individual networks that build the Cartesian product. The dispersion relation which controls the onset of the instability depends on a set of discrete wavelengths, the eigenvalues of the aforementioned Laplacians. Patterns can develop on the Cartesian network, if they are supported on at least one of its constitutive sub-graphs. Multiplex networks are also obtained under specific prescriptions. In this case, the criteria for the instability reduce to compact explicit formulae. Numerical simulations carried out for the Mimura Murray reaction kinetics confirm the adequacy of the proposed theory. PMID- 26245139 TI - Projecting excess emergency department visits and associated costs in Brisbane, Australia, under population growth and climate change scenarios. AB - The direct and indirect health effects of increasingly warmer temperatures are likely to further burden the already overcrowded hospital emergency departments (EDs). Using current trends and estimates in conjunction with future population growth and climate change scenarios, we show that the increased number of hot days in the future can have a considerable impact on EDs, adding to their workload and costs. The excess number of visits in 2030 is projected to range between 98-336 and 42-127 for younger and older groups, respectively. The excess costs in 2012-13 prices are estimated to range between AU$51,000-184,000 (0-64) and AU$27,000-84,000 (65+). By 2060, these estimates will increase to 229-2300 and 145-1188 at a cost of between AU$120,000-1,200,000 and AU$96,000-786,000 for the respective age groups. Improvements in climate change mitigation and adaptation measures are likely to generate synergistic health co-benefits and reduce the impact on frontline health services. PMID- 26245140 TI - Methane production and diurnal variation measured in dairy cows and predicted from fermentation pattern and nutrient or carbon flow. AB - Many feeding trials have been conducted to quantify enteric methane (CH(4)) production in ruminants. Although a relationship between diet composition, rumen fermentation and CH(4) production is generally accepted, the efforts to quantify this relationship within the same experiment remain scarce. In the present study, a data set was compiled from the results of three intensive respiration chamber trials with lactating rumen and intestinal fistulated Holstein cows, including measurements of rumen and intestinal digestion, rumen fermentation parameters and CH(4) production. Two approaches were used to calculate CH(4) from observations: (1) a rumen organic matter (OM) balance was derived from OM intake and duodenal organic matter flow (DOM) distinguishing various nutrients and (2) a rumen carbon balance was derived from carbon intake and duodenal carbon flow (DCARB). Duodenal flow was corrected for endogenous matter, and contribution of fermentation in the large intestine was accounted for. Hydrogen (H(2)) arising from fermentation was calculated using the fermentation pattern measured in rumen fluid. CH(4) was calculated from H(2) production corrected for H(2) use with biohydrogenation of fatty acids. The DOM model overestimated CH(4)/kg dry matter intake (DMI) by 6.1% (R(2)=0.36) and the DCARB model underestimated CH(4)/kg DMI by 0.4% (R(2)=0.43). A stepwise regression of the difference between measured and calculated daily CH(4) production was conducted to examine explanations for the deviance. Dietary carbohydrate composition and rumen carbohydrate digestion were the main sources of inaccuracies for both models. Furthermore, differences were related to rumen ammonia concentration with the DOM model and to rumen pH and dietary fat with the DCARB model. Adding these parameters to the models and performing a multiple regression against observed daily CH(4) production resulted in R 2 of 0.66 and 0.72 for DOM and DCARB models, respectively. The diurnal pattern of CH(4) production followed that of rumen volatile fatty acid (VFA) concentration and the CH(4) to CO(2) production ratio, but was inverse to rumen pH and the rumen hydrogen balance calculated from 4*(acetate+butyrate)/2*(propionate+valerate). In conclusion, the amount of feed fermented was the most important factor determining variations in CH(4) production between animals, diets and during the day. Interactions between feed components, VFA absorption rates and variation between animals seemed to be factors that were complicating the accurate prediction of CH(4). Using a ruminal carbon balance appeared to predict CH(4) production just as well as calculations based on rumen digestion of individual nutrients. PMID- 26245142 TI - The interaction of eugenol with cell membrane models at the air-water interface is modulated by the lipid monolayer composition. AB - Eugenol, a natural phenylpropanoid derivative with possible action in biological surfaces as microbicide, anesthetic and antioxidant, was incorporated in lipid monolayers of selected lipids at the air-water interface, representing cell membrane models. Interaction of eugenol with the lipids dipalmitoylphosphatidylcholine (DPPC), dioctadecyldimethylammonium bromide (DODAB), and dipalmitoylphosphatidylserine (DPPS) could be inferred by means of surface pressure-area isotherms and Polarization-Modulation Reflection-Absorption Spectroscopy. The interaction showed different effects on the different lipids. A higher monolayer expansion was observed for DPPS and DODAB, while more significant effects on the polar groups of the lipids were observed for DPPS and DPPC. These results pointed to the fact that the interaction of eugenol with lipid monolayers at the air-water interface is modulated by the lipid composition, which may be important to comprehend at the molecular level the interaction of this drug with biological surfaces. PMID- 26245141 TI - Diacetin, a reliable cue and private communication channel in a specialized pollination system. AB - The interaction between floral oil secreting plants and oil-collecting bees is one of the most specialized of all pollination mutualisms. Yet, the specific stimuli used by the bees to locate their host flowers have remained elusive. This study identifies diacetin, a volatile acetylated glycerol, as a floral signal compound shared by unrelated oil plants from around the globe. Electrophysiological measurements of antennae and behavioural assays identified diacetin as the key volatile used by oil-collecting bees to locate their host flowers. Furthermore, electrophysiological measurements indicate that only oil collecting bees are capable of detecting diacetin. The structural and obvious biosynthetic similarity between diacetin and associated floral oils make it a reliable cue for oil-collecting bees. It is easily perceived by oil bees, but can't be detected by other potential pollinators. Therefore, diacetin represents the first demonstrated private communication channel in a pollination system. PMID- 26245143 TI - Optical absorption spectra of human articular cartilage correlate with biomechanical properties, histological score and biochemical composition. AB - This study investigates the relationship between the optical response of human articular cartilage in the visible (VIS) and near infrared (NIR) spectral range and its matrix properties.Full-thickness osteochondral cores (dia. = 16 mm, n = 50) were extracted from human cadaver knees (N = 13) at four anatomical locations and divided into quadrants. Absorption spectra were acquired in the spectral range 400-1100 nm from one quadrant. Reference biomechanical, biochemical composition, histological, and cartilage thickness measurements were obtained from two other quadrants. A multivariate statistical technique based on partial least squares (PLS) regression was then employed to investigate the correlation between the absorption spectra and tissue properties.Our results demonstrate that cartilage optical response correlates with its function, composition and morphology, as indicated by the significant relationship between spectral predicted and measured biomechanical (79.0% ? R(2) ? 80.3%, p < 0.0001), biochemical (65.1% ? R(2) ? 81.0%, p < 0.0001), and histological scores ([Formula: see text] = 83.3%, p < 0.0001) properties. Significant correlation was also obtained with the non-calcified cartilage thickness ([Formula: see text] = 83.2%, p < 0.0001).We conclude that optical absorption of human cartilage in the VIS and NIR spectral range correlates with the overall tissue properties, thus providing knowledge that could facilitate development of systems for rapid assessment of tissue integrity. PMID- 26245145 TI - Molecular characteristics and evolutionary analysis of a very virulent infectious bursal disease virus. AB - Infectious bursal disease virus (IBDV) poses a significant threat to the poultry industry. Viral protein 2 (VP2), the major structural protein of IBDV, has been subjected to frequent mutations that have imparted tremendous genetic diversity to the virus. To determine how amino acid mutations may affect the virulence of IBDV, we built a structural model of VP2 of a very virulent strain of IBDV identified in China, vvIBDV Gx, and performed a molecular dynamics simulation of the interaction between virulence sites. The study showed that the amino acid substitutions that distinguish vvIBDV from attenuated IBDV (H253Q and T284A) favor a hydrophobic and flexible conformation of beta-barrel loops in VP2, which could promote interactions between the virus and potential IBDV-specific receptors. Population sequence analysis revealed that the IBDV strains prevalent in East Asia show a significant signal of positive selection at virulence sites 253 and 284. In addition, a signal of co-evolution between sites 253 and 284 was identified. These results suggest that changes in the virulence of IBDV may result from both the interaction and the co-evolution of multiple amino acid substitutions at virulence sites. PMID- 26245146 TI - mTOR and post-translational modifications rely on mitochondrion as the arsenal for cellular metabolism regulation. PMID- 26245147 TI - Resource partitioning along multiple niche axes drives functional diversity in parrotfishes on Caribbean coral reefs. AB - The recent loss of key consumers to exploitation and habitat degradation has significantly altered community dynamics and ecosystem function across many ecosystems worldwide. Predicting the impacts of consumer losses requires knowing the level of functional diversity that exists within a consumer assemblage. In this study, we document functional diversity among nine species of parrotfishes on Caribbean coral reefs. Parrotfishes are key herbivores that facilitate the maintenance and recovery of coral-dominated reefs by controlling algae and provisioning space for the recruitment of corals. We observed large functional differences among two genera of parrotfishes that were driven by differences in diet. Fishes in the genus Scarus targeted filamentous algal turf assemblages, crustose coralline algae, and endolithic algae and avoided macroalgae, while fishes in the genus Sparisoma preferentially targeted macroalgae. However, species with similar diets were dissimilar in other attributes, including the habitats they frequented, the types of substrate they fed from, and the spatial scale at which they foraged. These differences indicate that species that appear to be functionally redundant when looking at diet alone exhibit high levels of complementarity when we consider multiple functional traits. By identifying key functional differences among parrotfishes, we provide critical information needed to manage parrotfishes to enhance the resilience of coral-dominated reefs and reverse phase shifts on algal-dominated reefs throughout the wider Caribbean. Further, our study provides a framework for predicting the impacts of consumer losses in other species rich ecosystems. PMID- 26245144 TI - Glial regulation of the blood-brain barrier in health and disease. AB - The brain is the organ with the highest metabolic demand in the body. Therefore, it needs specialized vasculature to provide it with the necessary oxygen and nutrients, while protecting it against pathogens and toxins. The blood-brain barrier (BBB) is very tightly regulated by specialized endothelial cells, two basement membranes, and astrocytic endfeet. The proximity of astrocytes to the vessel makes them perfect candidates to influence the function of the BBB. Moreover, other glial cells are also known to contribute to either BBB quiescence or breakdown. In this review, we summarize the knowledge on glial regulation of the BBB during development, in homeostatic conditions in the adult, and during neuroinflammatory responses. PMID- 26245148 TI - Long-term patterns in estuarine fish growth across two climatically divergent regions. AB - Long-term ecological datasets are vital for investigating how species respond to changes in their environment, yet there is a critical lack of such datasets from aquatic systems. We developed otolith growth 'chronologies' to reconstruct the growth history of a temperate estuarine fish species, black bream (Acanthopagrus butcheri). Chronologies represented two regions in south-east Australia: South Australia, characterised by a relatively warm, dry climate, and Tasmania, characterised by a relatively cool, wet climate. Using a mixed modelling approach, we related inter-annual growth variation to air temperature, rainfall, freshwater inflow (South Australia only), and El Nino-Southern Oscillation events. Otolith chronologies provided a continuous record of growth over a 13- and 21-year period for fish from South Australia and Tasmania, respectively. Even though fish from Tasmania were sourced across multiple estuaries, they showed higher levels of growth synchronicity across years, and greater year-to-year growth variation, than fish from South Australia, which were sourced from a single, large estuary. Growth in Tasmanian fish declined markedly over the time period studied and was negatively correlated to temperature. In contrast, growth in South Australian fish was positively correlated to both temperature and rainfall. The stark contrast between the two regions suggests that Tasmanian black bream populations are more responsive to regional scale environmental variation and may be more vulnerable to global warming. This study highlights the importance of examining species response to climate change at the intra-specific level and further validates the emerging use of growth chronologies for generating long-term ecological data in aquatic systems. PMID- 26245149 TI - The Mukaiyama aldol reaction of in situ generated nitrosocarbonyl compounds: selective C-N bond formation and N-O bond cleavage in one-pot for alpha-amination of ketones. AB - A practical protocol for the alpha-amination of ketones (up to 99% yield) has been developed via the Mukaiyama aldol reaction of in situ generated nitrosocarbonyl compounds. The reaction with silyl enol ethers having a disilane (-SiMe2TMS) backbone proceeded not only with perfect N-selectivity but concomitant N-O bond cleavage was also accomplished. Such a cascade of C-N bond formation and N-O bond cleavage in a single step was heretofore unknown in the field of nitrosocarbonyl chemistry. A very high diastereoselectivity (dr = 19 : 1) was accomplished using (-)-menthol derived chiral nitrosocarbonyl compounds. PMID- 26245151 TI - Gram-scale synthesis of coordination polymer nanodots with renal clearance properties for cancer theranostic applications. AB - An ultrasmall hydrodynamic diameter is a critical factor for the renal clearance of nanoparticles from the body within a reasonable timescale. However, the integration of diagnostic and therapeutic components into a single ultrasmall nanoparticle remains challenging. In this study, pH-activated nanodots (termed Fe CPNDs) composed of coordination polymers were synthesized via a simple and scalable method based on coordination reactions among Fe(3+), gallic acid and poly(vinylpyrrolidone) at ambient conditions. The Fe-CPNDs exhibited ultrasmall (5.3 nm) hydrodynamic diameters and electrically neutral surfaces. The Fe-CPNDs also exhibited pH-activatable magnetic resonance imaging contrast and outstanding photothermal performance. The features of Fe-CPNDs greatly increased the tumour imaging sensitivity and facilitated renal clearance after injection in animal models in vivo. Magnetic resonance imaging-guided photothermal therapy using Fe CPNDs completely suppressed tumour growth. These findings demonstrate that Fe CPNDs constitute a new class of renal clearable nanomedicine for photothermal therapy and molecular imaging. PMID- 26245150 TI - Crystal structures of ryanodine receptor SPRY1 and tandem-repeat domains reveal a critical FKBP12 binding determinant. AB - Ryanodine receptors (RyRs) form calcium release channels located in the membranes of the sarcoplasmic and endoplasmic reticulum. RyRs play a major role in excitation-contraction coupling and other Ca(2+)-dependent signalling events, and consist of several globular domains that together form a large assembly. Here we describe the crystal structures of the SPRY1 and tandem-repeat domains at 1.2-1.5 A resolution, which reveal several structural elements not detected in recent cryo-EM reconstructions of RyRs. The cryo-EM studies disagree on the position of SPRY domains, which had been proposed based on homology modelling. Computational docking of the crystal structures, combined with FRET studies, show that the SPRY1 domain is located next to FK506-binding protein (FKBP). Molecular dynamics flexible fitting and mutagenesis experiments suggest a hydrophobic cluster within SPRY1 that is crucial for FKBP binding. A RyR1 disease mutation, N760D, appears to directly impact FKBP binding through interfering with SPRY1 folding. PMID- 26245152 TI - Chronic obstructive pulmonary disease in patients with end-stage kidney disease on hemodialysis. AB - The objectives of this study were to assess the prevalence of chronic obstructive pulmonary disease (COPD) in hemodialysis patients with spirometry and to examine the effects of fluid removal by hemodialysis on lung volumes. Patients >=18 years at two Danish hemodialysis centers were included. Forced expiratory volume in one second (FEV1 ), forced vital capacity (FVC), and FEV1 /FVC ratio were measured with spirometry before and after hemodialysis. The diagnosis of COPD was based on both the GOLD criteria and the lower limit of normal criteria. There were 372 patients in treatment at the two centers, 255 patients (69%) completed spirometry before dialysis and 242 of these (65%) repeated the test after. In the initial test, 117 subjects (46%) had airflow limitation indicative of COPD with GOLD criteria and 103 subjects (40.4%) with lower limit of normal criteria; COPD was previously diagnosed in 24 patients (9%). Mean FVC and FEV1 decreased mildly after dialysis (FVC: 2.84 to 2.79 L, P < 0.01. FEV1 : 1.97 to 1.93 L, P < 0.01) Hemodialysis did not affect the FEV1 /FVC ratio or number of subjects with airflow limitation indicative of COPD (113 vs. 120, P = 0.324; n = 242). COPD is a frequent and underdiagnosed comorbidity in patients on chronic hemodialysis. Spirometry should be considered in all patients on dialysis in order to address dyspnea adequately. Hemodialysis induced a small fall in mean FEV1 and FVC, which was more pronounced in patients with little or no fluid removal, but the FEV1 /FVC ratio and the number of subjects with airflow limitation indicative of COPD were not affected by dialysis. PMID- 26245153 TI - Reduction mammoplasty is beneficial in women with and without history of breast cancer. PMID- 26245154 TI - Deletion or inhibition of Fc gamma receptor 2B (CD32) prevents FVIII-specific activation of memory B cells in vitro. AB - Development of inhibitory antibodies against factor VIII (FVIII) is a severe complication of replacement therapy in haemophilia A. Patients with inhibitors are treated with high FVIII doses in the context of immune tolerance therapy (ITT). Data from haemophilia A mouse model suggest that high FVIII concentrations prevent the formation of antibody secreting cells (ASCs) from memory B cells (MBCs) by inducing apoptosis. Fc gamma receptor 2B (CD32) is an important regulator of B cell function, mediating inhibitory signals after cross-linking with the B cell receptor. Here, the role of CD32 in the regulation of FVIII specific MBCs was investigated using F8-/- and F8-/-CD32-/- knockout mice and monoclonal antibodies (mAbs). The initial immune response was similar between F8 /- and F8-/-CD32-/- mice, including concentration of anti-FVIII antibodies and number of FVIII-specific ASCs in spleen and bone marrow. In contrast, formation of ASCs from MBCs upon rhFVIII re-stimulation in vitro was abolished in F8-/-CD32 /- mice, whereas FVIII/anti-FVIII immune complexes significantly enhanced ASC formation in F8-/- mice. Inhibition of CD32 by mAbs or F(ab)2 fragments prevented ASC formation in a dose-dependent manner. Transfer of B cell-depleted splenocytes using CD45R (B220) depletion from CD32-competent mice did not restore ASC formation in F8-/-CD32-/- cells confirming that CD32 is required on B cells. We conclude that CD32 is a crucial regulator of FVIII-specific B cells and is required for the differentiation of MBCs into ASCs. Inhibition of CD32 could potentially improve the efficacy of FVIII in the context of ITT. PMID- 26245155 TI - Mortality in Brazilian community-dwelling older adults: 7 years of follow up in primary care. AB - AIM: To describe the main causes and factors associated with mortality in community-dwelling older adults in a county where the public health system covers most of the population. METHODS: We analyzed data from an existing cross sectional study of 2209 participants (age >=60 years) in a city in southeast Brazil where 92% of the population is served by a public system of primary care. Over a period of 7 years, 386 participants died and were included in the sample. We assessed the impacts that dependence on others for basic activities of daily living and instrumental activities of daily living, Geriatric Depression Scale scores, and health history have on mortality. RESULTS: The participants' mean age was 75.2 years (SD 8.2); 51.7% of the participants were women, and 51.3% had depressive symptoms. The main causes of death were circulatory diseases (40.3%), cancer (19.8%) and respiratory diseases (13.5%). Multivariate analysis showed that, taken together, the use of more than four medications per day, smoking, lower income, older age and dependence on others for a greater number of instrumental activities of daily living predicted death in this population. CONCLUSIONS: Understanding the factors that are associated with mortality can facilitate understanding, and aid in developing policies regarding primary care for the elderly. Geriatr Gerontol Int 2016; 16: 804-809. PMID- 26245156 TI - Long-term intracerebroventricular infusion of angiotensin II after kainate induced status epilepticus: Effects on epileptogenesis, brain damage, and diurnal behavioral changes. AB - Our previous studies revealed that Angiotensin (Ang) II has anticonvulsant effects in acute seizure models. However, data on its role in experimental models of epilepsy are missing. In the present study, we tested whether posttreatment with Ang II after kainate (KA)-induced status epilepticus (SE) can affect epileptogenesis, concomitant behavioral changes, and brain damage. The Wistar rats were intracerebroventricularly infused via osmotic mini-pumps with Ang II (1.52MUg/MUl/day for 28days) after SE. Spontaneous motor seizures (SMS) were video-recorded for up to three months. Locomotor activity, anxiety, and depression-like behavior were evaluated during the last week of drug infusion, while spatial memory was assessed during the 3rd month after SE. Angiotensin II decreased the latency for onset of the first SMS and increased the frequency of SMS two months after SE. The continuous peptide infusion exacerbated the KA induced hyperactivity and caused depression-like behavior. The reduced anxiety of KA-treated rats was alleviated by Ang II exposure. The KA-induced deficit in the hippocampal-dependent spatial memory was not influenced by Ang II. However, Ang II partially prevented the neuronal damage in the hippocampus, specifically in the CA1 area. The role of AT1 and AT2 receptor activation in the effects of the octapeptide is discussed. PMID- 26245158 TI - Endoscopic interlaminar approach for intracanal L5-S1 disc herniation: Classification of disc prolapse in relation to learning curve and surgical outcome. AB - INTRODUCTION: The full endoscopic interlaminar approach (FEILA) is a minimally invasive procedure to treat intracanal lumbar disc herniation not approachable by endoscopic transforaminal access. Disc prolapses have been classified into three categories according to their position and passing nerve root displacement: (i) type A, in which the nerve root is displaced medially; (ii) type B, in which the nerve root is displaced laterally; and (iii) type C, in which the nerve root is ventrally displaced. We focused on the FEILA technique because it was likely to involve few complications and that provided the advantages of the endoscopic approach. METHODS: We prospectively evaluated 100 consecutive cases of L5-S1 disc herniations operated on with FEILA, including 85 type A cases, 13 type B, and 2 type C. Patients were evaluated at discharge, 3 months, 6 months and 2 years. RESULTS: The operating time varied from 15 to 40 min. The use of drills and burrs was necessary to treat type B disc herniations; thus, it was preferable that these cases were operated on later in the learning curve. After surgery, 90% of neurological deficits improved. The Oswestry Disability Index and visual analog scale leg at last follow-up were 15 and 9, respectively. There were no major complications. There were five cases of recurrence; four of which were treated with same technique and with good results. CONCLUSION: FEILA is a safe procedure for the removal of intracanal L5-S1 disc herniations. The late follow-up confirms the stability of the results. We suggest treating type A prolapse at the beginning of the learning curve and type B herniations after sufficient experience in the use of the burrs has been achieved. PMID- 26245157 TI - Technologies That Assess the Location of Physical Activity and Sedentary Behavior: A Systematic Review. AB - BACKGROUND: The location in which physical activity and sedentary behavior are performed can provide valuable behavioral information, both in isolation and synergistically with other areas of physical activity and sedentary behavior research. Global positioning systems (GPS) have been used in physical activity research to identify outdoor location; however, while GPS can receive signals in certain indoor environments, it is not able to provide room- or subroom-level location. On average, adults spend a high proportion of their time indoors. A measure of indoor location would, therefore, provide valuable behavioral information. OBJECTIVE: This systematic review sought to identify and critique technology which has been or could be used to assess the location of physical activity and sedentary behavior. METHODS: To identify published research papers, four electronic databases were searched using key terms built around behavior, technology, and location. To be eligible for inclusion, papers were required to be published in English and describe a wearable or portable technology or device capable of measuring location. Searches were performed up to February 4, 2015. This was supplemented by backward and forward reference searching. In an attempt to include novel devices which may not yet have made their way into the published research, searches were also performed using three Internet search engines. Specialized software was used to download search results and thus mitigate the potential pitfalls of changing search algorithms. RESULTS: A total of 188 research papers met the inclusion criteria. Global positioning systems were the most widely used location technology in the published research, followed by wearable cameras, and radio-frequency identification. Internet search engines identified 81 global positioning systems, 35 real-time locating systems, and 21 wearable cameras. Real-time locating systems determine the indoor location of a wearable tag via the known location of reference nodes. Although the type of reference node and location determination method varies between manufacturers, Wi Fi appears to be the most popular method. CONCLUSIONS: The addition of location information to existing measures of physical activity and sedentary behavior will provide important behavioral information. PMID- 26245159 TI - Age, subjective stress, and depression after ischemic stroke. AB - The incidence of stroke among younger adults in the United States is increasing. Few studies have investigated the prevalence of depressive symptoms after stroke among different age groups or the extent to which subjective stress at the time of stroke interacts with age to contribute to post-stroke depression. The present study examined whether there exists an age gradient in survivors' level of depressive symptoms and explored the extent to which financial, family, and health-related stress may also impact on depression. Bivariate analyses (N = 322) indicated significant differences in depression and stress by age group, as well as differences in age and stress by 3-month depression status. Linear regression analyses indicated that survivors between the ages of 25-54 and 55-64 years old had, on average, significantly higher depressive symptom scores. Those with financial, family, and health-related stress at the time of stroke, irrespective of age, also had significantly higher scores. PMID- 26245160 TI - Dyadic associations between cancer-related stress and fruit and vegetable consumption among colorectal cancer patients and their family caregivers. AB - This study examined how stress from cancer affects fruit and vegetable consumption (FVC) in cancer patients and their family caregivers during the year following diagnosis. Colorectal cancer patients and their caregivers (92 dyads) completed questionnaires at two (T1), six (T2), and 12 months post-diagnosis (T3). Individuals reported perceived cancer-related stress (CRS) at T1 and days of adequate FVC at T1 through T3. Both patients and caregivers reported inadequate FVC during the first year post-diagnosis. Latent growth modeling with actor-partner interdependence modeling revealed that, at T1, one's own greater CRS was associated with one's partner having fewer concurrent days of adequate FVC (ps = .01). Patients' greater CRS predicted their own more pronounced rebound pattern in FVC (p = .01); both patients' and caregivers' CRS marginally predicted their partners' change in FVC (p = .09). Findings suggest that perceived stress from cancer hinders FVC around the diagnosis, but motivates positive dietary changes by the end of the first year. PMID- 26245161 TI - Contribution of CD24 polymorphisms to autoimmune disease: A meta-analysis. AB - PURPOSE: To determine the relationship between two CD24 polymorphisms, rs8734/rs52812045 and rs3838646, and autoimmune disease. DESIGN: Meta-analysis. METHODS: The Medline, EMBASE, Web of Science, and Cochrane Library databases were searched for studies reporting the association between CD24 polymorphisms and autoimmune disease. Two of the authors selected eligible studies and extracted and analyzed the data independently. RESULTS: Compared with carriers of the C allele (CC, CT, CT+CC), individuals homozygous for the T allele (TT) and heterozygous (CT+TT) at rs8734/rs52812045 have a higher incidence of autoimmune disease, whereas rs3838646 is not associated with autoimmune disease. Subgroup analysis found an increased risk of multiple sclerosis with the TT vs. CC, TT vs. CT, and TT vs. CC+CT alleles. CONCLUSION: The CD24 polymorphism rs8734/rs52812045 contributes to the development of autoimmune disease. PMID- 26245162 TI - Guidelines are essential to improving clinical outcomes in breast cancer patients. PMID- 26245163 TI - Reply: To PMID 25581113. PMID- 26245164 TI - Is There a Benefit to Modularity in 'Simpler' Femoral Revisions? AB - BACKGROUND: Modular revision femoral components allow the surgeon to make more precise intraoperative adjustments in anteversion and sizing, which may afford lower dislocation rates and improved osseointegration, but may not offer distinct advantages when compared with less expensive monoblock revision stems. QUESTIONS/PURPOSES: We compared modular and monoblock femoral components for revision of Paprosky Type I to IIIA femoral defects to determine (1) survivorship of the stems; and (2) complications denoted as intraoperative fracture, dislocation, or failure of osseointegration. METHODS: Between 2004 and 2010, participating surgeons at three centers revised 416 total hip arthroplasties (THAs) with Paprosky Type I to IIIA femoral defects. Of those with minimum 2-year followup (343 THAs, mean followup 51 +/- 13 months), 150 (44%) were treated with modular stems and 193 (56%) were treated with monoblock, cylindrical, fully porous-coated stems. During this time, modular stems were generally chosen when there was remodeling of the proximal femur into retroversion and/or larger canal diameters (usually > 18 mm). A total of 27 patients died (6%) with stems intact before 2 years, 46 THAs (13%) were lost to followup before 2 years for reasons other than death, and there was no differential loss to followup between the study groups. The modular stems included 101 with a cylindrical distal geometry (67%) and 49 with a tapered geometry (33%). Mean age (64 versus 68 years), percentage of women (53% versus 47%), and body mass index (31 versus 30 kg/m(2)) were not different between the two cohorts, whereas there was trend toward a slightly greater case complexity in the modular group (55% versus 65% Type 3a femoral defects, p = 0.06). Kaplan-Meier survivorship was calculated for the endpoint of aseptic revision. Proportions of complications in each cohort (dislocation, intraoperative fracture, and failure of osseointegration) were compared. RESULTS: Femoral component rerevision for any reason (including infection) was greater (OR, 2.01; 95% CI, 1.63-2.57; p = 0.03) in the monoblock group (27 of 193 [14%]) compared with the modular cohort (10 of 150 [7%]). Femoral component survival free from aseptic rerevision was greater in the modular group with 91% survival (95% CI, 89%-95%) at 9 years compared with 86% survival (95% CI, 83%-88%) for the monoblock group in the same timeframe. There was no difference in the proportion of mechanically relevant aseptic complications (30 of 193 [16%] in the monoblock group versus 34 of 150 [23%] in the modular group, p = 0.10; OR, 1.47; 95% CI, 0.86-2.53). There were more intraoperative fractures in the modular group (17 of 150 [11%] versus nine of 193 [5%]; OR, 2.2; 95% CI, 1.68-2.73; p = 0.02). There were no differences in the proportions of dislocation (13 of 193 [7%] monoblock versus 14 of 150 [9%] modular; OR, 0.96; 95% CI, 0.67-1.16; p = 0.48) or failure of osseointegration (eight of 193 [4%] monoblock versus three of 150 [2%] modular; OR, 1.92; 95% CI, 0.88-2.84; p = 0.19) between the two groups with the number of hips available for study. CONCLUSIONS: Although rerevisions were less common in patients treated with modular stems, aseptic complications such as intraoperative fractures were more common in that group, and the sample was too small to evaluate corrosion related or fatigue concerns associated with modularity. We cannot therefore conclude from this that one design is superior to the other. Larger studies and pooled analyses will need to be performed to answer this question, but we believe modularity should be avoided in more straightforward cases if possible. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26245165 TI - Can a Conical Implant Successfully Address Complex Anatomy in Primary THA? Radiographs and Hip Scores at Early Followup. AB - BACKGROUND: Total hip arthroplasty (THA) in patients with small or abnormal proximal femoral anatomy is challenging as a result of complex anatomic deformities in the hip. It is unclear which stem is the most appropriate for these patients. One possible implant design that may help meet this need is the modified Wagner Cone prosthesis, whose design consists of monoblock cone with splines; however, to our knowledge, no clinical results have been published using this implant. QUESTIONS/PURPOSES: We evaluated the hip scores and radiographic results (including signs of osseointegration and subsidence) of complex primary THA using the modified Wagner Cone cementless femoral component in patients with small or abnormal proximal femoral anatomic proportions. METHODS: Between 2006 and 2011, we performed 59 THAs on patients whose femoral geometry precluded the use of standard-sized implants. Of these, 49 (83%) received the modified Wagner Cone prosthesis. During this time, our indications for use of the Wagner Cone implant in such patients included: femoral neck retroversion, excessive anteversion of the femoral neck, or small proximal femora not suitable for standard implants. Of those, 40 patients with 49 THAs were available for radiographic and clinical followup at a minimum of 3 years, and no patients were lost to followup. The diagnosis included developmental dysplasia of hip (22 patients, 28 hips), secondary trauma or posttuberculosis osteoarthritis (nine patients, 10 hips), and hip disease secondary to other disorders (eight patients, nine hips) and osteonecrosis (one patients, two hips). Two versions of the stem with 135 degrees (28 hips) or 125 degrees (21 hips) neck angle versions were used to reestablish normal hip biomechanics. Version angle was chosen based on preoperative templating. Cementless cups with screws were used for the acetabulum. Mean followup was 4 years (range, 3-7 years). Study endpoints were the Harris hip score and radiographic evaluations by a surgeon not involved in the clinical care of the patients (QZ); radiographic analysis included evaluating for the presence or absence of signs of osseointegration (including Engh's criteria) and subsidence. RESULTS: The Harris hip score improved from a mean of 41 +/- 9 preoperatively to a mean of 85 +/- 10 at last followup (p < 0.01). The mean vertical subsidence was 1.5 +/- 1.1 mm. Radiographic evaluation demonstrated stability (no further subsidence) of all implants at last followup. Endosteal spot welds were found in 32 hips (65%). No progressive radiolucencies were observed. One patient (one hip) underwent revision surgery as a result of late infection; no other revisions were performed. CONCLUSIONS: The modified Wagner Cone femoral stem has provided improvements in hip scores and promising short term radiographic results at short-term followup in complex cementless THA associated with abnormal or small femoral anatomical proportions in which standard implants are inappropriate. Longer followup will be needed to see if these results endure. Randomized trials are needed to determine the optimal stem design for these patients. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26245166 TI - THA revisions using impaction allografting with mesh is durable for medial but not lateral acetabular defects. AB - BACKGROUND: Most acetabular revisions are managed with cementless hemispherical or elliptical metal implants relying on bone ingrowth. Nonetheless, loss of acetabular bone stock and inability to achieve secure component fixation represent challenges in the setting of revision total hip arthroplasty. Impaction bone grafting (IBG) using allograft represents one option for treatment of this problem. However, cup migration and bone graft resorption are limitations when IBG is used for large segmental defects, and the precise role of IBG as well as the use of mesh (and the kinds of defects for which mesh does not work well) in this setting remains unknown. QUESTIONS/PURPOSES: We therefore evaluated patients undergoing acetabular revision surgery using IBG and a cemented cup in large bone defects to determine (1) the frequency with which the hip center could be restored in hips with Paprosky 3A and 3B defects and in hips with or without the use of metallic mesh during surgery; (2) survivorship of IBG acetabular-revision reconstructions in patients with severe Paprosky 3A and 3B defects; and (3) risk factors for failure of the reconstruction, including the use of mesh and defect severity (3A versus 3B). METHODS: Between 1997 and 2009, we performed 226 acetabular revisions using IBG. During that time, indications for using IBG in this setting included Paprosky 3A and 3B defects without pelvic discontinuity. Of these, 204 (90.2%) were available for followup at a minimum of 5 years (mean, 10 years; range, 5-17 years). There were 100 hips with an intraoperative bone defect of Paprosky 3A and 104 with a 3B. Medial or rim acetabular uncontained defects were treated with medial and/or lateral metallic mesh in 142 hips. We determined the postoperative radiological cup position and acetabular reconstruction of the hip center according to Ranawat in both groups. We assessed the appearance of cup loosening and the possible risk factors with regression analysis. RESULTS: Mean postoperative acetabular abduction angle and vertical, horizontal, and hip rotation center distances improved (p < 0.001 in all parameters). Nine hips showed radiological loosening in the group with bone defect 3A and 16 in Group 3B. The survival rate for loosening at 15 years was 83% (95% confidence interval [CI], 71%-95%) for Group 3A and 73% (95% CI, 60%-84%) for Group 3B (p = 0.04). The survivorship for loosening when using mesh or not at 15 years was: no mesh 89% (95% CI, 74%-99%), medial mesh 85% (95% CI, 72%-97%), lateral mesh 80% (95% CI, 67%-91%), and medial and lateral meshes 54% (95% CI, 31%-76%) (p = 0.008). After controlling the most relevant confounding variables we found that the most important factor associated with loosening was lateral mesh use (p = 0.008; hazard ratio, 2.942; 95% CI, 1.328-6.516). CONCLUSIONS: IBG provides an improvement in reconstruction of the hip rotation center in acetabular revision surgery. Although results are good for contained or medial large defects, hips with a rim or lateral segmental defect may need other options for reconstruction of these challenging surgeries. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26245167 TI - Emergency Department Visits After Hand Surgery Are Common and Usually Related to Pain or Wound Issues. AB - BACKGROUND: As payment models shift toward a focus on value and reimbursement becomes increasingly tied to quality and patient experience, minimizing unexpected acute health needs has become a priority for both policymakers and clinical leaders. Despite recent emphasis on emergency department (ED) visits as a quality measure in surgery, little is known about the role of the ED in the early postoperative period after hand surgery. QUESTIONS/PURPOSES: The purpose of this study was to determine the rates, reasons, and factors associated with ED visits within 30 days of elective outpatient hand surgery. METHODS: Using our institutional database for 2009 through 2013, we assessed ED visit rates for 2332 patients undergoing carpal tunnel or trigger finger release. Medical records were manually reviewed to ascertain the primary reason for the ED visit. Multivariable logistic regression modeling was used to identify factors independently associated with ED use. RESULTS: A total of 67 patients (3%) experienced at least one ED visit within 30 days of hand surgery (carpal tunnel: 3%; trigger finger: 3%). Most visits (66%) occurred within the first 2 weeks of surgery, and 31% led to hospitalization. The most common reasons for ED visits were pain (18%) and wound issues (16%). Unmarried and medically infirm patients were more likely to visit the ED. CONCLUSIONS: ED visits after hand surgery are common, often related to the procedure, and potentially responsive to quality improvement initiatives. Targeted efforts to educate patients about pain management, wound care, and the expected course of recovery before surgery, together with close postoperative contact (eg, routine phone calls, facsimile correspondence by email, or secure messaging) may limit visits to the ED. LEVEL OF EVIDENCE: Level IV, prognostic study. PMID- 26245168 TI - Condensation agents determine the temperature-pressure stability of F-actin bundles. AB - Biological cells provide a large variety of rodlike filaments, including filamentous actin (F-actin), which can form meshworks and bundles. One key question remaining in the characterization of such network structures revolves around the temperature and pressure stabilities of these architectures as a way to understand why cells actively use proteins for forming them. The packing properties of F-actin in fascin- and Mg(2+) -induced bundles are compared, and significantly different pressure-temperature stabilities are observed because of marked differences in their nature of interaction, solvation, and packing efficiency. Moreover, differences are observed in their morphologies and disintegration scenarios. The pressure-induced dissociation of the actin bundles is reminiscent of a single unbinding transition as observed in other soft elastic manifolds. PMID- 26245169 TI - Influence of allelic Variations of hypoxia-related and DNA repair genes on patient outcome and toxicity in head and neck cancer treated with radiotherapy plus cetuximab. AB - Although cetuximab plus radiotherapy is a standard treatment for patients with inoperable head and neck squamous cell carcinoma (HNSCC), its efficacy varies greatly among individuals. To identify predictive markers of efficacy, we examined the effects of single nucleotide polymorphisms (SNPs) in hypoxia-related and DNA repair genes on the clinical outcome and occurrence of skin toxicity. We analyzed 61 consecutive patients with HNSCC for the presence of specific SNPs (HIF-1alpha, HIF-2alpha, HIF-1beta, VHL, FIH-1, XRCC1, and XRCC5). The results were then correlated with time to progression (TTP), overall survival (OS), and toxicity (epithelitis, mucositis, and folliculitis). The median TTP and OS were better in patients with severe vs mild mucositis (17 vs 7 months, p = 0.03; and 26 vs 12 months, p = 0.016, respectively) and folliculitis (10 vs 7 months, p = 0.01, and 26 vs 10 months, p < 0.001, respectively). Patients with the HIF-1alpha CT/TT genotype had better OS than those with the wild-type HIF-1alpha CC genotype (28 vs 13 months, p = 0.035). Patients with the XRCC5 GG/AA genotype had longer TTP than patients with the XRCC5 AG genotype (11 vs 7 months, p = 0.035). Severe skin toxicity and SNPs of HIF-1alpha and XRCC5 were associated with different outcomes among patients treated with radiotherapy plus cetuximab. PMID- 26245171 TI - Functional low vision in adults from Latin America: findings from population based surveys in 15 countries. AB - OBJECTIVE: To review data on functional low vision (FLV) (low vision-visual acuity (VA) < 6/18 (<20/60) to > perception of light (PL+) in the better eye-that is untreatable and uncorrectable) in adults aged 50 years or older from published population-based surveys from 15 countries in Latin America and the Caribbean. METHODS: Data from 15 cross-sectional, population-based surveys on blindness and visual impairment (10 national and five subnational) covering 55 643 people > 50 years old in 15 countries from 2003 to 2013 were reanalyzed to extract statistics on FLV. Eleven of the studies used the rapid assessment of avoidable blindness (RAAB) method and four used the rapid assessment of cataract surgical services (RACSS) method. For the 10 national surveys, age-and sex-specific prevalence of FLV was extrapolated against the corresponding population to estimate the total number of people > 50 years old with FLV. RESULTS: Age- and sex-adjusted prevalence of FLV in people > 50 years old ranged from 0.9% (Guatemala, Mexico, and Uruguay) to 2.2% (Brazil and Cuba) and increased by age. The weighted average prevalence for the 10 national surveys was 1.6%: 1.4% in men and 1.8% in women. For all 10 national studies, a total of 509 164 people > 50 years old were estimated to have FLV. Based on the 910 individuals affected, the main causes of FLV were age-related macular degeneration (weighted average prevalence of 26%), glaucoma (23%), diabetic retinopathy (19%), other posterior segment disease (15%), non-trachomatous corneal opacities (7%), and complications after cataract surgery (4%). CONCLUSIONS: FLV is expected to rise because of 1) the exponential increase of this condition by age, 2) increased life expectancy, and 3) the increase in people > 50 years old. These data can be helpful in planning and developing low vision services for the region; large countries such as Brazil and Mexico would need more studies. Prevention is a major strategy to reduce FLV, as more than 50% of it is preventable. PMID- 26245170 TI - Systematic review of the impact of sacral neuromodulation on clinical symptoms and gastrointestinal physiology. AB - BACKGROUND: Sacral neuromodulation (SNM) has emerged as a treatment option for faecal incontinence (FI). However, its objective effect on symptoms and anorectal function is inconsistently described. This study aimed to systematically review the impact of SNM on clinical symptoms and gastrointestinal physiology in patients with FI, including factors that may predict treatment outcome. METHODS: An electronic search of MEDLINE (1946-2014)/EMBASE database was performed in accordance with PRISMA guidelines. Articles that reported the relevant outcome measures following SNM were included. Clinical outcomes evaluated included: frequency of FI episodes, FI severity score and success rates. Its impact on anorectal and gastrointestinal physiology was also evaluated. RESULTS: Of 554 citations identified, data were extracted from 81 eligible studies. Meta-analysis of the data was precluded due to lack of a comparison group in most studies. After permanent SNM, 'perfect' continence was noted in 13-88% of patients. Most studies reported a reduction in weekly FI episodes (median difference of the mean -7.0 (range: -24.8 to -2.7)) and Wexner scores (median difference of the mean -9 (-14.9 to -6)). A trend towards improved resting and squeeze anal pressures and a reduction in rectal sensory volumes were noted. Studies failed to identify any consistent impact on other physiological parameters or clinicophysiological factors associated with success. CONCLUSION: SNM improves clinical symptoms and reduces number of incontinence episodes and severity scores in patients with FI, in part by improving anorectal physiological function. However, intervention studies with standardized outcome measures and physiological techniques are required to robustly assess the physiological impact of SNM. PMID- 26245172 TI - [Gender inequity in health in contexts of environmental risk from mining and industrial activity in Mexico]. AB - OBJECTIVE: Analyze how gender inequity manifests in contexts of poverty in different environmental risk scenarios in Mexico. METHODS: Qualitative design based on six discussion groups and 54 in-depth interviews with women from six exposed communities: two to environmental manganese in a mining district, two in an industrial corridor, and two bordering a sanitary landfill. A document review of environmental and health studies in each area was done to relate them to the women's perspective on the problem. RESULTS: In the three case studies, by gender roles, women stay at home and do housework and, therefore, are subject to intense environmental exposure when carrying out their daily tasks, such as house cleaning. Interview and discussion group results were found to be related to epidemiological study results. In the case of the mining district, women's perceptions are consistent with study comments on adverse cognitive effects of manganese exposure. In all three cases, there are serious limitations on women's political participation in environmental risk management. CONCLUSIONS: Due to conditions of inequity, women are highly exposed to environmental health risks and their social participation in solving environmental problems is quite limited. These results have social and environmental policy implications in the areas studied, especially with regard to risk assessment, management, and communication. PMID- 26245173 TI - [Strategies for development, follow-up, and assessment of care provided to women in the pregnancy-postnatal cycle]. AB - OBJECTIVE: To describe the development of a questionnaire for assessment of prenatal, birth, and postnatal care (Inventario de Avaliacao da Assistencia ao Pre-natal, Parto e Puerperio, IAAPPP), which was designed taking into consideration the experience of users of a public obstetric service. METHODS: This mixed methods research was performed in the city of Caico, state of Rio Grande do Norte, Brazil. The study consisted of two phases: in phase 1, focal groups were organized with 19 users of the health care system for identification of relevant issues for assessment of the pregnancy-postnatal cycle. The first draft of the questionnaire was also designed and tested for validity with seven of the 19 focal group participants; a second draft was produced and retested. In phase 2, the intra-class correlation coefficient was calculated to determine reproducibility. A pilot test was carried out to determine the applicability of the survey and the final version of the IAAPPP was developed. RESULTS: Based on the focal group discussions, the inventory was organized into four domains: 1) socioeconomic information, 2) obstetric history, 3) description of current obstetric experience and 4) assessment of follow-up. Domains 3 and 4 were subdivided into prenatal care, birthcare, postnatal care, and pregnancy-postnatal cycle. The answers of the women who evaluated the instrument for domain 4 were strongly correlated (>0.8), indicating reproducibility of the IAAPPP. CONCLUSIONS: The methodological model allowed us to identify needs and demands of women in the pregnancy-postnatal cycle, and allowed us to design a questionnaire that can be applied to other regions with similar sociocultural characteristics. PMID- 26245174 TI - [Impact of contraception counseling on choice of combined hormonal methods in Colombia]. AB - OBJECTIVE: Determine the impact of informed contraceptive counseling on choice of contraceptive method. METHODS: Multicenter descriptive study using before-and after evaluation in nine cities in Colombia. Women considering use of self administered combined hormonal methods at the time of consultation were invited to participate. They were asked about contraceptive method use and preference, following signing of informed consent. Later, they were given standardized medical advice on contraception and then asked again about contraceptive preference and reasons for their choice. RESULTS: The study enrolled 858 women. At the beginning of the study, 538 (62.7%) women were using the combined pill and 281 (32.8%) were not using any contraceptive method. Before receiving counseling, women showed a preference for the pill (62.7%), followed by the intravaginal ring (28.4%), and transdermal patch (14%). After counseling, preferences were as follows: pill (40.8%), intravaginal ring (31.5%), and transdermal patch (11.3%). After counseling, 32.5%, 26.8%, and 7.5% of those considering the pill, patch, and ring, respectively, changed their intended choice. Region of origin, employment status, desire to conceive a child in the future, and having a stable relationship showed a statistical relationship to choice of method. However, age, number of children, and level of education were not determining factors. CONCLUSIONS: Medical advice has an impact on choice of self-administered combined hormonal contraceptives, which helps women to use the method of their choice and improves adherence to the method in accordance with its particular conditions. PMID- 26245175 TI - [Analysis of age-period-cohort effect on breast cancer mortality in Brazil and regions]. AB - OBJECTIVE: To estimate the effect of age, period and birth cohort on mortality from breast cancer in Brazil and regions. METHODS: Data on mortality from breast cancer were analyzed for women aged > 30 years in Brazil and regions from 1980 to 2009. The effect of age, period, and birth cohort was calculated by Poisson regression model using estimable functions: deviations, curvatures and drift through the Epi library of R statistical software version 3.2.1. RESULTS: The mean mortality rate for the period was 22.3 per 100 000 women in Brazil. The highest rate was 32.4 deaths per 100 000 women in the South, and the lowest, 8.6 deaths per 100 000 women in the North. The analysis of birth cohorts showed a progressive increase in the risk of death in women born after the 1930s, except in the Southeast, where a decrease in relative risk was noted for this group. CONCLUSIONS: The analyses revealed a reduction in the risk of death from breast cancer in Brazil and in most regions for birth cohorts starting in the 1930s, and an increased in the risk of death starting in the 1990s until the period from 2000 to 2005. PMID- 26245176 TI - Health literature authored by nurses within the LAC region: a cross-sectional study. AB - OBJECTIVE: To analyze current trends and directions in Latin America and Caribbean (LAC) nursing research and identify areas that need development. METHODS: A search was conducted in PubMed and LILACS for studies published in English from 1 January 2008 to 26 June 2014 that met the inclusion criteria (health research conducted in the LAC region by authors with an explicit nursing affiliation working in a LAC country). Two reviewers assessed and extracted the data. RESULTS: More than 4 000 references met the inclusion criteria and 1 343 of those were published in English during the search time period. Although the research originated from 17 different countries, most of it was produced by Brazil. The majority of the studies were from academic institutions (67%), 23.9% involved multi-institutional collaboration, and 5.4% involved multi-country collaboration. Almost all of the studies (98%) were applied research and had a descriptive (55%) or qualitative (30%) design. The most prevalent topic was nursing care (23.4%). Health systems and services were the least studied topics. /About 25% of the studies contained some reference to United Nations Millennium Development Goals. CONCLUSIONS: The overwhelming majority of LAC countries rely on the scientific findings of a few leading countries in the region. Future directions should include the establishment of an agenda for the region and/or by country to define research priorities within the context of nursing practices. It is imperative for nurses to influence and conduct research in areas of policy and health systems and services given their important role in promoting, restoring, and maintaining health in individuals, and in helping to ensure universal access to health and universal health coverage. PMID- 26245177 TI - Moving toward universal access to health and universal health coverage: a review of comprehensive primary health care in Suriname. AB - OBJECTIVE: To provide an overview of comprehensive primary health care (CPHC) development and implementation in Suriname in peer-reviewed literature. METHODS: Building on work funded by the Teasdale-Corti Global Health Research Partnership Program/People's Health Movement, the authors searched MEDLINE, the Cochrane Library, and POPLINE for articles focused on CPHC within the Surinamese context. Two authors independently reviewed abstracts and then jointly reviewed the selected abstracts. The final selection was completed using a data extraction form. RESULTS: The initial search resulted in 1 556 abstracts. The initial review identified 58 articles. Only three of the 58 articles met the inclusion criteria for the final review. The three selected articles provided partial overviews of CPHC in Suriname and examples of its implementation, with a focus on the service delivery network in the interior of the country, which was designed to improve rural access to basic health care services by training community members as service providers. They also included examples of how preparations for health reform in Suriname in the late 1990s and early 2000s, influenced by global neoliberal reforms, led to expectations that disparities in health status, design of health system components, and service provision related to differences in power and historical context (e.g., the influence of medical professionals, political parties/ethnic groups, and wealthier populations concentrated in urban areas) would be addressed. CONCLUSIONS: Given the focus on primary health care in the Americas and the notable developments that have occurred in Surinamese health policy and health care, particularly in health care reform, the paucity of published research on CPHC in Suriname was an unexpected finding that may be partly due to prioritizing research on disease control rather than health policy and systems research. The limited amount of scientific literature on this topic 1) prevents clear understanding of CPHC development and implementation in Suriname and 2) underscores the need to strengthen the national health research system to better inform policies for moving the country toward universal health access and coverage to improve the health of all of its citizens. PMID- 26245178 TI - Gestational syphilis and stillbirth in the Americas: a systematic review and meta analysis. AB - OBJECTIVE: To perform a systematic review and meta-analysis of reported estimates of the association between gestational syphilis (GS) and stillbirth in the Americas region. METHODS: Cochrane Library, Embase, LILACS, MEDLINE/PubMed, PLOS, and ScienceDirect were searched for original research studies quantifying the relationship between GS and stillbirth in the region. A final sample of eight studies was selected. A cumulative meta-analysis plus four subgroup meta-analyses of study data on the association between maternal syphilis during pregnancy and stillbirth were conducted. The four meta-analyses were based on 1) definition of cases and the control; 2) syphilis treatment (presence or absence, effective or ineffective); 3) definition of stillbirth as "showing no signs of life at birth"; and 4) definition of stillbirth based on low birth weight and gestational age. Random-effects metaanalyses were used to calculate pooled estimates of stillbirth with exposure to GS, and each subgroup analysis was tested for heterogeneity. RESULTS: Women with GS had increased odds of stillbirth (pooled odds ratio (OR): 6.87; 95% confidence interval: 2.93, 16.08). There was considerable heterogeneity across the eight studies (percentage of variance (I2) = 95). The funnel plot was not statistically significant, pointing to a lack of publication bias. Increased odds of stillbirth among pregnant women with syphilis were also seen in all four subgroup meta-analyses. CONCLUSIONS: GS is a major contributing factor for stillbirths in the Americas. Interventions targeting GS are highly cost-effective and, along with high-quality point-of-care testing, should be implemented across the region to help reach the goal of eliminating congenital syphilis. PMID- 26245179 TI - Regulatory transparency: social, technical, and ethical aspects of clinical trial data access. AB - In the field of health regulation, enabling public access to data from clinical trials is a process currently undergoing consolidation by the principal regulators worldwide. This paper discusses recent developments in public policy regarding regulatory transparency, and the risks and benefits of a regulatory impact-analysis on clinical trial reports, from the perspective of the key stakeholders (i.e., patients, prescribers, government, society, industry, and regulators). Additionally, the social, technical, and ethical aspects of the datasharing process are highlighted, including access limits, commercially confidential data and patent rights, privacy of research subjects, arrangements and publicity tools, and clinical trials registration. Furthermore, perspectives on improvement and expansion of regulatory transparency policies are presented, contextualizing North American, Latin American, and European experiences, and highlighting in-teragency cooperation and collaboration initiatives that aim to harmonize health programs and regulatory convergence. PMID- 26245180 TI - A comprehensive protocol to evaluate the use of blood and its components in Latin America and the Caribbean. AB - Blood transfusion safety is a critical part of appropriate health care. Considering the limited information available on the use of blood and its components in Latin America and the Caribbean, the Grupo Cooperativo iberoamericano de Medicina Transfusional (Ibero-American Cooperative Group for Transfusion Medicine; GCIAMT), through its Research and International Affairs committees, carried out a project to develop a protocol that would facilitate the evaluation of blood usage at the country, jurisdiction, and institutional levels in varied country contexts. Experts in blood safety from the Pan American Health Organization (Washington, DC, United States), the University of Sao Paulo (Sao Paulo, Brazil), the Hemocentro of Sao Paulo (Sao Paulo, Brazil), and GCIAMT designed a 2-step comprehensive blood-use evaluation protocol: step 1 collects data from blood requests, and step 2, from medical charts. At a minimum, 1 000 analyzed requests are necessary; as such, study periods vary depending on the number of transfusion requests issued. An Internet-based application, the Modular Research System-Study Management System (MRS-SMS), houses the data and produces reports on how hospitals request blood, how blood is issued, who requires blood and blood components, and as an added benefit, how many blood units are wasted and what the real demand for blood is. PMID- 26245181 TI - [Urgent need to expand and adjust the offer of HIV screening in Ecuador]. PMID- 26245182 TI - [The Association Between Food Prices and the Blood Glucose Level of US Adults With Type 2 Diabetes]. AB - OBJECTIVES: We estimated the association between the price of healthy and less healthy food groups and blood sugar among US adults with type 2 diabetes. METHODS: We linked 1999-2006 National Health and Nutrition Examination Survey health information to food prices contained in the Quarterly Food-at-Home Price Database. We regressed blood sugar levels on food prices from the previous calendar quarter, controlling for market region and a range of other covariates. We also examined whether the association between food prices and blood sugar varies among different income groups. RESULTS: The prices of produce and low-fat dairy foods were associated with blood sugar levels of people with type 2 diabetes. Specifically, higher prices for produce and low-fat dairy foods were associated with higher levels of glycated hemoglobin and fasting plasma glucose 3 months later. Food prices had a greater association with blood sugar for low income people than for higher-income people, and in the expected direction. CONCLUSIONS: Higher prices of healthy foods were associated with increased blood sugar among people with type 2 diabetes. The association was especially pronounced among low-income people with type 2 diabetes. PMID- 26245184 TI - Polyaniline-nanodiamond fibers resulting from the self-assembly of nano-fibrils: a nanomechanical study. AB - Based on atomic force microscopy (AFM), torsional harmonics atomic force microscopy (TH-AFM, also referred to with the commercial name HarmoniXTM) allows one to perform a quantitative characterization of the mechanical properties of soft samples on the nanometer scale. In this work, such a technique has been employed to study the mechanical properties of self-assembled micrometric fibers of polyaniline (PANI) doped with nanodiamond (ND) particles and to investigate the role of ND in the assembly. In particular, besides PANI-ND fibers, other features, i.e., nano-fibrils and blobs, have also been observed on the sample, the mechanical properties of which have been determined and compared after correcting for the effect of the substrate and of the cylindrical geometry of nano-fibrils. Their similar mechanical properties suggest that PANI-ND micro fibers are constituted by self-assembly of nano-fibrils. Finally, the combination of nanomechanical characterization with energy dispersive X-ray (EDX) and Raman analyses allowed us to determine that softer blobs are residuals of amorphous PANI not polymerized in nano-fibrils. PMID- 26245183 TI - Computational Modeling of Subdural Cortical Stimulation: A Quantitative Spatiotemporal Analysis of Action Potential Initiation in a High-Density Multicompartment Model. AB - OBJECTIVE: Computational modeling studies were performed to identify presynaptic elements of cortical neurons that are activated by subdural electrical stimulation. MATERIALS AND METHODS: The computer model consists of layers of multicompartmental neurons arranged in 3D space in an anatomically realistic fashion inside a 4.8 * 4.8 * 3.4 mm volume of gray matter modeled as a homogenous and isotropic medium. The model was subjected to an electric field generated by a circular disk electrode. RESULTS: The initiation of presynaptic action potentials (PAPs) in neurons takes place predominantly in the axon initial segment (AIS) or ectopically in axonal branch terminals. PAPs that were initiated in only one axonal terminal were typically followed by a second PAP (spike duplet) resulting from the activation of the AIS by the antidromically propagating initial PAP. There were significant time delays (up to 0.5 ms) in the propagation of these ectopically initiated PAPs along the axons to nonactivated axonal branches and, associated with these delays, latencies in the occurrence of spike duplets in different axonal terminals. The effect of the dendritic arbor 3D structure on the AIS activation threshold was contingent on whether the net axonal and somato dendritic current flows made an antagonistic or synergetic contribution. CONCLUSIONS: This study examines the effects of subdural electrical stimulation on a high-density network consisting of several populations of multicompartment cell types. The effect of dendritic arbor structure on the axonal activation threshold is prominent in the case of multipolar neurons with large-diameter symmetric dendrites (basal/apical) that are oriented parallel to the electric field lines. The timing of presynaptic terminal activation after stimulation is not determined solely by the axonal delay (orthodromic propagation) but depends on the details of the applied stimulation field and axonal branching structure, which may be important factors in characterizing the effects of electrical stimulation in neuromodulation systems. PMID- 26245185 TI - Contaminants of Emerging Concern in Bats from the Northeastern United States. AB - We analyzed bat carcasses (Myotis lucifugus, M. sodalis, M. septentrionalis, and Eptesicus fuscus) from the northeastern United States for contaminants of emerging concern (CECs) such as polybrominated diphenyl ethers (PBDEs), and pharmaceuticals and personal care products. The CECs detected most frequently in samples were PBDEs (100 %), salicylic acid (81 %), thiabendazole (50 %), and caffeine (23 %). Other compounds detected in at least 15 % of bat samples were digoxigenin, ibuprofen, warfarin, penicillin V, testosterone, and N,N-diethyl meta-toluamide (DEET). The CECs present at the highest geometric mean wet weight concentrations in bat carcasses were bisphenol A (397 ng/g), SigmaPDBE congeners 28, 47, 99, 100, 153, and 154 (83.5 ng/g), triclosan (71.3 n/g), caffeine (68.3 ng/g), salicylic acid (66.4 ng/g), warfarin (57.6 ng/g), sulfathiazole (55.8 ng/g), tris(1-chloro-2-propyl) phosphate (53.8 ng/g), and DEET (37.2 ng/g). Bats frequently forage in aquatic and terrestrial habitats that may be subjected to discharges from wastewater-treatment plants, agricultural operations, and other point and nonpoint sources of contaminants. This study shows that some CECs are accumulating in the tissue of bats. We propose that CECs detected in bats have the potential to affect a number of physiological systems in bats including hibernation, immune function, and response to white-nose syndrome, a fungal disease causing population-level impacts to bats. PMID- 26245186 TI - Fatty acids from fat cell lipolysis do not activate an inflammatory response but are stored as triacylglycerols in adipose tissue macrophages. AB - AIMS/HYPOTHESIS: Activation of macrophages by fatty acids (FAs) is a potential mechanism linking obesity to adipose tissue (AT) inflammation and insulin resistance. Here, we investigated the effects of FAs released during adipocyte lipolysis on AT macrophages (ATMs). METHODS: Human THP-1 macrophages were treated with media from human multipotent adipose-derived stem (hMADS) adipocytes stimulated with lipolytic drugs. Macrophages were also treated with mixtures of FAs and an inhibitor of Toll-like receptor 4, since this receptor is activated by saturated FAs. Levels of mRNA and the secretion of inflammation-related molecules were measured in macrophages. FA composition was determined in adipocytes, conditioned media and macrophages. The effect of chronic inhibition or acute activation of fat cell lipolysis on ATM response was investigated in vivo in mice. RESULTS: Whereas palmitic acid alone activates THP-1, conditioned media from hMADS adipocyte lipolysis had no effect on IL, chemokine and cytokine gene expression, and secretion by macrophages. Mixtures of FAs representing de novo lipogenesis or habitual dietary conditions also had no effect. FAs derived from adipocyte lipolysis were taken up by macrophages and stored as triacylglycerol droplets. In vivo, chronic treatment with an antilipolytic drug did not modify gene expression and number of ATMs in mice with intact or defective Tlr4. Stimulation of adipocyte lipolysis increased storage of neutral lipids by macrophages without change in number and phenotype. CONCLUSIONS/INTERPRETATION: Our data suggest that adipocyte lipolysis does not activate inflammatory pathways in ATMs, which instead may act as scavengers of FAs. PMID- 26245187 TI - Modulation of inflammatory mediators in the trigeminal ganglion by botulinum neurotoxin type A: an organ culture study. AB - BACKGROUND: Onabotulinumtoxin type A (BoNT-A) has been found to reduce pain in chronic migraine. The aim of the present study was to ask if BoNT-A can interact directly on sensory mechanisms in the trigeminal ganglion (TG) using an organ culture method. METHODS: To induce inflammation, rat TGs were incubated for 24 hrs with either the mitogen MEK1/2 inhibitor U0126, BoNT-A or NaCl. After this the TGs were prepared for immunohistochemistry. Sections of the TG were then incubated with primary antibodies against CGRP (neuronal transmitter), iNOS (inflammatory marker), IL-1beta (Interleukin 1beta), SNAP-25 (synaptic vesicle docking protein) or SV2-A (Botulinum toxin receptor element). RESULTS: We report that CGRP, iNOS, IL-1beta, SNAP-25 and SV2-A were observed in fresh TG with a differential distribution. Interestingly, NaCl organ culture of the TG resulted in enhanced expression of CGRP and SNAP-25 in neurons and iNOS in SGCs. Co incubation with U0126 or BoNT-A retained the increased expression of SNAP-25, while it decreased the IL-1beta immunoreactivity in neurons. The iNOS expression in SGCs returned to levels observed in fresh specimens. Moreover, we observed no alteration SV2-A expression in SGCs. Thus, the overall picture is that both U0126 and BoNT-A have the ability to modify the expression of certain molecules in the TG. CONCLUSION: We hypothesize that chronic migraine might be associated with some degree of inflammation in the TG that could involve both neurons and SGCs. It is clinically well recognized that treatment with corticosteroids will reduce the symptoms of chronic migraine; however this remedy is associated with long term side effects. Understanding the mechanisms involved in the expressional alterations may suggest novel ways to modify the changes and indicate novel therapeutics. The results of the present work illustrate one way by which BoNT-A may modify these expressional alterations. PMID- 26245189 TI - Reply: To PMID 25545846. PMID- 26245188 TI - Headache in epilepsy: prevalence and clinical features. AB - BACKGROUND: Headache and epilepsy are two relatively common neurological disorders and their relationship is still a matter of debate. Our aim was to estimate the prevalence and clinical features of inter-ictal (inter-IH) and peri ictal headache (peri-IH) in patients with epilepsy. METHODS: All patients aged >= 17 years referring to our tertiary Epilepsy Centre were consecutively recruited from March to May 2011 and from March to July 2012. They underwent a semi structured interview including the International Classification Headache Disorders (ICHD-II) criteria to diagnose the lifetime occurrence of headache.chi(2)-test, t-test and Mann-Whitney test were used to compare clinical variables in patients with and without inter-IH and peri-IH. RESULTS: Out of 388 enrolled patients 48.5 % had inter-IH: migraine in 26.3 %, tension-type headache (TTH) in 19.1 %, other primary headaches in 3.1 %. Peri-IH was observed in 23.7 %: pre-ictally in 6.7 %, ictally in 0.8 % and post-ictally in 19.1 %. Comparing patients with inter-ictal migraine (102), inter-ictal TTH (74) and without inter IH (200), we found that pre-ictal headache (pre-IH) was significantly represented only in migraineurs (OR 3.54, 95 % CI 1.88-6.66, P < 0.001). Post-ictal headache (post-IH) was significantly associated with both migraineurs (OR 2.60, 95 % CI 1.85-3.64, P < 0.001) and TTH patients (OR 2.05, 95 % CI 1.41-2.98, P < 0.001). Moreover, post-IH was significantly associated with antiepileptic polytherapy (P < 0.001), high seizure frequency (P = 0.002) and tonic-clonic seizures (P = 0.043). CONCLUSIONS: Migraine was the most represented type of headache in patients with epilepsy. Migraineurs are more prone to develop pre-IH, while patients with any inter-IH (migraine or TTH) are predisposed to manifest a post IH after seizures. PMID- 26245190 TI - Potential barrier height at the grain boundaries of a poly-silicon nanowire. AB - We present measurements of the potential barrier height and its dependence on grain size in poly-silicon nanowire (P-SiNW) arrays. Measurements conducted using Kelvin probe force microscopy coupled with electrostatic simulations, enabled us also to extract the density of the grain boundary interface states and their energy distribution. In addition it was shown that the barrier height scales with the grain size as the square of the grain radius. PMID- 26245191 TI - Clinical characteristics of Japanese patients with axial spondyloarthritis, and short-term efficacy of adalimumab. AB - BACKGROUND: Ankylosing spondylitis (AS) is rarer in Japan than in Europe, probably because the European criteria, not well known by Japanese general physicians, regard AS as a progressive stage of axial spondyloarthritis (SpA). HLA-B27 is an important diagnostic marker of SpA; however, the incidence of the HLA-B27 allele is as low as 0.4 % in Japan. For Japanese SpA patients, other HLA alleles and clinical findings are required for earlier definitive diagnosis, for determining appropriate treatment timing, and for disease monitoring. METHODS: We investigated the HLA-B alleles of 36 patients clinically diagnosed with SpA. For 8 axial SpA patients we evaluated the short-term efficacy of subcutaneous adalimumab injections (40 mg every other week for >=11 months). Treatment efficacy was evaluated by use of the Bath Ankylosing Spondylitis Activity Index (BASDAI) score, and serum TNF-alpha and IL-6 levels were measured pre and post treatment. RESULTS: Among the 36 Japanese SpA patients, the HLA-B27 allele occurred infrequently (5.6 %) whereas the HLA-B44 and 61 alleles were the most frequently detected (25.0 %). We also detected severe bamboo spine on radiography in the absence of the HLA-B27 allele. All 8 patients with axial SpA experienced significant symptom improvement after adalimumab treatment; the HLA-B27 allele was absent from these patients. Serum TNF-alpha and IL-6 levels were elevated in cases with remarkable inflammatory pain and high disease activity. These cytokines decreased after therapy, however. Most patients with normal cytokine levels at baseline retained these low levels. CONCLUSIONS: The findings reveal the short-term efficacy of adalimumab. The remarkably low incidence of HLA-B27 among our patients indicates that HLA-B distribution is different from that in other countries. Serum TNF-alpha and IL-6 levels were not effective as biomarkers for cases without high disease activity, and further research with larger samples is needed. The efficacy of TNF blockers, however, suggested a potential localized TNF effect was present among SpA patients. PMID- 26245192 TI - Parent-child attachment, academic performance and the process of high-school dropout: a narrative review. AB - Poor academic performance is a strong predictor of school dropout. Researchers have tried to disentangle variables influencing academic performance. However, studies on preschool and early care variables are seldom examined when explaining the school dropout process. We reviewed the literature on the relationship between caregiver-child attachment and academic performance, including attachment studies from preschool years, seeking out potential contributions to academic performance and the dropout process. The review was organized according to a model of four main mediating hypotheses: the attachment-teaching hypothesis, the social network hypothesis, the attachment-cooperation hypothesis, and the attachment self-regulation hypothesis. The results of the review are summed up in a model. There is some support for all four hypotheses. The review indicates that attachment and early care contribute substantially to dropout and graduation processes. Mediation effects should be given far more attention in future research. PMID- 26245193 TI - An application of meta-analysis based on DerSimonian and Laird method. PMID- 26245194 TI - Eighteen-year follow-up report of the surveillance and prevention of an HIV/AIDS outbreak amongst plasma donors in Hebei Province, China. AB - BACKGROUND: There has been a clear increase in HIV-1 infection cases in recent years in Hebei Province, China, and transmission via blood is one of the risk factors in the early. This article aimed to investigate the HIV infection rate and control efficiency among the paid blood donor population over a period of 18 years. METHODS: From 1995-2013, HIV/AIDS cases among former blood donors in Hebei Province were registered and closely monitored to collect data of all-cause mortality, intervention measures to prevent family transmission, disease transmission between couples as well as between mothers and infants, and HAART therapy outcomes. RESULTS: A total of 326 cases were identified as directly infected with HIV/AIDS during plasma donation in Hebei Province. Of these, 146 cases (44.8%) were identified in the same year as infection; 180 cases (55.2%) were identified 1-18 years after infection because they did not participate in the 1995 screening. The final case was identified in February 2012. By 2013, the mortality rate and survival rate of plasma donor-related HIV/AIDS was 54.9% and 45.1%, respectively. The identified transmission rate between couples was 11.3% (8/71); this rate during the same year as infection was 3.3% (1/30), and the rate 4-17 years after HIV infection was 17.1% (7/41). Approximately 91.2% (145/159) of married women of childbearing age did not have children after being informed of HIV infection. Only 8.8% (14/159) of these women had children after being informed of HIV infection. The mother-to-infant transmission rate was 38.5% (5/13). The HAART coverage rate has increased from 10.1% (16/159) in 2003 to 83.6% (127/152) in 2013. Since 1999, the HIV mortality rate has trended up; by 2013, the cumulative mortality rate reached 54.9% (179/326). After HAART was initiated in China, the death rate decreased to some extent. Second generation transmission (via couple or mother-to-infant transmission) among blood donor related HIV cases accounted for approximately 4.0% (13/326). All first- or second generation cases were infected with HIV-1 subtype B. CONCLUSIONS: In this accident of HIV-infection among plasma donors in Hebei Province, a total of 339 direct and second-generation cases have been identified over 18 years of monitoring. Favorable clinical results have been achieved using intervention measurements and antiviral therapy. PMID- 26245195 TI - Biomarkers of pulmonary hypertension in patients with scleroderma: a case-control study. AB - INTRODUCTION: Significant pulmonary vascular disease is a leading cause of death in patients with scleroderma, and early detection and early medical intervention are important, as they may delay disease progression and improve survival and quality of life. Although several biomarkers have been proposed, there remains a need to define a reliable biomarker of early pulmonary vascular disease and subsequent development of pulmonary hypertension (PH). The purpose of this study was to define potential biomarkers for clinically significant pulmonary vascular disease in patients with scleroderma. METHODS: The circulating growth factors basic fibroblast growth factor, placental growth factor (PlGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor, and soluble VEGF receptor 1 (sFlt-1), as well as cytokines (interleukin [IL]-1beta IL-2, IL-4, IL 5, IL-8, IL-10, IL-12, IL-13, tumor necrosis factor-alpha, and interferon-gamma), were quantified in patients with scleroderma with PH (n = 37) or without PH (n = 40). In non-parametric unadjusted analyses, we examined associations of growth factor and cytokine levels with PH. In a subset of each group, a second set of earlier samples, drawn 3.0+/-1.6 years earlier, were assessed to determine the changes over time. RESULTS: sFlt-1 (p = 0.02) and PlGF (p = 0.02) were higher in the PH than in the non-PH group. sFlt-1 (rho = 0.3245; p = 0.01) positively correlated with right ventricular systolic pressure. Both PlGF (p = 0.03) and sFlt-1 (p = 0.04) positively correlated with the ratio of forced vital capacity to diffusing capacity for carbon monoxide (DLCO), and both inversely correlated with DLCO (p = 0.01). Both PlGF and sFlt-1 levels were stable over time in the control population. CONCLUSIONS: Our study demonstrated clear associations between regulators of angiogenesis (sFlt-1 and PlGF) and measures of PH in scleroderma and that these growth factors are potential biomarkers for PH in patients with scleroderma. Larger longitudinal studies are required for validation of our results. PMID- 26245196 TI - Controlled human malaria infection by intramuscular and direct venous inoculation of cryopreserved Plasmodium falciparum sporozoites in malaria-naive volunteers: effect of injection volume and dose on infectivity rates. AB - BACKGROUND: Controlled human malaria infection (CHMI) by mosquito bite is a powerful tool for evaluation of vaccines and drugs against Plasmodium falciparum malaria. However, only a small number of research centres have the facilities required to perform such studies. CHMI by needle and syringe could help to accelerate the development of anti-malaria interventions by enabling centres worldwide to employ CHMI. METHODS: An open-label CHMI study was performed with aseptic, purified, cryopreserved P. falciparum sporozoites (PfSPZ Challenge) in 36 malaria naive volunteers. In part A, the effect of the inoculation volume was assessed: 18 participants were injected intramuscularly (IM) with a dose of 2,500 PfSPZ divided into two injections of 10 uL (n = 6), 50 uL (n = 6) or 250 uL (n = 6), respectively. In part B, the injection volume that resulted in highest infectivity rates in part A (10 uL) was used to formulate IM doses of 25,000 PfSPZ (n = 6) and 75,000 PfSPZ (n = 6) divided into two 10-uL injections. Results from a parallel trial led to the decision to add a positive control group (n = 6), each volunteer receiving 3,200 PfSPZ in a single 500-uL injection by direct venous inoculation (DVI). RESULTS: Four/six participants in the 10-uL group, 1/6 in the 50-uL group and 2/6 in the 250-uL group developed parasitaemia. Geometric mean (GM) pre-patent periods were 13.9, 14.0 and 15.0 days, respectively. Six/six (100%) participants developed parasitaemia in the 25,000 and 75,000 PfSPZ IM and 3,200 PfSPZ DVI groups. GM pre-patent periods were 12.2, 11.4 and 11.4 days, respectively. Injection of PfSPZ Challenge was well tolerated and safe in all groups. CONCLUSIONS: IM injection of 75,000 PfSPZ and DVI injection of 3,200 PfSPZ resulted in infection rates and pre-patent periods comparable to the bite of five PfSPZ-infected mosquitoes. Remarkably, it required 23.4-fold more PfSPZ administered IM than DVI to achieve the same parasite kinetics. These results allow for translation of CHMI from research to routine use, and inoculation of PfSPZ by IM and DVI regimens. TRIAL REGISTRATION: ClinicalTrials.gov NCT01771848. PMID- 26245197 TI - Historical biogeography resolves the origins of endemic Arabian toad lineages (Anura: Bufonidae): Evidence for ancient vicariance and dispersal events with the Horn of Africa and South Asia. AB - BACKGROUND: The Arabian Peninsula is home to a unique fauna that has assembled and evolved throughout the course of major geophysical events, including the separation of the Arabian Plate from Africa and subsequent collision with Eurasia. Opportunities for faunal exchanges with particular continents occurred in temporally distinct periods, and the presence of African, Western Eurasian, and South Asian derived taxa on the Arabian Peninsula signifies the complexity of these historical biogeographic events. The six true toad species (family Bufonidae) endemic to Arabian Peninsula present a considerable taxonomic and biogeographic challenge because they are part of a global bufonid radiation, including several genera surrounding the Arabian Peninsula, and difficult to discriminate morphologically. As they could be derived from African, Western Eurasian, or South Asian toad groups, elucidating their evolutionary relationships has important implications for historical biogeography. Here, we analyze a global molecular data set of 243 bufonid lineages, with an emphasis on new sampling from the Horn of Africa, Western Eurasia, South Asia, and the Arabian Peninsula, to reconstruct the evolutionary relationships of the Arabian species. We produce a robust time-calibrated phylogeny to infer the biogeographic history of this group on and around the Arabian Peninsula. RESULTS: Our phylogenetic analyses indicate two of the endemic Arabian toad species, "Bufo" tihamicus and "Bufo" arabicus, evolved independently within the African genus Amietophrynus. We confirm the Arabian species Duttaphrynus dhufarensis is of South Asian origin, but do not find evidence for the Asian genus Duttaphrynus being present in the Horn of Africa, discrediting a previously proposed Asian bufonid dispersal event to Africa. We also do not find evidence of the African genus Amietophrynus occurring in South Asia, suggesting that unlike many other vertebrate taxa, toads have not used the Arabian Peninsula as a stepping-stone for trans-continental dispersal. Our divergence dating estimates strongly suggest the formation of the Red Sea drove simultaneous divergences between two of the Arabian species (A. tihamicus comb. nov. and A. arabicus comb. nov.) and their xclosest mainland African relatives in the Early Miocene. We estimate the divergence of D. dhufarensis with its closest South Asian relatives occurred in the mid to Late Miocene, suggesting the temporary or permanent land connections between the Arabian plate and Eurasia facilitated dispersal of this lineage to the Arabian Peninsula. CONCLUSIONS: The Arabian bufonid assemblage, despite being comparatively depauperate with respect to surrounding continents, exemplifies the faunal pattern of the Arabian Peninsula, namely being a complex admixture of African, Western Eurasian, and South Asian elements. The historical biogeographic patterns exhibited by Arabian toads and their allies are concordant with studies of other vertebrate taxa, building support for the role of major geological events in driving simultaneous vicariance and dispersal events around the Arabian Peninsula. Although many taxa or groups exhibiting disjunct Afro-Arabian distributions appear to have dispersed more recently from the Horn of Africa via a southern land bridge or overwater dispersal, both Amietophrynus tihamicus and A. arabicus likely represent true African relicts resulting from vicariance associated with the Red Sea formation, a pattern that so far is rare among the vertebrate species investigated. PMID- 26245198 TI - HMGB1: a novel protein that induced platelets active and aggregation via Toll like receptor-4, NF-kappaB and cGMP dependent mechanisms. AB - BACKGROUND: Thrombotic diseases are a group of prevalent and life-threatening diseases. Selective inhibition of pathological thrombosis holds the key to treat variety of thrombotic diseases. The pathological thrombosis can be induced by either tissue necrosis and deregulated inflammation. HMGB1, as an important proinflammatory cytokine and a late mediator, also involves on thrombosis disease. However, the underlying mechanisms are not fully understood. METHODS: Immunofluorescence, ELISA assay, Platelet Aggregation, Thromboelastogram (TEG) analyzes. Flow cytometric analysis and Western blot analysis were used to investigated the role of HMGB1 in platelet aggregation and obtained following observations. RESULTS: By doing so, we obtained the following observations: i) Highly purified HMGB1 recombinant protein induces platelet aggregation and secretion in a dose-dependent manner in the presence of serum. ii) Low concentration of extracellular HMGB1 could synergistically promote subthreshold concentration of collagen or thrombin induced platelet aggregation. iii) Extracellular HMGB1 promoted platelet aggregation in a platelet-expressed GPIIb/IIIa-dependent manner. iv) We proposed that extracellular HMGB1 seems to promote the phosphorylation of GPIIb/IIIa and subsequent platelet aggregation via TLR4/NF-kappaB and cGMP pathway. CONCLUSIONS: In this study, we provide evidence for the hypothesis that HMGB1 interact with platelet might play an important role in the haemostasis and thrombotic diseases. Our research might be provide an interesting avenue for the treatment of thrombotic diseases in the future. PMID- 26245199 TI - The trend of lead poisoning rate in Chinese population aged 0-18 years old: a meta-analysis. AB - BACKGROUND: Childhood lead poisoning is a public health problem gained widely attention for the health damage caused by lead exposure. Pediatrics defines lead poisoning as BLL of or higher than 10 MUg/dL, which leads to harmful effects in nervous system, hematological system and urinary system. This study investigates the percentage of 0-18 year old Chinese population with blood lead level (BLL) >=10 MUg/dL during 1990-2012 by searching epidemiologic studies from electronic database focused on BLL in mainland China. METHODS: Epidemiologic studies about BLL in China mainland between January 1990 and October 2012 were searched from electronic databases including CNKI, CBM disc, Wanfang Data, Pubmed and Medline. Data extraction, data analysis and risk of bias assessments were performed. RESULTS: Fifty-five articles were included in analysis containing 200,002 subjects, covering 19 provinces, autonomous regions and municipalities. The corrected pooled rate by trim and fill method under random effect model was 9 % (95 CI: 6 %, 12 %). The corrected pooled lead poisoning rate by trim and fill method was 28.1 % (95 % CI: 21.6 %, 34.6 %) from data published during 1990-2000, much higher than the rate during 2001-2005 (10.5 %, 95 % CI: 6.4 %, 14.5 %) and the rate during 2006-2012 (5.3 %, 95 % CI: 3.7 %, 7 %). The corrected pooled lead poisoning percentage in eastern zone (4.3 %, 95 % CI: 2 %, 6.6 %) was slightly lower than that in western zone (5.8 %, 95 % CI: 3.2 %, 8.5 %) and much lower than in central zone (8.5 %, 95 % CI: 4.9 %, 12.1 %). The corrected pooled rate of population living around mining area (70 %, 95 % CI: 62.7 %, 77.3 %) was much higher than that of population in urban area (9.6 %, 95 % CI: 7.1 %, 12.1 %), suburban area (23.6 %, 95 % CI: 17 %, 30.3 %), rural area (23.8 %, 95 % CI: 6.7 %, 40.9 %) and industrial area (57.5 %, 95 % CI: 28 %, 86.9 %). In male population, the corrected pooled rate (10 %, 95 % CI: 7 %, 13 %) was slightly higher than that in female population (7.7 %, 95 % CI: 5 %, 10.4 %). Considering different age groups, the lead poisoning prevalence gradually rose with the increase of age and reached peak level at preschool age, then declined slightly with age. CONCLUSION: This meta-analysis revealed lead exposure situation of Chinese population in recent decades which provide robust evidence for policy making. PMID- 26245200 TI - Science and engineering of nanodiamond particle surfaces for biological applications (Review). AB - Diamond has outstanding bulk properties such as super hardness, chemical inertness, biocompatibility, luminescence, to name just a few. In the nanoworld, in order to exploit these outstanding bulk properties, the surfaces of nanodiamond (ND) particles must be accordingly engineered for specific applications. Modification of functional groups on the ND's surface and the corresponding electrostatic properties determine their colloidal stability in solvents, formation of photonic crystals, controlled adsorption and release of cargo molecules, conjugation with biomolecules and polymers, and cellular uptake. The optical activity of the luminescent color centers in NDs depends on their proximity to the ND's surface and surface termination. In order to engineer the ND surface, a fundamental understanding of the specific structural features and sp(3)-sp(2) phase transformations on the surface of ND particles is required. In the case of ND particles produced by detonation of carbon containing explosives (detonation ND), it should also be taken into account that its structure depends on the synthesis parameters and subsequent processing. Thus, for development of a strategy of surface modification of detonation ND, it is imperative to know details of its production. In this review, the authors discuss ND particles structure, strategies for surface modification, electrokinetic properties of NDs in suspensions, and conclude with a brief overview of the relevant bioapplications. PMID- 26245201 TI - Double-stranded RNA evokes exacerbation in a mouse model of corticosteroid refractory asthma. AB - RNA viruses are a major cause of respiratory infections and are known to exacerbate asthma and other respiratory diseases. Our aim was to test the ability of poly(I:C) (polyinosinic:polycytidylic acid), a viral surrogate, to elicit exacerbation in a model of severe asthma driven by HDM (house dust mite) in FCA (Freund's complete adjuvant). Poly(I:C) was administered intranasally around the HDM challenge in FCA-HDM-sensitized animals. Changes in AHR (airway hyperresponsiveness), BALF (bronchoalveolar lavage fluid) inflammatory infiltrate, HDM-specific immunoglobulins and cytokine/chemokine release were evaluated at different points after the challenge. The effect of oral dexamethasone was also assessed. Exacerbation was achieved when poly(I:C) was administered 24 h before the HDM challenge and was characterized by enhanced AHR and an increase in the numbers of neutrophils, macrophages and lymphocytes in the BALF. Th1, Th2 and Th17 cytokines were also elevated at different time points after the challenge. Peribronchial and alveolar inflammation in lung tissue were also augmented. AHR and inflammatory infiltration showed reduced sensitivity to dexamethasone treatment. We have set up a model that mimics key aspects of viral exacerbation in a corticosteroid-refractory asthmatic phenotype which could be used to evaluate new therapies for this condition. PMID- 26245202 TI - Over the rainbow. AB - Shear stress in arteries, which is a measure of the force exerted by blood flow on the arterial wall, is associated with the location of lipid plaques that cause heart disease. In this study, a mathematical model of shear stress was combined with cross-sectional x-ray images of an artery taken using Computed Tomography (CT) scanning, allowing the authors to explore patterns of shearing stress and shed light on the role of arterial architecture in heart disease. PMID- 26245203 TI - Safe Zone for Medial Open-Wedge Supramalleolar Osteotomy of the Ankle: A Cadaveric Study. AB - BACKGROUND: The purpose of this present study was to determine the incidence of lateral cortical fracture depending on the plane of osteotomy in medial open wedge supramalleolar osteotomy (SMO) and to define a safe zone through which a medial open-wedge SMO could be performed with minimal risk of lateral cortical fracture. MATERIALS AND METHODS: Matched pairs of fresh-frozen human cadaver lower leg specimens were obtained from 7 males and 3 females (average age = 63.9 [range 49-75] years). In group A, a safe zone-level medial open-wedge SMO (plane of osteotomy oriented to the proximal one-third of the intrasyndesmosis) was performed, and in group B, a higher-level medial open-wedge SMO (plane of osteotomy oriented to the suprasyndesmosis) was performed. RESULTS: In group A, 7 of the 10 limbs had no lateral cortical fracture, and 3 had lateral cortical fracture, but all of the fractured limbs were stable during the medial open-wedge SMO procedure. In group B, 2 of 10 limbs had no lateral cortical fracture and 8 had lateral cortical fracture. Three of the 8 fractured limbs were stable, but 5 were unstable during the medial open-wedge SMO procedure. The incidence of lateral cortical fracture in group B was significantly higher compared to group A (P = .04). CONCLUSIONS: According to the present findings, lateral cortical fracture was less likely to occur when open-wedge SMO was at the plane of the proximal one-third of the intrasyndesmosis, the so-called "safe zone," than at the plane of the suprasyndesmosis. CLINICAL RELEVANCE: A safe zone for medial open-wedge SMO to prevent lateral cortical fracture during the medial open-wedge SMO procedure was identified. PMID- 26245204 TI - Entrenching an association between Islam, fear, and violence. PMID- 26245206 TI - Twenty top papers--the ones that got away and the results of the top six poll. PMID- 26245205 TI - Antidepressant medication use and trajectories of fasting plasma glucose, glycated haemoglobin, beta-cell function and insulin sensitivity: a 9-year longitudinal study of the D.E.S.I.R. cohort. AB - BACKGROUND: Use of antidepressants is seen to be a risk factor for type 2 diabetes, even though the underlying mechanisms remain unclear. We examined whether antidepressant use was associated with change in fasting plasma glucose, glycated haemoglobin (HbA1c), beta-cell function (HOMA2-%B) and insulin sensitivity (HOMA2-%S) over time. METHODS: Participants in the French D.E.S.I.R. cohort study included over 4700 men (48.1%) and women, free of diabetes, aged 30 65 years at baseline in 1994-96 (D.E.S.I.R. 0), who were followed for 9 years at 3-yearly intervals (D.E.S.I.R. 3, 1997-99; 6, 2000-02; 9, 2003-05). Antidepressant use, fasting plasma glucose, HbA1c, HOMA2-%B and HOMA2-%S were assessed concurrently at four medical examinations. Linear mixed models were used to examine the cross-sectional and longitudinal associations of time-dependent antidepressant use with changes in these four biological parameters. RESULTS: Mean fasting plasma glucose and HbA1c increased whereas HOMA2-%B and HOMA2-%S decreased over the follow-up. In a fully adjusted model, there were no differences in: mean fasting plasma glucose (beta = 0.01 mmol/l, P = 0.702); HbA1c (beta = 0.01 %, P = 0.738); HOMA2-%B (beta = 0.00, P = 0.812); or HOMA2-%S (beta =-0.01, P = 0.791) at baseline (1994-96) between antidepressant users and non-users. The interaction term with time also suggested no differences in the annual change in: fasting plasma glucose (beta = 0.00 mmol/l, P = 0.322); HbA1c (beta = 0.00 %, P = 0.496); HOMA2-%B (beta = 0.00, P = 0.609); or HOMA2-%S (beta = 0.00, P = 0.332) between antidepressant users and non-users. Similar associations were observed in analyses of type and cumulative use of antidepressants over follow-up. CONCLUSION: Our longitudinal data show that use of antidepressants is not associated with altered glucose metabolism, suggesting that the association between antidepressant use and diabetes reported by previous studies may not be causal. Detection bias or clinical ascertainment bias may account for much of this apparent association. PMID- 26245208 TI - Psychosocial Links Between Internet Use and Mental Health in Later Life: A Systematic Review of Quantitative and Qualitative Evidence. AB - Research on the role of information and communication technology (ICT) use for active aging is limited. The aim of this systematic review is to investigate the link between Internet use and mental health among older adults. The review was conducted based on searches in 9 electronic databases (2002-2014). A meta synthesis approach was applied, examining quantitative (18) and qualitative (14) studies. The findings from the synthesis of quantitative statistical data indicate an overall positive association between Internet use and mental health and its psychosocial covariates in later life. The psychosocial links between Internet use and mental health identified from the qualitative data were (a) enhanced interpersonal interaction at individual level, (b) increased access to resources within the community, and (c) empowered social inclusion at society level. The results highlight the multi-level psychosocial links between Internet use and mental health, which may be applied in initiatives targeting healthy aging in various settings. PMID- 26245207 TI - Potentiators of Defective DeltaF508-CFTR Gating that Do Not Interfere with Corrector Action. AB - Combination drug therapies under development for cystic fibrosis caused by the ?F508 mutation in cystic fibrosis transmembrane conductance regulator (CFTR) include a "corrector" to improve its cellular processing and a "potentiator" to improve its chloride channel function. Recently, it was reported that the approved potentiator N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4 dihydroquinoline-3-carboxamide (Ivacaftor) reduces ?F508-CFTR cellular stability and the efficacy of investigational correctors, including 3-(6-[([1-(2,2-difluoro 1,3-benzodioxol-5-yl)cyclopropyl]carbonyl) amino]-3-methyl-2-pyridinyl)-benzoic acid and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(1-[(2R)-2,3-dihydroxypropyl]-6 fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl), which might contribute to the modest reported efficacy of combination therapy in clinical trials. Here, we report the identification and characterization of potentiators that do not interfere with ?F508-CFTR stability or corrector action. High-throughput screening and structure-activity analysis identified several classes of potentiators that do not impair corrector action, including tetrahydrobenzothiophenes, thiooxoaminothiazoles, and pyrazole-pyrrole isoxazoles. The most potent compounds have an EC(50) for ?F508-CFTR potentiation down to 18 nM and do not reduce corrector efficacy in heterologous ?F508-CFTR expressing cells or primary cultures of ?F508/?F508 human bronchial epithelia. The DeltaF508-CFTR potentiators also activated wild-type and G551D CFTR, albeit weakly. The efficacy of combination therapy for cystic fibrosis caused by the ?F508 mutation may be improved by replacement of Ivacaftor with a potentiator that does not interfere with corrector action. PMID- 26245209 TI - The Manchester guidelines for contralateral risk-reducing mastectomy. AB - BACKGROUND: Rates of contralateral risk-reducing mastectomy (CRRM) are rising, despite a decreasing global incidence of contralateral breast cancer. Reasons for requesting this procedure are complex, and we have previously shown a variable practice amongst breast and plastic surgeons in England. We propose a protocol, based on a published systematic review, a national UK survey and the Manchester experience of CRRM. METHODS: We reviewed the literature for risk factors for contralateral breast cancer and have devised a 5-step process that includes history taking, calculating contralateral breast cancer risk, cooling off period/counselling, multi-disciplinary assessment and consent. Members of the multi-disciplinary team included the breast surgeon, plastic surgeon and geneticist, who formulated guidelines. RESULTS: A simple formula to calculate the life-time risk of contralateral breast cancer has been devised. This allows stratification of breast cancer patients into different risk-groups: low, above average, moderate and high risk. Recommendations vary according to different risk groups. CONCLUSION: These guidelines are a useful tool for clinicians counselling women requesting CRRM. Risk assessment is mandatory in this group of patients, and our formula allows evidence-based recommendations to be made. PMID- 26245213 TI - Clinical frailty syndrome assessment using inertial sensors embedded in smartphones. AB - The aim of this study was to identify the series of kinematic variables demonstrating the greatest precision in discriminating between the function of two groups of elderly persons (frail and non-frail) in the 10 m expanded timed up and go (ETUG) test using inertial sensors embedded in the iPhone 4((r)). A cross sectional study was conducted to identify the kinematic variables with the highest degree of precision in discriminating between the two groups. The predicted capability of the kinematic variables was evaluated using receiver operating characteristic curves. The sample comprised 30 participants over 65 years old, 14 frail and 16 non-frail, assessed for frailty syndrome using the Fried criteria. Acceleration variables discriminated between the participant groups in the study; specifically these were the peak negative acceleration variables for motion axes x, y and z. In terms of sensitivity, the values were greater than or equal to those for the variable traditionally used to discriminate in the ETUG test, namely time. The kinematic parameters obtained from the internal inertial sensors in the iPhone 4((r)) are promising additions to the ETUG analysis. There are encouraging signs that the analyses of these parameters in the separate phases of the ETUG procedure offer the potential for improved discrimination between frail and non-frail individuals. However, further in-depth study is required to verify the findings. PMID- 26245215 TI - Facial synkinesis as a first symptom of multiple sclerosis. AB - A 39-year-old woman was admitted to hospital because of a sensory hemisyndrome caused by a contrast-enhancing demyelinating lesion of the cervical cord. MRI, CSF examination and subsequent clinical and neuroradiological follow-up led to the diagnosis of multiple sclerosis. The patient had noticed an involuntary contraction of a small muscle fascicle on the right side of the chin for a year. Electromyographic and video recordings confirmed the synkinesis between the orbicularis oculi and lower facial muscles, a finding distinct from the myokymic discharges reported in multiple sclerosis and more similar to the synkinesis associated with hemifacial spasm. PMID- 26245214 TI - Adverse health behaviours are associated with depression and anxiety in multiple sclerosis: A prospective multisite study. AB - BACKGROUND: Depression and anxiety are common among people with multiple sclerosis (MS), as are adverse health behaviours, but the associations between these factors are unclear. OBJECTIVE: To evaluate the associations between cigarette smoking, alcohol use, and depression and anxiety in MS in a cross Canada prospective study. METHODS: From July 2010 to March 2011 we recruited consecutive MS patients from four MS clinics. At three visits over two years, clinical and demographic information was collected, and participants completed questionnaires regarding health behaviours and mental health. RESULTS: Of 949 participants, 75.2% were women, with a mean age of 48.6 years; most had a relapsing-remitting course (72.4%). Alcohol dependence was associated with increased odds of anxiety (OR: 1.84; 95% CI: 1.32-2.58) and depression (OR: 1.53; 95% CI: 1.05-2.23) adjusting for age, sex, Expanded Disability Status Scale (EDSS), and smoking status. Smoking was associated with increased odds of anxiety (OR: 1.29; 95% CI: 1.02-1.63) and depression (OR: 1.37; 95% CI: 1.04-1.78) adjusting for age, sex, EDSS, and alcohol dependence. Alcohol dependence was associated with an increased incidence of depression but not anxiety. Depression was associated with an increased incidence of alcohol dependence. CONCLUSION: Alcohol dependence and smoking were associated with anxiety and depression. Awareness of the effects of adverse health behaviours on mental health in MS might help target counselling and support for those 'at risk'. PMID- 26245216 TI - Implications of Infliximab Treatment Failure and Influence of Personalized Treatment on Patient-reported Health-related Quality of Life and Productivity Outcomes in Crohn's Disease. AB - BACKGROUND: This study assessed the effects of infliximab (IFX) treatment failure on patient-reported outcomes and explored the influence of using personalized treatment in this situation. METHODS: Sixty-nine Crohn's disease patients with IFX treatment failure were randomized to an intensified IFX regimen (n = 36) or personalized treatment defined by IFX and anti-IFX antibodies (n = 33). Health related quality of life evaluated with the Short Inflammatory Bowel Disease Questionnaire (IBDQ) and productivity evaluated with the Work Productivity and Activity Impairment Questionnaire (WPAI:CD) were assessed at treatment failure and after 4, 8, 12 and 20 weeks. RESULTS: Median IBDQ score at manifestation of IFX treatment failure was 40 and improved markedly in responders by 11 at weeks 4 and 8 (p < 0.001) and by 13 at weeks 12 and 20 (p < 0.001). Non-responders improved modestly at weeks 12 and 20 (increase of median 4, p < 0.05). Overall activity impairment was high at IFX failure (median 70%) and decreased substantially in responders (40-50%, p < 0.001) and to a lesser extent in non responders (15-40%, p < 0.05). In employed patients (55%), absenteeism was negligible during the entire study period. However, median presenteeism was 40% at manifestation of IFX failure and decreased only among responders across time (decrease 10-30%, p < 0.05). Although anti-tumour necrosis factor (TNF) therapy was discontinued in most patients handled by personalized treatment, IBDQ and WPAI:CD scores were similar in these patients compared with patients routinely dose-intensified on IFX. CONCLUSION: Regaining low disease activity after IFX failure is necessary for minimizing patient impairment and indirect disease related costs. A personalized treatment strategy does not have a negative influence on patient-reported outcomes. PMID- 26245217 TI - Development of Fibrosis in Acute and Longstanding Ulcerative Colitis. AB - BACKGROUND: Intestinal fibrosis is a process driven by chronic inflammation leading to increased presence of myofibroblasts and collagen deposition. Although strictures are rarely seen in ulcerative colitis [UC], longstanding disease is believed to cause fibrosis resulting in altered bowel function. METHODS: The presence of fibrosis was studied in colectomy specimens from patients with recent onset UC refractory to medical treatment [n = 13] and longstanding UC [n = 16], and colon cancer patients without UC [n = 7] as controls. Severity of inflammation was scored according to the Geboes score on haematoxylin and eosin stainings. Immunohistochemistry was performed to detect alpha-smooth muscle actin, fibronectin and collagen I and III. RESULTS: Colectomy specimens from patients with acute UC showed significantly more inflammation than those with longstanding disease [19 vs 9 points, p = 0.01]. Both acute and longstanding UC showed a thicker muscularis mucosa than controls [0.10 vs 0.10 vs 0.05 mm, respectively, p = 0.019]. An increase in collagen I and III deposition in the mucosa was observed in UC compared with controls (40% [30-75] vs 25% [10-25], p = 0.033), but this did not differ significantly among acute and longstanding UC patients. CONCLUSIONS: Collagen deposition is enhanced in UC compared with controls. However, UC collagen deposition does not increase significantly over time and does not seem to aggravate the entire fibrotic process. PMID- 26245219 TI - Post-Mating Sexual Behaviors of Oriental Storks (Ciconia boyciana) in Captivity. AB - Parental behaviors that vary by sex and breeding stage facilitate the survival of offspring in birds. Females invest in reproducing according to the level of direct and/or indirect benefits provided by males. Males face trade-offs from defending territories or nests, providing for the young, and seeking additional mating opportunities. We examined whether post-mating sexual behaviors such as courtship display and nest-building were associated with reproductive investments made by males and females in the current study. The oriental stork (Ciconia boyciana) is known as a solitary breeder that nests in tall trees and provides biparental care with long post-hatching development. We filmed parental behaviors in seven stork pairs in captivity for 655 hours (245 hours during nest-building, 218 hours during incubation, 328 hours during nestling, and 192 hours during the fledgling period). We found that paired mating behaviors such as synchronous allopreening and bill-clattering were highly skewed to the pre-incubation period. Males participated in nest-building more than females although both sexes shared similar parental care during the incubation and nestling period. Male nest building was negatively correlated with male nest attentiveness only during the nestling period. Our results suggest that male oriental storks with higher nest building effort might spend more time taking precautions against conspecific intruders or nest predators near the nests with chicks while the females were attending the nests in the form of biparental care. PMID- 26245218 TI - Regulation of Steroidogenesis, Development, and Cell Differentiation by Steroidogenic Factor-1 and Liver Receptor Homolog-1. AB - Steroidogenic factor-1 (SF-1) and liver receptor homolog-1 (LRH-1) belong to the nuclear receptor superfamily and are categorized as orphan receptors. In addition to other nuclear receptors, these play roles in various physiological phenomena by regulating the transcription of target genes. Both factors share very similar structures and exhibit common functions. Of these, the roles of SF-1 and LRH-1 in steroidogenesis are the most important, especially that of SF-1, which was originally discovered and named to reflect such roles. SF-1 and LRH-1 are essential for steroid hormone production in gonads and adrenal glands through the regulation of various steroidogenesis-related genes. As SF-1 is also necessary for the development of gonads and adrenal glands, it is also considered a master regulator of steroidogenesis. Recent studies have clearly demonstrated that LRH-1 also represents another master regulator of steroidogenesis, which similarly to SF-1, can induce differentiation of non-steroidogenic stem cells into steroidogenic cells. Here, we review the functions of both factors in these steroidogenesis-related phenomena. PMID- 26245220 TI - Effects of Visual Cues of a Moving Model Predator on Body Patterns in Cuttlefish Sepia pharaonis. AB - We examined the effects of predator-prey distance (PPD) and trajectory of the predator on the body patterns that the pharaoh cuttlefish, Sepia pharaonis, shows in response to a predator. A model predator moving in three different trajectories was presented to the cuttlefish: T1, approached the cuttlefish but bypassed above; T2, approached directly toward the cuttlefish; T3, bypassed the cuttlefish both vertically and horizontally. We divided the body patterns that the cuttlefish expressed into seven categories, i.e., "uniform light", "disruptive", "center circle", "dark square", "vertical stripe", "all dark" and "eyespots". In T1, the number of individuals that showed "dark square" increased as the model approached the cuttlefish, whereas the number of individuals that showed "disruptive" decreased. In T2, the number of individuals that showed "all dark" and "eyespots" increased as the model approached the cuttlefish. In T3, the number of individuals that showed "dark square" and "vertical stripe" increased as the model approached the cuttlefish, and it tended to decrease as the model receded from the cuttlefish. These results demonstrate that S. pharaonis changes its body patterns according to PPD and the trajectory of the predator, which would affect predation risk and/or predator perception. PMID- 26245221 TI - Lectin-Based Profiling of Coelomocytes in Holothuria scabra and Expression of Superoxide Dismutase in Purified Coelomocytes. AB - Coelomocytes are the first line of immune defense in marine animals. Their distributions are greatly variable even in the close animal species. In this study, we used lectin staining to aid in the classification and purification of these cells for further investigation of SOD distribution among coelomocytes of H. scraba. We classified coelomocytes into four types: type 1, lymphocytes; type 2, phagocytes; type 3, spherulocytes; and type 4, giant cells. Among four lectins used, Con A appeared to give a broad reactivity against most coelomocytes, except for giant cells. In addition, phagocytes usually engaged the highest fluorescent intensity with most lectins, with the exception of PNA, for which spherulocytes possessed the highest fluorescent intensity. Using FACS for fraction collection, it was found that F1 fraction contained the purest phagocyte population (> 95%), which was highly reactive with anti- superoxide dismutase (SOD) as revealed by immunoblotting and immunofluorescence staining, although some minor staining was also detected in spherulocytes. Our results thus provide a fundamental platform for comparing alterations that may happen to the population and SOD contents of coelomocytes when the sea cucumber is subjected to environmental changes that would activate their immune responses. PMID- 26245222 TI - Phylogeographic Study of Whip Scorpions (Chelicerata: Arachnida: Thelyphonida) in Japan and Taiwan. AB - Whip scorpions (Thelyphonida), comprising an order in the class Arachnida, are distributed from tropical to temperate zones. Two species occur exclusively in Japan and Taiwan, but the border of their distributional ranges is ambiguous in the Central Ryukyus (Japan). We collected new specimens from the Central Ryukyus and revealed that the border of distribution of the two species lies between the Central and Southern Ryukyus, i.e., the Kerama Gap. Moreover, the estimated divergence time (15.8 Mya) of the two species, based on the mitochondrial COI gene, was older than the recently estimated time (1.55 Mya) of formation of the Kerama Gap. These results highlight the risks of a priori assumption solely on the basis of geological data for applying it as a calibration point to some terrestrial animals in this region. Typopeltis stimpsonii was genetically divided into four lineages, two of which turned out to be endemic to the Okinawa Islands. All specimens from the main island of Japan and Shikoku were in one lineage, which was also found in the Amami Islands and Hachijojima Island. This suggests that these specimens may have been dispersed by human activity. Typopeltis crucifer included five genetic lineages. Species collected from Ishigakijima and Iriomotejima Islands were genetically diversified not between the borders of these islands but within Ishigakijima Island. This study also suggests that phylogenetic diversity of the species in the Southern Ryukyus have increased through two times of invasions from Taiwan. PMID- 26245223 TI - Interpopulation Comparison of Sex-Biased Mortality and Sexual Size Dimorphism in Sea-Run Masu Salmon, Oncorhynchus masou. AB - Evolutionary ecologists often expect that natural and sexual selection result in systematic co-occurrence patterns of sex-biased mortality and sexual size dimorphism (SSD) within animal species. However, whether such patterns actually occur in wild animals is poorly examined. The following expectation, the larger sex suffers higher mortality, was primarily tested here for apparently native sea run masu salmon (Oncorhynchus masou) in three populations in Hokkaido, Japan. Field surveys on sex ratios, body sizes, and ages of smolts and returning adults revealed that two of the three populations exhibited an expected pattern, a female-biased marine mortality and SSD, but one population demonstrated an unexpected co-occurrence of male-biased marine mortality and female-biased SSD. These female-biased SSDs were attributed to faster marine growth of females because of no sex difference in smolt body size. It has been previously suggested that breeding selection favoring large size generally act more strongly in females than in males in Japanese anadromous masu, as there is a weak sexual selection on adult males but universally intensive natural selection on adult females. Thus, this hypothesis explains female-biased SSDs well in all study populations. Interpopulation variation in sex-biased mortality found here might result from differences in marine predation and/or fishing pressures, given that selection driving female-biased SSD makes females forage more aggressively than males during the marine phase. Taken together, these results raise the possibility that evolutionary forces have shaped adaptive sex-specific foraging strategies under relationships between growth and mortality, resulting in co occurrence patterns of sex-biased mortality and SSD within animal species. PMID- 26245224 TI - Synchronous and Non-Synchronous Semelparity in Sibling Species of Pulmonates. AB - Diverse life histories have been documented in terrestrial pulmonates, which inhabit different regions in climate. Life history traits are often phenotypically plastic and vary depending on the environment. Thus, surveys using designs that control for the confounding effects of environment are needed to evaluate the evolutionary differences between populations of closely related species in the wild. We examined the life histories of sibling species of terrestrial pulmonate within two regions of similar climates. Bradybaena pellucida (BP) is endemic to Japanese islands, and has recently been expanding its distribution northeastward, whereas B. similaris (BS) has been introduced by humans into temperate and tropical regions worldwide. We found that these species exhibit discrete differences in population dynamics and life cycle, despite their close relatedness. The annual life cycle of BP is synchronized among individuals in a population. Thus, BP is univoltine with discontinuous generation. In contrast, BS individuals do not synchronize their growth or reproduction, and thus exhibit overlapping generations. Our results indicate that synchronized and non-synchronized population dynamics diverge relatively rapidly in semelparous pulmonates. This type of difference has not been documented in pulmonate life history, and may have been overlooked because only a few studies have explicitly compared life cycles of closely related species within the same climate. Our results provide a basis for further studies of life history evolution in pulmonates. PMID- 26245225 TI - Unionid Freshwater Mussels in Irrigation Ditches are Affected by Physical Environmental Factors and Proximity to Paddy Fields. AB - Irrigation ditches are the major habitat of lotic unionid mussels in Japan. To conserve and rebuild irrigation ditches facilitating mussel conservation, suitable physical environments must be clarified. The effect on mussels of paddy fields connected to ditches also needs to be determined. In this study, physical environmental factors that affect the density of unionid mussels were studied in irrigation ditches in Hikone City, Shiga Prefecture, Japan, to examine whether mussel densities were higher around paddy fields. Generalized linear models were used to analyze physical and paddy field environmental variables affecting mussel density. Our results show that sediment type, sediment softness, water depth, and flow velocity of irrigation ditches affect the density of unionid mussels; the effects of each environment factor and their relative importance differed by species. Specifically, the density of Nodularia douglasiae biwae was higher in ditches with sand-gravel sediment, soft sediment, and not adjoining paddy fields. The density of Pronodularia japanensis was higher in ditches with sand-gravel sediment and not adjoining paddy fields. The density of Lanceolaria grayana was higher in ditches with high flow velocity, not adjoining paddy fields, close to Lake Biwa. The density of Sinanodonta japonica was higher in ditches with mud sediment, shallow depth, high flow velocity, and not adjoining paddy fields. The densities of all four species were lower in irrigation ditches that were closely connected to paddy fields, suggesting that paddy drainage water negatively affects the survival of the mussels. PMID- 26245226 TI - Histochemical Characterization of Oocytes in the Pink Cuskeel (Genypterus blacodes). AB - In the present study we histochemically and lectinhistochemically characterized the growing oocytes of the pink cuskeel (Genypterus blacodes). We used histochemical methods for the localization and characterization of glycoconjugates (GCs) and lectin histochemical techniques for the identification of specific sugar residues. We analyzed presence and distribution of GCs in the different structures of the growing follicles (cortical alveoli, globules, yolk granules and zona radiata). During the initial stage of vitellogenesis, the oocytes presented small yolk granules composed of GCs that gradually increased during exogenous vitellogenesis. These GCs contained moderate quantities of alpha D-mannose, D-glucose, N-acetylglucosamine and N-acetyl-neuraminic acid. The cortical alveoli contained both neutral and carboxylated GCs, and lectin techniques detected N-acetylgalactosamine, galactose and L-fucose. The zona radiata showed a strong positive reaction to PAS and it reacted weakly with more specific techniques, such as KOH/PA*S and PA/Bh/KOH/PAS. This structure showed GCs with oxidizable vicinal diols, O-acyl sugars and sialic acid residues with different substitution types and presented N-acetylgalactosamine and L-fucose specific residues. The oocytes follicular envelope evidenced neutral and acidic non-sulfated GCs and high concentrations of alpha-D-mannose, D-glucose, galactose and N-acetylgalactosamine. The intergranular cytoplasmic GCs were mainly rich in alpha-D-mannose, D-glucose, N-acetylgalactosamine, N-acetylglucosamine and N acetyl-neuraminic acid. These results enhance the comprehension of the structure and functionality of the pink cuskeel ovarian follicles, and provide a useful tool for the study of this tissue in other teleost species. PMID- 26245227 TI - Fine Structure of the Integumentary Cuticles and Alimentary Tissues of Pycnophyid Kinorhynchs Pycnophyes oshoroensis and Kinorhynchus yushini (Kinorhyncha, Homalorhagida). AB - Integumentary and alimentary tissues were ultrastructurally examined in two pycnophyid kinorhynchs, Pycnophyes oshoroensis and Kinorhynchus yushini, to elucidate some aspects of their ecology. The body is entirely enveloped by an epicuticle layer with no gaps between cuticle plates and joints. The cuticular layer has a structure dense enough to prevent invasion by foreign organisms. The cuticular surface is overlaid by a mucus layer that may form a hydrophilic surface. The alimentary contents were heterogeneous, probably including some cellular components, such as chloroplast-like structures. Kinorhynchs likely break down food particles in the pharyngeal bulb by pressing it between the cuticulated epithelia. The pharyngeal crown was located in front of the pharyngeal bulb and had a thick wall with a striated sub-structure. Contraction of the pharyngeal bulb probably increases the internal pressure of the pharyngeal crown; this may be one reason for the thick wall of the pharyngeal crown. Nutrients appear to be taken up by midgut epithelial cells through both absorption via microvilli and endocytosis. Additionally, sperm tails in the testis of P. oshoroensis have unusual axonemes; i.e., an 18+9+2 pattern. PMID- 26245228 TI - Individual Flagellar Waveform Affects Collective Behavior of Chlamydomonas reinhardtii. AB - Bioconvection is a form of collective motion that occurs spontaneously in the suspension of swimming microorganisms. In a previous study, we quantitatively described the "pattern transition," a phase transition phenomenon that so far has exclusively been observed in bioconvection of the unicellular green alga Chlamydomonas. We suggested that the transition could be induced by changes in the balance between the gravitational and shear-induced torques, both of which act to determine the orientation of the organism in the shear flow. As both of the torques should be affected by the geometry of the Chlamydomonas cell, alteration in the flagellar waveform might change the extent of torque generation by altering overall geometry of the cell. Based on this working hypothesis, we examined bioconvection behavior of two flagellar mutants of Chlamydomonas reinhardtii, ida1 and oda2, making reference to the wild type. Flagella of ida1 beat with an abnormal waveform, while flagella of oda2 show a normal waveform but lower beat frequency. As a result, both mutants had swimming speed of less than 50% of the wild type. ida1 formed bioconvection patterns with smaller spacing than those of wild type and oda2. Two-axis view revealed the periodic movement of the settling blobs of ida1, while oda2 showed qualitatively similar behavior to that of wild type. Unexpectedly, ida1 showed stronger negative gravitaxis than did wild type, while oda2 showed relatively weak gravitaxis. These findings suggest that flagellar waveform, not swimming speed or beat frequency, strongly affect bioconvection behavior in C. reinhardtii. PMID- 26245229 TI - Trilobodrilus itoi sp. nov., with a Re-Description of T. nipponicus (Annelida: Dinophilidae) and a Molecular Phylogeny of the Genus. AB - The marine interstitial annelid Trilobodrilus itoi sp. nov., the sixth member of the genus, is described on the basis of specimens collected intertidally at Ishikari Beach, Hokkaido, Japan; this is the second species in the genus described from the Pacific Rim. In addition, T. nipponicus Uchida and Okuda, 1943 is re-described based on fresh topotypic material from Akkeshi, Hokkaido, Japan. From both species, we determined sequences of the nuclear 18S and 28S rRNA genes, and the mitochondrial cytochrome c oxidase subunit I (COI) gene. Molecular phylogenetic trees based on concatenated sequences of the three genes showed that T. itoi and T. nipponicus form a clade, which was the sister group to a clade containing the two European congeners T. axi Westheide, 1967 and T. heideri Remane, 1925. The Kimura two-parameter distance for COI was 22.5-22.7% between T. itoi and T. nipponicus, comparable with interspecific values in other polychaete genera. We assessed the taxonomic utility of epidermal inclusions and found that the known six species can be classified into three groups. PMID- 26245230 TI - Fibrillar cellular fibronectin supports efficient platelet aggregation and procoagulant activity. AB - The ability of cellular fibronectin, found in the vessel wall in a fibrillar conformation, to regulate platelet functions and trigger thrombus formation remains largely unknown. In this study, we evaluated how parietal cellular fibronectin can modulate platelet responses under flow conditions. A fibrillar network was formed by mechanically stretching immobilised dimeric cellular fibronectin. Perfusion of anticoagulated whole blood over this surface resulted in efficient platelet adhesion and thrombus growth. The initial steps of platelet adhesion and activation, as evidenced by filopodia extension and an increase in intracellular calcium levels (419 +/- 29 nmol/l), were dependent on integrins alpha5beta1 and alphaIIbbeta3. Subsequent thrombus growth was mediated by these integrins together with the GPIb-V-IX complex, GPVI and Toll-like receptor 4. The involvement of Toll-like receptor 4 could be conveyed via its binding to the EDA region of cellular fibronectin. Upon thrombus formation, the platelets became procoagulant and generated fibrin as revealed by video-microscopy. This work provides evidence that fibrillar cellular fibronectin is a strong thrombogenic surface which supports efficient platelet adhesion, activation, aggregation and procoagulant activity through the interplay of a series of receptors including integrins alpha5beta1 and alphaIIbbeta3, the GPIb-V-IX complex, GPVI and Toll like receptor 4. PMID- 26245231 TI - Street Food Environment in Maputo (STOOD Map): a Cross-Sectional Study in Mozambique. AB - BACKGROUND: Street food represents a cultural, social, and economic phenomenon that is typical of urbanized areas, directly linked with a more sedentary lifestyle and providing a very accessible and inexpensive source of nutrition. Food advertising may contribute to shaping consumers' preferences and has the potential to drive the supply of specific foods. OBJECTIVE: The purpose of this study is to characterize the street food offerings available to the urban population of Maputo, the capital city of Mozambique, and the billboard food advertising in the same setting. METHODS: People selling ready-to-eat foods, beverages, or snacks from venues such as carts, trucks, stands, and a variety of improvised informal setups (eg, shopping carts, trunks of cars, sides of vans, blankets on the sidewalk, etc) will be identified in the district of KaMpfumu. We will gather information about the actual food being sold through direct observation and interviews to vendors, and from the billboard advertising in the same areas. A second phase of the research entails collecting food samples to be analyzed in a specialized laboratory. The street food environment will be characterized, overall and according to socioeconomic and physical characteristics of the neighborhood, using descriptive statistics and spatial analysis. The study protocol was approved by the National Committee for Bioethics for Health in Mozambique. RESULTS: Data collection, including the identification of street food vending sites and billboard advertising, started on October 20, 2014, and lasted for 1 month. The collection of food samples took place in December 2014, and the bromatological analyses are expected to be concluded in August 2015. CONCLUSIONS: The district of KaMpfumu is the wealthiest and most urbanized in Maputo, and it is the area with the highest concentration and variety of street food vendors. The expected results may yield important information to assess the nutritional environment and the characteristics of the foods to which a great majority of the urban population living or working in Maputo are exposed. Furthermore, this study protocol provides a framework for a stepwise standardized characterization of the street food environment, comprising 3 steps with increasing complexity and demand for human and technical resources: Step 1 consists of the evaluation of food advertising in the streets; Step 2 includes the identification of street food vendors and the characterization of the products available; and Step 3 requires the collection of food samples for bromatological analyses. This structured approach to the assessment of the street food environment may enable within-country and international comparisons as well as monitoring of temporal trends. PMID- 26245233 TI - Thermodynamics of Fe3O4-Co3O4 and Fe3O4-Mn3O4 spinel solid solutions at the bulk and nanoscale. AB - High temperature oxide melt solution calorimetry has been performed to investigate the enthalpies of mixing (DeltamixH) of bulk and nanophase (1 x)Fe3O4-xM3O4 (M = Co, Mn) spinel solid solutions. The entropies of mixing (DeltamixS) were calculated from the configurational entropies based on cation distributions, and the Gibbs free energies of mixing (DeltamixG) were obtained. The DeltamixH and DeltamixG for the (1 -x)Fe3O4-xCo3O4 system are negative over the complete solid solution range, for both macroscopic and nanoparticulate materials. In (1 -x)Fe3O4-xMn3O4, the formation enthalpies of cubic Fe3O4 (magnetite) and tetragonal Mn3O4 (hausmannite) are negative for Mn3O4 mole fractions less than 0.67 and slightly positive for higher manganese content. Relative to cubic Fe3O4 and cubic Mn3O4 (stable at high temperature), the enthalpies and Gibbs energies of mixing are negative over the entire composition range. A combination of measured mixing enthalpies and reported Gibbs energies in the literature provides experimental entropies of mixing. The experimental entropies of mixing are consistent with those calculated from cation distributions for x > 0.3 but are smaller than those predicted for x < 0.3. This discrepancy may be related to the calculations, having treated Fe(2+) and Fe(3+) as distinguishable species. The measured surface energies of the (1 -x)Fe3O4 xM3O4 solid solutions are in the range of 0.6-0.9 J m(-2), similar to those of many other spinels. Because the surface energies are relatively constant, the thermodynamics of mixing at a given particle size throughout the solid solution can be considered independent of the particular particle size, thus confirming and extending the conclusions of a recent study on iron spinels. PMID- 26245232 TI - Low-noise encoding of active touch by layer 4 in the somatosensory cortex. AB - Cortical spike trains often appear noisy, with the timing and number of spikes varying across repetitions of stimuli. Spiking variability can arise from internal (behavioral state, unreliable neurons, or chaotic dynamics in neural circuits) and external (uncontrolled behavior or sensory stimuli) sources. The amount of irreducible internal noise in spike trains, an important constraint on models of cortical networks, has been difficult to estimate, since behavior and brain state must be precisely controlled or tracked. We recorded from excitatory barrel cortex neurons in layer 4 during active behavior, where mice control tactile input through learned whisker movements. Touch was the dominant sensorimotor feature, with >70% spikes occurring in millisecond timescale epochs after touch onset. The variance of touch responses was smaller than expected from Poisson processes, often reaching the theoretical minimum. Layer 4 spike trains thus reflect the millisecond-timescale structure of tactile input with little noise. PMID- 26245234 TI - Labile ruthenium(ii) complexes with extended phenyl-substituted terpyridyl ligands: synthesis, aquation and anticancer evaluation. AB - Ruthenium complexes have been considered as promising substitutes for cisplatin in cancer chemotherapy. However, novel ruthenium-based therapies are faced with some limitations, such as unimpressive cytotoxicity toward solid tumors. Herein, we designed and synthesized phenyl-substituted terpyridyl ruthenium(ii) complexes ([Ru(tpy)(bpy)Cl](+) (Ru1), [Ru(phtpy)(bpy)Cl](+) (Ru2) and [Ru(biphtpy)(bpy)Cl](+) (Ru3)) which exhibited distinctly different anticancer activity. Ru1-Ru3 all underwent moderate aquation in buffer solution and this process was significantly inhibited by high chloride concentration. Cancer cells were found to readily uptake the relatively hydrophobic Ru3, as quantified using inductively coupled plasma mass spectrometry (ICP-MS). Ru1 was found to be non cytotoxic (IC50 > 100 MUM) while Ru3 exhibited very promising cytotoxicity on both two-dimensional (2D) cancer cell monolayers and 3D MCTSs. An antiproliferative assay revealed that Ru3 significantly inhibited cellular DNA replication which ultimately induced apoptosis of cancer cells. PMID- 26245235 TI - Strontium ranelate analgesia in arthritis models is associated to decreased cytokine release and opioid-dependent mechanisms. AB - OBJECTIVE: We investigated the anti-inflammatory activity of strontium ranelate (SR) in arthritis models. MATERIALS AND METHODS: Rats received 1 mg zymosan (Zy) or saline intra-articularly. Other groups were subjected to anterior cruciate ligament transection in the right knee, as an osteoarthritis (OA) model, or a sham procedure. Joint pain was assessed using the articular incapacitation and paw-pressure tests. Cell influx and cytokines were measured in joint exudates. TREATMENT: Groups received either SR (30-300 mg/kg per os) or saline. RESULTS: SR dose-dependently and significantly inhibited joint pain in both Zy and OA models, while not altering cell influx. Naloxone administration significantly reversed SR analgesia. SR significantly reduced levels of Interleukin-1beta and tumor necrosis factor-alpha in Zy arthritis, whereas those of cytokine-induced neutrophil chemoattractant (CINC)-1 were not altered. CONCLUSIONS: SR provides analgesia in arthritis that is associated to inhibition of the release of inflammatory cytokines into inflamed joints. This effect is abrogated by administration of the opioid antagonist naloxone. PMID- 26245236 TI - DNA-hybrid-gated functional mesoporous silica for sensitive DNA methyltransferase SERS detection. AB - Mesoporous silica nanoparticles (MSNs) were used as a nano-carrier/amplifier to develop a novel MSN-SERS probe for DNA MTase detection. High sensitivity, good selectivity, and rapid analysis are achieved. PMID- 26245237 TI - Editorial 1/2016. PMID- 26245238 TI - In this issue: Ontologies a key concept in informatics and key for open definitions of cases, exposures, and outcome measures. PMID- 26245239 TI - An algorithm to improve diagnostic accuracy in diabetes in computerised problem orientated medical records (POMR) compared with an established algorithm developed in episode orientated records (EOMR). AB - BACKGROUND: An algorithm that detects errors in diagnosis, classification or coding of diabetes in primary care computerised medial record (CMR) systems is currently available. However, this was developed on CMR systems that are episode orientated medical records (EOMR); and do not force the user to always code a problem or link data to an existing one. More strictly problem orientated medical record (POMR) systems mandate recording a problem and linking consultation data to them. OBJECTIVE: To compare the rates of detection of diagnostic accuracy using an algorithm developed in EOMR with a new POMR specific algorithm. METHOD: We used data from The Health Improvement Network (THIN) database (N = 2,466,364) to identify a population of 100,513 (4.08%) patients considered likely to have diabetes. We recalibrated algorithms designed to classify cases of diabetes to take account of that POMR enforced coding consistency in the computerised medical record systems [In Practice Systems (InPS) Vision] that contribute data to THIN. We explored the different proportions of people classified as having type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) and with diabetes unclassifiable as either T1DM or T2DM. We compared proportions using chi-square tests and used Tukey's test to compare the characteristics of the people in each group. RESULTS: The prevalence of T1DM using the original EOMR algorithm was 0.38% (9,264/2,466,364), and for T2DM 3.22% (79,417/2,466,364). The prevalence using the new POMR algorithm was 0.31% (7,750/2,466,364) T1DM and 3.65% (89,990/2,466,364) T2DM. The EOMR algorithms also left more people unclassified 11,439 (12%), as to their type of diabetes compared with 2,380 (2.4%), for the new algorithm. Those people who were only classified by the EOMR system differed in terms of older age, and apparently better glycaemic control, despite not being prescribed medication for their diabetes (p < 0.005). CONCLUSION: Increasing the degree of problem orientation of the medical record system can improve the accuracy of recording of diagnoses and, therefore, the accuracy of using routinely collected data from CMRs to determine the prevalence of diabetes mellitus; data processing strategies should reflect the degree of problem orientation. PMID- 26245240 TI - Evaluating the usability of an interactive, bi-lingual, touchscreen-enabled breastfeeding educational programme: application of Nielson's heuristics. AB - The study purpose was to conduct heuristic evaluation of an interactive, bilingual touchscreen-enabled breastfeeding educational programme for Hispanic women living in rural settings in Nebraska. Three raters conducted the evaluation during May 2013 using principles of Nielson's heuristics. A total of 271 screens were evaluated and included: interface (n = 5), programme sections (n = 223) and educational content (n = 43). A total of 97 heuristic violations were identified and were mostly related to interface (8 violations/5 screens) and programme components (89 violations/266 screens). The most common heuristic violations reported were recognition rather than recall (62%, n = 60), consistency and standards (14%, n = 14) and match between the system and real world (9%, n = 9). Majority of the heuristic violations had minor usability issues (73%, n = 71). The only grade 4 heuristic violation reported was due to the visibility of system status in the assessment modules. The results demonstrated that the system was more consistent with Nielsen's usability heuristics. With Nielsen's usability heuristics, it is possible to identify problems in a timely manner, and help facilitate the identification and prioritisation of problems needing urgent attention at an earlier stage before the final deployment of the system. PMID- 26245241 TI - Structuring and coding in health care records: a qualitative analysis using diabetes as a case study. AB - BACKGROUND: Globally, diabetes mellitus presents a substantial and increasing burden to individuals, health care systems and society. Structuring and coding of information in the electronic health record underpin attempts to improve sharing and searching for information. Digital records for those with long-term conditions are expected to bring direct and secondary uses benefits, and potentially to support patient self-management. AIMS AND OBJECTIVES: We sought to investigate if how and why records for adults with diabetes were structured and coded and to explore a range of UK stakeholders' perceptions of current practice in the National Health Service. METHODS: We carried out a qualitative, theoretically informed case study of documenting health care information for diabetes in family practice and hospital settings in England, using semi structured interviews, observations, systems demonstrations and documentary data. RESULTS: We conducted 22 interviews and four on-site observations. With respect to secondary uses - research, audit, public health and service planning - interviewees clearly articulated the benefits of highly structured and coded diabetes data and it was believed that benefits would expand through linkage to other datasets. Direct, more marginal, clinical benefits in terms of managing and monitoring diabetes and perhaps encouraging patient self-management were also reported. We observed marked differences in levels of record structuring and/or coding between family practices, where it was high, and the hospital. We found little evidence that structured and coded data were being exploited to improve information sharing between care settings. CONCLUSIONS: Using high levels of data structuring and coding in records for diabetes patients has the potential to be exploited more fully, and lessons might be learned from successful developments elsewhere in the UK. A first step would be for hospitals to attain levels of health information technology infrastructure and systems use commensurate with family practices. PMID- 26245242 TI - Barriers and facilitators to health information exchange in low- and middle income country settings: a systematic review protocol. AB - INTRODUCTION: The ability to capture, exchange and use accurate information about patients and services is vital for building strong health systems, providing comprehensive and integrated patient care, managing public health risks and informing policies for public health and health financing. However, the organisational and technological systems necessary to achieve effective health information exchange are lacking in many low- and middle-income countries (LMIC). Developing strategies for addressing this depends on understanding the barriers and facilitators to health information exchange (HIE) at the individual, provider organisational, community, district, provincial and national levels. This systematic review aims to identify, critically appraise and synthesise the existing published evidence addressing these factors. OBJECTIVE: To assess what is known, from published/unpublished empirical studies, about barriers and facilitators to HIE in LMIC so as to identify issues that need to be addressed and approaches that can fruitfully be pursued in future improvement strategies. METHODS: We will conduct a systematic review to identify the empirical evidence base on the barriers and facilitators to HIE in LMIC. Two reviewers will independently search 11 major international and national databases for published, unpublished and in-progress qualitative, quantitative and mixed methods studies published during 1990-July 2014 in any language. These searches of scientific databases will be supplemented by the eligible reports available online. The included studies will be independently critically appraised using the Mixed Method Appraisal Tool, version 2011. A descriptive, narrative and interpretative synthesis of data will be undertaken. RESULTS: These will be presented in an article that will be published in the peerreviewed literature. The protocol is registered with the International Prospective Register for Systematic Reviews (PROSPERO) CRD 42014009826. PMID- 26245243 TI - Improving the measurement of longitudinal change in renal function: automated detection of changes in laboratory creatinine assay. AB - INTRODUCTION: Renal function is reported using the estimates of glomerular filtration rate (eGFR). However, eGFR values are recorded without reference to the particular serum creatinine (SCr) assays used to derive them, and newer assays were introduced at different time points across the laboratories in the United Kingdom. These changes may cause systematic bias in eGFR reported in routinely collected data, even though laboratory-reported eGFR values have a correction factor applied. DESIGN: An algorithm to detect changes in SCr that in turn affect eGFR calculation method was developed. It compares the mapping of SCr values on to eGFR values across a time series of paired eGFR and SCr measurements. SETTING: Routinely collected primary care data from 20,000 people with the richest renal function data from the quality improvement in chronic kidney disease trial. RESULTS: The algorithm identified a change in eGFR calculation method in 114 (90%) of the 127 included practices. This change was identified in 4736 (23.7%) patient time series analysed. This change in calibration method was found to cause a significant step change in the reported eGFR values, producing a systematic bias. The eGFR values could not be recalibrated by applying the Modification of Diet in Renal Disease equation to the laboratory reported SCr values. CONCLUSIONS: This algorithm can identify laboratory changes in eGFR calculation methods and changes in SCr assay. Failure to account for these changes may misconstrue renal function changes over time. Researchers using routine eGFR data should account for these effects. PMID- 26245244 TI - Health care provider perceptions of a query-based health information exchange: barriers and benefits. AB - BACKGROUND: Health information exchange (HIE) systems are implemented nationwide to integrate health information and facilitate communication among providers. The Nebraska Health Information Initiative is a state-wide HIE launched in 2009. OBJECTIVE: The purpose of this study was to conduct a comprehensive assessment of health care providers' perspectives on a query-based HIE, including barriers to adoption and important functionality for continued utilization. METHODS: We surveyed 5618 Nebraska health care providers in 2013. Reminder letters were sent 30 days after the initial mailing. RESULTS: A total of 615 questionnaires (11%) were completed. Of the 100 current users, 63 (63%) indicated satisfaction with HIE. The most common reasons for adoption among current or previous users of an HIE (N = 198) were improvement in patient care (N = 111, 56%) as well as receiving (N = 95, 48%) and sending information (N = 80, 40%) in the referral network. Cost (N = 233, 38%) and loss of productivity (N = 220, 36%) were indicated as the 'major barriers' to adoption by all respondents. Accessing a comprehensive patient medication list was identified as the most important feature of the HIE (N = 422, 69%). CONCLUSIONS: The cost of HIE access and workflow integration are significant concerns of health care providers. Additional resources to assist practices plan the integration of the HIE into a sustainable workflow may be required before widespread adoption occurs. The clinical information sought by providers must also be readily available for continued utilization. Query-based HIEs must ensure that medication history, laboratory results and other desired clinical information be present, or long term utilization of the HIE is unlikely. PMID- 26245245 TI - Using ontologies to improve semantic interoperability in health data. AB - The present-day health data ecosystem comprises a wide array of complex heterogeneous data sources. A wide range of clinical, health care, social and other clinically relevant information are stored in these data sources. These data exist either as structured data or as free-text. These data are generally individual person-based records, but social care data are generally case based and less formal data sources may be shared by groups. The structured data may be organised in a proprietary way or be coded using one-of-many coding, classification or terminologies that have often evolved in isolation and designed to meet the needs of the context that they have been developed. This has resulted in a wide range of semantic interoperability issues that make the integration of data held on these different systems changing. We present semantic interoperability challenges and describe a classification of these. We propose a four-step process and a toolkit for those wishing to work more ontologically, progressing from the identification and specification of concepts to validating a final ontology. The four steps are: (1) the identification and specification of data sources; (2) the conceptualisation of semantic meaning; (3) defining to what extent routine data can be used as a measure of the process or outcome of care required in a particular study or audit and (4) the formalisation and validation of the final ontology. The toolkit is an extension of a previous schema created to formalise the development of ontologies related to chronic disease management. The extensions are focused on facilitating rapid building of ontologies for time critical research studies. PMID- 26245246 TI - On the characteristic equation lambda = alpha1 + (alpha2 + alpha3lambda)e( lambda) and its use in the context of a cell population model. AB - In this paper we characterize the stability boundary in the (alpha1, alpha2) plane, for fixed alpha3 with -1 < alpha3 < +1, for the characteristic equation from the title. Subsequently we describe a nonlinear cell population model involving quiescence and show that this characteristic equation governs the (in)stability of the nontrivial steady state. By relating the parameters of the cell model to the alphai we are able to derive some biological conclusions. PMID- 26245247 TI - On heteroclinic cycles of competitive maps via carrying simplices. AB - We concentrate on the effects of heteroclinic cycles and the interplay of heteroclinic attractors or repellers on the boundary of the carrying simplices for low-dimensional discrete-time competitive systems. Based on the existence of the carrying simplex for the competitive mapping, we provide the criteria on stability of the heteroclinic cycle. This result can be seen as a discrete counterpart of that for the continuous-time systems. Several concrete discrete time competition models are further analyzed, which do admit heteroclinic cycles. The criteria on the stability of the heteroclinic cycle for each model are also given, which are comparable with the corresponding continuous-time models. PMID- 26245248 TI - Organochlorine pesticides and prostate cancer, Is there an association? A meta analysis of epidemiological evidence. AB - PURPOSE: The results of epidemiological studies about exposure to organochlorine pesticides (OCPs) and risk of prostate cancer (PC) are inconclusive. We conducted a meta-analysis to evaluate the association between exposure to specific OCPs and PC. METHODS: We searched PubMed, Scopus, and Web of science databases for case control and cohort studies published till March 2015 that provided data about exposure to OCPs and PC. We also contacted authors and hand-searched references of the included articles. We calculated pooled estimates using random effects model and explored heterogeneity between studies. RESULTS: We systematically reviewed 15 articles and based our meta-analysis on 10 articles covering nine case-control studies and a large prospective cohort study. Pooled estimates of PC for highest versus lowest exposed category to p,p'-DDE was 1.02 (0.69-1.35), I (2) = 12.7 %, p = 0.333, trans-nonachlor, 0.88 (0.45-1.31), I (2) = 0.00 %, p = 0.892, oxychlordane, 0.91 (0.46-1.35), hexachlorobenzene, 0.88 (0.18-1.57), I (2) = 36.0 %, p = 0.210 from combining results of studies that applied serum OCPs measurements among the general population. For DDT, stratifying studies by exposed population revealed homogeneity, pooled estimate for serum level measurement for the highest exposed versus the lowest exposed of the general population was 0.81 (0.95-1.26), I (2) = 0.00 %, p = 0.400, and for occupational exposure 1.30 (0.94-1.67), I (2) = 13.4 %, p = 0.315. A positive but also insignificant association was obtained for pooling results for high exposure to lindane among farmers and pesticide applicators, 1.56 (0.82-2.29), I (2) = 41.7 %, p = 0.180. CONCLUSIONS: The existing epidemiological data do not support the hypothesis that exposure to specific OCPs is associated with an increased incidence of PC in the general population. PMID- 26245249 TI - Africa's oesophageal cancer corridor: Do hot beverages contribute? AB - PURPOSE: Hot beverage consumption has been linked to oesophageal squamous cell cancer (EC), but its contribution to the poorly understood East African EC corridor is not known. METHODS: In a cross-sectional study of general-population residents in Kilimanjaro, North Tanzania, tea drinking temperatures and times were measured. Using linear regression models, we compared drinking temperatures to those in previous studies, by socio-demographic factors and tea type ("milky tea" which can be 50 % or more milk and water boiled together vs "black tea" which has no milk). RESULTS: Participants started drinking at a mean of 70.6 degrees C (standard deviation 3.9, n = 188), which exceeds that in all previous studies (p <= 0.01 for each). Tea type, gender and age were associated with drinking temperatures. After mutual adjustment for each other, milky tea drinkers drank their tea 1.9 degrees C (95 % confidence interval: 0.9, 2.9) hotter than drinkers of black tea, largely because black tea cooled twice as fast as milky tea. Men commenced drinking tea 0.9 degrees C (-0.2, 2.1) hotter than women did and finished their cups 30 (-9, 69) seconds faster. 70 % and 39 % of milky and black tea drinkers, respectively, reported a history of tongue burning. CONCLUSIONS: Hot tea consumption, especially milky tea, may be an important and modifiable risk factor for EC in Tanzania. The contribution of this habit to EC risk needs to be evaluated in this setting, jointly with that of the many risk factors acting synergistically in this multi-factorial disease. PMID- 26245251 TI - Commentary: Moving towards policy coherence in trade and health. AB - International trade has brought economic benefits to many countries, but the association of trade and investment liberalisation with poor health outcomes concerns the public health community. The need to secure more 'healthy' trade is a recognised priority, especially as countries move from global to regional/bilateral trade agreements - with greater public health risks. However, a transition towards 'healthier trade' may be hindered by worldview differences between the trade and health communities. There is a tendency for health actors to perceive trade as a threat to population health, and for trade actors to view health as a constraint to trade objectives of reducing barriers to cross-border commercial flows and economic growth. Unless such differing worldviews can be aligned, finding ways forward for addressing public health in trade policy is likely to be difficult. Moving forward will involve understanding the values and drivers of the respective groups, and developing solutions palatable to their various interests. Given the power imbalances between the two areas, it is likely that the health community will have to make the first moves in this respect. This article outlines the key issues involved and suggests areas where such moves have been, and may be made. PMID- 26245252 TI - Estrogen deficiency heterogeneously affects tissue specific stem cells in mice. AB - Postmenopausal disorders are frequently observed in various organs, but their relationship with estrogen deficiency and mechanisms remain unclear. As tissue specific stem cells have been found to express estrogen receptors, we examined the hypothesis that estrogen deficiency impairs stem cells, which consequently contributes to postmenopausal disorders. Six-week-old C57BL/6 female mice were ovariectomized, following which they received 17beta-estradiol replacement or vehicle (control). Sham-operated mice were used as healthy controls. All mice were killed for evaluation 2 months after treatments. Compared with the healthy control, ovariectomy significantly decreased uterine weight, which was partially recovered by 17beta-estradiol replacement. Ovariectomy significantly increased the numbers of c-kit-positive hematopoietic stem/progenitor cells in bone marrow, but impaired their capacity to grow mixed cell-type colonies in vitro. Estrogen replacement further increased the numbers of c-kit-positive hematopoietic stem/progenitor cells in bone marrow, without significantly affecting colony growth in vitro. The number of CD105-positive mesenchymal stem cells in bone marrow also significantly decreased after ovariectomy, but completely recovered following estrogen replacement. Otherwise, neither ovariectomy nor estrogen replacement changed the number of Pax7-positive satellite cells, which are a skeletal muscle-type stem cell. Estrogen deficiency heterogeneously affected tissue-specific stem cells, suggesting a likely and direct relationship with postmenopausal disorders. PMID- 26245254 TI - Fully automatic and nonparametric quantification of adipose tissue in fat-water separation MR imaging. AB - Despite increasing demand and research efforts, currently there is no consensus on the protocol for automated and reliable quantification of adipose tissue (AT) and visceral adipose tissue (VAT) using MRI. The purpose of this study was to propose a novel computational method with enhanced objectiveness for the quantification of AT and VAT in fat-water separation MRI. 3T data from IDEAL were acquired for the fat-water separation. Fat tissues were separated from nonfat regions (background air, bone, water, and other nonfat tissues) using K-means clustering (K = 2). From the binary fat mask, arm regions were separated from body based on the relative size of connected component. AT was obtained from the binary body fat mask. With the initial contour as the outer boundary of body fat, the subcutaneous adipose tissue (SAT) and VAT were separated using deformable model driven by a specifically generated deformation field pointing to the inner boundary of SAT. The proposed method was tested on 16 patients with dyslipidemia and evaluated by comparing the correlation with semi-automatic segmentation results. Good robustness was also observed in the proposed method from the Bland Altman plots. Compared to other established fat segmentation methods, the proposed method is highly objective for fat-water separation MRI with minimal variability induced by subjective parameter settings. PMID- 26245253 TI - Review of cellular mechanotransduction on micropost substrates. AB - As physical entities, living cells can sense and respond to various stimulations within and outside the body through cellular mechanotransduction. Any deviation in cellular mechanotransduction will not only undermine the orchestrated regulation of mechanical responses, but also lead to the breakdown of their physiological function. Therefore, a quantitative study of cellular mechanotransduction needs to be conducted both in experiments and in computational simulations to investigate the underlying mechanisms of cellular mechanotransduction. In this review, we present an overview of the current knowledge and significant progress in cellular mechanotransduction via micropost substrates. In the aspect of experimental studies, we summarize significant experimental progress and place an emphasis on the coupled relationship among cellular spreading, focal adhesion and contractility as well as the influence of substrate properties on force-involved cellular behaviors. In the other aspect of computational investigations, we outline a coupled framework including the biochemically motivated stress fiber model and thermodynamically motivated adhesion model and present their predicted biomechanical responses and then compare predicted simulation results with experimental observations to further explore the mechanisms of cellular mechanotransduction. At last, we discuss the future perspectives both in experimental technologies and in computational models, as well as facing challenges in the area of cellular mechanotransduction. PMID- 26245255 TI - Wearable pendant device monitoring using new wavelet-based methods shows daily life and laboratory gaits are different. AB - Morbidity and falls are problematic for older people. Wearable devices are increasingly used to monitor daily activities. However, sensors often require rigid attachment to specific locations and shuffling or quiet standing may be confused with walking. Furthermore, it is unclear whether clinical gait assessments are correlated with how older people usually walk during daily life. Wavelet transformations of accelerometer and barometer data from a pendant device worn inside or outside clothing were used to identify walking (excluding shuffling or standing) by 51 older people (83 +/- 4 years) during 25 min of 'free living' activities. Accuracy was validated against annotated video. Training and testing were separated. Activities were only loosely structured including noisy data preceding pendant wearing. An electronic walkway was used for laboratory comparisons. Walking was classified (accuracy >=97 %) with low false-positive errors (<=1.9%, kappa >= 0.90). Median free-living cadence was lower than laboratory-assessed cadence (101 vs. 110 steps/min, p < 0.001) but correlated (r = 0.69). Free-living step time variability was significantly higher and uncorrelated with laboratory-assessed variability unless detrended. Remote gait impairment monitoring using wearable devices is feasible providing new ways to investigate morbidity and falls risk. Laboratory-assessed gait performances are correlated with free-living walks, but likely reflect the individual's 'best' performance. PMID- 26245256 TI - Understanding complex biogeographic responses to climate change. AB - Predicting the extent and direction of species' range shifts is a major priority for scientists and resource managers. Seminal studies have fostered the notion that biological systems responding to climate change-impacted variables (e.g., temperature, precipitation) should exhibit poleward range shifts but shifts contrary to that expectation have been frequently reported. Understanding whether those shifts are indeed contrary to climate change predictions involves understanding the most basic mechanisms determining the distribution of species. We assessed the patterns of ecologically relevant temperature metrics (e.g., daily range, min, max) along the European Atlantic coast. Temperature metrics have contrasting geographical patterns and latitude or the grand mean are poor predictors for many of them. Our data suggest that unless the appropriate metrics are analysed, the impact of climate change in even a single metric of a single stressor may lead to range shifts in directions that would otherwise be classified as "contrary to prediction". PMID- 26245257 TI - Purification and Molecular Characterization of the Novel Highly Potent Bacteriocin TSU4 Produced by Lactobacillus animalis TSU4. AB - Bacterial infections causing fish diseases and spoilage during fish food processing and storage are major concerns in aquaculture. Use of bacteriocins has recently been considered as an effective strategy for prevention of bacterial infections. A novel bacteriocin produced by Catla catla gut isolates, Lactobacillus animalis TSU4, designated as bacteriocin TSU4 was purified to homogeneity by a three-step protocol. The molecular mass of bacteriocin TSU4 was 4117 Da determined by Q-TOF LC/MS analysis. Its isoelectric point was ~9. Secondary conformation obtained by circular dichroism spectroscopy showed molecular conformation with significant proportions of the structure in alpha helix (23.7 %) and beta-sheets (17.1 %). N-terminal sequencing was carried out by the Edman degradation method; partial sequence identified was NH2-SMSGFSKPHD. Bacteriocin TSU4 exhibited a wide range of antimicrobial activity, pH and thermal stability. It showed a bacteriocidal mode of action against the indicator strain Aeromonas hydrophila MTCC 646. Bacteriocin TSU4 is the first reported bacteriocin produced by fish isolate Lactobacillus animalis. The characterization of bacteriocin TSU4 suggested that it is a novel bacteriocin with potential value against infections of bacteria such as A. hydrophila MTCC 646 and Pseudomonas aeruginosa MTCC 1688 and application to prevent spoilage during food preservation. PMID- 26245258 TI - Continuous Decolorization of Acid Blue 62 Solution in an Enzyme Membrane Reactor. AB - This paper focuses on using an enzyme membrane reactor (EMR) for the effective continuous decolorization of Acid Blue 62 (AB62). The following factors were considered for the effective use of Cerrena unicolor laccase immobilized in the EMR volume: the enzyme was stable in six successive runs in a batch reactor; no aeration was necessary; AB62 and the oxidized products were sorbed onto the membrane but were not rejected; and the enzyme was stable in the EMR system. It is obvious that any continuous process must be predictable, and thus, the objective was to verify the process model experimentally. For this reason, a proper isoenzyme kinetic equation was selected and the parameters were evaluated. The obtained kinetic parameters were used to plan processes and to verify their applicability to long-term AB62 decolorization, and a very good agreement between the calculated and the measured data was obtained. In the main designed continuous decolorization process, the conversion reached 98 % and was stable for 4 days. The membrane reactor with C. unicolor laccase appears to be very promising for AB62 decolorization. PMID- 26245259 TI - Microbial Transglutaminase Separation by pH-Responsive Affinity Precipitation with Crocein Orange G as the Ligand. AB - A microbial transglutaminase (MTG) was efficiently purified by using pH responsive affinity precipitation with Crocein orange G (COG) as the affinity ligand. The docking method was used to identify the appropriate ligand. The molecular simulation results were compared with the label-free detection data analyzed by ForteBio's Octet. A pH-responsive polymer, PMMDN, was polymerized and subsequently coupled with COG as the ligand. The isoelectric point (pI) and recovery of PMMDN and PMMDN-COG were 4.51, 99.8,% and 4.78, 98.1 %, respectively. The optimal adsorption conditions were found to be a ligand density of 60.0 MUmol/g, pH 7.0, and 0.2 mol/L NaCl. The adsorption isotherm showed that the maximum adsorption capacity was 91.32 mg/g polymer and the dissociation constant was 0.021 mg/mL. Interaction information between PMMDN-COG and MTG in the whole process of affinity precipitation were obtained by Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). PB (0.02 mol/L pH 7.0) in 20.0 % glycol was used to elute the binding MTG from PMMDN-COG. Under these conditions, electrophoretically pure MTG was obtained in only one step with elution recoveries of 98.96 % (protein) and 95.09 % (activity). PMID- 26245260 TI - Immobilizing Yarrowia lipolytica Lipase Lip2 via Improvement of Microspheres by Gelatin Modification. AB - The purpose of this study was to investigate the feasibility of immobilizing Yarrowia lipolytica lipase lip2 on epoxy microspheres with or without gelatin modifications. The activity of lipase immobilized on gelatin-modified supports was twofold higher than those immobilized on native supports. There was no significant difference in the Michaelis-Menten constant (K M ) between the two immobilized lipases. However, lipase immobilized on gelatin modified supports showed an approximately fourfold higher V max than lipase immobilized on native supports. Lipase immobilization on the gelatin-modified support exhibited a significantly improved operational stability in an esterification system. After it was reused for a total of 35 batches, the ester conversion of lipase immobilized on gelatin-modified and native microspheres was 83 and 60 %, respectively. Furthermore, the immobilized lipase could be stored at 4 degrees C for 12 months without any loss of activity. PMID- 26245261 TI - High-Level Butanol Production from Cassava Starch by a Newly Isolated Clostridium acetobutylicum. AB - A new Clostridium acetobutylicum strain, exhibiting the ability to resist butanol stress and produce butanol, was identified and named GX01. Strain GX01 can use a wide variety of carbohydrates, especially cassava starch, to produce butanol. After the optimization of culture conditions, C. acetobutylicum GX01 could produce 27.3 g/L solvent, including 17.1 g/L butanol, 7.9 g/L acetone, and 2.3 g/L ethanol, from 100 g/L cassava flour and 3 g/L soybean meal. Furthermore, when its acetone-butanol-ethanol (ABE) fermentation was performed in 10- and 30-L bioreactors, the production of total solvent and butanol reached 29.2 and 18.3 g/L, respectively, and 28.8 and 18.8 g/L, respectively. Thus, the high level and stability of butanol production make strain GX01 a promising candidate for ABE fermentation using the low-cost cassava starch. PMID- 26245262 TI - Egg Dispersal in the Phasmatodea: Convergence in Chemical Signaling Strategies Between Plants and Animals? AB - Numerous tree species' seeds contain an 'elaiosome' that acts as a food reward for ants and thus induces dispersal of the seeds. Many stick and leaf insect species appear to have evolved a convergent adaptation for dispersal whereby the egg 'capitulum' serves to induce ants to pick up and carry their eggs. Here, we investigated whether the capitulum facilitates egg dispersal by ants in the Australian stick insect Eurycnema goliath. The total fatty acid composition of E. goliath egg capsules and egg capitula were characterized to identify potential signaling compounds. Removing capitula from E. goliath eggs significantly reduced the likelihood of eggs being carried into the nests of Rhytidoponera metallica ants. Furthermore, attaching capitula to inert objects (polystyrene balls) resulted in these objects being carried into nests by R. metallica. Several fatty acids were present on the egg capsule surface in only trace amounts, whereas they made up over 10% of the dry weight of egg capitula. The fatty acid composition of egg capitula consisted mostly of palmitic acid (C16:0), linoleic acid (C18: 2n6c), oleic acid (C18:1n9c), linolenic acid (C18:3n3), and stearic acid (C18:0). Previously reported research has found that a diglyceride lipid species of oleic acid induces carrying behavior in R. metallica when added to inert artificial stimuli. Therefore, we propose that the dispersal mechanism of E. goliath eggs has converged upon the same chemical signaling pathway used by plants to exploit ant behavior. PMID- 26245263 TI - Identification of the Alarm Pheromone of Hygia lativentris and Changes in Composition during Development. AB - Heteropteran insects produce a series of volatile compounds from their scent glands that protect them from predators and parasites. These compounds also play roles in chemical communication that elicit aggregation, dispersal, and mating behaviors. Hygia lativentris (Coreidae) adults frequently aggregate on host plants. When disturbed, they quickly disperse with the release of a sour smell, suggesting that these bugs possess an alarm pheromone in their secretions. This adult secretion-induced dispersal has been examined with a laboratory assay. Hexanal, the predominant component of the adult secretion was identified as a component of the alarm pheromone by evaluation of the adult bug's response time and escape distance from the chemical source. Physicochemical analyses with gas chromatography/mass spectrometry and nuclear magnetic resonance spectroscopy revealed that secretory components differed between nymphs and adults, and also during adult aging. Nymphs produced two unsaturated compounds, (E)-2-hexenal and (E)-4-oxo-2-hexenal, together with hexanal and 1-hexanol, which were found in all developmental stages. In adults, hexyl acetate was the major component of secretions within 3 days of emerging, while the amount of this ester decreased and those of hexanal, hexanoic acid, and hexanal trimer increased with aging. The decomposition of hexyl acetate into hexanal via 1-hexanol was attributed to the presence of esterases and alcohol dehydrogenases specifically found in adult secretory glands. In contrast, the formation of a hexanal trimer may be due to a non-enzymatic reaction under acidic conditions. PMID- 26245264 TI - Rituximab-based therapy and long-term control of autoimmune autonomic ganglionopathy. AB - We present a patient with autoimmune autonomic ganglionopathy (AAG) who had persistently positive ganglionic nicotinic acetylcholine receptor antibody levels despite immunosuppressive therapy. Rituximab-based therapy for an incidental lymphoma was associated with prolonged symptomatic and serological control of AAG. PMID- 26245265 TI - Temperature-dependent capillary forces at nano-contacts for estimating the heat conduction through a water meniscus. AB - The temperature dependence of the capillary forces at nano-sized contacts is investigated. Two different resistive scanning thermal microscopy (SThM) nanoprobes are used in this study. Measurements of the capillary forces are reported as a function of the probe temperature on hydrophilic samples of different thermal properties. These forces appear to be largely reduced for probe temperatures larger than a threshold temperature, where the value depends on the sample thermal conductance. This could pave the way to an alternative solution to reduce the stiction in nano/ micro-electromechanical (NEMS/MEMS) devices. The dimensions of the water meniscus at the probe-sample contact were then estimated. Moreover, these results help the evaluation of thermal conductance through the water meniscus. It is found, through this work, that the values of the thermal conductance through the water meniscus can represent 6% of those of the contact thermal conductance in the case of the KNT probe (from Kelvin nanotechnology). These values can be equal to 4% of those of thermal conduction in the cantilever sample air gap in the case of a doped-silicon probe. PMID- 26245266 TI - Reconstruction of micron resolution mouse brain surface from large-scale imaging dataset using resampling-based variational model. AB - Brain surface profile is essential for brain studies, including registration, segmentation of brain structure and drawing neuronal circuits. Recent advances in high-throughput imaging techniques enable imaging whole mouse brain at micron spatial resolution and provide a basis for more fine quantitative studies in neuroscience. However, reconstructing micron resolution brain surface from newly produced neuronal dataset still faces challenges. Most current methods apply global analysis, which are neither applicable to a large imaging dataset nor to a brain surface with an inhomogeneous signal intensity. Here, we proposed a resampling-based variational model for this purpose. In this model, the movement directions of the initial boundary elements are fixed, the final positions of the initial boundary elements that form the brain surface are determined by the local signal intensity. These features assure an effective reconstruction of the brain surface from a new brain dataset. Compared with conventional typical methods, such as level set based method and active contour method, our method significantly increases the recall and precision rates above 97% and is approximately hundreds-fold faster. We demonstrated a fast reconstruction at micron level of the whole brain surface from a large dataset of hundreds of GB in size within 6 hours. PMID- 26245267 TI - Qubit entanglement between ring-resonator photon-pair sources on a silicon chip. AB - Entanglement--one of the most delicate phenomena in nature--is an essential resource for quantum information applications. Scalable photonic quantum devices must generate and control qubit entanglement on-chip, where quantum information is naturally encoded in photon path. Here we report a silicon photonic chip that uses resonant-enhanced photon-pair sources, spectral demultiplexers and reconfigurable optics to generate a path-entangled two-qubit state and analyse its entanglement. We show that ring-resonator-based spontaneous four-wave mixing photon-pair sources can be made highly indistinguishable and that their spectral correlations are small. We use on-chip frequency demultiplexers and reconfigurable optics to perform both quantum state tomography and the strict Bell-CHSH test, both of which confirm a high level of on-chip entanglement. This work demonstrates the integration of high-performance components that will be essential for building quantum devices and systems to harness photonic entanglement on the large scale. PMID- 26245268 TI - Testis Morphology and Dichotomic Spermatogenesis in the Sugarcane Borer Diatraea saccharalis (F.) (Lepidoptera: Crambidae). AB - In the present study, we describe the testis morphology and spermatogenesis of the sugarcane borer, one of the most destructive pests of sugarcane, using light, transmission, and scanning electron microscopies. Diatraea saccharalis (F.) larvae have paired, kidney-shaped testes that are limited externally and divided into four follicles by tunica cells. The adults have two fused whitish and spherical testes that are divided into eight follicles and are composed of spermatogonia, spermatocyte, spermatid, and sperm bundles. The spermatogonia and spermatocyte cysts are located at the apical extremity of the follicle, while the spermatid cysts and sperm bundles are located at the basal extremity of the follicle. Inside of the cysts, which are formed by the somatic cells, the germ line cells develop synchronously and are interconnected by cytoplasmic bridges. Each cyst contains only apyrene or eupyrene, and none of the cysts contain both of the cells. The inner part of the apyrene cyst consists of an electron-dense cap as opposed to a nucleus. The eupyrene sperm contains a nucleus, acrosome, and reticular and lacinate appendages. Both of the sperm types have a "9 + 9 + 2" axoneme and two mitochondrial derivatives at the tail region. The spermatogenesis process and spermatozoa morphology are similar to that of other Lepidoptera. PMID- 26245269 TI - Oviposition Site Selection Structures Niche Partitioning Among Coccinellid Species in a Tropical Ecosystem. AB - The competitive exclusion hypothesis suggests that coexisting related species using similar resources in nature should partition their realized niches. This hypothesis has direct implications for conservation strategies using biological control, taking into consideration the shifts caused by the introduction of natural enemies in a local community. Such introductions typically lead to disruptions in species interactions and interfere with community structure. In this study, we asked whether community structure of aphidophagous lady beetles is determined by the distribution of specific plants and aphids. To answer this question, we describe the distribution patterns of lady beetles (adults, larvae, and egg clusters) relative to plants and aphids in eight crop ecosystems in a central region of Brazil. We used canonical correspondence analysis to evaluate lady beetle distribution relative to selected habitat variables. Cycloneda sanguinea L., Hippodamia convergens Guerin-Meneville, Harmonia axyridis Pallas, and Eriopis connexa Germar (Coleoptera: Coccinellidae) differed in their use of plants and aphids. The association of egg clusters with specific plants/aphids was stronger than that of larvae or adults. In conclusion, lady beetle species occupied different niches, indicating different patterns of habitat use that may facilitate their coexistence in crop ecosystems. Furthermore, immature individuals had more specific environmental associations than adults, likely because female choice of oviposition sites influences their distribution and thus lady beetle community structure. PMID- 26245270 TI - Corrigendum: Optoelectronic crystal of artificial atoms in strain-textured molybdenum disulphide. PMID- 26245271 TI - Phosphorylated epidermal growth factor receptor expression and KRAS mutation status in salivary gland carcinomas. AB - OBJECTIVES: Salivary gland carcinomas (e.g., adenoidcystic carcinoma or mucoepidermoid carcinoma) are rare and often unresectable head and neck tumors. They are also weakly affected by most chemotherapeutic drugs, which emphasize the need for further studies on this topic. In clinical practice, various drugs target the well-characterized EGFR pathway in many epithelial tumors. There is limited reliable data on phophorylated EGFR expression, such as activated conformation, in salivary gland tumors. MATERIALS AND METHODS: This study investigates the pEGFR expression in salivary gland carcinomas (n = 43). Three different carcinoma varieties, that represent >50 % of all salivary gland tumors, were included: adenoidcystic carcinoma (n = 23), mucoepidermoid carcinoma (n = 17), and adenocarcinoma NOS (not otherwise specified) (n = 3). The specimens were investigated by immunohistochemistry. Additionally, mutations of KRAS oncogene were screened with gene sequencing. The findings were correlated with clinical data by using SPSS. RESULTS: In 34 out of 43 specimens (79 %), a positive staining for pEGFR was found. Sex, tumor entity, tumor site, and grading had no significant correlation with pEGFR expression. A weak correlation was found for tumor size and pEGFR expression. Significant correlations were found for pEGFR expression with patient's age and lymph node metastasis (pN). No specimen showed a KRAS mutation in codon 12 or 13. CONCLUSION: Salivary gland carcinomas show a high expression of pEGFR. This high expression correlates with lymph node metastasis, which supports the hypothesis that a high pEGFR expression facilitates lymphogenous metastasis. Due to this pEGFR expression, status may be a negative predictive factor in salivary gland carcinoma diagnostics. Patients with pN-positive salivary gland cancer may benefit from EGFR-inhibiting drugs. CLINICAL RELEVANCE: The EGFR pathway may be a potential target for chemotherapy of advanced unresectable salivary gland carcinomas. PMID- 26245272 TI - Efficacy and safety of over-the-counter whitening strips as compared to home whitening with 10 % carbamide peroxide gel--systematic review of RCTs and metanalysis. AB - OBJECTIVES: The study aims to compare the efficacy and safety of over-the-counter whitestrips with the American Dental Association (ADA)-recommended home-whitening using the 10 % carbamide peroxide gel. MATERIALS AND METHODS: Randomized controlled trials (RCTs) comparing the clinical efficacy and safety of the whitestrips with the 10 % carbamide peroxide (10 % CP) gel applied on tray for tooth whitening in adults were searched at PubMed and Cochrane Central Register of Controlled Trials databases and selected up to October 2014. Efficacy of the whitening techniques was assessed through ?E, ?L, and ?b parameters, while side effects were analyzed as dichotomous variables. Data was extracted independently by two reviewers. Metanalysis was performed using random- and fixed-effect models (RevMan 5.3). RESULTS: Eight studies were included in the metanalysis. The metanalysis revealed no significant difference between the intervention groups for tooth-whitening efficacy measured as DeltaE (mean difference [MD]-0.53; 95 % CI [-1.72;0.66]; Z = 0.88; p = 0.38) and DeltaL (MD-0.22; 95 % CI [-0.81;0.36]; z = 0.75; p = 0.45); reduction of yellowing was higher with the whitestrips (MD 0.47; 95 % CI [-0.89; -0.06]; Z = 2.25; p = 0.02). Tooth sensitivity (risk ratio [RR] 1.17; 95 % CI [0.81-1.69]; Z = 0.81; p = 0.42) and gingival sensitivity (RR 0.76; 95 % CI [0.53-1.10]; Z = 1.44; p = 0.15) were similar, regardless of the whitening method used. The observed gingival irritation was higher when the 10 % CP gel was applied on tray (RR 0.43; 95 % CI [0.20-0.93]; Z = 2.14; p = 0.03). The quality of evidence generated was rated very low for all outcomes. CONCLUSIONS: There is no sound evidence to support the use of the whitening strips in detriment of the ADA-recommended technique based on the 10 % carbamide peroxide gel applied on tray. CLINICAL RELEVANCE: To the moment, there is no sound evidence in dental literature to suggest that the ADA-recommended whitening technique based on 10 % carbamide peroxide gel could be substituted by the whitening strips. The existing studies, with their limitations, revealed similar tooth whitening and tooth and gingival sensitivity for both whitening techniques. PMID- 26245273 TI - Evaluation of a possible association between a history of dentoalveolar injury and the shape and size of the nasopalatine canal. AB - OBJECTIVES: Maxillary incisors (MI) are often affected by dentoalveolar injury resulting in tooth devitalization and apical periodontitis. The aim of the present study was to analyze any association between a history of dentoalveolar injury and the shape and size of the nasopalatine canal (NC) using cone beam computed tomography (CBCT). MATERIAL AND METHODS: Patients were allocated to the trauma group if they had a history of dentoalveolar injury and a root filling in at least one MI and/or one missing MI. As controls, 100 matched-controlled (age and gender) patients were selected. NC dimensions including length, width at midway, and diameter of incisal and nasal foramen were measured in sagittal and axial CBCT planes. Furthermore, an evaluation of NC bulging signs, apical osteolysis of MI, and its fusion with NC was performed. RESULTS: In the trauma group (n = 96), 31.3 % had at least one missing MI, and 95.8 % had a root filling in a MI. The antero-posterior dimension of the incisive foramen (p = 0.02) and of the NC at midway (p = 0.04) was significantly larger in the trauma group. Significantly more cases with a bulging sign were found in the trauma (n = 19) than in the control group (n = 3, p = 0.001). An apical osteolysis was identified in 5.1 % of MI, and 12/38 did show a fusion with the NC. CONCLUSION: Wider dimensions of the NC and a bulging sign may suggest a former dentoalveolar injury to the anterior maxilla. Periapical osteolysis of central MI over 5 mm in diameter tends to fuse with the NC. CLINICAL RELEVANCE: In patients with a history of dentoalveolar injury and/or apical periodontitis, the NC should be evaluated on available CBCT images. Any inflammatory processes in the neighboring teeth should be recognized and eliminated as they may initiate bulging of the NC and/or the formation of a nasopalatine duct cyst (NPDC). NC with bulging signs should be monitored clinically and radiographically to diagnose a NPDC in an early stage. PMID- 26245274 TI - Relationship between periodontal parameters and plasma cytokine profiles in pregnant woman with preterm birth or low birth weight. AB - OBJECTIVES: The aim was to determine whether clinical periodontal parameters are associated with plasma anti- and/or pro-inflammatory cytokines in pregnant woman with preterm birth (PB) or low birth weight (LBW) neonates. MATERIALS AND METHODS: An observational case-control study was performed in 131 puerperal women: mothers of PB/LBW neonates (cases, n = 67) and mothers of full-term normal weight neonates (controls, n = 64). Sociodemographic and periodontal data was gathered from all participants, and interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL 17, IL-23, and tumor necrosis factor alpha (TNF-alpha) were determined in plasma. RESULTS: In multiple linear regression models, clinical attachment loss was associated with TNF-alpha (0.28 +/- 0.14; 95% confidence interval (CI) [0.006, 0.553]) and IL-1beta (0.43 +/- 0.21; 95%CI [0.018, 0.842]), independent of group membership. IL-1beta (-1.67 +/- 0.27, 95%CI [-2.199, -1.141]), IL-6 (-0.86 +/- 0.27; 95%CI [-1.389, -0.331]), and IL-8 (-3.84 +/- 0.50, 95%CI [-4.820, -2.860]) were lower, and IL-10 (0.86 +/- 0.26; 95%CI [0.350, 1.370]) was higher in cases versus controls after adjusting for potential confounders. CONCLUSIONS: Clinical attachment loss was associated with plasma TNF-alpha and IL-1beta levels. No plasma cytokine profiles suggestive of systemic inflammatory response were observed in the pregnant women with PB/LBW neonates. CLINICAL RELEVANCE: Clinical attachment loss, as the main periodontal measure, is associated with TNF-alpha and IL-1beta plasma levels in pregnant women. No relationship was found between PB/LBW and the markers of systemic inflammatory response assessed in this study. PMID- 26245275 TI - Comparison of chairside and laboratory CAD/CAM to conventional produced all ceramic crowns regarding morphology, occlusion, and aesthetics. AB - OBJECTIVES: There are many ways to produce all-ceramic crowns. Computer-aided design and computer-aided manufacturing (CAD/CAM) procedures compete against conventional fabricated restorations. As different methods of production may produce variable results, this study aims to compare chairside and laboratory based CAD/CAM systems to conventional crowns regarding their similarity to original tooth morphology, number of occlusal contacts, occlusal adjustment time, and subjective aesthetic perception. MATERIAL AND METHODS: Impressions of caries free jaws were taken, and the resulting gypsum casts were scanned with a laboratory scanner. Preparations for all-ceramic full crowns were performed on first molars, and three different restorations were made: CEREC restorations (CER), laboratory-produced CAD/CAM crowns (LABCAD), and conventional waxed up/pressed ceramic crowns (CONV). Time for occlusal adaptation and the number of occlusal contacts were noted. Two dentists performed aesthetic gradings of restorations. Statistical analysis included one-way ANOVA with least significant difference (LSD) post hoc test, t test, and Kruskal-Wallis test. RESULTS: Metrical deviations of the re-scanned crowns to the original, unprepared tooth surface were 220.55 +/- 54.31 MUm for CER, 265.94 +/- 61.39 for LABCAD, and 252.44 +/- 68.77 MUm for CONV group. One-way ANOVA showed significant lower deviations for the CER group. LABCAD crowns showed significantly more occlusal contacts, whereas CONV crowns required the least time for occlusal adaptation and showed excellent aesthetic gradings. CONCLUSION: All three methods had pros and cons regarding different parameters. Further improvements of CAD/CAM software shall lead to restorations comparable to conventional restorations in all aspects, especially in aesthetics. CLINICAL RELEVANCE: All tested methods of production for all-ceramic crowns produced clinically acceptable results. Thus, in an individual case, the method chosen can be determined by the dentist's preference. PMID- 26245276 TI - Identification of 3-Nitro-2,4,6-trihydroxybenzamide Derivatives as Photosynthetic Electron Transport Inhibitors by QSAR and Pharmacophore Studies. AB - In the present investigation, quantitative structure-activity relationship (QSAR) analysis was performed on a data set consisting of structurally diverse compounds in order to investigate the role of their structural features on their photosynthetic electron transport Inhibitors. The best 2D-QSAR model was selected, having correlation coefficient r (2) = 0.8544 and cross-validated squared correlation coefficient q (2) = 0.7139 with external predictive ability of pred_r (2) = 0.7753. The results obtained in this study indicate that the presence of hydroxy and nitro groups, expressed by the SsOHcount and SddsN (nitro) count, is the most relevant molecular property determining efficiency of photosynthetic inhibitory. Molecular field analysis was used to construct the best k-nearest neighbor (kNN-MFA)-based 3D-QSAR model using SA-PLS method, showing good correlative and predictive capabilities in terms of [Formula: see text] and [Formula: see text]. The pharmacophore model includes three features viz. hydrogen bond donor, hydrogen bond acceptor, and one aromatic feature. The developed model was found to be predictive and can be used to design potent photosynthetic electron transport activities prior to their synthesis for further lead modification. PMID- 26245277 TI - jEcho: an Evolved weight vector to CHaracterize the protein's posttranslational modification mOtifs. AB - Protein's posttranslational modification (PTM) represents a major dynamic regulation of protein functions after the translation of polypeptide chains from mRNA molecule. Compared with the costly and labor-intensive wet laboratory characterization of PTMs, the computer-based detection of PTM residues has been a major complementary technique in recent years. Previous studies demonstrated that the PTM-flanking positions convey different contributions to the computational detection of PTM residue, but did not directly translate this observation into the in silico PTM prediction. We propose a weight vector to represent the variant contributions of the PTM-flanking positions and use an evolutionary algorithm to optimize the vector. Even a simple nearest neighbor algorithm with the incorporated optimal weight vector outperforms the currently available algorithms. The algorithm is implemented as an easy-to-use computer program, jEcho version 1.0. The implementation language, Java, makes jEcho platform independent and visually interactive. The predicted results may be directly exported as publication-quality images or text files. jEcho may be downloaded from http://www.healthinformaticslab.org/supp/ . PMID- 26245278 TI - IL-17 sequestration via salivary gland gene therapy in a mouse model of Sjogren's syndrome suppresses disease-associated expression of the putative autoantigen Klk1b22. AB - INTRODUCTION: IL-17 has a putative role in the pathophysiology of Sjogren's syndrome (SS) and has been shown to be upregulated in the salivary glands of affected individuals. Sequestration of IL-17 with Adenoviral-mediated gene therapy has previously shown a benefit upon the SS-like phenotype in the Aec1/Aec2 mouse model. We sought to understand the proteomic consequences of IL 17 sequestration in the salivary gland of this mouse model as a means of illuminating the role of IL-17 in SS-like disease. METHODS: Ultrasound-assisted gene transfer (UAGT) was utilized to express a fusion protein composed of the extracellular portion of the IL-17 receptor fused to fragment of crystallization (Fc) in the submandibular glands of Aec1/Aec2 mice at 8 weeks of age. After confirming expression of the fusion protein and local and systemic sequestration of IL-17, proteomic profiling was performed on submandibular glands of a treated cohort of Aec1/Aec2 animals relative to the background strain and sham-treated animals. RESULTS: The most notable proteomic signatures of IL-17 sequestration on SS-like disease-related proteins were Kallikrein-related peptidases, including the putative autoantigen Klk1b22. IL-17 sequestration also notably led to an isoelectric shift, but not a molecular weight shift, of Kallikrein-1, attributed to phosphorylation. CONCLUSION: Non-viral IL-17 sequestration gene therapy in the salivary gland is feasible and downregulates expression of a putative SS autoantigen in the Aec1/Aec2 mouse. PMID- 26245279 TI - Effectiveness of a Medifast meal replacement program on weight, body composition and cardiometabolic risk factors in overweight and obese adults: a multicenter systematic retrospective chart review study. AB - BACKGROUND: Recent medical guidelines emphasize the importance of actively treating overweight and obesity with diet and lifestyle intervention to achieve >= 5% weight loss in a 6-month period. Commercial programs offer one approach provided there is evidence of their efficacy and safety. This study was conducted to evaluate the effectiveness of the Medifast(r) 4 & 2 & 1 PlanTM on weight loss, body composition and cardiometabolic risk factors in overweight and obese adults. METHODS: A systematic retrospective chart review of 310 overweight and obese clients following the Medifast 4 & 2 & 1 Plan at one of 21 Medifast Weight Control Centers(r) was conducted. Data were recorded electronically and key data points were independently verified. The primary endpoint was change from baseline body weight at 12 weeks. Within group paired t-tests were used to examine changes from baseline in a completers population. Differences between gender and age subgroups were examined using bivariate t-tests and mixed model regression analyses. RESULTS: For the primary endpoint at 12 weeks, body weight among completers (n = 185) was reduced by a mean of 10.9 +/- 5.6 kg (-10.1%, p < 0.0001), and at 24 weeks (n = 81) mean weight was reduced by 16.0 +/- 7.9 kg ( 14.3%). At 12 and 24 weeks, 85% and 96% of those remaining on the plan, respectively, had lost >= 5% of their baseline body weight. Lean mass was preserved to within 5% of baseline throughout the 24 weeks, and fat mass represented >= 80% of the body weight lost from 12 weeks onward. Men, women, seniors (>= 65 years), and non-seniors (<65 years) all had significant weight reductions with preservation of lean mass. Significant improvements in blood pressure, pulse and waist-to-hip ratio were observed. Mean weight regain among the subset who entered a formal maintenance phase was <2% during an average follow-up of 34 weeks. The meal plan was well tolerated, and program adherence was >85%. CONCLUSIONS: The 4 & 2 & 1 Plan used at Medifast Weight Control Centers was effective for weight loss, preservation of lean mass and improvement in cardiometabolic risk factors. The plan was generally well tolerated in a broad population of overweight and obese adults. #NCT02150837. PMID- 26245280 TI - What defines an adaptive radiation? Macroevolutionary diversification dynamics of an exceptionally species-rich continental lizard radiation. AB - BACKGROUND: Adaptive radiation theory posits that ecological opportunity promotes rapid proliferation of phylogenetic and ecological diversity. Given that adaptive radiation proceeds via occupation of available niche space in newly accessed ecological zones, theory predicts that: (i) evolutionary diversification follows an 'early-burst' process, i.e., it accelerates early in the history of a clade (when available niche space facilitates speciation), and subsequently slows down as niche space becomes saturated by new species; and (ii) phylogenetic branching is accompanied by diversification of ecologically relevant phenotypic traits among newly evolving species. Here, we employ macroevolutionary phylogenetic model-selection analyses to address these two predictions about evolutionary diversification using one of the most exceptionally species-rich and ecologically diverse lineages of living vertebrates, the South American lizard genus Liolaemus. RESULTS: Our phylogenetic analyses lend support to a density-dependent lineage diversification model. However, the lineage through-time diversification curve does not provide strong support for an early burst. In contrast, the evolution of phenotypic (body size) relative disparity is high, significantly different from a Brownian model during approximately the last 5 million years of Liolaemus evolution. Model-fitting analyses also reject the 'early-burst' model of phenotypic evolution, and instead favour stabilizing selection (Ornstein Uhlenbeck, with three peaks identified) as the best model for body size diversification. Finally, diversification rates tend to increase with smaller body size. CONCLUSIONS: Liolaemus have diversified under a density-dependent process with slightly pronounced apparent episodic pulses of lineage accumulation, which are compatible with the expected episodic ecological opportunity created by gradual uplifts of the Andes over the last ~25My. We argue that ecological opportunity can be strong and a crucial driver of adaptive radiations in continents, but may emerge less frequently (compared to islands) when major events (e.g., climatic, geographic) significantly modify environments. In contrast, body size diversification conforms to an Ornstein-Uhlenbeck model with multiple trait optima. Despite this asymmetric diversification between both lineages and phenotype, links are expected to exist between the two processes, as shown by our trait-dependent analyses of diversification. We finally suggest that the definition of adaptive radiation should not be conditioned by the existence of early-bursts of diversification, and should instead be generalized to lineages in which species and ecological diversity have evolved from a single ancestor. PMID- 26245281 TI - Correlates of HIV testing and receipt of test results in addiction health services in Los Angeles County. AB - BACKGROUND: HIV testing and receipt of HIV test results among individuals with substance use disorders is less than optimal. We examined rates and correlates of HIV testing and receipt of test results in one of the largest public addiction health services systems in the United States. METHODS: The study included 139,516 adult clients in treatment between 2006 and 2011. We used logistic regression models to examine associations between predisposing, enabling, and need factors and two dependent variables, HIV testing rates and receipt of test results. Associations were considered statistically significance at p < .01. RESULTS: We found that 64% of clients reported being tested for HIV, of whom 85% reported receiving their test results. Likelihood of being tested was positively associated with being female, a minority, homeless, employed, having prior treatment episodes, comorbidities, injection drug use, or a history of mental illness. It was negatively associated with alcohol or marijuana as primary drug. Receipt of test results was more likely among clients on medication (methadone or buprenorphine) or whose method of drug use was smoking, inhalation, or injecting; it was less likely among older clients and those with more outpatient psychiatric visits. CONCLUSIONS: Findings from this study may inform strategies and targeting of population groups to improve HIV testing practices and ultimately increase awareness of infection status among clients of addiction health services. PMID- 26245282 TI - Molecular typing and drug sensitivity testing of Mycobacterium tuberculosis isolated by a community-based survey in Ethiopia. AB - BACKGROUND: The identification of circulating TB strains in the community and drug sensitivity patterns is essential for the tuberculosis control program. This study was undertaken to identify M. tuberculosis strains circulating in selected communities in Ethiopia as well as to evaluate the drug sensitivity pattern of these strains. METHOD: This study was a continuation of the Ethiopian National TB Prevalence Survey that was conducted between 2010 and 2011. Culture-positive isolates of M. tuberculosis from previous study were typed using region of difference (RD) 9-based polymerase chain reaction (PCR) and spoligotyping. Drug sensitivity testing was conducted using the indirect proportion method on Lowenstein-Jensen media. RESULT: All 92 isolates were confirmed as M. tuberculosis by RD9-based PCR and spoligotyping of 91 of these isolates leds to the identification of 41 spoligotype patterns. Spoligotype revealed higher diversity (45 %) and among this 65.8 % (27/41) were not previously reported. The strains were grouped into 14 clusters consisting of 2-15 isolates. The dominant strains were SIT53, SIT149 and SIT37 consisting of 15, 11, and 9 isolates, respectively. Our study reveals 70 % (64/91) clustered strains and only 39.1 % (25/64) occurred within the same Kebele. Further assignment of the strains to the lineages showed that 74.7 % (68/91) belonged to Euro-American lineage, 18.6 % (17/91) to East Africa Indian lineage and the remaining 6.5 % (6/91) belonged to Indo-oceanic lineage. Valid drug susceptibility test results were available for 90 of the 92 isolates. Mono-resistance was observed in 27.7 % (25/90) and poly resistance in 5.5 % (5/90) of the isolates. Moreover, multi-drug resistance (MDR TB) was detected in 4.4 % of the isolates whilst the rest (60/90) were susceptible to all drugs. The highest level of mono-resistance, 26.6 % (24/90), was observed for streptomycin with majority (91.1 %) of streptomycin mono resistant strains belonging to the Euro-American lineage. CONCLUSION: In this study, the strains of M. tuberculosis circulating in selected sites of Ethiopia were identified along with the drug sensitivity patterns. Thus, these findings are useful for the TB Control Program of the country. PMID- 26245283 TI - Early diagnosis of Canavan syndrome: how can we get there? AB - Canavan syndrome is a rare genetic disorder characterised by progressive severe leukodystrophy involving the degeneration of white matter. Currently, there is no effective therapy, but after recent studies using early gene therapy, the outcome has appeared to improve. It is of fundamental importance to recognise signs of neonatal Canavan syndrome early on. We describe a case of neonatal Canavan syndrome in which diagnosis was made only at the fourth month of age. PMID- 26245284 TI - Recurrent major umbilical bleeding caused by omental varices in two patients with umbilical hernia and portal hypertension. PMID- 26245285 TI - Foreign bodies in the abdomen: self-harm and personality disorders. AB - A 52-year-old woman presented to the accident and emergency department 5 h after deliberately stabbing herself with two pens through her midline laparotomy scar. Her medical history included an emotionally unstable (borderline) personality disorder and she was currently an inpatient in a psychiatric hospital. She had multiple accident and emergency attendances with previous episodes of self-harm. Clinical examination revealed evidence of trauma to her midline laparotomy scar with congealed blood covering the puncture site. Her abdomen was soft and non tender on palpation. A chest radiograph revealed no air beneath her diaphragm and her abdominal radiograph identified a radiopacity in her upper right abdomen and dilated loops of small bowel. CT of the abdomen and pelvis confirmed two pens, with the lower pen tip reaching the pancreas. A midline laparotomy was performed and both foreign bodies were extricated unremarkably. The patient's postoperative recovery was uneventful. The second case involves a 22-year-old woman, a psychiatric hospital resident, presenting to the accident and emergency department 5 h after deliberately inserting the metal nib and inner plastic ink containing tube of a pen through her umbilicus. Her medical history included an emotionally unstable (borderline) personality disorder and paranoid schizophrenia. She had multiple accident and emergency department attendances with previous episodes of self-harm. Clinical examination revealed a soft, non tender abdomen. Her chest radiograph was unremarkable and her abdominal radiograph identified a radiopaque foreign body at the right upper quadrant of the abdomen. CT of the abdomen and pelvis confirmed a metallic foreign body in the small bowel mesentery. An exploratory laparotomy converted to a midline laparotomy was performed and the foreign body was extricated. The patient's postoperative recovery was uneventful. PMID- 26245286 TI - Multidisciplinary approach for management of a patient with fibrous dysplasia of maxilla. AB - Fibrous dysplasia is a non-neoplastic hamartomatous developmental fibro-osseous lesion of bone. Monostotic fibrous dysplasia is more common than the polyostotic form and usually involves jaw bones, ribs and femur. Maxillary lesions may extend to involve the maxillary sinus, zygoma, sphenoid bone and floor of the orbit and require surgical intervention resulting in an acquired defect of the involved site. A multidisciplinary team approach involving an oral pathologist, oral surgeon, oral medicine expert and maxillofacial prosthodontist is required for successful treatment and rehabilitation of such patients. This article describes a case of a patient with fibrous dysplasia of the left maxilla, which was successfully managed by integrating surgical intervention and postoperative rehabilitation, with a surgical obturator and an interim partial denture prosthesis that successfully limited the detrimental effects of surgery, and helped the patient in resocialisation, thereby improving her quality of life. PMID- 26245287 TI - An unusual case of abdominal sepsis following traumatic injury. AB - A 19-year-old woman presented to our emergency department with crampy abdominal pain and per rectal bleeding 2 weeks after falling from a horse. She had been taking regular non-steroidal anti-inflammatory drugs (NSAIDs) for analgaesia. On arrival, she was tachycardic and tachypnoeic, with a lactate of 7.3 mmol/L. 'FAST' ultrasonography was unremarkable and CT scan showed thickened wall of the transverse colon. She underwent flexible sigmoidoscopy, which demonstrated "patchy inflammation and an isolated area of severe deep ulceration with nodularity and oedema". A presumptive diagnosis of "Inflammatory Bowel Disease likely Crohn's", was made, and treated accordingly with steroids and Pentasa. Two months following discharge, the patient underwent a colonoscopy, showing a normal colon, however, "a few ulcers in the terminal ileum" were seen. She was seen by a gastroenterologist who deemed the most likely diagnosis to be NSAID-induced terminal ileitis and colitis. Having stopped the offending NSAID (and steroids), she has now made a full recovery. PMID- 26245288 TI - Much more than anxiety... AB - Pheochromocytoma and paraganglioma are rare neuroendocrine tumours in paediatric ages. We report a case of a 14-year-old girl referred to our oncology centre due to an abdominal mass. She had an 11-month history of paroxysmal episodes of headache, nausea, dizziness, palpitations and visual disturbances. Imaging studies showed a left paravertebral mass measuring 5.8 * 4.6 * 3.5 cm. Metaiodobenzylguanidine scintigraphy revealed an abnormal hyperfixation on the left upper quadrant. Chromogranin A was elevated, as well as normetanephrine. The patient was submitted to surgery during which a connection between this mass and the adrenal gland was found. A diagnosis of pheochromocytoma was performed. PMID- 26245291 TI - Transparency, reproducibility, credibility: announcing a pilot. PMID- 26245292 TI - Multifrequency electrical impedance tomography with total variation regularization. AB - Multifrequency electrical impedance tomography (MFEIT) reconstructs the distribution of conductivity by exploiting the dependence of tissue conductivity on frequency. MFEIT can be performed on a single instance of data, making it promising for applications such as stroke and cancer imaging, where it is not possible to obtain a 'baseline' measurement of healthy tissue. A nonlinear MFEIT algorithm able to reconstruct the volume fraction distribution of tissue rather than conductivities has been developed previously. For each volume, the fraction of a certain tissue should be either 1 or 0; this implies that the sharp changes of the fractions, representing the boundaries of tissue, contain all the relevant information. However, these boundaries are blurred by traditional regularization methods using [Formula: see text] norm. The total variation (TV) regularization can overcome this problem, but it is difficult to solve due to its non differentiability. Because the fraction must be between 0 and 1, this imposes a constraint on the MFEIT method based on the fraction model. Therefore, a constrained optimization method capable of dealing with non-differentiable problems is required. Based on the primal and dual interior point method, we propose a new constrained TV regularized method to solve the fraction reconstruction problem. The noise performance of the new MFEIT method is analysed using simulations on a 2D cylindrical mesh. Convergence performance is also analysed through experiments using a cylindrical tank. Finally, simulations on an anatomically realistic head-shaped mesh are demonstrated. The proposed MFEIT method with TV regularization shows higher spatial resolution, particularly at the edges of the perturbation, and stronger noise robustness, and its image noise and shape error are 20% to 30% lower than the traditional fraction method. PMID- 26245293 TI - Clinical utility of the Neurobehavioral Symptom Inventory validity scales to screen for symptom exaggeration following traumatic brain injury. AB - The purpose of this study was to examine the clinical utility of three recently developed validity scales (Validity-10, NIM5, and LOW6) designed to screen for symptom exaggeration using the Neurobehavioral Symptom Inventory (NSI). Participants were 272 U.S. military service members who sustained a mild, moderate, severe, or penetrating traumatic brain injury (TBI) and who were evaluated by the neuropsychology service at Walter Reed Army Medical Center within 199 weeks post injury. Participants were divided into two groups based on the Negative Impression Management scale of the Personality Assessment Inventory: (a) those who failed symptom validity testing (SVT-fail; n = 27) and (b) those who passed symptom validity testing (SVT-pass; n = 245). Participants in the SVT fail group had significantly higher scores (p<.001) on the Validity-10, NIM5, LOW6, NSI total, and Personality Assessment Inventory (PAI) clinical scales (range: d = 0.76 to 2.34). Similarly high sensitivity, specificity, positive predictive power (PPP), and negative predictive (NPP) values were found when using all three validity scales to differentiate SVT-fail versus SVT-pass groups. However, the Validity-10 scale consistently had the highest overall values. The optimal cutoff score for the Validity-10 scale to identify possible symptom exaggeration was >=19 (sensitivity = .59, specificity = .89, PPP = .74, NPP = .80). For the majority of people, these findings provide support for the use of the Validity-10 scale as a screening tool for possible symptom exaggeration. When scores on the Validity-10 exceed the cutoff score, it is recommended that (a) researchers and clinicians do not interpret responses on the NSI, and (b) clinicians follow up with a more detailed evaluation, using well-validated symptom validity measures (e.g., Minnesota Multiphasic Personality Inventory-2 Restructured Form, MMPI-2-RF, validity scales), to seek confirmatory evidence to support an hypothesis of symptom exaggeration. PMID- 26245295 TI - Structural and aggregate analyses of (Li salt + glyme) mixtures: the complex nature of solvate ionic liquids. AB - The structure and interactions of different (Li salt + glyme) mixtures, namely equimolar mixtures of lithium bis(trifluoromethylsulfonyl)imide, nitrate or trifluoroacetate salts combined with either triglyme or tetraglyme molecules, are probed using Molecular Dynamics simulations. structure factor functions, calculated from the MD trajectories, confirmed the presence of different amounts of lithium-glyme solvates in the aforementioned systems. The MD results are corroborated by S(q) functions derived from diffraction and scattering data (HEXRD and SAXS/WAXS). The competition between the glyme molecules and the salt anions for the coordination to the lithium cations is quantified by comprehensive aggregate analyses. Lithium-glyme solvates are dominant in the lithium bis(trifluoromethylsulfonyl)imide systems and much less so in systems based on the other two salts. The aggregation studies also emphasize the existence of complex coordination patterns between the different species (cations, anions, glyme molecules) present in the studied fluid media. The analysis of such complex behavior is extended to the conformational landscape of the anions and glyme molecules and to the dynamics (solvate diffusion) of the bis(trifluoromethylsulfonyl)imide plus triglyme system. PMID- 26245294 TI - A complementary role for tetraspanin superfamily member CD151 and ADP purinergic P2Y12 receptor in platelets. AB - P2Y12 receptor is required for sustained activation of integrin alphaIIbbeta3, irreversible platelet aggregation and thrombus stabilisation. Tetraspanin superfamily member CD151 associates with integrin alphaIIbbeta3 and plays critical roles in regulation of thrombus growth and stability in vivo. The possible functional relationship between P2Y12 and CD151 in a molecular cluster in platelets may affect thrombus formation. Hence our aim was to investigate the physical and functional requirements for this association in platelets. Our investigations reveal a specific and constitutive association between CD151 and P2Y12 receptor in human platelets shown by immunoprecipitation/western blot studies and by flow cytometry. Specifically, the prominent association involves CD151 with P2Y12 oligomers, and to a lesser extent P2Y12 monomers. This association is not altered by platelet aggregation induced by different agonists. There is also a distinct complex of tetraspanin CD151 with ADP purinergic receptor P2Y12 but not P2Y1. P2Y12 oligomer interaction with CD151 is selective as compared to other tetraspanins. To investigate the functional relationship between these receptors in platelets we used wild-type or CD151 knockout (KO) mice treated with either PBS or 50 mg/kg clopidogrel. CD151 KO mice treated with clopidogrel exhibited synergy in delayed kinetics of clot retraction, in PAR-4 and collagen-mediated platelet aggregation, platelet spreading on fibrinogen and without restricting cAMP inhibition. Clopidogrel treated CD151 KO arterioles showed smaller and less stable thrombi with increased tendency to embolise ex vivo and in vivo. These studies demonstrate a complementary role between CD151 and P2Y12 receptor in platelets in regulating thrombus growth and stability. PMID- 26245296 TI - Self-assembled and pyrolyzed carbon aerogels: an overview of their preparation mechanisms, properties and applications. AB - An overview of the synthesis conditions and mechanisms for the fabrication of different types of carbon aerogels, as well as the structural and functional properties of these materials, is presented here. In this overview, carbon aerogels are classified into three major categories: (i) conventional pyrolyzed organic-based carbon aerogels, which are products of the pyrolysis process of organic aerogels; (ii) self-assembled carbon aerogels, which are products of a reduction process; and (iii) nanocomposite carbon aerogels. Synthesis mechanisms for the sol-gel process of organic aerogels are reviewed using different mechanisms suggested in the literature. Moreover, the overall fabrication process of self-assembled carbon aerogels (graphene and carbon nanotube aerogels) is covered and the suggested mechanism for the gelation process of self-assembled carbon aerogels during the reduction process is investigated using reported mechanisms. The structural performance and functional properties (electrochemical and thermal properties) of different types of carbon aerogels are covered in detail. Moreover, different structural features of carbon aerogels and the influence of synthesis conditions on these structural characteristics are assessed and compared. Based on the literature results covered in this review paper, carbon aerogels are perfect candidates for the fabrication of ultra-low density supercapacitors, as well as thermal insulating materials. PMID- 26245298 TI - Effect of intramuscular injections of DL-alpha-tocopheryl acetate on growth performance and extracellular matrix of growing lambs. AB - The effect of intramuscular injections of vitamin E on growth, carcass traits, intramuscular collagen (IMC) characteristics and decorin of growing lambs was studied. A total of 24 15-day-old Ile de France suckling male lambs were divided into two groups and weekly intramuscular injections of DL-alpha-tocopheryl acetate (control group, 0 IU; Vitamin E treatment, 150 IU) were given until the lambs were 64 days old. Lambs were individually weighted at 15, 29, 43, 57 days of age and at slaughter (71 days old). Dry matter intake and average daily weight gain were recorded. Hot and cold carcass weights were recorded and dressing percentages were calculated after dressing and chilling (2 degrees C to 4 degrees C for 24 h). Carcass shrink losses were calculated as well. Longissimus muscle (LM) pH and area were measured. The pelvic limb was removed and its percentage was calculated based on cold carcass weight. IMC and decorin analyses were assessed on LM and semimembranosus muscle (SM). DL-alpha-tocopheryl acetate treatment reduced (P<0.05) collagen maturity and increased (P<0.05) decorin in both LM and SM muscles of growing lambs, while it did not affect IMC content. In addition, vitamin E did not influence growth, carcass weight, dressing percentage, carcass shrink losses and area of LM but decreased (P<0.05) the pelvic limb percentage. The LM pH values were higher (P<0.05) in vitamin group than in control group. Furthermore, different IMC characteristics between the muscles (P<0.01) were apparent. Multiple intramuscular injections of DL-alpha tocopheryl acetate influence extracellular matrix in lambs, which could affect meat tenderness. PMID- 26245299 TI - Staudinger Reactions for Selective Functionalization of Polysaccharides: A Review. AB - Staudinger reactions are frequently highly chemoselective and can occur under very mild conditions, so are attractive methods for efficient functionalization of polysaccharides. This review describes recent investigations that exploit Staudinger-related reactions to effectively alter physical and chemical properties of polysaccharides in order to make them more diversely applicable. Staudinger-related reactions, such as Staudinger reduction, Staudinger ligation, and traceless Staudinger ligation comprise a powerful family of techniques enabling preparation of a wide range of polysaccharide derivatives with excellent chemoselectivity and the potential for excellent regioselectivity when combined with other methods. The remarkably mild conditions of the Staudinger reactions, combined with the abiotic nature of the azide group, make these reactions exceptionally attractive for modification of intact biological entities, including living cells. PMID- 26245297 TI - Status of the Parkinson's disease gene family expression in non-small-cell lung cancer. AB - BACKGROUND: The purpose of this study is to detect the Parkinson's disease gene family mRNA relative expression in the non-small-cell lung cancer (NSCLC) tumor tissue and analyze the association between tumor characteristics and the Parkinson's disease gene family. METHODS: Tumor tissue and tumor-adjacent tissue of 114 NSCLC patients were collected and SYBR quantitative analysis was used to detect the relative expression level of nine Parkinson's disease gene mRNAs. Then, paired sample test, two-sided Student's t-test, or two-sided Wilcoxon rank sum test was performed to analyze the mRNA relative expression level of nine Parkinson's disease gene mRNAs in different gender, tumor histology, and tumor stage. RESULTS: Overexpression in the tumors was detected in 46/114 (40.35%) PARK1/4, 74/114 (64.91%) PARK2, 104/114 (91.23%) PARK5, 95/114 (83.33%) PARK6, 80/114 (70.18%) PARK7, 55/114 (48.25%) PARK8, 100/114 (87.72%) PARK9, 55/114 (48.25%) PARK15, and 99/114 (86.84%) glucocerebrosidase (GBA). Five genes PARK5 (91.23%), PARK6 (83.33%), PARK7 (70.18%), PARK9 (87.72%), and GBA (86.84%) were supposed to be overexpressed in the lung tumor tissues compared with tumor adjacent tissues. There was no significant difference in PARK1/4, PARK2, PARK5, PARK9, and GBA mRNA expression by different tumor stage, whereas, PARK6, PARK7, PARK8, and PARK15 mRNA expression were found to have significant difference in the comparison of different tumor stages. The expression of PARK6 (P=0.01, P=0.03) and PARK15 (P<0.001, P<0.001) were significantly higher in stages I and II when compared with stage III, respectively. NSCLC patients in stage I showed the higher expression PARK7 compared to the patients in stage II (P=0.003). CONCLUSIONS: The high expression of PARK6, PARK7, and PARK15 might lead to the occurrence of a primary NSCLC tumor, and the tumor with a decreasing expression of these three genes tends to be stages II and III. The results of our study indicate that the Parkinson's disease gene family may be a potential marker for the prediction of NSCLC. PMID- 26245300 TI - Occurrence, distribution and risks of antibiotics in urban surface water in Beijing, China. AB - The occurrence and distribution of 22 antibiotics, including eight fluoroquinolones, nine sulfonamides and five macrolides, were investigated in the urban surface waters in Beijing, China. A total of 360 surface water samples were collected from the main rivers and lakes in the urban area of Beijing monthly from July 2013 to June 2014 (except the frozen period). Laboratory analyses revealed that antibiotics were widely used and extensively distributed in the surface water of Beijing, and sulfonamides and fluoroquinolones were the predominant antibiotics with the average concentrations of 136 and 132 ng L(-1), respectively. A significant difference of antibiotic concentrations from different sampling sites was observed, and the southern and eastern regions of Beijing showed higher concentrations of antibiotics. Seasonal variation of the antibiotics in the urban surface water was also studied, and the highest level of antibiotics was found in November, which may be due to the low temperature and flow of the rivers during the period of cold weather. Risk assessment showed that several antibiotics might pose high ecological risks to aquatic organisms (algae and plants) in surface water, and more attention should be paid to the risk of antibiotics to the aquatic environment in Beijing. PMID- 26245301 TI - Isolation, characterization and mechanism of action of an antimicrobial peptide from Lecythis pisonis seeds with inhibitory activity against Candida albicans. AB - Antimicrobial peptides (AMPs) are produced by a range of organisms as a first line of defense against invaders or competitors. Owing to their broad antimicrobial activity, AMPs have attracted attention as a potential source of chemotherapeutic drugs. The increasing prevalence of infections caused by Candida species as opportunistic pathogens in immunocompromised patients requires new drugs. Lecythis pisonis is a Lecythydaceae tree that grows in Brazil. The AMPs produced by this tree have not been described previously. We describe the isolation of 12 fractions enriched in peptides from L. pisonis seeds. Of the 12 fractions, at 10 MUg/ml, the F4 fraction had the strongest growth inhibitory effect (53.7%) in Candida albicans, in addition to a loss of viability of 94.9%. The F4 fraction was separated into seven sub-fractions by reversed-phase chromatography. The F4.7' fraction had the strongest activity at 10 MUg/ml, inhibiting C. albicans growth by 38.5% and a 69.3% loss of viability. The peptide in F4.7' was sequenced and was found to be similar to plant defensins. For this reason, the peptide was named L. pisonis defensin 1 (Lp-Def1). The mechanism of action that is responsible for C. albicans inhibition by Lp-Def1 includes a slight increase of reactive oxygen species induction and a significant loss of mitochondrial function. The results described here support the future development of plant defensins, specifically Lp-Def1, as new therapeutic substances against fungi, especially C. albicans. PMID- 26245302 TI - Calculation of the clearance requirements for the development of a hemodialysis based wearable artificial kidney. AB - Wearable artificial kidney (WAK) has been considered an alternative to standard hemodialysis (HD) for many years. Although various novel WAK systems have been recently developed for use in clinical applications, the target performance or standard dose of dialysis has not yet been determined. To calculate the appropriate clearance for a HD-based WAK system for the treatment of patients with end-stage renal disease with various dialysis conditions, a classic variable volume two-compartment kinetic model was used to simulate an anuric patient with variable target time-averaged creatinine concentration (TAC), daily water intake volume, daily dialysis pause time, and patient body weight. A 70-kg anuric patient with a HD-based WAK system operating for 24 h required dialysis clearances of creatinine of at least 100, 50, and 25 mL/min to achieve TACs of 1.0, 2.0, and 4.0 mg/dL, respectively. The daily water intake volume did not affect the clearance required for dialysis under various conditions. As the pause time per day for the dialysis increased, higher dialysis clearances were required to maintain the target TAC. The present study provided theoretical dialysis doses for an HD-based WAK system to achieve various target TACs through relevant mathematical kinetic modeling. The theoretical results may contribute to the determination of the technical specifications required for the development of a WAK system. PMID- 26245303 TI - Complexins: small but capable. AB - Despite intensive research, it is still unclear how an immediate and profound acceleration of exocytosis is triggered by appropriate Ca(2+)-stimuli in presynaptic terminals. This is due to the fact that the molecular mechanisms of "docking" and "priming" reactions, which set up secretory vesicles to fuse at millisecond time scale, are extremely hard to study. Yet, driven by a fruitful combination of in vitro and in vivo analyses, our mechanistic understanding of Ca(2+)-triggered vesicle fusion has certainly advanced in the past few years. In this review, we aim to highlight recent progress and emerging views on the molecular mechanisms, by which constitutively forming SNAREpins are organized in functional, tightly regulated units for synchronized release. In particular, we will focus on the role of the small regulatory factor complexin whose function in Ca(2+)-dependent exocytosis has been controversially discussed for more than a decade. Special emphasis will also be laid on the functional relationship of complexin and synaptotagmin, as both proteins possibly act as allies and/or antagonists to govern SNARE-mediated exocytosis. PMID- 26245304 TI - Protein O-mannosylation is crucial for human mesencyhmal stem cells fate. AB - Human mesenchymal stem cells (MSC) are promising cell types in the field of regenerative medicine. Although many pathways have been dissected in the effort to better understand and characterize MSC potential, the impact of protein N- or O-glycosylation has been neglected. Deficient protein O-mannosylation is a pathomechanism underlying severe congenital muscular dystrophies (CMD) that start to develop at the embryonic developmental stage and progress in the adult, often in tissues where MSC exert their function. Here we show that O-mannosylation genes, many of which are putative or verified glycosyltransferases (GTs), are expressed in a similar pattern in MSC from adipose tissue, bone marrow, and umbilical cord blood and that their expression levels are retained constant during mesengenic differentiation. Inhibition of the first players of the enzymatic cascade, POMT1/2, resulted in complete abolishment of chondrogenesis and alterations of adipogenic and osteogenic potential together with a lethal effect during myogenic induction. Since to date, no therapy for CMD is available, we explored the possibility of using MSC extracellular vesicles (EVs) as molecular source of functional GTs mRNA. All MSC secrete POMT1 mRNA-containing EVs that are able to efficiently fuse with myoblasts which are among the most affected cells by CMD. Intriguingly, in a pomt1 patient myoblast line EVs were able to partially revert O-mannosylation deficiency and contribute to a morphology recovery. Altogether, these results emphasize the crucial role of protein O-mannosylation in stem cell fate and properties and open the possibility of using MSC vesicles as a novel therapeutic approach to CMD. PMID- 26245306 TI - Computational Field Shaping for Deep Brain Stimulation With Thousands of Contacts in a Novel Electrode Geometry. AB - OBJECTIVE: Deep brain stimulation (DBS) alleviates symptoms associated with some neurological disorders by stimulating specific deep brain targets. However, incomplete stimulation of the target region can provide suboptimal therapy, and spread of stimulation to tissue outside the target can generate side-effects. Existing DBS electrodes generate stimulation profiles that are roughly spherical, neither matching nor enabling the mapping of therapeutic targets. We present a novel electrode design and will perform computational modeling of the new design to investigate its use as a next generation DBS electrode. MATERIALS AND METHODS: Computational simulations of a finite element model are performed for both the novel electrode and for a commercially available DBS electrode. RESULTS: Computational modeling results show that this new electrode design is able to steer stimulation radially around the device, creating voltage distributions that may more closely match deep brain targets. CONCLUSION: The ability to better match the anatomy and compensate for targeting errors during implantation will enable strict localization of the generated stimulation fields to within target tissues, potentially providing more complete symptom alleviation while reducing the occurrence of side-effects. PMID- 26245307 TI - Differences in lifestyle, physical performance and quality of life between frail and robust Brazilian community-dwelling elderly women. AB - AIM: To investigate the lifestyles, physical performance and quality of life (QOL) of frail and robust Brazilian community-dwelling older women, and to identify risk factors for frailty. METHODS: Frailty was assessed using the Kihon Checklist. Lifestyles were assessed using a questionnaire. Physical performance was assessed by measuring walking speeds, performance on the one-leg stand test and the five-times chair stand test and handgrip strength. QOL was assessed using the Short Form-8 questionnaire. Participants were divided into frail and robust groups based on their total Kihon Checklist scores. RESULTS: A total of 109 participants (age 70.8 +/- 6.87 years) were included in this study (robust n = 85, frail n = 24). Differences in living structures (P < 0.001), financial satisfaction (P = 0.004) and the frequencies with which participants leave the house (P < 0.001) were found between groups. The frail group had more fallers (P = 0.047), and lower engagement in physical activity (P = 0.044), lower body mass indices (P = 0.043) and poorer nutritional status (P = 0.002), whereas robust older people showed better physical performance (walking speed P < 0.001, one-leg stand P = 0.021, handgrip strength P = 0.002) and higher QOL scores (general health P = 0.005, role-physical P = 0.013, bodily pain P = 0.002, vitality P = 0.001, social functioning P = 0.001, role-emotional P = 0.008). Multivariate regression analysis identified a slow usual walking speed and bodily pain as risk factors for frailty. CONCLUSIONS: Frail participants had higher indices for being housebound, and having financial dissatisfaction, a sedentary lifestyle, falls, and malnutrition. Furthermore, they showed poorer physical performance and QOL. An early, well-focused approach is crucial, especially for older adults who walk slowly and have bodily pain to preserve health and QOL. Geriatr Gerontol Int 2016; 16: 829-835. PMID- 26245308 TI - Asymmetric vinylogous Michael reaction of cyclic enones with silyloxy furans. AB - The asymmetric vinylogous Michael reaction of cyclohexenone/medium and large cyclic enones with 2-silyloxyfuran is still a synthetic challenge. In this report, we have explored 1,4-conjugate addition of an enantioselective chiral, primary diamine catalyzed, 2-silyloxy furan to various cyclic enones and beta substituted cyclic enones. The reaction provided syn-Michael adducts (cycloalkane connected gamma-butenolide) with good yields, diastereo and enantioselectivities. Furthermore, the synthetic potential of these syn-Michael adducts is demonstrated by 1,4-addition of nucleophiles on the butenolide substructure. PMID- 26245305 TI - Towards molecular mechanisms regulating the expression of galectins in cancer cells under microenvironmental stress conditions. AB - Galectins, a family of soluble beta-galactoside-binding proteins, serve as mediators of fundamental biological processes, such as cell growth, differentiation, adhesion, migration, survival, and death. The purpose of this review is to summarize the current knowledge regarding the ways in which the expression of individual galectins differs in normal and transformed human cells exposed to various stimuli mimicking physiological and pathological microenvironmental stress conditions. A conceptual point is being made and grounded that the modulation of galectin expression profiles is a key aspect of cellular stress responses. Moreover, this modulation might be precisely regulated at transcriptional and post-transcriptional levels in the context of non overlapping transcription factors and miRNAs specific to galectins. PMID- 26245309 TI - Temsirolimus targets multiple hallmarks of cancer to impede mesothelioma growth in vivo. AB - BACKGROUND AND OBJECTIVE: The mechanistic target of rapamycin (mTOR) promotes cancer cell proliferation and survival, transduces pro-angiogenic signals and regulates immune cell differentiation and function. We hypothesized that temsirolimus, an mTOR inhibitor, would curtail experimental mesothelioma progression in vivo by limiting tumour cell growth, abrogating tumour angiogenesis and modulating immune/inflammatory tumour milieu. METHODS: We produced flank and pleural syngeneic murine mesotheliomas by delivering AE17 and AB1 murine mesothelioma cells into the right flank or the pleural space of C57BL/6 and BALB/c mice, respectively. Animals were given five times/week intraperitoneal injections of 20 mg/kg temsirolimus or vehicle and were sacrificed on day 26 (flank) or on day 15 (pleural) post-tumour cell propagation. RESULTS: Temsirolimus limited mesothelioma growth in vivo by stimulating tumour cell apoptosis, inhibiting tumour angiogenesis, enhancing tumour lymphocyte abundance and blocking pro-tumour myeloid cell recruitment. Pleural fluid accumulation was significantly mitigated in AE17 but not in AB1 mesotheliomas. In vitro, temsirolimus hindered mesothelioma cell growth, NF-kappaB activation and macrophage migration. CONCLUSIONS: In conclusion, temsirolimus apart from inducing tumour cell apoptosis, targets tumour angiogenesis and influences inflammatory tumour microenvironment to halt experimental mesothelioma growth in vivo. PMID- 26245310 TI - A Prospective Study for Introducing Insulin Pens and Safety Needles in a Hospital Setting. The SANITHY Study. AB - BACKGROUND: to assess costs and safety of insulin pen devices and safety needles as compared to vial/syringes in hospitalized patients requiring insulin therapy in a General Hospital in Northern Italy. MATERIALS AND METHODS: in a prospective 9-month study, consecutive patients admitted to three Hospital Units received insulin therapy through either a traditional disposable syringe method, or pen/safety needles with dual-ended protection, or disposable safety syringes. We compared the median direct (insulin and devices) and indirect (insulin supply at discharge, insulin wastage) costs of a 10-day in-hospital insulin treatment in the 3 study groups, additionally accounting for the costs related to the observed needlestick injury rate. Patients' safety during in-hospital stay (hypo- and hyperglycemia episodes) and satisfaction were also assessed. RESULTS: N=360 patients (55% men, mean age 75.6 years, 57% with DM since >=10 years) were recruited in the study. Insulin pens had higher median direct cost than both traditional syringes (43 vs. 18 epsilon/patient, p<.0001) and safety syringes (21.5 epsilon/patient, p<.0001). However, when also indirect and injuries costs were taken into account, the estimated savings for using pens over traditional syringes were as high as 32 epsilon/patient (45.8 vs. 77.6 epsilon/patient, p value <.0001). No differences in patients' safety were observed. 74% and 12% of patients using pens and syringes would like to continue the method at home, respectively (p<0.0001). DISCUSSION: A selective use of individual pre-filled pens/safety needles for patients who are likely to continue insulin therapy at home may strongly reduce hospital diabetes treatment related costs. PMID- 26245311 TI - Reparixin attenuates neuronal injury in experimental Klebsiella pneumoniae meningoencephalitis through dual effects on neuroprotection and neuroinflammation. AB - AIMS: Bacterial meningitis causes high mortality and brain damage. The host immune response is associated with brain injury. Chemokine (C-X-C motif) (CXC) chemokines are neutrophil chemoattractants. This study focused on the beneficial effects of intracerebroventricular administration of reparixin, an inhibitor of chemokine (C-X-C motif) receptor (CXCR)1/2, to rats at 2 h following experimental Klebsiella pneumoniae meningoencephalitis. METHODS: We used a previously established meningoencephalitis animal model in which Sprague-Dawley rats were infected by K. pneumoniae. Sham and infected animals were treated with vehicle or reparixin and sacrificed at various time points. Leukocyte infiltration into cerebrospinal fluid (CSF) and brain as well as gene and protein expression of chemokines and receptors, and neuronal apoptosis were examined. Primary cultures of neuron/glia were infected with K. pneumoniae as an in vitro model of meningoencephalitis. RESULTS: Levels of chemokine (C-X-C motif) ligand (CXCL)2 in CSF time-dependently increased markedly as early as 2 h, and peaked at 8 h following infection and were much higher than those in serum collected simultaneously. Reparixin significantly reduced leukocyte infiltration into CSF and brain tissues, clinical illness, and brain cell apoptosis at 24 h. Reparixin reduced the elevated CSF concentrations of chemokines [CXCL1, CXCL2, chemokine (C C motif) ligand (CCL)2 and CCL5] and proinflammatory cytokines. Reparixin also reduced the expression of mRNA of various chemokines, chemokine receptors and proinflammatory cytokines in infected brain tissues. Using primary cultures that are devoid of leukocytes, we further observed that reparixin attenuated the neuronal, but not microglial cell death after infection. CONCLUSIONS: Reparixin not only reduces amplified inflammation, but also provides direct neuroprotective effects in K. pneumoniae meningoencephalitis. PMID- 26245312 TI - Damage-associated molecular patterns generated in osteoarthritis directly excite murine nociceptive neurons through Toll-like receptor 4. AB - OBJECTIVE: To determine whether selected damage-associated molecular patterns (DAMPs) present in the osteoarthritic (OA) joints of mice excite nociceptors through Toll-like receptor 4 (TLR-4). METHODS: The ability of S100A8 and alpha2 macroglobulin to excite nociceptors was determined by measuring the release of monocyte chemoattractant protein 1 (MCP-1) by cultured dorsal root ganglion (DRG) cells as well as by measuring the intracellular calcium concentration ([Ca(2+) ]i ) in cultured DRG neurons from naive mice or from mice that had undergone surgical destabilization of the medial meniscus (DMM) 8 weeks previously. The role of TLR-4 was assessed using TLR-4(-/-) cells or a TLR-4 inhibitor. The [Ca(2+) ]i in neurons within ex vivo intact DRGs was measured in samples from Pirt-GCaMP3 mice. Neuronal expression of the Tlr4 gene was determined by in situ hybridization. DMM surgery was performed in wild-type and TLR-4(-/-) mice; mechanical allodynia was monitored, and joint damage was assessed histologically after 16 weeks. RESULTS: DRG neurons from both naive and DMM mice expressed Tlr4. Both S100A8 and alpha2 -macroglobulin stimulated release of the proalgesic chemokine MCP-1 in DRG cultures, and the neurons rapidly responded to S100A8 and alpha2 -macroglobulin with increased [Ca(2+) ]i . Blocking TLR-4 inhibited these effects. Neurons within intact DRGs responded to the TLR-4 agonist lipopolysaccharide. In both of the calcium-imaging assays, it was primarily the nociceptor population of neurons that responded to TLR-4 ligands. TLR-4(-/-) mice were not protected from mechanical allodynia or from joint damage associated with DMM. CONCLUSION: Our experiments suggest a role of TLR-4 signaling in the excitation of nociceptors by selected DAMPs. Further research is needed to delineate the importance of this pathway in relation to OA pain. PMID- 26245313 TI - Learning feedback and feedforward control in a mirror-reversed visual environment. AB - When we learn a novel task, the motor system needs to acquire both feedforward and feedback control. Currently, little is known about how the learning of these two mechanisms relate to each other. In the present study, we tested whether feedforward and feedback control need to be learned separately, or whether they are learned as common mechanism when a new control policy is acquired. Participants were trained to reach to two lateral and one central target in an environment with mirror (left-right)-reversed visual feedback. One group was allowed to make online movement corrections, whereas the other group only received visual information after the end of the movement. Learning of feedforward control was assessed by measuring the accuracy of the initial movement direction to lateral targets. Feedback control was measured in the responses to sudden visual perturbations of the cursor when reaching to the central target. Although feedforward control improved in both groups, it was significantly better when online corrections were not allowed. In contrast, feedback control only adaptively changed in participants who received online feedback and remained unchanged in the group without online corrections. Our findings suggest that when a new control policy is acquired, feedforward and feedback control are learned separately, and that there may be a trade-off in learning between feedback and feedforward controllers. PMID- 26245314 TI - Rod- and cone-driven responses in mice expressing human L-cone pigment. AB - The mouse is commonly used for studying retinal processing, primarily because it is amenable to genetic manipulation. To accurately study photoreceptor driven signals in the healthy and diseased retina, it is of great importance to isolate the responses of single photoreceptor types. This is not easily achieved in mice because of the strong overlap of rod and M-cone absorption spectra (i.e., maxima at 498 and 508 nm, respectively). With a newly developed mouse model (Opn1lw(LIAIS)) expressing a variant of the human L-cone pigment (561 nm) instead of the mouse M-opsin, the absorption spectra are substantially separated, allowing retinal physiology to be studied using silent substitution stimuli. Unlike conventional chromatic isolation methods, this spectral compensation approach can isolate single photoreceptor subtypes without changing the retinal adaptation. We measured flicker electroretinograms in these mutants under ketamine-xylazine sedation with double silent substitution (silent S-cone and either rod or M/L-cones) and obtained robust responses for both rods and (L )cones. Small signals were yielded in wild-type mice, whereas heterozygotes exhibited responses that were generally intermediate to both. Fundamental response amplitudes and phase behaviors (as a function of temporal frequency) in all genotypes were largely similar. Surprisingly, isolated (L-)cone and rod response properties in the mutant strain were alike. Thus the LIAIS mouse warrants a more comprehensive in vivo assessment of photoreceptor subtype specific physiology, because it overcomes the hindrance of overlapping spectral sensitivities present in the normal mouse. PMID- 26245315 TI - Thalamic mechanisms underlying alpha-delta sleep with implications for fibromyalgia. AB - Alpha-delta sleep is the abnormal intrusion of alpha activity (8- to 13-Hz oscillations) into the delta activity (1- to 4-Hz oscillations) that defines slow wave sleep. Alpha-delta sleep is especially prevalent in fibromyalgia patients, and there is evidence suggesting that the irregularities in the sleep of these patients may cause the muscle and tissue pain that characterizes the disorder. We constructed a biophysically realistic mathematical model of alpha-delta sleep. Imaging studies in fibromyalgia patients suggesting altered levels of activity in the thalamus motivated a thalamic model as the source of alpha activity. Since sodium oxybate helps to alleviate the symptoms of fibromyalgia and reduces the amount of alpha-delta sleep in fibromyalgia patients, we examined how changes in the molecular targets of sodium oxybate affected alpha-delta activity in our circuit. Our model shows how alterations in GABAB currents and two thalamic currents, Ih (a hyperpolarization-activated current) and a potassium leak current, transform a circuit that normally produces delta oscillations into one that produces alpha-delta activity. Our findings suggest that drugs that reduce Ih conductances and/or increase potassium conductances, without necessarily increasing GABAB conductances, might be sufficient to restore delta sleep. Furthermore, they suggest that delta sleep might be restored by drugs that preferentially target these currents in the thalamus; such drugs might have fewer side effects than drugs that act systemically. PMID- 26245316 TI - Multivariate sensitivity to voice during auditory categorization. AB - Past neuroimaging studies have documented discrete regions of human temporal cortex that are more strongly activated by conspecific voice sounds than by nonvoice sounds. However, the mechanisms underlying this voice sensitivity remain unclear. In the present functional MRI study, we took a novel approach to examining voice sensitivity, in which we applied a signal detection paradigm to the assessment of multivariate pattern classification among several living and nonliving categories of auditory stimuli. Within this framework, voice sensitivity can be interpreted as a distinct neural representation of brain activity that correctly distinguishes human vocalizations from other auditory object categories. Across a series of auditory categorization tests, we found that bilateral superior and middle temporal cortex consistently exhibited robust sensitivity to human vocal sounds. Although the strongest categorization was in distinguishing human voice from other categories, subsets of these regions were also able to distinguish reliably between nonhuman categories, suggesting a general role in auditory object categorization. Our findings complement the current evidence of cortical sensitivity to human vocal sounds by revealing that the greatest sensitivity during categorization tasks is devoted to distinguishing voice from nonvoice categories within human temporal cortex. PMID- 26245317 TI - Alterations in functional thalamocortical connectivity following neonatal whisker trimming with adult regrowth. AB - Neonatal whisker trimming followed by adult whisker regrowth leads to higher responsiveness and altered receptive field properties of cortical neurons in corresponding layer 4 barrels. Studies of functional thalamocortical (TC) connectivity in normally reared adult rats have provided insights into how experience-dependent TC synaptic plasticity could impact the establishment of feedforward excitatory and inhibitory receptive fields. The present study employed cross-correlation analyses to investigate lasting effects of neonatal whisker trimming on functional connections between simultaneously recorded thalamic neurons and regular-spike (RS), presumed excitatory, and fast-spike (FS), presumed inhibitory, barrel neurons. We find that, as reported previously, RS and FS cells in whisker-trimmed animals fire more during the earliest phase of their whisker-evoked responses, corresponding to the arrival of TC inputs, despite a lack of change or even a slight decrease in the firing of thalamic cells that contact them. Functional connections from thalamus to cortex are stronger. The probability of finding TC-RS connections was twofold greater in trimmed animals and similar to the frequency of TC-FS connections in control and trimmed animals, the latter being unaffected by whisker trimming. Unlike control cases, trimmed RS units are more likely to receive inputs from TC units (TCUs) and have mismatched angular tuning and even weakly responsive TCUs make strong functional connections on them. Results indicate that developmentally appropriate tactile experience early in life promotes the differential thalamic engagement of excitatory and inhibitory cortical neurons that underlies normal barrel function. PMID- 26245318 TI - Functional changes in Tg P23H-1 rat retinal responses: differences between ON and OFF pathway transmission to the superior colliculus. AB - The morphological consequences of retinal photoreceptor degeneration are well documented. Much less is known about changes in visual function during degeneration and whether central visual structures directly reflect changes in retinal ganglion cell (RGC) function. To address this, we compared changes in visual function of RGCs and cells in the superior colliculus (SC) in transgenic (Tg) P23H-1 rats, a model of retinitis pigmentosa (RP), and wild-type (WT) rats at postnatal days 35-50 (P35-50) and P300. RGCs were classified on the basis of their responses to light: onset (ON), offset (OFF), or both (ON-OFF). The distribution of ON, OFF, and ON-OFF RGCs is similar between WT and P35 Tg P23H-1 rats. By P300, many Tg P23H-1 RGCs are nonresponsive (NR). At this age, there is a sharp decline in ON and ON-OFF RGCs, and the majority that remain are OFF RGCs. Spontaneous rhythmic activity was observed in many RGCs at P300, but only in OFF or NR RGCs. In the SC, WT and P50 Tg P23H-1 responses are similar. At P300, Tg P23H-1 ON SC responses declined but OFF responses increased. We examined postsynaptic glutamate receptor expression located on the bipolar cells (BC), where the ON and OFF pathways arise. At P150, metabotropic glutamate receptor 6 (mGluR6) expression is lower than in WT, consistent with a decrease in ON RGC responses. GluR4 expression, an ionotropic glutamate receptor associated with OFF BCs, appears similar to that in WT. The loss of ON responses in Tg P23H-1 RGCs and in the SC is conserved and related to reduced mGluR6 signaling. PMID- 26245319 TI - Stimulus-induced up states in the dorsal pallium of a weakly electric fish. AB - We investigated the response of putative novelty-detecting neurons in the pallium of an electric fish to electrosensory and acoustic stimuli. Extracellular and whole cell patch recordings were made from neurons in the dorsal pallial nucleus (DD) of Apteronotus leptorhynchus. DD neurons were typically quiescent and exhibited hyperpolarized resting membrane potentials. Stimulation induced, with a variable long latency, rapid though transient depolarization and spike discharge. The transition between resting and depolarized/spiking states resembled the transition to Up states seen in mammalian telencephalic neurons. PMID- 26245320 TI - Interpreting the electrophysiological power spectrum. AB - Recent experimental findings suggest that there may be rich physiological information embedded within the power spectrum of neurophysiological recordings, which, in addition to power in specific oscillatory frequencies, can be extracted with the appropriate model. This article reviews previous empirical and modeling results, as well as the canonical power law model that is often used to describe the power spectrum. In addition, a modified power law model with parameters estimating synaptic and spiking contributions is proposed. PMID- 26245321 TI - Modeling and simulating the neuromuscular mechanisms regulating ankle and knee joint stiffness during human locomotion. AB - This work presents an electrophysiologically and dynamically consistent musculoskeletal model to predict stiffness in the human ankle and knee joints as derived from the joints constituent biological tissues (i.e., the spanning musculotendon units). The modeling method we propose uses electromyography (EMG) recordings from 13 muscle groups to drive forward dynamic simulations of the human leg in five healthy subjects during overground walking and running. The EMG driven musculoskeletal model estimates musculotendon and resulting joint stiffness that is consistent with experimental EMG data as well as with the experimental joint moments. This provides a framework that allows for the first time observing 1) the elastic interplay between the knee and ankle joints, 2) the individual muscle contribution to joint stiffness, and 3) the underlying co contraction strategies. It provides a theoretical description of how stiffness modulates as a function of muscle activation, fiber contraction, and interacting tendon dynamics. Furthermore, it describes how this differs from currently available stiffness definitions, including quasi-stiffness and short-range stiffness. This work offers a theoretical and computational basis for describing and investigating the neuromuscular mechanisms underlying human locomotion. PMID- 26245322 TI - Rheumatoid Factor Is Associated With the Distribution of Hand Joint Destruction in Rheumatoid Arthritis. AB - OBJECTIVE: Rheumatoid arthritis (RA) is a chronic disease leading to joint destruction. Although many studies have addressed factors potentially correlated with the speed of joint destruction, less attention has been paid to the distribution of joint destruction in patients with RA. In this study, destruction of the hand bones in patients with RA was classified into 2 anatomic subgroups, the fingers and the non-fingers, with the aim of analyzing which factors are associated with destruction of the finger joints. METHODS: A total of 1,215 Japanese patients with RA were recruited from 2 different populations. The degree of joint destruction was assessed using the total modified Sharp/van der Heijde score (SHS) of radiographic joint damage. The SHS score of joint damage in the finger joints was used as the dependent variable, and the SHS score in the non finger joints was used as a covariate. Age, sex, disease duration, smoking, C reactive protein level, treatment for RA, and positivity for and levels of anti citrullinated protein antibodies and rheumatoid factor (RF) were evaluated as candidate correlates. Overall effect sizes were assessed in a meta-analysis. In addition, associations observed in the Japanese patients were compared to those in a cohort of 157 Dutch RA patients in the BeSt study (a randomized, controlled trial involving 4 different strictly specified treatment strategies for early RA). RESULTS: Not surprisingly, disease duration in Japanese patients with RA was associated with the finger SHS score (P <= 0.00037). Both positivity for and levels of RF showed significant associations with the finger SHS score after adjustment for covariates (P = 0.0022 and P = 8.1 * 10(-7) , respectively). These associations were also true in relation to the time-averaged finger SHS score. An association between RF positivity and the finger SHS score was also observed in Dutch patients with RA in the BeSt study (P = 0.049). CONCLUSION: Positivity for and levels of RF are associated with finger joint destruction independent of non finger joint destruction and other covariates. Our findings suggest that there are different mechanisms of joint destruction operating in the finger joints of patients with RA. PMID- 26245324 TI - The role of stable housing as a determinant of poverty-related quality of life in vulnerable individuals. AB - OBJECTIVE: The aim of this study was to identify potential socio-demographic and socio-economic determinants associated with quality of life (QoL) in impoverished individuals admitted in emergency departments (EDs) using a self-administered multidimensional poverty-related QoL questionnaire (PQoL) and a generic QoL questionnaire (Duke). DESIGN: cross-sectional study. SETTING: Ten EDs in France. PARTICIPANTS: All participants included in this study lived in impoverished conditions. INTERVENTION AND OUTCOME MEASURES: We collected socio-demographic information, economic data, and data related to the ED visit. Multiple linear regressions were performed to determine which variables were linked to QoL scores. RESULTS: Three-hundred and eighty-seven individuals were enrolled, and 378 (98%) responded to the QoL questionnaires. PQoL was significantly lower for single individuals (beta from -0.15 to -0.23), without a stable home (beta from 0.17 to -0.34) and individuals without general health coverage (beta = 0.20). Compared with men, women reported lower scores in the psychological well-being dimension (beta = -0.19) and higher scores in the relationships with friends dimension (beta = 0.17). CONCLUSIONS: Not having stable housing was the most important factor associated with low QoL in impoverished people. This finding demonstrates the need for support from policymakers at the national and local levels for these vulnerable populations. PMID- 26245325 TI - Biomechanical comparison of arthroscopic repair constructs for radial tears of the meniscus. AB - BACKGROUND: Radial tears of the meniscus represent a challenging clinical scenario because benign neglect and partial meniscectomy have both been shown to have negative biomechanical and long-term clinical consequences. HYPOTHESIS: Complex suture repair constructs have higher failure loads and stiffness values compared with simple constructs. STUDY DESIGN: Controlled laboratory study. METHODS: After radial transection of human cadaveric menisci, simulated tears were repaired arthroscopically by use of 1 of 4 repair constructs: (1) 2 inside out horizontal sutures, (2) 2 all-inside horizontal sutures, (3) an all-inside Mason-Allen construct consisting of 4 sutures, or (4) an all-inside construct consisting of a figure-of-8 suture plus 1 horizontal suture. Meniscus specimens were harvested and tested to failure on an Instron machine. The Kruskal-Wallis test was used to evaluate for significance of maximal failure load and stiffness between groups. RESULTS: The mean maximum failure loads were 64 +/- 20 N (inside out horizontal construct), 75 +/- 16 N (all-inside horizontal construct), 86 +/- 19 N (Mason-Allen construct), and 113 +/- 22 N (figure-of-8 plus horizontal construct). Interconstruct comparison revealed a statistically significant difference between the figure-of-8 plus horizontal construct and all 3 remaining constructs (P < .02) as well as the Mason-Allen construct when compared with the inside-out horizontal construct (P < .01). Statistical significance was not found between the all-inside horizontal construct and the Mason-Allen construct or between the all-inside horizontal construct and the inside-out horizontal construct (P = .2 and .7, respectively). Stiffness values were lower for the inside-out construct compared with the all-inside constructs (P < .05). CONCLUSION: Complex all-inside repair constructs had significantly higher failure loads than a conventional, simple inside-out suture repair construct for repair of radial meniscal tears. Stiffness values among the all-inside groups were greater than those for the inside-out group. CLINICAL RELEVANCE: Arthroscopic techniques are presented to produce stronger radial meniscal tear repairs. PMID- 26245326 TI - Evaluation of total body water in canine breeds by single-frequency bioelectrical impedance analysis method: specific equations are needed for accuracy. AB - BACKGROUND: Equations based on single-frequency bioelectrical impedance analysis at 50 kHz for determination of total body water content (TBW) have been previously validated in healthy non-sedated beagle dogs. We investigated whether these equations are predictive of TBW in various canine breeds by comparing the results of these equations with TBW values evaluated directly by deuterium oxide (D2O) dilution. METHODS: Total body water content of 13 healthy adult pet dogs of various breeds was determined directly using D2O dilution and indirectly using previous equations based on values obtained with a portable bioelectric impedance device. Paired Student's t-tests were used to compare TBW obtained by single frequency bioelectrical impedance analysis and D2O dilution. A p-value of <0.05 was considered statistically significant for all analyses. RESULTS: Significant differences were observed between TBW determined by the reference method and the values obtained with both predictive equations. CONCLUSIONS: The proposed equations including single-frequency bioelectrical impedance analysis parameters validated at 50 kHz in healthy adult beagles need to be modified including morphological parameters such as body size and shape in a first approach. As in humans, morphological-specific equations have to be developed and validated. PMID- 26245327 TI - Varied utilisation of health provision by Arab and Jewish residents in Israel. AB - INTRODUCTION: Provision of healthcare is considered a basic human right. Delivery and uptake is affected by many complex factors. Routine vaccinations are provided free of charge in Israel to all residents. The Palestinian Israeli Collaborative Research (PICR) group conducted research on vaccine impact at eight primary care facilities in east Jerusalem (EJ) and central Israel (IL) which allowed assessment and comparison of interactions of these Arab and Jewish populations, respectively, with healthcare services. METHODS: Families attending clinic with a child under five years old were invited to participate. Utilisation of healthcare was assessed using data from standardise questionnaires completed after enrolment, using proxies of vaccination status, antibiotic use, primary care physician and hospital visits as well as demographics such as household size. Differences between EJ and IL were assessed using chi squared tests; univariate analyses identified potential confounders which were tested in a multiple logistic regression model for any independent associations between region and outcome. RESULTS: Children in EJ were significantly more likely to live in larger households, with tobacco smokers, to have been breastfed, hospitalised and used antibiotics recently than those in IL, who were significantly more likely to have recently seen a primary care physician (all p < 0.01). Receipt of routine vaccinations, given at well baby clinics, was similar between the regions at above 95% (p = 0.11), except for influenza which was delivered separately at primary physician clinics to 5% (EJ) and 12% (IL). Receipt of pneumococcal vaccine when paid for separately was significantly higher in IL than EJ (3% vs 31%). Multivariate analysis identified the most important independent predictors of these differences as region, age and household size. CONCLUSIONS: Healthcare in Israel is of a very high standard, but it is not uniformly utilised within the community in all geographical areas, though in some key areas, such as uptake of most routine childhood vaccination, equality seems to be achieved. To ensure excellent healthcare is achieved across the population, inequalities must be addressed, for instance in health promotion and other activities, which could improve and normalise health outcomes. PMID- 26245328 TI - Physiological and condition-related traits in the gynogenetic-sexual Carassius auratus complex: different investments promoting the coexistence of two reproductive forms? AB - BACKGROUND: Carassius auratus complex is an extraordinary species complex including the diploid and polyploid forms exhibiting asexual and sexual reproduction modes. The coexistence of both forms in the same habitats is currently reported. The stable coexistence of asexual and sexual forms assumes some disadvantages for asexuals that balance the costs of sex. In our study, we hypothesized and tested the differences in physiological (including heamatological and immunological), growth-related, condition-related, and fitness related traits between gynogenetic females and sexuals. RESULTS: Our results revealed similar growth performance in gynogenetic females and sexuals measured by body size and weight, or expressed by condition factor. The energy allocation in reproduction measured by the relative size of gonads revealed no difference between gynogenetic and sexual females; in addition, both females in spawning expressed the same estradiol levels in blood plasma. We found a gender specific trade-off between investment in reproduction and immunocompetence (measured by the spleen-somatic index). Higher aerobic performance expressed by the heart index and higher oxygen-carrying capacity were found in sexual males, with increasing values before and during spawning. Our study evidenced significantly lower aerobic performance but higher oxygen-carrying capacity per erythrocyte in gynogenetic females when compared to sexuals. IgM production differed between gynogens and sexuals of C. auratus complex. CONCLUSIONS: Our study indicates that a similar amount of energy is invested by both gynogenetic and sexual females of C. auratus complex in reproductive behaviour. We suggest that lower aerobic performance in gynogens may represent their physiological disadvantage balancing the cost of sexual reproduction. A trade-off between the number of erythrocytes and the oxygen-carrying capacity per erythrocyte in sexual males and gynogenetic females may contribute to the coexistence of gynogenetic and sexual forms. In addition, the differences in specific immunity between gynogens and sexuals may also reduce the evolutionary disadvantage of sexual reproduction. In conclusion, we propose that several mechanisms contribute to the coexistence of the gynogenetic-sexual C. auratus complex. PMID- 26245329 TI - Loss of neuromonitoring signal during bilateral thyroidectomy: no systematic change in operative strategy according to a survey of the French Association of Endocrine Surgeons (AFCE). AB - BACKGROUND: Total thyroidectomy presents a risk of bilateral vocal cord paralysis, which can lead to compromised airway. Visual Recurrent Laryngeal Nerve (RLN) identification significantly decreases this risk of RLN lesion. Yet, an anatomically intact nerve is not always functional. Intraoperative neuromonitoring (IONM) allows to test in real time the function of the RLN. In case of loss of signal (LOS) on the first operated side, some authors recommend to stop the intervention. The purpose of this study was to characterize the operative strategy of the French-speaking surgeons in case of LOS on the first side in planned bilateral thyroidectomies. METHODS: An online questionnaire was sent to the surgeons of the French Association of Endocrine Surgeons (AFCE). RESULTS: We collected 69 responses (response rate: 42%). Forty-six surgeons (66%) used IONM. After a signal loss, 22% (N = 10) stopped the operation in all cases, 24% (N = 11) continued the operation in case of malignant disease and stopped in cases of benign disease, and 54% (N = 25) continued the operation contralaterally. CONCLUSIONS: The majority of surgeons continued the operation contralaterally as originally planned despite a loss of IONM signal at the end of the first side. PMID- 26245330 TI - Editor's reply to Lodhi, Mawas, Waqar, ElSayed and colleagues, Obeidalla, and Hamad. PMID- 26245331 TI - Use of a Continuous External Tissue Expander in Total Ankle Arthroplasty: A Novel Augment to Wound Closure. AB - Despite major improvements in surgical technique and implant designs in total ankle arthroplasty (TAA), wound healing complications are still commonly encountered. Not only do these problems delay postoperative recovery and threaten functional outcomes, they also carry an increased risk of progression to deep wound infection, which can jeopardize ultimate retention of the implant. In an effort to reduce the high frequency of wound-related complications after TAA, we have incorporated the use of continuous external tissue expansion (CETE) to augment our closures of the anterior ankle incision. CETE is an innovative technique that is currently being used to aid in the rapid closure of acute and chronic full thickness soft tissue defects, including fasciotomy wounds, high grade open fractures, and chronic foot ulcers. By exploiting the viscoelastic properties of the skin, this technique not only facilitates wound edge approximation of full thickness defects, it also helps take tension off tenuous incisions, thus allowing them to heal and reducing the chance for wound dehiscence. This is the first description of the use of an external tissue expander for the prevention of wound healing complications in the setting of TAA. Since introducing CETE to the closure of our TAA incisions, we have seen a decrease in the number of postoperative wound complications and time to wound healing. Based on our experience, we believe that the use of CETE for the prophylactic management of tenuous surgical incisions, specifically those used in the anterior approach to the ankle during TAA, is both safe and efficacious. LEVELS OF EVIDENCE: Level V: Technique tip. PMID- 26245332 TI - Potent and untested drugs sold as "dietary supplements". PMID- 26245333 TI - The relationship between the prescription of pyschotropic drugs and suicide rates in adults in England and Wales. AB - BACKGROUND: A few studies have demonstrated an inverse relationship between the general population and suicide rates and antidepressant prescribing rates. Correlations between general population suicide rates and prescribing rates of other psychotropic drugs have also been observed. There have not been any studies during the last decade. METHODS: The relationship between adult suicide rates and prescription rates of psychotropic drugs by the broad British National Formulary (BNF) categories, for individual psychotropic drug groups within the BNF categories (e.g. selective serotonin reuptake inhibitors) and for individual psychotropic drugs was examined over a 12-year period (1995-2006) was examined using Spearman's rank correlation. All data were ascertained from the archives of the Office for National Statistics. RESULTS: There was an absence of significant correlations between adult suicides rates and rates of prescriptions of psychotropic drugs in the broad BNF categories, individual psychotropic drug groups and individual psychotropic drugs. DISCUSSION: The findings may be due to methodological errors. Should the findings be accurate, then the following approaches require consideration to reduce suicide rates further: (i) development of strategies to ensure continued prescription of psychotropic drugs at the current level; (ii) development of strategies to improve non-pharmacological measures, including improved mental health services provision for adults, improved assessment of suicide risk, increased availability of psychosocial interventions and restricting the availability of methods of suicide; and (iii) development of strategies to implement improvement in distal risk (e.g. societal socio-economic status) and protective (e.g. societal educational attainment) factors for suicide at a societal level. PMID- 26245334 TI - International standardization of diagnostic criteria for vasospastic angina. AB - The Coronary Vasomotion Disorders International Study Group (COVADIS) was established to develop international standards for the diagnostic criteria of coronary vasomotor disorders. The first symposium held on the 4-5 September 2013 addressed the criteria for vasospastic angina, which included the following (i) nitrate-responsive angina, (ii) transient ischaemic electrocardiogram changes, and (iii) documented coronary artery spasm. Adoption of these diagnostic criteria will improve the clinical diagnosis of this condition and facilitate research in this field. PMID- 26245336 TI - Reply to letter to the editor: Comparison of retinal detachment surgery outcome among patients undergoing pars plana vitrectomy with and without relaxing retinotomy. PMID- 26245337 TI - Abnormal traction of the vitreous detected by swept-source optical coherence tomography is related to the maculopathy associated with optic disc pits. AB - BACKGROUND: Maculopathy associated with optic disc pits (ODP), which sometimes causes severe visual loss, usually appears in late childhood or early adulthood. However, it has long been unclear how the disease begins to develop at these ages. We evaluated the relationship between vitreous structure and maculopathy associated with ODP. METHODS: Six patients (seven eyes) with ODP were diagnosed between July 1990 and May 2013. Fundus photographs and swept-source optical coherence tomography (SS-OCT) images were evaluated retrospectively, and the vitreous at the vitreoretinal interface was visualized by reconstructing three dimensional SS-OCT images. Vitrectomy was performed in the eyes with maculopathy. RESULTS: Among the six patients, five had ODP in one eye each and one patient had bilateral ODP. The pits were mainly located in the temporal quadrant, and maculopathy, including retinoschisis and retinal detachment, was detected in five eyes associated only with the temporal pits. A flat retinal detachment was observed in four eyes and identified within the vascular arcade except in one eye. A posterior precortical vitreous pocket (PPVP) was observed in all eyes except in one eye without maculopathy. Reconstructing images from SS-OCT showed the vitreoretinal interface abnormalities around the optic disc and the macular area in all eyes, which was completely different from the vitreoretinal interface in the normal pediatric eye. Vitrectomy was performed in four eyes with retinal detachment to resect the abnormal vitreous traction. Posterior vitreous detachment was created in two eyes. Retinal reattachment was achieved in three eyes, and subretinal fluid receded in one eye. The visual acuity improved in all four eyes. CONCLUSIONS: Abnormal traction of the vitreous due to an abnormality of the vitreoretinal interface, which may be strengthened by the development of a PPVP, generates the maculopathy associated with ODP. PMID- 26245338 TI - Distinct patterns of spontaneous brain activity between children and adults with anisometropic amblyopia: a resting-state fMRI study. AB - PURPOSE: To detect the altered spontaneous brain activity patterns in children and adults with anisometropic amblyopia using resting-state functional magnetic resonance imaging (rs-fMRI) technique combined with the amplitude of low frequency fluctuation (ALFF) method. METHODS: Thirty-two monocular anisometropic amblyopia and 34 normal-sight controls were divided into child group and adult group. Rs-fMRI was performed in all participants and analysis of ALFF value within the whole brain was conducted in each subject. ALFF value differences between the patients and controls in the two groups were compared via an independent two-sample t test. RESULTS: The amblyopic children mainly exhibited increased ALFF in part of the bilateral calcarine (BA17), the left middle occipital gyrus (BA18/19), and the left postcentral gyrus (BA2). By contrast, the amblyopic adults showed decreased ALFF in the bilateral precuneus cortex (part of BA7), and the standardized ALFF value of bilateral precuneus were correlated with the amount of anisometropia of the amblyopic adults. CONCLUSIONS: Rs-fMRI is an effective noninvasive technique for exploring brain activity of the anisometropic amblyopia. Our findings demonstrated that brain activity changed both in amblyopic children and adults under the resting state, and revealed the differences in spontaneous activity patterns between the amblyopic children and adults. PMID- 26245339 TI - Polymorphisms in the CTSH gene may influence the progression of diabetic retinopathy: a candidate-gene study in the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987). AB - BACKGROUND: The incidence of type 1 diabetes mellitus (T1DM) is increasing globally, and as a consequence, more patients are affected by microvascular complications such as diabetic retinopathy (DR). The aim of this study was to elucidate possible associations between diabetes-related single-nucleotide polymorphisms (SNP) and the development of DR. METHODS: Three hundred and thirty nine patients with T1DM from the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987) went through an ophthalmic examination in 1995; 185 of these were reexamined in 2011. The development of DR was assessed by comparison of overall DR level between baseline and follow-up in the worst eye at baseline. Patients were graded on a modified version of the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and 20 SNPs were genotyped in 130 of the 185 patients. RESULTS: We found the CTSH/rs3825932 variant (C > T) was associated with reduced risk of progression to proliferative diabetic retinopathy (PDR) (OR [95 % CI] = 0.20 [0.07-0.56], p = 2.4 * 10(-3), padjust = 0.048) and ERBB3/rs2292239 variant (G > T) associated with increased risk of two-step progression (OR [95 % CI] = 2.76 [1.31-5.80], p = 7.5 * 10(-3), padjust = 0.15). The associations were independent of other known risk factors, such as HbA1c, sex, and diastolic blood pressure. CONCLUSION: In conclusion, CTSH/rs3825932 and ERBB3/rs2292239 SNPs were associated with reduced risk of progression to PDR and two-step progression of DR on the ETDRS scale accordingly. The variant CTSH remained statistically significant after adjusting for multiple testing. Our results suggest an overlap between genetic variants that confer risk of T1DM and progression of DR. PMID- 26245340 TI - Static characteristics and dynamic functionality of retinal vessels in longer eyes with or without pathologic myopia. AB - PURPOSE: To analyze major retinal vessels in eyes with high myopia by means of the Dynamic Vessel Analyzer (DVA) in order to gather insight on retinal vascular functionality and better understand why these eyes are resistant to diabetes related changes. METHODS: A total of 20 high-myopia eyes with pathologic myopia, 20 high-myopia eyes without pathologic myopia and 20 age- and sex-matched control subjects (without pathologic myopia) were included and compared. RESULTS: Dynamic analysis showed mean arterial dilation of 2.44 +/- 1.59 % in high-myopia eyes with pathologic myopia, 2.67 +/- 1.17 in high-myopia without pathologic myopia eyes, and 3.28 +/- 1.46 % in healthy eyes. Mean venous dilation was 3.45 +/- 1.82 %, 3.57 +/- 1.72, and 4.45 +/- 2.72 % respectively. Static analysis in high myopia eyes with pathologic myopia showed a mean central retinal artery equivalent (CRAE) of 171.6 +/- 24.3, a mean central retinal vein equivalent (CRVE) of 199.5 +/- 27.73, and a mean arteriovenous ratio (AVR) of 0.86 +/- 0.01. In patients with high myopia without pathologic myopia, we found a mean CRAE of 173 +/- 21.6, a mean CRVE of 198.2 +/- 18.8, and a mean AVR of 0.87 +/- 0.1. In control subjects, mean CRAE was 190.3 +/- 11.93, mean was CRVE 215.7 +/- 13.30, and mean AVR was 0.88 +/- 0.04. CONCLUSIONS: Static and dynamic tests revealed that in high-myopia eyes, the vessels at the retinal posterior pole have reduced diameter, but are functionally comparable to control subjects. This supports the hypothesis of reduced oxygen consumption in high-myopia eyes. PMID- 26245341 TI - Giant premacular bursa: a novel finding of the posterior vitreous in two patients with Stickler syndrome type 1 revealed by swept-source optical coherence tomography. PMID- 26245342 TI - Analysis of clinical features, treatment response, and prognosis among 61 elderly newly diagnosed multiple myeloma patients: a single-center report. AB - BACKGROUND: We identified the clinical features of 61 cases of multiple myeloma (MM) patients over 65 years and analyzed the treatment and prognosis of the era of new drugs in elderly patients. METHODS: We identified 61 newly diagnosed symptomatic multiple myeloma (NDMM) among elderly Chinese patients more than 65 years old diagnosed from 2006 to 2012. RESULTS: Of the 205 consecutive MM patients whom we reviewed, 61 (29.76%) cases were NDMM patients aged more than 65 years and the others were younger than 65 years old. Among them, 40 (65.6%) cases were in end-stage (ISS stage III); meanwhile, 19 (31.2%) cases of them had MM with extramedullary plasmacytoma (EMP), observed in 42.1% patients at diagnosis, and the top three incidence of position were spinal canal, pleural, and soft tissue. In the whole column, the median follow-up was 38 months and median age was 72.5 years. Patients received bortezomib- or thalidomide-containing regimens as initial therapy. Comparing the two treatment groups, the complete remission (CR)/near-complete remission (nCR) rate was significantly higher in the bortezomib-containing regimens (61.5 vs.18.18%, P=0.001), no difference in progression-free survival (PFS) and overall survival (OS). Patients of age over 75 years had shorter OS than those of age over 65 years (49 vs. 24 months, P=0.001). The patients with EMP had shorter OS than those without EMP in two age groups (32 vs. 42 and 15 vs. 24 months, P=0.017 and 0.024, respectively). CONCLUSIONS: The results highlight that patients over 75 years and MM with EMP have a poorer outcome. While the CR rate is higher in bortezomib-containing regimens, no significant improvement is noted in respect to the survival outcomes; also, it cannot overcome the negative influence on survival of age and MM with EMP in elderly patients. PMID- 26245343 TI - Expression and role of oncogenic miRNA-224 in esophageal squamous cell carcinoma. AB - BACKGROUND: Aberrant expression of miR-224 is associated with tumor development and progression. This study investigated the role of miR-224 in esophageal squamous cell carcinoma (ESCC) ex vivo and in vitro. METHODS: A total of 103 esophageal intraepithelial neoplasia, ESCC tissue specimens, and their matched distant normal tissues were collected to test miR-224 expression using qRT-PCR analysis. Western blot was used to quantify the level of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) and PHLPP2 in ESCC tissues. Cell viability, apoptosis, invasion, and colony formation assays were used to assess the altered phenotypes of esophageal cancer cell lines after miR-224 expression or inhibition. A luciferase reporter assay was used to confirm miR-224 binding to PHLPP1 and PHLPP2 mRNA. RESULTS: miR-224 was significantly overexpressed in esophageal intraepithelial neoplasia and ESCC tissues, while the expression of PHLPP1 and PHLPP2 proteins, the target genes of miR-224, was downregulated in ESCC tissues. miR-224 expression was associated with advanced clinical TNM stage, pathologic grade, and the level of PHLPP1 and PHLPP2 proteins in ESCC tissues. Ectopic overexpression of miR-224 promoted proliferation, migration, and invasion, but suppressed apoptosis of ESCC cells. miR-224 was able to bind to the 3' untranslated region (3'-UTR) of PHLPP1 and PHLPP2 mRNA to suppress their expression. CONCLUSIONS: The current study demonstrated that miR-224 acts as an oncogenic miRNA in ESCC, possibly by targeting PHLPP1 and PHLPP2. PMID- 26245344 TI - Preoperative abdominal muscle elongation with botulinum toxin A for complex incisional ventral hernia repair. AB - BACKGROUND: Surgical repair of recurrent abdominal incisional hernia(s) can be challenging due to complex operative conditions, intense post-operative pain, potential respiratory compromise and lateral muscle traction predisposing to early recurrence. We report our preliminary results with botulinum toxin A (BTA) injection causing flaccid paralysis (relaxation) of the lateral abdominal wall muscles prior to surgery. METHODS: A prospective pilot study measured the effect of preoperative BTA prior to elective repair of recurrent abdominal hernias. Under ultrasound control, 2 weeks prior to surgery, 50 units of BTA was injected into the external oblique, internal oblique and transversus abdominis muscles at three sites on each side of the lateral abdominal wall (total dose 300 units). Pre- and post-BTA abdominal computed tomography measured changes in abdominal wall muscle thickness and length. All hernias were repaired with laparoscopic or laparoscopic-assisted mesh techniques in a single or two-staged procedure. RESULTS: Eight patients received BTA injections which were tolerated with no complications. Post-BTA preoperative computed tomography showed a significant increase in mean length of lateral abdominal wall from 18.5 cm pre-BTA to 21.3 cm post-BTA (P = 0.017) with a mean unstretched length gain of 2.8 cm per side (range 0.8-6.0 cm). All hernias were surgically reduced with mesh with no early recurrence. CONCLUSION: Preoperative BTA injection prior to complex abdominal hernia repair is a safe procedure that causes flaccid relaxation, elongation and thinning of the lateral abdominal muscles and decrease in hernia defect. Although further evaluation is required, BTA injections may be a useful adjunct to surgical repair of complex incisional hernias. PMID- 26245345 TI - Lessons learnt during the process of setup and implementation of the voucher scheme in Eastern Uganda: a mixed methods study. AB - BACKGROUND: In spite of the investments made by the Ugandan Government, the utilisation of maternal health services has remained low, resulting in a high maternal mortality (438 maternal deaths per 100,000 live births). Aiming to reduce poor women's constraints to the utilisation of services, an intervention consisting of a voucher scheme and health system strengthening was implemented. This paper presents the lessons learnt during the setup and implementation of the intervention in Eastern Uganda, in order to inform the design and scale up of similar future interventions. METHODS: The key lessons were synthesised from a variety of project reports, as well as qualitative data drawn from six focus group discussions and four in-depth interviews conducted in the Buyende and Pallisa districts during the implementation phase of the voucher scheme. RESULTS AND CONCLUSIONS: To promote the successful implementation of interventions with demand and supply side initiatives, such as voucher schemes, the health system should be able to respond to the demand created by providing the additional required resources such as health workers, essential supplies and equipment. Involving a diverse, multi-sectoral group of stakeholders is important for addressing the different barriers experienced by women when seeking maternal health services. Voucher schemes should have a mechanism of detecting unintended consequences and mitigating them. Sustainability plans should be built into such interventions to maintain the gains achieved. Lastly, health policy planners can use this information to develop follow-up programmes to test modified versions that are more sustainable. Such programmes could use locally existing community structures for management and resource mobilisation for self-sustainment. PMID- 26245346 TI - Agonistic aptamer to the insulin receptor leads to biased signaling and functional selectivity through allosteric modulation. AB - Due to their high affinity and specificity, aptamers have been widely used as effective inhibitors in clinical applications. However, the ability to activate protein function through aptamer-protein interaction has not been well elucidated. To investigate their potential as target-specific agonists, we used SELEX to generate aptamers to the insulin receptor (IR) and identified an agonistic aptamer named IR-A48 that specifically binds to IR, but not to IGF-1 receptor. Despite its capacity to stimulate IR autophosphorylation, similar to insulin, we found that IR-A48 not only binds to an allosteric site distinct from the insulin binding site, but also preferentially induces Y1150 phosphorylation in the IR kinase domain. Moreover, Y1150-biased phosphorylation induced by IR-A48 selectively activates specific signaling pathways downstream of IR. In contrast to insulin-mediated activation of IR, IR-A48 binding has little effect on the MAPK pathway and proliferation of cancer cells. Instead, AKT S473 phosphorylation is highly stimulated by IR-A48, resulting in increased glucose uptake both in vitro and in vivo. Here, we present IR-A48 as a biased agonist able to selectively induce the metabolic activity of IR through allosteric binding. Furthermore, our study also suggests that aptamers can be a promising tool for developing artificial biased agonists to targeted receptors. PMID- 26245348 TI - Crosslinking reactions of 4-amino-6-oxo-2-vinylpyrimidine with guanine derivatives and structural analysis of the adducts. AB - DNA interstrand crosslinks (ICLs) are the primary mechanism for the cytotoxic activity of many clinical anticancer drugs, and numerous strategies for forming ICLs have been developed. One such method is using crosslink-forming oligonucleotides (CFOs). In this study, we designed a 4-amino-6-oxo-2 vinylpyrimidine (AOVP) derivative with an acyclic spacer to react selectively with guanine. The AOVP CFO exhibited selective crosslinking reactivity with guanine and thymine in DNA, and with guanine in RNA. These crosslinking reactions with guanine were accelerated in the presence of CoCl2, NiCl2, ZnCl2 and MnCl2. In addition, we demonstrated that the AOVP CFO was reactive toward 8-oxoguanine opposite AOVP in the duplex DNA. The structural analysis of each guanine and 8 oxoguanine adduct in the duplex DNA was investigated by high-resolution NMR. The results suggested that AOVP reacts at the N2 amine in guanine and at the N1 or N2 amines in 8-oxoguanine in the duplex DNA. This study demonstrated the first direct determination of the adduct structure in duplex DNA without enzyme digestion. PMID- 26245349 TI - Detecting Cognitive Impairment and Dementia in Deaf People: The British Sign Language Cognitive Screening Test. AB - To provide accurate diagnostic screening of deaf people who use signed communication, cognitive tests must be devised in signed languages with normative deaf samples. This article describes the development of the first screening test for the detection of cognitive impairment and dementia in deaf signers. The British Sign Language Cognitive Screening Test uses standardized video administration to screen cognition using signed, rather than spoken or written, instructions and a large norm-referenced sample of 226 deaf older people. Percentiles are provided for clinical comparison. The tests showed good reliability, content validity, and correlation with age, intellectual ability, and education. Clinical discrimination was shown between the normative sample and 14 deaf patients with dementia. This innovative testing approach transforms the ability to detect dementia in deaf people, avoids the difficulties of using an interpreter, and enables culturally and linguistically sensitive assessment of deaf signers, with international potential for adaptation into other signed languages. PMID- 26245347 TI - Extended molecular dynamics of a c-kit promoter quadruplex. AB - The 22-mer c-kit promoter sequence folds into a parallel-stranded quadruplex with a unique structure, which has been elucidated by crystallographic and NMR methods and shows a high degree of structural conservation. We have carried out a series of extended (up to 10 MUs long, ~50 MUs in total) molecular dynamics simulations to explore conformational stability and loop dynamics of this quadruplex. Unfolding no-salt simulations are consistent with a multi-pathway model of quadruplex folding and identify the single-nucleotide propeller loops as the most fragile part of the quadruplex. Thus, formation of propeller loops represents a peculiar atomistic aspect of quadruplex folding. Unbiased simulations reveal MUs scale transitions in the loops, which emphasizes the need for extended simulations in studies of quadruplex loops. We identify ion binding in the loops which may contribute to quadruplex stability. The long lateral-propeller loop is internally very stable but extensively fluctuates as a rigid entity. It creates a size-adaptable cleft between the loop and the stem, which can facilitate ligand binding. The stability gain by forming the internal network of GA base pairs and stacks of this loop may be dictating which of the many possible quadruplex topologies is observed in the ground state by this promoter quadruplex. PMID- 26245350 TI - Video observation of sharps handling and infection control practices during routine companion animal appointments. AB - BACKGROUND: Infection control in veterinary clinics is important for preventing pathogen spread between patients, staff and the public. There has been no direct evaluation of the use of many basic infection control practices, including sharps handling, environmental cleaning, and personal protective clothing (PPC), in companion animal clinics. The objective of this study was to describe these and other infection control practices associated with routine companion animal appointments in veterinary clinics in Ontario. RESULTS: Video observation of practices was performed in 51 clinics for approximately 3 weeks each as part of another study evaluating the effect of a poster campaign on hand hygiene compliance. Two small wireless surveillance cameras were used: one in an exam room, one in what was considered the most likely location for hand hygiene to be performed outside the exam room following an appointment. Video footage was coded and analyzed for 47 clinics, including 2713 appointments and 4903 individual staff-animal contacts. Recapping of a needle was seen in 84% (1137/1353) of appointments in which use was observed. Only one apparent needlestick injury (NSI) was seen, during recapping. Exam tables were cleaned and floors were mopped following 76% (2015/2646) and 7% (174/2643) of appointments, respectively. Contact time with spray used to clean the exam table ranged from 0-4611 s (mean 39 s, median 9 s). Appropriate PPC was worn for 72% (3518/4903) of staff-animal contacts. CONCLUSIONS: Although there was significant room for improvement in sharps handling behaviours in participating clinics, the number of observed NSIs was low. Contact time with environmental disinfectants and use of PPC could also be improved, as well as other basic infection control practices. Education and motivation of veterinary staff to use these simple measures more effectively could potentially have a significant impact on infection control in veterinary clinics for relatively little cost. PMID- 26245351 TI - Multivalent Pneumococcal Protein Vaccines Comprising Pneumolysoid with Epitopes/Fragments of CbpA and/or PspA Elicit Strong and Broad Protection. AB - Immunization with the pneumococcal proteins pneumolysin (Ply), choline binding protein A (CbpA), or pneumococcal surface protein A (PspA) elicits protective responses against invasive pneumococcal disease in animal models. In this study, we used different mouse models to test the efficacy of a variety of multivalent protein-based vaccines that comprised various combinations of full-length or peptide regions of the immunogens Ply, CbpA, or PspA: Ply toxoid with the L460D substitution (referred to herein as L460D); L460D fused with protective peptide epitopes from CbpA (YPT-L460D-NEEK [YLN]); L460D fused with the CD2 peptide containing the proline-rich region (PRR) of PspA (CD2-L460D); a combination of L460D and H70 (L460D+H70), a slightly larger PspA-derived peptide containing the PRR and the SM1 region; H70+YLN; and other combinations. Each mouse was immunized either intraperitoneally (i.p.) or subcutaneously (s.c.) with three doses (at 2 week intervals) of the various antigen combinations in alum adjuvant and then challenged in mouse models featuring different infection routes with multiple Streptococcus pneumoniae strains. In the i.p. infection sepsis model, H70+YLN consistently provided significant protection against three different challenge strains (serotypes 1, 2, and 6A); the CD2+YLN and H70+L460D combinations also elicited significant protection. Protection against intravenous (i.v.) sepsis (type 3 and 6A challenge strains) was largely dependent on PspA-derived antigen components, and the most protection was elicited by H70 with or without L460D or YLN. In a type 4 intratracheal (i.t.) challenge model that results in progression to meningitis, antigen combinations that contained YLN elicited the strongest protection. Thus, the trivalent antigen combination of H70+YLN elicited the strongest and broadest protection in diverse pneumococcal challenge models. PMID- 26245352 TI - Evaluation of the Specificity of Two Enzyme Immunoassays for Coccidioidomycosis by Using Sera from a Region of Endemicity and a Region of Nonendemicity. AB - Coccidioidomycosis (CM), a serious life-threatening fungal infection endemic to arid regions of the western United States and Mexico, can be challenging to diagnose in a timely manner. Commercially developed enzyme immunoassays (EIAs) (from Meridian Biosciences and Immuno-Mycologics [IMMY]) have provided faster, simpler means for serodiagnosis; however, independent evaluations have questioned EIA specificity, particularly IgM-positive/IgG-negative results. This study was conducted to evaluate EIA specificity among persons residing in Puerto Rico (n = 534), where CM is not endemic (who were not likely to have been exposed to Coccidioides spp.), compared to blood bank donors residing in Arizona (n = 1,218), where CM is endemic. Upon comparing serum reactivity between Puerto Rico and Arizona, the Meridian EIA showed a significant difference in IgG reactivity (0.37% versus 3.6%; P < 0.001) but not IgM reactivity (3.4% versus 2.4%; P = 0.31). No IgM-/IgG-reactive sera were detected among sera from Puerto Rico, compared to 7 (0.57%) sera from Arizona. Similar results were observed using the IMMY EIA, although significantly (P = 0.03) fewer IgM-reactive sera from Arizona were observed, compared to the Meridian EIA. EIA-reactive sera were also evaluated by immunodiffusion before and after 3- to 4-fold concentration of the sera. These results demonstrate that elevated IgG EIA reactivity is present in sera from healthy individuals in regions of endemicity and that IgM EIA reactivity observed in sera from individuals residing outside regions of endemicity is most likely nonspecific. Other criteria, including clinical and microbiological evaluations, should be taken into account when interpreting results from surveillance studies and other reporting measures. PMID- 26245353 TI - Large distribution and high sequence identity of a Copia-type retrotransposon in angiosperm families. AB - Retrotransposons are the main component of plant genomes. Recent studies have revealed the complexity of their evolutionary dynamics. Here, we have identified Copia25 in Coffea canephora, a new plant retrotransposon belonging to the Ty1 Copia superfamily. In the Coffea genomes analyzed, Copia25 is present in relatively low copy numbers and transcribed. Similarity sequence searches and PCR analyses show that this retrotransposon with LTRs (Long Terminal Repeats) is widely distributed among the Rubiaceae family and that it is also present in other distantly related species belonging to Asterids, Rosids and monocots. A particular situation is the high sequence identity found between the Copia25 sequences of Musa, a monocot, and Ixora, a dicot species (Rubiaceae). Our results reveal the complexity of the evolutionary dynamics of the ancient element Copia25 in angiosperm, involving several processes including sequence conservation, rapid turnover, stochastic losses and horizontal transfer. PMID- 26245355 TI - Molecular characterization of highly pathogenic avian influenza H5N8 viruses isolated from Baikal teals found dead during a 2014 outbreak in Korea. AB - Nineteen highly pathogenic avian influenza (HPAI) H5N8 viruses were isolated from wild birds in the Donglim reservoir in Gochang, Jeonbuk province, Korea, which was first reported to be an outbreak site on January 17, 2014. Most genes from the nineteen viruses shared high nucleotide sequence identities (i.e., 99.7% to 100%). Phylogenetic analysis showed that these viruses were reassortants of the HPAI H5 subtype and the H4N2 strain and that their hemagglutinin clade was 2.3.4.4, which originated from Eastern China. The hemagglutinin protein contained Q222 and G224 at the receptor-binding site. Although the neuraminidase protein contained I314V and the matrix 2 protein contained an S31N substitution, other mutations resulting in oseltamivir and amantadine resistance were not detected. No substitutions associated with increased virulence and enhanced transmission in mammals were detected in the polymerase basic protein 2 (627E and 701D). Non structural-1 was 237 amino acids long and had an ESEV motif with additional RGNKMAD amino acids in the C terminal region. These viruses caused deaths in the Baikal teal, which was unusual, and outbreaks occurred at the same time in both poultry and wild birds. These data are helpful for epidemiological understanding of HPAI and the design of prevention strategies. PMID- 26245354 TI - Unfoldome variation upon plant-pathogen interactions: strawberry infection by Colletotrichum acutatum. AB - Intrinsically disordered proteins (IDPs) are proteins that lack secondary and/or tertiary structure under physiological conditions. These proteins are very abundant in eukaryotic proteomes and play crucial roles in all molecular mechanisms underlying the response to environmental challenges. In plants, different IDPs involved in stress response have been identified and characterized. Nevertheless, a comprehensive evaluation of protein disorder in plant proteomes under abiotic or biotic stresses is not available so far. In the present work the transcriptome dataset of strawberry (Fragaria X ananassa) fruits interacting with the fungal pathogen Colletotrichum acutatum was actualized onto the woodland strawberry (Fragaria vesca) genome. The obtained cDNA sequences were translated into protein sequences, which were subsequently subjected to disorder analysis. The results, providing the first estimation of disorder abundance associated to plant infection, showed that the proteome activated in the strawberry red fruit during the active fungal propagation is remarkably depleted in disorder. On the other hand, in the resistant white fruit, no significant disorder reduction is observed in the proteins expressed in response to fungal infection. Four representative proteins, FvSMP, FvPRKRIP, FvPCD-4 and FvFAM32A like, predicted as mainly disordered and never experimentally characterized before, were isolated, and the absence of structure was validated at the secondary and tertiary level using circular dichroism and differential scanning fluorimetry. Their quaternary structure was also established using light scattering. The results are discussed considering the role of protein disorder in plant defense. PMID- 26245357 TI - The prevalence, impact and management of musculoskeletal disorders in older people living in care homes: a systematic review. AB - The aim was to systematically review the literature describing the prevalence, impact and current management of musculoskeletal pain in older people living in care homes. Published literature (AMED, CINAHL, EMBASE, psycINFO, MEDLINE, Cochrane Library) and unpublished literature (OpenGrey, the WHO International Clinical Trials Registry Platform, Current Controlled Trials, UK National Research Register Archive) were searched on 1 March 2015. All studies assessing the prevalence, impact and management of musculoskeletal disorders in older people living in care homes were included. Literature was appraised using the CASP cohort and qualitative critical appraisal tools. Data were analysed using descriptive statistical approaches, meta-analysis and meta-ethnography techniques. Twenty-four papers reporting the results of 263,775 care home residents in 12 countries were identified. The evidence base was moderate in quality. Prevalence of musculoskeletal pain for people in care homes was 30.2 % (95 % confidence intervals 29.9-30.5 %; n = 105,463). Care home residents reported that musculoskeletal pain had a significant impact on their perceived independence and overall ability to participate in everyday activities of daily living. Three papers which presented data on interventions demonstrated that whilst multi-component assessment and management packages did not significantly change clinical outcomes, these empowered care home staff to feel more confident in managing these patients. Musculoskeletal pain is a common problem in care homes worldwide, and residents report significant impact on their lives. However, there is uncertainty regarding how to assess and manage such pain. PROSPERO Registration Number: CRD42014009824. PMID- 26245356 TI - Quantitative and qualitative characterization of expanded CD4+ T cell clones in rheumatoid arthritis patients. AB - Rheumatoid arthritis (RA) is an autoimmune destructive arthritis associated with CD4(+) T cell-mediated immunity. Although expanded CD4(+) T cell clones (ECs) has already been confirmed, the detailed characteristics of ECs have not been elucidated in RA. Using combination of a single-cell analysis and next-generation sequencing (NGS) in TCR repertoire analysis, we here revealed the detailed nature of ECs by examining peripheral blood (PB) from 5 RA patients and synovium from 1 RA patient. When we intensively investigated the single-cell transcriptome of the most expanded clones in memory CD4(+) T cells (memory-mECs) in RA-PB, senescence related transcripts were up-regulated, indicating circulating ECs were constantly stimulated. Tracking of the transcriptome shift within the same memory-mECs between PB and the synovium revealed the augmentations in senescence-related gene expression and the up-regulation of synovium-homing chemokine receptors in the synovium. Our in-depth characterization of ECs in RA successfully demonstrated the presence of the specific immunological selection pressure, which determines the phenotype of ECs. Moreover, transcriptome tracking added novel aspects to the underlying sequential immune processes. Our approach may provide new insights into the pathophysiology of RA. PMID- 26245359 TI - An LC-MS/MS method for simultaneous determination of trantinterol and its major metabolite in rat plasma and its application to a comparative pharmacokinetic study. AB - Trantinterol is a novel beta2-adrenoceptor agonist, currently undergoing clinical trials for the treatment of asthma. We developed and validated an liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of trantinterol and its major metabolite, 1-carbonyl trantinterol (SPFFCOOH), in rat plasma. Aliquots (100MUL) of heparinized plasma samples were processed by protein precipitation with acetonitrile. Chromatographic separation used an Acquity UPLC BEH C18 column (2.1mm*50mm, 1.7MUm) and acetonitrile-0.1% formic acid (20:80, v/v) as mobile phase, at a flow rate of 0.25mL/min. The detection was performed on a triple-quadrupole tandem mass spectrometer with multiple-reaction monitoring (MRM) mode via electrospray ionization (ESI) source. The precursor-to-product ion transitions m/z 310.9->m/z 237.9 for trantinterol, m/z 324.9->m/z 251.9 for SPFFCOOH and m/z 368.0->m/z 294.0 for bambuterol (internal standard, IS) were used for quantification. The calibration curves were obtained in the concentration of 0.25-100ng/mL for both trantinterol and SPFFCOOH. The intra- and inter-day precision (relative standard deviations, RSD) values were below 15% and accuracy (relative error, RE) was from -4.3% to 6.6% at all quality control (QC) levels. The method was successfully applied to compare the pharmacokinetics of trantinterol and SPFFCOOH in male and female Wistar rats after a single oral administration of trantinterol. PMID- 26245358 TI - Surgery for synchronous colorectal cancers with double colonic anastomoses: A comparison of laparoscopic and open approaches. AB - INTRODUCTION: The aim of this study was to evaluate the safety of laparoscopic double colon resection and synchronous anastomosis for synchronous colorectal cancer. METHODS: We reviewed 42 consecutive patients who underwent double colon resection and synchronous anastomosis for synchronous colorectal cancer between 2000 and 2014. Clinical characteristics and short-term outcomes were compared between laparoscopic (n = 27) and open (n = 15) groups. RESULTS: There was no conversion to open surgery in the laparoscopic group. Operating time in the laparoscopic group was significantly longer than in the open group (373 vs 292 min), but estimated blood loss was significantly lower (40 vs 179 mL). Time to first flatus (1 vs 3 days) and length of hospital stay (12 vs 17 days) were significantly shorter in the laparoscopic group. The rate of postoperative complications was similar in both groups (19% vs 27%). The anastomotic leakage rate was 3.7% in the laparoscopic group and 20.0% in the open group. CONCLUSION: Laparoscopic surgery with double colon resection and synchronous anastomosis for synchronous colorectal cancers is safe and has greater short-term benefits than open surgery. It should be considered as a treatment option under optimal conditions. PMID- 26245360 TI - Determination of amphetamines in biological samples using electro enhanced solid phase microextraction-gas chromatography. AB - In this work, an ordered mesoporous carbon (OMC)/Nafion coated fiber for solid phase microextraction (SPME) was prepared and used as the working electrode for electro-enhanced SPME (EE-SPME) of amphetamines. The EE-SPME strategy is primarily based on the electro-migration and complementary charge interaction between fiber coating and ionic compounds. Compared with traditional SPME, EE SPME exhibited excellent extraction efficiency for amphetamine (AP) and methamphetamine (MA) with an enhancement factor of 7.8 and 12.1, respectively. The present strategy exhibited good linearity for the determination of AP and MA in urine samples in the range of 10-1000ngmL(-1) and 20-1000ngmL(-1), respectively. The detection limits were found to be 1.2ngmL(-1) for AP and 4.8ngmL(-1) for MA. The relative standard deviations were calculated to be 6.2% and 8.5% for AP and MA, respectively. Moreover, the practical application of the proposed method was demonstrated by analyzing the amphetamines in urine and serum samples with satisfactory results. PMID- 26245361 TI - Evaluating misoprostol content in pregnant women with hourly oral administration during labor induction by microElution solid phase extraction combined with liquid chromatography tandem mass spectrometry. AB - Misoprostol is a widely used alternative of prostaglandin for labor induction. Based on previous studies, we envision that small and frequent oral dosage of misoprostol is an effective method for labor induction. To monitor the misoprostol content during labor induction, a rapid, sensitive, and selective microElution solid phase extraction (MUElution SPE) combined with liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed. Using MUElution SPE could minimize the sample consumption and elution volume in order to maximize the sample enrichment and throughput. The misoprostol acid, a metabolite of misoprostol, was gradient separated in a Bidentate C18 column, then quantified by highly-selective reaction monitoring (H-SRM) in a total run time of 6min. The developed method was optimized and validated in human plasma, and showed linear range of 0.01-10ng/mL. The limit of detection (LOD) was 0.001ng/mL. The recovery ranged from 89.0 to 96.0%, and no significant matrix effect or carryover was observed. The precision, accuracy and stability were met with the criteria of U.S. FDA guidance. The developed method was successfully applied to evaluate misoprostol concentration during labor induction in pregnant women. The concentration-time profiles approves that hourly oral administration of misoprostol is a safe and effective method without drug accumulation for labor induction. PMID- 26245363 TI - Biomonitoring method for the determination of polycyclic aromatic hydrocarbons in hair by online in-tube solid-phase microextraction coupled with high performance liquid chromatography and fluorescence detection. AB - Polycyclic aromatic hydrocarbons (PAHs) are formed from the incomplete combustion or pyrolysis of organic matter during industrial processing and various human activities, but human exposure to PAHs has not yet been elucidated in detail. To assess long-term exposure to PAHs, we developed a simple and sensitive method for measuring PAHs in hair by online in-tube solid-phase microextraction using a CP Sil 19CB capillary column as an extraction device, followed by high-performance liquid chromatography using a Zorbax Eclipse PAH column and fluorescence detection. Seventeen PAHs could be analyzed simultaneously, with good linearity from 20 to 1000pg/mL each as determined using stable isotope-labeled PAH internal standards. The detection limits of PAHs were 0.5-20.4pg/mL. PAHs in human hair samples were extracted by ultrasonication in 50mM NaOH in methanol, and successfully analyzed without any interference peaks, with good recovery rates above 70% in spiked hair samples. Using this method, we evaluated the suitability of using hair PAHs as biomarkers for long-term exposure. PMID- 26245362 TI - Development and validation of a sensitive HPLC-MS/MS method for determination of chidamide (epidaza), a new benzamide class of selective histone deacetylase inhibitor, in human plasma and its clinical application. AB - Chidamide (epidaza), a new oral isotype-selective histone deacetylase inhibitor (HDACi), which is just approved in China for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in December 2014, is the first listed benzamide class of HDACi in the world, and is currently undergoing global clinical trials for solid tumor treatments. Here, we report a sensitive, rapid and robust HPLC-MS/MS method for determination of chidamide in human plasma. Plasma sample was subjected to a simple acetonitrile protein precipitation containing MS-275 used as an internal standard (IS). Chromatography was performed on a Hypersil GOLD C18 analytical column, using a gradient methanol/water mobile phase containing 0.1% formic acid. A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the positive ion mode. Selected reaction monitoring (SRM) using the precursor/ product transitions (m/z) of 391.1/265.1 for chidamide and 377.1/359.2 for IS were used for quantification, respectively. Good linearity was obtained in the range of 1 1000ng/mL. The method gave R.S.D.% values for precision always lower than 13.8% and R.E.% values for accuracy between -3.7 and 9.1%. In addition, the specificity, recovery, stability and matrix effect were satisfactory too. The method is now being successfully applied to plasma samples as part of an ongoing chidamide phase Ib clinical trial in patients with solid tumors, and had demonstrated consistent AUClast and t1/2 results with the published phase I pharmacokinetic data, which was also analyzed by this method, thus further confirming the reproducibility and accuracy during its clinical application. Considering the excellent performance of this method, it will continue being utilized for future clinical developments of chidamide and for routine monitoring of plasma exposure of chidamide during its clinical therapy. PMID- 26245364 TI - Application of microwave-assisted micro-solid-phase extraction for determination of parabens in human ovarian cancer tissues. AB - Parabens (alkyl esters of p-hydroxybenzoic acid) are widely used as preservatives in food, cosmetics and pharmaceutical products. However, weak estrogenicity of some parabens has been reported in several studies, which provided the impetus for this work. Here, a simple and efficient analytical method for quantifying parabens in cancer tissues has been developed. This technique involves the simultaneous use of microwave-assisted solvent extraction (MASE) and micro-solid phase extraction (MU-SPE), in tandem with high performance liquid chromatography (HPLC/UV) analysis for the determination of parabens. The pollutants studied included four parabens (methyl, ethyl, propyl and butyl parabens). Optimization of the experimental parameters for MASE and MU-SPE was performed. Good relative standard deviation (%RSD) ranged from 0.09 to 2.81% and high enrichment factors (27-314) were obtained. Coefficients of determination (r(2)) up to 0.9962 were obtained across a concentration range of 5.0-200ngg(-1). The method detection limits for parabens ranged from 0.005 to 0.0244ngg(-1). The procedure was initially tested on prawn samples to demonstrate its feasibility on a complex biological matrix. Preliminary studies on human ovarian cancer (OC) tissues showed presence of parabens. Higher levels of parabens were detected in malignant ovarian tumor tissues compared to benign tumor tissue samples. PMID- 26245365 TI - Human Pegivirus (HPgV; formerly known as GBV-C) inhibits IL-12 dependent natural killer cell function. AB - Human Pegivirus (HPgV, formally GB virus C) infects lymphocytes and NK cells in vivo, and infection is associated with reduced T cell and NK cell activation in HIV-infected individuals. The mechanism by which HPgV inhibits NK cell activation has not been assessed. Following IL-12 stimulation, IFNgamma expression was lower in HIV-HPgV co-infected subjects compared to HIV mono-infected subjects (p=0.02). In addition, HPgV positive human sera, extracellular vesicles containing E2 protein, recombinant E2 protein and synthetic E2 peptides containing a predicted Tyk2 interacting motif inhibited NK cell IL-12-mediated IFNgamma release. E2 protein also inhibited Tyk2 activation following IL-12 stimulation. In contrast, cytolytic NK cell function was not altered by HPgV. Inhibition of NK cell-induced proinflammatory/antiviral cytokines may contribute to both HPgV persistence and reduced immune activation during HIV-coinfection. Understanding mechanisms by which HPgV alters immune activation may contribute towards novel immunomodulatory therapies to treat HIV and inflammatory diseases. PMID- 26245366 TI - Bacteriophage P22 ejects all of its internal proteins before its genome. AB - Double-stranded DNA bacteriophages are highly pressurized, providing a force driving ejection of a significant fraction of the genome from its capsid. In P22 like Podoviridae, internal proteins ("E proteins") are packaged into the capsid along with the genome, and without them the virus is not infectious. However, little is known about how and when these proteins come out of the virus. We employed an in vitro osmotic suppression system with high-molecular-weight polyethylene glycol to study P22 E protein release. While slow ejection of the DNA can be triggered by lipopolysaccharide (LPS), the rate is significantly enhanced by the membrane protein OmpA from Salmonella. In contrast, E proteins are not ejected unless both OmpA and LPS are present and their ejection when OmpA is present is largely complete before any genome is ejected, suggesting that E proteins play a key role in the early stage of transferring P22 DNA into the host. PMID- 26245368 TI - Corrigendum: Fatty acid carbon is essential for dNTP synthesis in endothelial cells. PMID- 26245367 TI - Low correlation between household carbon monoxide and particulate matter concentrations from biomass-related pollution in three resource-poor settings. AB - Household air pollution from the burning of biomass fuels is recognized as the third greatest contributor to the global burden of disease. Incomplete combustion of biomass fuels releases a complex mixture of carbon monoxide (CO), particulate matter (PM) and other toxins into the household environment. Some investigators have used indoor CO concentrations as a reliable surrogate of indoor PM concentrations; however, the assumption that indoor CO concentration is a reasonable proxy of indoor PM concentration has been a subject of controversy. We sought to describe the relationship between indoor PM2.5 and CO concentrations in 128 households across three resource-poor settings in Peru, Nepal, and Kenya. We simultaneously collected minute-to-minute PM2.5 and CO concentrations within a meter of the open-fire stove for approximately 24h using the EasyLog-USB-CO data logger (Lascar Electronics, Erie, PA) and the personal DataRAM-1000AN (Thermo Fisher Scientific Inc., Waltham, MA), respectively. We also collected information regarding household construction characteristics, and cooking practices of the primary cook. Average 24h indoor PM2.5 and CO concentrations ranged between 615 and 1440 MUg/m(3), and between 9.1 and 35.1 ppm, respectively. Minute-to-minute indoor PM2.5 concentrations were in a safe range (<25 MUg/m(3)) between 17% and 65% of the time, and exceeded 1000 MUg/m(3) between 8% and 21% of the time, whereas indoor CO concentrations were in a safe range (<7 ppm) between 46% and 79% of the time and exceeded 50 ppm between 4%, and 20% of the time. Overall correlations between indoor PM2.5 and CO concentrations were low to moderate (Spearman rho between 0.59 and 0.83). There was also poor agreement and evidence of proportional bias between observed indoor PM2.5 concentrations vs. those estimated based on indoor CO concentrations, with greater discordance at lower concentrations. Our analysis does not support the notion that indoor CO concentration is a surrogate marker for indoor PM2.5 concentration across all settings. Both are important markers of household air pollution with different health and environmental implications and should therefore be independently measured. PMID- 26245369 TI - Structural biology: Hypoxia response becomes crystal clear. PMID- 26245370 TI - Corrigendum: Progesterone receptor modulates ERalpha action in breast cancer. PMID- 26245372 TI - Cell biology: Surviving import failure. PMID- 26245371 TI - Structural integration in hypoxia-inducible factors. AB - The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-alpha and ARNT (also called HIF-1beta) subunits. Here we describe crystal structures for each of mouse HIF-2alpha-ARNT and HIF-1alpha-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF 2alpha-ARNT and HIF-1alpha-ARNT, wherein ARNT spirals around the outside of each HIF-alpha subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-alpha mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets. PMID- 26245373 TI - A giant protogalactic disk linked to the cosmic web. AB - The specifics of how galaxies form from, and are fuelled by, gas from the intergalactic medium remain uncertain. Hydrodynamic simulations suggest that 'cold accretion flows'--relatively cool (temperatures of the order of 10(4) kelvin), unshocked gas streaming along filaments of the cosmic web into dark matter halos--are important. These flows are thought to deposit gas and angular momentum into the circumgalactic medium, creating disk- or ring-like structures that eventually coalesce into galaxies that form at filamentary intersections. Recently, a large and luminous filament, consistent with such a cold accretion flow, was discovered near the quasi-stellar object QSO UM287 at redshift 2.279 using narrow-band imaging. Unfortunately, imaging is not sufficient to constrain the physical characteristics of the filament, to determine its kinematics, to explain how it is linked to nearby sources, or to account for its unusual brightness, more than a factor of ten above what is expected for a filament. Here we report a two-dimensional spectroscopic investigation of the emitting structure. We find that the brightest emission region is an extended rotating hydrogen disk with a velocity profile that is characteristic of gas in a dark matter halo with a mass of 10(13) solar masses. This giant protogalactic disk appears to be connected to a quiescent filament that may extend beyond the virial radius of the halo. The geometry is strongly suggestive of a cold accretion flow. PMID- 26245374 TI - Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. AB - Most of the mitochondrial proteome originates from nuclear genes and is transported into the mitochondria after synthesis in the cytosol. Complex machineries which maintain the specificity of protein import and sorting include the TIM23 translocase responsible for the transfer of precursor proteins into the matrix, and the mitochondrial intermembrane space import and assembly (MIA) machinery required for the biogenesis of intermembrane space proteins. Dysfunction of mitochondrial protein sorting pathways results in diminishing specific substrate proteins, followed by systemic pathology of the organelle and organismal death. The cellular responses caused by accumulation of mitochondrial precursor proteins in the cytosol are mainly unknown. Here we present a comprehensive picture of the changes in the cellular transcriptome and proteome in response to a mitochondrial import defect and precursor over-accumulation stress. Pathways were identified that protect the cell against mitochondrial biogenesis defects by inhibiting protein synthesis and by activation of the proteasome, a major machine for cellular protein clearance. Proteasomal activity is modulated in proportion to the quantity of mislocalized mitochondrial precursor proteins in the cytosol. We propose that this type of unfolded protein response activated by mistargeting of proteins (UPRam) is beneficial for the cells. UPRam provides a means for buffering the consequences of physiological slowdown in mitochondrial protein import and for counteracting pathologies that are caused or contributed by mitochondrial dysfunction. PMID- 26245376 TI - Regenerative biology: Maintaining liver mass. PMID- 26245375 TI - Self-renewing diploid Axin2(+) cells fuel homeostatic renewal of the liver. AB - The source of new hepatocytes in the uninjured liver has remained an open question. By lineage tracing using the Wnt-responsive gene Axin2 in mice, we identify a population of proliferating and self-renewing cells adjacent to the central vein in the liver lobule. These pericentral cells express the early liver progenitor marker Tbx3, are diploid, and thereby differ from mature hepatocytes, which are mostly polyploid. The descendants of pericentral cells differentiate into Tbx3-negative, polyploid hepatocytes, and can replace all hepatocytes along the liver lobule during homeostatic renewal. Adjacent central vein endothelial cells provide Wnt signals that maintain the pericentral cells, thereby constituting the niche. Thus, we identify a cell population in the liver that subserves homeostatic hepatocyte renewal, characterize its anatomical niche, and identify molecular signals that regulate its activity. PMID- 26245377 TI - Propagation of conformational changes during MU-opioid receptor activation. AB - u-Opioid receptors (uORs) are G-protein-coupled receptors that are activated by a structurally diverse spectrum of natural and synthetic agonists including endogenous endorphin peptides, morphine and methadone. The recent structures of the MUOR in inactive and agonist-induced active states (Huang et al., ref. 2) provide snapshots of the receptor at the beginning and end of a signalling event, but little is known about the dynamic sequence of events that span these two states. Here we use solution-state NMR to examine the process of MUOR activation using a purified receptor (mouse sequence) preparation in an amphiphile membrane like environment. We obtain spectra of the MUOR in the absence of ligand, and in the presence of the high-affinity agonist BU72 alone, or with BU72 and a G protein mimetic nanobody. Our results show that conformational changes in transmembrane segments 5 and 6 (TM5 and TM6), which are required for the full engagement of a G protein, are almost completely dependent on the presence of both the agonist and the G protein mimetic nanobody, revealing a weak allosteric coupling between the agonist-binding pocket and the G-protein-coupling interface (TM5 and TM6), similar to that observed for the beta2-adrenergic receptor. Unexpectedly, in the presence of agonist alone, we find larger spectral changes involving intracellular loop 1 and helix 8 compared to changes in TM5 and TM6. These results suggest that one or both of these domains may play a role in the initial interaction with the G protein, and that TM5 and TM6 are only engaged later in the process of complex formation. The initial interactions between the G protein and intracellular loop 1 and/or helix 8 may be involved in G-protein coupling specificity, as has been suggested for other family A G-protein-coupled receptors. PMID- 26245378 TI - Molecular biology: It takes two to untangle. PMID- 26245379 TI - Structural insights into u-opioid receptor activation. AB - Activation of the MU-opioid receptor (MUOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for MUOR activation, here we report a 2.1 A X-ray crystal structure of the murine MUOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the MUOR binding pocket are subtle and differ from those observed for agonist-bound structures of the beta2-adrenergic receptor (beta2AR) and the M2 muscarinic receptor. Comparison with active beta2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the MUOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors. PMID- 26245380 TI - Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation. AB - Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states. Healthy metazoan cells effectively eliminate intracellular protein aggregates, indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock protein disaggregase HSP100 of non-metazoan HSP70-dependent protein disaggregation systems, and the human HSP70 system alone, even with the crucial HSP110 nucleotide exchange factor, has poor disaggregation activity in vitro. This unresolved conundrum is central to protein quality control biology. Here we show that synergic cooperation between complexed J-protein co-chaperones of classes A and B unleashes highly efficient protein disaggregation activity in human and nematode HSP70 systems. Metazoan mixed-class J-protein complexes are transient, involve complementary charged regions conserved in the J-domains and carboxy-terminal domains of each J-protein class, and are flexible with respect to subunit composition. Complex formation allows J-proteins to initiate transient higher order chaperone structures involving HSP70 and interacting nucleotide exchange factors. A network of cooperative class A and B J-protein interactions therefore provides the metazoan HSP70 machinery with powerful, flexible, and finely regulatable disaggregase activity and a further level of regulation crucial for cellular protein quality control. PMID- 26245382 TI - X-ray irradiation synthesis of PEG-coated Au-Pd nanoparticles. AB - We demonstrate that the combination of x-ray irradiation and capping by polyethylene glycol (PEG) produces excellent flexibility in controlling the structure of Au-Pd nanoparticles while preserving their catalytic performance. We specifically adopted two different fabrication methods: co-reduction and seed assisted reduction. In both cases, precursor composition plays an important role in controlling the phases and size of the bimetallic nanoparticles. The optimal catalytic performance is obtained with the highest Pd concentration and when the nanoparticles consist of a Au core and a Pd shell. PMID- 26245383 TI - The Addition of Gold and Tin to Bismuth-Triiridium Carbonyl Complexes. AB - The reaction of Ir3(CO)9(MU3-Bi) with PhAu(NHC) (1), where NHC = 1,3-bis(2,6 diisopropylphenylimidazol-2-ylidene), has yielded the compound Ir3(CO)8(Ph)(MU3 Bi)[MU-Au(NHC)] (2) by the loss of one CO ligand and the oxidative addition of the Au-C (phenyl) bond of 1 to one of the iridium atoms. The Au(NHC) group bridges one of the Ir-Bi bonds of the cluster. On the basis of X-ray crystal structural analysis and molecular orbital and quantum theory of atoms in molecules calculations, the Au-Bi interaction was determined to be substantial and is comparable in character to the Ir-Bi and Ir-Ir bonds in this cluster. Compound 2 reacts with 2 equiv of HSnPh3 to yield the compound Ir3(CO)7(SnPh3)2(MU3-Bi)[MU-Au(NHC)](MU-H) (3), which contains two terminally coordinated SnPh3 ligands. Compound 3 reacts with H2O to yield the compound Ir3(MU3-Bi)(CO)7[MU-Ph2Sn(OH)SnPh2][MU-Au(NHC)] (4) by cleavage of a phenyl ring from each of the SnPh3 ligands and formation of a bridging OH group between the two tin atoms to form a chelating Ph2Sn(OH)SnPh2 ligand. PMID- 26245381 TI - Structural basis for stop codon recognition in eukaryotes. AB - Termination of protein synthesis occurs when a translating ribosome encounters one of three universally conserved stop codons: UAA, UAG or UGA. Release factors recognize stop codons in the ribosomal A-site to mediate release of the nascent chain and recycling of the ribosome. Bacteria decode stop codons using two separate release factors with differing specificities for the second and third bases. By contrast, eukaryotes rely on an evolutionarily unrelated omnipotent release factor (eRF1) to recognize all three stop codons. The molecular basis of eRF1 discrimination for stop codons over sense codons is not known. Here we present cryo-electron microscopy (cryo-EM) structures at 3.5-3.8 A resolution of mammalian ribosomal complexes containing eRF1 interacting with each of the three stop codons in the A-site. Binding of eRF1 flips nucleotide A1825 of 18S ribosomal RNA so that it stacks on the second and third stop codon bases. This configuration pulls the fourth position base into the A-site, where it is stabilized by stacking against G626 of 18S rRNA. Thus, eRF1 exploits two rRNA nucleotides also used during transfer RNA selection to drive messenger RNA compaction. In this compacted mRNA conformation, stop codons are favoured by a hydrogen-bonding network formed between rRNA and essential eRF1 residues that constrains the identity of the bases. These results provide a molecular framework for eukaryotic stop codon recognition and have implications for future studies on the mechanisms of canonical and premature translation termination. PMID- 26245384 TI - Building capacity for African Primary Care Research. PMID- 26245385 TI - Reflections on Primary Health Care and Family Medicine in Botswana. PMID- 26245386 TI - Primary healthcare and family medicine in Kenya. PMID- 26245387 TI - Community involvement in health services at Namayumba and Bobi health centres: a case study. AB - BACKGROUND: Community involvement has been employed in the development of both vertical and horizontal health programmes. In Uganda, there is no empirical evidence on whether and how communities are involved in their health services.Aim and Setting: The aim of this study was to establish the existence of community involvement in health services and to identify its support mechanisms in Namayumba and Bobi health centres in Wakiso and Gulu districts, respectively. METHODS: Participants were selected with the help of a community mobiliser. Key informants were selected purposively depending on their expertise and the roles played in their respective communities. The focus group discussions and key informant interviews were audio-recorded and transcribed verbatim. The transcripts were analysed manually for emerging themes and sub-themes. RESULTS: Several themes emerged from the transcripts and we categorised them broadly into those that promote community involvement in health services and those that jeopardise it. Easy community mobilisation and several forms of community and health centre efforts promote community involvement, whilst lack of trust for health workers and poor communication downplay community involvement in their health services. CONCLUSION: Community involvement is low in health services in both Namayumba and Bobi health centres. PMID- 26245388 TI - Health sector responses to intimate partner violence: a literature review. AB - BACKGROUND: Intimate partner violence (IPV) is a common and serious public health concern, particularly in South Africa, but it is not well managed in primary care. AIM: This review aims to summarise the current state of knowledge regarding health sector-based interventions for IPV, their integration into health systems and services and the perspectives of service users and healthcare workers on IPV care, focusing on the South African context. METHOD: PubMed, CINAHL, PsycINFO and Google Scholar were searched between January 2012 and May 2014. All types of study design were included, critically appraised and summarised. RESULTS: Exposure to IPV leads to wide-ranging and serious health effects. There is sufficient evidence that intervening in IPV in primary care can improve outcomes. Women who have experienced IPV have described an appropriate response by healthcare providers to be non-judgmental, understanding and empathetic. IPV interventions that are complex, comprehensive and utilise systems-wide approaches have been most effective, but system- and society-level barriers hamper implementation. Gender inequities should not be overlooked when responding to IPV. CONCLUSION: Further evaluations of health sector responses to IPV are needed, in order to assist health services to determine the most appropriate models of care, how these can be integrated into current systems and how they can be supported in managing IPV. The need for this research should not prevent health services and healthcare providers from implementing IPV care, but rather should guide the development of rigorous contextually-appropriate evaluations. PMID- 26245389 TI - Overweight and obesity profiles in Niger Delta Region, Nigeria. AB - INTRODUCTION: Overweight and obesity are global public health problems because of their effect on individuals, families and communities. The objective of this study was to describe the profile of overweight and obesity amongst adult out patients in Uyo in the Niger Delta region of Nigeria. METHOD: This was a cross sectional descriptive study done between October 2011 and March 2012. Using a systematic sampling technique, 584 subjects aged 18-65 years were recruited; data were collected with a structured questionnaire. Subjects were measured for height, weight, waist and hip circumferences. Body mass index (BMI) and waist-hip ratio (WHR) were calculated. Subjects with a BMI of 25.0 kg/m2 - 29.9 kg/m2 were regarded as being overweight whilst a BMI of > 30.0 kg/m2 was regarded as obese. Subjects with a WHR of > 0.90 for men or > 0.85 for women were regarded as having abnormal WHR. RESULTS: Of the 584 subjects, 196 (36.6%) were men and 388 (66.4%) women. The mean age for men and women was 43.3 +/- 17.8 years and 50.2 +/- 13.6 years, respectively. The prevalence of overweight amongst men was 39.8% versus 31.7% for women; obesity in men was 28.0% versus 52.0% in women. Overweight and obesity were more prevalent in subjects aged 25-54 years and amongst married subjects. There was a significant relationship between obesity and television viewing (p = 0.003). Hypertension (p = 0.008) and osteoarthropathies (p = 0.043) were more prevalent amongst the obese than the non-obese subjects. CONCLUSION: Overweight and obesity are now common in our environment. There is therefore a need for more public education about the health consequences of big body size. PMID- 26245390 TI - Factors associated with patients' understanding of their management plan in Tshwane clinics. AB - BACKGROUND: This research focused on patients' views regarding healthcare services and identified factors associated with understanding of their management plan. AIM: To develop a baseline for patient-clinician collaboration and the extent to which patients felt included and understood their treatment plan. SETTING: Tshwane district (South Africa) public health outpatient clinics. METHOD: Medical students interviewed 447 patients in 22 clinics in Tshwane district. Agreement was measured by the percentage of cases in which patients and clinicians were in accord about a particular aspect of the consultation. RESULTS: About one-third of patients incorrectly answered questions on whether changes in lifestyle or diet were prescribed as part of their treatment. The likelihood that patients understood their plan was associated with seeing the same clinician three or more times;having a consultation in their same or a similar language; patient participation in the diagnosis;and feeling that the clinician had explained their health problems to them. CONCLUSIONS: There is need for greater emphasis on continuity of care, the clinicians' ability to speak the patient's language and involving patients in the consultation. PMID- 26245391 TI - Implementation of the principles of primary health care in a rural area of South Africa. AB - BACKGROUND: The philosophy of primary healthcare forms the basis of South Africa's health policy and provides guidance for healthcare service delivery in South Africa. Healthcare service provision in South Africa has shown improvement in the past five years. However, it is uncertain as to whether the changes have reached rural areas and if primary healthcare is implemented successfully in these areas. OBJECTIVES: The aim of this article is to explore the extent to which the principles of primary healthcare are implemented in a remote, rural setting in South Africa. METHOD: A descriptive, qualitative design was implemented. Data were collected through interviews and case studies with 36 purposively-sampled participants, then analysed through Interpretative Phenomenological Analysis. RESULTS: Findings indicated challenges with regard to client-centred care, provision of health promotion and rehabilitation, the way care was organised, the role of the doctor, health worker attitudes, referral services and the management of complex conditions. CONCLUSION: The principles of primary healthcare were not implemented successfully. The community was not involved in healthcare management, nor were users involved in their personal health management. The initiation of a community-health forum is recommended. Service providers, users and the community should identify and address the determinants of ill health in the community. Other recommendations include the training of service managers in the logistical management of ensuring a constant supply of drugs, using a Kombi-type vehicle to provide user transport for routine visits to secondary- and tertiary healthcare services and increasing the doctors' hours. PMID- 26245392 TI - Service delivery and coverage in primary healthcare in a community-health project in Ibadan, Nigeria. AB - BACKGROUND: Standard health-service delivery aimed toward improving maternal and child health status remains elusive in Nigeria because of inaccuracies in data documentation leading to a lack of relatively stable evidence. OBJECTIVES: Through a community-health project, this study tested the accuracy of record keeping in primary healthcare services in nine clinics run in Ibadan, Nigeria. METHODS: A validation exercise was performed through a sample of the 10 most recent names extracted from three registers maintained by each clinic. RESULTS: A review of the register covering a period of four years showed a steady increase in: fully-immunised children, registration for antenatal care during the first trimester of pregnancy, the number of women who attended antenatal care at least three times, the overall number of women who booked for antenatal care and women who delivered in Eniosa Community-Health Project facilities over the four-year period. It was possible to trace 86% of those selected from the antenatal care register, 88.9% of those from the birth register and 81.1%of those from the immunisation register. Four women who should have been included for antenatal care, seven who had delivered (but were not in the register) and 13 who reportedly received immunisation but were not listed were found during the validation exercise. CONCLUSION: This study concludes that the names appearing in the register are likely to represent valid events, but that the registers did not capture all such events in the community. PMID- 26245393 TI - Sociodemographic characteristics of persons committing suicide in Durban, South Africa: 2006-2007. AB - BACKGROUND: Suicidal behaviour is a leading contributor to the burden of disease worldwide and varies widely between countries. South African figures are amongst the highest in the world, with recent trends indicating a disturbing rise, especially amongst the younger age groups, across all races. AIM: This study analysed sociodemographic characteristics and trends relating to suicides committed in Durban, South Africa during the period of 2006-2007. METHOD: A retrospective analysis of suicidal deaths (during 2006-2007), extracted from autopsy registers at all three government-run mortuaries in Durban, was conducted. RESULTS: The total number of suicides in Durban increased by 6.68% from 2006 to 2007. Suicide accounted for an average of 8.8% of all non-natural deaths per year of the study. The overall suicide rates of 14.53 (2006) and 15.53 (2007) per 100 000 population are comparable with national and global figures. The majority of suicides occurred in single unemployed persons, men and younger age groups. The largest number of suicides per year was recorded in black people, followed by Indian, white and mixed-race people. Hanging was the preferred method in the majority of victims, followed by self-poisoning, shooting and jumping. CONCLUSIONS: The findings indicate a disturbingly high suicide rate amongst the various population and age groups in Durban. The dominant methods used may be influenced by ease of access. The reported trends may worsen unless there is a swift and decisive public health response and cohesive community-based programmes which include a supportive multidisciplinary network. PMID- 26245394 TI - Reasons for inpatients not to seek clarity at Dr George Mukhari Academic Hospital, Pretoria. AB - BACKGROUND: Healthcare practitioners should provide patients with information regarding their clinical conditions. Patients should also feel free to seek clarity on information provided. However, not all patients seek this clarity. OBJECTIVES: To explore the reasons inpatients gave for not seeking clarity on information that was received but not understood. METHODS: This was a qualitative arm of a larger study, titled 'Are inpatients aware of the admission reasons and management plans of their clinical conditions? A survey at a tertiary hospital in South Africa', conducted in 2010. Of the 264 inpatients who participated in the larger study, we extracted the unstructured responses from those participants (n = 152) who had indicated in the questionnaire that there was information they had not understood during their encounter with healthcare practitioners, but that they had nonetheless not sought clarity.Data were analysed thematically. RESULTS: Themes that emerged were that inpatients did not ask for clarity as they perceived healthcare practitioners to be 'too busy', aloof, non-communicators and sometimes uncertain about patients' conditions. Some inpatients had unquestioning trust in healthcare practitioners,whilst others had experiences of bad treatment. Inpatients had poor self-esteem, incapacitating clinical conditions, fear of bad news and prior knowledge of their clinical conditions. Some inpatients stated that they had no reason for not seeking clarity. CONCLUSION: The reasons for not seeking clarity were based on patients' experiences with the healthcare practitioners and their perceptions of the latter and of themselves. A programme should be developed in order to educate inpatients on effective communication with their healthcare practitioners. PMID- 26245395 TI - Emergency contraception amongst female college students--knowledge, attitude and practice. AB - BACKGROUND: Unwanted teenage pregnancies have a notable detrimental impact on the learners' trajectory and have been associated with jeopardising the students' educational progress and future career prospects. These pregnancies are mostly unplanned and unintended and many are terminated, either legally or illegally. AIM: The aim of this study was to explore the contributory role played by the knowledge, attitude and practices of female college students with respect to the utilisation of emergency contraceptives. SETTING: Three tertiary institutions in Dessie, Ethiopia. METHODS: Quantitative self-administered questionnaires were used to collect descriptive data from 352 female college students. RESULTS: The study revealed that there was a high percentage (78.3%) of unwanted pregnancies amongst those engaging in sex. Significantly, nearly half (43.3%) of these unwanted pregnancies resulted in abortion. Only 10% of the students sampled admitted to ever having used emergency contraception. Even though more than half (69.9%) of the students knew about emergency contraception, only 27% of them felt confident that they understood when it was most effective. CONCLUSION: These and other observed findings confirm the need for improvement of female college students' knowledge and timely utilisation of emergency contraception. PMID- 26245396 TI - Midwifery workforce profile in Limpopo Province referral hospitals. AB - BACKGROUND: In sub-Saharan Africa including South Africa, maternal mortality rates remain unacceptably high due to a shortage of registered nurses with advanced midwifery diplomas. OBJECTIVE: To determine the profile of registered nurses (RNs) involved in maternity care in public referral hospitals of the Limpopo Province, South Africa. METHOD: A cross-sectional descriptive study was conducted in all maternity units of Limpopo's public referral hospitals. The study population comprised of 210 registered nurses, who became the study sample. Data on their educational profile and work experience in midwifery was analysed using STATA version 9.0. RESULTS: The mean age of the 210 registered nurses was 44.5 +/- 9.1 years (range 21 to 62). The majority (152/210; 70%) were 40 years and older, 56% (117/210) had been working for more than 10 years, and 63/210 (30%) were due to retire within 10 years. Only 22% (46/210) had advanced midwifery diplomas, i.e. after their basic undergraduate training. Only six (2.9%) of the RNs providing maternity care in these referral hospitals were studying for advanced midwifery diplomas at the time of the study. CONCLUSION: This study demonstrated a shortage of registered nurses with advanced midwifery training/diplomas in referral hospitals of the Limpopo Province. This has a potentially negative effect in reducing the high maternal mortality rate in the province. PMID- 26245397 TI - Improving the quality of care for patients with hypertension in Moshupa District, Botswana: quality improvement cycle. AB - BACKGROUND: Although there are no prevalence studies on hypertension in Botswana, this condition is thought to be common and the quality of care to be poor. AIM: The aim of this project was to assess and improve the quality of primary care for hypertension. SETTING: Moshupa clinic and catchment area, Botswana. METHODS: Quality improvement cycle. RESULTS: Two hundred participants were included in the audit. Sixty-eight per cent were women with a mean age of 55 years. In the baseline audit none of the target standards were met. During the re-audit six months later, six out of nine structural target standards, five out of 11 process target standards and one out of two outcome target standards were achieved. Statistically-significant improvement in performance (p < 0.05) was shown in 10 criteria although the target standard was not always met. In the re-audit, the target of achieving blood pressure control (< 140/90) in 70% of patients was achieved. CONCLUSION: The quality of care for hypertension was suboptimal in our setting. Simple interventions were designed and implemented to improve the quality of care. These interventions led to significant improvement in structural and process criteria. A corresponding significant improvement in the control of blood pressure was also seen. PMID- 26245398 TI - Factors that influence contraceptive use amongst women in Vanga health district, Democratic Republic of Congo. AB - BACKGROUND: Contraception is often necessary in order to plan for children and without it there is a risk of unplanned pregnancies. In the Democratic Republic of Congo, this often results in abortions by untrained persons with resultant morbidity and mortality. AIM: To investigate the factors that influence contraceptive use amongst women of childbearing age in the Vanga health zone. METHODS: Cross-sectional survey using interviewer-administered questionnaires. RESULTS: Of the 384 women recruited, a majority (46.1%) were in the 31-40 year age group;52% had reached primary school and 88% did not have formal employment. One hundred and forty of the participants reported current use of contraception, with 60% of them using modern methods of contraception; 36.1% of them had begun using contraception before the age of 20; and the most common methods were oral contraceptive pills and injection, each accounting for 22.9%. There was variation in the duration of contraceptive use and the main reason for using contraception was to space children. Of the participants, 20.7% had been using contraception for more than two years. Seventy-seven (31.5%) of the women reported they did not use contraception because of a fear of side effects. Forty-four (18%) reported that they are unable to afford contraception, 38 (15.6%) had husbands who disapproved of contraceptive usage, 26 (10.6%) had a fear of infertility, 18 (7.4%) practised a religion that did not allow them to use contraception and 12 of the women (4.9%) did not use contraception because it was unavailable to them. CONCLUSION: Barriers to contraception in our study were fears of side effects and infertility, cost, male partner's objection, unavailability of contraception and religious beliefs. PMID- 26245399 TI - Patient knowledge of HIV and its treatment in South Africa. AB - BACKGROUND: Patients on antiretroviral therapy (ART) need to achieve a 90% adherence rate to ART in order to prevent disease progression and drug resistance. The patients' knowledge of ART and HIV is thus crucial to ensuring good adherence, decreased risk for drug resistance and cost-effective treatment for these patients. AIM: To determine the knowledge of infected patients with regard to HIV and the ART they were receiving. SETTING: The study was conducted at a comprehensive community health centre in a developing low socio-economic community near Cape Town, South Africa. METHODS: A quantitative descriptive correlative research design was applied. A sample consisting of 200 (8.5%) respondents was selected from a population of 2349. A multiple-choice questionnaire, comprising 29 questions, including 14 critical knowledge testing questions, was used in individual interviews conducted by either the researcher or fieldworker who assessed the respondents' knowledge regarding various key aspects of HIV and ART. RESULTS: Misconceptions regarding HIV and ART were revealed and scores for the 14 critical knowledge testing questions in the questionnaire revealed that 0% of the respondents had good knowledge, 20% had average knowledge and 80% had poor knowledge. CONCLUSION: The respondents on ART in this particular community health centre had poor knowledge of HIV and ART. This may contribute to poor adherence rates, increased drug resistance, disease progression and increased costs for the government with regard to treating such patients. Increased attention needs to be given to patient education. PMID- 26245400 TI - Body adiposity indices are associated with hypertension in a black, urban Free State community. AB - BACKGROUND: Non-communicable diseases, including hypertension, are increasing rapidly in resource-poor, developing countries amongst populations transitioning from traditional to westernised lifestyles; and are associated with excess weight. AIM: To investigate the relationship between hypertension and various indices of body adiposity in a transitioning, urban, black population. SETTING: Three hundred and thirty-nine adults (25-64 years) from a larger cross-sectional study (Assuring Health for All in the Free State) conducted in Mangaung, South Africa, were included. METHODS: Standard techniques were used to determine blood pressure, HIV status, body mass index (BMI), waist-to-height ratio (WHtR) and body adiposity index (BAI). RESULTS: Approximately 40% of the sample was HIV positive and 63.4% hypertensive, with the greatest risk of hypertension being amongst older men. Based on BMI, 23.0% were overweight and 32.1% obese. Waist-to height ratio showed that 58.6% had increased cardiovascular risk. Mean BAI was 34.1%, whilst 76.3% had a body fat percentage in the overweight/obese category. Waist circumference representing increased cardiovascular risk was found in 44.3% of women and 3.9% of men. Significant positive correlations between mean arterial bloodpressure and BMI (r = 0.261; p < 0.001), WHtR (r = 0.357; p < 0.001) and BAI (r = 0.245; p <0.001) were found. WHtR was a stronger predictor of mean arterial pressure than BMI or BAI. HIV status showed an inverse correlation with all adiposity indices (p < 0.001). CONCLUSION: Our findings promote WHtR as a practical screening tool for increased hypertension risk in populations undergoing westernisation, and support weight loss as afirst-line intervention for the prevention and management of hypertension. PMID- 26245401 TI - Price, availability and affordability of medicines. AB - BACKGROUND: Medicines play an important role in healthcare, but prices can be a barrier to patient care. Few studies have looked at the prices of essential medicines in low- and middle-income countries in terms of patient affordability. AIM: To determine the prices, availability and affordability of medicines along the supply chain in Swaziland. SETTING: Private- and public-sector facilities in Manzini, Swaziland. METHODS: The standardised methodology designed by the World Health Organization and Health Action International was used to survey 16 chronic disease medicines. Data were collected in one administrative area in 10 private retail pharmacies and 10 public health facilities. Originator brand (OB) and lowest-priced generic equivalent (LPG) medicines were monitored and these prices were then compared with international reference prices (IRPs). Affordability was calculated in terms of the daily wage of the lowest-paid unskilled government worker. RESULTS: Mean availability was 68% in the public sector. Private sector OB medicines were priced 32.4 times higher than IRPs, whilst LPGs were 7.32 times higher. OBs cost473% more than LPGs. The total cumulative mark-ups for individual medicines range from 190.99% - 440.27%. The largest contributor to add-on cost was the retail mark-up (31% - 53%). Standard treatment with originator brands cost more than a day's wage. CONCLUSION: Various policy measures such as introducing price capping at all levels of the medicine supply chain, may increase the availability, whilst at the same time reducing the prices of essential medicines for the low income population. PMID- 26245402 TI - Blood pressure control amongst patients living with hypertension presenting to an urban district hospital outpatient clinic in Kwazulu-Natal. AB - BACKGROUND: The prevalence of hypertension in South Africa has been estimated to be 20% of the adult population with over six million people being affected. Poor adherence to treatment plans lead to inadequate blood pressure control and high morbidity. Many studies have looked at factors contributing to poor blood pressure control in South Africa but few studies actually focus on district hospitals in Kwazulu-Natal in particular, despite the fact that the province has the most heterogeneous population in South Africa. METHOD: The study was a descriptive cross-sectional study conducted at the chronic out patient clinic of an urban district hospital involving 370 participants aged 18-90 years. RESULT: The study showed poorly controlled blood pressure in 58% of the participants. Only 35% knew their blood pressure results on the day of interview and 19.2% were aware of their target blood pressure. Good adherence was self-reported by 95% of the participants, whist 51.4% reported significant side-effects to medication. CONCLUSION: The majority of patients had poor knowledge about blood pressure and little awareness of their blood pressure reading. These may be precursors to poor blood pressure control and this needs further investigation. A high level of self reported adherence to medication did not translate into effective blood pressure control. A significant number reported medication side-effects which may have contributed to the poor blood pressure control. The high adherence rate may therefore have been over reported. An objective way tomeasure adherence will be necessary for future research. PMID- 26245403 TI - Community participation in malaria control strategy of intersect oral collaboration in Ghana: myth or reality? AB - BACKGROUND: For many years, malaria has been one of the main health concerns of the government of Ghana. The government has recently implemented a control strategy which will ensure the inclusion of the community members who were previously excluded from the process. Until now, however, scientific study on this strategy has been scanty. OBJECTIVES: The objectives were to investigate the level at which communities have been allowed to participate and to understand whether the idea of community participation in malaria control strategy is a myth or a reality. METHODS: Data were collected in the rural district of Ahafo-Ano South in the Ashanti region of Ghana. An exploratory qualitative approach was employed in order to ascertain the opinions of the local health officials and community members. The level of participation was measured using the framework of Arnstein's 'ladder' of participation, as developed in 1969. RESULTS: Evidence showed that the level of community participation was only tokenistic. Communities were only informed and/or consulted after decisions had been made, but the real engagement and negotiations were absent. Communities thus had limited opportunities to air their views in the planning process. CONCLUSION: This article has revealed that the government's vision of ensuring community participation in the malaria control policy-making process can be said to be a myth rather than a reality. PMID- 26245404 TI - Missed opportunities in child healthcare. AB - BACKGROUND: Various policies in health, such as Integrated Management of Childhood Illnesses, were introduced to enhance integrated service delivery in child healthcare. During clinical practice the researcher observed that integrated services may not be rendered. OBJECTIVES: This article describes the experiences of mothers that utilised comprehensive child health services in the Cape Metropolitan area of South Africa. Services included treatment for diseases; preventative interventions such as immunisation; and promotive interventions, such as improvement in nutrition and promotion of breastfeeding. METHOD: A qualitative, descriptive phenomenological approach was applied to explore the experiences and perceptions of mothers and/or carers utilising child healthcare services. Thirty percent of the clinics were selected purposively from the total population. A convenience purposive non-probability sampling method was applied to select 17 mothers who met the criteria and gave written consent. Interviews were conducted and recorded digitally using an interview guide. The data analysis was done using Tesch's eight step model. RESULTS: Findings of the study indicated varied experiences. Not all mothers received information about the Road to Health book or card. According to the mothers, integrated child healthcare services were not practised. The consequences were missed opportunities in immunisation, provision of vitamin A, absence of growth monitoring, feeding assessment and provision of nutritional advice. CONCLUSION: There is a need for simple interventions such as oral rehydration, early recognition and treatment of diseases, immunisation, growth monitoring and appropriate nutrition advice. These services were not offered diligently. Such interventions could contribute to reducing the incidence of child morbidity and mortality. PMID- 26245405 TI - An audit of diagnosis and treatment of tuberculosis in Ethiopia. AB - BACKGROUND: Despite the existence of national tuberculosis guidelines (NTG) in Ethiopia, the incidence and prevalence of tuberculosis did not decline markedly. Audits could attempt to determine whether or not healthcare professionals actually implemented these guidelines, as non-implementation could contribute to suboptimal tuberculosis treatment outcomes. AIM: To evaluate healthcare providers' implementation of Ethiopia's NTG during the diagnosis and treatment of tuberculosis in order to enhance tuberculosis treatment outcomes. METHODS: A descriptive, cross-sectional study design was used. RESULTS: Healthcare providers implemented the NTG during tuberculosis diagnosis for female (60.9%; n = 67) and male (56.1%; n = 69) patients. The correct numbers of anti-tuberculosis pills, complying with the NTG recommendations, were prescribed for 91.8% (n = 101) of the women and for 90.2% (n = 111) of the men. However, both over- and under prescriptions of anti-tuberculosis drugs occurred. There was an over-diagnosis of smear-negative pulmonary tuberculosis. Only 2.6% (n = 2) of the 76 smear-negative pulmonary tuberculosis patients had been diagnosed correctly. CONCLUSION: Implementation of the NTG should be enhanced, especially with regard to the diagnosis of smear-negative pulmonary tuberculosis patients and the correct prescription of anti-tuberculosis drugs. This would help to increase the number of correctly-diagnosed and -treated tuberculosis patients, improve tuberculosis treatment outcomes, decrease the spread of tuberculosis and prevent the development of multi-drug-resistant tuberculosis strains. PMID- 26245406 TI - Ethical considerations of mobile phone use by patients in KwaZulu-Natal: Obstacles for mHealth? AB - BACKGROUND: mHealth has the potential to facilitate telemedicine services, particularly in the developing world. Concern has been expressed about the confidentiality of health information that is relayed by mobile phone. AIM: We examined the habits and practices of mobile phone use by patients in KwaZulu Natal, South Africa. METHODS: We conducted a descriptive survey of two patient populations: 137 urban patients attending private practitioners and 139 patients in remote rural areas attending outpatient departments in Government-funded hospitals. The questionnaire covered several domains: demographics, mobile phone use, privacy and confidentiality and future use for health-related matters. RESULTS: Two hundred and seventy-six patients completed the questionnaire. We found that a third of our participants shared their mobile phone with others, 24% lent their phone to others and more than half received health-related messages for other people. Mobile phone theft was common, as was number changing. Thirty eight percent of the people were not able to afford airtime for more than a week in the past year and 22% of rural patients were unable to keep their phone charged. Mobile phone signal coverage was significantly worse in the rural areas than in urban areas. CONCLUSION: This study highlights the legal and ethical ramifications that these practices and findings will have on mHealth programmes in our setting. Healthcare providers and regulators will need to consider how patients use and manage their mobile phones when developing services and regulations. PMID- 26245407 TI - Integrating HIV care and treatment into primary healthcare: are clinics equipped? AB - BACKGROUND: The demand for HIV care and treatment services is increasing rapidly and strategies to sustain long-term care should be employed. The decentralisation and integration of HIV care and treatment services into primary healthcare (PHC) is vitally important in order to ensure optimal access to life-saving antiretroviral therapy and ongoing chronic care. Conversely, the PHC system is fraught with the current burden of disease. SETTING: The study was conducted in PHC clinics in the uMgungundlovu district, Kwa-Zulu Natal. AIM: The objectives of the study were to assess whether PHC clinics were equipped to deliver integrated HIV services and to evaluate the availability of resources as well as support systems for HIV care and treatment in PHC clinics. METHODS: A quantitative, cross sectional descriptive study was undertaken in 20 randomly-selected, eligible clinics in the uMgungundlovu district, KwaZulu-Natal, South Africa. An evaluation instrument was completed through observations and review of the clinic data records. Criteria were based on the World Health Organization's guide to indicators for antiretroviral programmes as well as South African HIV standards for PHC facilities. RESULTS: None of the clinics were equipped adequately. Clinics with a higher patient load had poorer scores, whilst clinics providing antiretroviral therapy were better equipped in terms of human resources and infrastructure. CONCLUSION: HIV services are an essential part of primary healthcare and clinics need to be equipped adequately in order to render this service. It is unlikely that the over-burdened health system would be able to cope with an increased number of patients on antiretroviral therapy in the long term, whilst maintaining quality of services, without support being given to PHC clinics. PMID- 26245408 TI - Prevention of mother-to-child transmission in HIV audit in Xhosa clinic, Mahalapye, Botswana. AB - BACKGROUND: The Mahalapye district health management team (DHMT) conducts regular audits to evaluate the standard of services delivered to patients, one of which is the prevention of mother-to-child-transmission (PMTCT) programme. Xhosa clinic is one of the facilities in Mahalapye which provides a PMTCT programme. AIM: This audit aimed to identify gaps between the current PMTCT clinical practice in Xhosa clinic and the Botswana PMTCT national guidelines. SETTING: This audit took place in Xhosa clinic in the urban village of Mahalapye, in the Central District of Botswana. METHODS: This was a retrospective audit using PMTCT Xhosa clinic records of pregnant mothers and HIV-exposed babies seen from January 2013 to June 2013. RESULTS: One hundred and thirty-three pregnant women registered for antenatal care. Twenty-five (19%) knew their HIV-positive status as they had been tested before their pregnancy or had tested HIV positive at their first antenatal clinic visit. More than two-thirds of the 115 pregnant women (69%) were seen at a gestational age of between 14 and 28 weeks. About two-thirds of the pregnant women (67%) took antiretroviral drugs. Of the 44 HIV-exposed infants, 39 (89%) were HIV DNA PCR negative at 6 weeks. Thirty-two (73%) children were given cotrimoxazole prophylaxis between 6 and 8 weeks. CONCLUSION: The PMTCT programme service delivery was still suboptimal and could potentially increase the mother to-child transmission of HIV. Daily monitoring mechanism to track those eligible could help to close the gap. PMID- 26245409 TI - Compliance of St Joseph's Hospital Roma, Lesotho with the National Tuberculosis Programme of Lesotho, 2007 and 2008. AB - BACKGROUND: In 2009 Lesotho had an estimated TB prevalence of 696 cases/100 000 population - the 4th highest in the world. This epidemic was characterised by high rates of death, treatment failure and unknown treatment outcomes. These adverse outcomes were attributable to a high rate of TB and/or HIV co-infection and weaknesses in the implementation of Lesotho's National Tuberculosis Programme (NTP). This study was conducted in St Joseph's Hospital, Roma (SJHR) to assess the implementation of the NTP. METHOD: Records of 993 patients entered into the SJHR TB register between 2007 and 2008 were reviewed. Patients' treatment details were extracted from the register, validated and analysed by STATA 10.0. RESULTS: Of 993 patients registered: 88% were new patients, 37% were diagnosed on sputum smear microscopy alone, 35% were diagnosed on sputum smear microscopy with chest X-ray, whilst 25% were diagnosed on chest X-ray alone. In addition: 33% were sputum smear positive, 45% were sputum smear negative, and 22% had extra pulmonary TB. As to treatment outcome: 26% were cured, 51% completed treatment, and 51% converted from sputum smear positive to sputum smear negative over six months, whilst 16% died. Regarding HIV, 77% of patients were tested for HIV and 59% had TB and/or HIV co-infection. Of ten NTP targets only the defaulter and treatment failure rate targets were met. CONCLUSION: Whilst only two out of ten NTP targets were met at SJHR in 2007-2008, improvements in TB case management were noted in 2008 which were probably due to the positive effects of audit on staff performance. PMID- 26245410 TI - Management of cryptococcal meningitis in a district hospital in KwaZulu-Natal: a clinical audit. AB - BACKGROUND: Despite the development of context-specific guidelines, cryptococcal meningitis (CCM) remains a leading cause of death amongst HIV-infected patients. Results from clinical audits in routine practice have shown critical gaps in clinicians' adherence to recommendations regarding the management of CCM. AIM: The aim of this study was to review the acute management of CCM at an urban district hospital in KwaZulu-Natal, South Africa with a view to making recommendations for improving care. SETTING: An urban district hospital in KwaZulu-Natal, South Africa. METHODS: A retrospective audit was performed on clinical records of all patients (age > 13 years) admitted to the hospital with a diagnosis of CCM between June 2011 and December 2012. RESULTS: Measurement of cerebrospinal fluid opening pressure at initial lumbar puncture (LP) was done rarely and only 23.4% of patients had therapeutic LPs. The majority of patients (117/127; 92.1%) received amphotericin B, however, only 19 of the 117 patients (16.2%) completed the 14-day treatment target. Amphotericin B-toxicity monitoring and prevention was suboptimal; however, in-patient referral for HIV counselling and testing was excellent. CONCLUSIONS: The quality of care of CCM based on selected process criteria showed gaps in routine care at the hospital despite the availability of context-specific guidelines. An action plan for improving care was developed based on stakeholders' feedback. A repeat audit should be conducted in the future in order to evaluate the impact of this plan and to ensure that improvements are sustained. PMID- 26245411 TI - The diabetic foot risks profile in Selebi Phikwe Government Hospital, Botswana. AB - AIM: The present study aimed: (1) to evaluate the proportion of each diabetic foot (DF) risk category, according to the International Working Group on the Diabetic Foot (IWGDF) consensus, in patients attending the diabetic clinic in Selebi Phikwe Government Hospital (SPGH) and (2) to examine some of the factors that may be associated with the progression to higher risk categories such as anthropometric measurements, blood pressure, glycosylated haemoglobin (HbA1c) and lipid profile. METHODS: A retrospective, cross sectional chart review of patients who had attended the diabetic clinic in SPGH from January 2013 to December 2013 was performed. Patients were included if they had undergone a foot examination. Patients with amputation due to accident were excluded. The DF risk category was assessed by determining the proportion of patients in each of four risk categories, as described by the IWGDF consensus. RESULTS: The study encompassed 144 records from patients reviewed for foot examination from January to December 2013. Patients' ages were between 16 and 85 years, 46 (40%) were male and 98 (60%) were female. The majority (122, [85%]) of patients were in DF risk category 0, whilst a limited number of patients were classified in risk category 1 (10, [6.9%]), risk category 2 (7, [4.9%]) and risk category 3 (5, [3.5%]). Most of the patients had the type 2 diabetes mellitus (139, [97%; 95% CI 92% - 99%]). Patients' ages were associated with the progressively higher DF risk categories. The adjusted odd ratio was 1.1 (95% CI 1.03-1.14; p = 0.004). CONCLUSION: The present study revealed that about 15% of patients attending the SPGH diabetic clinic were categorised in higher risk groups for diabetic foot; patients' ages were linked to the higher DF risk categories. PMID- 26245412 TI - Attitudes, knowledge and practices of healthcare workers regarding occupational exposure of pulmonary tuberculosis. AB - BACKGROUND: Healthcare-associated tuberculosis (TB) has become a major occupational hazard for healthcare workers (HCWs). HCWs are inevitably exposed to TB, due to frequent interaction with patients with undiagnosed and potentially contagious TB. Whenever there is a possibility of exposure, implementation of infection prevention and control (IPC) practices is critical. OBJECTIVE: Following a high incidence of TB among HCWs at Maluti Adventist Hospital in Lesotho, a study was carried out to assess the knowledge, attitudes and practices of HCWs regarding healthcare-associated TB infection and infection controls. METHODS: This was a cross-sectional study performed in June 2011; it involved HCWs at Maluti Adventist Hospital who were involved with patients and/or sputum. Stratified sampling of 140 HCWs was performed, of whom, 129 (92.0%) took part. A self-administered, semi-structured questionnaire was used. RESULTS: Most respondents (89.2%) had appropriate knowledge of transmission, diagnosis and prevention of TB; however, only 22.0% of the respondents knew the appropriate method of sputum collection. All of the respondents (100.0%) were motivated and willing to implement IPC measures. A significant proportion of participants (36.4%) reported poor infection control practices, with the majority of inappropriate practices being the administrative infection controls (> 80.0%). Only 38.8% of the participants reported to be using the appropriate N-95 respirator. CONCLUSION: Poor infection control practices regarding occupational TB exposure were demonstrated, the worst being the first-line administrative infection controls. Critical knowledge gaps were identified; however, there was encouraging willingness by HCWs to adapt to recommended infection control measures. Healthcare workers are inevitably exposed to TB, due to frequent interaction with patients with undiagnosed and potentially contagious TB. Implementation of infection prevention and control practices is critical whenever there is a possibility of exposure. PMID- 26245413 TI - Management of type 2 diabetes mellitus: adherence challenges in environments of low socio-economic status. AB - BACKGROUND: The efficacy of treatment for clients with diabetes is highly dependent on the individual's ability to manage the disease. Several constraints, such as poverty, illiteracy and insufficient resources (finances and specialised healthcare professionals), especially communities of low socio-economic status, could influence clients' ability to manage their disease. AIM: The main aim of this study was to outline the obstacles encountered by individuals with type 2 diabetes mellitus from an urban community with regard to management of their disease. SETTING: The study was conducted at a primary health care facility in the Western Cape, South Africa. METHODS: Ethical clearance was obtained from all relevant authorities. Eight (8) conveniently selected clients with type 2 diabetes mellitus per participating community healthcare centre (six approved centres in total) were invited to take part in focus group discussions. Twenty six clients, 15 females and 11 males, with a mean age of 58.92 years (SD = 7.33), agreed to participate. Audiotaped data were transcribed verbatim followed by content analysis and identification of themes. RESULTS: Themes that emerged were challenges with: a healthy eating plan, physical activity, financial constraints, other people's understanding of the disease, and service received at the community healthcare centre. Verbatim quotes were used to exemplify the themes. CONCLUSION: Clients with type 2 diabetes mellitus experienced several challenges in the management of their disease. These challenges should be addressed to assist with better glycaemic control and to curb the emergence of diabetic complications and their attendant cost implications. PMID- 26245414 TI - The effect of formal, neonatal communication-intervention training on mothers in kangaroo care. AB - BACKGROUND: Due to low-birth-weight, preterm birth, HIV and/or AIDS and poverty related factors, South Africa presents with an increased prevalence of infants at risk of language delay. A Kangaroo Mother Care (KMC) unit offers unique opportunities for training. AIM: The aim of the present study was to determine if formal, neonatal communication-intervention training had an effect on mothers' knowledge and communication interaction with their high-risk infants. METHODS: Three groups of mothers participated: Group 1 was trained whilst practicing KMC; Group 2 was not trained but practiced KMC; and Group 3 was also not trained but practiced sporadic KMC. Ten mothers per group were matched for age, education level and birth order of their infants. The individual training was based on graded sensory stimulation and responsive mother-infant communication interaction, which emphasised talking and singing by the mother. RESULTS: Significant differences were found in mother-infant communication interaction between all three groups, which indicated a positive effect on Group 1 with training. Group 2, KMC without training, also had a positive effect on interaction. However, Group 1 mothers with training demonstrated better knowledge of their infants and were more responsive during interaction than the other two groups. CONCLUSION: The present study suggests that neonatal communication intervention training adds value to a KMC programme. PMID- 26245415 TI - An examination of the factors fueling migration amongst Community Service practitioners. AB - BACKGROUND: Research is needed in order to understand the potential influence of the Bilateral Agreement between South Africa and the United Kingdom (UK), as well as other more recent international and local policies restricting movement of South African health workers abroad; and to determine what effect they have on the migration intentions and plans of health professionals in South Africa. AIM: The aims were to (1) explore the migration intentions and the factors that influence these intentions amongst Community Service (CS) nurses and doctors; (2) explore their views and opinions about the Bilateral Agreement between the UK and South Africa (SA) and other UK policies around the recruitment and employment of foreign health professionals; and (3) understand the impact of these policies on the migration plans of these CS doctors and nurses. METHOD: Qualitative focus groups and interviews were conducted with 23 CS doctors and nurses. To supplement this, 6 interviews were conducted with nurses and a doctor who had worked in the UK. RESULTS: A higher disposition toward moving abroad was apparent amongst those who had experienced a challenging and frustrating CS year. Poor working conditions, including long work hours, high patient loads and inadequate resources and equipment, as well as low salaries and the perceived ambivalence of the government to the complaints of health practitioners, were influencing decisions to migrate abroad. CONCLUSION: The findings suggest that government efforts to better manage, recognise and respect the work and contribution of health professionals to the country would go a long way toward retaining health professionals. PMID- 26245416 TI - The practices of isolating tuberculosis infectious patients at hospitals of Vhembe district, Limpopo Province. AB - BACKGROUND: Airborne infections pose a serious threat to susceptible individuals whenever they are together in confined spaces with patients coughing up tuberculosis (TB) bacilli. In healthcare facilities, those with infectious TB should, as far as possible, be isolated from non-infectious patients in order to prevent exposure to the infectious droplet nuclei generated by infected patients. AIM: This article aims to describe the use of masks and isolation of infectious TB patients at hospitals of Vhembe district, Limpopo Province in order to inform future policy and practices. SETTING: This study was conducted at seven of the eight hospitals in Vhembe district. METHODS: A cross-sectional qualitative design of a descriptive nature was used. Purposive sampling was used to select 57 focus group participants. Necessary approval, permission and clearance were obtained. The participants' rights were respected. RESULTS: This study confirmed that TB cubicles were not reserved for patients with infectious TB and that many TB inpatients at hospitals of Vhembe district were not isolated; masks were not used consistently or appropriately by patients, staff or visitors. Furthermore, the movement of TB inpatients in isolation was not restricted. CONCLUSIONS: There is an unnecessary risk of becoming infected with TB at the rural hospitals of Vhembe district as a result of incorrect isolation practices. The development and implementation of a quality control programme, as well as ongoing training at the hospital level, would improve the TB infection control measures practised by healthcare workers at hospitals in Vhembe district and reduce the risk of acquiring TB at these hospitals. PMID- 26245417 TI - Where there is no morphine: the challenge and hope of palliative care delivery in Tanzania. AB - BACKGROUND: In Tanzania, a country of 42 million, access to oral morphine is rare. AIM: To demonstrate the effectiveness of palliative care teams in reducing patients' pain and in increasing other positive life qualities in the absence of morphine; and to document the psychological burden experienced by their clinical providers, trained in morphine delivery, as they observed their patients suffering and in extreme pain. SETTING: One hundred and forty-fie cancer patients were included from 13 rural hospitals spread across Tanzania. METHOD: A mixed method study beginning with a retrospective quantitative analysis of cancer patients who were administered the APCA African POS tool four times. Bivariate analyses of the scores at time one and four were compared across the domains. The qualitative arm included an analysis of interviews with six nurses, each with more than fie years' palliative care experience and no access to strong opioids. RESULTS: Patients and their family caregivers identifid statistically signifiant (p < 0.001) improvements in all of the domains. Thematic analysis of nurse interviews described the patient and family benefis from palliative care but also their great distress when 'bad cases' arose who would likely benefi only from oral morphine. CONCLUSION: People living with chronic cancer-related pain who receive palliative care experience profound physical, spiritual and emotional benefis even without oral morphine. These results demonstrate the need for continued advocacy to increase the availability of oral morphine in these settings in addition to palliative care services. PMID- 26245418 TI - Risk factors for visual impairment and blindness amongst black adult diabetics receiving treatment at Government healthcare facilities in Mopani District, Limpopo province, South Africa. AB - BACKGROUND: Diabetes mellitus (DM) is a common systemic disease amongst Black South Africans. It may lead to diabetic retinopathy (DR), a common cause of visual impairment (VI) and blindness. DR may signifiantly increase the prevalence of VI and blindness. AIM: To assess risk factors for VI and blindness amongst a black diabetic South African population aged >= 40 years. SETTING: The study was conducted in seven Government healthcare facilities (two hospitals, four clinics and one health centre) in Mopani District, Limpopo province, South Africa. METHODS: This was a cross-sectional health facility-based quantitative study. Structured interviews were used to obtain information, which included sociodemographic profie, knowledge about DM and its ocular complications, presence of hypertension and accessibility to health facilities. Subsequently participants were examined for VI and blindness using an autorefractor, pinhole disc, ophthalmoscope and logMAR visual acuity chart. Anthropometric measurements (height, weight and waist) were also taken. Associations between 31 risk factors and VI as well as blindness were statistically examined. RESULTS: Participants (N = 225) included 161 women and 64 men aged 40-90 years (mean 61.5 +/- 10.49 years); 41.3% of them had VI and 3.6% were blind. Cataracts (76.8%) and DR (7.1%) were the common causes of compensated VI and blindness. Risk factors that were associated with VI and blindness were age, monthly income, compliance with losing weight and physical activity. CONCLUSION: Findings suggest that lifestyle intervention and appropriate eyecare programmes may reduce VI and blindness in this population. PMID- 26245420 TI - Human resources for health in Botswana: the results of in-country database and reports analysis. AB - BACKGROUND: Botswana is a large middle-income country in Southern Africa with a population of just over two million. Shortage of human resources for health is blamed for the inability to provide high quality accessible health services. There is however a lack of integrated, comprehensive and readily-accessible data on the health workforce. AIM: The aim of this study was to analyse the existing databases on health workforce in Botswana in order to quantify the human resources for health. METHOD: The Department of Policy, Planning, Monitoring and Evaluation at the Ministry of Health, Ministry of Education and Skills Development, the Botswana Health Professions Council, the Nursing and Midwifery Council of Botswana and the in-country World Health Organization office provided raw data on human resources for health in Botswana. RESULTS: The densities of doctors and nurses per 10 000 population were four and 42,respectively; three and 26 for rural districts; and nine and 77 for urban districts. The average vacancy rate in 2007 and 2008 was 5% and 13% in primary and hospital care, respectively, but this is projected to increase to 53% and 43%, respectively, in 2016. Only 21% of the doctors registered with the Botswana Health Professions Council were from Botswana, the rest being mainly from other African countries. Botswana trained 77% of its health workforce locally. CONCLUSION: Although the density of health workers is relatively high compared to the region, they are concentrated in urban areas, insufficient to meet the projected requirements and reliant on migrant professionals. PMID- 26245419 TI - The roles of community health workers in management of non-communicable diseases in an urban township. AB - BACKGROUND: Community health workers (CHWs) are increasingly being recognised as a crucial part of the health workforce in South Africa and other parts of the world. CHWs have taken on a variety of roles, including community empowerment, provision of services and linking communities with health facilities. Their roles are better understood in the areas of maternal and child health and infectious diseases (HIV infection, malaria and tuberculosis). AIM: This study seeks to explore the current roles of CHWs working with non-communicable diseases (NCDs). SETTING: The study was conducted in an urban township in Cape Town, South Africa. METHOD: A qualitative naturalistic research design utilising observations and in depth interviews with CHWs and their supervisors working in Khayelitsha was used. RESULTS: CHWs have multiple roles in the care of NCDs. They act as health educators, advisors, rehabilitation workers and support group facilitators. They further screen for complications of illness and assist community members to navigate the health system. These roles are shaped both by expectations of the health system and in response to community needs. CONCLUSION: This study indicates the complexities of the roles of CHWs working with NCDs. Understanding the actual roles of CHWs provides insights into not only the competencies required to enable them to fulfil their daily functions, but also the type of training required to fill the present gaps. PMID- 26245421 TI - Knowledge and attitudes of non-occupational HIV post-exposure prophylaxis amongst first- and second-year medical students at Stellenbosch University in South Africa. AB - BACKGROUND: Human immunodeficiency virus (HIV) infection is a worldwide problem, with 68% of infected people residing in sub-Saharan Africa. Antiretroviral therapy is used as post-exposure prophylaxis (PEP) to prevent infection in cases of occupational exposure, and use has recently been expanded to nonoccupational exposure. Studies have demonstrated a lack of awareness of non-occupational PEP (NOPEP) in the general population. AIM: The aim of this study was to evaluate knowledge and attitudes towards availability of, access to and use of NO-PEP amongst first- and second-year medical students. SETTING: Participants were medical undergraduates of Stellenbosch University in the Western Cape of South Africa who were registered in 2013. METHODS: A descriptive cross-sectional study of 169 students was performed. Data were collected using self-administered questionnaires handed out in a classroom in August 2013. Self-reported knowledge and attitudes towards NO-PEP and barriers to access to and use of NO-PEP were analysed using frequency tables. Associations between self-reported and objective knowledge of NO-PEP were analysed by odds ratios. RESULTS: Over 90% of students had good knowledge on HIV transmission, and about 75% knew how it can be prevented. Twenty eight per cent (n = 47) of students reported knowledge of NO PEP; 67% reported hearing about it from lecturers, whilst 1% reported hearing about it from their partner. Studentswho knew the correct procedure to take when a dose is forgotten were 2.4 times more likely to report knowledge of NO-PEP than those who did not know what to do when a dose is forgotten (p = 0.029). No other associations were statistically signifiant. CONCLUSION: Students had positive attitudes towards the use of NO-PEP and also identifid barriers to its use. Despite good knowledge of HIV prevention and transmission, knowledge on NO-PEP was poor. PMID- 26245422 TI - Patient satisfaction at accredited antiretroviral treatment sites in the Gert Sibande District. AB - BACKGROUND: Patient satisfaction has been used as a significant indicator of quality services provided by healthcare personnel. With the largest antiretroviral therapy (ART) programme in the world, the healthcare industry is struggling increasingly with challenges of meeting patients' requirements and expectations for quality ART service provision. This study was conducted in order to identify the importance of factors contributing to satisfaction or dissatisfaction. AIM: This study sought to explore and describe the general satisfaction or dissatisfaction of patients with accredited ART hospital sites at public health facilities in the Gert Sibande District, Mpumalanga and to identify factors contributing to either satisfaction or dissatisfaction. SETTING: Six hospitals that initiated ART in the district, participated in the study. METHOD: The study was conducted using a sample of 300 patients. Proportional random sampling was used in selecting the number of patients from each facility. A structured interview with each participating patient was conducted using a standardised structured questionnaire. The first available required number of patients that complied with requirements from each of the six hospitals was selected for the interview. Descriptive statistics were used to analyse data and data with qualitative aspects were captured and categorised manually. RESULTS: The major factors contributing to satisfaction included the availability of medicines and knowledge regarding how to take medication. Factors contributing to dissatisfaction on the part of the patients included confidentiality issues, long waiting periods, shortage of staff and dirty toilets. CONCLUSION: This study indicated general satisfaction with the ART-related services at the accredited ART hospital sites in the Gert Sibande District. Regular monitoring and evaluation are recommended. PMID- 26245423 TI - Working in rural areas--the experiences of Umthombo Youth Development Foundation graduates. AB - BACKGROUND: Recruiting and retaining healthcare professionals (HCPs) for rural areas is challenging throughout the world. Although rural origin HCPs have been identified as being the most likely to work in rural areas, only a small number of rural-origin South African scholars are trained as HCPs each year and many do not return to work in rural areas. AIM: The aim of this article was to present the experiences of rural-origin HCPs who returned to work in a rural area after graduation. SETTING: Umthombo Youth Development Foundation has been running an innovating rurally-based scholarship scheme since 1999. By December 2013, 184 students supported by the scheme had graduated and all had returned to work in a rural area for a period of time. METHODS: This was a qualitative study using a life history methodology to explore the educational experience of six rural origin HCPs working in rural areas. RESULTS: The four themes that emerged from the data were: (1) contribution to service delivery; (2) professional development (3) the challenges and frustrations of working in rural hospitals; and (4) the impact of working as an HCP. CONCLUSION: Rural-origin HCPs are willing to return and work in rural areas. However, context and content factors need to be addressed if a work-back scholarship scheme is to be along-term strategy for the recruitment and retention of HCPs. PMID- 26245424 TI - Knowledge, attitude and practice regarding lifestyle modification in type 2 diabetic patients. AB - BACKGROUND: The number of persons suffering from type 2 diabetes mellitus continues to rise worldwide and causes significant morbidity and mortality, especially in the developing world. Behaviour change and adoption of healthy lifestyle habits help to prevent or slow down the complications of type 2 diabetes mellitus. However, the knowledge and practice of healthy lifestyles in many diabetic patients have been inadequate. AIM: This study sought to establish the knowledge, attitude and practice regarding lifestyle modification amongst type 2 diabetic patients. SETTING: The diabetic clinic of Mamelodi hospital, Pretoria, Gauteng Province, South Africa. METHODS: A cross-sectional study was done using a structured questionnaire amongst 217 type 2 diabetic patients seen at the diabetic clinic of Mamelodi hospital. Baseline characteristics of the participants were obtained and their knowledge, attitude and practice regarding lifestyle modification were assessed. RESULTS: Of the 217 participants, 154 (71%) were obese and 15 (7%) were morbidly obese. The majority of respondents (92.2%) had poor knowledge of the benefits of exercise, weight loss and a healthy diet. What is interesting is that the majority (97.7%) demonstrated bad practices in relation to lifestyle modifications, although over four-fifths (84.3%) had a positive attitude toward healthy lifestyle modifications. CONCLUSION: Despite the positive attitudes of respondents toward healthy lifestyle modifications, the knowledge and practice regarding lifestyle modifications amongst type 2 diabetes mellitus participants seen at Mamelodi hospital were generally poor. PMID- 26245425 TI - An analysis of blood pressure measurement in a primary care hospital in Swaziland. AB - BACKGROUND: Measurement of blood pressure (BP) is done poorly because of both human and machine errors. AIM: To assess the difference between BP recorded in a pragmatic way and that recorded using standard guidelines; to assess differences between wrist- and mercury sphygmomanometerbased readings; and to assess the impact on clinical decision-making. SETTING: Royal Swaziland Sugar Corporation Mhlume hospital, Swaziland. METHOD: After obtaining consent, BP was measured in a pragmatic way by a nurse practitioner who made treatment decisions. Thereafter, patients had their BP re-assessed using standard guidelines by mercury (gold standard) and wrist sphygmomanometer. RESULTS: The prevalence of hypertension was 25%. The mean systolic BP was 143 mmHg (pragmatic) and 133 mmHg (standard) using a mercury sphygmomanometer; and 140 mmHg for standard BP assessed using wrist device. The mean diastolic BP was 90 mmHg, 87 mmHg and 91 mmHg for pragmatic, standard mercury and wrist, respectively. Bland Altman analyses showed that pragmatic and standard BP measurements were different and could not be interchanged clinically.Treatment decisions between those based on pragmatic BP and standard BP agreed in 83.3% of cases, whilst 16.7% of participants had their treatment outcomes misclassified. A total of 19.5% of patients were started erroneously on anti-hypertensive therapy based on pragmatic BP. CONCLUSION: Clinicians need to revert to basic good clinical practice and measure BP more accurately in order to avoid unnecessary additional costs and morbidity associated within correct treatment resulting from disease misclassification. Contrary to existing research,wrist devices need to be used with caution. PMID- 26245426 TI - Knowledge of HIV and benefits of male medical circumcision amongst clients in an urban area. AB - BACKGROUND: Male medical circumcision (MMC) has been shown to reduce the risk of HIV transmission in circumcised men by up to 60%. Following recommendations from the World Health Organization, South Africa adopted MMC as a preventative strategy against HIV in 2010 and set up circumcision camps across the country. Concerns have been raised about condom avoidance following MMC because of a mistaken belief about the benefits of MMC.Aim and setting: The aim of this study was to describe the profile and knowledge about HIV and circumcision amongst men presenting for MMC in an urban area in KwaZulu-Natal. METHODS: This was a cross sectional descriptive study of 394 clients over the age of 18 years who presented to two MMC sites in Durban between November 2012 and March 2013. A validated questionnaire was used to collect data. RESULTS: The mean age of clients presenting for MMC was 28 years. Most clients were black, single, unemployed and sexually active. The majority presented for MMC because they believed that MMC would reduce their risk of acquiring HIV infection. Knowledge about HIV transmission was very good and 86.3% of clients were aware that risky sexual behaviour such as condom avoidance could reverse the benefits of MMC. CONCLUSION: The knowledge of HIV and benefits of MMC was very good amongst those presenting for MMC. However as MMC is primarily a preventative strategy, innovative methods to promote MMC prior to first sexual encounter need to be explored. Further research is needed to determine whether the benefits of MMC on the reduction of HIV transmission are sustained in routine practice. PMID- 26245427 TI - Maternal complication prevention: evidence from a case-control study in southwest Nigeria. AB - BACKGROUND: The importance of strengthening maternal health services as a preventive intervention for morbidities and complications during pregnancy and delivery in developing countries cannot be over-emphasised, since use of prenatal health services improves maternal health outcomes. AIM: This study investigated differences in risk factors for maternal complications in booked and unbooked pregnant women in Nigeria, and provided evidence for their prevention. SETTING: The study was carried out in a postnatal ward in a secondary health facility. METHODS: This was a case-control study involving booked and unbooked pregnant women who had delivered. Consecutive enrolment of all unbooked pregnant women (cases) was done, and one booked pregnant woman (control) was enrolled and matched for age with each of these. Both groups were interviewed using a questionnaire, whilst records of delivery were extracted from the hospital files. Findings were subjected to logistical regression at a significance level of p < 0.05. RESULTS: Booked women had a lower median length of labour (10 hours) compared to unbooked women (13 hours). More women in the booked control group (139; 35.1%) than in the unbooked case group (96; 23.6%) reported at least one type of morbidity during the index pregnancy (p = 0.0004). Booking status was associated with a likelihood of spontaneous vaginal delivery. Young maternal age, low education, rural residence and low socio-economic status were associated with less likelihood of using prenatal services. Young maternal age, low education and intervention in the delivery were associated with a likelihood of experiencing a complication of delivery. CONCLUSION: Strengthening antenatal and secondary healthcare services as short- and medium term measures might be cost-effective as a preventive strategy in complications of pregnancy,whilst socio-economic dimensions of health are accorded priority in the long term. PMID- 26245428 TI - Health research in the Western Cape province, South Africa: lessons and challenges. AB - BACKGROUND: Health research can play a critical role in strengthening health systems.However, little monitoring of health research is conducted in African countries to identify whether research contributes to addressing local health priorities.Aim/Setting: To review the profile of research on the health service platform in the Western Cape province of South Africa which was approved by the health authorities over the period January 2011 to December 2012. METHODS: Databases held by both the Provincial and City of Cape Town health departments were reviewed. Descriptions of research institution, location of research, topic and funding size and source were analysed. RESULTS: Of the health research approved in the province, 56% of projects were located on the District Health Services platform and 70% were based in the Cape Metropolitan area. For projects reporting budgetary information, the total funding was US $29.2 million. The primary focus of research was on HIV and tuberculosis (TB), whilst relatively few studies addressed nutrition, mental health or injury and there was little health systems research. Research funding was dominated by very large grants from foreign funders for HIV and/or TB research. South African government sources comprised less than 8% of all health research funding. CONCLUSION: There is a partial mismatch of donor funding to local health priorities. Greater focus on neglected areas such as mental health, trauma, nutrition and non-communicable disease, as well as greater investment in health systems research, is needed. Unless governments increase funding for research and a culture of research translation is achieved, health research will have limited impact on both local and national priorities. PMID- 26245429 TI - Assessment of the impact of family physicians in the district health system of the Western Cape, South Africa. AB - BACKGROUND: In 2007, South Africa made family medicine a new speciality. Family physicians that have trained for this new speciality have been employed in the district health system since 2011. The aim of the present study was to explore the perceptions of district managers on the impact of family physicians on clinical processes, health system performance and health outcomes in the district health system (DHS) of the Western Cape. METHODS: Nine in-depth interviews were performed: seven with district managers and two with the chief directors of the metropolitan and rural DHS. Interviews were recorded, transcribed and analysed using the ATLAS-ti and the framework method. RESULTS: There was a positive impact on clinical processes for HIV/AIDS, TB, trauma, noncommunicable chronic diseases, mental health, maternal and child health. Health system performance was positively impacted in terms of access, coordination, comprehensiveness and efficiency. An impact on health outcomes was anticipated. The impact was not uniform throughout the province due to different numbers of family physicians and different abilities to function optimally. There was also a perception that the positive impact attributed to family physicians was in the early stages of development. Unanticipated effects included concerns with their roles in management and training of students, as well as tensions with career medical officers. CONCLUSION: Early feedback from district managers suggests that where family physicians are employed and able to function optimally, they are making a significant impact on health system performance and the quality of clinical processes. In the longer term, this is likely to impact on health outcomes. PMID- 26245430 TI - Body mass index of 16-year olds in urban Maseru, Lesotho. AB - BACKGROUND: Overweight and/or obesity amongst children and adolescents is a global epidemic with health consequences that track into adulthood. No data are currently available regarding overweight/obesity amongst adolescents in Lesotho.Aim and setting: To assess the prevalence of overweight and/or obesity and the associated risk factors amongst 16-year olds in urban Maseru, Lesotho. METHOD: A cross-sectional descriptive study was conducted on a systematic sample of 16-year olds ingrade four (N = 221; 56.6% girls) from randomly-selected schools in urban Maseru. Diet histories and data on lifestyle, physical activity and knowledge, attitudes and/or perceptions and practices regarding nutrition were obtained during structured interviews and body mass index (BMI) was determined. RESULTS: Amongst these 16-year olds, 27.2% girls and 8.3% boys were overweight and/or obese based on World Health Organization cut-offs for BMI; 39.8% were insufficiently active or inactive;6.4% used alcohol regularly; and 11.7% used tobacco. Whilst 28.1% reported no television watching/electronic gaming/computer usage (combined screen time) outside school, 23.6% reported >= 4 hours of combined screen time outside school. Most (91.4%) consumed < 3 servings of vegetables/day; 86.4% consumed < 2 servings of fruits/day; and 95.5% consumed < 2 servings of dairy/day. The majority consumed maize porridge (56.1%), bread (63.8%) and margarine/oil/fat (82.3%) daily and added sugar to their food (74.2%). Fruits, vegetables, dairy, meat, pulses and traditional foods were only consumed weekly or less often. Most bought from tuck shops (18.6% daily; 54.3% weekly). Various gaps in knowledge, perceptions and practices were identified that may benefit from educational intervention. CONCLUSIONS: The current study identifies westernised dietary and lifestyle changes, along with overweight and/or obesity, amongst 16-year old adolescents in Lesotho. PMID- 26245431 TI - Attitudes toward condom education amongst educators for Deaf and hard-of-hearing adolescents in South Africa. AB - BACKGROUND: Disabled adolescents are at a critical time in their psychosocial and sexual development. AIM: This study explores the attitudes of educators working in schools for Deaf and hard-of-hearing pupils in South Africa toward condom education for their pupils. METHODS: We conducted a combination of individual in depth and joint interviews with a total of 27 participants. The sample comprised educators, school psychologists, school nurses and teaching assistants. RESULTS: Results showed that educators were aware of the HIV risk for their pupils and reported the risk of sexual abuse or premature sexual activity as being risk factors for HIV infection. None of the schools had a written condom education policy. Whilst some schools were integrating condom education in existing school curricula, others faced moral or religious dilemmas in doing so. There were differences in attitudes, both amongst schools and amongst educators in the same schools. CONCLUSIONS: Given the context of a burgeoning HIV epidemic, it is vital to address adequate condom education in schools. PMID- 26245432 TI - African primary care research: choosing a topic and developing a proposal. AB - This is the first in a series of articles on primary care research in the African context. The aim of the series is to help build capacity for primary care research amongst the emerging departments of family medicine and primary care on the continent. Many of the departments are developing Masters of Medicine programmes in Family Medicine and their students will all be required to complete research studies as part of their degree. This series is being written with this audience in particular in mind--both the students who must conceptualise and implement a research project as well as their supervisors who must assist them.This article gives an overview of the African primary care context, followed by a typology of primary care research. The article then goes on to assist the reader with choosing a topic and defining their research question. Finally the article addresses the structure and contents of a research proposal and the ethical issues that should be considered. PMID- 26245433 TI - African primary care research: reviewing the literature. AB - This is the second article in the series on African primary care research. The article focuses on how to search for relevant evidence in the published literature that can be used in the development of a research proposal. The article addresses the style of writing required and the nature of the arguments for the social and scientific value of the proposed study, as well as the use of literature in conceptual frameworks and in the methods. Finally, the article looks at how to keep track of the literature used and to reference it appropriately. PMID- 26245434 TI - African primary care research: performing surveys using questionnaires. AB - The aim of this article is to provide practical guidance on conducting surveys and the use of questionnaires for postgraduate students at a Masters level who are undertaking primary care research. The article is intended to assist with writing the methods section of the research proposal and thinking through the relevant issues that apply to sample size calculation, sampling strategy, design of a questionnaire and administration of a questionnaire. The articleis part of a larger series on primary care research, with other articles in the series focusing on the structure of the research proposal and the literature review, as well as quantitative data analysis. PMID- 26245435 TI - African Primary Care Research: quantitative analysis and presentation of results. AB - This article is part of a series on Primary Care Research Methods. The article describes types of continuous and categorical data, how to capture data in a spreadsheet, how to use descriptive and inferential statistics and, finally, gives advice on how to present the results in text, figures and tables. The article intends to help Master's level students with writing the data analysis section of their research proposal and presenting their results in their final research report. PMID- 26245436 TI - African Primary Care Research: qualitative interviewing in primary care. AB - This article is part of a series on African Primary Care Research and focuses on the topic of qualitative interviewing in primary care. In particular it looks at issues of study design, sample size, sampling and interviewing in relation to individual and focus group interviews.There is a particular focus on helping postgraduate students at a Masters level to write their research proposals. PMID- 26245437 TI - African Primary Care Research: qualitative data analysis and writing results. AB - This article is part of a series on African primary care research and gives practical guidance on qualitative data analysis and the presentation of qualitative findings. After an overview of qualitative methods and analytical approaches, the article focuses particularly on content analysis, using the framework method as an example. The steps of familiarisation, creating a thematic index, indexing, charting, interpretation and confirmation are described. Key concepts with regard to establishing the quality and trustworthiness of data analysis are described. Finally, an approach to the presentation of qualitative findings is given. PMID- 26245438 TI - African primary care research: quality improvement cycles. AB - Improving the quality of clinical care and translating evidence into clinical practice is commonly a focus of primary care research. This article is part of a series on primary care research and outlines an approach to performing a quality improvement cycle as part of a research assignment at a Masters level. The article aims to help researchers design their quality improvement cycle and write their research project proposal. PMID- 26245439 TI - African primary care research: participatory action research. AB - This article is part of the series on African primary care research and focuses on participatory action research. The article gives an overview of the emancipatory-critical research paradigm, the key characteristics and different types of participatory action research. Following this it describes in detail the methodological issues involved in professional participatory action research and running a cooperative inquiry group. The article is intended to help students with writing their research proposal. PMID- 26245440 TI - African Primary Care Research: performing a programme evaluation. AB - This article is part of a series on Primary Care Research in the African context and focuses on programme evaluation. Different types of programme evaluation are outlined: developmental, process, outcome and impact. Eight steps to follow in designing your programme evaluation are then described in some detail: engage stakeholders; establish what is known; describe the programme; define the evaluation and select a study design; define the indicators; planand manage data collection and analysis; make judgements and recommendations; and disseminate the findings. Other articles in the series cover related topics such as writing your research proposal, performing a literature review, conducting surveys with questionnaires, qualitative interviewing and approaches to quantitative and qualitative data analysis. PMID- 26245441 TI - African Primary Care Research: writing a research report. AB - Presenting a research report is an important way of demonstrating one's ability to conduct research and is a requirement of most research-based degrees. Although known by various names across academic institutions, the structure required is mostly very similar, being based on the Introduction, Methods, Results, Discussion format of scientific articles.This article offers some guidance on the process of writing, aimed at helping readers to start and to continue their writing; and to assist them in presenting a report that is received positively by their readers, including examiners. It also details the typical components of the research report, providing some guidelines for each, as well as the pitfalls to avoid.This article is part of a series on African Primary Care Research that aims to build capacity for research particularly at a Master's level. PMID- 26245442 TI - Injustice to transsexual women in a hetero-normative healthcare system. AB - BACKGROUND: Transsexual women who are on the journey of sexual re-alignment will experience various health problems. These problems are related directly to the treatment regime that they are following in order to attain and maintain their physical embodiment as a woman. They are forced to negotiate a hetero-normative healthcare system in order to receive assistance and care for their health problems related to their sexual re-alignment process. AIM: The questions posed were: What are the unique health problems that transsexual women experience whilst on the journey of sexual re-alignment? What is the current context of the South African healthcare system in which transsexual women should negotiate healthcare? These questions were asked in order to explore the health problems with which transsexual women are faced and to describe the hetero-normative healthcare system in South Africa. METHOD: An electronic literature search was executed via the EBSCO host with specific inclusion and exclusion criteria. The search words that were used were: Transsexual/s and Health/Healthcare. All studies had to be peer reviewed and published in the English language, from January 1972 up until February 2013. Literature on transsexual children was excluded. RESULTS: Transsexual women have the potential to suffer significant side-effects from their sexual re-alignment treatment, including cardio-vascular problems, endocrine problems and mental ill-health. They are also vulnerable to HIV infection. They have poor access to quality holistic healthcare and this may lead an increase in the mortality and morbidity figures of women. CONCLUSION: A hetero-normative healthcare system has a negative impact on the health of transsexual women and will cause them to be marginalised. This could contribute to both homo- and trans-phobia that will in turn strengthen the belief that transsexual women are un-African. PMID- 26245443 TI - Mental healthcare in Kenya: exploring optimal conditions for capacity building. AB - The global burden of disease related to mental disorders is on the increase, with the World Health Organization (WHO) estimating that over 450 million people are affected worldwide. The Mental Health Global Action Program (mhGAP) was launched by the WHO in 2002 in order to address the widening gap in access to mental healthcare in low-income countries. Despite these efforts, access to mental healthcare in low-income countries remains poor and is often described as inadequate, inefficient and inequitable, with an 85% estimated treatment gap in low-income countries, as compared with 35% to 50% in high-income countries.In this article, the authors argue that integrating mental health services into primary healthcare settings through capacity building is vital with regard to achieving mhGAP goals. The article explores the challenges to and potential enablers for the improvement of the delivery of broad-based mental healthcare services in Kenya. The authors propose the integration of the conceptual dimensions of both the cosmopolitanism and capabilities approaches as a combined strategy for dealing with capacity building in heterogeneous settings such as Kenya. PMID- 26245446 TI - Scaling up Family Medicine in Uganda. AB - It is evident that politicians, health managers and academics are realising the potential contribution of Family Medicine to health systems in sub-Saharan Africa. The challenge is in training institutions to recruit and train enough Family Physicians in order to meet expectations. The 3rd Family Medicine Conference in Uganda, held in October 2013, explored innovative ways of scaling up Family Medicine training and practice in Uganda. PMID- 26245447 TI - African Primary Care Research: current situation, priorities and capacity building. PMID- 26245449 TI - Predictors and outcome of tetanus in newborns in slum areas of Karachi City: a case control study. AB - BACKGROUND: Tetanus in newborns, is an under-reported public health problem and a major cause of mortality in developing countries. This study aimed to determine the predictors and outcome of tetanus in newborn infants in the slums of Bin Qasim town, Karachi, Pakistan. METHODS: We conducted a case-control study at primary health care centers of slums of Bin-Qasim town, area located adjacent to Bin Qasim seaport in Karachi, from January 2003 to December 2013. Cases were infants aged <=30 days with tetanus, as defined by the World Health Organization. Controls were newborn infants aged <=30 days without Tetanus, who were referred for a checkup or minor illnesses. The case to control ratio was 1:2. RESULTS: We analyzed 26 cases and 52 controls. The case fatality was 70.8%. We identified four independent predictors of Tetanus in newborns: maternal education (only religious education with no formal education OR 51.95; 95% CI 3.69-731), maternal non-vaccination (OR 24.55; 95% CI 1.01-131.77), lack of a skilled birth attendant (OR 44.00; 95% CI 2.30-840.99), and delivery at home (OR 11.54; 95% CI 1.01 131.77). CONCLUSIONS: We identified several potentially modifiable socio demographic risk factors for Tetanus in newborns, including maternal education and immunization status, birth site, and lack of a skilled birth attendant. Prioritization of these risk factors could be useful for planning preventive and cost-effective measures. PMID- 26245450 TI - Theoretical studies of organotin(IV) complexes derived from ONO-donor type schiff base ligands. AB - In this work a molecular modeling study was carried out based on a series of organotin(IV) derivatives which were complexed with ONO-Donor type Schiff base ligands to build up a statistical data pool for researchers. For this purpose, various properties of the selected complexes such as energies, band gaps, chemical reactivity descriptors, polarizabilities, geometric parameters, (1)H NMR, (13)C-NMR chemical shifting values were obtained through density functional theory using B3LYP, CAM-B3LYP, TPSSTPSS, TPSSh, HCTH, wB97XD, and MN12SX functionals. Empirical dispersion corrections were incorporated for some functionals and solvent effects were also taken into account through applying polarizable continuum model (PCM). (1)H-NMR, (13)C-NMR chemical shifts were calculated via linear regression analysis using either gauge invariant atomic orbital (GIAO) or continuous set of gauge transformations (CSGT) methods. While structural properties were being explored, quantitative effects of utilized functionals and empirical dispersion corrections over calculated properties were shown in detail. PMID- 26245451 TI - Can Artemia Hatching Assay Be a (Sensitive) Alternative Tool to Acute Toxicity Test? AB - Artemia sp. is extensively used in ecotoxicity testing, despite criticisms inherent to both acute and long-term tests. Alternative endpoints and procedures should be considered to support the use of this biological model. The hatching process comprises several developmental steps and the cyst hatchability seems acceptable as endpoint criterion. In this study, we assessed the reliability of the hatching assay on A. franciscana by comparing with acute and long-term mortality tests, using two chemicals: Diethylene Glycol (DEG), Sodium Dodecyl Sulphate (SDS). Both DEG and SDS tests demonstrated a dose dependent hatching inhibition. The hatching test resulted more sensitive than acute mortality test and less sensitive than the long-term one. Results demonstrate the reliability and high sensitivity of this hatching assay on a short time lag and support its useful application in first-tier risk assessment procedures. PMID- 26245452 TI - Expression of Genes Involved in Porphyrin Biosynthesis Pathway in the Human Renal Cell Carcinoma. AB - Renal cell carcinoma (RCC) remains one of the greatest challenges of urological oncology and is the third leading cause of death in genitourinary cancers. Surgery may be curative when patients present with localized disease. Our previous results demonstrated the autofluorescence of blood PpIX in primary RCC mouse model and an increase in fluorescence intensity as a function of growth of the subcutaneous tumor mass. In another work, a nice correlation between the growth of the tumor mass and tissue fluorescence intensity was found. The aim of this study was to evaluate the expression profile of porphyrin biosynthesis pathway-related genes of human kidney cells. We used two kidney cell lines, one normal (HK2) and another malignant (Caki-1). Endogenous and 5-aminolevolinic acid (ALA) induced protoporphyrin IX (PpIX) HK2 and Caki-1 cells were analyzed by fluorescence spectroscopy. Real-time quantitative polymerase chain reaction (qRT PCR) was used to measure mRNA of those genes. Emission spectra were obtained by exciting the samples at 405 nm. For ALA untreated cells the maximum fluorescence intensity was detected at 635 nm. The mean peak area of emission spectra in both cells types increased linearly in function of cell number. Besides, basal levels of PpIX autofluorescence of each cell concentration of HK2 samples were significantly lower than those of Caki-1 samples. For ALA-treated cells the mean PpIX spectra shows PpIX emission peak at 635 nm with a shoulder at 700 nm. Analysis of PpIX fluorescence intensity ratio between tumor cells and HK2 cells showed that fluorescence intensity was, on average, 26 times greater in tumor cells than in healthy cells. qRT-PCR revealed that in Caki-1 ALA-treated cells, PEPT gene was significantly up-regulated and FECH and HO-1 genes were significantly down regulated in comparison with HK2 ALA-treated cells. In conclusion, our results demonstrate the preferential accumulation of ALA-induced PpIX in human RCC and also indicate that PEPT1, FECH and HO-1 genes are major contributors to this accumulation. PMID- 26245453 TI - DNA Interaction Studies and In Vitro Cytotoxicity of Newly Synthesized Steroidal Imidazolidinones. AB - New steroidal imidazolidinone derivatives (7-9) were synthesized after reacting steroidal thiosemicarbazones with oxalyl chloride in absolute ethanol. After characterization by spectral and analytical data, the interaction studies of compounds (7-9) with DNA were carried out by UV-vis, fluorescence spectroscopy, circular dichroism, molecular docking and gel electrophoresis. The compounds bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb; 2.31 * 10(4) M(-1), 2.57 * 10(4) M(-1) and 2.16 * 10(4) M(-1), respectively indicating the higher binding affinity of compound 8 towards DNA. Gel electrophoresis demonstrated that the compounds 7-9 show strong interaction during the cleavage activity with pBR322 DNA. The docking study suggested the intercalation of imidazolidinone moiety of steroid derivative in minor groove of DNA. During in vitro cytotoxicity, compounds 7-9 revealed potential toxicity against the different human cancer cells (MTT assay). Apoptotic degradation of DNA in presence of compounds 7-9 was analyzed by agarose gel electrophoresis and visualized by ethidium bromide staining (comet assay). FACS analysis shows that the compound 8 bring about cell cycle arrest at 7 MUM concentration. PMID- 26245454 TI - Characterization of the Dynamics of Photoluminescence Degradation in Aqueous CdTe/CdS Core-Shell Quantum Dots. AB - We investigate the effects of the excitation power on the photoluminescence spectra of aqueous CdTe/CdS core-shell quantum dots. We have focused our efforts on nanoparticles that are drop-cast on a silicon nitride substrate and dried out. Under such conditions, the emission intensity of these nanocrystals decreases exponentially and the emission center wavelength shifts with the time under laser excitation, displaying a behavior that depends on the excitation power. In the low-power regime a blueshift occurs, which we attribute to photo-oxidation of the quantum dot core. The blueshift can be suppressed by performing the measurements in a nitrogen atmosphere. Under high-power excitation the nanoparticles thermally expand and aggregate, and a transition to a redshift regime is then observed in the photoluminescence spectra. No spectral changes are observed for nanocrystals dispersed in the solvent. Our results show a procedure that can be used to determine the optimal conditions for the use of a given set of colloidal quantum dots as light emitters for photonic crystal optical cavities. PMID- 26245455 TI - Novel Fluorescent Phenazines : Synthesis, Characterization, Photophysical Properties and DFT Calculations. AB - The organic compounds with donor-pi-bridge-acceptor type of architecture are of great interest for application as semiconductors. The synthesized compounds are obtained from 4-morpholino naphthalene-1,2-dione and 4-(4-(diethylamino) phenyl)naphthalene-1,2-dione and mono substituted ortho-phenylene diamines by condensation reaction. The donor groups are morpholinyl and N,N-diethylamino phenyl moieties, whereas acceptors are substituted phenazines. The synthesized molecules were characterized by spectral analysis.. The effect of the substitution has been studied on the basis of photophysical properties of the molecules. The halochromism behaviour of the molecule shows that at low to moderate acidity they respond differently with two types of donors. DFT computations were used in conjunction with NMR analysis to determine the ratio of the positional isomers. PMID- 26245456 TI - Pyridoxal Based Fluorescent Chemosensor for Detection of Copper(II) in Solution With Moderate Selectivity and Live Cell Imaging. AB - A pyridoxal-based fluorescent probe HL was synthesized for the detection of Cu(2+) in methanol with moderate selectivity. Upon addition of Cu(2+), to the solution of the probe in methanol exhibited a remarkable change in emission at 500 nm. With the limit of detection of 10 MUM, the probe could well meet the recommended (less than 32 MUM in drinking water) of the World Health Organization (WHO). The intracellular Cu(2+) imaging behaviour of HL was carried out on HeLa cells. PMID- 26245457 TI - A new Dual-Channel Chemosensor Based on Chemodosimeter Approach for Detecting Cyanide in Aqueous Solution: a Combination of Experimental and Theoretical Studies. AB - A new colorimetric and fluorescent receptor 1 for the detection of CN(-) has been simply developed. Receptor 1 showed selectively colorimetric and fluorometric responses to CN(-) in a near-perfect aqueous solution, respectively. This sensor displayed an obvious color change from yellow to colorless upon selective binding with CN(-). In addition, it could function as an "OFF-ON type" fluorescent response through a nucleophilic addition mechanism. The binding mode of receptor 1 with CN(-) was proposed to be 1:1, based on Job plot, (1)H NMR titration and ESI-mass spectrometry analysis. Moreover, the sensing mechanism for CN(-) was theoretically supported by DFT and TD-DFT calculations. PMID- 26245458 TI - Noninvasive Spinal Cord Stimulation: Technical Aspects and Therapeutic Applications. AB - BACKGROUND: Electrical and magnetic trans-spinal stimulation can be used to increase the motor output of multiple spinal segments and modulate cortico-spinal excitability. The application of direct current through the scalp as well as repetitive transcranial magnetic stimulation are known to influence brain excitability, and hence can also modulate other central nervous system structures, including spinal cord. OBJECTIVE: This study aimed to evaluate the effects and the therapeutic usefulness of these noninvasive neuromodulatory techniques in healthy subjects and in the neurorehabilitation of patients with spinal cord disorders, as well as to discuss the possible mechanisms of action. A comprehensive review that summarizes previous studies using noninvasive spinal cord stimulation is lacking. METHODS: PubMed (MEDLINE) and EMBASE were systematically searched to identify the most relevant published studies. We performed here an extensive review in this field. RESULTS: By decreasing the spinal reflex excitability, electrical and magnetic trans-spinal stimulation could be helpful in normalizing reflex hyperexcitability and treating hypertonia in subjects with lesions to upper motor neurons. Transcutaneous spinal direct current stimulation, based on applying direct current through the skin, influences the ascending and descending spinal pathways as well as spinal reflex excitability, and there is increasing evidence that it also can induce prolonged functional neuroplastic changes. When delivered repetitively, magnetic stimulation could also modulate spinal cord functions; however, at present only a few studies have documented spastic-reducing effects induced by repetitive spinal magnetic stimulation. Moreover, paired peripheral and transcranial stimulation can be used to target the spinal cord and may have potential for neuromodulation in spinal cord-injured subjects. CONCLUSIONS: Noninvasive electrical and magnetic spinal stimulation may provide reliable means to characterize important neurophysiologic and pathophysiologic aspects of spinal cord function. Moreover, transcutaneous direct current stimulation and repetitive magnetic stimulation may hold therapeutic promise in patients with spinal cord disorders, although future well-controlled studies are needed to corroborate and extend the preliminary findings. PMID- 26245459 TI - Genome-wide identification of Calcineurin B-Like (CBL) gene family of plants reveals novel conserved motifs and evolutionary aspects in calcium signaling events. AB - BACKGROUND: Calcium ions, the most versatile secondary messenger found in plants, are involved in the regulation of diverse arrays of plant growth and development, as well as biotic and abiotic stress responses. The calcineurin B-like proteins are one of the most important genes that act as calcium sensors. RESULTS: In this study, we identified calcineurin B-like gene family members from 38 different plant species and assigned a unique nomenclature to each of them. Sequence analysis showed that, the CBL proteins contain three calcium binding EF-hand domain that contains several conserved Asp and Glu amino acid residues. The third EF-hand of the CBL protein was found to posses the D/E-x-D calcium binding sensor motif. Phylogenetic analysis showed that, the CBL genes fall into six different groups. Additionally, except group B CBLs, all the CBL proteins were found to contain N-terminal palmitoylation and myristoylation sites. An evolutionary study showed that, CBL genes are evolved from a common ancestor and subsequently diverged during the course of evolution of land plants. Tajima's neutrality test showed that, CBL genes are highly polymorphic and evolved via decreasing population size due to balanced selection. Differential expression analysis with cold and heat stress treatment led to differential modulation of OsCBL genes. CONCLUSIONS: The basic architecture of plant CBL genes is conserved throughout the plant kingdom. Evolutionary analysis showed that, these genes are evolved from a common ancestor of lower eukaryotic plant lineage and led to broadening of the calcium signaling events in higher eukaryotic organisms. PMID- 26245460 TI - Optimising contraction and alignment of cellular collagen hydrogels to achieve reliable and consistent engineered anisotropic tissue. AB - Engineered anisotropic tissue constructs containing aligned cell and extracellular matrix structures are useful as in vitro models and for regenerative medicine. They are of particular interest for nervous system modelling and regeneration, where tracts of aligned neurons and glia are required. The self-alignment of cells and matrix due to tension within tethered collagen gels is a useful tool for generating anisotropic tissues, but requires an optimal balance between cell density, matrix concentration and time to be achieved for each specific cell type. The aim of this study was to develop an assay system based on contraction of free-floating cellular gels in 96-well plates that could be used to investigate cell-matrix interactions and to establish optimal parameters for subsequent self-alignment of cells in tethered gels. Using C6 glioma cells, the relationship between contraction and alignment was established, with 60-80% contraction in the 96-well plate assay corresponding to alignment throughout tethered gels made using the same parameters. The assay system was used to investigate the effect of C6 cell density, collagen concentration and time. It was also used to show that blocking alpha1 integrin reduced the contraction and self-alignment of these cells, whereas blocking alpha2 integrin had little effect. The approach was validated by using primary astrocytes in the assay system under culture conditions that modified their ability to contract collagen gels. This detailed investigation describes a robust assay for optimising cellular self-alignment and provides a useful reference framework for future development of self-aligned artificial tissue. PMID- 26245461 TI - APTES-modified nanosilica--but neither APTES nor nanosilica--inhibits endothelial cell growth via arrest of cell cycle at G1 phase. AB - The adverse effects of nanomaterials on the living system have attracted considerable attention in the past few years. Such effects may come from either the core nanomaterials or the chemical agents used to modify the nanomaterials - the latter being largely overlooked. In a free form, these modifying agents might have little impact on living cells; however, they may exhibit distinct biological effects when they assemble into a larger dimension. Here, we report that (3 aminopropyl)triethoxysilane - a small molecule compound ubiquitously employed to functionalise nanosilica surface - could decrease the viability of human umbilical vein endothelial cells when it was grafted onto the nanosilica surface. However, intriguingly, such effect was not found in 3-aminopropyl)triethoxysilane itself, the unmodified silica nanoparticles or the 3-aminopropyl)triethoxysilane modified microparticles. Change of surface charge was excluded as a cause and apoptosis was not observed. Nevertheless, the 3-aminopropyl)triethoxysilane modified nanoparticles could exclusively arrest cell cycle at G1 phase. Our findings suggest that substances could gain 'new' functions at the nanoscale, which may not be found in their larger or smaller counterparts. Understanding of such effects will provide critical insights for better evaluation and thus safer use of nanomaterials, in particular those having been pre-modified with other agents. PMID- 26245462 TI - Returning an Employee With Newly Diagnosed Tetraplegia to Work. AB - A 41-year-old male manufacturing engineer had a spinal cord injury after being thrown from the horse he was riding and landing on his neck. His injury was a C5 fracture with complete lower limb and trunk paralysis and partial upper limb paralysis. He was transported to the emergency department and eventually to rehabilitation. This article describes this employee's return to work. PMID- 26245464 TI - A Security Guard With West Nile Virus Encephalitis. AB - A 57-year-old male working as a security supervisor in an office building was seen for return to work by the on-site occupational health nurse. He was observed to have slow gait as he entered the clinic waiting area, was pale, diaphoretic, and slow in responding to questions. His return to work note stated he was recovering from West Nile Virus (WNV). Implications for return to work are presented. PMID- 26245463 TI - Relationship Between Socio-Demographic Features, Work-Related Conditions, and Level of Anxiety Among Turkish Primary Health Care Workers. AB - The purpose of this study was to investigate the relationship among Turkish primary health care workers' socio-demographic characteristics, working conditions, and anxiety. A cross-sectional study was conducted with 88 of 103 (85.4%) eligible health care workers from the city of Mugla participating. The participants' average age was 31 years, 85.2% were university graduates, 30.7% were nurses, and 64.8% had been working between 11 and 20 years at the time of the study; 93.6% worked 8 hours each day or less. State anxiety scores for males (p = .016), health care workers age 31 or older (p = .035), nurse participants (p = .043), and individuals who had worked 11 or more years (p = .044) were significantly higher than the rest of the sample; however, trait anxiety scores for participants who did not work overtime and were not scheduled for shift work were significantly higher (p = .033 and p = .004, respectively) than the rest of the sample. According to the logistic regression analysis, risk factors for anxiety included being male and older than 31 years. PMID- 26245465 TI - Human Bite of a Staff Nurse on a Psychiatric Unit. AB - Occupational violence among health care professionals is a cause for concern, although often neglected especially in developing countries like India. Violence undermines the healing mission of the health care organization and interferes with the ability of the health care team to optimally contribute to positive patient outcomes. The authors discuss a case of a human bite of a staff nurse on a psychiatric unit in a tertiary care Indian hospital. The reported violence against this staff nurse lead to her admission for emergency care followed by emotional stress. Issues related to prevention of occupational violence are also discussed. PMID- 26245466 TI - The Non-linear Health Consequences of Living in Larger Cities. AB - Urbanization promotes economy, mobility, access, and availability of resources, but on the other hand, generates higher levels of pollution, violence, crime, and mental distress. The health consequences of the agglomeration of people living close together are not fully understood. Particularly, it remains unclear how variations in the population size across cities impact the health of the population. We analyze the deviations from linearity of the scaling of several health-related quantities, such as the incidence and mortality of diseases, external causes of death, wellbeing, and health care availability, in respect to the population size of cities in Brazil, Sweden, and the USA. We find that deaths by non-communicable diseases tend to be relatively less common in larger cities, whereas the per capita incidence of infectious diseases is relatively larger for increasing population size. Healthier lifestyle and availability of medical support are disproportionally higher in larger cities. The results are connected with the optimization of human and physical resources and with the non-linear effects of social networks in larger populations. An urban advantage in terms of health is not evident, and using rates as indicators to compare cities with different population sizes may be insufficient. PMID- 26245467 TI - Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: significance in claudin-low breast cancer cells. AB - BACKGROUND: The T-cell inhibitory molecule PD-L1 (B7-H1, CD274) is expressed on tumor cells of a subset of breast cancer patients. However, the mechanism that regulates PD-L1 expression in this group of patients is still not well identified. METHODS: We have used loss and gain of function gene manipulation approach, multi-parametric flow cytometry, large scale gene expression dataset analysis and immunohistochemistry of breast cancer tissue sections. RESULTS: Induction of epithelial to mesenchymal transition (EMT) in human mammary epithelial cells upregulated PD-L1 expression, which was dependent mainly on the activation of the PI3K/AKT pathway. Interestingly, gene expression signatures available from large cohort of breast tumors showed a significant correlation between EMT score and the PD-L1 mRNA level (p < 0.001). Strikingly, very strong association (p < 0.0001) was found between PD-L1 expression and claudin-low subset of breast cancer, which is known to have high EMT score. On the protein level, significant correlation was found between PD-L1 expression and standard markers of EMT (p = 0.005) in 67 breast cancer patients. Importantly, specific downregulation of PD-L1 in claudin-low breast cancer cells showed signs of EMT reversal as manifested by CD44 and Vimentin downregulation and CD24 upregulation. CONCLUSIONS: We have demonstrated a bidirectional effect between EMT status and PD-L1 expression especially in claudin-low subtype of breast cancer cells. Our findings highlights the potential dual benefit of anti-PD-L1 particularly in this subset of breast cancer patients that will likely benefit more from anti-PD-L1 targeted therapy as well as in monitoring biological changes upon treatment. PMID- 26245468 TI - Identification of Interleukin-1beta-Producing Monocytes That Are Susceptible to Pyronecrotic Cell Death in Patients With Neonatal-Onset Multisystem Inflammatory Disease. AB - OBJECTIVE: Spontaneous inflammatory responses initiated by NLRP3 mutations promote inflammasome-mediated interleukin-1beta (IL-1beta) processing and release and can induce rapid necrotic cell death. The cells that produce IL-1beta in neonatal-onset multisystem inflammatory disease (NOMID) have not been clearly identified, nor have the mechanisms mediating IL-1beta release and cell death been completely elucidated. METHODS: Whole blood cells were stimulated with lipopolysaccharide (LPS) in the presence of cathepsin B and caspase 1 inhibitors, followed by ATP treatment. Supernatants were collected and incubated with IL 1beta-capturing beads. Cells were fixed, permeabilized, and stained for a combination of cell surface and intracellular markers, and a novel flow cytometry bead-based assay was used to measure secreted IL-1beta. LPS-stimulated cells were also evaluated using immunofluorescence microscopy. RESULTS: Monocytes characterized by CD14(high) -CD16(low) expression and intracellular CD83 were increased in NOMID patients and were responsible for the majority of IL-1beta production in response to LPS stimulation. This population of monocytes also underwent a rapid death response with LPS alone that is temporally associated with IL-1beta and ASC release and has characteristic features of pyronecrotic but not pyroptotic cell death. Inhibition of cell death reduced IL-1beta production from NOMID patient cells. In addition, IL-1 triggered cell death in monocytes from NOMID patients. CONCLUSION: Our findings indicate that monocytes are the predominant IL-1beta-producing cell population in the peripheral blood of NOMID patients. Furthermore, they suggest that IL-1 receptor blockade may work in part by preventing pyronecrotic cell death, which may be an important target in NOMID and other forms of cryopyrin-associated periodic syndromes. PMID- 26245469 TI - Adhesion Properties of Human Oral Epithelial-Derived Cells to Zirconia. AB - BACKGROUND: Few studies have examined epithelial attachment to zirconia and the proliferative ability of epithelial cells on zirconia surfaces. PURPOSE: To evaluate the adhesion properties of zirconia materials for epithelial cell attachment and compare this with titanium and alumina. MATERIALS AND METHODS: Human oral epithelial cells were cultured on smooth-surfaced specimens of commercially pure titanium (cpTi), ceria-stabilized zirconia/alumina nano composite (P-NANOZR), yttria-stabilized zirconia (Cercon), and alumina oxide (inCoris AL). The cell morphology, the cell viability and mRNA of integrin beta4 , laminin gamma2 , catenin delta2 , and E-cadherin were evaluated by SEM, Cell Counting Kit-8, and real-time PCR, respectively. RESULTS: Morphology of cells attached to specimens was similar among all groups. The viable cell numbers on Cercon and inCoris AL after 24 hours culture were significantly higher than for cpTi. Integrin beta4 , laminin gamma2 , and catenin delta2 mRNA expression was not different among all groups. However, at 3 and 24 hours after incubation, E cadherin mRNA expression in the P-NANOZR group was significantly higher than for cpTi. CONCLUSION: Zirconia may support binding of epithelial cells through hemidesmosomes comparable with titanium. Furthermore, P-NANOZR may impart resistance to exogenous stimuli through strong intercellular contacts with peri implant mucosal cells when used as an abutment and implant superstructure. PMID- 26245470 TI - Comparison of right ventricular contractile abnormalities in hypertrophic cardiomyopathy versus hypertensive heart disease using two dimensional strain imaging: a cross-sectional study. AB - Hypertrophic cardiomyopathy (HCM) affects the right ventricle (RV) because of the anatomically hypertrophied septum and plausibly by extension of the myopathic process to the RV. We sought to investigate RV strain in patients with left ventricular hypertrophy secondary to either HCM or hypertension (H-LVH). Our cross-sectional study included 32 patients with HCM, 21 patients with H-LVH, and 11 healthy subjects, who were evaluated with transthoracic echocardiography. Using a dedicated software package, bi-dimensional acquisitions were analyzed to measure segmental longitudinal strain in apical views. Right ventricular global longitudinal strain (GLS) was calculated by averaging septal and right free wall strains. The HCM and H-LVH groups were comparable for age and demographic characteristics. Right ventricular tricuspid annular plane systolic excursion was not significantly different between HCM and H-LVH subjects. Moreover, RV GLS, septal and lateral RV myocardial strain were significantly impaired in patients with HCM (all p < 0.001). Regional and global RV strain parameters were not significantly impaired in H-LVH compared to healthy controls An RV GLS cut-off value of >14.9% differentiated HCM and H-LVH with a 90% sensitivity and a 95% specificity (p < 0.001). RV strain parameters are impaired in patients with HCM. Assessment of two-dimensional RV strain parameters could help differentiate between HCM and H-LVH. PMID- 26245471 TI - Regional left atrial function differentiation in patients with constrictive pericarditis and restrictive cardiomyopathy: a study using speckle tracking echocardiography. AB - Left atrial (LA) function plays an important role in the maintenance of cardiac output. However, whether assessment of regional LA myocardial dysfunction is useful for differentiating between CP and restrictive cardiomyopathy (RCM) remains unclear. Thirty-five patients with CP, 30 patients with RCM, and 30 healthy volunteers (controls) were enrolled in this study. The LA maximum volume (Vmax), LA minimal volume (Vmin), and LA volume before atrial contraction (Vpre a) were measured using the biplane modified Simpson's rule. All patients underwent two-dimensional speckle tracking echocardiography (STE). The peak systolic strain rate (SrS), early diastolic strain rate (SrE), and late diastolic strain rate (SrA) of the LA septum, LA lateral wall and superior walls were measured. The LA diastolic and systolic function was found to be reduced in patients with CP and RCM. The SrE in the LA superior wall and lateral wall were significantly decreased in patients with CP and RCM compared with controls (P < 0.001). The SrE of the LA septum in patients with CP was preserved compared to normal controls. Althouth the LA septal SrE in patients with CP was significantly reduced (P < 0.001). For the diagnosis of RCM, a cutoff value 1.40 for SrE of the LA septum showed a sensitivity of 94.7 % and a specificity of 89.7 %. The SrE in the LA superior wall and lateral wall were decreased while the LA septal SrE was preserved in patients with CP, indicating that the rigid pericardium might restrict myocardial motion and deformation in the lateral wall. The measurement of STE to determine the LA septal SrE can be helpful for differentiating between CP and RCM. PMID- 26245472 TI - Beyond stenotic degree assessment in carotid atherosclerotic lesions: single catheter near-infrared spectroscopy and intravascular ultrasound. PMID- 26245474 TI - How Current Direct-Acting Antiviral and Novel Cell Culture Systems for HCV are Shaping Therapy and Molecular Diagnosis of Chronic HCV Infection? AB - We have entered a new era of hepatitis C virus (HCV) therapy in which elimination of infection and disease is a real possibility. HCV cell culture models were instrumental for identification of therapeutic targets, testing candidate drugs, and profiling of therapeutic strategies. Here we describe current and novel methods of cell culture systems for HCV that are allowing investigation of HCV life cycle and virus-host interaction required for replication and propagation. The development of protocols to grow infectious virus in culture and generate hepatocyte cell lines from specific individuals hold great promise to investigate the mechanisms exploited by the virus to spread the infection and the host factors critical for HCV replication and propagation, or resistance to infection. Since host factors are presumably conserved and equally interacting with different HCV isolates and genotypes, the development of drugs targeting host factors essential for virus replication holds great promises in further increasing treatment efficacy. Refocusing of therapeutic goals also impacted in vitro diagnosis. The primary goal of anti-HCV therapy is to achieve a sustained virologic response (SVR) defined as "undetectable" HCV RNA genome in the serum or plasma at 12 to 24 weeks following the end of treatment. Use of direct antiviral agents has substantially changed the threshold of the viral load used to define SVR and led to a reassessment, as discussed herein, of result interpretation and requirements of clinically-approved, quantitative molecular assays. PMID- 26245475 TI - The Current Indications and the Benefits of Combining a beta3-Agonist with an Anticholinergic for the Treatment of OAB. AB - Combination therapy with anti-muscarinics (AMs) and beta3 agonists (beta3As) has recently been proposed as a possible treatment for the management of patients with Overactive Bladder (OAB). EVIDENCE ACQUISITION: A National Center for Biotechnology Information PubMed search for relevant articles published between 2007 and 2014 was performed by combining the following Patient population, Intervention, Comparison, Outcome (PICO) terms: overactive bladder, antimuscarinics, beta3 agonists, combination therapy, efficacy, tolerability and outcomes. Additional references were obtained from the reference list of full text manuscripts. Abstracts presented at the annual congresses of the European Association of Urology, American Urology Association and the International Continence Society were included. EVIDENCE SYNTHESIS: The combination therapy, in the management of OAB symptoms, has recently been investigated in animal models and in a phase II randomized clinical trial. Compared with AMs monotherapy, combination treatment improved mean voided volume per micturition, micturition frequency and reduced urgency episodes. No dose related trends in adverse events (AEs) were observed between combination group and monotherapy group. Incidence of constipation was slightly increased in combination therapy group. CONCLUSIONS: Combination therapy seems to be an effective and safe treatment in the management of OAB. However, further cost-effectiveness studies are needed to evaluate the definitive role of this approach for the management of patients with OAB. PMID- 26245476 TI - New Antimicrobial Approaches: Reuse of Old Drugs. AB - The global situation of antibiotic resistance and the reduction of investments in antibiotics research by the pharmaceutical industry suggest the need for specific cost-effective approaches in order to identify drugs for the therapy of many microbial infections. Among the viable alternative anti-infective compounds, drug repurposing, i.e. to find new uses for previously approved medicines, revealed some encouraging in vitro and in vivo results. In this article the reader has a panoramic view of the updated references on the strategies encountered during the repositioning process. New findings are reported about the anti-microbial efficacy of antipsychotic, cardiovascular, anti-inflammatory and anti-neoplastic drugs. This approach may enhance the portfolio of pharmaceutical companies reducing the need for pharmacokinetic and toxicity studies; the development of new uses of old drugs for different infectious diseases, leading to better health for patients, also in poor, tropical countries, appears to be having better results. PMID- 26245477 TI - New Perspectives in the Pharmacological Treatment of Non-Melanoma Skin Cancer. AB - Non-melanoma skin cancers are the most common malignancy in humans, with a basal/squamous cell carcinoma incidence ratio of 4:1 in immunocompetent patients. Basal cell carcinoma rarely metastasizes but commonly causes significant local tissue destruction and disfigurement, whereas squamous cell carcinoma is associated with a substantial risk of recurrence and metastasis; the prognosis in metastatic patients is poor. Surgical approaches give a cure rate greater than 90% if appropriately applied, on the basis of the characteristics of the primary tumors and of the patients, but in selected cases, medical treatment (5 fluorouracil, imiquimod, diclofenac and, more recently, ingenol mebutate) is preferable to invasive procedures and provides a good chance of cure, with generally excellent cosmetic outcomes. In case of advanced and metastatic non melanoma skin cancer, newly developed molecularly targeted therapy represents a reasonably promising alternative to classical cytostatics. In particular, the monoclonal antibody cetuximab, directed against the epidermal growth factor receptor, is effective and well-tolerated in squamous cell carcinoma patients. Moreover, the recent identification of mutations in the Hedgehog signaling pathway in basal cell carcinoma lead to the development of the smoothened Hedgehog pathway inhibitor vismodegib, that was recently approved for the treatment of locally advanced or metastatic basal cell carcinoma. In this review we provide an overview of the molecular pathways involved in NMSC pathogenesis, focusing on the mechanisms of action, indications, efficacy, side effects and contraindications of new medical treatments that specifically tackle molecular targets of these pathways. PMID- 26245478 TI - Burial, excavation, and preparation of primate skeletal material for morphological study. AB - Inclusion of osteological material in primatological research has a long history, and use of skeletal remains continues to be important in anatomical and anthropological research. Here we report a set of proven methods, including equipment, protocol, and procedure, which enable relatively simple acquisition of skeletal material from naturally deceased animals in field sites and sanctuaries. Such skeletal material, often with extensive accompanying life-history data, is a unique and valuable source of data for both academic and conservation-based research. PMID- 26245479 TI - Mazabraud's syndrome and thyroid cancer, a very rare and confusing association: a case report. AB - BACKGROUND: Mazabraud's syndrome is defined as the association between fibrous dysplasia and intramuscular myxomas. The syndrome was first described in 1967 and, up until now, less than 100 cases have been reported worldwide. Here we report the association between this rare syndrome and thyroid cancer. When a malignant disease occurs in a patient affected by this syndrome, the differential diagnosis between benign and malignant bone lesions should be undertaken carefully. CASE PRESENTATION: We report the case of a 57-year-old Caucasian male, admitted for diffuse bone pain localized in the left leg and for the presence of an indolent, slow-growing mass in the left shoulder. The patient also presented with a thyroid nodule, highly suggestive of a malignancy. The radiologic examination showed multiple osteolytic lesions. The suspicion of multiple myeloma or bone metastases arising from a thyroid cancer was considered. Electrophoresis of proteins was negative and therefore excluded the diagnosis of multiple myeloma; the thyroid surgery was indicated. Thyroidectomy confirmed the papillary thyroid carcinoma, and the bone lesions were considered to be metastases from the thyroid cancer. After surgery, under thyroid-stimulated hormonal conditions, the patient underwent radioiodine therapy and a post-therapy radioiodine whole body scan. The lack of radioiodine uptake, both in the bone lesions and shoulder mass, suggested the possibility of less differentiated, non-avid radioiodine lesions, or the absence of any relation between pathologies. Considering the low level of the specific tumor marker, thyroglobulin, a bone biopsy and resection of the shoulder mass were indicated. The final diagnosis was intramuscular myxoma with polyostotic fibrous dysplasia in the deltoid muscle (Mazabraud's syndrome). A completely incidental cerebral tumor lesion was also discovered. CONCLUSION: During the evolution of a malignant disease, Mazabraud's syndrome, known as the association of intramuscular myxoma with fibrous dysplasia, should be considered in the differential diagnosis of bone metastasis. This is the first report in the literature of Mazabraud's syndrome occurring in a patient with thyroid cancer. PMID- 26245480 TI - Article conflates academic standards at UMST with student radicalisation. PMID- 26245481 TI - Epidermoid cyst with unusual magnetic resonance characteristics and spinal extension. AB - Intracranial epidermoid cysts are generally located in the cerebellopontine and parasellar areas and appear hypo-dense on computed tomography and hypo-intense on T1-weighted magnetic resonance imaging. We report a case of an unusual epidermoid cyst of the cerebellopontine angle extending into the upper cervical canal that appeared hyper-dense on computed tomography scanning, hyper-intense on T1 weighted magnetic resonance (MR) images, and hypo-intense on T2-weighted MR images. PMID- 26245482 TI - Legitimating the illegitimate: How doctors manage their knowledge of the prestige of diseases. AB - Although the sociology of medicine has developed a rich body of research on patients' experiences and how they handle their illnesses, few analyses have examined doctors' concepts of disease. Building on previous research findings that doctors consider some diseases to be more worthy than others, this article focuses on how these differences in disease prestige are articulated and made logical. We presented a focus group panel of doctors a table of 38 diseases rank ordered by prestige according to the results of a previous quantitative study of doctors. We prompted a lively discussion among the doctors by asking them whether they were familiar with this rank order. In analysing how they managed the prestige knowledge presented to them, we focused on how they handled the value conflict between this informal rank order and the formal value of equality of treatment. Using positioning theory as a theoretical premise and a methodological tool, we found that the focus group participants created positions in their conversations that allowed them to present and discuss views on disease prestige that would be considered illegitimate if they were declared directly. However, they were able to do so without being forced to take a personal stand. Thus, we demonstrate how informal disease rankings can be produced and reproduced. PMID- 26245483 TI - NHS may have to charge for some services if spending does not increase, report warns. PMID- 26245484 TI - A biomechanical and subjective comparison of two powered ambulance cots. AB - This study investigated biomechanical effects of different leg folding/unfolding mechanisms used for loading/unloading two powered cots (Cots A and B) into and from a simulated ambulance. Sixteen experienced emergency medical service (EMS) workers loaded and unloaded cots with weights of 45, 68 and 91 kg placed on the cots to simulate patients. Peak back and shoulder/arm muscle activity was reduced 52-87% when using Cot A in comparison to Cot B. Peak ground reaction force (PGRF) was reduced by 74% with Cot A. Adding weight resulted in increased muscle activity and PGRF when using Cot B, but had little effect when using Cot A. Task time was longer with Cot A, though was not perceived unfavourably by participants. This study confirmed that it is possible to substantially reduce physical stress imposed on EMS workers when loading and unloading a cot to and from an ambulance through improvements in cot design. PRACTITIONER SUMMARY: This study compared two powered ambulance cots, one that lifts/lowers the front and rear wheels independently and one that lifts/lowers the four wheels simultaneously during ambulance loading and unloading. Measured muscle activity, ground reaction forces and operator perceptions support using cot designs that lift/lower the front and rear wheels independently. PMID- 26245487 TI - Control of layer stacking in CVD graphene under quasi-static condition. AB - The type of layer stacking in bilayer graphene has a significant influence on its electronic properties because of the contrast nature of layer coupling. Herein, different geometries of the reaction site for the growth of bilayer graphene by the chemical vapor deposition (CVD) technique and their effects on the nature of layer stacking are investigated. Micro-Raman mapping and curve fitting analysis confirmed the type of layer stacking for the CVD grown bilayer graphene. The samples grown with sandwiched structure such as quartz/Cu foil/quartz along with a spacer, between the two quartz plates to create a sealed space, resulted in Bernal or AB stacked bilayer graphene while the sample sandwiched without a spacer produced the twisted bilayer graphene. The contrast difference in the layer stacking is a consequence of the difference in the growth mechanism associated with different geometries of the reaction site. The diffusion dominated process under quasi-static control is responsible for the growth of twisted bilayer graphene in sandwiched geometry while surface controlled growth with ample and continual supply of carbon in sandwiched geometry along with a spacer, leads to AB stacked bilayer graphene. Through this new approach, an efficient technique is presented to control the nature of layer stacking. PMID- 26245486 TI - The Critical Role of Rab31 in Cell Proliferation and Apoptosis in Cancer Progression. AB - Rab31, a member of the Ras superfamily, is reported to play a role in tumor development and progression. However, the detailed role of Rab31 in proliferation and apoptosis of cancer cells is still unclear. Here, we used different cell lines, such as glioblastoma, and cervical cancer, to investigate the role of Rab31 in cancer progression. We found that Rab31 promotes U87 and SiHa cell proliferation via activation of G1/S checkpoint transitions, accompanied with an increase of cyclin D1, cyclin A, and cyclin B1. Meanwhile, Rab31 inhibits U87 and SiHa cell apoptosis, and decreased the BAX and PIG3 expression, but enhanced BCL2 expression. In addition, Rab31 induces N-cadherin, Vimentin, and Snail expression, and inhibits E-cadherin expression to regulate proliferation and migration. Besides, we observed that ERK1/2 and PI3k/AKT pathways are required for Rab31-induced cell proliferation and migration. In vivo, the knockdown of Rab31 suppresses tumor mass growth. In conclusion, our data highlight the crucial role of Rab31 in cancer progression, proliferation, and apoptosis, and indicates that Rab31 may be a useful and effective target for the clinical therapy of most cancers. PMID- 26245488 TI - Dairy Streptococcus thermophilus improves cell viability of Lactobacillus brevis NPS-QW-145 and its gamma-aminobutyric acid biosynthesis ability in milk. AB - Most high gamma-aminobutyric acid (GABA) producers are Lactobacillus brevis of plant origin, which may be not able to ferment milk well due to its poor proteolytic nature as evidenced by the absence of genes encoding extracellular proteinases in its genome. In the present study, two glutamic acid decarboxylase (GAD) genes, gadA and gadB, were found in high GABA-producing L. brevis NPS-QW 145. Co-culturing of this organism with conventional dairy starters was carried out to manufacture GABA-rich fermented milk. It was observed that all the selected strains of Streptococcus thermophilus, but not Lactobacillus delbrueckii subsp. bulgaricus, improved the viability of L. brevis NPS-QW-145 in milk. Only certain strains of S. thermophilus improved the gadA mRNA level in L. brevis NPS QW-145, thus enhanced GABA biosynthesis by the latter. These results suggest that certain S. thermophilus strains are highly recommended to co-culture with high GABA producer for manufacturing GABA-rich fermented milk. PMID- 26245489 TI - Highly Efficient Processing of Multi-photon States. AB - How to implement multi-qubit gates is an important problem in quantum information processing. Based on cross phase modulation, we present an approach to realizing a family of multi-qubit gates that deterministically operate on single photons as the qubits. A general n-qubit unitary operation is a typical example of these gates. The approach greatly relax the requirement on the resources, such as the ancilla photons and coherent beams, as well as the number of operations on the qubits. The improvement in this framework may facilitate large scale quantum information processing. PMID- 26245490 TI - FREIBURG NEUROPATHOLOGY CASE CONFERENCE: Ring Enhancing Lesion in an Immunocompromised Patient. PMID- 26245473 TI - Phylodynamics of H1N1/2009 influenza reveals the transition from host adaptation to immune-driven selection. AB - Influenza A H1N1/2009 virus that emerged from swine rapidly replaced the previous seasonal H1N1 virus. Although the early emergence and diversification of H1N1/2009 is well characterized, the ongoing evolutionary and global transmission dynamics of the virus remain poorly investigated. To address this we analyse >3,000 H1N1/2009 genomes, including 214 full genomes generated from our surveillance in Singapore, in conjunction with antigenic data. Here we show that natural selection acting on H1N1/2009 directly after introduction into humans was driven by adaptation to the new host. Since then, selection has been driven by immunological escape, with these changes corresponding to restricted antigenic diversity in the virus population. We also show that H1N1/2009 viruses have been subject to regular seasonal bottlenecks and a global reduction in antigenic and genetic diversity in 2014. PMID- 26245485 TI - Effects of hyperthermia on DNA repair pathways: one treatment to inhibit them all. AB - The currently available arsenal of anticancer modalities includes many DNA damaging agents that can kill malignant cells. However, efficient DNA repair mechanisms protect both healthy and cancer cells against the effects of treatment and contribute to the development of drug resistance. Therefore, anti-cancer treatments based on inflicting DNA damage can benefit from inhibition of DNA repair. Hyperthermia - treatment at elevated temperature - considerably affects DNA repair, among other cellular processes, and can thus sensitize (cancer) cells to DNA damaging agents. This effect has been known and clinically applied for many decades, but how heat inhibits DNA repair and which pathways are targeted has not been fully elucidated. In this review we attempt to summarize the known effects of hyperthermia on DNA repair pathways relevant in clinical treatment of cancer. Furthermore, we outline the relationships between the effects of heat on DNA repair and sensitization of cells to various DNA damaging agents. PMID- 26245491 TI - FeOx and Si nano-dots as dual Li-storage centers bonded with graphene for high performance lithium ion batteries. AB - A novel design based on both FeOx and Si nano-dots bonded with graphene (FeOx.Si@GNS) as dual lithium-storage centers is reported. They show high performance as anode materials for Li-ion batteries with a remarkable reversible capacity of 1160 mA h g(-1) at 0.2 A g(-1), fast charging/discharging rate, and long cycling life (e.g., a capacity retention of 81.7% at 2.0 A g(-1) after 600 cycles). The origin of these high performances comes from the key factors of the high theoretical specific capacity of FeOx and Si, the shorter Li-ion diffusion distance of both nano-dot structures, fast electron conductivity, and the strain relaxation due to volume variations of both nano-dots bonded with graphene nanosheets during cycles. PMID- 26245492 TI - Genetic characterization of four native Italian shepherd dog breeds and analysis of their relationship to cosmopolitan dog breeds using microsatellite markers. AB - Very little research into genetic diversity of Italian native dog breeds has been carried out so far. In this study we aimed to estimate and compare the genetic diversity of four native Italian shepherd dog breeds: the Maremma, Bergamasco, Lupino del Gigante and Oropa shepherds. Therefore, some cosmopolitan dog breeds, which have been widely raised in Italy for a long time past, have also been considered to check possible influence of these dog populations on the Italian autochthonous breeds considered here. A total of 212 individuals, belonging to 10 different dog breeds, were sampled and genotyped using 18 autosomal microsatellite loci. We analyzed the genetic diversity of these breeds, within breed diversity, breed relationship and population structure. The 10 breeds considered in this study were clearly genetically differentiated from each other, regardless of current population sizes and the onset of separate breeding history. The level of genetic diversity explained 20% of the total genetic variation. The level of H E found here is in agreement with that found by other studies. The native Italian breeds showed generally higher genetic diversity compared with the long established, well-defined cosmopolitan dog breeds. As the Border Collie seems closer to the Italian breeds than the other cosmopolitan shepherd dogs considered here, a possible utilization of this breed to improve working performance in Italian traditional working shepherd dogs cannot be ignored. The data and information found here can be utilized in the organization of conservation programs planned to reduce inbreeding and to minimize loss of genetic variability. PMID- 26245493 TI - Plasminogen activator inhibitor-1 4G/5G polymorphism, factor V Leiden, prothrombin mutations and the risk of VTE recurrence. AB - Plasminogen-activator inhibitor (PAI)-1 is an important inhibitor of the plasminogen/plasmin system. PAI-1 levels are influenced by the 4G/5G polymorphism in the PAI-1 promoter. We investigated the relationship between the PAI-1 polymorphism and VTE recurrence, and its possible modification by factor V Leiden (FVL) and prothrombin (PTM) mutations. Patients (n=1,069) from the Malmo Thrombophilia Study were followed from discontinuation of anticoagulant treatment until diagnosis of VTE recurrence or the end of the study (maximum follow-up 9.8 years). One hundred twenty-seven patients (11.9 %) had VTE recurrence. PAI-1 was genotyped by TaqMan PCR. Cox regression analysis adjusted for age, sex and acquired risk factors of VTE showed no evidence of an association between PAI-1 genotype and risk of VTE recurrence in the study population as a whole. However, by including an interaction term in the analysis we showed that FVL but not PTM modified the effect of PAI-1 genotype: patients with the 4G allele plus FVL had a higher risk of VTE recurrence [hazard ratio (HR) =2.3, 95 % confidence interval (CI) =1.5-3.3] compared to patients with the 4G allele but no FVL (reference group) or FVL irrespective of PAI-1 genotype (HR=1.8, 95 % CI=1.3-2.5). Compared to reference group, 5G allele irrespective of FVL was associated with lower risk of VTE recurrence only when compared with 4G allele together with FVL. In conclusion, FVL has a modifying effect on PAI-1 polymorphism in relation to risk of VTE recurrence. The role of PAI-1 polymorphism as a risk factor of recurrent VTE may be FVL dependent. PMID- 26245494 TI - Tricetin suppresses the migration/invasion of human glioblastoma multiforme cells by inhibiting matrix metalloproteinase-2 through modulation of the expression and transcriptional activity of specificity protein 1. AB - OBJECTIVE: Glioblastoma multiforme (GBM) is a severely invasive tumor that can be fatal because it is difficult to treat. Tricetin, a natural flavonoid, was demonstrated to inhibit the growth of various cancers, but the effect of tricetin on cancer motility is largely unknown. RESEARCH DESIGN AND METHODS: In the present study, we examined the anti-invasive properties of tricetin in huwman GBM cells. RESULTS: Our results showed that tricetin inhibited the migration/invasion of two GBM cell lines. We found that tricetin inhibited MMP-2 expression in the GBM cells. Real-time polymerase chain reaction and promoter activity assays indicated that tricetin inhibited MMP-2 expression at the transcriptional level. Such inhibitory effects were associated with the suppression of specificity protein-1 (SP-1) DNA-binding activity. An examination of clinical samples revealed a positive correlation between SP-1 and MMP-2 in glioma specimens, and higher expression levels were correlated with a worse probability of survival. Moreover, blocking the extracellular signal-regulated kinase (ERK) pathway also inhibited MMP-2-mediated cell motility, and further enhanced the anti-invasive ability of tricetin in GBM cells. CONCLUSIONS: SP-1 is an important target of tricetin for suppressing MMP-2-mediated cell motility in GBM cells, and a combination of tricetin and an ERK inhibitor may be a good strategy for preventing GBM invasion. PMID- 26245495 TI - Comparing the costs of three prostate cancer follow-up strategies: a cost minimisation analysis. AB - PURPOSE: Prostate cancer follow-up is traditionally provided by clinicians in a hospital setting. Growing numbers of prostate cancer survivors mean that this model of care may not be economically sustainable, and a number of alternative approaches have been suggested. The aim of this study was to develop an economic model to compare the costs of three alternative strategies for prostate cancer follow-up in Ireland-the European Association of Urology (EAU) guidelines, the National Institute of Health Care Excellence (NICE) guidelines and current practice. METHODS: A cost minimisation analysis was performed using a Markov model with three arms (EAU guidelines, NICE guidelines and current practice) comparing follow-up for men with prostate cancer treated with curative intent. The model took a health care payer's perspective over a 10-year time horizon. RESULTS: Current practice was the least cost efficient arm of the model, the NICE guidelines were most cost efficient (74 % of current practice costs) and the EAU guidelines intermediate (92 % of current practice costs). For the 2562 new cases of prostate cancer diagnosed in 2009, the Irish health care system could have saved ?760,000 over a 10-year period if the NICE guidelines were adopted. CONCLUSIONS: This is the first study investigating costs of prostate cancer follow-up in the Irish setting. While economic models are designed as a simplification of complex real-world situations, these results suggest potential for significant savings within the Irish health care system associated with implementation of alternative models of prostate cancer follow-up care. PMID- 26245496 TI - Validation of the Chinese version of EORTC QLQ-BM22 in patients with bone metastases. AB - PURPOSE: Our aim is to test the validity, reliability, and acceptability of the Chinese version of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Bone Metastases 22 (EORTC QLQ-BM22) module to assess health-related quality of life (HRQOL) in patients with bone metastases in China. METHODS: Patients with histological confirmation of malignancy and bone metastases from Tianjin Cancer Institution and Hospital from June 2013 to April 2014 were enrolled in this study. All patients self-administered the EORTC QLQ BM22 and the EORTC QLQ-C30. The Karnofsky Performance Scale (KPS) was performed to evaluate scores. The reliability and validity tests of the questionnaires were based on Cronbach's alpha coefficients, Pearson correlation test, and Wilcoxon rank sum nonparametric test. RESULTS: Internal consistency reliabilities of all the four scales were acceptable. Scales measuring similar HRQOL aspects were found to correlate with one another between EORTC QLQ-BM22 and EORTC QLQ-C30, but differences still existed. Significant differences were demonstrated in the scores of all four subscales of the QLQ-BM22 between the two KPS subgroups (KPS <= 80; KPS > 80). Meanwhile, the compliance for item completion of the QLQ-BM22 was satisfactory. CONCLUSIONS: The Chinese version of EORTC QLQ-BM22 is a reliable and valid instrument, which is appropriate for measuring the HRQOL of patients with bone metastases in China. PMID- 26245497 TI - Should clinicians always administer dexamethasone beyond 24 h after chemotherapy to control delayed nausea and vomiting caused by moderately emetogenic regimens? Insight from the re-evaluation of two randomized studies. AB - PURPOSE: Data from two noninferiority trials of a dexamethasone-sparing regimen were assessed for the impact of acute nausea and vomiting on delayed outcome in patients undergoing moderately emetogenic chemotherapy (MEC) or anthracycline plus cyclophosphamide (AC). METHODS: Chemo-naive patients were randomized to receive palonosetron (0.25 mg IV) plus dexamethasone (8 mg IV) on day 1 of chemotherapy, or the same regimen followed by oral dexamethasone on days 2 and 3 in the MEC (n = 237) and AC (n = 380) cohorts. Patients were divided into two groups according to whether or not they experienced vomiting and/or moderate-to severe nausea during the acute phase (high- and low-risk groups, respectively). Primary efficacy endpoint was the complete protection (CP) against delayed vomiting and moderate-to-severe nausea. Patient's satisfaction (0-100 mm visual analog scale) was also analyzed. RESULTS: Among the 209 low-risk patients undergoing MEC, delayed CP occurred in 82.9% of those who received single-dose dexamethasone and 89.8% of those who received 3-day dexamethasone (P = 0.165). Of the 271 low-risk patients undergoing AC, CP was achieved in 71.7 % of those treated with single-dose dexamethasone and 84.2% treated with 3-day dexamethasone (P = 0.019). In spite of these observations, the patient satisfaction data was not influenced by dexamethasone regimen. In both cohorts, occurrence of acute vomiting or moderate-to-severe nausea was the key independent-predictor for delayed vomiting or nausea, respectively. CONCLUSIONS: The dexamethasone-sparing regimen provides adequate delayed protection in patients undergoing MEC who are at low risk for delayed symptoms, and can still be discussed for low-risk AC patients as the daily difference in control is modest. Additional dexamethasone doses can be customized on the basis of occurrence or absence of acute symptoms in the first cycle of MEC and even AC. PMID- 26245500 TI - Concurrent persistent trigeminal artery with an intracranial aneurysm. PMID- 26245499 TI - The Antidepressant Effects of an mGlu2/3 Receptor Antagonist and Ketamine Require AMPA Receptor Stimulation in the mPFC and Subsequent Activation of the 5-HT Neurons in the DRN. AB - We have reported the antidepressant effects of both metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists and ketamine in several animal models, and proposed that serotonergic (5-HTergic) transmission is involved in these actions. Given that the projections from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DRN), where the majority of serotonin (5-HT) neurons exist, are reportedly involved in the antidepressant effects, in this study, we investigated using the forced swimming test (FST) of C57BL/6J male mice, the role of 5-HT neurons in the DRN regulated by the mPFC-DRN projections in the antidepressant effects of an mGlu2/3 receptor antagonist, LY341495, and ketamine. Following systemic administration/microinjection into the mPFC, both LY341495 and ketamine were found to exert antidepressant effects in the FST, and the effects were attenuated by depletion of 5-HT by treatment with an inhibitor of 5-HT synthesis, PCPA. The antidepressant effects of LY341495 and ketamine were also blocked by systemic administration/microinjection into the mPFC of an AMPA receptor antagonist, NBQX. Moreover, systemic administration/microinjection into the mPFC of LY341495 and ketamine significantly increased the c-Fos expression in the 5-HT neurons in the DRN, and the effect of systemic administration of these drugs on the neuronal c-Fos expression was attenuated by microinjection of NBQX into the mPFC. Our findings suggest that activation of 5-HT neurons in the DRN regulated by stimulation of the AMPA receptor in the mPFC may be involved in the antidepressant effects of an mGlu2/3 receptor antagonist and ketamine. PMID- 26245498 TI - Sex-Steroid Hormone Manipulation Reduces Brain Response to Reward. AB - Mood disorders are twice as frequent in women than in men. Risk mechanisms for major depression include adverse responses to acute changes in sex-steroid hormone levels, eg, postpartum in women. Such adverse responses may involve an altered processing of rewards. Here, we examine how women's vulnerability for mood disorders is linked to sex-steroid dynamics by investigating the effects of a pharmacologically induced fluctuation in ovarian sex steroids on the brain response to monetary rewards. In a double-blinded placebo controlled study, healthy women were randomized to receive either placebo or the gonadotropin releasing hormone agonist (GnRHa) goserelin, which causes a net decrease in sex steroid levels. Fifty-eight women performed a gambling task while undergoing functional MRI at baseline, during the mid-follicular phase, and again following the intervention. The gambling task enabled us to map regional brain activity related to the magnitude of risk during choice and to monetary reward. The GnRHa intervention caused a net reduction in ovarian sex steroids (estradiol and testosterone) and increased depression symptoms. Compared with placebo, GnRHa reduced amygdala's reactivity to high monetary rewards. There was a positive association between the individual changes in testosterone and changes in bilateral insula response to monetary rewards. Our data provide evidence for the involvement of sex-steroid hormones in reward processing. A blunted amygdala response to rewarding stimuli following a rapid decline in sex-steroid hormones may reflect a reduced engagement in positive experiences. Abnormal reward processing may constitute a neurobiological mechanism by which sex-steroid fluctuations provoke mood disorders in susceptible women. PMID- 26245501 TI - Case series and techniques of Descemet's Stripping Automated Endothelial Keratoplasty for severe bullous keratopathy after birth injury. AB - BACKGROUND: To evaluate clinical outcomes of Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) for severe bullous keratopathy that develop as a late complication of endothelial injury to the baby during forceps delivery at birth. CASE PRESENTATIONS: Four eyes (four patients; mean age, 51.5 years) with severe bullous keratopathy as a late complication of forceps delivery at birth were enrolled. All patients had amblyopia from childhood due to cloudy cornea. Nontheless, DSAEK was indicated in these patients for the irritation and severe light sensation caused by apparent bullous change of the injured cornea. All patients underwent DSAEK and two patients had simultaneous cataract surgery. Intraoperative and postoperative complications were recorded. Postoperative donor endothelial-cell densities (ECDs) were measured prospectively at six and 12 months and compared with preoperative values. Best corrected visual acuity (BCVA) was measured at 6 and 12 months postoperatively. All cases required corneal epithelial removal; two cases with simultaneous cataract surgeries required lens anterior capsule staining by trypan blue and illumination of the cornea for visualization. There were no cases of graft dislocation or primary graft failure. Mean BCVA improved from 0.06 to 0.15 at 6 months and to 0.38 at 12 months. Postoperative ECD was 2270 cells/mm(2) (mean loss, 24.4 %) at 6 months and 2130 (mean loss, 29.1 %) at 12 months. Postoperative intraocular pressure elevation was observed in two cases, and a rejection episode occurred in one case at 4 months postoperatively. CONCLUSIONS: In this case series, the clinical outcome of DSAEK for severe bullous keratopathy after forceps delivery was fair with rapid corneal clearance, which was comparable to uncomplicated cases. Cataract and DSAEK surgery was safely performed using techniques including epithelial removal, lens anterior capsule staining and illuminating the cornea, which enabled better visualization of the anterior chamber. PMID- 26245502 TI - The Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Risk Model: Part 1-Statistical Methodology. AB - BACKGROUND: This study's objective was to develop a risk model incorporating procedure type and patient factors to be used for case-mix adjustment in the analysis of hospital-specific operative mortality rates after congenital cardiac operations. METHODS: Included were patients of all ages undergoing cardiac operations, with or without cardiopulmonary bypass, at centers participating in The Society of Thoracic Surgeons Congenital Heart Surgery Database during January 1, 2010, to December 31, 2013. Excluded were isolated patent ductus arteriosus closures in patients weighing less than or equal to 2.5 kg, centers with more than 10% missing data, and patients with missing data for key variables. Data from the first 3.5 years were used for model development, and data from the last 0.5 year were used for assessing model discrimination and calibration. Potential risk factors were proposed based on expert consensus and selected after empirically comparing a variety of modeling options. RESULTS: The study cohort included 52,224 patients from 86 centers with 1,931 deaths (3.7%). Covariates included in the model were primary procedure, age, weight, and 11 additional patient factors reflecting acuity status and comorbidities. The C statistic in the validation sample was 0.858. Plots of observed-vs-expected mortality rates revealed good calibration overall and within subgroups, except for a slight overestimation of risk in the highest decile of predicted risk. Removing patient preoperative factors from the model reduced the C statistic to 0.831 and affected the performance classification for 12 of 86 hospitals. CONCLUSIONS: The risk model is well suited to adjust for case mix in the analysis and reporting of hospital-specific mortality for congenital heart operations. Inclusion of patient factors added useful discriminatory power and reduced bias in the calculation of hospital-specific mortality metrics. PMID- 26245503 TI - Impact of Patient Characteristics on Hospital-Level Outcomes Assessment in Congenital Heart Surgery. AB - BACKGROUND: Accurate hospital outcome measures in congenital heart surgery are important to multiple initiatives. While methods have been developed to account for differences in procedural case-mix, characteristics patients bring into the operation that may also vary across hospitals and influence outcome have received less attention. We evaluated the impact of these characteristics in a large cohort. METHODS: Patients undergoing congenital heart surgery at centers participating in The Society of Thoracic Surgeons Congenital Heart Surgery Database (2010 to 2013) with adequate data quality were included. Variation across hospitals in important patient characteristics was examined, and hospital operative mortality rates were compared with and without adjustment for patient characteristics. RESULTS: Overall, 86 centers (52,224 patients) were included. There was greater than twofold variation across hospitals for nearly all patient characteristics examined. For example, the proportion of a center's surgical population comprised of neonates ranged from 12.8% to 26.6% across hospitals; the proportion with a non-cardiac anomaly ranged from 0.7% to 5.0%. When hospital mortality rankings were evaluated based on "standard" (adjustment for differences in procedural case-mix alone) versus "full" models (adjustment for both differences in procedural case-mix and patient characteristics), 14.0% changed their ranking for mortality by 20 or greater positions, 34.9% of centers changed which mortality quartile they were classified in, and 14.0% changed their statistical classification (statistically higher, lower, or same-as-expected mortality). CONCLUSIONS: Characteristics of patients undergoing congenital heart surgery vary across centers and impact hospital outcomes assessment. Methods to assess outcomes and relative performance should account for these characteristics. PMID- 26245504 TI - The Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Risk Model: Part 2-Clinical Application. AB - BACKGROUND: The empirically derived 2014 Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Risk Model incorporates adjustment for procedure type and patient-specific factors. The purpose of this report is to describe this model and its application in the assessment of variation in outcomes across centers. METHODS: All index cardiac operations in The Society of Thoracic Surgeons Congenital Heart Surgery Database (January 1, 2010, to December 31, 2013) were eligible for inclusion. Isolated patent ductus arteriosus closures in patients weighing less than or equal to 2.5 kg were excluded, as were centers with more than 10% missing data and patients with missing data for key variables. The model includes the following covariates: primary procedure, age, any prior cardiovascular operation, any noncardiac abnormality, any chromosomal abnormality or syndrome, important preoperative factors (mechanical circulatory support, shock persisting at time of operation, mechanical ventilation, renal failure requiring dialysis or renal dysfunction (or both), and neurological deficit), any other preoperative factor, prematurity (neonates and infants), and weight (neonates and infants). Variation across centers was assessed. Centers for which the 95% confidence interval for the observed-to-expected mortality ratio does not include unity are identified as lower-performing or higher-performing programs with respect to operative mortality. RESULTS: Included were 52,224 operations from 86 centers. Overall discharge mortality was 3.7% (1,931 of 52,224). Discharge mortality by age category was neonates, 10.1% (1,129 of 11,144); infants, 3.0% (564 of 18,554), children, 0.9% (167 of 18,407), and adults, 1.7% (71 of 4,119). For all patients, 12 of 86 centers (14%) were lower-performing programs, 67 (78%) were not outliers, and 7 (8%) were higher-performing programs. CONCLUSIONS: The 2014 Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Risk Model facilitates description of outcomes (mortality) adjusted for procedural and for patient-level factors. Identification of low performing and high-performing programs may be useful in facilitating quality improvement efforts. PMID- 26245505 TI - Impact of type of surgery (laparoscopic versus open) on the time to initiation of adjuvant chemotherapy in operable rectal cancers. AB - PURPOSE: The COREAN (comparison of open vs. laparoscopic surgery for mid- and low rectal cancer after neoadjuvant chemoradiotherapy) and the MRC-CLASICC (Medical Research Council-conventional vs. laparoscopic-assisted surgery in colorectal cancer) trials have established the benefits of laparoscopic surgery in rectal cancers regarding shortened hospital stay and speedy recovery. A rapid postoperative recovery is essential for initiation of adjuvant therapy, especially in stage II/III rectal cancers. This study aimed to evaluate whether the type of surgery (laparoscopic or open) had any bearing on the time to initiation of adjuvant chemotherapy (TIAC) after complete radical surgical proctectomy. METHODS: A subset of 181 consecutive patients of operable rectal cancer, who underwent curative resection of the rectum (laparoscopic or open) and received postoperative adjuvant chemotherapy between July 2013 and December 2014 at a single institution, was studied. The TIAC and the factors determining the same, namely, type of surgery, age, gender, presence of complications, and body mass index, were analyzed. RESULTS: Of 181 patients, 57 underwent laparoscopic and 124 open resection. Overall complications were seen in 17.6 % (32) patients, 8 in the laparoscopic arm and 24 in the open arm. The median time to start adjuvant chemotherapy after surgery was 21.6 and 23.73 days (p = 0.94) in the laparoscopic and open groups, respectively. On multivariate analysis, the type of surgery (p = 0.398) did not influence the TIAC. The only factor that influenced the TIAC was postoperative complications (p = 0.001). CONCLUSION: Our study shows that laparoscopic surgery for rectal cancer did not lead to an earlier start of adjuvant chemotherapy. PMID- 26245506 TI - Conversion between geotropic and apogeotropic persistent direction-changing positional nystagmus. AB - CONCLUSION: Clinical features in the course of conversion differed between patients with SSNHL and cupulopathy, which indicates that the pathophysiology of persistent geotropic or apogeotropic DCPN and the mechanism of the change in nystagmus direction may differ between the two groups. OBJECTIVE: The aim of this study is to investigate clinical characteristics of 10 patients with persistent DCPN who exhibited a conversion of nystagmus direction between geotropic and apogeotropic, and discuss possible mechanisms. METHODS: Using video-oculography, serial examinations of nystagmus in a head-roll test were performed. RESULTS: Of these 10 patients, five had sudden sensorineural hearing loss (SSNHL) and the remaining five had cupulopathy. In SSNHL, direction of nystagmus changed from geotropic to apogeotropic in three patients and from apogeotropic to geotropic in two patients. In cupulopathy, persistent apogeotropic DCPN always preceded persistent geotropic DCPN. The change in nystagmus direction occurred earlier in patients with cupulopathy (1 or 2 days after vertigo onset) than in patients with SSNHL (4-23 days after vertigo onset). While the null plane was consistently identified on one side, regardless of the nystagmus direction in cupulopathy, it was not always identified on the side of hearing loss in SSNHL. PMID- 26245508 TI - Erratum to: FCGR3A-158 polymorphism influences the biological response to infliximab in Crohn's disease through affecting the ADCC activity. PMID- 26245507 TI - Musculoskeletal symptoms in patients with cryopyrin-associated periodic syndromes: a large database study. AB - OBJECTIVE: To determine the type and frequency of musculoskeletal symptoms at onset and during followup of cryopyrin-associated periodic syndromes (CAPS). METHODS: We retrospectively recorded the articular and muscular symptoms of patients with CAPS followed up in French hospitals. Data were presented as frequencies or the median (range), and patient groups were compared using chi square test, Fisher's exact test, and Mann-Whitney test. RESULTS: The study included 133 patients (33 children), 20 with familial cold autoinflammatory syndrome, 88 with Muckle-Wells syndrome, 22 with chronic infantile neurologic, cutaneous, articular syndrome, and 3 with unclassified CAPS. The median age was 35 years (range 0-78 years) at the time of the study, 1 year (range 0-41 years) at symptom onset, and 23 years (range 0-58 years) at diagnosis. The disease was sporadic in 17% of the patients. Cutaneous symptoms predominated at onset (77%), followed by articular symptoms (30%). The p.Thr348Met and p.Arg260Trp NLRP3 mutations were significantly associated with the presence and absence of articular symptoms at onset, respectively. During followup, 86% of the patients had musculoskeletal symptoms, 88% had arthralgia, and 58% had arthritis, but only 9% had joint destruction. Tendinopathies occurred in 21.5% of the patients, tender points in 16.5%, and myalgia in 33%. Only 3 patients had typical knee deformities. Radiographs were rarely obtained. Except for bone deformities, osteoarticular symptoms occurred at similar frequencies in the different CAPS phenotypes. CONCLUSION: Joint manifestations were frequent in all CAPS phenotypes. Bone deformities were rare. Musculoskeletal manifestations varied within given families but tended to worsen over time. PMID- 26245509 TI - Tonic spasms and short myelitis in an elderly woman--unique onset of neuromyelitis optica. AB - Neuromyelitis optica typically presents at a median age of 40-50 years. The myelitis is usually of acute onset, long (>3 vertebral segments) and causes severe sensorimotor and bladder and bowel disturbances. We describe a 73-year-old Caucasian woman with aquaporin-4 antibody-positive neuromyelitis optica whose index event was intermittent paroxysmal tonic spasms (and no other myelitis features) that recurred for 6 months and was associated with a short spinal cord lesion on MRI. This case reiterates recent observations that neuromyelitis optica can occur in older persons, and its myelitis can be 'short' and clinically mild. PMID- 26245510 TI - Restricting freedom of people with limited awareness of maintaining their well being: a legal quagmire. PMID- 26245511 TI - Sagging brain causing postural loss of consciousness: a case of severe spontaneous intracranial hypotension. PMID- 26245512 TI - Focal inhibitory seizures: a cause of recurrent transient weakness. AB - Focal seizures are usually manifest with stereotyped positive phenomena. However, seizures may also give negative phenomena, such as paralysis, speech arrest, neglect, atonia and numbness. We report a 39-year-old man with neurofibromatosis 2 who had recurrent stereotyped episodes of weakness affecting his right leg and right arm. His MR scan of brain showed numerous meningiomas, the largest of which was near the vertex, adjacent to the left side of the falx. Interictal electroencephalogram, MR cerebral angiogram and Doppler carotid artery ultrasound scan were normal. He was diagnosed with epilepsy and started on levetiracetam, with no subsequent attacks. We postulate his negative motor seizures related to a meningioma overlying the supplementary negative motor area in the mesial superior frontal gyrus, and discuss diagnostic criteria for inhibitory seizures. PMID- 26245513 TI - The evolving role of dabigatran etexilate in clinical practice. AB - INTRODUCTION: Stroke and venous thromboembolism (VTE) affect millions of patients. The vitamin K antagonist, warfarin, has been the main oral anticoagulant used to treat these conditions despite many limitations associated with its use. Recently, multiple novel oral anticoagulants have been approved and are reshaping how patients with atrial fibrillation (AF) at risk of stroke and patients with VTE are treated. The direct thrombin inhibitor, dabigatran etexilate , is among these novel agents that have been developed to overcome limitations with warfarin. AREAS COVERED: In this article, authors describe the pharmacokinetic and pharmacodynamic properties of dabigatran etexilate and summarize the clinical evidence and controversy surrounding its use in the US, Canada and Europe. EXPERT OPINION: Dabigatran has demonstrated similar efficacy and safety to enoxaparin for VTE prevention in patients undergoing hip and knee arthroplasty, and to warfarin for the treatment of VTE. Dabigatran (110 mg) is noninferior and dabigatran (150 mg) is superior to warfarin for stroke prevention in patients with nonvalvular AF, with a lower rate of intracranial hemorrhage reported at both doses. Apixaban, rivaroxaban and edoxaban provide alternate anticoagulant options to dabigatran. While there are many similarities, there are also significant differences to consider in agent selection based on patient specific characteristics. PMID- 26245514 TI - Morphological changes of the caudal cervical intervertebral foramina due to flexion-extension and compression-traction movements in the canine cervical vertebral column. AB - BACKGROUND: Previous studies in humans have reported that the dimensions of the intervertebral foramina change significantly with movement of the spine. Cervical spondylomyelopathy (CSM) in dogs is characterized by dynamic and static compressions of the neural components, leading to variable degrees of neurologic deficits and neck pain. Studies suggest that intervertebral foraminal stenosis has implications in the pathogenesis of CSM. The dimensions of the cervical intervertebral foramina may significantly change during neck movements. This could have implication in the pathogenesis of CSM and other diseases associated with radiculopathy such as intervertebral disc disease. The purpose of this study was to quantify the morphological changes in the intervertebral foramina of dogs during flexion, extension, traction, and compression of the canine cervical vertebral column. All vertebral columns were examined with magnetic resonance imaging prior to biomechanic testing. Eight normal vertebral columns were placed in Group 1 and eight vertebral columns with intervertebral disc degeneration or/and protrusion were assigned to Group 2. Molds of the left and right intervertebral foramina from C4-5, C5-6 and C6-7 were taken during all positions and loading modes. Molds were frozen and vertical (height) and horizontal (width) dimensions of the foramina were measured. Comparisons were made between neutral to flexion and extension, flexion to extension, and traction to compression in neutral position. RESULTS: Extension decreased all the foraminal dimensions significantly, whereas flexion increased all the foraminal dimensions significantly. Compression decreased all the foraminal dimensions significantly, and traction increased the foraminal height, but did not significantly change the foraminal width. No differences in measurements were seen between groups. CONCLUSIONS: Our results show movement-related changes in the dimensions of the intervertebral foramina, with significant foraminal narrowing in extension and compression. PMID- 26245515 TI - Public Health Implications of Changing Rodent Importation Patterns - United States, 1999-2013. AB - The United States imports a large volume of live wild and domestic animal species; these animals pose a demonstrated risk for introduction of zoonotic diseases. Rodents are imported for multiple purposes, including scientific research, zoo exhibits and the pet trade. Current U.S. public health regulatory restrictions specific to rodent importation pertain only to those of African origin. To understand the impacts of these regulations and the potential public health risks of international rodent trade to the United States, we evaluated live rodent import records during 1999-2013 by shipment volume and geographic origin, source (e.g. wild-caught versus captive- or commercially bred), intended purpose and rodent taxonomy. Live rodent imports increased from 2737 animals during 1999 to 173 761 animals during 2013. Increases in both the number and size of shipments contributed to this trend. The proportion of wild-captured imports declined from 75% during 1999 to <1% during 2013. Nearly all shipments during these years were imported for commercial purposes. Imports from Europe and other countries in North America experienced notable increases in volume. Gerbils and hamsters arriving from Europe and chinchillas, guinea pigs and hamsters arriving from other countries in North America were predominant taxa underlying this trend. After 2003, African-origin imports became sporadic events under the federal permit process. These patterns suggest development of large-scale captive rodent breeding markets abroad for commercial sale in the United States. While the shift from wild-captured imports alleviates many conservation concerns and risks for novel disease emergence, such consolidated sourcing might elevate exposure risks for zoonotic diseases associated with high-density rodent breeding (e.g. lymphocytic choriomeningitis or salmonellosis). A responsive border health system must periodically re-evaluate importation regulations in conjunction with key stakeholders to ensure a balance between the economic benefits of rodent trade against the potential public health risks. PMID- 26245516 TI - Relationship between white matter lesions and regional cerebral blood flow changes during longitudinal follow up in Alzheimer's disease. AB - AIM: The aim of the present study was to evaluate the relationship between baseline white matter lesions (WML) and changes in regional cerebral blood flow during longitudinal follow up of patients with Alzheimer's disease (AD). METHODS: A total of 38 patients with AD were included in the study (16 men, 22 women; mean age 77.8 years). All patients were evaluated using the Mini-Mental State Examination and brain perfusion single-photon emission computed tomography at baseline with an approximately 2-year follow up. The patients were divided into two subgroups according to the presence of WML on magnetic resonance imaging. Single-photon emission computed tomography data were analyzed using a voxel-by voxel group analysis with Statistical Parametric Mapping 8 and region of interest analysis using FineSRT. Changes in Mini-Mental State Examination scores and regional cerebral blood flow were analyzed using the Wilcoxon signed-rank test. RESULTS: Mean Mini-Mental State Examination scores in AD patients with WML significantly decreased from 19.4 +/- 4.8 to 15.5 +/- 6.5 (P = 0.003). Statistical Parametric Mapping 8 and FineSRT analysis showed more severe and widespread regional cerebral blood flow reduction, mainly in the frontal and mesial temporal regions in AD patients with WML compared with those without WML. CONCLUSION: Baseline WML could predict a rapid progression of cognitive and brain functional impairment during longitudinal follow up in AD. Geriatr Gerontol Int 2016; 16: 836-842. PMID- 26245518 TI - An A-site mixed-ammonium solid solution perovskite series of [(NH2 NH3 )x (CH3 NH3 )1-x ][Mn(HCOO)3 ] (x=1.00-0.67). AB - The A-site mixed-ammonium solid solutions of metal-organic perovskites [(NH2 NH3 )x (CH3 NH3 )1-x ][Mn(HCOO)3 ] (x=1.00-0.67) exhibit para- to ferroelectric diffuse phase transitions with lowered transition temperatures from x=1.00 to 0.67. These properties are due to the decreased framework distortion and polarization in their low temperature ferroelectric phases caused by the increased CH3 NH3 (+) concentration. PMID- 26245519 TI - Oxygen profiling of the unsaturated zone using direct push drilling. AB - A methodology for oxygen profile measurements in the unsaturated zone is developed based on direct push drilling using sampling liners equipped with homemade silicone septa. The oxygen measurement is carried out by puncturing the septum with a commercial retractable optode needle fitted with a fluorescent tip. Metrological characteristics and method validation were carried out under laboratory conditions using different levels of oxygen and various water contents. The relative standard deviations under dry and water saturated soil conditions were less than 0.3% and 5% for 0.5 mg L(-1) of oxygen and less than 2% and 3% for 9 mg L(-1). Field demonstrations in a calcareous-sandstone soil aquifer treatment system with a layered clayey, marl and sandstone lithology of widely different water contents provided down to 30 m deep profiles of the dissolved oxygen level with less than 1.5 m spatial resolution. A single sensor was used for over 50 field measurements, though recalibration was required after approximately 30 measurements due to the deterioration of the fluorescent tip. PMID- 26245520 TI - Is there an ice epidemic in Australia? PMID- 26245521 TI - In response to the Commentary to our systematic review 'Does adherence therapy improve medication adherence among patients with schizophrenia?'. PMID- 26245522 TI - Phytochemical analysis of Passiflora loefgrenii Vitta, a rich source of luteolin derived flavonoids with antioxidant properties. AB - OBJECTIVES: The paper describes the flavonoid composition of the aerial parts (young leaves, YL; adult leaves, AL; stems, ST) of Passiflora loefgrenii Vitta, a rare species native to Brazil, where it is traditionally used as food. Antioxidant potential has also been evaluated. To the best of our knowledge, no phytochemical and biological study on this species has been reported previously. METHODS: Compositional data have been acquired combining HPLC-diode array detector (DAD) and Electrospary ionization-tandem mass spectrometry (ESI-MS/MS) analyses. Antioxidant activity has been evaluated by the 2,2'-di-phenyl-1 picrylhydrazyl method. KEY FINDINGS: Glycosylated flavones, with luteolin as the main aglycone, can be regarded as biomarkers for this drug. Qualitative composition of the extracts from YL, AL and ST was similar. The bulk of the constituents was made up by 8-C-beta-glucosyl luteolin (orientin), 7-O-alpha rhamnosyl-6-C-beta-glucosyl luteolin and 6-C-alpha-rhamnosyl luteolin, which totally amounted to 16.57 (73%), 10.77 (74%) and 5.07 (77%) MUg/mg in YL, AL and ST, respectively. P. loefgrenii showed a good antioxidant activity (IC50 of 350 MUg/ml), higher than generally reported for other passifloras. CONCLUSIONS: P. loefgrenii, rich in luteolin glycosides, can be regarded as a good candidate to be explored for therapeutic properties other than the sedative one since it represents a rich source of valuable flavonoids with antioxidant potential. PMID- 26245523 TI - Mixed Connective Tissue Disease and Papillary Thyroid Cancer: A Case Report. AB - BACKGROUND: Mixed connective tissue disease (MCTD) is a connective tissue disorder characterized by high titers of distinct antibodies: U1 ribonucleoprotein with clinical features seen in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), dermatomyositis (DM), polymyositis, and scleroderma. The association of SLE and DM with various cancers of the thyroid has been reported in the literature. However, there have been no reports associating MCTD with thyroid cancer. CASE REPORT: We present a 58-year-old woman diagnosed with MCTD with co-morbid interstitial lung disease that has remained stable for 10 years, who developed papillary thyroid carcinoma (PTC) 10 years after initial diagnosis. CONCLUSIONS: We theorize that: 1) MCTD may have been a primary diagnosis complicated by PTC, or 2) MCTD may have been an initial presentation of paraneoplastic syndrome of silent PTC, because her symptoms of MCTD significantly improved after total thyroidectomy. To the best of our knowledge, this is the first case report to associate MCTD with PTC. It highlights the importance of maintaining a high index of suspicion for thyroid malignancy in MCTD patients. PMID- 26245524 TI - Relationship between muscle sympathetic nerve activity and aortic wave reflection characteristics in aerobic- and resistance-trained subjects. AB - PURPOSE: Increased arterial stiffness is associated with an impairment of ventricular-vascular coupling efficiency and increased risk of cardiovascular mortality. Recently, it has been suggested that an increase in arterial stiffness is associated with resistance exercise training. Therefore, the aims of this study were to compare augmentation index (AIx) and left ventricular wasted pressure energy (LVEW) as markers of arterial stiffness and ventricular-vascular coupling efficiency in young aerobic-trained (AT) and resistance (RT)-trained subjects. We also investigated the relationship of muscle sympathetic nerve activity (MSNA) and flow-mediated dilation (FMD) to AIx in both sets of subjects to determine if endothelial function or sympathetic outflow could explain any differences in arterial stiffness. METHOD: To achieve our aims, we measured MSNA in 15 male subjects (8 RT, 7 AT) using microneurography. We also used applanation tonometry of the radial pressure waveform to noninvasively synthesize aortic pressure waveforms. FMD was calculated as percent dilation of the radial artery from baseline following a 5 min occlusion. RESULT: RT subjects had an increased AIx (12 +/- 3 vs. -7 +/- 2; P < 0.01), LVEW (429 +/- 111 vs. -360 +/- 77; P < 0.01) and MSNA burst incidence (34 +/- 4 vs. 26 +/- 4; P < 0.01) when compared with AT subjects. There was no difference in FMD between groups. MSNA burst incidence was also significantly related to AIx in subjects (R (2) = 0.61; P < 0.01) with a distinct demarcation between RT and AT subjects. CONCLUSION: These results confirm previous reports of a positive association between MSNA and AIx in young male resistance-trained subjects. Furthermore, RT is associated with increased arterial stiffness and elevated sympathetic outflow. PMID- 26245526 TI - Evaluation of the Safety Detective Program: A Classroom-Based Intervention to Increase Kindergarten Children's Understanding of Home Safety Hazards and Injury Risk Behaviors to Avoid. AB - Home injuries are a leading cause of mortality and morbidity for young children. Most programs that aim to improve their knowledge of home safety have been narrowly focused on one injury type and/or required specialized personnel for delivery. The purpose of the current study was to evaluate the effectiveness of a new Safety Detective Program that was designed to teach young children (4-6 years) about several types of home safety hazards and unsafe behaviors, with the program delivered in a classroom setting by non-experts based on manualized training. The current study used a randomized group, pre-post design to evaluate the effectiveness of the program to increase children's knowledge and understanding of home safety hazards and injury-risk behaviors to avoid. Children participated in six structured sessions, covering burns, falls, drowning, and poisoning. Each session involved play-based activities (storybook, song, and game or craft) to teach main messages about hazards and injury-risk behaviors, a take home activity, and a parent information sheet about the injury type covered that day. An individually administered photo-sort task with follow-up interview was used to measure intervention and control group participants' knowledge and understanding of injury-risk behaviors before and after program delivery. Children in the intervention, but not the control, group exhibited significant gains in their knowledge and understanding of home safety hazards and injury-risk behaviors to avoid, establishing the effectiveness of the program. This evaluation indicates that the Safety Detective Program can be delivered in classrooms without requiring specialized personnel or extensive training and with positive changes obtained. The program holds much promise as a means of improving kindergarten children's understanding of a broad range of home hazards and injury risk behaviors that are relevant to their safety. PMID- 26245525 TI - Comparative genomic and genetic analysis of glioblastoma-derived brain tumor initiating cells and their parent tumors. AB - BACKGROUND: Glioblastoma (GBM) is a fatal cancer that has eluded major therapeutic advances. Failure to make progress may reflect the absence of a human GBM model that could be used to test compounds for anti-GBM activity. In this respect, the development of brain tumor-initiating cell (BTIC) cultures is a step forward because BTICs appear to capture the molecular diversity of GBM better than traditional glioma cell lines. Here, we perform a comparative genomic and genetic analysis of BTICs and their parent tumors as preliminary evaluation of the BTIC model. METHODS: We assessed single nucleotide polymorphisms (SNPs), genome-wide copy number variations (CNVs), gene expression patterns, and molecular subtypes of 11 established BTIC lines and matched parent tumors. RESULTS: Although CNV differences were noted, BTICs retained the major genomic alterations characteristic of GBM. SNP patterns were similar between BTICs and tumors. Importantly, recurring SNP or CNV alterations specific to BTICs were not seen. Comparative gene expression analysis and molecular subtyping revealed differences between BTICs and GBMs. These differences formed the basis of a 63 gene expression signature that distinguished cells from tumors; differentially expressed genes primarily involved metabolic processes. We also derived a set of 73 similarly expressed genes; these genes were not associated with specific biological functions. CONCLUSIONS: Although not identical, established BTIC lines preserve the core molecular alterations seen in their parent tumors, as well as the genomic hallmarks of GBM, without acquiring recurring BTIC-specific changes. PMID- 26245527 TI - Maybe Small Is Too Small a Term: Introduction to Advancing Small Sample Prevention Science. AB - Prevention research addressing health disparities often involves work with small population groups experiencing such disparities. The goals of this special section are to (1) address the question of what constitutes a small sample; (2) identify some of the key research design and analytic issues that arise in prevention research with small samples; (3) develop applied, problem-oriented, and methodologically innovative solutions to these design and analytic issues; and (4) evaluate the potential role of these innovative solutions in describing phenomena, testing theory, and evaluating interventions in prevention research. Through these efforts, we hope to promote broader application of these methodological innovations. We also seek whenever possible, to explore their implications in more general problems that appear in research with small samples but concern all areas of prevention research. This special section includes two sections. The first section aims to provide input for researchers at the design phase, while the second focuses on analysis. Each article describes an innovative solution to one or more challenges posed by the analysis of small samples, with special emphasis on testing for intervention effects in prevention research. A concluding article summarizes some of their broader implications, along with conclusions regarding future directions in research with small samples in prevention science. Finally, a commentary provides the perspective of the federal agencies that sponsored the conference that gave rise to this special section. PMID- 26245528 TI - Network analysis reveals a stress-affected common gene module among seven stress related diseases/systems which provides potential targets for mechanism research. AB - Chronic stress (CS) was reported to associate with many complex diseases and stress-related diseases show strong comorbidity; however, molecular analyses have not been performed to date to evaluate common stress-induced biological processes across these diseases. We utilized networks constructed by genes from seven genetic databases of stress-related diseases or systems to explore the common mechanisms. Genes were connected based on the interaction information of proteins they encode. A common sub-network constructed by 561 overlapping genes and 8863 overlapping edges among seven networks was identified and it provides a common gene module among seven stress-related diseases/systems. This module is significantly overlapped with network that constructed by genes from the CS gene database. 36 genes with high connectivity (hub genes) were identified from seven networks as potential key genes in those diseases/systems, 33 of hub genes were included in the common module. Genes in the common module were enriched in 190 interactive gene ontology (GO) functional clusters which provide potential disease mechanism. In conclusion, by analyzing gene networks we revealed a stress affected common gene module among seven stress-related diseases/systems which provides insight into the process of stress induction of disease and suggests potential gene and pathway candidates for further research. PMID- 26245529 TI - Absolute Proteome Analysis of Colorectal Mucosa, Adenoma, and Cancer Reveals Drastic Changes in Fatty Acid Metabolism and Plasma Membrane Transporters. AB - Colorectal cancer is a leading cause of cancer-related death. It develops from normal enterocytes, through a benign adenoma stage, into the cancer and finally into the metastatic form. We previously compared the proteomes of normal colorectal enterocytes, cancer and nodal metastasis to a depth of 8100 proteins and found extensive quantitative remodeling between normal and cancer tissues but not cancer and metastasis (Wisniewski et al. PMID 22968445). Here we utilize advances in the proteomic workflow to perform an in depth analysis of the normal tissue (N), the adenoma (A), and the cancer (C). Absolute proteomics of 10 000 proteins per patient from microdissected formalin-fixed and paraffin-embedded clinical material established a quantitative protein repository of the disease. Between N and A, 23% of all proteins changed significantly, 17.8% from A to C and 21.6% from N to C. Together with principal component analysis of the patient groups, this suggests that N, A, and C are equidistant but not on one developmental line. Our proteomics approach allowed us to assess changes in varied cell size, the composition of different subcellular components, and alterations in basic biological processes including the energy metabolism, plasma membrane transport, DNA replication, and transcription. This revealed several fold higher concentrations of enzymes in fatty acid metabolism in C compared with N, and unexpectedly, the same held true of plasma membrane transporters. PMID- 26245530 TI - Rho-kinase inhibitor fasudil reduces allergic airway inflammation and mucus hypersecretion by regulating STAT6 and NFkappaB. AB - BACKGROUND: Airway mucus hypersecretion is a key pathophysiological feature in asthma. Fasudil, a selective Rho-A/Rho kinase inhibitor, has been used in clinical trials to treat pulmonary hypertension. However, its function in modulating airway mucus hypersecretion in asthma remains undefined. OBJECTIVE: We examined whether fasudil, a selective Rho-A/Rho kinase inhibitor, affects the mucus hypersecretion by suppressing MUC5AC via signal transducer and activator of transcription factor 6 (STAT6) and nuclear factor-kappa B (NFkappaB) in mice and cells. METHODS: We measured mucus secretion and the expression of Rho-kinase in the airway tissue of patients with asthma. BALB/c mice were sensitized and challenged with ovalbumin (OVA) followed with fasudil treatment. The lung tissues were assessed for airway inflammation and mucus secretion. Cytokine levels and airway responsiveness were determined. STAT6 and NFkappaB were quantified by Western blot. 16HBE cells were stimulated with house dust mite (HDM) extracts. MUC5AC and muc5ac promoter activities were measured. Using siRNA to knockdown STAT6 in epithelial cells, we determined the impact of STAT6 on muc5ac promoter activity. NFkappaB nuclear translocation was observed with immunostaining. RESULTS: Fasudil administration significantly decreased the number of inflammatory cells, inflammation index in the lung and airway responsiveness. Fasudil also reduced mucous secretion and MUC5AC expression in OVA-challenged mice. Fasudil down-regulated the levels of IL-17, IL-4 and IL-13 in the lung tissue of OVA-challenged mice. Fasudil also decreased the expression and phosphorylation of NFkappaB and STAT6 as well as the nuclear translocation of NFkappaB. In addition, human airway epithelial cells (16HBE) were challenged with HDM extracts and then treated with fasudil. Fasudil inhibited HDM extract-induced MUC5AC expression, which is associated with a reduction in STAT6 and NFkappaB in epithelial cells. CONCLUSIONS AND CLINICAL RELEVANCE: These findings indicate that the Rho-A/Rho kinase inhibitor, fasudil, plays a negative regulatory role in allergen-induced mucus secretion and MUC5AC expression by regulating STAT6 and NFkappaB. PMID- 26245531 TI - Establishment of transgenic Rhazya stricta hairy roots to modulate terpenoid indole alkaloid production. AB - KEY MESSAGE: Transgenic hairy roots of R. stricta were developed for investigation of alkaloid accumulations. The contents of five identified alkaloids, including serpentine as a new compound, increased compared to non transformed roots. Rhazya stricta Decne. is a rich source of pharmacologically active terpenoid indole alkaloids (TIAs). In order to study TIA production and enable metabolic engineering, we established hairy root cultures of R. stricta by co-cultivating cotyledon, hypocotyl, leaf, and shoot explants with wild-type Agrobacterium rhizogenes strain LBA 9402 and A. rhizogenes carrying the pK2WG7 gusA binary vector. Hairy roots initiated from the leaf explants 2 to 8 weeks. Transformation was confirmed by polymerase chain reaction and in case of GUS clones with GUS staining assay. Transformation efficiency was 74 and 83% for wild type and GUS hairy root clones, respectively. Alkaloid accumulation was monitored by HPLC, and identification was achieved by UPLC-MS analysis. The influence of light (16 h photoperiod versus total darkness) and media composition (modified Gamborg B5 medium versus Woody Plant Medium) on the production of TIAs were investigated. Compared to non-transformed roots, wild-type hairy roots accumulated significantly higher amounts of five alkaloids. GUS hairy roots contained higher amounts two of alkaloids compared to non-transformed roots. Light conditions had a marked effect on the accumulation of five alkaloids whereas the composition of media only affected the accumulation of two alkaloids. By successfully establishing R. stricta hairy root clones, the potential of transgenic hairy root systems in modulating TIA production was confirmed. PMID- 26245533 TI - Effect of road blockages on local air pollution during the Hong Kong protests and its implications for air quality management. AB - Roadside air quality in urban areas is largely affected by the traffic emissions. Changes in emissions and transport control policy are often assumed to yield benefits in air quality, but have often not always been effective in producing perceptible improvements due to the complexity of meteorological conditions. This study evaluates the air quality before, during and after a temporary roadway blockage event in Hong Kong that took place during Hong Kong protests from late September to mid-December, 2014. The local regulatory air quality monitoring data from both roadside and general ambient stations were used to assess the impact of roadway blockages on the air quality. There was a public perception of improved air quality, but analysis of the data shows the changes can be difficult to discern. This study showed some benefits deriving from road blockages on the local air quality, but the impact was not always apparent because of seasonal variation in meteorological conditions and synoptic transport of pollutants. The finding suggests care is required before making policy changes based on claimed benefits of shifting transport routes. The study highlights the needs to remove seasonal and meteorological change when examining air pollution data to develop strategies to improve air quality. PMID- 26245532 TI - The sunflower transcription factor HaWRKY76 confers drought and flood tolerance to Arabidopsis thaliana plants without yield penalty. AB - KEY MESSAGE: Arabidopsis transgenic plants expressing the sunflower transcription factor HaWRKY76 exhibit increased yield and tolerance to drought and flood stresses. The genetic construct containing HaWRKY76 is proposed as a potential biotechnological tool to improve crops. Water deficit and water excess are abiotic stress factors that seriously affect crops worldwide. To increase the tolerance to such stresses without causing yield penalty constitutes a major goal for biotechnologists. In this survey, we report that HaWRKY76, a divergent sunflower WRKY transcription factor, is able to confer both dehydration and submergence tolerance to Arabidopsis transgenic plants without yield penalty. The expression pattern of HaWRKY76 was analyzed in plants grown in standard conditions and under different watering regimes indicating a regulation by water availability. The corresponding cDNA was isolated and cloned under the control of a constitutive promoter and Arabidopsis plants were transformed with this construct. These transgenic plants presented higher biomass, seed production and sucrose content than controls in standard growth conditions. Moreover, they exhibited tolerance to mild drought or flood (complete submergence/waterlogging) stresses as well as the same or increased yield, depending on the stress severity and plant developmental stage, compared with controls. Drought tolerance occurred via an ABA-independent mechanism and induction of stomatal closure. Submergence tolerance can be explained by the carbohydrate (sucrose and starch) preservation achieved through the repression of fermentation pathways. Higher cell membrane stability and chlorenchyma maintenance could be the nexus between tolerance responses in front of both stresses. Altogether, the obtained results indicated that HaWRKY76 can be a potential biotechnological tool to improve crops yield as well as drought and flood tolerances. PMID- 26245534 TI - The influence of urbanisation on macroinvertebrate biodiversity in constructed stormwater wetlands. AB - The construction of wetlands in urban environments is primarily carried out to assist in the removal of contaminants from wastewaters; however, these wetlands have the added benefit of providing habitat for aquatic invertebrates, fish and waterbirds. Stormwater quantity and quality is directly related to impervious area (roads, sealed areas, roofs) in the catchment. As a consequence, it would be expected that impervious area would be related to contaminant load and biodiversity in receiving waters such as urban wetlands. This study aimed to establish whether the degree of urbanisation and its associated changes to stormwater runoff affected macroinvertebrate richness and abundance within constructed wetlands. Urban wetlands in Melbourne's west and south east were sampled along a gradient of urbanisation. There was a significant negative relationship between total imperviousness (TI) and the abundance of aquatic invertebrates detected for sites in the west, but not in the south east. However macroinvertebrate communities were relatively homogenous both within and between all study wetlands. Chironomidae (non-biting midges) was the most abundant family recorded at the majority of sites. Chironomids are able to tolerate a wide array of environmental conditions, including eutrophic and anoxic conditions. Their prevalence suggests that water quality is impaired in these systems, regardless of degree of urbanisation, although the causal mechanism is unclear. These results show some dependency between receiving wetland condition and the degree of urbanisation of the catchment, but suggest that other factors may be as important in determining the value of urban wetlands as habitat for wildlife. PMID- 26245535 TI - Emerald ash borer and the urban forest: Changes in landslide potential due to canopy loss scenarios in the City of Pittsburgh, PA. AB - Emerald ash borer is expected to kill thousands of ash trees in the eastern U.S. This research develops tools to predict the effect of ash tree loss from the urban canopy on landslide susceptibility in Pittsburgh, PA. A spatial model was built using the SINMAP (Stability INdex MAPping) model coupled with spatially explicit scenarios of tree loss (0%, 25%, 50%, and 75% loss of ash trees from the canopy). Ash spatial distributions were estimated via Monte Carlo methods and available vegetation plot data. Ash trees are most prevalent on steeper slopes, likely due to urban development patterns. Therefore, ash loss disproportionately increases hillslope instability. A 75% loss of ash resulted in roughly 800 new potential landslide initiation locations. Sensitivity testing reveals that variations in rainfall rates, and friction angles produce minor changes to model results relative to the magnitude of parameter variation, but reveal high model sensitivity to soil density and root cohesion values. The model predictions demonstrate the importance of large canopy species to urban hillslope stability, particularly on steep slopes and in areas where soils tend to retain water. To improve instability predictions, better characterization of urban soils, particularly spatial patterns of compaction and species specific root cohesion is necessary. The modeling framework developed in this research will enhance assessment of changes in landslide risk due to tree mortality, improving our ability to design economically and ecologically sustainable urban systems. PMID- 26245536 TI - Disentangling environmental drivers of benthic invertebrate assemblages: The role of spatial scale and riverscape heterogeneity in a multiple stressor environment. AB - It is broadly acknowledged that freshwater ecosystems are affected by multiple stressors, but the relative importance of individual stressors in impairing riverine communities remains unclear. We investigated the impacts of multiple stressors, incorporating in-stream water quality, riparian and catchment land use and stream morphology, on riverine benthic invertebrate communities, while considering the spatial scales of factors and the heterogeneity of riverscapes. We performed a stepwise regression procedure linking 21 abiotic and 20 community metrics using Generalized Linear Models on data from 1018 river sites spread across Germany. High impact stressors (e.g., nutrients and water temperature) were identified for various community metrics. Both the combination of relevant stressors and their explanatory value differed significantly across streams of different sizes and ecoregions. In large rivers, the riparian land use was less important in determining community structure compared to lower order streams. Thus, possible mitigating effects of revegetated riparian buffer strips are likely to be overwhelmed by the influence of catchment-wide land use. Our results indicated substantial variability in stressors for the range of metrics studied, providing insight into potential target parameters for effective ecosystem management. To achieve long lasting successes in managing, protecting and restoring running waters, it is of vital importance to recognize the heterogeneity of riverscapes and to consider large-scale influences. PMID- 26245538 TI - Experimental evidence of crystalline hillocks created by irradiation of CeO2 with swift heavy ions: TEM study. AB - In this study, CeO2 was irradiated with 200 MeV Au ions at oblique incidence. Observation of as-irradiated samples by transmission electron microscopy (TEM) shows that hillocks are created not only at the wide surfaces, but also at the crack faces of the thin samples. Since the hillocks created at the crack faces can be imaged by TEM, their shape and crystallographic features can be revealed. From the images of hillocks created at the crack faces, many of the hillocks are found to be spherical. We present the first experimental evidence that hillocks created for CeO2 irradiated with swift heavy ions have a crystal structure whose lattice spacing and orientation coincide with those of the matrix. The mechanism of spherical crystalline hillock formation is discussed based on the present results. PMID- 26245537 TI - A multidisciplinary approach to the study of cultural heritage environments: Experience at the Palatina Library in Parma. AB - The aim of this paper is to describe a multidisciplinary approach including biological and particle monitoring, and microclimate analysis associated with the application of the Computational Fluid Dynamic (CFD). This approach was applied at the Palatina historical library in Parma. Monitoring was performed both in July and in December, in the absence of visitors and operators. Air microbial monitoring was performed with active and passive methods. Airborne particles with a diameter of >=0.3, >=0.5, >=1 and >=5 MUm/m3, were counted by a laser particle counter. The surface contamination of shelves and manuscripts was assessed with nitrocellulose membranes. A spore trap sampler was used to identify both viable and non-viable fungal spores by optical microscope. Microbiological contaminants were analyzed through cultural and molecular biology techniques. Microclimatic parameters were also recorded. An infrared thermal camera provided information on the surface temperature of the different building materials, objects and components. Transient simulation models, for coupled heat and mass-moisture transfer, taking into account archivist and general public movements, combined with the related sensible and latent heat released into the environment, were carried out applying the CFD-FE (Finite Elements) method. Simulations of particle tracing were carried out. A wide variability in environmental microbial contamination, both for air and surfaces, was observed. Cladosporium spp., Alternaria spp., Aspergillus spp., and Penicillium spp. were the most frequently found microfungi. Bacteria such as Streptomyces spp., Bacillus spp., Sphingomonas spp., and Pseudoclavibacter as well as unculturable colonies were characterized by molecular investigation. CFD simulation results obtained were consistent with the experimental data on microclimatic conditions. The tracing and distribution of particles showed the different slice planes of diffusion mostly influenced by the convective airflow. This interdisciplinary research represents a contribution towards the definition of standardized methods for assessing the biological and microclimatic quality of indoor cultural heritage environments. PMID- 26245539 TI - Coassembly-Directed Fabrication of an Exfoliated Form of Alternating Multilayers Composed of a Self-assembled Organoplatinum(II) Complex-Fullerene Dyad. AB - The self-assembly of covalently linked dyad 1a of cyclometalated organoplatinum(II) complex and fullerene afforded alternating multilayers of electron-rich and -deficient molecular components. On the other hand, the coassembly of 1a with organoplatinum(II) complex 2 having no fullerene moiety gave an exfoliated form of the multilayers, by inhibiting the interdigitation of organoplatinum(II) complex moieties of 1a. The coassembled 1a/2 transports both of the photogenerated holes and electrons, while the self-assembled 1a allows only the transportation of electrons under the same conditions. PMID- 26245540 TI - Human Milk Analysis Using Mid-Infrared Spectroscopy. AB - BACKGROUND: The composition of human milk is known to vary with length of gestation, stage of lactation, and other factors. Human milk contains all nutrients required for infant health but requires fortification to meet the needs of low-birth-weight infants. Without a known nutrient profile of the mother's milk or donor milk fed to a baby, the composition of the fortified product is only an estimate. Human milk analysis has the potential to improve the nutrition care of high-risk newborns by increasing the information about human milk composition. Equipment to analyze human milk is available, and the technology is rapidly evolving. This pilot study compares mid-infrared (MIR) spectroscopy to reference laboratory milk analysis. METHODS: After obtaining informed consent, we collected human milk samples from mothers of infants weighing <2 kg at birth. Duplicate samples were analyzed for macronutrients by MIR and by reference laboratory analysis including Kjeldahl for protein, Mojonnier for fat, and high pressure liquid chromatography for lactose. Intraclass correlation coefficients, Bland-Altman scatter plots, and paired t tests were used to compare the two methods. RESULTS: No significant differences were detected between the macronutrient content of human milk obtained by MIR vs reference laboratory analysis. CONCLUSIONS: MIR analysis appears to provide an accurate assessment of macronutrient content in expressed human milk from mothers of preterm infants. The small sample size of this study limits confidence in the results. Measurement of lactose is confounded by the presence of oligosaccharides. Human milk analysis is a potentially useful tool for establishing an individualized fortification plan. PMID- 26245541 TI - Perioperative Parenteral Nutrition in Adults With Inflammatory Bowel Disease: A Review of the Literature. AB - Inflammatory bowel disease (IBD) is a chronic inflammatory condition with numerous nutrition implications, including an increased risk of malnutrition and various nutrient deficiencies. Surgical interventions are often necessary in the treatment of IBD, and patients with IBD presenting for surgery often have multiple issues, including acute inflammatory processes, malnutrition, anemia, and infections, which may increase the likelihood of poor surgical outcomes. Thus, determining adjunctive treatments that may decrease postoperative complications is paramount. Although enteral nutrition (EN) is considered the preferred nutrition support modality when the gastrointestinal tract is accessible and functional, parenteral nutrition (PN) may provide a suitable alternative when the use of EN is not feasible. The aim of this review is to evaluate the currently available literature on the impact of perioperative PN on postoperative complications, disease severity, and nutrition status in adults with IBD. Six studies within the past 10 years investigated this topic and are analyzed here. Results indicate general trends toward improvements in postoperative outcomes, disease severity, and nutrition status associated with perioperative PN use. Although results appear promising, additional, larger studies with an emphasis on PN composition will improve our understanding of the benefits of perioperative PN in adults with IBD. PMID- 26245542 TI - Driving test. PMID- 26245543 TI - Trial and triumph. PMID- 26245544 TI - Train Africa's scientists in crisis response. PMID- 26245556 TI - How Ebola-vaccine success could reshape clinical-trial policy. PMID- 26245557 TI - Trailblazing cancer-physics project accused of losing ambition. PMID- 26245558 TI - Caution urged over editing DNA in wildlife (intentionally or not). PMID- 26245559 TI - Crumb of mouse brain reconstructed in full detail. PMID- 26245560 TI - Crucial ocean-acidification models come up short. PMID- 26245561 TI - Physicists announce graphene's latest cousin: stanene. PMID- 26245562 TI - The slow-chemistry movement. PMID- 26245563 TI - How to beat the next Ebola. PMID- 26245564 TI - Disease outbreak: Finish the fight against Ebola. PMID- 26245566 TI - Clarification. PMID- 26245565 TI - Ebola: Embed research in outbreak response. PMID- 26245570 TI - Herbaria: Plant collections find strength in numbers. PMID- 26245571 TI - Productivity: Social impacts of science metrics. PMID- 26245572 TI - Addiction: Protect the young from e-cigarettes. PMID- 26245573 TI - Pakistan: High-rise buildings worsened heatwave. PMID- 26245574 TI - Earthquake aftermath: Support Nepal to rebuild sustainably. PMID- 26245575 TI - David M. Raup (1933-2015). PMID- 26245576 TI - Network science: Destruction perfected. PMID- 26245577 TI - Diabetes: A smart insulin patch. PMID- 26245578 TI - Materials chemistry: A magnetic facelift for non-magnetic metals. PMID- 26245579 TI - Climate science: Uncertain future for vegetation cover. PMID- 26245580 TI - Beating the Stoner criterion using molecular interfaces. AB - Only three elements are ferromagnetic at room temperature: the transition metals iron, cobalt and nickel. The Stoner criterion explains why iron is ferromagnetic but manganese, for example, is not, even though both elements have an unfilled 3d shell and are adjacent in the periodic table: according to this criterion, the product of the density of states and the exchange integral must be greater than unity for spontaneous spin ordering to emerge. Here we demonstrate that it is possible to alter the electronic states of non-ferromagnetic materials, such as diamagnetic copper and paramagnetic manganese, to overcome the Stoner criterion and make them ferromagnetic at room temperature. This effect is achieved via interfaces between metallic thin films and C60 molecular layers. The emergent ferromagnetic state exists over several layers of the metal before being quenched at large sample thicknesses by the material's bulk properties. Although the induced magnetization is easily measurable by magnetometry, low-energy muon spin spectroscopy provides insight into its distribution by studying the depolarization process of low-energy muons implanted in the sample. This technique indicates localized spin-ordered states at, and close to, the metal molecule interface. Density functional theory simulations suggest a mechanism based on magnetic hardening of the metal atoms, owing to electron transfer. This mechanism might allow for the exploitation of molecular coupling to design magnetic metamaterials using abundant, non-toxic components such as organic semiconductors. Charge transfer at molecular interfaces may thus be used to control spin polarization or magnetization, with consequences for the design of devices for electronic, power or computing applications (see, for example, refs 6 and 7). PMID- 26245581 TI - Erosion of organic carbon in the Arctic as a geological carbon dioxide sink. AB - Soils of the northern high latitudes store carbon over millennial timescales (thousands of years) and contain approximately double the carbon stock of the atmosphere. Warming and associated permafrost thaw can expose soil organic carbon and result in mineralization and carbon dioxide (CO2) release. However, some of this soil organic carbon may be eroded and transferred to rivers. If it escapes degradation during river transport and is buried in marine sediments, then it can contribute to a longer-term (more than ten thousand years), geological CO2 sink. Despite this recognition, the erosional flux and fate of particulate organic carbon (POC) in large rivers at high latitudes remains poorly constrained. Here, we quantify the source of POC in the Mackenzie River, the main sediment supplier to the Arctic Ocean, and assess its flux and fate. We combine measurements of radiocarbon, stable carbon isotopes and element ratios to correct for rock derived POC. Our samples reveal that the eroded biospheric POC has resided in the basin for millennia, with a mean radiocarbon age of 5,800 +/- 800 years, much older than the POC in large tropical rivers. From the measured biospheric POC content and variability in annual sediment yield, we calculate a biospheric POC flux of 2.2(+1.3)(-0.9) teragrams of carbon per year from the Mackenzie River, which is three times the CO2 drawdown by silicate weathering in this basin. Offshore, we find evidence for efficient terrestrial organic carbon burial over the Holocene period, suggesting that erosion of organic carbon-rich, high latitude soils may result in an important geological CO2 sink. PMID- 26245582 TI - Lab-inventory management: Time to take stock. PMID- 26245584 TI - Effects of electroacupuncture at GB points on markers of osteoporosis and bodyweight in ovariectomised rats. AB - BACKGROUND: Based on a description of acupuncture to treat a bone disease resembling osteoporosis in the ancient text of Huangdi Neijing, we aimed to assess the effects of electroacupuncture (EA) at GB points in ovariectomised (OVX) rats. METHODS: 40 female Wistar rats were randomly divided into four groups (n=10 each): ovariectomised model group (OVX); ovariectomised group treated with EA at GB points (OVX+GB); ovariectomised group treated with EA at non-GB points (OVX+N) in the hindlimb; and a sham surgery group (Sham). Three months after ovariectomy, rats in the OVX+GB and OVX+N groups received EA treatment for 3 months. Urine, blood and femur samples were collected from each animal for analysis. RESULTS: Bodyweight (BW) in the OVX+GB group decreased after EA treatment, reaching a minimum of ~12% below the OVX and OVX+N groups at 1 month. Concentrations of urine deoxypyridinoline, a bone resorption marker, were significantly elevated in the OVX and OVX+N groups but not the OVX+GB group. Concentrations of serum bone specific alkaline phosphatase, a bone formation marker, were significantly higher in the OVX+GB group versus the Sham and OVX groups. Bone mineral density (BMD) did not differ between the OVX, OVX+GB and OVX+N groups, but was ~10% lower than the Sham group. However, BMD/BW in the OVX+GB group was significantly higher than in the OVX and OVX+N groups and similar to the Sham group. Histological assessment of the femur showed that EA at GB points improved the bone architecture. CONCLUSIONS: EA treatment at GB points had anti-osteoporotic effects in a rat model of osteoporosis. PMID- 26245585 TI - CT evaluation of acupuncture needles inserted into sacral foramina. AB - OBJECTIVE: To use CT scanning to evaluate the precision with which acupuncture needles can be inserted into sacral foramina to establish sacral nerve modulation by electroacupuncture. METHODS: The subjects were five adult women (mean age 71.6 years). These five cases were divided into two groups. In the first three subjects (group A) the intention was to insert acupuncture needles in the S3 and S4 foramina; in the remaining two subjects (group B) the intention was to insert acupuncture needles in the S2 and S3 foramina. RESULTS: CT scanning showed that in subject 1 of group A, the acupuncture needle intended for insertion in S3 was actually in the S4 foramen, and the acupuncture needle intended for insertion in S4 was actually distal to the sacral body. In subjects 2 and 3, the acupuncture needles were inserted accurately in the S3 and S4 foramina. In the three subjects who had acupuncture needles inserted in the S4 foramen, the tip of the acupuncture needle was an average distance of 6.0 mm from the rectum. The acupuncture needles inserted in subjects 4 and 5 of group B were inserted accurately into the S2 and S3 foramina. CONCLUSIONS: Inserting acupuncture needles into the sacral foramina of S2 and S3 at an angle of about 60 degrees has the potential to be used for sacral nerve modulation by repeated electroacupuncture stimulation. Needling may be less accurate in subjects with higher body mass index. Because of the potential risk of perforating the rectum with the needle, this technique must be used by specialists only. TRIAL REGISTRATION NUMBER: 2013-026. PMID- 26245586 TI - The Family Practitioner's role in the integrated continuum of cancer care. PMID- 26245587 TI - Chronic kidney disease in disadvantaged populations: The case of Africa. PMID- 26245588 TI - The characteristics of HIV and AIDS patients with deep vein thrombosis at Dr. George Mukhari Academic Hospital. AB - BACKGROUND: Deep vein thrombosis (DVT) is 10 times more prevalent in HIV and AIDS patients than in the general population and is more common in patients with severe immune suppression (CD4 < 200 cells/mL). Opportunistic infections render HIV and AIDS patients susceptible to a hypercoaguable state, including lower protein S levels. AIM AND SETTING: To present the profile of HIV and AIDS patients who developed DVT in the primary care wards of Dr. George Mukhari Academic Hospital (DGMAH), Garankuwa. METHODS: Cross-sectional study of clinical records of admitted HIV and AIDS patients without DVT to the primary care wards, DGMAH, from 01 February 2010 to 31 January 2011. RESULTS: Two hundred and twenty nine patients were admitted and 17 (7.4%) developed DVT. Of those that developed DVT, eight (47%) had infection with tuberculosis (TB), four (24%) had pneumonia and four (24%) had gastroenteritis. The risk of developing DVT was 8/94 (8.5%) in those with TB, 4/53 (7.5%) in those with gastroenteritis and 4/75 (5.3%) in those with pneumonia. The mean duration of stay was 14.1 days in those with DVT versus 4.0 days in those without. CONCLUSION: HIV (and AIDS) is a hypercoaguable state and the risk of DVT is relatively high in patients with opportunistic infections. HIV and AIDS patients who are admitted to hospital with opportunistic infections may benefit from anti-thrombotic prophylaxis and further studies are needed to evaluate this. PMID- 26245589 TI - A situational analysis of training for behaviour change counselling for primary care providers, South Africa. AB - BACKGROUND: Non-communicable diseases and associated risk factors (smoking, alcohol abuse, physical inactivity and unhealthy diet) are a major contributor to primary care morbidity and the burden of disease. The need for healthcare provider training in evidence-based lifestyle interventions has been acknowledged by the National Department of Health. However, local studies suggest that counselling on lifestyle modification from healthcare providers is inadequate and this may, in part, be attributable to a lack of training. AIM: This study aimed to assess the current training courses for primary healthcare providers in the Western Cape. SETTING: Stellenbosch University and University of Cape Town. METHODS: Qualitative interviews were conducted with six key informants (trainers of primary care nurses and registrars in family medicine) and two focus groups (nine nurses and eight doctors) from both Stellenbosch University and the University of Cape Town. RESULTS: Trainers lack confidence in the effectiveness of behaviour change counselling and in current approaches to training. Current training is limited by time constraints and is not integrated throughout the curriculum--there is a focus on theory rather than modelling and practice, as well as a lack of both formative and summative assessment. Implementation of training is limited by a lack of patient education materials, poor continuity of care and record keeping, conflicting lifestyle messages and an unsupportive organisational culture. CONCLUSION: Revising the approach to current training is necessary in order to improve primary care providers' behaviour change counselling skills. Primary care facilities need to create a more conducive environment that is supportive of behaviour change counselling. PMID- 26245590 TI - Knowledge and practices about multidrug-resistant tuberculosis amongst healthcare workers in Maseru. AB - BACKGROUND: To date, no study has been found that described the knowledge and practices of healthcare workers surrounding multidrug-resistant tuberculosis (MDR TB) in Lesotho. AIM AND SETTING: This study was conducted to fill this gap by investigating the knowledge level and practices surrounding MDR-TB amongst healthcare workers at Botsabelo Hospital in Maseru, Lesotho. METHOD: This was a cross-sectional survey conducted by means of a questionnaire designed specifically for this study. Data collected included sociodemographic and professional details; and responses to questions about knowledge and practices regarding MDR-TB. The questions ranged from the definition of MDR-TB to its treatment. Respondents' practices such as the use of masks, guidelines and patient education were also assessed. RESULTS: A response rate of 84.6%(110 out of 130) was achieved. The majority of participants were women (60%), married (71.8%) and nursing staff (74.5%). Overall, less than half (47.3%) of the participants had a good level of knowledge about MDR-TB. With regard to practice, about 83%of participants stated that they used protective masks whilst attending to MDR-TB patients. About two-thirds (66.4%) reported being personally involved in educating patients about MDR-TB; whilst about 55%stated that they referred to these guidelines. CONCLUSION: The level of knowledge about MDR-TB amongst healthcare workers at the study site was not at an acceptable level. Unsafe practices, such as not wearing protective masks and not referring to the MDR-TB treatment guidelines, were found to be associated with an insufficient level of knowledge about MDR-TB. An educational intervention is recommended for all healthcare providers at this facility. PMID- 26245591 TI - A survey to assess the extent of public-private mix DOTS in the management of tuberculosis in Zambia. AB - BACKGROUND: Involving all relevant healthcare providers in tuberculosis (TB) management through public-private mix (PPM) approaches is a vital element in the World Health Organization's (WHO) Stop TB Strategy. The control of TB in Zambia is mainly done in the public health sector, despite the high overall incidence rates. AIM: We conducted a survey to determine the extent of private-sector capacity, participation, practices and adherence to national guidelines in the control of TB. SETTING: This survey was done in the year 2012 in 157 facilities in three provinces of Zambia where approximately 85% of the country's private health facilities are found. METHODS: We used a structured questionnaire to interview the heads of private health facilities to assess the participation of the private health sector in TB diagnosis, management and prevention activities. RESULTS: Out of 157 facilities surveyed, 40.5% were from the Copperbelt, 4.4% from Central province and 55.1% from Lusaka province. Only 23.8% of the facilities were able to provide full diagnosis and management of TB patients. Although 47.4% of the facilities reported that they do notify their cases to the National TB control programme, the majority (62.7%) of these facilities did not show evidence of notifications. CONCLUSION: Our results show that the majority of the facilities that diagnose and manage TB in the private sector do not report their TB activities to the National TB Control Programme (NTP). There is a need for the NTP to improve collaboration with the private sector with respect to TB control activities and PPM for Directly Observed Treatment, Short Course (DOTS). PMID- 26245592 TI - School environment, socioeconomic status and weight of children in Bloemfontein, South Africa. AB - BACKGROUND: The continued existence of undernutrition, associated with a steady increase in the prevalence of overweight and obesity in children and adolescents, necessitates identification of factors contributing to this double burden of disease, in order for effective treatment and prevention programmes to be planned. AIM: To determine the nutritional status of 13-15-year-old children in Bloemfontein and its association with socioeconomic factors. SETTING: Bloemfontein, Free State Province, South Africa (2006). METHODS: This was a cross sectional analytical study. Randomly selected children (n = 415) completed structured questionnaires on socioeconomic status. The children's weight and height were measured and body mass index-for-age and height-for-age z-scores were computed according to World Health Organization growth standards in order to determine the prevalence of underweight, overweight, obesity and stunting. Waist circumference was measured to classify the children as having a high or very high risk for metabolic disease. RESULTS: Of the 415 children who consented to participate in the study, 14.9% were wasted and 3.4% were severely wasted. Only 6% of the children were overweight/obese. Significantly more boys (23.0%) were wasted than girls (10%) and severe stunting was also significantly higher in boys than in girls (10.3% and 4.2%, respectively). Children whose parents had graduate occupations were significantly more overweight/obese than those with parents working in skilled occupations. Stunting was significantly higher in low (31.4%) and medium (30.4%) socioeconomic groups compared to the high socioeconomic group (18.1%). CONCLUSION: A coexistence of underweight and overweight was found and gender and parental occupation were identified as being predictors of nutritional status. PMID- 26245593 TI - 'If you have a problem with your heart, you have a problem with your life': Self perception and behaviour in relation to the risk of ischaemic heart disease in people living with HIV. AB - BACKGROUND: Ischaemic heart disease (IHD) is a global health problem and specifically relevant in the African context, as the presence of risk factors for IHD is increasing. People living with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) (PLWHA) are at increased risk for IHD due to increased longevity, treatment-specific causes and viral effects. AIM: To determine the self-perception and behaviour in relation to risk for IHD in a cohort of South African PLWHA. METHODS: A qualitative study using semi structured interviews with a card-sort technique was used to gather data from 30 individuals at an HIV clinic in Johannesburg. Descriptive analysis and conventional content analysis were done to generate the findings. RESULTS: The median age of the cohort was 36.5 (31.8-45.0) years and they were mostly women (n = 25; 83.3%) who were employed (n = 17; 56.7%) and supporting dependents (n = 26; 86.7%). Fifteen (50%) participants did not perceive themselves at risk of IHD and reported having adequate coping behaviour, living a healthy lifestyle and being healthy since initiating therapy. Twelve (40%) did feel at risk because they experienced physical symptoms and had poor behaviour. Knowledge and understanding related to IHD, insight into own risk for IHD and health character in a context of HIV infection were three themes. CONCLUSION: This study highlights that participants did not perceive themselves to be at risk of IHD due to their HIV status or antiretroviral management. Education strategies are required in PLWHA to inform their personal risk perception for IHD. PMID- 26245594 TI - Review of the Umthombo Youth Development Foundation scholarship scheme, 1999 2013. AB - INTRODUCTION: Staffing of rural and remote facilities is a challenge throughout the world. Umthombo Youth Development Foundation (UYDF) has been running a rurally based scholarship scheme since 1999.The aim of this review is to present data on the number of students selected, their progress, graduation and work placement from inception of the scheme until 2013. METHODS: Data were extracted from the UYDF data base using a data collection template to ensure all important information was captured. RESULTS: Since 1999, 430 rural students across 15 health disciplines have been supported by UYDF. The annual pass rate has been greater than 89%, and less than 10% of students have been excluded from university. All graduates have spent time working in rural areas (excluding the 32 currently doing internships) and 72% (52/73) of those with no work-back obligation continue to work in rural areas. DISCUSSION AND CONCLUSION: The UYDF model is built around local selection, compulsory academic and peer mentoring and social support, comprehensive financial support and experiential holiday work. The results are encouraging and highlight the fact that rural students can succeed at university and will come back and work in rural areas. With 46% of the South African population situated rurally, greater thought and effort must be put into the recruitment and training of rural scholars as a possible solution to the staffing of rural healthcare facilities. The UYDF provides a model which could be replicated in other parts of South Africa. PMID- 26245595 TI - Rural Zulu women's knowledge of and attitudes towards medical male circumcision. AB - BACKGROUND: Medical male circumcision (MMC) is a key strategy in the South African HIV infection prevention package. Women may have a potentially powerful role in supporting such a strategy. Circumcision is not a traditional part of Zulu society, and Zulu women may have limited knowledge and ambivalent or negative attitudes towards MMC. AIM: This study employs quantitative data to expand insight into rural Zulu women's knowledge of and attitudes towards MMC, and is important as women could potentially yield a powerful positive or negative influence over the decisions of their partners and sons. SETTING: A hospital based antenatal clinic in rural KwaZulu-Natal. METHODS: Participants were 590 pregnant, mostly isiZulu-speaking women. Data on their knowledge of and attitude towards MMC were collected using a questionnaire and were analysed descriptively. RESULTS: The majority of the women supported MMC; however, knowledge of the potential benefits was generally poor. Most would encourage their partners and sons to undergo MMC. The preferred place for the procedure was a hospital. CONCLUSION: Zulu participants supported MMC and would support their partners and children being circumcised. Knowledge around potential benefits was worryingly poor, and further research into disseminating information is essential. The findings highlight the need for an expanded campaign of health education for women, and innovative means are suggested to enhance information accessibility. Reasons for preferring that MMC be carried out in hospital need to be explored further. PMID- 26245596 TI - Adherence of doctors to a clinical guideline for hypertension in Bojanala district, North-West Province, South Africa. AB - BACKGROUND: Clinical guidelines are systematically developed statements that assist practitioners and patients to make healthcare decisions for specific clinical circumstances. Non-adherence of doctors to guidelines is thought to contribute significantly to poor delivery of clinical care, resulting in poor clinical outcomes. AIM: To investigate adherence of doctors in rural district hospitals to clinical guidelines using the South African Hypertension Guideline 2006 as an example. SETTING: Four district hospitals in Bojanala district of North-West Province, South Africa. METHODS: A cross-sectional study determined adherence practices of doctors from records of patients with established hypertension seen at the four district hospitals. RESULTS: Of the 490 total records documented by 29 doctors, screening for co-morbidity or associated factors was carried out as follows: diabetes mellitus 99.2%, obesity 6.1%, smoking 53.5%, dyslipidaemia 36.9%, abdominal circumference 3.3%; organ damage: eye 0, kidney 82%, heart 43.5%, chronic kidney disease 38.2%, stroke/transient ischaemic attack 15.9%, heart failure 23.5%, advanced retinopathy 0.2%, coronary heart disease 23.7%, peripheral arterial disease 13.9%. Critical tests/measurements were documented in the following proportions: blood pressure 99.8%, weight 85.3%, height 65.7%, body mass index 3.1%, urinalysis 74.5%, lipogram 76.1%, urea/creatinine 80.4%, electrocardiogram 42.9%, blood glucose 100%; risk determination and grading: diagnosis by hypertension severity 19%, low added risk 57.1%, moderate added risk 64.7%, high added risk 89.6%, very high added risk 89.2%. Adherence to therapies was as follows: first-line guideline drugs 69.4%, second line 84.7%, third line 87.8% and fourth-line 89.6%. CONCLUSION: Overall adherence of doctors to treatment guidelines for hypertension was found to be low (51.9%). Low adherence rates were related to age (older doctors) and less clinical experience, and differed with regard to various aspects of the guidelines. PMID- 26245597 TI - Clinical Associate students' perception of the educational environment at the University of the Witwatersrand, Johannesburg. AB - BACKGROUND: An important determinant of a student's behaviour and performance is the school's teaching and learning environment. Evaluation of such an environment can explore methods to improve educational curricula and academic atmosphere. AIM: To evaluate the educational environment of the Bachelor of Clinical Medicine Practice programme as perceived by students at the University of the Witwatersrand, South Africa. SETTING: This cross-sectional study was conducted with all final-year students (n = 25) enrolled in 2011, with a response rate of 88% (n = 22). Students were in two groups based in the Gauteng and North-West provinces. METHODS: Data were collected using the Dundee Ready Educational Environmental Measure questionnaire, which was administered to all students. Total and mean scores for all questions were calculated for both groups. RESULTS: The learning environment was given an average score of 130/196 by the students. Individual subscales show that 'Academic self-perception' was rated the highest (25/32), whilst 'Social self-perception' had the lowest score (13/24). Positive aspects of the academic climate included: student competence and confidence development; student participation in class; constructive criticism provided; empathy in medical profession; and friendships created. Areas for improvement included: feedback provision to students; course time-tables; ensure non stressful course; provision of good support systems for students; and social life improvement. CONCLUSION: Students' perceptions of their learning environment were 'more positive' than negative. Results from this study will be used to draw lessons for improving the curriculum and learning environment, improve administrative processes and develop student support mechanisms in order to improve their academic experience. PMID- 26245598 TI - Factors influencing specialist outreach and support services to rural populations in the Eden and Central Karoo districts of the Western Cape. AB - BACKGROUND: Access to health care often depends on where one lives. Rural populations have significantly poorer health outcomes than their urban counterparts. Specialist outreach to rural communities is one way of improving access to care. A multifaceted style of outreach improves access and health outcomes, whilst a shifted outpatients style only improves access. In principle, stakeholders agree that specialist outreach and support (O&S) to rural populations is necessary. In practice, however, factors influence whether or not O&S reaches its goals, affecting sustainability.Aim and setting: Our aim was to better understand factors associated with the success or failure of specialist O&S to rural populations in the Eden and Central Karoo districts in the Western Cape. METHODS: An anonymous parallel three-stage Delphi process was followed to obtain consensus in a specialist and district hospital panel. RESULTS: Twenty eight specialist and 31 district hospital experts were invited, with response rates of 60.7%-71.4% and 58.1%-74.2% respectively across the three rounds. Relationships, communication and planning were found to be factors feeding into a service delivery versus capacity building tension, which affects the efficiency of O&S. The success of the O&S programme is dependent on a site-specific model that is acceptable to both the outreaching specialists and the hosting district hospital. CONCLUSION: Good communication, constructive feedback and improved planning may improve relationships and efficiency, which might lead to a more sustainable and mutually beneficial O&S system. PMID- 26245599 TI - Non-allopathic adjuvant management of osteoarthritis by alkalinisation of the diet. AB - BACKGROUND: Osteoarthritis (OA) is a chronic condition. Nonsteroidal anti inflammatory drugs recommended for treatment have serious adverse effects. A compelling body of anecdotal evidence alerted the authors to the therapeutic potential of dietary supplementation with Multiforce(r) (MF) Alkaline Powder for relief of OA symptoms. AIM: The aim of the study was to test the hypothesis that dietary supplementation with MF relieves clinical signs and symptoms of OA of the hands. SETTING: The study was done at the MEDSAC hospital in Somerset West, Western Cape, South Africa. METHODS: The research was conducted in two stages. An open interventional study (n = 40) confirmed the notion that MF 7.5 g twice daily is likely to be an effective alternative or adjunct for relief of symptoms of OA of the hands. The main study was conducted with 100 eligible, consenting volunteers (aged 47-89 years) according to a randomised, placebo-controlled, crossover design. Study duration was 56 days, 28 days per regimen; crossover to alternate regimens took place on day 28. RESULTS: Compared to placebo, MF intake over 28 days was associated with significant reductions ( p < 0.005) in pain, tenderness and stiffness of interphalangeal and metacarpophalangeal joints of the hand. Confirmation of systemic alkalinisation by MF, which is rich in organic anions in the form of citrate salts, was reflected by a significant and sustained increase in urine pH. CONCLUSION: A dietary supplement, Multiforce(r) Alkaline Powder, containing citrate salts which are converted into bicarbonate in vivo, was efficacious and safe as sole therapeutic intervention, significantly attenuating OA-associated signs and symptoms of the hands. PMID- 26245600 TI - Utilisation of a community-based health facility in a low-income urban community in Ibadan, Nigeria. AB - BACKGROUND: Primary healthcare is established to ensure that people have access to health services through facilities located in their community. However, utilisation of health facilities in Nigeria remains low in many communities. AIM: To assess the utilisation of community-based health facility (CBHF) amongst adults in Ibadan, Nigeria. SETTINGS: A low-income community in Ibadan North West Local Government Area of Oyo State. METHODS: A cross-sectional survey was conducted using a simple random sampling technique to select one adult per household in all 586 houses in the community. A semi-structured interviewer administered questionnaire was used to collect information on respondents' sociodemographic characteristics, knowledge and utilisation of the CBHF. Data analysis included descriptive statistics and association testing using the Chi square test at p = 0.05. RESULTS: The mean age of the respondents was 46.5 +/- 16.0 years; 46.0% were men and 81.0% married; 26% had no formal education and 38.0% had secondary-level education and above; traders constituted 52.0% of the sample; and 85.2% were of low socioeconomic standing; 90%had patronised the CBHF. The main reasons for non-utilisation were preference for general hospitals (13.8%) and self-medication (12.1%). Respondents who had secondary education and above, were in a higher socioeconomic class, who had good knowledge of the facility and were satisfied with care, utilised the CBHF three months significantly more than their counterparts prior to the study (p < 0.05). However, only satisfaction with care was found to be a significant predictor of utilisation of the CBHF. CONCLUSION: The utilisation of the CBHF amongst adults in the study setting is high, driven mostly by satisfaction with the care received previously. Self-medication, promoted by uncontrolled access to drugs through pharmacies and patent medicine stores, threatens this high utilisation. PMID- 26245601 TI - Cervical cancer screening: Safety, acceptability, and feasibility of a single visit approach in Bulawayo, Zimbabwe. AB - BACKGROUND: Cervical cancer is the commonest cancer amongst African women, and yet preventative services are often inadequate. AIM: The purpose of the study was to assess the safety, acceptability and feasibility of visual inspection with acetic acid and cervicography (VIAC) followed by cryotherapy or a loop electrical excision procedure (LEEP) at a single visit for prevention of cancer of the cervix. SETTING: The United Bulawayo Hospital, Zimbabwe. METHODS: The study was descriptive, using retrospective data extracted from electronic medical records of women attending the VIAC clinic. Over 24 months 4641 women visited the clinic and were screened for cervical cancer using VIAC. Cryotherapy or LEEP was offered immediately to those that screened positive. Treated women were followed up at three months and one year. RESULTS: The rate of positive results on VIAC testing was 10.8%. Of those who were eligible, 17.0% received immediate cryotherapy, 44.1% received immediate LEEP, 1.9% delayed treatment, and 37.0% were referred to a gynaecologist. No major complications were recorded after cryotherapy or LEEP. Amongst those treated 99.5% expressed satisfaction with their experience. Only 3.2% of those treated at the clinic had a positive result on VIAC one year later. The service was shown to be feasible to sustain over time with the necessary consumables. There were no service-related treatment postponements and the clinic staff and facility were able to meet the demand for the service. CONCLUSION: A single-visit approach using VIAC, followed by cryotherapy or LEEP, proved to be safe, acceptable and feasible in an urban African setting in Bulawayo, Zimbabwe. Outcomes a year later suggested that treatment had been effective. PMID- 26245602 TI - Familial and socio-economic correlates of somatisation disorder. AB - BACKGROUND: Somatisation disorder can result from an interplay between suboptimal family environment and socio-economic deprivation, which enhances the underlying cognitive tendency for this disorder. There are pertinent familial and socio economic factors associated with this disorder, but research addressing this is sparse. AIM AND SETTING: The study aims to evaluate family and socio-economic factors that are associated with somatisation disorder amongst patients presenting to the Family Medicine clinic, University College Hospital, Ibadan, Nigeria. METHODS: This is an observational case-control study of 120 participants who presented to the clinic between May and August 2009. Data collection was by interviewer-administered structured questionnaire using the World Health Organization Screener for Somatoform Disorder and Somatoform Disorder Schedule to ascertain somatisation in 60 patients who were then matched with 60 controls. The respondents' demographic and family data were also collected and their interpersonal relationships were assessed with the Family Relationship Index. RESULTS: The somatising patients were mostly females (70%), with a female to male ratio of 2.3:1 and mean age of 43.65 +/- 13.04 years.Living in a polygamous family (as any member of the family) was significantly related to somatisation (p = 0.04). Somatisation was also more common in people who were separated, divorced or widowed (p = 0.039). Somatisers from a lower social class or those earning below a dollar a day experienced poorer cohesion (p = 0.042) and more conflicts (p = 0.019) in their interpersonal relationship. CONCLUSION: This study was able to demonstrate that a polygamous family setting, disrupted marriage, low social status and financial constraints are correlates of somatisation. It is of essence to identify these factors in holistic management of somatising patients. PMID- 26245603 TI - Antimicrobial susceptibility profile of uropathogens in Maluti Adventist Hospital patients, 2011. AB - BACKGROUND: Urinary tract infections (UTIs) are amongst the most common infections encountered globally and are usually treated empirically based on bacterial resistance to antibiotics for a given region. Unfortunately in Lesotho, no published studies are available to guide doctors in the treatment of UTIs. Treatment protocols for Western countries have been adopted, which may not be applicable for this region. AIM: To determine the antimicrobial susceptibility profile of uropathogens in outpatients at the Maluti Adventist Hospital. SETTING: The study was conducted at the outpatient department of the Maluti Adventist Hospital in Mapoteng, Lesotho. METHODS: This was a prospective cross-sectional study using consecutive sampling of patients with clinical symptoms of UTI. Midstream urine samples were screened through chemistry and microscopy, then positive urine samples were cultured. The isolated uropathogens underwent antimicrobial susceptibility testing and inclusion continued until 200 culture samples were obtained. Descriptive statistics were used in the data analysis. RESULTS: The top five cultured uropathogens were Escherichia coli (61.5%), Staphylococcus aureus (14%), Pseudomonasspecies (6.5%), Enterococcus faecalis (5.5%) and Streptococcus agalactiae (5%). The isolated uropathogens showed low sensitivity to cotrimoxazole (32.5%-75.0%) and amoxicillin (33.2%-87.5%) and high sensitivity to ciprofloxacin (84.0%-95.1%) and nitrofurantoin (76.9%-100%). CONCLUSION: In the Maluti setting, cotrimoxazole and amoxicillin should be avoided as first-line drugs for the empirical treatment of community-acquired UTI. We recommend the use of nitrofurantoin as first choice. PMID- 26245604 TI - Healthcare provider and patient perspectives on diagnostic imaging investigations. AB - BACKGROUND: Much has been written about the patient-centred approach in doctor patient consultations. Little is known about interactions and communication processes regarding healthcare providers' and patients' perspectives on expectations and experiences of diagnostic imaging investigations within the medical encounter. Patients journey through the health system from the point of referral to the imaging investigation itself and then to the post-imaging consultation. AIM AND SETTING: To explore healthcare provider and patient perspectives on interaction and communication processes during diagnostic imaging investigations as part of their clinical journey through a healthcare complex. METHODS: A qualitative study was conducted, with two phases of data collection. Twenty-four patients were conveniently selected at a public district hospital complex and were followed throughout their journey in the hospital system, from admission to discharge. The second phase entailed focus group interviews conducted with providers in the district hospital and adjacent academic hospital (medical officers and family physicians, nurses, radiographers, radiology consultants and registrars). RESULTS: Two main themes guided our analysis: (1) provider perspectives; and (2) patient dispositions and reactions. Golden threads that cut across these themes are interactions and communication processes in the context of expectations, experiences of the imaging investigations and the outcomes thereof. CONCLUSION: Insights from this study provide a better understanding of the complexity of the processes and interactions between providers and patients during the imaging investigations conducted as part of their clinical pathway. The interactions and communication processes are provider patient centred when a referral for a diagnostic imaging investigation is included. PMID- 26245605 TI - Evaluation of universal newborn hearing screening in South African primary care. AB - BACKGROUND: Universal Newborn Hearing Screening (UNHC) is the gold standard toward early hearing detection and intervention, hence the importance of its deliberation within the South African context. AIM: To determine the feasibility of screening in low-risk neonates, using Otoacoustic Emissions (OAEs), within the Midwife Obstetric Unit (MOU) three-day assessment clinic at a Community Health Centre (CHC), at various test times following birth. METHOD: Within a quantitative, prospective design, 272 neonates were included. Case history interviews, otoscopic examinations and Distortion Product OAEs (DPOAEs) screening were conducted at two sessions (within six hours and approximately three days after birth). Data were analysed via descriptive statistics. RESULTS: Based on current staffing profile and practice, efficient and comprehensive screening is not successful within hours of birth, but is more so at the MOU three-day assessment clinic. Significantly higher numbers of infants were screened at session 2, with significantly less false-positive results. At session 1, only 38.1% of the neonates were screened, as opposed to more than 100% at session 2. Session 1 yielded an 82.1% rate of false positive findings, a rate that not only has important implications for the emotional well-being of the parents; but also for resource-stricken environments where expenditure has to be accounted for carefully. CONCLUSION: Current findings highlight the importance of studying methodologies to ensure effective reach for hearing screening within the South African context. These findings argue for UNHS initiatives to include the MOU three-day assessment to ensure that a higher number of neonates are reached and confounding variables such as vernix have been eliminated. PMID- 26245606 TI - Medical education and the quality improvement spiral: A case study from Mpumalanga, South Africa. AB - BACKGROUND: The short timeframe of medical students' rotations is not always conducive to successful, in-depth quality-improvement projects requiring a more longitudinal approach. AIM: To describe the process of inducting students into a longitudinal quality-improvement project,using the topic of the Mother- and Baby Friendly Initiative as a case study; and to explore the possible contribution of a quality-improvement project to the development of student competencies. SETTING: Mpumalanga clinical learning centres, where University of Pretoria medical students did their district health rotations. METHOD: Consecutive student groups had to engage with a hospital's compliance with specific steps of the Ten Steps to Successful Breastfeeding that form the standards for the Mother- and Baby-Friendly Initiative. Primary data sources included an on-site PowerPoint group presentation (n = 42), a written group report (n = 42) and notes of individual interviews in an end-of-rotation objectively structured clinical examination station (n = 139). RESULTS: Activities in each rotation varied according to the needs identified through the application of the quality improvement cycle in consultation with the local health team. The development of student competencies is described according to the roles of a medical expert in the CanMEDS framework: collaborator, health advocate, scholar, communicator, manager and professional. The exposure to the real-life situation in South African public hospitals had a great influence on many students, who also acted as catalysts for transforming practice. CONCLUSION: Service learning and quality improvement projects can be successfully integrated in one rotation and can contribute to the development of the different roles of a medical expert. More studies could provide insight into the potential of this approach in transforming institutions and student learning. PMID- 26245607 TI - Causes of mortality and associated modifiable health care factors for children (< 5-years) admitted at Onandjokwe Hospital, Namibia. AB - INTRODUCTION: Many countries, especially those from sub-Saharan Africa, are unlikely to reach the Millennium Development Goal for under-5 mortality reduction by 2015. This study aimed to identify the causes of mortality and associated modifiable health care factors for under-5 year-old children admitted to Onandjokwe Hospital, Namibia. METHOD: A descriptive retrospective review of the medical records of all children under five years who died in the hospital for the period of 12 months during 2013, using two different structured questionnaires targeting perinatal deaths and post-perinatal deaths respectively. RESULTS: The top five causes of 125 perinatal deaths were prematurity 22 (17.6%), birth asphyxia 19 (15.2%), congenital anomalies 16 (12.8%), unknown 13 (10.4%) and abruptio placenta 11 (8.8%). The top five causes of 60 post-perinatal deaths were bacterial pneumonia 21 (35%), gastroenteritis 12 (20%), severe malnutrition 6 (10%), septicaemia 6 (10%), and tuberculosis 4 (6.7%). Sixty-nine (55%) perinatal deaths and 42 (70%) post-perinatal deaths were potentially avoidable. The modifiable factors were: late presentation to a health care facility, antenatal clinics not screening for danger signs, long distance referral, district hospitals not providing emergency obstetric care, poor monitoring of labour and admitted children in the wards, lack of screening for malnutrition, failure to repeat an HIV test in pregnant women in the third trimester or during breastfeeding, and a lack of review of the urgent results of critically ill children. CONCLUSION: A significant number of deaths in children under 5-years of age could be avoided by paying attention to the modifiable factors identified in this study. PMID- 26245608 TI - Development of a training programme for primary care providers to counsel patients with risky lifestyle behaviours in South Africa. AB - BACKGROUND: We are facing a global epidemic of non-communicable disease (NCDs), which has been linked with four risky lifestyle behaviours. It is recommended that primary care providers (PCPs) provide individual brief behaviour change counselling (BBCC) as part of everyday primary care, however currently training is required to build capacity. Local training programmes are not sufficient to achieve competence. AIM: This study aimed to redesign the current training for PCPs in South Africa, around a new model for BBCC that would offer a standardised approach to addressing patients' risky lifestyle behaviours. SETTING: The study population included clinical nurse practitioners and primary care doctors in the Western Cape Province. METHODS: The analyse, design, develop, implement and evaluate (ADDIE) model provided a systematic approach to the analysis of learning needs, the design and development of the training programme, its implementation and initial evaluation. RESULTS: This study designed a new training programme for PCPs in BBCC, which was based on a conceptual model that combined the 5As (ask, alert, assess, assist and arrange) with a guiding style derived from motivational interviewing. The programme was developed as an eight-hour training programme that combined theory, modelling and simulated practice with feedback, for either clinical nurse practitioners or primary care doctors. CONCLUSION: This was the first attempt at developing and implementing a best practice BBCC training programme in our context, targeting a variety of PCPs, and addressing different risk factors. PMID- 26245609 TI - Quality of care for patients with non-communicable diseases in the Dedza District, Malawi. AB - INTRODUCTION: In Malawi, non-communicable diseases (NCDs) are thought to cause 28% of deaths in adults. The aim of this study was to establish the extent of primary care morbidity related to NCDs, as well as to audit the quality of care, in the primary care setting of Dedza District, central Malawi. METHODS: This study was a baseline audit using clinic registers and a questionnaire survey of senior health workers at 5 clinics, focusing on care for hypertension, diabetes, asthma and epilepsy. RESULTS: A total of 82,581 consultations were recorded, of which 2489 (3.0%) were for the selected NCDs. Only 5 out of 32 structural criteria were met at all 5 clinics and 9 out of 29 process criteria were never performed at any clinic. The only process criteria performed at all five clinics was measurement of blood pressure. The staff's knowledge on NCDs was basic and the main barriers to providing quality care were lack of medication and essential equipment, inadequate knowledge and guidelines, fee-for-service at two clinics, geographic inaccessibility and lack of confidence in the primary health care system by patients. CONCLUSION: Primary care morbidity from NCDs is currently low, although other studies suggest a significant burden of disease. This most likely represents a lack of utilisation, recognition, diagnosis and ability to manage patients with NCDs. Quality of care is poor due to a lack of essential resources, guidelines, and training. PMID- 26245610 TI - Adaptation and cross-cultural validation of the United States Primary Care Assessment Tool (expanded version) for use in South Africa. AB - BACKGROUND: Measuring primary care is important for health sector reform. The Primary Care Assessment Tool (PCAT) measures performance of elements essential for cost-effective care. Following minor adaptations prior to use in Cape Town in 2011, a few findings indicated a need to improve the content and cross-cultural validity for wider use in South Africa (SA). AIM: This study aimed to validate the United States of America-developed PCAT before being used in a baseline measure of primary care performance prior to major reform. SETTING: Public sector primary care clinics, users, practitioners and managers in urban and rural districts in the Western Cape Province. METHODS: Face value evaluation of item phrasing and a combination of Delphi and Nominal Group Technique (NGT) methods with an expert panel and user focus group were used to obtain consensus on content relevant to SA. Original and new domains and items with > = 70% agreement were included in the South African version--ZA PCAT. RESULTS: All original PCAT domains achieved consensus on inclusion. One new domain, the primary healthcare (PHC) team, was added. Three of 95 original items achieved < 70% agreement, that is consensus to exclude as not relevant to SA; 19 new items were added. A few items needed minor rephrasing with local healthcare jargon. The demographic section was adapted to local socio-economic conditions. The adult PCAT was translated into isiXhosa and Afrikaans. CONCLUSION: The PCAT is a valid measure of primary care performance in SA. The PHC team domain is an important addition, given its emphasis in PHC re-engineering. A combination of Delphi and NGT methods succeeded in obtaining consensus on a multi-domain, multi-item instrument in a resource-constrained environment. PMID- 26245611 TI - The impact of health service variables on healthcare access in a low resourced urban setting in the Western Cape, South Africa. AB - BACKGROUND: Health care access is complex and multi-faceted and, as a basic right, equitable access and services should be available to all user groups. OBJECTIVES: The aim of this article is to explore how service delivery impacts on access to healthcare for vulnerable groups in an urban primary health care setting in South Africa. METHODS: A descriptive qualitative study design was used. Data were collected through semi-structured interviews with purposively sampled participants and analysed through thematic content analysis. RESULTS: Service delivery factors are presented against five dimensions of access according to the ACCESS Framework. From a supplier perspective, the organisation of care in the study setting resulted in available, accessible, affordable and adequate services as measured against the DistrictHealth System policies and guidelines. However, service providers experienced significant barriers in provision of services, which impacted on the quality of care, resulting in poor client and provider satisfaction and ultimately compromising acceptability of service delivery. Although users found services to be accessible, the organisation of services presented them with challenges in the domains of availability, affordability and adequacy, resulting in unmet needs, low levels of satisfaction and loss of trust. These challenges fuelled perceptions of unacceptable services. CONCLUSION: Well developed systems and organisation of services can create accessible, affordable and available primary healthcare services, but do not automatically translate into adequate and acceptable services. Focussing attention on how services are delivered might restore the balance between supply (services) and demand (user needs) and promote universal and equitable access. PMID- 26245612 TI - How far does family physician supply correlate with district health system performance? AB - BACKGROUND: Since 2011, a new cadre of family physicians, with 4 years of postgraduate training, was deployed in the district health services of the Western Cape, and tasked with a considerable range of duties aimed at a general improvement in care and health outcomes. There is a need to evaluate the contribution of these family physicians to the district health system. AIM: To develop a methodology for describing the correlation between family physician supply and district health system performance, clinical processes and outcomes, and to measure this correlation at baseline. METHOD: A cross-sectional study was undertaken that analysed data at an ecological level for the period of 01 April 2011 to 31 March 2012. This was a pilot project analysing data from the first year of a 4-year project. The correlations between family physician supply and 18 health system indicators were assessed within a logic model. The supplies of other categories of staff were also measured. RESULTS: Although most of the correlations with family physicians were positive, the study was unable to demonstrate any strong or statistically significant correlations at baseline. There were significant correlations with other categories of staff. CONCLUSIONS: This study developed a methodology for monitoring the relationship between family physician supply using routinely collected indicators of health system performance, clinical processes and outcomes over time. Additional research will also be needed to investigate the impact of family physicians and triangulate findings as this methodology has many limitations and potential confounding factors. PMID- 26245613 TI - Erectile function in circumcised and uncircumcised men in Lusaka, Zambia: A cross sectional study. AB - BACKGROUND: Evidence from three randomised control trials in South Africa, Uganda and Kenya showing that male circumcision can reduce heterosexual transmission of human immunodeficiency virus (HIV) infection from infected females to their male partners by up to 60% has led to an increase in circumcisions in most African countries. This has created anxieties around possible deleterious effects of circumcision on erectile function (EF). AIM: To compare EF in circumcised and uncircumcised men aged 18 years and older. SETTING: Four primary healthcare facilities in Lusaka, Zambia. METHODS: Using a cross-sectional survey 478 participants (242 circumcised and 236 uncircumcised) from four primary healthcare facilities in Lusaka, Zambia were asked to complete the IIEF-5 questionnaire. EF scores were calculated for the two groups, where normal EF constituted an IIEF-5 score >= 22 (out of 25). RESULTS: Circumcised men had higher average EF scores compared to their uncircumcised counterparts, (p < 0.001). The prevalence of erectile dysfunction was lower in circumcised men (56%) compared to uncircumcised men (68%) (p < 0.05). EF scores were similar in those circumcised in childhood and those who had the procedure in adulthood, (p = 0.59). The groups did not differ significantly in terms of age, relationship status, smoking, alcohol and medication use. A statistically significant difference was observed in education levels, with the circumcision group having higher levels of education (p < 0.005). CONCLUSION: The higher EF scores in circumcised men show that circumcision does not confer adverse EF effects in men. These results suggest that circumcision can be considered safe in terms of EF. A definitive prospective study is needed to confirm these findings. PMID- 26245614 TI - Student perspectives on the value of rural electives. AB - BACKGROUND: Medical students in the Faculty of Health Sciences at the University of the Witwatersrand (Wits) in Johannesburg have the opportunity to do electives at the end of the first and third years of a four-year graduate-entry medical programme. Upon their return they are required to write a short portfolio report. Over the period 2005 to 2011, 402 students chose to do rural electives. AIM AND SETTING: To understand the value of rural electives from the perspective of medical students in the Faculty of Health Sciences at Wits, as derived from their assessment reports. METHODS: A review was conducted of 402 elective reports. Common themes were identified through repeated reading of the reports, and then content analysis was undertaken using these themes. RESULTS: Major themes identified were the reasons for choosing a rural facility for the elective, including going to a home community; benefits of the elective, especially in terms of clinical skills and personal growth; relationship issues; the multiple roles of the rural doctor, who is often a role model working in difficult conditions; and the challenges of rural electives. CONCLUSION: The electives were overwhelmingly positive and affirming experiences for students, who developed clinical skills and also learnt about both themselves and their chosen career. PMID- 26245615 TI - Auditing chronic disease care: Does it make a difference? AB - BACKGROUND: An integrated audit tool was developed for five chronic diseases, namely diabetes, hypertension, asthma, chronic obstructive pulmonary disease and epilepsy. Annual audits have been done in the Western Cape Metro district since 2009. The year 2012 was the first year that all six districts in South Africa's Western Cape Province participated in the audit process. AIM: To determine whether clinical audits improve chronic disease care in health districts over time. SETTING: Western Cape Province, South Africa. METHODS: Internal audits were conducted of primary healthcare facility processes and equipment availability as well as a folder review of 10 folders per chronic condition per facility. Random systematic sampling was used to select the 10 folders for the folder review. Combined data for all facilities gave a provincial overview and allowed for comparison between districts. Analysis was done comparing districts that have been participating in the audit process from 2009 to 2010 ('2012 old') to districts that started auditing recently ('2012 new'). RESULTS: The number of facilities audited has steadily increased from 29 in 2009 to 129 in 2012. Improvements between different years have been modest, and the overall provincial average seemed worse in 2012 compared to 2011. However, there was an improvement in the '2012 old' districts compared to the '2012 new' districts for both the facility audit and the folder review, including for eight clinical indicators, with '2012 new' districts being less likely to record clinical processes (OR 0.25, 95% CI 0.21-0.31). CONCLUSION: These findings are an indication of the value of audits to improve care processes over the long term. It is hoped that this improvement will lead to improved patient outcomes. PMID- 26245616 TI - A review of 'medical' knowledge of epilepsy amongst isiZulu-speaking patients at a regional hospital in KwaZulu-Natal. AB - BACKGROUND: Epilepsy is a common disorder in South Africa and the literature indicates that many patients do not access treatment. The reasons are complex and include a poor knowledge about causes, symptoms, diagnosis and treatment (medical knowledge). This study aimed to assess the medical knowledge of isiZulu-speaking people with epilepsy (PWE) who attend a combination regional and district hospital in the eThekwini district in KwaZulu-Natal Province. METHOD: This was a prospective, cross-sectional, descriptive study. Data were collected using a validated data collection tool for assessing the medical knowledge of PWE and analysed descriptively. RESULTS: The questionnaires were completed by 199 PWE, with the general level of schooling being low and half being unemployed. Knowledge around causes, symptoms, diagnosis and treatments was good, but there were significant gaps in knowledge that may affect morbidity and mortality. DISCUSSION: The findings will serve as a useful guide to develop both preventive and educational interventions to enhance knowledge around the causes and treatment of epilepsy in this population. It is important that such interventions also consider family and healthcare providers. CONCLUSION: There were considerable gaps in the medical knowledge of isiZulu-speaking PWE's, indicating the need for an educational intervention to improve their understanding of epilepsy. Further research is needed-using a range of tools to ensure that the data is reliable and valid-if the results are to be generalisable to the rest of the province and South Africa. PMID- 26245617 TI - Profile and correlates of functional status in elderly patients presenting at a primary care clinic in Nigeria. AB - BACKGROUND: Assessing the functional status of elderly patients is central in measuring their health outcome. Little is known about the functional status of elderly patients attending our primary care clinic in Nigeria. OBJECTIVE: To assess the correlates of functional status in elderly patients presenting at the General Outpatient Clinic of the University College Hospital, Ibadan, Nigeria. METHOD: A cross-sectional study of 360 randomly selected patients aged 60 years and above was undertaken to assess their functional status by scoring their basic activities of daily living (BADL) using the Modified Bathel Index. An interviewer administered questionnaire was used to obtain the socio-demographic data, anthropometric measurements and morbidities of each patient. RESULTS: The mean age was 69.1 +/- 6.6 years with a female-to-male ratio of 1.9: 1. The prevalence of overall functional disability (defined as when assistance was sought in the performance of at least one of the components of BADL) was 88.3%. The highest prevalence of functional disability was experienced in the area of personal hygiene and grooming (95.3%) and transferring from bed to chair (95.3%). Overall functional disability significantly increased with increasing age (chi2 for trend=14.004, p < 0.0001), living in a polygamous family unit (p = 0.025), and lack of formal education (p = 0.020). CONCLUSION: Functional disability was high amongst the elderly in this setting. Age, education, and living in a polygamous type of family unit had significant influence on the functional status. High premium should, therefore, be placed on considering these factors in reducing functional disability in the elderly. PMID- 26245618 TI - A theoretical alternative intraosseous infusion site in severely hypovolemic children. AB - BACKGROUND: Studies have shown that the venous system tends to collapse during hypovolemic shock. The use of the bone marrow space for infusions is an effective alternative, with the tibial insertion site being the norm. OBJECTIVES: This study was conducted to determine a quick intraosseous infusion method that could be an alternative to the tibial route in neonates during emergency situations. METHOD: A sample of 30 neonatal cadavers was dissected to explore a possible alternative to the tibial insertion site. The needle was inserted in the superolateral aspect of the humerus. The needle infusion site was then dissected to determine possible muscular and neurovascular damage that might occur during the administration of this procedure, with the greatest concern being the posterior circumflex humeral artery and axillary nerve exiting the quadrangular space. The distance of the needle insertion site was measured in relation to the soft tissue as well as to bony landmarks. RESULTS: The calculated 95% confidence interval shows that the needle can be safely inserted into the intraosseous tissue at the greater tubercle of the humerus 9.5 mm-11.1 mm from the acromion. This is about a little finger's width from the acromioclavicular joint. CONCLUSION: Anatomically, the described site is suggested to offer a safe alternative access point for emergency infusion in severely hypovolemic newborns and infants, without the risk of damage to any anatomical structures. PMID- 26245619 TI - Diabetic patients' perspectives on the challenges of glycaemic control. AB - INTRODUCTION: The factors affecting the control of diabetes are complex and varied. However, little is documented in the literature on the overall knowledge of diabetic patients about glycaemic control. This study explored the patients' perspectives on the challenges of glycaemic control. METHODS: In this qualitative study, semi-structured interviews were conducted with seventeen purposively selected diabetic patients with HBA1c >= 9% at Mthatha General Hospital, South Africa. The interviews were conducted in the isiXhosa language and were audiotaped. Two experienced qualitative researchers independently transcribed and translated the interviews.Thematic content analysis was conducted. RESULTS: Three main themes emerged: overall knowledge of diabetes and treatment targets, factors affecting the control of diabetes and how glycaemic control could be improved.The majority of the participants demonstrated poor knowledge of treatment targets for diabetes. The majority of the participants reported that lack of money affected their control of diabetes. Some of the participants reported that the nearest clinics do not have doctors; hence,they are compelled to travel long distances to see doctors. CONCLUSION: Poverty, lack of knowledge and access to doctors affect the control of diabetes in the rural communities of Mthatha, South Africa. The government should address recruitment and retention of doctors in primary health care. PMID- 26245620 TI - Opinions of South African optometry students about working in rural areas after graduation. AB - BACKGROUND: Eye and vision problems have been reported to be more prevalent in rural than urban areas; and a large proportion of South Africans live in the rural areas. AIM: To investigate the opinions of South African optometry students about working in rural areas after completion of their training and to identify factors that may influence their decisions. METHOD: This was a cross-sectional quantitative study using a survey instrument containing both closed and open ended, semi-structured questions. RESULTS: Four hundred and thirty-eight students responded to the questionnaire (85.4% response rate). Overall, many of the respondents did not want to open their first (66%) or second practices (64.6%) in the rural areas. However, most respondents from rural backgrounds reported that they would open their first (77.2%) or second (79.4%) practice in the rural areas. The main reasons cited by the respondents for their unwillingness to work in the rural areas were financial concerns (81.2%), personal safety (80.1%) and poor living conditions (75.3%), with a significantly higher number (p < 0.05) being from urban respondents for the latter two issues only. CONCLUSION: Many students were not in favour of opening practices in rural areas, but were willing to work for the government or a non-governmental organisation after graduation. Efforts should be made to address financial incentives, safety and living conditions in the rural areas. The results of this study have implications for the future of availability and accessibility of eye care services to those living in the rural and remote areas of the country. PMID- 26245621 TI - A discourse analysis of male sexuality in the magazine Intimacy. AB - BACKGROUND: The World Health Organization's publication, Developing sexual health programmes, states that the media is an important source of information about sexuality. Although the media can promote awareness of sexual health issues, it also acts as a vehicle for defining and regulating sex norms. In other words, the standards of 'normal' sex are in part defined by the media. Accordingly, it has become imperative to analyse the media's construction of sexual norms in order to reveal how they are related to specific ideological views. For the purposes of this study, the focus will be limited to analysing the South African publication Intimacy. AIM: The study aims to reveal how the sex advice articles written in Intimacy for women in regard to their male partner's sexuality reflect patriarchal and phallocentric ideologies. METHOD: A discourse analysis of the sex advice articles in the magazine Intimacy was conducted. It was informed by feminist theories of sexuality that seek to examine the ways in which texts are associated with male-centred versions of sexual pleasure. RESULTS: The discourse analysis identified a number of key themes regarding male sexuality. These include: (1) biological accounts of male sexuality; (2) phallocentric scripting of the sex act; and (3) the melodramatic penis. CONCLUSION: Constructions of male sexuality require the inclusion of alternative modes of male erotic pleasure. This requires texts that encourage men to explore and also to experiment with pleasurable feelings associated with non-genital erogenous zones of the body. PMID- 26245622 TI - Trends in task shifting in HIV treatment in Africa: Effectiveness, challenges and acceptability to the health professions. AB - BACKGROUND: Task shifting has been suggested to meet the demand for initiating and managing more patients on antiretroviral therapy. Although the idea of task shifting is not new, it acquires new relevance in the context of current healthcare delivery. AIM: To appraise current trends in task shifting related to HIV treatment programmes in order to evaluate evidence related to the effectiveness of this strategy in addressing human resource constraints and improving patient outcomes, challenges identified in practice and the acceptability of this strategy to the health professions. METHOD: Electronic databases were searched for studies published in English between January 2009 and December 2014. Keywords such as 'task shifting', 'HIV treatment', 'human resources' and 'health professions' were used. RESULTS: Evidence suggests that task shifting is an effective strategy for addressing human resource constraints in healthcare systems in many countries and provides a cost-effective approach without compromising patient outcomes. Challenges include inadequate supervision support and mentoring, absent regulatory frameworks, a lack of general health system strengthening and the need for monitoring and evaluation. The strategy generally seems to be accepted by the health professions although several arguments against task shifting as a long-term approach have been raised. CONCLUSION: Task shifting occurs in many settings other than HIV treatment programmes and is viewed as a key strategy for governing human resources for healthcare. It may be an opportune time to review current task shifting recommendations to include a wider range of programmes and incorporate initiatives to address current challenges. PMID- 26245623 TI - What keeps health professionals working in rural district hospitals in South Africa? AB - BACKGROUND: The theme of the 2014 Southern African Rural Health Conference was 'Building resilience in facing rural realities'. Retaining health professionals in South Africa is critical for sustainable health services. Only 12% of doctors and 19% of nurses have been retained in the rural areas. The aim of the workshop was to understand from health practitioners why they continued working in their rural settings. CONFERENCE WORKSHOP: The workshop consisted of 29 doctors, managers, academic family physicians, nurses and clinical associates from Southern Africa, with work experience from three weeks to 13 years, often in deep rural districts. Using the nominal group technique, the following question was explored, 'What is it that keeps you going to work every day?' Participants reflected on their work situation and listed and rated the important reasons for continuing to work. RESULTS: Five main themes emerged. A shared purpose, emanating from a deep sense of meaning, was the strongest reason for staying and working in a rural setting. Working in a team was second most important, with teamwork being related to attitudes and relationships, support from visiting specialists and opportunities to implement individual clinical skills. A culture of support was third, followed by opportunities for growth and continuing professional development, including teaching by outreaching specialists. The fifth theme was a healthy work-life balance. CONCLUSION: Health practitioners continue to work in rural settings for often deeper reasons relating to a sense of meaning, being part of a team that closely relate to each other and feeling supported. PMID- 26245625 TI - The next generation of Rwandan physicians with a primary health care mindset. PMID- 26245626 TI - Catalytic Oxygen Evolution by Cobalt Oxido Thin Films. AB - The contemporary demand to generate fuels from solar energy has stimulated intense effort to develop water splitting catalysts that can be coupled to light absorbing materials. Cobalt oxido catalyst (Co-OECs) films deposited from buffered Co(II) solutions have emerged as arguably the most studied class of heterogeneous oxygen evolution catalysts. The interest in these materials stems from their formation by self-assembly, their self-healing properties, and their promising catalytic activity under a variety of conditions. The structure and function of these catalysts are reviewed here together with studies of molecular Co-O cluster compounds, which have proven invaluable in elucidating the chemistry of the Co-OECs. PMID- 26245627 TI - ESTS Presidential Address - Creative destruction: a new era in the field of thoracic surgery. PMID- 26245628 TI - Clinical and haemodynamic outcomes in 658 patients receiving the Perceval sutureless aortic valve: early results from a prospective European multicentre study (the Cavalier Trial)?. AB - OBJECTIVES: The aim of the Cavalier trial was to evaluate the safety and performance of the Perceval sutureless aortic valve in patients undergoing aortic valve replacement (AVR). We report the 30-day clinical and haemodynamic outcomes from the largest study cohort with a sutureless valve. METHODS: From February 2010 to September 2013, 658 consecutive patients (mean age 77.8 years; 64.4% females; mean logistic EuroSCORE 10.2%) underwent AVR in 25 European Centres. Isolated AVRs were performed in 451 (68.5%) patients with a less invasive approach in 219 (33.3%) cases. Of the total, 40.0% were octogenarians. Congenital bicuspid aortic valve was considered an exclusion criterion. RESULTS: Implantation was successful in 628 patients (95.4%). In isolated AVR through sternotomy, the mean cross-clamp time and the cardiopulmonary bypass (CPB) time were 32.6 and 53.7 min, and with the less invasive approach 38.8 and 64.5 min, respectively. The 30-day overall and valve-related mortality rates were 3.7 and 0.5%, respectively. Valve explants, stroke and endocarditis occurred in 0.6, 2.1 and in 0.1% of cases, respectively. Preoperative mean and peak pressure gradients decreased from 44.8 and 73.24 mmHg to 10.24 and 19.27 mmHg at discharge, respectively. The mean effective orifice area improved from 0.72 to 1.46 cm(2). CONCLUSIONS: The current 30-day results show that the Perceval valve is safe (favourable haemodynamic effect and low complication rate), and can be implanted with a fast and reproducible technique after a short learning period. Short cross clamp and CPB times were achieved in both isolated and combined procedures. The Perceval valve represents a promising alternative to biological AVR, especially with a less invasive approach and in older patients. PMID- 26245630 TI - [Osteology: the bone in focus]. PMID- 26245629 TI - Preoperative intra-aortic counterpulsation in high-risk patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials?. AB - In contrast to the results of previous studies, recent randomized controlled trials (RCTs) failed to show a benefit of prophylactic aortic counterpulsation in high-risk patients undergoing cardiac surgery. The present analysis aims to redefine the effects of this treatment modality in the light of this new evidence. MEDLINE, EMBASE, CENTRAL/CCTR, Google Scholar and reference lists of relevant articles were searched for full-text articles of RCTs in English or German. Assessments for eligibility, relevance, study validity and data extraction were performed by two reviewers independently using prespecified criteria. The primary outcome was hospital mortality. A total of nine eligible RCTs with 1171 patients were identified: 577 patients were treated preoperatively with intra-aortic balloon pump (IABP) and 594 patients served as controls. The pooled odds ratio (OR) for hospital mortality (22 hospital deaths in the intervention arm, 54 in the control group) was 0.381 (95% CI 0.230-0.629; P < 0.001). The pooled analyses of five RCTs including only patients undergoing isolated on-pump coronary artery bypass grafting (n[IABP] = 348, n[control] = 347) also showed a statistically significant improvement in mortality for preoperative IABP implantation (fixed-effects model: OR 0.267, 95% CI 0.129 0.552, P < 0.001). The pooled OR for hospital mortality from two randomized off pump trials was 0.556 (fixed-effects model, 95% CI 0.207-1.493, P = 0.226). Preoperative aortic counterpulsation was associated with a significant reduction in low cardiac output syndrome (LCOS) in the total population (fixed-effects model: OR 0.330, 95% CI 0.214-0.508, P < 0.001) as well as in the subgroup of CAGB patients (fixed-effects model: OR 0.113, 95% CI 0.056-0.226, P < 0.001), whereas there was no benefit in the off-pump population (fixed-effects model: OR 0.555, 95% CI 0.209-1.474, P = 0.238). Preoperative IABP implantation was associated with a reduction of intensive care unit (ICU) stay in all investigated populations with a greater effect in the total population [fixed-effects model: standard mean difference (SMD) -0.931 +/- 0.198, P < 0.001] as well as in the subgroup of CAGB patients (fixed-effects model: SMD -1.240 +/- 0.156, P < 0.001), compared with the off-pump group (fixed-effects model: SMD -0.723 +/- 0.128, P < 0.001). Despite contradictory results from recent trials, the present study confirms the findings of previous meta-analyses that prophylactic aortic counterpulsation reduces hospital mortality, incidence of LCOS and ICU requirement in high-risk patients undergoing on-pump cardiac surgery. However, owing to small sample sizes and the lack of a clear-cut definition of high-risk patients, an adequately powered, prospective RCT is necessary to find a definite answer to the question, if certain groups of patients undergoing cardiac surgery benefit from a prophylactic IABP insertion. PMID- 26245631 TI - [Bone marrow edema and atraumatic necrosis of the femoral head : Therapy]. AB - BACKGROUND: An increase in interstitial bony fluid occurs in bone-marrow edema (BME). The exact pathogenetic processes still remain unknown. BME is an unspecific finding that can occur on its own or accompany multiple diseases and pathologies. GOAL: Literature review and presentation of new guidelines. MATERIAL AND METHODS: This is a narrative literature review followed by current advice for the therapy of atraumatic osteonecrosis of the hip, based on the recently published S3-guidelines for this disease. RESULTS AND DISCUSSION: The differentiation of at least 3 different etiologies is proposed (mechanic, reactive and ischemic). Difficult, but important, is the distinction between the mostly painful, but benign entities (BME syndrome, bone bruise) and the progressive pathologies (osteonecrosis, arthritis, CRPS, tumour). Treatment options are dependent on etiology and clinic and can often be symptomatic. Core decompression is the surgical gold standard, leading to immediate pressure relief and therefore reduction in pain. Recently, it was shown that intravenous administration of Iloprost and bisphosphonates are also effective in achieving a reduction of BME and pain, with considerable improvement in the accompanying symptoms. The combination of core decompression and infusion seems to be another possible optimization ofthe therapy, in particular in the treatment of osteonecrosis. PMID- 26245633 TI - Long-Term Evaluation of Changes in Operative Technique and Hardware-Related Complications With Deep Brain Stimulation. AB - BACKGROUND: Deep brain stimulation is the most frequent neurosurgical procedure for movement disorders. OBJECTIVE: While this elective procedure carries a low risk profile, it is not free of complications. As a new procedure, the pattern of complications changed with experience and modification of surgical technique and equipment. METHODS: This review analyzes the most common hardware-related complications that may occur and techniques to avoid them. It is a retrospective review of 432 patients undergoing 1077 procedures over a 14-year period by one surgeon with emphasis on the analysis of surgical technique and the changes over time. Comparisons were made pre and postimplementation of different surgical techniques over different time periods. The epochs relate to the learning curve, new equipment, and new techniques. RESULTS: Overall lead revision was observed at 5.7%, extension revision at 3.2%, infection rate at 1.2%, infarct without intracerebral hemorrhage at 0.8%, and intracerebral hemorrhage at 2.5% with a permanent deficit of 0.2%. An analysis and change in surgical technique which involved isolating the lead from the skin surface at both the cranial and retro auricular incision also demonstrated a substantial decrease in lead fracture rate and infection rate. There was no mortality. CONCLUSION: This large series of patients and long-term follow-up demonstrates that risks are very low in comparison with other neurosurgical procedures, but DBS is still an elective procedure that necessitates extensive care and precision. In a rapidly evolving field, attention to surgical technique is imperative and will keep rates of complications at a minimum. PMID- 26245632 TI - Breast Cancer Risk Perceptions among Relatives of Women with Uninformative Negative BRCA1/2 Test Results: The Moderating Effect of the Amount of Shared Information. AB - The most common result of BRCA1/2 mutation testing when performed in a family without a previously identified mutation is an uninformative negative test result. Women in these families may have an increased risk for breast cancer because of mutations in non-BRCA breast cancer predisposition genes, including moderate- or low-risk genes, or shared environmental factors. Genetic counselors often encourage counselees to share information with family members, however it is unclear how much information counselees share and the impact that shared information may have on accuracy of risk perception in family members. We evaluated 85 sisters and daughters of women who received uninformative negative BRCA1/2 results. We measured accuracy of risk perception using a latent variable model where accuracy was represented as the correlation between perceived risk (indicators = verbal and quantitative measures) and calculated risk (indicators = Claus and BRCAPRO). Participants who reported more information was shared with them by their sister or mother about her genetic counseling session had greater accuracy of risk perception (0.707, p = 0.000) than those who reported little information was shared (0.326, p = 0.003). However, counselees shared very little information; nearly 20 % of family members reported their sister or mother shared nothing with them about her genetic counseling. Family members were generally not aware of the existence of a genetic counseling summary letter. Our findings underscore the need for effective strategies that facilitate counselees to share information about their genetic counseling sessions. Such communication may help their relatives better understand their cancer risks and enhance risk appropriate cancer prevention. PMID- 26245634 TI - Does Quality of Care Matter? A Study of Adherence to National Comprehensive Cancer Network Guidelines for Patients with Locally Advanced Esophageal Cancer. AB - INTRODUCTION: The aim of this study was to assess whether adherence to National Comprehensive Cancer Network (NCCN) guidelines leads to differences in survival in patients diagnosed with locally advanced esophageal cancer. METHODS: This is a retrospective cohort study of patients with stage II and III esophageal cancer included in the Cancer Registry at the Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins Hospital from 2008 to 2013. Seven quality indicators were identified using the 2014 NCCN guidelines, and individual and overall quality measure scores were calculated and used to define low and high quality of care groups. RESULTS: One hundred forty-one patients met inclusion criteria, and 88 patients (62.4 %) were identified as receiving high-quality care. Adherence to guidelines ranged from 63.1 to 100.0 %, with an overall compliance of 81.3 %. Risk factors for receiving low quality of care included advanced age, non-white race, lower education level, and unspecified primary site of tumor. A significantly better overall survival was observed in patients who received high quality care (HR, 0.58; 95 %, 0.37-0.90, p = 0.015). CONCLUSIONS: Delivery of high-quality care is associated with improved survival in these patients. Efforts should be directed at minimizing disparities in treatment in regards to race and educational levels. PMID- 26245635 TI - Migration of Internal Pancreaticojejunostomy Stents into the Bile Ducts in Patients Undergoing Pancreatoduodenectomy. AB - PURPOSE: To investigate the incidence, complications, and risk factors of the migration of internal pancreaticojejunostomy (PJ) stents into the bile ducts in patients undergoing pancreatoduodenectomy. METHODS: Postoperative computed tomography (CT) and clinical data of 802 patients with CT-detectable internal PJ stents were reviewed to assess the occurrence of stent migration into the bile ducts and stent-induced complications with their clinical significance. Risk factors for stent migration and stent-induced complications were determined. RESULTS: Stent migration into the bile ducts occurred in 135 patients (16.8 %); 40 of these (29.6 %) showed stent-induced complications including bile duct stricture, stone, and liver abscess. Clinically significant complications were identified in only eight patients. Neither the stent length nor diameter was associated with stent migration. A small stent diameter, peripheral location of the stent, absence of stent remigration from the bile ducts to the intestine, and longer stent retention time in the bile ducts were risk factors of stent-induced complications. CONCLUSIONS: The incidence of internal PJ stent migration into the bile ducts was 16.8 %. Migrated stents frequently caused complications, although they were mostly subclinical. Stent-induced complications were associated with stent diameter and location, stent remigration to the intestine, and stent retention time in the bile ducts. PMID- 26245636 TI - Brief Report: Endothelial-Specific X-Box Binding Protein 1 Deficiency Limits Tumor Necrosis Factor-Induced Leukocyte Recruitment and Vasculitis. AB - OBJECTIVE: Endothelial cell activation by tumor necrosis factor (TNF) and associated leukocyte infiltration are hallmarks of vasculitis. The aim of this study was to investigate the potential role of the cellular stress-associated endothelial X-box binding protein 1 (XBP-1) transcription factor in TNF-induced endothelial cell inflammation and vasculitis. METHODS: Mice with an endothelial cell-specific XBP-1 deficiency were used in a modified local Shwartzman reaction (LSR) model of TNF-induced small vessel vasculitis. To address the contribution of XBP-1 to the TNF-mediated inflammatory response in endothelial cells, we examined the activation of XBP-1 expression by TNF as well as the effect of XBP-1 knockdown in endothelial cells on TNF-induced signaling, proinflammatory gene expression, and leukocyte-endothelial cell adhesion. RESULTS: The active spliced form of XBP-1 in endothelial cells was triggered by TNF. In addition, endothelial XBP-1 contributed to the sustained TNF-triggered NF-kappaB-dependent transcriptional activation of proinflammatory molecules, which was associated with leukocyte-endothelial cell adhesion. In the LSR model, endothelial cell specific XBP-1-deficient mice displayed significantly less vascular damage, accompanied by reduced perivascular neutrophil infiltration, as compared with wild-type mice. CONCLUSION: Endothelial XBP-1 is activated by TNF and regulates leukocyte-endothelial cell adhesion in vitro as well as neutrophil infiltration and vascular damage in murine vasculitis. PMID- 26245637 TI - First report of multi-drug resistant tuberculosis in a systemic lupus erythematosus patient. AB - BACKGROUND: Treatment of a multi-drug resistant tuberculosis (MDR-TB) patient is clinically challenging, requiring a minimum of 18 months of therapy. Its occurrence in a systemic lupus erythromatosus (SLE) patient may complicate management of both MDR-TB and SLE. This is the first descriptive report of MDR-TB in an SLE patient. CASE PRESENTATION: A 19-year old female receiving long-term prednisolone for SLE was diagnosed with MDR-TB. She was started on MDR-TB treatment regimen and prednisolone was replaced with azathioprine. After an initial response to therapy, patient experienced a flare of lupus symptoms. Imaging studies revealed avascular necrosis of right femoral head. She was then treated with intravenous methyl-prednisolone, followed by maintenance corticosteroid. Azathioprine was discontinued due to hematological toxicity and failure to control SLE. Her symptoms of lupus regressed and did not re-occur for the duration of her MDR-TB treatment. Patient was declared cured of MDR-TB after 18 months of ATT. She is currently scheduled for a total hip replacement surgery. CONCLUSIONS: This case highlights the challenges of simultaneously managing MDR TB and SLE in a patient due to their over-lapping signs and symptoms, drug-drug interactions, and the need for use of immunomodulatory agents in the absence of standard guidelines and documented previous experiences. Our experience underscores the importance of appropriate selection of treatment regimens for both MDR-TB and SLE. PMID- 26245638 TI - Outcome of second- and third-line Helicobacter pylori eradication therapies based on antimicrobial susceptibility testing. AB - OBJECTIVES: The objective of this study was to assess the outcome of antimicrobial susceptibility-guided therapies in Helicobacter pylori-infected individuals who had undergone unsuccessful prior eradication treatments. METHODS: From October 2004 to December 2013, 481 H. pylori-positive patients with prior unsuccessful eradication treatments were administered susceptibility-guided salvage eradication treatments. Six months on, treatment outcome was assessed by urea breath test, stool antigen ELISA, Helicobacter urease test or microbiology and/or histopathology. RESULTS: Resistance to metronidazole and clarithromycin was high in patients with prior unsuccessful eradication treatments and was dependent on the number of treatment failures. Susceptibility-guided salvage eradication treatments achieved eradication rates of nearly 70% in these patients. No particular regimen was significantly better than another. CONCLUSIONS: Antimicrobial susceptibility testing prevents prescription of inefficient antimicrobials and enables individualized and promising salvage treatments in patients with prior unsuccessful eradication treatments. PMID- 26245639 TI - Cell division inhibitors with efficacy equivalent to isoniazid in the acute murine Mycobacterium tuberculosis infection model. AB - OBJECTIVES: The increasing number of clinical strains resistant to one or more of the front-line TB drugs complicates the management of this disease. To develop next-generation benzimidazole-based FtsZ inhibitors with improved efficacy, we employed iterative optimization strategies based on whole bacteria potency, bactericidal activity, plasma and metabolic stability and in vivo efficacy studies. METHODS: Candidate benzimidazoles were evaluated for potency against Mycobacterium tuberculosis H37Rv and select clinical strains, toxicity against Vero cells and compound stability in plasma and liver microsomes. The efficacy of lead compounds was assessed in the acute murine M. tuberculosis infection model via intraperitoneal and oral routes. RESULTS: MICs of SB-P17G-A33, SB-P17G-A38 and SB-P17G-A42 for M. tuberculosis H37Rv and select clinical strains were 0.18 0.39 mg/L. SB-P17G-A38 and SB-P17G-A42 delivered at 50 mg/kg twice daily intraperitoneally or orally demonstrated efficacy in reducing the bacterial load by 5.7-6.3 log10 cfu in the lungs and 3.9-5.0 log10 cfu in the spleen. SB-P17G A33 delivered at 50 mg/kg twice daily intraperitoneally or orally also reduced the bacterial load by 1.7-2.1 log10 cfu in the lungs and 2.5-3.4 log10 cfu in the spleen. CONCLUSIONS: Next-generation benzimidazoles with excellent potency and efficacy against M. tuberculosis have been developed. This is the first report on benzimidazole-based FtsZ inhibitors showing an equivalent level of efficacy to isoniazid in an acute murine M. tuberculosis infection model. PMID- 26245640 TI - Pharmacokinetics of high dosage of linezolid in two morbidly obese patients authors' response. PMID- 26245641 TI - Characterization of a novel small plasmid carrying the florfenicol resistance gene floR in Haemophilus parasuis. PMID- 26245645 TI - Inkjet Fabrication of Copper Patterns for Flexible Electronics: Using Paper with Active Precoatings. AB - Low-cost solution-processing of highly conductive films is important for the expanding market of printed electronics. For roll-to-roll manufacturing, suitable flexible substrates and compatible postprocessing are essential. Here, custom developed coated papers are demonstrated to facilitate the inkjet fabrication of high performance copper patterns. The patterns are fabricated in ambient conditions using water-based CuO dispersion and intense pulsed light (IPL) processing. Papers using a porous CaCO3 precoating, combined with an acidic mesoporous absorption coating, improve the effectiveness and reliability of the IPL process. The processing is realizable within 5 ms, using a single pulse of light. A resistivity of 3.1 +/- 0.12 MUOmega.cm is achieved with 400 MUm wide conductors, corresponding to more than 50% of the conductivity of bulk copper. This is higher than previously reported results for IPL-processed copper. PMID- 26245644 TI - Transcriptomic and phytochemical analysis of the biosynthesis of characteristic constituents in tea (Camellia sinensis) compared with oil tea (Camellia oleifera). AB - BACKGROUND: Tea plants (Camellia sinensis) are used to produce one of the most important beverages worldwide. The nutritional value and healthful properties of tea are closely related to the large amounts of three major characteristic constituents including polyphenols (mainly catechins), theanine and caffeine. Although oil tea (Camellia oleifera) belongs to the genus Camellia, this plant lacks these three characteristic constituents. Comparative analysis of tea and oil tea via RNA-Seq would help uncover the genetic components underlying the biosynthesis of characteristic metabolites in tea. RESULTS: We found that 3,787 and 3,359 bud genes, as well as 4,042 and 3,302 leaf genes, were up-regulated in tea and oil tea, respectively. High-performance liquid chromatography (HPLC) analysis revealed high levels of all types of catechins, theanine and caffeine in tea compared to those in oil tea. Activation of the genes involved in the biosynthesis of these characteristic compounds was detected by RNA-Seq analysis. In particular, genes encoding enzymes involved in flavonoid, theanine and caffeine pathways exhibited considerably different expression levels in tea compared to oil tea, which were also confirmed by quantitative RT-PCR (qRT-PCR). CONCLUSION: We assembled 81,826 and 78,863 unigenes for tea and oil tea, respectively, based on their differences at the transcriptomic level. A potential connection was observed between gene expression and content variation for catechins, theanine and caffeine in tea and oil tea. The results demonstrated that the metabolism was activated during the accumulation of characteristic metabolites in tea, which were present at low levels in oil tea. From the molecular biological perspective, our comparison of the transcriptomes and related metabolites revealed differential regulatory mechanisms underlying secondary metabolic pathways in tea versus oil tea. PMID- 26245646 TI - Health-related quality of life in well-differentiated metastatic gastroenteropancreatic neuroendocrine tumors. AB - Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms capable of producing hormones. The development of new treatments has improved progression-free survival, albeit with increased toxicity. Health-related quality of life (HRQoL) has become an important endpoint in clinical research to evaluate patients' well-being in such a contradictory scenario. In this review, we examine key reported outcomes across clinical studies exploring HRQoL in patients with GEP-NETs. We have conducted a review of the literature using PubMed, The Cochrane Library, EMBASE, and Google Scholar. Selection criteria for articles were (1) publication in English between 1995 and 2014, (2) patients with GEP-NET, and (3) analysis of HRQoL, including mental health and psychological symptoms. Forty-nine studies met the inclusion criteria (31 clinical trials, 14 observational studies, and 4 developments of NET-specific HRQoL instruments). The scope and nature of the literature was diverse with 27 instruments used to measure aspects of HRQoL. EORTC QLQ-C30 was the most frequently used, in 38 of the 49 studies. Standardized measures revealed that in spite of generally good HRQoL, GEP-NET patients have specific psychological and physical complaints. The clinical benefit of somatostatin analogs and sunitinib has been clearly supported by HRQoL assessment. Improvement in HRQoL scores or symptom relief over time was also reported in 14 trials of peptide receptor radionuclide therapy, however the absence of randomized studies obviate definitive conclusions. We have also identified several unanswered questions that should be addressed in further research concerning chemotherapy, everolimus, surgery, local ablative therapies, and chemoembolization. Future research should incorporate GEP-NET-specific HRQoL instruments into phase III trials. This review may help both clinicians and researchers to select the most appropriate tools to assess changes in HRQoL in this population. PMID- 26245647 TI - MEF2B mutations in non-Hodgkin lymphoma dysregulate cell migration by decreasing MEF2B target gene activation. AB - Myocyte enhancer factor 2B (MEF2B) is a transcription factor with mutation hotspots at K4, Y69 and D83 in diffuse large B-cell lymphoma (DLBCL). To provide insight into the regulatory network of MEF2B, in this study, we analyse global gene expression and DNA-binding patterns. We find that candidate MEF2B direct target genes include RHOB, RHOD, CDH13, ITGA5 and CAV1, and that indirect target genes of MEF2B include MYC, TGFB1, CARD11, MEF2C, NDRG1 and FN1. MEF2B overexpression increases HEK293A cell migration and epithelial-mesenchymal transition, and decreases DLBCL cell chemotaxis. K4E, Y69H and D83V MEF2B mutations decrease the capacity of MEF2B to activate transcription and decrease its' effects on cell migration. The K4E and D83V mutations decrease MEF2B DNA binding. In conclusion, our map of the MEF2B regulome connects MEF2B to drivers of oncogenesis. PMID- 26245648 TI - How preparation to touch or grasp alters visual size perception. AB - Prior studies have suggested that visually guided actions are resistant to the effects of some pictorial size illusions, e.g., the maximum grip aperture component of a grasp for an element of the Ebbinghaus illusion display. We present evidence that when participants prepare to grasp, the reduction in illusion magnitude observed for action components is also present for conscious perceptual judgments. Our studies characterize how visual size perception changes when we choose to engage in different size-mediated behaviors. Even when the stimuli used were identical for two different tasks, we found that available information was processed differently. In the studies, participants always selected which of the two targets was larger. In some conditions, the context in which the targets were presented induced a visual illusion of size. We varied the sizes of target pairs to assess the magnitude of these visual illusions. In some tasks, participants indicated their size choice verbally. For other tasks, participants reached to grasp or touch the target that they perceived as larger. Illusion magnitudes were smaller when participants engaged in actions directed at a target or when participants imagined performing those actions. This shift in visual processing persisted for several minutes after participants switched back to a verbal, non-grasping, non-touch task. A motor interference task eliminated the reduction in illusion magnitude. PMID- 26245649 TI - Relationships between trait impulsivity and cognitive control: the effect of attention switching on response inhibition and conflict resolution. AB - This study examined the relationship between trait impulsivity and cognitive control, as measured by the Barratt Impulsiveness Scale (BIS) and a focused attention dichotic listening to words task, respectively. In the task, attention was manipulated in two attention conditions differing in their cognitive control demands: one in which attention was directed to one ear at a time for a whole block of trials (blocked condition) and another in which attention was switched pseudo-randomly between the two ears from trial to trial (mixed condition). Results showed that high impulsivity participants exhibited more false alarm and intrusion errors as well as a lesser ability to distinguish between stimuli in the mixed condition, as compared to low impulsivity participants. In the blocked condition, the performance levels of the two groups were comparable with respect to these measures. In addition, total BIS scores were correlated with intrusions and laterality index in the mixed but not the blocked condition. The findings suggest that high impulsivity individuals may be less prone to attentional difficulties when cognitive load is relatively low. In contrast, when attention switching is involved, high impulsivity is associated with greater difficulty in inhibiting responses and resolving cognitive conflict than is low impulsivity, as reflected in error-prone information processing. The conclusion is that trait impulsivity in a non-clinical population is manifested more strongly when attention switching is required than during maintained attention. This may have important implications for the conceptualization and treatment of impulsivity in both non-clinical and clinical populations. PMID- 26245650 TI - Multiparametric Phenotypic Screening System for Profiling Bioactive Compounds Using Human Fetal Hippocampal Neural Stem/Progenitor Cells. AB - Stem cell research has been progressing rapidly, contributing to regenerative biology and regenerative medicine. In this field, small-molecule compounds affecting stem cell proliferation/differentiation have been explored to understand stem cell biology and support regenerative medicine. In this study, we established a multiparametric screening system to detect bioactive compounds affecting the cell fate of human neural stem/progenitor cells (NSCs/NPCs), using human fetal hippocampal NSCs/NPCs, HIP-009 cells. We examined effects of 410 compounds, which were collected based on mechanisms of action (MOAs) and chemotypes, on HIP-009's cell fate (self-renewal, neuronal and astrocytic differentiation) and morphology by automated multiparametric assays and profiled induced cellular phenotypes. We found that this screening classified compounds with the same MOAs into subgroups according to additional pharmacological effects (e.g., mammalian target of rapamycin complex 1 [mTORC1] inhibitors and mTORC1/mTORC2 dual inhibitors among mTOR inhibitors). Moreover, it identified compounds that have off-target effects under matrix analyses of MOAs and structure similarities (e.g., neurotropic effects of amitriptyline among tri- and tetracyclic compounds). Therefore, this automated, medium-throughput and multiparametric screening system is useful for finding compounds that affect the cell fate of human NSCs/NPCs for supporting regenerative medicine and to fingerprint compounds based on human stem cells' multipotency, leading to understanding of stem cell biology. PMID- 26245651 TI - Retinoic acid-induced CHD5 upregulation and neuronal differentiation of neuroblastoma. AB - BACKGROUND: Chromodomain-helicase DNA binding protein 5 (CHD5) is an important tumor suppressor gene deleted from 1p36.31 in neuroblastomas (NBs). High CHD5 expression is associated with a favorable prognosis, but deletion or low expression is frequent in high-risk tumors. We explored the role of CHD5 expression in the neuronal differentiation of NB cell lines. METHODS: NB cell lines SH-SY5Y (SY5Y), NGP, SK-N-DZ, IMR5, LAN5, SK-N-FI, NB69 and SH-EP were treated with 1-10 MUM 13-cis-retinoic acid (13cRA) for 3-12 days. qRT-PCR and Western blot analyses were performed to measure mRNA and protein expression levels, respectively. Morphological differences were examined by both phase contrast and immunofluorescence studies. RESULTS: Treatment of SY5Y cells with 13cRA caused upregulation of CHD5 expression in a time- and dose-dependent manner (1, 5, or 10 MUM for 7 or 12 days) and also induced neuronal differentiation. Furthermore, both NGP and SK-N-DZ cells showed CHD5 upregulation and neuronal differentiation after 13cRA treatment. In contrast, 13cRA treatment of IMR5, LAN5, or SK-N-FI induced neither CHD5 expression nor neuronal differentiation. NB69 cells showed two different morphologies (neuronal and substrate adherent) after 12 days treatment with 10 MUM of 13cRA. CHD5 expression was high in the neuronal cells, but low/absent in the flat, substrate adherent cells. Finally, NGF treatment caused upregulation of CHD5 expression and neuronal differentiation in SY5Y cells transfected to express TrkA (SY5Y-TrkA) but not in TrkA-null parental SY5Y cells, and both changes were blocked by a pan-TRK inhibitor. CONCLUSIONS: Treatment with 13cRA induces neuronal differentiation only in NB cells that upregulate CHD5. In addition, NGF induced CHD5 upregulation and neuronal differentiation only in TrkA expressing cells. Together, these results suggest that CHD5 is downstream of TrkA, and CHD5 expression may be crucial for neuronal differentiation induced by either 13cRA or TrkA/NGF signaling. PMID- 26245654 TI - Functionalization of phosphorescent emitters and their host materials by main group elements for phosphorescent organic light-emitting devices. AB - Phosphorescent organic light-emitting devices (OLEDs) have attracted increased attention from both academic and industrial communities due to their potential practical application in high-resolution full-color displays and energy-saving solid-state lightings. The performance of phosphorescent OLEDs is mainly limited by the phosphorescent transition metal complexes (such as iridium(III), platinum(II), gold(III), ruthenium(II), copper(I) and osmium(II) complexes, etc.) which can play a crucial role in furnishing efficient energy transfer, balanced charge injection/transporting character and high quantum efficiency in the devices. It has been shown that functionalized main-group element (such as boron, silicon, nitrogen, phosphorus, oxygen, sulfur and fluorine, etc.) moieties can be incorporated into phosphorescent emitters and their host materials to tune their triplet energies, frontier molecular orbital energies, charge injection/transporting behavior, photophysical properties and thermal stability and hence bring about highly efficient phosphorescent OLEDs. So, in this review, the recent advances in the phosphorescent emitters and their host materials functionalized with various main-group moieties will be introduced from the point of view of their structure-property relationship. The main emphasis lies on the important role played by the main-group element groups in addressing the key issues of both phosphorescent emitters and their host materials to fulfill high performance phosphorescent OLEDs. PMID- 26245653 TI - HbA1c as screening for gestational diabetes mellitus in women with polycystic ovary syndrome. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes such as preeclampsia and macrosomia. Women with polycystic ovary syndrome (PCOS) are at increased risk of developing GDM. Today, GDM is diagnosed by oral glucose tolerance test (OGTT), a rather cumbersome test for the women and health care system. The objectives of this study were to investigate whether HbA1c in first trimester of pregnancy could be used as a screening test for GDM in first trimester and throughout pregnancy in order to reduce the number of OGTTs, and whether it could predict preeclampsia and macrosomia in women with PCOS. METHODS: Post hoc analyses of data from 228 women from a prospective, randomised, multicenter study comparing metformin to placebo from first trimester to delivery. Fasting and 2-h plasma glucose were measured during a 75 g OGTT in first trimester, gestational week 19 and 32 as well as fasting plasma glucose in gestational week 36. GDM was diagnosed by WHO criteria from 1999 in first trimester and throughout pregnancy and by modified IADPSG criteria (i.e. lacking the 1-h plasma glucose value) in first trimester. The diagnostic accuracy was assessed by logistic regression and ROC curve analysis. RESULTS: The area under the ROC curve for first trimester HbA1c for screening of GDM diagnosed by WHO criteria in first trimester was 0.60 (95 % CI 0.44-0.75) and 0.56 (95 % CI 0.47 0.65) for GDM diagnosed throughout pregnancy. Only 2.2 % (95 % CI 0.7-5.1 %) of the participants could have avoided OGTT. HbA1c was not statistically significantly associated with GDM diagnosed by modified IADPSG criteria in first trimester. However, first trimester HbA1c was statistically significantly associated with preeclampsia. Both HbA1c and GDM by WHO criteria in first trimester, but not by IADPSG, were negatively associated with birth weight. CONCLUSION: First trimester HbA1c can not be used to exclude or predict GDM in women with PCOS, but it might be better to predict preeclampsia than the GDM diagnosis. PMID- 26245655 TI - Association of CD34+ and CD90+ Stem Cells of Cord Blood with Neonatal Factors: A Cross-sectional Study. AB - OBJECTIVE: To characterize the primitive stem cell content of cord blood with regard to neonatal parameters. METHODS: In this cross-sectional study, CD34+ and CD90+ cells content were enumerated by flow-cytometry method. Their associations with various neonatal parameters like birth weight, gender, gestational age and mode of delivery were analyzed by univariate analysis. Multivariable linear regression model was then developed to further explain the effect of neonatal factors on these primitive cell counts. RESULTS: From a total of 106 recruited subjects, gender of the neonate did not have any influence on the expression of these proteins (CD34 and CD90) of cord blood stem cells or progenitors. Multi variable linear regression analysis using CD34+ and CD90+ cell counts as dependent variables revealed that birth weight and the mode of delivery were significant predictors of these cell counts. CONCLUSIONS: The present study suggests that birth weight and mode of delivery of the neonates influences cord blood stem cell yield. PMID- 26245657 TI - Old and New Drugs for Treatment of Stable Angina. PMID- 26245656 TI - Immunohistochemical expression of 8-oxo-7,8-dihydro-2'-deoxyguanosine in cytoplasm of tumour and adjacent normal mucosa cells in patients with colorectal cancer. AB - BACKGROUND: The aim of this research was to study the levels of 8-oxo-7,8-dihydro 2'-deoxyguanosine (8-oxodG) in tumour tissue samples of colorectal carcinoma based upon immunohistochemical detection and compare those results with patients' outcome. METHODS: Tumour blocks of patients surgically treated for colorectal cancer were evaluated by 8-oxodG immunohistochemical staining. The expression was analysed in 500 tumour cells. The percentage of positive cells, as well as staining intensity, was recorded, and Allred score was calculated. For each patient, data of age, gender, tumour size and location, margin status, histologic grade, tumour stage, lymph node status, vascular invasion, overall survival, and therapy protocols were collected. Tumour grade was divided into two groups as low and high grade. RESULTS: In this study, 146 consecutive patients with primary colorectal carcinoma were included. All data were available for 138 patients, and they were included in this research. There were 83 male and 55 female patients; the median age was 64 years (range 35-87 years). The results showed shorter 5- and 10-year survival in patients with 8-oxodG positive tumour cells (5-year survival, n=138, Mantel-Cox, chi-square 4.116, degree of freedom (df)=1, p<0.05; 10-year survival, n=134, Mantel-Cox, chi-square 4.374, df=1, p<0.05). The results showed a positive correlation between Allred score and high tumour grade (two tailed Spearman's rho 0.184; p<0.05), as well as with non-polypoid tumour growth (two-tailed Spearman's rho 0.198; p<0.05). There was no significant difference of 8-oxodG expression related to age, sex, blood group, size and tumour site, distance from the edge of the resected tumour margin, lymph nodes involvement, and vascular invasion. CONCLUSIONS: In this study, the positive correlation between 8-oxodG presence in the tumour cells, worse clinical outcome, higher tumour grade, and flat morphology was found. PMID- 26245658 TI - Ranolazine and its Antiarrhythmic Actions. AB - Ranolazine, a newly introduced, FDA-approved antianginal agent, has more recently been shown to have additional beneficial antiarrhythmic actions attributed to its inhibitory effect on both peak and late sodium current. The first clinical evidence of ranolazine's antiarrhythmic efficacy has been provided by the MERLIN TIMI 36 trial, which showed that ranolazine may suppress both supraventricular and ventricular arrhythmias in patients with non-ST-segment elevation acute coronary syndrome. An interesting observation of available studies is that ranolazine seems to be more effective in pathological conditions, such as heart failure, ischemia, tachyarrhythmias or long QT3 syndrome, and has little effect on normal myocytes. Importantly, the drug may have an antiarrhythmic effect without causing proarrhythmia. The mechanisms involved in the antiarrhythmic action of ranolazine, experimental and clinical data for its antiarrhythmic efficacy in suppressing atrial fibrillation and ventricular tachyarrhythmias, are herein reviewed. Current data from small randomized trials indicate that further larger randomized controlled trials are needed that will examine the antiarrhythmic effects of ranolazine and its potential use in patients with arrhythmias. PMID- 26245659 TI - Current Status of Antiplatelet Therapy in Acute Coronary Syndrome. AB - Antiplatelet therapy is a first-line medical treatment for patients with acute coronary syndrome (ACS). As percutaneous coronary interventions (PCI) increase in number and complexity, more patients must be treated with antiplatelet therapy for cardiovascular diseases in which arterial thrombosis plays a major role. Current anti-platelet therapy is highly effective in preventing atherothrombotic complications. Nevertheless, a significant number of patients continue to experience recurrent complications despite being properly treated, due to pharmacokinetics and interactions of drugs, genetic background and increased thrombus formation. This has lead to big research efforts to provide new antiplatelet drugs with better preventive properties without increased bleeding risk. Up to 8% of patients receiving 81 mg-dose of aspirin have significantly less platelet inhibition than those receiving higher dose. Patients with poor responsiveness to clopidogrel are at high risk of thromboembolic complications, especially in the setting of ACS and stent implantation. Several options have been proposed. Firstly, to increase loading and maintenance doses up to 600 mg and 75-mg twice daily associated with high-dose aspirin (300-325 mg). A second option would be to change from clopidogrel to new antiplatelet agents like prasugrel and ticagrelor which were investigated in large clinical trials in patients with different entities of ACS. Because of conflicting results & without large scale clinical studies, routine platelet function measurement cannot be recommended at this point of time. Prasugrel is an ADP-P2Y12 receptor inhibitor that has a faster and more consistent inhibitory effect of platelet aggregation and was shown to reduce cardiovascular mortality in the setting of ACS undergoing PCI. Subgroups with increased risk of bleeding were patients with prior stroke, age over 75 and body weight under 60 kg. In this population, prasugrel is discouraged despite its increased in efficacy. Ticagrelor binds reversibly to P2Y12 receptor. The reversibility action makes it attractive for situations when dual antiplatelet therapy needs to be interrupted. Both the drugs demonstrated superiority with respect to the primary composite endpoint. As compared to clopidogrel, both prasugrel and ticagrelor do not depend on loss-of-function genetic variants. The efficacy safety ratio of both compared to clopidogrel is better, even if both these compounds increased the risk of spontaneous major bleedings significantly. Due to lack of head-to-head comparison, potential differences between prasugrel and ticagrelor are hypothetical and both these drugs should be used according to guidelines. The novel intravenous antiplatelet cangrelor cut thrombotic complications of PCI with some increase in bleeding, a pooled analysis of the three CHAMPION(Cangrelor versus Standard Therapy to Achieve Optimal management of Platelet Inhibition) trials showed. Protease activated-receptor 1(PAR 1) antagonist vorapaxar did not reduce the primary composite ischemic end point in TRACER (Thrombin Receptor Antagonist Clinical Event reduction in acute coronary syndrome) trial, but major bleeding and intracranial hemorrhage rates were substantially increased. Further large randomized trials would be required to decide the superiority of one agent over another and the duration of the therapy. PMID- 26245660 TI - Systemic Hypertension in Patients with Aortic Stenosis: Clinical Implications and Principles of Pharmacological Therapy. AB - The treatment of systemic hypertension (HTN) in patients with Aortic stenosis (AS) requires a careful balance of lowering the systemic blood pressure without compromising vital organ perfusion and worsening of the symptoms of AS. Treatment of systemic HTN is beneficial because the combination of HTN and AS provides additional overload to the left ventricle. This leads to secondary Left ventricular hypertrophy (LVH), which has been shown to increase cardiovascular risks and mortality and thus early presentation of symptoms of AS. Additionally, presence of HTN may affect the accurate assessment of AS. Different treatment options are available, however no specific treatment guidelines have been established for patients with concomitant AS and HTN. Improved control of HTN is the key to prevent symptom progression and inadvertent early surgery. Angiotensin converting enzyme inhibitors (ACEi) and Angiotensin receptor blockers (ARB) appear to be beneficial. Reassessment of the aortic valve by echocardiography is recommended after HTN is well controlled before deciding on aortic valve replacement (AVR). PMID- 26245661 TI - Calcium Channel Blockers--Benefits Upon Vascular Biology in Hypertensive Patients. AB - Calcium channel blockers (CCB) are widely used in cardiovascular medicine expressing high hopes upon decreasing cardiovascular risk, morbidity and mortality. Here, the potency of CCBs on 58 Romanian asymptomatic hypertensive patients, with no atherothrombotic cardiovascular disease, was studied by clinical and in silico methods. In our study, arterial elasticity/stiffness was assessed; anthropometric, metabolic (lipidic) parameters were quantified. We concluded that lercanidipine 10 mg once daily, during three weeks, is able to dramatically improve central aortic systolic blood pressure, aortic pulse wave velocity. Lipid profile improvement is an essential condition to improve elastic vascular properties in order to decrease the risk for further cardiovascular events. Besides, the potency of lercanidipine is expressed as the contribution of molecular descriptors (van der Waals and solvent accessible surface areas), electronic (molecular polarisability) and hydrophobic (water/octanol partition coefficient) by means of blocker effect on calcium channel, compared with cilnidipine and other 30 dihydropyridines, using molecular simulation techniques. PMID- 26245662 TI - First Comprehensive Analysis of Outcomes in Adult Patients after Percutaneous Closure of Isolated Secundum Atrial Septal Defects. AB - BACKGROUND: Secundum atrial septal defect (ASD) is a common congenital heart defect in adults. If untreated, ASD leads to right ventricular (RV) failure, atrial arrhythmias, and pulmonary hypertension. The aim of this study is to analyze published data on outcomes and complications of percutaneous ASD closure in adults. METHODS: PubMed searches performed for published literature on percutaneous ASD closure using the terms ASD, ASD closure or repair, and percutaneous or transcatheter closure. RESULTS: A total of 23 studies, 1958 patients, were analyzed. Baseline characteristics showed mean age of 49.1 +/- 1.7 years, Qp:Qs of 2.2 +/- 0.05, defect size 19.4 +/- 1 and device size 24.0 +/- 0.7. The percentage of patients in NYHA class I, II and III was 42.4 +/- 6.3, 40.0 +/- 6.5, and 9.3 +/- 3.0, respectively. Mean follow-up was 12.6 +/- 4.9 months with a closure rate of 96.9% +/- 1.4. Echocardiographic parameters of improvement included decrease in RV volume from 157.2 to 100.2 mL (p = 0.02), RV end-diastolic dimensions from 40.8 to 32.4 mm (p < 0.0001) and pulmonary artery systolic pressures from 42.2+/-2.2 to 34.4+/-2.4 (p < 0.0001). The percentage of patients in NYHA class II and III decreased from 55+/-7.5 to 15.9+/-4.4 (p = 0.0013). At the end of follow-up, complications included 1% mortality rate, 0.8% device embolization, 5.8% new onset arrhythmias and 1.2% need for surgical closure. CONCLUSION: Our study confirms that percutaneous ASD closure in adults with moderate pulmonary hypertension and RV dilation is safe and effective with reverse remodeling and better functional capacity. Prospective studies are needed to evaluate efficacy of percutaneous ASD closure in adults with large defects, higher shunt ratios, and severe pulmonary hypertension. PMID- 26245663 TI - Factual errors in article on doctors and Islamic State. PMID- 26245664 TI - Editorial Commentary: Plethora of Respiratory Viruses and Respiratory Virus Data. PMID- 26245665 TI - Community Surveillance of Respiratory Viruses Among Families in the Utah Better Identification of Germs-Longitudinal Viral Epidemiology (BIG-LoVE) Study. AB - BACKGROUND: This study: (1) describes the viral etiology of respiratory illness by prospectively collecting weekly symptom diaries and nasal swabs from families for 1 year, (2) analyzed data by reported symptoms, virus, age, and family composition, and (3) evaluated the duration of virus detection. METHODS: Twenty six households (108 individuals) provided concurrent symptom and nasal swab data for 4166 person-weeks. The FilmArray polymerase chain reaction (PCR) platform (BioFire Diagnostics, LLC) was used to detect 16 respiratory viruses. Viral illnesses were defined as >=1 consecutive weeks with the same virus detected with symptoms reported in >=1 week. RESULTS: Participants reported symptoms in 23% and a virus was detected in 26% of person-weeks. Children younger than 5 years reported symptoms more often and were more likely to have a virus detected than older participants (odds ratio [OR] 2.47, 95% confidence interval [CI], 2.08-2.94 and OR 3.96, 95% CI, 3.35-4.70, respectively). Compared with single person households, individuals living with children experienced 3 additional weeks of virus detection. There were 783 viral detection episodes; 440 (56%) associated with symptoms. Coronaviruses, human metapneumovirus, and influenza A detections were usually symptomatic; bocavirus and rhinovirus detections were often asymptomatic. The mean duration of PCR detection was <=2 weeks for all viruses and detections of >=3 weeks occurred in 16% of episodes. Younger children had longer durations of PCR detection. CONCLUSIONS: Viral detection is often asymptomatic and occasionally prolonged, especially for bocavirus and rhinovirus. In clinical settings, the interpretation of positive PCR tests, particularly in young children and those who live with them, may be confounded. PMID- 26245666 TI - Sublethal dose of irradiation enhances invasion of malignant glioma cells through p53-MMP 2 pathway in U87MG mouse brain tumor model. AB - BACKGROUND: Glioblastoma is a highly lethal neoplasm that frequently recurs locally after radiotherapy, and most of these recurrences originate from near the irradiated target field. In the present study, we identified the effects of radiation on glioma invasion and p53, TIMP-2, and MMP-2 expression through in vitro and in vivo experiments. METHODS: The U87MG (wt p53) and U251 (mt p53) human malignant glioma cell lines were prepared, and the U2OS (wt 53) and Saos2 (del p53) osteosarcoma cell lines were used as p53 positive and negative controls. The four cell lines and p53 knock-downed U87MG cells received radiation (2-6 Gy) and were analyzed for expression of p53 and TIMP-2 by Western blot, and MMP-2 activity was detected by zymography. In addition, the effects of irradiation on directional invasion of malignant glioma were evaluated by implanting nude mice with bioluminescent u87-Fluc in vivo followed by MMP-2, p53, and TIMP-2 immunohisto-chemistry and in situ zymography. RESULTS: MMP-2 activity and p53 expression increased in proportional to the radiation dose in cell lines with wt p53, but not in the cell lines with del or mt p53. TIMP-2 expression did not increase in U87MG cells. MMP-2 activity decreased in p53 knock-downed U87MG cells but increased in the control group. Furthermore, radiation enhanced MMP-2 activity and increased tumor margin invasiveness in vivo. Tumor cells invaded by radiation overexpressed MMP-2 and p53 and revealed high gelatinolytic activity compared with those of non-radiated tumor cells. CONCLUSION: Radiation-induced upregulation of p53 modulated MMP-2 activity, and the imbalance between MMP-2 and TIMP-2 may have an important role in glioblastoma invasion by degrading the extracellular matrix. Bioluminescent "U87-Fluc"was useful for observing tumor formation without sacrifice after implanting tumor cells in the mouse brain. These findings suggest that the radiotherapy involved field for malignant glioma needs to be reconsidered, and that future trials should investigate concurrent pharmacologic therapies that inhibit invasion associated with radiotherapy. PMID- 26245667 TI - Cultivating duty of candour requires organisational leadership and culture. PMID- 26245668 TI - Inhibition of protein kinase C by isojacareubin suppresses hepatocellular carcinoma metastasis and induces apoptosis in vitro and in vivo. AB - Targeted inhibition of protein kinase C (PKC) inhibits hepatocellular carcinoma (HCC) proliferation and metastasis. We previously reported the cytotoxicity of a series of synthetic phenyl-substituted polyoxygenated xanthone derivatives against human HCC. In the current study, the most potent natural product, isojacareubin (ISJ), was synthesized, and its cellular-level antihepatoma activities were evaluated. ISJ significantly inhibited cell proliferation and was highly selective for HCC cells in comparison to nonmalignant QSG-7701 hepatocytes. Moreover, ISJ exhibited pro-apoptotic effects on HepG2 hepatoma cells, as well as impaired HepG2 cell migration and invasion. Furthermore, ISJ was a potent inhibitor of PKC, with differential actions against various PKC isotypes. ISJ selectively inhibited the expression of aPKC (PKCzeta) in the cytosol and the translocation of cytosolic PKCzeta to membrane site. ISJ also directly interacted with cPKC (PKCalpha) and nPKC (PKCdelta, PKCepsilon and PKCMU) and thereby inhibited the early response of major MAPK phosphorylation and the late response of HCC cell invasion and proliferation. In a hepatoma xenograft model, ISJ pretreatment resulted in significant antihepatoma activity in vivo. These findings identify ISJ as a promising lead compound for the development of new antihepatoma agents and may guide the search for additional selective PKC inhibitors. PMID- 26245669 TI - The Bounds Of Education In The Human Brain Connectome. AB - Inter-individual heterogeneity is evident in aging; education level is known to contribute for this heterogeneity. Using a cross-sectional study design and network inference applied to resting-state fMRI data, we show that aging was associated with decreased functional connectivity in a large cortical network. On the other hand, education level, as measured by years of formal education, produced an opposite effect on the long-term. These results demonstrate the increased brain efficiency in individuals with higher education level that may mitigate the impact of age on brain functional connectivity. PMID- 26245670 TI - [Osteosynthesis of Weber B ankle fractures using the one-third tubular plate and refixation of the syndesmosis]. AB - OBJECTIVE: Anatomical reconstruction and recovery to complete range of function of the upper ankle joint. Therefore, the most stable but least invasive osteosynthesis is required to enable the patient early functional mobilization. INDICATION: Supination and pronation fracture with luxation mechanism of the upper ankle joint with or without rupture of the syndesmosis. Open fracture of the distal fibula including displaced and instable fractures. CONTRAINDICATION: Severe peripheral arterial occlusive disease; contaminated open fractures (>= 2nd degree); pediatric fractures with open epiphyseal plate. SURGICAL TECHNIQUE: Supine position with ipsilateral slightly elevated hip and knee. Incision of about 8 cm length along the dorsal edge of the distal fibula. When reaching the lateral malleolus, a slight ventral angulation is necessary. Open reduction through this posterolateral approach. Secure the reposition using an interfragmentary lag screw and anatomically adjusted third tubular plate. Followed by a revision of the syndesmosis and transfixation using a tricortical position screw. POSTOPERATIVE MANAGEMENT: Mobilization on day 1 after surgery with reduced weight-bearing when position screw is not applied; when position screw is implanted with ground contact for 6 weeks. Removal of position screw under local anesthesia after 6 weeks and pain-controlled full weight-bearing. Removal of metal after 1.5 years. RESULTS: Open reduction using the third tubular plate and an interfragmentary lag screw through a dorsolateral approach used in 90 % of all Weber B fractures in our clinic. Additional revision of a ruptured syndesmosis performed in 70 % and transfixation through a position screw in 40 %. Persisting instability in the upper ankle joint significantly reduced after surgical treatment compared to a conservative approach. Revisions necessary in 3.7 % of patients and pseudarthrosis diagnosed in 0.9 %. It has been shown that the preoperative x-ray and clinical examination is limited in detecting a ruptured syndesmosis. PMID- 26245672 TI - Aspirin for primary prevention in diabetes mellitus: from the calculation of cardiovascular risk and risk/benefit profile to personalised treatment. AB - Type 2 diabetes mellitus is characterised by persistent thromboxane (TX) dependent platelet activation, regardless of disease duration. Low-dose aspirin, that induces a permanent inactivation of platelet cyclooxygenase (COX)-1, thus inhibiting TXA2 biosynthesis, should be theoretically considered the drug of choice. The most up-to-date meta-analysis of aspirin prophylaxis in this setting, which includes three trials conducted in patients with diabetes and six other trials in which such patients represent a subgroup within a broader population, reported that aspirin is associated with a non-significant decrease in the risk of vascular events, although the limited amount of available data precludes a precise estimate of the effect size. An increasing body of evidence supports the concept that less-than-expected response to aspirin may underlie mechanisms related to residual platelet hyper-reactivity despite anti-platelet treatment, at least in a fraction of patients. Among the proposed mechanisms, the variable turnover rate of the drug target (platelet COX-1) appears to represent the most convincing determinant of the inter-individual variability in aspirin response. This review intends to develop the idea that the understanding of the determinants of less-than-adequate response to aspirin in certain individuals, although not changing the paradigm of the indication to low-dose aspirin prescription in primary prevention, may help identifying, in terms of easily detectable clinical or biochemical characteristics, individuals who would attain inadequate protection from aspirin, and for whom different strategies should be challenged. PMID- 26245673 TI - Challenges Associated with Route of Administration in Neonatal Drug Delivery. AB - The administration of drugs to neonates poses significant challenges. The aim of this review was to provide insight into some of these challenges and resolutions that may be encountered with several of the most commonly used routes of administration and dosage forms in neonatal care, including oral, parenteral, transdermal, intrapulmonary, and rectal. Important considerations include fluctuations in stomach pH hours to years after birth, the logistics of setting up an intravenous infusion, the need for reduced particle size for aerosol delivery to the developing neonatal lung, and variation in perirectal venous drainage. Additionally, some of the recently developed technologies for use in neonatal care are described. While the understanding of neonatal drug delivery has advanced over the past several decades, there is still a deficiency of technologies and formulations developed specifically for this population. PMID- 26245674 TI - Prognosis and Clinicopathologic Features of Patients With Advanced Stage Isocitrate Dehydrogenase (IDH) Mutant and IDH Wild-Type Intrahepatic Cholangiocarcinoma. AB - BACKGROUND: Conflicting data exist regarding the prognostic impact of the isocitrate dehydrogenase (IDH) mutation in intrahepatic cholangiocarcinoma (ICC), and limited data exist in patients with advanced-stage disease. Similarly, the clinical phenotype of patients with advanced IDH mutant (IDHm) ICC has not been characterized. In this study, we report the correlation of IDH mutation status with prognosis and clinicopathologic features in patients with advanced ICC. METHODS: Patients with histologically confirmed advanced ICC who underwent tumor mutational profiling as a routine part of their care between 2009 and 2014 were evaluated. Clinical and pathological data were collected by retrospective chart review for patients with IDHm versus IDH wild-type (IDHwt) ICC. Pretreatment tumor volume was calculated on computed tomography or magnetic resonance imaging. RESULTS: Of the 104 patients with ICC who were evaluated, 30 (28.8%) had an IDH mutation (25.0% IDH1, 3.8% IDH2). The median overall survival did not differ significantly between IDHm and IDHwt patients (15.0 vs. 20.1 months, respectively; p = .17). The pretreatment serum carbohydrate antigen 19-9 (CA19-9) level in IDHm and IDHwt patients was 34.5 and 118.0 U/mL, respectively (p = .04). Age at diagnosis, sex, histologic grade, and pattern of metastasis did not differ significantly by IDH mutation status. CONCLUSION: The IDH mutation was not associated with prognosis in patients with advanced ICC. The clinical phenotypes of advanced IDHm and IDHwt ICC were similar, but patients with IDHm ICC had a lower median serum CA19-9 level at presentation. IMPLICATIONS FOR PRACTICE: Previous studies assessing the prognostic impact of the isocitrate dehydrogenase (IDH) gene mutation in intrahepatic cholangiocarcinoma (ICC) mainly focused on patients with early-stage disease who have undergone resection. These studies offer conflicting results. The target population for clinical trials of IDH inhibitors is patients with unresectable or metastatic disease, and the current study is the first to focus on the prognosis and clinical phenotype of this population and reports on the largest cohort of patients with advanced IDH mutant ICC to date. The finding that the IDH mutation lacks prognostic significance in advanced ICC is preliminary and needs to be confirmed prospectively in a larger study. PMID- 26245675 TI - Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2-Positive Breast Cancer. AB - BACKGROUND: The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete remission (pCR) rate compared with chemotherapy plus either trastuzumab or lapatinib. A biomarker program was prospectively planned to identify potential predictors of sensitivity to different treatments and to evaluate treatment effect on tumor biomarkers. MATERIALS AND METHODS: Overall, 121 breast cancer patients positive for human epidermal growth factor 2 (HER2) were randomly assigned to neoadjuvant chemotherapy plus trastuzumab, lapatinib, or both trastuzumab and lapatinib. Pre- and post-treatment samples were centrally evaluated for HER2, p95-HER2, phosphorylated AKT (pAKT), phosphatase and tensin homolog, Ki67, apoptosis, and PIK3CA mutations. Fresh-frozen tissue samples were collected for genomic analyses. RESULTS: A mutation in PIK3CA exon 20 or 9 was documented in 20% of cases. Overall, the pCR rates were similar in PIK3CA wild type and PIK3CA-mutated patients (33.3% vs. 22.7%; p = .323). For patients receiving trastuzumab plus lapatinib, the probability of pCR was higher in PIK3CA wild-type tumors (48.4% vs. 12.5%; p = .06). Ki67, pAKT, and apoptosis measured on the residual disease were significantly reduced from baseline. The degree of Ki67 inhibition was significantly higher in patients receiving the dual anti-HER2 blockade. The integrated analysis of gene expression and copy number data demonstrated that a 50-gene signature specifically predicted the lapatinib induced pCR. CONCLUSION: PIK3CA mutations seem to identify patients who are less likely to benefit from dual anti-HER2 inhibition. p95-HER2 and markers of phosphoinositide 3-kinase pathway deregulation are not confirmed as markers of different sensitivity to trastuzumab or lapatinib. IMPLICATIONS FOR PRACTICE: HER2 is currently the only validated marker to select breast cancer patients for anti-HER2 treatment; however, it is becoming evident that HER2-positive breast cancer is a heterogeneous disease. In addition, more and more new anti-HER2 treatments are becoming available. There is a need to identify markers of sensitivity to different treatments to move in the direction of treatment personalization. This study identified PIK3CA mutations as a potential predictive marker of resistance to dual anti-HER2 treatment that should be further studied in breast cancer. PMID- 26245676 TI - Perspectives of Medical Specialists on Sharing Decisions in Cancer Care: A Qualitative Study Concerning Chemotherapy Decisions With Patients With Recurrent Glioblastoma. AB - BACKGROUND: In cancer care, difficult decisions concerning advanced treatment need to be made, weighing possible life prolongation against harmful side effects. Treatment is frequently started, showing the need to explore how decisions are made. Little is known about the perspectives of physicians on sharing decision making with patients. This qualitative study aimed to describe the perspectives of medical specialists on the decision-making process with patients with glioblastoma concerning starting new treatment. METHODS: Qualitative interviews were held with medical specialists. One focus group was organized with medical professionals. Their opinions about elements of shared decision making and the applicability in the context of patients with glioblastoma were assessed. The topic list for the focus group was based on the analysis of the interviews. Qualitative analysis of the transcripts was performed by three researchers independently. RESULTS: Medical specialists considered shared decision making to be important; however, they did not adhere to its elements. Stopping treatment was not considered equal to continuing treatment. Exploration of the patients' wishes was done implicitly, and shared responsibility for the decision was not highly recognized. The main barriers to shared decision making were preferences of both patients and specialists for starting or continuing treatment and assumptions of physicians about knowing what patients want. CONCLUSION: Medical specialists recognized the importance of patient involvement but experienced difficulty in sharing decision making in practice. Elements of shared decision making are partly followed but do not guide decision making. To improve cancer care, education of medical specialists and adjustment to the elements are needed to involve patients. PMID- 26245677 TI - Highly Conserved Mitochondrial Genomes among Multicellular Red Algae of the Florideophyceae. AB - Two red algal classes, the Florideophyceae (approximately 7,100 spp.) and Bangiophyceae (approximately 193 spp.), comprise 98% of red algal diversity in marine and freshwater habitats. These two classes form well-supported monophyletic groups in most phylogenetic analyses. Nonetheless, the interordinal relationships remain largely unresolved, in particular in the largest subclass Rhodymeniophycidae that includes 70% of all species. To elucidate red algal phylogenetic relationships and study organelle evolution, we determined the sequence of 11 mitochondrial genomes (mtDNA) from 5 florideophycean subclasses. These mtDNAs were combined with existing data, resulting in a database of 25 florideophytes and 12 bangiophytes (including cyanidiophycean species). A concatenated alignment of mt proteins was used to resolve ordinal relationships in the Rhodymeniophycidae. Red algal mtDNA genome comparisons showed 47 instances of gene rearrangement including 12 that distinguish Bangiophyceae from Hildenbrandiophycidae, and 5 that distinguish Hildenbrandiophycidae from Nemaliophycidae. These organelle data support a rapid radiation and surprisingly high conservation of mtDNA gene syntheny among the morphologically divergent multicellular lineages of Rhodymeniophycidae. In contrast, we find extensive mitochondrial gene rearrangements when comparing Bangiophyceae and Florideophyceae and multiple examples of gene loss among the different red algal lineages. PMID- 26245679 TI - Enzymatic synthesis and modification of structured phospholipids: recent advances in enzyme preparation and biocatalytic processes. AB - Phospholipids (PLs) containing specific polar head groups and fatty acids, artificially synthesized from a complex mixture of natural PLs, have considerable industrial applications. The biocatalytic approaches to synthesizing structured PLs are of great interest because the enzymes used show high selectivity and performance under mild conditions, leading to the generation of products that cannot easily be obtained by chemical catalysis. Although the limited supply of phospholipases (e.g., phospholipase D) has thus far been an obstacle to the widespread use of enzymatic processing, recent advances in enzyme preparation have opened up various applications for PL modification. In this review, attempts to increase the productivity and utility of microbial phospholipases and lipases are presented. We also summarize recent developments in enzyme-catalyzed modification of PLs, focusing particularly on the relevant reactions, bioreactor design, and novel proof-of-concept experiments. PMID- 26245680 TI - A single-plasmid vector for transgene amplification using short hairpin RNA targeting the 3'-UTR of amplifiable dhfr. AB - Gene amplification using dihydrofolate reductase gene (dhfr) and methotrexate (MTX) is widely used for recombinant protein production in mammalian cells and is typically conducted in DHFR-deficient Chinese hamster ovary (CHO) cell lines. Generation of DHFR-deficient cells can be achieved by an expression vector incorporating short hairpin RNA (shRNA) that targets the 3'-untranslated region (UTR) of endogenous dhfr. Thus, shRNAs were designed to target the 3'-UTR of endogenous dhfr, and shRNA-2 efficiently down-regulated dhfr expression in CHO-K1 cells. A single gene copy of shRNA-2 also decreased the translational level of DHFR by 80% in Flp-In CHO cells. shRNA-2 was then incorporated into a plasmid vector expressing human erythropoietin (EPO) and an exogenous DHFR to develop EPO producing cells in the Flp-In system. The specific EPO productivity (q EPO) was enhanced by stepwise increments of MTX concentration, and differences in the amplification rate were observed in Flp-In CHO cells that expressed shRNA-2. In addition, the q EPO increased by more than 2.5-fold in the presence of 500 nM MTX. The mRNA expression level and gene copy numbers of dhfr were correlated with increased productivity in the cells, which is influenced by inhibition of endogenous dhfr. This study reveals that an expression vector including shRNA that targets the 3'-UTR of endogenous dhfr can enhance the transgene amplification rate and productivity by generating DHFR-deficient cells. This approach may be applied for amplifying the foreign gene in wild-type cell lines as a versatile single-plasmid vector. PMID- 26245678 TI - Effect of bacterial and host factors on Helicobacter pylori eradication therapy. AB - INTRODUCTION: A clearer understanding of the factors affecting the cure rate of Helicobacter pylori infection might lead to the development of novel prevention strategies and therapeutic targets. AREAS COVERED: This review covers two important issues that affect the eradication of H. pylori: bacterial and host factors. Several virulence factors have been shown to be predictors for gastroduodenal diseases. Successful treatment of H. pylori infection also depends on host genetic factors such as CYP2C19 and IL-1B. The latest evidence on host genetic factors is discussed. EXPERT OPINION: The authors identify three main targets for achieving effective eradication therapy. The first therapeutic target is to identify counter measures for antibiotic-resistant H. pylori strains. Thus, antibiotic susceptibility should be checked in all patients, ideally, before the start of eradication treatment. The second therapeutic target is the inhibition of acid suppression. Maintaining a high intragastric pH for 24 h increases the effectiveness of some antibiotics and the eradication effects for H. pylori. The third therapeutic target is to identify high-risk groups; the CYP2C19 and IL-1B polymorphisms are candidates for significant risk factors. A personalized medical approach will likely increase the cure rate of H. pylori infection. PMID- 26245681 TI - From mesophilic to thermophilic digestion: the transitions of anaerobic bacterial, archaeal, and fungal community structures in sludge and manure samples. AB - The shift of microbial communities during a transition from mesophilic anaerobic digestion (MAD) to thermophilic anaerobic digestion (TAD) was characterized in two treatments. One treatment was inoculated with sludge and the other was inoculated with manure. In this study, methane was produced both in MAD and TAD, but TAD has slightly more methane produced than MAD. A broad phylogenetic spectrum of bacterial, archaeal, and fungal taxa at thermophilic conditions was detected. Coprothermobacter, Bacillus, Haloplasma, Clostridiisalibacter, Methanobacterium, Methanothermobacter, Saccharomycetales, Candida, Alternaria, Cladosporium, and Penicillium were found almost exclusively in TAD, suggesting their adaptation to thermophilic conditions and ecological roles in digesting the organic compounds. The characterization of the lesser-known fungal community revealed that fungi probably constituted an important portion of the overall community within TAD and contributed to this process by degrading complex organic compounds. The shift of the microbial communities between MAD and TAD implied that temperature drastically affected the microbial diversity in anaerobic digestion. In addition, the difference in microbial communities between sludge and manure indicated that different source of inoculum also affected the microbial diversity and community. PMID- 26245683 TI - Involvement of quorum sensing genes in biofilm development and degradation of polycyclic aromatic hydrocarbons by a marine bacterium Pseudomonas aeruginosa N6P6. AB - Biofilm-forming and acyl homoserine lactone (AHL) synthase-positive Pseudomonas aeruginosa N6P6 was isolated from seawater after selective enrichment with two polycyclic aromatic hydrocarbons (PAHs), viz. phenanthrene and pyrene. AHL synthesis was detected qualitatively using bioreporter strains. This marine bacterium putatively synthesized N-(3-oxododecanoyl)-L-homoserine lactone and N butyryl-L-homoserine lactone, which were identified by TLC, GC-MS, and HPLC. Two quorum sensing (QS) genes coding for AHL synthase, i.e., lasI and rhlI, were identified in the bacterium. lasI and rhlI gene expression was studied during biofilm mode of growth at different phases using quantitative real-time PCR (qRT PCR). The expression of lasI increased with increase in biofilm growth. In contrast, the expression of rhlI decreased during log phase of biofilm growth. The changes in lasI/rhlI expression level had significant effects (P<0.05) on biofilm architecture and subsequent PAH degradation rate. Degradation of phenanthrene and pyrene by P. aeruginosa N6P6 was affected by biofilm growth and lasI expression. The respective phenanthrene degradation for 15, 24, 48, and 72 h old biofilm after 7 days was 21.5, 54.2, 85.6, and 85.7%. However, the corresponding pyrene degradation was 15, 18.28, 47.56, and 46.48%, respectively, after 7 days. A significant positive correlation (P<0.05) was observed between lasI expression and PAHs degradation. However, in the presence of tannic acid, a QS inhibitor (QSI), PAHs degradation, biofilm formation, and pyocyanin production reduced significantly which confirmed the pivotal role of QS in biodegradation of PAHs. The findings suggest that AHLs play a pivotal role during biofilm development and subsequent bioremediation of PAHs. PMID- 26245682 TI - Phage-protease-peptide: a novel trifecta enabling multiplex detection of viable bacterial pathogens. AB - Bacteriophages represent rapid, readily targeted, and easily produced molecular probes for the detection of bacterial pathogens. Molecular biology techniques have allowed researchers to make significant advances in the bioengineering of bacteriophage to further improve speed and sensitivity of detection. Despite their host specificity, bacteriophages have not been meaningfully leveraged in multiplex detection of bacterial pathogens. We propose a proof-of-principal phage based scheme to enable multiplex detection. Our scheme involves bioengineering bacteriophage to carry a gene for a specific protease, which is expressed during infection of the target cell. Upon lysis, the protease is released to cleave a reporter peptide, and the signal detected. Here we demonstrate the successful (i) modification of T7 bacteriophage to carry tobacco etch virus (TEV) protease; (ii) expression of TEV protease by Escherichia coli following infection by our modified T7, an average of 2000 units of protease per phage are produced during infection; and (iii) proof-of-principle detection of E. coli in 3 h after a primary enrichment via TEV protease activity using a fluorescent peptide and using a designed target peptide for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis (MALDI-TOF MS) analysis. This proof-of principle can be translated to other phage-protease-peptide combinations to enable multiplex bacterial detection and readily adopted on multiple platforms, like MALDI-TOF MS or fluorescent readers, commonly found in labs. PMID- 26245684 TI - Identification and biochemical characterization of a novel endo-type beta-agarase AgaW from Cohnella sp. strain LGH. AB - An agar-degrading bacterium, strain LGH, was isolated and identified as Cohnella sp. This strain had a capability of utilizing agar as a sole carbon source for growth and showed a strong agarolytic activity. A novel endo-type beta-agarase gene agaW, encoding a primary translation product of 891 amino acids, including a 26 amino acid signal peptide, was cloned and identified from a genomic library of strain LGH. The AgaW belonged to the glycoside hydrolase (GH) GH50 family, with less than 39% amino acid sequence similarity with any known protein, and hydrolyzed agarose into neoagarotetraose as the major end product and neoagarobiose as the minor end product through other neoagarooligosaccharide intermediates, such as neoagarohexaose. PMID- 26245685 TI - Sponge-associated actinobacterial diversity: validation of the methods of actinobacterial DNA extraction and optimization of 16S rRNA gene amplification. AB - Experiments were designed to validate the two common DNA extraction protocols (CTAB-based method and DNeasy Blood & Tissue Kit) used to effectively recover actinobacterial DNA from sponge samples in order to study the sponge-associated actinobacterial diversity. This was done by artificially spiking sponge samples with actinobacteria (spores, mycelia and a combination of the two). Our results demonstrated that both DNA extraction methods were effective in obtaining DNA from the sponge samples as well as the sponge samples spiked with different amounts of actinobacteria. However, it was noted that in the presence of the sponge, the bacterial 16S rRNA gene could not be amplified unless the combined DNA template was diluted. To test the hypothesis that the extracted sponge DNA contained inhibitors, dilutions of the DNA extracts were tested for six sponge species representing five orders. The results suggested that the inhibitors were co-extracted with the sponge DNA, and a high dilution of this DNA was required for the successful PCR amplification for most of the samples. The optimized PCR conditions, including primer selection, PCR reaction system and program optimization, further improved the PCR performance. However, no single PCR condition was found to be suitable for the diverse sponge samples using various primer sets. These results highlight for the first time that the DNA extraction methods used are effective in obtaining actinobacterial DNA and that the presence of inhibitors in the sponge DNA requires high dilution coupled with fine tuning of the PCR conditions to achieve success in the study of sponge-associated actinobacterial diversity. PMID- 26245686 TI - Symptomatic Control of Neuroendocrine Tumours with Everolimus. AB - Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, increases progression-free survival in patients with advanced neuroendocrine tumours. Patients with neuroendocrine tumours and symptomatic carcinoid have inferior health-related quality of life than those without symptoms. We aimed to evaluate the effect of everolimus on symptomatic control of neuroendocrine tumours. Fifteen patients with metastatic neuroendocrine disease pre-treated with depot octreotide received combination everolimus and octreotide (midgut = 8, pancreatic = 3, other = 4). Reasons for initiation of everolimus were progressive disease (PD) by response evaluation criteria in solid tumours (n = 5), worsening syndromic symptomology (n = 5), or both (n = 5). Symptomatic and objective response and toxicity were evaluated using standard criteria. 7/10 patients who were syndromic had improvements in symptomology, with a mean duration of symptom control 13.9 months (range 1-39). All 10 symptomatic patients had non pancreatic neuroendocrine (pNET) primaries, and with everolimus, 6/10 had reduced stool frequency, 3/7 had a reduction of asthenia, and 5/7 had reduced frequency and severity of flushing. Sixty percent of patients experienced any grade toxicities, including the following: 40% grade 1/2 stomatitis, 7% grade 3/4 stomatitis, 20% grade 1/2 rash, 13% diarrhoea, and one case of pneumonitis. In this cohort of 15 patients, we demonstrated that 70% of non pNET individuals with common carcinoid syndrome symptoms resistant to depot octreotide had improvement in these symptoms on institution of everolimus, with meaningful durations of symptom control. Although this data is observational, to our knowledge, this represents the largest analysis of carcinoid syndrome control with combined everolimus and octreotide. PMID- 26245687 TI - Non-immunoglobulin A mesangial immune complex glomerulonephritis in kidney transplants. AB - We have observed a predominantly mesangial non-immunoglobulin A immune complex mesangial glomerulopathy (MG) in renal transplants with mesangial deposits by immunofluorescence and electron microscopy. Clinicopathological features of 28 patients with MG were analyzed and compared with 28 transplant controls, matched for age, sex, ethnicity, donor type, estimated glomerular filtration rate, and interval from transplant to biopsy. Indications for biopsy in the MG group were allograft dysfunction in 64%, allograft dysfunction/proteinuria in 29%, and proteinuria in 7%. Biopsy indications in controls were allograft dysfunction (61%), allograft dysfunction/proteinuria (18%), proteinuria (14%), and delayed graft function (7%). Most MG cases had mild mesangial hypercellularity with endocapillary proliferation in 2 and crescents in 2 without fibrinoid necrosis. Immunoglobulin M-dominant deposits were present in 83%, and immunoglobulin G was dominant in 17% with mesangial deposits in 93% of cases by electron microscopy. Compared with controls, MG had higher Banff interstitial inflammation score (i) (P = .036) and was associated with concurrent acute T-cell-mediated rejection (P = .023), but not with acute or chronic antibody-mediated rejection. MG patients and controls had similar prevalence of polyomavirus nephropathy and Epstein-Barr virus infection. At follow-up, most MG patients had stable estimated glomerular filtration rate with no or stable proteinuria. Disease-specific graft survival was not different in MG versus controls. We conclude that, in view of the apparent self-limited nature of this lesion, additional treatment may not be required in these patients. Awareness of this lesion may thus spare patients unwarranted further intervention. PMID- 26245688 TI - Evaluating time between birth to cry or bag and mask ventilation using mobile delivery room timers in India: the NICHD Global Network's Helping Babies Breathe Trial. AB - BACKGROUND: The Golden Minute(r), the first minute following birth of a newborn, is a critical period for establishing ventilation after delivery, as emphasized in the Helping Babies Breathe(r) and other resuscitation training programs. Previous studies have reinforced training through observers' evaluation of this time period; although observation is useful for research, it may not be a sustainable method to support resuscitation practice in low-resource settings where few birth attendants are available. In order to reinforce resuscitation within The Golden Minute(r), we sought to develop a simple mobile delivery-room timer on an Android cell phone platform for birth attendants to use at the time of delivery. METHODS: We developed and evaluated a mobile delivery room timer to document the time interval from birth to the initiation of newborn crying/spontaneous respiration or bag and mask ventilation in a convenience sample of women who delivered in five hospitals in Karnataka, India. The mobile delivery room timer is an Android cell phone-based application that recorded key events including crowning, delivery, and crying/spontaneous respiration or bag and mask ventilation. The mobile delivery room timer recorded the birth attendant verbally indicating the time of crowning, birth-(defined as when the entire baby was delivered), crying/spontaneous respiration or bag and mask ventilation. The mobile delivery room timer results were validated in a subsample by a trained observer (nurse) who independently recorded the time between delivery and initiation of crying/spontaneous respiration or bag and mask ventilation. RESULTS: Of the total 4,597 deliveries, 2,107 (46%) were timed; a sample (n = 438) of these deliveries was also observed by a trained nurse. There was high concordance between the mobile delivery room timer and observed time elapsed between birth and crying/spontaneous respiration or ventilation (correlation =0.94, p < 0.0001). The majority of neonates in both groups cried/breathed spontaneously or received bag and mask ventilation by 1 min (430/438 by the timer vs. 433/438 for observer). CONCLUSIONS: We demonstrated that a simple mobile delivery room timer application was feasible to use during delivery and provided valid observations of the time to crying/spontaneous respiration or bag and mask ventilation. This type of tool may be useful in reinforcing neonatal resuscitation training and the need to ensure spontaneous or assisted ventilation by The Golden Minute(r). PMID- 26245690 TI - An Escherichia coli system for evolving improved light-controlled DNA-binding proteins. AB - Light-switchable proteins offer numerous opportunities as tools for manipulating biological systems with exceptional degrees of spatiotemporal control. Most designed light-switchable proteins currently in use have not been optimised using the randomisation and selection/screening approaches that are widely used in other areas of protein engineering. Here we report an approach for screening light-switchable DNA-binding proteins that relies on light-dependent repression of the transcription of a fluorescent reporter. We demonstrate that the method can be used to recover a known light-switchable DNA-binding protein from a random library. PMID- 26245691 TI - BAPX-1/NKX-3.2 acts as a chondrocyte hypertrophy molecular switch in osteoarthritis. AB - OBJECTIVE: Osteoarthritis (OA) development involves a shift of the articular chondrocyte phenotype toward hypertrophic differentiation via still poorly characterized mechanisms. The purpose of this study was to test our hypothesis that the function of BAPX-1/NKX-3.2 is impaired in OA chondrocytes and leads directly to loss of hypertrophic protection of the articular chondrocyte, which is central in the changing chondrocyte phenotype that drives OA. METHODS: Human articular chondrocytes (HACs; from healthy and OA donors) and SW-1353 chondrocytic cells were exposed to bone morphogenetic protein 7 (BMP-7), interleukin-1beta (IL-1beta), tumor necrosis factor, or OA synovial fluid (SF; 20% [volume/volume]). Loss-of-function and gain-of-function experiments for BAPX 1/NKX-3.2 were performed. Mouse experimental models of OA were used, and (immuno)histochemistry of tissue sections was performed. Gene and protein expression of BAPX-1/NKX-3.2 and chondrogenic, hypertrophic, and OA-related mediators were determined by real-time quantitative polymerase chain reaction analysis and immunoblotting. In addition, alkaline phosphatase (AP) activity and prostaglandin E2 levels were measured. RESULTS: BAPX-1/NKX-3.2 expression correlated negatively with expression of chondrocyte hypertrophic markers (RUNX 2, COL10A1, AP), cartilage-degrading enzymes (matrix metalloproteinase 13, ADAMTS 5), and mediators of inflammation (cyclooxygenase 2, IL-6) in healthy and OA chondrocytes, as well as in OA induced chondrocytes. BAPX-1/NKX-3.2 positivity was diminished in articular chondrocytes in the knee joints of mice with experimental OA. Knockdown of BAPX-1/NKX-3.2 in HACs did not influence the expression of SOX9, COL2A1, or aggrecan, but led to an acute hypertrophic shift in the HAC phenotype. Overexpression of BAPX-1/NKX-3.2 decreased hypertrophic gene expression in HACs. Furthermore, the hypertrophic OA chondrocyte phenotype could be counteracted by overexpression of BAPX-1/NKX-3.2 and by BMP-7 in a BAPX 1/NKX-3.2 dependent manner. CONCLUSION: Our findings indicate that BAPX-1/NKX-3.2 is a molecular switch that is involved in controlling the hypertrophic phenotype of the postdevelopmental (OA) articular chondrocyte. PMID- 26245692 TI - A family of molecular sieves containing framework-bound organic structure directing agents. AB - Organic structure-directing agents (OSDAs), such as quaternary ammonium cations and amines, used in the synthesis of zeolites and related crystalline microporous oxides usually end up entrapped inside the void spaces of the crystallized inorganic host lattice. But none of them is known to form direct chemical bonds to the framework of these industrially important catalysts and adsorbents. We demonstrate that ECR-40, currently regarded as a typical silicoaluminophosphate molecular sieve, constitutes instead a new family of inorganic-organic hybrid networks in which the OSDAs are covalently bonded to the inorganic framework. ECR 40 crystallization begins with the formation of an Al-OSDA complex in the liquid phase in which the Al is octahedrally coordinated. This unit is incorporated in the crystallizing ECR-40. Subsequent removal of framework-bound OSDAs generates Al-O-Al linkages in a fully tetrahedrally coordinated framework. PMID- 26245693 TI - Outcome of intravenous recombinant tissue plasminogen activator for acute ischemic stroke in patients aged over 80 years. AB - AIM: Practitioners are faced with a substantial challenge when considering recombinant tissue plasminogen activator (rt-PA) therapy for older patients with ischemic stroke. Patients aged over 80 years suffer from the most severe cerebral infarcts. The benefit of rt-PA treatment compared with single standard care only in stroke units remains to be clearly assessed. METHODS: We collected data from 321 patients aged over 80 years admitted for acute cerebral infarction to the stroke unit of Nancy University Hospital in France between 1 January 2009 and 31 December 2012. Patients were stratified into two groups: treated or not with rt PA. Baseline characteristics and outcome were collected and compared between both groups. Good outcome at 3 months was defined as modified Rankin Scale score <=2. RESULTS: The 55 patients treated with rt-PA had a higher National Institute of Health Stroke Scale score on admission than those without (15 vs 5; P < 0.001). They were more likely to have intracranial haemorrhage (20 vs 5%; P < 0.001) without an increased mortality rate (28 vs 27%; P = 0.95). Multivariate analysis showed a more favorable outcome (odds ratio 7, 95% confidence interval 3-16.5; P < 0.001). Slightly higher percentages of patients with modified Rankin Scale <=2 were found after intention-to-treat analysis (49 vs 45%) and after exclusion of patients with baseline modified Rankin Scale >2 (57 vs 54 %), but without reaching significance (P > 0.05). CONCLUSIONS: Rt-PA therapy would appear to improve prognosis in the elderly with ischemic stroke. This suggests that age alone should no longer be a barrier to rt-PA therapy. Geriatr Gerontol Int 2016; 16: 843-849. PMID- 26245694 TI - Combinatorial pathway engineering for optimized production of the anti-malarial FR900098. AB - As resistance to current anti-malarial therapeutics spreads, new compounds to treat malaria are increasingly needed. One promising compound is FR900098, a naturally occurring phosphonate. Due to limitations in both chemical synthesis and biosynthetic methods for FR900098 production, this potential therapeutic has yet to see widespread implementation. Here we applied a combinatorial pathway engineering strategy to improve the production of FR900098 in Escherichia coli by modulating each of the pathway's nine genes with four promoters of different strengths. Due to the large size of the library and the low screening throughput, it was necessary to develop a novel screening strategy that significantly reduced the sample size needed to find an optimal strain. This was done by using biased libraries that localize searching around top hits and home in on high-producing strains. By incorporating this strategy, a significantly improved strain was found after screening less than 3% of the entire library. When coupled with culturing optimization, a strain was found to produce 96 mg/L, a 16-fold improvement over the original strain. We believe the enriched library method developed here can be used on other large pathways that may be difficult to engineer by combinatorial methods due to low screening throughput. PMID- 26245695 TI - Andrographolide: A potent antituberculosis compound that targets Aminoglycoside 2'-N-acetyltransferase in Mycobacterium tuberculosis. AB - Tuberculosis (TB) still remains a major challenging infectious disease. The increased rate of emergence of multi-drug resistant and extensively-drug resistant strains of the organism has further complicated the situation, resulting in an urgent need for new anti-TB drugs. Antimycobacterial activity of Andrographis paniculata was evaluated using a rapid LRP assay and the probable targets were identified by docking analysis. The methanolic extract of A. paniculata showed maximum antimycobacterial activity at 250MUg/ml against all the tested strains of M. tuberculosis (H37Rv, MDR, and drug sensitive). Based on bioassay guided fractionation, andrographolide was identified as the potent molecule. With the docking analysis, both ICDH (Isocitrate Dehydrogenase) and AAC (Aminoglycoside 2'-N-acetyltransferase) were predicted as targets of andrographolide in M. tuberculosis. Molecular simulation revealed that, ICDH showed low binding affinity to andrographolide. However, for AAC, the andrographolide was observed to be well within the active site after 10ns of molecular simulation. This suggests that ACC (PDB ID 1M4I) could be the probable target for andrographolide. PMID- 26245696 TI - Molecular docking and dynamic simulation evaluation of Rohinitib - Cantharidin based novel HSF1 inhibitors for cancer therapy. AB - Recent developments in the target based cancer therapies have identified HSF1 as a novel non oncogenic drug target. The present study delineates the design and molecular docking evaluation of Rohinitib (RHT) - Cantharidin (CLA) based novel HSF1 inhibitors for target-based cancer therapy. Here, we exploited the pharmacophoric features of both the parent ligands for the design of novel hybrid HSF1 inhibitors. The RHT-CLA ligands were designed and characterized for ADME/Tox features, interaction with HSF1 DNA binding domain and their pharmacophoric features essential for interaction. From the results, amino acid residues Ala17, Phe61, His63, Asn65, Ser68, Arg71 and Gln72 were found crucial for HSF1 interaction with the Heat shock elements (HSE). The hybrid ligands had better affinity towards the HSF1 DNA binding domain, in comparison to RHT or CLA and interacted with most of the active site residues. Additionally, the HSF1-ligand complex had a reduced affinity towards HSE in comparison to native HSF1. Based on the results, ligand RC15 and RC17 were non carcinogenic, non mutagenic, completely biodegradable under aerobic conditions, had better affinity for HSF1 (1.132 and 1.129 folds increase respectively) and diminished the interaction of HSF1 with HSE (1.203 and 1.239 folds decrease respectively). The simulation analysis also suggested that the ligands formed a stable complex with HSF1, restraining the movement of active site residues. In conclusion, RHT-CLA hybrid ligands can be used as a potential inhibitor of HSF1 for non-oncogene target based cancer therapy. PMID- 26245697 TI - Anti-diabetic activity of peony seed oil, a new resource food in STZ-induced diabetic mice. AB - This study was conducted to investigate the components of a new resource food in China, peony seed oil (PSO) by GC-MS (gas chromatography-mass spectrometry), its inhibitory effects on carbohydrate hydrolyzing enzymes in vitro and its anti diabetic effects on mice induced by streptozotocin (STZ). The results showed that peony seed oil showed weak anti-alpha-amylase activity; however, strong anti alpha-glucosidase activity was noted. The GC-MS analysis of the oil showed 9 constituents of which alpha-linolenic acid was found to be the major component (38.66%), followed by linoleic acid (26.34%) and oleic acid (23.65%). The anti diabetic potential of peony seed oil was tested in STZ induced diabetic mice. Administration of peony seed oil and glibenclamide reduced the blood glucose level and the area under curve (AUC) in STZ induced diabetic mice. There were significant increases in body weight, liver glycogen content, serum insulin level, high-density lipoprotein cholesterol (HDL-C) and decreases in glycosylated hemoglobin (HbA1C), total serum cholesterol (TC), and triglyceride (TG) in test groups as compared to the untreated diabetic groups. In vivo antioxidant studies on STZ induced diabetic mice revealed the reduction of malondialdehyde (MDA) and increase of glutathione peroxides (GSH-px), superoxide dismutase (SOD), and glutathione (GSH). The results provided a sound rationale for future clinical trials of oral administration of peony seed oil to alleviate postprandial hyperglycemia in streptozotocin-induced diabetic mice. PMID- 26245698 TI - Use of betahistine in the treatment of peripheral vertigo. AB - CONCLUSION: Clinical studies and meta-analyses demonstrated that betahistine is effective and safe in the treatment of Meniere's disease, BPPV (benign paroxysmal positional vertigo), vestibular neuronitis, and other types of peripheral vertigo. OBJECTIVES: The goal of this paper is to review the pharmacological profile of betahistine and the evidence for its effectiveness and safety in the treatment of peripheral vertigo. METHODS: Selection criteria for the publications on betahistine included randomized clinical trials that evaluated the effectiveness and safety of betahistine vs placebo or active control in the treatment of peripheral vertigo. Recent meta-analyses were also included. Databases searched included PubMed, the Cochrane Ear, Nose and Throat Disorders Group Trials Register, and ICTRP. The review also presents an update on the mechanisms of action, pharmacodynamics, and pharmacokinetics of betahistine. RESULTS: Efficacy and safety of betahistine has been demonstrated in numerous clinical trials. The precise mechanism of action of betahistine is still not completely understood, but the clinical experience demonstrated the benefit of betahistine in different types of peripheral vertigo. In more than 40 years of clinical use, betahistine has shown an excellent safety profile with the usual dose range from 8-48 mg daily. According to clinical studies, betahistine 48 mg daily during 3 months is an effective and safe option for the treatment of peripheral vertigo. PMID- 26245700 TI - Significance of variants associated with resistance to NS5A inhibitors in Japanese patients with genotype 1b hepatitis C virus infection as evaluated using cycling-probe real-time PCR combined with direct sequencing. AB - BACKGROUND: Dual oral therapy with daclatasvir plus asunaprevir yielded an SVR rate of 85% among patients with genotype 1b HCV. Treatment failure mainly occurred in patients with pre-existing HCV with NS5A-Y93H mutation. The significance of the mutation was evaluated. METHODS: The percent of serum NS5A Y93H strains relative to the total strains was quantified using cycling-probe real-time PCR combined with direct sequencing in 444 patients with genotype 1b HCV, and the factors associated with mutation were analyzed. The mutation rates during interferon therapy were measured sequentially. RESULTS: NS5A-Y93H strains (1-100% of the total strains) were detected in 87 patients (19.6%). Mutant strains were detected more frequently among women than among men, in patients with a favorable allele in the IL28B-related gene SNP than among those with unfavorable alleles, and among patients without HCC and/or with serum AFP levels less than 6.0 ng/ml than among those with HCC and/or levels of 6.0 ng/ml or more. A multivariate analysis revealed that IL28B-related gene polymorphisms were significant factors associated with mutant strains. Although the frequency of patients with mutant strains was equivalent among patients depending on their previous interferon therapies, a sequential analysis during the interferon administrations revealed that the mutant strains disappeared earlier than the wild-type strains. CONCLUSIONS: NS5A-Y93H mutation was associated with sex, serum AFP levels, and IL28B-related gene polymorphisms in patients infected with genotype 1b HCV. The indications for NS5A inhibitor use should be determined based on these factors, since mutant strains seem to be sensitive to interferon. PMID- 26245701 TI - Effective prevention of pseudothrombocytopenia in feline blood samples with the prostaglandin I2 analogue Iloprost. AB - BACKGROUND: In vitro platelet aggregation in feline blood samples is a well-known phenomenon in veterinary clinical laboratories resulting in high numbers of pseudothrombocytopenia. Several attempts have been made to prevent or dissolve platelet aggregates in feline blood samples and to increase the reliability of feline platelet counts. Prostaglandin I2 (PGI2) is the most powerful endogenous inhibitor of platelet aggregation but unstable. Iloprost is a stable PGI2 analogue. The aims of the present study were (1) to evaluate the anti-aggregatory effect of Iloprost on feline platelet counts and to determine a useful concentration to inhibit platelet aggregation in EDTA samples from clinically healthy cats, (2) to investigate the effect of Iloprost on hematological blood parameters, and (3) to determine stability of Iloprost in K3-EDTA tubes for up to 16 weeks. From 20 clinically healthy cats blood was drawn from the jugular vein and immediately distributed in a 1.3 ml K3-EDTA tube, and two 1.3 ml K3-EDTA tubes containing 20 ng and 200 ng Iloprost, respectively. A complete blood cell count was performed on the Sysmex XT-2000iV and the Mythic 18 on eight consecutive time points after collection. Blood smears were evaluated for the presence of PLT aggregates. RESULTS: In the absence of Iloprost, pseudothrombocytopenia was observed in 50% of the investigated samples that led to significantly decreased optical PLT counts by a mean of 105 x10(3)/MUl, which could be prevented by the addition of 1 MUL (20 ng) Iloprost leading to an increase in PLT counts by a mean of 108 x10(3)/MUl. CONCLUSION: This is the first study showing an anti-aggregatory effect of the PGI2-analogue Iloprost in feline EDTA blood. In all clinically healthy cats investigated, pseudothrombocytopenia was prevented by adding Iloprost to EDTA tubes prior to blood collection. Furthermore, Iloprost was very useful in preventing falsely increased WBC counts in samples with platelet aggregates analyzed on impedance-based hematological instruments. Iloprost is preferable to PGI2 or PGE1 due to its stability and easy and safe handling properties. Cytological evaluations of blood smears as well as other hematological parameters were not influenced to a clinically significant degree by the presence of Iloprost. PMID- 26245702 TI - An update in treatment options for multiple myeloma in nontransplant eligible patients. AB - INTRODUCTION: Despite the fact that multiple myeloma (MM) is still an incurable disease, the outcome of patients who are eligible and ineligible for high-dose therapy has dramatically improved with the introduction of novel agents, that is proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs). However, this improvement is often not seen in elderly patients (above 75 years). AREAS COVERED: This review will focus on the impact of known prognostic factors in elderly MM patients, and risk factors to identify frail elderly patients. Furthermore, data on known and novel PIs and IMiDs, as well as data on other promising novel treatment strategies, chosen based on current practice and anticipated timely approval, will be discussed. Novel treatment strategies include the use of monoclonal antibodies, such as elotuzumab, daratumumab, SAR650984 and more targeted therapies, such as histone deacetylase inhibitors, kinesin spindle protein inhibitors, and selective inhibitors of nuclear export. EXPERT OPINION: Besides efficacy of treatment, toxicity and quality of life play an important role in treatment choice. Treatment and treatment dosing for the frail elderly as well as risk factors to identify the frail elderly require further consideration, as these patients frequently do not benefit from these novel agents due to early discontinuation of treatment due to toxicity. PMID- 26245703 TI - Preparation and characterization of spray-dried co-amorphous drug-amino acid salts. AB - OBJECTIVES: Recently, co-amorphous drug-amino acid mixtures were introduced as a promising alternative to other amorphous stabilization approaches such as the use of polymers to form glass solutions. So far, these co-amorphous mixtures have been mainly prepared via vibrational ball milling on a lab scale. In this study, spray-drying was investigated as a scale up preparation method for co-amorphous indomethacin (IND)-amino acid mixtures. In addition, the physico-chemical properties of the different co-amorphous systems were investigated with respect to the amino acids' ability towards co-amorphous salt formation. METHODS: The mixtures were characterized for their solid state properties using differential scanning calorimetry, thermogravimetric analysis and X-ray powder diffraction. Fourier-transform infrared spectroscopy was used to analyze molecular interactions. Furthermore, intrinsic dissolution behaviour, and physical stability at various storage conditions, were examined. KEY FINDINGS: Results showed that IND could be converted into an amorphous form in combination with the amino acids arginine (ARG), histidine (HIS) and lysine (LYS) by spray-drying. Solid state characterization revealed elevated glass transition temperatures for all mixtures compared with the pure amorphous drug due to co-amorphization with the amino acids. Furthermore, strong intermolecular interactions in the form of salt/partial salt formation between the drug and amino acids were seen for all blends. All mixtures were physically stable (>10 months) at room temperature and 40 degrees C under dry conditions. Intrinsic dissolution of the co-amorphous mixtures showed an improved dissolution behaviour under intestinal pH conditions for IND-ARG compared with the crystalline and amorphous forms of the drug. On the other hand, IND-LYS and IND-HIS revealed no significant improvement in the intrinsic dissolution rate of IND due to recrystallization of IND during dissolution. CONCLUSIONS: It could be shown that strong intermolecular interactions between drug and co-amorphous coformer that persist during the dissolution are crucial to prevent recrystallization and to enhance dissolution of a co-amorphous formulation. PMID- 26245704 TI - Correlation between Polymorphism of TRAIL Gene and Condition of Intervertebral Disc Degeneration. AB - BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been suggested to be related with the pathogenesis and progression of osteoarticular degenerations. This study therefore aimed to investigate the relationship between the polymorphism of the TRAIL gene and the pathogenesis and severity of intervertebral disc degeneration (IDD) via detection of serum TRAIL expression levels. MATERIAL AND METHODS: A total of 100 IDD patients in our hospital were recruited in the experimental group, while another cohort of 100 healthy individuals was employed as the control group. Blood samples collected from all people were quantified for TRAIL level using enzyme-linked immunosorbent assay (ELISA), in addition to allele and genotype frequency analysis via fluorescent PCR for TRAIL gene. RESULTS: At loci 1525 and 1529 in 3'-untranslated region (UTR) of 5th exon of TRAIL gene, 3 different genotypes were identified: experimental group had higher frequency of 1525CG/1595CC, 1525G and 1595C alleles, compared to the control group (p<0.05). Patients under Schneiderman grade IV had significantly higher allele frequency compared to those at grade II or III. Serum TRAIL level was also higher in the experimental group compared to the control group, and in grade IV patients compared to grade II or III patients (p<0.05). CONCLUSIONS: The G/C mutation at loci 1525/1595 of TRAIL gene may induce the progression of IDD, as the down-regulation of TRAIL can aggravate the severity of the disease. PMID- 26245705 TI - Overall morbidity but not mortality is increased in elderly patients following cytoreductive surgery and HIPEC. AB - BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) prolongs survival in selected patients with peritoneal metastases. Since this procedure is likely to be associated with increased morbidity and mortality, it remains controversial whether it is also suitable for patients older than 70 years. METHODS: Consecutive patients with radiographic evidence of peritoneal metastases (PM) were scheduled for CRS and HIPEC at the Comprehensive Cancer Center, University Hospital Tubingen, Germany. Clinical data were retrospectively analyzed categorizing patients with respect to age into elderly (age >= 70) and non-elderly patients (age < 70). RESULTS: Between June 2005 and March 2014, 381 patients with a median age of 55 [14-77] years could be enrolled with 29 patients (8 %) being at least 70 years old. Both groups were comparable for tumor-related parameters including PCI, CC-status, time in operating room, and visceral resections. However, there was a difference in patient-related factors such as cardio-pulmonary comorbidities and ASA score. We found no difference in overall and recurrence-free survival between the two groups. Surgery-related mortality was 0.9 % in patients younger than 70 years whereas no patient died in the elderly group. Overall morbidity was 47 % in the younger and 76 % in the elderly group (p = 0.048). There was no difference in Clavien-Dindo grade III-IV morbidity. Logistic regression analysis proved age as an independent risk factor for increased overall morbidity in elderly patients. CONCLUSION: In elderly patients, CRS and HIPEC are associated with increased overall morbidity but neither Dindo III-IV morbidity nor surgery-related mortality. PMID- 26245706 TI - Hand-assisted hybrid laparoscopic-robotic total proctocolectomy with ileal pouch- anal anastomosis. AB - PURPOSE: Few studies have reported minimally invasive total proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) and familial adenomatous polyposis (FAP). We herein report a novel hand-assisted hybrid laparoscopic-robotic technique for patients with FAP and UC. METHODS: Between February 2010 and March 2014, six patients underwent hand-assisted hybrid laparoscopic-robotic total proctocolectomy with IPAA. The abdominal colectomy was performed laparoscopically with hand assistance through a transverse suprapubic incision, also used to fashion the ileal pouch. The proctectomy was carried out with the da Vinci Surgical System. The IPAA was hand-sewn through a trans-anal approach. The procedure was complemented by a temporary diverting loop ileostomy. RESULTS: The mean hand-assisted laparoscopic surgery (HALS) time was 154.6 (+/ 12.8) min whereas the mean robotic time was 93.6 (+/-8.1) min. In all cases, a nerve-sparing proctectomy was performed, and no conversion to traditional laparotomy was required. The mean postoperative hospital stay was 13.2 (+/-7.4) days. No anastomotic leakage was observed. To date, no autonomic neurological disorders have been observed with a mean of 5.8 (+/-1.3) bowel movements per day. CONCLUSIONS: The hand-assisted hybrid laparoscopic-robotic approach to total proctocolectomy with IPAA has not been previously described. Our report shows the feasibility of this hybrid approach, which surpasses most of the limitations of pure laparoscopic and robotic techniques. Further experience is necessary to refine the technique and fully assess its potential advantages. PMID- 26245707 TI - Cross-sectional survey of the disaster preparedness of nurses across the Asia Pacific region. AB - Healthcare workers who have received disaster preparedness education are more likely to report a greater understanding of disaster preparedness. However, research indicates that current nursing curricula do not adequately prepare nurses to respond to disasters. This is the first study to assess Asia-Pacific nurses' perceptions about their level of disaster knowledge, skills, and preparedness. A cross-sectional survey was conducted with 757 hospital and community nurses in seven Asia-Pacific countries. Data were collected using the modified Disaster Preparedness Evaluation Tool. Participants were found to have overall low-to-moderate levels of disaster knowledge, skills and preparedness, wherein important gaps were identified. A majority of the variance in disaster preparedness scores was located at the level of the individual respondent, not linked to countries or institutions. Multilevel random effects modelling identified disaster experience and education as significant factors of positive perceptions of disaster knowledge, skills, and management. The first step toward disaster preparedness is to ensure frontline health workers are able to respond effectively to disaster events. The outcomes of this study have important policy and education implications. PMID- 26245708 TI - Quality of life in maltreated children and adult survivors of child maltreatment: a systematic review. AB - PURPOSE: To review data on health-related quality of life (HRQoL) in individuals with childhood trauma, including psychological maltreatment, physical maltreatment, sexual abuse, and neglect. METHODS: The literature search was conducted with pre-defined keywords using the following electronic bibliographic databases: EMBASE, PubMed, MEDLINE, CINAHL, PsyINFO, PSYNDEX, and Cochrane Database of Systematic Reviews. Further databases were searched for relevant dissertations. Study selection and data extraction were completed by two independent reviewers. RESULTS: The literature search yielded 1568 entries. Nineteen articles met all inclusion criteria and were retained for further analysis. Findings quite consistently showed significant negative associations between child maltreatment and both self- and proxy-rated HRQoL. Effect sizes range from small to large. Number of types of maltreatment and HRQoL were found to be negatively related. CONCLUSION: Data on HRQoL for maltreated children are still rare. Studies often investigate adult survivors of child maltreatment. Considering HRQoL in children and adolescents who suffered maltreatment would allow the planning of effective interventions and the evaluation of treatments to improve HRQoL of these children. PMID- 26245709 TI - Is the Oswestry Disability Index a valid measure of response to sacroiliac joint treatment? AB - PURPOSE: Disease-specific measures of the impact of sacroiliac (SI) joint pain on back/pelvis function are not available. The Oswestry Disability Index (ODI) is a validated functional measure for lower back pain, but its responsiveness to SI joint treatment has yet to be established. We sought to assess the validity of ODI to capture disability caused by SI joint pain and the minimum clinically important difference (MCID) after SI joint treatment. METHODS: Patients (n = 155) participating in a prospective clinical trial of minimally invasive SI joint fusion underwent baseline and follow-up assessments using ODI, visual analog scale (VAS) pain assessment, Short Form 36 (SF-36), EuroQoL-5D, and questions (at follow-up only) regarding satisfaction with the SI joint fusion and whether the patient would have the fusion surgery again. All outcomes were compared from baseline to 12 months postsurgery. The health transition item of the SF-36 and the satisfaction scale were used as external anchors to calculate MCID. MCID was estimated for ODI using four calculation methods: (1) minimum detectable change, (2) average ODI change of patients' subsets, (3) change difference between patients' subsets, and (4) receiver operating characteristic (ROC) curve. RESULTS: After SI fusion, patients improved significantly (p < .0001) on all measures: SI joint pain (48.8 points), ODI (23.8 points), EQ-5D (0.29 points), EQ 5D VAS (11.7 points), PCS (8.9 points), and MCS (9.2 points). The improvement in ODI was significantly correlated (p < .0001) with SI joint pain improvement (r = .48) and with the two external anchors: SF-36 health transition item (r = .49) and satisfaction level (r = .34). The MCID values calculated for ODI using the various methods ranged from 3.5 to 19.5 points. The ODI minimum detectable change was 15.5 with the health transition item as the anchor and 13.5 with the satisfaction scale as the anchor. CONCLUSIONS: ODI is a valid measure of change in SI joint health. Hence, researchers and clinicians may rely on ODI scores to measure disability caused by SI pain. We estimated the MCID for ODI to be 13-15 points, which falls within the range of that previously reported for lumbar back pain and indicates that an improvement in disability should be at least 15 % to be beyond random variation. PMID- 26245710 TI - Content validity of Patient-Reported Outcomes Measurement Information System (PROMIS) items in the context of HIV clinical care. AB - PURPOSE: To assess content validity and patient and provider prioritization of Patient-Reported Outcomes Measurement Information System (PROMIS) depression, anxiety, fatigue, and alcohol use items in the context of clinical care for people living with HIV (PLWH), and to develop and assess new items as needed. METHODS: We conducted concept elicitation interviews (n = 161), item pool matching, prioritization focus groups (n = 227 participants), and cognitive interviews (n = 48) with English-speaking (~75 %) and Spanish-speaking (~25 %) PLWH from clinical sites in Seattle, San Diego, Birmingham, and Boston. For each domain we also conducted item review and prioritization with two HIV provider panels of 3-8 members each. RESULTS: Among items most highly prioritized by PLWH and providers were those that included information regarding personal impacts of the concept being assessed, in addition to severity level. Items that addressed impact were considered most actionable for clinical care. We developed additional items addressing this. For depression we developed items related to suicide and other forms of self-harm, and for all domains we developed items addressing impacts PLWH and/or providers indicated were particularly relevant to clinical care. Across the 4 domains, 16 new items were retained for further psychometric testing. CONCLUSION: PLWH and providers had priorities for what they believed providers should know to provide optimal care for PLWH. Incorporation of these priorities into clinical assessments used in clinical care of PLWH may facilitate patient-centered care. PMID- 26245711 TI - Antibacterial and residual antimicrobial activities against Enterococcus faecalis biofilm: A comparison between EDTA, chlorhexidine, cetrimide, MTAD and QMix. AB - We compared the antibacterial and residual antimicrobial activities of five root canal irrigants (17% EDTA,2% chlorhexidine,0.2% cetrimide, MTAD, and QMix) in a model of Enterococcus faecalis biofilm formation. Sixty dentin blocks with 3-week E. faecalis biofilm were divided into six equal groups and flushed with irrigant for 2 min or left untreated. A blank control group was also established. Antibacterial activities of the irrigants were evaluated by counting colony forming units. To test residual antimicrobial activities, 280 dentin blocks were divided into seven equal groups and flushed with irrigant for 2 min or left untreated and then incubated with E. faecalis suspension for 48 h, or used as a blank. No bacteria were observed in the blank control group. The number of viable E. faecalis was significantly fewer in the irrigant-treated groups compared with the untreated control (P < 0.05). Among the five irrigants, QMix had the strongest antibacterial activity. Residual antimicrobial activities of CHX were significantly higher at 12 h, 24 h and 36 h compared to untreated control (P < 0.05). All five root canal irrigants were effective to some extent against E. faecalis, but QMix and CHX had the strongest, and CHX the longest (up to 36 h), antimicrobial activity. PMID- 26245712 TI - Salt-Responsive Zwitterionic Polymer Brushes with Tunable Friction and Antifouling Properties. AB - Development of smart, multifunction materials is challenging but important for many fundamental and industrial applications. Here, we synthesized and characterized zwitterionic poly(3-(1-(4-vinylbenzyl)-1H-imidazol-3-ium-3 yl)propane-1-sulfonate) (polyVBIPS) brushes as ion-responsive smart surfaces via the surface-initiated atom transfer radical polymerization. PolyVBIPS brushes were carefully characterized for their surface morphologies, compositions, wettability, and film thicknesses by atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), contact angle, and ellipsometer, respectively. Salt-responsive, switching properties of polyVBIPS brushes on surface hydration, friction, and antifouling properties were further examined and compared both in water and in salt solutions with different salt concentrations and counterion types. Collective data showed that polyVBIPS brushes exhibited reversible surface wettability switching between in water and saturated NaCl solution. PolyVBIPS brushes in water induced the larger protein absorption, higher surface friction, and lower surface hydration than those in salt solutions, exhibiting "anti polyelectrolyte effect" salt responsive behaviors. At appropriate ionic conditions, polyVBIPs brushes were able to switch to superlow fouling surfaces (<0.3 ng/cm(2) protein adsorption) and superlow friction surfaces (u ~ 10(-3)). The relationship between brush structure and its salt-responsive performance was also discussed. This work provides new zwitterionic surface-responsive materials with controllable antifouling and friction capabilities for multifunctional applications. PMID- 26245713 TI - Association of COMT and SLC6A3 polymorphisms with impulsivity, response inhibition and brain function. AB - Evidence of the genetic correlates of inhibitory control is scant. Two previously studied dopamine-related polymorphisms, COMT rs4680 and the SLC6A3 3' UTR 40-base pair VNTR (rs28363170), have been associated with response inhibition, however with inconsistent findings. Here, we investigated the influence of these two polymorphisms in a large healthy adult sample (N = 515) on a response inhibition battery including the antisaccade, stop-signal, go/no-go and Stroop tasks as well as a psychometric measure of impulsivity (Barratt Impulsiveness Scale) (Experiment 1). Additionally, a subsample (N = 144) was studied while performing the go/no-go, stop-signal and antisaccade tasks in 3T fMRI (Experiment 2). In Experiment 1, we did not find any significant associations of COMT or SLC6A3 with inhibitory performance or impulsivity. In Experiment 2, no association of COMT with BOLD was found. However, there were consistent main effects of SLC6A3 genotype in all inhibitory contrasts: Homozygosity of the 10R allele was associated with greater fronto-striatal BOLD response than genotypes with at least one 9R allele. These findings are consistent with meta-analyses showing that the 10R allele is associated with reduced striatal dopamine transporter expression, which in animal studies has been found to lead to increased extracellular dopamine levels. Our study thus supports the involvement of striatal dopamine in the neural mechanisms of cognitive control, in particular response inhibition. PMID- 26245714 TI - Long-Term Regulation of the Local Renin-Angiotensin System in the Myocardium of Spontaneously Hypertensive Rats by Feeding Bioactive Peptides Derived from Spirulina platensis. AB - This study investigated the long-term (8 weeks) anti-hypertensive effects of 10 mg/kg tripeptides isolated from Spirulina platensis, Ile-Gln-Pro (IQP) and Val Glu-Pro (VEP), and S. platensis hydrolysates (SH) on spontaneously hypertensive rats. The treatment period was 6 weeks, and observation continued for another 2 weeks. After treatment, weighted systolic blood pressure, weighted diastolic blood pressure, left ventricular mass index, and right ventricular mass index of groups treated with IQP, VEP, and SH were significantly lower than those of the group treated with distilled water, even when the treatments had been withdrawn for 2 weeks. Quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting showed the mRNA expression levels and protein/peptide concentrations of the main components of the renin angiotensin system in myocardium were significantly affected by treatment: angiotensin converting enzyme, angiotensin II, and angiotensin type 1 receptor were down regulated, whereas angiotensin type 2 receptor, angiotensin converting enzyme 2, angiotensin-(1-7), and Mas receptor were up-regulated. PMID- 26245715 TI - Fast Fourier transform scanning spreading resistance microscopy: a novel technique to overcome the limitations of classical conductive AFM techniques. AB - A new atomic force microscopy (AFM)-based technique named fast Fourier transform scanning spreading-resistance microscopy (FFT-SSRM) has been developed. FFT-SSRM offers the ability to isolate the local spreading resistance (Sr) from the parasitic series resistance (probe, bulk, and back contact). The parasitic series resistance limits the use of classical SSRM in confined volumes and on very highly doped materials, two increasingly important situations in nanoelectronic components. This is realized via a force modulation at controlled frequency (affecting the SR component) and the extraction of the resistance amplitude at the modulation frequency, performing an FFT-based lock-in deconvolution. A systematic evaluation of the FFT-SSRM performances (i.e., resolution, dynamic range, sensitivity, and repeatability) is presented. The impact of various parameters (i.e., modulation frequency and amplitude or cutoff frequency of the current amplifier) on the performances of FFT-SSRM has been evaluated. We demonstrate the possibility to overcome sensitivity losses due to tip saturation in highly doped material and the utility of the technique in two different structures, presenting isolated and confined volumes. PMID- 26245717 TI - Interaction of bovine serum albumin with N-acyl amino acid based anionic surfactants: Effect of head-group hydrophobicity. AB - The function of a protein depends upon its structure and surfactant molecules are known to alter protein structure. For this reason protein-surfactant interaction is important in biological, pharmaceutical, and cosmetic industries. In the present work, interactions of a series of anionic surfactants having the same hydrocarbon chain length, but different amino acid head group, such as l-alanine, l-valine, l-leucine, and l-phenylalanine with the transport protein, bovine serum albumin (BSA), were studied at low surfactant concentrations using fluorescence and circular dichroism (CD) spectroscopy, and isothermal titration calorimetry (ITC). The results of fluorescence measurements suggest that the surfactant molecules bind simultaneously to the drug binding site I and II of the protein subdomain IIA and IIIA, respectively. The fluorescence as well as CD spectra suggest that the conformation of BSA goes to a more structured state upon surfactant binding at low concentrations. The binding constants of the surfactants were determined by the use of fluorescence as well as ITC measurements and were compared with that of the corresponding glycine-derived surfactant. The binding constant values clearly indicate a significant head-group effect on the BSA-surfactant interaction and the interaction is mainly hydrophobic in nature. PMID- 26245716 TI - Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues. AB - Marrow adipose tissue (MAT) accumulates in diverse clinical conditions but remains poorly understood. Here we show region-specific variation in MAT adipocyte development, regulation, size, lipid composition, gene expression and genetic determinants. Early MAT formation in mice is conserved, whereas later development is strain dependent. Proximal, but not distal tibial, MAT is lost with 21-day cold exposure. Rat MAT adipocytes from distal sites have an increased proportion of monounsaturated fatty acids and expression of Scd1/Scd2, Cebpa and Cebpb. Humans also have increased distal marrow fat unsaturation. We define proximal 'regulated' MAT (rMAT) as single adipocytes interspersed with active haematopoiesis, whereas distal 'constitutive' MAT (cMAT) has low haematopoiesis, contains larger adipocytes, develops earlier and remains preserved upon systemic challenges. Loss of rMAT occurs in mice with congenital generalized lipodystrophy type 4, whereas both rMAT and cMAT are preserved in mice with congenital generalized lipodystrophy type 3. Consideration of these MAT subpopulations may be important for future studies linking MAT to bone biology, haematopoiesis and whole-body metabolism. PMID- 26245718 TI - Magnetic hyaluronic acid nanospheres via aqueous Diels-Alder chemistry to deliver dexamethasone for adipose tissue engineering. AB - Biopolymer-based nanospheres have great potential in the field of drug delivery and tissue regenerative medicine. In this work, we present a flexible way to conjugate a magnetic hyaluronic acid (HA) nanosphere system that are capable of vectoring delivery of adipogenic factor, e.g. dexamethasone, for adipose tissue engineering. Conjugation of nanospheres was established by aqueous Diels-Alder chemistry between furan and maleimide of HA derivatives. Simultaneously, a furan functionalized dexamethasone peptide, GQPGK, was synthesized and covalently immobilized into the nanospheres. The magnetic HA nanospheres were fabricated by encapsulating super-paramagnetic iron oxide nanoparticles, which exhibited quick magnetic sensitivity. The aqueous Diels-Alder chemistry made nanospheres high binding efficiency of dexamethasone, and the vectoring delivery of dexamethasone could be easily controlled by a external magnetic field. The potential application of the magnetic HA nanospheres on vectoring delivery of adipogenic factor was confirmed by co-culture of human adipose-derived stem cells (ASCs). In vitro cytotoxicity tests demonstrated that incorporation of dexamethasone into magnetic HA nanospheres showed high efficiency to promote ASCs viabilities, in particular under a magnetic field, which suggested a promising future for adipose regeneration applications. PMID- 26245719 TI - Fabricating sub-100nm conducting polymer nanowires by edge nanoimprint lithography. AB - In this paper, a convenient and universal strategy is reported to fabricate high resolution conducting polymer nanowires, combining edge nanoimprinting with gas etching. Based on this method, 81.3nm polypyrrole nanowires were obtained, which is much smaller than the original cavity. The resulting conducting polymer nanowires exhibit representative ohmic behavior and excellent sensitivity to NH3. This method may potentially be used to construct other organic nanoelectronic devices. PMID- 26245720 TI - A method to assist in the diagnosis of early diabetic retinopathy: Image processing applied to detection of microaneurysms in fundus images. AB - Diabetes increases the risk of developing any deterioration in the blood vessels that supply the retina, an ailment known as Diabetic Retinopathy (DR). Since this disease is asymptomatic, it can only be diagnosed by an ophthalmologist. However, the growth of the number of ophthalmologists is lower than the growth of the population with diabetes so that preventive and early diagnosis is difficult due to the lack of opportunity in terms of time and cost. Preliminary, affordable and accessible ophthalmological diagnosis will give the opportunity to perform routine preventive examinations, indicating the need to consult an ophthalmologist during a stage of non proliferation. During this stage, there is a lesion on the retina known as microaneurysm (MA), which is one of the first clinically observable lesions that indicate the disease. In recent years, different image processing algorithms, which allow the detection of the DR, have been developed; however, the issue is still open since acceptable levels of sensitivity and specificity have not yet been reached, preventing its use as a pre-diagnostic tool. Consequently, this work proposes a new approach for MA detection based on (1) reduction of non-uniform illumination; (2) normalization of image grayscale content to improve dependence of images from different contexts; (3) application of the bottom-hat transform to leave reddish regions intact while suppressing bright objects; (4) binarization of the image of interest with the result that objects corresponding to MAs, blood vessels, and other reddish objects (Regions of Interest-ROIs) are completely separated from the background; (5) application of the hit-or-miss Transformation on the binary image to remove blood vessels from the ROIs; (6) two features are extracted from a candidate to distinguish real MAs from FPs, where one feature discriminates round shaped candidates (MAs) from elongated shaped ones (vessels) through application of Principal Component Analysis (PCA); (7) the second feature is a count of the number of times that the radon transform of the candidate ROI, evaluated at the set of discrete angle values {0 degrees , 1 degrees , 2 degrees , ..., 180 degrees }, is characterized by a valley between two peaks. The proposed approach is tested on the public databases DiaretDB1 and Retinopathy Online Challenge (ROC) competition. The proposed MA detection method achieves sensitivity, specificity and precision of 92.32%, 93.87% and 95.93% for the diaretDB1 database and 88.06%, 97.47% and 92.19% for the ROC database. Theory, results, challenges and performance related to the proposed MA detecting method are presented. PMID- 26245721 TI - The influence of age at disease onset on disease activity and disability: results from the Ontario Best Practices Research Initiative. AB - This study aims to compare characteristics between late-onset rheumatoid arthritis (RA) and young-onset RA and determine the association between age at disease onset and disease severity. We cross-sectionally studied 971 patients at the time of entry into the Ontario Best Practices Research Initiative, a registry of RA patients followed up in routine care. We restricted patients to <=5 years of disease duration. Late-onset RA was defined as an onset >=60 years of age and young-onset RA <60 years. Group differences were compared, and multivariate linear regression models were used to test the influence of age at onset on Disease Activity Score in 28 Joints with erythrocyte sedimentation rate (DAS28 ESR), Clinical Disease Activity Index (CDAI), and Health Assessment Questionnaire (HAQ) scores. The swollen joint count (6.2 vs. 5.3), acute phase reactants (C reactive protein (CRP) 17.4 vs. 11.8 mg/L, ESR 30.6 vs. 21.5 mm/h), and comorbidity burden were higher in late-onset RA compared to young-onset RA (p < 0.01). Mean DAS28-ESR (4.6 vs. 4.3) and HAQ (1.2 vs. 1.1) scores were higher in late-onset RA patients (p < 0.05). Late-onset RA patients received more initial disease-modifying antirheumatic drug (DMARD) monotherapy and corticosteroids in comparison to greater DMARD/biologic combination therapy in young-onset RA patients (p < 0.05). Adjusted multivariate analyses showed that late-onset RA was independently associated with higher mean DAS28-ESR and HAQ scores, but not CDAI. Late-onset RA patients have greater disease activity that may contribute to disability early in the disease course. Despite this, initial treatment consists of less combination DMARD and biologic use in late-onset RA patients. This may have implications for future response to therapy and development of joint damage, disability, and comorbidities in this group. PMID- 26245722 TI - "You want to get on with the rest of your life": a qualitative study of health related quality of life in gout. AB - The objective of the study is to examine the impact of gout and its treatments on health-related quality of life (HRQOL) using focus group interviews. From the baseline phase of a cohort study of HRQOL in gout, 17 participants (15 males, mean age 71 years) with varying attack frequency and treatment with and without allopurinol participated in one of four focus group interviews. All interviews were audio-recorded and transcribed verbatim. Data was analysed thematically. Physical and psychosocial HRQOL in gout was affected by characteristics of acute gout (particularly the unpredictable nature of attacks, location of joint involved in an attack, pain and modifications in lifestyle), lack of understanding of gout by others (association with unhealthy lifestyle, symptoms ridiculed as non-severe and non-serious) as well as participants (not considered a disease) and the lack of information provided by physicians (about causes and pharmacological as well as non-pharmacological treatments of gout). Participants emphasised the impact of acute attacks of gout and prioritised dietary modifications and treatment of acute attacks over long-term urate-lowering therapy. Characteristics of acute gout, lack of understanding and information about gout and its treatments perpetuate poor HRQOL. HRQOL (maintenance of usual diet and reduced frequency of attacks) was associated with urate-lowering treatment. Better patient, public and practitioner education about gout being a chronic condition associated with co-morbidities and poor HRQOL may improve understanding and long-term treatment of gout. PMID- 26245723 TI - Genetic polymorphism of 3' untranslated region of zeta-chain associated protein kinase 70 kDa in southern Taiwanese patients with rheumatoid arthritis. AB - T cell activation participates in the pathogenesis of rheumatoid arthritis (RA), and the signaling molecule zeta-chain-associated protein kinase 70 kDa (ZAP-70) plays a crucial role in this process. Different mutations in the coding sequence of ZAP-70 are involved in a variety of immunological phenotypes, and recent evidence indicates that genetic variations within the 3' untranslated regions (UTR) of microRNA binding sites may affect the hybridization with target mRNAs, leading to phenotype changes with disease status. In this study, we evaluated the possible effect of ZAP-70 polymorphism as a genetic risk factor in RA by examining the single-nucleotide polymorphism in 100 patients and 100 ethnicity- and sex-matched healthy individuals from southern Taiwan. In both groups, the genotype distribution of rs2278699 in the 3' UTR was in the Hardy-Weinberg equilibrium. In RA, there were higher frequencies of the G allele (15.5 versus 8.0 %, odds ratio 2.1, P = 0.020) and significant differences in the trend of various genotypes (P = 0.024). The results suggest that genetic polymorphism in the 3' UTR of ZAP-70 is associated with RA susceptibility in southern Taiwanese. PMID- 26245724 TI - Effects of music on pain in patients with fibromyalgia. AB - Fibromyalgia syndrome (FMS) is a chronic syndrome characterized by diffuse musculoskeletal system pain and painful tender points in certain areas of the body. The aim of the investigation was to determine the effects of music on pain in fibromyalgia patients. This randomized clinical trial was carried out with 37 fibromyalgia outpatients as an experimental group (n = 21) and control group (n = 16) at a University Hospital Internal Medicine and Rheumatology Clinic between 1 June and 1 December 2014. The research instruments used were descriptive characteristics questionnaire, Visual Analogue Scale (VAS), music CD which includes water and wave sounds recommended by the Turkish Psychological Association for psychological relaxation, and pain evaluation form. According to the findings, the average age of patients was 43.59 years +/- 10.30, 94.6 % were women and 81.1 % were married. The fibromyalgia patients had the disease ranged from 1 month to 20 years, the average of disease duration was 23.6 +/- 45.5 months, and the average of pain intensity was 6.89 +/- 1.64 on the VAS. Average pain was reported in the experimental group in VAS on day 1 (5.45 +/- 2.73), day 7 (4.57 +/- 2.71), and day 14 (4.14 +/- 2.45), and significant reduction in pain in the listening music group was seen (p = 0.026). A repeated measure analysis of variance controlling for differences between days demonstrated a significant decrease in pain between day 1 and day 14 (p = 0.022). There was no significant decrease in pain among control group participants. The effect of music has been found to control pain in fibromyalgia patients. Music therapy should be suggested in pain management for fibromyalgia patients as an non-pharmacologic nursing intervention. PMID- 26245725 TI - Comparison of the functionality of pelvic floor muscles in women who practice the Pilates method and sedentary women: a pilot study. AB - INTRODUCTION AND HYPOTHESIS: The Pilates method is a form of physical exercise that improves the control of the core muscles, improving the conditioning of all the muscle groups that comprise the core, including the pelvic floor muscles (PFM). Thus, this study had the goal of verifying the existence of differences in the functioning of the PFM in women who practice the Pilates method and sedentary women. METHODS: This was an observational, cross-sectional pilot study. A sample size calculation was performed using preliminary data and it determined that the sample should have at least 24 individuals in each group. The participants were 60 women aged 20 to 40 years; 30 women practiced the Pilates method (PMG) and 30 were sedentary (SG). An anamnesis file was used to collect personal data and assess the knowledge and perception of the PFM. The Perina perineometer and vaginal palpation were used to determine the functionality of the PFM. RESULTS: There was no significant difference between the PMG and the SG in any of the variables analyzed. CONCLUSIONS: We concluded that the functionality of the PFM in younger women who practice the Pilates method is not different from that of sedentary women. PMID- 26245726 TI - Posterior tibial nerve stimulation in the management of lower urinary tract symptoms in patients with multiple sclerosis. AB - INTRODUCTION AND HYPOTHESIS: Bladder dysfunction is a frequent symptom complex in patients with multiple sclerosis (MS) and often compromises the patient's quality of life. Pharmacotherapy has been poorly studied in the MS population showing contradictory results and reduced compliance owing to intolerable side effects. A new neuromodulation technique known as percutaneous tibial nerve stimulation (PTNS) has shown good efficacy and safety in the treatment of neurogenic and non neurogenic lower urinary tract symptoms. In this article we review the literature and critically summarise the scientific evidence supporting the use of PTNS in the treatment of lower urinary tract symptoms (LUTS) in patients with MS. METHODS: We performed a computer-aided literature search in PubMed and EMBASE up to January 2015 to identify randomised controlled trials, case-control trials and prospective observational cohort studies. RESULTS: A total of 7 open-label, prospective studies and 313 MS patients were included. Three studies reported clinical and urodynamic outcomes at 3 to 9 months after PTNS; one study assessed the long-term efficacy of PTNS; two studies reported the acute effect of PTNS on urodynamic findings; one study assessed whether motor and sensory responses during PTNS could predict treatment outcome. None of the studies included a control group. CONCLUSIONS: Despite the very limited data PTNS seems an effective and safe treatment option in the management of LUTS in patients with MS. PMID- 26245727 TI - HPV Vaccine Uptake Among Canadian Youth and The Role of the Nurse Practitioner. AB - The human papillomavirus (HPV) infects approximately 550,000 Canadians annually. Cancers of the cervix, mouth, anus, throat and neck are caused by various strains of the virus. The virus also causes genital warts. The disease and economic burden of HPV is high. Primary prevention through vaccine administration prior to onset of sexual activity is evidenced as best practice. Two vaccines are available, Gardasil and Cervarix. Consistent with global practices in developed countries, these vaccines are currently publicly funded for females and provided in school-based clinics in all provinces and territories in Canada. Despite well documented efficacy with minimal adverse effects, the uptake of these vaccines remains low in all countries, including Canada. Although HPV immunization rates have increased, they remain significantly below the rates of other vaccine preventable diseases. This is puzzling since school-based clinics and public funding presumably increase vaccine access. Barriers explicated include family lack of knowledge about the vaccine, and attitudes that are not informed by science and epidemiology. There is evidence that a health provider's recommendation is the single biggest influence on uptake. However, not all providers are cognizant about emerging issues in this area, including controversies about universal coverage for boys as well as girls, new vaccines and more. Nurse practitioners are in a position to collaborate with public health agencies to expand knowledge and coverage across Canada. PMID- 26245728 TI - Motor Threshold: A Possible Guide to Optimizing Stimulation Parameters for Motor Cortex Stimulation. AB - OBJECTIVES: No widely accepted programming guidelines for motor cortex stimulation (MCS) exist. We propose that an individual's effective stimulation voltage can be predicted as their percentage of motor threshold (PMT). MATERIALS AND METHODS: Seven patients already successfully treated with MCS for neuropathic pain were included. Patients received stimulation that was the same as their baseline PMT ("medium"), 10% higher ("high") or 10% lower ("low") in a blinded, randomized study. Outcome was assessed after 14 days with the visual analogue scale for pain, the McGill pain questionnaire, and the SF-36 questionnaire. RESULTS: The best treatment response (mean VAS 3.4) was seen with the medium setting which was at a mean of 62% PMT. High and low settings both resulted in a significant increase in pain compared with the medium setting (mean VAS 6.0 and 6.3, respectively) and a significant decrease in SF-36 scores. No significant difference in pain control was observed between the high and low settings. The mean time from changes in treatment settings to reported change in pain level was 2.9 days (+/-1.0 day). CONCLUSIONS: We propose that the PMT represents an important parameter that measures the degree to which MCS may be affecting the motor cortex. A mean PMT of 62% was required for effective pain relief. Higher settings did not result in increased therapeutic efficacy but rather in a significant increase in pain. Targeting therapy to a PMT level may speed initial programming, allow more consistent longitudinal follow-up, and be a basis for a standardized programming paradigm. PMID- 26245729 TI - Capsule Commentary on Chodos et al., Hospitalization-Associated Disability in Adults Admitted to a Safety Net Hospital. PMID- 26245730 TI - Capsule commentary on Agarwal et al., Healthcare Expenditures Associated with Depression among Individuals with Osteoarthritis: Post-Regression Linear Decomposition Approach. PMID- 26245732 TI - Assessing the Accuracy of Three National Physician Sampling Frames. PMID- 26245731 TI - Low ALT Levels Independently Associated with 22-Year All-Cause Mortality Among Coronary Heart Disease Patients. AB - BACKGROUND: Low alanine aminotransferase (ALT) blood levels are known to be associated with frailty and increased risk of long-term mortality in certain populations. However, the contribution of this marker to long-term outcome has not been assessed in patients with chronic coronary heart disease. OBJECTIVE: The aim of the current study was to assess the association between low ALT values and long-term, 22.8-year, all-cause mortality in this population. PARTICIPANTS: We examined the association of low ALT (<17 IU/l) with long-term all-cause mortality in the Bezafibrate Infarction Prevention (BIP) Registry population. KEY RESULTS: Appropriate laboratory and survival data were available for 6,575 patients, without known liver pathology, included in the BIP registry, with a median follow up period of 22.8 years. The cumulative probability of all-cause mortality was significantly higher in the low ALT group compared with patients with higher ALT levels (65.6 % vs. 58.4 %; log-rank p < 0.001). Consistently, multivariate analysis, adjusted for multiple established predictors of mortality in this population, demonstrated that low ALT is independently associated with 11 % greater long-term (22.8 years) mortality risk [HR 1.11 (95 % confidence interval: 1.03-1.19; adjusted p < 0.01)]. CONCLUSIONS: Low ALT levels are associated with increased long-term mortality among middle-aged patients with stable coronary heart disease. This association remained statistically significant after adjustment for other well-established risk factors for mortality in this population. PMID- 26245733 TI - Health Literacy During Aging. PMID- 26245734 TI - Health Literacy During Aging. PMID- 26245735 TI - Radiation dose reduction during neurointerventional procedures by modification of default settings on biplane angiography equipment. AB - BACKGROUND: Neurointerventional procedures represent a significant source of ionizing radiation. We sought to assess the effect during neurointerventional procedures of varying default rates of radiation dose in fluoroscopy (F) and image acquisition (IA) modes, and frame rates during cine acquisition (CINE) on total X-ray dose, acquisition exposures, fluoroscopy time, and complications. METHODS: We retrospectively reviewed procedures performed with two radiation dose and CINE settings: a factory setting dose cohort (30 patients, F 45 nGy/pulse, IA 3.6 MUGy/pulse, factory CINE frame rate) and a reduced dose cohort (30 patients, F 32 nGy/pulse, IA 1.2 MUGy/pulse, with a decreased CINE frame rate). Total radiation dose, dose area product, number of acquisition exposures, fluoroscopy time, and complications were compared between the groups. Means comparisons (t tests) were employed to evaluate differences in the outcome variables between the two groups. p Value <0.05 was considered significant. RESULTS: The reduced dose cohort had a significant reduction in mean radiation dose (factory, 3650 mGy; reduced, 1650 mGy; p=0.005) and dose area product (factory, 34 700 MUGy*m(2); reduced, 15 000 MUGy*m(2); p=0.02). There were no significant differences between cohorts in acquisition exposure (p=0.73), fluoroscopy time (p=0.45), or complications. CONCLUSIONS: Significant reductions in radiation dose delivered by neurointerventional procedures can be achieved through simple modifications of default radiation dose in F and IA and frame rate during CINE without an increase in procedural complexity (fluoroscopy time) or rate of complications. PMID- 26245736 TI - Variability of results of recent acute endovascular trials: a statistical analysis. PMID- 26245737 TI - Editorial: Scleroderma: Bringing a Disease From Black-and-White Into Technicolor. PMID- 26245738 TI - Transient elevation in serum carcinoembryonic antigen while on adjuvant chemotherapy for colon cancer: Is this of prognostic importance? AB - AIMS: Serum carcinoembryonic antigen (CEA) is used to detect relapses from colon cancer following initial surgical or adjuvant treatment. There are little data on transient elevations of CEA while receiving chemotherapy in the adjuvant setting. We aimed to review patterns of change in CEA levels while receiving adjuvant chemotherapy and investigate associations between transient rises and patient survival. METHODS: A retrospective review of patients in Auckland with a new diagnosis of colon cancer in 2001 or 2005 was performed and CEA values were collected. Three patient groups were defined: no increase in CEA; transient elevation in CEA; and persistent elevation in CEA. Kaplan-Meier methods were used to estimate 5-year survival; Cox regression and log-rank P-values were used to compare survival. RESULTS: Sixty-one patients with stage II or III disease who had received adjuvant chemotherapy had sufficient CEA data to be included in the analysis. Patients were followed up for a minimum of 7.4 years (or death). The 5 year overall survival was higher in the transient elevation in CEA group 95.0% and the no increase in CEA group 85.2% compared with the persistent elevation in CEA group 42.9%. There was no statistically significant difference in overall survival between the transient elevation group and the no increase group (P = 0.2). CONCLUSIONS: The group with a transient elevation in CEA during adjuvant chemotherapy did not have a poorer prognosis compared with the group that had no increase in CEA. This will be further examined in a population-based New Zealand wide study of colorectal cancer diagnosis, treatment and outcome. PMID- 26245739 TI - Marriage Strategy of Structure and Composition Designs for Intensifying Ultrasound & MR & CT Trimodal Contrast Imaging. AB - Despite great efforts having been devoted to the design of multimodal imaging probe, almost all design principles of nanotheranostic agents subordinate to simple assemblies of building blocks, resulting in complex preparation process and discounted ability, that is, 1 + 1 < 2. In this report, a novel design strategy, marriage of structure design and composition design that can maximize imaging ability of each building block, ultimately achieving 1 + 1 >= 2, has been established. Moreover, a high-efficient ultrasound (US) & MR & CT trimodal contrast agent acts as model to instantiate this design strategy, wherein nanoparticles-induced nonlinear scattering and rattle-type structure-induced double scattering enhancing US imaging, and uniform distribution of Mn(2+) paramagentic centers and "core-satellite" structure of Au atoms favoring enhanced MR imaging and CT imaging, respectively have been validated, achieving optimization of structure design. Importantly, the selected components, silica, Au and MnO are endowed with excellent biocompatibility, displaying the marriage strategy of composition design with aforementioned structure optimization. In in vivo evaluations, such a biocompatible trimodal probe is demonstrated of excellent performance in intensifying CT, MR and US imaging in vivo, especially after positively charged modification by PEI promoting more probes retained in tumor. More importantly, as a universal design strategy, the involved principles in constructing such a US&MR&CT trimodal imaging probe promise great potentials in guiding designs of other materials-based multimodal imaging probe. PMID- 26245740 TI - Heart Failure in Women--Insights from the Framingham Heart Study. AB - In the latter half of the 20th century, among participants of the Framingham Heart Study, incidence of heart failure (HF) has declined by about a third in women but not in men and survival after the onset of HF has improved in both sexes; however, HF remains highly lethal with over 50% dying within 5 years after onset of HF. Overall, the 8-year relative risk of HF is 24% lower in women compared with men. The 8-year incidence rates of HF with preserved ejection fraction (HFPEF; EF >45%) and HF with reduced EF (HFREF; EF <= 45%) in women and HFPEF in men are similar; however, men have a 2-fold higher cumulative incidence of HFREF than HFPEF. The lifetime risk of HF is about 20% in both women and men at 40, 50, 60, 70, and 80 years of age. Contribution of hypertension and diabetes mellitus to the risk of HF was more prominent in women than in men. Serum levels of several biomarkers were distinctly different in women compared with men and had differential effects on left ventricular structure and function; however, the strength and direction of the association between biomarkers levels and HF risk were generally similar in women and men. In individuals with HF, about two-thirds of the underlying cause of death and about one-half of the immediate cause of death were due to cardiovascular causes. Non-cardiovascular underlying and immediate causes of death were more evident in HFPEF. PMID- 26245741 TI - Multiphoton harvesting metal-organic frameworks. AB - Multiphoton upconversion is a process where two or more photons are absorbed simultaneously to excite an electron to an excited state and, subsequently, the relaxation of electron gives rise to the emission of a photon with frequency greater than those of the absorbed photons. Materials possessing such property attracted attention due to applications in biological imaging, photodynamic therapy, three-dimensional optical data storage, frequency-upconverted lasing and optical power limiting. Here we report four-photon upconversion in metal-organic frameworks containing the ligand, trans, trans-9,10-bis(4 pyridylethenyl)anthracene. The ligand has a symmetrical acceptor-pi-donor-pi acceptor structure and a singlet biradical electronic ground state, which boosted its multiphoton absorption cross-sections. We demonstrate that the upconversion efficiency can be enhanced by Forster resonance energy transfer within host-guest metal-organic frameworks consisting of encapsulated high quantum yielding guest molecules. Using these strategies, metal-organic framework materials, which can exhibit frequency-upconverted photoluminescence excited by simultaneous multiphoton absorption, can be rationally designed and synthesized. PMID- 26245742 TI - Multi-modal imaging of tumor cellularity and Tryptophan metabolism in human Gliomas. AB - BACKGROUND: To assess gliomas using image-based estimation of cellularity, we utilized isotropic diffusion spectrum imaging (IDSI) on clinically feasible diffusion tensor imaging (DTI) and compared it with amino acid uptake measured by alpha[(11)C]methyl-L-tryptophan positron emission tomography (AMT-PET). METHODS: In 10 patients with a newly-diagnosed glioma, metabolically active tumor regions were defined in both FLAIR hyperintense areas and based on increased uptake on AMT-PET. A recently developed independent component analysis with a ball and stick model was extended to perform IDSI in clinical DTI data. In tumor regions, IDSI was used to define tumor cellularity which was compared between low and high grade glioma and correlated with the glioma proliferative index. RESULTS: The IDSI-derived cellularity values were elevated in both FLAIR and AMT-PET-derived regions of high-grade gliomas. ROC curve analysis found that the IDSI-derived cellularity can provide good differentiation of low-grade from high-grade gliomas (accuracy/sensitivity/specificity of 0.80/0.80/0.80). . Both apparent diffusion coefficient (ADC) and IDSI-derived cellularity showed a significant correlation with the glioma proliferative index (based on Ki-67 labeling; R = 0.95, p < 0.001), which was particularly strong when the tumor regions were confined to areas with high tryptophan uptake excluding areas with peritumoral edema. CONCLUSION: IDSI-MRI combined with AMT-PET may provide a multi-modal imaging tool to enhance pretreatment assessment of human gliomas by evaluating tumor cellularity and differentiate low-grade form high-grade gliomas. PMID- 26245743 TI - Functional and morphological study of retinal photoreceptor cell degeneration in transgenic rabbits with a Pro347Leu rhodopsin mutation. AB - PURPOSE: To investigate the process of retinal degeneration by analyzing the functional and morphological findings in transgenic rabbits with a Pro347Leu rhodopsin mutation. METHODS: Wild-type (WT) and transgenic (Tg) rabbits at ages 4, 8 and 12 months were used. We conducted functional evaluation by recording the changes in the pupil response to red and blue light stimulation and the amplitude of the electroretinography (ERG). Morphologically, rod and cone distribution was examined using light and electron microscopy. Immunostaining for the identification of retinal ganglion cells (RGCs) was also confirmed by injecting a TUJ-1 monoclonal antibody. RESULTS: Pupil constriction for infrared pupillography and the a- and b-waves for ERG in Tg rabbits decreased with increasing age; the differences were compared to the age-matched WT rabbits. The subnormal ERG in the Tg rabbits, especially the a-wave decrease and pupil constriction with a long latency time, was induced only during exposure to blue light stimulation at 12 months. Light and electron microscopic findings showed a progressive loss of photoreceptor cells over time manifesting by 8 months in the peripheral retina. Moreover, pyknotic nuclei of the outer nuclear layer in the center of the visual streak were observed. At 12 months, there was disappearance of the rods and ballooning degeneration of the cones. Some remaining RGCs had large cell bodies with long branching dendrites. CONCLUSIONS: The changes in the pupil light response and amplitude of the ERG could be used to predict the state of retinal degeneration in the Tg rabbit. PMID- 26245744 TI - Towards a scientific interpretation of the terroir concept: plasticity of the grape berry metabolome. AB - BACKGROUND: The definition of the terroir concept is one of the most debated issues in oenology and viticulture. The dynamic interaction among diverse factors including the environment, the grapevine plant and the imposed viticultural techniques means that the wine produced in a given terroir is unique. However, there is an increasing interest to define and quantify the contribution of individual factors to a specific terroir objectively. Here, we characterized the metabolome and transcriptome of berries from a single clone of the Corvina variety cultivated in seven different vineyards, located in three macrozones, over a 3-year trial period. RESULTS: To overcome the anticipated strong vintage effect, we developed statistical tools that allowed us to identify distinct terroir signatures in the metabolic composition of berries from each macrozone, and from different vineyards within each macrozone. We also identified non volatile and volatile components of the metabolome which are more plastic and therefore respond differently to terroir diversity. We observed some relationships between the plasticity of the metabolome and transcriptome, allowing a multifaceted scientific interpretation of the terroir concept. CONCLUSIONS: Our experiments with a single Corvina clone in different vineyards have revealed the existence of a clear terroir-specific effect on the transcriptome and metabolome which persists over several vintages and allows each vineyard to be characterized by the unique profile of specific metabolites. PMID- 26245745 TI - The new concept of ureteral access sheath with guidewire disengagement: One wire does it all. AB - PURPOSE: To prospectively evaluate the new Flexor(c)ParallelTM Rapid ReleaseTM (Cook((r)), Bloomington, IN, USA) access sheath (UAS) which allows the use of a single wire to serve as both safety and working guide. MATERIALS AND METHODS: Between June and September 2014, adult patients from five European centers who underwent flexible ureteroscopy (fURS) for therapeutic and diagnostic purposes were included. The 12/14Fr Flexor(c)ParallelTM UAS was evaluated. Data were collected and examined by both univariate and multivariate analyses. The UAS material and usage characteristics were rated per case by the surgeons on a scale from very bad to very good. RESULTS: In total, 134 UASs were used in 67 male and 67 female patients. Fifty percent of ureters (67 patients) were pre-stented. Ninety percent of the procedures were therapeutic. The overall successful insertion rate was 94 %. Pre-stenting status was the only independent factor for a successful access sheath insertion: 98.5 % of the pre-stented patients had a successful UAS placement vs. 82 % of non-pre-stented (p = 0.001, C.I. 95 %: 1.2). Evaluation of the material and radiopacity was considered very good in over 90 % of cases. Release of the guidewire, hydrophilic coating, gliding of the endoscope and repeatability were considered very good in over 80 %. There were two (1.4 %) UAS malfunctions and one submucosal lesion reported. CONCLUSIONS: The use of the Flexor(c)ParallelTM Rapid ReleaseTM (Cook((r)), Bloomington, IN, USA) with usage of a single guidewire in a prospective multicentric scenario was clinically applicable in the majority of cases. Pre-stenting increased the chance of a successful insertion from 82 to 98.5 %. PMID- 26245746 TI - Construct, content and face validity of the camera handling trainer (CHT): a new E-BLUS training task for 30 degrees laparoscope navigation skills. AB - PURPOSE: Assessing construct, face and content validity of the camera handling trainer (CHT), a novel low-fidelity training device for 30 degrees laparoscope navigation skills. METHODS: We developed a custom-designed box trainer with clinically based graphic targets. A total of 117 participants, stratified according to their previous experience (novice, competent, expert), took part to a CHT session and subsequently were asked to fill out a survey to assess the impact of the CHT on their 30 degrees laparoscope navigation skills. Sixty of them were also studied for task performance during a 1-h session, with multiple time measurements. RESULTS: All participants, regardless of the previous experience, significantly improved their performance after the CHT session. Regarding construct validity, the mean task performance on the last measurement for novice group was found to be comparable to the mean first attempt of both competent (p = 0.12) and expert (p = 0.24) participants. All participants agreed that "the CHT is a valid training tool" and that "the CHT should be part of the regular dry laboratory training sessions", assessing both face and content validity. Limitations include the need for assessment of predictive validity. CONCLUSIONS: The CHT is a valid training tool for 30 degrees laparoscope navigation and thus should be considered as one of the fundamental exercises during basic laparoscopic hands-on training sessions for urologists. PMID- 26245748 TI - State-dependent cooperation in burying beetles: parents adjust their contribution towards care based on both their own and their partner's size. AB - Handicapping experiments on species with biparental care show that a focal parent increases its contribution when its partner is handicapped. Such results are interpreted as evidence for negotiation, whereby each parent adjusts its amount of care to that of its partner. However, it is currently unclear whether the focal parent responds to a change in its handicapped partner's behaviour or state. To address this gap, we conducted an experiment on the burying beetle Nicrophorus vespilloides where we first generated different-sized males and females by varying the duration of larval development. We then used a 2 * 2 factorial design in which a small or large male was paired with a small or large female. Small females provided less direct care (food provisioning and interactions with larvae) than large females, and both males and females provided less direct care when paired with a small partner. Thus, the focal parent adjusted its contribution towards care based on both its own state and that of its partner. There was also evidence for negotiation between the two parents as the focal parent adjusted its contribution based on the amount of care by its partner. However, there was no evidence that negotiation accounted for how the focal parent responded to its partner's size. Our results have important implications for our understanding of biparental cooperation as they show that each parent adjusts its contribution not only based on the amount of care provided by its partner but also based on its own state and its partner's state. PMID- 26245747 TI - Risk of metastasis for T1a renal cell carcinoma. AB - INTRODUCTION: While active surveillance for small renal mass is gaining acceptance, controversy still continues on true metastatic potential of small renal cell carcinoma (RCC). Thus, we investigated the risks of synchronous/metachronous metastases and their potential predictors among T1a RCC patients who underwent surgical treatment. METHODS: We reviewed data from 2114 patients who received radical or partial nephrectomy for small renal tumor (<= 4 cm) from 1990 to 2013. For our study, patients were stratified into four different groups according to tumor size (group 1: 0-1.0 cm, group 2: 1.1-2.0 cm, group 3: 2.1-3.0 cm, group 4: 3.1-4.0 cm). Univariate and multivariate analyses were performed to analyze metastatic potentials according to tumor size and identify useful predictors of metastases. RESULTS: Among 1913 T1a RCC patients, there were low but nonnegligible rates of metastases (group 2: 1.1 %, group 3: 3.3 %, group 4: 6.0 %, respectively). Kaplan-Meier analysis showed significant differences in metastasis-free survivals between groups (p < 0.001). A linear positive association was observed between tumor size and metastatic rate (p < 0.001). Diabetic T1a RCC patients showed significantly inferior metastasis-free survival than nondiabetic counterparts (p = 0.003). Multivariate analysis revealed that tumor size and history of diabetes mellitus were independently associated with metastasis in T1a RCC. CONCLUSIONS: As T1a RCCs present low but nonnegligible risk of metastasis, patients with small renal mass should be counseled on such risk when offered active surveillance. Larger tumor size and history of diabetes mellitus may be associated with higher risk of metastasis in T1a RCC. PMID- 26245749 TI - Clinicopathologic and Immunophenotypic Characterization of 25 Cases of Acinic Cell Carcinoma with High-Grade Transformation. AB - Acinic cell carcinoma (AiCC) with high-grade transformation is a rare variant of AiCC composed of both a conventional low-grade (LG) AiCC and a separate high grade (HG) component. We describe here, the clinicopathologic and immunohistochemical features of 25 cases diagnosed between 1990 and 2015. Available tissue was analyzed and compared with a cohort of pure LG AiCC for the morphologic and immunophenotypic profile. Incidence was higher in females (1.8:1) than males with an overall mean age at presentation of 63.2 years. All tumors occurred in the parotid gland including 76% with facial nerve trunk and branches involvement. Most patients were treated with extensive resection and adjuvant therapy. Local recurrence or distant metastasis occurred in most patients, with 72.7% dead with disease (mean 2.9 years) and 3 patients alive with disease (mean 2.4 years). The majority of the tumors were composed of a LG microcystic AiCC and a HG component consisting of invasive lobules of undifferentiated cells with predominantly solid, cribriform, and glandular patterns. Acinic differentiation was still present in HG areas but aggressive features such as perineural invasion (76%), lymphovascular invasion (62%), positive margins (72%), high mitotic rate, atypical mitoses and/or comedonecrosis (86%) were easily identified. Compared to the pure LG AiCC, the cases with HG transformation showed significantly increased expression of cyclin-D1, p53 and Ki-67. Most HG areas of AiCC expressed membranous beta-catenin (92%) and were negative for p63 (three cases were focally positive), S100, SMA, androgen, and estrogen receptors. DOG1 expression was present in all LG AiCC tested with retained expression in 91% of cases with HG transformation, supporting acinic differentiation in the HG foci. Recognition of AiCC with high-grade transformation is imperative as more aggressive clinical management is warranted. PMID- 26245750 TI - Red/blue-shift dual-directional regulation of alpha-(Ca, Sr)2SiO4:Eu(2+) phosphors resulting from the incorporation content of Eu(2+)/Sr(2+) ions. AB - In this work, tunable emission from green to red and the inverse tuning from red to green in alpha-(Ca, Sr)2SiO4:Eu(2+) phosphors were demonstrated magically by varying the incorporation content of Eu(2+) and Sr(2+) ions, respectively. The tunable emission properties and the tuning mechanism of red-shift resulting from the Eu(2+) content as well as that of blue-shift induced by the Sr(2+) content were investigated in detail. As a result of fine-controlling the incorporation content of Eu(2+), the emission peak red-shifts from 541 nm to 640 nm. On the other hand, the emission peak inversely blue-shifts from 640 nm to 546 nm through fine-adjusting the incorporation content of Sr(2+). The excellent tuning characteristics for alpha-(Ca, Sr)2SiO4:Eu(2+) phosphors presented in this work exhibited their various application prospects in solid-state lighting combining with a blue chip or a near-UV chip. PMID- 26245751 TI - The prognostic value of dobutamine stress echocardiography amongst British Indian Asian and Afro-Caribbean patients: a comparison with European white patients. AB - BACKGROUND: The incidence of cardiovascular disease is considerably disparate among different racial and ethnic populations. While dobutamine stress echocardiography (DSE) has been shown to be useful in Caucasian patients, its role among ethnic minority groups remains unclear. This study aimed to investigate the prognostic importance of DSE in three ethnic groups in the UK. METHODS: DSE was performed on 6231 consecutive patients. After exclusions, 5329 patients formed the study (2676 [50.2%] Indian Asian, 2219 [41.6%] European white and 434 [8.1%] Afro-Caribbean). Study outcome measures were non-fatal cardiac events (NFCE) and all-cause mortality. RESULTS: There were 849 (15.9%) NFCE and 1365 (25.6%) deaths over a median follow-up period of 4.6 years. In total 1174 (22%) patients had inducible myocardial ischaemia during DSE, 859 (16.1%) had fixed wall motion abnormalities and 3645 (68.4%) patients had a normal study. Ethnicity did not predict events. Among the three ethnic groups, ischaemia on DSE was associated with 2 to 2.5 times the risk of non-fatal cardiac events and 1.2 to 1.4 times the risk of all-cause mortality. Peak wall motion score index was the strongest independent predictor of non-fatal cardiac events and all-cause mortality in all groups. The C statistic for the prediction of NFCE and all-cause mortality were significantly higher when DSE parameters were added to the standard risk factors for all ethnic groups. CONCLUSIONS: DSE is a strong predictor of NFCE and all-cause mortality and provides predictive information beyond that provided by standard risk factors in three major racial and ethnic groups. No major differences among racial and ethnic groups in the predictive value of DSE was detected. PMID- 26245753 TI - Statin use and mortality in rheumatoid arthritis: a general population-based cohort study. AB - BACKGROUND: Dual lipid-lowering and anti-inflammatory properties of statins may lead to survival benefits in patients with rheumatoid arthritis (RA). However, data on this topic are limited, and the role of statins in RA remains unclear. OBJECTIVES: To examine the association of statin use with overall mortality among patients with RA in a general population context. METHODS: We conducted an incident user cohort study with time-stratified propensity score matching using a UK general population database. The study population included individuals aged >=20 years who had a diagnosis of RA and had used at least one disease-modifying antirheumatic drug (DMARD) between January 2000 and December 2012. To closely account for potential confounders, we compared propensity score matched cohorts of statin initiators and comparators (non-initiators) within 1-year cohort accrual blocks. RESULTS: 432 deaths occurred during follow-up (mean 4.51 years) of the 2943 statin initiators for an incidence rate of 32.6/1000 person-years (PY), while the 513 deaths among 2943 matched comparators resulted in an incidence rate of 40.6/1000 PY. Baseline characteristics were well-balanced across the two groups. Statin initiation was associated with a 21% lower risk of all-cause mortality (HR=0.79, 95% CI 0.68 to 0.91). When we defined RA by its diagnosis code alone (not requiring DMARD use), the corresponding HR was 0.81 (95% CI 0.74 to 0.90). CONCLUSIONS: Statin initiation is associated with a lower risk of mortality among patients with RA. The magnitude of association is similar to that seen in previous randomised trials among the general population. PMID- 26245754 TI - Comparison of the efficacies of abatacept and tocilizumab in patients with rheumatoid arthritis by propensity score matching. AB - OBJECTIVE: To compare the clinical outcomes at 1 year after the treatment with either abatacept or tocilizumab in patients with rheumatoid arthritis in routine clinical practice. METHODS: To overcome potential bias in allocation to treatment with abatacept or tocilizumab, a propensity score based on multiple baseline characteristics variables was calculated and 102 of 194 patients treated with abatacept and 102 of 273 patients treated with tocilizumab were statistically extracted. Clinical outcomes were assessed. RESULTS: The baseline characteristics were statistically comparable. At week 52, 72%/69% of patients (abatacept/tocilizumab) were still receiving treatment. The Simplified Disease Activity Index (SDAI) decreased from 28.7/27.7 at baseline to 14.0/12.5 at week 52 with abatacept/tocilizumab, respectively. At week 52, the remission rates for abatacept/tocilizumab were 18%/20%, respectively. No statistical difference in clinical efficacy between abatacept and tocilizumab was seen. Moreover, a subanalysis showed that abatacept and tocilizumab had similar effectiveness with or without methotrexate. However, prognostic factors at baseline contributing to the Clinical Disease Activity Index at week 52 were different between the two groups by multiple regression analysis. A higher rheumatoid factor (RF) titre and lower SDAI at baseline were associated with lower SDAI at week 52 in patients treated with abatacept, whereas patients receiving tocilizumab with a lower Health Assessment Questionnaire Disability Index and who were biologics-naive at baseline had a lower SDAI at week 52. CONCLUSIONS: We compared patients treated with abatacept or tocilizumab after statistical adjustment by propensity score matching. Clinical efficacies, including SDAI, were comparable in both treatment groups. However, the predictive factors were different: abatacept appears to benefit patients with higher RF titres, and early induction of tocilizumab is an important factor for good clinical efficacy. PMID- 26245752 TI - Cluster randomized controlled trial protocol: addressing reproductive coercion in health settings (ARCHES). AB - BACKGROUND: Women ages 16-29 utilizing family planning clinics for medical services experience higher rates of intimate partner violence (IPV) and reproductive coercion (RC) than their same-age peers, increasing risk for unintended pregnancy and related poor reproductive health outcomes. Brief interventions integrated into routine family planning care have shown promise in reducing risk for RC, but longer-term intervention effects on partner violence victimization, RC, and unintended pregnancy have not been examined. METHODS/DESIGN: The 'Addressing Reproductive Coercion in Health Settings (ARCHES)' Intervention Study is a cluster randomized controlled trial evaluating the effectiveness of a brief, clinician-delivered universal education and counseling intervention to reduce IPV, RC and unintended pregnancy compared to standard-of-care in family planning clinic settings. The ARCHES intervention was refined based on formative research. Twenty five family planning clinics were randomized (in 17 clusters) to either a three hour training for all family planning clinic staff on how to deliver the ARCHES intervention or to a standard of-care control condition. All women ages 16-29 seeking care in these family planning clinics were eligible to participate. Consenting clients use laptop computers to answer survey questions immediately prior to their clinic visit, a brief exit survey immediately after the clinic visit, a first follow up survey 12 20 weeks after the baseline visit (T2), and a final survey 12 months after the baseline (T3). Medical record chart review provides additional data about IPV and RC assessment and disclosure, sexual and reproductive health diagnoses, and health care utilization. Of 4009 women approached and determined to be eligible based on age (16-29 years old), 3687 (92 % participation) completed the baseline survey and were included in the sample. DISCUSSION: The ARCHES Intervention Study is a community-partnered study designed to provide arigorous assessment of the short (3-4 months) and long-term (12 months) effects of a brief, clinician delivered universal education and counseling intervention to reduce IPC, RC and unintended pregnancy in family planning clinic settings. The trial features a cluster randomized controlled trial design, a comprehensive data collection schedule and a large sample size with excellent retention. TRIAL REGISTRATION: ClinicialTrials.gov NCT01459458. Registered 10 October 2011. PMID- 26245755 TI - EULAR-PReS points to consider for the use of imaging in the diagnosis and management of juvenile idiopathic arthritis in clinical practice. AB - To develop evidence based points to consider the use of imaging in the diagnosis and management of juvenile idiopathic arthritis (JIA) in clinical practice. The task force comprised a group of paediatric rheumatologists, rheumatologists experienced in imaging, radiologists, methodologists and patients from nine countries. Eleven questions on imaging in JIA were generated using a process of discussion and consensus. Research evidence was searched systematically for each question using MEDLINE, EMBASE and Cochrane CENTRAL. Imaging modalities included were conventional radiography, ultrasound, MRI, CT, scintigraphy and positron emission tomography. The experts used the evidence obtained from the relevant studies to develop a set of points to consider. The level of agreement with each point to consider was assessed using a numerical rating scale. A total of 13 277 references were identified from the search process, from which 204 studies were included in the systematic review. Nine points to consider were produced, taking into account the heterogeneity of JIA, the lack of normative data and consequent difficulty identifying pathology. These encompassed the role of imaging in making a diagnosis of JIA, detecting and monitoring inflammation and damage, predicting outcome and response to treatment, use of guided therapies, progression and remission. Level of agreement for each proposition varied according to the research evidence and expert opinion. Nine points to consider and a related research agenda for the role of imaging in the management of JIA were developed using published evidence and expert opinion. PMID- 26245756 TI - A psychometric analysis of outcome measures in peripheral spondyloarthritis. AB - OBJECTIVES: To assess the discriminatory capacity of various outcome measures and response criteria in patients with peripheral spondyloarthritis (pSpA). METHODS: Data originated from two randomised controlled trials, ABILITY-2 and Tnf Inhibition in PEripheral SpondyloArthritis (TIPES). Continuous outcome measures included patient's global assessment (PGA)/physician's global assessment of disease (PhGA), C-reactive protein (CRP), tender joint counts (TJC)/swollen joint counts (SJC), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and the Ankylosing Spondylitis Disease Activity Score (ASDAS). Dichotomous response criteria included Peripheral SpondyloArthritis Response Criteria (PSpARC), American College of Rheumatology (ACR), ASDAS and BASDAI response criteria. The capacity to discriminate between adalimumab and placebo groups was assessed by standardised mean differences (SMD) for continuous variables, and Pearson's chi(2) for dichotomous response criteria. RESULTS: Within each trial, the composite indices for axial SpA assessment, ASDAS-CRP (SMD: -0.63 and -0.89 in ABILITY-2 and the TIPES trial, respectively) and BASDAI (SMD: -0.50 and -0.73), and the single-item measures PGA (SMD: -0.47 and -1.12) and PhGA (SMD: -0.64 and 0.87) performed better than other single-item measures, such as CRP (SMD: -0.18 and -0.53), SJC or TJC. In general, the PSpARC and ACR response criteria discriminated better than ASDAS and BASDAI response criteria. CONCLUSIONS: The axial SpA-specific ASDAS-CRP and BASDAI, but also PGA and PhGA, demonstrated good discriminatory ability in patients with pSpA. The pSpA-specific pSpARC response criteria and the rheumatoid arthritis-specific ACR response criteria also discriminated well. To fully capture typical pSpA manifestations, it may be worth developing new pSpA-specific indices with better performance and face validity. TRIAL REGISTRATION NUMBERS: ABILITY-2: NCT01064856; TIPES: EUDRACT 2008-006885 27. PMID- 26245757 TI - Neutrophil microvesicles resolve gout by inhibiting C5a-mediated priming of the inflammasome. AB - OBJECTIVES: Gout is a highly inflammatory but self-limiting joint disease induced by the precipitation of monosodium urate (MSU) crystals. While it is well established that inflammasome activation by MSU mediates acute inflammation, little is known about the mechanism controlling its spontaneous resolution. The aim of this study was to analyse the role of neutrophil-derived microvesicles (PMN-Ecto) in the resolution of acute gout. METHODS: PMN-Ecto were studied in a murine model of MSU-induced peritonitis using C57BL/6, MerTK(-/-) and C5aR(-/-) mice. The peritoneal compartment was assessed for the number of infiltrating neutrophils (PMN), neutrophil microvesicles (PMN-Ecto), cytokines (interleukin 1beta, TGFbeta) and complement factors (C5a). Human PMN-Ecto were isolated from exudates of patients undergoing an acute gouty attack and functionally tested in vitro. RESULTS: C5a generated after the injection of MSU primed the inflammasome for IL-1beta release. Neutrophils infiltrating the peritoneum in response to C5a released phosphatidylserine (PS)-positive PMN-Ecto early on in the course of inflammation. These PMN-Ecto in turn suppressed C5a priming of the inflammasome and consequently inhibited IL-1beta release and neutrophil influx. PMN-Ecto mediated suppression required surface expression of the PS-receptor MerTK and could be reproduced using PS-expressing liposomes. In addition, ectosomes triggered the release of TGFbeta independent of MerTK. TGFbeta, however, was not sufficient to control acute MSU-driven inflammation in vivo. Finally, PMN-Ecto from joint aspirates of patients with gouty arthritis had similar anti inflammatory properties. CONCLUSIONS: PMN-Ecto-mediated control of inflammasome driven inflammation is a compelling concept of autoregulation initiated early on during PMN activation in gout. PMID- 26245758 TI - Deletion of angiotensin-converting enzyme 2 exacerbates renal inflammation and injury in apolipoprotein E-deficient mice through modulation of the nephrin and TNF-alpha-TNFRSF1A signaling. AB - BACKGROUND: The renin-angiotensin system (RAS) has been implicated in atherosclerotic lesions and progression to chronic kidney diseases. We examined regulatory roles of angiotensin-converting enzyme 2 (ACE2) in the apolipoprotein E (ApoE) knockout (KO) kidneys. METHODS: The 3-month-old wild-type, ApoEKO, ACE2KO and ApoE/ACE2 double-KO (DKO) mice in a C57BL/6 background were used. The ApoEKO mice were randomized to daily deliver either Ang II (1.5 mg/kg) and/or human recombinant ACE2 (rhACE2; 2 mg/kg) for 2 weeks. We examined changes in pro inflammatory cytokines, renal ultrastructure, and pathological signaling in mouse kidneys. RESULTS: Downregulation of ACE2 and nephrin levels was observed in ApoEKO kidneys. Genetic ACE2 deletion resulted in modest elevations in systolic blood pressure levels and Ang II type 1 receptor expression and reduced nephrin expression in kidneys of the ApoE/ACE2 DKO mice with a decrease in renal Ang-(1 7) levels. These changes were linked with marked increases in renal superoxide generation, NADPH oxidase (NOX) 4 and proinflammatory factors levels, including interleukin (IL)-1beta, IL-6, IL-17A, RANTES, ICAM-1, Tumor necrosis factor-alpha (TNF-alpha) and TNFRSF1A. Renal dysfunction and ultrastructure injury were aggravated in the ApoE/ACE2 DKO mice and Ang II-infused ApoEKO mice with increased plasma levels of creatinine, blood urea nitrogen and enhanced levels of Ang II in plasma and kidneys. The Ang II-mediated reductions of renal ACE2 and nephrin levels in ApoEKO mice were remarkably rescued by rhACE2 supplementation, along with augmentation of renal Ang-(1-7) levels. More importantly, rhACE2 treatment significantly reversed Ang II-induced renal inflammation, superoxide generation, kidney dysfunction and adverse renal injury in ApoEKO mice with suppression of the NOX4 and TNF-alpha-TNFRSF1A signaling. However, rhACE2 had no effect on renal NOX2 and TNFRSF1B expression and circulating lipid levels. CONCLUSIONS: ACE2 deficiency exacerbates kidney inflammation, oxidative stress and adverse renal injury in the ApoE-mutant mice through modulation of the nephrin, NOX4 and TNF-alpha-TNFRSF1A signaling. While rhACE2 supplementation alleviates inflammation, renal dysfunction and glomerulus injury in the ApoE mutant mice associated with upregulations of Ang-(1-7) levels and nephrin expression and suppression of the TNF-alpha-TNFRSF1A signaling. Strategies aimed at enhancing the ACE2/Ang-(1-7) actions may have important therapeutic potential for atherosclerotic renal injury and kidney diseases. PMID- 26245759 TI - Rational Design of Photonic Dust from Nanoporous Anodic Alumina Films: A Versatile Photonic Nanotool for Visual Sensing. AB - Herein, we present a systematic study on the development, optimisation and applicability of interferometrically coloured distributed Bragg reflectors based on nanoporous anodic alumina (NAA-DBRs) in the form of films and nanoporous microparticles as visual/colorimetric analytical tools. Firstly, we synthesise a complete palette of NAA-DBRs by galvanostatic pulse anodisation approach, in which the current density is altered in a periodic fashion in order to engineer the effective medium of the resulting photonic films in depth. NAA-DBR photonic films feature vivid colours that can be tuned across the UV-visible-NIR spectrum by structural engineering. Secondly, the effective medium of the resulting photonic films is assessed systematically by visual analysis and reflectometric interference spectroscopy (RIfS) in order to establish the most optimal nanoporous platforms to develop visual/colorimetric tools. Then, we demonstrate the applicability of NAA-DBR photonic films as a chemically selective sensing platform for visual detection of mercury(II) ions. Finally, we generate a new nanomaterial, so-called photonic dust, by breaking down NAA-DBRs films into nanoporous microparticles. The resulting microparticles (MUP-NAA-DBRs) display vivid colours and are sensitive towards changes in their effective medium, opening new opportunities for developing advanced photonic nanotools for a broad range of applications. PMID- 26245760 TI - Microarray Analysis Reveals Altered Lipid and Glucose Metabolism Genes in Differentiated, Ritonavir-Treated 3T3-L1 Adipocytes. AB - OBJECTIVE: HIV lipodystrophy is characterised by abnormal adipose tissue distribution and metabolism, as a result of altered adipocyte function and gene expression. The protease inhibitor ritonavir is associated with the development of lipodystrophy. Quantifying changes in adipogenic gene expression in the presence of ritonavir may help to identify therapeutic targets for HIV lipodystrophy. METHODS: Affymetrix Mouse Genome 430 2.0 oligonucleotide microarray was used to investigate gene expression in 3T3-L1 adipocytes treated with 20 umol/l ritonavir or vehicle control (ethanol). Pparg, Adipoq, Retn and Il6 expression were validated by real time RT-PCR. Transcriptional signalling through PPAR-gamma was investigated using a DNA-binding ELISA. Changes in adipocyte function were investigated through secreted adiponectin quantification using ELISA and Oil Red O staining for triglyceride storage. RESULTS: Expression of 389 genes was altered by more than 5-fold in the presence of ritonavir (all P < 0.001). Gene ontology analysis revealed down-regulation of genes responsible for adipocyte triglyceride accumulation including complement factor D (Cfd; 238.42-fold), Cidec (73.75-fold) and Pparg (5.63-fold). Glucose transport genes were also down-regulated including Adipoq (24.42-fold) and Glut4 (13.36-fold), while Il6 was up-regulated (10.39-fold). PPAR-gamma regulatory genes Cebpa (11.33 fold) and liver-X-receptor alpha (Nr1h3) were down-regulated. Changes in Pparg, Adipoq and Il6 were confirmed by RT-PCR. PPAR-gamma binding to its nuclear consensus site, adiponectin secretion and triglyceride accumulation were all reduced by ritonavir. CONCLUSION: Ritonavir had a significant effect on expression of genes involved in adipocyte differentiation, lipid accumulation and glucose metabolism. Down-regulation of Pparg may be mediated by changes in Cebpa, Lcn2 and Nr1h3. PMID- 26245761 TI - Severe lack of investment in electronic infrastructure in the NHS. PMID- 26245762 TI - Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report. AB - BACKGROUND: Metachromatic Leukodystrophy (MLD) is a rare, fatal demyelinating disorder with limited treatment options. Published outcomes after hematopoietic stem cell transplantation (HSCT) are scant and mixed. We report survival and function following HSCT for a large, single-center MLD cohort. METHODS: Transplant-related data, survival and serial measures (brain MRI, nerve conduction velocity (NCV), neurologic and neuropsychology evaluations) were reviewed. When possible, parental interviews informed current neurologic status, quality-of-life, and adaptive functioning. Gross motor and expressive functions for late-infantile (LI-MLD) and juvenile (J-MLD) patients were described using previously reported, MLD-specific scales. RESULTS: Forty patients with confirmed MLD have undergone HSCT at our center. Twenty-one (53 %) survive at a median 12 years post-HSCT. Most deaths (n = 17) were treatment-related; two died from disease progression. Survival did not depend upon MLD subtype or symptom status at transplant. LI-MLD patients survive beyond reported life expectancy in untreated disease. Abnormal brain MRI and peripheral nerve conduction velocities (NCV) were common before HSCT. Following transplant, fewer patients experienced MRI progression compared to NCV deterioration. Sixteen LI-MLD and J-MLD survivors were evaluable for long-term gross motor and/or expressive language functioning using existing MLD clinical scoring systems. While most J-MLD patients regressed, the aggregate cohort demonstrated superior retention of function compared to published natural history. Seventeen LI-MLD, J-MLD and adult subtype (A-MLD) survivors were evaluable for long-term adaptive functioning, activities of daily living, and/or cognition. Relative cognitive sparing was observed despite overall global decline. Five sibling pairs (one LI-MLD and four J-MLD), in which at least one underwent transplant in our cohort, were evaluable. Within each familial dyad, survival or function was superior for the treated sibling, or if both siblings were transplanted, for the pre-symptomatic sibling. CONCLUSIONS: HSCT is a viable treatment option for MLD, but has significant limitations. Later-onset phenotypes may benefit most from early, pre-symptomatic transplant. Until superior, novel treatment strategies are demonstrated, MLD patients should be carefully considered for HSCT. PMID- 26245764 TI - Serum thyroglobulin before and after iodization of salt: an 11-year DanThyr follow-up study. AB - OBJECTIVE: Our objective was to investigate individual serum thyroglobulin (Tg) changes in relation to iodine fortification (IF) and to clarify possible predictors of these changes. DESIGN: We performed a longitudinal population-based study (DanThyr) in two regions with different iodine intake at baseline: Aalborg (moderate iodine deficiency (ID)) and Copenhagen (mild ID). Participants were examined at baseline (1997) before the mandatory IF of salt (2000) and again at follow-up (2008) after IF. METHODS: We examined 2465 adults and a total of 1417 participants with no previous thyroid disease and without Tg-autoantibodies were included in the analyses. Serum Tg was measured by immunoradiometric method. We registered participants with a daily intake of iodine from supplements in addition to IF. RESULTS: Overall, the follow-up period saw no change in median Tg in Copenhagen (9.1/9.1 MUg/l, P=0.67) while Tg decreased significantly in Aalborg (11.4/9.0 MUg/l, P<0.001). Regional differences were evident before IF (Copenhagen/Aalborg, 9.1/11.4 MUg/l, P<0.001), whereas no differences existed after IF (9.1/9.0 MUg/l, P=1.00). Living in Aalborg (P<0.001) and not using iodine supplements at baseline (P=0.001) predicted a decrease in Tg whereas baseline thyroid enlargement (P=0.02) and multinodularity (P=0.01) were associated with an individual increase in Tg during follow-up. CONCLUSIONS: After IF we observed a decrease in median Tg in Aalborg and the previously observed regional differences between Aalborg and Copenhagen had levelled out. Likewise, living in Aalborg was a strong predictor of an individual decrease in serum Tg. Thus, even small differences in iodine intake at baseline were very important for the individual response to IF. PMID- 26245763 TI - A role for 11C-methionine PET imaging in ACTH-dependent Cushing's syndrome. AB - OBJECTIVE: We report our experience of functional imaging with (11)C-methionine positron emission tomography-computed tomography (PET-CT) co-registered with 3D gradient echo (spoiled gradient recalled (SPGR)) magnetic resonance imaging (MRI) in the investigation of ACTH-dependent Cushing's syndrome. DESIGN: Twenty patients with i) de novo Cushing's disease (CD, n=10), ii) residual or recurrent hypercortisolism following first pituitary surgery (+/-radiotherapy; n=8) or iii) ectopic Cushing's syndrome (n=2) were referred to our centre for functional imaging studies between 2010 and 2015. Six of the patients with de novo CD and five of those with persistent/relapsed disease had a suspected abnormality on conventional MRI. METHODS: All patients underwent (11)C-methionine PET-CT. For pituitary imaging, co-registration of PET-CT images with contemporaneous SPGR MRI (1 mm slice thickness) was performed, followed by detailed mapping of (11)C methionine uptake across the sella in three planes (coronal, sagittal and axial). This allowed us to determine whether suspected adenomas seen on structural imaging exhibited focal tracer uptake on functional imaging. RESULTS: In seven of ten patients with de novo CD, asymmetric (11)C-methionine uptake was observed within the sella, which co-localized with the suspected site of a corticotroph microadenoma visualised on SPGR MRI (and which was subsequently confirmed histologically following successful transsphenoidal surgery (TSS)). Focal (11)C methionine uptake that correlated with a suspected abnormality on pituitary MRI was seen in five of eight patients with residual or recurrent Cushing's syndrome following first TSS (and pituitary radiotherapy in two cases). Two patients elected to undergo repeat TSS with histology confirming a corticotroph tumour in each case. In two patients with the ectopic ACTH syndrome, (11)C-methionine was concentrated in sites of distant metastases, with minimal uptake in the sellar region. CONCLUSIONS: (11)C-methionine PET-CT can aid the detection of ACTH secreting tumours in Cushing's syndrome and facilitate targeted therapy. PMID- 26245765 TI - Mechanistic Insights into Sympathetic Neuronal Regeneration: Multitracer Molecular Imaging of Catecholamine Handling After Cardiac Transplantation. AB - BACKGROUND: Post-transplant reinnervation is a unique model to study sympathetic neuronal regeneration in vivo. The differential role of subcellular mechanisms of catecholamine handling in nerve terminals has not been investigated. METHODS AND RESULTS: Three different carbon-11-labeled catecholamines were used for positron emission tomography of transport (C-11 m-hydroxyephedrine, HED), vesicular storage (C-11 epinephrine, EPI), and metabolic degradation (C-11 phenylephrine). A 2-day protocol was used, including quantification of myocardial blood flow by N 13 ammonia. Resting myocardial blood flow and EPI, HED and phenylephrine retention were homogeneous in healthy volunteers (n=7). Washout was only observed for phenylephrine (T(1/2) 49+/-6 min). In nonrejecting, otherwise healthy heart transplant recipients (>1 year after surgery, n=10), resting myocardial blood flow was also homogenous. Regional catecholamine uptake of varying degrees was observed in the anterior left ventricular wall and septum. Overall, 24+/-19% of left ventricle showed HED uptake levels comparable with healthy volunteers, whereas it was only 8+/-7% for EPI (P=0.004 versus HED). Phenylephrine washout was not different from healthy volunteers in the area with restored EPI and HED retention (T(1/2) 41+/-7 min; P>0.05), but was significantly enhanced in the EPI/HED mismatch area (T(1/2) 36+/-8 min; P=0.008), consistent with inefficient vesicular storage and enhanced metabolic degradation. CONCLUSIONS: Regeneration of subcellular components of sympathetic nerve terminal function does not occur simultaneously. In the reinnervating transplanted heart, a region with normal catecholamine transport and vesicular storage is surrounded by a borderzone, where transport is already restored but vesicular storage remains inefficient, suggesting that vesicular storage is a more delicate mechanism. This observation may have implications for other pathologies involving cardiac autonomic innervation. PMID- 26245766 TI - Comparative Study of Outcomes among Patients with Polycystic Kidney Disease on Hemodialysis and Peritoneal Dialysis. AB - Polycystic kidney disease (PCKD) is the most common hereditary cause of end-stage renal disease, the complications of which may prevent the choice of peritoneal dialysis (PD). The aim of this study was to explore the effects of dialysis modality on outcomes in patients with PCKD. We extracted a cohort of 1417 adult patients with PCKD initiating long-term dialysis therapy in 1999-2010 from the Taiwan National Health Insurance Research Database, among which 125 patients chose PD. The patients on HD were older and had a higher comorbidity index compared to those on PD. We compared the risks for death, hospitalization and medical expenditures between the patients on PD and propensity-score matched patients on hemodialysis (HD). The overall survival did not differ between the patients on PD and HD. The patients on PD tended to have higher hazard ratios (HR) for the first episode of hospitalization (adjusted HR 1.34 [95% CI, 1.04 1.79]). The annual medical expenses were 10% lower for the patients on PD. PD is an equivalent choice of renal replacement therapy to HD for patients with PCKD in terms of survival. Although the patients on PD had a higher risk for hospitalization, the medical expenditure for PD was 10% lower. PMID- 26245767 TI - Immigration policy and birth weight: Positive externalities in Italian law. AB - A decade ago, the political party of the Italian center-right voted a law restricting immigration. The law became effective in early 2005, when the Italian parliament approved the decree for its application, but one of its articles, granting amnesty for illegal immigrant workers, became immediately effective in July 2002. As a result, 650,000 immigrants were granted the status of foreign nationals in Italy. In this paper, we examine whether the increase in the prevalence of "regular immigrants" has led to an improvement in health outcomes of babies born to migrant women, measured in terms of birth weight. Two hitherto unexploited birth sample surveys published by Italian Institute of Statistics were used for this study. Our estimates show that regularized immigration reduced the probability of low birth weight. PMID- 26245768 TI - UK doctors who go to Syria just want to alleviate suffering. PMID- 26245769 TI - Prognostic effect of mean platelet volume in patients with coronary artery disease. A systematic review and meta-analysis. AB - Large platelets with high haemostatic activity may lead to increased platelet aggregation.. Mean platelet volume (MPV), an indicator of platelet reactivity, may emerge as a prognostic marker in patients with coronary artery disease (CAD). It was the objective of this study to conduct a systematic review and meta analysis to assess prognostic effects of MPV on cardiovascular events (CVE) in CAD patients. We searched MEDLINE and SCOPUS from inception to January 2, 2014. All studies that reported MPV and the incidence of cardiovascular events in CAD patients were included. Two reviewers independently extracted the data. A random effects model was applied for pooling the mean difference of MPV between patients with vs without CVE. Among 30 eligible studies, eight studies reported mean difference of MPV between CVE groups, 11 studies reported MPV dichotomous into high vs low MPV groups, and 11 studies reported both. The pooled mean difference was 0.69 fL (95 %CI = 0.36, 1.01), i. e. patients with CVE had a MPV about 0.69 fL higher than non-CVE. Patients with higher MPV were about 12 % more likely to die than patients with lower MPV (RR 1.12; 95 %CI = 1.02-1.24). However, pooling these effects was based on high heterogeneity and the source of heterogeneity could not be identified. This might be explained by many differences among included studies (e. g. study population, outcomes of interest, analysate, time between blood collection and MPV analysis, etc). These findings suggest that MPV may be a useful prognostic marker in patients with CAD. PMID- 26245771 TI - Corrigendum. PMID- 26245770 TI - Statins for Primary Prevention of Cardiovascular Disease in Elderly Patients: Systematic Review and Meta-Analysis. AB - BACKGROUND: Statins have been shown to be beneficial in primary and secondary prevention settings; however, their role in the elderly remains a clinical conundrum, given that age-related factors could alter the risk-benefit ratio of statin treatment. This study aimed to critically evaluate the efficacy and safety of statins for primary prevention of cardiovascular disease (CVD) in the elderly. METHODS: We systematically reviewed randomized controlled trials comparing any statins with placebo or usual care for primary prevention of CVD in subjects aged >=65 years. Relative risks (RRs) using a random effects model were calculated and sensitivity analyses were performed to assess the robustness of findings. RESULTS: Eight studies (n = 25,952) were included in the meta-analysis. Statins significantly reduced the risks of composite major adverse cardiovascular events (RR 0.82, 95% CI 0.74-0.92), nonfatal myocardial infarction [MI] (0.75, 0.59 0.94) and total MI (0.74, 0.61-0.90). Treatment effects of statins were statistically insignificant in fatal MI (0.43, 0.09-2.01), stroke (fatal: 0.76, 0.24-2.45; nonfatal: 0.76, 0.53-1.11; total: 0.85, 0.68-1.06) and all-cause mortality (0.96, 0.88-1.04). Significant differences were not observed in myalgia (0.88, 0.69-1.13), elevation of hepatic transaminases (0.98, 0.71-1.34), new onset diabetes (1.07, 0.77-1.48), serious adverse events (1.00, 0.97-1.04) and discontinuation due to adverse events (1.10, 0.85-1.42). The occurrence of myopathy, rhabdomyolysis and cognitive impairment was largely unreported in the included trials. CONCLUSIONS: From a risk-benefit perspective, there is a role of statins for the primary prevention of major adverse cardiovascular events in elderly patients. Further studies are needed to ascertain the benefits of statins on fatal MI, stroke and all-cause mortality. PMID- 26245772 TI - A rare disease in an atypical location-Kimura's Disease of the upper extremity. AB - Kimura's disease is a rare chronic inflammatory disorder predominantly affecting young Asian male patients, occurring mainly in the head and neck regions. Kimura's disease of the upper extremity is extremely rare, and previous case reports in the literature show similar imaging characteristics with consistent location at the medial epitrochlear region, predominantly with unilateral involvement. We present the first reported case of Kimura's disease affecting the anterolateral aspect of the upper arm, sparing the medial epitrochlear region, illustrating that with typical MR appearance and serology, the involvement of this rare disease in an atypical location still warrants consideration of this diagnosis. There was also bilateral asymmetrical involvement in our patient, suggesting the possibility of a propensity for Kimura's disease affecting the upper extremities to have bilateral involvement, which may necessitate imaging of the clinically asymptomatic contralateral limb in these patients for early lesion identification and treatment. PMID- 26245773 TI - The extensor carpi ulnaris pseudolesion: evaluation with microCT, histology, and MRI. AB - OBJECTIVE: To determine if magic angle plays a role in apparent central increased signal intensity of the distal extensor carpi ulnaris tendon (ECU) on MRI, to see if histologic findings of tendon degeneration are associated with increased T1 or T2 tendon signal on MR imaging, and to determine the prevalence of the ECU "pseudolesion". MATERIALS AND METHODS: A standard 3 Tesla protocol was utilized to scan ten cadaveric wrists. A 40 mm length of 10 ECU and four extensor carpi radialis brevis (ECRB) tendons were immersion fixed before microCT scanning. Staining with Alcian blue, Masson's trichrome and Safranin O was performed before light microscopy. Fifty clinical wrist MRIs were also reviewed for the presence of increased T1 and/or T2 signal. RESULTS: Central increased T1 and/or T2 signal was observed in 9 of 10 cadaveric ECU tendons, but not in ECRB tendons. MicroCT and histology showed inter-tendinous matrix between the two distal heads of the ECU. Increased mucoid degeneration correlated with increased MRI signal intensity. The tendon fibers were at a maximum of 8.39 degrees to the longitudinal axis on microCT. Clinical MRIs showed increased T1 signal in 6%, increased T2 signal in 8%, increased T1 and T2 signal in 80%, and 6% showing no increased signal. CONCLUSION: Central increased T1 and/or T2 signal in the ECU tendon indicates the presence of normal inter-tendinous ground substance, with increased proteoglycan content (mucoid degeneration) responsible for increased signal intensity. None of the fibers were shown on microCT to approach the magic angle. PMID- 26245774 TI - Effects of low-frequency repetitive transcranial magnetic stimulation combined with intensive speech therapy on cerebral blood flow in post-stroke aphasia. AB - We provided an intervention to chronic post-stroke aphasic patients using low frequency repetitive transcranial magnetic stimulation (LF-rTMS) guided by a functional magnetic resonance imaging (fMRI) evaluation of language laterality, combined with intensive speech therapy (ST). We performed a single photon emission-computed tomography (SPECT) scan pre- and post-intervention and investigated the relationship between cerebral blood flow (CBF) and language function. Fifty right-handed chronic post-stroke aphasic patients were enrolled in the study. During their 11-day hospital admission, the patients received a 40 min session of 1-Hz LF-rTMS on the left or right hemisphere, according to language localization identified by the fMRI evaluation, and intensive ST daily for 10 days, except for Sunday. A SPECT scan and language evaluation by the Standard Language Test of Aphasia (SLTA) were performed at the time of admission and at 3 months following discharge. We calculated laterality indices (LIs) of regional CBF (rCBF) in 13 language-related Brodmann area (BA) regions of interest. In patients who received LF-rTMS to the intact right hemisphere (RH-LF rTMS), the improvement in the total SLTA score was significantly correlated with the pre- and post-intervention change of LI (DeltaLI) in BA44. In patients who received LF-rTMS to the lesional left hemisphere (LH-LF-rTMS), this association was not observed. Analyses of the SLTA subscales and rCBF DeltaLI demonstrated that in the RH-LF-rTMS group, the SLTA Speaking subscale scores were significantly correlated with DeltaLIs in BA11, 20, and 21, and the SLTA Writing subscale scores were significantly correlated with DeltaLIs in BA6 and 39. Conversely, in the LH-LF-rTMS group, the SLTA Speaking subscale scores were correlated with DeltaLI in BA10, and the SLTA Reading subscale scores were significantly correlated with DeltaLIs in BA13, 20, 22, and 44. Our results suggest the possibility that fMRI-guided LF-rTMS combined with intensive ST may affect CBF and contribute to the improvement of language function of post-stroke aphasic patients. LF-rTMS to the non-lesional and lesional hemispheres showed a difference in the associations between language performance and CBF. The results indicate that more effective rTMS intervention needs to be explored for patients who show right hemisphere language activation in an fMRI language evaluation. PMID- 26245775 TI - Acinetobacter albensis sp. nov., isolated from natural soil and water ecosystems. AB - We have studied the taxonomic position of a phenetically unique group of eight strains of the genus Acinetobacter which were isolated from soil and water samples collected in protected landscape areas in the Czech Republic. Each of the comparative sequence analyses of the 16S rRNA, gyrB and rpoB genes showed that the eight strains formed a cohesive and tight cluster (intracluster sequence identities of >= 99.9 %, >= 98.5 % and >= 97.7 %, respectively), which was clearly separated from all hitherto known species of the genus Acinetobacter ( <= 98.6 %, <= 84.5 % and <= 89.3 %, respectively). Congruent with these findings were the results of comparative sequence analysis of three additional housekeeping genes (gltA, pyrG and recA). This genotypic distinctness was mirrored by the uniqueness of the combination of a number of independent phenotypic markers including the whole-cell spectra produced by matrix-assisted laser desorption ionization time-of-flight (MALDI-ToF) MS and physiological and metabolic features. The most useful phenotypic features to differentiate the eight strains from all known species of the genus Acinetobacter were the ability to assimilate tricarballylate and the inability to grow at 35 degrees C or to assimilate ethanol or l-histidine. We conclude that the eight strains represent a novel environmental species for which the name Acinetobacter albensis sp. nov. is proposed. The type strain is ANC 4874T ( = CCUG 67281T = CCM 8611T). PMID- 26245776 TI - Clobazam and Aggression-Related Adverse Events in Pediatric Patients With Lennox Gastaut Syndrome. AB - BACKGROUND: Lennox-Gastaut syndrome is an intractable epileptic encephalopathy marked by frequent drop seizures. Most patients develop moderate intellectual disability and behavioral problems, including hyperactivity, aggressiveness, insecurity, and autistic features. Treatment with benzodiazepines, including clobazam, may increase aggression/behavioral problems in patients with Lennox Gastaut syndrome. Post hoc analyses of data from the OV-1012 trial assessed the potential for behavioral effects with clobazam treatment in pediatric (2 to 18 years) patients with Lennox-Gastaut syndrome. METHODS: OV-1012 was a phase 3, randomized, double-blind, parallel-group trial comprising a 4-week baseline period, 3-week titration period, and a 12-week maintenance period. Data from 194 patients were analyzed for a history of aggression/behavioral problems, occurrence of aggression-related adverse events, and by assessment of potential drug-related effects on four behavior domains of the Child Behavior Checklist. RESULTS: Twenty-nine aggression-related adverse events were reported for 27 (13.9%) patients. Similar percentages of clobazam-treated patients with and without a history of aggressive behavior experienced an aggression-related adverse event (16.7% versus 15.5%, respectively). In the medium- and high-dosage clobazam groups, onset of aggression-related adverse effects occurred within the 3-week titration period with 63.2% resolving by the end of the study. Aggression related adverse event onset and resolution were similar for the low-dosage clobazam and placebo groups. Analysis of baseline to postbaseline T scores for the behavior domains of the Child Behavior Checklist indicated no significant differences between clobazam and placebo. CONCLUSIONS: Post hoc analyses indicate that the overall rate of aggression with clobazam treatment was low and dosage dependent. Clobazam treatment was effective in reducing drop seizures regardless of aggression experience. PMID- 26245777 TI - Finding the "Conservation" in Conservation Genetics--Progress in Latin America. PMID- 26245778 TI - Delimiting Evolutionarily Significant Units of the Fish, Piaractus brachypomus (Characiformes: Serrasalmidae), from the Orinoco and Amazon River Basins with Insight on Routes of Historical Connectivity. AB - The freshwater fish Piaractus brachypomus is an economically important for human consumption both in commercial fisheries and aquaculture in all South American countries where it occurs. In recent years the species has decreased in abundance due to heavy fishing pressure. The species occurs in the Amazon and Orinoco basins, but lack of meristic differences between fishes from the 2 basins, and extensive migration associated with reproduction, have resulted in P. brachypomus being considered a single panmictic species. Analysis of 7 nuclear microsatellites, mitochondrial DNA sequences (D-loop and COI), and body shape variables demonstrated that each river basin is populated by a distinct evolutionarily significant unit (ESU); the 2 groups had an average COI divergence of 3.5% and differed in body depth and relative head length. Historical connection between the 2 basins most probably occurred via the Rupununi portal rather than via the Casiquiare canal. The 2 ESUs will require independent fishery management, and translocation of fisheries stocks between basins should be avoided to prevent loss of local adaptations or extinction associated with outbreeding depression. Introductions of fishes from the Orinoco basin into the Putumayo River basin, an Amazon basin drainage, and evidence of hybridization between the 2 ESUs have already been detected. PMID- 26245779 TI - Contrasting Genetic Structure and Diversity of Galaxias maculatus (Jenyns, 1848) Along the Chilean Coast: Stock Identification for Fishery Management. AB - Galaxias maculatus (Pisces: Galaxiidae) commonly known as "puye" has a disjunct distribution along the Southern Hemisphere including landlocked and migratory populations at latitudes over 30 degrees S in South America, Australia, Tasmania, and New Zealand. Chilean artisanal fishery of G. maculatus has become less important as a resource due to multiple factors including overexploitation, pollution, introduction of predators, and competitors. At the same time, the current conservation status of the species in Chile is still uncertain. Here, we used mtDNA control region sequences (925bp) to investigate main patterns of genetic diversity and structure in populations from 2 biogeographic areas along the Chilean coast. Extremely high levels of genetic diversity characterize the species, suggesting a low amount of influence of the last glacial cycle over its demography compared with other studies in freshwater and marine South American fishes. However, we recognized contrasting genetic patterns between the Intermediate Area (between 30 degrees S and 42 degrees S) and the Magellanic Province (between 42 degrees S and 56 degrees S). On the one hand, over a narrow geographical range (<200 km) each Intermediate Area estuarine population constitutes a different genetic unit. On the other hand, the Magellanic populations of the species exhibited low levels of differentiation in an area extending for more than 500 km. Such differences may be a consequence of different coastal configurations, oceanographic regimes, and Quaternary glacial histories. Finally, our results support the existence of different stock units for G. maculatus and this information should be integrated in future management strategies and aquaculture programs for this species. PMID- 26245780 TI - Conservation Genetics of the Scalloped Hammerhead Shark in the Pacific Coast of Colombia. AB - Previous investigations of the population genetics of the scalloped hammerhead sharks (Sphyrna lewini) in the Eastern Tropical Pacific have lacked information about nursery areas. Such areas are key to promoting conservation initiatives that can protect young sharks from threats such as overfishing. Here, we investigated the genetic diversity, phylogeography, and connectivity of S. lewini found in 3 areas of Colombia's Pacific coast: around Malpelo Island and in 2 National Natural Parks on the Colombian Pacific mainland (Sanquianga and Ensenada de Utria). We analyzed mtDNA control region (CR) sequences and genotyped 15 microsatellite loci in 137 samples of adults and juveniles. The mtDNA analyses showed haplotypes shared between the Colombian Pacific individuals sampled in this investigation and other areas in the Eastern Tropical Pacific, the Indo Pacific, and with sequences previously reported in Colombia (Buenaventura Port), as well as 4 unique haplotypes. Population assignment and paternity analyses detected 3 parent-offspring pairs between Malpelo and Sanquianga and 1 between Malpelo and Utria. These results indicate high genetic connectivity between Malpelo Island and the Colombian Pacific coast, suggesting that these 2 areas are nurseries for S. lewini. This is, to our knowledge, the first evidence of nursery areas identified for the scalloped hammerhead shark anywhere in the world. Additional conservation planning may be required to protect these nursery habitats of this endangered shark species. PMID- 26245781 TI - Population Structure of mtDNA Variation due to Pleistocene Fluctuations in the South American Maned Wolf (Chrysocyon brachyurus, Illiger, 1815): Management Units for Conservation. AB - The maned wolf (Chrysocyon brachyurus) is one of the largest South American canids, and conservation across this charismatic carnivore's large range is presently hampered by a lack of knowledge about possible natural subdivisions which could influence the population's viability. To elucidate the phylogeographic patterns and demographic history of the species, we used 2 mtDNA markers (D-loop and cytochrome b) from 87 individuals collected throughout their range, in Argentina, Bolivia, Brazil, and Uruguay. We found moderate levels of haplotype and nucleotide diversity, and the 14 D-loop haplotypes were closely related. Genetic structure results revealed 4 groups, and when coupled with model inferences from a coalescent analysis, suggested that maned wolves have undergone demographic fluctuations due to changes in climate and habitat during the Pleistocene glaciation period approximately 24000 years before present (YBP). This genetic signature points to an event that occurred within the timing estimated for the start of the contraction of the Cerrado around 50000 YBP. Our results reveal a genetic signature of population size expansion followed by contraction during Pleistocene interglaciations, which had similar impacts on other South American mammals. The 4 groups should for now be considered management units, within which future monitoring efforts should be conducted independently. PMID- 26245782 TI - Population Structure and Genetic Diversity of the Endangered South American Giant Otter (Pteronura brasiliensis) from the Orinoco Basin in Colombia: Management Implications and Application to Current Conservation Programs. AB - Endangered giant otters, Pteronura brasiliensis, are found along the Amazon and Orinoco rivers and most of their tributaries. Hunting in the mid-1970s pushed giant otter populations to the brink of extinction. We studied population structure and genetic diversity of giant otters from Colombia's Orinoco basin using analyses of partial mitochondrial DNA control region sequences obtained from scat material. We collected and analyzed 54 scat samples from 22 latrines, 2 tissue samples primarily from captive giant otters and 2 from hunted animals near Puerto Carreno and Puerto Inirida (Colombian Orinoco), as well as one tissue sample from Puerto Leguizamo (Colombian Amazon). Thirty-nine partial control region sequences were obtained (258bp), corresponding to 15 unique haplotypes. Most of these haplotypes, found in samples collected around Puerto Carreno, defined one phylogeographic group (phylogroup) not previously described. Higher genetic diversity in the Colombian Orinoco populations than in other South American populations suggests that this newly described phylogroup, as well as a second phylogroup defined from a few Colombian Orinoco and Amazon samples, should be considered distinct genetic management units. National conservation programs, particularly those aiming to establish protected areas, should manage these independently. Current Colombian confiscated animal reintroduction and captive reproduction programs should also consider such differentiation when determining reintroduction locations or improving husbandry practices. PMID- 26245783 TI - Genetic Variation and Structure in Contrasting Geographic Distributions: Widespread Versus Restricted Black-Tailed Prairie Dogs (Subgenus Cynomys). AB - Species of restricted distribution are considered more vulnerable to extinction because of low levels of genetic variation relative to widespread taxa. Species of the subgenus Cynomys are an excellent system to compare genetic variation and degree of genetic structure in contrasting geographic distributions. We assessed levels of genetic variation, genetic structure, and genetic differentiation in widespread Cynomys ludovicianus and restricted C. mexicanus using 1997bp from the cytochrome b and control region (n = 223 C. ludovicianus; 77 C. mexicanus), and 10 nuclear microsatellite loci (n = 207 and 78, respectively). Genetic variation for both species was high, and genetic structure in the widespread species was higher than in the restricted species. C. mexicanus showed values of genetic variation, genetic structure, and genetic differentiation similar to C. ludovicianus at smaller geographic scales. Results suggest the presence of at least 2 historical refuges for C. ludovicianus and that the Sierra Madre Occidental represents a barrier to gene flow. Chihuahua and New Mexico possess high levels of genetic diversity and should be protected, while Sonora should be treated as an independent management unit. For C. mexicanus, connectivity among colonies is very important and habitat fragmentation and habitat loss should be mitigated to maintain gene flow. PMID- 26245784 TI - Population Genetic Structure in Hyacinth Macaws (Anodorhynchus hyacinthinus) and Identification of the Probable Origin of Confiscated Individuals. AB - Understanding the intraspecific genetic composition of populations in different geographic locations is important for the conservation of species. If genetic variability is structured, conservation strategies should seek to preserve the diversity of units. Also, origin of individuals can be determined, which is important for guiding actions against animal trafficking. The hyacinth macaw (Anodorhynchus hyacinthinus) is located in allopatric regions, vulnerable to extinction and suffering animal trafficking pressure. Therefore, we characterized its population genetic structure based on 10 microsatellites from 98 individuals and 2123bp of mitochondrial sequence (ND5, cytochrome b, and ND2) from 80 individuals. Moderate to high levels of differentiation were observed among 3 geographic regions of Brazil: the north/northeast of the country, the north Pantanal, and the south Pantanal. Differentiation between the 2 regions within the Pantanal was not expected, as they are relatively close and there is no known barrier to macaw movement between these regions. These genetically differentiated groups were estimated to have diverged 16000 to 42000 years ago. The low genetic variability observed seems not to be the result of past bottlenecks, although a star-shaped haplotype network and the mismatch distribution suggest that there was recent demographic expansion in the north and northeast. Environmental changes in the Holocene could have caused this expansion. Given the genetic structure observed, the most probable regions of origin of 24 confiscated individuals were identified. Thus, these data helped to trace illegal traffic routes and identify natural populations that are being illegally harvested. PMID- 26245785 TI - Population Genetics of Jaguars (Panthera onca) in the Brazilian Pantanal: Molecular Evidence for Demographic Connectivity on a Regional Scale. AB - Habitat loss and fragmentation are important threats to carnivores worldwide, and can be especially intense for large predators. Jaguars have already been extirpated from over half of their original area of distribution, and few regions still maintain large populations. For these, detailed understanding is crucial for setting appropriate recovery targets in impacted areas. The Pantanal is among the best examples of a region with a large jaguar population in a healthy environment. Here, we analyzed 12 microsatellite loci to characterize genetic diversity and population structure of 52 jaguars sampled in 4 localities of the southern Pantanal, and compared them with prior studies of heavily fragmented populations of the Atlantic Forest. Although we observed some internal structure among the Pantanal localities, our results indicated that this area comprises a single population with high genetic variability. Moreover, our comparative analyses supported the hypothesis that the strong population structure observed in the Atlantic Forest derives from recent, anthropogenic fragmentation. We also observed significant but low levels of genetic differentiation between the Pantanal and Atlantic Forest populations, indicating recent connectivity between jaguars occurring in these biomes. Evidence for admixture between the Pantanal and a population on the western boundary of the Atlantic Forest corroborates the transitional nature of the latter area, where the jaguar population has already been extirpated. Our results can be used to understand jaguar population dynamics in a region that is less disturbed than the Atlantic forest, and to support the design of conservation strategies that maintain and restore natural connectivity among currently isolated areas. PMID- 26245786 TI - Effects of Forest Fragmentation on Genetic Diversity of the Critically Endangered Primate, the Pied Tamarin (Saguinus bicolor): Implications for Conservation. AB - We analyzed DNA at 9 microsatellite loci from hair samples of 73 pied tamarins (Saguinus bicolor) located in 3 urban forest fragments and a biological reserve in the city of Manaus, Amazonas, Brazil. The forest fragments had become isolated from the continuous forest 6-15 years prior to the time of sampling. Tests for reduction in population size showed that all groups from the urban forest fragments had undergone genetic bottlenecks. Pied tamarins in this region historically formed one biological population, and the fragments were connected by high levels of gene flow. These results indicate the need to implement a conservation plan that allows for connectivity between the urban fragments, as well as protection from further constriction. Such connectivity could be achieved via the creation and protection of corridors. In addition to the current population trends explained by anthropogenic actions, the species also shows a trend of long-term demographic decline that has resulted in approximately an order of magnitude decrease and began 13 thousand years ago. PMID- 26245787 TI - Reduced Genetic Diversity and Increased Dispersal in Guigna (Leopardus guigna) in Chilean Fragmented Landscapes. AB - Landscape fragmentation is often a major cause of species extinction as it can affect a wide variety of ecological processes. The impact of fragmentation varies among species depending on many factors, including their life-history traits and dispersal abilities. Felids are one of the groups most threatened by fragmented landscapes because of their large home ranges, territorial behavior, and low population densities. Here, we model the impacts of habitat fragmentation on patterns of genetic diversity in the guigna (Leopardus guigna), a small felid that is closely associated with the heavily human-impacted temperate rainforests of southern South America. We assessed genetic variation in 1798 base pairs of mitochondrial DNA sequences, 15 microsatellite loci, and 2 sex chromosome genes and estimated genetic diversity, kinship, inbreeding, and dispersal in 38 individuals from landscapes with differing degrees of fragmentation on Chiloe Island in southern Chile. Increased fragmentation was associated with reduced genetic diversity, but not with increased kinship or inbreeding. However, in fragmented landscapes, there was a weaker negative correlation between pairwise kinship and geographic distance, suggesting increased dispersal distances. These results highlight the importance of biological corridors to maximize connectivity in fragmented landscapes and contribute to our understanding of the broader genetic consequences of habitat fragmentation, especially for forest-specialist carnivores. PMID- 26245788 TI - Identifying Genetic Hotspots by Mapping Molecular Diversity of Widespread Trees: When Commonness Matters. AB - Conservation planning requires setting priorities at the same spatial scale at which decision-making processes are undertaken considering all levels of biodiversity, but current methods for identifying biodiversity hotspots ignore its genetic component. We developed a fine-scale approach based on the definition of genetic hotspots, which have high genetic diversity and unique variants that represent their evolutionary potential and evolutionary novelties. Our hypothesis is that wide-ranging taxa with similar ecological tolerances, yet of phylogenetically independent lineages, have been and currently are shaped by ecological and evolutionary forces that result in geographically concordant genetic patterns. We mapped previously published genetic diversity and unique variants of biparentally inherited markers and chloroplast sequences for 9 species from 188 and 275 populations, respectively, of the 4 woody dominant families of the austral temperate forest, an area considered a biodiversity hotspot. Spatial distribution patterns of genetic polymorphisms differed among taxa according to their ecological tolerances. Eight genetic hotspots were detected and we recommend conservation actions for some in the southern Coastal Range in Chile. Existing spatially explicit genetic data from multiple populations and species can help to identify biodiversity hotspots and guide conservation actions to establish science-based protected areas that will preserve the evolutionary potential of key habitats and species. PMID- 26245789 TI - Evolution and Conservation on Top of the World: Phylogeography of the Marbled Water Frog (Telmatobius marmoratus Species Complex; Anura, Telmatobiidae) in Protected Areas of Chile. AB - The Andean Altiplano has served as a complex setting throughout its history, driving dynamic processes of diversification in several taxa. We investigated phylogeographic processes in the Telmatobius marmoratus species complex occurring in this region by studying the geographic patterns of genetic variability, genealogies, and historical migration, using the cytochrome b (cyt-b) gene as a marker. DNA sequences from Telmatobius gigas and Telmatobius culeus, Bolivian species with an uncertain taxonomic status, were also included. Additionally, we evaluated the phylogenetic diversity (PD) represented within Chilean protected areas and the complementary contribution from unprotected populations. Phylogenetic reconstructions from 148 cyt-b sequences revealed 4 main clades, one of which corresponded to T. culeus. T. gigas was part of T. marmoratus clade indicating paraphyletic relationships. Haplotypes from Chilean and Bolivian sites were not reciprocally monophyletic. Geographic distribution of lineages, spatial Bayesian analysis, and migration patterns indicated that T. marmoratus displays a weaker geographic structure than expected based on habitat distribution and physiological requirements. Demographic and statistical phylogeography analyses pointed out to a scenario of recent population expansion and high connectivity events of a more recent age than the post Last Glacial Maximum, probably associated to more humid events in Altiplano. PD of T. marmoratus populations within protected areas represents 55.6% of the total estimated PD. The unprotected populations that would contribute the most to PD are Caquena and Quebe (21%). Recent evolutionary processes and paleoclimatic changes, potentially driving shifts in habitat connectivity levels and population sizes, could explain the phylogeographic patterns recovered herein. PMID- 26245790 TI - DNA Barcoding Identifies Illegal Parrot Trade. AB - Illegal trade threatens the survival of many wild species, and molecular forensics can shed light on various questions raised during the investigation of cases of illegal trade. Among these questions is the identity of the species involved. Here we report a case of a man who was caught in a Brazilian airport trying to travel with 58 avian eggs. He claimed they were quail eggs, but authorities suspected they were from parrots. The embryos never hatched and it was not possible to identify them based on morphology. As 29% of parrot species are endangered, the identity of the species involved was important to establish a stronger criminal case. Thus, we identified the embryos' species based on the analyses of mitochondrial DNA sequences (cytochrome c oxidase subunit I gene [COI] and 16S ribosomal DNA). Embryonic COI sequences were compared with those deposited in BOLD (The Barcode of Life Data System) while their 16S sequences were compared with GenBank sequences. Clustering analysis based on neighbor joining was also performed using parrot COI and 16S sequences deposited in BOLD and GenBank. The results, based on both genes, indicated that 57 embryos were parrots (Alipiopsitta xanthops, Ara ararauna, and the [Amazona aestiva/A. ochrocephala] complex), and 1 was an owl. This kind of data can help criminal investigations and to design species-specific anti-poaching strategies, and demonstrate how DNA sequence analysis in the identification of bird species is a powerful conservation tool. PMID- 26245791 TI - When You Get What You Haven't Paid for: Molecular Identification of "Douradinha" Fish Fillets Can Help End the Illegal Use of River Dolphins as Bait in Brazil. AB - The fishery for Calophysus macropterus, an Amazonian necrophagous catfish, is highly detrimental to river dolphins and caimans, which are deliberately killed for use as bait. In the Brazilian Amazon, this fishery has increased over the last decade, in spite of the rejection of scavenger fishes by Brazilian consumers. It was suspected that C. macropterus fillets were being sold in Brazilian markets, disguised as a fictitious fish (the "douradinha"). We collected 62 fillets from "douradinha" and other suspiciously named fish from 4 fish-processing plants sold at 6 markets in Manaus, in the Brazilian Amazon, and sequenced the cytochrome b gene to identify fillets to species. Sixty percent of fillets labeled "douradinha" or with other deceptive names were actually C. macropterus. Six other fish species of low commercial value were also found. The presence of dolphin tissue in the stomach contents of C. macropterus was confirmed by mtDNA control region sequencing. Our results formed the scientific basis for a moratorium on the fishing and fraudulent selling of C. macropterus, issued by the Brazilian Ministries of the Environment and Fisheries. Exposure of this fraud via the mass media can help end the illegal use of dolphins as bait in Brazil. PMID- 26245792 TI - Founded: Genetic Reconstruction of Lineage Diversity and Kinship Informs Ex situ Conservation of Cuban Amazon Parrots (Amazona leucocephala). AB - Captive breeding is a widespread conservation strategy, yet such programs rarely include empirical genetic data for assessing management assumptions and meeting conservation goals. Cuban Amazon parrots (Amazona leucocephala) are considered vulnerable, and multiple on-island captive populations have been established from wild-caught and confiscated individuals of unknown ancestry. Here, we used mitochondrial haplotypic and nuclear genotypic data at 9 microsatellite loci to quantify the extent and distribution of genetic variation within and among captive populations in Zapata Swamp and Managua, Cuba, and to estimate kinship among breeders (n = 88). Using Bayesian clustering analysis, we detected 2 distinct clusters within the Zapata population, one of which was shared with Managua. Individuals from the cluster unique to Zapata possessed mitochondrial haplotypes with affinities to Cuban subspecies (A. l. leucocephala, A. l. palmarum); the shared cluster was similar, but also included haplotypes closely related to the subspecies restricted to Cayman Brac (A. l. hesterna). Overall mean kinship was low within each captive population (-0.026 to -0.012), with 19 and 11 recommended breeding pairs in Zapata and Managua, respectively, ranked according to mean kinship and informed by molecular sexing. Our results highlight the importance of understanding population history within ex situ management programs, while providing genetic information to directly inform Cuban parrot conservation. PMID- 26245798 TI - Improving Care in Pediatric Neuro-oncology Patients: An Overview of the Unique Needs of Children With Brain Tumors. AB - Brain tumors represent the most common solid tumors in childhood, accounting for almost 25% of all childhood cancer, second only to leukemia. Pediatric central nervous system tumors encompass a wide variety of diagnoses, from benign to malignant. Any brain tumor can be associated with significant morbidity, even when low grade, and mortality from pediatric central nervous system tumors is disproportionately high compared to other childhood malignancies. Management of children with central nervous system tumors requires knowledge of the unique aspects of care associated with this particular patient population, beyond general oncology care. Pediatric brain tumor patients have unique needs during treatment, as cancer survivors, and at end of life. A multidisciplinary team approach, including advanced practice nurses with a specialty in neuro-oncology, allows for better supportive care. Knowledge of the unique aspects of care for children with brain tumors, and the appropriate interventions required, allows for improved quality of life. PMID- 26245799 TI - Seizure Action Plans Do Not Reduce Health Care Utilization in Pediatric Epilepsy Patients. AB - Management of pediatric epilepsy requires complex coordination of care. We hypothesized that an improved seizure management care plan would reduce health care utilization and improve outcomes. The authors conducted a cohort study with historical controls of 120 epilepsy patients before and after implementation of a "Seizure Action Plan." The authors evaluated for differences in health care utilization including emergency department visits, hospitalizations, clinic visits, telephone calls, and the percentage of emergency department visits that resulted in hospitalization in patients who did or did not have a Seizure Action Plan. The authors found that there was no decrease in these measures of health care utilization, and in fact the number of follow-up clinic visits was increased in the group with Seizure Action Plans (4.2 vs 3.3, P = .006). However, the study was underpowered to detect smaller differences. This study suggests that pediatric epilepsy quality improvement measures may require alternative approaches to reduce health care utilization and improve outcomes. PMID- 26245801 TI - Inherent structure length in metallic glasses: simplicity behind complexity. AB - One of the central themes in materials science is the structure-property relationship. In conventional crystalline metals, their mechanical behaviour is often dictated by well-defined structural defects such as dislocations, impurities, and twins. However, the structure-property relationship in amorphous alloys is far from being understood, due to great difficulties in characterizing and describing the disordered atomic-level structure. Herein, we report a universal, yet simple, correlation between the macroscopic mechanical properties (i.e., yield strength and shear modulus) and a unique characteristic structural length in metallic glasses (MGs). Our analysis indicates that this characteristic length can incorporate effects of both the inter-atomic distance and valence electron density in MGs, and result in the observed universal correlation. The current findings shed lights on the basic understanding of mechanical properties of MGs from their disordered atomic structures. PMID- 26245802 TI - Neutrophil Extracellular Trap Mitochondrial DNA and Its Autoantibody in Systemic Lupus Erythematosus and a Proof-of-Concept Trial of Metformin. AB - OBJECTIVE: Neutrophil extracellular traps (NETs) have been shown to play an important role in systemic lupus erythematosus (SLE) pathogenesis by activating plasmacytoid dendritic cells (PDCs) and the type I interferon (IFN) pathway. NETs composed of self-DNA are considered to be of nuclear origin and are a major source of anti-DNA autoantibody generation. This study was undertaken to evaluate whether mitochondrial DNA (mtDNA) resides in NETs, to evaluate whether mtDNA and anti-mtDNA antibodies cause dysregulation of the PDC-IFNalpha pathway, and to investigate the clinical implication in SLE. METHODS: Patients with SLE (n = 102), patients with rheumatoid arthritis (n = 30), and healthy donors (n = 40) were enrolled in in vitro studies. NETs were generated from phorbol 12-myristate 13-acetate (PMA)-stimulated peripheral neutrophils. Immunofluorescence staining was used to detect NET formation ex vivo and in lupus nephritis renal biopsy samples. The mtDNA levels and type I IFN-inducible gene scores were measured by quantitative polymerase chain reaction. Anti-mtDNA antibodies, anti-double stranded DNA (anti-dsDNA) antibodies, and IFNalpha were detected by enzyme-linked immunosorbent assay. Purified PDCs were stimulated by isolated NETs, mtDNA, or dsDNA, combined with anti-mtDNA or dsDNA IgG, or other culture conditions. Additional patients with SLE (n = 113) were enrolled in a proof-of-concept trial. We evaluated the efficacy and safety of metformin on a background of corticosteroids and conventional immunosuppressive agents in patients with mild or moderate lupus. The primary end point was the efficacy of metformin for reducing disease flare. RESULTS: We detected mtDNA in NETs, and anti-mtDNA antibody levels were elevated in SLE patients compared with controls and significantly correlated with IFN scores and the disease activity index. The presence of anti-mtDNA antibodies was disproportionately associated with lupus nephritis, and correlated better than anti-dsDNA antibody levels with the lupus nephritis activity index. Mitochondrial DNA was deposited in NETs in lupus nephritis renal biopsy specimens. In addition, mtDNA/anti-mtDNA were greater inducers of PDC IFNalpha production via Toll-like receptor engagement than dsDNA/anti-dsDNA. We assessed the effect of metformin on down-regulating the NET mtDNA-PDC-IFNalpha pathway. Metformin decreased PMA-induced NET formation and CpG stimulated PDC IFNalpha generation. A proof-of-concept trial of metformin add-on treatment of mild or moderate SLE resulted in decreases in clinical flares, prednisone exposure, and body weight. CONCLUSION: Our findings establish a link between mtDNA in NETs, anti-mtDNA antibodies, and PDC IFNalpha pathogenesis in SLE, and highlight that specific strategies to down-regulate this pathway, such as treatment with metformin, may be new approaches to treat SLE. PMID- 26245803 TI - A 26-year-old woman with respiratory decompensation in the immediate postpartum period at Mount Sinai Medical Center in New York City. PMID- 26245804 TI - Daytime sleepiness is independently associated with falls in older adults with dementia. AB - AIM: To examine whether elderly people with dementia have a higher prevalence of falls and sleep disturbances than those without dementia, and to determine the subjective sleep characteristics associated with falls in older adults with dementia. METHODS: This was a cross-sectional, population-based study derived from the data in the 2009 Taiwan National Health Interview Survey. A total of 123 older adults with dementia (aged 65 years or older), and 246 older adults without dementia who were randomly selected from the database were included. The occurrence of falls and subjective sleep characteristics (e.g. sleep hours, insomnia symptoms, daytime sleepiness, difficulty in breathing during sleep and daytime naps) were evaluated using the responses to the survey questions. RESULTS: The prevalence of falls in older adults with dementia were approximately twofold higher than that for those without dementia (27.6% vs 15.3%, P = 0.006). Older adults with dementia had longer sleep hours, and increased daytime sleepiness, daytime naps and difficulty in breathing during sleep (all P < 0.05) than those without dementia. Among older adults with dementia, daytime sleepiness was the only sleep characteristic that was significantly correlated to an increased risk of falls (adjusted odds ratio 5.56, 95% confidence interval 1.95 15.91) despite controlling for possible risk factors. CONCLUSIONS: Older adults with dementia had a higher prevalence of falls and sleep disturbances than that observed for those without dementia. Daytime sleepiness was an independent risk factor of falls in elderly people, with dementia after accounting for a range of covariates. Geriatr Gerontol Int 2016; 16: 850-855. PMID- 26245805 TI - Electronic personal health records for people with severe mental illness; a feasibility study. AB - BACKGROUND: Electronic Patient Health Records (ePHRs) contain information created, accessed, monitored and maintained by patients. This paper describes how an ePHR called myhealthlockerTM was used by people with severe mental illness to monitor and input their own health-related outcomes, and whether they derived any benefit from it. METHOD: Individuals using local secondary mental health services were provided with access to myhealthlocker, an ePHR which allowed them to monitor their health and input information from Patient Reported Outcome Measures (PROMs) across to their clinical record. Participants were given support to use myhealthlocker through drop-in sessions facilitated by an Occupational Therapist. Usage of the site was monitored over time. Surveys and interviews were used to investigate what participants thought about the intervention. RESULTS: 32 of 58 participants used the ePHR (where usage was defined by logging in at least twice and completing a PROM). Almost all participants who used the site had been referred from community rather than inpatient services. Of those who used the site, 26 out of 32 used it primarily or exclusively through supported drop-in sessions. Almost half of those participants who used the site had used it outside the drop-in sessions. Those who used the site found it useful (n = 32), and most said they would continue to use it (n = 27). There were no apparent differences in usage across gender, diagnosis, and length of service use history. Suggestions for improvement included a social networking component, and finding ways to engage clinicians. In particular, users valued the ability to monitor health outcomes over time. CONCLUSIONS: People with severe mental illness were able to use an ePHR and derive benefit from monitoring and inputting PROMs. Those who use the site are more likely to have been referred from community mental health services, and then supported to access the ePHR. PMID- 26245806 TI - Best (but oft-forgotten) practices: the multiple problems of multiplicity-whether and how to correct for many statistical tests. AB - Testing many null hypotheses in a single study results in an increased probability of detecting a significant finding just by chance (the problem of multiplicity). Debates have raged over many years with regard to whether to correct for multiplicity and, if so, how it should be done. This article first discusses how multiple tests lead to an inflation of the alpha level, then explores the following different contexts in which multiplicity arises: testing for baseline differences in various types of studies, having >1 outcome variable, conducting statistical tests that produce >1 P value, taking multiple "peeks" at the data, and unplanned, post hoc analyses (i.e., "data dredging," "fishing expeditions," or "P-hacking"). It then discusses some of the methods that have been proposed for correcting for multiplicity, including single-step procedures (e.g., Bonferroni); multistep procedures, such as those of Holm, Hochberg, and Sidak; false discovery rate control; and resampling approaches. Note that these various approaches describe different aspects and are not necessarily mutually exclusive. For example, resampling methods could be used to control the false discovery rate or the family-wise error rate (as defined later in this article). However, the use of one of these approaches presupposes that we should correct for multiplicity, which is not universally accepted, and the article presents the arguments for and against such "correction." The final section brings together these threads and presents suggestions with regard to when it makes sense to apply the corrections and how to do so. PMID- 26245807 TI - Impact of equol-producing capacity and soy-isoflavone profiles of supplements on bone calcium retention in postmenopausal women: a randomized crossover trial. AB - BACKGROUND: Postmenopausal estrogen depletion is a major contributing factor to bone loss. Soy isoflavones have variable effects on the prevention of postmenopausal bone loss, which is possibly related to the specific isoflavone content or the variable equol-producing capacity of individuals. OBJECTIVE: We aimed to determine the effects of the content of isoflavones in a soy supplement and the equol-producing ability of the individual on postmenopausal bone calcium retention. DESIGN: The study was a blinded, randomized, crossover intervention trial in 24 postmenopausal women who were prescreened for their ability to convert daidzein to equol. Women were equilibrated with (41)Ca before the intervention. Interventions were 5 soy isoflavone oral supplements (2 doses of a genistein-rich soy supplement and 3 doses of mixed isoflavones in various proportions) and a bisphosphonate (risedronate). Each intervention was given sequentially for 50 d followed by a 50-d washout period. The percentage of bone calcium retention was determined from the change in urinary (41)Ca:calcium. RESULTS: Interventions that ranged from 52 to 220 mg total isoflavones/d increased bone calcium retention between 3.4% and 7.6% (P < 0.05), which was a moderate effect compared with that of risedronate at 15.3% (95% CI: 7.1%, 22.7%; P = 0.0014). The most-effective soy intervention delivered 105.23 mg total isoflavones/d as genistein, daidzein, and glycitein in their natural ratios and increased bone calcium retention by 7.6% (95% CI: 4.9%, 10.2%; P < 0.0001). Genistein, at 52.85 mg/d, increased bone calcium retention by 3.4% (95% CI: 0.5%, 6.2%; P = 0.029); but there was no benefit at higher amounts (113.52 mg/d). There was no difference (P = 0.5) in bone calcium retention between equol producers and nonproducers. CONCLUSION: Soy isoflavones, although not as potent as risedronate, are effective bone-preserving agents in postmenopausal women regardless of their equol-producing status, and mixed isoflavones in their natural ratios are more effective than enriched genistein. This trial was registered at clinicaltrials.gov as NCT00244907. PMID- 26245808 TI - Accelerated protein digestion and amino acid absorption after Roux-en-Y gastric bypass. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) involves exclusion of major parts of the stomach and changes in admixture of gastro-pancreatic enzymes, which could have a major impact on protein digestion and amino acid absorption. OBJECTIVE: We investigated the effect of RYGB on amino acid appearance in the systemic circulation from orally ingested protein and from endogenous release. DESIGN: Nine obese glucose-tolerant subjects, with a mean body mass index (in kg/m(2)) of 39.2 (95% CI: 35.2, 43.3) and mean glycated hemoglobin of 5.3% (95% CI: 4.9%, 5.6%), were studied before and 3 mo after RYGB. Leucine and phenylalanine kinetics were determined under basal conditions and during 4 postprandial hours by intravenous infusions of [3,3,3-(2)H3]-leucine and [ring-(2)D5]-phenylalanine combined with ingestion of [1-(13)C]-leucine intrinsically labeled caseinate as the sole protein source of the meal. Changes in body composition were assessed by dual-energy X-ray absorptiometry. RESULTS: After RYGB, basal plasma leucine concentration did not change, but marked changes were seen postprandially with 1.7-fold increased peak concentrations (before-mean: 217 MUmol/L; 95% CI: 191, 243 MUmol/L; 3 mo-mean: 377 MUmol/L; 95% CI: 252, 502 MUmol/L; P = 0.012) and 2 fold increased incremental AUC (before-mean: 4.1 mmol ? min/L; 95% CI: 2.7, 5.5 mmol ? min/L; 3 mo-mean: 9.5 mmol ? min/L; 95% CI: 4.9, 14.2 mmol ? min/L; P = 0.032). However, the postprandial hyperleucinemia was transient, and concentrations were below basal concentrations in the fourth postprandial hour. These concentration differences were mainly caused by changes in leucine appearance rate from orally ingested caseinate: peak rate increased nearly 3-fold [before-mean: 0.5 MUmol/(kg fat-free mass ? min); 95% CI: 0.4, 0.5 MUmol/(kg fat free mass ? min); 3 mo-mean 1.4 MUmol/(kg fat-free mass ? min); 95% CI: 0.8, 1.9 MUmol/(kg fat-free mass ? min); P = 0.002], and time to peak was much shorter (before-mean: 173 min; 95% CI: 137, 209 min; 3 mo-mean: 65 min; 95% CI: 46, 84 min; P < 0.001). Only minor changes were seen in endogenous leucine release after RYGB. CONCLUSIONS: RYGB accelerates caseinate digestion and amino acid absorption, resulting in faster and higher but more transient postprandial elevation of plasma amino acids. Changes are likely mediated by accelerated intestinal nutrient entry and clearly demonstrate that protein digestion is not impaired after RYGB. This trial was registered at clinicaltrials.gov as NCT01559792. PMID- 26245809 TI - Dietary isoflavones, urinary isoflavonoids, and risk of ischemic stroke in women. AB - BACKGROUND: Hormone therapy has been shown to increase risk of ischemic stroke in women. Plant-derived estrogens, particularly soy isoflavones, are known to have some estrogenic effects and have been marketed as natural alternatives to hormone therapy. Concerns have been raised about whether high isoflavone exposure may be related to ischemic stroke risk as well. OBJECTIVE: We examined the dietary intake of isoflavones and the urinary excretion of isoflavonoids in relation to risk of ischemic stroke in women. DESIGN: A prospective cohort study was conducted in 66,832 Chinese women (aged 40-70 y) who had no cardiovascular disease or cancer at baseline. Usual dietary intakes were assessed via in-person interviews with the use of a validated food-frequency questionnaire. Incident strokes were ascertained during follow-up home visits and confirmed by medical records. We also conducted a nested case-control study in postmenopausal women who had never used hormone therapy, including 1422 incident ischemic stroke cases and 1422 controls individually matched by age, date and time of urine sample collection, time since last meal, and use of antibiotics. Urinary isoflavonoids were measured with the use of high-performance liquid chromatography coupled with mass spectrometry. RESULTS: During a mean follow-up of 10 y, 3110 incident ischemic strokes were verified. Dietary isoflavone intake was associated with increased risk of ischemic stroke; multivariable-adjusted HRs from lowest to highest quintiles were 1.00, 1.05, 1.10, 1.11, and 1.24, respectively (95% CI: 1.08, 1.42; P-trend = 0.002). In the case-control study, a similar positive association was observed for dietary isoflavones, but no significant associations were shown for the urinary isoflavonoid concentration [OR: 1.01 (95% CI: 0.77, 1.32) for comparison of extreme quintiles]. CONCLUSIONS: A habitually high intake of soy isoflavones may be associated with a modest but significant increase in risk of ischemic stroke in women. However, no association was shown for the urinary excretion of isoflavonoids. PMID- 26245810 TI - Sodium fluoride affects zebrafish behaviour and alters mRNA expressions of biomarker genes in the brain: Role of Nrf2/Keap1. AB - Sodium fluoride (NaF), used as pesticides and for industrial purposes are deposited in the water bodies and therefore affects its biota. Zebrafish exposed to NaF in laboratory condition showed hyperactivity and frequent surfacing activity, somersaulting and vertical swimming pattern as compared to the control group. Reactive oxygen species level was elevated and glutathione level was depleted along with increased malondialdehyde content in the brain. Levels of glutathione-s-transferase (GST), catalase (CAT) and superoxide dismutase were also elevated in the treatment groups. Expression of mRNA of nuclear factor erythroid 2 related factor 2 (Nrf2) and its inhibitor Kelch-like ECH-associated protein 1 (Keap1) during stress condition were observed along with Gst, Cat, NADPH: quinone oxidoreductase 1(Nqo1) and p38. Except Keap1, all other genes exhibited elevated expression. Nrf2/Keap1 proteins had similar expression pattern as their corresponding mRNA. The findings in this study might help to understand the molecular mechanism of fluoride induced neurotoxicity in fish. PMID- 26245811 TI - Chemical and microbial components of urban air PM cause seasonal variation of toxicological activity. AB - The chemical and microbial composition of urban air particulate matter (PM) displays seasonal variation that may affect its harmfulness on human health. We studied the in vitro inflammatory and cellular metabolic activity/cytotoxicity of urban air particulate samples collected in four size-ranges (PM10-2.5, PM2.5-1, PM1-0.2, PM0.2) during four seasons in relatively clean urban environment in Helsinki, Finland. The composition of the same samples were analyzed, including ions, elements, PAH compounds and endotoxins. In addition, microbial contribution on the detected responses was studied by inhibiting the endotoxin-induced responses with Polymyxin B both in the PM samples and by two different bacterial strains representing Gram-positive and -negative bacteria. Macrophage cell line (RAW 264.7) was exposed to the size segregated particulate samples as well as to microbe samples for 24h and markers of inflammation and cytotoxicity were analyzed. The toxicological responses were dependent on the dose as well as size range of the particles, PM10-2.5 being the most potent and smaller size ranges having significantly smaller responses. Samples collected during spring and autumn had in most cases the highest inflammatory activity. Soil components and other non-exhaust particulate emissions from road traffic correlated with inflammatory responses in coarse particles. Instead, PAH-compounds and K(+) had negative associations with the particle-induced inflammatory responses in fine particles, suggesting the role of incomplete biomass combustion. Endotoxin content was the highest in PM10-2.5 samples and correspondingly, the largest decrease in the responses by Polymyxin B was seen with the very same samples. We found also that inhibitory effect of Polymyxin B was not completely specific for Gram-negative bacteria. Thus, in addition to endotoxin, also other microbial components may have a significant effect on the toxicological responses by ambient particulate matter. PMID- 26245812 TI - Therapeutic effect of Chinese patent medicine "Wuhuanghu" on porcine infectious pleuropneumonia and its acute and subchronic toxicity as well as evaluation of safety pharmacology. AB - Chinese patent medicines play an important role in veterinary clinical use. The aim of this study is to research the anti-infection effect of Chinese patent medicine "Wuhuanghu" for the treatment of porcine infectious pleuropneumonia and to evaluate the safety of "Wuhuanghu" in order to provide a comprehensive understanding of its toxicity. The anti-infection results showed that the treatment with "Wuhuanghu" could significantly inhibit pneumonia and decrement of the pneumonia in high, medium and low doses of "Wuhuanghu" groups were 70.97%, 61.29% and 58.06% respectively. The acute toxicity test showed that rats in the highest group (5000mg/kg) had no death and no abnormal response, suggesting the LD50 of "Wuhuanghu" was more than 5000mg/kg. The subchronic toxicity study showed that hematology indexes in all groups had no obvious differences; blood biochemical index, only albumin and total cholesterol in middle and low doses of "Wuhuanghu" groups were significantly decreased when compared with control group. The clinical pathology showed that the target organ of "Wuhuanghu" was liver. The safety pharmacology study indicated that "Wuhuanghu" had no side effects on rats. In conclusion, "Wuhuanghu" has therapeutic and protective effects to porcine infectious pleuropneumonia in a dose-dependent manner and "Wuhuanghu" is a safe veterinary medicine. PMID- 26245813 TI - Cytogenetic biomonitoring of occupationally exposed workers to ashes from burning of sugar cane in Ahome, Sinaloa, Mexico. AB - Burning the sugar cane field before harvesting has a negative impact on both air and human health, however this issue had not been explored in Mexico. The objective of this work was to determine the chromosomal damage in workers from sugar cane burning fields in Sinaloa, Mexico. To this purpose, we analyzed 1000 cells of buccal exfoliated epithelia from 60 exposed workers and 60 non-exposed controls to determine micronucleus frequencies and other nuclear abnormalities. The results indicated significant higher values of micronucleus and nuclear abnormalities such as binucleate cells, pyknosis, karyolysis, chromatin condensation and nuclear buds frequencies in the exposed subjects compared to those that were not exposed. Our data indicates that sugar cane burning, that generates polycyclic aromatic hydrocarbons, represents a genotoxic risk for workers in this important sugar cane producing area in Mexico. PMID- 26245814 TI - Venous thromboembolism prophylaxis: a path toward more appropriate use. PMID- 26245815 TI - Entrepreneurship. AB - High-tech businesses are the driving force behind global knowledge-based economies. Academic institutions have positioned themselves to serve the high tech industry through consulting, licensing, and university spinoffs. The awareness of commercialization strategies and building an entrepreneurial culture can help academics to efficiently transfer their inventions to the market to achieve the maximum value. Here, the concept of high-tech entrepreneurship is discussed from lab to market in technology-intensive sectors such as nanotechnology, photonics, and biotechnology, specifically in the context of lab on-a-chip devices. This article provides strategies for choosing a commercialization approach, financing a startup, marketing a product, and planning an exit. Common reasons for startup company failures are discussed and guidelines to overcome these challenges are suggested. The discussion is supplemented with case studies of successful and failed companies. Identifying a market need, assembling a motivated management team, managing resources, and obtaining experienced mentors lead to a successful exit. PMID- 26245816 TI - Atrial natriuretic peptide modulates auditory brainstem response of rat. AB - CONCLUSION: These findings suggest that Atrial natriuretic peptide (ANP) exhibits an inhibitory effect on auditory brainstem response (ABR) and is involved in the neuromodulation of the auditory nervous system. OBJECTIVES: ANP may alter electrophysiological properties of the cochlea and play a role in auditory action. METHODS: This study was undertaken to examine and clarify the role of ANP in the rat auditory system using ABR audiometry. The mean ABR thresholds and the latencies for wave II at the ABR threshold altered at given frequencies throughout the study. RESULTS: Intra-arterial infusion of ANP (0.1 mg/kg, 4 mg/kg, and 8 mg/kg; bolus injection) resulted in a significant increase in ABR thresholds. A significant shift in the ABR wave II latency was observed at lower frequency (1 kHz and 2 kHz). There was a little change in latency at 20 kHz. Increased amount of ANP significantly altered the ABR in rats. PMID- 26245818 TI - Analysis of factors related to vagally mediated reflex bradycardia during gastrectomy. AB - PURPOSE: Because vagally mediated reflex bradycardia occurs frequently during gastrectomy and is potentially harmful, we compared the incidence of clinically significant reflex bradycardia between patients undergoing laparoscopic gastrectomy (LG) and open gastrectomy (OG) and examined whether the type of surgery (OG vs. LG) was an independent risk factor for clinically significant reflex bradycardia. METHODS: This prospective observational study evaluated 358 adult patients (age 18-70 years) who were undergoing elective OG or LG for gastric cancer resection. Symptomatic reflex bradycardia was defined as a sudden decrease in heart rate to <50 beats per minute (bpm), or to 50-59 bpm with a systolic blood pressure <70 mmHg, associated with a specific surgical maneuver. If bradycardia or hypotension developed, atropine or ephedrine was administered, in accordance with a predefined treatment protocol. RESULTS: The overall incidence of symptomatic reflex bradycardia was 24.6% (88/358). Univariate analysis revealed the incidence of symptomatic reflex bradycardia in the LG group was significantly lower than that in the OG group [13.0% (13/100) vs. 29.1% (75/258), p = 0.002]. Multivariate logistic regression analysis revealed that the type of surgery (OG vs. LG), advanced age, preoperative bradycardia, type of muscle relaxant (vecuronium vs. rocuronium), no use of intravenous remifentanil, and low core temperature, were independent risk factors for symptomatic reflex bradycardia (odds ratio 3.184; 95% confidence interval 1.490-6.800; p = 0.003). CONCLUSION: The LG approach was associated with a reduced risk of clinically significant reflex bradycardia compared with the OG approach. PMID- 26245819 TI - Evaluating the detailed position of the subclavian artery to avoid inadvertent subclavian artery puncture during right internal jugular vein catheterization. AB - PURPOSE: Central venous catheter placement is useful but is associated with complications. Inadvertent subclavian artery (SCA) puncture is a rare complication associated with internal jugular vein (IJV) catheterization. We determined the position of the SCA by ultrasonography, and propose a needle insertion position for avoiding inadvertent SCA puncture. METHODS: We positioned an ultrasound probe at an angle of 60 degrees to the skin to mimic a puncture needle halfway between the clavicle and the angle of the mandible (center) and moved the probe parallel to the right IJV (RIJV) toward the clavicle until locating the SCA. We measured the distance from the clavicle to the probe 60 and from the probe to the SCA (P60-SCA) where the SCA was visible by ultrasonography. RESULTS: For 50 volunteers with a mean age of 27.3 years, the center position was, on average, 67 mm from the clavicle. The image of the SCA appeared within 65 mm of the clavicle. P60-SCA differed significantly between men and women (p = 0.0058). For 45 volunteers, P60-SCA was <25 mm with the probe 65 mm from the clavicle on the skin. RIJVP-SCA averaged 4.4 mm. Only P60-SCA correlated well with BMI for men (r = 0.732, p = 0.0068). CONCLUSION: Puncturing the RIJV away from the center should avoid SCA puncture; puncturing it while approaching the clavicle is more dangerous. The exact location of the SCA varies from person to person; thus, confirming SCA position by ultrasonography is recommended every time before puncturing. PMID- 26245821 TI - Topical application of the hexane fraction of Lacistema pubescens reduces skin inflammation and cytokine production in animal model. AB - OBJECTIVES: The aim of this study was to investigate the acute topical anti inflammatory effect of the hexane fraction (HLP) of Lacistema pubescens in mice. METHODS: Ear oedema models induced by croton oil, arachidonic acid, phenol, histamine, ethyl phenyl propiolate and capsaicin. Histopathological analyses of ear tissue samples sensitized with croton oil were performed. Myeloperoxidase activity (MPO), the pro-inflammatory cytokine-inhibitory effect and dermatoxicity were also evaluated. KEY FINDINGS: HLP (1, 0.5 and 0.1 mg/ear) resulted in a substantial reduction in skin thickness or tissue weight on all models tested, except for capsaicin-induced ear oedema, similar to dexamethasone (0.1 mg/ear) and/or indomethacin (0.5 mg/ear). Histopathological analyses and neutrophil mediated MPO activity confirmed the topical anti-inflammatory effect of HLP. In addition, HLP reduced IL-1beta, IL-6 and tumour necrosis factor-alpha cytokine levels. Sitosterol-rich fraction (SRF), obtained from HLP fractionation, reduced ear oedema on croton oil and phenol models at the same dose of dexamethasone (0.1 mg/ear). No dermotoxicity was observed. CONCLUSIONS: The mechanism of action of HLP was associated with the inhibition of several pro-inflammatory mediators, including cytokines, arachidonic acid metabolites and histamine, which suggested a glucocorticoid-like effect, reinforced by the presence of the steroid sitosterol. This is the first report on anti-inflammatory activity of L. pubescens leaves. PMID- 26245822 TI - Pushing the rules: effects and aftereffects of deliberate rule violations. AB - Most of our daily life is organized around rules and social norms. But what makes rules so special? And what if one were to break a rule intentionally? Can we simply free us from the present set of rules or do we automatically adhere to them? How do rule violations influence subsequent behavior? To investigate the effects and aftereffects of violating simple S-R rule, we conducted three experiments that investigated continuous finger-tracking responses on an iPad. Our experiments show that rule violations are distinct from rule-based actions in both response times and movement trajectories, they take longer to initiate and execute, and their movement trajectory is heavily contorted. Data not only show differences between the two types of response (rule-based vs. violation), but also yielded a characteristic pattern of aftereffects in case of rule violations: rule violations do not trigger adaptation effects that render further rule violations less difficult, but every rule violation poses repeated effort on the agent. The study represents a first step towards understanding the signature and underlying mechanisms of deliberate rule violations, they cannot be acted out by themselves, but require the activation of the original rule first. Consequently, they are best understood as reformulations of existing rules that are not accessible on their own, but need to be constantly derived from the original rule, with an add-on that might entail an active tendency to steer away from mental representations that reflect (socially) unwanted behavior. PMID- 26245823 TI - Attention to future actions: the influence of instructed S-R versus S-S mappings on attentional control. AB - Even though there is ample evidence that planning future actions plays a role in attentional processing (e.g., Downing Visual Cognition 11:689-703, 2000; Soto et al., Trends in Cognitive Sciences 12:248-342, 2008), it is not clear to what extent planning in itself (rather than the prior experience of the planned actions) controls attention. We suggest that attention can be biased towards stimuli that are associated with instructions for tasks that will be performed in the future even if those tasks have not yet been experienced. We performed two experiments in which participants receive instructions in which some objects were associated with a response (i.e., instructed S-R objects; "Experiment 1") or a stimulus property (i.e., instructed S-S objects; "Experiment 2"), whereas control objects were not. However, before participants were required to perform the S-R task ("Experiment 1") or perform an S-S memory task ("Experiment 2"), they performed a visual probe task in which target objects and control objects served as irrelevant cues. Our results show that attention was biased towards the S-R objects (compared to control stimuli) but not to S-S objects. These findings suggest that future plans can bias attention toward specific stimuli, but only when these stimuli are associated with a specific action. We discuss these findings in light of research concerning automatic effects of instructions and theories that view attention as a selection-for-action mechanism. PMID- 26245824 TI - The journey into fatherhood: A grounded theory study. AB - The objective of this study was to explore the process of transition into fatherhood for Thai men from childbirth to the postpartum period. Forty-one first time Thai fathers were voluntarily recruited from two hospitals in Chiang Mai, Thailand, from December 2012 to June 2013. In-depth interviews were used to collect the data, which were analyzed based on grounded theory methodology. The basic social process that emerged as the core category was termed: "the journey into fatherhood." This process was divided into three phases: labor, delivery, and family beginning. Within this process, there were various situations, challenges, and pressures, which caused many changes of mood and feelings for the first-time fathers. Throughout this process, they applied various strategies to manage their concerns and needs, in order to develop into masterly fathers. Identifying the process of the journey into fatherhood provides nurses and midwives insight into the new fathers' experiences, which will enable them to be more sensitive, respectful, and effective caregivers. PMID- 26245825 TI - Recombinant lipoprotein-based vaccine candidates against C. difficile infections. AB - BACKGROUND: Opportunistically nosocomial infections in hospitalized patients are often related to Clostridium difficile infections (CDI) due to disruption of the intestinal micro-flora by antibiotic therapies during hospitalization. Clostridial exotoxins A and B (TcdA and TcdB) specifically bind to unknown glycoprotein(s) in the host intestine, disrupt the intestinal barrier leading to acute inflammation and diarrhea. The C-terminal receptor binding domain of TcdA (A-rRBD) has been shown to elicit antibody responses that neutralize TcdA toxicity in Vero cell cytotoxicity assays, but not effectively protect hamsters against a lethal dose challenge of C. difficile spores. To develop an effective recombinant subunit vaccine against CDI, A-rRBD was lipidated (rlipoA-RBD) as a rational design to contain an intrinsic adjuvant, a toll-like receptor 2 agonist and expressed in Escherichia coli. RESULTS: The purified rlipoA-RBD was characterized immunologically and found to have the following properties: (a) mice, hamsters and rabbits vaccinated with 3 MUg of rlipoA-RBD produced strong antibody responses that neutralized TcdA toxicity in Vero cell cytotoxicity assays; furthermore, the neutralization titer was comparable to those obtained from antisera immunized either with 10 MUg of TcdA toxoid or 30 MUg of A-rRBD; (b) rlipoA-RBD elicited immune responses and protected mice from TcdA challenge, but offered insignificant protection (10 to 20 %) against C. difficile spores challenge in hamster models; (c) only rlipoA-RBD formulated with B-rRBD consistently confers protection (90 to 100 %) in the hamster challenge model; and (d) rlipoA-RBD was found to be 10-fold more potent than A-rRBD as an adjuvant to enhancing immune responses against a poor antigen such as ovalbumin. CONCLUSION: These results indicate that rlipoA-RBD formulated with B-rRBD could be an excellent vaccine candidate for preclinical studies and future clinical trials. PMID- 26245826 TI - Heart failure and pulmonary arteriovenous malformations in a patient with hereditary hemorrhagic telangiectasia type 2. AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominantly inherited vascular-malformation syndrome associated with gene mutations including ENG, ACVRL1 and SMAD4 gene. Clinically indistinguishable HHT1 and HHT2 are caused by mutations in ENG and ACVRL1 gene, respectively. Generally, pulmonary arteriovenous malformations (PAVMs) and pulmonary arterial hypertension (PAH) are rare manifestations of HHT related to ACVRL1 gene mutations. We described a female patient with HHT2 whose clinical features included epistaxis, mucocutaneous telangiectases, systemic AVMs and PAH. She also suffered from severe iron deficiency anemia and recurrent heart failure. A genetic mutation analysis disclosed a missense mutation in exon 7 of ACVRL1 gene in this patient and her daughter. A nonsense mutation in exon 7 of ACVRL1 gene was detected in her brother and her niece. This case supports that PAVMs and PAH can be rare manifestations of HHT2 patients. PMID- 26245827 TI - The role of N-acetylcysteine in the treatment of thrombotic thrombocytopenic purpura. AB - Thrombotic thrombocytopenic purpura (TTP) is an acute, thrombotic microangiopathy with a high mortality rate if left untreated. Plasma exchange (PEX) is the current standard of care. However, a significant number of patients are refractory to this treatment. N-acetylcysteine (NAC) was recently suggested as a potential therapeutic adjunct for patients with TTP. This study reports a series of three patients with TTP successfully treated with NAC in addition to standard therapy. Detailed chart reviews on these patients were conducted. We discuss clinical features, laboratory findings and management of three patients who presented with microangiopathic hemolytic anemia and thrombocytopenia. Anti ADAMTS13 antibodies and low levels of ADAMTS13 were detected and confirmed the diagnosis of acquired TTP. Based upon their severe presentation or lack of response to initial treatment with PEX, corticosteroids and other immunosuppressive agents, NAC was added. Under this combined treatment, all three patients hada significant clinical improvement of symptoms with concurrent normalization of platelet count and ADAMTS13 activity level. This report highlights the potential therapeutic utility of NAC in the treatment of TTP. Randomized controlled studies will be required to better characterize the risk-to benefit ratio of NAC in the treatment of TTP. PMID- 26245829 TI - Enhanced Dispersion and Stability of Petroleum Coke Water Slurries via Triblock Copolymer and Xanthan Gum: Rheological and Adsorption Studies. AB - The rheology of petroleum coke (petcoke) water slurries was investigated with a variety of nonionic and anionic dispersants including poly(ethylene oxide) (PEO) b-poly(propylene oxide) (PPO)-b-PEO triblock copolymers (trade name: Pluronic, BASF), poly(vinyl alcohol) (PVA), polyvinylpyrrolidone (PVP), poly(ethylene oxide) (PEO), poly(carboxylate acid) (PCA), sodium lignosulfonate (SLS), and poly(acrylic acid) (PAA). Each effective dispersant system shared very similar rheological behavior to the others when examined at the same volume fraction from its maximum petcoke loading. Triblock copolymer, Pluronic F127 (F127), was found to be the best dispersant by comparing the maximum petcoke loading for each dispersant. The yield stress was measured as a function of petcoke loading and dispersant concentration for F127, and a minimum dispersant concentration was observed. An adsorption isotherm and atomic force microscopy (AFM) images reveal that this effective dispersion of petcoke particles by F127 is due to the formation of a uniform monolayer of brushes where hydrophobic PPO domains of F127 adhere to the petcoke surface, while hydrophilic PEO tails fill the gap between petcoke particles. F127 was then compared to other Pluronics with various PEO and PPO chain lengths, and the effects of surface and dispersant hydrophilicity were examined. Finally, xanthan gum (XG) was tested as a stabilizer in combination with F127 for potential industrial application, and F127 appears to break the XG aggregates into smaller aggregates through competitive adsorption, leading to an excellent degree of dispersion but the reduced stability of petcoke slurries. PMID- 26245828 TI - Herpes virus entry mediator licenses Listeria infection induced immunopathology through control of type I interferon. AB - Apoptosis of the splenic lymphocytes is often induced during the acute phase of Listeria infection in mice. However, the underlying mechanism remains incompletely understood. Here, we found that herpes virus entry mediator (HVEM) plays an important role for Listeria infection induced lymphocyte apoptosis. Mechanistically, HVEM is not directly involved in listeriolysin O (LLO) induced lymphocyte apoptosis or interferon beta induced T cell activation per se. Interestingly, HVEM is partially required for Listeria induced interferon (IFN)-I production in the spleen, particularly in macrophages. Consequently, the bystander activation of lymphocytes is significantly lower in HVEM deficient mice than that in wild-type (WT) mice upon Listeria infection. Thus, our results have revealed a novel role of HVEM on the regulation of IFN-I and immunopathology during Listeria infection. PMID- 26245830 TI - Development of an ELISA for the Detection of Azaspiracids. AB - Azaspiracids (AZAs) are a group of biotoxins that cause food poisoning in humans. These toxins are produced by small marine dinoflagellates such as Azadinium spinosum and accumulate in shellfish. Ovine polyclonal antibodies were produced and used to develop an ELISA for quantitating AZAs in shellfish, algal cells, and culture supernatants. Immunizing antigens were prepared from synthetic fragments of the constant region of AZAs, while plate coating antigen was prepared from AZA 1. The ELISA provides a sensitive and rapid analytical method for screening large numbers of samples. It has a working range of 0.45-8.6 ng/mL and a limit of quantitation for total AZAs in whole shellfish at 57 MUg/kg, well below the maximum permitted level set by the European Commission. The ELISA has good cross reactivity to AZA-1-10, -33, and -34 and 37-epi-AZA-1. Naturally contaminated Irish mussels gave similar results whether they were cooked or uncooked, indicating that the ELISA also detects 22-carboxy-AZA metabolites (e.g., AZA-17 and AZA-19). ELISA results showed excellent correlation with LC-MS/MS analysis, both for mussel extract spiked with AZA-1 and for naturally contaminated Irish mussels. The assay is therefore well suited to screening for AZAs in shellfish samples intended for human consumption, as well as for studies on AZA metabolism. PMID- 26245831 TI - Conservation of Regional Variation in Sex-Specific Sex Chromosome Regulation. AB - Regional variation in sex-specific gene regulation has been observed across sex chromosomes in a range of animals and is often a function of sex chromosome age. The avian Z chromosome exhibits substantial regional variation in sex-specific regulation, where older regions show elevated levels of male-biased expression. Distinct sex-specific regulation also has been observed across the male hypermethylated (MHM) region, which has been suggested to be a region of nascent dosage compensation. Intriguingly, MHM region regulatory features have not been observed in distantly related avian species despite the hypothesis that it is situated within the oldest region of the avian Z chromosome and is therefore orthologous across most birds. This situation contrasts with the conservation of other aspects of regional variation in gene expression observed on the avian sex chromosomes but could be the result of sampling bias. We sampled taxa across the Galloanserae, an avian clade spanning 90 million years, to test whether regional variation in sex-specific gene regulation across the Z chromosome is conserved. We show that the MHM region is conserved across a large portion of the avian phylogeny, together with other sex-specific regulatory features of the avian Z chromosome. Our results from multiple lines of evidence suggest that the sex specific expression pattern of the MHM region is not consistent with nascent dosage compensation. PMID- 26245832 TI - High-Resolution Global Analysis of the Influences of Bas1 and Ino4 Transcription Factors on Meiotic DNA Break Distributions in Saccharomyces cerevisiae. AB - Meiotic recombination initiates with DNA double-strand breaks (DSBs) made by Spo11. In Saccharomyces cerevisiae, many DSBs occur in "hotspots" coinciding with nucleosome-depleted gene promoters. Transcription factors (TFs) stimulate DSB formation in some hotspots, but TF roles are complex and variable between locations. Until now, available data for TF effects on global DSB patterns were of low spatial resolution and confined to a single TF. Here, we examine at high resolution the contributions of two TFs to genome-wide DSB distributions: Bas1, which was known to regulate DSB activity at some loci, and Ino4, for which some binding sites were known to be within strong DSB hotspots. We examined fine-scale DSB distributions in TF mutant strains by deep sequencing oligonucleotides that remain covalently bound to Spo11 as a byproduct of DSB formation, mapped Bas1 and Ino4 binding sites in meiotic cells, evaluated chromatin structure around DSB hotspots, and measured changes in global messenger RNA levels. Our findings show that binding of these TFs has essentially no predictive power for DSB hotspot activity and definitively support the hypothesis that TF control of DSB numbers is context dependent and frequently indirect. TFs often affected the fine-scale distributions of DSBs within hotspots, and when seen, these effects paralleled effects on local chromatin structure. In contrast, changes in DSB frequencies in hotspots did not correlate with quantitative measures of chromatin accessibility, histone H3 lysine 4 trimethylation, or transcript levels. We also ruled out hotspot competition as a major source of indirect TF effects on DSB distributions. Thus, counter to prevailing models, roles of these TFs on DSB hotspot strength cannot be simply explained via chromatin "openness," histone modification, or compensatory interactions between adjacent hotspots. PMID- 26245834 TI - pH-Sensitive polymer assisted self-aggregation of bis(pyrene) in living cells in situ with turn-on fluorescence. AB - Supramolecular self-assemblies with various nanostructures in organic and aqueous solutions have been prepared with desired functions. However, in situ construction of self-assembled superstructures in physiological conditions to achieve expected biological functions remains a challenge. Here, we report a supramolecular system to realize the in situ formation of nanoaggregates in living cells. The bis(pyrene) monomers were dispersed inside of hydrophobic domains of pH-sensitive polymeric micelles and delivered to the lysosomes of cells. In the acidic lysosomes, the bis(pyrene) monomers were released and self aggregated with turn-on fluorescence. We envision this strategy for in situ construction of supramolecular nanostructures in living cells will pave the way for molecular diagnostics in the future. PMID- 26245833 TI - In Vivo Transcriptional Activation Using CRISPR/Cas9 in Drosophila. AB - A number of approaches for Cas9-mediated transcriptional activation have recently been developed, allowing target genes to be overexpressed from their endogenous genomic loci. However, these approaches have thus far been limited to cell culture, and this technique has not been demonstrated in vivo in any animal. The technique involving the fewest separate components, and therefore the most amenable to in vivo applications, is the dCas9-VPR system, where a nuclease-dead Cas9 is fused to a highly active chimeric activator domain. In this study, we characterize the dCas9-VPR system in Drosophila cells and in vivo. We show that this system can be used in cell culture to upregulate a range of target genes, singly and in multiplex, and that a single guide RNA upstream of the transcription start site can activate high levels of target transcription. We observe marked heterogeneity in guide RNA efficacy for any given gene, and we confirm that transcription is inhibited by guide RNAs binding downstream of the transcription start site. To demonstrate one application of this technique in cells, we used dCas9-VPR to identify target genes for Twist and Snail, two highly conserved transcription factors that cooperate during Drosophila mesoderm development. In addition, we simultaneously activated both Twist and Snail to identify synergistic responses to this physiologically relevant combination. Finally, we show that dCas9-VPR can activate target genes and cause dominant phenotypes in vivo, providing the first demonstration of dCas9 activation in a multicellular animal. Transcriptional activation using dCas9-VPR thus offers a simple and broadly applicable technique for a variety of overexpression studies. PMID- 26245835 TI - Distinct frontal and amygdala correlates of change detection for facial identity and expression. AB - Recruitment of 'top-down' frontal attentional mechanisms is held to support detection of changes in task-relevant stimuli. Fluctuations in intrinsic frontal activity have been shown to impact task performance more generally. Meanwhile, the amygdala has been implicated in 'bottom-up' attentional capture by threat. Here, 22 adult human participants took part in a functional magnetic resonance change detection study aimed at investigating the correlates of successful (vs failed) detection of changes in facial identity vs expression. For identity changes, we expected prefrontal recruitment to differentiate 'hit' from 'miss' trials, in line with previous reports. Meanwhile, we postulated that a different mechanism would support detection of emotionally salient changes. Specifically, elevated amygdala activation was predicted to be associated with successful detection of threat-related changes in expression, over-riding the influence of fluctuations in top-down attention. Our findings revealed that fusiform activity tracked change detection across conditions. Ventrolateral prefrontal cortical activity was uniquely linked to detection of changes in identity not expression, and amygdala activity to detection of changes from neutral to fearful expressions. These results are consistent with distinct mechanisms supporting detection of changes in face identity vs expression, the former potentially reflecting top-down attention, the latter bottom-up attentional capture by stimulus emotional salience. PMID- 26245836 TI - Developmental differences in the neural mechanisms of facial emotion labeling. AB - Adolescence is a time of increased risk for the onset of psychological disorders associated with deficits in face emotion labeling. We used functional magnetic resonance imaging (fMRI) to examine age-related differences in brain activation while adolescents and adults labeled the emotion on fearful, happy and angry faces of varying intensities [0% (i.e. neutral), 50%, 75%, 100%]. Adolescents and adults did not differ on accuracy to label emotions. In the superior temporal sulcus, ventrolateral prefrontal cortex and middle temporal gyrus, adults show an inverted-U-shaped response to increasing intensities of fearful faces and a U shaped response to increasing intensities of happy faces, whereas adolescents show the opposite patterns. In addition, adults, but not adolescents, show greater inferior occipital gyrus activation to negative (angry, fearful) vs positive (happy) emotions. In sum, when subjects classify subtly varying facial emotions, developmental differences manifest in several 'ventral stream' brain regions. Charting the typical developmental course of the brain mechanisms of socioemotional processes, such as facial emotion labeling, is an important focus for developmental psychopathology research. PMID- 26245837 TI - Threat-related amygdala functional connectivity is associated with 5-HTTLPR genotype and neuroticism. AB - Communication between the amygdala and other brain regions critically regulates sensitivity to threat, which has been associated with risk for mood and affective disorders. The extent to which these neural pathways are genetically determined or correlate with risk-related personality measures is not fully understood. Using functional magnetic resonance imaging, we evaluated independent and interactive effects of the 5-HTTLPR genotype and neuroticism on amygdala functional connectivity during an emotional faces paradigm in 76 healthy individuals. Functional connectivity between left amygdala and medial prefrontal cortex (mPFC) and between both amygdalae and a cluster including posterior cingulate cortex, precuneus and visual cortex was significantly increased in 5 HTTLPR S' allele carriers relative to L(A)L(A) individuals. Neuroticism was negatively correlated with functional connectivity between right amygdala and mPFC and visual cortex, and between both amygdalae and left lateral orbitofrontal (lOFC) and ventrolateral prefrontal cortex (vlPFC). Notably, 5-HTTLPR moderated the association between neuroticism and functional connectivity between both amygdalae and left lOFC/vlPFC, such that S' carriers exhibited a more negative association relative to L(A)L(A) individuals. These findings provide novel evidence for both independent and interactive effects of 5-HTTLPR genotype and neuroticism on amygdala communication, which may mediate effects on risk for mood and affective disorders. PMID- 26245839 TI - Destructive tsunami-like wave generated by surf beat over a coral reef during Typhoon Haiyan. AB - Storm surges cause coastal inundation due to setup of the water surface resulting from atmospheric pressure, surface winds and breaking waves. Here we show that during Typhoon Haiyan, the setup generated by breaking waves near the fringing reef-protected town of Hernani, the Philippines, oscillated with the incidence of large and small wave groups, and steepened into a tsunami-like wave that caused extensive damage and casualties. Though fringing reefs usually protect coastal communities from moderate storms, they can exacerbate flooding during strong events with energetic waves. Typical for reef-type bathymetries, a very short wave-breaking zone over the steep reef face facilitates the freeing of infragravity-period fluctuations (surf beat) with little energy loss. Since coastal flood planning relies on phase-averaged wave modelling, infragravity surges are not being accounted for. This highlights the necessity for a policy change and the adoption of phase-resolving wave models for hazard assessment in regions with fringing reefs. PMID- 26245838 TI - Reward expectation regulates brain responses to task-relevant and task-irrelevant emotional words: ERP evidence. AB - We investigated the effect of reward expectation on the processing of emotional words in two experiments using event-related potentials (ERPs). A cue indicating the reward condition of each trial (incentive vs non-incentive) was followed by the presentation of a negative or neutral word, the target. Participants were asked to discriminate the emotional content of the target word in Experiment 1 and to discriminate the color of the target word in Experiment 2, rendering the emotionality of the target word task-relevant in Experiment 1, but task irrelevant in Experiment 2. The negative bias effect, in terms of the amplitude difference between ERPs for negative and neutral targets, was modulated by the task-set. In Experiment 1, P31 and early posterior negativity revealed a larger negative bias effect in the incentive condition than that in the non-incentive condition. However, in Experiment 2, P31 revealed a diminished negative bias effect in the incentive condition compared with that in the non-incentive condition. These results indicate that reward expectation improves top-down attentional concentration to task-relevant information, with enhanced sensitivity to the emotional content of target words when emotionality is task-relevant, but with reduced differential brain responses to emotional words when their content is task-irrelevant. PMID- 26245840 TI - Intercalation of 2-butyl-4-methylphenol to G-C rich region of DNA and the role of hydroxypropyl-beta-cyclodextrin. AB - The characteristics of binding of 2-tert-butyl-4-methylphenol (TBMP), a synthetic phenolic antioxidant with hydroxypropyl-beta-cyclodextrin (Hp-betaCD) and calf thymus DNA (ctDNA) were investigated by multi-spectroscopic techniques and molecular simulation. The results indicated that TBMP preferred to form a 1:1 inclusion complex with Hp-betaCD, with an inclusion constant of determined to be 7.15 * 10(3) L mol(-1). The intercalative mode of TBMP to ctDNA was supported by ctDNA melting temperature and relative viscosity studies, salt quenching effect, competitive binding with methylene blue and molecular modeling. The changes in Fourier transformed infrared (FT-IR) and circular dichroism (CD) spectra suggested that TBMP mainly bound to the G-C rich region with inducing a significant perturbation in B-like DNA structure. It was also found that Hp betaCD decreased the binding ability of TBMP with ctDNA, but did not affect the interactive mode between TBMP and ctDNA, and the formed inclusion complex of TBMP Hp-betaCD decomposed in the presence of ctDNA. This study may provide insights into the mechanism of binding of TBMP with ctDNA and the role of Hp-betaCD in the TBMP-ctDNA interaction. PMID- 26245841 TI - Regional universities and rural clinical schools contribute to rural medical workforce, a cohort study of 2002 to 2013 graduates. AB - INTRODUCTION: Rural clinical schools and regionally based medical schools have a major role in expanding the rural medical workforce. The aim of this cohort study was to compare location of practice of graduates from the University of Tasmania School of Medicine's clinical schools based in the larger cities of Hobart and Launceston (UTAS SoM), with those graduates who spent at least 1 year at the University of Tasmania School of Medicine's Rural Clinical School based in the smaller regional city of Burnie (UTAS RCS) in Australia. Specifically, the aim was to quantify the proportion who worked in an Australian regional or remote location, or in the regional cities and smaller towns within Tasmania. METHODS: The 2014 locations of practice of all graduates from the UTAS SoM and UTAS RCS between 2002 and 2013 were determined using the postcode listed in the Australian Health Practitioners Authority database. These postcodes were mapped against the Australian Bureau of Statistics Australian Standard Geographic Classification - Remoteness Areas (ASGC-RA) and the 2011 Census population data for Tasmania to define Modified Monash Model classifications. RESULTS: The study tracked 974 UTAS SoM graduates; 202 (21%) spent at least 1 year at the Rural Clinical School (UTAS RCS graduates). Students who had spent a year at the UTAS RCS were five times more likely to be working in RA3 to RA5 than those who hadn't spent a clinical year there (28% vs 7%, chi2(1)=59.5, p<0.0001) (odds ratio (OR) 4.9, 95% confidence interval (CI) 3.2-7.6). Using the Modified Monash Model, it was found that UTAS RCS graduates were nine times more likely (OR 9.0, 95%CI 4.7-17.2) to be working in the regional cities and smaller towns of Tasmania. CONCLUSIONS: This study adds to the growing evidence that training medical students in rural areas delivers graduates that work rurally. The additional year spent in a rural area, even when their medical school is in a regional city, significantly affects their workplace choices over the first 3 years post-graduation. PMID- 26245842 TI - Progranulin Overproduction Due to Fli-1 Deficiency Contributes to the Resistance of Dermal Fibroblasts to Tumor Necrosis Factor in Systemic Sclerosis. AB - OBJECTIVE: Progranulin is a growth factor that is active in wound repair and is an antagonist of tumor necrosis factor (TNF) receptors, regulating fibroblast activation, angiogenesis, and inflammation. Because long-standing activation of gene programs related to wound healing is a hallmark of systemic sclerosis (SSc), we sought to investigate the role of progranulin in SSc. METHODS: Progranulin expression levels in human and murine skin samples were determined by immunohistochemical analysis and quantitative reverse transcription-polymerase chain reaction. The role of progranulin in fibroblast activation was examined using a gene-silencing technique. Progranulin levels in serum obtained from 60 patients with SSc and 16 healthy control subjects were determined by enzyme linked immunosorbent assay. RESULTS: Progranulin expression was increased in SSc dermal fibroblasts compared with normal dermal fibroblasts, both in vivo and in vitro. Transcription factor Fli-1, a deficiency of which is involved in the activation of SSc dermal fibroblasts, served as a potent repressor of the progranulin gene, and Fli-1(+/-) mice and bleomycin-treated wild-type mice exhibited up-regulated expression of progranulin in dermal fibroblasts. SSc dermal fibroblasts were resistant to the antifibrotic effect of TNF, but this resistance was reversed by gene silencing of progranulin. Serum progranulin levels were elevated in patients with early diffuse cutaneous SSc (dcSSc), especially in those with inflammatory skin symptoms, and were positively correlated with the C-reactive protein level. CONCLUSION: Progranulin overproduction due to Fli-1 deficiency may contribute to the constitutive activation of SSc dermal fibroblasts by antagonizing the antifibrotic effect of TNF. Progranulin may also be involved in the inflammatory process associated with progressive skin sclerosis in early dcSSc. PMID- 26245843 TI - Incidence trends and age distribution of colorectal cancer by subsite in Guangzhou, 2000-2011. AB - INTRODUCTION: Colorectal cancer (CRC) is the third most common cancer in China. The incidence of CRC has been increasing in recent years. The aim of this study was to explore the incidence trends and the age distribution of CRC by subsite in Guangzhou between 2000 and 2011. METHODS: A total of 22,432 incident cases of CRC between 2000 and 2011 from Guangzhou Cancer Registry were identified. Crude incidence and age-standardized rates (ASRs), using the Segi's world standard population, were calculated for CRC and CRC subsites. The incidence trend was analyzed and the annual percentage change (APC) in incidence was calculated by using JoinPoint software. RESULTS: The crude incidence increased significantly from 23.4/10(5) in 2000 to 37.4/10(5) in 2011 for males and from 20.9/10(5) to 30.5/10(5) for females. The ASRs of CRC incidence stabilized during the period of 2000-2011 for both males and females. The ages at the onset of CRC for both males and females during 2010-2011 were significantly higher compared with those during 2000-2002 (males: t = 1.95, P = 0.05; females: t = 6.03, P < 0.01). For males aged 50-64 years, the CRC incidence increased by 8.50% annually (P = 0.04) during 2000-2004 and by 1.68% annually (P = 0.03) during 2005-2011. For females aged 65 years and older, the CRC incidence increased by 5.77% annually (P = 0.03) during 2000-2004. There were no significant changes for the CRC incidences in males aged 49 and younger and 65 years and older and females aged 64 years and younger during 2000-2004, or for those in all females as well as males aged 49 years and younger and 65 years and older during 2005-2011. The percentage of colon cancer in all CRCs increased significantly for both males and females between the periods of 2000-2002 and 2010-2011. The ASRs of descending colon and sigmoid colon cancer incidences increased significantly for females during 2005-2011 (APC, 5.51% and 1.08%, respectively, both P < 0.05). CONCLUSIONS: The crude incidence of CRC increased significantly between 2000 and 2011 because of the aging, whereas the ASRs kept stable. The percentage of colon cancer in all CRCs increased significantly. Further surveillance, research, and intervention are needed to identify the causes of these changes and to reduce the incidence and mortality of CRC. PMID- 26245844 TI - 4-Terminal Tandem Photovoltaic Cell Using Two Layers of PTB7:PC71BM for Optimal Light Absorption. AB - A 4-terminal architecture is proposed in which two thin active layers (<100 nm) of PTB7:PC71BM are deposited on a two-sided ITO covered glass substrate. By modeling the electric field distribution inside the multilayer structure and applying an inverse solving problem procedure, we designed an optimal device architecture tailored to extract the highest photocurrent possible. By adopting such a 4-terminal configuration, we numerically demonstrated that even when the two subcells use identical absorber materials, the performance of the 4-terminal device may overcome the performance of the best equivalent single-junction device. In an experimental implementation of such a 4-terminal device, we demonstrate the viability of the approach and find a very good match with the trend of the numerical predictions. PMID- 26245845 TI - Infiltrative Hepatocellular Carcinoma: Natural History and Comparison with Multifocal, Nodular Hepatocellular Carcinoma. AB - OBJECTIVE: The purpose of this study was to delineate infiltrating hepatocellular carcinoma (HCC) and to compare patient characteristics, tumor characteristics, and outcomes with patients presenting with HCC tumors of discrete, nodular morphology at a similar stage. METHODS: Patient demographic and tumor characteristics of 224 patients diagnosed with infiltrative or advanced discrete, nodular HCC at the University of Texas Southwestern Medical Center were collected between January 2005 and December 2011. Patient demographics, tumor characteristics, treatment regimens, and overall survival were analyzed between the two groups. RESULTS: Overall, 135 patients were diagnosed with infiltrative HCC compared with 89 patients with either T3a or T3b nodular, discrete HCC. Infiltrative HCC patients were more likely to have symptoms at presentation compared with the nodular HCC cohort, (95 vs. 78 %; p < 0.001). No difference in underlying liver function or etiology of liver disease between cohorts was observed. Patients with infiltrative HCC were more likely to have metastatic disease (53 vs. 35 %; p = 0.007) and malignant venous thrombus (75 vs. 62 %; p < 0.001) compared with the nodular group. Infiltrative HCC had a median survival of 1.9 months compared with 4.3 months in the nodular HCC group (p < 0.0001). Within the infiltrative HCC cohort, symptoms [hazard ratio (HR) 7.2, 95 % confidence interval (CI) 1.9-27], Child-Pugh class C (HR 3.9, 95 % CI 2.1-7.1), hepatic thrombus (HR 5.6, 95 % CI 1.9-16), and lack of treatment (HR 5.6, 95 % CI 2.1 14.6) were associated with worse survival. CONCLUSIONS: Infiltrative HCC had a worse outcome than nodular, discrete HCC most likely secondary to burden of tumor manifested by extrahepatic metastases, vascular invasion, higher alpha fetoprotein levels, and a high degree of symptoms. PMID- 26245846 TI - A spatial analysis of heat stress related emergency room visits in rural Southern Ontario during heat waves. AB - BACKGROUND: In Southern Ontario, climate change may have given rise to an increasing occurrence of heat waves since the year 2000, which can cause heat stress to the general public, and potentially have detrimental health consequences. Heat waves are defined as three consecutive days with temperatures of 32 degrees C and above. Heat stress is the level of discomfort. A variety of heat stress indices have been proposed to measure heat stress (e.g., the heat stress index (HSI)), and has been shown to predict increases in morbidity and/or mortality rates in humans and other species. Maps visualizing the distribution of heat stress can provide information about related health risks and insight for control strategies. Information to inform heat wave preparedness models in Ontario was previously only available for major metropolitan areas. METHODS: Hospitals in communities of fewer than 100,000 individuals were recruited for a pilot study by telephone. The number of people visiting the emergency room or 24 hour urgent care service was collected for a total of 27 days, covering three heat waves and six 3-day control periods from 2010-2012. The heat stress index was spatially predicted using data from 37 weather stations across Southern Ontario by geostatistical kriging. Poisson regression modeling was applied to determine the rate of increased number of emergency room visits in rural hospitals with respect to the HSI. RESULTS: During a heat wave, the average rate of emergency room visits was 1.11 times higher than during a control period (IRR = 1.11, CI95% (IRR) = (1.07,1.15), p <= 0.001). In a univariable model, HSI was not a significant predictor of emergency room visits, but when accounting for the confounding effect of a spatial trend polynomial in the hospital location coordinates, a one unit increase in HSI predicted an increase in daily emergency rooms visits by 0.4% (IRR = 1.004, CI95%(IRR) = (1.0005,1.007), p = 0.024) across the region. One high-risk cluster and no low risk clusters were identified in the southwestern portion of the study area by the spatial scan statistic during heat waves. The high-risk cluster is located in a region with high levels of heat stress during heat waves. CONCLUSIONS: This finding will aid hospitals and rural public health units in preventing and preparing for emergencies of foreseeable heat waves. Future research is needed to assess the relation between heat stress and individual characteristics and demographics of rural communities in Ontario. PMID- 26245847 TI - Does training sitting balance on a platform tilted 10 degrees to the weak side improve trunk control in the acute phase after stroke? A randomized, controlled trial. AB - BACKGROUND: Trunk performance and sitting balance, especially lateral sitting control, are important predictors of functional outcome after stroke. However, no studies have focused only on trunk function in the frontal plane for persons with acute-phase stroke. OBJECTIVE: To investigate the effects of lateral sitting training on a tilting platform in persons with stroke. METHODS: An assessor blinded, randomized, controlled trial was carried out involving inpatients at a stroke rehabilitation center. Patients were allocated to either an experimental group (n = 15) or a control group (n = 15). The experimental group sat without leg support on a platform tilted 10 degrees to the paretic side in the frontal plane, while the controls sat on a horizontal platform. Both groups were asked to move their trunk laterally from the paretic side to the nonparetic side. In addition to conventional therapy, this training was performed 60 times/session, with 6 sessions/week. Trunk function was assessed using the Trunk Control Test (TCT), and the ability to move the trunk laterally was evaluated kinematically. Measurements were performed at baseline and after training. Two-way repeated measures analysis of variance was used to test the significance between and within treatments for each dependent variable. RESULTS: None of the demographic data differed between the groups. After training, a significant improvement was noted in the experimental group compared to the controls in the TCT and the ability for lateral trunk transference (P < 0.05, 1 - beta = 0.98, effect size = 0.4). CONCLUSION: Lateral sitting training on the tilting platform improved the impaired trunk function of persons with stroke. PMID- 26245848 TI - Evidence of a link between resting energy expenditure and bone remodelling, glucose homeostasis and adipokine variations in adolescent girls with anorexia nervosa. AB - Low bone mass is a consequence of anorexia nervosa (AN). This study assessed the effects of energy deficiency on various bone and hormonal parameters. The interrelationships between energy deficiency and bone remodelling, glucose homeostasis and adipokines underscore the importance of preventing energy deficiency to limit demineralisation and hormonal alterations in AN patients. INTRODUCTION: Low areal bone mineral density (aBMD) is a well-known consequence of AN. However, the impact of reduced energy expenditure on bone metabolism is unknown. This study assessed the effects of energy deficiency on bone remodelling and its potential interactions with glucose homeostasis and adipose tissue derived hormones in AN, a clinical model for reduced energy expenditure. METHODS: Fifty women with AN and 50 age-matched controls (mean age 18.1 +/- 2.7 and 18.0 +/- 2.1 years, respectively) were enrolled. aBMD was determined with DXA. Resting energy expenditure (REEm), a marker of energy status, was indirectly assessed by calorimetry. Bone turnover markers, undercarboxylated osteocalcin (ucOC), parameters of glucose homeostasis, adipokines and growth factors were concomitantly evaluated. RESULTS: AN patients presented low aBMD at all bone sites. REEm, bone formation markers, ucOC, glucose, insulin, HOMA-IR, leptin and IGF-1 were significantly reduced, whereas the bone resorption marker, leptin receptor (sOB-R) and adiponectin were elevated in AN compared with CON. In AN patients, REEm was positively correlated with weight, BMI, whole body (WB) fat mass, WB fat-free soft tissue, markers of bone formation, glucose, insulin, HOMA IR, leptin and IGF-1 and negatively correlated with the bone resorption marker and sOB-R. Biological parameters, aBMD excepted, appeared more affected by the weight variation in the last 6 months than by the disease duration. CONCLUSIONS: The strong interrelationships between REEm and bone remodelling, glucose homeostasis and adipokines underscore the importance of preventing energy deficiency to limit short- and long-term bone demineralisation and hormonal alterations in AN patients. PMID- 26245850 TI - [Correlation of morphological and functional glaucoma diagnostics with macular OCT and perimetry with centrally condensed stimuli: German version]. AB - The presentation and measurement of the internal retinal layers by current optical coherence tomography (OCT) instruments allow a precise topographic localization of macular glaucomatous damage. Ganglion cell analysis in particular can reveal slight central defects and can effectively be correlated with perimetric strategies with centrally condensed stimuli, so that small glaucomatous defects can be confirmed earlier and more confidently. Progression can also be verified in the early stages of the disease as enlargement and deepening of small localized defects. Macular OCT (mOCT) cannot sufficiently detect peripheral glaucomatous defects and may be impaired by macular pathologies; therefore, mOCT should be combined with other morphometric examinations. In order to take advantage of the technical capabilities of current OCT devices appropriate perimetric strategies should also be applied. As the algorithms for documentation and evaluation of the results of current OCT instruments are far less advanced than the technical capabilities, OCT results still have to be visually scrutinized together with the visual field results to benefit from the technical possibilities provided by modern OCT devices. PMID- 26245849 TI - Hypophosphatasia: an overview of the disease and its treatment. AB - This review presents the current knowledge on hypophosphatasia, a rare genetic disease of very variable severity (from lethal to mild) and clinical presentation, caused by defective production of tissue-non-specific alkaline phosphatase (TNSALP). Hypophosphatasia can affect babies in utero as well as infants, children, and adults. The article first presents the genetics of TNSALP and its many known mutations underlying the disease. Then, it presents the epidemiology, classification, and clinical presentation of the six different forms of the disease (perinatal lethal, prenatal benign, infantile, childhood, adult, and odontohypophosphatasia) as well as the essential diagnostic clues. The last section on treatment presents a survey of the therapeutic approaches, up to the ongoing phase 2 studies of enzyme replacement therapy. PMID- 26245851 TI - Phase II study of cetuximab with irinotecan for KRAS wild-type colorectal cancer in Japanese patients. AB - AIM: Cetuximab improves the prognosis for wild-type KRAS metastatic colorectal cancer (MCRC). We evaluated the safety and efficacy of cetuximab in combination with irinotecan in Japanese patients with wild-type KRAS MCRC refractory to irinotecan, oxaliplatin and fluoropyrimidines. METHODS: Cetuximab was administered initially at a dose of 400 mg/m2 , followed by weekly infusions at 250 mg/m2 . Irinotecan was administered every 2 weeks at 150 mg/m2 . Primary endpoint was the incidence of grade 3/4 adverse events; secondary endpoints included overall survival (OS), progression-free survival (PFS), response rate (RR), time to treatment failure (TTF), and TTF for irinotecan. RESULTS: Thirty four patients were enrolled. Grade 3 or 4 toxicities were leucopenia (11.8%), neutropenia (23.5%), anemia (11.8%), fatigue (2.9%), anorexia (2.9%), diarrhea (14.7%) and hypomagnesemia (5.9%). Skin toxicities were as follows (any grade/grade 3): acne (94.2/8.8%), rash (55.9/0%), nail changes (75.5/8.8%) and hand-foot syndrome (55.9/5.9%). Median PFS was 6.0 months (95%CI; 4.7-7.4). Median OS was 12.9 months (95%CI; 10.0-15.9). RR was 26.4%. Median TTF was 5.1 months and median TTF for irinotecan was 5.0 months (95%CI; 4.3-5.6). CONCLUSION: Cetuximab with irinotecan therapy was well tolerated in Japanese patients with wild-type KRAS colorectal cancer refractory to irinotecan, oxaliplatin and fluoropyrimidine, thus demonstrating the feasibility of their usage. PMID- 26245852 TI - Determination of Hg(II) ions in sea food samples after extraction and preconcentration by novel Fe3O 4@SiO 2@polythiophene magnetic nanocomposite. AB - This work describes a novel Fe3O4@SiO2@polythiophene magnetic nanocomposite and its application in the preconcentration of Hg(II) ions. The parameters affecting the preconcentration procedure were opted by a Box-Behnken design through response surface methodology. Three factors (uptake time, magnetic nanosorbent amount, and pH of sample) were selected as the main factors affecting the sorption step, while four variables (type, volume and concentration of the eluent as well as the elution time) were selected as main factors in the optimization study of the elution step. Following the sorption and elution of Hg(II), it was quantified by cold vapor atomic absorption spectrometry. Under the optimum condition, the limit of detection was 0.02 ng mL(-1) and all the relative standard deviations were less than 9.2 %. The obtained sorption capacity of this new sorbent was 59 mg g(-1). Finally, this nanocomposite was successfully applied to the rapid extraction of trace quantities of Hg(II) ions in sea food samples and satisfactory results were obtained. PMID- 26245853 TI - Spatio-temporal surveillance of water based infectious disease (malaria) in Rawalpindi, Pakistan using geostatistical modeling techniques. AB - One of the features of medical geography that has made it so useful in health research is statistical spatial analysis, which enables the quantification and qualification of health events. The main objective of this research was to study the spatial distribution patterns of malaria in Rawalpindi district using spatial statistical techniques to identify the hot spots and the possible risk factor. Spatial statistical analyses were done in ArcGIS, and satellite images for land use classification were processed in ERDAS Imagine. Four hundred and fifty water samples were also collected from the study area to identify the presence or absence of any microbial contamination. The results of this study indicated that malaria incidence varied according to geographical location, with eco-climatic condition and showing significant positive spatial autocorrelation. Hotspots or location of clusters were identified using Getis-Ord Gi* statistic. Significant clustering of malaria incidence occurred in rural central part of the study area including Gujar Khan, Kaller Syedan, and some part of Kahuta and Rawalpindi Tehsil. Ordinary least square (OLS) regression analysis was conducted to analyze the relationship of risk factors with the disease cases. Relationship of different land cover with the disease cases indicated that malaria was more related with agriculture, low vegetation, and water class. Temporal variation of malaria cases showed significant positive association with the meteorological variables including average monthly rainfall and temperature. The results of the study further suggested that water supply and sewage system and solid waste collection system needs a serious attention to prevent any outbreak in the study area. PMID- 26245854 TI - A Secure and Robust User Authenticated Key Agreement Scheme for Hierarchical Multi-medical Server Environment in TMIS. AB - The telecare medicine information system (TMIS) helps the patients to gain the health monitoring facility at home and access medical services over the Internet of mobile networks. Recently, Amin and Biswas presented a smart card based user authentication and key agreement security protocol usable for TMIS system using the cryptographic one-way hash function and biohashing function, and claimed that their scheme is secure against all possible attacks. Though their scheme is efficient due to usage of one-way hash function, we show that their scheme has several security pitfalls and design flaws, such as (1) it fails to protect privileged-insider attack, (2) it fails to protect strong replay attack, (3) it fails to protect strong man-in-the-middle attack, (4) it has design flaw in user registration phase, (5) it has design flaw in login phase, (6) it has design flaw in password change phase, (7) it lacks of supporting biometric update phase, and (8) it has flaws in formal security analysis. In order to withstand these security pitfalls and design flaws, we aim to propose a secure and robust user authenticated key agreement scheme for the hierarchical multi-server environment suitable in TMIS using the cryptographic one-way hash function and fuzzy extractor. Through the rigorous security analysis including the formal security analysis using the widely-accepted Burrows-Abadi-Needham (BAN) logic, the formal security analysis under the random oracle model and the informal security analysis, we show that our scheme is secure against possible known attacks. Furthermore, we simulate our scheme using the most-widely accepted and used Automated Validation of Internet Security Protocols and Applications (AVISPA) tool. The simulation results show that our scheme is also secure. Our scheme is more efficient in computation and communication as compared to Amin-Biswas's scheme and other related schemes. In addition, our scheme supports extra functionality features as compared to other related schemes. As a result, our scheme is very appropriate for practical applications in TMIS. PMID- 26245855 TI - Low surface recombination velocity in solution-grown CH3NH3PbBr3 perovskite single crystal. AB - Organic-inorganic hybrid perovskites are attracting intense research effort due to their impressive performance in solar cells. While the carrier transport parameters such as mobility and bulk carrier lifetime shows sufficient characteristics, the surface recombination, which can have major impact on the solar cell performance, has not been studied. Here we measure surface recombination dynamics in CH3NH3PbBr3 perovskite single crystals using broadband transient reflectance spectroscopy. The surface recombination velocity is found to be 3.4+/-0.1 * 10(3) cm s(-1), ~2-3 orders of magnitude lower than that in many important unpassivated semiconductors employed in solar cells. Our result suggests that the planar grain size for the perovskite thin films should be larger than ~30 MUm to avoid the influence of surface recombination on the effective carrier lifetime. PMID- 26245856 TI - Structural and Photoconductivity Properties of Tellurium/PMMA Films. AB - Owing to the very brittle nature of tellurium powder, nanoscopic grains with an average size of 4.8 +/- 0.8 nm were produced by dry vibration milling technique using a mixer/mill apparatus. A novel material was obtained by binding the nanosized tellurium grains with poly(methyl methacrylate) (PMMA) polymer. The morphology, elemental composition, and structural and optical properties of Te/PMMA films were investigated. The prepared material was composed of hexagonal tellurium and alpha-phase of tellurium oxide. The electrical properties of the films were studied, for different electrode contact configurations, in dark condition and under white light illumination varying the optical power density from 2 to 170 mW/cm(2) and turning the light on and off cyclically. Data analysis shows that the photoconductivity of the film with sandwich contact configuration is a linear function of the light power density and increases more than 2 orders of magnitude as compared to the photoresponse of the film with coplanar contact configuration. PMID- 26245857 TI - Collision-spike Sputtering of Au Nanoparticles. AB - Ion irradiation of nanoparticles leads to enhanced sputter yields if the nanoparticle size is of the order of the ion penetration depth. While this feature is reasonably well understood for collision-cascade sputtering, we explore it in the regime of collision-spike sputtering using molecular-dynamics simulation. For the particular case of 200-keV Xe bombardment of Au particles, we show that collision spikes lead to abundant sputtering with an average yield of 397 +/- 121 atoms compared to only 116 +/- 48 atoms for a bulk Au target. Only around 31 % of the impact energy remains in the nanoparticles after impact; the remainder is transported away by the transmitted projectile and the ejecta. The sputter yield of supported nanoparticles is estimated to be around 80 % of that of free nanoparticles due to the suppression of forward sputtering. PMID- 26245858 TI - Hydrothermal Synthesis and Biocompatibility Study of Highly Crystalline Carbonated Hydroxyapatite Nanorods. AB - Highly crystalline carbonated hydroxyapatite (CHA) nanorods with different carbonate contents were synthesized by a novel hydrothermal method. The crystallinity and chemical structure of synthesized nanorods were studied by Fourier transform infrared spectroscopy (FTIR), X-ray photo-electronic spectroscopy (XPS), X-ray diffraction (XRD), Raman spectroscopy, and transmission electron microscopy (TEM). The biocompatibility of synthesized CHA nanorods was evaluated by cell viability and alkaline phosphatase (ALP) activity of MG-63 cell line. The biocompatibility evaluation results show that these CHA nanorods are biologically active apatites and potentially promising bone-substitute biomaterials for orthopedic application. PMID- 26245859 TI - Preparation and Properties of Double-Sided AgNWs/PVC/AgNWs Flexible Transparent Conductive Film by Dip-Coating Process. AB - The double-sided transparent conductive films of AgNWs/PVC/AgNWs using the silver nanowires and PVC substrate were fabricated by the dip-coating process followed by mechanical press treatment. The morphological and structural characteristics were investigated by scanning electron microscope (SEM) and atomic force microscope (AFM), the photoelectric properties and mechanical stability were measured by ultraviolet-visible spectroscopy (UV-vis) spectrophotometer, four point probe technique, 3M sticky tape test, and cyclic bending test. The results indicate that the structure and photoelectric performances of the AgNWs films were mainly affected by the dipping and lifting speeds. At the optimized dipping speed of 50 mm/min and lifting speed of 100 mm/min, the AgNWs are evenly distributed on the surface of the PVC substrate, and the sheet resistance of AgNWs film on both sides of PVC is about 60 Omega/sq, and the optical transmittance is 84.55 % with the figure of merit value up to 35.8. The film treated with the 10 MPa pressure shows excellent adhesion and low surface roughness of 17.8 nm and maintains its conductivity with the sheet resistance change of 17 % over 10,000 cyclic bends. PMID- 26245860 TI - Hexagonal nanoplates of NiO/CoO/Fe2O3 composite acting as an efficient photocatalytic and electrocatalytic water oxidation catalyst. AB - A unique hexagonal sheet-shaped NiO/CoO/Fe2O3 composite with irregularly shaped nanoparticles was fabricated for the first time through a simple co-precipitation and hydrothermal method. The NiO/CoO/Fe2O3 composite was characterized by numerous techniques (TEM, HRTEM, PXRD, EDX, ICP-AES, BET, and XPS) to confirm its structure and composition. This structure of the NiO/CoO/Fe2O3 composite may enhance the photocatalytic and electrocatalytic performance for water oxidation. Compared with NiO, CoO and Fe2O3, the NiO/CoO/Fe2O3 composite exhibits a lower overpotential and a much smaller Tafel slope of 49 mV dec(-1) for water oxidation. At the same time, the composite possesses beneficial ferromagnetic properties and superior stability; thus, it can be used repeatedly without any loss in activity. PMID- 26245861 TI - Stereoscopic neuroanatomy lectures using a three-dimensional virtual reality environment. AB - INTRODUCTION: Three-dimensional (3D) computer graphics are increasingly used to supplement the teaching of anatomy. While most systems consist of a program which produces 3D renderings on a workstation with a standard screen, the Dextrobeam virtual reality VR environment allows the presentation of spatial neuroanatomical models to larger groups of students through a stereoscopic projection system. MATERIALS AND METHODS: Second-year medical students (n=169) were randomly allocated to receive a standardised pre-recorded audio lecture detailing the anatomy of the third ventricle accompanied by either a two-dimensional (2D) PowerPoint presentation (n=80) or a 3D animated tour of the third ventricle with the DextroBeam. Students completed a 10-question multiple-choice exam based on the content learned and a subjective evaluation of the teaching method immediately after the lecture. RESULTS: Students in the 2D group achieved a mean score of 5.19 (+/-2.12) compared to 5.45 (+/-2.16) in the 3D group, with the results in the 3D group statistically non-inferior to those of the 2D group (p<0.0001). The students rated the 3D method superior to 2D teaching in four domains (spatial understanding, application in future anatomy classes, effectiveness, enjoyableness) (p<0.01). CONCLUSION: Stereoscopically enhanced 3D lectures are valid methods of imparting neuroanatomical knowledge and are well received by students. More research is required to define and develop the role of large-group VR systems in modern neuroanatomy curricula. PMID- 26245862 TI - Culture as a Moving Symbolic Border. AB - The aim of this paper is to propose the notion of culture as a symbolic moving border. Departing from both, Boesch's (1991) concept of culture as a symbolic field of action, and Herbst's (1995) co-genetic logic, I will discuss the dynamics of self-other relationships in terms of their potentiality as sources of movement in culture. A brief analysis of an empirical material is given in illustrative character of the ideas here exposed. PMID- 26245863 TI - Homologues of xenobiotic metabolizing N-acetyltransferases in plant-associated fungi: Novel functions for an old enzyme family. AB - Plant-pathogenic fungi and their hosts engage in chemical warfare, attacking each other with toxic products of secondary metabolism and defending themselves via an arsenal of xenobiotic metabolizing enzymes. One such enzyme is homologous to arylamine N-acetyltransferase (NAT) and has been identified in Fusarium infecting cereal plants as responsible for detoxification of host defence compound 2 benzoxazolinone. Here we investigate functional diversification of NAT enzymes in crop-compromising species of Fusarium and Aspergillus, identifying three groups of homologues: Isoenzymes of the first group are found in all species and catalyse reactions with acetyl-CoA or propionyl-CoA. The second group is restricted to the plant pathogens and is active with malonyl-CoA in Fusarium species infecting cereals. The third group generates minimal activity with acyl CoA compounds that bind non-selectively to the proteins. We propose that fungal NAT isoenzymes may have evolved to perform diverse functions, potentially relevant to pathogen fitness, acetyl-CoA/propionyl-CoA intracellular balance and secondary metabolism. PMID- 26245864 TI - Caustics and Rogue Waves in an Optical Sea. AB - There are many examples in physics of systems showing rogue wave behaviour, the generation of high amplitude events at low probability. Although initially studied in oceanography, rogue waves have now been seen in many other domains, with particular recent interest in optics. Although most studies in optics have focussed on how nonlinearity can drive rogue wave emergence, purely linear effects have also been shown to induce extreme wave amplitudes. In this paper, we report a detailed experimental study of linear rogue waves in an optical system, using a spatial light modulator to impose random phase structure on a coherent optical field. After free space propagation, different random intensity patterns are generated, including partially-developed speckle, a broadband caustic network, and an intermediate pattern with characteristics of both speckle and caustic structures. Intensity peaks satisfying statistical criteria for rogue waves are seen especially in the case of the caustic network, and are associated with broader spatial spectra. In addition, the electric field statistics of the intermediate pattern shows properties of an "optical sea" with near-Gaussian statistics in elevation amplitude, and trough-to-crest statistics that are near Rayleigh distributed but with an extended tail where a number of rogue wave events are observed. PMID- 26245865 TI - Orienting patients to greater opioid safety: models of community pharmacy-based naloxone. AB - The leading cause of adult injury death in the U.S.A. is drug overdose, the majority of which involves prescription opioid medications. Outside of the U.S.A., deaths by drug overdose are also on the rise, and overdose is a leading cause of death for drug users. Reducing overdose risk while maintaining access to prescription opioids when medically indicated requires careful consideration of how opioids are prescribed and dispensed, how patients use them, how they interact with other medications, and how they are safely stored. Pharmacists, highly trained professionals expert at detecting and managing medication errors and drug-drug interactions, safe dispensing, and patient counseling, are an under utilized asset in addressing overdose in the U.S. and globally. Pharmacies provide a high-yield setting where patient and caregiver customers can access naloxone-an opioid antagonist that reverses opioid overdose-and overdose prevention counseling. This case study briefly describes and provides two US state-specific examples of innovative policy models of pharmacy-based naloxone, implemented to reduce overdose events and improve opioid safety: Collaborative Pharmacy Practice Agreements and Pharmacy Standing Orders. PMID- 26245866 TI - Antibacterial activity of ethanolic extract and compounds from fruits of Tectona grandis (Verbenaceae). AB - BACKGROUND: Well known as teak, Tectona grandis is widely used in African folk medicine for its pharmacological relevance. In Cameroon, this species is a reputed laxative in the Northern Region while in the Western Region, it is used in the treatment of skin diseases and diarrhoea. MATERIALS AND METHODS: Separation and isolation of compounds were performed using different chromatographic methods while their structures were elucidated by spectroscopic techniques including MS and NMR, and by comparison of data with those reported in the literature. Isolated compounds as well as crude ethanol extract were tested for their antibacterial activities using broth micro-dilution method against four Gram negative bacteria strains Escherichia coli (ATCC 8739), Pseudomonas aeruginosa (PA 01), Klebsiella pneumonia (ATCC 11296) and Escherichia aerogenes (ATCC 13048). RESULTS: Three known compounds were isolated, including two quinones and one triterpene. They were identified as tectograndone (1), 6-methyl 1,4-dihydroxyanthraquinone (2), and 2beta-hydroxyursolic acid (3) respectively. Crude ethanol extract showed good activity against the bacteria strains tested with MIC of 64-256 MUg/mL. Among the isolated metabolites, 6-methyl-1,4 dihydroxyanthraquinone exhibited a strong activity against Escherichia aerogenes with MIC of 16 MUg/mL, while tectograndone showed a moderate activity against Escherichia coli with MIC of 32 MUg/mL. The antibacterial screening of the fruits of this plant as well as that of compounds 1 and 2 is reported herein for the first time. CONCLUSION: The research work presented here shows that Tectona grandis fruits possess compounds which could be developed in the treatment of bacterial diseases. PMID- 26245867 TI - [Hemolytic anemia]. AB - Hemolytic anemia can be caused by various hereditary or acquired diseases. Classification is usually based on corpuscular or extracorpuscular defects. Beside the anemia, laboratory testing indicates increased lactate dehydrogenase, unconjugated bilirubin and reticulocytes as well as reduced or absent plasma haptoglobin. Knowledge of further diagnostic procedures (e.g., Coombs test, schistocytes, hemoglobin electrophoresis or flow cytometric analysis) leads in many cases to an underlying disease with differentiated therapeutic options. Autoimmune hemolytic anemia (AIHA) is often associated with diseases as HIV, connective tissue disease, lymphomas or malignant tumors and the hemolytic process is preexisting in many cases. Thrombotic microvascular diseases (e.g., thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome) are further important causes of hemolytic anemia which need immediate diagnosis and treatment. PMID- 26245869 TI - An analysis of the intake of iodine-131 by a dairy herd post-Fukushima and the subsequent excretion in milk. AB - This study focuses on iodine-131 detected in milk samples from the Dairy Science Unit at Cal Poly, San Luis Obispo, California following events at the Fukushima Dai-ichi Nuclear Power Plant in March of 2011. The milk samples, collected between March 21 and April 11, 2011, were part of the Diablo Canyon Nuclear Power Plant Radiological Environmental Monitoring Program. A correlation is made between the integrated activity of iodine-131 found in milk and the integrated activities of iodine-131 of rainwater, vegetation and air samples that were collected from March 19 to April 18, 2011. A comparison is then made to previous studies conducted on dairy cattle that were administered controlled amounts of iodine-131 through ingestion. The comparison shows good agreement to the model which states that generally 1 percent of the activity of iodine-131 ingested by dairy cattle will be detected in harvested milk. Considering the environmental factors and the uncertainties involved, these data and calculated results derived from a real world situation provide an excellent application and confirmation of studies done under controlled settings. PMID- 26245870 TI - Spatial variability of the dose rate from (137)Cs fallout in settlements in Russia and Belarus more than two decades after the Chernobyl accident. AB - Radionuclides from the 1986 Chernobyl accident were released and dispersed during a limited period of time, but under widely varying weather conditions. As a result, there was a high geographical variation in the deposited radioactive fallout per unit area over Europe, depending on the released composition of fission products and the weather during the 10 days of releases. If the plume from Chernobyl coincided with rain, then the radionuclides were unevenly distributed on the ground. However, large variations in the initial fallout also occurred locally or even on a meter scale. Over the ensuing years the initial deposition may have been altered further by different weathering processes or human activities such as agriculture, gardening, and decontamination measures. Using measurements taken more than two decades after the accident, we report on the inhomogeneous distribution of the ground deposition of the fission product (137)Cs and its influence on the dose rate 1 m above ground, on both large and small scales (10ths of km(2) - 1 m(2)), in the Gomel-Bryansk area close to the border between Belarus and Russia. The dose rate from the deposition was observed to vary by one order of magnitude depending on the size of the area considered, whether human processes were applied to the surface or not, and on location specific properties (e.g. radionuclide migration in soil). PMID- 26245868 TI - Neuroinflammatory responses in diabetic retinopathy. AB - Diabetic retinopathy (DR) is a common complication of diabetes and has been recognized as a vascular dysfunction leading to blindness in working-age adults. It becomes increasingly clear that neural cells in retina play an important role in the pathogenesis of DR. Neural retina located at the back of the eye is part of the brain and a representative of the central nervous system. The neurosensory deficits seen in DR are related to inflammation and occur prior to the clinically identifiable vascular complications. The neural deficits are associated with abnormal reactions of retina glial cells and neurons in response to hyperglycemia. Improper activation of the innate immune system may also be an important contributor to the pathophysiology of DR. Therefore, DR manifests characteristics of both vasculopathy and chronic neuroinflammatory diseases. In this article, we attempt to provide an overview of the current understanding of inflammation in neural retina abnormalities in diabetes. Inhibition of neuroinflammation may represent a novel therapeutic strategy to the prevention of the progression of DR. PMID- 26245872 TI - The "paperless NHS" at the front line. PMID- 26245871 TI - Metformin can block precancerous progression to invasive tumors of bladder through inhibiting STAT3-mediated signaling pathways. AB - BACKGROUND: Metformin is the first line of oral antidiabetic drug in the biguanide class for treatment of type 2 diabetes. Increasing evidence has suggested that it is a potential anti-tumor drug. However, the mechanisms underlying inhibiting tumor development remain elusive, especially in bladder tumors. METHODS: T24 and J82 cell lines were used as an in vitro model, and 24 female SD rats were used to build an N-methyl-N-nitrosourea (MNU)-induced orthotopic rat bladder cancer model. Transfection of lentivirus-based shRNA was used to construct the STAT3-KNOCKDOWN T24 cell line. After metformin treatment, the viability of bladde cancer cells was determined by CCK8. Cell cycle distribution and apoptosis were assessed by flow cytometry. The migration and invasion abilities of cells were evaluated by wound healing and transwell asssays. The inactivation of stat3 pahtway was examined by qRTPCR, western blot and Immunofluorescence. RESULTS: Metformin can effectively inhibit precancerous progression to invasive cancer in an MNU-induced rat orthotopic bladder tumor model, although it could not completely suppress normal cells transforming into tumor cells. While the MNU could induce 50 % rats (4/8) to develop invasive bladder cancers, the rats co-administrated with metformin failed to develop invasive tumors but retained at precancerous or non-invasive stages, exhibiting as dysplasia, papillary tumor and/or carcinoma in situ (CIS). Accordingly, phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is a well known oncogene, was significantly inhibited in the tumors of rats treated with metformin. In vitro experiments revealed that the metformin could efficiently inhibit STAT3 activation, which was associated with the cell cycle arrest, reduction of cell proliferation, migration and invasiveness, and increase in apoptotic cell death of bladder cancer cell lines. CONCLUSIONS: These findings provide for the first time the evidence that metformin can block precancerous lesions progressing to invasive tumors through inhibiting the activation of STAT3 pathway, and may be used for treatment of the non-invasive bladder cancers to prevent them from progression to invasive tumors. PMID- 26245873 TI - Liposomal Formulation of Monovalent Cholesteryl Cytofectins with Acyclic Head Groups and Gene Delivery: A Systematic Review. AB - A large number of liposome-based non-viral gene and siRNA delivery systems include monovalent cholesteryl cytofectins with acyclic head groups in their formulations. Progress in their clinical development has, however, been hampered by relatively low transfection efficiencies. Structural differences between members of this class of cationic amphiphiles are located primarily in their linker, spacer and head group regions. This review examines the structural diversity encountered in each of these domains and seeks to identify those features linked to favourable transfection activity. Thus the ether linker, with its greater chemical and metabolic stability, is associated with higher transfection activity than ester, amide or carbamoyl tethers. While a medium length 6 atom spacer in the ether series is preferred over shorter spacers for enhanced activity, short (2 atom) to long (11 atom) spacers are effective in the more common carbamoyl series. For largely historic reasons, the dimethylamino head group has remained a popular cationic centre, but several studies have shown that the N-hydroxyethyl secondary amine functionality may be more effective in cytofectins. This observation has been attributed, in part, to the increased hydrophilicity of the head group and facilitated release of the nucleic acid cargo from liposomes in endosomal compartments. However, the hypothesis that the incorporation of each of these favourable chemical features into a single novel cytofectin may lead to superior transfection activity remains to be fully tested. PMID- 26245874 TI - Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): Proposal for a new diagnostic paradigm. AB - The diagnosis of von Willebrand disease (VWD) remains difficult in a significant proportion of patients. A Spanish multicentre study investigated a cohort of 556 patients from 330 families who were analysed centrally. VWD was confirmed in 480. Next generation sequencing (NGS) of the whole coding VWF was carried out in all recruited patients, compared with the phenotype, and a final diagnosis established. A total of 238 different VWF mutations were found, 154 were not included in the Leiden Open Variation Database (LOVD). Of the patients, 463 were found to have VWF mutation/s. A good phenotypic/genotypic association was estimated in 96.5% of the patients. One hundred seventy-four patients had two or more mutations. Occasionally a predominant phenotype masked the presence of a second abnormality. One hundred sixteen patients presented with mutations that had previously been associated with increased von Willebrand factor (VWF) clearance. RIPA unavailability, central phenotypic results disagreement and difficult distinction between severe type 1 and type 3 VWD prevented a clear diagnosis in 70 patients. The NGS study facilitated an appropriate classification in 63 of them. The remaining seven patients presented with a VWF novel mutation pending further investigation. In five patients with a type 3 and two with a type 2A or 2B phenotype with no mutation, an acquired von Willebrand syndrome (AVWS) was suspected/confirmed. These data seem to support NGS as a first line efficient and faster paradigm in VWD diagnosis. PMID- 26245875 TI - Classification of Prevention in Sports Medicine and Epidemiology. AB - It is today recognized that a large share of manifestations of ill health associated with sports participation is preventable and that a focus should be on implementation of effective prevention programs. One hindrance for implementation of effective preventive measures in sports medicine may be that an update of preventive frameworks to the current health challenges has not been performed. We introduce classifications of prevention that are adjusted to the health challenges faced by sports participants in the present day. To enable more precise characterizations of preventive measures, we find it necessary to describe them in two dimensions. In one dimension, pathological developments in the body are used as a basis for classification of preventive measures, while the other dimension classifies prevention on the grounds of epidemiological risk indicators. We conclude that longitudinal research combining diagnostic procedures, surveillance, and targeted interventions is needed to enable the introduction of prevention programs for athletes in the beginning of their sporting career at the pre-diagnostic stage, as well as suitable prevention measures for the adult elite athletes. A more distinct classification of prevention supports a specific and cost-effective planning and translation of sports injury prevention and safety promotion adjusted to the delivery settings, various injury types, and different groups of athletes. The present classifications constitute an additional conceptual foundation for such efforts. PMID- 26245877 TI - Management of Lead Encephalopathy with DMSA After Exposure to Lead-Contaminated Moonshine. AB - BACKGROUND: Lead encephalopathy is a severe manifestation of lead poisoning that can present with altered mental status and seizures and has been associated with illicit moonshine consumption. Lead encephalopathy has traditionally been treated using dimercaprol (British anti-Lewisite, BAL) and calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA). CASE REPORT: We describe a patient with lead encephalopathy related to lead-contaminated moonshine consumption, who was treated using dimercaptosuccinic acid (DMSA) due to a national shortage of CaNa2EDTA. A 66-year-old woman presented to a hospital with headache, irritability, and altered mental status. On hospital day 16, she was found to have a whole blood lead concentration of 148.2 MUg/dL and a 24-h urine lead concentration of 232 MUg/day. Due to a national shortage of CaNa2EDTA, the patient was given one dose of BAL and then started on DMSA via nasogastric tube. She dramatically improved over 4 days and was subsequently transitioned to oral DMSA and outpatient treatment. One day prior to discharge, her whole blood lead concentration was 47.2 MUg/dL and her mental status was normal. DMSA was used in lieu of CaNa2EDTA to treat the patient with lead encephalopathy. The patient subsequently experienced clinical improvement and declining whole blood level concentrations. CONCLUSION: Further prospective studies are needed to compare the efficacy of DMSA versus CaNa2EDTA in patients with lead encephalopathy. PMID- 26245876 TI - Gene expression patterns in CD4+ peripheral blood cells in healthy subjects and stage IV melanoma patients. AB - Melanoma patients exhibit changes in immune responsiveness in the local tumor environment, draining lymph nodes, and peripheral blood. Immune-targeting therapies are revolutionizing melanoma patient care increasingly, and studies show that patients derive clinical benefit from these newer agents. Nonetheless, predicting which patients will benefit from these costly therapies remains a challenge. In an effort to capture individual differences in immune responsiveness, we are analyzing patterns of gene expression in human peripheral blood cells using RNAseq. Focusing on CD4+ peripheral blood cells, we describe multiple categories of immune regulating genes, which are expressed in highly ordered patterns shared by cohorts of healthy subjects and stage IV melanoma patients. Despite displaying conservation in overall transcriptome structure, CD4+ peripheral blood cells from melanoma patients differ quantitatively from healthy subjects in the expression of more than 2000 genes. Moreover, 1300 differentially expressed genes are found in transcript response patterns following activation of CD4+ cells ex vivo, suggesting that widespread functional discrepancies differentiate the immune systems of healthy subjects and melanoma patients. While our analysis reveals that the transcriptome architecture characteristic of healthy subjects is maintained in cancer patients, the genes expressed differentially among individuals and across cohorts provide opportunities for understanding variable immune states as well as response potentials, thus establishing a foundation for predicting individual responses to stimuli such as immunotherapeutic agents. PMID- 26245878 TI - Utilizing an Ingestible Biosensor to Assess Real-Time Medication Adherence. AB - Medication adherence monitoring has relied largely on indirect measures of pill ingestion including patient self-report, pharmacy refills, electronically triggered pill bottles, and pill counts. Our objective is to describe an ingestible biosensor system comprising a radio-frequency identification (RFID) tagged gelatin capsule. Once the capsule dissolves in the stomach, the RFID tag activates to transmit a unique signal to a relay device which transmits a time stamped message to a cloud-based server that functions as a direct measure of medication adherence. We describe a constellation of mobile technologies that provide real-time direct measures of medication adherence. Optimizing connectivity, relay design, and interactivity with users are important in obtaining maximal acceptability. Potential concerns including gut retention of metallic components of the ingestible biosensor and drug dissolution within a gelatin capsule should be considered. An ingestible biosensor incorporated into a medication management system has the potential to improve medication compliance with real-time monitoring of ingestion and prompt early behavioral intervention. Integration of ingestible biosensors for multiple disease states may provide toxicologists with salient data early in the care of poisoned patients in the future. Further research on device design and interventions to improve adherence is needed and will shape the evolving world of medication adherence. PMID- 26245879 TI - The Feasibility and Acceptability of Google Glass for Teletoxicology Consults. AB - Teletoxicology offers the potential for toxicologists to assist in providing medical care at remote locations, via remote, interactive augmented audiovisual technology. This study examined the feasibility of using Google Glass, a head mounted device that incorporates a webcam, viewing prism, and wireless connectivity, to assess the poisoned patient by a medical toxicology consult staff. Emergency medicine residents (resident toxicology consultants) rotating on the toxicology service wore Glass during bedside evaluation of poisoned patients; Glass transmitted real-time video of patients' physical examination findings to toxicology fellows and attendings (supervisory consultants), who reviewed these findings. We evaluated the usability (e.g., quality of connectivity and video feeds) of Glass by supervisory consultants, as well as attitudes towards use of Glass. Resident toxicology consultants and supervisory consultants completed 18 consults through Glass. Toxicologists viewing the video stream found the quality of audio and visual transmission usable in 89 % of cases. Toxicologists reported their management of the patient changed after viewing the patient through Glass in 56 % of cases. Based on findings obtained through Glass, toxicologists recommended specific antidotes in six cases. Head-mounted devices like Google Glass may be effective tools for real-time teletoxicology consultation. PMID- 26245881 TI - British Islamic Medical Association's response to Islamic State articles. PMID- 26245880 TI - Barriers to Mental Health Treatment in Rural Older Adults. AB - OBJECTIVES: The purpose of this study was to identify the barriers to seeking mental health treatment experienced by rural older adults. We also examined if barriers differed by age and worry severity. METHODS: Participants were 478 rural older adults responding to a flyer for a psychotherapy intervention study. Interested participants were screened by telephone, and barriers to mental health treatment were assessed. Participants completed a demographic questionnaire and the Penn State Worry Questionnaire-Abbreviated. RESULTS: The most commonly reported barrier to treatment was the personal belief that "I should not need help." Other commonly reported barriers included practical barriers (cost, not knowing where to go, distance), mistrust of mental health providers, not thinking treatment would help, stigma, and not wanting to talk with a stranger about private matters. Multivariable analyses indicated that worry severity and younger age were associated with reporting more barriers. CONCLUSIONS: Multiple barriers interfere with older adults seeking treatment for anxiety and depression. Older age is associated with fewer barriers, suggesting that the oldest old may have found strategies for overcoming these barriers. Young-old adults may benefit from interventions addressing personal beliefs about mental health and alternative methods of service delivery. PMID- 26245883 TI - Norditerpenoid alkaloids from Delphinium anthriscifolium. AB - Two new norditerpenoid alkaloids with lycoctonine skeleton, anthriscifolcones A (1) and B (2), were isolated from the whole plant of Delphinium anthriscifolium var. Majus by extensive column chromatography. Their structures were established by IR, MS, (1)H NMR, (13)C NMR, and 2D NMR methods (including HSQC, (1)H-(1)H COSY, HMBC, and NOESY experiments). PMID- 26245884 TI - Critical anatomic region of nasopalatine canal based on tridimensional analysis: cone beam computed tomography. AB - The study aim of this was to define the critical anatomic region of the premaxilla by evaluating dimensions of nasopalatine canal, buccal bone plate (BBP) and palatal bone plate (PBP). 230 CBCTs were selected with both, one or no upper central incisors present (+/+, -/+, -/-) and periodontal condition was evaluated. T-student test, ANOVA, Pearson's correlation and a multivariant-linear regression model (MLRM) were used. Regarding gender, significant differences at level 1 (lower NC) were found for: buccal-palatal, transversal and sagittal NC diameters, and NC length (NCL). Regarding dental status, significant differences were found for: total BBP length (tBL) and PBP width (PW2) at level 2 (NCL midpoint). NCL was correlated with PW2, tBL, and PBP length at level 3 (foramina of Stenson level). An MLRM had a high prediction value for NCL (69.3%). Gender is related to NC dimensions. Dental status has an influence on BBP dimensions, but does not influence on NC and PBP. Periodontal condition should be evaluated for precise premaxillae analysis NC diameters at the three anatomical planes are related to each other, while NCL is related to BBP and PBP lengths. A third of premaxilla is taken up by NC, thus, establishing the critical anatomic region. PMID- 26245885 TI - Autoantibodies in prediction of the development of rheumatoid arthritis among healthy relatives of patients with the disease. AB - OBJECTIVE: Although blood bank-based studies have shown that rheumatoid arthritis (RA)-related autoantibodies are present before the onset of RA, information on their positive predictive value (PPV) for development of RA in healthy individuals is scarce. This study was undertaken to assess the 5-year PPV of serum IgM rheumatoid factor (IgM-RF) and anti-cyclic citrullinated peptide (anti CCP) for the development of RA among healthy relatives of patients with RA. METHODS: Healthy relatives of RA patients were invited to participate in a cohort study. At baseline, information on participants' medical history was obtained, and serum levels of IgM-RF and anti-CCP antibodies were determined (by nephelometry and second-generation anti-CCP enzyme-linked immunosorbent assay, respectively). The subjects were followed up every 4 months via a structured interview (Community Oriented Program for Control of Rheumatic Diseases [COPCORD] questionnaire). When the COPCORD questionnaire indicated possible arthritis, subjects underwent an in-office rheumatology assessment including joint count. The study end point was defined as fulfillment of the American College of Rheumatology criteria for RA. RESULTS: Eight hundred nineteen initially healthy relatives of 252 patients with RA were included (69% female, 41% offspring, mean +/- SD age 35 +/- 12 years). Eleven (1.3%) were positive for both anti-CCP-2 and RF, 12 (1.5%) only for anti-CCP-2, and 16 (2%) only for RF. RA developed in 17 (2.1%) of the relatives during the 5-year followup (3,313 person-years for the seronegative group and 60.8 person-years for the anti-CCP-2-positive group). The PPV was 64% when both anti-CCP-2 and RF were positive and 58% when only anti-CCP 2 was positive. Offspring of patients with RA had an independent 3-fold increased risk of developing RA. CONCLUSION: Results of the present study indicate that the magnitude of risk for developing RA in healthy relatives of patients with RA can be estimated using simple routine laboratory tests. PMID- 26245886 TI - Painless bilateral swelling of the face: think about cherubism. PMID- 26245887 TI - Dual catalysis for the redox annulation of nitroalkynes with indoles: enantioselective construction of indolin-3-ones bearing quaternary stereocenters. AB - The enantioselective redox annulation of nitroalkynes with indoles is enabled by gold/chiral phosphoric acid dual catalysis. A range of indolin-3-one derivatives bearing quaternary stereocenters at the C2 position were afforded in good yields and excellent enantioselectivities (up to 96 % ee) from readily available starting materials. PMID- 26245888 TI - Sarcopenia prevalence and factors associated with sarcopenia in older people living in a nursing home in Ankara Turkey. AB - AIM: Sarcopenia is prevalent in older people, and is related to survival and disability. There are no data on sarcopenia evaluated according to European Working Group on Sarcopenia in Older People criteria for nursing home residents in Turkey. We aimed to evaluate the prevalence of sarcopenia according to European Working Group on Sarcopenia in Older People criteria and associated factors with sarcopenia among nursing home residents in Turkey. METHODS: The study cohort consisted of individuals aged over 65 years and living in the Seyranbaglari Nursing Home and Rehabilitation Center in Ankara, Turkey. Besides demographic and medical data, Mini-Mental State Examination, activities of daily living, Mini-Nutritional Assessment, body mass index, calf circumference, gait speed and handgrip strength were also investigated. Muscle mass was evaluated by bioelectrical impedance analysis. Sarcopenia was diagnosed according to European Working Group on Sarcopenia in Older People criteria. RESULTS: A total of 141 older individuals were evaluated. Sarcopenia was found in 29% (n = 41) of the participants. Participants with sarcopenia were older and had low scores for activities of daily living, low body mass index, greater cognitive dysfunction, high malnutrition risk and low calf circumference. Body mass index and calf circumference were found to be associated with sarcopenia in multivariate logistic regression analysis. CONCLUSIONS: Almost one-third of older nursing home residents were diagnosed with sarcopenia according to European Working Group on Sarcopenia in Older People criteria in this study in Turkey. Calf circumference and body mass index were associated with increased risk of sarcopenia among nursing home residents. This is the first study evaluating sarcopenia using European Working Group on Sarcopenia in Older People criteria in Turkey. Geriatr Gerontol Int 2016; 16: 903-910. PMID- 26245889 TI - Recommended pre-test counseling points for noninvasive prenatal testing using cell-free DNA: a 2015 perspective. AB - Noninvasive prenatal testing (NIPT) using cell-free DNA is being offered to an increasing number of women. Comprehensive pre-test counseling is complicated by emerging information about the benefits and limitations of testing, as well as the potential to detect incidental findings. Genetic counselors are trained to facilitate informed decision-making; however, not all centers have access to these professionals. To aid in the informed consent process, we have summarized key points to be included in discussions with patients who are considering NIPT. PMID- 26245890 TI - Is PEP prescribed appropriately? AB - We describe the characteristics of HIV post-exposure prophylaxis (PEP) recipients and PEP indications at 56 Dean Street, a central London sexual health clinic. PEP was prescribed on 577 occasions. Most (97%) was given for unprotected anal intercourse. Over a fifth of exposures involved recreational drug use. Of the patients prescribed PEP, 5.9% were given PEP more than once in this period. As a snapshot of HIV risk behaviour, we note the prevalence of drug use, sex without condom use and group sex among PEP recipients. PMID- 26245891 TI - Impact of Aortic Valve Stenosis on Coronary Hemodynamics and the Instantaneous Effect of Transcatheter Aortic Valve Implantation. AB - BACKGROUND: Aortic valve stenosis (AS) induces compensatory alterations in left ventricular hemodynamics, leading to physiological and pathological alterations in coronary hemodynamics. Relief of AS by transcatheter aortic valve implantation (TAVI) decreases ventricular afterload and is expected to improve microvascular function immediately. We evaluated the effect of AS on coronary hemodynamics and the immediate effect of TAVI. METHODS AND RESULTS: Intracoronary pressure and flow velocity were simultaneously assessed at rest and at maximal hyperemia in an unobstructed coronary artery in 27 patients with AS before and immediately after TAVI and in 28 patients without AS. Baseline flow velocity was higher and baseline microvascular resistance was lower in patients with AS as compared with controls, which remained unaltered post-TAVI. In patients with AS, hyperemic flow velocity was significantly lower as compared with controls (44.5+/-14.5 versus 54.3+/-18.6 cm/s; P=0.04). Hyperemic microvascular resistance (expressed in mm Hg.cm.s(-1)) was 2.10+/-0.69 in patients with AS as compared with 1.80+/-0.60 in controls (P=0.096). Coronary flow velocity reserve in patients with AS was lower, 1.9+/-0.5 versus 2.7+/-0.7 in controls (P<0.001). Improvement in coronary hemodynamics after TAVI was most pronounced in patients without post-TAVI aortic regurgitation. In these patients (n=20), hyperemic flow velocity increased significantly from 46.24+/-15.47 pre-TAVI to 56.56+/-17.44 cm/s post-TAVI (P=0.003). Hyperemic microvascular resistance decreased from 2.03+/-0.71 to 1.66+/-0.45 (P=0.050). Coronary flow velocity reserve increased significantly from 1.9+/-0.4 to 2.2+/-0.6 (P=0.009). CONCLUSIONS: The vasodilatory reserve capacity of the coronary circulation is reduced in AS. TAVI induces an immediate decrease in hyperemic microvascular resistance and a concomitant increase in hyperemic flow velocity, resulting in immediate improvement in coronary vasodilatory reserve. PMID- 26245892 TI - Demystifying Complex Coronary Hemodynamics in Patients Undergoing Transcatheter Aortic Valve Replacement: Sowing the Seeds for Coronary Physiological Assessment in the Future? PMID- 26245893 TI - Supersoft lithography: candy-based fabrication of soft silicone microstructures. AB - We designed a fabrication technique able to replicate microstructures in soft silicone materials (E < 1 kPa). Sugar-based 'hard candy' recipes from the confectionery industry were modified to be compatible with silicone processing conditions, and used as templates for replica molding. Microstructures fabricated in soft silicones can then be easily released by dissolving the template in water. We anticipate that this technique will be of particular importance in replicating physiologically soft, microstructured environments for cell culture, and demonstrate a first application in which intrinsically soft microstructures are used to measure forces generated by fibroblast-laden contractile tissues. PMID- 26245894 TI - The effect of intra-tympanic dexamethasone on the vestibular function in patients with recurrent vertigo. AB - CONCLUSION: The low clinical efficacy of the treatment for patients included in this work correlates with no noticeable effect on the vestibular function. OBJECTIVE: To assess follow-up in patients with idiopathic and secondary Meniere's disease after treatment with intra-tympanic dexamethasone and correlate clinical findings with changes in the vestibular-ocular reflex elicited after stimulation of each of the six semicircular canals. METHODS: This is a single center retrospective review of patients presenting the clinical symptomatology of Meniere's disease treated with intra-tympanic dexamethasone. An audiometric evaluation was performed in each patient before and after treatment. The study cohort was divided into two groups: those evaluated after a short period of time and after a long period of time. RESULTS: The study included 30 patients, mean age = 61 years. Differences in mean pure-tone average before and after treatment were non-significant for both treated (0.61 dB, p = 0.723) and untreated (0.59 dB, p = 0.609) ears. Vestibular-ocular reflex gain averages in the treated ear after treatment were 0.73 (superior semicircular canal), 0.86 (horizontal semicircular canal), and 0.69 (posterior semicircular canal). The gain did not vary significantly in the Superior (p = 0.194), the Horizontal (p = 0.646), or the Posterior Semicircular Canal (p = 0.820). Similar were obtained for the untreated ear. PMID- 26245896 TI - Karyopherin alpha 3 and karyopherin alpha 4 proteins mediate the nuclear import of methyl-CpG binding protein 2. AB - Methyl-CpG binding protein 2 (MeCP2) is a nuclear protein with important roles in regulating chromatin structure and gene expression, and mutations in MECP2 cause Rett syndrome (RTT). Within the MeCP2 protein sequence, the nuclear localization signal (NLS) is reported to reside between amino acids 255-271, and certain RTT causing mutations overlap with the MeCP2 NLS, suggesting that they may alter nuclear localization. One such mutation, R270X, is predicted to interfere with the localization of MeCP2, but recent in vivo studies have demonstrated that this mutant remains entirely nuclear. To clarify the mechanism of MeCP2 nuclear import, we isolated proteins that interact with the NLS and identified karyopherin alpha 3 (KPNA3 or Kap-alpha3) and karyopherin alpha 4 (KPNA4 or Kap alpha4) as key binding partners of MeCP2. MeCP2-R270X did not interact with KPNA4, consistent with a requirement for an intact NLS in this interaction. However, this mutant retains binding to KPNA3, accounting for the normal localization of MeCP2-R270X to the nucleus. These data provide a mechanism for MeCP2 nuclear import and have implications for the design of therapeutics aimed at modulating the function of MeCP2 in RTT patients. PMID- 26245897 TI - Glioblastoma-derived Macrophage Colony-stimulating Factor (MCSF) Induces Microglial Release of Insulin-like Growth Factor-binding Protein 1 (IGFBP1) to Promote Angiogenesis. AB - Glioblastoma (grade IV glioma/GBM) is the most common primary adult malignant brain tumor with poor prognosis. To characterize molecular determinants of tumor stroma interaction in GBM, we profiled 48 serum cytokines and identified macrophage colony-stimulating factor (MCSF) as one of the elevated cytokines in sera from GBM patients. Both MCSF transcript and protein were up-regulated in GBM tissue samples through a spleen tyrosine kinase (SYK)-dependent activation of the PI3K-NFkappaB pathway. Ectopic overexpression and silencing experiments revealed that glioma-secreted MCSF has no role in autocrine functions and M2 polarization of macrophages. In contrast, silencing expression of MCSF in glioma cells prevented tube formation of human umbilical vein endothelial cells elicited by the supernatant from monocytes/microglial cells treated with conditioned medium from glioma cells. Quantitative proteomics based on stable isotope labeling by amino acids in cell culture showed that glioma-derived MCSF induces changes in microglial secretome and identified insulin-like growth factor-binding protein 1 (IGFBP1) as one of the MCSF-regulated proteins secreted by microglia. Silencing IGFBP1 expression in microglial cells or its neutralization by an antibody reduced the ability of supernatants derived from microglial cells treated with glioma cell-conditioned medium to induce angiogenesis. In conclusion, this study shows up-regulation of MCSF in GBM via a SYK-PI3K-NFkappaB-dependent mechanism and identifies IGFBP1 released by microglial cells as a novel mediator of MCSF induced angiogenesis, of potential interest for developing targeted therapy to prevent GBM progression. PMID- 26245898 TI - Hierarchal Autophagic Divergence of Hematopoietic System. AB - Autophagy is integral to hematopoiesis and protects against leukemogenesis. However, the fundamentals of the required molecular machinery have yet to be fully explored. Using conditional mouse models to create strategic defects in the hematopoietic hierarchy, we have shown that recovery capacities in stem cells and somatic cells differ if autophagy is impaired or flawed. An in vivo Atg7 deletion in hematopoietic stem cells completely ablates the autophagic response, leading to irreversible and ultimately lethal hematopoiesis. However, while no adverse phenotype is manifested in vivo by Atg7-deficient myeloid cells, they maintain active autophagy that is sensitive to brefeldin A, an inhibitor targeting Golgi derived membranes destined for autophagosome formation in alternative autophagy. Removing Rab9, a key regulatory protein, in alternative autophagy, disables autophagy altogether in Atg7-deficient macrophages. Functional analysis indicates that ATG7-dependent canonical autophagy is physiologically active in both hematopoietic stem cells and in terminally differentiated hematopoietic cells; however, only terminally differentiated cells such as macrophages are rescued by alternative autophagy if canonical autophagy is ineffective. Thus, it appears that hematopoietic stem cells rely solely on ATG7-dependent canonical autophagy, whereas terminally differentiated or somatic cells are capable of alternative autophagy in the event that ATG7-mediated autophagy is dysfunctional. These findings offer new insight into the transformational trajectory of hematopoietic stem cells, which in our view renders the autophagic machinery in stem cells more vulnerable to disruption. PMID- 26245899 TI - Ca2+ Binding/Permeation via Calcium Channel, CaV1.1, Regulates the Intracellular Distribution of the Fatty Acid Transport Protein, CD36, and Fatty Acid Metabolism. AB - Ca(2+) permeation and/or binding to the skeletal muscle L-type Ca(2+) channel (CaV1.1) facilitates activation of Ca(2+)/calmodulin kinase type II (CaMKII) and Ca(2+) store refilling to reduce muscle fatigue and atrophy (Lee, C. S., Dagnino Acosta, A., Yarotskyy, V., Hanna, A., Lyfenko, A., Knoblauch, M., Georgiou, D. K., Poche, R. A., Swank, M. W., Long, C., Ismailov, I. I., Lanner, J., Tran, T., Dong, K., Rodney, G. G., Dickinson, M. E., Beeton, C., Zhang, P., Dirksen, R. T., and Hamilton, S. L. (2015) Skelet. Muscle 5, 4). Mice with a mutation (E1014K) in the Cacna1s (alpha1 subunit of CaV1.1) gene that abolishes Ca(2+) binding within the CaV1.1 pore gain more body weight and fat on a chow diet than control mice, without changes in food intake or activity, suggesting that CaV1.1-mediated CaMKII activation impacts muscle energy expenditure. We delineate a pathway (Cav1.1-> CaMKII-> NOS) in normal skeletal muscle that regulates the intracellular distribution of the fatty acid transport protein, CD36, altering fatty acid metabolism. The consequences of blocking this pathway are decreased mitochondrial beta-oxidation and decreased energy expenditure. This study delineates a previously uncharacterized CaV1.1-mediated pathway that regulates energy utilization in skeletal muscle. PMID- 26245900 TI - The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism. AB - In colorectal cancers with oncogenic GTPase Kras (KRAS) mutations, inhibition of downstream MEK/ERK signaling has shown limited efficacy, in part because of failure to induce a robust apoptotic response. We studied the mechanism of apoptosis resistance in mutant KRAS cells and sought to enhance the efficacy of a KRAS-specific MEK/ERK inhibitor, GDC-0623. GDC-0623 was shown to potently up regulate BIM expression to a greater extent versus other MEK inhibitors in isogenic KRAS HCT116 and mutant KRAS SW620 colon cancer cells. ERK silencing enhanced BIM up-regulation by GDC-0623 that was due to its loss of phosphorylation at Ser(69), confirmed by a BIM-EL phosphorylation-defective mutant (S69G) that increased protein stability and blocked BIM induction. Despite BIM and BIK induction, the isogenic KRAS mutant versus wild-type cells remained resistant to GDC-0623-induced apoptosis, in part because of up-regulation of BCL XL. KRAS knockdown by a doxycycline-inducible shRNA attenuated BCL-XL expression. BCL-XL knockdown sensitized KRAS mutant cells to GDC-0623-mediated apoptosis, as did the BH3 mimetic ABT-263. GDC-0623 plus ABT-263 induced a synergistic apoptosis by a mechanism that includes release of BIM from its sequestration by BCL-XL. Furthermore, mutant KRAS activated p-STAT3 (Tyr(705)) in the absence of IL-6 secretion, and STAT3 knockdown reduced BCL-XL mRNA and protein expression. These data suggest that BCL-XL up-regulation by STAT3 contributes to mutant KRAS mediated apoptosis resistance. Such resistance can be overcome by potent BIM induction and concurrent BCL-XL antagonism to enable a synergistic apoptotic response. PMID- 26245901 TI - Itch WW Domains Inhibit Its E3 Ubiquitin Ligase Activity by Blocking E2-E3 Ligase Trans-thiolation. AB - Nedd4-family E3 ubiquitin ligases regulate an array of biologic processes. Autoinhibition maintains these catalytic ligases in an inactive state through several mechanisms. However, although some Nedd4 family members are activated by binding to Nedd4 family-interacting proteins (Ndfips), how binding activates E3 function remains unclear. Our data reveal how these two regulatory processes are linked functionally. In the absence of Ndfip1, the Nedd4 family member Itch can bind an E2 but cannot accept ubiquitin onto its catalytic cysteine. This is because Itch is autoinhibited by an intramolecular interaction between its HECT (homologous to the E6-AP carboxy terminus domain) and two central WW domains. Ndfip1 binds these WW domains to release the HECT, allowing trans-thiolation and Itch catalytic activity. This molecular switch also regulates the closely related family member WWP2. Importantly, multiple PY motifs are required for Ndfip1 to activate Itch, functionally distinguishing Ndfips from single PY-containing substrates. These data establish a novel mechanism for control of the function of a subfamily of Nedd4 E3 ligases at the level of E2-E3 trans-thiolation. PMID- 26245902 TI - Mitochondrial Disease-related Mutation G167P in Cytochrome b of Rhodobacter capsulatus Cytochrome bc1 (S151P in Human) Affects the Equilibrium Distribution of [2Fe-2S] Cluster and Generation of Superoxide. AB - Cytochrome bc1 is one of the key enzymes of many bioenergetic systems. Its operation involves a large scale movement of a head domain of iron-sulfur protein (ISP-HD), which functionally connects the catalytic quinol oxidation Qo site in cytochrome b with cytochrome c1. The Qo site under certain conditions can generate reactive oxygen species in the reaction scheme depending on the actual position of ISP-HD in respect to the Qo site. Here, using a bacterial system, we show that mutation G167P in cytochrome b shifts the equilibrium distribution of ISP-HD toward positions remote from the Qo site. This renders cytochrome bc1 non functional in vivo. This effect is remediated by addition of alanine insertions (1Ala and 2Ala) in the neck region of the ISP subunit. These insertions, which on their own shift the equilibrium distribution of ISP-HD in the opposite direction (i.e. toward the Qo site), also act in this manner in the presence of G167P. Changes in the equilibrium distribution of ISP-HD in G167P lead to an increased propensity of cytochrome bc1 to generate superoxide, which becomes evident when the concentration of quinone increases. This result corroborates the recently proposed model in which "semireverse" electron transfer back to the Qo site, occurring when ISP-HD is remote from the site, favors reactive oxygen species production. G167P suggests possible molecular effects of S151P (corresponding in sequence to G167P) identified as a mitochondrial disease-related mutation in human cytochrome b. These effects may be valid for other human mutations that change the equilibrium distribution of ISP-HD in a manner similar to G167P. PMID- 26245903 TI - Functional Characterization of Autoantibodies against Complement Component C3 in Patients with Lupus Nephritis. AB - Lupus nephritis (LN) is a complication of the autoimmune disease systemic lupus erythematosus. Because the complement system plays a critical role in orchestrating inflammatory and immune responses as well as in the clearance of immune complexes, autoreactivity to complement components may have considerable pathological consequences. Autoantibodies against the central complement component C3 have been reported in systemic lupus erythematosus, but their molecular mechanism and functional relevance are not well understood. The objective of this study was to evaluate the frequency and the functional properties of the anti-C3 autoantibodies. Anti-C3 autoantibodies were measured in plasma of 39 LN patients, and identification of their epitopes on the C3 molecule was performed. By using surface plasmon resonance, we analyzed the influence of patient-derived IgG antibodies on the interaction of C3b with Factor B, Factor H, and complement receptor 1. The capacity of these antibodies to dysregulate the C3 convertase on the surface of endothelial cell was measured by flow cytometry. Here we report that the frequency of anti-C3 autoantibodies in LN is ~30%. They inhibited interactions of the negative complement regulators Factor H and complement receptor 1 with C3b. An enhanced C3 deposition was also observed on human endothelial cells in the presence of C3 autoantibodies. In addition, anti C3 autoantibody levels correlated with disease activity. In conclusion, the anti C3 autoantibodies in LN may contribute to the autoimmune pathology by their capacity to overactivate the complement system. PMID- 26245904 TI - Neil2-null Mice Accumulate Oxidized DNA Bases in the Transcriptionally Active Sequences of the Genome and Are Susceptible to Innate Inflammation. AB - Why mammalian cells possess multiple DNA glycosylases (DGs) with overlapping substrate ranges for repairing oxidatively damaged bases via the base excision repair (BER) pathway is a long-standing question. To determine the biological role of these DGs, null animal models have been generated. Here, we report the generation and characterization of mice lacking Neil2 (Nei-like 2). As in mice deficient in each of the other four oxidized base-specific DGs (OGG1, NTH1, NEIL1, and NEIL3), Neil2-null mice show no overt phenotype. However, middle-aged to old Neil2-null mice show the accumulation of oxidative genomic damage, mostly in the transcribed regions. Immuno-pulldown analysis from wild-type (WT) mouse tissue showed the association of NEIL2 with RNA polymerase II, along with Cockayne syndrome group B protein, TFIIH, and other BER proteins. Chromatin immunoprecipitation analysis from mouse tissue showed co-occupancy of NEIL2 and RNA polymerase II only on the transcribed genes, consistent with our earlier in vitro findings on NEIL2's role in transcription-coupled BER. This study provides the first in vivo evidence of genomic region-specific repair in mammals. Furthermore, telomere loss and genomic instability were observed at a higher frequency in embryonic fibroblasts from Neil2-null mice than from the WT. Moreover, Neil2-null mice are much more responsive to inflammatory agents than WT mice. Taken together, our results underscore the importance of NEIL2 in protecting mammals from the development of various pathologies that are linked to genomic instability and/or inflammation. NEIL2 is thus likely to play an important role in long term genomic maintenance, particularly in long-lived mammals such as humans. PMID- 26245905 TI - The Role of the Phylogenetically Conserved Cochaperone Protein Droj2/DNAJA3 in NF kappaB Signaling. AB - The NF-kappaB pathway is a phylogenetically conserved signaling pathway with a central role in inflammatory and immune responses. Here we demonstrate that a cochaperone protein, Droj2/DNAJA3, is involved in the activation of canonical NF kappaB signaling in flies and in human cultured cells. Overexpression of Droj2 induced the expression of an antimicrobial peptide in Drosophila. Conversely, Droj2 knockdown resulted in reduced expression of antimicrobial peptides and higher susceptibility to Gram-negative bacterial infection in flies. Similarly, Toll-like receptor-stimulated IkappaB phosphorylation and NF-kappaB activation were suppressed by DNAJA3 knockdown in HEK293 cells. IkappaB kinase overexpression-induced NF-kappaB phosphorylation was also compromised in DNAJA3 knockdown cells. Our study reveals a novel conserved regulator of the NF-kappaB pathway acting at the level of IkappaB phosphorylation. PMID- 26245906 TI - Radiographic evaluation of indirect decompression of mini-open anterior retroperitoneal lumbar interbody fusion: oblique lateral interbody fusion for degenerated lumbar spondylolisthesis. AB - PURPOSE: Extreme lateral interbody fusion provides minimally invasive treatment of spinal deformity, but complications including nerve and psoas muscle injury have been noted. To avoid nerve injury, mini-open anterior retroperitoneal lumbar interbody fusion methods using an approach between the aorta and psoas, such as oblique lumbar interbody fusion (OLIF) have been applied. OLIF with percutaneous pedicle screws without posterior decompression can indirectly decompress the spinal canal in lumbar degenerated spondylolisthesis. In the current study, we examined the radiographic and clinical efficacy of OLIF for lumbar degenerated spondylolisthesis. METHODS: We assessed 20 patients with lumbar degenerated spondylolisthesis who underwent OLIF and percutaneous pedicle screw fixation without posterior laminectomy. MR and CT images and clinical symptoms were evaluated before and 6 months after surgery. Cross sections of the spinal canal were evaluated with MRI, and disk height, cross-sectional areas of intervertebral foramina, and degree of upper vertebral slip were evaluated with CT. Clinical symptoms including low back pain, leg pain, and lower extremity numbness were evaluated using a visual analog scale and the Oswestry Disability Index before and 6 months after surgery. RESULTS: After surgery, significant increases in axial and sagittal spinal canal diameter (12 and 32 %), spinal canal area (19 %), disk height (61 %), and intervertebral foramen areas (21 % on the right side, 39 % on the left), and significant decrease of upper vertebral slip (-9 %) were found (P < 0.05). Low back pain, leg pain, and lower extremity numbness were significantly reduced compared with before surgery (P < 0.05). CONCLUSIONS: Significant improvements in disk height and spinal canal area were found after surgery. Bulging of disks was reduced through correction, and stretching the yellow ligament may have decompressed the spinal canal. Lumbar anterolateral fusion without laminectomy may be useful for lumbar spondylolisthesis with back and leg symptoms. PMID- 26245907 TI - Hyperexcitability and sensitization of sodium channels of dorsal root ganglion neurons in a rat model of lumber disc herniation. AB - PURPOSE: Low back pain and sciatica are the most common symptoms of patients with lumbar disc herniation (LDH). The pathophysiology of lumbocrural pain and sciatica is not fully understood. The aim of the present study was to define the membrane properties and activities of voltage-gated sodium channels of dorsal root ganglion (DRG) neurons in a rat model of LDH. METHODS: LDH was established by transplantation of autologous nucleus pulposus (NP) to lumbar 5 and 6 spinal nerves (L5-L6 DRG) of adult male rats. Mechanical paw withdrawal threshold (PWT) and thermal paw withdrawal latency (PWL) were measured 1 day before and through 35 days after transplantation of NP. Changes in expression of VGSCs were determined by western blotting. L5-L6 DRGs neurons innervating the hindpaw were labeled with DiI and acutely dissociated for measuring excitability and sodium channel currents under whole-cell patch clamp configurations. RESULTS: NP transplantation significantly reduced the PWT and PWL in association with a significant reduction in rheobase and an increase in numbers of action potentials evoked by 2X and 3X rheobase current stimulation. Voltage-gated sodium current density was significantly enhanced in L5-L6 DRG neurons from LDH rats. The inactivation curve showed a leftward shift in LDH rats while activation curve did not significantly alter. However, NP transplantation remarkably enhanced expression of NaV1.7 and NaV1.8 in L5-L6 DRGs but not in T10-12 DRGs. CONCLUSION: These data suggest that NP application produces pain-related behavior and potentiates sodium current density of DRG neurons, which is most likely mediated by enhanced expression of NaV1.7 and NaV1.8. PMID- 26245909 TI - Antitumour effects of tetrazanbigen against human hepatocellular carcinoma QGY 7701 through inducing lipid accumulation in vitro and in vivo. AB - OBJECTIVES: Tetrazanbigen (TNBG) is a newly synthesized compound with an isoquinoline moiety, and its antitumour effects were evaluated in in-vitro and in vivo models. METHODS: 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay was used to measure the antiproliferative activity of TNBG on cancer cell lines. Antitumour activity of TNGB in vivo was also assessed in a xenograft model of human hepatocellular carcinoma QGY-7701 cell line. Cell cycle and cell apoptosis analysis was performed. KEY FINDINGS: TNBG exhibited strong antitumour efficacy against six human cancer cell lines with IC50 range of 2.13 8.01 MUg/ml. The IC50 of TNBG on normal hepatic cells was 11.25 MUg/ml. Lots of lipid droplets were observed in cytoplasm of human hepatocellular carcinoma QGY 7701 cells after treatment of TNBG. S phase arrest and apoptosis induction by TNBG were also found on QGY-7701 cells. Intraperitoneal injection of TNBG (1.5 mg/kg/day) resulted in significant decreases in tumour volume and tumour weight on nude mice bearing QGY-7701 cells xenografts. Results from pathological analysis in nude mice demonstrated that TNBG could induce lipid accumulation specifically in cancer tissue rather than in other normal organs, tissues and blood. CONCLUSIONS: These results suggested that TNBG might exert potent antitumour activity through inducing lipid accumulation in cancer cell. PMID- 26245911 TI - Expression of engrailed-family genes in the jumping bristletail and discussion on the primitive pattern of insect segmentation. AB - It has been shown that segmentation in the short-germ insects proceeds by a two step mechanism. The anterior region is simultaneously segmented in a manner similar to that in Drosophila, which is apparently unique to insects, and the rest of the posterior region is segmented sequentially by a mechanism involving a segmentation clock, which is derived from the common ancestor of arthropods. In order to propose the evolutionary scenario of insect segmentation, we examined segmentation in the jumping bristletail, the basalmost extant insect. Using probes for engrailed-family genes for in situ hybridization, we found no sign of simultaneous segmentation in the anterior region of the jumping bristletail embryos. All segments except the anteriormost segment are formed sequentially. This condition shown in the jumping bristletail embryos may represent the primitive pattern of insect segmentation. The intercalating formation of the intercalary segment is assumed to be a synapomorphic trait shared among all insects after the branching of the jumping bristletail. PMID- 26245910 TI - A cluster randomized-controlled trial of a community mobilization intervention to change gender norms and reduce HIV risk in rural South Africa: study design and intervention. AB - BACKGROUND: Community mobilization (CM) interventions show promise in changing gender norms and preventing HIV, but few have been based on a defined mobilization model or rigorously evaluated. The purpose of this paper is to describe the intervention design and implementation and present baseline findings of a Cluster Randomized Controlled Trial (RCT) of a two-year, theory-based CM intervention that aimed to change gender norms and reduce HIV risk in rural Mpumalanga province, South Africa. METHODS: Community Mobilizers and volunteer Community Action Teams (CATs) implemented two-day workshops, a range of outreach activities, and leadership engagement meetings. All activities were mapped onto six theorized mobilization domains. The intervention is being evaluated by a randomized design in 22 communities (11 receive intervention). Cross-sectional, population-based surveys were conducted with approximately 1,200 adults ages 18 35 years at baseline and endline about two years later. CONCLUSIONS: This is among the first community RCTs to evaluate a gender transformative intervention to change norms and HIV risk using a theory-based, defined mobilization model, which should increase the potential for impact on desired outcomes and be useful for future scale-up if proven effective. TRIAL REGISTRATION: ClinicalTrials.gov NCT02129530. PMID- 26245912 TI - Differences in apical and non-apical types of hypertrophic cardiomyopathy: a prospective analysis of clinical, echocardiographic, and cardiac magnetic resonance findings and outcome from 350 patients. AB - AIMS: Apical hypertrophic cardiomyopathy (ApHCM) is thought to have a favourable clinical outcome, compared with other types of HCM. We sought to investigate the clinical and anatomical differences in cardiovascular imaging between ApHCM and non-ApHCM. METHODS AND RESULTS: A total of 350 patients diagnosed with HCM underwent cardiovascular magnetic resonance (CMR) and echocardiography. All enrolled subjects were prospectively followed up for adverse clinical outcomes. Eighty-five patients were classified as ApHCM. On CMR, the amount and proportion of late gadolinium enhancement (LGE) as well as left ventricular volumetric parameters were evaluated. Echocardiographic evaluations included diastolic function and global strain. Patients with ApHCM were less likely to present with history of syncope and have less frequency of family history of sudden cardiac death than those with non-ApHCM. Functional class was also more favourable in ApHCM [frequency of New York Heart Association (NYHA) class I; 89.4 vs. 66.8%, P < 0.001]. LGE was less frequently detected (87.1 vs. 93.9%, P = 0.04), and the amount of LGE was significantly smaller in ApHCM (7.0 +/- 6.0 vs. 14.6 +/- 10.5%, P < 0.001). The E/e' level and left atrial volume index were also lower in ApHCM patients (all P < 0.001). During follow-up, a composite of adverse clinical events including cardiac death, admission for heart failure, and cerebrovascular accident was higher in patients with ApHCM than those with non-ApHCM (P = 0.01). CONCLUSION: ApHCM showed a relatively small burden of myocardial fibrosis and less severe diastolic dysfunction and subsequently more favourable clinical manifestations in comparison with other HCMs. This may be one explanation of why most patients with ApHCM show a benign course of disease compared with non-ApHCM. PMID- 26245913 TI - Polar plot maps by parametric strain echocardiography allow accurate evaluation of non-viable transmural scar tissue in ischaemic heart disease. AB - AIMS: Assessment of left ventricular (LV) transmural scar tissue in clinical practice is still challenging because magnetic resonance imaging (MRI) and nuclear techniques have limited access and cannot be performed extensively. The aim of this study was to verify whether parametric two-dimensional speckle tracking echocardiography (2D-STE) can more accurately localize and quantify LV transmural scar tissue in patients with healed myocardial infarct (MI) in comparison with MRI. METHODS AND RESULTS: Thirty-one consecutive patients (age 56 +/- 32 years, 29 males) with MRI and echocardiography performed after at least 6 months from an acute MI were studied. Apical LV longitudinal strain images by 2D STE and short-axis contrast images by MRI were analysed to generate parametric bull's eye maps showing the distribution of the LV transmural scar tissue, whose extension was measured by planimetry and expressed as a percentage of the total myocardial area. Twelve patients also had early 2D-STE and MRI examinations after the acute MI. 2D-STE accurately quantified the extent of transmural scar tissue vs. MRI (r = 0.86; limits of agreement 10.0 and -9.5%). Concordance between 2D STE and MRI for transmural scar tissue localization was high, with only 3.6% of discordant segments using an LV 16-segment model. Lin coefficients, intra-class correlation coefficients, and Bland-Altman analysis showed very good intra- and inter-observer reproducibility for 2D-STE evaluations. The transmural scar tissue area at 6 months could be predicted by early 2D-STE evaluation. CONCLUSION: 2D STE polar plots of LV longitudinal strain characterize transmural scar tissue accurately compared with MRI and may facilitate its assessment in clinical practice. PMID- 26245914 TI - Traumatic pulmonary valve injury following blunt chest trauma. PMID- 26245915 TI - Eyes only? Perceiving eye contact is neither sufficient nor necessary for attentional capture by face direction. AB - Direct eye contact and motion onset both constitute powerful cues that capture attention. Recent research suggests that (social) gaze and (non-social) motion onset influence information processing in parallel, even when combined as sudden onset direct gaze cues (i.e., faces suddenly establishing eye contact). The present study investigated the role of eye visibility for attention capture by these sudden onset face cues. To this end, face direction was manipulated (away or towards onlooker) while faces had closed eyes (eliminating visibility of eyes, Experiment 1), wore sunglasses (eliminating visible eyes, but allowing for the expectation of eyes to be open, Experiment 2), and were inverted with visible eyes (disrupting the integration of eyes and faces, Experiment 3). Participants classified targets appearing on one of four faces. Initially, two faces were oriented towards participants and two faces were oriented away from participants. Simultaneous to target presentation, one averted face became directed and one directed face became averted. Attention capture by face direction (i.e., facilitation for faces directed towards participants) was absent when eyes were closed, but present when faces wore sunglasses. Sudden onset direct faces can, hence, induce attentional capture, even when lacking eye cues. Inverted faces, by contrast, did not elicit attentional capture. Thus, when eyes cannot be integrated into a holistic face representation they are not sufficient to capture attention. Overall, the results suggest that visibility of eyes is neither necessary nor sufficient for the sudden direct face effect. PMID- 26245916 TI - Lysine requirement for growing-finishing immunocastrated male pigs. AB - Eighty boars (19.3 +/- 2.49 kg) were vaccinated twice (100 and 128 days of age) against gonadotropin releasing hormone (VivaxTM vaccine), for a randomised block design study aiming to evaluate five digestible lysine (DLys) level treatments, with three phase-feeding per treatments (9-8-7; 10-9-8; 11-10-9; 12-11-10 and 13 12-11 g/kg) during the growing-finishing phases (54-100, 100-128 and 128-155 days of age, respectively). Pigs were fed their respective diets ad libitum from 54 to 155 days and weighed at 100, 128 and 155 days. Pig loin (Longissimus dorsi) area, loin depth and backfat thickness were measured by ultrasound at 100 and 155 days. Hot carcass weight, meat quantity and meat yield were measured at slaughter. From 54 to 100 days (pre-immunocastration), DLys levels linearly improved pig feed conversion and loin area, the level of DLys for minimum feed conversion and maximum loin area was 13 g/kg. However, DLys levels had no effect on the performance of boars from 54 to 128 days (pre-immunocastration), nor on the performance and carcass parameters of immunocastrated male pigs between 54 and 155 days. A sequence of diets containing 9, 8 and 7 g/kg of DLys fed from 54 to 100, 100 to 128 and 128 to 155 days, respectively, meet the requirement of growing-finishing immunocastrated male pigs. PMID- 26245917 TI - Detection of Mycobacterium avium subsp. paratuberculosis in a sheep flock in Tuscany. AB - Paratuberculosis is an infectious disease which affects ruminants. In this work, a sheep flock in Garfagnana district (Tuscany, Italy) was examined by agar gel immune-diffusion (AGID) tests, culture, and PCR from feces, milk, tissue samples, and cheeses. At the first AGID test, 7/280 (2.5 %) animals were positive. From these animals, feces and milk samples were collected: 4/7 feces (57.14 %) and 2/7 milk samples (28.57 %) were positive to culture and 7/7 (100 %) feces samples and 1/7 milk samples (14.28 %) were positive to PCR; 2/4 (50 %) cheeses ripened for 14 days and 1/3 (33.33 %) cheese ripened for 20 days were positive to PCR, from which no viable microorganisms were isolated. Then, the AGID-positive animals were slaughtered and tissue samples were taken from one sheep with PCR-positive feces and milk: the liver, intestine, mesenteric lymph nodes, but not the spleen and mammary lymph nodes were positive to culture; all these samples were instead PCR-positive. After 1 year, a second AGID survey was performed on the remaining animals: 6/244 (2.45 %) subjects were positive to this test. Data obtained revealed the presence of paratuberculosis in a sheep population in Garfagnana. PMID- 26245918 TI - TEVAR Rescue of an Embolized Edwards SAPIEN XT Valve Following TAVR. AB - PURPOSE: To report a successful method of managing an embolized Edwards SAPIEN XT aortic valve prosthesis using a thoracic endovascular aortic repair rescue. CASE REPORT: An 84-year-old man underwent transcatheter aortic valve replacement using a 26-mm Edwards SAPIEN XT valve, which immediately embolized into the ascending aorta. Because of the severe tapering of the patient's transverse aortic arch, the embolized valve was unable to be maneuvered further down the aorta. Therefore, a Cook 36*80-mm Zenith Dissection Endovascular System (ZDES) bare metal stent was used on a compassionate basis to append the embolized valve between the patient's coronary artery ostia and the innominate artery takeoff within the ascending aorta, with no neurological or cardiovascular complications at 12-month follow-up. CONCLUSION: A Cook ZDES bare metal stent may be successfully used to append an embolized Edwards SAPIEN XT valve within the ascending aorta. PMID- 26245920 TI - Temperature-Dependent Sex Determination under Rapid Anthropogenic Environmental Change: Evolution at a Turtle's Pace? AB - Organisms become adapted to their environment by evolving through natural selection, a process that generally transpires over many generations. Currently, anthropogenically driven environmental changes are occurring orders of magnitude faster than they did prior to human influence, which could potentially outpace the ability of some organisms to adapt. Here, we focus on traits associated with temperature-dependent sex determination (TSD), a classic polyphenism, in a model turtle species to address the evolutionary potential of species with TSD to respond to rapid climate change. We show, first, that sex-ratio outcomes in species with TSD are sensitive to climatic variation. We then identify the evolutionary potential, in terms of heritability, of TSD and quantify the evolutionary potential of 3 key traits involved in TSD: pivotal temperature, maternal nest-site choice, and nesting phenology. We find that these traits display different patterns of adaptive potential: pivotal temperature exhibits moderate heritable variation, whereas nest-site choice and nesting phenology, with considerable phenotypic plasticity, have only modest evolutionary potential to alter sex ratios. Therefore, the most likely response of species with TSD to anthropogenically induced climate change may be a combination of microevolution in thermal sensitivity of the sex-determining pathway and of plasticity in maternal nesting behavior. PMID- 26245919 TI - Primary Self-EXPANDing Nitinol Stenting vs Balloon Angioplasty With Optional Bailout Stenting for the Treatment of Infrapopliteal Artery Disease in Patients With Severe Intermittent Claudication or Critical Limb Ischemia (EXPAND Study). AB - PURPOSE: To compare primary placement of a self-expanding nitinol stent to percutaneous transluminal angioplasty (PTA) with bailout stenting in infrapopliteal arteries of patients with severe intermittent claudication or critical limb ischemia (CLI). METHODS: In the EXPAND trial (ClinicalTrials.gov; identifier NCT00906022), 92 patients (mean age 72.9+/-9.5 years; 62 men) undergoing treatment for infrapopliteal stenosis in 11 European centers were randomized 1:1 to either self-expanding nitinol stenting with the Astron Pulsar/Pulsar-18 nitinol stent or PTA with bailout stenting. The primary endpoint was sustainable clinical improvement after 12 months, defined as a >=1-category increase for Rutherford category 3 patients or a >=2-category increase for CLI patients (Rutherford categories 4/5) compared with baseline. Furthermore, target lesion revascularization (TLR), mortality, and amputation were assessed after 12 months. RESULTS: Sustained clinical improvement at 1 year was observed in 74.3% of the patients treated with primary stenting and in 68.6% of the patients treated with PTA and bailout stenting (p>0.05). Kaplan-Meier estimates of freedom from TLR (76.6% and 77.6%), mortality (7.4% vs 2.1%), and amputation [8.9% (major 6.7%) vs 13.2% (major 8.7%)] at 1 year were not significantly different. CONCLUSION: Primary self-expanding nitinol stenting did not show statistically different clinical outcomes compared to angioplasty with bailout stenting for infrapopliteal lesions. PMID- 26245921 TI - Reef-Specific Patterns of Gene Expression Plasticity in Eastern Oysters (Crassostrea virginica). AB - Understanding the interaction between phenotypic plasticity and evolutionary processes is important for predicting a species' response to changing environment. Strong recurrent selection each generation may be an important process in highly fecund species with broad dispersal and extensive early mortality. We tested whether selection was associated with spatial divergence in gene expression plasticity for osmoregulation in the eastern oyster (Crassostrea virginica). We collected adult oysters from high and low salinity reefs within a single estuary and after 9 weeks of acclimation at 10 and 30 salinity, measured gene expression in 24 oysters using next-generation RNA sequencing technology. The oysters had significantly different expression (DE) in response to salinity treatments for 7936 (18.9%) transcripts overall, with planned contrasts showing 8* more DE in oysters from the high-salinity reef and 15* more DE between reefs when tested at 10 salinity. The reef-by-treatment interaction was also genomically pervasive (5858 DE transcripts, 13.9%). Inter-reef F ST for transcript SNPs averaged 0.0025 with the top 1% between 0.29 and 0.73. Transcripts containing "outlier" SNPs were significantly enriched for osmoregulatory genes and showed patterns of variation consistent with selection on the low-salinity reef. Both phenotypic plasticity and recurrent selection seem to be important factors determining the realized niche of oysters within estuaries. PMID- 26245922 TI - Effect of Temperature on the Aging rate of Li Ion Battery Operating above Room Temperature. AB - Temperature is known to have a significant impact on the performance, safety, and cycle lifetime of lithium-ion batteries (LiB). However, the comprehensive effects of temperature on the cyclic aging rate of LiB have yet to be found. We use an electrochemistry-based model (ECBE) here to measure the effects on the aging behavior of cycled LiB operating within the temperature range of 25 degrees C to 55 degrees C. The increasing degradation rate of the maximum charge storage of LiB during cycling at elevated temperature is found to relate mainly to the degradations at the electrodes, and that the degradation of LCO cathode is larger than graphite anode at elevated temperature. In particular, the formation and modification of the surface films on the electrodes as well as structural/phase changes of the LCO electrode, as reported in the literatures, are found to be the main contributors to the increasing degradation rate of the maximum charge storage of LiB with temperature for the specific operating temperature range. Larger increases in the Warburg elements and cell impedance are also found with cycling at higher temperature, but they do not seriously affect the state of health (SoH) of LiB as shown in this work. PMID- 26245923 TI - Surface Structure and Hydration of Sequence-Specific Amphiphilic Polypeptoids for Antifouling/Fouling Release Applications. AB - Amphiphilic polypeptoids can be designed with specific sequences of hydrophilic and hydrophobic units, which determine their surface properties for antifouling/fouling release purposes. Although the sequence-dependent surface structures of polypeptoids have been extensively investigated, e.g., with X-ray spectroscopy, their molecular structures under the aqueous conditions relevant to marine fouling have not been studied. In this work, we applied sum frequency generation (SFG) vibrational spectroscopy to study the surface structures and hydration of a series of amphiphilic polypeptoid coatings with different sequences in air and water. SFG spectra, in agreement with X-ray spectroscopy studies, revealed that the surface coverage of the hydrophilic N-(2 methoxyethyl)glycine (Nme) units in air is affected by both the number and position of the hydrophobic N-(heptafluorobutyl)glycine (NF) units in the peptoid chain and is negatively correlated with the surface concentration of the fluorine element. Our ability to probe the SFG signals of water molecules at the peptoid surface provides new information on the hydrated film properties. From these SFG signals and the time evolution of water contact angles on the polymers, we see that the hydrated film properties are also dependent upon the peptoid sequence. This work indicates that the surface presence of the Nme groups and the ability of the polymers to order and strongly hydrogen bond with interfacial water molecules determine their antifouling properties, whereas the surface restructuring rate upon contact with water affects their fouling release behaviors. PMID- 26245924 TI - Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice. AB - BACKGROUND: Recent evidence indicates that inhibition of histone deacetylase (HDAC) protects the heart against myocardial injury and stimulates endogenous angiomyogenesis. However, it remains unknown whether HDAC inhibition produces the protective effect in the diabetic heart. We sought to determine whether HDAC inhibition preserves cardiac performance and suppresses cardiac remodeling in diabetic cardiomyopathy. METHODS: Adult ICR mice received an intraperitoneal injection of either streptozotocin (STZ, 200 mg/kg) to establish the diabetic model or vehicle to serve as control. Once hyperglycemia was confirmed, diabetic mice received sodium butyrate (1%), a specific HDAC inhibitor, in drinking water on a daily basis to inhibit HDAC activity. Mice were randomly divided into following groups, which includes Control, Control + Sodium butyrate (NaBu), STZ and STZ + Sodium butyrate (NaBu), respectively. Myocardial function was serially assessed at 7, 14, 21 weeks following treatments. RESULTS: Echocardiography demonstrated that cardiac function was depressed in diabetic mice, but HDAC inhibition resulted in a significant functional improvement in STZ-injected mice. Likewise, HDAC inhibition attenuates cardiac hypertrophy, as evidenced by a reduced heart/tibia ratio and areas of cardiomyocytes, which is associated with reduced interstitial fibrosis and decreases in active caspase-3 and apoptotic stainings, but also increased angiogenesis in diabetic myocardium. Notably, glucose transporters (GLUT) 1 and 4 were up-regulated following HDAC inhibition, which was accompanied with increases of GLUT1 acetylation and p38 phosphorylation. Furthermore, myocardial superoxide dismutase, an important antioxidant, was elevated following HDAC inhibition in the diabetic mice. CONCLUSION: HDAC inhibition plays a critical role in improving cardiac function and suppressing myocardial remodeling in diabetic heart. PMID- 26245926 TI - Executive function, but not memory, associates with incident coronary heart disease and stroke. AB - OBJECTIVE: To evaluate the association of performance in cognitive domains executive function and memory with incident coronary heart disease and stroke in older participants without dementia. METHODS: We included 3,926 participants (mean age 75 years, 44% male) at risk for cardiovascular diseases from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) with Mini Mental State Examination score >=24 points. Scores on the Stroop Color-Word Test (selective attention) and the Letter Digit Substitution Test (processing speed) were converted to Z scores and averaged into a composite executive function score. Likewise, scores of the Picture Learning Test (immediate and delayed memory) were transformed into a composite memory score. Associations of executive function and memory were longitudinally assessed with risk of coronary heart disease and stroke using multivariable Cox regression models. RESULTS: During 3.2 years of follow-up, incidence rates of coronary heart disease and stroke were 30.5 and 12.4 per 1,000 person-years, respectively. In multivariable models, participants in the lowest third of executive function, as compared to participants in the highest third, had 1.85-fold (95% confidence interval [CI] 1.39-2.45) higher risk of coronary heart disease and 1.51-fold (95% CI 0.99-2.30) higher risk of stroke. Participants in the lowest third of memory had no increased risk of coronary heart disease (hazard ratio 0.99, 95% CI 0.74-1.32) or stroke (hazard ratio 0.87, 95% CI 0.57-1.32). CONCLUSION: Lower executive function, but not memory, is associated with higher risk of coronary heart disease and stroke. Lower executive function, as an independent risk indicator, might better reflect brain vascular pathologies. PMID- 26245927 TI - Is dominantly inherited Alzheimer disease a clone of sporadic Alzheimer disease? PMID- 26245925 TI - Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease. AB - OBJECTIVE: To investigate the associations of cerebral amyloidosis with concurrent cognitive performance and with longitudinal cognitive decline in asymptomatic and symptomatic stages of autosomal dominant Alzheimer disease (ADAD). METHODS: Two hundred sixty-three participants enrolled in the Dominantly Inherited Alzheimer Network observational study underwent neuropsychological evaluation as well as PET scans with Pittsburgh compound B. One hundred twenty one participants completed at least 1 follow-up neuropsychological evaluation. Four composite cognitive measures representing global cognition, episodic memory, language, and working memory were generated using z scores from a battery of 13 standard neuropsychological tests. General linear mixed-effects models were used to investigate the relationship between baseline cerebral amyloidosis and baseline cognitive performance and whether baseline cerebral amyloidosis predicts cognitive change over time (mean follow-up 2.32 years +/- 0.92, range 0.89-4.19) after controlling for estimated years from expected symptom onset, APOE epsilon4 allelic status, and education. RESULTS: In asymptomatic mutation carriers, amyloid burden was not associated with baseline cognitive functioning but was significantly predictive of longitudinal decline in episodic memory. In symptomatic mutation carriers, cerebral amyloidosis was correlated with worse baseline performance in multiple cognitive composites and predicted greater decline over time in global cognition, working memory, and Mini-Mental State Examination. CONCLUSIONS: Cerebral amyloidosis predicts longitudinal episodic memory decline in presymptomatic ADAD and multidomain cognitive decline in symptomatic ADAD. These findings imply that amyloidosis in the brain is an indicator of early cognitive decline and provides a useful outcome measure for early assessment and prevention treatment trials. PMID- 26245928 TI - Cognitive performance and poor long-term functional outcome after young stroke. AB - OBJECTIVE: To investigate the influence of cognitive performance on long-term functional outcome after ischemic stroke (IS) in young adults aged 18 through 50 years (young IS). METHODS: This study is part of a prospective cohort study among 277 stroke survivors with a young IS admitted to our department between January 1, 1980, and November 1, 2010. Functional outcome was assessed during follow-up between 2009 and 2012 with the modified Rankin Scale (mRS) and Instrumental Activities of Daily Living scale (IADL). Extensive neuropsychological investigation was performed. Logistic regression was used to calculate odds ratios (ORs) for a poor functional outcome (mRS >2 or IADL <8) for the 7 cognitive domains adjudicated for confounders. Cognitive function (continuous) as well as cognitive impairment (dichotomous) were studied. RESULTS: Only decline in working memory (OR 0.3, 95% confidence interval [CI] 0.1-0.6) was associated with poor functional outcome on the mRS. Except for decline in processing speed (OR 0.5, 95% CI 0.3-0.8) and working memory (OR 0.4, 95% CI 0.2-0.7), no relation was found with poor functional outcome on IADL. Impairment in none of the individual cognitive domains was related to long-term functional outcome, although impairment in global cognitive function was related to a poor functional outcome on the IADL (OR 4.8, 95% CI 1.7-14.0). CONCLUSIONS: On average, 11 years after young IS there was no clear relationship between long-term cognitive deficits and long-term functional outcome or IADL, stressing the need for further prospective studies with further development of sensitive measures of functional prognosis. PMID- 26245930 TI - Fabrication of high performance field-effect transistors and practical Schottky contacts using hydrothermal ZnO nanowires. AB - The production of large quantities of single crystalline semiconducting ZnO nanowires (NWs) at low cost can offer practical solutions to realizing several novel electronic/optoelectronic and sensor applications on an industrial scale. The present work demonstrates high-density single crystalline NWs synthesized by a multiple cycle hydrothermal process at ~100 degrees C. The high carrier concentration in such ZnO NWs is greatly suppressed by a simple low cost thermal annealing step in ambient air at ~450 degrees C. Single ZnO NW FETs incorporating these modified NWs are characterized, revealing strong metal work function-dependent charge transport, unobtainable with as-grown hydrothermal ZnO NWs. Single ZnO NW FETs with Al as source and drain (s/d) contacts show excellent performance metrics, including low off-state currents (fA range), high on/off ratio (10(5)-10(7)), steep subthreshold slope (<600 mV/dec) and excellent field effect carrier mobility (5-11 cm(2)/V-s). Modified ZnO NWs with platinum s/d contacts demonstrate excellent Schottky transport characteristics, markedly different from a reference ZnO NW device with Al contacts. This included abrupt reverse bias current-voltage saturation characteristics and positive temperature coefficient (~0.18 eV to 0.13 eV). This work is envisaged to benefit many areas of hydrothermal ZnO NW research, such as NW FETs, piezoelectric energy recovery, piezotronics and Schottky diodes. PMID- 26245931 TI - DELTA PREP: Building Capacity to Meet the Public Health Urgency of Intimate Partner Violence. PMID- 26245932 TI - Evaluation of DELTA PREP: A Project Aimed at Integrating Primary Prevention of Intimate Partner Violence Within State Domestic Violence Coalitions. AB - BACKGROUND: Intimate partner violence (IPV) has been recognized as a public health problem since the late 20th century. To spur IPV prevention efforts nationwide, the DELTA PREP Project selected 19 state domestic violence coalitions to build organizational prevention capacity and catalyze IPV primary prevention strategies within their states. OBJECTIVE: DELTA PREP's summative evaluation addressed four major questions: (1) Did coalitions improve their prevention capacity during the project period? (2) Did coalitions serve as catalysts for prevention activities within their states during the project period? (3) Was initial prevention capacity associated with the number of prevention activity types initiated by coalitions by the end of the project? (4) Did coalitions sustain their prevention activities 6 months after the end of the project period? RESULTS: DELTA PREP achieved its capacity-building goal, with all 19 participant coalitions integrating prevention within their organizations and serving as catalysts for prevention activities in their states. At 6 months follow up, coalitions had sustained almost all prevention activities they initiated during the project. Baseline prevention capacity (Beginner vs. Intermediate) was not associated with the number of prevention activity types coalitions implemented by the end of the project. CONCLUSION: Service and treatment organizations are increasingly asked to integrate a full spectrum of prevention strategies. Selecting organizations that have high levels of general capacity and readiness for an innovation like integrating a public health approach to IPV prevention will likely increase success in building an innovation-specific capacity, and in turn implementing an innovation. PMID- 26245933 TI - Using Action Planning to Build Organizational Capacity for the Prevention of Intimate Partner Violence. AB - The DELTA PREP Project aims to reduce risk for intimate partner violence (IPV). It engaged leadership and staff from 19 statewide domestic violence coalitions in building capacity to prevent IPV before it occurs (rather than solely responding to IPV). This article describes the process and outcomes associated with action planning to create coalition organizational change related to preventing IPV. Coalition staff and leadership planned for organizational changes in six goal areas: leadership, structures and processes, staffing, resource development, partnership development, and member agency development. Action planning was conducted during 2-day, in-person sessions that involved (a) review and refinement of coalition vision and mission statements, (b) interpretation of coalition assessments (for prevention capacity), (c) identification of specific organizational changes to be sought, and (d) specification of action steps for each proposed organizational change to be sought. The results show overall increases in the amounts, and variations in the kinds, of organizational changes that were facilitated by coalitions. Challenges related to action planning and future directions for capacity building among statewide IPV prevention coalitions are discussed. PMID- 26245934 TI - The DELTA PREP Initiative: Accelerating Coalition Capacity for Intimate Partner Violence Prevention. AB - BACKGROUND: The DELTA PREP Project aimed to build the prevention capacity of 19 state domestic violence coalitions by offering eight supports designed to promote prevention integration over a 3-year period: modest grant awards, training events, technical assistance, action planning, coaching hubs, the Coalition Prevention Capacity Assessment, an online workstation, and the online documentation support system. OBJECTIVES: Using quantitative and qualitative data, we sought to explain how coalitions integrated prevention within their structures and functions and document how DELTA PREP supports contributed to coalitions' integration process. RESULTS: We found that coalitions followed a common pathway to integrate prevention. First, coalitions exhibited precursors of organizational readiness, especially having prevention champions. Second, coalitions engaged in five critical actions: engaging in dialogue, learning about prevention, forming teams, soliciting input from the coalition, and action planning. Last, by engaging in these critical actions, coalitions enhanced two key organizational readiness factors-developing a common understanding of prevention and an organizational commitment to prevention. We also found that DELTA PREP supports contributed to coalitions' abilities to integrate prevention by supporting learning about prevention, fostering a prevention team, and engaging in action planning by leveraging existing opportunities. Two DELTA PREP supports-coaching hubs and the workstation-did not work as initially intended. From the DELTA PREP experience, we offer several lessons to consider when designing future prevention capacity-building initiatives. PMID- 26245935 TI - The Data-to-Action Framework: A Rapid Program Improvement Process. AB - Although health education programs may benefit from quality improvement methods, scant resources exist to help practitioners apply these methods for program improvement. The purpose of this article is to describe the Data-to-Action framework, a process that guides practitioners through rapid-feedback cycles in order to generate actionable data to improve implementation of ongoing programs. The framework was designed while implementing DELTA PREP, a 3-year project aimed at building the primary prevention capacities of statewide domestic violence coalitions. The authors describe the framework's main steps and provide a case example of a rapid-feedback cycle and several examples of rapid-feedback memos produced during the project period. The authors also discuss implications for health education evaluation and practice. PMID- 26245936 TI - KIF1-binding protein interacts with KIF3A in haploid male germ cells. AB - Male fertility relies on the production of functional spermatozoa. Spermatogenesis is a complex differentiation process that is characterized by meiosis and dramatic morphogenesis of haploid cells. Spermatogenesis involves active changes in the microtubular network to support meiotic divisions, cell polarization, the reshaping of the nucleus, and the formation of a flagellum. Previously, we have demonstrated that a microtubule-based anterograde transport motor protein KIF3A is required for the sperm tail formation and nuclear shaping during spermatogenesis. In this study, we show that KIF3A interacts with a KIF1 binding protein (KBP) in the mouse testis. We have characterized the expression and localization pattern of KBP during spermatogenesis and localized both KIF3A and KBP in the cytoplasm of round spermatids and manchette of elongating spermatids. Interestingly, KBP localized also in the late chromatoid body (CB) of elongating spermatids, whose function involves intracellular movement and association with the microtubular network. Altogether our results suggest a role for KBP in spermatid elongation and in the function of the late CB. PMID- 26245937 TI - An on-chip electrical transport spectroscopy approach for in situ monitoring electrochemical interfaces. AB - In situ monitoring electrochemical interfaces is crucial for fundamental understanding and continued optimization of electrocatalysts. Conventional spectroscopic techniques are generally difficult to implement for in situ electrochemical studies. Here we report an on-chip electrical transport spectroscopy approach for directly probing the electrochemical surfaces of metallic nanocatalysts in action. With a four-electrode device configuration, we demonstrate that the electrical properties of ultrafine platinum nanowires are highly sensitive and selective to the electrochemical surface states, enabling a nanoelectronic signalling pathway that reveals electrochemical interface information during in-device cyclic voltammetry. Our results not only show a high degree of consistency with generally accepted conclusions in platinum electrochemistry but also offer important insights on various practically important electrochemical reactions. This study defines a nanoelectronic strategy for in situ electrochemical surface studies with high surface sensitivity and surface specificity. PMID- 26245938 TI - Characterization of oncocytes in deep esophageal glands. AB - Deep esophageal glands play a vital role in the protection and regeneration of the esophageal mucosa. Conditions such as gastroesophageal reflux disease and Barrett's esophagus have been associated with a change in the usual glands by oncocytic metaplasia. However, little is known regarding the function of oncocytes or the relevance of this metaplastic change in the human esophagus. We hypothesized that oncocytes of deep esophageal glands also express markers characteristic of a ductal epithelial phenotype because similar oncocytes have been described as part of large ductal epithelial cells in salivary glands. We used immunohistochemical stains to define structural, functional, proliferative, and potential stem/progenitor characteristics of oncocytes. Oncocytes did not express mucins or lysozyme C, two molecules found in mucous cells and used for antimicrobial defense. Oncocytes did not express CK5, a cytokeratin found in myoepithelial cells and basal epithelial cells, but expressed CK7, a cytokeratin found in intralobular ductal epithelial cells and luminal epithelial cells of the main duct. Oncocytes expressed cystic fibrosis transmembrane conductance regulator and sodium/potassium ATPase, ion channels that play a role in bicarbonate secretion. Membrane-bound beta-catenin was detected in oncocytes, but these cells did not express the proliferative marker Ki67. Approximately, a third of oncocytes expressed SOX9 and p63, transcription factors expressed in epithelial progenitor cells in multiple organs. Moreover, oncocytes expressed CD44, a transmembrane Glycoprotein expressed in cancer stem cells. Taken together, our data show that oncocytes express markers of intralobular ductal epithelial cells and luminal epithelial cells of the main duct. Additionally, our observations suggest that oncocytes act as epithelial progenitor cells and play a role in bicarbonate secretion. Since oncocytic metaplasia is associated with conditions of chronic acid injury, it is possible that oncocytes replace the mucous cells in deep esophageal glands (dEG) as an adaptive change to counteract injury from acid reflux. The marker characterization suggests that oncocytes may originate from transdifferentiation of myoepithelial and mucous cells. This transdifferentiation might lead to an overall decrease of mucins production and secretion by the dEG and a subsequent reduction of the protection conferred by the viscoelastic mucous layer. PMID- 26245929 TI - Risk factors for poor visual outcome in patients with idiopathic intracranial hypertension. AB - OBJECTIVES: Determine potential risk factors for progressive visual field loss in the Idiopathic Intracranial Hypertension Treatment Trial, a randomized placebo controlled trial of acetazolamide in patients with idiopathic intracranial hypertension and mild visual loss concurrently receiving a low sodium, weight reduction diet. METHODS: Logistic regression and classification tree analyses were used to evaluate potential risk factors for protocol-defined treatment failure (>2 dB perimetric mean deviation [PMD] change in patients with baseline PMD -2 to -3.5 dB or >3 dB PMD change with baseline PMD -3.5 to -7 dB). RESULTS: Seven participants (6 on diet plus placebo) met criteria for treatment failure. The odds ratio for patients with grades III to V papilledema vs those with grades I and II was 8.66 (95% confidence interval [CI] 1.65-infinity, p = 0.025). A 1 unit decrease in the number of letters correct on the ETDRS (Early Treatment Diabetic Retinopathy Study) chart at baseline was associated with an increase in the odds of treatment failure by a factor of 1.16 (95% CI 1.04-1.30, p = 0.005). Compared with female participants, the odds ratio for male participants was 26.21 (95% CI 1.61-433.00, p = 0.02). The odds of treatment failure were 10.59 times higher (95% CI 1.63-116.83, p = 0.010) for patients with >30 transient visual obscurations per month vs those with <=30 per month. CONCLUSIONS: Male patients, those with high-grade papilledema, and those with decreased visual acuity at baseline were more likely to experience treatment failure. All but one of these patients were treated with diet alone. These patients should be monitored closely and be considered for aggressive treatment of their idiopathic intracranial hypertension. PMID- 26245939 TI - Using cultural immersion as the platform for teaching Aboriginal and Torres Strait Islander health in an undergraduate medical curriculum. AB - INTRODUCTION: In 2011 Bond University was looking for innovative ways to meet the professional standards and guidelines in Aboriginal and Torres Strait Islander health in its Bachelor of Medicine, Bachelor of Surgery (MBBS) curriculum. In 2012 Bond piloted a compulsory cultural immersion program for all first year students, which is now a usual part of the MBBS program. METHODS: Three phases were included - establishing an Indigenous health group, determining the Aboriginal and Torres Strait Islander educational content based on the professional standards and developing nine educational sessions and resources - as well as significant administrative processes. The cultural immersion was piloted in 2012 with 92 first year medical students. Following refinements it was repeated in 2013 with 95 students and in 2014 with 94 students. A comprehensive evaluation process was undertaken that included a paper-based evaluation form using a five-point Likert scale, as well as a confidential talking circle evaluation. The response rate was 95.4% (n=271, pooled cohort). Data were entered separately into SPSS and annual reports were written to the Faculty. Descriptive statistics are reported alongside themed qualitative data. RESULTS: The three combined student evaluation results were extremely positive. Students (n=271) strongly agreed that the workshop was well organised (M=4.3), that the facilitators contributed very positively to their experience (M=4.3), and that they were very satisfied overall with the activity (M=4.2). They agreed that the eight overall objectives had been well met (M=3.9-4.3). The nine sessions were highly evaluated with mean ratings of between 3.9 and 4.8. The 'best thing' about the immersion identified by more than half of the students was overwhelmingly (n=140) the Storytelling session, followed by bonding with the cohort, the Torres Strait Islander session and learning more about culture. The item identified as needing most improvement was the food (n=87), followed by the accommodation (n=65). CONCLUSIONS: The use of immersion in the early part of a cultural awareness program for medical students provides an extremely valuable platform from which to launch more detailed information about the history of Aboriginal and Torres Strait Islander Australia and its impact on the current health status of Aboriginal and Torres Strait Islander Australians. Doing this in a safe, supportive cross-cultural environment with highly skilled facilitators is essential. Key to success is strong leadership, commitment and support from Faculty level, a structured educational program and educating all staff and students about its importance throughout the journey. PMID- 26245941 TI - Release of Active Peptidyl Arginine Deiminases by Neutrophils Can Explain Production of Extracellular Citrullinated Autoantigens in Rheumatoid Arthritis Synovial Fluid. AB - OBJECTIVE: In the majority of patients with rheumatoid arthritis (RA), antibodies specifically recognize citrullinated autoantigens that are generated by peptidylarginine deiminases (PADs). Neutrophils express high levels of PAD and accumulate in the synovial fluid (SF) of RA patients during disease flares. This study was undertaken to test the hypothesis that neutrophil cell death, induced by either NETosis (extrusion of genomic DNA-protein complexes known as neutrophil extracellular traps [NETs]) or necrosis, can contribute to production of autoantigens in the inflamed joint. METHODS: Extracellular DNA was quantified in the SF of patients with RA, patients with osteoarthritis (OA), and patients with psoriatic arthritis (PsA). Release of PAD from neutrophils was investigated by Western blotting, mass spectrometry, immunofluorescence staining, and PAD activity assays. PAD2 and PAD4 protein expression, as well as PAD enzymatic activity, were assessed in the SF of patients with RA and those with OA. RESULTS: Extracellular DNA was detected at significantly higher levels in RA SF than in OA SF (P < 0.001) or PsA SF (P < 0.05), and its expression levels correlated with neutrophil concentrations and PAD activity in RA SF. Necrotic neutrophils released less soluble extracellular DNA compared to NETotic cells in vitro (P < 0.05). Higher PAD activity was detected in RA SF than in OA SF (P < 0.05). The citrullinated proteins PAD2 and PAD4 were found attached to NETs and also freely diffused in the supernatant. PAD enzymatic activity was detected in supernatants of neutrophils undergoing either NETosis or necrosis. CONCLUSION: Release of active PAD isoforms into the SF by neutrophil cell death is a plausible explanation for the generation of extracellular autoantigens in RA. PMID- 26245942 TI - Universal Health Coverage for Schizophrenia: A Global Mental Health Priority. AB - The growing momentum towards a global consensus on universal health coverage, alongside an acknowledgment of the urgency and importance of a comprehensive mental health action plan, offers a unique opportunity for a substantial scale-up of evidence-based interventions and packages of care for a range of mental disorders in all countries. There is a robust evidence base testifying to the effectiveness of drug and psychosocial interventions for people with schizophrenia and to the feasibility, acceptability and cost-effectiveness of the delivery of these interventions through a collaborative care model in low resource settings. While there are a number of barriers to scaling up this evidence, for eg, the finances needed to train and deploy community based workers and the lack of agency for people with schizophrenia, the experiences of some upper middle income countries show that sustained political commitment, allocation of transitional financial resources to develop community services, a commitment to an integrated approach with a strong role for community based institutions and providers, and a progressive realization of coverage are the key ingredients for scale up of services for schizophrenia. PMID- 26245943 TI - 'I now have a visual image in my mind and it is something I will never forget': an analysis of an arts-informed approach to health professions ethics education. AB - This paper reports on a study of an arts informed approach to ethics education in a health professions education context. The purpose of this study was to investigate students' reported learning experiences as a result of engagement with an arts-informed project in a health professions' ethics course. A hermeneutic phenomenological methodological approach was adopted for the study. The data were collected over 5 years, and involved analysis of 234 occupational therapy students' written reflections on learning. Phenomenological methods were used. Five key themes were identified with respect to students' reported learning including: becoming aware of values, (re) discovering creativity, coming to value reflection in professional life, deepening self-awareness, and developing capacities to imagine future practices. There appear to be a number of unique ways in which arts-informed approaches can contribute to health professions education including: activating imaginative engagement, fostering interpretive capacity, inspiring transformative understandings, offering new ways of knowing, deepening reflection, and heightening consciousness, while also enriching the inner life of practitioners. Innovative approaches are being used to introduce arts-informed practices in health professions curricula programs. The findings point to the promise of arts-informed approaches for advancing health sciences education. PMID- 26245944 TI - Peripartum cardiomyopathy: current knowledge and future directions. AB - Peripartum cardiomyopathy is a form of heart failure occurring at the end of pregnancy or early in the postpartum period. Women may recover, have persistent cardiac dysfunction or suffer complications and death. Women who are African American, older, hypertensive or have multiple gestation pregnancies have increased risk. Diagnosis and treatment may be delayed due to similarities between symptoms of normal pregnancy and heart failure. Echocardiography is essential for the diagnosis, and B-type natriuretic peptide can be helpful. Treatment for systolic heart failure must be adjusted during pregnancy, and anticoagulation may be indicated. Even after recovery, subsequent pregnancy confers substantial risk of worsening heart failure. Further investigations into the etiology, duration of treatment and risks for relapse are needed. PMID- 26245945 TI - Liposomes as carriers: not as innocent as one would like. PMID- 26245946 TI - Analytic laboratory performance of a point of care urine culture kit for diagnosis and antibiotic susceptibility testing. AB - Currently available point-of-care (POC) diagnostic tests for managing urinary tract infections (UTIs) in general practice are limited by poor performance characteristics, and laboratory culture generally provides results only after a few days. This laboratory evaluation compared the analytic performance of the POC UK Flexicult(TM) (Statens Serum Institut) (SSI) urinary kit for quantification, identification and antibiotic susceptibility testing and routine UK National Health Service (NHS) urine processing to an advanced urine culture method. Two hundred urine samples routinely submitted to the Public Health Wales Microbiology Laboratory were divided and: (1) analysed by routine NHS microbiological tests as per local laboratory standard operating procedures, (2) inoculated onto the UK Flexicult(TM) SSI urinary kit and (3) spiral plated onto Colorex Orientation UTI medium (E&O Laboratories Ltd). The results were evaluated between the NHS and Flexicult(TM )methods, and discordant results were compared to the spiral plating method. The UK Flexicult(TM) SSI urinary kit was compared to routine NHS culture for identification of a pure or predominant uropathogen at >= 10(5) cfu/mL, with a positive discordancy rate of 13.5% and a negative discordancy rate of 3%. The sensitivity and specificity were 86.7% [95% confidence interval (CI) 73.8-93.7] and 82.6% (95% CI 75.8-87.7), respectively. The UK Flexicult(TM) SSI urinary kit was comparable to routine NHS urine processing in identifying microbiologically positive UTIs in this laboratory evaluation. However, the number of false positive samples could lead to over-prescribing of antibiotics in clinical practice. The Flexicult(TM) SSI kit could be useful as a POC test for UTIs in primary care but further pragmatic evaluations are necessary. PMID- 26245947 TI - Morbidities after closure of ileostomy: analysis of risk factors. AB - PURPOSE: Low anterior resection is commonly performed for carcinoma of the distal rectum. Diverting ileostomy has been used to decrease the septic consequence of anastomotic leakage and to reduce the re-operation rate. Nevertheless, subsequent closure of ileostomy can be associated with considerable morbidities. This study aimed to evaluate the morbidities after closure of ileostomy and to identify possible risk factors associated with the morbidities. METHODS: Data of patients who underwent closure of ileostomy, after a previous low anterior resection and defunctioning ileostomy for rectal cancer, was reviewed retrospectively. Patient's demographics, coexisting morbidities, operative details, and post operative outcomes were analyzed. RESULTS: From January 2000 to September 2012, 213 patients who underwent ileostomy closure were included. Thirty-five patients developed post-operative complications. The overall complication rate was 16.4 %. The majority of complications could be managed by conservative treatment. Only one patient required re-operation due to intestinal obstruction. There was no 30 day mortality. Age >80 years was an independent risk factor for post-operative complications. Age >80 years was also an independent risk factor for developing urinary retention (p = 0.001) and prolonged ileus (p = 0.02). Closure of ileostomy with hand-sewn techniques showed a higher incidence of post-operative intestinal obstruction (p = 0.049) compared to closure using stapler. CONCLUSION: Closure of ileostomy following low anterior resection is associated with acceptable morbidities. Elderly patients tend to have a more complicated post operative course and require more medical attention. The use of stapler is the preferred method for ileostomy closure as it is associated with less post operative intestinal obstruction. PMID- 26245948 TI - Persistent perineal morbidity is common following abdominoperineal excision for rectal cancer. AB - PURPOSE: Short-term complications related to the perineal wound after abdominoperineal excision (APE) are a well-known problem. Perineal morbidity in the longer term is an almost unexplored area. The aim of this cross-sectional study was to investigate the prevalence of perineal symptoms 3 years after APE for rectal cancer, to identify potential risk factors and to explore the relationship between perineal morbidity and global quality of life. METHOD: All patients who underwent APE in Sweden between 2007 and 2009 (n = 1373) were identified through the Swedish Colorectal Cancer Registry. Surviving patients were contacted 3 years after surgery and asked about participation. A total of 545 patients completed a detailed questionnaire. Clinical data was collected from the registry and surgical charts. RESULTS: Perineal symptoms occurred in 50 % of all patients 3 years after APE and more frequently in women (58 vs. 44 %; p = 0.001). Delayed healing of the perineal wound (>4 weeks) occurred in 25 % of all patients and more frequently after extralevator APE (ELAPE) than after conventional APE (32 vs. 11 %, p < 0.001). Delayed healing was associated with an increased risk of more severe perineal symptoms (relative risk (RR) 1.50, 95 % confidence interval (95 % CI) 1.09-2.05). Patients with more severe perineal symptoms (n = 129) had a significantly lower global quality of life as measured by EQ-5D visual analogue scale (VAS; median 75 vs. 83 points on the 100-point scale; p < 0.001). CONCLUSION: Persistent perineal symptoms are common after APE and may have an impact on patients' quality of life. Delayed wound healing may be a risk factor for persistent symptoms. Further studies are needed to identify avoidable clinical factors for the development of persistent perineal morbidity. CLINICALTRIALS. GOV IDENTIFIER: NCT01296984. PMID- 26245949 TI - Anastomotic leakage after curative rectal cancer resection has no impact on long term survival: a propensity score analysis. AB - PURPOSE: Anastomotic leakage (AL) is a severe and frequent complication of rectal cancer resection, with an incidence rate of approximately 9 %. Although the impact of AL on morbidity and short-term mortality has been established, the literature is contradictory regarding its influence on long-term, cancer-specific survival. The present investigation assessed the long-term survival of 584 patients with stage I-III rectal cancer. METHODS: The 10-year overall survival and cancer-specific survival were analyzed in 584 patients from a single tertiary center. All patients had undergone curative rectal cancer resection between 1991 and 2010. Patients with and without AL were compared using both a multivariate Cox hazards model and propensity score analysis. RESULTS: A total of 64 patients developed AL (11.0 %, 95 % confidence interval (CI) = 8.7 to 13.8 %). The median follow-up was 5.2 years for all patients; and 7.4 years for patients still alive at the end of the investigated period. AL did persistently not impair cancer specific survival based on unadjusted Cox regression (hazard ratio of death (HR) = 1.27, 95 % CI = 0.65 to 2.48, P = 0.489); risk-adjusted Cox regression (HR = 1.10, 95 % CI = 0.54 to 2.20, P = 0.799); and propensity score matching (HR = 1.18, 95 % CI = 0.57 to 2.43, P = 0.660). CONCLUSIONS: Based on the present propensity score analysis, the oncologic outcomes in patients undergoing curative rectal cancer resections were not impaired by the development of anastomotic leakage. PMID- 26245950 TI - Stapled hemorrhoidopexy: functional results, recurrence rate, and prognostic factors in a single center analysis. AB - PURPOSE: Since its introduction, stapled hemorrhoidopexy (SHP), the so-called Longo procedure, became a widely accepted treatment option for prolapsing hemorrhoids. Nevertheless, from the early years, concerns grew about the early functional results and potential recurrences. In order to evaluate of SHP with special respect to early defecation disorders und recurrences, our single institute high-volume results were evaluated. METHOD: One thousand one hundred forty-four consecutive patients with SHP for prolapsing hemorrhoids were evaluated in a period from January 2007 to December 2013. In a prospective analysis, patients were followed with special respect to postoperative complications, functional disorders, mainly perianal irritation, stenosis, and recurrence. RESULTS: During the timeframe, a total of 663 men and 481 women were treated for prolapsing hemorrhoids. The mean age was 52.6 years (+/-14.4 years). Indication for surgery was prolapsing hemorrhoids in all cases. In addition to prolapse, 90 patients (7.9 %) suffered from bleeding, 96 patients (8.4 %) had itching, and 95 (8.3 %) had anal wetness; the mean operative time was 11 min (+/ 4 min). Patients were treated as inpatients; the mean hospital stay was 3 days (+/-1 day). Early complications were observed in 14 patients (1.2 %). The follow up revealed inflammatory reaction at the stapleline in 8 patients (0.7 %) and rectal stenosis in 22 cases (1.9 %), and recurrence was observed in 46 cases (4.0 %). CONCLUSION: The data presented here provide evidence that SHP is a save procedure with a very low rate for functional disorders and low recurrence rate. Therefore, in our hands, SHP remains standard for prolapsing hemorrhoids. PMID- 26245951 TI - Constipation in adults. AB - INTRODUCTION: Although there are defined criteria for the diagnosis of constipation, in practice, diagnostic criteria are less rigid and depend in part on the perception of normal bowel habit. Constipation is highly prevalent, with approximately 12 million general practitioner prescriptions for laxatives in England in 2001. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of medications in people with idiopathic chronic constipation? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). RESULTS: At this update, searching of electronic databases retrieved 356 studies published in this time period. After deduplication, 95 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 62 studies and the further review of 33 full publications. Of the 33 full articles evaluated, three systematic reviews and one RCT were added to the overview at this update. We performed a GRADE evaluation for four PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for three interventions, based on information relating to the effectiveness and safety of linaclotide, lubiprostone, and prucalopride. PMID- 26245952 TI - Implementing novel models of posttreatment care for cancer survivors: Enablers, challenges and recommendations. AB - AIM: The American Society of Clinical Oncology and US Institute of Medicine emphasize the need to trial novel models of posttreatment care, and disseminate findings. In 2011, the Victorian State Government (Australia) established the Victorian Cancer Survivorship Program (VCSP), funding six 2-year demonstration projects, targeting end of initial cancer treatment. Projects considered various models, enrolling people of differing cancer types, age and residential areas. We sought to determine common enablers of success, as well as challenges/barriers. METHODS: Throughout the duration of the projects, a formal "community of practice" met regularly to share experiences. Projects provided regular formal progress reports. An analysis framework was developed to synthesize key themes and identify critical enablers and challenges. Two external reviewers examined final project reports. Discussion with project teams clarified content. RESULTS: Survivors reported interventions to be acceptable, appropriate and effective. Strong clinical leadership was identified as a critical success factor. Workforce education was recognized as important. Partnerships with consumers, primary care and community organizations; risk stratified pathways with rapid re-access to specialist care; and early preparation for survivorship, self-management and shared care models supported positive project outcomes. Tailoring care to individual needs and predicted risks was supported. Challenges included: lack of valid assessment and prediction tools; limited evidence to support novel care models; workforce redesign; and effective engagement with community-based care and issues around survivorship terminology. CONCLUSION: The VCSP project outcomes have added to growing evidence around posttreatment care. Future projects should consider the identified enablers and challenges when designing and implementing survivorship care. PMID- 26245953 TI - Collaboration of general practitioners and exercise providers in promotion of physical activity a written survey among general practitioners. AB - BACKGROUND: General practitioners have an ideal position to motivate inactive patients to increase their physical activity. Most patients are able to exercise in regular local facilities outside the health care setting. The purpose of this study was to get insight into general practitioners perceptions and current practices regarding referral of patients to local exercise facilities. Furthermore, collaboration with exercise providers in the community was investigated, and motivators and barriers for referral. METHODS: A written questionnaire sent to a representative random sample of 800 Dutch general practitioners. Descriptive statistics and Chi(2) tests were used. RESULTS: All responding general practitioners (340) recommend their patients to take more exercise when necessary and 87 % say to refer patients sometimes. Limited motivation of the patient (44 %) and reduced health status (34 %) are the most mentioned barriers for advising patients to increase physical activity. When referred, most patients are send to a physical therapist (69 %) but also local exercise facilities were mentioned (54 %). The most important barrier for referring patients to local exercise activities are patients limited financial possibilities (46 %). Restricted knowledge of local exercise- or sport facilities was an additional barrier (19 %). There is little structural collaboration between general practitioners and exercise providers, but when collaboration exists general practitioners refer more often. Positive experiences of patients (67 %), affordable offers (59 %) and information of local exercise facilities (46 %) are seen as important promoting factors for referral. Although 32 % of the general practitioners think that good collaboration would be stimulating, regular meetings with sports and exercise providers were considered the least important for increasing referral (3 %). CONCLUSIONS: Dutch physicians have a positive attitude towards stimulating physical activity but referral to local exercise facilities is low. Referral is partly hindered by restricted knowledge of local exercise facilities. Although general practitioners think that collaboration is important for physical activity promotion, it should not cost them much extra time. A coordinator with knowledge of the local situation can facilitate contacts between GP practices and sports providers. PMID- 26245954 TI - Development of a modified cortisol extraction procedure for intermediately sized fish not amenable to whole-body or plasma extraction methods. AB - The corticosteroid hormone cortisol is the central mediator of the teleost stress response. Therefore, the accurate quantification of cortisol in teleost fishes is a vital tool for addressing fundamental questions about an animal's physiological response to environmental stressors. Conventional steroid extraction methods using plasma or whole-body homogenates, however, are inefficient within an intermediate size range of fish that are too small for phlebotomy and too large for whole-body steroid extractions. To assess the potential effects of hatchery induced stress on survival of fingerling hatchery-reared Spotted Seatrout (Cynoscion nebulosus), we developed a novel extraction procedure for measuring cortisol in intermediately sized fish (50-100 mm in length) that are not amenable to standard cortisol extraction methods. By excising a standardized portion of the caudal peduncle, this tissue extraction procedure allows for a small portion of a larger fish to be sampled for cortisol, while minimizing the potential interference from lipids that may be extracted using whole-body homogenization procedures. Assay precision was comparable to published plasma and whole-body extraction procedures, and cortisol quantification over a wide range of sample dilutions displayed parallelism versus assay standards. Intra-assay %CV was 8.54%, and average recovery of spiked samples was 102%. Also, tissue cortisol levels quantified using this method increase 30 min after handling stress and are significantly correlated with blood values. We conclude that this modified cortisol extraction procedure provides an excellent alternative to plasma and whole-body extraction procedures for intermediately sized fish, and will facilitate the efficient assessment of cortisol in a variety of situations ranging from basic laboratory research to industrial and field-based environmental health applications. PMID- 26245955 TI - Posterior Parietal Cortex Encoding of Dynamic Hand Force Underlying Hand-Object Interaction. AB - Major achievements of primate evolution are skilled hand-object interaction and tool use, both in part dependent on parietal cortex expansion. We recorded spiking activity from macaque inferior parietal cortex during directional manipulation of an isometric tool, which required the application of hand forces to control a cursor's motion on a screen. In areas PFG/PF, the activity of ~ 70% neurons was modulated by the hand force necessary to implement the desired target motion, reflecting an inverse model, rather than by the intended motion of the visual cursor (forward model). The population vector matched the direction and amplitude of the instantaneous force increments over time. When exposed to a new force condition, that obliged the monkey to change the force output to successfully bring the cursor to the final target, the activity of a consistent subpopulation of neurons changed in an orderly fashion and, at the end of a "Wash out" session, retained memory of the new learned association, at the service of predictive control of force. Our findings suggest that areas PFG/PF represent a crucial node of the distributed control of hand force, by encoding instantaneous force variations and serving as a memory reservoir of hand dynamics required for object manipulation and tool use. This is coherent with previous studies in humans showing the following: (1) impaired adaptation to a new force field under TMS parietal perturbation; (2) defective control of direction of hand force after parietal lesion; and (3) fMRI activation of parietal cortex during object manipulation requiring control of fine hand forces. SIGNIFICANCE STATEMENT: Skilled object manipulation and tool use are major achievements of primate evolution, both largely dependent on posterior parietal cortex (PPC) expansion. Neurophysiological and fMRI studies in macaque and humans had documented a crucial role of PPC in encoding the hand kinematics underlying these functions, leaving to premotor and motor areas the role of specifying the underlying hand forces. We recorded spiking activity from macaque PPC during manipulation of an isometric tool and found that population activity is not only modulated by the dynamic hand force and its change over time, but also retains memory of the exerted force, as a reservoir to guide of future hand action. This suggests parallel parietal encoding of hand dynamics and kinematics during object manipulation. PMID- 26245956 TI - Thalamic WNT3 Secretion Spatiotemporally Regulates the Neocortical Ribosome Signature and mRNA Translation to Specify Neocortical Cell Subtypes. AB - Neocortical development requires tightly controlled spatiotemporal gene expression. However, the mechanisms regulating ribosomal complexes and the timed specificity of neocortical mRNA translation are poorly understood. We show that active mRNA translation complexes (polysomes) contain ribosomal protein subsets that undergo dynamic spatiotemporal rearrangements during mouse neocortical development. Ribosomal protein specificity within polysome complexes is regulated by the arrival of in-growing thalamic axons, which secrete the morphogen Wingless related MMTV (mouse mammary tumor virus) integration site 3 (WNT3). Thalamic WNT3 release during midneurogenesis promotes a change in the levels of Ribosomal protein L7 in polysomes, thereby regulating neocortical translation machinery specificity. Furthermore, we present an RNA sequencing dataset analyzing mRNAs that dynamically associate with polysome complexes as neocortical development progresses, and thus may be regulated spatiotemporally at the level of translation. Thalamic WNT3 regulates neocortical translation of two such mRNAs, Foxp2 and Apc, to promote FOXP2 expression while inhibiting APC expression, thereby driving neocortical neuronal differentiation and suppressing oligodendrocyte maturation, respectively. This mechanism may enable targeted and rapid spatiotemporal control of ribosome composition and selective mRNA translation in complex developing systems like the neocortex. SIGNIFICANCE STATEMENT: The neocortex is a highly complex circuit generating the most evolutionarily advanced complex cognitive and sensorimotor functions. An intricate progression of molecular and cellular steps during neocortical development determines its structure and function. Our goal is to study the steps regulating spatiotemporal specificity of mRNA translation that govern neocortical development. In this work, we show that the timed secretion of Wingless-related MMTV (mouse mammary tumor virus) integration site 3 (WNT3) by ingrowing axons from the thalamus regulates the combinatorial composition of ribosomal proteins in developing neocortex, which we term the "neocortical ribosome signature." Thalamic WNT3 further regulates the specificity of mRNA translation and development of neurons and oligodendrocytes in the neocortex. This study advances our overall understanding of WNT signaling and the spatiotemporal regulation of mRNA translation in highly complex developing systems. PMID- 26245958 TI - Neural Signatures of Conscious Face Perception in an Inattentional Blindness Paradigm. AB - Previous studies suggest that early stages of face-specific processing are performed preattentively and unconsciously, whereas conscious perception emerges with late-stage (>300 ms) neuronal activity. A conflicting view, however, posits that attention is necessary for face-specific processing and that early-to-mid latency neural responses (~ 100-300 ms) correspond more closely with perceptual awareness. The current study capitalized on a recently developed method for manipulating attention and conscious perception during EEG recording (modified inattentional blindness paradigm) and used face stimuli that elicit a well known marker of early face processing, the N170 event-related potential (ERP). In Phase 1 of the experiment, subjects performed a demanding distracter task while line drawings of faces and matched control stimuli were presented in the center of their view. When queried, half of the subjects reported no awareness of the faces and were deemed inattentionally blind. In Phase 2, subjects performed the same distracter task, but now consciously perceived the face stimuli due to the intervening questioning. In Phase 3, subjects performed a discrimination task on the faces. Two primary contrasts were made: aware versus unaware (equally task irrelevant) and task-relevant versus task-irrelevant (equally aware). The N170 and a subsequent ERP component, the visual awareness negativity (~ 260-300 ms), were absent during inattentional blindness and present in the aware conditions. The P3b (> 300 ms) was absent for task-irrelevant faces, even when consciously perceived, and present only when the faces were task relevant. These results inform contemporary theories of conscious face perception in particular and visual attention and perceptual awareness in general. PMID- 26245957 TI - Functional Microarchitecture of the Mouse Dorsal Inferior Colliculus Revealed through In Vivo Two-Photon Calcium Imaging. AB - The inferior colliculus (IC) is an obligatory relay for ascending auditory inputs from the brainstem and receives descending input from the auditory cortex. The IC comprises a central nucleus (CNIC), surrounded by several shell regions, but the internal organization of this midbrain nucleus remains incompletely understood. We used two-photon calcium imaging to study the functional microarchitecture of both neurons in the mouse dorsal IC and corticocollicular axons that terminate there. In contrast to previous electrophysiological studies, our approach revealed a clear functional distinction between the CNIC and the dorsal cortex of the IC (DCIC), suggesting that the mouse midbrain is more similar to that of other mammals than previously thought. We found that the DCIC comprises a thin sheet of neurons, sometimes extending barely 100 MUm below the pial surface. The sound frequency representation in the DCIC approximated the mouse's full hearing range, whereas dorsal CNIC neurons almost exclusively preferred low frequencies. The response properties of neurons in these two regions were otherwise surprisingly similar, and the frequency tuning of DCIC neurons was only slightly broader than that of CNIC neurons. In several animals, frequency gradients were observed in the DCIC, and a comparable tonotopic arrangement was observed across the boutons of the corticocollicular axons, which form a dense mesh beneath the dorsal surface of the IC. Nevertheless, acoustically responsive corticocollicular boutons were sparse, produced unreliable responses, and were more broadly tuned than DCIC neurons, suggesting that they have a largely modulatory rather than driving influence on auditory midbrain neurons. SIGNIFICANCE STATEMENT: Due to its genetic tractability, the mouse is fast becoming the most popular animal model for sensory neuroscience. Nevertheless, many aspects of its neural architecture are still poorly understood. Here, we image the dorsal auditory midbrain and its inputs from the cortex, revealing a hitherto hidden level of organization and paving the way for the direct observation of corticocollicular interactions. We show that a precise functional organization exists in the mouse auditory midbrain, which has been missed by previous, more macroscopic approaches. The fine-scale distribution of sound-frequency tuning suggests that the mouse midbrain is more similar to that of other mammals than previously thought and contrasts with the more heterogeneous organization reported in imaging studies of auditory cortex. PMID- 26245959 TI - HuR Mediates Changes in the Stability of AChR beta-Subunit mRNAs after Skeletal Muscle Denervation. AB - Acetylcholine receptors (AChRs) are heteromeric membrane proteins essential for neurotransmission at the neuromuscular junction. Previous work showed that muscle denervation increases expression of AChR mRNAs due to transcriptional activation of AChR subunit genes. However, it remains possible that post-transcriptional mechanisms are also involved in controlling the levels of AChR mRNAs following denervation. We examined whether post-transcriptional events indeed regulate AChR beta-subunit mRNAs in response to denervation. First, in vitro stability assays revealed that the half-life of AChR beta-subunit mRNAs was increased in the presence of denervated muscle protein extracts. A bioinformatics analysis revealed the existence of a conserved AU-rich element (ARE) in the 3' untranslated region (UTR) of AChR beta-subunit mRNA. Furthermore, denervation of mouse muscle injected with a luciferase reporter construct containing the AChR beta-subunit 3'UTR, caused an increase in luciferase activity. By contrast, mutation of this ARE prevented this increase. We also observed that denervation increased expression of the RNA-binding protein human antigen R (HuR) and induced its translocation to the cytoplasm. Importantly, HuR binds to endogenous AChR beta-subunit transcripts in cultured myotubes and in vivo, and this binding is increased in denervated versus innervated muscles. Finally, p38 MAPK, a pathway known to activate HuR, was induced following denervation as a result of MKK3/6 activation and a decrease in MKP-1 expression, thereby leading to an increase in the stability of AChR beta-subunit transcripts. Together, these results demonstrate the important contribution of post-transcriptional events in regulating AChR beta-subunit mRNAs and point toward a central role for HuR in mediating synaptic gene expression. SIGNIFICANCE STATEMENT: Muscle denervation is a convenient model to examine expression of genes encoding proteins of the neuromuscular junction, especially acetylcholine receptors (AChRs). Despite the accepted model of AChR regulation, which implicates transcriptional mechanisms, it remains plausible that such events cannot fully account for changes in AChR expression following denervation. We show that denervation increases expression of the RNA-binding protein HuR, which in turn, causes an increase in the stability of AChR beta-subunit mRNAs in denervated muscle. Our findings demonstrate for the first time the contribution of post-transcriptional events in controlling AChR expression in skeletal muscle, and points toward a central role for HuR in mediating synaptic development while also paving the way for developing RNA-based therapeutics for neuromuscular diseases. PMID- 26245960 TI - Interspike Intervals Reveal Functionally Distinct Cell Populations in the Medial Entorhinal Cortex. AB - The superficial layers of the medial entorhinal cortex (MEC) contain spatially selective neurons that are crucial for spatial navigation and memory. These highly specialized neurons include grid cells, border cells, head-direction cells, and irregular spatially selective cells. In addition, MEC neurons display a large variability in their spike patterns at a millisecond time scale. In this study, we analyzed spike trains of neurons in the MEC superficial layers of mice and found that these neurons can be classified into two groups based on their propensity to fire spike doublets at 125-250 Hz. The two groups, labeled "bursty" and "non-bursty" neurons, differed in their spike waveforms and interspike interval adaptation but displayed a similar mean firing rate. Grid cell spatial periodicity was more commonly observed in bursty than in non-bursty neurons. In contrast, most neurons with head-direction selectivity or those that fired at the border of the environment were non-bursty neurons. During theta oscillations, both bursty and non-bursty neurons fired preferentially near the end of the descending phase of the cycle, but the spikes of bursty neurons occurred at an earlier phase than those of non-bursty neurons. Finally, analysis of spike-time crosscorrelations between simultaneously recorded neurons suggested that the two cell classes are differentially coupled to fast-spiking interneurons: bursty neurons were twice as likely to have excitatory interactions with putative interneurons as non-bursty neurons. These results demonstrate that bursty and non bursty neurons are differentially integrated in the MEC network and preferentially encode distinct spatial signals. SIGNIFICANCE STATEMENT: We report that neurons in the superficial layers of the medial entorhinal cortex can be classified based on their tendency to fire bursts of action potentials at 125-250 Hz. The relevance of this classification is demonstrated by the types of spatial information preferentially encoded by bursty and non-bursty neurons. Grid-like spatial periodicity is more commonly observed in bursty neurons, whereas most cells with head-direction selectivity or those that are firing at the border of the environment are non-bursty neurons. This work indicates that the spatial firing patterns of neurons in the medial entorhinal cortex can be predicted by electrophysiological features reflecting the synaptic inputs and/or integrating properties of the neurons. PMID- 26245962 TI - Payoff Information Biases a Fast Guess Process in Perceptual Decision Making under Deadline Pressure: Evidence from Behavior, Evoked Potentials, and Quantitative Model Comparison. AB - We used electroencephalography (EEG) and behavior to examine the role of payoff bias in a difficult two-alternative perceptual decision under deadline pressure in humans. The findings suggest that a fast guess process, biased by payoff and triggered by stimulus onset, occurred on a subset of trials and raced with an evidence accumulation process informed by stimulus information. On each trial, the participant judged whether a rectangle was shifted to the right or left and responded by squeezing a right- or left-hand dynamometer. The payoff for each alternative (which could be biased or unbiased) was signaled 1.5 s before stimulus onset. The choice response was assigned to the first hand reaching a squeeze force criterion and reaction time was defined as time to criterion. Consistent with a fast guess account, fast responses were strongly biased toward the higher-paying alternative and the EEG exhibited an abrupt rise in the lateralized readiness potential (LRP) on a subset of biased payoff trials contralateral to the higher-paying alternative ~ 150 ms after stimulus onset and 50 ms before stimulus information influenced the LRP. This rise was associated with poststimulus dynamometer activity favoring the higher-paying alternative and predicted choice and response time. Quantitative modeling supported the fast guess account over accounts of payoff effects supported in other studies. Our findings, taken with previous studies, support the idea that payoff and prior probability manipulations produce flexible adaptations to task structure and do not reflect a fixed policy for the integration of payoff and stimulus information. SIGNIFICANCE STATEMENT: Humans and other animals often face situations in which they must make choices based on uncertain sensory information together with information about expected outcomes (gains or losses) about each choice. We investigated how differences in payoffs between available alternatives affect neural activity, overt choice, and the timing of choice responses. In our experiment, in which participants were under strong time pressure, neural and behavioral findings together with model fitting suggested that our human participants often made a fast guess toward the higher reward rather than integrating stimulus and payoff information. Our findings, taken with findings from other studies, support the idea that payoff and prior probability manipulations produce flexible adaptations to task structure and do not reflect a fixed policy. PMID- 26245961 TI - Persistent Interneuronopathy in the Prefrontal Cortex of Young Adult Offspring Exposed to Ethanol In Utero. AB - Gestational exposure to ethanol has been reported to alter the disposition of tangentially migrating GABAergic cortical interneurons, but much remains to be elucidated. Here we first established the migration of interneurons as a proximal target of ethanol by limiting ethanol exposure in utero to the gestational window when tangential migration is at its height. We then asked whether the aberrant tangential migration of GABAergic interneurons persisted as an enduring interneuronopathy in the medial prefrontal cortex (mPFC) later in the life of offspring prenatally exposed to ethanol. Time pregnant mice with Nkx2.1Cre/Ai14 embryos harboring tdTomato-fluorescent medial ganglionic eminence (MGE)-derived cortical GABAergic interneurons were subjected to a 3 day binge-type 5% w/w ethanol consumption regimen from embryonic day (E) 13.5-16.5, spanning the peak of corticopetal interneuron migration in the fetal brain. Our binge-type regimen increased the density of MGE-derived interneurons in the E16.5 mPFC. In young adult offspring exposed to ethanol in utero, this effect persisted as an increase in the number of mPFC layer V parvalbumin-immunopositive interneurons. Commensurately, patch-clamp recording in mPFC layer V pyramidal neurons uncovered enhanced GABA-mediated spontaneous and evoked synaptic transmission, shifting the inhibitory/excitatory balance toward favoring inhibition. Furthermore, young adult offspring exposed to the 3 day binge-type ethanol regimen exhibited impaired reversal learning in a modified Barnes maze, indicative of decreased PFC dependent behavioral flexibility, and heightened locomotor activity in an open field arena. Our findings underscore that aberrant neuronal migration, inhibitory/excitatory imbalance, and thus interneuronopathy contribute to indelible abnormal cortical circuit form and function in fetal alcohol spectrum disorders. SIGNIFICANCE STATEMENT: The significance of this study is twofold. First, we demonstrate that a time-delimited binge-type ethanol exposure in utero during early gestation alters corticopetal tangential migration of GABAergic interneurons in the fetal brain. Second, our study is the first to integrate neuroanatomical, electrophysiological, and behavioral evidence that this "interneuronopathy" persists in the young adult offspring and contributes to enduring changes in (1) the distribution of parvalbumin-expressing GABAergic cortical interneurons in the medial prefrontal cortex, (2) GABA-mediated synaptic transmission that resulted in an inhibitory/excitatory synaptic imbalance, and (3) behavioral flexibility. These findings alert women of child-bearing age that fetal alcohol spectrum disorders can be rooted very early in fetal brain development, and reinforce evidence-based counseling against binge drinking even at the earliest stages of pregnancy. PMID- 26245963 TI - Functional Connectivity of Insula, Basal Ganglia, and Prefrontal Executive Control Networks during Hypoglycemia in Type 1 Diabetes. AB - Human brain networks mediating interoceptive, behavioral, and cognitive aspects of glycemic control are not well studied. Using group independent component analysis with dual-regression approach of functional magnetic resonance imaging data, we examined the functional connectivity changes of large-scale resting state networks during sequential euglycemic-hypoglycemic clamp studies in patients with type 1 diabetes and nondiabetic controls and how these changes during hypoglycemia were related to symptoms of hypoglycemia awareness and to concurrent glycosylated hemoglobin (HbA1c) levels. During hypoglycemia, diabetic patients showed increased functional connectivity of the right anterior insula and the prefrontal cortex within the executive control network, which was associated with higher HbA1c. Controls showed decreased functional connectivity of the right anterior insula with the cerebellum/basal ganglia network and of temporal regions within the temporal pole network and increased functional connectivity in the default mode and sensorimotor networks. Functional connectivity reductions in the right basal ganglia were correlated with increases of self-reported hypoglycemic symptoms in controls but not in patients. Resting state networks that showed different group functional connectivity during hypoglycemia may be most sensitive to glycemic environment, and their connectivity patterns may have adapted to repeated glycemic excursions present in type 1 diabetes. Our results suggest that basal ganglia and insula mediation of interoceptive awareness during hypoglycemia is altered in type 1 diabetes. These changes could be neuroplastic adaptations to frequent hypoglycemic experiences. Functional connectivity changes in the insula and prefrontal cognitive networks could also reflect an adaptation to changes in brain metabolic pathways associated with chronic hyperglycemia. SIGNIFICANCE STATEMENT: The major factor limiting improved glucose control in type 1 diabetes is the significant increase in hypoglycemia associated with insulin treatment. Repeated exposure to hypoglycemia alters patients' ability to recognize the autonomic and neuroglycopenic symptoms associated with low plasma glucose levels. We examined brain resting state networks during the induction of hypoglycemia in diabetic and control subjects and found differences in networks involved in sensorimotor function, cognition, and interoceptive awareness that were related to chronic levels of glycemic control. These findings identify brain regions that are sensitive to variations in plasma glucose levels and may also provide a basis for understanding the mechanisms underlying the increased incidence of cognitive impairment and affective disorders seen in patients with diabetes. PMID- 26245964 TI - Synaptotagmin-7 Is Essential for Ca2+-Triggered Delayed Asynchronous Release But Not for Ca2+-Dependent Vesicle Priming in Retinal Ribbon Synapses. AB - Most synapses release neurotransmitters in two phases: (1) a fast synchronous phase lasting a few milliseconds; and (2) a delayed "asynchronous" phase lasting hundreds of milliseconds. Ca(2+) triggers fast synchronous neurotransmitter release by binding to synaptotagmin-1, synaptotagmin-2, or synaptotagmin-9, but how Ca(2+) triggers delayed asynchronous release has long remained enigmatic. Recent results suggested that consistent with the Ca(2+)-sensor function of synaptotagmin-7 in neuroendocrine exocytosis, synaptotagmin-7 also functions as a Ca(2+) sensor for synaptic vesicle exocytosis but operates during delayed asynchronous release. Puzzlingly, a subsequent study postulated that synaptotagmin-7 is not a Ca(2+) sensor for release but mediates Ca(2+)-dependent vesicle repriming after intense stimulation. To address these issues, we here analyzed synaptic transmission at rod bipolar neuron-AII amacrine cell synapses in acute mouse retina slices as a model system. Using paired recordings, we show that knock-out of synaptotagmin-7 selectively impairs delayed asynchronous release but not fast synchronous release. Delayed asynchronous release was blocked in wild-type synapses by intracellular addition of high concentrations of the slow Ca(2+)-chelator EGTA, but EGTA had no effect in synaptotagmin-7 knock out neurons because delayed asynchronous release was already impaired. Moreover, direct measurements of vesicle repriming failed to uncover an effect of the synaptotagmin-7 knock-out on vesicle repriming. Our data demonstrate that synaptotagmin-7 is selectively essential for Ca(2+)-dependent delayed asynchronous release in retinal rod bipolar cell synapses, that its function can be blocked by simply introducing a slow Ca(2+) buffer into the cells, and that synaptotagmin-7 is not required for normal vesicle repriming. SIGNIFICANCE STATEMENT: How Ca(2+) triggers delayed asynchronous release has long remained enigmatic. Synaptotagmin-7 has been implicated recently as Ca(2+) sensor in mediating delayed asynchronous release, or vesicle repriming, in cultured neurons. To test the precise function of synaptotagmin-7 in a physiologically important synapse in situ, we have used pair recordings to study the synaptic transmission between retinal rod bipolar cells and AII amacrine cells. Our data demonstrate that the knock-out of synaptotagmin-7 selectively impaired delayed asynchronous release but not synchronous release. In contrast, the readily releasable vesicles after depletion recover normally in knock-out mice. Therefore, our findings extend our knowledge of synaptotagmins as Ca(2+) sensors in vesicle fusion and support the idea that synapses are governed universally by different synaptotagmin Ca(2+) sensors mediating distinct release. PMID- 26245965 TI - The Effect of Body Posture on Brain Glymphatic Transport. AB - The glymphatic pathway expedites clearance of waste, including soluble amyloid beta (Abeta) from the brain. Transport through this pathway is controlled by the brain's arousal level because, during sleep or anesthesia, the brain's interstitial space volume expands (compared with wakefulness), resulting in faster waste removal. Humans, as well as animals, exhibit different body postures during sleep, which may also affect waste removal. Therefore, not only the level of consciousness, but also body posture, might affect CSF-interstitial fluid (ISF) exchange efficiency. We used dynamic-contrast-enhanced MRI and kinetic modeling to quantify CSF-ISF exchange rates in anesthetized rodents' brains in supine, prone, or lateral positions. To validate the MRI data and to assess specifically the influence of body posture on clearance of Abeta, we used fluorescence microscopy and radioactive tracers, respectively. The analysis showed that glymphatic transport was most efficient in the lateral position compared with the supine or prone positions. In the prone position, in which the rat's head was in the most upright position (mimicking posture during the awake state), transport was characterized by "retention" of the tracer, slower clearance, and more CSF efflux along larger caliber cervical vessels. The optical imaging and radiotracer studies confirmed that glymphatic transport and Abeta clearance were superior in the lateral and supine positions. We propose that the most popular sleep posture (lateral) has evolved to optimize waste removal during sleep and that posture must be considered in diagnostic imaging procedures developed in the future to assess CSF-ISF transport in humans. SIGNIFICANCE STATEMENT: The rodent brain removes waste better during sleep or anesthesia compared with the awake state. Animals exhibit different body posture during the awake and sleep states, which might affect the brain's waste removal efficiency. We investigated the influence of body posture on brainwide transport of inert tracers of anesthetized rodents. The major finding of our study was that waste, including Abeta, removal was most efficient in the lateral position (compared with the prone position), which mimics the natural resting/sleeping position of rodents. Although our finding awaits testing in humans, we speculate that the lateral position during sleep has advantage with regard to the removal of waste products including Abeta, because clinical studies have shown that sleep drives Abeta clearance from the brain. PMID- 26245966 TI - Oligophrenin-1 Connects Exocytotic Fusion to Compensatory Endocytosis in Neuroendocrine Cells. AB - Oligophrenin-1 (OPHN1) is a protein with multiple domains including a Rho family GTPase-activating (Rho-GAP) domain, and a Bin-Amphiphysin-Rvs (BAR) domain. Involved in X-linked intellectual disability, OPHN1 has been reported to control several synaptic functions, including synaptic plasticity, synaptic vesicle trafficking, and endocytosis. In neuroendocrine cells, hormones and neuropeptides stored in large dense core vesicles (secretory granules) are released through calcium-regulated exocytosis, a process that is tightly coupled to compensatory endocytosis, allowing secretory granule recycling. We show here that OPHN1 is expressed and mainly localized at the plasma membrane and in the cytosol in chromaffin cells from adrenal medulla. Using carbon fiber amperometry, we found that exocytosis is impaired at the late stage of membrane fusion in Ophn1 knock out mice and OPHN1-silenced bovine chromaffin cells. Experiments performed with ectopically expressed OPHN1 mutants indicate that OPHN1 requires its Rho-GAP domain to control fusion pore dynamics. On the other hand, compensatory endocytosis assessed by measuring dopamine-beta-hydroxylase (secretory granule membrane) internalization is severely inhibited in Ophn1 knock-out chromaffin cells. This inhibitory effect is mimicked by the expression of a truncated OPHN1 mutant lacking the BAR domain, demonstrating that the BAR domain implicates OPHN1 in granule membrane recapture after exocytosis. These findings reveal for the first time that OPHN1 is a bifunctional protein that is able, through distinct mechanisms, to regulate and most likely link exocytosis to compensatory endocytosis in chromaffin cells. PMID- 26245967 TI - Inositol Hexakisphosphate Kinase-3 Regulates the Morphology and Synapse Formation of Cerebellar Purkinje Cells via Spectrin/Adducin. AB - The inositol hexakisphosphate kinases (IP6Ks) are the principal enzymes that generate inositol pyrophosphates. There are three IP6Ks (IP6K1, 2, and 3). Functions of IP6K1 and IP6K2 have been substantially delineated, but little is known of IP6K3's role in normal physiology, especially in the brain. To elucidate functions of IP6K3, we generated mice with targeted deletion of IP6K3. We demonstrate that IP6K3 is highly concentrated in the brain in cerebellar Purkinje cells. IP6K3 physiologically binds to the cytoskeletal proteins adducin and spectrin, whose mutual interactions are perturbed in IP6K3-null mutants. Consequently, IP6K3 knock-out cerebella manifest abnormalities in Purkinje cell structure and synapse number, and the mutant mice display deficits in motor learning and coordination. Thus, IP6K3 is a major determinant of cytoskeletal disposition and function of cerebellar Purkinje cells. SIGNIFICANCE STATEMENT: We identified and cloned a family of three inositol hexakisphosphate kinases (IP6Ks) that generate the inositol pyrophosphates, most notably 5-diphosphoinositol pentakisphosphate (IP7). Of these, IP6K3 has been least characterized. In the present study we generated IP6K3 knock-out mice and show that IP6K3 is highly expressed in cerebellar Purkinje cells. IP6K3-deleted mice display defects of motor learning and coordination. IP6K3-null mice manifest aberrations of Purkinje cells with a diminished number of synapses. IP6K3 interacts with the cytoskeletal proteins spectrin and adducin whose altered disposition in IP6K3 knock-out mice may mediate phenotypic features of the mutant mice. These findings afford molecular/cytoskeletal mechanisms by which the inositol polyphosphate system impacts brain function. PMID- 26245968 TI - Expressing Constitutively Active Rheb in Adult Neurons after a Complete Spinal Cord Injury Enhances Axonal Regeneration beyond a Chondroitinase-Treated Glial Scar. AB - After a spinal cord injury (SCI), CNS axons fail to regenerate, resulting in permanent deficits. This is due to: (1) the presence of inhibitory molecules, e.g., chondroitin sulfate proteoglycans (CSPG), in the glial scar at the lesion; and (2) the diminished growth capacity of adult neurons. We sought to determine whether expressing a constitutively active form of the GTPase Rheb (caRheb) in adult neurons after a complete SCI in rats improves intrinsic growth potential to result in axon regeneration out of a growth-supportive peripheral nerve grafted (PNG) into the SCI cavity. We also hypothesized that treating the glial scar with chondroitinase ABC (ChABC), which digests CSPG, would further allow caRheb transduced neurons to extend axons across the distal graft interface. We found that targeting this pathway at a clinically relevant post-SCI time point improves both sprouting and regeneration of axons. CaRheb increased the number of axons, but not the number of neurons, that projected into the PNG, indicative of augmented sprouting. We also saw that caRheb enhanced sprouting far rostral to the injury. CaRheb not only increased growth rostral and into the graft, it also resulted in significantly more regrowth of axons across a ChABC-treated scar into caudal spinal cord. CaRheb(+) neurons had higher levels of growth-associated-43, suggestive of a newly identified mechanism for mTOR-mediated enhancement of regeneration. Thus, we demonstrate for the first time that simultaneously addressing intrinsic and scar-associated, extrinsic impediments to regeneration results in significant regrowth beyond an extremely challenging, complete SCI site. SIGNIFICANCE STATEMENT: After spinal cord injury (SCI), CNS axons fail to regenerate, resulting in permanent deficits. This is due to the diminished growth capacity of adult neurons and the presence of inhibitory molecules in the scar at the lesion. We sought to simultaneously counter both of these obstacles to achieve more robust regeneration after complete SCI. We transduced neurons postinjury to express a constitutively active Rheb to enhance their intrinsic growth potential, transplanted a growth supporting peripheral nerve graft into the lesion cavity, and enzymatically modulated the inhibitory glial scar distal to the graft. We demonstrate, for the first time, that simultaneously addressing neuron-related, intrinsic deficits in axon regrowth and extrinsic, scar associated impediments to regeneration results in significant regeneration after SCI. PMID- 26245969 TI - Synaptic Basis for Differential Orientation Selectivity between Complex and Simple Cells in Mouse Visual Cortex. AB - In the primary visual cortex (V1), orientation-selective neurons can be categorized into simple and complex cells primarily based on their receptive field (RF) structures. In mouse V1, although previous studies have examined the excitatory/inhibitory interplay underlying orientation selectivity (OS) of simple cells, the synaptic bases for that of complex cells have remained obscure. Here, by combining in vivo loose-patch and whole-cell recordings, we found that complex cells, identified by their overlapping on/off subfields, had significantly weaker OS than simple cells at both spiking and subthreshold membrane potential response levels. Voltage-clamp recordings further revealed that although excitatory inputs to complex and simple cells exhibited a similar degree of OS, inhibition in complex cells was more narrowly tuned than excitation, whereas in simple cells inhibition was more broadly tuned than excitation. The differential inhibitory tuning can primarily account for the difference in OS between complex and simple cells. Interestingly, the differential synaptic tuning correlated well with the spatial organization of synaptic input: the inhibitory visual RF in complex cells was more elongated in shape than its excitatory counterpart and also was more elongated than that in simple cells. Together, our results demonstrate that OS of complex and simple cells is differentially shaped by cortical inhibition based on its orientation tuning profile relative to excitation, which is contributed at least partially by the spatial organization of RFs of presynaptic inhibitory neurons. SIGNIFICANCE STATEMENT: Simple and complex cells, two classes of principal neurons in the primary visual cortex (V1), are generally thought to be equally selective for orientation. In mouse V1, we report that complex cells, identified by their overlapping on/off subfields, has significantly weaker orientation selectivity (OS) than simple cells. This can be primarily attributed to the differential tuning selectivity of inhibitory synaptic input: inhibition in complex cells is more narrowly tuned than excitation, whereas in simple cells inhibition is more broadly tuned than excitation. In addition, there is a good correlation between inhibitory tuning selectivity and the spatial organization of inhibitory inputs. These complex and simple cells with differential degree of OS may provide functionally distinct signals to different downstream targets. PMID- 26245970 TI - Glutamate Receptors in the Central Nucleus of the Amygdala Mediate Cisplatin Induced Malaise and Energy Balance Dysregulation through Direct Hindbrain Projections. AB - Cisplatin chemotherapy is used commonly to treat a variety of cancers despite severe side effects such as nausea, vomiting, and anorexia that compromise quality of life and limit treatment adherence. The neural mechanisms mediating these side effects remain elusive despite decades of clinical use. Recent data highlight the dorsal vagal complex (DVC), lateral parabrachial nucleus (lPBN), and central nucleus of the amygdala (CeA) as potential sites of action in mediating the side effects of cisplatin. Here, results from immunohistochemical studies in rats identified a population of cisplatin-activated DVC neurons that project to the lPBN and a population of cisplatin-activated lPBN calcitonin gene related peptide (CGRP, a marker for glutamatergic neurons in the lPBN) neurons that project to the CeA, outlining a neuroanatomical circuit that is activated by cisplatin. CeA gene expressions of AMPA and NMDA glutamate receptor subunits were markedly increased after cisplatin treatment, suggesting that CeA glutamate receptor signaling plays a role in mediating cisplatin side effects. Consistent with gene expression results, behavioral/pharmacological data showed that CeA AMPA/kainate receptor blockade attenuates cisplatin-induced pica (a proxy for nausea/behavioral malaise in nonvomiting laboratory rodents) and that CeA NMDA receptor blockade attenuates cisplatin-induced anorexia and body weight loss in addition to pica, demonstrating that glutamate receptor signaling in the CeA is critical for the energy balance dysregulation caused by cisplatin treatment. Together, these data highlight a novel circuit and CGRP/glutamatergic mechanism through which cisplatin-induced malaise and energy balance dysregulation are mediated. SIGNIFICANCE STATEMENT: To treat cancer effectively, patients must follow prescribed chemotherapy treatments without interruption, yet most cancer treatments produce side effects that devastate quality of life (e.g., nausea, vomiting, anorexia, weight loss). Although hundreds of thousands of patients undergo chemotherapies each year, the neural mechanisms mediating their side effects are unknown. The current data outline a neural circuit activated by cisplatin chemotherapy and demonstrate that glutamate signaling in the amygdala, arising from hindbrain projections, is required for the full expression of cisplatin-induced malaise, anorexia, and body weight loss. Together, these data help to characterize the neural circuits and neurotransmitters mediating chemotherapy-induced energy balance dysregulation, which will ultimately provide an opportunity for the development of well tolerated cancer and anti-emetic treatments. PMID- 26245972 TI - Intrahippocampal Anisomycin Impairs Spatial Performance on the Morris Water Maze. AB - New memories are thought to be solidified (consolidated) by de novo synthesis of proteins in the period subsequent to learning. This view stems from the observation that protein synthesis inhibitors, such as anisomycin (ANI), administered during this consolidation period cause memory impairments. However, in addition to blocking protein synthesis, intrahippocampal infusions of ANI cause the suppression of evoked and spontaneous neural activity, suggesting that ANI could impair memory expression by simply preventing activity-dependent brain functions. Here, we evaluated the influence of intrahippocampal ANI infusions on allocentric spatial navigation using the Morris water maze, a task well known to require dorsal hippocampal integrity. Young, adult male Sprague Dawley rats were implanted with bilateral dorsal hippocampal cannulae, and their ability to learn the location of a hidden platform was assessed before and following infusions of ANI, TTX, or vehicle (PBS). Before infusion, all groups demonstrated normal spatial navigation (training on days 1 and 2), whereas 30 min following infusions (day 3) both the ANI and TTX groups showed significant impairments in allocentric navigation, but not visually cued navigation, when compared with PBS-treated animals. Spatial navigational deficits appeared to resolve on day 4 in the ANI and TTX groups, 24 h following infusion. These results show that ANI and TTX inhibit the on-line function of the dorsal hippocampus in a similar fashion and highlight the importance of neural activity as an intervening factor between molecular and behavioral processes. SIGNIFICANCE STATEMENT: The permanence of memories has long thought to be mediated by the production of new proteins, because protein synthesis inhibitors can block retrieval of recently learned information. However, protein synthesis inhibitors may have additional detrimental effects on neurobiological function. Here we show that anisomycin, a commonly used protein synthesis inhibitor in memory research, impairs on-line brain function in a way similar to an agent that eliminates electrical neural activity. Since disruption of neural activity can also lead to memory loss, it may be that memory permanence is mediated by neural rehearsal following learning. PMID- 26245971 TI - Loss of Local Astrocyte Support Disrupts Action Potential Propagation and Glutamate Release Synchrony from Unmyelinated Hippocampal Axon Terminals In Vitro. AB - Neuron-astrocyte interactions are critical for proper CNS development and function. Astrocytes secrete factors that are pivotal for synaptic development and function, neuronal metabolism, and neuronal survival. Our understanding of this relationship, however, remains incomplete due to technical hurdles that have prevented the removal of astrocytes from neuronal circuits without changing other important conditions. Here we overcame this obstacle by growing solitary rat hippocampal neurons on microcultures that were comprised of either an astrocyte bed (+astrocyte) or a collagen bed (-astrocyte) within the same culture dish. Astrocyte autaptic evoked EPSCs, but not IPSCs, displayed an altered temporal profile, which included increased synaptic delay, increased time to peak, and severe glutamate release asynchrony, distinct from previously described quantal asynchrony. Although we observed minimal alteration of the somatically recorded action potential waveform, action potential propagation was altered. We observed a longer latency between somatic initiation and arrival at distal locations, which likely explains asynchronous EPSC peaks, and we observed broadening of the axonal spike, which likely underlies changes to evoked EPSC onset. No apparent changes in axon structure were observed, suggesting altered axonal excitability. In conclusion, we propose that local astrocyte support has an unappreciated role in maintaining glutamate release synchrony by disturbing axonal signal propagation. SIGNIFICANCE STATEMENT: Certain glial cell types (oligodendrocytes, Schwann cells) facilitate the propagation of neuronal electrical signals, but a role for astrocytes has not been identified despite many other functions of astrocytes in supporting and modulating neuronal signaling. Under identical global conditions, we cultured neurons with or without local astrocyte support. Without local astrocytes, glutamate transmission was desynchronized by an alteration of the waveform and arrival time of axonal action potentials to synaptic terminals. GABA transmission was not disrupted. The disruption did not involve detectable morphological changes to axons of glutamate neurons. Our work identifies a developmental role for astrocytes in the temporal precision of excitatory signals. PMID- 26245974 TI - Opponent Identity Influences Value Learning in Simple Games. AB - Context plays a pivotal role in many decision-making scenarios, including social interactions wherein the identities and strategies of other decision makers often shape our behaviors. However, the neural mechanisms for tracking such contextual information are poorly understood. Here, we investigated how opponent identity affects human reinforcement learning during a simulated competitive game against two independent computerized opponents. We found that strategies of participants were affected preferentially by the outcomes of the previous interactions with the same opponent. In addition, reinforcement signals from the previous trial were less discriminable throughout the brain after the opponent changed, compared with when the same opponent was repeated. These opponent-selective reinforcement signals were particularly robust in right rostral anterior cingulate and right lingual regions, where opponent-selective reinforcement signals correlated with a behavioral measure of opponent-selective reinforcement learning. Therefore, when choices involve multiple contextual frames, such as different opponents in a game, decision making and its neural correlates are influenced by multithreaded histories of reinforcement. Overall, our findings are consistent with the availability of temporally overlapping, context-specific reinforcement signals. SIGNIFICANCE STATEMENT: In real-world decision making, context plays a strong role in determining the value of an action. Similar choices take on different values depending on setting. We examined the contextual dependence of reward based learning and reinforcement signals using a simple two-choice matching pennies game played by humans against two independent computer opponents that were randomly interleaved. We found that human subjects' strategies were highly dependent on opponent context in this game, a fact that was reflected in select brain regions' activity (rostral anterior cingulate and lingual cortex). These results indicate that human reinforcement histories are highly dependent on contextual factors, a fact that is reflected in neural correlates of reinforcement signals. PMID- 26245973 TI - Inhibition of Group I Metabotropic Glutamate Receptors Reverses Autistic-Like Phenotypes Caused by Deficiency of the Translation Repressor eIF4E Binding Protein 2. AB - Exacerbated mRNA translation during brain development has been linked to autism spectrum disorders (ASDs). Deletion of the eukaryotic initiation factor 4E (eIF4E)-binding protein 2 gene (Eif4ebp2), encoding the suppressor of mRNA translation initiation 4E-BP2, leads to an imbalance in excitatory-to-inhibitory neurotransmission and ASD-like behaviors. Inhibition of group I metabotropic glutamate receptors (mGluRs) mGluR1 and mGluR5 reverses the autistic phenotypes in several ASD mouse models. Importantly, these receptors control synaptic physiology via activation of mRNA translation. We investigated the potential reversal of autistic-like phenotypes in Eif4ebp2(-/-) mice by using antagonists of mGluR1 (JNJ16259685) or mGluR5 (fenobam). Augmented hippocampal mGluR-induced long-term depression (LTD; or chemically induced mGluR-LTD) in Eif4ebp2(-/-) mice was rescued by mGluR1 or mGluR5 antagonists. While rescue by mGluR5 inhibition occurs through the blockade of a protein synthesis-dependent component of LTD, normalization by mGluR1 antagonists requires the activation of protein synthesis. Synaptically induced LTD was deficient in Eif4ebp2(-/-) mice, and this deficit was not rescued by group I mGluR antagonists. Furthermore, a single dose of mGluR1 (0.3 mg/kg) or mGluR5 (3 mg/kg) antagonists in vivo reversed the deficits in social interaction and repetitive behaviors (marble burying) in Eif4ebp2(-/-) mice. Our results demonstrate that Eif4ebp2(-/-) mice serve as a relevant model to test potential therapies for ASD symptoms. In addition, we provide substantive evidence that the inhibition of mGluR1/mGluR5 is an effective treatment for physiological and behavioral alterations caused by exacerbated mRNA translation initiation. SIGNIFICANCE STATEMENT: Exacerbated mRNA translation during brain development is associated with several autism spectrum disorders (ASDs). We recently demonstrated that the deletion of a negative regulator of mRNA translation initiation, the eukaryotic initiation factor 4E-binding protein 2, leads to ASD-like behaviors and increased excitatory synaptic activity. Here we demonstrated that autistic behavioral and electrophysiological phenotypes can be treated in adult mice with antagonists of group I metabotropic glutamate receptors (mGluRs), which have been previously used in other ASD models (i.e., fragile X syndrome). These findings support the use of group I mGluR antagonists as a potential therapy that extends to autism models involving exacerbated mRNA translation initiation. PMID- 26245975 TI - Neurotensin Induces Presynaptic Depression of D2 Dopamine Autoreceptor-Mediated Neurotransmission in Midbrain Dopaminergic Neurons. AB - Increased dopaminergic signaling is a hallmark of severe mesencephalic pathologies such as schizophrenia and psychostimulant abuse. Activity of midbrain dopaminergic neurons is under strict control of inhibitory D2 autoreceptors. Application of the modulatory peptide neurotensin (NT) to midbrain dopaminergic neurons transiently increases activity by decreasing D2 dopamine autoreceptor function, yet little is known about the mechanisms that underlie long-lasting effects. Here, we performed patch-clamp electrophysiology and fast-scan cyclic voltammetry in mouse brain slices to determine the effects of NT on dopamine autoreceptor-mediated neurotransmission. Application of the active peptide fragment NT8-13 produced synaptic depression that exhibited short- and long-term components. Sustained depression of D2 autoreceptor signaling required activation of the type 2 NT receptor and the protein phosphatase calcineurin. NT application increased paired-pulse ratios and decreased extracellular levels of somatodendritic dopamine, consistent with a decrease in presynaptic dopamine release. Surprisingly, we observed that electrically induced long-term depression of dopaminergic neurotransmission that we reported previously was also dependent on type 2 NT receptors and calcineurin. Because electrically induced depression, but not NT-induced depression, was blocked by postsynaptic calcium chelation, our findings suggest that endogenous NT may act through a local circuit to decrease presynaptic dopamine release. The current research provides a mechanism through which augmented NT release can produce a long-lasting increase in membrane excitability of midbrain dopamine neurons. SIGNIFICANCE STATEMENT: Whereas plasticity of glutamate synapses in the brain has been studied extensively, demonstrations of plasticity at dopaminergic synapses have been more elusive. By quantifying inhibitory neurotransmission between midbrain dopaminergic neurons in brain slices from mice we have discovered that the modulatory peptide neurotensin can induce a persistent synaptic depression by decreasing dopamine release. This depression of inhibitory synaptic input would be expected to increase excitability of dopaminergic neurons. Induction of the plasticity can be pharmacologically blocked by antagonists of either the protein phosphatase calcineurin or neurotensin receptors, and persists surprisingly long after a brief exposure to the peptide. Since neurotensin-dopamine interactions have been implicated in hyperdopaminergic pathologies, these findings describe a synaptic mechanism that could contribute to addiction and/or schizophrenia. PMID- 26245976 TI - Mechanosensory Genes Pkd1 and Pkd2 Contribute to the Planar Polarization of Brain Ventricular Epithelium. AB - Directional beating of ependymal (E) cells' cilia in the walls of the ventricles in the brain is essential for proper CSF flow. E cells display two forms of planar cell polarity (PCP): rotational polarity of individual cilium and translational polarity (asymmetric positioning of cilia in the apical area). The orientation of individual E cells varies according to their location in the ventricular wall (location-specific PCP). It has been hypothesized that hydrodynamic forces on the apical surface of radial glia cells (RGCs), the embryonic precursors of E cells, could guide location-specific PCP in the ventricular epithelium. However, the detection mechanisms for these hydrodynamic forces have not been identified. Here, we show that the mechanosensory proteins polycystic kidney disease 1 (Pkd1) and Pkd2 are present in primary cilia of RGCs. Ablation of Pkd1 or Pkd2 in Nestin-Cre;Pkd1(flox/flox) or Nestin Cre;Pkd2(flox/flox) mice, affected PCP development in RGCs and E cells. Early shear forces on the ventricular epithelium may activate Pkd1 and Pkd2 in primary cilia of RGCs to properly polarize RGCs and E cells. Consistently, Pkd1, Pkd2, or primary cilia on RGCs were required for the proper asymmetric localization of the PCP protein Vangl2 in E cells' apical area. Analyses of single- and double heterozygous mutants for Pkd1 and/or Vangl2 suggest that these genes function in the same pathway to establish E cells' PCP. We conclude that Pkd1 and Pkd2 mechanosensory proteins contribute to the development of brain PCP and prevention of hydrocephalus. SIGNIFICANCE STATEMENT: This study identifies key molecules in the development of planar cell polarity (PCP) in the brain and prevention of hydrocephalus. Multiciliated ependymal (E) cells within the brain ventricular epithelium generate CSF flow through ciliary beating. E cells display location specific PCP in the orientation and asymmetric positioning of their cilia. Defects in this PCP can result in hydrocephalus. Hydrodynamic forces on radial glial cells (RGCs), the embryonic progenitors of E cells, have been suggested to guide PCP. We show that the mechanosensory proteins Pkd1 and Pkd2 localize to primary cilia in RGCs, and their ablation disrupts the development of PCP in E cells. Early shear forces on RGCs may activate Pkd1 and Pkd2 in RGCs' primary cilia to properly orient E cells. This study identifies key molecules in the development of brain PCP and prevention of hydrocephalus. PMID- 26245977 TI - Mothers' Experiences with Pastoral Care in Cases of Child Sexual Abuse. AB - This article reports on case study research with four mothers who asked for help from their pastors when they learned, or had reason to believe, that their husbands had sexually abused children in their families. In their own words, mothers gave accounts of how the pastors responded. Some were helpful and knowledgeable, some appeared bewildered, and others were hostile and blaming toward the women. This article will sensitize pastors and other pastoral counselors to issues that child sexual abuse raises. In addition, the research responds to Mahoney's (J Marriage Fam 72:805-827, 2010) observations about the scarcity of knowledge on whether religion helps or harms families during times of stress. PMID- 26245978 TI - Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif. AB - Lens epithelium-derived growth factor (LEDGF/p75) is an epigenetic reader and attractive therapeutic target involved in HIV integration and the development of mixed lineage leukaemia (MLL1) fusion-driven leukaemia. Besides HIV integrase and the MLL1-menin complex, LEDGF/p75 interacts with various cellular proteins via its integrase binding domain (IBD). Here we present structural characterization of IBD interactions with transcriptional repressor JPO2 and domesticated transposase PogZ, and show that the PogZ interaction is nearly identical to the interaction of LEDGF/p75 with MLL1. The interaction with the IBD is maintained by an intrinsically disordered IBD-binding motif (IBM) common to all known cellular partners of LEDGF/p75. In addition, based on IBM conservation, we identify and validate IWS1 as a novel LEDGF/p75 interaction partner. Our results also reveal how HIV integrase efficiently displaces cellular binding partners from LEDGF/p75. Finally, the similar binding modes of LEDGF/p75 interaction partners represent a new challenge for the development of selective interaction inhibitors. PMID- 26245979 TI - Survivors of gynecologic malignancies: impact of treatment on health and well being. AB - PURPOSE: While overall survival from gynecologic malignancies has greatly improved over the last three decades, required treatments can lead to multiple health issues for survivors. Our objective was to identify health concerns that gynecologic cancer survivors face. METHODS: A systematic, stratified sample of women with gynecologic malignancies was surveyed for 18 health issues occurring before, during, or after treatment. The impact of clinical features and treatment modality on health issues was assessed through multivariate logistic regression models. RESULTS: Of 2,546 surveys mailed, 622 were not received by eligible subjects secondary to invalid address, incorrect diagnosis, or death. Thus, 1924 survivors potentially received surveys. Of the 1,029 surveys (53.5%) completed, median age was 59 years; diagnoses included 29% cervical, 26% endometrial, 26% ovarian/primary peritoneal/fallopian tube, 12.1% vulvar, and 5.4% vaginal cancers. The most frequently reported health issues included fatigue (60.6%), sleep disturbance (54.9%), urinary difficulties (50.9%), sexual dysfunction (48.4%), neurologic issues (45.4%), bowel complaints (42.0%), depression (41.3%), and memory problems (41.2%). These rankings were consistent with patients' self reported rankings of "highest impact" personal issues. After controlling for demographic and clinical variables, multivariate analyses revealed that treatment modality impacted the odds of experiencing a given health issue. CONCLUSIONS: Our study demonstrates that gynecologic cancer survivors experience a high frequency of health conditions and highlights the association between treatment modality and specific health concerns. IMPLICATIONS FOR CANCER SURVIVORS: The study findings highlight the multiple health concerns experienced by gynecologic cancer survivors and suggest the potential for developing interventions to mitigate these concerns in survivorship. PMID- 26245980 TI - Highly luminescent charge-neutral europium(iii) and terbium(iii) complexes with tridentate nitrogen ligands. AB - We report on the synthesis of tridentate-nitrogen pyrazole-pyridine-tetrazole (L(1)H) and pyrazole-pyridine-triazole (L(2)H) ligands and their complexation with lanthanides (Ln = Gd(iii), Eu(iii) and Tb(iii)) resulting in stable, charge neutral complexes Ln(L(1))3 and Ln(L(2))3, respectively. X-ray crystallographic analysis of the complexes with L(1) ligands revealed tricapped trigonal coordination geometry around the lanthanide ions. All complexes show bright photoluminescence (PL) in the solid state, indicating efficient sensitization of the lanthanide emission via the triplet states of the ligands. In particular, the terbium complexes show high PL quantum yields of 65 and 59% for L(1) and L(2), respectively. Lower PL efficiencies of the europium complexes (7.5 and 9%, respectively) are attributed to large energy gaps between the triplet states of the ligands and accepting levels of Eu(iii). The triplet state energy can be reduced by introducing an electron withdrawing (EW) group at the 4 position of the pyridine ring. Such substitution of L(1)H with a carboxylic ester (COOMe) EW group leads to a europium complex with increased PL quantum yield of 31%. A comparatively efficient PL of the complexes dissolved in ethanol indicates that the lanthanide ions are shielded against nonradiative deactivation via solvent molecules. PMID- 26245981 TI - Is salt stress tolerance in Casuarina glauca Sieb. ex Spreng. associated with its nitrogen-fixing root-nodule symbiosis? An analysis at the photosynthetic level. AB - Casuarina glauca is an actinorhizal tree which establishes root-nodule symbiosis with N2-fixing Frankia bacteria. This plant is commonly found in saline zones and is widely used to remediate marginal soils and prevent desertification. The nature of its ability to survive in extreme environments and the extent of Frankia contribution to stress tolerance remain unknown. Thus, we evaluated the ability of C. glauca to cope with salt stress and the influence of the symbiosis on this trait. To this end, we analysed the impact of salt on plant growth, mineral contents, water relations, photosynthetic-related parameters and non structural sugars in nodulated vs. non-nodulated plants. Although the effects on photosynthesis and stomatal conductance started to become measurable in the presence of 200 mM NaCl, photochemical (e.g., photosynthetic electron flow) and biochemical (e.g., activity of photosynthetic enzymes) parameters were only strongly impaired when NaCl levels reached 600 mM. These results indicate the maintenance of high tissue hydration under salt stress, probably associated with enhanced osmotic potential. Furthermore, the maintenance of photosynthetic assimilation potential (A(max)), together with the increase in the quantum yield of down-regulated energy dissipation of PSII (Y(NPQ)), suggested a down regulation of photosynthesis instead of photo-damaging effects. A comparison of the impact of increasing NaCl levels on the activities of photosynthetic (RubisCO and ribulose-5 phosphate kinase) and respiratory (pyruvate kinase and NADH dependent malate dehydrogenase) enzymes vs. photosynthetic electron flow and fluorescence parameters, revealed that biochemical impairments are more limiting than photochemical damage. Altogether, these results indicate that, under controlled conditions, C. glauca tolerates high NaCl levels and that this capacity is linked to photosynthetic adjustments. PMID- 26245982 TI - Facile Synthesis of Carbon Nanosphere/NiCo2O4 Core-shell Sub-microspheres for High Performance Supercapacitor. AB - This paper introduced a process to prepare the carbon nanosphere (CNS)/NiCo2O4 core-shell sub-microspheres. That is: 1) CNSs were firstly prepared via a simple hydrothermal method; 2) a layer of NiCo2O4 precursor was coated on the CNS surface; 3) finally the composite was annealed at 350 degrees C for 2 hours in the air, and the CNS/NiCo2O4 core-shell sub-microspheres were obtained. This core shell sub-microsphere was prepared with a simple, economical and environmental friendly hydrothermal method, and was suitable for large-scale production, which expects a promising electrode candidate for high performance energy storage applications. Electrochemical experiments revealed that the composite exhibited remarkable electrochemical performances with high capacitance and desirable cycle life at high rates, such as: 1) the maximum specific capacitance was up to 1420 F/g at 1 A/g; 2) about 98.5% of the capacitance retained after 3000 charge discharge cycles; 3) the capacitance retention was about 72% as the current density increase from 1 A/g to 10 A/g. PMID- 26245983 TI - Crystal structures of Mycobacterium tuberculosis GlgE and complexes with non covalent inhibitors. AB - GlgE is a bacterial maltosyltransferase that catalyzes the elongation of a cytosolic, branched alpha-glucan. In Mycobacterium tuberculosis (M. tb), inactivation of GlgE (Mtb GlgE) results in the rapid death of the organism due to a toxic accumulation of the maltosyl donor, maltose-1-phosphate (M1P), suggesting that GlgE is an intriguing target for inhibitor design. In this study, the crystal structures of the Mtb GlgE in a binary complex with maltose and a ternary complex with maltose and a maltosyl-acceptor molecule, maltohexaose, were solved to 3.3 A and 4.0 A, respectively. The maltohexaose structure reveals a dominant site for alpha-glucan binding. To obtain more detailed interactions between first generation, non-covalent inhibitors and GlgE, a variant Streptomyces coelicolor GlgEI (Sco GlgEI-V279S) was made to better emulate the Mtb GlgE M1P binding site. The structure of Sco GlgEI-V279S complexed with alpha-maltose-C-phosphonate (MCP), a non-hydrolyzable substrate analogue, was solved to 1.9 A resolution, and the structure of Sco GlgEI-V279S complexed with 2,5-dideoxy-3-O-alpha-D glucopyranosyl-2,5-imino-D-mannitol (DDGIM), an oxocarbenium mimic, was solved to 2.5 A resolution. These structures detail important interactions that contribute to the inhibitory activity of these compounds, and provide information on future designs that may be exploited to improve upon these first generation GlgE inhibitors. PMID- 26245984 TI - [Whole-body ferromagnetic detector systems in clinical MRI]. AB - CLINICAL/METHODICAL ISSUE: In spite of technical and organizational measures, ferromagnetic objects still find their way into the magnetic resonance imaging (MRI) room and can cause severe injuries. STANDARD RADIOLOGICAL METHODS: A detailed patient education and MRI safety training for personnel are necessary to avoid MRI incidents with ferromagnetic objects. METHODICAL INNOVATIONS: Whole body ferromagnetic detection systems should increase patient safety and minimize risks for personnel and MRI equipment in the clinical routine. PERFORMANCE: In a clinical MRI setting, a screener system used for outpatients and inpatients (n = 400) identified unknown ferrous objects in 2 % of the cases. In two of these cases patients were found to be in possession of unknown foreign ferrous objects. Furthermore, a door guard system only used for outpatients (n = 2500) detected unknown ferromagnetic objects in 0.3 % of the cases. ACHIEVEMENTS: The number of ferrous objects that are unknowingly brought into the scanner room can be reduced with a whole body ferromagnetic detection system. For an optimal benefit of the system a ferrous-free environment and perfectly ferrous-free clothing for the medical personnel are necessary. In the clinical routine, the benefit of the system is limited particularly for immobile patients who have to remain in a horizontal position. PRACTICAL RECOMMENDATIONS: A whole body ferromagnetic detection system can complement but not replace patient education and MRI safety training. PMID- 26245985 TI - [Radiation dose in cerebral angiography and flat detector CT applications in neuroradiology]. AB - Flat detectors (FD) have completely replaced image intensifiers in angiography. Due to this development not only the image quality of 2D digital subtraction angiography series (2-D-DSA) could be improved but also the acquisition of computed tomography (CT)-like cross-sectional images (FD-CT) within the angio suite became feasible. These techniques are now being used in daily clinical routine. Only little information about effective doses of these applications to patients has been published in the literature. We describe the effective patient dose of current applications in the field of angiography and demonstrate strategies to minimize the dose to the patient. In addition, we compare FD-CT applications to standard multislice CT applications. PMID- 26245986 TI - [fMRI and DTI in delayed development of number processing]. AB - The neuronal correlate of the current cultural performance arose from developmental processes that can be observed by functional and anatomical magnetic resonance imaging. The velocity of these maturation processes occurs differently between adolescents, causing implications for both school career and academic performance. Regarding spatial-numerical cognition the myelinization of the superior longitudinal bundle appears to be crucial because this fiber connection intermediates between the linguistic nature of number words and conception of their spatial-numerical magnitude. The neuroscientific observation of anatomical brain maturation and its influence on school-relevant number processing may be helpful for educational purposes as well as for school psychology. PMID- 26245987 TI - Increased risk of venous thromboembolism in patients with bullous pemphigoid. The INVENTEP (INcidence of VENous ThromboEmbolism in bullous Pemphigoid) study. AB - Activation of blood coagulation has been demonstrated in bullous pemphigoid (BP), a rare autoimmune blistering disease, potentially leading to a prothrombotic state. In order to evaluate the incidence of venous thromboembolism (VTE) in BP, a cohort study was carried out on 432 BP patients (59% females; median age 76 years, interquartile range [IQR]: 68-82). At diagnosis, autoimmune bullous skin disorder intensity score (ABSIS) was calculated. VTE incidence was standardised with rates of the general population. Multivariable Cox proportional hazard model was used to estimate the hazard ratio of VTE according to ABSIS and concomitant risk factors. During a median follow-up of 4.2 years, 31 objectively-diagnosed VTE events were recorded. The incidence rate of VTE (per 1000 patient-years) was 17.2 overall (95% confidence interval [CI]: 11.1-23.2), 56.7 (95%CI: 33.0-80.4) during acute phase (22 VTE) and 6.3 (95%CI: 2.8-11.3) during remission (9 VTE). The standardised incidence ratio was 4.06 (95%CI: 2.73-5.65), higher during the acute phase (14.86, 95%CI: 9.20-21.88) than during remission (1.48, 0.66-2.63). The adjusted hazard ratio of VTE was 2.74 (95%CI: 1.07-7.04) for ABSIS > 48 vs ABSIS < 28, and 2.56 (95%CI: 1.00-6.70) in patients with >= 2 concomitant risk factors. In conclusion, BP patients have a 15-fold increased VTE risk during acute phase, proportional to disease severity and heightened by concomitant risk factors. PMID- 26245988 TI - Resonance-assisted stabilisation of hydrogen bonds probed by NMR spectroscopy and path integral molecular dynamics. AB - Path integral molecular dynamics and experimental NMR data are used to investigate resonance-assisted hydrogen bonds (RAHBs). When nuclear delocalisation is included in chemical shift calculations, the agreement with experiment is excellent, while static calculations show very poor performance. The results support the concept of RAHB, which has recently been questioned. PMID- 26245989 TI - Does an increase in modularity improve the outcomes of total shoulder replacement? Comparison across design generations. AB - BACKGROUND/PURPOSE: Modularity in total shoulder arthroplasty (TSA) has increased over the past 30 years. Our institution previously showed shoulders treated with modular humeral head/stem arthroplasties had similar outcomes to monoblock designs. Presently, we aim to update clinical follow-up of 2nd generation TSAs and assess how increased modularity affects early outcomes and survivorship across three generations of implants. MATERIALS AND METHODS: Between 1997 and 2001, 75 second generation modular TSA's were performed for primary osteoarthritis. Shoulders were followed for a minimum of 2 years or until reoperation, mean 7.4 years. Results were compared with first generation monoblock TSAs and third generation TSAs which offered multiple humeral head shape options to more precisely replicate patient anatomy. RESULTS: Second generation TSAs continue to show significant improvements in pain, elevation and external rotation: 90 % of shoulders were subjectively better at follow-up. Survivorship was estimated to be 89.0 % at 10 years. All generations showed similar pain relief, and improved range of motion and Neer ratings. Survivorship among the 3 groups was similar at 5 years but was estimated to be higher in the 1st generation group at 7 years. More glenoids were radiographically at risk in the 2nd and 3rd generation groups than in the 1st; however, this did not reach significance. INTERPRETATION: With extended mid-term follow-up, second generation anatomic TSA continues to provide improvements in pain and range of motion for primary OA. Implant modularity can facilitate surgery, but similar clinical outcomes can be expected regardless of modularity. LEVEL OF EVIDENCE: Level IV, Treatment study. PMID- 26245990 TI - A comprehensive analysis of CDC20 overexpression in common malignant tumors from multiple organs: its correlation with tumor grade and stage. AB - High expression of cell division cycle 20 homolog (CDC20), a key component of the spindle assembly checkpoint (SAC), has been reported in various malignancies and plays a vital role in tumorigenesis and progression. The goal of this study was to evaluate the utility of CDC20 immunostaining in a wide range of malignant tumors. CDC20 immunohistochemistry was evaluated in normal tissues and compared to the most frequently occurring malignant tumors in these tissues (bladder, breast, cervical, colonic, endometrial, gastric, head and neck, liver, lung, ovarian, pancreatic, prostatic, renal, thyroid carcinomas, and testicular seminoma). Normal/non-neoplastic tissues showed positive CDC20 expression in 19.44 % of all examined cases. CDC20 staining was negative in normal and non neoplastic tissues from the bladder, cervix, liver, stomach, and thyroid. From the all malignant tumors examined 55.7 % showed high CDC20 expression while low expression was found in 44.3 %. High expression of CDC20 was associated with high tumor grade in the bladder (p = 0.027), cervical (p = 0.032), colonic (p = 0.026), endometrial (p = 0.016), gastric (p = 0.033), liver (p = 0.028), ovarian (p = 0.044), prostatic (p = 0.040), and renal (p = 0.048) carcinomas. There was a significant correlation between high CDC20 expression and advanced tumor stage in carcinoma of the breast, colon, endometrium, and prostate (p = 0.021, p = 0.040, p = 0.047, p = 0.031, respectively). CDC20 expression may be useful as a biomarker of tumor prognosis and as a therapeutic target of human cancer. PMID- 26245991 TI - AFAP1-AS1, a long noncoding RNA upregulated in lung cancer and promotes invasion and metastasis. AB - Long noncoding RNAs (lncRNAs) have emerged as a major regulator of cancer. Significant fraction of lncRNAs is represented on widely used microarray platforms; however, many of which have no known function. To discover novel lung cancer-related lncRNAs, we analyzed the lncRNA expression patterns in five sets of previously published lung cancer gene expression profile data that were represented on Affymetrix HG-U133 Plus 2.0 array, and identified dysregulated lncRNAs in lung cancer. One lncRNA, actin filament associated protein 1 antisense RNA1 (AFAP1-AS1), was the most significantly upregulated in lung cancer and associated with poor prognosis. In vitro experiments demonstrated that AFAP1-AS1 knockdown significantly inhibited the cell invasive and migration capability in lung cancer cells. AFAP1-AS1 knockdown also increased the expression of its antisense protein coding gene, actin filament associated protein 1 (AFAP1), and affected the expression levels of several small GTPase family members and molecules in the actin cytokeratin signaling pathway, which suggested that AFAP1 AS1 promoted cancer cell metastasis via regulation of actin filament integrity. Our findings extend the number of noncoding RNAs functionally implicated in lung cancer progression and highlight the role of AFAP1-AS1 as potential prognostic biomarker and therapeutic target of lung cancer. PMID- 26245992 TI - UBE2S is associated with malignant characteristics of breast cancer cells. AB - Ubiquitination is essential for various biological processes, such as signal transduction, intracellular trafficking, and protein degradation. Accumulating evidence has demonstrated that ubiquitination plays a crucial role in cancer development. In this report, we examine the expression and function of ubiquitin conjugating enzyme E2S (UBE2S) in breast cancer. Immunohistochemical analysis revealed that UBE2S is highly expressed in breast cancer. The depletion of UBE2S by siRNA induced disruption of the actin cytoskeleton and focal adhesions. Interestingly, phosphorylation of FAK at Tyr397, which is important for the transduction of integrin-mediated signaling, was significantly reduced by UBE2S knockdown. We also show that UBE2S knockdown suppressed the malignant characteristics of breast cancer cells, such as migration, invasion, and anchorage-independent growth. Our results indicate that UBE2S could be a potential target for breast cancer treatment. PMID- 26245993 TI - Survivin splice variants and their diagnostic significance. AB - Survivin plays a crucial role in cell division particularly during the development of the fetus, in the onset and progression of most tumors and is found expressed in a few terminally differentiated cells. Altogether, there are ten splice variants of survivin, some of which are not yet satisfactorily characterized. Several isoforms may undergo homo/heterodimerization, particularly with the wild-type survivin to elicit a variety of biological functions. The detection of survivin and its splice variants not only suggests the onset, maintenance, and progression of cancer, but also the stage of certain cancers. Recent studies demonstrate that the presence of survivin in urine and blood samples of patients may suggest urogenital and bladder cancer hematologic malignancies, respectively. The expression of the survivin-3alpha splice variant is indicative of the onset and progression of breast cancer. Several companies have developed cancer diagnostic kits using survivin for detection of cancer. Some are also engaged in fine-tuning the type and stage-specific diagnosis of cancer based on survivin, its splice variants with and without other markers, such as hyaluronidase. Briefly, survivin and its splice variants hold a great biological significance, particularly in the diagnosis of cancer. PMID- 26245994 TI - Staphylococcal enterotoxin B/texosomes as a candidate for breast cancer immunotherapy. AB - A new recombinant construct made up of two components, texosomes (TEX) and staphylococcal enterotoxin B (SEB), showed cytostatic properties against several types of tumor cells in vitro. Here, we aimed to assess the construct's antitumor immunogenicity in a murine tumor model. SEB was anchored onto purified texosomes and was used for immunization of mice before challenge with 4T1 cells. Tumor size, survival time, necrosis, metastasis rate, and the levels of IL-2, IL-4, IL 17, IL-12, TNF-alpha, and IFN-gamma were measured. Immunization of the mice with TEX-SEB increased the stimulation index of splenocytes significantly compared with the PBS-treated mice (p < 0.01). In addition, there was a significant increase of TNF-alpha, IL-2, and IFN-gamma secreted from isolated splenocytes of the mice immunized by either TEX-SEB, TEX + SEB, TEX, or SEB in comparison with PBS (p < 0.001, p < 0.001, and p < 0.05, respectively), whereas no significant change of IL-4 secretion was observed in any treated groups. Finding from tumor tissue homogenate testing showed that the level of IL-17 and IFN-gamma among mice immunized with TEX-SEB was significantly lower than PBS-treated group (p < 0.05). IL-12, IL-4, and TNF-alpha levels were not significantly different from PBS- and TEX-SEB-immunized groups except in the SEB-immunized mice. Although TEX-SEB immunization relatively prolonged the survival of the mice, it had no inhibitory impact on tumor size. Pathologic manifestations showed the significant rise of necrosis after immunization with TEX-SEB compared to PBS (p < 0.01). Overall, our findings suggest that the presence of SEB rescues tumorigenesis effects of TEX making the construct an appropriate candidate for tumor immunotherapy. PMID- 26245995 TI - Novel T-cell assays for the discrimination of active and latent tuberculosis infection: the diagnostic value of PPE family. AB - OBJECTIVE: The diagnosis of active and latent tuberculosis remains a challenge. Although a new approach based on detecting Mycobacterium tuberculosis-specific T cells has been introduced, it cannot distinguish between latent infection and active disease. The aim of this study was to evaluate the diagnostic potential of interleukin-2 (IL-2) as biomarker after specific antigen stimulation with PE35 and PPE68 for the discrimination of active and latent tuberculosis infection (LTBI). METHOD: The production of IL-2 was measured in the antigen-stimulated whole-blood supernatants following stimulation with recombinant PE35 and PPE68. RESULTS: The discrimination performance (assessed by the area under ROC curve) for IL-2 following stimulation with recombinant PE35 and PPE68 between LTBI and patients with active TB were 0.837 [95 % confidence interval (CI) 0.72-0.97] for LTBI diagnosis and 0.75 (95 % CI 0.63-0.89) for active TB diagnosis, respectively. Applying the 6.4 pg/mL cut-off for IL-2 induced by PE35 in the present study population resulted in sensitivity of 78 %, specificity of 83 %, PPV of 83 % and NPV of 78 % for the discrimination of active TB and LTBI. In addition, a sensitivity of 81 %, specificity of 71 %, PPV of 68 and 83 % of NPV was reported based on the 4.4 pg/mL cut-off for IL-2 induced by PPE68. CONCLUSION: This study confirms IL-2 induced by PE35 and PPE68 as a sensitive and specific biomarker and highlights IL-2 as new promising adjunct markers for discriminating of LTBI and active TB disease. PMID- 26245996 TI - Expression of ROR1, pAkt, and pCREB in gastric adenocarcinoma. AB - The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transmembrane protein of receptor tyrosine kinase family. High expression of ROR1 is reported in many types of malignancies and is thought to be involved in tumor growth, apoptosis, and epithelial-mesenchymal transition. In this study, we examined the expression of ROR1, pAkt, and pCREB in gastric adenocarcinoma and analyzed with clinicopathologic factors and tumor proliferation. Tissue microarray blocks containing 424 gastric adenocarcinomas were used for immunohistochemical staining. Ki-67 labeling index was used for tumor proliferation activity. High expression of ROR1 (63%), pAkt (36%), and pCREB (20%) was observed in gastric adenocarcinomas, and expression of these proteins was well intercorrelated. ROR1 and pCREB expression was associated with Ki-67 labeling index (P < .001). Expression of pAkt and pCREB group showed longer survival in univariate analysis (P = .007 and P < .001, respectively). This is the first study that analyzed ROR1 expression in gastric adenocarcinoma tissue samples. We revealed that gastric adenocarcinomas highly express ROR1 and related proteins and its prognostic significance. ROR1 in gastric adenocarcinoma could be possible candidate of therapeutic target, and more comprehensive study is required. PMID- 26245997 TI - The interplay between drug-use behaviors, settings, and access to care: a qualitative study exploring attitudes and experiences of crack cocaine users in Rio de Janeiro and Sao Paulo, Brazil. AB - BACKGROUND: Despite the growing attention surrounding crack cocaine use in Brazil, little is understood about crack users' histories, use patterns and the interplay of drug-use behaviors, settings, and access/barriers to care. Qualitative studies seldom cross-compare findings regarding people who use crack from different settings. This study aims to explore the insights of regular crack users in two major Brazilian cities and to examine how social and contextual factors, including stigma and marginalization, influence initial use and a range of health and social issues. METHODS: In-depth interviews and focus groups were conducted with 38 adult crack cocaine users recruited from impoverished neighborhoods in Rio de Janeiro and Sao Paulo. Interviews and focus groups were audio recorded and transcribed verbatim. Qualitative analysis was carried out, and content was organized and analyzed by recurrent themes relevant to study interests. RESULTS: For study participants from both cities, frequent crack cocaine use plays a central role in daily life and leads to a range of physical, psychological, and social consequences. Common concerns among users include excessive crack use, engagement in risky habits, infrequent health service utilization, marginalization, and difficulty reducing use. CONCLUSIONS: Disadvantaged conditions in which many crack cocaine users grow up and live may perpetuate risk behaviors and stigma may further marginalize users from necessary health and recovery services. Reducing stigma and moralizing discourse related to drug use, especially among health professionals and law enforcement personnel, may help encourage users to seek necessary care. New harm-reduction-based care and treatment alternatives for marginalized drug users are being developed in parts of Brazil and elsewhere and should be adapted and expanded for other populations in need. PMID- 26245999 TI - Justified granulation aided noninvasive liver fibrosis classification system. AB - BACKGROUND: According to the World Health Organization 130-150 million (according to WHO) of people globally are chronically infected with hepatitis C virus. The virus is responsible for chronic hepatitis that ultimately may cause liver cirrhosis and death. The disease is progressive, however antiviral treatment may slow down or stop its development. Therefore, it is important to estimate the severity of liver fibrosis for diagnostic, therapeutic and prognostic purposes. Liver biopsy provides a high accuracy diagnosis, however it is painful and invasive procedure. Recently, we witness an outburst of non-invasive tests (biological and physical ones) aiming to define severity of liver fibrosis, but commonly used FibroTest(r), according to an independent research, in some cases may have accuracy lower than 50 %. In this paper a data mining and classification technique is proposed to determine the stage of liver fibrosis using easily accessible laboratory data. METHODS: Research was carried out on archival records of routine laboratory blood tests (morphology, coagulation, biochemistry, protein electrophoresis) and histopathology records of liver biopsy as a reference value. As a result, the granular model was proposed, that contains a series of intervals representing influence of separate blood attributes on liver fibrosis stage. The model determines final diagnosis for a patient using aggregation method and voting procedure. The proposed solution is robust to missing or corrupted data. RESULTS: The results were obtained on data from 290 patients with hepatitis C virus collected over 6 years. The model has been validated using training and test data. The overall accuracy of the solution is equal to 67.9 %. The intermediate liver fibrosis stages are hard to distinguish, due to effectiveness of biopsy itself. Additionally, the method was verified against dataset obtained from 365 patients with liver disease of various etiologies. The model proved to be robust to new data. What is worth mentioning, the error rate in misclassification of the first stage and the last stage is below 6.5 % for all analyzed datasets. CONCLUSIONS: The proposed system supports the physician and defines the stage of liver fibrosis in chronic hepatitis C. The biggest advantage of the solution is a human-centric approach using intervals, which can be verified by a specialist, before giving the final decision. Moreover, it is robust to missing data. The system can be used as a powerful support tool for diagnosis in real treatment. PMID- 26246000 TI - Effects of different interchain linkers on biological activity of an anti prostate cancer single-chain bispecific antibody. AB - BACKGROUND: A single-chain bispecific antibody (scBsAb; an engineered antibody), has promising clinical applications. Nonetheless, the effect of different interchain linkers on its activity is poorly understood. METHODS: Gene synthesis was used to splice the anti-gamma-seminoprotein single-chain antibody (anti-gamma Sm scFv) gene with the anti-CD3 single-chain antibody (anti-CD3 scFv) gene via different interchain peptide linkers. The Phyre2 software was used to predict spatial configuration of different scBsAbs. Eukaryotic expression vectors carrying scBsAbs were constructed by molecular cloning techniques and these plasmids were transfected into HeLa cells with liposomes. scBsAbs were purified by Ni(2+)-NTA agarose and analysed for antigen binding by an enzyme-linked immunosorbent assay (ELISA). Blood pharmacokinetics and inhibition of prostate tumour growth in nude mice were analysed in in vivo experiments. RESULTS: Bioinformatics analysis and prediction showed that none of the three linkers, Fc, 205C', and HSA, had a significant effect on protein folding of anti-gamma-Sm scFv or anti-CD3 scFv. Nevertheless, the spatial structures of the three linkers were noticeably different. Anti-gamma-Sm * anti-CD3 scBsAb with an Fc, 205C', or HSA linker was successfully constructed, and these antibodies had similar protein expression levels. ELISA showed that all the three scBsAbs bound to Jurkat cells and the LNCaP membrane antigen, although binding of (205C')scBsAb was weaker than that of the two parental scFvs (P < 0.05). In contrast, binding strength of (HSA)scBsAb and (Fc)scBsAb was close to that of the parental scFvs (P > 0.05). Pharmacokinetic analysis showed that the half-clearance time of the elimination phase (T(1/2beta)) for (HSA)scBsAb was the longest: up to 4.4 h. Compared with gamma-Sm ScFv, the three scBsAbs all had a much stronger inhibitory effect on the growth of prostate cancer (P < 0.05), but there were no significant differences among the three scBsAbs (P > 0.05). CONCLUSIONS: HSA is the optimal linker for the anti-gamma-Sm * anti-CD3 scBsAb and may improve antigen-binding affinity of antibodies and prolong physiological retention time. Interchain linkers affect the function of scBsAbs; these effects may have important implications for construction of antibodies. PMID- 26246002 TI - Positron kinetics in an idealized PET environment. AB - The kinetic theory of non-relativistic positrons in an idealized positron emission tomography PET environment is developed by solving the Boltzmann equation, allowing for coherent and incoherent elastic, inelastic, ionizing and annihilating collisions through positronium formation. An analytic expression is obtained for the positronium formation rate, as a function of distance from a spherical source, in terms of the solutions of the general kinetic eigenvalue problem. Numerical estimates of the positron range - a fundamental limitation on the accuracy of PET, are given for positrons in a model of liquid water, a surrogate for human tissue. Comparisons are made with the 'gas-phase' assumption used in current models in which coherent scattering is suppressed. Our results show that this assumption leads to an error of the order of a factor of approximately 2, emphasizing the need to accurately account for the structure of the medium in PET simulations. PMID- 26246003 TI - Comparison and validation of five scapulothoracic models for correcting soft tissue artefact through multibody optimisation. PMID- 26246001 TI - Alcohol consumption, endogenous estrogen and mammographic density among premenopausal women. AB - INTRODUCTION: Alcohol consumption may promote aromatization of androgens to estrogens, which may partly explain the observations linking alcohol consumption to higher breast cancer risk. Whether alcohol consumption is associated with endogenous estrogen levels, and mammographic density phenotypes in premenopausal women remains unclear. METHODS: Alcohol consumption was collected by self-report and interview, using semi quantitative food frequency questionnaires, and a food diary during seven days of a menstrual cycle among 202 premenopausal women, participating in the Energy Balance and Breast Cancer Aspects (EBBA) study I. Estrogen was assessed in serum and daily in saliva across an entire menstrual cycle. Computer-assisted mammographic density (Madena) was obtained from digitized mammograms taken between days 7-12 of the menstrual cycle. Multivariable regression models were used to investigate the associations between alcohol consumption, endogenous estrogen and mammographic density phenotypes. RESULTS: Current alcohol consumption was positively associated with endogenous estrogen, and absolute mammographic density. We observed 18 % higher mean salivary 17beta-estradiol levels throughout the menstrual cycle, among women who consumed more than 10 g of alcohol per day compared to women who consumed less than 10 g of alcohol per day (p = 0.034). Long-term and past-year alcohol consumption was positively associated with mammographic density. We observed a positive association between alcohol consumption (past year) and absolute mammographic density; high alcohol consumers (>=7 drinks/week) had a mean absolute mammographic density of 46.17 cm(2) (95 % confidence interval (CI) 39.39, 52.95), while low alcohol consumers (<1 drink/week) had a mean absolute mammographic density of 31.26 cm(2) (95 % CI 25.89, 36.64) (p-trend 0.001). After adjustments, high consumers of alcohol (>=7 drinks/week), had 5.08 (95 % CI 1.82, 14.20) times higher odds of having absolute mammographic density above median (>32.4 cm(2)), compared to low (<1 drink/week) alcohol consumers. CONCLUSION: Alcohol consumption was positively associated with daily endogenous estrogen levels and mammographic density in premenopausal women. These associations could point to an important area of breast cancer prevention. PMID- 26246004 TI - IgG Subclass Specificity Discriminates Restricted IgM Rheumatoid Factor Responses From More Mature Anti-Citrullinated Protein Antibody-Associated or Isotype Switched IgA Responses. AB - OBJECTIVE: To investigate the presence and patterns of specific IgG subclass recognition by IgM rheumatoid factor (IgM-RF) and IgA-RF with a newly developed enzyme-linked immunosorbent assay (ELISA), which can discriminate between polyspecific and restricted RF responses. METHODS: Polyspecific and restricted RF responses were determined with our ELISA, which uses individually coated recombinant IgG subclasses instead of polyclonal IgG as target antibodies. Fine specificity was determined using target antibodies with single amino acid mutations in the Fc region. RESULTS: In a screening panel of 93 sera that were previously found to be IgM-RF positive in a conventional RF assay, we were able to discriminate between sera with polyspecific IgM-RF responses (i.e., RF responses directed against all 4 IgG subclasses) and those with restricted IgM-RF responses, with low or absent relative reactivity against IgG2, IgG3, or IgG4. We found the largest variation for anti-IgG3 reactivity. Samples without detectable anti-IgG4 reactivity formed an independent group from the other restricted RF responses and the polyspecific RF responses. The specificity of these anti-IgG4 negative sera could be pinpointed to single amino acid differences between IgG1 and IgG4. Polyspecific RF responses more often showed signs of RF response maturation, with more isotype switching to IgA-RF, as compared to restricted RF responses. In a cohort of IgM-RF+ and/or anti-citrullinated protein antibody (ACPA)-positive arthralgia patients, we found restricted RF responses in 35% (49 of 140) of RF+/ACPA- patients, while RF+/ACPA+ patients, who have a much higher risk of developing rheumatoid arthritis, virtually always (123 of 128 [96%]) showed a polyspecific RF response. CONCLUSION: IgG subclass-specific RF distinguishes between immature restricted RF responses and potentially more pathogenic, ACPA-associated polyspecific responses. PMID- 26246005 TI - A cell-penetrating foldamer with a bioreducible linkage for intracellular delivery of DNA. AB - Despite significant advances in foldamer chemistry, tailored delivery systems based on foldamer architectures, which provide a high level of control over secondary structure, are curiously rare among non-viral technologies for transporting nucleic acids into cells. A potent pH-responsive, bioreducible cell penetrating foldamer (CPF) was developed through covalent dimerization of a short (8-mer) amphipathic oligourea sequence bearing histidine-type units. This CPF exhibits a high capacity to assemble with pDNA and mediates efficient delivery of nucleic acids into the cell. Furthermore, it does not adversely affect cellular viability and was shown to compare favorably with a cognate peptide transfection agent based on His-rich sequences. PMID- 26246006 TI - Influence of comorbidities on the efficacy of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease. AB - AIM: To evaluate the influence of comorbidities and aging on pulmonary rehabilitation (PR) efficacy in patients with chronic obstructive pulmonary disease (COPD). METHODS: This was a retrospective cohort study of patients with COPD attending an outpatient PR program. Comorbidity information was collected with the Charlson Index, BODE index and COPD-specific comorbidity test, and also included other common conditions not included in these indexes. The efficacy of PR was defined as a 54-m increase in 6-min walk distance or a four-point decrease in St. George's Respiratory Questionnaire score. Patients were divided into two age groups according to the median age of 72 years. RESULTS: A total of 21 of 52 patients (40%) showed a clinically significant benefit by the 6-min walk distance, and 29 patients (55.8%) by the St. George's Respiratory Questionnaire score. PR efficacy was not different between the elderly group and the younger group by either parameter. A total of 98% of the patients had at least one chronic comorbidity. Hypertension was the most frequently reported comorbidity (28.5%). Higher body mass index, Hospital Anxiety and Depression Scale anxiety score and St. George's Respiratory Questionnaire total score were associated with a good response to PR by the 6-min walk distance. None of the individual comorbidities or indexes were correlated with the efficacy of PR. Multiple logistic regression analysis showed that body mass index was independently associated with the response to PR. CONCLUSIONS: PR is equally effective in elderly and younger patients with COPD, with efficacy influenced by body mass index and anxiety. Geriatr Gerontol Int 2016; 16: 934-941. PMID- 26246012 TI - Biochemical Markers of Bone Turnover and their Role in Osteoporosis Diagnosis: A Narrative Review. AB - Osteoporosis diagnosis, which is nowadays generally made based on bone mineral density (BMD) measurements, suffers from certain limitations. Thus it is believed that bone turnover markers (BTMs) can help improve osteoporosis detection. The shifting interest toward this topic made us perform a review to gather information on existing markers and their role in osteoporosis diagnosis. Based on the results, in this review, a list of existing markers and some of their characteristics is provided. Moreover, a brief explanation of different types of variability met while using these markers is also described. Finally some of the patents provided for the diagnosis of these markers are presented. While the use of BTMs in osteoporosis diagnosis has certain advantages over BMD and clinical risk assessment tools, more studies are needed before they can be used as a separate tool in this regard. It could be concluded that despite the fact that BTMs are better than BMD not only in monitoring treatment but also in identifying those at-risk, the diagnostic value of BTMs in predicting osteoporosis is low, and thus a model is needed to assess several BTMs at the same time with higher accuracy and lower variability to overcome this limitation. PMID- 26246011 TI - Vector and reservoir control for preventing leishmaniasis. AB - BACKGROUND: Leishmaniasis is caused by the Leishmania parasite, and transmitted by infected phlebotomine sandflies. Of the two distinct clinical syndromes, cutaneous leishmaniasis (CL) affects the skin and mucous membranes, and visceral leishmaniasis (VL) affects internal organs. Approaches to prevent transmission include vector control by reducing human contact with infected sandflies, and reservoir control, by reducing the number of infected animals. OBJECTIVES: To assess the effects of vector and reservoir control interventions for cutaneous and for visceral leishmaniasis. SEARCH METHODS: We searched the following databases to 13 January 2015: Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS and WHOLIS, Web of Science, and RePORTER. We also searched trials registers for ongoing trials. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating the effects of vector and reservoir control interventions in leishmaniasis-endemic regions. DATA COLLECTION AND ANALYSIS: Two review authors independently searched for trials and extracted data from included RCTs. We resolved any disagreements by discussion with a third review author. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We included 14 RCTs that evaluated a range of interventions across different settings. The study methods were generally poorly described, and consequently all included trials were judged to be at high or unclear risk of selection and reporting bias. Only seven trials reported clinical outcome data which limits our ability to make broad generalizations to different epidemiological settings and cultures. Cutaneous leishmaniasisOne four-arm RCT from Afghanistan compared indoor residual spraying (IRS), insecticide-treated bednets (ITNs), and insecticide-treated bedsheets, with no intervention. Over 15 months follow-up, all three insecticide-based interventions had a lower incidence of CL than the control area (IRS: risk ratio (RR) 0.61, 95% confidence interval (CI) 0.38 to 0.97, 2892 participants, moderate quality evidence; ITNs: RR 0.32, 95% CI 0.18 to 0.56, 2954 participants, low quality evidence; ITS: RR 0.34, 95% CI 0.20 to 0.57, 2784 participants, low quality evidence). No difference was detected between the three interventions (low quality evidence). One additional trial of ITNs from Iran was underpowered to show a difference.Insecticide treated curtains were compared with no intervention in one RCT from Venezuela, where there were no CL episodes in the intervention areas over 12 months follow-up compared to 142 in control areas (RR 0.00, 95% CI 0.00 to 0.49, one trial, 2938 participants, low quality evidence).Personal protection using insecticide treated clothing was evaluated by two RCTs in soldiers, but the trials were underpowered to reliably detect effects on the incidence of CL (RR 0.40, 95% CI 0.13 to 1.20, two trials, 558 participants, low quality evidence). Visceral leishmaniasisIn a single RCT of ITNs versus no intervention from India and Nepal, the incidence of VL was low in both groups and no difference was detected (RR 0.99, 95% CI 0.46 to 2.15, one trial, 19,810 participants, moderate quality evidence).Two trials from Brazil evaluated the effects of culling infected dogs compared to no intervention or IRS. Although they report a reduction in seroconversion over 18 months follow up, they did not measure or report effects on clinical disease. AUTHORS' CONCLUSIONS: Using insecticides to reduce phlebotomine sandfly numbers may be effective at reducing the incidence of CL, but there is insufficient evidence from trials to know whether it is better to spray the internal walls of houses or to treat bednets, curtains, bedsheets or clothing. PMID- 26246013 TI - Resveratrol Pretreatment Ameliorates TNBS Colitis in Rats. AB - Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disease in humans constituting a major health concern today whose prevalence has been increasing over the world. Production of reactive oxygen species (ROS) and disturbed capacity of antioxidant defense in IBD subjects have been reported. Antioxidants may play a significant role in IBD treatment. This study aimed at evaluating ameliorative effects of intraperitoneal resveratrol pretreatment on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. Thirty five Wistar Albino female rats were divided equally into five groups. Inflammation was induced by the intrarectal administration of TNBS under anesthesia. Intraperitoneal administration of resveratrol (RSV) at a concentration of 10mg/kg/day for 5 days before the induction of colitis significantly reduced microscopy score and malondialdehyde (MDA) levels and increased glutathione peroxidase (GSH Px) activity compared to TNBS and vehicle groups. Also an insignificant increase in catalase (CAT) activity was observed in the RSV treated group compared to TNBS and vehicle groups. In this paper, the most recent patent on the identification and treatment of IBD was indicated. In conclusion, antioxidant RSV proved to have a beneficial effect on TNBS colitis in rats. In light of these advantageous results, the RSV can be considered as adjuvant agent in IBD treatments. PMID- 26246014 TI - The BMJ article wrongly taints medical teaching in Sudan. PMID- 26246015 TI - Merging drops in a Teflon tube, and transferring fluid between them, illustrated by protein crystallization and drug screening. AB - The ability to manipulate drops with small volumes has many practical applications. Current microfluidic devices generally exploit channel geometry and/or active external equipment to control drops. Here we use a Teflon tube attached to a syringe pump and exploit the properties of interfaces between three immiscible liquids to create particular fluidic architectures. We then go on to merge any number of drops (with volumes of micro- to nano-liters) at predefined points in time and space in the tube; for example, 51 drops were merged in a defined order to yield one large drop. Using a different architecture, specified amounts of fluid were transferred between 2 nl drops at specified rates; for example, 2.5 pl aliquots were transferred (at rates of ~500 fl s(-1)) between two drops through inter-connecting nano-channels (width ~40 nm). One proof-of principle experiment involved screening conditions required to crystallize a protein (using a concentration gradient created using such nano-channels). Another demonstrated biocompatibility; drugs were mixed with human cells grown in suspension or on surfaces, and the treated cells responded like those grown conventionally. Although most experiments were performed manually, moderate high throughput potential was demonstrated by mixing ~1000 different pairs of 50 nl drops in ~15 min using a robot. We suggest this reusable, low-cost, and versatile methodology could facilitate the introduction of microfluidics into workflows of many experimental laboratories. PMID- 26246016 TI - Saccular dysfunction in children with sensorineural hearing loss and auditory neuropathy/auditory dys-synchrony. AB - CONCLUSION: There is a correlation between the AN/AD disorder and the saccular dysfunction in children with severe sensorineural hearing loss, which means that saccular dysfunction can be a concomitant sign of AN/AD. In conclusion, the term of audio-vestibular dys-synchrony (AVS) is a more suitable description for this condition. OBJECTIVES: Patients with auditory neuropathy/auditory dys-synchrony (AN/AD) characteristically demonstrate poor neural responses from the vestibulocochlear nerve and brainstem while displaying evidence of intact outer hair cells function. Therefore, the objective of this study is studying of the relationship of the saccular dysfunction with AN/AD disorder in children with sensorineural hearing loss. METHODS: In this cross-sectional study, 100 children with bilateral severe-to-profound sensorineural hearing losses underwent audiologic tests and cervical vestibular-evoked myogenic potentials (cVEMPs) at the Audiology Department of Hamadan University of Medical Sciences (Hamadan, Iran). RESULTS: Eleven children with bilateral severe sensorineural hearing loss were given to unilateral AN/AD disorder (11 ears), and two children (4 ears) had bilateral AN/AD (total = 13 children). The ears with AN/AD took the form of unrepeatable or absent waves of ABR and presence of OAEs. The statistical analysis of an independent t-test between AN/AD ears as compared to non-AN/AD ears of these 13 children showed that the mean latencies of p13 and the mean latencies of n23 and the mean peak-to-peak amplitude had significant differences. PMID- 26246017 TI - Oxidative alpha,omega-diyne coupling as an approach towards novel peptidic macrocycles. AB - The Glaser-Hay diyne coupling proved to be an efficient cyclisation approach towards diyne containing peptidic macrocycles. A variety of tetrapeptide-based macrocyclic 1,3-diynes were obtained from O-propargylated serine or tyrosine residues using Cu(OAc)2.H2O and NiCl2 under an O2-atmosphere. The effect of the linear 1,3-diyne on peptide conformations was studied by NMR and compared with a macrocycle bearing a saturated linker. PMID- 26246018 TI - Deletion of capn4 Protects the Heart Against Endotoxemic Injury by Preventing ATP Synthase Disruption and Inhibiting Mitochondrial Superoxide Generation. AB - BACKGROUND: Our recent study has demonstrated that inhibition of calpain by transgenic overexpression of calpastatin reduces myocardial proinflammatory response and dysfunction in endotoxemia. However, the underlying mechanisms remain to be determined. In this study, we used cardiomyocyte-specific capn4 knockout mice to investigate whether and how calpain disrupts ATP synthase and induces mitochondrial superoxide generation during endotoxemia. METHODS AND RESULTS: Cardiomyocyte-specific capn4 knockout mice and their wild-type littermates were injected with lipopolysaccharides. Four hours later, calpain-1 protein and activity were increased in mitochondria of endotoxemic mouse hearts. Mitochondrial calpain-1 colocalized with and cleaved ATP synthase-alpha (ATP5A1), leading to ATP synthase disruption and a concomitant increase in mitochondrial reactive oxygen species generation during lipopolysaccharide stimulation. Deletion of capn4 or upregulation of ATP5A1 increased ATP synthase activity, prevented mitochondrial reactive oxygen species generation, and reduced proinflammatory response and myocardial dysfunction in endotoxemic mice. In cultured cardiomyocytes, lipopolysaccharide induced mitochondrial superoxide generation that was prevented by overexpression of mitochondria-targeted calpastatin or ATP5A1. Upregulation of calpain-1 specifically in mitochondria sufficiently induced superoxide generation and proinflammatory response, both of which were attenuated by ATP5A1 overexpression or mitochondria-targeted superoxide dismutase mimetics. CONCLUSIONS: Cardiomyocyte-specific capn4 knockout protects the heart against lipopolysaccharide-induced injury in endotoxemic mice. Lipopolysaccharides induce calpain-1 accumulation in mitochondria. Mitochondrial calpain-1 disrupts ATP synthase, leading to mitochondrial reactive oxygen species generation, which promotes proinflammatory response and myocardial dysfunction during endotoxemia. These findings uncover a novel mechanism by which calpain mediates myocardial dysfunction in sepsis. PMID- 26246020 TI - A randomized clinical study on postoperative pain comparing the Polysoft patch to the modified Kugel patch for transinguinal preperitoneal inguinal hernia repair. AB - PURPOSE: The transinguinal preperitoneal approach is a relatively new technique for inguinal hernia repair. Two types of memory-ring mesh are available in Japan: the modified Kugel patch (MK) and the Polysoft patch (PP). We tested the hypothesis that the PP is noninferior to the MK with respect to chronic postoperative pain. METHODS: An unblinded randomized controlled trial was conducted to assess the noninferiority of PP compared to MK with a 5 % noninferiority margin. A total of 442 inguinal hernia patients operated on from November 2010 to December 2012 were included in this study. The primary endpoint was the pain score assessed by the visual analog scale (VAS) (0-1 vs. 2-10) 1 year after surgery. RESULTS: The patients were randomized to the PP and MK groups (n = 221 each). One year after surgery, 206 patients (95.4 %) in the PP group and 182 patients (89.6 %) in the MK group rated pain at 0-1 on the VAS scale. According to this rating, the PP group appeared not to be inferior to the MK group (95 % confidence interval, 0.7-10.7 %, P < 0.05). Furthermore, crude superiority tests, adjusting for 1 month of pain, denoted that the outcomes were significantly improved with the PP compared to the MK. CONCLUSIONS: The use of the PP was noninferior to the MK with respect to the severity of postoperative chronic pain scores 12 months after surgery. PMID- 26246019 TI - Lifestyle, chronic diseases and self-rated health among Malaysian adults: results from the 2011 National Health and Morbidity Survey (NHMS). AB - BACKGROUND: Self-rated health (SRH) has been demonstrated as a valid and appropriate predictor of incident mortality and chronic morbidity. Associations between lifestyle, chronic diseases, and SRH have been reported by various population studies but few have included data from developing countries. The aim of this study was to determine the prevalence of poor SRH in Malaysia and its association with lifestyle factors and chronic diseases among Malaysian adults. METHODS: This study was based on 18,184 adults aged 18 and above who participated in the 2011 National Health and Morbidity Survey (NHMS). The NHMS was a cross sectional survey (two-stage stratified sample) designed to collect health information on a nationally representative sample of the Malaysian adult population. Data were obtained via face-to-face interviews using validated questionnaires. Two categories were used to measure SRH: "good" (very good and good) and "poor" (moderate, not good and very bad). The association of lifestyle factors and chronic diseases with poor SRH was examined using univariate and multivariate logistic regression. RESULTS: Approximately one-fifth of the Malaysian adult population (20.1 %) rated their health as poor (men: 18.4 % and women: 21.7 %). Prevalence increases with age from 16.2 % (aged 18-29) to 32.0 % (aged >=60). In the multivariate logistic regression analysis, lifestyle factors associated with poor SRH included: underweight (OR = 1.29; 95 % CI: 1.05-1.57), physical inactivity (OR = 1.25; 95 % CI: 1.11-1.39), former smoker (OR = 1.38; 95 % CI: 1.12-1.70), former drinker (OR = 1.27; 95 % CI: 1.01-1.62), and current drinker (OR = 1.35; 95 % CI: 1.08-1.68). Chronic diseases associated with poor SRH included: asthma (OR = 1.66; 95 % CI: 1.36-2.03), arthritis (OR = 1.87; 95 % CI: 1.52-2.29), hypertension (OR = 1.39; 95 % CI: 1.18-1.64), hypercholesterolemia (OR = 1.43; 95 % CI: 1.18-1.74), and heart disease (OR = 1.85; 95 % CI: 1.43-2.39). CONCLUSIONS: This study indicates that several unhealthy lifestyle behaviours and chronic diseases are significantly associated with poor SRH among Malaysian adults. Effective public health strategies are needed to promote healthy lifestyles, and disease prevention interventions should be enhanced at the community level to improve overall health. PMID- 26246021 TI - Differences between clinic blood pressure and morning home blood pressure, as shown by Bland-Altman plots, in a large observational study (HONEST study). AB - When interpreting home blood pressure (BP) measurements in hypertensive patients, differences between clinic and home BP should be noted. To investigate the differences between clinic and morning home BP in hypertensive patients, we analyzed clinic systolic BP (CSBP) and morning home systolic BP (MHSBP) data from the large-scale observational HONEST (Home BP measurement with Olmesartan Naive patients to Establish Standard Target blood pressure) study (n=21 340), using BP measurements obtained before starting olmesartan administration. We generated Bland-Altman plots, with the horizontal axis representing mean CSBP and MHSBP ([CSBP+MHSBP]/2) and the vertical axis representing the difference between CSBP and MHSBP (CSBP-MHSBP). We also did simulation experiments to explore factors affecting the results of the Bland-Altman plots. The difference between CSBP and MHSBP increased as the mean of the two values increased, and when the mean of CSBP and MHSBP was close to 140 mm Hg, the difference was theoretically 0 in average, although large interindividual BP variability existed in this BP range. Results were unaffected by factors such as previous antihypertensive treatment, age and concomitant diabetes or chronic kidney disease. Bland-Altman plots generated from simulated data of normal distribution showed that the slope of the regression line sloped upward, consistent with the results of the HONEST study, when the interindividual BP variability of MHSBP was less than that of CSBP. In conclusion, differences between mean CSBP and MHSBP may be caused by large interindividual variability in CSBP. Therefore, the differences between MHSBP and CSBP may vary between patient groups, which should be noted in the management of hypertension. PMID- 26246022 TI - A Novel Approach for the Treatment of Spider Veins. AB - BACKGROUND: Spider veins on the lower limbs are very common and have been reported to be present in 41% of women over 50. Sclerotherapy as a traditional treatment for spider veins has a low cost, though it may have adverse sequelae. Lasers have shown fewer but still substantial complications as well. Its lower efficacy relative to sclerotherapy has limited laser application for the treatment of spider veins. OBJECTIVES: To present a new alternative in management of spider veins which involves a low voltage current delivered via an insulated micro needle with beveled tip. METHODS: Thirty female patients were treated with the "Given Needle." The technique utilizes a micro needle with an insulated shaft with an exposed beveled tip, which is inserted into a hand piece connected to a mono-polar electrical generator. The needle is introduced through the skin into or on the spider vein. The current is then applied with obliteration of the vein. RESULTS: Twenty patients (66%) had more than a 70% resolution. The most common complication was skin erythema, which developed in 15 patients, followed by bruising in 13 patients. Both of these complications resolved in 2-3 weeks. CONCLUSIONS: A novel approach for the treatment of spider veins has been described. The development of an insulated micro needle with an exposed beveled tip utilizing low current has minimized adjacent tissue damage and improved efficacy. The low cost, low level of complications, and comparable results offer a valuable alternative to sclerotherapy and laser treatment. PMID- 26246023 TI - Periareolar Closure With Barbed Sutures. PMID- 26246024 TI - An external validation study of a clinical prediction rule for medical patients with suspected bacteraemia. AB - OBJECTIVE: The objective of this study was to externally validate a clinical prediction rule (CPR)-the 'Shapiro criteria'-to predict bacteraemia in an acute medical unit (AMU). METHODS: Prospectively collected data, retrospectively evaluated over 11 months in an AMU in the UK. From 4810 admissions, 635 patients (13%) had blood cultures (BCs) performed. The 100 cases of true bacteraemia were compared with a randomly selected sample of 100 control cases where BCs were sterile. RESULTS: To predict bacteraemia (at a cut-off score of two points), the Shapiro criteria had a sensitivity of 97% (95% CIs 91% to 99%), specificity 37% (28% to 47%), positive likelihood ratio 1.54 (1.3 to 1.8) and a negative likelihood ratio of 0.08 (0.03 to 0.25). The area under the receiver operating curve was 0.80 (0.74 to 0.86), and the Hosmer-Lemeshow p value was 0.45. CONCLUSIONS: A cut-off score of two points on the Shapiro criteria had high sensitivity to predict bacteraemia in a study of acute general medical admissions. Application of the rule in patients being considered for a BC could identify those at low risk of bacteraemia. Though the model demonstrated good discrimination, the lengthy number of variables (13) and difficulty automating the CPR may limit its use. PMID- 26246025 TI - Serotonergic mechanisms are involved in antidepressant-like effects of bisbenzylisoquinolines liensinine and its analogs isolated from the embryo of Nelumbo nucifera Gaertner seeds in mice. AB - OBJECTIVES: We attempted to ascertain if bisbenzylisoquinoline alkaloids, liensinine and isoliensinine from Nelumbo nucifera Gaertner have antidepressant like effects and compare the effects with those previously obtained by their analogue neferine. METHODS: Using mice, the forced swimming test (FST) was carried out after treatment with liensinine, isoliensinine and neferine. KEY FINDINGS: Liensinine and isoliensinine elicited antidepressant-like effects in mice after the FST. Anti-immobility effects of liensinine and isoliensinine were antagonized by the 5-hydroxytryptamine1 A (5-HT1 A ) receptor antagonist WAY 100635, but not by the alpha1 -adrenoceptor antagonist prazosin. The anti immobility effects of liensinine, isoliensinine and neferine were blocked by pretreatment with p-chlorophenylalanine (PCPA), which depletes serotonin (5-HT). CONCLUSIONS: These data suggest that liensinine and isoliensinine from Nelumbo nucifera Gaertner have antidepressant-like effects and that antidepressant-like effects of liensinine and its analogues are closely related to serotonergic mechanisms. PMID- 26246027 TI - Genome shuffling of the nonconventional yeast Pichia anomala for improved sugar alcohol production. AB - BACKGROUND: Sugar alcohols have been widely applied in the fields of food and medicine owing to their unique properties. Compared to chemical production, microbial production of sugar alcohols has become attractive because of its environmentally friendly and sustainable characteristics. Our previous study identified the nonconventional yeast Pichia anomala TIB-x229 as a potential producer of sugar alcohols from glucose. To further improve strain performance, we combined genome shuffling with optimized high throughput screening methods for the directed improvement of nonconventional yeast and complex phenotypes. RESULTS: To accelerate strain improvement, a practical genome shuffling procedure was developed and successfully applied in the nonconventional yeast P. anomala to increase sugar alcohol production. Through two rounds of genome shuffling, an improved P. anomala isolate GS2-3 could produce 47.1 g/L total sugar alcohols from 100 g/L glucose, which was 32.3% higher than the original strain. In this process, a simple and accurate colorimetric assay was optimized and used for high throughput screening of sugar alcohol-producing strains. Moreover, a fluorescence activated cell sorting method was developed to efficiently screen protoplast fusions for genome shuffling of nonconventional yeast. CONCLUSION: An efficient genome shuffling procedure was developed and applied to enhance the sugar alcohol production of the nonconventional yeast P. anomala. Our results provide a general platform for strain improvement of polyol-producing microorganisms or nonconventional microorganisms in the future. PMID- 26246028 TI - Palladium-Catalyzed Domino Synthesis of 4-Amino-3-acyl-2- naphthols via Isocyanide Chemoselective Insertion. AB - A novel and efficient strategy for the synthesis of sterically hindered 4-amino-3 acyl-2-naphthols through a palladium-catalyzed coupling reaction involving isocyanide chemselective insertion and domino isomerization has been developed. The methodology, which is in accordance with the principle of "atom and step economy", efficiently constructs 4-amino-3-acyl-2-naphthols in moderate to good yields. PMID- 26246029 TI - Examining PTSD treatment choice among individuals with subthreshold PTSD. AB - Subthreshold posttraumatic stress disorder (PTSD) is associated with impairment and has a prevalence rate comparable to full PTSD. Yet, little is known regarding treatment preferences among individuals with subthreshold PTSD, even though they seek trauma-related treatment at a similar rate to those with full PTSD. This study explored subthreshold diagnostic PTSD diagnostic category and treatment preference in undergraduate (N = 439) and trauma-exposed community (N = 203) samples. Participants completed the Posttraumatic Stress Diagnostic Scale (PDS), viewed standardized treatment rationales, and made a hypothetical PTSD treatment choice: prolonged exposure (PE), sertraline, combination treatment, or no treatment. The PDS was used to categorize individuals into four PTSD categories: no trauma exposure, trauma exposure only, subthreshold PTSD, and full PTSD. Within the samples, 8.9% (n = 39) of undergraduates and 16.7% (n = 34) of community members met subthreshold PTSD criteria. The majority of individuals with subthreshold PTSD in each sample reported impairment, 59.0% of undergraduates and 76.5% of community members. Within subthreshold PTSD groups, the most commonly selected treatments were PE (61.5%) for undergraduates and combination treatment (47.1%) for community members. Findings underscore the necessity of further examining subthreshold PTSD, which may hold important clinical implications for treatment processes and outcomes. PMID- 26246030 TI - Stabilization of weak ferromagnetism by strong magnetic response to epitaxial strain in multiferroic BiFeO3. AB - Multiferroic BiFeO3 exhibits excellent magnetoelectric coupling critical for magnetic information processing with minimal power consumption. However, the degenerate nature of the easy spin axis in the (111) plane presents roadblocks for real world applications. Here, we explore the stabilization and switchability of the weak ferromagnetic moments under applied epitaxial strain using a combination of first-principles calculations and group-theoretic analyses. We demonstrate that the antiferromagnetic moment vector can be stabilized along unique crystallographic directions ([110] and [-110]) under compressive and tensile strains. A direct coupling between the anisotropic antiferrodistortive rotations and the Dzyaloshinskii-Moria interactions drives the stabilization of the weak ferromagnetism. Furthermore, energetically competing C- and G-type magnetic orderings are observed at high compressive strains, suggesting that it may be possible to switch the weak ferromagnetism "on" and "off" under the application of strain. These findings emphasize the importance of strain and antiferrodistortive rotations as routes to enhancing induced weak ferromagnetism in multiferroic oxides. PMID- 26246031 TI - The relationship between narrative classification of obesity and support for public policy interventions. AB - In 2013, the American Medical Association made the controversial decision to classify obesity as a "disease" in the hopes of encouraging research, reducing stigma, and ultimately lowering the prevalence of the condition. Critics argued that the disease label would reduce feelings of personal responsibility among the obese and therefore discourage healthy self-regulation, a possibility that has received some recent support in the psychological literature. However, public health issues such as obesity are complex and depend not only on personal action, but also on wider societal trends such as social policy interventions. In the present study, we systematically investigated the relationship between four narrative classifications of obesity ("sin", "addiction", "disorder" and "environment") and support for a variety of policy interventions designed to address the issue. An initial norming study revealed that the obesity narratives differed reliably in how much they attributed blame for the condition to the individual versus the environment. A correlational study showed that participants who agreed with narratives that blamed the individual were more likely to support policy interventions that penalized people for being overweight while participants who agreed with narratives that blamed the environment were more likely to support policy interventions designed to protect people suffering from obesity. A follow-up experiment revealed that these narratives had causal power as well: participants exposed to just one of the narratives were more likely to support policy interventions consistent with the blame attribution of the narrative for both obesity as well as anorexia. Individual differences in political ideology and personal experience with weight issues also influenced agreement with the narratives and support for particular policy interventions across these studies. These findings suggest that public messaging campaigns that utilize extended narratives may be a useful tool for increasing support for effective policy interventions. PMID- 26246032 TI - Impact of the Kenya Cash Transfer for Orphans and Vulnerable Children on early pregnancy and marriage of adolescent girls. AB - There is promising evidence that poverty-targeted cash transfer programs can have positive impacts on adolescent transitions to adulthood in resource poor settings, however existing research is typically from small scale programs in diverse geographic and cultural settings. We provide estimates of the impact of a national unconditional cash transfer program, the Kenya Cash Transfer for Orphans and Vulnerable Children, on pregnancy and early marriage among females aged 12 to 24, four years after program initiation. The evaluation was designed as a clustered randomized controlled trial and ran from 2007 to 2011, capitalizing on the existence of a control group, which was delayed entry to the program due to budget constraints. Findings indicate that, among 1549 females included in the study, while the program reduced the likelihood of pregnancy by five percentage points, there was no significant impact on likelihood of early marriage. Program impacts on pregnancy appear to work through increasing the enrollment of young women in school, financial stability of the household and delayed age at first sex. The Kenyan program is similar in design to most other major national cash transfer programs in Eastern and Southern Africa, suggesting a degree of generalizability of the results reported here. Although the objective of the program is primarily poverty alleviation, it appears to have an important impact on facilitating the successful transition of adolescent girls into adulthood. PMID- 26246033 TI - Smoke-free air laws and quit attempts: Evidence for a moderating role of spontaneous self-affirmation. AB - BACKGROUND: In addition to their primary goal of protecting nonsmokers from secondhand smoke, smoke-free air laws may also encourage intentions to quit smoking, quit attempts, and cessation among smokers. However, laws may not encourage quitting if smokers feel threatened by them and react defensively. OBJECTIVE: This study examined whether spontaneous self-affirmation - the extent to which people think about their values or strengths when they feel threatened - may reduce smokers' reactance to smoke-free laws, enhancing the ability of the laws to encourage quitting. METHOD: We linked state-level information on the comprehensiveness of U.S. smoke-free laws (compiled in January, 2013 by the American Lung Association) with data from a U.S. health survey (Health Information National Trends Survey) collected from September-December, 2013 (N = 345 current smokers; 587 former smokers). RESULTS: Smoke-free laws interacted with self-affirmation to predict quit attempts in the past year and intentions to quit in the next six months: Smokers higher in self-affirmation reported more quit attempts and quit intentions if they lived in states with more comprehensive smoke-free laws. There was some evidence of a "boomerang" effect (i.e., less likelihood of making a quit attempt) among smokers low in self-affirmation if living in states with more comprehensive smoke-free laws, but this effect was significant only among smokers extremely low in self-affirmation. For quit intentions, there was no evidence for a boomerang effect of smoke-free laws even among smokers extremely low in self-affirmation. More comprehensive smoke-free laws were not associated with smoking status (former vs. current smoker) or average amount smoked per day, nor did they interact with self-affirmation to predict these outcomes. CONCLUSIONS: The impact of smoke-free policies on quit attempts and quit intentions may be moderated by psychological characteristics such as the tendency to spontaneously self-affirm. Follow-ups should experimentally manipulate self-affirmation and examine effects of smoke-free laws in controlled contexts. PMID- 26246034 TI - Morphology-dependent low macroscopic field emission properties of titania/titanate nanorods synthesized by alkali-controlled hydrothermal treatment of a metallic Ti surface. AB - One-dimensional (1D) and two-dimensional (2D) titania/titanate nanostructures are fabricated directly on a self-source metallic titanium (Ti) surface via in situ surface re-construction of a Ti substrate using potassium hydroxide (KOH) under a hydrothermal (HT) condition. The effect of temperature and the concentration of KOH on the variations in morphology and titania-to-titanate phase changes are studied and explained in detail. A growth model is proposed for the formation process of the platelet-to-nanorod conversion mechanism. The field emission (FE) properties of titania/titanate nanostructures are studied, and the effects of the morphologies (such as 1D nanorods, 2D nanoplatelets, and a mixture of 1D nanorods and 2D platelets) on the FE properties of the samples are investigated. The samples depict a reasonable low turn-on field and emission stability. The FE mechanism is observed to follow standard Fowler-Nordheim (FN) electron tunneling. The geometrical field enhancement factor (beta) is measured to be very high, and is compared with theoretical values calculated from various existing models to explore the feasibility of these models. The surface modification of metallic Ti by a simple non-lithographic bottom-up method and the low-macroscopic FE properties can provide a potential alternative to field emission displays for low power panel technology. PMID- 26246035 TI - Exogenous plant hormones and cyclotide expression in Viola uliginosa (Violaceae). AB - Plants from Violaceae produce cyclotides, peptides characterized by a circular peptide backbone and a cystine knot. This signature motif gives stability that can harness a wide spectrum of biological activities, with implications in plant defense and with applications in medicine and biotechnology. In the current work, cyclotide expressing in vitro cultures were established from Viola uliginosa. These cultures are useful models for studying biosynthesis of cyclotides and can also be used in their production. The cyclotide expression pattern is shown to be dependent on exogenous plant growth regulators, both on peptide and gene expression levels. The highest yields of cyclotides were obtained on media containing only a cytokinin and were correlated with storage material accumulation. Exposure to auxins decreased cyclotide production and caused shifting of the biosynthesis pattern to root specific cyclotides. The response to stimuli in terms of cyclotide expression pattern appears to be developmental, and related to polar auxin transportation and the auxin/cytokinin ratio regulating tissue differentiation. By the use of whole transcriptome shotgun sequencing (WTSS) and peptidomics, 20 cyclotide sequences from V. uliginosa (including 12 new) and 12 complete precursor proteins could be identified. The most abundant cyclotides were cycloviolacin O3 (CyO3), CyO8 and CyO13. A suspension culture was obtained that grew exponentially with a doubling time of approximately 3 days. After ten days of growth, the culture provided a yield of more than 4 mg CyO13 per gram dry mass. PMID- 26246036 TI - Assessment of overactive bladder in women antidepressant users. AB - PURPOSE: The aim of this study was to evaluate the relationship between overactive bladder (OAB) and use of antidepressants in women. METHODS: This is a prospective trial, and in total, 205 consecutive female (113 patient taking antidepressants for various disorders and 92 healthy controls) outpatients from our outpatients were enrolled in this study. The patients were also divided into those with OAB symptoms, OAB-Validated 8 (OAB-V8 score of >=8), and without OAB symptoms <8. The prevalence of OAB in the antidepressant users and healthy controls was compared. In addition, the prevalence of OAB was compared according to antidepressant type. RESULTS: The mean age of the participants was 36 +/- 13 years. The demographic data of the two groups (OAB-V8 >= 8 and OAB-V8 < 8) were similar. The Beck Depression Inventory, OAB-V8, and Incontinence Questionnaire- Short Form scores of the antidepressant users were significantly higher than those of the control group (p < 0.001, p < 0.001, and p = 0.001, respectively). The prevalence of OAB was significantly higher in antidepressant users (64 %) than in the control group (33 %) (p = 0.003). The highest prevalence of OAB was detected in patients taking fluoxetine (63.6 %), and the lowest was observed in those taking sertraline (42.3 %) (p = 0.038). CONCLUSION: There were more OAB symptoms in antidepressant users than in control group. Each SSRI and SNRI has a unique pharmacological profile, and this could explain the opposing reports in the literature. We recommend that patients taking antidepressants be carefully monitored for OAB symptoms. PMID- 26246037 TI - Post-renal transplantation anemia at 12 months: prevalence, risk factors, and impact on clinical outcomes. AB - PURPOSE: To investigate any association between post-transplantation anemia (PTA) and clinical outcomes following living donor kidney transplantation. METHODS: We retrospectively evaluated 887 patients who received living donor kidney transplantations at our medical center between January 2006 and December 2012 to evaluate whether PTA, defined as serum hemoglobin (Hb) levels of <130 g/l in men and <120 g/l in women, at 12 months is associated with post-transplant outcomes, including graft function, death-censored graft survival, or patient survival. RESULTS: The prevalence of PTA at 1, 3, 6, and 12 months was 84.3, 39.5, 26.2, and 21.6 %, respectively. Donor age [hazard ratio (HR), 1.03; 95 % confidence interval (CI) 1.01-1.05] and acute rejection (HR 2.13; 95 % CI 1.28-3.54) were found to be independent risk factors for PTA at 12 months. Recipient age (HR 0.98; 95 % CI 0.95-1.00), pre-transplantation Hb levels (HR 0.99; 95 % CI 0.98 1.00), and estimated glomerular filtration rates (eGFRs) at 12 months (HR 0.96; 95 % CI 0.94-0.97) were found to confer slight protection against PTA at 12 months. PTA at 12 months was associated with increased graft loss (HR 1.046; 95 % CI 1.045-1.046). For each increase in anemia degree, there was a 2.77-fold greater risk of graft loss (HR 2.77; 95 % CI 1.50-5.13). When stratified according to eGFR, PTA was found to be a predictor of graft loss in patients with an eGFR of <60 ml/min/1.73 m(2) (HR 4.57; 95 % CI 1.98-10.56) but not in patients with an eGFR of >60 ml/min/1.73 m(2) (HR 1.89; 95 % CI 0.13-27.78). PTA was not found to be a predictor of patient survival. CONCLUSIONS: Anemia is common after kidney transplantation, and its prevalence declines with time after transplantation. Presence of anemia at 12 months post-transplant was an independent predictor of graft loss, with higher risk of graft loss in patients with anemia and poorer kidney functions. PMID- 26246039 TI - Mode-selective vibrational modulation of charge transport in organic electronic devices. AB - The soft character of organic materials leads to strong coupling between molecular, nuclear and electronic dynamics. This coupling opens the way to influence charge transport in organic electronic devices by exciting molecular vibrational motions. However, despite encouraging theoretical predictions, experimental realization of such approach has remained elusive. Here we demonstrate experimentally that photoconductivity in a model organic optoelectronic device can be modulated by the selective excitation of molecular vibrations. Using an ultrafast infrared laser source to create a coherent superposition of vibrational motions in a pentacene/C60 photoresistor, we observe that excitation of certain modes in the 1,500-1,700 cm(-1) region leads to photocurrent enhancement. Excited vibrations affect predominantly trapped carriers. The effect depends on the nature of the vibration and its mode-specific character can be well described by the vibrational modulation of intermolecular electronic couplings. This presents a new tool for studying electron-phonon coupling and charge dynamics in (bio)molecular materials. PMID- 26246038 TI - Hematological parameters can predict the extent of coronary artery disease in patients with end-stage renal disease. AB - PURPOSE: Aside from traditional factors (e.g., diabetes, age, and hypertension), some hematological parameters, such as neutrophil-to-lymphocyte ratio (NLR), red blood cell distribution width (RDW), and mean platelet volume (MPV), have increasingly been reported as measures of systemic inflammation and atherosclerosis in patients with end-stage renal disease (ESRD). This study aimed to determine whether there is an association between these hematological parameters and the extent of coronary artery disease (CAD) in patients with ESRD. METHODS: A total of 149 consecutive ESRD patients (66 % males) without established CAD were studied. NLR, RDW, and MPV values in all patients were calculated from the complete blood count before coronary angiography. Angiographic views were assessed by an experienced interventional cardiologist, and the extent of CAD was evaluated by the Gensini score. The patients were divided into quartiles of the Gensini score. RESULTS: Age, time on dialysis, calcium-phosphorus product, C-reactive protein levels, NLR, and MPV were significantly different among the groups (all p < 0.05). The Gensini score was correlated with age, time on dialysis (both p < 0.001), NLR (p = 0.004), and C reactive protein levels (p = 0.034) and inversely correlated with left ventricular ejection fraction (p = 0.023). Multivariate regression analysis showed that age (p = 0.001), time on dialysis (p < 0.001), NLR (p = 0.001), and MPV (p = 0.005) were independent predictors of the extent of CAD. CONCLUSIONS: Aside from the well-known traditional factors, NLR and MPV are independent predictors of the extent of CAD in patients with ESRD. PMID- 26246040 TI - The effect of guided relaxation on cortisol and affect: Stress reactivity as a moderator. AB - Stress-reduction interventions have been linked with enhanced well-being and health. This study examined affect and cortisol in 111 individuals randomly assigned to a single 35-minute guided relaxation or a stress management lecture control group. Positive affect increased more in the relaxation compared to the control group ( F = 6.62, p = .01). Dispositional stress reactivity had a moderating influence ( R2 = .248, p < .001), such that individuals high in stress reactivity showed highest increases in positive affect to the relaxation. Results indicate that a single guided relaxation intervention improves positive affect among individuals high in stress reactivity. PMID- 26246041 TI - Magnitude of observer error using cone beam CT for prostate interfraction motion estimation: effect of reducing scan length or increasing exposure. AB - OBJECTIVE: Cone beam CT (CBCT) enables soft-tissue registration to planning CT for position verification in radiotherapy. The aim of this study was to determine the interobserver error (IOE) in prostate position verification using a standard CBCT protocol, and the effect of reducing CBCT scan length or increasing exposure, compared with standard imaging protocol. METHODS: CBCT images were acquired using a novel 7 cm length image with standard exposure (1644 mAs) at Fraction 1 (7), standard 12 cm length image (1644 mAs) at Fraction 2 (12) and a 7 cm length image with higher exposure (2632 mAs) at Fraction 3 (7H) on 31 patients receiving radiotherapy for prostate cancer. Eight observers (two clinicians and six radiographers) registered the images. Guidelines and training were provided. The means of the IOEs were compared using a Kruzkal-Wallis test. Levene's test was used to test for differences in the variances of the IOEs and the independent prostate position. RESULTS: No significant difference was found between the IOEs of each image protocol in any direction. Mean absolute IOE was the greatest in the anteroposterior direction. Standard deviation (SD) of the IOE was the least in the left-right direction for each of the three image protocols. The SD of the IOE was significantly less than the independent prostate motion in the anterior posterior (AP) direction only (1.8 and 3.0 mm, respectively: p = 0.017). IOEs were within 1 SD of the independent prostate motion in 95%, 77% and 96% of the images in the RL, SI and AP direction. CONCLUSION: Reducing CBCT scan length and increasing exposure did not have a significant effect on IOEs. To reduce imaging dose, a reduction in CBCT scan length could be considered without increasing the uncertainty in prostate registration. Precision of CBCT verification of prostate radiotherapy is affected by IOE and should be quantified prior to implementation. ADVANCES IN KNOWLEDGE: This study shows the importance of quantifying the magnitude of IOEs prior to CBCT implementation. PMID- 26246042 TI - Biological monitoring of Persistent Organic Pollutants in human milk in Israel. AB - BACKGROUND: The Stockholm Convention on Persistent Organic Pollutants (POPs) aims to eliminate or restrict the production and use of POPs around the globe. The Ministry of Health, collaborating with the Ministry of Environmental Protection, measured the exposure of the population to POPs as part of the WHO-coordinated exposure study. Human milk, with a relatively high fat content is a preferred matrix for the monitoring of exposure. METHODS: Donors of breast milk were recruited from three hospitals after signing informed consent forms. Breast milk was collected from 52 primipara women, aged 23-35, living in Israel for the last 10 years who gave birth to singleton full term healthy infants. Samples, collected at 3-17 weeks postpartum, were stored at -20 degrees C until sent to the WHO Reference Laboratory, State Laboratory for Chemical and Veterinary Analysis of Food (CVUA), in Frieburg, Germany for a single pooled analysis. Mothers were provided with the pooled analysis results. RESULTS: Out of over 50 Persistent Organic Pollutants listed in the analysis, 16, including aldrin, endrin, parlar and mirex were not found at detectable levels in the Israeli pooled sample. For the indicator compounds found at detectable levels, most were lower than those reported in European countries. DISCUSSION: Since 1982, levels of POPs contamination as measured in breast milk have declined significantly. This is likely due to restrictions on agricultural, industrial, and other uses of many POPs in Israel. Ongoing biomonitoring in Israel and inter-ministerial collaboration supports the elimination of POPs in the environment and human milk. PMID- 26246043 TI - A passive sampler based on solid phase microextraction (SPME) for sediment associated organic pollutants: Comparing freely-dissolved concentration with bioaccumulation. AB - The elevated occurrence of hydrophobic organic chemicals (HOCs) such as polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCBs) and legacy organchlorine pesticides (e.g. chlordane and DDT) in estuarine sediments continues to poses challenges for maintaining the health of aquatic ecosystems. Current efforts to develop and apply protective, science-based sediment quality regulations for impaired waterbodies are hampered by non-concordance between model predictions and measured bioaccumulation and toxicity. A passive sampler incorporating commercially available solid phase microextraction (SPME) fibers was employed in lab and field studies to measure the freely dissolved concentration of target HOCs (Cfree) and determine its suitability as a proxy for bioaccumulation. SPME deduced Cfree for organochlorines was highly correlated with tissue concentrations (Cb) of Macoma and Nereis spp. co-exposed in laboratory microcosms containing both spiked and naturally contaminated sediments. This positive association was also observed in situ for endemic bivalves, where SPME samplers were deployed for up to 1 month at an estuarine field site. The concordance between Cb and Cfree for PAH was more variable, in part due to likely biotransformation by model invertebrates. These results indicate that SPME passive samplers can serve as a proxy for bioaccumulation of sediment-associated organochlorines in both lab and field studies, reducing the uncertainty associated with model predictions that do not adequately account for differential bioavailability. PMID- 26246044 TI - LC-MS screening techniques for wastewater analysis and analytical data handling strategies: Sartans and their transformation products as an example. AB - A large number of anthropogenic trace contaminants such as pharmaceuticals, their human metabolites and further transformation products (TPs) enter wastewater treatment plants on a daily basis. A mixture of known, expected, and unknown molecules are discharged into the receiving aquatic environment because only partial elimination occurs for many of these chemicals during physical, biological and chemical treatment processes. In this study, an array of LC-MS methods from three collaborating laboratories was applied to detect and identify anthropogenic trace contaminants and their TPs in different waters. Starting with theoretical predictions of TPs, an efficient workflow using the combination of target, suspected-target and non-target strategies for the identification of these TPs in the environment was developed. These techniques and strategies were applied to study anti-hypertensive drugs from the sartan group (i.e., candesartan, eprosartan, irbesartan, olmesartan, and valsartan). Degradation experiments were performed in lab-scale wastewater treatment plants, and a screening workflow including an inter-laboratory approach was used for the identification of transformation products in the effluent samples. Subsequently, newly identified compounds were successfully analyzed in effluents of real wastewater treatment plants and river waters. PMID- 26246045 TI - Long-time monitoring of polychlorinated dibenzo-p-dioxins and dibenzofurans over a decade in the ambient air of Porto, Portugal. AB - As part of a monitoring program initiated in 1998 and conducted by IDAD - Institute for Environment and Development and supported by regional municipal solid waste (MSW) management authorities, an extensive database of dioxins' and furans' (PCDD/PCDF) concentrations in ambient air was collected in Porto, in two sites classified as suburban. The present paper summarizes the analytical results of PCDD/PCDF in ambient air obtained from 2001 to 2014 through this intensive monitoring work. The toxic equivalent (WHO-TEQ 1998) concentrations of the PCDD/PCDF in the air ranged from 8.2 to 904.4 fg TEQ m(-3), with an average and median values of 104.5 fg TEQ m(-3) and 49.8 fg TEQ m(-3), respectively. The PCDD/PCDF concentration trend in Porto's ambient air shows a clear drop of the annual average values occurred during the study period. The presence of seasonal variations is very clear in the present study. Winter levels (average: 154.3 fg TEQ m(-3)) are significantly higher than summer levels (average: 42.9 fg TEQ m( 3)). The PCDD/PCDF profiles' details show that several differences occurred over time. The homologue profiles presented changes and the PCDD congeners have decreased in terms of mass. The analysis of concentrations in combination with specific homologue and congener patterns of PCDD/PCDF allowed identification of potential emission sources. PMID- 26246047 TI - Is it possible to manage the symptoms of the menopause without estrogen? PMID- 26246046 TI - Nucleotide sequence composition adjacent to intronic splice sites improves splicing efficiency via its effect on pre-mRNA local folding in fungi. AB - RNA splicing is the central process of intron removal in eukaryotes known to regulate various cellular functions such as growth, development, and response to external signals. The canonical sequences indicating the splicing sites needed for intronic boundary recognition are well known. However, the roles and evolution of the local folding of intronic and exonic sequence features adjacent to splice sites has yet to be thoroughly studied. Here, focusing on four fungi (Saccharomyces cerevisiae, Schizosaccharomyces pombe, Aspergillus nidulans, and Candida albicans), we performed for the first time a comprehensive high resolution study aimed at characterizing the encoding of intronic splicing efficiency in pre-mRNA transcripts and its effect on intron evolution. Our analysis supports the conjecture that pre-mRNA local folding strength at intronic boundaries is under selective pressure, as it significantly affects splicing efficiency. Specifically, we show that in the immediate region of 12-30 nucleotides (nt) surrounding the intronic donor site there is a preference for weak pre-mRNA folding; similarly, in the region of 15-33 nt surrounding the acceptor and branch sites there is a preference for weak pre-mRNA folding. We also show that in most cases there is a preference for strong pre-mRNA folding further away from intronic splice sites. In addition, we demonstrate that these signals are not associated with gene-specific functions, and they correlate with splicing efficiency measurements (r = 0.77, P = 2.98 * 10(-21)) and with expression levels of the corresponding genes (P = 1.24 * 10(-19)). We suggest that pre-mRNA folding strength in the above-mentioned regions has a direct effect on splicing efficiency by improving the recognition of intronic boundaries. These new discoveries are contributory steps toward a broader understanding of splicing regulation and intronic/transcript evolution. PMID- 26246048 TI - Fluffy Periostitis Induced by Voriconazole. PMID- 26246049 TI - Challenges in Enforcing Home Smoking Rules in a Low-Income Population: Implications for Measurement and Intervention Design. AB - INTRODUCTION: Smoke-free homes reduce exposure to secondhand smoke, contribute to lower levels of consumption, and help smokers to quit. Even when home smoking rules are established however, they may not be consistently enforced. METHODS: This study uses data from a randomized controlled trial of a brief intervention to create smoke-free homes among callers to the United Way of Greater Atlanta 2-1 1. Participants with partial or full home smoking bans at 6-month follow-up were asked about enforcement challenges, rooms where smoking occurred, and exceptions to the rules. Air nicotine monitors were placed in a subset of homes. RESULTS: Participants (n = 286) were mostly female (84.6%) and African American (84.9%). Most were smokers (79.0%) and reported at least half of their friends and relatives smoked (63.3%). Among those with a full ban, 4.3% reported their rules were broken very often whereas 52.6% stated they were never broken. Bad weather and parties were the most common exceptions to rules. Among nonsmokers with full bans, 16% reported exposure to secondhand smoke in the home 1-3 days in the past week. In multivariate analyses, having a partial ban, being a nonsmoker, and living with three or more smokers predicted higher levels of enforcement challenges. CONCLUSIONS: Findings suggest the majority of households with newly adopted smoke-free rules had no or rare enforcement challenges, but about one fifth reported their rules were broken sometimes or very often. Interventions to create smoke-free homes should address enforcement challenges as newly adopted rules may be fragile in some households. IMPLICATIONS: Interventions that promote smoke-free homes should address enforcement challenges. PMID- 26246050 TI - Nondaily, Low-Rate Daily, and High-Rate Daily Smoking in Young Adults: A 17-Year Follow-Up. AB - INTRODUCTION: While overall tobacco consumption is declining in many countries, patterns of low-frequency smoking-such as nondaily and low-rate daily smoking appear to be increasing. We aimed firstly to describe differences in demographic, smoking- and quitting-related characteristics between nondaily and daily smokers in young adults; secondly, to determine the proportion of low-frequency smokers who transition to a higher rate of smoking by age 38 and factors associated with this. METHODS: We assessed a cohort of individuals born in Dunedin, New Zealand, in 1972-1973, at regular intervals from age 21 to age 38 years. Smokers were categorized as either nondaily, low-rate daily (ie, defined as five or less cigarettes per day) or high-rate daily smokers (six or more cigarettes per day). Descriptive statistics, linear and logistic regression were used. RESULTS: Nondaily smokers at age 21 tended to self-identify as nonsmokers. Both nondaily smokers and low-rate daily smokers reported higher readiness and confidence in quitting compared to high-rate daily smokers. Around 40% of the age 21 low-rate daily smokers reported smoking daily at age 38, compared to 13% of the nondaily smokers and 4% of the nonsmokers. Nondaily smoking at age 21 was associated with increased odds of being a daily smoker by age 38 (OR: 3.6; 95% CI = 1.7% to 7.8%) compared to nonsmokers. CONCLUSIONS: Different patterns of smoking are associated with differences in readiness to quit and confidence in quitting ability. For a considerable proportion of smokers, low-frequency smoking in young adulthood develops into daily smoking by adulthood. IMPLICATIONS: Low-frequency smoking, including nondaily smoking, in early adulthood is a significant risk factor for being a daily smoker in the long-term. Cessation interventions should be tailored to low-frequency smokers, taking into account differences between them and heavier smokers in terms of smoking motivation and quitting-related cognitions. PMID- 26246052 TI - Erratum to: The characteristics of intrinsic complex micro-contractile activity in isolated strips of the rat bladder. PMID- 26246051 TI - Zerumbone, a ginger sesquiterpene, induces apoptosis and autophagy in human hormone-refractory prostate cancers through tubulin binding and crosstalk between endoplasmic reticulum stress and mitochondrial insult. AB - Zerumbone, a natural monocyclic sesquiterpene, is the main component of the tropical plant Zingiber zerumbet Smith. Zerumbone induced antiproliferative and apoptotic effects against PC-3 and DU-145, two human hormone-refractory prostate cancer (HRPC) cell lines. Zerumbone inhibited microtubule assembly and induced an increase of MPM-2 expression (specific recognition of mitotic proteins). It also caused an increase of phosphorylation of Bcl-2 and Bcl-xL, two key events in tubulin-binding effect, indicating tubulin-binding capability and mitotic arrest to zerumbone action. Furthermore, zerumbone induced several cellular effects distinct from tubulin-binding properties. First, zerumbone significantly increased, while paclitaxel (as a tubulin-binding control) decreased, Mcl-1 protein expression. Second, paclitaxel but not zerumbone induced Cdk1 activity. Third, zerumbone other than paclitaxel induced Cdc25C downregulation. The data suggest that, in addition to targeting tubulin/microtubule, zerumbone may act on other targets for signaling transduction. Zerumbone induced mitochondrial damage and endoplasmic reticulum (ER) stress as evidenced by the loss of mitochondrial membrane potential and upregulation of GRP-78 and CHOP/GADD153 expression. Zerumbone induced an increase of intracellular Ca(2+) levels, a crosstalk marker between ER stress and mitochondrial insult, associated with the formation of active calpain I fragment. It induced apoptosis through a caspase-dependent way and caused autophagy as evidenced by dramatic LC3-II formation. In summary, the data suggest that zerumbone is a multiple targeting compound that inhibits tubulin assembly and induces a crosstalk between ER stress and mitochondrial insult, leading to apoptosis and autophagy in HRPCs. PMID- 26246054 TI - Laser-induced breakdown spectroscopy analysis of human deciduous teeth samples. AB - Laser-induced breakdown spectroscopy (LIBS) analysis of human deciduous teeth has been performed by employing Nd:YAG laser (1064 nm, 10 ns) for the evaluation of plasma parameters as well as elemental analysis. The plasma parameters, i.e., electron temperature and electron number density of laser-induced teeth plasma at various fluencies, have been evaluated. Both parameters show an increasing trend up to a certain value of laser fluence, i.e., 2.6 J/cm(2). With further increase in laser fluence up to a value of 3.9 J/cm(2), a decreasing trend is observed which is due to shielding effect. With further increase in laser fluence up to a maximum value of 10.5 J/cm(2), the insignificant changes in plasma parameters are observed which are attributed to saturation phenomenon governed by self regulating regime. Emission spectroscopy results exhibit that laser fluence is the controlling factor for both plasma parameters. The elemental analysis was also performed at constant laser fluence of 2.6 J/cm(2) by evaluating the variation in detected elemental concentration of Ca, Fe, Sr, Zn, and Pb in three different parts of human teeth, i.e., enamel, dentine, and cementum. The lower concentration of Ca as compared to the standard values of CaCO3 (self-fabricated pellet) reveals that enamel is the most deciduous part of the human teeth. However, at the same time, it is also observed that the highest concentration of micro minerals is also found in enamel, then in dentine, and lowest in cementum. Carious or unhealthy tooth is identified by enhanced concentration of micro minerals (Pb, Sr, Zn, and Fe). The highest concentration of micro minerals as compared to other parts of teeth (dentine and root cementum) and lower concentration of Ca as compared to standard CaCO3 pellet in enamel confirm that enamel is the most deciduous part of the teeth. PMID- 26246056 TI - [Not Available]. PMID- 26246053 TI - Bosentan, a mixed endothelin receptor antagonist, inhibits superoxide anion induced pain and inflammation in mice. AB - Bosentan is a mixed endothelin receptor antagonist widely used to treat patients with pulmonary arterial hypertension, and the emerging literature suggests bosentan as a potent anti-inflammatory drug. Superoxide anion is produced in large amounts during inflammation, stimulates cytokine production, and thus contributes to inflammation and pain. However, it remains to be determined whether endothelin contributes to the inflammatory response triggered by the superoxide anion. The present study investigated the effects of bosentan in a mouse model of inflammation and pain induced by potassium superoxide, a superoxide anion donor. Male Swiss mice were treated with bosentan (10-100 mg/kg) by oral gavage, 1 h before potassium superoxide injection, and the inflammatory response was evaluated locally and at spinal cord (L4-L6) levels. Bosentan (100 mg/kg) inhibited superoxide anion-induced mechanical and thermal hyperalgesia, overt pain-like behavior (abdominal writhings, paw flinching, and licking), paw edema, myeloperoxidase activity (neutrophil marker) in the paw skin, and leukocyte recruitment in the peritoneal cavity. Bosentan also inhibited superoxide anion-induced interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) production, while it enhanced IL-10 production in the paw skin and spinal cord. Bosentan inhibited the reduction of antioxidant capacity (reduced glutathione, ferric reducing antioxidant power, and ABTS radical scavenging ability) induced by the superoxide anion. Finally, we demonstrated that intraplantar injection of potassium superoxide induces the mRNA expression of prepro-endothelin-1 in the paw skin and spinal cord. In conclusion, our results demonstrated that superoxide anion-induced inflammation, pain, cytokine production, and oxidative stress depend on endothelin; therefore, these responses are amenable to bosentan treatment. PMID- 26246057 TI - [Intensive home treatment of adolescents in crisis: treat the parents along with 'psychiatric' adolescents]. AB - OBJECTIVE: To investigate whether a new intensive home treatment (IHT) model for adolescents with psychiatric problems is more effective or more efficient than previous treatment methods involving long-term clinical admission. DESIGN: Descriptive, retrospective study. METHOD: The previous treatment model for adolescents in crisis consisted of clinical admission for 6 months or longer. To implement the new treatment model, 4 admission wards with 34 beds were converted to 1 'high & intensive care' (HIC) ward with 7 beds, in combination with IHT care for the family in the home environment. Admission to the HIC is short-term, and the parents are admitted along with their child. The new model was used from May 2013. The number of patients receiving care, the length of treatment, patient satisfaction, the number of beds and the costs were investigated and compared with data from the years 2011 and 2012. RESULTS: In comparison with the previous treatment model, this IHT treatment model revealed that more adolescents could be treated in the course of 1 year (125 compared with 70 per year) with a shorter duration of treatment (2 weeks clinical admission if required and 4 months ambulatory treatment, compared with 6 to 7 months clinical treatment) and with lower costs (? 28,000 compared with ? 55,000) with the same level of patient satisfaction. CONCLUSION: Although initial treatment results are positive, more extensive investigation is required into treatment effectiveness and cost efficiency of the IHT model for adolescents over a longer period of time. PMID- 26246058 TI - [Stent placement or acute resection in colonic obstruction?]. AB - When choosing a treatment for obstructing left-sided colonic carcinoma, a distinction is made between patients with increased surgical risk and patients without increased surgical risk. Patients with increased surgical risk (age > 70 years or ASA class >= 3) do have an indication for stent placement as a bridge to elective surgery, or as an alternative, a decompressing colostomy. Acute resection is the treatment of choice in patients without increased surgical risk, given the oncological risk associated with guidewire-related or stent-related perforation. Stent placement is recommended as the palliative treatment for patients with malignant colonic obstruction, unless the patient is simultaneously being treated with angiogenesis inhibitors (e.g. bevacizumab) as these increase the risk of stent perforation. Expertise of at least 20 colonic stent procedures is required for stent placement. PMID- 26246059 TI - [Differences between generations: relevant for medical education in the Netherlands]. AB - Provision of care is increasingly being tailored to patients' wishes, which means that insight into the ideas, norms and values of the care-consumer are required. This approach is also beginning to filter through into medical education. We can differentiate generations on the basis of shared opinions, because groups with shared experiences usually share the same values. This is a useful line of approach if we wish to serve different generations of consumers better. At the moment there are four different generations influencing the setup and division of the healthcare services and relevant to medical education in the coming decades. Future education methods will have to be in line with the wishes of the generation from which new doctors come. In order to achieve better care for patients it is important to give 'thinking in generations' more attention in medical education. PMID- 26246060 TI - [Severe inflammation during recovery from neutropenia: the immune reconstitution inflammatory syndrome following chemotherapy]. AB - Immune reconstitution inflammatory syndrome (IRIS) occurs when a patient is recovering from a transient immunodeficiency and results in an uncontrolled inflammatory response to infectious agents and tissue damage. Symptoms such as fever and radiological signs seem to paradoxically appear or worsen, unmasking a previously unrecognized infection. The patient's clinical condition may then deteriorate as a result of increasing tissue damage and this may even lead to death. IRIS was initially described in patients suffering from a HIV infection who experienced immune recovery following the initiation of antiretroviral therapy. Increasingly, however, the syndrome is being reported in patients who are recovering from an episode of neutropenia following chemotherapy, hypomethylating agent use or a stem cell transplantation for the treatment of a solid tumour or haematological cancers. We describe two cases of IRIS following an episode of neutropenia in patients with a haematological malignancy and elaborate on the pathogenesis, diagnosis and treatment of IRIS in cancer patients. PMID- 26246061 TI - [The elderly patient with multiple rib fractures]. AB - Rib fractures resulting from blunt thoracic trauma occur frequently in the elderly. Even though these are usually due to a low impact trauma mechanism (e.g. a fall from standing height), rib fractures are associated with significant morbidity and mortality in the elderly patient. This unfavourable clinical course is most often caused by respiratory insufficiency due to lung oedema or pneumonia. This cases series presents three elderly patients who sustained multiple rib fractures and were subsequently admitted to a level I trauma centre for treatment and discusses diagnostic challenges and different treatment approaches for this population. More specifically, age-specific indications and contra-indications for intravenous or epidural analgesia and operative rib fixation are discussed. In addition, we show that a multidisciplinary approach, involving a trauma surgeon, anaesthetist, intensive care physician and physiotherapist, is paramount for the prevention of potentially lethal complications. PMID- 26246062 TI - [Revised NHG practice guideline 'Lumbosacral radicular syndrome']. AB - The Dutch College of General Practitioners (NHG) recently published the practice guideline 'Lumbosacral radicular syndrome'. This guideline provides general practitioners with guidance for the diagnostic workup and treatment of patients with lumbosacral radicular syndrome. In this article we discuss the most important changes and modifications to this guideline point by point. The most important recommendations for management are summarized in a flowchart. PMID- 26246063 TI - [Loperamide for acute infectious diarrhoea]. AB - Many physicians are resistant to the idea of prescribing loperamide for acute infectious traveller's diarrhoea and community-acquired diarrhoea because of the fear of possible adverse effects. Large randomized trials with loperamide, either alone or as an adjunct to antibiotic treatment, have in fact revealed positive rather than negative effects. International guidelines now often support the use of loperamide for the treatment of infectious diarrhoea without dysentery. There seems to be no reason to systematically avoid loperamide in patients with dysentery, but caution is advised. Loperamide can be used as monotherapy or as an adjunct to antibiotic treatment in immunocompetent adults with acute infectious traveller's diarrhoea or community-acquired diarrhoea without severe comorbidities. This can reduce both the frequency of diarrhoea and the time until the diarrhoea stops without the risk of severe complications. PMID- 26246064 TI - [A woman with a red demarcation of the tongue]. AB - A 68-year-old woman had a red demarcation of the tongue, without any discomfort. Because of the use of corticosteroid inhalations, it was thought that this was caused by median rhomboid glossitis, based on Candida albicans. Oral antimycotic therapy made the demarcation disappear, which confirmed the diagnosis. PMID- 26246065 TI - [Emil Kraepelin, grandfather of the DSM]. AB - The German psychiatrist Emil Kraepelin developed a statistical manual of psychiatric diseases long before the Diagnostic and Statistical Manual of Mental Disorders (DSM) was published. He classified numerous disorders in the 1880 s. During World War I he was one of the leading German psychiatrists, taking care of the thousands of 'Kriegsneurotiker'--though generally not with the intention of restoring sanity, but rather to get them back to the front or the weapons factory. The victory of the German nation, the 'Deutsche Volk', destined to rule, was more important than the fate of the psychologically sick or wounded individual patient. The feared degeneration of the German race had to be stopped, reason for Kraepelin to become involved with extreme right-wing and eugenic organisations. PMID- 26246066 TI - [Hormone therapy in prostate cancer; a pharmacotherapeutic challenge]. AB - Prostate cancer is the most common form of cancer in men in the Western world. One-third of the patients with localised prostate cancer will develop recurrent disease, localised disease spread or distant metastases. The presence of distant metastases is an indication for primary palliative hormone therapy. Intervention in the testosterone metabolism using hormone therapy is frequently accompanied by side effects and has a negative influence on the quality of life. Almost all prostate cancer patients show disease progression while on primary hormone therapy, despite having testosterone concentrations at castration level; they are then said to have castration-resistant prostate cancer (CRPC). The CYP17 inhibitor abiraterone and the non-steroidal anti-androgen enzalutamide are second generation hormone therapies for metastatic CRPC both before and after treatment with standard docetaxel-based chemotherapy. Abiraterone and enzalutamide can lead to many interactions with other drugs or food. This can lead to higher or lower levels of both the hormone therapy and comedications. PMID- 26246067 TI - Stroke 2015, Combined 26th ASM of the Stroke Society of Australasia and 11th Australasian Nursing & Allied Health Stroke Conference SMART STROKES, Melbourne, Australia. PMID- 26246069 TI - Concomitant cannabis abuse/dependence in patients treated with opioids for non cancer pain. AB - BACKGROUND AND OBJECTIVES: Cannabis use is common among patients taking prescription opioids, although rates of concomitant cannabis use disorder (CUD) have been largely unexamined. CUD may increase safety risks in those taking opioid pain medications but it is unknown whether cannabis and opioids function as substitutes (cannabis use is associated with less prescription opioid use), or rather as complements (cannabis is associated with increased use of prescription opioids). METHODS: We examined rates of CUD in a national sample of Veterans Health Administration (VHA) patients (n = 1,316,464) with non-cancer pain diagnoses receiving opioid medications in fiscal year 2012. Using bivariate analysis to identify potentially confounding variables associated with CUD (e.g., psychotropic medication, other substance use disorders) in this population, we then utilized logistic regression to examine rates of cannabis use disorder among individuals receiving different numbers of opioid prescriptions (0, 1-2, 3-10, 11 19, 20+). RESULTS: Descriptive analysis, largely confirmed by logistic regression, demonstrated that greater numbers of prescription opioid fills were associated with greater likelihood of CUD. This relationship was reduced somewhat for those receiving the most opioid prescriptions (20+) in the logistic regression, which controlled for potentially confounding variables. DISCUSSION AND CONCLUSIONS: These results warrant increased attention to CUDs among patients receiving numerous opioid prescriptions. Increasing legalization of cannabis is likely to further increase use and abuse of cannabis in patients prescribed opioids. SCIENTIFIC SIGNIFICANCE: These findings suggest that clinicians should be alert to concomitant CUD and prescription opioid use, as these substances appear to complement each other. PMID- 26246068 TI - Antiretroviral Medication Adherence and Amplified HIV Transmission Risk Among Sexually Active HIV-Infected Individuals in Three Diverse International Settings. AB - Successful biomedical prevention/treatment-as-prevention (TasP) requires identifying individuals at greatest risk for transmitting HIV, including those with antiretroviral therapy (ART) nonadherence and/or 'amplified HIV transmission risk,' defined as condomless sex with HIV-uninfected/unknown-status partners when infectious (i.e., with detectable viremia or STI diagnosis according to Swiss criteria for infectiousness). This study recruited sexually-active, HIV-infected patients in Brazil, Thailand, and Zambia to examine correlates of ART nonadherence and 'amplified HIV transmission risk'. Lower alcohol use (OR = .71, p < .01) and higher health-related quality of life (OR = 1.10, p < .01) were associated with greater odds of ART adherence over and above region. Of those with viral load data available (in Brazil and Thailand only), 40 % met Swiss criteria for infectiousness, and 29 % had 'amplified HIV transmission risk.' MSM had almost three-fold (OR = 2.89, p < .001) increased odds of 'amplified HIV transmission risk' (vs. heterosexual men) over and above region. TasP efforts should consider psychosocial and contextual needs, particularly among MSM with detectable viremia. PMID- 26246070 TI - Ethical Reflections on Genetic Enhancement with the Aim of Enlarging Altruism. AB - When it comes to caring about and helping those in need, our imaginations tend to be weak and our motivation tends to be parochial. This is a major moral problem in view of how much unmet need there is in the world and how much material capacity there is to address that need. With this problem in mind, the present paper will focus on genetic means to the enhancement of a moral capacity-a disposition to altruism-and of a cognitive capacity that facilitates use of the moral capacity: the ability to grasp vividly the needs of individuals who are unknown and not present. I will address two questions, with more extensive attention to the first question. First, assuming we had excellent reason to believe that the enhancements were safe, effective, and available to all who desired them, would seeking these enhancements be inherently morally acceptable that is, free of inherent wrongness? Second, would it be wise for a society to pursue these enhancements? I will defend an affirmative answer to the first question while leaving the second question open. PMID- 26246071 TI - The influence of the local oxygen vacancy concentration on the piezoresponse of strontium titanate thin films. AB - In this study, the influence of the local oxygen vacancy concentration on piezoresponse force microscopy (PFM) measurements was investigated. Ultra-thin single-crystalline SrTiO3 thin films were deposited on niobium doped SrTiO3 substrates and analyzed using a combined PFM and local conductive atomic force microscopy (LC-AFM) measurement setup. After applying different polarization voltages between +/-2 V and +/-5 V to the thin films, we simultaneously observed an anomalous contrast in the piezoresponse amplitude and phase signal as well as a changed local conductivity in the exact same region. Since classic ferroelectricity can be excluded as the reason for the observed contrast, an influence of the local oxygen vacancy concentration on the piezoresponse is considered. Additionally, the surface potential was measured using Kelvin probe force microscopy (KPFM) revealing a change in surface potential in the regions of the applied voltage. The observed relaxation of the surface potential over time was fitted to a local oxidation reaction of the previously reduced regions of the ultra-thin SrTiO3 film. We propose a model that relates the local oxygen vacancy concentration to the surface potential. The influence of the oxygen vacancy concentration on the PFM measurements is explained. PMID- 26246072 TI - Role for microglia in sex differences after ischemic stroke: importance of M2. AB - Inflammation plays a critical role in the pathogenesis of ischemic stroke. This process depends, in part, upon proinflammatory factors released by activated resident central nervous system (CNS) microglia (MG). Previous studies demonstrated that transfer of IL-10(+) B-cells reduced infarct volumes in male C57BL/6 J recipient mice when given 24 h prior to or therapeutically at 4 or 24 h after experimental stroke induced by 60 min middle cerebral artery occlusion (MCAO). The present study assesses possible sex differences in immunoregulation by IL-10(+) B-cells on primary male vs. female MG cultured from naive and ischemic stroke-induced mice. Thus, MG cultures were treated with recombinant (r)IL-10, rIL-4 or IL-10(+) B-cells after lipopolysaccharide (LPS) activation and evaluated by flow cytometry for production of proinflammatory and anti inflammatory factors. We found that IL-10(+) B-cells significantly reduced MG production of TNF-alpha, IL-1beta and CCL3 post-MCAO and increased their expression of the anti-inflammatory M2 marker, CD206, by cell-cell interactions. Moreover, MG from female vs. male mice had higher expression of IL-4 and IL-10 receptors and increased production of IL-4, especially after treatment with IL 10(+) B-cells. These findings indicate that IL-10-producing B-cells play a crucial role in regulating MG activation, proinflammatory cytokine release and M2 phenotype induction, post-MCAO, with heightened sensitivity of female MG to IL-4 and IL-10. This study, coupled with our previous demonstration of increased numbers of transferred IL-10(+) B-cells in the ischemic hemisphere, provide a mechanistic basis for local regulation by secreted IL-10 and IL-4 as well as direct B-cell/MG interactions that promote M2-MG. PMID- 26246074 TI - Correction. PMID- 26246073 TI - Structural basis for drug-induced allosteric changes to human beta-cardiac myosin motor activity. AB - Omecamtiv Mecarbil (OM) is a small molecule allosteric effector of cardiac myosin that is in clinical trials for treatment of systolic heart failure. A detailed kinetic analysis of cardiac myosin has shown that the drug accelerates phosphate release by shifting the equilibrium of the hydrolysis step towards products, leading to a faster transition from weak to strong actin-bound states. The structure of the human beta-cardiac motor domain (cMD) with OM bound reveals a single OM-binding site nestled in a narrow cleft separating two domains of the human cMD where it interacts with the key residues that couple lever arm movement to the nucleotide state. In addition, OM induces allosteric changes in three strands of the beta-sheet that provides the communication link between the actin binding interface and the nucleotide pocket. The OM-binding interactions and allosteric changes form the structural basis for the kinetic and mechanical tuning of cardiac myosin. PMID- 26246075 TI - A qualitative cancer screening study with childhood sexual abuse survivors: experiences, perspectives and compassionate care. AB - OBJECTIVE: The childhood sexual abuse (CSA) survivor population is substantial and survivors have been identified as part of the population who were under screened or never-screened for breast, cervical and colon cancer. Our objective was to learn CSA survivor perspectives on, and experiences with, breast, cervical and colon cancer screening with the intention of generating recommendations to help healthcare providers improve cancer screening participation. DESIGN: A pragmatic constructivist qualitative study involving individual, semistructured, in-depth interviews was conducted in January 2014. Thematic analysis was used to describe CSA survivor perspectives on cancer screening and identify potential facilitators for screening. PARTICIPANTS: A diverse purposive sample of adult female CSA survivors was recruited. The inclusion criteria were: being a CSA survivor, being in a stable living situation, where stable meant able to meet one's financial needs independently, able to maintain supportive relationships, having participated in therapy to recover from past abuse, and living in a safe environment. 12 survivors were interviewed whose ages ranged from the early 40s to mid-70s. Descriptive saturation was reached after 10 interviews. SETTING: Interviews were conducted over the phone or Internet. CSA survivors were primarily from urban and rural Ontario, but some resided elsewhere in Canada and the USA. RESULTS: The core concept that emerged was that compassionate care at every level of the healthcare experience could improve cancer screening participation. Main themes included: desire for holistic care; unique needs of patients with dissociative identity disorder; the patient-healthcare provider relationship; appointment interactions; the cancer screening environment; and provider assumptions about patients. CONCLUSIONS: Compassionate care can be delivered by: building a relationship; practising respect; focusing attention on the patient; not rushing the appointment; keeping the environment positive and comfortable; maintaining patient dignity; sharing control whenever possible; explaining procedures; and using laughter to reduce power imbalance through shared humanity. PMID- 26246076 TI - Relationship between education levels and booster counselling sessions on smoking cessation among Chinese smokers. AB - OBJECTIVES: Although various effective interventions are available to help individuals quit smoking, the effect of educational levels on cessation rates has rarely been studied, and of the few intervention studies on this topic, the results have been conflicting. DESIGN AND SETTING: From October 2008 to August 2013, a partly retrospective non-randomised study was conducted in a smoking cessation clinic of a large general hospital in Beijing, China. PARTICIPANTS: In total, 547 Chinese smokers who sought treatment were divided into two groups: a face-to-face counselling group (FC, n=149) and an FC group subjected to four telephone follow-up sessions (FCF, n=398). OUTCOMES: We evaluated self-reported cessation rates by day 7 and after 6 and 12 months and stratified the two groups by education levels. RESULTS: The 7-day and 6-month and 12-month continuous cessation rates of smokers of low education levels in the FC group at the time of the 12-month follow-up were 12.5%, 7.1% and 7.1%, respectively, which were lower than those of the highly educated smokers (16.1%, 12.9% and 9.7%, respectively). The results were opposite for the FCF group. The corresponding results for the highly educated smokers of the FCF group were 25.0%, 17.2% and 10.3%, respectively, which were lower than those for the smokers of low education levels (28.3%, 22.9% and 18.1%, respectively). However, significant differences were observed only among the FCF group participants who had experienced 12 months of continuous abstinence, and the crude OR for these individuals was recorded at 0.52 (0.29 to 0.93), p=0.03. A stepwise logistic regression showed that education levels may play a role in various intervention methods. Being married and higher Fagerstrom test scores were also predictors of cessation tendencies. CONCLUSIONS: Education levels may affect the benefits of booster counselling sessions on smoking cessation among Chinese smokers. PMID- 26246077 TI - Retrospective study of the predictors of mortality and radiographic deterioration in 782 patients with nodular/bronchiectatic Mycobacterium avium complex lung disease. AB - OBJECTIVES: Some patients with nodular/bronchiectatic Mycobacterium avium complex lung disease (NB MAC-LD) deteriorate and die. The main aim of the study is to evaluate the prognostic factors and radiographic outcomes in patients with NB MAC LD. SETTING: Retrospective single-centre review. PARTICIPANTS: 782 HIV-negative patients with NB MAC-LD treated at our institution in Japan. PRIMARY AND SECONDARY OUTCOME MEASURES: All-cause and MAC-LD progression mortality rates and the prognostic factors, and radiographic deterioration rates and the prognostic factors. RESULTS: Mean age was 68.1 years, and median follow-up period was 4.3 years. Death from any cause and progression of MAC lung disease (MAC-LD) occurred in 130 (16.6%), and 19 (2.4%) patients, respectively. All-cause and MAC-LD progression 10-year mortality rates were 27.4% and 4.8%, respectively. In 536 patients with MAC-LD who were followed-up for more than 1 year, radiographic deterioration occurred in 221 (41.2%) patients and median time-to-radiographic deterioration was 9 years. A multivariate Cox proportional hazard model showed male sex, older age, body mass index <18.5 kg/m(2), absence of bloody sputum, hypoalbuminaemia and erythrocyte sedimentation rate >40 mm/h to be negative prognostic factors for all-cause mortality, and the presence of idiopathic pulmonary fibrosis, haemoglobin <11.3 mg/dL, C reactive protein >1.0 mg/dL and the presence of cavity to be negative prognostic factors for radiographic deterioration. CONCLUSIONS: Only 2.4% of patients with NB MAC-LD died from MAC-LD progression. As clinical trials testing the effectiveness of drug therapy in patients with NB MAC-LD are being designed and implemented, the primary end point could be time-to-radiographic deterioration, and trial patients need to be stratified according to these prognostic factors before randomisation. PMID- 26246079 TI - Erratum. PMID- 26246078 TI - What are the most effective behaviour change techniques to promote physical activity and/or reduce sedentary behaviour in inactive adults? A systematic review protocol. AB - INTRODUCTION: Large proportions of the population are not meeting recommended levels of physical activity and have increasingly sedentary lifestyles. Low levels of physical activity are predictive of poor health outcomes and time spent sedentary is related to a host of risk factors independently of physical activity levels. Building an evidence base of the best approaches to intervene in the lifestyles of inactive individuals is crucial in preventing long-term disease, disability and higher mortality rates. METHODS AND ANALYSIS: Systematic searches will be conducted on all relevant databases (eg, PubMed, Scopus, CINAHL, PsycINFO). Studies will be included if they assess interventions aimed at changing physical activity or sedentary behaviour levels in adults (over 18) who are inactive and do not suffer from chronic conditions. Studies must also be randomised controlled trials (RCTs), have a primary outcome of physical activity or sedentary behaviour, and measure outcomes at least 6 months after intervention completion. Studies will be coded using the Behaviour Change Technique (BCT) taxonomy v1 and Template for Intervention Description and Replication (TIDieR) guidelines. 2 reviewers will independently screen full-text articles and extract data on study characteristics, participants, BCTs, intervention features and outcome measures. Study quality will also be assessed independently by 2 reviewers using the Cochrane risk of bias tool. A meta-analysis will be considered if there is sufficient homogeneity across outcomes. GRADE criteria will be used to assess quality of evidence. DISSEMINATION: This will be the first review to systematically appraise interventions aimed at changing the physical activity or sedentary behaviour of inactive individuals using RCT designs with a 6-month follow-up post-intervention. This review will better inform intervention designers targeting inactive populations and inform the design of a future complex intervention. REVIEW REGISTRATION NUMBER: This protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 17 October 2014 (registration number: CRD42014014321). PMID- 26246080 TI - Treating tobacco dependence in older adults: a survey of primary care clinicians' knowledge, attitudes, and practice. AB - BACKGROUND: The benefits of smoking cessation among older people are well documented. Despite this, evidence suggests that older smokers are rarely engaged in smoking cessation efforts, and that existing tobacco dependence treatments require further tailoring to the specific needs of older smokers. This study assesses the knowledge, attitudes, and clinical practice of primary care clinicians in relation to addressing tobacco dependence among older people. METHODS: A cross-sectional survey of 427 NHS primary care clinicians in a large English city was conducted using modified version of a previously validated questionnaire. RESULTS: One hundred and seventy one clinicians (40 % response rate) completed the survey. While the majority (90.0 %) of respondents reported enquiring regularly about older patients' smoking status, just over half (59.1 %) reported providing older patients with smoking cessation support. A lack of awareness in relation to the prevalence and impact of smoking in later life were apparent: e.g. only 47 % of respondents were aware of that approximately 10 life years are lost due to smoking related disease, and only 59 % knew that smoking can reduce the effectiveness of medication prescribed for conditions common in later life. Self-reported attendance at smoking-related training was significantly associated with proactive clinical practice. CONCLUSIONS: There is a need to improve clinicians' knowledge, in relation to smoking and smoking cessation in older patients and to build clinician confidence in seizing teachable moments. PMID- 26246081 TI - Fatal primary cutaneous cryptococcosis: case report and review of published literature. AB - OBJECTIVE: Cryptococcus is an opportunistic yeast with a worldwide distribution that primarily causes significant infections in immunocompromised individuals, generally by affecting the respiratory tract. But primary cutaneous cryptococcosis (PCC) without systemic infection is rare. We report a case of PCC in a patient with nephrotic syndrome. METHODS: The 23-year-old man developed severe necrotising cellulitis on both the anterior and posterior of his trunk following a massage. He had been treated with systemic corticosteroids over 20 months for nephrotic syndrome. A skin biopsy of the wound area revealed cutaneous vasculitis and chronic inflammation with yeast-like organisms. Periodic acid Schiff (PAS) staining indicated that the structures were consistent with Cryptococcus. A Cryptococcus neoformans infection was confirmed by culture. Azole therapy was begun, and the skin ulcers gradually stopped disseminating. However, the patient died following continuous capillary haemorrhage on the 22 day since admission. CONCLUSION: Cryptococcus is crucial to be considered in the differential diagnosis of subcutaneous necrosis in any patient on immunosuppressive therapy. PMID- 26246083 TI - A pair of highly biotolerated diamagnetic and paramagnetic iron(ii) complexes displaying electroneutrality. AB - A pair of structurally analogous macrocyclic iron(ii) complexes with a magnetic off-on relationship is reported that exhibit electroneutrality at neutral pH and high stability in physiological media. This has been achieved by external charge compensation using nicotinate pendent arms. No contact toxicity was observed for cells up to 4 mM for the low-spin and 2 mM for the high-spin complex. These results are a necessary precursor to the future design of turn-on probes with elevated biotolerance. PMID- 26246082 TI - Mechanistic analysis of ghrelin-O-acyltransferase using substrate analogs. AB - Ghrelin-O-Acyltransferase (GOAT) is an 11-transmembrane integral membrane protein that octanoylates the metabolism-regulating peptide hormone ghrelin at Ser3 and may represent an attractive target for the treatment of type II diabetes and the metabolic syndrome. Protein octanoylation is unique to ghrelin in humans, and little is known about the mechanism of GOAT or of related protein-O acyltransferases HHAT or PORC. In this study, we explored an in vitro microsomal ghrelin octanoylation assay to analyze its enzymologic features. Measurement of Km for 10-mer, 27-mer, and synthetic Tat-peptide-containing ghrelin substrates provided evidence for a role of charge interactions in substrate binding. Ghrelin substrates with amino-alanine in place of Ser3 demonstrated that GOAT can catalyze the formation of an octanoyl-amide bond at a similar rate compared with the natural reaction. A pH-rate comparison of these substrates revealed minimal differences in acyltransferase activity across pH 6.0-9.0, providing evidence that these reactions may be relatively insensitive to the basicity of the substrate nucleophile. The conserved His338 residue was required both for Ser3 and amino-Ala3 ghrelin substrates, suggesting that His338 may have a key catalytic role beyond that of a general base. PMID- 26246084 TI - RasGRF1 regulates the hypothalamic-pituitary-adrenal axis specifically in early adolescent female mice. AB - Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the induction and prolongation of a variety of psychiatric disorders. As such, much effort has been made to understand the molecular mechanisms involved in its control. However, the vast majority of the studies on the HPA axis have used adult animals, and among these the majority has used males. Here we show that in knockout mice lacking the guanine nucleotide exchange factor, RasGRF1, habituation to 30 min/day of restraint stress is markedly accelerated, such that these mice do not display elevated corticosterone levels or enhanced locomotion after 7 days of stress exposure, like WT mice do. Strikingly, this phenotype is present in early-adolescent female RasGRF1 knockout mice, but not in their early-adolescent male, mid-adolescent female, adult female or adult male counterparts. Moreover, not only is there a clear response to restraint stress in early-adolescent female RasGRF1 knockout mice, their response after one, three and five exposures is magnified approximately threefold compared to WT mice. These findings imply that distinct mechanisms exist to regulate the HPA axis in early-adolescent females that involves RasGRF1. A full understanding of how RasGRF1 controls the HPA axis response to stress may be required to design effective strategies to combat stress-associated psychiatric disorders initiated in young females. PMID- 26246085 TI - Differences in the regeneration traits of Potamogeton crispus turions from macrophyte- and phytoplankton-dominated lakes. AB - Potamogeton crispus is widely used in submerged macrophyte restoration in China. Turions are an important means of reproduction in this species. To compare the regeneration abilities of P. crispus turions in macrophyte- and phytoplankton dominated lakes, we collected P. crispus turions from a macrophyte-dominated lake (Liangzi Lake) and a phytoplankton-dominated lake (Taihu Lake). Both lakes are important lakes in the middle and lower reaches of the Yangtze River in China. Our field survey revealed that the turions from the phytoplankton-dominated lake had smaller sizes and higher concentrations of total nitrogen (TN) and total phosphorus (TP) than did those from the macrophyte-dominated lake. Rapid sprouting of the turions from the phytoplankton-dominated lake in 32 days was observed under experimental conditions, although the sprout sizes (heights and biomass) were smaller than those from the macrophyte-dominated lake. Compared with sprouted turions from macrophyte-dominated lake, the sprouted turions from the phytoplankton-dominated lake accumulated higher soluble sugar (SS) but lower starch and free amino acid (FAA) concentrations. A 12-day interval sprout removal treatment significantly stimulated the re-sprouting of turions from both lakes, but scale-leaf-removal treatments had no effect. This study provides evidence that the regeneration strategies of P. crispus turions differ in macrophyte- and phytoplankton-dominated lakes. PMID- 26246086 TI - Congenital Chikungunya Virus Infection in Sincelejo, Colombia: A Case Series. AB - Congenital chikungunya virus (CHIK) infection has been infrequently reported, even more so during the current 2013-15 outbreak in Latin America. In this study, the consequences of CHIK on pregnancy outcomes and particularly consequences in infants born to infected women were assessed in a case series from a single private institution in the north of Colombia. During September 2014 to February 2015, seven pregnant women with serological and reverse transcription-polymerase chain reaction-positive test for CHIK delivered eight infants with CHIK. These newborns required admission to pediatric intensive care, and related support, owing to severe clinical manifestations, which included respiratory distress, sepsis, necrotizing enterocolitis, meningoencephalitis, myocarditis, edema, bullous dermatitis and pericarditis. There were three deaths (case fatality rate of 37.5%). Pregnant women and newborns with CHIK long term should be followed up, given the implications of chronic sequelae (e.g. chronic inflammatory rheumatism in women) as well as recently described neurocognitive impairment in infants. PMID- 26246087 TI - Bacillus clausii for Prevention of Late-onset Sepsis in Preterm Infants: A Randomized Controlled Trial. AB - BACKGROUND OF THE STUDY: Preterm infants are managed with antibiotics for sepsis, including suspected or probable sepsis. This leads to a delayed and abnormal colonization of the gut with potentially pathogenic organisms and a microbiome, which lacks biodiversity and increases the risk for late-onset sepsis (LOS). Probiotics have been proven to reduce the risk for necrotizing enterocolitis, but evidence for prevention of LOS is inconclusive. Probiotic effect depends also on the strain used, dose and indication for use. This study evaluated Bacillus clausii probiotic administered prophylactically to preterm neonates for prevention of LOS. OBJECTIVES: To study B.clausii given prophylactically to preterm neonates for prevention of LOS. DESIGN: Double-blinded, placebo controlled, randomized trial. SETTINGS: Tertiary care neonatal unit in India. PARTICIPANTS: Consecutive preterm neonates <34 weeks, admitted from 1 March 2012 to 28 February 2014 were stratified as extreme preterm and very preterm. INTERVENTION: Randomized to receive either probiotic or placebo for 6 weeks, discharge from hospital, death or occurrence of sepsis, whichever was earlier. PRIMARY OUTCOME: Incidence of definite and probable LOS in probiotic group compared with placebo. RESULTS: Of 326 eligible preterm infants, 244 were enrolled and 82 were excluded. Of these, 120 were stratified as extreme preterm and randomized to receive placebo (n = 59) and probiotic (n = 61). Of 124 babies stratified as very preterm, an equal number was randomized to receive placebo (n = 62) and probiotic (n = 62). There was no significant difference in the incidence of LOS between the two arms in the extreme preterm group [29% vs. 23%; relative risk (RR) 1.27; 95% confidence interval (CI) 0.88-1.66; p = 0.36] and the very preterm group (13% vs. 10%; RR 1.33; 95% CI 0.96-1.70; p = 0.32). Full feeds were achieved significantly faster in the probiotic group in both the extreme preterm (RR 0.82; 95% CI 0.74-0.88) and the very preterm (RR 0.67; 95% 0.32-0.77). CONCLUSIONS: Prophylactic administration of B.clausii to preterm neonates did not result in a significant difference in the incidence of LOS as compared with placebo. PMID- 26246088 TI - The thorax morphology of Epiophlebia (Insecta: Odonata) nymphs--including remarks on ontogenesis and evolution. AB - The species of Epiophlebia are unique among the recent Odonata in showing a mixture of morphological characters of dragonflies (Anisoptera) and damselflies (Zygoptera). The status of the four described extant species of Epiophlebia is disputable from a genetic as well as from a morphological point of view. Here we present an analysis of the thoracic musculature of different nymphal instars of Epiophlebia laidlawi and Epiophlebia superstes to elucidate their morphology and ontogenetic development. In total, 75 muscles have been identified in the thorax of Epiophlebia. This represents the highest number of thoracic muscles ever found in any odonate. It includes six muscles that are reported for the first time for Odonata, and three of these are even new for Pterygota. In total, our results indicate that Epiophlebia has the most ancestral thoracic morphology among Odonata. PMID- 26246089 TI - The clinical characteristics and treatment of cerebral AVM in pregnancy. AB - Cerebral arteriovenous malformation (AVM) in pregnancy is a complex situation and there is no agreement on its hemorrhage risk and treatment. Although studies on bleeding risk of cerebral AVMs in pregnancy are very few, and they provide different results, pregnancy will increase the hemorrhagic risk of AVM and ruptured cerebral AVM in pregnancy should be actively treated. After intracranial hemorrhage, cerebral angiography should be performed for pregnant women shielded correctly. Cerebral angiography could clearly demonstrate the characteristics of cerebral AVM. Results from the literature show that the radiation dose of endovascular and stereotactic radiotherapy for cerebral AVM in pregnancy was below the safety value and was safe. For an unruptured AVM in pregnancy, if there are no bleeding factors, e.g. no coexisting aneurysm, smooth venous drainage, no venous ectasia, or high risk of treatment, then it should be observed conservatively. PMID- 26246090 TI - Congenital basis of posterior fossa anomalies. AB - The classification of posterior fossa congenital anomalies has been a controversial topic. Advances in genetics and imaging have allowed a better understanding of the embryologic development of these abnormalities. A new classification schema correlates the embryologic, morphologic, and genetic bases of these anomalies in order to better distinguish and describe them. Although they provide a better understanding of the clinical aspects and genetics of these disorders, it is crucial for the radiologist to be able to diagnose the congenital posterior fossa anomalies based on their morphology, since neuroimaging is usually the initial step when these disorders are suspected. We divide the most common posterior fossa congenital anomalies into two groups: 1) hindbrain malformations, including diseases with cerebellar or vermian agenesis, aplasia or hypoplasia and cystic posterior fossa anomalies; and 2) cranial vault malformations. In addition, we will review the embryologic development of the posterior fossa and, from the perspective of embryonic development, will describe the imaging appearance of congenital posterior fossa anomalies. Knowledge of the developmental bases of these malformations facilitates detection of the morphological changes identified on imaging, allowing accurate differentiation and diagnosis of congenital posterior fossa anomalies. PMID- 26246091 TI - Costello syndrome: Analysis of the posterior cranial fossa in children with posterior fossa crowding. AB - This study aimed to assess changes in the posterior cranial fossa (PCF) to shed light on the mechanism of cerebellar herniation in children with Costello syndrome (CS) and posterior fossa crowding. We performed a morphovolumetric PCF analysis on brain magnetic resonance imaging (MRI) in seven children with CS (mean age 31 +/- 16 months) comparing the MRI scans with those of seven age matched healthy subjects.PCF volume (PCFV), PCF brain volume (PCFBV) and cerebellar volume (CeV) were assessed on axial T2-weighted MRI. Morphometric parameters (diameters of the foramen magnum, tentorial angle, basiocciput, supraocciput, basisphenoid and exocciput lengths) were measured on sagittal T1 weighted MRI. The volume of the cerebrospinal fluid (CSF) spaces was calculated as PCFV minus PCFBV.Five out of seven CS children showed tonsillar herniation in the upper cervical canal; no child had hydrocephalus but three out of seven children showed ventriculomegaly. In addition, the PCFV/PCFBV ratio, PCFV, CSF spaces volume, basiocciput, basisphenoid and exocciput lengths and latero-lateral and antero-posterior diameters of the foramen magnum were significantly reduced, whereas no significant changes were found in supraocciput length, PCFBV, CeV or hindbrain volume. The volumetric reduction of the PCF due to bony posterior fossa hypoplasia is a predisposing factor for developing cerebellar tonsillar herniation through the foramen magnum in children with CS. The altered anatomy of the foramen magnum and upward expansion of the PCF secondary to an increased tentorial slope serves to explain the possible mechanism of cerebellar herniation in patients with CS. PMID- 26246092 TI - Non-infantile variant of desmoplastic ganglioglioma: Conventional and advanced MR imaging characteristics. AB - Desmoplastic infantile ganglioglioma is a paediatric brain tumor that is commonly seen in the infantile age group. Literature on the non-infantile variant of this low-grade supratentorial neoplasm is very scarce, except for a few case reports. Herein, we report a case of desmoplastic non-infantile ganglioglioma occurring at the age of 6 years and describe its conventional and advanced magnetic resonance imaging characteristics. PMID- 26246093 TI - Parietal intradiploic encephalocele: Report of a case and review of the literature. AB - Encephaloceles consist of brain tissue and meninges that has herniated through a skull defect, usually located in the midline. They are seen more commonly in children and very rarely in adults. We present a case of an 84-year-old patient who was incidentally diagnosed with a lytic bone lesion in the right parietal intradiploic space, after computed tomography of the head was performed. A magnetic resonance imaging scan of the brain showed herniation of brain tissue through the defect. Magnetic resonance imaging was crucial in demonstrating the presence of parenchyma and its continuity with the rest of the brain, consequently distinguishing it from other entities. We report the imaging findings of a parietal indradiploic encephalocele with its differential diagnosis and a review of the relevant literature. PMID- 26246094 TI - Endovascular embolization of pial arteriovenous fistula fed from P1 segment of posterior cerebral artery in 12 years old girl: case report and review of literature. AB - OBJECTIVE: Intracranial pial arteriovenous fistulas (PAVFs) are rare vascular lesions with peculiar epidemiological, morphological, and pathophysiological characteristics. Since there is no nidus, PAVF treatment has been performed by direct disconnection of the arteriovenous communication via a surgical, endovascular, or a combined approach. We aim to outline the relevant variables to consider in planning an endovascular treatment strategy. METHODS: We present a case of a 12 year old girl with a single feeder PAVF originating from the first segment (P1) of the left posterior cerebral artery with a varicose venous drainage into the right cavernous sinus. RESULTS: We report the successful endovascular exclusion of the fistula with the release of a total of 27 detachable platinum coils with no complications at follow-up. Treatment strategy and nuances are discussed along with a review of the literature. CONCLUSIONS: Morphology, age, embolization strategies, and materials are the different variables to be analyzed in the endovascular treatment of such lesions. PMID- 26246095 TI - Cerebral sinovenous thrombosis in a child with Crohn's disease, otitis media, and meningitis. AB - Pediatric cerebral sinovenous thrombosis (CSVT) is associated with high morbidity and mortality. Severe long-term sequelae are reported in up to 48% of children. The most frequent location of CSVT in children is the superficial venous system. We present the neuroimaging findings using both computed tomography and magnetic resonance imaging (MRI) in a 10-year-old child with extensive superficial CSVT. Our report aims to stress the importance of awareness of risk factors in suspecting and rapidly diagnosing CSVT. The application of targeted conventional and advanced MRI sequences is the diagnostic tool of choice in children at risk of or with clinically suspected CSVT. PMID- 26246096 TI - Ectopic anterior cerebellum (ala lobule centralis). AB - In this case report we present an adolescent girl who was referred to our radiology department for assessment with advanced magnetic resonance (MR) imaging on suspicion of low-grade quadrigeminal cistern neoplasm on 1.5 Tesla MR examination. We were able to evaluate detailed cerebellar anatomy more clearly, and detected that the lesion was compatible with ectopic cerebellar tissue (a very rare developmental variation) on submillimetric 3-dimensional (3D) images from a 3 Tesla MR unit which has a 32-channel head coil. Our findings were further supported by diffusion tensor imaging which clearly indicated that the lesion was a part of the cerebellum. Furthermore, MR spectroscopic metabolite ratios were in accordance with the characteristics of normal neuronal tissue. As far we know there is no published report that contains similar findings to those of our patient. In conclusion, cranial MR images, if possible in 3D format (with very small isotropic voxels) should be obtained for the precise diagnosis of the lesions located in this region; in addition, the differential diagnostic list should be well known and advanced imaging techniques should be used when necessary. PMID- 26246097 TI - Pre-operative fMRI localization of the supplementary motor area and its relationship with postoperative speech deficits. AB - INTRODUCTION: Neurosurgery of the supplementary motor area (SMA) is associated with transient speech defects. We investigated whether SMA laterality correlates with postoperative speech defects. MATERIALS AND METHODS: The authors reviewed 17 patients with SMA-area lesion resection and preoperative language fMRI. SMA laterality was calculated by comparison of voxel activation in paired SMAs by hand-drawn regions of interest (ROIs) (drawn by a neuroradiologist), and compared with qualitative assessment by two neuroradiologists. Postoperative speech defects before and after surgery were assessed by chart review. RESULTS: Six patients developed new speech defects that resolved within several months. Two of the patients had a pre-existing speech defect that had developed after prior SMA area surgery. All these patients had left-sided lesions, while none of the four patients with a right-sided lesion developed a speech defect. Neuroradiologists' assessment of SMA laterality agreed with ROI calculation for the SMAs that were lateralized. However, for the SMAs in the "codominant" range by ROI, the neuroradiologists felt that all but one of the cases clearly lateralized, with the exception deemed indeterminate or codominant. No correlation between laterality of SMA and speech defect was identified. Twelve patients showed lateralization contralateral to the lesion. CONCLUSIONS: fMRI lateralization does not correlate with transient speech defects that developed from SMA-area surgery. Qualitative/visual assessment of SMA laterality was superior to ROI calculation because of the close proximity and possible overlap of signal from midline SMA. A majority of patients showed SMA lateralization contralateral to the SMA lesion. PMID- 26246098 TI - Cerebral cavernous malformations associated to meningioma: High penetrance in a novel family mutated in the PDCD10 gene. AB - Multiple familial meningiomas occur in rare genetic syndromes, particularly neurofibromatosis type 2. The association of meningiomas and cerebral cavernous malformations (CCMs) has been reported in few patients in the medical literature. The purpose of our study is to corroborate a preferential association of CCMs and multiple meningiomas in subjects harbouring mutations in the PDCD10 gene (also known as CCM3). Three members of an Italian family affected by seizures underwent conventional brain Magnetic Resonance Imaging (MRI) with gadolinium contrast agent including gradient echo (GRE) imaging. The three CCM-causative genes were sequenced by Sanger method. Literature data reporting patients with coexistence of CCMs and meningiomas were reviewed. MRI demonstrated dural-based meningioma like lesions associated to multiple parenchymal CCMs in all affected individuals. A disease-causative mutation in the PDCD10 gene (p.Gln112PhefsX13) was identified. Based on neuroradiological and molecular data as well as on literature review, we outline a consistent association between PDCD10 mutations and a syndrome of CCMs with multiple meningiomas. This condition should be considered in the differential diagnosis of multiple/familial meningioma syndromes. In case of multiple/familial meningioma the use of appropriate MRI technique may include GRE and/or susceptibility-weighted imaging (SWI) to rule out CCM. By contrast, proper post-gadolinium scans may aid defining dural lesions in CCM patients and are indicated in PDCD10-mutated individuals. PMID- 26246099 TI - MR spectroscopy of intracranial tuberculomas: A singlet peak at 3.8 ppm as potential marker to differentiate them from malignant tumors. AB - PURPOSE: The diagnosis of intracranial tuberculomas is often challenging. Our purpose is to describe the most common metabolic patterns of tuberculomas by MR spectroscopy (MRS) with emphasis on potential specific markers. METHODS: Single voxel MRS short echo time was performed in 13 cases of tuberculomas proven by histology and/or response to anti-mycobacterial therapy. For comparison MRS was also performed in 19 biopsy-proven malignant tumors (13 high-grade gliomas and six metastasis). Presence of metabolic peaks was assessed visually and categorical variables between groups were compared using chi-square. Metabolite ratios were compared using Mann-Whitney test and diagnostic accuracy of the metabolite ratios was compared using receiver-operating characteristic (ROC) curves analysis. RESULTS: Spectroscopic peaks representing lipids and glutamate/glutamine (Glx) as well as a peak at ~3.8 ppm were well defined in 77% (10/13), 77% (10/13) and 69% (nine of 13) of tuberculomas, respectively. Lipid and Glx peaks were also present in most of the malignant lesions, 79% (15/19) and 74% (14/19) respectively. However, a peak at ~3.8 ppm was present in only 10% (two of 19) of the tumor cases (p < 0.001). Higher Cho/Cr and mI/Cr ratios helped discriminate malignant lesions with an area under the ROC curve of 0.86 (SE: 0.078, p < 0.002, CI: 0.7-1) and 0.8 (SE: 0.1, p < 0.009, CI: 0.6-1), respectively. Threshold values between 1.7-1.9 for Cho/Cr and 0.8-0.9 for mI/Cr provided high specificity (91% for both metabolites) and adequate sensitivity (75% and 80%, respectively) for discrimination of malignant lesions. CONCLUSION: A singlet peak at ~3.8 ppm is present in the majority of tuberculomas and absent in most malignant tumors, potentially a marker to differentiate these lesions. The assignment of the peak is difficult from our analysis; however, guanidinoacetate (Gua) is a possibility. Higher Cho/Cr and mI/Cr ratios should favor malignant lesions over tuberculomas. The presence of lipids and Glx is non specific. PMID- 26246100 TI - Perfusion computed tomography of intracranial meningiomas: In vivo correlation of cerebral blood volume and vascular permeability. AB - BACKGROUND: A noninvasive method to predict the grade of a meningioma would be desirable since it would anticipate information about tumour nature, recurrence and improve tumour management and outcomes. The aim of the present study was to assess the ability of perfusion computed tomography (PCT) technique in predicting the meningioma grade before surgery. Data from PCT, such as cerebral blood volume (CBV) and permeability surface (PS), were correlated with immunohistolopathological information. METHODS: Twenty-three patients with a diagnosis of intracranial meningioma underwent PCT for pre-surgical evaluation of CBV and PS. During surgery, samples from the centre and periphery of the tumour were obtained. Two correspondent regions of interest (ROIs) were drawn on CBV and PS maps. Central and peripheral CBV and PS mean values were calculated. PCT parameters were correlated to CD-34 and endoglin. RESULTS: There was a positive correlation between PS and CD-34. No correlation was found between PS values and endoglin, CBV values and CD-34 and endoglin values. CONCLUSION: Our findings suggest that PCT may support conventional morphological imaging in predicting meningioma grading before surgery. PMID- 26246101 TI - Cerebral vascular malformations: Time-resolved CT angiography compared to DSA. AB - PURPOSE: The purpose of this article is to prospectively test the hypothesis that time-resolved CT angiography (TRCTA) on a Toshiba 320-slice CT scanner enables the same characterization of cerebral vascular malformation (CVM) including arteriovenous malformation (AVM), dural arteriovenous fistula (DAVF), pial arteriovenous fistula (PAVF) and developmental venous anomaly (DVA) compared to digital subtraction angiography (DSA). MATERIALS AND METHODS: Eighteen (eight males, 10 females) consecutive patients (11 AVM, four DAVF, one PAVF, and two DVA) underwent 19 TRCTA (Aquillion one, Toshiba) for suspected CVM diagnosed on routine CT or MRI. One patient with a dural AVF underwent TRCTA and DSA twice before and after treatment. Of the 18 patients, 13 were followed with DSA (Artis, Siemens) within two months of TRCTA. Twenty-three sequential volume acquisitions of the whole head were acquired after injection of 50 ml contrast at the rate of 4 ml/sec. Two patients with DVA did not undergo DSA. Two TRCTA were not assessed because of technical problems.TRCTAs were independently reviewed by two neuroradiologists and DSA by two other neuroradiologists and graded according to the Spetzler-Martin classification, Borden classification, overall diagnostic quality, and level of confidence. Weighted kappa coefficients (k) were calculated to compare reader's assessment of DSA vs TRCTA. RESULTS: There was excellent (k = 0.83 and 1) to good (k = 0.56, 0.61, 0.65 and 0.67) agreement between the different possible pairs of neuroradiologists for the assessment of vascular malformations. CONCLUSION: TRCTA may be a sufficient noninvasive substitute for conventional DSA in certain clinical situations. PMID- 26246102 TI - Combined use of stent angioplasty and mechanical thrombectomy for acute tandem internal carotid and middle cerebral artery occlusion. AB - PURPOSE: Tandem internal carotid and middle cerebral artery occlusion carries a grave prognosis, with intravenous and intra-arterial thrombolytics having low efficacy. Currently, endovascular therapy is a promising means for treatment in which the proximal carotid lesion can be treated with angioplasty and stenting, whilst mechanical thrombectomy can be used for the treatment of the distal occlusion. Two approaches can be used - the antegrade (proximal-to-distal) approach or the retrograde (distal-to-proximal) approach, although there has not yet been any consensus on which is the better approach. CASE REPORT: We present two patients with tandem occlusions, one treated using the antegrade and one using the retrograde approach, with different revascularization outcomes, despite having similar functional outcome on follow-up. CONCLUSION: The combined use of stent angioplasty and mechanical thrombectomy can be used to treat tandem occlusions, and with procedural modifications, the antegrade approach may more easily achieve technical success. PMID- 26246103 TI - Delayed cerebral ischemia associated with reversible cerebral vasoconstriction in a patient with Moyamoya disease with intraventricular hemorrhage: Case report. AB - We describe a case of cerebral infarctions caused by transient vasoconstrictions in the posterior circulation 2 weeks after intraventricular hemorrhage without subarachnoid hemorrhage in a 35-year-old patient with Moyamoya disease. To our knowledge, this is the first case report where diffuse segmental vasoconstrictions of the basilar and posterior cerebral arteries were recognized after intraventricular hemorrhage in Moyamoya disease. The patient complained of severe and acute-onset headache 14 days after the intraventricular hemorrhage, which had a different character and severity from the one she complained of at the onset of intraventricular hemorrhage. Finally, headache disappeared within 1 month and vasoconstriction resolved in 2 months. Reversible cerebral vasoconstriction syndrome was under consideration for the etiology of her condition because of the "thunderclap" characteristics of the headache and the delayed timing of occurrence of the vasoconstriction. This case report informs and alerts neurologists, neurosurgeons and neuroradiologists who observe and treat patients with Moyamoya disease that vasoconstriction in the posterior circulation may occur after intraventricular hemorrhage in these patients. PMID- 26246104 TI - Rare complication of anterior communicating artery aneurysm coiling: Transient retrograde amnesia. AB - Amnesia is an unusual and rare complication following endovascular coiling of intracranial aneurysms. We present a case of anterior communicating artery (ACOM) aneurysm in which the patient developed retrograde amnesia following endovascular coiling of the aneurysm. On imaging there was infarct involving bilateral fornices. The patient showed significant clinical improvement on follow up. PMID- 26246105 TI - Perforation of superior thyroid artery by guidewire during carotid artery stenting. AB - BACKGROUND AND AIM: Although carotid artery stenting (CAS) has become a common treatment for carotid artery stenosis, some complications occur related to the procedures. Perforation of an external carotid artery (ECA) branch is a rare complication. CASE DESCRIPTION: An 83-year-old man presented with gait disturbance and dysarthria. MRI demonstrated a fresh cerebral infarction in the watershed territory of the left cerebrum and severe stenosis of the left internal carotid artery (ICA). He underwent CAS for the left ICA stenosis. After the procedure, the patient complained of discomfort of the throat. Swelling of the neck was observed and angiography showed extravasation of contrast medium from the superior thyroid artery. The patient was immediately sedated and intubated. Strict control of the blood pressure was continued. Two days after CAS, the tracheal tube was extracted. He was discharged without deficit on the 17th post stenting day. CONCLUSION: Injury of ECA branches is a potential complication when a guidewire is inserted during advancement of the materials. It may be life threatening due to associated respiratory problems. Once bleeding from the ECA is suspected, close observation of the patient's neck and respiration and immediate intervention are necessary. PMID- 26246106 TI - Acute presentation of brachial plexus schwannoma secondary to infarction. AB - Schwannomas of the brachial plexus are rare and typically present as slowly growing masses. We describe a case of a 37-year-old female who presented with acute onset of severe left upper extremity pain. Magnetic resonance imaging (MRI) showed a 2.3 * 2.1 cm peripherally enhancing centrally cystic lesion in the left axilla, along the cords of the left brachial plexus, with significant surrounding edema and enhancement. The mass was surgically removed. Pathology was consistent with a schwannoma with infarction. The pain completely resolved immediately after surgery. PMID- 26246107 TI - Does evaluator experience have an impact on the diagnosis of lumbar spine instability in dynamic MRI? Interobserver agreement study. AB - OBJECTIVES: We aimed to evaluate interobserver agreement in the definition of spine instability among spine neuroradiologists with or without experience in dynamic magnetic resonance imaging (MRI). MATERIAL AND METHODS: Two expert neuroradiologists and two residents retrospectively evaluated the pre-operative dynamic MRI examinations of patients with vertebral instability. Segmental motion, defined as excessive (more than 3 mm) translational motion from supine to upright, was investigated in 103 subjects (309 segments) using kinetic MRI. Radiographic parameters which can help indicate segmental instability include disc degeneration, facet joint osteoarthritis, and ligament flavum hypertrophy. These three radiographic parameters were simultaneously evaluated, and the combinations corresponding to significant segmental instability at each level were determined. The agreement among the neuroradiologists was calculated using the kappa coefficient. All patients had neurosurgical intervention to stabilize the spine. RESULTS: Agreement was high among experienced and non-experienced neuroradiologists. Agreement was nearly perfect for spinal location of spinal instability. CONCLUSIONS: This study demonstrates that the experience of the evaluator has a low impact on the assessment of spinal instability if correct classification is used. The interobserver agreement confirms the usefulness and safety of kinetic MRI in the correct diagnosis of spinal instability even by less experienced evaluators. PMID- 26246108 TI - Epiglottic masses identified on CT imaging: A case report and review of the broad differential diagnosis. AB - Epiglottic masses may be cystic, granulomatous, infectious, benign or malignant neoplastic, or manifestations of a systemic disease. When large in size, the airway may become obstructed, and when accompanied by suspicious features such as cartilaginous invasion, extension to the pre-epiglottic or para-glottic spaces, or lymphadenopathy, the radiologist must consider malignancy as a primary differential diagnosis. However, when only benign features are identified, the differential diagnosis is broad. We present a 65-year-old female with an incidental 1 cm exophytic, pedunculated, papillomatous lesion on the laryngeal surface of the epiglottis discovered upon endoscopic evaluation for dyspepsia and heartburn. Because of her risk factors for malignancy, CT scan was requested and revealed only benign features. Subsequent excisional biopsy revealed a benign squamous papilloma; however, multiple additional differential considerations were entertained preoperatively. PMID- 26246109 TI - Brain atrophy and physical disability in primary progressive multiple sclerosis: A volumetric study. AB - Grey matter atrophy has been shown in primary progressive multiple sclerosis (PPMS), but its association with physical incapacity is unclear. We submitted 19 patients with PPMS to a neurological evaluation and brain magnetic resonance imaging (MRI) with volumetric analysis using FreeSurfer. We found no relation between the Expanded Disability Status Scale or disease duration and the grey matter or white matter structures analysed. Lesion load was negatively correlated with cortical and subcortical grey matter volumes, but not with total white matter volume. We concluded that physical disability in PPMS is not directly related to brain atrophy and that focal inflammatory white matter lesions may contribute to progressive neuronal degeneration. INTRODUCTION: Primary progressive multiple sclerosis (PPMS) is characterized by chronic progression since onset, with predominant involvement of the spinal cord and prominent neurodegeneration. Grey matter atrophy has been shown in patients with PPMS, but its association with clinical incapacity is uncertain. We investigated the relationship between regional brain atrophy and physical disability in patients with PPMS. METHODS: Patients with an established diagnosis of PPMS underwent a neurological evaluation followed by brain MRI at 1.5 T. Volumetric analysis was performed with FreeSurfer software, and evaluated the neocortex, total white matter, total subcortical grey matter, putamen, caudate, globus pallidus, thalamus, hippocampus, brainstem, corpus callosum and pre-central gyrus volumes. Clinical data obtained included physical disability as measured by the Expanded Disability Status Scale (EDSS). RESULTS: Nineteen patients were included, 14 female (73.7%), mean age of 55.7 (SD 7.6) and mean disease duration of 13.0 years (SD 8.8). Median EDSS score was 6.0 (3.5-8.0). The average T1 lesion load (4.9 cm3, SD 3.4) and T2 load (10.5 cm3, SD 9.9) did not relate to disease duration. There was no significant correlation between EDSS score or disease duration and the cortical grey matter, deep grey matter or white matter structures analysed. Lesion load was negatively correlated with cortical and subcortical grey matter volumes (p < 0.05), but not with total white matter volume. CONCLUSIONS: Physical disability in PPMS is not directly related to brain volume loss. Grey matter atrophy correlates with lesion load in patients with PPMS, indicating that focal inflammatory white matter lesions may contribute to progressive neuronal degeneration. PMID- 26246110 TI - A donor thrombomodulin gene variation predicts graft-versus-host disease development and mortality after bone marrow transplantation. AB - Thrombomodulin, encoded by the THBD gene, is a critical regulator of coagulation and innate immunity. Its gene variant (rs3176123, 2729A>C) in the 3' untranslated region has been reported to be associated with vasculopathies. The present study analyzed the impact of THBD variation on transplant outcomes in a cohort of 317 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor A/C or C/C genotype vs. the donor A/A genotype resulted in a lower incidence of grades II-IV acute graft-versus-host disease [GVHD; hazard ratio (HR) 0.66; 95 % confidence interval (CI) 0.44-0.99; P = 0.05] according to a multivariate analysis. In patients with grades II-IV acute GVHD, the donor A/C or C/C genotype vs. the donor A/A genotype was associated with significantly better overall survival rates (HR 0.45; 95 % CI 0.21-0.99, P = 0.05), while this effect was absent in other patients. A functional analysis using lymphocytes obtained from healthy individuals revealed that the 2729C allele has a higher level of THBD mRNA than the 2729A allele. These findings suggest the functional relevance of the rs3176123 variation and indicate that higher thrombomodulin expression by individuals with the 2729C allele likely accounts for their decreased risk for acute GVHD development and subsequent mortality. PMID- 26246112 TI - Therapy persistence in newly diagnosed non-valvular atrial fibrillation treated with warfarin or NOAC. A cohort study. AB - Efforts to reduce stroke in atrial fibrillation (AF) have focused on increasing physician adherence to oral anticoagulant (OAC) guidelines, but high early vitamin K antagonist (VKA) discontinuation is a limitation. We compared persistence of non-VKA OAC (NOAC) with VKA treatment in the first year after OAC inception for incident AF in real-world practice. We studied 27,514 anticoagulant naive patients with incident non-valvular AF between January 2011 and May 2014 in the UK primary care Clinical Practice Research Datalink, with full medication use linkage: mean age 74.2 +/- 12.4, 45.7% female, mean follow-up 1.9 +/- 1.1 years. After treatment initiation and follow-up until 1/2015, the proportion remaining on OAC at one year (persistence) was estimated using competing risk survival analyses. OAC was commenced <= 90 days after incident AF in 13,221 patients (48.1%): 12,307 VKA and 914 NOAC (apixaban, dabigatran, rivaroxaban). Amongst those treated with OAC, the proportion commencing NOAC increased from zero in 1/2011 to 27.0% in 5/2014, and OAC prescriptions for CHA2DS2VASc score >= 2 (guideline adherence) increased from 41.2% to 65.5%. Persistence with OAC declined over 12 months to 63.6% for VKA and 79.2% for NOAC (p< 0.0001). Persistence for those with CHA2DS2VASc >= 2 was significantly greater for NOAC (83.0%) than VKA (65.3%, p< 0.0001) at one year and all earlier time points. Comparison of VKA and NOAC cohorts matched on individual CHA2DS2VASc components showed consistent results. In conclusion, persistence was significantly higher with NOAC than VKA, and could alone lead to fewer cardioembolic strokes. Increased guideline adherence following NOAC introduction could further decrease AF stroke burden. PMID- 26246111 TI - [Follow-up of urological tumor treatment]. AB - Follow-up of patients after curative treatment of urological cancer is an important component of the treatment of patients. The aim of the follow-up is to monitor the success of treatment and to identify local or distant recurrences early to be able to initiate further treatment. Investigations used for the monitoring should follow the principle "as much as necessary, as little as possible". The interval and method of follow-up investigations should be based on the risk of recurrence for the individual patient. In recent years follow-up schemes have been improved and, for example in testicular cancer, have been adjusted to the individual risk group. In contrast, for other tumors, such as metastatic bladder carcinoma, recommendations for follow-up do not seem to be individualized. This article therefore gives an overview on current recommendations and evidence for the follow-up of the most important genitourinary tumor types. PMID- 26246113 TI - Important Treatment Modalities for Symptomatic Malignant Pericardial Effusions. PMID- 26246114 TI - Evaluating Progress in the Global Surgical Crisis: Contrasting Access to Emergency and Essential Surgery and Safe Anesthesia Around the World. AB - INTRODUCTION: Since 2007, observations reveal that low- and middle-income countries (LICs and LMICs) experience similar surgical access and safety issues, though the etiology of these challenges varies by country. The collective voice of surveys completed to date has pushed the agenda for the inclusion of safe surgery and anesthesia within global health discussions. Comparison of four countries across the world shows similar basic progress as well as ongoing surgical and anesthesia needs in resource-challenged countries. By studying these common needs, a comprehensive plan to provide infrastructure and personnel support can work in multiple austere settings. METHODS: A standardized survey tool published, designed, and developed initially by the Harvard Humanitarian Initiative and modified at Vanderbilt University was completed in Guatemala, Guyana, Laos, and Mozambique. The survey assessed eight key areas of essential surgical care: access to and availability of surgical services, access to human resources, essential infrastructure (including access to water, electricity, sanitation, blood products, and essential medicines including supplemental oxygen), surgical outcomes, operating room information and procedures, equipment, International Organization, and Non-Government Organization provision of surgical care. These results were compared and contrasted to evaluate resource challenges and assets in each country. RESULTS: A total of 49 hospitals were surveyed in this comparison cohort. The results reveal common needs for emergency and essential surgery in each country, but some differences in human and capital resources exist. While minimal resources exist, all surgical sites provided running water, electricity, and oxygen-assets not seen in previous surveys as recent as 2011. CONCLUSION: The most basic needs to provide essential surgery are now present in LICs and LMICs. Many more resources are needed to ensure access to safe surgery and anesthesia. The next steps to provide essential surgery must include common solutions for access to surgery and anesthesia, and an evaluation of patient safety in these endeavors through the perioperative mortality rate. PMID- 26246116 TI - Influence of Parental Conflict Resolution Strategies on Hispanic College Women's Experiences With Verbal Aggression. AB - The study investigates the relation between interparental verbal aggression, parent-daughter verbal aggression, and verbal aggression in female Hispanic college student's dating relationships ( N = 599). Results showed that mothers' high levels of verbal conflict with fathers were predictive of having high levels of verbal conflicts with their daughters. This in turn, predicted daughters' use of verbal conflict with their intimate partner. Similarly, fathers' high levels of verbal conflict with mothers were predictive of having high levels of verbal conflicts with their daughters. However, this was not found to be predictive of daughters' use of verbal conflict with their intimate partner. PMID- 26246115 TI - Factors Determining Outcome After Surgery for Chronic Groin Pain Following a Lichtenstein Hernia Repair. AB - BACKGROUND: Some patients develop chronic groin pain after a Lichtenstein hernia repair. Previous studies have demonstrated beneficial effects of removal of entrapped inguinal nerves or a meshectomy in patients with chronic pain after open inguinal hernia mesh repair. Factors determining success following this remedial surgery are unknown. The aim of the study was to identify potential patient- or surgery-related factors predicting the surgical efficacy for inguinodynia following Lichtenstein repair. METHODS: Consecutive adult patients with a history of persistent pain following Lichtenstein repair who underwent remedial surgery were analysed using univariate analysis. Significant confounders (p < 0.05) were combined in a multivariate logistic regression model using a backward stepwise regression method. RESULTS: A total of 136 groin pain operations were available for analysis. Factors contributing to success were removal of a meshoma (OR 4.66) or a neuroma (OR 5.60) and the use of spinal anaesthesia (OR 4.38). In contrast, female gender (OR 0.30) and preoperative opioid use (OR 0.38) were significantly associated with a less favourable outcome. Using a multivariate analysis model, surgery under spinal anaesthesia (OR 4.04), preoperative use of opioids (OR 0.37), and meshoma removal (OR 5.31) greatly determined surgical outcome. CONCLUSIONS: Pain reduction after remedial surgery for chronic groin pain after Lichtenstein repair is more successful if surgery is performed under spinal anaesthesia compared to general anaesthesia. Removal of a meshoma must be considered as success rates are optimized following these measures. Patients using opioids preoperatively have less favourable outcomes. PMID- 26246117 TI - Perceptions of Dating Violence and Associated Correlates: A Study of College Young Adults. AB - The purpose of this study was to better understand young adults' perceptions of what behaviors constitute intimate partner violence (IPV) and the correlates of these perceptions using a comprehensive measure of IPV perceptions and behaviors. Participants were undergraduates (aged 18-25), including 357 women and 346 men ( N = 703) from the midwestern region of the United States, who completed surveys for course credit. Results demonstrated that young women and men on average reported that acts of physical, sexual, and psychological IPV were abusive. However, young women generally rated these behaviors as more abusive than young men, male-to-female (M-to-F) IPV was viewed as more abusive than female-to-male (F-to-M) IPV, and physical IPV was considered the most abusive form of IPV, followed by sexual IPV, which was rated as more abusive than psychological IPV. Furthermore, among men, a history of IPV perpetration and victimization generally predicted decreased perceptions that acts were abusive; however, among women, histories of IPV perpetration and victimization were generally unrelated to abuse perceptions. These data underscore the importance of the inclusion of psychoeducation about the seriousness of all forms of IPV in IPV prevention programming and the importance of situation-specific and targeted IPV prevention messages. Moreover, future research is needed to replicate and better understand the explanatory mechanisms underlying the relationships among a history of IPV, abuse perceptions, and gender. PMID- 26246118 TI - Desistance From Sexual Offending: Behavioral Change Without Cognitive Transformation. AB - The treatment and management of sexual offenders has long been focused on risk and recidivism. As a consequence, the phenomenon of desistance from sexual offending has only recently gained research attention. Unsurprisingly, the area of theory building to account for this empirical reality has been slow. Although a number of psychological theories of behavioral change and criminological theories of desistance exist, a comprehensive theoretical understanding of desistance from sexual offending is lacking. A theme common across a number of theories of internal desistance is cognitive transformation and specifically, one's readiness for and willingness to change. This study tested the relevance of that particular theme for a sample of 45 men convicted of sexual offenses who are living offense-free lives in the community. In contrast to this theme, long-term desistance was observed in most cases in the absence of any initial desire for intervention. The impact of current approaches such as mandatory treatment is discussed and implications for future research and practice are presented. PMID- 26246119 TI - Reproductive Coercion by Male Sexual Partners: Associations With Partner Violence and College Women's Sexual Health. AB - Reproductive coercion (RC) involves indirect and direct partner behaviors that interfere with effective contraceptive use. RC has been identified as a correlate of intimate partner violence (IPV) among ethnically diverse women sampled from urban health clinics or shelters. Research is needed to determine whether RC is experienced more generally by young women and, if so, whether RC is associated with IPV, multiple indicators of sexual health, or both. In the present study, sexually active undergraduate women ( N = 223, 80% Caucasian/White) provided self report data on their sexual health and behaviorally specific lifetime experiences of both RC and partner physical violence. About 30% reported experiencing RC from a male sexual partner. Most commonly, RC involved condom manipulation or refusal within an adolescent dating relationship. Experiences of RC and partner violence were not independent; half of the women who reported RC also reported experiencing partner physical violence. Women with a history of RC reported a significantly reduced rate of contraceptive use during last vaginal sex and lower contraceptive and sexual self-efficacy. Additional research on the sociocultural and relational contexts of RC is needed. PMID- 26246120 TI - Social Determinants of Married Women's Attitudinal Acceptance of Intimate Partner Violence. AB - Informed by the social determinants of health (SDH) framework, this study examined whether women's attitudinal acceptance of intimate partner violence (IPV) varies according to material circumstances, such as characteristics of their communities. Data were obtained from the sixth Bangladesh Demographic Health Surveys (BDHS) of 2011, a cross-sectional and secondary population-based study that covers the entire population residing in noninstitutional dwelling units in Bangladesh. The sample included 16,480 married women living in 600 communities who were 15 to 49 years old. Results showed that community characteristics were significantly associated with married women's attitudes toward IPV. The associations, however, were considerably more complicated than previously thought. Community poverty and wife beating justification were inversely related, such that regardless of their socioeconomic status (SES), living in poorer communities increased women's likelihood of condemning IPV ( p < .001). Also, unexpectedly, as illiteracy increased in the community, women's likelihood of viewing IPV as justified decreased ( p < .01). Living in communities with strong patriarchal norms was associated with greater tolerance for IPV ( p < .001). Use of the SDH framework in this study provided empirical evidence of the importance of social determinants in determining risk for attitudinal acceptance of IPV among women, which can be targeted for future research and intervention. PMID- 26246121 TI - Transferability of the electrospray ionization efficiency scale between different instruments. AB - For the first time, quantitative electrospray (ESI) ionization efficiencies (IE), expressed as logIE values, obtained on different mass-spectrometric setups (four mass analyzers and four ESI sources) are compared for 15 compounds of diverse properties. The general trends of change of IE with molecular structure are the same with all experimental setups. The obtained IE scales could be applied on different setups: there were no statistically significant changes in the order of ionization efficiency and the root mean of squared differences of the logIE values of compounds between the scales compiled on different instruments were found to be between 0.21 and 0.55 log units. The results show that orthogonal ESI source geometry gives better differentiating power and additional pneumatic assistance improves it even more. It is also shown that the ionization efficiency values are transferable between different mass-spectrometric setups by three anchoring points and a linear model. The root mean square error of logIE prediction ranged from 0.24 to 0.72 depending on the instrument. This work demonstrates for the first time the inter-instrument transferability of quantitative electrospray ionization efficiency data. Graphical Abstract ?. PMID- 26246122 TI - Thermal lensing effect of CS2 studied with femtosecond laser pulses. AB - By chopping 820 nm 18 femtosecond (fs)-laser pulses, continuously generated by a self-mode locked Ti:Al2O3 laser at 82 MHz, into trains with both train-width and train-to-train separation considerably longer than the thermal diffusivity time constant tauth of CS2, we conducted Z-scan measurements on it at various times relative to the leading pulse of each train (T's). As a result, we observed negative nonlinear refraction strengthening with T within tauth and gradually stabilizing with T exceeding tauth. We quantitatively explain the experimental results in terms of the thermal lensing effect. In particular, we attribute the heat generation to non-radiative relaxation of libration excited by individual 18 fs-pulses via stimulated Raman scattering. In contrast to the commonly held view of multi-photon excitation, we propose and verify a new heat-generating mechanism for the thermal lensing effect in CS2. PMID- 26246123 TI - Governing the research-care divide in clinical biobanking: Dutch perspectives. AB - Biobanking, the large-scale, systematic collection of data and tissue for open ended research purposes, is on the rise, particularly in clinical research. The infrastructures for the systematic procurement, management and eventual use of human tissue and data are positioned between healthcare and research. However, the positioning of biobanking infrastructures and transfer of tissue and data between research and care is not an innocuous go-between. Instead, it involves changes in both domains and raises issues about how distinctions between research and care are drawn and policed. Based on an analysis of the emergence and development of clinical biobanking in the Netherlands, this article explores how processes of bio-objectification associated with biobanking arise, redefining the ways in which distinctions between research and clinical care are governed. PMID- 26246124 TI - A role for vancomycin epicutaneous skin testing in the evaluation of perioperative anaphylaxis. PMID- 26246125 TI - The ratio of mean daily IgG increment/mean daily dose in immunoglobulin replacement therapy in primary antibody deficiencies. PMID- 26246126 TI - Apps for food allergy: A critical assessment. PMID- 26246127 TI - Artery first approach to pancreatoduodenectomy: current status. AB - BACKGROUND: The need for an early determination of resectability and before an irreversible step is taken during pancreatoduodenectomy promoted the development of an 'artery first approach' (AFA). The aim of this study was to review the current evidence related to this approach, with particular reference to margins and survival. METHODS: An electronic search was performed in MEDLINE, EMBASE and PubMed databases from 1960 to 2015 using both subject headings (MeSH) and truncated word searches to identify all published related articles to this topic. RESULTS: Six different AFAs have been published. Four studies evaluated the impact of AFA on perioperative outcomes and survival. Three studies showed no difference in the perioperative outcomes, margin status, lymph node yield and survival while one study showed improved margin status and survival comparing AFA with standard resection. CONCLUSION: The current evidence regarding the benefits of AFA in relation to decreasing margin positivity or increasing survival is sparse. Further larger studies and randomized controlled trails are needed to ascertain the benefits of AFA. PMID- 26246128 TI - Autoimmune disease-associated haplotypes of BLK exhibit lowered thresholds for B cell activation and expansion of Ig class-switched B cells. AB - OBJECTIVE: B lymphoid kinase (BLK) is associated with rheumatoid arthritis (RA) and several other B cell-associated autoimmune disorders. BLK risk variants are consistently associated with reduced BLK expression, but the mechanisms by which reduced expression alters human B cell function to confer autoimmune disease susceptibility are unknown. This study was undertaken to characterize the BLK risk haplotype and to determine associated B cell functional phenotypes involved in autoimmunity. METHODS: The BLK risk haplotype association with RA (determined using whole-genome sequencing data) was confirmed in 2,526 RA cases and 2,134 controls. Peripheral blood mononuclear cells (PBMCs) from RA patients, healthy adults, and umbilical cord blood were used to study B cell functional phenotypes associated with the BLK risk genotype. Association of the BLK haplotype with B cell phenotypes was analyzed using cell culture and flow cytometry. RESULTS: Two insertion/deletions were found on the RA risk haplotype in BLK, and the reduction in BLK expression associated with the risk haplotype was confirmed in primary B lymphocytes. Carriers of the RA-associated haplotype had evidence of lower basal B cell receptor (BCR) signaling activity, yet their B cells were hyperactivatable, with enhanced up-regulation of CD86 after BCR crosslinking and greater T cell stimulatory capacity. The number of isotype-switched memory B cells was also significantly increased in subjects carrying the risk haplotype. CONCLUSION: A major mechanism underlying the BLK association with autoimmune disease involves lowered thresholds for BCR signaling, enhanced B cell-T cell interactions, and altered patterns of isotype switching. PMID- 26246129 TI - Phosphothreonine as a catalytic residue in peptide-mediated asymmetric transfer hydrogenations of 8-aminoquinolines. AB - Phosphothreonine (pThr) was found to constitute a new class of chiral phosphoric acid (CPA) catalyst upon insertion into peptides. To demonstrate the potential of these phosphopeptides as asymmetric catalysts, enantioselective transfer hydrogenations of a previously underexplored substrate class for CPA-catalyzed reductions were carried out. pThr-containing peptides lead to the observation of enantioselectivities of up to 94:6 e.r. with 2-substituted quinolines containing C8-amino functionality. NMR studies indicate that hydrogen-bonding interactions promote strong complexation between substrates and a rigid beta-turn catalyst. PMID- 26246131 TI - Molecular Mixed-Metal Manganese Oxido Cubanes as Precursors to Heterogeneous Oxygen Evolution Catalysts. AB - Well-defined mixed-metal [CoMn3 O4 ] and [NiMn3 O4 ] cubane complexes were synthesized and used as precursors for heterogeneous oxygen evolution reaction (OER) electrocatalysts. The discrete clusters were dropcasted onto glassy carbon (GC) and indium tin oxide (ITO) electrodes, and the OER activities of the resulting films were evaluated. The catalytic surfaces were analyzed by various techniques to gain insight into the structure-function relationships of the electrocatalysts' heterometallic composition. Depending on preparation conditions, the Co-Mn oxide was found to change metal composition during catalysis, while the Ni-Mn oxides maintained the NiMn3 ratio. XAS studies provided structural insights indicating that the electrocatalysts are different from the molecular precursors, but that the original NiMn3 O4 cubane-like geometry was maintained in the absence of thermal treatment (2-Ni). In contrast, the thermally generated 3-Ni develops an oxide-like extended structure. Both 2-Ni and 3-Ni undergo structural changes upon electrolysis, but they do not convert into the same material. The observed structural motifs in these heterogeneous electrocatalysts are reminiscent of the biological oxygen-evolving complex in Photosystem II, including the MMn3 O4 cubane moiety. The reported studies demonstrate the use of discrete heterometallic oxide clusters as precursors for heterogeneous water oxidation catalysts of novel composition and the distinct behavior of two sets of mixed metal oxides. PMID- 26246132 TI - Psychosocial factors of caregiver burden in child caregivers: results from the new national study of caregiving. AB - BACKGROUND: Over 50 million informal caregivers in the United States provide care to an aging adult, saving the economy hundreds of billions of dollars annually from costly hospitalization or institutionalization. Despite the benefits associated with caregiving, caregiver stress can lead to negative physical and mental health consequences, or "caregiver burden". Given these potential negative consequences of caregiver burden, it is important not only to understand the multidimensional components of burden but to also understand the experience from the perspective of the caregiver themselves. Therefore, the objectives of our study are to use exploratory factor analysis to obtain a set of latent factors among a subset of caregiver burden questions identified in previous studies and assess their reliability. METHODS: All data was obtained from the 2011 National Study of Caregiving (NSOC). Exploratory factor analysis (EFA) was performed to identify a set of latent factors assessing four domains of caregiver burden in "child caregivers": those informal caregivers who provide care to a parent or stepparent. Sensitivity analysis was also conducted by repeating the EFA on demographic subsets of caregivers. RESULTS: After multiple factor analyses, four consistent caregiver burden factors emerged from the 23 questions analyzed: Negative emotional, positive emotional, social, and financial. Reliability of each factor varied, and was strongest for the positive emotional domain for caregiver burden. These domains were generally consistent across demographic subsets of informal caregivers. CONCLUSION: These results provide researchers a more comprehensive understanding of caregiver burden to target interventions to protect caregiver health and maintain this vital component of the US health care system. PMID- 26246134 TI - Role of electrostatic interactions for ligand recognition and specificity of peptide transporters. AB - BACKGROUND: Peptide transporters are membrane proteins that mediate the cellular uptake of di- and tripeptides, and of peptidomimetic drugs such as beta-lactam antibiotics, antiviral drugs and antineoplastic agents. In spite of their high physiological and pharmaceutical importance, the molecular recognition by these transporters of the amino acid side chains of short peptides and thus the mechanisms for substrate binding and specificity are far from being understood. RESULTS: The X-ray crystal structure of the peptide transporter YePEPT from the bacterium Yersinia enterocolitica together with functional studies have unveiled the molecular bases for recognition, binding and specificity of dipeptides with a charged amino acid residue at the N-terminal position. In wild-type YePEPT, the significant specificity for the dipeptides Asp-Ala and Glu-Ala is defined by electrostatic interaction between the in the structure identified positively charged Lys314 and the negatively charged amino acid side chain of these dipeptides. Mutagenesis of Lys314 into the negatively charged residue Glu allowed tuning of the substrate specificity of YePEPT for the positively charged dipeptide Lys-Ala. Importantly, molecular insights acquired from the prokaryotic peptide transporter YePEPT combined with mutagenesis and functional uptake studies with human PEPT1 expressed in Xenopus oocytes also allowed tuning of human PEPT1's substrate specificity, thus improving our understanding of substrate recognition and specificity of this physiologically and pharmaceutically important peptide transporter. CONCLUSION: This study provides the molecular bases for recognition, binding and specificity of peptide transporters for dipeptides with a charged amino acid residue at the N-terminal position. PMID- 26246133 TI - Characterization of emerging Newcastle disease virus isolates in China. AB - BACKGROUND: Newcastle disease (ND) is a devastating worldwide disease of poultry characterized by increased respiration, circulatory disturbances, hemorrhagic enteritis, and nervous signs. Sequence analysis shows several amino acid residue substitutions at neutralizing epitopes on the F and HN proteins of recent Shaanxi strains. Both Cross protection and cross serum neutralization tests revealed that the traditional vaccine strains were unable to provide full protection for the flocks. METHODS: To better understand the epidemiology of Newcastle disease outbreak, a portion of the F gene and the full-length HN gene were amplified from Shaanxi isolates by reverse transcription-polymerase chain reaction (RT-PCR) and then conducted sequence and phylogenetic analyzes. In pathogenicity analysis, both high intra-cerebral pathogenicity index (ICPI) and mean death time (MDT) tests of chicken embryo were carried out. Furthermore, a cross-protection experiment in which specific-pathogen-free chickens vaccinated with a LaSota vaccine strain were challenged by the recent Shaanxi strain was also performed. RESULTS: Nine Newcastle disease (ND) virus (NDV) isolates which were recovered from ND outbreaks in chicken flocks in China were genotypically and pathotypically characterized. Amino acid sequence analysis revealed that all the recent Shaanxi-isolated NDVs have (112)R-R-Q-K-R-F(117) for the C-terminus of the F2 protein and exhibit high ICPI and MDT of chicken embryos, suggesting that they were all classified as velogenic type of NDVs. Phylogenetic analysis of these isolates showed that they belong to subgenotype VIId that have been implicated in the recent outbreaks in northwestern China. The percentage of amino acid sequence identity of F protein between recent Shaanxi stains and five vaccine strains was in the range of 81.9 %-88.1 %, while the percentage of amino acid sequence identity of HN protein between recent Shaanxi strains and vaccine strains was in the range of 87.4 %-91.2 %. Furthermore, a number of amino acid residue substitutions at neutralizing epitopes on the F and HN proteins of these isolates were observed, which may lead to the change of antibody recognition and neutralization capacity. A cross-protection experiment indicated that specific pathogen-free chickens vaccinated with a LaSota vaccine strain was not capable of providing full protection for the flocks that were challenged by the recent Shaanxi strain. CONCLUSIONS: Taken together, our findings reveal that recent Shannxi NDVstrains exhibit antigenic variations that could be responsible for recent outbreaks of NDVs in northwestern China. PMID- 26246135 TI - Erratum to: Isolated hepatic perfusion as a treatment for uveal melanoma liver metastases (the SCANDIUM trial): study protocol for a randomized controlled trial. PMID- 26246136 TI - Regional patterns of postglacial changes in the Palearctic mammalian diversity indicate retreat to Siberian steppes rather than extinction. AB - We examined the presence of possible Recent refugia of Pleistocene mammalian faunas in Eurasia by analysing regional differences in the mammalian species composition, occurrence and extinction rates between Recent and Last Glacial faunas. Our analyses revealed that most of the widespread Last Glacial species have survived in the central Palearctic continental regions, most prominently in Altai-Sayan (followed by Kazakhstan and East European Plain). The Recent Altai Sayan and Kazakhstan regions show species compositions very similar to their Pleistocene counterparts. The Palearctic regions have lost 12% of their mammalian species during the last 109,000 years. The major patterns of the postglacial changes in Palearctic mammalian diversity were not extinctions but rather radical shifts of species distribution ranges. Most of the Pleistocene mammalian fauna retreated eastwards, to the central Eurasian steppes, instead of northwards to the Arctic regions, considered Holocene refugia of Pleistocene megafauna. The central Eurasian Altai and Sayan mountains could thus be considered a present-day refugium of the Last Glacial biota, including mammals. PMID- 26246137 TI - What do home videos tell us about early motor and socio-communicative behaviours in children with autistic features during the second year of life--An exploratory study. AB - BACKGROUND: Little is known about the first half year of life of individuals later diagnosed with autism spectrum disorders (ASD). There is even a complete lack of observations on the first 6 months of life of individuals with transient autistic behaviours who improved in their socio-communicative functions in the pre-school age. AIM: To compare early development of individuals with transient autistic behaviours and those later diagnosed with ASD. STUDY DESIGN: Exploratory study; retrospective home video analysis. SUBJECTS: 18 males, videoed between birth and the age of 6 months (ten individuals later diagnosed with ASD; eight individuals who lost their autistic behaviours after the age of 3 and achieved age-adequate communicative abilities, albeit often accompanied by tics and attention deficit). METHOD: The detailed video analysis focused on general movements (GMs), the concurrent motor repertoire, eye contact, responsive smiling, and pre-speech vocalisations. RESULTS: Abnormal GMs were observed more frequently in infants later diagnosed with ASD, whereas all but one infant with transient autistic behaviours had normal GMs (p<0.05). Eye contact and responsive smiling were inconspicuous for all individuals. Cooing was not observable in six individuals across both groups. CONCLUSIONS: GMs might be one of the markers which could assist the earlier identification of ASD. We recommend implementing the GM assessment in prospective studies on ASD. PMID- 26246138 TI - Neonatal neurobehavior after therapeutic hypothermia for hypoxic ischemic encephalopathy. AB - BACKGROUND: Perinatal hypoxic ischemic encephalopathy (HIE) is a major cause of neurodevelopmental impairment including cerebral palsy and intellectual disability. Brain magnetic resonance imaging is the gold standard for acute assessment of cerebral injury in HIE. Limited data are available regarding the significance of clinically manifested neurobehavioral impairments in the neonatal period. AIM: To evaluate brain structure-function relationships in newborns with HIE using diffusion tensor imaging (DTI) and the NICU Network Neurobehavioral Scale (NNNS). STUDY DESIGN: Prospective observational study with secondary longitudinal component. SUBJECTS: Forty-five newborns (62% male) with HIE referred for therapeutic hypothermia who underwent MRI and neurobehavioral assessment prior to discharge. OUTCOME MEASURES: DTI was performed at median age of 8 days (range 5-16) and NNNS at median 12 days of life (range 5-20, postmenstrual age 40+/-2 weeks). Developmental assessment with the Bayley Scales of Infant Development-II was performed at median age of 21.6 months (range 20.8 30.6). RESULTS: Significant associations were observed between DTI corticospinal tract integrity and NNNS neuromotor performance in HIE newborns. Neonatal neuromotor performance was also related to later early childhood motor outcomes. CONCLUSIONS: NNNS performed after therapeutic hypothermia in newborns with HIE can identify neuromotor abnormalities that are related to microstructural brain injury in the corticospinal tract and later motor outcomes in early childhood. These data support the NNNS as a valid early functional assessment of perinatal brain injury. PMID- 26246139 TI - Ubiquitination as a Mechanism To Transport Soluble Mycobacterial and Eukaryotic Proteins to Exosomes. AB - Exosomes are extracellular vesicles of endocytic origin that function in intercellular communication. Our previous studies indicate that exosomes released from Mycobacterium tuberculosis-infected macrophages contain soluble mycobacterial proteins. However, it was unclear how these secreted proteins were targeted to exosomes. In this study, we determined that exosome production by the murine macrophage cell line RAW264.7 requires the endosomal sorting complexes required for transport and that trafficking of mycobacterial proteins from phagocytosed bacilli to exosomes was dependent on protein ubiquitination. Moreover, soluble mycobacterial proteins, when added exogenously to RAW264.7 or human HEK293 cells, were endocytosed, ubiquitinated, and released via exosomes. This suggested that endocytosed proteins could be recycled from cells through exosomes. This hypothesis was supported using the tumor-associated protein He4, which, when endocytosed by RAW264.7 or HEK293 cells, was transported to exosomes in a ubiquitin-dependent manner. Our data suggest that ubiquitination is a modification sufficient for trafficking soluble proteins within the phagocytic/endocytic network to exosomes. PMID- 26246140 TI - Hepatic Stellate Cells Inhibit T Cells through Active TGF-beta1 from a Cell Surface-Bound Latent TGF-beta1/GARP Complex. AB - Hepatic stellate cells (HSCs) inhibit T cells, a process that could help the liver to maintain its immunoprivileged status. HSCs secrete latent TGF-beta1, but the detailed mechanisms by which latent TGF-beta1 is activated and whether it plays any role in HSC-mediated T cell suppression remain unclear. Glycoprotein A repetitions predominant (GARP) is a surface marker of activated regulatory T cells. GARP binds latent TGF-beta1 for its activation, which is critical for regulatory T cells to suppress effector T cells; however, it is still unclear whether GARP is present on HSCs and whether it has any impact on HSC function. In this study, we found that TGF-beta1(+/-) HSCs, which produce reduced levels of TGF-beta1, showed decreased potency in inhibiting T cells. We also found that pharmaceutical or genetic inhibition of the TGF-beta1 signaling pathway reduced the T cell-inhibiting activity of HSCs. Additionally, using isolated primary HSCs, we demonstrated that GARP was constitutively expressed on HSCs. Blocking GARP function or knocking down GARP expression significantly impaired the potency of HSCs to suppress the proliferation of and IFN-gamma production from activated T cells, suggesting that GARP is important for HSCs to inhibit T cells. These results demonstrate the unexpected presence of GARP on HSCs and its significance in regard to the ability of HSCs to activate latent TGF-beta1 and thereby inhibit T cells. Our study reveals a new mechanism for HSC-mediated immune regulation and potentially for other conditions, such as liver fibrosis, that involve HSC secreted TGF-beta1. PMID- 26246141 TI - A Detailed Characterization of the Dysfunctional Immunity and Abnormal Myelopoiesis Induced by Severe Shock and Trauma in the Aged. AB - The elderly are particularly susceptible to trauma, and their outcomes are frequently dismal. Such patients often have complicated clinical courses and ultimately die of infection and sepsis. Recent research has revealed that although elderly subjects have increased baseline inflammation as compared with their younger counterparts, the elderly do not respond to severe infection or injury with an exaggerated inflammatory response. Initial retrospective analysis of clinical data from the Glue Grant trauma database demonstrated that despite a similar frequency, elderly trauma patients have worse outcomes to pneumonia than younger subjects do. Subsequent analysis with a murine trauma model also demonstrated that elderly mice had increased mortality after posttrauma Pseudomonas pneumonia. Blood, bone marrow, and bronchoalveolar lavage sample analyses from juvenile and 20-24-mo-old mice showed that increased mortality to trauma combined with secondary infection in the aged are not due to an exaggerated inflammatory response. Rather, they are due to a failure of bone marrow progenitors, blood neutrophils, and bronchoalveolar lavage cells to initiate and complete an emergency myelopoietic response, engendering myeloid cells that fail to clear secondary infection. In addition, elderly people appeared unable to resolve their inflammatory response to severe injury effectively. PMID- 26246142 TI - Loss of Phagocytic and Antigen Cross-Presenting Capacity in Aging Dendritic Cells Is Associated with Mitochondrial Dysfunction. AB - Impaired functionality of dendritic cells (DCs) significantly contributes to decreased adaptive immune responses in aged hosts. The expression of MHC-peptide on the DC surface is the critical first step in T cell priming, but few studies have addressed the effect of aging on Ag acquisition, processing, and presentation by DCs. In this study, we show that aged murine DCs were less efficient in the cross-presentation of cell-associated Ag and subsequently in the cross-priming of CD8(+) T cells than were their young counterparts. The decreased cross-presentation was associated with a reduction in the frequency of CD8alpha DCs and merocytic (CD8alpha(-)CD11b(-))DCs that could endocytose cell-associated Ag, as well as the number and the size of the endocytosed particles in the DC that did internalize cell-associated materials. Mechanistically, phagocytic capacity has been associated with mitochondrial activity and membrane potential (Deltapsim). Aged DCs exhibited profound signs of mitochondrial dysfunction, illustrated by lower Deltapsim, reduced ATP turnover and coupling efficiency, decreased baseline oxidative phosphorylation, and greater proton leak and reactive oxygen species (ROS) production. Mimicking the aged metabolic phenotype in young DCs by pharmacologic manipulation indicated that the reductions in Deltapsim and ATP impeded the phagocytic capacity whereas ROS interfered with a later step in the cross-presentation process. Conversely, in vitro scavenging of ROS partially restored cross-presentation by aged DCs. Taken together, these data suggest that improvement of aged DC functionality might be feasible in the elderly by targeting metabolic dysfunction or its downstream sequelae, thereby opening new avenues for enhancing vaccine efficiency in this population. PMID- 26246143 TI - Defective NK Cells in Acute Myeloid Leukemia Patients at Diagnosis Are Associated with Blast Transcriptional Signatures of Immune Evasion. AB - Acute myeloid leukemia (AML) is a heterogeneous group of malignancies that may be sensitive to the NK cell antitumor response. However, NK cells are frequently defective in AML. In this study, we found in an exploratory cohort (n = 46) that NK cell status at diagnosis of AML separated patients in two groups with a different clinical outcome. Patients with a deficient NK cell profile, including reduced expression of some activating NK receptors (e.g., DNAX accessory molecule 1, NKp46, and NKG2D) and decreased IFN-gamma production, had a significantly higher risk of relapse (p = 0.03) independently of cytogenetic classification in multivariate analysis. Patients with defective NK cells showed a profound gene expression decrease in AML blasts for cytokine and chemokine signaling (e.g., IL15, IFNGR1, IFNGR2, and CXCR4), Ag processing (e.g., HLA-DRA, HLA-DRB1, and CD74) and adhesion molecule pathways (e.g., PVR and ICAM1). A set of 388 leukemic classifier genes defined in the exploratory cohort was independently validated in a multicentric cohort of 194 AML patients. In total, these data evidenced the interplay between NK cells and AML blasts at diagnosis allowing an immune-based stratification of AML patients independently of clinical classifications. PMID- 26246144 TI - Loss of Phosphatase and Tensin Homolog in APCs Impedes Th17-Mediated Autoimmune Encephalomyelitis. AB - The PI3K signaling cascade in APCs has been recognized as an essential pathway to initiate, maintain, and resolve immune responses. In this study, we demonstrate that a cell type-specific loss of the PI3K antagonist phosphatase and tensin homolog (PTEN) in myeloid cells renders APCs toward a regulatory phenotype. APCs deficient for PTEN exhibit reduced activation of p38 MAPK and reduced expression of T cell-polarizing cytokines. Furthermore, PTEN deficiency leads to upregulation of markers for alternative activation, such as Arginase 1, with concomitant downregulation of inducible NO synthase in APCs in vitro and in vivo. As a result, T cell polarization was dysfunctional in PTEN(-/-) APCs, in particular affecting the Th17 cell subset. Intriguingly, mice with cell type specific deletions of PTEN-targeting APCs were protected from experimental autoimmune encephalomyelitis, which was accompanied by a pronounced reduction of IL-17- and IL-22-producing autoreactive T cells and reduced CNS influx of classically activated monocytes/macrophages. These observations support the notion that activation of the PI3K signaling cascade promotes regulatory APC properties and suppresses pathogenic T cell polarization, thereby reducing the clinical symptoms and pathology of experimental autoimmune encephalomyelitis. PMID- 26246146 TI - Cultivating candour about our mistakes. PMID- 26246145 TI - Adequacy of the Measurement Capability of Fatty Acid Compositions and Sterol Profiles to Determine Authenticity of Milk Fat Through Formulation of Adulterated Butter. AB - In this research a comparison has been made between the fatty acid and sterol compositions of Iranian pure butter and three samples of adulterated butter. These samples were formulated using edible vegetable fats/oils with similar milk fat structures including palm olein, palm kernel and coconut oil to determine the authenticity of milk fat. The amount of vegetable fats/oils used in the formulation of the adulterated butter was 10%. The adulterated samples were formulated so that their fatty acid profiles were comforted with acceptable levels of pure butter as specified by the Iranian national standard. Based on the type of the vegetable oil/fat, fatty acids such as C4:0, C12:0 and C18:2 were used as indicators for the adulterated formulations. According to the standard method of ISO, the analysis was performed using gas chromatography. The cholesterol contents were 99.71% in pure butter (B1), and 97.61%, 98.48% and 97.98% of the total sterols in the samples adulterated with palm olein, palm kernel and coconut oil (B2, B3 and B4), respectively. Contents of the main phytosterol profiles such as beta-sitosterol, stigmasterol and campesterol were also determined. The beta-sitosterol content, as an indicator of phytosterols, was 0% in pure butter, and 1.81%, 1.67% and 2.16%, of the total sterols in the adulterated samples (B2, B3 and B4), respectively. Our findings indicate that fatty acid profiles are not an efficient indicator for butter authentication. Despite the increase in phytosterols and the reduction in cholesterol and with regard to the conformity of the sterol profiles of the edible fats/oils used in the formulations with Codex standards, lower cholesterol and higher phytosterols contents should have been observed. It can therefore be concluded that sterol measurement is insufficient to verify the authenticity of the milk fat in butter. It can therefore be concluded that sterol measurement is insufficient in verifying the authenticity of milk fat. PMID- 26246147 TI - The mental health, quality of life and life satisfaction of internally displaced persons living in Nakuru County, Kenya. AB - BACKGROUND: Internally displaced persons (IDPs) are among the most vulnerable people in the world today. Previous research highlights that conflict-induced forced displacement can cause problems with mental health and wellbeing. This study aimed to contribute to this body of knowledge by investigating the mental health, quality of life, and life satisfaction among IDPs living in Nakuru, Kenya. METHODS: A questionnaire that included the General Health Questionnaire 12, Satisfaction with Life Scale, and a modified version of the WHO Quality of Life-BREF tool was used for data collection. The questionnaire also included an open-ended question inviting qualitative responses about their experience as an IDP. The questionnaire was distributed through a three-stage sampling approach across four refugee camps from four regions of the Nakuru County in Kenya. RESULTS: One hundred IDPs participated in this study. All participants scored substantially higher than the applied GHQ-12 threshold for caseness (mean GHQ-12 score = 28.7, SD = 3.6). Quality of life and life satisfaction scores were also very poor (M = 10.24, SD = 1.9; M = 6.82, SD = 1.5 respectively). The qualitative results reflected these findings with statements reflecting suicidal thoughts, unhappiness with the government, lack of support, and fear for themselves and their children. Significantly higher GHQ-12 scores were found among older IDPs (rho = .202, sig = .046), widowers compared to married IDPs (mean difference = 2.41, SE = .885, sig = .027), while lower scores were found among IDPs who reported having friends as a source of support (U = 834, sig = .045), while quality of life scores were higher among IDPs who reported receiving governmental support (U = 248, sig = .018). CONCLUSION: The findings revealed poor levels of mental health, quality of life and life satisfaction. Older, widowed IDPs and those who did not perceive support from friends or the government were found to be at the highest risk of poor health and wellbeing. PMID- 26246148 TI - Engaging patients around the risks of opioid misuse in the emergency department. PMID- 26246149 TI - Prognostic factors of craniopharyngioma with special reference to autocrine/paracrine signaling: underestimated implication of growth hormone receptor. AB - BACKGROUND: Craniopharyngioma is a slow-growing tumor classified as benign, but tight adhesion and significant local infiltration to the vital structures are common. In spite of improvement of modern microsurgery techniques and precise anatomical understanding not few cases of this tumor recur, and long-term tumor control and maintenance of quality of life are sometimes difficult. However, very little is known about the effects of the molecular characters of craniopharyngioma on the prognosis. METHODS: Ninety eight cases of craniopharyngioma surgically treated at the Department of Neurosurgery, Tohoku University Hospital and Kohnan Hospital from April 1996 to May 2014, 45 males and 53 females aged from 2 to 80 years (mean, 40.84 years) were retrospectively reviewed, and postoperative outcomes and the possible involvement of the autocrine/paracrine mechanism were investigated. The patients were followed up at intervals of 6 months to assess tumor recurrence, and clinical outcomes were correlated with the findings of immunohistochemical examinations used growth hormone receptor (GHR) and downstream hormones. The follow-up period ranged from 3 to 209 months. RESULTS: Hormone expression was examined in 88 patients, of which 46 specimens (52.3 %) showed high expression of GHR. The GHR high expression group had a significantly shorter duration of postoperative stable disease compared with the low expression group (logrank test, p = 0.007). Simultaneous high expression of growth hormone (GH) and GHR was found in 33 specimens (37.5 %), and the high expression group had a significantly shorter duration of postoperative stable disease compared with the low expression group (logrank test, p = 0.011). No other hormones showed statistically significant differences in outcomes. CONCLUSIONS: High expression of GHR is associated with shorter duration of postoperative stable disease in patients with craniopharyngioma. If the surgical specimens were craniopharyngiomas with high GHR expression, GH supplementation would be introduced quite prudently. PMID- 26246151 TI - An efficient method for the synthesis of selenium modified nucleosides: its application in the synthesis of Se-adenosyl-L-selenomethionine (SeAM). AB - In this paper, we report that a versatile method for the synthesis of 5'-selenium modified nucleosides has been explored on the basis of a 2-(trimethylsilyl)ethyl (TSE) selenyl group as a selenating donor. We demonstrate the broad utility of this method through direct introduction of various functional groups into 5'-TSE selenonucleosides. This original method offers additional advantages for the preparation of these compounds, such as high functional group tolerance, ready availability of various electrophilic reagents, mild conditions, simple operation, and good yields. The utility of this approach is further demonstrated by the synthesis of Se-adenosyl-L-selenomethionine (SeAM) as a chemical reporter for methyltransferases. PMID- 26246150 TI - An artificial neural network for membrane-bound catechol-O-methyltransferase biosynthesis with Pichia pastoris methanol-induced cultures. AB - BACKGROUND: Membrane proteins are important drug targets in many human diseases and gathering structural information regarding these proteins encourages the pharmaceutical industry to develop new molecules using structure-based drug design studies. Specifically, membrane-bound catechol-O-methyltransferase (MBCOMT) is an integral membrane protein that catalyzes the methylation of catechol substrates and has been linked to several diseases such as Parkinson's disease and Schizophrenia. Thereby, improvements in the clinical outcome of the therapy to these diseases may come from structure-based drug design where reaching MBCOMT samples in milligram quantities are crucial for acquiring structural information regarding this target protein. Therefore, the main aim of this work was to optimize the temperature, dimethylsulfoxide (DMSO) concentration and the methanol flow-rate for the biosynthesis of recombinant MBCOMT by Pichia pastoris bioreactor methanol-induced cultures using artificial neural networks (ANN). RESULTS: The optimization trials intended to evaluate MBCOMT expression by P. pastoris bioreactor cultures led to the development of a first standard strategy for MBCOMT bioreactor biosynthesis with a batch growth on glycerol until the dissolved oxygen spike, 3 h of glycerol feeding and 12 h of methanol induction. The ANN modeling of the aforementioned fermentation parameters predicted a maximum MBCOMT specific activity of 384.8 nmol/h/mg of protein at 30 degrees C, 2.9 mL/L/H methanol constant flow-rate and with the addition of 6% (v/v) DMSO with almost 90% of healthy cells at the end of the induction phase. These results allowed an improvement of MBCOMT specific activity of 6.4-fold in comparison to that from the small-scale biosynthesis in baffled shake-flasks. CONCLUSIONS: The ANN model was able to describe the effects of temperature, DMSO concentration and methanol flow-rate on MBCOMT specific activity, as shown by the good fitness between predicted and observed values. This experimental procedure highlights the potential role of chemical chaperones such as DMSO in improving yields of recombinant membrane proteins with a different topology than G-coupled receptors. Finally, the proposed ANN shows that the manipulation of classic fermentation parameters coupled with the addition of specific molecules can open and reinforce new perspectives in the optimization of P. pastoris bioprocesses for membrane proteins biosynthesis. PMID- 26246152 TI - Effect of thrombus aspiration on postprocedural outcomes in elderly patients with acute ST-elevation myocardial infarction. AB - AIM: The effects of thrombus aspiration (TA) during primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) have been evaluated in several studies. The aim of the present study was to evaluate postprocedural outcomes in elderly STEMI patients who have a tendency for vasoconstruction and decreased coronary flow reserve. METHODS: A total of 124 patients (aged >=65 years) with STEMI who underwent primary PCI (71.2% men, 29.8% women, mean age 74 +/- 7 years) were enrolled in the study. Patients were divided into two groups according to intervention with and without TA. Acute angiographic, electrocardiographic and echocardiographic results were compared between the two groups. RESULTS: TA was carried out in 42 patients (33.8%). Baseline clinical characteristics and predischarge echocardiographic features did not differ between TA(+) and TA(-) patients (ejection fraction 37.26 +/- 8.91 vs 38.53 +/- 11.18, P = 0.558, wall motion index 1.69 +/- 0.38 vs 1.76 +/- 0.37, P = 0.316, septal E' 0.058 +/- 0.022 vs 0.053 +/- 0.015, P = 0.267, E/E' 11.82 +/- 4.30 vs 13.12 +/- 5.09, P = 0.370). Acute angiographic and electrocardiographic results did not differ between the two groups, but were slightly better in the thrombectomy group than those without TA corrected TIMI frame count (31.63 +/- 16.33 vs 34.97 +/- 15.81, P = 0.197, TIMI-3 88.1% vs 79.3%, P = 0.223, ST segment resolution 81.3% vs 70.3%, P = 0.250). CONCLUSIONS: Thrombectomy during primary PCI has no effect on postprocedural outcomes in an elderly group with STEMI. Geriatr Gerontol Int 2015; ??: ??-??. PMID- 26246154 TI - Whole-exome sequencing reveals a novel frameshift mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in the Indian population. AB - Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degenerations caused by mutations in at least 50 genes. To identify genetic mutations underlying autosomal recessive RP (arRP), we performed whole-exome sequencing study on two consanguineous marriage Indian families (RP-252 and RP 182) and 100 sporadic RP patients. Here we reported novel mutation in FAM161A in RP-252 and RP-182 with two patients affected with RP in each family. The FAM161A gene was identified as the causative gene for RP28, an autosomal recessive form of RP. By whole-exome sequencing we identified several homozygous genomic regions, one of which included the recently identified FAM161A gene mutated in RP28-linked arRP. Sequencing analysis revealed the presence of a novel homozygous frameshift mutation p.R592FsX2 in both patients of family RP-252 and family RP 182. In 100 sporadic Indian RP patients, this novel homozygous frameshift mutation p.R592FsX2 was identified in one sporadic patient ARRP-S-I-46 by whole exome sequencing and validated by Sanger sequencing. Meanwhile, this homozygous frameshift mutation was absent in 1000 ethnicity-matched control samples screened by direct Sanger sequencing. In conclusion, we identified a novel homozygous frameshift mutations of RP28-linked RP gene FAM161A in Indian population. PMID- 26246155 TI - Frequent genomic rearrangements of BRCA1 associated protein-1 (BAP1) gene in Japanese malignant mesothelioma-characterization of deletions at exon level. AB - Malignant mesothelioma (MM) is an asbestos-related malignancy arising from surface serosal cells of pleural and peritoneal cavities. Somatic mutations of BRCA1 associated protein-1 (BAP1) gene were recently found in MM as well as in uveal melanoma and kidney cancer among the Caucasian and Japanese people. However, frequency of mutations varies among the reported studies, which might be due to presence of undetected gross rearrangements of BAP1 gene that might escape detection by sequencing strategy. We investigated the presence and frequency of gross genomic rearrangements in the BAP1 gene by multiplex ligation-dependent probe amplification (MLPA) in 17 Japanese cases of MM tumors. We found five tumors with partial deletion of BAP1 gene; each tumors displayed partial deletion of exons 1-4 (MM39), exons 1-5 (MM48), exons 11-17 (MM57), exons 1-15 (MM19) and exons 1-16 (MM21). Two tumors (MM34, MM14) had biallelic deletion and four tumors (MM29, MM35, MM45 and MM56) had monoallelic deletion of entire BAP1 gene. Therefore, MLPA analysis revealed large gene rearrangements of BAP1 gene in 65% of MM (11/17). Unusually high frequency of large deletions indicates that the 3p21 chromosomal region surrounding BAP1 gene is structurally unstable. MLPA was useful in characterizing both monoallelic and biallelic deletion of BAP1 gene precisely at exon level. PMID- 26246156 TI - Association of common variants in H2AFZ gene with schizophrenia and cognitive function in patients with schizophrenia. AB - Recently, the H2AFZ gene was reported in relation to schizophrenia in Japanese males. A two-stage case-control study was designed to investigate the association of the H2AFZ gene with schizophrenia and its relationship with cognitive function in Han Chinese patients with schizophrenia. This study included a testing set with 1115 patients and 2289 controls and a validation set with 1843 patients and 3155 controls. A total of 10 single-nucleotide polymorphisms (SNPs) in the H2AFZ gene were genotyped, and both independent data sets were analyzed in association with SNP and gender. The rs2276939 SNP was found to be significantly associated with schizophrenia, particularly in males. A similar pattern was observed in our two-stage study on conducting further imputation and haplotype association analyses. In addition, two of the SNPs (rs61203457 and rs2276939) and cognitive functioning were found to interact significantly when processing the perseverative error in the Wisconsin Card Sorting Test. Our findings suggest that the H2AFZ gene may confer a risk for schizophrenia and contribute to the impairment of executive function in Han Chinese patients with schizophrenia. These findings augment our current state of knowledge regarding the risk of schizophrenia and the impairment of cognitive performance in patients with this disorder. PMID- 26246157 TI - Distinct roles of basal forebrain cholinergic neurons in spatial and object recognition memory. AB - Recognition memory requires processing of various types of information such as objects and locations. Impairment in recognition memory is a prominent feature of amnesia and a symptom of Alzheimer's disease (AD). Basal forebrain cholinergic neurons contain two major groups, one localized in the medial septum (MS)/vertical diagonal band of Broca (vDB), and the other in the nucleus basalis magnocellularis (NBM). The roles of these cell groups in recognition memory have been debated, and it remains unclear how they contribute to it. We use a genetic cell targeting technique to selectively eliminate cholinergic cell groups and then test spatial and object recognition memory through different behavioural tasks. Eliminating MS/vDB neurons impairs spatial but not object recognition memory in the reference and working memory tasks, whereas NBM elimination undermines only object recognition memory in the working memory task. These impairments are restored by treatment with acetylcholinesterase inhibitors, anti dementia drugs for AD. Our results highlight that MS/vDB and NBM cholinergic neurons are not only implicated in recognition memory but also have essential roles in different types of recognition memory. PMID- 26246158 TI - Tissue-specific expression pattern and histological distribution of NLRP3 in Chinese yellow chicken. AB - Pathogen-associated molecular patterns (PAMPs) play important role in inflammation which means response of the host to stimuli. NOD-like receptor protein 3 (NLRP3) inflammasome is involved in the onset and development of inflammation. NLRP3, as one of the most important inflammasome sensors, has significant effect on the regulation of inflammasome activation to avoid the consequences of over activation. Up to date, there are no detailed tissue specific expression and distribution data about NLPR3 in chicken. Here, NLRP3 of Chinese yellow chicken was cloned and sequence analyzed, the polyclonal antibody was produced by purified protein of recombinant prokaryotic expression. Relative expression levels and tissue distribution of NLRP3 were investigated by real-time quantitative PCR and immunohistochemical analysis, respectively. The results showed that NLRP3 gene is highly variable between mammalian and avian. The nucleotide homology of NLRP3 between yellow chicken and Bos taurus, Hainan black goat, Sus scrofa, Callithrix jacchus, Homo sapiens, Macaca mulatta, Mus musculus and Rattus norvegicus were 54.2%, 53.9%, 53.7%, 55.4%, 54.3%, 54.5%, 53.5% and 53.7%. NLRP3 expressed in all detected tissues and higher in the trachea are lung than in other tissues. Cytoplasmic expression of NLRP3 was detected in ciliated epithelial cells, basal cells and cells in lamina propria of trachea, alveolar epithelial cells, cardiac muscle cells, cerebral cortex neurons, epithelial reticular cells of the spleen, and lymphocytes of medulla in stannius follicle, liver cells and the renal tubule epithelial cells. The results will help to elucidate the role of NLRP3 of different tissues in inflammatory diseases of chicken and provide a basis for further investigations in the function and evolution of NLRP3 in different species, which would be helpful for further research on avian inflammatory diseases. PMID- 26246159 TI - Treatment trial of clinically ill corroboree frogs with chytridiomycosis with two triazole antifungals and electrolyte therapy. AB - Chytridiomycosis caused by the pathogen Batrachochytrium dendrobatidis is an important cause of amphibian declines globally, and is the worst pathogen on record for causing biodiversity loss. The critically endangered southern corroboree frog, Pseudophryne corroboree, is functionally extinct in the wild and is surviving in captive assurance colonies. These captive colonies must remain disease free, and there is no known treatment for corroboree frogs with terminal chytridiomycosis. In this study we tested two triazole antifungals (itraconazole and voriconazole) coupled with aggressive electrolyte therapy on moribund corroboree frogs with severe chytridiomycosis. Six moribund frogs were given 20 mL baths of 0.5 MUg/mL itraconazole for 5 min/day for 5 days coupled with electrolyte injections every 8 h for 3 days followed by every 12 h for 3 days. Six other moribund frogs were given 1 mL drops of 1.25 MUg/mL voriconazole daily for 7 days coupled with the aggressive electrolyte therapy. While only one animal survived this treatment regime, time until death was extended for all animals by at least 3 days and infection load decreased by an average of 89.3%. Our results suggest there is potential for recovery of terminally ill P. corroboree, and we suggest further trials include antibiotics as well as exploring variations on the above treatment regime with other antifungals. PMID- 26246160 TI - Iron deficiency anemia at admission for labor and delivery is associated with an increased risk for Cesarean section and adverse maternal and neonatal outcomes. AB - BACKGROUND: Maternal iron deficiency anemia (IDA) impacts placenta and fetus. We evaluated effects of IDA at admission for delivery on cesarean rates, and adverse maternal and neonatal outcomes. STUDY DESIGN AND METHODS: Medical records from Jerusalem (2005-2012) identified women with a live-birth singleton fetus in cephalic presentation of any gestational age and excluded planned cesarean, chronic/gestational diseases identified with anemia. Study population was divided into anemic and non-anemic women using WHO criteria. MAIN OUTCOME MEASURES: cesarean rate, and adverse outcomes (maternal: packed cells transfusion, early post-partum hemorrhage, preterm delivery; and neonatal: 5' Apgar < 7, Neonatal Intensive Care Unit [NICU] admission, extreme birthweights). Continuous variable analysis and multivariate backward step-wise logistic regression models were prepared with Odds Ratios (OR) and 95% confidence intervals (CI). RESULTS: In all, 96,066 deliveries were registered, of which 75,660 (78.8%) were included. IDA was present in 7,977 women (10.5%). Anemia at birth was significantly associated with cesarean section (OR 1.30; 95%CI, 1.13-1.49, p < 0.001), packed cells transfusion (OR 5.48; 95%CI, 4.57-6.58, p < 0.001), preterm delivery (OR 1.54; 95%CI, 1.36-1.76, p < 0.001), macrosomia (OR 1.23; 95%CI, 1.12-1.35, p < 0.001), Large for Gestational Age (OR 1.29; 95%CI, 1.20-1.39, p < 0.001), Apgar 5' < 7 (OR 2.21; 95%CI, 1.84-2.64, p < 0.001), and NICU admission (OR 1.28; 95%CI, 1.04-1.57, p = 0.018). CONCLUSION: Iron deficiency anemia at delivery is associated with an increased risk for cesarean section and adverse maternal and neonatal outcomes in otherwise healthy women. Monitoring/correction of hemoglobin concentrations even in late pregnancy may prevent these adverse events. PMID- 26246161 TI - Maternal protein restriction reduces perlecan at mid-metanephrogenesis in rats. AB - AIM: Maternal dietary protein restriction reduces nephron number in offspring and increases the risk of cardiovascular and chronic kidney diseases. Perlecan is the major basement membrane/extracellular matrix heparan sulfate proteoglycan (HSPG) that plays a crucial role in nephron formation. This study was to determine whether maternal dietary protein restriction during pregnancy leads to an abnormal perlecan expression pattern during kidney development and a correlation with aberrant cell proliferation and apoptosis. METHODS: Pregnant Sprague-Dawley rats were divided into two groups, maintained on either a low-protein diet (MLP group) or a normal-protein diet (MNP group). Kidneys were dissected from embryos of different kidney development stages. Real-time PCR and immunohistochemistry were performed to detect the transcript level of rHSPG2, the coding gene of perlecan, and its protein expression pattern. Apoptosis and proliferation cell were detected by TUNEL system and Ki67 marker. RESULTS: Embryonic weights and nephron number were significantly affected by maternal low protein diets. The transcript level of rHSPG2 in the MLP group was significantly lower at embryonic day 18 and the neonatal period. Immunohistochemistry study was consistent with the RT-PCR results. The proliferation level of the MLP group was significantly lower than the MNP group at E18 and more apoptotic cells was detected in MLP newborn. CONCLUSION: Maternal protein restriction reduced the expression of perlecan and lead aberrant cell proliferation and apoptosis during mid metanephrogenesis in offspring. This data may provide new evidence to understand the mechanism of reduced nephron number due to maternal protein restriction and enlighten solution. PMID- 26246162 TI - Heart rate dynamics distinguish among atrial fibrillation, normal sinus rhythm and sinus rhythm with frequent ectopy. AB - Atrial fibrillation (AF) is usually detected by inspection of the electrocardiogram waveform, a task made difficult when the signal is distorted by noise. The RR interval time series is more frequently available and accurate, yet linear and nonlinear time series analyses that detect highly varying and irregular AF are vulnerable to the common finding of frequent ectopy. We hypothesized that different nonlinear measures might capture characteristic features of AF, normal sinus rhythm (NSR), and sinus rhythm (SR) with frequent ectopy in ways that linear measures might not. To test this, we studied 2722 patients with 24 h ECG recordings in the University of Virginia Holter database. We found dynamical phenotypes for the three rhythm classifications. As expected, AF records had the highest variability and entropy, and NSR the lowest. SR with ectopy could be distinguished from AF, which had higher entropy, and from NSR, which had different fractal scaling, measured as higher detrended fluctuation analysis slope. With these dynamical phenotypes, we developed successful classification strategies, and the nonlinear measures improved on the use of mean and variability alone, even after adjusting for age. Final models using all variables had excellent performance, with positive predictive values for AF, NSR and SR with ectopy as high as 97, 98 and 90%, respectively. Since these classifiers can reliably detect rhythm changes utilizing segments as short as 10 min, we envision their application in noisy settings and in personal monitoring devices where only RR interval time series may be available. PMID- 26246163 TI - Influence of auto-cross-linked hyaluronic acid gel on pregnancy rate and hysteroscopic outcomes following surgical removal of intra-uterine adhesions. AB - OBJECTIVE: To determine the effect of the use of auto-cross-linked hyaluronic acid (ACP) gel following hysteroscopic surgery on the prevention of intra-uterine adhesions (IUAs) and the pregnancy rate. STUDY DESIGN: An observational retrospective study of 90 patients who underwent hysteroscopic removal of IUAs was conducted between 2008 and 2013 at a tertiary university care centre. Thirty two patients received ACP gel during hysteroscopic removal of IUAs, and the remaining 58 patients did not receive ACP gel. Controls were matched to cases according to infertility and severity of IUAs using the American Society for Reproductive Medicine (ASRM) score. Four to six weeks after surgery, patients underwent diagnostic hysteroscopy to determine the re-occurrence of IUAs or the presence of adhesions. The patients were contacted by telephone to answer a questionnaire concerning their fertility. The main outcomes were pregnancy rate and postoperative IUAs. RESULTS: Pregnancy (viable or not) rates were not influenced by the use of ACP gel. The viable pregnancy rate was eight of 24 (33.3%) in the ACP gel group and 12 of 49 (24.5%) in the control group (p=0.427). The mean interval between surgery and pregnancy was 11.8 [standard deviation (SD) 10.5] months in the ACP group compared with 13.4 (SD 14.1) months in the control group (p=0.744). The mean ASRM score after surgery (hysteroscopic diagnosis at 4 6 weeks postoperatively) was equivalent in the two groups: 2.7 (SD 3.0) in the ACP gel group vs 2.6 (SD 3.2) in the control group (p=0.854). The mean follow-up was 45.2 months (interquartile range 33.2-52.7), with a loss to follow-up of 25% in the ACP gel group compared with 15.5% in the control group (p=0.817). CONCLUSION: Application of ACP gel did not prevent recurrence of IUAs and was not associated with an increased pregnancy rate. ACP gel should be used with caution pending assessment in a randomized control trial in a larger population. PMID- 26246164 TI - Analysis of food intake profile among women from the oasis of southeastern Morocco. AB - Nutritional status is the best indicator of the global well-being of women and food intake is known to reflect a healthy diet. The aim of this study was to assess the influence of socioeconomic status on the food intake in women living in the southeastern oasis of Morocco by exploring their nutritional intake through 24-h dietary recall (n=387). Analysis of the relationship between food intake and the socioeconomic characteristics in women showed a positive correlation between daily vegetable, cereals, red and white meat intake and region of residence (p<0.001, p=0.005, p=0.001 and p=0.04 respectively). The number of persons living at home showed a positive significant correlation with the daily intake of vegetables (p=0.01) and beverage (p=0.004). For fish and cereals, a positive significant correlation with the occupation variable has been shown (p=0.04 and p<0.001 respectively). In addition, a positive correlation has been noticed between the daily intake of vegetables, cereals, white meat, and dairy product and family status in housing (p=0.03, p=0.02, p=0.03 and p=0.04 respectively). In conclusion, the level of education, family size and occupation influence the daily intake of food in this region. PMID- 26246165 TI - Neuroprotective therapies: Preclinical reproducibility is only part of the problem. AB - Among the many unknowns in the translational path to developing drugs for acute stroke, addressing the reproducibility of preclinical data is only one piece of a multifaceted and incomplete puzzle (Llovera et al., this issue). PMID- 26246166 TI - Results of a preclinical randomized controlled multicenter trial (pRCT): Anti CD49d treatment for acute brain ischemia. AB - Numerous treatments have been reported to provide a beneficial outcome in experimental animal stroke models; however, these treatments (with the exception of tissue plasminogen activator) have failed in clinical trials. To improve the translation of treatment efficacy from bench to bedside, we have performed a preclinical randomized controlled multicenter trial (pRCT) to test a potential stroke therapy under circumstances closer to the design and rigor of a clinical randomized control trial. Anti-CD49d antibodies, which inhibit the migration of leukocytes into the brain, were previously investigated in experimental stroke models by individual laboratories. Despite the conflicting results from four positive and one inconclusive preclinical studies, a clinical trial was initiated. To confirm the preclinical results and to test the feasibility of conducting a pRCT, six independent European research centers investigated the efficacy of anti-CD49d antibodies in two distinct mouse models of stroke in a centrally coordinated, randomized, and blinded approach. The results pooled from all research centers revealed that treatment with CD49d-specific antibodies significantly reduced both leukocyte invasion and infarct volume after the permanent distal occlusion of the middle cerebral artery, which causes a small cortical infarction. In contrast, anti-CD49d treatment did not reduce lesion size or affect leukocyte invasion after transient proximal occlusion of the middle cerebral artery, which induces large lesions. These results suggest that the benefits of immune-targeted approaches may depend on infarct severity and localization. This study supports the feasibility of performing pRCTs. PMID- 26246167 TI - A targeted real-time early warning score (TREWScore) for septic shock. AB - Sepsis is a leading cause of death in the United States, with mortality highest among patients who develop septic shock. Early aggressive treatment decreases morbidity and mortality. Although automated screening tools can detect patients currently experiencing severe sepsis and septic shock, none predict those at greatest risk of developing shock. We analyzed routinely available physiological and laboratory data from intensive care unit patients and developed "TREWScore," a targeted real-time early warning score that predicts which patients will develop septic shock. TREWScore identified patients before the onset of septic shock with an area under the ROC (receiver operating characteristic) curve (AUC) of 0.83 [95% confidence interval (CI), 0.81 to 0.85]. At a specificity of 0.67, TREWScore achieved a sensitivity of 0.85 and identified patients a median of 28.2 [interquartile range (IQR), 10.6 to 94.2] hours before onset. Of those identified, two-thirds were identified before any sepsis-related organ dysfunction. In comparison, the Modified Early Warning Score, which has been used clinically for septic shock prediction, achieved a lower AUC of 0.73 (95% CI, 0.71 to 0.76). A routine screening protocol based on the presence of two of the systemic inflammatory response syndrome criteria, suspicion of infection, and either hypotension or hyperlactatemia achieved a lower sensitivity of 0.74 at a comparable specificity of 0.64. Continuous sampling of data from the electronic health records and calculation of TREWScore may allow clinicians to identify patients at risk for septic shock and provide earlier interventions that would prevent or mitigate the associated morbidity and mortality. PMID- 26246168 TI - Structure-based drug design identifies polythiophenes as antiprion compounds. AB - Prions cause transmissible spongiform encephalopathies for which no treatment exists. Prions consist of PrP(Sc), a misfolded and aggregated form of the cellular prion protein (PrP(C)). We explore the antiprion properties of luminescent conjugated polythiophenes (LCPs) that bind and stabilize ordered protein aggregates. By administering a library of structurally diverse LCPs to the brains of prion-infected mice via osmotic minipumps, we found that antiprion activity required a minimum of five thiophene rings bearing regularly spaced carboxyl side groups. Solid-state nuclear magnetic resonance analyses and molecular dynamics simulations revealed that anionic side chains interacted with complementary, regularly spaced cationic amyloid residues of model prions. These findings allowed us to extract structural rules governing the interaction between LCPs and protein aggregates, which we then used to design a new set of LCPs with optimized binding. The new set of LCPs showed robust prophylactic and therapeutic potency in prion-infected mice, with the lead compound extending survival by >80% and showing activity against both mouse and hamster prions as well as efficacy upon intraperitoneal administration into mice. These results demonstrate the feasibility of targeted chemical design of compounds that may be useful for treating diseases of aberrant protein aggregation such as prion disease. PMID- 26246169 TI - Automated identification of abnormal respiratory ciliary motion in nasal biopsies. AB - Motile cilia lining the nasal and bronchial passages beat synchronously to clear mucus and foreign matter from the respiratory tract. This mucociliary defense mechanism is essential for pulmonary health, because respiratory ciliary motion defects, such as those in patients with primary ciliary dyskinesia (PCD) or congenital heart disease, can cause severe sinopulmonary disease necessitating organ transplant. The visual examination of nasal or bronchial biopsies is critical for the diagnosis of ciliary motion defects, but these analyses are highly subjective and error-prone. Although ciliary beat frequency can be computed, this metric cannot sensitively characterize ciliary motion defects. Furthermore, PCD can present without any ultrastructural defects, limiting the use of other detection methods, such as electron microscopy. Therefore, an unbiased, computational method for analyzing ciliary motion is clinically compelling. We present a computational pipeline using algorithms from computer vision and machine learning to decompose ciliary motion into quantitative elemental components. Using this framework, we constructed digital signatures for ciliary motion recognition and quantified specific properties of the ciliary motion that allowed high-throughput classification of ciliary motion as normal or abnormal. We achieved >90% classification accuracy in two independent data cohorts composed of patients with congenital heart disease, PCD, or heterotaxy, as well as healthy controls. Clinicians without specialized knowledge in machine learning or computer vision can operate this pipeline as a "black box" toolkit to evaluate ciliary motion. PMID- 26246170 TI - Immune-mediated pathology in Duchenne muscular dystrophy. AB - Immunological and inflammatory processes downstream of dystrophin deficiency as well as metabolic abnormalities, defective autophagy, and loss of regenerative capacity all contribute to muscle pathology in Duchenne muscular dystrophy (DMD). These downstream cascades offer potential avenues for pharmacological intervention. Modulating the inflammatory response and inducing immunological tolerance to de novo dystrophin expression will be critical to the success of dystrophin-replacement therapies. This Review focuses on the role of the inflammatory response in DMD pathogenesis and opportunities for clinical intervention. PMID- 26246171 TI - The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling. AB - Mitochondria serve as platforms for innate immunity. The mitochondrial antiviral signalling (MAVS) protein forms aggregates that elicit robust type-I interferon induction on viral infection, but persistent MAVS signalling leads to host immunopathology; it remains unknown how these signalling aggregates are resolved. Here we identify the mitochondria-resident E3 ligase, MARCH5, as a negative regulator of MAVS aggregates. March5(+/-) mice and MARCH5-deficient immune cells exhibit low viral replication and elevated type-I interferon responses to RNA viruses. MARCH5 binds MAVS only during viral stimulation when MAVS forms aggregates, and these interactions require the RING domain of MARCH5 and the CARD domain of MAVS. MARCH5, but not its RING mutant (MARCH5(H43W)), reduces the level of MAVS aggregates. MARCH5 transfers ubiquitin to Lys7 and Lys500 of MAVS and promotes its proteasome-mediated degradation. Our results indicate that MARCH5 modulates MAVS-mediated antiviral signalling, preventing excessive immune reactions. PMID- 26246172 TI - Parametrized rectal dose and associations with late toxicity in prostate cancer radiotherapy. AB - OBJECTIVE: We investigated possible associations between planned dose-volume parameters and rectal late toxicity in 170 patients having radical prostate cancer radiotherapy. METHODS: For each patient, the rectum was outlined from anorectal junction to sigmoid colon, and rectal dose was parametrized using dose volume (DVH), dose-surface (DSH) and dose-line (DLH) histograms. Generation of DLHs differed from previous studies in that the rectal dose was parametrized without first unwrapping onto 2-dimensional dose-surface maps. Patient-reported outcomes were collected using a validated Later Effects in Normal Tissues Subjective, Objective, Management and Analytic questionnaire. Associations between dose and toxicity were assessed using a one-sided Mann-Whitney U test. RESULTS: Associations (p < 0.05) were found between equieffective dose (EQD23) and late toxicity as follows: overall toxicity with DVH and DSH at 13-24 Gy; proctitis with DVH and DSH at 25-36 Gy and with DVH, DSH and DLH at 61-67 Gy; bowel urgency with DVH and DSH at 10-20 Gy. None of these associations met statistical significance following the application of a Bonferroni correction. CONCLUSION: Independently confirmed associations between rectal dose and late toxicity remain elusive. Future work to increase the accuracy of the knowledge of the rectal dose, either by accounting for interfraction and intrafraction rectal motion or via stabilization of the rectum during treatment, may be necessary to allow for improved dose-toxicity comparisons. ADVANCES IN KNOWLEDGE: This study is the first to use parametrized DLHs to study associations with patient-reported toxicity for prostate radiotherapy showing that it is feasible to model rectal dose mapping in three dimensions. PMID- 26246173 TI - Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement From the American Heart Association and the American Diabetes Association. AB - Cardiovascular disease risk factor control as primary prevention in patients with type 2 diabetes mellitus has changed substantially in the past few years. The purpose of this scientific statement is to review the current literature and key clinical trials pertaining to blood pressure and blood glucose control, cholesterol management, aspirin therapy, and lifestyle modification. We present a synthesis of the recent literature, new guidelines, and clinical targets, including screening for kidney and subclinical cardiovascular disease for the contemporary management of patients with type 2 diabetes mellitus. PMID- 26246174 TI - Intramural Ventricular Septal Defect Is a Distinct Clinical Entity Associated With Postoperative Morbidity in Children After Repair of Conotruncal Anomalies. AB - BACKGROUND: Intramural ventricular septal defects (VSDs) are interventricular communications through right ventricular free wall trabeculations that can occur after repair of conotruncal anomalies. We assessed the prevalence of residual intramural VSDs and their effect on postoperative course. METHODS AND RESULTS: Children who underwent biventricular repair of a conotruncal anomaly from January 1, 2006, to June 30, 2013, and had a postoperative transthoracic echocardiogram were included. Images were reviewed for residual intramural or nonintramural VSDs. The primary outcome was a composite of mortality, extracorporeal membrane oxygenation use, and need for subsequent catheter or surgical VSD closure. The secondary outcome was postoperative hospital length of stay. A residual VSD was present in 256 of the 442 subjects (58%), of which 231 (90%) were <2 mm in size. Forty-nine patients (11%) had intramural VSDs, and 207 (47%) had nonintramural VSDs. Patients with intramural VSDs were more likely to reach the primary composite outcome compared with those with nonintramural VSDs or no residual VSD (14 of 49 [29%] versus 15 of 207 [7%] versus 6 of 186 [3%]; P<0.0001). In addition, those with intramural VSDs had longer postoperative hospital length of stay compared with those with nonintramural VSDs or no residual VSD (20 days [interquartile range, 11-42 days] versus 7 days [interquartile range, 5-14 days] versus 6 days [interquartile range, 4-11 days]; P=0.0001). These associations remained significant after adjustment for known risk factors for poor outcomes, including residual VSD size and operative complexity. CONCLUSIONS: Among residual VSDs after repair of conotruncal anomalies, intramural VSDs are uniquely associated with postoperative morbidity, mortality, and longer postoperative hospital length of stay. It is important to recognize intramural VSDs in the postoperative period. PMID- 26246175 TI - Clinical Effectiveness of Statin Therapy After Ischemic Stroke: Primary Results From the Statin Therapeutic Area of the Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) Study. AB - BACKGROUND: In patients with ischemic stroke, data on the real-world effectiveness of statin therapy for clinical and patient-centered outcomes are needed to better inform shared decision making. METHODS AND RESULTS: Patient Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) is a Patient-Centered Outcomes Research Institute-funded research program designed with stroke survivors to evaluate the effectiveness of poststroke therapies. We linked data on patients >=65 years of age enrolled in the Get With The Guidelines-Stroke Registry to Medicare claims. Two-year to postdischarge outcomes of those discharged on a statin versus not on a statin were adjusted through inverse probability weighting. Our coprimary outcomes were major adverse cardiovascular events and home time (days alive and out of a hospital or skilled nursing facility). Secondary outcomes included all-cause mortality, all-cause readmission, cardiovascular readmission, and hemorrhagic stroke. From 2007 to 2011, 77 468 patients who were not taking statins at the time of admission were hospitalized with ischemic stroke; of these, 71% were discharged on statin therapy. After adjustment, statin therapy at discharge was associated with a lower hazard of major adverse cardiovascular events (hazard ratio, 0.91; 95% confidence interval, 0.87-0.94), 28 more home-time days after discharge (P<0.001), and lower all-cause mortality and readmission. Statin therapy at discharge was not associated with increased risk of hemorrhagic stroke (hazard ratio, 0.94; 95% confidence interval, 0.72-1.23). Among statin-treated patients, 31% received a high-intensity dose; after risk adjustment, these patients had outcomes similar to those of recipients of moderate-intensity statin. CONCLUSION: In older ischemic stroke patients who were not taking statins at the time of admission, discharge statin therapy was associated with lower risk of major adverse cardiovascular events and nearly 1 month more home time during the 2-year period after hospitalization. PMID- 26246176 TI - Polymorphobacter fuscus sp. nov., isolated from permafrost soil, and emended description of the genus Polymorphobacter. AB - Strain D40PT, representing a novel Gram-stain-negative, obligately aerobic, bacteriochlorophyll a-containing bacterium of the alpha-4 subgroup of the phylum Proteobacteria, was isolated from permafrost soil of Kunlun mountains gap, Qinghai-Tibet plateau. Cells were non-motile rod-cocci and formed brown-pigmented colonies. According to the absorption spectrum, carotenoids and two different photosynthetic light-harvesting complexes, an LHI complex and a B800-835-type peripheral LHII complex, were present in the cells. The strain was oxidase negative and catalase-positive. The predominant fatty acids of strain D40PT were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), C17 : 1omega6c and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). The main polar lipids were phosphatidylethanolamine, phosphatidylglycerol, unidentified phospholipid, two glycolipids and sphingoglycolipid. The major respiratory quinone was ubiquinone-10, whereas ubiquinone-9 was present in smaller amounts. The 16S rRNA gene sequence similarity to the closest phylogenetic relative, Polymorphobacter multimanifer JCM 18140T, was 97.5 %. DNA-DNA relatedness (DeltaTm) between strain D40PT and P. multimanifer was 12.4 degrees C. The G+C content of the genomic DNA of strain D40PT was 67.4 mol%. Accordingly, the strain represents a novel species, for which the name Polymorphobacter fuscus sp. nov. is proposed. The type strain is D40PT ( = CGMCC 1.12714T = JCM 19740T). An emended description of the genus Polymorphobacter is also proposed. PMID- 26246179 TI - Should risk-reducing surgery in women from hereditary breast ovarian cancer families be confined to removal of the fallopian tubes with ovarian conservation? PMID- 26246177 TI - Statistical modeling implicates neuroanatomical circuit mediating stress relief by 'comfort' food. AB - A history of eating highly palatable foods reduces physiological and emotional responses to stress. For instance, we have previously shown that limited sucrose intake (4 ml of 30 % sucrose twice daily for 14 days) reduces hypothalamic pituitary-adrenocortical (HPA) axis responses to stress. However, the neural mechanisms underlying stress relief by such 'comfort' foods are unclear, and could reveal an endogenous brain pathway for stress mitigation. As such, the present work assessed the expression of several proteins related to neuronal activation and/or plasticity in multiple stress- and reward-regulatory brain regions of rats after limited sucrose (vs. water control) intake. These data were then subjected to a series of statistical analyses, including Bayesian modeling, to identify the most likely neurocircuit mediating stress relief by sucrose. The analyses suggest that sucrose reduces HPA activation by dampening an excitatory basolateral amygdala-medial amygdala circuit, while also potentiating an inhibitory bed nucleus of the stria terminalis principle subdivision-mediated circuit, resulting in reduced HPA activation after stress. Collectively, the results support the hypothesis that sucrose limits stress responses via plastic changes to the structure and function of stress-regulatory neural circuits. The work also illustrates that advanced statistical methods are useful approaches to identify potentially novel and important underlying relationships in biological datasets. PMID- 26246178 TI - Interpretation of an Extended Autoantibody Profile in a Well-Characterized Australian Systemic Sclerosis (Scleroderma) Cohort Using Principal Components Analysis. AB - OBJECTIVE: To determine the relationships between systemic sclerosis (SSc) related autoantibodies, as well as their clinical associations, in a well characterized Australian patient cohort. METHODS: Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data. RESULTS: A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures. CONCLUSION: Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease. PMID- 26246180 TI - Psychological strength assessed in late adolescence and risk for criminal behavior: a Swedish prospective cohort and twin analysis. AB - BACKGROUND: Certain personality traits predispose to criminal behavior (CB). We further clarify this relationship in a Swedish national sample. METHOD: Psychological strength (PS) was assessed on a nine-point scale at personal interview in 1 653 721 Swedish men aged 18-20 years. We examined the association between PS and total, violent and recurrent CB over the lifetime (logistic regression), prospectively (Cox regression) and by bivariate Cholesky decomposition in 2507 monozygotic and 2244 dizygotic twin pairs (OpenMx). RESULTS: Examining linear effects by logistic regression, PS was robustly associated with lifetime risk of total CB (per point, odds ratio = 0.74) and even more strongly associated with risk for violent (0.69) and recurrent CB (0.52). Prospective predictions of these three forms of CB by PS were similar, with hazard ratios of 0.80, 0.73 and 0.54, respectively. Twin modeling demonstrated that, for all three CB types, the association with PS arose almost entirely from familial effects. Common shared environment accounted for 72, 56 and 43% of the phenotypic correlation between PS and, respectively, total, violent and recurrent CB. Parallel figures for common genetic effects were for 24, 37 and 54%, respectively. CONCLUSIONS: PS is strongly related to risk for total CB, and even more strongly for violent and, especially, recurrent CB. This association is probably not causal but rather results from shared familial risk factors that make an impact both on PS and risk for CB. PS has a stronger overall correlation with more severe criminal outcomes and a higher proportion of that correlation results from common genetic factors. PMID- 26246181 TI - Poly-L-Arginine Acts Synergistically with LPS to Promote the Release of IL-6 and IL-8 via p38/ERK Signaling Pathways in NCI-H292 Cells. AB - Major basic protein (MBP) derived from activated eosinophil can exacerbate atopic asthma induced by lipopolysaccharide (LPS). The pharmacological function of MBP can be mimicked by poly-L-arginine (PLA), however, the potential signaling mechanisms of LPS-PLA-induced release of the inflammatory cytokines interleukin (IL)-6 and IL-8 remain unclear. In the present study, airway epithelia NCI-H292 cell lines were treated with LPS and/or PLA. We found that the expression levels of IL-6 and IL-8 induced by LPS-PLA were increased significantly compared with that in untreated cells. Meanwhile, the phosphorylation of p38 MAPK and ERK1/2 was also up-regulated dramatically by LPS-PLA, but this increase could be blocked by specific inhibitor. Importantly, blocking the phosphorylation of p38 MAPK and ERK1/2 reduced the expression levels of IL-6 and IL-8 as well. Collectively, LPS PLA-induced release of IL-6 and IL-8 from NCI-H292 cells may be due to the synergistic activation of p38 MAPK and ERK1/2 signaling transduction pathways. PMID- 26246182 TI - Colorimetric and fluorometric discrimination of geometrical isomers (maleic acid vs fumaric acid) with real-time detection of maleic acid in solution and food additives. AB - Heterobis imine Schiff base probe L is able to discriminate geometrical isomers (maleic acid vs fumaric acid) through sharp colorimetric as well as fluorogenic responses even conspicuous with the naked eye. Colorimetric as well as fluorogenic sensing of maleic acid among various carboxylic acids was also demonstrated in ethanol-buffer medium. Sensing behavior of L was corroborated by (1)H NMR spectra, mass spectrometry, and theoretical calculations. Subsequently sensing behavior of L was used to probe maleic acid in starch rich food samples. PMID- 26246183 TI - Ultrafast fluorescence spectroscopy reveals a dominant weakly-emissive population of fibril bound thioflavin-T. AB - In this communication, using sub-picosecond resolved fluorescence upconversion spectroscopy, we discover that despite a large fluorescence enhancement observed for thioflavin-T in insulin fibrils, the majority of fibril bound thioflavin-T undergoes efficient ultrafast conformational relaxation, and thus does not contribute to the characteristic fluorescence enhancement. PMID- 26246184 TI - Medical Humanitarianism Under Atmospheric Violence: Health Professionals in the 2013 Gezi Protests in Turkey. AB - During the 2013 Gezi protests in Turkey, volunteering health professionals provided on-site medical assistance to protesters faced with police violence characterized by the extensive use of riot control agents. This led to a government crackdown on the medical community and the criminalization of "unauthorized" first aid amidst international criticisms over violations of medical neutrality. Drawing from ethnographic observations, in-depth interviews with health care professionals, and archival research, this article ethnographically analyzes the polarized encounter between the Turkish government and medical professionals aligned with social protest. I demonstrate how the context of "atmospheric violence"-the extensive use of riot control agents like tear gas-brings about new politico-ethical spaces and dilemmas for healthcare professionals. I then analyze how Turkish health professionals framed their provision of health services to protestors in the language of medical humanitarianism, and how the state dismissed their claims to humanitarian neutrality by criminalizing emergency care. Exploring the vexed role that health workers and medical organizations played in the Gezi protests and the consequent political contestations over doctors' ethical, professional, and political responsibilities, this article examines challenges to medical humanitarianism and neutrality at times of social protest in and beyond the Middle East. PMID- 26246185 TI - People with diagnosed HIV infection not attending for specialist clinical care: UK national review. AB - BACKGROUND: Regular clinical care is important for the well-being of people with HIV. We sought to audit and describe the characteristics of adults with diagnosed HIV infection not reported to be attending for clinical care in the UK. METHODS: Public Health England (PHE) provided clinics with lists of patients diagnosed or seen for specialist HIV care in 2010 but not linked to a clinic report or known to have died in 2011. Clinics reviewed case-notes of these individuals and completed questionnaires. A nested case-control analysis was conducted to compare those who had remained in the UK in 2011 while not attending care with individuals who received specialist HIV care in both 2010 and 2011. RESULTS: Among 74,418 adults living with diagnosed HIV infection in the UK in 2010, 3510 (4.7%) were not reported as seen for clinical care or died in 2011. Case note reviews and outcomes were available for 2255 (64%) of these: 456 (20.2%) remained in the UK and did not attend care; 590 (26.2%) left UK; 508 (22.6%) received care in the UK: 73 (3.2%) died and 628 (27.8%) had no documented outcome. Individuals remaining in the UK and not attending care were more likely to be treatment naive than those in care, but duration since HIV diagnosis was not significant. HIV/AIDS related hospitalisations were observed among non-attenders. CONCLUSION: Retention in UK specialist HIV care is excellent. Our audit indicates that the 'true' loss to follow up rate in 2011 was <2.5% with no evidence of health tourism. Novel interventions to ensure high levels of clinic engagement should be explored to minimise disease progression among non-attenders. PMID- 26246187 TI - Inhibition of stationary phase respiration impairs persister formation in E. coli. AB - Bacterial persisters are rare phenotypic variants that temporarily tolerate high antibiotic concentrations. Persisters have been hypothesized to underlie the recalcitrance of biofilm infections, and strategies to eliminate these cells have the potential to improve treatment outcomes for many hospital-treated infections. Here we investigate the role of stationary phase metabolism in generation of type I persisters in Escherichia coli, which are those that are formed by passage through stationary phase. We find that persisters are unlikely to derive from bacteria with low redox activity, and that inhibition of respiration during stationary phase reduces persister levels by up to ~1,000-fold. Loss of stationary phase respiratory activity prevents digestion of endogenous proteins and RNA, which yields bacteria that are more capable of translation, replication and concomitantly cell death when exposed to antibiotics. These findings establish bacterial respiration as a prime target for reducing the number of persisters formed in nutrient-depleted, non-growing populations. PMID- 26246188 TI - DNA barcoding reveals the protogyne and deutogyne of Tegolophus celtis sp. nov. (Acari: Eriophyidae). AB - A few eriophyoid mites have two forms of adult female, called protogyne and deutogyne. The latter form is thought to increase survival under unfavorable conditions. The two forms have distinct morphological characters, which often cause them to be recognized as different species. Molecular species delimitation provides a useful tool to solve these misunderstandings. Here we describe a new species of eriophyoid mite, Tegolophus celtis sp. nov., that has protogyne and deutogyne forms infesting Chinese hackberry, Celtis sinensis Pers. (Cannabaceae), an ornamental tree in China. The two forms can be easily differentiated by body shape (fusiform and triangular, respectively) and body color (light yellow and red, respectively). The putative protogyne and deutogyne forms of T. celtis were identified by using fragments of three genes, a mitochondrial gene (COI) and two nuclear genes (18S rRNA and 28S rRNA). Kimura-2-parameter distances of these three fragmental sequences were between 0.0% and 0.9%. Phylogenetic topologies strongly support the occurrence of the protogyne and deutogyne forms with high bootstrap and Bayesian values. The population structure of T. celtis changed with the seasons, with deutogynes being most abundant in summer and protogynes being most abundant in spring. The new species described herein are vagrants on their host plants. PMID- 26246189 TI - First detection of prey DNA in Hygrobates fluviatilis (Hydrachnidia, Acari): a new approach for determining predator-prey relationships in water mites. AB - Up to now our knowledge of water mite diet has been fragmentary. It is derived from observations in the field and laboratory or from a few selective laboratory experiments on food choice. In the present study, we were able to detect chironomid DNA in water mite bodies for the first time using molecular methods. Prey DNA was detected in virtually all Hygrobates fluviatilis (Hygrobatidae) that were fed on chironomid larvae after a starvation period of up to approximately 1 week. From the shortest interval (1 h after feeding) to the longest period after feeding (50 h) the relative amount of detected prey DNA was significantly reduced. In addition, there was a relationship between the relative amount of prey DNA and the assumed amount of the ingested prey (classified in categories of the dead prey which reflect the increasing ingestion of the mites and the decreasing body content of the prey individuals). The results of our study indicate that similar molecular analyses will be a powerful tool for diet investigations of mites from the field on various taxonomic resolutions of prey taxa. Moreover, the results of food selection experiments from the laboratory could be compared to evidence of predation by individuals from the field. For many mite taxa, especially ones which turned out to be difficult to breed in the laboratory (e.g. by unknown diet), the new methods might enable us to gain the first ever data on diet and thus may help us to consider the role of water mites in food webs more adequately in the future. PMID- 26246190 TI - Expression level and immunolocalization of de novo methyltransferase 3 protein (TuDNMT3) in adult females and males of the two-spotted spider mite, Tetranychus urticae. AB - DNA methylation is an epigenetic mechanism for regulating developmental and other important processes in eukaryotes. Several essential components of the DNA methylation machinery have been identified, such as DNA methyltransferases. In the two-spotted spider mite, Tetranychus urticae Koch, we have identified one DNA methyltransferase 3 gene (Tudnmt3) and tentatively investigated its potential role in adult females and males. Here, to better elucidate the functional role of Tudnmt3, its protein structure, expression and localization were subjected to more detailed analyses. Bioinformatic analyses clearly showed that the structure of TuDNMT3 was highly conserved, with several vital amino acid residues for the activation and stabilization of its confirmation. Western blot analyses revealed that this protein was expressed in both genders, with higher expression in adult females, which was inconsistent with the gene expression, suggesting translational regulation of Tudnmt3. Subsequent immunodetection provided supportive evidence for higher expression of the TuDNMT3 protein in adult females and indicated that this protein was generally localized in the cytoplasm and that its expression was predominantly confined to the genital region of spider mites, strengthening the hypothesis that de novo methylation mediated by Tudnmt3 in gonad development or gametogenesis has a different mechanism from maintenance methyltransferase. PMID- 26246191 TI - Allelopathic effects of Ailanthus altissima extracts on Microcystis aeruginosa growth, physiological changes and microcystins release. AB - The use of allelochemicals has been proved an environmentally friendly and promising method to control harmful algal blooms. This study was conducted to explore the application potential of Ailanthus altissima (A. altissima) extracts in Microcystis aeruginosa (M. aeruginosa) control for the first time. Four treatments with A. altissima extractions (25mgL(-1), 50mgL(-1), 100mgL(-1), and 200mgL(-1) respectively) and a control group were built to investigate the effects of A. altissima on the growth, cellular microstructure and cell viability, physiological changes, and release of extracellular matters. Results showed that the cell density of M. aeruginosa was effectively inhibited by A. altissima extract, and the inhibition rates were dose-dependent within 5d. Especially for the treatment with 200mgL(-1) of extract, the inhibitory rates remains above 90% after 5d exposure. In addition, A. altissima effectively decreased the amount of extracellular cyanotoxin microcystins and destroyed the photosynthesis-related structure of algae cell during the experimental period. The results demonstrated the A. altissima extracts can be used as an effective and safe algicide to control algal blooms. However, it must be noted that specific compounds responsible for algicidal effect should be isolated and identified to explore inhibition mechanism of A. altissima in future study. PMID- 26246192 TI - Struvite-based phosphorus recovery from the concentrated bioeffluent by using HFO nanocomposite adsorption: Effect of solution chemistry. AB - Here we reported struvite-based phosphorous recovery from the concentrated desorption effluent of a proprietary hydrated ferric oxide (HFO) nanocomposite (HFO-201) system, and the effect of solution chemistry (alkalinity, salinity, and dissolved organic matter (DOM)) on struvite formation was particularly focused on. The optimum P recovery rate (~97%) and high quality struvite was obtained at 25 degrees C, pH 9.0-9.5, and the molar Mg:NH4:P ratio of 1.4:4:1. The reaction reached equilibrium within ~30min, much faster than the reported high purity struvite formation at neutral pH (several days required). It largely relied on the absence of Ca(2+) in the desorption effluent due to the Donnon co-ion effect exerted by HFO-201. Thermodynamic modelling with Stockholm humic model revealed that the presence of salinity and DOM resulted in a lower saturation index (SI) of struvite, thus inhibiting P recovery by struvite. Nevertheless, it is favorable to form struvite of large particle size. In addition, increasing the molar Mg:NH4:P ratio from 1:1:1 to 1.4:4:1 could significantly weaken the adverse effect of the high salinity and DOM. Direct addition of Ca(2+) could also result in phosphorous recovery, but the P content of the resultant solid (~4.4%) is much lower than the formed struvite (~17%). The results indicated that struvite process is a very attractive option to recover P from the desorption effluent, and the effect of solution chemistry is crucial to optimize the process. PMID- 26246193 TI - Molecular and chemical dialogues in bacteria-protozoa interactions. AB - Protozoan predation of bacteria can significantly affect soil microbial community composition and ecosystem functioning. Bacteria possess diverse defense strategies to resist or evade protozoan predation. For soil-dwelling Pseudomonas species, several secondary metabolites were proposed to provide protection against different protozoan genera. By combining whole-genome transcriptome analyses with (live) imaging mass spectrometry (IMS), we observed multiple changes in the molecular and chemical dialogues between Pseudomonas fluorescens and the protist Naegleria americana. Lipopeptide (LP) biosynthesis was induced in Pseudomonas upon protozoan grazing and LP accumulation transitioned from homogeneous distributions across bacterial colonies to site-specific accumulation at the bacteria-protist interface. Also putrescine biosynthesis was upregulated in P. fluorescens upon predation. We demonstrated that putrescine induces protozoan trophozoite encystment and adversely affects cyst viability. This multifaceted study provides new insights in common and strain-specific responses in bacteria-protozoa interactions, including responses that contribute to bacterial survival in highly competitive soil and rhizosphere environments. PMID- 26246195 TI - Linear Cu(i) chalcogenones: synthesis and application in borylation of unsymmetrical alkynes. AB - The syntheses and structures of copper(i) chalcogenone complexes are described. The homoleptic mononuclear copper(i) complexes [(IPr[double bond, length as m dash]E)2Cu]ClO4, IPr[double bond, length as m-dash]E, 1,3-bis(2,6 diisopropylphenyl)imidazoline-2-thione (1) and 1,3-bis(2,6 diisopropylphenyl)imidazoline-2-selone (2); [(IMes[double bond, length as m dash]E)2Cu]ClO4, IMes[double bond, length as m-dash]E, 1,3-bis(2,4,6 trimethylphenyl)imidazole-2-thione (3) and 1,3-bis(2,4,6 trimethylphenyl)imidazole-2-selone (4); [(IPr[double bond, length as m dash]E)2Cu]BF4, E = S (5); E = Se (6) and [(IMes[double bond, length as m dash]E)2Cu]BF4, E = S (7); E = Se (8) are formed from the reduction of copper(ii) to copper(i) with the corresponding imidazoline-2-chalcogenones. X-ray structure analyses of seven compounds (1-3 and 5-8) show that the copper(i) ion is in a perfect linear coordination, while 4 is in quasi-linear geometry. Molecules 2, 4, 6 and 8 are the first structurally characterized homoleptic copper(i) selone complexes. The optical and thermal properties of imidazoline-2-chalcogenones and their copper(i) derivatives are investigated. These complexes are able to act as catalysts in regioselective borylation of numerous unsymmetrical alkynes, yielding synthetically useful vinylboronates. Among catalysts 1-8, catalyst 4 is highly selective towards the regioselective boron addition of 1-phenyl-1-propyne. PMID- 26246194 TI - Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver. AB - MicroRNAs (miRNAs) are important regulators and potential therapeutic targets of metabolic disease. In this study we show by in vivo administration of locked nucleic acid (LNA) inhibitors that suppression of endogenous miR-29 lowers plasma cholesterol levels by ~40%, commensurate with the effect of statins, and reduces fatty acid content in the liver by ~20%. Whole transcriptome sequencing of the liver reveals 883 genes dysregulated (612 down, 271 up) by inhibition of miR-29. The set of 612 down-regulated genes are most significantly over-represented in lipid synthesis pathways. Among the up-regulated genes are the anti-lipogenic deacetylase sirtuin 1 (Sirt1) and the anti-lipogenic transcription factor aryl hydrocarbon receptor (Ahr), the latter of which we demonstrate is a direct target of miR-29. In vitro radiolabeled acetate incorporation assays confirm that pharmacologic inhibition of miR-29 significantly reduces de novo cholesterol and fatty acid synthesis. Our findings indicate that miR-29 controls hepatic lipogenic programs, likely in part through regulation of Ahr and Sirt1, and therefore may represent a candidate therapeutic target for metabolic disorders such as dyslipidemia. PMID- 26246196 TI - Piperlongumine induces apoptosis and autophagy in human lung cancer cells through inhibition of PI3K/Akt/mTOR pathway. AB - Piperlongumine (PL), a natural alkaloid present in the fruit of the Long pepper, is known to exhibit notable anti-cancer effects. Nonetheless, the anti-tumor effect of PL in lung cancer cells still remains unclear. In the present study, we reported the chemotherapeutic effects of PL using in vitro and in vivo models. We showed that PL displayed potent anti-neoplastic activity against lung cancer A549 cells as well as corresponding docetaxel-resistant A549/DTX cells. In addition, we found that PL induced apoptosis in both A549 and A549/DTX cells. PL also induced autophagy in A549/DTX cells. Moreover, autophagy-specific inhibitors (3 methyladenine) or Beclin1 and Atg 5 small interfering RNAs (siRNAs) enhanced PL induced apoptosis, indicating that PL-mediated autophagy may protect A549/DTX cells from undergoing apoptotic cell death. Furthermore, we observed the inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway by PL. Finally, PL inhibited the growth of A549/DTX xenograft tumors, which was associated with inhibition of cell proliferation, induction of apoptosis of tumor cells and decreased expression of p-Akt and p mTOR in tumor xenograft tissues. In summary, our study demonstrated that PL induced apoptosis and autophagy through modulation of the PI3K/Akt/mTOR pathway in human lung cancer cells. This study may provide a rationale for future clinical application using PL as a chemotherapeutic agent for lung cancer. PMID- 26246197 TI - Monocytes play different roles in stimulating T cells in obese diabetic individuals. AB - Type 2 diabetes (T2D) is a chronic metabolic disorder, which was also found to involve a series of inflammatory disorders, including accumulation of macrophages and T cells in the adipose tissue, increased proinflammatory cytokine production, shifting of macrophage composition toward M1-type, and skewing of peripheral blood T cells toward IL-17 productions. However, these studies were primarily conducted in obese mouse models and/or human subjects with higher BMI, and may not reflect the role of the immune system in non-obese T2D pathogenesis. Here, we examined T cell and monocyte cytokine expression and function in both non-obese and obese T2D patients. We found that IFN-g production by circulating T cells were increased in both non-obese and obese T2D subjects, while IL-17 is only upregulated in obese T2D subjects. Also, circulating monocytes from obese T2D subjects had significantly higher IL-6 production than their counterparts in non obese T2D subjects. Moreover, monocytes from non-obese T2D subjects could support IFN-g but not IL-17 production in vitro, while that from obese T2D subjects supported both IFN-g and IL-17 production. Together, our results revealed that the role immune system plays in T2D pathogenesis is more complicated than previously thought, and is affected by the person's BMI. PMID- 26246198 TI - The moderating effects of perceived emotional benefits on inhalant initiation among American Indian and white youth. AB - BACKGROUND: Inhalant use co-occurs with emotional distress. Inhalant use may be a means of self-medicating distress, but more recent study focuses on the cognitive appraisal of personal benefits of using substances. OBJECTIVES: Objectives were to determine whether emotional distress variables predict early versus later initiation of inhalant use, whether such relationships differ between American Indian and white youth, and whether perceived emotional benefits of inhalant use moderates the relationship between emotional distress and stage of inhalant initiation. METHODS: Data were from a study of 7-12th grade American Indian youth who live on or near reservations. A total of 856 students from 32 schools surveyed from 2009 to 2012, who reported having used inhalants (American Indian = 683; white = 173), were surveyed about age first use of inhalants, levels of emotional distress, and perceived benefits of inhalant use. SEM models were used to assess study objectives. RESULTS: Depression and anger did not discriminate between early and later initiation. Lower self-esteem related to earlier initiation, but only among American Indian students. Perceived emotional benefits of inhalant use did not moderate the relationship between self-esteem and stage of initiation. DISCUSSION AND CONCLUSIONS: Among middle school and high school American Indian and white youth living on or near American Indian reservations, emotional distress is not strongly related to stage of inhalant initiation. SCIENTIFIC SIGNIFICANCE: These findings raise questions about the timing and strength of relationship between emotional distress and early inhalant initiation. Prospective studies are need to assess this relationship more fully. PMID- 26246199 TI - Interactions of Escherichia coli molecular chaperone HtpG with DnaA replication initiator DNA. AB - The bacterial chaperone high-temperature protein G (HtpG), a member of the Hsp90 protein family, is involved in the protection of cells against a variety of environmental stresses. The ability of HtpG to form complexes with other bacterial proteins, especially those involved in fundamental functions, is indicative of its cellular role. An interaction between HtpG and DnaA, the main initiator of DNA replication, was studied both in vivo, using a bacterial two hybrid system, and in vitro with a modified pull-down assay and by chemical cross linking. In vivo, this interaction was demonstrated only when htpG was expressed from a high copy number plasmid. Both in vitro assays confirmed HtpG-DnaA interactions. PMID- 26246200 TI - Maternal and neonatal dietary intake of balanced n-6/n-3 fatty acids modulates experimental colitis in young adult rats. AB - BACKGROUND: The imbalance of n-6 and n-3 polyunsaturated fatty acids in the maternal diet impairs intestinal barrier development and sensitizes the colon response to inflammatory insults in the young rats. With a view to overcoming this issue, we designed this study to investigate the effect of maternal and neonatal intake of different proportions of n-6/n-3 fatty acids on colon inflammation in the young adult rats. METHODS: Female Wistar rats were assigned into four groups, and each group fed one of four semisynthetic diets, namely n-6, low n-3, n-6/n-3 and n-3 fatty acids for 8 weeks prior to mating, during gestation and lactation periods. At weaning, the pups were separated from the dams and fed diet similar to the mothers. Colitis was induced on postnatal day 35, by administering 2 % dextran sulfate sodium in drinking water for 10 days. Colitis was assessed based on the clinical and inflammatory markers in the colon. Fatty acid analysis was done in liver, RBC, colon and spleen. RESULTS: A balanced n-6/n-3 PUFA diet significantly improved the body weight loss, rectal bleeding and mortality in rats. This was associated with lower myeloperoxidase activity, nitric oxide, prostaglandin E2, TNF-alpha and IL-6, IL-8, COX-2 and iNOS levels in the colon tissues. Fatty acid analysis has shown that the arachidonic acid/docosahexaenoic acid ratio was significantly lower in liver, RBC, colon and spleen in n-6/n-3 and n-3 diet groups. CONCLUSION: We demonstrate that balanced n 6/n-3 PUFA supplementation in maternal and neonatal diet alters systemic AA/DHA ratio and attenuates colon inflammation in the young adult rats. PMID- 26246201 TI - Iodine nutritional status in the adult population of Shandong Province (China) prior to salt reduction program. AB - PURPOSE: Tremendous differences in iodine status and daily iodine intake persist across provinces of China. The objective of the present study was to evaluate the iodine status and dietary iodine intake of Shandong adults before the implementation of the salt reduction program and a new salt iodization standard. METHODS: Data from a baseline survey of the Shandong and Ministry of Health Action on Salt Reduction and Hypertension project (2011) were analyzed. The iodine contents of 1949 24-h urine samples and 136 drinking water samples were assayed. Daily urinary iodine excretion and daily iodine intake were calculated, analyzed, stratified by different analytical variables and compared with Chinese Dietary Reference Values. RESULTS: The median urinary iodine concentration and median daily iodine intake of Shandong adults were 248.5 MUg/L and 368.2 MUg/day, respectively. The median iodine intake of different groups was between the estimated average requirements and the upper limit, except group in water iodine >300 MUg/L with median iodine intake of 1200.7 MUg/L. Salt intake and iodine levels in drinking water related to iodine intake significantly. CONCLUSIONS: Shandong adults had more than adequate iodine nutrition, and the dietary iodine intake of the population was generally appropriate and safe except residents in high water iodine areas. In the context of the implementation of a salt reduction program and a new salt iodization standard, the iodine status of high water iodine areas may remain in the recommended level, but in low water iodine areas, the risk of inadequate iodine intake may increase, needing monitoring of urine iodine excretion, dietary iodine intake and iodized salt consumption regularly. PMID- 26246203 TI - [Professional politics = dare more medicine!]. PMID- 26246202 TI - Energy and macronutrient intakes and adherence to dietary guidelines of infants and toddlers in Belgium. AB - PURPOSE: Early feeding habits may have a significant impact on later body composition and health. The knowledge on dietary habits is, however, still limited for older infants and toddlers. Therefore, we aimed to: (1) assess the average daily energy and macronutrient intakes and to identify their major foods sources; (2) compare it to the nationally and internationally recommended dietary intake (RDI). METHODS: A food survey (January-February 2012) was conducted in a cohort of healthy infants and toddlers, stratified for age, gender, region, occupation and socio-economic status of the mother and week and weekend days. The national dietary software programme Nubel((r)) was used to analyse nutritional values. RESULTS: We included 92 (19.8 %) 6-to 12-month-olds, 200 (43.0 %) 13- to 24-month-olds and 173 (37.2 %) 25- to 36-month-olds in the analysis. Median energy intake was 15-20 % above the RDI of 79-82 kcal/kg/day. Nearly, all children had a protein intake above the RDI, and for 156 (33.5 %), this was above the upper tolerable limit of 15 % of total energy intake. The median fat intake increased with increasing age and was slightly below the RDI. Mean water and carbohydrate intake were in accordance with the RDI. Fibre intake was below the RDI of 15 g/d for 93.1 % of the oldest and 83.5 % of the middle age group (p < 0.01). Milk is the most important source for energy en macronutrients until the age of 2 years. CONCLUSIONS: Energy and especially protein intakes are too high, while fat and fibre intakes are too low in Belgian infants and toddlers. PMID- 26246204 TI - [Founded out of protest, committed to consensus, and determined]. PMID- 26246205 TI - [The working group "Staff physicians" in the Professional Association of German Urologists. Rationale and objective]. PMID- 26246206 TI - [Outpatient specialized medical care. Opportunities for a new care structure]. PMID- 26246207 TI - [Errare humanum est--making mistakes not desirable?]. PMID- 26246208 TI - [Prevascularization of an in vitro buccal mucosa equivalent for regeneration of the urethra]. AB - For reconstructive interventions on the urethra the use of autologous buccal mucosa has a proven value. The aim of this study was to generate an in vitro preparation which is already infiltrated by capillary-like structures and is more rapidly incorporated after implantation. Commercially available collagen matrices which have been approved for use in humans were used as the substrate. Application possibilities of such artificial tissue in addition to reconstruction of the urethra include coverage of large defects in the oral, neck, nasal and aural areas, in gynecology and in ophthalmology. PMID- 26246209 TI - [Specialist uro-oncological rehabilitation after treatment for prostate cancer- update 2015. Position statement of the working group on "rehabilitation of urological and nephrological diseases" of the German Society of Urology with respect to current S3 guidelines]. AB - After uro-oncological primary therapy of prostate cancer the quality of life of patients is often limited. The adequate and prompt treatment of specific urological functional, physical and mental deficits has a decisive influence on the quality of life. These deficits can be recorded using instruments for measuring the quality of life, in particular the QLQ-C30 of the European Organization for Research and Treatment of Cancer (EORTC) and the SF-36 questionnaires. The quality of life is the most important parameter for quality assurance of the results. The primary objectives are the therapy of postoperative functional disorders, in particular urinary incontinence and erectile dysfunction in addition to overcoming the disease. The "urological triad" plays a central role in recovering the quality of life and patient satisfaction. PMID- 26246210 TI - [When and how to surgically treat juvenile varicocele?]. PMID- 26246211 TI - [Residents' program for the 2015 Congress of the German Society for Urology]. PMID- 26246212 TI - ["Utilitarian system" : Heine's legacy poem "legs, to each man two were given" with his lyrical comments on the field of urology]. AB - The chequered biography as well as the enormous and controversial impact history of the poet Heinrich Heine form the notably changing sum of, in his time but also with a view to the future, the more than difficult and manifold relationships from political, social, religious, cultural and economic as well as industrial historical conditions and problems. The works and personality of the poet can rightly be characterized by the subtitle as a current biography laced with innuendo as "the discovery of the European intellectual". PMID- 26246213 TI - Diarylamino-substituted tetraarylethene (TAE) as an efficient and robust hole transport material for 11% methyl ammonium lead iodide perovskite solar cells. AB - We report the synthesis and characterisation of tetra{4-[N,N-(4,4' dimethoxydiphenylamino)]phenyl}ethene () as an efficient and robust hole transport material for its application in methyl ammonium lead iodide (MAPI) perovskite solar cells. The solar cells show light-to-energy conversion efficiencies as high as 11.0% under standard measurement conditions without the need of additional dopants. PMID- 26246214 TI - Mini-gene assays confirm the splicing effect of deep intronic variants in the factor VIII gene. PMID- 26246215 TI - Early Stage Hepatocellular Carcinomas Not Feasible for Ultrasound-Guided Radiofrequency Ablation: Comparison of Transarterial Chemoembolization Alone and Combined Therapy with Transarterial Chemoembolization and Radiofrequency Ablation. AB - PURPOSE: To report the results of combined therapy with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) for early stage hepatocellular carcinoma (HCC) considered infeasible for ultrasound (US)-guided RFA in comparison with those of TACE monotherapy. METHODS: From January 2007 through December 2010, 91 patients with early or very early stage HCC infeasible for US-guided RFA received either TACE alone (TACE group; n = 54) or TACE immediately followed by RFA (TACE-RFA group; n = 37) as a first-line treatment. 1 month tumor response, time to progression (TTP), and overall survival (OS) rates were calculated. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: TACE-RFA group showed a better 1-month tumor response than TACE group (P < .001). The mean TTP was 29.7 +/- 3.4 months (95 % confidence intervals [CIs] 23.0-36.5) in TACE group and 34.9 +/- 2.8 months (95% CIs 29.4-40.4) in TACE-RFA group. TACE-RFA group had a significantly longer TTP (P = .014). Cumulative 1-, 2-, and 3-year OS rates in the TACE and TACE-RFA groups were 91, 79, and 71% and 100, 97, and 93%, respectively (P = .008). Initial treatment of TACE was found to be the only significant risk factor for tumor progression and OS in multivariate analysis. CONCLUSION: TACE-RFA combination therapy appears superior to TACE monotherapy in terms of 1-month tumor response, TTP, and OS when performed for early stage HCC infeasible for US guided RFA. PMID- 26246217 TI - Finite pulse effects in CPMG pulse trains on paramagnetic materials. AB - The Carr-Purcell-Meiboom-Gill (CPMG) sequence is commonly used in high resolution NMR spectroscopy and in magnetic resonance imaging for the measurement of transverse relaxation in systems that are subject to diffusion in internal or external gradients and is superior to the Hahn echo measurement, which is more sensitive to diffusion effects. Similarly, it can potentially be used to study dynamic processes in electrode materials for lithium ion batteries. Here we compare the (7)Li signal decay curves obtained with the CPMG and Hahn echo sequences under static conditions (i.e., in the absence of magic angle spinning) in paramagnetic materials with varying transition metal ion concentrations. Our results indicate that under CPMG pulse trains the lifetime of the (7)Li signal is substantially extended and is correlated with the strength of the electron nuclear interaction. Numerical simulations and analytical calculations using Floquet theory suggest that the combination of large interactions and a train of finite pulses, results in a spin locking effect which significantly slows the signal's decay. While these effects complicate the interpretation of CPMG-based investigations of diffusion and chemical exchange in paramagnetic materials, they may provide a useful approach to extend the signal's lifetime in these often fast relaxing systems, enabling the use of correlation experiments. Furthermore, these results highlight the importance of developing a deeper understanding of the effects of the large paramagnetic interactions during multiple pulse experiments in order to extend the experimental arsenal available for static and in situ NMR investigations of paramagnetic materials. PMID- 26246216 TI - Hyponatremia Following High-Volume D5W Hydrodissection During Thermal Ablation. PMID- 26246218 TI - Reduced Fertility and Altered Epididymal and Sperm Integrity in Mice Lacking ADAM7. AB - The mammalian epididymis is a highly convoluted tubule that connects the testis to the vas deferens. Its proper functions in sperm transport, storage, and maturation are essential for male reproduction. One of the genes predominantly expressed in the epididymis is ADAM7 (a disintegrin and metalloprotease 7). Previous studies have shown that ADAM7 synthesized in the epididymis is secreted into the epididymal lumen and is then transferred to sperm membranes, where it forms a chaperone complex that is potentially involved in sperm fertility. In this study, we generated and analyzed mice with a targeted disruption in the Adam7 gene. We found that the fertility of male mice was modestly but significantly reduced by knockout of Adam7. Histological analyses revealed that the cell heights of the epithelium were dramatically decreased in the caput of the epididymis of Adam7-null mice, suggesting a requirement for ADAM7 in maintaining the integrity of the epididymal epithelium. We found that sperm from Adam7-null mice exhibit decreased motility, tail deformation, and altered tyrosine phosphorylation, indicating that the absence of ADAM7 leads to abnormal sperm functions and morphology. Western blot analyses revealed reduced levels of integral membrane protein 2B (ITM2B) and ADAM2 in sperm from Adam7-null mice, suggesting a requirement for ADAM7 in normal expression of sperm membrane proteins involved in sperm functions. Collectively, our study demonstrates for the first time that ADAM7 is required for normal fertility and is important for the maintenance of epididymal integrity and for sperm morphology, motility, and membrane proteins. PMID- 26246219 TI - Estradiol Elicits Proapoptotic and Antiproliferative Effects in Human Trophoblast Cells. AB - During the first trimester of pregnancy, appropriate regulation of estradiol (E2) is essential for normal placental development. Previous studies demonstrate that premature elevation in E2 concentrations can lead to abnormal placentation, but have not fully elaborated the mechanism of this effect in the first-trimester trophoblast. Our aim was to determine whether E2 elicits trophoblast cell death or inhibits proliferation. The first-trimester human cytotrophoblast cell line HTR-8/SVneo was cultured in phenol red-free medium containing charcoal-stripped serum and treated with 17beta-E2 at concentrations between 0 and 100 nM. TUNEL and invasion assays indicated that E2 significantly increased cell death and reduced cell invasion at 10 nM, and nuclear Ki67 expression revealed that it decreased cell proliferation at 1 nM. A similar effect on cell death was observed in first-trimester placental explants. The E2 antagonist fulvestrant blocked all effects of E2. Immunohistochemistry showed that protein expression of proapoptotic caspases 3, 8, and 9 increased at E2 concentrations of 25 nM and greater, whereas expression of antiapoptotic BCL2-alpha decreased at E2 concentrations of 10 nM and greater. Additionally, treatments with estrogen receptor (ER) alpha-specific and ERbeta-specific agonists at concentrations between 0 and 1000 nM indicated that only ERalpha mediates E2's effects, although immunohistochemistry and Western immunoblotting showed that HTR-8/SVneo cells and placental explants express both ERalpha and ERbeta. Taken together, these findings reveal the interplay between elevated serum E2 and apoptosis in the first trimester of pregnancy. These factors could be associated with pregnancy complications including infertility and uteroplacental insufficiency. PMID- 26246220 TI - Kisspeptin Antagonists Reveal Kisspeptin 1 and Kisspeptin 2 Differential Regulation of Reproduction in the Teleost, Morone saxatilis. AB - The importance of kisspeptin in regulating vertebrate reproduction has been well established, but the exact mechanism continues to unfold. Unlike mammals, many lower vertebrates possess a dual kisspeptin system, Kiss1 and Kiss2. To decipher the roles of the kisspeptins in fish, we identified two potential kisspeptin antagonists, pep 234 and pep 359, by screening analogs for their ability to inactivate striped bass Kiss1 and Kiss2 receptors expressed in COS7 cells. Pep 234 (a mammalian KISS1 antagonist) antagonizes Kiss1r signaling activated by Kiss1 and Kiss2, and pep 359 (a novel analog) antagonizes Kiss2 activation of both receptors. In vitro studies using brain slices demonstrated that only Kiss2 can upregulate the expression of the hypophysiotropic gnrh1, which was subsequently diminished by pep 234 and pep 359. In primary pituitary cell cultures, the two antagonists revealed a complex network of putative endogenous and exogenous regulation by kisspeptin. While both kisspeptins stimulate Fsh expression and secretion, Kiss2 predominately induces Lh secretion. Pep 234 and 359 treatment of spawning males hindered sperm production. This effect was accompanied with decreased brain gnrh1 and gnrh2 mRNA levels and peptide content in the pituitary, and increased levels of pituitary Lh, probably due to attenuation of Lh release. Strikingly, the mRNA levels of arginine-vasotocin, the neurons of which in the preoptic area coexpress kiss2r, were dramatically reduced by the antagonists. Our results demonstrate differential actions of Kiss1 and Kiss2 systems along the hypothalamic-pituitary axis and interactions with other neuropeptides, and further reinforce the importance of kisspeptin in the execution of spawning. PMID- 26246222 TI - Correlates of Depression and Burnout Among Residents in a Lebanese Academic Medical Center: a Cross-Sectional Study. AB - OBJECTIVES: This study aims to assess the prevalence of depressive symptoms, severity of burnout, and suicidal ideation among residents in a range of specialties and to identify factors that are associated with these symptoms. METHODS: A cross-sectional study was carried out at the American University of Beirut Medical Center between August and October 2013. In total, 118 out of 311 eligible residents responded. The survey included general sociodemographic questions and standardized validated tools to measure depressive symptomatology (PHQ-9), burnout (burnout measure), anxiety (GAD-7), alcohol use (AUDIT), and drug abuse (DAST-10). RESULTS: Overall, 22% of the residents qualified for major depressive symptomatology. Stressful personal life events and burnout were significantly associated with depression. Drug abuse, but neither alcohol abuse nor anxiety, was associated with depression. Twenty-seven percent of the residents met criteria for burnout. Additionally, 13% of residents had suicidal ideation, which was significantly associated with the severity of depression and not using mental health services. CONCLUSIONS: These findings increase awareness regarding the vulnerability of residents internationally. Addressing the mental health of residents is a pressing issue, and training programs need to actively address the psychological well-being of residents. PMID- 26246221 TI - Geography of follicle formation in the embryonic mouse ovary impacts activation pattern during the first wave of folliculogenesis. AB - During embryonic development, mouse female germ cells enter meiosis in an anterior-to-posterior wave believed to be driven by retinoic acid. It has been proposed that ovarian follicle formation and activation follow the same general wave of meiotic progression; however, the precise anatomic specification of these processes has not been delineated. Here, we created a mouse line using Mvh, Gdf9, and Zp3 promoters to drive distinct temporal expression of three fluorescent proteins in the oocytes and to identify where the first follicle cohort develops. The fluorescent profile revealed that the first growing follicles consistently appeared in a specific region of the ovary, the anterior-dorsal region, which led us to analyze if meiotic onset occurred earlier in the dorsal ovarian region. Surprisingly, in addition to the anterior-to-posterior wave, we observed an early meiotic entry in the ventral region of the ovary. This additional anatomic stratification of meiosis contrasts with the localization of the initial follicle formation and activation in the dorsal region of the ovary. Therefore, our study suggests that the specification of cortical and medullar areas in the ventral and dorsal regions on the ovary, rather than the onset of meiosis, impacts where the first follicle activation event occurs. PMID- 26246223 TI - Measures of Total Energy Expenditure and Its Components Using the Doubly Labeled Water Method in Rehabilitating Burn Children. AB - BACKGROUND: A persistent hypermetabolic state delays anabolism and growth in burned children. However, our own clinical experience has been that resting energy expenditure (REE) is not increased during the rehabilitative phase, suggesting other contributing factors. We measured total energy expenditure (TEE) and its components in rehabilitating pediatric burn patients to identify the basis for accelerated energy metabolism in this population. MATERIALS AND METHODS: Children admitted with initial burns of 20% of their total body surface area (TBSA) or greater were enrolled into this prospective, descriptive study. TEE was measured using the doubly labeled water method over a 7-day period. During that period, REE was measured on 2 days by indirect calorimetry. Activity energy expenditure (AEE) was assessed using a physical activity monitoring device for a 24-hour period. TEE and REE were compared with sex-specific, age-matched, and weight-matched norms using the Dietary Reference Intakes (DRI) standards. RESULTS: Ten children with an average burn size of 53.7% +/- 20% (range, 27%-82%) of TBSA completed this study. Their mean age and weight were 10.4 +/- 5.5 years and 35.8 +/- 16.4 kg, respectively. Daily TEE averaged 66 kcal/kg and was 1.08% of reference DRI. REE was 92% +/- 25% of predicted basal metabolic rate, not exceeding 120% as a maximum value in any child. CONCLUSIONS: TEE and REE in rehabilitating burn children are comparable to reference standards. Increased REE was not typical in our population, but measures of AEE were commonly high. PMID- 26246224 TI - Implementation of the Ten Steps to Successful Breastfeeding programme in DR Congo. PMID- 26246226 TI - The debate that shouldn't be. PMID- 26246225 TI - Ten Steps to Successful Breastfeeding programme to promote early initiation and exclusive breastfeeding in DR Congo: a cluster-randomised controlled trial. AB - BACKGROUND: Optimisation of breastfeeding practices could reduce high mortality rates in children younger than 5 years, but in DR Congo, despite near-universal breastfeeding initiation and nine of ten children still breastfeeding at 1 year of age, exclusivity remains a difficulty. We assessed the effect on breastfeeding outcomes of a short-cut implementation of a programme called the Ten Steps to Successful Breastfeeding, the key component of the Baby-Friendly Hospital Initiative (BFHI). METHODS: We did a cluster-randomised controlled trial and randomly assigned health-care clinics in Kinshasa, DR Congo, to standard care (control group), BFHI steps 1-9 (steps 1-9 group), or BFHI steps 1-9 plus additional support during well-child visits (steps 1-10 group) with computer generated random numbers used to assign matched pairs to study groups. Mothers at these clinics who had given birth to one healthy baby during enrolment, and who expressed their intentions of visiting a well-baby session at the same clinic, were eligible and received the treatment assigned to their clinic. Mother-infant pairs were excluded if the mothers intended to attend well-baby clinic visits at a different health facility, or to travel before the child was aged at least 6 months. Participants and independent interviewers were masked to group assignment (ie, they were recruited after randomisaion and training of the clinic staff and were not informed of the study scheme), but clinical staff were unmasked. BFHI steps 1-9 and 1-10 were given by health-care staff trained with the WHO/UNICEF BFHI course. The primary outcomes were breastfeeding initiation within 1 h of birth and exclusive breastfeeding at age 14 and 24 weeks, assessed at face-to face interviews in the clinic. Analysis was by intention to treat. Prevalence ratios (PR) were adjusted for cluster effects and baseline characteristics. This trial is registered at ClinicalTrials.gov, number NCT01428232, and is closed to new participants. FINDINGS: Between May 24, and Aug 25, 2012, we randomly assigned two eligible clinics to control, two to BFHI steps 1-9, and two to BFHI steps 1-10. We enrolled 975 eligible mother-infant pairs (304 in the control group, 363 in the steps 1-9 group, and 308 in the steps 1-10 group). 230 (76%) of infants in the control group, 263 (72%) in the steps 1-9 group, and 220 (71%) in the steps 1-10 group were breastfed within 1 h of birth; these results did not differ significantly between groups. Prevalence of exclusive breastfeeding at age 14 weeks was 89 (29%) in the control group, 237 (65%) in the steps 1-9 group (adjusted PR 2.20, 95% CI 1.73-2.77), and 129 (42%) in the steps 1-10 group (1.40, 1.13-1.74). At age 24 weeks, the prevalence of exclusive breastfeeding was 36 (12%) in the control group, 131 (36%) in the steps 1-9 group (3.50, 2.76 4.43), and 43 (14%) in the steps 1-10 group (1.31, 0.91-1.89). INTERPRETATION: In the setting of health-care clinics in DR Congo with a high proportion of mothers initiating breastfeeding, implementation of basic training in BFHI steps 1-9 had no additional effect on initiation of breastfeeding but significantly increased exclusive breastfeeding at 6 months of age. Additional support based on the same training materials and locally available breastfeeding support materials, offered during well-child visits (ie, step 10) did not enhance this effect, and might have actually lessened it. PMID- 26246227 TI - Brief report: lack of replication of an association between anti-citrullinated fibrinogen and subclinical atherosclerosis in patients with rheumatoid arthritis. AB - OBJECTIVE: Results of a recent study suggested that the excess cardiovascular (CV) risk observed in patients with rheumatoid arthritis (RA) could be partially explained by the presence of immune complexes of antibodies against citrullinated proteins that locally promote and perpetuate inflammation and progression of atherosclerotic plaques. The present study was undertaken to attempt to replicate one of the observations supporting this hypothesis, i.e., association between anti-citrullinated fibrinogen (anti-Cit-fibrinogen) positivity and subclinical atherosclerosis. METHODS: Three surrogate markers of atherosclerosis were assessed in 124 RA patients with no previous history of CV events: carotid intima media thickness (CIMT) assessed by carotid ultrasonography, carotid plaques assessed by carotid ultrasonography, and Coronary Artery Calcification Score (CACS) determined by multidetector computed tomography (CT) scanning. We analyzed the relationship of these 3 subclinical atherosclerosis markers to the presence and levels of autoantibodies, including anti-Cit-fibrinogen, anti-cyclic citrullinated peptide 2 (anti-CCP-2), and rheumatoid factor (RF). RESULTS: Carotid plaques and CIMT >0.90 mm were present in 69.4% and 15.3%, of the patients, respectively, and the CACS was moderate or high in 21.0%. None of these surrogate markers of atherosclerosis showed a significant association with positivity for or the level of anti-Cit-fibrinogen antibodies (either against the whole protein [present in 33.9% of the patients] or against an immunodominant peptide [present in 23.4%]), anti-CCP-2 (present in 60.7%), or RF (present in 58.1%) in this series of patients with RA. CONCLUSION: Our results do not support the notion that there is a relationship between anti-Cit-fibrinogen antibodies and subclinical atherosclerosis in RA, thus calling into question the claim that these antibodies have a role in the increased risk of CV disease observed in patients with RA. PMID- 26246228 TI - Non-healing enterocutaneous fistula caused by mesh migration. PMID- 26246229 TI - An Idle-State Detection Algorithm for SSVEP-Based Brain-Computer Interfaces Using a Maximum Evoked Response Spatial Filter. AB - Although accurate recognition of the idle state is essential for the application of brain-computer interfaces (BCIs) in real-world situations, it remains a challenging task due to the variability of the idle state. In this study, a novel algorithm was proposed for the idle state detection in a steady-state visual evoked potential (SSVEP)-based BCI. The proposed algorithm aims to solve the idle state detection problem by constructing a better model of the control states. For feature extraction, a maximum evoked response (MER) spatial filter was developed to extract neurophysiologically plausible SSVEP responses, by finding the combination of multi-channel electroencephalogram (EEG) signals that maximized the evoked responses while suppressing the unrelated background EEGs. The extracted SSVEP responses at the frequencies of both the attended and the unattended stimuli were then used to form feature vectors and a series of binary classifiers for recognition of each control state and the idle state were constructed. EEG data from nine subjects in a three-target SSVEP BCI experiment with a variety of idle state conditions were used to evaluate the proposed algorithm. Compared to the most popular canonical correlation analysis-based algorithm and the conventional power spectrum-based algorithm, the proposed algorithm outperformed them by achieving an offline control state classification accuracy of 88.0 +/- 11.1% and idle state false positive rates (FPRs) ranging from 7.4 +/- 5.6% to 14.2 +/- 10.1%, depending on the specific idle state conditions. Moreover, the online simulation reported BCI performance close to practical use: 22.0 +/- 2.9 out of the 24 control commands were correctly recognized and the FPRs achieved as low as approximately 0.5 event/min in the idle state conditions with eye open and 0.05 event/min in the idle state condition with eye closed. These results demonstrate the potential of the proposed algorithm for implementing practical SSVEP BCI systems. PMID- 26246230 TI - A surgical view on the treatment of Madelung's disease. AB - Benign symmetrical lipomatosis (Madelung's disease) is a rare condition of unclear aetiology characterized by numerous, unencapsulated lipomatous deposits. The only effective treatment is by surgical intervention; however, there is no consensus in the optimal approach. We present the case of a patient who required staged, multi-modality treatment to achieve disease quiescence. The case highlights the usefulness of magnetic resonance imaging as a tool for assessment as well as preoperative planning. PMID- 26246231 TI - One-Electron Oxidation of a Disilicon(0) Compound: An Experimental and Theoretical Study of [Si2](+) Trapped by N-Heterocyclic Carbenes. AB - One-electron oxidation of the disilicon(0) compound Si2(Idipp)2 (1, Idipp = 1,3 bis(2,6-diisopropylphenyl)imidazolin-2-ylidene) with [Fe(C5Me5)2][B(Ar(F))4] (Ar(F) = C6H3-3,5-(CF3)2) affords selectively the green radical salt [Si2(Idipp)2][B(Ar(F))4] (1-[B(Ar(F))4). Oxidation of the centrosymmetric 1 occurs reversibly at a low redox potential (E1/2 = -1.250 V vs. Fc(+)/Fc), and is accompanied by considerable structural changes as shown by single-crystal X-ray structural analysis of 1-B(Ar(F))4. These include a shortening of the Si-Si bond, a widening of the Si-Si-CNHC angles, and a lowering of the symmetry, leading to a quite different conformation of the NHC substituents at the two inequivalent Si sites in 1(+). Comparative quantum chemical calculations of 1 and 1(+) indicate that electron ejection occurs from the symmetric (n+) combination of the Si lone pairs (HOMO). EPR studies of 1-B(Ar(F))4 in frozen solution verified the inequivalency of the two Si sites observed in the solid-state, and point in agreement with the theoretical results to an almost equal distribution of the spin density over the two Si atoms, leading to quite similar (29)Si hyperfine coupling tensors in 1(+). EPR studies of 1-B(Ar(F))4 in liquid solution unraveled a topomerization with a low activation barrier that interconverts the two Si sites in 1(+). PMID- 26246237 TI - Tumor necrosis factor (TNF)-receptor 1 and 2 mediate homeostatic synaptic plasticity of denervated mouse dentate granule cells. AB - Neurological diseases are often accompanied by neuronal cell death and subsequent deafferentation of connected brain regions. To study functional changes after denervation we generated entorhino-hippocampal slice cultures, transected the entorhinal pathway, and denervated dentate granule cells in vitro. Our previous work revealed that partially denervated neurons respond to the loss of input with a compensatory, i.e., homeostatic, increase in their excitatory synaptic strength. TNFalpha maintains this denervation-induced homeostatic strengthening of excitatory synapses. Here, we used pharmacological approaches and mouse genetics to assess the role of TNF-receptor 1 and 2 in lesion-induced excitatory synaptic strengthening. Our experiments disclose that both TNF-receptors are involved in the regulation of denervation-induced synaptic plasticity. In line with this result TNF-receptor 1 and 2 mRNA-levels were upregulated after deafferentation in vitro. These findings implicate TNF-receptor signaling cascades in the regulation of homeostatic plasticity of denervated networks and suggest an important role for TNFalpha-signaling in the course of neurological diseases accompanied by deafferentation. PMID- 26246239 TI - Beyond bar charts. AB - Probiotic treatments are thought to increase the levels of commensal bacterial species that populate the human gut, causing no harm to their host and playing an important role in maintaining gut health. This study is an investigation of the effect of a probiotic treatment on the level of a known commensal bacterium in the guts of healthy human subjects, which was significantly increased with probiotic treatment compared with a control. The authors concluded that the probiotic may thus help to promote gut health. PMID- 26246238 TI - Differences in utility scores obtained through Brazilian and UK value sets: a cross-sectional study. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic disease associated with several impacts; especially regarding patients' health-related quality of life (HRQL). EuroQol 5 Dimensions questionnaire (EQ-5D) provides self-reported analysis of HRQL and utility scores. Although the British algorithm to convert EQ-5D responses into utility is the most used in the literature, national settings is more appropriate for health policy decision makers. A Brazilian algorithm is available, but not used in MS patients yet. Primarily, this study aimed to address potential differences in utility scores obtained through Brazilian and British value sets. Secondary objective was to determine the role of disability, fatigue and patients socio-demographic and clinical characteristics relevant to MS on the utility scores reported by Brazilian patients. METHODS: Cross-sectional study with MS patients treated in 8 Brazilian sites. Patients were interviewed about socio-demographic and clinical characteristics, self-reported disability level, HRQL and impact of fatigue on daily living. Disability level, HRQL and impact of fatigue were assessed using the Expanded Disability Status Scale (EDSS) and the Brazilian versions of EQ-5D-3 L and Modified Fatigue Impact Scale (MFIS BR), respectively. Patients were classified in subgroups according to EDSS (mild: 0-3; moderate: 4-6.5; severe: >7) and the self-perceived impact of fatigue (absent: <= 38 points; low: 39-58; high: >= 59). EQ-5D-3 L data was converted into a utility index using an algorithm developed by a Brazilian research group (QALY Brazil) and also the UK algorithm. Differences between utility scores were analysed through Wilcoxon test. RESULTS: Two hundred and ten patients were included in the study. Utility index mean scores of 0.59 (SD = 0.22) and 0.56 (SD = 0.32) for the Brazilian and UK algorithms were observed, respectively, without statistically significant difference for the distribution of data (p = 0.586). However, when utility scores were lower than 0.5, Brazilian algorithm provided higher estimates than UK with a better agreement between the scores found closer to 1. The same trend was observed when data was stratified for EDSS and impact of fatigue, with statistically significant difference between scores in categories of mild/severe disabilities and absent/high impact of fatigue. CONCLUSIONS: Results suggest that Brazilian value set provided higher utility scores than the UK, particularly for measures below 0.5. PMID- 26246240 TI - Transfection of brain capillary endothelial cells in primary culture with defined blood-brain barrier properties. AB - BACKGROUND: Primary brain capillary endothelial cells (BCECs) are a promising tool to study the blood-brain barrier (BBB) in vitro, as they maintain many important characteristics of the BBB in vivo, especially when co-cultured with pericytes and/or astrocytes. A novel strategy for drug delivery to the brain is to transform BCECs into protein factories by genetic modifications leading to secretion of otherwise BBB impermeable proteins into the central nervous system. However, a huge challenge underlying this strategy is to enable transfection of non-mitotic BCECs, taking a non-viral approach. We therefore aimed to study transfection in primary, non-mitotic BCECs cultured with defined BBB properties without disrupting the cells' integrity. METHODS: Primary cultures of BCECs, pericytes and astrocytes were generated from rat brains and used in three different in vitro BBB experimental arrangements, which were characterised based on a their expression of tight junction proteins and other BBB specific proteins, high trans-endothelial electrical resistance (TEER), and low passive permeability to radiolabeled mannitol. Recombinant gene expression and protein synthesis were examined in primary BCECs. The BCECs were transfected using a commercially available transfection agent TurbofectTM to express the red fluorescent protein HcRed1-C1. The BCECs were transfected at different time points to monitor transfection in relation to mitotic or non-mitotic cells, as indicated by fluorescence-activated cell sorting analysis after 5-and 6-carboxylfluorescein diacetate succinidyl ester incorporation. RESULTS: The cell cultures exhibited important BBB characteristics judged from their expression of BBB specific proteins, high TEER values, and low passive permeability. Among the three in vitro BBB models, co-culturing with BCECs and astrocytes was well suited for the transfection studies. Transfection was independent of cell division and with equal efficacy between the mitotic and non-mitotic BCECs. Importantly, transfection of BCECs exhibiting BBB characteristics did not alter the integrity of the BCECs cell layer. CONCLUSIONS: The data clearly indicate that non-viral gene therapy of BCECs is possible in primary culture conditions with an intact BBB. PMID- 26246242 TI - The influence of expertise on essence beliefs for mental and medical disorder categories. AB - Research suggests that expertise in a specific category domain influences categorization. Work related to beliefs about mental disorders finds that laypeople treat mental disorders as if they do have causal essences, while clinicians do not-differences that may be attributable to expertise (Ahn, Flanagan, Marsh, & Sanislow, 2006). To test whether reduced beliefs in essences are indicative of an overall influence of expertise or a demonstration of a phenomenon specific to expertise in the mental health domain we compared beliefs about mental and medical disorders held by practicing physicians (n = 43; 19 primary care and 24 non-psychiatry specialists) and laypeople (n = 40). We found differences between these groups in beliefs held concerning the necessity of removing shared category features to effectively cure disorders. While laypeople endorsed the idea that the cause needed to be removed to cure both mental and medical disorders, this endorsement decreased with expertise. Primary care providers were less willing to endorse this for mental disorders than for medical disorders. Our results support the notion that the reduction of beliefs concerning the existence of essences is a unique effect of expertise in the mental health domain, and does not extend to other areas of expertise. In physicians, this reduction of essentialist beliefs was most evident in questions regarding treatment. Similarities and differences to the results from Ahn et al. (2006) are discussed. PMID- 26246243 TI - Molecular epidemiology of porcine reproductive and respiratory syndrome viruses isolated from 1991 to 2013 in Taiwan. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) was first identified in Taiwan in 1991, but the genetic diversity and evolution of PRRSV has not been thoroughly investigated over the past 20 years. The aim of this study was to bridge the gap in understanding of its molecular epidemiology. A total of 31 PRRSV strains were collected and sequenced. The sequences were aligned using the MUSCLE program, and phylogenetic analysis were performed by the maximum likelihood method and the neighbor-joining method using MEGA 5.2 software. In the early 1990s, two prototype strains, WSV and MD001 of the North American genotype, were first identified. Over the years, both viruses evolved separately. The population dynamics of PRRSV revealed that the strains of the MD001 group were predominant in Taiwan. Evolution was manifested in changes in the nsp2 and ORF5 genes. In addition, a suspected newly invading exotic strain was recovered in 2013, suggesting that international spread is still taking place and that it is affecting the population dynamics. Overall, the results provide an important basis for vaccine development for the control and prevention of PRRS. PMID- 26246241 TI - Vitamin D supplementation for the prevention of type 2 diabetes in overweight adults: study protocol for a randomized controlled trial. AB - BACKGROUND: Despite Australia's sunny climate, low vitamin D levels are increasingly prevalent. Sun exposure is limited by long working hours, an increase in time spent indoors, and sun protection practices, and there is limited dietary vitamin D fortification. While the importance of vitamin D for bone mineralization is well known, its role as a protective agent against chronic diseases, such as type 2 diabetes and cardiovascular disease, is less understood. Observational and limited intervention studies suggest that vitamin D might improve insulin sensitivity and secretion, mainly via its anti-inflammatory properties, thereby decreasing the risk of development and progression of type 2 diabetes. The primary aim of this trial is to investigate whether improved plasma concentrations of 25-hydroxyvitamin D (25(OH)D), obtained through vitamin D supplementation, will increase insulin sensitivity and insulin secretion. A secondary aim is to determine whether these relationships are mediated by a reduction in underlying subclinical inflammation associated with obesity. METHODS/DESIGN: Fifty overweight but otherwise healthy nondiabetic adults between 18 and 60 years old, with low vitamin D levels (25(OH)D < 50 nmol/l), will be randomly assigned to intervention or placebo. At baseline, participants will undergo a medical review and anthropometric measurements, including dual X-ray absorptiometry, an intravenous glucose tolerance test, muscle and fat biopsies, a hyperinsulinemic euglycemic clamp, and questionnaires assessing diet, physical activity, sun exposure, back and knee pain, and depression. The intervention group will receive a first dose of 100,000 IU followed by 4,000 IU vitamin D (cholecalciferol) daily, while the placebo group will receive apparently identical capsules, both for a period of 16 weeks. All measurements will be repeated at follow-up, with the primary outcome measure expressed as a change from baseline in insulin sensitivity and secretion for the intervention group compared with the placebo group. Secondary outcome measures will compare changes in anthropometry, cardiovascular risk factors, and inflammatory markers. DISCUSSION: The trial will provide much needed clinical evidence on the impact of vitamin D supplementation on insulin resistance and secretion and its underlying mechanisms, which are relevant for the prevention and management of type 2 diabetes. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT02112721 . PMID- 26246244 TI - Identification of a functional PRSS1 promoter variant in linkage disequilibrium with the chronic pancreatitis-protecting rs10273639. PMID- 26246245 TI - A challenging case of multiple splenic and pancreatic lesions in a patient with Crohn's disease. PMID- 26246246 TI - Barrett's oesophagus: size does matter. PMID- 26246247 TI - Capillary and winding transitions in a confined cholesteric liquid crystal. AB - We consider a Lebwohl-Lasher model of chiral particles confined in a planar cell (slit pore) under different boundary conditions, and solve it using mean-field theory. The phase behaviour of the system with respect to temperature and pore width is studied. Two phenomena are observed: (i) an isotropic-cholesteric transition, which exhibits an oscillatory structure with respect to pore width, and (ii) an infinite set of winding transitions caused by commensuration effects between cholesteric pitch and pore width. The latter transitions have been predicted and analysed by other authors for cholesterics confined in a fixed pore and subjected to an external field promoting the uniaxial nematic phase; here we induce winding transitions solely from geometry by changing the pore width at zero external field (a setup recently explored in atomic-force microscopy experiments). In contrast with previous studies, we obtain the phase diagram in the temperature vs. pore width plane, including the isotropic-cholesteric transition, the winding transitions and their complex relationship. In particular, the structure of winding transitions terminates at the capillary isotropic-cholesteric transition via triple points where the confined isotropic phase coexists with two cholesterics with different helix indices. For symmetric and asymmetric monostable plate anchorings the phase diagrams are qualitatively similar. PMID- 26246248 TI - "Impact of Smoking Cessation Treatment" on Lung Function and Response Rate in EGFR Mutated Patients: A Short-Term Cohort Study. AB - BACKGROUND: Erlotinib is a validated drug "for the treatment of patients affected by advanced unresectable non small cell lung cancer (NSCLC) with EGFR mutations". We want to focus on potential functional benefits deriving from a combined therapy containing TKI (erlotinib) and a nicotinic partial agonist (varenicicline) in smokers. METHODS: we analyzed the records of patients affected by NSCLC treated undergoing "first line therapy with Erlotinib" and smoking cessation (with varenicicline). Response to therapy was evaluated by CT scan. Data concerning clinical history, smoking habit, nicotine dependence were collected after three months from the beginning of the recruitment. Pulmonary function tests including spirometry with pletismographic technique and exhaled carbon monoxide (CO) were performed with recording of resistances, flows, volumes. A group of ten current smokers affected by NSCLC with EGFR activating mutation and concurrent mild COPD undergoing anti-EGFR treatment without smoking cessation was used to compare clinical and functional data. A control group of NSCLC wild type with mild COPD undergoing smoking cessation was assessed for functional data. RESULTS: Twenty-five patients were enrolled. All of them reported partial response at CT re-evaluation. All functional indexes and parameters were improved after combined treatment a significant increase of FEV1 level and a decrease of exhaled CO. In particular, a mean increase of FEV1 from 1.93 (SD 0.48) to 2.03(SD 0.46) liters was recorded. A notable reduction of sRAW (specific resistances) was also observed. The improvement of some parameters such as CO, heart rate (HR), sRAW and FEV1 resulted statistically significant. A better response to therapy was found "in the study group compared to the second group of mutated NSCLC patients". In this second group, we also observed an improvement of functional obstructive parameters although it was less remarkable than study group. Only sRAW and FEF 25/75 were significantly increased. The group of NSCLC wild type undergoing only smoking cessation showed a lower increase of FEV1 by about 50 ml compared to the first group. CONCLUSION: The combination of anti-EGFR treatment and concurrent therapy for smoking cessation seems to be more effective than erlotinib alone in improving lung function and clinical response in advanced NSCLC patients with EGFR-mutations. It is conceivable that erlotinib may potentiate the action of varenicline. We have also outlined some relevant patents concerning varenicline and EGFR-TKI. PMID- 26246249 TI - An intervention of active TB case finding among smokers attending routine primary care facilities in China: an exploratory study. AB - BACKGROUND: Smoking is an important risk factor of TB. However, no studies have been conducted to identify TB cases from smokers. We assessed the process and initial impact of active case finding among smokers at primary care facilities in a setting with high smoking rates and TB burden. METHODS: A prospective quasi experimental study was conducted in para-urban communities in Yunnan China between September 2013 and June 2014. Smokers attending primary care facilities in the intervention group were prescribed chest X-rays if they had diabetes or TB symptoms, or were elders or close contacts of TB patients. Those with X-rays suggestive of TB were referred to TB dispensaries for diagnosis. Passive case finding was practiced in the control group. RESULTS: In the intervention group, we screened 471 smokers with high risks of TB, of whom 73% took chest X-ray examinations. Eight TB cases were diagnosed, reflecting a 1.7% yield rate of all screened smokers. Smokers with diabetes (OR 6.003, 95% CI 1.057-34.075) were more likely to have TB compared with those without. In total, the intervention group reported significantly higher TB notification rate compared with the control group (38.6 vs 22.9 per 100 000, p=0.016). CONCLUSIONS: Active case finding among smokers with high risks of TB was feasible and contributed to improved notification rates. PMID- 26246250 TI - The potential for the establishment of new arbovirus transmission cycles in Europe. AB - Mosquito-borne viruses are an increasing health threat to humans, and potentially other vertebrates, in areas where they have not previously existed or from which they had been eradicated. Chikungunya virus emergence exemplifies how multiple factors can act synergistically resulting in rapid, large-scale redistribution and establishment. Despite our increased capacity to collect and analyze large amounts of data, we still lack epidemiological models to facilitate accurate predictions of when and where new diseases may occur. Models focusing on climate changes may have long-term value; however, there is an urgent need for mathematical modeling of viral epidemiology to enable forecasting immediate or near-term threats. PMID- 26246251 TI - Diagnostic accuracy of rK28-based immunochromatographic rapid diagnostic tests for visceral leishmaniasis: a prospective clinical cohort study in Sudan. AB - BACKGROUND: Rapid diagnostic tests (RDTs) for visceral leishmaniasis (VL) based on rK39 antigen showed suboptimal sensitivity in East Africa. A prospective clinical cohort study in Sudan was designed to validate a novel rK28-based RDT for Leishmania donovani VL. METHODS: Patients (n=285) suspected of VL by residency, fever for >=2 weeks, splenomegaly with no prior reported VL, and negative for malaria were consecutively enrolled at three Sudanese sites in 2012 2013 and informed consent obtained. Two human readers, who were blinded to the clinical status and other RDT results, evaluated patient whole blood (WB) and serum on the rK28 RDT. Based on Leishmania parasite detection in lymph node or bone marrow aspirates (Giemsa-stained smears or culture in Novy-MacNeal-Nicolle medium), patients were categorized as VL cases (n=200) or VL controls (n=85). RESULTS: The rK28 RDT had high specificity using either WB (100% [85/85]) or serum (97.6% [83/85]) and exhibited greater sensitivity (WB, 92.5% [185/200]; serum, 94.5% [189/200]) than a direct agglutination test performed with the same sera (92.9% [79/85] and 83.5% [167/200] for specificity and sensitivity, respectively). Two blinded readers scored a given WB or serum sample the same on the rK28 RDT 99.6% and 100% of the time, respectively. A reader scored each individual donor's paired WB and serum rK28 RDT results the same 97.2% of the time. CONCLUSIONS: An inexpensive rK28 RDT that performs robustly with WB or serum will be valuable for diagnosing cases of VL in East Africa. PMID- 26246252 TI - Consumption profile and factors associated with the ingestion of beer and distilled beverages among elderly Brazilians: Gender differences. AB - AIM: To estimate the prevalence of the consumption of beer and distilled beverages and associated factors among Brazilian older adults residing in a highly populated city in Brazil, highlighting the factors associated with frequent consumption and differences in consumption between men and women. METHODS: It was a cross-sectional, analytic study carried out by means of probability samples of conglomerates of older adults (aged 65-74 years). Descriptive analysis, univariate analysis and estimates of multivariate models through logistic regression (OR, 95% CI) were realized. RESULTS: 500 of the 736 evaluated seniors were included in the present analysis. 128 (27.3%), 103 (21.3%) and 167 (34.9%) of the seniors indicate past or current use of beer, distilled beverages and frequent use of alcohol, respectively. The consumption of beer was associated with use of tobacco between women; and with marital status and schooling between men. The consumption of distilled beverages was associated with schooling and use of tobacco between women; and age and use of tobacco in men. Daily or weekly use was associated with schooling and use of tobacco between women; age and the use of tobacco between men. CONCLUSION: In the elderly population studied, a noteworthy prevalence of the consumption of beer and distilled beverages was identified, and this use was associated with personal and behavioral determinants. Similar associations related to frequent (daily or weekly) consumption were also identified. Significant differences in the profile of consumption were identified between men and women, with more abusive use among men. Geriatr Gerontol Int 2016; 16: 810-820. PMID- 26246253 TI - Blindness to institutional betrayal by the APA. PMID- 26246254 TI - How to characterize the public health workforce based on essential public health operations? environmental public health workers in the Netherlands as an example. AB - BACKGROUND: Public health workforce planning and policy development require adequate data on the public health workforce and the services provided. If existing data sources do not contain the necessary information, or apply to part of the workforce only, primary data collection is required. The aim of this study was to develop a strategy to enumerate and characterize the public health workforce and the provision of essential public health operations (EPHOs), and apply this to the environmental public health workforce in the Netherlands as an example. METHODS: We specified WHO's EPHOs for environmental public health and developed an online questionnaire to assess individual involvement in these. Recruitment was a two-layered process. Through organisations with potential involvement in environmental public health, we invited environmental public health workers (n = 472) to participate in a national survey. Existing benchmark data and a group of national environmental public health experts provided opportunities for partial validity checks. RESULTS: The questionnaire was well accepted and available benchmark data on physicians supported the results of this study regarding the medical part of the workforce. Experts on environmental public health recognized the present results on the provision of EPHOs as a reasonable reflection of the actual situation in practice. All EPHOs were provided by an experienced, highly educated and multidisciplinary workforce. 27 % of the total full-time equivalents (FTEs) was spent on EPHO 'assuring governance for health'. Only 4 % was spent on 'health protection'. The total FTEs were estimated as 0.66 /100,000 inhabitants. CONCLUSIONS: Characterisation of the public health workforce is feasible by identification of relevant organisations and individual workers on the basis of EPHOs, and obtaining information from those individuals by questionnaire. Critical factors include the operationalization of the EPHOS into the field of study, the selection and recruitment of eligible organisations and the response rate within organisations.. When existing professional registries are incomplete or do not exist, this strategy may provide a start to enumerate the quantity and quality of the public health within or across countries. PMID- 26246255 TI - Meniscal Transplantation in Symptomatic Patients Under Fifty Years of Age: Survivorship Analysis. AB - BACKGROUND: The purpose of this study was to prospectively evaluate the long-term results and survivorship of meniscal transplantation in a consecutive series of patients. METHODS: Forty cryopreserved menisci were implanted into thirty-eight patients. Survival end points were transplant removal, revision, or tibiofemoral compartment pain with daily activities. A worst-case scenario was also calculated for patients who did not have symptoms related to the transplant; in this scenario, additional end points were grade-3 signal intensity, extrusion (>50% of meniscal width), or tear on magnetic resonance imaging; signs of meniscal tear on examination; or radiographic loss of joint space. The Cincinnati Knee and International Knee Documentation Committee rating systems were used. RESULTS: All patients were followed for a mean postoperative time of eleven years. The estimated probabilities of transplant survival were 88% at five years, 63% at ten years, and 40% at fifteen years. Worst-case survival rate estimates were 73% at five years, 68% at seven years, 48% at ten years, and 15% at fifteen years. The mean time to failure was 8.2 years for medial transplants and 7.6 years for lateral transplants. The functional analysis detected significant improvements for pain, swelling, the patient's perception of the knee condition, walking, stair-climbing, and squatting (p < 0.05). CONCLUSIONS: The survivorship analysis showed that, at ten years, 63% had not required subsequent surgery and were asymptomatic with daily activities. However, this percentage decreased to 40% at fifteen years. Although the data indicated that the majority of cryopreserved meniscal transplants may fail in the long term, the resolution of symptoms and improvement in function for several years justifies the procedure in young patients who are symptomatic after meniscectomy. Patients should be advised that the procedure is not curative in the long term and additional surgery will most likely be required. PMID- 26246256 TI - Chronic Suppression of Periprosthetic Joint Infections with Oral Antibiotics Increases Infection-Free Survivorship. AB - BACKGROUND: The clinical benefit of chronic suppression with oral antibiotics as a salvage treatment for periprosthetic joint infection is unclear. The purpose of this study was to compare infection-free prosthetic survival rates between patients who received chronic oral antibiotics and those who did not following irrigation and debridement with polyethylene exchange or two-stage revision for periprosthetic joint infection. METHODS: We reviewed the records on all irrigation and debridement procedures with polyethylene exchange and two-stage revisions performed at our institution from 1996 to 2010 for hip or knee periprosthetic joint infection. Of 625 patients treated with a total of 655 eligible revisions, ninety-two received chronic oral antibiotics for a minimum of six months and were eligible for inclusion in our study. These patients were compared with a matched cohort (ratio of 1:3) who did not receive chronic oral antibiotics. RESULTS: The five-year infection-free prosthetic survival rate was 68.5% (95% confidence interval [CI] = 59.2% to 79.3%) for the antibiotic suppression group and 41.1% (95% CI = 34.9% to 48.5%) for the non-suppression group (hazard ratio [HR] = 0.63, p = 0.008). Stratification by the type of surgery and the infecting organism showed a higher five-year survival rate for the patients in the suppression group who underwent irrigation and debridement with polyethylene exchange (64.7%) compared with those in the non-suppression group who underwent irrigation and debridement with polyethylene exchange (30.4%, p < 0.0001) and a higher five-year survival rate for the patients in the suppression group who had a Staphylococcus aureus infection (57.4%) compared with those in the non-suppression group who had a Staphylococcus aureus infection (40.1%, p = 0.047). CONCLUSIONS: Chronic suppression with oral antibiotics increased the infection-free prosthetic survival rate following surgical treatment for periprosthetic joint infection. Patients who underwent irrigation and debridement with polyethylene exchange and those who had a Staphylococcus aureus infection had the greatest benefit. PMID- 26246257 TI - Rotator Cuff Lesions in Patients with Stiff Shoulders: A Prospective Analysis of 379 Shoulders. AB - BACKGROUND: Idiopathic adhesive capsulitis is defined as a frozen shoulder with severe and global range-of-motion loss of unknown etiology. The purpose of our study was to clarify the prevalence of rotator cuff lesions according to patterns and severity of range-of-motion loss in a large cohort of patients with stiff shoulders. METHODS: Rotator cuff pathology was prospectively investigated with use of magnetic resonance imaging (MRI) or ultrasonography in a series of 379 stiff shoulders; patients with traumatic etiology, diabetes, or radiographic abnormalities were excluded. Eighty-nine shoulders demonstrated severe and global loss of passive motion (<=100 degrees of forward flexion, <=10 degrees of external rotation with the arm at the side, and internal rotation not more cephalad than the L5 level) and were classified as having severe and global loss of motion (Group 1). The remaining 290 shoulders were divided into two groups: those with severe but not global loss (Group 2; 111 shoulders) and mild to moderate limitation (Group 3; 179 shoulders). RESULTS: Among all shoulders, imaging demonstrated an intact rotator cuff in 51%, a full-thickness tear in 35%, and a partial-thickness tear in 15%. In Group 1, 91% had an intact rotator cuff and 9% had a partial-thickness rotator cuff tear. No patient in this group demonstrated a full-thickness tear. In Group 2 and Group 3, respectively, 44% and 35% of the shoulders were intact, 17% and 16% had a partial-thickness tear, and 39% and 50% had a full-thickness tear. CONCLUSIONS: Shoulder stiffness with severe and global loss of passive range of motion is not associated with full thickness rotator cuff tears, although some patients may have a partial-thickness tear. Shoulders with severe and global loss of range of motion at a first visit are likely to be cases of idiopathic adhesive capsulitis and may not require further imaging studies. PMID- 26246258 TI - The Scarf Osteotomy with Minimally Invasive Lateral Release for Treatment of Hallux Valgus Deformity: Intermediate and Long-Term Results. AB - BACKGROUND: Little is known about the long-term results of surgical correction of hallux valgus deformity, in particular, the recurrence rate and factors leading to recurrence. METHODS: Of one hundred and eight patients (115 feet) who underwent a Scarf osteotomy, ninety-three patients (ninety-three feet) were examined at an average duration of follow-up of 124 months. Clinical examination before surgery and at the time of final follow-up included an evaluation of range of motion, pain as measured with a visual analog scale, and American Orthopaedic Foot & Ankle Society (AOFAS) scores. The Foot and Ankle Outcome Score (FAOS) was also assessed postoperatively. Radiographic data were evaluated preoperatively, at six weeks postoperatively, and at the time of final follow-up. Additional radiographic data were available for seventy-nine patients of the same patient cohort at an average of twenty-seven months postoperatively. RESULTS: The median overall AOFAS score improved from 57 points preoperatively to 95 points at the time of final follow-up. All radiographic measurements (hallux valgus angle [HVA], intermetatarsal angle [IMA], distal metatarsal articular angle [DMAA], and sesamoid bone position) showed significant (p < 0.05) improvement at the time of final follow-up compared with preoperatively. The rate of recurrence (an HVA of >=20 degrees ) at the time of final follow-up was 30%. We were unable to determine if recurrence resulted in functional impairment or consequences for quality of life. CONCLUSIONS: The recurrence rate after ten years was 30%, and a higher final HVA resulted in higher pain levels. The limitations imposed by nonvalidated outcome measures precluded conclusions about the influence of HVA on function or quality of life. PMID- 26246259 TI - Lateral Tibiocalcaneal Angle As a Determinant for Percutaneous Achilles Tenotomy for Idiopathic Clubfeet. AB - BACKGROUND: The aim of the present study was to evaluate the clinical value of using the lateral tibiocalcaneal (LTiC) angle, measured on a lateral radiograph made with the foot and ankle in maximal dorsiflexion, instead of the ankle dorsiflexion (ADF) angle, measured on physical examination, as a determining indicator of the need for percutaneous Achilles tenotomy after Ponseti serial cast treatment of idiopathic clubfoot. METHODS: We identified patients with idiopathic clubfoot who had been treated at our institution between March 2006 and June 2012. After exclusion of patients with Dimeglio grade-I clubfoot and those followed for less than two years, 125 idiopathic clubfeet were evaluated. The clubfeet were grouped according to their LTiC and ADF angles, after which we evaluated the clinical outcomes of each group and investigated the prognostic effects of each angle-based decision regarding whether to perform percutaneous Achilles tenotomy. RESULTS: Patients with a favorable LTiC angle (<=80 degrees ) showed no sagittal relapse even though none underwent percutaneous Achilles tenotomy. In contrast, patients with an unfavorable LTiC angle (>80 degrees ) had a high chance of sagittal relapse if percutaneous Achilles tenotomy had not been performed, even when they had a favorable ADF angle (>=15 degrees ). The LTiC angle-based decision showed the most significant prognostic value in multivariate analyses of relapse-free and surgery-free survival rates. CONCLUSIONS: The LTiC angle measured on simple radiographs is a more objective and prognostic indicator of the need for percutaneous Achilles tenotomy, as compared with the ADF angle measured on physical examination, in patients with idiopathic clubfoot. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 26246260 TI - Factors Affecting Length of Stay, Readmission, and Revision After Shoulder Arthroplasty: A Population-Based Study. AB - BACKGROUND: Increased length of hospital stay, hospital readmission, and revision surgery are adverse outcomes that increase the cost of elective orthopaedic procedures, such as shoulder arthroplasty. Awareness of the factors related to these adverse outcomes will help surgeons and medical centers design strategies for minimizing their occurrence and for managing their associated costs. METHODS: We analyzed data from the New York Statewide Planning and Research Cooperative System on 17,311 primary shoulder arthroplasties performed from 1998 to 2011 to identify factors associated with extended lengths of hospitalization after surgery, readmission within ninety days, and surgical revision. RESULTS: The factors associated with each of these three adverse outcomes were different. Longer lengths of hospital stay were associated with female sex, advanced patient age, Medicaid insurance, comorbidities, fracture as the diagnosis for arthroplasty, higher hospital case volumes, and lower surgeon case volumes. Readmission was associated with advanced patient age and medical comorbidities. The most common diagnoses for readmission within ninety days were fluid and electrolyte imbalance (28%), acute pulmonary problems (21%), cardiac arrhythmia (20%), heart failure (15%), acute myocardial infarction (10%), and urinary tract infection (10%). Revision was associated with younger patient age and osteoarthritis or traumatic arthritis. The most common diagnoses at the time of revision surgery were unspecified mechanical complications of the implant (60%), shoulder pain (18%), dislocation of the prosthetic joint (12%), component loosening (10%), a broken prosthesis (8%), a cuff tear (7%), and infection (7%). CONCLUSIONS: A small number of easily identified characteristics (sex, age, race, insurance type, comorbidities, diagnosis, and provider case volumes) were significantly associated with longer lengths of stay, readmission, and revision surgery. Consideration of these factors and their effects may guide efforts to improve patient safety and to manage the costs associated with these adverse outcomes. PMID- 26246261 TI - Biomechanical Basis of Shoulder Osseous Deformity and Contracture in a Rat Model of Brachial Plexus Birth Palsy. AB - BACKGROUND: The purpose of this study was to investigate the relative contributions of two proposed mechanisms, strength imbalance and impaired longitudinal muscle growth, to osseous and postural deformity in a rat model of brachial plexus birth palsy (BPBP). METHODS: Thirty-two Sprague-Dawley rat pups were divided into four groups on the basis of surgical interventions to induce a strength imbalance, impaired growth, both a strength imbalance and impaired growth (a combined mechanism), and a sham condition in the left forelimb. Maximum passive external shoulder rotation angle (ERmax) was measured bilaterally at four and eight weeks postoperatively. After the rats were killed at eight weeks, the glenohumeral geometry (on microcomputed tomography) and shoulder muscle architecture properties were measured bilaterally. RESULTS: Bilateral muscle mass and optimal length differences were greatest in the impaired growth and combined mechanism groups, which also exhibited >15 degrees lower ERmax (p < 0.05; four weeks postoperatively), 14 degrees to 18 degrees more glenoid declination (p < 0.10), and 0.76 to 0.94 mm more inferior humeral head translation (p < 0.10) on the affected side. Across all four groups, optimal muscle length was significantly correlated with at least one osseous deformity measure for six of fourteen muscle compartments crossing the shoulder on the affected side (p < 0.05). In the strength imbalance group, the glenoid was 5 degrees more inclined and the humeral head was translated 7.5% more posteriorly on the affected side (p < 0.05). CONCLUSIONS: Impaired longitudinal muscle growth and shoulder deformity were most pronounced in the impaired growth and combined mechanism groups, which underwent neurectomy. Strength imbalance was associated with osseous deformity to a lesser extent. CLINICAL RELEVANCE: Treatments to alleviate shoulder deformity should address mechanical effects of both strength imbalance and impaired longitudinal muscle growth, with an emphasis on developing new treatments to promote growth in muscles affected by BPBP. PMID- 26246262 TI - Mental Health Medication Use Correlates with Poor Outcome After Femoroacetabular Impingement Surgery in a Military Population. AB - BACKGROUND: Femoroacetabular impingement is a common cause of hip pain in young adults. Several preoperative risk factors for poor outcomes with surgery have been identified; however, to our knowledge, no study has attempted to determine the effect of psychiatric comorbidity on outcomes with femoroacetabular impingement surgery. METHODS: A retrospective review was performed on active-duty patients at one institution undergoing surgery for femoroacetabular impingement over five years. Medical records were reviewed for demographic characteristics, radiographic data, and history of mental health medication use. Return-to-duty status was considered the primary outcome measure. Outcome scores obtained included modified Harris hip scores, Single Assessment Numeric Evaluation scores, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, patient satisfaction, and Veterans RAND-12 scores. Patients taking mental health medication were compared with those who were not with regard to return to duty and validated patient-reported outcome measures. RESULTS: Ninety-three patients (mean age, 32.2 years) were available for follow-up at a mean duration of 3.6 years. Of the seventeen patients discharged from service postoperatively, twelve (71%) were taking mental health medications. One-third (twenty-five) of seventy six patients who returned to duty were taking mental health medication and this difference was significant (p < 0.006). Patients taking mental health medication had significantly poorer modified Harris hip scores (p < 0.02), WOMAC scores (p < 0.0008), and Veterans RAND-12 mental scores (p < 0.001). Antidepressant, antipsychotic, and multiple mental health medication use were all predictive of medical discharge due to hip pain. CONCLUSIONS: Psychiatric comorbidities are an important risk factor in active-duty military personnel undergoing surgery for femoroacetabular impingement. Mental health medication use is associated with poorer outcome scores and can significantly lower the possibility of returning to active-duty status. PMID- 26246263 TI - Database and Registry Research in Orthopaedic Surgery: Part I: Claims-Based Data. AB - The use of large-scale national databases for observational research in orthopaedic surgery has grown substantially in the last decade, and the data sets can be grossly categorized as either administrative claims or clinical registries. Administrative claims data comprise the billing records associated with the delivery of health-care services. Orthopaedic researchers have used both government and private claims to describe temporal trends, geographic variation, disparities, complications, outcomes, and resource utilization associated with both musculoskeletal disease and treatment. Medicare claims comprise one of the most robust data sets used to perform orthopaedic research, with >45 million beneficiaries. The U.S. government, through the Centers for Medicare & Medicaid Services, often uses these data to drive changes in health policy. Private claims data used in orthopaedic research often comprise more heterogeneous patient demographic samples, but allow longitudinal analysis similar to that offered by Medicare claims. Discharge databases, such as the U.S. National Inpatient Sample, provide a wide national sampling of inpatient hospital stays from all payers and allow analysis of associated adverse events and resource utilization. Administrative claims data benefit from the high patient numbers obtained through a majority of hospitals. Using claims, it is possible to follow patients longitudinally throughout encounters irrespective of the location of the institution delivering health care. Some disadvantages include lack of precision of ICD-9 (International Classification of Diseases, Ninth Revision) coding schemes. Much of these data are expensive to purchase, complicated to organize, and labor-intensive to manipulate--often requiring trained specialists for analysis. Given the changing health-care environment, it is likely that databases will provide valuable information that has the potential to influence clinical practice improvement and health policy for years to come. PMID- 26246264 TI - Industry Financial Relationships in Orthopaedic Surgery: Analysis of the Sunshine Act Open Payments Database and Comparison with Other Surgical Subspecialties. AB - BACKGROUND: Industry financial relationships for orthopaedic surgeons in the United States are now publicly reported in the Sunshine Act Open Payments database. We sought to present these data in a more easily understandable format and to describe how industry relationships in orthopaedic surgery compare with other surgical subspecialties. METHODS: The Open Payments database was searched for all records of industry financial relationships for orthopaedic surgeons. Data analyzed included the value of reported financial relationships per surgeon, the type of financial relationship, and geographic region. Similar analytics were collected for neurological surgery, urology, plastic surgery, and otolaryngology. Data were normalized to the overall number of providers in each subspecialty in the United States from the American Medical Association 2012 data. RESULTS: For 12,320 orthopaedic surgeons, 58,127 industry financial relationships were reported, with a total value of $80.2 million. Royalties or licensing fees, which were received by 1.7% of U.S. orthopaedic surgeons, accounted for 69.5% of the total monetary value of payments to orthopaedic surgeons. Between August and December 2013, 50.1% of U.S. orthopaedic surgeons had a reported financial relationship. Orthopaedics had the second lowest percentage of physicians with industry financial relationships among the five surgical subspecialties studied. The overall value of payments per orthopaedic surgeon was higher than in the other subspecialties, driven by the large value of royalties and licensing. CONCLUSIONS: One-half of U.S. orthopaedic surgeons have industry financial relationships reported in the Open Payments database. Orthopaedic surgeons are less likely than most surgical subspecialists to receive industry payments, and the majority of the overall value of orthopaedic financial relationships is driven by a small number of orthopaedic surgeons receiving royalties and licensing for reimbursable innovation within the field. PMID- 26246265 TI - Bunion Surgery Works--Except When It Doesn't: Commentary on an article by Peter Bock, MD, et al.: "The Scarf Osteotomy with Minimally Invasive Lateral Release for Treatment of Hallux Valgus Deformity. Intermediate and Long-Term Results". PMID- 26246266 TI - Halophilic microbial communities in deteriorated buildings. AB - Halophilic microorganisms were traditionally isolated from an aquatic environment. There has been little research conducted into halophiles inhabiting the terrestrial environment in which historic monuments deteriorate. Salt efflorescence deposited on the walls is an observed phenomenon on the surface of historic buildings, and would favour the growth of halophiles. However, some conditions have to be fulfilled in order for efflorescence to occur: (1) the presence of salts, (2) porosity, (3) a source of water. Salt crystallization influences the material structure (cracking, detachment, material loss), but active growth of halophilic microorganisms may be a serious threat to historic materials as well, leading to aesthetical changes such as coloured biofilms, orange to pink or even violet stains. This is why it is important to investigate halophilic microorganisms, taking into consideration both the environmental conditions they need to grow in, material characteristics they inhabit, the mechanisms they possess to cope with osmotic stress, and the methods that should be applied for their identification. PMID- 26246267 TI - Functional analysis of filipin tailoring genes from Streptomyces filipinensis reveals alternative routes in filipin III biosynthesis and yields bioactive derivatives. AB - BACKGROUND: Streptomyces filipinensis is the industrial producer of filipin, a pentaene macrolide, archetype of non-glycosylated polyenes, and widely used for the detection and the quantitation of cholesterol in biological membranes and as a tool for the diagnosis of Niemann-Pick type C disease. Genetic manipulations of polyene biosynthetic pathways have proven useful for the discovery of products with improved properties. Here, we describe the late biosynthetic steps for filipin III biosynthesis and strategies for the generation of bioactive filipin III derivatives at high yield. RESULTS: A region of 13,778 base pairs of DNA from the S. filipinensis genome was isolated, sequenced, and characterized. Nine complete genes and two truncated ORFs were located. Disruption of genes proved that this genomic region is part of the biosynthetic cluster for the 28-membered ring of the polyene macrolide filipin. This set of genes includes two cytochrome P450 monooxygenase encoding genes, filC and filD, which are proposed to catalyse specific hydroxylations of the macrolide ring at C26 and C1' respectively. Gene deletion and complementation experiments provided evidence for their role during filipin III biosynthesis. Filipin III derivatives were accumulated by the recombinant mutants at high yield. These have been characterized by mass spectrometry and nuclear magnetic resonance following high-performance liquid chromatography purification thus revealing the post-polyketide steps during polyene biosynthesis. Two alternative routes lead to the formation of filipin III from the initial product of polyketide synthase chain assembly and cyclization filipin I, one trough filipin II, and the other one trough 1'-hydroxyfilipin I, all filipin III intermediates being biologically active. Moreover, minimal inhibitory concentration values against Candida utilis and Saccharomyces cerevisiae were obtained for all filipin derivatives, finding that 1' hydroxyfilipin and especially filipin II show remarkably enhanced antifungal bioactivity. Complete nuclear magnetic resonance assignments have been obtained for the first time for 1'-hydroxyfilipin I. CONCLUSIONS: This report reveals the existence of two alternative routes for filipin III formation and opens new possibilities for the generation of biologically active filipin derivatives at high yield and with improved properties. PMID- 26246268 TI - High-density lipoprotein cholesterol efflux capacity as a relevant predictor of atherosclerotic coronary disease. AB - BACKGROUND: We examined the clinical relevance of high-density lipoprotein cholesterol (HDL-C) efflux capacity from macrophage (cholesterol efflux capacity) as a predictor of atherosclerotic coronary artery disease (CAD) in comparison with that of conventional coronary and lipid risk variables in Japanese daily practice. METHODS AND RESULTS: Fasting blood sampling, including 6 routinely measured dyslipidemia-related variables, was performed at the time of coronary angiography (CAG) or multi-slice coronary computed tomography (MSCT) between January 2011 and January 2013. CAD, defined as native coronary atherosclerosis stenosis >50% by CAG or MSCT, was identified in 182 patients (CAD group), but not in 72 patients (non-CAD group). Cholesterol efflux capacity, measured using a cell-based efflux system in (3)[H]-cholesterol-labeled J774 macrophages in apolipoprotein B-depleted plasma, was significantly impaired in the CAD group compared with the non-CAD group (0.86 +/- 0.26 vs. 1.02 +/- 0.38; p = 0.001). After adjusting 15 patient and dyslipidemia-related variables using a propensity score matching analysis produced 55 patients in each arm, cholesterol efflux capacity in the CAD group remained to be significant compared with the non-CAD group (0.83 +/- 0.24 vs. 0.97 +/- 0.36; p = 0.019). Stepwise logistic regression analysis using a backward method after the baseline adjustment showed that cholesterol efflux capacity (odds ratio [OR]: 0.23; 95% confidence interval [CI]: 0.056-0.91; p = 0.037) was the single predictor of CAD, while other variables including HDL-C (p = 0.088) and apolipoprotein (apo) A-I (p = 0.681) were removed owing to those insignificance. The area under the receiver operating characteristic curve after the baseline adjustment was 0.67 (95% CI: 0.51-0.73, p = 0.048 by Hosmer-Lemeshow goodness-of-fit statistics). CONCLUSIONS: The present observational study conducted under daily clinical practice confirmed that cholesterol efflux capacity is a clinically relevant predictor of CAD among the conventional coronary risk factors and dyslipidemia-related variables. PMID- 26246269 TI - Economic evaluations of interventions to manage hyperphosphataemia in adult haemodialysis patients: A systematic review. AB - Managing hyperphosphataemia in haemodialysis patients is resource-intensive. A search for cost-effective interventions in this field is needed to inform decisions on the allocation of healthcare resources. NHSEED, MEDLINE, EMBASE and CINAHL were searched for full economic evaluations of hyperphosphataemia-managing interventions in adult haemodialysis patients, published between 2004 and 2014, in English, French, Dutch or German. Incremental cost-effectiveness ratios of the interventions were up-rated to 2013US$ using Purchasing Power Parity conversion rates and Consumer Price Indices. The quality of included studies was assessed using the Extended Consensus on Health Economic Criteria List. Twelve out of the 1681 retrieved records fulfilled the inclusion criteria. They reported only on one aspect of hyperphosphataemia management, which is the use of phosphate binders (calcium-based and calcium-free, in first-line and sequential use). No economic evaluations of other phosphorus-lowering interventions were found. The included articles derived from five countries and most of them were funded by pharmaceutical companies. The incremental cost-effectiveness ratios of phosphate binders ranged between US$11 461 and US$157 760 per quality-adjusted life-year gained. Calcium-based binders (especially calcium acetate) appear to be the optimal cost-effective first- and second-line therapy in prevalent patients, while the calcium-free binder, lanthanum carbonate, might provide good value for money, as second-line therapy, in incident patients. The studies' overall quality was suboptimal. Drawing firm conclusions was not possible due to the quality heterogeneity and inconsistent results. Future high-quality economic evaluations are needed to confirm the findings of this review and to address other interventions to manage hyperphosphataemia in this population. PMID- 26246270 TI - A novel curve fitting method for AV optimisation of biventricular pacemakers. AB - In this study, we designed and tested a new algorithm, which we call the 'restricted parabola', to identify the optimum atrioventricular (AV) delay in patients with biventricular pacemakers. This algorithm automatically restricts the hemodynamic data used for curve fitting to the parabolic zone in order to avoid inadvertently selecting an AV optimum that is too long.We used R, a programming language and software environment for statistical computing, to create an algorithm which applies multiple different cut-offs to partition curve fitting of a dataset into a parabolic and a plateau region and then selects the best cut-off using a least squares method. In 82 patients, AV delay was adjusted and beat-to-beat systolic blood pressure (SBP) was measured non-invasively using our multiple-repetition protocol. The novel algorithm was compared to fitting a parabola across the whole dataset to identify how many patients had a plateau region, and whether a higher hemodynamic response was achieved with one method.In 9/82 patients, the restricted parabola algorithm detected that the pattern was not parabolic at longer AV delays. For these patients, the optimal AV delay predicted by the restricted parabola algorithm increased SBP by 1.36 mmHg above that predicted by the conventional parabolic algorithm (95% confidence interval: 0.65 to 2.07 mmHg, p-value = 0.002).AV optima selected using our novel restricted parabola algorithm give a greater improvement in acute hemodynamics than fitting a parabola across all tested AV delays. Such an algorithm may assist the development of automated methods for biventricular pacemaker optimisation. PMID- 26246271 TI - Human amniotic epithelial cells as feeder layer to derive and maintain human embryonic stem cells from poor-quality embryos. AB - Data from the literature suggest that human embryonic stem cell (hESC) lines used in research do not genetically represent all human populations. The derivation of hESC through conventional methods involve the destruction of viable human embryos, as well the use of mouse embryonic fibroblasts as a feeder layer, which has several drawbacks. We obtained the hESC line (Amicqui-1) from poor-quality (PQ) embryos derived and maintained on human amniotic epithelial cells (hAEC). This line displays a battery of markers of pluripotency and we demonstrated the capacity of these cells to produce derivates of the three germ layers. PMID- 26246272 TI - Induced pluripotent stem cells (iPSCs) derived from frontotemporal dementia patient's peripheral blood mononuclear cells. AB - Peripheral blood mononuclear cells (PBMC) were donated by a patient with clinically diagnosed frontotemporal dementia (FTD). Induced pluripotent stem cells (iPSCs) were developed using integration-free CytoTune-iPS Sendai Reprogramming factors which include Sendai virus particles of the four Yamanaka factors Oct, Sox2, Klf4, and c-Myc. PMID- 26246273 TI - Determination of selected cardiovascular active compounds in environmental aquatic samples--Methods and results, a review of global publications from the last 10 years. AB - In recent years cardiovascular diseases were the second most common cause of death worldwide. Therefore, the consumption of cardiovascular drugs is high, which might result in an increase of them in the environment. The major source of aquatic environmental contamination is still effluents of wastewater treatment plants (WWTPs). Unfortunately removal of cardiovascular active compounds and/or their metabolites in WWTP is still unsatisfactory. Among microbial and abiotic degradation of these compounds during wastewater processes, photolysis and photodegradation of cardiovascular drugs also play an important role. New formed compounds may be more toxic or retain the properties of parent compounds. Thus the main goal of this paper was to provide a detailed and comprehensive review of used analytical methods, coupled to liquid chromatography-tandem mass spectrometry, to determine the presence of cardiovascular compounds in surface waters as well as WTTPs effluents and influents. Exhaustive preparation for mass spectrometry detection and quantitation including samples pre-treatment, and the common problem of the matrix effect are thoroughly explored in this paper. Additionally, the article provides some hints in respect of recently noted problematic issue related to the availability of specific standards for the analysis of drug's metabolites. Furthermore, information concerning the metabolism of cardiovascular active compounds including differences in metabolism within enantiomers is described. This article also touches on the problems associated with environmental risk assessment due to the presence of cardiovasculars in the environment. The paper also tries to explain differences in concentrations among cardiovascular compounds between countries worldwide. PMID- 26246274 TI - Sorption of Cu(2+) on humic acids sequentially extracted from a sediment. AB - In addition to the diverse properties of humic acids (HAs) extracted from different soils or sediments, chemical compositions, functional groups and structures of HAs extracted from a single soil or sediment could also be diverse and thus significantly affect sorption of heavy metals, which is a key process controlling the transfer, transformation and fate of heavy metals in the environment. In this study, we sequentially extracted four HA fractions from a single sediment and conducted the sorption experiments of Cu(2+) on these HA fractions. Our results showed that aromaticity and acidic group content of HA fraction decreased with increasing extraction. Earlier extracted HA fraction had higher sorption capacity and affinity for Cu(2+). There were two fractions of adsorbed Cu(2+) on HAs, i.e., ion exchanged fraction and surface bonded fraction, which can be captured mechanically by the bi-Langmuir model with good isotherm fitting. The ion exchanged fraction had larger sorption capacity but lower sorption affinity, compared with the surface bonded fraction. The dissociated carboxyl groups of HAs were responsible for both fractions of Cu(2+) sorption, due to the more Cu(2+) sorption on the earlier extracted HA fraction with more carboxyl groups and at higher pH. The intensive competition between H(+) and the exchangeable Cu(2+) could result in the decrease of ion exchanged capacity and affinity for Cu(2+) on HAs. PMID- 26246275 TI - Changes in the chemical composition of an acidic soil treated with marble quarry and marble cutting wastes. AB - Soil acidity greatly affects the availability of plant nutrients. The level of soil acidity can be adjusted by treating the soil with certain additives. The objective of this study was to determine the effect of marble quarry waste (MQW) and marble cutting waste (MCW) on the chemical composition and the acidity of a soil. Marble wastes at different rates were applied to an acid soil. Their effectiveness in neutralizing the soil pH was compared with that of agricultural lime. The changes in the chemical composition of the soil were also evaluated with column test at the end of a 75-day incubation period. The results indicated that the MQW and MCW applications significantly increased the soil pH (from 4.71 up to 6.54), the CaCO3 content (from 0.33% up to 0.75%), and the exchangeable Ca (from 14.79 cmol kg(-1) up to 21.18 cmol kg(-1)) and Na (from 0.57 cmol kg(-1) up to 1.07 cmol kg(-1)) contents, but decreased the exchangeable K (from 0.46 cmol kg(-1) down to 0.28 cmol kg(-1)), the plant-available P (from 25.56 mg L(-1) down to 16.62 mg L(-1)), and the extractable Fe (from 259.43 mg L(-1) down to 55.4 mg L(-1)), Cu (from 1.97 mg L(-1) down to 1.42 mg L(-1)), Mn (from 17.89 mg L(-1) down to 4.61 mg L(-1)) and Zn (from 7.88 mg L(-1) down to 1.56 mg L(-1)) contents. In addition, the Cd (from 0.060 mg L(-1) down to 0.046 mg L(-1)), Ni (from 0.337 mg L(-1) down to 0.092 mg L(-1)) and Pb (from 28.00 mg L(-1) down to 20.08 mg L(-1)) concentrations decreased upon the treatment of the soil with marble wastes. PMID- 26246276 TI - Concentrations and patterns of polychlorinated naphthalenes in surface sediment samples from Wuxi, Suzhou, and Nantong, in East China. AB - The concentrations and patterns of polychlorinated naphthalenes (PCNs) were determined in surface sediment samples from Wuxi, Suzhou, and Nantong, in the Yangtze River Delta (East China), which has become urbanized rapidly. The total PCN (tri- to octachlorinated naphthalenes) concentrations in the samples from Wuxi, Suzhou, and Nantong were 0.89-40, 2.8-4600, and 0.60-34 ng/gdry weight, respectively. Unexpectedly high PCN concentrations were found in four of the sediment samples. The PCN concentrations were much higher in the samples from the Beijing-Hangzhou Grand Canal than in the samples from the Yangtze River. The toxic equivalent (TEQ) concentrations (determined from the concentrations of the "dioxin-like" PCNs) ranged from 1.45*10(-7) to 2.16 ng TEQ/g, and the congeners CN-66/67 and CN-73 were the predominant contributors to the TEQs. Independent samples t-tests were performed, and no significant differences were found between the PCN concentrations in the samples from the metropolitan area and the development zone when the four development-zone samples that contained very high PCN concentrations were excluded. The PCN profiles were dominated by the hexa- to octachlorinated naphthalene homologs. The CN-66/67 to CN-71/72 and CN-66 to CN-67 concentration ratios were used to identify specific PCN sources. Emissions from chemical and other industrial plants were found to have strongly influenced the PCN concentrations in sediment in the study area. PMID- 26246277 TI - Degradation of emerging contaminants from water under natural sunlight: The effect of season, pH, humic acids and nitrate and identification of photodegradation by-products. AB - Both photodegradation and hydrolysis of non-steroidal anti-inflammatory drugs (NSAIDs) and endocrine disrupting chemicals (EDCs) were investigated in order to evaluate their photochemical fate in aquatic environment and to assess the effect of season and specific characteristics of water (pH, humic acids and nitrate concentration) on the removal of target EDCs and NSAIDs through photodegradation. An additional objective was the identification of the photodegradation by products of specific NSAIDs and their dependence on irradiation time. Selected compounds' transformation was investigated under natural sunlight radiation while control experiments were conducted in the dark. As expected, most of compounds' degradation rate decreased with decreasing light intensity between two different experimental periods. Most of the tested compounds exhibited different rates of degradation during direct and indirect photolysis. The degradation rate of the selected compounds increased in the presence of NO3(-) and the photodegradation rate was higher for some compounds in alkaline than in acidic solution. The effect of humic acids' presence in the water depends on the absorbance spectrum of the compound and the produced photosensitizers. More specifically, humic acids act as inner filter toward most of the selected NSAIDs and as photosensitizers toward most of the EDCs. The results of the irradiation experiments in the presence of both humic acids and NO3(-), indicate that the direct photolysis is much more efficient than indirect photochemical processes. Finally, several degradation by-products of ketoprofen and diclofenac were identified in the samples, exposed to sunlight. The dependence of these by-products on radiation time is also demonstrated. PMID- 26246278 TI - Including Memory Friction in Single- and Two-State Quantum Dynamics Simulations. AB - We present a simple computational algorithm that allows for the inclusion of memory friction in a quantum dynamics simulation of a small, quantum, primary system coupled to many atoms in the surroundings. We show how including a memory friction operator, F, in the primary quantum system's Hamiltonian operator builds memory friction into the dynamics of the primary quantum system. We show that, in the harmonic, semi-classical limit, this friction operator causes the classical phase-space centers of a wavepacket to evolve exactly as if it were a classical particle experiencing memory friction. We also show that this friction operator can be used to include memory friction in the quantum dynamics of an anharmonic primary system. We then generalize the algorithm so that it can be used to treat a primary quantum system that is evolving, non-adiabatically on two coupled potential energy surfaces, i.e., a model that can be used to model H atom transfer, for example. We demonstrate this approach's computational ease and flexibility by showing numerical results for both harmonic and anharmonic primary quantum systems in the single surface case. Finally, we present numerical results for a model of non-adiabatic H atom transfer between a reactant and product state that includes memory friction on one or both of the non-adiabatic potential energy surfaces and uncover some interesting dynamical effects of non-memory friction on the H atom transfer process. PMID- 26246279 TI - Design of a platform technology for systemic delivery of siRNA to tumours using rolling circle transcription. AB - For therapeutic applications of siRNA, there are technical challenges with respect to targeted and systemic delivery. We here report a new siRNA carrier, RNAtr NPs, in a way that multiple tandem copies of RNA hairpins as a result of rolling circle transcription (RCT) can be readily adapted in tumour-targeted and systemic siRNA delivery. RNAtr NPs provide a means of condensing large amounts of multimeric RNA transcripts into the compact nanoparticles, especially without the aid of polycationic agents, and thus reduce the risk of immunogenicity and cytotoxicity by avoiding the use of synthetic polycationic reagents. This strategy allows the design of a platform technology for systemic delivery of siRNA to tumour sites, because RCT reaction, which enzymatically generates RNA polymers in multiple copy numbers at low cost, can lead to directly accessible routes to targeted and systemic delivery. Therefore, RNAtr NPs suggest great potentials as the siRNA therapeutics for cancer treatment. PMID- 26246280 TI - Computed tomographic pulmonary changes in patients with chronic rhinosinusitis. AB - OBJECTIVE: To investigate whether patients with a diagnosis of chronic rhinosinusitis (CRS) show characteristic pulmonary changes on chest CT compared with a control group without sinusopathy. METHODS: This retrospective, observational study included patients with and without a diagnosis of CRS who underwent CT examination of the lungs between 2012 and 2014. Two radiologists, who were blinded for the presence of CRS, reviewed the scans for the presence of any abnormalities consensually. The chi(2) test was used for correlative analysis, with a significance level of 0.05. RESULTS: A total of 123 CT series (51.2% from male patients, mean age 41 +/- 16 years) were reviewed, including those from 59 (48%) patients with a diagnosis of CRS. Patients with CRS were more likely than the control group to exhibit atelectasis, bronchiolectasis, centrilobular nodules and ground-glass opacities (all p < 0.05), with a significant predilection for middle lobe and lingular involvement observed (p < 0.001). Other abnormalities, such as bronchial wall thickening and air trapping, did not differ between groups. CONCLUSION: Atelectatic changes, ground-glass opacities, bronchiolectasis and centrilobular nodules are the most frequent abnormalities associated with CRS, with peculiar middle lobe and lingular involvement observed on chest CT examinations. ADVANCES IN KNOWLEDGE: CRS is a frequent disorder that displays typical pulmonary changes at CT. The recognition of such findings can prevent patients with this condition from undergoing unnecessary investigations that might be based on the presence of the aforementioned radiological features. PMID- 26246281 TI - CT pulmonary densitovolumetry in patients with acromegaly: a comparison between active disease and controlled disease. AB - OBJECTIVE: Our purpose was to compare the findings of CT pulmonary densitovolumetry and pulmonary function in patients with active acromegaly and controlled acromegaly and, secondarily, to correlate these findings. METHODS: 11 patients with active acromegaly, 18 patients with controlled acromegaly and 17 control subjects, all non-smokers, underwent quantification of lung volume using multidetector CT (Q-MDCT) and pulmonary function tests. RESULTS: Patients with active acromegaly had larger total lung mass (TLM) values than the controls and larger amounts of non-aerated compartments than the other two groups. Patients with active acromegaly also had larger amounts of poorly aerated compartments than the other two groups, a difference that was observed in both total lung volume (TLV) and TLM. TLV as measured by inspiratory Q-MDCT correlated significantly with total lung capacity, whereas TLV measured using expiratory Q MDCT correlated significantly with functional residual capacity. CONCLUSION: Patients with active acromegaly have more lung mass and larger amounts of non aerated and poorly aerated compartments. There is a relationship between the findings of CT pulmonary densitovolumetry and pulmonary function test parameters. ADVANCES IN KNOWLEDGE: Although the nature of our results demands further investigation, our data suggest that both CT pulmonary densitovolumetry and pulmonary function tests can be used as useful tools for patients with acromegaly by assisting in the prediction of disease activity. PMID- 26246282 TI - Safety incident reporting in emergency radiology: analysis of 1717 safety incident reports. AB - The aim of this article is to describe the incidence and types of safety reports logged in the radiology safety incident reporting system in our emergency radiology section over an 8-year period. Electronic incident reporting system of our institute was searched for the variables in emergency radiology. All reports from April 2006 to June 2014 were included and deindentified. The following event classifications were investigated in radiography, CT, and MRI modalities: diagnostic test orders, ID/documentation/consent, safety/security/conduct, service coordination, surgery/procedure, line/tube, fall, medication/IV safety, employee general incident, environment/equipment, adverse drug reaction, skin/tissue, and diagnosis/treatment. A total of 881,194 emergency radiology examinations were performed during the study period, 1717 (1717/881,194 = 0.19 %) of which resulted in safety reports. Reports were classified into 14 different categories, the most frequent of which were "diagnostic test orders" (481/1717 = 28 % total incident reports), "medication/IV safety" (302/1717 = 18 % total incident reports), and "service coordination" (204/1717 = 12 % total incident reports). X-ray had the highest report rate (873/1717 = 50 % total incident reports), followed by CT (604/1717 = 35 % total incident reports) and MRI (240/1717 = 14 % total incident reports). Forty-six percent of safety incidents (789/1717) caused no harm and did not reach the patient, 36 % (617/1717) caused no harm but reached the patient, 18 % (308/1717) caused temporary or minor harm/ damage, and less than 1 % caused permanent or major harm/ damage or death. Our study shows an overall safety incident report rate of 0.19 % in emergency radiology including radiography, CT, and MRI modalities. The most common safety incidents were diagnostic test orders, medication/IV safety, and service coordination. PMID- 26246283 TI - Enhancement of paclitaxel-induced breast cancer cell death via the glycogen synthase kinase-3beta-mediated B-cell lymphoma 2 regulation. AB - Glycogen synthase kinase-3beta (GSK-3beta) is a serine/threonine protein kinase that is known to mediate cancer cell death. Here, we show that B-cell lymphoma 2 (Bcl-2), an anti-apoptotic protein, is regulated by GSK-3beta and that GSK-3beta mediated regulation of Bcl-2 is crucial for mitochondrial-dependent cell death in paclitaxel-stimulated cells. We demonstrate that MCF7 GSK-3beta siRNA cells are more sensitive to cell death than MCF7 GFP control cells and that in the absence of GSK-3beta, Bcl-2 levels are reduced, a result enhanced by paclitaxel. Paclitaxel-induced JNK (c-Jun N-terminal kinase) activation is critical for Bcl-2 modulation. In the absence of GSK-3beta, Bcl-2 was unstable in an ubiquitination dependent manner in both basal- and paclitaxeltreated cells. Furthermore, we demonstrate that GSK-3beta-mediated regulation of Bcl-2 influences cytochrome C release and mitochondrial membrane potential. Taken together, our data suggest that GSK-3beta-dependent regulation of Bcl-2 is crucial for mitochondria dependent cell death in paclitaxel-mediated breast cancer therapy. PMID- 26246286 TI - FDA grants four-month delay for some track-and-trace provisions. PMID- 26246284 TI - Gecko proteins induce the apoptosis of bladder cancer 5637 cells by inhibiting Akt and activating the intrinsic caspase cascade. AB - Gecko proteins have long been used as anti-tumor agents in oriental medicine, without any scientific background. Although anti-tumor effects of Gecko proteins on several cancers were recently reported, their effect on bladder cancer has not been investigated. Thus, we explored the anti-tumor effect of Gecko proteins and its cellular mechanisms in human bladder cancer 5637 cells. Gecko proteins significantly reduced the viability of 5637 cells without any cytotoxic effect on normal cells. These proteins increased the Annexin-V staining and the amount of condensed chromatin, demonstrating that the Gecko proteinsinduced cell death was caused by apoptosis. Gecko proteins suppressed Akt activation, and the overexpression of constitutively active form of myristoylated Akt prevented Gecko proteins-induced death of 5637 cells. Furthermore, Gecko proteins activated caspase 9 and caspase 3/7. Taken together, our data demonstrated that Gecko proteins suppressed the Akt pathway and activated the intrinsic caspase pathway, leading to the apoptosis of bladder cancer cells. [BMB Reports 2015; 48(9): 531 536]. PMID- 26246287 TI - Combination product approved for chronic heart failure. PMID- 26246285 TI - Wnt5a attenuates the pathogenic effects of the Wnt/beta-catenin pathway in human retinal pigment epithelial cells via down-regulating beta-catenin and Snail. AB - Activation of the Wnt/beta-catenin pathway plays a pathogenic role in age-related macular degeneration (AMD) and is thus a potential target for the development of therapeutics for this disease. Here, we demonstrated that Wnt5a antagonized beta catenin response transcription (CRT) induced with Wnt3a by promoting beta-catenin phosphorylation at Ser33/Ser37/Thr41 and its subsequent degradation in human retinal pigment epithelial (RPE) cells. Wnt5a decreased the levels of vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-alpha), and nuclear factor-kappaB (NF-kappaB), which was up-regulated by Wnt3a. Furthermore, Wnt5a increased E-cadherin expression and decreased cell migration by down regulating Snail expression, thereby abrogating the Wnt3a-induced epithelial mesenchymal transition (EMT) in human RPE cells. Our findings suggest that Wnt5a suppresses the pathogenic effects of canonical Wnt signaling in human RPE cells by promoting beta-catenin phosphorylation and degradation. Therefore, Wnt5a has significant therapeutic potential for the treatment of AMD. PMID- 26246288 TI - Pharmacists engage C-suite on profession's value. PMID- 26246289 TI - Workflow key to providing Medicare transitional care services, pharmacists find. PMID- 26246290 TI - Development of ambulatory care pharmacist positions under financial constraints. PMID- 26246291 TI - Opposing pharmacists' participation in capital punishment: The right thing to do. PMID- 26246292 TI - Once-daily aminoglycoside dosing: An update on current literature. AB - PURPOSE: The advantages and disadvantages of once-daily versus conventional dosing of aminoglycoside antibiotics are reviewed. SUMMARY: Although administration of multiple daily doses remains the standard method of aminoglycoside dosing, once-daily dosing may provide enhanced clinical efficacy and reduced toxicity in selected patient populations; demonstrated pharmacokinetic and pharmacodynamic advantages include enhanced postantibiotic effect and an increased likelihood of a high ratio of serum peak concentration to minimum inhibitory concentration. Published evidence identified in a MEDLINE search covering the period 1985-2014 indicates that once-daily high-dose aminoglycoside therapy generally provides clinical effectiveness equivalent or superior to that of multiple-daily dosing. The risk of nephrotoxicity appears to be comparable with once- and multiple-daily aminoglycoside dosing. Several nomograms have been developed to facilitate once-daily dosing; the Hartford nomogram (using a dose of 7 mg/kg) is the most extensively tested and generally considered the most reliable. However, although those nomograms are convenient to use and may reduce expenses, a daily dosing regimen determined by individualized pharmacokinetic monitoring is likely to be more effective for achieving specific serum concentrations and may be a preferable approach for some patients. Patients who are pregnant or have liver failure, severe renal insufficiency, serious illness, or nutritional deficiency are not appropriate candidates for once-daily dosing. CONCLUSION: Once-daily aminoglycoside dosing is an effective, well established method to achieve therapeutic efficacy while limiting the risk of toxicity and simplifying the processes of dosing and monitoring. PMID- 26246293 TI - Development of a computerized monitoring program to identify narcotic diversion in a pediatric anesthesia practice. AB - PURPOSE: Development of an operational reporting dashboard designed to correlate data from multiple sources to help detect potential drug diversion by automated dispensing cabinet (ADC) users is described. METHODS: A commercial business intelligence platform was used to create a dashboard tool for rapid detection of unusual patterns of ADC transactions by anesthesia service providers at a large pediatric hospital. By linking information from the hospital's pharmacy information management system (PIMS) and anesthesia information management system (AIMS) in an associative data model, the "narcotic reconciliation dashboard" can generate various reports to help spot outlier activity associated with ADC dispensing of controlled substances and documentation of medication waste processing. RESULTS: The dashboard's utility was evaluated by "back-testing" the program with historical data on an actual episode of diversion by an anesthesia provider that had not been detected through traditional methods of PIMS and AIMS data monitoring. Dashboard-generated reports on key metrics (e.g., ADC transaction counts, discrepancies in dispensed versus reconciled amounts of narcotics, PIMS-AIMS documentation mismatches) over various time frames during the period of known diversion clearly indicated the diverter's outlier status relative to other authorized ADC users. CONCLUSION: A dashboard program for correlating ADC transaction data with pharmacy and patient care data may be an effective tool for detecting patterns of ADC use that suggest drug diversion. PMID- 26246294 TI - Compatibility of butorphanol with granisetron in 0.9% sodium chloride injection packaged in glass bottles or polyolefin bags. AB - PURPOSE: The stability of admixtures containing butorphanol and granisetron in polyolefin bags and glass bottles stored at 4 and 25 degrees C was studied. METHODS: Commercial solutions of butorphanol tartrate and granisetron hydrochloride were combined and further diluted with 0.9% sodium chloride injection to final concentrations of butorphanol tartrate 0.08 mg/mL and granisetron 0.03 or 0.06 mg/mL; the resulting mixtures were packaged in polyolefin bags and glass bottles. The admixtures were assessed for periods of up to 48 hours after storage at 25 degrees C without protection from room light and up to 14 days at 4 degrees C with protection from room light. The chemical stability of the admixtures was evaluated by a validated high-performance liquid chromatography (HPLC) method and by measurement of pH values. Solution appearance and color were assessed by observing the samples against room light and dark backgrounds. RESULTS: HPLC analysis demonstrated that the percentages of the initial concentrations of butorphanol and granisetron in the various solutions remained above 97% during the testing period. No changes in color or turbidity were observed in any of the prepared solutions. Throughout this period, pH values remained stable. CONCLUSION: Admixtures of butorphanol tartrate 0.08 mg/mL and granisetron 0.03 or 0.06 mg/mL in 0.9% sodium chloride injection in polyolefin bags or glass bottles remained stable for 48 hours when stored at 25 degrees C exposed to room light and for 14 days when stored at 4 degrees C protected from room light. PMID- 26246295 TI - Significant publications on infectious diseases pharmacotherapy in 2014. AB - PURPOSE: The most important articles on infectious diseases (ID) pharmacotherapy published in the peer-reviewed literature in 2014, as nominated and selected by panels of pharmacists and others with ID expertise, are summarized. SUMMARY: Members of the Houston Infectious Diseases Network were asked to nominate articles published in 2014 from prominent peer-reviewed journals that were felt to have a major impact in the field of ID pharmacotherapy. A list of 19 nominated articles on general ID-related topics and 9 articles specifically related to human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) was compiled. In a national online survey, members of the Society of Infectious Diseases Pharmacists (SIDP) were asked to select from the list 10 general ID articles believed to have made a significant contribution to the field of ID pharmacotherapy and 1 article contributing to HIV/AIDS pharmacotherapy. Of the 291 SIDP members surveyed, 134 (46%) and 56 (19%) participated in the selection of general ID-related articles and HIV/AIDS-related articles, respectively. The 11 highest-ranked papers (10 general ID-related articles, 1 HIV/AIDS-related article) are summarized here. CONCLUSION: With the vast number of articles published each year, it is difficult to remain up-to-date on current, significant ID pharmacotherapy publications. This review of significant publications in 2014 may be helpful by lessening this burden. PMID- 26246296 TI - Lean back, listen, and own up. PMID- 26246297 TI - Inaugural address of the Incoming President: Building bridges to pharmacy's future: Optimizing patient outcomes. PMID- 26246298 TI - 2015 Report of the President and Chair of the Board: ASHP: Setting the standard for the future of pharmacy practice. PMID- 26246304 TI - Professional Policies Approved by the 2015 ASHP House of Delegates. PMID- 26246299 TI - 2015 Report of the Chief Executive Officer: Leading the way to transform the profession of pharmacy. PMID- 26246306 TI - Cyclin D1 Loss Distinguishes Prostatic Small-Cell Carcinoma from Most Prostatic Adenocarcinomas. AB - PURPOSE: Small-cell neuroendocrine differentiation in prostatic carcinoma is an increasingly common resistance mechanism to potent androgen deprivation therapy (ADT), but can be difficult to identify morphologically. We investigated whether cyclin D1 and p16 expression can inform on Rb functional status and distinguish small-cell carcinoma from adenocarcinoma. EXPERIMENTAL DESIGN: We used gene expression data and immunohistochemistry to examine cyclin D1 and p16 levels in patient-derived xenografts (PDX), and prostatic small-cell carcinoma and adenocarcinoma specimens. RESULTS: Using PDX, we show proof-of-concept that a high ratio of p16 to cyclin D1 gene expression reflects underlying Rb functional loss and distinguishes morphologically identified small-cell carcinoma from prostatic adenocarcinoma in patient specimens (n = 13 and 9, respectively). At the protein level, cyclin D1, but not p16, was useful to distinguish small-cell carcinoma from adenocarcinoma. Overall, 88% (36/41) of small-cell carcinomas showed cyclin D1 loss by immunostaining compared with 2% (2/94) of Gleason score 7-10 primary adenocarcinomas at radical prostatectomy, 9% (4/44) of Gleason score 9-10 primary adenocarcinomas at needle biopsy, and 7% (8/115) of individual metastases from 39 patients at autopsy. Though rare adenocarcinomas showed cyclin D1 loss, many of these were associated with clinical features of small-cell carcinoma, and in a cohort of men treated with adjuvant ADT who developed metastasis, lower cyclin D1 gene expression was associated with more rapid onset of metastasis and death. CONCLUSIONS: Cyclin D1 loss identifies prostate tumors with small-cell differentiation and may identify a small subset of adenocarcinomas with poor prognosis. Clin Cancer Res; 21(24); 5619-29. (c)2015 AACR. PMID- 26246307 TI - Incidence of Malignancies in Patients With Antineutrophil Cytoplasmic Antibody Associated Vasculitis Diagnosed Between 1991 and 2013. AB - OBJECTIVE: To investigate the incidence of malignancies during longitudinal followup of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), and to examine the effect of immunosuppressive therapy on malignancy risk in these patients. METHODS: The study population consisted of patients with histopathologically confirmed AAV, diagnosed between 1991 and 2013 at a large university hospital. The mean duration of followup was 10 years. Malignancy incidence was assessed using the Dutch National Pathology Database. Incidence rates from the Netherlands Cancer Registry were used to compare malignancy incidence in the AAV cohort to that in the general Dutch population. RESULTS: Thirty-six of 138 patients with AAV developed a total of 85 malignancies during a mean followup of 9.7 years. The sex-, age-, and calendar year-adjusted malignancy risk was 2.21-fold higher (95% confidence interval [95% CI] 1.64-2.92) than that in the general population. Non-melanoma skin cancers occurred most frequently (standardized incidence ratio 4.23 [95% CI 2.76-6.19]). The incidence rates of other malignancies were not significantly increased. Malignancy risk was associated with the duration of cyclophosphamide (CYC) therapy and, interestingly, was not increased in patients who had received CYC for <1 year. CONCLUSION: Patients with AAV have a higher risk of malignancy than the general population, but this risk is accounted for solely by non-melanoma skin cancers. Over the years, the risk of other malignancies-specifically bladder and hematologic malignancies-has decreased in patients with AAV. This finding reflects ongoing efforts to reduce CYC exposure by developing new treatment regimens. PMID- 26246308 TI - Effect of Chloroxylon swietenia Dc bark extracts against Culex quinquefasciatus, Aedes aegypti, and Anopheles stephensi larvae. AB - Mosquitoes are the vector of more diseases and cause major health problems like malaria, dengue, chikungunya, and lymphatic filariasis. This article deals with the mosquito larvicidal activity of Chloroxylon swietenia Dc bark extracts against late third instar larvae of Culex quinquefasciatus, Aedes aegypti, and Anopheles stephensi. Methanolic crude extract of Ch. swietenia bark was obtained by soxhlet apparatus and aqueous crude extract by cold percolation method. The range of concentrations of the crude extracts used was 50, 100, 150, 200, and 250 ppm. The mortality and lethal concentration (LC50 and LC90) was calculated after a 24-h exposure period. Both the extracts showed trustworthy larvicidal activity. The larvicidal activity of the methanol extract of Ch. swietenia bark was higher than the aqueous extract, and the LC50 and the LC90 values of the methanol extract were found to be 124.70 and 226.26 MUg/ml (Ae. aegypti), 130.57 and 234.67 ppm (Cu. quinquefasciatus), and 137.55 and 246.09 ppm (An. stephensi). The LC50 and the LC90 values of the aqueous extract were found to be 133.10 and 238.93 ppm (Ae. aegypti), 136.45 and 242.47 ppm (Cu. quinquefasciatus), and 139.43 and 248.64 ppm (An. stephensi). No mortality was observed in the control. Methanolic crude extract Ch. swietenia bark shows higher activity against An. stephensi than the other two tested larvae and aqueous extract. The results of the present study propose a possible way for further investigations to find out the active molecule responsible for the larvicidal activity of Ch. swietenia bark extracts. PMID- 26246309 TI - Making progress towards food security: evidence from an intervention in three rural districts of Rwanda. AB - OBJECTIVE: Determining interventions to address food insecurity and poverty, as well as setting targets to be achieved in a specific time period have been a persistent challenge for development practitioners and decision makers. The present study aimed to assess the changes in food access and consumption at the household level after one-year implementation of an integrated food security intervention in three rural districts of Rwanda. DESIGN: A before-and-after intervention study comparing Household Food Insecurity Access Scale (HFIAS) scores and household Food Consumption Scores (FCS) at baseline and after one year of programme implementation. SETTING: Three rural districts of Rwanda (Kayonza, Kirehe and Burera) where the Partners In Health Food Security and Livelihoods Program (FSLP) has been implemented since July 2013. SUBJECTS: All 600 households enrolled in the FSLP were included in the study. RESULTS: There were significant improvements (P<0.001) in HFIAS and FCS. The median decrease in HFIAS was 8 units (interquartile range (IQR) -13.0, -3.0) and the median increase for FCS was 4.5 units (IQR -6.0, 18.0). Severe food insecurity decreased from 78% to 49%, while acceptable food consumption improved from 48% to 64%. The change in HFIAS was significantly higher (P=0.019) for the poorest households. CONCLUSIONS: Our study demonstrated that an integrated programme, implemented in a setting of extreme poverty, was associated with considerable improvements towards household food security. Other government and non-government organizations' projects should consider a similar holistic approach when designing structural interventions to address food insecurity and extreme poverty. PMID- 26246310 TI - Obsessive-compulsive disorder in the postpartum period: diagnosis, differential diagnosis and management. AB - Childbirth can trigger or exacerbate a variety of psychiatric disorders but the extant literature has focused primarily on mood disorders. Obsessive-compulsive disorder (OCD) after childbirth can occur alone or in combination with other psychiatric disorders such as major depressive disorder. Due to the general lack of awareness of the relationship between childbirth and OCD among clinicians as well as patients, the disorder may be underdiagnosed or misdiagnosed as major depressive disorder. This article describes the prevalence, clinical features, common psychiatric comorbidities, differential diagnosis and potential consequences of underdiagnosis or misdiagnosis. Using case vignettes strategies for its detection and clinical management are suggested. Finally, areas in need of further research are proposed. PMID- 26246311 TI - Uncontrolled blood pressure and risk of sleep apnea among blacks: findings from the Metabolic Syndrome Outcome (MetSO) study. AB - Uncontrolled blood pressure (BP) is linked to increased risk of obstructive sleep apnea (OSA). However, few studies have assessed the impact of this relationship among blacks with metabolic syndrome (MetS). Data for this study were collected from 1035 blacks (mean age=62+/-13 years) enrolled in the Metabolic Syndrome Outcome study. Patients with a score ?6 on the Apnea Risk Evaluation System were considered at risk for OSA. Of the sample, 77.1% were low-to-high OSA risk and 92.3% were hypertensive, of which 16.8% had uncontrolled BP levels. Analysis also showed that 60.4% were diabetic, 8.9% had a stroke history, 74.3% had dyslipidemia, 69.8% were obese and 30.9% had a history of heart disease. Logistic regression analyses were employed to investigate associations between uncontrolled BP and OSA risk, while adjusting for known covariates. Findings showed that uncontrolled BP independently increased the odds of OSA risk twofold (odds ratio=2.02, 95% confidence interval=1.18-3.48, P<0.05). In conclusion, our findings show that uncontrolled BP was associated with a twofold greater risk of OSA among blacks, suggesting that those with MetS and who have uncontrolled BP should be screened for the presence of OSA. PMID- 26246312 TI - Slowed ageing, welfare, and population problems. AB - Biological studies have demonstrated that it is possible to slow the ageing process and extend lifespan in a wide variety of organisms, perhaps including humans. Making use of the findings of these studies, this article examines two problems concerning the effect of life extension on population size and welfare. The first--the problem of overpopulation--is that as a result of life extension too many people will co-exist at the same time, resulting in decreases in average welfare. The second--the problem of underpopulation--is that life extension will result in too few people existing across time, resulting in decreases in total welfare. I argue that overpopulation is highly unlikely to result from technologies that slow ageing. Moreover, I claim that the problem of underpopulation relies on claims about life extension that are false in the case of life extension by slowed ageing. The upshot of these arguments is that the population problems discussed provide scant reason to oppose life extension by slowed ageing. PMID- 26246313 TI - Museum samples reveal rapid evolution by wild honey bees exposed to a novel parasite. AB - Understanding genetic changes caused by novel pathogens and parasites can reveal mechanisms of adaptation and genetic robustness. Using whole-genome sequencing of museum and modern specimens, we describe the genomic changes in a wild population of honey bees in North America following the introduction of the ectoparasitic mite, Varroa destructor. Even though colony density in the study population is the same today as in the past, a major loss of haplotypic diversity occurred, indicative of a drastic mitochondrial bottleneck, caused by massive colony mortality. In contrast, nuclear genetic diversity did not change, though hundreds of genes show signs of selection. The genetic diversity within each bee colony, particularly as a consequence of polyandry by queens, may enable preservation of genetic diversity even during population bottlenecks. These findings suggest that genetically diverse honey bee populations can recover from introduced diseases by evolving rapid tolerance, while maintaining much of the standing genetic variation. PMID- 26246315 TI - Does Sexual Satisfaction Change With Relationship Duration? AB - Despite a large body of empirical literature on sexual satisfaction, its development over the course of a relationship is still unclear. Only a small number of studies, most of which have relied on cross-sectional data of convenience samples, have explicitly focused on relationship duration, and empirical evidence is mixed. We analyzed how sexual satisfaction changes over the course of a relationship using three waves of the German Family Panel study (pairfam). We concentrated our analyses on young and middle-aged heterosexual individuals in committed relationships (N = 2,814) and applied fixed effects regression models, which have the advantage of estimations based on changes within individuals over time. We found a positive development of sexual satisfaction in the first year of a relationship, followed by a steady decline. This pattern persisted even when controlling for the frequency of intercourse, although the effects were, in part, mediated by intercourse frequency. We explained the non-linear effect of relationship duration on sexual satisfaction with an initial learning effect regarding partner-specific sexual skills, which is then outweighed by a decline in passion at later stages of a relationship. Moreover, we found significant effects for the control variables of health status, intimacy in couple communication, and conflict style, as expected. In contrast to past research, however, cohabitation and marriage were not found to play a role for sexual satisfaction in our data. Further research is required to deepen the understanding of the reasons why sexual satisfaction changes with relationship duration. PMID- 26246314 TI - Reducing ventilator-associated pneumonia in neonatal intensive care unit using "VAP prevention Bundle": a cohort study. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is a serious health care associated infection, resulting in high morbidity and mortality. It also prolongs hospital stay and drives up hospital costs. Measures employed in preventing ventilator-associated pneumonia in developing countries are rarely reported. In this study we tried to assess the efficacy of our designed "VAP prevention bundle" in reducing VAP rate in our neonatal intensive care unit (NICU). METHOD: This prospective before-and-after study was conducted at university hospital NICU, all neonates who had mechanical ventilation for >= 48 h were eligible. VAP rates were evaluated before (phase-I) and after (phase-II) full implementation of comprehensive preventive measures specifically designed by our infection control team. RESULTS: Of 143 mechanically ventilated neonates, 73 patients developed VAP (51%) throughout the study period (2500 mechanical ventilation days). The rate of VAP was significantly reduced from 67.8% (42/62) corresponding to 36.4 VAP episodes/1000 mechanical ventilation days (MV days) in phase-I to 38.2% (31/81) corresponding to 23 VAP/1000 MV days (RR 0.565, 95% confidence interval 0.408 0.782, p = 0.0006) after VAP prevention bundle implementation (phase-II). Parallel significant reduction in MV days/case were documented in post intervention period (21.50 +/- 7.6 days in phase-I versus 10.36 +/- 5.2 days in phase-II, p = 0.000). There were a trend toward reduction in NICU length of stay (23.9 +/- 10.3 versus 22.8 +/- 9.6 days, p = 0.56) and overall mortality (25% versus 17.3%, p = 0.215) between the two phases but didn't reach statistical significance. The commonest micro-organisms isolated throughout the study were gram-negative bacteria (63/66, 95.5%) particularly Klebsilla pneumonia (55/66, 83.4%). CONCLUSION: Implementation of multifaceted infection control bundle resulted in reduction of VAP rate, length of stay in our NICU. PMID- 26246316 TI - Misrepresentation of evidence favoring early normalizing surgery for atypical sex anatomies: response to Baratz and Feder (2015). PMID- 26246317 TI - ATR signaling cooperates with ATM in the mechanism of low dose hypersensitivity induced by carbon ion beam. AB - Little work has been done on the mechanism of low dose hyper-radiosensitivity (HRS) and later appeared radioresistance (termed induced radioresistance (IRR)) after irradiation with medium and high linear energy transfer (LET) particles. The aim of this study was to find out whether ATR pathway is involved in the mechanism of HRS induced by high LET radiation. GM0639 cells and two ATM deficient/mutant cells, AT5BIVA and AT2KY were irradiated by carbon ion beam. Thymidine block technique was developed to enrich the G2-phase population. Radiation induced early G2/M checkpoint was quantitatively assess with dual parameter flow cytometry by detecting the cells positive for phospho-histone H3. The involvement of ATR pathway in HRS/IRR response was detected with pretreatment of specific inhibitors prior to carbon ion beam. The link between the early G2/M checkpoint and HRS/IRR under carbon ion beam was first confirmed in GM0639 cells, through the enrichment of cell population in G2-phase or with Aurora kinase inhibitor that attenuates the transition from G2 to M phase. Interestingly, the early G2/M arrest could still be observed in ATM deficient/mutant cells with an effect of ATR signaling, which was discovered to function in an LET-dependent manner, even as low as 0.2Gy for carbon ion radiation. The involvement of ATR pathway in heavy particles induced HRS/IRR was determined with the specific ATR inhibitor in GM0639 cells, which affected the HRS/IRR occurrence similarly as ATM inhibitor. These data demonstrate that ATR pathway may cooperate with ATM in the mechanism of low dose hypersensitivity induced by carbon ion beam. PMID- 26246318 TI - Food restriction-induced augmentation of heroin seeking in female rats: manipulations of ovarian hormones. AB - RATIONALE: Food restriction augments heroin seeking in chronically food restricted male rats under withdrawal, an effect not yet examined in female rats. Importantly, women and female rats possess an increased vulnerability to drugs of abuse, which may be mediated by fluctuations in ovarian hormones. OBJECTIVES: We investigated the role of estradiol and progesterone in augmented heroin seeking in chronically food-restricted female rats, under withdrawal. METHODS: Female rats self-administered heroin for 10-12 days and were then allowed unrestricted (sated) or restricted access to food (FDR; ~10 % reduction in body weight) for 14 days. On day 14, rats underwent a heroin-seeking test. Exp. 1: Rats underwent ovariectomy or sham surgery and were treated with a low dose of estradiol (5.0 % in cholesterol; subcutaneous capsule). Exp. 2: Rats underwent ovariectomy and were administered with a high dose of estradiol (0.5 mg/kg; subcutaneous) for 8 days before testing. Exp. 3: Progesterone injections (2.0 mg/kg; subcutaneous) were administered 24 h and 2 h before testing. RESULTS: Food restriction resulted in augmented heroin seeking, compared to sated controls. While ovariectomy had no effect, estradiol replacement attenuated the food restriction effect. Injections of progesterone had no effect on heroin seeking in either the sated or FDR groups. CONCLUSIONS: The effect of food restriction on heroin seeking in female rats under withdrawal is as robust as previously found in males. Interestingly, estradiol replacement, but not progesterone, attenuates the food restriction effect in the ovariectomized rats, possibly due to its anorexic properties. PMID- 26246319 TI - Ultrafast excited-state dynamics and fluorescence deactivation of near-infrared fluorescent proteins engineered from bacteriophytochromes. AB - Near-infrared fluorescent proteins, iRFPs, are recently developed genetically encoded fluorescent probes for deep-tissue in vivo imaging. Their functions depend on the corresponding fluorescence efficiencies and electronic excited state properties. Here we report the electronic excited state deactivation dynamics of the most red-shifted iRFPs: iRFP702, iRFP713 and iRFP720. Complementary measurements by ultrafast broadband fluorescence and absorption spectroscopy show that single exponential decays of the excited state with 600~700 ps dominate in all three iRFPs, while photoinduced isomerization was completely inhibited. Significant kinetic isotope effects (KIE) were observed with a factor of ~1.8 in D2O, and are interpreted in terms of an excited-state proton transfer (ESPT) process that deactivates the excited state in competition with fluorescence and chromophore mobility. On this basis, new approaches for rational molecular engineering may be applied to iRFPs to improve their fluorescence. PMID- 26246320 TI - A Healthy Dietary Pattern at Midlife, Combined with a Regulated Energy Intake, Is Related to Increased Odds for Healthy Aging. AB - BACKGROUND: Few studies have investigated the long-term impact of overall dietary patterns (DPs) on healthy aging (HA), and current findings are inconsistent. OBJECTIVE: Our study's objective was to investigate the association between empirically derived DPs in midlife and HA after 13 y of follow-up. METHODS: Baseline dietary data from repeated 24-h dietary records (on average, 10 records per participant) of a subsample of the SU.VI.MAX (SUpplementation en Vitamines et Mineraux AntioXydants) study allowed extraction of 2 DPs with the use of principal components analysis on 37 food groups. HA was assessed in 2007-2009 among 2796 participants of the SU.VI.MAX study aged 45-60 y at baseline (1994 1995), who were initially free of diabetes, cardiovascular disease, and cancer. HA was defined as not developing any major chronic disease, good physical and cognitive functioning, no limitations in instrumental activities of daily living, no depressive symptoms, no health-related limitations in social life, good overall self-perceived health, and no function-limiting pain. The association between DPs (in tertiles) and HA was evaluated by using multivariable logistic regression, and a potential interaction with energy intake was investigated. RESULTS: A "Western" and a "healthy" DP were identified. After adjustment for a large number of potential confounders, there was no significant association between the Western DP and HA. Moreover, the healthy pattern was not associated with HA among subjects with high (i.e., greater than or equal to the median) energy intake. Among subjects with low (i.e., less than the median) energy intake, on the other hand, higher scores on the healthy DP were related to higher odds of HA (OR for tertile 3 vs. tertile 1: 1.49; 95% CI: 1.11, 2.00; P-trend = 0.01). CONCLUSION: Adherence to a healthy diet in midlife that provides micronutrients, fiber, and antioxidants while regulating energy intake may help to promote HA. PMID- 26246321 TI - Six and 12 Weeks of Caloric Restriction Increases beta Cell Function and Lowers Fasting and Postprandial Glucose Concentrations in People with Type 2 Diabetes. AB - BACKGROUND: Caloric restriction alone has been shown to improve insulin action and fasting glucose metabolism; however, the mechanism by which this occurs remains uncertain. OBJECTIVE: We sought to quantify the effect of caloric restriction on beta cell function and glucose metabolism in people with type 2 diabetes. METHODS: Nine subjects (2 men, 7 women) with type 2 diabetes [BMI (in kg/m(2)): 40.6 +/- 1.4; age: 58 +/- 3 y; glycated hemoglobin: 6.9% +/- 0.2%] were studied using a triple-tracer mixed meal after withdrawal of oral diabetes therapy. The oral minimal model was used to measure beta cell function. Caloric restriction limited subjects to a pureed diet (<900 kcal/d) for the 12 wk of study. The studies were repeated after 6 and 12 wk of caloric restriction. RESULTS: Fasting glucose concentrations decreased significantly from baseline after 6 wk of caloric restriction with no further reduction after a further 6 wk of caloric restriction (9.8 +/- 1.3, 5.9 +/- 0.2, and 6.2 +/- 0.3 mmol/L at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.01) because of decreased fasting endogenous glucose production (EGP: 20.4 +/- 1.1, 16.2 +/- 0.8, and 17.4 +/- 1.1 MUmol . kg(-1) . min(-1) at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.03). These changes were accompanied by an improvement in beta cell function measured by the disposition index (189 +/- 51, 436 +/- 68, and 449 +/- 67 10(-14) dL . kg(-1) . min(-2) . pmol(-1) at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.01). CONCLUSIONS: Six weeks of caloric restriction lowers fasting glucose and EGP with accompanying improvements in beta cell function in people with type 2 diabetes. An additional 6 wk of caloric restriction maintained the improvement in glucose metabolism. This trial was registered at clinicaltrials.gov as NCT01094054. PMID- 26246323 TI - Citrulline and Nonessential Amino Acids Prevent Fructose-Induced Nonalcoholic Fatty Liver Disease in Rats. AB - BACKGROUND: Fructose induces nonalcoholic fatty liver disease (NAFLD). Citrulline (Cit) may exert a beneficial effect on steatosis. OBJECTIVE: We compared the effects of Cit and an isonitrogenous mixture of nonessential amino acids (NEAAs) on fructose-induced NAFLD. METHODS: Twenty-two male Sprague Dawley rats were randomly assigned into 4 groups (n = 4-6) to receive for 8 wk a 60% fructose diet, either alone or supplemented with Cit (1 g . kg(-1) . d(-1)), or an isonitrogenous amount of NEAAs, or the same NEAA-supplemented diet with starch and maltodextrin instead of fructose (controls). Nutritional and metabolic status, liver function, and expression of genes of hepatic lipid metabolism were determined. RESULTS: Compared with controls, fructose led to NAFLD with significantly higher visceral fat mass (128%), lower lean body mass (-7%), insulin resistance (135%), increased plasma triglycerides (TGs; 67%), and altered plasma amino acid concentrations with decreased Arg bioavailability (-27%). This was corrected by both NEAA and Cit supplementation. Fructose caused a 2-fold increase in the gene expression of fatty acid synthase (Fas) and 70% and 90% decreases in that of carnitine palmitoyl-transferase 1a and microsomal TG transfer protein via a nearly 10-fold higher gene expression of sterol regulatory element-binding protein-1c (Srebp1c) and carbohydrate-responsive element-binding protein (Chrebp), and a 90% lower gene expression of peroxisome proliferator activated receptor alpha (Ppara). NEAA or Cit supplementation led to a Ppara gene expression similar to controls and decreased those of Srebp1c and Chrebp in the liver by 50-60%. Only Cit led to Fas gene expression and Arg bioavailability similar to controls. CONCLUSION: In our rat model, Cit and NEAAs effectively prevented fructose-induced NAFLD. On the basis of literature data and our findings, we propose that NEAAs may exert their effects specifically on the liver, whereas Cit presumably acts at both the hepatic and whole-body level, in part via improved peripheral Arg metabolism. PMID- 26246322 TI - Higher Total Protein Intake and Change in Total Protein Intake Affect Body Composition but Not Metabolic Syndrome Indexes in Middle-Aged Overweight and Obese Adults Who Perform Resistance and Aerobic Exercise for 36 Weeks. AB - BACKGROUND: Studies assessing the effects of protein supplementation on changes in body composition (BC) and health rarely consider the impact of total protein intake (TPro) or the change in TPro (CTPro) from participants' usual diets. OBJECTIVE: This secondary data analysis assessed the impact of TPro and CTPro on changes in BC and metabolic syndrome (MetS) indexes in overweight and obese middle-aged adults who participated in an exercise training program. METHODS: Men and women [n = 117; age: 50 +/- 0.7 y, body mass index (BMI; in kg/m(2)): 30.1 +/ 0.3; means +/- SEs] performed resistance exercise 2 d/wk and aerobic exercise 1 d/wk and consumed an unrestricted diet along with 200-kcal supplements (0, 10, 20, or 30 g whey protein) twice daily for 36 wk. Protein intake was assessed via 4-d food records. Multiple linear regression model and stratified analysis were applied for data analyses. RESULTS: Among all subjects, TPro and CTPro were inversely associated (P < 0.05) with changes in body mass, fat mass (FM), and BMI. Changes in BC were different (P < 0.05) among groups that consumed <1.0 (n = 43) vs. >=1.0 to <1.2 (n = 29) vs. >=1.2 g . kg(-1) . d(-1) (n = 45). The TPro group with >=1.0 to <1.2 g .: kg(-1) .: d(-1) reduced FM and %FM and increased percentage of LM (%LM) compared with the lowest TPro group, whereas the TPro group with >=1.2 g .: kg(-1) .: d(-1) presented intermediate responses on changes in FM, %FM, and %LM. The gain in LM was not different among groups. In addition, MetS indexes were not influenced by TPro and CTPro. CONCLUSIONS: In conjunction with exercise training, higher TPro promoted positive changes in BC but not in MetS indexes in overweight and obese middle-aged adults. Changes in TPro from before to during the intervention also influenced BC responses and should be considered in future research when different TPro is achieved via diet or supplements. This trial was registered at clinicaltrials.gov as NCT00812409. PMID- 26246324 TI - Silicon-Enriched Restructured Pork Affects the Lipoprotein Profile, VLDL Oxidation, and LDL Receptor Gene Expression in Aged Rats Fed an Atherogenic Diet. AB - BACKGROUND: Research has shown that silicon can play an important role in protecting against degenerative diseases. Restructuring pork by partially disassembling meat permits the incorporation of active components with potential functional effects. However, there has been no research to date on the impact that silicon, as a functional ingredient in restructured pork (RP), has on lipoprotein composition, metabolism, and oxidation. OBJECTIVE: This study was designed to evaluate the effect of silicon-enriched RP on lipemia, lipoprotein profile, and oxidation markers of aged rats fed high-fat, high-energy, cholesterol-enriched diets. METHODS: RP samples similar to commercial sausages (16% protein and 22% fat, wt:wt) were prepared by mixing lean pork and lard alone or with silicon (1.3 g Si/kg fresh matter) under controlled conditions and then freeze-dried. Saturated fat-rich diets were designed by mixing 78.3% purified diet with 21.7% freeze-dried RP. Three groups composed of 8 aged male Wistar rats (1 y old) were fed for 8 wk a control RP (C) diet, a cholesterol-enriched RP (Chol-C) diet [C diet enriched with 1.26% cholesterol plus 0.25% cholic acid, or a cholesterol and silicon-enriched RP (Chol-Si) diet (same as the Chol-C diet but containing silicon)]. Plasma lipid concentrations, lipoprotein profile, the degree of VLDL oxidation, and LDL receptor gene (Ldlr) expression were tested. RESULTS: Compared with the C diet, the Chol-C diet did not modify food intake or body weight but significantly increased (P < 0.05) plasma cholesterol (32%) and total lipids (19%), VLDL and intermediate density lipoprotein + LDL cholesterol (both >600%), total lipids and proteins (both >300%), and the degree of VLDL oxidation [conjugated dienes >250%; thiobarbituric acid-reactive substance (TBARS), 900%] and reduced Ldlr expression (64%) and liver arylesterase activity (54%). The Chol-Si diet partially normalized changes induced by the Chol-C diet. Compared with the Chol-C group, Chol-Si rats had lower VLDL compound concentrations (P < 0.001; e.g., 75% less VLDL cholesterol) and VLDL oxidation (65% less conjugated dienes and 85% less TBARS) but greater Ldlr expression (200%). CONCLUSIONS: Silicon added to RP strongly counterbalanced the negative effect of high-cholesterol-ingestion, functioning as an active hypocholesterolemic, hypolipemic, and antioxidative dietary ingredient in aged rats. PMID- 26246325 TI - Higher Maternal Plasma n-3 PUFA and Lower n-6 PUFA Concentrations in Pregnancy Are Associated with Lower Childhood Systolic Blood Pressure. AB - BACKGROUND: Suboptimal maternal diet during pregnancy might lead to fetal cardiovascular adaptations with persistent consequences in the offspring. OBJECTIVE: We assessed the associations of maternal polyunsaturated fatty acid (PUFA) concentrations during pregnancy with childhood blood pressure. METHODS: In a population-based prospective cohort study among 4455 mothers and their children, we measured maternal second-trimester n-3 (omega-3) and n-6 (omega-6) PUFA concentrations in plasma glycerophospholipids and expressed n-3 and n-6 PUFAs as proportions of total PUFAs (wt%). Childhood blood pressure was measured at the median age of 6.0 y (95% range: 5.7-7.9 y). We used linear regression models to assess the associations of maternal PUFA wt% with childhood blood pressure at 6 y. RESULTS: Higher total maternal n-3 PUFA wt% and, specifically, docosahexaenoic acid (DHA; 22:6n-3) wt% were associated with lower childhood systolic blood pressure [differences: -0.28 (95% CI: -0.54, -0.03) and -0.29 mm Hg (95% CI: -0.54, -0.03) per SD increase of total n-3 PUFAs and DHA wt%, respectively], but not with childhood diastolic blood pressure. Total maternal n 6 PUFA wt% was positively associated with childhood systolic blood pressure [differences: 0.36 mm Hg (95% CI: 0.09, 0.62) per SD increase of total n-6 PUFA wt%], but not with childhood diastolic blood pressure. A higher n-6:n-3 PUFA ratio was associated with higher childhood systolic blood pressure (P < 0.05). Pregnancy and childhood characteristics only partly explained the observed associations. CONCLUSIONS: Higher maternal plasma n-3 PUFA and lower n-6 PUFA concentrations during pregnancy are associated with a lower systolic blood pressure in childhood. Further studies are needed to replicate these findings, explore the underlying mechanisms, and examine the long-term cardiovascular consequences. PMID- 26246326 TI - Oral Glutamine Supplementation Protects Female Mice from Nonalcoholic Steatohepatitis. AB - BACKGROUND: Genetic factors, a diet rich in fat and sugar, and an impaired intestinal barrier function are critical in the development of nonalcoholic steatohepatitis (NASH). The nonessential amino acid glutamine (Gln) has been suggested to have protective effects on intestinal barrier function but also against the development of liver diseases of various etiologies. OBJECTIVE: The effect of oral Gln supplementation on the development of Western-style diet (WSD) induced NASH in mice was assessed. METHODS: Female 6- to 8-wk-old C57BL/6J mice were pair-fed a control (C) diet or a WSD alone or supplemented with 2.1 g l Gln/kg body weight for 6 wk (C+Gln or WSD+Gln). Indexes of liver damage, lipid peroxidation, and glucose metabolism and endotoxin concentrations were measured. RESULTS: Although Gln supplementation had no effect on the loss of the tight junction protein occludin, the increased portal endotoxin and fasting glucose concentrations found in WSD-fed mice, markers of liver damage (e.g., nonalcoholic fatty liver disease activity score and number of neutrophils in the liver) were significantly lower in the WSD+Gln group than in the WSD group (~47% and ~60% less, respectively; P < 0.05). Concentrations of inducible nitric oxide synthase (iNOS) protein and 3-nitrotyrosin protein adducts were significantly higher in livers of WSD-fed mice than in all other groups (~8.6- and ~1.9-fold higher, respectively, compared with the C group; P < 0.05) but did not differ between WSD+Gln-, C-, and C+Gln-fed mice. Hepatic tumor necrosis factor alpha and plasminogen activator inhibitor 1 concentrations were significantly higher in WSD fed mice (~1.6- and ~1.8-fold higher, respectively; P < 0.05) but not in WSD+Gln fed mice compared with C mice. CONCLUSION: Our data suggest that the protective effects of oral Gln supplementation on the development of WSD-induced NASH in mice are associated with protection against the induction of iNOS and lipid peroxidation in the liver. PMID- 26246328 TI - Fluoride solid electrolytes: investigation of the tysonite-type solid solutions La1-xBaxF3-x (x < 0.15). AB - Pure tysonite La1-xBaxF3-x solid solutions for x < 0.15 were prepared by solid state synthesis in a platinum tube under an azote atmosphere with subsequent quenching for 0.07 <=x < 0.15. The solid solutions were studied by X-ray, electron and neutron diffractions and by (19)F NMR and impedance spectroscopy. The evolution of the cell parameters obeying Vegard's rule was determined for 0 < x<= 0.15 and atomic position parameters were accurately refined for x = 0.03, 0.07 and 0.10. The chemical pressure induced by large Ba(2+) cations leads to an increase of the unit cell parameters. Fluorine environment and mobilities are discussed on the basis of the results of neutron diffraction and (19)F solid state NMR. The F1 subnetwork is lacunar; fluorine exchange occurs according to the order: F1-F1 and F1-F2,3. 2D EXSY NMR spectra of La0.97Ba0.03F2.97 reveal, for the first time, a chemical exchange between F2 and F3 sites that requires two successive jumps. The ionic conductivity was evaluated from sintered pellets and different shaping methods were compared. The only structural features which could explain the conductivity maximum are a crossover together with a smaller dispersion of F1-F1,2,3 distances at x = 0.05-0.07. PMID- 26246327 TI - High-throughput sequencing enhanced phage display enables the identification of patient-specific epitope motifs in serum. AB - Phage display is a prominent screening technique with a multitude of applications including therapeutic antibody development and mapping of antigen epitopes. In this study, phages were selected based on their interaction with patient serum and exhaustively characterised by high-throughput sequencing. A bioinformatics approach was developed in order to identify peptide motifs of interest based on clustering and contrasting to control samples. Comparison of patient and control samples confirmed a major issue in phage display, namely the selection of unspecific peptides. The potential of the bioinformatic approach was demonstrated by identifying epitopes of a prominent peanut allergen, Ara h 1, in sera from patients with severe peanut allergy. The identified epitopes were confirmed by high-density peptide micro-arrays. The present study demonstrates that high throughput sequencing can empower phage display by (i) enabling the analysis of complex biological samples, (ii) circumventing the traditional laborious picking and functional testing of individual phage clones and (iii) reducing the number of selection rounds. PMID- 26246329 TI - Examination of Gossypol-Pluronic Micelles as Potential Radiosensitizers. AB - Chemoradiotherapy, the combination of chemotherapy and radiotherapy to treat cancer, has the potential to enhance local therapeutic effects and simultaneously treat systemic disease. However, chemoradiotherapy may also enhance normal tissue effects leading to both acute and late toxicities. Furthermore, subtherapeutic chemoradiotherapy may result in aggressive tumor repopulation. Tumor-specific radiosensitizing chemotherapy may yield a synergistic therapeutic effect and avoid augmentation of normal tissue toxicity. In this study, the radiosensitizing effects of gossypol were investigated. Also, Pluronics were studied for gossypol solubilization and co-radiosensitization effects. Gossypol inhibits Bcl-2 and Bcl XL, antiapoptotic proteins that are overexpressed in various cancer cells. Pluronic micelles (P85, F88, L35, and P123) effectively encapsulated gossypol, raising its water solubility by more than 1000-fold. Cytotoxic, anticlonogenic, and radiosensitizing effects were evaluated to characterize gossypol and Pluronic combinations. Gossypol and P85 had the strongest antiproliferative effect on A549 human lung adenocarcinoma cells in a cell viability assay. The IC50 value was seven times lower than gossypol only treatment (330 +/- 70 nM vs 2400 +/- 400 nM, (mean +/- SE)). Gossypol and P85 showed significant inhibition of clonogenic survival, approximately 30% inhibition, compared to treatment with gossypol alone. An experimental sequencing study demonstrated greater inhibition of clonogenic survival when drug treatment followed radiation compared to a sequence of drug treatment followed by radiation. These results suggest that Pluronic micelles readily solubilize gossypol and that the combination of gossypol and P85 may augment the therapeutic effects of ionizing radiation. PMID- 26246330 TI - Incidence of adverse cutaneous drug reactions in 22,866 Chinese inpatients: a prospective study. AB - Cutaneous adverse drug reactions (ADRs) are common. However, no prospective study assessing cutaneous ADRs is available for Chinese populations. This study aimed to assess the incidence, manifestations, causative drugs, and other factors related to cutaneous ADRs. A total of 22,866 inpatients were surveyed prospectively from January to April 2012 at the Peking Union Medical College Hospital. Only cutaneous ADRs induced by systemic drugs were considered. Fifty cases were confirmed as cutaneous ADRs, for an estimated incidence of 2.2 per 1000 during this period (95 % confidence interval 1.6-2.8). Cases of cutaneous ADRs comprised 69 % females, while 63 % of all inpatients were female (chi (2) = 0.641, P = 0.427). The department of infectious diseases was the most frequently involved department. Morbilliform exanthema (40 %) was the most frequent cutaneous ADR, followed by urticaria (23.1 %). Anti-infection drugs (36.9 %) caused most cases of cutaneous ADRs, followed by iodinated contrast media (ICM, 18.5 %) and non-steroidal anti-inflammatory drugs (NSAIDs, 18.5 %). The most frequently associated disorders were cancer (24 %), infection (22 %), cardiovascular and cerebrovascular diseases (20 %), and autoimmune diseases (18 %). In this first prospective study assessing the incidence of cutaneous ADRs in China, anti-infection drugs were the most commonly involved drugs, followed by ICM and NSAIDs. No evidence of increased cutaneous ADR incidence in AIDS or SLE patients was observed. Our findings indicate that cancer and its treatments were often related to cutaneous ADRs in China. PMID- 26246331 TI - Understanding crop genetic diversity under modern plant breeding. AB - KEY MESSAGE: Maximizing crop yield while at the same time minimizing crop failure for sustainable agriculture requires a better understanding of the impacts of plant breeding on crop genetic diversity. This review identifies knowledge gaps and shows the need for more research into genetic diversity changes under plant breeding. Modern plant breeding has made a profound impact on food production and will continue to play a vital role in world food security. For sustainable agriculture, a compromise should be sought between maximizing crop yield under changing climate and minimizing crop failure under unfavorable conditions. Such a compromise requires better understanding of the impacts of plant breeding on crop genetic diversity. Efforts have been made over the last three decades to assess crop genetic diversity using molecular marker technologies. However, these assessments have revealed some temporal diversity patterns that are largely inconsistent with our perception that modern plant breeding reduces crop genetic diversity. An attempt was made in this review to explain such discrepancies by examining empirical assessments of crop genetic diversity and theoretical investigations of genetic diversity changes over time under artificial selection. It was found that many crop genetic diversity assessments were not designed to assess diversity impacts from specific plant breeding programs, while others were experimentally inadequate and contained technical biases from the sampling of cultivars and genomes. Little attention has been paid to theoretical investigations on crop genetic diversity changes from plant breeding. A computer simulation of five simplified breeding schemes showed the substantial effects of plant breeding on the retention of heterozygosity over generations. It is clear that more efforts are needed to investigate crop genetic diversity in space and time under plant breeding to achieve sustainable crop production. PMID- 26246332 TI - 'Bigger data' on scale-dependent effects of invasive species on biodiversity cannot overcome confounded analyses: a comment on Stohlgren & Rejmanek (2014). AB - A recent study by Stohlgren & Rejmanek (SR: Stohlgren TJ, Rejmanek M. 2014 Biol. Lett. 10. (doi:10.1098/rsbl.2013.0939)) purported to test the generality of a recent finding of scale-dependent effects of invasive plants on native diversity; dominant invasive plants decreased the intercept and increased the slope of the species-area relationship. SR (2014) find little correlation between invasive species cover and the slopes and intercepts of SARs across a diversity of sites. We show that the analyses of SR (2014) are inappropriate because of confounding causality. PMID- 26246333 TI - A blueprint for vocal learning: auditory predispositions from brains to genomes. AB - Memorizing and producing complex strings of sound are requirements for spoken human language. We share these behaviours with likely more than 4000 species of songbirds, making birds our primary model for studying the cognitive basis of vocal learning and, more generally, an important model for how memories are encoded in the brain. In songbirds, as in humans, the sounds that a juvenile learns later in life depend on auditory memories formed early in development. Experiments on a wide variety of songbird species suggest that the formation and lability of these auditory memories, in turn, depend on auditory predispositions that stimulate learning when a juvenile hears relevant, species-typical sounds. We review evidence that variation in key features of these auditory predispositions are determined by variation in genes underlying the development of the auditory system. We argue that increased investigation of the neuronal basis of auditory predispositions expressed early in life in combination with modern comparative genomic approaches may provide insights into the evolution of vocal learning. PMID- 26246334 TI - A global synthesis of survival estimates for microbats. AB - Accurate survival estimates are needed to construct robust population models, which are a powerful tool for understanding and predicting the fates of species under scenarios of environmental change. Microbats make up 17% of the global mammalian fauna, yet the processes that drive differences in demographics between species are poorly understood. We collected survival estimates for 44 microbat species from the literature and constructed a model to determine the effects of reproductive, feeding and demographic traits on survival. Our trait-based model indicated that bat species which produce more young per year exhibit lower apparent annual survival, as do males and juveniles compared with females and adults, respectively. Using 8 years of monitoring data for two Australian species, we demonstrate how knowledge about the effect of traits on survival can be incorporated into Bayesian survival analyses. This approach can be applied to any group and is not restricted to bats or even mammals. The incorporation of informative priors based on traits can allow for more timely construction of population models to support management decisions and actions. PMID- 26246335 TI - Scale-dependent impacts of invasive species: a reply to Chase et al. (2015). PMID- 26246336 TI - Naturally segregating loci exhibit epistasis for fitness. AB - The extent to which gene interaction or epistasis contributes to fitness variation within populations remains poorly understood, despite its importance to a myriad of evolutionary questions. Here, we report a multi-year field study estimating fitness of Mimulus guttatus genetic lines in which pairs of naturally segregating loci exist in an otherwise uniform background. An allele at QTL x5b-a locus originally mapped for its effect on flower size-positively affects survival if combined with one genotype at quantitative trait locus x10a (aa) but has negative effects when combined with the other genotypes (Aa and AA). The viability differences between genotypes parallel phenotypic differences for the time and node at which a plant flowers. Viability is negatively correlated with fecundity across genotypes, indicating antagonistic pleiotropy for fitness components. This trade-off reduces the genetic variance for total fitness relative to the individual fitness components and thus may serve to maintain variation. Additionally, we find that the effects of each locus and their interaction often vary with the environment. PMID- 26246337 TI - A call for full annual cycle research in animal ecology. AB - For vertebrates, annual cycles are organized into a series of breeding and non breeding periods that vary in duration and location but are inextricably linked biologically. Here, we show that our understanding of the fundamental ecology of four vertebrate classes has been limited by a severe breeding season research bias and that studies of individual and population-level responses to natural and anthropogenic change would benefit from a full annual cycle perspective. Recent emergence of new analytical and technological tools for studying individual and population-level animal movement could help reverse this bias. To improve understanding of species biology and reverse the population declines of many vertebrate species, a concerted effort to move beyond single season research is vital. PMID- 26246338 TI - Ten years and counting. PMID- 26246339 TI - Evaluation of Tp-E Interval and Tp-E/QT Ratio in Patients with Aortic Stenosis. AB - BACKGROUND: The risk of syncope and sudden cardiac death due to ventricular arrhythmias increased in patients with aortic stenosis (AS). Recently, it was shown that Tp-e interval, Tp-e/QT, and Tp-e/QTc ratio can be novel indicators for prediction of ventricular arrhythmias and mortality. We aimed to investigate the association between AS and ventricular repolarization using Tp-e interval and Tp e/QT ratio. METHODS: Totally, 105 patients with AS and 60 control subjects were enrolled to this study. The severity of AS was defined by transthoracic echocardiographic examination. Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios were measured from the 12-lead electrocardiogram. RESULTS: Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios were significantly increased in parallel to the severity of AS (P < 0.001, P = 0.001, and P = 0.001, respectively). Also, it was shown that Tp e/QTc ratio had significant positive correlation with mean aortic gradient (r = 0.192, P = 0.049). In multivariate logistic regression analysis, Tp-e/QTc ratio and left ventricular mass were found to be independent predictors of severe AS (P = 0.03 and P = 0.04, respectively). CONCLUSIONS: Our study showed that Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios were increased in patients with severe AS. Tp-e/QTc ratio and left ventricular mass were found as independent predictors of severe AS. PMID- 26246340 TI - The SAMe-TT2R2 score and quality of anticoagulation in AF: Can we predict which patient benefits from anticoagulation? PMID- 26246343 TI - Importance of the ultrasound in cubital tunnel syndrome. AB - We report a case of a patient with cubital tunnel syndrome caused by presence of a non-thrombotic vein in the cubital tunnel. Cubital tunnel syndrome is a symptom complex caused by the compression of the ulnar nerve at the elbow. It is the second most common peripheral compression neuropathy. Ulnar compression at the elbow can be clinically diagnosed; however, an electroneurographic examination is necessary to confirm the diagnosis. Sonography and MRI may be required to locate nerve lesions, but primarily to evaluate the causes of compression. We decided to report this case because it shows the importance of the ultrasound in the diagnosis of the cause of compressions, including those rare and unexpected. PMID- 26246341 TI - Anatomic basis and clinical application of the distally based medialis pedis flaps. AB - BACKGROUND: Soft-tissue defects of the forefoot are difficult to cover adequately, particularly, although multiple options for reconstruction are available. This study especially focused on the vascularization of the medial side of the foot and the determination of the contribution of the nutrient vessels to medialis pedis flap viability. METHODS: Thirty cadavers were available for this anatomical study. Microdissection was conducted under a microscope, and details of the course and distribution and the communication of the first plantar metatarsal artery with the fascial vascular network of the medial side of the foot were recorded. Clinically, six cases of soft-tissue defects at the forefoot region were reconstructed with distally based medialis pedis flap. RESULTS: The perforator of the first plantar metatarsal artery pierces in the superficial fascia of the medial aspect of the foot 2.2 +/- 0.7 cm proximal to the first metatarsophalangeal joint, vascularize the skin of the medial plantar region. The anatomical study showed that the vasculature pattern could roughly be classified into two types. In terms of clinical application, all flaps completely survived, and one patient had partial loss of skin graft. CONCLUSION: The perforators of the medialis pedis flap are presented constant. The forefoot region can be repaired by the distally based medialis pedis flap on the perforator of the medial plantar artery of the hallux or the first plantar metatarsal artery perforator with medial plantar vein, medial plantar cutaneous nerve and nutrient vessels. PMID- 26246342 TI - The meniscal insertion of the knee anterolateral ligament. AB - PURPOSE: The aim of this study is to characterize in detail the meniscal insertion of the anterolateral ligament (ALL) of the knee, establishing parameters regarding the circumference of the lateral meniscus and the popliteal muscle tendon (PMT) groove in addition to its histological analysis. METHODS: A total of 33 knees of cadavers were dissected. The ALL and the lateral meniscus were removed en bloc. After removal of the anatomical specimen, the meniscus circumference, the ALL insertion points on the external surface of the lateral meniscus, and the PMT groove were measured. Eight menisci were subjected to histological analysis. RESULTS: The ALL was found in all dissections performed. The ALL insertion occurred macroscopically in the transition between the anterior horn and the lateral meniscus body, specifically beginning at 36.0% and ending at 41.9% of the meniscal circumference, occupying a mean area of 5.6 mm. The distance between the end of the ALL meniscal insertion and the beginning of the PMT groove averaged 12.9 mm. In the histological evaluation, in longitudinal sections, we observed dense collagen fibers of the ligament inserting on the external surface of the meniscus. It is possible to observe a spreading of collagen fibers at the moment of meniscal insertion. CONCLUSIONS: The ALL meniscal insertion was found in all dissected specimens, beginning with approximately 36% of the meniscal outer diameter, 12.9 mm anterior to the beginning of the PMT groove. The histological analysis confirmed the presence of true ligamentous tissue in the dissected specimens. PMID- 26246344 TI - Influence of medical student career aims on ophthalmic surgical simulator performance (part of the international forum for ophthalmic simulation studies). AB - BACKGROUND: To evaluate whether medical students who have expressed a strong desire to pursue ophthalmology as a career perform simulated ophthalmic surgical tasks to a higher level than medical students whose interests lie elsewhere. METHODS: All participants were fourth or fifth year students at University College London (UCL) Medical School, London, UK. One cohort was recruited from the Moorfields Academy, an ophthalmic forum designed to enhance collaboration and innovation within the specialty. These students were therefore seen as highly motivated, expressing a desire to pursue a career in ophthalmology. The other cohort of students was invited to participate during their fourth year UCL Ophthalmology attachment, but expressed interest in non-ophthalmic disciplines. Participants carried out a single attempt of three modules on the Eyesi Surgical Simulator, and total and mean scores were calculated out of 100. RESULTS: 13 academy and 15 non-academy students were enrolled. The overall mean scores were 51/100 for the academy group, range 0-97, and 45.5/100 for the non-academy group, range 0-90 (p=0.49). Scores for precision testing, forceps training and capsulorrhexis training for academy versus non-academy were 45.8 versus 37.8 (p=0.61), 57.1 versus 52.3 (p=0.8) and 50.2 versus 46.4 (p=0.55), respectively. CONCLUSIONS: This study is the first to suggest that medical students with a strong career interest in ophthalmology do not perform microsurgical tasks to a higher level than medical students who have no goal in this area. This also indicates variation in scores between novices, which may serve as a pitfall in the use of simulators as a tool for entry into training. PMID- 26246345 TI - Atrial and ventricular tachyarrhythmias in military personnel. AB - Although rare, sudden cardiac death does occur in British military personnel. In the majority of cases, the cause is considered to be a malignant ventricular tachyarrhythmia, which can be precipitated by a number of underlying pathologies. Conversely, a tachyarrhythmia may have a more benign and treatable cause, yet the initial clinical symptoms may be similar, making differentiation difficult. This is an overview of the mechanisms underlying the initiation and propagation of arrhythmias and the various pathological conditions that predispose to arrhythmia genesis, classified according to which parts of the heart are involved: atrial tachyarrhythmias, atrial and ventricular, as well as those affecting the ventricles alone. It encompasses atrial tachycardia, atrial flutter, supraventricular tachycardias and ventricular tachycardias, including the more commonly encountered inherited primary electrical diseases, also known as the channelopathies. The clinical features, investigation and management strategies are outlined. The occupational impact-in serving military personnel and potential recruits-is described, with explanations relating to the different conditions and their specific implication on continued military service. PMID- 26246346 TI - Managing the military patient with syncope. AB - Syncope is a relatively common occurrence in military populations. It is defined as a transient loss of consciousness due to global cerebral hypoperfusion, characterised by a rapid onset, short duration and a spontaneous and complete recovery. While the symptom of syncope is easily elicited, discovering the mechanism can be more problematic and may require a plethora of diagnostic tests. The aim of this paper is to review current evidence pertaining to the classification, investigation and management of syncope, from a military perspective. Emphasis is placed on assisting primary healthcare professionals in the assessment and management of syncope, in the UK and on operations, while providing explicit guidance on risk. The occupational limitations required in safely managing patients with syncope are stressed along with the potential long term limitations. PMID- 26246347 TI - Coronary artery disease in the military patient. AB - Ischaemic heart disease is the most common cause of sudden death in the UK, and the most common cardiac cause of medical discharge from the Armed Forces. This paper reviews current evidence pertaining to the diagnosis and management of coronary artery disease from a military perspective, encompassing stable angina and acute coronary syndromes. Emphasis is placed on the limitations inherent in the management of acute coronary syndromes in the deployed environment. Occupational issues affecting patients with coronary artery disease are reviewed. Consideration is also given to the potential for coronary artery disease screening in the military, and the management of modifiable cardiovascular disease risk factors, to help decrease the prevalence of coronary artery disease in the military population. PMID- 26246348 TI - Deep vein thrombosis and pulmonary embolism in the military patient. AB - OBJECTIVES: Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, is a common, potentially lethal condition and a cause of long term morbidity and functional limitation. This paper is a clinical review focused on military epidemiology, evidence-based recommendations for prevention, diagnosis and management of VTE and occupational considerations in a military population. METHODS: A literature review was conducted through Pubmed and Embase for systematic reviews, meta-analyses and clinical trials relating to VTE. Guidelines from the National Institute for Health and Care Excellence, British Thoracic Society and the American College of Chest Physicians were reviewed and recommendations considered. RESULTS: Acute morbidity from VTE can range from limb pain and swelling to life-threatening cardiovascular compromise. Long-term sequelae include postthrombotic syndrome, chronic thrombosis and pulmonary hypertension. Diagnosis should follow a validated pathway depending on the patient's prerest probability. The management of the condition should vary with attention to risk stratification. DISCUSSION: Prompt initiation of anticoagulation reduces symptoms, rates of recurrent VTE and death but treatment must be balanced against the risk of major haemorrhage. Military operations expose personnel to a unique combination of risk factors for VTE and operating in austere environments can increase the challenge of diagnosis, prognostication and management. Furthermore, there are implications for troop attrition, operational readiness and return to work. PMID- 26246349 TI - Cardiomyopathies and the Armed Forces. AB - Cardiomyopathies are a group of heterogeneous myocardial diseases that are frequently inherited and are a recognised cause of premature sudden cardiac death in young individuals. Incomplete expressions of disease and the overlap with the physiological cardiac manifestations of regular intensive exercise create diagnostic challenges in young athletes and military recruits. Early identification is important because sudden death in the absence of prodromal symptoms is a common presentation, and there are several therapeutic strategies to minimise this risk. This paper examines the classification and clinical features of cardiomyopathies with specific reference to a military population and provides a detailed account of the optimum strategy for diagnosis, indications for specialist referral and specific guidance on the occupational significance of cardiomyopathy. A 27-year-old Lance Corporal Signaller presents to his Regimental medical officer (RMO) after feeling 'light-headed' following an 8 mile unloaded run. While waiting to see the RMO, the medical sergeant records a 12-lead ECG. The ECG is reviewed by the RMO immediately prior to the consultation and shows voltage criteria for left ventricular (LV) hypertrophy and inverted T-waves in II, III, aVF and V1-V3 (Figure 1). This Lance Corporal is a unit physical training instructor and engages in >10 h of aerobic exercise per week. He is a non-smoker and does not have any significant medical history. PMID- 26246350 TI - Myocarditis and the military patient. AB - Myocarditis, simply defined as inflammation of the heart muscle, is a commonly encountered cardiac disease in primary and secondary care, both in the UK and on Operational deployments. In the UK Armed Forces, myocarditis results in deaths as well as the premature termination of military careers on medical grounds. The aetiology is usually the result of a number of infectious aetiologies with viruses being the most common pathogens in the vast majority of cases. However, it may also be the result of autoimmune activation, chemical or pharmacological toxins, environmental insult or hypersensitivity reactions. Particular aetiologies that are more likely to be seen in a military population are discussed and include certain infections, smallpox vaccine, and hyperthermia and hypothermia. The clinical features can be highly variable ranging from an asymptomatic infection to fulminant heart failure. Features pertinent to the military doctor, including the natural history, investigative modalities and management strategies, with a particular emphasis on the occupational impact of myocarditis in the UK Armed Forces are reviewed. PMID- 26246351 TI - Atrial fibrillation in the military patient: a review. AB - Atrial fibrillation (AF) is the most common sustained atrial arrhythmia, and increases an individual's risk of morbidity and mortality from cardiovascular and thromboembolic events. In this article, we review the pathophysiology and clinical presentations of AF and describe appropriate investigations and management likely to be appropriate for a military population, in line with current National Institute for Health and Care Excellence and European Society of Cardiology guidelines. The implications for the individual's Medical Employment Standard in the UK Armed Forces, with specific reference to specific military occupational activities such as aviation, diving and driving occupationally, are also reviewed. PMID- 26246352 TI - Dyslipidaemia and the military patient. AB - Dyslipidaemias refer to abnormal levels of circulating lipids and high cholesterol and is related to cardiovascular death. This paper examines the types and prevalence of dyslipidaemia with specific reference to a military population and describes who to target in screening strategies used to detect people with abnormal lipid profiles. The diagnostic limits for a diagnosis of dyslipidaemia are explored. Finally, medical management of hyperlipidaemia is discussed and how this may affect military medical grading. PMID- 26246354 TI - Correcting for Sample Heterogeneity in Methylome-Wide Association Studies. AB - Epigenome-wide association studies (EWAS) face many of the same challenges as genome-wide association studies (GWAS), but have an added challenge in that the epigenome can vary dramatically across cell types. When cell-type composition differs between cases and controls, this leads to spurious associations that may obscure true associations. We have developed a computational method, FaST-LMM EWASher, which automatically corrects for cell-type composition without needing explicit knowledge of it. In this chapter, we provide a tutorial on using FaST LMM-EWASher for DNA methylation data and discuss data analysis strategies. PMID- 26246353 TI - Sendai Virus-Based Reprogramming of Mesenchymal Stromal/Stem Cells from Umbilical Cord Wharton's Jelly into Induced Pluripotent Stem Cells. AB - In an attempt to bring pluripotent stem cell biology closer to reaching its full potential, many groups have focused on improving reprogramming protocols over the past several years. The episomal modified Sendai virus-based vector has emerged as one of the most practical ones. Here we describe reprogramming of mesenchymal stromal/stem cells (MSC) derived from umbilical cord Wharton's Jelly into induced pluripotent stem cells (iPSC) using genome non-integrating Sendai virus-based vectors. The detailed protocols of iPSC colony cryopreservation (vitrification) and adaption to feeder-free culture conditions are also included. PMID- 26246355 TI - The Design and Optimization of DNA Methylation Pyrosequencing Assays Targeting Region-Specific Repeat Elements. AB - Epigenetic modifications, such as DNA methylation, can contribute to gene regulation and chromosomal stability. There are several methods and techniques available for methylation analysis, ranging from global methylation to gene specific targeted regions. Bisulfite conversion enables numerous methodologies to be used for downstream applications, including pyrosequencing which measures DNA methylation at an individual CpG site level. This allows specific regions of interest to be targeted for DNA methylation analysis. Designing and optimizing pyrosequencing assays correctly is vital for the interpretation of results.Dysregulation of DNA methylation has been implicated in human diseases, with regions such as repeat elements commonly altered. Human population studies investigating these tend to use consensus sequences to target repeat elements. However, these elements have high mutational rates, particularly Alu sequences, which could lead to assay bias and masking of changes at a regional level. Therefore, it may be more beneficial to target specific repeat elements depending upon their chromosomal location, rather than analyzing overall methylation levels. PMID- 26246356 TI - Neurological patients and their lower limb orthotics: An observational pilot study about acceptance and satisfaction. AB - BACKGROUND: Although an orthotic device of the lower limb improves the functionality of neurological patients, anecdotally clinical experience suggests that the compliance is rather limited. OBJECTIVES: The aim was to determine the satisfaction and acceptance of a lower limb orthotic device. STUDY DESIGN: A qualitative observational pilot study with a mix-method design. METHODS: Adult neurological patients who had a prescribed lower limb orthotic device were included. One published and clinically used questionnaire about satisfaction (D Quest) and one ad hoc constructed questionnaire about acceptance of the orthotic device (MIRAD-ACCORT questionnaire) were used for data collection. RESULTS: In total, 33 patients participated (28 ankle-foot orthotic device, 3 knee-ankle-foot orthotic device and 2 other types). In general, they were satisfied about their orthotic device and the services. Less than one-fourth of the patients had some negative comments about the 'visual aspects' and the 'ability to hide' of their orthotic device. These, however, had a lower priority when compared with functionality, which was reported as a main advantage and is a reason for continuing the use of their orthotic device. CONCLUSION: Patients were satisfied in relation to their lower limb orthotic device. With regard to acceptance, it can be concluded that factors associated with functionality and comfort are more important than the aesthetic and psychological aspects of the orthotic device. Clinical relevance Patients were satisfied with their lower limb orthotic device. Some patients had some negative comments about the 'aesthetics aspects' and the 'ability to hide' their orthotic device. However, improvements in functionality were mostly reported as a main advantage and a reason for continuing the use of their orthotic device. PMID- 26246358 TI - The evaporation behavior of sessile droplets from aqueous saline solutions. AB - Quantitative experiments on the evaporation from sessile droplets of aqueous saline (NaCl) solutions show a strong dependence on salt concentration and droplet shape. The experiments were performed with seven decades of initial NaCl concentrations, with various droplet sizes and with different contact angles. The evaporation rate is significantly lower for high salt concentrations and small contact angles than what is expected from the well-accepted diffusion-controlled evaporation scenario for sessile droplets, even if the change of the vapor pressure due to the salt is taken into account. Particle tracking velocimetry reveals that this modification of the evaporation behavior is caused by marangoni flows that are induced by surface tension gradients originating from the local evaporative peripheral salt enrichment. In addition it is found that already very low salt concentrations lead to a pinning of the three phase contact line. Whereas droplets with concentration >=10(-6) M NaCl are pinned as soon as evaporation starts, droplets with lower salt concentration do evaporate in a constant contact angle mode. Aside from new, fundamental insights the findings are also relevant for a better understanding of the widespread phenomenon of corrosion initiated by sessile droplets. PMID- 26246357 TI - Blood brain barrier impairment is associated with cerebrospinal fluid markers of neuronal damage in HIV-positive patients. AB - Blood brain barrier impairment occurs early in the course of infection by HIV and it may persist in a subset of patients despite effective antiretroviral treatment. We tested the hypothesis that HIV-positive patients with dysfunctional blood brain barrier may have altered biomarkers of neuronal damage. In adult HIV positive highly active antiretroviral treatment (HAART)-treated patients (without central nervous system infections and undergoing lumbar punctures for clinical reasons) cerebrospinal fluid albumin to serum ratios (CSAR), total tau, phosphorylated tau, 1-42 beta amyloid, and neopterin were measured. In 101 adult patients, cerebrospinal fluid-to-serum albumin ratios were 4.8 (3.7-6.1) with 12 patients (11.9%) presenting age-defined impaired blood brain barrier. A significant correlation was observed between CSAR and total tau (p = 0.005), phosphorylated tau (p = 0.008), and 1-42 beta amyloid (p = 0.040). Patients with impaired blood brain barrier showed significantly higher total tau (201.6 vs. 87.3 pg/mL, p = 0.010), phosphorylated tau (35.3 vs. 32.1 ng/mL, p = 0.035), and 1-42 beta amyloid (1134 vs. 830 pg/mL, p = 0.045). Despite effective antiretroviral treatment, blood brain barrier impairment persists in some HIV positive patients: it is associated with markers of neuronal damage and it was not associated with CSF neopterin concentrations. PMID- 26246359 TI - Is it time to leave the family? Comment on the editorial by Gladman. PMID- 26246360 TI - Surgical excision for non-familial hypertrophic Darier's disease. PMID- 26246361 TI - Photoacoustic and photothermal cytometry using photoswitchable proteins and nanoparticles with ultrasharp resonances. AB - In the article by E. I. Galanzha et al. (doi: http://dx.doi.org/10.1002/jbio.201300140), published in J. Biophotonics 8, 81-93 (2015), the Conflict of Interest statement is missing. This erratum is published to correct this. PMID- 26246365 TI - Latency of auditory evoked potential monitoring the effects of general anesthetics on nerve fibers and synapses. AB - Auditory evoked potential (AEP) is an effective index for the effects of general anesthetics. However, it's unknown if AEP can differentiate the effects of general anesthetics on nerve fibers and synapses. Presently, we investigated AEP latency and amplitude changes to different acoustic intensities during pentobarbital anesthesia. Latency more regularly changed than amplitude during anesthesia. AEP Latency monotonically decreased with acoustic intensity increase (i.e., latency-intensity curve) and could be fitted to an exponential decay equation, which showed two components, the theoretical minimum latency and stimulus-dependent delay. From the latency-intensity curves, the changes of these two components (?L and ?I) were extracted during anesthesia. ?L and ?I monitored the effect of pentobarbital on nerve fibers and synapses. Pentobarbital can induce anesthesia, and two side effects, hypoxemia and hypothermia. The hypoxemia was not related with ?L and ?I. However, ?L was changed by the hypothermia, whereas ?I was changed by the hypothermia and anesthesia. Therefore, we conclude that, AEP latency is superior to amplitude for the effects of general anesthetics, ?L monitors the effect of hypothermia on nerve fibers, and ?I monitors a combined effect of anesthesia and hypothermia on synapses. When eliminating the temperature factor, ?I monitors the anesthesia effect on synapses. PMID- 26246366 TI - Concordance of absolute and relative plasma volume changes and stability of Fcells in routine hemodialysis. AB - Central hematocrit (H) measurements are currently used to track the degree of ultrafiltration-induced hemoconcentration with the aim to detect and prevent excessive intravascular fluid depletion during hemodialysis (HD). Failure to maintain hemodynamic stability is commonly attributed to the misinterpretation of H caused by an unaccountable increase in Fcells , the ratio of whole-body hematocrit to H. It was the aim to examine Fcells under everyday conditions in a group of stable HD patients. Absolute plasma volume (Vp ) and H were concomitantly measured during routine HD in the extracorporeal system in hourly intervals by noninvasive and continuous technology (CritLine-Instrument-III) and indocyanine green dye dilution to derive relative plasma volumes from Vp and H (RPVp , RPVH ), respectively, and to calculate Fcells . Thirteen patients were studied during two midweek treatments (n = 26). Both absolute Vp (P < 0.05) and relative plasma volumes RPVH (P < 0.001) decreased during HD. Vp at any time point was positively correlated to RPVH (r = 0.52). Moreover, relative plasma volumes RPVH and RPVp determined by independent techniques were identical and showed negligible bias (-0.2%) but considerable limits of agreement (-15.6% to +15.3%). Fcells was stable and in the range of 0.9 +/- 0.05 throughout HD and not different from the value assumed at the beginning of HD. Although Fcells remains constant in patients on routine dialysis and relative plasma volumes (RPVH and RPVp ) determined by independent techniques are therefore comparable, the variability of experimental conditions during dialysis and the limited accuracy of absolute volume measurements using available technology continues to complicate the ultrafiltration control problem. PMID- 26246367 TI - The association between metabolic syndrome and the risk of urothelial carcinoma of the bladder: a case-control study in China. AB - BACKGROUND: Evidence of the association of metabolic syndrome (MetS) with cancer risk is accumulating. However, uncertainties still exist as to the link of MetS with bladder cancer. This study aimed to assess the relationship between MetS and the risk of urothelial carcinoma of the bladder (UC) in a Chinese population. METHODS: We retrospectively analyzed clinicopathological data of 972 newly diagnosed UC patients and 1098 cancer-free controls matched to the cases by age and gender. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression in both unadjusted and adjusted models. RESULTS: MetS was not significantly associated with the overall UC risk (p=0.08). However, a significant association of MetS with UC was observed in female patients (p=0.006). Diabetes mellitus (crude OR 1.339, 95% CI 1.079-1.662, p=0.008; adjusted OR 1.767, 95% CI 1.308-2.386, p<0.001) and hypertriglyceridemia (crude OR 1.245, 95% CI 1.018-1.522, p=0.033; adjusted OR 1.254, 95% CI 1.020 1.542, p=0.032) were significantly associated with UC risk. As the number of MetS components increased, the UC risk was elevated. Having three or more (versus zero) components of MetS was significantly related to risk of overall UC (OR 1.315; 95% CI 1.006-1.719; p=0.045) and non-muscle invasive bladder cancer (OR 1.354; 95% CI 1.019-1.798; p=0.037). CONCLUSIONS: The present study indicated a marginal association between MetS and UC risk, and a significant association with UC risk in female patients. The results need to be evaluated in large-scale prospective cohorts. PMID- 26246368 TI - "First Stop Dying". AB - This article offers an ethnographic account of the "self-projects" of inmate graduates of Louisiana State Penitentiary's (aka "Angola's") unique prison seminary program. Angola's Inmate Minister program deploys seminary graduates in bivocational pastoral service roles throughout America's largest maximum-security prison. Drawing upon the unique history of Angola, inmates establish their own churches and serve in lay-ministry capacities in hospice, cellblock visitation, tier ministry, officiating inmate funerals, and through tithing with "care packages" for indigent prisoners. Four themes of positive criminology prominently emerge from inmate narratives: (a) the importance of respectful treatment of inmates by correctional administrations, (b) the value of building trusting relationships for prosocial modeling and improved self-perception, PMID- 26246369 TI - Reframing Serial Murder Within Empirical Research. AB - Empirical research on serial murder is limited due to the lack of consensus on a definition, the continued use of primarily descriptive statistics, and linkage to popular culture depictions. These limitations also inhibit our understanding of these offenders and affect credibility in the field of research. Therefore, this comprehensive overview of a sample of 508 cases (738 total offenders, including partnered groups of two or more offenders) provides analyses of solo male, solo female, and partnered serial killers to elucidate statistical differences and similarities in offending and adjudication patterns among the three groups. This analysis of serial homicide offenders not only supports previous research on offending patterns present in the serial homicide literature but also reveals that empirically based analyses can enhance our understanding beyond traditional case studies and descriptive statistics. Further research based on these empirical analyses can aid in the development of more accurate classifications and definitions of serial murderers. PMID- 26246370 TI - Women's Health in Queensland Prisons. AB - Internationally, best practice for prison health care recommends transferring health service provision from corrections to health authorities. Although it is expected that this change will result in improved health care, there is little evidence of evaluation. This article used qualitative interviews with health service providers to gain insight into the health needs of women's prisons in Queensland, Australia, both prior to and after the transition in health care service provision. We found that service providers identified that problems persisted regardless of service provider and that improvement required increased resources and more fundamental structural changes within prison environments. PMID- 26246371 TI - Functional implications of the interaction between HscB and IscU in the biosynthesis of FeS clusters. AB - In bacteria, HscB is the cochaperone of HscA in modulating the transfer of 2Fe2S clusters from a cluster-loaded form of the scaffold protein IscU to acceptor apoproteins. HscB binding to the IscU apoform (apoIscU) reportedly impairs the structural flexibility of apoIscU, but the effects of HscB on cluster formation on IscU have never been assessed. We report that presence of HscB impaired the rate-but not the equilibrium-of the appearance of the distinctive circular dichroism signals associated with formation of a stable 2Fe-2S cluster on IscU in reconstitution experiments. This impairment: (1) was independent of the source of cluster sulfide; (2) was not observed for HscB mutants unable to bind IscU; (3) implied formation of a 1/1 HscB/IscU complex; (4) was not observed for a D39A mutant of IscU, with a much more rigid structure than wt IscU. The cluster species assembled on IscU in the presence of HscB were transferred to apoferredoxin at a slower rate than those formed in the absence of HscB, unless ATP and HscA were also present. At contrast, HscB was found to improve the "catalytic" function of IscU with respect to cluster assembly in the presence of a large apoferredoxin excess. Thus, the HscB/IscU interaction may modulate formation and transfer of FeS clusters by accelerating cluster biosynthesis when appropriate target apoproteins are abundant or by slowing it down when the rate of apoprotein synthesis is slow, and cluster-loaded IscU is more likely to play a role as a "FeS storage" protein. PMID- 26246372 TI - Mechanistic information on the nitrite-controlled reduction of aquacob(III)alamin by ascorbate at physiological pH. AB - The interaction with nitric oxide (NO) is an important aspect of the biological activity of vitamin B12 (Cbl). Whereas the formation of nitroxylcobalamin (CblNO) via the binding of NO to reduced CblCo(II) has been studied in detail before, the possible intracellular formation of CblNO via reduction of nitrocobalamin (CblNO2) is still questionable. To study this further, spectroscopic and kinetic studies on the reaction of CblNO2 with the intracellular antioxidant ascorbic acid (Asc) were performed in aqueous solution at the physiological pH of 7.2. It was found that the redox pathway of this reaction requires anaerobic conditions as a result of the rapid re-oxidation of reduced CblCo(II). In the studied system, both CblOH2 and CblNO2 are reduced to CblCo(II) by ascorbate at pH 7.2, the CblOH2 complex being two orders of magnitude more reactive than CblNO2. Clear evidence for redox cycling between CblOH2/CblNO2 and CblCo(II) under aerobic conditions was observed as an induction period during which all oxygen was used prior to the formation of CblCo(II) in the presence of an excess of ascorbate. No evidence for the intermediate formation of CblNO or NO radicals during the reduction of CblNO2 could be found. Nitrocob(III)alamin can be reduced by ascorbic acid under physiological conditions. The products of the reaction are cob(II)alamin and nitrite ion. This reaction is ca. 200 times slower than the one involving aquacob(III)alamin. PMID- 26246373 TI - Erratum to: Medicines availability for non-communicable diseases: the case for standardized monitoring. PMID- 26246375 TI - Time scales for drainage and imbibition in gellified foams: application to decontamination processes. AB - We probe the drainage and imbibition dynamics of foams in which the continuous aqueous phase is a transient gel-like network. To produce these foams, we provide a new method - a PVA (polyvinyl alcohol) solution is first foamed and then a cross-linker, Borax, is added, which binds reversibly to the PVA chains. The resulting foams are ultra-stable-over a month. We find that the typical time for gravitational drainage of the continuous phase can be slowed down from hours to several weeks by tuning the Borax concentration. We show that the Borax concentration controls both the bulk viscosity of the continuous phase and the surface viscosity of the air-water interfaces. From these results we suggest that the PVA molecules adsorbed at the bubble interfaces are highly cross-linked by the Borax molecules. We find that the capillary rise of a dyed liquid into these foams is orders of magnitude faster than the drainage flow, meaning that these foams can quickly absorb liquids. These results show that these foams could be used to clean or decontaminate surfaces covered with liquid wastes. Indeed we show that the PVA-Borax foam can easily be spread on a surface, absorb a liquid without destabilizing and be dried afterward to recover the waste. PMID- 26246374 TI - Study of the snail intermediate hosts of urogenital schistosomiasis in Niakhar, region of Fatick, West central Senegal. AB - BACKGROUND: Schistosoma haematobium is the most widespread schistosome species in Senegal and occurs in several regions of the country especially in the Sudan Sahelian zone. The aims of the study were i) to determine the freshwater species ii) to ascertain the role of the identified snail species in the transmission of S. haematobium and iii) to study the impact of drought on the snails. METHODS: Snails were sampled each year in 17 sites from July to November-December 2012 and 2013. At each snail survey, snails were grouped by village, counted, identified according to shell morphology and the rates of schistosome cercarial shedding recorded. The shell height of the snails collected in July was measured and classified into four groups according to their size in order to determine those that are open to aestivation. RESULTS: B. senegalensis and B. umbilicatus were the only snails intermediate hosts collected in the Niakhar study area. B. senegalensis is found in all the 17 sampling sites while B. umbilicatus was only found in one site out of the many surveyed. The total number of B. senegalensis collected in 2012 and 2013 was 1032 and 8261 respectively. A total of 901 and 6432 B. senegalensis were tested for Schistosoma spp. infestation in 2012 and 2013 respectively. For B. umbilicatus, 58 snails were collected and tested in 2012. In 2013, 290 were collected and 281 tested. The overall rates of schistosome cercarial shedding were 0% in 2012 and 0.12% in 2013 for B. senegalensis and 13.79 and 4.98% in 2012 and 2013 respectively for B. umbilicatus. For both species collected in July, size group 3 individuals (7-9.9 mm) were the most numerous, 63.6 and 57.8% for B. senegalensis and B. umbilicatus respectively. B. umbilicatus was reported for the first time in the region of Fatick located in the old ecological zone of Sine-Saloum, is able to maintain Schistosoma spp. larvae during 7 months of drought and may transmit the disease in early July, increasing the period and the risk of transmission. CONCLUSION: This study recommends an adaptation of snail control strategies at pond cycles and ecology of the snails in these seasonal foci. Malacological control strategies must take into account these phenomena of drought resistance and the capacity of some snails to maintain parasite during aestivation. The treatment of ponds with Bayluscide at the end of the rainy season in November and upon onset of rains in July would be more advantageous to the control of snails thereby reducing transmission of urogenital schistosomiasis in the Niakhar area. PMID- 26246376 TI - Quality controls. AB - Some steroid drugs are designed for clinical use to combat muscle-wasting diseases, but are also used by athletes to improve their performance by increasing muscle strength or endurance. This study investigated the effect of one steroid drug on the number of times a weight could be lifted by healthy male subjects as a measure of endurance. The ratio of number of lifts performed with a steroid-injected arm versus a sham-injected control arm increased with the drug dose; the authors therefore concluded that the drug improved endurance. PMID- 26246377 TI - Early symptoms of Alzheimer's disease in Japan and Taiwan. AB - AIM: The effects of Alzheimer's disease (AD) are making a major impact on the socioeconomic status of older adults in society. The recognition of early symptoms and clinical presentation are crucial issues to foster early diagnosis and treatment in order to have better therapeutic outcomes. METHODS: We recruited clinically diagnosed AD patients at the very mild stage in the Clinical Dementia Rating scale 0.5 and mild stage Clinical Dementia Rating scale 1.0 in Taiwan and Japan. Psychometrics including the Ascertain Dementia 8 (AD8) questionnaire were administered to collect and compare the differences of the clinical presentation of the participants from the two countries. RESULTS: A total of 1189 participants, 641 from Taiwan and 548 from Japan, were recruited in the present study. In the very mild dementia group with Clinical Dementia Rating scale 0.5, apart from AD8-2: reduced interest in hobbies/activities (P = 0.056) and AD8-4: trouble learning how to use a tool, appliance or gadget (P = 0.224), other AD8 subitems were significantly different between the two countries. Japanese participants had a higher reported frequency of AD8-5: forgetting the correct month or year (82.7%) than that (57.9%) in Taiwanese (P < 0.001). Taiwanese participants had a higher reported frequency in AD8-1: problems with judgment (20.3%), AD8-3: repeats questions, stories or statements (67.5%), AD8-6: difficulty handling complicated financial affairs (32.5%); AD8-7: difficulty remembering appointments (53.8%); and AD8-8: consistent problems with thinking and/or memory (89.3%) than those in Japanese participants. CONCLUSION: Early symptoms of AD in both countries are different. The frequently reported early symptoms are important for primary physicians and the general population so that they can recognize the disease in the early stage so as to have a better therapeutic outcome. Such efforts would increase the awareness of dementia in the general population. Geriatr Gerontol Int 2016; 16: 797-803. PMID- 26246379 TI - Ex vivo expansion of hematopoietic stem cells. AB - Ex vivo expansion of hematopoietic stem cells (HSCs) would benefit clinical applications in several aspects, to improve patient survival, utilize cord blood stem cells for adult applications, and selectively propagate stem cell populations after genetic manipulation. In this review we summarize and discuss recent advances in the culture systems of mouse and human HSCs, which include stroma/HSC co-culture, continuous perfusion and fed-batch cultures, and those supplemented with extrinsic ligands, membrane transportable transcription factors, complement components, protein modification enzymes, metabolites, or small molecule chemicals. Some of the expansion systems have been tested in clinical trials. The optimal condition for ex vivo expansion of the primitive and functional human HSCs is still under development. An improved understanding of the mechanisms for HSC cell fate determination and the HSC culture characteristics will guide development of new strategies to overcome difficulties. In the future, development of a combination treatment regimen with agents that enhance self-renewal, block differentiation, and improve homing will be critical. Methods to enhance yields and lower cost during collection and processing should be employed. The employment of an efficient system for ex vivo expansion of HSCs will facilitate the further development of novel strategies for cell and gene therapies including genome editing. PMID- 26246381 TI - Diagnosis and Surgical Management of Congenital Laxity of the Fibularis Musculotendinous Unit Resulting in Hyperextension of the Tarsus in 14 Calves. AB - OBJECTIVE: To describe the diagnosis and surgical management of congenital laxity of the fibularis tendon resulting in hyperextension of the tarsus in calves. STUDY DESIGN: Case series. ANIMALS: Fourteen calves (3 unilateral, 11 bilateral) diagnosed with congenital tarsal instability caused by laxity of the fibularis musculotendinous unit resulting in hyperextension of the tarsus. METHODS: Diagnosis was made by clinical and radiologic assessments. The tarsus was surgically prepared and an incision made on the dorsal surface of the tarsus after intrathecal anesthesia with the calf sedated. A locking-loop suture (4 loops) was applied to the fibularis tendon using polyglactin 910. The free ends of the suture were then tied to the shank of a cortical bone screw inserted in the proximal metatarsus. RESULTS: The calves were evaluated on postoperative days 15, 30, and 60 and were walking normally. CONCLUSION: Congenital tarsal instability because of laxity of the fibularis musculotendoninous unit is described and surgical treatment directed at shortening the tendon shows promising results. PMID- 26246380 TI - Hydrogen sulfide suppresses transforming growth factor-beta1-induced differentiation of human cardiac fibroblasts into myofibroblasts. AB - In heart disease, transforming growth factor-beta1 (TGF-beta1) converts fibroblasts into myofibroblasts, which synthesize and secrete fibrillar type I and III collagens. The purpose of the present study was to investigate how hydrogen sulfide (H2S) suppresses TGF-beta1-induced differentiation of human cardiac fibroblasts to myofibroblasts. Human cardiac fibroblasts were serum starved in fibroblast medium for 16 h before exposure to TGF-beta1 (10 ng mL(-1)) for 24 h with or without sodium hydrosulfide (NaHS, 100 umol L(-1), 30 min pretreatment) treatment. NaHS, an exogenous H2S donor, potently inhibited the proliferation and migration of TGF-beta1-induced human cardiac fibroblasts and regulated their cell cycle progression. Furthermore, NaHS treatment led to suppression of fibroblast differentiation into myofibroblasts, and reduced the levels of collagen, TGF-beta1, and activated Smad3 in TGF-beta1-induced human cardiac fibroblasts in vitro. We therefore conclude that H2S suppresses TGF-beta1 stimulated conversion of fibroblasts to myofibroblasts by inhibiting the TGF beta1/Smad3 signaling pathway, as well as by inhibiting the proliferation, migration, and cell cycle progression of human cardiac myofibroblasts. These effects of H2S may play significant roles in cardiac remodeling associated with heart failure. PMID- 26246382 TI - Determinants of HIV, viral hepatitis and STI prevention needs among African migrants in Germany; a cross-sectional survey on knowledge, attitudes, behaviors and practices. AB - BACKGROUND: Migrants from sub-Saharan Africa (MisSA) are a relevant sub-group for HIV-transmission in Germany. A total of 10-15 % of all newly diagnosed cases are MisSA, and approximately one third acquired HIV in Germany. There is limited information on knowledge, attitudes, behaviors and practices (KABP) regarding sexual health in African communities residing in Germany. METHODS: From October December 2013 we conducted a cross-sectional survey on KABP regarding HIV, viral hepatitis (HEP), and sexually transmitted infections (STI) among MisSA in Hamburg as a community-based participatory research project to identify knowledge gaps, sexual risk behavior regarding HIV/HEP/STI, HIV/STI-testing history and attitudes toward people living with HIV (PLWH). Trained peer researchers recruited participants through outreach. Questionnaires in German, English or French were either administered face-to-face or self-completed. Questions on knowledge about HIV/HEP/STI presented true statements; participants were asked if they knew the information before. To detect differences in sub-groups, unadjusted odds ratios (OR) were calculated, and a multivariate analysis for knowledge on HIV/HEP/STI was performed. RESULTS: The final sample included 569 participants of whom 57 % were men. Most participants originated from Western and Central sub-Saharan Africa. Median time living in Germany was 6 years. Overall, 28 % had a university degree and 54 % reported a good level of German language. Over 80 % knew the risks for HIV transmission. A total of 44 % of respondents wrongly assumed that an HIV-diagnosis might lead to deportation and 64 % were not aware of the free and anonymous local HIV/STI-testing service. The proportion of participants with knowledge of presented facts on HEP varied from 40-58 %. The respective proportion on STI was 28-68 % and better among women compared to men (44 % vs. 54 %; OR = 1.45; 95 % CI 1.22-1.74). Men reported more often casual sex partners than women (43 % vs. 23 %; OR = 2.6; 95 % CI 1.7-4.0), and more frequently a previous STI (58 % vs. 39 %; OR = 2.1; 95 % CI 1.1-4.1). Overall, 16 % of women reported a history of sexual violence. The majority of respondents (75 %) reported that they would treat PLWH like any other person. CONCLUSION: Study participants demonstrated good knowledge on HIV-transmission but knowledge gaps regarding HIV/STI-testing services, HEP and STI. This calls for targeted interventions providing more information about these topics in African communities in Hamburg and possibly also elsewhere. PMID- 26246383 TI - Spatial patterns of incident malaria cases and their household contacts in a single clinic catchment area of Chongwe District, Zambia. AB - BACKGROUND: Reactive case detection (RACD) for malaria is a strategy that may be used to complement passive surveillance, as passive surveillance fails to identify infections that are asymptomatic or do not seek care. The spatial and seasonal patterns of incident (index) cases reported at a single clinic in Chongwe District were explored. METHODS: A RACD strategy was implemented from June 2012 to June 2013 in a single catchment area in Chongwe District. Incident (index) cases recorded at the clinic were followed up at their household, and all household contacts were tested for malaria using rapid diagnostic tests (RDTs). GPS coordinates were taken at each index household. Spatial analyses were conducted to assess characteristics related to clustering, cluster detection and spatial variation in risk of index houses. Effects of season (rainy versus dry), distance to the clinic and distance to the main road were considered as modifying factors. Lastly, logistic regression was used to identify factors associated with the proportion of household contacts testing RDT positive. RESULTS: A total of 426 index households were enrolled, with 1,621 household contacts (45% RDT positive). Two space-time clusters were identified in the rainy season, with ten times and six times higher risk than expected. Significantly increased spatial clustering of index households was found in the rainy season as compared to the dry season (based on K-function methodology). However, no seasonal difference in mapped spatial intensity of index households was identified. Logistic regression analysis identified two main factors associated with a higher proportion of RDT positive household contacts. There was a 41% increased odds of RDT positive household contacts in households where the index case was under 5 years of age [OR = 1.41, 95% confidence intervals (1.15, 1.73)]. For every 500-m increase in distance from the road, there was a 5% increased odds of RDT positive household contacts [OR = 1.05 (1.02, 1.07)], controlling for season. DISCUSSION: Areas of increased report of malaria persist after controlling for distance to the clinic and main road. Clinic-based interventions will miss asymptomatic, non-care seeking infections located farther from the road. RACD may identify additional infections missed at the clinic. PMID- 26246384 TI - Author's reply to ElSayed and colleagues, Obeidalla, and Hamad. PMID- 26246385 TI - Au-Catalyzed Pentannulation Reaction of Propargylic Esters Occurring at C(sp(3)) H Site. AB - A gold-catalyzed cascade cyclization reaction of easily accessible propargylic esters to cyclopentenones has been developed. This transformation features an unprecedented pentannulation reaction of propargylic esters which occurs at an unactivated C(sp(3))-H site to efficiently produce functionalized mono-, bis-, and tricyclic cyclopentenones. PMID- 26246386 TI - Plasma levels of matrix metalloproteinase-2 and -9 in male and female patients with cirrhosis of different aetiologies. AB - BACKGROUND: Liver fibrosis and cirrhosis may be reversible in some circumstances. Reliable diagnostic tests are necessary for monitoring hepatic fibrogenesis. Matrix metalloproteinase (MMP)-2 and MMP-9 are two of the major MMPs in the circulation and may be most relevant to hepatic fibrosis. The behaviour of MMPs may be significantly different in men and women and may also differ in cases of cirrhosis of various aetiologies. AIMS: To evaluate the manifestations of MMP-2 and MMP-9 in liver cirrhosis of different aetiologies in men and women and to compare these patterns with those of healthy controls. METHODS: We measured MMP-2 and MMP-9 levels in plasma samples from 112 patients with cirrhosis and 112 age- and gender-matched healthy controls. We then correlated these MMP levels with gender and disease aetiology. RESULTS: Plasma MMP-2 concentrations in patients showed a trend towards increasing values with cirrhosis severity and were markedly increased in patients regardless of gender and aetiology compared with healthy controls (p<0.0001). Plasma mean MMP-9 levels were comparable in patients with cirrhosis and controls, but increased with disease severity. They were significantly lower in patients (130.5 ng/mL), female patients (85.4 ng/mL) and male patients (150.4 ng/mL) with mild cirrhosis than in controls (163.2 ng/mL), female controls (162.5 ng/mL) and male controls (163.3 ng/mL) (p=0.001, 0.041 and 0.009, respectively). MMP-2 and MMP-9 concentrations were not significantly different between genders among controls and among various patient subgroups. CONCLUSIONS: Plasma MMP-2 level may be a useful diagnostic marker for monitoring hepatic fibrogenesis in patients with disease of different aetiologies. PMID- 26246387 TI - Neuromagnetic effects of pico-Tesla stimulation. AB - We used a double-blind experimental design to look for an effect of pico-Tesla magnetic stimulation in healthy subjects. Pico-Tesla stimulation is thought to increase the dominant frequency of 2-7 Hz oscillations in the human brain. We used magnetoencephalography to measure resting state brain activity. Each subject had two separate recording sessions consisting of three runs in between which they were given real or sham pT stimulation. We then tried to predict the real and sham stimulation sessions based on changes in the mean peak frequency in the 2-7 Hz band. Our predictions for these individual runs were 8 out of 14 at chance level (p = 0.39). After unblinding, we found no significant effect (p = 0.11) of an increase in the frequency range (2-7 Hz) across the subject group. Finally, we performed a Bayesian model comparison between the effect size predicted from previous clinical studies and a null model. Even though this study had a sensitivity advantage of at least one order of magnitude over previous work, we found the null model to be significantly (2000 times) more likely. PMID- 26246389 TI - Host entry by gamma-herpesviruses--lessons from animal viruses? AB - The oncogenicity of gamma-herpesviruses (gammaHVs) motivates efforts to control them and their persistence makes early events key targets for intervention. Human gammaHVs are often assumed to enter naive hosts orally and infect B cells directly. However, neither assumption is supported by direct evidence, and vaccination with the Epstein-Barr virus (EBV) gp350, to block virion binding to B cells, failed to reduce infection rates. Thus, there is a need to re-evaluate assumptions about gammaHV host entry. Given the difficulty of analysing early human infections, potentially much can be learned from animal models. Genomic comparisons argue that gammaHVs colonized mammals long before humans speciation, and so that human gammaHVs are unlikely to differ dramatically in behaviour from those of other mammals. Murid Herpesvirus-4 (MuHV-4), which like EBV and the Kaposi's Sarcoma-associated Herpesvirus (KSHV) persists in memory B cells, enters new hosts via olfactory neurons and exploits myeloid cells to spread. Integrating these data with existing knowledge of human and veterinary gammaHVs suggests a new model of host entry, with potentially important implications for infection control. PMID- 26246390 TI - The politics of publishing: debating the value of impact factor in medical anthropology. PMID- 26246388 TI - Loneliness, eudaimonia, and the human conserved transcriptional response to adversity. AB - BACKGROUND: Chronic social adversity activates a conserved transcriptional response to adversity (CTRA) marked by increased expression of pro-inflammatory genes and decreased expression of antiviral- and antibody-related genes. Recent findings suggest that some psychological resilience factors may help buffer CTRA activation, but the relative impact of resilience and adversity factors remains poorly understood. Here we examined the relative strength of CTRA association for the two best-established psychological correlates of CTRA gene expression-the risk factor of perceived social isolation (loneliness) and the resilience factor of eudaimonic well-being (purpose and meaning in life). METHODS: Peripheral blood samples and validated measures of loneliness and eudaimonic well-being were analyzed in 108 community-dwelling older adults participating in the longitudinal US Health and Retirement Study (56% female, mean age 73). Mixed effect linear model analyses quantified the strength of association between CTRA gene expression and measures of loneliness and eudaimonic well-being in separate and joint analyses. RESULTS: As in previous studies, separate analyses found CTRA gene expression to be up-regulated in association with loneliness and down regulated in association with eudaimonic well-being. In joint analyses, effects of loneliness were completely abrogated whereas eudaimonic well-being continued to associate with CTRA down-regulation. Similar eudaimonia-dominant effects were observed for positive and negative affect, optimism and pessimism, and anxiety symptoms. All results were independent of demographic and behavioral health risk factors. CONCLUSIONS: Eudaimonic well-being may have the potential to compensate for the adverse impact of loneliness on CTRA gene expression. Findings suggest a novel approach to targeting the health risks associated with social isolation by promoting purpose and meaning in life. PMID- 26246391 TI - A C-H bond activation-based catalytic approach to tetrasubstituted chiral allenes. AB - Enantioselective synthesis of fully substituted allenes has been a challenge due to the non-rigid nature of the axial chirality, which spreads over three carbon atoms. Here we show the commercially available simple Rh complex may catalyse the CMD (concerted metalation/deprotonation)-based reaction of the readily available arenes with sterically congested tertiary propargylic carbonates at ambient temperature affording fully substituted allenes. It is confirmed that the excellent designed regioselectivity for the C-C triple bond insertion is induced by the coordination of the carbonyl group in the directing carbonate group as well as the steric effect of the tertiary O-linked carbon atom. When an optically active carbonate was used, surprisingly high efficiency of chirality transfer was realized, affording fully substituted allenes in excellent enantiomeric excess (ee). PMID- 26246392 TI - The processus vaginalis transection method is superior to the simple prophylactic procedure for prevention of inguinal hernia after radical prostatectomy. AB - BACKGROUND: We compared retrospectively the efficacy of two methods for prevention of post-radical prostatectomy inguinal hernia: blunt dissection of the peritoneum at the internal inguinal ring, and isolation of the spermatic cord from the peritoneum (simple prophylactic procedure) and transection of the processus vaginalis. METHODS: Of the 367 patients who underwent open radical retropubic prostatectomy for clinically localized prostate cancer between February 2005 and March 2012 at Saitama Cancer Center Hospital, 344 patients whose follow-up period was more than 2 years were enrolled in this study. Of these patients, 178 patients received the simple prophylactic procedure and 57 underwent processus vaginalis transection. We evaluated the risk factors for inguinal hernia (age; anastomotic stricture post radical prostatectomy; prophylactic procedures for inguinal hernia; previous history of abdominal surgery; previous inguinal hernia surgery; body mass index) using univariate and multivariate analysis. The effects of the two prophylactic procedures on incidence of inguinal hernia were analyzed using Kaplan-Meier plots. RESULTS: The incidence of inguinal hernia was 24.8 % in those not undergoing the prophylactic procedure; 18.5 % in those undergoing the simple prophylactic procedure; and 0.00 % in those undergoing the processus vaginalis transection procedure (p < 0.001). In univariate and multivariate analysis, undergoing the processus vaginalis transection procedure and high body mass index were significant predictors for hernia-free survival after radical prostatectomy. CONCLUSION: Our data suggest that the processus vaginalis transection procedure is superior to the simple prophylactic procedure for the prevention of inguinal hernia after radical prostatectomy. PMID- 26246393 TI - More than meets the eye? Factors that affect target selection by plant miRNAs and heterochromatic siRNAs. AB - MicroRNAs, which target mRNAs for post-transcriptional regulation, and heterochromatic siRNAs, which target chromatin causing DNA methylation, make up the majority of the endogenous regulatory small RNA pool in most plant specimens. They both function to guide Argonaute proteins to targeted nucleic acids on the basis of complementarity. Recent work on plant miRNA-target interactions has clarified the general ''rules' of complementarity, while also providing several intriguing exceptions to these rules. In addition, emerging evidence suggests that several factors besides miRNA-target complementarity affect plant miRNA function. For heterochromatic siRNAs, recent work has made progress towards comprehensively identifying potential target regions, but numerous fundamental questions remain to be answered. PMID- 26246394 TI - The menopause transition: interview with Ellen W Freeman. AB - Ellen W Freeman is a Research Professor in the Department of Obstetrics/Gynecology and the Department of Psychiatry at the University of Pennsylvania School of Medicine in Philadelphia (PA, USA). She directs the PMS research program and is co-director of the Human Behavior and Reproduction unit in the Department of Obstetrics and Gynecology. She received her AB in history in Smith College in Northampton, Massachusetts and her MS and PhD in social research from Bryn Mawr College in Bryn Mawr, Pennsylvania. She has published more than 200 scientific articles, book chapters, reviews and abstracts on premenstrual syndromes, perimenopause, adolescent pregnancy, infertility and related topics as well as a book on teenage pregnancy. In addition, she has lectured extensively worldwide on mood disorders and menopause in women. She is also a member of the editorial boards of Medscape, Archives of Women's Mental Health and Mental Fitness: Psychiatry, OB/GYN, Primary Care and is a Fellow in the College of Physicians of Philadelphia. PMID- 26246396 TI - Venipuncture does not affect adrenocorticotropic hormone concentration in horses. PMID- 26246397 TI - Survey of the UK veterinary profession 2: sources of information used by veterinarians. AB - Access to the most up-to-date evidence is an important cornerstone for veterinarians attempting to practice in an evidence-based manner; therefore, an understanding of what and how information is accessed is vital. The aim of this study was to identify what resources the UK veterinary profession access and regard as most useful. Based on questionnaires received from veterinarians, the Veterinary Times was nominated as most often read journal or magazine by respondents (n=3572, 79 per cent). In Practice (n=3224, 82 per cent) and the Veterinary Record (n=165, 34 per cent) were seen as most useful by clinicians, and non-clinicians, respectively. Google was the most often nominated electronic resource by all respondents (n=3076, 71 per cent), with Google (n=459, 23 per cent) and PubMed (n=60, 17 per cent) seen as most useful by clinicians and non clinicians, respectively. The abstract and conclusion sections were the most read parts of scientific manuscripts nominated by all respondents. When looking for assistance with difficult cases, colleagues were the common information choice for clinicians. Different sections of the veterinary profession access information, and deem resources useful, in different ways. Access to good quality evidence is important for the practice of evidence-based veterinary medicine, and therefore, researchers should think about disseminating their findings in a targeted way for optimal use by the profession. PMID- 26246398 TI - CXCR4/CXCL12 signaling impacts enamel progenitor cell proliferation and motility in the dental stem cell niche. AB - Dental stem cells are located at the proximal ends of rodent incisors. These stem cells reside in the dental epithelial stem cell niche, termed the apical bud. We focused on identifying critical features of a chemotactic signal in the niche. Here, we report that CXCR4/CXCL12 signaling impacts enamel progenitor cell proliferation and motility in dental stem cell niche cells. We report cells in the apical bud express CXCR4 mRNA at high levels while expression is restricted in the basal epithelium (BE) and transit-amplifying (TA) cell regions. Furthermore, the CXCL12 ligand is present in mesenchymal cells adjacent to the apical bud. We then performed gain- and loss-of-function analyses to better elucidate the role of CXCR4 and CXCL12. CXCR4-deficient mice contain epithelial cell aggregates, while cell proliferation in mutant incisors was also significantly reduced. We demonstrate in vitro that dental epithelial cells migrate toward sources of CXCL12, whereas knocking down CXCR4 impaired motility and resulted in formation of dense cell colonies. These results suggest that CXCR4 expression may be critical for activation of enamel progenitor cell division and that CXCR4/CXCL12 signaling may control movement of epithelial progenitors from the dental stem cell niche. PMID- 26246399 TI - Transient up- and down-regulation of expression of myosin light chain 2 and myostatin mRNA mark the changes from stratified hyperplasia to muscle fiber hypertrophy in larvae of gilthead sea bream (Sparus aurata L.). AB - Hyperplasia and hypertrophy are the two mechanisms by which muscle develops and grows. We study these two mechanisms, during the early development of white muscle in Sparus aurata, by means of histology and the expression of structural and regulatory genes. A clear stage of stratified hyperplasia was identified early in the development of gilthead sea bream but ceased by 35 dph when hypertrophy took over. Mosaic recruitment of new white fibers began as soon as 60 dph. The genes mlc2a and mlc2b were expressed at various levels during the main phases of hyperplasia and hypertrophy. The genes myog and mlc2a were significantly up-regulated during the intensive stratified formation of new fibers and their expression was significantly correlated. Expression of mstn1 and igf1 increased at 35 dph, appeared to regulate the hyperplasia-to-hypertrophy transition, and may have stimulated the expression of mlc2a, mlc2b and col1a1 at the onset of mosaic hyperplasia. The up-regulation of mstn1 at transitional phases in muscle development indicates a dual regulatory role of myostatin in fish larval muscle growth. PMID- 26246400 TI - Expression of Slug in S100beta-protein-positive cells of postnatal developing rat anterior pituitary gland. AB - Among heterogeneous S100beta-protein-positive (S100beta-positive) cells, star like cells with extended cytoplasmic processes, the so-called folliculo-stellate cells, envelop hormone-producing cells or interconnect homophilically in the anterior pituitary. S100beta-positive cells are known, from immunohistochemistry, to emerge from postnatal day (P) 10 and to proliferate and migrate in the parenchyma of the anterior pituitary with growth. Recent establishment of S100beta-GFP transgenic rats expressing specifically green fluorescent protein (GFP) under the control of the S100beta-promoter has allowed us to observe living S100beta-positive cells. In the present study, we first confirmed that living S100beta-positive cells in tissue cultures of S100beta-GFP rat pituitary at P5 were present prior to P10 by means of confocal laser microscopy and that they proliferated and extended their cytoplasmic processes. Second, we examined the expression of the Snail-family zinc-finger transcription factors, Snail and Slug, to investigate the mechanism behind the morphological changes and the proliferation of S100beta-positive cells. Interestingly, we detected Slug expression in S100beta-positive cells and its increase together with development in the anterior pituitary. To analyze downstream of SLUG in S100beta-positive cells, we utilized specific small interfering RNA for Slug mRNAs and observed that the expression of matrix metalloprotease (Mmp) 9, Mmp14 and chemokine Cxcl12 was down-regulated and that morphological changes and proliferation were decreased. Thus, our findings suggest that S100beta-positive cells express Slug and that its expression is important for subsequent migration and proliferation. PMID- 26246395 TI - Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. AB - OBJECTIVES: This review examines the pharmacokinetics, modes of action and therapeutic properties of the anti-malarial drugs, hydroxychloroquine (HCQ) and chloroquine (CQ), in the treatment of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and related conditions, as well as osteoarthritis (OA). KEY FINDINGS: Both HCQ and CQ have historically been employed successfully for the treatment of SLE and RA for over 70 years. HCQ has been used extensively for SLE where it has a good reputation for controlling the dermatological complications in SLE. It has also been reported to effectively control the symptoms of Sjogren's syndrome, as well as preventing thrombosis in phospholipid antibody (aPL) syndrome. In RA and SLE, HCQ is preferred because of the lower incidence of gastrointestinal adverse reactions compared with CQ and it might have a lower risk of ocular adverse reactions. There is increasing evidence that HCQ may reduce atherosclerosis and risks of cardiovascular disease in rheumatic patients. Both HCQ and CQ have been shown to improve glycaemia and reduce the risks of type II diabetes mellitus. Although both HCQ and CQ are effective in low moderate RA, HCQ is now preferred as part of combination therapy for more severe disease. The advantages of combination therapy are that the doses of the individual drugs may be lowered so reducing adverse reactions. Both HCQ and CQ are diastereoisomers, have basic properties and are given as the sulphate and phosphate salts. While being relatively well absorbed orally and with good bioavailability, they have long and variable plasma terminal elimination half lives (approximately 40-60 days). This reflects their high volume of distribution, V D (HCQ 44,000L; CQ 65,000L) which extends into aqueous compartments, long mean residence time (HCQ 1300 h; CQ 900 h) and with about half the drugs (metabolites) undergoing renal clearance. The strong binding to melanin reflects the ocular injury and dermatological properties of these drugs. The consensus is that the occurrence of ocular adverse reactions can be minimised by close attention to the dose (which should be set on a body weight basis) with regular (e.g. quarterly) retinal examination. Although HCQ and CQ can pass through the placenta, the use of these drugs during pregnancy does not appear to risk harm to the baby and might be beneficial to the mother with SLE and her child by controlling the SLE disease activity, which is known to be an important factor affecting pregnancy outcome. The modes of action of HCQ and CQ in these arthritides represent somewhat of an enigma. Undoubtedly, these drugs have multiple actions related, in part, their ability to accumulate in lysosomes and autophagosomes of phagocytic cells as well as affecting MHC Class II expression and antigen presentation; actions of the production of pro-inflammatory cytokines [e.g. interleukin-1 (IL-1) tumour necrosis factor-alpha (TNFalpha)]; control of toll-like receptor-9 activation; and leucocyte generation of reactive oxygen species (ROS); i.e. antioxidant activity. The actions of these drugs on T and B cells are less clear but may depend on these leucocyte-mediated actions. Anti malarials also protect against cytokine-mediated cartilage resorption. This and other actions may underlie the potential benefits in treating OA. The exact relationships of these various actions, mostly determined in vitro, have not been specifically defined in vivo or ex vivo in relation to clinical efficacy. OUTCOMES: HCQ and CQ have a good reputation for being effective and relatively safe treatments in SLE, mild-moderate RA and Sjogren's syndrome. There is need for (a) more information on their mode of action in relation to the control of these diseases, (b) scope for developing formulations that have improved pharmacokinetic and therapeutic properties and safety, and (c) further exploring their use in drug combinations not only with other disease modifying agents but also with biologics. PMID- 26246401 TI - Association between miscarriage and cardiovascular disease in a Scottish cohort. AB - OBJECTIVE: To assess if miscarriage, whether consecutive or not, is associated with an increased risk of subsequent cardiovascular disease. METHODS: A cohort study was performed using women with at least one miscarriage or live birth recorded from 1950 to 2010 in the Aberdeen Maternity and Neonatal Databank. The exposed groups consisted of women with non-consecutive, two consecutive or three or more consecutive miscarriages; the unexposed group consisted of all women with at least one live birth and no miscarriages. Women were linked to Scottish Morbidity Records for hospital admissions for cardiovascular conditions, cardiac surgery and death registrations. Main outcome measures were ischaemic heart disease, cerebrovascular disease and a composite outcome of any disease of circulatory system. A sensitivity analysis was performed dividing the women into those who had one, two or three or more miscarriages irrespective of whether these events were consecutive or not. RESULTS: After excluding women with pre existing hypertension, type 1 diabetes mellitus, kidney disease and 'disease of circulatory system', 60,105 women were analysed; 9419 with non-consecutive, 940 with two consecutive, 167 with three or more consecutive miscarriages and 49,579 with no miscarriage. In the multivariate analyses, a significant association was found between ischaemic heart disease and women with two (HRs 1.75 (95% CI 1.22 to 2.52)) or three or more (HR 3.18 (95% CI 1.49 to 6.80)) consecutive miscarriages. Similar patterns of risk were observed in the sensitivity analysis. CONCLUSION: Women with a history of two or more miscarriages, irrespective of whether consecutive or not, appear to have an increased risk of ischaemic heart disease. PMID- 26246402 TI - Coronary vasomotor function in infarcted and remote myocardium after primary percutaneous coronary intervention. AB - OBJECTIVE: In patients with acute myocardial infarction (AMI), coronary vasomotor function is impaired in the myocardial territory supplied by the culprit artery and in remote myocardium supplied by angiographically normal vessels. The aim was to investigate the temporal evolution of coronary vasodilatory reserve in patients with AMI by use of [(15)O]H2O positron emission tomography, after successful percutaneous coronary intervention. METHODS: 44 patients with AMI and successful revascularisation by percutaneous coronary intervention were included. Subjects were examined 1 week and 3 months after AMI with [(15)O]H2O positron emission tomography to assess the coronary flow reserve (CFR). CFR was defined as the ratio of myocardial blood flow (MBF) during hyperaemia and rest. Additionally, 45 age-matched and sex-matched subjects underwent similar scanning procedures and served as controls. RESULTS: At baseline, CFR averaged 1.81+/-0.66 in infarcted myocardium versus 2.51+/-0.81 in remote myocardium (p<0.01). In comparison, CFR in the control group averaged 4.16+/-1.45 (p=0.001 vs both). During follow-up, the CFR increased to 2.74+/-0.85 in infarcted myocardium (p<0.01), and to 2.85+/-0.70 in remote myocardium (p<0.01). This was predominantly due to an increase in hyperaemic MBF, from 1.62+/-0.54 mL/min/g to 2.19+/-0.68 mL/min/g in infarcted myocardium (p<0.001), and 2.17+/-0.54 mL/min/g to 2.60+/-0.65 mL/min/g in remote myocardium (p<0.001). CONCLUSIONS: CFR in infarcted and remote myocardium is impaired 1 week after AMI. After 3 months vasomotor function partially recovers. However, as compared with control patients, MBF remains impaired in culprit and reference territories in patients with AMI. CLINICAL TRIAL REGISTRATION: NTR3164. PMID- 26246403 TI - High nutrient availability reduces the diversity and stability of the equine caecal microbiota. AB - BACKGROUND: It is well known that nutrient availability can alter the gut microbiota composition, while the effect on diversity and temporal stability remains largely unknown. METHODS: Here we address the equine caecal microbiota temporal stability, diversity, and functionality in response to diets with different levels of nutrient availability. Hay (low and slower nutrient availability) versus a mixture of hay and whole oats (high and more rapid nutrient availability) were used as experimental diets. RESULTS: We found major effects on the microbiota despite that the caecal pH was far from sub-clinical acidosis. We found that the low nutrient availability diet was associated with a higher level of both diversity and temporal stability of the caecal microbiota than the high nutrient availability diet. These observations concur with general ecological theories, suggesting a stabilising effect of biological diversity and that high nutrient availability has a destabilising effect through reduced diversity. CONCLUSION: Nutrient availability does not only change the composition but also the ecology of the caecal microbiota. PMID- 26246404 TI - Sphingosine-1-phosphate inhibits IL-1-induced expression of C-C motif ligand 5 via c-Fos-dependent suppression of IFN-beta amplification loop. AB - The neuroinflammation associated with multiple sclerosis involves activation of astrocytes that secrete and respond to inflammatory mediators such as IL-1. IL-1 stimulates expression of many chemokines, including C-C motif ligand (CCL) 5, that recruit immune cells, but it also stimulates sphingosine kinase-1, an enzyme that generates sphingosine-1-phosphate (S1P), a bioactive lipid mediator essential for inflammation. We found that whereas S1P promotes IL-1-induced expression of IL-6, it inhibits IL-1-induced CCL5 expression in astrocytes. This inhibition is mediated by the S1P receptor (S1PR)-2 via an inhibitory G-dependent mechanism. Consistent with this surprising finding, infiltration of macrophages into sites of inflammation increased significantly in S1PR2(-/-) animals. However, activation of NF-kappaB, IFN regulatory factor-1, and MAPKs, all of which regulate CCL5 expression in response to IL-1, was not diminished by the S1P in astrocytes. Instead, S1PR2 stimulated inositol 1,4,5-trisphosphate-dependent Ca(++) release and Elk-1 phosphorylation and enhanced c-Fos expression. In our study, IL-1 induced the IFNbeta production that supports CCL5 expression. An intriguing finding was that S1P induced c-Fos-inhibited CCL5 directly and also indirectly through inhibition of the IFN-beta amplification loop. We propose that in addition to S1PR1, which promotes inflammation, S1PR2 mediates opposing inhibitory functions that limit CCL5 expression and diminish the recruitment of immune cells. PMID- 26246405 TI - Unique ability of pandemic influenza to downregulate the genes involved in neuronal disorders. AB - Pandemic influenza remains as a substantial threat to humans with a widespread panic worldwide. In contrast, seasonal (non-pandemic) has a mild non-lethal infection each year. The underlying mechanisms governing the detrimental effects of pandemic influenza are yet to be known. Transcriptomic-based network discovery and gene ontology (GO) analysis of host response to pandemic influenza, compared to seasonal influenza, can shed light on the differential mechanisms which pandemic influenza is employed during evolution. Here, using microarray data of infected ferrets with pandemic and seasonal influenza (as a model), we evaluated the possible link between altered genes after pandemic infection with activation of neuronal disorders. To this end, we utilized novel computational biology techniques including differential transcriptome analysis, network construction, GO enrichment, and GO network to investigate the underlying mechanisms of pandemic influenza infection and host interaction. In comparison to seasonal influenza, pandemic influenza differentially altered the expression of 31 genes with direct involvement in activity of central nervous system (CNS). Network topology highlighted the high interactions of IRF1, NKX2-1 and NR5A1 as well as MIR27A, MIR19A, and MIR17. TGFB2, NCOA3 and SP1 were the central transcription factors in the networks. Pandemic influenza remarkably downregulated GPM6A and GTPase. GO network demonstrated the key roles of GPM6A and GTPase in regulation of important functions such as synapse assembly and neuron projection. For the first time, we showed that besides interference with cytokine/chemokine storm and neuraminidase enzyme, H1N1 pandemic influenza is able to directly affect neuronal gene networks. The possibility of application of some key regulators such as GPM6A protein, MIR128, and MIR367 as candidate therapeutic agents is discussed. The presented approach established a new way to unravel unknown pathways in virus associated CNS dysfunction by utilizing global transcriptomic data, network and GO analysis. PMID- 26246407 TI - Evaluation of postoperative pain at the stoma site in patients who underwent a single-port Hartmann's procedure. AB - INTRODUCTION: The aims of this retrospective study were to evaluate postoperative pain at the stoma site in patients who underwent a single-port Hartmann's procedure (SPH) and to compare the SPH to the multiport Hartmann's procedure (MPH) in terms of postoperative pain. METHODS: We studied 17 consecutive patients who underwent SPH or MPH for left colon cancer. Postoperative pain was evaluated from postoperative day 1 to 7 with the Numeric Rating Scale. RESULTS: The postoperative pain score at the stoma site was highest on postoperative day 2 (Numeric Rating Scale score = 3.6). The duration of narcotics use was significantly shorter in the SPH group than in the MPH group (2.1 vs 3.3 days; P = 0.012). The rescue analgesia was administered fewer times in the SPH group than in the MPH group (1.3 vs 4.6; P = 0.012), and the duration of rescue analgesia use was shorter (1.1 vs 3.7 days; P = 0.013). The worst Numeric Rating Scale score in the SPH group was significantly lower than that in the MPH group on postoperative day 3 (1.9 vs 4.1; P = 0.031). CONCLUSIONS: Postoperative pain at the stoma site was highest on postoperative day 2. The SPH was associated with less postoperative pain than the MPH. PMID- 26246406 TI - ABCC8 R1420H Loss-of-Function Variant in a Southwest American Indian Community: Association With Increased Birth Weight and Doubled Risk of Type 2 Diabetes. AB - Missense variants in KCNJ11 and ABCC8, which encode the KIR6.2 and SUR1 subunits of the beta-cell KATP channel, have previously been implicated in type 2 diabetes, neonatal diabetes, and hyperinsulinemic hypoglycemia of infancy (HHI). To determine whether variation in these genes affects risk for type 2 diabetes or increased birth weight as a consequence of fetal hyperinsulinemia in Pima Indians, missense and common noncoding variants were analyzed in individuals living in the Gila River Indian Community. A R1420H variant in SUR1 (ABCC8) was identified in 3.3% of the population (N = 7,710). R1420H carriers had higher mean birth weights and a twofold increased risk for type 2 diabetes with a 7-year earlier onset age despite being leaner than noncarriers. One individual homozygous for R1420H was identified; retrospective review of his medical records was consistent with HHI and a diagnosis of diabetes at age 3.5 years. In vitro studies showed that the R1420H substitution decreases KATP channel activity. Identification of this loss-of-function variant in ABCC8 with a carrier frequency of 3.3% affects clinical care as homozygous inheritance and potential HHI will occur in 1/3,600 births in this American Indian population. PMID- 26246408 TI - Deep brain stimulation in mental health: Review of evidence for clinical efficacy. AB - OBJECTIVE: There is increasing interest in the use of deep brain stimulation as a treatment for psychiatric disorders. In this review, we consider the evidence for the effectiveness of deep brain stimulation for psychiatric indications, with a primary focus on obsessive compulsive disorder and major depressive disorder. METHODS: Case reports, case series and clinical trials where deep brain stimulation was primarily utilised in the treatment of a psychiatric disorder, including obsessive compulsive disorder, major depressive disorder, anorexia nervosa or an addictive disorder were identified. The evidence for the effectiveness of deep brain stimulation in the treatment of obsessive compulsive disorder and major depressive disorder was reviewed with studies clustered by the site of implantation. RESULTS: The majority of identified manuscripts report small case series or single cases. A limited number of studies have reported some form of randomised or blinded stimulation comparison. All of these comparative reports have included small samples of subjects (less than 20 per study in total) compromising the feasibility of making statistical comparison between outcomes in the comparison phases. The two exceptions to this have been industry-sponsored studies conducted in the treatment of major depressive disorder. However, both were stopped prematurely due to concerns about poor efficacy. CONCLUSIONS: There is insufficient evidence at this point in time to support the use of deep brain stimulation as a clinical treatment for any psychiatric disorder outside of research and programmes where formal outcome data are being systematically collated. While some promising initial data exist to support its potential efficacy for a number of psychiatric conditions, further research is required to establish optimal implantation targets, patient characteristics associated with positive therapeutic outcomes and optimal deep brain stimulation parameters and parameter-programming methods. PMID- 26246410 TI - Climate changes and solar cycles recorded at the Holocene Parana Delta, and their impact on human population. AB - The Parana delta, growing at a rate of c. 2 km(2) yr(-1) since 6,000 yrs, is one of the most complete records of the Late Holocene in southern South America. The evolution of this 17,400 km(2) delta enclosed in Plata estuary, can be tracked by a series of 343 successive coastal-ridges showing a c.11 years period, in coincidence with sunspot cycle, also found in some North Hemisphere coastal-ridge successions. The Parana delta shifted from fluvial, to wave-dominated, and back to the present fluvial-dominated delta, in response to climate changes associated with wind activity correlating with South American glacial cycles. The wave dominated windy period coincides with the activation of the Pampean Sand Sea, suggesting desert conditions prevailed on the Pampas between 5,300 and 1,700 yrs, in coincidence with scarce or absent pre-historic aborigine remains ("archeological silence"). Further warmer and less windy conditions allowed human repopulation. Results suggest that aside the solar forcing, both short and medium term climate changes controlled delta evolution. An important learning is that a slight cooling would turn the highly productive pampas, into that unproductive desert and, given the lack of artificial irrigation systems, changing present-day warmhouse into a cooling cycle might be economically catastrophic for the region. PMID- 26246409 TI - Structural basis for the blockade of MATE multidrug efflux pumps. AB - Multidrug and toxic compound extrusion (MATE) transporters underpin multidrug resistance by using the H(+) or Na(+) electrochemical gradient to extrude different drugs across cell membranes. MATE transporters can be further parsed into the DinF, NorM and eukaryotic subfamilies based on their amino-acid sequence similarity. Here we report the 3.0 A resolution X-ray structures of a protonation mimetic mutant of an H(+)-coupled DinF transporter, as well as of an H(+)-coupled DinF and a Na(+)-coupled NorM transporters in complexes with verapamil, a small molecule pharmaceutical that inhibits MATE-mediated multidrug extrusion. Combining structure-inspired mutational and functional studies, we confirm the biological relevance of our crystal structures, reveal the mechanistic differences among MATE transporters, and suggest how verapamil inhibits MATE mediated multidrug efflux. Our findings offer insights into how MATE transporters extrude chemically and structurally dissimilar drugs and could inform the design of new strategies for tackling multidrug resistance. PMID- 26246411 TI - Assessment of the Dissociation Energetics of Some Selected Ligand Drugs Bound on Human Serum Albumin by Differential Scanning Calorimetry. AB - Drug-protein binding may play a role in the thermal energetics of protein denaturation and could lead to the determination of its equilibrium dissociation parameter. The aim of this study was to assess the energetics of a drug that was bound to human serum albumin (HSA) during thermal denaturation. Drugs that were bound at a single high-affinity primary binding site on HSA, including diazepam and ibuprofen, were employed. Commercial HSA was treated with charcoal to remove stabilizers and adjusted to 20% w/v in a pH 7.4 buffered solution. Serial concentrations of individual drugs up to 0.16 mmole/g-protein were added to the cleaned HSA solutions whereas diazepam was added to a commercial HSA solution. Samples were subjected to differential scanning calorimetry (DSC) set to run from 37 to 90 degrees C at 3.0 degrees C/min. Binding of the drug slightly increased the denaturing temperature of the cleaned HSA due to a shift in the equilibrium toward the native protein bound with the drug. Diazepam depressed the denaturing temperature of the commercial HSA by competing with the stabilizers already bound to the primary site of the HSA. This yielded not only the HSA-stabilizer but also the HSA-diazepam type complexes that exhibited a different denaturation process. A rational approximation of the Lumry-Eyring protein denaturation model was used to treat the DSC endotherms. The approximated scheme: [Formula: see text] was successfully fitted to the data. It was used to determine the dissociation parameters for diazepam and ibuprofen bound to the HSA. These results were comparable to those obtained from other methods. PMID- 26246412 TI - Excessive weight gain during pregnancy and risk of macrosomia: a meta-analysis. AB - PURPOSE: This meta-analysis aimed to estimate the relation between excessive gestational weight gain and macrosomia. METHODS: We performed a meta-analysis by searching PubMed, EMBASE and the Cochrane library for English-language literature from inception to 1 October 2014. Studies assessing the relationship between excessive gestational weight gain and macrosomia were included. Characteristics including study design, country, sample size, definition of macrosomia, adjusted odds ratios, CIs and adjustment factors were extracted independently by two reviewers. Summary odds ratios were calculated by using a random-effects model meta-analysis. RESULTS: 15 relevant articles were eligible for the meta-analysis. Incorporated by random-effect model before the heterogeneity tests, the value of OR was 2.35 (95 % CI: 1.95, 2.85). Stratified analysis showed no differences regarding different study design, definition of macrosomia and location of study. There was no indication of a publication bias either from the result of Egger's test (P = 0.572) or Begg's test (P = 0.572). CONCLUSIONS: Our meta-analysis indicated that excessive gestational weight gain might increase the risk of macrosomia. PMID- 26246413 TI - Effects of GnRHa on early embryonic development in mice receiving cyclophosphamide. AB - PURPOSE: There is a controversy whether GnRH agonist can reduce the deleterious effects of chemotherapy to prevent ovarian failure. We aimed to examine the possible protective effects of a gonadotrophin-releasing hormone agonist (GnRHa) on the fertilization rate and sequential embryonic development in mouse oocytes exposed to Cy. METHODS: Mice were assigned to three groups of six animals each. A single dose of 75 mg/kg Cy was given intraperitoneally to the Cy mice group. The subcutaneous GnRHa injection was initiated 1 week before and continued for 1 week after the Cy injection in the GnRHa + Cy group. The animals given cyclophosphamide mated 1 week after the Cy injection. At the end of the injection period, the animals underwent a superovulation regime with pregnant mare serum gonadotrophin and human chorionic gonadotrophin and were mated. Early embryos were collected at 48 h after mating. The control group received only the superovulation regime and then mated. RESULTS: Cyclophosphamide caused a significant decrease in the fertilization rate (p < 0.001), whereas the GnRHa improved the rate when compared to control group. The GnRHa induced a marked increase in the rate for 2-cell embryos compared with the Cy group (p = 0.003). In both Cy-injected groups, the rates for the 4-cell embryos were lower than those of the control animals (p < 0.001). However, this rate was higher in the GnRHa + Cy group than in the only Cy group. Morphologically abnormal embryos showed such characteristics as condensed cytoplasm, milky cytoplasm, fragmentation, and an empty zona pellucida. CONCLUSION: These results demonstrated that the GnRHa preserved the oocyte capability to develop into an embryo against ovarian toxic chemotherapy. Thus, we suggest that GnRHa cotreatment could increase the number and quality of early embryos in mice. PMID- 26246414 TI - Quality of sex life in endometriosis patients with deep dyspareunia before and after laparoscopic treatment. AB - PURPOSE: The present work aims at showing how dyspareunia linked to endometriosis can affect the life of fertile age women and how surgical treatment of endometriosis can relieve painful symptoms and consequently improve sex and social life. METHODS: From a cohort of 320 women with a clinical and instrumental diagnosis of pelvic endometriosis, 67 patients were selected. These patients had deep dyspareunia that underwent laparoscopic surgical treatment. All the patients had filled out a pre- and post-surgery questionnaire. RESULTS: Six months after laparoscopic treatment, a significant reduction of dyspareunia was recorded, per VAS scores. A statistically significant improvement in sex life was observed between the pre- and post-surgical condition: in particular, an increased number of coituses and of non-difficult coituses, a higher number of patients who declared that pain did not negatively affect sexual pleasure and of patients achieving orgasm. CONCLUSIONS: The quality of the sex life in patients with endometriosis and dyspareunia showed significant improvement 6 months after laparoscopic treatment. In view of the diagnostic delay characterizing this disease and confirmed by our results, it is essential to involve a multidisciplinary team to assess all the signs and symptoms of endometriosis that may appear in a women of fertile age. This clinical approach is able to ensure a treatment that is as personalized as possible and an appropriate follow-up also with the objective of preserving reproductive performance. PMID- 26246415 TI - Measurement of oxidative stress in the follicular fluid of infertility patients with an endometrioma. AB - PURPOSE: Follicular fluid (FF) might reflect the environment during follicle and oocyte growth, and an evaluation of oxidative stress in the FF might be useful in predicting oocyte quality. In order to measure the oxidative stress (OS) in the FF from a single follicle of patients with endometrioma (EM), we evaluated whether an EM might affect the environment of follicular growth. METHODS: Between December 2011 and July 2013, 26 patients with a unilateral EM (EM group) and 29 without EM (control group) were enrolled in this study. The FF was obtained during the first puncture of follicular aspiration, and was stored at -30 degrees C until it was assayed. A Free Radical Elective Evaluator (WISMERLL, USA) was used to perform d-ROM and BAP tests to measure oxidative stress (U.CARR) and antioxidant power (MUmol/L). RESULTS: The d-ROM values in the EMC and control groups were 328.7 +/- 97.8 and 414.9 +/- 84.2, respectively, and the BAP values for the two groups were 2474.3 +/- 432.0 and 2552.8 +/- 435.58, respectively. These values were similar between the two groups (mean +/- SD). The number of patients with a modified BAP/d-ROM ratio of <1.0 in the EM group was similar to that for the control group at 16 and 15, respectively (61.5 and 51.7 %). CONCLUSIONS: The oxidative stress and antioxidant potential in the FF of the patients with unilateral EM showed values similar to those without an EM. Therefore, we concluded that EMs do not affect the environment for follicle growth during ART treatment. PMID- 26246416 TI - Directional reversals enable Myxococcus xanthus cells to produce collective one dimensional streams during fruiting-body formation. AB - The formation of a collectively moving group benefits individuals within a population in a variety of ways. The surface-dwelling bacterium Myxococcus xanthus forms dynamic collective groups both to feed on prey and to aggregate during times of starvation. The latter behaviour, termed fruiting-body formation, involves a complex, coordinated series of density changes that ultimately lead to three-dimensional aggregates comprising hundreds of thousands of cells and spores. How a loose, two-dimensional sheet of motile cells produces a fixed aggregate has remained a mystery as current models of aggregation are either inconsistent with experimental data or ultimately predict unstable structures that do not remain fixed in space. Here, we use high-resolution microscopy and computer vision software to spatio-temporally track the motion of thousands of individuals during the initial stages of fruiting-body formation. We find that cells undergo a phase transition from exploratory flocking, in which unstable cell groups move rapidly and coherently over long distances, to a reversal mediated localization into one-dimensional growing streams that are inherently stable in space. These observations identify a new phase of active collective behaviour and answer a long-standing open question in Myxococcus development by describing how motile cell groups can remain statistically fixed in a spatial location. PMID- 26246417 TI - Predicting global community properties from uncertain estimates of interaction strengths. AB - The community matrix measures the direct effect of species on each other in an ecological community. It can be used to determine whether a system is stable (returns to equilibrium after small perturbations of the population abundances), reactive (perturbations are initially amplified before damping out), and to determine the response of any individual species to perturbations of environmental parameters. However, several studies show that small errors in estimating the entries of the community matrix translate into large errors in predicting individual species responses. Here, we ask whether there are properties of complex communities one can still predict using only a crude, order of-magnitude estimate of the community matrix entries. Using empirical data, randomly generated community matrices, and those generated by the Allometric Trophic Network model, we show that the stability and reactivity properties of systems can be predicted with good accuracy. We also provide theoretical insight into when and why our crude approximations are expected to yield an accurate description of communities. Our results indicate that even rough estimates of interaction strengths can be useful for assessing global properties of large systems. PMID- 26246418 TI - Injury data of major international field hockey tournaments. AB - BACKGROUND: Detailed injury data are not available for international tournaments in field hockey. We investigated the epidemiology of field hockey injuries during major International Hockey Federation (Federation Internationale de Hockey, FIH) tournaments in 2013. MATERIALS AND METHODS: FIH injury reports were used for data collection. All major FIH tournaments for women (n=5) and men (n=11) in 2013 were included. The main focus of this study was to assess the pattern, time, site on the pitch, body site and mechanism of each of the injuries. We calculated the average number of injuries per match and the number of injuries per 1000 player match hours. RESULTS: The average number of injuries was 0.7 (95% CI 0.5 to 1.0) per match in women's tournaments and 1.2 (95% CI 0.8 to 1.7) per match in men's tournaments. The number of injuries per 1000 player match hours ranged from 23.4 to 44.2 (average 29.1; 95% CI 18.6 to 39.7) in women and 20.8 to 90.9 (average 48.3; 95% CI 30.9 to 65.8) in men. Most injuries occurred in the circle (n=25, 50%, in women, n=95, 51%, in men). The rate of injuries increased after the first quarter. Injuries to the head and face (n=20, 40%) were most common in women. The head/face (n=51, 27%) and the thigh/knee (n=52, 28%) were equally affected in men. The ball caused the most injuries, followed by the stick, collisions and tripping/falling. There were no deaths or injuries that required hospital treatment in the entire cohort. SUMMARY: Field hockey has a low incidence of acute injuries during competition. PMID- 26246419 TI - Are inflammatory cells increased in painful human tendinopathy? A systematic review. AB - BACKGROUND: The role of inflammation in tendinopathy has historically been a subject of significant controversy. Our primary aim was to determine whether inflammatory cell numbers were increased in painful human tendinopathy versus healthy control tendons. Our secondary aim was to assess whether the inflammatory cells had been linked with symptoms or disease stage. METHODS: We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines of the Medline database using specific search criteria. Only studies measuring inflammatory cells using specific markers in tissue from human patients with the clinical diagnosis of tendinopathy were included. Inclusion was agreed on by 2 independent researchers on review of abstracts or full-text using specific predetermined criteria. The search yielded 5 articles in total. RESULTS: There were increased numbers of macrophages (4 studies) and mast cells (3 studies) in tendinopathic versus healthy control tissues. One study demonstrated increased numbers of T cells in tendinopathic tissue versus healthy control tendons. There were reduced numbers of T cells (1 study), macrophages (2 studies) and mast cells (2 studies) in torn tendon versus intact tendinopathic tissue. CONCLUSIONS: The existing evidence supports the hypothesis that increased numbers of inflammatory cells are present in pathological tendons. The lack of high quality quantitative studies in this area demonstrates a clear need for future research to better understand the role of inflammation in tendinopathy. PMID- 26246420 TI - Learning to tune the antero-posterior propulsive forces during walking: a necessary skill for mastering upright locomotion in toddlers. AB - This study examines the process of learning to walk from a functional perspective. To move forward, one must generate and control propulsive forces. To achieve this, it is necessary to create and tune a distance between the centre of mass (CoM) and the centre of pressure (CoP) along the antero-posterior axis. We hypothesize that learning to walk consists of learning how to calibrate these self-generated propulsive forces to control such distance. We investigated this question with six infants (three girls and three boys) who we followed up weekly for the first 8 weeks after the onset of walking and then biweekly until they reached 14-16 weeks of walking experience. The infants' walking patterns (kinematics and propelling forces) were captured via synched motion analysis and force plate. The results show that the distance between the CoM and the CoP along the antero-posterior axis increased rapidly during the first months of learning to walk and that this increase was correlated with an increase in velocity. The initial small values of (CoM-CoP) observed at walking onset, coupled with small velocity are interpreted as the solution infants adopted to satisfy a compromise between the need to generate propulsive forces to move forward while simultaneously controlling the disequilibrium resulting from creating a with distance between the CoM and CoP. PMID- 26246422 TI - Caring for sex workers. PMID- 26246421 TI - Deacetylation of alpha-tubulin and cortactin is required for HDAC6 to trigger ciliary disassembly. AB - Cilia play important roles in sensing extracellular signals and directing fluid flow. Ciliary dysfunction is associated with a variety of diseases known as ciliopathies. Histone deacetylase 6 (HDAC6) has recently emerged as a major driver of ciliary disassembly, but little is known about the downstream players. Here we provide the first evidence that HDAC6-mediated deacetylation of alpha tubulin and cortactin is critical for its induction of ciliary disassembly. HDAC6 is localized in the cytoplasm and enriched at the centrosome and basal body. Overexpression of HDAC6 decreases the levels of acetylated alpha-tubulin and cortactin without affecting the expression or localization of known ciliary regulators. We also find that overexpression of alpha-tubulin or cortactin or their acetylation-deficient mutants enhances the ability of HDAC6 to induce ciliary disassembly. In addition, acetylation-mimicking mutants of alpha-tubulin and cortactin counteract HDAC6-induced ciliary disassembly. Furthermore, HDAC6 stimulates actin polymerization, and inhibition of actin polymerization abolishes the activity of HDAC6 to trigger ciliary disassembly. These findings provide mechanistic insight into the ciliary role of HDAC6 and underscore the importance of reversible acetylation in regulating ciliary homeostasis. PMID- 26246423 TI - Ex Vivo Assessment of Drug Activity in Patient Tumor Cells as a Basis for Tailored Cancer Therapy. AB - Although medical cancer treatment has improved during the past decades, it is difficult to choose between several first-line treatments supposed to be equally active in the diagnostic group. It is even more difficult to select a treatment after the standard protocols have failed. Any guidance for selection of the most effective treatment is valuable at these critical stages. We describe the principles and procedures for ex vivo assessment of drug activity in tumor cells from patients as a basis for tailored cancer treatment. Patient tumor cells are assayed for cytotoxicity with a panel of drugs. Acoustic drug dispensing provides great flexibility in the selection of drugs for testing; currently, up to 80 compounds and/or combinations thereof may be tested for each patient. Drug response predictions are obtained by classification using an empirical model based on historical responses for the diagnosis. The laboratory workflow is supported by an integrated system that enables rapid analysis and automatic generation of the clinical referral response. PMID- 26246424 TI - HBP21, a chaperone of heat shock protein 70, functions as a tumor suppressor in hepatocellular carcinoma. AB - Inactivation of tumor suppressor genes, caused by genetic and epigenetic alterations, is one of the key issues in the development and progression of cancer. To identify and characterize cancer related genes in hepatocellular carcinoma (HCC) pathogenesis, transcriptome sequencing has been applied to compare expression profiles between tumor and non-tumor tissues. Among the down regulated genes, heat shock binding protein 21 (HBP21) was selected for further study. In this study, down-regulation of HBP21 was frequently detected in primary HCCs (87/120, 72.5%), which was significantly associated with advanced clinical stage (P = 0.049), poor differentiation (P = 0.018) and poor prognosis (P = 0.026). Further study found that down-regulation of HBP21 in HCC was mainly caused by allele loss and promoter methylation. Functional study found that HBP21 could inhibit tumor cell growth rate, foci formation and colony formation in soft agar, and tumor formation in nude mice when it was transfected into HCC cells. Molecular study found that HBP21 could promote cell apoptosis, especially under adverse conditions such as heat and chemotherapeutic agent treatment. As a chaperone of heat shock protein 70 (HSP70), HBP21 could inhibit interaction between HSP70 and Bax, increased Bax protein translocation from cytoplasm to mitochondria, and subsequently increased the release of cytochrome c into cytoplasm, and finally induced apoptosis. Clinically, HBP21 could be used as a prognostic biomarker for HCC outcome prediction and might be also as a novel therapeutic agent in HCC treatment. PMID- 26246426 TI - High prevalence of subclinical hypothyroidism and nodular thyroid disease in patients on hemodialysis. AB - Chronic kidney disease has been known to affect thyroid hormone metabolism. Low serum levels of T3 and T4 are the most remarkable laboratorial findings. A high incidence of goiter and nodules on thyroid ultrasonography has been reported in patients with end-stage renal disease (ESRD). Our objective is to evaluate the prevalence of laboratorial and morphologic alterations in the thyroid gland in a cohort of patients with ESRD on hemodialysis (HD). Sixty-one patients with ESRD on HD were selected and compared with 43 healthy subjects matched by age, gender, and weight. Patients were submitted to thyroid ultrasonography. T3, free T4 (FT4), thyroid-stimulating hormone, antithyroglobulin, and antithyroperoxidase antibodies were measured. The mean age of patients with ESRD was 47.4 +/- 12.3 and 61% were women. ESRD was mainly caused by hypertensive nephrosclerosis and diabetic nephropathy. Mean thyroid volume, as determined by ultrasonography, was similar in both groups. Patients with ESRD had more hypoechoic nodules when compared with the control group (24.1% vs. 7.9%, P = 0.056). Mean serum FT4 and T3 levels were significantly lower in patients with ESRD, and subclinical hypothyroidism was more prevalent in patients with ESRD (21.82% vs. 7.14% control group, P = 0.04). Titers of antithyroid antibodies were similar in both groups. ESRD was associated with a higher prevalence of subclinical hypothyroidism and lower levels of T3 and FT4. Almost a quarter of patients showed thyroid nodules >10 mm. Periodic ultrasound evaluation and assessment of thyroid function are recommended in patients with ESRD on HD. PMID- 26246425 TI - Black raspberries suppress colonic adenoma development in ApcMin/+ mice: relation to metabolite profiles. AB - Freeze-dried black raspberries (BRBs) have demonstrated chemopreventive effects in a dietary intervention trial with human colorectal cancer patients. The aim of this study was to investigate BRB-caused metabolite changes using the Apc(Min/+) mouse as a model of human colorectal cancer. Wild-type (WT) mice were fed control diet, and Apc(Min/+) mice were fed either control diet or control diet supplemented with 5% BRBs for 8 weeks. Colonic and intestinal polyp size and number were measured. A non-targeted metabolomic analysis was conducted on colonic mucosa, liver and fecal specimens. Eight weeks of BRB treatment significantly decreased intestinal and colonic polyp number and size in Apc(Min/+) mice. The apc gene mutation significantly changed 52 metabolites in colonic mucosa associated with increased amino acid and decreased lipid metabolites, as well as 39 liver and 8 fecal metabolites. BRBs significantly reversed 23 apc-regulated metabolites, including 13 colonic mucosa, 8 liver and 2 fecal metabolites that were involved in amino acid, glutathione, lipid and nucleotide metabolism. Of these, changes in eight metabolites were linearly correlated with decreased colonic polyp number and size in BRB-treated Apc(Min/+) mice. Elevated levels of putrescine and linolenate in Apc(Min/+) mice were significantly decreased by BRBs. Ornithine decarboxylase expression, the key enzyme in putrescine generation, was fully suppressed by BRBs. These results suggest that BRBs produced beneficial effects against colonic adenoma development in Apc(Min/+) mice and modulated multiple metabolic pathways. The metabolite changes produced by BRBs might potentially reflect the BRB-mediated chemopreventive effects in colorectal cancer patients. PMID- 26246427 TI - Proximal tubule NHE3 activity is inhibited by beta-arrestin-biased angiotensin II type 1 receptor signaling. AB - Physiological concentrations of angiotensin II (ANG II) upregulate the activity of Na(+)/H(+) exchanger isoform 3 (NHE3) in the renal proximal tubule through activation of the ANG II type I (AT1) receptor/G protein-coupled signaling. This effect is key for maintenance of extracellular fluid volume homeostasis and blood pressure. Recent findings have shown that selective activation of the beta arrestin-biased AT1 receptor signaling pathway induces diuresis and natriuresis independent of G protein-mediated signaling. This study tested the hypothesis that activation of this AT1 receptor/beta-arrestin signaling inhibits NHE3 activity in proximal tubule. To this end, we determined the effects of the compound TRV120023, which binds to the AT1R, blocks G-protein coupling, and stimulates beta-arrestin signaling on NHE3 function in vivo and in vitro. NHE3 activity was measured in both native proximal tubules, by stationary microperfusion, and in opossum proximal tubule (OKP) cells, by Na(+)-dependent intracellular pH recovery. We found that 10(-7) M TRV120023 remarkably inhibited proximal tubule NHE3 activity both in vivo and in vitro. Additionally, stimulation of NHE3 by ANG II was completely suppressed by TRV120023 both in vivo as well as in vitro. Inhibition of NHE3 activity by TRV120023 was associated with a decrease in NHE3 surface expression in OKP cells and with a redistribution from the body to the base of the microvilli in the rat proximal tubule. These findings indicate that biased signaling of the beta-arrestin pathway through the AT1 receptor inhibits NHE3 activity in the proximal tubule at least in part due to changes in NHE3 subcellular localization. PMID- 26246428 TI - Imaging of oxygen gradients in giant umbrella cells: an ex vivo PLIM study. AB - O2 plays a pivotal role in aerobic metabolism and regulation of cell and tissue function. Local differences and fluctuations in tissue O2 levels are well documented; however, the physiological significance of O2 microgradients, particularly at the subcellular level, remains poorly understood. Using the cell penetrating phosphorescent O2 probe Pt-Glc and confocal fluorescence microscopy, we visualized O2 distribution in individual giant (>100-MUm) umbrella cells located superficially in the urinary bladder epithelium. We optimized conditions for in vivo phosphorescent staining of the inner surface of the mouse bladder and subsequent ex vivo analysis of excised live tissue. Imaging experiments revealed significant (<=85 MUM) and heterogeneous deoxygenation within respiring umbrella cells, with radial O2 gradients of up to 40 MUM across the cell, or ~0.6 MUM/MUm. Deeply deoxygenated (5-15 MUM O2) regions were seen to correspond to the areas enriched with polarized mitochondria. Pharmacological activation of mitochondrial respiration decreased oxygenation and O2 gradients in umbrella cells, while inhibition with antimycin A dissipated the gradients and caused gradual reoxygenation of the tissue to ambient levels. Detailed three-dimensional maps of O2 distribution potentially can be used for the modeling of intracellular O2 dependent enzymatic reactions and downstream processes, such as hypoxia-inducible factor signaling. Further ex vivo and in vivo studies on intracellular and tissue O2 gradients using confocal imaging can shed light on the molecular mechanisms regulating O2-dependent (patho)physiological processes in the bladder and other tissues. PMID- 26246430 TI - Inverse Correlation between the Atrial Fibrillatory Rate and the Ventricular Repolarization Time: Observations at Baseline and after an Intravenous Infusion of a Combined Potassium and Sodium Current Blocker. AB - BACKGROUND: The atrial fibrillatory rate (AFR) and the ventricular rate and repolarization (QTcF) were studied at baseline and under the influence of the combined potassium and sodium current blocker AZD7009. METHODS: Ninety-two patients with atrial fibrillation (AF) were randomized to an intravenous infusion of AZD7009 or placebo. The atrial fibrillatory activity in lead V1 was extracted using spatiotemporal QRST cancellation. The exponential decay (ED) characterized the degree of atrial signal organization. RESULTS: The mean (SD) AFR at baseline was 396 +/- 57 (range 253-584) and 410 +/- 33 (range 363-469) bpm in patients randomized to AZD7009 and placebo, respectively. The AFR decreased within the first minutes of the AZD7009 infusion and reached its minimum of 235 +/- 34 bpm after 18 minutes. On placebo, the AFR was unchanged. On AZD7009, the ED decreased from 1.2 +/- 0.3 to reach its lowest level at 0.7 +/- 0.2 after 14 minutes. The ventricular rate did not change significantly over time. The AFR was statistically significantly related to the ventricular repolarization at baseline, the QTcF being longer at lower AFR values, and this relationship remained during and after AZD7009. In the full multivariate linear regression model, including age, sex, left ventricular ejection fraction, QRS duration, heart rate, QTcF, AF episode duration, AF history duration, and right atrial or left atrial size, only QTcF and age were statistically significantly correlated with the AFR. The correlation remained when the uncorrected QT interval was used. CONCLUSIONS: The QTcF was inversely correlated with AFR, both at baseline and during administration of AZD7009. The AFR was not correlated with the ventricular rate. PMID- 26246429 TI - Separating myoblast differentiation from muscle cell fusion using IGF-I and the p38 MAP kinase inhibitor SB202190. AB - The p38 MAP kinases play critical roles in skeletal muscle biology, but the specific processes regulated by these kinases remain poorly defined. Here we find that activity of p38alpha/beta is important not only in early phases of myoblast differentiation, but also in later stages of myocyte fusion and myofibrillogenesis. By treatment of C2 myoblasts with the promyogenic growth factor insulin-like growth factor (IGF)-I, the early block in differentiation imposed by the p38 chemical inhibitor SB202190 could be overcome. Yet, under these conditions, IGF-I could not prevent the later impairment of muscle cell fusion, as marked by the nearly complete absence of multinucleated myofibers. Removal of SB202190 from the medium of differentiating myoblasts reversed the fusion block, as multinucleated myofibers were detected several hours later and reached ~90% of the culture within 30 h. Analysis by quantitative mass spectroscopy of proteins that changed in abundance following removal of the inhibitor revealed a cohort of upregulated muscle-enriched molecules that may be important for both myofibrillogenesis and fusion. We have thus developed a model system that allows separation of myoblast differentiation from muscle cell fusion and should be useful in identifying specific steps regulated by p38 MAP kinase mediated signaling in myogenesis. PMID- 26246431 TI - Identification of beta-sitosterol and stigmasterol in Bambusa bambos (L.) Voss leaf extract using HPLC and its estrogenic effect in vitro. AB - Focus of the study is to identify a safe alternate to Hormone Replacement Therapy by identifying the presence of beta-sitosterol and stigmasterol in the hydroalcoholic extract of Bambusa bambos using HPTLC and RP-HPLC-PDA; by evaluating the estrogenic effects of extract containing beta-sitosterol and stigmasterol on the growth of MCF-7 cells in vitro. Plant material was identified by DNA sequencing analysis. Presence of beta-sitosterol and stigmasterol was confirmed by HPTLC and direct RP-HPLC-PDA. Peaks with retention time about 19.13 and 21.16min were found to be stigmasterol and beta-sitosterol in extract. Extract was not cytotoxic to MCF-7 cells in any of the dilutions. It induced cell proliferation and all the dilutions except <500MUg/ml have significantly increased cell multiplication. 15.6, 31.2, 62.5 and 125MUg/ml of HEBB have shown influence on the proliferation rates similar to the standard 17beta-estradiol. The results suggest that HEBB might be used as a safe alternative to estrogen replacement therapies. PMID- 26246432 TI - Oral presentations - XLII Annual ESAO Congress, 2-5 September 2015, Leuven, Belgium. AB - Abstracts from the XLII Congress of the European Society for Artificial Organs, 2 5 September 2015, Leuven, Belgium. PMID- 26246433 TI - Posters - XLII Annual ESAO Congress, 2-5 September 2015, Leuven, Belgium. AB - Abstracts from the XLII Congress of the European Society for Artificial Organs, 2 5 September 2015, Leuven, Belgium. PMID- 26246435 TI - Neural Excitability and Singular Bifurcations. AB - We discuss the notion of excitability in 2D slow/fast neural models from a geometric singular perturbation theory point of view. We focus on the inherent singular nature of slow/fast neural models and define excitability via singular bifurcations. In particular, we show that type I excitability is associated with a novel singular Bogdanov-Takens/SNIC bifurcation while type II excitability is associated with a singular Andronov-Hopf bifurcation. In both cases, canards play an important role in the understanding of the unfolding of these singular bifurcation structures. We also explain the transition between the two excitability types and highlight all bifurcations involved, thus providing a complete analysis of excitability based on geometric singular perturbation theory. PMID- 26246436 TI - Cognitive dysfunction associated with pain and quality of life in chronic rhinosinusitis. AB - BACKGROUND: Cognitive dysfunction and its relationship to both pain and disease specific quality of life (QOL) in chronic rhinosinusitis (CRS) have not been investigated previously. We sought to analyze the correlations of pain and disease-specific QOL with cognitive function in CRS. METHODS: Adults with CRS were prospectively enrolled in a cross-sectional study. Participants' cognitive function was assessed using the Cognitive Failures Questionnaire. Pain was characterized using the Short-Form McGill Pain Questionnaire (SF-MPQ) and the Brief Pain Inventory Short Form. Disease-specific QOL was ascertained using the Rhinosinusitis Disability Index (RSDI) and 22-item Sinonasal Outcome Test (SNOT 22). Disease severity was assessed using nasal endoscopy and computed tomography. Bivariate correlations of pain and cognitive dysfunction, disease-specific QOL, and clinical measures of disease severity were ascertained. RESULTS: In patients with CRS (n = 70) there was a significant correlation between cognitive dysfunction and pain severity scores (Spearman's correlation [R(s)] = 0.321, p < 0.01). A similar correlation was identified with pain interference (R(s) = 0.317, p < 0.01) and cognitive dysfunction scores. This is mirrored by a significant correlation between another measure of pain severity, the SF-MPQ and cognitive dysfunction (R(s) = 0.498, p < 0.01). In patients with CRS there was a significant correlation between disease-specific QOL scores and cognitive function scores as measured by the SNOT-22 (R(s) = 0.395, p < 0.01) and the RSDI (R(s) = 0.528, p < 0.01). CONCLUSION: In patients with CRS, increasing pain and worse QOL are associated with cognitive dysfunction. Possible mechanisms for this cognitive dysfunction include differential neural activation secondary to chronic pain and/or the sequela of a chronic inflammatory state. PMID- 26246437 TI - Obituary. PMID- 26246439 TI - Pollination Services of Mango Flower Pollinators. AB - Measuring wild pollinator services in agricultural production is very important in the context of sustainable management. In this study, we estimated the contribution of native pollinators to mango fruit set production of two mango cultivars Mangifera indica (L). cv. 'Sala' and 'Chok Anan'. Visitation rates of pollinators on mango flowers and number of pollen grains adhering to their bodies determined pollinator efficiency for reproductive success of the crop. Chok Anan failed to produce any fruit set in the absence of pollinators. In natural condition, we found that Sala produced 4.8% fruit set per hermaphrodite flower while Chok Anan produced 3.1% per flower. Hand pollination tremendously increased fruit set of naturally pollinated flower for Sala (>100%), but only 33% for Chok Anan. Pollinator contribution to mango fruit set was estimated at 53% of total fruit set production. Our results highlighted the importance of insect pollinations in mango production. Large size flies Eristalinus spp. and Chrysomya spp. were found to be effective pollen carriers and visited more mango flowers compared with other flower visitors. PMID- 26246438 TI - Neural activity in monkey amygdala during performance of a multisensory operant task. AB - In this paper, we study the potential involvement of monkey amygdala in the evaluation of value encoding of visual and auditive stimuli associated with reward or no reward. We recorded the activity of 93 extracellular neurons from the monkey right amygdala, while performing a multisensory operant task. The activity of 78 task-related neurons was studied. Of these, 13 neurons (16%) responded to the value of visual stimuli, 22 neurons (28%) responded after the presentation of visual stimuli, 22 neurons (28%) showed an inhibition around the lever-pressing and were classified as action related neurons and 22 neurons (28%) responded after reward delivery. These findings suggest that neurons in the amygdala play a role in encoding value and processing visual information, participate in motor regulation and are sensitive to reward. The activity of these neurons did not change in the evaluation of auditive stimuli. These data support the hypothesis that amygdala neurons are specific to each sensory modality and that different groups of amygdala neurons process visual and auditive information. PMID- 26246440 TI - Natural Enemies of the Frankliniella Complex Species (Thysanoptera: Thripidae) in Ataulfo Mango Agroecosystems. AB - A field survey was conducted in Ataulfo mango (Mangifera indica L.) orchards in Chiapas, Mexico, with the objective of determining the natural enemies of the Frankliniella complex species (Thysanoptera: Thripidae). Seven species of this genus feed and reproduce in large numbers during the mango flowering. Two representative orchards were selected: the orchard "Tres A" characterized by an intensive use of agrochemicals directed against thrips, and the orchard "La Escondida" that did not spray insecticides. During mango flowering, five inflorescences were randomly collected every 5 d in both orchards, for a total of 18 sampling dates. Results revealed the presence of 18 species of arthropods that were found predating on Frankliniella. There were 11 species in the families Aeolothripidae, Phlaeothripidae, Formicidae, Anthocoridae and Chrysopidae; and seven species of spiders in the families Araneidae, Tetragnathidae, and Uloboridae. Over 88% of predators were anthocorids, including, Paratriphleps sp. (Champion), Orius insidiosus (Say), Orius tristicolor (White), and O. perpunctatus (Reuter). The orchard that did not spray insecticides had a significantly higher number of predators suggesting a negative effect of the insecticides on the abundance of these organisms. PMID- 26246442 TI - Cancer survival in England still lags behind similar countries, study shows. PMID- 26246441 TI - Seasonal Changes in the Caste Distribution of Foraging Populations of Formosan Subterranean Termite in New Orleans, Louisiana. AB - This study examined the relationship between temperature, precipitation, soil composition, levels of feeding damage, and the caste distribution (workers, soldiers, nymphs) of the Formosan subterranean termite, Coptotermes formosanus Shiraki, collected in underground monitoring stations over a 12 mo period. Because nymphs are the caste that develops into alates, the seasonal abundance of nymphs was examined over a 5 yr period. Numbers of workers, soldiers, and soldier/worker ratio were significantly affected by month. Recruitment and retention of foraging termites in stations was significantly affected by the level of feeding damage. The number of nymphs collected in monitoring stations was highly variable. In the 12 mo test, there was a significant correlation between numbers of nymphs and level of feeding damage, temperature, precipitation, and soil composition. Over a 5 yr period, significantly more nymphs were collected in 2011 than in 2007 and 2008. Peak nymph collections varied from year to year. Overall, peak nymph collections were more likely to occur in Mar., Sept., and Oct. Increasing our knowledge of the environmental factors that influence recruitment and retention of foraging termites in monitoring stations could influence termite bait placement and improve baiting strategies for termite control. Identifying the key factors that cause aggregations of nymphs in underground stations could increase our ability to predict the intensity and location of alate swarms. PMID- 26246444 TI - Inferior Vena Cava Filters: Indications, Outcomes, and Evidence. AB - OPINION STATEMENT: Filter technology seems relatively stable, although absorbable devices are an area of investigational interest. The indications for filter placement remain controversial, with wide variations in adherence to guidelines, and relatively poor quality of data about the specific prophylactic indications of trauma or bariatric surgery. The outcomes of filters are not well-defined despite widespread clinical use, and good data remains difficult to obtain. Several larger database and institutional retrospective studies support the notions that while filters prevent pulmonary embolism, they may be associated with venous thrombotic complications. Some subsets of cancer patients may be at increased risk of these complications, but whether the filter or the underlying hypercoagulable state is the cause is not clear. Lastly, although the benefits of filter retrieval are widely assumed (but not proven), filter retrieval rates remain lower than expected. The single most influential factor in improving filter retrieval rates is dedicated follow-up with intent to retrieve the filter. PMID- 26246445 TI - Early memories: Clinical relevance and significance. AB - OBJECTIVE: The purpose of this research was to examine earliest memories in patients with a mental disorder and their clinical relevance to diagnosis and treatment. METHOD: A semi-structured early memory questionnaire was developed and 50 patients with anxiety, depression or a psychotic disorder were interviewed. A thematic analysis was conducted to extract dominant themes from the qualitative data. RESULTS: Family events, play, and receiving attention were dominant themes of pleasant memories, while unpleasant memories consisted of fear-provoking situations, abuse/violence, and death-related themes. Participants were able to recall the feelings they had experienced at the time of their earliest memories and most participants stated that their first memories had significant impact in their lives. CONCLUSIONS: The findings of this exploratory study suggest that earliest memories may be of clinical significance for diagnostic and therapeutic interventions in psychiatry. PMID- 26246443 TI - The Imperial College Cambridge Manchester (ICCAM) platform study: An experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part A: Study description. AB - Drug and alcohol dependence are global problems with substantial societal costs. There are few treatments for relapse prevention and therefore a pressing need for further study of brain mechanisms underpinning relapse circuitry. The Imperial College Cambridge Manchester (ICCAM) platform study is an experimental medicine approach to this problem: using functional magnetic resonance imaging (fMRI) techniques and selective pharmacological tools, it aims to explore the neuropharmacology of putative relapse pathways in cocaine, alcohol, opiate dependent, and healthy individuals to inform future drug development. Addiction studies typically involve small samples because of recruitment difficulties and attrition. We established the platform in three centres to assess the feasibility of a multisite approach to address these issues. Pharmacological modulation of reward, impulsivity and emotional reactivity were investigated in a monetary incentive delay task, an inhibitory control task, and an evocative images task, using selective antagonists for u-opioid, dopamine D3 receptor (DRD3) and neurokinin 1 (NK1) receptors (naltrexone, GSK598809, vofopitant/aprepitant), in a placebo-controlled, randomised, crossover design. In two years, 609 scans were performed, with 155 individuals scanned at baseline. Attrition was low and the majority of individuals were sufficiently motivated to complete all five sessions (n=87). We describe herein the study design, main aims, recruitment numbers, sample characteristics, and explain the test hypotheses and anticipated study outputs. PMID- 26246446 TI - A case report using the mental state examination scale (MSES): a tool for measuring change in mental state. AB - OBJECTIVE: There is a need for a simple and brief tool that can be used in routine clinical practice for the quantitative measurement of mental state across all diagnostic groups. The main utilities of such a tool would be to provide a global metric for the mental state examination, and to monitor the progression over time using this metric. METHOD: We developed the mental state examination scale (MSES), and used it in an acute inpatient setting in routine clinical work to test its initial feasibility. RESULTS: Using a clinical case, the utility of MSES is demonstrated in this paper. When managing the patient described, the MSES assisted the clinician to assess the initial mental state, track the progress of the recovery, and make timely treatment decisions by quantifying the components of the mental state examination. CONCLUSION: MSES may enhance the quality of clinical practice for clinicians, and potentially serve as an index of universal mental healthcare outcome that can be used in clinical practice, service evaluation, and healthcare economics. PMID- 26246447 TI - GLYCOLATE OXIDASE3, a Glycolate Oxidase Homolog of Yeast l-Lactate Cytochrome c Oxidoreductase, Supports l-Lactate Oxidation in Roots of Arabidopsis. AB - In roots of Arabidopsis (Arabidopsis thaliana), l-lactate is generated by the reduction of pyruvate via l-lactate dehydrogenase, but this enzyme does not efficiently catalyze the reverse reaction. Here, we identify the Arabidopsis glycolate oxidase (GOX) paralogs GOX1, GOX2, and GOX3 as putative l-lactate metabolizing enzymes based on their homology to CYB2, the l-lactate cytochrome c oxidoreductase from the yeast Saccharomyces cerevisiae. We found that GOX3 uses l lactate with a similar efficiency to glycolate; in contrast, the photorespiratory isoforms GOX1 and GOX2, which share similar enzymatic properties, use glycolate with much higher efficiencies than l-lactate. The key factor making GOX3 more efficient with l-lactate than GOX1 and GOX2 is a 5- to 10-fold lower Km for the substrate. Consequently, only GOX3 can efficiently metabolize l-lactate at low intracellular concentrations. Isotope tracer experiments as well as substrate toxicity tests using GOX3 loss-of-function and overexpressor plants indicate that l-lactate is metabolized in vivo by GOX3. Moreover, GOX3 rescues the lethal growth phenotype of a yeast strain lacking CYB2, which cannot grow on l-lactate as a sole carbon source. GOX3 is predominantly present in roots and mature to aging leaves but is largely absent from young photosynthetic leaves, indicating that it plays a role predominantly in heterotrophic rather than autotrophic tissues, at least under standard growth conditions. In roots of plants grown under normoxic conditions, loss of function of GOX3 induces metabolic rearrangements that mirror wild-type responses under hypoxia. Thus, we identified GOX3 as the enzyme that metabolizes l-lactate to pyruvate in vivo and hypothesize that it may ensure the sustainment of low levels of l-lactate after its formation under normoxia. PMID- 26246448 TI - Meta-Analysis of Arabidopsis KANADI1 Direct Target Genes Identifies a Basic Growth-Promoting Module Acting Upstream of Hormonal Signaling Pathways. AB - An intricate network of antagonistically acting transcription factors mediates the formation of a flat leaf lamina of Arabidopsis (Arabidopsis thaliana) plants. In this context, members of the class III homeodomain leucine zipper (HD-ZIPIII) transcription factor family specify the adaxial domain (future upper side) of the leaf, while antagonistically acting KANADI transcription factors determine the abaxial domain (future lower side). Here, we used a messenger RNA sequencing approach to identify genes regulated by KANADI1 (KAN1) and subsequently performed a meta-analysis combining our data sets with published genome-wide data sets. Our analysis revealed that KAN1 acts upstream of several genes encoding auxin biosynthetic enzymes. When exposed to shade, we found three YUCCA genes, YUC2, YUC5, and YUC8, to be transcriptionally up-regulated, which correlates with an increase in the levels of free auxin. When ectopically expressed, KAN1 is able to transcriptionally repress these three YUC genes and thereby block shade-induced auxin biosynthesis. Consequently, KAN1 is able to strongly suppress shade avoidance responses. Taken together, we hypothesize that HD-ZIPIII/KAN form the basis of a basic growth-promoting module. Hypocotyl extension in the shade and outgrowth of new leaves both involve auxin synthesis and signaling, which are under the direct control of HD-ZIPIII/KAN. PMID- 26246449 TI - Mechanistic Insights in Ethylene Perception and Signal Transduction. AB - The gaseous hormone ethylene profoundly affects plant growth, development, and stress responses. Ethylene perception occurs at the endoplasmic reticulum membrane, and signal transduction leads to a transcriptional cascade that initiates diverse responses, often in conjunction with other signals. Recent findings provide a more complete picture of the components and mechanisms in ethylene signaling, now rendering a more dynamic view of this conserved pathway. This includes newly identified protein-protein interactions at the endoplasmic reticulum membrane, as well as the major discoveries that the central regulator ETHYLENE INSENSITIVE2 (EIN2) is the long-sought phosphorylation substrate for the CONSTITUTIVE RESPONSE1 protein kinase, and that cleavage of EIN2 transmits the signal to the nucleus. In the nucleus, hundreds of potential gene targets of the EIN3 master transcription factor have been identified and found to be induced in transcriptional waves, and transcriptional coregulation has been shown to be a mechanism of ethylene cross talk. PMID- 26246450 TI - Regulation of Nicotine Biosynthesis by an Endogenous Target Mimicry of MicroRNA in Tobacco. AB - The interaction between noncoding endogenous target mimicry (eTM) and its corresponding microRNA (miRNA) is a newly discovered regulatory mechanism and plays pivotal roles in various biological processes in plants. Tobacco (Nicotiana tabacum) is a model plant for studying secondary metabolite alkaloids, of which nicotine accounts for approximately 90%. In this work, we identified four unique tobacco-specific miRNAs that were predicted to target key genes of the nicotine biosynthesis and catabolism pathways and an eTM, novel tobacco miRNA (nta) eTMX27, for nta-miRX27 that targets QUINOLINATE PHOSPHORIBOSYLTRANSFERASE2 (QPT2) encoding a quinolinate phosphoribosyltransferase. The expression level of nta miRX27 was significantly down-regulated, while that of QPT2 and nta-eTMX27 was significantly up-regulated after topping, and consequently, nicotine content increased in the topping-treated plants. The topping-induced down-regulation of nta-miRX27 and up-regulation of QPT2 were only observed in plants with a functional nta-eTMX27 but not in transgenic plants containing an RNA interference construct targeting nta-eTMX27. Our results demonstrated that enhanced nicotine biosynthesis in the topping-treated tobacco plants is achieved by nta-eTMX27 mediated inhibition of the expression and functions of nta-miRX27. To our knowledge, this is the first report about regulation of secondary metabolite biosynthesis by an miRNA-eTM regulatory module in plants. PMID- 26246452 TI - Massive hiatus hernia complicated by jaundice. AB - Giant para-oesophageal hernia may include pancreas with pancreatic complication and rarely jaundice. Repair is feasible and durable by laparoscopy. Magnetic resonance cholangiopancreatography is diagnostic. PMID- 26246451 TI - Role of Ethylene and Its Cross Talk with Other Signaling Molecules in Plant Responses to Heavy Metal Stress. AB - Excessive heavy metals (HMs) in agricultural lands cause toxicities to plants, resulting in declines in crop productivity. Recent advances in ethylene biology research have established that ethylene is not only responsible for many important physiological activities in plants but also plays a pivotal role in HM stress tolerance. The manipulation of ethylene in plants to cope with HM stress through various approaches targeting either ethylene biosynthesis or the ethylene signaling pathway has brought promising outcomes. This review covers ethylene production and signal transduction in plant responses to HM stress, cross talk between ethylene and other signaling molecules under adverse HM stress conditions, and approaches to modify ethylene action to improve HM tolerance. From our current understanding about ethylene and its regulatory activities, it is believed that the optimization of endogenous ethylene levels in plants under HM stress would pave the way for developing transgenic crops with improved HM tolerance. PMID- 26246453 TI - Barriers and facilitators to shelter utilization among homeless young adults. AB - Rates of shelter use among homeless youth are low compared to use of other supportive services, yet research on barriers to shelter use has been conducted in limited regions, specifically in West Coast or Midwest cities. Additionally, while studies have generally focused on barriers to shelter use, studies on what might facilitate shelter use are lacking. This study explores barriers and facilitators to shelter use among homeless young adults from a large city in the Southwest region. Focus groups were conducted with a diverse sample of 49 homeless young adults ages 18-24. Drawing on models of health service use, findings were categorized into two domains--attitudinal and access. Themes related to attitudinal barriers include stigma/shame and self-reliance/pride. Attitudinal facilitators include the desire to extricate themselves from street life and turn their lives in a new direction. Access-related themes include barriers such as a lack of shelters and services available to meet the needs of youth, adverse shelter conditions, staff attitudes that are not acceptable to youth, restrictive shelter rules, restrictive definitions of homelessness, and a desire to differentiate themselves from older homeless individuals. Certain characteristics or circumstances (e.g., being pregnant), having supportive others, and shelters' ability to connect them to other services emerged as access facilitators to shelter use. Implications for policymakers, service providers, and future research are discussed. PMID- 26246454 TI - Factors predicting perioperative delirium and acute exacerbation of behavioral and psychological symptoms of dementia based on admission data in elderly patients with proximal femoral fracture: A retrospective study. AB - AIM: To examine factors predicting the onset of perioperative delirium and acute exacerbation of behavioral and psychological symptoms of dementia (BPSD), based on patient background, operative background and laboratory data obtained on admission, in elderly patients with proximal femoral fracture. METHODS: The participants were 152 patients (aged >70 years) who underwent surgery between 1 November 2012 and 31 March 2014. The participants were classified into group B (with onset of perioperative delirium or acute exacerbation of BPSD, n = 52), or group N, (without onset, n = 100), and risk factors were retrospectively examined. Onset was judged based on the presence or absence of common items; that is, "hallucination and delusion," "disturbing speech," "excitatory behavior" and "altered sleep-wake cycle." The participants were observed for 1 week after admission. RESULTS: The incidence of perioperative delirium or acute exacerbation of BPSD was 34.2% in total. In univariate analysis, the incidence was significantly higher (P < 0.005) in group B for the age, history of dementia and serum albumin level items. In multivariate analysis, history of dementia, serum albumin level and peripheral lymphocyte count (odds ratio 3.55, 0.17, 1.00, respectively) were identified as independent predictive factors. In the subanalysis, the incidence was 91.3% in the group with a history of dementia, serum albumin level <3.7 g/dL and peripheral lymphocyte count < 1200/MUL. CONCLUSIONS: History of dementia, a low serum albumin level and low peripheral lymphocyte count were found to be useful factors for predicting the onset of perioperative delirium and acute exacerbation of BPSD. Geriatr Gerontol Int 2016; 16: 821-828. PMID- 26246455 TI - Outcomes of open partial nephrectomies performed by Australian trainees. AB - BACKGROUND: Partial nephrectomy (PN) has become the standard of care for small renal tumours, with open partial nephrectomy (OPN) being superseded by minimally invasive PN. Advances in minimal access surgery have resulted in fewer relative contraindications, with subsequently fewer OPN being performed. Consequentially, trainees have less opportunity to gain skills and experience in open renal surgery. The aims of this study were to assess the standard of OPN performed by Australian urological trainees and to define whether OPN is a safe and suitable training opportunity. METHOD: A retrospective review was undertaken on patients who underwent OPN performed by urology trainees from 2010 to 2014 at two training hospitals in Western Australia. Data collected included patient demographics, surgical and oncological outcomes and morbidity. RESULTS: Sixty patients underwent OPN, with a mean age of 56 years. Most tumours were single, with mean size 31 mm. Mean operative time was 157 min, with a mean cold ischaemic time of 27 min. Mean pre- and post-operative creatinine levels were equivalent (77 MUmol/L). The overall complication rate was 18%, with no documented urinary leaks, and 1.7% blood transfusion rate. Median length of stay was 4 days. There were no oncological positive margins or recurrence after a median follow-up of 2 years. CONCLUSION: Our data support the notion that Australian urological trainees can perform the majority of OPN cases, with equivalent oncological outcomes. We would advocate that when an OPN is being performed, the supervising consultant should use the case as an adjuvant for open renal surgery training. PMID- 26246456 TI - Current-induced giant polarization rotation using a ZnO single crystal doped with nitrogen ions. AB - Giant polarization rotation in a ZnO single crystal was experimentally demonstrated based on a novel phenomenon occurring at the nanometric scale. The ZnO crystal was doped with N(+) and N(2+) ions serving as p-type dopants. By applying an in-plane current using a unique arrangement of electrodes on the device, current-induced polarization rotation of the incident light was observed. From the results of experimental demonstrations and discussions, it was verified that this novel behavior originates from a specific distribution of dopants and the corresponding light-matter interactions in a nanometric space, which are allowed by the existence of such a dopant distribution. PMID- 26246457 TI - Environmentally Driven Increases in Type 2 Diabetes and Obesity in Pima Indians and Non-Pimas in Mexico Over a 15-Year Period: The Maycoba Project. AB - OBJECTIVE: The global epidemics of type 2 diabetes and obesity have been attributed to the interaction between lifestyle changes and genetic predisposition to these diseases. We compared the prevalences of type 2 diabetes and obesity in Mexican Pima Indians, presumed to have a high genetic predisposition to these diseases, to those in their non-Pima neighbors, both of whom over a 15-year period experienced a transition from a traditional to a more modern lifestyle. RESEARCH DESIGN AND METHODS: Prevalence of diabetes, impaired fasting glucose, impaired glucose tolerance, and obesity in Mexican Pimas (n = 359) and non-Pima Mexicans (n = 251) were determined in 2010 using methods identical to those used in 1995. RESULTS: During this 15-year period, age adjusted diabetes prevalence was unchanged in Pima men (5.8% in 1995 vs. 6.1% in 2010) yet increased in non-Pima men from 0.0 to 8.6% (P < 0.05). Diabetes prevalence tended to increase in both Pima women (9.4 vs. 13.4%) and non-Pima women (4.8 vs. 9.5%). Age-adjusted prevalence of obesity increased significantly in all groups (6.6 vs. 15.7% in Pima men; 8.5 vs. 20.5% in non-Pima men; 18.9. vs 36.3% in Pima women; 29.5 vs. 42.9% in non-Pima women). CONCLUSIONS: Type 2 diabetes prevalence increased between 1995 and 2010 in non-Pima men, and to a lesser degree in women of both groups, but it did not increase in Pima men. Prevalence of obesity increased among Pimas and non-Pimas of both sexes. These changes occurred concomitantly with an environmental transition from a traditional to a more modernized lifestyle. PMID- 26246458 TI - Randomized, Double-Blind, Phase 3 Trial of Triple Therapy With Dapagliflozin Add on to Saxagliptin Plus Metformin in Type 2 Diabetes. AB - OBJECTIVE: To compare the efficacy and safety of treatment with dapagliflozin versus that with placebo add-on to saxagliptin plus metformin in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin treatment. RESEARCH DESIGN AND METHODS: Patients receiving treatment with stable metformin (stratum A) (screening HbA1c level 8.0-11.5% [64-102 mmol/mol]) or stable metformin and a dipeptidyl peptidase-4 (DPP-4) inhibitor (stratum B) (HbA1c 7.5-10.5% [58-91 mmol/mol]) for >=8 weeks received open-label saxagliptin 5 mg/day and metformin for 16 weeks (stratum A) or 8 weeks (stratum B) (saxagliptin replaced any DPP-4 inhibitor). Patients with inadequate glycemic control (HbA1c 7-10.5% [53-91 mmol/mol]) were randomized to receive placebo or dapagliflozin 10 mg/day plus saxagliptin and metformin. The primary end point was the change in HbA1c from baseline to week 24. Secondary end points included fasting plasma glucose (FPG) level, 2-h postprandial glucose (PPG) level, body weight, and proportion of patients achieving an HbA1c level of <7% (53 mmol/mol). RESULTS: Treatment with dapagliflozin add-on to saxagliptin plus metformin resulted in a greater mean HbA1c reduction than placebo (-0.82 vs. -0.10% [-9 vs. -1.1 mmol/mol], P < 0.0001). Significantly greater reductions in FPG level, 2-h PPG level, and body weight were observed, and more patients achieved an HbA1c level of <7% (53 mmol/mol) with treatment with dapagliflozin versus placebo. Adverse events were similar across treatment groups, with a low overall risk of hypoglycemia (~1%). Genital infections developed in more patients with dapagliflozin treatment (5%) than with placebo (0.6%). CONCLUSIONS: Triple therapy with dapagliflozin add-on to saxagliptin plus metformin improves glycemic control and is well tolerated in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin therapy. PMID- 26246460 TI - Editorial: inflammatory activity in symptomatic knee osteoarthritis: not all inflammation is local. PMID- 26246461 TI - Bioethics: Under the Skin and on the Surface. PMID- 26246462 TI - Effects of triclosan and triclocarban on the growth inhibition, cell viability, genotoxicity and multixenobiotic resistance responses of Tetrahymena thermophila. AB - The information about adverse effects of emerging contaminants on aquatic protozoa is very scarce. The growth inhibition effect, cell viability, genotoxicity and multixenobiotic resistance (MXR) responses of two commonly used antimicrobial agents, triclosan (TCS) and triclocarban (TCC) to protozoan Tetrahymena thermophila were investigated in this study. The results revealed that TCS and TCC can inhibit the growth of T. thermophila with 24h EC50 values of 1063 and 295MUgL(-1), respectively. The impairment of plasma membrane was observed after 2h exposure of TCS or TCC at the level of mg/L. Furthermore, it is noticeable that at environmentally relevant concentration (1.0MUgL(-1)), both TCS and TCC can lead to statistically significant DNA damage in T. thermophila, while the inhibition of growth and change of cell viability cannot be observed. Our results firstly provide the evidence for genotoxic effects of TCS and TCC on the freshwater protozoan. Additionally, both TCS and TCC were found to inhibit the efflux transporter activities, with the inhibitory potencies of 39% and 40% (using verapamil as a model inhibitor), respectively. Particularly, TCC could significantly down-regulate the expression of MXR related gene Abcb15, which encodes the membrane efflux protein that acting as P-gp in T. thermophila. The results raise the awareness of potential aquatic ecological and human health risks from the exposure of TCS and TCC, as they might potentiate the toxic effects by chemosensitizing with co-existing toxicants. PMID- 26246463 TI - Doses of rosuvastatin, atorvastatin and simvastatin that induce equal reductions in LDL-C and non-HDL-C: Results from the VOYAGER meta-analysis. AB - BACKGROUND: Achieving the greatest reduction in atherogenic lipoproteins requires the optimum dose and potency of statin. Using data from the VOYAGER meta analysis, we determined doses of rosuvastatin, atorvastatin and simvastatin that induce equal reductions in low-density lipoprotein cholesterol (LDL-C) and non high-density lipoprotein cholesterol (non-HDL-C). METHODS: Least squares mean percentage change in LDL-C and non-HDL-C was calculated using 38,052 patient exposures to rosuvastatin 5-40 mg, atorvastatin 10-80 mg and simvastatin 10-80 mg. Equipotent doses were estimated by linear interpolation between actual adjacent doses. RESULTS: Rosuvastatin 5 mg reduced LDL-C by 39% and non-HDL-C by 35%. Equivalent reductions in LDL-C required atorvastatin 15 mg or simvastatin 39 mg. Equivalent reductions in non-HDL-C required atorvastatin 14 mg or simvastatin 42 mg. Rosuvastatin 10 mg reduced LDL-C by 44% and non-HDL-C by 40%. Equivalent reductions in LDL-C required atorvastatin 29 mg or simvastatin 72 mg. Equivalent reductions in non-HDL-C required atorvastatin 27 mg or simvastatin 77 mg. Rosuvastatin 20 mg reduced LDL-C by 50% and non-HDL-C by 45%. Equivalent reductions in LDL-C and non-HDL-C required atorvastatin 70 mg and atorvastatin 62 mg, respectively, and were not achieved with the maximum 80 mg dose of simvastatin. Rosuvastatin 40 mg reduced LDL-C by 55% and non-HDL-C by 50%. Comparable reductions were not achieved with the maximum 80 mg doses of atorvastatin or simvastatin. CONCLUSIONS: Regarding reductions in LDL-C and non HDL-C, each rosuvastatin dose is equivalent to doses 3-3.5 times higher for atorvastatin and 7-8 times higher for simvastatin. PMID- 26246464 TI - Formation and characterization of the boron dicarbonyl complex [B(CO)2](-). AB - We report the synthesis and spectroscopic characterization of the boron dicarbonyl complex [B(CO)2 ](-) . The bonding situation is analyzed and compared with the aluminum homologue [Al(CO)2 ](-) using state-of-the-art quantum chemical methods. PMID- 26246465 TI - Brief intervention in emergency department does not reduce partner violence in women, US study shows. PMID- 26246459 TI - Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement From the American Heart Association and the American Diabetes Association. AB - Cardiovascular disease risk factor control as primary prevention in patients with type 2 diabetes mellitus has changed substantially in the past few years. The purpose of this scientific statement is to review the current literature and key clinical trials pertaining to blood pressure and blood glucose control, cholesterol management, aspirin therapy, and lifestyle modification. We present a synthesis of the recent literature, new guidelines, and clinical targets, including screening for kidney and subclinical cardiovascular disease for the contemporary management of patients with type 2 diabetes mellitus. PMID- 26246466 TI - Outcome of patients with primary refractory diffuse large B cell lymphoma after R CHOP treatment. AB - Primary refractory diffuse large B cell lymphoma (DLBCL) following R-CHOP chemotherapy is a major concern. We identified 1126 patients with DLBCL treated with R-CHOP from 2000 to 2009, of whom 166 (15 %) had primary refractory disease. Of the 75/166 (45 %) who were age <70 years and had been planned for stage directed curative therapy, 43 (57 %) were primary nonresponders and 32 (43 %) relapsed within 3 months of completing R-CHOP. Thirty of 75 (40 %) patients had serious comorbidity and organ dysfunction precluding intensive treatment and had palliative treatment only. Twelve of 45 (27 %) patients responded to second-line treatment and underwent ASCT. The median overall survival for the 75 patients was 10 months with only seven patients alive without evidence of disease at follow-up ranging from 14 to 106 months. Primary refractory DLBCL after R-CHOP has a very poor outcome with only anecdotal survivors independent of the intended treatment approach. PMID- 26246467 TI - Use of a Patient-Activated Event Recording System in Patients with Tachycardic Palpitations: How Long to Follow Up? AB - INTRODUCTION: Palpitations are a common symptom causing patients to consult a cardiologist, yet diagnosing a potential cardiac origin can be difficult. In patients with a nondiagnostic Holter-ECG, external loop-recorders are an additional tool to diagnose the clinical arrhythmia in these patients. The aim of our study was to evaluate the additional value of an external, patient-activated loop recorder and to determine the optimal time of follow up needed to achieve a symptom-rhythm correlation with the device. METHODS AND RESULTS: A total of 1404 patients presented to our outpatient clinic between November 2011 and November 2014 for first time evaluation of symptomatic arrhythmias. Of a total of 91 patients were included (age 43.6+/-18.1; 69.2% female) in the study. All patients presented with tachycardic palpitations and a 48-hour Holter-ECG that did not detect relevant arrhythmias. All patients were given a "leadless" patient activated event-recording system and regular follow-up visits were scheduled after 3, 6, and 12 months. Within a maximum follow-up time of 1 year, 72 patients (79.1%) recorded at least one ECG with the device. Of the recorded ECGs, 51% were recorded within the first week after the device was handed out. This figure rises to 80% and 93% after 1 and 2 months. The last recording was after 174 days. CONCLUSION: For patients with tachycardic palpitations, the external "leadess" event recorders are effective in achieving a symptom-rhythm correlation. A follow up of 2 months will suffice to establish a diagnosis in a large majority of this patient group. PMID- 26246468 TI - Role of PAR-4 in ovarian cancer. AB - Prostate apoptosis response-4 (PAR-4) is considered as a tumour suppressor due to its ability to selectively induce cell apoptosis in most cancer cells. However little is known about the role of PAR-4 in ovarian cancer. In this study, we investigated for the first time the role of PAR-4 in ovarian carcinogenesis. We showed that PAR-4 mRNA level is not significantly different between healthy and cancer ovarian cells. Immunohistochemistry on ovarian tissue showed that ovarian cancer cells are positive for PAR-4 nuclear and cytoplasmic staining whereas ovarian healthy cells are negative for PAR-4 nuclear staining. We then studied the role of PAR-4 in cell apoptosis. We determined that PAR-4 induces cell apoptosis in response to stimuli, in vitro, but is also involved in the relocation of GRP78 from endoplasmic reticulum to the cell surface of ovarian cancer cell line (SKOV-3 cells). In ovo, PAR-4 decreases ovarian tumour development and increases the response to taxol treatment. These observations suggest that PAR-4 is a very interesting therapeutic target against ovarian carcinogenesis. PMID- 26246469 TI - Upregulated long non-coding RNA AFAP1-AS1 expression is associated with progression and poor prognosis of nasopharyngeal carcinoma. AB - Altered expression of long noncoding RNAs (lncRNAs) associated with human carcinogenesis. We performed a cDNA microarray analysis of lncRNA expression in 12 cases of nasopharyngeal carcinoma (NPC) and 4 non-tumor nasopharyngeal epitheliums. One lncRNA, actin filament associated protein 1 antisense RNA1 (AFAP1-AS1), was identified and selected for further study. AFAP1-AS1 expression was upregulated in NPC and associated with NPC metastasis and poor prognosis. In vitro experiments demonstrated that AFAP1-AS1 knockdown significantly inhibited the NPC cell migration and invasive capability. AFAP1-AS1 knockdown also increased AFAP1 protein expression. Proteomic and bioinformatics analyses suggested that AFAP1-AS1 affected the expression of several small GTPase family members and molecules in the actin cytokeratin signaling pathway. AFAP1-AS1 promoted cancer cell metastasis via regulation of actin filament integrity. AFAP1 AS1 might be a potential novel marker that can predict cancer patient prognosis and as a potential therapeutic target for NPC. PMID- 26246470 TI - 'Cut from the same cloth': Shared microsatellite variants among cancers link to ectodermal tissues-neural tube and crest cells. AB - The pluripotent cells of the embryonic ectodermal tissues are known to be a precursor for multiple tumor types. The adaptability of these cells is a trait exploited by cancer. We previously described cancer-associated microsatellite loci (CAML) shared between glioblastoma (GBM) and lower-grade gliomas. Therefore, we hypothesized that these variants, identified from germline DNA, are shared by cancers from tissues originating from ectodermal tissues: neural tube cells (NTC) and crest cells (NCC). Using exome sequencing data from four cancers with origins to NTC and NCC, a 'signature' of loci significant to each cancer (p-value <= 0.01) was created and compared with previously identified CAML from breast cancer. The results of this analysis show that variant loci among the cancers with tissue origins from NTC/NCC were closely linked. Signaling pathways linked to genes with non-coding CAML genotypes revealed enriched connections to hereditary, neurological, and developmental disease or disorders. Thus, variants in genes from tissues initiating from NTC/NCC, if recurrently detected, may indicate a common etiology. Additionally, CAML genotypes from non-tumor DNA may predict cancer phenotypes and are common to shared embryonic tissues of origin. PMID- 26246471 TI - Analysis of small nucleolar RNAs in sputum for lung cancer diagnosis. AB - Molecular analysis of sputum presents a noninvasive approach for diagnosis of lung cancer. We have shown that dysregulation of small nucleolar RNAs (snoRNAs) plays a vital role in lung tumorigenesis. We have also identified six snoRNAs whose changes are associated with lung cancer. Here we investigated if analysis of the snoRNAs in sputum could provide a potential tool for diagnosis of lung cancer. Using qRT-PCR, we determined expressions of the six snoRNAs in sputum of a training set of 59 lung cancer patients and 61 cancer-free smokers to develop a biomarker panel, which was validated in a testing set of 67 lung cancer patients and 69 cancer-free smokers for the diagnostic performance. The snoRNAs were robustly measurable in sputum. In the training set, a panel of two snoRNA biomarkers (snoRD66 and snoRD78) was developed, producing 74.58% sensitivity and 83.61% specificity for identifying lung cancer. The snoRNA biomarkers had a significantly higher sensitivity (74.58%) compared with sputum cytology (45.76%) (P < 0.05). The changes of the snoRNAs were not associated with stage and histology of lung cancer (All P >0.05). The performance of the biomarker panel was confirmed in the testing cohort. We report for the first time that sputum snoRNA biomarkers might be useful to improve diagnosis of lung cancer. PMID- 26246472 TI - Systematic dissection of phenotypic, functional, and tumorigenic heterogeneity of human prostate cancer cells. AB - Human cancers are heterogeneous containing stem-like cancer cells operationally defined as cancer stem cells (CSCs) that possess great tumor-initiating and long term tumor-propagating properties. In this study, we systematically dissect the phenotypic, functional and tumorigenic heterogeneity in human prostate cancer (PCa) using xenograft models and >70 patient tumor samples. In the first part, we further investigate the PSA-/lo PCa cell population, which we have recently shown to harbor self-renewing long-term tumor-propagating cells and present several novel findings. We show that discordant AR and PSA expression in both untreated and castration-resistant PCa (CRPC) results in AR+PSA+, AR+PSA-, AR-PSA-, and AR PSA+ subtypes of PCa cells that manifest differential sensitivities to therapeutics. We further demonstrate that castration leads to a great enrichment of PSA-/lo PCa cells in both xenograft tumors and CRPC samples and systemic androgen levels dynamically regulate the relative abundance of PSA+ versus PSA /lo PCa cells that impacts the kinetics of tumor growth. We also present evidence that the PSA-/lo PCa cells possess distinct epigenetic profiles. As the PSA-/lo PCa cell population is heterogeneous, in the second part, we employ two PSA- (Du145 and PC3) and two PSA+ (LAPC9 and LAPC4) PCa models as well as patient tumor cells to further dissect the clonogenic and tumorigenic subsets. We report that different PCa models possess distinct tumorigenic subpopulations that both commonly and uniquely express important signaling pathways that could represent therapeutic targets. Our results have important implications in understanding PCa cell heterogeneity, response to clinical therapeutics, and cellular mechanisms underlying CRPC. PMID- 26246473 TI - Tankyrase inhibitors attenuate WNT/beta-catenin signaling and inhibit growth of hepatocellular carcinoma cells. AB - Deregulated WNT/beta-catenin signaling contributes to the development of a subgroup of hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide. Within this pathway, the tankyrase enzymes (TNKS1 and TNKS2) degrade AXIN and thereby enhance beta-catenin activity. We evaluate TNKS enzymes as potential therapeutic targets in HCC, and the anti-tumor efficacy of tankyrase inhibitors (XAV939, and its novel nitro-substituted derivative WXL-8) in HCC cells. Using semi-quantitative RT-PCR, we found significantly elevated levels of TNKS1/2 mRNA in tumor liver tissues compared to adjacent non-tumor livers, at protein levels only TNKS1 is increased. In HepG2, Huh7cells, siRNA-mediated knockdown suppression of endogenous TNKS1 and TNKS2 reduced cell proliferation, together with decreased nuclear beta-catenin levels. XAV939 and WXL-8 inhibited cell proliferation and colony formation in HepG2, Huh7, and Hep40 cells (p < 0.05), with stabilization of AXIN1 and AXIN2, and decreased beta-catenin protein levels. XAV939 and WXL-8 also attenuated rhWNT3A-induced TOPflash luciferase reporter activity in HCC cells, indicating reduced beta-catenin transcriptional activity, consistent with decreased nuclear beta-catenin levels. In vivo, intra tumor injections of XAV939 or WXL-8 significantly inhibited the growth of subcutaneous HepG2 xenografts (P < 0.05). We suggest that tankyrase inhibition is a potential therapeutic approach for treating a subgroup HCC with aberrant WNT/beta-catenin signaling pathway. PMID- 26246475 TI - Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes. AB - Clinical genetic testing of BRCA1 and BRCA2 is commonly performed to identify specific individuals at risk for breast and ovarian cancers who may benefit from prophylactic therapeutic interventions. Unfortunately, it is evident that deleterious BRCA1 alleles demonstrate variable penetrance and that many BRCA1 variants of unknown significance (VUS) exist. In order to further refine hereditary risks that may be associated with specific BRCA1 alleles, we performed gene targeting to establish an isogenic panel of immortalized human breast epithelial cells harboring eight clinically relevant BRCA1 alleles. Interestingly, BRCA1 mutations and VUS had distinct, quantifiable phenotypes relative to isogenic parental BRCA1 wild type cells and controls. Heterozygous cells with known deleterious BRCA1 mutations (185delAG, C61G and R71G) demonstrated consistent phenotypes in radiation sensitivity and genomic instability assays, but showed variability in other assays. Heterozygous BRCA1 VUS cells also demonstrated assay variability, with some VUS demonstrating phenotypes more consistent with deleterious alleles. Taken together, our data suggest that BRCA1 deleterious mutations and VUS can differ in their range of tested phenotypes, suggesting they might impart varying degrees of risk. These results demonstrate that functional isogenic modeling of BRCA1 alleles could aid in classifying BRCA1 mutations and VUS, and determining BRCA allele cancer risk. PMID- 26246474 TI - Mitochondria, calcium, and tumor suppressor Fus1: At the crossroad of cancer, inflammation, and autoimmunity. AB - Mitochondria present a unique set of key intracellular functions such as ATP synthesis, production of reactive oxygen species (ROS) and Ca2+ buffering. Mitochondria both encode and decode Ca2+ signals and these interrelated functions have a direct impact on cell signaling and metabolism. High proliferative potential is a key energy-demanding feature shared by cancer cells and activated T lymphocytes. Switch of a metabolic state mediated by alterations in mitochondrial homeostasis plays a fundamental role in maintenance of the proliferative state. Recent studies show that tumor suppressors have the ability to affect mitochondrial homeostasis controlling both cancer and autoimmunity. Herein, we discuss established and putative mechanisms of calcium-dependent regulation of both T cell and tumor cell activities. We use the mitochondrial protein Fus1 as a case of tumor suppressor that controls immune response and tumor growth via maintenance of mitochondrial homeostasis. We focus on the regulation of mitochondrial Ca2+ handling as a key function of Fus1 and highlight the mechanisms of a crosstalk between Ca2+ accumulation and mitochondrial homeostasis. Given the important role of Ca2+ signaling, mitochondrial Ca2+ transport and ROS production in the activation of NFAT and NF-kappaB transcription factors, we outline the importance of Fus1 activities in this context. PMID- 26246477 TI - A case of a huge gastroepiploic arterial aneurysm. AB - An 85-year-old man complaining of vague abdominal discomfort was admitted to our hospital. A pulsatile 8 * 7-cm mass in the right upper abdomen was noticed on clinical examination. Computed tomography of the abdomen showed a huge arterial aneurysm in the right gastroepiploic artery, and the left gastroepiploic artery was meandering and expanding. An image diagnosis of gastroepiploic arterial aneurysm (GEAA) was made. Because of the huge size of the aneurysm and the predicted high risk of perforation, surgical intervention was planned. The aneurysm was identified in the greater curve and was found to adhere firmly to the transverse colon. Partial resection of the stomach, aneurysmectomy and partial resection of the transverse colon were performed. Clinically, splanchnic arterial aneurysms are rare. Among them, GEAA is especially rare. We report a rare case of a huge GEAA that was treated successfully by surgery. PMID- 26246476 TI - Loss of tumor suppressors KAI1 and p27 identifies a unique subgroup of primary melanoma patients with poor prognosis. AB - Primary melanoma, a highly aggressive malignancy, exhibits heterogeneity in biologic behaviors, clinical characteristics, metastasis potential and mortality. The present study sought to identify the molecular signatures that define a subgroup of primary melanomas with high risks of metastasis and mortality. First, we identified the markers that best differentiated metastatic melanomas from primary melanomas by examining the expression of seven previously reported biomarkers (BRAF, Dicer, Fbw7, KAI1, MMP2, p27 and Tip60) in a training cohort consisting of 145 primary melanomas and 105 metastatic melanomas. KAI1 and p27, both tumor suppressors, emerged as best candidates. Loss of both tumor suppressors occurred in the majority (74.29%) of metastatic melanomas. Further, a subset (metastatic like, or "ML", 33.10%) of primary melanomas also lost these two tumor suppressors. Kaplan-Meier analysis indicated that ML subgroup of primary melanoma patients had much worse 5 year survival compared with other primary melanoma patients (P = 0.002). The result was confirmed in an independent validation cohort with 92 primary melanomas (P = 0.030) and in the combined cohort with 237 melanoma patients (P = 3.00E-4). Additionally, compared to KAI1 and p27 as an individual prognostic marker, the combined signature is more closely associated with melanoma patient survival (P = 0.025, 0.264 and 0.009, respectively). In conclusion, loss of both KAI1 and p27 defines a subgroup of primary melanoma patients with poor prognosis. This molecular signature may help in metastatic melanoma diagnosis and may provide information useful in identifying high-risk primary melanoma patients for more intensive clinical surveillance in the future. PMID- 26246478 TI - Perceiving what you intend to do from what you do: evidence for embodiment in social interactions. AB - Although action and perception are central components of our interactions with the external world, the most recent experimental investigations also support their implications in the emotional, decision-making, and goal ascription processes in social context. In this article, we review the existing literature supporting this view and highlighting a link between reach-to-grasp motor actions and social communicative processes. First, we discuss the most recent experimental findings showing how the social context subtly influences the execution of object-oriented motor actions. Then, we show that the kinematic characteristics of object-oriented motor actions are modulated by the actor's social intention. Finally, we demonstrate that naive observers can implicitly take advantage of these kinematic effects for their own motor productions. Considered together, these data are compatible with the embodied cognition framework stating that cognition, and in our case social cognition, is grounded in knowledge associated with past sensory and motor experiences. PMID- 26246479 TI - Systematic review and network meta-analysis: neoadjuvant chemoradiotherapy for locoregional esophageal cancer. AB - OBJECTIVE: Neoadjuvant chemoradiotherapy improves survival in patients with locoregional esophageal cancer. This study compares the efficacy of two common regimens, paclitaxel plus platinum and platinum plus 5-fluorouracil, based on overall survival. METHODS: We performed a systematic review and network meta analysis of randomized trials comparing paclitaxel plus platinum-neoadjuvant chemoradiotherapy or and platinum plus 5-fluorouracil-neoadjuvant chemoradiotherapy with surgery alone. The outcome was the hazard ratios for death in the entire population and the two major histologic subgroups, squamous cell carcinoma and adenocarcinoma. RESULTS: Ten clinical trials were included. Compared with surgery alone, the hazard ratios [95% credible interval (CrI)] in the entire, squamous cell carcinoma, and adenocarcinoma population were 0.63 (0.50-0.80), 0.50 (0.36-0.71) and 0.74 (0.54-1.01) for paclitaxel plus platinum, and 0.79 (0.68-0.92), 0.82 (0.67-1.01) and 0.81 (0.63-1.05) for platinum plus 5 fluorouracil, respectively. When paclitaxel plus platinum was compared with platinum plus 5-fluorouracil, the hazard ratios (95% CrI) in the entire, squamous cell carcinoma, and adenocarcinoma population were 0.80 (0.60-1.06), 0.61 (0.41 0.91) and 0.91 (0.61-1.36), respectively. The probability of paclitaxel plus platinum being ranked the optimal treatment for the entire, squamous cell carcinoma, and adenocarcinoma population was 94.2, 99.1 and 67.6%, respectively. CONCLUSIONS: Neoadjuvant chemoradiotherapy with paclitaxel plus platinum regimen seemed to be a better treatment than platinum plus 5-fluorouracil regimen for locoregional esophageal cancer, especially for squamous cell carcinoma. PMID- 26246480 TI - A Phase III study of oral steroid administration versus local steroid injection therapy for the prevention of esophageal stricture after endoscopic submucosal dissection (JCOG1217, Steroid EESD P3). AB - A randomized Phase III trial commenced in Japan in September 2014. Endoscopic local steroid injection has been commonly used and considered acceptable as the current standard treatment for the prevention of esophageal stricture after endoscopic submucosal dissection for superficial esophageal cancer. The purpose of this study is to confirm the superiority of prophylactic oral steroid administration following endoscopic submucosal dissection in terms of stricture free survival over endoscopic local steroid injection for patients with superficial esophageal cancer. A total of 360 patients will be accrued from 35 Japanese institutions within 2.5 years. The primary endpoint is stricture-free survival, and the secondary endpoints are the number of endoscopic balloon dilations for 12 weeks after endoscopic submucosal dissection, adverse events, serious adverse events and the proportion of patients with dysphagia score <=1 at 12 weeks after endoscopic submucosal dissection. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000015064 (http://www.umin.ac.jp/ctr/index.htm). PMID- 26246481 TI - Intensive vs. Standard Post-Operative Surveillance in High-Risk Breast Cancer Patients (INSPIRE): Japan Clinical Oncology Group Study JCOG1204. AB - This Phase III trial aims to determine the superiority of intensive follow-up to standard follow-up in terms of overall survival in high-risk breast cancer patients, who are expected to have recurrence rates of over 30% within 5 years after surgery. Eligible patients are randomized either to the intensive follow-up group or to the standard follow-up group; the former will undergo physical examination, bone scintigraphy, chest computed tomography, abdominal computed tomography, brain magnetic resonance imaging/computed tomography and frequent tumor marker evaluations, whereas the latter will undergo physical examination at the same frequency and tumor markers will be evaluated once a year. Mammography once a year is planned for both groups. The primary endpoint is overall survival. Patient accrual was started in November 2013. A total of 1700 patients will be enrolled for 3 years and followed up for 7 years after closure of accrual. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000012429. PMID- 26246482 TI - Clinical and Analytical Performance of the Onclarity HPV Assay Using the VALGENT Framework. AB - As the demand for human papillomavirus (HPV)-related cervical screening increases, emerging HPV tests must be evaluated robustly using well-annotated samples, such as those generated in the Validation of HPV Genotyping Tests (VALGENT) framework. Through VALGENT, we assessed the performance of the BD Onclarity HPV assay, which detects 14 high-risk (HR) types and resolves six individual types and three groups of types. Consecutive samples from a screening population (n = 1,000), enriched with cytologically abnormal samples (n = 300), that had been tested previously with the GP5+/6+ PCR enzyme immunoassay (EIA) and the GP5+/6+ PCR LMNX assay (Diassay) were tested with the Onclarity assay. Type specific HPV prevalences were analyzed according to age and cytological result. The accuracy of the Onclarity assay for the detection of cervical intraepithelial neoplasia grade 2+ (CIN2+) and CIN3+ was assessed relative to the GP5+/6+ EIA results by using noninferiority criteria. Overall agreement and type-specific agreement between the Onclarity assay and the GP5+/6+ LMNX assay were assessed. The prevalence of HPV types 16, 18, 31, and 45 increased with the severity of cytological results (P for trend, <0.05). For the detection of CIN2+, the Onclarity assay had a relative sensitivity of 1.02 (95% confidence interval [CI], 0.99 to 1.05; P < 0.001 for noninferiority) and a relative specificity of 0.99 (95% CI, 0.97 to 1.00; P = 0.186 for noninferiority). The kappa for agreement between the Onclarity assay and the GP5+/6+ LMNX assay for HR-HPV was 0.92 (95% CI, 0.89 to 0.94), and values for the six individual types ranged from 0.78 (95% CI, 0.68 to 0.87) for HPV-52 to 0.96 (95% CI, 0.93 to 0.99) for HPV-16. These data suggest that the Onclarity assay offers applications for clinical workstreams while providing genotyping information that may be useful for risk stratification beyond types 16 and 18. PMID- 26246483 TI - Quantitative Microplate-Based Growth Assay for Determination of Antifungal Susceptibility of Histoplasma capsulatum Yeasts. AB - Standardized methodologies for determining the antifungal susceptibility of fungal pathogens is central to the clinical management of invasive fungal disease. Yeast-form fungi can be tested using broth macrodilution and microdilution assays. Reference procedures exist for Candida species and Cryptococcus yeasts; however, no standardized methods have been developed for testing the antifungal susceptibility of yeast forms of the dimorphic systemic fungal pathogens. For the dimorphic fungal pathogen Histoplasma capsulatum, susceptibility to echinocandins differs for the yeast and the filamentous forms, which highlights the need to employ Histoplasma yeasts, not hyphae, in antifungal susceptibility tests. To address this, we developed and optimized methodology for the 96-well microtiter plate-based measurement of Histoplasma yeast growth in vitro. Using optical density, the assay is quantitative for fungal growth with a dynamic range greater than 30-fold. Concentration and assay reaction time parameters were also optimized for colorimetric (MTT [3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide] reduction) and fluorescent (resazurin reduction) indicators of fungal vitality. We employed this microtiter-based assay to determine the antifungal susceptibility patterns of multiple clinical isolates of Histoplasma representing different phylogenetic groups. This methodology fulfills a critical need for the ability to monitor the effectiveness of antifungals on Histoplasma yeasts, the morphological form present in mammalian hosts and, thus, the form most relevant to disease. PMID- 26246484 TI - Application of Isothermal Amplification Techniques for Identification of Madurella mycetomatis, the Prevalent Agent of Human Mycetoma. AB - Appropriate diagnosis and treatment of eumycetoma may vary significantly depending on the causative agent. To date, the most common fungus causing mycetoma worldwide is Madurella mycetomatis. This species fails to express any recognizable morphological characteristics, and reliable identification can therefore only be achieved with the application of molecular techniques. Recombinase polymerase amplification (RPA) and loop-mediated isothermal amplification (LAMP) are proposed as alternatives to phenotypic methods. Species specific primers were developed to target the ribosomal DNA (rDNA) internal transcribed spacer (ITS) region of M. mycetomatis. Both isothermal amplification techniques showed high specificity and sufficient sensitivity to amplify fungal DNA and proved to be appropriate for detection of M. mycetomatis. Diagnostic performance of the techniques was assessed in comparison to conventional PCR using biopsy specimens from eumycetoma patients. RPA is reliable and easy to operate and has the potential to be implemented in areas where mycetoma is endemic. The techniques may be expanded to detect fungal DNA from environmental samples. PMID- 26246485 TI - Laboratory Investigation of the First Case of Botulism Caused by Clostridium butyricum Type E Toxin in the United States. AB - We report here the laboratory investigation of the first known case of botulism in the United States caused by Clostridium butyricum type E. This investigation demonstrates the importance of extensive microbiological examination of specimens, which resulted in the isolation of this organism. PMID- 26246486 TI - Lab-on-Chip-Based Platform for Fast Molecular Diagnosis of Multidrug-Resistant Tuberculosis. AB - We evaluated the performance of the molecular lab-on-chip-based VerePLEX Biosystem for detection of multidrug-resistant tuberculosis (MDR-TB), obtaining a diagnostic accuracy of more than 97.8% compared to sequencing and MTBDRplus assay for Mycobacterium tuberculosis complex and rifampin and isoniazid resistance detection on clinical isolates and smear-positive specimens. The speed, user friendly interface, and versatility make it suitable for routine laboratory use. PMID- 26246488 TI - Identification of scalp EEG circadian variation using a novel correlation sum measure. AB - OBJECTIVE: In this paper, we propose a novel method to determine the circadian variation of scalp electroencephalogram (EEG) in both individual and group levels using a correlation sum measure, quantifying self-similarity of the EEG relative energy across waking epochs. APPROACH: We analysed EEG recordings from central parietal and occipito-parietal montages in nine healthy subjects undergoing a 72 h ultradian sleep-wake cycle protocol. Each waking epoch (~ 1 s) of every nap opportunity was decomposed using the wavelet packet transform, and the relative energy for that epoch was calculated in the desired frequency band using the corresponding wavelet coefficients. Then, the resulting set of energy values was resampled randomly to generate different subsets with equal number of elements. The correlation sum of each subset was then calculated over a range of distance thresholds, and the average over all subsets was computed. This average value was finally scaled for each nap opportunity and considered as a new circadian measure. MAIN RESULTS: According to the evaluation results, a clear circadian rhythm was identified in some EEG frequency ranges, particularly in 4-8 Hz and 10 12 Hz. The correlation sum measure not only was able to disclose the circadian rhythm on the group data but also revealed significant circadian variations in most individual cases, as opposed to previous studies only reporting the circadian rhythms on a population of subjects. Compared to a naive measure based on the EEG absolute energy in the frequency band of interest, the proposed measure showed a clear superiority using both individual and group data. Results also suggested that the acrophase (i.e., the peak) of the circadian rhythm in 10 12 Hz occurs close to the core body temperature minimum. SIGNIFICANCE: These results confirm the potential usefulness of the proposed EEG-based measure as a non-invasive circadian marker. PMID- 26246487 TI - A differentially expressed set of microRNAs in cerebro-spinal fluid (CSF) can diagnose CNS malignancies. AB - Central Nervous System malignancies often require stereotactic biopsy or biopsy for differential diagnosis, and for tumor staging and grading. Furthermore, stereotactic biopsy can be non-diagnostic or underestimate grading. Hence, there is a compelling need of new diagnostic biomarkers to avoid such invasive procedures. Several biological markers have been proposed, but they can only identify specific prognostic subtype of Central Nervous System tumors, and none of them has found a standardized clinical application.The aim of the study was to identify a Cerebro-Spinal Fluid microRNA signature that could differentiate among Central Nervous System malignancies.CSF total RNA of 34 neoplastic and of 14 non diseased patients was processed by NanoString. Comparison among groups (Normal, Benign, Glioblastoma, Medulloblastoma, Metastasis and Lymphoma) lead to the identification of a microRNA profile that was further confirmed by RT-PCR and in situ hybridization.Hsa-miR-451, -711, 935, -223 and -125b were significantly differentially expressed among the above mentioned groups, allowing us to draw an hypothetical diagnostic chart for Central Nervous System malignancies.This is the first study to employ the NanoString technique for Cerebro-Spinal Fluid microRNA profiling. In this article, we demonstrated that Cerebro-Spinal Fluid microRNA profiling mirrors Central Nervous System physiologic or pathologic conditions. Although more cases need to be tested, we identified a diagnostic Cerebro-Spinal Fluid microRNA signature with good perspectives for future diagnostic clinical applications. PMID- 26246489 TI - Lipid raft-mediated Fas/CD95 apoptotic signaling in leukemic cells and normal leukocytes and therapeutic implications. AB - Plasma membrane is now recognized to contain tightly packed cholesterol/sphingolipid-rich domains, known as lipid or membrane rafts, which are more ordered than the surrounding lipid bilayer. Lipid rafts are crucial for the compartmentalization of signaling processes in the membrane, mostly involved in cell survival and immune response. However, in the last 15 years, a large body of evidence has also identified raft platforms as scaffolds for the recruitment and clustering of death receptor Fas/CD95 and downstream signaling molecules, leading to the concept of death-promoting lipid rafts. This raft-Fas/CD95 coclustering was first described at the early 2000s as the underlying mechanism for the proapoptotic action of the alkylphospholipid analog edelfosine in leukemic cells, hence facilitating protein-protein interactions and conveying apoptotic signals independently of Fas/CD95 ligand. Edelfosine induces apoptosis in hematologic cancer cells and activated T-lymphocytes. Fas/CD95 raft coclustering is also promoted by Fas/CD95 ligand, agonistic Fas/CD95 antibodies, and additional antitumor drugs. Thus, death receptor recruitment in rafts is a physiologic process leading to cell demise that can be pharmacologically modulated. This redistribution and local accumulation of apoptotic molecules in membrane rafts, which are usually accompanied by displacement of survival signaling molecules, highlight how alterations in the apoptosis/survival signaling balance in specialized membrane regions modulate cell fate. Membrane rafts might also modulate apoptotic and nonapoptotic death receptor signaling. Here, we discuss the role of lipid rafts in Fas/CD95-mediated apoptotic cell signaling in hematologic cancer cells and normal leukocytes, with a special emphasis on their involvement as putative therapeutic targets in cancer and autoimmune diseases. PMID- 26246490 TI - Holter monitoring for the screening of cardiac disease in diabetes mellitus: The non-invasive Holter monitoring observation of new cardiac events in diabetics study. AB - We investigated the usefulness of Holter monitoring to detect cardiac disease and predict future cardiovascular risk in asymptomatic diabetic patients. This is a multi-centre, prospective study in 406 asymptomatic diabetic patients. They were categorized into three groups based on findings of Holter monitoring. A total of 377 met inclusion criteria and were classified as low (n = 172), moderate (n = 136) and high risk (n = 69). In total, 86 in moderate and 53 in high risk receive further evaluation. In total, 29 in moderate and 25 in high risk were diagnosed as cardiac disease and 12 required additional treatment, including coronary intervention. Over 1.8 years of mean follow-up, 11 (16.5 per 1000 person-years) experienced cardiovascular events. The cumulative incidence in moderate and high risk was higher than that in low risk (p = 0.029 and p = 0.014, respectively). Our study suggests that Holter monitoring may be a useful screening tool to detect cardiac disease and predict future cardiovascular risk in asymptomatic diabetic patients. PMID- 26246491 TI - Proteomic research of high-glucose-activated endothelial microparticles and related proteins to Alzheimer's disease. AB - The study was designed to discover the biological function of endotheliocyte derived microparticles in diabetes condition. A quantitative shotgun proteomics methodology was performed to study the proteome of these high-glucose-activated endothelial microparticles. A total of 1428 proteins were identified, containing 1421 and 1423 proteins in control and high-glucose groups, respectively. According to the ExoCarta database, 669 proteins have previously been identified in microparticles. The proteins associated with disease were identified in this study, and notably, 30 proteins have been reported to be associated with Alzheimer's disease, including amyloid beta A4 protein. Besides, the peptide abundance of amyloid beta A4 protein from control group was much less than that from high-glucose group. In conclusion, this work revealed the proteome of endothelial microparticles in mimic diabetes condition and provided a new proteomic evidence for Alzheimer's disease to be counted as the type 3 diabetes. PMID- 26246492 TI - Anion homeostasis is important for non-lytic release of BK polyomavirus from infected cells. AB - BK polyomavirus (BKPyV) is a member of a family of potentially oncogenic viruses, whose reactivation can cause severe pathological conditions in transplant patients, leading to graft rejection. As with many non-enveloped viruses, it is assumed that virus release occurs through lysis of the host cell. We now show the first evidence for a non-lytic release pathway for BKPyV and that this pathway can be blocked by the anion channel inhibitor DIDS. Our data show a dose dependent effect of DIDS on the release of BKPyV virions. We also observed an accumulation of viral capsids in large LAMP-1-positive acidic organelles within the cytoplasm of cells upon DIDS treatment, suggesting potential late endosome or lysosome-related compartments are involved in non-lytic BKPyV release. These data highlight a novel mechanism by which polyomaviruses can be released from infected cells in an active and non-lytic manner, and that anion homeostasis regulation is important in this pathway. PMID- 26246494 TI - Recoverin depletion accelerates cone photoresponse recovery. AB - The neuronal Ca(2+)-binding protein Recoverin has been shown to regulate phototransduction termination in mammalian rods. Here we identify four recoverin genes in the zebrafish genome, rcv1a, rcv1b, rcv2a and rcv2b, and investigate their role in modulating the cone phototransduction cascade. While Recoverin-1b is only found in the adult retina, the other Recoverins are expressed throughout development in all four cone types, except Recoverin-1a, which is expressed only in rods and UV cones. Applying a double flash electroretinogram (ERG) paradigm, downregulation of Recoverin-2a or 2b accelerates cone photoresponse recovery, albeit at different light intensities. Exclusive recording from UV cones via spectral ERG reveals that knockdown of Recoverin-1a alone has no effect, but Recoverin-1a/2a double-knockdowns showed an even shorter recovery time than Recoverin-2a-deficient larvae. We also showed that UV cone photoresponse kinetics depend on Recoverin-2a function via cone-specific kinase Grk7a. This is the first in vivo study demonstrating that cone opsin deactivation kinetics determine overall photoresponse shut off kinetics. PMID- 26246493 TI - The intimate genetics of Drosophila fertilization. AB - The union of haploid gametes at fertilization initiates the formation of the diploid zygote in sexually reproducing animals. This founding event of embryogenesis includes several fascinating cellular and nuclear processes, such as sperm-egg cellular interactions, sperm chromatin remodelling, centrosome formation or pronuclear migration. In comparison with other aspects of development, the exploration of animal fertilization at the functional level has remained so far relatively limited, even in classical model organisms. Here, we have reviewed our current knowledge of fertilization in Drosophila melanogaster, with a special emphasis on the genes involved in the complex transformation of the fertilizing sperm nucleus into a replicated set of paternal chromosomes. PMID- 26246495 TI - Dissecting the function of Atg1 complex in Dictyostelium autophagy reveals a connection with the pentose phosphate pathway enzyme transketolase. AB - The network of protein-protein interactions of the Dictyostelium discoideum autophagy pathway was investigated by yeast two-hybrid screening of the conserved autophagic proteins Atg1 and Atg8. These analyses confirmed expected interactions described in other organisms and also identified novel interactors that highlight the complexity of autophagy regulation. The Atg1 kinase complex, an essential regulator of autophagy, was investigated in detail here. The composition of the Atg1 complex in D. discoideum is more similar to mammalian cells than to Saccharomyces cerevisiae as, besides Atg13, it contains Atg101, a protein not conserved in this yeast. We found that Atg101 interacts with Atg13 and genetic disruption of these proteins in Dictyostelium leads to an early block in autophagy, although the severity of the developmental phenotype and the degree of autophagic block is higher in Atg13-deficient cells. We have also identified a protein containing zinc-finger B-box and FNIP motifs that interacts with Atg101. Disruption of this protein increases autophagic flux, suggesting that it functions as a negative regulator of Atg101. We also describe the interaction of Atg1 kinase with the pentose phosphate pathway enzyme transketolase (TKT). We found changes in the activity of endogenous TKT activity in strains lacking or overexpressing Atg1, suggesting the presence of an unsuspected regulatory pathway between autophagy and the pentose phosphate pathway in Dictyostelium that seems to be conserved in mammalian cells. PMID- 26246496 TI - Low nourishment of B-vitamins is associated with hyperhomocysteinemia and oxidative stress in newly diagnosed cardiac patients. AB - We are currently witnessing a dramatic change in lifestyle and food choices that is accompanied with an increase in the rate of morbidity and mortality from cardiovascular diseases (CVD). Although studies have reported an association of CVD with hyperhomocysteinemia-mediated oxidative stress, the biochemical basis is not known. This case-control study was aimed to evaluate the nutritional and biochemical status of B-vitamins in relation to hyperhomocysteinemia and oxidative stress in newly diagnosed cardiac patients. The retrospective dietary intake of the study subjects (cases and controls) was estimated using a semi quantitative food frequency questionnaire, and fasting blood samples were drawn to assess their serum levels of B-vitamins (folate, vitamins B6 and B12), homocysteine (HCY), and oxidative stress indices such as glutathione (GSH), total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrites and nitrates (NN). It was observed that the cases had a lower dietary intake of B-vitamins as compared to their matched control subjects as well as to the corresponding recommended dietary allowances. Biochemical analysis of cases, as compared to controls, indicated depletion of GSH, impairment of TAC, and an elevation in the serum levels of HCY, MDA, and NN. These results suggest that lower status (dietary intake and serum levels) of B-vitamins is involved in the etiology of hyperhomocysteinemia and oxidative stress, the typical risk factors for CVD. PMID- 26246497 TI - Haploinsufficiency for either one of the type-II regulatory subunits of protein kinase A improves the bone phenotype of Prkar1a+/- mice. AB - Carney Complex (CNC), a human genetic syndrome predisposing to multiple neoplasias, is associated with bone lesions such as osteochondromyxomas (OMX). The most frequent cause for CNC is PRKAR1A deficiency; PRKAR1A codes for type-I regulatory subunit of protein kinase A (PKA). Prkar1a(+/-) mice developed OMX, fibrous dysplasia-like lesions (FDL) and other tumors. Tumor tissues in these animals had increased PKA activity due to an unregulated PKA catalytic subunit and increased PKA type II (PKA-II) activity mediated by the PRKAR2A and PRKAR2B subunits. To better understand the effect of altered PKA activity on bone, we studied Prkar2a and Prkar2b knock out (KO) and heterozygous mice; none of these mice developed bone lesions. When Prkar2a(+/-) and Prkar2b(+/-) mice were used to generate Prkar1a(+/-)Prkar2a(+/-) and Prkar1a(+/-)Prkar2b(+/-) animals, bone lesions formed that looked like those of the Prkar1a(+/-) mice. However, better overall bone organization and mineralization and fewer FDL lesions were found in both double heterozygote groups, indicating a partial restoration of the immature bone structure observed in Prkar1a(+/-) mice. Further investigation indicated increased osteogenesis and higher new bone formation rates in both Prkar1a(+/ )Prkar2a(+/-) and Prkar1a(+/-)Prkar2b(+/-) mice with some minor differences between them. The observations were confirmed with a variety of markers and studies. PKA activity measurements showed the expected PKA-II decrease in both double heterozygote groups. Thus, haploinsufficiency for either of PKA-II regulatory subunits improved bone phenotype of mice haploinsufficient for Prkar1a, in support of the hypothesis that the PRKAR2A and PRKAR2B regulatory subunits were in part responsible for the bone phenotype of Prkar1a(+/-) mice. PMID- 26246498 TI - A new variant in signal peptide of the human luteinizing hormone receptor (LHCGR) affects receptor biogenesis causing leydig cell hypoplasia. AB - The human luteinizing hormone/chorionic gonadotropin receptor (LHCGR) plays a fundamental role in male and female reproduction. In males, loss-of-function mutations in LHCGR have been associated with distinct degrees of impairment in pre- and postnatal testosterone secretion resulting in a variable phenotypic spectrum, classified as Leydig cell hypoplasia (LCH) type 1 (complete LH resistance and disorder of sex differentiation) and type 2 (partial LH resistance with impaired masculinization and fertility). Here, we report the case of an adolescent who came to the pediatric endocrinologist at the age of 12 years old for micropenis and cryptorchidism. Testis biopsy showed profound LCH and absent germinal line elements (Sertoli-only syndrome). The sequence analysis of the LHCGR gene showed the presence of a compound heterozygosity, being one variation, c.1847C>A p.S616Y, already described in association to Hypergonadotropic Hypogonadism, and the other, c.29 C>T p.L10P, a new identified variant in the putative signal peptide (SP) of LHCGR. Functional and structural studies provide first evidence that LHCGR have a functional and cleavable SP required for receptor biogenesis. Moreover, we demonstrate the pathogenic role of the novel p.L10P allelic variant, which has to be considered a loss-of-function mutation significantly contributing, in compound heterozygosity with p.S616Y, to the LCH type 2 observed in our patient. PMID- 26246499 TI - Endogenous DUX4 expression in FSHD myotubes is sufficient to cause cell death and disrupts RNA splicing and cell migration pathways. AB - Facioscapulohumeral muscular dystrophy (FSHD) is caused by chromatin relaxation that results in aberrant expression of the transcription factor Double Homeobox 4 (DUX4). DUX4 protein is present in a small subset of FSHD muscle cells, making its detection and analysis of its effects historically difficult. Using a DUX4 activated reporter, we demonstrate the burst expression pattern of endogenous DUX4, its method of signal amplification in the unique shared cytoplasm of the myotube, and FSHD cell death that depends on its activation. Transcriptome analysis of DUX4-expressing cells revealed that DUX4 activation disrupts RNA metabolism including RNA splicing, surveillance and transport pathways. Cell signaling, polarity and migration pathways were also disrupted. Thus, DUX4 expression is sufficient for myocyte death, and these findings suggest mechanistic links between DUX4 expression and cell migration, supporting recent descriptions of phenotypic similarities between FSHD and an FSHD-like condition caused by FAT1 mutations. PMID- 26246501 TI - Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns. AB - The role of rare missense variants in disease causation remains difficult to interpret. We explore whether the clustering pattern of rare missense variants (MAF < 0.01) in a protein is associated with mode of inheritance. Mutations in genes associated with autosomal dominant (AD) conditions are known to result in either loss or gain of function, whereas mutations in genes associated with autosomal recessive (AR) conditions invariably result in loss-of-function. Loss of-function mutations tend to be distributed uniformly along protein sequence, whereas gain-of-function mutations tend to localize to key regions. It has not previously been ascertained whether these patterns hold in general for rare missense mutations. We consider the extent to which rare missense variants are located within annotated protein domains and whether they form clusters, using a new unbiased method called CLUstering by Mutation Position. These approaches quantified a significant difference in clustering between AD and AR diseases. Proteins linked to AD diseases exhibited more clustering of rare missense mutations than those linked to AR diseases (Wilcoxon P = 5.7 * 10(-4), permutation P = 8.4 * 10(-4)). Rare missense mutation in proteins linked to either AD or AR diseases was more clustered than controls (1000G) (Wilcoxon P = 2.8 * 10(-15) for AD and P = 4.5 * 10(-4) for AR, permutation P = 3.1 * 10(-12) for AD and P = 0.03 for AR). The differences in clustering patterns persisted even after removal of the most prominent genes. Testing for such non-random patterns may reveal novel aspects of disease etiology in large sample studies. PMID- 26246500 TI - A new mouse model for stationary night blindness with mutant Slc24a1 explains the pathophysiology of the associated human disease. AB - Mutations that affect calcium homeostasis (Ca(2+)) in rod photoreceptors are linked to retinal degeneration and visual disorders such as retinitis pigmentosa and congenital stationary night blindness (CSNB). It is thought that the concentration of Ca(2+) in rod outer segments is controlled by a dynamic balance between influx via cGMP-gated (CNG) channels and extrusion via Na(+)/Ca(2+), K(+) exchangers (NCKX1). The extrusion-driven lowering of rod [Ca(2+)]i following light exposure controls their light adaptation and response termination. Mutant NCKX1 has been linked to autosomal-recessive stationary night blindness. However, whether NCKX1 contributes to light adaptation has not been directly tested and the mechanisms by which human NCKX1 mutations cause night blindness are not understood. Here, we report that the deletion of NCKX1 in mice results in malformed outer segment disks, suppressed expression and function of rod CNG channels and a subsequent 100-fold reduction in rod responses, while preserving normal cone responses. The compensating loss of CNG channel function in the absence of NCKX1-mediated Ca(2+) extrusion may prevent toxic Ca(2+) buildup and provides an explanation for the stationary nature of the associated disorder in humans. Surprisingly, the lack of NCKX1 did not compromise rod background light adaptation, suggesting additional Ca(2+)-extruding mechanisms exist in these cells. PMID- 26246502 TI - E-cadherin-defective gastric cancer cells depend on Laminin to survive and invade. AB - Epithelial-cadherin (Ecad) deregulation affects cell-cell adhesion and results in increased invasiveness of distinct human carcinomas. In gastric cancer, loss of Ecad expression is a common event and is associated with disease aggressiveness and poor prognosis. However, the molecular mechanisms underlying the invasive process associated to Ecad dysfunction are far from understood. We hypothesized that deregulation of cell-matrix interactions could play an important role during this process. Thus, we focussed on LM-332, which is a major matrix component, and in Ecad/LM-332 crosstalk in the process of Ecad-dependent invasion. To verify whether matrix deregulation was triggered by Ecad loss, we used the Drosophila model. To dissect the key molecules involved and unveil their functional significance, we used gastric cancer cell lines. The relevance of this relationship was then confirmed in human primary tumours. In vivo, Ecad knockdown induced apoptosis; nonetheless, at the invasive front, cells ectopically expressed Laminin A and betaPS integrin. In vitro, we demonstrated that, in two different gastric cancer cell models, Ecad-defective cells overexpressed Laminin gamma2 (LM-gamma2), beta1 and beta4 integrin, when compared with Ecad-competent ones. We showed that LM-gamma2 silencing impaired invasion and enhanced cell death, most likely via pSrc and pAkt reduction, and JNK activation. In human gastric carcinomas, we found a concomitant decrease in Ecad and increase in LM gamma2. This is the first evidence that ectopic Laminin expression depends on Ecad loss and allows Ecad-dysfunctional cells to survive and invade. This opens new avenues for using LM-gamma2 signalling regulators as molecular targets to impair gastric cancer progression. PMID- 26246503 TI - Impact of leg blood flow restriction during walking on central arterial hemodynamics. AB - Walking exercise with limb blood flow restriction (BFR) has been shown to increase muscular mass and strength even if it is performed at low exercise intensities. Despite mounting evidence for its efficacy and the increasing popularity, the safety of BFR exercise in relation to cardiac loads has not been established. The aim of this study was to determine the response of central hemodynamics during the BFR exercise to assess its impact on cardiac load. Fifteen apparently healthy sedentary or recreationally active adults (10 men and 5 women, 27 +/- 1 yr) underwent five bouts of 2-min constant treadmill walking at 2 mph with 1-min rest intervals either with or without BFR on both proximal thighs. Beat-by-beat blood pressure and hemodynamics (via Modelflow method) were measured, and central arterial hemodynamics were evaluated with pulse wave analyses via general transfer function. Incident wave amplitude (IWA) and reflected wave amplitude (RWA) were obtained by the wave separation analysis. Peripheral systolic blood pressure (SBP) increased more substantially during walking with BFR (43 +/- 5% vs. baseline) than without BFR (11 +/- 4% vs. baseline). Aortic SBP did not change significantly during walking without BFR, but there was a substantial elevation in aortic SBP (43 +/- 5% vs. baseline) during walking with BFR. Significant effect of BFR was seen in IWA but not in RWA. These findings suggest that even during slow-speed walking, leg BFR induces substantial hypertensive responses in the aorta. However, this response could not be explained by the augmented wave reflection. PMID- 26246505 TI - Exercise training does not affect anthracycline antitumor efficacy while attenuating cardiac dysfunction. AB - Highly effective anthracyclines, like doxorubicin (DOX), have limited clinical use due to protracted cardiotoxic effects. While exercise is known to be cardioprotective, it is unclear whether exercise compromises chemotherapy treatment efficacy. To determine the effect of exercise training on DOX antitumor efficacy as well as DOX-induced cardiotoxicity, female Fisher 344 rats were randomly assigned to sedentary + saline (SED+SAL), SED+DOX, wheel run exercise training + SAL (WR+SAL), or WR+DOX. On week 11, animals were inoculated with 1*10(6) MatBIII tumor cells. Once tumors reached ~1 cm in diameter, animals were treated with 12 mg/kg of DOX or SAL. Animals were killed 1, 3, or 5 days following treatment. Tumor growth and cardiac function were measured at each interval. DOX accumulation and multidrug resistance protein (MRP) expression were quantified in tumor and heart tissue. No significant difference (P > 0.05) existed between DOX-treated SED and WR groups for tumor measurements. Exercise preserved cardiac function up to 5 days following DOX treatment. Exercise reduced ventricular DOX accumulation and upregulated ventricular MPR1 and MPR2. In contrast, no differences were observed in DOX accumulation or MRP expression in tumors of SED and WR animals. Endurance exercise had no effect on DOX antitumor efficacy as evidenced by a definitive DOX-induced reduction in tumor growth in both the SED and WR groups. Although exercise did not affect the antitumor efficacy of DOX, it still provided protection against cardiac dysfunction. These effects may be mediated by the degree of DOX tissue accumulation secondary to the regulation of MRP expression. PMID- 26246504 TI - Reduced placental amino acid transport in response to maternal nutrient restriction in the baboon. AB - Intrauterine growth restriction increases the risk of perinatal complications and predisposes the infant to diabetes and cardiovascular disease in later life. Mechanisms by which maternal nutrient restriction (MNR) reduces fetal growth are poorly understood. We hypothesized that MNR decreases placental amino acid (AA) transporter activity, leading to reduced transplacental transfer of AAs. Pregnant baboons were fed either a control (ad libitum, n = 7), or MNR diet (70% of control diet, n = 7) from gestational day (GD) 30. At GD 165 (0.9 gestation), placentas (n = 7 in each group) were collected, and microvillous plasma membrane vesicles (MVM) isolated. MVM system A and system L AA transport was determined in vitro using radiolabeled substrates and rapid filtration techniques. In vivo transplacental AA transport was assessed by infusing nine (13)C- or (2)H-labeled essential AA as a bolus into the maternal circulation (n = 5 control, n = 4 MNR) at cesarean section. A fetal vein-to-maternal artery mole percent excess ratio for each essential AA was calculated. Fetal and placental weights were significantly reduced in the MNR group compared with controls (P < 0.01). The activity of system A and system L was markedly reduced by 73 and 84%, respectively, in MVM isolated from baboon placentas at GD 165 following MNR (P < 0.01). In vivo, the fetal vein-to-maternal artery mole percent excess ratio was significantly reduced for leucine, isoleucine, methionine, phenylalanine, threonine, and tryptophan in MNR baboons (P < 0.05). This is the first study to investigate placental AA transport in a nonhuman primate model of MNR. We demonstrate that the downregulation of system A and system L activity in syncytiotrophoblast MVM in MNR leads to decreased transplacental AA transport and, consequently, reduced circulating fetal AA concentrations, a potential mechanism linking maternal undernutrition to reduced fetal growth. PMID- 26246506 TI - Gene expression of peripheral blood mononuclear cells is affected by cold exposure. AB - Because of the discovery of brown adipose tissue (BAT) in humans, there is increased interest in the study of induction of this thermogenic tissue as a basis to combat obesity and related complications. Cold exposure is one of the strongest stimuli able to activate BAT and to induce the appearance of brown-like (brite) adipocytes in white fat depots (browning process). We analyzed the potential of peripheral blood mononuclear cells (PBMCs) to reflect BAT and retroperitoneal white adipose tissue (rWAT) response to 1-wk cold acclimation (4 degrees C) at different ages of rat development (1, 2, 4, and 6 mo). As expected, cold exposure increased fatty acid beta-oxidation capacity in BAT and rWAT (increased Cpt1a expression), explaining increased circulating nonesterified free fatty acids and decreased adiposity. Cold exposure increased expression of the key thermogenic gene, Ucp1, in BAT and rWAT, but only in 1-mo-old animals. Additionally, other brown/brite markers were affected by cold during the whole developmental period studied in BAT. However, in rWAT, cold exposure increased studied markers mainly at early age. PBMCs did not express Ucp1, but expressed other brown/brite markers, which were cold regulated. Of particular interest, PBMCs reflected adipose tissue-increased Cpt1a mRNA expression in response to cold (in older animals) and browning induction occurring in rWAT of young animals (1 mo) characterized by increased Cidea expression and by the appearance of a high number of multilocular CIDE-A positive adipocytes. These results provide evidence pointing to PBMCs as an easily obtainable biological material to be considered to perform browning studies with minimum invasiveness. PMID- 26246507 TI - Transient impairment of dynamic renal autoregulation in early diabetes mellitus in rats. AB - Renal autoregulation is impaired in early (1 wk) diabetes mellitus (DM) induced by streptozotocin, but effective in established DM (4 wk). Furthermore nitric oxide synthesis (NOS) inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) significantly improved autoregulation in early DM but not in established DM. We hypothesized that autoregulation is transiently impaired in early DM because of increased NO availability in the kidney. Because of the conflicting evidence available for a role of NO in DM, we tested the hypothesis that DM reduces autoregulation effectiveness by reducing the spatial similarity of autoregulation. Male Long-Evans rats were divided into control (CON) and diabetic (DM; streptozotocin) groups and followed for either 1 wk (CON1, n = 6; DM1, n = 5) or 4 wk (CON4, n = 7; DM4, n = 7). At the end of the experiment, dynamic autoregulation was assessed in isoflurane-anesthetized rats by whole kidney RBF during baseline, NOS1 inhibition, and nonselective NOS inhibition. Kidney surface perfusion, monitored with laser speckle contrast imaging, was used to assess spatial heterogeneity of autoregulation. Autoregulation was significantly impaired in DM1 rats and not impaired in DM4 rats. L-NAME caused strong renal vasoconstriction in all rats, but did not significantly affect autoregulation dynamics. Autoregulation was more spatially heterogeneous in DM1, but not DM4. Therefore, our results, which are consistent with transient impairment of autoregulation in DM, argue against the hypothesis that this impairment is NO dependent, and suggest that spatial properties of autoregulation may also contribute to reduced autoregulatory effectiveness in DM1. PMID- 26246508 TI - Vascular versus tubular renin: role in kidney development. AB - Renin, the key regulated enzyme of the renin-angiotensin system regulates blood pressure, fluid-electrolyte homeostasis, and renal morphogenesis. Whole body deletion of the renin gene results in severe morphological and functional derangements, including thickening of renal arterioles, hydronephrosis, and inability to concentrate the urine. Because renin is found in vascular and tubular cells, it has been impossible to discern the relative contribution of tubular versus vascular renin to such a complex phenotype. Therefore, we deleted renin independently in the vascular and tubular compartments by crossing Ren1(c fl/fl) mice to Foxd1-cre and Hoxb7-cre mice, respectively. Deletion of renin in the vasculature resulted in neonatal mortality that could be rescued with daily injections of saline. The kidneys of surviving mice showed the absence of renin, hypertrophic arteries, hydronephrosis, and negligible levels of plasma renin. In contrast, lack of renin in the collecting ducts did not affect kidney morphology, intra-renal renin, or circulating renin in basal conditions or in response to a homeostatic stress, such as sodium depletion. We conclude that renin generated in the renal vasculature is fundamental for the development and integrity of the kidney, whereas renin in the collecting ducts is dispensable for normal kidney development and cannot compensate for the lack of renin in the vascular compartment. Further, the main source of circulating renin is the kidney vasculature. PMID- 26246509 TI - Respiratory muscle weakness in the Zucker diabetic fatty rat. AB - The obesity epidemic is considered one of the most serious public health problems of the modern world. Physical therapy is the most accessible form of treatment; however, compliance is a major obstacle due to exercise intolerance and dyspnea. Respiratory muscle atrophy is a cause of dyspnea, yet little is known of obesity induced respiratory muscle dysfunction. Our objective was to investigate whether obesity-induced skeletal muscle wasting occurs in the diaphragm, the main skeletal muscle involved in inspiration, using the Zucker diabetic fatty (ZDF) rat. After 14 wk, ZDF rats developed obesity, hyperglycemia, and insulin resistance, compared with lean controls. Hemodynamic analysis revealed ZDF rats have impaired cardiac relaxation (P = 0.001) with elevated end-diastolic pressure (P = 0.006), indicative of diastolic dysfunction. Assessment of diaphragm function revealed weakness (P = 0.0296) in the absence of intrinsic muscle impairment in ZDF rats. Diaphragm morphology revealed increased fibrosis (P < 0.0001), atrophy (P < 0.0001), and reduced myosin heavy-chain content (P < 0.001), compared with lean controls. These changes are accompanied by activation of the myostatin signaling pathway with increased serum myostatin (P = 0.017), increased gene expression (P = 0.030) in the diaphragm and retroperitoneal adipose (P = 0.033), and increased SMAD2 phosphorylation in the diaphragm (P = 0.048). Here, we have confirmed the presence of respiratory muscle atrophy and weakness in an obese, diabetic model. We have also identified a pathological role for myostatin signaling in obesity, with systemic contributions from the adipose tissue, a nonskeletal muscle source. These findings have significant implications for future treatment strategies of exercise intolerance in an obese, diabetic population. PMID- 26246510 TI - Co-participation of paternal and maternal genomes before the blastocyst stage is not required for full-term development of mouse embryos. PMID- 26246511 TI - New insights into the structural basis of DNA recognition by HINa and HINb domains of IFI16. AB - Interferon gamma-inducible protein 16 (IFI16) senses DNA in the cytoplasm and the nucleus by using two tandem hematopoietic interferon-inducible nuclear (HIN) domains, HINa and HINb, through the cooperative assembly of IFI16 filaments on double-stranded DNA (dsDNA). The role of HINa in sensing DNA is not clearly understood. Here, we describe the crystal structure of the HINa domain in complex with DNA at 2.55 A resolution and provide the first insight into the mode of DNA binding by the HINa domain. The structure reveals the presence of two oligosaccharide/nucleotide-binding (OB) folds with a unique DNA-binding surface. HINa uses loop L45 of the canonical OB2 fold to bind to the DNA backbone. The dsDNA is recognized as two single strands of DNA. Interestingly, deletion of HINb compromises the ability of IFI16 to induce IFN-beta, while HINa mutants impaired in DNA binding enhance the production of IFN-beta. These results shed light on the roles of IFI16 HIN domains in DNA recognition and innate immune responses. PMID- 26246512 TI - Slow- and fast-twitch hindlimb skeletal muscle phenotypes 12 wk after 5/6 nephrectomy in Wistar rats of both sexes. AB - This study describes fiber-type adaptations in hindlimb muscles, the interaction of sex, and the role of hypoxia on this response in 12-wk 5/6 nephrectomized rats (Nx). Contractile, metabolic, and morphological features of muscle fiber types were assessed in the slow-twitch soleus and the fast-twitch tibialis cranialis muscles of Nx rats, and compared with sham-operated controls. Rats of both sexes were considered in both groups. A slow-to-fast fiber-type transformation occurred in the tibialis cranialis of Nx rats, particularly in males. This adaptation was accomplished by impaired oxidative capacity and capillarity, increased glycolytic capacity, and no changes in size and nuclear density of muscle fiber types. An oxidative-to-glycolytic metabolic transformation was also found in the soleus muscle of Nx rats. However, a modest fast-to-slow fiber-type transformation, fiber hypertrophy, and nuclear proliferation were observed in soleus muscle fibers of male, but not of female, Nx rats. Serum testosterone levels decreased by 50% in male but not in female Nx rats. Hypoxia-inducible factor-1alpha protein level decreased by 42% in the tibialis cranialis muscle of male Nx rats. These data demonstrate that 12 wk of Nx induces a muscle-specific adaptive response in which myofibers do not change (or enlarge minimally) in size and nuclear density, but acquire markedly different contractile and metabolic characteristics, which are accompanied by capillary rarefaction. Muscle function and sex play relevant roles in these adaptations. PMID- 26246513 TI - Endothelin contributes to blunted renal autoregulation observed with a high-salt diet. AB - Autoregulation of renal blood flow (RBF) is an essential function of the renal microcirculation that has been previously shown to be blunted by excessive dietary salt. Endogenous endothelin 1 (ET-1) is increased following a high-salt (HS) diet and contributes to the control of RBF but the differential effects of ET-1 on renal microvessel autoregulation in response to HS remain to be established. We hypothesized that a HS diet increases endothelin receptor activation in normal Sprague-Dawley rats and blunts autoregulation of RBF. The role of ET-1 in the blunted autoregulation produced by a HS diet was assessed in vitro and in vivo using the blood-perfused juxtamedullary nephron preparation and anesthetized rats, respectively. Using highly selective antagonists, we observed that blockade of either ETA or ETB receptors was sufficient to restore normal autoregulatory behavior in afferent arterioles from HS-fed rats. Additionally, normal autoregulatory behavior was restored in vivo in HS-fed rats by simultaneous ETA and ETB receptor blockade, whereas blockade of ETB receptors alone showed significant improvement of normal autoregulation of RBF. Consistent with this observation, autoregulation of RBF in ETB receptor-deficient rats fed HS was similar to both ETB-deficient rats and transgenic control rats on normal salt diets. These data support the hypothesis that endogenous ET-1, working through ETB and possibly ETA receptors, contributes to the blunted renal autoregulatory behavior in rats fed a HS diet. PMID- 26246514 TI - Alcohol Dependence, Co-occurring Conditions and Attributable Burden. AB - AIMS: Alcohol dependence is associated with high rates of co-occurring disorders which impact health-related quality of life (HRQoL) and add to the cost-of illness. This study investigated the burden of alcohol dependence and associated co-occurring conditions on health and productivity. METHODS: A cross-sectional survey was conducted in eight European countries. Physicians (Psychiatrists and General Practitioners) completed patient record forms, which included assessment of co-occurring conditions, and patients completed matching self-completion forms. Drinking risk level (DRL) was calculated and the relationship between DRL, co-occurring conditions, work productivity, hospitalisations and rehabilitation stays was explored. RESULTS: Data were collected for 2979 alcohol-dependent patients (mean age 48.8 +/- 13.6 years; 70% male). In total, 77% of patients suffered from moderate-to-severe co-occurring psychiatric and/or somatic conditions. High DRL was significantly associated with depression, greater work productivity losses, increased hospitalisations and rehabilitation stays. Co occurring conditions were significantly associated with poorer HRQoL and decreased work productivity, with a statistical trend towards an increased frequency of rehabilitation stays. CONCLUSIONS: Alcohol-dependent patients manifest high rates of co-occurring psychiatric and somatic conditions, which are associated with impaired work productivity and HRQoL. The continued burden of illness observed in these already-diagnosed patients suggests an unmet need in both primary and secondary care. PMID- 26246515 TI - Does Shared Decision Making in Cancer Treatment Improve Quality of Life? A Systematic Literature Review. AB - BACKGROUND: The growing consensus espousing the use of shared decision making (SDM) in cancer treatment has coincided with the rise of health care evaluation paradigms that emphasize quality of life (QOL) as a central outcome measure. This review systematically examines the association between treatment SDM and QOL outcomes in cancer. METHODS: A range of bibliographic databases and gray literature sources was searched. The search retrieved 16,726 records, which were screened by title, abstract, and full text to identify relevant studies. The review included 17 studies with a range of study designs and populations. Data were extracted on study methods, participants, setting, study or intervention description, outcomes, main findings, secondary findings, and limitations. Quality appraisal was used, in conjunction with a narrative approach, to synthesize the evidence. RESULTS: The review found weak, but suggestive, evidence for a positive association between perceived patient involvement in decision making, a central dimension of SDM, and QOL outcomes in cancer. The review did not find evidence for an inverse association between SDM and QOL. The poor methodological quality and heterogeneity of the extant literature constrained the derived conclusions. In addition, the literature commonly treated various subscales of QOL instruments as separate outcomes, increasing the probability of spurious findings. CONCLUSIONS: There is weak evidence that aspects of shared decision-making approaches are positively associated with QOL outcomes and very little evidence of a negative association. The extant literature largely assessed patient involvement, only capturing one aspect of the shared decision-making construct, and is of poor quality, necessitating robust studies examining the association. PMID- 26246516 TI - The CREATE Method for Expressing Continuous Outcome Data in Absolute Terms for Use in Patient Treatment Decision Aids: A Validation Study. AB - BACKGROUND: Patient decision aids (PtDAs) supplement advice from health care professionals by communicating the absolute risk or benefit of treatment options (i.e., X/100). As such, PtDAs have been amenable to binary outcomes only. We aimed to develop and test the validity of the Conversion to Risk Estimates through Application of Normal Theory (CREATE) method for estimating absolute risk based on continuous outcome data. METHODS: CREATE is designed to derive an estimate of the proportion of those who experience a clinically relevant degree of change (CRDoC). We used a 2-stage validation process using real and simulated change score data, respectively. First, using raw data from published intervention trials, we calculated the proportion of patients with a CRDoC and compared that with our CREATE-derived estimate using chi-square tests of association. Second, 200,000 simulated distributions of change scores were generated with widely varying distribution characteristics. Actual and CREATE derived estimates were compared for each simulated distribution, and relative differences were summarized graphically. RESULTS: The absolute difference between the estimated and actual CRDoC did not exceed 5% for any of the samples based on real data. Applying the CREATE method to 200,000 simulated scenarios demonstrated that the CREATE method should be avoided for outcomes where the underlying distribution can be reasonably assumed to have high levels of skew or kurtosis. CONCLUSION: Our results suggest that standard statistical theory can be used to estimate continuous outcomes in absolute terms with reasonable accuracy for use in PtDAs; caution is advised if outcome summary statistics are assumed to have been derived from highly skewed distributions. PMID- 26246517 TI - Cowden's syndrome with immunodeficiency. AB - BACKGROUND: Cowden's syndrome is a rare, autosomal dominant disease caused by mutations in the phosphoinositide 3-kinase and phosphatase and tensin homolog (PTEN) gene. It is associated with hamartomatous polyposis of the gastrointestinal tract, mucocutaneous lesions and increased risk of developing certain types of cancer. In addition to increased risk of tumour development, mutations in PTEN have also been associated with autoimmunity in both mice and humans. Until now, however, an association between Cowden's syndrome and immune deficiency has been reported in a single patient only. METHODS AND RESULTS: Two patients with Cowden's syndrome and an increased frequency of infections were investigated for possible underlying immunodeficiency. In one patient, hypogammaglobulinaemia with a functional antibody deficiency was identified, while the other patient had a persisting CD4+ T cell lymphopenia (with normal antibody production). CONCLUSIONS: Our data indicate that Cowden's syndrome may be associated with both T cell and B cell immune dysfunction. We recommend that patients with Cowden's syndrome and an increased frequency of infections are investigated for associated immunodeficiency. PMID- 26246518 TI - Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses. AB - BACKGROUND: Heparan sulfate proteoglycans are vital components of the extracellular matrix and are essential for cellular homeostasis. Many genes are involved in modulating heparan sulfate synthesis, and when these genes are mutated, they can give rise to early-onset developmental disorders affecting multiple body systems. Herein, we describe a consanguineous family of four sibs with a novel disorder, which we designate as seizures-scoliosis-macrocephaly syndrome, characterised by seizures, intellectual disability, hypotonia, scoliosis, macrocephaly, hypertelorism and renal dysfunction. METHODS: Our application of autozygosity mapping and whole-exome sequencing allowed us to identify mutations in the patients. To confirm the autosomal-recessive mode of inheritance, all available family members were genotyped. We also studied the effect of these mutations on protein expression and function in patient cells and using an in vitro system. RESULTS: We identified two homozygous mutations p.Met87Arg and p.Arg95 Cys in exostosin 2, EXT2, a ubiquitously expressed gene that encodes a glycosyltransferase required for heparan sulfate synthesis. In patient cells, we observed diminished EXT2 expression and function. We also performed an in vitro assay to determine which mutation has a larger effect on protein expression and observed reduced EXT2 expression in constructs expressing either one of the mutations but a greater reduction when both residues were mutated. CONCLUSIONS: In short, we have unravelled the genetic basis of a new recessive disorder, seizures-scoliosis-macrocephaly syndrome. Our results have implicated a well-characterised gene in a new developmental disorder and have further illustrated the spectrum of phenotypes that can arise due to errors in glycosylation. PMID- 26246519 TI - Charcot-Marie-Tooth diseases: an update and some new proposals for the classification. AB - BACKGROUND: Charcot-Marie-Tooth (CMT) disease, the most frequent form of inherited neuropathy, is a genetically heterogeneous group of disorders of the peripheral nervous system, but with a quite homogeneous clinical phenotype (progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss and usually decreased tendon reflexes). Our aim was to review the various CMT subtypes identified at the present time. METHODS: We have analysed the medical literature and performed a historical retrospective of the main steps from the individualisation of the disease (at the end of the nineteenth century) to the recent knowledge about CMT. RESULTS: To date, >60 genes (expressed in Schwann cells and neurons) have been implicated in CMT and related syndromes. The recent advances in molecular genetic techniques (such as next-generation sequencing) are promising in CMT, but it is still useful to recognise some specific clinical or pathological signs that enable us to validate genetic results. In this review, we discuss the diagnostic approaches and the underlying molecular pathogenesis. CONCLUSIONS: We suggest a modification of the current classification and explain why such a change is needed. PMID- 26246521 TI - Does Amphetamine Enhance Your Health? On the Distinction between Health and "Health-like" Enhancements. AB - It is an imperative within health care, medicine, and public health to restore, preserve, and enhance health. Therefore, it is important to determine what kinds of enhancement are increases in health and what kinds are not. Taking as its point of departure two conceptions of health, namely, "manifest health" and "fundamental health," the paper discusses various means used to enhance ability and well-being, and if those means, such as wheelchairs, implants, medicines, stimulants, or narcotics, enhance health. The fact that some means that enhance ability or well-being are not usually considered health enhancing, for example, narcotics, constitutes a problem. The paper ends with a discussion of some suggestions about how to distinguish between those enhancements that are health related and those that are not. One plausible idea holds that an enhancement is health related when the substance, or aid, increases ability or well-being, is integrated into the body, and does not harm the individual's fundamental health. PMID- 26246520 TI - Genes Unite Executive Functions in Childhood. AB - Individual differences in children's executive functions (EFs) are relevant for a wide range of normal and atypical psychological outcomes across the life span, but the origins of variation in children's EFs are not well understood. We used data from a racially and socioeconomically diverse sample of 505 third- through eighth-grade twins and triplets from the Texas Twin Project to estimate genetic and environmental influences on a Common EF factor and on variance unique to four core EF domains: inhibition, switching, working memory, and updating. As has been previously demonstrated in young adults, the Common EF factor was 100% heritable, which indicates that correlations among the four EF domains are entirely attributable to shared genetic etiology. Nonshared environmental influences were evident for variance unique to individual domains. General EF may thus serve as an early life marker of genetic propensity for a range of functions and pathologies later in life. PMID- 26246522 TI - Severe Obesity and the Ambivalence of Attending Physical Activity: Exploring Lived Experiences. AB - Physical activity is considered fundamental in lifestyle interventions. We explore experiences of physical activity prior to, during, and following a 10- to 14-week inpatient lifestyle modification program, including high volume of physical activity, for the treatment of severe obesity. Eight participants from a prospective clinical trial were selected to participate in a complementary qualitative study. The participants' experiences with physical activity during and following the treatment program represented different opposites: "pain and pleasure," "desire and duty," and "bubble and battle." We summarized the findings into one overall theme: "the ambivalence of attending physical activity." The ambivalence is experienced as a shift in how participants experience physical activity during the intervention period and as an ongoing, dynamic, and constantly shifting experience during such activity. To address and reflect upon such experiences with the participants, and acknowledge ambivalence as a legitimate part of being physically active, might be important within obesity treatment. PMID- 26246523 TI - The Framing and Fashioning of Therapeutic Citizenship Among People Living With HIV Taking Antiretroviral Therapy in Uganda. AB - In this article, we examine how people living with HIV (PLWH) were able to reconceptualize or "reframe" their understanding of HIV and enhance their capacity to self-manage the condition. Two in-depth interviews were held with 38 PLWH (20 women, 18 men) selected from three government and nongovernment antiretroviral therapy (ART) delivery sites in Wakiso District, and the narratives analyzed. ART providers played an important role in shaping participants' HIV self-management processes. Health workers helped PLWH realize that they could control their condition, provided useful concepts and language for emotional coping, and gave advice about practical self-management tasks, although this could not always be put into practice. ART providers in this setting were spaces for the development of a collective identity and a particular form of therapeutic citizenship that encouraged self-management, including adherence to ART. Positive framing institutions are important for many PLWH in resource-limited settings and the success of ART programs. PMID- 26246524 TI - Unilateral cancer-associated retinopathy: a case report. AB - We write to report a rare case of unilateral cancer-associated retinopathy previously undocumented in the literature. Cancer-associated retinopathy is an uncommon paraneoplastic syndrome. It is characterised by retinal antigen autoantibodies causing rod and cone dysfunction and abnormal electroretinography findings with consequent progressive visual loss.Our patient, known to have a primary cervical intraepithelial neoplasia, presented with unilateral blurred vision as well as a disturbance in colour and night vision. Electroretinography findings of reduced a and b waves in the right eye, together with a fundoscopic appearance of a mottled retinal pigment epithelium, attenuated blood vessels and optic disc pallor were consistent with unilateral cancer-associated retinopathy. Posterior subtenon injections of triamcinolone were administered to control active disease. With periocular steroid injections, at 4 years, our patient's visual acuity remained relatively stable and her condition persisted strictly unilaterally. Cancer-associated retinopathy may be the first presenting sign of an underlying malignancy or may indicate its recurrence. Moreover, in patients with a diagnosed gynaecological malignancy, visual symptoms could reflect cancer associated retinopathy. In our patient visual symptoms came secondary to the diagnosis of cancer. PMID- 26246525 TI - The JDE's Peer Education: Reviews of the Literature (PERLs). PMID- 26246526 TI - An Outcomes Study of 40 Years of Graduates of a General Practice Dental Residency. AB - Assessing program quality and outcomes is essential to improve postgraduate dental education. This study's aims were to document career direction and practice patterns of graduates of the Brigham and Women's Hospital (BWH) General Practice Residency (GPR), to compare BWH GPR outcomes to those of other American GPRs, and to identify characteristics of the BWH GPR program that trainees valued. This was a retrospective cohort study with a sample comprised of BWH GPR graduates between 1973 and 2013. Outcomes examined included pursuit of specialty training and positions on academic or hospital staff. Data sources were a survey of BWH GPR graduates and published national surveys. Of the 190 BWH graduates (95% of total) who were located and contacted, 133 (70% response rate) completed the survey. Compared to national survey data, BWH GPR graduates were significantly more likely to be specialists, full-time hospital staff, or full time or part-time dental school faculty. Most BWH graduates (96.2%) ranked the program as outstanding or good. Faculty characteristics were considered by BWH graduates to be the most important factors in judging program quality. Since faculty characteristics were the most important factors in residents' judgment of program quality, GPR programs should recruit, maintain, and develop a quality faculty in order to attract students. PMID- 26246527 TI - Dental Hygienists' Experiences with Motivational Interviewing: A Qualitative Study. AB - The effectiveness of Motivational Interviewing (MI) to change health behaviors is well documented. Previous studies support use of MI to change oral health behaviors in the areas of early childhood caries and periodontal diseases, but research is limited due to the sparse number of oral health care providers with training in MI. The University of Missouri-Kansas City (UMKC) formally integrated MI training into its dental hygiene curriculum five years ago. Summative program evaluation of UMKC's MI training shows that it effectively equips graduates with MI skills. The aim of this qualitative study was to use semi-structured interviews with nine program alumni to provide insight into the experiences of MI trained dental hygienists in clinical practice. All interviews were captured with a digital voice recorder, were transcribed, and were resubmitted to the interviewees for checking. Five themes emerged from the data analysis: salience, best practices, barriers, facilitators, and lessons learned. These dental hygienists strongly valued and embraced the spirit of MI. They reported feeling strongly that it should be part of all dental hygiene curricula, and they upheld MI as a best practice. The participants approved of their MI instruction as a whole but felt it was difficult and sometimes not viable in practice. They reported that MI training had improved their communication skills and increased treatment acceptance. Time, difficulty, and managing patient resistance were the most often cited barriers, while a supportive climate and creating a routine were the most often cited facilitators. PMID- 26246528 TI - Do Quantitative Measures of Research Productivity Correlate with Academic Rank in Oral and Maxillofacial Surgery? AB - Academic promotion is linked to research productivity. The purpose of this study was to assess the correlation between quantitative measures of academic productivity and academic rank among academic oral and maxillofacial surgeons. This was a cross-sectional study of full-time academic oral and maxillofacial surgeons in the United States. The predictor variables were categorized as demographic (gender, medical degree, research doctorate, other advanced degree) and quantitative measures of academic productivity (total number of publications, total number of citations, maximum number of citations for a single article, I-10 index [number of publications with >= 10 citations], and h-index [number of publications h with >= h citations each]). The outcome variable was current academic rank (instructor, assistant professor, associate professor, professor, or endowed professor). Descriptive, bivariate, and multiple regression statistics were computed to evaluate associations between the predictors and academic rank. Receiver-operator characteristic curves were computed to identify thresholds for academic promotion. The sample consisted of 324 academic oral and maxillofacial surgeons, of whom 11.7% were female, 40% had medical degrees, and 8% had research doctorates. The h-index was the most strongly correlated with academic rank (rho = 0.62, p < 0.001). H-indexes of >= 4, >= 8, and >= 13 were identified as thresholds for promotion to associate professor, professor, and endowed professor, respectively (p < 0.001). This study found that the h-index was strongly correlated with academic rank among oral and maxillofacial surgery faculty members and thus suggests that promotions committees should consider using the h-index as an additional method to assess research activity. PMID- 26246529 TI - Comparative Effectiveness of Dental Anatomy Carving Pedagogy: A Systematic Review. AB - The aim of this study was to review the effectiveness of methods used for teaching dental anatomy carving to dental students in operative dentistry as evaluated in published studies. This systematic review is described in accordance with the PRISMA statement. Two independent reviewers performed a systematic literature search of research published from January 1945 until May 2014. Seven databases were screened: MedLine (PubMed), Lilacs, IBECS, Web of Science, Scopus, SciELO, and The Cochrane Library. After removing duplicates, only studies using dental carving to assess the practical knowledge of anatomy were selected. The tabulated data were organized by title of article, names of authors, number of students assessed, assessment method, material used, groups tested, main results, and conclusions. The methodology quality was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions. Initially, 2,258 studies were identified in all databases. Five articles met the eligibility criteria and were included in this review. According to these studies, the geometric method, teaching step-by-step along with the teacher, and adjuvant methods such as the use of tutors and teaching through digital media with DVDs proved to be effective in improving learning. There is no standard technique that is widely accepted for the teaching of dental carving, nor is there an appropriately validated method of evaluation to verify whether the teaching methods used are effective for the acquisition of skills and expertise in dental anatomy by students. PMID- 26246530 TI - The Landscape of Predoctoral Endodontic Education in the United States and Canada: Results of a Survey. AB - Few recent surveys have examined the contemporary landscape of predoctoral endodontic education in the United States and Canada, but anecdotal reports suggest that current dental students have difficulty obtaining adequate clinical endodontic experiences. The aims of this study were to quantify the clinical endodontic experiences of current U.S. and Canadian dental students, to explore the issues surrounding their clinical endodontic competence, and to ask more broadly if current graduating dentists are competent to perform endodontic procedures. In August 2014, a hyperlink to a web-based survey with 27 questions was emailed to the 67 predoctoral endodontic directors of U.S. and Canadian dental schools using a list provided by the American Association of Endodontists. Out of these 67 possible participants, 40 responded, for a response rate of 60%. The findings were varied. The average 2014 graduate completed 5.9 (+/- 2.4) root canal treatments on live patients, and 69% of the respondents voiced concern regarding a shortage of patient experiences. A majority (59%) of the respondents reported thinking that the supply of endodontic patients has decreased and that students have an inadequate supply of endodontic patients. This study found that a clear majority of predoctoral endodontics directors perceived a shortage of patient experiences for their students although, in reality, the number of completed clinical cases appeared to be unchanged since 1975. In addition, 36% of the respondents reported feeling that their 2014 graduates were not competent to perform molar endodontic treatment in their practices. PMID- 26246531 TI - Patient Demonstration Videos in Predoctoral Endodontic Education: Aspects Perceived as Beneficial by Students. AB - The aim of this study was to assess the perceived benefits of video-mediated demonstrations in learning endodontics. Participants in the study were 75 third year students enrolled in the undergraduate dentistry program at Karolinska Institute, Stockholm, Sweden. After the endodontic preclinical course, the students were introduced to the treatment protocol in the clinic by watching two live patient-demonstrated videos. The first video demonstrated how to communicate with the patient and perform diagnosis and root canal instrumentation. The second video illustrated how to perform bacterial sampling and root canal filling. After the students watched each video, a questionnaire was used to evaluate their opinions about various steps of the endodontic treatment protocol and the benefit of such educational material for their practice. Of the total 75 students, 72 completed the first questionnaire (96% response rate), and 65 completed the second questionnaire (87% response rate). The results showed that the students perceived high value in the video demonstrations related to treatment procedure. A statistically significant difference was observed between the perceived benefits of the first and second sessions in communication and treatment procedure (p<0.001). Further studies are needed to assess improvement in the design and delivery format for video demonstrations to enhance their effectiveness as a teaching modality for endodontics. PMID- 26246532 TI - Campus-Based, Community-Based, and Philanthropic Contributions to Predoctoral Pediatric Dental Clinical Education: Two Years of Experiences at One Dental College. AB - The aim of this study was to investigate the contribution of a tiered predoctoral pediatric dentistry clinical education model to competency achievement by dental students over a two-year clinical education. Retrospective data were obtained for academic years 2012-13 and 2013-14 from three sources: a campus-based, dental school-housed clinic; division-directed clinics in community-based pediatric and special needs clinics (DDC); and clinics affiliated with the dental college's community-based dental education (CBDE) program, the OHIO Project (OP). A fourth dataset was obtained for the same two-year period from a biannual clinic event held at the college in conjunction with Give Kids a Smile Day (GKAS). Procedures considered essential to the care of children were sorted by 12 dental codes from all services for patients 18 years of age and younger. The dental school clinic provided 11,060 procedures; the DDC, 28,462; the OP, 17,863; and GKAS, 2,028. The two-year total was 59,433 procedures. Numbers of diagnostic and preventive procedures were 19,441, restorative procedures were 13,958, and pulp and surgical procedures were 7,392. Site contribution ranged from 52.2 to 144.9 procedures per attending student, with the DDC yielding the highest per student average for each year (126.4 and 144.9) and the dental school clinic the lowest (52.2 and 53.1). This study found that a combination of school-based, community-based, and philanthropic pediatric dental experiences offered a large number of essential pediatric dentistry experiences for predoctoral dental students, with CBDE opportunities offering the largest contribution. PMID- 26246533 TI - Communication Skills in Dental Students: New Data Regarding Retention and Generalization of Training Effects. AB - Previous studies have shown that a communications program using patient instructors (PIs) facilitates data-gathering and interpersonal skills of third year dental students. The aim of this study was to address the question of whether those skills are retained into the students' fourth year and generalized from the classroom to the clinic. In the formative training phase, three cohorts of D3 students (N=1,038) at one dental school received instruction regarding effective patient-doctor communication; interviewed three PIs and received PI feedback; and participated in a reflective seminar with a behavioral science instructor. In the follow-up competency phase, fourth-year students performed two new patient interviews in the clinic that were observed and evaluated by clinical dental faculty members trained in communications. Mean scores on a standardized communications rating scale and data-gathering assessment were compared over training and follow-up sessions and between cohorts with a linear mixed model. The analysis showed that the third-year students' mean communication and data gathering scores increased with each additional encounter with a PI (p<0.05) and that communication scores were not only maintained but increased during the fourth-year follow-up competency evaluations (p<0.05). Based on changes in the communications curriculum, prior instruction facilitated the students' clinical communication performance at baseline (p<0.05). This study suggests that the current Clinical Communications program improved students' data-gathering and interpersonal skills. Those skills were maintained and generalized through completion of the D4 students' summative competency performance in a clinical setting. PMID- 26246534 TI - Evaluation of a Comprehensive Tobacco Dependence Treatment Program: Dental Students' Perceptions of Preparedness and Clinical Practice. AB - The aims of this study were to assess dental students' perceptions of their preparedness for providing treatment for tobacco dependence and to determine if their training resulted in successful practice in the dental school clinic. Since the tobacco dependence treatment program began at the University of Detroit Mercy School of Dentistry, all third- and fourth-year dental students have been required to complete an online survey about their attitudes and experience with tobacco dependence treatment. This descriptive study and retrospective analysis utilized these survey data from the initiation of the program in fall 2002 through 2010 (615 third-year and 590 fourth-year students, for a total of 1,205, all of whom participated in the surveys). The results showed that most of the students believed they were at least adequately prepared to provide treatment. The majority said they ask patients about tobacco use and advise patients about its negative health consequences, yet the average of their perception of patient interest in quitting was below 18%. Although the students reported being at least adequately prepared to assess patient interest in quitting, their assessment was much lower than the nearly 70% of U.S. tobacco users that general studies have found are interested in quitting. These students' perception of such low patient interest reflects a misconception they may have about their own preparedness, and it suggests a barrier exists for them in providing effective tobacco dependence treatment services. This perception signals a need for curriculum and assessment changes to increase the effectiveness of this school's tobacco dependence treatment program. PMID- 26246535 TI - Ability of Dental Students in Spain to Identify Potentially Malignant Disorders and Oral Cancer. AB - The aim of this study was to assess the ability of students at the School of Dentistry, Complutense University of Madrid, Spain, to diagnose oral cancer and other potentially malignant disorders, as well as to compare their ability at different stages of the learning process and evaluate their knowledge retention. Students were surveyed after they had studied oral medicine and oral pathology at two time points: midway through and near the end of their studies. The survey consisted of questions about 40 photographs of benign oral lesions, malignant oral lesions, and potentially malignant disorders. The response rate for all groups was greater than 70%. The results showed that these students' overall success rate in differentiating benign from malignant lesions averaged 73.9%. When the distinction for potentially malignant disorders was included, their average overall success rate decreased to 42.8% (p<0.001). Furthermore, the students' average success rate was at its lowest at the end of the dental program (p<0.001). Results from this study suggest that, given these students' difficulties in identifying potentially malignant disorders, an increased emphasis on cancer education in the dental curriculum may be needed for future practitioners to master this ability. PMID- 26246536 TI - Dental School Administrators' Attitudes Towards Providing Support Services for LGBT-Identified Students. AB - A lack of curriculum time devoted to teaching dental students about the needs of lesbian, gay, bisexual, and transgendered (LGBT) health care patient needs and biases against LGBT students and faculty have been reported. Understanding dental school administrators' attitudes about LGBT students' needs might provide further insight into these long-standing issues. The aims of this study were to develop a survey to assess dental administrators' attitudes regarding the support services they believe LGBT-identified students need, to identify dental schools' current diversity inclusion policies, and to determine what types of support dental schools currently provide to LGBT students. A survey developed with the aid of a focus group, cognitive interviewing, and pilot testing was sent to 136 assistant and associate deans and deans of the 65 U.S. and Canadian dental schools. A total of 54 responses from 43 (66%) schools were received from 13 deans, 29 associate deans, and 11 assistant deans (one participant did not report a position), for a 40% response rate. The findings suggest there is a considerable lack of knowledge or acknowledgment of LGBT dental students' needs. Future studies are needed to show the importance of creating awareness about meeting the needs of all dental student groups, perhaps through awareness campaigns initiated by LGBT students. PMID- 26246537 TI - Psychometric Validation of the Academic Motivation Scale in a Dental Student Sample. AB - The Academic Motivation Scale is one of the most frequently used instruments to assess academic motivation. It relies on the self-determination theory of human motivation. However, motivation has been understudied in dental education. Therefore, to address the lack of valid instruments to assess academic motivation in dental education and contribute to future research in the field, the aim of this study was to analyze the psychometric properties of this instrument in a sample of dental students. Participants were 989 Chilean undergraduate dental students (86% response rate) who completed a survey containing a Chilean face valid version of the Spanish Academic Motivation Scale and three other motivation related instruments to assess the survey's construct and criterion validity. Later, 76 of the students (out of 100 invited) took the survey again to assess its test-retest stability. The instrument's construct validity was supported by the superior goodness of fit of the seven-subscale Academic Motivation Scale over competing models through confirmatory factor analysis and by the expected correlations among its subscales. The concurrent criterion validity was supported by the confirmation of correlations between its subscales and external criteria. Adequate internal consistency and test-retest correlations were also found. The evidence from this study suggests that the Academic Motivation Scale is a preliminarily valid and reliable instrument to assess motivation in the predoctoral dental context. Future research in this area is needed to confirm or refute these results. PMID- 26246538 TI - Peer Education: Reviews of the Literature (PERLs). PMID- 26246539 TI - Ebola, viewed through a lens of African epidemiology. PMID- 26246541 TI - Diagnostic value of serum CA125, CA19-9 and CA15-3 in endometriosis: A meta analysis. AB - AIM: To evaluate the diagnostic value of serum cancer antigen (CA)125, CA19-9 and CA15-3 concentrations in endometriosis. METHODS: Case-control studies evaluating CA125, CA19-9 and CA15-3 and endometriosis, published between January 2000 and November 2014 were retrieved from PubMed((r)) and Google Scholar. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated. Subgroup analyses were carried out by ethnicity and disease stage (early, stage I/II; advanced, stage III/IV). RESULTS: The analysis included 12 case-control studies (963 cases, 855 controls). CA125 was associated with endometriosis in the overall population (SMD 0.82, 95% CI 0.72, 0.92), Caucasian subgroup (SMD 1.08, 95% CI 0.96, 1.19), and early (SMD 1.20, 95% CI 0.93, 1.48) or advanced disease (SMD 1.29, 95% CI 1.04, 1.55). CA19-9 was associated with endometriosis in the overall population (SMD 0.48, 95% CI 0.24, 0.72), Caucasian subgroup (SMD 0.31, 95% CI 0.07, 0.55), Asian subgroup (SMD 9.65, 95% CI 7.88, 11.42) and advanced disease (SMD 0.60, 95% CI 0.34, 0.87). CA15-3 was significantly associated with advanced disease (SMD 0.47, 95% CI 0.09, 0.84). CONCLUSIONS: Serum CA125 and CA19 9 may represent useful biomarkers for the noninvasive diagnosis of endometriosis. PMID- 26246540 TI - Reaching the poor with health interventions: programme-incidence analysis of seven randomised trials of women's groups to reduce newborn mortality in Asia and Africa. AB - BACKGROUND: Efforts to end preventable newborn deaths will fail if the poor are not reached with effective interventions. To understand what works to reach vulnerable groups, we describe and explain the uptake of a highly effective community-based newborn health intervention across social strata in Asia and Africa. METHODS: We conducted a secondary analysis of seven randomised trials of participatory women's groups to reduce newborn mortality in India, Bangladesh, Nepal and Malawi. We analysed data on 70,574 pregnancies. Socioeconomic and sociodemographic differences in group attendance were tested using logistic regression. Qualitative data were collected at each trial site (225 focus groups, 20 interviews) to understand our results. RESULTS: Socioeconomic differences in women's group attendance were small, except for occasional lower attendance by elites. Sociodemographic differences were large, with lower attendance by young primigravid women in African as well as in South Asian sites. The intervention was considered relevant and interesting to all socioeconomic groups. Local facilitators ensured inclusion of poorer women. Embarrassment and family constraints on movement outside the home restricted attendance among primigravid women. Reproductive health discussions were perceived as inappropriate for them. CONCLUSIONS: Community-based women's groups can help to reach every newborn with effective interventions. Equitable intervention uptake is enhanced when facilitators actively encourage all women to attend, organise meetings at the participants' convenience and use approaches that are easily understandable for the less educated. Focused efforts to include primigravid women are necessary, working with families and communities to decrease social taboos. PMID- 26246542 TI - Vulnerability of individual fish to capture by trawling is influenced by capacity for anaerobic metabolism. AB - The harvest of animals by humans may constitute one of the strongest evolutionary forces affecting wild populations. Vulnerability to harvest varies among individuals within species according to behavioural phenotypes, but we lack fundamental information regarding the physiological mechanisms underlying harvest induced selection. It is unknown, for example, what physiological traits make some individual fish more susceptible to capture by commercial fisheries. Active fishing methods such as trawling pursue fish during harvest attempts, causing fish to use both aerobic steady-state swimming and anaerobic burst-type swimming to evade capture. Using simulated trawling procedures with schools of wild minnows Phoxinus phoxinus, we investigate two key questions to the study of fisheries-induced evolution that have been impossible to address using large scale trawls: (i) are some individuals within a fish shoal consistently more susceptible to capture by trawling than others?; and (ii) if so, is this related to individual differences in swimming performance and metabolism? Results provide the first evidence of repeatable variation in susceptibility to trawling that is strongly related to anaerobic capacity and swimming ability. Maximum aerobic swim speed was also negatively correlated with vulnerability to trawling. Standard metabolic rate was highest among fish that were least vulnerable to trawling, but this relationship probably arose through correlations with anaerobic capacity. These results indicate that vulnerability to trawling is linked to anaerobic swimming performance and metabolic demand, drawing parallels with factors influencing susceptibility to natural predators. Selection on these traits by fisheries could induce shifts in the fundamental physiological makeup and function of descendent populations. PMID- 26246543 TI - No conclusive evidence that corvids can create novel causal interventions. PMID- 26246544 TI - Rate of novel host invasion affects adaptability of evolving RNA virus lineages. AB - Although differing rates of environmental turnover should be consequential for the dynamics of adaptive change, this idea has been rarely examined outside of theory. In particular, the importance of RNA viruses in disease emergence warrants experiments testing how differing rates of novel host invasion may impact the ability of viruses to adaptively shift onto a novel host. To test whether the rate of environmental turnover influences adaptation, we experimentally evolved 144 Sindbis virus lineages in replicated tissue-culture environments, which transitioned from being dominated by a permissive host cell type to a novel host cell type. The rate at which the novel host 'invaded' the environment varied by treatment. The fitness (growth rate) of evolved virus populations was measured on each host type, and molecular substitutions were mapped via whole genome consensus sequencing. Results showed that virus populations more consistently reached high fitness levels on the novel host when the novel host 'invaded' the environment more gradually, and gradual invasion resulted in less variable genomic outcomes. Moreover, virus populations that experienced a rapid shift onto the novel host converged upon different genotypes than populations that experienced a gradual shift onto the novel host, suggesting a strong effect of historical contingency. PMID- 26246545 TI - Moral parochialism and contextual contingency across seven societies. AB - Human moral judgement may have evolved to maximize the individual's welfare given parochial culturally constructed moral systems. If so, then moral condemnation should be more severe when transgressions are recent and local, and should be sensitive to the pronouncements of authority figures (who are often arbiters of moral norms), as the fitness pay-offs of moral disapproval will primarily derive from the ramifications of condemning actions that occur within the immediate social arena. Correspondingly, moral transgressions should be viewed as less objectionable if they occur in other places or times, or if local authorities deem them acceptable. These predictions contrast markedly with those derived from prevailing non-evolutionary perspectives on moral judgement. Both classes of theories predict purportedly species-typical patterns, yet to our knowledge, no study to date has investigated moral judgement across a diverse set of societies, including a range of small-scale communities that differ substantially from large highly urbanized nations. We tested these predictions in five small-scale societies and two large-scale societies, finding substantial evidence of moral parochialism and contextual contingency in adults' moral judgements. Results reveal an overarching pattern in which moral condemnation reflects a concern with immediate local considerations, a pattern consistent with a variety of evolutionary accounts of moral judgement. PMID- 26246546 TI - Complex relationships between species niches and environmental heterogeneity affect species co-occurrence patterns in modelled and real communities. AB - Species co-occurrence analysis is commonly used to assess how interspecific interactions dictate community assembly. Non-random co-occurrences, however, may also emerge from niche differences as well as environmental heterogeneity. The relationships between species co-occurrence patterns, environmental heterogeneity and species niches are not fully understood, due to complex interactions among them. To analyse the relationships among these patterns and processes, I developed synthetic community models and analysed a large dataset of tree species across the conterminous United States. Niche overlap and environmental heterogeneity had significant and contrasting effects on species co-occurrence patterns, in both modelled and real communities. Niche breadth, in turn, affected the effect sizes of both variables on species co-occurrence patterns. The effect of niche breadth on the relationship between co-occurrence and niche overlap was markedly consistent between modelled and real communities, while its effect on the relationship between co-occurrence and environmental heterogeneity was mostly consistent between real and modelled data. The results of this analysis highlight the complex and interactive effects of species niche overlap, niche breadth and environmental heterogeneity on species co-occurrence patterns. Therefore, inferring ecological processes from co-occurrence patterns without accounting for these fundamental characteristics of species and environments may lead to biased conclusions. PMID- 26246547 TI - Historical drivers of extinction risk: using past evidence to direct future monitoring. AB - Global commitments to halt biodiversity decline mean that it is essential to monitor species' extinction risk. However, the work required to assess extinction risk is intensive. We demonstrate an alternative approach to monitoring extinction risk, based on the response of species to external conditions. Using retrospective International Union for Conservation of Nature Red List assessments, we classify transitions in the extinction risk of 497 mammalian carnivores and ungulates between 1975 and 2013. Species that moved to lower Red List categories, or remained Least Concern, were classified as 'lower risk'; species that stayed in a threatened category, or moved to a higher category of risk, were classified as 'higher risk'. Twenty-four predictor variables were used to predict transitions, including intrinsic traits (species biology) and external conditions (human pressure, distribution state and conservation interventions). The model correctly classified up to 90% of all transitions and revealed complex interactions between variables, such as protected areas (PAs) versus human impact. The most important predictors were: past extinction risk, PA extent, geographical range size, body size, taxonomic family and human impact. Our results suggest that monitoring a targeted set of metrics would efficiently identify species facing a higher risk, and could guide the allocation of resources between monitoring species' extinction risk and monitoring external conditions. PMID- 26246548 TI - Fishing, fast growth and climate variability increase the risk of collapse. AB - Species around the world have suffered collapses, and a key question is why some populations are more vulnerable than others. Traditional conservation biology and evidence from terrestrial species suggest that slow-growing populations are most at risk, but interactions between climate variability and harvest dynamics may alter or even reverse this pattern. Here, we test this hypothesis globally. We use boosted regression trees to analyse the influences of harvesting, species traits and climate variability on the risk of collapse (decline below a fixed threshold) across 154 marine fish populations around the world. The most important factor explaining collapses was the magnitude of overfishing, while the duration of overfishing best explained long-term depletion. However, fast growth was the next most important risk factor. Fast-growing populations and those in variable environments were especially sensitive to overfishing, and the risk of collapse was more than tripled for fast-growing when compared with slow-growing species that experienced overfishing. We found little evidence that, in the absence of overfishing, climate variability or fast growth rates alone drove population collapse over the last six decades. Expanding efforts to rapidly adjust harvest pressure to account for climate-driven lows in productivity could help to avoid future collapses, particularly among fast-growing species. PMID- 26246549 TI - Cooperation, clumping and the evolution of multicellularity. AB - The evolution of multicellular organisms represents one of the major evolutionary transitions in the history of life. A potential advantage of forming multicellular clumps is that it provides an efficiency benefit to pre-existing cooperation, such as the production of extracellular 'public goods'. However, this is complicated by the fact that cooperation could jointly evolve with clumping, and clumping could have multiple consequences for the evolution of cooperation. We model the evolution of clumping and a cooperative public good, showing that (i) when considered separately, both clumping and public goods production gradually increase with increasing genetic relatedness; (ii) in contrast, when the traits evolve jointly, a small increase in relatedness can lead to a major shift in evolutionary outcome-from a non-clumping state with low public goods production to a cooperative clumping state with high values of both traits; (iii) high relatedness makes it easier to get to the cooperative clumping state and (iv) clumping can be inhibited when it increases the number of cells that the benefits of cooperation must be shared with, but promoted when it increases relatedness between those cells. Overall, our results suggest that public goods sharing can facilitate the formation of well-integrated cooperative clumps as a first step in the evolution of multicellularity. PMID- 26246550 TI - Constraining the role of early land plants in Palaeozoic weathering and global cooling. AB - How the colonization of terrestrial environments by early land plants over 400 Ma influenced rock weathering, the biogeochemical cycling of carbon and phosphorus, and climate in the Palaeozoic is uncertain. Here we show experimentally that mineral weathering by liverworts-an extant lineage of early land plants partnering arbuscular mycorrhizal (AM) fungi, like those in 410 Ma-old early land plant fossils, amplified calcium weathering from basalt grains threefold to sevenfold, relative to plant-free controls. Phosphate weathering by mycorrhizal liverworts was amplified 9-13-fold over plant-free controls, compared with fivefold to sevenfold amplification by liverworts lacking fungal symbionts. Etching and trenching of phyllosilicate minerals increased with AM fungal network size and atmospheric CO2 concentration. Integration of grain-scale weathering rates over the depths of liverwort rhizoids and mycelia (0.1 m), or tree roots and mycelia (0.75 m), indicate early land plants with shallow anchorage systems were probably at least 10-fold less effective at enhancing the total weathering flux than later-evolving trees. This work challenges the suggestion that early land plants significantly enhanced total weathering and land-to-ocean fluxes of calcium and phosphorus, which have been proposed as a trigger for transient dramatic atmospheric CO2 sequestration and glaciations in the Ordovician. PMID- 26246551 TI - The building of a biodiversity hotspot across a land-bridge in the Mediterranean. AB - Many of the macroevolutionary processes that have shaped present-day phylogenetic patterns were caused by geological events such as plate tectonics and temporary land-bridges. The study of spatial patterns of phylogenetic diversity can provide insights into these past events. Here we focus on a western Mediterranean biodiversity hotspot located in the southern Iberian Peninsula and northwest Africa, two regions that are separated by the Strait of Gibraltar. We explore the spatial structure of the phylogenetic relationships within and across large-scale plant assemblages. Significant turnover in terminal lineages tends to occur between landmasses, whereas turnover in deep lineages tends to occur within landmasses. Plant assemblages in the western ecoregions of this hotspot tend to be phylogenetically overdispersed but are phylogenetically clustered on its eastern margins. We discuss our results in the light of potential scenarios of niche evolution (or conservatism) and lineage diversification. The significant turnover between landmasses suggests a common scenario of allopatric speciation that could have been facilitated by the intermittent joining of the two continents. This may have constituted an important stimulus for diversification and the emergence of this western Mediterranean biodiversity hotspot. PMID- 26246552 TI - Early and adult social environments have independent effects on individual fitness in a social vertebrate. AB - Evidence that the social environment at critical stages of life-history shapes individual trajectories is accumulating. Previous studies have identified either current or delayed effects of social environments on fitness components, but no study has yet analysed fitness consequences of social environments at different life stages simultaneously. To fill the gap, we use an extensive dataset collected during a 24-year intensive monitoring of a population of Alpine marmots (Marmota marmota), a long-lived social rodent. We test whether the number of helpers in early life and over the dominance tenure length has an impact on litter size at weaning, juvenile survival, longevity and lifetime reproductive success (LRS) of dominant females. Dominant females, who were born into a group containing many helpers and experiencing a high number of accumulated helpers over dominance tenure length showed an increased LRS through an increased longevity. We provide evidence that in a wild vertebrate, both early and adult social environments influence individual fitness, acting additionally and independently. These findings demonstrate that helpers have both short- and long term effects on dominant female Alpine marmots and that the social environment at the time of birth can play a key role in shaping individual fitness in social vertebrates. PMID- 26246553 TI - Historical data as a baseline for conservation: reconstructing long-term faunal extinction dynamics in Late Imperial-modern China. AB - Extinction events typically represent extended processes of decline that cannot be reconstructed using short-term studies. Long-term archives are necessary to determine past baselines and the extent of human-caused biodiversity change, but the capacity of historical datasets to provide predictive power for conservation must be assessed within a robust analytical framework. Local Chinese gazetteers represent a more than 400-year country-level dataset containing abundant information on past environmental conditions and include extensive records of gibbons, which have a restricted present-day distribution but formerly occurred across much of China. Gibbons show pre-twentieth century range contraction, with significant fragmentation by the mid-eighteenth century and population loss escalating in the late nineteenth century. Isolated gibbon populations persisted for about 40 years before local extinction. Populations persisted for longer at higher elevations, and disappeared earlier from northern and eastern regions, with the biogeography of population loss consistent with the contagion model of range collapse in response to human demographic expansion spreading directionally across China. The long-term Chinese historical record can track extinction events and human interactions with the environment across much longer timescales than are usually addressed in ecology, contributing novel baselines for conservation and an increased understanding of extinction dynamics and species vulnerability or resilience to human pressures. PMID- 26246554 TI - The importance of mechanisms for the evolution of cooperation. AB - Studies aimed at explaining the evolution of phenotypic traits have often solely focused on fitness considerations, ignoring underlying mechanisms. In recent years, there has been an increasing call for integrating mechanistic perspectives in evolutionary considerations, but it is not clear whether and how mechanisms affect the course and outcome of evolution. To study this, we compare four mechanistic implementations of two well-studied models for the evolution of cooperation, the Iterated Prisoner's Dilemma (IPD) game and the Iterated Snowdrift (ISD) game. Behavioural strategies are either implemented by a 1 : 1 genotype-phenotype mapping or by a simple neural network. Moreover, we consider two different scenarios for the effect of mutations. The same set of strategies is feasible in all four implementations, but the probability that a given strategy arises owing to mutation is largely dependent on the behavioural and genetic architecture. Our individual-based simulations show that this has major implications for the evolutionary outcome. In the ISD, different evolutionarily stable strategies are predominant in the four implementations, while in the IPD each implementation creates a characteristic dynamical pattern. As a consequence, the evolved average level of cooperation is also strongly dependent on the underlying mechanism. We argue that our findings are of general relevance for the evolution of social behaviour, pleading for the integration of a mechanistic perspective in models of social evolution. PMID- 26246555 TI - Association between the dopamine D4 receptor gene exon III variable number of tandem repeats and political attitudes in female Han Chinese. AB - Twin and family studies suggest that political attitudes are partially determined by an individual's genotype. The dopamine D4 receptor gene (DRD4) exon III repeat region that has been extensively studied in connection with human behaviour, is a plausible candidate to contribute to individual differences in political attitudes. A first United States study provisionally identified this gene with political attitude along a liberal-conservative axis albeit contingent upon number of friends. In a large sample of 1771 Han Chinese university students in Singapore, we observed a significant main effect of association between the DRD4 exon III variable number of tandem repeats and political attitude. Subjects with two copies of the 4-repeat allele (4R/4R) were significantly more conservative. Our results provided evidence for a role of the DRD4 gene variants in contributing to individual differences in political attitude particularly in females and more generally suggested that associations between individual genes, and neurochemical pathways, contributing to traits relevant to the social sciences can be provisionally identified. PMID- 26246557 TI - Correction to: Can reduced predation offset negative effects of sea louse parasites on chum salmon? PMID- 26246556 TI - Parasites in bloom: flowers aid dispersal and transmission of pollinator parasites within and between bee species. AB - The dispersal of parasites is critical for epidemiology, and the interspecific vectoring of parasites when species share resources may play an underappreciated role in parasite dispersal. One of the best examples of such a situation is the shared use of flowers by pollinators, but the importance of flowers and interspecific vectoring in the dispersal of pollinator parasites is poorly understood and frequently overlooked. Here, we use an experimental approach to show that during even short foraging periods of 3 h, three bumblebee parasites and two honeybee parasites were dispersed effectively onto flowers by their hosts, and then vectored readily between flowers by non-host pollinator species. The results suggest that flowers are likely to be hotspots for the transmission of pollinator parasites and that considering potential vector, as well as host, species will be of general importance for understanding the distribution and transmission of parasites in the environment and between pollinators. PMID- 26246558 TI - Correction to 'Does climate limit species richness by limiting individual species' ranges?'. PMID- 26246559 TI - The extended evolutionary synthesis: its structure, assumptions and predictions. AB - Scientific activities take place within the structured sets of ideas and assumptions that define a field and its practices. The conceptual framework of evolutionary biology emerged with the Modern Synthesis in the early twentieth century and has since expanded into a highly successful research program to explore the processes of diversification and adaptation. Nonetheless, the ability of that framework satisfactorily to accommodate the rapid advances in developmental biology, genomics and ecology has been questioned. We review some of these arguments, focusing on literatures (evo-devo, developmental plasticity, inclusive inheritance and niche construction) whose implications for evolution can be interpreted in two ways-one that preserves the internal structure of contemporary evolutionary theory and one that points towards an alternative conceptual framework. The latter, which we label the 'extended evolutionary synthesis' (EES), retains the fundaments of evolutionary theory, but differs in its emphasis on the role of constructive processes in development and evolution, and reciprocal portrayals of causation. In the EES, developmental processes, operating through developmental bias, inclusive inheritance and niche construction, share responsibility for the direction and rate of evolution, the origin of character variation and organism-environment complementarity. We spell out the structure, core assumptions and novel predictions of the EES, and show how it can be deployed to stimulate and advance research in those fields that study or use evolutionary biology. PMID- 26246560 TI - Human Cytotoxic T Lymphocyte-Mediated Acute Liver Failure and Rescue by Immunoglobulin in Human Hepatocyte Transplant TK-NOG Mice. AB - Hepatitis B virus (HBV)-specific cytotoxic T lymphocytes (CTLs) are critical in eliminating infection. We developed an animal model in which HBV-infected human hepatocytes are targeted by HBV-specific CTLs. After HBV inoculation in human hepatocyte-transplanted herpes simplex virus type-1 thymidine kinase-NOG mice, human peripheral blood mononuclear cells (PBMCs) were administered, and albumin, HBV DNA, alanine aminotransferase (ALT), and cytokine levels were analyzed. Histopathological and flow-cytometric analysis of infiltrating human immune cells were performed, and the efficacy of CTL-associated antigen-4 immunoglobulin (CTLA4Ig) against liver damage was evaluated. PBMC treatment resulted in massive hepatocyte damage with elevation of ALT, granzyme A, and gamma interferon and decrease in albumin and HBV DNA. The number of liver-infiltrating human lymphocytes and CD8-positive cells was significantly higher in HBV-infected mice. HBV-specific CTLs were detected by core and polymerase peptide-major histocompatibility complex-tetramer, and the population of regulatory T cells was significantly decreased in HBV-infected mice. Serum hepatitis B surface (HBs) antigen became negative, and HBs antibody appeared. CTLA4Ig treatment strongly inhibited infiltration of mononuclear cells. CTLA4Ig treatment will be used to treat patients who develop severe acute hepatitis B to prevent liver transplantation or lethality. This animal model is useful for virological and immunological analysis of HBV infection and to develop new therapies for severe acute hepatitis B. IMPORTANCE: Without liver transplantation, some HBV-infected patients will die from severe liver damage due to acute overreaction of the immune system. No effective treatment exists, due in part to the lack of a suitable animal model. An animal model is necessary to investigate the mechanism of hepatitis and to develop therapeutic strategies to prevent acute liver failure in HBV infection. We developed an animal model in which HBV-infected human hepatocytes are targeted by human HBV-specific CTLs. In this model, HBV-infected human hepatocytes were transplanted into severely immunodeficient NOG mice in order to reconstruct elements of the human immune system. Using this model, we found that CTL-associated antigen-4 immunoglobulin was able to suppress damage to HBV-infected hepatocytes, suggesting an approach to treatment. This animal model is useful for virological and immunological analysis of HBV infection and to develop new therapies for severe acute hepatitis B. PMID- 26246561 TI - Structural and Functional Diversity of Nairovirus-Encoded Nucleoproteins. AB - The nairoviruses include assorted tick-borne bunyaviruses that are emerging as causative agents of infectious diseases among humans and animals. As negative sense single-stranded RNA (-ssRNA) viruses, nairoviruses encode nucleoprotein (NP) that encapsidates the genomic RNA and further forms ribonucleoprotein (RNP) complex with viral RNA-dependent RNA polymerase (RdRp). We previously revealed that the monomeric NP encoded by Crimean-Congo hemorrhagic fever virus (CCHFV) presents a racket-shaped structure and shows unusual DNA-specific endonuclease activity. To examine the structural and biological variation of nairovirus encoded NPs, here, we systematically solved the crystal structures of NPs encoded by various nairoviruses, including Hazara virus (HAZV), Kupe virus (KUPV), and Erve virus (ERVEV). Combined with biochemical analysis, our results generate a clearer picture to aid in the understanding of the functional diversity of nairovirus-encoded NPs and the formation of nairovirus RNPs. IMPORTANCE: Nairoviruses comprise several tick-borne bunyaviruses that are emerging as causative agents of infectious diseases among humans and animals; however, little is known of the nairovirus genome assembly and transcription mechanisms. Based on the previous study of CCHFV NP reported by different research groups, we systematically investigate here the structural and functional diversity among three different nairoviruses. This work provides important information on nairovirus nucleoprotein function and the formation of RNPs. PMID- 26246562 TI - Global Database-Driven Assessment of HIV-1 Adaptation to the Immune Repertoires of Human Populations. AB - Associations between HIV-1 cytotoxic T lymphocyte (CTL) escape mutations and their restricting human leukocyte antigen (HLA) alleles imply that HIV could adapt to divergent HLA repertoires of human populations globally. Using publicly available databases, we examine the relationship between the frequencies of 19 experimentally validated CTL escape mutations in HIV-1 reverse transcriptase and their restricting HLA alleles in 59 countries. From these extensive data, we find evidence of differential HIV adaptations to human populations at only a limited number of the studied epitope sites. PMID- 26246563 TI - Role for a Zinc Finger Protein (Zfp111) in Transformation of 208F Rat Fibroblasts by Jaagsiekte Sheep Retrovirus Envelope Protein. AB - The native envelope gene (env) of Jaagsiekte sheep retrovirus (JSRV) also acts as an oncogene. To investigate the mechanism of transformation, we performed yeast 2 hybrid screening for cellular proteins that interact with Env. Among several candidates, we identified mouse or rat zinc finger protein 111 (zfp111). The interaction between Env and Zfp111 was confirmed through in vivo coimmunoprecipitation assays. Knockdown of endogenous Zfp111 caused a decrease in cell transformation by JSRV Env, while overexpression of Zfp111 increased overall Env transformation, supporting a role for Zfp111 in Env transformation. Knockdown of Zfp111 had no effect on the growth rate of parental rat 208F cells, while it decreased the proliferation rate of JSRV-transformed 208F cells, suggesting that JSRV-transformed cells became dependent on Zfp111. In addition, Zfp111 preferentially bound to a higher-mobility form of JSRV Env that has not been described previously. The higher-mobility form of Env (P70(env)) was found exclusively in the nuclear fraction, and size of its polypeptide backbone was the same as that of the cytoplasmic Env polyprotein (Pr80(env)). The differences in glycosylation between the two versions of Env were characterized. These results identify a novel cellular protein, Zfp111, that binds to the JSRV Env protein, and this binding plays a role in Env transformation. These results indicate that JSRV transformation also involves proteins and interactions in the nucleus. IMPORTANCE: The envelope protein (Env) of Jaagsiekte sheep retrovirus (JSRV) is an oncogene, but its mechanism of cell transformation is still unclear. Here we identified seven candidate cellular proteins that can interact with JSRV Env by yeast two-hybrid screening. This study focused on one of the seven candidates, zinc finger protein 111 (Zfp111). Zfp111 was shown to interact with JSRV Env in cells and to be involved in JSRV transformation. Moreover, coexpression of JSRV Env and Zfp111 led to the identification of a novel nuclear form of the JSRV Env protein that binds Zfp111. Nuclear Env was found to differ by glycosylation from the cytoplasmic Env precursor to the virion envelope proteins. These results suggest that JSRV Env transformation may involve nuclear events such as an alteration in transcription mediated by Env-Zfp111 interactions. PMID- 26246564 TI - A Druggable Pocket at the Nucleocapsid/Phosphoprotein Interaction Site of Human Respiratory Syncytial Virus. AB - Presently, respiratory syncytial virus (RSV), the main cause of severe respiratory infections in infants, cannot be treated efficiently with antivirals. However, its RNA-dependent polymerase complex offers potential targets for RSV specific drugs. This includes the recognition of its template, the ribonucleoprotein complex (RNP), consisting of genomic RNA encapsidated by the RSV nucleoprotein, N. This recognition proceeds via interaction between the phosphoprotein P, which is the main polymerase cofactor, and N. The determinant role of the C terminus of P, and more particularly of the last residue, F241, in RNP binding and viral RNA synthesis has been assessed previously. Here, we provide detailed structural insight into this crucial interaction for RSV polymerase activity. We solved the crystallographic structures of complexes between the N-terminal domain of N (N-NTD) and C-terminal peptides of P and characterized binding by biophysical approaches. Our results provide a rationale for the pivotal role of F241, which inserts into a well-defined N-NTD pocket. This primary binding site is completed by transient contacts with upstream P residues outside the pocket. Based on the structural information of the N-NTD:P complex, we identified inhibitors of this interaction, selected by in silico screening of small compounds, that efficiently bind to N and compete with P in vitro. One of the compounds displayed inhibitory activity on RSV replication, thereby strengthening the relevance of N-NTD for structure-based design of RSV specific antivirals. IMPORTANCE: Respiratory syncytial virus (RSV) is a widespread pathogen that is a leading cause of acute lower respiratory infections in infants worldwide. RSV cannot be treated efficiently with antivirals, and no vaccine is presently available, with the development of pediatric vaccines being particularly challenging. Therefore, there is a need for new therapeutic strategies that specifically target RSV. The interaction between the RSV phosphoprotein P and the ribonucleoprotein complex is critical for viral replication. In this study, we identified the main structural determinants of this interaction, and we used them to screen potential inhibitors in silico. We found a family of molecules that were efficient competitors of P in vitro and showed inhibitory activity on RSV replication in cellular assays. These compounds provide a basis for a pharmacophore model that must be improved but that holds promises for the design of new RSV-specific antivirals. PMID- 26246565 TI - Establishment of a Zebrafish Infection Model for the Study of Wild-Type and Recombinant European Sheatfish Virus. AB - Amphibian-like ranaviruses include pathogens of fish, amphibians, and reptiles that have recently evolved from a fish-infecting ancestor. The molecular determinants of host range and virulence in this group are largely unknown, and currently fish infection models are lacking. We show that European sheatfish virus (ESV) can productively infect zebrafish, causing a lethal pathology, and describe a method for the generation of recombinant ESV, establishing a useful model for the study of fish ranavirus infections. PMID- 26246567 TI - Novel Bat Influenza Virus NS1 Proteins Bind Double-Stranded RNA and Antagonize Host Innate Immunity. AB - We demonstrate that novel bat HL17NL10 and HL18NL11 influenza virus NS1 proteins are effective interferon antagonists but do not block general host gene expression. Solving the RNA-binding domain structures revealed the canonical NS1 symmetrical homodimer, and RNA binding required conserved basic residues in this domain. Interferon antagonism was strictly dependent on RNA binding, and chimeric bat influenza viruses expressing NS1s defective in this activity were highly attenuated in interferon-competent cells but not in cells unable to establish antiviral immunity. PMID- 26246566 TI - Murine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity. AB - Generating neutralizing antibodies (nAbs) is a major goal of many current HIV-1 vaccine efforts. To be of practical value, these nAbs must be both potent and cross-reactive in order to be capable of preventing the transmission of the highly diverse and generally neutralization resistant (Tier-2) HIV-1 strains that are in circulation. The HIV-1 envelope glycoprotein (Env) spike is the only target for nAbs. To explore whether Tier-2 nAbs can be induced by Env proteins, we immunized conventional mice with soluble BG505 SOSIP.664 trimers that mimic the native Env spike. Here, we report that it is extremely difficult for murine B cells to recognize the Env epitopes necessary for inducing Tier-2 nAbs. Thus, while trimer-immunized mice raised Env-binding IgG Abs and had high-quality T follicular helper (Tfh) cell and germinal center (GC) responses, they did not make BG505.T332N nAbs. Epitope mapping studies showed that Ab responses in mice were specific to areas near the base of the soluble trimer. These areas are not well shielded by glycans and likely are occluded on virions, which is consistent with the lack of BG505.T332N nAbs. These data inform immunogen design and suggest that it is useful to obscure nonneutralizing epitopes presented on the base of soluble Env trimers and that the glycan shield of well-formed HIV Env trimers is virtually impenetrable for murine B cell receptors (BCRs). IMPORTANCE: Human HIV vaccine efficacy trials have not generated meaningful neutralizing antibodies to circulating HIV strains. One possible hindrance has been the lack of immunogens that properly mimic the native conformation of the HIV envelope trimer protein. Here, we tested the first generation of soluble, native-like envelope trimer immunogens in a conventional mouse model. We attempted to generate neutralizing antibodies to neutralization-resistant circulating HIV strains. Various vaccine strategies failed to induce neutralizing antibodies to a neutralization-resistant HIV strain. Further analysis revealed that mouse antibodies targeted areas near the bottom of the soluble envelope trimers. These areas are not easily accessible on the HIV virion due to occlusion by the viral membrane and may have resulted from an absence of glycan shielding. Our results suggest that obscuring the bottom of soluble envelope trimers is a useful strategy to reduce antibody responses to epitopes that are not useful for virus neutralization. PMID- 26246568 TI - Topography of the Human Papillomavirus Minor Capsid Protein L2 during Vesicular Trafficking of Infectious Entry. AB - The human papillomavirus (HPV) capsid is composed of the major capsid protein L1 and the minor capsid protein L2. During entry, the HPV capsid undergoes numerous conformational changes that result in endosomal uptake and subsequent trafficking of the L2 protein in complex with the viral DNA to the trans-Golgi network. To facilitate this transport, the L2 protein harbors a number of putative motifs that, if capable of direct interaction, would interact with cytosolic host cell factors. These data imply that a portion of L2 becomes cytosolic during infection. Using a low concentration of digitonin to selectively permeabilize the plasma membrane of infected cells, we mapped the topography of the L2 protein during infection. We observed that epitopes within amino acid residues 64 to 81 and 163 to 170 and a C-terminal tag of HPV16 L2 are exposed on the cytosolic side of intracellular membranes, whereas an epitope within residues 20 to 38, which are upstream of a putative transmembrane region, is luminal. Corroborating these findings, we also found that L2 protein is sensitive to trypsin digestion during infection. These data demonstrate that the majority of the L2 protein becomes accessible on the cytosolic side of intracellular membranes in order to interact with cytosolic factors to facilitate vesicular trafficking. IMPORTANCE: In order to complete infectious entry, nonenveloped viruses have to pass cellular membranes. This is often achieved through the viral capsid protein associating with or integrating into intracellular membrane. Here, we determine the topography of HPV L2 protein in the endocytic vesicular compartment, suggesting that L2 becomes a transmembrane protein with a short luminal portion and with the majority facing the cytosolic side for interaction with host cell transport factors. PMID- 26246569 TI - Identification of Host Cell Factors Associated with Astrovirus Replication in Caco-2 Cells. AB - Astroviruses are small, nonenveloped viruses with a single-stranded positive sense RNA genome causing acute gastroenteritis in children and immunocompromised patients. Since positive-sense RNA viruses have frequently been found to replicate in association with membranous structures, in this work we characterized the replication of the human astrovirus serotype 8 strain Yuc8 in Caco-2 cells, using density gradient centrifugation and free-flow zonal electrophoresis (FFZE) to fractionate cellular membranes. Structural and nonstructural viral proteins, positive- and negative-sense viral RNA, and infectious virus particles were found to be associated with a distinct population of membranes separated by FFZE. The cellular proteins associated with this membrane population in infected and mock-infected cells were identified by tandem mass spectrometry. The results indicated that membranes derived from multiple cell organelles were present in the population. Gene ontology and protein-protein interaction network analysis showed that groups of proteins with roles in fatty acid synthesis and ATP biosynthesis were highly enriched in the fractions of this population in infected cells. Based on this information, we investigated by RNA interference the role that some of the identified proteins might have in the replication cycle of the virus. Silencing of the expression of genes involved in cholesterol (DHCR7, CYP51A1) and fatty acid (FASN) synthesis, phosphatidylinositol (PI4KIIIbeta) and inositol phosphate (ITPR3) metabolism, and RNA helicase activity (DDX23) significantly decreased the amounts of Yuc8 genomic and antigenomic RNA, synthesis of the structural protein VP90, and virus yield. These results strongly suggest that astrovirus RNA replication and particle assembly take place in association with modified membranes potentially derived from multiple cell organelles. IMPORTANCE: Astroviruses are common etiological agents of acute gastroenteritis in children and immunocompromised patients. More recently, they have been associated with neurological diseases in mammals, including humans, and are also responsible for different pathologies in birds. In this work, we provide evidence that astrovirus RNA replication and virus assembly occur in contact with cell membranes potentially derived from multiple cell organelles and show that membrane-associated cellular proteins involved in lipid metabolism are required for efficient viral replication. Our findings provide information to enhance our knowledge of astrovirus biology and provide information that might be useful for the development of therapeutic interventions to prevent virus replication. PMID- 26246570 TI - Host Determinants of Prion Strain Diversity Independent of Prion Protein Genotype. AB - Phenotypic diversity in prion diseases can be specified by prion strains in which biological traits are propagated through an epigenetic mechanism mediated by distinct PrP(Sc) conformations. We investigated the role of host-dependent factors on phenotypic diversity of chronic wasting disease (CWD) in different host species that express the same prion protein gene (Prnp). Two CWD strains that have distinct biological, biochemical, and pathological features were identified in transgenic mice that express the Syrian golden hamster (SGH) Prnp. The CKY strain of CWD had a shorter incubation period than the WST strain of CWD, but after transmission to SGH, the incubation period of CKY CWD was ~150 days longer than WST CWD. Limited proteinase K digestion revealed strain-specific PrP(Sc) polypeptide patterns that were maintained in both hosts, but the solubility and conformational stability of PrP(Sc) differed for the CWD strains in a host-dependent manner. WST CWD produced PrP(Sc) amyloid plaques in the brain of the SGH that were partially insoluble and stable at a high concentration of protein denaturant. However, in transgenic mice, PrP(Sc) from WST CWD did not assemble into plaques, was highly soluble, and had low conformational stability. Similar studies using the HY and DY strains of transmissible mink encephalopathy resulted in minor differences in prion biological and PrP(Sc) properties between transgenic mice and SGH. These findings indicate that host-specific pathways that are independent of Prnp can alter the PrP(Sc) conformation of certain prion strains, leading to changes in the biophysical properties of PrP(Sc), neuropathology, and clinical prion disease. IMPORTANCE: Prions are misfolded pathogenic proteins that cause neurodegeneration in humans and animals. Transmissible prion diseases exhibit a spectrum of disease phenotypes and the basis of this diversity is encoded in the structure of the pathogenic prion protein and propagated by an epigenetic mechanism. In the present study, we investigated prion diversity in two hosts species that express the same prion protein gene. While prior reports have demonstrated that prion strain properties are stable upon infection of the same host species and prion protein genotype, our findings indicate that certain prion strains can undergo dramatic changes in biological properties that are not dependent on the prion protein. Therefore, host factors independent of the prion protein can affect prion diversity. Understanding how host pathways can modify prion disease phenotypes may provide clues on how to alter prion formation and lead to treatments for prion, and other, human neurodegenerative diseases of protein misfolding. PMID- 26246571 TI - Soluble Envelope Glycoprotein Trimers from a CD4-Independent HIV-1 Elicit Antibody-Dependent Cellular Cytotoxicity-Mediating Antibodies in Guinea Pigs. AB - CD4-independent HIV-1 variants can infect coreceptor-expressing cells lacking CD4. The envelope (Env) glycoproteins on these HIV-1 variants expose a coreceptor binding site that overlaps some CD4-induced (CD4i) epitopes. Reports have demonstrated that CD4i antibodies mediate antibody-dependent cellular cytotoxicity (ADCC). Here we investigated the immunogenicity of soluble Env trimers (sgp140) from a CD4-independent HIV-1 in guinea pigs and found that the sgp140 elicited ADCC-mediating antibodies. Therefore, these sgp140 might be useful in vaccine regimens aimed at eliciting ADCC responses. PMID- 26246572 TI - Constitutive Activation of Interleukin-13/STAT6 Contributes to Kaposi's Sarcoma Associated Herpesvirus-Related Primary Effusion Lymphoma Cell Proliferation and Survival. AB - Activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway has been associated with numerous human malignancies, including primary effusion lymphomas (PELs). PEL, a cancerous proliferation of B cells, is caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Previously we identified constitutive phosphorylation of STAT6 on tyrosine 641 (p-STAT6(C)) in PEL cell lines BC3 and BCBL1; however, the molecular mechanism leading to this activation remains unclear. Here we demonstrate that STAT6 activation tightly correlates with interleukin-13 (IL-13) secretion, JAK1/2 tyrosine phosphorylation, and reduced expression of SHP1 due to KSHV infection. Moreover, p-STAT6(C) and reduction of SHP1 were also observed in KS patient tissue. Notably, blockade of IL-13 by antibody neutralization dramatically inhibits PEL cell proliferation and survival. Taken together, these results suggest that IL-13/STAT6 signaling is modulated by KSHV to promote host cell proliferation and viral pathogenesis. IMPORTANCE: STAT6 is a member of signal transducer and activator of transcription (STAT) family, whose activation is linked to KSHV-associated cancers. The mechanism through which STAT6 is modulated by KSHV remains unclear. In this study, we demonstrated that constitutive activation of STAT6 in KSHV-associated PEL cells results from interleukin-13 (IL 13) secretion and reduced expression of SHP1. Importantly, we also found that depletion of IL-13 reduces PEL cell growth and survival. This discovery provides new insight that IL-13/STAT6 plays an essential role in KSHV pathogenesis. PMID- 26246574 TI - Virus-Like Vesicle-Based Therapeutic Vaccine Vectors for Chronic Hepatitis B Virus Infection. AB - More than 500,000 people die each year from the liver diseases that result from chronic hepatitis B virus (HBV) infection. Therapeutic vaccines, which aim to elicit an immune response capable of controlling the virus, offer a potential new treatment strategy for chronic hepatitis B. Recently, an evolved, high-titer vaccine platform consisting of Semliki Forest virus RNA replicons that express the vesicular stomatitis virus glycoprotein (VSV G) has been described. This platform generates virus-like vesicles (VLVs) that contain VSV G but no other viral structural proteins. We report here that the evolved VLV vector engineered to additionally express the HBV middle surface envelope glycoprotein (MHBs) induces functional CD8 T cell responses in mice. These responses were greater in magnitude and broader in specificity than those obtained with other immunization strategies, including recombinant protein and DNA. Additionally, a single immunization with VLV-MHBs protected mice from HBV hydrodynamic challenge, and this protection correlated with the elicitation of a CD8 T cell recall response. In contrast to MHBs, a VLV expressing HBV core protein (HBcAg) neither induced a CD8 T cell response in mice nor protected against challenge. Finally, combining DNA and VLV-MHBs immunization led to induction of HBV-specific CD8 T cell responses in a transgenic mouse model of chronic HBV infection. The ability of VLV-MHBs to induce a multispecific T cell response capable of controlling HBV replication, and to generate immune responses in a tolerogenic model of chronic infection, indicates that VLV vaccine platforms may offer a unique strategy for HBV therapeutic vaccination. IMPORTANCE: HBV infection is associated with significant morbidity and mortality. Furthermore, treatments for chronic infection are suboptimal and rarely result in complete elimination of the virus. Therapeutic vaccines represent a unique approach to HBV treatment and have the potential to induce long-term control of infection. Recently, a virus-based vector system that combines the nonstructural proteins of Semliki Forest virus with the VSV glycoprotein has been described. In this study, we used this system to construct a novel HBV vaccine and demonstrated that the vaccine is capable of inducing virus-specific immune responses in mouse models of acute and chronic HBV replication. These findings highlight the potential of this new vaccine system and support the idea that highly immunogenic vaccines, such as viral vectors, may be useful in the treatment of chronic hepatitis B. PMID- 26246573 TI - Hydrodynamic and Membrane Binding Properties of Purified Rous Sarcoma Virus Gag Protein. AB - Previously, no retroviral Gag protein has been highly purified in milligram quantities and in a biologically relevant and active form. We have purified Rous sarcoma virus (RSV) Gag protein and in parallel several truncation mutants of Gag and have studied their biophysical properties and membrane interactions in vitro. RSV Gag is unusual in that it is not naturally myristoylated. From its ability to assemble into virus-like particles in vitro, we infer that RSV Gag is biologically active. By size exclusion chromatography and small-angle X-ray scattering, Gag in solution appears extended and flexible, in contrast to previous reports on unmyristoylated HIV-1 Gag, which is compact. However, by neutron reflectometry measurements of RSV Gag bound to a supported bilayer, the protein appears to adopt a more compact, folded-over conformation. At physiological ionic strength, purified Gag binds strongly to liposomes containing acidic lipids. This interaction is stimulated by physiological levels of phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] and by cholesterol. However, unlike HIV-1 Gag, RSV Gag shows no sensitivity to acyl chain saturation. In contrast with full-length RSV Gag, the purified MA domain of Gag binds to liposomes only weakly. Similarly, both an N-terminally truncated version of Gag that is missing the MA domain and a C-terminally truncated version that is missing the NC domain bind only weakly. These results imply that NC contributes to membrane interaction in vitro, either by directly contacting acidic lipids or by promoting Gag multimerization. IMPORTANCE: Retroviruses like HIV assemble at and bud from the plasma membrane of cells. Assembly requires the interaction between thousands of Gag molecules to form a lattice. Previous work indicated that lattice formation at the plasma membrane is influenced by the conformation of monomeric HIV. We have extended this work to the more tractable RSV Gag. Our results show that RSV Gag is highly flexible and can adopt a folded-over conformation on a lipid bilayer, implicating both the N and C termini in membrane binding. In addition, binding of Gag to membranes is diminished when either terminal domain is truncated. RSV Gag membrane association is significantly less sensitive than HIV Gag membrane association to lipid acyl chain saturation. These findings shed light on Gag assembly and membrane binding, critical steps in the viral life cycle and an untapped target for antiretroviral drugs. PMID- 26246575 TI - Hepatitis C Virus Envelope Glycoprotein E1 Forms Trimers at the Surface of the Virion. AB - In hepatitis C virus (HCV)-infected cells, the envelope glycoproteins E1 and E2 assemble as a heterodimer. To investigate potential changes in the oligomerization of virion-associated envelope proteins, we performed SDS-PAGE under reducing conditions but without thermal denaturation. This revealed the presence of SDS-resistant trimers of E1 in the context of cell-cultured HCV (HCVcc) as well as in the context of HCV pseudoparticles (HCVpp). The formation of E1 trimers was found to depend on the coexpression of E2. To further understand the origin of E1 trimer formation, we coexpressed in bacteria the transmembrane (TM) domains of E1 (TME1) and E2 (TME2) fused to reporter proteins and analyzed the fusion proteins by SDS-PAGE and Western blotting. As expected for strongly interacting TM domains, TME1-TME2 heterodimers resistant to SDS were observed. These analyses also revealed homodimers and homotrimers of TME1, indicating that such complexes are stable species. The N-terminal segment of TME1 exhibits a highly conserved GxxxG sequence, a motif that is well documented to be involved in intramembrane protein-protein interactions. Single or double mutations of the glycine residues (Gly354 and Gly358) in this motif markedly decreased or abrogated the formation of TME1 homotrimers in bacteria, as well as homotrimers of E1 in both HCVpp and HCVcc systems. A concomitant loss of infectivity was observed, indicating that the trimeric form of E1 is essential for virus infectivity. Taken together, these results indicate that E1E2 heterodimers form trimers on HCV particles, and they support the hypothesis that E1 could be a fusion protein. IMPORTANCE: HCV glycoproteins E1 and E2 play an essential role in virus entry into liver cells as well as in virion morphogenesis. In infected cells, these two proteins form a complex in which E2 interacts with cellular receptors, whereas the function of E1 remains poorly understood. However, recent structural data suggest that E1 could be the protein responsible for the process of fusion between viral and cellular membranes. Here we investigated the oligomeric state of HCV envelope glycoproteins. We demonstrate that E1 forms functional trimers after virion assembly and that in addition to the requirement for E2, a determinant for this oligomerization is present in a conserved GxxxG motif located within the E1 transmembrane domain. Taken together, these results indicate that a rearrangement of E1E2 heterodimer complexes likely occurs during the assembly of HCV particles to yield a trimeric form of the E1E2 heterodimer. Gaining structural information on this trimer will be helpful for the design of an anti-HCV vaccine. PMID- 26246576 TI - Neuraminidase of Influenza A Virus Binds Lysosome-Associated Membrane Proteins Directly and Induces Lysosome Rupture. AB - As a recycling center, lysosomes are filled with numerous acid hydrolase enzymes that break down waste materials and invading pathogens. Recently, lysosomal cell death has been defined as "lysosomal membrane permeabilization and the consequent leakage of lysosome contents into cytosol." Here, we show that the neuraminidase (NA) of H5N1 influenza A virus markedly deglycosylates and degrades lysosome associated membrane proteins (LAMPs; the most abundant membrane proteins of lysosome), which induces lysosomal rupture, and finally leads to cell death of alveolar epithelial carcinoma A549 cells and human tracheal epithelial cells. The NA inhibitors peramivir and zanamivir could effectively block the deglycosylation of LAMPs, inhibit the virus cell entry, and prevent cell death induced by the H5N1 influenza virus. The NA of seasonal H1N1 virus, however, does not share these characteristics. Our findings not only reveal a novel role of NA in the early stage of the H5N1 influenza virus life cycle but also elucidate the molecular mechanism of lysosomal rupture crucial for influenza virus induced cell death. IMPORTANCE: The integrity of lysosomes is vital for maintaining cell homeostasis, cellular defense and clearance of invading pathogens. This study shows that the H5N1 influenza virus could induce lysosomal rupture through deglycosylating lysosome-associated membrane proteins (LAMPs) mediated by the neuraminidase activity of NA protein. NA inhibitors such as peramivir and zanamivir could inhibit the deglycosylation of LAMPs and protect lysosomes, which also further interferes with the H5N1 influenza virus infection at early stage of life cycle. This work is significant because it presents new concepts for NA's function, as well as for influenza inhibitors' mechanism of action, and could partially explain the high mortality and high viral load after H5N1 virus infection in human beings and why NA inhibitors have more potent therapeutic effects for lethal avian influenza virus infections at early stage. PMID- 26246577 TI - Suppressor of Cytokine Signaling 3 Is an Inducible Host Factor That Regulates Virus Egress during Ebola Virus Infection. AB - Ebola virus (EBOV) initially targets monocytes and macrophages, which can lead to the release of proinflammatory cytokines and chemokines. These inflammatory cytokines are thought to contribute to the development of circulatory shock seen in fatal EBOV infections. The VP40 matrix protein is a key viral structural protein that is critical for virion egress. Physical and functional interactions between VP40 and host proteins such as Tsg101 and Nedd4 facilitate efficient release of VP40-driven virus-like particles (VLPs) and infectious virus. Here, we show that host suppressor of cytokine signaling 3 (SOCS3) can also bind to EBOV VP40, leading to enhanced ubiquitinylation and egress of VP40. Indeed, titers of infectious EBOV derived from SOCS3 knockout mouse embryonic fibroblasts (MEFs) were significantly reduced compared to those from wild-type (WT) MEFs at 24 and 48 h postinfection. Importantly, this reduced virus yield could be rescued back to WT levels by exogenously expressing SOCS3. Lastly, we show that SOCS3 expression is induced by EBOV glycoprotein (GP) expression and that VLPs containing EBOV VP40 and GP induced production of proinflammatory cytokines, which induced SOCS3 for negative-feedback regulation. These data indicate that host innate immune protein SOCS3 may play an important role in budding and pathogenesis of EBOV. IMPORTANCE: The VP40 matrix protein is a key structural protein critical for Ebola virus budding. Physical and functional interactions between VP40 and host proteins such as Tsg101 and Nedd4 facilitate efficient release of VLPs and infectious virus. We reported that host TLR4 is a sensor for Ebola GP on VLPs and that the resultant TLR4 signaling pathways lead to the production of proinflammatory cytokines. Host SOCS3 regulates the innate immune response by controlling and limiting the proinflammatory response through negative-feedback inhibition of cytokine receptors. We present evidence that Ebola virus VLPs stimulate induction of SOCS3 as well as proinflammatory cytokines, and that expression of human SOCS3 enhances budding of Ebola VLPs and infectious virus via a mechanism linked to the host ubiquitinylation machinery. PMID- 26246578 TI - Dolutegravir-Selected HIV-1 Containing the N155H and R263K Resistance Substitutions Does Not Acquire Additional Compensatory Mutations under Drug Pressure That Lead to Higher-Level Resistance and Increased Replicative Capacity. AB - We have previously shown that the addition of the raltegravir/elvitegavir (RAL/EVG) primary resistance mutation N155H to the R263K dolutegravir (DTG) resistance mutation partially compensated for the fitness cost imposed by R263K while also slightly increasing DTG resistance in vitro (K. Anstett, T. Mesplede, M. Oliveira, V. Cutillas, and M. A. Wainberg, J Virol 89:4681-4684, 2015, doi:10.1128/JVI.03485-14). Since many patients failing RAL/EVG are given DTG as part of rescue therapy, and given that the N155H substitution often is found in combination with other compensatory resistance mutations in such individuals, we investigated the effects of multiple such substitutions within integrase (IN) on each of integrase function, HIV-1 infectivity, and levels of drug resistance. To this end, each of the L74M, E92Q, T97A, E157Q, and G163R substitutions were introduced into NL4.3 subtype B HIV-1 vectors harboring N155H and R263K in tandem [termed NL4.3IN(N155H/R263K)]. Relevant recombinant integrase enzymes also were expressed, and purified and biochemical assays of strand transfer efficiency as well as viral infectivity and drug resistance studies were performed. We found that the addition of T97A, E157Q, or G163R somewhat improved the affinity of INN155H/R263K for its target DNA substrate, while the presence of L74M or E92Q had a negative effect on this process. However, viral infectivity was significantly decreased from that of NL4.3IN(N155H/R263K) after the addition of each tertiary mutation, and no increases in levels of DTG resistance were observed. This work shows that the compensatory mutations that evolve after N155H under continued DTG or RAL/EVG pressure in patients are unable to improve either enzyme efficiency or viral infectivity in an N155H/R263K background. IMPORTANCE: In contrast to other drugs, dolutegravir has not selected for resistance in HIV positive individuals when used in first-line therapy. We had previously shown that HIV containing the primary raltegravir/elvitegravir resistance substitution N155H could select for R263K under dolutegravir pressure and that this virus was fit and displayed low-level resistance to dolutegravir (Anstett et al., J Virol 89: 4681-4684). Therefore, the current study aimed to uncover whether accessory mutations that appear after N155H in response to raltegravir/elvitegravir were compatible with N155H and R263K. We found, however, that the addition of a third mutation negatively impacted both the enzyme and the virus in terms of activity and infectivity without large shifts in integrase inhibitor resistance. Thus, it is unlikely that these substitutions would be selected under dolutegravir pressure. These data support the hypothesis that primary resistance against DTG cannot evolve through RAL/EVG resistance pathways and that the selection of R263K leads HIV into an evolutionary dead-end. PMID- 26246579 TI - Hemagglutinin-Neuraminidase Balance Influences the Virulence Phenotype of a Recombinant H5N3 Influenza A Virus Possessing a Polybasic HA0 Cleavage Site. AB - Although a polybasic HA0 cleavage site is considered the dominant virulence determinant for highly pathogenic avian influenza (HPAI) H5 and H7 viruses, naturally occurring virus isolates possessing a polybasic HA0 cleavage site have been identified that are low pathogenic in chickens. In this study, we generated a reassortant H5N3 virus that possessed the hemagglutinin (HA) gene from H5N1 HPAI A/swan/Germany/R65/2006 and the remaining gene segments from low pathogenic A/chicken/British Columbia/CN0006/2004 (H7N3). Despite possessing the HA0 cleavage site GERRRKKR/GLF, this rH5N3 virus exhibited a low pathogenic phenotype in chickens. Although rH5N3-inoculated birds replicated and shed virus and seroconverted, transmission to naive contacts did not occur. To determine whether this virus could evolve into a HPAI form, it underwent six serial passages in chickens. A progressive increase in virulence was observed with the virus from passage number six being highly transmissible. Whole-genome sequencing demonstrated the fixation of 12 nonsynonymous mutations involving all eight gene segments during passaging. One of these involved the catalytic site of the neuraminidase (NA; R293K) and is associated with decreased neuraminidase activity and resistance to oseltamivir. Although introducing the R293K mutation into the original low-pathogenicity rH5N3 increased its virulence, transmission to naive contact birds was inefficient, suggesting that one or more of the remaining changes that had accumulated in the passage number six virus also play an important role in transmissibility. Our findings show that the functional linkage and balance between HA and NA proteins contributes to expression of the HPAI phenotype. IMPORTANCE: To date, the contribution that hemagglutinin-neuraminidase balance can have on the expression of a highly pathogenic avian influenza virus phenotype has not been thoroughly examined. Reassortment, which can result in new hemagglutinin-neuraminidase combinations, may have unpredictable effects on virulence and transmission characteristics of a virus. Our data show the importance of the neuraminidase in complementing a polybasic HA0 cleavage site. Furthermore, it demonstrates that adaptive changes selected for during the course of virus evolution can result in unexpected traits such as antiviral drug resistance. PMID- 26246580 TI - Evasion of the Innate Immune Type I Interferon System by Monkeypox Virus. AB - The vaccinia virus (VACV) E3 protein has been shown to be important for blocking activation of the cellular innate immune system and allowing viral replication to occur unhindered. Mutation or deletion of E3L severely affects viral host range and pathogenesis. While the monkeypox virus (MPXV) genome encodes a homologue of the VACV E3 protein, encoded by the F3L gene, the MPXV gene is predicted to encode a protein with a truncation of 37 N-terminal amino acids. VACV with a genome encoding a similarly truncated E3L protein (VACV-E3LDelta37N) has been shown to be attenuated in mouse models, and infection with VACV-E3LDelta37N has been shown to lead to activation of the host antiviral protein kinase R pathway. In this report, we present data demonstrating that, despite containing a truncated E3 homologue, MPXV phenotypically resembles a wild-type (wt) VACV rather than VACV-E3LDelta37N. Thus, MPXV appears to contain a gene or genes that can suppress the phenotypes associated with an N-terminal truncation in E3. The suppression maps to sequences outside F3L, suggesting that the suppression is extragenic in nature. Thus, MPXV appears to have evolved mechanisms to minimize the effects of partial inactivation of its E3 homologue. IMPORTANCE: Poxviruses have evolved to have many mechanisms to evade host antiviral innate immunity; these mechanisms may allow these viruses to cause disease. Within the family of poxviruses, variola virus (which causes smallpox) is the most pathogenic, while monkeypox virus is intermediate in pathogenicity between vaccinia virus and variola virus. Understanding the mechanisms of monkeypox virus innate immune evasion will help us to understand the evolution of poxvirus innate immune evasion capabilities, providing a better understanding of how poxviruses cause disease. PMID- 26246582 TI - Importation and Recombination Are Responsible for the Latest Emergence of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus in China. AB - In China, a majority of the highly pathogenic porcine reproductive and respiratory syndrome (HP-PRRSV) strains were seeded by the 2006 outbreak. However, the most recently emerged (2013-2014) HP-PRRSV strain has a very different genetic background. It is a NADC30-like PRRSV strain recently introduced from North America that has undergone genetic exchange with the classic HP-PRRSV strains in China. Subsequent isolation and characterization of this variant suggest high pathogenicity, so it merits special attention in control and vaccine strategies. PMID- 26246581 TI - Turnover Rate of NS3 Proteins Modulates Bluetongue Virus Replication Kinetics in a Host-Specific Manner. AB - Bluetongue virus (BTV) is an arbovirus transmitted to livestock by midges of the Culicoides family and is the etiological agent of a hemorrhagic disease in sheep and other ruminants. In mammalian cells, BTV particles are released primarily by virus-induced cell lysis, while in insect cells they bud from the plasma membrane and establish a persistent infection. BTV possesses a ten-segmented double stranded RNA genome, and NS3 proteins are encoded by segment 10 (Seg-10). The viral nonstructural protein 3 (NS3) plays a key role in mediating BTV egress as well as in impeding the in vitro synthesis of type I interferon in mammalian cells. In this study, we asked whether genetically distant NS3 proteins can alter BTV-host interactions. Using a reverse genetics approach, we showed that, depending on the NS3 considered, BTV replication kinetics varied in mammals but not in insects. In particular, one of the NS3 proteins analyzed harbored a proline at position 24 that leads to its rapid intracellular decay in ovine but not in Culicoides cells and to the attenuation of BTV virulence in a mouse model of disease. Overall, our data reveal that the genetic variability of Seg-10/NS3 differentially modulates BTV replication kinetics in a host-specific manner and highlight the role of the host-specific variation in NS3 protein turnover rate. IMPORTANCE: BTV is the causative agent of a severe disease transmitted between ruminants by biting midges of Culicoides species. NS3, encoded by Seg-10 of the BTV genome, fulfills key roles in BTV infection. As Seg-10 sequences from various BTV strains display genetic variability, we assessed the impact of different Seg 10 and NS3 proteins on BTV infection and host interactions. In this study, we revealed that various Seg-10/NS3 proteins alter BTV replication kinetics in mammals but not in insects. Notably, we found that NS3 protein turnover may vary in ovine but not in Culicoides cells due to a single amino acid residue that, most likely, leads to rapid and host-dependent protein degradation. Overall, this study highlights that genetically distant BTV Seg-10/NS3 influence BTV biological properties in a host-specific manner and increases our understanding of how NS3 proteins contribute to the outcome of BTV infection. PMID- 26246583 TI - Natural variation of ambient dose rate in the air of Izu-Oshima Island after the Fukushima Daiichi Nuclear Power Plant accident. AB - The ambient dose rate in air and radioactivity concentration in soil samples collected on Izu-Oshima Island were observed in 2012, 2013 and 2014, i.e. 1, 2 and 3 years after the severe accident at the Fukushima Daiichi Nuclear Power Plant. A car-borne survey for the ambient dose rate in air was carried out for the entire island. Soil samples were collected for the radioactivity concentration measurements from 22 points. The ambient dose rates in air were 36 nGy h(-1) in 2012, 34 nGy h(-1) in 2013 and 29 nGy h(-1) in 2014. The corresponding radioactivity concentrations in those years for (134)Cs were 53, 39 and 29 Bq kg(-1) and for (137)Cs, 87, 73 and 75 Bq kg(-1). All the values have decreased every year. PMID- 26246584 TI - Evaluation of the dose enhancement of combined 10B + 157Gd neutron capture therapy (NCT). AB - An innovative molecule, GdBLDL, for boron neutron capture therapy (BNCT) has been developed and its effectiveness as a BNCT carrier is currently under evaluation using in vivo experiments on small animal tumour models. The molecule contains both (10)B (the most commonly used NCT agent) and (157)Gd nuclei. (157)Gd is the second most studied element to perform NCT, mainly thanks to its high cross section for the capture of low-energy neutrons. The main drawback of (157)Gd neutron capture reaction is the very short range and low-energy secondary charged particles (Auger electrons), which requires (157)Gd to be very close to the cellular DNA to have an appreciable biological effect. Treatment doses were calculated by Monte Carlo simulations to ensure the optimised tumour irradiation and the sparing of the healthy organs of the irradiated animals. The enhancement of the absorbed dose due to the simultaneous presence of (10)B and (157)Gd in the experimental set-up was calculated and the advantage introduced by the presence of (157)Gd was discussed. PMID- 26246586 TI - Screening Amazon's Mechanical Turk for Adults With ADHD. AB - OBJECTIVE: Researchers are increasingly using Amazon's Mechanical Turk (MTurk; www.mturk.com) to recruit study participants. However, the utility of MTurk for investigations of ADHD in adulthood is unknown. METHOD: A total of 6,526 MTurk workers (median age range = 26-35 years) completed an online screening survey assessing their diagnostic histories and symptoms of ADHD, as well as relevant demographic correlates and diagnostic comorbidity. RESULTS: The prevalence of MTurk workers who reported being diagnosed as children and as adults, and the percentage of workers whose ADHD appeared to persist from childhood into adulthood, are consistent with those observed in "offline" samples. Relative to MTurk workers diagnosed with ADHD as adults, workers diagnosed with ADHD as children were more likely to be male and without college degrees, as well as less likely to have comorbid depression or anxiety disorders. CONCLUSION: Amazon's MTurk holds promise as a recruitment tool for studying adults with ADHD. PMID- 26246585 TI - Analysis of Phosphorylation-dependent Protein Interactions of Adhesion and Degranulation Promoting Adaptor Protein (ADAP) Reveals Novel Interaction Partners Required for Chemokine-directed T cell Migration. AB - Stimulation of T cells leads to distinct changes of their adhesive and migratory properties. Signal propagation from activated receptors to integrins depends on scaffolding proteins such as the adhesion and degranulation promoting adaptor protein (ADAP)(1). Here we have comprehensively investigated the phosphotyrosine interactome of ADAP in T cells and define known and novel interaction partners of functional relevance. While most phosphosites reside in unstructured regions of the protein, thereby defining classical SH2 domain interaction sites for master regulators of T cell signaling such as SLP76, Fyn-kinase, and NCK, other binding events depend on structural context. Interaction proteomics using different ADAP constructs comprising most of the known phosphotyrosine motifs as well as the structured domains confirm that a distinct set of proteins is attracted by pY571 of ADAP, including the zeta-chain-associated protein kinase of 70 kDa (ZAP70). The interaction of ADAP and ZAP70 is inducible upon stimulation either of the T cell receptor (TCR) or by chemokine. NMR spectroscopy reveals that the N-terminal SH2 domains within a ZAP70-tandem-SH2 construct is the major site of interaction with phosphorylated ADAP-hSH3(N) and microscale thermophoresis (MST) indicates an intermediate binding affinity (Kd = 2.3 MUm). Interestingly, although T cell receptor dependent events such as T cell/antigen presenting cell (APC) conjugate formation and adhesion are not affected by mutation of Y571, migration of T cells along a chemokine gradient is compromised. Thus, although most phospho-sites in ADAP are linked to T cell receptor related functions we have identified a unique phosphotyrosine that is solely required for chemokine induced T cell behavior. PMID- 26246588 TI - Variation in Presentation, Diagnosis, and Management of Children and Adolescents With ADHD Across European Countries. AB - OBJECTIVE: To characterize differences in presentation, diagnosis, and management of children/adolescents with ADHD in six European countries. METHOD: Physicians abstracted clinical records for patients aged 6 to 17 years, diagnosed from 2004 to 2007 and treated for >=2 years. Documentation included impairment due to core ADHD symptoms and additional ADHD symptoms/behaviors at diagnosis, diagnostic approach, and treatment modality. RESULTS: Study included 779 patients treated by 340 physicians. Prevalence of ADHD subtypes (inattention, hyperactivity/impulsivity, or combined) was similar across countries. Mean scores for core and noncore symptom impairment varied and were highest in Italy and the United Kingdom. Variability was noted in diagnostic approach; 95% of physicians in the Netherlands used Diagnostic and Statistical Manual of Mental Disorders (4th edition) criteria versus 10% in Germany. Differences were reported for initial treatment modality, treatment switching, and physician-reported treatment outcomes. CONCLUSION: European countries varied in diagnostic approaches and practice management of children/adolescents with ADHD. PMID- 26246587 TI - Validity of Sluggish Cognitive Tempo in South America: An Initial Examination Using Mother and Teacher Ratings of Chilean Children. AB - OBJECTIVE: To examine the validity of sluggish cognitive tempo (SCT) and ADHD inattention (ADHD-IN) symptoms in children from Chile. METHOD: Mothers and teachers rated SCT, ADHD-IN, ADHD-hyperactivity/impulsivity (ADHD-HI), oppositional defiant disorder (ODD), anxiety, depression, academic impairment, social impairment, and peer rejection (teachers only) in 652 Chilean children (55% boys) aged 6 to 14 years. RESULTS: For both mother and teacher ratings, the eight SCT symptoms and nine ADHD-IN symptoms showed substantial loadings on their respective factors (convergent validity) along with loadings close to zero on the alternative factor (discriminant validity). ADHD-IN showed a uniquely stronger relationship than SCT with ADHD-HI and ODD whereas SCT showed a uniquely stronger relationship than ADHD-IN with anxiety and depression. Although ADHD-IN uniquely predicted academic impairment and social difficulties, SCT did not. CONCLUSION: This study provides the first evidence for the validity of SCT among children outside of North America or Western Europe. PMID- 26246589 TI - Faking ADHD? Symptom Validity Testing and Its Relation to Self-Reported, Observer Reported Symptoms, and Neuropsychological Measures of Attention in Adults With ADHD. AB - OBJECTIVE: To compare ADHD patients who failed a symptom validity test with those who passed the test to explore whether there are signs of negative response bias on group level. METHOD: In our outpatient department, 196 adults were diagnosed with ADHD using a comprehensive diagnostic strategy featuring a detailed clinical history, clinical interview, observer rating, several self-rating scales, and neuropsychological attention tests. The Amsterdam Short Term Memory Test (AKGT) was applied as a symptom validity measure. RESULTS: Sixty-three patients (32.1%) scored below the AKGT cutoff level. The two groups did not significantly differ regarding self-report and observer ratings. Those who failed the AKGT had higher reaction time variabilities in selective, auditory and visual divided attention, and higher omission errors in sustained attention. CONCLUSION: We found no strong indicators for negative response bias in ADHD patients who failed a symptom validity test. New measures and approaches to detect feigned ADHD should be developed. PMID- 26246592 TI - Socioeconomic Status and the Prevalence of Type 2 Diabetes Among Adults in Northwest China. AB - PURPOSE: The purpose of the study was to investigate (1) the associations of socioeconomic status, lifestyle risk factors, and the prevalence of newly diagnosed type 2 diabetes and (2) the mediating effects of lifestyle risk factors on the association of socioeconomic status and the prevalence of newly diagnosed type 2 diabetes among Chinese adults in northwest China. METHODS: Based on a correlational design and random multistage sampling in communities (N = 3243), data were collected through face-to-face interviews and anthropometric measurements. Education, occupation, and income were considered indicators of socioeconomic status. RESULTS: Approximately 7.5% persons interviewed had newly diagnosed type 2 diabetes. Chi-square analyses showed that higher socioeconomic indicators (higher income, nonmanual occupation) were associated with increased risk. Lifestyle risk factors, including alcohol use, unhealthy diet, and higher body mass index, were significantly positively associated with type 2 diabetes. Adjusting for demographic characteristics, hierarchical logistic regression analyses showed that unhealthy diet and high body mass index were significantly associated with type 2 diabetes. CONCLUSIONS: Higher incomes and nonmanual occupations were related to a greater prevalence of type 2 diabetes, and high body mass index mediated these associations. These findings suggest that interventions for type 2 diabetes in China should be targeted at populations with high socioeconomic status and nonmanual occupations to reduce lifestyle risk factors and prevent diabetes. PMID- 26246593 TI - PETS-D: Impact on Diabetes Management Outcomes. AB - OBJECTIVE: To evaluate the efficacy of Parent Education Through Simulation Diabetes (PETS-D; clinical trial registration NCT01517269) for parents of children <13 years old newly diagnosed with type 1 diabetes with 3 parent education vignette sessions using human patient simulation (HPS) as compared with formal parent-nurse education sessions (vignette only) regarding diabetes knowledge, problem-solving skills, hypoglycemia fear, anxiety, and self-efficacy. DESIGN AND METHODS: Subjects were randomized to the HPS parent diabetes education or the vignette-only arm. Using linear mixed modeling, we compared HPS and vignette-only groups at 2, 6, and 14 weeks. Effect modification of treatment by dichotomized child's age (<6 and >= 6 years old) and parent education (<= high school and >high school) was also tested. All analyses were intent to treat and adjusted for baseline outcome level and clustering within site. RESULTS: We recruited 191 parents (116 children). Mean baseline A1C was 12%. Overall treatment-related differences were modest. There was a statistically significant effect modification of HPS by child's age, with a larger HPS benefit among parents of younger children for several outcomes: A1C (8.16% vs 9.48% in control; P = .006), lower state anxiety (P = .0094), and higher fear of hypoglycemia (P = .03) for parents of children <6 years old in the HPS group. CONCLUSIONS: Modest treatment-related differences may reflect ceiling/floor effects in many of the outcomes; we also compared HPS with another intervention rather than to usual education. Parents of younger children receiving the intervention may feel more comfortable with lower A1C levels because of management awareness gleaned from the HPS experience. Future research will include a retrospective case-control study of very young children. PMID- 26246594 TI - Comment on Pladevall et al, "A Randomized Controlled Trial to Provide Adherence Information and Motivational Interviewing to Improve Diabetes and Lipid Control". PMID- 26246595 TI - Detecting and Managing Diabetes Mellitus and Prediabetes in Patients With Acute Stroke. AB - PURPOSE: The purpose of the study was to determine the prevalence of undiagnosed diabetes mellitus (DM) and prediabetes (pre-DM) in acute stroke patients, to evaluate recommendations of diabetes treatment and follow-up care in a hospital setting, and to examine 1-year readmission rates based on admission A1C measure. METHODS: This retrospective study comprised 200 patients randomly selected from 1095 patients admitted with an acute stroke and an A1C measurement during admission. DM and pre-DM prevalence levels were determined per A1C level. Recommendations for diabetes treatment during and after hospitalization were assessed; charts were reviewed for readmission. RESULTS: Among 200 patients, 43% had known DM, and 0.5% had pre-DM. Among 113 patients without history of DM or pre-DM, 61.9% had A1C 5.7% to 6.4% (39-46 mmol/mol), and 8.8% had A1C >=6.5% (48 mmol/mol). None of the newly diagnosed pre-DM and 60% of newly diagnosed DM were documented. Only 7 of newly diagnosed DM or pre-DM patients received diabetes education. For patients with known DM and A1C >=7.0% (53 mmol/mol), 40.5% registered no change of diabetic regimen. Few patients were recommended for diabetes follow-up care. Patients with A1C >=6.5% or <5.7% were more likely to be readmitted for any reason within 1 year (33.3% and 31.6%, respectively) than patients with A1C levels of 5.7% to 6.4% (16.5%). CONCLUSIONS: The majority of acutely admitted stroke patients without known DM or pre-DM had A1C >=5.7%. Newly diagnosed DM or pre-DM patients received inadequate diabetes education and follow up care. These findings provide significant opportunities for improving acute stroke management. PMID- 26246596 TI - National Role Delineation Study of the Board Certification for Advanced Diabetes Management: Evidence-Based Support of the New Test Content Outline. AB - PURPOSE: The purpose of this comprehensive role delineation study of the Board Certification for Advanced Diabetes Management (BC-ADM) examination was to ensure its content validity. METHOD: The comprehensive role delineation study was conducted in 3 phases. In the first phase, a panel of 12 currently credentialed BC-ADM subject matter experts produced a list of practice domains, a unique set of content subdomains for each, and a series of knowledge statements for every subdomain. In the second phase, a validation study survey consisting of 3 sections was created. The first section was to rate each subdomain on three factors: criticality, frequency, and point in career at which knowledge is first used. The second section asked respondents to estimate the percentage of the examination to dedicate to the four domains. The third section captured demographic information of the respondents. A total of 667 BC-ADMs and 18 physicians were invited to take the survey. In the third phase, the subject matter expert panel analyzed the survey results and determined the weight that the domains and subdomains should have on the 150-item BC-ADM examination. RESULTS: Final domain weights and the corresponding number of items for the BC ADM examination are provided in this report; these constitute the BC-ADM examination blueprint. CONCLUSIONS: The national role delineation study reported here for the BC-ADM examination ensures that it is reflective of the current practice and required knowledge of the advanced diabetes manager. PMID- 26246597 TI - Autophosphorylation of the Smk1 MAPK is spatially and temporally regulated by Ssp2 during meiotic development in yeast. AB - Smk1 is a meiosis-specific MAPK that controls spore wall morphogenesis in Saccharomyces cerevisiae. Although Smk1 is activated by phosphorylation of the threonine (T) and tyrosine (Y) in its activation loop, it is not phosphorylated by a dual-specificity MAPK kinase. Instead, the T is phosphorylated by the cyclin dependent kinase (CDK)-activating kinase, Cak1. The Y is autophosphorylated in an intramolecular reaction that requires a meiosis-specific protein named Ssp2. The meiosis-specific CDK-like kinase, Ime2, was previously shown to positively regulate Smk1. Here we show that Ime2 activity is required to induce the translation of SSP2 mRNA at anaphase II. Ssp2 protein is then localized to the prospore membrane, the structure where spore wall assembly takes place. Next the carboxy-terminal portion of Ssp2 forms a complex with Smk1 and stimulates the autophosphorylation of its activation-loop Y residue. These findings link Ime2 to Smk1 activation through Ssp2 and define a developmentally regulated mechanism for activating MAPK at specific locations in the cell. PMID- 26246598 TI - Epidermal growth factor-stimulated Akt phosphorylation requires clathrin or ErbB2 but not receptor endocytosis. AB - Epidermal growth factor (EGF) binding to its receptor (EGFR) activates several signaling intermediates, including Akt, leading to control of cell survival and metabolism. Concomitantly, ligand-bound EGFR is incorporated into clathrin-coated pits--membrane structures containing clathrin and other proteins--eventually leading to receptor internalization. Whether clathrin might regulate EGFR signaling at the plasma membrane before vesicle scission is poorly understood. We compared the effect of clathrin perturbation (preventing formation of, or receptor recruitment to, clathrin structures) to that of dynamin2 (allowing formation of clathrin structures but preventing EGFR internalization) under conditions in which EGFR endocytosis is clathrin dependent. Clathrin perturbation by siRNA gene silencing, with the clathrin inhibitor pitstop2, or knocksideways silencing inhibited EGF-simulated Gab1 and Akt phosphorylation in ARPE-19 cells. In contrast, perturbation of dynamin2 with inhibitors or by siRNA gene silencing did not affect EGF-stimulated Gab1 or Akt phosphorylation. EGF stimulation enriched Gab1 and phospho-Gab1 within clathrin structures. ARPE-19 cells have low ErbB2 expression, and overexpression and knockdown experiments revealed that robust ErbB2 expression bypassed the requirement for clathrin for EGF-stimulated Akt phosphorylation. Thus clathrin scaffolds may represent unique plasma membrane signaling microdomains required for signaling by certain receptors, a function that can be separated from vesicle formation. PMID- 26246599 TI - Phosphorylation-dependent inhibition of Cdc42 GEF Gef1 by 14-3-3 protein Rad24 spatially regulates Cdc42 GTPase activity and oscillatory dynamics during cell morphogenesis. AB - Active Cdc42 GTPase, a key regulator of cell polarity, displays oscillatory dynamics that are anticorrelated at the two cell tips in fission yeast. Anticorrelation suggests competition for active Cdc42 or for its effectors. Here we show how 14-3-3 protein Rad24 associates with Cdc42 guanine exchange factor (GEF) Gef1, limiting Gef1 availability to promote Cdc42 activation. Phosphorylation of Gef1 by conserved NDR kinase Orb6 promotes Gef1 binding to Rad24. Loss of Rad24-Gef1 interaction increases Gef1 protein localization and Cdc42 activation at the cell tips and reduces the anticorrelation of active Cdc42 oscillations. Increased Cdc42 activation promotes precocious bipolar growth activation, bypassing the normal requirement for an intact microtubule cytoskeleton and for microtubule-dependent polarity landmark Tea4-PP1. Further, increased Cdc42 activation by Gef1 widens cell diameter and alters tip curvature, countering the effects of Cdc42 GTPase-activating protein Rga4. The respective levels of Gef1 and Rga4 proteins at the membrane define dynamically the growing area at each cell tip. Our findings show how the 14-3-3 protein Rad24 modulates the availability of Cdc42 GEF Gef1, a homologue of mammalian Cdc42 GEF DNMBP/TUBA, to spatially control Cdc42 GTPase activity and promote cell polarization and cell shape emergence. PMID- 26246600 TI - Ezrin regulates focal adhesion and invadopodia dynamics by altering calpain activity to promote breast cancer cell invasion. AB - Up-regulation of the cytoskeleton linker protein ezrin frequently occurs in aggressive cancer types and is closely linked with metastatic progression. However, the underlying molecular mechanisms detailing how ezrin is involved in the invasive and metastatic phenotype remain unclear. Here we report a novel function of ezrin in regulating focal adhesion (FA) and invadopodia dynamics, two key processes required for efficient invasion to occur. We show that depletion of ezrin expression in invasive breast cancer cells impairs both FA and invadopodia turnover. We also demonstrate that ezrin-depleted cells display reduced calpain mediated cleavage of the FA and invadopodia-associated proteins talin, focal adhesion kinase (FAK), and cortactin and reduced calpain-1-specific membrane localization, suggesting a requirement for ezrin in maintaining proper localization and activity of calpain-1. Furthermore, we show that ezrin is required for cell directionality, early lung seeding, and distant organ colonization but not primary tumor growth. Collectively our results unveil a novel mechanism by which ezrin regulates breast cancer cell invasion and metastasis. PMID- 26246601 TI - Requirement of the FATC domain of protein kinase Tel1 for localization to DNA ends and target protein recognition. AB - Two large phosphatidylinositol 3-kinase-related protein kinases (PIKKs), ATM and ATR, play a central role in the DNA damage response pathway. PIKKs contain a highly conserved extreme C-terminus called the FRAP-ATM-TRRAP-C-terminal (FATC) domain. In budding yeast, ATM and ATR correspond to Tel1 and Mec1, respectively. In this study, we characterized functions of the FATC domain of Tel1 by introducing substitution or truncation mutations. One substitution mutation, termed tel1-21, and a truncation mutation, called tel1-DeltaC, did not significantly affect the expression level. The tel1-21 mutation impaired the cellular response to DNA damage and conferred moderate telomere maintenance defect. In contrast, the tel1-DeltaC mutation behaved like a null mutation, conferring defects in both DNA damage response and telomere maintenance. Tel1-21 protein localized to DNA ends as effectively as wild-type Tel1 protein, whereas Tel1-DeltaC protein failed. Introduction of a hyperactive TEL1-hy mutation suppressed the tel1-21 mutation but not the tel1-DeltaC mutation. In vitro analyses revealed that both Tel1-21 and Tel1-DeltaC proteins undergo efficient autophosphorylation but exhibit decreased kinase activities toward the exogenous substrate protein, Rad53. Our results show that the FATC domain of Tel1 mediates localization to DNA ends and contributes to phosphorylation of target proteins. PMID- 26246602 TI - Replication stress in early S phase generates apparent micronuclei and chromosome rearrangement in fission yeast. AB - DNA replication stress causes genome mutations, rearrangements, and chromosome missegregation, which are implicated in cancer. We analyze a fission yeast mutant that is unable to complete S phase due to a defective subunit of the MCM helicase. Despite underreplicated and damaged DNA, these cells evade the G2 damage checkpoint to form ultrafine bridges, fragmented centromeres, and uneven chromosome segregations that resembles micronuclei. These micronuclei retain DNA damage markers and frequently rejoin with the parent nucleus. Surviving cells show an increased rate of mutation and chromosome rearrangement. This first report of micronucleus-like segregation in a yeast replication mutant establishes underreplication as an important factor contributing to checkpoint escape, abnormal chromosome segregation, and chromosome instability. PMID- 26246603 TI - Lamins position the nuclear pores and centrosomes by modulating dynein. AB - Lamins, the type V nuclear intermediate filament proteins, are reported to function in both interphase and mitosis. For example, lamin deletion in various cell types can lead to an uneven distribution of the nuclear pore complexes (NPCs) in the interphase nuclear envelope, whereas deletion of B-type lamins results in spindle orientation defects in mitotic neural progenitor cells. How lamins regulate these functions is unknown. Using mouse cells deleted of different combinations or all lamins, we show that lamins are required to prevent the aggregation of NPCs in the nuclear envelope near centrosomes in late G2 and prophase. This asymmetric NPC distribution in the absence of lamins is caused by dynein forces acting on NPCs via the dynein adaptor BICD2. We further show that asymmetric NPC distribution upon lamin depletion disrupts the distribution of BICD2 and p150 dynactin on the nuclear envelope at prophase, which results in inefficient dynein-driven centrosome separation during prophase. Therefore lamins regulate microtubule-based motor forces in vivo to ensure proper NPC distribution in interphase and centrosome separation in the mitotic prophase. PMID- 26246604 TI - Division of labor among oxidoreductases: TMX1 preferentially acts on transmembrane polypeptides. AB - The endoplasmic reticulum (ER) is the site of maturation for secretory and membrane proteins in eukaryotic cells. The lumen of the mammalian ER contains >20 members of the protein disulfide isomerase (PDI) superfamily, which ensure formation of the correct set of intramolecular and intermolecular disulfide bonds as crucial, rate-limiting reactions of the protein folding process. Components of the PDI superfamily may also facilitate dislocation of misfolded polypeptides across the ER membrane for ER-associated degradation (ERAD). The reasons for the high redundancy of PDI family members and the substrate features required for preferential engagement of one or the other are poorly understood. Here we show that TMX1, one of the few transmembrane members of the family, forms functional complexes with the ER lectin calnexin and preferentially intervenes during maturation of cysteine-containing, membrane-associated proteins while ignoring the same cysteine-containing ectodomains if not anchored at the ER membrane. As such, TMX1 is the first example of a topology-specific client protein redox catalyst in living cells. PMID- 26246605 TI - STUbL-mediated degradation of the transcription factor MATalpha2 requires degradation elements that coincide with corepressor binding sites. AB - The yeast transcription factor MATalpha2 (alpha2) is a short-lived protein known to be ubiquitylated by two distinct pathways, one involving the ubiquitin conjugating enzymes (E2s) Ubc6 and Ubc7 and the ubiquitin ligase (E3) Doa10 and the other operating with the E2 Ubc4 and the heterodimeric E3 Slx5/Slx8. Although Slx5/Slx8 is a small ubiquitin-like modifier (SUMO)-targeted ubiquitin ligase (STUbL), it does not require SUMO to target alpha2 but instead directly recognizes alpha2. Little is known about the alpha2 determinants required for its Ubc4- and STUbL-mediated degradation or how these determinants substitute for SUMO in recognition by the STUbL pathway. We describe two distinct degradation elements within alpha2, both of which are necessary for alpha2 recognition specifically by the Ubc4 pathway. Slx5/Slx8 can directly ubiquitylate a C terminal fragment of alpha2, and mutating one of the degradation elements impairs this ubiquitylation. Surprisingly, both degradation elements identified here overlap specific interaction sites for alpha2 corepressors: the Mcm1 interaction site in the central alpha2 linker and the Ssn6 (Cyc8) binding site in the alpha2 homeodomain. We propose that competitive binding to alpha2 by the ubiquitylation machinery and alpha2 cofactors is balanced so that alpha2 can function in transcription repression yet be short lived enough to allow cell-type switching. PMID- 26246607 TI - Folate deficiency impairs decidualization and alters methylation patterns of the genome in mice. AB - Existing evidence suggests that adverse pregnancy outcomes are closely related with dietary factors. Previous studies in mice have focused on the harm of folate deficiency (FD) on development of embryo, while the effect of low maternal folate levels on maternal intrauterine environment during early pregnancy remains unclear. Since our previous study found that FD treatment of mice causes no apparent defects in embryo implantation but is accompanied by female subfertility, we next chose to investigate a potential role of FD on molecular events after implantation. We observed that the decidual bulges began to be stunted on pregnancy day 6. The results of functional experiments in vivo and in vitro showed that FD inhibited the process of endometrial decidualization. It has been confirmed that DNA methylation participates in decidualization, and folate as a methyl donor could change the methylation patterns of genes. Thus, we hypothesized that FD impairs maternal endometrial decidualization by altering the methylation profiles of related genes. Reduced representation bisulphite sequencing was carried out to detect the methylation profiles of endometrium on pregnancy day 6-8, which is equivalent to the decidualization period in mice. The results confirmed that FD changes the methylation patterns of genome, and GO analysis of the differentially methylated regions revealed that the associated genes mainly participate in biological adhesion, biological regulation, cell proliferation, development, metabolism and signalling. In addition, we found some candidates for regulators of decidual transformation, such as Nr1h3 and Nr5a1. The data indicate that FD inhibits decidualization, possibly by altering methylation patterns of the genome in mice. PMID- 26246606 TI - The nucleoporin ALADIN regulates Aurora A localization to ensure robust mitotic spindle formation. AB - The formation of the mitotic spindle is a complex process that requires massive cellular reorganization. Regulation by mitotic kinases controls this entire process. One of these mitotic controllers is Aurora A kinase, which is itself highly regulated. In this study, we show that the nuclear pore protein ALADIN is a novel spatial regulator of Aurora A. Without ALADIN, Aurora A spreads from centrosomes onto spindle microtubules, which affects the distribution of a subset of microtubule regulators and slows spindle assembly and chromosome alignment. ALADIN interacts with inactive Aurora A and is recruited to the spindle pole after Aurora A inhibition. Of interest, mutations in ALADIN cause triple A syndrome. We find that some of the mitotic phenotypes that we observe after ALADIN depletion also occur in cells from triple A syndrome patients, which raises the possibility that mitotic errors may underlie part of the etiology of this syndrome. PMID- 26246608 TI - Host manipulation by an ichneumonid spider ectoparasitoid that takes advantage of preprogrammed web-building behaviour for its cocoon protection. AB - Host manipulation by parasites and parasitoids is a fascinating phenomenon within evolutionary ecology, representing an example of extended phenotypes. To elucidate the mechanism of host manipulation, revealing the origin and function of the invoked actions is essential. Our study focused on the ichneumonid spider ectoparasitoid Reclinervellus nielseni, which turns its host spider (Cyclosa argenteoalba) into a drugged navvy, to modify the web structure into a more persistent cocoon web so that the wasp can pupate safely on this web after the spider's death. We focused on whether the cocoon web originated from the resting web that an unparasitized spider builds before moulting, by comparing web structures, building behaviour and silk spectral/tensile properties. We found that both resting and cocoon webs have reduced numbers of radii decorated by numerous fibrous threads and specific decorating behaviour was identical, suggesting that the cocoon web in this system has roots in the innate resting web and ecdysteroid-related components may be responsible for the manipulation. We also show that these decorations reflect UV light, possibly to prevent damage by flying web-destroyers such as birds or large insects. Furthermore, the tensile test revealed that the spider is induced to repeat certain behavioural steps in addition to resting web construction so that many more threads are laid down for web reinforcement. PMID- 26246609 TI - Preconditioning in the reef-building coral Pocillopora damicornis and the potential for trans-generational acclimatization in coral larvae under future climate change conditions. AB - Coral reefs are globally threatened by climate change-related ocean warming and ocean acidification (OA). To date, slow-response mechanisms such as genetic adaptation have been considered the major determinant of coral reef persistence, with little consideration of rapid-response acclimatization mechanisms. These rapid mechanisms such as parental effects that can contribute to trans generational acclimatization (e.g. epigenetics) have, however, been identified as important contributors to offspring response in other systems. We present the first evidence of parental effects in a cross-generational exposure to temperature and OA in reef-building corals. Here, we exposed adults to high (28.9 degrees C, 805 uatm P(CO2)) or ambient (26.5 degrees C, 417 uatm P(CO2)) temperature and OA treatments during the larval brooding period. Exposure to high treatment negatively affected adult performance, but their larvae exhibited size differences and metabolic acclimation when subsequently re-exposed, unlike larvae from parents exposed to ambient conditions. Understanding the innate capacity corals possess to respond to current and future climatic conditions is essential to reef protection and maintenance. Our results identify that parental effects may have an important role through (1) ameliorating the effects of stress through preconditioning and adaptive plasticity, and/or (2) amplifying the negative parental response through latent effects on future life stages. Whether the consequences of parental effects and the potential for trans-generational acclimatization are beneficial or maladaptive, our work identifies a critical need to expand currently proposed climate change outcomes for corals to further assess rapid response mechanisms that include non-genetic inheritance through parental contributions and classical epigenetic mechanisms. PMID- 26246611 TI - A Chinese alligator in heliox: formant frequencies in a crocodilian. AB - Crocodilians are among the most vocal non-avian reptiles. Adults of both sexes produce loud vocalizations known as 'bellows' year round, with the highest rate during the mating season. Although the specific function of these vocalizations remains unclear, they may advertise the caller's body size, because relative size differences strongly affect courtship and territorial behaviour in crocodilians. In mammals and birds, a common mechanism for producing honest acoustic signals of body size is via formant frequencies (vocal tract resonances). To our knowledge, formants have to date never been documented in any non-avian reptile, and formants do not seem to play a role in the vocalizations of anurans. We tested for formants in crocodilian vocalizations by using playbacks to induce a female Chinese alligator (Alligator sinensis) to bellow in an airtight chamber. During vocalizations, the animal inhaled either normal air or a helium/oxygen mixture (heliox) in which the velocity of sound is increased. Although heliox allows normal respiration, it alters the formant distribution of the sound spectrum. An acoustic analysis of the calls showed that the source signal components remained constant under both conditions, but an upward shift of high-energy frequency bands was observed in heliox. We conclude that these frequency bands represent formants. We suggest that crocodilian vocalizations could thus provide an acoustic indication of body size via formants. Because birds and crocodilians share a common ancestor with all dinosaurs, a better understanding of their vocal production systems may also provide insight into the communication of extinct Archosaurians. PMID- 26246610 TI - Genetically based low oxygen affinities of felid hemoglobins: lack of biochemical adaptation to high-altitude hypoxia in the snow leopard. AB - Genetically based modifications of hemoglobin (Hb) function that increase blood O2 affinity are hallmarks of hypoxia adaptation in vertebrates. Among mammals, felid Hbs are unusual in that they have low intrinsic O2 affinities and reduced sensitivities to the allosteric cofactor 2,3-diphosphoglycerate (DPG). This combination of features compromises the acclimatization capacity of blood-O2 affinity and has led to the hypothesis that felids have a restricted physiological niche breadth relative to other mammals. In seeming defiance of this conjecture, the snow leopard (Panthera uncia) has an extraordinarily broad elevational distribution and occurs at elevations above 6000 m in the Himalayas. Here, we characterized structural and functional variation of big cat Hbs and investigated molecular mechanisms of Hb adaptation and allosteric regulation that may contribute to the extreme hypoxia tolerance of the snow leopard. Experiments revealed that purified Hbs from snow leopard and African lion exhibited equally low O2 affinities and DPG sensitivities. Both properties are primarily attributable to a single amino acid substitution, beta2His->Phe, which occurred in the common ancestor of Felidae. Given the low O2 affinity and reduced regulatory capacity of feline Hbs, the extreme hypoxia tolerance of snow leopards must be attributable to compensatory modifications of other steps in the O2 transport pathway. PMID- 26246612 TI - AtCOX10, a protein involved in haem o synthesis during cytochrome c oxidase biogenesis, is essential for plant embryogenesis and modulates the progression of senescence. AB - Cytochrome c oxidase (CcO) biogenesis requires several accessory proteins implicated, among other processes, in copper and haem a insertion. In yeast, the farnesyltransferase Cox10p that catalyses the conversion of haem b to haem o is the limiting factor in haem a biosynthesis and is essential for haem a insertion in CcO. In this work, we characterized AtCOX10, a putative Cox10p homologue from Arabidopsis thaliana. AtCOX10 was localized in mitochondria and was able to restore growth of a yeast Deltacox10 null mutant on non-fermentable carbon sources, suggesting that it also participates in haem o synthesis. Plants with T DNA insertions in the coding region of both copies of AtCOX10 could not be recovered, and heterozygous mutant plants showed seeds with embryos arrested at early developmental stages that lacked CcO activity. Heterozygous mutant plants exhibited lower levels of CcO activity and cyanide-sensitive respiration but normal levels of total respiration at the expense of an increase in alternative respiration. AtCOX10 seems to be implicated in the onset and progression of senescence, since heterozygous mutant plants showed a faster decrease in chlorophyll content and photosynthetic performance than wild-type plants after natural and dark-induced senescence. Furthermore, complementation of mutants by expressing AtCOX10 under its own promoter allowed us to obtain plants with T-DNA insertions in both AtCOX10 copies, which showed phenotypic characteristics comparable to those of wild type. Our results highlight the relevance of haem o synthesis in plants and suggest that this process is a limiting factor that influences CcO activity levels, mitochondrial respiration, and plant senescence. PMID- 26246613 TI - NH4+ protects tomato plants against Pseudomonas syringae by activation of systemic acquired acclimation. AB - NH4 (+) nutrition provokes mild toxicity by enhancing H2O2 accumulation, which acts as a signal activating systemic acquired acclimation (SAA). Until now, induced resistance mechanisms in response to an abiotic stimulus and related to SAA were only reported for exposure to a subsequent abiotic stress. Herein, the first evidence is provided that this acclimation to an abiotic stimulus induces resistance to later pathogen infection, since NH4 (+) nutrition (N-NH4 (+)) induced resistance (NH4 (+)-IR) against Pseudomonas syringae pv tomato DC3000 (Pst) in tomato plants was demonstrated. N-NH4 (+) plants displayed basal H2O2, abscisic acid (ABA), and putrescine (Put) accumulation. H2O2 accumulation acted as a signal to induce ABA-dependent signalling pathways required to prevent NH4 (+) toxicity. This acclimatory event provoked an increase in resistance against later pathogen infection. N-NH4 (+) plants displayed basal stomatal closure produced by H2O2 derived from enhanced CuAO and rboh1 activity that may reduce the entry of bacteria into the mesophyll, diminishing the disease symptoms as well as strongly inducing the oxidative burst upon Pst infection, favouring NH4 (+)-IR. Experiments with inhibitors of Put accumulation and the ABA-deficient mutant flacca demonstrated that Put and ABA downstream signalling pathways are required to complete NH4 (+)-IR. The metabolic profile revealed that infected N NH4 (+) plants showed greater ferulic acid accumulation compared with control plants. Although classical salicylic acid (SA)-dependent responses against biotrophic pathogens were not found, the important role of Put in the resistance of tomato against Pst was demonstrated. Moreover, this work revealed the cross talk between abiotic stress acclimation (NH4 (+) nutrition) and resistance to subsequent Pst infection. PMID- 26246614 TI - Carpel size, grain filling, and morphology determine individual grain weight in wheat. AB - Individual grain weight is a major yield component in wheat. To provide a comprehensive understanding of grain weight determination, the carpel size at anthesis, grain dry matter accumulation, grain water uptake and loss, grain morphological expansion, and final grain weight at different positions within spikelets were investigated in a recombinant inbred line mapping population of bread wheat (Triticum aestivum L.)*spelt (Triticum spelta L.). Carpel size, grain dry matter and water accumulation, and grain dimensions interacted strongly with each other. Furthermore, larger carpels, a faster grain filling rate, earlier and longer grain filling, more grain water, faster grain water absorption and loss rates, and larger grain dimensions were associated with higher grain weight. Frequent quantitative trait locus (QTL) coincidences between these traits were observed, particularly those on chromosomes 2A, 3B, 4A, 5A, 5DL, and 7B, each of which harboured 16-49 QTLs associated with >12 traits. Analysis of the allelic effects of coincident QTLs confirmed their physiological relationships, indicating that the complex but orderly grain filling processes result mainly from pleiotropy or the tight linkages of functionally related genes. After grain filling, distal grains within spikelets were smaller than basal grains, primarily due to later grain filling and a slower initial grain filling rate, followed by synchronous maturation among different grains. Distal grain weight was improved by increased assimilate availability from anthesis. These findings provide deeper insight into grain weight determination in wheat, and the high level of QTL coincidences allows simultaneous improvement of multiple grain filling traits in breeding. PMID- 26246615 TI - Breeding crops for improved mineral nutrition under climate change conditions. PMID- 26246617 TI - Chromatin and Epigenetics. PMID- 26246616 TI - Tubulin perturbation leads to unexpected cell wall modifications and affects stomatal behaviour in Populus. AB - Cortical microtubules are integral to plant morphogenesis, cell wall synthesis, and stomatal behaviour, presumably by governing cellulose microfibril orientation. Genetic manipulation of tubulins often leads to abnormal plant development, making it difficult to probe additional roles of cortical microtubules in cell wall biogenesis. Here, it is shown that expressing post translational C-terminal modification mimics of alpha-tubulin altered cell wall characteristics and guard cell dynamics in transgenic Populus tremula x alba that otherwise appear normal. 35S promoter-driven transgene expression was high in leaves but unusually low in xylem, suggesting high levels of tubulin transgene expression were not tolerated in wood-forming tissues during regeneration of transformants. Cellulose, hemicellulose, and lignin contents were unaffected in transgenic wood, but expression of cell wall-modifying enzymes, and extractability of lignin-bound pectin and xylan polysaccharides were increased in developing xylem. The results suggest that pectin and xylan polysaccharides deposited early during cell wall biogenesis are more sensitive to subtle tubulin perturbation than cellulose and matrix polysaccharides deposited later. Tubulin perturbation also affected guard cell behaviour, delaying drought-induced stomatal closure as well as light-induced stomatal opening in leaves. Pectins have been shown to confer cell wall flexibility critical for reversible stomatal movement, and results presented here are consistent with microtubule involvement in this process. Taken together, the data show the value of growth-compatible tubulin perturbations for discerning microtubule functions, and add to the growing body of evidence for microtubule involvement in non-cellulosic polysaccharide assembly during cell wall biogenesis. PMID- 26246618 TI - Bringing Anatomy Back into the Equation. PMID- 26246620 TI - Training Malaysian Pharmacy Undergraduates with Knowledge and Skills on Smoking Cessation. AB - OBJECTIVE: To evaluate the feasibility of an online training module, Certified Smoking Cessation Service Provider (CSCSP), developed for practicing pharmacists to equip pharmacy students with knowledge necessary for smoking cessation counseling and to assess the changes in student knowledge and skills regarding smoking cessation following training. DESIGN: Sixty third-year and 80 fourth-year pharmacy undergraduates (N=140) were given access to an online module, the main intervention in the study. Two linkable questionnaires were administered to assess students' preintervention and postintervention knowledge. For the third year students, an additional role-play training component was incorporated, and student skills were assessed during week 14 with an Objective Structured Clinical Examination (OSCE). ASSESSMENT: Preintervention and postintervention knowledge assessments were completed by 130 (92.8%) students. Sixty-six students scored above 50% for the knowledge component postintervention, compared to 13 at preintervention, demonstrating significant improvement (x2(1, N=130)=32, p=0.003). All third-year students completed the intervention, and 66.7% were able to counsel excellently for smoking cessation, scoring more than 80%. CONCLUSION: The CSCSP online module developed for practicing professionals was found suitable for equipping pharmacy undergraduates with knowledge on smoking cessation topics. The module, along with role-play training, also equipped students with knowledge and skills to provide smoking cessation counseling. PMID- 26246619 TI - Anaerobic biosynthesis of the lower ligand of vitamin B12. AB - Vitamin B12 (cobalamin) is required by humans and other organisms for diverse metabolic processes, although only a subset of prokaryotes is capable of synthesizing B12 and other cobamide cofactors. The complete aerobic and anaerobic pathways for the de novo biosynthesis of B12 are known, with the exception of the steps leading to the anaerobic biosynthesis of the lower ligand, 5,6 dimethylbenzimidazole (DMB). Here, we report the identification and characterization of the complete pathway for anaerobic DMB biosynthesis. This pathway, identified in the obligate anaerobic bacterium Eubacterium limosum, is composed of five previously uncharacterized genes, bzaABCDE, that together direct DMB production when expressed in anaerobically cultured Escherichia coli. Expression of different combinations of the bza genes revealed that 5 hydroxybenzimidazole, 5-methoxybenzimidazole, and 5-methoxy-6 methylbenzimidazole, all of which are lower ligands of cobamides produced by other organisms, are intermediates in the pathway. The bza gene content of several bacterial and archaeal genomes is consistent with experimentally determined structures of the benzimidazoles produced by these organisms, indicating that these genes can be used to predict cobamide structure. The identification of the bza genes thus represents the last remaining unknown component of the biosynthetic pathway for not only B12 itself, but also for three other cobamide lower ligands whose biosynthesis was previously unknown. Given the importance of cobamides in environmental, industrial, and human-associated microbial metabolism, the ability to predict cobamide structure may lead to an improved ability to understand and manipulate microbial metabolism. PMID- 26246621 TI - Supercritical Fluid Extraction and Chromatography of Lipids in Bilberry. AB - A supercritical fluid extraction (SFE) method has been developed for the extraction of lipids in bilberry. Experimental design was used to optimize pressure, temperature and extraction time using CO2 as solvent. Best SFE condition for total lipids was 450 bar, 60 degrees C and 45 min. The SFE method was compared to conventional Bligh & Dyer (B&D) extraction. The amount of fatty acid methyl esters (FAME) was found to be 4.84 +/- 0.06 mg and 4.564 +/- 0.003 mg per g of the freeze-dried bilberry sample for the developed SFE and B&D methods, respectively, while the amount of total lipids was found to be 54.40 +/- 6.06 mg and 65.70 +/- 0.67 mg per g of sample for SFE and B&D, respectively. This discrepancy between FAME and total lipids could be explained by the presence of wax esters, sterol esters, carotenoids and phospholipids, as determined by supercritical fluid chromatography. PMID- 26246622 TI - Semiparametric estimation for the additive hazards model with left-truncated and right-censored data. AB - Survival data from prevalent cases collected under a cross-sectional sampling scheme are subject to left-truncation. When fitting an additive hazards model to left-truncated data, the conditional estimating equation method (Lin & Ying, 1994), obtained by modifying the risk sets to account for left-truncation, can be very inefficient, as the marginal likelihood of the truncation times is not used in the estimation procedure. In this paper, we use a pairwise pseudolikelihood to eliminate nuisance parameters from the marginal likelihood and, by combining the marginal pairwise pseudo-score function and the conditional estimating function, propose an efficient estimator for the additive hazards model. The proposed estimator is shown to be consistent and asymptotically normally distributed with a sandwich-type covariance matrix that can be consistently estimated. Simulation studies show that the proposed estimator is more efficient than its competitors. A data analysis illustrates application of the method. PMID- 26246623 TI - Ponies on Sable Island - A comment. PMID- 26246624 TI - Veterinary schools - which ones are the best? PMID- 26246625 TI - An ethicist's commentary on scientific authorship. PMID- 26246626 TI - Ontario: Index case of highly pathogenic avian influenza H5N2 in Ontario. PMID- 26246627 TI - The effects of preoperative oral administration of carprofen or tramadol on postoperative analgesia in dogs undergoing cutaneous tumor removal. AB - This prospective, blinded, controlled clinical study compared the effects of pre emptive oral administration of carprofen or tramadol on pain scores and analgesic requirement in dogs undergoing cutaneous tumor removal. Thirty-six client-owned dogs presenting for cutaneous tumor removal were randomly assigned to receive carprofen, tramadol, or no treatment prior to surgery. Pain was assessed using a visual analog scale (VAS), the Modified Glasgow Composite Measure Pain Score (MGCMPS), and algometry at enrollment, prior to premedication, at extubation, then hourly for the first 4 h, and every 4 h for 24 h. Dogs scoring >= 7 (MGCMPS), or having a VAS measurement >= 40 mm were given rescue analgesia. There were no significant differences in pain VAS, MGCMPS, or algometry. There were no differences in rescue analgesia requirement, or time to rescue analgesia among groups. Carprofen, tramadol, or no pre-emptive analgesia, combined with pre operative hydromorphone and rescue analgesia, resulted in satisfactory analgesia in the 24-hour postoperative period. PMID- 26246628 TI - Subcutaneous administration of paclitaxel in dogs with cancer: A preliminary study. AB - Intravenous paclitaxel has been underused in dogs due to severe and acute hypersensitivity reactions. Subcutaneous (SC) administration of paclitaxel and its safety are unknown. In this preliminary study, SC administration of paclitaxel was evaluated for hypersensitivity reactions and toxicity in 21 dogs with advanced cancer. Dogs received 1 to 5 paclitaxel doses, ranging from 85 to 170 mg/m(2), SC every 14 or 21 days. A total of 40 paclitaxel doses were administered and none of the 21 dogs developed systemic or acute local hypersensitivity reactions. Severe skin lesions at the injection site developed in 2 dogs after the 4th injection at the same location. Grade 4 neutropenia was observed in 50% of the dogs 5 days after the first treatment at 115 mg/m(2) (n = 14). Two animals developed Grade 5 diarrhea and died likely due to hemodynamic failure or sepsis. Paclitaxel can be administered SC in dogs with no hypersensitivity reaction. PMID- 26246629 TI - Short- and long-term effects of platelet-rich plasma upon healthy equine joints: Clinical and laboratory aspects. AB - This study aimed to verify whether transient inflammatory reactions incited by the administration of intra-articular platelet-rich plasma (PRP) affected joint components through short- and long-term in vivo evaluation of inflammatory biomarkers and extracellular matrix degradation products in synovial fluid. The effects of PRP were analyzed in a short phase protocol (SPP) and in a prolonged phase protocol (PPP), using saline-injected joints as controls. In the SPP, higher white blood cell counts and prostaglandin E2 and total protein concentrations were observed in the synovial fluid of PRP-treated joints (P < 0.05). There were no differences between the interleukin-1beta, interleukin-1 receptor antagonist protein, tumor necrosis factor-alpha, chondroitin sulfate, or hyaluronic acid concentrations between PRP and saline injected joints. In the PPP, there were no differences in evaluated parameters between groups. PRP injection elicits a mild and self-limiting inflammatory response shortly after administration, without long-term deleterious effects on joint homeostasis. PMID- 26246630 TI - Disease risks associated with free-ranging wild boar in Saskatchewan. AB - This study investigated the disease status of Saskatchewan's feral wild boar population. Whole carcasses, tissue samples, and/or serum from 81 hunter-killed boars from Saskatchewan were submitted to the Canadian Wildlife Health Cooperative (CWHC) between 2009 and 2014. Serological tests were negative for PRRS, H1N1, and H3N2 swine influenza, PCV-2, and TGE/PRCV in 22/22 boars and for Toxoplasma gondii and Mycoplasma hyopneumoniae in 20/20 boars. Of 20 boars whose sera were tested 20 were positive for Actinobacillus pleuropneumoniae, with 7 positive for, among other strains, serotype 14; 16 were positive for Lawsonia intracellularis, 1 was positive and 6 were suspicious for Salmonella spp. Polymerase chain reaction tests were negative for PRRS and PCV2 in 58/58 boars and positive for Torque teno virus in 1/8 boars. Digestion assays were negative for Trichinella spp. in 22/22 boars. The high seroprevalence of A. pleuropneumoniae serotype 14 is noteworthy as this serotype has not been previously reported in North America. PMID- 26246631 TI - Single ultrasound-guided platelet-rich plasma injection for treatment of supraspinatus tendinopathy in dogs. AB - The effect of a single platelet-rich plasma injection for supraspinatus tendinopathy was assessed in 10 dogs. Subjective (owner-assessed) improvement in lameness and function were seen in 40% of dogs with improved tendon heterogeneity and echogenicity in 60%. There were no significant changes in gait reaction forces 6 wk after treatment. PMID- 26246632 TI - Utility of inline milk fat and protein ratio to diagnose subclinical ketosis and to assign propylene glycol treatment in lactating dairy cows. AB - The objective was to identify a fat-to-protein ratio (FPR) cut-off to diagnose subclinical ketosis (SCK) and to evaluate the effect of propylene glycol (PPG) treatment of cows with high FPR. The optimized cut-off was > 1.42; sensitivity (Se) = 92%; specificity (Sp) = 65%. A cut-off > 1.5 was selected for the PPG trial for balanced Se-Sp. Fat-to-protein ratio cut-offs > 1.25, 1.35, 1.50, 1.60, and 1.70 resulted in Se-Sp of 100% to 49%, 96% to 59%, 75% to 78%, 33% to 90%, and 8% to 96%, respectively. The proportions of cows with FPR > 1.25, 1.35, 1.42, 1.50, 1.60, and 1.70 were 60%, 50%, 44%, 30%, 14%, and 6%, respectively. Incidences of clinical ketosis and milk yield were similar between cows that received 400 mL of PPG (n = 34) and control cows (n = 38). Prevalence of SCK at enrollment was 29.2%; therefore, FPR > 1.5 is not indicated for treatment. Lower cut-offs should be used for screening. PMID- 26246633 TI - Novel treatment of equine odontoclastic tooth resorption and hypercementosis of incisor teeth in a 22-year-old Arabian mare. AB - Equine odontoclastic tooth resorption and hypercementosis is a rarely reported condition in the incisor and canine teeth of older horses. Histologically, there is internal and external resorption of the tooth with formation of excessive cementum. Once lesions become infected or supragingival this condition is very painful. The clinical manifestation, diagnosis and treatment of hypercementosis in an Arabian mare are described. PMID- 26246634 TI - Effect of maternal ketoacidosis on the ovine fetus. AB - Ketoacidosis during pregnancy carries significant risk of intrauterine fetal demise, but little is known about the impact of ketoacids on the ovine fetus. We report a case series of maternal ketoacidosis in ewes. Maternal ketoacidosis may result in biochemical and acid-base fetal abnormalities associated with changes in feto-placental unit perfusion. PMID- 26246635 TI - Pre-operative fibrous osteodystrophy and severe, refractory, post-operative hypocalcemia following parathyroidectomy in a dog. AB - A 13-year-old dog exhibited dramatic, radiographic osteopenia consistent with fibrous osteodystrophy secondary to primary hyperparathyroidism. Following parathyroidectomy, the dog developed severe, prolonged hypocalcemia, but was successfully treated and discharged 32 d after surgery. A variety of factors may have contributed to this dog's hypocalcemia including hypoparathyroidism and hungry bone syndrome. PMID- 26246636 TI - Meningoencephalitis associated with disseminated sarcocystosis in a free-ranging moose (Alces alces) calf. AB - A wild moose (Alces alces) calf was presented for necropsy due to severe neurologic signs. Histopathologic examination revealed multisystemic inflammation with intralesional mature and immature schizonts. Schizonts in the brain reacted positively to Sarcocystis spp. polyclonal antibodies. Gene sequencing of PCR amplified DNA identified the species as Sarcocystis alceslatrans. PMID- 26246637 TI - Treatment of diplomonad intestinal parasites with magnesium sulphate at a commercial rainbow trout (Oncorhynchus mykiss) facility. AB - Rainbow trout (average weight of 2 g) in fresh water experienced high mortality and were infected with a diplomonad intestinal parasite. Tanks of fish experienced an immediate reduction in mortality after an in-feed treatment with 3% Epsom salts for 2 d. Treatments had to be applied several times, but in each case there was a similar reduction in mortality. PMID- 26246638 TI - Veterinary reporting of animal welfare concerns. PMID- 26246640 TI - Painful and depressing communication. PMID- 26246639 TI - Veterinarians without Borders/Veterinaires sans frontieres-Canada - The first 10 years (2005-2015). PMID- 26246641 TI - A sub-nW 2.4 GHz Transmitter for Low Data-Rate Sensing Applications. AB - This paper presents the design of a narrowband transmitter and antenna system that achieves an average power consumption of 78 pW when operating at a duty cycled data rate of 1 bps. Fabricated in a 0.18 um CMOS process, the transmitter employs a direct-RF power oscillator topology where a loop antenna acts as a both a radiative and resonant element. The low-complexity single-stage architecture, in combination with aggressive power gating techniques and sizing optimizations, limited the standby power of the transmitter to only 39.7 pW at 0.8 V. Supporting both OOK and FSK modulations at 2.4 GHz, the transmitter consumed as low as 38 pJ/bit at an active-mode data rate of 5 Mbps. The loop antenna and integrated diodes were also used as part of a wireless power transfer receiver in order to kick-start the system power supply during energy harvesting operation. PMID- 26246643 TI - Learning and Collective Knowledge Construction With Social Media: A Process Oriented Perspective. AB - Social media are increasingly being used for educational purposes. The first part of this article briefly reviews literature that reports on educational applications of social media tools. The second part discusses theories that may provide a basis for analyzing the processes that are relevant for individual learning and collective knowledge construction. We argue that a systems theoretical constructivist approach is appropriate to examine the processes of educational social media use, namely, self-organization, the internalization of information, the externalization of knowledge, and the interplay of externalization and internalization providing the basis of a co-evolution of cognitive and social systems. In the third part we present research findings that illustrate and support this systems-theoretical framework. Concluding, we discuss the implications for educational design and for future research on learning and collective knowledge construction with social media. PMID- 26246642 TI - Fighting for Intelligence: A Brief Overview of the Academic Work of John L. Horn. AB - John L. Horn (1928-2006) was a pioneer in multivariate thinking and the application of multivariate methods to research on intelligence and personality. His key works on individual differences in the methodological areas of factor analysis and the substantive areas of cognition are reviewed here. John was also our mentor, teacher, colleague, and friend. We overview John Horn's main contributions to the field of intelligence by highlighting 3 issues about his methods of factor analysis and 3 of his substantive debates about intelligence. We first focus on Horn's methodological demonstrations describing (a) the many uses of simulated random variables in exploratory factor analysis; (b) the exploratory uses of confirmatory factor analysis; and (c) the key differences between states, traits, and trait-changes. On a substantive basis, John believed that there were important individual differences among people in terms of cognition and personality. These sentiments led to his intellectual battles about (d) Spearman's g theory of a unitary intelligence, (e) Guilford's multifaceted model of intelligence, and (f) the Schaie and Baltes approach to defining the lack of decline of intelligence earlier in the life span. We conclude with a summary of John Horn's unique approaches to dealing with common issues. PMID- 26246644 TI - Chlorinated herbicides in fish, birds and mammals in the Baltic Sea. AB - The aim of the present work was to determine the concentration levels, as well as accumulation and magnification coefficients, of triazine derivatives in herring gulls and Baltic grey seals 11 years after a ban on their use in the EU and eight after their exclusion in Poland. Dead birds were collected in the coastal zone of the Gulf of Gdansk in the years 2010-2012. The grey seals, on the other hand, were from before 2007, when s-triazine derivatives were still in use. Triazine herbicides (atrazine, simazine, propazine, terbutrine, prometrone, prometrine and ametrine) were found in the muscles and livers of birds and mammals and also in fish. The obtained results indicated the presence of all the assayed triazines in whole Baltic herring and their livers, while fish muscles were found to be free of prometrone and ametrine. In the muscles and liver of the grey seal, no ametrine, propazine or terbutrine were found, while prometrine was found in the liver of only one specimen. Research showed that simazine did not accumulate and magnify in marine birds and mammals. Atrazine became accumulated in the liver of birds and mammals while magnification was determined in their muscles. The accumulation of ametrine was found in the muscles of seals. PMID- 26246645 TI - HYPOTHESIS TESTING FOR HIGH-DIMENSIONAL SPARSE BINARY REGRESSION. AB - In this paper, we study the detection boundary for minimax hypothesis testing in the context of high-dimensional, sparse binary regression models. Motivated by genetic sequencing association studies for rare variant effects, we investigate the complexity of the hypothesis testing problem when the design matrix is sparse. We observe a new phenomenon in the behavior of detection boundary which does not occur in the case of Gaussian linear regression. We derive the detection boundary as a function of two components: a design matrix sparsity index and signal strength, each of which is a function of the sparsity of the alternative. For any alternative, if the design matrix sparsity index is too high, any test is asymptotically powerless irrespective of the magnitude of signal strength. For binary design matrices with the sparsity index that is not too high, our results are parallel to those in the Gaussian case. In this context, we derive detection boundaries for both dense and sparse regimes. For the dense regime, we show that the generalized likelihood ratio is rate optimal; for the sparse regime, we propose an extended Higher Criticism Test and show it is rate optimal and sharp. We illustrate the finite sample properties of the theoretical results using simulation studies. PMID- 26246646 TI - Modeling Protein Expression and Protein Signaling Pathways. AB - High-throughput functional proteomic technologies provide a way to quantify the expression of proteins of interest. Statistical inference centers on identifying the activation state of proteins and their patterns of molecular interaction formalized as dependence structure. Inference on dependence structure is particularly important when proteins are selected because they are part of a common molecular pathway. In that case, inference on dependence structure reveals properties of the underlying pathway. We propose a probability model that represents molecular interactions at the level of hidden binary latent variables that can be interpreted as indicators for active versus inactive states of the proteins. The proposed approach exploits available expert knowledge about the target pathway to define an informative prior on the hidden conditional dependence structure. An important feature of this prior is that it provides an instrument to explicitly anchor the model space to a set of interactions of interest, favoring a local search approach to model determination. We apply our model to reverse-phase protein array data from a study on acute myeloid leukemia. Our inference identifies relevant subpathways in relation to the unfolding of the biological process under study. PMID- 26246647 TI - Quantification and statistical significance analysis of group separation in NMR based metabonomics studies. AB - Currently, no standard metrics are used to quantify cluster separation in PCA or PLS-DA scores plots for metabonomics studies or to determine if cluster separation is statistically significant. Lack of such measures makes it virtually impossible to compare independent or inter-laboratory studies and can lead to confusion in the metabonomics literature when authors putatively identify metabolites distinguishing classes of samples based on visual and qualitative inspection of scores plots that exhibit marginal separation. While previous papers have addressed quantification of cluster separation in PCA scores plots, none have advocated routine use of a quantitative measure of separation that is supported by a standard and rigorous assessment of whether or not the cluster separation is statistically significant. Here quantification and statistical significance of separation of group centroids in PCA and PLS-DA scores plots are considered. The Mahalanobis distance is used to quantify the distance between group centroids, and the two-sample Hotelling's T2 test is computed for the data, related to an F-statistic, and then an F-test is applied to determine if the cluster separation is statistically significant. We demonstrate the value of this approach using four datasets containing various degrees of separation, ranging from groups that had no apparent visual cluster separation to groups that had no visual cluster overlap. Widespread adoption of such concrete metrics to quantify and evaluate the statistical significance of PCA and PLS-DA cluster separation would help standardize reporting of metabonomics data. PMID- 26246648 TI - Extensive geographic and ontogenetic variation characterizes the trophic ecology of a temperate reef fish on southern California (USA) rocky reefs. AB - Interactions between predator and prey act to shape the structure of ecological communities, and these interactions can differ across space. California sheephead Semicossyphus pulcher are common predators of benthic invertebrates in kelp beds and rocky reefs in southern California, USA. Through gut content and stable isotope (delta13C and ?15N) analyses, we investigated geographic and ontogenetic variation in trophic ecology across 9 populations located at island and mainland sites throughout southern California. We found extensive geographic variation in California sheephead diet composition over small spatial scales. Populations differed in the proportion of sessile filter/suspension feeders or mobile invertebrates in the diet. Spatial variation in diet was highly correlated with other life history and demographic traits (e.g. growth, survivorship, reproductive condition, and energy storage), in addition to proxies of prey availability from community surveys. Multivariate descriptions of the diet from gut contents roughly agreed with the spatial groupings of sites based on stable isotope analysis of both California sheephead and their prey. Ontogenetic changes in diet occurred consistently across populations, despite spatial differences in size structure. As California sheephead increase in size, diets shift from small filter feeders, like bivalves, to larger mobile invertebrates, such as sea urchins. Our results indicate that locations with large California sheephead present, such as many marine reserves, may experience increased predation pressure on sea urchins, which could ultimately affect kelp persistence. PMID- 26246649 TI - Effect of Acting Experience on Emotion Expression and Recognition in Voice: Non Actors Provide Better Stimuli than Expected. AB - Both in the performative arts and in emotion research, professional actors are assumed to be capable of delivering emotions comparable to spontaneous emotional expressions. This study examines the effects of acting training on vocal emotion depiction and recognition. We predicted that professional actors express emotions in a more realistic fashion than non-professional actors. However, professional acting training may lead to a particular speech pattern; this might account for vocal expressions by actors that are less comparable to authentic samples than the ones by non-professional actors. We compared 80 emotional speech tokens from radio interviews with 80 re-enactments by professional and inexperienced actors, respectively. We analyzed recognition accuracies for emotion and authenticity ratings and compared the acoustic structure of the speech tokens. Both play-acted conditions yielded similar recognition accuracies and possessed more variable pitch contours than the spontaneous recordings. However, professional actors exhibited signs of different articulation patterns compared to non-trained speakers. Our results indicate that for emotion research, emotional expressions by professional actors are not better suited than those from non-actors. PMID- 26246650 TI - Elucidating the relation between childhood emotional abuse and depressive symptoms in adulthood: The mediating role of maladaptive interpersonal processes. AB - OBJECTIVE: The purpose of this study is to assess the potential unique and relative mediating effects of three interpersonal risk factors (i.e., excessive reassurance-seeking [ERS], negative feedback seeking [NFS], and rejection sensitivity [RS]) in the relationship between childhood emotional abuse (CEA) and depressive symptoms. METHOD: One hundred eighty-five undergraduates were followed over a four-month interval. Participants completed assessments of childhood abuse history, ERS, NFS, and RS, and depressive symptoms at baseline, as well as depressive symptoms at four-month followup. RESULTS: Findings from single mediator analyses indicated that RS and NFS, but not ERS, mediated the relationship between CEA and prospective depressive symptoms, after accounting for childhood sexual and physical abuse, as well as baseline depressive symptoms. In our multi-mediator model, only RS remained a significant mediator of the relationship between CEA and prospective depressive symptoms. CONCLUSIONS: The current study provides preliminary evidence that negative behavioral styles may function as a mechanism linking prior experiences of CEA to subsequent depressive symptoms. Clinical implications of these findings suggest that targeting maladaptive behavioral tendencies, particularly RS, may be an effective adjunct in behavioral modification treatments of CEA victims at risk for depression. PMID- 26246651 TI - Short-Term Resilience Processes in the Family. AB - The authors review naturalistic studies of short-term processes that appear to promote resilience in children in the context of everyday family life and argue that warm and supportive family interactions foster resilience through their cumulative impact on children's emotional and physiological stress response systems. In the short-term, these family interactions promote the experience and expression of positive emotion and healthy patterns of diurnal cortisol. Over time, these internal resources - a propensity to experience positive emotion and a well-functioning hypothalamic-pituitary-adrenal axis system -enhance a child's capacity to avoid, or limit, the deleterious effects of adversity. This article highlights naturalistic research methods that are well suited to the study of these short-term resilience processes and points to clinical applications of our conceptual and methodological approach. PMID- 26246652 TI - A Bayesian hierarchical model for inference across related reverse phase protein arrays experiments. AB - We consider inference for functional proteomics experiments that record protein activation over time following perturbation under different dose levels of several drugs. The main inference goal is the dependence structure of the selected proteins. A critical challenge is the lack of sufficient data under any one drug and dose level to allow meaningful inference on dependence structure. We propose a hierarchical model to implement the desired inference. The key element of the model is a shared dependence structure on (latent) binary indicators of protein activation. PMID- 26246653 TI - Using image synthesis for multi-channel registration of different image modalities. AB - This paper presents a multi-channel approach for performing registration between magnetic resonance (MR) images with different modalities. In general, a multi channel registration cannot be used when the moving and target images do not have analogous modalities. In this work, we address this limitation by using a random forest regression technique to synthesize the missing modalities from the available ones. This allows a single channel registration between two different modalities to be converted into a multi-channel registration with two mono-modal channels. To validate our approach, two openly available registration algorithms and five cost functions were used to compare the label transfer accuracy of the registration with (and without) our multi-channel synthesis approach. Our results show that the proposed method produced statistically significant improvements in registration accuracy (at an alpha level of 0.001) for both algorithms and all cost functions when compared to a standard multi-modal registration using the same algorithms with mutual information. PMID- 26246654 TI - The Difference between Growth Factor Expression after Single and Multiple Fractures: Preliminary Results in Human Fracture Healing. AB - OBJECTIVES: Circulating levels of VEGF-A (Vascular Endothelia Growth Factor-A), TGF-beta1 (Transforming Growth Factor-beta 1), and M-CSF (Macrophage-Colony Stimulating Factor) were found to be predictors of bone healing and therefore prognostic criteria of delayed bone healing or nonunion. The aim of this study was to evaluate a potential rise of these markers in patients with multiple fractures of long bones compared to patients with single fractured long bone. METHODS: 92 patients were included in the study and finally after excluding all female patients 45 male patients were left for final analysis and divided into the single or multiple fracture group. TGF-beta1, M-CSF, and VEGF-A serum levels were analysed over a time period of two weeks. RESULTS: MCSF serum concentrations were higher in the group with multiple fractures as also TGF-beta1 serum concentrations were at one and two weeks after trauma. No statistically significant difference was observed in the VEGF-A serum concentrations of both groups at either measurement point. CONCLUSION: We did observe a correlation between the quantity of the M-CSF and TGF-beta1 expressions in serum and the number of fractured bones; surprisingly there was no statistically significant difference in the serum levels between patients with single and multiple fractures of long bones. PMID- 26246655 TI - Tactical deception to hide sexual behaviour: macaques use distance, not visibility. AB - Although tactical deception (TD) may be employed to hide sexual behaviour, there is as yet no firm evidence for it. Hiding may be guided by cognitive mechanisms consistent with either no, low or high level TD, such as exploiting male peripheral positions (no TD), creating distance (TD level 1) or hiding behind screens (TD level 1.5 which involves visual perspective taking (VPT)). Macaques are capable of VPT in a food context, suggesting that they may employ TD level 1.5. We investigated, in an observational study with temporarily provided hiding screens, which strategy was used to hide sexual behaviour in captive groups of two macaque species (Macaca mulatta and Macaca fascicularis). Sexual behaviour only sporadically took place near screens, and the few copulations near screens were not systematically hidden from the alpha male, precluding TD level 1.5. Instead, both females and non-alpha males were at a larger distance from the alpha male during sexual interactions than otherwise, consistent with TD level 1. Creating peripheral locations (TD level 1) may be effective in improving sexual opportunities in many species. PMID- 26246656 TI - Conspecific recognition and aggression reduction to familiars in newly weaned, socially plastic mammals. AB - Recognising conspecifics and behaving appropriately towards them is a crucial ability for many species. Grey seals (Halichoerus grypus) show varying capabilities in this regard: mother-pup recognition has been demonstrated in some geographical populations but is absent in others, yet there is evidence that individuals aggregate with prior associates. The recognition capabilities of newly weaned grey seal pups were investigated using class recognition trials within the habituation/dishabituation paradigm. Trials took place in pens, using pairs of individuals that either had previously cohabited (familiar) or that had never met before (stranger). Frequencies of olfactory and visual investigative behaviours ('checks') and aggressive interactions were recorded during trials. Familiar individuals recognised each other: paired strangers showed significantly more checks and aggressive interactions than were seen in trials pairing familiars. Oxytocin concentrations in post-trial plasma samples were analysed to investigate the underlying physiology modulating recognition abilities; however, no significant differences were detected between familiar or stranger trials. This study demonstrates that at a young age, grey seals can recognise individuals they have previously encountered. Recognition abilities in this species have adaptive value by allowing the reduction of costly aggressive interactions between familiar conspecifics, which is often cited as the first step towards the evolution of sociality in a species. This study is the first with wild subjects to find conspecific recognition abilities in a pinniped species outside of reproductive contexts. It demonstrates that even largely solitary species can be capable of recognition and pro-social behaviours that benefit them during times when they must aggregate. PMID- 26246658 TI - Supratracheal laryngectomy: current indications and contraindications. AB - Cancer of the larynx in the intermediate/advanced stage still presents a major challenge in terms of controlling the disease and preserving the organ. Supratracheal partial laryngectomy (STPL) has been described as a function sparing surgical procedure for laryngeal cancer with sub-glottic extension. The aim of the present multi-institutional study was to focus on the indications and contraindications, both local and general, for this type of surgery based on the long-term oncological and functional results. We analysed the clinical outcomes of 142 patients with laryngeal cancer staged pT2-pT4a who underwent STPL. Five year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS) and loco-regional control (LRC) rates were: glottic pT2 [71.4%, 95.2%, 76.0%, 76.0%], glottic-transglottic pT3 [85.3%, 91.1%, 86.4%, 88.7%], and pT4a [73.2%, 88.1%, 52.7%, 60.7%], respectively. DFS and LRC prevalences at 5 years were greatly affected by pT4a staging. Five-year laryngeal function preservation (LFP) and laryngectomy free survival (LFS) were: glottic pT2 [90.9%, 95.2%], glottic-transglottic pT3 [84.4%, 93.1%], and pT4a [63.7%, 75.5%], respectively, being affected by pT staging and age 65 >= years (LFP 54.1%). As a result of Type III open horizontal partial laryngectomies (OPHLs) (supratracheal laryngectomies), the typical subsites of local failure inside the larynx were the mucosa at the passage between the remnant larynx and trachea, the mucosa at the level of the posterior commissure and the contralateral cricoarytenoid unit as well as outside the larynx at the level of the outer surface of the remnant larynx. For patients with glottic or transglottic tumours and with sub-glottic extension, the choice of STPL can be considered to be effective, not only in prognostic terms, but also in terms of functional results. PMID- 26246657 TI - Nimodipine in otolaryngology: from past evidence to clinical perspectives. AB - As L-type voltage-gated calcium channels (VGCCs) control Ca(2+) influx and depolarisation of cardiac and vascular smooth muscle, they represent a specific therapeutic target for calcium channel blockers (CCBs), which are approved and widely used to treat hypertension, myocardial ischaemia and arrhythmias. L-type currents also play a role in calcium entry in the sensory cells of the inner ear. In hair cells of both cochlea and labyrinth, calcium cytoplasmic influx is the first physiological process that activates complex intracellular enzymatic reactions resulting in neurotransmitter release. Excessive calcium ion entry into sensory cells, as a consequence of L-VGCCs malfunction is responsible for over activation of phospholipase A2 and C, protein kinase II and C, nitric oxide synthase and both endonucleases and depolymerases, which can cause membrane damage and cellular death if the cytoplasmic buffering capacity is overcome. Nimodipine, a highly lipophilic 1-4 dihydropyridine that easily crosses the brain blood barrier, is generally used to reduce the severity of neurological deficits resulting from vasospasm in patients with subarachnoid haemorrhage. Moreover, due to its selective blocking activity on L-channel calcium currents, nimodipine is also suggested to be an effective countermeasure for cochlear and vestibular dysfunctions known as channelopathies. Indeed, experimental data in amphibians and mammalians indicate that nimodipine has a stronger efficacy than other CCBs (aminopyridine, nifedipine) on voltage-dependent whole-cell currents within hair cells at rest and it is the only agent that is also effective during their mechanically induced depolarisation. In humans, the efficacy of nimodipine is documented in the medical management of peripheral vestibular vertigo, sensorineural hearing loss and tinnitus, even in a pathology as complex as Meniere's disease. Nimodipine is also considered useful in the prophylaxis of damage to the facial and cochlear nerves caused by ablative surgery of cerebellopontine tumours; it has been recently hypothesised to accelerate functional recovery of recurrent nerve lesions during thyroid cancer surgery. Further trials with adequate study design are needed to test the efficacy of nimodipine in the treatment of vertigo due to cerebrovascular disease and vestibular migraine. PMID- 26246659 TI - A novel approach emphasising intra-operative superficial margin enhancement of head-neck tumours with narrow-band imaging in transoral robotic surgery. AB - The primary goal of surgical oncology is to obtain a tumour resection with disease-free margins. Transoral robotic surgery (TORS) for surgical treatment of head-neck cancer is commensurate with standard treatments. However, the likelihood of positive margins after TORS is up to 20.2% in a recent US survey. The aim of this study is to evaluate the efficacy and the feasibility of narrow band imaging (NBI) during TORS in order to improve the ability to achieve disease free margins during tumour excision. The present study was conducted at the ENT, Head- Neck Surgery and Oral Surgery Unit, Department of Special Surgery, Morgagni Pierantoni Hospital, Azienda USL Romagna. From March 2008 to January 2015, 333 TORS were carried out for malignant and benign diseases. For the present study, we retrospectively evaluated 58 biopsy-proven squamous cell carcinoma patients who underwent TORS procedures. Patients were divided into 2 groups: (1) 32 who underwent TORS and intra-operative NBI evaluation (NBI-TORS); (2) 21 who underwent TORS with standard intra-operative white-light imaging (WLITORS). Frozen section analysis of margins on surgical specimens showed a higher rate of negative superficial lateral margins in the NBI-TORS group compared with the WLI TORS group (87.9% vs. 57.9%, respectively, p = 0.02). The sensitivity and specificity of intra-operative use of NBI, respectively, were 72.5% and 66.7% with a negative predictive value of 87.9%. Tumour margin enhancement provided by NBI associated with magnification and 3-dimensional view of the surgical field might increase the capability to achieve an oncologically-safe resection in challenging anatomical areas where minimal curative resection is strongly recommended for function preservation. PMID- 26246661 TI - Transorbital transnasal endoscopic combined approach to the anterior and middle skull base: a laboratory investigation. AB - Orbital approaches provide significant trajectory to the skull base and are used with differently designed pathways. The aim of this study is to investigate the feasibility of a combined transorbital and transnasal approach to the anterior and middle cranial fossa. Cadaveric dissection of five silicon-injected heads was used. A total of 10 bilateral transorbital approaches and 5 extended endonasal approaches were performed. Identification of surgical landmarks, main anatomical structures, feasibility of a combined approach and reconstruction of the superior orbital defect were examined. Rod lens endoscope (with 0 degrees and 45 degrees lenses) and endoscopic instruments were used to complete the dissection. The transorbital approach showed good versatility and provides the surgeon with a direct route to the anterior and middle cranial fossa. The transorbital avascular plane showed no conflict with major nerves or vessels. Large exposure area from crista galli to the third ventricle was demonstrated with significant control of different neurovascular structures. A combined transorbital transnasal approach provides considerable value in terms of extent of exposure and free hand movement of the two surgeons, and allows better visualisation and control of the ventral skull base, thus overcoming the current surgical limits of a single approach. Combination of these two minimally invasive approaches should reduce overall morbidity. Clinical trials are needed to evaluate the virtual applications of this approach. PMID- 26246660 TI - Salvage surgery in post-chemoradiation laryngeal and hypopharyngeal carcinoma: outcome and review. AB - Our objective was to evaluate recurrence patterns of hypopharyngeal and laryngeal carcinoma after chemoradiation and options for salvage surgery, with special emphasis on elderly patients. In a retrospective study all patients who underwent chemoradiation for hypopharyngeal and laryngeal carcinoma in a tertiary care academic center from 1990 through 2010 were evaluated. Primary outcome measures were the survival and complication rates of patients undergoing salvage surgery, especially in elderly patients. Secondary outcome measures were the predictors for salvage surgery for patients with locoregional recurrence after failed chemoradiotherapy. A review of the literature was performed. Of the 136 included patients, 60 patients had recurrent locoregional disease, of whom 22 underwent salvage surgery. Fifteen patients underwent a total laryngectomy with neck dissection(s) and 7 neck dissection without primary tumour surgery. Independent predictors for salvage surgery within the group of 60 patients with recurrent disease, were age under the median of 59 years (p = 0.036) and larynx vs. hypopharynx (p = 0.002) in multivariate analyses. The complication rate was 68% (14% major and 54% minor), with fistulas in 23% of the patients. Significantly more wound related complications occurred in patients with current excessive alcohol use (p = 0.04). Five-year disease free control rate of 35%, overall survival rate of 27% and disease specific survival rate of 35% were found. For the 38 patients who were not suitable for salvage surgery, median survival was 12 months. Patients in whom the tumour was controlled had a 5-year overall survival of 70%. In patients selected for salvage surgery age was not predictive for complications and survival. In conclusion, at two years follow-up after chemoradiation 40% of the patients were diagnosed with recurrent locoregional disease. One third underwent salvage surgery with 35% 5-year disease specific survival and 14% major complications. Older patients selected for salvage surgery had a similar complication rate and survival as younger patients. PMID- 26246662 TI - Vertigo in childhood: proposal for a diagnostic algorithm based upon clinical experience. AB - The aim of this paper is to analyse, after clinical experience with a series of patients with established diagnoses and review of the literature, all relevant anamnestic features in order to build a simple diagnostic algorithm for vertigo in childhood. This study is a retrospective chart review. A series of 37 children underwent complete clinical and instrumental vestibular examination. Only neurological disorders or genetic diseases represented exclusion criteria. All diagnoses were reviewed after applying the most recent diagnostic guidelines. In our experience, the most common aetiology for dizziness is vestibular migraine (38%), followed by acute labyrinthitis/neuritis (16%) and somatoform vertigo (16%). Benign paroxysmal vertigo was diagnosed in 4 patients (11%) and paroxysmal torticollis was diagnosed in a 1-year-old child. In 8% (3 patients) of cases, the dizziness had a post-traumatic origin: 1 canalolithiasis of the posterior semicircular canal and 2 labyrinthine concussions, respectively. Meniere's disease was diagnosed in 2 cases. A bilateral vestibular failure of unknown origin caused chronic dizziness in 1 patient. In conclusion, this algorithm could represent a good tool for guiding clinical suspicion to correct diagnostic assessment in dizzy children where no neurological findings are detectable. The algorithm has just a few simple steps, based mainly on two aspects to be investigated early: temporal features of vertigo and presence of hearing impairment. A different algorithm has been proposed for cases in which a traumatic origin is suspected. PMID- 26246663 TI - Osseointegrated implants in patients with auricular defects: a case series study. AB - Several surgical solutions have been proposed for reconstruction of the auricle in patients whose ear is missing as a result of a traumatic accident, cancer resection, or a congenital condition. These include insertion of an autogenous rib cartilage framework or a porous polymeric material into an expanded postauricular pocket. Reconstruction with rib cartilage has given good results, but requires more than one surgical step and adverse events can occur at both the donor and acceptor site, while cases of prosthesis rejection have been described following application of polymeric prostheses with the expanded postauricular pocket technique. The use of a titanium dowel-retained silicone prosthetic pinna, fixed to temporal bone, has recently been proposed. This surgical technique is particularly indicated after resection of the pinna in cancer patients and in cases of traumatic auricular injury. Bone-anchored titanium implants provided the 15 patients in this study with a safe, reliable, adhesive-free method of anchoring auricular prostheses. The prostheses allowed recovery of normal appearance and all patients were completely satisfied with their reconstructions. No surgical complications, implant failures, or prosthetic failures were encountered. PMID- 26246665 TI - Mandibular reconstruction using fibula free flap harvested using a customised cutting guide: how we do it. AB - Free fibula flap is routinely used for mandibular reconstructions. For contouring the flap, multiple osteotomies should be shaped to reproduce the native mandibular contour. The bone segments should be fixed using a reconstructive plate. This plate is usually manually bent by the surgeon during surgery. This method is efficient, but during reconstruction it is complicated to reproduce the complex 3D conformation of the mandible and recreate a normal morphology with a mandibular profile as similar as possible to the original; any aberration in its structural alignment may lead to aesthetic and function alterations due to malocclusion or temporomandibular disorders. In order to achieve better morphological and functional outcomes, we have performed a customised flap harvest using cutting guides. This study demonstrates how we have performed customised mandibular reconstruction using CAD-CAM fibular cutting guides in 20 patients undergoing oncological segmental resection. PMID- 26246664 TI - Auricular reconstruction of congenital microtia: personal experience in 225 cases. AB - Microtia is a congenital disease with various degrees of severity, ranging from the presence of rudimentary and malformed vestigial structures to the total absence of the ear (anotia). The complex anatomy of the external ear and the necessity to provide good projection and symmetry make this reconstruction particularly difficult. The aim of this work is to report our surgical technique of microtic ear correction and to analyse the short and long term results. From 2000 to 2013, 210 patients affected by microtia were treated at the Maxillo Facial Surgery Division, Head and Neck Department, University Hospital of Parma. The patient population consisted of 95 women and 115 men, aged from 7 to 49 years. A total of 225 reconstructions have been performed in two surgical stages basing of Firmin's technique with some modifications and refinements. The first stage consists in fabrication and grafting of a three-dimensional costal cartilage framework. The second stage is performed 5-6 months later: the reconstructed ear is raised up and an additional cartilaginous graft is used to increase its projection. A mastoid fascial flap together with a skin graft are then used to protect the cartilage graft. All reconstructions were performed without any major complication. The results have been considered satisfactory by all patients starting from the first surgical step. Low morbidity, the good results obtained and a high rate of patient satisfaction make our protocol an optimal choice for treatment of microtia. The surgeon's experience and postoperative patient care must be considered as essential aspects of treatment. PMID- 26246666 TI - Physiology and prospects of bimanual tracheoesophageal brass instrument play. AB - This study investigated whether trachea pressures during brass instrument play of laryngectomised patients are within the range of those measured during tracheoesophageal voicing, and whether application of an automatic speaking valve can 'free' both hands to play a brass instrument. Objective assessment of voicing and music playing parameters was carried out in 2 laryngectomised patients with a low-pressure indwelling voice-prosthesis able to play brass instruments (tenor horn and slide trombone): sound pressure levels in dB, maximum phonation time in seconds and trachea pressures in mmHg; videofluoroscopy, stroboscopy and digital high speed endoscopy to assess neoglottis vibration and opening. The dynamic range of the voice in the patients was 29 and 20 dB, and maximum phonation time was 22 and 19 sec, respectively; intratracheal pressures during voicing varied from 7 mmHg for the softest /a/ to 49 mmHg for the loudest /a/. For brass instrument play, the intratracheal pressures varied from 14 mmHg for the softest tone to 48 mmHg for the loudest tone. Imaging confirmed earlier findings that the neoglottis is closing and vibrating during voicing and remains 'open' without vibrations during music play, indicating good neoglottis control and innervation. From these objective measurements, we can conclude that trachea pressures during brass instrument play are within physiological ranges for tracheoesophageal voicing with a low-pressure indwelling voice-prosthesis. Furthermore, it was shown that application of a stable baseplate for retaining an automatic speaking valve and an additional customisable 'neck brace' makes bimanual play possible again. PMID- 26246667 TI - Temporo-mandibular joint chondrosarcoma: Case report and review of the literature. AB - Chondrosarcoma is a malignant mesenchymal tumour of cartilaginous origin. It represents 11% of all malignant primary bone tumours, and the pelvis, ribs, femur and humerus are most frequently involved. Chondrosarcoma of the head and neck region is a rare disease, and represents approximately 0.1% of all head and neck neoplasms. This report describes a rare localisation of chondrosarcoma in a 56 year-old man who presented with swelling in the right preauricular area and mild limitation and pain in the mouth opening. Since 1959, just a few cases of temporomandibular joint (TMJ) chondrosarcoma have been described. Computed tomography revealed a large mass (39 x 46 x 40 mm) in the right preauricular and parotid region with morpho-structural alterations of the condyle and an intense periostotic reaction. The tumour was treated by total parotidectomy and condylotomy. The VII cranial nerve was preserved. Histopathologic examination revealed a low grade chondrosarcoma with a 50% proliferation index. At present, the patient is still receiving routine follow-up after radiotherapy and physiotherapy. PMID- 26246668 TI - Audiological findings in a case of cerebellar angioreticuloma. AB - The aetiology of neurosensorial damage with unilateral hearing loss and/or tinnitus and dizziness can often be difficult to determine because they may be caused wide variety of pathologic processes and a variety of diagnostic tests are needed in initial evaluation. In this paper, the authors describe, the techniques and indications of neuroimaging for evaluation of auditory symptoms. Auditory brainstem response (ABR) testing is still the choice when condition is suspected. We present a study of one patient with unilateral tinnitus, with no significant hearing loss and normal ABR: the patient underwent MRI of the district brain and the internal auditory channel (AIC) that showed the presence of a rare intracranial neoplasm, namely cerebellar angioreticuloma. PMID- 26246669 TI - Battling illness with wellness: a qualitative case study of a young rapper's experiences with music therapy. AB - Mental health difficulties are connected with major interpersonal and social challenges. Recent qualitative research indicates that music therapy can facilitate many of the core elements found to promote social recovery and social inclusion, findings also reflected in results from a growing body of effect studies. The objective of this study was to explore how music therapy might afford possibilities for social recovery to one man with psychosis admitted to a psychiatric intensive care unit. This was achieved by means of a qualitative case study featuring a description of the music therapeutic process alongside first hand accounts of the participant's subjective experiences. The data were analysed using interpretative phenomenological analysis (IPA). The findings are presented in a narrative form reflecting processes and activities considered particularly important for the process of social recovery. Theoretical perspectives from the recovery literature and current perspectives in music therapy are discussed with a view to the possible use of music therapy for strengthening agency, (re)building identity, developing positive relationships, and expanding social networks. PMID- 26246670 TI - The development of Music in Dementia Assessment Scales (MiDAS). AB - There is a need to develop an outcome measure specific to music therapy in dementia that reflects a holistic picture of the therapy process and outcome. This study aimed to develop a clinically relevant and scientifically robust music therapy outcome measure incorporating the values and views of people with dementia. Focus groups and interviews were conducted to obtain qualitative data on what music meant to people with dementia and the observed effects of music. Expert and peer consultations were conducted at each stage of the measure development to maximise its content validity. The new measure was field-tested by clinicians in a care home. Feedback from the clinicians and music therapy experts were incorporated during the review and refinement process of the measure. A review of the existing literature, the experiential results and the consensus process enabled the development of the new outcome measure "Music in Dementia Assessment Scales (MiDAS)". Analysis of the qualitative data identified five key areas of the impact of music on people with dementia and they were transformed as the five Visual Analogue Scale (VAS) items: levels of Interest, Response, Initiation, Involvement and Enjoyment. MiDAS comprises the five VAS items and a supplementary checklist of notable positive and negative reactions from the individual. This study demonstrates that it is possible to design and develop an easy to apply and rigorous quantitative outcome measure which has a high level of clinical relevance for people with dementia, care home staff and music therapists. PMID- 26246671 TI - Identification and Prevention: Underutilized Tools in Diabetes Treatment? PMID- 26246672 TI - SGLT-2 Inhibitors: A New Mechanism for Glycemic Control. AB - Glucosuria, the presence of glucose in the urine, has long been regarded as a consequence of uncontrolled diabetes. However, glucose excretion can be induced by blocking the activity of the renal sodium-glucose cotransporter 2 (SGLT-2). This mechanism corrects hyperglycemia independently of insulin. This article provides an overview of the paradigm shift that triggered the development of the SGLT-2 inhibitor class of agents and summarizes the available evidence from clinical studies to date. PMID- 26246673 TI - Older Adults' Perceived Challenges With Health Care Providers Treating Their Type 2 Diabetes and Comorbid Conditions. AB - Type 2 diabetes and comorbidity represent serious health problems to the aging population. This qualitative study aimed to describe older adults' perceived challenges with providers treating their type 2 diabetes and other chronic conditions. Older adults perceived a general unwillingness from their providers to treat their multiple health conditions and address their individual preferences for care. Older adults may require more in-depth communication with their providers in addition to individualized treatment plans that address their preferences for comorbidity management. PMID- 26246674 TI - Impact of Performance-Improvement Strategies on the Clinical Care and Outcomes of Patients With Type 2 Diabetes. PMID- 26246675 TI - Abdominal Pain and Weight Loss in New-Onset Type 1 Diabetes. PMID- 26246676 TI - Respiratory Failure in the Course of Treatment of Diabetic Ketoacidosis. PMID- 26246677 TI - Optimizing the Care of Patients With Type 2 Diabetes Using Incretin-Based Therapy: Focus on GLP-1 Receptor Agonists. PMID- 26246678 TI - Workplace Checkup: Keeping Patients With Diabetes Employed and Safe on the Job. PMID- 26246679 TI - Continuing Educational Inertia? PMID- 26246680 TI - Evaluation of Ward Management of Diabetic Ketoacidosis. AB - Ward management of diabetic ketoacidosis (DKA) using subcutaneous insulin in specific patient populations is safe and effective, but insulin administered by continuous infusion has not been analyzed in this setting. This retrospective cohort study utilizing a nursing-driven, continuous infusion insulin calculator demonstrated safe and effective treatment of patients with DKA on medicine wards. PMID- 26246681 TI - Dietary Sodium Intake in Type 2 Diabetes. AB - Patients with type 2 diabetes have an increased risk for cardiovascular and chronic kidney disease. Superimposed hypertension further increases the risk and is associated with increased dietary sodium intake. There are few data available on dietary sodium intake in type 2 diabetes. The aim of this study was to quantify dietary sodium intake in a cohort of self-referred patients with type 2 diabetes and to identify sociodemographic characteristics associated with it. Sodium intake in this cohort was far greater than current recommendations. Increased awareness of sodium intake in this population might lead to target interventions to reduce sodium intake and potentially improve long-term outcomes. PMID- 26246682 TI - Evaluating Diabetes Outcomes and Costs Within an Ambulatory Setting: A Strategic Approach Utilizing a Clinical Decision Support System. PMID- 26246683 TI - Play of Chance Versus Concerns Regarding Dipeptidyl Peptidase-4 Inhibitors: Heart Failure and Diabetes. PMID- 26246684 TI - A Case of Skin, and Secondarily Generalized, Reaction to Insulin Injection. PMID- 26246685 TI - Severe Hypertriglyceridemia Causing High Anion Gap Metabolic Acidosis in a Patient With Severe Insulin Resistance. PMID- 26246686 TI - An Evaluation of the Current Type 2 Diabetes Guidelines: Where They Converge and Diverge. PMID- 26246687 TI - Socioecological Determinants of Prediabetes and Type 2 Diabetes: Agenda for Action. PMID- 26246688 TI - The Season for Plums ... and for Laser and Light-Based Device Meetings. PMID- 26246689 TI - Effect of Er: YAG or Nd:YAG Laser Exposure on Fluorosed and Non-Fluorosed Root Surfaces: An In Vitro Study. AB - BACKGROUND AND AIMS: Fluorosis affects tooth mineralization. The therapeutic benefit provided by lasers on fluorosed and non fluorosed cementum requires studying and comparing. The aim of this study was to evaluate and compare the root surface changes following Er:YAG or Nd:YAG laser irradiation on periodontally healthy fluorosed versus non-fluorosed teeth by scanning electron microscopy (SEM). MATERIALS AND METHODS: A total of 76 periodontally healthy fluorosed (FH) and non-fluorosed (NFH) teeth specimens were included in this study. In one group, the experimental root specimens were irradiated using Er:YAG or with Nd:YAG laser in the other. A SEM evaluation was performed to assess the laser induced ultra structural changes in the root surface followed by statistical analysis using Fisher's exact test. RESULTS: It was observed that both FH and NFH groups were similarly affected by Nd:YAG or Er:YAG laser. However, the former caused more surface changes than the latter on melting of surface (p=0.12 for FH and p=0.08 for NFH), and Er:YAG laser caused more smear layer formation (p=0.51 for FH and p=0.16 for NFH). CONCLUSION: RESULTS suggest that undesirable morphological changes were observed almost similarly in FH and NFH groups using Er:YAG or Nd:YAG laser. Hence further in-vitro studies at lower energy settings followed by clinical trials are required in this aspect. PMID- 26246690 TI - Lethal effect of blue light-activated hydrogen peroxide, curcumin and erythrosine as potential oral photosensitizers on the viability of Porphyromonas gingivalis and Fusobacterium nucleatum. AB - OBJECTIVES: Recently, photodynamic therapy (PDT) has been introduced as a new modality in oral bacterial decontamination. Current research aims to evaluate the effect of photodynamic killing of visible blue light in the presence of hydrogen peroxide, curcumin and erythrosine as potential oral photosensitizers on Porphyromonas gingivalis associated with periodontal bone loss and Fusobacterium nucleatum associated with soft tissue inflammation. MATERIALS AND METHODS: Standard suspension of P. gingivalis and F. nucleatum were exposed to Light Emitting Diode (LED) (440-480 nm) in combination with erythrosine (22 um), curcumin (60 uM) and hydrogen peroxide (0.3 mM) for 5 min. Bacterial samples from each treatment groups (radiation-only group, photosensitizer-only group and blue light-activated photosensitizer group) were subcultured onto the surface of agar plates. Survival of these bacteria was determined by counting the number of colony forming units (CFU) after incubation. RESULTS: RESULTS for antibacterial assays on P. gingivalis confirmed that curcumin, Hydrogen peroxide and erythrosine alone exerted a moderate bactericidal effect which enhanced noticeably in conjugation with visible light. The survival rate of P. gingivalis reached zero present when the suspension exposed to blue light-activated curcumin and hydrogen peroxide for 2 min. Besides, curcumin exerted a remarkable antibacterial activity against F. nucleatum in comparison with erythrosine and hydrogen peroxide (P=0.00). Furthermore, the bactericidal effect of visible light alone on P. gingivalis as black-pigmented bacteria was significant. CONCLUSION: Our result suggested that visible blue light in the presence of erythrosine, curcumin and hydrogen peroxide would be consider as a potential approach of PDT to kill the main gramnegative periodontal pathogens. From a clinical standpoint, this regimen could be established as an additional minimally invasive antibacterial treatment of plaque induced periodontal pathologies. PMID- 26246691 TI - Management of a soft tissue tumor in a child with Worster Drought syndrome using 810 nm diode laser - A case report. AB - BACKGROUND AND AIMS: An out-patient surgical procedure in the paediatric age group is a tough task for a surgeon, more so when compounded with mentally challenging conditions like cerebral palsy. Every step involved, either administration of local anaesthesia or handling sharp surgical instruments around the face or achieving haemostasis, can be a challenge, with compromise on patient safety. Neither undue restraint nor general anaesthesia is advisable, considering the magnitude of the procedure. In such cases, a safe, rapid and effective technique that can be comfortably performed under topical anaesthesia without use of sharp instruments or needles would be an ideal option. The purpose of this paper is to highlight one such situation, where an intra-oral soft tissue tumor was safely and effectively ablated using diode laser, under topical anaesthesia in a child with cerebral palsy concurrent with Worster Drought syndrome. RESULTS: Topical anaesthesia provided adequate conditions to ablate the tumor. A bloodless field was achieved, with no need for sutures. The procedure was completed in less than half the time required for a conventional approach. Postoperative follow-up of 3 months showed complete healing with no recurrence. CONCLUSIONS: Portable diode lasers are an effective tool for minor oral surgical procedures in paediatric population especially, children who are mentally challenged. PMID- 26246692 TI - Changes of Motivational Variables in Patients with Multiple Sclerosis in an Exercise Intervention: Associations between Physical Performance and Motivational Determinants. AB - OBJECTIVES: This study examines the effects of a standardized fitness training on motivational factors such as the intention to be physically active, self efficacy, perceived barriers, counterstrategies, and exercise specific social support in patients with progressive Multiple Sclerosis (MS) and the relation of these factors to physical performance. METHODS: Moderately disabled patients with secondary or primary progressive MS (Expanded Disability Status Scale of 4-6) were randomized to a training group or a waitlist control group. Patients completed on average 20 sessions of training tailored to their individual fitness at baseline over a course of 8-12 weeks. Motivational variables (stage of change according to the transtheoretical model (TTM), self-efficacy, perceived barriers, counterstrategies, and exercise specific social support) were assessed via questionnaires at baseline and follow-up. RESULTS: Forty patients completed the trial. We found significant effects on stages of change (p = .016) and self efficacy (p = .014) and a trend in counterstrategies (p = .08). Significant correlations between change of physical performance during the exercise training and change in the TTM, perceived barriers, and counterstrategies were detected. CONCLUSION: This study indicates that tailored individual endurance training could stabilize self-efficacy and increase exercise motivation in patients with progressive MS. Motivational variables were related to the physical performance. PMID- 26246693 TI - Processing Sentences with Literal versus Figurative Use of Verbs: An ERP Study with Children with Language Impairments, Nonverbal Impairments, and Typical Development. AB - Forty native Italian children (age 6-15) performed a sentence plausibility judgment task. ERP recordings were available for 12 children with specific language impairment (SLI), 11 children with nonverbal learning disabilities (NVLD), and 13 control children. Participants listened to verb-object combinations and judged them as acceptable or unacceptable. Stimuli belonged to four conditions, where concreteness and congruency were manipulated. All groups made more errors responding to abstract and to congruent sentences. Moreover, SLI participants performed worse than NVLD participants with abstract sentences. ERPs were analyzed in the time window 300-500 ms. SLI children show atypical, reversed effects of concreteness and congruence as compared to control and NVLD children, respectively. The results suggest that linguistic impairments disrupt abstract language processing more than visual-motor impairments. Moreover, ROI and SPM analyses of ERPs point to a predominant involvement of the left rather than the right hemisphere in the comprehension of figurative expressions. PMID- 26246694 TI - Rehabilitation Outcomes: Ischemic versus Hemorrhagic Strokes. AB - Background. Ischemic and hemorrhagic strokes have different pathophysiologies and possibly different long-term cerebral and functional implications. Hemorrhagic strokes expose the brain to irritating effects of blood and ischemic strokes reflect localized or diffuse cerebral vascular pathology. Methods. Participants were individuals who suffered either an ischemic (n = 172) or hemorrhagic stroke (n = 112) within the past six months and were involved in a postacute neurorehabilitation program. Participants completed three months of postacute neurorehabilitation and the Mayo Portland Adaptability Inventory-4 (MPAI-4) at admission and discharge. Admission MPAI-4 scores and level of functioning were comparable. Results. Group ANOVA comparisons show no significant group differences at admission or discharge or difference in change scores. Both groups showed considerably reduced levels of productivity/employment after discharge as compared to preinjury levels. Conclusions. Though the pathophysiology of these types of strokes is different, both ultimately result in ischemic injuries, possibly accounting for lack of findings of differences between groups. In the present study, participants in both groups experienced similar functional levels across all three MPAI-4 domains both at admission and discharge. Limitations of this study include a highly educated sample and few outcome measures. PMID- 26246696 TI - Basic Physics Revisited for a Surgeon. PMID- 26246695 TI - Association of Inflammation with Metabolic Syndrome among Low-Income Rural Kazakh and Uyghur Adults in Far Western China. AB - This study focused on low-income rural and nomadic minority people residing in China's far west and investigated their relationship between inflammatory markers (IL-6, hsCRP, FFA, and adiponectin) and MS and ethnic differences. And it found that improving behavioral lifestyle by education or using drugs to control inflammation may prevent MS. These observations may benefit low-income populations. PMID- 26246697 TI - In Vivo Healing Effects of Ankaferd Blood Stopper on the Residual Pancreatic Tissue in a Swine Model of Distal Pancreatectomy. AB - The aim of this study was to determine whether intraoperative Ankaferd blood stopper (ABS) application into the pancreatic channel and to the pancreatic remnant surface following distal pancreatectomy can or cannot prevent postoperative pancreatic fistula formation. Three pigs underwent distal pancreatectomy under general anesthesia. In two of the pigs, 0.5 ml of ABS was applied to the stump surface area after adding 0.5 ml of ABS into the pancreatic channel. The remaining one animal served as the control. The pigs were sacrificed on the seventh postoperative day for autopsy. The pancreatic remnants from the animals were then taken for histopathological analyses. It was observed that the oral intake had been broken and abdominal distention had developed in the control pig following on the third postoperative day. However, no significant clinical changes were observed in the ABS-applied pigs. In the autopsy, it was found that the control pig had generalized peritonitis with pancreatic necrosis. On the other hand, the ABS-applied pigs had either macroscopically and microscopically normal pancreatic tissue architecture with an occluded Wirsung duct at the pancreatic stump. It was concluded that application of ABS on the transected surface and into the pancreatic channel could prevent pancreatic fistula formation and improve wound healing in the residual pancreatic tissue following distal pancreatectomy. PMID- 26246698 TI - Study of Surgical Emergencies of Tubercular Abdomen in Developing Countries. AB - To study the various modes of presentation, diagnosis, and management of surgical emergencies of tubercular abdomen. This prospective study of surgical emergencies of tubercular abdomen was conducted in 50 patients who attended our surgical emergency from 2006 to 2008. Patients were evaluated thoroughly with history, physical examination, routine investigations, and special investigations such as ELISA, PCR, barium studies of gastrointestinal tract, and diagnostic laparoscopy as required and managed with medical and surgical treatment as necessary. The most of patients were from rural areas, in the third to sixth decades with slight male preponderance. Abdominal pain, vomiting, and constipation were commonest presenting symptoms. About 20 % patients had history of pulmonary tuberculosis and 16 % patients presented with ascites. PCR for blood and ascitic fluid was positive in 72 and 87.5 % patients, respectively. About 24 % patients were managed nonoperatively and responded to ATT. About 76 % patients needed surgery among which one-fifth of patients were operated in emergency. Procedures like adhesiolysis of gut (47.3 %), strictureplasty (10.5 %), resection anastomosis (5.2 %), right hemicolectomy (5.2 %), and ileotransverse anastomosis (7.8 %) were performed in 30 patients and peritoneal biopsy and lymph node biopsy in the remaining 8 patients. Both medically and surgically managed patients were put on antitubercular therapy. Abdominal tuberculosis is a disease of middle-aged rural people, presenting commonly with abdominal pain and vomiting with right lower abdominal tenderness. PCR (blood and ascites) for tuberculosis is much more sensitive than IgM ELISA (blood and ascites). The most of patients required surgical procedures and all patients responded dramatically to antitubercular therapy symptomatically with increase in the hemoglobin level and decrease in ESR. PMID- 26246699 TI - Outcome Assessment of Operative Treatment of Humeral Shaft Fractures by Antegrade Unreamed Humeral Nailing (UHN). AB - The purpose of this study was to assess the outcome of humeral shaft fractures treated with Unreamed Humeral Nailing (UHN) system. Fixation of the humeral shaft fractures in this study was performed by minimal incision UHN system, without using its distal locking properties. Forty one patients were treated this way. Functional status of shoulder and elbow were evaluated using Society of the American Shoulder and Elbow Surgery (SASES) scoring system. During follow up period, no superficial or deep infections were observed. Mean union time was 13 weeks. Shoulder and elbow functions using SASES scale were excellent or good in 93 % of the patients. Complications included delayed union in 3(7.3 %), nonunion in 2(4.8 %) and radial nerve palsy in 1(2.4 %). Antegrade unreamed humeral Nailing is an acceptable, safe and reliable treatment for humeral shaft fractures. PMID- 26246700 TI - Evaluation of Injuries Caused by Penetrating Chest Traumas in Patients Referred to the Emergency Room. AB - The aim of the study was to determine the frequency of different injuries caused by penetrating chest traumas, and also the cause and type of trauma and its accompanying injuries. This is a cross-sectional descriptive study, carried out on all patients referred to the emergency room of Shahid Bahonar Hospital, Kerman, from March 2000 to September 2008, due to penetrating chest trauma. The required information including age, sex, cause of trauma, type and site of injury, and accompanying injury was obtained and used to fill out a questionnaire and then was analyzed. 828 patients were included in the study; most of them were in the age range of 20-29. Of the patients, 97.6 % were males. The most frequent cause of trauma was stabbing, and the most frequent injuries following the trauma were pneumothorax and hemothorax. Orthopedic trauma was the most frequent accompanying injury. The most commonly used diagnostic method was plain chest radiography. In 93 % of the patients, the chest tube was placed and thoracotomy was performed for 97 % of the patients. Shahid Bahonar Hospital is a referral Trauma Centre and treats large number of chest trauma patients. Most patients need only chest tube placement as a definitive treatment. PMID- 26246701 TI - Urgent Redo-Laparotomies: Patterns and Outcome-A Single Centre Experience. AB - A proportion of the operations performed in a surgical gastroenterology department are unplanned repeat laparotomies for complications of the original procedure. We examined why, in our department, these 'redo' laparotomies were performed and what was their outcome. We retrospectively analyzed 6530 patients operated between September 1996 - December 2010, of these 257 redo laparotomies were performed in 193(2.5 %) patients. There were 138 males and 55 females who had a mean age of 42 years (range 7-68 years). Eighty one (42 %) of the index surgeries were elective and 112 (58 %) performed in the emergency situation. Pancreas was the commonest organ for the index operation {50 (25.9 %)}, followed by the colon and rectum {45 (23.3 %)} and the small bowel {36 (18.7 %)}. Postoperative bleeding was the most common cause for re-exploration 66 (34.2 %) followed by an abscess or fluid collection that required surgical drainage 57 (29.6 %). The mortality rate after redo laparotomies was 33.2 % with sepsis and multi-organ failure being the commonest cause of death. Urgent redo-laparotomies that are performed following complicated abdominal operations have a high mortality rate. Postoperative bleeding, intrabdominal abscess and peritonitis are the commonest cause for redo-laparotomy. Multiple redolaparotomies and associated co-morbid conditions are significant predictors of mortality. PMID- 26246702 TI - DACH1 Expresison in Osteosarcoma and Its Relationship with Proliferation and Angiogenesis. AB - The aim of this study was to investigate the expression of DACH1 in osteosarcoma as well as its relationship with cell proliferation and angiogenesis in the tumor. DACH1 expression was detected by immunohistochemical staining in the serial sections of the osteosarcoma. The microvessel density (MVD) was counted by CD34 immunohistochemical staining, and immunohistochemical staining of PCNA staining showed the cell proliferation. The impacts of DACH1 expression on tumor proliferation and angiogenesis were evaluated by statistics. The DACH1 had different expression patterns in different osteosarcoma. Conventional osteosarcoma showed stronger DACH1 staining (conventional vs. parosteal: P = 0.037; conventional vs. periosteal: P = 0.028) and more PCNA-positive tumor cells than parosteal and periosteal osteosarcoma (conventional vs. parosteal: P = 0.041; conventional vs. periosteal: P = 0.045), the difference was significant. In addition, conventional osteosarcoma showed more cytoplasmic staining of DACH1 than parosteal and periosteal (conventional vs. parosteal: P = 0.023; conventional vs. periosteal: P = 0.030). Parosteal and periosteal osteosarcoma showed no significant difference in DACH1 expression and cell proliferation index. On the other hand, DACH1 different expression patterns showed significantly different impacts on angiogenesis. In spite of the different subtypes of osteosarcoma, the MVD showed a significant difference in cytoplasmic and nuclear expression patterns of DACH1 (nuclear expression vs. cytoplasmic expression: 5.72 +/- 1.19 vs. 9.65 +/- 1.24, P = 0.042). Moreover, in the conventional osteosarcoma, the MVD also showed a significant difference in DACH1 cytoplasmic and nuclear staining (nuclear expression vs. cytoplasmic expression: 5.58 +/- 0.71 vs. 13.65 +/- 1.30, P = 0.019). However, the DACH1 expression intensity showed no significant different impacts on MVD of all kinds of osteosarcoma. DACH1 had different expression patterns and intensity. Cytoplasmic and nuclear expression of DACH1 might play different roles in cell proliferation and angiogenesis of osteosarcoma. Cytoplasmic DACH1 might promote cell proliferation and be associated with angiogenesis. PMID- 26246704 TI - HandPort Laparoscopic Surgery-Review and Current Status. AB - HandPort laparoscopic surgery is a hybrid operation that allows the surgeon to introduce his nondominant hand into abdominal cavity through the port while maintaining pneumoperitoneum. It also helps to gain experience and expertise to learn advanced laparoscopic procedures. The common surgeries where HandPort is useful are laparoscopic splenectomy, colectomies, and donor nephrectomies. HandPort facilitates dissection and extraction of specimens. Hand in abdomen restores tactile sensation which is lacking in laparoscopic procedures. It reduces operative time, increases technical expertise of surgeon, and decreases blood loss. This article reviews the current status of HandPort laparoscopic surgery, the various HandPort devices, and their use. PMID- 26246703 TI - Risk Assessment Tool for Pressure Ulcer Development in Indian Surgical Wards. AB - The aims of this paper were to compare the predictive validity of three pressure ulcer (PU) risk scales-the Norton scale, the Braden scale, and the Waterlow scale and to choose the most appropriate calculator for predicting PU risk in surgical wards of India. This is an observational prospective cohort study in a tertiary educational hospital in New Delhi among 100 surgical ward patients from April to July 2011. The main outcomes measured included sensitivity, specificity, positive predictive value (PVP) and negative predictive value (PVN), and the area under the curve of the receiver operating characteristic (ROC) curve of the three PU risk assessment scales. Based on the cutoff points found most appropriate in this study, the sensitivity, specificity, PVP, and PVN were as follows: the Norton scale (cutoff, 16) had the values of 95.6, 93.5, 44.8, and 98.6, respectively; the Braden scale (cutoff, 17) had values of 100, 89.6, 42.5, and 100, respectively; and the Waterlow scale (cutoff, 11) had 91.3, 84.4, 38.8, and 97, respectively. According to the ROC curve, the Norton scale is the most appropriate tool. Factors such as physical condition, activity, mobility, body mass index (BMI), nutrition, friction, and shear are extremely significant in determining risk of PU development (p < 0.0001). The Norton scale is most effective in predicting PU risk in Indian surgical wards. BMI, mobility, activity, nutrition, friction, and shear are the most significant factors in Indian surgical ward settings with necessity for future comparison with established scales. PMID- 26246705 TI - Persistent Mullerian Duct Syndrome (PMDS): a Rare Anomaly the General Surgeon Must Know About. AB - Persistent Mullerian duct syndrome is a rare condition occasionally encountered in men with normal phenotype but with presence of Mullerian duct structures. In India, owing to neglect and lack of facilities, we encounter this condition in adult males. We encountered on the same day in the operation theatre two phenotypic males aged 40 years and 10 months who had inguinal hernia on one side along with contralateral undescended testis. Both patients intraoperatively had uterus with fallopian tubes and underwent subtotal hysterectomy with preservation of vas. Repair of inguinal hernia with fixation of the testis in the scrotum was done. Though rare, every surgeon operating upon inguinal hernia or undescended testes or cryptorchidism needs to know about the presence of the uterus in a phenotypic male patient at any age. High degree of suspicion and awareness is needed to diagnose this condition. Early treatment is needed to maintain fertility and to prevent the occurrence of malignancy in remnant mullerian structures. PMID- 26246706 TI - Are Nephroenteric Fistulas Only a Surgical Trouble? AB - Nephroenteric fistulas can be secondary to different etiologies, the most common of which are pyelocolic fistulas. The absence of pathognomonic symptoms and the heterogeneity of presentation can sometimes result in a delay in diagnosis. We report on three cases: a pyelo-duodenal fistula secondary to kidney stones and subsequent pyonephrosis, a pyelocolic fistula due to inveterate ureteral stones with hydropyonephrosis, and a rare case of posttraumatic pyelocolic fistula. All patients were treated with radical nephrectomy and resection of the involved intestinal tract. Fistulas of the kidney with the gastrointestinal tract are complex not only for the surgical treatment, which is mandatory in the majority of cases, but also for clinical and instrumental diagnosis. Severe infection is a major concern due to the admixture of the enteric bacterial flora with the urinary tract. Nephroenteric fistulas require skilled surgical procedures, close control of the septic risk, management of patient's overall medical condition, and balance between invasive and conservative approach. PMID- 26246707 TI - Acinar Cell Carcinoma of the Pancreas: A Literature Review and Update. AB - Pancreatic acinar cell carcinoma is a rare tumour, accounting for only about 1 % of all pancreatic tumours. The long-term survival for patients with acinar cell carcinoma is significantly better than the long-term survival of patients with pancreatic adenocarcinoma. As no large series of patients with acinar cell carcinomas exist, our understanding of this disease comes mainly from small case series and case reports. Aggressive surgical resection with negative margins is associated with long-term survival in these more favourable pancreatic cancers. There are no clear treatment guidelines for patients in whom complete surgical resection with curative intent is not possible. Acinar cell carcinomas are chemoresponsive to agents that have activity against pancreatic adenocarcinomas and colorectal carcinomas because of the shared genetic alterations between these cancers. The role of neoadjuvant or adjuvant chemoradiotherapy remains unproven. The aim of this article is to present current knowledge on acinar cell carcinoma and comprehensive review of available literature. PMID- 26246708 TI - Anastomotic Recurrence of Colon Cancer-is it a Local Recurrence, a Second Primary, or a Metastatic Disease (Local Manifestation of Systemic Disease)? AB - The aim of this study is to review the literature to find out the exact etiology of anastomotic cancers of colon post resection and differentiate them between a recurrence, second primary, and metastatic disease (local manifestation of systemic disease). Web-based literature search was done, and datas collected. We searched PubMed for papers using the keywords colon cancer recurrence, anastomotic recurrence, and recurrent colon carcinoma. We also searched for systematic review in the same topic. In addition, we used our personal referrence archive. Anastomotic recurrences of colon are postulated to arise due to inadequate margins, tumor implantation by exfoliated cells, altered biological properties of bowel anastomosis, and missed synchronous lesions. Some tumors are unique with repeated recurrence after repeated resection. Duration after primary surgery plays a major role in differentiating recurrent and second primary lesions. Repeated recurrences after repeated resections have to be considered a manifestation of systemic disease or metastatic disease due to the virulence of the disease. A detailed analysis and study of patients with colonic anastomotic lesion are required to differentiate it between a recurrent, a second primary lesion, and a metastatic disease (local manifestation of a systemic disease). The nomenclature is significant to study the survival of these patients, as a second primary lesion will have different survival compared to that of recurrent lesions. PMID- 26246709 TI - Large Recurrent Phyllodes Tumour. AB - This is a case report of 45-year-old woman with recurrent phyllodes tumour. Although these tumours are not very rare and one finds them occasionally in day to-day practice, we report here a case of recurrent phyllodes tumour that was treated by a simple mastectomy 1 year back, and it recurred very fast and attained enormous dimensions without any local ulceration. PMID- 26246710 TI - Unilateral Amazia. AB - Amazia refers to a condition where one or both of the mammary glands are absent in which the nipple and areola remain present, breast parenchyma is absent, and it may be unilateral or bilateral. We present a case of unilateral amazia. On literature review, very few cases were reported. PMID- 26246711 TI - Lethal Bubbles. AB - The present paper reports the case of a hyperacute gaseous gangrene diffuse to the whole body. PMID- 26246712 TI - Posterior Sagittal Mesh Rectopexy (PSMR) and Anal Encirclement with Polypropylene Mesh for Correction of Complete Rectal Prolapse-a New Application. AB - The posterior sagittal route is utilized as an alternative to the abdominal and perineal routes for the operation of a complete rectal prolapse (syn. procidentia). A mesh is interposed between the rectum and sacrum. The mesh also acts as a sling suspended from the sacrum. The levator muscle is repaired from behind. Anal encirclement is made to correct a patulous anus. PMID- 26246713 TI - Contralateral Spinal Accessory Nerve Transfer: A New Technique in Panavulsive Brachial Plexus Palsy. AB - Brachial plexus avulsion results from excessive stretching and can occur secondary to motor vehicle accidents, mainly in motorcyclists. In a 28-year-old man with panavulsive brachial plexus palsy, we describe an alternative technique to repair brachial plexus avulsion and to stabilize and preserve shoulder function by transferring the contralateral spinal accessory nerve to the suprascapular nerve. We observed positive clinical and electromyographic results in sternocleidomastoid, trapezius, supraspinatus, infraspinatus, pectoralis, triceps, and biceps, with good outcome and prognosis for shoulder function at 12 months after surgery. This technique provides a unique opportunity for patients suffering from severe brachial plexus injuries and lacking enough donor nerves to obtain shoulder stability and mobility while avoiding bone fusion and preserving functionality of the contralateral shoulder with favorable postoperative outcomes. PMID- 26246714 TI - Contraindication and End Point of Gastrografin Trial in Adhesive Small Bowel Obstruction. AB - It is important to know the contraindication and end point of Gastrografin trial in adhesive small bowel obstruction. PMID- 26246715 TI - Accidental Intra-arterial Cannulation: an Unusual Case. PMID- 26246716 TI - Three statistical experimental designs for enhancing yield of active compounds from herbal medicines and anti-motion sickness bioactivity. AB - BACKGROUND: Since antiquity, Zingiber officinale (ginger), pogostemonis herba, and radix aucklandiae have been used as traditional Chinese medicines to remit gastrointestinal discomfort. Recent evidences also show the efficacy of the three herbal medicines against nausea and vomiting. OBJECTIVE: To optimize the CO2 supercritical fluid extraction (SFE-CO2) conditions for ginger and the ethanol reflux extraction conditions for radix aucklandiae, control the quality of pogostemonis herba essential oil, and evaluate anti-motion sickness activity of the compound recipes composed of the three herbal medicine extracts. MATERIALS AND METHODS: Two orthogonal array designs L9 (3)(4) were employed to optimize the SFE-CO2 conditions for enhancing yield of 6-gingerol from ginger and the ethanol reflux extraction conditions for enhancing yield of costunolide and dehydrocostus lactone from radix aucklandiae; a uniform design U5(5(3)) was applied for evaluation of anti-motion sickness activity of the compound recipes. RESULTS: Extraction pressure (P < 0.01), extraction temperature and extraction time (P < 0.05) have significant effects on the yield of 6-gingerol from ginger by SFE-CO2; ethanol concentration (P < 0.01) and times of repeating extraction (P < 0.05) have significant effects on the total yield of costunolide and dehydrocostus lactone from radix aucklandiae by ethanol reflux extraction; the anti-motion sickness effects of the optimized compound recipe composed of the three herbal medicine extracts were markedly better than those of dimenhydrinate. CONCLUSION: The compound recipe composed of ginger, pogostemonis herba, and radix aucklandiae could be developed as a promising anti-motion sickness medicine. PMID- 26246717 TI - Purification and characterization of an anticoagulant oligopeptide from Whitmania pigra Whitman. AB - BACKGROUND: Dried Whitmania pigra is used for the treatment of cardiovascular and cerebrovascular diseases in traditional Chinese medicine and hot water and alcohol extracts also have anticogulant activity. However, a lower molecular weight and more stable anticogulant is needed. OBJECTIVE: The objective of the following study is to purify and characterize of an anticoagulant oligopeptide from Hirudo (Whitmania pigra Whitman). MATERIALS AND METHODS: Gel filtration on Sephadex G-50, ion exchange on diethylaminoethyl-cellulose, and semi-prepared high-performance liquid chromatography were used to purify Hirudo. Automated coagulation analyzer was used for evaluating anticoagulant activity. Molecular weight was measured by Matrix-assisted laser desorption ionization time of flight mass spectrometry. Amino acid sequence of the oligopeptide was measured by amino acid sequence analyzer. RESULTS: A new anticoagulant, named whitide, isolated from Hirudo was purified, with a molecular weight 1997.1 Da. Amino acid sequence of the oligopeptide was identified as Gly-Pro-ALa-Gly-Hyp-Val-Gly-Ala-Hyp-Gly-Gly Hyp-Gly-Val-Arg-Gly-Leu-Hyp-Gly-Asp-Arg-Gly. The results revealed that its amino acid sequence had strong homology to various types of collagen. CONCLUSION: Whitide might be an orally anticoagulant for its hot and trypsin stable. PMID- 26246718 TI - Anti-aging effect of polysaccharide from Bletilla striata on nematode Caenorhabditis elegans. AB - BACKGROUND: Polysaccharide isolated from Bletilla striata, a well-known traditional Chinese medicine (Bletilla striata polysaccharide [BSP]) has been found to play important roles in endothelial cells proliferation, inducible nitric oxide stimulation, wound healing acceleration and other processes. Recent studies found that B. striata has anti-oxidative properties, however, potential anti-aging effects of BSP in whole organisms has not been characterized. OBJECTIVE: To investigate whether BSP has anti-aging effects on Caenorhabditis elegans. MATERIALS AND METHODS: After treatment with BSP, the lifespan, locomotion ability, and stress resistance of C. elegans was determined. To provide insight into the underlying mechanism for the anti-aging effect of BSP, we measured its effect on bacterial growth, brood size of C. elegans, and the insulin/insulin-like growth factor (IGF) signaling pathway. RESULTS: After BSP treatment, the lifespan of C. elegans was extended, and its locomotion ability and stress resistance were increased. BSP was found to have no effect on bacterial growth or on reproduction of C. elegans, However, mRNA levels of age-1 and hcf-1 were reduced after BSP treatment. Additionally, we observed that BSP did not extend the lifespan of daf-16 mutant animals. CONCLUSION: BSP produces an anti-aging effect on C. elegans through the insulin/IGF signaling pathway and holds promise for future development as a functional food. PMID- 26246719 TI - A study of pharmacokinetic interactions among co-existing ingredients in Viscum coloratum after intravenous administration of three different preparations to rats. AB - BACKGROUND: Viscum coloratum (Komar) Nakai, known as Hujisheng in china, has been widely used as a herb medicine to treat a variety of diseases, including cardiovascular diseases, cancer, hypertension, hepatitis and hemorrhage. OBJECTIVE: The aim was to investigate pharmacokinetic interactions among co existing ingredients in V. coloratum after intravenous administration of three different preparations (four monomer solutions, the mixture of them and Viscum coloratum extracts) to rats. MATERIALS AND METHODS: After protein precipitation pretreatment with plasma samples, high performance liquid chromatographic methods were developed and applied to quantitatively determinate the four components [syringin (Syri), homoeriodictyol-7-O-beta-D-glycoside (Hedt-III), homoeriodictyol-7-O-beta-D-apiose (1 -> 2)-beta-D-glycoside (Hedt-II) and homoeriodictyol-7-O-beta-D-apiosiyl-(1 -> 5)-beta-D-apiosyl-(1 -> 2)-beta-D glycoside (Hedt-I)]. The pharmacokinetic parameters (Area under the curve [AUC(0 t)], AUC(0-infinity), t 1/2) were calculated using DAS 2.1 software (Chinese Pharmacological Society, Shanghai, China) and compared statistically by One-way analysis of variance using SPSS software (18.0, Chicago, IL, USA) with P < 0.05 considered statistically significant. RESULTS: Good linearities were achieved in the measured concentration range with R (2) it0.9920. Precision, accuracy and extraction recovery were all within the acceptable range. For Syri, there was a significant difference only on t 1/2 among three treatment groups. For Hedt-I, Hedt II and Hedt-III, three flavonoid glycosides, the change of AUC(0-t), AUC(0 infinity) and t 1/2 were markedly distinctive and even converse. CONCLUSION: Complex, extensive pharmacokinetic interactions were observed among these components in V. coloratum. They were mutually influenced by the in vivo absorption, distribution, metabolism and elimination. The result suggested traditional Chinese medicine was a complicated system, and we should take a scientific and dialectic view in the research and development processes. PMID- 26246720 TI - Optimization of ultrasonic-assisted extraction of antioxidant compounds from Guava (Psidium guajava L.) leaves using response surface methodology. AB - OBJECTIVE: To optimization of extraction of antioxidant compounds from guava (Psidium guajava L.) leaves and showed that the guava leaves are the potential source of antioxidant compounds. MATERIALS AND METHODS: The bioactive polysaccharide compounds of guava leaves (P. guajava L.) were obtained using ultrasonic-assisted extraction. Extraction was carried out according to Box Behnken central composite design, and independent variables were temperature (20 60 degrees C), time (20-40 min) and power (200-350 W). The extraction process was optimized by using response surface methodology for the highest crude extraction yield of bioactive polysaccharide compounds. RESULTS: The optimal conditions were identified as 55 degrees C, 30 min, and 240 W. 1,1-diphenyl-2-picryl-hydrazyl and hydroxyl free radical scavenging were conducted. CONCLUSION: The results of quantification showed that the guava leaves are the potential source of antioxidant compounds. PMID- 26246721 TI - Selective and cost-effective protocol to separate bioactive triterpene acids from plant matrices using alkalinized ethanol: Application to leaves of Myrtaceae species. AB - BACKGROUND: Triterpenes as betulinic (BA), oleanolic (OA) and ursolic acids (UA) have increasingly gained therapeutic relevance due to their wide scope of pharmacological activities. To fit large-scale demands, exploitable sources of these compounds have to be found and simple, cost-effective methods to extract them developed. Leaf material represents the best plant sustainable raw material. To obtain triterpene acid-rich extracts from leaves of Eugenia, Psidium and Syzygium species (Myrtaceae) by directly treating the dry plant material with alkalinized hydrated ethanol. This procedure was adapted from earlier methods to effect depolymerization of the leaf cutin. MATERIALS AND METHODS: Extracts were prepared by shaking the milled dry leaves in freshly prepared 2% NaOH in 95% EtOH solution (1:4 w/v) at room temperature for 6 h. Working up the product in acidic aqueous medium led to clear precipitates in which BA, OA and UA were quantified by gas chromatography. RESULTS: Pigment-free and low-polyphenol content extracts (1.2-2.8%) containing 6-50% of total triterpene acids were obtained for the six species assayed. UA (7-20%) predominated in most extracts, but BA preponderated in Eugenia florida (39%). Carried out in parallel, n-hexane defatted leaves led to up to 9% enhancement of total acids in the extracts. The hydroalcoholate treatment of Myrtaceae species dry leaves proved to be a cost-effective and environmentally friendly method to obtain triterpene acids, providing them be resistant to alkaline medium. These combined techniques might be applicable to other plant species and tissues. PMID- 26246722 TI - A direct protein kinase B-targeted anti-inflammatory activity of cordycepin from artificially cultured fruit body of Cordyceps militaris. AB - BACKGROUND: Cordyceps militaris is one of well-known medicinal mushrooms with anti-inflammatory, anti-cancer, anti-diabetic, and anti-obesity activities. OBJECTIVE: The objective of the following study is to isolate chemical components from the ethanol extract (Cm-EE) from Cordyceps militaris and to evaluate their anti-inflammatory activities. MATERIALS AND METHODS: Column chromatographic separation was performed and anti-inflammatory roles of these compounds were also examined by using NO production and protein kinase B (AKT) activity assays. RESULTS: From Cm-EE, 13 constituents, including trehalose (1), cordycepin (2), 6 hydroxyethyladenosine (3), nicotinic amide (4), butyric acid (5), beta dimorphecolic acid (6), alpha-dimorphecolic acid (7), palmitic acid (8), linoleic acid (9), cordycepeptide A (10), 4-(2-hydroxy-3-((9E,12E)-octadeca-9,12 dienoyloxy)propoxy)-2-(trimethylammonio)butanoate (11), 4-(2-hydroxy-3 (palmitoyloxy)propoxy)-2-(trimethylammonio)butanoate (12), and linoleic acid methyl ester (13) were isolated. Of these components, compound 2 displayed a significant inhibitory effect on NO production in lipopolysaccharide (LPS) activated RAW264.7 cells. Furthermore, this compound strongly and directly suppressed the kinase activity of AKT, an essential signalling enzyme in LPS induced NO production, by interacting with its ATP binding site. CONCLUSION: C. militaris could have anti-inflammatory activity mediated by cordycepin-induced suppression of AKT. PMID- 26246723 TI - Profiling of components of rhizoma et radix polygoni cuspidati by high performance liquid chromatography with ultraviolet diode-array detector and ion trap/time-of-flight mass spectrometric detection. AB - INTRODUCTION: Rhizoma et Radix Polygoni Cuspidati (Huzhang in Chinese, HZ) is a traditional medicinal plant in China. Many of the components of HZ have been proved to be bioactive while it is difficult to conduct a comprehensive chemical profiling of HZ as a consequence of the absence of efficient separation system and sensitive detective means. We developed a simple and effective method for comprehensive characterization of constituents in HZ. OBJECTIVE: To develop a simple and effective method to characterize the components in HZ and provide useful information for subsequent metabolic studies of HZ. MATERIALS AND METHODS: The components in HZ aqueous extract were characterized by using high performance liquid chromatography with UV diode-array detector (HPLC-DAD) and ion trap/time of-flight mass spectrometric detection (HPLC-IT/TOF). Stilbenes, anthraquinones, gallates and tannins, naphthalenes and some other compounds were identified and confirmed by diagnostic fragment ions with accurate mass measurements, characteristic fragmentation pathways and relevant published literatures. RESULTS: Among the 238 constituents detected in HZ, a total number of 74 constituents were identified unambiguously or tentatively, including 29 compounds reported for the first time in HZ. CONCLUSION: The identification and structure elucidation of these chemicals provided essential data for quality control and further in vivo metabolic studies of HZ. Key words: Polygonum cuspidatum, HPLC DAD, HPLC-IT/TOF, qualitative analysis. PMID- 26246724 TI - Traditional medicine yanggyuksanhwa-tang inhibits adipogenesis and suppresses proliferator-activated receptor-gamma expression in 3T3-L1 cells. AB - BACKGROUND: Yanggyuksanhwa-tang (YGSHT) is a specific traditional Korean herbal formula for Soyangin according to Sasang constitutional philosophy. Although its biological activities against inflammation and cerebral infarction have been reporting, there is no information about the adipogenic activity of YGSHT. In the present study, we investigated the anti-adipogenic activity of YGSHT to evaluate effects of YGSHT on adipogenesis in vitro. MATERIALS AND METHODS: Using 3T3-L1 preadipocytes, we induced the cellular differentiation into adipocytes by adding insulin. Anti-adipogenic activity of YGSHT was measured by oil red O staining, triglyceride assay, glycerol-3-phosphate dehydrogenase (GPDH) activity test, and leptin assay. RESULTS: YGSHT extract had no significant cytotoxicity in preadipocytes or differentiated adipocytes. YGSHT reduced the number of lipid droplets and content of triglyceride in adipose cells. YGSHT also significantly inhibited GPDH activity and decreased leptin production compared with control adipocytes. Down-regulation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) expression at the messenger RNA level was observed in YGSHT-treated adipocytes. CONCLUSION: Taken together, our data suggest that YGSHT has potential as an anti-obesity drug candidate. PMID- 26246725 TI - Simultaneous determination of four active components in rat plasma by ultra-high performance liquid chromatography tandem-mass spectrometry/mass spectrometry and its application to a pharmacokinetic study after oral administration of Callicarpa nudiflora extract. AB - BACKGROUND: Callicarpa nudiflora has been commonly used as a Chinese folk medicine for resolving toxin, dispersing edema and hemostasis; however, its pharmacokinetic (PK) behavior remains unknown. In our present study, a simple and sensitive ultra-high performance liquid chromatography tandem mass spectrometry method was firstly developed on simultaneous determination and PK study of four active components (luteoloside, dracocephaloside, juncein and nudifloside) following the oral administration of C. nudiflora extract to investigate their PK profiles. MATERIALS AND METHODS: Chromatographic separation was achieved on a Phenomenex((r)) Kinetex C18 column (50 mm * 2.1 mm, 1.7 MUm) with gradient elution using a mobile phase consisted of acetonitrile (A) and 0.050/00 formic acid in water (B). The quantitation was carried out by multiple reaction monitoring using electrospray ionization in the negative ion mode. RESULTS: Calibration curves offered satisfactory linearity, with correlation coefficients >0.99 for all compounds within the concentration range. The low limits of quantification were 1.03 ng/mL for luteoloside, 1.16 ng/mL for dracocephaloside, 0.82 ng/mL for juncein and 0.88 ng/mL for nudifloside, respectively. The intra- and inter-day precisions (relative standard deviation) were within 7.4% and the accuracies (relative error) ranged from -7.4% to 7.9%. CONCLUSION: This method was successfully applied to the PK studies of luteoloside, dracocephaloside, juncein and nudifloside in rat plasma after oral administration of C. nudiflora extract, four analytes exhibited quick absorption with peak concentrations occurring at around 25 min and eliminated rapidly. PMID- 26246726 TI - Region-selective biosynthesis of artemisinic acid glycosides by crown galls of Panax quinquefolium and their in vitro antitumor activities. AB - BACKGROUND: The biosynthesis of artemisinin derivatives is one of the interesting subjects. Artemisinic acid (AA) has been widely studied as a supposed intermediate in the biosynthetic pathway leading to artemisinin in Artemisia annua. OBJECTIVE: To investigate the bioconversion of AA by transgenic crown galls of Panax quinquefolium. MATERIALS AND METHODS: AA was administered into crown galls of P. quinquefolium and co-cultured for 2 days. The methanol extract was separated by column chromatography, and the structures of two biosynthesis products were elucidated by physicochemical and spectroscopic methods. Co-culture time curves on conversion were also established. In addition, the effects of AA on the growth and ginsenosides production of crown galls of P. quinquefolium were investigated. Furthermore, the in vitro antitumor activities of AA and two glycosides against HepG2 cell line were evaluated by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl-tetrazolium bromide (MTT) assay. RESULTS: Glycosylation of AA by crown galls of P. quinquefolium was observed, and two region-selectively glycosylated products were obtained (AA-1, AA-2), involving one new compound (AA 2). Their structures were elucidated to be AA beta-D-glucopyranosyl ester (AA-1) and AA beta-D-glucopyranosyl-(2 -> 1)-beta-D-glucopyranosyl ester (AA-2). The maximum yield of AA-1 was 19.3% on the 1(st) co-culture day while that of AA-2 was 59.1% on the 2(nd) day. MTT assay showed that the activity of monosaccharide glycoside (AA-1) was better than that of disaccharide glycoside (AA-2). CONCLUSION: Two AA glycosides involved one new compound with potential antitumor activity were obtained by region-selective biosynthesis with crown galls of P. quinquefolium. PMID- 26246727 TI - Protective effect of calycosin-7-O-beta-D-glucopyranoside against oxidative stress of BRL-3A cells induced by thioacetamide. AB - BACKGROUND: Calycosin-7-O-beta-D-glucopyranoside (CG) is a natural isoflavone found in traditional Chinese medicines Astragali Radix (AR). OBJECTIVE: Calycosin 7-O-beta-D-glucopyranoside, an isoflavone isolated from AR, has been found to have potent antioxidantive effects. This study was designed to investigate whether CG prevents oxidative stress induced by thioacetamide (TAA). MATERIALS AND METHODS: BRL-3A cells were pretreated with different concentrations of CG (10, 20, 40 mg/mL) for 12 h and then exposed to 0.18 mol/L TAA for 2 h. The cell viability were examined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium assay, total antioxidant capacity, malondialdehyde (MDA) and the activity of antioxidant enzymes, including catalase, glutathione peroxidase and superoxide dismutase were determined by microplate method. Reactive oxygen species (ROS) generation was quantified by the 2',7'-dichlorofluorescin-diacetate method. Protein and mRNA expression of CYP2E1 were determined by western blotting and real-time PCR. RESULTS: The cell oxidative stress was significantly increased after 2 h of TAA exposure. Pretreatment of BRL-3A cells with CG significantly increased the activities of antioxidant enzymes, scavenged ROS and reduced MDA production. CG decreased the expression of CYP2E1, and ultimately decreased TAA induced BRL-3A cells oxidative stress. CONCLUSIONS: Calycosin-7-O-beta-D glucopyranoside has a protective effect against TAA-induced oxidative stress in BRL-3A cells, and that the underlying mechanism involves in scavenging of ROS and the modulating expression of CYP2E1. PMID- 26246728 TI - The ethanolic extract of Juglans sinensis leaves and twigs attenuates CCl4 induced hepatic oxidative stress in rats. AB - BACKGROUND: The nuts of Juglans sinensis Dode, walnut tree, are rich in unsaturated fatty acids and bioactive compounds with antioxidant activity on liver damages. However, hepatoprotective activity of the leaves and twigs of J. sinensis have not intensively studied yet. OBJECTIVE: Hepatoprotective activity of the refined ethanolic extract of J. sinensis (JSE3) was evaluated using carbon tetrachloride (CCl4)-intoxicated rats. MATERIALS AND METHODS: Hepatotoxicity was induced in Sprague Dawley rats by intraperitoneal injection of CCl4 for 6 weeks in the presence or absence of JSE3 (100 and 200 mg/kg body weight). The hepatoprotective activity of JSE3 was assessed by biochemical parameters including plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), and antioxidant enzymes, such as superoxide dismutase (SOD), glutathione reductase, glutathione peroxide, reduced glutathione and oxidized glutathione, along with histopathological studies on hepatic tissue. RESULTS: JSE3 significantly decreased the elevated levels of AST and ALT and restored the reduced levels of antioxidant enzymes. JSE3 also decreased the amounts of collagen content accumulated by CCl4 intoxication. CONCLUSION: These results suggested that the refined extract of J. sinensis may have a potential to be developed as a therapeutic agent to treat hepatic diseases, such as fatty liver and hepatic fibrosis. PMID- 26246729 TI - Simultaneous quantification of crocetin esters and picrocrocin changes in Chinese saffron by high-performance liquid chromatography-diode array detector during 15 years of storage. AB - BACKGROUND: Saffron, which is made up of the dried stigmas of Crocus sativus L., has been successfully cultivated in China since 1970s and Zhejiang province is now the largest producing area in China, but the contents of crocetin esters and picrocrocin in saffron from Zhejiang province has not been determined simultaneously by high-performance liquid chromatography (HPLC) and changes of these constituents in Chinese saffron during storage for years has not been studied. OBJECT: To establish a simple method quantification of the five main compounds including picrocrocin and four crocetin esters in saffron from main producing areas of China and study the influence of storage time on the changes of saffron constituents. MATERIALS AND METHODS: A simple, sensitive, and accurate HPLC method was developed for simultaneous determination of five major active components in saffron and eight samples which collected from the same farm of Zhejiang province in different years were analyzed. RESULTS: The correlation coefficient values (R (2) > 0.9997) indicated good correlations between the investigated compounds' concentrations and their peak areas within the test ranges. The limits of quantification and detection of the five compounds were 0.53-2.76 MUg/mL and 0.11-0.77 MUg/mL, respectively. The recoveries ranged from 94.67% to 101.31%, and the overall relative standard deviations for intra-day and inter-day were lower than 3.49%. The method was applied to study the changes of crocetin esters and picrocrocin contents in saffron samples during 15 years of storage. The losses of crocetin esters and picrocrocin in saffron with 1 -year storage were 52.2% and 54.3%, respectively. The trend then declined during subsequent storage. CONCLUSION: The developed method can be applied to the intrinsic quality control of saffron. PMID- 26246730 TI - Microwave-assisted extraction of polysaccharides from Yupingfeng powder and their antioxidant activity. AB - BACKGROUND: Microwave-assisted reflux extraction of polysaccharides YPF-P from the famous Chinese traditional drug, Yupingfeng powder, optimization of extracting conditions and evaluation of their antioxidant activity were conducted in this study. RESULTS: Single factor effect trends were achieved through yields and contends of YPF-P obtained from different extracting conditions. Then through a three-level, four-variable Box-Behnken design of response surface methodology adopting yield as response, the optimal conditions were determined as follows: Material/solvent ratio 1:23.37, microwave power 560 W, Extraction temperature 64 degrees C, and extraction time 9.62 min. Under the optimal conditions, the YPF-P extraction yield was 3.23%, and its content was detected as 38.52%. In antioxidant assays, the YPF-P was tested to possess 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities with an IC50 value of 0.262 mg/ml. In addition, YPF-P was also proved to have relatively low ferric reducing antioxidant power (FRAP), compared to Vc, through FRAP assay. CONCLUSION: In the microwave assisted reflux extraction research, good YPF-P yield was achieved from materials with relatively low YPF-P content. And for the first time, both DPPH and FRAP assays were conducted on YPF-P, which proved that the antioxidant activity of YPF-P contributed to the functions of this medicine. PMID- 26246731 TI - Simultaneous determination of nine marker compounds in the traditional Korean medicine, Dangguisu-san by high-performance liquid chromatography. AB - BACKGROUND: Dangguisu-san (DGSS) has been widely used to treat ecchymosis, blood stagnation and pain resulting from physical shock in Korea. OBJECTIVE: A high performance liquid chromatography-photodiode array detection (HPLC-PDA) method for simultaneous analysis of nine components, albiflorin (1), paeoniflorin (2), liquiritin (3), nodakenin (4), coumarin (5), liquiritigenin (6), cinnamic acid (7), cinnamaldehyde (8), and glycyrrhizin (9) in DGSS extract has been developed for the first time. MATERIALS AND METHODS: The analytical column for separation of the nine constituents used a Gemini C18 column kept at 40 degrees C by the gradient elution with 1.0% (v/v) acetic acid in water and 1.0% (v/v) acetic acid in acetonitrile as mobile phase. The flow rate was 1.0 mL/min and the injection volume was 10 MUL. RESULTS: Calibration curves of all compounds showed good linearity (r (2) >= 0.9999) within the test ranges. The limits of detection and quantification for all analytes were 0.01-0.27 MUg/mL and 0.04-0.89 MUg/mL, respectively. All recoveries of the nine marker compounds were 96.62-102.47% with relative standard deviations (RSD) <1.72%. The RSDs of intra-day and inter-day precision were <1.32% and 1.61%, respectively. The amounts of the nine marker components ranged from 0.10 mg/g to 13.71 mg/g. CONCLUSION: The developed and validated HPLC-PDA method may help for the quality control of DGSS. PMID- 26246732 TI - Simultaneous determination of three sesquiterpene lactones in Aucklandia lappa Decne by high-performance liquid chromatography. AB - BACKGROUND: Aucklandia lappa Decne, a well-known traditional herbal medicine, is used for the treatment of asthma, rheumatism, coughs, tuberculosis, and many other diseases. OBJECTIVE: We performed simultaneous analysis of three sesquiterpene lactones, costunolide (1), dehydrocostus lactone (2), and alantolactone (3), obtained from a 70% methanol extract of A. lappa using high performance liquid chromatography-photodiode array (HPLC-PDA) techniques. MATERIALS AND METHODS: The compounds 1-3 were separated using a reversed-phase SunFireTM C18 analytical column kept at 35 degrees C by the isocratic elution with distilled water and acetonitrile as mobile phase. The flow rate was 1.0 mL/min, and the injection volume was 10 MUL. RESULTS: The established analytical method showed high linearity, with a correlation coefficient >=0.9999. The limit of detection and the limit of quantification of compounds 1-3 were 0.06-0.13 MUg/mL and 0.21-0.42 MUg/mL, respectively. The recovery of the compounds 1-3 was 97.27-103.00%. The intra- and inter-day relative standard deviations were 0.09 0.97% and 0.09-1.06%, respectively. The amounts of the compounds 1-3 were 17.32, 28.26, and 0.01 mg/g, respectively. CONCLUSION: The established and validated HPLC-PDA method may be help for the quality control of herbal medicine, A. lappa. PMID- 26246733 TI - Total saponins from Discorea nipponica makino ameliorate urate excretion in hyperuricemic rats. AB - OBJECTIVE: The objective was to study the mechanism of reducing level of the uric acid by rhizoma dioscoreae nipponese. MATERIALS AND METHODS: A total of 40 rats were divided into four groups: A normal group, hyperuricemia group, benzbromarone group (9 mg/kg) and total saponins from rhizoma dioscoreae nipponese (TDN) group (40 mg/kg). Adenine (100 mg/kg) and ethambutol (250 mg/kg) were used to induce hyperuricemic rats. Immunohistochemical and Western blotting methods were used to detect the mRNA and proteins expressions of rat organic anion transporter1 (rOAT1), rat organic anion transporter3 (rOAT3) and rat urate transporter1 (rURAT1) in the kidneys of different groups. RESULTS: It was found that the reduced concentration of blood uric acid was due to the enhancement of renal uric acid excretion. It was realized by up-regulating proteins expressions of rOAT1 and rOAT3 and down-regulating of rURAT1. CONCLUSION: The findings suggested that there were uricosuric effects of TDN by regulating renal organic ion transporters in hyperuricemic animals. Altogether, TDN may be a good Chinese herb in treating hyperuricemia, even a potential drug for gouty arthritis. PMID- 26246734 TI - Optimization of induction, subculture conditions, and growth kinetics of Angelica sinensis (Oliv.) Diels callus. AB - BACKGROUND: Angelica sinensis (Oliv.) Diels is an important traditional Chinese medicine, and the medicinal position is its root. This perennial herb grows vigorously only in specific areas and the environment. Tissue culture induction of callus and plant regeneration is an important and effective way to obtain large scale cultures of A. sinensis. OBJECTIVE: The objective was to optimize the inductive, subculture conditions, and growth kinetics of A. sinensis. MATERIALS AND METHODS: Tissue culture conditions for A. sinensis were optimized using leaves and petioles (types I and II) as explants source. Murashige and Skoog (MS) and H media supplemented with 30 g/L sucrose, 7.5 g/L agar, and varying concentrations of plant growth regulators were used for callus induction. In addition, four different basal media supplemented with 1.0 mg/L 2,4 dichlorophenoxy acetic acid (2,4-D), 0.2 mg/L 6-benzyladenine (BA) and 30 g/L sucrose were optimized for callus subculture. Finally, growth kinetics of A. sinensis cultured on different subculture media was investigated based on callus properties, including fresh weight, dry weight, medium pH, callus relative fresh weight growth, callus relative growth rate (CRGR), and sucrose content. RESULTS: MS medium supplemented with 5 mg/L alpha-naphthaleneacetic acid, 0.5 mg/L BA, 0.7 mg/L 2,4-D, 30 g/L sucrose and 7.5 g/L agar resulted in optimal callus induction in A. sinensis while petiole I was found as the best plant organ for callus induction. The B5 medium supplemented with 1.0 mg/L 2,4-D, 0.2 mg/L BA and 30 g/L sucrose displayed the best results in A. sinensis callus subculture assays. CONCLUSION: The optimized conditions could be one of the most potent methods for large-scale tissue culture of A. sinensis. PMID- 26246735 TI - Neuroprotective activity of parawixin 10, a compound isolated from Parawixia bistriata spider venom (Araneidae: Araneae) in rats undergoing intrahippocampal NMDA microinjection. AB - BACKGROUND: Parawixia bistriata is a semi-colonial spider found mainly in southeastern of Brazil. Parawixin 10 (Pwx 10) a compound isolated from this spider venom has been demonstrated to act as neuroprotective in models of injury regulating the glutamatergic neurotransmission through glutamate transporters. OBJECTIVES: The aim of this work was to evaluate the neuroprotective effect of Pwx 10 in a rat model of excitotoxic brain injury by N-methyl-D-aspartate (NMDA) injection. MATERIAL AND METHODS: Male Wistar rats have been used, submitted to stereotaxic surgery for saline or NMDA microinjection into dorsal hippocampus. Two groups of animals were treated with Pwx 10. These treated groups received a daily injection of the Pwx 10 (2.5 mg/MUL) in the right lateral ventricle into rats pretreated with NMDA, always at the same time, each one starting the treatment 1 h or 24 h. Nissl staining was performed for evaluating the extension and efficacy of the NMDA injury and the neuroprotective effect of Pwx 10. RESULTS: The treatment with Pwx 10 showed neuroprotective effect, being most pronounced when the compound was administrated from 1 h after NMDA in all hippocampal subfields analyzed (CA1, CA3 and hilus). CONCLUSION: These results indicated that Pwx 10 may be a good template to develop therapeutic drugs for treating neurodegenerative diseases, reinforcing the importance of continuing studies on its effects in the central nervous system. PMID- 26246736 TI - Metabolic fingerprinting to understand therapeutic effects and mechanisms of silybin on acute liver damage in rat. AB - BACKGROUND: Metabolic fingerprinting is a rapid and noninvasive analysis, representing a powerful approach for the characterization of phenotypes and the distinction of specific metabolic states due to environmental alterations. It has become a valuable analytical approach for the characterization of phenotypes and is the rapidly evolving field of the comprehensive measurement of ideally all endogenous metabolites in bio-samples. Silybin has displayed bright prospects in the prevention and therapy of liver injury, and we had conducted a preliminary exploration on the molecular mechanism of the hepatoprotective effects of silybin. Because the knowledge on the metabolic responses of an acute liver damage rat to the silybin is still scarce, metabolic fingerprinting can provide relevant information on the intrinsic metabolic adjustments. MATERIALS AND METHODS: Here, the physiological and metabolic changes in the acute liver damage rat were investigated by performing a metabolic analysis. The phenotypic response was assessed by liquid chromatography/mass spectrometry (LC/MS) combined with pattern recognition approaches such as principal components analysis and partial least squares projection to supervised latent structures and discriminant analysis. Multivariate analysis of the data showed trends in scores plots that were related to the concentration of the silybin. RESULTS: Results indicate 10 ions (7 upregulated and 3 downregulated) as differentiating metabolites. Key observations include perturbations of metabolic pathways linked to glutathione metabolism, tryptophan metabolism, cysteine and methionine metabolism, etc., Overall, this investigation illustrates the power of the LC/MS combined with the pattern recognition methods that can engender new insights into silybin affecting on metabolism pathways of an acute liver damage rat. CONCLUSION: The present study demonstrates that the combination of metabolic fingerprinting with appropriate chemometric analysis is a valuable approach for studying cellular responses to silybin drug and can provide additional insight into the mechanisms. PMID- 26246737 TI - Application of microscopy technique and high-performance liquid chromatography for quality assessment of the flower bud of Tussilago farfara L. (Kuandonghua). AB - BACKGROUND: Quality control is one of the bottleneck problems limiting the application and development of traditional Chinese medicine (TCM). In recent years, microscopy and high-performance liquid chromatography (HPLC) techniques have been frequently applied in the quality control of TCM. However, studies combining conventional microscopy and HPLC techniques for the quality control of the flower bud of Tussilago farfara L. (Kuandonghua) have not been reported. OBJECTIVE: This study was undertaken to evaluate the quality of the flower bud of T. farfara L. and to establish the relationships between the quantity of pollen grains and four main bioactive constituents: tussilagone, chlorogenic acid, rutin and isoquercitrin. MATERIALS AND METHODS: In this study, microscopic examination was used to quantify microscopic characteristics of the flower bud of T. farfara L., and the chemical components were determined by HPLC. The data were analyzed by Statistical Package for the Social Sciences statistics software. RESULTS: The results of the analysis showed that tussilagone, chlorogenic acid, rutin and isoquercitrin were significantly correlated with the quantity of pollen grains in the flower bud of T. farfara L. There is a positive correlation between them. From these results, it can be deduced that the flower bud of T. farfara L. with a greater quantity of pollen grains should be of better quality. CONCLUSION: The study showed that the established method can be helpful for evaluating the quality of the flower bud of T. farfara L. based on microscopic characteristic constants and chemical quantitation. PMID- 26246738 TI - Biological activities of Croton palanostigma Klotzsch. AB - BACKGROUND: Different species of Croton are used in traditional Amazonian medicine. Among the popular uses are treatment of bacterial diseases, poorly healing wounds and fevers. OBJECTIVE: This study evaluated the antileishmanial, antiplasmodial and antimicrobial activities of the extracts and diterpenes of Croton palanostigma Klotzsch (Euphorbiaceae). MATERIALS AND METHODS: Leaves and bark were extracted with dichloromethane and methanol. The bark dichloromethane extract (BDE) was chromatographed on a column, obtaining cordatin and aparisthman. The extracts and diterpenes were assayed thought agar disk diffusion method and their bactericidal or fungicidal effects were evaluated by minimum bactericidal or fungicidal concentration. The antiplasmodial activity was evaluated after 24 and 72 h of exposition. The antileishmanial activity was performed on promastigotes forms of Leishmania amazonensis. RESULTS: The bark methanol extract (BME) and cordatin were not active against any microbial strains tested; BDE and leaves methanol extract (LME) were positive for Pseudomonas aeruginosa and aparisthman was positive for Candida albicans. In the determination of the minimum bactericidal concentration, neither of them were active in the highest concentration tested. The extracts and diterpenes were inactive in Plasmodium falciparum, except the LME in 72 h. Any extract was shown to be active in promastigote forms of L. amazonensis. CONCLUSION: These results indicate that the BDE and LME did not inhibit the bacterial growth, then they probably had bacteriostatic effect. LME presented activity in P. falciparum. PMID- 26246739 TI - Phytochemical screening, antioxidant and antibacterial activities of extracts prepared from different tissues of Schinus terebinthifolius Raddi that occurs in the coast of Bahia, Brazil. AB - BACKGROUND: Schinus terebinthifolius is widely used in traditional medicine by Brazilian quilombola and indigenous communities for treatment of several diseases. Extracts from different tissues are being used to produce creams to treat cervicitis and cervicovaginitis. However, most studies are limited to the assessment of the essential oils and extracts obtained from the leaves. OBJECTIVE: The aim was to evaluate antioxidant and antibacterial activities, to assess the phytochemical profile and to quantify total phenolic compounds of various extracts prepared from S. terebinthifolius grown in the coast of Bahia, Brazil. MATERIALS AND METHODS: Extracts were obtained by hot continuous extraction (soxhlet) and by maceration. Quantification of phenolic compounds was performed using the Folin-Ciocalteu method and antioxidant properties were assessed by 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay. Phytochemical screening was performed as described by in the literature and antibacterial activity against Enterococcus faecalis (ATCC 29212) was determined by the microdilution broth assay. RESULTS: Extraction method greatly affected the metabolite profile of the extracts. Antioxidant activity varied between 21.92% and 85.76%, while total phenols ranged between 5.44 and 309.03 mg EAG/g of extract. Leaf extract obtained with soxhlet showed minimum inhibitory concentration (MIC) of 15.62 MUg/mL, while stem extract obtained by maceration was able to inhibit the growth of E. faecalis at 62.5 MUg/mL. Stem bark extracts showed a MIC of 500 MUg/mL for both extraction methods, while no inhibition was observed for fruit extracts. CONCLUSION: In general, total phenolic content, antioxidant and antibacterial activities were higher in samples obtained by soxhlet. Our results provide important clues in order to identify alternative sources of bioactive compounds that can be used to develop new drugs. PMID- 26246740 TI - Chemical constituents and antioxidant activity of the essential oil from leaves of Annona vepretorum Mart. (Annonaceae). AB - BACKGROUND: Annona vepretorum (AV) is a native tree from Caatinga biome (semiarid region of Brazil) popularly known as "araticum" and "pinha da Caatinga." OBJECTIVE: This study was carried out to evaluate the chemical constituents and antioxidant activity (AA) of the essential oil from the leaves from AV (EO-Av) collected in Petrolina, Pernambuco, Brazil. MATERIALS AND METHODS: Fresh leaves of AV were cut into pieces, and subjected to distillation for 2 h in a clevenger type apparatus. Gas chromatograph (GC) analyses were performed using a mass spectrometry/flame ionization detector. The identification of the constituents was assigned on the basis of comparison of their relative retention indices. The antioxidant ability of the EO was investigated through two in vitro models such as radical scavenging activity using 2,2-diphenyl-1-picrylhydrazyl method and beta-carotene-linoleate-model system. The positive controls (ascorbic acid, butylated hydroxyanisole and butylated hydroxytoluene) were those using the standard solutions. Assays were carried out in triplicate. RESULTS: The oil showed a total of 21 components, and 17 were identified, representing 93.9% of the crude EO. Spathulenol (43.7%), limonene (20.5%), caryophyllene oxide (8.1%) and alpha-pinene (5.5%) were found to be the major individual constituents. Spathulenol and caryophyllene oxide could be considered chemotaxonomic markers of these genera. The EO demonstrated weak AA. PMID- 26246741 TI - A high performance liquid chromatography with ultraviolet method for Eschweilera nana leaves and their anti-inflammatory and antioxidant activities. AB - BACKGROUND: Eschweilera nana Miers is a tree widely distributed in Cerrado, Brazil. OBJECTIVE: In this study, we aimed to describe its phytochemical properties and antioxidant and topical anti-inflammatory effects for the first time, as well validate an high performance liquid chromatography with ultraviolet/visible (HPLC-UV-Vis) method for the separation and quantification of the main components (hyperoside and rutin) in the hydroalcoholic extract of E. nana leaves. MATERIALS AND METHODS: Structural identification of compounds in E. nana extract was performed by analysis of spectral data by (1)H nuclear magnetic resonance, (13)C nuclear magnetic resonance and/or ESI/EM. The HPLC-UV-Vis method was validated according International Conference on Harmonization (ICH) parameters. The 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) method were used for determination of in vitro antioxidant activities and the croton oil-induced inflammation for evaluation of in vivo anti-inflammatory effects. RESULTS: Hyperoside, rutin, alpha-amirin, beta-amirin, beta-sitosterol, and stigmasterol were identified in the hydroalcoholic extract of E. nana leaves. HPLC-UV-Vis was validated according to ICH parameters. Furthermore, in vitro and in vivo assays demonstrated that the hydroalcoholic extract and methanol fraction showed significant antioxidant and topical anti-inflammatory effects, as they were able to reduce ear edema induced by croton-oil application. CONCLUSIONS: This research showed the first phytochemical study of E. nana extract and their biological activities may be associated with the presence of flavonoids in the extracts. PMID- 26246742 TI - Luteolin is a bioflavonoid that attenuates adipocyte-derived inflammatory responses via suppression of nuclear factor-kappaB/mitogen-activated protein kinases pathway. AB - BACKGROUND: Inflammation of adipocytes has been a therapeutic target for treatment of obesity and metabolic disorders which cause insulin resistance and hence lead to type II diabetes. Luteolin is a bioflavonoid with many beneficial properties such as antioxidant, antiproliferative, and anti-cancer. OBJECTIVES: To elucidate the potential anti-inflammatory response and the underlying mechanism of luteolin in 3T3-L1 adipocytes. MATERIALS AND METHODS: We stimulated 3T3-L1 adipocytes with the mixture of tumor necrosis factor-alpha, lipopolysaccharide, and interferon-gamma (TLI) in the presence or absence of luteolin. We performed Griess' method for nitric oxide (NO) production and measure mRNA and protein expressions by real-time polymerase chain reaction and western blotting, respectively. RESULTS: Luteolin opposed the stimulation of inducible nitric oxide synthase and NO production by simultaneous treatment of adipocytes with TLI. Furthermore, it reduced the pro-inflammatory genes such as cyclooxygenase-2, interleukin-6, resistin, and monocyte chemoattractant protein 1. Furthermore, luteolin improved the insulin sensitivity by enhancing the expression of insulin receptor substrates (IRS1/2) and glucose transporter-4 via phosphatidylinositol-3K signaling pathway. This inhibition was associated with suppression of Ikappa-B-alpha degradation and subsequent inhibition of nuclear factor-kappaB (NF-kappaB) p65 translocation to the nucleus. In addition, luteolin blocked the phosphorylation of ERK1/2, c-Jun N-terminal Kinases and also p38 mitogen-activated protein kinases (MAPKs). CONCLUSIONS: These results illustrate that luteolin attenuates inflammatory responses in the adipocytes through suppression of NF-kappaB and MAPKs activation, and also improves insulin sensitivity in 3T3-L1 cells, suggesting that luteolin may represent a therapeutic agent to prevent obesity-associated inflammation and insulin resistance. PMID- 26246743 TI - In situ pressurized biphase acid hydrolysis, a promising approach to produce bioactive diosgenin from the tubers of Dioscorea Zingiberensis. AB - BACKGROUND: The tubers of Dioscorea zingiberensis, is the most favorable plant material for the production of diosgenin, an important bioactive steroidal sapogenin and requisite precursor of cortin, contraceptive and sex hormone, which is the only desired product after steroidal saponins from the tubers are hydrolyzed. OBJECTIVE: A novel technology, in situ pressurized biphase acid hydrolysis was constructed for the first time to simplify extraction process, increase extraction yield and decrease the consumption of mineral acids. MATERIALS AND METHODS: The method developed in this study has been optimized and verified through orthogonal design for experiments, in which the effect and their significance of four factors including molarity of acid, temperature, extraction duration and sample quantity have been investigated. Then, the comparison was conducted among the newly developed method and other reported methods. The diosgenin was also isolated by column chromatography, followed by mass spectrometry and nuclear magnetic resonance analysis for structural confirmation. RESULTS: It was found that temperature is the factor of the most influence and the highest extraction yield at 2.21% has been achieved while the hydrolysis was performed at 140 degrees C for 1.5 h in 0.20M H2SO4 solution with petroleum ether under an uncontrolled pressurized condition. And, compared to the others, the increment in the extraction yield of new method was 20.8 ~ 74.0%, and the consumption of H2SO4 was reduced by 17 times at most. CONCLUSION: This method is a much cleaner and more efficient approach for extraction of diosgenin from the tubers, and is promising to be applied in pharmaceutical industry. PMID- 26246744 TI - On-line quantitative monitoring of liquid-liquid extraction of Lonicera japonica and Artemisia annua using near-infrared spectroscopy and chemometrics. AB - BACKGROUND: Liquid-liquid extraction of Lonicera japonica and Artemisia annua (JQ) plays a significant role in manufacturing Reduning injection. Many process parameters may influence liquid-liquid extraction and cause fluctuations in product quality. OBJECTIVE: To develop a near-infrared (NIR) spectroscopy method for on-line monitoring of liquid-liquid extraction of JQ. MATERIALS AND METHODS: Eleven batches of JQ extraction solution were obtained, ten for building quantitative models and one for assessing the predictive accuracy of established models. Neochlorogenic acid (NCA), chlorogenic acid (CA), cryptochlorogenic acid (CCA), isochlorogenic acid B (ICAB), isochlorogenic acid A (ICAA), isochlorogenic acid C (ICAC) and soluble solid content (SSC) were selected as quality control indicators, and measured by reference methods. NIR spectra were collected in transmittance mode. After selecting the spectral sub-ranges, optimizing the spectral pretreatment and neglecting outliers, partial least squares regression models were built to predict the content of indicators. The model performance was evaluated by the coefficients of determination (R (2)), the root mean square errors of prediction (RMSEP) and the relative standard error of prediction (RSEP). RESULTS: For NCA, CA, CCA, ICAB, ICAA, ICAC and SSC, R (2) was 0.9674, 0.9704, 0.9641, 0.9514, 0.9436, 0.9640, 0.9809, RMSEP was 0.0280, 0.2913, 0.0710, 0.0590, 0.0815, 0.1506, 1.167, and RSEP was 2.32%, 4.14%, 3.86%, 5.65%, 7.29%, 6.95% and 4.18%, respectively. CONCLUSION: This study demonstrated that NIR spectroscopy could provide good predictive ability in monitoring of the content of quality control indicators in liquid-liquid extraction of JQ. PMID- 26246745 TI - Flavonoids isolated from Lespedeza cuneata G. Don and their inhibitory effects on nitric oxide production in lipopolysaccharide-stimulated BV-2 microglia cells. AB - BACKGROUND: Lespedeza cuneata (Dum. Cours.) G. Don, a perennial legume native to Eastern Asia, has been used therapeutically in traditional Asian medicine to protect the function of liver, kidneys and lungs. However, its effect on inflammatory nitric oxide (NO) production and the active constituents have not yet been explored. OBJECTIVE: In this study, we investigated the phytochemical constituents of L. cuneata and evaluated their effect on NO production using lipopolysaccharide (LPS)-stimulated BV2 cells. MATERIALS AND METHODS: The 80% methanol extract of the aerial part of L. cuneata were used for the isolation of flavonoids. The isolated compounds were elucidated by various spectroscopic methods including nuclear magnetic resonance and mass spectrometry spectrometry. To evaluate the effect on inflammatory NO production, LPS-stimulated murine microglia BV-2 cells were used as a screening system. RESULTS: Nine flavonoids were isolated from the aerial parts of L. cuneata. Among the isolated flavonoids, compounds 4, 5, 7 and 9 are reported from the genus Lespedeza for the first time. Moreover, compounds 1 and 6 showed significant inhibitory effects on NO production in LPS-stimulated BV2 cells without cell toxicity. CONCLUSION: In this study, nine flavonoids were isolated from L. cuneata. Among the compounds, only 1 and 6, which have free hydroxyl groups at both C3 and C7 showed significant inhibitory activity on NO production in LPS-stimulated BV2 cells. These results suggested L. cuneata and its flavonoid constituents as possible candidate for the treatment of various inflammatory diseases. PMID- 26246746 TI - Quantification of maltol in Korean ginseng (Panax ginseng) products by high performance liquid chromatography-diode array detector. AB - BACKGROUND: Maltol, as a type of phenolic compounds, is produced by the browning reaction during the high-temperature treatment of ginseng. Thus, maltol can be used as a marker for the quality control of various ginseng products manufactured by high-temperature treatment including red ginseng. For the quantification of maltol in Korean ginseng products, an effective high-performance liquid chromatography-diode array detector (HPLC-DAD) method was developed. MATERIALS AND METHODS: The HPLC-DAD method for maltol quantification coupled with a liquid liquid extraction (LLE) method was developed and validated in terms of linearity, precision, and accuracy. An HPLC separation was performed on a C18 column. RESULTS: The LLE methods and HPLC running conditions for maltol quantification were optimized. The calibration curve of the maltol exhibited good linearity (R (2) = 1.00). The limit of detection value of maltol was 0.26 MUg/mL, and the limit of quantification value was 0.79 MUg/mL. The relative standard deviations (RSDs) of the data of the intra- and inter-day experiments were <1.27% and 0.61%, respectively. The results of the recovery test were 101.35-101.75% with an RSD value of 0.21-1.65%. The developed method was applied successfully to quantify the maltol in three ginseng products manufactured by different methods. CONCLUSION: The results of validation demonstrated that the proposed HPLC-DAD method was useful for the quantification of maltol in various ginseng products. PMID- 26246748 TI - Calling All Educators: Let Us Know Your Educational Needs. PMID- 26246749 TI - Older Adults and Diabetes: Preface. PMID- 26246747 TI - Effect of modified Bo-yang-Hwan-o-Tang, a polyherbal medicine on the hippocampal neuronal damage in a rat model of global ischemia. AB - BACKGROUND: Chronic cerebral hypoperfusion has been well-characterized as a common pathological status contributing to vascular dementia (VD). In this study, the neuroprotective effect of modified Bo-yang-Hwan-O Tang (mBHT), a polyherbal medicine for ischemic stroke, was investigated in a rat model for global ischemia. MATERIALS AND METHODS: Global ischemia model was prepared in Sprague Dawley rats by the permanent occlusion of bilateral common carotid arteries (two vessel occlusion [2VO])-induced chronic cerebral hypoperfusion. mBHT at doses of 250 and 500 mg/kg was orally administrated for 4 weeks once a day, 24 h after 2VO. Histopathological change of the hippocampal region was observed by hematoxylin and eosin, Nissl, and Fluoro-Jade B staining and immunohistochemistry with anti-glial fibrillary acidic protein and anti-neuronal nuclei antibodies. The expression of Bax, Bcl-2, and caspase-3 was investigated in the hippocampus by Western blot. The nuclear factor-kappa B (NF-kappaB) expression was also analyzed in hippocampal CA1 region using immunofluorescence staining. RESULTS: The administration of mBHT at doses of 250 and 500 mg/kg significantly inhibited chronic cerebral hypoperfusion-induced neuronal damage and astroglial activation in the hippocampal CA1 region in 2VO rats. mBHT increased the NF-kappaB expression in the CA1 neuronal cells but decreased in activated astrocytes. In addition, mBHT significantly decreased the hippocampal expression of Bax and caspase-3 and increased the Bcl-2 expression in 2VO rats. CONCLUSIONS: Our data indicate that mBHT has a neuroprotective property in VD induced by chronic cerebral hypoperfusion through inhibiting the hippocampal neuronal damage and astrogliosis. PMID- 26246750 TI - Guest Editor. PMID- 26246751 TI - Management of Type 1 Diabetes in Older Adults. AB - Older adults with type 1 diabetes are at high risk for severe hypoglycemia and may have serious comorbid conditions. Problems with cognition, mobility, dexterity, vision, hearing, depression, and chronic pain interfere with the ability to follow complex insulin regimens. With the development of geriatric syndromes, unpredictable eating, and frailty, treatment regimens must be modified with the goal of minimizing hypoglycemia and severe hyperglycemia and maximizing quality of life. PMID- 26246752 TI - Physiological Changes in Older Adults and Their Effect on Diabetes Treatment. AB - In Brief Physiological changes associated with aging have the potential to affect the treatment of diabetes. However, evidence regarding treatment of diabetes in geriatric patients has been limited, especially for "oldest-old" patients. Recent research has provided greater insight into the risks and benefits of treatment, and new guidelines provide more specific information regarding treatment goals in older people with diabetes and encourage greater individualization of treatment. PMID- 26246753 TI - Nutrition Considerations for the Growing Population of Older Adults With Diabetes. AB - The growing older adult population and its higher incidence of diabetes are creating demands on health care providers to address the special needs of these patients. Because nutrition is essential to the proper treatment and self management of diabetes, clinicians must develop and adopt various strategies to address some of the common nutritional, lifestyle, and self-management barriers that older adults face. Nutrition assessments of older adults with diabetes should be comprehensive, with attention to each patient's unique nutritional needs. Constructing a realistic nutrition care plan is essential for success. This article addresses some of the key nutrition-related aspects of diabetes self care in older adults with diabetes. PMID- 26246754 TI - Special Considerations for Older Adults With Diabetes Residing in Skilled Nursing Facilities. AB - About 25% of all residents of skilled nursing facilities (SNFs) have diabetes, and that proportion is expected to increase. SNF residents with diabetes have special needs related to nutrition, hydration, physical activity, and medical therapy. Vigilant assessment and maintenance of safety is also crucial for such patients, including but not limited to issues such as hyper- and hypoglycemia, polypharmacy, falls, lower-extremity problems, and transitions of care. Interventions to provide stable glycemic control; ensure adequate nutrition, hydration, and physical activity; decrease polypharmacy; prevent falls; facilitate transitions of care; and improve the diabetes-related knowledge of SNF staff can help to meet these needs. Although this article focuses on SNFs, many of the topics covered also apply to elderly people with diabetes in other long term care settings. PMID- 26246755 TI - Listening to Older Adults' Values and Preferences for Type 2 Diabetes Care: A Qualitative Study. AB - Individuals' values and preferences have a considerable impact on their motivation and, therefore, their willingness to follow treatment recommendations. This qualitative study aimed to describe older adults' values and preferences for type 2 diabetes care. Older adults valued an effective physician-patient treatment relationship and quality of life in their diabetes care. They preferred physicians who knew them as a person and were honest about their diabetes treatment and progression of the illness. When developing treatment plans, providers should assess the effect that treatment will likely have on older adults' health, while explicitly acknowledging their values and preferences for care as a prelude to better patient-centered care and potentially shared decision making. PMID- 26246756 TI - "Es como uno bomba de tiempo [It's like a time bomb]": A Qualitative Analysis of Perceptions of Diabetes Among First-Degree Relatives of Latino Patients With Diabetes. AB - Background. The South Bronx, a largely Latino community, has become an epicenter of the diabetes epidemic in New York City. In this community, nondiabetic first degree relatives of people with diabetes are prime targets for intervention. Therefore, the objective of this study was to explore the knowledge of diabetes and attitudes toward health behavior modification of Latino adults who are first degree relatives of people with diabetes. Methods. Participants were recruited from three settings in the South Bronx (a community-based organization, a faith based organization, and a taxi station). The Common Sense Model was used to develop focus-group items. This model provides a framework for exploring illness representations along five domains: identity, cause, consequences, timeline, and perceptions of curability. Responses were transcribed verbatim, and data analysis proceeded in the following order: data immersion, assignment of codes, grouping of key concepts to form categories, and construction of higher-order themes. Results. Of the 115 potential participants identified, 53 were found to be eligible, and 23 of these participated in the focus group. Of these, 20 were Dominicans, 2 were Puerto Ricans, and 1 was Salvadorian. The mean age was 46.39 years, 35% were women, 61% were married, and 26% had less than a high school education. Qualitative analyses resulted in 547 codes that were grouped into 52 concepts, from which 9 categories and 4 overarching themes emerged. The dominant themes were 1) family, genetics, and culture play a major role in the etiology of diabetes; 2) being Latino and having a first-degree relative with diabetes makes getting diabetes inevitable, and, like a time bomb exploding, it is destined to happen; 3) once one develops diabetes, the physical and emotional consequences are devastating and destructive; and 4) diabetes can be "cured" through healthy eating and with insulin. Conclusions.In this study, first-degree relatives of patients with diabetes were knowledgeable about the risks and consequences of diabetes. However, some participants felt that being Latino and having a first degree relative with diabetes made one destined to have diabetes. Addressing this misperception through culturally tailored interventions has implications for diabetes prevention and may help to stem the diabetes epidemic in Latino communities. PMID- 26246757 TI - Treatment of Mild Hypoglycemia. PMID- 26246758 TI - Diabetes Prevention and Management: The Thrill Is Not Gone. PMID- 26246759 TI - Improving the Lives of All People Affected by Type 2 Diabetes. PMID- 26246760 TI - The Food and Drug Administration and the Future of Drug Development for the Treatment of Diabetes. PMID- 26246761 TI - Pharmacotherapy of Diabetes: Past, Present, and Future: Preface. PMID- 26246762 TI - Guest Editor. PMID- 26246763 TI - A Brief History of the Development of Diabetes Medications. AB - This article provides an overview of the development of insulins, oral agents, and noninsulin injectable agents used in the management of hyperglycemia in patients with diabetes. It also briefly reviews the pharmacological impact and salient side effects of these medications. PMID- 26246764 TI - Personalized Diabetes Management: Moving from Algorithmic to Individualized Therapy. AB - Management of individuals with type 2 diabetes involves complex decision-making to attain good glycemic control. A personalized approach to the care of these individuals provides a unique management plan for each patient. This article reviews some of the important variables that require consideration for management of individuals with type 2 diabetes. We also provide a scoring scale to help clinicians make appropriate decisions regarding A1C targets while caring for these patients. PMID- 26246765 TI - Update on Safety Issues Related to Antihyperglycemic Therapy. AB - The American Diabetes Association emphasizes the importance of individualized patient care in the management of diabetes. One of the important considerations in choosing an antihyperglycemic agent is its side-effect and safety profile. This article reviews the common and clinically significant side effects of each class of agents, including ways to prevent and overcome their occurrence. PMID- 26246766 TI - Novel Agents for the Treatment of Type 2 Diabetes. AB - In Brief Impaired insulin secretion, increased hepatic glucose production, and decreased peripheral glucose utilization are the core defects responsible for the development and progression of type 2 diabetes. However, the pathophysiology of this disease also includes adipocyte insulin resistance (increased lipolysis), reduced incretin secretion/sensitivity, increased glucagon secretion, enhanced renal glucose reabsorption, and brain insulin resistance/neurotransmitter dysfunction. Although current diabetes management focuses on lowering blood glucose, the goal of therapy should be to delay disease progression and eventual treatment failure. Recent innovative treatment approaches target the multiple pathophysiological defects present in type 2 diabetes. Optimal management should include early initiation of combination therapy using multiple drugs with different mechanisms of action. This review examines novel therapeutic options that hold particular promise. PMID- 26246767 TI - Depression and Risk Perceptions in Older African Americans With Diabetes. AB - Objective. The purpose of this study is to describe the impact of depression on perceptions of risks to health, diabetes self-management practices, and glycemic control in older African Americans with type 2 diabetes. Methods. The authors analyzed data on depression, risk perceptions, diabetes self-management, and A1C in African Americans with type 2 diabetes. T-tests, chi(2), and multivariate regression were used to analyze the data. Results. The sample included 177 African Americans (68% women) whose average age was 72.8 years. Thirty-four participants (19.2%) met criteria for depression. Compared to nondepressed participants, depressed participants scored significantly higher on Personal Disease Risk (the perception of being at increased risk for various medical problems), Environmental Risk (i.e., increased risk for environmental hazards), and Composite Risk Perception (i.e., overall perceptions of increased risk); adhered less to diabetes self-management practices; and had marginally worse glycemic control. Depression and fewer years of education were independent predictors of overall perception of increased health risks. Conclusion. Almost 20% of older African Americans with type 2 diabetes in this study were depressed. Compared to nondepressed participants, they tended to have fewer years of education, perceived themselves to be at higher risk for multiple health problems, and adhered less to diabetes self-management practices. It is important for diabetes educators to recognize the impact of low education and the fatalistic perceptions that depression engenders in this population. PMID- 26246769 TI - The Patient-Centered Medical Neighborhood and Diabetes Care. PMID- 26246770 TI - Insulin Pump Class: Back to the Basics of Pump Therapy. PMID- 26246768 TI - New Diabetes Nutrition Therapy Recommendations: What You Need to Know. PMID- 26246771 TI - Targeting Diabetes Distress: The Missing Piece of the Successful Type 1 Diabetes Management Puzzle. PMID- 26246772 TI - Inpatient Glycemic Management: What Are the Goals and How Do We Achieve Them?: Preface. PMID- 26246773 TI - Guest Editor. PMID- 26246774 TI - The Mealtime Challenge: Nutrition and Glycemic Control in the Hospital. AB - In Brief Multiple staff members and departments have a responsibility for various aspects of nutrition therapy for glycemic management in the hospital setting. Implementation is initiated by physicians, nurse practitioners, and physician's assistants and planned and operationalized by registered dietitians. Meals are delivered by food service staff, and nurses monitor and integrate glycemic control components into patients' medical treatment plan. Although nutrition therapy is recognized as an important aspect of care in the hospital setting, it can also be challenging to appropriately coordinate meals with blood glucose monitoring and insulin administration. This article addresses current mealtime practices and recommendations to improve these processes in acute care. PMID- 26246775 TI - Addressing Glycemic Targets from Diagnosis to Discharge. AB - On any given day, from 25 to 50% of all hospitalized patients meet criteria for a diagnosis of diabetes, prediabetes, or hyperglycemia. It is essential for all health care providers, including diabetes clinicians, to examine current processes to ensure the delivery of the highest quality care, with a focus on glucose control, improved outcomes, and patient safety from admission through discharge. PMID- 26246776 TI - Point-of-Care Blood Glucose Meter Accuracy in the Hospital Setting. AB - Point-of-care (POC) tests provide analytical information that can be used to make decisions at patients' bedside, as opposed to laboratory tests that must be run at a central laboratory. POC testing is a widely used tool to enable immediate determination of glucose levels in hospitalized patients and facilitate rapid treatment decisions in response to fluctuations in glycemia. Accurate POC glucose testing requires attention to various factors before, during, and after performance of tests. These include 1) proper preparation of test sites to avoid preanalytical errors, 2) proper identification of tested patients whose physiological status permits sampled capillary specimens to correlate with central venous blood glucose levels to avoid analytical errors, and 3) proper documentation of the fidelity of meter results with the medical record to avoid postanalytical errors. PMID- 26246778 TI - Diabetes Champions: Culture Change Through Education. AB - In Brief This article describes a diabetes champion program in its fifth year of operation. This educational intervention was designed to increase direct diabetes patient education and has grown into a vehicle for improving quality of care and patient safety and reducing gaps in the transitions of care. PMID- 26246779 TI - Transitions in Care from the Hospital to Home for Patients With Diabetes. AB - In Brief Diabetes is a common coexisting chronic condition among older adults that can complicate a hospitalization and transition back to the community. The Transitional Care Model, which offers a set of time-limited, hospital-to-home services coordinated by a master's-prepared advanced practice nurse, is one option that could improve outcomes for patients with diabetes. A descriptive case study is presented. PMID- 26246777 TI - Pharmacotherapy for Hyperglycemia in Noncritically Ill Hospitalized Patients. AB - In Brief Hyperglycemia in the hospital setting affects 38-46% of noncritically ill hospitalized patients. Evidence from observational studies indicates that inpatient hyperglycemia, in patients with and without diabetes, is associated with increased risks of complications and mortality. Substantial evidence indicates that correction of hyperglycemia through insulin administration reduces hospital complications and mortality in critically ill patients, as well as in general medicine and surgery patients. This article provides a review of the evidence on the different therapies available for hyperglycemia management in noncritically ill hospitalized patients. PMID- 26246780 TI - Best Practices for Interdisciplinary Care Management by Hospital Glycemic Teams: Results of a Society of Hospital Medicine Survey Among 19 U.S. Hospitals. AB - Objective. The Society for Hospital Medicine (SHM) conducted a survey of U.S. hospital systems to determine how nonphysician providers (NPPs) are utilized in interdisciplinary glucose management teams. Methods. An online survey grouped 50 questions into broad categories related to team functions. Queries addressed strategies that had proven successful, as well as challenges encountered. Fifty surveys were electronically distributed with an invitation to respond. A subset of seven respondents identified as having active glycemic committees that met at least every other month also participated in an in-depth telephone interview conducted by an SHM Glycemic Advisory Panel physician and NPP to obtain further details. The survey and interviews were conducted from May to July 2012. Results. Nineteen hospital/hospital system teams completed the survey (38% response rate). Most of the teams (52%) had existed for 1-5 years and served 90-100% of noncritical care, medical critical care, and surgical units. All of the glycemic control teams were supported by the use of protocols for insulin infusion, basal bolus subcutaneous insulin orders, and hypoglycemia management. However, > 20% did not have protocols for discontinuation of oral hypoglycemic agents on admission or for transition from intravenous to subcutaneous insulin infusion. About 30% lacked protocols assessing A1C during the admission or providing guidance for insulin pump management. One-third reported that glycemic triggers led to preauthorized consultation or assumption of care for hyperglycemia. Institutional knowledge assessment programs were common for nurses (85%); intermediate for pharmacists, nutritionists, residents, and students (40-45%); and uncommon for fellows (25%) and attending physicians (20%). Many institutions were not monitoring appropriate use of insulin, oral agents, or insulin protocol utilization. Although the majority of teams had a process in place for post discharge referrals and specific written instructions were provided, only one fourth were supported with written protocols to standardize medication, education, equipment, and follow-up instructions. Conclusion. Inpatient glycemic control teams with NPPs often function in environments without a full set of measurement, education, standardization, transition, and order tools. Executive hospital leaders, community partners, and the glycemic control teams themselves need to address these deficiencies to optimize team effectiveness. PMID- 26246781 TI - Sustainability of Improved Glycemic Control After Diabetes Self-Management Education. AB - Objective. The purpose of this study was to evaluate glycemic control as measured by A1C during a 2-year period after patients received diabetes self-management education (DSME). Methods. Patients who completed DSME in 2009 and received medical follow-up with A1C measurements for at least 2 years after DSME were included in the evaluation. Primary endpoints were changes in A1C from before to immediately after, 1 year after, and 2 years after DSME. Secondary outcomes included the effects of the following factors on change in A1C: sex, duration of diabetes, uncontrolled diabetes (A1C >= 9%), health insurance coverage, and self reported education level. Results. Forty-three patients were included in the evaluation. Mean A1C before DSME was 10.2 +/- 3.7%. Mean A1C after DSME was 7.8 +/- 2.2% (P < 0.0001), a 23.5% reduction. Mean A1C at 1 and 2 years after DSME was 7.8 +/- 2.1% for each year and remained unchanged from just after DSME to 1 and 2 years after DSME (P > 0.05). Patients with a duration of diabetes of < 1 year had a significantly greater reduction in mean A1C than those with a duration of diabetes >= 1 year (28.7 and 20.2%, respectively, P = 0.001). Conclusion. DSME improved glycemic control to a substantial degree, and the effect was sustained for up to 2 years. Although the reduction in A1C was significant for all patients receiving DSME, there was a significantly greater reduction for patients who had a duration of diabetes of < 1 year than for those with a duration of diabetes > 1 year. PMID- 26246782 TI - How Sweet Is It? The Use of Benchmarking to Optimize Inpatient Glycemic Control. PMID- 26246783 TI - Continuous Insulin Infusion: When, Where, and How? PMID- 26246785 TI - Treatment of Internal Hemorrhoids by Endoscopic Sclerotherapy with Aluminum Potassium Sulfate and Tannic Acid. AB - Objective. A new sclerosing agent for hemorrhoids, aluminum potassium sulfate and tannic acid (ALTA), is attracting attention as a curative treatment for internal hemorrhoids without resection. The outcome and safety of ALTA sclerotherapy using an endoscope were investigated in the present study. Materials and Methods. Subjects comprised 83 internal hemorrhoid patients (61 males and 22 females). An endoscope was inserted and retroflexed in the rectum, and a 1st-step injection was applied to the upper parts of the hemorrhoids. The retroflexed scope was returned to the normal position, and 2nd-4th-step injections were applied to the middle and lower parts of the hemorrhoids under direct vision. The effects of endoscopic ALTA sclerotherapy were determined by evaluating the condition of the hemorrhoids using an anoscope and interviewing the patient 28 days after the treatment. Results. A cure, improvement, and failure were observed in 54 (65.1%), 27 (32.5%), and 2 (2.4%) patients, respectively, treated with ALTA. Complications developed in 4 patients (mild fever in 3 and hematuria in 1). Recurrence occurred in 9.6%. Conclusions. The results of the present study suggest that endoscopic ALTA has the potential to become a useful and minimally invasive approach for ALTA sclerotherapy. PMID- 26246786 TI - Heading off depressive illness evolution and progression to treatment resistance. AB - Viewing recurrent depression as a potentially progressive illness may help transform treatment toward earlier, more consistent intervention and prevention. Evidence indicates that recurrent stressors, episodes of depression, and bouts of substance abuse can each show sensitization (increased reactivity upon repetition) and cross-sensitization to the others, and drive illness progression and treatment resistance. These long-lasting increases in pathological responsivity appear to be mediated by epigenetic mechanisms involving alterations in chemical marks placed on DNA and histories. These types of sensitization effects are amenable to clinical attempts at amelioration and prevention, and provide treatment targets and strategies to minimize the likelihood of illness progression to treatment resistance. PMID- 26246784 TI - The Characterization of Feces and Urine: A Review of the Literature to Inform Advanced Treatment Technology. AB - The safe disposal of human excreta is of paramount importance for the health and welfare of populations living in low income countries as well as the prevention of pollution to the surrounding environment. On-site sanitation (OSS) systems are the most numerous means of treating excreta in low income countries, these facilities aim at treating human waste at source and can provide a hygienic and affordable method of waste disposal. However, current OSS systems need improvement and require further research and development. Development of OSS facilities that treat excreta at, or close to, its source require knowledge of the waste stream entering the system. Data regarding the generation rate and the chemical and physical composition of fresh feces and urine was collected from the medical literature as well as the treatability sector. The data were summarized and statistical analysis was used to quantify the major factors that were a significant cause of variability. The impact of this data on biological processes, thermal processes, physical separators, and chemical processes was then assessed. Results showed that the median fecal wet mass production was 128 g/cap/day, with a median dry mass of 29 g/cap/day. Fecal output in healthy individuals was 1.20 defecations per 24 hr period and the main factor affecting fecal mass was the fiber intake of the population. Fecal wet mass values were increased by a factor of 2 in low income countries (high fiber intakes) in comparison to values found in high income countries (low fiber intakes). Feces had a median pH of 6.64 and were composed of 74.6% water. Bacterial biomass is the major component (25-54% of dry solids) of the organic fraction of the feces. Undigested carbohydrate, fiber, protein, and fat comprise the remainder and the amounts depend on diet and diarrhea prevalence in the population. The inorganic component of the feces is primarily undigested dietary elements that also depend on dietary supply. Median urine generation rates were 1.42 L/cap/day with a dry solids content of 59 g/cap/day. Variation in the volume and composition of urine is caused by differences in physical exertion, environmental conditions, as well as water, salt, and high protein intakes. Urine has a pH 6.2 and contains the largest fractions of nitrogen, phosphorus, and potassium released from the body. The urinary excretion of nitrogen was significant (10.98 g/cap/day) with urea the most predominant constituent making up over 50% of total organic solids. The dietary intake of food and fluid is the major cause of variation in both the fecal and urine composition and these variables should always be considered if the generation rate, physical, and chemical composition of feces and urine is to be accurately predicted. PMID- 26246787 TI - Pharmacological approaches to the challenge of treatment-resistant depression. AB - Although monoaminergic antidepressants revolutionized the treatment of Major Depressive Disorder (MDD) over a half-century ago, approximately one third of depressed patients experience treatment-resistant depression (TRD). Such patients account for a disproportionately large burden of disease, as evidenced by increased disability, cost, human suffering, and suicide. This review addresses the definition, causes, evaluation, and treatment of unipolar TRD, as well as the major treatment strategies, including optimization, augmentation, combination, and switch therapies. Evidence for these options, as outlined in this review, is mainly focused on large-scale trials or meta-analyses. Finally, we briefly review emerging targets for antidepressant drug discovery and the novel effects of rapidly acting antidepressants, with a focus on ketamine. PMID- 26246789 TI - Comorbidity between post-traumatic stress disorder and major depressive disorder: alternative explanations and treatment considerations. AB - Approximately half of people with post-traumatic stress disorder (PTSD) also suffer from Major Depressive Disorder (MDD). The current paper examines evidence for two explanations of this comorbidity. First, that the comorbidity reflects overlapping symptoms in the two disorders. Second, that the co-occurrence of PTSD and MDD is not an artifact, but represents a trauma-related phenotype, possibly a subtype of PTSD. Support for the latter explanation is inferred from literature that examines risk and biological correlates of PTSD and MDD, including molecular processes. Treatment implications of the comorbidity are considered. PMID- 26246788 TI - Treatment of affective disorders in cardiac disease. AB - Patients with cardiovascular disease (CVD) commonly have syndromal major depression, and depression has been associated with an increased risk of morbidity and mortality. Prevalence of depression is between 17% and 47% in CVD patients. Pharmacologic and psychotherapeutic interventions have long been studied, and in general are safe and somewhat efficacious in decreasing depressive symptoms in patients with CVD. The impact on cardiac outcomes remains unclear. The evidence from randomized controlled clinical trials indicates that antidepressants, especially selective serotonin uptake inhibitors, are overwhelmingly safe, and likely to be effective in the treatment of depression in patients with CVD. This review describes the prevalence of depression in patients with CVD, the physiological links between depression and CVD, the treatment options for affective disorders, and the clinical trials that demonstrate efficacy and safety of antidepressant medications and psychotherapy in this patient population. Great progress has been made in understanding potential mediators between major depressive disorder and CVD--both health behaviors and shared biological risks such as inflammation. PMID- 26246790 TI - Applications of magnetic resonance imaging for treatment-resistant late-life depression. AB - Late-life depression (LLD) is a growing public and global health concern with diverse clinical manifestations and etiology. This literature review summarizes neuroimaging findings associated with depression in older adults and treatment response variability. LLD has been associated with cerebral atrophy, diminished myelin integrity, and cerebral lesions in frontostriatal-limbic regions. These associations help explain the depression-executive dysfunction syndrome observed in LLD, and support cerebrovascular burden as a pathogenic mechanism. Furthermore, this review suggests that neuroimaging determinants of treatment resistance also reflect cerebrovascular burden. Of the theoretical etiologies of LLD, cerebrovascular burden may mediate treatment resistance. This review proposes that neuroimaging has the potential for clinical translation. Controlled trials may identify neuroimaging biomarkers that may inform treatment by identifying depressed adults likely to remit with pharmacotherapy, identifying individualized therapeutic dose, and facilitating earlier treatment response measures. Neuroimaging also has the potential to similarly inform treatment response variability from treatment with aripiprazole (dopamine modulator) and buprenorphine (opiate modulator). PMID- 26246791 TI - Depression in adolescents and young adults with cancer. AB - Adolescents and young adults (AYAs) with cancer are at risk for depression due to disruptions in their developmental trajectory, greater physical symptom burden, and increased likelihood of developing aggressive disease. Rates of depression and other psychological disorders are substantially higher in AYAs with cancer when compared with older adults. Psychiatrists caring for these patients must consider the age-appropriate developmental context of these patients along with familial and medical factors that may influence the presentation and treatment of depression. Previous research suggests that psychosocial interventions specifically designed for AYA patients are promising, but studies of psychopharmacology treatments for depression are lacking. There is a pressing need for prospective studies and controlled clinical trials that evaluate the optimal strategies for treating depression in this patient group. PMID- 26246792 TI - Assessment and treatment of mood disorders in the context of substance abuse. AB - Recognition and management of mood symptoms in individuals using alcohol and/or other drugs represent a daily challenge for clinicians in both inpatient and outpatient treatment settings. Diagnosis of underlying mood disorders in the context of ongoing substance abuse requires careful collection of psychiatric history, and is often critical for optimal treatment planning and outcomes. Failure to recognize major depression or bipolar disorders in these patients can result in increased relapse rates, recurrence of mood episodes, and elevated risk of completed suicide. Over the past decade, epidemiologic research has clarified the prevalence of comorbid mood disorders in substance-dependent individuals, overturning previous assumptions that depression in these patients is simply an artifact of intoxication and/or withdrawal, therefore requiring no treatment. However, our understanding of the bidirectional relationships between mood and substance use disorders in terms of their course(s) of illness and prognoses remains limited. Like-wise, strikingly little treatment research exists to guide clinical decision making in co-occurring mood and substance use disorders, given their high prevalence and public health burden. Here we overview what is known and the salient gaps of knowledge where data might enhance diagnosis and treatment of these complicated patients. PMID- 26246793 TI - Treatment-refractory anxiety; definition, risk factors, and treatment challenges. AB - A sizable proportion of psychiatric patients will seek clinical evaluation and treatment for anxiety symptoms reportedly refractory to treatment. This apparent lack of response is either due to "pseudo-resistance" (a failure to have received and adhered to a recognized and effective treatment or treatments for their condition) or to true "treatment resistance." Pseudo-resistance can be due to clinician errors in selecting and delivering an appropriate treatment effectively, or to patient nonadherence to a course of treatment. True treatment resistance can be due to unrecognized exogenous anxiogenic factors (eg, caffeine overuse, sleep deprivation, use of alcohol or marijuana) or an incorrect diagnosis (eg, atypical bipolar illness, occult substance abuse, attention deficit-hyperactivity disorder). Once the above factors are eliminated, treatment should focus on combining effective medications and cognitive behavioral therapy, combining several medications (augmentation), or employing novel medications or psychotherapies not typically indicated as first-line evidence-based anxiety treatments. PMID- 26246794 TI - Optimizing the treatment of mood disorders in the perinatal period. AB - The perinatal period is a time of high risk for women with unipolar and bipolar mood disorders. We discuss treatment considerations for perinatal mood disorders, including unipolar and bipolar depression as well as postpartum psychosis. We further explore the unique issues faced by women and their families across the full trajectory of the perinatal period from preconception planning through pregnancy and following childbirth. Treatment of perinatal mood disorders requires a collaborative care approach between obstetrics practitioners and mental health providers, to ensure that a thoughtful risk : benefit analysis is conducted. It is vital to consider the risks of the underlying illness versus risks of medication exposure during pregnancy or lactation. When considering medication treatment, attention must be paid to prior medication trials that were most efficacious and best tolerated. Lastly, it is important to assess the impact of individual psychosocial stressors and lifestyle factors on treatment response. PMID- 26246795 TI - Challenges in the diagnosis and treatment of depression in autism spectrum disorders across the lifespan. AB - Diagnosis and treatment of comorbid neuropsychiatric illness is often a secondary focus of treatment in individuals with autism spectrum disorder (ASD), given that substantial impairment may be caused by core symptoms of ASD itself. However, psychiatric comorbidities, including depressive disorders, are common and frequently result in additional functional impairment, treatment costs, and burden on caregivers. Clinicians may struggle to appropriately diagnose depression in ASD due to communication deficits, atypical presentation of depression in ASD, and lack of standardized diagnostic tools. Specific risk and resilience factors for depression in ASD across the lifespan, including level of functioning, age, family history, and coping style, have been suggested, but require further study. Treatment with medications or psychotherapy may be beneficial, though more research is required to establish guidelines for management of symptoms. This review will describe typical presentations of depression in individuals with ASD, review current information on the prevalence, assessment, and treatment of comorbid depression in individuals with ASD, and identify important research gaps. PMID- 26246797 TI - Autism symptoms in toddlers with Down syndrome: a descriptive study. AB - BACKGROUND: Research suggests that children with Down syndrome may be at increased risk of having an autism spectrum disorder; however, previous studies have not utilized comprehensive, state-of-the-art diagnostic tools to address the question of comorbid autism and Down syndrome. METHOD: Comprehensive evaluations for autism were conducted in 20 2-year-old children with Down syndrome. The Autism Diagnostic Observation Schedule-Generic (ADOS-G) and the Autism Diagnostic Interview-Revised (ADI-R) were administered by experienced clinicians, who then determined if the child presented with significant symptoms of autism. Eighteen children participated in a follow-up evaluation at age 4 years. RESULTS: Three children (15%) met criteria for an autism spectrum disorder at both time points, and two (10%) for autistic disorder. Case descriptions are provided. Several children presented with difficulties in communication and play, but did not show problems in core social relatedness. The ADOS-G, if used alone, over-identifies autism in toddlers with Down syndrome. CONCLUSIONS: Clinical judgement is critical in diagnosing autism in Down syndrome. Young children may show some signs of autism (particularly in the area of communication) and not have the disorder. Children who have comorbid Down syndrome and autism are particularly challenged, relative to their peers without autism. PMID- 26246796 TI - Neurobiologically informed treatment for adults with anorexia nervosa: a novel approach to a chronic disorder. AB - Anorexia nervosa (AN) is a severe and debilitating disorder with significant medical and psychological sequelae. To date, there are no effective treatments for adults, resulting in high rates of chronicity, morbidity, and mortality. Recent advances in brain imaging research have led to an improved understanding of etiology and specific neurobiological mechanisms underlying symptoms. Despite this, there are no treatments focused on targeting symptoms using this empirically supported mechanistic understanding of the illness. Updated treatment approaches focused on targeting neurobiological mechanisms underlying core AN symptomatology are necessary to improve treatment out-comes for this population. Neurobiologically Enhanced With Family Eating Disorder Trait Response Treatment (NEW FED TR) is a neurobiologically informed treatment targeting key temperament constructs associated with the illness through the delivery of psychoeducation and skills training to patients and nominated carers. PMID- 26246798 TI - Comparative analysis of the labelling of nanotechnologies across four stakeholder groups. AB - Societies are constantly challenged to develop policies around the introduction of new technologies, which by their very nature contain great uncertainty. This uncertainty gives prominence to varying viewpoints which are value laden and have the ability to drastically shift policy. The issue of nanotechnologies is a prime example. The labelling of products that contain new technologies has been one policy tool governments have used to address concerns around uncertainty. Our study develops evidence regarding opinions on the labelling of products made by nanotechnologies. We undertook a computer-assisted telephone (CATI) survey of the Australian public and those involved in nanotechnologies from the academic, business and government sectors using a standardised questionnaire. Analysis was undertaken using descriptive and logistic regression techniques. We explored reluctance to purchase as a result of labelling products which contained manufactured nanomaterials both generally and across five broad products (food, cosmetics/sunscreens, medicines, pesticides, tennis racquets/computers) which represent the broad categories of products regulated by differing government agencies in Australia. We examined the relationship between reluctance to purchase and risk perception, trust, and familiarity. We found irrespective of stakeholder, most supported the labelling of products which contained manufactured nanomaterials. Perception of risk was the main driver of reluctance to purchase, while trust and familiarity were likely to have an indirect effect through risk perception. Food is likely to be the greatest product impacted by labelling. Risk perception surrounding nanotechnologies and label 'framing' on the product are key issues to be addressed in the implementation of a labelling scheme. PMID- 26246799 TI - Metal organic framework synthesis in the presence of surfactants: towards hierarchical MOFs? AB - The effect of synthesis pH and H2O/EtOH molar ratio on the textural properties of different aluminium trimesate metal organic frameworks (MOFs) prepared in the presence of the well-known cationic surfactant cetyltrimethylammonium bromide (CTAB) at 120 degrees C was studied with the purpose of obtaining a MOF with hierarchical pore structure. Depending on the pH and the solvent used, different topologies were obtained (namely, MIL-96, MIL-100 and MIL-110). On the one hand, MIL-110 was obtained at lower temperatures than those commonly reported in the literature and without additives to control the pH; on the other hand, MIL-100 with crystallite sizes as small as 30 +/- 10 nm could be easily synthesized in a mixture of H2O and EtOH with a H2O/EtOH molar ratio of 3.4 at pH 2.6 in the presence of CTAB. The resulting material displays a hierarchical porosity that combines the microporosity from the MOF and the non-ordered mesopores defined in between the MOF nanoparticles. Interestingly, the maximum of the pore size distribution could be varied between 3 and 33 nm. Finally, at pH 2.5 and using water as a solvent, platelets of MIL-96, a morphology never observed before for this MOF, were synthesized with a (001) preferential crystal orientation, the (001) plane running parallel to the bipyramidal cages of the MIL-96 topology. PMID- 26246800 TI - Dimethylfumarate protects against TNF-alpha-induced secretion of inflammatory cytokines in human endothelial cells. AB - BACKGROUND: Inflammation, angiogenesis and oxidative stress have been implicated in the pathogenesis of various vascular diseases. Recent evidence suggests that dimethylfumarate (DMF), an antiposriatic and anti-multiple sclerosis agent, possesses anti-inflammatory, anti-oxidative and anti-angiogenic properties. Here, we analyze the influence of DMF on TNF-alpha-induced expression of the important pro-inflammatory and pro-atherogenic chemokine MCP-1 and investigate the underlying mechanisms of this expression. FINDINGS: We analyzed constitutive and TNF-alpha-induced expression of MCP-1 in human umbilical vascular endothelial cells (HUVEC) +/- DMF treatment via enzyme-linkes immunosorbent assay (ELISA). DMF significantly inhibited the protein expression levels in a time- and concentration-dependent manner. Furthermore, MCP-1 mRNA expression was also reduced in response to DMF, as demonstrated by RT-PCR. Thus, the regulation occurs at the transcriptional level. Interestingly, DMF prolonged the TNF-alpha induced p38 and JNK phosphorylation in HUVEC, as demonstrated by Western blot analysis; however, the p38 and JNK inhibitor SB203580 did not affect the DMF conveyed suppression of TNF-alpha-induced MCP-1 expression. DMF suppressed the TNF-alpha-induced nuclear translocation and phosphorylation (Serine 536) of p65 in these cells. These results were additionally approved by p65 luciferase promoter assays. Furthermore, we found that DMF slightly inhibited the early degradation of IkappaBalpha. In addition, we verified our results using other important inflammatory cytokines such as CCL-5, PDGF-BB, GM-CSF and IL-6. CONCLUSION: DMF suppresses various TNF-alpha-induced pro-inflammatory and pro atherogenic cytokines/chemokines in human endothelial cells. This action is regulated by reduced p65 activity and nuclear translocation, which can be explained in part by the reduced early degradation of IkappaBalpha and more important the reduced phosphorylation of p65 at Serine 536. These effects were independent of the p38, PI3K and p42/44 signaling pathways. As a result, DMF might be suitable for treating patients with vascular diseases. PMID- 26246801 TI - Propriety conditions for the Bayesian autologistic model - Inference for histone modifications. AB - Motivated by inference for a set of histone modifications we consider an improper prior for an autologistic model. We state sufficient conditions for posterior propriety under a constant prior on the coefficients of an autologistic model. We use known results for a multinomial logistic regression to prove posterior propriety under the autologistic model. The conditions are easily verified. PMID- 26246802 TI - Metabolic Consequences of LDHA inhibition by Epigallocatechin Gallate and Oxamate in MIA PaCa-2 Pancreatic Cancer Cells. AB - Lactate dehydrogenase A (LDHA) is the enzyme that converts pyruvate to lactate and oxidizes the reduced form of nicotinamide adenine dinucleotide (NADH) to NAD+. Several human cancers including the pancreas display elevated expression of LDHA. Because of its essential role in cancer metabolism, LDHA has been considered to be a potential target for cancer therapy. Recently, we have shown that a green tea extract significantly down-regulated LDHA in HPAF-II pancreatic cancer cells using global proteomics profiling. The present study is to investigate how EGCG, a major biological active constituent of green tea, targets the metabolism of human pancreatic adenocarcinoma MIA PaCa-2 cells. We compared the effect of EGCG to that of oxamate, an inhibitor of LDHA, on the multiple metabolic pathways as measured by extracellular lactate production, glucose consumption, as well as intracellular aspartate and glutamate production, fatty acid synthesis, acetyl-CoA, RNA ribose and deoxyribose. Specific metabolic pathways were studied using [1, 2-13C2]-d-glucose as the single precursor metabolic tracer. Isotope incorporations in metabolites were analyzed using gas chromatography/mass spectrometry (GC/MS) and stable isotope-based dynamic metabolic profiling (SiDMAP). We found that the EGCG treatment of MIA PaCa-2 cells significantly reduced lactate production, anaerobic glycolysis, glucose consumption and glycolytic rate that are comparable to the inhibition of LDHA by oxamate treatment. Significant changes in intracellular glucose carbon re distribution among major glucose-utilizing macromolecule biosynthesis pathways in response to EGCG and oxamate treatment were observed. The inhibition of LDHA by EGCG or oxamate impacts on various pathways of the cellular metabolic network and significantly modifies the cancer metabolic phenotype. These results suggest that phytochemical EGCG and LDHA inhibitor oxamate confer their anti-cancer activities by disrupting the balance of flux throughout the cellular metabolic network. PMID- 26246803 TI - Understanding Complete Pathologic Response in Oesophageal Cancer: Implications for Management and Survival. AB - Despite significant improvement over recent decades, oesophageal cancer survival rates remain poor. Neoadjuvant chemoradiotherapy followed by oesophageal resection is mainstay of therapy for resectable oesophageal tumours. Operative morbidity and mortality associated with oesophagectomy remain high and complications arise in up to 60% of patients. Management strategies have moved towards definitive chemoradiotherapy for a number of tumour sites (head and neck, cervical, and rectal) particularly for squamous pathology. We undertook to perform a review of the current status of morbidity and mortality associated with oesophagectomy, grading systems determining pathologic response, and data from clinical trials managing patients with definitive chemoradiotherapy to inform a discussion on the topic. PMID- 26246804 TI - Gastric Electrical Stimulation with the Enterra System: A Systematic Review. AB - Background. Gastric electrical stimulation (GES) is a surgically implanted treatment option for refractory gastroparesis. Aim. To systematically appraise the current evidence for the use of gastric electrical stimulation and suggest a method of standardisation of assessment and follow-up in these patients. Methods. A systematic review of PubMed, Web of Science, DISCOVER, and Cochrane Library was conducted using the keywords including gastric electrical stimulation, gastroparesis, nausea, and vomiting and neuromodulation, stomach, central nervous system, gastric pacing, electrical stimulation, and gastrointestinal. Results. 1139 potentially relevant articles were identified, of which 21 met the inclusion criteria and were included. The quality of studies was variable. There was a variation in outcome measures and follow-up methodology. Included studies suggested significant reductions in symptom severity reporting over the study period, but improvements in gastric emptying time were variable and rarely correlated with symptom improvement. Conclusion. The evidence in support of gastric electrical stimulation is limited and heterogeneous in quality. While current evidence has shown a degree of efficacy in these patients, high-quality, large clinical trials are needed to establish the efficacy of this therapy and to identify the patients for whom this therapy is inappropriate. A consensus view on essential preoperative assessment and postoperative measurement is needed. PMID- 26246805 TI - The Benefits and Risks of Prophylactic Central Neck Dissection for Papillary Thyroid Carcinoma: Prospective Cohort Study. AB - Objectives. This study evaluated the benefits of performing prophylactic central neck dissection (CND) with total thyroidectomy (TT) in management of papillary thyroid carcinoma (PTC) patients who were clinically node-negative at presentation. Methods. A total of 257 patients with stage T1 or T2 PTC and without preoperative evidence of lymph node involvement (N0) were enrolled in this prospective study. The patients were randomly assigned to two groups: (1) a total thyroidectomy (TT) group (n = 104) or (2) a TT plus CND group (n = 153). The two groups were compared for their perioperative data, complication rates, disease recurrence rates, and clinical outcomes. Results. The two groups of patients were similar in age, sex ratio, follow-up duration, and tumor size (P = 0.227, 0.359, 0.214, and 0.878, resp.). The two groups showed similar rates of disease recurrence (3.9% in the TT group versus 3.3% in the TT plus CND group); however, complications occurred more frequently in the TT plus CND group; especially transient hypocalcemia (P = 0.043). Conclusions. Patients treated with TT plus CND had a higher rate of complications with similar recurrence rate. We believe that CND may not be routinely recommended when treating patients with PTC. PMID- 26246806 TI - Graves' Orbitopathy. PMID- 26246807 TI - Pituitary Insufficiency and Hyperprolactinemia Associated with Giant Intra- and Suprasellar Carotid Artery Aneurysm. AB - Pituitary insufficiency secondary to internal carotid artery (ICA) aneurysm is a very rare condition. Its prevalence is reported as 0.17% (Heshmati et al., 2001). We present a case of pituitary insufficiency and hyperprolactinemia secondary to suprasellar giant intracranial aneurysm. A 71-year-old man was admitted to our clinic with symptoms of hypopituitarism, hyperprolactinemia, and visual field defect. His pituitary MRI and cerebral angiography revealed a giant saccular aneurysm filling suprasellar cistern arising from the ophthalmic segment of the right ICA. Endovascular treatment was performed on the patient to decrease the mass effect of aneurysm and improve the hypophysis dysfunction. After treatment, his one-year follow-up showed the persistence of hypophysis insufficiency, decrease of prolactin (PRL) level, and normal visual field. An intracranial aneurysm can mimic the appearance and behavior of a pituitary adenoma. Intracranial aneurysms should be taken into consideration in the situation of hypopituitarism and hyperprolactinemia. It is important to distinguish them because their treatment approach is different from the others. PMID- 26246808 TI - Umbilical Cord Tissue-Derived Cells as Therapeutic Agents. AB - Although the characteristics of SC, including UC-derived cells, are a dramatically discussed issue, this review will focus particularly on some controversial issues regarding clinical utility of cells isolated from UC tissue. UC-derived cells have several advantages compared to other types and sources of stem cells. The impact of UC topography on cell characteristics is briefly discussed. The necessity to adapt existing methods of cell isolation and culturing to GMP conditions is mentioned, as well as possible cryopreservation of this material. Light is shed on some future perspectives for UC-derived cells. PMID- 26246809 TI - Use of Adult Stem Cells for Cartilage Tissue Engineering: Current Status and Future Developments. AB - Due to their low self-repair ability, cartilage defects that result from joint injury, aging, or osteoarthritis, are the most often irreversible and are a major cause of joint pain and chronic disability. So, in recent years, researchers and surgeons have been working hard to elaborate cartilage repair interventions for patients who suffer from cartilage damage. However, current methods do not perfectly restore hyaline cartilage and may lead to the apparition of fibro- or hypertrophic cartilage. In the next years, the development of new strategies using adult stem cells, in scaffolds, with supplementation of culture medium and/or culture in low oxygen tension should improve the quality of neoformed cartilage. Through these solutions, some of the latest technologies start to bring very promising results in repairing cartilage from traumatic injury or chondropathies. This review discusses the current knowledge about the use of adult stem cells in the context of cartilage tissue engineering and presents clinical trials in progress, as well as in the future, especially in the field of bioprinting stem cells. PMID- 26246810 TI - Coal Mine Air Pollution and Number of Children Hospitalizations because of Respiratory Tract Infection: A Time Series Analysis. AB - To analyze the relationship between levels of air pollution and number of children hospitalizations because of respiratory tract infection in Shenmu County, the data regarding meteorological factors, environmental pollutants, that is SO(2) and NO(2), Particulate Matter 10 (PM10), and hospitalizations of children less than 16 years of age was collected during the time duration of November 2009 to October 2012. Using SAS 9.3, descriptive data analysis for meteorological and environmental factors and hospital admissions were performed along with main air pollutants determination. Using the statistical software R 3.0.1, a generalized additive Poisson regression model was established, the linear fitting models of the air pollutant concentrations and meteorological factors were introduced considering the lag effect, and the relative risk of the main atmospheric pollutants on children hospitalization was evaluated. The results showed that the primary air pollutant in Shenmu County is PM10 and its Pearson correlation coefficient with Air Pollution Index (API) is 0.917. After control of long term climate trend, "week day effect," meteorological factors, and impact of other contaminants, it was found that, on the same day and during the lag of 1 to 10 days, PM10 concentrations had no significant effect on children hospitalization rate. PMID- 26246811 TI - An Annotated Checklist of the Human and Animal Entamoeba (Amoebida: Endamoebidae) Species- A Review Article. AB - BACKGROUND: The number of valid of pathogen and non-pathogen species of Entamoeba has continuously increased in human and animals. This review is performed to provide an update list and some summarized information on Entamoeba species, which were identified up to the 2014. METHODS: We evaluated the Entamoeba genus with a broad systematic review of the literature, books and electronic databases until February 2014. The synonyms, hosts, pathogenicity and geographical distribution of valid species were considered and recorded. Repeated and unrelated cases were excluded. RESULTS: Totally 51 defined species of Entamoeba were found and arranged by the number of nuclei in mature cyst according to Levin's grouping. Seven of these species within the 4 nucleate mature cysts group and 1 species with one nucleate mature cyst are pathogen. E. histolytica, E. invadence, E. rananrum and E. anatis causes lethal infection in human, reptiles, amphibians and brides respectively, four species causes non-lethal mild dysentery. The other species were non-pathogen and are important to differential diagnosis of amoebiasis. CONCLUSION: There are some unknown true species of Entamoeba that available information on the morphology, hosts, pathogenicity and distribution of them are still very limited and more considerable investigation will be needed in order to clarify the status of them. PMID- 26246812 TI - Current Status of Acanthamoeba in Iran: A Narrative Review Article. AB - BACKGROUND: Free-living amoebae belonging to the genus Acanthamoeba have an environmental distribution. Amoebic keratitis due to these protozoan parasites continue to rise in Iran and worldwide. In Iran, there are various researches regarding both morphological and molecular identification of Acanthamoeba spp. in environmental and clinical samples. However, there is no thorough review about Acanthamoeba genotypes and their distribution in environmental sources such as water, dust and biofilm in Iran. Besides, according to increasing cases of Amoebic keratitis in the region awareness regarding the pathogenic potential of these sight-threatening amoebae is of utmost importance. METHODS: We conducted a thorough review based on the database sources such as MEDLINE, PubMed and Google scholar. No restrictions were placed on study date, study design or language of publication. We searched all valuable and relevant information considering the occurrence of the Acanthamoeba in both environmental and clinical samples. RESULTS: According to our thorough review Acanthamoeba belonging to T4 genotype is the most prevalent type strain in environmental and clinical samples in several regions in Iran and worldwide, however, there are reports regarding Acanthamoeba belonging to other genotypes such as T2, T3, T5, T6 and T11 and the mentioned point could leads us to more researches with the goal of presenting the real genotype dominance of Acanthamoeba and related disease in the country. CONCLUSION: Overall, the present review will focus on present status of genotypes of Acanthamoeba in Iran during recent years. PMID- 26246813 TI - Cloning and Expression of Recombinant Plasmid Containing P36/LACK Gene of Leishmania infantum Iranian Strain. AB - BACKGROUND: There are several methods, such as vaccination, to control visceral leishmaniasis. Although there is no efficient vaccine, it seem DNA vaccination with stimulates both cellular and humoral immunity apparently is the best way. The aim of this study was cloning and expression of LACK gene, a 36kD protein, as a candidate protein for vaccination against Iranian L. infantum. METHODS: Iranian strain of L. infantum [MCAN/IR/07/Moheb-gh] was used as a template for PCR to amplify LACK gene. The LACK gene was cloned in pTZ57R/T vector and after confirmation it was digested by restriction enzymes (BamH1) and cloned in pcDNA3.1 expression vector. Recombinant plasmid was extracted and analyzed by sequencing, restriction digestion analysis and PCR reaction. The pc- LACK recombinant plasmid was purified from transformed E.coli (DH5alpha) and its expression was analyzed by SDS-PAGE and Western blot. RESULTS: The results of sequencing, restriction digestion analysis and PCR reaction revealed that LACK gene was cloned correctly in pcDNA3.1 vector and the results of SDS PAGE and Western blot emphasized that LACK protein of Iranian L. infantum is a well expressed protein. CONCLUSION: We amplified, cloned and expressed Iranian L. infantum LACK gene successfully. PMID- 26246814 TI - Anti-Toxoplasma Activity of 2-(Naphthalene-2-gammalthiol)-1H Indole. AB - BACKGROUND: This study was undertaken to evaluate the viability, infectivity and immunity of Toxoplasma gondii tachyzoites exposed to 2-(naphthalene-2-ylthio)-1H indole. METHODS: Tachyzoites of RH strain were incubated in various concentrations of 2-(naphthalene-2-ylthio)-1H-indole (25-800 MUM) for 1.5 hours. Then, they were stained by PI and analyzed by Fluorescence-activated cell sorting (FACS). To evaluate the infectivity, the tachyzoites exposed to the different concentrations of the compound were inoculated to 10 BALB/c mice groups. For Control, parasites exposed to DMSO (0.2% v/v) were also intraperitoneally inoculated into two groups of mice. The immunity of the exposed tachyzoites was evaluated by inoculation of the naive parasite to the survived mice. RESULTS: The LD50 of 2-(naphthalene-2-ylthio)-1H-indole was 57 MUmol. The longevity of mice was dose dependent. Five mice out of group 400MUmol and 3 out of group 800MUmol showed immunization to the parasite. CONCLUSION: Our findings demonstrated the toxoplasmocidal activity of the compound. The presence of a well-organized transporter mechanism for indole compounds within the parasite in conjunction with several effective mechanisms of these compounds on Toxoplasma viability would open a window for production of new drugs and vaccines. PMID- 26246815 TI - Occurrence of Potentially Pathogenic Bacterial-Endosymbionts in Acanthamoeba Spp. AB - BACKGROUND: Acanthamoeba- bacteria interactions enable pathogenic bacteria to tolerate harsh conditions and lead to transmission to the susceptible host. The present study was aimed to address the presence of bacterial endosymbionts of Acanthamoeba isolated from recreational water sources of Tehran, Iran. To the best of our knowledge this is the first study regarding occurrence of bacteria in environmental Acanthamoeba spp. in Iran. METHODS: A total of 75 samples of recreational water sources were collected. Samples were cultured on non- nutrient agar 1.5% plates. Positive Acanthamoeba spp. were axenically grown. DNA extraction and PCR reaction was performed using JDP1-2 primers. All positive samples of Acanthamoeba were examined for the presence of endosymbionts using staining and molecular methods. The PCR products were then sequenced in order to determine the genotypes of Acanthamoeba and bacteria genera. RESULTS: Out of 75 samples, 16 (21.3%) plates were positive for Acanthamoeba according to the morphological criteria. Molecular analysis revealed that Acanthamoeba belonged to T4 and T5 genotypes. Five isolates (35.7%) were positive for bacterial endosymbionts using staining method and PCR test. Sequencing of PCR products confirmed the presence of Pseudomonas aeruginosa and Agrobacterium tumefasiens. CONCLUSION: The presence of Acanthamoeba bearing pathogenic endosymbionts in water sources leads us to public health issues including improved sanitation and decontamination measures in recreational water sources in order to prevent amoebae-related infection. To the best of our knowledge this is the first report regarding the isolation of A. tumefasiens from Acanthamoeba in Iran and worldwide. PMID- 26246816 TI - Phylogenetic Study of Haemonchus Species from Iran Based On Morpho-Molecular Characterization. AB - BACKGROUND: Haemonchosis has a negative effect on the farming industry throughout the world, especially in the tropic and sub-tropic countries. The present study was carried out to differentiate Haemonchus species from its main hosts in Iran, including sheep, goat and camel. METHODS: The identification took place based on the morphometrics of the spicules and molecular characters. Two hundred seventy adult male nematodes were collected from the abomasums of different ruminants (90 samples from each animal) at the slaughterhouses from different localities in Iran. Samples were morphologically identified according to the spicules' morphometric measurements. In the section on molecular study, 10 samples of each Haemonchus isolates were genetically examined. A simple PCR-restriction fragment length polymorphism (PCR-RFLP) assay of the second internal transcribed spacer of ribosomal DNA (ITS2-rDNA) were described to confirm the PCR results. RESULTS: PCR RFLP profile obtained from the restriction enzyme HPa1 in H. contortus and H. longistipes indicated 1 (278 bp) and 2 (113 and 135 bp) different fragments, respectively. The morphological parameters clearly distinguish H. contortus from H. longistipes. Moreover, regarding the ITS2-rDNA, sequences of 295 bp and 314 bp were obtained from H. contortus and H. longistipes, respectively. CONCLUSION: The genotypic results are in agreement with the phenotypic findings of both species. PMID- 26246817 TI - Cloning and Sequence Analysis of Recombinant Plasmodium vivax Merozoite Surface Protein 1 (PvMSP-142 kDa) In pTZ57R/T Vector. AB - BACKGROUND: Carboxy-terminal 42 kDa region of Plasmodium vivax merozoite surface protein-1 is considered as an important antigen in blood stage. Since, this region has been observed to be polymorphic among isolates of P. vivax, it is significant to survey on different regions of this antigen in various areas of the world. METHODS: In the present study, the genetic diversity of cloned PvMSP 142 kDa gene from an Iranian patient is analyzed. Parasite DNA was extracted from a P. vivax - infected patient in Iran. The region of PvMSP-142 kDa was amplified by PCR, cloned into pTZ57R/T vector and then sequenced. RESULTS: Sequencing of cloned PvMSP-142 kDa gene clearly has a high degree of homology (95%) with reference Sal-I sequence and also with the homogeneous sequences from some studied countries (97%). Thirty eight SNPs (single nucleotide polymorphism) were identified in cloned PvMSP-142 kDa gene which the mutations had localized in the 33 kDa fragment (PvMSP-133 kDa), while there was nearly no variation in the 19 kDa fragment (PvMSP-119 kDa). 2 out of 38 mutations were found as to be novel haplotypes. CONCLUSION: High similarity of cloned PvMSP-142 kDa gene in comparison to reference sequence and other sequences could be beneficial as a remarkable molecular marker for serological diagnostic kits of P. vivax in malarious neighboring countries of Iran and around the world. PMID- 26246818 TI - Comparison of Scolicidal Effects of Amphotricin B, Silver Nanoparticles,_and Foeniculum vulgare Mill on Hydatid Cysts Protoscoleces. AB - BACKGROUND: Surgery is the preferred treatment for hydatid cyst (cystic echinococcosis, CE). At present, various scolicidal agents have been used for inactivation of protoscoleces during surgery, but they are associated with adverse side effects. The aim of the present study was to evaluate the scolicidal effects of amphotricin B, Silver nano particles, Foeniculum vulgare Mill, essential oil and hypertonic saline against protoscoleces of hydatid cyst on an in vitro model. METHODS: Protoscoleces were aseptically aspirated from the naturally infected livers of sheep and goats. Various concentrations of AmB (2.5 20 mg/ml), Ag-NPs (0.5-4 mg/ml), F. vulgare essential oil (0.125-1 mg/ml) and hypertonic saline (10-20%) were used for 5-60 min. Eosin exclusion test was used to determine the viability of protoscoleces. RESULTS: Maximum protoscolicidal effect of AmB and Ag-NPs was found at concentrations of 20 and 4 mg/mL, resulting in only 82.3% and 71.6% of the protoscoleces after 60 min of incubation, respectively. In contrast, F. vulgare essential oil at concentration of 1 mg/ml and hypertonic saline 20% killed 100% protoscoleces after 5 and 10 min of exposure, respectively. CONCLUSION: The results indicated weak scolicidal activity of AmB and Ag-NPs; whereas F. vulgare essential oil had potent scolicidal activity against protoscoleces of hydatid cyst that revealed the potential of F. vulgare as a natural source for the production of new scolicidal agent for use in hydatid cyst surgery. However, further studies will be needed to confirm these results by checking the essential oil and its active component in the in vivo model. PMID- 26246819 TI - Abnormalities of Endocytosis, Phagocytosis, and Development Process in Dictyostelium Cells That Over-Express Acanthamoeba castellanii Metacaspase Protein. AB - BACKGROUND: Acanthamoeba castellanii forms a resistant cyst that protects the parasite against the host's immune response. Acanthamoeba Type-I metacaspase (Acmcp) is a caspase-like protein that has been found to be expressed during the encystations. Dictyostelium discoideum is an organism closely related to Acanthamoeba useful for studying the molecular function of this protozoan caspase like protein. METHODS: The full length of Acmcp and a mutated version of the same gene, which lacks the proline rich N-terminal region (Acmcp-dpr), were cloned into the pDneo2a-GFP vector separately. The pDneo2a-GFP-Acmcp and pDneo2a GFPAcmcp-dpr were electro-transfected into wild type D. discoideum cells to create cell lines that over-expressed Acmcp or Acmcp-dpr. RESULTS: Both cell lines that over-expressed Acmcp and Acmcp-dpr showed a significant increase in the fluid phase internalization and phagocytosis rate compared to the control cells. Additionally, the cells expressing the Acmcp-dpr mutant were unable to initiate early development and failed to aggregate or form fruiting bodies under starvation conditions, whereas Acmcp over-expressing cells showed the opposite phenomena. Quantitative cell death analysis provided additional support for these findings. CONCLUSION: Acmcp is involved in the processes of endocytosis and phagocytosis. In addition, the proline rich region in Acmcp is important for cellular development in Dictyostelium. Given its important role in the development process, metacaspase protein is proposed as a candidate drug target against infections caused by A. castellanii. PMID- 26246820 TI - The Use of Recombinant 31 kDa Antigens of Trichinella spiralis for Serodiagnosis of Experimental Trichinellosis. AB - BACKGROUND: We have previously reported that a 31 kDa protein was screened from the excretory-secretory (ES) proteins of Tichinella spiralis muscle larvae (ML) by immunoproteomics using early infection sera, and the gene encoding a 31 kDa protein from T. spiralis was cloned and expressed in an E. coli expression system. In this study, the recombinant 31 kDa antigens were used for detection of anti-Trichinella antibodies in serum of experimentally infected mice by ELISA. METHODS: Anti-Trichinella IgG antibodies in sera of mice infected with Trichinella were assayed by ELISA with recombinant 31 kDa antigens, and its sensitivity and specificity were compared with ELISA with ES antigen. RESULTS: The sensitivity and specificity of ELISA with recombinant antigens was 96.67% (29/30) and 96.87% (62/64), compared with 100% (30/30) and 98.44% (63/64) of ELISA with ES antigens was (P>0.05). In heavily, moderately and lightly infected mice (500, 300 and 100 larvae/mouse), anti-Trichinella antibodies were firstly detected by ELISA with recombinant antigens at 8, 12 and 14 dpi, respectively; then increased rapidly with a detection rate of 100% respectively at 28, 22 and 30 dpi. While the antibodies were firstly detected by ELISA with ES antigens at 10, 8 and 10 dpi, respectively, the antibody positive rate reached 100% at 14, 12 and 22 dpi, respectively. CONCLUSION: The recombinant 31 kDa antigens of T. spirali had a good sensitivity and specificity for detecting anti-Trichinella antibodies and might be the potential diagnostic antigen for trichinellosis. PMID- 26246821 TI - Conjugated Linoleic Acid Stimulates Apoptosis in RH and Tehran Strains of Toxoplasma gondii, in Vitro. AB - BACKGROUND: The aim of this study was to evaluate the effects of conjugated linoleic acid (CLA) on apoptosis of tachyzoites of T. gondii, RH strain (type I) and the cyst-forming Tehran strain (type II) in vitro. METHODS: Toxoplasma strains were injected into the peritoneal cavity of BALB/c mice. The Tehran strain forms cysts in the brain of mice. Bradyzoites within the cysts are reactivated to proliferative tachyzoites, by dexamethasone. Tachyzoites were aspirated from the peritoneum of infected mice, and the percentage of viable parasites was estimated with trypan blue staining. Tachyzoites were inoculated into HeLa cells cultivated in DMEM medium. Different concentrations of CLA were evaluated on T. gondii in HeLa cells by the tetrazolium (MTT) colorimetric assay. Differentiation between apoptosis and cell death was determined by flow cytometry using Annexin V and propidium iodide (PI) double staining. The statistical analysis performed by GraphPad Prism version 6.00. RESULTS: CLA induces apoptosis in virulent (RH) and avirulent (Tehran) strains of T. gondii. The results of MTT indicated that CLA could decrease the proliferation of tachyzoites of both strains in HeLa cells. CONCLUSION: Conjugated linoleic acid has anti toxoplasmacidal activity on tachyzoites of T. gondii. Therefore, we recommended further studies on this component in order to achieve a new drug against the parasite. PMID- 26246822 TI - Macracanthorhynchus hirudinaceus Eggs in Canine Coprolite from the Sasanian Era in Iran (4(th)/5(th) Century CE). AB - Present paper is the second publication introducing the paleoparasitological findings from animal coprolites obtained from archeological site of Chehrabad salt mine in northwestern Iran. The current archeological site is located in northwest of Iran, dated to the Sassanian Era (4(th)/5(th) century CE). In the summer 2012 the carnivore coprolite was obtained within the layers in the mine and were thoroughly analyzed for parasites using TSP rehydration technique. Eggs of 0 were successfully retrieved from the examined coprolite and were confidently identified based on reliable references. Identifying of M. hirudinaceus eggs in paleofeces with clear appearance as demonstrated herein, is much due to appropriate preservation condition has been existed in the salt mine .The present finding could be regarded as the oldest acanthocephalan infection in Iran. PMID- 26246823 TI - Detection of Acanthamoeba and Toxoplasma in River Water Samples by Molecular Methods in Iran. AB - BACKGROUND: Free-living amoebae such as Acanthamoeba species may act as carriers of Cryptosporidium and Toxoplasma oocysts, thus, may play an important role in the water-borne transmission of these parasites. In the present study, a loop mediated isothermal amplification (LAMP) method for detection of Toxoplasma and a PCR assay were developed for investigation of Acanthamoeba in environmental water samples. METHODS: A total of 34 samples were collected from the surface water in Guilan Province. Water samples were filtrated with membrane filters and followed by DNA extraction. PCR and LAMP methods used for detection of the protozoan parasites Acanthamoeba and Toxoplasma respectively. RESULTS: Totally 30 and 2 of 34 samples were positive for Acanthamoeba and Toxoplasma oocysts respectively. Two samples were positive for both investigated parasites. CONCLUSION: The investigated water supplies, are contaminated by Toxoplasma and Acanthamoeba (oo)cystes. Acanthamoeba may play an important role in water-borne transmission of Toxoplasma in the study area. For the first time in Iran, protocol of LAMP method was used effectively for the detection of Toxoplasma in surface water samples in Iran. PMID- 26246824 TI - Evaluation of Apoptotic and Antileishmanial Activities of Artemisinin on Promastigotes and BALB/C Mice Infected with Leishmania major. AB - BACKGROUND: In leishmaniasis, some drugs prescribed for treatment have toxic effects and there are reports about drug resistance in some countries. Due to this fact, using herbal drugs such as artemisinin with good efficacy and low toxic effect might be suitable. METHODS: We evaluated the apoptotic effect of artemisinin on Leishmania major in vitro and the antileishmanial activities of artemisinin on leishmaniasis in BALB/c mice and at the end INF-gamma and IL-4 cytokines levels were detected by ELISA in spleen cell culture supernatants. During treatment the lesion size and survival rate were measured each four and ten days, respectively. RESULTS: Percentage of early and late apoptosis in promastigotes of control group and promastigotes treated with 10, 25, 50 and 100 MUg/ml of artemisinin after 48 h were 0.13, 16.04, 41.23, 49.03 and 81.83, respectively. The IFN-gamma in ointment treated group were higher than those of other groups (P<0.05). The in vivo results showed that ointment compounds healed the lesions more effectively rather than intraperitoneal injection method (P<0.05). The survival rate of mice 150 days after challenge in treated group with ointment of artemisinin was 66% while all mice in control groups were died. CONCLUSION: All of in vitro results represented that this drug had antileishmanial effects and these results were confirmed by evaluation effects in vivo condition of leishmaniasis. Interestingly, according to these results it can be concluded that this drug has antileishmanial effects in vitro and in vivo conditions. Artemisinin induces cytotoxic effect on L. major via apoptosis related mechanism. PMID- 26246825 TI - Prevalence and Intensity of Paramphistomum Spp. In Cattle from South-Eastern Iran. AB - BACKGROUND: Parasitological investigations on paramphistomosis were carried out over a 12-month period in the southeast of Iran to determine the prevalence and intensity of this disease. METHODS: A total of 1000 cattle, Sistani breed (n= 450) and Brahman breed (n= 550) of all sex and age groups were inspected at random for the presence of paramphistomidae flukes in Zabol slaughterhouse from December 2012 to October 2013. RESULTS: Paramphistomes were found in 369 of 1000 necropsied cows (36.9%; 95% CI: 30.1-41.9%), with significant higher prevalence of infection in Brahman breed than in Sistani breed (51% vs 19.3%). No significant correlation between prevalence, intensity of infection, sex and age of cattle was noted. Despite the difference in the seasonal variations of prevalence, and the relation between the intensity of infection and season, these were not statistically significant. The mean intensity of infection in Brahman breed was higher (652.66 +/- 281.5) than Sistani breed (123.32 +/- 32.2). The identification of stained trematodes to the species revealed 40, 20, 20, 15 and 5% Gastrothylax crumenifer, Cotylophoron cotylophorom, Paramphistomum cervi, Carmyerius spatiosus, Explanatum explanatum, respectively. CONCLUSION: The present results will contribute to our understanding of the epidemiology of paramphistomumosis in southeastern Iran. PMID- 26246826 TI - Histological Changes of the Ovary in Pregnant Mice Vaginally Exposed to Toxoplasma gondii. AB - BACKGROUND: Congenital toxoplasmosis is one cause of abortion. Infection can disrupt ovarian cycles and because toxoplasmosis is an infectious disease may have a similar effect on the ovaries. The purpose of this study was to investigate the pathological changes in the ovaries due to toxoplasmosis. METHODS: Tachyzoites of Toxoplasma gondii were harvested from peritoneal fluid of mice, experimentally infected. Two females and one male mouse were housed per cage for mating in the overnight. The pregnant mice were divided into experimental and control groups. Experimental group were infected by parasite but the control group received the normal saline. The experimental and control mice were euthanized. Ovaries and uterine horns of animals were removed and prepared for light microscopy. RESULTS: Ovaries of infected pregnant mice presented gross morphological differences compared to the control groups. In ovaries of experimental groups, changes of corpus luteum were observed. The comparison of experimental and control groups revealed that the number of primary follicles, secondary follicle, atretic primary follicles and atretic secondary follicles had significant differences (P<=0.001). CONCLUSION: Toxoplasma gondii alters ovarian follicular growth and development in mice. In addition, it alters number of different phases of follicles and corpus luteum in ovaries of mice. PMID- 26246827 TI - The First Identification of Encephalitozoon cuniculi Infection in an Animal Care Worker in Turkey. AB - BACKGROUND: As a zoonotic pathogen, Encephalitozoon cuniculi is a cause of serious disease in animals and people. The present study was to evaluate the health status examination of this seropositive animal care worker in our previous study. METHODS: Blood samples were taken from five workers. CIA test was applied to detect antibodies against E. cuniculi in blood serum. The indirect immunofluorescence antibody test was used as confirmation test. Seropositive worker had a complete medical examination. RESULTS: Only one worker was found to be seropositive according to the results of the serological test. Sera positive to E. cuniculi was confirmed with IFAT and spores were detected in the urine sample of the worker. The worker was treated with albendazole. CONCLUSION: Rabbits should be examined routinely for the presence of anti-E. cuniculi antibody. People working with laboratory animal should avoid contact with urine and faeces of infected or pay attention to personal hygiene. PMID- 26246828 TI - Soil Contamination with Toxocara Spp. Eggs in Public Parks of Mashhad and Khaf, North East of Iran. AB - BACKGROUND: Toxocariasis is an important disease caused by the larvae of parasitic worms such as Toxocara canis and T. cati. Public parks can be the source of toxocariasis for small children. This survey was conducted to determine the prevalence of Toxocara spp. ova in parks of Mashhad and Khaf northeastern Iran. METHODS: In this descriptive cross-sectional study, performed in November 2011 to June 2012, overall, 340 soil samples were collected from 39 parks of Mashhad and 29 parks in Khaf city. Flotation method and direct smear were used, and the samples were evaluated using a light microscope. The results were analyzed using SPSS version 19 and Chi-square test. RESULTS: In the evaluation of 195 and 145 soil samples, 18 (9.2%) and 16 cases (11.3%) of contamination with Toxocara spp. eggs were detected, respectively. CONCLUSION: Although the prevalence of Toxocara eggs in soil samples was low, parks can be a source of Toxocara infection of children in these areas. PMID- 26246829 TI - Seroprevalence of Encephalitozoon cuniculi in Humans and Rabbits in China. AB - BACKGROUND: Encephalitozoon cuniculi is a microsporidian parasite commonly found in rabbits that can infect humans, causing encephalitozoonosis. Our objective in this study was to evaluate the seroprevalence of this parasite in rabbits and humans in China. METHODS: Overall, 300 serum samples each from clinically healthy rabbit and human were collected from three regions of China (Sichuan Province, Chongqing Municipality and Jilin Province) from January to September 2013 and tested for anti-E. Cuniculi antibodies using an ELISA. RESULTS: An overall seroprevalence of E. cuniculi was recorded as 56/300 (18.76%) and 29/300 (9.76%) in rabbit and human sera, respectively. The seropositivity of rabbit samples collected from Jilin province was 41%, which was significantly higher (P<0.01) than Sichuan Province (9%) and Chongqing Municipality (6%). Three breeds of rabbit were used in the present study and antibody detection in Rex Rabbit was significantly (P<0.01) higher than Japanese White and New Zealand Rabbit. In human, Jilin province was more prevalent (18%) followed by Sichuan Province (6%) and Chongqing Municipality (5%). CONCLUSIONS: The E. cuniculi was present and widespread among healthy rabbits and humans in China. PMID- 26246830 TI - Hoarseness as the Presenting Symptom of Visceral Leishmaniasis with Muco Cutaneous Lesions: A Case Report. AB - Herein, a 28-year-old man with hoarseness, skin and oral lesions is presented. At the time of admission, the patient had an erythematous plaque on his chin near his lower lip and an erythematous-violaceous plaque on his palate near the opening of the pharynx and 20 kg weight lost in last one year. The biopsy of his skin lesions by hematoxylin and eosin staining revealed an infiltration of the dermis by lymphoplasma and histiocytic cells with a loose granuloma formation suggestive of leishmaniasis. Biopsy of mucosal lesions revealed Leishman bodies in dermis. PCR was performed on the specimens of skin, bone marrow, mucosa, and saliva, the results were positive. The pathogenic agent was identified as Leishmania major by the nested PCR. Serologic tests including direct agglutination test (DAT) and indirect immunofluorescence test (IFAT) were positive with high titers of anti-L. infantum antibodies (1:102400 versus 1:800, respectively), indicative of visceral involvement. The patient responded to a combination of miltefosine and meglumine antimoniate (Glucantime(r)). Visceral involvement due to L. major is rarely reported. To the best of our knowledge, probably hoarseness due to L. major has not been previously reported from Iran. PMID- 26246831 TI - Regurgitations in a Lamb with Acute Coenurosis-A case Report. AB - Coenurosis is a disease of the central nervous system in sheep, caused by Coenurus cerebralis, the larval stage of Multiceps multiceps, which inhabits the small intestine of Canidae. A case of regurgitations in a 2.5 month old lamb with acute coenurosis is being reported. The lamb was presented with a sudden onset of ataxia and regurgitations for 10 days. The post-mortem examination revealed 4 immature C. cerebralis cysts between 0.5 and 1.5 cm in diameter located in the brainstem and cerebellum, and histopathological examination revealed multifocal pyogranulomatous meningoencephalitis, so a diagnosis of acute coenurosis was established. Thus, acute coenurosis should be included in the differential diagnosis of regurgitations in lambs. PMID- 26246832 TI - The etiology and prevention of breast cancer. AB - Metabolism of estrogens via the catechol estrogen pathway is characterized by a balanced set of activating and protective enzymes (homeostasis). Disruption of homeostasis, with excessive production of catechol estrogen quinones, can lead to reaction of these quinones with DNA to form depurinating estrogen-DNA adducts. Some of the mutations generated by these events can lead to initiation of breast cancer. A wealth of evidence, from studies of metabolism, mutagenicity, cell transformation and carcinogenicity, demonstrates that estrogens are genotoxic. Women at high risk for breast cancer, or diagnosed with the disease, have relatively high levels of depurinating estrogen-DNA adducts compared to normal risk women. The dietary supplements N-acetylcysteine and resveratrol can inhibit formation of catechol estrogen quinones and their reaction with DNA to form estrogen-DNA adducts, thereby preventing initiation of breast cancer. PMID- 26246833 TI - Cytotoxic Activity and Chemical Composition of the Root Extract from the Mexican Species Linum scabrellum: Mechanism of Action of the Active Compound 6 Methoxypodophyllotoxin. AB - The cytotoxic activity and the chemical composition of the dichloromethane/methanol root extract of Linum scabrellum Planchon (Linaceae) were analyzed. Using NMR spectra and mass spectrometry analyses of the extract we identified eight main constituents: oleic acid (1), octadecenoic acid (2), stigmasterol (3), alpha-amyrin (4), pinoresinol (5), 6 methoxypodophyllotoxin (6), coniferin (7), and 6-methoxypodophyllotoxin-7-O-beta-D-glucopyranoside (8). By using the sulforhodamine B assay, an important cytotoxic activity against four human cancer cell lines, HF6 colon (IC50 = 0.57 MUg/mL), MCF7 breast (IC50 = 0.56 MUg/mL), PC3 prostate (IC50 = 1.60 MUg/mL), and SiHa cervical (IC50 = 1.54 MUg/mL), as well as toward the normal fibroblasts line HFS-30 IC50 = 1.02 MUg/mL was demonstrated. Compound 6 (6-methoxypodophyllotoxin) was responsible for the cytotoxic activity exhibiting an IC50 value range of 0.0632 to 2.7433 ug/mL against the tested cell lines. Cell cycle studies with compound 6 exhibited a cell arrest in G2/M of the prostate PC3 cancer cell line. Microtubule disruption studies demonstrated that compound 6 inhibited the polymerization of tubulin through its binding to the colchicine site (binding constant K b = 7.6 * 10(6) M( 1)). A dose-response apoptotic effect was also observed. This work constitutes the first investigation reporting the chemical composition of L. scabrellum and the first study determining the mechanism of action of compound 6. PMID- 26246834 TI - Advances in Patient Classification for Traditional Chinese Medicine: A Machine Learning Perspective. AB - As a complementary and alternative medicine in medical field, traditional Chinese medicine (TCM) has drawn great attention in the domestic field and overseas. In practice, TCM provides a quite distinct methodology to patient diagnosis and treatment compared to western medicine (WM). Syndrome (ZHENG or pattern) is differentiated by a set of symptoms and signs examined from an individual by four main diagnostic methods: inspection, auscultation and olfaction, interrogation, and palpation which reflects the pathological and physiological changes of disease occurrence and development. Patient classification is to divide patients into several classes based on different criteria. In this paper, from the machine learning perspective, a survey on patient classification issue will be summarized on three major aspects of TCM: sign classification, syndrome differentiation, and disease classification. With the consideration of different diagnostic data analyzed by different computational methods, we present the overview for four subfields of TCM diagnosis, respectively. For each subfield, we design a rectangular reference list with applications in the horizontal direction and machine learning algorithms in the longitudinal direction. According to the current development of objective TCM diagnosis for patient classification, a discussion of the research issues around machine learning techniques with applications to TCM diagnosis is given to facilitate the further research for TCM patient classification. PMID- 26246835 TI - Immediate Effects of Kinesiology Taping of Quadriceps on Motor Performance after Muscle Fatigued Induction. AB - Objectives. The purpose of this cross-sectional single-blind study was to investigate the immediate effects of Kinesiology taping of quadriceps on motor performance after muscle fatigued induction. Design. Randomized controlled cross sectional design. Subjects. Forty-five subjects participated in this study. Participants were divided into three groups: Kinesiology taping group, placebo taping group, and nontaping group. Methods. Subjects performed short-term exercise for muscle fatigued induction, followed by the application of each intervention. Peak torque test, one-leg single hop test, active joint position sense test, and one-leg static balance test were carried out before and after the intervention. Results. Peak torque and single-leg hopping distance were significantly increased when Kinesiology taping was applied (p < 0.05). But there were no significant effects on active joint position sense and single-leg static balance. Conclusions. We proved that Kinesiology taping is effective in restoring muscle power reduced after muscle fatigued induction. Therefore, we suggest that Kinesiology taping is beneficial for fatigued muscles. PMID- 26246836 TI - Xuezhikang Capsule for Type 2 Diabetes with Hyperlipemia: A Systematic Review and Meta-Analysis of Randomized Clinical Trails. AB - Objective. To evaluate the efficacy and safety of Xuezhikang capsule treating type 2 diabetes with hyperlipidemia. Methods. We searched six databases to identify relevant studies published before January 2015. Two review authors independently extracted data and assessed the Cochrane risk of bias tool. We resolved disagreements with this assessment through discussion and a decision was achieved by consensus. Results. We included 21 studies (1548 participants). Treatment courses were at least 8 weeks. Overall, the risk of bias of included trials was unclear. Among them, 16 studies could conduct meta-analysis. The result showed that compared with routine group (5 studies), Xuezhikang group had more effect on decreasing TC, TG, LDL-C, and rising HDL-C. However, compared with statins group (11 studies), Xuezhikang group has less effect on decreasing TC, TG, and rising HDL-C. Meanwhile, two groups had no statistical differences of LDL C level. Conclusion. Xuezhikang capsule may be effective for treating type 2 diabetes with hyperlipemia. Our findings should be considered cautiously due to unclear risk of bias of the included studies and low methodological quality. Therefore, more strictly designed large-scale randomized clinical trials are needed to evaluate the efficacy of Xuezhikang capsule in type 2 diabetes with hyperlipemia. PMID- 26246837 TI - Effects of Different Local Moxibustion-Like Stimuli at Zusanli (ST36) and Zhongwan (CV12) on Gastric Motility and Its Underlying Receptor Mechanism. AB - The aim of this study was to explore the "intensity-response" relationship in local moxibustion-like stimuli- (LMS-) modulated gastric motility and its underlying receptor mechanism. Based on the thermal pain threshold (43 degrees C), 41 degrees C, 43 degrees C, and 45 degrees C LMS were separately applied to ST36 or CV12 for 180 s among ASIC3 knockout (ASIC3-/-) mice, TRPV1 knockout (TRPV1-/-) mice, and their homologous wild-type C57BL/6 mice (n = 8 in each group). Gastric motility was continuously measured by an intrapyloric balloon, and the amplitude, integral, and frequency of gastric motility during LMS were compared with those of initial activities. We found that both 43 degrees C and 45 degrees C LMS at ST36 induced significantly facilitated effect of gastric motility (P < 0.05), while LMS at CV12 induced inhibited effects (P < 0.05). 41 degrees C LMS had no significant impact on gastric motility. Compared with C57BL/6 mice, the facilitatory effect at ST36 and inhibitive effect of LMS at CV12 were decreased significantly in TRPV1-/- mice (P < 0.05; P < 0.01) but not changed markedly in ASIC3-/- mice (P > 0.05). These results suggest that there existed an "intensity-response" relationship between temperature in LMS and its effects on gastric motility. TRPV1 receptor played a crucial role in the LMS modulated gastric motility. PMID- 26246839 TI - Genistein Attenuates Nonalcoholic Steatohepatitis and Increases Hepatic PPARgamma in a Rat Model. AB - Nonalcoholic steatohepatitis (NASH) has become a global chronic liver disease, but no effective medicine has been proven to cure it. This study investigated the protective effects of genistein, a phytoestrogen, on NASH and examined whether it has any effect on hepatic PPARgamma. Male Sprague-Dawley rats were divided into four groups: control group fed ad libitum with standard rat diet, NASH group fed ad libitum with high-fat diet to induce NASH and NASH + Gen8 group and NASH + Gen16 group fed with high-fat diet plus intragastric administration of 8 or 16 mg/kg genistein once daily. After 6 weeks, liver samples were collected to determine MDA, TNF-alpha, PPARgamma, and histopathology. The findings were that levels of hepatic MDA and TNF-alpha increased in NASH group, but 16 mg/kg genistein reduced these levels significantly. Downregulation of hepatic PPARgamma was observed in NASH group, but genistein significantly upregulated the expression of PPARgamma in both NASH + Gen groups. The histological appearance of liver in NASH group presented pathological features of steatohepatitis which were diminished in both NASH + Gen groups. The results suggest that genistein attenuates the liver histopathology of NASH with upregulation of hepatic PPARgamma, reduction of oxidative stress, and inhibition of inflammatory cytokine. PMID- 26246838 TI - Preparation, Characterization, and Pharmacological Activity of Cymbopogon winterianus Jowitt ex Bor (Poaceae) Leaf Essential Oil of beta-Cyclodextrin Inclusion Complexes. AB - This study aimed to evaluate the orofacial antinociceptive effect of the Cymbopogon winterianus essential oil (LEO) complexed in beta-cyclodextrin (LEO CD) and to assess the possible involvement of the central nervous system (CNS). The LEO was extracted, chromatographed, and complexed in beta-cyclodextrin. The complex was characterized by differential scanning calorimetry (DSC) and thermogravimetry derivative (TG/DTG). Male Swiss mice (2-3 months) were treated with LEO-CD (50-200 mg/kg, p.o.), vehicle (distilled water, p.o.), or standard drug (i.p.) and subjected to the orofacial nociception formalin-, capsaicin-, and glutamate-induced. After the formalin test, the animals were perfused and the brains subjected to immunofluorescence for Fos. The rota-rod test (7 rpm/min) was carried out. Geraniol (37.57%) was the main compound of LEO. DSC and TG/DTG proved the complexation. The orofacial nociceptive behavior was significantly (p < 0.05) reduced. The number of Fos-positive cells was significantly changed in the dorsal raphe nucleus (p < 0.01), locus coeruleus (p < 0.001), trigeminal nucleus (p < 0.05), and trigeminal thalamic tract (p < 0.05). LEO-CD did not cause changes in motor coordination in the rota-rod test. Thus, our results suggested that LEO-CD has an orofacial antinociceptive profile, probably mediated by the activation of the CNS without changing the motor coordination. PMID- 26246840 TI - Evaluation of Toxicity and Antimicrobial Activity of an Ethanolic Extract from Leaves of Morus alba L. (Moraceae). AB - This work evaluated an ethanolic extract from Morus alba leaves for toxicity to Artemia salina, oral toxicity to mice, and antimicrobial activity. Phytochemical analysis revealed the presence of coumarins, flavonoids, tannins, and triterpenes in the extract, which did not show toxicity to A. salina nauplii. No mortality and behavioral alterations were detected for mice treated with the extract (300 and 2000 mg/kg b.w.) for 14 days. However, animals that received the highest dose showed reduced MCV and MCHC as well as increased serum alkaline phosphatase activity. In treatments with the extract at both 300 and 2000 mg/kg, there was a reduction in number of leukocytes, with decrease in percentage of lymphocytes and increase in proportion of segmented cells. Histopathological analysis of organs from mice treated with the extract at 2000 mg/kg revealed turgidity of contorted tubules in kidneys, presence of leukocyte infiltration around the liver centrilobular vein, and high dispersion of the spleen white pulp. The extract showed antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Candida krusei, Candida tropicalis, and Aspergillus flavus. In conclusion, the extract contains antimicrobial agents and was not lethal for mice when ingested; however, its use requires caution because it promoted biochemical, hematological, and histopathological alterations. PMID- 26246841 TI - A Systematic Overview of Reviews for Complementary and Alternative Therapies in the Treatment of the Fibromyalgia Syndrome. AB - Objectives. This systematic overview of reviews aimed to summarize evidence and methodological quality from systematic reviews of complementary and alternative medicine (CAM) for the fibromyalgia syndrome (FMS). Methods. The PubMed/MEDLINE, Cochrane Library, and Scopus databases were screened from their inception to Sept 2013 to identify systematic reviews and meta-analyses of CAM interventions for FMS. Methodological quality of reviews was rated using the AMSTAR instrument. Results. Altogether 25 systematic reviews were found; they investigated the evidence of CAM in general, exercised-based CAM therapies, manipulative therapies, Mind/Body therapies, acupuncture, hydrotherapy, phytotherapy, and homeopathy. Methodological quality of reviews ranged from lowest to highest possible quality. Consistently positive results were found for tai chi, yoga, meditation and mindfulness-based interventions, hypnosis or guided imagery, electromyogram (EMG) biofeedback, and balneotherapy/hydrotherapy. Inconsistent results concerned qigong, acupuncture, chiropractic interventions, electroencephalogram (EEG) biofeedback, and nutritional supplements. Inconclusive results were found for homeopathy and phytotherapy. Major methodological flaws included missing details on data extraction process, included or excluded studies, study details, and adaption of conclusions based on quality assessment. Conclusions. Despite a growing body of scientific evidence of CAM therapies for the management of FMS systematic reviews still show methodological flaws limiting definite conclusions about their efficacy and safety. PMID- 26246842 TI - Significant Geometry Features in Tongue Image Analysis. AB - The shape of a human tongue and its relation to a patients' state, either healthy or diseased (and if diseased which disease), is quantitatively analyzed using geometry features by means of computerized methods in this paper. Thirteen geometry features based on measurements, distances, areas, and their ratios are extracted from tongue images captured by a specially designed device with color correction. Using the features, 5 tongue shapes (rectangle, acute and obtuse triangles, square, and circle) are defined based on traditional Chinese medicine (TCM). Classification of the shapes is subsequently carried out with a decision tree. A large dataset consisting of 672 images comprising of 130 healthy and 542 disease examples (labeled according to Western medical practices) are tested. Experimental results show that the extracted geometry features are effective at tongue shape classification (coarse level). Even if more than one disease class belongs to the same shape, the disease classes can still be discriminated via fine level classification using a combination of the geometry features, with an average accuracy of 76.24% for all shapes. PMID- 26246844 TI - Costus afer Possesses Carbohydrate Hydrolyzing Enzymes Inhibitory Activity and Antioxidant Capacity In Vitro. AB - Diabetes mellitus is a metabolic disorder of glucose metabolism which correlates with postprandial hyperglycemia and oxidative stress. Control of blood glucose level is imperative in the management of diabetes. The present study tested the hypothesis that Costus afer, an antihyperglycemic medicinal plant, possesses inhibitory activity against carbohydrate hydrolyzing enzymes. Hexane, ethyl acetate, methanol, and water extracts were prepared from the leaf, stem, and rhizome of C. afer and subjected to phytochemical screening, assayed for alpha amylase and alpha-glucosidase inhibitory activities and antioxidant capacity (determined by total phenolic and total flavonoids contents, ferric reducing antioxidant power (FRAP), and DPPH radical scavenging activity). All extracts inhibited alpha-amylase and alpha-glucosidase activities. Ethyl acetate rhizome and methanol leaf extracts exhibited the best inhibitory activity against alpha amylase and alpha-glucosidase (IC50: 0.10 and 5.99 mg/mL), respectively. Kinetic analysis revealed two modes of enzyme inhibition (competitive and mixed). All extracts showed antioxidant capacity, with hexane extracts exhibiting the best activity. DPPH assay revealed that methanol leaf, rhizome, and ethyl acetate stem extracts (IC50 < 5 mg/mL) were the best antioxidants. The presence of bioactive compounds such as flavonoids, alkaloids, phenols, and tannins may account for the antioxidant capacity and carbohydrate hydrolyzing enzyme inhibitory activity of C. afer. PMID- 26246843 TI - Osthole: A Review on Its Bioactivities, Pharmacological Properties, and Potential as Alternative Medicine. AB - This paper reviews the latest understanding of biological and pharmacological properties of osthole (7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one), a natural product found in several medicinal plants such as Cnidium monnieri and Angelica pubescens. In vitro and in vivo experimental results have revealed that osthole demonstrates multiple pharmacological actions including neuroprotective, osteogenic, immunomodulatory, anticancer, hepatoprotective, cardiovascular protective, and antimicrobial activities. In addition, pharmacokinetic studies showed osthole uptake and utilization are fast and efficient in body. Moreover, the mechanisms of multiple pharmacological activities of osthole are very likely related to the modulatory effect on cyclic adenosine monophosphate (cAMP) and cyclic adenosine monophosphate (cGMP) level, though some mechanisms remain unclear. This review aims to summarize the pharmacological properties of osthole and give an overview of the underlying mechanisms, which showcase its potential as a multitarget alternative medicine. PMID- 26246845 TI - Identification of a botanical inhibitor of intestinal diacylglyceride acyltransferase 1 activity via in vitro screening and a parallel, randomized, blinded, placebo-controlled clinical trial. AB - BACKGROUND: Diacylglyceride acyltransferase 1 (DGAT1) is the enzyme that adds the final fatty acid on to a diacylglyceride during triglyceride (TG) synthesis. DGAT1 plays a key role in the repackaging of dietary TG into circulating TG rich chylomicrons. A growing amount of research has indicated that an exaggerated postprandial circulating TG level is a risk indicator for cardiovascular and metabolic disorders. The aim of this research was to identify a botanical extract that inhibits intestinal DGAT1 activity and attenuates postprandial hypertriglyceridemia in overweight and obese humans. METHODS: Twenty individual phytochemicals and an internal proprietary botanical extract library were screened with a primary cell-free DGAT1 enzyme assay that contained dioleoyl glycerol and palmitoleoyl Coenzyme A as substrates plus human intestinal microsomes as the DGAT1 enzyme source. Botanical extracts with IC50 values < 100 MUg/mL were evaluated in a cellular DGAT1 assay. The cellular DGAT1 assay comprised the analysis of (14)C labeled TG synthesis in cells incubated with (14)C-glycerol and 0.3 mM oleic acid. Lead botanical extracts were then evaluated in a parallel, double-blind, placebo-controlled clinical trial. Ninety healthy, overweight and obese participants were randomized to receive 2 g daily of placebo or individual botanical extracts (the investigational product) for seven days. Serum TG levels were measured before and after consuming a high fat meal (HFM) challenge (0.354 L drink/shake; 77 g fat, 25 g carbohydrate and 9 g protein) as a marker of intestinal DGAT1 enzyme activity. RESULTS: Phenolic acids (i.e., gallic acid) and polyphenols (i.e., cyanidin) abundantly found in nature appeared to inhibit DGAT1 enzyme activity in vitro. Four polyphenolic rich botanical extracts were identified from in vitro evaluation in both cell-free and cellular model systems: apple peel extract (APE), grape extract (GE), red raspberry leaf extract (RLE) and apricot/nectarine extract (ANE) (IC50 = 1.4, 5.6, and 10.4 and 3.4 MUg/mL, respectively). In the seven day clinical trial, compared to placebo, only GE significantly reduced the baseline subtracted change in serum TG AUC following consumption of the HFM (AUC = 281 +/- 37 vs. 181 +/- 30 mg/dL*h, respectively; P = 0.021). Chromatographic characterization of the GE revealed a large number of closely eluting components containing proanthocyanidins, catechins, anthocyanins and their secondary metabolites that corresponded with the observed DGAT1 enzyme inhibition in the cell-free model. CONCLUSION: These data suggest that a dietary GE has the potential to attenuate postprandial hypertriglyceridemia in part by the inhibition of intestinal DGAT1 enzyme activity without intolerable side effects. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov NCT02333461. PMID- 26246846 TI - Family economic strengthening and mental health functioning of caregivers for AIDS-affected children in rural Uganda. AB - In sub-Saharan Africa, many extended families assume the role of caregivers for children orphaned by AIDS (AIDS-affected children). The economic and psychological stress ensued from caregiving duties often predispose caregivers to poor mental health outcomes. Yet, very few studies exist on effective interventions to support these caregivers. Using data from a randomized controlled trial called Suubi-Maka (N = 346), this paper examines whether a family economic strengthening intervention among families caring for AIDS affected children (ages 12-14) in Uganda would improve the primary caregivers' mental health functioning. The Suubi-Maka study comprised of a control condition (n = 167) receiving usual care for AIDS-affected children, and a treatment condition (n = 179) receiving a family economic strengthening intervention, including matched savings accounts, and financial planning and management training to incentivize families to save money for education and/or family-level income generating projects. This paper uses data from baseline/pre-intervention (wave 1) interviews with caregivers and 12-month post-intervention initiation (wave 2). The caregiver's mental health measure adapted from previous studies in sub- Saharan Africa had an internal consistency of .88 at wave 1 and .90 at wave 2. At baseline, the two study groups did not significantly differ on caregiver's mental health functioning. However, at 12-month follow-up, multiple regression analysis located significant differences between the two study groups on mental health functioning. Specifically, following the intervention, caregivers in the treatment condition reported positive improvements on their mental health functioning, especially in the symptom areas of obsession-compulsion, interpersonal sensitivity, hostility, and psychoticism. Findings point to a need for programs and policies aimed at supporting caregivers of AIDS-affected children to begin to consider incorporating family-level economic strengthening components in their usual care protocols, especially in low-resource countries of sub-Saharan Africa. Economic empowerment programming may help enhance the well being of caregivers and their families. PMID- 26246847 TI - Effect of distribution of educational material to mothers on duration and severity of diarrhoea and pneumonia, Midlands Province, Zimbabwe: a cluster randomized controlled trial. AB - BACKGROUND: Exclusive breastfeeding rates remain low in most countries in sub Saharan Africa. We assessed the effects of a mother-based intervention on duration of diarrhoea and pneumonia in communities that were trained and those not trained in community infant and young child feeding (cIYCF) in Midlands Province, Zimbabwe. METHODS: We evaluated communities with village health workers who received training in cIYCF and the distribution of educational materials (newsletter) to mothers in promotion of exclusive breastfeeding using a two-by two factorial cluster randomized controlled trial. The trial arms included clusters trained in cIYCF only, clusters with mothers that received a newsletter only, clusters that received both interventions and clusters receiving no intervention. Consenting mother-infant pairs identified within 72 hours of delivery were followed up at 14 and 20 weeks where duration of diarrhoea and pneumonia as well as severity of diarrhoea was assessed. Clusters were facility catchment areas assigned by an independent statistician using randomization generated by a computer using Stata 10. All admitting facilities and facilities at borders were excluded as buffer zones and eight clusters were analysed. Nutritionists who collected data were not aware of the hypothesis being tested and analysis was by intention-to-treat. RESULTS: A total of 357 mother-infant pairs were available for analysis in all the clusters. The interaction between cIYCF training and the newsletter was statistically significant at 14 weeks (p = 0.022). The mean duration of diarrhoea was 2.9 (SD = 0.9) days among infants of mothers who resided in communities trained and received a newsletter compared to 5.2 (SD = 1.1) days in communities that received neither. The protective efficacy of the cIYCF plus newsletter was 76% during the first 20 weeks of life. In the two way ANOVA, the newsletter was more effective on duration of pneumonia (p = 0.010) at 14 weeks and remained significantly effective at 20 weeks (p < 0.0001). CONCLUSIONS: A combined community and distribution of a newsletter to mothers on promotion of exclusive breastfeeding reduces duration of diarrhoea at 14 weeks. At 20 weeks, the newsletter worked better for both duration of diarrhoea and pneumonia compared to cIYCF training alone. PMID- 26246848 TI - Dual Energy Method for Breast Imaging: A Simulation Study. AB - Dual energy methods can suppress the contrast between adipose and glandular tissues in the breast and therefore enhance the visibility of calcifications. In this study, a dual energy method based on analytical modeling was developed for the detection of minimum microcalcification thickness. To this aim, a modified radiographic X-ray unit was considered, in order to overcome the limited kVp range of mammographic units used in previous DE studies, combined with a high resolution CMOS sensor (pixel size of 22.5 MUm) for improved resolution. Various filter materials were examined based on their K-absorption edge. Hydroxyapatite (HAp) was used to simulate microcalcifications. The contrast to noise ratio (CNR tc ) of the subtracted images was calculated for both monoenergetic and polyenergetic X-ray beams. The optimum monoenergetic pair was 23/58 keV for the low and high energy, respectively, resulting in a minimum detectable microcalcification thickness of 100 MUm. In the polyenergetic X-ray study, the optimal spectral combination was 40/70 kVp filtered with 100 MUm cadmium and 1000 MUm copper, respectively. In this case, the minimum detectable microcalcification thickness was 150 MUm. The proposed dual energy method provides improved microcalcification detectability in breast imaging with mean glandular dose values within acceptable levels. PMID- 26246849 TI - Dynamical Analysis of an SEIT Epidemic Model with Application to Ebola Virus Transmission in Guinea. AB - In order to investigate the transmission mechanism of the infectious individual with Ebola virus, we establish an SEIT (susceptible, exposed in the latent period, infectious, and treated/recovery) epidemic model. The basic reproduction number is defined. The mathematical analysis on the existence and stability of the disease-free equilibrium and endemic equilibrium is given. As the applications of the model, we use the recognized infectious and death cases in Guinea to estimate parameters of the model by the least square method. With suitable parameter values, we obtain the estimated value of the basic reproduction number and analyze the sensitivity and uncertainty property by partial rank correlation coefficients. PMID- 26246850 TI - Modelling Optimal Control of Cholera in Communities Linked by Migration. AB - A mathematical model for the dynamics of cholera transmission with permissible controls between two connected communities is developed and analysed. The dynamics of the disease in the adjacent communities are assumed to be similar, with the main differences only reflected in the transmission and disease related parameters. This assumption is based on the fact that adjacent communities often have different living conditions and movement is inclined toward the community with better living conditions. Community specific reproduction numbers are given assuming movement of those susceptible, infected, and recovered, between communities. We carry out sensitivity analysis of the model parameters using the Latin Hypercube Sampling scheme to ascertain the degree of effect the parameters and controls have on progression of the infection. Using principles from optimal control theory, a temporal relationship between the distribution of controls and severity of the infection is ascertained. Our results indicate that implementation of controls such as proper hygiene, sanitation, and vaccination across both affected communities is likely to annihilate the infection within half the time it would take through self-limitation. In addition, although an infection may still break out in the presence of controls, it may be up to 8 times less devastating when compared with the case when no controls are in place. PMID- 26246851 TI - Spatial distribution of temporal dynamics in anthropogenic fires in miombo savanna woodlands of Tanzania. AB - BACKGROUND: Anthropogenic uses of fire play a key role in regulating fire regimes in African savannas. These fires contribute the highest proportion of the globally burned area, substantial biomass burning emissions and threaten maintenance and enhancement of carbon stocks. An understanding of fire regimes at local scales is required for the estimation and prediction of the contribution of these fires to the global carbon cycle and for fire management. We assessed the spatio-temporal distribution of fires in miombo woodlands of Tanzania, utilizing the MODIS active fire product and Landsat satellite images for the past ~40 years. RESULTS: Our results show that up to 50.6% of the woodland area is affected by fire each year. An early and a late dry season peak in wetter and drier miombo, respectively, characterize the annual fire season. Wetter miombo areas have higher fire activity within a shorter annual fire season and have shorter return intervals. The fire regime is characterized by small-sized fires, with a higher ratio of small than large burned areas in the frequency-size distribution (beta = 2.16 +/- 0.04). Large-sized fires are rare, and occur more frequently in drier than in wetter miombo. Both fire prevalence and burned extents have decreased in the past decade. At a large scale, more than half of the woodland area has less than 2 years of fire return intervals, which prevent the occurrence of large intense fires. CONCLUSION: The sizes of fires, season of burning and spatial extent of occurrence are generally consistent across time, at the scale of the current analysis. Where traditional use of fire is restricted, a reassessment of fire management strategies may be required, if sustainability of tree cover is a priority. In such cases, there is a need to combine traditional and contemporary fire management practices. PMID- 26246852 TI - CombAlign: a code for generating a one-to-many sequence alignment from a set of pairwise structure-based sequence alignments. AB - BACKGROUND: In order to better define regions of similarity among related protein structures, it is useful to identify the residue-residue correspondences among proteins. Few codes exist for constructing a one-to-many multiple sequence alignment derived from a set of structure or sequence alignments, and a need was evident for creating such a tool for combining pairwise structure alignments that would allow for insertion of gaps in the reference structure. RESULTS: This report describes a new Python code, CombAlign, which takes as input a set of pairwise sequence alignments (which may be structure based) and generates a one to-many, gapped, multiple structure- or sequence-based sequence alignment (MSSA). The use and utility of CombAlign was demonstrated by generating gapped MSSAs using sets of pairwise structure-based sequence alignments between structure models of the matrix protein (VP40) and pre-small/secreted glycoprotein (sGP) of Reston Ebolavirus and the corresponding proteins of several other filoviruses. The gapped MSSAs revealed structure-based residue-residue correspondences, which enabled identification of structurally similar versus differing regions in the Reston proteins compared to each of the other corresponding proteins. CONCLUSIONS: CombAlign is a new Python code that generates a one-to-many, gapped, multiple structure- or sequence-based sequence alignment (MSSA) given a set of pairwise sequence alignments (which may be structure based). CombAlign has utility in assisting the user in distinguishing structurally conserved versus divergent regions on a reference protein structure relative to other closely related proteins. CombAlign was developed in Python 2.6, and the source code is available for download from the GitHub code repository. PMID- 26246853 TI - Mental health of displaced and returnee populations: Insight from the Sri Lankan post-conflict experience. AB - The month of May 2015 marked the sixth year since the end of conflict in Sri Lanka. The cause of death, destruction and displacement, three decades of conflict has had a major impact on health, especially on mental health of those affected by forced displacement. Post-conflict regions of Sri Lanka has seen improvements in many areas, including resettlement of displaced populations and rebuilding of health-related infrastructure. However, substantial gaps exist around the management of health needs among returnee populations, especially in the area of psychosocial health. Long-term mental health and resilience trajectories of those affected by prolonged displacement and experiencing return migration during post-conflict periods remain important, yet critically understudied areas. PMID- 26246854 TI - Quantitative proteomics analysis of an ethanol- and a lactate-producing mutant strain of Synechocystis sp. PCC6803. AB - BACKGROUND: This study aimed at exploring the molecular physiological consequences of a major redirection of carbon flow in so-called cyanobacterial cell factories: quantitative whole-cell proteomics analyses were carried out on two (14)N-labelled Synechocystis mutant strains, relative to their (15)N-labelled wild-type counterpart. Each mutant strain overproduced one specific commodity product, i.e. ethanol or lactic acid, to such an extent that the majority of the incoming CO2 in the organism was directly converted into the product. RESULTS: In total, 267 proteins have been identified with a significantly up- or down regulated expression level. In the ethanol-producing mutant, which had the highest relative direct flux of carbon-to-product (>65%), significant up regulation of several components involved in the initial stages of CO2 fixation for cellular metabolism was detected. Also a general decrease in abundance of the protein synthesizing machinery of the cells and a specific induction of an oxidative stress response were observed in this mutant. In the lactic acid overproducing mutant, that expresses part of the heterologous l-lactate dehydrogenase from a self-replicating plasmid, specific activation of two CRISPR associated proteins, encoded on the endogenous pSYSA plasmid, was observed. RT qPCR was used to measure, of nine of the genes identified in the proteomics studies, also the adjustment of the corresponding mRNA level. CONCLUSION: The most striking adjustments detected in the proteome of the engineered cells were dependent on the specific product formed, with, e.g. more stress caused by lactic acid- than by ethanol production. Up-regulation of the total capacity for CO2 fixation in the ethanol-producing strain was due to hierarchical- rather than metabolic regulation. Furthermore, plasmid-based expression of heterologous gene(s) may induce genetic instability. For selected, limited, number of genes a striking correlation between the respective mRNA- and the corresponding protein expression level was observed, suggesting that for the expression of these genes regulation takes place primarily at the level of gene transcription. PMID- 26246855 TI - Xpp1 regulates the expression of xylanases, but not of cellulases in Trichoderma reesei. AB - BACKGROUND: The ascomycete Trichoderma reesei is industrially used for the production of cellulases. During the production process xylanases are co secreted, which uses energy and nutrients. Cellulases and xylanases share the same main regulators, which makes a knowledge-based strain design difficult. However, previously a cis-element in the promoter of the main xylanase-encoding gene was identified as binding site for a putative repressor. Subsequently, three candidate repressors were identified in a pull-down approach. The expression of the most promising candidate, Xpp1 (Xylanase promoter-binding protein 1), was reported to be up-regulated on the repressing carbon source d-glucose and to bind the cis-element in vitro. RESULTS: In this study, Xpp1 was deleted and over expressed in T. reesei. An in vivo DNA-footprint assay indicated that Xpp1 binds a palindromic sequence in the xyn2 promoter. Comparison of the deletion, the over expression, and the parent strain demonstrated that Xpp1 regulates gene expression of xylanolytic enzymes at later cultivation stages. Xpp1 expression was found to be up-regulated, additionally to d-glucose, by high d-xylose availability. These findings together with the observed xyn2 transcript levels during growth on xylan suggest that Xpp1 is the mediator of a feedback mechanism. Notably, Xpp1 has neither influence on the d-xylose metabolism nor on the expression of cellulases. CONCLUSIONS: Xpp1 as regulator acting on the expression of xylanases, but not cellulases, is a highly promising candidate for knowledge based strain design to improve the cellulases-to-xylanases ratio during industrial cellulase production. PMID- 26246856 TI - The role of visualization and 3-D printing in biological data mining. AB - BACKGROUND: Biological data mining is a powerful tool that can provide a wealth of information about patterns of genetic and genomic biomarkers of health and disease. A potential disadvantage of data mining is volume and complexity of the results that can often be overwhelming. It is our working hypothesis that visualization methods can greatly enhance our ability to make sense of data mining results. More specifically, we propose that 3-D printing has an important role to play as a visualization technology in biological data mining. We provide here a brief review of 3-D printing along with a case study to illustrate how it might be used in a research setting. RESULTS: We present as a case study a genetic interaction network associated with grey matter density, an endophenotype for late onset Alzheimer's disease, as a physical model constructed with a 3-D printer. The synergy or interaction effects of multiple genetic variants were represented through a color gradient of the physical connections between nodes. The digital gene-gene interaction network was then 3-D printed to generate a physical network model. CONCLUSIONS: The physical 3-D gene-gene interaction network provided an easily manipulated, intuitive and creative way to visualize the synergistic relationships between the genetic variants and grey matter density in patients with late onset Alzheimer's disease. We discuss the advantages and disadvantages of this novel method of biological data mining visualization. PMID- 26246857 TI - The future of genomic medicine education in Africa. AB - There are many challenges and opportunities for Africans in the emerging area of genome medicine. In particular, there is a need for investment in local education using real-world African genetic data sets. Cloud-based computing platforms offer one solution for engaging the next generation of biomedical scientists in tackling disease in Africa, and by extension, the world. PMID- 26246858 TI - Erratum to: Brave new epigenomes: the dawn of epigenetic engineering. AB - [This corrects the article DOI: 10.1186/s13073-015-0185-8.]. PMID- 26246859 TI - MHEALTH INTERVENTION DEVELOPMENT TO SUPPORT PATIENTS WITH ACTIVE TUBERCULOSIS. AB - BACKGROUND: Mobile Health (mHealth) based interventions have been increasingly used to improve a broad range of health outcomes. However, few researchers have reported on the process or the application of theory to guide the development of mHealth based interventions, or specifically for tuberculosis (TB) treatment management. AIMS: To describe the steps, process, and considerations in developing a text messaging-based intervention to promote treatment adherence and provide support to patients with active TB. METHODS: Traditional qualitative techniques, including semi-structured interviews, field notes, content analysis, iterative coding, and thematic analysis, were used to design and document the intervention development with a multidisciplinary team of researchers, clinicians, administrators, and patients who were in active TB treatment. The Information-Motivation-Behavioral Skills (IMB) model was used to guide the coding scheme for content analysis of patient-directed TB educational material and intervention development. RESULTS: The development steps included: a) establishing intervention components, including justifications, considerations, timing and frequency of components; b) developing educational messages, including cultural adaption, text or short message service (SMS) formatting, and prioritizing message delivery order; and c) determining implementation protocol. A set of 16 IMB-based messages were developed for the educational component. Final intervention development was achieved in 3 months. CONCLUSION: A collaborative approach and application of a theory to guide the intervention design and development is supported. Although a collaborative approach was more time consuming, it resulted in a more responsive, culturally appropriate, and comprehensive intervention. Considerations for developing a text messaging based intervention are provided and may serve as a guide for similar interventions. Further empirical evidence is needed for applying the IMB model for adherence promotion in TB efforts. PMID- 26246860 TI - DNA methylation signature of interleukin 1 receptor type II in asthma. AB - Interleukin 1 and its receptors are associated with allergic diseases such as asthma. In the present study, we measured DNA methylation at the IL1R1 and IL1R2 gene loci and assessed for associations with asthma-related phenotypes and gene expressions. We found that asthmatic and atopic individuals have higher IL1R2 promoter DNA methylation than control subjects. Additionally, we observed a negative correlation between DNA methylation at the IL1R2 promoter and IL1R2 mRNA expression. These results suggest for the first time that IL1R2 promoter DNA methylation is associated with its gene repression in allergic diseases such as asthma. PMID- 26246861 TI - A varying T cell subtype explains apparent tobacco smoking induced single CpG hypomethylation in whole blood. AB - BACKGROUND: Many recent epigenetic studies report that cigarette smoking reduces DNA methylation in whole blood at the single CpG site cg19859270 within the GPR15 gene. RESULTS: Within two independent cohorts, we confirmed the differentially expression of the GPR15 gene when smokers and non-smokers subjects are compared. By validating the GPR15 protein expression at the cellular level, we found that the observed decreased methylation at this site in white blood cells (WBC) of smokers is mainly caused by the high proportion of CD3+GPR15+ expressing T cells in peripheral blood. In current smokers, the percentage of GPR15+ cells among CD3+ T cells in peripheral blood is significantly higher (15.5 +/- 7.2 %, mean +/ standard deviation) compared to non-smokers (3.7 +/- 1.6 %). Treatment of peripheral blood mononuclear cell (PBMC) cultures with aqueous cigarette smoke extract did not induce a higher proportion of this T cell subtype. CONCLUSIONS: Our results underline that DNA hypomethylation at cg19859270 site, observed in WBCs of smokers, did not arise by direct effect of tobacco smoking compounds on methylation of DNA but rather by the enrichment of a tobacco-smoking-induced lymphocyte population in the peripheral blood. PMID- 26246862 TI - Use of two indicators for the socio-environmental risk analysis of Northern Mexico under three climate change scenarios. AB - The aims of this study were to (1) find critical areas susceptible to the degradation of natural resources according to local erosion rates and aridity levels, which were used as environmental quality indicators, and (2) identify areas of risk associated with the presence of natural hazards according to three climate change scenarios defined for Mexico. The focus was the municipality of Lerdo, Durango (25.166 degrees to 25.783 degrees N and 103.333 degrees to 103.983 degrees W), which has dry temperate and very dry climates (BSohw and BWhw). From the Global Circulation Models, downscaling techniques for the dynamic modeling of environmental processes using climate data, historical information, and three regionalized climate change scenarios were applied to determine the impacts from laminar wind erosion rates (LWER) and aridity indices (AI). From the historic period to scenario A2 (ScA2, 2010-2039), regarding greenhouse gas emissions, the LWER was predicted to reach 147.2 t ha-1 year-1, representing a 0.5 m thickness over nearly 30 years and a change in the AI from 9.3 to 8.7. This trend represents an increase in drought for 70.8 % of the study area and could affect 90 % of the agricultural activities and approximately 80 % of the population living in the southeastern Lerdense territory. PMID- 26246863 TI - The effect of a fireworks event on the amount and elemental concentration of deposited dust collected in the city of Debrecen, Hungary. AB - Many social celebrations in urban areas are followed by fireworks show. The organic and inorganic pollutants emitted during detonations are expected to affect the ambient air quality of these celebration sites. The environmental aspects of fireworks events are usually investigated by analyzing the concentration and composition of airborne particulate matter, while there is limited information regarding the effect of fireworks on the elemental concentration of deposited dust. In this study, foliage dust samples were collected in the city of Debrecen (Hungary) before and after the fireworks show, organized on the 20th of August for the celebration of a historical event. Leaf samples (Tilia tomentosa) were collected around the location of the area of festivities. The sampling sites were further divided into five areas: city center (center), Southeast (SE), Southwest (SW), Northeast (NE), and Northwest (NW). We found that the amount of deposited dust particles increased significantly after the fireworks show compared to the background; we also found significant differences in the amount of dust deposition between the different locations of the city. A statistically higher level of Ca, Mg, and Sr was detected in samples collected after the display compared to those collected during the previous days, while the concentration of other studied elements were not statistically different from the background level. Our study confirmed previous findings that the relatively high altitude of detonations allows chemicals to disperse in the fine and ultrafine aerosol fractions; thus, the emitted pollutants by fireworks shows do not increase the level of elements as markedly in deposited dust as in the inhalable fraction. PMID- 26246864 TI - Migration and Regional Differences in Access to Local Family Networks Among 60 year olds in Sweden. AB - Regional variations in access to local family networks has implications for future care burdens in different regions as well as the living conditions for both older and younger generations. The geographical distance between family members is a long-term consequence of accumulated migration and non-migration undertaken by the individual as well as other family members. This study contributes to this subject through offering a description of regional disparities in the access to local family networks among 60-year olds in Sweden. Additionally, this paper aims to analyse this pattern as an outcome of long distance migration processes. The empirical study is based on Swedish register data, with a focus on 60-year olds in Sweden, linking them to their adult children, siblings and parents as well as in-laws. The dataset includes total population, where it is possible to identify family networks in their geographical context on various geographic scales, down to a neighbourhood level. As expected, results indicate that families in metropolitan areas are the most concentrated geographically while the left behind parent, embedded in a local network in their own and older generation, is a small category in urban areas but quite common in some rural municipalities. It is also shown that access to local family networks not only varies on a broad rural-urban scale but also locally, between neighbourhoods within metropolitan areas. PMID- 26246865 TI - Nonparametric Bayesian Bi-Clustering for Next Generation Sequencing Count Data. AB - Histone modifications (HMs) play important roles in transcription through post translational modifications. Combinations of HMs, known as chromatin signatures, encode specific messages for gene regulation. We therefore expect that inference on possible clustering of HMs and an annotation of genomic locations on the basis of such clustering can contribute new insights about the functions of regulatory elements and their relationships to combinations of HMs. We propose a nonparametric Bayesian local clustering Poisson model (NoB-LCP) to facilitate posterior inference on two-dimensional clustering of HMs and genomic locations. The NoB-LCP clusters HMs into HM sets and lets each HM set define its own clustering of genomic locations. Furthermore, it probabilistically excludes HMs and genomic locations that are irrelevant to clustering. By doing so, the proposed model effectively identifies important sets of HMs and groups regulatory elements with similar functionality based on HM patterns. PMID- 26246866 TI - BAYESIAN SPARSE GRAPHICAL MODELS FOR CLASSIFICATION WITH APPLICATION TO PROTEIN EXPRESSION DATA. AB - Reverse-phase protein array (RPPA) analysis is a powerful, relatively new platform that allows for high-throughput, quantitative analysis of protein networks. One of the challenges that currently limit the potential of this technology is the lack of methods that allow for accurate data modeling and identification of related networks and samples. Such models may improve the accuracy of biological sample classification based on patterns of protein network activation and provide insight into the distinct biological relationships underlying different types of cancer. Motivated by RPPA data, we propose a Bayesian sparse graphical modeling approach that uses selection priors on the conditional relationships in the presence of class information. The novelty of our Bayesian model lies in the ability to draw information from the network data as well as from the associated categorical outcome in a unified hierarchical model for classification. In addition, our method allows for intuitive integration of a priori network information directly in the model and allows for posterior inference on the network topologies both within and between classes. Applying our methodology to an RPPA data set generated from panels of human breast cancer and ovarian cancer cell lines, we demonstrate that the model is able to distinguish the different cancer cell types more accurately than several existing models and to identify differential regulation of components of a critical signaling network (the PI3K-AKT pathway) between these two types of cancer. This approach represents a powerful new tool that can be used to improve our understanding of protein networks in cancer. PMID- 26246867 TI - Propofol Attenuates Small Intestinal Ischemia Reperfusion Injury through Inhibiting NADPH Oxidase Mediated Mast Cell Activation. AB - Both oxidative stress and mast cell (MC) degranulation participate in the process of small intestinal ischemia reperfusion (IIR) injury, and oxidative stress induces MC degranulation. Propofol, an anesthetic with antioxidant property, can attenuate IIR injury. We postulated that propofol can protect against IIR injury by inhibiting oxidative stress subsequent from NADPH oxidase mediated MC activation. Cultured RBL-2H3 cells were pretreated with antioxidant N acetylcysteine (NAC) or propofol and subjected to hydrogen peroxide (H2O2) stimulation without or with MC degranulator compound 48/80 (CP). H2O2 significantly increased cells degranulation, which was abolished by NAC or propofol. MC degranulation by CP further aggravated H2O2 induced cell degranulation of small intestinal epithelial cell, IEC-6 cells, stimulated by tryptase. Rats subjected to IIR showed significant increases in cellular injury and elevations of NADPH oxidase subunits p47(phox) and gp91(phox) protein expression, increases of the specific lipid peroxidation product 15-F2t Isoprostane and interleukin-6, and reductions in superoxide dismutase activity with concomitant enhancements in tryptase and beta-hexosaminidase. MC degranulation by CP further aggravated IIR injury. And all these changes were attenuated by NAC or propofol pretreatment, which also abrogated CP-mediated exacerbation of IIR injury. It is concluded that pretreatment of propofol confers protection against IIR injury by suppressing NADPH oxidase mediated MC activation. PMID- 26246868 TI - The Effect of Age on Osteogenic and Adipogenic Differentiation Potential of Human Adipose Derived Stromal Stem Cells (hASCs) and the Impact of Stress Factors in the Course of the Differentiation Process. AB - Human adipose tissue is a great source of autologous mesenchymal stem cells (hASCs), which are recognized for their vast therapeutic applications. Their ability to self-renew and differentiate into several lineages makes them a promising tool for cell-based therapies in different types of degenerative diseases. Thus it is crucial to evaluate age-related changes in hASCs, as the elderly are a group that will benefit most from their considerable potential. In this study we investigated the effect of donor age on growth kinetics, cellular senescence marker levels, and osteogenic and adipogenic potential of hASCs. It also has been known that, during life, organisms accumulate oxidative damage that negatively affects cell metabolism. Taking this into consideration, we evaluated the levels of nitric oxide, reactive oxygen species, and superoxide dismutase activity. We observed that ROS and NO increase with aging, while SOD activity is significantly reduced. Moreover cells obtained from older patients displayed senescence associated features, for example, beta-galactosidase activity, enlarged morphology, and p53 protein upregulation. All of those characteristics seem to contribute to decreased proliferation potential of those cells. Our results suggest that due to aging some cellular modification may be required before applying aged cells efficiently in therapies such as tissue engineering and regenerative medicine. PMID- 26246869 TI - Ginkgolide B Inhibits JAM-A, Cx43, and VE-Cadherin Expression and Reduces Monocyte Transmigration in Oxidized LDL-Stimulated Human Umbilical Vein Endothelial Cells. AB - AIM: To investigate the effect of ginkgolide B on junction proteins and the reduction of monocyte migration in oxidized low-density lipoprotein- (ox-LDL-) treated endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) were used in the present study. Immunofluorescence and Western blot were performed to determine the expression of junctional adhesion molecule-A (JAM-A), connexin 43 (Cx43), and vascular endothelial cadherin (VE-cadherin). Monocyte migration was detected by the Transwell assay. RESULTS: ox-LDL stimulation increased JAM-A expression by 35%, Cx43 expression by 24%, and VE-cadherin expression by 37% in HUVECs. Ginkgolide B (0.2, 0.4, and 0.6 mg/mL) dose dependently abolished the expression of these junction proteins. The monocyte transmigration experiments showed that the level of monocyte migration was sixfold higher in the ox-LDL-treated group than in the control group. Ginkgolide B (0.6 mg/mL) nearly completely abolished monocyte migration. Both ginkgolide B and LY294002 suppressed Akt phosphorylation and the expression of these junction proteins in ox-LDL-treated endothelial cells. These results suggest that the ginkgolide B-induced inhibition of junction protein expression is associated with blockade of the PI3K/Akt pathway. CONCLUSION: Ginkgolide B suppressed junction protein expression and reduced monocyte transmigration that was induced by ox LDL. Ginkgolide B may improve vascular permeability in atherosclerosis. PMID- 26246870 TI - Best Practice Guidelines in Assessment, Risk Reduction, Management, and Surveillance for Post-Breast Cancer Lymphedema. AB - Breast cancer-related lymphedema (LE) is a progressive, chronic disease that affects millions of cancer survivors and primarily results from surgical lymphatic vessel/node removal and radiation therapy. Patient education and support for importance of early detection is essential in helping health care providers detect lymphedema early, when there is the best chance to prevent progression. Improved imaging and surgical techniques have decreased the incidence of LE; however, effective risk-reduction and treatment have historically lacked the level of evidence necessary to standardize effective treatment. The purpose of this article is to report an extensive review of literature, including highlighted multidisciplinary studies within the past three years, in order to update best practice guidelines in assessment, risk reduction, management, and surveillance for post-breast cancer lymphedema. PMID- 26246872 TI - A Comparative Study of Serum and Follicular Fluid Leptin Concentrations among Explained Infertile, Unexplained Infertile and Fertile Women. AB - BACKGROUND: The relationship between metabolism and reproduction has been always considered as an important topic in female endocrinology. It seems that leptin is one of the involved factors in infertility. Leptin, in addition to regulating body weight plays an important role in regulation of endocrine, reproductive and immune systems. The aim of this stduy is to compare serum and follicular fluid leptin concentrations in order to find the role of leptin level in infertility. MATERIALS AND METHODS: This case-control study was performed from September 2010 to March 2013. A total of 90 women referred to the Infertility Center of Afzalipour Hos- pital, Kerman, Iran, and divided into three equal groups (n=30/per group) of explained infertile (including 4 subgroups), unexplained infertile and normal fertile (control group). The three groups were matched in regard to demographic features [age: 20-40 years and body mass index (BMI): 20 25]. In order to determine leptin level, blood sample and fol- licular fluid were taken one hour prior and at the time of follicular puncture, respectively. Serum and follicular fluid leptin levels were measured using enzyme-linked immune sorbent assay (ELISA). Data were analyzed using descriptive-analytic tests, like Mann- Whitney and Kruskal Wallis tests, through Statistical Package for the Social Sciences (SPSS) version 16. RESULTS: In explained infertile and fertile groups, as opposed to unexplained infertile group, mean leptin level was lower in follicular fluid than in serum. Mean follicular fluid leptin concentration in women with unexplained infertility was higher com- pared to the other two groups. Women with unexplained infertility had lower level of serum leptin in comparison to the other two groups. Follicular fluid leptin level in all subgroups of explained infertile group was lower as compared to unexplained and fertile women. CONCLUSION: The results suggested that high leptin level of follicular fluid is one of the main factors involved in infertility. PMID- 26246871 TI - Varicocele-Induced Infertility in Animal Models. AB - Varicocele is characterized by abnormal tortuosity and dilation of the veins of the pampiniform plexus within the spermatic cord. Although several reports show the mechanisms by which the varicocele exerts its infertility impact, the exact pathophysiology for varicocele-induced inflammation and its relationship with testicular endocrine disruption remain largely unknown. This review article will update previous findings by discussing the pathophysiology of long term-induced varicocele in rats. Testicular endocrine disruption in experimentally-induced varicocele, new findings related to biochemical alterations in germinal epithelium, and sperm cells apoptosis are highlighted. Recent observations show that varicocele down-regulates first and second maturation divisions, results in Leydig and Sertoli cell inflammation, and increases immune cell infiltration in the testes of the rat as an animal model. Ultimately, previous findings of our laboratory have revealed that varicocele decreased sperm motility, viability and severe DNA damage. Damage in sperm significantly lowers the animal's fertility potential. Varicocele not only exerts its pathologic impact by lowering the testicular antioxidant capacity but it also down-regulates first and second maturation divisions by exerting biochemical alterations such as reducing the intracytoplasmic carbohydrate ratio in germinal epithelium. PMID- 26246873 TI - Cut-Off Levels of Anti-Mullerian Hormone for The Prediction of Ovarian Response, In Vitro Fertilization Outcome and Ovarian Hyperstimulation Syndrome. AB - BACKGROUND: Evaluation of anti-mullerian hormone (AMH) cut-off levels in as- sisted reproductive technology (ART) as predictive factor for individualization of stimulation protocols and to avoid ovarian hyperstimulation syndrome (OHSS). MATERIALS AND METHODS: In a retrospective study, 177 infertile patients were as- sessed for AMH in serum and follicular fluid (FF) on the day of follicular puncture (FP), between 2012 and 2013 in Kiel, Germany. AMH levels and pregnancy rates were compared between low, moderate and high responders and cut-off levels of low and high responders. AMH cut-off levels in pathological cases were evaluated in analysis 1 (OHSS) and in analysis 2 [polycystic ovarian syndrome, (PCOS)] and compared in analysis 3 to normal endocrinological parameters. RESULTS: AMH levels in FF were higher than in serum (P<0.001). AMH levels in serum and FF increased from low through moderate to high responders (P<0.001). Pregnancy rates were 14.7, 23.3 and 44.9% (P=0.009), respectively. AMH cut-off level for poor responders was 0.61 ng/ml in serum with a pregnancy rate of 13.8 and 37.1% for below and above of this level, respectively. For FF, it was 1.43 ng/ml. AMH levels in analysis 1 and 2 were significantly higher than in analysis 3 (P=0.001). AMH cut-off level for OHSS was 1.5 ng/ml in serum with OHSS rates of 80.8 and 19.2 % for above and below of the level, respectively. For FF, it was 2.7 ng/ml. PCOS patients had an AMH cut-off level of 3.9 ng/ml in serum and 6.8 ng/ml in FF, resulting in a PCOS rate of 100% above this level. CONCLUSION: AMH levels can help to assess ovarian response potential and guide ovarian stimulation while avoiding OHSS. PMID- 26246874 TI - Pregnancy Outcome after Office Microhysteroscopy in Women with Unexplained Infertility. AB - BACKGROUND: Hysteroscopy offers diagnostic accuracy and the ability to treat uterine pathology. The current study aimed to review the findings and feasibility of the proposed office-based diagnostic and operative microhysteroscopy in previously diagnosed wom- en with unexplained infertility and to evaluate the post-microhysteroscopic pregnancy outcome in a-year follow-up period. MATERIALS AND METHODS: This prospective controlled study was conducted between 2006 and 2013. Two hundreds women with unexplained infertility were randomized into two groups: A. study group including 100 women recruited for office micohysteroscopic session and B. control group including 100 without the proposed microhysteroscopic intervention. A malleable fiberoptic 2-mm, 0 and 30 degrees angled hysteroscopy along with an operative channel for grasping forceps, scissors, or coaxial bipolar electrode were used for both diagnostic and operative indications. The findings, complications, and patient tolerance were recorded. A-year follow-up of pregnancy outcome for both groups was also performed. RESULTS: Seventy cases (70%) of patients had a normal uterine cavity. Twenty wom- en (20%) had endometrial polyps. Other pathology included submucous myomas in 3 cases (3%), intrauterine adhesions in 3 cases (3%), polypoid endometrium in 3 cases (3%), and bicornuate uterus in one case (1%). The pathological findings were treated in all patients without complication. Also a year follow-up of the to- tal developing cumulative pregnancy rate (CPR) was evaluated in groups A and B (control). Group A revealed the total CPR of 28.5%, among which 25% in women without pathology, 40% in women with endometrial polyps, 23% in women with adhesions, 33% in women with polypoid endometrium, and 21% in those with bi- cornuate uterus. However, A-year follow-up of spontaneous pregnancy outcome in group B showed a total CPR of 15%. CONCLUSION: Women tolerance, safety, and feasibility of simultaneous operative correc- tion make the proposed office microhysteroscopy an ideal and routine procedure in order to diagnose and to treat missed intrauterine abnormalities, especially in cases with un- explained infertility, with additional improvement of the pregnancy outcome after the procedure. PMID- 26246875 TI - Association of Glomerular Filtration Rate with Inflammation in Polycystic Ovary Syndrome. AB - BACKGROUND: We aimed to estimate the glomerular filtration rate (GFR) in women with polycystic ovary syndrome (PCOS) and to determine the relationship between GFR with C-reactive protein (CRP) and uric acid. MATERIALS AND METHODS: In this cross-sectional study, one-hundred and forty PCOS women and 60 healthy subjects were evaluated. The study was carried out at Endocrinol- ogy Outpatient Clinic, Erzurum Training and Research Hospital, Erzurum, Turkey, from December 2010 to January 2011. GFRs were estimated by Modification of Diet in Renal Disease (MDRD) formula. CRP, urinary albumin excretion (UAE) and uric acid levels were also measured. RESULTS: GFRs were significantly higher in PCOS group than control (135.24 +/- 25.62 vs. 114.92 +/- 24.07 ml/min per 1.73 m(2)). CRP levels were significantly higher in PCOS patients (4.4 +/- 3.4 vs. 2.12 +/- 1.5 mg/l). The PCOS group had significantly higher serum uric acid levels (4.36 +/- 1.3 mg/dl vs. 3.2 +/- 0.73 mg/dl). There was also significantly higher proteinuria level in PCOS patients. CONCLUSION: Even though PCOS patients had higher GFR, serum uric acid and UAE val- ues than control patients, the renal function was within normal limits. Increased GFR in PCOS women positively correlates with elevated serum CRP and uric acid. PMID- 26246876 TI - Effect of Surgical Removal of Endometriomas on Cyclic and Non-cyclic Pelvic Pain. AB - BACKGROUND: Endometriosis is a complex disease with a spectrum of pain symptoms from mild dysmenorrhea to debilitating pelvic pain. There is no concrete evidence in the literature whether endometriotic cyst per se, causes pain spectrum related to the disease. The aim of the present study was to evaluate the effect of surgical removal of endome- triomas on pain symptoms. MATERIALS AND METHODS: In this prospective, observational, before-after study, which was conducted between March 2012 and January 2013 in Training and Research Hospital,Adana, Turkey, a total of 23 patients including 16 sexually active and 7 vir- gin symptomatic women were questioned for non-cyclic pelvic pain (NCPP), intensity of the NCPP, presence of cyclic dysmenorrhea, and dyspareunia before and after the endometrioma operation. Participants who were sonographically diagnosed and later pathologically confirmed as having endometrioma without sign and symptoms of deep infiltrative endometriosis (DIE) were also questioned for pain symptoms before and after the laparoscopic removal of cyst wall. Patients with intraabdominal adhesions, history of pelvic inflammatory disease, and pathological diagnosis other than endometrioma were excluded. No ancillary procedures were applied for pain management, but if pain was present, pelvic peritoneal endometriotic lesions were ablated beside the removal of ovar- ian endometriotic cysts. RESULTS: Out of 23 cases with endometrioma, 91 and 78% reported to have NCPP and dysmenorrhea, respectively, before the operation, while 60 and 48%, respec- tively, after the operation (McNemar's test, P=0.016 for both figures). Among the sexually active cases, 31% (5/16) had dyspareunia before the operation and only 1 case reported the pain relief after the operation (McNemar's test, P=1). Intensity of NCPP were reported to be none (8.7%), moderate (21.7%), severe (56.5%) and un- bearable (13%) before the operation and decreased to none (43.5%), mild (43.5%), moderate (4.3%) and severe (8.7%) after the operation (Wilcoxon signed-rank test, P<0.001). CONCLUSION: In symptomatic cases with ovarian endometrioma, without sign and symptoms of DIE, laparoscopic removal of the cysts with/without ablation of the peritoneal endometriotic lesions yields relief of NCPP and cyclic dysmenorrhea, but not dyspareunia. PMID- 26246877 TI - Assessment of Correlation between Androgen Receptor CAG Repeat Length and Infertility in Infertile Men Living in Khuzestan, Iran. AB - BACKGROUND: The androgen receptor (AR) gene contains a polymorphic trinucleotide repeat that encodes a polyglutamine tract in its N-terminal transactivation domain (N- TAD). We aimed to find a correlation between the length of this polymorphic tract and azoospermia or oligozoospermia in infertile men living in Khuzestan, Iran. MATERIALS AND METHODS: In this case-control study during two years till 2010, we searched for microdeletions in the Y chromosome in 84 infertile male patients with normal karyotype who lived in Khuzestan Province, Southwest of Iran. All cases (n=12) of azoospermia or oligozoospermia resulting from Y chromosome microdele- tions were excluded from our study. The number of CAG repeats in exon 1 of the AR gene was determined in 72 patients with azoospermia or oligozoospermia and in 72 fertile controls, using the polymerase chain reaction (PCR) and polyacrylamide gel electrophoresis. RESULTS: Microdeletions were detected in 14.3% (n=12) patients suffering severe oligozoospermia. The mean CAG repeat length was 18.99 +/- 0.35 (range, 11-26) and 19.96 +/- 0.54 (range, 12-25) in infertile males and controls, respectively. Also in the infertile group, the most common allele was 19 (26.38%), while in controls, it was 25 (22.22%). CONCLUSION: Y chromosome microdeletions could be one of the main reasons of male infertility living in Khuzestan Province, while there was no correlation between CAG length in AR gene with azoospermia or oligozoospermia in infertile men living in Khuzestan, Iran. PMID- 26246878 TI - Expression Levels of PPARgamma and CYP-19 in Polycystic Ovarian Syndrome Primary Granulosa Cells: Influence of omega-3 Fatty Acid. AB - BACKGROUND: The omega-3 fatty acid (omega-3 fatty acid) such as eicosapentaenoic acid (EPA) is currently used in the clinic as a nutritional supplement in the treatment of poly- cystic ovarian syndrome (PCOS). The present study was designed to investigate the ef- fect of EPA on the expression levels of peroxisome proliferator-activated receptor gamma (PPARgamma) and cytochrome P450 aromatase (encoded by the CYP-19) in primary cultured granulosa cells (GC) from patients undergoing in vitro fertilization (IVF), and also to compare these effects with those in GC of PCOS patients. MATERIALS AND METHODS: In this experimental study, human GC were isolated, pri- mary cultured in vitro, exposed to a range of concentrations of the EPA and in- vestigated with respect to gene expression levels of PPARgamma and CYP-19 using real time-polymerase chain reaction (PCR). The participants (n=30) were the patients admitted to the IVF Center in February March 2013 at Alzahra Hospital, Tabriz, Iran, who were divided into two groups as PCOS (n=15) and non-PCOS (n=15) women (controls). RESULTS: All doses of the EPA significantly induced PPARgamma mRNA gene expression level as compared to the control recombinant follicle stimulating hormone (rFSH) alone condi- tion. High doses of EPA in the presence of rFSH produced a stimulatory effect on expres- sion level of PPARgamma (2.15-fold, P=0.001) and a suppressive effect (0.56-fold, P=0.01) on the expression level of CYP-19, only in the PCOS GC. CONCLUSION: EPA and FSH signaling pathway affect differentially on the gene ex- pression levels of PPARgamma and CYP-19 in PCOS GC. Altered FSH-induced PPARgamma activity in PCOS GC may modulate the CYP-19 gene expression in response to EPA, and possibly modulates the subsequent steroidogenesis of these cells. PMID- 26246879 TI - Association of Two Polymorphisms in H2B.W Gene with Azoospermia and Severe Oligozoospermia in An Iranian Population. AB - BACKGROUND: During spermatogenesis, the H2B family, member W (H2B.W) gene, en- codes a testis specific histone that is co-localized with telomeric sequences and has the potential role to mediate the sperm-specific chromatin remodeling. Previously H2B.W genetic variants were reported to be involved in susceptibility to spermatogenesis im- pairment. In the present study, two single nucleotide polymorphisms (SNPs) in 5?UTR and exon 1 of H2B.W gene were examined to investigate possible association of these polymorphisms with male infertility in Iranian population. MATERIALS AND METHODS: This case control study was conducted in Royan institute during four-year period (2010-2013). Genetic alteration of two SNPs loci, -9C>T and 368A>G, in H2B.W gene were indicated in 92 infertile men who were divided into two main groups includ- ing azoospermia (n=46) and sever oligozoospermia (n=46), while there was 60 fertile men as control group. Azoosperima was also divided into three sub-groups including sertoli cell only syndrome (SCOS, n=21), complete maturation arrest (CMA, n=17) and hypo spermatogenesis (n=8) according to testicular biopsy. For analysis, polymerase chain reaction-restriction frag- ment length polymorphism (PCR-RFLP) technique was applied. RESULTS: The frequency of allele -9T was significantly higher in CMA group than in patients with SCOS (P<0.05). The haplotype TA (corresponding to simultaneous occur- rence of -9T and 368A) compared with haplotype CA (corresponding to simultaneous occurrence of -9C and 368A) in patients suffering from CMA significantly increased, compared with patients had SCOS (P<0.05). However, statistical studies indicated that in general, the distribution frequencies of -9C>T and 368A>G had no significant difference between the infertile groups and control (P=0.859 and P=0.812, respectively). CONCLUSION: This investigation showed that SNP -9C>T might be contribute to CMA in azoo- spermic patients and SNP 368A>G had no correlation with male infertility in Iranian population. PMID- 26246880 TI - Blastocyst Morphology Holds Clues Concerning The Chromosomal Status of The Embryo. AB - BACKGROUND: Embryo morphology has been proposed as an alternative marker of chro- mosomal status. The objective of this retrospective cohort study was to investigate the association between the chromosomal status on day 3 of embryo development and blas- tocyst morphology. MATERIALS AND METHODS: A total of 596 embryos obtained from 106 cycles of intra- cytoplasmic sperm injection (ICSI) followed by preimplantation genetic aneuploidy screening (PGS) were included in this retrospective study. We evaluated the relation- ship between blastocyst morphological features and embryonic chromosomal altera- tion. RESULTS: Of the 564 embryos with fluorescent in situ hybridization (FISH) results, 200 reached the blastocyst stage on day 5 of development. There was a significantly high- er proportion of euploid embryos in those that achieved the blastocyst stage (59.0%) compared to embryos that did not develop to blastocysts (41.2%) on day 5 (P<0.001). Regarding blastocyst morphology, we observed that all embryos that had an abnormal inner cell mass (ICM) were aneuploid. Embryos with morphologically normal ICM had a significantly higher euploidy rate (62.1%, P<0.001). As regards to the trophectoderm (TE) morphology, an increased rate of euploidy was observed in embryos that had nor- mal TE (65.8%) compared to embryos with abnormal TE (37.5%, P<0.001). Finally, we observed a two-fold increase in the euploidy rate in high-quality blastocysts with both high-quality ICM and TE (70.4%) compared to that found in low-quality blastocysts (31.0%, P<0.001). CONCLUSION: Chromosomal abnormalities do not impair embryo development as ane- uploidy is frequently observed in embryos that reach the blastocyst stage. A high-quality blastocyst does not represent euploidy of chromosomes 13, 14, 15, 16, 18, 21, 22, X and Y. However, aneuploidy is associated with abnormalities in the ICM morphology. Further studies are necessary to confirm whether or not the transfer of blastocysts with low-quality ICM should be avoided. PMID- 26246881 TI - Timing of The First Zygotic Cleavage Affects Post-Vitrification Viability of Murine Embryos Produced In Vivo. AB - BACKGROUND: Timing of the first zygotic cleavage is an accurate predictor of embryo quality. Embryos that cleaved early (EC) have been shown to exhibit higher develop- mental viability compared to those that cleaved at a later period (LC). However, the vi- ability of EC embryos in comparison to LC embryos after vitrification is unknown. The present study aims to investigate the post vitrification developmental viability of murine EC versus LC embryos. MATERIALS AND METHODS: In this experimental study, female ICR mice (6-8 weeks old) were superovulated and cohabited with fertile males for 24 hours. Afterwards, their ovi- ducts were excised and embryos harvested. Embryos at the 2-cell stage were catego- rized as EC embryos, while zygotes with two pronuclei were categorized as LC embryos. Embryos were cultured in M16 medium supplemented with 3% bovine serum albumin (BSA) in a humidified 5% CO2atmosphere. Control embryos were cultured until the blastocyst stage without vitrification. Experimental embryos at the 2 cell stage were vitri- fied for one hour using 40% v/v ethylene glycol, 18% w/v Ficoll-70 and 0.5 M sucrose as the cryoprotectant. We recorded the numbers of surviving embryos from the control and experimental groups and their development until the blastocyst stage. Results were analyzed using the chi-square test. RESULTS: A significantly higher proportion of EC embryos (96.7%) from the control group developed to the blastocyst stage compared with LC embryos (57.5%, P<0.0001). Similarly, in the experimental group, a significantly higher percentage of vitrified EC embryos (69.4%) reached the blastocyst stage compared to vitrified LC embryos (27.1%, P<0.0001). CONCLUSION: Vitrified EC embryos are more vitrification tolerant than LC embryos. Prese- lection of EC embryos may be used as a tool for selection of embryos that exhibit higher developmental competence after vitrification. PMID- 26246882 TI - Beneficial Effects of Nitric Oxide Induced Mild Oxidative Stress on Post-Thawed Bull Semen Quality. AB - BACKGROUND: Cryopreservation of semen requires optimized conditions to minimize the harmful effects of various stresses. The main approach for protection of sperm against stress is based on the use of antioxidants and cryoprotectants, which are described as defensive methods. Recently, the application of controlled mild stressors has been de- scribed for activation of a temporary response in oocyte, embryo and somatic cells. In this study a sub-lethal oxidative stress induced by precise concentrations of nitric oxide (NO) has been evaluated for sperm during cryopreservation. MATERIALS AND METHODS: In this experimental study, we used different concentrations of NO [0 uM (NO-0), 0.01 uM (NO-0.01), 0.1 uM (NO-0.1), 1 uM (NO-1), 10 uM (NO-10) and 100 uM (NO-100)] during cryopreservation of bull semen. Their effects on post-thawed sperm quality that included motility and velocity parameters, plasma mem- brane functionality, acrosome integrity, apoptosis status, mitochondrial activity and lipid peroxidation after freezing thawing were investigated. RESULTS: Exposure of sperm before freezing to NO-1 significantly increased total motility (88.4 +/- 2.8%), progressive motility (50.4 +/- 3.2%) and average path velocity (VAP, 53.8 +/- 3.1 um/s) compared to other extenders. In addition, NO-1 significantly increased plasma mem- brane functionality (89.3 +/- 2.9%) compared to NO-0 (75.3 +/- 2.9%), NO-0.01 (78.3 +/- 2.9%), NO-0.1 (76.4 +/- 2.9%), NO-10 (64 +/- 2.9%) and NO-100 (42 +/- 2.9%). Sperm exposed to NO-1 produced the highest percentage of viable (85.6 +/- 2.3%) and the lowest percentage of apoptotic (10.8 +/- 2.4%) spermatozoa compared to the other extenders. Also, NO-100 resulted in a higher percentage of dead spermatozoa (27.1 +/- 2.7%) compared to the other extenders. In terms of mitochondrial activity, there was no significant difference among NO-0 (53.4 +/- 3.2), NO-0.01 (52.1 +/- 3.2), NO-0.1 (50.8 +/- 3.2) and NO-1 (53.1 +/- 3.2). For acrosome integrity, no significant different was observed in sperm exposed to different concentrations of NO. CONCLUSION: Induction of sub-lethal oxidative stress with 1 uM NO would be beneficial for cryopreservation of bull semen. PMID- 26246883 TI - The Effectiveness of Emotionally Focused Therapy on Enhancing Marital Adjustment and Quality of Life among Infertile Couples with Marital Conflicts. AB - BACKGROUND: The purpose of this study is to investigate the efficacy of emotionally fo- cused therapy (EFT-C) on promoting marital adjustment of infertile couples with marital conflicts by improving quality of life. MATERIALS AND METHODS: This is a semi-experimental study with a pre- and post-test design in which 30 infertile couples (60 individuals) were chosen by purposive sampling. Couples were randomly divided into two groups, sample and control, of 15 couples each. Next, couples in the sample population answered questionnaires for marital adjustment, sexual satisfaction and quality of life after which they received 10 sessions of EFT-C. RESULTS: Pre- and post-tests showed that EFT-C had a significant effect on marital adjust- ment and quality of life. CONCLUSION: According to the results, EFT-C had a significant, positive effect on en- hancement of marital adjustment. Life quality of infertile couples significantly increased via application of EFT-C. This approach improved the physical, psychological and social relationships of infertile couples and enhanced their social environment. PMID- 26246884 TI - Effect of Telephone-Based Support on Postpartum Depression: A Randomized Controlled Trial. AB - BACKGROUND: Postpartum depression (PPD) is one public health issue that affects both maternal and child health. This research studies the effect of health volunteers' telephone- based support on decreasing PPD. MATERIALS AND METHODS: This randomized controlled trial evaluated 203 women who had uncomplicated deliveries. The women completed the Edinburg Postnatal Depres- sion Scale (EPDS), 10 to 15 days after childbirth in order to be assessed for pre-trial depression scores. The cut-off point for depression was considered to be a score of >10. We randomly assigned 54 eligible mothers (n=27 per group) with mild and moderate de- pression to the intervention and control groups. In both groups, mothers received routine postpartum care. The intervention group additionally received telephone support from health volunteers. A questionnaire was used to gather demographic and obstetric infor- mation. By the end of the 6thweek, mothers completed the EPDS to be reassessed for depression after intervention. Data were analyzed using the chi-square, Fisher's exact, t- and paired t tests. RESULTS: The mean depression scores before intervention (10 to 15 days after childbirth) in the intervention and control groups did not significantly differ (P=0.682). Depres- sion scores of the intervention and control groups showed a significant difference after 6 weeks (P=0.035). In addition, there was a significant decrease in depression for the intervention and control groups (P=0.045). CONCLUSION: Health volunteer telephone-based support effectively decreased PPD and may be beneficial to women with symptoms of mild and moderate PPD (Registration number: IRCT201202159027N1). PMID- 26246885 TI - An Evaluation of Iranian Judges' Decisions about The Act of Embryo Donation. AB - Embryo donation was one of the infertility treatment methods introduced to the Iranian legal system in 2003 (Act of Embryo Donation) and its by-law passed in 2005 after nu- merous discussions. Embryo donation is a new legal issue in Iran. No similar act has been previously legis- lated in the legal system; however, on the other hand, the importance of the judicial pro- cedure in its execution cannot be ignored since during this treatment process the infertile couples must refer to the court. In this paper, we analyzed 80 court decisions that concerned permission for embryo do- nation during 2006-2011. The decisions were made for couples who requested this treat- ment and referred to Avicenna Fertility Center (Tehran, Iran). In this study, we analyzed the decisions and regulations for the demands, in addition to the medical and legal view- points of the judges. The differences among the judges' decisions and in the ways of investigating were discussed. PMID- 26246886 TI - Endometrial Adenocarcinoma in A 31-Year Old Woman: A Case Report. AB - Endometrial adenocarcinoma (EC) usually occurs after menopause, whereas in 2-14% of cases, it occurs in young patients (less than 40 years old) who may desire to keep their fertility. It is of importance to evaluate women for EC when they develop polycystic ovarian syndrome and abnormal uterine bleeding. Its treatment includes hysterectomy, bilateral salpingo-oo- phorectomy and pelvic lymphadenectomy and in some cases, radiation therapy. We report a case of EC in a 31-year-old woman who presented to Royan Institute. She complained about oligomenorrhea with a 10-year history of primary infertility. PMID- 26246887 TI - Laparoscopic Management of Heterotopic Interstitial Pregnancy with Subsequent Term Delivery. AB - A 35 year-old woman at 7-week gestational age was referred to our hospital. The patient was diagnosed with the heterotopic interstitial pregnancy by transvaginal ultrasonogra- phy after receiving in vitro fertilization (IVF) and embryo transfer. Laparoscopic excision and curettage was successfully performed at 8.4 gestational age under general anesthesia and the patient was discharged 2 days after operation without any post-operative complications. The woman had normal antenatal follow-up and deliv- ered a healthy baby at term by cesarean section. PMID- 26246888 TI - Experience of group conversations in rehabilitation medicine: methodological approach and pilot study. AB - The restoring of equilibrium after a traumatic event makes it possible to give a new significance to patients' existence, and healthcare professionals simultaneously find themselves very close to questions of pain and disability. For these reasons, we introduced weekly group meetings of healthcare professionals and patients suffering from vascular, traumatic or neurological accidents, and meetings of professionals only at the Neurocognitive Rehabilitation Day Hospital of the University of Milan Bicocca. The aim of this paper is to identify possible indicators of changes in patients' existence through a conversational analysis, describing the experience at the light of methodological approach and reporting the results of a pilot observational study. The patient meetings began in October 2011 and led to a process of greater closeness and trust that was expressed by means of words, gestures, emotional participation, and non-verbal communication. The pilot considers the evolution of indicators in a sample of 14 patients for a period of 9 months and a timeframe of 3 months. Supportive interventions decreased while elements of sharing progressively increased, leading to progressive increased consciousness of both self and the disease. The group of professionals found that being together allowed them to distinguish performance as the use of their technical skills from understanding the other and his/her experience as part of their own, and not only linked to the disease. The professionals' reflections on their experiences led to the emergence of two possible ways of looking at a patient: as somebody other than me or somebody other like me. PMID- 26246889 TI - pSTR Finder: a rapid method to discover polymorphic short tandem repeat markers from whole-genome sequences. AB - BACKGROUND: Whole-genome sequencing is performed routinely as a means to identify polymorphic genetic loci such as short tandem repeat loci. We have developed a simple tool, called pSTR Finder, which is freely available as a means of identifying putative polymorphic short tandem repeat (STR) loci from data generated from genome-wide sequences. The program performs cross comparisons on the STR sequences generated using the Tandem Repeats Finder based on multiple genome samples in a FASTA format. These comparisons generate reports listing identical, polymorphic, and different STR loci when comparing two samples. METHODS: The web site http://forensic.mc.ntu.edu.tw:9000/PSTRWeb/Default has been developed as a means to identify polymorphic STR loci within complex mass genome sequences. The program was developed to generate a series of user-friendly reports. RESULTS: As proof of concept for the program, four FASTA genome sequence samples of human chromosome X (AC_000155.1, CM000685.1, NC_018934.2, and CM000274.1) were obtained from GenBank and were analyzed for the presence of putative STR regions. The sequences within AC-000155.1 were used as an initial reference sequence from which there were 5443 identical and 4305 polymorphic STR loci identified using a repeat unit of 1-6 and 10 bp as the flanking sequence either side of the putative STR loci. A reliability test was used to compare five FASTA samples, which had sections of DNA sequence removed to mimic partial or fragmented DNA sequences, to determine whether pSTR Finder can efficiently and consistently find identical, polymorphic, and different STR loci. CONCLUSIONS: From the mass of DNA sequence data, the project was found to reproducibly identify polymorphic STR loci and generate user-friendly reports detailing the number and location of these potential polymorphic loci. This freely available program was found to be a useful tool to find polymorphic STR within whole-genome sequence data in forensic genetic studies. PMID- 26246890 TI - An incremental boundary study on parafoveal preprocessing in children reading aloud: Parafoveal masks overestimate the preview benefit. AB - Parafoveal preprocessing is an important factor for efficient reading and, in eye movement studies, is typically investigated by means of parafoveal masking: Valid previews are compared to instances in which masks prevent preprocessing. A long held assumption was that parafoveal preprocessing, as assessed by this technique, only reflects facilitation (i.e., a preview benefit). Recent studies, however, suggested that the benefit estimate is inflated due to interference of the parafoveal masks, i.e., the masks inflict processing costs. With children from Grades 4 and 6, we administered the novel incremental priming technique. The technique manipulates the salience of the previews by systematically varying its perceptibility (i.e., by visually degrading the previews). This technique does not require a baseline condition, but makes it possible to determine whether a preview induces facilitation or interference. Our salience manipulation of valid previews revealed a preview benefit in the children of both Grades. For two commonly used parafoveal masks, we observed interference corroborating the notion that masks are not a proper baseline. With the novel incremental boundary technique, in contrast, one can achieve an accurate estimate of the preview benefit. PMID- 26246891 TI - Working memory, reading ability and the effects of distance and typicality on anaphor resolution in children. AB - We investigated the time course of anaphor resolution in children and whether this is modulated by individual differences in working memory and reading skill. The eye movements of 30 children (10-11 years) were monitored as they read short paragraphs in which (1) the semantic typicality of an antecedent and (2) its distance in relation to an anaphor were orthogonally manipulated. Children showed effects of distance and typicality on the anaphor itself and also on the word to the right of the anaphor, suggesting that anaphoric processing begins immediately but continues after the eyes have left the anaphor. Furthermore, children showed no evidence of resolving anaphors in the most difficult condition (distant atypical antecedent), suggesting that anaphoric processing that is demanding may not occur online in children of this age. Finally, working memory capacity and reading comprehension skill affect the magnitude and time course of typicality and distance effects during anaphoric processing. PMID- 26246893 TI - A pilot survey of junior doctors' attitudes and awareness around medication review: time to change our educational approach? AB - OBJECTIVES: Our aim was to explore junior doctors' attitudes and awareness around concepts related to medication review, in order to find ways to change the culture for reviewing, altering and stopping inappropriate or unnecessary medicines. Having already demonstrated the value of team working with senior doctors and pharmacists and the use of a medication review tool, we are now looking to engage first year clinicians and undergraduates in the process. METHOD: An online survey about medication review was distributed among all 42 foundation year one (FY1) doctors at the Chelsea and Westminster Hospital NHS Foundation Trust in November 2014. Descriptive statistics were used for analysis. RESULTS: Twenty doctors completed the survey (48%). Of those, 17 believed that it was the pharmacist's duty to review medicines; and 15 of 20 stated the general practitioner (GP). Sixteen of 20 stated that they would consult a senior doctor first before stopping medication. Eighteen of 20 considered the GP and consultant to be responsible for alterations, rather than themselves. Sixteen of 20 respondents were not aware of the availability of a medication review tool. Seventeen of 20 felt that more support from senior staff would help them become involved with medication review. CONCLUSIONS: Junior doctors report feeling uncomfortable altering mediations without consulting a senior first. They appear to be building confidence with prescribing in their first year but not about the medication review process or questioning the drugs already prescribed. Consideration should be given to what we have termed a 'bottom-up' educational approach to provide early experience of and change the culture around medication review, to include the education of undergraduate and foundation doctors and pharmacists. PMID- 26246892 TI - GATA2(-/-) human ESCs undergo attenuated endothelial to hematopoietic transition and thereafter granulocyte commitment. AB - BACKGROUND: Hematopoiesis is a progressive process collectively controlled by an elaborate network of transcription factors (TFs). Among these TFs, GATA2 has been implicated to be critical for regulating multiple steps of hematopoiesis in mouse models. However, whether similar function of GATA2 is conserved in human hematopoiesis, especially during early embryonic development stage, is largely unknown. RESULTS: To examine the role of GATA2 in human background, we generated homozygous GATA2 knockout human embryonic stem cells (GATA2 (-/-) hESCs) and analyzed their blood differentiation potential. Our results demonstrated that GATA2 (-/-) hESCs displayed attenuated generation of CD34(+)CD43(+) hematopoietic progenitor cells (HPCs), due to the impairment of endothelial to hematopoietic transition (EHT). Interestingly, GATA2 (-/-) hESCs retained the potential to generate erythroblasts and macrophages, but never granulocytes. We further identified that SPI1 downregulation was partially responsible for the defects of GATA2 (-/-) hESCs in generation of CD34(+)CD43(+) HPCs and granulocytes. Furthermore, we found that GATA2 (-/-) hESCs restored the granulocyte potential in the presence of Notch signaling. CONCLUSION: Our findings revealed the essential roles of GATA2 in EHT and granulocyte development through regulating SPI1, and uncovered a role of Notch signaling in granulocyte generation during hematopoiesis modeled by human ESCs. PMID- 26246894 TI - Xander: employing a novel method for efficient gene-targeted metagenomic assembly. AB - BACKGROUND: Metagenomics can provide important insight into microbial communities. However, assembling metagenomic datasets has proven to be computationally challenging. Current methods often assemble only fragmented partial genes. RESULTS: We present a novel method for targeting assembly of specific protein-coding genes. This method combines a de Bruijn graph, as used in standard assembly approaches, and a protein profile hidden Markov model (HMM) for the gene of interest, as used in standard annotation approaches. These are used to create a novel combined weighted assembly graph. Xander performs both assembly and annotation concomitantly using information incorporated in this graph. We demonstrate the utility of this approach by assembling contigs for one phylogenetic marker gene and for two functional marker genes, first on Human Microbiome Project (HMP)-defined community Illumina data and then on 21 rhizosphere soil metagenomic datasets from three different crops totaling over 800 Gbp of unassembled data. We compared our method to a recently published bulk metagenome assembly method and a recently published gene-targeted assembler and found our method produced more, longer, and higher quality gene sequences. CONCLUSION: Xander combines gene assignment with the rapid assembly of full length or near full-length functional genes from metagenomic data without requiring bulk assembly or post-processing to find genes of interest. HMMs used for assembly can be tailored to the targeted genes, allowing flexibility to improve annotation over generic annotation pipelines. This method is implemented as open source software and is available at https://github.com/rdpstaff/Xander_assembler. PMID- 26246895 TI - Prevalence of different comorbidities in COPD patients by gender and GOLD stage. AB - BACKGROUND: Several comorbidities frequently affect COPD progression. Aim of the study was to assess the prevalence of main comorbidities by gender and disease severity in a cohort of COPD patients referring for the first time to a specialist institution. METHODS: The study was a non-interventional, cross sectional investigation carried out via automatic and anonymous selection from the institutional data base over the period 2012-2015. Inclusion criteria were: subjects of both sex aged >=40 years; diagnosis of COPD according to GOLD guidelines 2014; the availability of a complete clinical record file. Variables collected were: lung function; smoking history; BMI; the Charlson Comorbidity Index (CCI); number and kind of comorbidities for each patient. RESULTS: At least one comorbidity of clinical relevance was found in 78.6 % of patients, but at least two in 68.8 %, and three or more were found in 47.9 % of subjects. Mean CCI was 3.4 +/- 1.6sd. The overall prevalence was 2.6 comorbidities per patient, but 2.5 in males, and 3.0 in females, respectively (p < 0.05). Cardio-vascular disorders were the most frequent, but significantly more frequent in males (44.7 vs 30.7 %, respectively), while the metabolic, the digestive and the osteo articular disorders were prevailing in females (12.4 vs 9.2; 14.2 vs 4.8, and 6.0 vs 3.8, respectively). In particular, chronic cor pumonale and arrhythmias mainly prevailed in men and congestive heart failure in females, while arterial hypertension resulted equally distributed. As concerning respiratory disorders, pneumonia, pleural effusions and chronic respiratory failure were more frequently found in men, while bronchiectasis and asthma-COPD overlap syndrome (ACOS) in females. Anaemia, gall bladder stones, osteoporosis and spontaneous fractures mostly prevailed in females, while gastric disorders of inflammatory origin and arthrosis were more frequent in males. Cognition disorders, dementia and signs of degenerative brain disorders were more frequently found in men, while depression in females. Finally, lung cancer was at the first place in men, but at the second in females. CONCLUSIONS: All comorbidities increased their prevalence progressively up to the last stage of COPD severity, except the cardio-vascular and the metabolic ones which dropped in the IV GOLD stage, presumably due to the high mortality rate in this severe COPD stage. The gender-dependency of comorbidities was confirmed in general terms, even if lung cancer proved a dramatic increase almost independently of sex. PMID- 26246896 TI - Granzyme B mediated function of Parvovirus B19-specific CD4(+) T cells. AB - A novel conception of CD4(+) T cells with cytolytic potential (CD4(+) CTL) is emerging. These cells appear to have a part in controlling malignancies and chronic infections. Human parvovirus B19 can cause a persistent infection, yet no data exist on the presence of B19-specific CD4(+) CTLs. Such cells could have a role in the pathogenesis of some autoimmune disorders reported to be associated with B19. We explored the cytolytic potential of human parvovirus B19-specific T cells by stimulating peripheral blood mononuclear cell (PBMC) with recombinant B19-VP2 virus-like particles. The cytolytic potential was determined by enzyme immunoassay-based quantitation of granzyme B (GrB) and perforin from the tissue culture supernatants, by intracellular cytokine staining (ICS) and by detecting direct cytotoxicity. GrB and perforin responses with the B19 antigen were readily detectable in B19-seropositive individuals. T-cell depletion, HLA blocking and ICS experiments showed GrB and perforin to be secreted by CD4(+) T cells. CD4(+) T cells with strong GrB responses were found to exhibit direct cytotoxicity. As anticipated, ICS of B19-specific CD4(+) T cells showed expected co-expression of GrB, perforin and interferon gamma (IFN-gamma). Unexpectedly, also a strong co expression of GrB and interleukin 17 (IL-17) was detected. These cells expressed natural killer (NK) cell surface marker CD56, together with the CD4 surface marker. To our knowledge, this is the first report on virus-specific CD4(+) CTLs co-expressing CD56 antigen. Our results suggest a role for CD4(+) CTL in B19 immunity. Such cells could function within both immune regulation and triggering of autoimmune phenomena such as systemic lupus erythematosus (SLE) or rheumatoid arthritis. PMID- 26246897 TI - Clinical development methodology for infusion-related reactions with monoclonal antibodies. AB - Infusion-related reactions (IRRs) are common with monoclonal antibodies (mAbs) and timely related to drug administration and have been reported as anaphylaxis, anaphylactoid reactions and cytokine release syndrome, among other terms used. We address risk management measures for individual patients and for the study and propose a consistent reporting approach in an attempt to allow cross-molecule comparisons. Once the symptoms of IRR have resolved, the mAb may be restarted. Rechallenge should not be done for suspected IgE-mediated anaphylaxis and Grade 4 IRRs. Management of IRRs for subsequent patients includes administration of premedication, which, however, does not prevent IgE-mediated anaphylaxis. Reporting approach: (1) Report as IRRs, reactions occurring during or within 24 h after an infusion. Negative skin Prick test and absent or undetectable allergen specific IgE levels have high negative predictive value for an IgE-mediated allergic reaction. If IgE-mediated anaphylaxis is suspected based on medical history and/or laboratory test results, the reaction should be reported as suspected (IgE mediated) anaphylaxis. (2) Collect signs and symptoms with grades to allow characterization of IRRs. IRRs pathogenesis is of scientific interest and has impact on drug development. Animal toxicology studies are neither predictive of severe IRRs nor of anaphylaxis in human. Preclinical tests should be further developed to identify patients at risk for severe IRRs, for complement activation-related pseudoallergy and for IgE-mediated anaphylaxis. The proposed approach should help standardizing data collection and analysis of IRRs in an attempt to enable comparisons across molecules. PMID- 26246899 TI - Stimulation of osteoblast differentiation with guided ultrasound waves. AB - BACKGROUND: Ultrasound induces mechanical vibration and heat, causing differentiation and proliferation in osteoblasts. All known in vitro evaluations of ultrasound are, however, performed with longitudinal ultrasound waves. We addressed a question: Do other forms of ultrasound waves, such as guided waves (longitudinal and guided flexural) transduced at a remote location, enhance differentiation of osteoblast cells? METHODS: In this study, we employed guided Lamb waves that were induced in a borosilicate glass slide (cortical bone mimic). An average energy of 10-30 mW/cm(2) for 20 min per day was applied to MC3T3 osteoblast-like cells, which were placed 30-75 mm distant from the transducer. RESULTS: The result revealed that guided waves significantly stimulated the differentiation and mineralization of MC3T3 cells. In particular, guided waves elevated mRNA expression levels of bone formation-related genes such as alkaline phosphatase, osteopontin, osteocalcin, osteoprotegerin, and bone sialoprotein on days 8 and 16. In addition, the amount of mineralization found via Alizarin red staining was increased by 157 % (p = 0.034). The amount of mineralization was found to be independent of distance from the transducer (p = 0.967). CONCLUSION: We demonstrate herein that ultrasound in a form of guided Lamb waves is capable of inducing osteoblast differentiation in vitro, and it may enable the stimulation of osteoblasts in vivo over a distance from the site of ultrasound application. PMID- 26246898 TI - Examination of the potential association of stress with morbidity and mortality outcomes in patient with heart failure. AB - OBJECTIVES: The high mortality and morbidity rates associated with heart failure are still not well explained. A few psychosocial factors have been studied and explain some of this risk, but other factors, like stress, remain largely unexplored in heart failure. This study aimed to (1) examine the association of stress with 6-month cardiac event-free survival, (2) examine the relationship of stress with salivary cortisol, and (3) examine the association of salivary cortisol level with 6-month cardiac event-free survival. METHOD: A total of 81 heart failure patients participated. Stress was measured using the brief Perceived Stress Scale. Cortisol was measured from unstimulated whole expectorated saliva. Cox regression analyses were used to determine whether stress predicted event-free survival, and if salivary cortisol predicted event free survival. Linear and multiple regressions were used to determine the association of stress with salivary cortisol. RESULTS: Stress was not a significant predictor of event-free survival in heart failure (heart rate = 1.06; 95% confidence interval = 0.95-1.81; p = 0.32). Salivary cortisol was a significant predictor of event-free survival in the unadjusted model (heart rate = 2.30; 95% confidence interval = 0.99-5.927; p = 0.05), but not in the adjusted model. Stress (beta 1.06; 95% confidence interval = 0.95-1.18; p = 0.32) was not a significant predictor of salivary cortisol level. CONCLUSION: Stress is a complex phenomenon, and our measure of stress may not have captured it well. Alternatively, the physical stressors acting in heart failure produce levels of neurohormonal activation that mask the effects of psychosocial stressors or an indirect association of stress with outcomes that is mediated through another construct. Future studies are needed to investigate stress in patients with heart failure to provide definitive answers. PMID- 26246900 TI - On the use of exposure therapy in the treatment of anxiety disorders: a survey among cognitive behavioural therapists in the Netherlands. AB - BACKGROUND: Although research has shown exposure therapy to have earned its rank among empirically supported treatments (ESTs) for anxiety disorders, several US based studies suggest it to be underused in clinical practice. Data on exposure use in Europe is mainly lacking, whereas its state of dissemination in countries such as the Netherlands has remained uncharted. Therefore, this study examined the use of exposure therapy among members of the Dutch Association for Behavioural and Cognitive Therapy (VGCt), as well as explored therapist, educational and contextual variables that could facilitate its dissemination in clinical practice. METHODS: Respondents (n = 490) were surveyed on clinical interventions used in their treatment for social anxiety disorder, phobia, OCD and panic disorder. Data was collected on the use of (disorder) specific interventions, therapists' attitudes on exposure, treatment experience, current educational status, educational background and workplace characteristics. RESULTS: Analysis of the data showed that most therapists implemented exposure frequently, but that exposure use still warrants improvement, specifically for certain (disorder-specific) interventions that were accordingly underused. Confirming our hypothesis, we found that clinicians who practiced exposure regularly also reported a greater willingness to use the treatment, perceived the method as more credible, and saw fewer barriers for its usage than those who did so less. The use of (disorder-) specific interventions, such as in vivo exposure (therapist as well as self-directed), exposure and response prevention for OCD, and interoceptive exposure for panic disorder, was positively related to level of education. While most were satisfied with the training they had received, therapists did report a need for additional instruction in targeted practical, empirical, and diagnostic skills. CONCLUSIONS: Our findings support the conclusion that the dissemination of exposure therapy in the Netherlands progresses well, but that education in certain (disorder-specific) techniques merits augmentation. To bridge the gap between research and clinical practice, future research should therefore focus on new, preferably blended approaches to training clinicians in exposure techniques. PMID- 26246901 TI - STAAR: improving the reliability of care coordination and reducing hospital readmissions in an academic medical centre. AB - SETTING: Massachusetts General Hospital embarked on a 4-year project to reduce readmissions in a high volume general medicine unit (November 2009 to September 2013). OBJECTIVE: To reduce 30-day readmissions to 10% through improved care coordination. DESIGN: As a before-after study, a total of 7586 patients admitted to the medicine unit during the intervention period included 2620 inpatients meeting high risk for readmission criteria. Of those, 2620 patients received nursing interventions and 539 patients received pharmacy interventions. INTERVENTION: The introduction of a Discharge Nurse (D/C RN) for patient/family coaching and a Transitional Care Pharmacist (TC PharmD) for predischarge medication reconciliation and postdischarge patient phone calls. Other interventions included modifications to multidisciplinary care rounds and electronic medication reconciliation. MAIN OUTCOME MEASURE: All-cause 30-day readmission rates. RESULTS: Readmission rates decreased by 30% (21% preintervention to 14.5% postintervention) (p<0.05). From July 2010 to December 2011, rates of readmission among high-risk patients who received the D/C RN intervention with or without the TC PharmD medication reconciliation/education intervention decreased to 15.9% (p=0.59). From January to June 2010, rates of readmission among high-risk patients who received the TC PharmD postdischarge calls decreased to 12.9% (p=0.55). From June 2010 to December 2011, readmission rates for patients on the medical unit that did not receive the designated D/C RN or TC PharmD interventions decreased to 15.8% (p=0.61) and 16.2% (0.31), respectively. CONCLUSIONS: A multidisciplinary approach to improving care coordination reduced avoidable readmissions both among those who received interventions and those who did not. This further demonstrated the importance of multidisciplinary collaboration. PMID- 26246902 TI - 'Care for Stroke', a web-based, smartphone-enabled educational intervention for management of physical disabilities following stroke: feasibility in the Indian context. AB - INTRODUCTION: Stroke rehabilitation is a process targeted towards restoration or maintenance of the physical, mental, intellectual and social abilities of an individual affected by stroke. Unlike high-income countries, the resources for stroke rehabilitation are very limited in many low-income and middle-income countries (LMICs). Provision of cost-effective, post-stroke multidisciplinary rehabilitation services for the stroke survivors therefore becomes crucial to address the unmet needs and growing magnitude of disability experienced by the stroke survivors in LMICs. In order to meet the growing need for post-stroke rehabilitation services in India, we developed a web-based Smartphone-enabled educational intervention for management of physical disabilities following a stroke. METHODS: On the basis of the findings from the rehabilitation needs assessment study, guidance from the expert group and available evidence from systematic reviews, the framework of the intervention content was designed. Web based application designing and development by Professional application developers were subsequently undertaken. RESULTS: The application is called 'Care for Stroke'. It is a web-based educational intervention for management of physical disabilities following a stroke. This intervention is developed for use by the Stroke survivors who have any kind of rehabilitation needs to independently participate in his/her family and social roles. DISCUSSION: 'Care for stroke' is an innovative intervention which could be tested not just for its feasibility and acceptability but also for its clinical and cost-effectiveness through rigorously designed, randomised clinical trials. It is very important to test this intervention in LMICs where the rehabilitation and information needs of the stroke survivors seem to be substantial and largely unmet. PMID- 26246903 TI - Visual Electrodiagnostic Testing in Birdshot Chorioretinopathy. AB - Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune posterior uveitis that can affect the visual function and, if left untreated, can lead to sight threatening complications and loss of central vision. We performed a systematic search of the literature focused on visual electrophysiology studies, including electroretinography (ERG), electrooculography (EOG), and visual evoked potentials (VEP), used to monitor the progression of BSCR and estimate treatment efficacy. Many reports were identified, including using a variety of methodologies and patient populations, which makes a direct comparison of the results difficult, especially with some of the earlier studies using nonstandardized methodology. Several different electrophysiological parameters, like EOG Arden's ratio and the multifocal ERG response densities, are reported to be widely affected. However, informal consensus emerged in the past decade that the full-field ERG light adapted 30 Hz flicker peak time is one of the most sensitive electrophysiological parameters. As such, it has been used widely in clinical trials to evaluate drug safety and efficacy and to guide therapeutic decisions in clinical practice. Despite its wide use, a well-designed longitudinal multicenter study to systematically evaluate and compare different electrophysiological methods or parameters in BSCR is still lacking but would benefit both diagnostic and therapeutic decisions. PMID- 26246904 TI - Association between Secondary and Primary Sjogren's Syndrome in a Large Collection of Lupus Families. AB - Objective. Systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS) share clinical and immunogenetic features and may occur together. We undertook this study to determine the risk of primary SS among SLE-unaffected relatives of SLE patients and whether or not primary and secondary SS tended to occur in the same families. Methods. We collected clinical and serological data on 2694 SLE patients, 7390 SLE-unaffected relatives of the SLE patients, and 1470 matched controls. Results. Of the 2694 subjects with SLE, 548 had secondary SS, while 71 of their 7390 SLE-unaffected relatives had primary SS. None of the 1470 controls had SS as defined herein (p = 5 * 10(-5) compared to SLE-unaffected relatives). Of the 71 SLE-unaffected relatives with primary SS, 18 (25.3%) had an SLE affected family member with secondary SS, while only 530 of the 7319 (7.2%) SLE unaffected relatives without SS did so (p = 1 * 10(-8)). Conclusion. Among families identified for the presence of SLE, primary and secondary SS tend to occur within the same families. These results highlight the commonalities between these two forms of SS, which in fact correspond to the same disease. PMID- 26246906 TI - Urine Monocyte Chemoattractant Protein-1 and Lupus Nephritis Disease Activity: Preliminary Report of a Prospective Longitudinal Study. AB - Objective. This longitudinal study aimed to determine the urine monocyte chemoattractant protein-1 (uMCP-1) levels in patients with biopsy-proven lupus nephritis (LN) at various stages of renal disease activity and to compare them to current standard markers. Methods. Patients with LN-active or inactive-had their uMCP-1 levels and standard disease activity markers measured at baseline and 2 and 4 months. Urinary parameters, renal function test, serological markers, and renal SLE disease activity index-2K (renal SLEDAI-2K) were analyzed to determine their associations with uMCP-1. Results. A hundred patients completed the study. At each visit, uMCP-1 levels (pg/mg creatinine) were significantly higher in the active group especially with relapses and were significantly associated with proteinuria and renal SLEDAI-2K. Receiver operating characteristic (ROC) curves showed that uMCP-1 was a potential biomarker for LN. Whereas multiple logistic regression analysis showed that only proteinuria and serum albumin and not uMCP-1 were independent predictors of LN activity. Conclusion. uMCP-1 was increased in active LN. Although uMCP-1 was not an independent predictor for LN activity, it could serve as an adjunctive marker when the clinical diagnosis of LN especially early relapse remains uncertain. Larger and longer studies are indicated. PMID- 26246905 TI - Understanding and Managing Pregnancy in Patients with Lupus. AB - Systemic lupus erythematosus (SLE) is a chronic, multisystemic autoimmune disease that occurs predominantly in women of fertile age. The association of SLE and pregnancy, mainly with active disease and especially with nephritis, has poorer pregnancy outcomes, with increased frequency of preeclampsia, fetal loss, prematurity, growth restriction, and newborns small for gestational age. Therefore, SLE pregnancies are considered high risk condition, should be monitored frequently during pregnancy and delivery should occur in a controlled setting. Pregnancy induces dramatic immune and neuroendocrine changes in the maternal body in order to protect the fetus from immunologic attack and these modifications can be affected by SLE. The risk of flares depends on the level of maternal disease activity in the 6-12 months before conception and is higher in women with repeated flares before conception, in those who discontinue useful medications and in women with active glomerulonephritis at conception. It is a challenge to differentiate lupus nephritis from preeclampsia and, in this context, the angiogenic and antiangiogenic cytokines are promising. Prenatal care of pregnant patients with SLE requires close collaboration between rheumatologist and obstetrician. Planning pregnancy is essential to increase the probability of successful pregnancies. PMID- 26246907 TI - Sustained Weight Loss with Vagal Nerve Blockade but Not with Sham: 18-Month Results of the ReCharge Trial. AB - BACKGROUND/OBJECTIVES: Vagal block therapy (vBloc) is effective for moderate to severe obesity at one year. SUBJECTS/METHODS: The ReCharge trial is a double blind, randomized controlled clinical trial of 239 participants with body mass index (BMI) of 40 to 45 kg/m or 35 to 40 kg/m with one or more obesity-related conditions. Interventions were implantation of either vBloc or Sham devices and weight management counseling. Mixed models assessed percent excess weight loss (%EWL) and total weight loss (%TWL) in intent-to-treat analyses. At 18 months, 142 (88%) vBloc and 64 (83%) Sham patients remained enrolled in the study. RESULTS: 18-month weight loss was 23% EWL (8.8% TWL) for vBloc and 10% EWL (3.8% TWL) for Sham (P < 0.0001). vBloc patients largely maintained 12-month weight loss of 26% EWL (9.7% TWL). Sham regained over 40% of the 17% EWL (6.4% TWL) by 18 months. Most weight regain preceded unblinding. Common adverse events of vBloc through 18 months were heartburn/dyspepsia and abdominal pain; 98% of events were reported as mild or moderate and 79% had resolved. CONCLUSIONS: Weight loss with vBloc was sustained through 18 months, while Sham regained weight between 12 and 18 months. vBloc is effective with a low rate of serious complications. PMID- 26246908 TI - Placebo-Controlled Discontinuation of Long-Term Acid-Suppressant Therapy: A Randomised Trial in General Practice. AB - Objective. To investigate whether patients on long-term antisecretory medication need to continue treatment to control symptoms. Methods. A double-blinded randomised placebo-controlled trial in general practices in Denmark. Patients aged 18-90 who were treated with antisecretory drugs on a long-term basis were randomized to esomeprazole 40 mg or identical placebo. Outcome measures were time to discontinuation with trial medication due to failed symptom control analysed as survival data. The proportion of patients stopping trial medication during the one-year follow-up was estimated. Results. A total of 171 patients were included with a median prior duration of antisecretory treatment of four years (range: 0.5 to 14.6 years). 86 patients received esomeprazole 40 mg and 85 patients received placebo. At 12 months, statistically significantly more patients in the placebo group had discontinued (73% (62/85)) compared with the esomeprazole group (21% (18/86); p < 0.001). Conclusions. Long-term users of antisecretory drugs showed a preference for the active drug compared to placebo. However, 27% of patients continued on placebo throughout the study and did not need to reinstitute usual treatment. One in five patients treated with esomeprazole discontinued trial medication due to unsatisfactory symptom control. Discontinuation of antisecretory treatment should be considered in long-term users of antisecretory drugs. This trial is registered with Trial registration ClinicalTrials.gov ID: NCT00120315. PMID- 26246909 TI - Anatomical Study of the Ulnar Nerve Variations at High Humeral Level and Their Possible Clinical and Diagnostic Implications. AB - Background. Descriptive evaluation of nerve variations plays a pivotal role in the usefulness of clinical or surgical practice, as an anatomical variation often sets a risk of nerve palsy syndrome. Ulnar nerve (UN) is one amongst the major nerves involved in neuropathy. In the present anatomical study, variations related to ulnar nerve have been identified and its potential clinical implications discussed. Materials and Method. We examined 50 upper limb dissected specimens for possible ulnar nerve variations. Careful observation for any aberrant formation and/or communication in relation to UN has been carried out. Results. Four out of 50 limbs (8%) presented with variations related to ulnar nerve. Amongst them, in two cases abnormal communication with neighboring nerve was identified and variation in the formation of UN was noted in remaining two limbs. Conclusion. An unusual relation of UN with its neighboring nerves, thus muscles, and its aberrant formation might jeopardize the normal sensori-motor behavior. Knowledge about anatomical variations of the UN is therefore important for the clinicians in understanding the severity of ulnar nerve neuropathy related complications. PMID- 26246910 TI - Pes Anserinus Structural Framework and Constituting Tendons Are Grossly Aberrant in Nigerian Population. AB - We evaluated the morphological framework of the pes anserinus in both knees of ten Nigerian cadavers and we observed high degree of variability in its morphology and location. The pes anserinus inserted specifically on the superior half of the media border of the tibia, as far inferiorly as 124.44 mm to the tibial tuberosity (prolonged insertion). The insertion was also joined to the part of tibia close to the tibia tuberosity (90%) and to the fascia cruris (10%). The initial insertion point of the pes anserinus was always found at the level of the tibia tuberosity. We found out that accessory bands of sartorius, gracilis, or semitendinosus were part of the pes anserinus in 95% of all occasions studied whereas the combined occurrence of monotendinosus sartorius, gracilis, and semitendinosus tendons was found in only 5% of all occasions. The pes anserinus did not conform to the layered pattern and the tendons of sartorius, gracilis, or semitendinosus were short. The inferior prolongation of the pes anserinus connotes extended surface area of attachment to support the mechanical pull from the hamstring muscles. This information will be useful in precise location and grafting of the pes anserinus. PMID- 26246911 TI - Current Patterns of Management of Advanced Prostate Cancer in Routine Clinical Practice in Spain. AB - Objective. To describe urologists' practice patterns when managing patients with advanced prostate cancer (PCa) in Spain. Methods. This was an observational study conducted by 120 urologists using retrospective data of advanced PCa patients attending hospitals and outpatient centers. Results. Urologists evaluated a total of 375 patients (mean age: 75 years; ECOG 0-1: 77%; mean serum PSA levels at study entry: 50.5 ng/Ml). Approximately 50% of patients had bone metastases, and 60.6% experienced pain as the main symptom of progressive disease. Primary androgen deprivation therapy (ADT) use was 99.7%, with continuous ADT as the dominant strategy (91.9%). After failure of initial ADT, antiandrogen withdrawal was the next method most commonly used in 57% of patients. Choice of secondary hormonal treatment was made mostly by urologists (96%), who continued to monitor patients. Patient follow-up after chemotherapy and supportive care were mainly done in urology units, although responsibility was shared with medical oncologists and radiologists. Conclusion. The urologists' attitudes towards management of PCa in the routine practice in Spain show the urologist as an integral component even when patients progress to advanced stages of the disease. PMID- 26246912 TI - Evaluation of the Quilting Technique for Reduction of Postmastectomy Seroma: A Randomized Controlled Study. AB - Background. Postmastectomy seroma causes patients' discomfort, delays starting the adjuvant therapy, and may increase the possibility of surgical site infection. Objective. To evaluate quilting of the mastectomy flaps with obliteration of the axillary space in reducing postmastectomy seroma. Methods. A randomized controlled study was carried out among 120 females who were candidates for mastectomy and axillary clearance. The intervention group (N = 60) with quilting and the control group without quilting. All patients were followed up routinely for immediate and late complications. Results. There were no significant differences between the two groups as regards the demographic characteristics, postoperative pathological finding, and the immediate postoperative complications. The incidence of seroma was significantly lower in the intervention group compared with the control group (20% versus 78.3%, P < 0.001). Additionally, the intervention group had a shorter duration till seroma resolution (9 days versus 11 days, P < 0.001) and a smaller volume of drainage (710 mL versus 1160 mL, P < 0.001) compared with the control group. Conclusion. The use of mastectomy with quilting of flaps and obliteration of the axillary space is an efficient method to significantly reduce the postoperative seroma in addition to significantly reducing the duration and volume of wound drainage. Therefore we recommend quilting of flaps as a routine step at the end of any mastectomy. PMID- 26246913 TI - A rare case of Kussmaul Disease (Sialodochitis Fibrinosa). AB - Sialodochitis fibrinosa (or commonly known as Kussmaul Disease) is a rare salivary gland disease characterized by recurrent salivary gland swelling and pain as a result of mucofibrinous plugs. Typically patients have a history of multiply recurrent glandular swelling, dehydration and/or decreased salivary flow, thick secretions from Stensen's or Wharton's duct, and/or history of allergic diseases. Retention of mucofibrinous plugs may lead to acute suppurative parotitis and chronic sialadenitis ultimately. The diagnosis is one of exclusion, and treatment is based on symptomatology and largely supportive. PMID- 26246914 TI - Neural Plasticity of Mild Tinnitus: An fMRI Investigation Comparing Those Recently Diagnosed with Tinnitus to Those That Had Tinnitus for a Long Period of Time. AB - Objectives. The aim of the study was to compare differences in neural correlates of tinnitus in adults with recent onset and others who had the disorder for longer than a year. Design. A total of 25 individuals with tinnitus were divided into groups based on the amount of time for which they had experienced tinnitus: <1 year (RTIN) or >1 year (LTIN). Subjects underwent an fMRI scan while listening to affective sounds from the International Affective Digital Sounds database. Resting state functional connectivity data were also collected. Results. The RTIN group recruited the posterior cingulate and insula to a greater extent than the LTIN group when processing affective sounds. In addition, we found that the LTIN group engaged more frontal regions when listening to the stimuli compared to the RTIN group. Lastly, we found increased correlations between the default mode network and the precuneus in RTIN patients compared to LTIN at rest. Conclusion. Our results suggest that the posterior cingulate and insula may be associated with an early emotional reaction to tinnitus in both task and resting states. Over time, tinnitus patients may recruit more frontal regions to better control their emotional response and exhibit altered connectivity in the default mode network. PMID- 26246916 TI - Preterm Caesarean Delivery in a Parturient with Candida parapsilosis Endocarditis. AB - We present the first documented case of Candida parapsilosis infective endocarditis in a pregnant patient. While the incidence of infective endocarditis during pregnancy is rare, the incidence of C. parapsilosis endocarditis is even rarer. The numerous specific risks and decision making processes regarding this case are presented. PMID- 26246917 TI - Aortico-Left Atrial Fistula: A Rare Complication of Bioprosthetic Aortic Valve Endocarditis Secondary to Enterococcus faecalis. AB - Paravalvular aortic root abscess with intracardiac fistula formation is an exceedingly rare complication of infective endocarditis. This condition is even more rarely encountered in patients with bioprosthetic valve endocarditis. We report an unusual case of a 68-year-old Bosnian female with a bioprosthetic aortic valve, who developed an extensive aortic root abscess, complicated by an aortico-left atrial intracardiac fistula. This case illustrates that a high index of suspicion, prompt diagnosis by echocardiography, proper antibiotic therapy, and early surgical intervention are crucial to improving treatment outcomes for this rare condition. PMID- 26246918 TI - Takotsubo Cardiomyopathy: A New Perspective in Asthma. AB - Takotsubo cardiomyopathy (TCM) is an entity of reversible cardiomyopathy known for its association with physical or emotional stress and may mimic myocardial infarction. We report an exceedingly rare case of albuterol-induced TCM with moderate asthma exacerbation. An interesting association that may help in understanding the etiology of TCM in the asthmatic population. Although the prognosis of TCM is excellent, it is crucial to recognize beta agonists as a potential stressor. PMID- 26246915 TI - Dopaminergic Regulation of Striatal Interneurons in Reward and Addiction: Focus on Alcohol. AB - Corticobasal ganglia networks coursing through the striatum are key structures for reward-guided behaviors. The ventral striatum (nucleus accumbens (nAc)) and its reciprocal connection with the ventral tegmental area (VTA) represent a primary component of the reward system, but reward-guided learning also involves the dorsal striatum and dopaminergic inputs from the substantia nigra. The majority of neurons in the striatum (>90%) are GABAergic medium spiny neurons (MSNs), but both the input to and the output from these neurons are dynamically controlled by striatal interneurons. Dopamine is a key neurotransmitter in reward and reward-guided learning, and the physiological activity of GABAergic and cholinergic interneurons is regulated by dopaminergic transmission in a complex manner. Here we review the role of striatal interneurons in modulating striatal output during drug reward, with special emphasis on alcohol. PMID- 26246919 TI - Flucytosine Pharmacokinetics in a Critically Ill Patient Receiving Continuous Renal Replacement Therapy. AB - Purpose. A case report evaluating flucytosine dosing in a critically ill patient receiving continuous renal replacement therapy. Summary. This case report outlines an 81-year-old male who was receiving continuous venovenous hemofiltration (CVVH) for acute renal failure and was being treated with flucytosine for the treatment of disseminated Cryptococcus neoformans infection. Due to patient specific factors, flucytosine was empirically dose adjusted approximately 50% lower than intermittent hemodialysis (iHD) recommendations and approximately 33% lower than CRRT recommendations. Peak and trough levels were obtained, which were supratherapeutic, and pharmacokinetic parameters were calculated. The patient experienced thrombocytopenia, likely due to elevated flucytosine levels, and flucytosine was ultimately discontinued. Conclusion. Despite conservative flucytosine dosing for a patient receiving CVVH, peak and trough serum flucytosine levels were supratherapeutic (120 MUg/mL at 2 hours and 81 MUg/mL at 11.5 hours), which increased drug-related adverse effects. The results indicate that this conservative dosing regimen utilizing the patient's actual body weight was too aggressive. This case report provides insight into flucytosine dosing in CVVH, a topic that has not been investigated previously. Further pharmacokinetic studies of flucytosine dosing in critically ill patients receiving CVVH are needed in order to optimize pharmacokinetic and pharmacodynamic parameters while avoiding toxic flucytosine exposure. PMID- 26246920 TI - Idiopathic Basal Ganglia Calcification Presented with Impulse Control Disorder. AB - Primary familial brain calcification (PFBC), also referred to as Idiopathic Basal Ganglia Calcification (IBGC) or "Fahr's disease," is a clinical condition characterized by symmetric and bilateral calcification of globus pallidus and also basal ganglions, cerebellar nuclei, and other deep cortical structures. It could be accompanied by parathyroid disorder and other metabolic disturbances. The clinical features are dysfunction of the calcified anatomic localization. IBGC most commonly presents with mental damage, convulsion, parkinson-like clinical picture, and neuropsychiatric behavior disorders; however, presentation with impulse control disorder is not a frequent presentation. In the current report, a 43-year-old male patient who has been admitted to psychiatry policlinic with the complaints of aggressive behavior episodes and who has been diagnosed with impulse control disorder and IBGC was evaluated in the light of the literature. PMID- 26246921 TI - Acute Promyelocytic Leukemia Presenting with Severe Marrow Fibrosis. AB - We report a case of acute promyelocytic leukemia (APL) presenting with severely fibrotic marrow. There are four other reports of similar cases in the literature. Our patient was treated with All-Transretinoic Acid- (ATRA-) containing induction chemotherapy, followed by consolidation and maintenance therapy. He achieved a complete morphologic remission with adequate count recovery in a timely fashion, and later a molecular remission was documented. The patient remains in molecular remission and demonstrates normal blood counts now more than 4 years after induction. Since the morphological appearance may not be typical and the bone marrow may not yield an aspirate for cytogenetic analysis, awareness of such entity is important to make a correct diagnosis of this potentially curable disease. PMID- 26246922 TI - Acute Myopericarditis Likely Secondary to Disseminated Gonococcal Infection. AB - Disseminated gonococcal infection (DGI) is a rare complication of primary infection with Neisseria gonorrhoeae. Cardiac involvement in this condition is rare, and is usually limited to endocarditis. However, there are a number of older reports suggestive of direct myocardial involvement. We report a case of a 38-year-old male with HIV who presented with chest pain, pharyngitis, tenosynovitis, and purpuric skin lesions. Transthoracic echocardiogram showed acute biventricular dysfunction. Skin biopsy showed diplococci consistent with disseminated gonococcal infection, and treatment with ceftriaxone improved his symptoms and ejection fraction. Though gonococcal infection was never proven with culture or nucleic acid amplification testing, the clinical picture and histologic findings were highly suggestive of DGI. Clinicians should consider disseminated gonococcal infection when a patient presents with acute myocarditis, especially if there are concurrent skin and joint lesions. PMID- 26246923 TI - A 28-Year-Old Woman with Fever, Weight Loss, Pancytopenia, and Multiple Hepatosplenic and Bone Lesions. AB - Brucellosis is a systemic zoonotic infection that can involve any organ or system in the body. It may present with a broad spectrum of clinical manifestations. Considering such myriad presentations, brucellosis should always be considered in the differential diagnosis of any febrile illness in a compatible epidemiological context. Here, we report a rare presentation of acute brucellosis with multifocal osteomyelitis and hepatosplenic lesions. PMID- 26246924 TI - Acute Brucellosis with Splenic Infarcts: A Case Report from a Tertiary Care Hospital in Saudi Arabia. AB - Splenic infarction is an extremely rare and unique presentation of brucellosis. Only few cases have been reported worldwide. We here report a case of a young man, presenting with acute onset of fever, left hypochondial pain, and vomiting. Further evaluation revealed multiple splenic infarcts and positive blood culture for brucellosis despite negative transesophageal echocardiography for endocarditis. Significant improvement in clinical symptoms and splenic lesions was achieved after six weeks of combination therapy against brucellosis. PMID- 26246925 TI - A Case of Primary Breast Diffuse Large B-Cell Lymphoma Treated with Chemotherapy Followed by Elective Field Radiation Therapy: A Brief Treatment Pattern Review from a Radiation Oncologist's Point of View. AB - We here report a case of primary breast lymphoma (PBL). A 44-year-old woman presented with a painless mass in the right breast. Fine needle aspiration cytology and excisional biopsy were performed. Excisional biopsy revealed low grade lymphoma, which was subsequently confirmed with histopathology and diagnosed as diffuse large B-cell lymphoma (DLBCL). A chest computed tomography scan revealed a 3.5 cm sized breast mass with skin thickening and a small sized lymphadenopathy in the ipsilateral axilla. Radiation therapy including the right whole breast and ipsilateral axilla and supraclavicular lymph node was performed after the patient received four courses of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab) chemotherapy. At the follow-up period of 42 months, the patient is surviving with no evidence of disease. No morbidities occurred in this patient during the follow-up period. We also briefly review the current practice pattern in PBL patients with DLBCL. PMID- 26246926 TI - Postpartum Sacral Stress Fracture: An Atypical Case Report. AB - Sacral stress fractures are common in elderly people. However, sacral stress fracture should be always screened in the differential diagnoses of low back pain during the postpartum period. We present a case of sacral fracture in a thirty six-year-old woman with low back pain and severe right buttock pain two days after cesarean section delivery of a 3.9 Kg baby. The diagnosis was confirmed by MRI and CT scan, while X-ray was unable to detect the fracture. Contribution of mechanical factors during the cesarean section is not a reasonable cause of sacral fracture. Pregnancy and lactation could be risk factors for sacral stress fracture even in atraumatic delivery such as cesarean section. Our patient had no risk factors for osteoporosis except for pregnancy and lactation. Transient or focal osteoporosis is challenging to assess and it cannot be ruled out even if serum test and mineral density are within the normal range. PMID- 26246927 TI - Fetal Rhabdomyoma of the Right Tonsil with Polyp-Like Appearance. AB - Skeletal muscle neoplasms, in contrast to other groups of tumors, are almost malignant. The benign variant, rhabdomyoma, is distinctly rare. Rhabdomyomas can be classified generally into two types: cardiac and extracardiac. Extracardiac rhabdomyoma can be further divided into three subtypes: adult, fetal, and genital type. Adult rhabdomyoma is the most common subtype of rhabdomyoma even though it remains relatively rare. Fetal rhabdomyomas are less common than the adult type. In this paper we report a rare case of a fetal rhabdomyoma with polyp-like appearance originating from right tonsil. Punch biopsy and then right tonsillectomy were performed for complete excision. There was no obvious recurrence. PMID- 26246928 TI - Slow Progression of Cognitive Dysfunction of Alzheimer's Disease in Sexagenarian Women with Schizophrenia. AB - Although both schizophrenia (SCZ) and Alzheimer's disease (AD) are among the most common psychiatric diseases, the interaction of these two is not well-understood. We investigated three women with SCZ who developed AD in their 60s. The patients presented with cognitive dysfunction such as loss of recent memory, which was confirmed by both clinical observations and neuropsychological tests. Their magnetic resonance and functional imaging findings were consistent with AD. Their brain atrophy advanced significantly during a 6-year observation period. However, their global cognitive function did not deteriorate significantly during this period. Although the cognitive reserve model might account for this discrepancy, our results suggest some interactions between the neuropathology of SCZ and AD and warrant further research. PMID- 26246929 TI - Multiple Bronchogenic and Gastroenteric Cysts Arising from the Stomach in a Patient with Abdominal Pain. AB - Bronchogenic cysts arising from the stomach are uncommon. We discuss a young female patient with presumed enteric duplication cysts who was found to have three bronchogenic and gastroenteric cysts upon pathologic review. We discuss the pathophysiology of bronchogenic cysts and their malignant potential. PMID- 26246930 TI - Laparoscopic Repair of Internal Transmesocolic Hernia of Transverse Colon. AB - Introduction. Internal hernias are often misdiagnosed because of their rarity, with subsequent significant morbidity. Case Presentation. A 61-year-old Japanese man with no history of surgery was referred for intermittent abdominal pain. CT suggested the presence of a transmesocolic internal hernia. The patient underwent a surgical procedure and was diagnosed with transmesocolic internal hernia. We found internal herniation of the small intestine loop through a defect in the transverse mesocolon, without any strangulation of the small intestine. We were able to complete the operation laparoscopically. The patient's postoperative course was uneventful and the patient was discharged on postoperative day 6. Discussion. Transmesocolic hernia of the transverse colon is very rare. Transmesocolic hernia of the sigmoid colon accounts for 60% of all other mesocolic hernias. Paraduodenal hernias are difficult to distinguish from internal mesocolic transverse hernias. We can rule out paraduodenal hernias with CT. Conclusion. The patient underwent a surgical procedure and was diagnosed with transmesocolic internal hernia. We report a case of a transmesocolic hernia of the transverse colon with intestinal obstruction that was diagnosed preoperatively and for which laparoscopic surgery was performed. PMID- 26246931 TI - Unusual Causes of Abrupt Anuria Early Post-Renal Transplantation. AB - Renal transplantation using living donors has superior outcomes in comparison to deceased donor transplantation and results in immediate allograft function in a majority of cases. Rarely may allograft be nonfunctional from the beginning, or anuria is noted after a period of good urine output. Surgical causes for anuria should be high on the differential diagnosis in immediate-to-early posttransplant period, especially in an unsensitized recipient. We present two unusual causes of early onset anuria after living related renal transplantation where early surgical reexploration salvaged renal allografts with excellent long term outcomes. PMID- 26246932 TI - Intravesical Migration of Missed Intrauterine Device Associated with Stone Formation: A Case Report and Review of the Literature. AB - Intrauterine device is the most widely used method of reversible contraception. It may cause various complications including perforation of uterus. In this case, 44-year-old woman was presented with lower urinary tract symptoms after six years of insertion. Patient has no remarkable physical or laboratory finding but abdominal ultrasound revealed a 27 mm hyperechogenicity, suggestive of foreign body or calculus on the posterior bladder wall which was removed endoscopically. This case highlights the need of immediate and periodic evaluation of women with intrauterine device to avoid missing serious complications. PMID- 26246933 TI - Adult Patient with Synchronous Gastrointestinal Stromal Tumor and Xp11 Translocation-Associated Renal Cell Carcinoma: A Unique Case Presentation with Discussion and Review of Literature. AB - Gastrointestinal stromal tumor (GIST) is the most common primary mesenchymal tumor of the gastrointestinal tract. This entity comprises a wide spectrum of tumors that vary from benign to overtly malignant, with the majority of these tumors harboring oncogenic mutations of the KIT receptor tyrosine kinase that can aid in diagnosis as well as in targeted therapy. Although the majority of GISTs are sporadic, there are forms that are associated with a variety of syndromes including Carney-Stratakis syndrome and neurofibromatosis type 1, as well as a subset of familial GIST syndromes that are caused by germline mutations in KIT or PDGFRA. Here, we describe an unusual case of a patient who was found to have a large abdominal GIST with an incidentally found Xp11 translocation-associated renal carcinoma. The karyotype of the renal carcinoma revealed an unbalanced rearrangement involving an (X;22) translocation at Xp11.2 and 22p11.2, which has not been reported in the literature. Although GISTs have shown an association with other primary malignant neoplasms, including simultaneous presence with unilateral clear cell renal cell carcinoma and bilateral papillary renal cell carcinomas, we describe the first reported case of synchronous GIST and Xp11 translocation-associated renal cell carcinoma. PMID- 26246934 TI - Bone Indices in Thyroidectomized Patients on Long-Term Substitution Therapy with Levothyroxine Assessed by DXA and HR-pQCT. AB - Background. Studies on bone effects of long-term substitution therapy with levothyroxine (LT4) have shown discrepant results. Previous studies have, however, not evaluated volumetric bone mineral densities (vBMD), bone structure, and strength using high resolution peripheral quantitative computed tomography (HR-pQCT) and finite element analysis (FEA). Using a cross-sectional design, we aimed to determine whether BMD, structure, and strength are affected in hypothyroid patients on LT4 substitution therapy. Methods. We compared 49 patients with well-substituted hypothyroidism with 49 age- and gender-matched population based controls. Areal BMD was assessed by DXA, vBMD and bone geometry by HR-pQCT, and bone strength by FEA. Results. Patients had been thyroidectomized due to thyroid cancer (10%) and nontoxic (33%) or toxic goiter (57%). 82% were women. TSH levels did not differ between groups, but patients had significantly higher levels of T4 (p < 0.001) and lower levels of T3 (p < 0.01). Compared to controls, patients had higher levels of magnesium (p < 0.05), whereas ionized calcium and PTH were lower (p < 0.05). Bone scans did not reveal any differences in BMD, bone geometry, or strength. Conclusion. If patients with hypothyroidism are well-substituted with LT4, the disease does not affect bone indices to any major degree. PMID- 26246935 TI - Polymorphism in the Vesicular Monoamine Transporter 2 Gene Decreases the Risk of Parkinson's Disease in Han Chinese Men. AB - Background. Polymorphisms rs363371 and rs363324 in the vesicular monoamine transporter 2 (VMAT2) gene have been associated with risk of PD in an Italian population, and our aim is to investigate the association between the two single nucleotide polymorphisms and PD in Han Chinese. Methods. 561 Han Chinese PD patients and 491 healthy age- and gender-matched controls were genotyped using Ligase detection reaction (LDR) method. Result. Both of patient and control groups showed similar genotype frequencies between patients and controls at both rs363371 and rs363324, as well as similar minor A allele frequencies at rs363371 (P = 0.452) and rs363324 (P = 0.413). None of the observed haplotypes showed a significant association with PD. Subgroup analysis by gender and age at onset revealed a significant association between the A allele of rs363371 and PD in Han Chinese males relative to healthy controls (OR 0.799, 95% CI 0.665 to 0.959, P = 0.016), and this association remained significant after adjusting for age (OR 0.785, 95% CI 0.652 to 0.945, P = 0.011). Conclusion. These results suggest that polymorphism of VMAT2 locus is associated with risk of PD in Han Chinese overall but that the A allele at rs363371 may protect against PD in Han Chinese males. PMID- 26246936 TI - Mortality and Financial Burden of Periprosthetic Fractures of the Femur. AB - OBJECTIVE: This study examines patient factors to identify risks of 12-month mortality following periprosthetic femur fractures. Hospital charges were analyzed to quantify the financial burden for treatment modalities. METHODS: Data were retrospectively analyzed from a prospective database at a university hospital setting. One-hundred and thirteen patients with a periprosthetic fracture of the proximal or distal femur were identified. Risk factors for 12 month mortality were analyzed, and financial data were compared between the various treatment modalities. RESULTS: In all, 14% of patients died (16 of 113) within 3 months and the 1-year mortality was 17.7% (20 of 113). Patients who died within 1 year had higher hospital charges (US$33 880 +/- 25 051 vs US$22 886 +/- 16 841; P = .01) and were older (87.6 +/- 8.5 vs 81.5 +/- 8.6; P = .004). Logistic regression analysis revealed age was the only significant predictor of 1 year mortality (P = .029, odds ratio 1.1). Analysis of financial data revealed 4 distinct groups (P < .05 between groups). Distal femoral revision arthroplasty (RA-DF) generated the highest hospital charges of US$91 035 +/- 25 579 (n = 3). The second most highly charged group included proximal femoral fractures treated with revision arthroplasty (US$34 078 +/- 17 832; n = 20) and hemi/total hip arthroplasty (THA; US$41 556 +/- 23 651; n = 8). The third most charged group underwent open reduction internal fixation of the proximal (US$18 706 +/- 6829; n = 35) and distal (US$22 381 +/- 10 835; n = 35) femur. Nonoperative treatment generated the lowest charges (US$6426 +/- 2899; n = 11). On average, the hospital lost money treating patients with RA-DF (US$-19 080 +/- 2022 per patient) and hemi/THA (US$-6594 +/- 9305 per patient), while all other treatment groups were profitable. CONCLUSION: One-year mortality after periprosthetic femur fractures was 17.7%, is mostly influenced by age, and 80% of deaths occur within 3 months. Patients treated with primary/revision arthroplasty generate more hospital charges than internal fixation. The average patient treated with revision arthroplasty of the distal femur or hemi/THA for a periprosthetic femur fractures resulted in net financial losses for the hospital. PMID- 26246937 TI - Spinal Manipulative Therapy for Chronic Lower Back Pain in Older Veterans: A Prospective, Randomized, Placebo-Controlled Trial. AB - INTRODUCTION: Chronic lower back pain (CLBP) is problematic in older veterans. Spinal manipulative therapy (SMT) is commonly utilized for CLBP in older adults, yet there are few randomized placebo-controlled trials evaluating SMT. METHODS: The purpose of the study was to compare the effectiveness of SMT to a sham intervention on pain (Visual Analogue Scale, SF-36 pain subscale), disability (Oswestry Disability Index), and physical function (SF-36 subscale, Timed Up and Go) by performing a randomized placebo-controlled trial at 2 Veteran Affairs Clinics. RESULTS: Older veterans (>= 65 years of age) who were naive to chiropractic were recruited. A total of 136 were included in the study with 69 being randomly assigned to SMT and 67 to sham intervention. Patients were treated 2 times per week for 4 weeks assessing outcomes at baseline, 5, and 12 weeks postbaseline. Both groups demonstrated significant decrease in pain and disability at 5 and 12 weeks. At 12 weeks, there was no significant difference in pain and a statistically significant decline in disability scores in the SMT group when compared to the sham intervention group. There were no significant differences in adverse events between the groups. CONCLUSIONS: The SMT did not result in greater improvement in pain when compared to our sham intervention; however, SMT did demonstrate a slightly greater improvement in disability at 12 weeks. The fact that patients in both groups showed improvements suggests the presence of a nonspecific therapeutic effect. PMID- 26246938 TI - Predictors of Postoperative Cognitive Decline in Very Old Patients With Hip Fracture: A Retrospective Analysis. AB - BACKGROUND: To investigate incidence and predictors of the various postoperative cognitive declines in old patients with hip fracture. METHODS: This retrospective chart study evaluated 411 patients (age >=80 years, follow-up 5 years). After exclusion of 82 patients (preexisting dementia or delirium), 70 patients showing either diagnosed postoperative delirium (POD; group 1; N = 18, 5.5%) or an unspecified cognitive dysfunction and behavior (group 2; N = 52, 15.8%) were analyzed and compared with those without any acute postoperative cerebral impairment (control group; N = 259, 78.7%). Medical history, anesthesiological, orthopedic, and rehabilitation data were assessed using the medical database of the hospital information system. Relative ratio was calculated with Fisher exact test: P value Bonferroni corrected <=.003. RESULTS: Acute cognitive complications were observed in 70 (21.3%) patients. Our data in group 1 showed that patients with a medical history of stroke (relative risk [RR] = 16.2, P = .0001) or nicotine abuse (RR = 14.4, P = .001) and perioperative surgical bleeding (RR = 6.54, P = .002) are more likely to develop POD. Unspecified cognitive dysfunction and behavior (group 2) was significantly associated with a medical history of stroke (RR = 12.5, P = .0001) and postoperatively with depression (RR = 3.32, P = .001). In the follow-up, significantly more patients in group 1 (55.6%, RR = 21.8, P = .0001) and group 2 (13.5%, RR = 3.88, P = .001) developed dementia as compared to controls (1.9%). Mortality did not differ significantly between the groups (group 1: RR = 1.75, P = .5 and group 2: RR = 0.66, P = 1.0). CONCLUSION: These data show that various predictors can identify a greater likelihood of developing postoperative cognitive decline in very old patients with hip fracture. Not identifying or labeling of POD limits the opportunity for evaluation, treatment, and planning. Thus, routine cognitive assessments need to be performed in the scope of multidisciplinary orthogeriatric comanagement. PMID- 26246939 TI - Geriatric High-Energy Polytrauma With Orthopedic Injuries: Clinical Predictors of Mortality. AB - BACKGROUND: The impact of orthopedic injuries in the elderly patient with multi trauma and the effect of operative fixation on these injuries have not been thoroughly evaluated. METHODS: We reviewed geriatric patients (aged 65 and older) between 2004 and 2010 at a level 1 trauma center who sustained high-energy polytrauma (injury and severity score [ISS] >= 16) with associated orthopedic injuries. Patients were excluded if they had severe head and spine injuries, died on arrival, or had low-energy mechanisms of injury. Logistic regression was conducted to identify factors that predict mortality. RESULTS: There were 154 patients who comprised our study group with an average age of 76 years and an ISS of 23. There were 96 males and 58 females. Overall, 52 patients died within 1 year of their admission: 21 patients during their initial hospital stay and 31 patients within 1 year following admission. In all, 64 (42%) patients underwent operative stabilization of their orthopedic injuries. Increased mortality was seen (P < .05) in female patients, those with lower admission Glasgow coma score, and those who underwent orthopedic surgery. Patients had worse outcomes if they sustained femur (P = .014), clavicle, or scapular fractures (P = .027). Other factures associated with higher mortality included pelvic/acetabular injury requiring surgery (P = .019) or spine fractures treated nonoperatively (P = .014). CONCLUSION: The effect of orthopedic injuries on this geriatric polytrauma group contribute to worse outcomes when they included clavicle, scapula, and femur fractures. We also found that pelvic/acetabular fractures treated operatively and nonoperative spine fractures were associated with higher mortality rates. Risk/benefit consideration is suggested when contemplating operative intervention in these patients. PMID- 26246940 TI - Pelvic Insufficiency Fractures. AB - Pelvic insufficiency fractures may occur in the absence of trauma or as a result of low-energy trauma in osteoporotic bone. With a growing geriatric population, the incidence of pelvic insufficiency fracture has increased over the last 3 decades and will continue to do so. These fractures can cause considerable pain, loss of independence, and economic burden to both the patient and the health care system. While many of these injuries are identified and treated based on plain radiographs, some remain difficult to diagnose. The role of advanced imaging in these cases is discussed. In addition to treating the fracture, medical comorbidities contributing to osteoporosis should be identified and corrected. Specific attention has been given to 25-OH serum vitamin D screening and repletion. Treatment generally consists of providing pain control and assisting patients with mobilization while allowing weight bearing as tolerated. In those unable to do so, invasive techniques such as sacroplasty as well as internal fixation may be beneficial. The role of operative fixation in insufficiency fractures is also discussed. PMID- 26246941 TI - Smoking Cessation Related to Improved Patient-Reported Pain Scores Following Spinal Care in Geriatric Patients. AB - INTRODUCTION: We examined rates of smoking cessation and the effect of smoking cessation on pain and disability scores in a geriatric patient population. METHODS: Prospectively maintained database records of 6779 patients treated for painful spinal disorders were examined. The mean duration of care was 8 months. Multivariate statistical analysis was performed with independent variables including smoking status, secondary gain status, gender, treatment type, depression, and age. RESULTS: Of the patients seeking care for painful spinal disorders, 8.9% over the age of 55 smoked compared with 23.9% of those under 55 years of age. Rates of smoking cessation did not differ for those older than 55 years (25.1%) and younger patients (26.1%). Current smokers in both age-groups reported greater pain than those who had never smoked in all pain ratings (P < .001). Mean improvement in reported pain over the course of treatment was significantly different in nonsmokers and current smokers in both age-groups (P < .001). Those who quit smoking during the course of care reported greater improvement in pain than those who continued to smoke. The mean improvement in pain ratings was clinically significant in patients in all 3 groups of nonsmokers whereas those who continued to smoke had no clinically significant improvement in reported pain. CONCLUSION: The results support the need for smoking cessation programs, given a strong association between improved patient-reported pain and smoking cessation. Fewer older patients smoke but they are equally likely to quit. PMID- 26246942 TI - ASA Grade and Elderly Patients With Femoral Neck Fracture. AB - PURPOSE: This prospective study was designed to evaluate the effect of American Society of Anaesthesiologists (ASA) score on time to surgery, length of hospital stay, and 30-day mortality in elderly patients with femoral neck fracture. METHODS: A total of 249 patients admitted with femoral neck fracture were included in the study. Mean age was 84 years (95% confidence interval 83 to 85). Two patients were ASA I, 110 patients were ASA II, 125 were ASA III, and 12 were ASA IV. RESULTS: The mean time to surgery was 18.9 hours for ASA I patients, 34.4 hours for ASA II patients, 42.8 hours for ASA III patients, and 61 hours for ASA IV patients (P = .005). The mean hospital stay was 11.5 days (6.3-15.2) for ASA I patients, 17.6 days (4.2-98.8) for ASA II patients, 22.9 days (4.1-120.3) for ASA III patients, and 29 days (2.4-86.0) for ASA IV patients (P = .026); 85% of the patients who died within 30 days of admission were of ASA III-IV. CONCLUSION: Our study shows that patients with higher ASA score have delay in surgery, longer hospital stay, and increase in 30-day mortality. We conclude that ASA grade is a simple and effective tool to predict the above-mentioned outcomes in these patients. PMID- 26246943 TI - Redefining the Economics of Geriatric Orthopedics. AB - INTRODUCTION: The heath care system in the United States is in the midst of a transition, in large part to help accommodate an older and more medically complex population. Central to the current evolution is the reassessment of value based on the cost utility of a particular procedure compared to alternatives. The existing contribution of geriatric orthopedics to the societal burden of disease is substantial, and literature focusing on the economic value of treating elderly populations with musculoskeletal injuries is growing. MATERIALS AND METHODS: A literature review of peer-reviewed publications and abstracts related to the cost effectiveness of treating geriatric patients with orthopedic injuries was carried out. RESULTS: In our review, we demonstrate that while cost-utility studies generally demonstrate net society savings for most orthopedic procedures, geriatric populations often contribute to negative net society savings due to decreased working years and lower salaries while in the workforce. However, the incremental cost-effective ratio for operative intervention has been shown to be below the financial willingness to treat threshold for common procedures including joint replacement surgery of the knee (ICER US$8551), hip (ICER US$17 115), and shoulder (CE US$957) as well as for spinal procedures and repair of torn rotator cuffs (ICER US$12 024). We also discuss the current trends directed toward improving institutional value and highlight important complementary next steps to help overcome the growing demands of an older, more active society. CONCLUSION: The geriatric population places a significant burden on the health care system. However, studies have shown that treating this demographic for orthopedic-related injuries is cost effective and profitable for providers under certain scenarios. PMID- 26246944 TI - Osteoporotic Hip and Spine Fractures: A Current Review. AB - Hip and spine fractures represent just a portion of the burden of osteoporosis; however, these fractures require treatment and often represent a major change in lifestyle for the patient and their family. The orthopedic surgeon plays a crucial role, not only in the treatment of these injuries but also providing guidance in prevention of future osteoporotic fractures. This review provides a brief epidemiology of the fractures, details the surgical techniques, and outlines the current treatment guidelines for orthopedic surgeons. PMID- 26246945 TI - A Comparison of Complications of Total Wrist Fusion and Silastic Arthroplasty. PMID- 26246946 TI - Bundled Payments for Elective Primary Total Knee Arthroplasty: An Analysis of Medicare Administrative Data. AB - Bundled payments have been proposed as a mechanism for restraining health care spending for total knee arthroplasty (TKA), but empirical data are limited. We used Medicare data to examine variation in payments for TKA during a window extending 30 days before to 90 days after TKA for 167 186 patients who underwent elective primary TKA in 2009. Mean Medicare payment was US$23 656. We found that 2.5% of patients incurred payments of >US$50 000 (0.2% >US$100 000). Payments were lower for men and for non-Hispanic whites but higher for patients with greater comorbidity. Episode-of-care payment for primary TKA varies substantially depending upon patient demographics and comorbidity. To the extent that similar patients tend to be clustered within hospitals, bundled payments could inadvertently cause financial harm to certain health systems while rewarding others. PMID- 26246947 TI - Fragility Hip Fractures in Elderly Patients in Bhubaneswar, India (2012-2014): A Prospective Multicenter Study of 1031 Elderly Patients. AB - Elderly patients with hip fracture constitute Single Largest Group of Emergency Orthopaedics Admissions. In 2050, 6.26 million hip fractures worldwide, approximately 50%, will occur in Asia. Only small number of reports on incidence of hip fractures in the Asian population exist. India lacks data registry for fragility hip fractures, therefore, the magnitude and standard of patient care are not known. A prospective multicenter study was conducted from January 2012 to April 2014 to describe population-based longitudinal trends, namely, age-specific incidence, fracture type, timing of presentation, kilometers traveled, timing of surgery, hospital stay, man hours lost, pressure ulcers, weight bearing, 30-day return, 3-month mortality, and so on, of fragility hip fractures. A total of 1031 patients were included with 59.7% females and 40.3% of male patients, with a female-male ratio of 1.5:1. Commonest mode: Falls 45%. 56.4% IT fractures. 66.2%patients operated, Operative/Conservative Ratio of 2.8:1. Patients travel a mean distance of 86.4 kilometers for quality treatment. Of the patients, 85.9 % presented late due to ignorance and misguiding quack practice. Incidence of delayed surgery was 69.3%. Persistent electrolytes imbalance and hyperglycemia normalized in 81.2% by second or third postoperative day. The man hours lost was 157.85 hours/person. Medical complications was more (90%) in patients who had delays in surgeries and presentation. Mortality rate was 6.2 %. Patients travel long for quality treatment, most of them are misguided, present late with significant complications and sufferings, and their pockets half drained depriving them off best treatment. Early presentation and operation have better prognosis and rehabilitation, facilitates early return to work, and independence. Increased pressure sores, infections, hospital stay, treatment cost, depression, and mortality are directly related to delays in surgeries and presentation. Estimated losses according to lost man hours may go up to 10 million dollars. PMID- 26246948 TI - Assessing Bone Mineral Density Following Acute Hip Fractures: The Role of Computed Tomography Attenuation. AB - OBJECTIVES: In older patients, bone mineral density (BMD) diminishes with age, increasing susceptibility to femoral neck fractures. Evidence has emerged that patients who should have dual x-ray absorptiometry scans to evaluate their bone health are not doing so. Because computed tomography (CT) attenuation has now been correlated with BMD thresholds relating to osteoporosis, virtually any existing CT scan that includes the L1 vertebra can be used to assess BMD. This study evaluates the utility of CT attenuation in characterizing BMD in patients after femoral neck fractures. METHODS: The electronic medical records of adults who presented to a level I trauma center with hip fractures were evaluated for eligibility. Those with a CT scan of the abdomen or other CT scan with a complete view of the L1 vertebra were included. To measure attenuation, a region of interest was selected to include the body of the L1 vertebra in the axial plane and exclude the cortices and posterior venous complex. RESULTS: Of the 589 patients reviewed, 217 met inclusion criteria; 112 were aged 18 to 64, while 105 were >=65. Eight (7.1%) patients in the younger cohort had a mean CT attenuation below the 110-HU threshold set for 90% specificity, whereas 31 (29.5%) patients in the older cohort had a mean CT attenuation below this threshold. Using the 160 HU threshold set for 90% sensitivity, 39 (34.8%) patients of the younger cohort and 74 (70%) patients of the older cohort were osteoporotic; all differences in CT attenuation by age were strongly significant (P < .0001). CONCLUSIONS: A significantly larger proportion of older patients with hip fractures had osteoporosis, helping validate the utility of CT attenuation in this context. In addition, a large proportion of these patients already had these images available, thus potentially helping limit cost and unnecessary medical investigations. PMID- 26246949 TI - Comparing Survival Following Hip Fracture Repair in VHA and Non-VHA Facilities. AB - INTRODUCTION: Although postsurgical outcomes are similar between Veterans Health Administration (VHA) and non-VHA hospitals for many procedures, no studies have compared 30-day and 1-year survival following hip fracture repair. Therefore, this study compared survival of veterans aged 65 years and older treated in VHA hospitals with a propensity-matched cohort of Medicare beneficiaries in non-VHA hospitals. MATERIALS AND METHODS: Retrospective cohort study of 1894 hip fracture repair patients in VHA or non-VHA hospitals between 2003 and 2005. Current Procedural Terminology codes identified 3542 male patients aged >65 years who had hip fracture repair between 2003 and 2005 in the Veterans Affairs' National Surgical Quality Improvement Program database. The Medicare comparison sample was drawn from 2003 to 2005 Medicare Part A inpatient hospital claims files. To create comparable VHA and Medicare cohorts, patients were propensity score matched on age, admission source (community vs. nursing home), repair type, comorbidity index, race, year, and region. Thirty-day and 1-year survival after surgery were compared between cohorts after further adjustment for selected comorbidities, year of surgery, and pre- and postsurgical length of hospital stay using logistic regression. RESULTS: Odds of survival were significantly better in the Medicare than the VHA cohort at 30 days (1.68, 95% CI 1.15-2.44) and 1 year (1.35, 95% CI 1.08-1.69). CONCLUSION: Medicare beneficiaries with hip fracture repair in non-VHA hospitals had better survival than veterans in VHA hospitals. Whether this is driven by unobserved patient characteristics or systematic care differences is unknown. PMID- 26246950 TI - Geriatric Patients With Fractures Below the Hip are Medically Similar to Geriatric Patients With Hip Fracture. AB - The objective of this study was to compare a cohort of geriatric patients with operatively managed isolated fractures below the hip to a cohort of geriatric patients with operatively managed isolated hip fractures. All patients greater than 59 years of age admitted to our institution for surgical care of an isolated lower extremity fracture during a 3-year period were included. Patients were divided into 2 cohorts: BTH (fracture below the subtrochanteric region of the femur) and HIP (proximal femoral fracture at subtrochanteric region or proximal). We identified 141 patients included in cohort BTH and 205 patients included in cohort HIP. HIP patients were older (P < .01) and less obese (P < .01) but were otherwise very similar. An extensive comorbidity review revealed that the 2 cohorts were similar, with the exception of an increased incidence of dementia (P = .012) or glaucoma (P = .04) in HIP patients and of peripheral neuropathy (P = .014) in BTH patients. HIP patients were more likely to be under active antiosteoporotic medication management and were more likely to be receiving pharmacological anticoagulation at the time of admission. HIP patients and BTH patients were similar with regard to necessity of assistance with ambulation preinjury, but HIP patients were less likely to reside independently at home than were BTH patients (P < .001). HIP patients were also less likely to be discharged directly home from the hospital (P < .001). Geriatric patients with fractures below the hip are medically similar to geriatric patients with hip fracture. Medical comanagement protocols have been extensively published that improve care of geriatric patients with hip fracture; consideration should be given to similar protocol-driven medical comanagement programs for geriatric patients with fractures below the hip. PMID- 26246951 TI - Orthopedic Trauma and Aging: It Isn't Just About Mortality. AB - The elderly (age 70+) patient with orthopedic trauma is a rapidly growing subset of patients in the United States. Due to increased medical comorbidities and decreased physiological reserve, morbidity and mortality after trauma may significantly differ from those patients younger than 70 years old. A retrospective review was performed to investigate the effect of age on orthopedic trauma. A total of 870 records of patients with orthopedic trauma from 2006 to 2009 at our Level One trauma center were reviewed. A database was created to include demographics, type and number of comorbid conditions at presentation, injuries, intensive care unit (ICU) and hospital length of stay, and description of the fracture. Patients aged 70 years and older had an increased number of comorbidities per person (3.3214-P < .0001). Length of stay in patients aged 70 years and older was not significantly greater than that of the younger patients. They spent an average of 14.76 days in the hospital compared to 13.42 days for the combined younger patients (P = .45), but they spent significantly (P < .0001) more of their stay in the ICU (52.74% vs 34.9% for the younger cohorts). The number of fractures per patient was lower (1.66) in the 70 and older age-group when compared to younger populations (P < .0001). The 70 and older group was more likely to have their injury due to a fall and less likely to have solid organ injuries. As the number of elderly patients increase, continued research in the management of elderly patients with trauma can lead to protocols and practice guidelines to improve outcomes. PMID- 26246952 TI - Combined Type II Odontoid Fracture With Axis Anterior Arch Fracture: A Case Report in an Elderly Patient. AB - Associated fractures of the atlas and axis are frequent, particularly in the elderly patients following a simple low-energy fall. This injury can be easily misdiagnosed on initial plain radiographs, and therefore computed tomography scan is a useful adjunct in patients with a degenerative spine. There is still no consensus as to the optimal treatment of combined axis-atlas fractures, and the majority of authors propose a therapeutic strategy dependent on the odontoid fracture pattern. We describe a combined atlas and axis fracture in a 92-year-old patient who was managed with nonoperative treatment in a rigid collar. The association of C1 anterior arch with a C2 type II odontoid fracture is a rare combination, which to our knowledge has never been reported following nonoperative treatment. There was a good functional outcome at 1-year follow-up with the fracture progressing to a fibrous nonunion of the odontoid process. PMID- 26246953 TI - Early Results of a Geriatric Hip Fracture Program in India for Femoral Neck Fracture. AB - Geriatric hip fractures are a challenging clinical problem throughout the world. Hip fracture services have been shown to shorten time to surgery, decrease the cost of admissions, and improve the outcomes. We instituted a geriatric hip fracture program for comanagement of these injuries by orthopedic and internal medicine teams at our hospital in India. From January 2010 till December 2011, 119 patients with a femoral neck fracture were treated with cemented modular hemiarthroplasty under this program using a cost-effective Indian implant. The cohort included 63 males and 56 females with a mean age of 70.7 years (range 55 98 years). Hypertension (n = 42) and diabetes mellitus (n = 29) were the most common comorbidities. The follow-up period ranged from 12 to 37 months with an average of 24 months. The surgery was performed within 24 hours of admission in 60.5% (n = 72) patients. The use of antiplatelet drugs was the most common reason for delay of surgery. The mean length of hospital stay was 10.4 days (range 3-24 days) with 77% (n = 92) of patients discharged within 1 week of admission. On follow-up, good to excellent Harris hip scores were seen in 88% of patients with 76% of patients returning to the preinjury ambulatory status. The mortality rate was 6% at 6 months follow-up and 10.9% at 2 years. Our study shows that a hip fracture program can be instituted in India. The program helped us in achieving the goal of early surgery, mobilization, and discharge from hospital with decreased mortality. PMID- 26246954 TI - Utility of Arthroscopic Surgery for Osteoarthritis of the Knee. AB - Currently, there is no consensus as to which patients would benefit most from arthroscopic surgery of the knee. Recently published randomized trials have shown limited efficacy for arthroscopic debridement and partial meniscectomy in patients with knee osteoarthritis. However, these clinical trials and others are limited by methodological problems. Indeed, many surgeons believe that arthroscopic surgery is indicated in a select group of patients, namely those with mild osteoarthritis and associated meniscal injury. More level I evidence will be required to better define the role of arthroscopic surgery in patients with osteoarthritis of the knee. PMID- 26246956 TI - Foreword. PMID- 26246958 TI - Metastatic Melanoma Induced Metabolic Changes in C57BL/6J Mouse Stomach Measured by 1H NMR Spectroscopy. AB - Melanoma is a malignant tumor of melanocytes with high capability of invasion and rapid metastasis to other organs. Malignant melanoma is the most common metastatic malignancy found in Gastrointestinal Tract (GI). In this work, the 1H NMR-based metabolomics approach is used to investigate the metabolite profile differences of stomach tissue extracts of metastatic B16-F10 melanoma and control groups in C57BL/6J mouse and to search for specific metabolite biomarker candidates. Principal Component Analysis (PCA), an unsupervised multivariate data analysis method, is used to detect possible outliers, while Orthogonal Projection to Latent Structure (OPLS), a supervised multivariate data analysis method, is employed to evaluate important metabolites responsible for discriminating the control and the melanoma groups. Both PCA and OPLS results reveal that the melanoma group can be well separated from its control group. Among the 50 identified metabolites, it is found that the concentrations of 19 metabolites are significantly changed with the levels of O-phosphocholine and hypoxanthine down regulated while the levels of isoleucine, leucine, valine, isobutyrate, threonine, cadaverine, alanine, glutamate, glutamine, methionine, citrate, asparagine, tryptophan, glycine, serine, uracil, and formate up-regulated in the melanoma group. These significantly changed metabolites are associated with multiple biological pathways and may be potential biomarkers for metastatic melanoma in stomach. PMID- 26246959 TI - Proteomic Profiling of Early Chronic Pulmonary Hypertension: Evidence for Both Adaptive and Maladaptive Pathology. AB - BACKGROUND: The molecular mechanisms governing right atrial (RA) and ventricular (RV) hypertrophy and failure in chronic pulmonary hypertension (CPH) remain unclear. The purpose of this investigation was to characterize RA and RV protein changes in CPH and determine their adaptive versus maladaptive role on hypertrophic development. METHODS: Nine dogs underwent sternotomy and RA injection with 3 mg/kg dehydromonocrotaline (DMCT) to induce CPH (n=5) or sternotomy without DMCT (n=4). At 8-10 weeks, RA and RV proteomic analyses were completed after trypsinization of cut 2-D gel electrophoresis spots and peptide sequencing using mass spectrometry. RESULTS: In the RV, 13 protein spots were significantly altered with DMCT compared to Sham. Downregulated RV proteins included contractile elements: troponin T and C (-1.6 fold change), myosin regulatory light chain 2 (-1.9), cellular energetics modifier: fatty-acid binding protein (-1.5), and (3) ROS scavenger: superoxide dismutase 1 (-1.7). Conversely, beta-myosin heavy chain was upregulated (+1.7). In the RA, 22 proteins spots were altered including the following downregulated proteins contractile elements: tropomyosin 1 alpha chain (-1.9), cellular energetic proteins: ATP synthase ( 1.5), fatty-acid binding protein (-2.5), and (3) polyubiquitin (-3.5). Crystallin alpha B (hypertrophy inhibitor) was upregulated in both the RV (+2.2) and RA (+2.6). CONCLUSIONS: In early stage hypertrophy there is adaptive upregulation of major RA and RV contractile substituents and attenuation of the hypertrophic response. However, there are multiple indices of maladaptive pathology including considerable cellular stress associated with aberrancy of actin machinery activity, decreased efficiency of energy utilization, and potentially decreased protein quality control. PMID- 26246960 TI - Beyond the Glands: An in-Depth Perspective of Neurological Manifestations in Sjogren's Syndrome. AB - Primary Sjogren's Syndrome (pSjS) is an autoimmune disease characterized by sicca (xerophthalmia or xerostomia) symptoms, anti-SS-A (Ro) or anti-SS-B (La) autoantibodies, and lymphocytic infiltrates in the exocrine glands. Disease incidence is estimated to be 0.1-3% of the general population with 0.4-3.1 million individuals in the US with women being nine times more likely to be afflicted with SjS than men. The frequency continues to rise accompanied with the multi-factorial etiology making it a challenging disease to manage and treat. Treatment of this disease remains problematic due to the lack of therapeutic treatments relying on replacement therapies such as artificial saliva and eye lubricants or immunosuppressive agents. To further complicate the management of the disease, there are number of multi-systemic manifestations specifically peripheral neuropathy associated with later stage of disease onset. Increasingly, there is mounting evidence that suggests the involvement of central nervous system. It remains to be determined the underlying cause and effect of the dysregulated immune response and the neuropathy associated with SjS. In this review, we provided an in-depth look at key neurological dysfunctions documented to occur in pSjS. Specifically, we discussed the prevalence, symptomology, and current treatments. PMID- 26246961 TI - Emerging Roles of Herpesvirus microRNAs During In Vivo Infection and Pathogenesis. AB - Herpesviridae constitutes a large family of double-stranded DNA viruses that are associated with a wide range of diseases, including herpetic lesions, birth defects, and cancer. Herpesviruses establish lifelong latent infections in part because they are exceptionally adept at modulating the virus/host interface. New insights into the numerous roles of microRNAs (miRNAs) in cell biology, along with the recent appreciation that nearly every host transcript is targeted by at least one miRNA, has fundamentally changed our conceptualization of the virus/host relationship. The identification of miRNAs expressed from nearly all human herpesvirus genomes has led to the speculation that these short non-coding transcripts play essential roles in herpesvirus biology. Because the activity of miRNAs depends upon the transcriptome of the cell in which they are expressed, in vivo systems will be essential for defining the true biological relevance of herpesvirus miRNAs. This review will specifically focus on experimental systems which have investigated the functional role of herpesvirus-encoded miRNAs in viral biology and pathogenesis in vivo. PMID- 26246962 TI - Mouse Models as Predictors of Human Responses: Evolutionary Medicine. AB - Mice offer a number of advantages and are extensively used to model human diseases and drug responses. Selective breeding and genetic manipulation of mice have made many different genotypes and phenotypes available for research. However, in many cases, mouse models have failed to be predictive. Important sources of the prediction problem have been the failure to consider the evolutionary basis for species differences, especially in drug metabolism, and disease definitions that do not reflect the complexity of gene expression underlying disease phenotypes. Incorporating evolutionary insights into mouse models allow for unique opportunities to characterize the effects of diet, different gene expression profiles, and microbiomics underlying human drug responses and disease phenotypes. PMID- 26246957 TI - A Guide to Improving the Care of Patients with Fragility Fractures, Edition 2. AB - Over the past 4 decades, much has been learned about the pathophysiology and treatment of osteoporosis, the prevention of fragility fractures, and the perioperative management of patients who have these debilitating injuries. However, the volume of published literature on this topic is staggering and far too voluminous for any clinician to review and synthesize by him or herself. This manuscript thoroughly summarizes the latest research on fragility fractures and provides the reader with valuable strategies to optimize the prevention and management of these devastating injuries. The information contained in this article will prove invaluable to any health care provider or health system administrator who is involved in the prevention and management of fragility hip fractures. As providers begin to gain a better understanding of the principles espoused in this article, it is our hope that they will be able to use this information to optimize the care they provide for elderly patients who are at risk of or who have osteoporotic fractures. PMID- 26246963 TI - Klebsiella pneumoniae subsp. pneumoniae-bacteriophage combination from the caecal effluent of a healthy woman. AB - A sample of caecal effluent was obtained from a female patient who had undergone a routine colonoscopic examination. Bacteria were isolated anaerobically from the sample, and screened against the remaining filtered caecal effluent in an attempt to isolate bacteriophages (phages). A lytic phage, named KLPN1, was isolated on a strain identified as Klebsiella pneumoniae subsp. pneumoniae (capsular type K2, rmpA (+)). This Siphoviridae phage presents a rosette-like tail tip and exhibits depolymerase activity, as demonstrated by the formation of plaque-surrounding haloes that increased in size over the course of incubation. When screened against a panel of clinical isolates of K. pneumoniae subsp. pneumoniae, phage KLPN1 was shown to infect and lyse capsular type K2 strains, though it did not exhibit depolymerase activity on such hosts. The genome of KLPN1 was determined to be 49,037 bp (50.53 %GC) in length, encompassing 73 predicted ORFs, of which 23 represented genes associated with structure, host recognition, packaging, DNA replication and cell lysis. On the basis of sequence analyses, phages KLPN1 (GenBank: KR262148) and 1513 (a member of the family Siphoviridae, GenBank: KP658157) were found to be two new members of the genus "Kp36likevirus." PMID- 26246964 TI - Preliminary needs assessment of mobile technology use for healthcare among homeless veterans. AB - Background. Homeless veterans have complex healthcare needs, but experience many barriers to treatment engagement. While information technologies (IT), especially mobile phones, are used to engage patients in care, little is known about homeless veterans' IT use. This study examines homeless veterans' access to and use of IT, attitudes toward health-related IT use, and barriers to IT in the context of homelessness. Methods. Qualitative interviews were conducted with 30 homeless veterans in different housing programs in Boston, MA, ranging from emergency shelters to supportive transitional housing that allow stays of up to 2 years. Interviews were conducted in person, audio recorded and then transcribed. Three researchers coded transcripts. Inductive thematic analysis was used. Results. Most participants (90%) had a mobile phone and were receptive to IT use for health-related communications. A common difficulty communicating with providers was the lack of a stable mailing address. Some participants were using mobile phones to stay in touch with providers. Participants felt mobile-phone calls or text messages could be used to remind patients of appointments, prescription refills, medication taking, and returning for laboratory results. Mobile phone text messaging was seen as convenient, and helped participants stay organized because necessary information was saved in text messages. Some reported concerns about the costs associated with mobile phone use (calls and texting), the potential to be annoyed by too many text messages, and not knowing how to use text messaging. Conclusion. Homeless veterans use IT and welcome its use for health-related purposes. Technology-assisted outreach among this population may lead to improved engagement in care. PMID- 26246965 TI - Using affective knowledge to generate and validate a set of emotion-related, action words. AB - Emotion concepts are built through situated experience. Abstract word meaning is grounded in this affective knowledge, giving words the potential to evoke emotional feelings and reactions (e.g., Vigliocco et al., 2009). In the present work we explore whether words differ in the extent to which they evoke 'specific' emotional knowledge. Using a categorical approach, in which an affective 'context' is created, it is possible to assess whether words proportionally activate knowledge relevant to different emotional states (e.g., 'sadness', 'anger', Stevenson, Mikels & James, 2007a). We argue that this method may be particularly effective when assessing the emotional meaning of action words (e.g., Schacht & Sommer, 2009). In study 1 we use a constrained feature generation task to derive a set of action words that participants associated with six, basic emotional states (see full list in Appendix S1). Generation frequencies were taken to indicate the likelihood that the word would evoke emotional knowledge relevant to the state to which it had been paired. In study 2 a rating task was used to assess the strength of association between the six most frequently generated, or 'typical', action words and corresponding emotion labels. Participants were presented with a series of sentences, in which action words (typical and atypical) and labels were paired e.g., "If you are feeling 'sad' how likely would you be to act in the following way?" ... 'cry.' Findings suggest that typical associations were robust. Participants always gave higher ratings to typical vs. atypical action word and label pairings, even when (a) rating direction was manipulated (the label or verb appeared first in the sentence), and (b) the typical behaviours were to be performed by the rater themselves, or others. Our findings suggest that emotion-related action words vary in the extent to which they evoke knowledge relevant for different emotional states. When measuring affective grounding, it may then be appropriate to use categorical ratings in conjunction with unimodal measures, which assess the 'magnitude' to which words evoke feelings (e.g., Newcombe et al., 2012). Towards this aim we provide a set of emotion-related action words, accompanied by generation frequency and rating data, which show how strongly each word evokes knowledge relevant to basic emotional states. PMID- 26246966 TI - Diagnostic inertia in dyslipidaemia: results of a preventative programme in Spain. AB - Others have analysed the relationship between inadequate behaviour by healthcare professionals in the diagnosis of dyslipidaemia (diagnostic inertia) and the history of cardiovascular risk factors. However, since no study has assessed cardiovascular risk scores as associated factors, we carried out a study to quantify diagnostic inertia in dyslipidaemia and to determine if cardiovascular risk scores are associated with this inertia. In the Valencian Community (Spain), a preventive programme (cardiovascular, gynaecologic and vaccination) was started in 2003 inviting persons aged >=40 years to undergo a health check-up at their health centre. This cross-sectional study examined persons with no known dyslipidaemia seen during the first six months of the programme (n = 16, 905) but whose total cholesterol (TC) was >=5.17 mmol/L. Diagnostic inertia was defined as lack of follow-up to confirm/discard the dyslipidaemia diagnosis. Other variables included in the analysis were gender, history of cardiovascular risk factors/cardiovascular disease, counselling (diet/exercise), body mass index (BMI), age, blood pressure, fasting blood glucose and lipids. TC was grouped as >=/<6.20 mmol/L. In patients without cardiovascular disease and <75/<=65 years (n = 15, 778/13, 597), the REGICOR (REgistre GIroni del COr)/SCORE (Systematic COronary Risk Evaluation) cardiovascular risk functions were used to classify risk (high/low). Inertia was quantified and the adjusted odds ratios calculated from multivariate models. In the overall sample, the rate of diagnostic inertia was 52% (95% CI [51.2-52.7]); associated factors were TC >= 6.20 mmol/L, high or "not measured" BMI, hypertension, smoking and higher values of fasting blood glucose, systolic blood pressure and TC. In the REGICOR sample, the rate of diagnostic inertia was 51.9% (95% CI [51.1-52.7]); associated factors were REGICOR high and high or "not measured" BMI. In the SCORE sample the rate of diagnostic inertia was 51.7% (95% CI [50.9-52.5]); associated factors were SCORE high and high or "not measured" BMI. Diagnostic inertia existed in over half the patients and was associated with a greater cardiovascular risk. PMID- 26246967 TI - Suffering and mental health among older people living in nursing homes-a mixed methods study. AB - Background. Knowledge about mixed-methods perspectives that examine anxiety, depression, social support, mental health and the phenomenon of suffering among cognitively intact NH residents is scarce. We aimed to explore suffering and mental health among cognitively intact NH residents. Methods. This study used a mixed-methods design to explore different aspects of the same phenomena of interest to gain a more comprehensive understanding. The qualitative core component comprised a qualitative interview from 18 nursing home residents (>=65 years) about experiences related to pain, grief and loss. The supplementary component comprised interview from the same respondents using the SF-36 Health Survey subscales, the Hospital Anxiety and Depression Scale and the Social Provisions Scale. Results. The individual descriptions reveal suffering caused by painful experiences during life. The quantitative results indicated that symptoms of anxiety and depression were related to mental health and symptoms of anxiety were related to bodily pain and emotional role limitations. Attachment and social integration were associated with vitality and social functioning. Discussion. To improve the situation, more attention should be paid to the residents' suffering related to anxiety, depression and psychosocial relations. PMID- 26246968 TI - Frailty as a predictor of short-term adverse outcomes. AB - The objectives of this study were to compare how different frailty measures (Frailty Phenotype/FP, Groningen Frailty Indicator/GFI and Tilburg Frailty Indicator/TFI) predict short-term adverse outcomes. Secondarily, adopting a multidimensional approach to frailty (integral conceptual model-TFI), this study aims to compare how physical, psychological and social frailty predict the outcomes. A longitudinal study was carried out with 95 community-dwelling elderly. Participants were assessed at baseline for frailty, determinants of frailty, and adverse outcomes (healthcare utilization, quality of life, disability in basic and instrumental activities of daily living/ADL and IADL). Ten months later the outcomes were assessed again. Frailty was associated with specific healthcare utilization indicators: the FP with a greater utilization of informal care; GFI with an increased contact with healthcare professionals; and TFI with a higher amount of contacts with a general practitioner. After controlling for the effect of life-course determinants, comorbidity and adverse outcome at baseline, GFI predicted IADL disability and TFI predicted quality of life. The effect of the FP on the outcomes was not significant, when compared with the other measures. However, when comparing TFI's domains, the physical domain was the most significant predictor of the outcomes, even explaining part of the variance of ADL disability. Frailty at baseline was associated with adverse outcomes at follow-up. However, the relationship of each frailty measure (FP, GFI and TFI) with the outcomes was different. In spite of the role of psychological frailty, TFI's physical domain was the determinant factor for predicting disability and most of the quality of life. PMID- 26246969 TI - Sexual dimorphism and allometry in the sphecophilous rove beetle Triacrus dilatus. AB - The rove beetle Triacrus dilatus is found in the Atlantic forest of South America and lives in the refuse piles of the paper wasp Agelaia vicina. Adults of T. dilatus are among the largest rove beetles, frequently measuring over 3 cm, and exhibit remarkable variation in body size. To examine sexual dimorphism and allometric relationships we measured the length of the left mandible, ocular distance and elytra. We were interested in determining if there are quantifiable differences between sexes, if there are major and minor forms within each sex and if males exhibit mandibular allometry. For all variables, a t-test was run to determine if there were significant differences between the sexes. Linear regressions were run to examine if there were significant relationships between the different measurements. A heterogeneity of slopes test was used to determine if there were significant differences between males and females. Our results indicated that males had significantly larger mandibles and ocular distances than females, but the overall body length was not significantly different between the sexes. Unlike most insects, both sexes showed positive linear allometric relationships for mandible length and head size (as measured by the ocular distance). We found no evidence of major and minor forms in either sex. PMID- 26246970 TI - Mechanistic pathways of mercury removal from the organomercurial lyase active site. AB - Bacterial populations present in Hg-rich environments have evolved biological mechanisms to detoxify methylmercury and other organometallic mercury compounds. The most common resistance mechanism relies on the H(+)-assisted cleavage of the Hg-C bond of methylmercury by the organomercurial lyase MerB. Although the initial reaction steps which lead to the loss of methane from methylmercury have already been studied experimentally and computationally, the reaction steps leading to the removal of Hg(2+) from MerB and regeneration of the active site for a new round of catalysis have not yet been elucidated. In this paper, we have studied the final steps of the reaction catalyzed by MerB through quantum chemical computations at the combined MP2/CBS//B3PW91/6-31G(d) level of theory. While conceptually simple, these reaction steps occur in a complex potential energy surface where several distinct pathways are accessible and may operate concurrently. The only pathway which clearly emerges as forbidden in our analysis is the one arising from the sequential addition of two thiolates to the metal atom, due to the accumulation of negative charges in the active site. The addition of two thiols, in contrast, leads to two feasible mechanistic possibilities. The most straightforward pathway proceeds through proton transfer from the attacking thiol to Cys159 , leading to its removal from the mercury coordination sphere, followed by a slower attack of a second thiol, which removes Cys96. The other pathway involves Asp99 in an accessory role similar to the one observed earlier for the initial stages of the reaction and affords a lower activation enthalpy, around 14 kcal mol(-1), determined solely by the cysteine removal step rather than by the thiol ligation step. Addition of one thiolate to the intermediates arising from either thiol attack occurs without a barrier and produces an intermediate bound to one active site cysteine and from which Hg(SCH3)2 may be removed only after protonation by solvent-provided H3O(+). Thiolate addition to the active site (prior to any attack by thiols) leads to pathways where the removal of the first cysteine becomes the rate-determining step, irrespective of whether Cys159 or Cys96 leaves first. Comparisons with the recently computed mechanism of the related enzyme MerA further underline the important role of Asp99 in the energetics of the MerB reaction. Kinetic simulation of the mechanism derived from our computations strongly suggests that in vivo the thiolate-only pathway is operative, and the Asp-assisted pathway (as well as the conversion of intermediates of the thiolate pathway into intermediates of the Cys-assisted pathway) is prevented by steric factors absent from our model and related to the precise geometry of the organomercurial binding pocket. PMID- 26246971 TI - Interpreting pathologies in extant and extinct archosaurs using micro-CT. AB - Palaeopathology offers unique insight to the healing strategies of extinct organisms, permitting questions concerning bone physiology to be answered in greater depth. Unfortunately, most palaeopathological studies are confined to external morphological interpretations due to the destructive nature of traditional methods of study. This limits the degree of reliable diagnosis and interpretation possible. X-ray MicroTomography (micro-CT, XMT) provides a non destructive means of analysing the internal three-dimensional structure of pathologies in both extant and extinct individuals, at higher resolutions than possible with medical scanners. In this study, we present external and internal descriptions of pathologies in extant and extinct archosaurs using XMT. This work demonstrates that the combination of external/internal diagnosis that X-ray microtomography facilitates is crucial when differentiating between pathological conditions. Furthermore, we show that the use of comparative species, both through direct analysis and from the literature, provides key information for diagnosing between vertebrate groups in the typical pathological conditions and physiological processes. Micro-CT imaging, combined with comparative observations of extant species, provides more detailed and reliable interpretation of palaeopathologies. Micro-CT is an increasingly accessible tool, which will provide key insights for correctly interpreting vertebrate pathologies in the future. PMID- 26246972 TI - Distinct mechanical behavior of HEK293 cells in adherent and suspended states. AB - The mechanical features of individual animal cells have been regarded as indicators of cell type and state. Previously, we investigated the surface mechanics of cancer and normal stromal cells in adherent and suspended states using atomic force microscopy. Cancer cells possessed specific mechanical and actin cytoskeleton features that were distinct from normal stromal cells in adherent and suspended states. In this paper, we report the unique mechanical and actin cytoskeletal features of human embryonic kidney HEK293 cells. Unlike normal stromal and cancer cells, the surface stiffness of adherent HEK293 cells was very low, but increased after cell detachment from the culture surface. Induced actin filament depolymerization revealed that the actin cytoskeleton was the underlying source of the stiffness in suspended HEK293 cells. The exclusive mechanical response of HEK293 cells to perturbation of the actin cytoskeleton resembled that of adherent cancer cells and suspended normal stromal cells. Thus, with respect to their special cell-surface mechanical features, HEK293 cells could be categorized into a new class distinct from normal stromal and cancer cells. PMID- 26246973 TI - Spectrum of tablet computer use by medical students and residents at an academic medical center. AB - Introduction. The value of tablet computer use in medical education is an area of considerable interest, with preliminary investigations showing that the majority of medical trainees feel that tablet computers added value to the curriculum. This study investigated potential differences in tablet computer use between medical students and resident physicians. Materials & Methods. Data collection for this survey was accomplished with an anonymous online questionnaire shared with the medical students and residents at Southern Illinois University School of Medicine (SIU-SOM) in July and August of 2012. Results. There were 76 medical student responses (26% response rate) and 66 resident/fellow responses to this survey (21% response rate). Residents/fellows were more likely to use tablet computers several times daily than medical students (32% vs. 20%, p = 0.035). The most common reported uses were for accessing medical reference applications (46%), e-Books (45%), and board study (32%). Residents were more likely than students to use a tablet computer to access an electronic medical record (41% vs. 21%, p = 0.010), review radiology images (27% vs. 12%, p = 0.019), and enter patient care orders (26% vs. 3%, p < 0.001). Discussion. This study shows a high prevalence and frequency of tablet computer use among physicians in training at this academic medical center. Most residents and students use tablet computers to access medical references, e-Books, and to study for board exams. Residents were more likely to use tablet computers to complete clinical tasks. Conclusions. Tablet computer use among medical students and resident physicians was common in this survey. All learners used tablet computers for point of care references and board study. Resident physicians were more likely to use tablet computers to access the EMR, enter patient care orders, and review radiology studies. This difference is likely due to the differing educational and professional demands placed on resident physicians. Further study is needed better understand how tablet computers and other mobile devices may assist in medical education and patient care. PMID- 26246974 TI - Spatio-temporal variability in the distribution of ground-dwelling riparian spiders and their potential role in water-to-land energy transfer along Hong Kong forest streams. AB - Terrestrial predators have been shown to aggregate along stream margins during periods when the emergence of adult aquatic insects is high. Such aggregation may be especially evident when terrestrial surroundings are relatively unproductive, and there are steep productivity gradients across riparia. In tropical forests, however, the productivity of inland terrestrial habitats may decrease the resource gradient across riparia, thus lessening any tendency of terrestrial predators to aggregate along stream margins. We elucidated the spatio-temporal variability in the distribution of ground-dwelling spiders and terrestrial arthropod prey within the riparia of two forest streams in tropical Hong Kong by sampling arthropods along transects at different distances from the streams during the wet and dry seasons. Environmental variables that may have influenced spider distributions were also measured. The vast majority of ground-dwelling predators along all transects at both sites were spiders. Of the three most abundant spiders captured along stream margins, Heteropoda venatoria (Sparassidae) and Draconarius spp. (Agelenidae) were terrestrially inclined and abundant during both seasons. Only Pardosa sumatrana (Lycosidae) showed some degree of aggregation at the stream banks, indicating a potential reliance on aquatic insect prey. Circumstantial evidence supports this notion, as P. sumatrana was virtually absent during the dry season when aquatic insect emergence was low. In general, forest-stream riparia in Hong Kong did not appear to be feeding hotspots for ground-dwelling predators. The lack of aggregation in ground-dwelling spiders in general may be attributed to the low rates of emergence of aquatic insects from the study streams compared to counterpart systems, as well as the potentially high availability of terrestrial insect prey in the surrounding forest. Heteropoda venatoria, the largest of the three spiders maintained a high biomass (up to 28 mg dry weight/m(2)) in stream riparia, exceeding the total standing stock of all other spiders by 2-80 times. The biomass and inland distribution of H. venatoria could make it a likely conduit for the stream-to-land transfer of energy. PMID- 26246975 TI - Ligature-induced peri-implant infection in crestal and subcrestal implants: a clinical and radiographic study in dogs. AB - Objective. The aim of this study was to assess the influence of implant-abutment interface (IAI) placement depths on peri-implant tissues in the presence of ligature-induced peri-implant inflammation. Materials and Methods. Two implants with screwed-in IAIs (SI) and two implants with tapped-in IAIs (TI) were inserted in one side of the mandible in six dogs eight weeks after tooth extraction. Four experimental groups were constituted: SI placed crestally, SI placed 1.5 mm subcrestally, TI placed crestally and TI placed 1.5 mm subcrestally. After 12 weeks, the healing abutments were connected. Four weeks later, cotton floss ligatures were placed around the abutments to promote plaque accumulation. Clinical and radiographic examinations were performed at 0, 6 and 12 weeks after ligature placement. The effects of the IAI placement depths on clinical and radiographic parameters were assessed. Results. The alterations of peri-implant probing depths, clinical attachment levels, distances from the IAI to the first bone-implant contact (IAI-fBIC) and depths of infrabony defect were significant larger in the subcrestal groups compared with the crestal groups during the plaque accumulation period. The alterations of clinical attachment levels, IAI fBIC, depth of the infrabony defect and horizontal bone loss were not significantly different between the SI and TI groups after ligature placement. Conclusion. Tissue destruction in subcrestal implants may be more serious than that in crestal implants in the presence of inflamed peri-implant mucosa. PMID- 26246976 TI - On the challenges of drawing conclusions from p-values just below 0.05. AB - In recent years, researchers have attempted to provide an indication of the prevalence of inflated Type 1 error rates by analyzing the distribution of p values in the published literature. De Winter & Dodou (2015) analyzed the distribution (and its change over time) of a large number of p-values automatically extracted from abstracts in the scientific literature. They concluded there is a 'surge of p-values between 0.041-0.049 in recent decades' which 'suggests (but does not prove) questionable research practices have increased over the past 25 years.' I show the changes in the ratio of fractions of p-values between 0.041-0.049 over the years are better explained by assuming the average power has decreased over time. Furthermore, I propose that their observation that p-values just below 0.05 increase more strongly than p-values above 0.05 can be explained by an increase in publication bias (or the file drawer effect) over the years (cf. Fanelli, 2012; Pautasso, 2010, which has led to a relative decrease of 'marginally significant' p-values in abstracts in the literature (instead of an increase in p-values just below 0.05). I explain why researchers analyzing large numbers of p-values need to relate their assumptions to a model of p-value distributions that takes into account the average power of the performed studies, the ratio of true positives to false positives in the literature, the effects of publication bias, and the Type 1 error rate (and possible mechanisms through which it has inflated). Finally, I discuss why publication bias and underpowered studies might be a bigger problem for science than inflated Type 1 error rates, and explain the challenges when attempting to draw conclusions about inflated Type 1 error rates from a large heterogeneous set of p-values. PMID- 26246979 TI - The Role of Aromaticity, Hybridization, Electrostatics, and Covalency in Resonance-Assisted Hydrogen Bonds of Adenine-Thymine (AT) Base Pairs and Their Mimics. AB - Invited for this issues cover are Dr. Celia Fonseca Guerra from the VU University of Amsterdam and her collaborators at the University of Girona. The cover picture shows H-bonds in the adenine-thymine Watson-Crick base pair. An essential part of these H-bonds is their covalent component arising from donor-acceptor interactions between N or O lone pairs and the N-H antibonding sigma* acceptor orbital. This charge-transfer interaction is represented by green figures walking on the pedestrian crossing, connecting the bases. This covalent component is the reason why H-bonds between DNA and/or unsaturated model bases are significantly stronger than those between analogous saturated bases. This contrasts sharply with the classical picture of predominantly electrostatic H-bonds which is not only incomplete in terms of a proper bonding mechanism, but also fails to explain the trend in stability. For more details, see the Full Paper on p. 318 ff. PMID- 26246980 TI - Graphical Abstract: ChemistryOpen 3/2015. PMID- 26246977 TI - Improvement in vision: a new goal for treatment of hereditary retinal degenerations. AB - Introduction: Inherited retinal degenerations (IRDs) have long been considered untreatable and incurable. Recently, one form of early-onset autosomal recessive IRD, Leber congenital amaurosis (LCA) caused by mutations in RPE65 (retinal pigment epithelium-specific protein 65 kDa) gene, has responded with some improvement of vision to gene augmentation therapy and oral retinoid administration. This early success now requires refinement of such therapeutics to fully realize the impact of these major scientific and clinical advances. Areas covered: Progress toward human therapy for RPE65-LCA is detailed from the understanding of molecular mechanisms to preclinical proof-of-concept research to clinical trials. Unexpected positive and complicating results in the patients receiving treatment are explained. Logical next steps to advance the clinical value of the therapeutics are suggested. Expert opinion: The first molecularly based early-phase therapies for an IRD are remarkably successful in that vision has improved and adverse events are mainly associated with surgical delivery to the subretinal space. Yet, there are features of the gene augmentation therapeutic response, such as slowed kinetics of night vision, lack of foveal cone function improvement and relentlessly progressive retinal degeneration despite therapy, that still require research attention. PMID- 26246982 TI - Spotlights on our sister journals: ChemistryOpen 3/2015. PMID- 26246983 TI - Strategic Application of Residence-Time Control in Continuous-Flow Reactors. AB - As a sustainable alternative for conventional batch-based synthetic techniques, the concept of continuous-flow processing has emerged in the synthesis of fine chemicals. Systematic tuning of the residence time, a key parameter of continuous reaction technology, can govern the outcome of a chemical reaction by determining the reaction rate and the conversion and by influencing the product selectivity. This review furnishes a brief insight into flow reactions in which high chemo- and/or stereoselectivity can be attained by strategic residence-time control and illustrates the importance of the residence time as a crucial parameter in sustainable method development. Such a fine reaction control cannot be performed in conventional batch reaction set-ups. PMID- 26246985 TI - 'Nano-impacts': An Electrochemical Technique for Nanoparticle Sizing in Optically Opaque Solutions. AB - Typical laser-dependent methods such as nanoparticle tracking analysis (NTA) and dynamic light scattering (DLS) are not able to detect nanoparticles in an optically opaque medium due to scattering or absorption of light. Here, the electrochemical technique of 'nano-impacts' was used to detect nanoparticles in solution in the presence of high levels of alumina particulates causing a milky white suspension. Using the 'nano-impacts' method, silver nanoparticles were successfully detected and sized in the model opaque medium. The results obtained compared well with those using transmission electron microscopy (TEM), an ex situ method for nanoparticle size determination. The ability to use the 'nano-impacts' method in media unmeasurable to competitor techniques confers a significant advantage on the electrochemical approach. PMID- 26246986 TI - Design and Synthesis of Mixed Oligomers with Thiophenes, Dithienothiophene S,S Dioxides, Thieno[3,4]pyrazines and 2,1,3-Benzothiadiazoles: Flipper Screening for Mechanosensitive Systems. AB - Monomers with large surface area and high quantum yield, that is fluorescent flippers, have been engineered into twisted push-pull oligomers to create membrane probes with high mechanosensitivity and long fluorescence lifetime. Here, the synthesis and characterization of thieno[3,4]pyrazines and 2,1,3 benzothiadiazoles are described in comparison with the original dithienothiophene S,S-dioxides. Dithienothiophene S,S-dioxide flippers are confirmed as the best reported so far, and poor results with single flipper probes support that two flippers are needed for the probe to really "swim", that is, for high mechanosensitivity. PMID- 26246987 TI - Uniform Functionalization of High-Quality Graphene with Platinum Nanoparticles for Electrocatalytic Water Reduction. AB - Graphene-metal composites have potential as novel catalysts due to their unique electrical properties. Here, we report the synthesis of a composite material comprised of monodispersed platinum nanoparticles on high-quality graphene obtained by using two different exfoliation techniques. The material, prepared via an easy, low-cost and reproducible procedure, was evaluated as an electrocatalyst for the hydrogen evolution reaction. The turnover frequency at zero overpotential (TOF0 in 0.1 m phosphate buffer, pH 6.8) was determined to be approximately 4600 h(-1). This remarkably high value is likely due to the optimal dispersion of the platinum nanoparticles on the graphene substrate, which enables the material to be loaded with only very small amounts of the noble metal (i.e., Pt) despite the very highly active surface. This study provides a new outlook on the design of novel materials for the development of robust and scalable water splitting devices. PMID- 26246984 TI - Recent Advances in Voltammetry. AB - Recent progress in the theory and practice of voltammetry is surveyed and evaluated. The transformation over the last decade of the level of modelling and simulation of experiments has realised major advances such that electrochemical techniques can be fully developed and applied to real chemical problems of distinct complexity. This review focuses on the topic areas of: multistep electrochemical processes, voltammetry in ionic liquids, the development and interpretation of theories of electron transfer (Butler-Volmer and Marcus-Hush), advances in voltammetric pulse techniques, stochastic random walk models of diffusion, the influence of migration under conditions of low support, voltammetry at rough and porous electrodes, and nanoparticle electrochemistry. The review of the latter field encompasses both the study of nanoparticle modified electrodes, including stripping voltammetry and the new technique of 'nano-impacts'. PMID- 26246988 TI - Ferric Phosphate Hydroxide Microstructures Affect Their Magnetic Properties. AB - Uniformly sized and shape-controlled nanoparticles are important due to their applications in catalysis, electrochemistry, ion exchange, molecular adsorption, and electronics. Several ferric phosphate hydroxide (Fe4(OH)3(PO4)3) microstructures were successfully prepared under hydrothermal conditions. Using controlled variations in the reaction conditions, such as reaction time, temperature, and amount of hexadecyltrimethylammonium bromide (CTAB), the crystals can be grown as almost perfect hyperbranched microcrystals at 180 degrees C (without CTAB) or relatively monodisperse particles at 220 degrees C (with CTAB). The large hyperbranched structure of Fe4(OH)3(PO4)3 with a size of ~19 MUm forms with the "fractal growth rule" and shows many branches. More importantly, the magnetic properties of these materials are directly correlated to their size and micro/nanostructure morphology. Interestingly, the blocking temperature (T B) shows a dependence on size and shape, and a smaller size resulted in a lower T B. These crystals are good examples that prove that physical and chemical properties of nano/microstructured materials are related to their structures, and the precise control of the morphology of such functional materials could allow for the control of their performance. PMID- 26246989 TI - Preparation and Characterization of Chitosan Thin Films on Mixed-Matrix Membranes for Complete Removal of Chromium. AB - Herein we present a new approach for the complete removal of Cr(VI) species, through reduction of Cr(VI) to Cr(III), followed by adsorption of Cr(III). Reduction of chromium from water is an important challenge, as Cr(IV) is one of the most toxic substances emitted from industrial processes. Chitosan (CS) thin films were developed on plain polysulfone (PSf) and PSf/TiO2 membrane substrates by a temperature-induced technique using polyvinyl alcohol as a binder. Structure property elucidation was carried out by X-ray diffraction, microscopy, spectroscopy, contact angle measurement, and water uptake studies. The increase in hydrophilicity followed the order: PSf < PSf/TiO2 < PSf/TiO2/CS membranes. Use of this thin-film composite membrane for chromium removal was investigated with regards to the effects of light and pH. The observations reveal 100 % reduction of Cr(VI) to Cr(III) through electrons and protons donated from OH and NH2 groups of the CS layer; the reduced Cr(III) species are adsorbed onto the CS layer via complexation to give chromium-free water. PMID- 26246990 TI - Surfactant-Free and Controlled Synthesis of Hexagonal CeVO4 Nanoplates: Photocatalytic Activity and Superhydrophobic Property. AB - Nanomaterials with both superhydrophobic surface properties as well as photocatalytic activities could have important industrial applications. Herein, we synthesized CeVO4 nanocrystals with hexagonal nanoplate structures from the reaction of decavanadate (K6V10O28?9 H2O) and CeCl3?H2O precursors via a hydrothermal method. This synthetic route has four advantages: 1) the reaction condition is relatively mild, 2) it doesn't need surfactants or templates, 3) it requires no expensive equipment, and 4) products are of higher purity. During synthesis, solution pH, and reaction temperature were found to play important roles in determining the growth process and final morphologies of the CeVO4 products. These products were characterized spectrophotometrically and via scanning and transmission electron microscopy. Furthermore, the wettability of the as-synthesized film CeVO4 nanoplates was studied by measuring water contact angle (CA). The largest CA measured was at 169.5 degrees for a glass substrate treated with 0.06 g mL(-1) CeVO4 followed by 2 % 1 H, 1 H, 2 H, 2 H perfluorodecyltriethoxysilane. Finally, the CeVO4 nanoplates exhibited excellent photocatalytic activity in degradation of rhodamine B (RhB) under UV irradiation and was stable even after repeated cycles of use. PMID- 26246991 TI - Quantum Chemical Calculations and Experimental Validation of the Photoclick Reaction for Fluorescent Labeling of the 5' cap of Eukaryotic mRNAs. AB - Bioorthogonal click reactions are powerful tools to specifically label biomolecules in living cells. Considerable progress has been made in site specific labeling of proteins and glycans in complex biological systems, but equivalent methods for mRNAs are rare. We present a chemo-enzymatic approach to label the 5' cap of eukaryotic mRNAs using a bioorthogonal photoclick reaction. Herein, the N7-methylated guanosine of the 5' cap is enzymatically equipped with an allyl group using a variant of the trimethylguanosine synthase 2 from Giardia lamblia (GlaTgs2). To elucidate whether the resulting N (2)-modified 5' cap is a suitable dipolarophile for photoclick reactions, we used Kohn-Sham density functional theory (KS-DFT) and calculated the HOMO and LUMO energies of this molecule and nitrile imines. Our in silico studies suggested that combining enzymatic allylation of the cap with subsequent labeling in a photoclick reaction was feasible. This could be experimentally validated. Our approach generates a turn-on fluorophore site-specifically at the 5' cap and therefore presents an important step towards labeling of eukaryotic mRNAs in a bioorthogonal manner. PMID- 26246992 TI - Revisiting Aromaticity and Chemical Bonding of Fluorinated Benzene Derivatives. AB - The electron delocalization of benzene (C6H6) and hexafluorobenzene (C6F6) was analyzed in terms of the induced magnetic field, nucleus-independent chemical shift (NICS), and ring current strength (RCS). The computed out-of-plane component of the induced magnetic field at a distance (r) greater than or equal to 1.0 A above the ring center correlates well (R (2)>0.99) with the RCS value. According to these criteria, fluorination has two effects on the C6 skeleton; concomitantly, the resonant effects diminish the pi electron delocalization and the inductive effects decrease the charge density at the ring center and therefore reduce the magnitude of the paratropic current generated in this region. The equilibrium between both effects decreases aromaticity in the fluorinated benzene derivatives. These results can be extrapolated to determine the aromaticity of any derivative within the series of fluorinated benzene derivatives (C6H(6-n)F n , where n=1-5). PMID- 26246993 TI - Influence of Polarity and Activation Energy in Microwave-Assisted Organic Synthesis (MAOS). AB - The aim of this work was to determine the parameters that have decisive roles in microwave-assisted reactions and to develop a model, using computational chemistry, to predict a priori the type of reactions that can be improved under microwaves. For this purpose, a computational study was carried out on a variety of reactions, which have been reported to be improved under microwave irradiation. This comprises six types of reactions. The outcomes obtained in this study indicate that the most influential parameters are activation energy, enthalpy, and the polarity of all the species that participate. In addition to this, in most cases, slower reacting systems observe a much greater improvement under microwave irradiation. Furthermore, for these reactions, the presence of a polar component in the reaction (solvent, reagent, susceptor, etc.) is necessary for strong coupling with the electromagnetic radiation. We also quantified that an activation energy of 20-30 kcal mol(-1) and a polarity (MU) between 7-20 D of the species involved in the process is required to obtain significant improvements under microwave irradiation. PMID- 26246994 TI - The Role of Aromaticity, Hybridization, Electrostatics, and Covalency in Resonance-Assisted Hydrogen Bonds of Adenine-Thymine (AT) Base Pairs and Their Mimics. AB - Hydrogen bonds play a crucial role in many biochemical processes and in supramolecular chemistry. In this study, we show quantum chemically that neither aromaticity nor other forms of pi assistance are responsible for the enhanced stability of the hydrogen bonds in adenine-thymine (AT) DNA base pairs. This follows from extensive bonding analyses of AT and smaller analogs thereof, based on dispersion-corrected density functional theory (DFT). Removing the aromatic rings of either A or T has no effect on the Watson-Crick bond strength. Only when the smaller mimics become saturated, that is, when the hydrogen-bond acceptor and donor groups go from sp (2) to sp (3), does the stability of the resulting model complexes suddenly drop. Bonding analyses based on quantitative Kohn-Sham molecular orbital theory and corresponding energy decomposition analyses (EDA) show that the stronger hydrogen bonds in the unsaturated model complexes and in AT stem from stronger electrostatic interactions as well as enhanced donor acceptor interactions in the sigma-electron system, with the covalency being responsible for shortening the hydrogen bonds in these dimers. PMID- 26246995 TI - Nickel(II) Complexes Bearing 4-Arylimino-1,2,3-trihydroacridines: Synthesis, Characterization, and Ethylene Oligomerization. AB - Nickel(II) complexes have attracted much attention as a new generation of olefin catalysts since the alpha-diiminonickel complex was discovered as a highly efficient procatalyst for ethylene polymerization. A series of novel 4-arylimino 1,2,3-trihydroacridylnickel(II) dihalide complexes was synthesized in a one-pot reaction of 2,3-dihydroacridine-4-one and different anilines with nickel(II) chloride or nickel(II) bromide 1,2-dimethoxyethane complex. The complexes were characterized by infrared spectroscopy and elemental analysis. The molecular structures of the representative complexes 4-(2,6-diisopropylphenylimino)-1,2,3 trihydroacridylnickel(II) dichloride (C3), 4-(2,4,6-trimethylphenylimino)-1,2,3 trihydroacridylnickel dichloride(II) (C4), and 4-(2,4,6-trimethylphenylimino) 1,2,3-trihydroacridylnickel(II) dibromide (C9) were confirmed by single-crystal X ray crystallography, revealing a distorted tetrahedral geometry around the nickel(II) of C3 and distorted trigonal bipyramidal geometry for C4 and C9. With the activation of trimethylaluminium (TMA), all nickel(II) complexes exhibited good activity for ethylene oligomerization, and oligomer products ranged from butene (C4) to hexadecene (C16). PMID- 26246996 TI - Design and Evaluation of Tumor-Specific Dendrimer Epigenetic Therapeutics. AB - Histone deacetylase inhibitors (HDACi) are promising therapeutics for cancer. HDACi alter the epigenetic state of tumors and provide a unique approach to treat cancer. Although studies with HDACi have shown promise in some cancers, variable efficacy and off-target effects have limited their use. To overcome some of the challenges of traditional HDACi, we sought to use a tumor-specific dendrimer scaffold to deliver HDACi directly to cancer cells. Here we report the design and evaluation of tumor-specific dendrimer-HDACi conjugates. The HDACi was conjugated to the dendrimer using an ester linkage through its hydroxamic acid group, inactivating the HDACi until it is released from the dendrimer. Using a cancer cell model, we demonstrate the functionality of the tumor-specific dendrimer HDACi conjugates. Furthermore, we demonstrate that unlike traditional HDACi, dendrimer-HDACi conjugates do not affect tumor-associated macrophages, a recently recognized mechanism through which drug resistance emerges. We anticipate that this new class of cell-specific epigenetic therapeutics will have tremendous potential in the treatment of cancer. PMID- 26246997 TI - Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents. AB - This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl) 1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs. PMID- 26246998 TI - Colorimetric Cyanide Chemosensor Based on 1',3,3',4-Tetrahydrospiro[chromene-2,2' indole]. AB - A new class of chemosensors based on the 1',3,3',4-tetrahydrospiro[chromene-2,2' indole] ring system, which detects cyanide with high specificity, is described. These chemosensors show a distinct color change when treated with cyanide in acetonitrile solution buffered with sodium phosphate, and this procedure is not affected by the presence of other common anions. The chemisensors exhibit high sensitivity to low concentrations of cyanide, meeting the European Union water quality control criterion of sensitivity below 0.05 mg L(-1), and show a very fast response within tens of seconds. The mechanism for detection is rationalized by the nucleophilic substitution of the phenolic oxygen atom at the indoline C-2 atom by the cyanide anion to form a stable indolylnitrile adduct and to generate the colored 4-nitrophenolate chromophore. These chemosensors can be synthesized by a simple procedure from commercially available starting materials. PMID- 26247000 TI - A New Fluorescence Turn-On Probe for Aluminum(III) with High Selectivity and Sensitivity, and its Application to Bioimaging. AB - The development of novel selective probes with high sensitivity for the detection of Al(3+) is widely considered an important research goal due to the importance of such probes in medicine, living systems and the environment. Here, we describe a new fluorescent probe, N'-(4-diethylamino-2-hydroxybenzylidene)-2 hydroxybenzohydrazide (1), for Al(3+). Probe 1 was evaluated in a solution of acetonitrile/water (1:1 v/v). Compared with previously reported probes for Al(3+), probe 1 can be synthesized easily and in high yield. A Job plot confirmed that probe 1 is able to complex Al(3+) in a 1:1 ratio, and the binding constant was determined to be 4.25*10(8) m(-1). Moreover, the detection limit was as low as 6.7*10(-9) m, suggesting that probe 1 has a high sensitivity. Common coexistent metal ions, such as K(+), Co(2+), Ca(2+), Ba(2+), Ni(2+), Pb(2+), Hg(2+), Ce(2+), Zn(2+), Cd(2+), Fe(3+), showed little or no interference in the detection of Al(3+) in solution, demonstrating the high selectivity of the probe. Finally, the ability of probe 1 to act as a fluorescent probe for Al(3+) in living systems was evaluated in Gram-negative bacteria, Escherichia coli, and confocal laser scanning microscopy confirmed its utility. The results of this study suggest that 1 has appropriate properties to be developed for application as a fluorescent probe of Al(3+) for use in biological studies. PMID- 26246999 TI - Trichocyanines: a Red-Hair-Inspired Modular Platform for Dye-Based One-Time-Pad Molecular Cryptography. AB - Current molecular cryptography (MoCryp) systems are almost exclusively based on DNA chemistry and reports of cryptography technologies based on other less complex chemical systems are lacking. We describe herein, as proof of concept, the prototype of the first asymmetric MoCryp system, based on an 8-compound set of a novel bioinspired class of cyanine-type dyes called trichocyanines. These novel acidichromic cyanine-type dyes inspired by red hair pigments were synthesized and characterized with the aid of density functional theory (DFT) calculations. Trichocyanines consist of a modular scaffold easily accessible via an expedient condensation of 3-phenyl- or 3-methyl-2H-1,4-benzothiazines with N dimethyl- or o-methoxyhydroxy-substituted benzaldehyde or cinnamaldehyde derivatives. The eight representative members synthesized herein can be classified as belonging to two three-state systems tunable through four different control points. This versatile dye platform can generate an expandable palette of colors and appears to be specifically suited to implement an unprecedented single use asymmetric molecular cryptography system. With this system, we intend to pioneer the translation of digital public-key cryptography into a chemical-coding one-time-pad-like system. PMID- 26247001 TI - Supported Sulfonic Acids: Solid Catalysts for Batch and Continuous-Flow Synthetic Processes. PMID- 26247002 TI - Cationic Antimicrobial Peptides (AMPs): Thermodynamic Characterization of Peptide Lipid Interactions and Biological Efficacy of Surface-Tethered Peptides. PMID- 26247003 TI - Establishing Clinical Relevance in Preclinical Alzheimer's Disease. PMID- 26247004 TI - Endpoints for Pre-Dementia AD Trials: A Report from the EU/US/CTAD Task Force. AB - For Alzheimer's disease treatment trials that focus on the pre-dementia stage of disease, outcome measures are needed that will enable assessment of disease progression in patients who are clinically normal. The EU/US CTAD Task Force, an international collaboration of investigators from industry, academia, non-profit foundations, and regulatory agencies, met in Philadelphia, Pennsylvania, USA, on November 19, 2014 to discuss existing and novel outcome assessments that may be useful in pre-dementia trials. Composite measures that assess changes in episodic memory, executive function, global cognition, and global function have recently been developed by a number of groups and appear to be sensitive at this stage. Functional measures that involve real-life complex tasks also appear to capture early subtle changes in pre-dementia subjects and have the advantage of representing clinically meaningful change. Patient reported outcomes and novel CSF and imaging biomarkers have also shown promise. More studies are needed to validate all of these tests in the pre-dementia population. Many of them have been incorporated as exploratory measures in ongoing or planned trials. PMID- 26247005 TI - The role of PET quantification in cardiovascular imaging. AB - Positron Emission Tomography (PET) has several clinical and research applications in cardiovascular imaging. Myocardial perfusion imaging with PET allows accurate global and regional measurements of myocardial perfusion, myocardial blood flow and function at stress and rest in one exam. Simultaneous assessment of function and perfusion by PET with quantitative software is currently the routine practice. Combination of ejection fraction reserve with perfusion information may improve the identification of severe disease. The myocardial viability can be estimated by quantitative comparison of fluorodeoxyglucose (18FDG) and rest perfusion imaging. The myocardial blood flow and coronary flow reserve measurements are becoming routinely included in the clinical assessment due to enhanced dynamic imaging capabilities of the latest PET/CT scanners. Absolute flow measurements allow evaluation of the coronary microvascular dysfunction and provide additional prognostic and diagnostic information for coronary disease. Standard quantitative approaches to compute myocardial blood flow from kinetic PET data in automated and rapid fashion have been developed for 13N-ammonia, 15O water and 82Rb radiotracers. The agreement between software methods available for such analysis is excellent. Relative quantification of 82Rb PET myocardial perfusion, based on comparisons to normal databases, demonstrates high performance for the detection of obstructive coronary disease. New tracers, such as 18F-flurpiridaz may allow further improvements in the disease detection. Computerized analysis of perfusion at stress and rest reduces the variability of the assessment as compared to visual analysis. PET quantification can be enhanced by precise coregistration with CT angiography. In emerging clinical applications, the potential to identify vulnerable plaques by quantification of atherosclerotic plaque uptake of 18FDG and 18F-sodium fluoride tracers in carotids, aorta and coronary arteries has been demonstrated. PMID- 26247006 TI - The evaluation of a scoring system in airway management after oral cancer surgery. AB - BACKGROUND: The purpose of this retrospective study was to investigate the usefulness of tracheostomy scoring system in the decision of postoperative airway management in oral cancer patients. MATERIALS AND METHODS: A total of 104 patients were reviewed in this retrospective study, who underwent radical resection with or without neck dissection and free flap reconstruction due to oral cancer. The patients were classified into three groups according to the timing of the extubation; extubated groups (n = 51), overnight intubation group (n = 45), and tracheostomy group (n = 8). Cameron's score was used to evaluate the relation between the state of the patient's airway and the type of the operation. RESULTS: Tracheostomy was performed in eight patients (8/104, 7.7 %). A total of 22 patients (21.2 %) had more than 5 points of which 17 patients (77.3 %) did not have a tracheostomy and any postoperative emergency airway problems. The tracheostomy scores were significantly different among the three groups. Hospital stay showed a significant correlation with the tracheostomy score. CONCLUSIONS: The scoring system did not quite agree with the airway management of the authors' clinic; however, it can be one of the clinical factors predicting the degree of the postoperative airway obstruction and surgical aggressiveness for recovery. The further studies are needed for clinically more reliable scoring systems. PMID- 26247007 TI - Preliminary clinic study on computer assisted mandibular reconstruction: the positive role of surgical navigation technique. AB - BACKGROUND: The objectives of the present study were to investigate the reliability and outcomes of computer-assisted techniques in mandibular reconstruction with a fibula flap and verify whether the surgical navigation system was feasible in mandible reconstructive surgery. METHODS: Eight cases were enrolled in the computer assisted surgery (CAS) group and 14 cases in the traditional group. The shaping and fixation of the fibula grafts were guided by computer assisted techniques, which could be monitored with the BrainLAB surgical navigation system. The variation of mandible configuration was evaluated by CT measurement in the Mimics software, including the variation of length, width, height and gonial angle of the mandible. The 3D facial soft tissue alteration was also analyzed in 3D chromatogram by Geomagic software. RESULTS: All 22 fibula flaps survived. The mandibular configurations and facial contours had a better clinic result in the CAS group. The length, width, height and gonial angle of the reconstructive mandible were more similar to the original one. The Wilcoxon rank sum test analysis suggested significant differences in the measurements. The chromatographic analysis also visually showed superiority over the traditional group. CONCLUSIONS: The computer assisted surgical navigation method used in mandibular reconstruction is feasible and precise for clinical application. The contour of the reconstructed mandible and facial symmetry are improved with computer techniques. PMID- 26247008 TI - Prevalence of Depressive Symptoms and Related Factors in Japanese Employees: A Comparative Study between Surveys from 2007 and 2010. AB - Aims. The aim of this study was to examine the prevalence of depressive symptoms and their related factors in Japan. The results were analyzed to identify the relationship between high scores on the CES-D, sociodemographic status, and employment-related variables. Methods. Employees in Akita prefecture completed the Center for Epidemiologic Studies Depression Scale (CES-D) during a survey period between November and December 2010. The cutoff point for the CES-D scores was 16 or above (high scorers). Results. Data from 1,476 employees indicated that 44.2% had high scores on the CES-D. Sociodemographic and occupation-related factors associated with a high risk of depression were being female, young age, fewer hours of sleep on weekdays, and working over 8 hours per day, whereas drinking alcohol one to two days per week, albeit only in men, was significantly associated with a low risk of depression. The present results were consistent with the results of a previous survey completed in 2007; however, the present results regarding job categories and smoking behavior were not significantly associated with depression and thus were inconsistent with the 2007 survey data. Conclusions. These results can be useful as benchmark values for the CES-D and might help predict depressive disorders. PMID- 26247009 TI - Transcriptomes That Confer to Plant Defense against Powdery Mildew Disease in Lagerstroemia indica. AB - Transcriptome analysis was conducted in two popular Lagerstroemia cultivars: "Natchez" (NAT), a white flower and powdery mildew resistant interspecific hybrid and "Carolina Beauty" (CAB), a red flower and powdery mildew susceptible L. indica cultivar. RNA-seq reads were generated from Erysiphe australiana infected leaves and de novo assembled. A total of 37,035 unigenes from 224,443 assembled contigs in both genotypes were identified. Approximately 85% of these unigenes have known function. Of them, 475 KEGG genes were found significantly different between the two genotypes. Five of the top ten differentially expressed genes (DEGs) involved in the biosynthesis of secondary metabolites (plant defense) and four in flavonoid biosynthesis pathway (antioxidant activities or flower coloration). Furthermore, 5 of the 12 assembled unigenes in benzoxazinoid biosynthesis and 7 of 11 in flavonoid biosynthesis showed higher transcript abundance in NAT. The relative abundance of transcripts for 16 candidate DEGs (9 from CAB and 7 from NAT) detected by qRT-PCR showed general agreement with the abundances of the assembled transcripts in NAT. This study provided the first transcriptome analyses in L. indica. The differential transcript abundance between two genotypes indicates that it is possible to identify candidate genes that are associated with the plant defenses or flower coloration. PMID- 26247010 TI - Rank-One and Transformed Sparse Decomposition for Dynamic Cardiac MRI. AB - It is challenging and inspiring for us to achieve high spatiotemporal resolutions in dynamic cardiac magnetic resonance imaging (MRI). In this paper, we introduce two novel models and algorithms to reconstruct dynamic cardiac MRI data from under-sampled k - t space data. In contrast to classical low-rank and sparse model, we use rank-one and transformed sparse model to exploit the correlations in the dataset. In addition, we propose projected alternative direction method (PADM) and alternative hard thresholding method (AHTM) to solve our proposed models. Numerical experiments of cardiac perfusion and cardiac cine MRI data demonstrate improvement in performance. PMID- 26247011 TI - Umami the Fifth Basic Taste: History of Studies on Receptor Mechanisms and Role as a Food Flavor. AB - Three umami substances (glutamate, 5'-inosinate, and 5'-guanylate) were found by Japanese scientists, but umami has not been recognized in Europe and America for a long time. In the late 1900s, umami was internationally recognized as the fifth basic taste based on psychophysical, electrophysiological, and biochemical studies. Three umami receptors (T1R1 + T1R3, mGluR4, and mGluR1) were identified. There is a synergism between glutamate and the 5'-nucleotides. Among the above receptors, only T1R1 + T1R3 receptor exhibits the synergism. In rats, the response to a mixture of glutamate and 5'-inosinate is about 1.7 times larger than that to glutamate alone. In human, the response to the mixture is about 8 times larger than that to glutamate alone. Since glutamate and 5'-inosinate are contained in various foods, we taste umami induced by the synergism in daily eating. Hence umami taste induced by the synergism is a main umami taste in human. PMID- 26247012 TI - Artemisia princeps Inhibits Biofilm Formation and Virulence-Factor Expression of Antibiotic-Resistant Bacteria. AB - In this study, we used ethanol extract of A. princeps and investigated its antibacterial effects against MRSA. Ethanol extract of A. princeps significantly inhibited MRSA growth and organic acid production during glucose metabolism at concentrations greater than 1 mg/mL (P < 0.05). MRSA biofilm formation was observed using scanning electron microscopy (SEM) and safranin staining. A. princeps extract was found to inhibit MRSA biofilm formation at concentrations higher than 2 mg/mL significantly (P < 0.05). Bactericidal effects of the A. princeps were observed using confocal laser microscopy, which showed that A. princeps was bactericidal in a dose-dependent manner. Using real-time PCR, expression of mecA, an antibiotic-resistance gene of MRSA, was observed, along with that of sea, agrA, and sarA. A. princeps significantly inhibited mecA, sea, agrA, and sarA, mRNA expression at the concentrations greater than 1 mg/mL (P < 0.05). The phytochemical analysis of A. princeps showed a relatively high content of organic acids and glycosides. The results of this study suggest that the ethanol extract of A. princeps may inhibit proliferation, acid production, biofilm formation, and virulence gene expressions of MRSA, which may be related to organic acids and glycosides, the major components in the extract. PMID- 26247013 TI - The Effect of Latent Toxoplasma gondii Infection on the Immune Response in HIV Infected Patients. AB - A relationship between latent toxoplasmosis and the immune system during HIV disease is poorly understood. Therefore, the aim of this follow-up study was to characterize immunological parameters in HIV-infected patients with latent toxoplasmosis and noninfected individuals. A total of 101 HIV-infected patients were enrolled in the study. The patients were classified into two groups based on anti-Toxoplasma gondii antibodies: a group of 55 toxoplasma-positive persons (TP) and a group of 46 toxoplasma-negative persons (TN). Absolute counts of several lymphocyte subsets decreased in the TP group, namely, T cells (p = 0.007), B cells (p = 0.002), NK cells (p = 0.009), CD4 T cells (p = 0.028), and CD8 T cells (p = 0.004). On the other hand, the percentage of CD8 T cells expressing CD38 and HLA-DR significantly increased during the follow-up in the TP group (p = 0.003, p = 0.042, resp.) as well as the intensity of CD38 and HLA-DR expression (MFI) on CD8 T cells (p = 0.001, p = 0.057, resp.). In the TN group, analysis of the kinetics of immunological parameters revealed no significant changes over time. In conclusion, the results suggest that latent T. gondii infection modulates the immune response during HIV infection. PMID- 26247014 TI - Pregnancy Rate after Controlled Ovarian Hyperstimulation and Intrauterine Insemination for the Treatment of Endometriosis following Surgery. AB - OBJECTIVE: To compare pregnancy rate after controlled ovarian hyperstimulation and intrauterine insemination (COH-IUI) with no treatment in patients with endometriosis-associated infertility treated with laparoscopy. DESIGN: A clinical cohort study. SETTING: University-level tertiary care center. PATIENTS: 238 women with various stages of endometriosis after laparoscopic treatment. INTERVENTIONS: Either COH-IUI or follow-up for 12 months. MAIN OUTCOME MEASURES: The primary outcome measures were clinical pregnancy and live birth rate. Predictive factors evaluated were female age, maternal BMI, and duration of infertility. RESULTS: The pregnancy rate attained after the integrated laparoscopy-COH-IUI approach was 53.4%, while it was significantly lower (38.5%) in the control group. Similarly, a significant difference was observed in live births (48.3% versus 34.2%). Patients with severe endometriosis were less likely to achieve pregnancy (38%) and live birth (35%) than their counterparts with milder forms (57% and 53%). CONCLUSIONS: In patients with endometriosis-based infertility, surgery followed by COH-IUI is more effective than surgery alone. PMID- 26247015 TI - Antibiofilm Activity of Chilean Propolis on Streptococcus mutans Is Influenced by the Year of Collection. AB - The chemical composition of propolis varies according to factors that could have an influence on its biological properties. Polyphenols from propolis have demonstrated an inhibitory effect on Streptococcus mutans growth. However, it is not known if different years of propolis collection may affect its activity. We aimed to elucidate if the year of collection of propolis influences its activity on Streptococcus mutans. Polyphenol-rich extracts were prepared from propolis collected in three different years, characterized by LC-MS and quantified the content of total polyphenols and flavonoids groups. Finally, was evaluated the antibacterial effect on Streptococcus mutans and the biofilm formation. Qualitative differences were observed in total polyphenols, flavones, and flavonols and the chemical composition between the extracts, affecting the strength of inhibition of biofilm formation but not the antimicrobial assays. In conclusion, chemical composition of propolis depends on the year of collection and influences the strength of the inhibition of biofilm formation. PMID- 26247016 TI - Validation of Quantitative Measurements in Cardiovascular Imaging. PMID- 26247018 TI - A Multimodal User Authentication System Using Faces and Gestures. AB - As a novel approach to perform user authentication, we propose a multimodal biometric system that uses faces and gestures obtained from a single vision sensor. Unlike typical multimodal biometric systems using physical information, the proposed system utilizes gesture video signals combined with facial images. Whereas physical information such as face, fingerprints, and iris is fixed and not changeable, behavioral information such as gestures and signatures can be freely changed by the user, similar to a password. Therefore, it can be a countermeasure when the physical information is exposed. We aim to investigate the potential possibility of using gestures as a signal for biometric system and the robustness of the proposed multimodal user authentication system. Through computational experiments on a public database, we confirm that gesture information can help to improve the authentication performance. PMID- 26247019 TI - Evaluation of Synergetic Anticancer Activity of Berberine and Curcumin on Different Models of A549, Hep-G2, MCF-7, Jurkat, and K562 Cell Lines. AB - Ayurvedic system of medicine is using Berberis aristata and Curcuma longa herbs to treat different diseases including cancer. The study was performed to evaluate the synergetic anticancer activity of Berberine and Curcumin by estimating the inhibition of the cell proliferation by cytotoxicity assay using MTT method on specified human cell lines (A549, Hep-G2, MCF-7, Jurkat, and K562). All the cells were harvested from the culture and seeded in the 96-well assay plates at seeding density of 2.0 * 10(4) cells/well and were incubated for 24 hours. Test items Berberine with Curcumin (1 : 1), Curcumin 95% pure, and Berberine 95% pure were exposed at the concentrations of 1.25, 0.001, and 0.5 mg/mL, respectively, and incubated for a period of 48 hours followed by dispensing MTT solution (5 mg/mL). The cells were incubated at 37 +/- 1 degrees C for 4 hours followed by addition of DMSO for dissolving the formazan crystals and absorbance was read at 570 nm. Separate wells were prepared for positive control, controls (only medium with cells), and blank (only medium). The results had proven the synergetic anticancer activity of Berberine with Curcumin inducing cell death greater percentage of >77% when compared to pure curcumin with <54% and pure Berberine with <45% on average on all cell line models. PMID- 26247021 TI - Assessing the Impact of Mechanical Damage on Full-Thickness Porcine and Human Skin Using an In Vitro Approach. AB - For most xenobiotics, the rates of percutaneous absorption are limited by diffusion through the horny layer of skin. However, percutaneous absorption of chemicals may seriously increase when the skin is damaged. The aim of this work was to develop an in vitro representative model of mechanically damaged skins. The epidermal barrier was examined following exposure to a razor, a rotating brush, and a microneedle system in comparison to tape-stripping which acted as a reference. Excised full-thickness skins were mounted on a diffusion chamber in order to evaluate the effect of injuries and to mimic physiological conditions. The transepidermal water loss (TEWL) was greatly increased when the barrier function was compromised. Measurements were made for all the damaged biopsies and observed histologically by microscopy. On human and porcine skins, the tape stripping application (0 to 40 times) showed a proportional increase in TEWL which highlights the destruction of the stratum corneum. Similar results were obtained for all cosmetic instruments. This is reflected in our study by the nonsignificant difference of the mean TEWL scores between 30 strips and mechanical damage. For a specific appreciation, damaged skins were then selected to qualitatively evaluate the absorption of a chlorogenic acid solution using fluorescence microscopy. PMID- 26247017 TI - Innate Immunity and Biomaterials at the Nexus: Friends or Foes. AB - Biomaterial implants are an established part of medical practice, encompassing a broad range of devices that widely differ in function and structural composition. However, one common property amongst biomaterials is the induction of the foreign body response: an acute sterile inflammatory reaction which overlaps with tissue vascularisation and remodelling and ultimately fibrotic encapsulation of the biomaterial to prevent further interaction with host tissue. Severity and clinical manifestation of the biomaterial-induced foreign body response are different for each biomaterial, with cases of incompatibility often associated with loss of function. However, unravelling the mechanisms that progress to the formation of the fibrotic capsule highlights the tightly intertwined nature of immunological responses to a seemingly noncanonical "antigen." In this review, we detail the pathways associated with the foreign body response and describe possible mechanisms of immune involvement that can be targeted. We also discuss methods of modulating the immune response by altering the physiochemical surface properties of the biomaterial prior to implantation. Developments in these areas are reliant on reproducible and effective animal models and may allow a "combined" immunomodulatory approach of adapting surface properties of biomaterials, as well as treating key immune pathways to ultimately reduce the negative consequences of biomaterial implantation. PMID- 26247022 TI - The Surgical Treatment of Severe Endometriosis Positively Affects the Chance of Natural or Assisted Pregnancy Postoperatively. AB - OBJECTIVE: To report reproductive outcomes following laparoscopic surgical excision of histologically confirmed r-ASRM stage III-IV endometriosis. STUDY DESIGN: A retrospective cohort study was performed at the Royal Hospital for Women, a university teaching hospital, Sydney, Australia. Women who had fertility preserving laparoscopic excision of stage III-IV endometriosis from 1997 to 2009 were contacted regarding reproductive outcomes. RESULTS: In the study period, 355 women underwent surgery for stage III-IV endometriosis. Follow-up data are available for 253/355 (71%) women. Postoperatively, 142/253 (56%) women attempted to conceive with a conception rate of 104/142 (73%). Confidence intervals for pregnancy for women who were attempting conception (including the nonresponders) range from 104/262 (40%) to 224/262 (85%). Median time to conception was 12 months. No positive prognostic factors for pregnancy were identified on regression analyses. CONCLUSIONS: These data provide information to women with suspected severe disease preoperatively concerning their likely postoperative fertility outcomes. Ours is a population with severe endometriosis, rather than an infertile population with endometriosis, so caution needs to be applied when applying these data to women with fertility issues alone. PMID- 26247023 TI - Quantification of Hepatorenal Index for Computer-Aided Fatty Liver Classification with Self-Organizing Map and Fuzzy Stretching from Ultrasonography. AB - Accurate measures of liver fat content are essential for investigating hepatic steatosis. For a noninvasive inexpensive ultrasonographic analysis, it is necessary to validate the quantitative assessment of liver fat content so that fully automated reliable computer-aided software can assist medical practitioners without any operator subjectivity. In this study, we attempt to quantify the hepatorenal index difference between the liver and the kidney with respect to the multiple severity status of hepatic steatosis. In order to do this, a series of carefully designed image processing techniques, including fuzzy stretching and edge tracking, are applied to extract regions of interest. Then, an unsupervised neural learning algorithm, the self-organizing map, is designed to establish characteristic clusters from the image, and the distribution of the hepatorenal index values with respect to the different levels of the fatty liver status is experimentally verified to estimate the differences in the distribution of the hepatorenal index. Such findings will be useful in building reliable computer aided diagnostic software if combined with a good set of other characteristic feature sets and powerful machine learning classifiers in the future. PMID- 26247020 TI - Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. AB - Bone tissue is continuously remodeled through the concerted actions of bone cells, which include bone resorption by osteoclasts and bone formation by osteoblasts, whereas osteocytes act as mechanosensors and orchestrators of the bone remodeling process. This process is under the control of local (e.g., growth factors and cytokines) and systemic (e.g., calcitonin and estrogens) factors that all together contribute for bone homeostasis. An imbalance between bone resorption and formation can result in bone diseases including osteoporosis. Recently, it has been recognized that, during bone remodeling, there are an intricate communication among bone cells. For instance, the coupling from bone resorption to bone formation is achieved by interaction between osteoclasts and osteoblasts. Moreover, osteocytes produce factors that influence osteoblast and osteoclast activities, whereas osteocyte apoptosis is followed by osteoclastic bone resorption. The increasing knowledge about the structure and functions of bone cells contributed to a better understanding of bone biology. It has been suggested that there is a complex communication between bone cells and other organs, indicating the dynamic nature of bone tissue. In this review, we discuss the current data about the structure and functions of bone cells and the factors that influence bone remodeling. PMID- 26247024 TI - Cochlear Dummy Electrodes for Insertion Training and Research Purposes: Fabrication, Mechanical Characterization, and Experimental Validation. AB - To develop skills sufficient for hearing preservation cochlear implant surgery, surgeons need to perform several electrode insertion trials in ex vivo temporal bones, thereby consuming relatively expensive electrode carriers. The objectives of this study were to evaluate the insertion characteristics of cochlear electrodes in a plastic scala tympani model and to fabricate radio opaque polymer filament dummy electrodes of equivalent mechanical properties. In addition, this study should aid the design and development of new cochlear electrodes. Automated insertion force measurement is a new technique to reproducibly analyze and evaluate the insertion dynamics and mechanical characteristics of an electrode. Mechanical properties of MED-EL's FLEX(28), FLEX(24), and FLEX(20) electrodes were assessed with the help of an automated insertion tool. Statistical analysis of the overall mechanical behavior of the electrodes and factors influencing the insertion force are discussed. Radio opaque dummy electrodes of comparable characteristics were fabricated based on insertion force measurements. The platinum-iridium wires were replaced by polymer filament to provide sufficient stiffness to the electrodes and to eradicate the metallic artifacts in X-ray and computed tomography (CT) images. These low-cost dummy electrodes are cheap alternatives for surgical training and for in vitro, ex vivo, and in vivo research purposes. PMID- 26247025 TI - Rotavirus Infects Human Biliary Epithelial Cells and Stimulates Secretion of Cytokines IL-6 and IL-8 via MAPK Pathway. AB - Biliary atresia (BA) is an infantile inflammatory cholangiopathy of unknown etiology although epidemiologic studies and animal models utilizing rotavirus (RV) have suggested a role for viral infection. Proinflammatory and profibrotic cytokines have been detected in infants with BA. The purpose of our study was to investigate the susceptibility of human cholangiocytes (H69 cells) to infection with RRV and to determine if this infection resulted in cytokine secretion. Infection of H69 cells by RRV was noncytolytic and resulted in a time-dependent increase in the release of both infectious virions and cytokines IL-6 and IL-8 into the supernate. The greatest difference in cytokine supernatant levels between infected and mock-infected cells was noted at 24 hours postinfection (h p.i.) for IL-8, 556 +/- 111 versus 77 +/- 68 pg/mL (p < 0.0001), and at 48 h p.i. for IL-6, 459 +/- 64 versus 67 +/- 2 pg/mL (p < 0.0001). Production of both cytokines following RRV infection was significantly reduced by pretreating the H69 cells with inhibitors of mitogen-activated protein kinase (MAPK). Conclusion. RRV can infect human cholangiocytes resulting in the production of proinflammatory and profibrotic cytokines via the MAPK pathway. RRV-infected H69 cells could be a useful model system for investigating the viral hypothesis of BA. PMID- 26247026 TI - Animal Models of Human Pathology 2014. PMID- 26247028 TI - Towards a Food Safety Knowledge Base Applicable in Crisis Situations and Beyond. AB - In case of contamination in the food chain, fast action is required in order to reduce the numbers of affected people. In such situations, being able to predict the fate of agents in foods would help risk assessors and decision makers in assessing the potential effects of a specific contamination event and thus enable them to deduce the appropriate mitigation measures. One efficient strategy supporting this is using model based simulations. However, application in crisis situations requires ready-to-use and easy-to-adapt models to be available from the so-called food safety knowledge bases. Here, we illustrate this concept and its benefits by applying the modular open source software tools PMM-Lab and FoodProcess-Lab. As a fictitious sample scenario, an intentional ricin contamination at a beef salami production facility was modelled. Predictive models describing the inactivation of ricin were reviewed, relevant models were implemented with PMM-Lab, and simulations on residual toxin amounts in the final product were performed with FoodProcess-Lab. Due to the generic and modular modelling concept implemented in these tools, they can be applied to simulate virtually any food safety contamination scenario. Apart from the application in crisis situations, the food safety knowledge base concept will also be useful in food quality and safety investigations. PMID- 26247027 TI - Pathophysiology and Immune Dysfunction in Endometriosis. AB - Endometriosis is an estrogen-dependent, chronic, proinflammatory disease prevalent in 10% of women of reproductive age worldwide. Characterized by the growth of endometrium-like tissue in aberrant locations outside of the uterus, it is responsible for symptoms including chronic pelvic pain, dysmenorrhea, and subfertility that degrade quality of life of women significantly. In Canada, direct and indirect economic cost of endometriosis amounts to 1.8 billion dollars, and this is elevated to 20 billion dollars in the United States. Despite decades of research, the etiology and pathophysiology of endometriosis still remain to be elucidated. This review aims to bring together the current understanding regarding the pathogenesis of endometriosis with specific focus on mechanisms behind vascularization of the lesions and the contribution of immune factors in facilitating lesion establishment and development. The role of hormones, immune cells, and cytokine signaling is highlighted, in addition to discussing the current pharmaceutical options available for management of pain symptoms in women with endometriosis. PMID- 26247029 TI - Noninflammatory Joint Contractures Arising from Immobility: Animal Models to Future Treatments. AB - Joint contractures, defined as the limitation in the passive range of motion of a mobile joint, can be classified as noninflammatory diseases of the musculoskeletal system. The pathophysiology is not well understood; limited information is available on causal factors, progression, the pathophysiology involved, and prediction of response to treatment. The clinical heterogeneity of joint contractures combined with the heterogeneous contribution of joint connective tissues to joint mobility presents challenges to the study of joint contractures. Furthermore, contractures are often a symptom of a wide variety of heterogeneous disorders that are in many cases multifactorial. Extended immobility has been identified as a causal factor and evidence is provided from both experimental and epidemiology studies. Of interest is the involvement of the joint capsule in the pathophysiology of joint contractures and lack of response to remobilization. While molecular pathways involved in the development of joint contractures are being investigated, current treatments focus on physiotherapy, which is ineffective on irreversible contractures. Future treatments may include early diagnosis and prevention. PMID- 26247030 TI - Reduction in Endometrioma Size with Three Months of Aromatase Inhibition and Progestin Add-Back. AB - The purpose of this study was to assess the impact of 3 months of aromatase inhibition together with progestin add-back on ovarian endometrioma size. This prospective cohort study was performed at University Medical Center (UC San Diego). Women trying to conceive were excluded. After informed consent, all women were treated with the aromatase inhibitor letrozole (5 mg/d) with norethindrone acetate (5 mg/d) add-back for 3 months. Pre- and posttreatment assessments of endometrioma sizes were performed by ultrasound. The impact of treatment on pain was determined using the patient assessed endpoints of the Biberoglu and Behrman scale. These included assessing dysmenorrhea, dyspareunia, and nonmenstrual pelvic pain each on a scale from 0 to 3. The primary endpoint of this study was the change in ultrasound documented endometrioma size. Fourteen endometriomas in 8 consecutive women were treated for 3 m. Mean endometrioma diameter decreased 50% from 4.6 +/- 1.6 cm to 2.3 +/- 1.6 cm (mean +/- SD). This represents a 75% decrease in endometrioma volume. Endometriosis symptoms of dysmenorrhea, dyspareunia, and nonmenstrual pelvic pain also improved with treatment. In conclusion, a 3-month course of high dose aromatase inhibition with progestin add back significantly reduces ovarian endometrioma size and warrants further investigation. PMID- 26247031 TI - Biometrics Analysis and Evaluation on Korean Makgeolli Using Brainwaves and Taste Biological Sensor System. AB - There are several methods available in measuring food taste. The sensory evaluation, for instance, is a typical method for panels to test of taste and recognize smell with their nose by measuring the degree of taste characteristic, intensity, and pleasure. There are many issues entailed in the traditional sensory evaluation method such as forming a panel and evaluation cost; moreover, it is only localized in particular areas. Accordingly, this paper aimed to select food in one particular area, and compare and review the content between sensory evaluations using a taste biological sensor, as well as presenting an analysis of brainwaves using EEG and finally a proposal of a new method for sensory evaluation. In this paper, the researchers have conducted a sensory evaluation whereas a maximum of nine points were accumulated by purchasing eight types of rice wine. These eight types of Makgeolli were generalized by generating multidimensional data with the use of TS-5000z, thus learning mapping points and scaling them. The contribution of this paper, therefore, is to overcome the disadvantages of the sensory evaluation with the usage of the suggested taste biological sensor system. PMID- 26247032 TI - Nanostructures Control the Hepatocellular Responses to a Cytotoxic Agent "Cisplatin". AB - In drug discovery programs, the alteration between in vivo and in vitro cellular responses to drug represents one of the main challenges. Since the variation in the native extracellular matrix (ECM) between in vivo and 2D in vitro conditions is one of the key reasons for such discrepancies, thus the utilization of substrate that likely mimics ECM characteristics (topography, stiffness, and chemical composition) is needed to overcome such problem. Here, we investigated the role of substrate nanotopography as one of the major determinants of hepatic cellular responses to a chemotherapeutic agent "cisplatin." We studied the substratum induced variations in cisplatin cytotoxicity; a higher cytotoxic response to cisplatin was observed for cells cultured on the nanopattern relative to a flat substrate. Moreover, the nanofeatures with grating shapes that mimic the topography of major ECM protein constituents (collagen) induced alterations in the cellular orientation and chromatin condensation compared to flat surfaces. Accordingly, the developments of biomimetic substrates with a particular topography could have potentials in drug development analyses to reflect more physiological mimicry conditions in vitro. PMID- 26247033 TI - Utility of C-Reactive Protein Levels for Early Prediction of Dengue Severity in Adults. AB - Dengue has broad clinical presentation with unpredictable clinical evolution and outcome. We aimed to evaluate the utility of C-reactive protein (CRP) levels for distinguishing between mild and severe cases in the early phase of the dengue illness. We retrospectively evaluated adults with dengue from 2006 to 2014, according to 1997 and 2009 World Health Organization (WHO) criteria for severity. Of 191 included patients, 32.9% had nonshock dengue hemorrhagic fever (DHF), 3.1% dengue shock syndrome (DSS), and 7.9% severe dengue. The risk of DHF/DSS and severe dengue is significantly related to the increasing levels of CRP. Of 191 patients, 97 had CRP levels measured during the febrile (days 1-3); 85 during the critical (days 4-6); and 9 during the convalescent (days 7-10) illness phases. During the febrile phase, there was significant higher CRP level for DSS versus DF/nonshock DHF and severe dengue versus nonsevere dengue, with CRP cutoff level 30.1 mg/L (area under the receiver operating characteristic curve (AUC), 0.938; 100% sensitivity, 76.3% specificity) and 24.2 mg/L (AUC, 0.717; 70% sensitivity, 71.3% specificity), respectively. Our study highlights the utility of the CRP levels in early prediction of DSS and severe dengue in adult patients. PMID- 26247034 TI - A Multilayer Secure Biomedical Data Management System for Remotely Managing a Very Large Number of Diverse Personal Healthcare Devices. AB - In this paper, a multilayer secure biomedical data management system for managing a very large number of diverse personal health devices is proposed. The system has the following characteristics: the system supports international standard communication protocols to achieve interoperability. The system is integrated in the sense that both a PHD communication system and a remote PHD management system work together as a single system. Finally, the system proposed in this paper provides user/message authentication processes to securely transmit biomedical data measured by PHDs based on the concept of a biomedical signature. Some experiments, including the stress test, have been conducted to show that the system proposed/constructed in this study performs very well even when a very large number of PHDs are used. For a stress test, up to 1,200 threads are made to represent the same number of PHD agents. The loss ratio of the ISO/IEEE 11073 messages in the normal system is as high as 14% when 1,200 PHD agents are connected. On the other hand, no message loss occurs in the multilayered system proposed in this study, which demonstrates the superiority of the multilayered system to the normal system with regard to heavy traffic. PMID- 26247036 TI - Complications of Diabetes. PMID- 26247035 TI - The Different Effects of BMI and WC on Organ Damage in Patients from a Cardiac Rehabilitation Program after Acute Coronary Syndrome. AB - One of the purposes of cardiac rehabilitation (CR) after acute coronary syndrome (ACS) is to monitor and control weight of the patient. Our study is to compare the different obesity indexes, body mass index (BMI), and waist circumference (WC), through one well-designed CR program (CRP) with ACS in Guangzhou city of Guangdong Province, China, in order to identify different effects of BMI and WC on organ damage. In our work, sixty-one patients between October 2013 and January 2014 fulfilled our study. We collected the vital signs by medical records, the clinical variables of body-metabolic status by fasting blood test, and the organ damage variables by submaximal exercise treadmill test (ETT) and ultrasonic cardiogram (UCG) both on our inpatient and four-to-five weeks of outpatient part of CRP after ACS. We mainly used two-tailed Pearson's test and liner regression to evaluate the relationship of BMI/WC and organ damage. Our results confirmed that WC could be more accurate than BMI to evaluate the cardiac function through the changes of left ventricular structure on the CRP after ACS cases. It makes sense of early diagnosis, valid evaluation, and proper adjustment to ACS in CRP of the obesity individuals in the future. PMID- 26247037 TI - Impact of Inherited Prothrombotic Disorders on the Long-Term Clinical Outcome of Percutaneous Transluminal Angioplasty in Patients with Diabetes. AB - The aim of our study was to analyse inherited thrombotic disorders that influence the long-term outcome of PTA. Methods. Diabetic patients with peripheral arterial disease (PAD) treated by PTA in our centre between 2008 and 2011 were included in the study. Patients were divided into unsuccessful PTA group (75 patients), successful PTA group (58 patients), and control group (65 patients, with diabetes but no PAD). Diagnosis of inherited thrombotic disorders included mutation in factor V (Leiden), factor II (prothrombin), and mutation in genes for methylenetetrahydrofolate reductase-MTHFR (C677T and A1298C). Results. The genotypic frequency of Leiden allele G1691A was significantly associated with a risk of unsuccessful PTA in comparison with successful PTA group and control group (OR 8.8 (1.1-70.6), p = 0.041, and OR 9.8 (1.2-79.2), p = 0.032, resp.). However, we only observed a trend for the association of the prothrombin allele G20210A and risk of PTA failure. The frequencies of alleles of MTHFR 677 or 1298 did not differ significantly among the groups. Conclusion. Our study showed higher frequency of heterozygous form of Leiden mutation in diabetic patients with unsuccessful outcome of PTA in comparison with patients with successful PTA and diabetic patients without PAD. PMID- 26247039 TI - The Ability of Secretory Leukocyte Protease Inhibitor to Inhibit Apoptosis in Monocytes Is Independent of Its Antiprotease Activity. AB - Secretory Leukocyte Protease Inhibitor (SLPI) is a serine protease inhibitor produced by epithelial and myeloid cells with anti-inflammatory properties. Research has shown that SLPI exerts its anti-inflammatory activity by directly binding to NF-kappaB DNA binding sites and, in so doing, prevents binding and subsequent transcription of proinflammatory gene expression. In the current study, we demonstrate that SLPI can inhibit TNF-alpha-induced apoptosis in U937 cells and peripheral blood monocytes. Specifically, SLPI inhibits TNF-alpha induced caspase-3 activation and DNA degradation associated with apoptosis. We go on to show that this ability of SLPI to inhibit apoptosis is not dependent on its antiprotease activity as antiprotease deficient variants of SLPI can also inhibit TNF-alpha-induced apoptosis. This reduction in monocyte apoptosis may preserve monocyte function during inflammation resolution and promote infection clearance at mucosal sites. PMID- 26247038 TI - Intradermal DNA Electroporation Induces Cellular and Humoral Immune Response and Confers Protection against HER2/neu Tumor. AB - Skin represents an attractive target for DNA vaccine delivery because of its natural richness in APCs, whose targeting may potentiate the effect of vaccination. Nevertheless, intramuscular electroporation is the most common delivery method for ECTM vaccination. In this study we assessed whether intradermal administration could deliver the vaccine into different cell types and we analyzed the evolution of tissue infiltrate elicited by the vaccination protocol. Intradermal electroporation (EP) vaccination resulted in transfection of different skin layers, as well as mononuclear cells. Additionally, we observed a marked recruitment of reactive infiltrates mainly 6-24 hours after treatment and inflammatory cells included CD11c(+). Moreover, we tested the efficacy of intradermal vaccination against Her2/neu antigen in cellular and humoral response induction and consequent protection from a Her2/neu tumor challenge in Her2/neu nontolerant and tolerant mice. A significant delay in transplantable tumor onset was observed in both BALB/c (p <= 0,0003) and BALB-neuT mice (p = 0,003). Moreover, BALB-neuT mice displayed slow tumor growth as compared to control group (p < 0,0016). In addition, while in vivo cytotoxic response was observed only in BALB/c mice, a significant antibody response was achieved in both mouse models. Our results identify intradermal EP vaccination as a promising method for delivering Her2/neu DNA vaccine. PMID- 26247040 TI - The Human Mesenchymal Stromal Cell-Derived Osteocyte Capacity to Modulate Dendritic Cell Functions Is Strictly Dependent on the Culture System. AB - In vitro differentiation of mesenchymal stromal cells (MSC) into osteocytes (human differentiated osteogenic cells, hDOC) before implantation has been proposed to optimize bone regeneration. However, a deep characterization of the immunological properties of DOC, including their effect on dendritic cell (DC) function, is not available. DOC can be used either as cellular suspension (detached, Det-DOC) or as adherent cells implanted on scaffolds (adherent, Adh DOC). By mimicking in vitro these two different routes of administration, we show that both Det-DOC and Adh-DOC can modulate DC functions. Specifically, the weak downregulation of CD80 and CD86 caused by Det-DOC on DC surface results in a weak modulation of DC functions, which indeed retain a high capacity to induce T-cell proliferation and to generate CD4(+)CD25(+)Foxp3(+) T cells. Moreover, Det-DOC enhance the DC capacity to differentiate CD4(+)CD161(+)CD196(+) Th17-cells by upregulating IL-6 secretion. Conversely, Adh-DOC strongly suppress DC functions by a profound downregulation of CD80 and CD86 on DC as well as by the inhibition of TGF-beta production. In conclusion, we demonstrate that different types of DOC cell preparation may have a different impact on the modulation of the host immune system. This finding may have relevant implications for the design of cell-based tissue-engineering strategies. PMID- 26247041 TI - It's complicated: criteria for policy decisions for the clinical integration of genome-scale sequencing for reproductive decision making. PMID- 26247042 TI - Medical genetics and genomic medicine in Chile: opportunities for improvement. PMID- 26247043 TI - SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR. AB - Proximal spinal muscular atrophy (SMA) is an early-onset motor neuron disease characterized by loss of alpha-motor neurons and associated muscle atrophy. SMA is caused by deletion or other disabling mutation of survival motor neuron 1 (SMN1). In the human genome, a large duplication of the SMN-containing region gives rise to a second copy of this gene (SMN2) that is distinguishable by a single nucleotide change in exon 7. Within the SMA population, there is substantial variation in SMN2 copy number; in general, those individuals with SMA who have a high SMN2 copy number have a milder disease. Because SMN2 functions as a disease modifier, its accurate copy number determination may have clinical relevance. In this study, we describe the development of an assay to assess SMN1 and SMN2 copy numbers in DNA samples using an array-based digital PCR (dPCR) system. This dPCR assay can accurately and reliably measure the number of SMN1 and SMN2 copies in DNA samples. In a cohort of SMA patient-derived cell lines, the assay confirmed a strong inverse correlation between SMN2 copy number and disease severity. Array dPCR is a practical technique to determine, accurately and reliably, SMN1 and SMN2 copy numbers from SMA samples. PMID- 26247044 TI - Structural and functional influences of coagulation factor XIII subunit B heterozygous missense mutants. AB - The coagulation factor XIII(FXIII) is a plasma circulating heterotetrameric protransglutaminase that acts at the end of the coagulation cascade by covalently cross-linking preformed fibrin clots (to themselves and to fibrinolytic inhibitors) in order to stabilize them against fibrinolysis. It circulates in the plasma as a heterotetramer composed of two homomeric catalytic Factor XIIIA2 (FXIIIA2) and two homomeric protective/carrier Factor XIIIB2 subunit (FXIIIB2). Congenital deficiency of FXIII is of two types: severe homozygous/compound heterozygous FXIII deficiency which results in severe bleeding symptoms and mild heterozygous FXIII deficiency which is associated with mild bleeding (only upon trauma) or an asymptomatic phenotype. Defects in the F13B gene (Factor XIIIB subunit) occur more frequently in mild FXIII deficiency patients than in severe FXIII deficiency. We had recently reported secretion-related defects for seven previously reported F13B missense mutations. In the present study we further analyze the underlying molecular pathological mechanisms as well as the heterozygous expression phenotype for these mutations using a combination of in vitro heterologous expression (in HEK293T cells) and confocal microscopy. In combination with the in vitro work we have also performed an in silico solvated molecular dynamic simulation study on previously reported FXIIIB subunit sushi domain homology models in order to predict the putative structure-functional impact of these mutations. We were able to categorize the mutations into the following functional groups that: (1) affect antigenic stability as well as binding to FXIIIA subunit, that is, Cys5Arg, Cys316Phe, and Pro428Ser (2) affect binding to FXIIIA subunit with little or no influence on antigenic stability, that is, Ile81Asn and Val401Gln c) influence neither aspects and are most likely causality linked polymorphisms or functional polymorphisms, that is, Leu116Phe and Val217Ile. The Cys5Arg mutation was the only mutation to show a direct secretion-based defect since the mutated protein was observed to accumulate in the endoplasmic reticulum. PMID- 26247045 TI - Global epidemiology of Familial Mediterranean fever mutations using population exome sequences. AB - Familial Mediterranean fever (FMF) is an inherited disorder characterized by recurrent episodes of fever accompanied by sterile peritonitis, arthritis, and pleuritis. Many mutations in the MEFV gene have been identified as causing FMF. However, accompanying epidemiological information remains quite scarce except in some Mediterranean countries, and the degree of penetrance has been a subject of controversy. Here, I established a genetic epidemiology of full FMF mutations using two population exome studies. Of 57 mutations associated with FMF, 22 were detected in a total of 9007 individuals from two exome sequences. Exome-based epidemiology revealed the carrier rates of FMF in 28 populations in 19 countries by individual mutation and showed strong population specificity for the MEFV mutations. Unexpectedly high carrier rates suggested that some mutations are benign variants with no pathological significance and highlighted the need for caution in analyzing MEFV mutations. Similar approach could be used to uncover the incomplete or no penetrance of mutations in most inherited disorders. PMID- 26247046 TI - Novel pathogenic variants and genes for myopathies identified by whole exome sequencing. AB - Neuromuscular diseases (NMD) account for a significant proportion of infant and childhood mortality and devastating chronic disease. Determining the specific diagnosis of NMD is challenging due to thousands of unique or rare genetic variants that result in overlapping phenotypes. We present four unique childhood myopathy cases characterized by relatively mild muscle weakness, slowly progressing course, mildly elevated creatine phosphokinase (CPK), and contractures. We also present two additional cases characterized by severe prenatal/neonatal myopathy. Prior extensive genetic testing and histology of these cases did not reveal the genetic etiology of disease. Here, we applied whole exome sequencing (WES) and bioinformatics to identify likely causal pathogenic variants in each pedigree. In two cases, we identified novel pathogenic variants in COL6A3. In a third case, we identified novel likely pathogenic variants in COL6A6 and COL6A3. We identified a novel splice variant in EMD in a fourth case. Finally, we classify two cases as calcium channelopathies with identification of novel pathogenic variants in RYR1 and CACNA1S. These are the first cases of myopathies reported to be caused by variants in COL6A6 and CACNA1S. Our results demonstrate the utility and genetic diagnostic value of WES in the broad class of NMD phenotypes. PMID- 26247047 TI - Critical roles for WDR72 in calcium transport and matrix protein removal during enamel maturation. AB - Defects in WDR72 (WD repeat-containing protein 72) cause autosomal recessive hypomaturation amelogenesis imperfecta. We generated and characterized Wdr72 knockout/lacZ-knockin mice to investigate the role of WDR72 in enamel formation. In all analyses, enamel formed by Wdr72 heterozygous mice was indistinguishable from wild-type enamel. Without WDR72, enamel mineral density increased early during the maturation stage but soon arrested. The null enamel layer was only a tenth as hard as wild-type enamel and underwent rapid attrition following eruption. Despite the failure to further mineralize enamel deposited during the secretory stage, ectopic mineral formed on the enamel surface and penetrated into the overlying soft tissue. While the proteins in the enamel matrix were successfully degraded, the digestion products remained inside the enamel. Interactome analysis of WDR72 protein revealed potential interactions with clathrin-associated proteins and involvement in ameloblastic endocytosis. The maturation stage mandibular incisor enamel did not stain with methyl red, indicating that the enamel did not acidify beneath ruffle-ended ameloblasts. Attachment of maturation ameloblasts to the enamel layer was weakened, and SLC24A4, a critical ameloblast calcium transporter, did not localize appropriately along the ameloblast distal membrane. Fewer blood vessels were observed in the papillary layer supporting ameloblasts. Specific WDR72 expression by maturation stage ameloblasts explained the observation that enamel thickness and rod decussation (established during the secretory stage) are normal in the Wdr72 null mice. We conclude that WDR72 serves critical functions specifically during the maturation stage of amelogenesis and is required for both protein removal and enamel mineralization. PMID- 26247048 TI - Pseudoexon activation increases phenotype severity in a Becker muscular dystrophy patient. AB - We report a dystrophinopathy patient with an in-frame deletion of DMD exons 45 47, and therefore a genetic diagnosis of Becker muscular dystrophy, who presented with a more severe than expected phenotype. Analysis of the patient DMD mRNA revealed an 82 bp pseudoexon, derived from intron 44, that disrupts the reading frame and is expected to yield a nonfunctional dystrophin. Since the sequence of the pseudoexon and canonical splice sites does not differ from the reference sequence, we concluded that the genomic rearrangement promoted recognition of the pseudoexon, causing a severe dystrophic phenotype. We characterized the deletion breakpoints and identified motifs that might influence selection of the pseudoexon. We concluded that the donor splice site was strengthened by juxtaposition of intron 47, and loss of intron 44 silencer elements, normally located downstream of the pseudoexon donor splice site, further enhanced pseudoexon selection and inclusion in the DMD transcript in this patient. PMID- 26247049 TI - Splicing analysis for exonic and intronic mismatch repair gene variants associated with Lynch syndrome confirms high concordance between minigene assays and patient RNA analyses. AB - A subset of DNA variants causes genetic disease through aberrant splicing. Experimental splicing assays, either RT-PCR analyses of patient RNA or functional splicing reporter minigene assays, are required to evaluate the molecular nature of the splice defect. Here, we present minigene assays performed for 17 variants in the consensus splice site regions, 14 exonic variants outside these regions, and two deep intronic variants, all in the DNA mismatch-repair (MMR) genes MLH1, MSH2, MSH6, and PMS2, associated with Lynch syndrome. We also included two deep intronic variants in APC and PKD2. For one variant (MLH1 c.122A>G), our minigene assay and patient RNA analysis could not confirm the previously reported aberrant splicing. The aim of our study was to further investigate the concordance between minigene splicing assays and patient RNA analyses. For 30 variants results from patient RNA analyses were available, either performed by our laboratory or presented in literature. Some variants were deliberately included in this study because they resulted in multiple aberrant transcripts in patient RNA analysis, or caused a splice effect other than the prevalent exon skip. While both methods were completely concordant in the assessment of splice effects, four variants exhibited major differences in aberrant splice patterns. Based on the present and earlier studies, together showing an almost 100% concordance of minigene assays with patient RNA analyses, we discuss the weight given to minigene splicing assays in the current criteria proposed by InSiGHT for clinical classification of MMR variants. PMID- 26247050 TI - Behavioral abnormalities are common and severe in patients with distal 22q11.2 microdeletions and microduplications. AB - We describe six individuals with microdeletions and microduplications in the distal 22q11.2 region detected by microarray. Five of the abnormalities have breakpoints in the low-copy repeats (LCR) in this region and one patient has an atypical rearrangement. Two of the six patients with abnormalities in the region between LCR22 D-E have hearing loss, which has previously been reported only once in association with these abnormalities. We especially note the behavioral/neuropsychiatric problems, including the severity and early onset, in patients with distal 22q11.2 rearrangements. Our patients add to the genotype phenotype correlations which are still being generated for these chromosomal anomalies. PMID- 26247051 TI - Accurate genetic diagnosis of Finnish pulmonary arterial hypertension patients using oligonucleotide-selective sequencing. AB - The genetic basis of pulmonary arterial hypertension (PAH) among Finnish PAH patients is poorly understood. We adopted a novel-targeted next-generation sequencing (NGS) approach called Oligonucleotide-Selective Sequencing (OS-Seq) and developed a custom data analysis and interpretation pipeline to identify pathogenic base substitutions, insertions, and deletions in seven genes associated with PAH (BMPR2, BMPR1B, ACVRL1, ENG, SMAD9, CAV1, and KCNK3) from Finnish PAH patients. This study represents the first clinical study with OS-Seq technology on patients suffering from a rare genetic disorder. We analyzed DNA samples from 21 Finnish PAH patients, whose BMPR2 and ACVRL1 mutation status had been previously studied using Sanger sequencing. Our sequencing panel covered 100% of the targeted base pairs with >15* sequencing depth. Pathogenic base substitutions were identified in the BMPR2 gene in 29% of the Finnish PAH cases. Two of the pathogenic variant-positive patients had been previously tested negative using Sanger sequencing. No clinically significant variants were identified in the six other PAH genes. Our study validates the use of targeted OS Seq for genetic diagnostics of PAH and revealed pathogenic variants that had been previously missed using Sanger sequencing. PMID- 26247052 TI - A rigorous approach for selection of optimal variant sets for carrier screening with demonstration of clinical utility. AB - Carrier screening for certain diseases is recommended by major medical and Ashkenazi Jewish (AJ) societies. Most carrier screening panels test only for common, ethnic-specific variants. However, with formerly isolated ethnic groups becoming increasingly intermixed, this approach is becoming inadequate. Our objective was to develop a rigorous process to curate all variants, for relevant genes, into a database and then apply stringent clinical validity classification criteria to each in order to retain only those with clear evidence for pathogenicity. The resulting variant set, in conjunction with next-generation DNA sequencing (NGS), then affords the capability for an ethnically diverse, comprehensive, highly specific carrier-screening assay. The clinical utility of our approach was demonstrated by screening a pan-ethnic population of 22,864 individuals for Bloom syndrome carrier status using a BLM variant panel comprised of 50 pathogenic variants. In addition to carriers of the common AJ founder variant, we identified 57 carriers of other pathogenic BLM variants. All variants reported had previously been curated and their clinical validity documented, or were of a type that met our stringent, preassigned validity criteria. Thus, it was possible to confidently report an increased number of Bloom's syndrome carriers compared to traditional, ethnicity-based screening, while not reducing the specificity of the screening due to reporting variants of unknown clinical significance. PMID- 26247054 TI - Involvement of prefrontal cortex in scalar implicatures: evidence from magnetoencephalography. AB - The present study investigated the neural correlates of the realisation of scalar inferences, i.e., the interpretation of some as meaning some but not all. We used magnetoencephalography, which has high temporal resolution, to measure neural activity while participants heard stories that included the scalar inference trigger some in contexts that either provide strong cues for a scalar inference or provide weaker cues. The middle portion of the lateral prefrontal cortex (Brodmann area 46) showed an increased response to some in contexts with fewer cues to the inference, suggesting that this condition elicited greater effort. While the results are not predicted by traditional all-or-nothing accounts of scalar inferencing that assume the process is always automatic or always effortful, they are consistent with more recent gradient accounts which predict that the speed and effort of scalar inferences is strongly modulated by numerous contextual factors. PMID- 26247055 TI - Integrating HIV and palliative care: ending the false dichotomy. PMID- 26247056 TI - Soil Parameter Mapping and Ad Hoc Power Analysis to Increase Blocking Efficiency Prior to Establishing a Long-Term Field Experiment. AB - The spatial heterogeneity of soil and weed populations poses a challenge to researchers. Unlike aboveground variability, below-ground variability is more difficult to discern without a strategic soil sampling pattern. While blocking is commonly used to control environmental variation, this strategy is rarely informed by data about current soil conditions. Fifty georeferenced sites were located in a 0.65 ha area prior to establishing a long-term field experiment. Soil organic matter (OM) and weed seed bank populations were analyzed at each site and the spatial structure was modeled with semivariograms and interpolated with kriging to map the surface. These maps were used to formulate three strategic blocking patterns and the efficiency of each pattern was compared to a completely randomized design and a west to east model not informed by soil variability. Compared to OM, weeds were more variable across the landscape and had a shorter range of autocorrelation, and models to increase blocking efficiency resulted in less increase in power. Weeds and OM were not correlated, so no model examined improved power equally for both parameters. Compared to the west to east blocking pattern, the final blocking pattern chosen resulted in a 7 fold increase in power for OM and a 36% increase in power for weeds. PMID- 26247057 TI - Reliable Adaptive Video Streaming Driven by Perceptual Semantics for Situational Awareness. AB - A novel cross-layer optimized video adaptation driven by perceptual semantics is presented. The design target is streamed live video to enhance situational awareness in challenging communications conditions. Conventional solutions for recreational applications are inadequate and novel quality of experience (QoE) framework is proposed which allows fully controlled adaptation and enables perceptual semantic feedback. The framework relies on temporal/spatial abstraction for video applications serving beyond recreational purposes. An underlying cross-layer optimization technique takes into account feedback on network congestion (time) and erasures (space) to best distribute available (scarce) bandwidth. Systematic random linear network coding (SRNC) adds reliability while preserving perceptual semantics. Objective metrics of the perceptual features in QoE show homogeneous high performance when using the proposed scheme. Finally, the proposed scheme is in line with content-aware trends, by complying with information-centric-networking philosophy and architecture. PMID- 26247058 TI - Algebraic Hyperstructures of Vague Soft Sets Associated with Hyperrings and Hyperideals. AB - We apply the classical theory of hyperrings to vague soft sets to derive the concepts of vague soft hyperrings, vague soft hyperideals, and vague soft hyperring homomorphism. The properties and structural characteristics of these concepts are also studied and discussed. Furthermore, the relationship between the concepts introduced here and the corresponding concepts in classical hyperring theory and soft hyperring theory is studied and investigated. PMID- 26247059 TI - Surgical Audit of Patients with Ileal Perforations Requiring Ileostomy in a Tertiary Care Hospital in India. AB - Introduction. Ileal perforation peritonitis is a frequently encountered surgical emergency in the developing countries. The choice of a procedure for source control depends on the patient condition as well as the surgeon preference. Material and Methods. This was a prospective observational study including 41 patients presenting with perforation peritonitis due to ileal perforation and managed with ileostomy. Demographic profile and operative findings in terms of number of perforations, site, and size of perforation along with histopathological findings of all the cases were recorded. Results. The majority of patients were male. Pain abdomen and fever were the most common presenting complaints. Body mass index of the patients was in the range of 15.4-25.3 while comorbidities were present in 43% cases. Mean duration of preoperative resuscitation was 14.73 + 13.77 hours. Operative findings showed that 78% patients had a single perforation; most perforations were 0.6-1 cm in size and within 15 cm proximal to ileocecal junction. Mesenteric lymphadenopathy was seen in 29.2% patients. On histopathological examination, nonspecific perforations followed by typhoid and tubercular perforations respectively were the most common. Conclusion. Patients with ileal perforations are routinely seen in surgical emergencies and their demography, clinical profile, and intraoperative findings may guide the choice of procedure to be performed. PMID- 26247060 TI - METABOLIC EFFECTS OF MARIJUANA USE AMONG BLACKS. AB - BACKGROUND: Increased legalization of marijuana has resulted in renewed interest in its effects on body weight and cardiometabolic risk. Conflicting data exist regarding marijuana effects on body weight, waist circumference as well as lipid profiles, blood pressure and cardiovascular disease. Furthermore, there is a dearth of data available on this effect in the black population. OBJECTIVE: To assess the metabolic profile and cardiovascular risk factors as well as body weight and waist circumference among urban black marijuana users. METHODS: A cross sectional study design involving 100 patients seen in a Family Practice clinic at University hospital of Brooklyn, NY, USA, over a period of 3 months from January 2014 to March 2014. Participants were administered a questionnaire regarding marijuana use, and other associated behaviors. Socio-demographic, laboratory, and clinical data were collected. We report measures of central tendencies, and dispersion for continuous variables and the frequency of distribution for categorical variables. RESULTS: Of the 100 patients surveyed, 57% were females. The mean (+/-SEM) age of the entire cohort was 46.3 years+/ 1.5; range, 19-78 years. The mean body mass index (BMI) was 29.6 kg/m2+/-0.73; SBP=128.0 mmHg+/-1.69; DBP=76.1 mmHg+/-1.17. Current marijuana users had the lowest waist circumference compared to former or never users respectively (32.9+/ 0.66 vs. 35.9+/-0.88 vs. 33.4+/-0.74), p<0.01. Diastolic blood pressure in mmHg was significantly higher among former marijuana users compared to current or never users, (80.0+/-2.1 vs. 73.3+/-2.3 vs. 73.4+/-1.6), p<0.01. Current marijuana users showed a tendency (not statistically significant) towards lower total cholesterol, Triglycerides (TG), High Density Lipoprotein (HDL) cholesterol, Low Density Lipoprotein (LDL)-cholesterol, body mass index (BMI) and systolic blood pressure, compared to former users or never users. CONCLUSION: Current marijuana use is associated with significantly lower waist circumference, compared to former users and never users. Except for diastolic BP that was significantly lower among current users, other metabolic parameters showed tendency towards favorable profile. Further studies are needed to characterize the metabolic effects and to elucidate mechanisms of actions of marijuana in view of its rapid rate of utilization in the USA and around the world. PMID- 26247061 TI - Multi-sensor physical activity recognition in free-living. AB - Physical activity monitoring in free-living populations has many applications for public health research, weight-loss interventions, context-aware recommendation systems and assistive technologies. We present a system for physical activity recognition that is learned from a free-living dataset of 40 women who wore multiple sensors for seven days. The multi-level classification system first learns low-level codebook representations for each sensor and uses a random forest classifier to produce minute-level probabilities for each activity class. Then a higher-level HMM layer learns patterns of transitions and durations of activities over time to smooth the minute-level predictions. [Formula: see text]. PMID- 26247062 TI - Segmentation of the Aortic Valve Apparatus in 3D Echocardiographic Images: Deformable Modeling of a Branching Medial Structure. AB - 3D echocardiographic (3DE) imaging is a useful tool for assessing the complex geometry of the aortic valve apparatus. Segmentation of this structure in 3DE images is a challenging task that benefits from shape-guided deformable modeling methods, which enable inter-subject statistical shape comparison. Prior work demonstrates the efficacy of using continuous medial representation (cm-rep) as a shape descriptor for valve leaflets. However, its application to the entire aortic valve apparatus is limited since the structure has a branching medial geometry that cannot be explicitly parameterized in the original cm-rep framework. In this work, we show that the aortic valve apparatus can be accurately segmented using a new branching medial modeling paradigm. The segmentation method achieves a mean boundary displacement of 0.6 +/- 0.1 mm (approximately one voxel) relative to manual segmentation on 11 3DE images of normal open aortic valves. This study demonstrates a promising approach for quantitative 3DE analysis of aortic valve morphology. PMID- 26247063 TI - Mercury-induced fragmentation of n-decane and n-undecane in positive mode ion mobility spectrometry. AB - Ion mobility spectrometry is a well-known technique for trace gas analysis. Using soft ionization techniques, fragmentation of analytes is normally not observed, with the consequence that analyte spectra of single substances are quite simple, i.e. showing in general only one peak. If the concentration is high enough, an extra cluster peak involving two analyte molecules can often be observed. When investigating n-alkanes, different results regarding the number of peaks in the spectra have been obtained in the past using this spectrometric technique. Here we present results obtained when analyzing n-alkanes (n-hexane to n-undecane) with a pulsed electron source, which show no fragmentation or clustering at all. However, when investigating a mixture of mercury and an n-alkane, a situation quite typical in the oil and gas industry, a strong fragmentation and cluster formation involving these fragments has been observed exclusively for n-decane and n-undecane. PMID- 26247064 TI - Silver nanostructures in laser desorption/ionization mass spectrometry and mass spectrometry imaging. AB - Silver nanoparticles have been successfully applied as a matrix replacement for the laser desorption/ionization time-of-flight mass spectrometry (LDI-ToF-MS). Nanoparticles, producing spectra with highly reduced chemical background in the low m/z region, are perfectly suited for low-molecular weight compound analysis and imaging. Silver nanoparticles (AgNPs) can efficiently absorb ultraviolet laser radiation, transfer energy to the analyte and promote analyte desorption, but also constitute a source of silver ions suitable for analyte cationisation. This review provides an overview of the literature on silver nanomaterials as non conventional desorption and ionization promoters in LDI-MS and mass spectrometry imaging. PMID- 26247065 TI - A label-free and time-resolved luminescence strategy for the detection of proteins based on DNA-Tb(3+) luminescence quenched by graphene oxide. AB - A sensitive, label-free and time-resolved luminescent aptasensor to detect proteins was developed based on the DNA-enhanced time-resolved luminescence of Tb(3+) and graphene oxide (GO). We found that the DNA no matter with a G quadruplex structure or not could greatly enhance the long-lived emission of Tb(3+), and the luminescence of DNA-Tb(3+) could be effectively quenched by GO after the DNA-Tb(3+) was adsorbed onto GO. The target protein combined with an aptamer to form a protein/DNA complex restrained the quenching of DNA-Tb(3+) emission by GO. Thrombin and a 29-mer anti-thrombin aptamer were employed as a model analyte and a recognition element. There is a good linear relationship between the aptamer-Tb(3+) complex luminescence with the thrombin concentrations of 1 to 100 nM with a low detection limit of 0.8 nM. Since the time-resolved luminescence can eliminate the unspecific background fluorescence, the proposed aptasensor has been successfully applied in complicated biological samples for thrombin detection. This novel strategy presents a potential universal method for detection of other molecules. PMID- 26247066 TI - In situ forming interpenetrating hydrogels of hyaluronic acid hybridized with iron oxide nanoparticles. AB - Four derivatives of hyaluronic acid (HA) bearing thiol (HA-SH), hydrazide (HA hy), 2-dithiopyridyl (HA-SSPy), and aldehyde groups (HA-al) respectively were synthesized. Thiol and 2-dithiopyridyl as well as hydrazide and aldehyde make up two chemically orthogonal pairs of chemo-selective functionalities that allow in situ formation of interpenetrating (IPN) disulfide and hydrazone networks simultaneously upon the mixing of the above derivatives at once. The formation of IPN was demonstrated by comparing it with the formulations of the same total HA concentration but lacking one of the reactive components. The hydrogel composed of all four components was characterized by a larger elastic modulus than those of the control single networks (either disulfide or hydrazone) and the three component formulations gave the softest hydrogels. Moreover, a hydrazone cross linkage was designed to contain a 1,2-diol fragment. This allowed us to partially disassemble one type of network in the IPN leaving another one unaffected. In particular, treatment of the IPN with either sodium periodate or dithiothreitol resulted in disassembly of the hydrazone and disulfide networks respectively and thus softening of the hydrogel. Contrarily, the single network hydrogels completely dissolved under the corresponding conditions. In corroboration with this, enzymatic degradation of the IPN by hyaluronidase was also substantially slower than the degradation of the single networks. In order to further improve the mechanical properties of the elaborated injectable IPN, it has been in situ hybridized with iron oxide nanoparticles (IONPs). The mesh size of the IPN was smaller than the size of the IONPs resulting in the retention of nanoparticles in the matrix under equilibrium swelling conditions. However, these nanoparticles were released upon enzymatic degradation suggesting their use as MRI tags for non invasive tracking of the hydrogel material in vivo. Additionally, this injectable hybridized hydrogel with encapsulated IONPs can be used in hyperthermia cancer therapy. PMID- 26247067 TI - Stem Cells and Aging: What's Next? PMID- 26247068 TI - Alan Hall (1952-2015). PMID- 26247069 TI - Retraction notice to "Liver conversion of docosahexaenoic and arachidonic acids from their 18-carbon precursors in rats on a DHA-free but alpha-LNA-containing n 3 PUFA adequate diet". PMID- 26247070 TI - Obituary: Mary F Lyon (1925-2014). PMID- 26247071 TI - In memoriam: Donald Metcalf (1929-2014)--A historical perspective of his contributions to hematology. PMID- 26247073 TI - Obituary: Dr. Steph J. Dieleman. PMID- 26247072 TI - Multifocal Clinical Performance Improvement Across 21 Hospitals. AB - Improving quality and safety across an entire healthcare system in multiple clinical areas within a short time frame is challenging. We describe our experience with improving inpatient quality and safety at Kaiser Permanente Northern California. The foundations of performance improvement are a "four-wheel drive" approach and a comprehensive driver diagram linking improvement goals to focal areas. By the end of 2011, substantial improvements occurred in hospital acquired infections (central-line-associated bloodstream infections and Clostridium difficile infections); falls; hospital-acquired pressure ulcers; high alert medication and surgical safety; sepsis care; critical care; and The Joint Commission core measures. PMID- 26247074 TI - Abstracts of the Second International Symposium and Imaging Workshop Giant Cell Arteritis, Polymyalgia Rheumatica and Large Vessel Vasculitis. PMID- 26247075 TI - The Impact of a Research Ethics Training Program: Romania as a Case Study. AB - Case Western Reserve University's (CWRU) Training Program in International Research Ethics, funded by the Fogarty International Center, has been ongoing in Romania since 2000. The program consists of multiple components: a U.S.- based MA degree program for long-term trainees, Romania-based short courses, a U.S.-based opportunity for mid-and senior-level personnel to develop collaborative writing or research projects and present lectures, and a newsletter and various Internet based activities. We evaluated the impact of the training program on bioethics in Romania through a survey of the training program's long-term trainees, a literature search for trainee publications, interviews with key informants, and identification of key events during the course of the program. Findings indicate that the program has had a considerable impact in the field of bioethics through trainee authorship of peer-reviewed publications, books, and chapters; trainee career trajectories that encompass activities related to research ethics; and the development of a Romania-based master's degree program in bioethics and a Center of Bioethics and Health Policy. We attribute these achievements to the establishment of strong relationships between CWRU in Cleveland and the University of Medicine and Pharmacy Gr. T. Popa in Iasi, Romania, prior to the initiation of the training program; collaboration with key Romania-based institutional partners that are equally invested in the program's success; reliance of the program on a solid theoretical framework; ongoing program responsiveness to trainee and country needs; and a sustained commitment of time, expertise, and funding by the funders, sponsors, and in-country collaborators. PMID- 26247076 TI - IN MEMORIAM: FLOYD DUNN (1924-2015). PMID- 26247077 TI - Long-Term Recall of Elements of Informed Consent: A Pilot Study Comparing Traditional and Computer-Based Consenting. PMID- 26247078 TI - Challenges Conducting Multicenter Translational Research: Promoting Adherence to Childhood Obesity Guidelines. PMID- 26247079 TI - IRB Requirements and Review Processes: Criminal Justice Faculty Members' Compliance and Satisfaction. PMID- 26247080 TI - Positive Social Impacts Related to Participation in an HIV Prevention Trial Involving People Who Inject Drugs. PMID- 26247095 TI - Chiral Holmium Complex-Catalyzed Synthesis of Hydrocarbazole from Siloxyvinylindole and Its Application to the Enantioselective Total Synthesis of (-)-Minovincine. AB - The catalytic and enantioselective total synthesis of (-)-minovincine has been accomplished. The key highly substituted hydrocarbazole derivative was obtained by an asymmetric Diels-Alder reaction of siloxyvinylindole catalyzed by 0.5 mol % of a chiral holmium complex. The Diels-Alder adduct was converted to a tetracyclic intermediate in a one-pot procedure. No waste stereoisomers were produced throughout the entire total synthesis. PMID- 26247096 TI - Controllable Grain Morphology of Perovskite Absorber Film by Molecular Self Assembly toward Efficient Solar Cell Exceeding 17%. AB - The highly developed crystallization process with respect to perovskite thin films is favorable for efficient solar cells. Here, an innovative intermolecular self-assembly approach was employed to retard the crystallization of PbI2 in dimethylformamide (DMF) by additional solvent of dimethyl sulfoxide (DMSO), which was proved to be capable of coordinating with PbI2 by coordinate covalent bond. The obtained PbI2(DMSO)x (0 <= x <= 1.86) complexes tend to be closely packed by means of intermolecular self-assembly. Afterward, an intramolecular exchange of DMSO with CH3NH3I (MAI) enabled the complexes to deform their shape and finally to reorganize to be an ultraflat and dense thin film of CH3NH3PbI3. The controllable grain morphology of perovskite thin film allows obtaining a power conversion efficiency (PCE) above 17% and a stabilized power output above 16% within 240 s by controlling DMSO species in the complex-precursor system (CPS). The present study gives a reproductive and facile strategy toward high quality of perovskite thin films and efficient solar cells. PMID- 26247097 TI - Low Level of Resistance in Enterococci Isolated in Four Hospitals, Marseille, France. AB - Enterococci are gram-positive cocci responsible for various infections worldwide, and their prevalence of antibiotic resistance greatly varies worldwide. This study investigates the prevalence of resistance to antibiotics in enterococci from patients admitted in the four university hospitals of Marseille between January 2013 and September 2014. Two thousand nine hundred seventy-six patients bacteria couples were identified (2,507 Enterococcus faecalis and 469 Enterococcus faecium) in the four university hospitals of Marseille. 1.3%, 8.9%, 1.4%, and 0% of E. faecalis strains were resistant to amoxicillin, gentamicin, teicoplanin, and vancomycin, respectively, and 83.9%, 49.2%, 1.3%, and 0.2% of E. faecium strains were resistant to amoxicillin, gentamicin, teicoplanin, and vancomycin, respectively. Resistance to aminoglycosides and vancomycin in strains isolated from blood cultures was significantly lower than that of most European countries included in the 2012 European Antimicrobial Resistance Surveillance Network report. Our low percentage of antibiotic resistance in enterococci is likely due to a low level of E. faecium infections, underlining the need to implement surveillance systems, especially to monitor the E. faecalis/E. faecium ratio evolution in blood cultures and others. PMID- 26247098 TI - Risk of Developing Coronary Artery Disease in Patients with Type 2 Diabetes Receiving Traditional Chinese Medicine Therapy. AB - OBJECTIVES: To compare risk of developing coronary artery disease (CAD) between diabetic patients receiving Traditional Chinese Medicine (TCM) therapy and those treated by Western medicine (WM). METHODS: This prospective cohort study included 13,655 diabetic patients receiving solely TCM and 435,165 patients treated exclusively by WM. Study patients were identified from Taiwan's National Health Insurance (NHI) ambulatory claims in 2000-2001. These patients were then linked to the 2000-2008 NHI inpatient claims, searching for possible new onset of hospitalization for CAD. A Cox proportional hazard model and logistic regression model were used to assess the hazard ratio of CAD admission and odds ratio (OR) of higher rates of admission for CAD in relation to TCM. RESULTS: During 9 years of follow-up, 2607 diabetic patients with TCM were hospitalized for CAD, representing a cumulative incidence rate of 19.1% and an incidence density of 50.5 per 1000 person-years. The corresponding figures for patients treated by WM were 24.1% and 72.7 per 1000 person-years. Compared with the patients treated by WM, those treated by TCM were associated with a slightly reduced, but insignificantly, adjusted OR of CAD admission (0.96; 95% confidence interval, 0.92-1.01). Moreover, the adjusted OR for a higher rate (>=0.212 admission per person-year) of CAD admission for the patients with TCM was also insignificantly decreased at 0.97. CONCLUSIONS: After adjustment for prior co-morbidity score, risk or rate of CAD admission did not significantly differ between diabetic patients receiving TCM therapy and those treated by WM, suggesting that TCM is as efficacious as WM in preventing diabetes from being complicated with CAD. PMID- 26247100 TI - Persistent Luminescence of Tenebrescent Na8Al6Si6O24(Cl,S)2: Multifunctional Optical Markers. AB - Na8Al6Si6O24(Cl,S)2 materials were prepared with a solid state reaction. The products were studied using X-ray powder diffraction, reflectance measurements as well as X-ray fluorescence, conventional and persistent luminescence, nuclear magnetic resonance, and electron paramagnetic resonance spectroscopies. All materials containing sulfur showed purple tenebrescence, which persisted 2 days in a lit room at room temperature. Considerable blue persistent luminescence peaking at 460 nm and lasting for 1 h was obtained, as well. Persistent luminescence was obtained with irradiation at 365 nm, while tenebrescence required 254 nm. The materials show great promise as low-cost multifunctional optical markers. PMID- 26247099 TI - Predictors of high on-clopidogrel platelet reactivity in patients with acute coronary syndrome. AB - High on-clopidogrel platelet reactivity (HPR) is a predictor of ischemic events after percutaneous coronary intervention. We conducted a prospective cohort study to identify variables related to HPR in acute coronary syndrome patients who are at high thrombotic risk. We enrolled 463 patients undergoing urgent coronary angiography. Platelet reactivity was measured 12-36 hours after 600 mg clopidogrel loading with multiple electrode aggregometry (Multiplate(r) analyzer, Roche, Basel, Switzerland, 6.4 uM ADP). HPR was defined by the consensus cut-off area under the curve >46 U. The rate of HPR was 16.0%. We analyzed simple clinical and laboratory parameters with backward multivariate logistic regression and identified the following predictors of HPR: platelet count (per G/L, OR: 1.0073, 95% CI: 1.0035-1.0112, p = 0.0002), CRP level (per mg/L, OR: 1.0077, 95% CI: 1.0016-1.01372, p = 0.01), and active smoking (OR: 0.51, 95% CI: 0.29-0.89, p = 0.02). We developed and internally validated a risk prediction model demonstrating moderate discriminative capacity (area-under-the-receiver operating characteristic curve = 0.67). In conclusion, we found a relatively low rate of high on-clopidogrel platelet reactivity (16.0%) even in an acute patient cohort. HPR measured by Multiplate was associated with high platelet count and CRP level on admission and was inversely related to active smoking. The model with rapidly available simple parameters might help to identify individuals at risk for HPR in the acute setting. PMID- 26247101 TI - To connect or not to connect? Modelling the optimal degree of centralisation for wastewater infrastructures. AB - The strong reliance of most utility services on centralised network infrastructures is becoming increasingly challenged by new technological advances in decentralised alternatives. However, not enough effort has been made to develop planning tools designed to address the implications of these new opportunities and to determine the optimal degree of centralisation of these infrastructures. We introduce a planning tool for sustainable network infrastructure planning (SNIP), a two-step techno-economic heuristic modelling approach based on shortest path-finding and hierarchical-agglomerative clustering algorithms to determine the optimal degree of centralisation in the field of wastewater management. This SNIP model optimises the distribution of wastewater treatment plants and the sewer network outlay relative to several cost and sewer design parameters. Moreover, it allows us to construct alternative optimal wastewater system designs taking into account topography, economies of scale as well as the full size range of wastewater treatment plants. We quantify and confirm that the optimal degree of centralisation decreases with increasing terrain complexity and settlement dispersion while showing that the effect of the latter exceeds that of topography. Case study results for a Swiss community indicate that the calculated optimal degree of centralisation is substantially lower than the current level. PMID- 26247103 TI - Duplex real-time PCR method for the detection of sesame (Sesamum indicum) and flaxseed (Linum usitatissimum) DNA in processed food products. AB - The development of a duplex real-time polymerase chain reaction (PCR) method allowing the simultaneous detection of sesame and flaxseed DNA in commercial food products is described. This duplex real-time PCR technique is based in the design of sesame- and flaxseed-specific primers based on the ITS1 region and two TaqMan fluorescent probes. The method was positive for sesame and flaxseed, and showed no cross-reactivity for all other heterologous plant and animal species tested. Sesame and flaxseed could be detected in a series of model samples with defined raw and heat-treated sesame in flaxseed, and flaxseed in sesame, respectively, with detection limits of 1.3 mg kg(-1) for sesame and 1.4 mg kg(-1) for flaxseed. The applicability of the assay for determining sesame and flaxseed in different food matrices was investigated by analysing a total of 238 commercial foodstuffs. This PCR method is useful for highly selective and sensitive detection of traces of sesame and flaxseed in commercial food products. PMID- 26247104 TI - Social smile reproducibility using 3-D stereophotogrammetry and reverse engineering technology. AB - OBJECTIVE: To assess the range of social smile reproducibility using 3-D stereophotogrammetry and reverse engineering technology. MATERIALS AND METHODS: Social smile images of white adolescents (N = 15, mean age = 15.4 +/-1.5 years; range = 14-17 years) were obtained using 3dMDFlex (3dMD, Atlanta, Ga). Each participant was asked to produce 16 social smiles at 3-minute intervals. All images were obtained in natural head position. Alignment of images, segmentation of smile area, and 3-D deviation analysis were carried out using Geomagic Control software (3D Systems Inc, Cary, NC). A single image was taken as a reference, and the remaining 15 images were compared with the reference image to evaluate positive and negative deviations. The differences between the mean deviation limits of participants with the highest and the lowest deviations and the total mean deviations were evaluated using Bland-Altman Plots. RESULTS: Minimum and maximum deviations of a single image from the reference image were 0.34 and 2.69 mm, respectively. Lowest deviation between two images was within 0.5 mm and 1.54 mm among all participants (mean, 0.96 +/- 0.21 mm), and the highest deviation was between 0.41 mm and 2.69 mm (mean, 1.53 +/- 0.46 mm). For a single patient, when all alignments were considered together, the mean deviation was between 0.32 +/- 0.10 mm and 0.59 +/- 0.24 mm. Mean deviation for one image was between 0.14 and 1.21 mm. CONCLUSIONS: The range of reproducibility of the social smile presented individual variability, but this variation was not clinically significant or detectable under routine clinical observation. PMID- 26247102 TI - Comparative genomic analyses of transport proteins encoded within the genomes of Leptospira species. AB - Select species of the bacterial genus Leptospira are causative agents of leptospirosis, an emerging global zoonosis affecting nearly one million people worldwide annually. We examined two Leptospira pathogens, Leptospira interrogans serovar Lai str. 56601 and Leptospira borgpetersenii serovar Hardjo-bovis str. L550, as well as the free-living leptospiral saprophyte, Leptospira biflexa serovar Patoc str. 'Patoc 1 (Ames)'. The transport proteins of these leptospires were identified and compared using bioinformatics to gain an appreciation for which proteins may be related to pathogenesis and saprophytism. L. biflexa possesses a disproportionately high number of secondary carriers for metabolite uptake and environmental adaptability as well as an increased number of inorganic cation transporters providing ionic homeostasis and effective osmoregulation in a rapidly changing environment. L. interrogans and L. borgpetersenii possess far fewer transporters, but those that they have are remarkably similar, with near equivalent representation in most transporter families. These two Leptospira pathogens also possess intact sphingomyelinases, holins, and virulence-related outer membrane porins. These virulence-related factors, in conjunction with decreased transporter substrate versatility, indicate that pathogenicity was accompanied by progressively narrowing ecological niches and the emergence of a limited set of proteins responsible for host invasion. The variability of host tropism and mortality rates by infectious leptospires suggests that small differences in individual sets of proteins play important physiological and pathological roles. PMID- 26247105 TI - Accurate Characterization of Ion Transport Properties in Binary Symmetric Electrolytes Using In Situ NMR Imaging and Inverse Modeling. AB - We used NMR imaging (MRI) combined with data analysis based on inverse modeling of the mass transport problem to determine ionic diffusion coefficients and transference numbers in electrolyte solutions of interest for Li-ion batteries. Sensitivity analyses have shown that accurate estimates of these parameters (as a function of concentration) are critical to the reliability of the predictions provided by models of porous electrodes. The inverse modeling (IM) solution was generated with an extension of the Planck-Nernst model for the transport of ionic species in electrolyte solutions. Concentration-dependent diffusion coefficients and transference numbers were derived using concentration profiles obtained from in situ (19)F MRI measurements. Material properties were reconstructed under minimal assumptions using methods of variational optimization to minimize the least-squares deviation between experimental and simulated concentration values with uncertainty of the reconstructions quantified using a Monte Carlo analysis. The diffusion coefficients obtained by pulsed field gradient NMR (PFG-NMR) fall within the 95% confidence bounds for the diffusion coefficient values obtained by the MRI+IM method. The MRI+IM method also yields the concentration dependence of the Li(+) transference number in agreement with trends obtained by electrochemical methods for similar systems and with predictions of theoretical models for concentrated electrolyte solutions, in marked contrast to the salt concentration dependence of transport numbers determined from PFG-NMR data. PMID- 26247106 TI - Computational Study of Drug Binding Affinity to Influenza A Neuraminidase Using Smooth Reaction Path Generation (SRPG) Method. AB - Assessment of accurate drug binding affinity to a protein remains a challenge for in silico drug development. In this research, we used the smooth reaction path generation (SRPG) method to calculate binding free energies and determine potential of mean forces (PMFs) along the smoothed dissociation paths of influenza A neuraminidase and its variants with oseltamivir (Tamiflu) and zanamivir (Relenza) inhibitors. With the gained results, we found that the binding free energies of neuraminidase A/H5N1 in WT and two mutants (including H274Y and N294S) with oseltamivir and zanamivir show good agreement with experimental results. Additionally, the thermodynamic origin of the drug resistance of the mutants was also discussed from the PMF profiles. PMID- 26247107 TI - Application of Mitochondrial DNA Technologies in Wildlife Investigation - Species Identification. AB - Forensic science laboratories are increasingly requested to investigate crimes involving wildlife and to examine nonhuman biological tissue. The illegal trade in endangered species has led to a need to use methods, accepted by the forensic community and acceptable to a court of law, that will identify species that are present from seized samples and to determine whether the ownership of the samples contravenes any legislation. The use of genetic loci on the mitochondrial genome has become standard with the cytochrome b gene being the best described and utilized of the mitochondrial genes. The amplification of part or all of the gene and comparison to stored DNA sequences held on DNA databases such as EMBL (by the European Molecular Biology Laboratory) or GenBank (by the National Institutes of Health) can lead to the identification of the species. Examination of single nucleotide polymorphisms is possible in the case of highly degraded samples. The testing methods available have led to the successful prosecution of traders in endangered or protected species. PMID- 26247108 TI - Correlation of Drug-Testing Results - Immunoassay versus Gas Chromatography-Mass Spectrometry. AB - The need for and prevalence of workplace drug-testing programs mandate the development of an effective and efficient two-step test strategy. Successful implementation of the two-step test strategy relies on the establishment of a reasonable correlation between the preliminary and the confirmatory test data and the selection of an appropriate cutoff for each test step. Correlations of test data derived form these two test steps were most commonly studied qualitatively by comparing the positive/negative test result concluded by these two test steps; however, when instrument-based immunoassays (IA) are used in the preliminary test step, the resulting "semiquantitative" and "apparent" concentration of the targeted analyte can be quantitatively correlated to the analyte concentration as determined by gas chromatography-mass spectrometry (GC-MS). Specimens selected for quantitative correlation studies should be clinical specimens with the distributions of metabolites similar to that present in test specimens; if the resulting correlation data are to be used for selecting appropriate/corresponding cutoffs for these two test steps, the concentrations of the targeted analyte in these specimens should also be within a narrow range centering on the proposed GC MS cutoff concentration. Among the very significant number of reports correlating IA and GC-MS test data, cannabis and urine are the most common drug category and test specimen studied. The degree of correlation between IA and the GC-MS test data varies with the IA reagent manufacturers, and even with manufacture dates/lots of those supplied by the same manufacturer. The most important factors underlying the observed degree of correlation are undoubtedly the cross-reacting characteristics of the antibody and the metabolite distribution pattern of the drug of concern. Over time, specificities of IA reagents have been optimized so that the two-step test strategy can be most effectively and efficiently applied using the cutoffs mandated by workplace drug-testing programs. The nature of correlation and the selection of appropriate/corresponding cutoffs between IA and GC-MS test data derived from alternate biological matrices are yet to be fully understood and established. PMID- 26247109 TI - Disease-Induced Anomalous Human Microsatellite DNA - Implication in Forensic DNA Typing. AB - Short tandem repeat (STR) markers adopted for forensic applications are generally stable and have been proved effective for the analysis of many archival pathology specimens and postmortem tissues. However, recent studies on STR typing of cancerous samples have shown misinterpreted profiles caused by two types of genetic alterations in tumor materials: microsatellite instability (MSI, contractions or expansions of a heterozygous allele) and loss of heterozygosity (LOH). Forensic STR typing of tumor material is unlikely; however, under rare circumstances, these may be the only samples available. This article reviews literature information in the following areas: unusual sample types encountered in casework; possible causes of STR alterations; genetic diseases associated with CODIS 13 markers; and forensic evaluation of commercial STR markers used in solid tumor tissues. Literature information suggested that STR-associated events observed in unusual cases may not be readily explained by known biological and disease processes. In actual practice, false profiles would only arise from complete LOH (rather than allelic imbalance) and MSI. Adoption of different analysis methods and various sets of genetic markers in profiling may lead to inconsistent results. When comparing profiling data reported by different laboratories, one should also note whether the same methodology was applied to the same set of genetic markers used for the evaluation of the disease tissues. To avoid misinterpretations, each tumor type should be evaluated individually, as various disease types may exhibit distinct behavior nature. PMID- 26247110 TI - The "Starch Wars" and the Early History of DNA Profiling. AB - Just as the movie Star Wars had a prequel, so did the "DNA Wars"-the series of legal, scientific, and personal battles that took place over the admissibility of forensic DNA evidence from 1989 to 1994. Between the late 1970s and the mid 1980s, another forensic identification technique became mired in controversy: electrophoresis-based blood protein analysis. Although the debates over blood analysis were every bit as rancorous and frustrating to almost everybody involved - so much so that they became known as the "Starch Wars" - their importance has not been adequately appreciated in the recent history of forensic science. After reviewing the early history of blood typing, I will describe the development of the Multi-System approach to blood protein analysis that took place in California from 1977 to 1978. I will then elucidate the history of the Starch Wars, and demonstrate the ways that they shaped subsequent disputes over DNA evidence, especially in California. I will show that: (a) many of the forensic scientists, law enforcement officials, and lawyers who became prominent players in the DNA Wars were deeply involved in the court cases involving protein electrophoresis; and (b) many of the issues that became controversial in the disputes over DNA evidence first emerged in the Starch Wars. In the conclusion, I will suggest various ways to improve the quality of forensic science based on my analysis of the Starch Wars. PMID- 26247111 TI - Removal of diclofenac and sulfamethoxazole from synthetic municipal waste water in microcosm downflow constructed wetlands: Start-up results. AB - The objectives of this study were to investigate the start-up removal of pharmaceutical compounds diclofenac and sulfamethoxazole in microcosm downflow constructed wetlands and their effect on the performance of the studied constructed wetlands, and also to assess the effect of plants on the removal of these compounds. The experimental system that was used in this 86-day experiment consisted of 24 columns filled up to 70 cm with predominantly sandy material. Four types of columns were used (six replicates) depending on the presence of plants (Phalaris arundinacea L. var. picta L.) and the presence of pharmaceutical compounds in the influent. The influent was synthetic municipal waste water to which a mixture of 5 mg/L of diclofenac and 5 mg/L of sulfamethoxazole was added. The observed removal of diclofenac was moderate (approx. 50%) and the removal of sulfamethoxazole was relatively low (24-30%). It was found that the removal of diclofenac and sulfamethoxazole was not affected by the vegetation. The presence of diclofenac and sulfamethoxazole in the influent had significant effect on the effluent concentration of N-NO3 and the water loss in the columns, which in both cases were lower than in the control columns. The scope for further research was discussed. PMID- 26247112 TI - A NOVEL DOUBLE MUTATION VAL648ILE AND VAL804LEU OF RET PROTO-ONCOGENE IN MULTIPLE ENDOCRINE NEOPLASIA TYPE 2. AB - OBJECTIVE: We report the case of a female patient with multiple endocrine neoplasia type 2A (MEN2A) who was found to have a double mutation in the RET (rearranged during transfection) proto-oncogene. METHODS: RET mutational analysis was performed by Sanger DNA sequencing. RESULTS: The proband was a compound heterozygote for the RET germline mutations Val648Ile and Val804Leu on exons 11 and 14, respectively. Genetic analysis of family members showed the presence of the Val648Ile mutation in all except 1 daughter who carried the Val804Leu mutation. However, none of them showed any clinical, biochemical, or histologic signs of neoplastic disease either in the thyroid or adrenal gland. Furthermore, a daughter and the proband's sister who underwent a prophylactic thyroidectomy did not show pathologic evidence of C-cell disease. CONCLUSIONS: We hypothesize that the combined effect of the 2 mutations may have induced the development of pheochromocytoma (PHEO) in our patient. Thus, in the presence of single RET induced mild medullary thyroid cancer (MTC) phenotype, the search for additional genetic anomalies may lead to the discovery of rare but potentially more aggressive double mutation genotypes. PMID- 26247113 TI - ON THE EDGE OF DISEASE. PMID- 26247114 TI - PRACTICAL BARRIERS TO IMPLEMENTATION OF THYROID CANCER GUIDELINES IN THE ASIA PACIFIC REGION. AB - OBJECTIVE: Numerous published guidelines have described the optimal management of thyroid cancer. However, these rely on the clinical availability of diagnostic and therapeutic modalities. We hypothesized that the availability of medical resources and economic circumstances vary in Asia-Pacific countries, making it difficult to implement guideline recommendations into clinical practice. METHODS: We surveyed participants at the 2009 and 2013 Congresses of the Association of Southeast Asian Nations Federation of Endocrine Societies by distributing questionnaires to attendees at registration. RESULTS: Responses were obtained from 268 respondents in 2009 and 163 respondents in 2013. Similar to the high prevalence of low-risk thyroid cancer observed in the Surveillance, Epidemiology, and End Results database, across the Asia-Pacific countries surveyed in 2009 and 2013, 50 to 100% of the respondents from the Philippines, Malaysia, Singapore, China, Taiwan, Thailand, Hong Kong, Korea, and Sri Lanka reported that more than 50% of the patients had low-risk thyroid cancer on follow-up. Importantly, there was much variation with regards to the perceived availability of investigation and treatment modalities. CONCLUSION: We found a wide variation in clinicians' perception of availability of diagnostic and therapeutic modalities in the face of a rise in thyroid cancer incidence and thyroid cancer management guidelines that emphasized their importance. The lack of availability of management tools and treatments will prove to be a major barrier to the implementation of thyroid cancer management guidelines in Southeast Asia, and likely in other parts of the world as well. PMID- 26247115 TI - SHORT-TERM DECLINE IN PROLACTIN CONCENTRATIONS CAN PREDICT FUTURE PROLACTIN NORMALIZATION, TUMOR SHRINKAGE, AND TIME TO REMISSION IN MEN WITH MACROPROLACTINOMAS. AB - OBJECTIVE: To identify early follow-up measures that will predict the dynamics of prolactin (PRL) decrease and adenoma shrinkage in men harboring macroprolactinomas. METHODS: A single-center historical prospective study including a consecutive group of 71 men with pituitary macroadenomas (>=10 mm) and hyperprolactinemia (PRL >7 times the upper limit of normal [ULN]) treated medically with cabergoline. Comparisons of PRL normalization rates were performed according to PRL levels achieved at 6 months, maximal adenoma shrinkage during follow-up, and other patient characteristics. Correlations were analyzed to identify characteristics of PRL suppression dynamics. RESULTS: PRL levels after 6 months of treatment correlated positively with current PRL levels (r = 0.74; P<.001), with time to PRL normalization (r = 0.75; P<.001), and with adenoma diameter following treatment (r = 0.38; P = .01). Adenoma shrinkage depicted by first magnetic resonance imaging on treatment correlated with maximal adenoma shrinkage during follow-up (r = 0.56; P = .006). Five patients had nadir PRL levels >=3 times the ULN (51 ng/mL) and showed slower response to cabergoline treatment, with consistently higher PRL levels compared with responding patients throughout follow-up (mean 6-month PRL levels, 519 +/- 403 ng/mL versus 59 +/- 118 ng/mL; P<.001). CONCLUSION: Six-month PRL level might serve as a surrogate marker for PRL normalization and adenoma shrinkage dynamics among men harboring macroprolactinomas. PMID- 26247116 TI - A preliminary study suggests that walk-to-run transition is consistent with mechanical optimization. PMID- 26247117 TI - Metastatic liver tumour segmentation from discriminant Grassmannian manifolds. AB - The early detection, diagnosis and monitoring of liver cancer progression can be achieved with the precise delineation of metastatic tumours. However, accurate automated segmentation remains challenging due to the presence of noise, inhomogeneity and the high appearance variability of malignant tissue. In this paper, we propose an unsupervised metastatic liver tumour segmentation framework using a machine learning approach based on discriminant Grassmannian manifolds which learns the appearance of tumours with respect to normal tissue. First, the framework learns within-class and between-class similarity distributions from a training set of images to discover the optimal manifold discrimination between normal and pathological tissue in the liver. Second, a conditional optimisation scheme computes non-local pairwise as well as pattern-based clique potentials from the manifold subspace to recognise regions with similar labelings and to incorporate global consistency in the segmentation process. The proposed framework was validated on a clinical database of 43 CT images from patients with metastatic liver cancer. Compared to state-of-the-art methods, our method achieves a better performance on two separate datasets of metastatic liver tumours from different clinical sites, yielding an overall mean Dice similarity coefficient of [Formula: see text] in over 50 tumours with an average volume of 27.3 mm(3). PMID- 26247118 TI - Preformulation studies and optimization of sodium alginate based floating drug delivery system for eradication of Helicobacter pylori. AB - The aim of this study was to design a local, floating, mucoadhesive drug delivery system containing metronidazole for Helicobacter pylori eradication. Face centered central composite design (with three factors, in three levels) was used for evaluation and optimization of in vitro floating and dissolution studies. Sodium alginate (X1), low substituted hydroxypropyl cellulose (L-HPC B1, X2) and sodium bicarbonate (X3) concentrations were the independent variables in the development of effervescent floating tablets. All tablets showed acceptable physicochemical properties. Statistical analysis revealed that tablets with 5.00% sodium alginate, 38.63% L-HPC B1 and 8.45% sodium bicarbonate content showed promising in vitro floating and dissolution properties for further examinations. Optimized floating tablets expressed remarkable floating force. Their in vitro dissolution studies were compared with two commercially available non-floating metronidazole products and then microbiologically detected dissolution, ex vivo detachment force, rheological mucoadhesion studies and compatibility studies were carried out. Remarkable similarity (f1, f2) between in vitro spectrophotometrically and microbiologically detected dissolutions was found. Studies revealed significant ex vivo mucoadhesion of optimized tablets, which was considerably increased by L-HPC. In vivo X-ray CT studies of optimized tablets showed 8h gastroretention in rats represented by an animation prepared by special CT technique. PMID- 26247119 TI - Physical stability of solid dispersions with respect to thermodynamic solubility of tadalafil in PVP-VA. AB - The aim of this paper was to evaluate physical stability of solid dispersions in respect to the drug, tadalafil (Td), in vinylpyrrolidone and vinyl acetate block copolymer (PVP-VA). Nine solid dispersions of Td in PVP-VA (Td/PVP-VA) varied in terms of quantitative composition (1:9-9:1, w/w) were successfully produced by spray-drying. Their amorphous nature, supersaturated character and molecular level of mixing (a solid solution structure) were subsequently confirmed using DSC, PXRD, SEM and calculation of Hansen total solubility parameters. Due to thermal degradation of both components before the melting point of Td (302.3 degrees C), an approach based on the drug crystallization from the supersaturated solid dispersion was selected to calculate the solubility of Td in the polymer. Annealing of the Td/PVP-VA solid dispersion (1:1, w/w) at selected temperatures above its Tg resulted in different stable solid dispersions. According to the Gordon-Taylor equation their new Tgs gave the information about the quantitative composition which corresponded to the thermodynamic solubility of Td in PVP-VA at given temperatures of annealing. The obtained relationship was fitted to the exponential function, with the calculated solubility of Td of 20.5% at 25 degrees C. This value was in accordance with the results of hot stage polarizing light microscopy as well as stability tests carried out at 80 degrees C and 0% RH, in which Td solid dispersions containing 10-20% of the drug were the only systems that did not crystallize within two months. A thermal analysis protocol utilizing a fast heating rate was shown to generate Td solubility data complementing the solid dispersion method. The Flory-Huggins model applied for the Td/PVP-VA system yielded the solubility value of 0.1% at 25 degrees C, showing the lack of applicability in this case. PMID- 26247120 TI - Chemotropic sensing in fungus-plant interactions. AB - Growth of fungal hyphae is guided by a variety of chemical gradients, including nutrients, mating pheromones or host compounds. Over 100 years after chemotropism was first reported in fungus-plant interactions, our knowledge on the host signals, fungal receptors and cellular pathways is still rudimentary. Genetic analysis in the model organisms Saccharomyces cerevisiae and Neurospora crassa has provided valuable insights into the chemotropic machinery of the fungal hypha. Moreover, recent studies in the root-infecting pathogen Fusarium oxysporum reveal an unanticipated complexity in chemotropic sensing of nutrient sources, peptide pheromones and host plant signals. PMID- 26247121 TI - VIGS, HIGS and FIGS: small RNA silencing in the interactions of viruses or filamentous organisms with their plant hosts. AB - Recent evidence indicates two-way traffic of silencing RNA between filamentous organisms and their plant hosts. There are also indications that suppressors of RNA silencing are transferred from filamentous organisms into host plant cells where they influence the innate immune system. Here I use virus disease as a template for interpretation of RNA silencing in connection with filamentous organisms and infected plant cells. I propose that host plant interactions of these organisms are influenced by RNA silencing networks in which there are: small interfering RNAs from the host that are transported into the filamentous organism and vice versa; silencing suppressors from the organism that are transported into the host; endogenous small interfering RNAs and micro RNAs that target components of the innate immune system or endogenous suppressors of the innate immune system. PMID- 26247122 TI - Transcriptional networks in the nitrate response of Arabidopsis thaliana. AB - Nitrogen is an essential macronutrient for plants and its availability is a key determinant of plant growth and development and crop yield. Besides their nutritional role, N nutrients and metabolites are signals that activate signaling pathways that modulate many plant processes. Because the most abundant inorganic N source for plants in agronomic soils is nitrate, much of the work to understand plant N-signaling has focused on this nutrient. Over the last years, several studies defined a comprehensive catalog of nitrate-responsive genes, involved in nitrate transport, metabolism and a variety of other processes. Despite significant progress in recent years, primarily using Arabidopsis thaliana as a model system, the molecular mechanisms by which nitrate elicits changes in transcript abundance are still not fully understood. Here we highlight recent advancements in identifying key transcription factors and transcriptional mechanisms that orchestrate the gene expression response to changes in nitrate availability in A. thaliana. PMID- 26247123 TI - Plasmodesmata: a signaling hub at the cellular boundary. AB - Effective intercellular communication is crucial for the survival of plants. Because plant cells are encased in rigid cell walls, direct cell-to-cell exchange of cytoplasmic content is only possible through plasmodesmata (PD), membrane lined nanotubes that connect the cytoplasm of adjacent cells. PD are highly dynamic communication channels that can undergo various structural and functional modifications. Recent findings in the field suggest that defense signaling pathways are tightly linked to the regulation of PD, and the restriction of PD mediated cell-to-cell communication is an essential innate immune response to microbial pathogens. Moreover, several plasma membrane-bound signaling components, including receptor-like kinases that are known to have non-cell autonomous function or pathogen perception at the cell periphery, are found to also partition to PD. These findings hint at the novel role of PD as a signaling hub for both symplasmic and cross-membrane pathways. PMID- 26247124 TI - Advances in understanding cis regulation of the plant gene with an emphasis on comparative genomics. AB - The plant gene model remains largely an extrapolation from animals, with the cis functional unit, the gene, cast as a dynamic looping structure. Molecular genetics with model plants continues to make advances; highlighted here are quantitative-occupancy results from the Arabidopsis thaliana (Arabidopsis) Phytochrome-Interacting bHLH transcription Factors (PIF) quartet. Compared to this complex snapshot, results from chromatin occupancy and other Encyclopedia of DNA Elements (ENCODE)-like approaches increase our transcription factor-motif cognate library, but regulation cannot by itself be inferred from binding. Complementary published Arabidopsis conserved noncoding sequence lists are compared, evaluated, merged, and released. Comparative genomic approaches have identified a cis modifier of a gene's expression-hypothetically, a transposon based 'rheostat'-that works in all cells, times and places. PMID- 26247125 TI - Modeling plant development: from signals to gene networks. AB - Mathematical modeling has become a common tool in plant developmental biology. Indeed, it allows for the prediction of complex and often unintuitive dynamics of the molecular networks driving plant development. This has enabled the test of their possible involvement in robust and specific developmental processes. Modeling has also been fruitful in predicting new interactions within gene networks, such as the Arabidopsis circadian clock. A new challenge is to integrate patterning issues with tissue growth and biomechanics. The development of new tools to gain resolution in data collection as well as new frameworks to confront models and data might provide even more robust predictions. PMID- 26247126 TI - Could the Quality of Published Ecotoxicological Research Be Better? PMID- 26247127 TI - Determination of the relative percentage distribution of THCA and Delta(9)-THC in herbal cannabis seized in Austria - Impact of different storage temperatures on stability. AB - Cannabis is globally by far the most widespread illicit drug of abuse. Especially since its legalization in some of the US, controversies about the legal status of cannabis for recreational and medical use have come up. Delta(9) Tetrahydrocannabinol (Delta(9)-THC), which is the major active ingredient in cannabis products, is mainly responsible for the psychoactive effects. Its inactive biosynthetic precursor tetrahydrocannabinolic acid (THCA) is present in different quantities in fresh and undried cannabis plants. Under influence of drying, temperature and UV exposure it decomposes to Delta(9)-THC. In this study, a quantification of Delta(9)-THC and THCA was carried out to check the stability of cannabis samples. The determination of the degradation of THCA to Delta(9)-THC in 29 cannabis products seized in Austria was monitored by HPLC-UV. Mobile phase consisted of a 25mM triethylammoniumphosphate buffer (pH 3.0) and acetonitrile (36:64). A common LiChrospher((r)) 100 RP-18 column was utilized as stationary phase. To check the influence of low as well as high temperature on the degradation process of the cannabinoid THCA to Delta(9)-THC, samples were stored in a freezer or in a drying cabinet for a specified time period. It was shown successfully that high storage temperatures led to a more rapid and complete decomposition of THCA to Delta(9)-THC while at low temperatures only slight or no changes of the percentage distribution were determined. PMID- 26247128 TI - Quantitative determination of n-butane metabolites in three cases of butane sniffing death. AB - Butane is an addictive volatile substance like toluene. We report three forensic autopsy cases of sudden death that occurred while sniffing n-butane and isobutane from portable gas cartridges. n-Butane and isobutane were detected in all three cases. In cases 1-3, n-butane concentrations in heart blood were 54.3, 25.5, and 30.7MUg/mL, respectively. These concentrations were considered fatal according to the previous reports. In addition, n-butane metabolites (2-butanol and 2 butanone) were detected in cases 1 and 3 but not in case 2. Blood levels of 2 butanol and 2-butanone were 6.5 and 1.8MUg/mL, respectively, in case 1, and 6.3 and 5.6MUg/mL, respectively, in case 3. According to the police investigation, the decedent in case 1 had misused butane gas for more than 6 months in the period leading up to death. The decedent in case 3 also had a history of chronic misuse of butane gas. There was no history of chronic misuse of butane gas by the decedent in case 2. It was suspected that he attempted suicide via inhalation of butane gas using a plastic bag, leading to a rapid death. The presence or absence of n-butane metabolites might reflect the way of butane inhalation, such as the frequency and duration. Although additional experimental and case studies are necessary to establish the forensic applications of n-butane metabolite detection, it may be a useful method to understand the decedents' pattern of butane sniffing before death. PMID- 26247129 TI - Crosstalk between toll-like receptors and hypoxia-dependent pathways in health and disease. AB - Toll-like receptors (TLRs) play an important role in shaping the host immune response to infection and inflammation. Tissue hypoxia is a common microenvironmental feature of infected and inflamed tissues. Furthermore, hypoxia significantly impacts the development of immune and inflammatory responses through the regulation of host innate and adaptive immunity. Here, we will discuss current knowledge in relation to the crosstalk that exists between toll like receptor- and hypoxia-dependent signaling pathways in health and disease. PMID- 26247130 TI - Predictors of cost-effectiveness of selected COPD treatments in primary care: UNLOCK study protocol. PMID- 26247131 TI - Changing Treatment Patterns of ROP at a Tertiary Medical Center Between 2002 and 2012. AB - BACKGROUND AND OBJECTIVE: To clinically correlate and evaluate the screening and treatment patterns of retinopathy of prematurity by a single physician at a tertiary care center between 2002 and 2012. PATIENTS AND METHODS: A group of 10,924 newborns screened for ROP between 2002 and 2012 were retrospectively analyzed in a consecutive case series. Records of the neonatal intensive care unit (NICU) at Jackson Memorial Hospital/Bascom Palmer Eye Institute were reviewed to identify patients clinically diagnosed with retinopathy of prematurity who underwent treatment. RESULTS: Laser photocoagulation was used to treat 231 of 10,924 (2.1%). Of these 231 patients, 176 (76.2%) were included in the study (55 infants were excluded because they were referred from outside institutions for advanced ROP). Of the 176 treated patients, 89 (50.6%) were male and 87 (49.4%) were female. The average birth weight was 687.3 g. The mean gestational age was 24.8 weeks. The mean time between birth and treatment was 3 months. Of the 176 patients, 31 required re-treatment with laser photocoagulation. The rates of treatment and retreatment significantly declined with the experience of the treating physician ( P < .01). Retinal detachment occurred in two of 176 patients (1.1%). CONCLUSION: Experience is essential in delivering optimal care in a complex disease such as ROP. Between 2002 and 2012, the rate of treatment and retreatment significantly decreased. Possible reasons include improvements in neonatal care, but it is more likely that the rate of treatment and re-treatment is inversely proportional to the ophthalmologist's experience with and comfort in managing ROP. PMID- 26247132 TI - Treatment and diagnosis of congenital fourth nerve palsies: an update. AB - PURPOSE OF REVIEW: This review discusses recent advances in our understanding of the pathology, diagnosis, and treatment of congenital fourth nerve palsies. RECENT FINDINGS: High-definition MRI, which can now more accurately image the trochlear nerve, has increased our understanding of the pathology of fourth nerve palsies. A more sensitive two-step test is proposed to replace the three-step Parks-Bielschowsky test. Procedures strengthening the superior oblique tendon can be performed with a low incidence of secondary Brown syndrome. SUMMARY: Recent MRI studies have shown two pathological mechanisms associated with congenital superior oblique palsies. Superior oblique tuck combined with inferior oblique recession is a very effective way of eliminating head tilt secondary to congenital fourth nerve palsies. PMID- 26247133 TI - Esotropia associated with high myopia. AB - PURPOSE OF REVIEW: The aim of the present article is to describe the pathophysiology of esotropia associated with high myopia, commonly known as heavy eye syndrome, and discuss the preoperative evaluation and surgical options in these complex patients. RECENT FINDINGS: Numerous studies have looked to determine the cause of esotropia in patients with high myopia. Orbital imaging has shown a nasal displacement of the superior rectus muscle and an inferior displacement of the lateral rectus muscle. As such, traditional resection recession surgery can be ineffective in these patients. Instead, correcting the deviant muscles paths is necessary. Recent studies have shown that loop myopexy with or without medial rectus recession can be performed without sclera fixation sutures to correct the underlying pathophysiology. SUMMARY: Heavy eye syndrome or strabismus fixus is a rare restrictive strabismus. Careful preoperative evaluation must be performed in order to correctly diagnose these patients. If posterior globe prolapse with superior and lateral rectus muscle displacement is seen, loop myopexy can be a well tolerated and effective procedure in treating heavy eye syndrome. PMID- 26247134 TI - Vertical rectus transpositions in sixth nerve palsies. AB - PURPOSE OF REVIEW: There are many surgical options to address a sixth nerve palsy including transpositions of the vertical recti to the lateral rectus. This review will summarize the results from variations on transpositions as they apply to sixth nerve palsies. RECENT FINDINGS: Transposition of both vertical recti with posterior fixation creates the greatest correction of esotropia in primary position with largest field of single vision. Transposition of the superior rectus alone preserving anterior segment circulation achieves effects similar to transposition without posterior fixation. Augmentation with partial transposition also creates similar improvement in esotropia with possibilities for adjustable sutures and circulation preservation. SUMMARY: These various options on transpositions allow options to specifically address surgeon preferences and patient needs to select the appropriate surgery. PMID- 26247135 TI - Management of infantile esotropia. AB - PURPOSE OF REVIEW: Surgical treatment has been the accepted mode of treatment for infantile esotropia for decades. The present review of recent literature evaluates the current standing of: type of surgery performed and best timing of surgery to achieve optimal results. RECENT FINDINGS: Recent studies suggest that early surgical intervention is of benefit by improving the probability of developing stereopsis. A significant advantage of the type of surgical intervention has yet to be demonstrated by the current studies. Botulinum toxin continues to be used for treatment of infantile esotropia, although it has not been shown to be a superior treatment. SUMMARY: Although many theories exist, the true cause of infantile esotropia remains unknown. The literature suggests that treatment before age 2 and perhaps even earlier improves the potential for binocular vision. After significant review of literature, it is clear that surgery is the treatment of choice for infantile esotropia but no method has a clear advantage. Efforts to define the best surgical procedure and timing of surgery through prospective, randomized multicenter trials are warranted. PMID- 26247136 TI - Cervical occupational hazards in ophthalmic plastic surgery. AB - PURPOSE OF REVIEW: To increase awareness of cervical musculoskeletal disorders (cMSD) in ophthalmic plastic surgeons (OPS) and review strategies for management and prevention. RECENT FINDINGS: There are objective data that show OPS spend the majority of their time operating in awkward, prolonged, static, asymmetric postures. These postures increase cervical load and cMSD. Loupes and headlamps further increase this cervical loading by 40%. Risk for cMSD is not limited to the operating room. Muscular demands in the anterior deltoid and cervical trapezius are increased in slit lamp biomicroscopy and indirect ophthalmoscopy. Furthermore, the majority of the office visit is spent keyboarding into the electronic medical record which is associated with cMSD. Habitual postural faults result from these cumulative exposures. These must be addressed to prevent further insult and debilitating injury. Successful management requires education in neutral posture, therapeutic exercise, environmental adjustments in the workplace and home, and supported neutral sleep posture. SUMMARY: The risks of cMSD in OPS are well established, and nearly 10% of cervical injury will end a career. Neck pain must not be ignored, and experienced professional help is critical. A long-term approach that incorporates exercise, manual therapy, and education is essential for management and prevention. PMID- 26247137 TI - The many facets of dacryoadenitis. AB - PURPOSE OF REVIEW: To review the spectrum of lacrimal gland inflammation, with particular reference to the old condition, idiopathic dacryoadenitis, and the new, immunoglobulin G4 (IgG4)-related dacryoadenitis. RECENT FINDINGS: Idiopathic dacryoadenitis remains the most common inflammatory lesion of the lacrimal gland, for which surgical treatment is successful. There is mounting evidence that the presence of IgG4-positive plasma cells in a lacrimal gland specimen is nonspecific, for being found in other inflammatory lacrimal gland lesions, even lymphoproliferative ones. To identify IgG4-related dacryoadenitis, particularly when there is no documented disease elsewhere, the criteria have been strengthened toward abundant IgG4-positive plasma cell counting. SUMMARY: The gold standard of diagnosis of noninfectious lacrimal gland inflammation is tissue biopsying, which is commonly therapeutic in the case of idiopathic dacryoadenitis. Although it was initially suggested that IgG4-related dacryoadenitis is a possible cause of idiopathic dacryoadenitis, it becomes obvious that it has more resemblance to the lymphoproliferative tumors. PMID- 26247138 TI - Standardized Active Middle-Ear Implant Coupling to the Short Incus Process. AB - INTRODUCTION: Active middle-ear implants with floating-mass transducer (FMT) technology are used to treat mild-to-severe sensorineural hearing losses. The standard surgical approach for incus vibroplasty is a mastoidectomy and a posterior tympanotomy, crimping the FMT to the long incus process. An alternative fixation side with less surgical trauma might be the short incus process and incus body.The aim of this study was to develop and test a short incus process coupling device for its functional properties in temporal bone preparations and clinical practice. MATERIALS AND METHODS: An extended antrotomy and a posterior tympanotomy were performed in 10 fresh human temporal bones. As a control for normal middle-ear function, the tympanic membrane was stimulated acoustically, and the vibration of the stapes footplate was measured using laser Doppler vibrometry. FMT-induced vibration responses of the stapes were then measured for standard attachment at the long process and for 2 types of couplers designed for attachment at the short process of the incus (SP1 and SP2 coupler). Additionally, the functional outcome in 2 patients provided with an SP2 coupler was assessed postoperatively at 2 weeks, 3 months, and then 11 months, using pure-tone audiometry, auditory thresholds for frequency-modulated (warble) tones, vibroplasty thresholds, and speech audiometry in quiet and noise. RESULTS: For the SP2 coupler, velocity-amplitude responses in temporal-bone preparations showed generally similar mean amplitudes as compared with the standard coupling of the FMT to the long process but with clearly increased mean amplitudes between 0.7 and 1.5 kHz and with reduced interindividual variation between 0.5 and 3 kHz. The clinical data of 2 patients with mild-to-severe sensory hearing loss showed good vibroplasty thresholds and convincing results for speech audiometry in quiet (Freiburger monosyllables at 65 dB SPL, 23 +/- 31% unaided versus 83 +/- 4% aided) and noise (Hochmair-Schulz-Moser-test at 65 dB SPL at 10 dB SNR, 32 +/- 45% unaided and 42 +/- 29% aided). CONCLUSION: The attachment of the FMT to the short incus process with the SP2 coupler leads to good mechanical and functional coupling in an experimental setup and clinical practice. PMID- 26247139 TI - Prediction of protein folding rates from simplified secondary structure alphabet. AB - Protein folding is a very complicated and highly cooperative dynamic process. However, the folding kinetics is likely to depend more on a few key structural features. Here we find that secondary structures can determine folding rates of only large, multi-state folding proteins and fails to predict those for small, two-state proteins. The importance of secondary structures for protein folding is ordered as: extended beta strand > alpha helix > bend > turn > undefined secondary structure>310 helix > isolated beta strand > pi helix. Only the first three secondary structures, extended beta strand, alpha helix and bend, can achieve a good correlation with folding rates. This suggests that the rate limiting step of protein folding would depend upon the formation of regular secondary structures and the buckling of chain. The reduced secondary structure alphabet provides a simplified description for the machine learning applications in protein design. PMID- 26247140 TI - Network-based identification of reliable bio-markers for cancers. AB - Finding bio-markers for complex disease from gene expression profiles attracts extensive attentions for its potential use in diagnosis, therapy, and drug design. In this paper we propose a network-based method to seek high-confident bio-markers from candidate genes collected in the literature. The algorithm includes three consequent steps. First, one can collect the proposed bio-markers in literature as being the preliminary candidate; Second, a spanning-tree based threshold can be used to reconstruct gene networks for normal and cancer samples; Third, by jointly using of degree changes and distribution of the candidates in communities, one can filter out the low-confident genes. The survival candidates are high-confident genes. Specially, we consider expression profiles for carcinoma of colon. A total of 34 preliminary bio-markers collected from literature are evaluated and a set of 16 genes are proposed as high confident bio markers, which behave high performance in distinguishing normal and cancer samples. PMID- 26247141 TI - The evolutionary advantage of haploid versus diploid microbes in nutrient-poor environments. AB - Sexual eukaryotic organisms are characterized by haploid and diploid nuclear phases. In many organisms, growth and development occur in both haploid and diploid phases, and the relative length of these phases exhibits considerable diversity. A number of hypotheses have been put forward to explain the maintenance of this diversity of life cycles and the advantage of being haploid versus that of being diploid. The nutrient-limitation hypothesis postulates that haploid cells, because they are small and thus have a higher surface area to volume ratio, are advantageous in nutrient-poor environments. In this paper, we examine this hypothesis theoretically and determine the conditions under which it holds. On the basis of our analysis, we make the following predictions. First, the relative advantages of different ploidy levels strongly depend on the ploidy dependent energy conversion efficiency and the scaling of mortality with cell size. Specifically, haploids enjoy a higher intrinsic population growth rate than diploids do under nutrient-poor conditions, but under nutrient-rich conditions the intrinsic population growth rate of diploids is higher, provided that the energy conversion efficiency of diploids is higher than that of haploids and the scaling of mortality with cell size is weak. Second, differences in nutrient concentration in the inflowing medium have almost no effect on the relative advantage of ploidy levels at population equilibrium. Our study illustrates the importance of explicit modeling of microbial life history and population dynamics to understand the evolution of ploidy levels. PMID- 26247142 TI - Post-transcriptional regulation of ribosomal protein genes during serum starvation in Entamoeba histolytica. AB - Ribosome synthesis involves all three RNA polymerases which are co-ordinately regulated to produce equimolar amounts of rRNAs and ribosomal proteins (RPs). Unlike model organisms where transcription of rRNA and RP genes slows down during stress, in E. histolytica rDNA transcription continues but pre-rRNA processing slows down and unprocessed pre-rRNA accumulates during serum starvation. To investigate the regulation of RP genes under stress we measured transcription of six selected RP genes from the small- and large-ribosomal subunits (RPS6, RPS3, RPS19, RPL5, RPL26, RPL30) representing the early-, mid-, and late-stages of ribosomal assembly. Transcripts of these genes persisted in growth-stressed cells. Expression of luciferase reporter under the control of two RP genes (RPS19 and RPL30) was studied during serum starvation and upon serum replenishment. Although luciferase transcript levels remained unchanged during starvation, luciferase activity steadily declined to 7.8% and 15% of control cells, respectively. After serum replenishment the activity increased to normal levels, suggesting post-transcriptional regulation of these genes. Mutations in the sequence -2 to -9 upstream of AUG in the RPL30 gene resulted in the phenotype expected of post-transcriptional regulation. Transcription of luciferase reporter was unaffected in this mutant, and luciferase activity did not decline during serum starvation, showing that this sequence is required to repress translation of RPL30 mRNA, and mutations in this region relieve repression. Our data show that during serum starvation E. histolytica blocks ribosome biogenesis post transcriptionally by inhibiting pre-rRNA processing on the one hand, and the translation of RP mRNAs on the other. PMID- 26247143 TI - Cardiopulmonary resuscitation quality and patient survival outcome in cardiac arrest: A systematic review and meta-analysis. AB - AIM: To conduct a systematic review and meta-analysis to determine whether cardiopulmonary resuscitation (CPR) quality, as indicated by parameters such as chest compression depth, compression rate and compression fraction, is associated with patient survival from cardiac arrest. METHODS: Five databases were searched (MEDLINE, Embase, CINAHL, Scopus and Cochrane) as well as the grey literature (MedNar). To satisfy inclusion criteria, studies had to document human cases of in- or out-of hospital cardiac arrest where CPR quality had been recorded using an automated device and linked to patient survival. Where indicated (I(2)<75%), meta-analysis was undertaken to examine the relationship between individual CPR quality parameters and either survival to hospital discharge (STHD) or return of spontaneous circulation (ROSC). RESULTS: Database searching yielded 8,842 unique citations, resulting in the inclusion of 22 relevant articles. Thirteen were included in the meta-analysis. Chest compression depth was significantly associated with STHD (mean difference (MD) between survivors and non-survivors 2.59 mm, 95% CI: 0.71, 4.47); and with ROSC (MD 0.99 mm, 95% CI: 0.04, 1.93). Within the range of approximately 100-120 compressions per minute (cpm), compression rate was significantly associated with STHD; survivors demonstrated a lower mean compression rate than non-survivors (MD -1.17 cpm, 95% CI: -2.21, 0.14). Compression fraction could not be examined by meta-analysis due to high heterogeneity, however a higher fraction appeared to be associated with survival in cases with a shockable initial rhythm. CONCLUSIONS: Chest compression depth and rate were associated with survival outcomes. More studies with consistent reporting of data are required for other quality parameters. PMID- 26247144 TI - Per-Protocol and Pre-Defined population analysis of the LINC study. AB - OBJECTIVE: To perform two predefined sub-group analyses within the LINC study and evaluate if the results were supportive of the previous reported intention to treat (ITT) analysis. METHODS: Predefined subgroup analyses from the previously published LINC study were performed. The Per-Protocol population (PPP) included the randomized patients included in the ITT-population but excluding those with violated inclusion or exclusion criteria and those that did not get the actual treatment to which the patient was randomized. In the Pre-Defined population (PDP) analyses patients were also excluded if the dispatch time to ambulance arrival at the address exceeded 12 min, there was a non-witnessed cardiac arrest, or if it was not possible to determine whether the arrest was witnessed or not, and those cases where LUCAS was not brought to the scene at the first instance. RESULTS: After exclusion from the 2589 patients within the ITT-population, the Per-Protocol analysis was performed in 2370 patients and the Pre-Defined analysis within 1133 patients. There was no significant difference in 4-h survival of patients between the mechanical-CPR group and the manual-CPR group in the Per Protocol population; 279 of 1172 patients (23.8%) versus 281 of 1198 patients (23.5%) (risk difference -0.35%, 95% C.I. -3.1 to 3.8, p=0.85) or in the Pre Defined population; 176 of 567 patients (31.0%) versus 192 of 566 patients (33.9%) (risk difference -2.88%, 95% C.I. -8.3 to 2.6, p=0.31). There was no difference in any of the second outcome variables analyzed in the Pre-Protocol or Pre-Defined populations. CONCLUSIONS: The results from these predefined sub-group analyses of the LINC study population did not show any difference in 4h survival or in secondary outcome variables between patients treated with mechanical-CPR or manual-CPR. This is consistent with the previously published ITT analysis. PMID- 26247145 TI - Color-coded prefilled medication syringes decrease time to delivery and dosing errors in simulated prehospital pediatric resuscitations: A randomized crossover trial. AB - BACKGROUND: Medication dosing errors remain commonplace and may result in potentially life-threatening outcomes, particularly for pediatric patients where dosing often requires weight-based calculations. Novel medication delivery systems that may reduce dosing errors resonate with national healthcare priorities. Our goal was to evaluate novel, prefilled medication syringes labeled with color-coded volumes corresponding to the weight-based dosing of the Broselow Tape, compared to conventional medication administration, in simulated prehospital pediatric resuscitation scenarios. METHODS: We performed a prospective, block-randomized, cross-over study, where 10 full-time paramedics each managed two simulated pediatric arrests in situ using either prefilled, color-coded syringes (intervention) or their own medication kits stocked with conventional ampoules (control). Each paramedic was paired with two emergency medical technicians to provide ventilations and compressions as directed. The ambulance patient compartment and the intravenous medication port were video recorded. Data were extracted from video review by blinded, independent reviewers. RESULTS: Median time to delivery of all doses for the intervention and control groups was 34 (95% CI: 28-39) seconds and 42 (95% CI: 36-51) seconds, respectively (difference=9 [95% CI: 4-14] seconds). Using the conventional method, 62 doses were administered with 24 (39%) critical dosing errors; using the prefilled, color-coded syringe method, 59 doses were administered with 0 (0%) critical dosing errors (difference=39%, 95% CI: 13-61%). CONCLUSIONS: A novel color-coded, prefilled syringe decreased time to medication administration and significantly reduced critical dosing errors by paramedics during simulated prehospital pediatric resuscitations. PMID- 26247147 TI - Fungal colonization of the brain: anatomopathological aspects of neurological cryptococcosis. AB - Brain infection by the fungus Cryptococcus neoformans results in an estimated 500,000 human deaths per annum. Colonization of the central nervous system (CNS) by C. neoformans causes different clinical syndromes that involve interaction of a number of fungal components with distinct brain cells. In this manuscript, our literature review confirmed the notion that the Cryptococcus field is expanding rapidly, but also suggested that studies on neuropathogenesis still represent a small fraction of basic research activity in the field. We therefore discussed anatomical and physiological aspects of the brain during infection by C. neoformans, in addition to mechanisms by which brain resident cells interact with the fungus. This review suggests that multiple efforts are necessary to improve the knowledge on how C. neoformans affects brain cells, in order to enable the generation of new therapeutic tools in a near future. PMID- 26247146 TI - Time-Dependent Effects of Ethanol on BK Channel Expression and Trafficking in Hippocampal Neurons. AB - BACKGROUND: The large conductance Ca(2+) - and voltage-activated K(+) channel (BK) is an important player in molecular and behavioral alcohol tolerance. Trafficking and surface expression of ion channels contribute to the development of addictive behaviors. We have previously reported that internalization of the BK channel is a component of molecular tolerance to ethanol (EtOH). METHODS: Using primary cultures of hippocampal neurons, we combine total internal reflection fluorescence microscopy, electrophysiology, and biochemical techniques to explore how exposure to EtOH affects the expression and subcellular localization of endogenous BK channels over time. RESULTS: Exposure to EtOH changed the expression of endogenous BK channels in a time-dependent manner at the perimembrane area (plasma membrane and/or the area adjacent to it), while total protein levels of BK remain unchanged. These results suggest a redistribution of the channel within the neurons rather than changes in synthesis or degradation rates. Our results showed a temporally nonlinear effect of EtOH on perimembrane expression of BK. First, there was an increase in BK perimembrane expression after 10 minutes of EtOH exposure that remained evident after 3 hours, although not correlated to increases in functional channel expression. In contrast, after 6 hours of EtOH exposure, we observed a significant decrease in both BK perimembrane expression and functional channel expression. Furthermore, after 24 hours of EtOH exposure, perimembrane levels of BK had returned to baseline. CONCLUSIONS: We report a complex time-dependent pattern in the effect of EtOH on BK channel trafficking, including successive increases and decreases in perimembrane expression and a reduction in active BK channels after 3 and 6 hours of EtOH exposure. Possible mechanisms underlying this multiphasic trafficking are discussed. As molecular tolerance necessarily underlies behavioral tolerance, the time-dependent alterations we see at the level of the channel may be relevant to the influence of drinking patterns on the development of behavioral tolerance. PMID- 26247148 TI - The neurotoxic effects of vitamin A and retinoids. AB - Vitamin A (retinol) and its congeners - the retinoids - participate in a panoply of biological events, as for instance cell differentiation, proliferation, survival, and death, necessary to maintain tissue homeostasis. Furthermore, such molecules may be applied as therapeutic agents in the case of some diseases, including dermatological disturbances, immunodeficiency, and cancer (mainly leukemia). In spite of this, there is a growing body of evidences showing that vitamin A doses exceeding the nutritional requirements may lead to negative consequences, including bioenergetics state dysfunction, redox impairment, altered cellular signaling, and cell death or proliferation, depending on the cell type. Neurotoxicity has long been demonstrated as a possible side effect of inadvertent consumption, or even under medical recommendation of vitamin A and retinoids at moderate to high doses. However, the exact mechanism by which such molecules exert a neurotoxic role is not clear yet. In this review, recent data are discussed regarding the molecular findings associated with the vitamin A related neurotoxicity. PMID- 26247149 TI - Toxicological Evaluation of Anti-Scrapie Trimethoxychalcones and Oxadiazoles. AB - An altered form of the cellular prion protein, the PrPScor PrPRes, is implicated in the occurrence of the still untreatable transmissible spongiform encephalopathies. We have previously synthesized and characterized aromatic compounds that inhibit protease-resistant prion protein (PrPRes) accumulation in scrapie-infected cells. These compounds belong to different chemical classes, including acylhydrazones, chalcones and oxadiazoles. Some of the active compounds were non-toxic to neuroblastoma cells in culture and seem to possess drugable properties, since they are in agreement with the Lipinski's rule of 5 and present desirable pharmacokinetic profiles as predicted in silico. Before the evaluation of the in vivo efficacy of the aromatic compounds in scrapie-infected mice, safety assessment in healthy mice is needed. Here we used Swiss mice to evaluate the acute toxicity profile of the six most promising anti-prionic compounds, the 2,4,5-trimethoxychalcones (J1, J8, J20 and J35) and the 1,3,4-oxadiazoles (Y13 and Y17). One single oral administration (300 mg/kg) of J1, J8, J20, J35, Y13 and Y17 or repeated intraperitoneal administration (10 mg/kg, 3 times a week, for 4 weeks) of J1, J8 and J35, did not elicit toxicity in mice. We strongly believe that the investigated trimethoxychalcones and oxadiazoles are interesting compounds to be further analyzed in vivo against prion diseases. PMID- 26247150 TI - New approaches to the treatment of orphan genetic disorders: Mitigating molecular pathologies using chemicals. AB - With the advance and popularization of molecular techniques, the identification of genetic mutations that cause diseases has increased dramatically. Thus, the number of laboratories available to investigate a given disorder and the number of subsequent diagnosis have increased over time. Although it is necessary to identify mutations and provide diagnosis, it is also critical to develop specific therapeutic approaches based on this information. This review aims to highlight recent advances in mutation-targeted therapies with chemicals that mitigate mutational pathology at the molecular level, for disorders that, for the most part, have no effective treatment. Currently, there are several strategies being used to correct different types of mutations, including the following: the identification and characterization of translational readthrough compounds; antisense oligonucleotide-mediated splicing redirection; mismatch repair; and exon skipping. These therapies and other approaches are reviewed in this paper. PMID- 26247151 TI - Mesenchymal stem cells for the treatment of neurodegenerative and psychiatric disorders. AB - Mesenchymal stem cells (MSCs) are multipotent progenitor cells that have the capacity to differentiate into all lineages of mesodermal origin, e.g., cartilage, bone, and adipocytes. MSCs have been identified at different stages of development, including adulthood, and in different tissues, such as bone marrow, adipose tissue and umbilical cord. Recent studies have shown that MSCs have the ability to migrate to injured sites. In this regard, an important characteristic of MSCs is their immunomodulatory and anti-inflammatory effects. For instance, there is evidence that MSCs can regulate the immune system by inhibiting proliferation of T and B cells. Clinical interest in the use of MSCs has increased considerably over the past few years, especially because of the ideal characteristics of these cells for regenerative medicine. Therapies with MSCs have shown promising results neurodegenerative diseases, in addition to regulating inflammation, they can promote other beneficial effects, such as neuronal growth, decrease free radicals, and reduce apoptosis. Notwithstanding, despite the vast amount of research into MSCs in neurodegenerative diseases, the mechanism of action of MSCs are still not completely clarified, hindering the development of effective treatments. Conversely, studies in models of psychiatric disorders are scarce, despite the promising results of MSCs therapies in this field as well. PMID- 26247152 TI - Antioxidant, analgesic and anti-inflammatory effects of lavender essential oil. AB - Several studies have investigated the antinociceptive, immunomodulatory and anti inflammatory properties of compounds found in the lavender essential oil (LEO), however to date, there is still lack of substantial data. The objective of this study was to assess the antioxidant, anti-inflammatory and antinociceptive effects of lavender essential oil. The 1,1-diphenyl-2-picrylhydrazyl radical decolorization assay was used for antioxidant activity evaluation. The anti inflammatory activity was tested using two models of acute inflammation: carrageenan-induced pleurisy and croton oil-induced ear edema. The antinociceptive activity was tested using the pain model induced by formalin. LEO has antioxidant activity, which is dose-dependent response. The inflammatory response evoked by carrageenan and by croton oil was reduced through the pre treatment of animals with LEO. In the pleurisy model, the drug used as positive control, dexamethasone, was more efficacious. However, in the ear swelling, the antiedematogenic effect of the oil was similar to that observed for dexamethasone. In the formalin test, LEO consistently inhibited spontaneous nociception and presented a similar effect to that of tramadol. The results of this study reveal (in vivo) the analgesic and anti-inflammatory activities of LEO and demonstrates its important therapeutic potential. PMID- 26247153 TI - D-glyceric aciduria. AB - Inherited metabolic diseases are a heterogeneous group of diseases caused by a punctual defect in cell metabolism, resulting in the accumulation of toxic intermediate metabolites or in the lack of important biomolecules for adequate cell functioning. D-glyceric aciduria is an inherited disease caused by a deficiency of glycerate 2-kinase activity, whose pathophysiological mechanisms remain unknown. The main clinical and neurological symptoms seen in affected patients include progressive encephalopathy, hypotonia, psychomotor and mental retardation, microcephaly, seizures, speech delay, metabolic acidosis, and even death. In this review we shall discuss these clinical and biochemical findings, as well as diagnosis and treatment of affected patients in order to raise awareness about this condition. PMID- 26247154 TI - A structural perspective on the mechanisms of quorum sensing activation in bacteria. AB - Bacteria are able to synchronize the population behavior in order to regulate gene expression through a cell-to-cell communication mechanism called quorum sensing. This phenomenon involves the production, detection and the response to extracellular signaling molecules named autoinducers, which directly or indirectly regulate gene expression in a cell density-dependent manner. Quorum sensing may control a wide range of biological processes in bacteria, such as bioluminescence, virulence factor production, biofilm formation and antibiotic resistance. The autoinducers are recognized by specific receptors that can either be membrane-bound histidine kinase receptors, which work by activating cognate cytoplasmic response regulators, or cytoplasmic receptors acting as transcription factors. In this review, we focused on the cytosolic quorum sensing regulators whose three-dimensional structures helped elucidate their mechanisms of action. Structural studies of quorum sensing receptors may enable the rational design of inhibitor molecules. Ultimately, this approach may represent an effective alternative to treat infections where classical antimicrobial therapy fails to overcome the microorganism virulence. PMID- 26247155 TI - Acute administration of fenproporex increased acetylcholinesterase activity in brain of young rats. AB - Fenproporex is the second most commonly amphetamine-based anorectic consumed worldwide; this drug is rapidly converted into amphetamine, in vivo, and acts by increasing dopamine levels in the synaptic cleft. Considering that fenproporex effects on the central nervous system are still poorly known and that acetylcholinesterase is a regulatory enzyme which is involved in cholinergic synapses and may indirectly modulate the release of dopamine, the present study investigated the effects of acute administration of fenproporex on acetylcholinesterase activity in brain of young rats. Young male Wistar rats received a single injection of fenproporex (6.25, 12.5 or 25mg/kg i.p.) or vehicle (2% Tween 80). Two hours after the injection, the rats were killed by decapitation and the brain was removed for evaluation of acetylcholinesterase activity. Results showed that fenproporex administration increased acetylcholinesterase activity in the hippocampus and posterior cortex, whereas in the prefrontal cortex, striatum and cerebellum the enzyme activity was not altered. In conclusion, in the present study we demonstrated that acute administration of fenproporex exerts an effect in the cholinergic system causing an increase in the activity of acetylcholinesterase in a dose-dependent manner in the hippocampus and posterior cortex. Thus, we suggest that the imbalance in cholinergic homeostasis could be considered as an important pathophysiological mechanism underlying the brain damage observed in patients who use amphetamines such as fenproporex. PMID- 26247156 TI - Efficacy of Topical 5% Acyclovir-1% Hydrocortisone Cream (ME-609) for Treatment of Herpes Labialis: a systematic review. AB - We performed a systematic review with the objective of verifying the efficacy of topical use 5% Acyclovir-1% Hydrocortisone cream compared to the placebo group for herpes simplex labialis treatment. We performed a literature search using MEDLINE, Embase, BIOSIS, LILACS, Scopus, Grey literature, the Cochrane Central Register of Controlled Trials, the ISI Web of Science and IBECS from 1990 to June 2014. We reported the outcomes using relative risk (RR) with 95% confidence intervals. The literature search yielded 180 potentially relevant publications. Reviews of the reference lists yielded two further citations. Among these papers, two were considered eligible for inclusion in this review. Both trials included 1,213 patients. A meta-analysis of these studies showed a RR = 0.77, (95% CI 0.70 0.86; p<0.001).This result suggests that an early episodic treatment with the combination of an antiviral and a steroid is beneficial for herpes simplex labialis treatment. PMID- 26247157 TI - Contrasting mechanisms of de novo copy number mutagenesis suggest the existence of different classes of environmental copy number mutagens. AB - While gene copy number variations (CNVs) are abundant in the human genome, and often are associated with disease consequences, the mutagenic pathways and environmental exposures that cause these large structural mutations are understudied relative to conventional nucleotide substitutions in DNA. The members of the environmental mutagenesis community are currently seeking to remedy this deficiency, and there is a renewed interest in the development of mutagenicity assays to identify and characterize compounds that may induce de novo CNVs in humans. To achieve this goal, it is critically important to acknowledge that CNVs exist in two very distinct classes: nonrecurrent and recurrent CNVs. The goal of this commentary is to emphasize the deep contrasts that exist between the proposed pathways that lead to these two mutation classes. Nonrecurrent de novo CNVs originate primarily in mitotic cells through replication-dependent DNA repair pathways that involve microhomologies (<10 bp), and are detected at higher frequency in children of older fathers. In contrast, recurrent de novo CNVs are most often formed in meiotic cells through homologous recombination between nonallelic large low-copy repeats (>10,000 bp), without an associated paternal age effect. Given the biological differences between the two CNV classes, it is our belief that nonrecurrent and recurrent CN mutagens will probably differ substantially in their modes of action. Therefore, each CNV class may require their own uniquely designed assays, so that we as a field may succeed in uncovering the broadest possible spectrum of environmental CN mutagens. PMID- 26247158 TI - Correction: Bisphosphonate-functionalized hyaluronic acid showing selective affinity for osteoclasts as a potential treatment for osteoporosis. AB - Correction for 'Bisphosphonate-functionalized hyaluronic acid showing selective affinity for osteoclasts as a potential treatment for osteoporosis' by Sujit Kootala et al., Biomater. Sci., 2015, 3, 1197-1207. PMID- 26247159 TI - Tunneling holes in microparticles to facilitate the transport of lithium ions for high volumetric density batteries. AB - Microscale materials generally have a higher tap density than that of random nanoparticles. Therefore, microparticles have been attracting much attention for application as high volumetric density electrodes for lithium ion batteries. However, microparticles have much longer electrolyte diffusion and Li-ion migration length and less accessibility to the electrolyte than that of nanoparticles. Therefore, it will be interesting to tunnel-holes in the high volumetric density microparticles to facilitate the reversible storage of lithium ions. Here, tunnel-like holes were generated in microparticles to dramatically increase the accessibility of the active materials to facilitate the lithium ion transfer. A plausible formation mechanism to explain the generation of tunnel like holes was proposed based on time-course experiments and intensive characterization. Impressively, the as-prepared microbeads with tunnels demonstrated dramatically improved performance compared to the solid microbeads without tunnels in lithium ion storage. The microparticles with tunnels could achieve comparable electrochemical performances to those nanoparticles reported in the literature, suggesting that microparticles, properly tuned, could be promising candidates as negative electrodes for lithium-ion batteries and worthy of further studies. We also directly measured the volumetric density of the microparticles. We would like to highlight that a superior volumetric capacity of 514 mA h cm(-3) has been achieved. We hope to promote more frequent use of the unit mA h cm(-3) in addition to the conventional unit mA h g(-1) in the battery community. PMID- 26247160 TI - Structural characteristics of the acquired optic disc pit and the rate of progressive retinal nerve fiber layer thinning in primary open-angle glaucoma. AB - IMPORTANCE: The optic disc pit (ODP) has been considered a region of localized susceptibility to the damage of glaucoma. OBJECTIVE: To determine whether the rate of retinal nerve fiber layer (RNFL) thinning differs according to the presence and structural characteristics of an ODP in primary open-angle glaucoma. DESIGN, SETTING, AND PARTICIPANTS: We performed a prospective case-control study that included 163 eyes with primary open-angle glaucoma (83 with an ODP and 80 without an ODP) from Glaucoma Clinic of Seoul National University Bundang Hospital. Participants were enrolled from the ongoing Investigating Glaucoma Progression Study from January 1, 2012, through May 31, 2014. Mean (SD) follow-up was 3.32 (0.49) years (through May 31, 2014). Optic nerve heads underwent swept source optical coherence tomography (OCT) to determine the presence of focal lamina cribrosa alteration and its structural characteristics. Eyes with and without photographic ODPs and corresponding microscopic laminar alterations were assigned to the ODP and non-ODP groups, respectively. The rates of progressive thinning of global and 6 sectoral spectral-domain OCT RNFL thicknesses were determined by linear regression and compared between the 2 groups. We used a general linear model to determine the factors associated with the rate of RNFL thinning; data obtained from September 21, 2009, through May 31, 2014, were used to calculate the rate of RNFL thinning. MAIN OUTCOMES AND MEASURES: The relationship between the presence and structural characteristics of ODPs and the rate of progressive OCT RNFL thinning. RESULTS: Thinning of the RNFL was faster in the ODP group than in the non-ODP group in the global (mean [SD], -1.44 [1.31] vs -0.93 [1.10] [95% CI, -0.97 to -0.19] MUm/y; P = .008), temporoinferior (mean [SD], -4.17 [4.15] vs -1.97 [3.26] [95% CI, -3.36 to -1.04] MUm/y; P < .001), and temporal (mean [SD], -1.92 [2.62] vs -0.89 [1.62] [95% CI, -1.70 to -0.35] MUm/y; P = .003) sectors. The rate of RNFL thinning was maximum in the temporoinferior sector (mean [SD], -4.17 [4.15] MUm/y) and corresponded to the frequency distribution of ODPs. Regression analysis revealed that faster global RNFL thinning was related to a higher untreated intraocular pressure (beta = -0.07; 95% CI, -0.11 to -0.03; P = .001), episodes of disc hemorrhage (beta = -0.74; 95% CI, -1.79 to 0.31; P = .003), the presence of beta-zone parapapillary atrophy (beta = -0.47; 95% CI, -1.13 to 0.20; P = .02), and the presence of ODPs (beta = 0.41; 95% CI, -1.14 to 0.32; P = .02). The maximum rate of RNFL thinning was associated with higher untreated intraocular pressure (beta = -0.24; 95% CI, 0.35 to -0.13; P < .001), disc hemorrhage (beta = -1.54; 95% CI, -2.88 to -0.19; P < .001), and the presence (beta = -1.04; 95% CI, -2.14 to 0.07; P = .004), far peripheral location (beta = -1.75; 95% CI, -3.05 to -0.46; P = .008), and partial thickness depth (beta = -1.45; 95% CI, -2.75 to -0.16; P = .03) of an ODP. CONCLUSIONS AND RELEVANCE: The presence and structural characteristics of ODPs were associated with global and focal progression as assessed by the rate of OCT RNFL thinning. The assessment of ODP structure using swept-source OCT may help to predict the location of future progression. PMID- 26247161 TI - The Arc of Health Literacy. PMID- 26247162 TI - Sonographically Guided Posterior Cruciate Ligament Injections: Technique and Validation. AB - OBJECTIVE: To describe and validate a technique for sonographically guided posterior cruciate ligament (PCL) injections. DESIGN: Prospective, cadaveric laboratory investigation. SETTING: Procedural skills laboratory. SUBJECTS: Eight unembalmed, cadaveric, mid-thigh-knee specimens (4 left knees and 4 right knees) obtained from 4 male and 4 female donors aged 57 to 64 years (mean 60.8 years) with body mass indices of 27.7 to 36.5 kg/m(2) (mean 32 kg/m(2)). METHODS: A 5-2 MHz curvilinear probe and a 22-gauge, 78-mm stainless steel needle was used to inject 2 mL of diluted blue latex into the PCL of each specimen using an in plane, caudad-to-cephalad approach. At a minimum of 24 hours postinjection, each specimen was dissected to assess the presence and distribution of latex within the PCL. MAIN OUTCOME: Presence and distribution of latex within the PCL. RESULTS: All 8 injections accurately delivered latex throughout the PCL, including the tibial and femoral footprints. In 2 of 8 specimens (25%), a small amount of latex was noted to extend beyond the PCL and into the joint space. No specimens exhibited evidence of needle injury of latex infiltration with respect to the popliteal neurovascular bundle, menisci, hyaline cartilage, or anterior cruciate ligament. CONCLUSIONS: Sonographically guided intraligamentous PCL injections are technically feasible and can be performed with a high degree of accuracy. Sonographically guided PCL injections should be considered for research and clinical purposes to deliver therapeutic agents into the PCL postinjury or postreconstruction. PMID- 26247163 TI - Effects of Noxious Electrical Stimulation and Eccentric Exercise on Pain Sensitivity in Asymptomatic Individuals. AB - BACKGROUND: Achilles tendinopathy is a common overuse injury in running and jumping athletes. Currently, we do not understand why some conservative interventions (eg, noxious electrical stimulation and eccentric training) may reduce the pain associated with tendinopathy. OBJECTIVE: To determine whether noxious electrical stimulation (NES) or eccentric contractions would alter pain sensitivity around the asymptomatic Achilles tendon. DESIGN: A double-blind trial with block-randomization by gender into 3 intervention arms: NES, eccentric contractions, or low-intensity cycling. PARTICIPANTS: A total of 40 volunteers with no current pain conditions started the study, and 39 completed follow-up testing. METHODS: Participants underwent 2 baseline sessions to assess pain sensitivity response stability of pressure pain threshold (PPT), heat pain threshold (HPT), and heat temporal summation (HTS) over the Achilles tendon. Immediately after the second baseline session, participants performed 1 session of an intervention and were tested immediately postintervention and the next morning. Eccentric-only plantarflexor exercise was performed (4 sets of 15 repetitions) using full bodyweight and slow, 5-second contractions. Noxious electrical stimulation was applied to the Achilles for 20 minutes and dosed to the subjects' pain tolerance. Low-intensity cycling was dosed (60-70 W for 20 minutes) to minimize occurrence of exercise-induced hypoalgesia. The PPT was the primary outcome measure. RESULTS: For PPT, both NES (P < .001) and eccentric (P = .003) groups were less sensitive to pressure immediately posttreatment, and the eccentric group maintained this effect through the next morning (P = .043). No group differences were seen for HPT, but the NES (P = .031) and eccentric (P = .036) groups had less HTS the next morning. CONCLUSIONS: A single session of eccentric exercise and NES can produce immediate and next-day reductions in pain sensitivity in asymptomatic adults. The immediacy of these effects points toward a neurophysiologic mechanism. Future research needs to be performed in clinical populations and to assess any cumulative effects to repetitive intervention. PMID- 26247164 TI - Risk of New or Recurrent Cancer in Patients With Inflammatory Bowel Disease and Previous Cancer Exposed to Immunosuppressive and Anti-Tumor Necrosis Factor Agents. AB - BACKGROUND & AIMS: Our understanding of malignancy associated with immunosuppression in patients with inflammatory bowel disease (IBD) comes from studies of individuals with no history of cancer. We investigated whether patients with IBD and a history of cancer who were subsequently immunosuppressed have an increased risk of developing incident cancer. METHODS: We performed a retrospective analysis of data from 333 patients with IBD treated at 8 academic medical centers who developed cancer and subsequently received treatment with anti-tumor necrosis factor (TNF), anti-TNF with an antimetabolite (thiopurines, methotrexate), antimetabolites, or no subsequent exposure to immunosuppressive agents (controls). We collected data on their primary outcomes of incident cancers (new or recurrent). Hazard ratios (HRs) were calculated by using Cox proportional hazards and Kaplan-Meier survival curves; study groups were compared by using the log-rank test. RESULTS: During the follow-up period, 90 patients (27%) developed an incident cancer. Patient characteristics between groups differed, but matching was not possible because of the relatively small sample sizes. There was no difference in time to incident cancer (P = .14) or type of incident cancer (P = .61) among the 4 groups. After adjusting for recurrence risk for type of prior cancer, there was no difference in risk of incident cancer (HR for anti-TNF, 0.32; 95% confidence interval [CI], 0.09-1.09; HR for anti-TNF with an antimetabolite, 0.64; 95% CI, 0.26-1.59; HR for an antimetabolite, 1.08; 95% CI, 0.54-2.15) or time to subsequent cancer between study arms (P = .22). CONCLUSION: On the basis of a retrospective study, in patients with IBD and a history of cancer, exposure to an anti-TNF agent or an antimetabolite after cancer was not associated with an increased risk of incident cancer, compared with patients who did not receive immunosuppression. Larger, matched, prospective studies are needed to confirm these findings. PMID- 26247165 TI - Reply: To PMID 24036054. PMID- 26247166 TI - Antimicrobials in Cirrhotic Patients After Upper Gastrointestinal Hemorrhage: One Size No Longer Fits All. PMID- 26247167 TI - Efficacy of Proton Pump Inhibitor Drugs for Inducing Clinical and Histologic Remission in Patients With Symptomatic Esophageal Eosinophilia: A Systematic Review and Meta-Analysis. AB - BACKGROUND & AIMS: Proton pump inhibitor (PPI) therapy might lead to clinical and histologic remission in a significant proportion of patients with symptomatic esophageal eosinophilia (>15 eos/high-power field). We aimed to evaluate systematically the efficacy of PPI therapy for these patients. METHODS: A search in MEDLINE, EMBASE, and SCOPUS databases, and the American Gastroenterological Association Institute, American College of Gastroenterology, and United European Gastroenterology meetings abstract books, was performed. Primary outcomes were clinical response and histologic remission (<15 eos/high-power field) after PPI therapy. Secondary outcomes were the influence on the response to PPIs of age group, study design/quality, PPI type, doses and interval dosing, and pH monitoring results. Data were pooled using a random-effects model. RESULTS: Thirty-three studies (11 prospective studies) comprising 619 patients with symptomatic esophageal eosinophilia (188 children and 431 adults) were included. PPI therapy led to a clinical response in 60.8% (95% confidence interval, 48.38% 72.2%; I(2) = 80.2) and histologic remission in 50.5% (95% confidence interval, 42.2%-58.7%; I(2) = 67.5) of patients. No differences were observed regarding the study population (children vs adults), the type of publication, or its quality. PPIs were nonsignificantly more effective in prospective studies (52.6% vs 39.1%) administered twice daily compared with once daily (55.9% vs 49.7%), and with pathologic pH monitoring (65.4% vs 49.3%). A significant publication bias in favor of studies reporting histologic responses to PPIs was observed. CONCLUSIONS: PPI therapy induces clinicohistologic remission in half of patients with symptomatic esophageal eosinophilia. This finding should be interpreted with caution because of poor-quality evidence, heterogeneity, and publication bias. PMID- 26247168 TI - Neuroendocrine Carcinoma of the Gallbladder Accompanied by Pancreaticobiliary Maljunction. PMID- 26247169 TI - Reply: To PMID 25460557. PMID- 26247170 TI - Atypical haemolytic uraemic syndrome treated with the complement inhibitor eculizumab: the experience of the Australian compassionate access cohort. AB - BACKGROUND/AIM: This study aimed to report the clinical characteristics and outcomes of Australian patients treated with eculizumab for atypical haemolytic uraemic syndrome (aHUS). METHODS: A retrospective cohort study was undertaken of all patients in Australia treated with eculizumab provided in a compassionate access programme for a clinical diagnosis of aHUS using prospectively collected clinical data. RESULTS: A total of 10 patients with a median age of 23.5 years (interquartile range (IQR) 24.83 years) received compassionate access eculizumab for aHUS in Australia. Eight patients were female, and three had a family history of aHUS. Three received eculizumab for an initial acute aHUS presentation, three for relapsing and refractory acute aHUS, two for de novo aHUS post-renal transplantation, and one each for aHUS recurrence post-transplantation and facilitation of transplantation with a history of aHUS. The median duration of eculizumab therapy has been 911.5 days (IQR 569 days) with a cumulative exposure of 9184 days. At baseline all patients had renal and extra-renal aHUS involvement, with up to three non-renal organs affected. All but one patient, who died from uncontrollable gastrointestinal aHUS manifestations, have continued. The nine continuing patients achieved remission of aHUS. Two of the four patients requiring renal replacement therapy (RRT) at eculizumab commencement subsequently ceased RRT. Clinical events occurring in this cohort while on eculizumab treatment included neutropenia (two), posterior reversible encephalopathy syndrome (one), cardiomyopathy (one), pulmonary embolus (one), antibody-mediated rejection resulting in renal graft failure (one), iron deficiency (one), gastrointestinal haemorrhage (one) and death (one). CONCLUSION: Eculizumab has been an effective therapy for aHUS in this cohort, including when other therapies have failed. PMID- 26247172 TI - Ca(2+) Signalling in Endothelial Progenitor Cells: Friend or Foe? AB - Endothelial progenitor cells (EPCs) are mobilized either from the bone marrow and/or the arterial to replace dysfunctional endothelial cells and rescue blood perfusion in ischemic tissues. In addition, they may contribute to the angiogenic switch, thereby sustaining tumour growth and metastatization. Understanding the molecular mechanisms utilized by vascular endothelial growth factor (VEGF) to stimulate EPCs might unveil novel targets to enhance their clinical outcome in regenerative medicine and to adverse tumour vascularisation. VEGF stimulates peripheral blood-derived EPCs to undergo repetitive Ca(2+) oscillations shaped by the interaction between inositol-1,4,5-trisphosphate (InsP3 )-dependent Ca(2+) release and store-operated Ca(2+) entry (SOCE). However, the Ca(2+) machinery underlying VEGF-induced Ca(2+) spikes changes in umbilical cord blood-derived EPCs, which require TRPC3-mediated Ca(2+) entry to trigger the interplay between InsP3 and SOCE. Surprisingly, VEGF fails to elicit pro-angiogenic Ca(2+) signals when EPCs derive from renal cellular carcinoma patients, thus questioning the suitability of VEGFR-2 as a target for anti-angiogenic treatments in these individuals. The lack of response to VEGF is likely due to the dramatic rearrangement of the Ca(2+) toolkit occurring in RCC-derived EPCs. Finally, primary myelofibrosis-derived EPCs display a further pattern of reorganization of the Ca(2+) machinery and proliferate independently of SOCE. Thus, the Ca(2+) machinery in human ECFCs is extremely plastic and may change depending on the physio-pathological background of the donor. As a consequence, the Ca(2+) toolkit could properly be used to enhance the regenerative outcome of cell-based therapy or adverse tumor vascularisation. PMID- 26247173 TI - Assembly synthesis of Cu2O-on-Cu nanowires with visible-light-enhanced photocatalytic activity. AB - New Cu2O-on-Cu nanowires (NWs) are constructed to develop the visible-light driven activity of photocatalysts via the facile self-assembly of Cu2O nanoparticles (NPs) on a Cu NW surface assisted by a structure director, followed in situ reduction. In the resultant Cu2O-on-Cu NWs, the Cu2O NPs, with a diameter of 10 nm, show good distribution on the 50 nm-sized Cu single-crystal NWs. Owing to the band-gap adjusting effect and high electron transportation, the coupling of narrow-band-gap semiconductor Cu2O and excellent conductor Cu can lead to the markedly enhanced high visible light photocatalytic activity of Cu2O-on-Cu NWs toward the degradation of dye pollutants including Rhodamine B (RhB), methyl orange (MO) and methyl blue (MB). The as-designed Cu2O-on-Cu heterostructured NWs exhibit higher performance for the catalytic degradation of dye compounds than pure Cu2O. Nearly 60%, 100%, and 85% conversion with reaction rate constants (k) of 0.0137, 0.0746 and 0.0599 min(-1) can be achieved for the degradation of RhB, MO and MB, respectively. Besides the highly efficient transportation of electrons, Cu NWs have a strong capacity for oxygen activation, which results in the gathering of negative charges and rich chemisorbed oxygen onto the surface. This may be responsible for the high catalytic efficiency of the Cu2O-on-Cu NWs toward the degradation of organic pollutants. PMID- 26247171 TI - Diketopyrrolopyrrole-Based Semiconducting Polymer Nanoparticles for In Vivo Photoacoustic Imaging. AB - Diketopyrrolopyrrole-based semiconducting polymer nanoparticles with high photostability and strong photoacoustic brightness are designed and synthesized, which results in 5.3-fold photoacoustic signal enhancement in tumor xenografts after systemic administration. PMID- 26247174 TI - Middle region of the Borrelia burgdorferi surface-located protein 1 (Lmp1) interacts with host chondroitin-6-sulfate and independently facilitates infection. AB - Borrelia burgdorferi surface-located membrane protein 1, also known as Lmp1, has been shown to play critical roles in pathogen evasion of host-acquired immune defences, thereby facilitating persistent infection. Lmp1 possesses three regions representing potentially discrete domains: Lmp1N, Lmp1M and Lmp1C. Because of its insignificant homology to known proteins, how Lmp1 or its specific regions contribute to microbial biology and infection remains enigmatic. Here, we show that distinct from Lmp1N and Lmp1C, Lmp1M is composed of at least 70% alpha helices and completely lacks recognizable beta sheets. The region binds to host glycosaminoglycan chondroitin-6-sulfate molecules and facilitates mammalian cell attachment, suggesting an adhesin function of Lmp1M. Phenotypic analysis of the Lmp1-deficient mutant engineered to produce Lmp1M on the microbial surface suggests that Lmp1M can independently support B. burgdorferi infectivity in murine hosts. Further exploration of functions of Lmp1 distinct regions will shed new light on the intriguing biology and infectivity of spirochetes and help develop novel interventions to combat Lyme disease. PMID- 26247175 TI - From Nanofibrous Hollow Microspheres to Nanofibrous Hollow Discs and Nanofibrous Shells. AB - Nano- and microsized structures are of central importance to advanced materials and nanotechnologies, which have tremendously impacted both biomedical and physical sciences. Herein, novel emulsification and thermally induced phase separation (TIPS) techniques to fabricate linear polymers into nanofibrous hollow objects are reported for the first time. Through manipulating the emulsification conditions, the evolution of the emulsion structure can be controlled and nanofibrous hollow microspheres with a controllable opening size and nano-fibrous shells can be fabricated. Through adjusting the rheological properties of the emulsions, nanofibrous hollow discs are also created. A new mechanistic hypotheses of the nanofibrous hollow object formation is proposed: the nano- and microscaled structures are independently determined by TIPS and the emulsification process, respectively. Guided by this theory, the nanofiber formation conditions for two further additional polymers (polyacrylonitrile and Nylon) under TIPS are identified, and solid/nanofibrous non-hollow/hollow microspheres are created from these two additional polymers under TIPS and emulsification for the first time. Therefore, the developed strategy is applicable to various polymer systems, and can broadly impact nano- and microfabrication technologies. PMID- 26247176 TI - Identification of Hb Wayne and its effects on HbA1c measurement by 5 methods. AB - BACKGROUND: The World Health Organization and the American and Canadian Diabetes Associations approved HbA1c >6.5% as diagnostic for type 2 diabetes mellitus (T2DM). Hb variants and/or their chemically modified species can interfere with HbA1c measurements. We recently described a patient with Hb Wayne trait who was misdiagnosed with T2DM based on falsely elevated HbA1c. Hb Wayne is a clinically silent variant that exists as two isoforms: Hb Wayne I (Asn 139) and Hb Wayne II (Asp 139). METHODS: Hemoglobinopathy investigation was performed by HPLC (Bio-Rad VARIANT-II), alkaline and acid electrophoresis (Sebia Hydrasis2), capillary zone electrophoresis (Sebia CAPILLARYS2TM) and DNA sequencing. HbA1c was measured by five methods. RESULTS: Hb Wayne eluted as two small fractions with retention times of 1.0 and 1.46min on the HPLC (Bio-Rad VARIANT-II). Alkaline gel and capillary electrophoresis showed two small bands migrating faster than HbA. Hb Wayne generated spuriously high results on the Bio-Rad VARIANT-II Turbo 2.0, no results on the Tosoh G8, and did not interfere with either the Sebia CAPILLARYS2TM or immunoassays from Roche (tinaquant) and Siemens (Bayer DCA2000+). Based on the Hb Wayne HPLC profile of 3 patients, an algorithm was developed to facilitate its detection, which identified 9 additional patients with Hb Wayne trait. CONCLUSIONS: We characterize Hb Wayne by chromatographic and electrophoretic techniques and show the effect of Hb Wayne on five common HbA1c methodologies. We developed a quality assurance tool to assist in detecting Hb Wayne trait during HbA1c analysis on the Bio-Rad VARIANT-IITM Turbo 2.0. PMID- 26247177 TI - Lymphocyte surface molecules as immune activation biomarkers. AB - Immunosuppression is mandatory after solid organ transplantation between HLA mismatched individuals. It is a lifelong therapy that needs to be closely monitored to avoid under- and over-immunosuppression. For many drugs, pharmacokinetic monitoring has been proven to be beneficial. However, the therapeutic ranges are statistically derived surrogate markers for the effects that cannot predict the individual response of single patients. Better tailored immunosuppression biomarkers are needed that indicate immune activation. T cells are critically involved in organ rejection, and the means to assess their activation state may be promising to individualize immunosuppressive therapies. Activated T cells can be monitored with flow cytometry based on surface molecules that are typically up regulated or with molecules that are cleaved off the cell surface. Among these molecules are the interleukin-2 receptor (CD25); transferrin receptor (CD71); the T cell co-stimulatory molecules CD28, CD69, and CD154 and sCD30, which is a member of the TNF-alpha family. The effect of immunosuppressive drugs on T cell activation can be recorded with indirect cell function assays or by directly monitoring activated T cells in whole blood. Soluble proteins can be measured with immunoassays. This review provides a summary of the experimental and clinical studies investigating the potential of surface molecules as a tool for immune monitoring. It critically discusses the obstacles and shortcomings from an analytical and diagnostic perspective that are currently preventing their use in multicenter trials and clinical routine monitoring of transplant patients. PMID- 26247179 TI - Discrimination and common mental disorders of undergraduate students of the Universidade Federal de Santa Catarina. AB - INTRODUCTION: The pathogenic and consistent effect of discrimination on mental health has been largely documented in the literature. However, there are few studies measuring multiple types of discrimination, evaluating the existence of a dose-response relationship or investigating possible effect modifiers of such an association. OBJECTIVE: To investigate the association between experiences of discrimination attributed to multiple reasons and common mental disorders, including the adjustment for potential confounders, assessment of dose-response relations, and examination of effect modifiers in undergraduate students from southern Brazil. METHODS: In the first semester of 2012, 1,023 students from the Universidade Federal de Santa Catarina answered a self-administered questionnaire on socio-demographic characteristics, undergraduate course, experiences of discrimination and common mental disorders. Associations were analyzed through logistic regression models, estimation of Odds Ratios and 95% confidence intervals (95%CI). RESULTS: The study results showed that students reporting discrimination at high frequency and intensity were 4.4 (95%CI 1.6 - 12.4) times more likely to present common mental disorders. However, the relationship between discrimination and common mental disorders was protective among Electrical Engineering students, when compared to Accounting Sciences students who did not report discrimination. CONCLUSION: The findings suggest that the dose-response relationship between experiences of discrimination and common mental disorders reinforces the hypothetical causal nature of this association. Nevertheless, the modification of effect caused by the undergraduate course should be considered in future studies for a better understanding and measurement of both phenomena. PMID- 26247180 TI - Influence of individual and socio-environmental factors on self-rated health in adolescents. AB - OBJECTIVE: This study aimed to determine if individual and socio-environmental characteristics can influence the self-rated health among Brazilian adolescents. METHODS: It included 1,042 adolescents from 11 to 17 years old who participated in the Beaga Health Study (Estudo Saude em Beaga), a multistage household survey in an urban setting. Logistic regression analyses were performed to determine the association between the self-rated health and the following explanatory variables: sociodemographic factors, social support, lifestyle, physical and psychological health. RESULTS: Good/very good and reasonable/poor/very poor self rated health were reported by 88.5 and 11.5% of adolescents, respectively. The data on sociodemographic factors (SES), social support, lifestyle, psychological and physical health were associated with poor self-rated health (p <= 0.05). The associated variables were: age 14 - 17 years (OR =1.71; 95%CI 1.06 - 2.74), low SES (OR =1.68; 95%CI 1.05 - 2.69), few (OR = 2.53; 95%CI 1.44 - 4.46) and many quarrels in family (OR = 9.13; 95%CI 4.53 - 18.39), report of unkind and unhelpful peers (OR = 2.21; 95%CI 1.11 - 4.43), consumption of fruits < 5 times a week (OR = 1.78; 95CI% 1.07 - 2.95), physical inactivity (OR = 2.31; 95%CI 1.15 - 4.69), overweight (OR = 2.42; 95%CI 1.54 - 3.79) and low level of life satisfaction (OR = 2.31; 95%CI 1.34 - 3.98). CONCLUSIONS: Poor self-rated health among adolescents was associated with individual and socio-environmental characteristics related to family, school and neighborhood issues. Quantifying the self-rated health according to the theoretical framework of the child's well being should help in arguing that self-rated health might be a strong indicator of social inequities for the studied population. PMID- 26247178 TI - Histidine Orientation Modulates the Structure and Dynamics of a de Novo Metalloenzyme Active Site. AB - The ultrafast dynamics of a de novo metalloenzyme active site is monitored using two-dimensional infrared spectroscopy. The homotrimer of parallel, coiled coil alpha-helices contains a His3-Cu(I) metal site where CO is bound and serves as a vibrational probe of the hydrophobic interior of the self-assembled complex. The ultrafast spectral dynamics of Cu-CO reveals unprecedented ultrafast (2 ps) nonequilibrium structural rearrangements launched by vibrational excitation of CO. This initial rapid phase is followed by much slower ~40 ps vibrational relaxation typical of metal-CO vibrations in natural proteins. To identify the hidden coupled coordinate, small molecule analogues and the full peptide were studied by QM and QM/MM calculations, respectively. The calculations show that variation of the histidines' dihedral angles in coordinating Cu controls the coupling between the CO stretch and the Cu-C-O bending coordinates. Analysis of different optimized structures with significantly different electrostatic field magnitudes at the CO ligand site indicates that the origin of the stretch-bend coupling is not directly due to through-space electrostatics. Instead, the large, ~3.6 D dipole moments of the histidine side chains effectively transduce the electrostatic environment to the local metal coordination orientation. The sensitivity of the first coordination sphere to the protein electrostatics and its role in altering the potential energy surface of the bound ligands suggests that long-range electrostatics can be leveraged to fine-tune function through enzyme design. PMID- 26247181 TI - Hepatitis B vaccination in adolescents living in Campinas, Sao Paulo, Brazil. AB - INTRODUCTION: Viral hepatitis is an important public health problem in Brazil and around the world. OBJECTIVE: To evaluate vaccination coverage against hepatitis B in adolescents and to identify the associated factors and reasons for non adherence. METHODS: A cross-sectional population-based study with sampling by clusters and in two stages, carried out from records of 702 adolescents aged 11 to 19 years old, non-institutionalized, living in an urban area of Campinas, Sao Paulo, Brazil, in 2008/2009. The data were obtained from the Health Survey in the city of Campinas (ISACamp). RESULTS: The prevalence of vaccination (3 doses) was 72.2%. An independent and negative association with the vaccine was observed for the adolescents who were not born in the municipality. The orientation of a health care provider was positively and significantly associated with vaccination. The main reasons for non-adherence were the lack of orientation and not considering the vaccine necessary. Socioeconomic factors, health behaviors and conditions did not restrict the access to vaccination, but the coverage was below the target established by the Ministry of Health in Brazil. CONCLUSION: Health education programs, addressing the importance of vaccination to prevent the disease; strategies to actively reach out adolescents that did not complete the schedule; as well as orientation from the health care professional about the benefits of the vaccine to the adolescents, parents and guardians can extend the vaccination coverage. PMID- 26247182 TI - Dental fluorosis: prevalence and associated factors in 12-year-old schoolchildren in Goiania, Goias. AB - OBJECTIVE: To describe the prevalence of dental fluorosis, to investigate its association with individual and contextual variables among 12-year-old schoolchildren, and to determine whether there were changes in the prevalence of this condition from 2003 to 2010. METHODS: This cross-sectional study used data from an oral health survey carried out in Goiania, Goias, in 2010 (n = 2,075), and secondary data from the files of the local health authority. Clinical data were collected through oral examinations in public and private schools. The dependent variable was the presence of dental fluorosis, assessed using the Dean Index. The independent individual variables were sociodemographic characteristics (the child's gender and race, and the mother's level of schooling) and those related to clinical conditions (caries experience, evaluated using Decayed, Missing, and Filled teeth index; and presence of periodontal calculus and/or bleeding, evaluated using Community Periodontal Index). The contextual variables were linked to the school (type and existence of toothbrushing program) and its geographic location in the city's health districts. The Rao-Scott test was performed, and the percentage difference between the prevalences in the period from 2003 to 2010 was calculated. RESULTS: The prevalence of dental fluorosis in 2010 was 18.7%, being distributed as very mild (11.2%), mild (4.4%), moderate (2.6%), and severe (0.5%). No significant association was found between prevalence of dental fluorosis and the investigated variables. The prevalence of fluorosis increased 230% from 2003 to 2010, and such difference was significant. CONCLUSIONS: The prevalence of dental fluorosis was low, predominantly of the very mild degree, has increased over a 7-year period, and was not associated with the individual or contextual factors studied. PMID- 26247183 TI - Absence of routine medical consultation among hypertensive and/or diabetic elders: an epidemiological study based on the Brazilian National Household Survey 2008. AB - OBJECTIVE: This exploratory study aimed to investigate the predisposing, enabling and health need characteristics associated with lack of medical visits in the last 12 months, among 23,620 elderly hypertensive and/or diabetic individuals. METHODS: In this research, we used the theoretical behavioral model of Andersen and Newman for use of health services. The data analyzed were produced by the health supplement of the Brazilian National Household Survey (PNAD) 2008, nationwide. To identify the associations, we used the Poisson regression model, which estimates the prevalence ratios and confidence intervals of 95%, considering the significance level of 5%. RESULTS: The results showed that 10.6% of the study population did not consult the doctor in the period considered, and the prevalence was higher among hypertensive subjects (10.5%) than among diabetic ones (7.1%). The lack of medical consultation was negatively associated with female sex and increasing age (predisposing characteristics), with health insurance coverage (enabling characteristic), worse self-rated health, chronic health conditions selected and the presence of hypertension associated with diabetes (health needs), while the fact of living in the Northeast, North and Midwest appeared positively associated with the event under investigation. CONCLUSION: These results corroborate those observed in national and international studies and show evidence of inequality and inequity in the use of medical consultation for this population, based on the findings related to health plan coverage and geographic region. PMID- 26247184 TI - Demographic, health conditions, and lifestyle factors associated with urinary incontinence in elderly from Florianopolis, Santa Catarina, Brazil. AB - OBJECTIVE: To determine the prevalence and factors associated with urinary incontinence in the elderly population of Florianopolis, in the State of Santa Catarina, Brazil. METHODS: We used data from EpiFloripa Idoso 2009/2010 survey, a cross-sectional population-based study including 1,705 elderly of both the sexes. Poisson's regression (crude and adjusted analysis) was applied to verify the association between the urinary incontinence outcome and exploratory variables (sociodemographic, lifestyle, and health conditions). RESULTS: Among the elderly, 29.4% reported urinary incontinence; 36.3% were women and 17.0% men. The factors associated with greater prevalence of urinary incontinence were being female, aged more than 70 years old, having 0 to 4 schooling years, being insufficiently active, having bronchitis or asthma, stroke or cerebral ischemia, presenting mild or moderate/severe dependence, and polypharmacy. CONCLUSION: The prevalence of urinary incontinence was high among the investigated elderly. Sociodemographic variables and those related to lifestyle and health conditions were associated with higher prevalence of urinary incontinence. Knowledge of the factors associated with urinary incontinence in aged individuals can guide actions to reduce and prevent this important issue, which affects the elderly. PMID- 26247185 TI - Correlates of excessive daytime sleepiness in community-dwelling older adults: an exploratory study. AB - Excessive daytime sleepiness (EDS) imposes a wide range of adverse health-related outcomes in older people, such as disability, which impair everyday activities and may increase the risk of fall. Few studies have explored EDS in Brazilian older people living in the community who are typically cared in primary health services. This study aims to investigate the prevalence of EDS and its sociodemographic, physical and mental health correlates among community-dwelling older adults. This is an exploratory, population-based study derived from Frailty in Brazilian Older Adults (FIBRA) study including adults aged 65 years and older. Participants with a score >= 11 points on the Epworth Sleepiness Scale were considered as having excessive daytime sleepiness. A structured, multidimensional questionnaire was used to investigate sociodemographic, physical and mental health, and self-rated health variables. The sample was composed of 776 older adults, of whom 21% (n = 162) presented excessive daytime sleepiness. Multivariate regression analysis revealed that EDS is associated with obesity (OR = 1.50; 95%CI 1.02 - 2.20), urinary incontinence (OR = 1.53; 95%CI 1.01 - 2.31), poor self-rated health (OR = 1.54; 95%CI 1.06 - 2.24), and depression symptoms (OR = 1.49; 95%CI 1.00 - 2.20). Our results suggest that healthcare professionals should identify older adults with EDS and implement intervention strategies to minimize the negative impact of the co-occurrence of this condition with obesity, depression and urinary incontinence over health and quality of life. PMID- 26247186 TI - Factors associated with lip and oral cavity cancer. AB - PURPOSE: This study aimed to identify factors associated with the occurrence of primary cancer of the lip and oral cavity regions compared to other types of head and neck cancers according to demographic, socioeconomic data and lifestyle, in Brazil, from 2000 to 2011. METHODS: A study was conducted using Hospital Cancer Records (Instituto Nacional do Cancer), from 2000 to 2011, totaling 23,153 cases. Data were analyzed by binary logistic regression (response category: primary cancers located in the lip and oral cavity; comparison category; other types of primary cancer in the head and neck, which does not affect the lip and oral cavity) at a significance level alpha = 5%. RESULTS: The study showed factors associated with higher incidence of cancer in the lip and oral cavity: being of advanced age (OR = 1.16), not having a family history of cancer (OR = 2.38), alcohol consumption (OR = 1.17); former tobacco use (OR = 1.51) or current tobacco use (OR = 1.65); having a previous diagnosis of cancer without treatment (OR =1.66). Being female (OR = 0.92), having completed basic (OR = 0.71) and higher (OR = 0.46) education and having previous diagnosis of cancer with treatment (OR = 0.74) constituted factors associated with lower prevalence of cancer of the lip and oral cavity. CONCLUSION: Age, absence of family history of cancer, smoking habits and alcohol consumption, and previous diagnosis of cancer without treatment were associated with a higher incidence of cancer of the lip and oral cavity. PMID- 26247187 TI - Dental pain and associated factors in 2 to 4-year-old children in Goiania. AB - OBJECTIVE: To investigate the prevalence of dental pain and associated factors in 2-4-year-old children in Goiania (GO). METHODS: Cross-sectional study using home interviews with parents or guardians and anthropometric measures. The sample consisted of 385 children from 2 to 4 years old. The variables analyzed were: dental pain sometime in their lives, and demographic, socioeconomic and health related factors (health condition, diet, nutritional status and behavior). Bivariate analysis and logistic regression were performed, based on a hierarchical model for risk assessment, considering the sample weights. RESULTS: Dental pain prevalence was 9.9% (95%CI 7.4 - 13.1). After adjustment for other variables, children whose mothers had low education level and those who regularly consumed artificial powder juice containing sugar were more likely to have dental pain (OR = 3.03 and 2.15, respectively). CONCLUSION: It was concluded that one in ten children had dental pain, and the prevalence was associated with low education level of the mother and the regular consumption of artificial powder juice. PMID- 26247188 TI - Dental caries in 12-year-old schoolchildren: multilevel analysis of individual and school environment factors in Goiania. AB - The aim of this study was to investigate the association between dental caries index among 12-year-old schoolchildren and individual and contextual factors related to the schools in the city of Goiania, Goias, Brazil. A cross-sectional study was carried out with 2,075 schoolchildren using the 2010 National Survey of Oral Health methodology. The dependent variable was the decayed, missing, and filled teeth (DMFT) index and the independent variables were individual (sex, race, and maternal education) and contextual ones (type of school, health district, and the presence of oral programs). Multilevel analysis and log-linear negative binominal regression were performed, considering the complex sampling design. Mean DMFT index was 1.51. Female students, whose mothers had lower schooling, those attending public schools, located in districts with the worst socioeconomic indicators, and covered by the Family Health Strategy had higher caries levels. The dental caries index was low and associated with the schoolchildren sociodemographic characteristics and factors related to the schools, showing inequalities in distribution. PMID- 26247189 TI - Readiness for behavioral change and variation in food consumption among adolescents from a school-based community trial in Duque de Caxias, RJ. AB - OBJECTIVE: To investigate the influence of the stage of readiness for changes in food consumption variation among adolescents participating in school-based community trial in Duque de Caxias (RJ), Brazil. METHODS: It is a secondary analysis of a one-year randomized community trial to prevent excessive weight gain in students attending the 5th grade in 20 public schools in the municipality of Duque de Caxias. The activities conducted discouraged the consumption of sweetened beverages and cookies and encouraged the consumption of fruits and beans. A food frequency questionnaire was applied at the beginning and at the end of the study. The stages of readiness for behavioral change vary in a scale from (1) "I don't think of changing diet" to (5) "I'm already changing my diet successfully". For the longitudinal analyses, we used generalized linear mixed models. RESULTS: There was a greater change in the consumption of fruit and soft drinks among participants in the intervention group who were in the action stage, compared to participants who did not think about changing their diet. CONCLUSION: The proposed strategy may be used to identify population groups with motivation for changes in dietary behavior. PMID- 26247190 TI - Health information systems and pesticide poisoning at Pernambuco. AB - INTRODUCTION: Understanding the epidemiologic profile of a particular disease is key to undertake health actions. To that end, information systems that present quality data help in the decision-making process and demonstrate the impact of the problems. OBJECTIVE: To analyze the contribution of health information systems for the characterization of pesticide poisoning through SINAN, CEATOX and SIM in the State of Pernambuco. METHOD: In this study, the completeness and consistency of the data were assessed, as well as the epidemiological profile of pesticide poisoning in Pernambuco in the period from 2008 to 2012, based on the following Health Information Systems: Center for Toxicological Assistance of Pernambuco (CEATOX), Notifiable Diseases Information System (SINAN) and Mortality Information System (SIM). RESULTS: The data revealed incompleteness and inconsistencies in information. Regarding the profile, females are more affected in the morbidity profile, and men have a higher mortality rate. Poisoning was more frequent in young adults with low educational level. With regard to the circumstances, most of the cases were suicide attempts, unique acute cases and not related to work. Despite suggesting underreporting, the data showed that persons engaged in agriculture are most commonly affected. CONCLUSION: The strengthening of these systems is necessary for the generation of consistent information that support health policies for the population groups involved. PMID- 26247191 TI - Prevalence of hearing problems and associated factors in an agricultural company in southern Brazil. AB - OBJECTIVE: To describe the prevalence and to analyze the factors associated with hearing problems in an agricultural company. METHODS: This was a cross-sectional study, and the participants consisted entirely of employees of an agricultural company in southern Brazil. The workforce of the company was composed of several different occupations. The research instrument was a semi-structured questionnaire administered by interview. RESULTS: Of the 326 workers of the company, there were 273 (83.8%) respondents, and the prevalence of hearing problems was n = 42 (15.4%) among the participants of the study. The hearing problems were associated with lower schooling, with the operating occupational group, the technical assistance group and the general services group. The self reported health conditions associated with hearing problems were depression and nervousness or irritation. The occupational exposures associated with hearing problems were noise, dust, vibration, oils and solvents, and toxic gases. CONCLUSION: There was an intermediate prevalence of hearing problems in relation to other studies. It was possible to observe the need to implement strategies aiming at the prevention of hearing problems that primarily contemplate modifiable aspects, such as the use of personal protective equipment, as well as improvements in the conditions, organization and work environment. PMID- 26247192 TI - Health risks due to pre-harvesting sugarcane burning in Sao Paulo State, Brazil. AB - After 2003, a new period of expansion of the sugarcane culture began in Brazil. Pre-harvesting burning of sugarcane straw is an agricultural practice that, despite the nuisance for the population and pollution generated, still persisted in over 70% of the municipalities of Sao Paulo State in 2010. In order to study the distribution of this risk factor, an ecological epidemiological study was conducted associating the rates of deaths and hospital admissions for respiratory diseases, for each municipality in the State, with the exposure to the pre harvesting burning of sugarcane straw. A Bayesian multivariate regression model, controlled for the possible effects of socioeconomic and climate (temperature, humidity, and rainfall) variations, has been used. The effect on health was measured by the standardized mortality and morbidity ratio. The measures of exposure to the pre-harvesting burning used were: percentage of the area of sugarcane harvested with burning, average levels of aerosol, and number of outbreaks of burning. The autocorrelation between data was controlled using a neighborhood matrix. It was observed that the increase in the number of outbreaks of burning was significantly associated with higher rates of hospital admissions for respiratory disease in children under five years old. Pre-harvesting burning of sugarcane effectively imposes risk to population health and therefore it should be eliminated. PMID- 26247193 TI - Factors associated with musculoskeletal pain among teachers: sociodemographics aspects, general health and well-being at work. AB - INTRODUCTION: Musculoskeletal pain is one of the most frequent complaints among teachers, compromising their health and quality of life. OBJECTIVE: To estimate the prevalence of musculoskeletal pain among teachers, assessing their occurrence according to sociodemographic characteristics, general health and well-being at work. METHODS: An exploratory cross-sectional study conducted with 525 teachers. During activities of continuing education, the teachers completed a self administered questionnaire containing questions about sociodemographic factors, general health, well-being at work and musculoskeletal pain. RESULTS: The overall prevalence of musculoskeletal pain was equal to 73.5%. The most common musculoskeletal pains were localized in the shoulders (31.6%), upper back (27.8%), neck (27.2%) and ankles and/or feet (24.0%). Circulatory and respiratory problems and Common Mental Disorders were associated with pain in the shoulders, upper back, neck and ankles and/or feet. Well- being at work is associated with pain in the shoulders, neck and ankles and/or feet. CONCLUSION: It is necessary to deepen the knowledge about musculoskeletal pain among teachers, exploring the biological, ergonomic, occupational and psychosocial mechanisms of teaching, as well as invest in practices that improve the relationship of coexistence between workers and activities that enhance the comfort and reduce referred pain. PMID- 26247194 TI - Contribution of cohort studies in the analysis of oral health in children and adolescents in Sobral, Ceara. AB - The main objective of this study was to identify the oral health status of the child population in a northeastern Brazilian municipality as a strategy to carry out subsequent longitudinal studies to investigate the main determinants of oral diseases in the specific age groups of teenagers and young adults. Epidemiological investigations and interviews were conducted in households by research teams. In the first study, a DMFT (decayed, missing, and filled teeth) score of 1.66 was found for 9-year-olds; although only 23% children aged between 5 and 6 years were caries-free, 32.7% had gingival bleeding and 9.5% were diagnosed with severe malocclusion problems. The second wave of the cohort indicated that the incidence of caries increased progressively according to age, from 1.60 in 12-year-old adolescents to 2.28 in those aged 15. Toothache in the past 6 months, maternal income and school meals, adjusted for the perception of need for treatment, maternal education, and dental visit at least once were the variables associated with high incidence of dental caries. Data collection for the third wave of the cohort is currently underway. Socioeconomic factors and access to health services were associated with the incidence of caries. PMID- 26247195 TI - The use of the International Classification of Functioning, Disability and Health in health surveys: a reflexion on its limits and possibilities. PMID- 26247197 TI - The Importance of Moisture in Hybrid Lead Halide Perovskite Thin Film Fabrication. AB - Moisture, in the form of ambient humidity, has a significant impact on methylammonium lead halide perovskite films. In particular, due to the hygroscopic nature of the methylammonium component, moisture plays a significant role during film formation. This issue has so far not been well understood and neither has the impact of moisture on the physical properties of resultant films. Herein, we carry out a comprehensive and well-controlled study of the effect of moisture exposure on methylammonium lead halide perovskite film formation and properties. We find that films formed in higher humidity atmospheres have a less continuous morphology but significantly improved photoluminescence, and that film formation is faster. In photovoltaic devices, we find that exposure to moisture, either in the precursor solution or in the atmosphere during formation, results in significantly improved open-circuit voltages and hence overall device performance. We then find that by post-treating dry films with moisture exposure, we can enhance photovoltaic performance and photoluminescence in a similar way. The enhanced photoluminescence and open-circuit voltage imply that the material quality is improved in films that have been exposed to moisture. We determine that this improvement stems from a reduction in trap density in the films, which we postulate to be due to the partial solvation of the methylammonium component and "self-healing" of the perovskite lattice. This work highlights the importance of controlled moisture exposure when fabricating high-performance perovskite devices and provides guidelines for the optimum environment for fabrication. Moreover, we note that often an unintentional water exposure is likely responsible for the high performance of solar cells produced in some laboratories, whereas careful synthesis and fabrication in a dry environment will lead to lower-performing devices. PMID- 26247198 TI - Corrole-ferrocene and corrole-anthraquinone dyads: synthesis, spectroscopy and photochemistry. AB - Two different donor-acceptor systems based on corrole-ferrocene and corrole anthraquinone having the 'Olefin Bridge' at the beta-pyrrole position have been designed and synthesized. Both the dyads corrole-ferrocene () and corrole anthraquinone () are characterized by elemental analysis, ESI-MS, (1)H NMR, UV Visible, fluorescence spectroscopies (steady-state, femtosecond time-resolved), femtosecond transient absorption spectroscopy (fs-TA) and electrochemical methods. (1)H-NMR shows that two doublets at 6.50 and 7.25(delta) ppm belong to vinylic protons, which are characteristic of the formation of dyads. UV-Visible absorption spectra showed that dyads are merely superpositions of their respective constituent monomers and dominated by corrole S1 <- S0 (Q-band) and S2 <- S0 (Soret band) transitions with a systematic red-shift of both Soret and Q bands along with the broadening of the bands. A prominent splitting of the Soret band for both the dyads is observed due to bulky substitutions at the peripheral position, which deviate from the planarity of the corrole macrocycle. Both the dyads exhibit significant fluorescence emission quenching (95-97%) of corrole emission compared to the free-base corrole monomer. Emission quenching is attributed to the excited-state intramolecular photoinduced electron transfer (PET) from corrole to anthraquinone in the dyad, whereas in the dyad it is reversed. The electron-transfer rates (kET) for and were found to be 3.33 * 10(11) and 2.78 * 10(10) s(-1), respectively. Despite their very different driving forces, charge separation (CS) and charge recombination (CR) are found to be in identical timescales. PMID- 26247196 TI - Alcohol Intoxication Impairs Mesopic Rod and Cone Temporal Processing in Social Drinkers. AB - BACKGROUND: Alcohol-related driving accidents and fatalities occur most frequently at nighttime and at dawn, that is, a mesopic lighting condition in which visual processing depends on both rod and cone photoreceptors. The temporal functions of the rod and cone pathways are critical for driving in this lighting condition. However, how alcohol influences the temporal functions in the rod and cone pathways at mesopic light levels is inconclusive. To address this, this study investigated whether an acute intoxicating dose of alcohol impairs rod- and/or cone-mediated critical fusion frequency (CFF; the lowest frequency of which an intermittent or flickering light stimulus is perceived as steady). METHODS: In Experiment I, we measured the CFFs for 3 types of visual stimuli (rod stimulus alone, cone stimulus alone, and the mixture of both stimuli types), under 3 illuminant light levels (dim illuminance: 2 Td; low illuminance: 20 Td; and medium illuminance: 80 Td) in moderate-heavy social drinkers before and after they consumed an intoxicating dose of alcohol (0.8 g/kg) compared with a placebo beverage. In Experiment II, we examined whether the illuminance level (dark vs. light) of the visual area surrounding the test stimuli alters alcohol's effect on the temporal processing of rods and cones. RESULTS: The results showed that compared with placebo, alcohol significantly reduced CFFs of all stimulus types at all illuminance levels. Furthermore, alcohol intoxication produced a larger impairment on rod-pathway-mediated CFFs under light versus dark surround. CONCLUSIONS: These results indicate that alcohol intake slows down rod and cone pathway-mediated temporal processing. Further research may elucidate whether this effect may play a role in alcohol-related injury and accidents, which often occur under low-light conditions. PMID- 26247199 TI - Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington's Disease. AB - Huntington's Disease (HD) is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. We have created an HD mouse model that resolves the effects of the inherited and somatic expansions. We show here that suppressing somatic expansion substantially delays the onset of disease in littermates that inherit the same disease-length allele. Furthermore, a pharmacological inhibitor, XJB-5-131, inhibits the lengthening of the repeat tracks, and correlates with rescue of motor decline in these animals. The results provide evidence that pharmacological approaches to offset disease progression are possible. PMID- 26247200 TI - Inflammatory and Angiogenic Factors at Mid-Pregnancy Are Associated with Spontaneous Preterm Birth in a Cohort of Tanzanian Women. AB - RESEARCH QUESTION: Preterm birth (PTB) is the leading cause of perinatal mortality worldwide, with the greatest burden occurring in resource-constrained settings. Based on the hypothesis that altered placental angiogenesis and inflammation early in pregnancy lead to PTB, we examined whether levels of inflammatory and angiogenic mediators, measured early in pregnancy, were predictive of spontaneous PTB (sPTB). STUDY DESIGN: Plasma samples were collected from a prospective cohort of primigravid Tanzanian women between 12-27 weeks gestation. A panel of 18 markers was screened on a training cohort of 426 women. Markers associated with sPTB in the training cohort were repeated in a test cohort of 628 women. All markers were measured by ELISA. FINDINGS: In both the training and test cohorts plasma levels of IL-18BP, sICAM-1, sEndoglin and CHI3L1 were elevated and Leptin was lower at enrollment in women who subsequently experienced sPTB. In multivariate analysis women with plasma levels of CHI3L1, C5a, sICAM-1, AngptL3, sEndgolin, sFlt-1 and IL-18BP in the highest quartile had an increased risk of sPTB compared with those in the lowest quartile. Women with Leptin and Ang2 in the highest quartile had a reduced risk of sPTB compared with women in the lowest quartile. IMPLICATIONS: Levels of angiogenic and inflammatory mediators measured at mid-pregnancy were associated with subsequent sPTB. These findings provide insight into mechanisms underlying sPTB and suggest biomarkers that may have clinical utility in risk-stratifying pregnancies. PMID- 26247201 TI - Functional Role of NRF2 in Cervical Carcinogenesis. AB - Nuclear factor erythroid-2-related factor 2 (NFE2L2) is a transcription factor associated with resistance to chemotherapy and increased tumor growth. NRF2 is repressed by the inhibitor Keap1. The Keap1-NRF2 pathway is dysfunctional in multiple tumor types. Among Uighur women, the incidence of cervical squamous cell carcinoma (CSCC) and cervical intraepithelial neoplasia (CIN) was associated with elevated nuclear expression of NRF2 and decreased cytoplasmic expression of Keap1. Up-regulation of nuclear NRF2 was significantly associated with reduced cytoplasmic Keap1 expression. NRF2 positivity and Keap1 negativity were frequently associated with more advanced tumors (i.e., higher histological grade, lymph node involvement, and higher tumor stages) (p<0.05 for all). Methylated CpG islands in the Keap1 gene promoter in cervical cancer tissue were identified using MassARRAY. Moreover, promoter hypermethylation of this gene was significantly associated with decreased protein expression and increased nuclear NRF2 expression in cervical cancer tissues. Overexpression and knockdown of NRF2 in CSCC cell lines showed that NRF2 promotes proliferation, inhibits apoptosis, and enhances migration and invasion. These studies support the concept that epigenetic changes regulate expression of Keap1 in cervical cancer tissues. The association of NRF2 expression with aggressive tumor behavior suggests that NRF2 may be a marker of poor prognosis in patients with cervical cancer. PMID- 26247202 TI - Distinct Phylogeographic Structures of Wild Radish (Raphanus sativus L. var. raphanistroides Makino) in Japan. AB - Coastal plants with simple linear distribution ranges along coastlines provide a suitable system for improving our understanding of patterns of intra-specific distributional history and genetic variation. Due to the combination of high seed longevity and high dispersibility of seeds via seawater, we hypothesized that wild radish would poorly represent phylogeographic structure at the local scale. On the other hand, we also hypothesized that wild radish populations might be geographically differentiated, as has been exhibited by their considerable phenotypic variations along the islands of Japan. We conducted nuclear DNA microsatellite loci and chloroplast DNA haplotype analyses for 486 samples and 144 samples, respectively, from 18 populations to investigate the phylogeographic structure of wild radish in Japan. Cluster analysis supported the existence of differential genetic structures between the Ryukyu Islands and mainland Japan populations. A significant strong pattern of isolation by distance and significant evidence of a recent bottleneck were detected. The chloroplast marker analysis resulted in the generation of eight haplotypes, of which two haplotypes (A and B) were broadly distributed in most wild radish populations. High levels of variation in microsatellite loci were identified, whereas cpDNA displayed low levels of genetic diversity within populations. Our results indicate that the Kuroshio Current would have contributed to the sculpting of the phylogeographic structure by shaping genetic gaps between isolated populations. In addition, the Tokara Strait would have created a geographic barrier between the Ryukyu Islands and mainland Japan. Finally, extant habitat disturbances (coastal erosion), migration patterns (linear expansion), and geographic characteristics (small islands and sea currents) have influenced the expansion and historical population dynamics of wild radish. Our study is the first to record the robust phylogeographic structure in wild radish between the Ryukyu Islands and mainland Japan, and might provide new insight into the genetic differentiation of coastal plants across islands. PMID- 26247203 TI - Nicotinic alpha4 Receptor-Mediated Cholinergic Influences on Food Intake and Activity Patterns in Hypothalamic Circuits. AB - Nicotinic acetylcholine receptors (nAChRs) play an important role in regulating appetite and have been shown to do so by influencing neural activity in the hypothalamus. To shed light on the hypothalamic circuits governing acetylcholine's (ACh) regulation of appetite this study investigated the influence of hypothalamic nAChRs expressing the alpha4 subunit. We found that antagonizing the alpha4beta2 nAChR locally in the lateral hypothalamus with di hydro-beta-erythroidine (DHbetaE), an alpha4 nAChR antagonist with moderate affinity, caused an increase in food intake following free access to food after a 12 hour fast, compared to saline-infused animals. Immunocytochemical analysis revealed that orexin/hypocretin (HO), oxytocin, and tyrosine hydroxylase (TH) containing neurons in the A13 and A12 of the hypothalamus expressed the nAChR alpha4 subunit in varying amounts (34%, 42%, 50%, and 51%, respectively) whereas melanin concentrating hormone (MCH) neurons did not, suggesting that DHbetaE mediated increases in food intake may be due to a direct activation of specific hypothalamic circuits. Systemic DHbetaE (2 mg/kg) administration similarly increased food intake following a 12 hour fast. In these animals a subpopulation of orexin/hypocretin neurons showed elevated activity compared to control animals and MCH neuronal activity was overall lower as measured by expression of the immediate early gene marker for neuronal activity cFos. However, oxytocin neurons in the paraventricular hypothalamus and TH-containing neurons in the A13 and A12 did not show differential activity patterns. These results indicate that various neurochemically distinct hypothalamic populations are under the influence of alpha4beta2 nAChRs and that cholinergic inputs to the lateral hypothalamus can affect satiety signals through activation of local alpha4beta2 nAChR-mediated transmission. PMID- 26247204 TI - Radiographic Structural Damage Is Worse in the Dominant than the Non-Dominant Hand in Individuals with Early Rheumatoid Arthritis. AB - OBJECTIVE: The relationship between mechanical stress and radiographic progression in rheumatoid arthritis (RA) is unclear. The assumption is that mechanical stress is greater in the dominant hand. Therefore, the aim of the present study was to compare the presence and progression of erosions and joint space narrowing (JSN) in the dominant and non-dominant hand. METHODS: Data from 194 patients recently diagnosed with seropositive RA, and with hand radiographs taken at the time of diagnosis and at 2-year follow-up, were analyzed retrospectively. Radiographs were scored using the van der Heijde-modified Sharp Score (HSS) method. Each joint group within each hand was rated separately by two independent examiners in a double-blinded manner. RESULTS: One hundred and ninety four patients were enrolled (80% female, 88% positive rheumatoid factor, 92% positive anti-citrullinated protein antibody, and 95.4% right-handed). The baseline, follow-up erosion and JSN HSS were significantly higher in the dominant hand than in the non-dominant hand. The annual rate of radiographic progression was also higher in the dominant hand. The erosive progression in the wrist joints varied significantly according to handedness, but the erosion in the proximal interphalangeal joints and metacarpophalangeal joints was similar in both hands. The radiographic progression was associated with the dominant hand, an abnormal baseline C-reactive protein level, and joint damage at baseline. There was no significant difference in bone mineral density between the right and left hands. CONCLUSION: Radiological damage was worse and progressed faster in the dominant hand, suggesting that mechanical stress is associated with radiographic joint damage in early and active RA. PMID- 26247206 TI - Religion Does Matter for Climate Change Attitudes and Behavior. AB - Little research has focused on the relationship between religion and climate change attitudes and behavior. Further, while there have been some studies examining the relationship between environmental attitudes and religion, most are focused on Christian denominations and secularism, and few have examined other religions such as Buddhism. Using an online survey of 1,927 Australians we examined links between membership of four religious groupings (Buddhists, Christian literalists and non-literalists, and Secularists) and climate change attitudes and behaviors. Differences were found across religious groups in terms of their belief in: (a) human induced climate change, (b) the level of consensus among scientists, (c) their own efficacy, and (d) the need for policy responses. We show, using ordinal regression, that religion explains these differences even after taking into account socio-demographic factors, knowledge and environmental attitude, including belief in man's dominion over nature. Differences in attitude and behavior between these religious groups suggest the importance of engaging denominations to encourage change in attitudes and behavior among their members. PMID- 26247205 TI - Arginine Thiazolidine Carboxylate Stimulates Insulin Secretion through Production of Ca2+-Mobilizing Second Messengers NAADP and cADPR in Pancreatic Islets. AB - Oxothiazolidine carboxylic acid is a prodrug of cysteine that acts as an anti diabetic agent via insulin secretion and the formation of the Ca2+-mobilizing second messenger, cyclic ADP-ribose (cADPR). Here we show that a hybrid compound, arginine thiazolidine carboxylate (ATC), increases cytoplasmic Ca2+ in pancreatic beta-cells, and that the ATC-induced Ca2+ signals result from the sequential formation of two Ca2+-mobilizing second messengers: nicotinic acid adenine dinucleotide phosphate (NAADP) and cADPR. Our data demonstrate that ATC has potent insulin-releasing properties, due to the additive action of its two components; thiazolidine carboxylate (TC) and L-arginine. TC increases glutathione (GSH) levels, resulting in cAMP production, followed by a cascade pathway of NAADP/nitric oxide (NO)/cGMP/cADPR synthesis. L-arginine serves as the substrate for NO synthase (NOS), which results in cADPR synthesis via cGMP formation. Neuronal NOS is specifically activated in pancreatic beta-cells upon ATC treatment. These results suggest that ATC is an ideal candidate as an anti diabetic, capable of modulating the physiological Ca2+ signalling pathway to stimulate insulin secretion. PMID- 26247209 TI - [Regression models for risk-factor assessment]. PMID- 26247207 TI - A Pan-GTPase Inhibitor as a Molecular Probe. AB - Overactive GTPases have often been linked to human diseases. The available inhibitors are limited and have not progressed far in clinical trials. We report here a first-in-class small molecule pan-GTPase inhibitor discovered from a high throughput screening campaign. The compound CID1067700 inhibits multiple GTPases in biochemical, cellular protein and protein interaction, as well as cellular functional assays. In the biochemical and protein interaction assays, representative GTPases from Rho, Ras, and Rab, the three most generic subfamilies of the GTPases, were probed, while in the functional assays, physiological processes regulated by each of the three subfamilies of the GTPases were examined. The chemical functionalities essential for the activity of the compound were identified through structural derivatization. The compound is validated as a useful molecular probe upon which GTPase-targeting inhibitors with drug potentials might be developed. PMID- 26247208 TI - Effects of Neuromuscular Electrical Stimulation on the Masticatory Muscles and Physiologic Sleep Variables in Adults with Cerebral Palsy: A Novel Therapeutic Approach. AB - Cerebral palsy (CP) is a term employed to define a group of non-progressive neuromotor disorders caused by damage to the immature or developing brain, with consequent limitations regarding movement and posture. CP may impair orapharygeal muscle tone, leading to a compromised chewing function and to sleep disorders (such as obstructive sleep apnea). Thirteen adults with CP underwent bilateral masseter and temporalis neuromuscular electrical stimulation (NMES) therapy. The effects on the masticatory muscles and sleep variables were evaluated using electromyography (EMG) and polysomnography (PSG), respectively, prior and after 2 months of NMES. EMG consisted of 3 tests in different positions: rest, mouth opening and maximum clenching effort (MCE). EMG values in the rest position were 100% higher than values recorded prior to therapy for all muscles analyzed (p < 0.05); mean mouth opening increased from 38.0 +/- 8.0 to 44.0 +/- 10.0 cm (p = 0.03). A significant difference in MCE was found only for the right masseter. PSG revealed an improved in the AHI from 7.2+/-7.0/h to 2.3+/-1.5/h (p < 0.05); total sleep time improved from 185 min to 250 min (p = 0.04) and minimun SaO2 improved from 83.6 +/- 3.0 to 86.4 +/- 4.0 (p = 0.04). NMES performed over a two-month period led to improvements in the electrical activity of the masticatory muscles at rest, mouth opening, isometric contraction and sleep variables, including the elimination of obstructive sleep apnea events in patients with CP. Trial registration: ReBEC RBR994XFS http://www.ensaiosclinicos.gov.br. PMID- 26247210 TI - Impact of Maternal Death on Household Economy in Rural China: A Prospective Path Analysis. AB - OBJECTIVES: The present study aimed to explore the inter-relationships among maternal death, household economic status after the event, and potential influencing factors. METHODS: We conducted a prospective cohort study of households that had experienced maternal death (n = 195) and those that experienced childbirth without maternal death (n = 384) in rural China. All the households were interviewed after the event occurred and were followed up 12 months later. Structural equation modeling was used to test the relationship model, utilizing income and expenditure per capita in the following year after the event as the main outcome variables, maternal death as the predictor, and direct costs, the amount of money offset by positive and negative coping strategies, whether the husband remarried, and whether the newborn was alive as the mediators. RESULTS: In the following year after the event, the path analysis revealed a direct effect from maternal death to lower income per capita (standardized coefficient = -0.43, p = 0.041) and to lower expenditure per capita (standardized coefficient = -0.51, p<0.001). A significant indirect effect was found from maternal death to lower income and expenditure per capita mediated by the influencing factors of higher direct costs, less money from positive coping methods, more money from negative coping, and the survival of the newborn. CONCLUSION: This study analyzed the direct and indirect effects of maternal death on a household economy. The results provided evidence for better understanding the mechanism of how this event affects a household economy and provided a reference for social welfare policies to target the most vulnerable households that have suffered from maternal deaths. PMID- 26247211 TI - Evidence of Subclinical mtDNA Alterations in HIV-Infected Pregnant Women Receiving Combination Antiretroviral Therapy Compared to HIV-Negative Pregnant Women. AB - INTRODUCTION: Combination antiretroviral therapy (cART) can effectively prevent vertical transmission of HIV but there is potential risk of adverse maternal, foetal or infant effects. Specifically, the effect of cART use during pregnancy on mitochondrial DNA (mtDNA) content in HIV-positive (HIV+) women is unclear. We sought to characterize subclinical alterations in peripheral blood mtDNA levels in cART-treated HIV+ women during pregnancy and the postpartum period. METHODS: This prospective longitudinal observational cohort study enrolled both HIV+ and HIV-negative (HIV-) pregnant women. Clinical data and blood samples were collected at three time points in pregnancy (13-<23 weeks, 23-<30 weeks, 30-40 weeks), and at delivery and six weeks post-partum in HIV+ women. Peripheral blood mtDNA to nuclear DNA (nDNA) ratio was measured by qPCR. RESULTS: Over a four year period, 63 HIV+ and 42 HIV- women were enrolled. HIV+ women showed significantly lower mtDNA/nDNA ratios compared to HIV- women during pregnancy (p = 0.003), after controlling for platelet count and repeated measurements using a multivariable mixed-effects model. Ethnicity, gestational age (GA) and substance use were also significantly associated with mtDNA/nDNA ratio (p<=0.02). Among HIV+ women, higher CD4 nadir was associated with higher mtDNA/nDNA ratios (p<0.0001), and these ratio were significantly lower during pregnancy compared to the postpartum period (p<0.0001). CONCLUSIONS: In the context of this study, it was not possible to distinguish between mtDNA effects related to HIV infection versus cART therapy. Nevertheless, while mtDNA levels were relatively stable over time in both groups during pregnancy, they were significantly lower in HIV+ women compared to HIV- women. Although no immediate clinical impact was observed on maternal or infant health, lower maternal mtDNA levels may exert long-term effects on women and children and remain a concern. Improved knowledge of such subclinical alterations is another step toward optimizing the safety and efficacy of cART regimens during pregnancy. PMID- 26247212 TI - Inter-Ethnic/Racial Facial Variations: A Systematic Review and Bayesian Meta Analysis of Photogrammetric Studies. AB - BACKGROUND: Numerous facial photogrammetric studies have been published around the world. We aimed to critically review these studies so as to establish population norms for various angular and linear facial measurements; and to determine inter-ethnic/racial facial variations. METHODS AND FINDINGS: A comprehensive and systematic search of PubMed, ISI Web of Science, Embase, and Scopus was conducted to identify facial photogrammetric studies published before December, 2014. Subjects of eligible studies were either Africans, Asians or Caucasians. A Bayesian hierarchical random effects model was developed to estimate posterior means and 95% credible intervals (CrI) for each measurement by ethnicity/race. Linear contrasts were constructed to explore inter-ethnic/racial facial variations. We identified 38 eligible studies reporting 11 angular and 18 linear facial measurements. Risk of bias of the studies ranged from 0.06 to 0.66. At the significance level of 0.05, African males were found to have smaller nasofrontal angle (posterior mean difference: 8.1 degrees , 95% CrI: 2.2 degrees 13.5 degrees ) compared to Caucasian males and larger nasofacial angle (7.4 degrees , 0.1 degrees -13.2 degrees ) compared to Asian males. Nasolabial angle was more obtuse in Caucasian females than in African (17.4 degrees , 0.2 degrees 35.3 degrees ) and Asian (9.1 degrees , 0.4 degrees -17.3 degrees ) females. Additional inter-ethnic/racial variations were revealed when the level of statistical significance was set at 0.10. CONCLUSIONS: A comprehensive database for angular and linear facial measurements was established from existing studies using the statistical model and inter-ethnic/racial variations of facial features were observed. The results have implications for clinical practice and highlight the need and value for high quality photogrammetric studies. PMID- 26247213 TI - Is there any difference between angiotensin converting enzyme inhibitors and angiotensin receptor blockers for heart failure? AB - Angiotensin receptor blockers are usually considered as equivalent to angiotensin converting enzyme inhibitors for patients with heart failure and low-ejection fraction. Some guidelines even recommend the former as first line treatment given their better adverse effects profile. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified four systematic reviews including eight pertinent randomized controlled trials. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded angiotensin receptor blockers and angiotensin converting enzyme inhibitors probably have a similar effect on mortality, and they might be equivalent in reducing hospitalization risk too. Treatment withdrawal due to adverse effects is probably lower with angiotensin receptor blockers than with angiotensin converting enzyme inhibitors. PMID- 26247214 TI - Quo vadis, Psychiatry? PMID- 26247215 TI - A Deese-Roediger-McDermott study of trauma memory among employees of New York City companies affected by the September 11, 2001, attacks. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) has been found to be associated with abnormalities in memory function. This relationship has not previously been studied using the Deese-Roediger-McDermott (DRM) false memory paradigm in disaster-exposed populations. METHODS: Three years after the September 11, 2001 (9/11) attacks, 281 participants from a volunteer sample of 379, recruited from 8 companies directly affected by the attacks, completed an interview about their disaster experience, a structured diagnostic interview, and the DRM paradigm. RESULTS: It was hypothesized that participants with PTSD would demonstrate more associative errors, termed false alarms to critical lures, compared to those without PTSD. This hypothesis was not supported; the only predictor of false alarms to critical lures was direct 9/11 trauma exposure. CONCLUSIONS: The finding that 9/11 trauma-exposure was associated with false alarms to critical lures suggests that neural processing of trauma-exposure memory may involve associative elements of overgeneralization coupled with insufficient inhibition of responses to related but harmless stimuli. Future research will be needed to differentiate psychopathology, such as PTSD, from physiological fight-or-flight responses to trauma. PMID- 26247216 TI - The effect of childhood abuse on the risk of adult obesity. AB - BACKGROUND: The purpose of this study was to assess the association between childhood abuse and adult obesity. METHODS: We performed a comprehensive meta analysis, which included studies that reported odds ratio (OR) estimates with 95% confidence intervals (CI). Summary estimates of association were obtained using a random-effects model. Heterogeneity among studies was evaluated using Cochran Q and I2 statistics. RESULTS: A total of 22 cohort studies (3 prospective, 19 retrospective) were included in this meta-analysis. The pooled OR was 1.23 (95% CI, 1.16-1.31). All 4 subcategories of abuse were associated with adult obesity: physical abuse (OR, 1.26; 95% CI, 1.10-1.42), psychological abuse (OR, 1.20; 95% CI, 1.07-1.33), sexual abuse (OR, 1.22; 95% CI, 1.05-1.38), and neglect (OR, 1.22; 95% CI, 1.12-1.32). Moreover, dose-response analysis showed that severe abuse (OR, 1.38; 95% CI, 1.14-1.1.62) was significantly associated with adult obesity compared with light/moderate abuse (OR, 1.01; 95% CI, 0.84-1.18). Although slight publication bias was observed (Egger test P = .05), effect sizes remained statistically significant in sensitivity analyses. CONCLUSIONS: This research demonstrated a remarkably consistent association between childhood abuse and adult obesity. Medical practitioners need to be aware of the important role of childhood abuse in the development of obesity. PMID- 26247217 TI - Longitudinal course of body-focused repetitive behaviors in obsessive-compulsive disorder. AB - BACKGROUND: The course of body-focused repetitive behaviors (BFRBs) (eg, trichotillomania, skin picking, and nail biting) has received scant research attention. We sought to understand the longitudinal course of BFRBs over an 8 year period and whether the co-occurrence of a BFRB with obsessive-compulsive disorder (OCD) affects the course of OCD. METHODS: Three hundred ninety-five participants with OCD completed annual interviews using the Longitudinal Interval Follow-up Evaluation to estimate BFRB and OCD symptom severity during each week of follow-up. RESULTS: Of the 395 participants, 83 (21%) had a co-occurring BFRB. In almost one-half of the participants, BFRB onset occurred before OCD. Participants with OCD and BFRB spent the majority of the rating period experiencing full BFRB symptoms. Having a BFRB was associated with spending less time in remission from OCD. CONCLUSIONS: Although BFRBs have long been known to be common in individuals with OCD, these data demonstrate that most individuals who have a co-occurring BFRB with OCD do not experience BFRB remission and that having a BFRB predicts a worse course for OCD. PMID- 26247218 TI - Repetitive transcranial magnetic stimulation for treatment of major depressive disorder with comorbid generalized anxiety disorder. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has shown promising results in treating individuals with behavioral disorders such as major depressive disorder (MDD), posttraumatic stress disorder, obsessive-compulsive disorder, and social anxiety disorder. A number of applications of rTMS to different regions of the left and right prefrontal cortex have been used to treat these disorders, but no study of treatment for MDD with generalized anxiety disorder (GAD) has been conducted with application of rTMS to both the left and right prefrontal cortex. We hypothesized that applying low-frequency rTMS to the right dorsolateral prefrontal cortex (DLPFC) before applying it to the left DLPFC for the treatment of depression would be anxiolytic in patients with MDD with GAD. METHODS: Thirteen adult patients with comorbid MDD and GAD received treatment with rTMS in an outpatient setting. The number of treatments ranged from 24 to 36 over 5 to 6 weeks. Response was defined as a >= 50% reduction in symptoms from baseline, and remission was defined as a score of < 5 for anxiety symptoms on the 7-item Generalized Anxiety Disorder (GAD-7) scale and < 8 for depressive symptoms on the 21-item Hamilton Rating Scale for Depression (HAM-D 21). RESULTS: At the end of the treatment period, for the GAD-7 scale, 11 out of 13 (84.6%) patients' anxiety symptoms were in remission, achieving a score of < 5 on the GAD-7, and 10 out of 13 patients (76.9%) achieved a HAM-D-21 score of < 8 for depressive symptoms. CONCLUSIONS: In this small pilot study of 13 patients with comorbid MDD and GAD, significant improvement in anxiety symptoms along with depressive symptoms was achieved in a majority of patients after bilateral rTMS application. PMID- 26247219 TI - Omega-3 fatty acids for atypical antipsychotic-associated hypertriglyceridemia. AB - BACKGROUND: The objective of this open-label, preliminary study was to assess the efficacy of omega-3 fatty acids for treating dyslipidemia associated with use of atypical antipsychotics. METHODS: Participants treated with atypical antipsychotics who had hypertriglyceridemia (> 200 mg/dL) and/or hypercholesterolemia (> 250 mg/dL) were enrolled in an open trial and received omega-3 fatty acids (Lovaza) for up to 16 weeks. Serum lipid profiles were re assessed at 8 and 16 weeks. RESULTS: Twenty-eight participants with dyslipidemia enrolled in the trial; 16 were evaluable with post-baseline assessments. There was an average decrease in triglyceride levels of 54.13 +/- 83.44 mg/dL (P = .04). A more pronounced benefit of omega-3 supplementation was observed in participants with elevated triglyceride levels at baseline (> 200 mg/dL), compared with those with elevated cholesterol values but normal or more modestly elevated triglyceride levels at enrollment. Participants with hypertriglyceridemia at baseline (n = 10, > 200 mg/dL) experienced a mean decrease in triglyceride levels of 75.8 +/- 28.71 mg/dL, a significantly larger decrease than was observed among all participants (P = .005). CONCLUSIONS: Omega 3 supplementation reduced triglyceride levels but not levels of total cholesterol. Recruitment and retention in this study was challenging, and could indicate a lack of screening for dyslipidemia among atypical antipsychotic users/prescribers or could reflect the over-the- counter availability of omega-3 fatty acids. PMID- 26247220 TI - NMDA receptor antagonists for depression: Critical considerations. AB - BACKGROUND: Research studies suggest that glutamate dysfunction, in particular N methyl-D-aspartate receptors (NMDARs) abnormalities, may be involved in the pathophysiology of major neuropsychiatric conditions. Increased glutamatergic excitotoxic activity may be found in some brain circuits of patients with major depression. According to several published reports, NMDAR antagonists may exert antidepressant activity, but the molecular changes associated with abnormal glutamatergic neurotransmission remain unclear. METHODS: We have critically reviewed the current literature in order to investigate the role of NMDAR antagonists in major depression. RESULTS: NMDAR antagonists, such as ketamine, may be considered novel and promising pharmacological options for the rapid treatment of treatment-resistant depression patients. This is in contrast to the delayed action of the currently available antidepressant medications. Studies suggest that glutamatergic receptor modulation may enhance neuroplasticity mechanisms and neurogenesis together with the release of some neurotransmitters. Unfortunately, the use of ketamine is currently limited by some transient adverse events, including dissociative symptoms. CONCLUSIONS: Targeting NMDARs using antagonists represents an important alternative antidepressant option in major depression. However, NMDAR antagonists may exert different actions based on the differential brain location of NMDAR. PMID- 26247221 TI - Near-lethal violent suicide attempt in a 15-year old adolescent with no prior psychiatric history following ingestion of 'N-Bomb' drug. PMID- 26247222 TI - Paroxysmal perceptual alteration in a schizophrenic patient treated with paliperidone: A case report. PMID- 26247223 TI - Facile Preparation of Hierarchical Structures Using Crystallization-Kinetics Driven Self-Assembly. AB - Hierarchical structures (HSs) constructed by nanoparticle-based building blocks possess not only the properties of the primary building blocks but also collective properties of the assemblies. Here we report the facile preparation of hierarchical Ag nanoparticles/polyhedral oligomeric silsequioxane molecule (POSS) hybrid branched structures within tens of seconds by using spin-coating and doctor-blade methods. An assembly mechanism mainly controlled by POSS crystallization kinetics and space resistance of Ag nanoparticles toward the diffusion of POSS molecules was tentatively proposed. It was demonstrated as a universal method for the preparation of hierarchical hybrid branched structures on arbitrary substrates, as well as by using other different POSS and inorganic nanoparticles. As a demonstration, Ag hierarchical structures obtained by heat treatment exhibit excellent SERS performance with enhancement factors as high as on the order of 10(7), making them promising sensors for the detection of trace amount of analyte adsorbed on the surface. Two-dimensional SERS mapping was also demonstrated by using a direct imaging system with high mapping speed and high resolution. Moreover, the substrates with Ag hierarchical structures were used as a SERS sensor for in situ detection due to the excellent SERS performance and stability of the structures. PMID- 26247224 TI - Advanced in the Forensic Analysis of Glass Fragments with a Focus on Refractive Index and Elemental Analysis. AB - Advances in technology provide forensic scientists with better tools to detect, to identify, and to individualize small amounts of trace evidence that have been left at a crime scene. The analysis of glass fragments can be useful in solving cases such as hit and run, burglaries, kidnappings, and bombings. The value of glass as "evidentiary material" lies in its inherent characteristics such as: (a) it is a fragile material that is often broken and hence commonly found in various types of crime scenes, (b) it can be easily transferred from the broken source to the scene, suspect, and/or victim, (c) it is relatively persistent, (d) it is chemically stable, and (e) it has measurable physical and chemical properties that can provide significant evidence of an association between the recovered glass fragments and the source of the broken glass. Forensic scientists have dedicated considerable effort to study and improve the detection and discrimination capabilities of analytical techniques in order to enhance the quality of information obtained from glass fragments. This article serves as a review of the developments in the application of both traditional and novel methods of glass analysis. The greatest progress has been made with respect to the incorporation of automated refractive index measurements and elemental analysis to the analytical scheme. Glass examiners have applied state-of-the-art technology including elemental analysis by sensitive methods such as ICPMS and LA ICP-MS. A review of the literature regarding transfer, persistence, and interpretation of glass is also presented. PMID- 26247225 TI - Current Trends in Forensic Paint Examination. AB - Paints and coatings have been recognized as a useful type of forensic evidence for several decades. During this time the materials themselves, the analytical methods used to examine them, and the legal environment surrounding the use of scientific evidence in courts have all changed. This paper is not intended to provide a comprehensive bibliography on the topic, but rather to provide a concise overview of past and current trends in the forensic examination of paints and coatings in light of these changes. PMID- 26247226 TI - Particle Analysis in Forensic Science. AB - Microscopic trace evidence includes particles from many sources such as biologicals, soil, building materials, metals, explosives, gunshot residues, and cosmetics. The particles are identified by morphological analysis, microscopy, and chemical analysis. Their identity is confirmed by comparison with reference materials or other comparison samples. The probative value of particles of forensic interest depends on their nature and the circumstances of their presence. PMID- 26247227 TI - Yellow mealworm larvae (Tenebrio molitor, L.) as a possible alternative to soybean meal in broiler diets. AB - The aim of the study was to evaluate the feasibility of replacing soybean meal (SBM) with Tenebrio molitor larvae (TML) meal in broiler diets. A total of 80 30 d-old male Shaver brown broilers were divided into two groups fed on two isoproteic and isoenergetic diets differing for protein source (SBM vs. TML). Up to 62 d of age, body weight and feed intake were recorded weekly and body weight gain, feed conversion ratio (FCR), protein efficiency ratio (PER) and European efficiency factor (EEF) were calculated. At 62 d, blood samples were collected from 16 birds/group for evaluation of blood profiles. Feed intake was not different between groups considering the entire period of the trial. The FCR was more favourable in the TML than SBM group from 46 d of age and in the entire period of the trial (4.13 vs. 3.62). The PER was higher in the SBM than in the TML group (1.92 vs. 1.37) while the EEF was higher in broilers fed on the TML diet (132.6 vs. 156.2). Albumin-to-globulin ratio was higher in broilers fed on SBM than in the other group (0.44 vs. 0.30). aspartate aminotransferase and alanine aminotransferase were higher in TML than SBM (195.1 vs. 178.6 U/l and 82.07 vs. 46.71 U/l, respectively). Uric acid was higher in broilers fed on SBM than TML (5.40 vs. 4.16 mg/dl). TML did not affect feed intake and growth rate of broilers from 30 to 62 d of age when compared to an isoproteic and isoenergetic SBM diet, but FCR of the TML group was more favourable than that of the SBM group. The lowest albumin-to-globulin ratio in broilers fed on TML suggests a higher immune response, probably due to the prebiotic effects of chitin. PMID- 26247228 TI - Comparison of the scanning linear estimator (SLE) and ROI methods for quantitative SPECT imaging. AB - In quantitative emission tomography, tumor activity is typically estimated from calculations on a region of interest (ROI) identified in the reconstructed slices. In these calculations, unpredictable bias arising from the null functions of the imaging system affects ROI estimates. The magnitude of this bias depends upon the tumor size and location. In prior work it has been shown that the scanning linear estimator (SLE), which operates on the raw projection data, is an unbiased estimator of activity when the size and location of the tumor are known. In this work, we performed analytic simulation of SPECT imaging with a parallel hole medium-energy collimator. Distance-dependent system spatial resolution and non-uniform attenuation were included in the imaging simulation. We compared the task of activity estimation by the ROI and SLE methods for a range of tumor sizes (diameter: 1-3 cm) and activities (contrast ratio: 1-10) added to uniform and non uniform liver backgrounds. Using the correct value for the tumor shape and location is an idealized approximation to how task estimation would occur clinically. Thus we determined how perturbing this idealized prior knowledge impacted the performance of both techniques. To implement the SLE for the non uniform background, we used a novel iterative algorithm for pre-whitening stationary noise within a compact region. Estimation task performance was compared using the ensemble mean-squared error (EMSE) as the criterion. The SLE method performed substantially better than the ROI method (i.e. EMSE(SLE) was 23 174 times lower) when the background is uniform and tumor location and size are known accurately. The variance of the SLE increased when a non-uniform liver texture was introduced but the EMSE(SLE) continued to be 5-20 times lower than the ROI method. In summary, SLE outperformed ROI under almost all conditions that we tested. PMID- 26247229 TI - Understanding the Excited State Behavior of Cyclometalated Bis(tridentate)ruthenium(II) Complexes: A Combined Experimental and Theoretical Study. AB - The synthesis and characterization of the donor-acceptor substituted cyclometalated ruthenium(II) polypyridine complex isomers [Ru(dpb-NHCOMe)(tpy COOEt)](PF6) 1(PF6) and [Ru(dpb-COOEt)(tpy-NHCOMe)](PF6) 2(PF6) (dpbH = 1,3 dipyridin-2-ylbenzene, tpy = 2,2';6,2"-terpyridine) with inverted functional group pattern are described. A combination of resonance Raman spectroscopic and computational techniques shows that all intense visible range absorption bands arise from mixed Ru -> tpy/Ru -> dpb metal-to-ligand charge transfer (MLCT) excitations. 2(PF6) is weakly phosphorescent at room temperature in fluid solution and strongly emissive at 77 K in solid butyronitrile matrix, which is typical for ruthenium(II) polypyridine complexes. Density functional theory calculations revealed that the weak emission of 2(PF6) arises from a (3)MLCT state that is efficiently thermally depopulated via metal-centered ((3)MC) excited states. The activation barrier for the deactivation process was estimated experimentally from variable-temperature emission spectroscopic measurements as 11 kJ mol(-1). In contrast, 1(PF6) is nonemissive at room temperature in fluid solution and at 77 K in solid butyronitrile matrix. Examination of the electronic excited states of 1(PF6) revealed a ligand-to-ligand charge-transfer ((3)LL'CT) as lowest-energy triplet state due to the very strong push-pull effect across the metal center. Because of the orthogonality of the participating ligands, emission from the (3)LL'CT is symmetry-forbidden. Hence, in this type of complex a stronger push-pull effect does not increase the phosphorescence quantum yields but completely quenches the emission. PMID- 26247230 TI - Synthesis of Vinyl Chlorides via Triphosgene-Pyridine Activation of Ketones. AB - Herein, we describe a mild method to prepare aliphatic and aromatic vinyl chlorides from their corresponding ketones via triphosgene-pyridine activation in dichloromethane at reflux. The mechanism of this reaction is proposed to involve formation of a putative alpha-chloro pyridinium carbamate intermediate, which appeared to readily undergo E2 elimination in the presence of pyridine. PMID- 26247231 TI - Application of Shape Similarity in Pose Selection and Virtual Screening in CSARdock2014 Exercise. AB - To evaluate the applicability of shape similarity in docking-based pose selection and virtual screening, we participated in the CSARdock2014 benchmark exercise for identifying the correct docking pose of inhibitors targeting factor XA, spleen tyrosine kinase, and tRNA methyltransferase. This exercise provides a valuable opportunity for researchers to test their docking programs, methods, and protocols in a blind testing environment. In the CSARdock2014 benchmark exercise, we have implemented an approach that uses ligand 3D shape similarity to facilitate docking-based pose selection and virtual screening. We showed here that ligand 3D shape similarity between bound poses could be used to identify the native-like pose from an ensemble of docking-generated poses. Our method correctly identified the native pose as the top-ranking pose for 73% of test cases in a blind testing environment. Moreover, the pose selection results also revealed an excellent correlation between ligand 3D shape similarity scores and RMSD to X-ray crystal structure ligand. In the virtual screening exercise, the average RMSD for our pose prediction was found to be 1.02 A, and it was one of the top performances achieved in CSARdock2014 benchmark exercise. Furthermore, the inclusion of shape similarity improved virtual screening performance of docking-based scoring and ranking. The coefficient of determination (r(2)) between experimental activities and docking scores for 276 spleen tyrosine kinase inhibitors was found to be 0.365 but reached 0.614 when the ligand 3D shape similarity was included. PMID- 26247232 TI - Excited-State Proton Transfer in Resveratrol and Proposed Mechanism for Plant Resistance to Fungal Infection. AB - Steady-state and time-resolved fluorescence techniques were employed to study the photophysics and photochemistry of trans-resveratrol. trans-Resveratrol is found in large quantities in fungi-infected grapevine-leaf tissue and plays a direct role in the resistance to plant disease. We found that trans-resveratrol in liquid solution undergoes a trans-cis isomerization process in the excited state at a rate that depends partially on the solvent viscosity, as was found in previous studies on trans-stilbene. The hydroxyl groups of the phenol moieties in resveratrol are weak photoacids. In water and methanol solutions containing weak bases such as acetate, a proton is transferred to the base within the lifetime of the excited state. When resveratrol is adsorbed on cellulose (also a component of the plant's cell wall), the cis-trans process is slow and the lifetime of the excited state increases from several tens of picoseconds in ethanol to about 1.5 ns. Excited-state proton transfer occurs when resveratrol is adsorbed on cellulose and acetate ions are in close proximity to the phenol moieties. We propose that proton transfer from excited resveratrol to the fungus acid-sensing chemoreceptor is one of the plant's resistance mechanisms to fungal infection. PMID- 26247233 TI - MET-XAlign: a metabolite cross-alignment tool for LC/MS-based comparative metabolomics. AB - Liquid chromatography/mass spectrometry (LC/MS) metabolite profiling has been widely used in comparative metabolomics studies; however, LC/MS-based comparative metabolomics currently faces several critical challenges. One of the greatest challenges is how to effectively align metabolites across different LC/MS profiles; a single metabolite can give rise to multiple peak features, and the grouped peak features that can be used to construct a spectrum pattern of single metabolite can vary greatly between biochemical experiments and even between instrument runs. Another major challenge is that the observed retention time for a single metabolite can also be significantly affected by experimental conditions. To overcome these two key challenges, we present a novel metabolite based alignment approach entitled MET-XAlign to align metabolites across LC/MS metabolomics profiles. MET-XAlign takes the deduced molecular mass and estimated compound retention time information that can be extracted by our previously published tool, MET-COFEA, and aligns metabolites based on this information. We demonstrate that MET-XAlign is able to cross-align metabolite compounds, either known or unknown, in LC/MS profiles not only across different samples but also across different biological experiments and different electrospray ionization modes. Therefore, our proposed metabolite-based cross-alignment approach is a great step forward and its implementation, MET-XAlign, is a very useful tool in LC/MS-based comparative metabolomics. MET-XAlign has been successfully implemented with core algorithm coding in C++, making it very efficient, and visualization interface coding in the Microsoft.NET Framework. The MET-XAlign software along with demonstrative data is freely available at http://bioinfo.noble.org/manuscript-support/met-xalign/ . PMID- 26247234 TI - Apolipoprotein C3 Gene Variants and Risk of Developing Type 2 Diabetes in Saudi Subjects. AB - BACKGROUND: Apolipoprotein C3 (ApoC3) is a major constituent of VLDL and is a modulator of triglyceride metabolism. Recent genetic studies have implicated several ApoC3 gene polymorphisms in the development of insulin resistance and type 2 diabetes mellitus (T2DM). Considering the high prevalence of T2DM in Saudi Arabia, we sought to examine the possible association of ApoC3 gene variants with diabetes risk in Saudi population. METHODS: The 3238C>G and -482C>T polymorphisms of ApoC3 gene were studied in 268 T2DM patients and 255 healthy controls by TaqMan probe based real time polymerase chain reaction assays. RESULTS: Diabetic patients displayed significantly increased systolic blood pressure, fasting plasma glucose, insulin resistance, and dyslipidemia compared to control. Patients also had markedly elevated plasma VLDL levels. Genotype distribution of 3238C>G polymorphism was significantly different between patients and control. Consistently, this variant was found to be significantly associated with T2DM risk. Contrastingly, no significant relationship was found between -482C>T polymorphism and T2DM risk. Association of disease risk with 3238C>G polymorphism remained significant even after accounting for the established risk factors. Genotype-based stratification revealed a significant correlation of GG genotype of 3238C>G with elevated plasma triglycerides, insulin resistance, and VLDL, whereas the TT genotype of -482C>T correlated with elevated triglyceride and VLDL levels. CONCLUSIONS: Thus, 3238C>G polymorphism of ApoC3 gene appears to augment the propensity to develop T2DM, while -482C>T to negatively affect lipid metabolism in Saudi subjects. PMID- 26247235 TI - RADIOTHERAPY VERSUS RADIOSURGERY IN TREATING PATIENTS WITH ACROMEGALY: A SYSTEMATIC REVIEW AND META-ANALYSIS. AB - OBJECTIVE: When patients with acromegaly have residual disease following surgery, adjuvant radiation therapy is considered. Both stereotactic radiosurgery (SRS) and conventional fractionated radiotherapy (RT) are utilized. We conducted a systematic review and meta-analysis to synthesize the existing evidence and compare outcomes for SRS and RT in patients with acromegaly. METHODS: We searched Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through April 2014 for studies in which SRS or RT were used in patients with acromegaly. Outcomes evaluated were serum insulin-like growth factor-I (IGF-I) and growth hormone (GH) levels, biochemical remission, all-cause mortality, hypopituitarism, headaches, and secondary malignancies. We pooled outcomes using a random-effects model. RESULTS: The final search yielded 30 eligible studies assessing 2,464 patients. Compared to RT, SRS was associated with a nonsignificant increase in remission rate at the latest follow-up period (52% vs. 36%; P = .14) and a significantly lower follow-up IGF-I level (-409.72 MUg/L vs. -102 MUg/L, P = .002). SRS had a lower incidence of hypopituitarism than RT; however, the difference was not statistically significant (32% vs. 51%, respectively; P = .05). CONCLUSION: SRS may be associated with better biochemical remission, and it had a lower risk of hypopituitarism with at least 1 deficient axis when compared with RT; however, the confidence in such evidence is very low due to the noncomparative nature of the studies, high heterogeneity, and imprecision. PMID- 26247236 TI - RADIOFREQUENCY ABLATION FOR BENIGN THYROID NODULES--A LOOK TOWARDS THE FUTURE OF INTERVENTIONAL THYROIDOLOGY. PMID- 26247237 TI - Thrombin generation in two families with MYH9-related platelet disorder. AB - MYH9-related platelet disorders are inherited macrothrombocytopenias with additional clinical manifestations including renal failure, hearing loss, pre senile cataract, and inclusion bodies in leucocytes that are present in different combinations. The MYH9 gene codes for the cytoplasmic contractile protein non muscular myosin heavy chain IIA, present in several tissues. The bleeding tendency is usually mild to moderate but rarely, thrombotic complications are also seen. We report on the thrombin generation potential (ETP) in patients with MYH9-related disease with and without arterial thrombosis. In family A, four affected members [c.5521G>A mutation causing p.(Glu1841Lys)] were evaluated. Three of them had a moderate bleeding tendency and in two renal insufficiency and hearing loss were already present. These two patients had an arterial thrombosis (myocardial infarction and pons infarction, respectively) before 50 years of age. In family B, two members were affected [c.4679T>G, resulting in p.(Val1560Gly)]. Their bleeding tendency was mild (bleeding scores 4 and 3, respectively). Thrombelastography (ROTEM) was normal in all six individuals. ETP was below the normal range in family B. However, in family A, the two members affected by thrombosis had a normal ETP, indicating that other factors compensated for the low platelet count and might have contributed to the arterial thrombosis. PMID- 26247239 TI - WITHDRAWN: Effect of Vibram FiveFingers Minimalist Shoes on the Abductor Hallucis Muscle. AB - Ahead of Print article withdrawn by publisher. PMID- 26247240 TI - IVD nutrition processes under compressive load: a finite deformation model. PMID- 26247238 TI - "I Felt Like It Was God's Hands Putting the Needles In": A Qualitative Analysis of the Experience of Acupuncture for Chronic Pain in a Low-Income, Ethnically Diverse, and Medically Underserved Patient Population. AB - OBJECTIVES: To examine the experience of patients from a low-income, ethnically diverse medically underserved population receiving acupuncture for chronic pain. DESIGN: Qualitative analysis using inductive thematic analysis of interviews with participants from an acupuncture trial. SETTINGS/LOCATION: Four community health centers in the Bronx, New York. PARTICIPANTS: Thirty-seven adults with chronic neck or back pain or osteoarthritis who participated in a previous acupuncture trial. INTERVENTIONS: Up to 14 weekly acupuncture treatments. OUTCOME MEASURES: Pain and quality of life were examined in the original trial; this study examines qualitative outcomes. RESULTS: The themes grouped naturally into three domains of the acupuncture experience: the decision-making process, the treatment experience, and the effect of acupuncture on health. Regarding decision-making, important factors were a willingness to try something new even if you do not necessarily "believe" in it or have specifically positive expectations; a sense that medications were not working for their pain, that they also caused significant adverse effects, and that natural strategies might be preferable; and a feeling of desperation. Cost and access were significant barriers to acupuncture treatment. Regarding the process of acupuncture, the open and personal communication with the acupuncturist was an important factor, as were the sense that the process of acupuncture related to a natural process of healing or correction within the body and that part of making acupuncture successful required being open to the power of the mind to generate a positive outcome. Regarding the effect of treatment, notable aspects were the deep sense of rest and relaxation participants reported during treatment as well as the benefit they experienced for conditions other than pain. CONCLUSIONS: The themes that emerged in this ethnically diverse, low-income population were very similar to those that have emerged over the past decade of qualitative research on the acupuncture experience in other patient populations. PMID- 26247241 TI - Phytoextraction of trace elements by water hyacinth in contaminated area of gold mine tailing. AB - The ability of water hyacinth (Eichhornia crassipes) to uptake Ag, Ba, Cd, Mo, and Pb from waters in gold mine tailing area was studied. All experiments were carried out in the field conditions without using of model system. Bioconcentration (BCF) and translocation factors (TF) as well as elements accumulation by plant in different points of tailings-impacted area were evaluated. It has been shown that water hyacinth demonstrates high ability to accumulate Mo, Pb, and Ba with BCF values 24,360 +/- 3600, 18,800 +/- 2800 and 10,040 +/- 1400, respectively and is efficient in translocation of Mo and Cd. The general trend of the plant accumulation ability in relation to the studied elements corresponds to their concentration in the medium. As the distance from tailings increases, concentration of Ag, Ba and Pb in plant decreases more clearly than that of Cd, while the amount of Mo accumulated by plant doesn't drop significantly in accordance with its concentration in water. Under the conditions of the confluence of river Ur and drainage stream Ba and Ag can be considered as potential candidates for phytomining. PMID- 26247242 TI - Measurement of State-Specific Association Constants in Allosteric Sensors through Molecular Stapling and NMR. AB - Allostery is a ubiquitous mechanism to control biological function and arises from the coupling of inhibitory and binding equilibria. The extent of coupling reflects the inactive vs active state selectivity of the allosteric effector. Hence, dissecting allosteric determinants requires quantification of state specific association constants. However, observed association constants are typically population-averages, reporting on overall affinities but not on allosteric coupling. Here we propose a general method to measure state-specific association constants in allosteric sensors based on three key elements, i.e., state-selective molecular stapling through disulfide bridges, competition binding saturation transfer experiments and chemical shift correlation analyses to gauge state populations. The proposed approach was applied to the prototypical cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA-RIalpha), for which the structures of the inactive and active states are available, as needed to design the state-selective disulfide bridges. Surprisingly, the PKA-RIalpha state specific association constants are comparable to those of a structurally homologous domain with ~10(3)-fold lower cAMP-affinity, suggesting that the affinity difference arises primarily from changes in the position of the dynamic apo inhibitory equilibrium. PMID- 26247243 TI - Co-administration of Apelin and T4 protects inotropic and chronotropic changes occurring in hypothyroid rats. AB - BACKGROUND: One of the most important thyroid hormone targets is the cardiovascular system. Hemodynamic changes, such as decreased resting heart rate (HR), myocardial contractility, and cardiac output, and increased diastolic pressure and systemic vascular resistance, have been observed in hypothyroid patients. Moreover, in these patients, ECG changes include sinus bradycardia and low voltage complexes (P waves or QRS complexes). OBJECTIVE: This study aimed at evaluating the prophylactic effect of apelin on HR changes and QRS voltage that occur in propylthiouracil (PTU)-induced hypothyroid rats. METHOD: In this study, 48 adult male Wistar rats weighing 170-235g were randomly divided into 6 groups: Control group (normal saline ip injection + tap water gavage); P group (PTU 0.05%, in drinking water); A group (apelin 200 ug.kg-1.day-1, ip); PA group [co administration of PTU and apelin]; PT group [co-administration of PTU + T4 (0.2 mg/g per day, gavage)]; and PAT group (co-administration of PTU, apelin and T4). All experiments were performed for 28 consecutive days, and then the animals were anesthetized with an ip injection of ketamine (80 mg/kg) and xylazine (12 mg/kg). Lead II electrocardiogram was recorded to calculate HR and QRS voltage. RESULTS: Heart rate and QRS voltage increased more significantly in the hypothyroid group that consumed both apelin and T4 (201 +/- 4 beat/min, 0.71 +/- 0.02 mv vs. hypothyroid 145 +/- 9 beat/min, 0.563 +/- 0.015 mv; respectively). CONCLUSION: The co-administration of apelin and T4 showed a protective effect on QRS voltage and HR in PTU-induced hypothyroid rats. PMID- 26247244 TI - Performance of surgical risk scores to predict mortality after transcatheter aortic valve implantation. AB - BACKGROUND: Predicting mortality in patients undergoing transcatheter aortic valve implantation (TAVI) remains a challenge. OBJECTIVES: To evaluate the performance of 5 risk scores for cardiac surgery in predicting the 30-day mortality among patients of the Brazilian Registry of TAVI. METHODS: The Brazilian Multicenter Registry prospectively enrolled 418 patients undergoing TAVI in 18 centers between 2008 and 2013. The 30-day mortality risk was calculated using the following surgical scores: the logistic EuroSCORE I (ESI), EuroSCORE II (ESII), Society of Thoracic Surgeons (STS) score, Ambler score (AS) and Guaragna score (GS). The performance of the risk scores was evaluated in terms of their calibration (Hosmer-Lemeshow test) and discrimination [area under the receiver-operating characteristic curve (AUC)]. RESULTS: The mean age was 81.5 +/- 7.7 years. The CoreValve (Medtronic) was used in 86.1% of the cohort, and the transfemoral approach was used in 96.2%. The observed 30-day mortality was 9.1%. The 30-day mortality predicted by the scores was as follows: ESI, 20.2 +/- 13.8%; ESII, 6.5 +/- 13.8%; STS score, 14.7 +/- 4.4%; AS, 7.0 +/- 3.8%; GS, 17.3 +/- 10.8%. Using AUC, none of the tested scores could accurately predict the 30-day mortality. AUC for the scores was as follows: 0.58 [95% confidence interval (CI): 0.49 to 0.68, p = 0.09] for ESI; 0.54 (95% CI: 0.44 to 0.64, p = 0.42) for ESII; 0.57 (95% CI: 0.47 to 0.67, p = 0.16) for AS; 0.48 (95% IC: 0.38 to 0.57, p = 0.68) for STS score; and 0.52 (95% CI: 0.42 to 0.62, p = 0.64) for GS. The Hosmer-Lemeshow test indicated acceptable calibration for all scores (p > 0.05). CONCLUSIONS: In this real world Brazilian registry, the surgical risk scores were inaccurate in predicting mortality after TAVI. Risk models specifically developed for TAVI are required. PMID- 26247246 TI - Lowering pulmonary wedge pressure after heart transplant: pulmonary compliance and resistance effect. AB - BACKGROUND: Right ventricular (RV) afterload is an important risk factor for post heart transplantation (HTx) mortality, and it results from the interaction between pulmonary vascular resistance (PVR) and pulmonary compliance (CPA). Their product, the RC time, is believed to be constant. An exception is observed in pulmonary hypertension because of elevated left ventricular (LV) filling pressures. OBJECTIVE: Using HTx as a model for chronic lowering of LV filling pressures, our aim was to assess the variations in RV afterload components after transplantation. METHODS: We retrospectively studied 159 patients with right heart catheterization before and after HTx. The effect of Htx on hemodynamic variables was assessed. RESULTS: Most of the patients were male (76%), and the mean age was 53 +/- 12 years. HTx had a significant effect on the hemodynamics, with normalization of the LV and RV filling pressures and a significant increase in cardiac output and heart rate (HR). The PVR decreased by 56% and CPA increased by 86%. The RC time did not change significantly, instead of increasing secondary to pulmonary wedge pressure (PWP) normalization after HTx as expected. The expected increase in RC time with PWP lowering was offset by the increase in HR (because of autonomic denervation of the heart). This effect was independent from the decrease of PWP. CONCLUSION: The RC time remained unchanged after HTx, notwithstanding the fact that pulmonary capillary wedge pressure significantly decreased. An increased HR may have an important effect on RC time and RV afterload. Studying these interactions may be of value to the assessment of HTx candidates and explaining early RV failure after HTx. PMID- 26247248 TI - [Reflections about the impact caused by the Food and Drug Administration (FDA) warning against uterine and/or fibroid power morcellation]. PMID- 26247247 TI - Ergospirometry and echocardiography in early stage of heart failure with preserved ejection fraction and in healthy individuals. AB - BACKGROUND: Heart failure with preserved ejection fraction is a syndrome characterized by changes in diastolic function; it is more prevalent among the elderly, women, and individuals with systemic hypertension (SH) and diabetes mellitus. However, in its early stages, there are no signs of congestion and it is identified in tests by adverse remodeling, decreased exercise capacity and diastolic dysfunction. OBJECTIVE: To compare doppler, echocardiographic (Echo), and cardiopulmonary exercise test (CPET) variables - ergospirometry variables - between two population samples: one of individuals in the early stage of this syndrome, and the other of healthy individuals. METHODS: Twenty eight outpatients diagnosed with heart failure according to Framingham's criteria, ejection fraction > 50% and diastolic dysfunction according to the european society of cardiology (ESC), and 24 healthy individuals underwent Echo and CPET. RESULTS: The group of patients showed indexed atrial volume and left ventricular mass as well as E/E' and ILAV/A' ratios significantly higher, in addition to a significant reduction in peak oxygen consumption and increased VE/VCO2 slope, even having similar left ventricular sizes in comparison to those of the sample of healthy individuals. CONCLUSION: There are significant differences between the structural and functional variables analyzed by Echo and CPET when comparing two population samples: one of patients in the early stage of heart failure with ejection fraction greater than or equal to 50% and another of healthy individuals. PMID- 26247249 TI - [Blockade of AT1 receptor of Angiotensin II reduces the number of antral follicles in female rats with obesity induced by cafeteria diet]. AB - PURPOSE: To evaluate the follicular development of female Wistar rats with obesity induced by the cafeteria diet, submitted to the administration of losartan (LOS), an antagonist of the AT1 receptor of Angiotensin II. METHODS: At weaning (21 days of age), female Wistar rats were randomly divided, into two groups: control (CTL) that received standard chow and cafeteria (CAF) that received a cafeteria diet, a highly palatable and highly caloric diet. At 70 days of age, at the beginning of the reproductive age, animals of the CAF group were subdivided into two groups (n = 15/group): CAF, that received water, and CAF+LOS, that received LOS for 30 days. The CTL group also received water by gavage. At 100 days of age, the animals were euthanized and body weight (BW) as well as the retroperitoneal, perigonadal and subcutaneous fat weights were analyzed. The right ovaries were isolated for counting the number of primary, secondary, antral and mature follicles. Plasma levels of FSH, LH, prolactin and progesterone hormones were analyzed. The results were expressed as mean +/- standard error of the mean. Data were analyzed statistically by one-way ANOVA followed by the Newman-Keuls post-test (p < 0.05). RESULTS: BW and fat weight, as well as the number of antral follicles, were higher in the CAF group compared to the CTL group. However, FSH and LH levels were lower in CAF animals compared to CTL animals. LOS administration attenuated the reduction of FSH and LH levels. Progesterone and PRL levels were similar among groups. CONCLUSION: LOS could improve follicular development in obese females and could be used as an adjunctive drug in the treatment of infertility associated with obesity. PMID- 26247250 TI - Criteria for prediction of metastatic axillary lymph nodes in early-stage breast cancer. AB - PURPOSE: To estimate the likelihood of axillary lymph node involvement for patients with early-stage breast cancer, based on a variety of clinical and pathological factors. METHODS: A retrospective analysis was done in hospital databases from 1999 to 2007. Two hundred thirty-nine patients were diagnosed with early-stage breast cancer. Predictive factors, such as patient age, tumor size, lymphovascular invasion, histological grade and immunohistochemical subtype were analyzed to identify variables that may be associated with axillary lymph node metastasis. RESULTS: Patients with tumors that are negative for estrogen receptor, progesterone receptor, and HER2 had approximately a 90% lower chance of developing lymph node metastasis than those with luminal A tumors (e.g., ER+ and/or PR+ and HER2-) - Odds Ratio: 0.11; 95% confidence interval: 0.01-0.88; p=0.01. Furthermore, the risk for lymph node metastasis of luminal A tumors seemed to decrease as patient age increased, and it was directly correlated with tumor size. CONCLUSION: The molecular classification of early-stage breast cancer using immunohistochemistry may help predicting the probability of developing axillary lymph node metastasis. Further studies are needed to optimize predictions for nodal involvement, with the aim of aiding the decision-making process for breast cancer treatment. PMID- 26247251 TI - [The role of the symptomatic and asymptomatic sexual partners in the recurrent vulvovaginitis]. AB - PURPOSE: To identify the predominant species and the role of sexual partners in the maintenance of recurrent vulvovaginitis by Candida spp. METHODS: A prospective study of 830 patients aged 18 to 65 years with yeast vaginitis was performed between August 2007 and March 2012. Patients with diabetes mellitus, AIDS or taking corticosteroids, antibiotics or hormone therapy and immunosuppressed patients, patients using vaginal douches, spermicides or intrauterine devices were excluded from the study. Candida species were identified by phenotypic and genotypic methods. The chi-square test was used to correlate the presence of Candida spp. in male partners with the recurrence of vaginitis. RESULTS: The fungal agent was isolated from a total of 40 women, 24 with recurrent vaginitis and from 15 of their sexual partners, 10 of whom were asymptomatic while 5 were symptomatic. There was agreement of the species found in the couple in 100% of recurrences. C. albicans (62.4 and 60%), C. glabrata (29.1 and 33.3%) and C. guilliermondii species were identified. Candida tropicalis (4.1%) was isolated from only one patient. Candida albicans was isolated from the remaining 16 women who had uncomplicated vaginitis. C. glabrata was isolated from only two of the asymptomatic partners. CONCLUSION: There was a predominance of C. albicans and symptomatic or asymptomatic partners can play an important role as a reservoir and source of transmission of yeast, especially in cases of recurrent vulvovaginitis. PMID- 26247252 TI - [Body image of pregnant women: association with sociodemographic, anthropometric, and obstetric variables]. AB - PURPOSE: To compare body attitudes of pregnant women in various body mass index categories, during different gestational periods and under gestational risk conditions, as well as to analyze the association of the study variables with the body attitudes of pregnant women. METHODS: We included 386 pregnant women in all gestational periods, aged 18 to 46 years (mean 29.32 +/- 6.04 years ), who attended prenatal care in the public and private sectors of a city in Southeastern Brazil, excluding women with incomplete data. The instruments for assessment were "Body Attitudes Questionnaire", "Criterio de Classificacao Economica Brasil", and a sociodemographic questionnaire. In addition, anthropometric and obstetric data were collected. Descriptive, comparative, and correlational statistical analyses were performed. RESULTS: The body attitudes of pregnant women were similar in all pregnancy trimesters (F = 0.39; p = 0.9). Negative body attitudes increased gradually among low weight (108.2 +/- 12.5), appropriate weight (116.2 +/- 16.0), overweight (125.1 +/- 14.3), and obese (132.9 +/- 16.4) groups, and among pregnancy women with normal (120.0 +/- 17.1) and high-risk pregnancies (124.9 +/- 16.7). The sociodemographic, economic, and obstetric variables did not influence the variance of body attitudes. The body mass index explained 11.3% of the variance of body attitudes in pregnant women. CONCLUSIONS: Nutritional status and risk conditions showed an association with negative body image and should therefore be evaluated in pregnant women for a better maternal and child health. PMID- 26247253 TI - [Eating habits of pregnant and non-pregnant women: are there differences?]. AB - PURPOSE: To determine the eating behavior of pregnant women assisted by primary health care and to compare it with women at childbearing age in Brazilian capitals. METHODS: A cross-sectional study conducted on 256 pregnant women in the second trimester of gestation, selected by drawing lots from those assisted by primary health care units of a municipality in the state of Sao Paulo in 2009/2010. Eating habits were investigated via a questionnaire adapted from the VIGITEL system, consisting of questions about eating habits in general and the frequency and consumption characteristics of food groups/specific foods. For tis comparison, we used the indicators reported by the VIGITEL system for women at childbearing age in Brazilian capitals in 2010. The analyses involved the presentation of frequency distribution and descriptive statistics with comparisons according to the age group. RESULTS: Most patients had breakfast every day (86.7%) and 45.7% habitually exchanged a main meal for a snack once or twice a week. A daily consumption of fruit, raw salad and vegetables was not reported by 48.8%, 41.8% and 55.1% of the women, respectively. Fish was reported to never or almost never be consumed by 64.4% of the pregnant women. At least once a week, 69.9% of them reported the consumption of soda, and 86.4% of wafers/cookies. The comparison between the pregnant women and women at childbearing age in capitals showed a close similar prevalence of overweight, and no difference in the regular consumption of fruit and vegetables. Meat containing excess of fat and whole milk were more consumed by pregnant women, with differences reported in all the age groups analyzed. On the other hand, the pregnant women reported a less regular intake of soft drinks. CONCLUSIONS: The actions that need to be performed in prenatal care are various and very important, promoting the consumption of specific foods and providing guidelines about eating behavior, while reinforcing healthy eating habits already present. PMID- 26247254 TI - [Prevalence of congenital abnormalities identified in fetuses with 13, 18 and 21 chromosomal trisomy]. AB - PURPOSE: To describe the prevalence of malformations found in fetuses with trisomy of chromosomes 13, 18 and 21 by identifying the most frequent within each condition. METHODS: A retrospective cross-sectional study with the analysis of trisomy cases of chromosomes 13, 18 and 21 diagnosed through fetal karyotype obtained by amniocentesis/cordocentesis, between October 1994 and May 2014, at a Teaching Hospital in Brazil Southern Region. Malformations identified through morphological ultrasonography were described and, subsequently, confirmed in newborn examinations and/or fetal autopsy. The results were analyzed using Fisher's test and analysis of variance (ANOVA), with a 5% level of significance (p=0.05). RESULTS: Sixty-nine cases of trisomy were diagnosed among 840 exams; nine were excluded due to outcome outside Hospital de Clinicas de Porto Alegre or incomplete records, remaining 60 cases (nine cases of chromosome 13 trisomy, 26 of chromosome 18, and 25 of chromosome 21). In all three groups, heart disease occurred in most cases; the ventricular septal defect was more prevalent and occurred in 66.7% of the trisomy 13 group. Gastrointestinal abnormalities were more prevalent in the trisomy 18 group, especially omphalocele (38.5%; p<0.01). Genitourinary anomalies were more significantly frequent in the trisomy 13 group (pyelectasis, 55.6% - p<0.01; ambiguous genitalia, 33.3% - p=0.01). Central nervous system defects were identified in all cases of trisomy 13. Facial cracks were significantly more prevalent among fetuses with trisomy 13 (66.7%; p<0.01). Hand and feet malformations significantly differed among the trisomy groups. Hand defects occurred in 50% of trisomy 18 cases, and in 44.4% of all trisomy 13 cases (p<0.01); congenital clubfoot was more common in the trisomy 18 group, being detected in 46.2% of fetuses (p<0.01). The abnormalities were found in 50.9, 27.3 and 21.7% of trisomy 18, 13 and 21 cases respectively. CONCLUSION: Many fetal malformations identified at ultrasound are suggestive of trisomy and represent an important tool for etiologic diagnosis and prenatal and pre-conception genetic counseling. PMID- 26247255 TI - [Gestational trophoblastic neoplasia after spontaneous normalization of human chorionic gonadotropin in patient with partial hydatidiform mole]. AB - We report here a case of gestational trophoblastic neoplasia after spontaneous normalization of human chorionic gonadotropin in a patient with a partial hydatidiform mole. This is the second occurrence of this event to be reported and the first one with proven immunohistochemical evidence. Besides showing the treatment for this pregnancy complication, this case report discusses the possibility of reducing the duration of post-molar follow-up, as well as strategies for early recognition of gestational trophoblastic neoplasia after spontaneous remission of molar pregnancy. PMID- 26247256 TI - Massive Localized Vulval Lymphedema, With Lymphangiomas of the Labia Majora, Misdiagnosed as Viral Warts. PMID- 26247257 TI - Endocervical Crypt Involvement by CIN2-3 as a Predictor of Cytology Recurrence After Excisional Cervical Treatment. AB - OBJECTIVE: The primary objective was to determine whether endocervical crypt involvement (ECI) by cervical intraepithelial neoplasia (CIN) on the excised cervical tissue after large loop excision of the transformation zone (LLETZ) represents a predictor of cytology recurrence. Secondary objective was to identify the ability of a pretreatment cervical punch biopsy to predict cytology recurrence. MATERIALS AND METHODS: This was a case series study conducted in an NHS hospital. Women with LLETZ treatment performed over a 2-year period (2010 2011) were identified through our colposcopy database. Women with previous cervical treatment, cervical cancer on cone histopathology, or missing follow-up data were excluded. RESULTS: A group of 526 eligible women was identified over the study period. Crypt involvement was not a predictor of recurrence in the total sample. However, in the subgroup of women with CIN2-3 on pretreatment punch biopsy and with ECI on cone specimen in comparison to those without ECI, we identified an increased risk for overall cytology recurrence (HR, 3.1; 95% CI, 1.04-9.28; P = 0.043) and a trend for increased risk of high-grade cytology recurrence (HR, 4.62; 95% CI, 0.84-25.28; P = 0.07). A pretreatment punch biopsy showing crypt involvement by CIN2-3 was indicative of women at risk for abnormal cytology after excision. In women with CIN2-3 on pretreatment punch biopsy and ECI on excised tissue, the high-grade cytology recurrence was significantly reduced if more than 1.9 cm of cervix was removed. CONCLUSIONS: It seems that the presence of crypt involvement on the excised cervix in the subgroup of women with CIN2-3 on pretreatment punch biopsy is predictive of cytology recurrence. PMID- 26247258 TI - Perinatal High-Grade Cervical Cytology: A Case Series From a Safety Net Institution. AB - OBJECTIVE: To describe the outcomes of women with high-grade cervical cytology in pregnancy and to identify factors that predict completion of appropriate postpartum follow-up. METHODS: We describe a case series of all patients with high-grade cervical cytology collected during pregnancy between 2007 and 2011 at a single institution. Patients were considered adherent with follow-up if they received any kind of postpartum evaluation or treatment for their cervical dysplasia at our institution within 9 months of delivery. RESULTS: Of 138 women with high-grade cervical cytology in pregnancy, 87 (63%) had high-grade squamous intraepithelial lesion, 47 (34%) had atypical squamous cells that cannot rule out high-grade (ASC-H), and 4 (3%) had atypical glandular cells (AGC). Most patients (81%) underwent colposcopy during pregnancy. A total of 48 patients (43%) had biopsies performed, 26 (54%) were CIN 2 or 3, and one (2%) was adenocarcinoma in situ (AIS). A total of 97 (70%) of 138 patients completed recommended postpartum follow-up, resulting in the detection of one additional case of AIS and one case of invasive adenocarcinoma. Hispanic ethnicity (odds ratio [OR], 3.6; confidence interval [CI], 1.4-9.1), being married (OR, 4.5; CI, 1.6-12.4), being employed (OR, 3.7; CI, 1.3-10.5), and CIN2 or 3 on antenatal biopsy (OR, 9.8; CI, 2.0 47.9) were all significantly associated with completion of postpartum follow-up. CONCLUSION: Colposcopy during pregnancy resulted in the detection of one case of AIS. Postpartum evaluation and treatment detected an additional case of AIS as well as one case of invasive cervical adenocarcinoma. Whereas certain demographic characteristics were associated with completion of recommended follow-up, the strongest association is with a high-grade biopsy during pregnancy. PMID- 26247259 TI - Lower Anogenital Tract Disease Therapy Outcomes, COMET, and CROWN: Call for Research Submissions. AB - OBJECTIVES: There is a problem of inconsistent and inappropriate outcome selection for research studies. We can improve the relevance of research results for women and for their physicians and clinicians by encouraging researchers to critically evaluate outcome measures, and use valid, appropriate, standardized measures. To this purpose, and to facilitate synthesis of the evidence, outcomes reported by clinical studies should be standardized for different disease conditions through the development of core outcome sets (COS). METHODS: There is an international effort for reaching consensus on outcome measures and establishing COS that represent agreed-upon standardized collections of outcome measures that will be reported in all studies within a clinical area. Across clinical specialties, the Core Outcome Measures in Effectiveness Trials (COMET) initiative launched in 2010. In 2014, the editors of women's health journals answered the challenge of COMET and formed the Core Outcomes in Women's Health initiative. The Journal of Lower Genital Tract Diseases is a participating member of the Core Outcomes in Women's Health consortium. RESULTS: There is broad inconsistency in outcome measures and reporting in the field of lower anogenital tract diseases. No core outcome sets currently exist. Suggested target conditions in anogenital disease are vulvar dermatoses, cervical intraepithelial neoplasia, and vulvodynia. CONCLUSIONS: Investigators are encouraged to conduct secondary systematic research to determine previously reported primary outcome measures and suggest domains for COS. Core Outcomes in Women's health initiative and COMET encourage the formation of consensus panels of stakeholders (researchers, health care providers, patients, and others) to recommend outcome domains and COS and then publish their report. PMID- 26247260 TI - Use of Smartphones as Adjuvant Tools for Cervical Cancer Screening in Low Resource Settings. AB - OBJECTIVES: Our aim was to evaluate the feasibility and performance of smartphone digital images for the detection of cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) as an adjunct to a conventional visual inspection approach with acetic acid (VIA) and Lugol's iodine (VILI), in comparison with detection by histopathologic examination. METHODS: Three hundred women were primarily screened for human papillomavirus (HPV) using self-collected vaginal specimens. Human papillomavirus-positive women were then invited for VIA and VILI, which were interpreted as (i) nonpathological, (ii) pathological or, (iii) inconclusive. Cervical smearing, endocervical brushing, and cervical biopsies were performed. Digital images of the cervix were taken with a smartphone and evaluated offsite by experienced health care providers. Sensitivity and specificity for CIN2+ were compared between on-site and off-site observers, using histopathological diagnosis as the criterion standard. RESULTS: Eighty-eight HPV-positive women were screened for cervical cancer. Overall, 7 cases of CIN2+ (8.0%) were diagnosed using biopsy specimens. The on-site physician obtained a sensitivity of 28.6% (95% confidence interval [95% CI], 3.7-71) and a specificity of 87.2% (95% CI, 77.7- 93.7). The off-site physicians obtained a sensitivity ranging between 42.9% (95% CI, 9.9-81.6; p = 1) and 85.7% (95% CI, 42.1-99.6; p = .13) and a specificity between 48.1% (95% CI, 36.5- 59.7; p < .001) and 79.2% (95% CI, 68.5 87.6; p = .10). Comparison between observers did not reach significance. Observers assessed 95.6% of all images as very good or acceptable for interpretation purpose. CONCLUSION: Smartphone images may be a useful adjunct to conventional VIA and VILI for the detection of CIN2+ and improve cervical cancer screening in low-resource settings. PMID- 26247261 TI - Study Design Algorithm. AB - OBJECTIVES: To aid authors in correctly naming their study design, to assist readers and reviewers who must decide what the design was for some published studies, and to provide consistency in evaluating the design of published studies, especially for those conducting systematic reviews and evidence synthesis. METHODS: An annotated algorithm method is used to prompt serial questions and analysis to identify a single study design. RESULTS: The algorithm begins with a research article. Primary clinical research is divided into experimental and observational studies. Key determinants include identifying the study question and the population, intervention, comparison, and outcome. Experimental therapy and prognosis studies are subdivided into 4 design types. Observational therapy and prognosis studies are subdivided into 7 design types. Experimental diagnosis and screening studies are subdivided into 2 types. Observational diagnosis and screening studies are subdivided into 5 types. CONCLUSIONS: An annotated algorithm may be used by authors, readers, and reviewers to consistently determine the design of clinical research studies. PMID- 26247262 TI - Visual Inspection of Cervix With Acetic Acid as a Screening Modality for Cervical Cancer. AB - OBJECTIVE: To assess feasibility and suitability of visual inspection of cervix with acetic acid (VIA) in detecting cervical intraepithelial neoplasia (CIN), and compare it with Papanicolaou test. METHODS: This was a diagnostic accuracy cross sectional study conducted at an Egyptian teaching hospital, where 784 women were offered Papanicolaou test, VIA, colposcopy, and cervical biopsy. RESULTS: Histopathologically confirmed CIN 2/3 was noted in 26 cases (3.3%) and cervical cancer in 3 cases (0.4%). Twenty-seven (93.1%) of these 29 cases of CIN 2+, including one invasive cancer, were suggested by VIA. The test sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) to detect CIN 2+ were 93.1%, 90.6%, 26.6%, and 99.7%, respectively. Positive likelihood ratio (LR +) and negative likelihood ratio (LR-) for VIA were 9.90 (95% confidence interval [CI], 7.77-12.62) and 0.08 (95% CI, 0.02-0.29), respectively. Twenty-six cases (89.7%) of CIN 2+ were suggested by Papanicolaou test, whereas all 3 cancers were missed by this test. Papanicolaou test sensitivity, specificity, PPV, and NPV to detect CIN 2+ were 89.7%, 99.1%, 78.8%, and 99.6%, respectively. Positive likelihood ratio and LR- for the Papanicolaou test were 96.7 (95% CI, 45.78-204.23) and 0.10 (95% CI, 0.04-0.3), respectively. Colposcopy suggested 28 cases (96.6%) of CIN 2+, including 2 cancers. Colposcopy sensitivity, specificity, PPV, and NPV to detect CIN 2+ were 96.6%, 99.2%, 82.4%, and 99.9%, respectively. CONCLUSION: Visual inspection of the cervix with acetic acid is a feasible and suitable screening test for cervical cancer in under resourced settings in developing countries. Its performance is comparable to the Papanicolaou test. PMID- 26247263 TI - Ketamine Abuse Syndrome: Hepatobiliary and Urinary Pathology Among Adolescents in Flushing, NY. AB - OBJECTIVES: Ketamine is a recreational drug widely abused in East Asia and also in certain subpopulations of the United States. Many US clinicians are unaware of abuse symptoms, leading to misdiagnosis and missed opportunities for intervention. We will discuss clinical patterns that should alert a clinician to the possibility of ketamine abuse. METHODS: We present 6 adolescent patients who presented to the pediatric emergency department and inpatient wards with urinary and hepatobiliary symptoms in the setting of ketamine abuse. RESULTS: We identified 6 patients with confirmed ketamine abuse who presented with epigastric pain or urinary pain. All had laboratory and radiographic evidence of disease. CONCLUSIONS: Ketamine abuse is associated with a distinctive pattern of symptoms involving the urinary and hepatobiliary systems. PMID- 26247264 TI - Developments and controversies in coronary physiology and imaging. PMID- 26247265 TI - The index of microcirculatory resistance in the physiologic assessment of the coronary microcirculation. AB - The coronary microcirculation plays a critical role in normal cardiac physiology as well as in many disease states. However, methods to evaluate the function of the coronary microvessels have been limited by technical and theoretical issues. Recently, the index of microcirculatory resistance (IMR) has been proposed and validated as a simple and specific invasive method of assessing the coronary microcirculation. By relying on the thermodilution theory and using a pressure temperature sensor guidewire, IMR provides a measurement of the minimum achievable microcirculatory resistance in a target coronary artery territory, enabling a quantitative assessment of the microvascular integrity. Unlike indices such as coronary flow reserve, IMR is highly reproducible and independent of hemodynamic changes. In ST-elevation myocardial infarction, IMR predicts myocardial recovery and long-term mortality, whereas in patients with stable coronary artery disease, preintervention IMR predicts the occurrence of periprocedural myocardial infarction. Increasingly, research has focused on IMR guided interventions of the microcirculation, with the aim of preventing and/or treating the microcirculatory dysfunction that commonly accompanies the epicardial coronary disease. In the present review, we will discuss the theoretical and practical basis for IMR, the clinical studies supporting it, and the future lines of research using this novel tool. PMID- 26247266 TI - Use of fractional flow reserve in different anatomical subsets. PMID- 26247267 TI - Beyond FAMOUS-NSTEMI: the evolving role of fractional flow reserve in patients with acute coronary syndromes. AB - Fractional flow reserve (FFR) is a well-established method of assessing haemodynamically significant coronary artery stenoses that has demonstrated improved outcomes when used to guide revascularization decisions in patients with stable coronary artery disease. However, the role of FFR in the setting of acute coronary syndrome (ACS) remains uncertain. The recently published FAMOUS-NSTEMI trial was a pilot study that demonstrated the safety of routine FFR in ACS patients as well as its impact upon refining management decisions in patients with stenoses of varying severity in nonculprit arteries. The goal of this review is to summarize the current literature of the utility of FFR in the ACS population and highlight the role that the results of FAMOUS-NSTEMI may have on future study and management in this area. PMID- 26247268 TI - Assessment of left main artery stenosis with fractional flow reserve is affected by downstream stenosis in the left anterior descending artery. PMID- 26247269 TI - Invasive physiologic and anatomic multimodality assessment of myocardial bridging. PMID- 26247270 TI - Comprehensive assessment of epicardial and microcirculatory involvement in coronary artery disease. PMID- 26247271 TI - Advances in three-dimensional coronary imaging and computational fluid dynamics: is virtual fractional flow reserve more than just a pretty picture? AB - Percutaneous coronary intervention (PCI) has shown a high success rate in the treatment of coronary artery disease. The decision to perform PCI often relies on the cardiologist's visual interpretation of coronary lesions during angiography. This has inherent limitations, particularly due to the low resolution and two dimensional nature of angiography. State-of-the-art modalities such as three dimensional quantitative coronary angiography, optical coherence tomography and invasive fractional flow reserve (FFR) may improve clinicians' understanding of both the anatomical and physiological importance of coronary lesions. While invasive FFR is the gold standard technique for assessment of the haemodynamic significance of coronary lesions, recent studies have explored a surrogate for FFR derived solely from three-dimensional reconstruction of the invasive angiogram, and therefore eliminating need for a pressure wire. Utilizing advanced computational fluid dynamics research, this virtual fractional flow reserve (vFFR) has demonstrated reasonable correlation with invasive measurements and remains an intense area of ongoing study. However, at present, several limitations and computational fluid dynamic assumptions may preclude vFFR from widespread clinical use. This review demonstrates the tight integration of advanced three-dimensional imaging techniques and vFFR in assessing coronary artery disease, reviews the advantages and disadvantages of such techniques and attempts to provide a glimpse of how such advances may benefit future clinical decision-making during PCI. PMID- 26247272 TI - Optical coherence tomography to evaluate coronary stent implantation and complications. AB - Coronary optical coherence tomography (OCT) is now an established imaging technique in many catheterization laboratories worldwide. With its near histological view of the vessel wall and lumen interface, it offers unprecedented imaging quality to improve our understanding of the pathophysiology of atherosclerosis, plaque vulnerability, and vascular biology. Not only is OCT used to accurately detect atherosclerotic plaque and optimize stent position, but it can further characterize plaque composition, quantify stent apposition, and assess stent tissue coverage. Given that its resolution of 15 MUm is well above that of angiography and intravascular ultrasound, OCT has become the invasive imaging method of choice to examine the interaction between stents and the vessel wall. This review focuses on the application of OCT to examine coronary stents, the mechanisms of stent complications, and future directions of OCT-guided intervention. PMID- 26247273 TI - Complex, diffuse in-stent atherosclerosis over a decade following bare metal stenting. PMID- 26247274 TI - Serial three-dimensional optical coherence tomography to assess contained coronary artery perforation. PMID- 26247275 TI - Optical coherence tomography guiding intervention in acute coronary syndrome. PMID- 26247276 TI - Physiological assessment of coronary lesion severity: fractional flow reserve versus nonhyperaemic indices. AB - Coronary angiography alone cannot accurately identify the haemodynamic impact of a coronary artery stenosis. Current international guidelines for myocardial revascularization recommend that inducible ischaemia should be demonstrated before the consideration of percutaneous coronary intervention. Invasive physiological assessment of coronary stenosis severity has increasingly been utilized for this purpose and use of the best validated technique, fractional flow reserve (FFR), has been shown to improve clinical outcomes in patients with stable and unstable coronary artery disease. This has led to the use of FFR being recommended in international revascularization guidelines, despite which, clinical uptake has been limited. One potential reason for slow adoption has been the requirement for maximal hyperaemia at the time of FFR measurement, usually achieved by the administration of pharmacological vasodilators such as adenosine. In some healthcare systems, adenosine is expensive and, in addition, its use can be associated with significant, albeit transient, adverse effects that patients (and some operators) find uncomfortable. Consequently, several methods of nonhyperaemic lesion assessment and their potential role in decision making have been reported. In this review we will review and discuss the current evidence for hyperaemic and nonhyperaemic methods of lesion assessment. We will also look at hybrid strategies that utilize both hyperaemic and nonhyperaemic methods as a means of potentially maintaining diagnostic accuracy while minimizing the requirement for adenosine administration and discuss whether or not they represent viable clinical alternatives. PMID- 26247278 TI - Reply: To PMID 25811725. PMID- 26247279 TI - Reply: To PMID 25738235. PMID- 26247280 TI - Incorrect use of metered-dose inhalers in adult patients at a hospital in Callao, Peru, 2014: cross-sectional study. AB - BACKGROUND: Inhalation therapy has proven to be the best way to control the asthma and chronic obstructive pulmonary disease symptoms. The most commonly used delivery system to control these symptoms is the metered-dose inhaler. The primary goal of this study is to demonstrate an association between incorrect inhaler use and patient age. METHODS: This is a cross-sectional study, performed at Centro Medico Naval ?Cirujano Mayor Santiago Tavara?, in Callao, Peru, in 2014. Patients older than 18 years that used metered-dose inhalers were included. We used film recordings of patients using a metered-dose inhaler and compared their technique with the recommendations on the guidelines on the correct use of inhalers of the Spanish Society of Pneumology and Thoracic Surgery (SEPAR). The main variables measured were age and incorrect inhaler use. The results were analyzed with the Chi squared test for bivariate analysis, and for multivariate analysis we used the Poisson regression model with robust variance. RESULTS: We included 378 patients in the analysis; 167 were older than 60 years. An association was found between incorrect inhalator technique and age (p=0.014) (PR 1.19 95% CI 1.03 to 1.37). The highest prevalence of incorrect technique was found in the young adult population (88%). There was no association between the incorrect technique and the person who taught it (p=0.114). Finally, this study showed that 81.2% of the study population presented an incorrect inhalation technique. CONCLUSIONS: The percentage of incorrect inhaler use, in the general population is high. Even if we found no association between an incorrect technique and the person who taught it; still, there is a high percentage of errors and it was even demonstrated that being instructed by a pulmonologist does not guarantee a correct performance of metered-dose inhaler inhalations. PMID- 26247281 TI - Specimen Adulteration and Substitution in Workplace Drug Testing. AB - Throughout the history of workplace drug testing, individuals have attempted to subvert their drug test results to mask their use of illegal drugs. Urine workplace specimens have been subject to tampering, from early attempts involving household chemicals and simple dilution or substitution to current attempts using the multitude of readily available commercial adulteration and substitution products. The manufacturers of such products continue to alter product composition or develop new products to bypass detection procedures and policies implemented by drug testing laboratories and regulatory agencies. This article provides a chronological review of laboratory and regulatory efforts to combat the problem, and presents data from studies on selected commercial adulterant products by the Department of Health and Human Services. PMID- 26247282 TI - Specimen Validity Testing SVT) - Effects of Oxidizing Agents on Drugs in Urine and Procedures for Detection. AB - Since the inception of the drug-testing program in the U.S. Armed Forces in 1982, urine adulteration with the intent to conceal drug use has been a serious problem to forensic scientists. Initially, drug users tried almost anything that was available at the collection sites. Soon they recognized that certain chemicals could be used to destroy some drugs and interfere with the testing procedures. Some drug analytes, in particular morphine and 11-nor-delta-9 tetrahydrocannabinol-9-carboxylic acid, a metabolite of delta-9 tetrahydrocannabinol, could not be detected in presence of some oxidizing agents. As the use of adulterants increased, specimen validity testing was introduced by the Department of Health and Human Services in 2004. While specific reagents could be used to test nitrite, chromate, and iodine, test procedures for many other oxidizing agents were not available. In an attempt to detect most oxidants, a different approach has been introduced to identify urines adulterated with oxidizing adulterants. In this approach, the oxidizing property of normal urine is compared with that of urine containing oxidizing agents. In the procedure, samples are allowed to interact with excess ferrous (Fe2+) ions and then with chromogenic compounds. In the presence of oxidants, Fe2+ ions with low reduction potential (E0 0.771 V) are immediately oxidized to ferric (Fe3+) ions, which then change the chromogenic compounds to colored chromogens. Specific spectral pattern and intensity are the keys in quantification of oxidants in urine (milliEquivalent/liter, mE/L). The method appeared to be promising in differentiating normal urine from urine adulterated with oxidizing agents. Some oxidizing adulterants in urine are unstable. If reduced, it could be reconverted to the oxidizing agents and tested by the general oxidant test. PMID- 26247283 TI - A Decade Revisited - Forensic and Clinical Applications of Hair Testing. AB - Hair testing for metals in clinical and forensic applications began in the 1950s whereas drugs of abuse testing in hair did not begin until the early 1980s. Hair testing has continued to develop as indicated by the publication of more than 300 scientific manuscripts focusing on applications of hair analysis in the past 10 years alone. This review describes many disciplines of hair testing cited in journals and books over the past decade including forensic drug screening, clinical testing, death investigations, and the potential use of newer applications such as reinstatement of driving privileges, detection of doping agents, and testing for drugs used in a criminal act. Each discipline is explained and further details are then illustrated through actual case studies and investigational resultss. PMID- 26247284 TI - Hair Testing for Drugs - Challenges for Interpretation. AB - While testing hair for drugs of abuse has become more widely used in the past 30 years, significant challenges still remain to the interpretation of the results from these tests. Of primary concern is the likelihood of unwitting contamination from the environment producing a result indicative of drug use. It is imperative that this possibility be controlled and understood so that results from hair testing can be appropriately interpreted. Presently, truly unique metabolites are needed for many drugs (THC-COOH being a notable exception) since the mechanisms of decontamination processes used for hair are still poorly understood. While there is evidence that many drugs preferentially bind to melanin and that darker hair contains more drug, it is unclear how this translates into the interpretation of results for a population. Cosmetic treatments likely reduce the amount of drug systemically incorporated into hair and thus present a challenge of inappropriately negative interpretation. In addition, hair damaged as a result of cosmetic treatment may be at increased risk for environmental contamination. The asynchronous nature of human hair growth can also complicate results by obscuring the timeline of drug deposition. Lastly, the analytical variation of quantitative values has been demonstrated by several proficiency testing systems throughout the world to be high and method specific. Thus, while hair testing may be able to provide information about exposure to drugs, it is difficult at present to obtain reproducible results that can be unquestionably related to drug ingestion or to infer that the absence of drug in a hair sample is positive proof of no drug usage. Many questions still remain to be addressed by mechanistic understanding of drug deposition and retention in hair. PMID- 26247285 TI - Legal Review for Testing of Drugs in Hair. AB - The legal issues associated with hair drug testing in general have significant differences from issues associated with urine drug testing. Discussed are cases that illuminate these differences. The issues in hair testing are not yet settled and legal precedent has not been forthcoming. Among the issues discussed is the admissibility of hair testing results based on its acceptance as scientific evidence. Some state jurisdictions still require that scientific evidence must be generally accepted in the scientific discipline where it belongs. The federal courts and an increasing number of state courts are using a less stringent standard and do not require majority acceptance by the scientific community. In some cases hair testing has been shown to be less intrusive than the use of other body samples, thus avoiding Fourth Amendment issues. However, a racial bias issue still exists based on the higher melanin content in the hair of African Americans. A substantial issue is also whether environmental contamination of hair can be differentiated from the internal administration of a drug. The courts are also increasingly utilizing the differences between the time required for a drug or its metabolite to appear in a hair sample or urine sample in adjudicating cases. PMID- 26247286 TI - One-Step Process for High-Performance, Adhesive, Flexible Transparent Conductive Films Based on p-Type Reduced Graphene Oxides and Silver Nanowires. AB - This work demonstrates a one-step process to synthesize uniformly dispersed hybrid nanomaterial containing silver nanowires (AgNWs) and p-type reduced graphene (p-rGO). The hybrid nanomaterial was coated onto a polyethylene terephthalate (PET) substrate for preparing high-performance flexible transparent conductive films (TCFs). The p-rGO plays the role of bridging discrete AgNWs, providing more electron holes and lowering the resistance of the contacted AgNWs; therefore, enhancing the electrical conductivity without sacrificing too much transparence of the TCFs. Additionally, the p-rGO also improves the adhesion between AgNWs and substrate by covering the AgNWs on the substrate tightly. The study shows that coating of the hybrid nanomaterials on the PET substrate demonstrates exceptional optoelectronic properties with a transmittance of 94.68% (at a wavelength of 550 nm) and a sheet resistance of 25.0 +/- 0.8 Omega/sq. No significant variation in electric resistance can be detected even when the film was subjected to a bend loading with a radius of curvature of 5.0 mm or the film was loaded with a reciprocal tension or compression for 1000 cycles. Furthermore, both chemical corrosion resistance and haze effect were improved when p-rGO was introduced. The study shows that the fabricated flexible TCFs have the potential to replace indium tin oxide film in the optoelectronic industry. PMID- 26247287 TI - What are the effects of adding azathioprine to corticosteroids in polymyositis? AB - The treatment of polymyositis is based on corticosteroid therapy, with addition of azathioprine for non responsive cases or as an attempt to diminish corticosteroids requirements. However, there is no clear evidence of its benefit in controlling symptoms. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified only one systematic review including one pertinent randomized trial. We generated a summary of findings following the GRADE approach. We concluded there is uncertainty if azathioprine improves or not muscular strength in polymyositis because the certainty of the evidence is very low. PMID- 26247288 TI - A Conversation with Adam Heller. AB - Adam Heller, Ernest Cockrell Sr. Chair in Engineering Emeritus of the John J. McKetta Department of Chemical Engineering at The University of Texas at Austin, recalls his childhood in the Holocaust and his contributions to science and technology that earned him the US National Medal of Technology and Innovation in a conversation with Elton J. Cairns, Professor of Chemical and Biomolecular Engineering at the University of California, Berkeley. Dr. Heller, born in 1933, describes the enslavement of his father by Hungarians in 1942; the confiscation of his family's home, business, and all its belongings in 1944; and his incarceration in a brick factory with 18,000 Jews who were shipped by the Hungarians to be gassed by Germans in Auschwitz. Dr. Heller and his immediate family survived the Holocaust and arrived in Israel in 1945. He studied under Ernst David Bergmann at the Hebrew University, and then worked at Bell Laboratories and GTE Laboratories, where he headed Bell Lab's Electronic Materials Research Department. At GTE Laboratories, he built in 1966 the first neodymium liquid lasers and in 1973 with Jim Auborn conceived and engineered the lithium thionyl chloride battery, one of the first to be manufactured lithium batteries, which is still in use. After joining the faculty of engineering of The University of Texas at Austin, he cofounded with his son Ephraim Heller TheraSense, now a major part of Abbott Diabetes Care, which produced a microcoulometer that made the monitoring of glucose painless by accurately measuring the blood glucose concentration in 300 nL of blood. He also describes the electrical wiring of enzymes, the basis for Abbott's state-of-the-art continuous glucose monitoring system. He discusses his perspective of reducing the risk of catastrophic global warming in a wealth-accumulating, more-energy consuming world and provides advice for students entering careers in science or engineering. PMID- 26247289 TI - Gasification of Woody Biomass. AB - Interest in biomass to produce heat, power, liquid fuels, hydrogen, and value added chemicals with reduced greenhouse gas emissions is increasing worldwide. Gasification is becoming a promising technology for biomass utilization with a positive environmental impact. This review focuses specifically on woody biomass gasification and recent advances in the field. The physical properties, chemical structure, and composition of biomass greatly affect gasification performance, pretreatment, and handling. Primary and secondary catalysts are of key importance to improve the conversion and cracking of tars, and lime-enhanced gasification advantageously combines CO2 capture with gasification. These topics are covered here, including the reaction mechanisms and biomass characterization. Experimental research and industrial experience are investigated to elucidate concepts, processes, and characteristics of woody biomass gasification and to identify challenges. PMID- 26247290 TI - Current Trends and Challenges in Biointerfaces Science and Engineering. AB - The cellular microenvironment is extremely complex, and a plethora of materials and methods have been employed to mimic its properties in vitro. In particular, scientists and engineers have taken an interdisciplinary approach in their creation of synthetic biointerfaces that replicate chemical and physical aspects of the cellular microenvironment. Here the focus is on the use of synthetic materials or a combination of synthetic and biological ligands to recapitulate the defined surface chemistries, microstructure, and function of the cellular microenvironment for a myriad of biomedical applications. Specifically, strategies for altering the surface of these environments using self-assembled monolayers, polymer coatings, and their combination with patterned biological ligands are explored. Furthermore, methods for augmenting an important physical property of the cellular microenvironment, topography, are highlighted, and the advantages and disadvantages of these approaches are discussed. Finally, the progress of materials for prolonged stem cell culture, a key component in the translation of stem cell therapeutics for clinical use, is featured. PMID- 26247291 TI - Clean Water for Developing Countries. AB - Availability of safe drinking water, a vital natural resource, is still a distant dream to many around the world, especially in developing countries. Increasing human activity and industrialization have led to a wide range of physical, chemical, and biological pollutants entering water bodies and affecting human lives. Efforts to develop efficient, economical, and technologically sound methods to produce clean water for developing countries have increased worldwide. We focus on solar disinfection, filtration, hybrid filtration methods, treatment of harvested rainwater, herbal water disinfection, and arsenic removal technologies. Simple, yet innovative water treatment devices ranging from use of plant xylem as filters, terafilters, and hand pumps to tippy taps designed indigenously are methods mentioned here. By describing the technical aspects of major water disinfection methods relevant for developing countries on medium to small scales and emphasizing their merits, demerits, economics, and scalability, we highlight the current scenario and pave the way for further research and development and scaling up of these processes. This review focuses on clean drinking water, especially for rural populations in developing countries. It describes various water disinfection techniques that are not only economically viable and energy efficient but also employ simple methodologies that are effective in reducing the physical, chemical, and biological pollutants found in drinking water to acceptable limits. PMID- 26247292 TI - Group Contribution Methods for Phase Equilibrium Calculations. AB - The development and design of chemical processes are carried out by solving the balance equations of a mathematical model for sections of or the whole chemical plant with the help of process simulators. For process simulation, besides kinetic data for the chemical reaction, various pure component and mixture properties are required. Because of the great importance of separation processes for a chemical plant in particular, a reliable knowledge of the phase equilibrium behavior is required. The phase equilibrium behavior can be calculated with the help of modern equations of state or g(E)-models using only binary parameters. But unfortunately, only a very small part of the experimental data for fitting the required binary model parameters is available, so very often these models cannot be applied directly. To solve this problem, powerful predictive thermodynamic models have been developed. Group contribution methods allow the prediction of the required phase equilibrium data using only a limited number of group interaction parameters. A prerequisite for fitting the required group interaction parameters is a comprehensive database. That is why for the development of powerful group contribution methods almost all published pure component properties, phase equilibrium data, excess properties, etc., were stored in computerized form in the Dortmund Data Bank. In this review, the present status, weaknesses, advantages and disadvantages, possible applications, and typical results of the different group contribution methods for the calculation of phase equilibria are presented. PMID- 26247293 TI - Biocatalysis: A Status Report. AB - This review describes the status of the fields of biocatalysts and enzymes, as well as existing drawbacks, and recent advances in the areas deemed to represent drawbacks. Although biocatalysts are often highly active and extremely selective, there are still drawbacks associated with biocatalysis as a generally applicable technique: the lack of designability of biocatalysts; their limits of stability; and the insufficient number of well-characterized, ready-to-use biocatalysts. There has been significant progress on the following fronts: (a) novel protein engineering tools, both experimental and computational, have significantly enhanced the toolbox for biocatalyst development. (b) The deactivation of biocatalysts under various stresses can be described quantitatively via rational models. There are several cases of spectacular leaps of stabilization after accumulating all stabilizing mutations found in earlier rounds. The concept that stabilization against one type of stress commonly also stabilizes against other types of stress is now experimentally considerably better founded than a few years ago. PMID- 26247294 TI - Depth-of-interaction measurement in a single-layer crystal array with a single ended readout using digital silicon photomultiplier. AB - We present the first experimental evaluation of a depth-of-interaction (DOI) positron emission tomography (PET) detector using a digital silicon photomultiplier (dSiPM). To measure DOI information from a mono-layer array of scintillation crystals with a single-ended readout, our group has previously proposed and developed a new method based on light spread using triangular reflectors. Since this method relies on measurement of the light distribution, dSiPM, which has a fully digital interface, has several merits for our DOI measurement. The DOI PET detector comprised of a dSiPM sensor (DPC-3200-22-44) coupled with a 14 * 14 array of 2 mm * 2 mm * 20 mm unpolished LGSO crystals. All crystals were covered with triangular reflectors. To obtain a good performance of the DOI PET detector, several parameters of detector were selected as a preliminary experiment. Detector performance was evaluated with the selected parameters and the optimal experimental setup, and a DOI measurement was conducted by irradiating the crystal block at five DOI positions spaced at intervals of 4 mm. Maximum-likelihood estimation was employed for DOI positioning and the optimal DOI estimation scheme was also investigated in this study. As a result, the DOI PET detector showed clear crystal identification. The energy resolution (full-width at half-maximum (FWHM)) averaged over all depths was 10.21% +/- 0.15% at 511 keV, and time resolution averaged over all depths was 1198.61 +/- 39.70 ps FWHM. The average DOI positioning accuracy for all depths was 74.22% +/- 6.77%, which equates to DOI resolution of 4.67 mm. Energy and DOI resolutions were uniform over all crystal positions except for the back parts of the array. Furthermore, additional simulation studies were conducted to verify the results of our DOI measurement method that is combined with dSiPM technology. In conclusion, our continuous DOI PET detector coupled with dSiPM is a promising PET/MRI detector with DOI-encoding capability. PMID- 26247295 TI - Uranium Hydridoborates: Synthesis, Magnetism, and X-ray/Neutron Diffraction Structures. AB - While uranium hydridoborate complexes containing the [BH4](-) moiety have been well-known in the literature for many years, species with functionalized borate centers remained considerably rare. We were now able to prepare several uranium hydridoborates (1-4) with amino-substituted borate moieties with high selectivity by smooth reaction of [Cp*2UMe2] (Cp* = C5Me5) and [Cp'2UMe2] (Cp' = 1,2,4 tBu3C5H2) with the aminoborane H2BN(SiMe3)2. A combination of nuclear magnetic resonance spectroscopy, deuteration experiments, magnetic SQUID measurements, and X-ray/neutron diffraction studies was used to verify the anticipated molecular structures and oxidation states of 1-4 and helped to establish a linear tridentate coordination mode of the borate anions. PMID- 26247296 TI - Friedel-Crafts Coupling of Electron-Deficient Benzoylacetones Tuned by Remote Electronic Effects. AB - Acid-catalyzed electrophilic aromatic substitution for C-C bond formation, commonly referred to as the Friedel-Crafts reaction in recognition of its discoverers, has been one of the most useful reactions in organic chemistry for over a century. However, the Friedel-Crafts reaction cannot occur on a benzene ring having a strongly electron withdrawing group, such as an acyl group, which deactivates the aromatic ring toward electrophilic substitutions and remains a major challenge. Herein, the synthesis of naphthoquinones and 1,3-indandiones, bearing two acyl groups at positions ortho to each other on a benzene ring, are demonstrated by means of copper-catalyzed intramolecular aerobic oxidative acylation of benzoylacetone derivative precursors. This unusual Friedel-Crafts reaction reveals a new activation mode for the in situ polarity reverse of an electron-deficient aromatic ring to a reactive, electron-rich ring tuned by remote electronic effects. PMID- 26247297 TI - Complementary IMAC enrichment methods for HLA-associated phosphopeptide identification by mass spectrometry. AB - Phosphorylation events within cancer cells often become dysregulated, leading to oncogenic signaling and abnormal cell growth. Phosphopeptides derived from aberrantly phosphorylated proteins that are presented on tumors and not on normal tissues by human leukocyte antigen (HLA) class I molecules are promising candidates for future cancer immunotherapies, because they are tumor specific and have been shown to elicit cytotoxic T cell responses. Robust phosphopeptide enrichments that are suitable for low input amounts must be developed to characterize HLA-associated phosphopeptides from clinical samples that are limited by material availability. We present two complementary mass spectrometry compatible, iron(III)-immobilized metal affinity chromatography (IMAC) methods that use either nitrilotriacetic acid (NTA) or iminodiacetic acid (IDA) in-house fabricated columns. We developed these protocols to enrich for subfemtomole-level phosphopeptides from cell line and human tissue samples containing picograms of starting material, which is an order of magnitude less material than what is commonly used. In addition, we added a peptide esterification step to increase phosphopeptide specificity from these low-input samples. To date, hundreds of phosphopeptides displayed on melanoma, ovarian cancer, leukemia and colorectal cancer have been identified using these highly selective phosphopeptide enrichment protocols in combination with a program called 'CAD Neutral Loss Finder' that identifies all spectra containing the characteristic neutral loss of phosphoric acid from phosphorylated serine and threonine residues. This methodology enables the identification of HLA-associated phosphopeptides presented by human tissue samples containing as little as nanograms of peptide material in 2 d. PMID- 26247298 TI - Molecular characterization of neuronal cell types based on patterns of projection with Retro-TRAP. AB - Retro-TRAP (translating ribosome affinity purification) technology enables the synthesis of molecular and neuroanatomical information through the use of transgenic and viral approaches. In contrast to other methods that are used to profile neural circuits such as laser-capture microdissection and FACS, Retro TRAP is a high-throughput methodology that requires minimal specialized instrumentation. Retro-TRAP uses an anti-GFP ribosomal tag (expressed virally or using transgenesis) to immunoprecipitate translating mRNAs from any population of neurons that express GFP. The protocol detailed here describes the rapid extraction of molecular information from neural circuits in mice using retrograde tracing GFP-expressing viruses. This approach can be used to identify novel cell types, as well as to molecularly profile cell types for which Cre-driver lines are available, in defined presynaptic loci. The current protocol describes a method for extracting translating mRNA from any neural circuit accessible by stereotaxic injection and manual dissection, and it takes 2-4 weeks. Although it is not described here, this mRNA can then be used in downstream processing applications such as quantitative PCR (qPCR) and high-throughput RNA sequencing to obtain 'molecular connectomic' information. PMID- 26247299 TI - Synthesis of 1,2,3,6-Tetrahydropyridines via Aminophosphate Enabled Anionic Cascade and Acid Catalyzed Cyclization Approaches. AB - Two new approaches for forming 1,2,3,6-tetrahydropyridines are reported. Both reactions employ a strategic phosphate substituent on the nitrogen atom. In the presence of an additional phosphate substituent (X = P = O(OEt)2) an anionic cascade can by triggered upon treatment with base. Alternatively, when X = H the same 1,2,3,6-tetrahydropyridine product can be accessed via an acid catalyzed cyclization. PMID- 26247300 TI - The Relationship Between the Metabolic Syndrome and Systolic Inter-Arm Systolic Blood Pressure Difference in Korean Adults. AB - BACKGROUND: The present study was conducted to assess the relationship between metabolic syndrome and systolic inter-arm blood pressure difference (sIAD) in Korean adults. METHODS: This study included 410 adults (235 males, 175 females) who were over 30 years old and had undergone a health check from July to December in 2013. RESULTS: The incidence of high sIAD and metabolic syndrome were 23.4% and 23.2%, respectively. Key study results were as follows: First, the sIAD levels increased significantly with an increase in metabolic syndrome score (p<0.001), shown by sIAD levels after adjusted the variables that affect sIAD levels (age, gender, smoking, drinking, exercising, total cholesterol, and body mass index). These were 4.6+/-0.7 mmHg for metabolic syndrome score (MSS) 0; 5.8+/-0.5 mmHg for MSS 1; 6.2+/-0.6 mmHg for MSS 2, 9.2+/-0.8 mmHg for MSS 3; and 9.9+/-1.2 mmHg for MSS >=4 (p<0.001). Second, the sIAD level of the metabolic syndrome group (9.3+/-0.7 mmHg) was significantly higher (p<0.001) than for the nonmetabolic syndrome group (5.7+/-0.3 mmHg). CONCLUSIONS: In conclusion, metabolic syndrome and an increased number of its components are associated with the sIAD levels in Korean adults. PMID- 26247301 TI - Enhancing monoclonal antibody activity in chronic lymphocytic leukemia. PMID- 26247302 TI - Age-related differences in time-based prospective memory: The role of time estimation in the clock monitoring strategy. AB - Time-based prospective memory (TBPM) is required when it is necessary to remember to perform an action at a specific future point in time. This type of memory has been found to be particularly sensitive to ageing, probably because it requires a self-initiated response at a specific time. In this study, we sought to examine the involvement of temporal processes in the time monitoring strategy, which has been demonstrated to be a decisive factor in TBPM efficiency. We compared the performance of young and older adults in a TBPM task in which they had to press a response button every minute while categorising words. The design allowed participants to monitor time by checking a clock whenever they decided. Participants also completed a classic time-production task and several executive tasks assessing inhibition, updating and shifting processes. Our results confirm an age-related lack of accuracy in prospective memory performance, which seems to be related to a deficient strategic use of time monitoring. This could in turn be partially explained by age-related temporal deficits, as evidenced in the duration production task. These findings suggest that studies designed to investigate the age effect in TBPM tasks should consider the contribution of temporal mechanisms. PMID- 26247304 TI - An epimer of deoxynivalenol: purification and structure identification of 3-epi deoxynivalenol. AB - In an investigation of deoxynivalenol (DON)-transformation products by Devosia mutans 17-2-E-8, the major product was identified as 3-epi-DON. This DON transformation product was analysed by liquid chromatography and identified by congruent retention time and UV/Vis spectrum, as well as mass spectrometric data. Nuclear magnetic resonance (NMR) experiments including correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC) and nuclear overhauser effect (NOE) were conducted for structural characterisation of 3-epi-DON. High speed counter-current chromatography (HSCCC) was applied to scale up the separation of 3-epi-DON from DON in a D. mutans 17-2-E-8 culture. From the culture where 100 mg DON was applied, 56 mg of 3-epi-DON (purity of 96.8%) was obtained from the HSCCC. The purified 3-epi-DON will be used for toxicological characterisation studies of this chemical. PMID- 26247305 TI - The protective effect of pomegranate extract against cisplatin toxicity in rat liver and kidney tissue. AB - OBJECTIVES: The purpose of this study was to perform a histopathological investigation, at the light microscopy level, of the protective effects of pomegranate extract in cisplatin-induced liver and kidney damage in rats. MATERIAL AND METHODS: Twenty-eight adult male Wistar albino rats were randomly divided into four groups of seven animals: Group 1: Control; Group 2: Treated for 10 consecutive days by gavage with pomegranate juice (2 ml/kg/day); Group 3: Injected intraperitoneally with cisplatin (8 mg/kg body weight, single dose) onset of the day 5, and Group 4: Treated by gavage with pomegranate juice 10 days before and after a single injection of cisplatin onset of the day 5. After 10 days, the animals were sacrificed and their kidneys and liver tissue samples were removed from each animal after experimental procedures. Cisplatin-induced renal and hepatic toxicity and the effect of pomegranate juice were evaluated by histopatological examinations. RESULTS: In the kidney tissue, pomegranate juice significantly ameliorated cisplatin-induced structural alterations when compared with the cisplatin alone group. But in the liver tissue, although pomegranate juice attenuated the cisplatin-induced toxicity only in two rats, significant improvement was not observed. CONCLUSION: In conclusion, these results demonstrate that the anti-oxidant pomegranate juice might have a protective effect against cisplatin-induced toxicity in rat kidney, but not in liver. Pomegranate juice could be beneficial as a dietary supplement in patients receiving chemotherapy medications. PMID- 26247306 TI - Associations between low levels of serum uric acid and cardiometabolic parameters. AB - INTRODUCTION: Elevated serum uric acid (SUA) levels are associated with increased cardiovascular risk. OBJECTIVE: To evaluate the association between SUA levels and cardiometabolic parameters. MATERIALS AND METHODS: SUA levels and metabolic parameters were evaluated in 139 subjects, divided into low (<5 mg/dl) and high SUA group (>=5 mg/dl). RESULTS: In low SUA group, SUA levels directly correlated with creatinine, body mass index, waist circumference, blood pressure, glucose and insulin levels, triglyceride and C-reactive protein levels. In high SUA group, SUA levels directly correlated with body weight, triglyceride, C-reactive protein, and inversely correlated with HDL-cholesterol concentrations. DISCUSSION AND CONCLUSIONS: High SUA levels were linked with several cardiometabolic parameters, and low SUA levels were linearly correlated with recognized cardiovascular risk factors. Therefore, increasing SUA levels - even at low concentration - could be associated with higher cardiovascular risk. Thus the range of normality for SUA level should be further analysed. PMID- 26247307 TI - Blue-green emissive cationic iridium(III) complexes using partially saturated strongly-donating guanidyl-pyridine/-pyrazine ancillary ligands. AB - A new class of cationic iridium(III) complexes of the form [(C(?)N)2Ir(N(?)N)][PF6] is reported, where C(?)N = cyclometallating 2 phenylpyridinato, ppy, or 2-(2,4-difluorophenyl)-5'-methylpyridinato, dFMeppy, and N(?)N = guanidyl-pyridine, gpy, or -pyrazine, gpz, as the ancillary ligand. A large blue-shift in the emission coupled with a 7-to-9 fold enhancement in photoluminescence quantum yield and microsecond emission lifetimes were observed for the complexes containing the partially saturated gpy ligand as compared to the benchmark complex [(ppy)2Ir(bpy)][PF6], C1, where bpy is 2,2'-bipyridine. PMID- 26247308 TI - Synthesis and molecular modelling studies of novel sulphonamide derivatives as dengue virus 2 protease inhibitors. AB - Development of antivirals for dengue is now based on rational approach targeting the enzymes involved in its life cycle. Among the targets available for inhibition of dengue virus, non-structural protein NS2B-NS3 protease is considered as a promising target for the development of anti-dengue agents. In the current study we have synthesized a series of 4-(1,3-dioxo-2,3-dihydro-1H isoindol-2-yl)benzene-1-sulphonamide derivatives and screened for DENV2 protease activity. Compounds 16 and 19 showed IC50 of DENV2 Protease activity with 48.2 and 121.9MUM respectively. Molecular docking and molecular dynamic simulation studies were carried out to know the binding mode responsible for the activity. MD simulations revealed that, NS2B/NS3 protease was more stable when it binds with the active compound. Structure optimization of the lead compounds 16 and 19 and their co-crystallization studies are underway. PMID- 26247309 TI - A new monoterpene glucoside and complete assignments of dihydroflavonols of Pulicaria jaubertii: potential cytotoxic and blood pressure lowering activity. AB - One new monoterpene glucoside and five dihydroflavonols were isolated for the first time from the aerial parts of Pulicaria jaubertii and identified as p menthane-2-O-beta-D-glucopyranoside [1], dihydroquercetin (taxifolin) [2], 7,3' di-O-methyltaxifolin [3], 3'-O-methyltaxifolin [4], 7-O-methyltaxifolin (padmatin) [5] and 7-O-methyl-dihydrokampferol (7-O-methylaromadenderin) [6]. The structures of these compounds were unambiguously assigned on the basis of NMR spectroscopic data ((1)H, (13)C, DEPT, HSQC, HMBC) and MS analysis. 2D-NMR methods required revision of assignments of H-6 and H-8 for dihydroflavonol compounds. Possible cytotoxic activity as well as blood pressure (BP) lowering activity were tested. The alcoholic extract showed cytotoxic activity against prostate carcinoma (PC-3), breast carcinoma (MCF-7) and hepatocellular carcinoma (HepG-2) human cell lines with IC50 19.1, 20.0 and 24.1 MUg, respectively. The higher dose levels of the alcoholic extract significantly reduced normal BP of rats in a dose-dependent manner. PMID- 26247310 TI - Assessment of holocellulose for the production of bioethanol by conserving Pinus radiata cones as renewable feedstock. AB - Renewable and green energy sources are much sought. Bioethanol is an environmentally friendly transportation fuel. Pine cones from Pinus radiata were shown to be a potential feedstock for the production of bioethanol. Alkaline (NaOH) pretreatment was carried out to delignify the lignocellulosic material and generate holocellulose (72 wt. % yield). The pretreated biomass was hydrolysed using HCl as catalyst under microwave irradiation and hydrothermal conditions. Microwave irradiation was found to be better than the hydrothermal process. Microwave irradiation accelerated the hydrolysis of biomass (42 wt. % conversion) with the reaction conditions being 3 M HCl and 5 min of irradiation time. Interestingly, even the xylose, which is the major component of the hydrolyzate was found to be metabolized to ethanol using Baker's yeast (Saccharomyces cerevisiae) under the experimental conditions. 5.7 g of ethanol could be produced from 100 g of raw pine cones. PMID- 26247312 TI - Freestanding eggshell membrane-based electrodes for high-performance supercapacitors and oxygen evolution reaction. AB - A type of freestanding, light-weight eggshell membrane-based electrode is demonstrated for supercapacitors and for oxygen evolution reaction (OER) catalysis. As a widely available daily waste, eggshell membranes have unique porous three-dimensional grid-like fibrous structures with relatively high surface area and abundant macropores, allowing for effective conjugation of carbon nanotubes and growth of NiCo2O4 nanowire arrays, an effective supercapacitor material and OER catalyst. The three-dimensional fibrous eggshell membrane frameworks with carbon nanotubes offer efficient pathways for charge transport, and the macropores between adjacent fibers are fully accessible for electrolytes and bubble evolution. As a supercapacitor, the eggshell membrane/carbon nanotube/NiCo2O4 electrode shows high specific capacitances at current densities from 1 to 20 A g(-1), with excellent capacitance retention (>90%) at 10 A g(-1) for over 10,000 cycles. When employed as an OER catalyst, this eggshell membrane-based electrode exhibits an OER onset potential of 1.53 V vs. the reversible hydrogen electrode (RHE), and a stable catalytic current density of 20 mA cm(-2) at 1.65 V vs. the RHE. PMID- 26247311 TI - Corpus callosotomy versus vagus nerve stimulation for atonic seizures and drop attacks: A systematic review. AB - Atonic seizures are debilitating and poorly controlled with antiepileptic medications. Two surgical options are primarily used to treat medically refractory atonic seizures: corpus callosotomy (CC) and vagus nerve stimulation (VNS). However, given the uncertainty regarding relative efficacy and surgical complications, the best approach for affected patients is unclear. The PubMed database was queried for all articles describing the treatment of atonic seizures and drop attacks with either corpus callosotomy or VNS. Rates of seizure freedom, >50% reduction in seizure frequency, and complications were compared across the two patient groups. Patients were significantly more likely to achieve a >50% reduction in seizure frequency with CC versus VNS (85.6% versus 57.6%; RR: 1.5; 95% CI: 1.1-2.1). Adverse events were more common with VNS, though typically mild (e.g., 22% hoarseness and voice changes), compared with CC, where the most common complication was the disconnection syndrome (13.2%). Both CC and VNS are well tolerated for the treatment of refractory atonic seizures. Existing studies suggest that CC is potentially more effective than VNS in reducing seizure frequency, though a direct study comparing these techniques is required before a definitive conclusion can be reached. PMID- 26247313 TI - Mediator Variables in Headache Research: Methodological Critique and Exemplar Using Self-Efficacy as a Mediator of the Relationship Between Headache Severity and Disability. AB - BACKGROUND: Despite advances in headache medicine, there remains little research on process-related variables that mediate relations between headache and outcomes, as well as limited dissemination of optimal statistical methodology for conducting mediation analyses. The present paper thus aims to promote and demonstrate a contemporary approach to mediation analysis as applied to headache. METHODS: An overview of a contemporary path-analytic approach to mediation analysis is presented, with an empirical exemplar for illustrative purposes. In the exemplar, headache management self-efficacy (HMSE) was proposed as a mediator between headache severity and disability. The sample included 907 young adults (M age = 19.03 [SD = 2.26]; 70.8% female) with primary headache. Direct and indirect effects of headache severity on headache disability through HMSE were assessed using the espoused methods. RESULTS: Pain severity was positively associated with headache disability (beta = 2.91, 95% confidence interval [CI; 2.62, 3.19]) and negatively associated with HMSE (beta = -3.50, 95% CI [-4.24, -2.76]); HMSE was negatively associated with headache disability (beta = 0.07, 95% CI [-0.09, 0.04]). A positive indirect effect of pain severity on disability through HMSE was identified (point estimate = 0.24, 95% CI [0.14, 0.34]); thus, self-efficacy mediated the association between pain severity and disability. The proposed mediation model accounted for 38% of total variance in disability (P < .001). CONCLUSIONS: There is a need for theory-driven and statistically rigorous mediation analyses within the headache literature. In one exemplar application, self-efficacy partially accounted for the disability resulting from headache. We advocate for increased attention to intervening variables in headache via dissemination of contemporary mediation analyses. PMID- 26247314 TI - Integrating Social-Contextual and Intrapersonal Mechanisms of "Maturing Out": Joint Influences of Familial-Role Transitions and Personality Maturation on Problem-Drinking Reductions. AB - BACKGROUND: "Maturing out" of problem drinking is associated with both role transitions (e.g., getting married) and personality development. However, little is known concerning how these 2 mechanisms jointly influence problem-drinking desistance. This study investigated whether salutary effects of role transitions and personality occur at different points in young-adult development and whether they mediate one another's effects. METHODS: Participants were initially recruited as first-year undergraduates, with family history of alcoholism overrepresented by design (N = 489). Using 4 waves of data at roughly ages 21, 25, 29, and 34, cross-lagged panel models estimated prospective relations among familial-role transitions (marriage or parenthood), personality (disinhibition, conscientiousness, and neuroticism), and problem drinking. RESULTS: Mixed support was found for the prediction of roles being more strongly associated with earlier maturing out of problem drinking and personality being more strongly associated with later maturing out. Regarding mediation, no evidence was found for the expectation that role effects would be mediated by personality. However, results did support mediation of personality effects by role transitions. Specifically, lower disinhibition and higher conscientiousness in emerging adulthood predicted role adoption, which, in turn, predicted later problem-drinking reductions. Family history of alcoholism also distally influenced these mediation processes. CONCLUSIONS: The differential timing of role and personality effects is consistent with the notion of decreasing contextual influences and increasing intrapersonal influences across development. In light of role incompatibility theory, results suggest that, over the course of development, the association of familial roles with problem drinking may increasingly reflect problem-drinking effects on role entry (i.e., role selection) and decreasingly reflect role entry effects on problem drinking (i.e., role socialization). As emerging-adult disinhibition and conscientiousness were associated with an apparent developmental cascade of both direct and indirect effects, findings highlight their potential importance as etiologic mechanisms and intervention targets. PMID- 26247315 TI - Freeze-dried dog sperm: Dynamics of DNA integrity. AB - Freeze-drying (FD) has been proposed as an alternative method to preserve spermatozoa. During the FD procedure, sperm DNA might become damaged by both freezing and drying stresses caused by the endonucleases, the oxidative stress and the storage conditions. We examined the DNA integrity of dog sperm freeze dried with two kinds of chelating agents in FD buffers and storage at two different temperatures. Ejaculated sperm from four dogs were suspended in basic medium (10 mM Tris-HCl buffer+50 mM NaCl) supplemented with 50 mM EGTA or with 50 mM EDTA and then freeze-dried. Sperm samples were stored at 4 degrees C as room temperature, and the analysis of DNA damage was performed after a month and 5 months of storage using a Sperm Chromatin Dispersion test. We found four different sperm populations according to the size of the halos around the sperm head: (1) absent halo, (2) <6 MUm, (3) 6-10 MUm, (4) >10 MUm. All of them coexisted in each freeze-dried dog semen samples and differed significantly among different treatments. The highest percentage of spermatozoa with halo >10 MUm was obtained when the semen samples were freeze-dried in EDTA medium and stored at room temperature for five months. Results suggested that both, the kind of chelating agent as well as storage temperature and period, influenced DNA integrity of freeze-dried dog sperm. PMID- 26247316 TI - Changes in mitochondrial function in porcine vitrified MII-stage oocytes and their impacts on apoptosis and developmental ability. AB - The purpose of this study was to investigate the changes in mitochondria in porcine MII-stage oocytes after open pulled straw (OPS) vitrification and to determine their roles in apoptosis and in vitro developmental ability. The mitochondrial membrane potential (DeltaPsim), reactive oxygen species (ROS) level, adenosine-5'-triphosphate (ATP) concentration, mitochondrial distribution, mitochondrial ultrastructure, early-stage apoptosis with Annexin V-FITC staining, survival rate, parthenogenetic developmental ability and related gene expression were measured in the present experiments. The results showed that: (1) the mitochondrial DeltaPsim of vitrified-thawed oocytes (1.05) was lower than that of fresh oocytes 1.24 (P<0.05). (2) ROS level in the OPS vitrification group was much higher than that of the fresh group, while the ATP concentration was much lower than that of fresh group (P<0.05). (3) Early-stage apoptosis rate from the OPS vitrification group (57.6%) was much higher than that of fresh group (8.53%) (P<0.05), and the survival rate and parthenogenetic cleavage rate of OPS vitrified oocytes were much lower than those from fresh ones (P<0.05). (4) Vitrification not only disrupted the mitochondrial distribution of porcine MII stage oocytes, but also damaged the mitochondrial ultrastructure. (5) After vitrification, the gene expression level of Dnm1 was up-regulated, and other four genes (SOD1, Mfn2, BAX and Bcl2) were down-regulated. The present study suggested that not only the morphology and function of mitochondria were damaged greatly during the vitrification process, but also early-stage apoptosis was observed after vitrification. Intrinsic mitochondrial pathway could be in involved in the occurrence of apoptosis in vitrified-thawed porcine oocytes. PMID- 26247317 TI - Implantable cardioverter-defibrillator and wait-list outcomes in pediatric patients awaiting heart transplantation. AB - BACKGROUND: Implantable cardioverter-defibrillators (ICDs) reduce the incidence of sudden cardiac death (SCD) in adults with end-stage heart failure; however, their efficacy in pediatric patients awaiting heart transplantation is not well established. OBJECTIVES: This study sought to investigate the role of ICDs in preventing SCD and waiting list mortality as well as to determine risk factors for SCD in pediatric patients listed for heart transplantation. METHODS: We queried the United Network for Organ Sharing database for all pediatric patients (age <=18 years) listed for heart transplantation (2005-2014). The Cox proportional hazards model was used to identify risk factors for SCD and all cause mortality. RESULTS: A total of 5072 mostly White (55%) male (55%) patients (mean age 6.2 +/- 6.5 years) were identified, of whom 426 (8.3%) had ICD at listing. At 6 months, 65% underwent heart transplantation, 15% died (4% died of SCD), and 20% were alive. In a multivariable model, United Network for Organ Sharing status 1B (hazard ratio [HR] 0.52; 95% confidence interval [CI] 0.29 0.95; P = .03), myocarditis (HR 0.19; 95% CI 0.05-0.77; P = .02), restrictive cardiomyopathy (HR 0.19; 95% CI 0.05-0.76; P = .02), and dilated cardiomyopathy (HR 0.32; 95% CI 0.20-0.52; P < .001) were associated with lower SCD risk, while younger age at listing (HR 0.94 per year; 95% CI 0.90-0.98; P = .003) was associated with higher SCD risk. ICD at listing was not associated with reduced SCD (P = .12), all-cause mortality, or delisting (P = .57). CONCLUSION: In pediatric patients listed for heart transplantation, the risk of SCD remains low and does not differ between patients with and without an ICD at listing. PMID- 26247318 TI - Esophageal infrared thermography during atrial fibrillation ablation. PMID- 26247319 TI - Effect of circadian variability in frequency of premature ventricular complexes on left ventricular function. AB - BACKGROUND: Frequent idiopathic premature ventricular complexes (PVCs) can result in a reversible form of cardiomyopathy. OBJECTIVE: The purpose of this study was to assess the impact of variability in PVC frequency throughout the day on PVC induced cardiomyopathy. METHODS: The subjects of this study were 107 consecutive patients (58 men [54%]; mean age 49.7 +/- 15.0 years; left ventricular ejection fraction 50.4% +/- 11.4%) referred for ablation of frequent PVCs. All patients underwent 24-hour Holter monitoring before the ablation procedure. The circadian variation in PVC burden was determined and correlated with the presence or absence of cardiomyopathy. RESULTS: A total of 43 patients (40%) had cardiomyopathy. Patients with cardiomyopathy had an ejection fraction of 38.4% +/ 6.9%, a higher PVC burden (28.5% +/- 11.5% vs 19.5% +/- 10.5%; P = .0001), less variability in circadian PVC distribution (coefficient of variation hourly: 31.5% +/- 21% vs 59.8% +/- 32.4%; P = .0001), and more frequent interpolated PVCs (20 patients [47%] vs 15 patients [23%]; P = 0.022), and were more frequently asymptomatic than patients without cardiomyopathy (56% vs 19%; P = .0001). In multivariate analysis, consistency in PVC burden throughout the day was an independent predictor of PVC-induced cardiomyopathy (odds ratio 16.3; 95% confidence interval 1.7-155.3; p = 0.015). CONCLUSION: In patients with frequent PVCs, consistency in hourly PVC frequency throughout the day is an independent predictor of PVC-induced cardiomyopathy. PMID- 26247320 TI - Frontal dynamic aphasia in progressive supranuclear palsy: Distinguishing between generation and fluent sequencing of novel thoughts. AB - Frontal dynamic aphasia is characterised by a profound reduction in spontaneous speech despite well-preserved naming, repetition and comprehension. Since Luria (1966, 1970) designated this term, two main forms of dynamic aphasia have been identified: one, a language-specific selection deficit at the level of word/sentence generation, associated with left inferior frontal lesions; and two, a domain-general impairment in generating multiple responses or connected speech, associated with more extensive bilateral frontal and/or frontostriatal damage. Both forms of dynamic aphasia have been interpreted as arising due to disturbances in early prelinguistic conceptual preparation mechanisms that are critical for language production. We investigate language-specific and domain general accounts of dynamic aphasia and address two issues: one, whether deficits in multiple conceptual preparation mechanisms can co-occur; and two, the contribution of broader cognitive processes such as energization, the ability to initiate and sustain response generation over time, to language generation failure. Thus, we report patient WAL who presented with frontal dynamic aphasia in the context of progressive supranuclear palsy (PSP). WAL was given a series of experimental tests that showed that his dynamic aphasia was not underpinned by a language-specific deficit in selection or in microplanning. By contrast, WAL presented with a domain-general deficit in fluent sequencing of novel thoughts. The latter replicated the pattern documented in a previous PSP patient (Robinson, et al., 2006); however, unique to WAL, generating novel thoughts was impaired but there was no evidence of a sequencing deficit because perseveration was absent. Thus, WAL is the first unequivocal case to show a distinction between novel thought generation and subsequent fluent sequencing. Moreover, WAL's generation deficit encompassed verbal and non-verbal responses, showing a similar (but more profoundly reduced) pattern of performance to frontal patients with an energization deficit. In addition to impaired generation of novel thoughts, WAL presented with a concurrent strategy generation deficit, both falling within the second form of dynamic aphasia comprised of domain-general conceptual preparation mechanisms. Thus, within this second form of dynamic aphasia, concurrent deficits can co-occur. Overall, WAL presented with the second form of dynamic aphasia and was impaired in the generation of novel thoughts and internally-generated strategies, in the context of PSP and bilateral frontostriatal damage. PMID- 26247321 TI - The Conference Facilitator Model: Improving the Value of Conference Attendance for Attendees and the Organization. AB - Healthcare leaders face a multitude of priorities demanding their attention and resources, from patient, employee safety and hospital-acquired conditions to predicting future revenue in the context of healthcare reform. Assessing value requires balancing outcomes and experience with cost. How does allocating funds for professional nursing conferences measure up? What is a valid return on investment when we send staff nurses to professional conferences, specifically the annual Magnet(r) conference? The following article describes how Cincinnati Children's Hospital Medical Center answered these questions and redefined the expectations for conference attendees while enhancing the experience and the reportable outcomes for practice and the organization. PMID- 26247323 TI - Rare-earth metal pi-complexes of reduced arenes, alkenes, and alkynes: bonding, electronic structure, and comparison with actinides and other electropositive metals. AB - Rare-earth metal complexes of reduced pi ligands are reviewed with an emphasis on their electronic structure and bonding interactions. This perspective discusses reduced carbocyclic and acyclic pi ligands; in certain categories, when no example of a rare-earth metal complex is available, a closely related actinide analogue is discussed. In general, rare-earth metals have a lower tendency to form covalent interactions with pi ligands compared to actinides, mainly uranium. Despite predominant ionic interactions in rare-earth chemistry, covalent bonds can be formed with reduced carbocyclic ligands, especially multiply reduced arenes. PMID- 26247322 TI - DNA damage induced by the anticodon nuclease from a Pichia acaciae killer strain is linked to ribonucleotide reductase depletion. AB - Virus like element (VLE) encoded killer toxins of Pichia acaciae and Kluyveromyces lactis kill target cells through anticodon nuclease (ACNase) activity directed against tRNA(Gln) and tRNA(Glu) respectively. Not only does tRNA cleavage disable translation, it also affects DNA integrity as well. Consistent with DNA damage, which is involved in toxicity, target cells' mutation frequencies are elevated upon ACNase exposure, suggesting a link between translational integrity and genome surveillance. Here, we analysed whether ACNase action impedes the periodically and highly expressed S-phase specific ribonucleotide reductase (RNR) and proved that RNR expression is severely affected by PaT. Because RNR catalyses the rate-limiting step in dNTP synthesis, mutants affected in dNTP synthesis were scrutinized with respect to ACNase action. Mutations elevating cellular dNTPs antagonized the action of both the above ACNases, whereas mutations lowering dNTPs aggravated toxicity. Consistently, prevention of tRNA cleavage in elp3 or trm9 mutants, which both affect the wobble uridine modification of the target tRNA, suppressed the toxin hypersensitivity of a dNTP synthesis mutant. Moreover, dNTP synthesis defects exacerbated the PaT ACNase sensitivity of cells defective in homologous recombination, proving that dNTP depletion is responsible for subsequent DNA damage. PMID- 26247324 TI - The azo dye Disperse Red 13 and its oxidation and reduction products showed mutagenic potential. AB - Common water pollutants, azo dyes and their degradation products have frequently shown toxicity, including carcinogenic and mutagenic effects, and can induce serious damage in aquatic organisms and humans. In the present study, the mutagenic potential of the azo dye Disperse Red 13 (DR13) was first evaluated using the Micronucleus Assay in human lymphocytes. Subsequently, in order to mimic hepatic biotransformation, controlled potential electrolysis was carried out with a DR13 solution using a Potentiostat/Galvanostat. In addition, a DR13 solution was oxidized using S9 (homogenate of rat liver cells). DR13 oxidation and the reduction products were identified using HPLC-DAD and GC/MS, and their mutagenic potential investigated by way of a Salmonella/microsome assay using TA98 and YG1041 strains, with no S9. The original azo dye DR13 induced chromosomal damage in human lymphocytes, and the respective oxidation and reduction products also showed mutagenic activity, as detected by the Salmonella/microsome assay. Furthermore sulfate 2-[(4-aminophenyl)ethylamino] ethanol monohydrate, 2-chloro-4-nitro-benzamine, 4-nitro-benzamine and 2 (ethylphenylamine)-ethanol were identified as products of the DR13 reduction/oxidation reactions. Thus it was concluded that the contamination of water effluents with DR13 is a health risk not only due to the dye itself, but also due to the possibility of drinking contaminated water, considering the harmful compounds that can be produced after hepatic biotransformation. PMID- 26247326 TI - Single-Layer Light-Emitting Diodes Using Organometal Halide Perovskite/Poly(ethylene oxide) Composite Thin Films. AB - Organometal halide perovskite and poly(ethylene oxide) composite thin films are studied. Single-layer light-emitting diodes using the composite thin film sandwiched between indium tin oxide and indium-gallium eutectic alloy exhibit a low turn-on voltage and high brightness because of the ionic conductivity of the composite film and the formation of a p-i-n homojunction. PMID- 26247325 TI - Effects of different periods of gastric ischaemia in the viability of the tissue of body, fundus and antrum region of rabbit stomach. AB - BACKGROUND: Despite the rich vascular arcade of the stomach, gastric ischemia represents an important medical challenge and can be the consequence of obstructive or non-obstructive vascular processes of pathological or iatrogenic origin. AIM: To assess the effects of acute gastric ischaemia on the different regions of the stomach. METHOD: Fifteen New Zeland rabbits were divided into three groups: group 1, animals were observed during 3 h; group 2, during 6 h; group 3, during 12 h. Rabbit stomachs were subjected to devascularization of the greater and lesser curvatures. After predetermined time, the stomachs were removed for macro and microscopic studies. RESULTS: Haemorrhagic necrosis was more marked in the gastric fundus and body. In contrast, the antropylorus remained preserved in 80% of the animals. Necrosis of the gastric body and fundus mucosa were observed in all animals after 6 h and 12 h of ischaemia. CONCLUSION: Acute gastric ischaemia in rabbits produces haemorrhagic necrosis of the gastric fundus and body even in a short period of time. Beside this, the antropyloric region was significantly more resistant to ischaemia. PMID- 26247327 TI - Therapist-Aided Exposure for Women with Lifelong Vaginismus: Mediators of Treatment Outcome: A Randomized Waiting List Control Trial. AB - INTRODUCTION: Therapist-aided exposure seems an effective treatment for lifelong vaginismus, but mechanisms of action have not yet been established. AIM: The purpose of the present study was to investigate whether treatment outcome of a therapist-aided exposure treatment was mediated by changes in positive and negative penetration beliefs or feelings of sexual disgust. METHODS: Participants with lifelong vaginismus were allocated at random to a 3-month exposure (n = 35) or a waiting list control condition (n = 35). MAIN OUTCOME MEASURE: Full intercourse was assessed daily during 12 weeks. Secondary outcome measures (complaints about vaginismus and coital pain) were assessed at baseline and after 12 weeks. Possible mediators: penetration beliefs (catastrophic pain beliefs, genital incompatibility beliefs, perceived control beliefs) and feelings of sexual disgust were assessed at baseline and 6 weeks. RESULTS: Treatment outcome (coital frequency, symptoms of vaginismus, and coital pain) at 12 weeks was mediated by changes in negative and positive penetration beliefs at 6 weeks, in particular by more pronounced reduction of catastrophic pain penetration beliefs. No evidence was found that changes in feelings of sexual disgust mediated treatment outcome. CONCLUSION: The results strongly suggest that therapist-aided exposure affects negative penetration beliefs and that these changes in negative penetration beliefs mediate treatment outcome in women with lifelong vaginismus. Implications for treatment are discussed. PMID- 26247328 TI - Mercury in mercury(II)-spiked soils is highly susceptible to plant bioaccumulation. AB - Heavy metal phytotoxicity assessments usually use soluble metal compounds in spiked soils to evaluate metal bioaccumulation, growth inhibition and adverse effects on physiological parameters. However, exampling mercury phytotoxicity for barley (Hordeum vulgare) this paper highlights unsuitability of this experimental approach. Mercury(II) in spiked soils is extremely bioavailable, and there experimentally determined bioaccumulation is significantly higher compared to reported mercury bioaccumulation efficiency from soils collected from mercury polluted areas. Our results indicate this is not affected by soil sorption capacity, thus soil ageing and formation of more stable mercuric complexes with soil fractions is necessary for reasonable metal phytotoxicity assessments. PMID- 26247329 TI - An ab initio investigation on the ground electronic state of chlorine monoxide and its singly charged cation and anion. AB - The MRCI method has been utilized to calculate the equilibrium structure of the ground electronic state for the ClO radical and its singly charged cation and anion, ClO(+) and ClO(-). The augmented correlation-consistent basis sets up through sextuple-zeta quality are used to derive equilibrium structural parameters, potential energy curves and spectroscopic constants of the systems. Two extrapolating schemes enable us to remove the basis set truncation error and to estimate the complete basis set limit. Corrections of core-valence correlation and relativistic effect are included in our calculations. By solving the radial Schrodinger equation of nuclear motion, the vibrational energy levels as well as rotational and centrifugal distortion constants of the ground electronic states for the three species are obtained. Ionization potentials and the electron affinities are also obtained on the RCCSD(T)/AV6Z level. The knowledge extracted from this work are anticipated to extend our understanding on molecular characteristics of the ClO(n) (n=-1, 0, +1) systems and can serve as guidelines for further experimental or theoretical researches. PMID- 26247330 TI - Effect of obesity on the effectiveness of hormonal contraceptives: an individual participant data meta-analysis. AB - OBJECTIVE: The objective of this investigation was to assess the potential effect of obesity on the effectiveness of hormonal contraceptives (HCs). STUDY DESIGN: A meta-analysis was conducted using individual participant data directly from the Phase 3 clinical trials of combination oral contraceptives (COCs) rather than extracting summary data from literature. Trials selected were reviewed by the US Food and Drug Administration (FDA) between 2000 and 2012, conducted in North America, had more than six 28-day cycle equivalents of exposure, and had readily retrievable participant-level data. Contraceptive effectiveness was measured by the Pearl Index (PI: the number of pregnancies per 100 woman-years) in women aged 18-35 at risk of unintended pregnancy. The incidence rate ratio (IRR), a ratio of PIs for obese women (defined as body mass index [BMI] >=30 kg/m(2)) compared to non-obese women (BMI <30 kg/m(2)) was calculated. A Cox proportional-hazard regression model with fixed and random-effects were used to estimate hazard ratios (HRs) for unintended pregnancy in obese women compared to non-obese women. RESULTS: Seven clinical trials with COCs (N=14,024: 2707 obese and 11,317 non obese women) met the inclusion criteria for the meta-analysis. The PI for each trial varied: 2.05-5.08 for obese and 1.84-3.80 for non-obese women. The pooled PI estimated using direct weighted average method was 3.14 (95% CI: 2.33-4.22) for obese and 2.53 (95% CI: 1.88-3.41) for non-obese women. The pooled IRRs estimated using direct weighted average and Mantel-Haenszel adjustment methods were comparable: 1.37 (95% CI: 1.02-1.84) and 1.43 (95% CI: 1.07-1.92), respectively. The overall HR of 1.44 (95% CI: 1.06-1.95; p=.018) in the meta analysis suggested a 44% higher pregnancy rate during COC use for obese women after adjusting for age and race. IMPLICATIONS STATEMENT: Obesity may increase the risk of unintended pregnancy in women using COCs; more data on obese women from ongoing and future Phase 3 clinical trials are necessary to allow further evaluation of this topic. CONCLUSIONS: Results of this meta-analysis suggest that obese women may have a higher pregnancy rate during COC use compared to non-obese women. Future analysis should assess differences in pharmacodynamics or compliance that could potentially account for the observed difference in unintended pregnancy rates. PMID- 26247331 TI - Perceiving objects by their function: An EEG study on feature saliency and prehensile affordances. AB - We examined the feature saliency and prehensile/motor affordance effects that are visually elicited by a graspable object's most salient features and graspable part, respectively. EEG was recorded from participants who attended a photo of an object, and responded to a left- or right-pointing arrow, which was overlaid on the object 1000 ms after object onset. Analysis of response times demonstrated the presence of a feature saliency effect. Lateralization of posterior alpha suppression showed that attention was initially directed to the object's (most salient) functional end. Pre-movement frontocentral beta suppression and the modulation of the P3 component showed that a response compatible to the functional end was activated before arrow onset. Moreover, lateralization of pre movement posterior and central alpha suppression indicated a behaviorally masked affordance effect. This suggests that the two effects may occur independently, but without specific attention orienting instructions, the feature saliency effect dominates a potential prehensile affordance effect. PMID- 26247332 TI - Excuse me, but did the IPD-work consortium just "falsify" the job-strain model? PMID- 26247333 TI - Through the portal: Effect anticipation in the central bottleneck. AB - Ample evidence suggests that motor actions are generated by mentally recollecting their sensory consequences, i.e., via effect anticipations. There is less evidence, though, on the capacity limitations that such effect anticipations suffer from. In the present paper we aim to overcome shortcomings of previous research on this issue by extending the set of empirical indicators of effect anticipations and by using trial-wise instead of block-wise manipulations. In four experiments using the locus of slack- and the effect propagation-logic, we found conclusive evidence for effect anticipation taking place in the capacity limited central bottleneck. These findings extend previous research suggesting an overlap of a "response selection" process as assumed in traditional stage theory and effect anticipation processes as assumed in effect-based ideomotor models of action control. PMID- 26247336 TI - The effect of water on the binding of glycosaminoglycan saccharides to hydroxyapatite surfaces: a molecular dynamics study. AB - Classical molecular dynamics (MD) simulations have been employed to study the interaction of the saccharides glucuronic acid (GlcA) and N-acetylgalactosamine (GalNAc) with the (0001) and (0110) surfaces of the mineral hydroxyapatite (HAP). GlcA and GalNAc are the two constituent monosaccharides of the glycosaminoglycan chondroitin sulfate, which is commonly found in bone and cartilage and has been implicated in the modulation of the hydroxyapatite biomineralization process. MD simulations of the mineral surfaces and the saccharides in the presence of solvent water allowed the calculation of the adsorption energies of the saccharides on the HAP surfaces. The calculations show that GalNAc interacts with HAP principally through the sulfate and the carbonyl of acetyl amine groups, whereas the GlcA interacts primarily through the carboxylate functional groups. The mode and strength of the interaction depends on the orientation of the saccharide with respect to the surface and the level of disruption of the layer of water competing with the saccharide for adsorption sites on the HAP surface, suggesting that chondroitin 4-sulfate binds to the layer of solvent water rather than to HAP. PMID- 26247338 TI - Hypofractionation for Early-Stage Breast Cancer: No More Excuses. PMID- 26247339 TI - Editorial - Special issue on mechanobiology. PMID- 26247337 TI - Development and Validation of a Mortality Prediction Model for Patients Receiving 14 Days of Mechanical Ventilation. AB - OBJECTIVES: The existing risk prediction model for patients requiring prolonged mechanical ventilation is not applicable until after 21 days of mechanical ventilation. We sought to develop and validate a mortality prediction model for patients earlier in the ICU course using data from day 14 of mechanical ventilation. DESIGN: Multicenter retrospective cohort study. SETTING: Forty medical centers across the United States. PATIENTS: Adult patients receiving at least 14 days of mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Predictor variables were measured on day 14 of mechanical ventilation in the development cohort and included in a logistic regression model with 1-year mortality as the outcome. Variables were sequentially eliminated to develop the ProVent 14 model. This model was then generated in the validation cohort. A simplified prognostic scoring rule (ProVent 14 Score) using categorical variables was created in the development cohort and then tested in the validation cohort. Model discrimination was assessed by the area under the receiver operator characteristic curve. Four hundred ninety-one patients and 245 patients were included in the development and validation cohorts, respectively. The most parsimonious model included age, platelet count, requirement for vasopressors, requirement for hemodialysis, and nontrauma admission. The area under the receiver operator characteristic curve for the ProVent 14 model using continuous variables was 0.80 (95% CI, 0.76-0.83) in the development cohort and 0.78 (95% CI, 0.72-0.83) in the validation cohort. The ProVent 14 Score categorized age at 50 and 65 years old and platelet count at 100*10(9)/L and had similar discrimination as the ProVent 14 model in both cohorts. CONCLUSION: Using clinical variables available on day 14 of mechanical ventilation, the ProVent 14 model can identify patients receiving prolonged mechanical ventilation with a high risk of mortality within 1 year. PMID- 26247340 TI - A Brief History of the Indiana University Center for Studies of Law in Action and the Robert F. Borkenstein Course on Alcohol and High Safety. AB - For the past 50 years, the Indiana University Robert F. Borkenstein Course on Alcohol and Highway Safety, founded by Professor Robert F. Borkenstein in 1958, has made a unique and lasting contribution to that subject by providing expert level short-course instruction to more than 5,000 registrants from North America and many international locations. Since 1971, the course has been sponsored and presented by the Indiana University Center for Studies of Law in Action, also established by Prof. Borkenstein. The center has been involved in three primary missions in the field of alcohol, drugs, and traffic safety: (a) To carry out and facilitate research; (b) to present short courses and engage in other educational activities; and (c) to serve as a repository for information, available to educators, practitioners, and researchers. The pervasive and cumulative accomplishments of the Robert F. Borkenstein Course and the Indiana University Center for Studies of Law in Action were recognized in August 2007 by conferral of the Widmark Institutional Award by the International Council on Alcohol, Drugs, and Traffic Safety - the highest international honor in that field for outstanding contributions by a nongovernmental organization. This article recounts the history and accomplishments of the course and the center, as a tribute to both, and to Prof. Borkenstein, and to illuminate the path that led to the 16th ICADTS Widmark Institutional Award. PMID- 26247341 TI - Certification Programs for Criminalists - Historical Development. AB - Certification is the process by which individual practitioners of a profession are deemed competent, by a peer review process, to practice that profession. Criminalistics is a rather young profession, and until the recent publicity occasioned by a myriad of television dramas and documentaries, a rather obscure one. There has been little oversight of the profession and little call for such oversight until the 1970s. The calls for oversight primarily came from those outside the profession and with only a peripheral interest in the profession. In response, the profession itself began to consider the development of a process of self-review and to establish certification criteria (a) by which the competence of practitioners could be assessed in a way that would be acceptable to practitioners; (b) equitable to the diverse jobs requirements of various practitioners; useful for external evaluation by users of professional services; and, above all, (c) be a realistic method to evaluate the ability of the practitioner to engage in the professional practice of forensic science. Professional certification of criminalists was first suggested at a meeting of the California Association of Criminalists (CAC) in 1975. This initial proposal was taken to the broader national criminalistics community through the efforts of the Criminalistics Certification Study Committee (CCSC) beginning in 1976. Subjected in 1978 to a national referendum of practitioners, CCSC's proposal was rejected. Undaunted by national rejection, in 1986 the CAC renewed efforts to develop a certification process for its members, which resulted in the offering of the first certification examination in 1989. Since the initial certification examination by the CAC, certification of criminalists has evolved through the activities of the American Board of Criminalistics (ABC). Efforts have been continuously made to refine the process to more closely reflect the demands of the profession. The evolution has been slow, sometimes painful, and not always successful; however, a major revamping of the certification examination process was taking place in 2007. PMID- 26247342 TI - Liquid Chromatography-Tandem Mass Spectrometry Analysis of Opioids, Benzodiazepines, Cannabinoids, Amphetamines, and Cocaine in Biological and Other Specimens. AB - The use of liquid chromatography (LC) coupled with tandem mass spectrometry (MS/MS) or single-stage mass spectrometry (MS) is making significant inroads in the analyst's compendium of instrumentation available for the analysis of drugs in biological fluids, tissues, and other specimens of interest. LC/MS(/MS) has the unique capability of analyzing substances frequently not analyzable by any other means. Furthermore, LC/MS(/MS), particularly LC/MS/MS instrumentation, has shown a precipitous drop in cost, making it more accessible to the smaller laboratories. As such, an increasing number of methods for the analysis of drugs of abuse have been published using LC/MS(/MS) - in particular, those methods associated with LC/MS/MS. However, these methods are not without certain endemic problems/limitations such as ion source selection, matrix effects, endogenous interferences, and interlibrary matching of spectra. This review seeks to show what progress is being made to circumvent the perceived limitations of LC/MS(/MS). It presents methodologies for selected drugs of abuse (opioids, benzodiazepines, cannabinoids, cocaine, and the amphetamines) that have been developed in recent years for analysis in blood, urine, hair, and oral fluids, as well as certain other specimens. Emphasis is primarily directed toward those methodologies that have been developed recently for LC/MS/MS, but LC/MS methods are also addressed where appropriate. PMID- 26247343 TI - An efficient algorithm for the contig ordering problem under algebraic rearrangement distance. AB - Assembling a genome from short reads currently obtained by next-generation sequencing techniques often results in a collection of contigs, whose relative position and orientation along the genome being sequenced are unknown. Given two sets of contigs, the contig ordering problem is to order and orient the contigs in each set such that the genome rearrangement distance between the resulting sets of ordered and oriented contigs is minimized. In this article, we utilize the permutation groups in algebra to propose a near-linear time algorithm for solving the contig ordering problem under algebraic rearrangement distance, where the algebraic rearrangement distance between two sets of ordered and oriented contigs is the minimum weight of applicable rearrangement operations required to transform one set into the other. PMID- 26247344 TI - A multiscale filter for noise reduction of low-dose cone beam projections. AB - The Poisson or compound Poisson process governs the randomness of photon fluence in cone beam computed tomography (CBCT) imaging systems. The probability density function depends on the mean (noiseless) of the fluence at a certain detector. This dependence indicates the natural requirement of multiscale filters to smooth noise while preserving structures of the imaged object on the low-dose cone beam projection. In this work, we used a Gaussian filter, exp(-x2/2sigma(2)(f)) as the multiscale filter to de-noise the low-dose cone beam projections. We analytically obtained the expression of sigma(f), which represents the scale of the filter, by minimizing local noise-to-signal ratio. We analytically derived the variance of residual noise from the Poisson or compound Poisson processes after Gaussian filtering. From the derived analytical form of the variance of residual noise, optimal sigma(2)(f)) is proved to be proportional to the noiseless fluence and modulated by local structure strength expressed as the linear fitting error of the structure. A strategy was used to obtain the reliable linear fitting error: smoothing the projection along the longitudinal direction to calculate the linear fitting error along the lateral direction and vice versa. The performance of our multiscale filter was examined on low-dose cone beam projections of a Catphan phantom and a head-and-neck patient. After performing the filter on the Catphan phantom projections scanned with pulse time 4 ms, the number of visible line pairs was similar to that scanned with 16 ms, and the contrast-to-noise ratio of the inserts was higher than that scanned with 16 ms about 64% in average. For the simulated head-and-neck patient projections with pulse time 4 ms, the visibility of soft tissue structures in the patient was comparable to that scanned with 20 ms. The image processing took less than 0.5 s per projection with 1024 * 768 pixels. PMID- 26247345 TI - Copper-Catalyzed Intramolecular Dehydrogenative Amidation of Unactivated C(sp(3)) H Bonds Using O2 as the Sole Oxidant. AB - In this work, an aerobic copper-catalyzed intramolecular C(sp(3))-H amidation has been disclosed, which presents a rare example of copper-catalyzed functionalization of an unactivated C(sp(3))-H bond with O2 as the sole oxidant. In addition, a new protocol for the preparation of a removable 5-methoxyquinolyl moiety has been documented. PMID- 26247346 TI - Intercalated degrees and research projects: building academic foundations. PMID- 26247347 TI - Does vitamin C prevent the occurrence of complex regional pain syndrome in patients with extremity trauma requiring surgery? AB - The complex regional pain syndrome is a neuroinflammatory pathology that affects the central and peripheral nervous system, characterized by disproportional pain in relation to the trauma experimented by the patient. It has been proposed that vitamin C could prevent the development of this syndrome in patients with limb trauma and surgery. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified two systematic reviews that indentified four primary studies, including one randomized controlled trial. We generated a summary of findings table following the GRADE approach. We concluded it is uncertain whether vitamin C prevents complex regional pain syndrome because the certainty of the evidence is very low. PMID- 26247349 TI - Catalytic [3 + 2] Cycloaddition through Ring Cleavage of Simple Cyclopropanes with Isocyanates. AB - The catalytic synthesis of gamma-butyrolactams was established via [3 + 2] cycloaddition of cyclopropanes with isocyanates. An organotin iodide ate complex, MgBr(+)[Bu2SnBrI2](-), was employed as an effective catalyst. Simple cyclopropanes that lack aryl or vinyl substituents were useful precursors. Even acyl cyclopropanes were applicable. The hybrid characteristics of a tin complex, acidic MgBr(+) with nucleophilic tin iodide, was responsible for the catalytic reaction. PMID- 26247348 TI - The variability and seasonality of the environmental reservoir of Mycobacterium bovis shed by wild European badgers. AB - The incidence of Mycobacterium bovis, the causative agent of bovine tuberculosis, has been increasing in UK cattle herds resulting in substantial economic losses. The European badger (Meles meles) is implicated as a wildlife reservoir of infection. One likely route of transmission to cattle is through exposure to infected badger urine and faeces. The relative importance of the environment in transmission remains unknown, in part due to the lack of information on the distribution and magnitude of environmental reservoirs. Here we identify potential infection hotspots in the badger population and quantify the heterogeneity in bacterial load; with infected badgers shedding between 1 * 10(3) 4 * 10(5) M. bovis cells g(-1) of faeces, creating a substantial and seasonally variable environmental reservoir. Our findings highlight the potential importance of monitoring environmental reservoirs of M. bovis which may constitute a component of disease spread that is currently overlooked and yet may be responsible for a proportion of transmission amongst badgers and onwards to cattle. PMID- 26247350 TI - Bayesian methods for the design and analysis of noninferiority trials. AB - The gold standard for evaluating treatment efficacy of a medical product is a placebo-controlled trial. However, when the use of placebo is considered to be unethical or impractical, a viable alternative for evaluating treatment efficacy is through a noninferiority (NI) study where a test treatment is compared to an active control treatment. The minimal objective of such a study is to determine whether the test treatment is superior to placebo. An assumption is made that if the active control treatment remains efficacious, as was observed when it was compared against placebo, then a test treatment that has comparable efficacy with the active control, within a certain range, must also be superior to placebo. Because of this assumption, the design, implementation, and analysis of NI trials present challenges for sponsors and regulators. In designing and analyzing NI trials, substantial historical data are often required on the active control treatment and placebo. Bayesian approaches provide a natural framework for synthesizing the historical data in the form of prior distributions that can effectively be used in design and analysis of a NI clinical trial. Despite a flurry of recent research activities in the area of Bayesian approaches in medical product development, there are still substantial gaps in recognition and acceptance of Bayesian approaches in NI trial design and analysis. The Bayesian Scientific Working Group of the Drug Information Association provides a coordinated effort to target the education and implementation issues on Bayesian approaches for NI trials. In this article, we provide a review of both frequentist and Bayesian approaches in NI trials, and elaborate on the implementation for two common Bayesian methods including hierarchical prior method and meta-analytic-predictive approach. Simulations are conducted to investigate the properties of the Bayesian methods, and some real clinical trial examples are presented for illustration. PMID- 26247351 TI - Cotton fabric functionalisation with menthol/PCL micro- and nano-capsules for comfort improvement. AB - OBJECTIVE: Cotton functionalisation with poly-E-caprolactone (PCL) micro- and nano-capsules containing menthol was carried out with the aim of introducing a long-lasting refreshing sensation. MATERIALS AND METHODS: The preparation of the polymer micro- and nano-capsules was carried out by solvent displacement technique. A confined impinging jets mixer was used in order to ensure fast mixing and generate a homogeneous environment where PCL and menthol can self assemble. RESULTS: The micro- and nano-capsules and the functionalised fabrics were characterised by means of DSC, FT-IR spectroscopy and SEM imaging. Micro- and nano-capsules of different size, from about 200 to about 1200 nm, were obtained varying menthol to PCL ratio (from 0.76 to 8), overall concentration and flow rate (i.e. mixing conditions). The inclusion of menthol was confirmed by DSC analysis. DISCUSSION AND CONCLUSION: A patch test was carried out by 10 volunteers. Micro-capsules were found to be effective in conferring the fabric a refreshing sensation without altering skin physiology. PMID- 26247352 TI - Relationships between Religion and Two Forms of Homonegativity in Europe--A Multilevel Analysis of Effects of Believing, Belonging and Religious Practice. AB - This paper examines relationships between religion and two forms of homonegativity across 43 European countries using a bivariate response binary logistic multilevel model. The model analyzes effects of religious believing, belonging and practice on two response variables: a) a moral rejection of homosexuality as a practice and b) intolerance toward homosexuals as a group. The findings indicate that both forms of homonegativity are prevalent in Europe. Traditional doctrinal religious believing (belief in a personal God) is positively related to a moral rejection of homosexuality but to a much lesser extent associated with intolerance toward homosexuals as a group. Members of religious denominations are more likely than non-members to reject homosexuality as morally wrong and to reject homosexuals as neighbors. The analysis found significant differences between denominations that are likely context-dependent. Attendance at religious services is positively related to homonegativity in a majority of countries. The findings vary considerably across countries: Religion is more strongly related to homonegativity in Western than in Eastern Europe. In the post-soviet countries homonegativity appears to be largely a secular phenomenon. National contexts of high religiosity, high perceived government corruption, high income inequality and shortcomings in the implementation of gay rights in the countries' legislations are statistically related to higher levels of both moralistic homonegativity and intolerance toward homosexuals as a group. PMID- 26247353 TI - Antiproliferative and antibacterial activity of some glutarimide derivatives. AB - Antiproliferative and antibacterial activities of nine glutarimide derivatives (1 9) were reported. Cytotoxicity of compounds was tested toward three human cancer cell lines, HeLa, K562 and MDA-MB-453 by MTT assay. Compound 7 (2-benzyl-2 azaspiro[5.11]heptadecane-1,3,7-trione), containing 12-membered ketone ring, was found to be the most potent toward all tested cell lines (IC50 = 9-27 MUM). Preliminary screening of antibacterial activity by a disk diffusion method showed that Gram-positive bacteria were more susceptible to the tested compounds than Gram-negative bacteria. Minimum inhibitory concentration (MIC) determined by a broth microdilution method confirmed that compounds 1, 2, 4, 6-8 and 9 inhibited the growth of all tested Gram-positive and some of the Gram-negative bacteria. The best antibacterial potential was achieved with compound 9 (ethyl 4-(1-benzyl 2,6-dioxopiperidin-3-yl)butanoate) against Bacillus cereus (MIC 0.625 mg/mL; 1.97 * 10(-3 )mol/L). Distinction between more and less active/inactive compounds was assessed from the pharmacophoric patterns obtained by molecular interaction fields. PMID- 26247354 TI - Synthesis and anticandidal evaluation of new benzothiazole derivatives with hydrazone moiety. AB - In this study, we have performed the synthesis of new N'-(arylidene)-4 [(benzothiazol-2-yl)thio]butanoylhydrazide derivatives (3a-s) bearing azole moiety and hydrazone group in a lipophilic structural framework. The target compounds were prepared by a three step synthetic procedure starting from 2 mercaptobenzothiazole. The structures of the target compounds were elucidated by IR, (1)H NMR, (13)C NMR spectra and elemental analysis. The antifungal activity of the obtained compounds has been determined against a number of clinic and fluconazole-resistant Candida strains by using microdilution method. Compounds (3a-3s) exhibited anticandidal activity in different ratios varying between the range of MIC: 50 and 200 ug/mL. PMID- 26247355 TI - Synthesis of mono Mannich bases of 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1 one and evaluation of their cytotoxicities. AB - Chalcones and Mannich bases are a group of compounds known for their cytotoxicities. In this study restricted chalcone analogue, compound 2-(4 hydroxybenzylidene)-2,3-dihydroinden-1-one MT1, was used as a starting compound to synthesize new mono Mannich bases since Mannich bases may induce more cytotoxicity than chalcone analogue that they are derived from by producing additional alkylating center for cellular thiols. In this study, cyclic and acyclic amines were used to synthesize Mannich bases. All compounds were tested against Ca9-22 (gingival carcinoma), HSC-2, HSC-3 and HSC-4 (oral squamous cell carcinoma) as tumour cell lines and HGF (gingival fibroblasts), HPC (pulp cells) and HPLF (periodontal ligament fibroblasts) human normal oral cells as non tumour cell lines. Cytotoxicity, selectivity index (SI) values and potency selectivity expression (PSE) values expressed as a percentage were determined for the compounds. According to data obtained, the compound MT8 with the highest PSE value bearing N-methylpiperazine moiety seems to be a good candidate to develop new cytotoxic compounds and is suited for further investigation. PMID- 26247356 TI - Development of the Assessment of Belief Conflict in Relationship-14 (ABCR-14). AB - PURPOSE: Nurses and other healthcare workers frequently experience belief conflict, one of the most important, new stress-related problems in both academic and clinical fields. METHODS: In this study, using a sample of 1,683 nursing practitioners, we developed The Assessment of Belief Conflict in Relationship-14 (ABCR-14), a new scale that assesses belief conflict in the healthcare field. Standard psychometric procedures were used to develop and test the scale, including a qualitative framework concept and item-pool development, item reduction, and scale development. We analyzed the psychometric properties of ABCR 14 according to entropy, polyserial correlation coefficient, exploratory factor analysis, confirmatory factor analysis, average variance extracted, Cronbach's alpha, Pearson product-moment correlation coefficient, and multidimensional item response theory (MIRT). RESULTS: The results of the analysis supported a three factor model consisting of 14 items. The validity and reliability of ABCR-14 was suggested by evidence from high construct validity, structural validity, hypothesis testing, internal consistency reliability, and concurrent validity. The result of the MIRT offered strong support for good item response of item slope parameters and difficulty parameters. However, the ABCR-14 Likert scale might need to be explored from the MIRT point of view. Yet, as mentioned above, there is sufficient evidence to support that ABCR-14 has high validity and reliability. CONCLUSION: The ABCR-14 demonstrates good psychometric properties for nursing belief conflict. Further studies are recommended to confirm its application in clinical practice. PMID- 26247357 TI - Bisulfite Conversion of DNA: Performance Comparison of Different Kits and Methylation Quantitation of Epigenetic Biomarkers that Have the Potential to Be Used in Non-Invasive Prenatal Testing. AB - INTRODUCTION: Epigenetic alterations, including DNA methylation, play an important role in the regulation of gene expression. Several methods exist for evaluating DNA methylation, but bisulfite sequencing remains the gold standard by which base-pair resolution of CpG methylation is achieved. The challenge of the method is that the desired outcome (conversion of unmethylated cytosines) positively correlates with the undesired side effects (DNA degradation and inappropriate conversion), thus several commercial kits try to adjust a balance between the two. The aim of this study was to compare the performance of four bisulfite conversion kits [Premium Bisulfite kit (Diagenode), EpiTect Bisulfite kit (Qiagen), MethylEdge Bisulfite Conversion System (Promega) and BisulFlash DNA Modification kit (Epigentek)] regarding conversion efficiency, DNA degradation and conversion specificity. METHODS: Performance was tested by combining fully methylated and fully unmethylated lambda-DNA controls in a series of spikes by means of Sanger sequencing (0%, 25%, 50% and 100% methylated spikes) and Next Generation Sequencing (0%, 3%, 5%, 7%, 10%, 25%, 50% and 100% methylated spikes). We also studied the methylation status of two of our previously published differentially methylated regions (DMRs) at base resolution by using spikes of chorionic villus sample in whole blood. RESULTS: The kits studied showed different but comparable results regarding DNA degradation, conversion efficiency and conversion specificity. However, the best performance was observed with the MethylEdge Bisulfite Conversion System (Promega) followed by the Premium Bisulfite kit (Diagenode). The DMRs, EP6 and EP10, were confirmed to be hypermethylated in the CVS and hypomethylated in whole blood. CONCLUSION: Our findings indicate that the MethylEdge Bisulfite Conversion System (Promega) was shown to have the best performance among the kits. In addition, the methylation level of two of our DMRs, EP6 and EP10, was confirmed. Finally, we showed that bisulfite amplicon sequencing is a suitable approach for methylation analysis of targeted regions. PMID- 26247359 TI - Correction: Barriers to and Facilitators of Compliance with Clinic-Based Cervical Cancer Screening: Population-Based Cohort Study of Women Aged 23-60 Years. PMID- 26247358 TI - Dendritic Cells Cause Bone Lesions in a New Mouse Model of Histiocytosis. AB - Langerhans cell histiocytosis (LCH) is a rare disease caused by the clonal accumulation of dendritic Langerhans cells, which is often accompanied by osteolytic lesions. It has been reported that osteoclast-like cells play a major role in the pathogenic bone destruction seen in patients with LCH and these cells are postulated to originate from the fusion of DCs. However, due to the lack of reliable animal models the pathogenesis of LCH is still poorly understood. In this study, we have established a mouse model of histiocytosis- recapitulating human disease for osteolytic lesions seen in LCH patients. At 12 weeks after birth, severe bone lesions were observed in our multisystem histiocytosis (Mushi) model, when CD8alpha conventional dendritic cells (DCs) are transformed (MuTuDC) and accumulate. Most importantly, our study demonstrates that bone loss in LCH can be accounted for the transdifferentiation of MuTuDCs into functional osteoclasts both in vivo and in vitro. Moreover, we have shown that injected MuTuDCs reverse the osteopetrotic phenotype of oc/oc mice in vivo. In conclusion, our results support a crucial role of DCs in bone lesions in histiocytosis patients. Furthermore, our new model of LCH based on adoptive transfer of MuTuDC lines, leading to bone lesions within 1-2 weeks, will be an important tool for investigating the pathophysiology of this disease and ultimately for evaluating the potential of anti-resorptive drugs for the treatment of bone lesions. PMID- 26247360 TI - The Bordetella Secreted Regulator BspR Is Translocated into the Nucleus of Host Cells via Its N-Terminal Moiety: Evaluation of Bacterial Effector Translocation by the Escherichia coli Type III Secretion System. AB - Bordetella bronchiseptica is genetically related to B. pertussis and B. parapertussis, which cause respiratory tract infections in humans. These pathogens possess a large number of virulence factors, including the type III secretion system (T3SS), which is required for the delivery of effectors into the host cells. In a previous study, we identified a transcriptional regulator, BspR, that is involved in the regulation of the T3SS-related genes in response to iron starved conditions. A unique feature of BspR is that this regulator is secreted into the extracellular milieu via the T3SS. To further characterize the role of BspR in extracellular localization, we constructed various truncated derivatives of BspR and investigated their translocation into the host cells using conventional translocation assays. In this study, the effector translocation was evaluated by the T3SS of enteropathogenic E. coli (EPEC), since the exogenous expression of BspR triggers severe repression of the Bordetella T3SS expression. The results of the translocation assays using the EPEC T3SS showed that the N terminal 150 amino acid (aa) residues of BspR are sufficient for translocation into the host cells in a T3SS-dependent manner. In addition, exogenous expression of BspR in HeLa cells demonstrated that the N-terminal 100 aa residues are involved in the nuclear localization. In contrast, the N-terminal 54 aa residues are sufficient for the extracellular secretion into the bacterial culture supernatant via the EPEC T3SS. Thus, BspR is not only a transcriptional regulator in bacteria cytosol, but also functions as an effector that translocates into the nuclei of infected host cells. PMID- 26247361 TI - Downstream Warming and Headwater Acidity May Diminish Coldwater Habitat in Southern Appalachian Mountain Streams. AB - Stream-dwelling species in the U.S. southern Appalachian Mountains region are particularly vulnerable to climate change and acidification. The objectives of this study were to quantify the spatial extent of contemporary suitable habitat for acid- and thermally sensitive aquatic species and to forecast future habitat loss resulting from expected temperature increases on national forest lands in the southern Appalachian Mountain region. The goal of this study was to help watershed managers identify and assess stream reaches that are potentially vulnerable to warming, acidification, or both. To our knowledge, these results represent the first regional assessment of aquatic habitat suitability with respect to the combined effects of stream water temperature and acid-base status in the United States. Statistical models were developed to predict July mean daily maximum water temperatures and air-water temperature relations to determine potential changes in future stream water temperatures. The length of stream considered suitable habitat for acid- and thermally sensitive species, based on temperature and acid neutralizing capacity thresholds of 20 degrees C and 50 MUeq/L, was variable throughout the national forests considered. Stream length displaying temperature above 20 degrees C was generally more than five times greater than the length predicted to have acid neutralizing capacity below 50 MUeq/L. It was uncommon for these two stressors to occur within the same stream segment. Results suggested that species' distributional shifts to colder, higher elevation habitats under a warming climate can be constrained by acidification of headwater streams. The approach used in this study can be applied to evaluate climate change impacts to stream water resources in other regions. PMID- 26247362 TI - A Defective Meiotic Outcome of a Failure in Homologous Pairing and Synapsis Is Masked by Meiotic Quality Control. AB - Successful gamete production is ensured by meiotic quality control, a process in which germ cells that fail in bivalent chromosome formation are eliminated during meiotic prophase. To date, numerous meiotic mutants have been isolated in a variety of model organisms, using defects associated with a failure in bivalent formation as hallmarks of the mutant. Presumably, the meiotic quality control mechanism in those mutants is overwhelmed. In these mutants, all germ cells fail in bivalent formation, and a subset of cells seem to survive the elimination process and develop into gametes. It is possible that mutants that are partially defective in bivalent formation were missed in past genetic screens, because no evident meiotic defects associated with failure in bivalent formation would have been detectable. Meiotic quality control effectively eliminates most failed germ cells, leaving predominately successful ones. Here, we provide evidence supporting this possibility. The Caenorhabditis elegans mrg-1 loss-of-function mutant does not appear to be defective in bivalent formation in diakinesis oocytes. However, defects in homologous chromosome pairing and synapsis during the preceding meiotic prophase, prerequisites for successful bivalent formation, were observed in most, but not all, germ cells. Failed bivalent formation in the oocytes became evident once meiotic quality control was abrogated in the mrg-1 mutant. Both double-strand break repair and synapsis checkpoints are partly responsible for eliminating failed germ cells in the mrg-1 mutant. Interestingly, removal of both checkpoint activities from the mrg-1 mutant is not sufficient to completely suppress the increased germline apoptosis, suggesting the presence of a novel meiotic checkpoint mechanism. PMID- 26247363 TI - Titanium Dioxide Nanoparticles Trigger Loss of Function and Perturbation of Mitochondrial Dynamics in Primary Hepatocytes. AB - Titanium dioxide (TiO2) nanoparticles are one of the most highly manufactured and employed nanomaterials in the world with applications in copious industrial and consumer products. The liver is a major accumulation site for many nanoparticles, including TiO2, directly through intentional exposure or indirectly through unintentional ingestion via water, food or animals and increased environmental contamination. Growing concerns over the current usage of TiO2 coupled with the lack of mechanistic understanding of its potential health risk is the motivation for this study. Here we determined the toxic effect of three different TiO2 nanoparticles (commercially available rutile, anatase and P25) on primary rat hepatocytes. Specifically, we evaluated events related to hepatocyte functions and mitochondrial dynamics: (1) urea and albumin synthesis using colorimetric and ELISA assays, respectively; (2) redox signaling mechanisms by measuring reactive oxygen species (ROS) production, manganese superoxide dismutase (MnSOD) activity and mitochondrial membrane potential (MMP); (3) OPA1 and Mfn-1 expression that mediates the mitochondrial dynamics by PCR; and (4) mitochondrial morphology by MitoTracker Green FM staining. All three TiO2 nanoparticles induced a significant loss (p < 0.05) in hepatocyte functions even at concentrations as low as 50 ppm with commercially used P25 causing maximum damage. TiO2 nanoparticles induced a strong oxidative stress in primary hepatocytes. TiO2 nanoparticles exposure also resulted in morphological changes in mitochondria and substantial loss in the fusion process, thus impairing the mitochondrial dynamics. Although this study demonstrated that TiO2 nanoparticles exposure resulted in substantial damage to primary hepatocytes, more in vitro and in vivo studies are required to determine the complete toxicological mechanism in primary hepatocytes and subsequently liver function. PMID- 26247364 TI - Calmodulin Methyltransferase Is Required for Growth, Muscle Strength, Somatosensory Development and Brain Function. AB - Calmodulin lysine methyl transferase (CaM KMT) is ubiquitously expressed and highly conserved from plants to vertebrates. CaM is frequently trimethylated at Lys-115, however, the role of CaM methylation in vertebrates has not been studied. CaM KMT was found to be homozygously deleted in the 2P21 deletion syndrome that includes 4 genes. These patients present with cystinuria, severe intellectual disabilities, hypotonia, mitochondrial disease and facial dysmorphism. Two siblings with deletion of three of the genes included in the 2P21 deletion syndrome presented with cystinuria, hypotonia, a mild/moderate mental retardation and a respiratory chain complex IV deficiency. To be able to attribute the functional significance of the methylation of CaM in the mouse and the contribution of CaM KMT to the clinical presentation of the 2p21deletion patients, we produced a mouse model lacking only CaM KMT with deletion borders as in the human 2p21deletion syndrome. No compensatory activity for CaM methylation was found. Impairment of complexes I and IV, and less significantly III, of the mitochondrial respiratory chain was more pronounced in the brain than in muscle. CaM KMT is essential for normal body growth and somatosensory development, as well as for the proper functioning of the adult mouse brain. Developmental delay was demonstrated for somatosensory function and for complex behavior, which involved both basal motor function and motivation. The mutant mice also had deficits in motor learning, complex coordination and learning of aversive stimuli. The mouse model contributes to the evaluation of the role of methylated CaM. CaM methylation appears to have a role in growth, muscle strength, somatosensory development and brain function. The current study has clinical implications for human patients. Patients presenting slow growth and muscle weakness that could result from a mitochondrial impairment and mental retardation should be considered for sequence analysis of the CaM KMT gene. PMID- 26247365 TI - Estrogens Correlate with PELP1 Expression in ER Positive Breast Cancer. AB - The Proline-, glutamic acid- and leucine-rich protein 1 (PELP1) is an estrogen receptor (ER) coactivator and a proto-oncogene known to be deregulated in endocrine cancers. In breast cancer, PELP1 overexpression has been associated with endocrine therapy resistance. Although PELP1 is known to be regulated by estrogens in vitro, its association with estrogen levels within the tissue of breast cancer patients has not previously been assessed. Here, we determined PELP1 mRNA expression levels in paired samples of normal and malignant breast tissue obtained from 32 postmenopausal and 11 premenopausal women. In the total sample set, PELP1 levels were higher in tumors compared to normal breast tissue (P = 0.041). Among postmenopausal women, PELP1 tumor levels correlated positively with estrone (E1) and estradiol (E2) levels in both normal tissue (r = 0.543, P = 0.003 and r = 0.601, P = 0.001, respectively) and plasma (r = 0.392, P = 0.053 and r = 0.403, P = 0.046, respectively). Analyzing all ER+ tumors (n = 26), PELP1 correlated positively with E1 and E2 in tumor tissue (r = 0.562, P = 0.003 and r = 0.411, P = 0.037, respectively) and normal tissue (r = 0.461, P = 0.018 and r = 0.427, P = 0.030, respectively) in addition to plasma E1, E2 and estrone sulphate (E1S) concentrations (r = 0.576, P = 0.003, r = 0.456, P = 0.025 and r = 0.406, P = 0.049, respectively). Finally, PELP1 correlated positively with ER mRNA (ESR1) (r = 0.553, P = 0.026) in ER+ tumors, whereas a negative association between PELP1 and ESR1 (r = -0.733, P = 0.010) was observed in ER- breast tumors. Taken together, tumor PELP1 mRNA expression is associated with estrogen levels in breast cancer, suggesting a potentially important role of PELP1 in ER+ breast cancer growth in vivo. PMID- 26247366 TI - The Usual Suspects: Comparison of the Relative Roles of Potential Urban Chikungunya Virus Vectors in Australia. AB - The global re-emergence of chikungunya virus (CHIKV) over the last decade presents a serious public health risk to Australia. An increasing number of imported cases further underline the potential for local transmission to occur if local mosquitoes bite an infected traveller. Laboratory experiments have identified a number of competent Australian mosquito species, including the primary vectors of CHIKV abroad, Aedes aegypti and Aedes albopictus, and local endemic species Aedes vigilax and Aedes notoscriptus. The implication of these additional endemic species as potential vectors has generated much uncertainty amongst public health professionals regarding their actual role in CHIKV transmission in the field. Using data estimated from or documented in the literature, we parameterise a simple vectorial capacity model to evaluate the relative roles of Australian mosquito species in potential CHIKV transmission. The model takes into account a number of key biological and ecological variables which influence the role of a species in field transmission, including population density, human feeding rates, mosquito survival rates and vector competence. We confirm the relative importance of Ae. aegypti and Ae. albopictus in sustaining potential CHIKV transmission in Australia. Even at maximum estimated densities and human feeding rates, Ae. vigilax and Ae. notoscriptus are likely to play a relatively minor role in CHIKV transmission, when compared with either Ae. aegypti or Ae. albopictus. This relatively straightforward analysis has application for any region where mosquito species have been incriminated in vector competence experiments, but where their actual role in CHIKV transmission has not been established. PMID- 26247367 TI - Widening the Access to HIV Testing: The Contribution of Three In-Pharmacy Testing Programmes in Spain. AB - BACKGROUND AND OBJECTIVE: Spain has implemented several in-pharmacy HIV testing programmes performed by pharmacists as part of their everyday routine. We aim to assess the feasibility and the main outcomes of three programmes implemented in three Spanish regions with different sociological profiles and also different epidemiology for HIV. METHODS: The characteristics of the 24151 people tested between 2009 and 2013 at 74 urban pharmacies are studied. We compare the main outcomes of the programmes with those of each Regional HIV Surveillance System (RHSS) assessing the contribution to the total new diagnosis in each region and if priority groups are being reached. RESULTS: 45.7% were heterosexual men (MSW), 14.4% men who have sex with men (MSM), and 27% women. The 35% were younger than 30 and 9.6% foreigners. The 52% were previously untested, and women were the most likely to be untested. The three programmes altogether diagnosed 226 people, resulting in a global prevalence of 0.9% (95%CI: 0.8-1.1); 3.4% in MSM (95%CI: 2.8-4.0). The prevalence among Spaniards was 0.8% (0.7-1.0) vs. 2.2 (1.6-2.9) among foreigners. The percentages of MSM diagnosed by all three programmes were higher than the one reported by their respective RHSS. Thirty four percent of the reactive MSM and the 71.4% of the reactive MSW did not have a previous HIV test although big testing history differences were observed across the programmes. Altogether, these services contributed with the 10.6% of all HIV diagnoses in these regions. CONCLUSIONS: In-pharmacy HIV testing programmes are a valuable testing option, having been able to uncover 1 out of 10 the new diagnoses reported in each region. They showed a good capacity of reaching and diagnosing previously untested populations, not only a priority population such as MSM but also heterosexual population who are more affected by delayed diagnosis. They seem to be particularly suitable for regions without large cities and specific HIV diagnostic services. PMID- 26247369 TI - Conflict and metacognitive control: the mismatch-monitoring hypothesis of how others' knowledge states affect recall. AB - Information about others' success in remembering is frequently available. For example, students taking an exam may assess its difficulty by monitoring when others turn in their exams. In two experiments, we investigated how rememberers use this information to guide recall. Participants studied paired associates, some semantically related (and thus easier to retrieve) and some unrelated (and thus harder). During a subsequent cued recall test, participants viewed fictive information about an opponent's accuracy on each item. In Experiment 1, participants responded to each cue once before seeing the opponent's performance and once afterwards. Participants reconsidered their responses least often when the opponent's accuracy matched the item difficulty (easy items the opponent recalled, hard items the opponent forgot) and most often when the opponent's accuracy and the item difficulty mismatched. When participants responded only after seeing the opponent's performance (Experiment 2), the same mismatch conditions that led to reconsideration even produced superior recall. These results suggest that rememberers monitor whether others' knowledge states accord or conflict with their own experience, and that this information shifts how they interrogate their memory and what they recall. PMID- 26247368 TI - Gene Therapy Fully Restores Vision to the All-Cone Nrl(-/-) Gucy2e(-/-) Mouse Model of Leber Congenital Amaurosis-1. AB - Mutations in GUCY2D are the cause of Leber congenital amaurosis type 1 (LCA1). GUCY2D encodes retinal guanylate cyclase-1 (retGC1), a protein expressed exclusively in outer segments of photoreceptors and essential for timely recovery from photoexcitation. Recent clinical data show that, despite a high degree of visual disturbance stemming from a loss of cone function, LCA1 patients retain normal photoreceptor architecture, except for foveal cone outer segment abnormalities and, in some patients, foveal cone loss. These results point to the cone-rich central retina as a target for GUCY2D replacement. LCA1 gene replacement studies thus far have been conducted in rod-dominant models (mouse) or with vectors and organisms lacking clinical translatability. Here we investigate gene replacement in the Nrl(-/-) Gucy2e(-/-) mouse, an all-cone model deficient in retGC1. We show that AAV-retGC1 treatment fully restores cone function, cone-mediated visual behavior, and guanylate cyclase activity, and preserves cones in treated Nrl(-/-) Gucy2e(-/-) mice over the long-term. A novel finding was that retinal function could be restored to levels above that in Nrl( /-) controls, contrasting results in other models of retGC1 deficiency. We attribute this to increased cyclase activity in treated Nrl(-/-) Gucy2e(-/-) mice relative to Nrl(-/-) controls. Thus, Nrl(-/-) Gucy2e(-/-) mice possess an expanded dynamic range in ERG response to gene replacement relative to other models. Lastly, we show that a candidate clinical vector, AAV5-GRK1-GUCY2D, when delivered to adult Nrl(-/-) Gucy2e(-/-) mice, restores retinal function that persists for at least 6 months. Our results provide strong support for clinical application of a gene therapy targeted to the cone-rich, central retina of LCA1 patients. PMID- 26247370 TI - High-content assay for measuring intracellular growth of Leishmania in human macrophages. AB - Leishmania species are sandfly-transmitted protozoan parasites that cause a spectrum of diseases, ranging from localized skin lesions to fatal visceral disease, in more than 12 million people worldwide. These parasites primarily target macrophages in their mammalian hosts and proliferate as non-motile amastigotes in the phagolysosomal compartment of these cells. High-throughput screens for measuring Leishmania growth within this intracellular niche are needed to identify host and parasite factors that are required for virulence and to identify new drug candidates. Here we describe the development of a new high content imaging method for quantifying the intracellular growth of Leishmania mexicana parasites in THP-1 macrophages. Wild-type parasites were pre-stained with the fluorescent dye CellTracker(TM) Orange CMRA and used to infect THP-1 macrophages in 384-well plates. Infected and uninfected macrophages were subsequently stained with CellTracker Green CMFDA, allowing accurate quantitation of the number of parasites per macrophage using separate detector channels. We validated this method for use in high-content drug screening by examining the dose dependence of known anti-leishmanial drugs on intracellular growth. Unlike previous protocols, this method does not require the generation of transgenic fluorescent or bioluminescent parasite lines and can be readily adapted for screening different Leishmania species, strains, or mutant lines in a wide range of phagocytic host cell types. PMID- 26247371 TI - Preserved Filamentous Microbial Biosignatures in the Brick Flat Gossan, Iron Mountain, California. AB - A variety of actively precipitating mineral environments preserve morphological evidence of microbial biosignatures. One such environment with preserved microbial biosignatures is the oxidized portion of a massive sulfide deposit, or gossan, such as that at Iron Mountain, California. This gossan may serve as a mineralogical analogue to some ancient martian environments due to the presence of oxidized iron and sulfate species, and minerals that only form in acidic aqueous conditions, in both environments. Evaluating the potential biogenicity of cryptic textures in such martian gossans requires an understanding of how microbial textures form biosignatures on Earth. The iron-oxide-dominated composition and morphology of terrestrial, nonbranching filamentous microbial biosignatures may be distinctive of the underlying formation and preservation processes. The Iron Mountain gossan consists primarily of ferric oxide (hematite), hydrous ferric oxide (HFO, predominantly goethite), and jarosite group minerals, categorized into in situ gossan, and remobilized iron deposits. We interpret HFO filaments, found in both gossan types, as HFO-mineralized microbial filaments based in part on (1) the presence of preserved central filament lumina in smooth HFO mineral filaments that are likely molds of microbial filaments, (2) mineral filament formation in actively precipitating iron-oxide environments, (3) high degrees of mineral filament bending consistent with a flexible microbial filament template, and (4) the presence of bare microbial filaments on gossan rocks. Individual HFO filaments are below the resolution of the Mars Curiosity and Mars 2020 rover cameras, but sinuous filaments forming macroscopic matlike textures are resolvable. If present on Mars, available cameras may resolve these features identified as similar to terrestrial HFO filaments and allow subsequent evaluation for their biogenicity by synthesizing geochemical, mineralogical, and morphological analyses. Sinuous biogenic filaments could be preserved on Mars in an iron-rich environment analogous to Iron Mountain, with the Pahrump Hills region and Hematite Ridge in Gale Crater as tentative possibilities. PMID- 26247372 TI - Assembling of a functional cyclodextrin-decorated upconversion luminescence nanoplatform for cysteine-sensing. AB - A novel rhodamine-oxaldehyde (RHO) functionalized beta-NaYF4:Yb(3+)/Er(3+) upconversion nanoparticle (UCNP) for specific detection of cysteine (Cys) in aqueous solution was achieved through a Forster resonance energy transfer (FRET) process. Based on self-assembling interaction, hydrophobic upconversion nanoparticles could be modified with alpha-cyclodextrin to make them water dispersible. PMID- 26247373 TI - Mechanistic Insights into the Palladium-Catalyzed Aziridination of Aliphatic Amines by C-H Activation. AB - Detailed kinetic studies and computational investigations have been performed to elucidate the mechanism of a palladium-catalyzed C-H activation aziridination. A theoretical rate law has been derived that matches with experimental observations and has led to an improvement in the reaction conditions. Acetic acid was found to be beneficial in controlling the formation of an off-cycle intermediate, allowing a decrease in catalyst loading and improved yields. Density functional theory (DFT) studies were performed to examine the selectivities observed in the reaction. Evidence for electronic-controlled regioselectivity for the cyclopalladation step was obtained by a distortion-interaction analysis, whereas the aziridination product was justified through dissociation of acetic acid from the palladium(IV) intermediate preceding the product-forming reductive elimination step. The understanding of this reaction mechanism under the synthesis conditions should provide valuable assistance in the comprehension and design of palladium-catalyzed reactions on similar systems. PMID- 26247374 TI - Asymmetric synthesis and biological activities of natural product (+) balasubramide and its derivatives. AB - The natural product (+)-balasubramide (3j) and its derivatives (3a-3i) were synthesized using a two-step asymmetric synthesis, and the biological activities of 3a-3j were determined in vitro. Methyl (2S,3R)-(+)-3-phenyloxirane-2 carboxylate (1h), the asymmetric synthesis of which was described in a previous paper, was selected as the starting material. Compounds 3a-3j were evaluated for their neuroprotective, antioxidative, and anti-neuroinflammatory effects. (+) Balasubramide and its derivatives with different electronegative groups in the 6 phenyl ring produced little neuroprotection and antioxidation, but induced potent anti-neuroinflammatory effects in BV-2 microglial cells (with the exception of 3g). Compound 3c, with a trifluoromethyl group in its 6-phenyl ring, was a particularly potent anti-neuroinflammatory agent. These results demonstrated that the electronegativity of the 6-phenyl ring of (+)-balasubramide is an important determinant of its inhibitory effect on neuroinflammation. More electronegative substituents result in more potent anti-neuroinflammatory effects. Moreover, cytotoxicity assays indicated no significant effects of the tested compounds. PMID- 26247375 TI - Influence of environmental enrichment vs. time-of-day on behavioral repertoire of male albino Swiss mice. AB - Environmental enrichment (EE) is a non-pharmacological manipulation that promotes diverse forms of benefits in the central nervous system of captive animals. It is thought that EE influences animal behavior in a specie-(strain)-specific manner. Since rodents in general present different behaviors during distinct periods of the day, in this study we aimed to investigate the influence of time-of-day on behavioral repertoire of Swiss mice that reared in EE. Forty male Swiss mice (21days old) were housed in standard (SC) or enriched conditions (EC) for 60days. Behavioral assessments were conducted during the light phase (in presence of light) or dark phase (in absence of light) in the following tasks: open field, object recognition and elevated plus maze. First, we observed that the locomotor and exploratory activities are distinct between SC and EC groups only during the light phase. Second, we observed that "self-protective behaviors" were increased in EC group only when mice were tested during the light phase. However, "less defensive behaviors" were not affected by both housing conditions and time-of day. Third, we showed that the performance of EE animals in object recognition task was improved in both light and dark conditions. Our findings highlight that EE-induced alterations in exploratory and emotional behaviors are just evident during light conditions. However, EE-induced cognitive benefits are remarkable even during dark conditions, when exploratory and emotional behaviors were similar between groups. PMID- 26247376 TI - The role of the anterolateral ligament in ACL insufficient and reconstructed knees on rotatory stability: A biomechanical study on human cadavers. AB - Studies suggest that the anterolateral ligament (ALL) is important for knee stability. The purpose was to clarify ALL's effect on rotatory and anterior posterior stability in the anterior cruciate ligament (ACL)-insufficient and reconstructed knees and the effect of reconstruction of an insufficient ALL. Eighteen cadaveric knees were included. Stability was tested for intact (+ALL), detached (-ALL) and reconstructed (+ reALL) ALL, with ACL removed (-ACL) and reconstructed (+ACL) in six combinations. All were tested in 0, 30, 60, and 90 degrees C flexion. Anterior-posterior stability was measured with a rolimeter. Rotation with a torque of 8.85 Nm was measured photographically. The ALL was well defined in 78% of knees. ACL reconstruction had a significant effect on anterior posterior stability. Detaching the ALL had a significant effect on internal rotatory stability and on anterior-posterior stability in ACL-insufficient knees. Reconstruction of ACL and ALL reestablished knee stability. The appearance of the ALL was not uniform. The ALL was an internal rotational stabilizer. Anatomical ALL reconstruction in combination with ACL reconstruction could reestablish stability. ALL reconstruction might be considered in patients with combined ACL and ALL tears, but the clinical effect should be established in a controlled clinical study. PMID- 26247377 TI - Novel adsorption and photocatalytic oxidation for removal of gaseous toluene by V doped TiO2/PU under visible light. AB - In this study, V was used as a dopant to defect into the TiO2 lattice, leading to formation of Ti(3+) and V(4+) in the lattice. The presence of Ti(3+) and V(4+) introduced into the TiO2 lattice increased the electron-hole pair generation capacity and electron-hole pair separation efficiency of the TiO2, leading to enhancement of the photocatalytic activity of the photocatalyst. Porous polyurethane (PU) was used to immobilize the V-doped TiO2 by creating chemical bonds. The use of porous substrate contributed to the increased adsorption ability of the enhanced photocatalyst, as well as expanded its application for the removal of toluene from aerosols. Under dark conditions, the V-TiO2/PU only exhibited adsorption ability for toluene treatment in aerosol. Under visible light conditions, the V-TiO2/PU exhibited high photocatalytic oxidation ability for the removal of toluene in aerosol. The photocatalytic oxidation ability was found to depend on the V to TiO2 ratio. The optimal V content in V/TiO2 for enhancing the photocatalytic activity of TiO2 was determined to be 6 wt%. Even under visible light irradiation, the 6% V-TiO2/PU sample could photocatalytically remove 80% of the toluene in 200-ppmV inlet gas, while 89.3% of the removed amount was mineralized into CO2 and H2O. PMID- 26247378 TI - Evaluating the cement stabilization of arsenic-bearing iron wastes from drinking water treatment. AB - Cement stabilization of arsenic-bearing wastes is recommended to limit arsenic release from wastes following disposal. Such stabilization has been demonstrated to reduce the arsenic concentration in the Toxicity Characteristic Leaching Procedure (TCLP), which regulates landfill disposal of arsenic waste. However, few studies have evaluated leaching from actual wastes under conditions similar to ultimate disposal environments. In this study, land disposal in areas where flooding is likely was simulated to test arsenic release from cement stabilized arsenic-bearing iron oxide wastes. After 406 days submersed in chemically simulated rainwater, <0.4% of total arsenic was leached, which was comparable to the amount leached during the TCLP (<0.3%). Short-term (18 h) modified TCLP tests (pH 3-12) found that cement stabilization lowered arsenic leaching at high pH, but increased leaching at pH<4.2 compared to non-stabilized wastes. Presenting the first characterization of cement stabilized waste using MUXRF, these results revealed the majority of arsenic in cement stabilized waste remained associated with iron. This distribution of arsenic differed from previous observations of calcium-arsenic solid phases when arsenic salts were stabilized with cement, illustrating that the initial waste form influences the stabilized form. Overall, cement stabilization is effective for arsenic-bearing wastes when acidic conditions can be avoided. PMID- 26247379 TI - Ecotoxicology of bromoacetic acid on estuarine phytoplankton. AB - Bromoacetic acid is formed when effluent containing chlorine residuals react with humics in natural waters containing bromide. The objective of this research was to quantify the effects of bromoacetic acid on estuarine phytoplankton as a proxy for ecosystem productivity. Bioassays were used to measure the EC50 for growth in cultured species and natural marine communities. Growth inhibition was estimated by changes in chlorophyll a concentrations measured by fluorometry and HPLC. The EC50s for cultured Thalassiosira pseudonana were 194 mg L(-1), 240 mg L(-1) for Dunaliella tertiolecta and 209 mg L(-1) for Rhodomonas salina. Natural phytoplankton communities were more sensitive to contamination with an EC50 of 80 mg L(-1). Discriminant analysis suggested that bromoacetic acid additions cause an alteration of phytoplankton community structure with implications for higher trophic levels. A two-fold EC50 decrease in mixed natural phytoplankton populations affirms the importance of field confirmation for establishing water quality criteria. PMID- 26247380 TI - Catecholate-siderophore produced by As-resistant bacterium effectively dissolved FeAsO4 and promoted Pteris vittata growth. AB - The impact of siderophore produced by arsenic-resistant bacterium Pseudomonas PG12 on FeAsO4 dissolution and plant growth were examined. Arsenic hyperaccumulator Pteris vittata was grown for 7 d in 0.2-strength Fe-free Hoagland solution containing FeAsO4 mineral and PG12-siderophore or fungal siderophore desferrioxamine B (DFOB). Standard siderophore assays indicated that PG12-siderophore was catecholate-type. PG12-siderophore was more effective in promoting FeAsO4 dissolution, and Fe and As plant uptake than DFOB. Media soluble Fe and As in PG12 treatment were 34.6 and 3.07 MUM, 1.6- and 1.4-fold of that in DFOB. Plant Fe content increased from 2.93 to 6.24 g kg(-1) in the roots and As content increased from 14.3 to 78.5 mg kg(-1) in the fronds. Besides, P. vittata in PG12 treatment showed 2.6-times greater biomass than DFOB. While P. vittata fronds in PG12 treatment were dominated by AsIII, those in DFOB treatment were dominated by AsV (61-77%). This study showed that siderophore-producing arsenic resistant rhizobacteria may have potential in enhancing phytoremediation of arsenic-contaminated soils. PMID- 26247381 TI - Surface charge-transfer complex formation of catechol on titanium(IV) oxide and the application to bio-sensing. AB - Adsorption properties of 2-hydroxyphenol (catechol) on TiO2 particles has been studied at 298K. The adsorption proceeds from the aqueous solution with the Langmuir type behavior. Diffuse reflectance infrared spectra of the catechol adsorbed TiO2 suggested that catechol is adsorbed on TiO2 solution via the chelation to the surface Ti ions. The adsorption induces a strong absorption in the whole visible region, of which intensity increases with an increase in the adsorption amount. Photoelectrochemical experiments and molecular orbital calculations indicate that the absorption stems from the charge-transfer (CT) transition from the HOMO of catechol to the conduction band of TiO2. Time courses for the adsorption of catechol on mesoporous TiO2 nanocrystalline film-coated glass was traced by measuring the change in the absorbance of the CT band, and analyzed on the basis of the Langmuir model. This study would present a new simple technique for sensing of important biomolecules bearing the catechol moiety. PMID- 26247382 TI - A methacrylate-based polymeric imidazole ligand yields quantum dots with low cytotoxicity and low nonspecific binding. AB - This paper assesses the biocompatibility for fluorescence imaging of colloidal nanocrystal quantum dots (QDs) coated with a recently-developed multiply-binding methacrylate-based polymeric imidazole ligand. The QD samples were purified prior to ligand exchange via a highly repeatable gel permeation chromatography (GPC) method. A multi-well plate based protocol was used to characterize nonspecific binding and toxicity of the QDs toward human endothelial cells. Nonspecific binding in 1% fetal bovine serum was negligible compared to anionically stabilized QD controls, and no significant toxicity was detected on 24h exposure. The nonspecific binding results were confirmed by fluorescence microscopy. This study is the first evaluation of biocompatibility in QDs initially purified by GPC and represents a scalable approach to comparison among nanocrystal-based bioimaging scaffolds. PMID- 26247383 TI - Prevalence of hepatitis C virus in Brazil's inmate population: a systematic review. AB - OBJECTIVE To estimate the prevalence of hepatitis C virus infection in Brazil's inmate population. METHODS Systematic review on hepatitis C virus infection in the inmate population. Brazilian studies published from January 1, 1989 to February 20, 2014 were evaluated. The methodological quality of the studies was assessed using a scale of 0 to 8 points. RESULTS Eleven eligible studies were analyzed and provided data on hepatitis C virus infection among 4,375 inmates from seven states of Brazil, with a mean quality classification of 7.4. The overall hepatitis C virus prevalence among Brazilian inmates was 13.6% (ranging from 1.0% to 41.0%, depending on the study). The chances of inmates being seropositive for hepatitis C virus in the states of Minas Gerais (MG), Sergipe (SE), Mato Grosso do Sul (MS), Rio Grande do Sul (RS), Goias (GO) and Espirito Santo (ES) were 84.0% (95%CI 0.06;0.45), 92.0% (95%CI 0.04;0.13), 88.0% (95%CI 0.09;0.18), 74.0% (95%CI 0.16;0.42), 84.0% (95%CI 0.08;0.31) and 89.0% (95%CI 0.01;0.05) respectively, lower than that observed in the Sao Paulo state (seroprevalence of 29.3%). The four studies conducted in the city of Sao Paulo revealed a lower prevalence in more recent studies compared to older ones. CONCLUSIONS The highest prevalence of hepatitis C virus infection in Brazil's inmate population was found in Sao Paulo, which may reflect the urban diversity of the country. Despite Brazilian studies having good methodological quality to evaluate the prevalence of the hepatitis C virus, they are scarce and lack data on risk factors associated with this infection, which could support decisions on prevention and implementation of public health policies for Brazilian prisons. PMID- 26247384 TI - Effect of the exposure to maternal smoking during pregnancy and childhood on the body mass index until adolescence. AB - OBJECTIVE Investigate the effect of exposure to smoking during pregnancy and early childhood on changes in the body mass index (BMI) from birth to adolescence. METHODS A population-based cohort of children (0-5 years old) from Cuiaba, Midwest Brazil, was assessed in 1999-2000 (n = 2,405). Between 2009 and 2011, the cohort was re-evaluated. Information about birth weight was obtained from medical records, and exposure to smoking during pregnancy and childhood was assessed at the first interview. Linear mixed effects models were used to estimate the association between exposure to maternal smoking during pregnancy and preschool age, and the body mass index of children at birth, childhood and adolescence. RESULTS Only 11.3% of the mothers reported smoking during pregnancy, but most of them (78.2%) also smoked during early childhood. Among mothers who smoked only during pregnancy (n = 59), 97.7% had smoked only in the first trimester. The changes in body mass index at birth and in childhood were similar for children exposed and those not exposed to maternal smoking. However, from childhood to adolescence the rate of change in the body mass index was higher among those exposed only during pregnancy than among those who were not exposed. CONCLUSIONS Exposure to smoking only during pregnancy, especially in the first trimester, seems to affect changes in the body mass index until adolescence, supporting guidelines that recommend women of childbearing age to stop smoking. PMID- 26247385 TI - Performance evaluation of hospitals that provide care in the public health system, Brazil. AB - OBJECTIVE To analyze if size, administrative level, legal status, type of unit and educational activity influence the hospital network performance in providing services to the Brazilian Unified Health System. METHODS This cross-sectional study evaluated data from the Hospital Information System and the Cadastro Nacional de Estabelecimentos de Saude (National Registry of Health Facilities), 2012, in Sao Paulo, Southeastern Brazil. We calculated performance indicators, such as: the ratio of hospital employees per bed; mean amount paid for admission; bed occupancy rate; average length of stay; bed turnover index and hospital mortality rate. Data were expressed as mean and standard deviation. The groups were compared using analysis of variance (ANOVA) and Bonferroni correction. RESULTS The hospital occupancy rate in small hospitals was lower than in medium, big and special-sized hospitals. Higher hospital occupancy rate and bed turnover index were observed in hospitals that include education in their activities. The hospital mortality rate was lower in specialized hospitals compared to general ones, despite their higher proportion of highly complex admissions. We found no differences between hospitals in the direct and indirect administration for most of the indicators analyzed. CONCLUSIONS The study indicated the importance of the scale effect on efficiency, and larger hospitals had a higher performance. Hospitals that include education in their activities had a higher operating performance, albeit with associated importance of using human resources and highly complex structures. Specialized hospitals had a significantly lower rate of mortality than general hospitals, indicating the positive effect of the volume of procedures and technology used on clinical outcomes. The analysis related to the administrative level and legal status did not show any significant performance differences between the categories of public hospitals. PMID- 26247386 TI - Profile of women who carried out smoking cessation treatment: a systematic review. AB - OBJECTIVE Analyze the profile of women, in health services, who carry out treatment for smoking cessation. METHODS Systematic review that used the following sources of information: Cummulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Biblioteca Virtual em Saude (BVS), Scopus and Web of Science. We included quantitative studies that addressed the characterization of women, in health services, who carried out treatment for smoking cessation, resulting in 12 articles for analysis. The assessment of the methodological quality of the studies was performed using the instrument MAStARI from Joanna Briggs Institute. RESULTS The predominant profile of women who carried out treatment for smoking cessation in health services was composed of white, married, employed, and highly level educated women. Women who carried out the treatment for smoking cessation in specialized services had a more advanced age, were white, were married and had a diagnosis of depression. The quality level of most studies was moderate. CONCLUSIONS The profile of women who carry out treatment for smoking cessation, either in general or specialized health services, is composed of white, married, and highly level educated women. Publications about smoking women are scarce and the lack of Brazilian studies characterizing the profile of women who start treatment for smoking cessation shows the need for studies that explore this subject. PMID- 26247387 TI - Alteration of Membrane Compositional Asymmetry by LiCoO2 Nanosheets. AB - Given the projected massive presence of redox-active nanomaterials in the next generation of consumer electronics and electric vehicle batteries, they are likely to eventually come in contact with cell membranes, with biological consequences that are currently not known. Here, we present nonlinear optical studies showing that lithium nickel manganese cobalt oxide nanosheets carrying a negative zeta-potential have no discernible consequences for lipid alignment and interleaflet composition in supported lipid bilayers formed from zwitterionic and negatively charged lipids. In contrast, lithiated and delithiated LiCoO2 nanosheets having positive and neutral zeta-potentials, respectively, alter the compositional asymmetry of the two membrane leaflets, and bilayer asymmetry remains disturbed even after rinsing. The insight that some cobalt oxide nanoformulations induce alterations to the compositional asymmetry in idealized model membranes may represent an important step toward assessing the biological consequences of their predicted widespread use. PMID- 26247388 TI - Attentional Bias and Approach/Avoidance Tendencies Do Not Predict Relapse or Time to Relapse in Alcohol Dependency. AB - BACKGROUND: Implicit processes such as attentional bias (AB) and automatic approach/avoidance tendencies (AA) play a role in substance use disorders. Whether these processes can predict a relapse in alcohol-dependent patients is still unclear and must be examined in more detail than has been done previously. We aimed to establish whether AB and AA measured during treatment would predict relapse in alcohol-dependent patients. We also investigated whether these implicit processes predicted time to relapse better than a more common binary relapse variable. METHODS: A total of 50 alcohol-dependent outpatients undergoing treatment completed the study. Patients completed the Addiction Stroop Task, which assesses AB, and the relevant Stimulus-Response Compatibility Task, which measures AA. Time to relapse was assessed 1, 2, and 3 months after the bias assessment. RESULTS: Twenty patients (40%) relapsed during the follow-up period. The average time to relapse was 40 days after the first session. Overall, participants had an AB for alcohol-related stimuli and a tendency to avoid these stimuli. Neither relapse nor time to relapse was predicted by either bias type. CONCLUSIONS: Although both AB and avoidance tendencies were present in our sample, these measures did not predict relapse or time to relapse in an outpatient alcohol-dependent sample in the following 3 months. Future research should focus on studying the predictive value of these biases in the short term, for example, using ecological momentary assessment techniques to assess implicit processes shortly before a relapse. PMID- 26247389 TI - Vibrant Science Needed for Future Society. AB - Chemists needed: Society is currently facing manifold challenges, many of which were created in part or in whole by humans. Editorial Board Chairman Ryoji Noyori comments on chemists' role in securing peace and prosperity for current and future generations. PMID- 26247390 TI - Direct synthesis of methyl phosphoramidates in carbohydrates. AB - A direct installation of a methyl phosphoramidate group by using methyl benzylphosphoramidochloridate into carbohydrates and amino acid is described. This one-step synthesis is efficient for both primary and secondary alcohols and exhibited excellent regioselectivity and functional group compatibility. Formation of a single diastereomer is observed in certain cases. The N-benzyl protecting group on methyl phosphoramidates is easily removed under mild conditions. PMID- 26247391 TI - A fibril-based structural constitutive theory reveals the dominant role of network characteristics on the mechanical behavior of fibroblast-compacted collagen gels. AB - In this paper, we present a general, fibril-based structural constitutive theory which accounts for three material aspects of crosslinked filamentous materials: the single fibrillar force response, the fibrillar network model, and the effects of alterations to the fibrillar network. In the case of the single fibrillar response, we develop a formula that covers the entropic and enthalpic deformation regions, and introduce the relaxation phase to explain the observed force decay after crosslink breakage. For the filamentous network model, we characterize the constituent element of the fibrillar network in terms its end-to-end distance vector and its contour length, then decompose the vector orientation into an isotropic random term and a specific alignment, paving the way for an expanded formalism from principal deformation to general 3D deformation; and, more important, we define a critical core quantity over which macroscale mechanical characteristics can be integrated: the ratio of the initial end-to-end distance to the contour length (and its probability function). For network alterations, we quantitatively treat changes in constituent elements and relate these changes to the alteration of network characteristics. Singular in its physical rigor and clarity, this constitutive theory can reproduce and predict a wide range of nonlinear mechanical behavior in materials composed of a crosslinked filamentous network, including: stress relaxation (with dual relaxation coefficients as typically observed in soft tissues); hysteresis with decreasing maximum stress under serial cyclic loading; strain-stiffening under uniaxial tension; the rupture point of the structure as a whole; various effects of biaxial tensile loading; strain-stiffening under simple shearing; the so-called "negative normal stress" phenomenon; and enthalpic elastic behaviors of the constituent element. Applied to compacted collagen gels, the theory demonstrates that collagen fibrils behave as enthalpic elasticas with linear elasticity within the gels, and that the macroscale nonlinearity of the gels originates from the curved fibrillar network. Meanwhile, the underlying factors that determine the mechanical properties of the gels are clarified. Finally, the implications of this study on the enhancement of the mechanical properties of compacted collagen gels and on the cellular mechanics with this model tissue are discussed. PMID- 26247392 TI - Difference in the binocular rivalry rate between depressive episodes and remission. AB - Binocular rivalry refers to a phenomenon in which, when different images are presented to each eye simultaneously, perception alternates spontaneously between monocular views rather than being a superposition of the two images. Recently, the involvement of serotonin systems has been reported to be related to the phenomenon. There is abundant evidence for abnormalities of the serotonin systems in depression and the antidepressants that enhance 5-HT transmission, which in turn improves mood and behavior. However, the available data with respect to rivalry rates in depression are less clear. Therefore, we aimed to explore whether perceptual rivalry was affected by a dysfunctional serotonin system in patients with depression and whether there was a rivalry rate difference between episode and remission states in depression patients. Twenty-eight patients with depression and 30 healthy controls were recruited in the study. We assessed the rivalry rate and the 17-item Hamilton Depression Rating Scale (HAMD) in patients with depression during clinical episode and remission states. The results suggested that alternation rates for patients during episodes were significantly slower than during remission and than in healthy controls. Also, alternation rates for patients during remission were slower than in healthy controls. These results may provide further clues to serotonergic neural systems contributing to the dynamics of perception rivalry and may foster enlightenment regarding the field of binocular rivalry in psychiatric disorders other than bipolar disorder. PMID- 26247393 TI - Female rats express a conditioned object preference for receipt of sexual stimulation. AB - Female rats alternately approach and avoid the male rat during copulation, potentially reflecting appetitive and aversive aspects of mating, respectively. We developed a novel classical conditioning procedure, conditioned object preference (COP), to test whether female rats show increased approach toward a conditioned stimulus associated directly with receipt of sexual stimulation. During conditioning, one scented object was paired with an appetitive stimulus and a different object plus scent was paired with a control stimulus on a separate day. After conditioning, preference for each object was evaluated with a choice task. Experiment 1 was conducted to verify the procedure. Rats exhibited a significant COP for 1mg/kg amphetamine, indicating that the conditioned object preference procedure is an effective tool for evaluating the rewarding nature of a treatment. In Experiment 2, paced mating to one ejaculation and experimenter delivered artificial vaginocervical stimulation (aVCS) each induced a COP. The robust COPs for paced mating and aVCS support the notion that female rats experience a reward state during receipt of sexual stimulation. Moreover, the data suggest that any aversive aspects of receipt of sexual stimulation do not overshadow the appetitive effects. PMID- 26247394 TI - Detection and Quantification of beta-Amyloid, Pyroglutamyl Abeta, and Tau in Aged Canines. AB - Canine cognitive dysfunction syndrome is an age-associated disorder that resembles many aspects of human Alzheimer disease. The characterization of canine cognitive dysfunction syndrome has been restricted to selected laboratory dogs and mongrels, thereby limiting our knowledge of potential breed-related and age related differences. We examined the brains of 24 dogs from various breeds. The frontal cortex, hippocampus, and entorhinal cortex were investigated. Deposits of beta-amyloid (Abeta) and tau were analyzed phenotypically and quantified stereologically. In all dogs aged 10 years or older, plaques containing pyroglutamyl Abeta and Abeta8-17 were detected. Within the ventral hippocampus, significantly more pyroglutamyl Abeta plaques were deposited in small and medium dogs than in large dogs. Hyperphosphorylated tau with formation of neurofibrillary tangles was observed in 3 animals aged 13 to 15 years. This study provides the first investigation of pyroglutamyl Abeta in comparison with total Abeta (as shown by Abeta8-17 immunoreactivity) in dogs of different breeds, sizes, and ages. Our results indicate that canine cognitive dysfunction syndrome is relatively common among aged canines, thereby emphasizing the relevance of such populations to translational Alzheimer disease research. PMID- 26247395 TI - Quantitative Real-Time Quaking-Induced Conversion Allows Monitoring of Disease Modifying Therapy in the Urine of Prion-Infected Mice. AB - Prion diseases are fatal neurodegenerative diseases characterized by accumulation of the pathogenic prion protein PrP in the brain. We established quantitative real-time quaking-induced conversion for the measurement of minute amounts of PrP in body fluids such as urine. Using this approach, we monitored the efficacy of antiprion therapy by quantifying the seeding activity of PrP from the brain and urine of mice after prion infection. We found that the aggregation inhibitor anle138b decreased the levels of PrP in the brain and urine. Importantly, variations of PrP levels in the urine closely corresponded to those in the brain. Our findings indicate that quantification of urinary PrP enables measurement of prion disease progression in body fluids and can substitute for immunodetection in brain tissue. We expect PrP quantification biologic fluids (such as urine and cerebrospinal fluid) with quantitative real-time quaking-induced conversion to emerge as a valuable noninvasive diagnostic tool for monitoring disease progression and the efficacy of therapeutic approaches in animal studies and human clinical trials of prion diseases. Moreover, highly sensitive methods for quantifying pathologic aggregate seeds might provide novel molecular biomarkers for other neurodegenerative diseases that may involve prion-like mechanisms (protein aggregation and spreading), such as Alzheimer disease and Parkinson disease. PMID- 26247396 TI - The toxicity of the Aggregatibacter actinomycetemcomitans cytolethal distending toxin correlates with its phosphatidylinositol-3,4,5-triphosphate phosphatase activity. AB - The Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) induces G2 arrest and apoptosis in lymphocytes and other cell types. We have shown that the active subunit, CdtB, exhibits phosphatidylinositol-3,4,5 triphosphate (PIP3) phosphatase activity, leading us to propose that Cdt toxicity is the result of PIP3 depletion and perturbation of phosphatidylinositol-3-kinase (PI-3K)/PIP3/Akt signalling. To further explore this relationship, we have focused our analysis on identifying residues that comprise the catalytic pocket and are critical to substrate binding rather than catalysis. In this context, we have generated several CdtB mutants and demonstrate that, in each instance, the ability of the toxin to induce cell cycle arrest correlates with retention of phosphatase activity. We have also assessed the effect of Cdt on downstream components of the PI-3K signalling pathway. In addition to depletion of intracellular concentrations of PIP3, toxin-treated lymphocytes exhibit decreases in pAkt and pGSK3beta. Further analysis indicates that toxin-treated cells exhibit a concomitant loss in Akt activity and increase in GSK3beta kinase activity consistent with observed changes in their phosphorylation status. We demonstrate that cell susceptibility to Cdt is dependent upon dephosphorylation and concomitant activation of GSK3beta. Finally, we demonstrate that, in addition to lymphocytes, HeLa cells exposed to a CdtB mutant that retains phosphatase activity and not DNase activity undergo G2 arrest in the absence of H2AX phosphorylation. Our results provide further insight into the mode of action by which Cdt may function as an immunotoxin and induce cell cycle arrest in target cells such as lymphocytes. PMID- 26247397 TI - Spin-frustration in a new spin-1/2 oxyfluoride system (Cu13(VO4)4(OH)10F4) constructed by alternatively distorted kagome-like and triangular lattices. AB - A novel copper compound, Cu13(VO4)4(OH)10F4, featuring two types of two dimensional extended kagome-like and triangular lattices, exhibits long-range antiferromagnetic ordering at ~3 K, a strong spin-frustration effect with f = 21 and a spin-flop transition at 5 T. PMID- 26247398 TI - A robust Correntropy-based method for analyzing multisample aCGH data. AB - This paper presents a new method for analyzing array comparative genomic hybridization (aCGH) data based on Correntropy. A new formulation based on low rank aCGH data and Correntropy is proposed and its solution is presented based on Half-Quadratic method. Compared to existing methods, the proposed method is more robust to high corruptions and various kinds of noise. Moreover, it analyzes all aCGH profiles relating to a data set simultaneously. Experimental results illustrate the robustness of the proposed method when the noise is non-Gaussian and show its excellent performance in other cases. PMID- 26247400 TI - Comparison of conventional Papanicolaou cytology samples with liquid-based cervical cytology samples from women in Pernambuco, Brazil. AB - In the present study, we compared the performance of a ThinPrep cytological method with the conventional Papanicolaou test for diagnosis of cytopathological changes, with regard to unsatisfactory results achieved at the Central Public Health Laboratory of the State of Pernambuco. A population-based, cross-sectional study was performed with women aged 18 to 65 years, who spontaneously sought gynecological services in Public Health Units in the State of Pernambuco, Northeast Brazil, between April and November 2011. All patients in the study were given a standardized questionnaire on sociodemographics, sexual characteristics, reproductive practices, and habits. A total of 525 patients were assessed by the two methods (11.05% were under the age of 25 years, 30.86% were single, 4.4% had had more than 5 sexual partners, 44% were not using contraception, 38.85% were users of alcohol, 24.38% were smokers, 3.24% had consumed drugs previously, 42.01% had gynecological complaints, and 12.19% had an early history of sexually transmitted diseases). The two methods showed poor correlation (k=0.19; 95%CI=0.11-0.26; P<0.001). The ThinPrep method reduced the rate of unsatisfactory results from 4.38% to 1.71% (chi2=5.28; P=0.02), and the number of cytopathological changes diagnosed increased from 2.47% to 3.04%. This study confirmed that adopting the ThinPrep method for diagnosis of cervical cytological samples was an improvement over the conventional method. Furthermore, this method may reduce possible losses from cytological resampling and reduce obstacles to patient follow-up, improving the quality of the public health system in the State of Pernambuco, Northeast Brazil. PMID- 26247401 TI - Two-Inch-Sized Perovskite CH3 NH3 PbX3 (X = Cl, Br, I) Crystals: Growth and Characterization. AB - Two-inch-sized perovskite crystals, CH3 NH3 PbX3 (X=I, Br, Cl), with high crystalline quality are prepared by a solution-grown strategy. The availability of large perovskite crystals is expected to transform its broad applications in photovoltaics, optoelectronics, lasers, photodetectors, LEDs, etc., just as crystalline silicon has done in revolutionizing the modern electronics and photovoltaic industries. PMID- 26247402 TI - The effects of over expressing aquaporins on the cryopreservation of hepatocytes. AB - During cryopreservation, aquaporins are critical in regulating water transport across cellular membranes and preventing osmotic damages. Hepatocytes express aquaporin (AQP) 0, 8, 9, 11, and 12; this study investigates whether increasing the localization of AQP8 on the cellular membrane would improve cell viability by increasing water transport during cryopreservation. Primary rat hepatocytes were cultured and treated with dibutyryl cAMP (Bt(2)cAMP) or glucagon to increase the expression of AQP8 at the cellular membrane via translocation. This phenomenon is verified through two experiments - confocal immunofluorescence microscopy and cell shrinkage analysis. The immunofluorescence results showed increase in AQP8 on the cellular membrane of treated cells, and cell shrinkage analysis showed an increase in water transport of treated cells compared to controls. Primary rat hepatocytes were treated with Bt(2)cAMP or glucagon and cryopreserved using standard protocols in a controlled rate freezer. This resulted in a significant increase in the cell viability on warming. These results indicate that Bt(2)cAMP or glucagon treated hepatocytes had increased expression of aquaporin in the cellular membrane, increased water transport during cryopreservation, and increased post-thaw viability. PMID- 26247403 TI - Lentivirus-mediated RNA Interference Targeting LAPTM4B Inhibits Human Ovarian Cancer Cell Invasion In Vitro. AB - LAPTM4B (lysosome-associated protein transmembrane 4 beta) play an important role in several human carcinomas. We examines the effects of RNA interference mediated downregulation of human lysosomal-associated protein transmembrane 4 beta expression on the biological behavior of the human serous adenocarcinoma cell line NIH:OVCAR3. This study investigated the expression level of lysosomal associated protein transmembrane 4 beta in several ovarian cancer cell lines. RNA interference mediated by recombinant lentiviral vectors expressing an artificial lysosomal-associated protein transmembrane 4 beta miRNA was used to induce long lasting downregulation of lysosomal-associated protein transmembrane 4 beta gene expression in NIH:OVCAR3 cells. Lysosomal-associated protein transmembrane 4 beta expression as well as the motility, migration potential, and proliferation of the tumor cells was measured by flow cytometry, real-time polymerase chain reaction, Western blot analysis, transwell migration assays, wound healing assays, and cell counting kit-8 assays. In addition, the cell cycle analysis utilized fluorescence activated cell sorting. Four recombinant plasmid expression vectors encoding premiRNAs against lysosomal-associated protein transmembrane 4 beta (pcDNA LAPTM4B-miR-1, -2, -3, and-4) were constructed and transfected into 293T cells, which overexpress lysosomal-associated protein transmembrane 4 beta. The recombinant lentiviral vector for lysosomal-associated protein transmembrane 4 beta RNA interference was packaged with pcDNA-LAPTM4B-miR-3, which had the highest interfering efficiency, thereby successfully generating stable transfectants. Compared with the control cells, the LAPTM4B-miRNA-transfected NIH:OVCAR3 cells exhibited significant decreases in cell motility and invasion. Furthermore, LAPTM4B depletion resulted in a significant decrease in proliferating cell nuclear antigen, vascular endothelial growth factor, MMP2, MMP9, and CDK12 expression. We propose that lysosomal-associated protein transmembrane 4 beta expression may be an oncogene-inducing feature of invasive ovarian cancer cells and may be a potential therapeutic target for ovarian cancer treatment. PMID- 26247404 TI - Distribution of putative xenogeneic silencers in prokaryote genomes. AB - Gene silencing is an important function as it keeps newly acquired foreign DNA repressed, thereby avoiding possible deleterious effects in the host organism. Known transcriptional regulators associated with this process are called xenogeneic silencers (XS) and belong to either the H-NS, Lsr2, MvaT or Rok families. In the work described here we looked for XS-like regulators and their distribution in prokaryotic organisms was evaluated. Our analysis showed that putative XS regulators similar to H-NS, Lsr2, MvaT or Rok are present only in bacteria (31.7%). This does not exclude the existence of alternative XS in the rest of the organisms analyzed. Additionally, of the four XS groups evaluated in this work, those from the H-NS family have diversified more than the other groups. In order to compare the distribution of these putative XS regulators we also searched for other nucleoid-associated proteins (NAPs) not included in this group such as Fis, EbfC/YbaB, HU/IHF and Alba. Results showed that NAPs from the Fis, EbfC/YbaB, HU/IHF and Alba families are widely (94%) distributed among prokaryotes. These NAPs were found in multiple combinations with or without XS like proteins. In regard with XS regulators, results showed that only XS proteins from one family were found in those organisms containing them. This suggests specificity for this type of regulators and their corresponding genomes. PMID- 26247405 TI - Authors' reply: Calculation of population attributable risk should to be based on robust estimates. PMID- 26247406 TI - Removal of fluoride contamination in water by three aquatic plants. AB - Phytoremediation, popularly known as 'green technology' has been employed in the present investigation to examine the potential of fluoride removal from water by some aquatic plants. Fluoride contamination in drinking water is very much prevalent in different parts of the world including India. Batch studies were conducted using some aquatic plants e.g., Pistia stratiotes, Eichhornia crassipes, and Spirodela polyrhiza which profusely grow in natural water bodies. The experimental data exhibited that all the above three aquatic floating macrophytes could remove fluoride to some relative degree of efficiency corresponding to initial concentration of fluoride 3, 5, 10, 20 mg/l after 10 days exposure time. Result showed that at lower concentration level i.e., 3 mg/L removal efficiency of Pistia stratiotes (19.87%) and Spirodela polyrhiza (19.23%) was found to be better as compared to Eichhornia crassipes (12.71%). Some of the physiological stress induced parameters such as chlorophyll a, chlorophyll b, total chlorophyll, carotenoid, total protein, catalase, and peroxidase were also studied to explore relative damage within the cell. A marginal stress was imparted among all the plants for lower concentration values (3 mg/L), whereas at 20 mg/l, maximum damage was observed. PMID- 26247407 TI - Twisting Tourniquet((c)) Technique: introducing Schnogh, a novel device and its effectiveness in treating primary and secondary lymphedema of extremities. AB - Twisting Tourniquet((c)) or in Thai "Schnogh" is a new invention for compression therapy of lymphedema. Twisting Tourniquet((c)) Technique (TTT) is totally noninvasive for lymphedema management. After the amazing successful evidence in the first series of 28 patients, we have conducted preliminary studies in lymphedema clinics. It was found that the combination of gradually increasing constriction force by Schnogh until desired pressure was reached and maintained for 15 min, followed by a 5-min release, doing repeatedly this compression decompression for at least 10 sessions a day, can generate acceptable results. The aim of the study was to evaluate the scientific effectiveness and establish a treatment protocol of TTT proposed as a therapeutic approach for clinical management of lymphedema. During 2006-2013, from over 3500 patients, 647 with primary/secondary lymphedema passed inclusion criteria, 307 for upper, and 340 for lower extremity. In the 5-day course of TTT, each day patients underwent 10 sessions of a 15-min compression followed by a 5-min decompression. Vegan diet was encouraged as an adjuvant therapy. Among lymphedema patients whose spectrum of edema severity ranged from mild to gigantic, TTT yielded an average volume reduction rate (VR) at 50.2% and 55.6%, making the average edema reduction volume attained at 463 and 1856 mL for upper and lower limb, respectively. The uniformed practice by Schnogh which supports a continual compression-decompression maneuver over 3.5 h daily for five consecutive days could induce an average VR at above half of the swelling in extremities of 647 patients. Schnogh is therefore effective in clinical management of lymphedema under TTT treatment of fibroblastic interstitium. PMID- 26247408 TI - MicroRNA-141-3p and miR-200a-3p regulate insulin-like growth factor 2 during mouse placental development. AB - Insulin-like growth factor 2 (IGF2) plays a vital role in fetal and placental development throughout gestation. Placental expression of IGF2 decreases substantially in intra-uterine growth restriction (IUGR) and Igf2 null mice develop small placentas. In this report, we examined the role of microRNAs in regulating Igf2 gene expression during mouse placental development. Using bioinformatic analysis, we have identified microRNAs that have conserved binding sites in the 3'-UTR of Igf2. Using luciferase reporter assay, we demonstrated that miR141-3p and miR-200a-3p mimics substantially down regulated relative luciferase activity by binding to 3'-UTR of Igf2, which was reversed by using miR141-3p and miR-200a-3p inhibitors. Furthermore, in a similar assay, use of Igf2 3'-UTR that lacked the binding site for the microRNAs did not have any effect on luceiferase activity. Interestingly, the expression of miR141-3p and miR-200a-3p were inversely and temporally correlated to the expression of IGF2 during mouse placental development. Overexpression of miR141-3p and miR-200a-3p in mouse trophoblast stem cells suppressed endogenous expression of IGF2. Consequently, IGF2 silencing by miR141-3p and miR-200a-3p diminished Akt activation in mouse trophoblast stem cells. Our study provides evidence for regulation of Igf2 by microRNAs and further elucidates the role of miR141-3p and miR-200a-3p in the mouse placental development. PMID- 26247409 TI - Hemispheric association and dissociation of voice and speech information processing in stroke. AB - As we listen to someone speaking, we extract both linguistic and non-linguistic information. Knowing how these two sets of information are processed in the brain is fundamental for the general understanding of social communication, speech recognition and therapy of language impairments. We investigated the pattern of performances in phoneme versus gender categorization in left and right hemisphere stroke patients, and found an anatomo-functional dissociation in the right frontal cortex, establishing a new syndrome in voice discrimination abilities. In addition, phoneme and gender performances were most often associated than dissociated in the left hemisphere patients, suggesting a common neural underpinnings. PMID- 26247410 TI - Arrhythmic activity in the left frontal eye field facilitates conscious visual perception in humans. AB - The frontal eye field (FEF) is a brain region involved in several processes relevant for visual performance, including visuo-spatial attention, conscious access and decision-making. Prior research has causally demonstrated that high beta FEF activity in the right hemisphere enhances conscious visual perception, an outcome that is in agreement with evidence of neural synchronization along a right dorsal fronto-parietal network during attentional orienting and a right hemisphere dominance for visuospatial processing. Nonetheless, frontal regions in the left hemisphere have also been shown to modulate perceptual performance. To causally explore the neural basis of these modulations, we delivered high-beta frequency-specific bursts of transcranial magnetic stimulation (TMS) to the left FEF and report that, in this region, these patterns failed to modulate conscious perception. In contrast, non-frequency-specific TMS patterns yielded visual performance improvements similar to those formerly causally associated to the induction of high-beta activity on its right-hemisphere homotopic area. This noise-induced facilitation of conscious vision suggests a relevant role of the left frontal cortex in visual perception. Furthermore, taken together with prior causal right-FEF evidence, our study indicates that frontal regions of each hemisphere employ different coding strategies to modulate conscious perception. PMID- 26247411 TI - Anabaena sp. mediated bio-oxidation of arsenite to arsenate in synthetic arsenic (III) solution: Process optimization by response surface methodology. AB - Blue green algae Anabaena sp. was cultivated in synthetic arsenite solution to investigate its bio-oxidation potential for arsenic species. Response surface methodology (RSM) was employed based on a 3-level full factorial design considering four factors, viz. initial arsenic (III) concentration, algal dose, temperature and time. Bio-oxidation (%) of arsenic (III) was considered as response for the design. The study revealed that about 100% conversion of As (III) to As (V) was obtained for initial As (III) concentration of 2.5-7.5 mg/L at 30 degrees C for 72 h of exposure using 3 g/L of algal dose signifying a unique bio-oxidation potential of Anabaena sp. The dissolved CO2 (DCO2) and oxygen (DO) concentration in solution was monitored during the process and based on the data, a probable mechanism was proposed wherein algal cell acts like a catalytic membrane surface and expedites the bio-oxidation process. Bioaccumulation of arsenic, as well as, surface adsorption on algal cell was found considerably low. Lipid content of algal biomass grown in arsenite solution was found slightly lower than that of algae grown in synthetic media. Toxicity effects on algal cells due to arsenic exposure were evaluated in terms of comet assay and chlorophyll a content which indicated DNA damage to some extent along with very little decrease in chlorophyll a content. In summary, the present study explored the potential application of Anabaena sp. as an ecofriendly and sustainable option for detoxification of arsenic contaminated natural water with value-added product generation. PMID- 26247412 TI - Geochemistry of rare earth elements in a passive treatment system built for acid mine drainage remediation. AB - Rare earth elements (REE) were used to assess attenuation processes in a passive system for acid mine drainage treatment (Jales, Portugal). Hydrochemical parameters and REE contents in water, soils and sediments were obtained along the treatment system, after summer and winter. A decrease of REE contents in the water resulting from the interaction with limestone after summer occurs; in the wetlands REE are significantly released by the soil particles to the water. After winter, a higher water dynamics favors the AMD treatment effectiveness and performance since REE contents decrease along the system; La and Ce are preferentially sequestered by ochre sludge but released to the water in the wetlands, influencing the REE pattern of the creek water. Thus, REE fractionation occurs in the passive treatment systems and can be used as tracer to follow up and understand the geochemical processes that promote the remediation of AMD. PMID- 26247413 TI - Interactive effects of sulfadiazine and Cu(II) on their sorption and desorption on two soils with different characteristics. AB - Antibiotics and heavy metals often coexist in soils due to land application of animal wastes and other sources of inputs. The aim of this study is to evaluate the interaction of Cu(II) and sulfadiazine (SDZ) regarding to their sorption and desorption on Brown soil (BS, luvisols) and Red soil (RS, Udic Ferrosols) using batch experiments. The presence of Cu(II) significantly enhanced sorption of SDZ on BS at pH>5.0, and this trend increased with increasing pH, which was mainly ascribed to the formation of ternary complexes of Cu-SDZ-soil and/or SDZ-Cu-soil. In contrast, Cu(II) only slightly increased SDZ sorption on RS at pH<5.0 due to the decrease of equilibrium solution pH, whereas it hardly affected SDZ sorption at pH>5.0 because RS had high oxides contents and low affinity for Cu(II). In addition, Cu(II) inhibited SDZ desorption from BS but promoted SDZ desorption from RS, which was related to their different sorption mechanisms. The presence of SDZ exerted no significant effect on the sorption of Cu(II) on the two soils at pH<6.5 because of its low sorption coefficients (Kd), while slightly decreased Cu(II) sorption at pH>6.5 by forming water-soluble complexes. Furthermore, SDZ had little effect on Cu(II) desorption from the two soils at natural pH. These results indicate that soil characteristics strongly influence the interactions of Cu(II) and SDZ on their sorption and desorption on soils. PMID- 26247414 TI - Synthetic Model of the Oxygen-Evolving Center: Photosystem II under the Spotlight. AB - The oxygen-evolving center (OEC) in photosystem II catalyzes a water splitting reaction. Great efforts have already been made to artificially synthesize the OEC, in order to elucidate the structure-function relationship and the mechanism of the reaction. Now, a new synthetic model makes the best mimic yet of the OEC. This recent study opens up the possibility to study the mechanism of photosystem II and photosynthesis in general for applications in renewable energy and synthetic biology. PMID- 26247415 TI - Promoting ethylene epoxidation on gold nanoclusters: self and CO induced O2 activation. AB - We have investigated the epoxidation of ethylene heterogeneously catalyzed by small gold nanoclusters based on density functional theory calculations. A promising trimolecular Langmuir-Hinshelwood mechanism via co-adsorbed ethylene- and CO-assisted reaction is addressed which provides significant insights into the fundamental catalytic mechanism for ethylene oxidation on small Au nanoclusters. O2 activation is found to be a key step for accelerating ethylene oxidation. Especially, the coadsorbed neighboring CO is found to be more robust for promoting the activation of the O-O bond, resulting in the formation of epoxide and CO2 due to the barrierless process. The new CO-promoted oxidation mechanism has also been clarified by the ab initio MD simulations. PMID- 26247416 TI - Time to Onset of Sustained Postoperative Pain Relief (SuPPR): Evaluation of a New Systems-level Metric for Acute Pain Management. AB - OBJECTIVES: Prior work on postoperative pain trajectories has examined pain score changes over time using daily averages of pain scores. However, little is known about the time required until patients consistently report minimal postoperative pain. MATERIALS AND METHODS: We conducted a retrospective cohort study of surgical case data from 7293 adult patients to examine the impact of age, sex, and the type of surgery on the time to sustained postoperative pain relief (SuPPR). We defined SuPPR as the time required until a patient reports the first of multiple (2, 3, 4, or 5 sequential measurements; eg, SuPPR-2, SuPPR-3), uninterrupted, mild pain scores (<=4/10). RESULTS: Overall, SuPPR times ranged from 3 minutes for SuPPR-2 and 9 minutes for SuPPR-5 to 160.1 hours for SuPPR-2 and 183.1 hours for SuPPR-5. For the SuPPR-2 outcome, the median time to event was 10.9 hours (interquartile range, 3 to 26.1 h) after surgery. For the SuPPR-5 outcomes, the median time to event was 31.5 hours (interquartile range, 17.8 to 54.2 h) after surgery. The peak median difference between 2 sequential SuPPR definitions was between SuPPR-3 and SuPPR-2 at 9 hours, with subsequent decreases to 6.5 hours between SuPPR-4 and SuPPR-3, and 5.2 hours between SuPPR-5 and SuPPR 4. There were statistically different differences across SuPPR-2 through SuPPR-5 definitions by age, sex, and type of surgery. DISCUSSION: Although additional analyses are necessary, SuPPR may represent a novel method for evaluating acute pain service performance. PMID- 26247417 TI - Differences in the Acute Toxic Effects of Breast Radiotherapy by Fractionation Schedule: Comparative Analysis of Physician-Assessed and Patient-Reported Outcomes in a Large Multicenter Cohort. AB - IMPORTANCE: Randomized trials have established the long-term safety and efficacy of hypofractionated whole-breast radiotherapy, but little is known about the acute toxic effects experienced by patients treated with hypofractionation as compared with conventional fractionation, particularly in real-world settings and from the patient's own perspective. OBJECTIVE: To evaluate prospectively collected data on acute toxic effects and patient-reported outcomes in a cohort treated with varying radiation fractionation schemes in practices collaborating in the Michigan Radiation Oncology Quality Consortium (MROQC). DESIGN, SETTING, AND PARTICIPANTS: We compared toxic effects in patients receiving hypofractionation (HF) vs conventional fractionation (CF) during treatment (through 7 days after treatment) and in follow-up (posttreatment days 8-210), after adjustment for sociodemographic, clinical, and treatment characteristics. The MROQC includes academic and community radiation oncology practices across Michigan. All 2604 patients who received adjuvant whole-breast radiotherapy after lumpectomy for unilateral breast cancer at MROQC participating sites from October 2011 through June 2014 were registered; we analyzed 2309 for whom there was a comprehensive physician toxicity evaluation within 1 week of completion of radiotherapy and at least 1 weekly toxicity evaluation during treatment. EXPOSURES: Hypofractionation vs CF. MAIN OUTCOMES AND MEASURES: Physicians reported dermatitis, pain, fatigue, and other common toxic effects associated with breast radiotherapy at baseline, weekly during radiotherapy, and in follow up. Patients who consented also rated their own experiences, including breast pain, fatigue, and being bothered by symptoms. RESULTS: Of the 2309 evaluable patients, 578 received HF. During treatment, after adjustment for sociodemographic, clinical, and treatment factors, patients receiving CF had significantly higher maximum physician-assessed skin reaction (moist desquamation, 28.5% vs 6.6%, P < .001; grade >=2 dermatitis, 62.6% vs 27.4%, P < .001), self-reported pain (moderate/severe pain, 41.1% vs 24.2%, P = .003), burning/stinging bother (often/always, 38.7% vs 15.7%, P = .002), hurting bother (33.5% vs 16.0%, P = .001), swelling bother (29.6% vs 15.7%, P = .03), and fatigue (29.7% vs 18.9%, P = .02) but slightly greater absence of skin induration in follow-up (84.5% vs 81.2%, P = .02). No significant differences were observed in any other measured outcomes during follow-up extending through 6 months. CONCLUSIONS AND RELEVANCE: Hypofractionation not only improves convenience but also may reduce acute pain, fatigue, and the extent to which patients are bothered by dermatitis in patients with breast cancer undergoing whole-breast radiotherapy. PMID- 26247418 TI - Difluorosialic acids, potent novel influenza virus neuraminidase inhibitors, induce fewer drug resistance-associated neuraminidase mutations than does oseltamivir. AB - Neuraminidase inhibitors (NAIs), including the most frequently prescribed oral therapeutic oseltamivir, play a critical role in the control of severe influenza virus (IFV) infections. However, recent reports of spread of an oseltamivir resistant H1N1 pandemic strain in individuals who have never been exposed to oseltamivir highlight an urgent need for new antivirals against NAI-resistant IFVs. Difluorosialic acids (DFSAs) are a novel class of anti-IFV NAIs designed based on the mechanism of action of IFV NA, and distinguished by their covalent inhibition mode and their high structural similarity to the natural substrate, sialic acid. These characteristics should render the development of resistance a less rapid process. In this report, we evaluated the relative propensity of influenza A virus (IFV-A) NA to develop resistance against the DFSA class of inhibitor by passaging IFV-A strains in vitro in the presence of either oseltamivir or a representative DFSA (FeqGuDFSA). All the passage-selected lines gained mutations in hemagglutinin. Among the 12 oseltamivir-resistant passaged lines, five gained NA mutations and four of these were the well-defined H275Y mutation that causes oseltamivir resistance. In contrast, out of 15 DFSA-passaged lines, only 2 lines gained NA mutations. Further, NA inhibition assays indicated that these mutations did not change the sensitivity of NA to DFSA and thus the resistance to DFSA was not conferred by these NA mutations. These results strongly suggest that, compared to oseltamivir, IFV is less prone to development of resistance against DFSAs through NA mutations. PMID- 26247419 TI - A suppressive effect of Sp1 recruitment to the first leader 5' splice site region on L4-22K-mediated activation of the adenovirus major late promoter. AB - Transcription from the adenovirus major late promoter (MLP) requires binding of late phase-specific factors to the so-called DE element located approximately 100 base pairs downstream of the MLP transcriptional start site. The adenovirus L4 22K protein binds to the DE element and stimulates transcription from the MLP via a DE sequence-dependent mechanism. Here we use a transient expression approach to show that L4-22K binds to an additional site downstream of the MLP start site, the so-called R1 region, which includes the major late first leader 5' splice site. Binding of L4-22K to R1 has a suppressive effect on MLP transcription. L4 22K binds to the distal part of R1 and stimulates the recruitment of Sp1 and other cellular factors to a site overlapping the first leader 5' splice site. Binding of Sp1 to the 5' splice site region had an inhibitory effect on L4-22K activated MLP transcription. PMID- 26247420 TI - Bisphenol A increases BeWo trophoblast survival in stress-induced paradigms through regulation of oxidative stress and apoptosis. AB - Bisphenol A (BPA) is ubiquitous in the environment and is reported to be present at high concentrations in placental tissue, where its presence raises concerns over its potential to disrupt placental function. This report investigates how BPA interferes with the survival of human choriocarcinoma BeWo cells (a model of placental trophoblasts) under stress-induced paradigms reminiscent of pathways activated in placental development. These include conditions that promote oxidative stress (glutathione depletion) and apoptosis (serum withdrawal) or mimic hypoxia (HIF-1alpha accumulation via dimethyloxalylglycine treatment). Treatment of BeWo cells with BPA during stress-induced paradigms led to a consistent and significant increase in cell viability, with a concomitant increase in glutathione levels and a reduction in apoptosis. Assessment of the antioxidant capacity of BPA revealed its ability to quench reactive oxygen species and reduce the levels generated during glutathione and serum depletion. BPA was also able to reduce the activation of the antioxidant response element (ARE) through mediation of its activators, nuclear factor erythroid related factor family members (Nrf's). Indeed, the expression and nuclear translocation of Nrf2 (an important ARE activator) were impaired by BPA, while Nrf1 and Nrf3 expression levels were increased. Furthermore, BPA increased the levels of the anti-apoptotic proteins (Bcl-2 and Hsp70) and decreased HIF-1alpha levels during stress-induced conditions. Together, these results indicate that BPA inhibits trophoblast cell death under conditions of cellular stress. This could have implications on placental trophoblasts during development. PMID- 26247421 TI - Mass Spectra and Cross-Contribution of Ion Intensity Between Drug Analytes and Their Isotopically Labelled Analogs - Common Opioids and Their Derivatives. AB - For the quantitation of most drugs and their metabolites, GC-MS is currently the preferred method and isotopically labeled analogs of the analytes are the internal standards (ISs) of choice. Under this analytical setting, chemical derivatization (CD) plays a critical role in the sample preparation process. In addition to meeting the conventional objectives of CD, products derived from the selected CD method must generate ions suitable for designating the analyte and the IS; these ions cannot have significant cross-contribution (CC), i.e., contribution to the intensity of the ions designating the analyte by the IS, and vice versa. With this in mind, the authors have reviewed literature and information provided by manufacturers, searching for suitable CD reagents, CD methods, and isotopically labeled analogs of the analytes related to the following 11 opioids: heroin, 6-acetylmorphine, morphine, hydromorphone, oxymorphone, 6-acetylcodeine, codeine, hydrocodone, dihydrocodeine, oxycodone, and noroxycodone. These analytes and ISs were derivatized with various derivatization groups, followed by GCMS analysis. The resulting MS data are systematically presented in two forms: (a) full-scan mass spectra; and (b) CC data of ion-pairs with potential for designating the analytes and their respective ISs. Many (if not most) of these full-scan mass spectra are not yet available in the literature and should be of reference value to laboratories engaged in the analysis of these drugs/metabolites. Full-scan MS data were further used to select ion-pairs with potential for designating the analytes and ISs in quantitative analysis protocols. The CC data of these ion-pairs were evaluated using data collected in selected ion monitoring mode and systematically tabulated, readily available for analysts searching for this important analytical parameter. PMID- 26247422 TI - Beyond a Fluorescent Probe: Inhibition of Cell Division Protein FtsZ by mant-GTP Elucidated by NMR and Biochemical Approaches. AB - FtsZ is the organizer of cell division in most bacteria and a target in the quest for new antibiotics. FtsZ is a tubulin-like GTPase, in which the active site is completed at the interface with the next subunit in an assembled FtsZ filament. Fluorescent mant-GTP has been extensively used for competitive binding studies of nucleotide analogs and synthetic GTP-replacing inhibitors possessing antibacterial activity. However, its mode of binding and whether the mant tag interferes with FtsZ assembly function were unknown. Mant-GTP exists in equilibrium as a mixture of C2'- and C3'-substituted isomers. We have unraveled the molecular recognition process of mant-GTP by FtsZ monomers. Both isomers bind in the anti glycosidic bond conformation: 2'-mant-GTP in two ribose puckering conformations and 3'-mant-GTP in the preferred C2' endo conformation. In each case, the mant tag strongly interacts with FtsZ at an extension of the GTP binding site, which is also supported by molecular dynamics simulations. Importantly, mant-GTP binding induces archaeal FtsZ polymerization into inactive curved filaments that cannot hydrolyze the nucleotide, rather than straight GTP hydrolyzing assemblies, and also inhibits normal assembly of FtsZ from the Gram negative bacterium Escherichia coli but is hydrolyzed by FtsZ from Gram-positive Bacillus subtilis. Thus, the specific interactions provided by the fluorescent mant tag indicate a new way to search for synthetic FtsZ inhibitors that selectively suppress the cell division of bacterial pathogens. PMID- 26247423 TI - Prostate Cancer Screening Among American Indians and Alaska Natives: The Health and Retirement Survey, 1996-2008. AB - INTRODUCTION: Among US men, prostate cancer is the leading malignancy diagnosed and the second leading cause of cancer death. Disparities in cancer screening rates exist between American Indians/Alaska Natives and other racial/ethnic groups. Our study objectives were to examine prostate screening at 5 time points over a 12-year period among American Indian/Alaska Native men aged 50 to 75 years, and to compare their screening rates to African American men and white men in the same age group. METHODS: We analyzed Health and Retirement Study data for 1996, 1998, 2000, 2004, and 2008. Prostate screening was measured by self-report of receipt of a prostate examination within the previous 2 years. Age-adjusted prevalence was estimated for each year. We used regression with generalized estimating equations to compare prostate screening prevalence by year and race. RESULTS: Our analytic sample included 119 American Indian/Alaska Native men (n = 333 observations), 1,359 African American men (n = 3,704 observations), and 8,226 white men (n = 24,292 observations). From 1996 to 2008, prostate screening rates changed for each group: from 57.0% to 55.7% among American Indians/Alaska Natives, from 62.0% to 71.2% among African Americans, and from 68.6% to 71.3% among whites. Although the disparity between whites and African Americans shrank over time, it was virtually unchanged between whites and American Indians/Alaska Natives. CONCLUSION: As of 2008, American Indians/Alaska Natives were less likely than African Americans and whites to report a prostate examination within the previous 2 years. Prevalence trends indicated a modest increase in prostate cancer screening among African Americans and whites, while rates remained substantially lower for American Indians/Alaska Natives. PMID- 26247424 TI - Length of Stay and Deaths in Diabetes-Related Preventable Hospitalizations Among Asian American, Pacific Islander, and White Older Adults on Medicare, Hawai'i, December 2006-December 2010. AB - INTRODUCTION: The objective of this study was to compare in-hospital deaths and length of stays for diabetes-related preventable hospitalizations (D-RPHs) in Hawai'i for Asian American, Pacific Islander, and white Medicare recipients aged 65 years or older. METHODS: We considered all hospitalizations of older (>65 years) Japanese, Chinese, Native Hawaiians, Filipinos, and whites living in Hawai'i with Medicare as the primary insurer from December 2006 through December 2010 (n = 127,079). We used International Classification of Diseases - 9th Revision (ICD-9) codes to identify D-RPHs as defined by the Agency for Healthcare Research and Quality. Length of stays and deaths during hospitalization were compared for Asian American and Pacific Islander versus whites in multivariable regression models, adjusting for age, sex, location of residence (Oahu, y/n), and comorbidity. RESULTS: Among the group studied, 1,700 hospitalizations of 1,424 patients were D-RPHs. Native Hawaiians were significantly more likely to die during a D-RPH (odds ratio [OR], 3.92; 95% confidence interval [CI], 1.42-10.87) than whites. Filipinos had a significantly shorter length of stay (relative risk [RR], 0.77; 95% CI, 0.62-0.95) for D-RPH than whites. Among Native Hawaiians with a D-RPH, 59% were in the youngest age group (65-75 y) whereas only 6.3% were in the oldest (>=85 y). By contrast, 23.2% of Japanese were in the youngest age group, and 32.2% were in the oldest. CONCLUSION: This statewide study found significant differences in the clinical characteristics and outcomes of D-RPHs for Asian American and Pacific Islanders in Hawai'i. Native Hawaiians were more likely to die during a D-RPH and were hospitalized at a younger age for a D-RPH than other studied racial/ethnic groups. Focused interventions targeting Native Hawaiians are needed to avoid these outcomes. PMID- 26247425 TI - Food Insecurity and Body Mass Index: A Longitudinal Mixed Methods Study, Chelsea, Massachusetts, 2009-2013. AB - INTRODUCTION: Cross-sectional studies show an association between food insecurity and higher body mass index (BMI), but this finding has not been evaluated longitudinally. Patient perspectives on food choice in resource-constrained environments are not well understood. The objective of this study was to evaluate the longitudinal association between food insecurity and BMI. METHODS: This mixed methods study used both a retrospective matched cohort and focus groups. For the quantitative analysis, all patients in a community health center who reported food insecurity from October 2009 through March 2010 (n = 457) were followed through August 2013 and compared with controls matched by age, sex, and race/ethnicity (n = 1,974). We evaluated the association between food insecurity and change in BMI by using linear, mixed effects longitudinal models. The qualitative analysis included patients with food insecurity, stratified by BMI. Qualitative data were analyzed by using open coding and grounded theory. RESULTS: The mean age of participants was 51 years; 61% were women, and 73% were Hispanic. Baseline BMI was similar in food insecure participants and matched controls. After adjustment in longitudinal analyses, food insecurity was associated with greater increase in BMI (0.15 kg/m(2) per year more than controls, P < .001). Themes identified in 4 focus groups included attitudes and knowledge about food, food access, and food practices. Participants with BMI of 30 kg/m(2) or less highlighted skills such as budgeting and portion control. CONCLUSION: Food insecurity is associated with increase in BMI. The skills of food insecure participants who were not obese, such as portion control and budgeting, may be useful in weight management interventions for vulnerable patients. PMID- 26247427 TI - On-line 3D motion estimation using low resolution MRI. AB - Image processing such as deformable image registration finds its way into radiotherapy as a means to track non-rigid anatomy. With the advent of magnetic resonance imaging (MRI) guided radiotherapy, intrafraction anatomy snapshots become technically feasible. MRI provides the needed tissue signal for high fidelity image registration. However, acquisitions, especially in 3D, take a considerable amount of time. Pushing towards real-time adaptive radiotherapy, MRI needs to be accelerated without degrading the quality of information. In this paper, we investigate the impact of image resolution on the quality of motion estimations. Potentially, spatially undersampled images yield comparable motion estimations. At the same time, their acquisition times would reduce greatly due to the sparser sampling. In order to substantiate this hypothesis, exemplary 4D datasets of the abdomen were downsampled gradually. Subsequently, spatiotemporal deformations are extracted consistently using the same motion estimation for each downsampled dataset. Errors between the original and the respectively downsampled version of the dataset are then evaluated. Compared to ground-truth, results show high similarity of deformations estimated from downsampled image data. Using a dataset with (2.5 mm)3 voxel size, deformation fields could be recovered well up to a downsampling factor of 2, i.e. (5 mm)3. In a therapy guidance scenario MRI, imaging speed could accordingly increase approximately fourfold, with acceptable loss of estimated motion quality. PMID- 26247426 TI - Beyond Neighborhood Food Environments: Distance Traveled to Food Establishments in 5 US Cities, 2009-2011. AB - INTRODUCTION: Accurate conceptualizations of neighborhood environments are important in the design of policies and programs aiming to improve access to healthy food. Neighborhood environments are often defined by administrative units or buffers around points of interest. An individual may eat and shop for food within or outside these areas, which may not reflect accessibility of food establishments. This article examines the relevance of different definitions of food environments. METHODS: We collected data on trips to food establishments using a 1-week food and travel diary and global positioning system devices. Spatial-temporal clustering methods were applied to identify homes and food establishments visited by study participants. RESULTS: We identified 513 visits to food establishments (sit-down restaurants, fast-food/convenience stores, malls or stores, groceries/supermarkets) by 135 participants in 5 US cities. The average distance between the food establishments and homes was 2.6 miles (standard deviation, 3.7 miles). Only 34% of the visited food establishments were within participants' neighborhood census tract. Buffers of 1 or 2 miles around the home covered 55% to 65% of visited food establishments. There was a significant difference in the mean distances to food establishments types (P = .008). On average, participants traveled the longest distances to restaurants and the shortest distances to groceries/supermarkets. CONCLUSION: Many definitions of the neighborhood food environment are misaligned with individual travel patterns, which may help explain the mixed findings in studies of neighborhood food environments. Neighborhood environments defined by actual travel activity may provide more insight on how the food environment influences dietary and food shopping choices. PMID- 26247428 TI - Electrocatalytic H2 Evolution by Supramolecular Ru(II)-Rh(III)-Ru(II) Complexes: Importance of Ligands as Electron Reservoirs and Speciation upon Reduction. AB - The supramolecular water reduction photocatalysts [{(Ph2phen)2Ru(dpp)}2RhX2](PF6)5 (Ph2phen = 4,7-diphenyl-1,10-phenanthroline, dpp =2,3-bis(2-pyridyl)pyrazine X = Cl, Br) are efficient electrocatalysts for the reduction of CF3SO3H, CF3CO2H, and CH3CO2H to H2 in DMF or DMF/H2O mixtures. The onset of catalytic current occurs at -0.82 V versus Ag/AgCl for CF3SO3H, -0.90 V for CF3CO2H, and -1.1 V for CH3CO2H with overpotentials of 0.61, 0.45, and 0.10 V, respectively. In each case, catalysis is triggered by the first dpp ligand reduction implicating the dpp as an electron reservoir in catalysis. A new species with Epc ~ -0.75 V was observed in the presence of stoichiometric amounts of strong acid, and its identity is proposed as the Rh(H)(III/II) redox couple. H2 was produced in 72-85% Faradaic yields and 95-116 turnovers after 2 h and 435 turnovers after 10 h of bulk electrolysis. The identities of Rh(I) species upon reduction have been studied. In contrast to the expected dissociation of halides in the Rh(I) state, the halide loss depends on solvent and water content. In dry CH3CN, in which Cl(-) is poorly solvated, a [Ru] complex dissociates and [(Ph2phen)2Ru(dpp)Rh(I)Cl2](+) and [(Ph2phen)2Ru(dpp)](2+) are formed. In contrast, for X = Br(-), the major product of reduction is the intact trimetallic Rh(I) complex [{(Ph2phen)2Ru(dpp)}2Rh(I)](5+). Chloride loss in CH3CN is facilitated by addition of 3 M H2O. In DMF, the reduced species is [{(Ph2phen)2Ru(dpp)}2Rh(I)](5+) regardless of X = Cl(-) or Br(-). PMID- 26247429 TI - Chiral Bicyclic Guanidine-Catalyzed Enantioselective Sulfenylation of Oxindoles and Benzofuran-2(3H)-ones. AB - A chiral bicyclic guanidine-catalyzed enantioselective sulfenylation of 3 substituted oxindoles to N-(sulfanyl)succinimides has been developed. A series of unprecedented 3-sulfenylated oxindoles, such as 3-benzyl/alkyl-substituted 3 benzyl/alkyloxindoles, were obtained with high enantioselectivities (up to 98% ee). This methodology is also effective for the first asymmetric sulfenylation of benzofuran-2(3H)-ones, providing 3-benzyl-3-benzylthio-substituted benzofuran 2(3H)-ones with satisfactory results (up to 95% ee). PMID- 26247430 TI - Asymmetries in kinesin-2 and cytoplasmic dynein contributions to melanosome transport. AB - The mechanisms involved in bidirectional transport along microtubules remain largely unknown. We explored the collective action of kinesin-2 and dynein motors during transport of melanosomes in Xenopus laevis melanophores. These motors are attached to organelles through accessory proteins establishing a complex molecular linker. We determined both the stiffness of this linker and the organelles speed and observed that these parameters depended on the organelle size and cargo direction. Our results suggest that melanosome transport is driven by two dissimilar teams: whereas dynein motors compete with kinesin-2 affecting the properties of plus-end directed organelles, kinesin-2 does not seem to play a similar role during minus-end transport. PMID- 26247431 TI - Functionality of Class A and Class B J-protein co-chaperones with Hsp70. AB - At their C-termini, cytosolic Hsp70s have an EEVD tetrapeptide that interacts with J-protein co-chaperones of the B, but not A, class. This interaction is required for partnering with yeast B-type J-proteins in protein folding. Here we report conservation of this feature. Human B-type J-proteins also have a stringent EEVD requirement. Human A-type J-proteins function less well than their yeast orthologs with Hsp70DeltaEEVD. Changes in the zinc binding domain, a domain absent in B-type J-proteins, overcomes this partial EEVD dependence. Our results suggest that the structurally similar A- and B-class J-proteins of the cytosol have evolved conserved, yet distinct, features that enhance specialized functionality of Hsp70 machinery. PMID- 26247432 TI - Cellular mechanism of oral absorption of solidified polymer micelles. AB - Oral delivery of poorly soluble and permeable drugs represents a significant challenge in drug development. The oral delivery of drugs remains to be the ultimate route of any drugs. However, in many cases, drugs are not absorbed well in the gastrointestinal tract, or they lose their activity. Polymer micelles were recognized as an effective carrier system for drug encapsulation, and are now studied as a vehicle for oral delivery of insoluble compounds. We characterized the properties of monomethoxy polyethylene glycol-poly lactic acid (mPEG-PLA) micelles, and visualized their internalization in mouse small intestine. Using Caco-2 cells as a cellular model, we studied the kinetics of particle uptake, their transport, and the molecular mechanism of their intestinal absorption. Moreover, by inhibiting specific endocytosis pathways, pharmacologically and genetically, we found that mPEG-PLA nanoparticle endocytosis is mediated by clathrin in an energy-dependent manner, and that the low-density lipoprotein receptor is involved. FROM THE CLINICAL EDITOR: Many current drugs used are non water soluble and indeed, the ability to deliver these drugs via the gastrointestinal tract remains the holy grail for many researchers. The authors in this paper developed monomethoxy polyethylene glycol-poly lactic acid (mPEG PLA) micelles as a drug nanocarrier, and studied the mechanism of uptake across intestinal cells. The findings should improve our current understanding and point to the development of more nanocarriers. PMID- 26247433 TI - School Start Times for Middle School and High School Students - United States, 2011-12 School Year. AB - Adolescents who do not get enough sleep are more likely to be overweight; not engage in daily physical activity; suffer from depressive symptoms; engage in unhealthy risk behaviors such as drinking, smoking tobacco, and using illicit drugs; and perform poorly in school. However, insufficient sleep is common among high school students, with less than one third of U.S. high school students sleeping at least 8 hours on school nights. In a policy statement published in 2014, the American Academy of Pediatrics (AAP) urged middle and high schools to modify start times as a means to enable students to get adequate sleep and improve their health, safety, academic performance, and quality of life. AAP recommended that "middle and high schools should aim for a starting time of no earlier than 8:30 a.m.". To assess state-specific distributions of public middle and high school start times and establish a pre-recommendation baseline, CDC and the U.S. Department of Education analyzed data from the 2011-12 Schools and Staffing Survey (SASS). Among an estimated 39,700 public middle, high, and combined schools* in the United States, the average start time was 8:03 a.m. Overall, only 17.7% of these public schools started school at 8:30 a.m. or later. The percentage of schools with 8:30 a.m. or later start times varied greatly by state, ranging from 0% in Hawaii, Mississippi, and Wyoming to more than three quarters of schools in Alaska (76.8%) and North Dakota (78.5%). A school system start time policy of 8:30 a.m. or later provides teenage students the opportunity to achieve the 8.5-9.5 hours of sleep recommended by AAP and the 8-10 hours recommended by the National Sleep Foundation. PMID- 26247434 TI - Alcohol-Impaired Driving Among Adults - United States, 2012. AB - Alcohol-impaired driving crashes account for approximately one third of all crash fatalities in the United States. In 2013, 10,076 persons died in crashes in which at least one driver had a blood alcohol concentration (BAC) >=0.08 grams per deciliter (g/dL), the legal limit for adult drivers in the United States. To estimate the prevalence, number of episodes, and annual rate of alcohol-impaired driving, CDC analyzed self-reported data from the 2012 Behavioral Risk Factor Surveillance System (BRFSS) survey. An estimated 4.2 million adults reported at least one alcohol-impaired driving episode in the preceding 30 days, resulting in an estimated 121 million episodes and a national rate of 505 episodes per 1,000 population annually. Alcohol-impaired driving rates varied by more than fourfold among states, and were highest in the Midwest U.S. Census region. Men accounted for 80% of episodes, with young men aged 21-34 years accounting for 32% of all episodes. Additionally, 85% of alcohol-impaired driving episodes were reported by persons who also reported binge drinking, and the 4% of the adult population who reported binge drinking at least four times per month accounted for 61% of all alcohol-impaired driving episodes. Effective strategies to reduce alcohol impaired driving include publicized sobriety checkpoints, enforcement of 0.08 g/dL BAC laws, requiring alcohol ignition interlocks for everyone convicted of driving while intoxicated, and increasing alcohol taxes. PMID- 26247435 TI - Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices, United States, 2015-16 Influenza Season. AB - This report updates the 2014 recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding the use of seasonal influenza vaccines. Updated information for the 2015-16 season includes 1) antigenic composition of U.S. seasonal influenza vaccines; 2) information on influenza vaccine products expected to be available for the 2015-16 season; 3) an updated algorithm for determining the appropriate number of doses for children aged 6 months through 8 years; and 4) recommendations for the use of live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) when either is available, including removal of the 2014-15 preferential recommendation for LAIV for healthy children aged 2 through 8 years. Information regarding topics related to influenza vaccination that are not addressed in this report is available in the 2013 ACIP seasonal influenza recommendations. PMID- 26247436 TI - Vital Signs: Estimated Effects of a Coordinated Approach for Action to Reduce Antibiotic-Resistant Infections in Health Care Facilities - United States. AB - BACKGROUND: Treatments for health care-associated infections (HAIs) caused by antibiotic-resistant bacteria and Clostridium difficile are limited, and some patients have developed untreatable infections. Evidence-supported interventions are available, but coordinated approaches to interrupt the spread of HAIs could have a greater impact on reversing the increasing incidence of these infections than independent facility-based program efforts. METHODS: Data from CDC's National Healthcare Safety Network and Emerging Infections Program were analyzed to project the number of health care-associated infections from antibiotic resistant bacteria or C. difficile both with and without a large scale national intervention that would include interrupting transmission and improved antibiotic stewardship. As an example, the impact of reducing transmission of one antibiotic resistant infection (carbapenem-resistant Enterobacteriaceae [CRE]) on cumulative prevalence and number of HAI transmission events within interconnected groups of health care facilities was modeled using two distinct approaches, a large scale and a smaller scale health care network. RESULTS: Immediate nationwide infection control and antibiotic stewardship interventions, over 5 years, could avert an estimated 619,000 HAIs resulting from CRE, multidrug-resistant Pseudomonas aeruginosa, invasive methicillin-resistant Staphylococcus aureus (MRSA), or C. difficile. Compared with independent efforts, a coordinated response to prevent CRE spread across a group of inter-connected health care facilities resulted in a cumulative 74% reduction in acquisitions over 5 years in a 10-facility network model, and 55% reduction over 15 years in a 102-facility network model. CONCLUSIONS: With effective action now, more than half a million antibiotic resistant health care-associated infections could be prevented over 5 years. Models representing both large and small groups of interconnected health care facilities illustrate that a coordinated approach to interrupting transmission is more effective than historical independent facilitybased efforts. IMPLICATIONS FOR PUBLIC HEALTH: Public health-led coordinated prevention approaches have the potential to more completely address the emergence and dissemination of these antibiotic-resistant organisms and C. difficile than independent facility-based efforts. PMID- 26247437 TI - Lack of Measles Transmission to Susceptible Contacts from a Health Care Worker with Probable Secondary Vaccine Failure - Maricopa County, Arizona, 2015. AB - On January 23, 2015, the Maricopa County Department of Public Health (MCDPH) was notified of a suspected measles case in a nurse, a woman aged 48 years. On January 11, the nurse had contact with a patient with laboratory-confirmed measles associated with the Disneyland theme park-related outbreak in California. On January 21, she developed a fever (103 degrees F [39.4 degrees C]), on January 23 she experienced cough and coryza, and on January 24, she developed a rash. The patient was instructed to isolate herself at home. On January 26, serum, a nasopharyngeal swab, and a urine specimen were collected. The following day, measles infection was diagnosed by real time reverse transcription polymerase chain reaction testing of the nasopharyngeal swab and urine specimen and by detection of measles-specific immunoglobulin (Ig)M and IgG in serum by enzyme linked immunosorbent assay. Because of her symptoms and laboratory results, the patient was considered to be infectious. PMID- 26247438 TI - Heat-related mortality projections for cardiovascular and respiratory disease under the changing climate in Beijing, China. AB - Because heat-related health effects tend to become more serious at higher temperatures, there is an urgent need to determine the mortality projection of specific heat-sensitive diseases to provide more detailed information regarding the variation of the sensitivity of such diseases. In this study, the specific mortality of cardiovascular and respiratory disease in Beijing was initially projected under five different global-scale General Circulation Models (GCMs) and two Representative Concentration Pathways scenarios (RCPs) in the 2020s, 2050s, and 2080s compared to the 1980s. Multi-model ensembles indicated cardiovascular mortality could increase by an average percentage of 18.4%, 47.8%, and 69.0% in the 2020s, 2050s, and 2080s under RCP 4.5, respectively, and by 16.6%,73.8% and 134% in different decades respectively, under RCP 8.5 compared to the baseline range. The same increasing pattern was also observed in respiratory mortality. The heat-related deaths under the RCP8.5 scenario were found to reach a higher number and to increase more rapidly during the 21(st) century compared to the RCP4.5 scenario, especially in the 2050s and the 2080s. The projection results show potential trends in cause-specific mortality in the context of climate change, and provide support for public health interventions tailored to specific climate-related future health risks. PMID- 26247439 TI - 6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors. AB - From a whole-organism high throughput screen of approximately 87000 compounds against Trypanosoma brucei brucei, we recently identified eight new unique compounds for the treatment of human African trypanosomiasis. In an effort to understand the structure-activity relationships around these compounds, we report for the first time our results on a new class of trypanocides, the pyrazine carboxamides. Attracted by the low molecular weight (270 g.mol(-1)) of our starting hit (9) and its potency (0.49 MUM), the SAR around the core was explored, leading to compounds having an EC50 as low as 25 nM against T. b. brucei and being more than 1500 times less toxic against mammalian L6 and HEK293 cell lines. The most potent compounds in the series were exquisitely selective for T. brucei over a panel of other protozoan parasites, showing an excellent correlation with the human infective parasite Trypanosoma brucei rhodesiense, the most potent compound (65) having an EC50 of 24 nM. The compounds are highly drug like and are able to penetrate the CNS, their only limitation currently being their rate of microsomal metabolism. To that effect, efforts to identify potential metabolites of selected compounds are also reported. PMID- 26247440 TI - Utilization of d-PTFE Barriers for Post-Extraction Bone Regeneration in Preparation for Dental Implants. AB - Guided bone regeneration (GBR) can be used to restore a defective alveolar ridge after extractions before or in combination with implant placement. It may also be employed after extractions to reduce crestal bone resorption and maximize bone fill of sockets. Resorbable or nonresorbable barriers (eg, expanded polytetrafluoroethylene [e-PTFE]) can be used when performing GBR procedures, but they need to be completely submerged to attain optimal results. Dense polytetrafluoroethylene (d-PTFE) is a type of nonresorbable barrier that circumvents the necessity to attain primary closure after placement of bone grafts, thereby reducing patient morbidity. This article addresses topics pertaining to d-PTFE utilization, including characteristics and advantages of d PTFE barriers, time needed for osteoid tissue to become impervious to penetration by flap connective tissue, relevant clinical studies, and limitations of available data. Clinical photographs and radiographs of successfully treated cases are presented to illustrate the efficacy of d-PTFE barriers in regenerating defective bony plates after extractions. PMID- 26247441 TI - Abutment Emergence Profile and Its Effect on Peri-Implant Tissues. AB - Peri-implant tissues differ markedly from those around the natural dentition. A thorough understanding of these tissues allows the restoring clinician to predictably manage and shape them through the use of a provisional restoration. The emergence profile of the implant abutment can be designed so as to maximize tissue volume following an immediate loading scenario, and modified later to manipulate and shape the tissue to its desired position. Employing a provisional restoration and carefully manipulating the emergence profile provides in-situ testing of the patient's biology and adaptation, helping the clinician accommodate patient expectations. PMID- 26247442 TI - Solving the Challenge of the Severely Compromised Implant in the Esthetic Zone: An Interdisciplinary Care Case. AB - Considered to be an excellent treatment option for the replacement of lost or missing teeth, dental implants can dramatically improve a patient's quality of life. Patient selection, clinical skill, and maintenance are all factors that can significantly affect outcome. This case report highlights problems encountered in what many would consider to be a straightforward case: extraction of a fractured root, implant placement, and restoration in an otherwise dentally and medically fit and healthy patient. The report exposes some of the issues that could potentially result in what could be deemed an implant catastrophe and then explores possible treatment options to help rectify the failures. Finally, the authors describe the treatment provided--a periodontal-prosthodontic solution- and report on the 4-year post-treatment follow-up. PMID- 26247443 TI - A Complex Implant-Supported Reconstruction with Monolithic-Minimally Veneered Zirconia: A Clinical Report. AB - The purpose of this case report is to highlight the issues of treating a complex maxillary and mandibular fixed, implant-supported reconstruction. It discusses the use of established evidence-based information along with recently developed supporting digital technologies for diagnostics and laboratory procedures, combined with high-strength zirconia ceramic and acrylic materials (polymethyl methacrylate) for provisionals and prototypes. These developments have created an accurate and precise workflow to provide reliable long-term performance and esthetic outcomes without the associated prevalence of damage and wear with previously used restorative materials. PMID- 26247444 TI - Surgical and Prosthetic Management of Implants: Single and Full-Arch Reconstruction. AB - Whether it's a single tooth or multiple teeth, tooth loss has esthetic, functional, and health implications. Replacing multiple teeth can be especially complicated due to the loss of surrounding structures, often making it necessary to use additional procedures--eg, bone grafting--to solve the problems that arise. Fortunately, modern techniques and materials in dentistry enable clinicians to replace and mimic lost teeth in a realistic, healthy, and functional way like no other field in medicine. This report discusses two cases that involve multiple subspecialties working synergistically to accomplish ideal tooth replacement and emphasizes the importance of proper diagnosis, treatment planning, and execution of surgical and restorative therapy to achieve optimal results. PMID- 26247445 TI - Subclassification and Clinical Management of Extraction Sockets with Labial Dentoalveolar Dehiscence Defects. AB - Immediate implant therapy involving implants placed into intact Type 1 extraction sockets has become a consistent clinical technique. The classification of Type 2 extraction sockets, where the mucosal tissues are present but there is a midfacial osseous dehiscence defect, has been described according to the extent of the buccal bone plate absence. The literature has offered different techniques in the treatment of Type 2 sockets; however, the extent of the defect has never been defined or delineated. In this article, the authors describe a subclassification of Type 2 sockets: Type 2A presents with a dehiscence defect roughly 5 mm to 6 mm from the free gingival margin (FGM) involving the coronal one-third of the labial bone plate; Type 2B presents with a dehiscence defect involving the middle one-third of the labial plate, approximately 7 mm to 9 mm from the FGM; and in Type 2C the dehiscence defect involves the apical one-third of the labial osseous plate roughly 10 mm or greater from the FGM. The authors also offer a protocol and technique employing immediate implant placement, guided bone regeneration, and bone graft containment with a custom two-piece healing abutment that can lead to consistent and satisfactory clinical outcomes in low smile-line patients. The treatment protocol and sequence is outlined in a clinical case presentation involving a Type 2B socket. PMID- 26247446 TI - Intraoral Digital Impressioning for Dental Implant Restorations Versus Traditional Implant Impression Techniques. AB - Over the course of the past two to three decades, intraoral digital impression systems have gained acceptance due to high accuracy and ease of use as they have been incorporated into the fabrication of dental implant restorations. The use of intraoral digital impressions enables the clinician to produce accurate restorations without the unpleasant aspects of traditional impression materials and techniques. This article discusses the various types of digital impression systems and their accuracy compared to traditional impression techniques. The cost, time, and patient satisfaction components of both techniques will also be reviewed. PMID- 26247447 TI - Optimal design of perturbations for individual two-compartment pharmacokinetic analysis. AB - We consider the optimal design of pharmacokinetic studies in patients that receive intermittent hemodialysis and intravenous antibiotic. Hemodialysis perturbs the pharmacokinetic system, providing additional opportunity for study. Designs that allocate measurements to occur exclusively during hemodialysis are shown to be viable alternatives to conventional designs, where all measurements occur outside of hemodialysis. Furthermore, hybrid designs with both conventional and intradialytic measurements have nearly double the efficiency of conventional designs. Convex optimal design and Monte Carlo techniques were used to simultaneously optimize hemodialysis event characteristics and sampling times, accounting for population pharmacokinetic heterogeneity. We also present several related methodological innovations. PMID- 26247448 TI - [Maternal and perinatal risk factors for neonatal morbidity: a narrative literature review]. AB - Newborn diseases increase neonatal mortality rates, so a literature review was conducted to establish the risk factors related to maternal and peripartum morbidity affecting the newborn. We searched the following electronic databases: Cumed, EBSCO, LILACS, IBECS and PubMed/MEDLINE. We used specific terms and Boolean operators in Spanish, Portuguese and English. We included longitudinal and cross-sectional descriptive studies, as well as case-control and cohort studies, systematic reviews and meta-analysis, spanning from 2010 to 2015 that responded the topic of interest. The included studies show that multiple maternal and perinatal conditions are risk factors for significant increase of neonatal morbidity, which are described in this narrative review. PMID- 26247449 TI - Accelerometric and dynamometric measurements of the impact shock of the equine forelimb and hindlimb at high speed trot on six different tracks - preliminary study in one horse. PMID- 26247451 TI - Outcomes of Pars Plana Vitrectomy for Patients With Vitreomacular Traction. AB - BACKGROUND AND OBJECTIVE: To evaluate clinical and optical coherence tomography (OCT) outcomes of pars plana vitrectomy (PPV) for patients with vitreomacular traction (VMT). PATIENTS AND METHODS: Noncomparative, interventional, consecutive case series from 2007 to 2014. RESULTS: Of the 37 study eyes, patients were grouped according to the extent of VMT evident on OCT. Group 1 (18 eyes) had intraretinal cysts on OCT. Group 2 (19 eyes) had both intraretinal cysts and subretinal fluid. Visual acuity (VA) improved at least one line or more in 76% of eyes postoperatively. Postoperative VA was not significantly different across the two groups (P > .36). Postoperatively, a macular hole developed in 4 eyes (10%). After reoperation, three of four eyes achieved macular hole closure. CONCLUSIONS: Patients with VMT achieve visual and OCT improvements after PPV. Postoperative macular hole formation is uncommon but can be successfully repaired with further surgery. PMID- 26247450 TI - Combined 23-Gauge PPV and Scleral Buckle Versus 23-Gauge PPV Alone for Primary Repair of Pseudophakic Rhegmatogenous Retinal Detachment. AB - BACKGROUND AND OBJECTIVE: This review compares 23-gauge pars plana vitrectomy (PPV) alone versus combined 23-gauge pars plana vitrectomy and scleral buckle (PPV/SB) for primary repair of pseudophakic rhegmatogenous retinal detachment (RRD). PATIENTS AND METHODS: A retrospective review of 70 eyes that underwent 23 gauge PPV and 43 eyes that received 23-gauge PPV/SB for pseudophakic RRD. Minimum follow-up was 3 months. Outcome measures included anatomical success, visual acuity, and complication rates. RESULTS: The 23-gauge PPV group achieved primary anatomical success in 58 of 70 cases (83%). Primary success in the PPV/SB group occurred in 36 of 43 cases (84%). Final anatomical success was achieved in all 113 cases (100%). The difference in primary success rates was not statistically significant (P = 1.000, Fisher exact test). Average visual acuity for macula-on RRDs in the PPV group showed a +0.07 logMAR improvement (P = .580) versus a +1.34 improvement (P < .001) in macula-off PPV cases. SB/PPV macula-on cases showed a decrease in logMAR visual acuity by -0.06 (P = .380) while macula-off SB/PPV cases improved by +1.28 (P = .002). There were no significant complications in either group. CONCLUSION: Both 23-gauge PPV and PPV/SB are effective procedures for repairing pseudophakic RRD and exhibit similar rates of success. PMID- 26247452 TI - Predictability of Recurrent Exudation and Subretinal Hemorrhaging in Neovascular Age-Related Macular Degeneration With Indocyanine Green Angiography. AB - BACKGROUND AND OBJECTIVE: To report the predictability of recurrent exudation and subretinal hemorrhaging after treatment extension in neovascular age-related macular degeneration (AMD) through assessment of interval changes in choroidal neovascularization (CNV) size on indocyanine green (ICG) angiography. PATIENTS AND METHODS: The charts of patients with neovascular AMD who underwent bevacizumab therapy using a treat-and-extend protocol were retrospectively reviewed over a 12-month period. RESULTS: An increase of 33% or more in CNV surface area on ICG angiography from 4 to 6 weeks, 6 to 8 weeks, and 8 to 10 weeks was observed in patients whose treatment interval could not be extended from 6 to 8 weeks, 8 to 10 weeks, and 10 to 12 weeks, respectively, and this was significant compared to patients whose treatment interval was successfully extended during those respective intervals (P < .0001, P = .0002, P = .0004, respectively). CONCLUSION: CNV size change on ICG angiography can predict which patients are likely to experience recurrent exudation and/or subretinal hemorrhaging after treatment extension using treat-and-extend bevacizumab. PMID- 26247453 TI - Serous Index of Pigment Epithelial Detachments in Neovascular Age-Related Macular Degeneration Predicts Response to Anti-Vascular Endothelial Growth Factor Treatment. AB - BACKGROUND AND OBJECTIVE: To determine whether optical density measurements of pigment epithelial detachments (PEDs) in neovascular age-related macular degeneration (AMD) can predict the response to treatment with anti-VEGF therapy. PATIENTS AND METHODS: Retrospective review of SD-OCT scans of 21 eyes of 21 patients with neovascular AMD and PED. Response to treatment was determined using SD-OCT volumetric analysis. The authors used optical density measurements of PED lesions on SD-OCT images to calculate the serous index, which is a measure of the serous component of PEDs. RESULTS: The serous index was found to correlate with the response to anti-VEGF treatment (r = .69, P = .0005), and to be predictive of the response to treatment (P = .007). CONCLUSION: The serous index of PEDs can help predict the response to anti-VEGF treatment. This measure may be useful in decisions regarding switching anti-VEGF agents in the clinical care of patients with neovascular AMD and PED. PMID- 26247454 TI - Surgical Outcomes for Persistent Macular Hole After Ocriplasmin. AB - BACKGROUND AND OBJECTIVE: To report surgical and visual acuity outcomes in eyes with unresolved full-thickness macular hole (FTMH) after treatment with ocriplasmin who subsequently underwent vitrectomy. PATIENTS AND METHODS: Retrospective case series of four eyes. Vision and anatomy via optical coherence tomography (OCT) were assessed before and after intravitreal ocriplasmin as well as 6 months after subsequent vitrectomy. RESULTS: Initial visual acuity ranged from 20/70 to 20/200. OCT showed focal vitreomacular traction (VMT) with FTMH ranging from 136 to 311 um in diameter. Following ocriplasmin, VMT released in all four eyes without closure of the FTMH. All FTMHs enlarged over follow-up after ocriplasmin (mean increase 133 um). Subsequent vitrectomy led to anatomic FTMH closure in all eyes. Final vision improved in all eyes (20/30 to 20/70). CONCLUSION: Initial ocriplasmin treatment of FTMH in this series of patients did not reduce the effectiveness of vitrectomy, which was required for definitive FTMH repair. PMID- 26247455 TI - Long-term Choroidal Thickness Changes After Acute Solar Retinopathy. AB - BACKGROUND AND OBJECTIVE: To identify long-term changes in choroidal thickness after solar retinopathy. PATIENTS AND METHODS: The study included 25 eyes of 25 men with acute solar retinopathy. Ocular examination, best corrected visual acuity (BCVA), and retinal and choroidal thickness measurements obtained using spectral-domain optical coherence tomography were evaluated. RESULTS: The mean follow-up was 6.1 +/- 0.4 months. The initial BCVA decreased in the affected eyes (P < .001). The mean BCVA (logMAR) improved significantly from 0.16 +/- 0.06 to 0.03 +/- 0.05 at 6 months (P < .001). There were no significant differences in the initial retinal and choroidal thicknesses between the affected and other eyes, while there was a significant decrease in the mean macular thickness and mean macular volume at 1 month and the mean choroidal thickness increased (P < .001). CONCLUSION: Significant retinal and choroidal thickness changes occurred after solar retinopathy. The changes in choroidal thickness suggest that the effects of solar retinopathy might not be limited to the retina. PMID- 26247456 TI - Comorbidity and Health Care Resource Use Among Commercially Insured Non-Elderly Patients With Diabetic Macular Edema. AB - BACKGROUND AND OBJECTIVE: Diabetic macular edema (DME) is a leading cause of blindness for non-elderly adults; however, health care-associated burden data from this population is lacking. The authors describe health care-associated burden in non-elderly patients with DME compared to those with diabetes and no DME. PATIENTS AND METHODS: In this retrospective, large-cohort study examines enrollment and health care claims (2007 to 2011) from a national database of insured patients aged 18 to 63 years (mean: 51). Comorbidity and health care utilization differences between patients with DME (n = 24,326) and matched controls with diabetes but no DME (n = 122,710) were analyzed over 1 and 3 years. RESULTS: DME patients had significantly more baseline comorbidities, and generally developed them at a higher rate over the study. Health care resource utilization rates were significantly higher in DME patients for every category analyzed. Patients with DME averaged more than 10 health care visits more than those with diabetes but no DME (25.5 vs 14.9; P < .001). CONCLUSION: Working-age patients with DME exhibit a complicated comorbidity profile and high associated burden of health care consumption. Considering this burden is critical for managing this complex population. PMID- 26247457 TI - Surgical Management of Anterior Chamber Migration of a Dexamethasone Intravitreal Implant. AB - BACKGROUND AND OBJECTIVE: Anterior chamber migration of the dexamethasone intravitreal implant (Ozurdex; Allergan, Irvine, CA) may lead to corneal edema and elevated intraocular pressure, warranting removal of the implant. MATERIALS AND METHODS: A 59-year-old patient with a history of prior vitrectomy, a posterior chamber intraocular lens with a disrupted posterior capsule, and a large inferior peripheral iridectomy presented with decreased vision due to corneal edema following dexamethasone intravitreal implant injection. The authors describe their technique for implant removal, which uses standard vitreoretinal instrumentation, viscoelastic, a modified Sheets glide, and angled forceps in order to avoid fragmentation of the implant and limit iatrogenic morbidity. RESULTS: The implant was successfully explanted. Postoperatively, the patient experienced improvement in the corneal edema, and after Descemet's stripping endothelial keratoplasty achieved a final best corrected visual acuity of 20/60 at final 12-month follow-up. CONCLUSION: Patients with aphakic lens status, anterior chamber intraocular lens with a disrupted posterior capsule, posterior chamber intraocular lens and a ruptured capsule, prior vitrectomy, and large peripheral iridectomies may be susceptible to migration of dexamethasone intravitreal implants into the anterior chamber. PMID- 26247459 TI - Macular Cavernous Hemangioma Associated With Peripheral Vascular Anomalies and Nonperfusion. AB - Retinal cavernous hemangiomas are benign vascular anomalies that are typically unilateral and located outside of the macula. Fluorescein angiography findings include an early slow-filling, non-leaking lesion with late intermixed lobules of hyperfluorescence and hypofluoresence secondary to plasma and erythrocyte sedimentation. We present a novel case of unilateral macular cavernous hemangioma with bilateral peripheral vascular anomalies and nonperfusion. This may represent a phenotypic variation of hemangiomas that, in conjunction with recent histopathologic and genetic findings, may aid in future therapies for a disease that has been traditionally observed due to slow progression. PMID- 26247458 TI - Wyburn-Mason Syndrome Associated With Cutaneous Reactive Angiomatosis and Central Retinal Vein Occlusion. AB - Retinal venous occlusive events are a rare complication of arteriovenous malformations of the retina found in Wyburn-Mason syndrome. The authors present a case of a 28-year-old man diagnosed with Wyburn-Mason syndrome and cutaneous reactive angiomatosis, a reactive angioproliferative disorder induced by vascular occlusion. He developed a central retinal vein occlusion complicated by macular edema and received treatment with intravitreal bevacizumab, which led to resolution of the edema. To the best of the authors' knowledge, this is the first report of an anti- vascular endothelial growth factor agent employed as an effective treatment for macular edema in the setting of Wyburn-Mason syndrome. The association between Wyburn-Mason syndrome and cutaneous reactive angiomatosis is also a novel finding. PMID- 26247460 TI - Leukostasis Retinopathy: A New Clinical Manifestation of Chronic Myeloid Leukemia With Severe Hyperleukocytosis. AB - The authors report a new clinical manifestation of chronic myeloid leukemia. A 41 year-old man presented with significant visual loss, leading to a diagnosis of chronic myeloid leukemia. His white blood count exceeded that of any previously reported case of the disease with documented retinal findings (562,000/mm(3)), and clinical evaluation revealed the blockage of temporal retinal vessels by white blood cells. Hematologic findings resolved within 1 month of chemotherapy with dasatinib, and further treatment with intravitreal anti-VEGF agents resulted in the complete resolution of fundus findings. The authors propose that leukostasis retinopathy be recognized as a clinical manifestation of this life threatening disease. PMID- 26247462 TI - 8 Questions with Dr. Puliafito. PMID- 26247461 TI - Association Between Growth of Geographic Atrophy and the Complement Factor I Locus. AB - The association between the growth of geographic atrophy (GA) and a single nucleotide polymorphism (SNP) in the complement factor I (CFI) locus was investigated in the COMPLETE trial. Growth of GA at 52 weeks in eyes without the CFI at-risk allele was slightly faster than the growth in eyes with the CFI at risk allele (P >= .72). The authors of the current study found that in contrast to the faster growth rate reported in CFI-positive eyes from the MAHALO trial, the CFI positive eyes in the COMPLETE trial did not grow faster, and this analysis included 24 eyes that met the MAHALO eligibility criteria. PMID- 26247463 TI - Prognostic Fifteen-Gene Signature for Early Stage Pancreatic Ductal Adenocarcinoma. AB - The outcomes of patients treated with surgery for early stage pancreatic ductal adenocarcinoma (PDAC) are variable with median survival ranging from 6 months to more than 5 years. This challenge underscores an unmet need for developing personalized medicine strategies to refine the current treatment decision-making process. To derive a prognostic gene signature for patients with early stage PDAC, a PDAC cohort from Moffitt Cancer Center (n = 63) was used with overall survival (OS) as the primary endpoint. This was further evaluated using an independent microarray cohort dataset (Stratford et al: n = 102). Technical validation was performed by NanoString platform. A prognostic 15-gene signature was developed and showed a statistically significant association with OS in the Moffitt cohort (hazard ratio [HR] = 3.26; p<0.001) and Stratford et al cohort (HR = 2.07; p = 0.02), and was independent of other prognostic variables. Moreover, integration of the signature with the TNM staging system improved risk prediction (p<0.01 in both cohorts). In addition, NanoString validation showed that the signature was robust with a high degree of reproducibility and the association with OS remained significant in the two cohorts. The gene signature could be a potential prognostic tool to allow risk-adapted stratification of PDAC patients into personalized treatment protocols; possibly improving the currently poor clinical outcomes of these patients. PMID- 26247466 TI - Correction: Perceived Stigma towards Leprosy among Community Members Living Close to Nonsomboon Leprosy Colony in Thailand. PMID- 26247464 TI - Genome-Wide Loss of Heterozygosity and DNA Copy Number Aberration in HPV-Negative Oral Squamous Cell Carcinoma and Their Associations with Disease-Specific Survival. AB - Oral squamous cell cancer of the oral cavity and oropharynx (OSCC) is associated with high case-fatality. For reasons that are largely unknown, patients with the same clinical and pathologic staging have heterogeneous response to treatment and different probability of recurrence and survival, with patients with Human Papillomavirus (HPV)-positive oropharyngeal tumors having the most favorable survival. To gain insight into the complexity of OSCC and to identify potential chromosomal changes that may be associated with OSCC mortality, we used Affymtrix 6.0 SNP arrays to examine paired DNA from peripheral blood and tumor cell populations isolated by laser capture microdissection to assess genome-wide loss of heterozygosity (LOH) and DNA copy number aberration (CNA) and their associations with risk factors, tumor characteristics, and oral cancer-specific mortality among 75 patients with HPV-negative OSCC. We found a highly heterogeneous and complex genomic landscape of HPV-negative tumors, and identified regions in 4q, 8p, 9p and 11q that seem to play an important role in oral cancer biology and survival from this disease. If confirmed, these findings could assist in designing personalized treatment or in the creation of models to predict survival in patients with HPV-negative OSCC. PMID- 26247465 TI - Phylogeny of Echinoderm Hemoglobins. AB - BACKGROUND: Recent genomic information has revealed that neuroglobin and cytoglobin are the two principal lineages of vertebrate hemoglobins, with the latter encompassing the familiar myoglobin and alpha-globin/beta-globin tetramer hemoglobin, and several minor groups. In contrast, very little is known about hemoglobins in echinoderms, a phylum of exclusively marine organisms closely related to vertebrates, beyond the presence of coelomic hemoglobins in sea cucumbers and brittle stars. We identified about 50 hemoglobins in sea urchin, starfish and sea cucumber genomes and transcriptomes, and used Bayesian inference to carry out a molecular phylogenetic analysis of their relationship to vertebrate sequences, specifically, to assess the hypothesis that the neuroglobin and cytoglobin lineages are also present in echinoderms. RESULTS: The genome of the sea urchin Strongylocentrotus purpuratus encodes several hemoglobins, including a unique chimeric 14-domain globin, 2 androglobin isoforms and a unique single androglobin domain protein. Other strongylocentrotid genomes appear to have similar repertoires of globin genes. We carried out molecular phylogenetic analyses of 52 hemoglobins identified in sea urchin, brittle star and sea cucumber genomes and transcriptomes, using different multiple sequence alignment methods coupled with Bayesian and maximum likelihood approaches. The results demonstrate that there are two major globin lineages in echinoderms, which are related to the vertebrate neuroglobin and cytoglobin lineages. Furthermore, the brittle star and sea cucumber coelomic hemoglobins appear to have evolved independently from the cytoglobin lineage, similar to the evolution of erythroid oxygen binding globins in cyclostomes and vertebrates. CONCLUSION: The presence of echinoderm globins related to the vertebrate neuroglobin and cytoglobin lineages suggests that the split between neuroglobins and cytoglobins occurred in the deuterostome ancestor shared by echinoderms and vertebrates. PMID- 26247467 TI - Environmental Costs of Government-Sponsored Agrarian Settlements in Brazilian Amazonia. AB - Brazil has presided over the most comprehensive agrarian reform frontier colonization program on Earth, in which ~1.2 million settlers have been translocated by successive governments since the 1970's, mostly into forested hinterlands of Brazilian Amazonia. These settlements encompass 5.3% of this ~5 million km2 region, but have contributed with 13.5% of all land conversion into agropastoral land uses. The Brazilian Federal Agrarian Agency (INCRA) has repeatedly claimed that deforestation in these areas largely predates the sanctioned arrival of new settlers. Here, we quantify rates of natural vegetation conversion across 1911 agrarian settlements allocated to 568 Amazonian counties and compare fire incidence and deforestation rates before and after the official occupation of settlements by migrant farmers. The timing and spatial distribution of deforestation and fires in our analysis provides irrefutable chronological and spatially explicit evidence of agropastoral conversion both inside and immediately outside agrarian settlements over the last decade. Deforestation rates are strongly related to local human population density and road access to regional markets. Agrarian settlements consistently accelerated rates of deforestation and fires, compared to neighboring areas outside settlements, but within the same counties. Relocated smallholders allocated to forest areas undoubtedly operate as pivotal agents of deforestation, and most of the forest clearance occurs in the aftermath of government-induced migration. PMID- 26247468 TI - School Performance: A Matter of Health or Socio-Economic Background? Findings from the PIAMA Birth Cohort Study. AB - BACKGROUND: Performance in primary school is a determinant of children's educational attainment and their socio-economic position and health inequalities in adulthood. We examined the relationship between five common childhood health conditions (asthma symptoms, eczema, general health, frequent respiratory infections, and overweight), health related school absence and family socio economic status on children's school performance. METHODS: We used data from 1,865 children in the Dutch PIAMA birth cohort study. School performance was measured as the teacher's assessment of a suitable secondary school level for the child, and the child's score on a standardized achievement test (Cito Test). Both school performance indicators were standardised using Z-scores. Childhood health was indicated by eczema, asthma symptoms, general health, frequent respiratory infections, overweight, and health related school absence. Children's health conditions were reported repeatedly between the age of one to eleven. School absenteeism was reported at age eleven. Highest attained educational level of the mother and father indicated family socio-economic status. We used linear regression models with heteroskedasticity-robust standard errors for our analyses with adjustment for sex of the child. RESULTS: The health indicators used in our study were not associated with children's school performance, independently from parental educational level, with the exception of asthma symptoms (-0.03 z-score / -0.04 z-score with Cito Test score after adjusting for respectively maternal and paternal education) and missing more than 5 schooldays due to illness (-0.18 z-score with Cito Test score and -0.17 z-score with school level assessment after adjustment for paternal education). The effect estimates for these health indicators were much smaller though than the effect estimates for parental education, which was strongly associated with children's school performance. CONCLUSION: Children's school performance was affected only slightly by a number of common childhood health problems, but was strongly associated with parental education. PMID- 26247469 TI - Acute Unilateral Vestibular Failure Does Not Cause Spatial Hemineglect. AB - OBJECTIVES: Visuo-spatial neglect and vestibular disorders have common clinical findings and involve the same cortical areas. We questioned (1) whether visuo spatial hemineglect is not only a disorder of spatial attention but may also reflect a disorder of higher cortical vestibular function and (2) whether a vestibular tone imbalance due to an acute peripheral dysfunction can also cause symptoms of neglect or extinction. Therefore, patients with an acute unilateral peripheral vestibular failure (VF) were tested for symptoms of hemineglect. METHODS: Twenty-eight patients with acute VF were assessed for signs of vestibular deficits and spatial neglect using clinical measures and various common standardized paper-pencil tests. Neglect severity was evaluated further with the Center of Cancellation method. Pathological neglect test scores were correlated with the degree of vestibular dysfunction determined by the subjective visual vertical and caloric testing. RESULTS: Three patients showed isolated pathological scores in one or the other neglect test, either ipsilesionally or contralesionally to the VF. None of the patients fulfilled the diagnostic criteria of spatial hemineglect or extinction. CONCLUSIONS: A vestibular tone imbalance due to unilateral failure of the vestibular endorgan does not cause spatial hemineglect, but evidence indicates it causes mild attentional deficits in both visual hemifields. PMID- 26247471 TI - Khat Chewing Habits in the Population of the Jazan Region, Saudi Arabia: Prevalence and Associated Factors. AB - The use of khat (Catha edulis) is a major public health and social problem that is believed to be growing globally. The khat chewing habit is prevalent in all areas of the Jazan region, Kingdom of Saudi Arabia (KSA). However, few studies have been conducted at the community level to investigate the khat chewing habits in this area. This study was conducted with the aim of assessing the prevalence and predictors of khat chewing among the Jazan community population. A cross sectional study was conducted with a sample (n = 4,500) of the Jizani population who attended primary heath care centers in Jazan region. The participants were selected using a two-stage cluster random sampling. A structured questionnaire was used for data collection. The overall lifetime prevalence of khat chewing was 33.2% (95% CI 31.8-34.7) and was significantly higher for males 42.2% (95% CI 40.4-43.9) than for females 11.3% (95% CI 9.6-13.1) (P < 0.001). Current khat chewers accounted for 28.7% (95% CI 27.4-30.1) of the population sampled; 36.9% (95% CI 35.2-38.6) of whom were males, which is a significantly higher percentage than the 8.7% (95% CI 7.3-10.4) of current khat chewers who were females (P < 0.001). The multivariate logistic regression analysis suggests that the most important independent predictors of khat chewing were having a friend who chewed khat (OR = 20.1, P < 0.001), participant's smoking status (OR) = 3.9, P < 0.001), friend's smoking status (OR = 2.2, P < 0.001), gender (OR = 2.2, P < 0.001) and educational level (OR = 1.5, P < 0.05). A large proportion of the Jizani populations chew khat. Government and non-governmental organizations NGOs should design and strengthen community prevention programs to curb the high prevalence of khat use. PMID- 26247472 TI - Coordinated Evolution of Influenza A Surface Proteins. AB - The surface proteins hemagglutinin (HA) and neuraminidase (NA) of human influenza A virus evolve under selection pressures to escape adaptive immune responses and antiviral drug treatments. In addition to these external selection pressures, some mutations in HA are known to affect the adaptive landscape of NA, and vice versa, because these two proteins are physiologically interlinked. However, the extent to which evolution of one protein affects the evolution of the other one is unknown. Here we develop a novel phylogenetic method for detecting the signatures of such genetic interactions between mutations in different genes - that is, inter-gene epistasis. Using this method, we show that influenza surface proteins evolve in a coordinated way, with mutations in HA affecting subsequent spread of mutations in NA and vice versa, at many sites. Of particular interest is our finding that the oseltamivir-resistance mutations in NA in subtype H1N1 were likely facilitated by prior mutations in HA. Our results illustrate that the adaptive landscape of a viral protein is remarkably sensitive to its genomic context and, more generally, that the evolution of any single protein must be understood within the context of the entire evolving genome. PMID- 26247473 TI - No Association of Blood Type O With Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1. AB - CONTEXT: An association between ABO blood type and the development of cancer, in particular, pancreatic cancer, has been reported in the literature. An association between blood type O and neuroendocrine tumors in multiple endocrine neoplasia type 1 (MEN1) patients was recently suggested. Therefore, blood type O was proposed as an additional factor to personalize screening criteria for neuroendocrine tumors in MEN1 patients. OBJECTIVE: The aim of this study was to assess the association between blood type O and the occurrence of neuroendocrine tumors in the national Dutch MEN1 cohort. DESIGN: This is a cohort study using the Dutch National MEN1 database, which includes more than 90% of the Dutch MEN1 population. Demographic and clinical data were analyzed by blood type. Chi-square tests and Fisher exact tests were used to determine the association between blood type O and occurrence of neuroendocrine tumors. A cumulative incidence analysis (Gray's test) was performed to assess the equality of cumulative incidence of neuroendocrine tumors in blood type groups, taking death into account as a competing risk. RESULTS: The ABO blood type of 200 of 322 MEN1 patients was known. Demographic and clinical characteristics were similar among blood type O and non-O type cohorts. The occurrence of neuroendocrine tumors of the lung, thymus, pancreas, and gastrointestinal tract was equally distributed across the blood type O and non-O type cohorts (Grays's test for equality; P = 0.72). Furthermore, we found no association between blood type O and the occurrence of metastatic disease or survival. CONCLUSIONS: An association between blood type O and the occurrence of neuroendocrine tumors in MEN1 patients was not confirmed. For this reason, the addition of the blood type to screening and surveillance practice seems not to be of additional value for identifying MEN1 patients at risk for the development of neuroendocrine tumors, metastatic disease, or a shortened survival. PMID- 26247470 TI - Cenicriviroc, a Novel CCR5 (R5) and CCR2 Antagonist, Shows In Vitro Activity against R5 Tropic HIV-2 Clinical Isolates. AB - BACKGROUND: Maraviroc activity against HIV-2, a virus naturally resistant to different HIV-1 antiretroviral drugs, has been recently demonstrated. The aim of this study was to assess HIV-2 susceptibility to cenicriviroc, a novel, once daily, dual CCR5 and CCR2 antagonist that has completed Phase 2b development in HIV-1 infection. METHODS: Cenicriviroc phenotypic activity has been tested using a PBMC phenotypic susceptibility assay against four R5-, one X4- and one dual tropic HIV-2 clinical primary isolates. All isolates were obtained by co cultivation of PHA-activated PBMC from distinct HIV-2-infected CCR5-antagonist naive patients included in the French HIV-2 cohort and were previously tested for maraviroc susceptibility using the same protocol. HIV-2 tropism was determined by phenotypic assay using Ghost(3) cell lines. RESULTS: Regarding the 4 R5 HIV-2 clinical isolates tested, effective concentration 50% EC50 for cenicriviroc were 0.03, 0.33, 0.45 and 0.98 nM, similar to those observed with maraviroc: 1.13, 0.58, 0.48 and 0.68 nM, respectively. Maximum percentages of inhibition (MPI) of cenicriviroc were 94, 94, 93 and 98%, similar to those observed with maraviroc (93, 90, 82, 100%, respectively). The dual- and X4-tropic HIV-2 strains were resistant to cenicriviroc with EC50 >1000 nM and MPI at 33% and 4%, respectively. CONCLUSIONS: In this first study assessing HIV-2 susceptibility to cenicriviroc, we observed an in vitro activity against HIV-2 R5-tropic strains similar to that observed with maraviroc. Thus, cenicriviroc may offer a once-daily treatment opportunity in the limited therapeutic arsenal for HIV-2. Clinical studies are warranted. PMID- 26247474 TI - Free and Cell Wall-Bound Polyamines under Long-Term Water Stress Applied at Different Growth Stages of *Triticosecale Wittm. AB - BACKGROUND: Long-stemmed and semi-dwarf cultivars of triticale were exposed to water stress at tillering, heading and anthesis stage. Quantitative determination of free and cell wall-bound polyamines, i.e. agmatine, cadaverine, putrescine, spermidine and spermine, was supplemented with an analysis of quantitative relationships between free and cell wall-bound polyamines. RESULTS: The content of free and cell wall-bound polyamines varied depending on the development stage, both under optimal and water stress conditions. Drought-induced increase in free agmatine content was observed at all developmental stages in long-stemmed cultivar. A depletion of spermidine and putrescine was also reported in this cultivar, and spermidine was less abundant in semi-dwarf cultivar exposed to drought stress at the three analyzed developmental stages. Changes in the content of the other free polyamines did not follow a steady pattern reflecting the developmental stages. On the contrary, the content of cell wall-bound polyamines gradually increased from tillering, through heading and until anthesis period. CONCLUSION: Water stress seemed to induce a progressive decrease in the content of free polyamines and an accumulation of cell wall-bound polyamines. PMID- 26247475 TI - Chemical Composition of Micrometer-Sized Filaments in an Aragonite Host by a Miniature Laser Ablation/Ionization Mass Spectrometer. AB - Detection of extraterrestrial life is an ongoing goal in space exploration, and there is a need for advanced instruments and methods for the detection of signatures of life based on chemical and isotopic composition. Here, we present the first investigation of chemical composition of putative microfossils in natural samples using a miniature laser ablation/ionization time-of-flight mass spectrometer (LMS). The studies were conducted with high lateral (~15 MUm) and vertical (~20-200 nm) resolution. The primary aim of the study was to investigate the instrument performance on micrometer-sized samples both in terms of isotope abundance and element composition. The following objectives had to be achieved: (1) Consider the detection and calculation of single stable isotope ratios in natural rock samples with techniques compatible with their employment of space instrumentation for biomarker detection in future planetary missions. (2) Achieve a highly accurate chemical compositional map of rock samples with embedded structures at the micrometer scale in which the rock matrix is easily distinguished from the micrometer structures. Our results indicate that chemical mapping of strongly heterogeneous rock samples can be obtained with a high accuracy, whereas the requirements for isotope ratios need to be improved to reach sufficiently large signal-to-noise ratio (SNR). PMID- 26247477 TI - Information presentation format moderates the unconscious-thought effect: The role of recollection. AB - The unconscious-thought effect occurs when distraction improves complex decision making. In two experiments using the unconscious-thought paradigm, we investigated the effect of presentation format of decision information (i) on memory for decision-relevant information and (ii) on the quality of decisions made after distraction, conscious deliberation or immediately. We used the process-dissociation procedure to measure recollection and familiarity. The two studies showed that presenting information blocked per criterion led participants to recollect more decision-relevant details compared to a presentation by option. Moreover, a Bayesian meta-analysis of the two studies provided strong evidence that conscious deliberation resulted in better decisions when the information was presented blocked per criterion and substantial evidence that distraction improved decision quality when the information was presented blocked per option. Finally, Study 2 revealed that the recollection of decision-relevant details mediated the effect of presentation format on decision quality in the deliberation condition. This suggests that recollection contributes to conscious deliberation efficacy. PMID- 26247478 TI - Modulation of sulfur partial pressure in sulfurization to significantly improve the photoelectrochemical performance over the Cu2ZnSnS4 photocathode. AB - Cu2ZnSnS4 photocathodes with excellent photoelectrochemical properties were fabricated via a facile method of adjusting the sulfur partial pressure in a semi closed system, which achieved a maximum photocurrent-density of 1.8 mA cm(-2) under irradiation of a solar simulator which is 9-fold larger than that synthesized in an open system. PMID- 26247476 TI - Heart Rate Variability Analysis in an Experimental Model of Hemorrhagic Shock and Resuscitation in Pigs. AB - BACKGROUND: The analysis of heart rate variability (HRV) has been shown as a promising non-invasive technique for assessing the cardiac autonomic modulation in trauma. The aim of this study was to evaluate HRV during hemorrhagic shock and fluid resuscitation, comparing to traditional hemodynamic and metabolic parameters. METHODS: Twenty anesthetized and mechanically ventilated pigs were submitted to hemorrhagic shock (60% of estimated blood volume) and evaluated for 60 minutes without fluid replacement. Surviving animals were treated with Ringer solution and evaluated for an additional period of 180 minutes. HRV metrics (time and frequency domain) as well as hemodynamic and metabolic parameters were evaluated in survivors and non-survivors animals. RESULTS: Seven of the 20 animals died during hemorrhage and initial fluid resuscitation. All animals presented an increase in time-domain HRV measures during haemorrhage and fluid resuscitation restored baseline values. Although not significantly, normalized low-frequency and LF/HF ratio decreased during early stages of haemorrhage, recovering baseline values later during hemorrhagic shock, and increased after fluid resuscitation. Non-surviving animals presented significantly lower mean arterial pressure (43+/-7 vs 57+/-9 mmHg, P<0.05) and cardiac index (1.7+/-0.2 vs 2.6+/-0.5 L/min/m2, P<0.05), and higher levels of plasma lactate (7.2+/-2.4 vs 3.7+/-1.4 mmol/L, P<0.05), base excess (-6.8+/-3.3 vs -2.3+/-2.8 mmol/L, P<0.05) and potassium (5.3+/-0.6 vs 4.2+/-0.3 mmol/L, P<0.05) at 30 minutes after hemorrhagic shock compared with surviving animals. CONCLUSIONS: The HRV increased early during hemorrhage but none of the evaluated HRV metrics was able to discriminate survivors from non-survivors during hemorrhagic shock. Moreover, metabolic and hemodynamic variables were more reliable to reflect hemorrhagic shock severity than HRV metrics. PMID- 26247479 TI - Association of Obesity with Onset of Puberty and Sex Hormones in Chinese Girls: A 4-Year Longitudinal Study. AB - OBJECTIVE: To examine the influence of childhood obesity on the early onset of puberty and sex hormones in girls. METHODS: Healthy girls with different percentages of body fat at baseline (40 obese, 40 normal, and 40 lean) were recruited from three elementary schools in Shenyang, China. These girls (mean age 8.5 years) were also matched by height, school grade, Tanner stage, and family economic status at baseline. Anthropometry, puberty characteristics, and sex hormone concentrations were measured at baseline and at each follow-up visit. The generalized estimating equation model and analysis of variance for repeated measures using a generalized linear model were used to determine the differences in puberty characteristics and sex hormones among three groups. RESULTS: Over 4 years, mean age of breast II onset was earlier among obese girls (8.8 years) than normal girls (9.2 years) and lean girls (9.3 years). The prevalence (%) of early maturation in the obese, normal, and lean groups was 25.9%, 11.1%, and 7.4%, respectively. Obesity was associated with an increased risk for breast stage II (year 2: RR, 6.3; 95% CI, 1.9-21.1 and year 3: RR, 6.9; 95% CI, 0.8-60.1). None of the girls experienced menarche in the first year; however, by the fourth year 50.0% of obese girls had menarche onset, which was higher than normal weight (27.5%) and lean girls (8.1%). The mean estradiol level increased with age in the obese, normal, and lean groups. The mean estradiol concentration was higher in obese girls than in normal and lean girls throughout the 4-year period (P<0.05). CONCLUSIONS: Childhood obesity contributes to early onset of puberty and elevated levels of estradiol in girls. PMID- 26247480 TI - Fine-Tuning of beta-Substitution to Modulate the Lowest Triplet Excited States: A Bioinspired Approach to Design Phosphorescent Metalloporphyrinoids. AB - Learning nature's approach to modulate photophysical properties of NIR porphyrinoids by fine-tuning beta-substituents including the number and position, in a manner similar to naturally occurring chlorophylls, has the potential to circumvent the disadvantages of traditional "extended pi-conjugation" strategy such as stability, molecular size, solubility, and undesirable pi-pi stacking. Here we show that such subtle structural changes in Pt(II) or Pd(II) cis/trans porphodilactones (termed by cis/trans-Pt/Pd) influence photophysical properties of the lowest triplet excited states including phosphorescence, Stokes shifts, and even photosensitization ability in triplet-triplet annihilation reactions with rubrene. Prominently, the overall upconversion capability (eta, eta = epsilon.Phi(UC)) of Pd or Pt trans-complex is 10(4) times higher than that of cis analogue. Nanosecond time-resolved infrared (TR-IR) spectroscopy experiments showed larger frequency shift of nu(C?O) bands (ca. 10 cm(-1)) of cis-complexes than those of trans-complexes in the triplet excited states. These spectral features, combining with TD-DFT calculations, suggest the strong electronic coupling between the lactone moieties and the main porphyrin chromophores and thus the importance of precisely positioning beta-substituents by mimicking chlorophylls, as an alternative to "extended pi-conjugation", in designing NIR active porphyrinoids. PMID- 26247481 TI - Allosteric role of the amino-terminal A/B domain on corticosteroid transactivation of gar and human glucocorticoid receptors. AB - We studied the role of the A/B domain at the amino terminus of gar (Atractosterus tropicus) and human glucocorticoid receptors (GRs) on transcriptional activation by various glucocorticoids. In transient transfection assays, dexamethasone [DEX] and cortisol had a lower half-maximal response (EC50) for transcriptional activation of full length gar GR than of human GR. Both GRs had similar responses to corticosterone, while 11-deoxycortisol had a lower EC50 for gar GR than for human GR. In contrast, constructs of gar GR and human GR consisting of their hinge (D domain), ligand binding domain (LBD) (E domain) fused to a GAL4 DNA binding domain (DBD) had a higher EC50 (weaker response) for all glucocorticoids. To study the role of the A/B domain, which contains an intrinsically disordered region, we investigated steroid activation of chimeric gar GR and human GR, in which their A/B domains were exchanged. Replacement of human A/B domains with the gar A/B domains yielded a chimeric GR with a lower EC50 for DEX and cortisol, while the EC50 increased for these steroids for the human A/B-gar C/E chimera, indicating that gar A/B domains contributes to the lower EC50 of gar GR for glucocorticoids. Our data suggests that allosteric signaling between the A/B domains and LBD influences transcriptional activation of human and gar GR by different steroids, and this allosteric mechanism evolved over 400 million years before gar and mammals separated from a common ancestor. PMID- 26247482 TI - Outcomes of simultaneous heart-kidney and lung-kidney transplantations: the Australian and New Zealand experience. AB - BACKGROUND: Heart or lung transplantation alone in individuals with significant pre-existing renal impairment results in high mortality and morbidity. Simultaneous heart-kidney (SHK) or simultaneous lung-kidney (SLK) transplantation may be considered in patients with dual organ failure not suitable for single organ transplantation. AIM: We aimed to outline the Australian and New Zealand experience of SHK and SLK transplantations, focussing on patient characteristics and survival. METHODS: We analysed all SHK and SLK transplants performed in four centres across Australia and New Zealand between 1990 and 2014. RESULTS: Over the study period, 35 SHK and 3 SLK transplants were performed across 4 transplant centres. Mean age at transplantation for SHK transplants was 45 years, and for SLK transplant was 27 years. The most common aetiology of renal failure was glomerulonephritis. Most SHK transplant patients (77%) required renal replacement therapy prior to transplantation, with only one of the three patients undergoing SLK transplant, dialysis dependent. One-year survival for the cohort was 79%, which is lower than reported for single organ transplantation. However, 5- and 10 year survivals of 76% and 68%, respectively, were comparable. Isolated renal graft loss was seen in five patients, with only one patient successfully re transplanted and the rest commencing dialysis. CONCLUSION: The Australian and New Zealand experience of SHK and SLK includes 38 patients with a high 1-year mortality, but excellent 5- and 10-year survivals. Based on this, it seems reasonable to continue to offer combined organ transplantation to select patients with dual organ failure. PMID- 26247483 TI - The applied model of imagery use: Examination of moderation and mediation effects. AB - The applied model of mental imagery use proposed an interaction effect between imagery type and imagery ability. This study had two aims: (a) the examination of imagery ability as a moderating variable between imagery type and dispositional flow, and (b) the testing of alternative mediation models. The sample consisted of 367 athletes from Scotland and Australia, who completed the Sport Imagery Questionnaire, Sport Imagery Ability Questionnaire, and Dispositional Flow Scale 2. Hierarchical regression analysis showed direct effects of imagery use and imagery ability on flow, but no significant interaction. Mediation analysis revealed a significant indirect path, indicating a partially mediated relationship (P = 0.002) between imagery use, imagery ability, and flow. Partial mediation was confirmed when the effect of cognitive imagery use and cognitive imagery ability was tested, and a full mediation model was found between motivational imagery use, motivational imagery ability, and flow. The results are discussed in conjunction with potential future research directions on advancing theory and applications. PMID- 26247484 TI - Recurrence rate and outcome of postterm pregnancy, a national cohort study. AB - OBJECTIVE: To assess the recurrence rate of postterm delivery (gestational age at or beyond 42+0 weeks or 294 days) and to describe maternal and perinatal outcomes after previous postterm delivery. STUDY DESIGN: From the longitudinal linked Netherlands Perinatal Registry database, we selected all singleton primiparous women who delivered between 37+0 and 42+6 weeks with a subsequent singleton pregnancy from 1999 to 2007. We excluded congenital abnormalities. We compared the recurrence rate of postterm delivery and risk of antenatal fetal death in women with and without a postterm delivery in their first pregnancy. We compared perinatal outcome (composite of perinatal mortality, Apgar score <7 and birth injury) and adverse maternal outcome (composite of maternal death, abruptio placentae, PPH>1000ml and blood transfusions) between women with a recurrent and a de novo postterm second pregnancy. RESULTS: Our study population consisted of 233,327 women of whom 17,874 (7.7%) delivered postterm in the first pregnancy. In the second pregnancy, 2678 (15%) women had a recurrent postterm delivery compared to 8698 (4%) women with a de novo postterm delivery (odds ratio (OR) 4.2 95% confidence interval (CI) 4.0-4.4). Subgroup analysis in recurrent and de novo postterm delivery showed no differences in composite perinatal and composite maternal outcome (OR 1.0; CI 0.7-1.5, p=0.90 and OR 1.1, CI 0.9-1.4, p=0.16), adjusted for fetal position and mode of delivery). CONCLUSIONS: Women with a postterm delivery in the first pregnancy have a higher risk of recurrent postterm delivery. Our data suggest that there is no difference in the composite adverse perinatal outcome between recurrent and de novo postterm delivery. PMID- 26247486 TI - Comparing Methods for Repair of the External Valve: One More Step Toward a Unified View of Lateral Wall Insufficiency. PMID- 26247485 TI - Tumor necrosis factor-alpha gene promoter methylation in Japanese adults with chronic periodontitis and rheumatoid arthritis. AB - BACKGROUND AND OBJECTIVE: Over-expression of tumor necrosis factor-alpha (TNF alpha) plays a pathological role in chronic periodontitis (CP) and rheumatoid arthritis (RA), which might be regulated by the epigenetic mechanism. The aim of the present study was to evaluate whether there is a unique methylation profile of the TNF-alpha gene promoter in blood cells of individuals with CP and RA. MATERIAL AND METHODS: The study participants consisted of 30 Japanese adults with RA (RA group), 30 race-matched adults with CP only (CP group) and 30 race-matched healthy controls (H group). Genomic DNA isolated from peripheral blood was modified by sodium bisulfite and analyzed, by direct sequencing, to investigate DNA methylation of the TNF-alpha gene promoter region. The level of TNF-alpha produced in mononuclear cells stimulated with Porphyromonas gingivalis lipopolysaccharide was determined using ELISA. RESULTS: Twelve cytosine-guanine dinucleotide (CpG) motifs were identified in the TNF-alpha promoter fragment from -343 to +57 bp. The CP group showed a significantly higher methylation rate and frequency at -72 bp than the H group (p < 0.01). The RA group exhibited significantly higher methylation rates at seven CpG motifs (-302, -163, -119, 72, -49, -38 and +10 bp), and significantly higher methylation frequencies at six CpG motifs (-163, -119, -72, -49, -38 and +10 bp), than the H group (p < 0.01 for all comparisons). The levels of TNF-alpha produced were significantly different between individuals with and without methylation at -163 bp (p = 0.03). CONCLUSION: These results suggest that the hypermethylated status of CpG motifs in the TNF-alpha gene promoter in blood cells may be unique to Japanese adults with CP and RA. PMID- 26247487 TI - Binge Drinking and Perceived Neighborhood Characteristics Among Mexican Americans Residing on the U.S.-Mexico Border. AB - BACKGROUND: This study examines the association between perceived neighborhood violence, perceived neighborhood collective efficacy, and binge drinking among Mexican Americans residing on the U.S.-Mexico border. METHODS: Data were collected from a multistage cluster sample of adult Mexican Americans residing in the U.S.-Mexico border areas of California, Arizona, New Mexico, and Texas (N = 1,307). The survey weighted response rate was 67%. Face-to-face interviews lasting approximately 1 hour were conducted in respondents' homes in English or Spanish. Path analysis was used to test whether collective efficacy mediated the impact of perceived neighborhood violence on binge drinking. RESULTS: Among 30+ year-old women, perceived neighborhood collective efficacy mediated the effects of perceived neighborhood violence on binge drinking in a theoretically predicted way: Lower perceptions of violence predicted an increased perception of collective efficacy, which in turn, predicted less binge drinking. Direct effects of violence perceptions on binge were nonsignificant. Younger 18- to 29-year-old women showed a similar (but nonsignificant) pattern of effects. Perceived collective efficacy also mediated the effects of perceived violence on binge drinking among men, but in opposite ways for older and younger men. Older men showed the same mediating effect as older women, but the effect reversed among younger men due to a strong, positive relation between collective efficacy and binge drinking. There were also age differences in the direct effect of violence perceptions on binge drinking: Perceptions of violence predicted more binge drinking among young men, but less among older men. CONCLUSIONS: These results highlight the complexity of people's responses to neighborhood characteristics in regard to their drinking. Young men in particular seem to react very differently to perceptions of collective efficacy than other groups. However, among both men and women, collective efficacy may come to play an increasingly important protective role in health outcomes with age. PMID- 26247488 TI - Estimating Disease Duration in Cross-sectional Surveys. AB - BACKGROUND: In some common episodic conditions, such as diarrhea, respiratory infections, or fever, episode duration can reflect disease severity. The mean episode duration in a population can be estimated if both the incidence and prevalence of the condition are known. In this article, we discuss how an estimator of the average episode duration may be obtained based on prevalence alone if data are collected for two consecutive units of time (usually days) in the same person. METHODS: We derive a maximum likelihood estimator of episode duration, explore its behavior through a simulation study, and illustrate its use through a real example. RESULTS: We show that for two consecutive days, the estimator of the mean episode duration in a population equals one plus twice the ratio of the number of subjects with the condition on both days to the number of subjects with only 1 day ill. The estimator can be extended to account for 3 or 4 consecutive days. The estimator assumes nonoverlapping episodes and a time constant incidence rate and is more precise for shorter than for longer average episode durations. CONCLUSION: The proposed method allows estimating the mean duration of disease episodes in cross-sectional studies and is applicable to large demographic and health surveys in low-income settings that routinely collect data on diarrhea and respiratory illness. The method may further be used for the calculation of the duration of infectiousness if test results are available for two consecutive days, such as paired throat swabs for influenza. PMID- 26247489 TI - Fine Particulates, Preterm Birth, and Membrane Rupture in Rochester, NY. AB - BACKGROUND: It remains unclear whether fine particulate (PM2.5) exposure affects risk of preterm birth and prelabor rupture of membranes. Unmeasured, poorly measured, and undiscovered individual-level confounders might have introduced bias into past studies that relied on between-women comparisons. METHODS: This was a longitudinal study of preterm birth and prelabor rupture of membranes in Rochester, NY, 2004-2012 (N = 3,264 women, N = 7,121 singleton births). We used conditional logistic regression to match pregnancies to the same woman and estimate the odds of each outcome associated with average PM2.5 concentrations during each trimester and whole pregnancy. RESULTS: For preterm birth, adjusted odds ratios (95% confidence interval) for 1 MUg/m increase in PM2.5 in the first trimester, second trimester, third trimester, and whole pregnancy were 1.11 (1.04, 1.18), 1.09 (1.02, 1.16), 1.06 (1.00, 1.13), and 1.17 (1.07, 1.28), respectively. For prelabor rupture of membranes, corresponding odds ratios were 1.00 (0.97, 1.04), 0.99 (0.96, 1.02), 0.99 (0.96, 1.03), and 0.99 (0.94, 1.04), respectively. CONCLUSION: Risk of preterm birth was greater for pregnancies with elevated PM2.5 exposure than other pregnancies to the same women at lower exposure. We did not observe an association between PM2.5 concentrations and prelabor rupture of membranes. PMID- 26247490 TI - Prenatal Exposure to Traffic-related Air Pollution and Child Behavioral Development Milestone Delays in Japan. AB - BACKGROUND: Recent studies suggest that prenatal exposure to outdoor air pollution is associated with unfavorable neurodevelopment in children. We examined associations between prenatal exposure to traffic-related air pollution and child behavioral development milestone delays, using data from a nationwide population-based longitudinal survey in Japan, where the participants were recruited in 2001 and followed. METHODS: Particulate matter, nitrogen dioxide, and sulfur dioxide concentrations during the 9 months before birth were obtained at the municipality level and assigned to the participants who were born in the corresponding municipality. We analyzed data from singleton births with linked pollution data available (N = 33,911 at the maximum). We used responses to survey questions about age-appropriate behaviors at ages 2.5 and 5.5 years as indicators of behavioral development. We conducted multilevel logistic regression analysis, adjusting for individual and municipality-level variables. RESULTS: Air pollution exposure during gestation was positively associated with the risk of some developmental milestone delays at both ages. Specifically, air pollution was associated with verbal and fine motor development at age 2.5 years, and with behaviors related to inhibition and impulsivity at 5.5 years. In the fully adjusted models, odds ratios following one-interquartile-range increase in nitrogen dioxide and suspended particulate matter were 1.24 (95% confidence interval: 1.07, 1.43) for inability to compose a two-phrase sentence at ages 2.5 and 1.10 (1.05, 1.16) for inability to express emotions at age 5.5 years, respectively. CONCLUSIONS: Prenatal exposure to traffic-related air pollution was associated with behavioral development milestone delays of children in a nationally representative sample in Japan. PMID- 26247491 TI - Experimental design, modeling and optimization of polyplex formation between DNA oligonucleotides and branched polyethylenimine. AB - The complexes formed by DNA and polycations have received great attention owing to their potential application in gene therapy. In this study, the binding efficiency between double-stranded oligonucleotides (dsDNA) and branched polyethylenimine (B-PEI) has been quantified by processing of the images captured from the gel electrophoresis assays. The central composite experimental design has been employed to investigate the effects of controllable factors on the binding efficiency. On the basis of experimental data and the response surface methodology, a multivariate regression model has been constructed and statistically validated. The model has enabled us to predict the binding efficiency depending on experimental factors, such as concentrations of dsDNA and B-PEI as well as the initial pH of solution. The optimization of the binding process has been performed using simplex and gradient methods. The optimal conditions determined for polyplex formation have yielded a maximal binding efficiency close to 100%. In order to reveal the mechanism of complex formation at the atomic-scale, a molecular dynamic simulation has been carried out. According to the computation results, B-PEI amine hydrogen atoms have interacted with oxygen atoms from dsDNA phosphate groups. These interactions have led to the formation of hydrogen bonds between macromolecules, stabilizing the polyplex structure. PMID- 26247492 TI - Rhodium(II)-Catalyzed Annulation of Azavinyl Carbenes Through Ring-Expansion of 1,3,5-Trioxane: Rapid Access to Nine-Membered 1,3,5,7-Trioxazonines. AB - The rhodium(II)-catalyzed denitrogenative coupling of N-alkylsulfonyl 1,2,3 triazoles with 1,3,5-trioxane led to nine-membered-ringed trioxazonines in moderate-to-good yields. 1,3,5-Trioxane, acting as an oxygen nucleophile, reacted with the alpha-aza-vinylcarbene intermediate, giving rise to ylide formation, which was probably the key step in the reaction. Triazoles that contained aryl substituents with various electronic and steric features on the C4 carbon atom were well-tolerated. The synthesis of trioxazonine derivatives was achieved through a one-pot, two-step procedure from 1-mesylazide and a terminal alkyne by combining Cu(I)-catalyzed 1,3-dipolar cycloaddition and rhodium-catalyzed transformations. PMID- 26247493 TI - Fear extinction memory performance in a sample of stable, euthymic patients with bipolar disorder. AB - OBJECTIVES: Affective dysregulation is a core feature of bipolar disorder (BD). Abnormalities in neural circuits underlying affect regulation have been observed in BD, specifically in the structure and function of the amygdala and orbital frontal cortex (OFC). Fear extinction is an automatic affect regulatory process relying on neural circuits that are abnormal in BD. Thus, fear extinction might be useful in probing automatic affect regulation deficits in BD. We tested the hypothesis that BD is associated with reduced ability to extinguish fear responses. METHODS: We examined fear conditioning, extinction, and extinction memory recall in a sample of stable, euthymic participants with BD (n=19) vs. healthy comparison participants (n=32). A limited number of subjects (BD: n=12; healthy comparison: n=11) underwent structural MRI scanning to examine cortical size associations with extinction recall. RESULTS: Both healthy comparison and BD participants were successful in acquiring a fear response, but BD participants responded with greater startle to both threat and safety cues. Both groups showed significant extinction. The BD group showed superior extinction recall. Extinction recall was associated with right rostral middle frontal cortex thickness across groups, whereas right OFC surface area was associated with recall only in healthy comparisons. LIMITATIONS: Limitations include use of a stable, highly screened sample and a relatively small number of participants available for MRI analysis. CONCLUSIONS: Increased fear reactivity may be related to a "trait" disruption in BD patients similar to that previously described in anxiety disorders. This task may be useful for probing automatic affect regulatory processes in BD, and understanding treatment response. PMID- 26247494 TI - Atrial structure and function and its implications for current and emerging treatments for atrial fibrillation. AB - Left atrial (LA) structure and function are intimately related to the clinical phenotypes of atrial fibrillation (AF), and have direct implications for the success or otherwise of various therapeutic strategies. In conjunction with intrinsic structural characteristics of the LA, pathological remodelling to a large extent dictates the clinical course of AF. Remodelling is a product of the physiological and structural plasticity of the LA in disease states (including AF itself), and manifests as electrical, physical and structural changes that promote the substrate necessary for AF maintenance. The degree of remodelling impacts upon the efficacy of pharmacological, non-pharmacological and interventional treatments for AF. Evolving therapies seek to specifically target these processes although presently, several remain in the development phase. Catheter ablation (CA) is now firmly established as a highly effective treatment for AF, although increasing its efficacy in the remodelled LA of more severe AF phenotypes remains an ongoing challenge. PMID- 26247495 TI - Advances in the prevention and treatment of atrial fibrillation. PMID- 26247496 TI - Long QT syndrome: how effective therapy in a single patient favorably influenced the long-term clinical course and genetic understanding of this hereditary disorder. AB - The story of the long QT syndrome involved a chance interaction that took place in 1957 when Dr. Moss was shown a unique series of ECGs with a prolonged QT interval in a young deaf boy whose recurrent syncope culminated in sudden death. Who could have predicted that this clinical experience would lead to innovative and effective new therapy for a patient with the long QT syndrome several years later and the subsequent formation of the International Long QT Registry? This Registry has stimulated interactions among and between patients and physicians and has enhanced collaborations involving clinical, genetic, and basic-science investigators. The net result has been a significant improvement in the diagnosis, treatment, and outcome of patients with the long QT syndrome and an overall advancement in the science of medicine - two of the many satisfactions that physicians can experience in the clinical practice of medicine. PMID- 26247497 TI - Analysis of the lipid profiles in a section of bovine brain via non-catalytic rapid methylation. AB - The main focus of this study is to mechanistically introduce a new qualitative and quantitative technique for mapping the lipid profile of a sectional brain via non-catalytic transesterification reaction (i.e., pseudo catalytic reaction in the presence of porous materials). One of the biggest technical advances achieved in this study is the qualitative and quantitative analysis of lipid from bovine brain in trace quantities in the magnitude of MUg via the non-catalytic pathway. Moreover, newly introduced derivatization in this work showed high tolerance against impurities (i.e., water and extractives). PMID- 26247498 TI - The "biological chamber" method - use of autologous platelet-rich plasma (PRP) in the treatment of poorly healing lower-leg ulcers of venous origin. AB - Wound healing is a complex pathophysiological process, in which platelets play a crucial role. Platelet alpha-granules release growth factors to the wound bed; the factors are necessary in the healing process. In chronic wounds, such as poorly healing lower-leg ulcers of venous origin, there is decreased activity of multiple growth factors, so the concept of exogenous delivery of such factors seems a logical strategy. Platelet-rich plasma therapy in patients with lower-leg ulcers of venous origin combined with conventional treatment methods (previously ineffective in these patients) seems, based on our observation, an important adjunct leading to recovery. The aim of the study was to present an original method of autologous platelet-rich plasma application through the creation of a sort of "biological chamber" containing a concentrate of growth factors. MATERIAL AND METHODS: The described therapy was implemented in 10 patients, who had been ineffectively treated for more than one year in the outpatient setting. Patients with exacerbation of inflammatory process, signs of wound infection and ankle brachial pressure index < 0.8 were excluded from the study. After the application of platelet-rich plasma, further treatment was continued with the use of moist therapy and compression therapy according to a uniform regimen. RESULTS: Complete healing was achieved within 4-10 weeks from the beginning of the product administration in all patients. CONCLUSION: The presented method seems technically simple, effective and relatively inexpensive. PMID- 26247499 TI - Problems concerning patients' qualification for surgical procedures allowing for evaluation of the condition of axillary fossa lymph nodes in the radical treatment of breast cancer. AB - The presence of metastases in the lymph nodes of the axillary fossa is the most important prognostic factor in patients with breast cancer. The surgical treatment option required for evaluation of the condition of the axillary lymph nodes depends on the results of a preoperative physical examination of the patients. The aim of the study was to evaluate the correctness of breast cancer patients' qualification to surgical procedures allowing for evaluation of the condition of the axillary lymph nodes. MATERIAL AND METHODS: A retrospective analysis of a group of 963 patients with a diagnosed malignancy of the breast, treated surgically in the period from 01 Jan 2011 to 29 Feb 2012. Depending on the result of evaluation of the axillary lymph node clinical condition, the patients underwent sentinel lymph node biopsy or elective axillary lymphadenectomy. RESULTS: In 27.4% of patients subjected to excision of the sentinel lymph node, metastatic lesions were found in the lymph nodes removed during the procedure. In most cases (98.1%) that concerned the lymph nodes of the lower part of the axilla. In 17.4% of patients, metastases were located also in the middle or upper part (9%). In the group of patients primarily qualified to lymphadenectomy, the metastatic lesions in the axillary lymph nodes were diagnosed in 67.2% of patients. They were most commonly located in the lower part of the axillary fossa (in 96.7% of cases), and in 68.8% of patients in the middle or upper part (35.8%). CONCLUSIONS: Biopsy of the sentinel lymph node in patients with clinically advanced breast cancer is an effective and safe method of evaluation of the condition of the axillary fossa lymph nodes. A high rate of false positive results concerning the clinical stage of the disease requires changing the rules of patients' qualification to elective axillary lymphadenectomy. PMID- 26247500 TI - Long term results of the use of compression anastomosis clips (CAC) in gastrointestinal surgery - the first report. AB - The aim of the study was to present the first long-term results on the clinical use of compression anastomosis clips (CAC) in upper and lower gastrointestinal tract anastomoses. MATERIAL AND METHODS: The study included 50 patients who underwent anastomosis of the upper (n = 32) or lower GI tract (n = 18) with the use of CAC. In the period of 6-7 months after the surgery, patients underwent endoscopic examination and computed tomography evaluation of the anastomosis. Each anastomosis was evaluated macro and microscopically. The width of anastomoses was evaluated using a 4-point-scale for grading stenosis. RESULTS: Of the 50 patients who underwent anastomosis with compression anastomosis clip, 28 (56%) patients reported to the follow-up examination within 190-209 days of the execution of the anastomosis. Among the 22 patients who did not report to the study, 18 (36%) patients died within 91-154 days from the execution of the anastomosis (mean 122 days), 4 (8%) patients were impossible to contact after discharge from hospital. Two mild stenoses (I0) were diagnosed; 1 of them was found in the gastroenterostomy and 1 in Braun enteroenterostomy. Microscopic changes were diagnosed in 4 anastomoses (3 gastroenterostomies, 1 Braun enteroenterostomy). Anastomoses were well-formed and wide, scars in the line of anastomoses were thin. CONCLUSIONS: During the period of 6 months after the anastomoses performed using CAC have been formed, they were evaluated as unobstructed and functioning properly; therefore, they can be safely performed within the upper and lower gastrointestinal tract. PMID- 26247501 TI - The usefulness of the Mannheim Peritonitis Index score in assessing the condition of patients treated for peritonitis. AB - The aim of the study was to verify the Mannheim Peritonitis Index (MPI) suitability to determine the probability of death among patients in Polish population operated due to peritonitis and to assess the possibility of using the Index to determine the risk of postoperative complications, relaparotomy and need for postoperative hospitalization in intensive care unit. MATERIAL AND METHODS: Retrospective analysis covered 168 patients (M: F = 83: 85, mean age = 48.45 years, SD +/- 22.2) treated for peritonitis. The MPI score was calculated for each patient. According to MPI results, patients were divided to the appropriate groups (<21, 21-29, > 29) and within analyzed. The statistical analysis used Chi square, Mann Withney U and Kolmogorov-Smirnov test. The best cut-off point for MPI was calculated on the basis of ROC analisys. RESULTS: Mortality in the study group was 13.1%. In groups <21, 21-29 and > 29 points according to MPI mortality was 1.75%, 28.13% and 50% respectively, the difference was statistically significant (p = 0.0124). Significant differences were observed in mortality depending on the diagnosis. Based on the ROC curve the cut-off point was identified as 32 with an accuracy of 85.9% and AUC = 81%. There has been a significant correlation between the MPI count and and the occurrence of: cardio respiratory failure, acidosis, electrolyte imbalance, surgical wound complications, the need for treatment in the intensive care unit after surgery. CONCLUSIONS: The MPI is a simple and effective predictor of death among patients operated due to peritonitis. It can also provide assistance in assessing the risk of postoperative complications and the need for treatment in the intensive care unit. PMID- 26247502 TI - Preoperative pancreatic duct stenting in patients undergoing laparoscopic pancreatic surgery - a preliminary report. AB - Laparoscopic surgery is becoming an approved technique in pancreatic surgery. It offers some advantages over an open approach due to shorter hospital stay and decreased complication rate. Regardless the technique the most significant problem of pancreatic surgery is postoperative pancreatic fistula. There are numerous methods attempted at reduction of its incidence. One of the possibilities is preoperative pancreatic duct stenting. It aims at decreasing the pressure in the pancreatic duct, which is supposed to facilitate pancreatic juice flow to the duodenum. The aim of the study was to determine the role of preoperative pancreatic duct stenting in pancreatic surgery. MATERIAL AND METHODS: Nineteen patients undergoing laparoscopic pancreatic resection were enrolled into the study. Prior to the surgery, all of the patients were submitted for the Endoscopic Retrograde Choleangiopancreatography (ERCP) with pancreatic duct stenting. Following the subsequent laparoscopic pancreatic resection, all patients were monitored to detect the pancreatic fistula appearance. The pancreatic stent was removed 6-8 weeks after the surgery. RESULTS: With an exception of two patients, all other patients underwent successful ERCP with pancreatic duct stenting before the surgery. In one case the placement of the prosthesis failed due to a tortuous pancreatic duct. Five patients had an episode of acute pancreatitis including two severe courses as a complication of preoperative ERCP. One of the patient died due to severe GI bleeding 2 weeks after stenting. Among the procedures there were 15 distal pancreatectomies, two enucleations of the tumor localized in the uncinate process and in the body of the pancreas and one central pancreatectomy. The median time of surgery duration was 186 minutes (90-300; +/-56). No conversions to an open approach were necessary. Likewise, there was neither any major complications reported in a postoperative course nor incidence of pancreatic fistula in any of the patients undergoing surgery. CONCLUSIONS: Preoperative pancreatic duct stenting can decrease the incidence of pancreatic fistula. However, a number of serious complications exceed the potential benefit of this method. PMID- 26247503 TI - Large diaphragmatic hernia subject to successful reconstruction - case report. AB - The study presented a case of a large left-sided diaphragmatic hernia treated by means of successful phrenic reconstruction. The above-mentioned are very challenging considering general surgery, although reluctantly supplied in General Surgery Departments. PMID- 26247504 TI - Conservative surgery for pancreatic neck transection. AB - Pancreas is the fourth solid organ injured in blunt abdominal trauma. Isolated pancreatic injury is present in less than 1% of patients. As it is associated with high morbidity and mortality, management is controversial. Isolated pancreatic trauma cases with pancreatic neck transection following blunt abdominal trauma were analyzed. All these patients were treated with immediate surgery involving lesser sac drainage and feeding jejunostomy only. Authors conclude that lesser sac drainage can be used as an alternative to distal pancreatectomy or pancreaticojejunostomy or pancreaticogastrostomy. PMID- 26247505 TI - Endoscopic esophageal self-expanding stent implantation WallFlexTM (Boston Scientific) in the management of a gastrocutaneous fistula, as a complication of sleeve bariatric gastrectomy. AB - The study presented a case of a gastrocutaneous fistula, as a result of bariatric sleeve gastrectomy. The discussion considered the main pathogenesis, etiology, diagnostics and endoscopic treatment using the implantation of covered esophageal stents. Special attention was placed upon the multifactorial origin of this life threatening clinical condition, typical for bariatric surgery. PMID- 26247506 TI - Surgical treatment of gall-bladder cancer. AB - Despite the aggressive nature and poor prognosis of gall-bladder cancer there is a group of patients who can achieve significant benefits from a radical surgical treatment. The possibility of obtaining long-term survival, even in case of patients with locally advanced cancer and metastases to regional lymph nodes, prompts to verify nihilistic approach to the treatment of this disease. Obviously such therapy can and should be performed only in centers specializing in hepatobiliary surgery. Due to the high recurrence rate, most of which are systemic, the hope of improving treatment outcomes should be sought in the use of combination therapy, based on a new chemotherapy and chemoradiotherapy regimens with the addition of targeted therapy. Unfortunately, the current application of these methods did not bring the expected benefits. PMID- 26247507 TI - Effects of long-term administration of aspartame on biochemical indices, lipid profile and redox status of cellular system of male rats. AB - BACKGROUND: Aspartame (N-L-alpha-aspartyl-L-phenylalanine-1-methyl ester) (ASP) is a synthetic sweetener used in foods and its safety remains controversial. The study was designed to investigate the effects of long-term administration of aspartame on redox status, lipid profile and biochemical indices in tissues of male Wistar rats. METHODS: Rats were assigned into four groups and given distilled water (control), aspartame at doses of 15 mg/kg (ASP 1), 35 mg/kg (ASP 2) and 70 mg/kg (ASP 3) daily by oral gavage for consecutive 9 weeks. RESULTS: Administration of ASP 2 and ASP 3 significantly increased the weight of liver and brain, and relative weight of liver of rats. Lipid peroxidation products significantly increased in the kidney, liver and brain of rats at all doses of ASP with concomitant depletion of antioxidant parameters, viz. glutathione-s transferase, glutathione peroxidase, superoxide dismutase, catalase and reduced glutathione. Furthermore, ASP 2 and ASP 3 significantly increased the levels of gamma glutamyl transferase by 70% and 85%; alanine aminotransferase by 66% and 117%; aspartate aminotransferase by 21% and 48%; urea by 72% and 58% and conjugated bilirubin by 63% and 64%, respectively. Also, ASP 2 and ASP 3 significantly increased the levels of total cholesterol, triglycerides and low density lipoprotein cholesterol in the rats. Histological findings showed that ASP 2 and ASP 3 caused cyto-architectural changes such as degeneration, monocytes infiltration and necrotic lesions in brain, kidney and liver of rats. CONCLUSIONS: Aspartame may induce redox and lipid imbalance in rats via mechanism that involves oxidative stress and depletion of glutathione-dependent system. PMID- 26247508 TI - Immunomodulatory activity of methanol leaf extracts of Cameroonian medicinal plants. AB - BACKGROUND: Medicinal plants have been used for centuries and have become part of complementary medicine worldwide because of their health benefits. Some have been successfully used directly in the treatment and prevention of infectious diseases or indirectly by stimulating the immune system. In the present study, the immunomodulatory activity of the methanol extracts of Adenocarpus mannii, Caucalis melanantha, Ocimum gratissimum, Asystasia intrusa and Clematis chinensis leaves was investigated. METHODS: The extracts were prepared by maceration of dry leaves' powder in methanol. Phytochemical analysis was carried out by chemical reaction methods. The activity of plant extracts was evaluated in in vitro cell cultures by measuring their effect on nitric oxide production by peritoneal macrophages, the proliferation of lymphocytes and the cytotoxic effect on macrophages. The A. mannii extract was further evaluated at 50 and 100 mg/kg body weight in mice for the stimulation of delayed-type hypersensitivity (DTH) reactions and the ability to reverse the myelosuppression induced by cyclophosphamide. RESULTS: All the extract inhibited nitric oxide production by peritoneal macrophages, the highest activity was achieved with C. chinensis extract. However, these extracts did not significantly affect the viability of macrophages. A. mannii, A. intrusa and C. chinensis extracts exhibited stimulatory activity on peripheral blood lymphocytes, whereas C. melanantha and O. gratissimum extracts displayed inhibitory activity. In vivo, the A. mannii extract significantly increased the DTH reaction in mice from 50 mg/kg. This extract also showed a significant increase in the white blood cells and relative weight of the spleen and liver. CONCLUSIONS: These results suggest that the A. mannii, C. melanantha, O. gratissimum, A. intrusa and C. chinensis methanol extracts possess immunomodulatory activity. This constitutes additional data on the well-known biological properties of these plants. PMID- 26247509 TI - Amelioration of chronic inflammation and oxidative stress indices in diabetic Wistar rats using methanol leaf extract of Bridelia micrantha (Hochst) Baill. (Euphorbiaceae). AB - BACKGROUND: Ethnopharmacological practitioners in Nigeria have used aqueous and ethanol extracts of Bridelia micrantha leaves to manage conditions associated with inflammation, and these include diabetes, chest pain, edema, arthritis and joint pains. This study aimed to evaluate the effects of methanol leaf extract of B. micrantha on chronic inflammation and oxidative stress which accompany diabetic conditions, in streptozotocin-induced diabetic Albino Wistar rats. METHODS: The dried leaves were extracted by percolation in 80% methanol:water for 72 h after which the mixture was filtered using Whatman No. 1 (11 MUm) filter papers. Acute toxicity studies were done using Wistar rats and given orally up to a dose of 2,000 mg/kg. The animals were monitored for 48 h. The experimental design involved five (5) groups of six (6) albino Wistar diabetic rats each. Groups A, B and C rats received 100, 200 and 400 mg/kg B. micrantha respectively while groups D (negative control) and E (positive control) rats received 10 mL/kg normal saline and 200 mg/kg acetylsalicylic acid (ASA) respectively by gastric gavage for 7 days. Two sterilized cotton pellets (10 mg each) were implanted subcutaneously into both sides of the dorsal area of each diabetic rat in all the groups. Post cotton pellet implantation, rats in three groups (A, B and C) were treated with 100, 200 and 400 mg/kg B. micrantha extract, while those in two groups (D and E) were treated with acetyl salicylic acid (ASA 200 mg/kg) and normal saline (10 mL/kg) respectively by gastric gavage for 7 days. Serum obtained from the animals on Day 8 of the cotton pellet test were used for malondialdehyde (MDA), catalase, superoxide dismutase (SOD) and glutathione (GSH) assays. RESULTS: The administration of the leaf extract up to a dose of 2,000 mg/kg to rats produced absolutely no death or observable signs of toxicity in 48 h. The cotton pellet granuloma weights in 200 mg/kg (44.88+/-1.2 mg), 400 mg/kg (42.10+/-1.2 mg) B. micrantha extract treated groups and ASA at 200 mg/kg (43.25+/-1.8 mg) were significantly lower compared to weight of granuloma (85.50+/-3.2 mg) obtained in the group treated with normal saline. Serum malondialdehyde (MDA) level in the 200 mg/kg (3.32+/-0.72 nmol/mL) and 400 mg/kg (1.88+/-1.27 nmol/mL) B. micrantha extract treated groups were significantly (p<0.05) lower compared to MDA level (6.88+/-0.79 nmol/mL) in the serum of normal saline treated group. Treatment of diabetic rats with the B. micrantha extract also caused significant (p<0.05) elevation in serum catalase, SOD and GSH levels. CONCLUSIONS: The study showed that B. micrantha methanol leaf extract significantly inhibited some chronic inflammation and oxidative stress parameters in diabetes mellitus. PMID- 26247510 TI - Physical Fitness Assessment Across the Disability Spectrum in Persons With Multiple Sclerosis: A Comparison of Testing Modalities. AB - BACKGROUND AND PURPOSE: Appropriate assessment of physical fitness (ie, aerobic capacity and muscular strength) is necessary for the design and evaluation of exercise training in multiple sclerosis (MS). However, this is challenging in persons with substantial disability, because of physical inaccessibility and insensitivity of certain exercise testing modalities. This study compared different methods of measuring cardiorespiratory (arm ergometer vs recumbent stepper) and muscular (hand-held dynamometry vs computerized dynamometry) fitness across the MS disability spectrum. Associations between physical fitness and other measures that represented all domains of the International Classification of Functioning, Disability and Health (ICF) were also examined. METHODS: Sixty four participants with MS completed 2 symptom-limited cardiorespiratory fitness and muscular strength tests. We also assessed disability, cognition, fatigue, walking speed and endurance, health-related quality of life, and activities of daily living. RESULTS: Across all levels of disability, peak aerobic capacity assessed by recumbent stepping was higher compared with arm ergometry (P < 0.001). Peak torque of the knee extensors and knee flexors was significantly higher assessed by computerized dynamometry compared with hand-held dynamometry (P < 0.001). Aerobic capacity and peak torque decreased as a function of increasing disability (P < 0.001). Significant, moderate to strong correlations were observed between the physical fitness measures and measures representing all domains of the ICF, irrespective of the fitness testing mode. DISCUSSION AND CONCLUSIONS: Overall, peak physical capacity was higher when assessed by recumbent stepping and computerized dynamometry. The assessment and prescription of exercise in MS should be based on these modalities to provide the most appropriate stimulus for exercise training adaptations. There continues to be an important association between physical fitness and other measures that represent all domains of the ICF, regardless of fitness assessment mode.Video Abstract available for additional insights from the authors (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/JNPT/A109). PMID- 26247511 TI - Neurorehabilitation Strategies Focusing on Ankle Control Improve Mobility and Posture in Persons With Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: The neuromuscular impairments seen in the ankle plantarflexors have been identified as a primary factor that limits the mobility and standing postural balance of individuals with multiple sclerosis (MS). However, few efforts have been made to find effective treatment strategies that will improve the ankle plantarflexor control. Our objective was to determine whether an intensive 14-week neurorehabilitation protocol has the potential to improve the ankle plantarflexor control of individuals with MS. The secondary objectives were to determine whether the protocol would also improve postural control, plantarflexion strength, and mobility. METHODS: Fifteen individuals with MS participated in a 14-week neurorehabilitation protocol, and 20 healthy adults served as a comparison group. The primary measure was the amount of variability in the submaximal steady-state isometric torque, which assessed plantarflexor control. Secondary measures were the Sensory Organization Test composite score, maximum plantarflexion torque, and the spatiotemporal gait kinematics. RESULTS: There was less variability in the plantarflexion torques after the neurorehabilitation protocol (preintervention, 4.15% +/- 0.5%; postintervention, 2.27% +/- 0.3%). In addition, there were less postural sway (preintervention, 51.87 +/- 0.2 points; postintervention, 67.8 +/- 0.5 points), greater plantarflexion strength (preintervention, 0.46 +/- 0.04 Nm/kg; postintervention, 0.57 +/- 0.05 Nm/kg), and faster walking speeds (preferred preintervention, 0.71 +/- 0.05 m/s; preferred postintervention, 0.81 +/- 0.05 m/s; fast-as-possible preintervention, 0.95 +/- 0.06 m/s; postintervention, 1.11 +/- 0.07 m/s). All of the outcome variables matched or trended toward those seen in the controls. DISCUSSION AND CONCLUSIONS: The outcomes of this exploratory study suggest that the neurorehabilitation protocol employed in this investigation has the potential to promote clinically relevant improvements in the ankle plantarflexor control, standing postural balance, ankle plantarflexion strength, and the mobility of individuals with MS. Video abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A110). PMID- 26247512 TI - The Toxoplasma gondii rhoptry protein ROP18 is an Irga6-specific kinase and regulated by the dense granule protein GRA7. AB - In mice, avirulent strains (e.g. types II and III) of the protozoan parasite Toxoplasma gondii are restricted by the immunity-related GTPase (IRG) resistance system. Loading of IRG proteins onto the parasitophorous vacuolar membrane (PVM) is required for vacuolar rupture resulting in parasite clearance. In virulent strain (e.g. type I) infections, polymorphic effector proteins ROP5 and ROP18 cooperate to phosphorylate and thereby inactivate mouse IRG proteins to preserve PVM integrity. In this study, we confirmed the dense granule protein GRA7 as an additional component of the ROP5/ROP18 kinase complex and identified GRA7 association with the PVM by direct binding to ROP5. The absence of GRA7 results in reduced phosphorylation of Irga6 correlated with increased vacuolar IRG protein amounts and attenuated virulence. Earlier work identified additional IRG proteins as targets of T. gondii ROP18 kinase. We show that the only specific target of ROP18 among IRG proteins is in fact Irga6. Similarly, we demonstrate that GRA7 is strictly an Irga6-specific virulence effector. This identifies T. gondii GRA7 as a regulator for ROP18-specific inactivation of Irga6. The structural diversity of the IRG proteins implies that certain family members constitute additional specific targets for other yet unknown T. gondii virulence effectors. PMID- 26247514 TI - Correction: perfluoropropenyl-containing phosphines from HFC replacements. AB - Correction for 'Perfluoropropenyl-containing phosphines from HFC replacements' by Alan K. Brisdon et al., Dalton Trans., 2015, DOI: 10.1039/c5dt02043c. PMID- 26247513 TI - Effects of deletion of the transcription factor Nrf2 and benzo [a]pyrene treatment on ovarian follicles and ovarian surface epithelial cells in mice. AB - Polycyclic aromatic hydrocarbons, like benzo[a]pyrene (BaP), are ubiquitous environmental pollutants and potent ovarian toxicants. The transcription factor NRF2 is an important regulator of the cellular response to electrophilic toxicants like BaP and to oxidative stress. NRF2 regulates transcription of genes involved in the detoxification of reactive metabolites of BaP and reactive oxygen species. We therefore hypothesized that Nrf2-/- mice have accelerated ovarian aging and increased sensitivity to the ovarian toxicity of BaP. A single injection of BaP dose-dependently depleted ovarian follicles in Nrf2+/+ and Nrf2 /- mice, but the effects of BaP were not enhanced in the absence of Nrf2. Similarly, Nrf2-/- mice did not have increased ovarian BaP DNA adduct formation compared to Nrf2+/+ mice. Ovarian follicle numbers did not differ between peripubertal Nrf2-/- and Nrf2+/+ mice, but by middle age, Nrf2-/- mice had significantly fewer primordial follicles than Nrf2+/+ mice, consistent with accelerated ovarian aging. PMID- 26247515 TI - Acceptability, feasibility and perceived satisfaction of the use of the Atraumatic Restorative Treatment approach for people with disability. AB - Unmet caries treatment need is prevalent among people with disability, partly due to difficulties cooperating with conventional dental treatment. This study compared Atraumatic Restorative Treatment (ART) with conventional restorative treatment (CRT) in the clinic and under general anaesthesia (GA), in terms of feasibility, acceptability and respondent satisfaction in patients referred for special care dentistry. Patients referred for dental restorative care were treated using either ART or CRT approach. Acceptance, feasibility and level of satisfaction with the treatment provided were assessed. ANOVA with Bonferroni correction and Chi-square tests investigated differences in age, gender and Visual Analogue Scale satisfaction scores. A total of 66 patients (mean 13.6 +/- 7.8 years) were included and 43 respondents chose ART. ART was feasible for 47 patients, with optimal placement of restorations for 79% of all patients receiving ART. CRT in the clinic was chosen by 15 respondents and was feasible for 5 (33%). Local anaesthesia was required for 4 of the 47 patients receiving ART and for 3 of the 5 patients receiving CRT in the clinic. Neither ART nor CRT could be performed in the clinic for 14 patients who were treated under GA (21%). Respondent satisfaction was higher for those receiving ART than CRT (in the clinic and under GA). It was concluded that ART is a satisfactory, feasible, acceptable and effective approach to restorative dental treatment in patients with disability who have difficulty coping with conventional treatment. More research is now required to confirm these results in a larger study population. PMID- 26247516 TI - Effect of foods and drinks on primary tooth enamel after erosive challenge with hydrochloric acid. AB - The aim of this study was to evaluate the effect of industrialised foods and drinks on primary tooth enamel previously eroded with hydrochloric acid (HCl). The crowns of one hundred two specimens were subjected to an erosive challenge with HCl and randomly divided into six groups (n = 17): Chocolate Milk (Toddynho(r) - Pepsico) - negative control; Petit Suisse Yogurt (Danoninho(r) - Danone); Strawberry Yogurt (Vigor); Apple puree (Nestle); Fermented Milk (Yakult(r) - Yakult); and Home Squeezed Style Orange Juice (del Valle) - positive control. The 28-day immersion cycles for the test products were performed twice daily and were interspersed with exposure of the test substrate to artificial saliva. Measurements of enamel surface microhardness (SMH) were performed initially, after immersion in HCl and at 7, 14, 21 and 28 days of experimentation. A two-way ANOVA, according to a split-plot design, followed by the sum of squares decomposition and Tukey's test, revealed a significant effect for the interaction between Foods and Drinks and Length of Exposure (p < 0.00001). Orange juice resulted in greater mineral loss of enamel after 28 days. None of the test products was associated with recovery of tooth enamel microhardness. PMID- 26247517 TI - Individual and contextual determinants of malocclusion in 12-year-old schoolchildren in a Brazilian city. AB - The aim of this study was to describe malocclusion prevalence and its association with individual and contextual factors among Brazilian 12-year-old schoolchildren. This cross-sectional study included data from an oral health survey carried out in Goiania, Brazil (n = 2,075), and data from the files of the local health authority. The data were collected through oral clinical examinations. The Dental Aesthetic Index (DAI) was used to assess occlusion. The presence of malocclusion (DAI > 25) was used as the dependent variable. The individual independent variables consisted of adolescents' sex and race and their mothers' level of schooling. The clinical variables were caries experience and presence of adverse periodontal condition (calculus and/or gingival bleeding). The contextual variables included type of school and the location of schools in the city's health districts. The Rao-Scott test and multilevel logistic regression were performed. The prevalence of malocclusion was 40.1%. In the final model, significantly higher rates of malocclusion were found among those who attended schools located in less affluent health districts and whose mothers had fewer years of education. Rates were also higher among those presenting calculus and/or gingival bleeding. Malocclusion demonstrated a high prevalence rate and the inequalities in its distribution were determined by individual and contextual factors. PMID- 26247518 TI - Oral mucosal lesions and their association with sociodemographic, behavioral, and health status factors. AB - The aim of this study was to evaluate the frequency of oral mucosal lesions and their associations with sociodemographic, health, and behavioral factors in a southern Brazilian population. Information was collected from participants (n = 801) using a structured questionnaire during an oral cancer screening campaign held at an agribusiness show in southern Brazil in 2009. Data were described using frequency distributions or means and standard deviations. Associations between independent variables and outcomes were assessed using the Chi-squared test. A total of 465 lesions were detected (actinic cheilitis: n = 204, 25.5%; candidiasis: n = 50, 6.2%; fibrous inflammatory hyperplasia: n = 42, 5.2%; ulceration, n = 33, 4.1%; hemangioma: n = 14, 1.7%; leukoplakia: n = 11, 1.4%). Candidiasis, actinic cheilitis, and fibrous inflammatory hyperplasia were associated significantly with literacy. Actinic cheilitis was also associated significantly with sun exposure and hat use, and leukoplakia was associated with smoking. The high frequency of oral mucosal lesions observed highlights the importance of education about risk factors. Additionally, training of health professionals, mainly those from public health services, in the use of preventive and community education strategies is needed. PMID- 26247520 TI - First clinical implementation of audiovisual biofeedback in liver cancer stereotactic body radiation therapy. AB - This case report details a clinical trial's first recruited liver cancer patient who underwent a course of stereotactic body radiation therapy treatment utilising audiovisual biofeedback breathing guidance. Breathing motion results for both abdominal wall motion and tumour motion are included. Patient 1 demonstrated improved breathing motion regularity with audiovisual biofeedback. A training effect was also observed. PMID- 26247521 TI - In memoriam Professor Andrzej Roszkiewicz (27.05.1941-12.09.2014). PMID- 26247519 TI - Drosophila KASH-domain protein Klarsicht regulates microtubule stability and integrin receptor localization during collective cell migration. AB - During collective migration of the Drosophila embryonic salivary gland, cells rearrange to form a tube of a distinct shape and size. Here, we report a novel role for the Drosophila Klarsicht-Anc-Syne Homology (KASH) domain protein Klarsicht (Klar) in the regulation of microtubule (MT) stability and integrin receptor localization during salivary gland migration. In wild-type salivary glands, MTs became progressively stabilized as gland migration progressed. In embryos specifically lacking the KASH domain containing isoforms of Klar, salivary gland cells failed to rearrange and migrate, and these defects were accompanied by decreased MT stability and altered integrin receptor localization. In muscles and photoreceptors, KASH isoforms of Klar work together with Klaroid (Koi), a SUN domain protein, to position nuclei; however, loss of Koi had no effect on salivary gland migration, suggesting that Klar controls gland migration through novel interactors. The disrupted cell rearrangement and integrin localization observed in klar mutants could be mimicked by overexpressing Spastin (Spas), a MT severing protein, in otherwise wild-type salivary glands. In turn, promoting MT stability by reducing spas gene dosage in klar mutant embryos rescued the integrin localization, cell rearrangement and gland migration defects. Klar genetically interacts with the Rho1 small GTPase in salivary gland migration and is required for the subcellular localization of Rho1. We also show that Klar binds tubulin directly in vitro. Our studies provide the first evidence that a KASH-domain protein regulates the MT cytoskeleton and integrin localization during collective cell migration. PMID- 26247522 TI - The use of reflectance confocal microscopy in selected inflammatory skin diseases. AB - Reflectance confocal microscopy is a modern, non-invasive diagnostic method that enables real-time imaging of the epidermis and upper layers of the dermis with nearly histological precision and high contrast. The application of this technology to skin imaging during the last years has resulted in progress of dermatological diagnosis, providing virtual access to living skin, without the need for conventional histopathology. The presented method potentially has broad application in the diagnosis of skin diseases. This article provides a summary of the latest reports and previous achievements in the field of reflectance confocal microscopy. General characteristics of confocal images in selected inflammatory skin diseases are presented. PMID- 26247523 TI - Can the histological type of colorectal cancer determine the carcinogenesis pathway? AB - Colorectal cancer (CRC) is the most common type of gastrointestinal cancer and has three major pathways of carcinogenesis. About 80% of genomic instability concerns chromosomal instability (CIN); the rest is connected with either microsatellite instability (MSI) or CpG island methylation. Some MSI-related cancers are associated with Lynch syndrome, whereas others are caused by sporadic, acquired hypermethylation of the promoter of the MLH1 gene. These tumours have distinctive clinical and histopathological features. They may be poorly differentiated, accompanied by Crohn's-like lymphocytic infiltration and have a pushing margin. MSI-high (MSI-H) phenotype has a slightly better prognosis. We investigated 46 classic CRCs using histochemical and immunohistochemical methods (p53, MLH1, MSH2, MSH6). Based on the results, we divided patients into 4 groups. Tumours from the first and second group (27 cases) expressed the loss of MSI markers and presented a characteristic clinical and morphological image. The other 19 cases lacked significant immunohistochemical or microscopic features. These require further molecular studies to evaluate their carcinogenesis. Discovery of MSI in colorectal tumours should be taken into account in the management of patients. They do not respond to 5-fluorouracil or anti-EGFR therapy, especially the sporadic ones with BRAF mutations. PMID- 26247524 TI - Extramammary Paget's disease: evaluation of the adnexal status of 53 cases. AB - Extramammary Paget's disease (EMPD) is a distinct form of malignant skin neoplasm. The clinicopathological significance of cutaneous adnexal involvement in EMPD has not been investigated in detail. Surgical specimens were obtained from 53 patients with primary EMPD. Tumor involvement of cutaneous adnexal structures was evaluated using histological parameters. The degree of involvement was scored on a scale of 0-2: 0, no involvement; 1, involvement of the upper portion of the adnexa; 2, involvement of the lower portion of the adnexa. A score of 2 was regarded as significant. The presence of comedo necrosis was also examined. Adnexal involvement was identified in 46 cases (86.8%). Comedo necrosis was observed in 6 cases (11.3%). The proportions of each parameter in in situ cases were as follows: significant adnexal involvement (score 2) in 15/26 (57.7%), and comedo necrosis in 3/26 (11.5%). The corresponding proportions in cases with invasion were 21/27 (77.8%) and 3/27 (11.1%), respectively. No significant differences in adnexal involvement and comedo necrosis were detected between in situ EMPD and invasive EMPD (p>0.05). The current study suggests that the degree of adnexal involvement and the presence of comedo necrosis are not associated with tumor progression in EMPD. PMID- 26247525 TI - Multifocal/multicentric breast carcinomas showing intertumoural heterogeneity: a comparison of histological tumour type and Nottingham histological grade of primary tumour and lymph node metastasis. AB - Our study aimed to compare the histological tumour type and Nottingham histological grade of invasive tumour foci in multifocal/multicentric breast carcinomas with those in corresponding axillary lymph node (LN) metastases. We reassessed slides from consecutive multiple breast carcinomas surgically treated with axillary LN dissection (2007-2012). 155 (19.23%) of 806 cases had multiple breast cancer, of which 115 (74.19%) cases had identical morphology. Of these, 85 (73.91%) cases had axillary LN metastases morphologically identical to the originating breast tumours. 32 of the 40 (80%) cases with different morphology had axillary LN metastases; in most heterogeneous cases with differences in grade (87.5%), the grade of metastases was identical to the grade of the tumour foci with the highest histological grade, and in 33.33% of cases the grade in LN was concordant with the grade of smaller foci. Among the 18 cases heterogeneous in histological type with axillary metastases, 33.33% presented heterogeneous histological types in LN, and 22.22% of them were only concordant with the histological type of the smaller tumour foci. The morphological aspects of axillary LN metastases correspond to the highest histological grade and/or histological tumour type with unfavourable prognosis, which does not necessarily appear in the largest tumour focus. PMID- 26247526 TI - Prognostic value of PIK3CA mutation status, PTEN and androgen receptor expression for metastasis-free survival in HER2-positive breast cancer patients treated with trastuzumab in adjuvant setting. AB - Resistance to trastuzumab in patients with HER2-overexpressing breast cancer is associated with higher risk of progression or cancer death, and might be related to activation of PI3K/AKT/mTOR and Ras/Raf/MAPK signaling cascades and a decreased level of their inhibitor (PTEN). HER2-overexpressing breast cancer patients (n=75) treated with radical local therapy and trastuzumab in adjuvant setting were included into the study. Deoxyribonucleic acid isolated from paraffin sections was used to assess mutational status of the PIK3CA gene (p.H1047R and p.E545K mutations) by the quantitative polymerase chain reaction technique. Expression of selected proteins (ER, PgR, AR, Ki-67, EGFR) was assessed using immunohistochemistry. In the studied group we found significantly higher Ki-67LI in EGFR-positive carcinomas (p=0.048). Moreover, EGFR immunonegativity was observed more frequently in low-grade (G1/G2) carcinomas as well as in estrogen/progesterone and androgen receptor immunopositive tumors (p=0.042, p=0.016, p=0.044, respectively). Favorable metastasis-free survival was observed in patients with pN0 and pN1 (vs. pN2+3) stage (p=0.040) and with tumors characterized by low Ki-67LI (<=50% vs. >50%) (p=0.014). Patients with tumor androgen receptor immunonegativity (weak or lack of expression) or strong PTEN expression survived 3 years without metastases (p=0.007). The results of our study suggest that androgen receptor and PTEN status might be considered as indicators of trastuzumab sensitivity. PMID- 26247527 TI - Sebaceous carcinoma of the breast: report of four cases and review of the literature. AB - Sebaceous carcinoma of the breast is an exceedingly rare neoplasm. Little is known about the behavior and prognosis of this type of breast cancer. We report clinical, histological and immunohistochemical features of four cases of breast carcinoma with prominent (at least 50%) sebaceous differentiation. The tumors occurred in four women, aged 25-66, and were composed of cords, lobules and solid sheets of tumor cells with sebaceous differentiation, comprising 50-90% of the tumor mass. The second component consisted of cells with non-vacuolated cytoplasm, present mostly around the periphery of the lobules, or which formed separate tumor sheets with no evidence of sebaceous differentiation and were indistinguishable from a classical ductal carcinoma. Immunohistochemically, three tumors expressed hormone receptors; all cases were HER2-negative and had retained expression of the DNA mismatch repair proteins. Three patients had axillary lymph node metastases, and two patients had distant metastases: one in the liver, lung and bones, and one in the mediastinal and supraclavicular lymph nodes. One patient died 28 months after diagnosis, indicating that mammary sebaceous carcinoma is a potentially aggressive neoplasm. In contrast to extraocular cutaneous sebaceous carcinomas, mammary sebaceous carcinoma is probably unrelated to Muir-Torre syndrome. It should be differentiated from morphologically similar but biologically distinct lipid-rich carcinoma. PMID- 26247528 TI - Renal interstitial mast cell count is significantly higher in membranoproliferative glomerulonephritis than in class IV lupus nephritis. AB - Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus; in LN class IV morphologic lesions may be similar to the lesions in primary membranoproliferative glomerulonephritis (MPGN). The aim of the study was to compare the counts of tryptase-positive and chymase-positive mast cells between LN class IV and MPGN. The material consisted of 61 renal biopsies: 32 with lupus nephritis class IV, and 29 with membranoproliferative glomerulonephritis. Chymase and tryptase-positive cells were stained by immunohistochemistry and subsequently counted. The mean count of chymase-positive mast cells was 21.94 for the whole group, 12.66 for LN class IV and 32.18 for MPGN. The mean count of tryptase-positive cells was 34.94 hpf for the entire group, 22.98 for LN class IV and 48. 13 for MPGN. The differences between lupus nephritis and membranoproliferative glomerulonephritis were significant both for chymase- and tryptase-positive cells. Both chymase-positive MC counts and tryptase-positive MC counts correlated with relative interstitial volume (RIV) (R=0.35 and R=0.28, respectively) and with creatinine level (R=0.35 and R=0.43, respectively). There was also a significant correlation between age, creatinine level and RIV (R=0.28 and R=0.26, respectively). PMID- 26247529 TI - Epstein-Barr virus DNA in colorectal carcinoma in Iranian patients. AB - Colorectal cancer is an often fatal cancer with a rapidly increasing incidence. Current mortality is estimated to be approximately 600,000 per year, and both environmental and genetic factors are involved in its etiology. Viral and bacterial factors have a proven role in the incidence of approximately 20% of cancers. In the present study, the Epstein-Barr virus (EBV) was detected in 50 colorectal adenocarcinomas, 12 colon adenomas, and 38 control tissue samples using polymerase chain reaction (PCR). Epstein-Barr virus DNA was identified in 19 of the adenocarcinoma tissues, 1 adenoma tissue and 24 control specimens. In total, 15.8% (3/18) of the colorectal samples in the well-differentiated grade, 79% (15/30) in the moderately differentiated, and 5.2% (1/2) in the poorly differentiated grade tested positive for viral infection. Epstein-Barr virus was more prevalent in the moderately differentiated grade. Statistical analysis did not suggest a significant association between EBV and the incidence of colorectal cancer. However, it appears that the virus stimulates progression of the malignancy. PMID- 26247530 TI - Evaluation of the role of Epstein-Barr virus in cases of nodal or extranodal T- and NK-cell lymphoma using eber in situ hybridization. AB - Various racial and geographic differences have been observed in studies questioning the role of Epstein-Barr virus (EBV) infection in the etiology of T- and NK-cell lymphomas. The aim of this study was to evaluate the relationship of EBV with nodal or extranodal (skin excluded) T- and NK-cell lymphoma subtypes encountered in our geographic area. Sixty-two cases of peripheral T-cell lymphoma were included in the study. EBV-encoded early RNA (EBER) was detected by in situ hybridization. The distributions of T- and NK-cell lymphoma subtypes were as follows: 32 peripheral T-cell lymphomas, unspecified (PTCL, NOS), 13 anaplastic large-cell lymphomas (ALCL), 8 angioimmunoblastic T-cell lymphomas (AITCL), 4 extranodal NK/T-cell lymphomas, nasal type (NKTCL), 3 enteropathy-type T-cell lymphomas (ETTCL), 1 hepatosplenic T-cell lymphoma (HSTCL), and 1 subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Using a cut-off value of >25% of EBER positive neoplastic lymphoid cells, EBV was positive in 22.6% of all cases. According to subtype, the neoplastic cells of 31.3% of PTCL, NOS and 100% of extranodal NKTCL, nasal type were EBER positive, whereas some cases of ALCL, AITCL, and ETTCL presented EBER-positive non-neoplastic cells, and all cells of HSTCL and SPTCL were EBV negative. Extranodal NKTCL, nasal type, presented the strongest association with EBV, followed by PTCL, NOS. PMID- 26247531 TI - A positive correlation between immunohistochemical expression of CD31 and mast cell tryptase in odontogenic tumors. AB - In this study, we compared mast cell tryptase and CD31 expression between odontogenic tumors with the aim of predicting the clinical behavior of these lesions at the time of initial biopsy. We also evaluated the correlation between mast cell tryptase and CD31 expression to clarify the role of mast cells (MCs) in the growth of odontogenic tumors. Immunohistochemical staining with anti-MC tryptase and anti-CD31 antibodies was performed on 48 cases of odontogenic tumors including solid ameloblastoma (SAM), unicystic ameloblastoma (UAM), odontogenic myxoma (OM), cystic calcifying odontogenic tumor (CCOT) and adenomatoid odontogenic tumor (AOT). Ten high power fields were analyzed for each sample. Total MC count was significantly increased in SAM compared to other odontogenic tumors (p<0.05). Microvessel density was statistically higher in SAM and AOT compared to remaining odontogenic tumors (p<0.05). A significant correlation was observed between MCs and microvessels in odontogenic tumors (p=0.018, r=0.34). Our findings suggest a role for MCs in aggressive clinical behavior of odontogenic tumors. The significant correlation found between MC count and microvessel density in odontogenic tumors is in agreement with the theory of participation of MCs in tumor progression. Targeting MC activity may represent an important nonsurgical therapeutic approach, especially for aggressive odontogenic tumors. PMID- 26247532 TI - Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms. AB - The study represents a comprehensive retrospective morphological and immunohistochemical profiling of pancreatic neuroendocrine neoplasms (PNENs) in order to reveal the associations between morphological and molecular parameters. The local tumour spread (T), presence of metastases in regional lymph nodes (N) and distant organs (M), tumour grade (G) and resection line status (R) by pathology findings (pTNMGR), mitotic activity, perineural, vascular and lymphatic invasion were assessed in 16 surgically resected PNENs. By immunohistochemistry, expression of Ki-67, p53, p27, p21, cyclin D1, Bcl-2, E-cadherin, CD44, vimentin, cyclooxygenase 2 (COX-2), microvascular density, and cytokeratin (CK) spectrum, along with neuroendocrine, intestinal and squamous markers were detected. Descriptive statistics, Chi-square test, Spearman's rank correlation, Mann Whitney and Kruskal-Wallis methods were applied; p<0.05 was considered significant. Ki-67, CK19, p63, vimentin and COX-2 were significantly up-regulated in PNENs in comparison to benign pancreatic islets. A complex network of morphological and molecular associations was identified. Ki-67 correlated with PNEN size (p=0.022), the World Health Organization 2004 and 2010 classification grades (p=0.021 and p=0.002), stage (p=0.028) and mitotic count (p=0.007) but among molecular markers--with CK19 (p=0.033) and vimentin (p=0.045). CK19 was significantly up-regulated in PNENs, having higher pT (p=0.018), pR (p=0.025), vascular (p=0.020), perineural (p=0.026) and lymphatic invasion (p=0.043). In conclusion, proliferation activity (by Ki-67), E-cadherin, vimentin and CK19 are important molecular characteristics of PNENs due to significant associations with morphological tumour characteristics, pTNMGR and invasive growth. PMID- 26247533 TI - Extracardiac rhabdomyomas--presentation of two cases with analysis of AKT/mTOR and ERK1/2 signaling. AB - Extracardiac rhabdomyomas (RM) are very rare benign tumors with a poorly understood pathogenesis. In this report we describe two RM cases--a sublingual adult type tumor and a genital type tumor involving the uterine cervix. The patho clinical characteristics, as well as the pioneer immunohistochemical analysis of ERK1/2 and AKT/mTOR pathway status is included. The expression of key proteins involved in above signaling gives new insight into the biology of extracardiac RM. PMID- 26247534 TI - Letter to the Editor: Diffuse TTF-1 expression in a case of Merkel cell carcinoma. PMID- 26247535 TI - Effects of extended growth periods on subcellular distribution, chemical forms, and the translocation of cadmium in Impatiens walleriana. AB - Impatiens walleriana plants accumulate sufficiently high concentrations of cadmium (Cd) for this species to be considered a potential Cd hyperaccumulator. Rooted cuttings were grown hydroponically for 25 and 50 days in solutions spiked with various Cd concentrations. The subcellular distribution and chemical forms of Cd in different organs were analyzed, and its upward translocation was also assessed. The plants accumulated large amounts of Cd; the Cd concentration in the roots and shoots reached 120-1900 and 60-1600 mg/kg, respectively. Regardless of the growth period, the Cd accumulated in the roots was primarily compartmentalized in the soluble fraction or ethanol and deionized water extractable chemical forms with high migration abilities. Translocation to the shoots was followed by an association of Cd mainly in the cell wall or with pectate and protein. The roots' Cd showed a high migration capacity for predicting the shoots' Cd concentrations. Different exposure periods significantly affected the subcellular distribution of Cd in the stems, and thus the upward translocation. PMID- 26247536 TI - Association between abdominal fat distribution, adipocytokines and metabolic alterations in obese low-birth-weight children. AB - BACKGROUND: In addition to obesity, low birth weight (LBW) has been proposed as another independent risk factor associated with cardiovascular disease and type 2 diabetes mellitus. OBJECTIVE: This study aimed to evaluate the influence of birth weight on abdominal fat distribution, adipocytokine levels and associated metabolic alterations in obese children. METHODS: A cross-sectional study was conducted in 92 children. Children were divided into three groups according to their body mass index and birth weight. Glucose and insulin (0 and 120 min), lipid profile and adipocytokines were measured. Abdominal fat distribution was assessed by magnetic resonance imaging. RESULTS: Obese LBW children had higher fasting glucose (P = 0.054) and insulin (P < 0.001), and 120 min glucose (P < 0.001) and insulin levels (P < 0.001), such as increased HOMA-IR (homeostasis model assessment of insulin resistance index) (P < 0.001). Obesity and LBW were associated with lower concentrations of high molecular weight (HMW) adiponectin ( 2.38 [IC 95% -4.27; -0.42, P = 0.018]) and higher subcutaneous adipose tissue (SAT) (28.05 [IC 95% 0.40; 55.7, P = 0.047]) compared with NBW obese children, independent of age or sex. CONCLUSIONS: LBW in obese children is associated with lower HMW adiponectin, increased insulin resistance and greater SAT. PMID- 26247537 TI - Serotonin enhances urinary bladder nociceptive processing via a 5-HT3 receptor mechanism. AB - Serotonin from the descending pain modulatory pathway is critical to nociceptive processing. Its effects on pain modulation may either be inhibitory or facilitatory, depending on the type of pain and which receptors are involved. Little is known about the role of serotonergic systems in bladder nociceptive processing. These studies examined the effect of systemic administration of the serotonin precursor, 5-hydroxytryptophan (5-HTP), on normal bladder and somatic sensation in rats. ELISA was used to quantify peripheral and central changes in serotonin and its major metabolite following 5-HTP administration, and the potential role of the 5-HT3 receptor on changes in bladder sensation elicited by 5-HTP was investigated. 5-HTP produced bladder hypersensitivity and somatic analgesia. The pro-nociceptive effect of 5-HTP was attenuated by intrathecal, but not systemic, ondansetron. Peripheral increases in serotonin, its metabolism and rate of turnover were detectable within 30min of 5-HTP administration. Significant enhancement of serotonin metabolism was observed centrally. These findings suggest that 5-HTP increases serotonin, which may then affect descending facilitatory systems to produce bladder hypersensitivity via activation of spinal 5-HT3 receptors. PMID- 26247538 TI - Effects of activation and blockade of orexin A receptors in the medial preoptic area on food intake in male rats. AB - It has been shown that activation of type 1 orexinergic receptors (ORX1) in several parts of the hypothalamus stimulate food intake. Orexin A receptive sites for food intake exist primarily in a narrow band of the hypothalamus that is known to be involved in control of energy homeostasis. The present study aimed to investigate the role of orexin receptors in the medial preoptic area (MPOA) on food intake in rats. Twenty-four male rats weighing 200-250g were divided into three groups (n=8 in each group). Rats were cannulated using stereotaxic coordinates above the MPOA. Normal saline was microinjected into the MPOA in the control group. Another group received intra MPOA microinjection of SB334867, a selective antagonist for ORX1 receptors. In the other group, orexin A was microinjected (0.5MUl of 1MUmol) into the MPOA. Food intake was measured in metabolic cages. The statistical significance of differences between groups was detected by a one way ANOVA. A value of p<0.05 was considered significant. There was no significant difference in food consumption between saline and SB334867 treated groups. However, activation of the orexin receptor in the MPOA significantly increased food intake during the 2 and 8h after orexin A microinjection. Our results showed that during ad libitum access to food, activation but not blockade of the MPOA ORX1 receptor can increase food intake in a time-dependent manner. The role of these receptors in hunger and appetite stimulation requires further study. PMID- 26247539 TI - Electrophysiological and firing properties of neurons: Categorizing soloists and choristers in primary visual cortex. AB - Visual processing in the cortex involves various aspects of neuronal properties such as morphological, electrophysiological and molecular. In particular, the neural firing pattern is an important indicator of dynamic circuitry within a neuronal population. Indeed, in microcircuits, neurons act as soloists or choristers wherein the characteristical activity of a 'soloist' differs from the firing pattern of a 'chorister'. Both cell types correlate their respective firing rate with the global populational activity in a unique way. In the present study, we sought to examine the relationship between the spike shape (thin spike neurons and broad spike neurons) of cortical neurons recorded from V1, their firing levels and their propensity to act as soloists or choristers. We found that thin spike neurons, which exhibited higher levels of firing, generally correlate their activity with the neuronal population (choristers). On the other hand, broad spike neurons showed lower levels of firing and demonstrated weak correlations with the assembly (soloists). A major consequence of the present study is: estimating the correlation of neural spike trains with their neighboring population is a predictive indicator of spike waveforms and firing level. Indeed, we found a continuum distribution of coupling strength ranging from weak correlation-strength (attributed to low-firing neurons) to high correlation-strength (attributed to high-firing neurons). The tendency to exhibit high- or low-firing is conducive to the spike shape of neurons. Our results offer new insights into visual processing by showing how high-firing rate neurons (mostly thin spike neurons) could modulate the neuronal responses within cell assemblies. PMID- 26247540 TI - On the particular importance of vibrational contributions to the static electrical properties of model linear molecules under spatial confinement. AB - The influence of the spatial confinement on the electronic and vibrational contributions to longitudinal electric-dipole properties of model linear molecules including HCN, HCCH and CO2 is discussed. The effect of confinement is represented by two-dimensional harmonic oscillator potential of cylindrical symmetry, which mimics the key features of various types of trapping environments like, for instance, nanotubes or quantum well wires. Our results indicate that in general both (electronic and vibrational) contributions to (hyper)polarizabilities diminish upon spatial confinement. However, since the electronic term is particularly affected, the relative importance of vibrational contributions is larger for confined species. This effect increases also with the degree of anharmonicity of vibrational motion. PMID- 26247541 TI - Artifact-Free Quantification and Sequencing of Rare Recombinant Viruses by Using Drop-Based Microfluidics. AB - Recombination is an important driver in the evolution of viruses and thus is key to understanding viral epidemics and improving strategies to prevent future outbreaks. Characterization of rare recombinant subpopulations remains technically challenging because of artifacts such as artificial recombinants, known as chimeras, and amplification bias. To overcome this, we have developed a high-throughput microfluidic technique with a second verification step in order to amplify and sequence single recombinant viruses with high fidelity in picoliter drops. We obtained the first artifact-free estimate of in vitro recombination rate between murine norovirus strains MNV-1 and WU20 co-infecting a cell (P(rec) = 3.3 * 10(-4) +/- 2 * 10(-5) ) for a 1205 nt region. Our approach represents a time- and cost-effective improvement over current methods, and can be adapted for genomic studies requiring artifact- and bias-free selective amplification, such as microbial pathogens, or rare cancer cells. PMID- 26247542 TI - Effect of CH4/O2 ratio on fatty acid profile and polyhydroxybutyrate content in a heterotrophic-methanotrophic consortium. AB - Understanding the role of heterotrophic-methanotrophic (H-Meth) communities is important for improvement of methane (CH4) oxidation capacities (MOC) particularly in conjunction with bio-product development in industrial bio filters. Initially, a H-Meth consortium was established and enriched from marine sediments and characterized by next generation sequencing of the 16s rDNA gene. The enriched consortium was subjected to 10-50% CH4 (i.e., 0.20-1.6 CH4/O2 ratios) to study the effects on MOCs, biomass growth, fatty acid profiles and biopolymer (e.g. polyhydroxybutyrate; PHB) content. Methylocystis, Methylophaga and Pseudoxanthomonas dominated the H-Meth consortium. Culture enrichment of the H-Meth consortium resulted in 15-20-folds higher MOC compared to seed sediments. Increasing CH4 concentration (and decreased O2 levels) yielded higher MOCs, but did not improve total fatty acid contents. PHB contents varied between 2.5% and 8.5% independently of CH4/O2 ratios. The results suggest that H-Meth consortia could potentially be used in industrial bio-filters for production of biopolymer/biofuel precursors from CH4. PMID- 26247544 TI - Effect of Blue Light on the Electronic and Structural Properties of Bilirubin Isomers: Insights into the Photoisomerization and Photooxidation Processes. AB - The central process of neonatal phototherapy by employing blue light has been attributed to the configurational conversion of (4Z,15Z)-bilirubin to (4Z,15E). Indeed, photoisomerization is the early photochemical event during this procedure. However, in this paper, we show that the bilirubin solutions under continuous blue light exposure undergo a photooxidation process. To ascertain the role of this photodegradation in the phototherapy, we evaluated UV-visible absorption spectra obtained from bilirubin solutions in CHCl3, milli-Q water, and physiological saline, as well as FTIR spectroscopy for bilirubin in CHCl3. These analyses also showed that the first 2 h of phototherapy are the most relevant period. In addition, quantum molecular modeling using B3LYP/6-31G(d,p) and ZINDO/S-CIS was performed to evaluate the electronic and structural properties of four bilirubin isomers, showing that the (4Z,15E)-bilirubin isomer is the most polar configuration. Therefore, it can be more soluble in aqueous environments than the other configurations. This clarifies why this is the faster isomer excreted during the phototherapy. PMID- 26247543 TI - Acute and Short-term Toxic Effects of Conventionally Fractionated vs Hypofractionated Whole-Breast Irradiation: A Randomized Clinical Trial. AB - IMPORTANCE: The most appropriate dose fractionation for whole-breast irradiation (WBI) remains uncertain. OBJECTIVE: To assess acute and 6-month toxic effects and quality of life (QOL) with conventionally fractionated WBI (CF-WBI) vs hypofractionated WBI (HF-WBI). DESIGN, SETTING, AND PARTICIPANTS: Unblinded randomized trial of CF-WBI (n = 149; 50.00 Gy/25 fractions + boost [10.00-14.00 Gy/5-7 fractions]) vs HF-WBI (n = 138; 42.56 Gy/16 fractions + boost [10.00-12.50 Gy/4-5 fractions]) following breast-conserving surgery administered in community based and academic cancer centers to 287 women 40 years or older with stage 0 to II breast cancer for whom WBI without addition of a third field was recommended; 76% of study participants (n = 217) were overweight or obese. Patients were enrolled from February 2011 through February 2014 and observed for a minimum of 6 months. INTERVENTIONS: Administration of CF-WBI or HF-WBI. MAIN OUTCOMES AND MEASURES: Physician-reported acute and 6-month toxic effects using National Cancer Institute Common Toxicity Criteria, and patient-reported QOL using the Functional Assessment of Cancer Therapy for Patients with Breast Cancer (FACT-B). All analyses were intention to treat, with outcomes compared using the chi2 test, Cochran-Armitage test, and ordinal logistic regression. RESULTS: Of 287 participants, 149 were randomized to CF-WBI and 138 to HF-WBI. Treatment arms were well matched for baseline characteristics, including FACT-B total score (HF WBI, 120.1 vs CF-WBI, 118.8; P = .46) and individual QOL items such as somewhat or more lack of energy (HF-WBI, 38% vs CF-WBI, 39%; P = .86) and somewhat or more trouble meeting family needs (HF-WBI, 10% vs CF-WBI, 14%; P = .54). Maximum physician-reported acute dermatitis (36% vs 69%; P < .001), pruritus (54% vs 81%; P < .001), breast pain (55% vs 74%; P = .001), hyperpigmentation (9% vs 20%; P = .002), and fatigue (9% vs 17%; P = .02) during irradiation were lower in patients randomized to HF-WBI. The rate of overall grade 2 or higher acute toxic effects was less with HF-WBI than with CF-WBI (47% vs 78%; P < .001). Six months after irradiation, physicians reported less fatigue in patients randomized to HF-WBI (0% vs 6%; P = .01), and patients randomized to HF-WBI reported less lack of energy (23% vs 39%; P < .001) and less trouble meeting family needs (3% vs 9%; P = .01). Multivariable regression confirmed the superiority of HF-WBI in terms of patient-reported lack of energy (odds ratio [OR], 0.39; 95% CI, 0.24-0.63) and trouble meeting family needs (OR, 0.34; 95% CI, 0.16-0.75). CONCLUSIONS AND RELEVANCE: Treatment with HF-WBI appears to yield lower rates of acute toxic effects than CF-WBI as well as less fatigue and less trouble meeting family needs 6 months after completing radiation therapy. These findings should be communicated to patients as part of shared decision making. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01266642. PMID- 26247545 TI - Bioactive ginger constituents alleviate protein glycation by trapping methylglyoxal. AB - Considerable evidence suggests that long-term pathological diabetes is a result of the accumulation of tissue macromolecules that have been progressively modified by nonenzymatic glycation of protein. Methylglyoxal (MGO) is a highly reactive endogenous dicarbonyl metabolite derived from multiple sources such as glucose and lipids and is thought to contribute greatly to protein glycation and the formation of advanced glycation end products (AGEs). In this study, we demonstrated for the first time that both [6]-shogaol (6S) and [6]-gingerol (6G), the major active components in ginger, markedly trapped MGO in vitro and consequently formed mono-MGO adducts, 6S-MGO and 6G-MGO, which were purified from the respective chemical reaction and characterized as novel compounds by NMR experiments and LC-MS/MS approaches. We revealed that the alpha-carbon of the carbonyl group in the side chain of 6S or 6G is the major active site for trapping MGO. We also demonstrated that 6S and 6G could effectively inhibit the formation of MGO-induced AGEs via trapping MGO in a time-dependent manner in the human serum albumin (HSA)-MGO system. Mono-MGO adducts, 6S-MGO and 6G-MGO, were determined to be the major conjugates in 6S- and 6G-treated HSA-MGO assays, respectively, using LC-ESI-MS techniques. These findings showed the potential effects of 6S and 6G on the prevention of protein glycation, suggesting regular consumption of ginger root extract may attenuate the progression of MGO associated diabetic complications in patients. PMID- 26247546 TI - Clay-Shoveler Fracture in a Paddler: A Case Report. AB - Clay-shoveler fracture is a fracture of the spinous process of lower cervical and upper thoracic vertebrae. It has only rarely been reported as being caused by an overuse sports injury. This case report describes the first reported clay shoveler fracture in a paddler. A 51-year-old male paddler, preparing for a paddling adventure over 630 km, felt a click and a sharp pain paravertebrally on the level of the upper thoracic vertebrae while paddling. Sonar investigation did not reveal any muscular injury but computed tomography revealed a fracture of the spinous process of T1. In this case, it is a stress injury due to excessive paddling over a short period of time. This fracture causes debilitating pain in the acute phase and is mainly treated conservatively. PMID- 26247547 TI - Effects of Competition Rule Changes on the Incidence of Head Kicks and Possible Concussions in Taekwondo. AB - OBJECTIVE: Competition rules related to head kicks (HKs) in sparing-taekwondo (S TKD) were changed in 2009, resulting in more points awarded to the head attacker. The objective of this research is to measure the incidence of HKs and to analyze the characteristics of situations leading up to and after HKs in a postrule change competition. DESIGN: Descriptive epidemiology study using video analysis. SETTING: The final matches of the World Taekwondo Championships (WTCs) in 2011 and 2013. PARTICIPANTS: A total of 1760 athletes participated in both WTCs. Sixty four athletes, who had won elimination-round matches and were 15 years or older, competed in final matches. MAIN OUTCOME MEASURES: The final matches-a total of 64 matches including 95 rounds-were analyzed using an anatomical and outcome coding scheme for HKs. RESULTS: Overall, a total of 30 athletes experienced receiving one or more HKs during 2 WTCs (469 HKs per 1000 athlete-exposures (A-E), 95% confidence interval = 296, 642). Female athletes showed higher incidences of HKs than male. A trend of increasing incidence of HKs was observed in the females. The HKs occurred more frequently among competitors in lightweight categories and those of similar height (49%). CONCLUSIONS: Overall, the frequency of HKs seems to have increased compared with matches before 2009. A sharp increase in the numbers of HKs is evident among the elite female athletes. To prevent receiving an HK, updated game strategies such as training for blocking skills, and safety guidelines for HKs, or revisions to rules are needed. CLINICAL RELEVANCE: The recent changes to competition rules promoting the use of HKs may have resulted in an increasing frequency of HKs compared with research findings before these changes. Multiple HKs occur frequently in S-TKD; care needs to be taken to avoid possible acute/chronic consequences. PMID- 26247548 TI - Climbing Has a Positive Impact on Low Back Pain: A Prospective Randomized Controlled Trial. AB - OBJECTIVE: Comparison of climbing versus no treatment to treat chronic low back pain. DESIGN: Prospective randomized controlled trial. SETTING: Tertiary. PARTICIPANTS: A total of 30 patients with chronic low back pain were recruited and randomly assigned to 2 different groups: climbing and control. The inclusion criteria were defined as chronic low back pain, age between 18 and 45 years, body mass index lower than 25, and no climbing experience. INTERVENTIONS: Patients in the climbing group were instructed to climb 5 different climbing routes. A climbing activity of 10 sessions in 8 weeks, at least once a week with a minimum duration of 1 hour, was mandatory. MAIN OUTCOME MEASURES: The participants were examined before (T0) and after therapy (8 weeks, T8) and after another 6 weeks (T14). The outcome was evaluated using Oswestry Disability Index, Visual Analog Scale (VAS), Likert scale, and magnetic resonance imaging (MRI). Radiologists evaluating MRI were blinded. The study was performed as a single-center study. RESULTS: Evaluating the Oswestry Disability Index, a significant difference in the time course between the 2 groups was detected (P = 0.022). Significant improvements comparing climbing and control group were also found when assessing VAS in a minimal finger-floor-distance position (P = 0.048). Patients in the climbing group showed a reduction in size of disc protrusion. CONCLUSIONS: Climbing may be an effective and low-cost therapy option for people with chronic low back pain. CLINICAL RELEVANCE: Low back pain is a very common disease but still a challenge to treat. Therapy strategies vary from conservative ones, pharmacological treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and weak opioids, to invasive treatment with acupuncture, injections, and operative reconstruction. Some can be costly and not without risks. For instance, many people who use NSAIDs are at risk of common side effects such as gastrointestinal complications (irritation, ulcers, and bleeding) that may lead to hospitalization. Climbing could offer reduction of pain and better performance in daily life, because it offers a closed chain muscle training that has the potential to improve posture, perception of the trunk midline, and muscle control. Climbing may also lead to a better adherence to continuing treatment than traditional physical therapy and exercise due to a more exciting aspect of the sports activity. PMID- 26247549 TI - Relationship Between Short Sleep Duration and Preseason Concussion Testing. AB - OBJECTIVE: Baseline, preseason assessment of cognition, symptoms, and balance has been recommended as part of a comprehensive sport concussion management program. We examined the relationship between sleep and baseline test results. We hypothesized that adolescents who slept fewer hours the night before would report more symptoms and perform more poorly on cognitive testing than students who had a full night sleep. DESIGN: Cross-sectional observation study. SETTING: Preseason concussion testing for high school athletes. PARTICIPANTS: A large sample (n = 2928) of student athletes from Maine, USA, between the ages of 13 and 18 years completed preseason testing. Participants with developmental problems, a history of treatment for neurological or psychiatric problems, recent concussion, or 3 or more prior concussions were excluded. ASSESSMENT OF RISK FACTORS: Athletes were divided into 4 groups based on their sleep duration the night before testing. MAIN OUTCOME MEASURES: Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT; ImPACT Applications, Inc, Pittsburgh, PA) cognitive composite scores and the embedded Post-Concussion Symptom Scale. RESULTS: Sleep was not related to any ImPACT cognitive composite score, after covarying for age and controlling for multiple comparisons. In contrast, there were sleep duration, sex, and sleep duration by sex effects on the Post-Concussion Symptom Scale. The effect of sleep duration on symptom reporting was more pronounced in girls. Supplementary analyses suggested that sleep insufficiency was associated with a diverse array of postconcussion-like symptoms. CONCLUSIONS: Poor sleep the night before baseline or postinjury testing may be an important confound when assessing postconcussion symptoms. Girls may be more vulnerable to experiencing and reporting symptoms following insufficient sleep. CLINICAL RELEVANCE: Clinicians should routinely ask how the athlete slept the night before preseason baseline testing and consider deferring the symptom assessment or later retesting athletes who slept poorly. PMID- 26247550 TI - Pregame Sore Throat, Postgame Intensive Care Unit. AB - A collegiate football athlete presented, on game day, with an acute onset of sore throat. He was afebrile, speaking in full sentences, without signs of respiratory distress. His examination was negative for lymphadenopathy or tonsillar enlargement or exudate. Twelve hours after initial presentation, he developed acute epiglottitis. He underwent urgent fiberoptic intubation and was empirically treated with broad-spectrum antibiotics and corticosteroids. Currently, there are no published reports of acute epiglottitis in athletes. Consequently, there is no evidence to guide return to play decisions. Return to play, following acute epiglottitis, should include resolution of symptoms and a graded return to play, taking into consideration the level of deconditioning the athlete experienced from hospitalization. PMID- 26247551 TI - Update and Overview of Spinal Injuries in Canadian Ice Hockey, 1943 to 2011: The Continuing Need for Injury Prevention and Education. AB - OBJECTIVE: To identify spinal injuries in Canadian ice hockey from 2006 to 2011 and to discuss data from 1943 to 2011 and impact of injury prevention programs. DESIGN: Data about spinal injuries with and without spinal cord injury in ice hockey have been collected by ThinkFirst's (now Parachute Canada) Canadian Ice Hockey Spinal Injuries Registry since 1981 through questionnaires from practitioners, ice hockey organizations, and media. SETTING: All Canadian provinces and territories. PARTICIPANTS: All registered Canadian ice hockey players. ASSESSMENT OF RISK FACTORS: Age, gender, level of play, location, mechanism of injury. MAIN OUTCOME MEASURES: Incidence, incidence rate, prevalence, and nature (morbidity) of the injuries. RESULTS: Between 2006 and 2011, 44 cases occurred, 4 (9.1%) of which were severe. The incidence in the recent years continues to be lower than the peak years. From 1943 to 2011, 355 cases have been documented, primarily males (97.7%) and cervical spine injuries (78.9%), resulting from impact with the boards (64.2%). Check or push from behind (36.0%) was still the most common cause of injury, although slightly lower during 2006 to 2011. From 1943 to 2011, Prince Edward Island, New Brunswick, and British Columbia/Yukon had the highest injury rates. Ontario and Quebec continued to show markedly different injury rates, with Ontario more than twice that of Quebec. CONCLUSIONS: Current data for 2006 to 2011 indicate that spinal injuries in ice hockey continue to occur, although still at lower rates than the peak years 1982 to 1995. It is imperative to continue educating players and team officials about spinal injury prevention and to reinforce the rules against checking or pushing from behind to reduce the incidence of these serious injuries. PMID- 26247552 TI - Blue nevus with tubule and pseudoacini formation. PMID- 26247553 TI - Gold cluster-labeled thermosensitive liposmes enhance triggered drug release in the tumor microenvironment by a photothermal effect. AB - Stimulus-triggered drug release based on the liposomal drug delivery platform has been studied vigorously to increase drug release at the target site. Although the delivery system has been developed, an effective carrier system is needed to achieve effective therapeutic efficacy. Therefore, we focused on the development of gold cluster bound thermosensitive liposomes (G-TSL), which are capable of triggered drug release when stimulated by external near-infrared (NIR) irradiation in the tumor microenvironment. The size of doxorubicin (DOX)-loaded G TSL (DOX/G-TSL) was 171.5 +/- 8.3 nm, and the efficiency of DOX encapsulation was up to 90%. The release of DOX from DOX/G-TSL was increased 70% by NIR irradiation (1.50 W/cm(2) for 0.5 min) compared to non-gold-coated TSL. Consequentially, the gold cluster on the TSL enabled the light-controlled DOX release through the photothermal conversion of the energy of NIR-absorbed light, leading to membrane destabilization. Cell cytotoxicity of DOX/G-TSL was also increased by their NIR irradiation-triggered DOX release compared to non-NIR-irradiated DOX/G-TSL. In addition, we demonstrated the therapeutic efficacy of DOX/G-TSL against the MDA MB-231 tumor model. The NIR-irradiated DOX/G-TSL treatment showed greater therapeutic efficacy than that of the non-NIR-irradiated DOX/G-TSL and control (p<0.05). Taken together, DOX/G-TSL has the potential for remote-triggered drug release upon stimulation with NIR irradiation in the tumor microenvironment, and may be applied to a broad range of photothermal-based disease therapies. PMID- 26247554 TI - Estimated Glomerular Filtration Rate in Renal Transplantation: The Nephrologist in the Mist. AB - BACKGROUND: Formulas do not estimate renal function with acceptable precision and accuracy. METHODS: We compared 51 creatinine-based and/or cystatin c-based formulas with a gold standard (iohexol plasma clearance) in 193 renal transplant recipients using concordance correlation coefficient, total deviation index, coverage probability and the error in chronic kidney disease (CKD) stage classification. RESULTS: No formula showed a concordance correlation coefficient greater than 0.90 (average for creatinine-based formulas: ~0.70 and for cystatin c-based formulas: ~0.85). A wide total deviation index was observed: approximately 70% (creatinine-based) and approximately 50% (cystatin c-based), indicating that 90% of the estimations showed bounds of error of +/-70% or +/ 50%, respectively, compared with the gold standard. No formula included 90% of the estimations within a coverage probability of +/-10%. Half the CKD stages classified by creatinine-based formulas were incorrect, mainly due to overestimation of renal function. One of 3 CKD stages diagnosed by cystatin c based formulas was incorrect, with both overestimation and underestimation. Overall, the formulas showed very low precision and accuracy and a high degree of error in reflecting real renal function. CONCLUSIONS: In conclusion, formulas do not properly reflect renal function in kidney transplantation, which makes their use in clinical practice unreliable. Moreover, their use in clinical trials should be avoided. PMID- 26247555 TI - Cytomegalovirus Infection After Intestinal/Multivisceral Transplantation: A Single-Center Experience With 210 Cases. AB - BACKGROUND: Cytomegalovirus (CMV) infection is the most prevalent infectious complication after solid organ transplantation, and recipients of isolated intestinal transplantation (IIT)/multivisceral transplantation (MVT) are among those at the highest risk. Limited clinical data exist regarding CMV infection after IIT/MVT. The aim of this study is to analyze risk factors for posttransplant CMV infection and to assess the efficacy and validity of our prophylaxis and treatment regimens in intestinal transplantation. METHODS: Medical records of 210 IIT/MVT patients were retrospectively reviewed. Posttransplant CMV prophylaxis regimen consisted of ganciclovir followed by 1 year of valganciclovir. The addition of CMV immunoglobulin (CMVIG) was decided according to donor/recipient CMV serostatus (D/R). All results of CMV PCR and/or pp65 antigenemia, and pathological reports were reviewed. Time to the incidence of CMV infection (viremia and/or tissue invasive disease) and risk factors for CMV infection were investigated. RESULTS: CMV infection was observed in 34 of 210 (16%) with a median onset of 347 days. Rejection was significantly associated with CMV infection (P = 0.01, odds ratio = 2.61). In the high-risk serostatus group (D+/R-), prophylactic CMVIG and induction with high-dose rabbit antithymocyte globulin (>10 mg/kg) were associated with a lower CMV infection rate on univariate analysis. The CMVIG remained to be an independent factor on multivariate analysis (P = 0.04, hazard ratio = 0.93/dose). Mortality associated with CMV infection occurred in 4, and CMV infection adversely affected patient survival (P = 0.001, hazard ratio = 2.71). CONCLUSIONS: Prophylaxis with CMVIG and appropriate induction with rabbit antithymocyte globulin may be important to reduce CMV infection in high-risk serostatus group (D+/R-). PMID- 26247556 TI - The Role of Liver Sinusoidal Endothelial Cells in Induction of Carbohydrate Reactive B Cells Tolerance Through the Programmed Death 1/Programmed Death Ligand 1 Pathway. AB - BACKGROUND: A spontaneous tolerance of B cells responding to blood group antigens frequently develops in ABO-incompatible pediatric liver transplantation (LT). Liver sinusoidal endothelial cells (LSECs), which exclusively express blood group antigens in the liver, possess a capacity to induce alloantigen-specific tolerance. In this study, we elucidated the role of LSECs in the tolerance induction of blood group antigen-reactive B cells after ABO-incompatible LT using mice that lack galactose-alpha(1,3)galactose (Gal) epitopes resembling blood group carbohydrate antigens. METHODS: Using adoptive transfer of LSECs from wild type (WT) C57BL/6J mice to congenic alpha1,3-galactosyltransferase gene knockout (GalT) mice, we established orthotropic GalT -> GalT LSEC chimera mice. Anti-Gal Ab (antibody) production was evaluated after immunization of GalT -> GalT LSEC chimera mice with Gal rabbit RBC. RESULTS: Adoptive transfer of LSECs isolated from WT GalT mice via the portal vein resulted in persistent engraftment of Gal LSECs in congenic GalT mouse livers. Only when GalT mice were splenectomized before LSEC inoculation, the GalT -> GalT LSEC chimera lost the ability to produce anti-Gal Abs. The administration of blocking monoclonal Abs (mAbs) against programmed death ligand 1 to the splenectomized GalT -> GalT LSEC chimera resulted in the recovery of anti-Gal Ab production. CONCLUSIONS: These findings suggest that LSECs take a part in tolerization of immature but not mature B cells specifically for Gal. Furthermore, the programmed death 1/programmed death ligand 1 pathway likely plays a crucial role in the mechanisms underlying spontaneous tolerization of B cells responding to ABO-blood group antigens in LT. PMID- 26247557 TI - Recurrence of Focal and Segmental Glomerulosclerosis After Transplantation. AB - Focal segmental glomerulosclerosis, which is a common glomerular disorder, manifests clinically with a nephrotic syndrome and has a high propensity for recurrence after kidney transplantation. The pathophysiology is currently unknown, and podocytes appear to be the target of one or several circulating factor(s) that lead to the recurrence of proteinuria after kidney transplantation. Identifying these circulating factor(s) and cells involved in its synthesis remains elusive; however, recently, our research on podocyte cytoskeleton biology has opened a new era of treatment. This review will highlight recent progress in the physiopathology of focal segmental glomerulosclerosis recurrence after transplantation and its treatment. PMID- 26247558 TI - Functionalization of Platinum Complexes for Biomedical Applications. AB - Platinum-based anticancer drugs are the mainstay of chemotherapy regimens in clinic. Nevertheless, the efficacy of platinum drugs is badly affected by serious systemic toxicities and drug resistance, and the pharmacokinetics of most platinum drugs is largely unknown. In recent years, a keen interest in functionalizing platinum complexes with bioactive molecules, targeting groups, photosensitizers, fluorophores, or nanomaterials has been sparked among chemical and biomedical researchers. The motivation for functionalization comes from some of the following demands: to improve the tumor selectivity or minimize the systemic toxicity of the drugs, to enhance the cellular accumulation of the drugs, to overcome the tumor resistance to the drugs, to visualize the drug molecules in vitro or in vivo, to achieve a synergistic anticancer effect between different therapeutic modalities, or to add extra functionality to the drugs. In this Account, we present different strategies being used for functionalizing platinum complexes, including conjugation with bisphosphonates, peptides, receptor-specific ligands, polymers, nanoparticles, magnetic resonance imaging contrast agents, metal chelators, or photosensitizers. Among them, bisphosphonates, peptides, and receptor-specific ligands are used for actively targeted drug delivery, polymers and nanoparticles are for passively targeted drug delivery, magnetic resonance imaging contrast agents are for theranostic purposes, metal chelators are for the treatment or prevention of Alzheimer's disease (AD), and photosensitizers are for photodynamic therapy of cancers. The rationales behind these designs are explained and justified at the molecular or cellular level, associating with the requirements for diagnosis, therapy, and visualization of biological processes. To illustrate the wide range of opportunities and challenges that are emerging in this realm, representative examples of targeted drug delivery systems, anticancer conjugates, anticancer theranostic agents, and anti-AD compounds relevant to functionalized platinum complexes are provided. All the examples exhibit new potential of platinum complexes for future applications in biomedical areas. The emphases of this Account are placed on the functionalization for targeted drug delivery and theranostic agents. In the end, a general assessment of various strategies has been made according to their major shortcomings and defects. The original information in this Account comes entirely from literature appearing since 2010. PMID- 26247562 TI - Photoluminescence Properties of Efficient Blue-Emitting Phosphor alpha Ca1.65Sr0.35SiO4:Ce(3+): Color Tuning via the Substitutions of Si by Al/Ga/B. AB - A series of Ce(3+)-doped alpha-Ca1.65Sr0.35SiO4 (CSSO) phosphors without and with the substitutions of Si by Al/Ga/B were synthesized via the high-temperature solid-state reaction process. X-ray diffraction patterns and Rietveld refinements were used to demonstrate the successful incorporations of Al/Ga/B into CSSO:Ce(3+). Without Al/Ga/B, the Ce(3+) singly doped CSSO phosphors present intense blue emission, which correspond to the broad emission bands in visible region with the wavelength range from 360 to 580 nm upon 350 nm excitation. The optimal emission intensity occurs in CSSO:0.05Ce(3+) sample with the emission peak wavelength at 436 nm. With the introduction of Al/Ga/B into the CSSO:0.05Ce(3+), the emission peak shifts from 436 to 457/465/446 nm under 365 nm excitation, respectively. The red shift of Ce(3+) emission is attributed to the polyhedral distortion of the cations, resulting in the enhancement of crystal field spitting due to the variations of the adjacent (Al/Ga/B,Si)O4 polyhedron. Moreover, the temperature-dependent photoluminescence was determined to be of light impact to CSSO:Ce(3+) with the introduction of Al/Ga/B. This research is useful for enriching the emission colors of Ce(3+)-activated phosphors. PMID- 26247563 TI - An Oxidative Macrobicyclic Ring Opening of a Triptycene to a Highly Functionalized Fluorene Derivative. AB - The treatment of hexamethoxytriptycenes with nitric acid leads to an unprecedented oxidative ring opening of the triptycene scaffold, resulting in a new class of fluorene derivatives with a nitroquinone unit. Preliminary investigations of the influence of chain length of alkyl substituents at the triptycene bridgeheads to the reaction have been performed, revealing that exclusively the methyl-substituted hexamethoxytriptycene does not undergo an oxidative ring opening reaction. PMID- 26247564 TI - All-cause Mortality Associated with TNF-alpha Inhibitors in Rheumatoid Arthritis: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: To compare mortality data obtained from randomized controlled trials for the 5 tumor necrosis factor-alpha (TNF-alpha) inhibitors used in the treatment of rheumatoid arthritis. METHODS: A systematic review of articles published up to November 2014 was performed using electronic databases. We included randomized, controlled trials, with a follow-up period of at least 24 weeks, comparing TNF-alpha inhibitors to placebo or disease-modifying antirheumatic drugs. The primary outcome was the occurrence of all-cause mortality. RESULTS: Twenty-three studies were selected. These articles included 6525 patients in the anti-TNF-alpha group and 3523 in the control group. The duration of patient follow-up ranged from 24 to 104 weeks. The risk of all-cause mortality in patients receiving TNF-alpha inhibitors was not significantly different from those receiving the comparator (odds ratio 1.32; 95% confidence interval, 0.76-2.29). Subgroup analyses with respect to the molecule used, the dose received, the use of TNF-alpha inhibitors as monotherapy or combination therapy, or the quality of the trial did not modify the findings. CONCLUSION: This meta-analysis performed on a large number of patients and including the 5 TNF-alpha inhibitors currently available shows no increased risk of medium-term all-cause mortality in patients with rheumatoid arthritis. PMID- 26247565 TI - Regular Physical Activity: Forgotten Benefits. PMID- 26247566 TI - Negative Secular Trends in Medicine: Student Debt. PMID- 26247567 TI - Howard Wilbur Jones, Jr., M.D.: a giant in our midst. PMID- 26247568 TI - Liquid nitrogen vapor is comparable to liquid nitrogen for storage of cryopreserved human sperm: evidence from the characteristics of post-thaw human sperm. AB - OBJECTIVE: To compare the differences in the characteristics of post-thaw human sperm after storage in either liquid nitrogen (LN2; -196 degrees C) or LN2 vapor (-167 degrees C). DESIGN: Experimental study. SETTING: University hospital. PATIENT(S): Thirty healthy volunteers who agreed to donate their normal semen samples for infertility or research were included in the study. INTERVENTION(S): Semen samples (n = 30) were divided into eight aliquots and frozen. Four aliquots of each human semen sample were stored in LN2 (-196 degrees C), and the other four aliquots were stored in LN2 vapor (-167 degrees C). After 1, 3, 6, or 12 months, samples were thawed and analyzed. MAIN OUTCOME MEASURE(S): The motility was evaluated by the manual counting method. The viability was estimated by eosin staining. The morphology was analyzed by Diff-Quik staining. The sperm DNA integrity was determined with acridine orange fluorescent staining, and acrosin activity was assayed by the modified Kennedy method. RESULT(S): The characteristics of post-thaw human sperm, including motility, viability, morphology, DNA integrity, and acrosin activity, showed no significant difference between LN2 and LN2 vapor storage for the different time periods. CONCLUSION(S): LN2 vapor was comparable to LN2 in post-thaw sperm characteristics, suggesting that LN2 vapor may be substituted for LN2 for the long-term storage of human sperm. PMID- 26247569 TI - Current issues in the design and analysis of stepped wedge trials. AB - The use of stepped wedge designs in cluster-randomized trials and implementation studies has increased rapidly in recent years but there remains considerable debate regarding the merits of the design. We discuss three key issues in the design and analysis of stepped wedge trials - time-on-treatment effects, treatment effect heterogeneity and cohort studies. PMID- 26247570 TI - Motivating first-time, group O blood donors to return: Rationale and design of a randomized controlled trial of a post-donation telephone interview. AB - First-time blood donors are essential to the US donor pool, providing nearly a third of all donations. Unfortunately, there are a wide variety of obstacles to repeat donation and new donors are extremely difficult to retain. Because each donor experiences a unique set of deterrents, we developed a post-donation interview based on motivational interview principles in order to flexibly address individual barriers. The primary aim of this randomized clinical trial is to examine retention of first-time, group O blood donors who are randomly assigned to receive either a telephone-delivered interview with motivational and action planning components or a standard-of-care control call approximately six weeks after their donation. Measures of donation attitude, perceived behavioral control, intention, and motivational autonomy will be measured before and after the telephone contact using online surveys, and donation attempts will be tracked for one year using blood center donor databases. We hypothesize that, compared to controls, donors who receive the telephone interview will be more likely to make a donation attempt over the following year. In addition, we will examine possible mechanisms of action of the interview using key predictors of donation behavior as described by Self Determination Theory (i.e., motivational autonomy) and the Theory of Planned Behavior (i.e., attitude, perceived behavioral control, and intention). Results of this intervention may help to support a novel strategy to enhance retention of selected blood donors in an effort to better meet the nation's blood supply needs. PMID- 26247571 TI - The burden of ambient temperature on years of life lost in Guangzhou, China. AB - Limited evidence is available on the association between temperature and years of life lost (YLL). We applied distributed lag non-linear model to assess the nonlinear and delayed effects of temperature on YLL due to cause-/age-/education specific mortality in Guangzhou, China. We found that hot effects appeared immediately, while cold effects were more delayed and lasted for 14 days. On average, 1 degrees C decrease from 25(th) to 1(st) percentile of temperature was associated with an increase of 31.15 (95%CI: 20.57, 41.74), 12.86 (8.05, 17.68) and 6.64 (3.68, 9.61) YLL along lag 0-14 days for non-accidental, cardiovascular and respiratory diseases, respectively. The corresponding estimate of cumulative hot effects (1 degrees C increase from 75(th) to 99(th) percentile of temperature) was 12.71 (-2.80, 28.23), 4.81 (-2.25, 11.88) and 2.81 (-1.54, 7.16). Effect estimates of cold and hot temperatures-related YLL were higher in people aged up to 75 years and persons with low education level than the elderly and those with high education level, respectively. The mortality risks associated with cold and hot temperatures were greater on the elderly and persons with low education level. This study highlights that YLL provides a complementary method for assessing the death burden of temperature. PMID- 26247572 TI - Genetically Engineered Plant Viral Nanoparticles Direct Neural Cells Differentiation and Orientation. AB - An important aim of tissue engineering is to design biomimetic materials with specific cell binding motifs and precisely controlled structural organization, thereby providing biochemical and physical cues for desired cellular behaviors. Previously, our group generated genetically modified tobacco mosaic virus (TMV) displaying integrin binding motifs, RGD1, RGD7, PSHRN3, P15, and DGEA. The resulting rod-like virus particles displaying integrin binding motifs were biocompatible with Neuro 2A (N2a), a mouse neural crest-derived cell line, and could promote the neurite outgrowth of N2a. The genetically modified viruses could be assembled with aligned orientation in the capillary by applying a shear force. The resulting aligned substrates were able to dictate directional neurite outgrowth of N2a cells. Therefore, this method could be potentially applied for neural tissue engineering, as a neural conduit for repairing peripheral nerve injuries. PMID- 26247573 TI - Study on Antitumor Platinum(II) Complexes of Chiral Diamines with Dicyclic Species as Steric Hindrance. AB - A series of platinum(II) complexes, characteristic of chiral trans bicyclo[2.2.2]octane-7,8-diamine as ligand possessing dicyclic steric hindrance, were designed and synthesized. Biological evaluation showed that almost all complexes had cytotoxic activity against the tested cancer cell lines, among which most of chiral (R,R)-enantiomeres had stronger cytotoxicity than their (S,S)-counterparts, and 2a, [trans-bicyclo[2.2.2]octane-7R,8R-diamine](oxalato O,O')platinum(II), is the most effective agent. Significantly, its counterpart, 2b, was much more sensitive to cisplatin resistant SGC7901/CDDP cancer cell line at a higher degree than 2a. Docking study and agarose gel electrophoresis revealed that the interaction of 2a with DNA was similar to that of oxaliplatin. Western blot analysis demonstrated that 2a could induce a better effect than cisplatin on a mitochondrial-dependent apoptosis pathway. Kinetic study indicated that the dicyclic ligand can accelerate the reaction rate of the complex. PMID- 26247574 TI - MicroRNA-345 induces apoptosis in pancreatic cancer cells through potentiation of caspase-dependent and -independent pathways. AB - BACKGROUND: Previously, miR-345 was identified as one of the most significantly downregulated microRNAs in pancreatic cancer (PC); however, its functional significance remained unexplored. METHODS: miR-345 was overexpressed in PC cells by stable transfection, and its effect on growth, apoptosis and mitochondrial membrane potential was examined by WST-1, Hoechst-33342/Annexin-V, and JC-1 staining, respectively. Gene expression was examined by quantitative reverse transcription-PCR and/or immunoblotting, and subcellular fractions prepared and caspase-3/7 activity determined by commercially available kits. miR-345 target validation was performed by mutational analysis and luciferase-reporter assay. RESULTS: miR-345 is significantly downregulated in PC tissues and cell lines relative to normal pancreatic cells, and its expression decreases gradually in PC progression model cell lines. Forced expression of miR-345 results in reduced growth of PC cells because of the induction of apoptosis, accompanied by a loss in mitochondrial membrane potential, cytochrome-c release, caspases-3/7 activation, and PARP-1 cleavage, as well as mitochondrial-to-nuclear translocation of apoptosis-inducing factor. These effects could be reversed by the treatment of miR-345-overexpressing PC cells with anti-miR-345 oligonucleotides. BCL2 was characterised as a novel target of miR-345 and its forced-expression abrogated the effects of miR-345 in PC cells. CONCLUSIONS: miR 345 downregulation confers apoptosis resistance to PC cells, and its restoration could be exploited for therapeutic benefit. PMID- 26247576 TI - Cost-effectiveness of combinatorial pharmacogenomic testing for treatment resistant major depressive disorder patients. AB - OBJECTIVES: To describe the lifetime outcomes and economic implications of combinatorial pharmacogenomic (CPGx) testing versus treatment as usual (TAU) psychopharmacologic medication selection for a representative major depressive disorder patient who has not responded to previous treatment(s). STUDY DESIGN: Markov state-transition analysis based on clinical studies. METHODS: Clinical validity and utility were based on published findings in prospective clinical studies of a commercially available CPGx test. Data for quality of life, direct costs, and indirect costs were extracted from meta-analyses of published literature on clinical studies and claims databases. Outcomes were assessed from a societal perspective, and included differences between the CPGx and the TAU strategies in quality-adjusted life-years (QALYs), cumulative direct and indirect costs, and cost per QALY gained. RESULTS: CPGx improved the treatment response rate by 70% (1.7 times as high as that with TAU), increasing QALYs by 0.316 years. With these health benefits, CPGx is expected to save $3711 in direct medical costs per patient and $2553 in work productivity costs per patient over the lifetime. The cost-effectiveness of CPGx testing was robust over a wide range of variation in the input parameters, including the scenario when testing efficacy was set to its lower limit. CONCLUSIONS: CPGx testing has been shown by prospective studies to modify treatment decisions for patients nonresponsive to previous treatment(s), with increased rates of treatment response. These effects are projected to increase quality-adjusted survival, and to save both direct and indirect costs to individual patients and society generally. PMID- 26247577 TI - The role of nurse practitioners in primary healthcare. AB - OBJECTIVES: The employment of more nurse practitioners (NPs) is one of the most promising ways to expand the capacity of medical group practices. The objective of this study was to determine the association of NPs with patient-level cost and quality of care. STUDY DESIGN: Eighty-five primary care medical group practices were matched with 315,000 Medicare patients. Per beneficiary per year total costs and quality of care were calculated from Medicare claims data. Data were analyzed using multivariate regression analysis. METHODS: A national sample of primary care medical group practices based on responses to the 2009 Medical Group Management Association Performance Survey. The cost variable was annual risk adjusted Medicare expenditures per capita for patients attributed to a practice. There were 5 quality of care measures. RESULTS: Employing NPs in primary care practices is associated with increased risk-adjusted patient cost for up to 1 NP for every 2 physicians, but cost decreases as the number of NPs per physician increases. There was little evidence of systematic association of NPs with quality of care or the practice's net revenue. CONCLUSIONS: Primary care medical group practices need to evaluate the alternate clinical roles of their NPs and develop models that optimize cost and quality of care. Practices that have employed more than 1 NP for every 2 physicians appear to have lower per capita Medicare spending with no adverse effects on quality. Research now needs to explore these causalities. PMID- 26247575 TI - Target gene mutational pattern in Lynch syndrome colorectal carcinomas according to tumour location and germline mutation. AB - BACKGROUND: We previously reported that the target genes in sporadic mismatch repair (MMR)-deficient colorectal carcinomas (CRCs) in the distal colon differ from those occurring elsewhere in the colon. This study aimed to compare the target gene mutational pattern in microsatellite instability (MSI) CRC from Lynch syndrome patients stratified by tumour location and germline mutation, as well as with that of sporadic disease. METHODS: A series of CRC from Lynch syndrome patients was analysed for MSI in genes predicted to be selective MSI targets and known to be involved in several pathways of colorectal carcinogenesis. RESULTS: The most frequently mutated genes belong to the TGF-beta superfamily pathway, namely ACVR2A and TGFBR2. A significantly higher frequency of target gene mutations was observed in CRC from patients with germline mutations in MLH1 or MSH2 when compared with MSH6. Mutations in microsatellite sequences (A)7 of BMPR2 and (A)8 of MSH3 were significantly more frequent in the distal CRC. Additionally, we observed differences in MSH3 and TGFBR2 mutational frequency between Lynch syndrome and sporadic MSI CRC regarding tumour location. CONCLUSIONS: Our results indicate that the pattern of genetic changes differs in CRC depending on tumour location and between Lynch syndrome and sporadic MSI CRC, suggesting that carcinogenesis can occur by different pathways even if driven by generalised MSI. PMID- 26247578 TI - Stimulating comprehensive medication reviews among Medicare Part D beneficiaries. AB - OBJECTIVES: To assess the impact of a patient engagement intervention utilizing the Medication User Self-Evaluation (MUSE) tool on the completion percentage of comprehensive medication reviews (CMRs) among Medicare Part D beneficiaries. STUDY DESIGN: A case-control study. METHODS: Beneficiaries from 2 Medicare Part D plans were randomly assigned to 3 study arms (1 control arm plus 2 intervention arms for 2011 and 2012, respectively). Each beneficiary who participated in the MUSE intervention met 3 inclusion criteria and was matched with a single control group beneficiary based on: gender; age (within 5-year interval); plan type (ie, Medicare Prescription Drug Plan, Medicare Advantage Prescription Drug Plan); number of unique prescriptions; pharmacy medication therapy management (MTM) training status; and time period (2011, 2012). The outcome of interest was whether or not the beneficiary received a CMR in the 6 months following the index date. Generalized estimating equation (GEE) models were used to compare CMR percentages over time and between MUSE intervention groups. This study used MTM service claims data. RESULTS: The final sample of 1015 beneficiaries received MUSE intervention, of which 1007 were successfully matched to a control beneficiary. The estimated odds of having a CMR among those who received the MUSE intervention were 2 times that of their counterparts (P = .0048) across both study years. CONCLUSIONS: Given the strong evidence found for a positive association between participation in a CMR and the MUSE intervention, Part D plans could use the MUSE to engage targeted beneficiaries in using pharmacist provided MTM services. PMID- 26247579 TI - Medication adherence and measures of health plan quality. AB - OBJECTIVES: Medication adherence is increasingly being considered as a measure for performance-based reimbursement contracts in healthcare systems. However, the association between health outcomes and adherence at the plan level is unknown. STUDY DESIGN: Retrospective analysis of medical and pharmacy claims from a large private sector claims database from 2000 to 2009. METHODS: We compared plan-level measures of medication adherence and health outcomes for patients with diabetes and congestive heart failure (CHF). Plan performance was based on average rates of disease complications. Medication adherence was calculated as the percent of patients having 80% of days covered for medications treating diabetes or CHF. Both adherence and outcomes were adjusted for patient differences using multivariate regression. Plans were stratified into low, moderate, and high adherence, based on adherence in the bottom quartile, middle 2 quartiles, and top quartile, respectively. RESULTS: Average adherence varied significantly across plans. Plans with low adherence to diabetes medications had adjusted rates of uncontrolled diabetes admissions of 13.2 per 1000 patients, compared with 11.2 in moderate adherence plans and 8.3 in high adherence plans (P < .001). The adjusted rate of CHF-related hospitalization was 15.3% in low adherence plans, compared with 12.4% in moderate adherence plans and 12.2% in high adherence plans (P < .001). These patterns were consistent across different types of complications for both diabetes and CHF. CONCLUSIONS: Private health plans vary considerably in average adherence to medications treating chronic diseases. Plans with higher average adherence had lower rates of disease complications, suggesting that medication adherence measures are potentially useful tools for improving the performance of health plans. PMID- 26247580 TI - How will provider-focused payment reform impact geographic variation in Medicare spending? AB - OBJECTIVES: The Institute of Medicine has recently argued against a value index as a mechanism to address geographic variation in spending and instead promoted payment reform targeted at individual providers. It is unknown whether such provider-focused payment reform reduces geographic variation in spending. STUDY DESIGN: We estimated the potential impact of 3 Medicare provider-focused payment policies-pay-for-performance, bundled payment, and accountable care organizations on geographic variation in Medicare spending across Hospital Referral Regions (HRRs). We compared geographic variation in spending, measured using the coefficient of variation (CV) across HRRs, between the baseline case and a simulation of each of the 3 policies. METHODS: Policy simulation based on 2008 national Medicare data combined with other publicly available data. RESULTS: Compared with the baseline (CV, 0.171), neither pay-for-performance nor accountable care organizations would change geographic variation in spending (CV, 0.171), while bundled payment would modestly reduce geographic variation (CV, 0.165). CONCLUSIONS: In our models, the bundled payment for inpatient and post acute care services in Medicare would modestly reduce geographic variation in spending, but neither accountable care organizations nor pay-for-performance appear to have an impact. PMID- 26247581 TI - Provider behavior and treatment intensification in diabetes care. AB - OBJECTIVES: To review the literature relating to treatment intensification in diabetes care and provider traits. STUDY DESIGN: Literature review and synthesis. METHODS: A literature search was conducted using PubMed and Google Scholar for papers published in or after 2000 that examined treatment intensification in diabetes care. Results from the searches were combined with a conventional Google search and a supplemental review of papers that were identified from reference lists of identified studies. RESULTS: The majority of papers that were identified used administrative data to assess treatment intensification, and these showed that individuals with diabetes and elevated glucose frequently do not receive timely changes in therapy in response to hyperglycemia. Relatively few reports address provider and practice characteristics associated with these treatment decisions. Many of the studies focusing on the relationship between provider traits and treatment intensification are based on small studies in a limited number of practices. Factors such as practice size, location, or experience in treating patients with diabetes were often not addressed in the literature despite their potentially far-reaching impact on treatment. CONCLUSIONS: Our literature search on treatment intensification in diabetes care shows that the majority of papers using administrative data to assess treatment intensification suggest that care is often discordant with recommended guidelines. However, there is a dearth of literature based on large databases examining physician and practice traits related to this discordance. Better understanding physician behavior and practice traits associated with treatment intensification may permit greater targeting of interventions aimed at improving care. PMID- 26247582 TI - A proposed approach for analyzing post-study therapy effect in survival analysis. AB - Clinical trials that explore long-term endpoints may confound the analysis when post-study therapy effects are considered. This article introduces a procedure to mediate the effects of confounding and allow inferences of first-line experimental treatments in the presence of post-study therapy. The procedure is evaluated by intensive simulation analyses and applied to an analysis of a clinical cancer trial. PMID- 26247584 TI - Evidence of dynamic postural control performance in parkour landing. PMID- 26247583 TI - Dietary Docosahexaenoic Acid Improves Cognitive Function, Tissue Sparing, and Magnetic Resonance Imaging Indices of Edema and White Matter Injury in the Immature Rat after Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is the leading cause of acquired neurologic disability in children. Specific therapies to treat acute TBI are lacking. Cognitive impairment from TBI may be blunted by decreasing inflammation and oxidative damage after injury. Docosahexaenoic acid (DHA) decreases cognitive impairment, oxidative stress, and white matter injury in adult rats after TBI. Effects of DHA on cognitive outcome, oxidative stress, and white matter injury in the developing rat after experimental TBI are unknown. We hypothesized that DHA would decrease early inflammatory markers and oxidative stress, and improve cognitive, imaging and histologic outcomes in rat pups after controlled cortical impact (CCI). CCI or sham surgery was delivered to 17 d old male rat pups exposed to DHA or standard diet for the duration of the experiments. DHA was introduced into the dam diet the day before CCI to allow timely DHA delivery to the pre weanling pups. Inflammatory cytokines and nitrates/nitrites were measured in the injured brains at post-injury Day (PID) 1 and PID2. Morris water maze (MWM) testing was performed at PID41-PID47. T2-weighted and diffusion tensor imaging studies were obtained at PID12 and PID28. Tissue sparing was calculated histologically at PID3 and PID50. DHA did not adversely affect rat survival or weight gain. DHA acutely decreased oxidative stress and increased anti inflammatory interleukin 10 in CCI brains. DHA improved MWM performance and lesion volume late after injury. At PID12, DHA decreased T2-imaging measures of cerebral edema and decreased radial diffusivity, an index of white matter injury. DHA improved short- and long-term neurologic outcomes after CCI in the rat pup. Given its favorable safety profile, DHA is a promising candidate therapy for pediatric TBI. Further studies are needed to explore neuroprotective mechanisms of DHA after developmental TBI. PMID- 26247585 TI - Medicare Part D coverage gap: race, gender, and cost-related medication nonadherence. AB - This study examined whether the Medicare Part D coverage gap directly and indirectly affects the relationship between race, gender, and cost-related nonadherence (CRN). Using a nationally representative sample (N = 1,157), this study found that racial disparities in CRN existed under Medicare Part D. However, reaching the coverage gap mediated differences in CRN between older Blacks and Whites. The coverage gap was associated with CRN and poorer health and lower income were associated with CRN after accounting for coverage gap status. Findings highlight the need to help vulnerable populations avoid CRN and for greater consideration of racial inequities in future policy decisions. PMID- 26247586 TI - Opportunities for biomarkers with potential clinical use in oral cancer. PMID- 26247587 TI - Is Increased Echogenicity Related to a Decrease in Glomerular Filtration Rate? Objective Measurements in Pediatric Solitary Kidney Patients--A Retrospective Analysis. AB - Quantitative measurements of renal echogenicity using a graphic program show close correlation with renal histology in adult patients, but this has neither been applied in pediatric patients nor correlated with glomerular filtration rate (GFR). To determine the direct relationship between echogenicity and GFR, we retrospectively analyzed 91 patients with a solitary functioning kidney under the age of 10, who underwent ultrasonography and serum cystatin C evaluation on a single day between January 2013 and December 2014. Echogenicity was quantified as previously reported. Echogenicity and kidney length were correlated with age matched values of serum cystatin C-based GFR. Evaluation was performed at a median age of 17.1 months. GFR was low for age in eight of 54 right solitary kidney patients and four of 37 left solitary kidney patients. The right kidney liver ratio was significantly elevated in the right decreased GFR group, while the left kidney-spleen ratio was not different in the left decreased GFR group. Age-matched longitudinal kidney length ratios were similar between the decreased and normal GFR groups for both sides. This is the first report to objectively prove the relationship between echogenicity and renal function in patients with a right solitary kidney. The right kidney-liver echogenicity ratio, measured objectively, showed feasibility in clinical practice as it showed a close relationship with decreased renal function when increased. However, absolute kidney echogenicity values, or the left kidney-spleen echogenicity ratio, were not independent markers for decreased renal function. PMID- 26247588 TI - Mechanism of Cisplatin-Induced Cytotoxicity Is Correlated to Impaired Metabolism Due to Mitochondrial ROS Generation. AB - The chemotherapeutic use of cisplatin is limited by its severe side effects. In this study, by conducting different omics data analyses, we demonstrated that cisplatin induces cell death in a proximal tubular cell line by suppressing glycolysis- and tricarboxylic acid (TCA)/mitochondria-related genes. Furthermore, analysis of the urine from cisplatin-treated rats revealed the lower expression levels of enzymes involved in glycolysis, TCA cycle, and genes related to mitochondrial stability and confirmed the cisplatin-related metabolic abnormalities. Additionally, an increase in the level of p53, which directly inhibits glycolysis, has been observed. Inhibition of p53 restored glycolysis and significantly reduced the rate of cell death at 24 h and 48 h due to p53 inhibition. The foremost reason of cisplatin-related cytotoxicity has been correlated to the generation of mitochondrial reactive oxygen species (ROS) that influence multiple pathways. Abnormalities in these pathways resulted in the collapse of mitochondrial energy production, which in turn sensitized the cells to death. The quenching of ROS led to the amelioration of the affected pathways. Considering these observations, it can be concluded that there is a significant correlation between cisplatin and metabolic dysfunctions involving mROS as the major player. PMID- 26247589 TI - Transgenic Mouse Bioassay: Evidence That Rabbits Are Susceptible to a Variety of Prion Isolates. AB - Interspecies transmission of prions is a well-established phenomenon, both experimentally and under field conditions. Upon passage through new hosts, prion strains have proven their capacity to change their properties and this is a source of strain diversity which needs to be considered when assessing the potential risks associated with consumption of prion contaminated protein sources. Rabbits were considered for decades to be a prion resistant species until proven otherwise recently. To determine the extent of rabbit susceptibility to prions and to assess the effects of passage of different prion strains through this species a transgenic mouse model overexpressing rabbit PrPC was developed (TgRab). Intracerebral challenges with prion strains originating from a variety of species including field isolates (ovine SSBP/1 scrapie, Nor98- scrapie; cattle BSE, BSE-L and cervid CWD), experimental murine strains (ME7 and RML) and experimentally obtained ruminant (sheepBSE) and rabbit (de novo NZW) strains were performed. On first passage TgRab were susceptible to the majority of prions (Cattle BSE, SheepBSE, BSE-L, de novo NZW, ME7 and RML) tested with the exception of SSBP/1 scrapie, CWD and Nor98 scrapie. Furthermore, TgRab were capable of propagating strain-specific features such as differences in incubation periods, histological brain lesions, abnormal prion (PrPd) deposition profiles and proteinase-K (PK) resistant western blotting band patterns. Our results confirm previous studies proving that rabbits are not resistant to prion infection and show for the first time that rabbits are susceptible to PrPd originating in a number of other species. This should be taken into account when choosing protein sources to feed rabbits. PMID- 26247591 TI - Multifaceted Modelling of Complex Business Enterprises. AB - We formalise and present a new generic multifaceted complex system approach for modelling complex business enterprises. Our method has a strong focus on integrating the various data types available in an enterprise which represent the diverse perspectives of various stakeholders. We explain the challenges faced and define a novel approach to converting diverse data types into usable Bayesian probability forms. The data types that can be integrated include historic data, survey data, and management planning data, expert knowledge and incomplete data. The structural complexities of the complex system modelling process, based on various decision contexts, are also explained along with a solution. This new application of complex system models as a management tool for decision making is demonstrated using a railway transport case study. The case study demonstrates how the new approach can be utilised to develop a customised decision support model for a specific enterprise. Various decision scenarios are also provided to illustrate the versatility of the decision model at different phases of enterprise operations such as planning and control. PMID- 26247590 TI - Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis and Low Cardiovascular Risk: The Role of von Willebrand Factor Activity. AB - BACKGROUND: To evaluate association between von Willebrand factor (vWF) activity, inflammation markers, disease activity, and subclinical atherosclerosis in patients with rheumatoid arthritis (RA) and low cardiovascular risk. METHODS: Above mentioned parameters were determined in blood samples of 74 non-diabetic, normotensive, female subjects, with no dyslipidemia(42 patients, 32 matched healthy controls, age 45.3+/-10.0 vs. 45.2+/-9.8 years). Intima-media thickness (IMT) was measured bilaterally, at common carotid, bifurcation, and internal carotid arteries. Subclinical atherosclerosis was defined as IMT>IMTmean+2SD in controlsat each carotid level and atherosclerotic plaque as IMT>1.5 mm. Majority of RA patients were on methotrexate (83.3%), none on steroids >10 mg/day or biologic drugs. All findings were analysed in the entire study population and in RA group separately. RESULTS: RA patients with subclinical atherosclerosis had higher vWF activity than those without (133.5+/-69.3% vs. 95.3+/-36.8%, p<0.05). Predictive value of vWF activity for subclinical atherosclerosis was confirmed by logistic regression. vWF activity correlated significantly with erythrocyte sedimentation rate, fibrinogen, modified disease activity scores (mDAS28-ESR, mDAS28-CRP), modified Health Assessment Questionnaire (p<0.01 for all), duration of smoking, number of cigarettes/day, rheumatoid factor concentration (p<0.05 for all), and anti-CCP antibodies (p<0.01). In the entire study population, vWF activity was higher in participants with subclinical atherosclerosis (130+/-68% vs. 97+/-38%, p<0.05) or atherosclerotic plaques (123+/-57% vs. 99+/-45%, p<0.05) than in those without. Duration of smoking was significantly associated with vWF activity (beta 0.026, p = 0.039). CONCLUSIONS: We demonstrated association of vWF activity and subclinical atherosclerosis in low-risk RA patients as well as its correlation with inflammation markers, all parameters of disease activity, and seropositivity. Therefore, vWF might be a valuable marker of early atherosclerosis in RA patients. PMID- 26247594 TI - Primary Aldosteronism: Seismic Shifts. PMID- 26247592 TI - Salecan Enhances the Activities of beta-1,3-Glucanase and Decreases the Biomass of Soil-Borne Fungi. AB - Salecan, a linear extracellular polysaccharide consisting of beta-1,3-D-glucan, has potential applications in the food, pharmaceutical and cosmetic industries. The objective of this study was to evaluate the effects of salecan on soil microbial communities in a vegetable patch. Compositional shifts in the genetic structure of indigenous soil bacterial and fungal communities were monitored using culture-dependent dilution plating, culture-independent PCR-denaturing gradient gel electrophoresis (DGGE) and quantitative PCR. After 60 days, soil microorganism counts showed no significant variation in bacterial density and a marked decrease in the numbers of fungi. The DGGE profiles revealed that salecan changed the composition of the microbial community in soil by increasing the amount of Bacillus strains and decreasing the amount of Fusarium strains. Quantitative PCR confirmed that the populations of the soil-borne fungi Fusarium oxysporum and Trichoderma spp. were decreased approximately 6- and 2-fold, respectively, in soil containing salecan. This decrease in the amount of fungi can be explained by salecan inducing an increase in the activities of beta-1,3 glucanase in the soil. These results suggest the promising application of salecan for biological control of pathogens of soil-borne fungi. PMID- 26247597 TI - Letter to the Editor: Mortality Predictors and Prevention of Cardiovascular Events in High-Risk Patients With Diabetes. PMID- 26247598 TI - Response to the Letter by Eyuboglu M., et al. PMID- 26247599 TI - Letter to the Editor: Adrenocortical Insufficiency Following Glucocorticosteroid Treatment. PMID- 26247600 TI - Response to the Letter by Lindholm, et al. PMID- 26247601 TI - Interview Investigation of Insecure Attachment Styles as Mediators between Poor Childhood Care and Schizophrenia-Spectrum Phenomenology. AB - BACKGROUND: Insecure attachment styles have received theoretical attention and some initial empirical support as mediators between childhood adverse experiences and psychotic phenomena; however, further specificity needs investigating. The present interview study aimed to examine (i) whether two forms of poor childhood care, namely parental antipathy and role reversal, were associated with subclinical positive and negative symptoms and schizophrenia-spectrum personality disorder (PD) traits, and (ii) whether such associations were mediated by specific insecure attachment styles. METHOD: A total of 214 nonclinical young adults were interviewed for subclinical symptoms (Comprehensive Assessment of At Risk Mental States), schizophrenia-spectrum PDs (Structured Clinical Interview for DSM-IV Axis II Disorders), poor childhood care (Childhood Experience of Care and Abuse Interview), and attachment style (Attachment Style Interview). Participants also completed the Beck Depression Inventory-II and all the analyses were conducted partialling out the effects of depressive symptoms. RESULTS: Both parental antipathy and role reversal were associated with subclinical positive symptoms and with paranoid and schizotypal PD traits. Role reversal was also associated with subclinical negative symptoms. Angry-dismissive attachment mediated associations between antipathy and subclinical positive symptoms and both angry-dismissive and enmeshed attachment mediated associations of antipathy with paranoid and schizotypal PD traits. Enmeshed attachment mediated associations of role reversal with paranoid and schizotypal PD traits. CONCLUSIONS: Attachment theory can inform lifespan models of how adverse developmental environments may increase the risk for psychosis. Insecure attachment provides a promising mechanism for understanding the development of schizophrenia-spectrum phenomenology and may offer a useful target for prophylactic intervention. PMID- 26247604 TI - Phytoremediation of soils contaminated with phenanthrene and cadmium by growing willow (Salix * aureo-pendula CL 'j1011'). AB - To assess the phytoremediation potential of an autochthonous willow (Salix * aureo-pendula CL 'J1011') for phenanthrene (PHE)-contaminated soils and PHE cadmium (PHE-Cd) co-contaminated soils, we conducted field experiments in the lower reaches of the Yangtze River, China. Ethylenediaminetetraacetic acid (EDTA) and ethyl lactate were tested for individual and combined effects on the phytoremediation efficiency. For PHE-contaminated soils, willow plus ethyl lactate resulted in significant removal of PHE from soils after 45 days, and the PHE concentration in the shoots was significantly higher with than without ethyl lactate. For PHE-Cd co-contaminated soils, both willow plus EDTA and willow plus EDTA and ethyl lactate led to a significant decrease in the concentrations of PHE and Cd in the soils after 45 days, whereas willow alone did not. The PHE and Cd concentrations in the willow shoots were significantly enhanced in the presence of EDTA alone and with ethyl lactate, except for the PHE concentration in stems with EDTA alone. Under the same treatment, the presence of Cd had no significant influence on the PHE removal from soils. The results indicate the feasibility of using this willow together with both EDTA and ethyl lactate for the simultaneous removal of PHE and Cd from soils. PMID- 26247602 TI - Extremophilic 50S Ribosomal RNA-Binding Protein L35Ae as a Basis for Engineering of an Alternative Protein Scaffold. AB - Due to their remarkably high structural stability, proteins from extremophiles are particularly useful in numerous biological applications. Their utility as alternative protein scaffolds could be especially valuable in small antibody mimetic engineering. These artificial binding proteins occupy a specific niche between antibodies and low molecular weight substances, paving the way for development of innovative approaches in therapeutics, diagnostics, and reagent use. Here, the 50S ribosomal RNA-binding protein L35Ae from the extremophilic archaea Pyrococcus horikoshii has been probed for its potential to serve as a backbone in alternative scaffold engineering. The recombinant wild type L35Ae has a native-like secondary structure, extreme thermal stability (mid-transition temperature of 90 degrees C) and a moderate resistance to the denaturation by guanidine hydrochloride (half-transition at 2.6 M). Chemical crosslinking and dynamic light scattering data revealed that the wild type L35Ae protein has a propensity for multimerization and aggregation correlating with its non-specific binding to a model cell surface of HEK293 cells, as evidenced by flow cytometry. To suppress these negative features, a 10-amino acid mutant (called L35Ae 10X) was designed, which lacks the interaction with HEK293 cells, is less susceptible to aggregation, and maintains native-like secondary structure and thermal stability. However, L35Ae 10X also shows lowered resistance to guanidine hydrochloride (half-transition at 2.0M) and is more prone to oligomerization. This investigation of an extremophile protein's scaffolding potential demonstrates that lowered resistance to charged chemical denaturants and increased propensity to multimerization may limit the utility of extremophile proteins as alternative scaffolds. PMID- 26247605 TI - Biocidal Properties of a Glycosylated Surface: Sophorolipids on Au(111). AB - Classical antibacterial surfaces usually involve antiadhesive and/or biocidal strategies. Glycosylated surfaces are usually used to prevent biofilm formation via antiadhesive mechanisms. We report here the first example of a glycosylated surface with biocidal properties created by the covalent grafting of sophorolipids (a sophorose unit linked by a glycosidic bond to an oleic acid) through a self-assembled monolayer (SAM) of short aminothiols on gold (111) surfaces. The biocidal effect of such surfaces on Gram+ bacteria was assessed by a wide combination of techniques including microscopy observations, fluorescent staining, and bacterial growth tests. About 50% of the bacteria are killed via alteration of the cell envelope. In addition, the roles of the sophorose unit and aliphatic chain configuration are highlighted by the lack of activity of substrates modified, respectively, with sophorose-free oleic acid and sophorolipid-derivative having a saturated aliphatic chain. This system demonstrates thus the direct implication of a carbohydrate in the destabilization and disruption of the bacterial cell envelope. PMID- 26247603 TI - Lineage-Specific Changes in Biomarkers in Great Apes and Humans. AB - Although human biomedical and physiological information is readily available, such information for great apes is limited. We analyzed clinical chemical biomarkers in serum samples from 277 wild- and captive-born great apes and from 312 healthy human volunteers as well as from 20 rhesus macaques. For each individual, we determined a maximum of 33 markers of heart, liver, kidney, thyroid and pancreas function, hemoglobin and lipid metabolism and one marker of inflammation. We identified biomarkers that show differences between humans and the great apes in their average level or activity. Using the rhesus macaques as an outgroup, we identified human-specific differences in the levels of bilirubin, cholinesterase and lactate dehydrogenase, and bonobo-specific differences in the level of apolipoprotein A-I. For the remaining twenty-nine biomarkers there was no evidence for lineage-specific differences. In fact, we find that many biomarkers show differences between individuals of the same species in different environments. Of the four lineage-specific biomarkers, only bilirubin showed no differences between wild- and captive-born great apes. We show that the major factor explaining the human-specific difference in bilirubin levels may be genetic. There are human-specific changes in the sequence of the promoter and the protein-coding sequence of uridine diphosphoglucuronosyltransferase 1 (UGT1A1), the enzyme that transforms bilirubin and toxic plant compounds into water soluble, excretable metabolites. Experimental evidence that UGT1A1 is down regulated in the human liver suggests that changes in the promoter may be responsible for the human-specific increase in bilirubin. We speculate that since cooking reduces toxic plant compounds, consumption of cooked foods, which is specific to humans, may have resulted in relaxed constraint on UGT1A1 which has in turn led to higher serum levels of bilirubin in humans. PMID- 26247606 TI - The crutch of context-dependency: Effects of contextual support and constancy on acquisition and retention. AB - Paired associates (Tagalog-English word pairs) were studied and practiced with pairs superimposed over pictorial contexts, and tested with no context cues. On every retrieval practice (RP) incidental or conceptually supportive contexts were repeatedly shown with the same pair (constant context condition), or else new contexts were shown on every RP trial (varied context condition). Incidental contexts in the constant condition and supportive contexts in both constant and varied context conditions facilitated practice scores, but left learning susceptible to forgetting when context cues were not provided. In contrast, varying incidental contexts during practice resulted in slower acquisition, but greater retention in the absence of context cues. The results show that varying incidental contexts during practice can be a desirable difficulty. PMID- 26247607 TI - Putting the Brakes on Huntington Disease in a Mouse Experimental Model. PMID- 26247608 TI - Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease. AB - Amyloidogenesis has been implicated in a broad spectrum of diseases in which amyloid protein is invariably misfolded and deposited in cells and organs. Alzheimer's disease is one of the most devastating ailments among amyloidogenesis induced dementia. The amyloid beta (Abeta) peptide derived from amyloid precursor protein (APP) is misfolded and deposited as plaques in the brain, which are said to be the hallmark of Alzheimer's disease. In normal brains physiological concentration of the Abeta peptide has been indicated to be involved in modulating neurogenesis and synaptic plasticity. However, excess Abeta production, its aggregation and deposition deleteriously affect a large number of biologically important pathways leading to neuronal cell death. Targeting Abeta production, Abeta aggregation or its clearance from the brain has been an active area of research for preventing or curing AD. Our Feature Article intends to detail the aggregation mechanism, the physiological role of the Abeta peptide, elaborate its toxic effects, and outline the different classes of molecules designed in the last two years to inhibit amyloidogenic APP processing, Abeta oligomerization or fibrillogenesis and to modulate different pathways for active clearance of Abeta from the brain. PMID- 26247609 TI - Relative Mechanical Strengths of Weak Bonds in Sonochemical Polymer Mechanochemistry. AB - The mechanical strength of scissile chemical bonds plays a role in material failure and in the mechanical activation of latent reactivity, but quantitative measures of mechanical strength are rare. Here, we report the relative mechanical strength of polymers bearing three putatively "weak" scissile bonds: the carbon nitrogen bond of an azobisdialkylnitrile (<30 kcal mol(-1)), the carbon-sulfur bond of a thioether (71-74 kcal mol(-1)), and the carbon-oxygen bond of a benzylphenyl ether (52-54 kcal mol(-1)). The mechanical strengths are assessed in the context of chain scission triggered by pulsed sonication of polymer solutions, by using two complementary techniques: (i) the competition within a single polymer chain between the bond scission of interest and the nonscissile mechanochemical ring opening of gem-dichlorocyclopropane mechanophores and (ii) the molecular weights at long (4 h) sonication times of multimechanophore polymers. The two methods produce a consistent story: in contrast to their thermodynamic strengths, the relative mechanical strengths of the three weak bonds are azobisdialkylnitrile (weakest) < thioether < benzylphenyl ether. The greater mechanical strength of the benzylphenyl ether relative to the thermodynamically stronger carbon-sulfur bond is ascribed to poor mechanochemical coupling, at least in part as a result of the rehybridization that accompanies carbon-oxygen bond scission. PMID- 26247610 TI - RECK-Mediated beta1-Integrin Regulation by TGF-beta1 Is Critical for Wound Contraction in Mice. AB - Fibroblasts are critical for wound contraction; a pivotal step in wound healing. They produce and modify the extracellular matrix (ECM) required for the proper tissue remodeling. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a key regulator of ECM homeostasis and turnover. However, its role in wound contraction is presently unknown. Here we describe that Transforming growth factor type beta1 (TGF-beta1), one of the main pro-fibrotic wound-healing promoting factors, decreases RECK expression in fibroblasts through the Smad and JNK dependent pathways. This TGF-beta1 dependent downregulation of RECK occurs with the concomitant increase of beta1-integrin, which is required for fibroblasts adhesion and wound contraction through the activation of focal adhesion kinase (FAK). Loss and gain RECK expression experiments performed in different types of fibroblasts indicate that RECK downregulation mediates TGF beta1 dependent beta1-integrin expression. Also, reduced levels of RECK potentiate TGF-beta1 effects over fibroblasts FAK-dependent contraction, without affecting its cognate signaling. The above results were confirmed on fibroblasts derived from the Reck+/- mice compared to wild type-derived fibroblasts. We observed that Reck+/- mice heal dermal wounds more efficiently than wild type mice. Our results reveal a critical role for RECK in skin wound contraction as a key mediator in the axis: TGF-beta1-RECK-beta1-integrin. PMID- 26247611 TI - Ageing is associated with reduction of mechanically-induced activation of Smad2/3P signaling in articular cartilage. AB - OBJECTIVE: Mechanical signals control key cellular processes in articular cartilage. Previously we have shown that mechanical compression is an important ALK5/Smad2/3P activator in cartilage explants. However, age-related changes in the cartilage are known to affect tissue mechanosensitivity and also ALK5/Smad2/3P signaling. We have investigated whether ageing of cartilage is associated with an altered response to mechanical compression. DESIGN: Articular cartilage explants of two different age groups (young-6-36 months old, aged-6 - 13 years old) were subjected to dynamic mechanical compression with 3 MPa (physiological) or 12 MPa (excessive) load. Subsequently, essential cartilage extracellular matrix (ECM) components and tissue growth factors gene expression was measured in young and aged cartilage by QPCR. Furthermore, the ability of young and aged cartilage, to activate the Smad2/3P signaling in response to compression was analyzed and compared. This was done by immunohistochemical (IH) Smad2P detection and Smad3-responsive gene expression analysis. RESULTS: Aged cartilage showed a highly reduced capacity for mechanically-mediated activation of Smad2/3P signaling when compared to young cartilage. Compression of aged cartilage, induced collagen type II (Col2a1) and fibronectin (Fn1) expression to a far lesser extent than in young cartilage. Additionally, in aged cartilage no mechanically mediated up-regulation of bone morphogenetic protein 2 (Bmp2) and connective tissue growth factor (Ctgf) was observed. CONCLUSIONS: We identified age-related changes in cellular responses to mechanical stimulation of articular cartilage. We propose that these changes might be associated with age-related alterations in cartilage functioning and can underlie mechanisms for development of age-related cartilage diseases like osteoarthritis (OA). PMID- 26247612 TI - Intermittent cyclic mechanical tension promotes endplate cartilage degeneration via canonical Wnt signaling pathway and E-cadherin/beta-catenin complex cross talk. AB - OBJECTIVE: This study aimed to investigate the role of the Wnt/beta-catenin signaling pathway and E-cadherin/beta-catenin complex in intermittent cyclic mechanical tension (ICMT)-induced endplate cartilage degeneration. DESIGN: beta Catenin expression was measured in disc samples obtained from patients with disc degeneration and those with cervical vertebrae fracture or dislocation. Histological staining was performed to examine the disc tissue morphology and extracellular matrix after application of ICMT in vitro and in vivo. Multiple strategies were employed to examine activation of Wnt/beta-catenin signaling after ICMT application in vivo and in vitro. Co-immunoprecipitation was performed to examine the interaction between E-cadherin and beta-catenin. Pathway-specific inhibitors and an E-cadherin expression plasmid were used to regulate Wnt/beta catenin signaling and E-cadherin expression. RESULTS: beta-Catenin protein expression was elevated significantly, whereas cartilaginous genes were down regulated in endplate cartilage samples obtained from patients with disc degeneration. ICMT loading led to Wnt/beta-catenin signaling activation and the loss of the chondrogenic phenotype of endplate chondrocytes in both an in vivo rabbit model and in vitro endplate chondrocyte culture system. Inhibition of Wnt/beta-catenin signaling suppressed the decrease in ICMT-induced cartilaginous gene expression. Furthermore, E-cadherin expression was inhibited by ICMT stimulation, resulting in a decrease in the interaction between E-cadherin and beta-catenin proteins. Over-expression of E-cadherin rescued the cartilaginous gene expression by enhancing the interaction between E-cadherin and beta-catenin proteins. CONCLUSIONS: ICMT promotes endplate cartilage degeneration via activation of Wnt/beta-catenin signaling and suppression of physical protein protein interactions between E-cadherin and beta-catenin. PMID- 26247613 TI - Evidence of improved fluid management in patients receiving haemodialysis following a self-affirmation theory-based intervention: A randomised controlled trial. AB - OBJECTIVE: Haemodialysis patients are at risk of serious health complications; yet, treatment non-adherence remains high. Warnings about health risks associated with non-adherence may trigger defensive reactions. We studied whether an intervention based on self-affirmation theory reduced resistance to health-risk information and improved fluid treatment adherence. DESIGN: In a cluster randomised controlled trial, 91 patients either self-affirmed or completed a matched control task before reading about the health-risks associated with inadequate fluid control. OUTCOME MEASURES: Patients' perceptions of the health risk information, intention and self-efficacy to control fluid were assessed immediately after presentation of health-risk information. Interdialytic weight gain (IDWG), excess fluid removed during haemodialysis, is a clinical measure of fluid treatment adherence. IDWG data were collected up to 12 months post intervention. RESULTS: Self-affirmed patients had significantly reduced IDWG levels over 12 months. However, contrary to predictions derived from self affirmation theory, self-affirmed participants and controls did not differ in their evaluation of the health-risk information, intention to control fluid or self-efficacy. CONCLUSION: A low-cost, high-reach health intervention based on self-affirmation theory was shown to reduce IDWG over a 12-month period, but the mechanism by which this apparent behaviour change occurred is uncertain. Further work is still required to identify mediators of the observed effects. PMID- 26247614 TI - Components of Metabolic Syndrome as Risk Factors for Hearing Threshold Shifts. AB - BACKGROUND: Hearing loss was a common, chronically disabling condition in the general population and had been associated with several inflammatory diseases. Metabolic syndrome, which was associated with insulin resistance and visceral obesity, was considered a chronic inflammatory disease. To date, few attempts had been made to establish a direct relationship between hearing loss and metabolic syndrome. The aim of the present study was to investigate the relationship between metabolic syndrome and hearing loss by analyzing the data in the reports of the National Health and Nutrition Examination Survey 1999-2004. METHODS: This study included 2100 participants aged <= 65 years who enrolled in the National Health and Nutrition Examination Survey (1999-2004). We examined the relationship between the presence of different features of metabolic syndrome in the participants and their pure-tone air-conduction hearing thresholds, including low frequency and high-frequency thresholds. RESULTS: After adjusting for potential confounders, such as age, medical conditions, and smoking status, the participants with more components of metabolic syndrome were found to have higher hearing thresholds than those with fewer components of metabolic syndrome (p < 0.05 for a trend). The low-frequency hearing threshold was associated with individual components of metabolic syndrome, such as abdominal obesity, high blood pressure, elevated triglycerides, and a low level of high-density lipoprotein cholesterol (HDL-C) (p < 0.05 for all parameters). CONCLUSIONS: The results indicated that the presence of a greater number of components of metabolic syndrome was significantly associated with the hearing threshold in the US adult population. Among the components of metabolic syndrome, the most apparent association was observed between low HDL and hearing loss. PMID- 26247615 TI - Prevalence of hepatic osteodystrophy and vitamin D deficiency in cirrhosis. AB - BACKGROUND: Hepatic osteodystrophy (HO) is a major complication of cirrhosis. However, the prevalence of HO in a general cirrhotic patient population is not well defined as previous studies were in single aetiology or pre-liver transplant patients. AIMS: The aims of this study were to investigate the prevalence of HO and vitamin D deficiency in patients with cirrhosis of mixed aetiology and disease severity and to determine the risk factors for HO. METHODS: This is a single-centre cross-sectional study of all patients newly diagnosed with cirrhosis between September 2009 and December 2012. All patients underwent bone mineral density assessment using dual energy X-ray absorptiometry within 3 months of diagnosis. Demographic and biochemical factors, severity of underlying liver disease, previous fragility fractures, smoking status and alcohol use were collected on diagnosis. Logistic regression analysis was used to assess risk factors for HO. RESULTS: Among the 406 patients (67% males), the median (range) age was 56 years (21-85) and most (84%) were Childs-Pugh A or B with a median (range) model for end-stage liver disease score of 11 (5-40). Alcohol (41%) was the most common underlying aetiology. The prevalence of HO and vitamin D deficiency (<=50 nmol/L) was 56% and 54%, respectively, and previous fragility fractures had occurred in 3%. Increasing age (odds ratio (95% confidence interval): 1.49 per 10 years (1.02-2.18), P = 0.04), excessive alcohol intake (2.34 (1.03-5.32), P = 0.04) and lower body mass index (0.92 per kg/m2 (0.87 0.98), P = 0.009) were independent risk factors for HO. CONCLUSION: There is a high prevalence of HO and vitamin D deficiency in patients with cirrhosis at presentation irrespective of disease severity or underlying aetiology. PMID- 26247616 TI - Tracking Seed Fates of Tropical Tree Species: Evidence for Seed Caching in a Tropical Forest in North-East India. AB - Rodents affect the post-dispersal fate of seeds by acting either as on-site seed predators or as secondary dispersers when they scatter-hoard seeds. The tropical forests of north-east India harbour a high diversity of little-studied terrestrial murid and hystricid rodents. We examined the role played by these rodents in determining the seed fates of tropical evergreen tree species in a forest site in north-east India. We selected ten tree species (3 mammal-dispersed and 7 bird-dispersed) that varied in seed size and followed the fates of 10,777 tagged seeds. We used camera traps to determine the identity of rodent visitors, visitation rates and their seed-handling behavior. Seeds of all tree species were handled by at least one rodent taxon. Overall rates of seed removal (44.5%) were much higher than direct on-site seed predation (9.9%), but seed-handling behavior differed between the terrestrial rodent groups: two species of murid rodents removed and cached seeds, and two species of porcupines were on-site seed predators. In addition, a true cricket, Brachytrupes sp., cached seeds of three species underground. We found 309 caches formed by the rodents and the cricket; most were single-seeded (79%) and seeds were moved up to 19 m. Over 40% of seeds were re-cached from primary cache locations, while about 12% germinated in the primary caches. Seed removal rates varied widely amongst tree species, from 3% in Beilschmiedia assamica to 97% in Actinodaphne obovata. Seed predation was observed in nine species. Chisocheton cumingianus (57%) and Prunus ceylanica (25%) had moderate levels of seed predation while the remaining species had less than 10% seed predation. We hypothesized that seed traits that provide information on resource quantity would influence rodent choice of a seed, while traits that determine resource accessibility would influence whether seeds are removed or eaten. Removal rates significantly decreased (p < 0.001) while predation rates increased (p = 0.06) with seed size. Removal rates were significantly lower for soft seeds (p = 0.002), whereas predation rates were significantly higher on soft seeds (p = 0.01). Our results show that murid rodents play a very important role in affecting the seed fates of tropical trees in the Eastern Himalayas. We also found that the different rodent groups differed in their seed handling behavior and responses to changes in seed characteristics. PMID- 26247617 TI - Human hair analysis in relation to similar environmental and occupational exposure. AB - The aim of this work was to assess the influence of various factors on the elemental composition of the investigated hair samples. The studied population consisted of students of Faculty of Chemistry at Lodz University of Technology and included 95 subjects. The following elements: Co, Cr, Cu, Li, Sr, Pb were determined by inductively coupled plasma time-of-flight mass spectrometry ICP-TOF MS. The obtained results were elaborated using Statistica ver. 10.0 software. Statistically significant differences were observed for the content of Cr, Li, Pb and Sr as the impact of sex, and Sr-as the effect of cosmetic treatment. Based on the calculated Spearman correlation coefficients, a statistically significant correlation between the concentration of pairs of metals were found for Pb=f(Co, Cr, Cu); Sr=f(Cu); Li=f(Cr), Cr=f(Li, Pb), Co=f(Pb) and Cu=f(Pb, Sr). A statistically negative correlation was obtained for Sr-Li. In the population two groups were distinguished: males and females; smokers and non-smokers. PMID- 26247618 TI - Resisted adduction in hip neutral is a superior provocation test to assess adductor longus pain: An experimental pain study. AB - The criterion of long-standing groin pain diagnoses in athletes usually relies on palpation and clinical tests. An experimental pain model was developed to examine the clinical tests under standardized conditions. Pain was induced by hypertonic saline injected into the proximal adductor longus (AL) tendon or rectus femoris (RF) tendon in 15 healthy male participants. Isotonic saline was injected contralaterally as a control. Pain intensity was assessed on a visual analog scale (VAS). Resisted hip adduction at three different angles and trunk flexion were completed before, during, and after injections. Pain provocation in the presence of experimental pain was recorded as a true positive compared with pain provocation in the non-pain conditions. Similar peak VAS scores were found after hypertonic saline injections into the AL and RF and both induced higher VAS scores than isotonic saline (P < 0.01). Adduction at 0 degrees had the greatest positive likelihood ratio (+LR = 2.8, 95%CI: 1.09-7.32) with 45 degrees (-LR = 0.0, 95%CI: 0.00-1.90) and 90 degrees (-LR = 0.0, 95%CI: 0.00-0.94) having the lowest negative LR. This study indicates that the 0 degrees hip adduction test resisted at the ankles optimizes the diagnostic procedure without compromising diagnostic capacity to identify experimental groin pain. Validation in clinical populations is warranted. PMID- 26247619 TI - Costal Cartilage Lateral Crural Strut Graft vs Cephalic Crural Turn-in for Correction of External Valve Dysfunction. AB - IMPORTANCE: External nasal valve dysfunction (EVD) is a common cause of nasal obstruction. OBJECTIVE: To evaluate costal cartilage lateral crural strut grafts vs cephalic crural turn-in to support the weak lateral crus in patients with EVD. DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study, patients with clinically diagnosed EVD were assessed at the Tertiary Rhinologic Center and underwent a costal cartilage underlay graft to the lateral crus or a cephalic turn-in cruralplasty. MAIN OUTCOMES AND MEASURES: Assessment of patient benefit was based on 22-Item Sinonasal Outcome Test (SNOT-22) and Nasal Obstruction Symptom Evaluation Scale (NOSE) scores. A Likert scale was also used to assess overall function and cosmesis. Objective assessment included postdecongestion nasal peak inspiratory flow, nasal airway resistance, and minimum cross-sectional area. RESULTS: Forty-one patients (mean [SD] 35.38 [12.73] years of age; 25 [61%] female) were assessed. Cephalic turn-in maneuver was used for 25 (61%) patients; costal cartilage lateral crural strut grafts, 16 (39%) patients. Costal cartilage grafts were used in patients undergoing revision but other baseline data were similar. Follow-up was mean 10.58 (7.52) months. All patients had significantly improved visual analog scale, SNOT-22, NOSE, patient-reported function, and cosmesis scores. The only objective test that improved was nasal peak inspiratory flow (114.76 [60.48] L/min vs 126.46 [61.17] L/min; P = .02). CONCLUSIONS AND RELEVANCE: Both techniques were effective in improving patient-reported outcomes and nasal peak inspiratory flow. Both are functionally and cosmetically viable options for correction of EVD. LEVEL OF EVIDENCE: 2. PMID- 26247620 TI - A novel GYPB-A-B hybrid gene responsible for Ss and MN typing discrepancies. AB - BACKGROUND: Transfusion support of S-s- patients is very challenging but can now be alleviated by genotyping mutations in the GYPB gene to predict their U- or U+(var) phenotype. However, the phenotype predicted by genotyping does not always correspond to the observed phenotype of red blood cells (RBCs), which requires further investigation to avoid such a typing discrepancy in the future. In this study, we elucidated the case of an S-s- female patient of African origin who was predicted to be S+s- by our genotyping platform. STUDY DESIGN AND METHODS: Long range polymerase chain reaction (PCR) amplification and extended Sanger sequencing were required. RESULTS: The Ss typing discrepancy in the proband resulted from a converted GYPB allele that encodes neither S nor s due to the replacement of Exon B4 of GYPB by the homologous Exon A4 of GYPA. In this novel GYPB-A-B hybrid gene, the GYPA segment actually starts just downstream of Exon B2, causing a MN typing discrepancy too. While the proband's RBCs were M+N-, the genotyping predicted the M+N+ phenotype. CONCLUSION: The reported GYPB-A-B hybrid gene constitutes a limitation for the accurate prediction of the MN and Ss phenotypes by current genotyping methods. A PCR assay was therefore developed to detect its presence. PMID- 26247622 TI - Cu-mediated direct regioselective C-2 chlorination of indoles. AB - Cu-mediated C-2 chlorination of indoles was accomplished with copper(ii) chloride through the use of a directing pyrimidyl protection group. A highly regioselective manner can be achieved on a range of indole substrates with excellent functional group tolerance. PMID- 26247621 TI - CaMKIIalpha-GluA1 Activity Underlies Vulnerability to Adolescent Binge Alcohol Drinking. AB - BACKGROUND: Binge drinking during adolescence is associated with increased risk for developing alcohol use disorders; however, the neural mechanisms underlying this liability are unclear. In this study, we sought to determine whether binge drinking alters expression or phosphorylation of 2 molecular mechanisms of neuroplasticity, calcium/calmodulin-dependent kinase II alpha (CaMKIIalpha) and the GluA1 subunit of AMPA receptors (AMPARs) in addiction-associated brain regions. We also asked whether activation of CaMKIIalpha-dependent AMPAR activity escalates binge-like drinking. METHODS: To address these questions, CaMKIIalphaT286 and GluA1S831 protein phosphorylation and expression were assessed in the amygdala and striatum of adolescent and adult male C57BL/6J mice immediately after voluntary binge-like alcohol drinking (blood alcohol >80 mg/dl). In separate mice, effects of the CaMKIIalpha-dependent GluA1S831 phosphorylation (pGluA1S831 )-enhancing drug tianeptine were tested on binge-like alcohol consumption in both age groups. RESULTS: Binge-like drinking decreased CaMKIIalphaT286 phosphorylation (pCaMKIIalphaT286 ) selectively in adolescent amygdala with no effect in adults. Alcohol also produced a trend for reduced pGluA1S831 expression in adolescent amygdala but differentially increased pGluA1S831 in adult amygdala. No effects were observed in the nucleus accumbens or dorsal striatum. Tianeptine increased binge-like alcohol consumption in adolescents but decreased alcohol consumption in adults. Sucrose consumption was similarly decreased by tianeptine pretreatment in both ages. CONCLUSIONS: These data show that the adolescent and adult amygdalae are differentially sensitive to effects of binge-like alcohol drinking on plasticity-linked glutamate signaling molecules. Tianeptine-induced increases in binge-like drinking only in adolescents suggest that differential CaMKIIalpha-dependent AMPAR activation may underlie age-related escalation of binge drinking. PMID- 26247623 TI - Efficient removal of free and nitrilotriacetic acid complexed Cd(II) from water by poly(1-vinylimidazole)-grafted Fe3O4@SiO2 magnetic nanoparticles. AB - Poly(1-vinylimidazole)-grafted Fe3O4@SiO2 magnetic nanoparticles (FSPV) were developed to remove both free Cd(II) and nitrilotriacetic acid (NTA) complexed Cd(II) from water. The adsorption capacity of NTA-complexed Cd(II) (42.1 mg/g) was larger than that of free Cd(II) (24.8 mg/g). Free Cd(II) and NTA-complexed Cd(II) could be reduced from 50 MUg/L to below 5 MUg/L within 10 and 20 min, respectively. FSPV could effectively remove trace free and NTA-complexed Cd(II) over broad pH ranges of 5-10 and 5-11, respectively. Moreover, the presence of seven coexisting ions (up to 100 mM) including four cations (Na(+), K(+), Ca(2+), and Mg(2+)) and three anions (Cl(-), NO3(-), and SO4(2-)) all slightly promoted the removal of both free and NTA-complexed Cd(II) onto FSPV. The removal of free Cd(II) or NTA-complexed Cd(II) was not obviously affected by the presence of Ni(II) and Co(II) (50 MUg/L), humic acid (up to 3 mg/L as TOC) or alginate (up to 8 mg/L as TOC). In addition, FSPV could be regenerated with 10 mM HCl in 10 min, and the removal of both types of Cd(II) maintained above 95% in five consecutive adsorption/regeneration cycles. Therefore, FSPV could be utilized as promising adsorbent for both free and NTA-complexed Cd(II). PMID- 26247624 TI - HP-PRRSV is attenuated by de-optimization of codon pair bias in its RNA-dependent RNA polymerase nsp9 gene. AB - There is an urgent need to develop new vaccines against highly pathogenic PRRS virus (HP-PRRSV) variant in China. The actual use of each codon pairs is more or less frequent than that of the statistical prediction and codon pair bias (CPB) usage affects gene translation. We "shuffled" the existing codons in HP-PRRSV genes GP5, M, nsp2 and nsp9, so that the CPB of these genes could be more negative. De-optimization of nsp9, the RNA-dependent RNA polymerase, significantly decreased PRRSV replication in porcine alveolar macrophages (PAMs). In vitro study showed that HV-nsp9(min) and HV-nsp29(min) were remarkably attenuated in PAMs, and inoculation of pigs with 2 ml*10(5.0) TCID50/ml of HV nsp9(min) or HV-nsp29(min) did not cause PRRS. Importantly, pigs immunized with HV-nsp29(min) were fully protected against different HP-PRRSV strains' lethal challenges. Our results imply that the CPB de-optimized HV-nsp29(min) has the potential to be used as a live vaccine candidate against HP-PRRSV. PMID- 26247625 TI - Bifunctional Perovskite Oxide Catalysts for Oxygen Reduction and Evolution in Alkaline Media. AB - Oxygen electrocatalysis, namely of the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER), governs the performance of numerous electrochemical energy systems such as reversible fuel cells, metal-air batteries, and water electrolyzers. However, the sluggish kinetics of these two reactions and their dependency on expensive noble metal catalysts (e.g, Pt or Ir) prohibit the sustainable commercialization of these highly innovative and in demand technologies. Bifunctional perovskite oxides have emerged as a new class of highly efficient non-precious metal catalysts (NPMC) for oxygen electrocatalysis in alkaline media. In this review, we discuss the state-of-the art understanding of bifunctional properties of perovskites with regards to their OER/ORR activity in alkaline media and review the associated reaction mechanisms on the oxides surface and the related activity descriptors developed in the recent literature. We also summarize the present strategies to modify their electronic structure and to further improve their performance for the ORR/OER through highlighting the new concepts relating to the role of surface redox chemistry and oxygen deficiency of perovskite oxides for the ORR/OER activity. In addition, we provide a brief account of recently developed advanced perovskite nanocarbon hybrid bifunctional catalysts with much improved performances. PMID- 26247626 TI - Does iodine excess lead to hypothyroidism? Evidence from a case-control study in India. AB - BACKGROUND: Iodine deficiency disorders have been known to mankind since antiquity and various researchers elucidated the role of iodine in its causation. However, recent evidence shows that the entire control program ignored multi causality and association of increased iodine intake with hypothyroidism. This study was conducted to assess differences of iodine intake as measured by urinary iodine excretion (UIE) between cases of hypothyroidism and healthy controls. METHODS: A case-control study was conducted with three groups (cases, hospital controls and community controls) in two cities of India. Patients with overt hypothyroidism were cases (n = 150) and were compared with age, sex and socioeconomic status-matched hospital (n = 154) and community (n = 488) controls. Thyroid function tests (T3, T4, TSH) were used as diagnostic and inclusion criteria. TPOAb and UIE estimation were carried out for all study participants. RESULTS: Mean values of TPOAb and UIE were higher in cases as compared to hospital controls as well as community controls (p <0.05). With a cut off of 34 IU/mL for TPOAb, more cases had an anti-TPO level >34 as compared to hospital controls (p <0.001) as well as community controls (p <0.001); OR, 0.06 (95% CI, 0.03, 0.12) and 0.08 (0.05, 0.12), respectively. For UIE cut-off of 300 MUg/L, more cases than hospital controls (p = 0.090) and community controls (p = 0.001) had higher levels; OR, 0.671, (0.422, 1.066) and 0.509, (0.348, 0.744), respectively. CONCLUSION: The study has clearly shown that cases of hypothyroidism are associated with excess iodine intake. Cohort studies to generate further evidence and an eco-social epidemiological approach have been suggested as the way forward. PMID- 26247627 TI - The Pain Experience of Patients Hospitalized With Inflammatory Bowel Disease: A Phenomenological Study. AB - Pain is personal, subjective, and best treated when the patient's experience is fully understood. Hospitalization contributes to the physical and psychological complications of acute and chronic pain experienced by patients with inflammatory bowel disease (IBD). The purpose of this qualitative phenomenological study was to develop an understanding of the unique experience of pain in hospitalized patients with an admitting diagnosis of IBD and related care or surgery. Following institutional review board approval, purposeful sampling was used to recruit 16 patients (11 female, 5 male, mean age 41.8 years) from two 36-bed colorectal units of a large academic medical center in the Midwest. Individual, audio-recorded interviews were conducted by a researcher at each participant's bedside. Recordings and transcripts were systematically reviewed by the research team using Van Manen's approach to qualitative analysis. Subsequently, 5 major themes were identified among the data: feeling discredited and misunderstood, desire to dispel the stigma, frustration with constant pain, need for caregiver knowledge and understanding, and nurse as connector between patient and physician. Hospitalized patients with IBD have common issues with pain care. Nurses caring for them can provide better pain management when they understand these issues/themes. Further research into the themes discovered here is recommended. PMID- 26247628 TI - Peirce's cenopythagorean categories, Merleau-Ponty's chiasmatic entrelacs and Grothendieck's Resume. AB - We present Peirce's cenopythagorean categories and Merleau-Ponty's entrelacs and chiasma, as universal phenomenological tools, particularly useful for a better understanding of dynamic, non-classical, non-separated contemporary mathematics. As a case study, we revisit Grothendieck's Resume, and we explore its extremely rich mathematical, semiotical and phenomenological entanglements. PMID- 26247629 TI - Evaluation of UV radiation-induced toxicity and biophysical changes in various skin cells with photo-shielding molecules. AB - Ultraviolet radiation (UVR) triggers many complex events in different types of skin cells, including benign, malignant and normal cells. Chromophores present in these cells play a crucial role in various cellular processes. Unprecedented methods are required for the real-time monitoring of changes in an in vitro model exposed to intermittent mild and intense UVR to determine the mechanisms underlying cell degeneration and the effects of unexpected toxic, agonist and antagonist agents. This study reports the analytical application of a whole cell based sensor platform for examining the biophysical effects of UVR. We used human keratinocyte, melanocyte and fibroblast cell lines to determine the normal, pathological and protective roles of UVR. In addition, we examined the real-time morphological, biophysical and biomechanical changes associated with cell degeneration induced by UVR at 254 and 365 nm. Information on UVR-induced changes in the cytoskeleton ultrastructure, cellular integrity, cell spreading area, actin microfilament distribution inflammation, microtubule damage, membrane damage, rupture and death was characterized by examining the loss or increase in biophysical and biomechanical properties of these cells. All cells exposed to UVR at 254 and 365 nm showed a significant increase in surface roughness and stiffness in a time-dependent manner. UVR-induced toxicity in differently pigmented skin cells was compared with that in cells pretreated with melanin, keratin and basic fibroblast growth factor to analyze the shielding efficiency of these agents. Melanin exerted a significant shielding effect compared to the other two agents. The biophysical and biomechanical information obtained in this study could advance our understanding of the UVR-induced degeneration process, and help in developing new interventions strategies. PMID- 26247630 TI - Discovery of benzo[e]pyridoindolones as kinase inhibitors that disrupt mitosis exit while erasing AMPK-Thr172 phosphorylation on the spindle. AB - Aurora kinases play an essential role in mitotic progression and are attractive targets in cancer therapy. The first generation of benzo[e]pyridoindole exhibited powerful aurora kinase inhibition but their low solubility limited further development. Grafting a pyperidine-ethoxy group gives rise to a hydrosoluble inhibitor: compound C5M.C5M could efficiently inhibit the proliferation of cells from different origins. C5M prevented cell cycling, induced a strong mitotic arrest then, cells became polyploid and finally died. C5M did not impair the spindle checkpoint, the separation of the sister chromatids and the transfer of aurora B on the mid-zone. C5M prevented histone H3 phosphorylation at mitotic entry and erased AMPK-Thr172 phosphorylation in late mitosis. With this unique profile of inhibition, C5M could be useful for understanding the role of phospho Thr172-AMPK in abscission and the relationship between the chromosomal complex and the energy sensing machinery.C5M is a multikinase inhibitor with interesting preclinical characteristics: high hydro-solubility and a good stability in plasma. A single dose prevents the expansion of multicellular spheroids. C5M can safely be injected to mice and reduces significantly the development of xenograft. The next step will be to define the protocol of treatment and the cancer therapeutic field of this new anti-proliferative drug. PMID- 26247631 TI - Regulation of split anergy in natural killer cells by inhibition of cathepsins C and H and cystatin F. AB - Freshly isolated human primary NK cells induce preferential lysis of Oral Squamous Carcinoma Stem Cells (OSCSCs) when compared to differentiated Oral Squamous Carcinoma Cells (OSCCs), while anti-CD16 antibody and monocytes induce functional split anergy in primary NK cells by decreasing the cytotoxic function of NK cells and increasing the release of IFN-gamma. Since NK92 cells have relatively lower levels of cytotoxicity when compared to primary NK cells, and have the ability to increase secretion of regulatory cytokines IL-10 and IL-6, we used these cells as a model of NK cell anergy to identify and to study the upstream regulators of anergy. We demonstrate in this paper that the levels of truncated monomeric cystatin F, which is known to inhibit the functions of cathepsins C and H, is significantly elevated in NK92 cells and in anergized primary NK cells. Furthermore, cystatin F co-localizes with cathepsins C and H in the lysosomal/endosomal vesicles of NK cells. Accordingly, the mature forms of aminopeptidases cathepsins C and H, which regulate the activation of effector granzymes in NK cells, are significantly decreased, whereas the levels of pro cathepsin C enzyme is increased in anergized NK cells after triggering of the CD16 receptor. In addition, the levels of granzyme B is significantly decreased in anti-CD16mAb and target cell anergized primary NK cells and NK92 cells. Our study provides the cellular and molecular mechanisms by which target cells may utilize to inhibit the cytotoxic function of NK cells. PMID- 26247632 TI - Targeted expression of BikDD combined with metronomic doxorubicin induces synergistic antitumor effect through Bax activation in hepatocellular carcinoma. AB - Conventional chemotherapy is commonly used to treat advanced non-resectable hepatocellular carcinoma (HCC) but this treatment modality has not demonstrated convincing survival benefit in HCC patients. Our previous studies indicated that targeted expression of therapeutic BikDD driven by a liver cancer-specific alpha fetoprotein promoter/enhancer (eAFP) in the VISA backbone (eAFP-VISA-BikDD) significantly and specifically kills HCC cells in multiple orthotopic animal models. To enhance its therapeutic efficacy, we combined eAFP-VISA-BikDD with chemotherapeutic agents and found that eAFP-VISA-BikDD plus doxorubicin (Dox) or 5-fluorouracil (5-FU) demonstrated synergistic cytotoxicity in HCC cells. Specifically, the combination of eAFP-VISA-BikDD plus Dox markedly induced apoptosis via increased Bax mitochondrial translocation and cytoplasmic cytochrome c release. Compared with either agent alone, a low dose of Dox combined with eAFP-VISA-BikDD induced better antitumor effect and prolonged longer survival of mice in two orthotopic liver cancer xenograft models. Our findings provide strong preclinical support for evaluating the combined therapy of eAFP-VISA-BikDD and Dox in a clinical setting as a treatment option for HCC. PMID- 26247633 TI - TRIM66 overexpresssion contributes to osteosarcoma carcinogenesis and indicates poor survival outcome. AB - TRIM66 belongs to the family of tripartite motif (TRIM)-containing proteins. Alterations in TRIM proteins have been implicated in several malignancies. This study was aimed at elucidating the expression and biological function of TRIM66 in osteosarcoma. Here, TRIM66 expression level was higher in osteosarcoma tissues than in normal tissues. High TRIM66 expression was correlated with high rate of local recurrence and lung metastasis, and short survival time. Then, we found that knockdown of TRIM66 in two osteosarcoma cell lines, MG63 and HOS, significantly inhibited cell proliferation and induced G1-phase arrest. Moreover, inhibition of TRIM66 in osteosarcoma cells significantly induced cell apoptosis, while remarkably inhibited cell migration, invasion as well as tumorigenicity in nude mice. Gene set enrichment analysis in Gene Expression Omnibus dataset revealed that apoptosis, epithelial-mesenchymal transition (EMT) and transforming growth factor-beta (TGF-beta) signaling pathway-related genes were enriched in TRIM66 higher expression patients, which was confirmed by western blot analysis in osteosarcoma cells with TRIM66 silenced. In conclusion, TRIM66 may act as an oncogene through suppressing apoptosis pathway and promoting TGF-beta signaling in osteosarcoma carcinogenesis. TRIM66 may be a prognostic factor and potential therapeutic target in osteosarcoma. PMID- 26247634 TI - Transanal anorectal stricturoplasty using the Heineke-Mikulicz principle: a novel technique. AB - AIM: Current surgical options for the treatment of rectal stricture are either technically difficult or result in a high rate of recurrence. We describe the results of a simple and potentially effective technique of transanal stricturoplasty using the Heineke-Mikulicz principle. METHOD: The medical records and a prospectively maintained database of patients with rectal stricture were searched. Those who underwent transanal stricturoplasty for an anorectal stricture from 2007 to 2013 were studied retrospectively. Morbidity, length of hospital stay and the rates of success and recurrence were recorded. RESULTS: Fifteen patients with a symptomatic rectal stricture who failed dilatation underwent transanal stricturoplasty. The types of stricture included strictures in Crohn's disease (n = 7) and anastomotic stricture after stapled ileoanal anastomosis for ulcerative colitis (n = 4), after stapled hemorrhoidopexy (n = 3) and after low anterior resection for rectal cancer (n =1). The median (range) distance of the stricture from the dentate line was 4 (0-6) cm. Recurrence of symptoms after anal dilatation occurred at a median of 3 (1-4) weeks. The median follow up after transanal stricturoplasty was 21 (6-88) months. Two patients had symptomatic recurrence at 12 months and both underwent a repeat transanal stricturoplasty, resulting in persistent patency of the strictured area at the time of the last follow up, 10 and 26 months, respectively, after repeat transanal stricturoplasty. The remaining 13 had a satisfactory result. CONCLUSION: Despite the retrospective nature of this report and the small sample size and short follow up, the results strongly suggest that transanal Heineke Mikulicz-type stricturoplasty is a promising treatment for this important condition. This operation is easy to perform and may result in success. PMID- 26247635 TI - Examining the Relationship Between Productivity Loss Trajectories and Work Disability Outcomes Using the Panel Study of Income Dynamics. AB - OBJECTIVE: To identify trajectories of productivity loss and examine the relationship between the trajectories and work disability outcomes. METHODS: Latent class growth analysis of productivity loss was estimated for the ages of 25 to 44 years in the Panel Study of Income Dynamics (N = 4960). Differences among the trajectories for work disability outcomes for the ages of 25 to 64 years were estimated using logistic regression and analysis of variance. RESULTS: A five-group trajectory model was identified with a no-risk, low-risk, high-risk, early-onset increasing risk, and late-onset increasing risk group. The likelihood of ever experiencing permanent disability or receiving Social Security Disability Insurance between the ages of 25 and 64 years differed across the trajectories with the early-onset and high-risk groups having the greatest likelihood and the no-risk trajectory having the lowest likelihood of work disability. CONCLUSIONS: Productivity loss trajectories are highly related to work disability outcomes. PMID- 26247636 TI - What Occupational Health Needs Arise in Workplaces Following Disasters? A Joint Analysis of Eight Cases of Disaster in Japan. AB - OBJECTIVE: To identify occupational health needs arising after disasters. METHODS: Using semistructured interviews with expert informants, we jointly analyzed the needs arising in eight disaster cases that threatened the lives or health of workers in Japan. RESULTS: Various types of health issues occurred in a wide range of employees. In total, we identified 100 needs in six phases after disasters and classified them across nine categories of worker characteristics. The proportion of health needs on the list that were applicable in each case varied from 13% to 49%. More needs arose when the companies were responsible for the disaster and when employee lives were lost. We also assessed the list as fairly comprehensive. CONCLUSIONS: The list developed in this study is expected to be effective for anticipating occupational health needs after disasters. PMID- 26247637 TI - Assessment of the Biological Effects of Welding Fumes Emitted From Metal Active Gas and Manual Metal Arc Welding in Humans. AB - OBJECTIVE: Emissions from a particular welding process, metal inert gas brazing of zinc-coated steel, induce an increase in C-reactive protein. In this study, it was investigated whether inflammatory effects could also be observed for other welding procedures. METHODS: Twelve male subjects were separately exposed to (1) manual metal arc welding fumes, (2) filtered air, and (3) metal active gas welding fumes for 6 hours. Inflammatory markers were measured in serum before, and directly, 1 and 7 days after exposure. RESULTS: Although C-reactive protein concentrations remained unchanged, neutrophil concentrations increased directly after exposure to manual metal arc welding fumes, and endothelin-1 concentrations increased directly and 24 hours after exposure. After exposure to metal active gas and filtered air, endothelin-1 concentrations decreased. CONCLUSIONS: The increase in the concentrations of neutrophils and endothelin-1 may characterize a subclinical inflammatory reaction, whereas the decrease of endothelin-1 may indicate stress reduction. PMID- 26247638 TI - Longitudinal Assessment of Blood Cholinesterase Activities Over 2 Consecutive Years Among Latino Nonfarmworkers and Pesticide-Exposed Farmworkers in North Carolina. AB - OBJECTIVE: This study (1) describes patterns of whole blood total cholinesterase, acetylcholinesterase, and butyrylcholinesterase activities across the agricultural season, comparing farmworkers and nonfarmworkers; and (2) explores differences between farmworkers' and non-farmworkers' likelihood of cholinesterase depression. METHODS: Blood samples from 210 Latino male farmworkers and 163 Latino workers with no occupational pesticide exposure collected 8 times across 2 agricultural seasons were analyzed. Mean cholinesterase activity levels and depressions 15% or more were compared by month. RESULTS: Farmworkers had significantly lower total cholinesterase and butyrylcholinesterase activities in July and August and lower acetylcholinesterase activity in August. Farmworkers had significantly greater likelihood of cholinesterase depression for each cholinesterase measure across the agricultural season. SIGNIFICANCE: A repeated-measures design across 2 years with a nonexposed control group demonstrated anticholinesterase effects in farmworkers. Current regulations designed to prevent pesticide exposure are not effective. PMID- 26247639 TI - High Job Demands, Job Strain, and Iso-Strain are Risk Factors for Sick Leave due to Mental Disorders: A Prospective Swedish Twin Study With a 5-Year Follow-Up. AB - OBJECTIVE: To investigate whether psychosocial work environment and health behaviors are risk factors for sick leave due to mental disorders, and whether familial confounding (genetics and shared environment) explains the associations. METHODS: Respondents (n = 11,729), given to complete a questionnaire in 2004 to 2006, were followed up approximately 5 years for sick leave spells due to mental disorders, using national registry data. Data were analyzed using logistic regression, and conditional logistic regression for twin pairs discordant for sick leave (cotwin control). RESULTS: High job demands, job strain, and iso strain were independent risk factors for sick leave due to mental disorders. Familial factors seem to be of importance in the associations between job support, smoking, a combination of unhealthy behaviors and sick leave. CONCLUSIONS: Improving the psychosocial work environment may be effective in preventing sick leave due to mental disorders. PMID- 26247640 TI - Developing Surveillance Methodology for Agricultural and Logging Injury in New Hampshire Using Electronic Administrative Data Sets. AB - OBJECTIVE: Agriculture and logging rank among industries with the highest rates of occupational fatality and injury. Establishing a nonfatal injury surveillance system is a top priority in the National Occupational Research Agenda. Sources of data such as patient care reports (PCRs) and hospitalization data have recently transitioned to electronic databases. METHODS: Using narrative and location codes from PCRs, along with International Classification of Diseases, 9th Revision, external cause of injury codes (E-codes) in hospital data, researchers are designing a surveillance system to track farm and logging injury. RESULTS: A total of 357 true agricultural or logging cases were identified. CONCLUSIONS: These data indicate that it is possible to identify agricultural and logging injury events in PCR and hospital data. Multiple data sources increase catchment; nevertheless, limitations in methods of identification of agricultural and logging injury contribute to the likely undercount of injury events. PMID- 26247641 TI - The Immediate and Sustained long-Term Changes in Daytime Sleepiness After Participation in a Workplace Pedometer Program: A Prospective Cohort Study. AB - OBJECTIVE: To assess the potential benefit of a workplace physical activity program on daytime sleepiness. METHODS: A total of 685 participants of a 4-month workplace physical activity program were assessed for daytime sleepiness (Epworth Sleepiness Scale [ESS]) at baseline, 4 months (postprogram), and 12 months. Changes in ESS were analyzed using multilevel mixed linear regression. RESULTS: In the total population, no changes in ESS scores were observed; 0 to 4 months: 0.2 (95% CI: -0.5 to 0.0), 4 to 12 months: 0.1 (95% CI: -0.2 to 0.4). In participants with baseline excessive daytime sleepiness (ESS > 10, n = 109), ESS scores improved significantly by -2.2 (95% CI: -3.0 to -1.4) at 4 months, sustained at 12 months; and almost half no longer had excessive daytime sleepiness by end of program. CONCLUSIONS: This study suggests that for employees with excessive daytime sleepiness, short- and long-term improvement in daytime sleepiness may be an unforeseen benefit of workplace physical activity programs. PMID- 26247642 TI - Economic Analysis of the Return-on-Investment of a Worksite Wellness Program for a Large Multistate Retail Grocery Organization. AB - OBJECTIVE: The objective of this study is to measure the return on investment (ROI) of the Price Chopper/Golub Corporation employee population who participate in wellness programs available to them. METHODS: Medical claims data, risk level, and presence of comorbidities such as diabetes and heart disease were compared in a matched retrospective cohort of participants and nonparticipants, with 2008, 2009, and 2010 serving as measurement years. Program costs and estimated savings were used to calculate an ROI of $4.33 for every dollar invested in wellness programs. RESULTS: Reductions in medical costs were observed at several risk and participation levels, with an average savings of $133 per participant and a 3 year savings estimate of $285,706. CONCLUSIONS: The positive ROI and savings estimate indicate that wellness interventions added economic value to Price Chopper/Golub Corporation. PMID- 26247643 TI - Occupational Exposure to Aluminum and Alzheimer Disease: A Meta-Analysis. AB - OBJECTIVE: We conducted a meta-analysis to systematically quantify the association between occupational exposure to aluminum and risk of Alzheimer disease (AD). METHODS: Electronic database searches were conducted up to March 2015 for controlled studies. Study quality was assessed using the Newcastle Ottawa Scale. RESULTS: Three retrospective case-control studies, involving 1056 participants, met the criteria for inclusion. All studies used surrogate informants to ascertain exposure. Occupational aluminum exposure was not associated with AD (odds ratio, 1.00; 95% confidence interval, 0.59 to 1.68), even in sensitivity analysis excluding studies with low-quality assessment scores (odds ratio, 1.06; 95% confidence interval, 0.36 to 3.10). CONCLUSIONS: The findings of the present meta-analysis do not support a causative role of aluminum in the pathogenesis of AD. Nevertheless, in the absence of prospective studies with more precise ascertainment of exposure, a role for aluminum cannot be definitively excluded. PMID- 26247645 TI - Part-Time Work and Physical Activity in American High School Students. AB - OBJECTIVE: To compare physical activity (PA) in American high school students who work part-time with those who do not work. METHODS: Data were obtained from the National Health and Nutrition Examination Survey 2003 to 2006 (n = 791). Work status was self-reported and PA was measured using accelerometers. RESULTS: In males, adjusted for age, race, and poverty-income ratio, workers averaged greater counts per minute, less sedentary time, and greater moderate-to-vigorous PA compared with nonworkers. In females, workers and nonworkers had similar counts per minute, whereas nonworkers had somewhat greater moderate-to-vigorous PA. There was a work-by-school status interaction on sedentary time (P = 0.021), whereby work was associated with less sedentary time among students not on break from school. CONCLUSIONS: In American high school students, work is associated with greater PA in males and a different composition of PA in females. PMID- 26247644 TI - Health Care Expenditures for University and Academic Medical Center Employees Enrolled in a Pilot Workplace Health Partner Intervention. AB - OBJECTIVE: To evaluate the impact of a pilot workplace health partner intervention delivered by a predictive health institute to university and academic medical center employees on per-member, per-month health care expenditures. METHODS: We analyzed the health care claims of participants versus nonparticipants, with a 12-month baseline and 24-month intervention period. Total per-member, per-month expenditures were analyzed using two-part regression models that controlled for sex, age, health benefit plan type, medical member months, and active employment months. RESULTS: Our regression results found no statistical differences in total expenditures at baseline and intervention. Further sensitivity analyses controlling for high cost outliers, comorbidities, and propensity to be in the intervention group confirmed these findings. CONCLUSIONS: We find no difference in health care expenditures attributable to the health partner intervention. The intervention does not seem to have raised expenditures in the short term. PMID- 26247646 TI - Further Trends in Work-Related Musculoskeletal Disorders: A Comparison of Risk Factors for Symptoms Using Quality of Work Life Data From the 2002, 2006, and 2010 General Social Survey. AB - OBJECTIVE: To report trends for the risk of musculoskeletal disorders. METHODS: Three Quality of Work Life surveys examine the risk factors for musculoskeletal disorders. RESULTS: Findings similar for several risk factors, but differences across the reporting years may reflect economic conditions. Respondent numbers in 2010 were reduced, some risk factors had pattern changes, and there were sex and age differences. Trend analysis showed most significant changes were for the "work fast" risk factor. New 2010 "physical effort" item showed sex differences, and items reflective of total worker health showed strong associations with "back pain" and "pain in arms." CONCLUSIONS: Intervention strategies should focus on physical exposures and psychosocial risk factors (work stress, safety climate, job satisfaction, supervisor support, work fast, work freedom, work time) that have been consistently related to reports of musculoskeletal disorders. Economic conditions will influence some psychosocial risk factors. PMID- 26247649 TI - Arterial Stiffness in Patients With Occupational Metal Exposure: Role of Antihypertensive Drugs and Statins. PMID- 26247650 TI - To the Editor. PMID- 26247651 TI - Creating History. PMID- 26247652 TI - Continuing Professional Development in Australia: Barriers and Support. AB - Mandatory continuing professional development (CPD) requirements for nurses are common throughout the world, with CPD being required in Australia since 2010. Many barriers to CPD have been identified. In Australia, state and territory governments have implemented supports to help nurses overcome these barriers. PMID- 26247653 TI - Use of Technology to Promote Effective Medication Adherence. AB - Ineffective medication adherence among older adults can lead to the exacerbation of chronic health conditions, hospital admissions, and other avoidable health care costs. As hospitals increasingly focus on population health, the use of technology in patient homes is one approach to increase overall adherence with medications. The successful use of technology can reduce the number of medication errors, including missed doses, taking extra doses, and taking the wrong drug. PMID- 26247654 TI - International Perspectives in Leadership Development: Part I. AB - In this first part of a two-part series, leadership development perspectives are shared from interviews and experiences gained while visiting Taiwan and China. Each country has a distinctive culture and needs, yet both are rapidly rising to strengthen the leadership capacity of nurses and are increasingly a source of advances in global leadership and organizational science. PMID- 26247655 TI - Preparing Educators to Implement Flipped Classrooms as a Teaching Strategy. AB - Educators are not able to change teaching strategies unless they have experience with a new strategy. A 4-hour course was developed to support educators to teach differently. PMID- 26247656 TI - The Elephant in the Room: Nursing and Nursing Power on an Interprofessional Team. AB - Notions of competency development frequently underlie discussions of interprofessional education and practice. Yet, by focusing primarily on the development of competencies, the discourse remains at a surface level, thus obscuring the root of many of the tensions that commonly occur in interprofessional collaborative teamwork. This qualitative study explored how perceptions of status influenced participation on an interprofessional team. Findings indicate that underlying tensions exist, despite an overarching commitment in both interprofessional practice and client-centered care. In particular, notions of perceived power, voice, and status intersected to create a narrative about the role and status of nursing in an interprofessional team. Both nurses and non-nurses recognized the influence of this narrative on team dynamics and function. This narrative was enacted through verbal and nonverbal behaviors, with passive and active resistance often appearing as a strategy used by nurses to address perceived power imbalances. This study has implications for interprofessional education and practice as it relates to nursing. PMID- 26247658 TI - Transforming Education for Electronic Health Record Implementation. AB - Outcomes are an integral part of health care. Over the years, the educational team at the authors' hospital has sought effective, realistic options for electronic health record (EHR) training that ensures standardized documentation of patient data by nursing personnel. Thus, providers will have easily available access and clinicians will experience confidence in the proficiency of their skills to use the EHR. This article describes the transformation from an instructor-led classroom training plan into a focused clinician workflow training pathway using Benner's novice-to-expert model and Lowe's five Key Principles for Successful EHR Training. Multiple teaching strategies have been incorporated into the education plan, including a computer skills assessment test, an EHR proficiency tool, web-based training modules, clinical (or specialty) scenarios, followed by practice in learning laboratories. The educational plan has produced individualized EHR learning, confident nursing performance, and overall unit management satisfaction. PMID- 26247659 TI - Use of Workshops to Develop Nurses' and Nursing Students' Writing Skills. AB - Workshops have been described in the literature as a strategy for preparing nurses to publish their work and develop their writing skills. Articles about the use of workshops for these purposes have not been integrated systematically. Seventeen articles were included in the current review. The workshop method has been found to be effective for preparing nurses to write for publication and for improving nurses' and nursing students' writing skills. However, workshops must be combined with one-to-one mentoring and feedback on writing to be successful. PMID- 26247660 TI - Brief Bedside Refresher Training to Practice Cardiopulmonary Resuscitation Skills in the Ambulatory Surgery Center Setting. AB - Cardiac arrest can occur in any health care setting at any time, requiring nursing staff to be prepared to quickly and adequately perform basic cardiopulmonary resuscitation (CPR). Currently, the American Heart Association certifies health care providers in Basic Life Support (BLS) for a 2-year period, but evidence indicates that psychomotor skills decline well before the end of the certification time frame. Nurses in the ambulatory surgery setting expressed concern regarding their ability to implement CPR successfully, given the infrequent occurrence of cardiac and respiratory arrests. Using a study by Niles et al. as a model, the authors piloted the implementation of brief CPR refresher training at the bedside of an ambulatory surgery center to assess and increase nurse confidence in BLS skills. PMID- 26247661 TI - Neurotoxicant exposure during pregnancy is a confounder for assessment of iodine supplementation on neurodevelopment outcome. AB - CONTEXT: The developing brain is vulnerable to iodine deficiency (ID) and environmental neuro-toxicants. OBJECTIVES: To assess neurocognitive development of children whose mothers have received (or not) iodine supplementation during pregnancy, in an area of borderline ID, while assessing in utero exposure to environmental neuro-toxicants. DESIGN/PATIENTS: Among 86 children born from normal euthyroid women who participated in our prospective interventional study on iodine supplementation (150 MUg/day) started early in pregnancy, 44 (19 with iodine supplementation, 25 controls) were assessed at two years using the Bayley test. Information on parents' education and habits (smoking), and on child development was recorded. Thyroid tests at each trimester of pregnancy and on cord blood (CB) were available, as well as milk concentrations of selected environmental compounds known for their neurotoxicity, including heavy metals and PCBs. RESULTS: There was no difference in Bayley tests for children born to mothers with and without iodine supplementation, but sample size was small. Language and Social-Emotional Scales were negatively correlated with TBG at all times tested, while PCB 118 correlated negatively with all Language scales. Among maternal and CB thyroid tests, only CB thyroglobulin, the best marker of iodine status, correlated (negatively) with neurodevelopment scales (Motor and Expressive Language). CONCLUSIONS: This pilot study suggests that PCB118 has a negative impact on neurocognitive development, possibly mitigating the benefit of iodine supplementation in an area of borderline ID. We propose that exposure to environmental neurotoxicants should be taken into account when designing studies on the benefit of iodine supplementation in pregnancy. The potential interactions between TBG, environmental neurotoxicants and brain development warrant further studies. PMID- 26247662 TI - Prenatal alcohol exposure, adaptive function, and entry into adult roles in a prospective study of young adults. AB - INTRODUCTION: Although many studies have demonstrated effects of prenatal alcohol exposure (PAE) on physical, cognitive, and behavioral development in children, few have focused on the long term effects on adults. In this study, data are presented on adaptive function and entry into adult roles in a community sample of young adults with PAE. The expectation was that prenatally exposed adults would show lower adaptive functioning and more difficulty with entry into adult roles than the non-exposed control group and that these effects would be related to the severity of PAE effects. METHOD: The predominantly African-American, low income sample included adults with a wide range of prenatal exposure (n = 123) as well as control groups for socioeconomic (SES) (n =5 9) and disability (n = 54) status. The mothers of the alcohol-exposed and SES-control group participants were recruited before birth and offspring have been followed up periodically. The disability control group was recruited in adolescence. The adults were interviewed about adaptive function in day-to-day life and adult role entry. Collateral adults who were well-acquainted with each participant were interviewed concerning adaptive function. RESULTS: Results showed that adults who were dysmorphic and/or cognitively affected by PAE had difficulty with adaptive function and entry into adult roles. Males showing cognitive effects with no physical effects were the most severely affected. Results for exposed adults not showing physical or cognitive effects were similar to or more positive than those of the control group for most outcomes. CONCLUSION: PAE has long-term effects on adaptive outcomes in early adulthood. Additional research should focus on possible interventions at this transition and on factors contributing to the adjustment of the exposed, but unaffected participants. PMID- 26247663 TI - Oxygen deficient layered double perovskite as an active cathode for CO2 electrolysis using a solid oxide conductor. AB - A-site ordered PrBaMn2O(5+delta) was investigated as a potential cathode for CO2 electrolysis using a La(0.9)Sr(0.1)Ga(0.8)Mg(0.2)O3 (LSGM) electrolyte. The A site ordered layered double perovskite, PrBaMn2O(5+delta), was found to enhance electrocatalytic activity for CO2 reduction on the cathode side since it supports mixed valent transition metal cations such as Mn, which could provide high electrical conductivity and maintain a large oxygen vacancy content, contributing to fast oxygen ion diffusion. It was found that during the oxidation of the reduced PrBaMn2O(5+delta) (O5 phase) to PrBaMn2O(6-delta) (O6 phase), a reversible oxygen switchover in the lattice takes place. In addition, here the successful CO2 electrolysis was measured in LSGM electrolyte with this novel oxide electrode. It was found that this PrBaMn2O(5+delta), layered perovskite cathode exhibits a performance with a current density of 0.85 A cm(-2) at 1.5 V and 850 degrees C and the electrochemical properties were also evaluated by impedance spectroscopy. PMID- 26247664 TI - The negative prognostic impact of bone metastasis with a tumor mass. AB - OBJECTIVE: Typically, bone metastasis causes osteolytic and osteoblastic lesions resulting from the interactions of tumor cells with osteoclasts and osteoblasts. In addition to these interactions, tumor tissues may grow inside bones and cause mass lesions. In the present study, we aimed to demonstrate the negative impact of a tumor mass in a large cohort of patients with bone metastatic cancer. METHODS: Data from 335 patients with bone metastases were retrospectively reviewed. For the analysis, all patients were divided into three subgroups with respect to the type of bone metastasis: osteolytic, osteoblastic, or mixed. The patients were subsequently categorized as having bone metastasis with or without a tumor mass, and statistically significant differences in median survival and 2 year overall survival were observed between these patients (the median survival and 2-year overall survival were respectively 3 months and 16% in patients with a tumor mass and 11 months and 26% in patients without a tumor mass; p<0.001). RESULTS: According to multivariate analysis, the presence of bone metastasis with a tumor mass was found to be an independent prognostic factor (p=0.011, hazard ratio: 1.62, 95% confidence interval: 1.11-1.76). Bone metastasis with a tumor mass was more strongly associated with osteolytic lesions, other primary diseases (except for primary breast and prostate cancers), and spinal cord compression. CONCLUSION: Bone metastasis with a tumor mass is a strong and independent negative prognostic factor for survival in cancer patients. PMID- 26247665 TI - Ocular risk management in patients undergoing general anesthesia: an analysis of 39,431 surgeries. AB - OBJECTIVE: This study sought to describe and analyze ocular findings associated with nonocular surgery in patients who underwent general anesthesia. METHODS: The authors retrospectively collected a series of 39,431 surgeries using standardized data forms. RESULTS: Ocular findings were reported in 9 cases (2.3:10,000), which involved patients with a mean age of 58.9+/-19.5 years. These cases involved patients classified as ASA I (33%), ASA II (55%) or ASA III (11%). General anesthesia with propofol and remifentanil was used in 4 cases, balanced general anesthesia was used in 4 cases, and regional block was used in combination with balanced general anesthesia in one case. Five patients (55%) underwent surgery in the supine position, one patient (11%) underwent surgery in the lithotomy position, two patients (22%) underwent surgery in the prone position, and one patient (11%) underwent surgery in the lateral position. Ocular hyperemia was detected in most (77%) of the 9 cases with ocular findings; pain/burning of the eyes, visual impairment, eye discharge and photophobia were observed in 55%, 11%, 11% and 11%, respectively, of these 9 cases. No cases involved permanent ocular injury or vision loss. CONCLUSION: Ophthalmological findings after surgeries were uncommon, and most of the included patients were relatively healthy. Minor complications, such as dehydration or superficial ocular trauma, should be prevented by following systematic protocols that provide appropriate ocular occlusion with a lubricating ointment and protect the eye with an acrylic occluder. These procedures will refine the quality of anesthesia services and avoid discomfort among patients, surgeons and anesthesia staff. PMID- 26247666 TI - Flow-through anastomosis using a T-shaped vascular pedicle for gracilis functioning free muscle transplantation in brachial plexus injury. AB - OBJECTIVE: In gracilis functioning free muscle transplantation, the limited caliber of the dominant vascular pedicle increases the complexity of the anastomosis and the risk of vascular compromise. The purpose of this study was to characterize the results of using a T-shaped vascular pedicle for flow-through anastomosis in gracilis functioning free muscle transplantation for brachial plexus injury. METHODS: The outcomes of patients with brachial plexus injury who received gracilis functioning free muscle transplantation with either conventional end-to-end anastomosis or flow-through anastomosis from 2005 to 2013 were retrospectively compared. In the flow-through group, the pedicle comprised a segment of the profunda femoris and the nutrient artery of the gracilis. The recipient artery was interposed by the T-shaped pedicle. RESULTS: A total of 46 patients received flow-through anastomosis, and 25 patients received conventional end-to-end anastomosis. The surgical time was similar between the groups. The diameter of the arterial anastomosis in the flow-through group was significantly larger than that in the end-to-end group (3.87 mm vs. 2.06 mm, respectively, p<0.001), and there were significantly fewer cases of vascular compromise in the flow-through group (2 [4.35%] vs. 6 [24%], respectively, p=0.019). All flaps in the flow-through group survived, whereas 2 in the end-to-end group failed. Minimal donor-site morbidity was noted in both groups. CONCLUSIONS: Flow-through anastomosis in gracilis functioning free muscle transplantation for brachial plexus injury can decrease the complexity of anastomosis, reduce the risk of flap loss, and allow for more variation in muscle placement. PMID- 26247667 TI - Treatment with dasatinib or nilotinib in chronic myeloid leukemia patients who failed to respond to two previously administered tyrosine kinase inhibitors--a single center experience. AB - OBJECTIVE: To evaluate hematological, cytogenetic and molecular responses as well as the overall, progression-free and event-free survivals of chronic myeloid leukemia patients treated with a third tyrosine kinase inhibitor after failing to respond to imatinib and nilotinib/dasatinib. METHODS: Bone marrow karyotyping and real-time quantitative polymerase chain reaction were performed at baseline and at 3, 6, 12 and 18 months after the initiation of treatment with a third tyrosine kinase inhibitor. Hematologic, cytogenetic and molecular responses were defined according to the European LeukemiaNet recommendations. BCR-ABL1 mutations were analyzed by Sanger sequencing. RESULTS: We evaluated 25 chronic myeloid leukemia patients who had been previously treated with imatinib and a second tyrosine kinase inhibitor. Nine patients were switched to dasatinib, and 16 patients were switched to nilotinib as a third-line therapy. Of the chronic phase patients (n=18), 89% achieved a complete hematologic response, 13% achieved a complete cytogenetic response and 24% achieved a major molecular response. The following BCR-ABL1 mutations were detected in 6/14 (43%) chronic phase patients: E255V, Y253H, M244V, F317L (2) and F359V. M351T mutation was found in one patient in the accelerated phase of the disease. The five-year overall, progression-free and event-free survivals were 86, 54 and 22% (p<0.0001), respectively, for chronic phase patients and 66%, 66% and 0% (p<0.0001), respectively, for accelerated phase patients. All blast crisis patients died within 6 months of treatment. Fifty-six percent of the chronic phase patients lost their hematologic response within a median of 23 months. CONCLUSIONS: Although the responses achieved by the third tyrosine kinase inhibitor were not sustainable, a third tyrosine kinase inhibitor may be an option for improving patient status until a donor becomes available for transplant. Because the long-term outcome for these patients is poor, the development of new therapies for resistant chronic myeloid leukemia patients is necessary. PMID- 26247668 TI - The effect of elemene on lung adenocarcinoma A549 cell radiosensitivity and elucidation of its mechanism. AB - OBJECTIVE: To investigate the effect of elemene on the radiosensitivity of A549 cells and its possible molecular mechanism. METHODS: Apoptosis of A549 cells was detected by flow cytometry and fluorescence microscopy. The effect of double strand break (DSB) damage repair in A549 cells was evaluated using the neutral comet assay. Protein expression levels were detected using western blotting, and the correlation between protein levels was analyzed. RESULTS: Elemene exhibited a radiosensitizing effect on A549 cells. The level of apoptosis induced by elemene combined with radiation was significantly greater (p<0.01) than that elicited by either radiation or elemene alone. Following radiation and subsequent repair for 24 h, the tail intensity of A549 cells treated with a combination of elemene and radiation was greater than that of cells treated with either elemene or radiation alone (p<0.01). This result indicates that elemene inhibits cellular DSB repair. Both elemene combined with radiation and radiation alone decreased the protein expression of DNA-PKcs and Bcl-2 compared to elemene alone (p<0.01), while p53 protein expression was increased (p<0.01). A negative correlation was observed between DNA-PKcs and p53 expression (r=-0.569, p=0.040), while a positive correlation was found between DNA-PKcs and Bcl-2 expression (r=0.755, p=0.012). CONCLUSIONS: Elemene exhibits a radiosensitizing effect on A549 cells, and its underlying molecular mechanism of action may be related to the downregulation of DNA-PKcs gene expression. PMID- 26247669 TI - Non-alcoholic steatohepatitis-related liver cirrhosis is increasing in China: a ten-year retrospective study. AB - OBJECTIVE: Little is known about metabolic factors in cirrhotic patients in China. Therefore, we aimed to quantify the prevalence of both metabolic factors and non-alcoholic steatohepatitis-related liver cirrhosis in China. METHODS: The medical records of 1,582 patients diagnosed with liver cirrhosis from June 2003 to July 2013 at Daping Hospital (Chongqing, China) were retrospectively reviewed through a computer-generated search. RESULTS: Serum hepatitis B virus surface antigen was present in 1,083 (68.5%) patients, and hepatitis B was found to be the only etiological factor in 938 (59.3%) of all patients. Obesity, diabetes mellitus, and arterial hypertension were observed in 229 (14.5%), 159 (10.1%), and 129 (8.2%) patients, respectively. From 2012-2013, the proportion of non alcoholic steatohepatitis-related liver cirrhosis increased to 3.2%, whereas the average proportion of non-alcoholic steatohepatitis-related liver cirrhosis in the previous ten years was 1.9%. The incidence of hepatocellular carcinoma was much higher in males than in females (6.3% vs. 3.7%, respectively, p=0.036). Obesity and diabetes mellitus did not significantly increase the incidence of hepatocellular carcinoma in the whole cirrhotic group. The presence of hepatitis B virus was the only risk factor for hepatocellular carcinoma in cirrhotic patients (p<0.001). CONCLUSIONS: Although hepatitis B virus remains the main etiology of liver cirrhosis in China, steatohepatitis-related liver cirrhosis is increasing in frequency. Hepatitis B virus was the sole significant risk factor for hepatocellular carcinoma in the whole cirrhotic group in the present study, in contrast to obesity and diabetes mellitus, for which only a trend of increased hepatocellular carcinoma was found. PMID- 26247670 TI - Glutamine treatment attenuates hyperglycemia-induced mitochondrial stress and apoptosis in umbilical vein endothelial cells. AB - OBJECTIVE: The aim of this study was to determine the in vitro effect of glutamine and insulin on apoptosis, mitochondrial membrane potential, cell permeability, and inflammatory cytokines in hyperglycemic umbilical vein endothelial cells. MATERIALS AND METHODS: Human umbilical vein endothelial cells were grown and subjected to glutamine and insulin to examine the effects of these agents on the hyperglycemic state. Mitochondrial function and the production of inflammatory cytokines were assessed using fluorescence analysis and multiple cytotoxicity assays. Apoptosis was analyzed by the terminal deoxynucleotidyl transferase dUTP nick end-labeling assay. RESULTS: Glutamine maintains the integrity of the mitochondria by reducing the cell permeability and cytochrome c levels and increasing the mitochondrial membrane potential. The cytochrome c level was significantly (p<0.005) reduced when the cells were treated with glutamine. An apoptosis assay revealed significantly reduced apoptosis (p<0.005) in the glutamine-treated cells. Moreover, glutamine alone or in combination with insulin modulated inflammatory cytokine levels. Interleukin-10, interleukin-6, and vascular endothelial growth factor were up-regulated while tumor necrosis factor-alpha was down-regulated after treatment with glutamine. CONCLUSION: Glutamine, either alone or in combination with insulin, can positively modulate the mitochondrial stress and cell permeability in umbilical vein endothelial cells. Glutamine regulates the expression of inflammatory cytokines and maintains the balance of the mitochondria in a cytoprotective manner. PMID- 26247671 TI - Effect of hypertonic saline treatment on the inflammatory response after hydrochloric acid-induced lung injury in pigs. AB - OBJECTIVES: Hypertonic saline has been proposed to modulate the inflammatory cascade in certain experimental conditions, including pulmonary inflammation caused by inhaled gastric contents. The present study aimed to assess the potential anti-inflammatory effects of administering a single intravenous dose of 7.5% hypertonic saline in an experimental model of acute lung injury induced by hydrochloric acid. METHODS: Thirty-two pigs were anesthetized and randomly allocated into the following four groups: Sham, which received anesthesia and were observed; HS, which received intravenous 7.5% hypertonic saline solution (4 ml/kg); acute lung injury, which were subjected to acute lung injury with intratracheal hydrochloric acid; and acute lung injury + hypertonic saline, which were subjected to acute lung injury with hydrochloric acid and treated with hypertonic saline. Hemodynamic and ventilatory parameters were recorded over four hours. Subsequently, bronchoalveolar lavage samples were collected at the end of the observation period to measure cytokine levels using an oxidative burst analysis, and lung tissue was collected for a histological analysis. RESULTS: Hydrochloric acid instillation caused marked changes in respiratory mechanics as well as blood gas and lung parenchyma parameters. Despite the absence of a significant difference between the acute lung injury and acute lung injury + hypertonic saline groups, the acute lung injury animals presented higher neutrophil and tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6 and IL 8 levels in the bronchoalveolar lavage analysis. The histopathological analysis revealed pulmonary edema, congestion and alveolar collapse in both groups; however, the differences between groups were not significant. Despite the lower cytokine and neutrophil levels observed in the acute lung injury + hypertonic saline group, significant differences were not observed among the treated and non treated groups. CONCLUSIONS: Hypertonic saline infusion after intratracheal hydrochloric acid instillation does not have an effect on inflammatory biomarkers or respiratory gas exchange. PMID- 26247672 TI - Operative versus nonoperative treatment for displaced midshaft clavicle fractures: a meta-analysis based on current evidence. AB - Literature searches of the Cochrane Library, PubMed, EMBASE, Web of Science, LILACS, China National Knowledge Infrastructure, and Wanfang Data databases were performed from 1966 to September 2014. Only randomized and quasi-randomized controlled clinical trials comparing operative and nonoperative treatments for displaced midshaft clavicle fractures were included. Data collection and extraction, quality assessment, and data analyses were performed according to the Cochrane standards. Thirteen studies were considered in the meta-analysis. Constant scores and the Disabilities of the Arm, Shoulder and Hand scores were improved in the operative fixation group at a follow up of one year or more. The nonunion and symptomatic malunion rates were significantly lower in the operative group. Additionally, the nonoperative group had a higher likelihood of neurological symptoms compared with the operative group. A significantly higher risk of complications was found in patients treated conservatively than in those who underwent operative fixation. However, when patients with nonunion and symptomatic malunion were excluded from the analysis, no significant differences in the complication rate were found. We concluded that based on the current clinical reports, operative treatment is superior to nonoperative treatment in the management of displaced midshaft clavicle fractures. However, we do not support the routine use of primary operative fixation for all displaced midshaft clavicle fractures in adults. PMID- 26247673 TI - The association between the rs11196218A/G polymorphism of the TCF7L2 gene and type 2 diabetes in the Chinese Han population: a meta-analysis. AB - Transcription factor 7-like 2 has been shown to be associated with type 2 diabetes mellitus in multiple ethnic groups in recent years. In the Chinese Han population in particular, numerous studies have evaluated the association between the rs11196218A/G polymorphism of the transcription factor 7-like 2 gene and type 2 diabetes mellitus. However, the results have been inconsistent, so we performed a meta-analysis to assess the association. Odds ratio and 95% confidence interval values were calculated using a random-effects model or a fixed-effects model based on heterogeneity analysis. The quality of the included studies was evaluated using the Newcastle-Ottawa Scale. Subgroup analyses were conducted based on conformity with Hardy-Weinberg equilibrium in the control group as well as on other variables, such as age, sex and body mass index. Sensitivity analysis was also performed to detect heterogeneity and to assess the stability of the results. In total, 10 case-control studies comprising 7,491 cases and 12,968 controls were included in this meta-analysis. The combined analysis indicated that the rs11196218A/G polymorphism was not associated with type 2 diabetes mellitus (G vs. A, OR=1.04, 95% CI=0.97-1.13, p=0.28). The subgroup analyses also did not show any association between the rs11196218A/G polymorphism and the risk of type 2 diabetes mellitus. Furthermore, the results of the subgroup analyses indicated that the absence of an association was not influenced by age, sex or body mass index. The results of the sensitivity analysis verified the reliability and stability of this meta-analysis. In conclusion, this study indicated that there is no significant association between the rs11196218A/G polymorphism and the risk of type 2 diabetes mellitus in the Chinese Han population. PMID- 26247674 TI - Mechanisms of ventilatory control: who is really in charge? PMID- 26247675 TI - Piling on the pressure to combat acute respiratory distress syndrome: a PEEP into the future? PMID- 26247676 TI - Corrigendum. PMID- 26247679 TI - Thrombin promotes the expression of Ccnd1 gene in RPE cells through the activation of converging signaling pathways. AB - The breakdown of the blood-retina barrier exposes retinal pigment epithelium (RPE) to serum components, thrombin among them. In addition to coagulation, thrombin acting through Protease-Activated Receptors (PARs 1-4) participates in a number of processes including cell proliferation, transformation, and migration. The purpose of this study was to identify interacting signaling pathways by which the activation of PAR1 by thrombin triggers cyclin D1 gene (Ccnd1) expression and the proliferation of RPE cells, characteristic of proliferative vitreoretinopathy (PVR). Our results demonstrate that thrombin induces the expression of the c-fos gene (c-fos), the activation of the (fos/jun) AP-1 site and the expression of Ccnd1, in precise correlation with the activation of CREB. Although the expression of both, c-fos and Ccnd1 requires the activation of conventional PKC isoforms and PI3K, downstream signaling from PI3K differs for both genes. Whereas the expression of c-fos requires PI3K-induced PDK1/Akt activity, that of Ccnd1 is mediated by PDK1-independent PKCzeta signaling. Additionally, CREB activation may contribute to the induction of Ccnd1 expression through binding to the Ca/CRE element in the Ccnd1 gene promoter. Since cyclin D1 is a key regulator of cell cycle G1/S phase progression essential for proliferation, these findings further strengthen the critical involvement of thrombin in the development of proliferative retinopathies and may provide pharmacologic targets for the prevention or treatment of these diseases. PMID- 26247678 TI - Hyaluronan cable formation by ocular trabecular meshwork cells. AB - Hyaluronan (HA) in the ocular trabecular meshwork (TM) is a critical modulator of aqueous humor outflow. Individual HA strands in the pericellular matrix can coalesce to form cable-like structures, which have different functional properties. Here, we investigated HA structural configuration by TM cells in response to various stimuli known to stimulate extracellular matrix (ECM) remodeling. In addition, the effects of HA cable induction on aqueous outflow resistance was determined. Primary TM cell cultures grown on tissue culture treated plastic were treated for 12-48 h with TNFalpha, IL-1alpha, or TGFbeta2. TM cells grown on silicone membranes were subject to mechanical stretch, which induces synthesis and activation of ECM proteolytic enzymes. HA structural configuration was investigated by HA binding protein (HAbp) staining and confocal microscopy. HAbp-labeled cables were induced by TNFalpha, TGFbeta2 and mechanical stretch, but not by IL-1alpha. HA synthase (HAS) gene expression was quantitated by quantitative RT-PCR and HA concentration was measured by ELISA assay. By quantitative RT-PCR, HAS-1, -2, and -3 genes were differentially up-regulated and showed temporal differences in response to each treatment. HA concentration was increased in the media by TNFalpha, TGFbeta2 and IL-1alpha, but mechanical stretch decreased pericellular HA concentrations. Immunofluorescence and Western immunoblotting were used to investigate the distribution and protein levels of the HA-binding proteins, tumor necrosis factor-stimulated gene-6 (TSG-6) and inter-alpha-inhibitor (IalphaI). Western immunoblotting showed that TSG-6 and IalphaI were increased by TNFalpha, TGFbeta2 and IL-1alpha, but mechanical stretch reduced their levels. The underlying substrate appears to affect the identity of IalphaI.TSG-6.HA complexes since different complexes were detected when TM cells were grown on a silicone substrate compared to a rigid plastic surface. Porcine anterior segments were perfused with 10 MUg/ml polyinosinic:polycytidylic acid (polyI:C), a potent inducer of HA cables, and outflow rates were monitored for 72 h. PolyI:C had no significant effect on outflow resistance in porcine anterior segments perfused at physiological pressure. Collectively, HAS gene expression, HA concentration and configuration are differentially modified in response to several treatments that induce ECM remodeling in TM cells. In ocular TM cells, our data suggests that the most important determinant of HA cable formation appears to be the ratio of HA chains produced by the different HAS genes. However, the act of rearranging pericellular HA into cable-like structures does not appear to influence aqueous outflow resistance. PMID- 26247680 TI - Nordihydroguaiaretic acid ameliorates cisplatin induced nephrotoxicity and potentiates its anti-tumor activity in DMBA induced breast cancer in female Sprague-Dawley rats. AB - Cisplatin is a widely used antineoplastic drug, but its clinical usefulness is limited due to dose dependent nephrotoxicity. Nordihydroguaiaretic acid (NDGA) is a natural compound with broad pharmacological properties like antioxidant, anti inflammatory and anticancer activity. The present study was undertaken to evaluate the possible beneficial effects of NDGA on cisplatin induced nephrotoxicity as well as its anticancer activity in rats bearing DMBA induced mammary tumors. The effect of NDGA on cisplatin induced nephrotoxicity was evaluated by checking serum nephrotoxicity markers, antioxidant enzymes and inflammatory markers level and kidney histopathology. NDGA induced amelioration of cisplatin nephrotoxicity was clearly visible from significant reductions in serum blood urea nitrogen (86.51 g/dl) and creatinine (5.30 g/dl) levels and significant improvement in body weight change (-10.34 g) and kidney weight (728 mg/kg). The protective effect of NDGA against cisplatin induced nephrotoxicity in the rats was further confirmed by significant restoration of antioxidant enzymes like SOD (86.28% inhibition), inflammatory markers like TNF-alpha (34.6 pg/ml) and histopathological examination. Moreover, our results showed that NDGA potentiated anti-breast cancer activity of cisplatin through an increment in the expression of antioxidant enzymes like SOD (85.35% inhibition) in breast cancer tissue. These results indicated that NDGA potentiated the anti-breast cancer activity of cisplatin, which was clearly evident from the tumor volume and % tumor inhibition in breast cancer rats. The current study demonstrated that NDGA may modify the therapeutic effect of cisplatin in DMBA induced breast cancer in female Sprague-Dawley rats. PMID- 26247681 TI - Onwards and upwards - aphid flight trends follow climate change. AB - The world faces an uncertain future; climate change and the concerns about the security of food production feature prominently on political and scientific agendas world-wide. In this issue, Bell et al. (), drawing on the unique 50-year data set amassed by the suction trap network run by the Rothamsted Insect Survey (RIS), elucidate the mechanisms advancing aphid phenology under climate change and show how by using biological traits we can make predictions about emerging crop pests. Here, I discuss their findings in the context of phenological coincidence and host plant availability. PMID- 26247682 TI - Dependence of photoinduced bending behavior of diarylethene crystals on irradiation wavelength of ultraviolet light. AB - The dependence of the photoinduced bending behavior of diarylethene crystals on the ultraviolet light irradiation wavelength was investigated. When irradiated with 365 nm light, a crystal of 1,2-bis(5-methyl-2-phenyl-4 thiazolyl)perfluorocyclopentene (1a) bends toward the incident light. On the other hand, when irradiated with 380 nm light, the crystal of 1a first bends away from the light source and then bends toward the incident light. To explain this bending behavior, we propose a comprehensive mechanism based on the depth of the photochromic reaction from the crystal surface. This mechanism is successfully supported by the change of cell parameters associated with the photochromic reaction upon irradiation with 380 nm light, which was determined by in situ X ray crystallographic analysis. PMID- 26247683 TI - EAS Consensus Panel statement on homozygous FH. PMID- 26247685 TI - Mass transfer of PBDEs from plastic TV casing to indoor dust via three migration pathways--A test chamber investigation. AB - Polybrominated diphenyl ethers (PBDEs) are widely detected in humans with substantial exposure thought to occur in indoor environments and particularly via contact with indoor dust. Despite this, knowledge of how PBDEs migrate to indoor dust from products within which they are incorporated is scarce. This study utilises an in-house designed and built test chamber to investigate the relative significance of different mechanisms via which PBDEs transfer from source materials to dust, using a plastic TV casing treated with the Deca-BDE formulation as a model source. Experiments at both room temperature and 60 degrees C revealed no detectable transfer of PBDEs from the TV casing to dust via volatilisation and subsequent partitioning. In contrast, substantial transfer of PBDEs to dust was detected when the TV casing was abraded using a magnetic stirrer bar. Rapid and substantial PBDE transfer to dust was also observed in experiments in which dust was placed in direct contact with the source. Based on these experiments, we suggest that for higher molecular weight PBDEs like BDE 209; direct dust:source contact is the principal pathway via which source-to-dust transfer occurs. PMID- 26247684 TI - A comparison of glycated albumin and glycosylated hemoglobin for the screening of diabetes mellitus in Taiwan. AB - OBJECTIVE: Glycated albumin (GA) values reflect an average plasma glucose level over approximately 2-4 weeks, and the assay is stable and can be run on serum or plasma. The aim of this study was to determine the universality and the clinical utility of GA in screening for diabetes mellitus. METHODS: Subjects consisted of 2192 male and female residents in Yi-lan County, Northern Taiwan (mean age 60.1 years), of whom 54.2% (n = 1188) had previously been diagnosed and treated for diabetes. Fasting blood samples were obtained to measure HbA1c, plasma glucose, serum GA, insulin, and measures of kidney and liver function. The reference values for these parameters were determined. Data from patients with diabetes and non-diabetic controls were also compared. RESULTS: Mean GA values were 13.8% in controls and 18.1% in diabetic subjects (31.2% higher, p < 0.0001), while mean HbA1c values were 5.6% in controls and 7.2% in diabetic subjects (29.2% higher, p < 0.0001). The 95th percentile values for GA and HbA1c in controls were 16.1% and 6.2%, respectively. Our suggested GA and HbA1c cut-points for prediabetes at the 75th percentile of the normal population would be 14.6% and 5.8%, respectively. For both parameters, values greater than these cut-points provided a reasonable degree of specificity and sensitivity for risk of having diabetes, while a GA value of 16.5% corresponds to an HbA1c level of 6.5%, diagnostic of diabetes. CONCLUSION: These data indicate that GA values can be used as a surrogate parameter for HbA1c in screening for prediabetes and diabetes mellitus. PMID- 26247686 TI - Perinatal dioxin exposure and the neurodevelopment of Vietnamese toddlers at 1 year of age. AB - Dioxin concentrations remain elevated in both the environment and in humans residing near former US Air Force bases in South Vietnam. This may potentially have adverse health effects, particularly on infant neurodevelopment. We followed 214 infants whose mothers resided in a dioxin-contaminated area in Da Nang, Vietnam, from birth until 1 year of age. Perinatal exposure to dioxins was estimated from toxic equivalent (TEQ) levels of polychlorinated dibenzodioxins and polychlorinated dibenzofurans (PCDDs/Fs-TEQ), and 2,3,7,8-tetrachlorodibenzo p-dioxin (2,3,7,8-TetraCDD) concentrations in breast milk. In infants, daily dioxin intake (DDI) was used as an index of postnatal exposure through breastfeeding. Neurodevelopment of toddlers was assessed using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). No significant differences in neurodevelopmental scores were exhibited for cognitive, language or motor functions between four exposure groups of PCDDs/Fs-TEQ or 2,3,7,8 TetraCDD. However, social-emotional scores were decreased in the high PCDDs/Fs TEQ group and the high 2,3,7,8-TetraCDD group compared with those with mild exposure, after adjusting for confounding factors. Cognitive scores in the mild, moderate, and high DDI groups were significantly higher than those in low DDI group, but there were no differences in cognitive scores among the three higher DDI groups. These results suggest that perinatal exposure to dioxins may affect social-emotional development of 1-year-old toddlers, without diminishing global neurodevelopmental function. PMID- 26247687 TI - Insights into tetrabromobisphenol A adsorption onto soils: Effects of soil components and environmental factors. AB - Concerns regarding tetrabromobisphenol A (TBBPA), the most widely utilized brominated flame retardant in the world, are growing because of the wide application and endocrine-disrupting potential of this compound. To properly assess its environmental impacts, it is important to understand the mobility and fate of TBBPA in soil environments. In this study, the effects of soil components, dissolved organic carbon (DOC) and heavy metal cations on TBBPA adsorption onto two Chinese soils (red soil and black soil) were investigated using batch sorption experiments. The desorption behavior of TBBPA when the two soils are irrigated with eutrophicated river water was also investigated. The results showed that pH greatly affects the adsorptive behavior of TBBPA in soils. Iron oxide minerals and phyllosilicate minerals are both active surfaces for TBBPA sorption, in addition to soil organic matter (SOM). DOC (50 mg OC L(-1)) exhibited a limited effect on TBBPA sorption only under neutral conditions. TBBPA sorption was only minimally affected by the heavy metals (Cu2+, Pb2+ and Cd2+) in the studied pH range. Eutrophicated river water significantly enhanced the desorption of TBBPA from red soil due to the change in soil solution pH. These findings indicate that mobility of TBBPA in soils is mainly associated with soil pH, organic matter and clay fractions: it will be retained by soils or sediments with high organic matter and clay fractions under acidic conditions but becomes mobile under alkaline conditions. PMID- 26247688 TI - Water supply sustainability and adaptation strategies under anthropogenic and climatic changes of a meso-scale Mediterranean catchment. AB - Assessing water supply sustainability is crucial to meet stakeholders' needs, notably in the Mediterranean. This region has been identified as a climate change hot spot, and as a region where water demand is continuously increasing due to population growth and the expansion of irrigated areas. The Herault River catchment (2500 km2, France) is a typical example and a negative trend in discharge has been observed since the 1960s. In this context, local stakeholders need to evaluate possible future changes in water allocation capacity in the catchment, using climate change, dam management and water use scenarios. A modelling framework that was already calibrated and validated on this catchment over the last 50 years was used to assess whether water resources could meet water demands at the 2030 horizon for the domestic, agricultural and environmental sectors. Water supply sustainability was evaluated at the sub-basin scale according to priority allocations using a water supply capacity index, frequency of unsatisfactory years as well as the reliability, resilience and sustainability metrics. Water use projections were based on the evolution of population, per-unit water demand, irrigated areas, water supply network efficiency, as well as on the evaluation of a biological flow. Climate projections were based on an increase in temperature up to 2 degrees C and a decrease in daily precipitation by 20%. Adaptation strategies considered reducing per-unit water demand for the domestic sector and the importation of water volume for the agricultural sector. The dissociated effects of water use and climatic constraints on water supply sustainability were evaluated. Results showed that the downstream portions would be the more impacted as they are the most exploited ones. In the domestic sector, sustainability indicators would be more degraded by climate change scenarios than water use constraints. In the agricultural sector the negative impact of water use scenarios would be stronger. The environmental sector would be hardly satisfied especially in summer with low resilience levels. The adaptation strategies considered in this study would not be sufficient to cope with both anthropogenic and climate changes. Other strategies were discussed based on known examples in the Mediterranean context. PMID- 26247689 TI - Depletion of selenium in blood, liver and muscle from beef heifers previously fed forages containing high levels of selenium. AB - Beef heifers which had grazed 'Jose' tall wheatgrass (TWG; Thinopyrum ponticum var. 'Jose'; 10 heifers) and creeping wildrye (CWR; Leymus triticoides var. 'Rio'; 10 heifers) with high levels of Se (>2 mg/kg DM) due to growth in saline soils, accumulated high Se levels in blood, liver and muscle (Juchem et al., 2012). We determined the decrease in Se levels in blood, liver and muscle from these heifers, particularly the decrease of Se in muscle, in order to determine the maximum feeding length of a low Se diet (LSeD) required sustaining Se enriched beef. Immediately after grazing, all heifers were fed a LSeD containing <0.30 mg/kg DM for 209 d. Blood, liver and muscle samples, as well as body weight (BW), were collected at the beginning and end of the LSeD feeding period and at intermediate times. After grazing, CWR and TWG heifers had similar BW, but TWG heifers had higher levels of Se in whole blood (1.19 versus 0.81 mg/L), liver (2.67 versus 2.12 mg/kg wet weight (WW)), and muscle tissue (0.87 versus 0.63 mg/kg WW) than CWR heifers. The Se levels decreased with exposure time to the LSeD and, at 82 d of feeding the LSeD, Se levels were 77 (liver), 49 (blood) and 31% (muscle) lower. The BW gains for both groups were ~0.5 kg/d during the first 82 d of feeding, but increased thereafter. Levels of Cu in serum (0.28 versus 0.50 mg/L) and liver (1.14 versus 22.9 mg/kg WW) were lower at the end of grazing in TWG heifers, and suggested a potential Cu deficiency. Grazing forages with high Se levels can result in Se-enriched beef, but a LSeD feeding period of <82 d is required to maintain enrichment. PMID- 26247690 TI - Anthropogenic impact on diffuse trace metal accumulation in river sediments from agricultural reclamation areas with geochemical and isotopic approaches. AB - A better understanding of anthropogenic impact can help assess the diffuse trace metal accumulation in the agricultural environment. In this study, both river sediments and background soils were collected from a case study area in Northeast China and analyzed for total concentrations of six trace metals, four major elements and three lead isotopes. Results showed that Pb, Cd, Cu, Zn, Cr and Ni have accumulated in the river sediments after about 40 years of agricultural development, with average concentrations 1.23-1.71 times higher than local soil background values. Among them Ni, Cr and Cu were of special concern and they may pose adverse biological effects. By calculating enrichment factor (EF), it was found that the trace metal accumulation was still mainly ascribed to natural weathering processes, but anthropogenic contribution could represent up to 40.09% of total sediment content. For Pb, geochemical and isotopic approaches gave very similar anthropogenic contributions. Principal component analysis (PCA) further suggested that the anthropogenic Pb, Cu, Cr and Ni inputs were mostly related to the regional atmospheric deposition of industrial emissions and gasoline combustion, which had a strong affinity for iron oxides in the sediments. Concerning Cd, however, it mainly originated from local fertilizer applications and was controlled by sediment carbonates. PMID- 26247691 TI - Occurrence and removal of estrogens, progesterone and testosterone in three constructed wetlands treating municipal sewage in the Czech Republic. AB - Estrogenic hormones, progesterone and testosterone are endocrine-disrupting chemicals and their presence in aquatic environments represents a potentially adverse environmental and public health impact. There is a considerable amount of information about removal of estrogens, progesterone and testosterone in conventional wastewater treatment plants, namely activated sludge systems. However, the information about removal of these compounds in constructed wetlands is very limited. Three constructed wetlands with horizontal subsurface flow in the Czech Republic have been selected to evaluate removal of estrogens (estrone, estriol, 17beta-estradiol, 17alpha-ethinylestradiol), testosterone and progesterone. Monitored constructed wetlands for 100, 150 and 200 PE have been in operation for more than 10 years and all systems exhibit very high treatment efficiency for organics and suspended solids. The results indicate that removal of all estrogens, progesterone and testosterone was high and only estrone was found in the outflow from one constructed wetland in concentrations above the limit of quantification 1 ng l(-1). The limits of quantification for other estrogens, i.e., 10 ng l(-1) for estriol, 1 ng l(-1) for 17beta-estradiol and 2 ng l(-1) for 17alpha-ethinylestradiol were not exceeded in the outflow of all monitored constructed wetlands. Also, for progesterone and testosterone, all outflow concentrations were below the LOQ of 0.5 ng l(-1). The results indicated that constructed wetlands with horizontal subsurface flow are a promising technology for elimination of estrogens, progesterone and testosterone from municipal sewage but more information is needed to confirm this finding. PMID- 26247692 TI - Characterisation of microcontaminants in Darwin Harbour, a tropical estuary of northern Australia undergoing rapid development. AB - The detection of microcontaminants in aquatic environments raises concerns about their potential to exert ecotoxicological effects and impact human health. In contrast to freshwater habitats, little information is available on environmental concentrations in urban estuarine and marine environments. This study investigated an extensive range of organic and inorganic microcontaminants in the Darwin Harbour catchment, a tropical estuary in northern Australia undergoing rapid urbanisation and industrial development. We sampled wastewater effluent and surface water from seven sites in Darwin Harbour for pharmaceuticals and personal care products, alkylphenols, hormones, pesticides, herbicides and metals. In vitro bioassays were used to estimate the (anti)estrogenic and (anti)androgenic activities of samples. Seventy-nine of 229 organic microcontaminants analysed were detected at concentrations ranging from 0.01 to 20 MUg/L, with acesulfame, paracetamol, cholesterol, caffeine, DEET and iopromide detected at the highest concentrations in wastewater effluent (20 MUg/L, 17 MUg/L, 11 MUg/L, 11 MUg/L, 10 MUg/L and 7.6 MUg/L, respectively). Levels of estrogenic activity ranged from estradiol equivalency quotients (EEQs) of <0.10 to 6.29+/-0.16 ng/L while levels of androgenic activity ranged from dihydrotestosterone equivalency quotients (DHTEQs) of <3.50 to 138.23+/-3.71 ng/L. Environmental concentrations of organic microcontaminants were comparable to ranges reported from aquatic environments worldwide with sewage effluent discharges representing the dominant source of entry into Darwin Harbour. The measured concentration range of DEET was higher than ranges reported in previous studies. PMID- 26247693 TI - The potential impact of an inter-basin water transfer project on nutrients (nitrogen and phosphorous) and chlorophyll a of the receiving water system. AB - Any inter-basin water transfer project would cause complex physical, chemical, hydrological and biological changes to the receiving system. The primary channel of the middle route of the South-to-North Water Transfer Project has a total length of 1267 km. There is a significant difference between the physical, chemical and biological characteristics of the originating and receiving drinking water conservation districts. To predict the impacts of this long-distance inter basin water transfer project on the N&P (nitrogen and phosphorus) concentrations and eutrophication risk of the receiving system, an environmental fluid dynamics code (EFDC) model was applied. The calibrated model accurately reproduced the hydrodynamic, water quality and the entire algal bloom process. Thirteen scenarios were defined to fully understand the N&P and chlorophyll a (Chl a) variation among different hydrological years, different quantity and timing of water transfer, and different inflows of N&P concentrations. The results showed the following: (a) The water transfer project would not result in a substantial difference to the trophic state of the Miyun reservoir in any of the hydrological years. (b) The area affected by the water transfer did not involve the entire reservoir. To minimize the impact of water transfer on N&P nutrients and Chl a, water should be transferred as uniform as possible with small discharge. (c) The variation in Chl a was more sensitive to an increase in P than an increase in N for the transferred water. The increased percentages of the average Chl a concentration when water was transferred in the spring, summer and autumn were 7.76%, 16.67% and 16.45%. Our findings imply that special attention should be given to prevent P increment of the transferred water from May to October to prevent algal blooms. The results provide useful information for decision makers about the quantity and timing of water transfers. PMID- 26247694 TI - The Streptomyces metabolite anhydroexfoliamycin ameliorates hallmarks of Alzheimer's disease in vitro and in vivo. AB - Anhydroexfoliamycin (1) and undecylprodigiosin (2) have been previously described as neuroprotective molecules against oxidative stress in neurons. Since oxidative stress is strongly correlated with neurodegenerative diseases, we have evaluated their effects over the principal hallmarks of Alzheimer's disease (AD). Both compounds were tested in vitro in two different neuroblastoma cellular models, one for amyloid precursor protein metabolism studies (BE(2)-M17) and another one specific for taupathology in AD (SH-SY5Y-TMHT441). Amyloid-beta (Abeta) levels, beta-secretase (BACE1) activity, tau phosphorylation, extracellular signal regulated kinase (ERK) and glycogen synthase kinase-3beta (GSK3beta) expression were analyzed and while undecylprodigiosin (2) produced poor results, anhydroexfoliamycin (1) strongly inhibited GSK3beta, reducing tau phosphorylation in vitro (0.1 MUM). A competitive assay of anhydroexfoliamycin (1) and the specific c-Jun N-terminal kinase (JNK) inhibitor, SP600125, showed that the reduction of the phosphorylated tau levels is mediated by the JNK pathway in SH SY5Y-TMHT441 cells. Thus, this compound was tested in vivo by intraperitoneal administration in 3xTg-AD mice, confirming the positive results registered in the in vitro assays. This work presents anhydroexfoliamycin (1) as a promising candidate for further studies in drug development against neurodegenerative diseases. PMID- 26247695 TI - Electrophysiological evidence for voltage-gated calcium channel 2 (Cav2) modulation of mechano- and thermosensitive spinal neuronal responses in a rat model of osteoarthritis. AB - Osteoarthritis (OA) remains one of the greatest healthcare burdens in western society, with chronic debilitating pain-dominating clinical presentation yet therapeutic strategies are inadequate in many patients. Development of better analgesics is contingent on improved understanding of the molecular mechanisms mediating OA pain. Voltage-gated calcium channels 2.2 (Cav2.2) play a critical role in spinal nociceptive transmission, therefore blocking Cav2.2 activity represents an attractive opportunity for OA pain treatment, but the only available licensed Cav2.2 antagonist ziconitide (PrilatTM) is of limited use. TROX-1 is an orally available, use dependent and state-selective Cav2 antagonist, exerting its analgesic effect primarily via Cav2.2 blockade, with an improved therapeutic window compared with ziconitide. Using a rat model of monosodium iodoacetate (MIA), 2 mg, induced OA we used in vivo electrophysiology to assess the effects of spinal or systemic administration of TROX-1 on the evoked activity of wide dynamic range spinal dorsal horn neurons in response to electrical, natural mechanical (dynamic brush and von Frey 2, 8, 26 and 6 g) and thermal (40, 45 and 45 degrees C) stimuli applied to the peripheral receptive field. MIA injection into the knee joint resulted in mechanical hypersensitivity of the ipsilateral hind paw and weight-bearing asymmetry. Spinal administration of TROX 1 (0.1 and 1 MUg/50 MUl) produced a significant dose-related inhibition of dynamic brush, mechanical (von Frey filament (vF) 8, 26 and 60 g) and noxious thermal-(45 and 48 degrees C) evoked neuronal responses in MIA rats only. Systemic administration of TROX-1 produced a significant inhibition of the mechanical-(vF 8, 26 and 60 g) evoked neuronal responses in MIA rats. TROX-1 did not produce any significant effect on any neuronal measure in Sham controls. Our in vivo electrophysiological results demonstrate a pathological state-dependent effect of TROX-1, which suggests an increased functional role of Cav2, likely Cav2.2, channels in mediating OA pain. PMID- 26247697 TI - JAMA Oncology Patient Page. The Evolution of a Cancer. PMID- 26247696 TI - N,O-Chelating Four-Membered Metallacyclic Titanium(IV) Complexes for Atom Economic Catalytic Reactions. AB - Titanium, as the second most abundant transition metal in the earth's crust, lends itself as a sustainable and inexpensive resource in catalysis. Its nontoxicity and biocompatibility are also attractive features for handling and disposal. Titanium has excelled as a catalyst for a broad range of transformations, including ethylene and alpha-olefin polymerizations. However, many reactions relevant to fine chemical synthesis have preferrentially employed late transition metals, and reactive, inexpensive early transition metals have been largely overlooked. In addition to promising reactivity, titanium complexes feature more robust character compared with some other highly Lewis-acidic metals such as those found in the lanthanide series. Since the advent of modulating ligand scaffolds, titanium has found use in a growing variety of reactions as a versatile homogeneous catalyst. These catalytic transformations include hydrofunctionalization reactions (adding an element-hydrogen (E-H) bond across a C-C multiple bond), as well as the ring-opening polymerization of cyclic esters, all of which are atom-economic transformations. Our investigations have focused on tight bite angle monoanionic N,O-chelating ligands, forming four-membered metallacycles. These ligand sets, including amidates, ureates, pyridonates, and sulfonamidates, have flexible binding modes offering a range of stable and reactive intermediates necessary for catalytic activity. Additionally, the simple form of these ligands leads to easily prepared proligands, along with facile tuning of steric and electronic factors. A sterically bulky titanium amidate complex has proven to be a leading catalyst for the selective formation of anti Markovnikov addition products via intermolecular hydroamination of terminal alkynes, while sterically less demanding titanium pyridonates have opened the path to the selective formation of amine substituted cycloalkanes via the intramolecular hydroaminoalkylation of aminoalkenes over the competing hydroamination pathway. Sulfonamidates have boosted reactivity for hydrofunctionalization and polymerization reactions compared with amide ligands not bearing a sulfonyl group. N,O-Chelated titanium complexes have been used to synthesize ultrahigh molecular weight polyethylene and have been utilized in the challenging task of realizing equal incorporation of two different cyclic esters in a random ring-opening copolymerization. These discrete complexes have allowed for careful study of fundamental coordination chemistry and stoichiometric organometallic investigations. With inexpensive starting materials and modular ligands, titanium N,O-chelated complexes are well-suited to address the challenges of achieving greener chemical processes while accessing useful reaction manifolds for sustainable synthesis. PMID- 26247698 TI - State-to-State Quantum Dynamics of Reactions O((3)P) + HD (v = 0-1, j = 0) -> OH+D and OD+H: Reaction Mechanism and Vibrational Excitation. AB - Time-dependent quantum wave packet dynamics calculations have been performed in order to characterize the dynamics and mechanism of O((3)P) + HD (v = 0-1, j = 0) -> OH+D and OD+H reactive collisions using the adiabatic potential energy surface by Rogers et al. [J. Phys. Chem. A 2000, 104, 2308] Special attention has been paid to the calculations and discussion of the state resolved integral and differential cross sections and the product state distributions. In addition, the intramolecular isotopic branching ratio has been determined. The results revealed that the OD + H is the favored product channel and the product OH has the same quantum number v as the reactant HD. For low collision energy, the product angular distributions concentrate in the backward region being consistent with a rebounding mechanism. In the case of higher collision energy, the stripping collisions with larger impact parameters tend to produce sideways and forward scatterings, especially for the HD vibrationally excited state. The cross section and intramolecular isotopic branching ratio are in agreement with the previous theoretical results. A cartoon depiction collision model is built and works well for our calculation results. PMID- 26247699 TI - Health-Related Quality of Life in Community-Dwelling Persons Living With Enterocutaneous Fistulas. AB - PURPOSE: The purpose of this study was to measure health-related quality of life (HRQOL) of community-dwelling patients with enterocutaneous fistulas (ECFs). DESIGN: The study was nonexperimental and used mixed methods, incorporating both quantitative and qualitative techniques to guide data collection and analysis. SUBJECTS AND SETTING: Participants were recruited using a nonprobability, convenience sampling strategy. Patients living with ECFs in the community were identified by an ET nurse at St. Michael's Hospital in Toronto, Ontario, Canada. INSTRUMENT: The questionnaire incorporated a modified version of the Stoma Quality of Life Scale (SQOLS); specifically, the term stoma was replaced with enterocutaneous fistula. The SQOLS is divided into 2 sections: The first queries overall satisfaction with life, and the second section queries 5 domains related to HRQOL, work/social functioning, sexual/body image, stoma (altered to query ECF) function, financial concerns, and skin irritation. This modified version of the SQOLS underwent face and content validation from clinicians with expertise in ECF management. METHODS: Questionnaires were distributed to eligible participants over a 20-month period in 2009 to 2010. Sixteen questionnaires were completed and returned yielding a response rate of 47.1%. RESULTS: Health-related quality of life was negatively affected by an ECF, as evidenced by low scores across all domains. The median scores for overall satisfaction with life in general in the past month were low (median scores 2.75 and 2.25, respectively) out of a possible score of 10. Respondents' median scores on 5 HRQOL domains queried by the SQOLS were also low at 25 to 39.59 out of 100. Thematic analysis of patient comments revealed a loss of normalcy, constant worry about the ECF and management of adjacent skin, depression and anxiety, and discomfort associated with presence of the ECF. The few positive comments primarily focused on support provided by family and caregivers. CONCLUSIONS: Findings from this study reveal that an ECF exerts a markedly negative impact on HRQOL that may be partially ameliorated by support from family and caregivers. PMID- 26247701 TI - Validation of the Children's Eating Behaviour Questionnaire in a low-income preschool-aged sample in the United States. AB - The Children's Eating Behaviour Questionnaire (CEBQ; Wardle, Guthrie, Sanderson, & Rapoport, 2001) is a widely used measure of child eating behaviors. Yet, only one study has examined the factor structure of the CEBQ among low-income children. In the current study, we examined the internal consistency, factor structure, and validity of the CEBQ among 1002 low-income preschool-age children recruited from Head Start locations in the United States. Confirmatory Factor Analysis indicated the CEBQ evidenced a reasonable fit to the data. Results also indicate that CEBQ subscales demonstrate good internal reliability (alpha's >= .70) and validity, with 7 of the 8 subscales associated with children's BMI z scores in the expected directions. Equivalent factor loadings and indicator means across White and Black non-Hispanic participants were found, supporting measurement invariance between these two groups. In sum, our study supports the factor structure of the CEBQ among low-income preschool-aged children in the United States. PMID- 26247702 TI - Table for two: The effects of familiarity, sex and gender on food choice in imaginary dining scenarios. AB - INTRODUCTION: Existing research suggests that eating behaviours may be used to modify self-presentation and that process may be different for women compared to men. We aimed to assess how people make different food choices in situations of varying self-presentation demand. METHOD: Via an online survey, eligible participants (n = 216; 64% female: not on a restrictive diet or severely obese/underweight) were allocated to one of four experimental conditions manipulating the familiarity (close friend v acquaintance) and sex of an eating companion (same v opposite sex). All participants were asked to imagine they were eating out with one of the manipulated companions, and were presented with a menu and asked to order items. Menu choices were used to calculate the total kilojoules ordered, percentage of kilojoules from fats and number of low-fat options selected. To assess differences in impression management, participants completed the Paulhus Deception scale. RESULTS: Despite successful manipulation checks, analyses of covariance (controlling for levels of hunger) revealed no main or interaction effects for familiarity and sex composition for any of the menu choice outcomes assessed. Impression management scores differed for sex composition (main effect only) with participants who imagined dining with someone of the same gender (M = 2.05, SE = 0.90) having higher impression management scores than those imagining dining with an opposite sex companion (M = 1.27, SE = 0.83). CONCLUSION: We found preliminary support that gender composition could alter impression management demands but this did not translate to differences in food choice. PMID- 26247703 TI - Our landscapes, our livestock, ourselves: Restoring broken linkages among plants, herbivores, and humans with diets that nourish and satiate. AB - We contend that palates link herbivores and humans with landscapes and consider how these relationships have changed historically. An attuned palate, which enables herbivores to meet needs for nutrients and self-medicate to rectify maladies, evolves from three interrelated processes: flavor-feedback associations, availability of phytochemically rich foods, and learning in utero and early in life to eat nourishing combinations of foods. That occurs when wild or domestic herbivores forage on phytochemically rich landscapes, is less common when domestic herbivores forage on monoculture pastures, is close to zero for herbivores in feedlots, and is increasingly rare for people who forage in modern food outlets. Unlike our ancestors, the palates of many individuals are no longer linked in healthy ways with landscapes. Industrial farming and selection for yield, appearance, and transportability diminished the flavor, phytochemical richness, and nutritive value of fruits and vegetables for humans. Phytochemically impoverished pastures and feedlot diets can adversely affect the health of livestock and the flavor and nutritive value of meat and milk products for humans. While flavors of produce, meat, and dairy have become blander, processed foods have become more desirable as people have learned to link synthetic flavors with feedback from energy-rich compounds that obscure nutritional sameness and diminish health. Thus, the roles plants and animals once played in nutrition have been usurped by processed foods that are altered, fortified, and enriched in ways that can adversely affect appetitive states and food preferences. The need to amend foods, and to take nutrient supplements, could be reduced by creating phytochemically rich plants and herbivores and by creating cultures that know how to combine foods into meals that nourish and satiate. PMID- 26247704 TI - Perceptions of food healthiness among free-living women. AB - BACKGROUND: Improving our understanding of food-related healthiness perception may be beneficial to assist those with eating- and weight-related problems. PURPOSE: This study replicates and extends prior work by examining normative and person-specific predictors of the perceived healthiness of foods in a sample of free-living women. METHODS: One hundred sixty-nine women from the community judged the healthiness of 104 foods that varied in fat, fiber, sugar, and protein content. Mixed-effects modeling estimated normative influences of food-specific and individual-specific characteristics on each participant's utilization of the nutrients when judging healthiness. RESULTS: When judging healthiness, free living women relied substantially on fat and fiber independently of other nutrients. In contrast, reliance on fat and fiber was moderated by the presence of protein and sugar. Three bivariate interactions emerged between: 1) fiber and sugar; 2) fat and protein; and 3) fiber and protein. Binge-eating symptoms and frequency of healthy food consumption positively correlated with independent reliance on fat as a predictor of perceived healthiness. CONCLUSIONS: Public health campaigns should continue to encourage free-living women to consume adequate amounts of protein. Additionally, free-living women should be reminded that the presence of sugar in foods without nourishing components (i.e., fiber, protein) is problematic, and consuming these foods in excess should be avoided. Healthy food consumption appears to enhance perceptions of food healthiness. PMID- 26247705 TI - Orthotic Management of Deformational Plagiocephaly: Consensus Clinical Standards of Care. AB - OBJECTIVE: To establish consensus on definitive, actionable standards for the management of deformational plagiocephaly. DESIGN: Three-stage Delphi Survey process based on best practice statements obtained through literature review. SETTING: Electronic survey delivery. PARTICIPANTS: Review panel of 10 multidisciplinary subject matter experts (SMEs); survey panel of 30 cranial orthotists. RESULTS: Fifty-four best practice statements were accepted in four categories: diagnosis, presentation and severity, initiating treatment, and management principles. CONCLUSIONS: Clinical practice can be guided en route to robust evidence as to the efficacy of various plagiocephaly management strategies, in pursuit of definitive standards. PMID- 26247706 TI - Comparative Evaluation of the Pharyngeal Airways and Related Soft Tissues of Unilateral and Bilateral Cleft Lip and Palate Patients With the Noncleft Individuals. AB - AIM: This study is a comparison of pharyngeal airways and associated soft tissues of unilateral and bilateral cleft lip and palate patients with the noncleft individuals. MATERIALS AND METHODS: Twenty-four unilateral cleft lip and palate patients (UCLP), 21 bilateral cleft lip and palate patients (BCLP), and 26 noncleft patients (NC) between ages 15 to 17 were included in the study. Eleven linear, 1 angular, and 1 proportional measurements were carried out on pretreatment lateral cephalometric head films of these individuals. RESULTS: The nasopharyngeal depths were markedly reduced in BCLP when compared with the NC (P < .001) and UCLP (P < .01) with a significant difference (P < .01) also among UCLP and NC. Minimum space behind the tongue concerning BCLP and UCLP were significantly lower compared to the NC (P < .001 and P < .01, respectively). In pairwise comparison among the clefts, BCLP showed significant (P < .05) narrowing of this distance. Tongue heights and velar lengths were significantly (P < .001) lower in cleft groups compared to the controls. Similarly, the hyoid bone was positioned in a significantly (P < .01) anterior and inferior direction in cleft patients. Comparison of the mean ratio of velar length to nasopharyngeal depth of the three groups revealed significant (P < .001) inadequacies in cleft patients with significantly (P < .05) more severely reduced values in BCLP. CONCLUSION: Pharyngeal airways and involved soft tissues of cleft patients show serious inadequacies compared to controls, with significant diversities among cleft types pertaining to some of the parameters investigated. It should be kept in mind that these variations can influence function in terms of respiration and phonation. PMID- 26247707 TI - Ultrasound Evaluation of Primary Alveolar Grafting in Cleft Lip/Palate Treatment: Development of a Novel Sonographic Grading System. AB - OBJECTIVE: To explore ultrasonographic evaluation of primary alveolar repair in cleft lip/palate patients and develop a grading system to assess outcomes of graft success. DESIGN: Sixteen patients with an average age of 2 years 1 month had sonograms performed at various points in their treatment to determine the feasibility of ultrasound in visualizing alveolar bone defects and changes over time postgrafting. A total of 23 sonograms were performed: 21 at an average of 12 months postoperatively and 2 at an average of 1 month preoperatively. MAIN OUTCOME MEASURES: A 10-point grading system was developed assessing three categories: locations of lateral bone bridging across the cleft, quantification of residual defects with air or fluid channels, and locations of calcification. Three operators graded 10 sonograms to assess interobserver reliability, and the scores were also validated against dental radiographs in patients old enough for radiographic imaging. RESULTS: Linear weighted kappa statistics revealed substantial interobserver agreement for total scores, with an average kappa value of .708. In limited patients with radiographs, a total score of 9/10 correlated with a Chelsea score of 6.5/8 and category A. CONCLUSIONS: Sonographic evaluation, coupled with this novel grading system, shows potential for early assessment of outcomes of graft success when evaluating new techniques of primary alveolar grafting. PMID- 26247708 TI - The Burden of Care for Children With Unilateral Cleft Lip: A Systematic Review of Revision Surgery. AB - OBJECTIVE: To identify the average rate of revision surgery following cleft lip repair. DESIGN: PubMed, CINAHL, and SCOPUS were searched from database inception through March 2013 using the search terms cleft lip and surgery. Two investigators independently screened all abstracts and determined eligibility from review of full manuscripts using prespecified inclusion and exclusion criteria. Strengths and limitation of the studies were assessed, followed by qualitative synthesis. The I(2) test of homogeneity was performed to determine if meta-analysis was appropriate. RESULTS: The search identified 3034 articles. Of those, 45 met the inclusion criteria. Studies were primarily case series and retrospective cohort studies, with only one randomized controlled trial. One third of studies (n = 15) did not describe how the study sample was selected. Follow-up duration was not reported in one-fourth of studies (n = 11). Nasolabial aesthetics were reported in 44% of studies (n = 20). The incidence of revision surgery ranged from 0% to 100%. Meta-analysis was precluded because of study heterogeneity (I(2) = 97%). CONCLUSIONS: The average incidence of cleft lip revision surgery cannot be estimated from the published literature, due to significant heterogeneity among existing reports and limited study quality. To provide valid information about the burden of care for unilateral cleft lip, a population-based or multicenter longitudinal cohort study is necessary; this study should measure the number of surgical procedures and the patient's aesthetic outcomes. PMID- 26247709 TI - Taurodontism, Root Dilaceration, and Tooth Transposition: A Radiographic Study of a Population With Nonsyndromic Cleft Lip and/or Palate. AB - OBJECTIVES: In an effort to contribute to proper dental planning and define possible dental phenotypes of nonsyndromic cleft lip and/or palate (CL/P), this study aimed to investigate the occurrence of taurodontism, root dilaceration, and tooth transposition in persons with nonsyndromic CL/P, specifically analyzing the differences among gender, cleft types, and the most affected teeth. DESIGN: This retrospective study analyzed 974 panoramic x-rays from nonsyndromic Brazilians older than 16 years and categorized into the following four groups: group 1, 250 persons with unilateral cleft lip and palate; group 2, 250 persons with unilateral cleft lip; group 3, 224 persons with cleft palate; and a control group of 250 persons without clefts. Radiographs were digitalized with a scanner and analyzed. RESULTS: In the Brazilian population studied, the prevalence of taurodontism was 60.4% in group 1, 62.4% in group 2, 67.0% in group 3, and 42.8% in the control group. Root dilacerations had a prevalence of 31.2% in group 1, 29.6% in group 2, 26.3% in group 3, and 27.2% in the control group. The teeth most affected by taurodontism were 17 and 27; whereas root dilacerations were most common in teeth 38 and 48. No tooth transpositions were found in any radiograph analyzed. CONCLUSIONS: Taurodontism is significantly more prevalent in Brazilians with nonsyndromic CL/P than in persons without clefts; whereas the prevalence of root dilaceration no different from that in the control group. However, root dilacerations in anterior teeth were increased in groups 1 and 2 when compared to the control group. PMID- 26247710 TI - Achieving Consensus in the Measurement of Psychological Adjustment to Cleft Lip and/or Palate. AB - BACKGROUND: Psychological adjustment to cleft lip/palate is multifaceted and can fluctuate over time and across different situations. Consequently, a comprehensive understanding of adjustment is difficult to capture, and the challenge of achieving consensus among researchers and clinicians regarding key constructs and processes is considerable. Numerous measures have been used in research and clinical audit, resulting in conflicting findings and difficulties in evidencing the value of psychological intervention. The launch of the world's largest cleft lip/palate cohort study has provided an opportunity to standardize data collection across the United Kingdom. OBJECTIVE: To describe the collaborative process used to achieve consensus in the academic and clinical measurement of psychological adjustment to cleft lip/palate. RESULTS: Extensive work based on existing literature and clinical experience has resulted in a conceptual framework comprising six domains of adjustment and corresponding risk/protective factors that are measureable across key developmental time points. Driven by this framework, a core pack of standardized measures has been selected according to psychometric properties, clinical utility, and pragmatic considerations. CONCLUSIONS: To date, these measures have been implemented within a UK-wide longitudinal cohort study (at diagnosis, 18 months, 3 years, 5 years, and 8 years) and adopted into the national routine clinical audit protocol for cleft lip/palate at age 5. Further data collection points will follow as the cohorts age. Over time, consistency in data collection will allow researchers to address some of the key unanswered questions in relation to psychological adjustment to cleft lip/palate. PMID- 26247711 TI - Developmental alterations in centrosome integrity contribute to the post-mitotic state of mammalian cardiomyocytes. AB - Mammalian cardiomyocytes become post-mitotic shortly after birth. Understanding how this occurs is highly relevant to cardiac regenerative therapy. Yet, how cardiomyocytes achieve and maintain a post-mitotic state is unknown. Here, we show that cardiomyocyte centrosome integrity is lost shortly after birth. This is coupled with relocalization of various centrosome proteins to the nuclear envelope. Consequently, postnatal cardiomyocytes are unable to undergo ciliogenesis and the nuclear envelope adopts the function as cellular microtubule organizing center. Loss of centrosome integrity is associated with, and can promote, cardiomyocyte G0/G1 cell cycle arrest suggesting that centrosome disassembly is developmentally utilized to achieve the post-mitotic state in mammalian cardiomyocytes. Adult cardiomyocytes of zebrafish and newt, which are able to proliferate, maintain centrosome integrity. Collectively, our data provide a novel mechanism underlying the post-mitotic state of mammalian cardiomyocytes as well as a potential explanation for why zebrafish and newts, but not mammals, can regenerate their heart. PMID- 26247713 TI - Single-Molecule-Magnet Behavior in a [2 * 2] Grid Dy(III)4 Cluster and a Dysprosium-Doped Y(III)4 Cluster. AB - Thanks to the MeCN hydrolysis in situ reaction, a [2 * 2] square grid Dy(III)4 cluster based on a polypyridyl triazolate ligand, [Dy4(OH)2(bpt)4(NO3)4(OAc)2] (1), was separated successfully and characterized through single-crystal X-ray diffraction and SQUID magnetometry. The frequency-dependent signals in the out-of phase component of the susceptibility associated with slow relaxation of the magnetization confirmed that complex 1 displays single-molecule magnet (SMM) behavior. Two distinct slow magnetic relaxation processes, with effective energy barriers Ueff1 = 93 cm(-1) for fast relaxation and Ueff2 = 143 cm(-1) for slow relaxation observed under a zero direct-current field, are mainly attributed to the origin of single-ion behavior, which can be further acknowledged by the magnetic investigation of a dysprosium-doped yttrium cluster. Besides, it should be noted that complex 1 represents so far the highest energy barrier among the pure Dy(III)4 SMMs. PMID- 26247714 TI - Stability, Reactivity, Selectivity, Catalysis, and Predictions of 1,3,2,5 Diazadiborinine: Computational Insight into a Boron-Boron Frustrated Lewis Pair. AB - Recent progress in frustrated Lewis pairs (FLPs) has attracted increasing attention. However, most of the FLPs are composed of Lewis basic phosphines and Lewis acidic boranes. In 2015, Kinjo and co-workers reported the first intramolecular boron-boron FLP, namely, 1,3,2,5-diazadiborinine (1), which showed high regioselectivity in the reactions with methyl trifluoromethansulfonate, phenylacetylene, and CO2. More interestingly, the activation of CO2 was found to be reversible when the temperature was elevated to 90 degrees C. Here, we performed thorough density functional theory (DFT) calculations to understand the stability, reactivity, and selectivity of 1. The electronic effects and favorable orbital overlap of 1 with substrates play a crucial role in the reactivity and regioselectivity. On the basis of the results, several organic substrates activated by 1, including aldehyde, ketone, imine, hydrogen, ammonia, phosphine, and silane, were explored computationally. The results show that the combination of aldehyde, ketone, imine, and silane are reversible, especially at elevated temperatures. Finally, we modeled the hydrophosphination of Me2PH and phenylacetylene catalyzed by 1. The rate-determining step is the hydrophosphination with an activation barrier of 31.7 kcal/mol, indicating that the process might be possible. Our results may open an avenue to design new organocatalysts. PMID- 26247712 TI - Dendritic sodium spikes are required for long-term potentiation at distal synapses on hippocampal pyramidal neurons. AB - Dendritic integration of synaptic inputs mediates rapid neural computation as well as longer-lasting plasticity. Several channel types can mediate dendritically initiated spikes (dSpikes), which may impact information processing and storage across multiple timescales; however, the roles of different channels in the rapid vs long-term effects of dSpikes are unknown. We show here that dSpikes mediated by Nav channels (blocked by a low concentration of TTX) are required for long-term potentiation (LTP) in the distal apical dendrites of hippocampal pyramidal neurons. Furthermore, imaging, simulations, and buffering experiments all support a model whereby fast Nav channel-mediated dSpikes (Na dSpikes) contribute to LTP induction by promoting large, transient, localized increases in intracellular calcium concentration near the calcium-conducting pores of NMDAR and L-type Cav channels. Thus, in addition to contributing to rapid neural processing, Na-dSpikes are likely to contribute to memory formation via their role in long-lasting synaptic plasticity. PMID- 26247715 TI - Characterization of metabolic profile of intact non-tumor and tumor breast cells by high-resolution magic angle spinning nuclear magnetic resonance spectroscopy. AB - (1)H high-resolution magic angle spinning nuclear magnetic resonance ((1)H HR-MAS NMR) spectroscopy was used to analyze the metabolic profile of an intact non tumor breast cell line (MCF-10A) and intact breast tumor cell lines (MCF-7 and MDA-MB-231). In the spectra of MCF-10A cells, six metabolites were assigned, with glucose and ethanol in higher concentrations. Fifteen metabolites were assigned in MCF-7 and MDA-MB-231 (1)H HR-MAS NMR spectra. They did not show glucose and ethanol, and the major component in both tumor cells was phosphocholine (higher in MDA-MB-231 than in MCF-7), which can be considered as a tumor biomarker of breast cancer malignant transformation. These tumor cells also show acetone signal that was higher in MDA-MB-231 cells than in MCF-7 cells. The high acetone level may be an indication of high demand for energy in MDA-MB-231 to maintain cell proliferation. The higher acetone and phosphocholine levels in MDA-MB-231 cells indicate the higher malignance of the cell line. Therefore, HR-MAS is a rapid reproducible method to study the metabolic profile of intact breast cells, with minimal sample preparation and contamination, which are critical in the analyses of slow-growth cells. PMID- 26247716 TI - Disease specific modules and hub genes for intervention strategies: A co expression network based approach for Plasmodium falciparum clinical isolates. AB - Systems biology approaches that are based on gene expression and bioinformatics analysis have been successful in predicting the functions of many genes in Plasmodium falciparum, a protozoan parasite responsible for most of the deaths due to malaria. However, approaches that can provide information about the biological processes that are active in this parasite in vivo during complicated malaria conditions have been scarcely deployed. Here we report the analysis of a weighted gene co-expression based network for P. falciparum, from non-cerebral clinical complications. Gene expression profiles of 20 P. falciparum clinical isolates were utilized to construct the same. A total of 20 highly interacting modules were identified post network creation. In 12 of these modules, at least 10% of the member genes, were found to be differentially regulated in parasites from patient isolates showing complications, when compared with those from patients with uncomplicated disease. Enrichment analysis helped identify biological processes like oxidation-reduction, electron transport chain, protein synthesis, ubiquitin dependent catabolic processes, RNA binding and purine nucleotide metabolic processes as associated with these modules. Additionally, for each module, highly connected hub genes were identified. Detailed functional analysis of many of these, which have known annotated functions underline their importance in parasite development and survival. This suggests, that other hub genes with unknown functions may also be playing crucial roles in parasite biology, and, are potential candidates for intervention strategies. PMID- 26247717 TI - CYP2B6 poor metaboliser alleles involved in efavirenz and nevirapine metabolism: CYP2B6*9 and CYP2B6*18 distribution in HIV-exposed subjects from Dschang, Western Cameroon. AB - The prescription of patients' tailored anti-infectious treatments is the ultimate goal of pharmacogenetics/genomics applied to antimicrobial treatments, providing a basis for personalized medicine. Despite the efforts to screen Africans for alleles underlying defective metabolism for a panel of different drugs, still more research is necessary to clarify the interplay between host genetic variation and treatments' response. HIV is a major infectious disease in sub Saharan African countries, and the main prescribed anti-HIV combination therapy includes efavirenz (EFV) or nevirapine (NVP). The two drugs are both mainly metabolised by cytochrome P450 2B6 liver enzyme (CYP2B6). Defective variants of CYP2B6 gene, leading to higher drug exposure with subsequent possible side effects and low compliance, are well known. However, little is known about CYP2B6 alleles in Cameroon where only one study was done on this subject. The main objective of the present work is to assess, in a subset of HIV-exposed subjects from Dschang in West Cameroon, the prevalence of two SNPs in the CYP2B6 gene: 516G>T (rs3745274) and 983T>C (rs28399499), both associated to a defective EFV and NVP metabolism. We analyzed 168 DNA samples collected during two cross sectional surveys performed in Dschang, West Cameroon. In the population studied the observed allele frequencies of 516G>T and 983T>C were 44.35% (95%CI, 36.84 51.86%) and 12.80% (95%CI, 7.75-17.85%), respectively. Moreover, concerning the CYP2B6 expected phenotypes, 28.57% of the population showed a poor metaboliser phenotype, while 27.38% and 44.05% showed an extensive (wild-type) and an intermediate metaboliser phenotype, respectively. Here we found that an important fraction of the subjects is carrying EFV/NVP poor metaboliser alleles. Our findings could help to improve the knowledge about the previewed efficacy of anti HIV drug therapy in Cameroon. Finally, we designed a new method of detection for the 983T>C genetic variation that can be applied in resource-limited laboratories. PMID- 26247718 TI - Is the evolution of Hantavirus driven by its host? PMID- 26247719 TI - High rates of co-infection of Dengue and Chikungunya virus in Odisha and Maharashtra, India during 2013. AB - Dengue viral (DENV) infection is endemic in different parts of India and because of similar primary signs and symptoms, Chikungunya virus (CHIKV) is mostly undiagnosed. Hence, we investigated 204 suspected Dengue cases in a hospital based cross-sectional study in Odisha, India in 2013. It was observed that 50 samples were positive for DENV only, 28 were positive for CHIKV only and interestingly, 28 patients were co-infected with both DENV and CHIKV. Additionally, a total of 18 confirmed Dengue samples from Maharashtra, India were screened for CHIKV and out of those, 15 were co-infected. All CHIKV strains were of East Central South African (ECSA) type and serotype 2 (genotype IV) was predominant in the DENV samples. Additionally, Dengue serotype 1 and 3 were also detected during this time. Further, sequence analysis of E1 gene of CHIKV strains revealed that two substitution mutations (M269V and D284E) were observed in almost 50% strains and they were from co-infected patients. Similarly, sequence analysis of C-prM gene showed the presence of five substitution mutations, (G70S, L72F, N90S, S93N and I150L) in all serotype 1 and two consistent mutations (A101V and V112A) in serotype 2 Dengue samples. Together, it appears that a significantly high number of dengue patients (43, 44.8%) were co-infected with DENV and CHIKV during this study. This emphasizes the need of a routine diagnosis of CHIKV along with DENV for febrile patients. This will be useful in early and proper recognition of infecting pathogen to study the correlation of clinical symptoms with single or co-infection which will ultimately help to implement proper patient care in future. PMID- 26247720 TI - Enhanced HIV-1 surveillance using molecular epidemiology to study and monitor HIV 1 outbreaks among intravenous drug users (IDUs) in Athens and Bucharest. AB - BACKGROUND: A significant increase in HIV-1 diagnoses was reported among Injecting Drug Users (IDUs) in the Athens (17-fold) and Bucharest (9-fold) metropolitan areas starting 2011. METHODS: Molecular analyses were conducted on HIV-1 sequences from IDUs comprising 51% and 20% of the diagnosed cases among IDUs during 2011-2013 for Greece and Romania, respectively. Phylodynamic analyses were performed using the newly developed birth-death serial skyline model which allows estimating of important epidemiological parameters, as implemented in BEAST programme. RESULTS: Most infections (>90%) occurred within four and three IDU local transmission networks in Athens and Bucharest, respectively. For all Romanian clusters, the viral strains originated from local circulating strains, whereas in Athens, the local strains seeded only two of the four sub-outbreaks. Birth-death skyline plots suggest a more explosive nature for sub-outbreaks in Bucharest than in Athens. In Athens, two sub-outbreaks had been controlled (Re<1.0) by 2013 and two appeared to be endemic (Re~1). In Bucharest one outbreak continued to expand (Re>1.0) and two had been controlled (Re<1.0). The lead times were shorter for the outbreak in Athens than in Bucharest. CONCLUSIONS: Enhanced molecular surveillance proved useful to gain information about the origin, causal pathways, dispersal patterns and transmission dynamics of the outbreaks that can be useful in a public health setting. PMID- 26247721 TI - Rabbit haemorrhagic disease virus 2 (RHDV2) outbreak in Azores: Disclosure of common genetic markers and phylogenetic segregation within the European strains. AB - Rabbit haemorrhagic disease virus 2 (RHDV2) is widespread in several countries of Western Europe, but it has not been introduced to other continents. However, between late 2014 and early 2015, the presence of RHDV2 was confirmed outside of the European continent, in the Azores, initially in the islands of Graciosa, Flores, S. Jorge and Terceira. In this study we report the subsequent detection of RHDV2 in wild rabbits from the islands of Faial, St. Maria and S. Miguel, and display the necropsy and microscopic examination data obtained, which showed lesions similar to those induced by classical strains of RHDV, with severe affection of lungs and liver. We also disclose the result of a genetic investigation carried out with RHDV2 positive samples from wild rabbits found dead in the seven islands. Partial vp60 sequences were amplified from 27 tissue samples. Nucleotide analysis showed that the Azorean strains are closely related to each other, sharing a high genetic identity (>99.15%). None of the obtained sequences were identical to any RHDV2 sequence publically known, hampering a clue for the source of the outbreaks. However, Bayesian and maximum likelihood phylogenetic analyses disclosed that Azorean strains are more closely related to a few strains from Southern Portugal than with any others presently known. In the analysed region comprising the terminal 942 nucleotides of the vp60 gene, four new single nucleotide polymorphisms (SNP) were identified. Based on the present data, these four SNPs, which are unique in the strains from Azores, may constitute putative molecular geographic markers for Azorean RHDV2 strains, if they persist in the future. One of these variations is a non-synonymous substitution that involves the replacement of one amino acid in a hypervariable region of the capsid protein. PMID- 26247722 TI - ARHI (DIRAS3)-mediated autophagy-associated cell death enhances chemosensitivity to cisplatin in ovarian cancer cell lines and xenografts. AB - Autophagy can sustain or kill tumor cells depending upon the context. The mechanism of autophagy-associated cell death has not been well elucidated and autophagy has enhanced or inhibited sensitivity of cancer cells to cytotoxic chemotherapy in different models. ARHI (DIRAS3), an imprinted tumor suppressor gene, is downregulated in 60% of ovarian cancers. In cell culture, re-expression of ARHI induces autophagy and ovarian cancer cell death within 72 h. In xenografts, re-expression of ARHI arrests cell growth and induces autophagy, but does not kill engrafted cancer cells. When ARHI levels are reduced after 6 weeks, dormancy is broken and xenografts grow promptly. In this study, ARHI-induced ovarian cancer cell death in culture has been found to depend upon autophagy and has been linked to G1 cell-cycle arrest, enhanced reactive oxygen species (ROS) activity, RIP1/RIP3 activation and necrosis. Re-expression of ARHI enhanced the cytotoxic effect of cisplatin in cell culture, increasing caspase-3 activation and PARP cleavage by inhibiting ERK and HER2 activity and downregulating XIAP and Bcl-2. In xenografts, treatment with cisplatin significantly slowed the outgrowth of dormant autophagic cells after reduction of ARHI, but the addition of chloroquine did not further inhibit xenograft outgrowth. Taken together, we have found that autophagy-associated cancer cell death and autophagy-enhanced sensitivity to cisplatin depend upon different mechanisms and that dormant, autophagic cancer cells are still vulnerable to cisplatin-based chemotherapy. PMID- 26247723 TI - Hexokinase 2 controls cellular stress response through localization of an RNA binding protein. AB - Subcellular localization of RNA-binding proteins is a key determinant of their ability to control RNA metabolism and cellular stress response. Using an RNAi based kinome-wide screen, we identified hexokinase 2 (HK2) as a regulator of the cytoplasmic accumulation of hnRNP A1 in response to hypertonic stress and human rhinovirus infection (HRV). We show that inhibition of HK2 expression or pharmacological inhibition of HK2 activity blocks the cytoplasmic accumulation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), restores expression of B cell lymphoma-extra large (Bcl-xL), and protects cells against hypertonic stress induced apoptosis. Reduction of HK2 protein levels by knockdown results in decreased HRV replication, a delay in HRV-induced cell death, and a reduced number of infected cells, all of which can be rescued by forced expression of a cytoplasm-restricted hnRNP A1. Our data elucidate a novel role for HK2 in cellular stress response and viral infection that could be exploited for therapeutic intervention. PMID- 26247724 TI - DRP1 inhibition rescues retinal ganglion cells and their axons by preserving mitochondrial integrity in a mouse model of glaucoma. AB - Glaucoma is the leading cause of irreversible blindness and is characterized by slow and progressive degeneration of the optic nerve head axons and retinal ganglion cell (RGC), leading to loss of visual function. Although oxidative stress and/or alteration of mitochondrial (mt) dynamics induced by elevated intraocular pressure (IOP) are associated with this neurodegenerative disease, the mechanisms that regulate mt dysfunction-mediated glaucomatous neurodegeneration are poorly understood. Using a mouse model of glaucoma, DBA/2J (D2), which spontaneously develops elevated IOP, as well as an in vitro RGC culture system, we show here that oxidative stress, as evidenced by increasing superoxide dismutase 2 (SOD2) and mt transcription factor A (Tfam) protein expression, triggers mt fission and loss by increasing dynamin-related protein 1 (DRP1) in the retina of glaucomatous D2 mice as well as in cultured RGCs exposed to elevated hydrostatic pressure in vitro. DRP1 inhibition by overexpressing DRP1 K38A mutant blocks mt fission and triggers a subsequent reduction of oxidative stress, as evidenced by decreasing SOD2 and Tfam protein expression. DRP1 inhibition promotes RGC survival by increasing phosphorylation of Bad at serine 112 in the retina and preserves RGC axons by maintaining mt integrity in the glial lamina of glaucomatous D2 mice. These findings demonstrate an important vicious cycle involved in glaucomatous neurodegeneration that starts with elevated IOP producing oxidative stress; the oxidative stress then leads to mt fission and a specific form of mt dysfunction that generates further oxidative stress, thus perpetuating the cycle. Our findings suggest that DRP1 is a potential therapeutic target for ameliorating oxidative stress-mediated mt fission and dysfunction in RGC and its axons during glaucomatous neurodegeneration. Thus, DRP1 inhibition may provide a new therapeutic strategy for protecting both RGCs and their axons in glaucoma and other optic neuropathies. PMID- 26247725 TI - The potential of mesenchymal stem cells in the management of radiation enteropathy. AB - Although radiotherapy is effective in managing abdominal and pelvic malignant tumors, radiation enteropathy is still unavoidable. This disease severely affects the quality of life of cancer patients due to some refractory lesions, such as intestinal ischemia, mucositis, ulcer, necrosis or even perforation. Current drugs or prevailing therapies are committed to alleviating the symptoms induced by above lesions. But the efficacies achieved by these interventions are still not satisfactory, because the milieus for tissue regeneration are not distinctly improved. In recent years, regenerative therapy for radiation enteropathy by using mesenchymal stem cells is of public interests. Relevant results of preclinical and clinical studies suggest that this regenerative therapy will become an attractive tool in managing radiation enteropathy, because mesenchymal stem cells exhibit their pro-regenerative potentials for healing the injuries in both epithelium and endothelium, minimizing inflammation and protecting irradiated intestine against fibrogenesis through activating intrinsic repair actions. In spite of these encouraging results, whether mesenchymal stem cells promote tumor growth is still an issue of debate. On this basis, we will discuss the advances in anticancer therapy by using mesenchymal stem cells in this review after analyzing the pathogenesis of radiation enteropathy, introducing the advances in managing radiation enteropathy using regenerative therapy and exploring the putative actions by which mesenchymal stem cells repair intestinal injuries. At last, insights gained from the potential risks of mesenchymal stem cell-based therapy for radiation enteropathy patients may provide clinicians with an improved awareness in carrying out their studies. PMID- 26247726 TI - NSC-87877 inhibits DUSP26 function in neuroblastoma resulting in p53-mediated apoptosis. AB - Dual specificity protein phosphatase 26 (DUSP26) is overexpressed in high-risk neuroblastoma (NB) and contributes to chemoresistance by inhibiting p53 function. In vitro, DUSP26 has also been shown to effectively inhibit p38 MAP kinase. We hypothesize that inhibiting DUSP26 will result in decreased NB cell growth in a p53 and/or p38-mediated manner. NSC-87877 (8-hydroxy-7-[(6-sulfo-2-naphthyl)azo] 5-quinolinesulfonic acid), a novel DUSP26 small molecule inhibitor, shows effective growth inhibition and induction of apoptosis in NB cell lines. NB cell lines treated with small hairpin RNA (shRNA) targeting DUSP26 also exhibit a proliferation defect both in vitro and in vivo. Treatment of NB cell lines with NSC-87877 results in increased p53 phosphorylation (Ser37 and Ser46) and activation, increased activation of downstream p38 effector proteins (heat shock protein 27 (HSP27) and MAP kinase-activated protein kinase 2 (MAPKAPK2)) and poly ADP ribose polymerase/caspase-3 cleavage. The cytotoxicity resulting from DUSP26 inhibition is partially reversed by knocking down p53 expression with shRNA and also by inhibiting p38 activity with SB203580 (4-[4-(4-fluorophenyl)-2-(4 methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine). In an intrarenal mouse model of NB, NSC-87877 treatment results in decreased tumor growth and increased p53 and p38 activity. Together, these results suggest that DUSP26 inhibition with NSC 87877 is an effective strategy to induce NB cell cytotoxicity in vitro and in vivo through activation of the p53 and p38 mitogen-activated protein kinase (MAPK) tumor-suppressor pathways. PMID- 26247727 TI - p53- and p73-independent activation of TIGAR expression in vivo. AB - TIGAR (TP53-induced glycolysis and apoptosis regulator) functions as a fructose 2,6-bisphosphatase and its expression results in a dampening of the glycolytic pathway, while increasing antioxidant capacity by increasing NADPH and GSH levels. In addition to being a p53 target, p53-independent expression of TIGAR is also seen in many human cancer cell lines that lack wild-type p53. Although human TIGAR expression can be induced by p53, TAp63 and TAp73, mouse TIGAR is less responsive to the p53 family members and basal levels of TIGAR expression does not depend on p53 or TAp73 expression in most mouse tissues in vivo. Although mouse TIGAR expression is clearly induced in the intestines of mice following DNA damaging stress such as ionising radiation, this is also not dependent on p53 or TAp73. PMID- 26247728 TI - Scaffolding protein Homer1a protects against NMDA-induced neuronal injury. AB - Excessive N-methyl-D-aspartate receptor (NMDAR) activation and the resulting activation of neuronal nitric oxide synthase (nNOS) cause neuronal injury. Homer1b/c facilitates NMDAR-PSD95-nNOS complex interactions, and Homer1a is a negative competitor of Homer1b/c. We report that Homer1a was both upregulated by and protected against NMDA-induced neuronal injury in vitro and in vivo. The neuroprotective activity of Homer1a was associated with NMDA-induced Ca2+ influx, oxidative stress and the resultant downstream signaling activation. Additionally, we found that Homer1a functionally regulated NMDAR channel properties in neurons, but did not regulate recombinant NR1/NR2B receptors in HEK293 cells. Furthermore, we found that Homer1a detached the physical links among NR2B, PSD95 and nNOS and reduced the membrane distribution of NMDAR. NMDA-induced neuronal injury was more severe in Homer1a homozygous knockout mice (KO, Homer1a-/-) when compared with NMDA-induced neuronal injury in wild-type mice (WT, Homer1a+/+). Additionally, Homer1a overexpression in the cortex of Homer1a-/- mice alleviated NMDA-induced neuronal injury. These findings suggest that Homer1a may be a key neuroprotective endogenous molecule that protects against NMDA-induced neuronal injury by disassembling NR2B-PSD95-nNOS complexes and reducing the membrane distribution of NMDARs. PMID- 26247729 TI - Adiponectin receptor-mediated signaling ameliorates cerebral cell damage and regulates the neurogenesis of neural stem cells at high glucose concentrations: an in vivo and in vitro study. AB - In the central nervous system (CNS), hyperglycemia leads to neuronal damage and cognitive decline. Recent research has focused on revealing alterations in the brain in hyperglycemia and finding therapeutic solutions for alleviating the hyperglycemia-induced cognitive dysfunction. Adiponectin is a protein hormone with a major regulatory role in diabetes and obesity; however, its role in the CNS has not been studied yet. Although the presence of adiponectin receptors has been reported in the CNS, adiponectin receptor-mediated signaling in the CNS has not been investigated. In the present study, we investigated adiponectin receptor (AdipoR)-mediated signaling in vivo using a high-fat diet and in vitro using neural stem cells (NSCs). We showed that AdipoR1 protects cell damage and synaptic dysfunction in the mouse brain in hyperglycemia. At high glucose concentrations in vitro, AdipoR1 regulated the survival of NSCs through the p53/p21 pathway and the proliferation- and differentiation-related factors of NSCs via tailless (TLX). Hence, we suggest that further investigations are necessary to understand the cerebral AdipoR1-mediated signaling in hyperglycemic conditions, because the modulation of AdipoR1 might alleviate hyperglycemia induced neuropathogenesis. PMID- 26247730 TI - MicroRNA-587 antagonizes 5-FU-induced apoptosis and confers drug resistance by regulating PPP2R1B expression in colorectal cancer. AB - Drug resistance is one of the major hurdles for cancer treatment. However, the underlying mechanisms are still largely unknown and therapeutic options remain limited. In this study, we show that microRNA (miR)-587 confers resistance to 5 fluorouracil (5-FU)-induced apoptosis in vitro and reduces the potency of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. Further studies indicate that miR-587 modulates drug resistance through downregulation of expression of PPP2R1B, a regulatory subunit of the PP2A complex, which negatively regulates AKT activation. Knockdown of PPP2R1B expression increases AKT phosphorylation, which leads to elevated XIAP expression and enhanced 5-FU resistance; whereas rescue of PPP2R1B expression in miR-587-expressing cells decreases AKT phosphorylation/XIAP expression, re-sensitizing colon cancer cells to 5-FU-induced apoptosis. Moreover, a specific and potent AKT inhibitor, MK2206, reverses miR-587-conferred 5-FU resistance. Importantly, studies of colorectal cancer specimens indicate that the expression of miR-587 and PPP2R1B positively and inversely correlates with chemoresistance, respectively, in colorectal cancer. These findings indicate that the miR-587/PPP2R1B/pAKT/XIAP signaling axis has an important role in mediating response to chemotherapy in colorectal cancer. A major implication of our study is that inhibition of miR-587 or restoration of PPP2R1B expression may have significant therapeutic potential to overcome drug resistance in colorectal cancer patients and that the combined use of an AKT inhibitor with 5-FU may increase efficacy in colorectal cancer treatment. PMID- 26247731 TI - Syncytial apoptosis signaling network induced by the HIV-1 envelope glycoprotein complex: an overview. AB - Infection by human immunodeficiency virus-1 (HIV-1) is associated with a progressive decrease in CD4 T-cell numbers and the consequent collapse of host immune defenses. The major pathogenic mechanism of AIDS is the massive apoptotic destruction of the immunocompetent cells, including uninfected cells. The latter process, also known as by-stander killing, operates by various mechanisms one of which involves the formation of syncytia which undergo cell death by following a complex pathway. We present here a detailed and curated map of the syncytial apoptosis signaling network, aimed at simplifying the whole mechanism that we have characterized at the molecular level in the last 15 years. The map was created using Systems Biology Graphical Notation language with the help of CellDesigner software and encompasses 36 components (proteins/genes) and 54 interactions. The simplification of this complex network paves the way for the development of novel therapeutic strategies to eradicate HIV-1 infection. Agents that induce the selective death of HIV-1-elicited syncytia might lead to the elimination of viral reservoirs and hence constitute an important complement to current antiretroviral therapies. PMID- 26247732 TI - Chop deficiency prevents UUO-induced renal fibrosis by attenuating fibrotic signals originated from Hmgb1/TLR4/NFkappaB/IL-1beta signaling. AB - Renal fibrosis, particularly tubulointerstitial fibrosis is considered to be the final manifestation of almost all chronic kidney diseases (CKDs). Herein we demonstrated evidence that CHOP-related ER stress is associated with the development of renal fibrosis in both CKD patients and unilateral ureteral obstruction (UUO)-induced animals, and specifically, mice deficient in Chop were protected from UUO-induced renal fibrosis. Mechanistic studies revealed that loss of Chop protected tubular cells from UUO-induced apoptosis and secondary necrosis along with attenuated Hmgb1 passive release and active secretion. As a result, Chop deficiency suppressed Hmgb1/TLR4/NFkappaB signaling, which then repressed UUO-induced IL-1beta production. Consequently, the IL-1beta downstream Erk1/2 activity and its related c-Jun transcriptional activity were reduced, leading to attenuated production of TGF-beta1 following UUO insult. It was further noted that reduced IL-1beta production also inhibited UUO-induced PI3K/AKT signaling, and both of which ultimately protected mice from UUO-induced renal fibrosis. Together, our data support that suppression of CHOP expression could be a viable therapeutic strategy to prevent renal fibrosis in patients with CKDs. PMID- 26247733 TI - Protein tyrosine kinase 6 promotes ERBB2-induced mammary gland tumorigenesis in the mouse. AB - Protein tyrosine kinase 6 (PTK6) expression, activation, and amplification of the PTK6 gene have been reported in ERBB2/HER2-positive mammary gland cancers. To explore contributions of PTK6 to mammary gland tumorigenesis promoted by activated ERBB2, we crossed Ptk6-/- mice with the mouse mammary tumor virus-ERBB2 transgenic mouse line expressing activated ERBB2 and characterized tumor development and progression. ERBB2-induced tumorigenesis was significantly delayed and diminished in mice lacking PTK6. PTK6 expression was induced in the mammary glands of ERBB2 transgenic mice before tumor development and correlated with activation of signal transducer and activator of transcription 3 (STAT3) and increased proliferation. Disruption of PTK6 impaired STAT3 activation and proliferation. Phosphorylation of the PTK6 substrates focal adhesion kinase (FAK) and breast cancer anti-estrogen resistance 1 (BCAR1; p130CAS) was decreased in Ptk6-/- mammary gland tumors. Reduced numbers of metastases were detected in the lungs of Ptk6-/- mice expressing activated ERBB2, compared with wild-type ERBB2 transgenic mice. PTK6 activation was detected at the edges of ERBB2-positive tumors. These data support roles for PTK6 in both ERBB2-induced mammary gland tumor initiation and metastasis, and identify STAT3, FAK, and BCAR1 as physiologically relevant PTK6 substrates in breast cancer. Including PTK6 inhibitors as part of a treatment regimen could have distinct benefits in ERBB2/HER2-positive breast cancers. PMID- 26247734 TI - Silencing NFBD1/MDC1 enhances the radiosensitivity of human nasopharyngeal cancer CNE1 cells and results in tumor growth inhibition. AB - NFBD1 functions in cell cycle checkpoint activation and DNA repair following ionizing radiation (IR). In this study, we defined the NFBD1 as a tractable molecular target to radiosensitize nasopharyngeal carcinoma (NPC) cells. Silencing NFBD1 using lentivirus-mediated shRNA-sensitized NPC cells to radiation in a dose-dependent manner, increasing apoptotic cell death, decreasing clonogenic survival and delaying DNA damage repair. Furthermore, downregulation of NFBD1 inhibited the amplification of the IR-induced DNA damage signal, and failed to accumulate and retain DNA damage-response proteins at the DNA damage sites, which leaded to defective checkpoint activation following DNA damage. We also implicated the involvement of NFBD1 in IR-induced Rad51 and DNA-dependent protein kinase catalytic subunit foci formation. Xenografts models in nude mice showed that silencing NFBD1 significantly enhanced the antitumor activity of IR, leading to tumor growth inhibition of the combination therapy. Our studies suggested that a combination of gene therapy and radiation therapy may be an effective strategy for human NPC treatment. PMID- 26247735 TI - Tyr1068-phosphorylated epidermal growth factor receptor (EGFR) predicts cancer stem cell targeting by erlotinib in preclinical models of wild-type EGFR lung cancer. AB - Tyrosine kinase inhibitors (TKIs) have shown strong activity against non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. However, a fraction of EGFR wild-type (WT) patients may have an improvement in terms of response rate and progression-free survival when treated with erlotinib, suggesting that factors other than EGFR mutation may lead to TKI sensitivity. However, at present, no sufficiently robust clinical or biological parameters have been defined to identify WT-EGFR patients with greater chances of response. Therapeutics validation has necessarily to focus on lung cancer stem cells (LCSCs) as they are more difficult to eradicate and represent the tumor-maintaining cell population. Here, we investigated erlotinib response of lung CSCs with WT-EGFR and identified EGFR phosphorylation at tyrosine1068 (EGFRtyr1068) as a powerful biomarker associated with erlotinib sensitivity both in vitro and in preclinical CSC-generated xenografts. In contrast to the preferential cytotoxicity of chemotherapy against the more differentiated cells, in EGFRtyr1068 cells, erlotinib was even more active against the LCSCs compared with their differentiated counterpart, acquiring potential value as CSC-directed therapeutics in the context of WT-EGFR lung cancer. Although tumor growth was inhibited to a similar extent during erlotinib or chemotherapy administration to responsive tumors, erlotinib proved superior to chemotherapy in terms of higher tolerability and reduced tumor aggressiveness after treatment suspension, substantiating the possibility of preferential LCSC targeting, both in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) tumors. We conclude that EGFRtyr1068 may represent a potential candidate biomarker predicting erlotinib response at CSC-level in EGFR-WT lung cancer patients. Finally, besides its invariable association with erlotinib sensitivity in EGFR-WT lung CSCs, EGFRtyr1068 was associated with EGFR-sensitizing mutations in cell lines and patient tumors, with relevant diagnostic, clinical and therapeutic implications. PMID- 26247738 TI - Low-value care for acute sinusitis encounters: who's choosing wisely? AB - OBJECTIVES: To assess acute sinusitis (AS) encounters in primary care (PC), urgent care (UC), and emergency department (ED) settings for adherence to recommendations to avoid low-value care. STUDY DESIGN: A retrospective, observational study of adult AS encounters (2010-2012) within a large integrated healthcare system. METHODS: We compared ED and UC encounters with PC visits, adjusting for differences in patient characteristics. PRIMARY OUTCOMES: adherence to recommendations to avoid antibiotics and a computed tomography (CT) scan of the face, head, or sinuses. SECONDARY OUTCOMES: length of symptoms and adherence with AS recommendations. RESULTS: Of 152,774 AS encounters, 89.2% resulted in antibiotics and 1.1% resulted in a CT scan. Compared with PC encounters, ED encounters were less likely to result in antibiotics (adjusted odds ratio [AOR], 0.57; 95% CI, 0.50-0.65) but more likely to result in a CT scan (AOR, 59.4; 95% CI, 51.3-68.7), while UC encounters were more likely to result in both antibiotics (AOR, 1.12; 95% CI, 1.08-1.17) and CT imaging (AOR, 2.4; 95% CI, 2.1 2.7). Chart review of encounters resulting in antibiotics found that 50% were inappropriately prescribed for symptoms of <=7 days' duration (95% CI, 41%-58%), while 35% were appropriately prescribed for symptoms of >=14 days' duration (95% CI, 27%-44%). Only 29% (95% CI, 22%-36%) of encounters were consistent with guideline-adherent care. CONCLUSIONS: AS encounters in an integrated health system infrequently result in CT imaging, but antibiotic treatment is common. Differences exist across acute care settings, but improved antibiotic stewardship is needed in all settings. PMID- 26247737 TI - Assessment of p53 and ATM functionality in chronic lymphocytic leukemia by multiplex ligation-dependent probe amplification. AB - The ATM-p53 DNA-damage response (DDR) pathway has a crucial role in chemoresistance in CLL, as indicated by the adverse prognostic impact of genetic aberrations of TP53 and ATM. Identifying and distinguishing TP53 and ATM functional defects has become relevant as epigenetic and posttranscriptional dysregulation of the ATM/p53 axis is increasingly being recognized as the underlying cause of chemoresistance. Also, specific treatments sensitizing TP53- or ATM-deficient CLL cells are emerging. We therefore developed a new ATM-p53 functional assay with the aim to (i) identify and (ii) distinguish abnormalities of TP53 versus ATM and (iii) enable the identification of additional defects in the ATM-p53 pathway. Reversed transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) was used to measure ATM and/or p53-dependent genes at the RNA level following DNA damage using irradiation. Here, we showed that this assay is able to identify and distinguish three subgroups of CLL tumors (i.e., TP53 defective, ATM-defective and WT) and is also able to detect additional samples with a defective DDR, without molecular aberrations in TP53 and/or ATM. These findings make the ATM-p53 RT-MLPA functional assay a promising prognostic tool for predicting treatment responses in CLL. PMID- 26247736 TI - MiR-26a functions oppositely in osteogenic differentiation of BMSCs and ADSCs depending on distinct activation and roles of Wnt and BMP signaling pathway. AB - MicroRNAs (miRNAs) emerge as important regulators of stem cell lineage commitment and bone development. MiRNA-26a (miR-26a) is one of the important miRNAs regulating osteogenic differentiation of both bone marrow-derived mesenchymal stem cells (BMSCs) and adipose tissue-derived mesenchymal stem cells (ADSCs). However, miR-26a functions oppositely in osteogenic differentiation of BMSCs and ADSCs, suggesting distinct post-transcriptional regulation of tissue-specific MSC differentiation. However, the molecular basis is largely unknown. Here, we report that the function of miR-26a is largely depended on the intrinsic signaling regulation network of MSCs. Using bioinformatics and functional assay, we confirmed that miR-26a potentially targeted on GSK3beta and Smad1 to regulate Wnt and BMP signaling pathway. Overall comparative analysis revealed that Wnt signaling was enhanced more potently and played a more important role than BMP signaling in osteogenic differentiation of BMSCs, whereas BMP pathway was more essential for promoting osteogenic differentiation of ADSCs. The distinct activation pattern and role of signaling pathways determined that miR-26a majorly targeted on GSK3beta to activate Wnt signaling for promoting osteogenic differentiation of BMSCs, whereas it inhibited Smad1 to suppress BMP signaling for interfering with the osteogenic differentiation of ADSCs. Taken together, our study demonstrated that BMSCs and ADSCs applied different signaling pathway to facilitate their osteogenic differentiation, which determined the inverse function of miR-26a. The distinct transcriptional regulation and post transcriptional regulation network suggested the intrinsic molecular differences between tissue-specific MSCs and the complexity in MSC research and MSC-based cell therapy. PMID- 26247739 TI - Usefulness of pharmacy claims for medication reconciliation in primary care. AB - OBJECTIVES: Methods for efficient medication reconciliation are increasingly important in primary care. Aggregated pharmacy data within the native electronic health record (EHR) may create a new opportunity for efficient and systematic medication reconciliation in practice. Our objective was to identify the prevalence and predictors of medication discrepancies between pharmacy claims data and the medication list in a primary care EHR. STUDY DESIGN: Retrospective cohort study. METHODS: We conducted a retrospective cohort study of patients prescribed a new antihypertensive in a large primary care practice network between January 2011 and September 2012. We compared patients' active medications recorded in the practice EHR with those listed in pharmacy claims data available through the EHR. The primary outcome was the presence of a medication discrepancy. RESULTS: Of 609 patients, 468 (76.9%) had at least 1 medication discrepancy. Significant predictors of discrepancies included the total medication count (odds ratio [OR], 2.18; 95% CI, 1.85-2.57) and having a recent emergency department visit (OR, 2.58; 95% CI, 1.03-6.45). The identified discrepancies included 171 patients (28.1%) with 229 controlled substance discrepancies. CONCLUSIONS: Our study revealed a high rate of discrepancies between pharmacy claims data and the provider medication list. Aggregated pharmacy claims data available through the EHR may be an important tool to facilitate medication reconciliation in primary care. PMID- 26247740 TI - Determinants of Medicare plan choices: are beneficiaries more influenced by premiums or benefits? AB - OBJECTIVES: To evaluate the sensitivity of Medicare beneficiaries to premiums and benefits when selecting healthcare plans after the introduction of Part D. STUDY DESIGN: We matched respondents in the 2008 Medicare Current Beneficiary Survey to the Medicare Advantage (MA) plans available to them using the Bid Pricing Tool and previously unavailable data on beneficiaries' plan choices. METHODS: We estimated a 2-stage nested logit model of Medicare plan choice decision making, including the decision to choose traditional fee-for-service (FFS) Medicare or an MA plan, and for those choosing MA, which specific plan they chose. RESULTS: Beneficiaries living in areas with higher average monthly rebates available from MA plans were more likely to choose MA rather than FFS. When choosing MA plans, beneficiaries are roughly 2 to 3 times more responsive to dollars spent to reduce cost sharing than reductions in their premium. We calculated an elasticity of plan choice with respect to the monthly MA premium of -0.20. Beneficiaries with lower incomes are more sensitive to plan premiums and cost sharing than higher income beneficiaries. CONCLUSIONS: MA plans appear to have a limited incentive to aggressively price their products, and seem to compete primarily over reduced beneficiary cost sharing. Given the limitations of the current plan choice environment, policies designed to encourage the selection of lower-cost plans may require increasing premium differences between plans and providing the tools to enable beneficiaries to easily assess those differences. PMID- 26247742 TI - No longer a unicorn: improving health through accountable care organizations. PMID- 26247741 TI - ACA-mandated elimination of cost sharing for preventive screening has had limited early impact. AB - OBJECTIVES: The Affordable Care Act eliminated patient cost sharing for evidence based preventive care, yet the impact of this policy on colonoscopy and mammography rates is unclear. We examined the elimination of cost sharing among small business beneficiaries of Humana, a large national insurer. STUDY DESIGN: This was a retrospective interrupted time series analysis of whether the change in cost-sharing policy was associated with a change in screening utilization, using grandfathered plans as a comparison group. METHODS: We compared beneficiaries in small business nongrandfathered plans that were required to eliminate cost sharing (intervention) with those in grandfathered plans that did not have to change cost sharing (control). There were 63,246 men and women aged 50 to 64 years eligible for colorectal cancer screening, and 30,802 women aged 50 to 64 years eligible for breast cancer screening. The primary outcome variables were rates of colonoscopy and mammography per person-month, with secondary analysis of colonoscopy rates coded as preventive only. RESULTS: There was no significant change in the level or slope of colonoscopy and mammography utilization for intervention plans relative to the control plans. There was also no significant relevant change among those colonoscopies coded as preventive. CONCLUSIONS: The results suggest that the implementation of the policy is not having its intended effects, as cost sharing rates for colonoscopy and mammography did not change substantially, and utilization of colonoscopy and mammography changed little, following this new policy approach. PMID- 26247743 TI - Chloe's Law: A Powerful Legislative Movement Challenging a Core Ethical Norm of Genetic Testing. AB - Since the early 1970s, the ethical norm governing counselors involved in testing and screening for genetic conditions related to reproduction has been strict neutrality. Counseling about reproductive genetics was to be patient centered but nondirective. Many advocates for people with Down syndrome believe that high abortion rates following a diagnosis of this condition show an unfounded bias against those with Down syndrome. These advocates have succeeded in enacting federal and state legislation that requires women who receive a prenatal diagnosis of Down syndrome to receive positive information about the condition, thereby ending the nominal goal of value-neutral counseling and setting the stage for further normative shifts in clinical reproductive genetics as counseling expands because of cell-free testing. PMID- 26247744 TI - Mixture-based gatekeeping procedures for multiplicity problems with multiple sequences of hypotheses. AB - Complex multiplicity problems arise in drug development programs with several sets of clinical objectives. This article considers a common setting with two sources of multiplicity induced by the analysis of multiple dose levels based on ordered endpoints. This results in multiplicity problems with multiple sequences of null hypotheses of no effect. Type I error rate inflation in problems of this type is typically addressed by using gatekeeping procedures that account for the hierarchical structure of the trial objectives. A general method for building gatekeeping procedures, known as the mixture method, tends to be conservative in problems with several sequences of hypotheses. This article defines a modified mixture method and shows that this method provides a power advantage over the standard mixture method. In addition, it is demonstrated that in special cases the modified mixture method allows for a stepwise testing algorithm, which facilities the implementation of gatekeeping procedures and general decision making. The new methodology is illustrated using two clinical trial examples. PMID- 26247745 TI - Enhanced Lithium-Ion Storage Capability of a Bismuth Sulfide/Graphene Oxide/Poly(3,4-ethylenedioxythiophene) Composite. AB - A Bi2 S3 /graphene oxide (GO) composite enwrapped by a poly(3,4 ethylenedioxythiophene) (PEDOT) coating was prepared for the first time for use as an anode in Li-ion batteries. Pristine Bi2 S3 nanoflowers and composites of Bi2 S3 /GO and Bi2 S3 /GO/PEDOT were assembled into half cells with Li metal as the counter electrode, and initial discharge capacities of 833, 1020, and 1300 mAh g(-1) , respectively, were obtained. Composites of Bi2 S3 /GO/PEDOT and Bi2 S3 /GO showed superior cycling stability and better rate capability than pristine Bi2 S3 . GO provides highly conducting interconnections, which allow facile propagation of electrons during charge/discharge, and this improves the ion uptake capability of the Bi2 S3 nanoflowers and also increases the rate capability. PEDOT furnishes a protective coating that prevents detachment of the material from the current collector during cycling, and it also imparts better cycling stability to the Bi2 S3 /GO/PEDOT composite. PMID- 26247746 TI - Conception and evaluation of a 3D musculoskeletal finite element foot model. PMID- 26247747 TI - The natural degradation of benzophenone at low concentration in aquatic environments. AB - The natural degradation caused by sun irradiation and microbes in aquatic environments is of major significance in the elimination process of benzophenone (BP). In this study, the fate of BP in surface water at a low concentration of 10 MUg/L was investigated, including both photodegradation and microbial degradation. The result showed that the photodegradation rate of BP was affected by several parameters such as the initial concentration, continuous input, and the presence of the analogue, ions and small molecules. Meanwhile, the rate of microbial degradation of BP was mainly influenced by the kind and amount of microbes in the environmental water. PMID- 26247748 TI - Energy performance indicators of wastewater treatment: a field study with 17 Portuguese plants. AB - The energy costs usually represent the second largest part of the running costs of a wastewater treatment plant (WWTP). It is therefore crucial to increase the energy efficiency of these infrastructures and to implement energy management systems, where quantitative performance metrics, such as performance indicators (PIs), play a key role. This paper presents energy PIs which cover the unit energy consumption, production, net use from external sources and costs, and the results used to validate them and derive their reference values. The results of a field study with 17 Portuguese WWTPs (5-year period) were consistent with the results obtained through an international literature survey on the two key parcels of the energy balance--consumption and production. The unit energy consumption showed an overall inverse relation with the volume treated, and the reference values reflect this relation for trickling filters and for activated sludge systems (conventional, with coagulation/filtration (C/F) and with nitrification and C/F). The reference values of electrical energy production were derived from the methane generation potential (converted to electrical energy) and literature data, whereas those of energy net use were obtained by the difference between the energy consumption and production. PMID- 26247749 TI - Influence of dissolved oxygen concentration on the start-up of the anammox-based process: ELAN(r). AB - The anammox-based process ELAN(r) was started-up in two different sequencing batch reactor (SBR) pilot plant reactors treating municipal anaerobic digester supernatant. The main difference in the operation of both reactors was the dissolved oxygen (DO) concentration in the bulk liquid. SBR-1 was started at a DO value of 0.4 mg O2/L whereas SBR-2 was started at DO values of 3.0 mg O2/L. Despite both reactors working at a nitrogen removal rate of around 0.6 g N/(L d), in SBR-1, granules represented only a small fraction of the total biomass and reached a diameter of 1.1 mm after 7 months of operation, while in SBR-2 the biomass was mainly composed of granules with an average diameter of 3.2 mm after the same operational period. Oxygen microelectrode profiling revealed that granules from SBR-2 where only fully penetrated by oxygen with DO concentrations of 8 mg O2/L while granules from SBR-1 were already oxygen penetrated at DO concentrations of 1 mg O2/L. In this way granules from SBR-2 performed better due to the thick layer of ammonia oxidizing bacteria, which accounted for up to 20% of all the microbial populations, which protected the anammox bacteria from non suitable liquid media conditions. PMID- 26247750 TI - Enhancing nitrogen and phosphorus removal in the BUCT-IFAS process by bypass flow strategy. AB - A University of Cape Town process coupled with integrated fixed biofilm and activated sludge system was modified by bypass flow strategy (BUCT-IFAS) to enhance nitrogen and phosphorus removal from the wastewater containing insufficient carbon source. This process was operated under different bypass flow ratios (lambda were 0, 0.4, 0.5, 0.6 and 0.7, respectively) to investigate the effect of different operational modes on the nitrogen (N) and phosphorus (P) removal efficiency (lambda=0 was noted as common mode, other lambda were noted as bypass flow mode), and optimizing the N and P removal efficiency by altering the lambda. Results showed that the best total nitrogen (TN) and total phosphorus (TP) removal performances were achieved at lambda of 0.6, the effluent TN and TP averaged 14.0 and 0.4 mg/L meeting discharge standard (TN<15 mg/L, TP<0.5 mg/L). Correspondingly, the TN and TP removal efficiencies were 70% and 94%, respectively, which were 24 and 41% higher than those at lambda of 0. In addition, the denitrification and anoxic P-uptake rates were increased by 23% and 23%, respectively, compared with those at lambda of 0. These results demonstrated that the BUCT-IFAS process was an attractive method for enhancing nitrogen and phosphorus removal from wastewater containing insufficient carbon source. PMID- 26247751 TI - Evaluation of EPS extraction protocols from anaerobic sludge for gel-based proteomic studies. AB - Despite the importance of anaerobic sludge extracellular polymeric substances (EPSs), their characterization is limited to information regarding their chemical classes and molecular size. This work explores the possibility of using proteomic techniques to study the proteins present in this matrix. Thus, this paper compares eight EPS extraction methods regarding extraction yield, protein/carbohydrate ratio, size distribution profile and suitability to sodium dodecyl sulfate-polyacrylamide gel electrophoresis analyses. Despite the differences found in quantification and size exclusion chromatography assays, the band profile found for all methods was very similar. Considering the band pattern, extraction time and background level, heating method followed by ammonium sulfate precipitation proved to be the most appropriate method for gel based analyses of anaerobic sludge EPS proteins. PMID- 26247752 TI - Investigation of the effects of temperature and sludge characteristics on odors and VOC emissions during the drying process of sewage sludge. AB - Sludge drying is a necessary step for sludge disposal. In this study, sludge was collected from two wastewater treatment plants, and dried at different temperatures in the laboratory. The emission of odor and total volatile organic compounds (TVOCs) during the sludge drying process were determined by an online odor monitoring system. The volatile organic compounds (VOCs) in off-gas were analyzed by gas chromatography-mass spectrometry. Results showed that sludge with 30% moisture content could be obtained in 51 minutes under drying temperature 100 degrees C but only within 27 minutes under 150 degrees C. Concentration of odor, TVOCs, sulfur-containing compounds (SCCs), and amines were changed with drying temperature and sludge sources. The maximum concentration of odor, TVOCs, SCCs, and amines were 503.13 ppm, 3.01 ppm, 8.15 ppm, and 11.27 ppm, respectively, at drying temperature 100 degrees C. These values reached 1,250.79, 8.10, 53.51, and 37.80 ppm when sludge dried at 150 degrees C. Odor concentration had a close relationship with emission of SCCs, amines, and TVOCs. The main VOCs released were benzene series and organic acid. Potential migration of substances in sludge was examined via analysis of off-gas and condensate, aiming to provide scientific data for effective sludge treatment and off-gas control. PMID- 26247753 TI - Field application of a planted fixed bed reactor (PFR) for support media and rhizosphere investigation using undisturbed samples from full-scale constructed wetlands. AB - This study presents a novel method for investigations on undisturbed samples from full-scale horizontal subsurface-flow constructed wetlands (HSSFCW). The planted fixed bed reactor (PFR), developed at the Helmholtz Center for Environmental Research (UFZ), is a universal test unit for planted soil filters that reproduces the operational conditions of a constructed wetland (CW) system in laboratory scale. The present research proposes modifications on the PFR original configuration in order to allow its operation in field conditions. A mobile device to obtain undisturbed samples from real-scale HSSFCW was also developed. The experimental setting is presented with two possible operational configurations. The first allows the removal and replacement of undisturbed samples in the CW bed for laboratory investigations, guaranteeing sample integrity with a mobile device. The second allows the continuous operation of the PFR and undisturbed samples as a fraction of the support media, reproducing the same environmental conditions outside the real-scale system. Investigations on the hydrodynamics of the adapted PFR were carried out with saline tracer tests, validating the proposed adaptation. Six adapted PFR units were installed next to full-scale HSSFCW beds and fed with interstitial liquid pumped from two regions of planted and unplanted support media. Fourteen points were monitored along the system, covering carbon fractions, nitrogen and sulfate. The results indicate the method as a promising tool for investigations on CW support media, rhizosphere and open space for studies on CW modeling, respirometry, kinetic parameters, microbial communities, redox potential and plant influence on HSSFCW. PMID- 26247754 TI - Effect of organic fouling on micro-pollutant rejection in membrane bioreactor treating municipal solid waste landfill leachate. AB - Effect of membrane fouling on the removal of micro-pollutants from municipal solid waste landfill leachate, i.e. 4-methyl-2,6-di-tert-butylphenol (BHT), bisphenol A (BPA), and bis(2-ethylhexyl)phthalate (DEHP), in membrane bioreactor (MBR) was investigated. Modifications of membrane surface properties were analyzed to determine their relationship with their removals. Membrane fouling was simulated with foulants of different particle sizes on cellulose acetate (CA) microfiltration membrane to investigate the effect of foulant characteristics on BHT, BPA, and DEHP retention in the filtration experiment. The rejection efficiencies of the organic micro-pollutants in the MBR were 82-97% by fouled membrane, and 70-90% by cleaned membrane. The fouled membrane provided higher rejection of micro-pollutants from about 5% for BPA and BHT to 19% for DEHP. These improvements were due to the modification of membrane surface characteristics in terms of surface morphology, and contact angle after membrane fouling. The degree of rejection was found to be dependent upon the characteristics of foulant deposited on CA membrane surface. Increasing foulant particle size and its density shifted the mechanism of micro-pollutant rejection from membrane pore narrowing to pore blocking and cake formation while increasing pollutant adsorption capacity onto the foulant layer. PMID- 26247755 TI - Effect of carbon sources on nitrous oxide emission in a modified Ludzak Ettinger process. AB - Effect of methanol and glycerol on nitrous oxide (N2O) emission in two laboratory scale modified Ludzak Ettinger (MLE) processes was investigated during three distinct periods: dissolved oxygen (DO) control by intermittent aeration with a DO controller, and high and low aeration rates. N2O consumption rate in an anoxic tank and aeration mode influenced N2O emission rates from the MLE processes. In the DO control period, N2O emission rate from the glycerol-fed MLE process was higher than the methanol-fed counterpart, likely caused by a higher N2O consumption rate in an anoxic tank of the methanol-fed process. During the period of a higher aeration rate, N2O emission rates from both processes were comparable. In contrast, during the period of a lower aeration rate, N2O emission rate from the methanol-fed MLE process was higher than that from the glycerol-fed counterpart likely because of a higher degree of nitrite accumulation, corroborated by statistical analysis. N2O consumption activities of biomasses fed with the different carbon sources were distinct. However, the high activity did not necessarily result in a decrease in N2O emission rate from an aerobic tank and the effect of nitrite on the emission was stronger under the tested conditions. PMID- 26247756 TI - Cultivation of rice for animal feed with circulated irrigation of treated municipal wastewater for enhanced nitrogen removal: comparison of cultivation systems feeding irrigation water upward and downward. AB - To achieve enhanced nitrogen removal, we modified a cultivation system with circulated irrigation of treated municipal wastewater by using rice for animal feed instead of human consumption. The performance of this modified system was evaluated through a bench-scale experiment by comparing the direction of circulated irrigation (i.e. passing through paddy soil upward and downward). The modified system achieved more than three times higher nitrogen removal (3.2 g) than the system in which rice for human consumption was cultivated. The removal efficiency was higher than 99.5%, regardless of the direction of circulated irrigation. Nitrogen in the treated municipal wastewater was adsorbed by the rice plant in this cultivation system as effectively as chemical fertilizer used in normal paddy fields. Circulated irrigation increased the nitrogen released to the atmosphere, probably due to enhanced denitrification. Neither the circulation of irrigation water nor its direction affected the growth of the rice plant and the yield and quality of harvested rice. The yield of rice harvested in this system did not reach the target value in normal paddy fields. To increase this yield, a larger amount of treated wastewater should be applied to the system, considering the significant amount of nitrogen released to the atmosphere. PMID- 26247757 TI - Anaerobic digestion of waste biomass from the production of L-cystine in suspended-growth bioreactors. AB - Waste biomass from the industrial production of the amino acid L-cystine contains above-average concentrations of organic pollutants and significant concentrations of nitrogen and sulfur. The specific biogas production (SBP) of waste biomass was monitored in parallel suspended-growth laboratory anaerobic bioreactors. After severe inhibition was observed, three different procedures were applied to inhibited reactor sludge to counter-attack the inhibitory effects of sulfides, respectively hydrogen sulfide: micro-aeration, dilution with water and precipitation by ferrous iron cations. The performance of bioreactors was weekly monitored. Organic loading rates (as chemical oxygen demand, COD) ranged from 1.07 to 1.97 g L(-1) d(-1). At the end of the experimentation, SBP averaged 217, 300 and 320 l kg(-1) COD with a methane content of 21%, 52% and 54%; specific sludge production averaged 133, 111 and 400 g total solids kg(-1) COD, and inhibition was 49%, 27% and 25%; for the applied procedures of micro-aeration, dilution and precipitation respectively. PMID- 26247758 TI - Nitrite and nitrate as electron acceptors for biological sulphide oxidation. AB - Autotrophic denitrification with sulphide using nitrate (R1) and nitrite (R2) as electron acceptor was investigated at bench scale. Different solids retention times (SRT) (5 and 20 d) have been tested in R1 while R2 was operated at SRT=13 d. The results indicated that the process allows complete sulphide removal to be achieved in all tested conditions. Tested sulphide loads were estimated from the H2S produced in a pilot-scale anaerobic digester treating vegetable tannery primary sludge; nitrogen loads originated from the nitrification of the supernatant. Average nitrogen removal efficiencies higher than 80% were observed in all the tested conditions once steady state was reached. A maximum specific nitrate removal rate equal to 0.35 g N-NO3- g VSS(-1) d(-1) was reached in R1. Due to sulphide limitation, incomplete denitrification was observed and nitrite and thiosulphate tend to accumulate especially in the presence of variable environmental conditions in both R1 and R2. Lower SRT caused higher NO2accumulated/NO3reduced ratios (0.22 and 0.24, with SRT of 5 d and 20 d, respectively) using nitrate as electron acceptor in steady-state condition. Temperature decrease caused sudden NO2accumulated/NO3reduced ratio increase in R1 and NO2- removal decrease in R2. PMID- 26247759 TI - Enhanced phosphorus removal in the DAF process by flotation scum recycling for advanced treatment of municipal wastewater. AB - To remove phosphorus (P) from municipal wastewater, various types of advanced treatment processes are being actively applied. However, there is commonly a space limit in municipal wastewater treatment plants (MWTPs). For that reason, the dissolved air flotation (DAF), which is well known for small space and flexible application process, is preferred as an additive process to enhance the removal of P. A series of experiments were conducted to investigate the feasibility of flotation scum recycling for effective P removal from a MWTP using a DAF pilot plant over 1 year. The average increases in the removal efficiencies due to flotation scum recycling were 22.6% for total phosphorus (T-P) and 18.3% for PO4-P. A higher removal efficiency of T-P was induced by recycling the flotation scum because a significant amount of Al components remained in the flotation scum. The increase in T-P removal efficiency, due to the recycling of flotation scum, shifted from the boundary of the stoichiometric precipitate to the equilibrium control region. Flotation scum recycling may contribute to improving the quality of treated water and reducing treatment costs by minimizing the coagulant dosage required. PMID- 26247760 TI - Removal of cadmium(II) ions from aqueous solution using Ni (15 wt.%)-doped alpha Fe2O3 nanocrystals: equilibrium, thermodynamic, and kinetic studies. AB - The present publication investigates the performance of nanocrystalline Ni (15 wt.%)-doped alpha-Fe2O3 as an effective nanomaterial for the removal of Cd(II) ions from aqueous solutions. The nanocrystalline Ni-doped alpha-Fe2O3 powders were prepared by mechanical alloying, and characterized by X-ray diffraction and a vibrating sample magnetometer. Batch-mode experiments were realized to determine the adsorption equilibrium, kinetics, and thermodynamic parameters of toxic heavy metal ions by Ni (15 wt.%)-doped alpha-Fe2O3. The adsorption isotherms data were found to be in good agreement with the Langmuir model. The adsorption capacity of Cd(II) ion reached a maximum value of about 90.91 mg g(-1) at 328 K and pH 7. The adsorption process kinetics was found to comply with pseudo-second-order rate law. Thermodynamic parameters related to the adsorption reaction, free energy change, enthalpy change and entropy change, were evaluated. The found values of free energy and enthalpy revealed a spontaneous endothermic adsorption-process. Moreover, the positive entropy suggests an increase of randomness during the process of heavy metal removal at the adsorbent-solution interface. PMID- 26247761 TI - Factors affecting trihalomethane formation and speciation during chlorination of reclaimed water. AB - A hybrid process with membrane bioreactor (MBR) and powdered activated carbon (PAC), PAC/MBR, was used for real municipal wastewater treatment and reuse. The roles of chlorine dose, contact time, pH and bromide in trihalomethane (THM) formation and speciation during chlorination of the reclaimed water were investigated. Total trihalomethane (TTHM) yield exponentially increased to maximum with increasing chlorine dose (correlation coefficient R2=0.98). Prolonging substrate chlorine contact time significantly promoted TTHM formation. Less than 40% of THMs formed in the first 24 h, indicating that the PAC/MBR effluent organic matters were mostly composed of slow-reacting precursors. Increasing pH and bromide concentration facilitated THM formation. Higher chlorine dose and contact time enhanced chloro-THM formation. The bromo-THM formation was favored at near neutral condition. Despite the variation of chlorine dose, contact time and pH, the yield of THM species in order was usually CHCl3>CHBrCl2>CHBr2Cl>CHBr3. However, THM speciation shifted from chlorinated species to brominated species with increasing bromide concentration. PMID- 26247762 TI - Micellar-enhanced ultrafiltration for the solubilization of various phenolic compounds with different surfactants. AB - Micellar-enhanced ultrafiltration (MEUF) was applied to the separation of phenolic compounds p-nitrophenol (PNP), p-chlorophenol (PCP), p-cresol (PC) and phenol (P) from effluents using a hydrophilic polyethersulfone ultrafiltration membrane. Cationic cetylpyridinium chloride (CPC), nonionic TX-100 and anionic sodium dodecyl benzene sulfonate (SDBS) were chosen as the surfactants. Several important parameters, i.e. the separation efficiency, the distribution coefficient of phenolic compounds and the removal ratio of surfactants, were investigated. It was shown that the separation efficiency and the distribution coefficient of phenolic compounds ascended with the increasing surfactant concentration and could be arranged as the following order: PNP>PCP>PC>P. Moreover, in the case of phenolic compound separation, CPC achieved the highest treatment efficiency, and the separation efficiency of SDBS was a little lower than that of TX-100. The removal ratios of the same surfactant when treating different phenolic effluents were nearly similar. However, when treating the same phenolic compound, the sequence of the surfactant rejection was in the following order: TX-100>CPC>SDBS. These results indicate that CPC has a distinct superiority in the treatment of phenolic effluents via the MEUF process, and PNP easily solubilizes in the surface of the micelles. PMID- 26247763 TI - Optimization of a mainstream nitritation-denitritation process and anammox polishing. AB - This paper deals with an almost 1-year long pilot study of a nitritation denitritation process that was followed by anammox polishing. The pilot plant treated real municipal wastewater at ambient temperatures. The effluent of high rate activated sludge process (hydraulic retention time, HRT=30 min, solids retention time=0.25 d) was fed to the pilot plant described in this paper, where a constant temperature of 23 degrees C was maintained. The nitritation denitritation process was operated to promote nitrite oxidizing bacteria out selection in an intermittently aerated reactor. The intermittent aeration pattern was controlled using a strategy based on effluent ammonia and nitrate+nitrite concentrations. The unique feature of this aeration control was that fixed dissolved oxygen set-point was used and the length of aerobic and anoxic durations were changed based on the effluent ammonia and nitrate+nitrite concentrations. The anaerobic ammonia oxidation (anammox) bacteria were adapted in mainstream conditions by allowing the growth on the moving bed bioreactor plastic media in a fully anoxic reactor. The total inorganic nitrogen (TIN) removal performance of the entire system was 75+/-15% during the study at a modest influent chemical oxygen demand (COD)/NH4+-N ratio of 8.9+/-1.8 within the HRT range of 3.1-9.4 h. Anammox polishing contributed 11% of overall TIN removal. Therefore, this pilot-scale study demonstrates that application of the proposed nitritation-denitritation system followed by anammox polishing is capable of relatively high nitrogen removal without supplemental carbon and alkalinity at a low HRT. PMID- 26247764 TI - Study of cyanide wastewater treatment by dispersion supported liquid membrane using trioctylamine and kerosene as liquid membrane. AB - A certain amount of cyanide is present in wastewater of various industrial processes, such as wet extraction of gold, coal processing, electroplating and other industries. In this work, an experimental study regarding transport of cyanide through a dispersion supported liquid membrane was performed. A model was established to describe the reaction and transport of CN(I) in the supported liquid membrane and the mass transfer kinetics equations were deduced. Through mass transfer kinetic equation it was derived that, when the carrier concentration was under certain conditions, there was a linear relationship between the reciprocal of the permeability coefficient of CN(I) (1/Pc) and n-th power of the concentration of H+ (cnH+), and the parameters Deltaa(deltaa/da) and Deltao(delta0/d0) could be obtained from the slope and intercept of the straight line. Then the diffusion coefficient do and the diffusion layer thickness deltao of the phase interface between the feed phase and membrane phase could be calculated. Factors affecting migration of CN(I) were analyzed, and the stable removal rate of CN(I) was more than 90% with carrier concentration (%TOA) of 2%, feed phase pH of 4, initial CN(I) concentration of 30 mg/L, stirring time of 1 hour, volume ratio of membrane solution to NaOH solution of 2:1, strip phase concentration of 2 mol/L. The results showed that the overall mass transfer rate increased first and then decreased with an increase of TOA concentration, organic to-strip volume ratio, and strip concentration. Furthermore, the transport percentage of CN(I) was increased, the stability of membrane was enhanced, and the lifetime of the membrane was extended. PMID- 26247765 TI - Effective carbon and nutrient treatment solutions for mixed domestic-industrial wastewater in India. AB - The present study evaluates effectiveness of up-flow anaerobic sludge blanket (UASB) reactor followed by two post-anaerobic treatment options, namely free surface, up-flow constructed wetland (FUP-CW) and oxygen-limited anaerobic nitrification/denitrification (OLAND) processes in treating sewage from the peri urban areas in India receiving illegal industrial infiltrations. The UASB studies yielded robust results towards fluctuating strength of sewage and consistently removed 87-98% chemical oxygen demand (COD) at a hydraulic retention time of 1.5 2 d. The FUP-CW removed 68.5+/-13% COD, 68+/-3% NH4+-N, 38+/-5% PO4(3-)-P, 97.6+/ 5% suspended particles and 97+/-13% fecal coliforms. Nutrient removal was found to be limiting in FUP-CW, especially in winter. Nitrogen removal in the OLAND process were 100 times higher than the FUP-CW process. Results show that UASB followed by FUP-CW can be an excellent, decentralized sewage treatment option, except during winter when nutrient removal is limited in FUP-CW. Hence, the study proposes bio-augmentation of FUP-CW with OLAND biomass for overall improvement in the performance of UASB followed by FUP-CW process. PMID- 26247766 TI - Rheological behaviors of anaerobic granular sludge in a spiral symmetry stream anaerobic bioreactor. AB - The rheological behaviors of the anaerobic granular sludge (AGS) in a spiral symmetry stream anaerobic bioreactor (SSSAB) were investigated. Shear-thinning behavior, thixotropic behavior, concentration-viscosity behavior and temperature viscosity behavior were evaluated based on the constitutive equation of the AGS. The results indicated that the Herschel-Bulkley model was able to adequately describe the constitutive relation of AGS in the SSSAB. The AGS also showed shear thinning behavior as well as thixotropic behavior. The critical shear rate and network strength of the AGS were 61.8 s(-1) and 497.0 W m(-3), respectively. The relationship between the apparent viscosity and the sludge concentration was illustrated and explained by the Woodcock formula. The relationship between apparent viscosity of the AGS and temperature could be modeled using the Arrhenius equation. The AGS was significantly thermo-sensitive and its mean energy of activation was 14.640 kJ mol(-1). Notably, it was necessary to consider such behaviors in the hydrodynamic modeling of SSSAB in which shear condition, sludge concentration and temperature were in non-uniform distribution. PMID- 26247767 TI - Catatonia and cannabis withdrawal: A case report. AB - BACKGROUND: Catatonia is a severe motor syndrome found in approximately 10% of all acute psychiatric hospital admissions. It can occur in various psychiatric diseases. The authors report the first case report of catatonia during cannabis withdrawal. CASE PRESENTATION: Mr. A, a 32-year-old man, reported to have smoked approximately 20 g of cannabis daily since the age of 11. Mr. A was incarcerated and was reported 3 weeks later to the medical department for having completely ceased talking and eating. At admission in the authors' department, the patient presented with classical catatonia symptoms (Bush-Francis Catatonia Rating Scale [BFCRS] score = 39/69). All laboratory results and brain magnetic resonance imaging (MRI) were normal. Six weeks after his admission and treatments by lorazepam and memantine, his BFCRS score was 0/69. DISCUSSION: This single case study highlights the previously underreported emergence of physical and motor symptoms following cannabis withdrawal. Pathophysiological aspects of abrupt cannabis cessation contributing to gamma-aminobutyric acid (GABA)/glutamate balance dysregulation and to catatonia are discussed. PMID- 26247768 TI - Case report of excessive hand sweating that alters blood sugar measurements. AB - We present a clinical case that we did not find described in literature and yet is quite common in primary care. The patient described is female with a diagnosis of diabetes mellitus treated with insulin and poor clinical response according to glycated haemoglobin measurements. In addition to the main diagnosis, she also shows excessive sweating in palms and feet, which explains why her blood sugar levels were wrong. This also led to treatment adjustments that were carried out with disregard to her true plasma glucose concentration. To conclude, this case report highlights the importance of treating subjects in lieu of separate conditions, as well as the need of a team approach to patients in care. PMID- 26247769 TI - The Effects of Perioperative Music Interventions in Pediatric Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: Music interventions are widely used, but have not yet gained a place in guidelines for pediatric surgery or pediatric anesthesia. In this systematic review and meta-analysis we examined the effects of music interventions on pain, anxiety and distress in children undergoing invasive surgery. DATA SOURCES: We searched 25 electronic databases from their first available date until October 2014. STUDY SELECTION: Included were all randomized controlled trials with a parallel group, crossover or cluster design that included pediatric patients from 1 month to 18 years old undergoing minimally invasive or invasive surgical procedures, and receiving either live music therapy or recorded music. DATA EXTRACTION AND SYNTHESIS: 4846 records were retrieved from the searches, 26 full text reports were evaluated and data was extracted by two independent investigators. MAIN OUTCOME MEASURES: Pain was measured with the Visual Analogue Scale, the Coloured Analogue Scale and the Facial Pain Scale. Anxiety and distress were measured with an emotional index scale (not validated), the Spielberger short State Trait Anxiety Inventory and a Facial Affective Scale. RESULTS: Three RCTs were eligible for inclusion encompassing 196 orthopedic, cardiac and day surgery patients (age of 1 day to 18 years) receiving either live music therapy or recorded music. Overall a statistically significant positive effect was demonstrated on postoperative pain (SMD -1.07; 95%CI-2.08; -0.07) and on anxiety and distress (SMD -0.34 95% CI -0.66; -0.01 and SMD -0.50; 95% CI 0.84; - 0.16. CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis indicates that music interventions may have a statistically significant effect in reducing post-operative pain, anxiety and distress in children undergoing a surgical procedure. Evidence from this review and other reviews suggests music therapy may be considered for clinical use. PMID- 26247770 TI - The Spleen Plays No Role in Nephrotoxic Serum Nephritis, but Constitutes a Place of Compensatory Haematopoiesis. AB - BACKGROUND: The spleen has been implicated in the pathogenesis of immune-complex glomerulonephritis by initiating and resolving adaptive immune responses. Thus, we aimed to evaluate the role of the spleen in experimental nephrotoxic serum nephritis (NTS). METHODS: In order to accelerate the disease, animals were subjected to NTS by preimmunizing male C57BL/6J mice with rabbit IgG three days before injecting the rabbit anti-glomerular basement antiserum, or were immunized only. A group underwent splenectomy before NTS induction. RESULTS: We observed enlargement of the spleen with a maximum at 14 days after NTS induction or immunization only. Splenectomized mice were found to develop albuminuria and renal histological changes comparable to sham-operated controls. Nevertheless, anaemia was aggravated in mice after splenectomy. During the course of NTS, we detected CD41+ megakaryocytes and Ter119+ erythroid precursor cells in the spleen of mice with NTS and of immunized mice. Ter119+Cxcr4+ cells and the binding partner Cxcl12 increased in the spleen, and decreased in the bone marrow. This was accompanied by a significant systemic increase of interferon-gamma in the serum. CONCLUSIONS: In summary, splenectomy does not influence the course of NTS per se, but is involved in concomitant anaemia. Extramedullary haematopoiesis in the spleen is probably facilitated through the migration of Cxcr4+ erythroid precursor cells from the bone marrow to the spleen via a Cxcl12 gradient and likely arises from the suppressive capacity of chronic inflammation on the bone marrow. PMID- 26247771 TI - Illuminating Targets of Bacterial Secretion. PMID- 26247772 TI - Vascular Risk Factors in Patients with Different Subtypes of Ischemic Stroke May Affect Their Outcome after Intravenous tPA. AB - Intravenous (i.v.) tissue-type plasminogen activator (tPA) is the only approved noninvasive therapy for acute ischemic stroke (AIS). However, after tPA treatment, the outcome of patients with different subtypes of stroke according to their vascular risk factors remains to be elucidated. We aim to explore the relationship between the outcome and different risk factors in patients with different subtype of acute strokes treated with i.v. tPA. Records of patients in this cohort were reviewed. Data collected and analysed included the demographics, vascular risk factors, baseline National Institutes of Health Stroke Scale (NIHSS) scores, 90-day modified Rankin Scores (mRS), and subtypes of stroke. By using the 90-day mRS, patients were dichotomized into favorable versus unfavorable outcome in each subtype of stroke. We identified the vascular risk factors that are likely associated with the poor outcome in each subtype. Among 570 AIS patients received i.v. tPA, 217 were in the large artery atherosclerosis (LAA) group, 146 in the small vessel occlusion (SVO) group, and 140 in the cardioaortic embolism (CE) group. Lower NIHSS score on admission was related to favorable outcome in patients in all subtypes. Patients with history of dyslipidemia were likely on statin treatment before their admission and hence less likely to have elevated cholesterol level on admission. Therefore, there was a possible paradoxical effect on the outcome in patients with LAA and SVO subtypes of strokes. SVO patients with history of diabetes had higher risk of unfavorable outcome. SVO patients had favorable outcome if their time from onset to treatment was short. In conclusion, the outcome of patients treated with i.v. tPA may be related to different vascular risk factors associated with different subtypes of stroke. PMID- 26247773 TI - Environmental Interactions and Epistasis Are Revealed in the Proteomic Responses to Complex Stimuli. AB - Ultimately, the genotype of a cell and its interaction with the environment determine the cell's biochemical state. While the cell's response to a single stimulus has been studied extensively, a conceptual framework to model the effect of multiple environmental stimuli applied concurrently is not as well developed. In this study, we developed the concepts of environmental interactions and epistasis to explain the responses of the S. cerevisiae proteome to simultaneous environmental stimuli. We hypothesize that, as an abstraction, environmental stimuli can be treated as analogous to genetic elements. This would allow modeling of the effects of multiple stimuli using the concepts and tools developed for studying gene interactions. Mirroring gene interactions, our results show that environmental interactions play a critical role in determining the state of the proteome. We show that individual and complex environmental stimuli behave similarly to genetic elements in regulating the cellular responses to stimuli, including the phenomena of dominance and suppression. Interestingly, we observed that the effect of a stimulus on a protein is dominant over other stimuli if the response to the stimulus involves the protein. Using publicly available transcriptomic data, we find that environmental interactions and epistasis regulate transcriptomic responses as well. PMID- 26247774 TI - Quantitative Trait Loci for Salinity Tolerance Identified under Drained and Waterlogged Conditions and Their Association with Flowering Time in Barley (Hordeum vulgare. L). AB - INTRODUCTION: Salinity is one of the major abiotic stresses affecting crop production via adverse effects of osmotic stress, specific ion toxicity, and stress-related nutritional disorders. Detrimental effects of salinity are also often exacerbated by low oxygen availability when plants are grown under waterlogged conditions. Developing salinity-tolerant varieties is critical to overcome these problems, and molecular marker assisted selection can make breeding programs more effective. METHODS: In this study, a double haploid (DH) population consisting of 175 lines, derived from a cross between a Chinese barley variety Yangsimai 1 (YSM1) and an Australian malting barley variety Gairdner, was used to construct a high density molecular map which contained more than 8,000 Diversity Arrays Technology (DArT) markers and single nucleotide polymorphism (SNP) markers. Salinity tolerance of parental and DH lines was evaluated under drained (SalinityD) and waterlogged (SalinityW) conditions at two different sowing times. RESULTS: Three quantitative trait loci (QTL) located on chromosome 1H, single QTL located on chromosomes 1H, 2H, 4H, 5H and 7H, were identified to be responsible for salinity tolerance under different environments. Waterlogging stress, daylight length and temperature showed significant effects on barley salinity tolerance. The QTL for salinity tolerance mapped on chromosomes 4H and 7H, QSlwd.YG.4H, QSlwd.YG.7H and QSlww.YG.7H were only identified in winter trials, while the QTL on chromosome 2H QSlsd.YG.2H and QSlsw.YG.2H were only detected in summer trials. Genes associated with flowering time were found to pose significant effects on the salinity QTL mapped on chromosomes 2H and 5H in summer trials. Given the fact that the QTL for salinity tolerance QSlsd.YG.1H and QSlww.YG.1H-1 reported here have never been considered in the literature, this warrants further investigation and evaluation for suitability to be used in breeding programs. PMID- 26247775 TI - Magnesium and iron deficiencies alter Cd accumulation in Salix viminalis L. AB - Evidence exists that Cd and certain nutrient elements, such as Fe and Mg, could share similar mechanisms of plant uptake and accumulation. Here we report that Mg and Fe deficiency in mature plants of Salix viminalis, grown in hydroponic solutions containing 5 ug ml(-1) of Cd, caused a significant increase in Cd accumulation in roots, stems and leaves. Cd (ug g(-1) dry weight) was determined following three treatments: 1) Cd treatment in complete nutrient solution; 2) Cd treatment with Fe deficiency; and 3) Cd treatment with Mg deficiency, yielding, respectively: in young leaves (65.3, 76.1, and 92.2), mature leaves (51.5 to 76.3 and 87.1), upper stems (80.6, 116.8, and 130.6) lower stems (67.2, 119, and 102.3), roots (377.1, 744.8, and 442,5). Our results suggest that Cd utilizes the same uptake and transport pathways as Mg and Fe. Evidence exists that Mg and Fe uptake and translocation could be further facilitated by plants as an adaptive response to deficiency of these elements. Such physiological reaction could additionally stimulate Cd accumulation. Although Cd uptake was mostly confined in roots, high Cd content in aerial plant parts (51.5-130.6 ug g(-1)) indicates that the analysed Salix viminalis genotype is suitable for phytoextraction. PMID- 26247777 TI - Li5Cr7Ti6O25 as a novel negative electrode material for lithium-ion batteries. AB - Novel submicron Li5Cr7Ti6O25, which exhibits excellent rate capability, high cycling stability and fast charge-discharge performance is constructed using a facile sol-gel method. The insights obtained from this study will benefit the design of new negative electrode materials for lithium-ion batteries. PMID- 26247776 TI - Slip Interface Imaging Predicts Tumor-Brain Adhesion in Vestibular Schwannomas. AB - PURPOSE: To test the clinical feasibility and usefulness of slip interface imaging (SII) to identify and quantify the degree of tumor-brain adhesion in patients with vestibular schwannomas. MATERIALS AND METHOD: S With institutional review board approval and after obtaining written informed consent, SII examinations were performed in nine patients with vestibular schwannomas. During the SII acquisition, a low-amplitude mechanical vibration is applied to the head with a pillow-like device placed in the head coil and the resulting shear waves are imaged by using a phase-contrast pulse sequence with motion-encoding gradients synchronized with the applied vibration. Imaging was performed with a 3 T magnetic resonance (MR) system in less than 7 minutes. The acquired shear motion data were processed with two different algorithms (shear line analysis and calculation of octahedral shear strain [OSS]) to identify the degree of tumor brain adhesion. Blinded to the SII results, neurosurgeons qualitatively assessed tumor adhesion at the time of tumor resection. Standard T2-weighted, fast imaging employing steady-state acquisition (FIESTA), and T2-weighted fluid-attenuated inversion recovery (FLAIR) imaging were reviewed to identify the presence of cerebral spinal fluid (CSF) clefts around the tumors. The performance of the use of the CSF cleft and SII to predict the degree of tumor adhesion was evaluated by using the kappa coefficient and McNemar test. RESULTS: Among the nine patients, SII agreed with the intraoperative assessment of the degree of tumor adhesion in eight patients (88.9%; 95% confidence interval [CI]: 57%, 98%), with four of four, three of three, and one of two cases correctly predicted as no adhesion, partial adhesion, and complete adhesion, respectively. However, the T2-weighted, FIESTA, and T2-weighted FLAIR images that used the CSF cleft sign to predict adhesion agreed with surgical findings in only four cases (44.4% [four of nine]; 95% CI: 19%, 73%). The kappa coefficients indicate good agreement (0.82 [95% CI: 0.5, 1]) for the SII prediction versus surgical findings, but only fair agreement (0.21 [95% CI: -0.21, 0.63]) between the CSF cleft prediction and surgical findings. However, the difference between the SII prediction and the CSF cleft prediction was not significant (P = .103; McNemar test), likely because of the small sample size in this study. CONCLUSION: SII can be used to predict the degree of tumor-brain adhesion of vestibular schwannomas and may provide a method to improve preoperative planning and determination of surgical risk in these patients. PMID- 26247778 TI - A Small-Molecule Photoactivatable Optical Sensor of Transmembrane Potential. AB - This paper discloses the design, synthesis, and imaging applications of the first member of a new class of SPOTs, small-molecule photoactivatable optical sensors of transmembrane potential. SPOT2.1.Cl features an established voltage-sensitive dye, VoltageFluor2.1.Cl--or VF--capped with a dimethoxy-o-nitrobenzyl (DMNB) caging group to effectively diminish fluorescence of the VF dye prior to uncaging. SPOT2.1.Cl localizes to cell membranes and displays weak fluorescence until photoactivated. Illumination generates the parent VF dye which then optically reports on changes in the membrane voltage. After photoactivation with spatially restricted light, SPOT2.1.Cl-loaded cells display bright, voltage sensitive fluorescence associated with the plasma membrane, while neighboring cells remain dark. Activated SPOT reports on action potentials in single trials. SPOT can be activated in neuron cell bodies or uncaged in dendrites to enable structural tracing via "backfilling" of the dye to the soma, followed by functional imaging in the labeled cell. The combination of cellular specificity achieved through spatially defined patterns of illumination, coupled with the fast, sensitive, and noncapacitive voltage sensing characteristics of VF dyes makes SPOT2.1.Cl a useful tool for interrogating both structure and function of neuronal systems. PMID- 26247779 TI - Gene Expression Profile in the Liver of BALB/c Mice Infected with Fasciola hepatica. AB - BACKGROUND: Fasciola hepatica infection still remains one of the helminthic neglected tropical diseases (NTDs). It has a huge worldwide distribution, affecting mainly cattle and, sometimes, human beings. In addition to data reported about the immunological response induced by helminthic infections and that induced by Fasciola hepatica, little is known about the gene expression profile in its organ target, the liver, which is where adult worms are established and live for long periods of time, causing its characteristic pathology. In the present work, we study both the early and late gene expression profiles in the livers of mice infected with F. hepatica metacercariae using a microarray-based methodology. METHODOLOGY: A total of 9 female-6-week-old BALB/c mice (Charles River Laboratories, Barcelona, Spain) weighing 20 to 35 g were used for the experiments. Two groups of BALB/c mice were orally infected with seven F. hepatica metacercariae, and the other group remained untreated and served as a control. Mice were humanely euthanized and necropsied for liver recovery, histological assessment of hepatic damage, RNA isolation, microarray design and gene expression analysis on the day of infection (t0), seven days post-infection (t7) and twenty-one days post-infection (t21). RESULTS: We found that F. hepatica infection induces the differential expression of 128 genes in the liver in the early stage of infection and 308 genes in the late stage, and most of them are up regulated. The Ingenuity Pathway Analysis revealed significant changes in the pathways related to metabolism, biosynthesis and signaling as well as genes implicated in inducing liver-toxicity, injury and death. CONCLUSION: The present study provides us insights at the molecular level about the underlying mechanisms used by F. hepatica, leading to liver damage and its subsequent pathophysiology. The expression pattern obtained here could also be used to explain the lack of association between infection with F. hepatica and cholangiocarcinoma. However, more studies should be performed to confirm this hypothesis. PMID- 26247780 TI - Constitutive Activation of an Anthocyanin Regulatory Gene PcMYB10.6 Is Related to Red Coloration in Purple-Foliage Plum. AB - Cherry plum is a popular ornamental tree worldwide and most cultivars are selected for purple foliage. Here, we report the investigation of molecular mechanism underlying red pigmentation in purple-leaf plum 'Ziyeli' (Prunus cerasifera Ehrhar f. atropurpurea (Jacq.) Rehd.), which shows red color pigmentation in fruit (flesh and skin) and foliage. Six anthocyanin-activating MYB genes, designated PcMYB10.1 to PcMYB10.6, were isolated based on RNA-Seq data from leaves of cv. Ziyeli. Of these PcMYB10 genes, five (PcMYB10.1 through PcMYB10.5) show distinct spatial and temporal expression patterns, while the PcMYB10.6 gene is highly expressed in all the purple-coloured organs of cv. Ziyeli. Constitutive activation of PcMYB10.6 is closely related to red pigmentation in the leaf, fruit (flesh and skin), and sepal. However, the PcMYB10.6 activation cannot induce red pigmentation in the petal of cv. Ziyeli during late stages of flower development due to due to a lack of expression of PcUFGT. The inhibition of red pigmentation in the petal of cherry plum could be attributed to the high-level expression of PcANR that directs anthocyanidin flux to proanthocyanidin biosynthesis. In addition, PcMYB10.2 is highly expressed in fruit and sepal, but its expression cannot induce red pigmentation. This suggests the PcMYB10 gene family in cherry plum may have diverged in function and PcMYB10.2 plays little role in the regulation of red pigmentation. Our study provides for the first time an example of constitutive activation of an anthocyanin-activating MYB gene in Prunus although its underlying mechanism remains unclear. PMID- 26247781 TI - Psychosocial Stress Increases Salivary Alpha-Amylase Activity Independently from Plasma Noradrenaline Levels. AB - Salivary alpha-amylase activity (sAA) and plasma noradrenaline (NA) concentrations are often considered to be surrogate markers of sympathetic activation in response to stress. However, despite accumulating evidence for a close association between sAA and noradrenaline and other indicators of sympathetic activity, reliability and generality of this relation remains unclear. We employed the Trier Social Stress Test (TSST) in order to directly compare the responses in sAA and NA to psychological stress in healthy volunteers (n = 23). The TSST significantly increased sAA and NA plasma levels with no significant differences in females and males. However, when subjects were divided according to their NA responses into low versus high responders, both groups did not significantly differ in their sAA before, during or after stress exposure. These data suggest that in response to acute psychological stress both plasma NA levels and sAA reflect sympathetic activity, however seemed to increase independently from each other. PMID- 26247783 TI - Growth and geographical variation in the use of cardiac imaging in Australia. AB - BACKGROUND AND AIM: Growth rates and regional differences in the use of cardiac imaging are potential metrics of quality of care. This study sought to define growth and regional variation in outpatient cardiac imaging in Australia. METHODS: Analyses are based on the rate of outpatient transthoracic echocardiography (TTE), transoesophageal echocardiography (TOE) and stress echocardiography (SE) and single-photon emission computed tomography (SPECT) per 100 000 people in each geographic insurance region in Australia (Medicare local, ML). Numbers of tests from 2002 to 2013 were obtained from Medicare Australia Statistics, and the number of doctors was obtained from the Health Workforce data. Demographic data (total population, rural areas and quintiles of disadvantage) were obtained from census data. RESULTS: Over the past 11 years, TTE reimbursements/100 000 people increased from 1780 to 3497 (8.8% annualised growth), TOE from 33 to 61, SE from 181 to 947 and SPECT from 287 to 337. SE had the biggest increment, an average growth rate of 38.5%/year. The relationships between the use of each cardiac imaging techniques and demographic, medical and illness factors were analysed in outpatient tests reimbursed in 2012. For each additional medical practitioner per 1000 people, there was an increase in the rate of TTE (beta = 1.25 (95% confidence interval CI: 1.17-1.33), P < 0.001), and TOE use (beta = 1.13 (1.04-1.24), P = 0.005), independent of regional burden of cardiovascular disease and social determinants. For SPECT the largest independent correlate for testing was the percentage of women within the ML; each additional percentage increase resulted in doubling of the rate of testing (beta = 2.25 (1.72-2.94), P < 0.001). CONCLUSION: Variation in the use of TTE in Australia does not appear illness related and may be evidence of under- and overutilisation. An appropriate use process may contain this variation. PMID- 26247782 TI - SLIRP Regulates the Rate of Mitochondrial Protein Synthesis and Protects LRPPRC from Degradation. AB - We have studied the in vivo role of SLIRP in regulation of mitochondrial DNA (mtDNA) gene expression and show here that it stabilizes its interacting partner protein LRPPRC by protecting it from degradation. Although SLIRP is completely dependent on LRPPRC for its stability, reduced levels of LRPPRC persist in the absence of SLIRP in vivo. Surprisingly, Slirp knockout mice are apparently healthy and only display a minor weight loss, despite a 50-70% reduction in the steady-state levels of mtDNA-encoded mRNAs. In contrast to LRPPRC, SLIRP is dispensable for polyadenylation of mtDNA-encoded mRNAs. Instead, deep RNA sequencing (RNAseq) of mitochondrial ribosomal fractions and additional molecular analyses show that SLIRP is required for proper association of mRNAs to the mitochondrial ribosome and efficient translation. Our findings thus establish distinct functions for SLIRP and LRPPRC within the LRPPRC-SLIRP complex, with a novel role for SLIRP in mitochondrial translation. Very surprisingly, our results also demonstrate that mammalian mitochondria have a great excess of transcripts under basal physiological conditions in vivo. PMID- 26247784 TI - Validating Internal Control Genes for the Accurate Normalization of qPCR Expression Analysis of the Novel Model Plant Setaria viridis. AB - Employing reference genes to normalize the data generated with quantitative PCR (qPCR) can increase the accuracy and reliability of this method. Previous results have shown that no single housekeeping gene can be universally applied to all experiments. Thus, the identification of a suitable reference gene represents a critical step of any qPCR analysis. Setaria viridis has recently been proposed as a model system for the study of Panicoid grasses, a crop family of major agronomic importance. Therefore, this paper aims to identify suitable S. viridis reference genes that can enhance the analysis of gene expression in this novel model plant. The first aim of this study was the identification of a suitable RNA extraction method that could retrieve a high quality and yield of RNA. After this, two distinct algorithms were used to assess the gene expression of fifteen different candidate genes in eighteen different samples, which were divided into two major datasets, the developmental and the leaf gradient. The best-ranked pair of reference genes from the developmental dataset included genes that encoded a phosphoglucomutase and a folylpolyglutamate synthase; genes that encoded a cullin and the same phosphoglucomutase as above were the most stable genes in the leaf gradient dataset. Additionally, the expression pattern of two target genes, a SvAP3/PI MADS-box transcription factor and the carbon-fixation enzyme PEPC, were assessed to illustrate the reliability of the chosen reference genes. This study has shown that novel reference genes may perform better than traditional housekeeping genes, a phenomenon which has been previously reported. These results illustrate the importance of carefully validating reference gene candidates for each experimental set before employing them as universal standards. Additionally, the robustness of the expression of the target genes may increase the utility of S. viridis as a model for Panicoid grasses. PMID- 26247785 TI - Multiplex Y-STRs analysis using the ion torrent personal genome machine (PGM). AB - Massively parallel sequencing (MPS) technologies allow parallel sequencing analyses of many targeted regions of multiple samples at desirable depth of coverage. Routine use of MPS for forensic genetics is on the horizon. In this study, we explore the application of MPS technology in forensic Y-STR analysis. We designed a multiplex assay with 13 Y-STR loci (DYS19, DYS389 I, DYS389 II, DYS390, DYS391, DYS392, DYS437, DYS438, DYS439, DYS448, DYS456, DYS635, GATA-H4) for the purpose of MPS. The multiplex Y-STR assay was amplified in 42 unrelated male individuals and amplicons were sequenced simultaneously using the ion torrent personal genome machine (PGM) system. All loci were detected successfully, except for DYS389 II that exhibited a failure rate of 1.8% due to the relatively long amplicon sizes. We observed 7, 3, 2, 6 and 5 new alleles, respectively in DYS389 II, DYS390, DYS437, DYS448 and DYS635 due to the presence of sub-repeat composition differences, and a new allele in DYS438 because of nucleotide substitution. One allele of DYS390 was inconsistent with allele call from conventional capillary electrophoresis (CE) because of 4 bp deletions upstream of the core repeat unit. This study demonstrates that Y-STR typing by MPS can provide more genetic information, holding the promise for high discriminatory power. PMID- 26247786 TI - Combined PDGFR and HDAC Inhibition Overcomes PTEN Disruption in Chordoma. AB - BACKGROUND: The majority of chordomas show activation of the platelet-derived growth factor receptor (PDGFR). Based on in vitro intertumoral variation in response to recombinant PDGF protein and PDGFR inhibition, and variable tumor response to imatinib, we hypothesized that chordomas resistant to PDGFR inhibition may possess downstream activation of the pathway. METHODS: Molecular profiling was performed on 23 consecutive chordoma primary tissue specimens. Primary cultures established from 20 of the 23 specimens, and chordoma cell lines, UCH-1 and UCH-2, were used for in vitro experiments. RESULTS: Loss of heterozygosity (LOH) at the phosphatase and tensin homolog (PTEN) locus was observed in 6 specimens (26%). PTEN disruption statistically correlated with increased Ki-67 proliferation index, an established marker of poor outcome for chordoma. Compared to wild type, PTEN deficient chordomas displayed increased proliferative rate, and responded less favorably to PDGFR inhibition. PTEN gene restoration abrogated this growth advantage. Chordomas are characterized by intratumoral hypoxia and local invasion, and histone deacetylase (HDAC) inhibitors are capable of attenuating both hypoxic signaling and cell migration. The combination of PDGFR and HDAC inhibition effectively disrupted growth and invasion of PTEN deficient chordoma cells. CONCLUSIONS: Loss of heterozygosity of the PTEN gene seen in a subset of chordomas is associated with aggressive in vitro behavior and strongly correlates with increased Ki-67 proliferative index. Combined inhibition of PDGFR and HDAC attenuates proliferation and invasion in chordoma cells deficient for PTEN. PMID- 26247788 TI - Are Autonomous and Controlled Motivations School-Subjects-Specific? AB - This research sought to test whether autonomous and controlled motivations are specific to school subjects or more general to the school context. In two cross sectional studies, 252 elementary school children (43.7% male; mean age = 10.7 years, SD = 1.3 years) and 334 junior high school children (49.7% male, mean age = 14.07 years, SD = 1.01 years) were administered a questionnaire assessing their motivation for various school subjects. Results based on structural equation modeling using the correlated trait-correlated method minus one model (CTCM-1) showed that autonomous and controlled motivations assessed at the school subject level are not equally school-subject-specific. We found larger specificity effects for autonomous (intrinsic and identified) than for controlled (introjected and external) motivation. In both studies, results of factor loadings and the correlations with self-concept and achievement demonstrated that more evidence of specificity was obtained for autonomous regulations than for controlled ones. These findings suggest a new understanding of the hierarchical and multidimensional academic structure of autonomous and controlled motivations and of the mechanisms involved in the development of types of regulations for school subjects. PMID- 26247789 TI - Predictors of individual adaptation to high-volume or high-intensity endurance training in recreational endurance runners. AB - The aim of this study was to investigate factors that can predict individual adaptation to high-volume or high-intensity endurance training. After the first 8 week preparation period, 37 recreational endurance runners were matched into the high-volume training group (HVT) and high-intensity training group (HIT). During the next 8-week training period, HVT increased their running training volume and HIT increased training intensity. Endurance performance characteristics, heart rate variability (HRV), and serum hormone concentrations were measured before and after the training periods. While HIT improved peak treadmill running speed (RSpeak ) 3.1 +/- 2.8% (P < 0.001), no significant changes occurred in HVT (RSpeak : 0.5 +/- 1.9%). However, large individual variation was found in the changes of RSpeak in both groups (HVT: -2.8 to 4.1%; HIT: 0-10.2%). A negative relationship was observed between baseline high-frequency power of HRV (HFPnight ) and the individual changes of RSpeak (r = -0.74, P = 0.006) in HVT and a positive relationship (r = 0.63, P = 0.039) in HIT. Individuals with lower HFP showed greater change of RSpeak in HVT, while individuals with higher HFP responded well in HIT. It is concluded that nocturnal HRV can be used to individualize endurance training in recreational runners. PMID- 26247787 TI - Cone and rod loss in Stargardt disease revealed by adaptive optics scanning light ophthalmoscopy. AB - IMPORTANCE: Stargardt disease (STGD1) is characterized by macular atrophy and flecks in the retinal pigment epithelium. The causative ABCA4 gene encodes a protein localizing to photoreceptor outer segments. The pathologic steps by which ABCA4 mutations lead to clinically detectable retinal pigment epithelium changes remain unclear. We investigated early STGD1 using adaptive optics scanning light ophthalmoscopy. OBSERVATIONS: Adaptive optics scanning light ophthalmoscopy imaging of 2 brothers with early STGD1 and their unaffected parents was compared with conventional imaging. Cone and rod spacing were increased in both patients (P < .001) with a dark cone appearance. No foveal cones were detected in the older brother. In the younger brother, foveal cones were enlarged with low density (peak cone density, 48.3 * 103 cones/mm2). The ratio of cone to rod spacing was increased in both patients, with greater divergence from normal approaching the foveal center, indicating that cone loss predominates centrally and rod loss increases peripherally. Both parents had normal photoreceptor mosaics. Genetic testing revealed 3 disease-causing mutations. CONCLUSIONS AND RELEVANCE: This study provides in vivo images of rods and cones in STGD1. Although the primary clinical features of STGD1 are retinal pigment epithelial lesions, adaptive optics scanning light ophthalmoscopy reveals increased cone and rod spacing in areas that appear normal in conventional images, suggesting that photoreceptor loss precedes clinically detectable retinal pigment epithelial disease in STGD1. PMID- 26247790 TI - Population pharmacokinetic and pharmacodynamic analyses from a 4-month intradose escalation and its subsequent 12-month dose titration studies for a human monoclonal anti-FGF23 antibody (KRN23) in adults with X-linked hypophosphatemia. AB - X-linked hypophosphatemia (XLH) is an inherited metabolic bone disease with abnormally elevated serum FGF23 resulting in low renal maximum threshold for phosphate reabsorption, low serum phosphate (Pi) and 1,25-dihydroxyvitamin D levels with subsequent development of short stature and skeletal deformities. KRN23 is a novel human anti-FGF23 antibody for the treatment of XLH. The pharmacokinetics (PK) and pharmacodynamics (PD) models of KRN23 were assessed following subcutaneous dosing every 28 days over an initial 4-month dose escalation (0.05-0.6 mg/kg) and a subsequent 12-month titration period (0.1-1.0 mg/kg) in XLH adults. The PK of KRN23 was described by a 1-compartmental model with first-order absorption and elimination at doses >=0.1 mg/kg. The elimination half-life was 17.8 days. Covariates did not affect KRN23 PK. Mean peak serum Pi was attained 7-10 days after dosing and progressively increased following each of the initial 4 doses with comparable peak values attained following the sixth through tenth doses with a slight decrease thereafter. A PK-PD model with a maximum effect (Emax ) and a time-varying effective concentration to reach 50% of Emax (EC50,t ) described data adequately. Typical Emax was 1.5 mg/dL. Typical EC50,t was 1780 ng/mL and 5999 ng/mL after first and last dose, respectively. PMID- 26247791 TI - Large platelets but not putative endothelial progenitor cells are associated with low strut coverage after drug-eluting stent implantation. AB - OBJECTIVES: This study assessed whether different subsets of circulating endothelial and putative endothelial progenitor cells (CEC and EPC) correlate with stent strut coverage (SSC) using second generation optical coherence tomography (OCT). BACKGROUND: Due to the lack of imaging modalities with a resolution down to the magnitude of a few cells, the influence of EPC on endothelialisation of drug-eluting stents has not been assessed in patients. METHODS: In 37 patients, SSC of everolimus-eluting stents was assessed by OCT 5 7months after stent implantation. Different subsets of EPC (CD34(+)KDR(+), CD34(+)KDR(+)CD45(dim), CD133(+), CD3(+)CD31(+)), CEC (CD31(+)CD45(-)CD146(+)), and CD31(+)CD45(-)CD146(-) representing large platelets were analysed by flow cytometry, including viability analyses with 7-AAD. Statistical analysis comprised univariate regression analysis and multivariable models integrating OCT and flow cytometry data as well as clinical variables. RESULTS: SSC and frequency of different cell types were highly comparable with previously published data. EPC defined in part by KDR expression were mostly non-viable. On univariate and in multivariable models, no association between EPC counts and strut coverage was detected. For CD31(+)CD45(-)CD146(-) counts, representing large platelets, an inverse relationship with strut coverage was identified by a multivariable regression model adjusting for age, sex, diabetes mellitus, NYHA and CCS class, CRP, serum triglycerides, glucose and creatinine (beta=-9.42, p=0.006). CONCLUSIONS: There was no significant association between EPC or CEC and healing after drug-eluting stent implantation. Yet, CD31(+)CD45(-)CD146(-) cells were associated with low SSC. These data suggest that large platelets may represent a more important mediator of late stent endothelialisation than EPC. PMID- 26247792 TI - Incidence, prevalence and outcome of rheumatic heart disease in South Africa: a systematic review of contemporary studies. AB - BACKGROUND: Twenty years after its first democratic election, South Africa is experiencing a health transition. The impact of change on the incidence, prevalence and outcome of rheumatic heart disease (RHD) is unknown. METHODS: We conducted a systematic overview of the incidence, prevalence and outcomes of RHD in South Africa over the past two decades according to a published protocol. RESULTS: The overall crude incidence of symptomatic RHD was 24.7 per 100,000 (95% confidence interval (CI) 22.1 to 27.4) population per annum among adults (>13years) in Soweto, while the prevalence of asymptomatic echocardiographic RHD in schoolchildren was 20.2 cases per 1000 children (95% CI 15.3 to 26.2) in Cape Town. The 60-day mortality after admission with acute heart failure due to RHD was 24.8% (95% CI 13.6% to 42.5%) and 180-day mortality was 35.4% (95% CI 21.6% to 54.4%). Postoperative mortality at 30days was 2% (95% CI 0.0% to 4%). Post surgical survival was over 75% at 5years, and over 70% at 10years. Cause-specific mortality rate per 100,000 population decreased from 1.27 (95% CI 1.17 to 1.39) in 1997 to 0.7 (95% CI 0.63 to 0.78) in 2012. CONCLUSIONS: The incidence of symptomatic RHD in adults and prevalence of asymptomatic RHD in schoolchildren are high in South Africa. Mortality was high in patients with RHD-related heart failure, although post-surgical morbidity and mortality were low. Mortality attributed to RHD may be falling at a population level. PMID- 26247793 TI - Cardiac resynchronization therapy defibrillator at the end of battery life: in an era of economic uncertainty, do super-responders provide an opportunity for resource optimization? PMID- 26247794 TI - The importance of evaluating patients with MINOCA (myocardial infarction with non obstructive coronary arteries). PMID- 26247795 TI - Late presentation of traumatic aortic regurgitation. PMID- 26247796 TI - A diagnostic algorithm to optimize data collection and interpretation of Ripple Maps in atrial tachycardias. AB - BACKGROUND: Ripple Mapping (RM) is designed to overcome the limitations of existing isochronal 3D mapping systems by representing the intracardiac electrogram as a dynamic bar on a surface bipolar voltage map that changes in height according to the electrogram voltage-time relationship, relative to a fiduciary point. OBJECTIVE: We tested the hypothesis that standard approaches to atrial tachycardia CARTOTM activation maps were inadequate for RM creation and interpretation. From the results, we aimed to develop an algorithm to optimize RMs for future prospective testing on a clinical RM platform. METHODS: CARTO-XPTM activation maps from atrial tachycardia ablations were reviewed by two blinded assessors on an off-line RM workstation. Ripple Maps were graded according to a diagnostic confidence scale (Grade I - high confidence with clear pattern of activation through to Grade IV - non-diagnostic). The RM-based diagnoses were corroborated against the clinical diagnoses. RESULTS: 43 RMs from 14 patients were classified as Grade I (5 [11.5%]); Grade II (17 [39.5%]); Grade III (9 [21%]) and Grade IV (12 [28%]). Causes of low gradings/errors included the following: insufficient chamber point density; window-of-interest<100% of cycle length (CL); <95% tachycardia CL mapped; variability of CL and/or unstable fiducial reference marker; and suboptimal bar height and scar settings. CONCLUSIONS: A data collection and map interpretation algorithm has been developed to optimize Ripple Maps in atrial tachycardias. This algorithm requires prospective testing on a real-time clinical platform. PMID- 26247797 TI - Value of epsilon wave in lead aVR in an 83-year old male patient with arrhythmogenic cardiomyopathy. PMID- 26247798 TI - Comparative associations between angiotensin converting enzyme inhibitors, angiotensin receptor blockers and their combination, and outcomes in patients with heart failure and reduced ejection fraction. AB - BACKGROUND: Angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are recommended in heart failure with reduced ejection fraction (HFREF), but there is limited data on ARB vs. ACE-I and their combination in unselected populations. The purpose of this study was to compare the associations between the use of ACE-I, ARB and their combination, and outcomes in HFREF. METHODS AND RESULTS: We prospectively studied 22,947 patients with HFREF (ejection fraction<40%) enrolled in the Swedish Heart Failure Registry who received ACE-I but not ARB (n=15,801, 69%), ARB but not ACE-I (n=4335, 19%), their combination (n=571, 2%) or neither (n=2240, 10%). As compared with ACE-I alone, the hazard ratios (HRs) for ARB alone for all-cause mortality was 0.97 (95% CI=0.91-1.03; p=0.27), for HF hospitalization 1.08 (CI=1.02-1.15; p<0.01) and for the composite outcome 1.03 (CI=0.99-1.08; p=0.15). ACE-I and ARB combination had for death HR=0.98 (95% CI=0.84-1.14; p=0.76), for HF hospitalization HR=1.49 (CI=1.33-1.68; p<0.01) and for the composite outcome HR=1.35 (CI=1.21-1.50; p<0.01). Use of neither ACE-I nor ARB was associated with HR for death 1.41 (CI=1.33-1.50; p<0.01), for HF hospitalization 1.16 (CI=1.08 1.25; p<0.01) and for the composite outcome 1.28 (CI=1.21-1.35; p<0.01). CONCLUSION: This large generalizable analysis confirms the current recommendation of using ACE-I as first choice in HFREF. ARB can be considered an alternative in patients who cannot use ACE-I but should not routinely replace ACE-I. The combination of ACE-I and ARB was not associated with additional benefit over either one alone, and may potentially be harmful. PMID- 26247799 TI - Executive Functions and Motivation as Moderators of the Relationship Between Automatic Associations and Alcohol Use in Problem Drinkers Seeking Online Help. AB - BACKGROUND: Dual process models posit that problem drinking is maintained by an imbalance between relatively strong automatic processes and weak controlled processes, a combination of executive functions and motivation. Few studies have examined how the interplay between automatic processes and executive functions is affected by motivation to change. This study examined this relationship in problem drinkers seeking online help to change their alcohol use. It was expected that executive functions (i.e., working memory, response inhibition) would moderate the relationship between automatic (valence and approach) associations and alcohol use and that this effect would be stronger in individuals with strong motivation to change. METHODS: A sample of 302 problem drinkers (mean age: 51.7 years) participated in this study as part of the baseline assessment before an Internet intervention. Participants completed an online version of the brief Implicit Association Test (valence and approach associations), the self-ordered pointing task (working memory), the Stroop task (response inhibition), the Readiness to Change Questionnaire (motivation to change), and the Timeline Follow Back Questionnaire (alcohol use). Hierarchical moderated regression analysis was used to test the 4 hypothesized 3-way interactions. RESULTS: As expected, the interaction between valence associations and working memory only predicted alcohol use among individuals with strong motivation. This pattern was neither found for response inhibition nor for approach associations. CONCLUSIONS: Results provide partial support for the moderating role of motivation in the interplay between automatic processes and executive functions. Future studies should investigate this relationship in participants with the full range of motivation and alcohol use. PMID- 26247800 TI - Determination of mepitiostane metabolites in human urine by liquid chromatography/tandem mass spectrometry for sports drug testing. AB - Mepitiostane (2alpha,3alpha-epithio-17beta-(1-methoxycyclopentyloxy)-5alpha androstane), which is a prodrug of epitiostanol (2alpha,3alpha-epitio-5alpha androstane-17beta-ol), is an epitiosteroid having anti-estrogenic and weak androgenic anabolic activities. The World Anti-Doping Agency prohibits the misuse of mepitiostane by athletes. Detection of the urinary metabolites epitiostanol sulfoxide and epitiostanol was studied using liquid chromatography/mass spectrometry (LC-MS) for doping control purposes. The use of LC-MS provided advantages over gas chromatography/mass spectrometry for detecting heat labile steroids because epitiostanol and epitiostanol sulfoxide were primarily pyrolized to 5alpha-androst-2-en-17beta-ol. The method consists of enzymatic hydrolysis using beta-glucuronidase (Escherichia coli), liquid-liquid extraction, and subsequent ultra-performance liquid chromatography/electrospray-tandem mass spectrometry. Epitiostanol sulfoxide was determined at urinary concentrations of 0.5-50ng/mL, recovery was 76.2-96.9%, and assay precision was calculated as 0.9 1.7% (intra-day) and 2.0-6.6% (inter-day). Epitiostanol was determined at urinary concentrations of 0.5-50ng/mL, recovery was 26.1-35.6% and assay precision was calculated as 4.1-4.6% (intra-day) and 3.3-8.5% (inter-day). The limits of detection for epitiostanol sulfoxide and epitiostanol were 0.05ng/mL and 0.10ng/mL, respectively. Epitiostanol sulfoxide and epitiostanol, as their gluco conjugates, were identified in human urine after oral administration of 10mg mepitiostane. Epitiostanol sulfoxide and epitiostanol could be detected up to 48h and 24h after administration, respectively. The results showed that the detection window of epitiostanol is much shorter than that of epitiostanol sulfoxide. The LC-MS detection of urinary epitiostanol sulfoxide, a specific metabolite with a sulphur atom in its molecular structure, is likely to be able to identify the abuse of mepitiostane. PMID- 26247801 TI - Exploring Sustainable Rocket Fuels: [Imidazolyl-Amine-BH2](+)-Cation-Based Ionic Liquids as Replacements for Toxic Hydrazine Derivatives. AB - The application of hypergolic ionic liquids as propellant fuels is a newly emerging area in the fields of chemistry and propulsion science. Herein, a new class of [imidazolyl-amine-BH2](+)-cation-based ionic liquids, which included fuel-rich anions, such as dicyanamide (N(CN)2(-)) and cyanoborohydride (BH3CN(-)) anions, were synthesized and characterized. As expected, all of the ionic liquids exhibited spontaneous combustion upon contact with the oxidizer 100 % HNO3. The densities of these ionic liquids varied from 0.99-1.12 g cm(-3), and the heats of formation, predicted based on Gaussian 09 calculations, were between -707.7 and 241.8 kJ mol(-1). Among them, the salt of compound 5, that is, (1-allyl-1H imidazole-3-yl)-(trimethylamine)-dihydroboronium dicyanamide, exhibited the lowest viscosity (168 MPa s), good thermal properties (Tg <-70 degrees C, Td >130 degrees C), and the shortest ignition-delay time (18 ms) with 100 % HNO3. These ionic fuels, as "green" replacements for toxic hydrazine-derivatives, may have potential applications as bipropellant formulations. PMID- 26247802 TI - Criteria-Based Resource Allocation: A Tool to Improve Public Health Impact. AB - OBJECTIVE: Resource allocation in local public health (LPH) has been reported as a significant challenge for practitioners and a Public Health Services and Systems Research priority. Ensuring available resources have maximum impact on community health and maintaining public confidence in the resource allocation process are key challenges. A popular strategy in health care settings to address these challenges is Program Budgeting and Marginal Analysis (PBMA). This case study used PBMA in an LPH setting to examine its appropriateness and utility. DESIGN: The criteria-based resource allocation process PBMA was implemented to guide the development of annual organizational budget in an attempt to maximize the impact of agency resources. Senior leaders and managers were surveyed postimplementation regarding process facilitators, challenges, and successes. SETTING: Canada's largest autonomous LPH agency. RESULTS: PBMA was used to shift 3.4% of the agency budget from lower-impact areas (through 34 specific disinvestments) to higher-impact areas (26 specific reinvestments). Senior leaders and managers validated the process as a useful approach for improving the public health impact of agency resources. However, they also reported the process may have decreased frontline staff confidence in senior leadership. CONCLUSIONS: In this case study, PBMA was used successfully to reallocate a sizable portion of an LPH agency's budget toward higher-impact activities. PBMA warrants further study as a tool to support optimal resource allocation in LPH settings. PMID- 26247803 TI - Albinism in a patient with mutations at both the OA1 and OCA3 loci. PMID- 26247804 TI - Nursing home report card and performance gap. AB - BACKGROUND: With the aging of our society, concerns about the quality of nursing homes have been increasing. The Nursing Home Compare (NHC) report card is believed to reduce information asymmetry between the facility and potential residents and, consequently, improve nursing home quality. However, there is limited evidence about how nursing homes use this publicly disseminated performance information. PURPOSE: The aim of this study was to analyze the performance gap between nursing home administrators' self-assessment and the NHC report card performance ratings and explore the factors contributing to the gap. METHODOLOGY: All 515 Medicare- and Medicaid-certified nursing homes in Indiana were surveyed between August and December 2013. The response rate was approximately 45%. The survey data were compared with the NHC data to identify the gap. Ordered logistic regression analysis was conducted. FINDINGS: Despite voluntary participation, a reasonably high response rate, and anonymity, this study found that 62% of respondents either under- or overrated their facilities' performance, with the majority overrating their performance. The following factors were associated with a smaller performance gap: nonprofit or government owned status, higher staffing levels, a higher percentage of hours worked by registered nurses, and a higher market concentration. Longer work experience and greater county occupancy rates were associated with a larger performance gap. PRACTICE IMPLICATIONS: The significant gap implies that administrators either do not regularly review the NHC report card or do not concur with the NHC ratings. To reduce the gap and thereby improve performance, it is necessary to stabilize the administrators' position so that administrators know how they stand in the market and are consequently better equipped to successfully respond to the market. Facilities may also need to provide regular training on current technologies and facilitate use of the NHC report card, targeting administrators who are old and have many years of work experience. PMID- 26247805 TI - Mechanistic insights into the ANRORC-like rearrangement between methylhydrazine and 1,2,4-oxadiazole derivatives. AB - We herein present the first in-depth theoretical study devoted to elucidate the mechanism of the reaction between 1,2,4-oxadiazole derivatives and methylhydrazine. For this purpose, the reaction between methylhydrazine and some polyfluoroaryl-1,2,4-oxadiazoles has been employed as a model reaction. The analysis of the potential energy surface (PES) indicates that the most favorable path involves an initial amine attack at the C(2') site of the aryl moiety to yield an aryl-hydrazine intermediate whose thermodynamic stability appears as the main determinant of the favored reaction path. Next, the cyclization step leading to a spiro intermediate through a favored 5-exo-trig process appears as the rate determining step. Additionally, this study highlights the relevance of the torsional strain effects on the favored ANRORC pathway. Finally, both the origins of the substituent effects on the regioselectivity patterns as well as the need of using a large excess of nucleophile to afford the favored ANRORC pathway are discussed. PMID- 26247806 TI - Carboxylic-group-functionalized single-walled carbon nanohorns as peroxidase mimetics and their application to glucose detection. AB - Carboxylic-group-functionalized single-walled carbon nanohorns (SWCNHs-COOH) have been found to possess peroxidase-like activity for the first time. Similar to natural peroxidase, SWCNHs-COOH can catalyze the oxidation of 3,3',5,5' tetramethylbenzidine by H2O2 to produce a blue color solution. Compared with horseradish peroxidase, SWCNHs-COOH exhibit higher activity and stability under harsh reaction conditions. The catalytic activity of SWCNHs-COOH depends on the concentration of H2O2. A colorimetric method for glucose detection was developed by combining the SWCNH-COOH catalytic reaction and the generation of H2O2 by the enzymatic oxidation of glucose with glucose oxidase. Taking into account the advantages of good stability, high biocompatibility in aqueous solutions, being metal-catalyst free, and high purity, SWCNHs-COOH are expected to have potential applications in biotechnology and clinical diagnostics as enzymatic mimics. PMID- 26247807 TI - Home advantage? Decomposition across the freshwater-estuarine transition zone varies with litter origin and local salinity. AB - Expected increases in the frequency and intensity of storm surges and river flooding may greatly affect the relative salinity of estuarine environments over the coming decades. In this experiment we used detritus from three contrasting environments (marine Fucus vesiculosus; estuarine Spartina anglica; terrestrial Quercus robur) to test the prediction that the decomposition of the different types of litter would be highest in the environment with which they are associated. Patterns of decomposition broadly fitted our prediction: Quercus detritus decomposed more rapidly in freshwater compared with saline conditions while Fucus showed the opposite trend; Spartina showed an intermediate response. Variation in macro-invertebrate assemblages was detected along the salinity gradient but with different patterns between estuaries, suggesting that breakdown rates may be linked in part to local invertebrate assemblages. Nonetheless, our results suggest that perturbation of salinity gradients through climate change could affect the process of litter decomposition and thus alter nutrient cycling in estuarine transition zones. Understanding the vulnerability of estuaries to changes in local abiotic conditions is important given the need to better integrate coastal proceses into a wider management framework at a time when coastlines are increasingly threatened by human activities. PMID- 26247808 TI - A balanced view of the cerebrospinal fluid composition and functions: Focus on adult humans. AB - In this review, a companion piece to our recent examination of choroid plexus (CP), the organ that secretes the cerebrospinal fluid (CSF), we focus on recent information in the context of reliable older data concerning the composition and functions of adult human CSF. To accomplish this, we define CSF, examine the methodology employed in studying the CSF focusing on ideal or near ideal experiments and discuss the pros and cons of several widely used analogical descriptions of the CSF including: the CSF as the "third circulation," the CSF as a "nourishing liquor," the similarities of the CSF/choroid plexus to the glomerular filtrate/kidney and finally the CSF circulation as part of the "glymphatic system." We also consider the close interrelationship between the CSF and extracellular space of brain through gap junctions and the paucity of data suggesting that the cerebral capillaries secrete a CSF-like fluid. Recently human CSF has been shown to be in dynamic flux with heart-beat, posture and especially respiration. Functionally, the CSF provides buoyancy, nourishment (e.g., vitamins) and endogenous waste product removal for the brain by bulk flow into the venous (arachnoid villi and nerve roots) and lymphatic (nasal) systems, and by carrier-mediated reabsorptive transport systems in CP. The CSF also presents many exogenous compounds to CP for metabolism or removal, indirectly cleansing the extracellular space of brain (e.g., of xenobiotics like penicillin). The CSF also carries hormones (e.g., leptin) from blood via CP or synthesized in CP (e.g., IGF-2) to the brain. In summary the CP/CSF, the third circulation, performs many functions comparable to the kidney including nourishing the brain and contributing to a stable internal milieu for the brain. These tasks are essential to normal adult brain functioning. PMID- 26247809 TI - Mother-infant dyadic reparation and individual differences in vagal tone affect 4 month-old infants' social stress regulation. AB - Infants' social stress regulation (i.e., reactivity and recovery) might be affected by mother-infant dyadic functioning and infants' vagal tone (i.e., respiratory sinus arrhythmia, RSA). This study investigated the role of a specific dyadic functioning feature (i.e., dyadic reparation) and individual differences in vagal tone regulation (i.e., RSA suppression vs. non-suppression) in relation to social stress regulation in 4-month-old infants. A total of 65 mother-infant dyads participated in the face-to-face still-face paradigm. Social stress reactivity and recovery were measured as negative emotionality during Still-Face and Reunion episodes, respectively. RSA was measured during Play, Still-Face, and Reunion episodes. Suppressors had higher dyadic reparation during Play and higher recovery from social stress compared with non-suppressors. Higher reparation during Play was associated with lower reactivity and higher recovery only for suppressors. Findings suggest a joint role of infants' RSA individual differences and dyadic reparation in affecting infants' social stress regulation at 4 months of age. PMID- 26247810 TI - Orientation biases for facial emotion recognition during childhood and adulthood. AB - Facial emotion recognition develops slowly, with continuing changes in performance observable up to 10 years of age and beyond. In the current study, we chose to examine how the use of specific low-level visual features for emotion recognition may change during childhood. Adults exhibit information biases for face recognition; specific spatial frequency and orientation sub-bands make a larger contribution to recognition than others. This means that depending on the specific task (e.g., identification, emotion recognition), participants will perform worse when some features are removed from the original image and better when those features are included. One example of such an information bias for face recognition is the differential contribution of horizontal orientation energy relative to vertical orientation energy; adult participants are better able to recognize faces and categorize their emotional expressions when horizontal information is included than when only vertical information is included. Although several recent studies have demonstrated various ways in which horizontal orientation energy (and so-called "bar-codes" for face appearance) contribute to adult face processing, there have been as yet no studies describing how such a bias emerges developmentally that may offer insight into the mechanisms underlying the slow development of facial emotion recognition. In the current study, we compared children's (5- and 6-year-olds and 7- and 8-year-olds) and adults' performance in a simple emotion categorization task using orientation filtered faces to determine the extent to which horizontal and vertical orientation energy contributed to recognition as a function of age. We found that although all three participant groups exhibited a clear bias favoring the use of horizontal orientation energy, the nature of this bias differed as a function of age. Specifically, 5- and 6-year-olds exhibited a disproportionate performance cost when vertical orientation energy was all that was available relative to when stimuli were limited to horizontal orientation energy. One feature of the development of facial emotion recognition, thus, appears to be the capability to use suboptimal or weakly diagnostic information to support recognition. PMID- 26247811 TI - Complex regulation of CREB-binding protein by homeodomain-interacting protein kinase 2. AB - CREB-binding protein (CBP) and p300 are transcriptional coactivators involved in numerous biological processes that affect cell growth, transformation, differentiation, and development. In this study, we provide evidence of the involvement of homeodomain-interacting protein kinase 2 (HIPK2) in the regulation of CBP activity. We show that HIPK2 interacts with and phosphorylates several regions of CBP. We demonstrate that serines 2361, 2363, 2371, 2376, and 2381 are responsible for the HIPK2-induced mobility shift of CBP C-terminal activation domain. Moreover, we show that HIPK2 strongly potentiates the transcriptional activity of CBP. However, our data suggest that HIPK2 activates CBP mainly by counteracting the repressive action of cell cycle regulatory domain 1 (CRD1), located between amino acids 977 and 1076, independently of CBP phosphorylation. Our findings thus highlight a complex regulation of CBP activity by HIPK2, which might be relevant for the control of specific sets of target genes involved in cellular proliferation, differentiation and apoptosis. PMID- 26247812 TI - Capsaicin Fluidifies the Membrane and Localizes Itself near the Lipid-Water Interface. AB - Capsaicin is the chemical responsible for making some peppers spicy hot, but additionally it is used as a pharmaceutical to alleviate different pain conditions. Capsaicin binds to the vanilloid receptor TRPV1, which plays a role in coordinating chemical and physical painful stimuli. A number of reports have also shown that capsaicin inserts in membranes and its capacity to modify them may be part of its molecular mode of action, affecting the activity of other membrane proteins. We have used differential scanning calorimetry, X-ray diffraction, (31)P NMR, and (2)H NMR spectroscopy to show that capsaicin increases the fluidity and disorder of 1,2-palmitoyl-sn-glycero-3-phosphocholine membrane models. By using (1)H NOESY MAS NMR based on proton-proton cross-peaks between capsaicin and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine resonances, we determined the location profile of this molecule in a fluid membrane concluding that it occupies the upper part of the phospholipid monolayer, between the lipid-water interface and the double bond of the acyl chain in position sn-2. This location explains the disorganization of the membrane of both the lipid-water interface and the hydrophobic palisade. PMID- 26247814 TI - Detection and enumeration of circulating tumor cells based on their invasive property. AB - Circulating tumor cells (CTCs) are in limited numbers and heterogeneous, making their detection, isolation, and enumeration a major challenge. To overcome these difficulties, we developed a novel method to detect and enumerate CTCs with invasive property. Our assay consists of three simple steps: enrichment, Matrigel invasion assay, and immunostaining. We have validated this method using mouse xenograft tumor models and confirmed its utility in human cancer patients. Our method does not require special equipment and antigen expression for CTC selection, is less likely to be affected by the heterogeneity of the CTCs, and could be applicable to virtually all cancers. Most important, our method enumerates invasive CTCs, which may allow more accurate correlations with clinical outcome and treatment response compared with other CTC detection methods. PMID- 26247815 TI - The adaptive potential of maternal stress exposure in regulating population dynamics. AB - Ecologists, evolutionary biologists and biomedical researchers are investing great effort in understanding the impact maternal stress may have on offspring phenotypes. Bian et al. advance this field by providing evidence that density induced maternal stress programs offspring phenotypes, resulting in direct consequences on their fitness and population dynamics, but doing so in a context dependent manner. They suggest that intrinsic state alterations induced by maternal stress may be one ecological factor generating delayed density-dependent effects. This research highlights the connection between maternal stress and population dynamics, and the importance of understanding the adaptive potential of such effects in a context-dependent manner. PMID- 26247816 TI - Selective Serotonin Reuptake Inhibitors Plus Phosphodiesterase-5 Inhibitors for Premature Ejaculation: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To evaluate the efficacy and safety of combination therapy with selective serotonin reuptake inhibitors (SSRIs) and phosphodiesterase-5 (PDE-5) inhibitors for the treatment of premature ejaculation (PE). METHODS: A systematic search of EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews was undertaken to identify articles that referred to the use of a combination of SSRIs and PDE-5 inhibitors for the treatment of PE. A meta-analysis of these clinical studies was performed. The post-treatment intravaginal ejaculatory latency time (IELT) and adverse events (AEs) were used in this meta-analysis. RESULTS: Six publications involving 971 patients were included in the meta-analysis. In the analysis, we found significantly improved IELT in the combination use group compared with the use of SSRIs (mean differences [MD], 1.01; 95% confidence interval [CI], 0.61-1.41; P <.01) or PDE-5 inhibitors alone (MD, 1.11; 95% CI, 0.79-1.43; P <.01) for PE whether or not these patients suffered from erectile dysfunction. Combined treatment was more efficacious than use of PDE-5 inhibitors alone on sexual satisfaction. Although the occurrence of drug-related AEs in the combination use group was higher than that in the use of SSRIs or PDE-5 inhibitors alone group (37.5% vs 25.63%, P <.01), the most common AEs were mild and tolerable. CONCLUSION: The combined use of SSRIs and PDE-5 inhibitors provided additive favorable effects in men with PE compared with SSRIs or PDE-5 inhibitors monotherapy and was generally well tolerated. PMID- 26247817 TI - Tailoring the surface properties of LiNi(0.4)Mn(0.4)Co(0.2)O2 by titanium substitution for improved high voltage cycling performance. AB - The present study aims to provide insights into the behavior of LiNi0.4Mn0.4Co0.2O2 (NMC442) and LiNi0.4Mn0.4Co0.18Ti0.02O2 (NMC442-Ti02) cathode materials under galvanostatic cycling to high potentials, in the context of previous work which predicted that Ti-substituted variants should deliver higher capacities and exhibit better cycling stability than the unsubstituted compounds. It is found that NMC cathodes containing Ti show equivalent capacity fading but greater specific capacity than those without Ti in the same potential range. When repeatedly charged to the same degree of delithiation, NMC cathodes containing Ti showed better capacity retention. Soft X-ray absorption spectroscopy (XAS) spectra for Mn and Co indicated increased reduction in these elements for NMC cathodes without Ti, indicating that the substitution of Ti for Co acts to suppress the formation of a high impedance rock salt phase at the surface of NMC cathode particles. The results of this study validate the adoption of a facile change to existing NMC chemistries to improve cathode capacity retention under high voltage cycling conditions. PMID- 26247818 TI - Breast Cancer Diagnosed During Pregnancy: Adapting Recent Advances in Breast Cancer Care for Pregnant Patients. AB - Breast cancer during pregnancy (BCP), although rare, is becoming more common and treatment should be as similar as possible to that for nonpregnant young patients with breast cancer. A group of specialists convened to review current guidelines and provide guidance on how recent advances in breast cancer diagnosis and treatment can be adapted for pregnant patients. The majority of patients with BCP will be considered for treatment during the pregnancy. Premature delivery should be avoided whenever possible. Most treatments, including sentinel lymph node biopsy, systemic therapy with taxanes, platinum agents, or dose-dense treatment can be safely given during pregnancy, after careful risk/benefit assessment for mother and child. Chemotherapy is contraindicated during the first trimester because of a higher risk of fetal malformations but is feasible in the second and third trimesters. Other treatments such as radiation therapy or anti-human epidermal growth receptor 2 treatment are in general not indicated during pregnancy but might be considered in some instances. Patient data should be collected in a systematic way whenever possible. PMID- 26247819 TI - Evolution of Self-Organized Task Specialization in Robot Swarms. AB - Division of labor is ubiquitous in biological systems, as evidenced by various forms of complex task specialization observed in both animal societies and multicellular organisms. Although clearly adaptive, the way in which division of labor first evolved remains enigmatic, as it requires the simultaneous co occurrence of several complex traits to achieve the required degree of coordination. Recently, evolutionary swarm robotics has emerged as an excellent test bed to study the evolution of coordinated group-level behavior. Here we use this framework for the first time to study the evolutionary origin of behavioral task specialization among groups of identical robots. The scenario we study involves an advanced form of division of labor, common in insect societies and known as "task partitioning", whereby two sets of tasks have to be carried out in sequence by different individuals. Our results show that task partitioning is favored whenever the environment has features that, when exploited, reduce switching costs and increase the net efficiency of the group, and that an optimal mix of task specialists is achieved most readily when the behavioral repertoires aimed at carrying out the different subtasks are available as pre-adapted building blocks. Nevertheless, we also show for the first time that self organized task specialization could be evolved entirely from scratch, starting only from basic, low-level behavioral primitives, using a nature-inspired evolutionary method known as Grammatical Evolution. Remarkably, division of labor was achieved merely by selecting on overall group performance, and without providing any prior information on how the global object retrieval task was best divided into smaller subtasks. We discuss the potential of our method for engineering adaptively behaving robot swarms and interpret our results in relation to the likely path that nature took to evolve complex sociality and task specialization. PMID- 26247820 TI - A programmable microfluidic static droplet array for droplet generation, transportation, fusion, storage, and retrieval. AB - We present a programmable microfluidic static droplet array (SDA) device that can perform user-defined multistep combinatorial protocols. It combines the passive storage of aqueous droplets without any external control with integrated microvalves for discrete sample dispensing and dispersion-free unit operation. The addressable picoliter-volume reaction is systematically achieved by consecutively merging programmable sequences of reagent droplets. The SDA device is remarkably reusable and able to perform identical enzyme kinetic experiments at least 30 times via automated cross-contamination-free removal of droplets from individual hydrodynamic traps. Taking all these features together, this programmable and reusable universal SDA device will be a general microfluidic platform that can be reprogrammed for multiple applications. PMID- 26247821 TI - Simultaneous infection of human papillomavirus and poxvirus. PMID- 26247822 TI - Assessment of the characteristics of circulating follicular helper T-like cells in systemic lupus erythematosus: comment on the article by Choi et al. PMID- 26247823 TI - Techniques and principles of endoscopic treatment of benign gastrointestinal strictures. AB - PURPOSE OF REVIEW: The fundamental goal of treating any stenosis is luminal enlargement to ameliorate the underlying obstructive symptoms. Symptoms depend on the etiology and the site of the stricture and may include dysphagia, nausea and vomiting, abdominal pain, obstipation, or frank bowel obstruction. This article compares the various current technologies available for the treatment of gastrointestinal stenoses with regard to ease and site of application, patient tolerance, safety and efficacy data, and cost-benefit ratio. RECENT FINDINGS: Recent studies indicate that gastrointestinal dilation and stenting have evolved to a point at which in many if not most situations they can be the first line therapy and potentially the final therapy needed to treat the underlying condition. SUMMARY: Following techniques and principles in the management of gastrointestinal strictures would allow for the well tolerated and effective treatment of most patients with the tools currently available today. PMID- 26247824 TI - Circulating Betatrophin Correlates with Triglycerides and Postprandial Glucose among Different Glucose Tolerance Statuses--A Case-Control Study. AB - PURPOSE: Previous researches of betatrophin on glucose and lipids metabolism under insulin-resistant condition have reached controversial conclusions. To further identify the possible impact of betatrophin, we measured the circulating betatrophin levels in newly diagnosed type 2 diabetes (T2DM) patients, and in subjects with both impaired glucose tolerance (IGT) and normal glucose tolerance (NGT) and investigated the relationship between serum betatrophin and other clinical parameters in these patients with different glucose tolerance statuses. METHODS: A total of 460 permanent residents of the Fengxian District, aged 40-60 years, were enrolled. Based on the results of a 75 g oral glucose tolerance test, we selected newly diagnosed T2DM (n = 50) patients and subjects with IGT (n = 51) and NGT (n = 50) according to their age, gender and body mass index (18-28 kg/m2). Anthropometric parameters, glycosylated haemoglobin, blood lipids and fasting insulin were measured. Serum betatrophin concentrations were determined via ELISA. RESULTS: Serum betatrophin levels in T2DM patients were increased significantly compared with IGT and NGT groups, and decreased in subjects with better islet beta cell function. Serum betatrophin was positively correlated with triglyceride, 2-hour postprandial glucose, alanine aminotransferase and aspartate transaminase after adjusting for age, sex and body mass index in all subjects. Multiple regression analysis showed that 2-hour postprandial glucose was independently associated with serum betatrophin significantly. CONCLUSIONS: Circulating betatrophin is increased in newly-diagnosed T2DM patients and positively correlated with the triglycerides and postprandial glucose levels. The results suggest that betatrophin may participate in glucose and triglycerides metabolism. PMID- 26247825 TI - [Pleomorphic adenoma on heterotopic salivary inclusion: case report and literature review]. AB - Heterotopic salivary gland tissue is the presence of salivary tissue outside of the salivary glands. It is an uncommon condition but it can be the source of the full spectrum of salivary gland diseases. We present a rare case of pleomorphic adenoma developing from heterotopic salivary gland tissue in an upper neck lymph node not related to the major salivary glands. This article reviews the difficulty of the differential diagnosis with other cervical masses, embryogenesis, clinical manifestations and treatment of this condition. PMID- 26247826 TI - Prophylactic efficacy of S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07) against sulfur mustard induced lung toxicity in mice. AB - OBJECTIVE: The present study was planned to investigate the prophylactic efficacy of S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07), against topically applied SM induced pulmonary toxicity in mouse. MATERIALS AND METHODS: Animals were pretreated with S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07) (249.4 mg/kg by oral gavage) 30 minutes before SM exposure. The SM (6.48 mg/kg) was applied on hair clipped dorsocaudal region (percutaneous) of the animal. The animals were sacrificed on day 1, 3, 5 and 7. The biochemical changes those were observed in the bronchoalveolar lavage (BAL) fluid and lung tissue included protein, LDH, MPO, beta-glucuronidase, MMP-2, MMP-9, activated macrophages, reduced glutathione and lipid peroxidation level. RESULTS AND DISCUSSION: Pretreatment with DRDE-07 (0.2 LD50) attenuated SM-induced changes at all time point tested. BAL fluid biochemical endpoints indicated epithelial and endothelial cell damages as evidenced by increase in BAL protein, LDH level and increased number of activated macrophages. The increased myeloperoxidase activity and beta-glucuronidase level exhibited the degranulation of neutrophils due to SM toxicity in lung. The zymogrphy analysis of BAL fluid showed a significant increase in matrix metalloproteases (MMP) activity due to inflammatory cells accumulation. CONCLUSION: Thirty minutes pretreatment with DRDE-07 decreased vascular permeability reduced the inflammation and oxidative stress, hence may be recommended as a potential prophylactic agent for SM intoxication. PMID- 26247827 TI - Surface Chemistry of Nanocellulose Fibers Directs Monocyte/Macrophage Response. AB - The effect of surface functionalization of nanofibrillated cellulose (NFC) on monocyte/macrophage (MM) behavior is investigated to understand how the physicochemical properties of nanocelluloses influence the interactions of such materials with biological systems. Films of anionic (a-), cationic (c-), and unmodified (u-) NFC were synthesized and characterized in terms of surface charge. THP-1 monocytes were cultured on the surface of the films for 24 h in the presence and absence of lipopolysaccharide, and the cell response was evaluated in terms of cell adhesion, morphology, and secretion of TNF-alpha, IL-10, and IL 1ra. The results show that MMs cultured on carboxymethylated-NFC films (a-NFC) are activated toward a proinflammatory phenotype, whereas u-NFC promotes a mild activation of the studied cells. The presence of hydroxypropyltrimethylammonium groups on c-NFC, however, does not promote the activation of MMs, indicating that c-NFC closely behaves as an inert material in terms of MM activation. None of the materials is able to directly activate the MMs toward an anti-inflammatory response. These results may provide a foundation for the design of future NFC based materials with the ability to control MM activation and may expand the use of NFC in biomedical applications. PMID- 26247828 TI - Concordance of next generation sequence-based and sequence specific oligonucleotide probe-based HLA-DRB1 genotyping. AB - Next generation sequencing (NGS) of clonally amplified DNA, using Roche 454 technology, was used to genotype HLA-DRB1, DRB3, DRB4, and DRB5 loci (exon 2 only) from a set of 993 samples from newborns with maternally-reported African American ancestry. DRB1 exon 2 was genotyped previously on the same sample set using sequence-specific oligonucleotide probe (SSOP) technology. Comparison of the genotype calls from both methods indicated concordance of 92.3%. Some discordance was expected due to the higher resolution of NGS data, compared to SSOP data. This resulted from selection of the incorrect allele from the ambiguity string produced by SSOP genotyping. Of 76 discordant genotypes, only three were due to resolution of ambiguity with the NGS method. The low percent of changes due to the increased resolution of the NGS method instills confidence in the overall value of previous data genotyped with moderate resolution methods, i.e., the vast majority of alleles present in a population are those that are detectable at moderate resolution. The remaining 73 discordant genotypes resulted from preventable errors in sample handling, data interpretation, and data entry. These results underscore the potential for error that can result from factors such as low quality genomic DNA, manual data entry, and interpretation of marginal genotyping results. Optimization of genomic DNA quality, automation of genotyping steps wherever possible, and use of the highest resolution technology available can lead to dramatic improvements in HLA genotype data quality. NGS based methodology generated data of superior quality and accuracy compared to the SSOP system. PMID- 26247831 TI - Interdisciplinarity and Infectious Diseases: An Ebola Case Study. PMID- 26247832 TI - The relationship between the changes in the level of progesterone and the outcome of in vitro fertilization-embryo transfer. AB - We observed the effects of changes in progesterone (P) during late follicular phases on the treatment outcome of in vitro fertilization-embryo transfer (IVF ET) and intracytoplasmic sperm injection (ICSI) in patients with different ovarian responses. The data of 8,575 cycles of patients receiving gonadotropin releasing hormone (GnRH) agonist using the long protocol were retrospectively analyzed. According to the number of oocytes retrieved, the cycles were divided into poor ovarian response group (oocyte retrieval <5), intermediate ovarian response group (5<= oocyte retrieval <=15), and high ovarian response group (oocyte retrieval >=16). We found that in the poor ovarian response group, the clinical pregnancy rate was not significantly associated with both the level of P or the day of human chorionic gonadotrophin (hCG) and the duration of pre-hCG P elevation (p = 0.66 and p = 0.1874). In intermediate and high ovarian response groups, the clinical pregnancy rate was inversely related to both the level of P on the day of hCG administration and the duration of pre-hCG P elevation (all p < 0.0001). The cut-off values of serum P level on the day of hCG administration were 1 ng/ml and 1.75 ng/ml in intermediate and high ovarian response groups, respectively. The cut-off values of pre-hCG P elevation duration were obtained on day 1 in the intermediate ovarian response group, and days 1 or 3 in the high ovarian response group. After correcting for other confounding factors, multivariate logistic regression analysis indicated that P level on the day of hCG administration was not associated with clinical pregnancy rates, but pre-hCG P elevation duration was negatively associated with clinical pregnancy rate in the intermediate and high ovarian response groups. P level is associated with clinical pregnancy rate only in the patients with intermediate or high ovarian response. The longer the duration of pre-hCG P 1 ng/ml, the lower the clinical pregnancy rate. PMID- 26247833 TI - Raloxifene glucuronidation in liver and intestinal microsomes of humans and monkeys: contribution of UGT1A1, UGT1A8 and UGT1A9. AB - 1. Raloxifene is an antiestrogen that has been marketed for the treatment of osteoporosis, and is metabolized into 6- and 4'-glucuronides by UDP glucuronosyltransferase (UGT) enzymes. In this study, the in vitro glucuronidation of raloxifene in humans and monkeys was examined using liver and intestinal microsomes and recombinant UGT enzymes (UGT1A1, UGT1A8 and UGT1A9). 2. Although the K(m) and CL(int) values for the 6-glucuronidation of liver and intestinal microsomes were similar between humans and monkeys, and species differences in Vmax values (liver microsomes, humans > monkeys; intestinal microsomes, humans < monkeys) were observed, no significant differences were noted in the K(m) or S50, Vmax and CL(int) or CLmax values for the 4' glucuronidation of liver and intestinal microsomes between humans and monkeys. 3. The activities of 6-glucuronidation in recombinant UGT enzymes were UGT1A1 > UGT1A8 >UGT1A9 for humans, and UGT1A8 > UGT1A1 > UGT1A9 for monkeys. The activities of 4'-glucuronidation were UGT1A8 > UGT1A1 > UGT1A9 in humans and monkeys. 4. These results demonstrated that the profiles for the hepatic and intestinal glucuronidation of raloxifene by microsomes were moderately different between humans and monkeys. PMID- 26247834 TI - Inhibition of CYP3A4 and CYP1A2 by Aegle marmelos and its constituents. AB - 1. Aegle marmelos (bael) is a popular tree in India and other Southeast Asian countries. The fruit is usually consumed as dried, fresh or juice, and is reported to have a high nutritional value and many perceived health benefits. Despite its edible nature and therapeutic properties, no studies are reported regarding its effects on major drug metabolizing enzymes. 2. This study was aimed to evaluate the inhibitory potential of methanolic extract of A. marmelos fruit and its constituents (three furanocoumarins, namely marmelosin, marmesinin and 8 hydroxypsoralen, and 1 alkaloid, aegeline) towards major Cytochrome P450 enzymes (CYP3A4, 2D6, 1A2, 2C9 and 2C19) using human liver microsomes and recombinant CYPs. 3. The methanolic extract and marmelosin was found to be competitive and time-dependant inhibitor of CYP3A4. While reversible and non-competitive inhibition was observed for CYP1A2. Time-dependent inhibition of CYP3A4 was not affected by the addition of reduced glutathione. Marmesinin showed moderate inhibition of CYP3A4 and 1A2, while aegeline was a very weak inhibitor of CYP3A4 and showed no inhibition for CYP1A2 isoform. No significant inhibition of recombinant CYP2D6, 2C9, and 2C19 was seen with the extract or its constituents. 4. This is the first report of CYP3A4 and CYP1A2 inhibition by A. marmelos extract and one of its furanocoumarins, marmelosin. Further studies are warranted to determine if acute or prolonged use of bael fruit could affect the pharmacokinetics of drugs that are substrates of CYP3A4 or CYP1A2. PMID- 26247835 TI - Oxidation of pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene by human cytochrome P450 2A13. AB - 1. The polycyclic hydrocarbons (PAHs), pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene, were found to induce Type I binding spectra with human cytochrome P450 (P450) 2A13 and were converted to various mono- and di-oxygenated products by this enzyme. 2. Pyrene was first oxidized by P450 2A13 to 1-hydroxypyrene which was further oxidized to di-oxygenated products, i.e. 1,8- and 1,6 dihydroxypyrene. Of five other human P450s examined, P450 1B1 catalyzed pyrene oxidation to 1-hydroxypyrene at a similar rate to P450 2A13 but was less efficient in forming dihydroxypyrenes. P450 2A6, a related human P450 enzyme, which did not show any spectral changes with these four PAHs, showed lower activities in oxidation of these compounds than P450 2A13. 3. 1-Nitropyrene and 1 acetylpyrene were also found to be efficiently oxidized by P450 2A13 to several oxygenated products, based on mass spectrometry analysis. 4. Molecular docking analysis supported preferred orientations of pyrene and its derivatives in the active site of P450 2A13, with lower interaction energies (U values) than observed for P450 2A6 and that several amino acid residues (including Ala-301, Asn-297 and Ala-117) play important roles in directing the orientation of these PAHs in the P450 2A13 active site. In addition, Phe-231 and Gly-329 were found to interact with pyrene to orient this compound in the active site of P450 1B1. 5. These results suggest that P450 2A13 is one of the important enzymes that oxidizes these PAH compounds and may determine how these chemicals are detoxicated and bioactivated in humans. PMID- 26247836 TI - Identification of genes regulating TRAIL-induced apoptosis in rheumatoid arthritis fibroblasts-like synoviocytes. AB - We previously described that sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis varied in rheumatoid arthritis fibroblasts-like synoviocytes (RAFLS) from one patient to another and was correlated with disease severity. Therefore, we screened for genes differentially expressed in RAFLS sensitive and resistant to TRAIL-induced apoptosis. The sensitivity of RAFLS was defined based on the percentage of TRAIL induced apoptosis: 0-10% for resistant cells and >25% for sensitive RAFLS. We performed transcriptomic comparison between RAFLS-S (n=6) and RAFLS-R (n=6) and then examined the implication of identified candidates in the regulation of apoptosis using small interference RNA (siRNA). Microarray analysis revealed 10 functional genes differentially expressed according to TRAIL sensitivity. These factors are implicated in different functions, such as the respiratory chain (ND3), the transport of lipids (OSBP2, PLTP), the regulation of signaling linked to extracellular factors (SULF2, GALNT1, SIAE) or the regulation of gene expression (TET2 and LARP6). We confirmed differential expression for GALNT1 and LARP6 by quantitative reverse transcriptase-PCR. Using siRNA extinction, we demonstrated the implication of GALNT1, SULF2 and LARP6 in the control of TRAIL induced responses. These results are of particular interest as GALNT1 and LARP6 have been implicated in the regulation of cell death and may represent interesting targets to induce apoptosis of RAFLS. PMID- 26247837 TI - Key roles of Tyr 10 in Cu bound Abeta complexes and its relevance to Alzheimer's disease. AB - Recent studies show that the accumulation of redox-active Cu mediates the aggregation of amyloid beta-peptide (Abeta) and conspicuous oxidative damage to the brain in Alzheimer's disease (AD). However, the key roles for Tyr 10 in Abeta Cu(II) complex and its potential biological relevance to AD etiology under oxidative stress, were not stressed enough. Interestingly, our results indicated that Abeta40 (not Abeta16)-Cu(II) complex showed obviously enhanced peroxidase activity than free Cu(II). Although Tyr 10 was not the residue binding Cu(II), the mutation of Tyr 10 residue in Abeta40 decreased the peroxidase activity of Abeta40-Cu(II) complex, and the mutation of Tyr 10 could inhibit Abeta40 aggregation. Under oxidative and nitrative stress conditions, the Abeta-Cu(II) complex caused oxidation and nitration of the Abeta Tyr 10 residue through peroxidase-like reactions, where the formation of Cu(I) and hydroxyl radical (OH) was proposed as a chemical mechanism. We also showed that, when Abeta40 aggregates were bound to Cu(II), they retained peroxidase-like activity. Therefore, Tyr 10 residue is pivotal in Abeta-Cu(II) complex and shows important relevance to oxidative stress, implicating the novel significance of Tyr 10 residue as well as Abeta-Cu(II) complex in the pathology of AD. PMID- 26247838 TI - The effect of TGF-beta-induced epithelial-mesenchymal transition on the expression of intracellular calcium-handling proteins in T47D and MCF-7 human breast cancer cells. AB - The contribution of Ca(2+) in TGF-beta-induced EMT is poorly understood. We aimed to confirm the effect of TGF-beta on the gene expression of intracellular calcium handling proteins and to investigate the potential underlying mechanisms in TGF beta-induced EMT. T47D and MCF-7 cells were cultured in vitro and treated with TGF-beta. The mRNA expression of EMT marker genes and intracellular calcium handling proteins were quantified by qRT-PCR. qRT-PCR and Western blot analysis results verified the changes of EMT marker gene expression. Furthermore, we found that TGF-beta induced cell morphological changes significantly with an increase of cell surface area and cell length. These results indicated that TGF-beta induced EMT. The mRNA expression levels of SPCA1, SPCA2 and MCU were not influenced by TGF-beta treatment, while NCX1 expression was decreased in T47D cells. In addition, the mRNA levels of SERCAs and IP3Rs were significantly changed due to TGF-beta-induced EMT. The TGF-beta-treated T47D cells exhibited markedly greater response to ATP than the control cells, and the descent velocity of cytosolic calcium concentration was faster in TGF-beta-treated cells than in control cells. This is the first report to demonstrate that TGF-beta-induced EMT in human breast cancer cells is associated with alterations in endoplasmic reticulum calcium homeostasis. PMID- 26247839 TI - Modifications of excitatory and inhibitory transmission in rat hippocampal pyramidal neurons by acute lithium treatment. AB - The acute effects of high-dose Li(+) treatment on glutamatergic and GABAergic transmissions were studied in the "synaptic bouton" preparation of isolated rat hippocampal pyramidal neurons by using focal electrical stimulation. Both action potential-dependent glutamatergic excitatory and GABAergic inhibitory postsynaptic currents (eEPSC and eIPSC, respectively) were dose-dependently inhibited in the external media containing 30-150 mM Li(+), but the sensitivity for Li(+) was greater tendency for eEPSCs than for eIPSCs. When the effects of Li(+) on glutamate or GABAA receptor-mediated whole-cell responses (IGlu and IGABA) elicited by an exogenous application of glutamate or GABA were examined in the postsynaptic soma membrane of CA3 neurons, Li(+) slightly inhibited both IGlu and IGABA at the 150 mM Li(+) concentration. Present results suggest that acute treatment with high concentrations of Li(+) acts preferentially on presynaptic terminals, and that the Li(+)-induced inhibition may be greater for excitatory than for inhibitory transmission. PMID- 26247841 TI - Life-History Traits of the Model Organism Pristionchus pacificus Recorded Using the Hanging Drop Method: Comparison with Caenorhabditis elegans. AB - The nematode Pristionchus pacificus is of growing interest as a model organism in evolutionary biology. However, despite multiple studies of its genetics, developmental cues, and ecology, the basic life-history traits (LHTs) of P. pacificus remain unknown. In this study, we used the hanging drop method to follow P. pacificus at the individual level and thereby quantify its LHTs. This approach allowed direct comparisons with the LHTs of Caenorhabditis elegans recently determined using this method. When provided with 5*10(9) Escherichia coli cells ml(-1) at 20 degrees C, the intrinsic rate of natural increase of P. pacificus was 1.125 (individually, per day); mean net production was 115 juveniles produced during the life-time of each individual, and each nematode laid an average of 270 eggs (both fertile and unfertile). The mean age of P. pacificus individuals at first reproduction was 65 h, and the average life span was 22 days. The life cycle of P. pacificus is therefore slightly longer than that of C. elegans, with a longer average life span and hatching time and the production of fewer progeny. PMID- 26247842 TI - Blister roof grafting, cultured melanocytes transplantation and non-cultured epidermal cell suspension transplantation in treating stable vitiligo: A mutual self-control study. AB - OBJECTIVES: To compare the efficacy of blister roof grafting (BG), cultured melanocytes transplantation (CMT) and non-cultured epidermal cell suspension transplantation (NCES) in the treatment of stable vitiligo. METHODS: In each person of 83 vitiligo patients one vitiligo macule was selected and divided in three areas for separate treatment with BG, CMT and NCES in the same session. The results were evaluated 12-month post-surgery for the extent of repigmentation and color match. RESULTS: A satisfactory result (>50% repigmentation) was achieved in 92%, 82% and 81% of the 83 patients with the BG, CMT and NCES methods, respectively. Significant differences between the BG and CMT groups (p = 0.038), and between BG and NCES groups (p = 0.017) were observed, but not between the CMT and NCES groups (p = 0.986). The extent of repigmentation on the head neck and trunk was superior to that of the extremities by all the three methods. A difference in the time of onset of repigmentation was observed, with repigmentation first appearing after 10 days, 20-30 days and >30 days in the BG, CMT and NCES groups, respectively. CONCLUSIONS: All the three methods are safe and effective to treat vitiligo. Future studies with larger groups are warranted to confirm our results. PMID- 26247843 TI - Desired Improvement Tool (DIT): A tool to assess desire for improvement in psoriasis patients. AB - No validated instrument exists to measure desire for improvement in psoriasis patients. To address this void, we conducted a single-center longitudinal study of 268 moderate-to-severe psoriasis patients to psychometrically validate the Desired Improvement Tool (DIT). The DIT is a single-item instrument scored 0-5 by the patient. A 0 indicates the patient is satisfied with disease level and does not desire further treatment. A 5 indicates a large amount of improvement is desired. The DIT demonstrated high test-retest reliability (Spearman, r = 0.97). Predictive and construct validity were moderate-to-high: r = 0.70 for BSA, 0.67 for PASI, and 0.56 for PGA and r = 0.67 for Life Quality Assessment (LQA), respectively. A sensitivity analysis revealed the DIT responded to changes in BSA. As a psychometrically valid tool, the DIT may guide clinical management of psoriasis patients by capturing an important clinical construct in an expedient and quantifiable manner. PMID- 26247840 TI - Multicenter Comparison of Lung and Oral Microbiomes of HIV-infected and HIV uninfected Individuals. AB - RATIONALE: Improved understanding of the lung microbiome in HIV-infected individuals could lead to better strategies for diagnosis, therapy, and prophylaxis of HIV-associated pneumonias. Differences in the oral and lung microbiomes in HIV-infected and HIV-uninfected individuals are not well defined. Whether highly active antiretroviral therapy influences these microbiomes is unclear. OBJECTIVES: We determined whether oral and lung microbiomes differed in clinically healthy groups of HIV-infected and HIV-uninfected subjects. METHODS: Participating sites in the Lung HIV Microbiome Project contributed bacterial 16S rRNA sequencing data from oral washes and bronchoalveolar lavages (BALs) obtained from HIV-uninfected individuals (n = 86), HIV-infected individuals who were treatment naive (n = 18), and HIV-infected individuals receiving antiretroviral therapy (n = 38). MEASUREMENTS AND MAIN RESULTS: Microbial populations differed in the oral washes among the subject groups (Streptococcus, Actinomyces, Rothia, and Atopobium), but there were no individual taxa that differed among the BALs. Comparison of oral washes and BALs demonstrated similar patterns from HIV uninfected individuals and HIV-infected individuals receiving antiretroviral therapy, with multiple taxa differing in abundance. The pattern observed from HIV infected individuals who were treatment naive differed from the other two groups, with differences limited to Veillonella, Rothia, and Granulicatella. CD4 cell counts did not influence the oral or BAL microbiome in these relatively healthy, HIV-infected subjects. CONCLUSIONS: The overall similarity of the microbiomes in participants with and without HIV infection was unexpected, because HIV-infected individuals with relatively preserved CD4 cell counts are at higher risk for lower respiratory tract infections, indicating impaired local immune function. PMID- 26247844 TI - An Exploration of Molecular Correlates Relevant to Radiation Combined Skin-Burn Trauma. AB - BACKGROUND: Exposure to high dose radiation in combination with physical injuries such as burn or wound trauma can produce a more harmful set of medical complications requiring specialist interventions. Currently these interventions are unavailable as are the precise biomarkers needed to help both accurately assess and treat such conditions. In the present study, we tried to identify and explore the possible role of serum exosome microRNA (miRNA) signatures as potential biomarkers for radiation combined burn injury (RCBI). METHODOLOGY: Female B6D2F1/J mice were assigned to four experimental groups (n = 6): sham control (SHAM), burn injury (BURN), radiation injury (RI) and combined radiation skin burn injury (CI). We performed serum multiplex cytokine analysis and serum exosome miRNA expression profiling to determine novel miRNA signatures and important biological pathways associated with radiation combined skin-burn trauma. PRINCIPAL FINDINGS: Serum cytokines, IL-5 and MCP-1, were significantly induced only in CI mice (p<0.05). From 890 differentially expressed miRNAs identified, microarray analysis showed 47 distinct miRNA seed sequences significantly associated with CI mice compared to SHAM control mice (fold change >= 1.2, p<0.05). Furthermore, only two major miRNA seed sequences (miR-690 and miR-223) were validated to be differentially expressed for CI mice specifically (fold change >= 1.5, p<0.05). CONCLUSIONS: Serum exosome miRNA signature data of adult mice, following RCBI, provides new insights into the molecular and biochemical pathways associated with radiation combined skin-burn trauma in vivo. PMID- 26247845 TI - Selective multifaceted E3 ubiquitin ligases barricade extreme defense: Potential therapeutic targets for neurodegeneration and ageing. AB - Efficient and regular performance of Ubiquitin Proteasome System and Autophagy continuously eliminate deleterious accumulation of nonnative protiens. In cellular quality control system, E3 ubiquitin ligases are significant employees for defense mechanism against abnormal toxic proteins. Few findings indicate that lack of functions of E3 ubiquitin ligases can be a causative factor of neurodevelopmental disorders, neurodegeneration, cancer and ageing. However, the detailed molecular pathomechanism implying E3 ubiquitin ligases in cellular functions in multifactorial disease conditions are not well understood. This article systematically represents the unique characteristics, molecular nature, and recent developments in the knowledge of neurobiological functions of few crucial E3 ubiquitin ligases. Here, we review recent literature on the roles of E6-AP, HRD1 and ITCH E3 ubiquitin ligases in the neuro-pathobiological mechanisms, with precise focus on the processes of neurodegeneration, and thereby propose new lines of potential targets for therapeutic interventions. PMID- 26247846 TI - 17beta-Estradiol and testosterone in sarcopenia: Role of satellite cells. AB - The loss of muscle mass and strength with aging, referred to as sarcopenia, is a prevalent condition among the elderly. Although the molecular mechanisms underlying sarcopenia are unclear, evidence suggests that an age-related acceleration of myocyte loss via apoptosis might be responsible for muscle perfomance decline. Interestingly, sarcopenia has been associated to a deficit of sex hormones which decrease upon aging. The skeletal muscle ability to repair and regenerate itself would not be possible without satellite cells, a subpopulation of cells that remain quiescent throughout life. They are activated in response to stress, enabling them to guide skeletal muscle regeneration. Thus, these cells could be a key factor to overcome sarcopenia. Of importance, satellite cells are 17beta-estradiol (E2) and testosterone (T) targets. In this review, we summarize potential mechanisms through which these hormones regulate satellite cells activation during skeletal muscle regeneration in the elderly. The advance in its understanding will help to the development of potential therapeutic agents to alleviate and treat sarcopenia and other related myophaties. PMID- 26247847 TI - Growth changes of eighteen herbaceous angiosperms induced by Hexahydro-1,3,5 trinitro-1,3,5-triazine (RDX) in soil. AB - Study objectives were to describe and quantify growth responses (tolerance as shoot and root biomass accumulation) to soil-applied Hexahydro-1,3,5-trinitro 1,3,5-triazine (RDX) treatments of eighteen terrestrial, herbaceous, angiospermous species and also; to determine how much of RDX, RDX transformation products, total N and RDX-derived N accumulated in the foliage. RDX altered growth of eighteen plant species or cultivars at levels of 100, 500, and 1,000 mg kg(-1)dry soil in a 75-d greenhouse study. Sixteen species or cultivars exhibited growth inhibition while two were stimulated in growth by RDX. A maximum amount of foliar RDX in a subset of three plant species was 36.0 mg per plant in Coronilla varia. Foliar concentrations of transformation products of RDX were low relative to RDX in the subset of three species. The proportion of RDX-N with respect to total N was constant, suggesting that foliar RDX transformation did not explain differences in tolerance. There was a delta (15)N shift towards that of synthetic RDX in foliage of the three species at a level of 1,000 mg kg(-1) RDX, proportional in magnitude to uptake of N from RDX and tolerance ranking.Reddened leaf margins for treated Sida spinosa indicate the potential of this species as a biosensor for RDX. PMID- 26247849 TI - Could Have Gone Wrong: Effects of Abrupt Changes in Migratory Behaviour on Harvest in a Waterbird Population. AB - To sustainably exploit a population, it is crucial to understand and reduce uncertainties about population processes and effects of harvest. In migratory species, management is challenged by geographically separated changing environmental conditions, which may cause unexpected changes in species distribution and harvest. We describe the development in the harvest of Svalbard breeding pink-footed geese (Anser brachyrhynchus) in relation to the observed trajectory and migratory behaviour of the population. In autumn, geese migrate via stopover sites in Norway and Denmark (where they are hunted) to wintering grounds in the Netherlands and Belgium (where they are protected). In Denmark and Norway harvesting increased stepwise during the 2000s. The increase in the population size only partly explained the change. The change corresponded to a simultaneous stepwise increase in numbers of geese staging in Denmark throughout autumn and winter; geese also moved further inland to feed which collectively increased their exposure to hunting. In Norway the increase in harvest reflected greater utilisation of lowland farmland areas by geese, increasing their hunting exposure. The study demonstrates how changes in migratory behaviour can abruptly affect exposure to hunting, which showed a functional response to increased temporal and spatial availability of geese. The harvest has now reached a level likely to cause a population decline. It highlights the need for flexible, internationally coordinated hunting regulations and reliable up-to-date population estimates and hunting bag statistics, which are rare in European management of migratory waterbirds. Without such information decisions are left with judgments based on population estimates, which often have time lags of several years between recording and reporting, hampering possibilities for the timely adjustment of management actions. PMID- 26247848 TI - Quantifying the Socio-Economic Benefits of Reducing Industrial Dietary Trans Fats: Modelling Study. AB - BACKGROUND: Coronary Heart Disease (CHD) remains a leading cause of UK mortality, generating a large and unequal burden of disease. Dietary trans fatty acids (TFA) represent a powerful CHD risk factor, yet to be addressed in the UK (approximately 1% daily energy) as successfully as in other nations. Potential outcomes of such measures, including effects upon health inequalities, have not been well quantified. We modelled the potential effects of specific reductions in TFA intake on CHD mortality, CHD related admissions, and effects upon socioeconomic inequalities. METHODS & RESULTS: We extended the previously validated IMPACTsec model, to estimate the potential effects of reductions (0.5% & 1% reductions in daily energy) in TFA intake in England and Wales, stratified by age, sex and socioeconomic circumstances. We estimated reductions in expected CHD deaths in 2030 attributable to these two specific reductions. Output measures were deaths prevented or postponed, life years gained and hospital admissions. A 1% reduction in TFA intake energy intake would generate approximately 3,900 (95% confidence interval (CI) 3,300-4,500) fewer deaths, 10,000 (8,800-10,300) (7% total) fewer hospital admissions and 37,000 (30,100-44,700) life years gained. This would also reduce health inequalities, preventing five times as many deaths and gaining six times as many life years in the most deprived quintile compared with the most affluent. A more modest reduction (0.5%) would still yield substantial health gains. CONCLUSIONS: Reducing intake of industrial TFA could substantially decrease CHD mortality and hospital admissions, and gain tens of thousands of life years. Crucially, this policy could also reduce health inequalities. UK strategies should therefore aim to minimise industrial TFA intake. PMID- 26247850 TI - How CO2 Interacts with Carboxylic Acids: A Rotational Study of Formic Acid-CO2. AB - The rotational spectra of the 1:1 formic acid-carbon dioxide molecular complex and of its monodeuterated isotopologues are analysed in the 6.5-18.5 and 59.6 74.4 GHz frequency ranges using a pulsed jet Fourier transform microwave spectrometer and a free-jet absorption millimetre wave spectrometer, respectively. Precise values of the rotational and quartic centrifugal distortion constants are obtained from the measured frequencies, and quadrupole coupling constants are determined from the deuterium hyperfine splittings. Structural parameters are estimated from the moments of inertia and their differences among isotopologues: the complex has a planar structure with the two subunits held together by a HC(O)OH???O=C=O (2.075 A) and a HC(OH)O???CO2 (2.877 A) interactions. The ab initio intermolecular binding energy, obtained at the counterpoise corrected MP2/aug-cc-pVTZ level of calculation, is De =17 kJ mol( 1). PMID- 26247851 TI - Isometric point of lateral femoral condyle analysis with in vitro kinematic study in order to position the extra-articular part of an ACL reconstruction. PMID- 26247852 TI - Estimation of K-WAIS-IV Premorbid Intelligence in South Korea: Development of the KPIE-IV. AB - OBJECTIVE: The accurate estimation of premorbid intellectual functioning in patients with known or suspected cognitive impairment is crucial for clinicians. However, there is no reliable method for estimating premorbid intelligence in South Korea. The purpose of this study was to develop the Korea Premorbid Intelligence Estimate (KPIE) as an estimate of the premorbid intellectual functioning. METHOD: Data from the Korean WAIS-IV standardization sample were used to generate several Full Scale Intelligence Quotient (FSIQ) estimation formulas using demographic variables and current WAIS-IV subtest performance. The standardization sample (N = 1216) was randomly divided into two groups: the first group was used to develop the formulas and the second group was used to validate the prediction equations. Age, education, gender, region of the country, and select subtest raw scores (Vocabulary, Information, Matrix Reasoning, and Visual Puzzle) were used as predictor variables. RESULTS: Five KPIE-4 equations were generated. Estimated FSIQ derived from the KPIE-4 equation is highly correlated with K-WAIS-IV FSIQ. CONCLUSIONS: The resulting formulas for estimating premorbid FSIQ were highly significant and precise in predicting FSIQ scores of participants in the K-WAIS-IV normative sample. These equations provide a means for clinicians to estimate intellectual functioning in adults, and can be utilized as a method of estimating individuals premorbid functioning. PMID- 26247853 TI - Energy Impacts of Wide Band Gap Semiconductors in U.S. Light-Duty Electric Vehicle Fleet. AB - Silicon carbide and gallium nitride, two leading wide band gap semiconductors with significant potential in electric vehicle power electronics, are examined from a life cycle energy perspective and compared with incumbent silicon in U.S. light-duty electric vehicle fleet. Cradle-to-gate, silicon carbide is estimated to require more than twice the energy as silicon. However, the magnitude of vehicle use phase fuel savings potential is comparatively several orders of magnitude higher than the marginal increase in cradle-to-gate energy. Gallium nitride cradle-to-gate energy requirements are estimated to be similar to silicon, with use phase savings potential similar to or exceeding that of silicon carbide. Potential energy reductions in the United States vehicle fleet are examined through several scenarios that consider the market adoption potential of electric vehicles themselves, as well as the market adoption potential of wide band gap semiconductors in electric vehicles. For the 2015-2050 time frame, cumulative energy savings associated with the deployment of wide band gap semiconductors are estimated to range from 2-20 billion GJ depending on market adoption dynamics. PMID- 26247854 TI - Unconventional Transmission at Conventional Synapses of an Inhibitory Interneuron. AB - The AII amacrine cell (AII) is a key information hub in the retina, allowing rod driven signals to piggyback onto cone-dominated circuitry. In this issue, Balakrishnan et al. (2015) use capacitance recordings to unravel mechanisms of inhibitory synaptic transmission by AIIs. PMID- 26247855 TI - Dendritic Inhibitory Synapses Punch above Their Weight. AB - Mullner et al. (2015) show that single inhibitory synapses placed in the right location on the dendritic tree can exert a powerful impact on backpropagating action potentials in hippocampal pyramidal neurons by controlling local Ca(2+) influx with MUm and ms precision. PMID- 26247856 TI - Norepinephrine and Corticotropin-Releasing Hormone: Partners in the Neural Circuits that Underpin Stress and Anxiety. AB - Norepinephrine and corticotropin-releasing hormone (CRH) have long been implicated in the response to stress. In this issue of Neuron, McCall et al. (2015) show that CRH projections from the central amygdala drive tonic locus coeruleus activity that evokes acute anxiety responses and place aversion. PMID- 26247857 TI - Towards an Individualized Delineation of Functional Neuroanatomy. AB - The functional neuroanatomy of the human brain is known to vary between individuals, yet current descriptions are based on group-averaged data. Laumann et al. (2015) present data from one highly sampled individual and show unique fine-grained differences representing subject-specific functional architecture. PMID- 26247859 TI - Building the Neuronal Microtubule Cytoskeleton. AB - Microtubules are one of the major cytoskeletal components of neurons, essential for many fundamental cellular and developmental processes, such as neuronal migration, polarity, and differentiation. Microtubules have been regarded as critical structures for stable neuronal morphology because they serve as tracks for long-distance transport, provide dynamic and mechanical functions, and control local signaling events. Establishment and maintenance of the neuronal microtubule architecture requires tight control over different dynamic parameters, such as microtubule number, length, distribution, orientations, and bundling. Recent genetic studies have identified mutations in a wide variety of tubulin isotypes and microtubule-related proteins in many of the major neurodevelopmental and neurodegenerative diseases. Here, we highlight the functions of the neuronal microtubule cytoskeleton, its architecture, and the way its organization and dynamics are shaped by microtubule-related proteins. PMID- 26247858 TI - Nociception, Pain, Negative Moods, and Behavior Selection. AB - Recent neuroimaging studies suggest that the brain adapts with pain, as well as imparts risk for developing chronic pain. Within this context, we revisit the concepts for nociception, acute and chronic pain, and negative moods relative to behavior selection. We redefine nociception as the mechanism protecting the organism from injury, while acute pain as failure of avoidant behavior, and a mesolimbic threshold process that gates the transformation of nociceptive activity to conscious pain. Adaptations in this threshold process are envisioned to be critical for development of chronic pain. We deconstruct chronic pain into four distinct phases, each with specific mechanisms, and outline current state of knowledge regarding these mechanisms: the limbic brain imparting risk, and the mesolimbic learning processes reorganizing the neocortex into a chronic pain state. Moreover, pain and negative moods are envisioned as a continuum of aversive behavioral learning, which enhance survival by protecting against threats. PMID- 26247860 TI - Using Grid Cells for Navigation. AB - Mammals are able to navigate to hidden goal locations by direct routes that may traverse previously unvisited terrain. Empirical evidence suggests that this "vector navigation" relies on an internal representation of space provided by the hippocampal formation. The periodic spatial firing patterns of grid cells in the hippocampal formation offer a compact combinatorial code for location within large-scale space. Here, we consider the computational problem of how to determine the vector between start and goal locations encoded by the firing of grid cells when this vector may be much longer than the largest grid scale. First, we present an algorithmic solution to the problem, inspired by the Fourier shift theorem. Second, we describe several potential neural network implementations of this solution that combine efficiency of search and biological plausibility. Finally, we discuss the empirical predictions of these implementations and their relationship to the anatomy and electrophysiology of the hippocampal formation. PMID- 26247861 TI - Synaptic Consolidation Normalizes AMPAR Quantal Size following MAGUK Loss. AB - The mechanisms controlling synapse growth and maintenance are of critical importance for learning and memory. The MAGUK family of synaptic scaffolding proteins is abundantly expressed at glutamatergic central synapses, but their importance in controlling the synaptic content of glutamate receptors is poorly understood. Here, we use a chained RNAi-mediated knockdown approach to simultaneously remove PSD-93, PSD-95, and SAP102, the MAGUKs previously shown to be responsible for synaptic localization of glutamate receptors. We find that MAGUKs are specifically responsible for creating functional synapses after initial spine formation by filling functionally silent spines with glutamate receptors. Removal of the MAGUKs causes a transient reduction in AMPA receptor quantal size followed by synaptic consolidation resulting in a normalization of quantal size at the few remaining functional synapses. Consolidation requires signaling through L-type calcium channels, CaM kinase kinase, and the GluA2 AMPA receptor subunit, akin to a homeostatic process. PMID- 26247862 TI - Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a. AB - Major depressive disorder is among the most commonly diagnosed disabling mental diseases. Several non-pharmacological treatments of depression upregulate adenosine concentration and/or adenosine A1 receptors (A1R) in the brain. To test whether enhanced A1R signaling mediates antidepressant effects, we generated a transgenic mouse with enhanced doxycycline-regulated A1R expression, specifically in forebrain neurons. Upregulating A1R led to pronounced acute and chronic resilience toward depressive-like behavior in various tests. Conversely, A1R knockout mice displayed an increased depressive-like behavior and were resistant to the antidepressant effects of sleep deprivation (SD). Various antidepressant treatments increase homer1a expression in medial prefrontal cortex (mPFC). Specific siRNA knockdown of homer1a in mPFC enhanced depressive-like behavior and prevented the antidepressant effects of A1R upregulation, SD, imipramine, and ketamine treatment. In contrast, viral overexpression of homer1a in the mPFC had antidepressant effects. Thus, increased expression of homer1a is a final common pathway mediating the antidepressant effects of different antidepressant treatments. PMID- 26247864 TI - Precision of Inhibition: Dendritic Inhibition by Individual GABAergic Synapses on Hippocampal Pyramidal Cells Is Confined in Space and Time. AB - Inhibition plays a fundamental role in controlling neuronal activity in the brain. While perisomatic inhibition has been studied in detail, the majority of inhibitory synapses are found on dendritic shafts and are less well characterized. Here, we combine paired patch-clamp recordings and two-photon Ca(2+) imaging to quantify inhibition exerted by individual GABAergic contacts on hippocampal pyramidal cell dendrites. We observed that Ca(2+) transients from back-propagating action potentials were significantly reduced during simultaneous activation of individual nearby inhibitory contacts. The inhibition of Ca(2+) transients depended on the precise spike-timing (time constant < 5 ms) and declined steeply in the proximal and distal direction (length constants 23-28 MUm). Notably, Ca(2+) amplitudes in spines were inhibited to the same degree as in the shaft. Given the known anatomical distribution of inhibitory synapses, our data suggest that the collective inhibitory input to a pyramidal cell is sufficient to control Ca(2+) levels across the entire dendritic arbor with micrometer and millisecond precision. PMID- 26247863 TI - Synaptic Vesicle Exocytosis at the Dendritic Lobules of an Inhibitory Interneuron in the Mammalian Retina. AB - Ribbon synapses convey sustained and phasic excitatory drive within retinal microcircuits. However, the properties of retinal inhibitory synapses are less well known. AII-amacrine cells are interneurons in the retina that exhibit large glycinergic synapses at their dendritic lobular appendages. Using membrane capacitance measurements, we observe robust exocytosis elicited by the opening of L-type Ca(2+) channels located on the lobular appendages. Two pools of synaptic vesicles were detected: a small, rapidly releasable pool and a larger and more slowly releasable pool. Depending on the stimulus, either paired-pulse depression or facilitation could be elicited. During early postnatal maturation, the coupling of the exocytosis Ca(2+)-sensor to Ca(2+) channel becomes tighter. Light evoked depolarizations of the AII-amacrine cell elicited exocytosis that was graded to light intensity. Our results suggest that AII-amacrine cell synapses are capable of providing both phasic and sustained inhibitory input to their postsynaptic partners without the benefit of synaptic ribbons. PMID- 26247865 TI - Local Field Potentials Encode Place Cell Ensemble Activation during Hippocampal Sharp Wave Ripples. AB - Whether the activation of spiking cell ensembles can be encoded in the local field potential (LFP) remains unclear. We address this question by combining in vivo electrophysiological recordings in the rat hippocampus with realistic biophysical modeling, and explore the LFP of place cell sequence spiking ("replays") during sharp wave ripples. We show that multi-site perisomatic LFP amplitudes, in the ~150-200 Hz frequency band, reliably reflect spatial constellations of spiking cells, embedded within non-spiking populations, and encode activation of local place cell ensembles during in vivo replays. We find spatiotemporal patterns in the LFP, which remain consistent between sequence replays, in conjunction with the ordered activation of place cell ensembles. Clustering such patterns provides an efficient segregation of replay events from non-replay-associated ripples. This work demonstrates how spatiotemporal ensemble spiking is encoded extracellularly, providing a window for efficient, LFP-based detection and monitoring of structured population activity in vivo. PMID- 26247866 TI - Acute Stress Impairs Self-Control in Goal-Directed Choice by Altering Multiple Functional Connections within the Brain's Decision Circuits. AB - Important decisions are often made under stressful circumstances that might compromise self-regulatory behavior. Yet the neural mechanisms by which stress influences self-control choices are unclear. We investigated these mechanisms in human participants who faced self-control dilemmas over food reward while undergoing fMRI following stress. We found that stress increased the influence of immediately rewarding taste attributes on choice and reduced self-control. This choice pattern was accompanied by increased functional connectivity between ventromedial prefrontal cortex (vmPFC) and amygdala and striatal regions encoding tastiness. Furthermore, stress was associated with reduced connectivity between the vmPFC and dorsolateral prefrontal cortex regions linked to self-control success. Notably, alterations in connectivity pathways could be dissociated by their differential relationships with cortisol and perceived stress. Our results indicate that stress may compromise self-control decisions by both enhancing the impact of immediately rewarding attributes and reducing the efficacy of regions promoting behaviors that are consistent with long-term goals. PMID- 26247868 TI - Pharmacokinetics of tulathromycin in edible tissues of healthy and experimentally infected pigs with Actinobacillus pleuropneumoniae. AB - The aim of this study was the comparison of the tissue pharmacokinetics of tulathromycin in healthy pigs and pigs experimentally infected with Actinobacillus pleuropneumoniae (App). Tulathromycin was given to 24 healthy and 24 infected pigs by intramuscular injection at a single dosage of 2.5 mg kg(-1) body weight (b.w.). Pigs were euthanised at each group and then samples of liver, kidney, muscle, injection site and skin with fat were taken at scheduled time points. Drug concentrations were determined by LC-MS/MS. In this study, higher values of the area under the concentration-time curves (AUC) were calculated in all tissue samples taken from infected than healthy pigs. In pigs with App the AUCs of liver, kidney, muscle, skin with fat and injection site were 1111, 1973, 235, 181 and 2931 mg kg(-1) h, while in pigs without inflammation they were 509, 1295, 151, 111 and 1587 mg kg(-1) h, respectively. Maximum drug tissue concentrations (Cmax) in infected animals were 2370, 6650, 2016, 666 and 83,870 ug kg(-1), while in healthy pigs they were 1483, 6677, 1733, 509 and 55,006 ug kg(-1), respectively. The eliminations half-times (T1/2) were respectively longer in all tissue samples taken from infected animals (from 157.3 to 187.3 h) than in healthy ones (from 138.6 to 161.2 h). The tulathromycin tissue concentrations were significantly higher (p < 0.05) in all tissue samples of the infected pigs compared with the healthy animals at 360 h (from 0.0014 to 0.0280) and at 792 h (from 0.0007 to 0.0242) after drug administration. The results suggest that the tissue pharmacokinetic properties and residue depletion of tulathromycin can be influenced by the disease state of animals. PMID- 26247867 TI - Modularity in the Organization of Mouse Primary Visual Cortex. AB - Layer 1 (L1) of primary visual cortex (V1) is the target of projections from many brain regions outside of V1. We found that inputs to the non-columnar mouse V1 from the dorsal lateral geniculate nucleus and feedback projections from multiple higher cortical areas to L1 are patchy. The patches are matched to a pattern of M2 muscarinic acetylcholine receptor expression at fixed locations of mouse, rat, and monkey V1. Neurons in L2/3 aligned with M2-rich patches have high spatial acuity, whereas cells in M2-poor zones exhibited high temporal acuity. Together M2+ and M2- zones form constant-size domains that are repeated across V1. Domains map subregions of the receptive field, such that multiple copies are contained within the point image. The results suggest that the modular network in mouse V1 selects spatiotemporally distinct clusters of neurons within the point image for top-down control and differential routing of inputs to cortical streams. PMID- 26247869 TI - Scan-Rescan Reproducibility of High Resolution Magnetic Resonance Imaging of Atherosclerotic Plaque in the Middle Cerebral Artery. AB - PURPOSE: To evaluate the scan-rescan reproducibility of high-resolution magnetic resonance imaging (MRI) of middle cerebral artery (MCA) plaque, and calculate the number of subjects needed for future longitudinal clinical studies. MATERIAL AND METHODS: Twenty two patients with MCA plaque were scanned twice by a T2-weighted fast-spin-echo sequence at 3T. Areas and volumes of MCA lumen, total vessel and plaque were quantified and compared between two repeated scans. Agreement and measurement error was quantified by intraclass correlation coefficient (ICC) and coefficient of variance (CV) as defined by standard deviation (SD) of pair wise difference / mean. Sample size needed to detect 5% to 20% changes in area/volume was calculated using 80% power and 5% significance level. RESULTS: There was no significant different between the area and volume measurements of two repeated scans (p>0.05) with good agreement (ICC range 0.97-0.98 for area and 0.99 for volume). Relatively small measurement errors were observed with CVs range 6.1% 11.8% for area quantification and 4.9%-8.0% for volume quantification. Volume measurements tended to have 19.7% to 32.2% smaller CVs compared with area measurements. Sample size calculation showed a group of 47 patients was sufficient to detect 5% to 10% changes in MCA area/volume. CONCLUSION: High resolution MRI is feasible for quantifying intracranial plaque area and volume in longitudinal clinical studies with low scan-rescan variability. Volume measurement tends to be more reproducible compared with area measurements. PMID- 26247871 TI - On-surface construction of a metal-organic Sierpinski triangle. AB - Through a careful design of the molecular precursor we have successfully constructed the metal-organic Sierpinski triangles on Au(111) via on-surface coordination chemistry, which is demonstrated by the interplay of high-resolution STM imaging and DFT calculations. The coordination Sierpinski triangles show high stabilities as evidenced by room temperature STM imaging, and could withstand a thermal treatment up to 450 K. PMID- 26247870 TI - Maternal Antioxidant Levels in Pregnancy and Risk of Preeclampsia and Small for Gestational Age Birth: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Oxidative stress in preeclampsia and small for gestational age (SGA) birth suggests antioxidant supplementation could prevent these conditions. However, it remains unclear whether maternal antioxidant levels are systematically lower in these pregnancies. OBJECTIVE: To conduct a systematic review of the association between maternal antioxidant levels during pregnancy and preeclampsia or SGA. METHODS: We searched PubMed, Embase, and several other databases from 1970-2013 for observational studies that measured maternal blood levels of non-enzymatic antioxidants (vitamins A, C, E, and carotenoids) during pregnancy or within 72 hours of delivery. The entire review process was done in duplicate. Study quality was assessed using the Newcastle-Ottawa Scale and additional questions. We pooled the standardized mean difference (SMD) across studies, stratified by outcome and pregnancy trimester, and investigated heterogeneity using meta-regression. RESULTS: We reviewed 1,882 unique citations and 64 studies were included. Most studies were small with important risk of bias. Among studies that addressed preeclampsia (n = 58) and SGA (n = 9), 16% and 66%, respectively, measured levels prior to diagnosis. The SMDs for vitamins A, C, and E were significantly negative for overall preeclampsia, but not for mild or severe preeclampsia subtypes. Significant heterogeneity was observed in all meta-analyses and most could not be explained. Evidence for lower carotenoid antioxidants in preeclampsia and SGA was limited and inconclusive. Publication bias appears likely. CONCLUSIONS: Small, low-quality studies limit conclusions that can be drawn from the available literature. Observational studies inconsistently show that vitamins C and E or other antioxidants are lower in women who develop preeclampsia or SGA. Reverse causality remains a possible explanation for associations observed. New clinical trials are not warranted in light of this evidence; however, additional rigorous observational studies measuring antioxidant levels before clinical detection of preeclampsia and SGA may clarify whether levels are altered at a causally-relevant time of pregnancy. PMID- 26247872 TI - Chorismatase Mechanisms Reveal Fundamentally Different Types of Reaction in a Single Conserved Protein Fold. AB - Chorismatases are a class of chorismate-converting enzymes involved in the biosynthetic pathways of different natural products, many of them with interesting pharmaceutical characteristics. So far, three subfamilies of chorismatases are described that convert chorismate into different (dihydro )benzoate derivatives (CH-FkbO, CH-Hyg5, and CH-XanB2). Until now, the detailed enzyme mechanism and the molecular basis for the different reaction products were unknown. Here we show that the CH-FkbO and CH-Hyg5 subfamilies share the same protein fold, but employ fundamentally different reaction mechanisms. While the FkbO reaction is a typical hydrolysis, the Hyg5 reaction proceeds intramolecularly, most likely via an arene oxide intermediate. Two nonconserved active site residues were identified that are responsible for the different reaction mechanisms in CH-FkbO and CH-Hyg5. Further, we propose an additional amino acid residue to be responsible for the discrimination of the CH-XanB2 subfamily, which catalyzes the formation of two different hydroxybenzoate regioisomers, likely in a single active site. A multiple sequence alignment shows that these three crucial amino acid positions are located in conserved motifs and can therefore be used to assign unknown chorismatases to the corresponding subfamily. PMID- 26247873 TI - High-Level Expression of microRNA-21 in Peripheral Blood Mononuclear Cells Is a Diagnostic and Prognostic Marker in Prostate Cancer. AB - AIMS: Our study aimed to evaluate the diagnostic and prognostic values of microRNA-21 (miR-21) expression levels in peripheral blood mononuclear cells (PBMCs) for prostate cancer (PCa). METHODS: Between February 2010 and June 2014, 75 consecutive patients with localized PCa confirmed by radical prostatectomy and biopsy were enrolled as the case group. Among them, 25 patients were confirmed with recurrence or metastasis (R/M) (PCa with R/M group) and 50 patients without R/M (PCa without R/M group). During the same period, 75 healthy volunteers were enrolled as the control group. Blood was collected from all subjects, and PBMCs were isolated. Relative miR-21 expression levels from the PBMCs were determined by fluorescence real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: The relative miR-21 expression levels in the preoperative case group was significantly higher than that in the postoperative case group and the control group (both p<0.001). miR-21 expression levels were associated with tumor differentiation, clinical stage, and lymph node metastasis (all p<0.001). Furthermore, miR-21 expression levels in PCa patients with R/M were significantly higher than that in PCa patients without R/M and healthy controls (both p<0.001). Receiver operating characteristic (ROC) curve analysis revealed that the cut-off point of miR-21 for diagnosis of PCa was 0.9 with a sensitivity of 87.5% and a specificity of 85.7%. CONCLUSIONS: Our study demonstrates that high miR-21 expression levels in PBMCs were correlated with the presence, recurrence, and metastasis of PCa and that this may be a useful biomarker for screening PCa and monitoring the risk of PCa recurrence and metastasis. PMID- 26247874 TI - An IPTG Inducible Conditional Expression System for Mycobacteria. AB - Conditional expression strains serve as a valuable tool to study the essentiality and to establish the vulnerability of a target under investigation in a drug discovery program. While essentiality implies an absolute requirement of a target function, vulnerability provides valuable information on the extent to which a target function needs to be depleted to achieve bacterial growth inhibition followed by cell death. The critical feature of an ideal conditional expression system is its ability to tightly regulate gene expression to achieve the full spectrum spanning from a high level of expression in order to support growth and near zero level of expression to mimic conditions of gene knockout. A number of bacterial conditional expression systems have been reported for use in mycobacteria. The utility of an isopropylthiogalactoside (IPTG) inducible system in mycobacteria has been reported for protein overexpression and anti-sense gene expression from a replicating multi-copy plasmid. Herein, we report the development of a versatile set of non-replicating IPTG inducible vectors for mycobacteria which can be used for generation of conditional expression strains through homologous recombination. The role of a single lac operator versus a double lac operator to regulate gene expression was evaluated by monitoring the expression levels of beta-galactosidase in Mycobacterium smegmatis. These studies indicated a significant level of leaky expression from the vector with a single lac operator but none from the vector with double lac operator. The significance of the double lac operator vector for target validation was established by monitoring the growth kinetics of an inhA, a rpoB and a ftsZ conditional expression strain grown in the presence of different concentrations of IPTG. The utility of this inducible system in identifying target specific inhibitors was established by screening a focussed library of small molecules using an inhA and a rpoB conditional expression strain. PMID- 26247875 TI - Immunology and evolvement of the adenovirus prime, MVA boost Ebola virus vaccine. AB - The 2014 Ebola virus outbreak caused an order of magnitude more deaths in a single outbreak than all previous known outbreaks combined, affecting both local and international public health, and threatening the security and economic stability of the countries in West Africa directly confronting the outbreak. The severity of the epidemic lead to a global response to assist with patient care, outbreak control, and deployment of vaccines. The latter was possible due to the long history of basic and clinical research aimed at identifying a safe and effective vaccine to protect against Ebola virus infection. This review highlights the immunology, development, and progress of vaccines based on replication-defective adenovirus vectors, culminating in the successful launch of the first Phase III trial of an Ebola virus vaccine. PMID- 26247876 TI - Temporal artery biopsy in giant cell arteritis. PMID- 26247877 TI - Photocontrolled micellar aggregation of amphiphilic DNA-azobenzene conjugates. AB - We demonstrate the reversible micellar aggregation of a DNA-azobenzene conjugate in aqueous conditions, in which the photoisomerization of the initially apolar trans-azobenzene moiety to the polar cis isomer causes disassembly of the aggregates. The molecular basis for this phenomena is a change in the hydrophobic/hydrophilic balance of the conjugate as the more polar cis azobenzene isomer is formed upon exposure to 365 nm irradiation. The conjugates were prepared by copper-free Click chemistry between an azide-modified, 53-base ssDNA and a cyclooctyne derivative of azobenzene. The photocontrolled aggregation of the conjugate was studied by dynamic light scattering and atomic force microscopy. The reversible micellar aggregation for a DNA-azobenzene conjugate has not been previously reported and holds promise for photocontrolled drug delivery applications. PMID- 26247878 TI - Cerebrospinal fluid concentrations of tenofovir and emtricitabine in the setting of HIV-1 protease inhibitor-based regimens. PMID- 26247879 TI - Hepatic Enzyme Alterations in HIV Patients on Antiretroviral Therapy: A Case Control Study in a Hospital Setting in Ghana. AB - BACKGROUND: Diagnosing hepatic injury in HIV infection can be a herculean task for clinicians as several factors may be involved. In this study, we sought to determine the effects of antiretroviral therapy (ART) and disease progression on hepatic enzymes in HIV patients. METHODS: A case-control study conducted from January to May 2014 at the Akwatia Government Hospital, Eastern region, Ghana, The study included 209 HIV patients on ART (designated HIV-ART) and 132 ART-naive HIV patients (designated HIV-Controls). Data gathered included demography, clinical history and results of blood tests for hepatic enzymes. We employed the Fisher's, Chi-square, unpaired t-test and Pearson's correlation in analysis, using GraphPad Prism and SPSS. A P value < 0.05 was considered significant. RESULTS: Median CD4 lymphocyte count of HIV-ART participants (604.00 cells/mm3) was higher than that of HIV-Controls (491.50 cells/mm3; P = 0.0005). Mean values of ALP, ALT, AST and GGT did not differ between the two groups compared (P > 0.05). There was a significant positive correlation between hepatic enzymes (ALP, ALT, AST and GGT) for both groups (p < 0.01 each). Duration of ART correlated positively with ALT (p < 0.05). The effect size of disease progression on hepatic enzymes for both groups was small. CONCLUSION: Antiretroviral therapy amongst this population has minimal effects on hepatic enzymes and does not suggest modifications in therapy. Hepatic injury may occur in HIV, even in the absence of ART and other traditional factors. Monitoring of hepatic enzymes is still important in HIV patients. PMID- 26247880 TI - A Label-Free Proteomic Analysis on Competent Larvae and Juveniles of the Pacific Oyster Crassostrea gigas. AB - Current understandings on the molecular mechanisms underlying bivalve metamorphosis are still fragmentary, and a comprehensive description is required. In this study, using a large-scale label-free proteomic approach, we described and compared the proteomes of competent larvae (CL) and juveniles (JU) of the Pacific oyster, Crassostrea gigas. A total of 788 proteins were identified: 392 in the CL proteome and 636 in the JU proteome. Gene Ontology analysis of the proteome from each sample revealed active metabolic processes in both stages. Further quantitative analyses revealed 117 proteins that were differentially expressed between the two samples. These proteins were divided into eight groups: cytoskeleton and cell adhesion, protein synthesis and degradation, immunity and stress response, development of particular tissues, signal regulation, metabolism and energy supply, transport, and other proteins. A certification experiment using real-time PCR assay confirmed 20 of 30 examined genes exhibited the same trends at the mRNA and protein levels. The differentially expressed proteins may play roles in tissue remodeling, signal transduction, and organ development during and after metamorphosis. Novel roles were proposed for some differentially expressed proteins, such as chymotrypsin. The results of this work provide an overview of metamorphosis and post-metamorphosis development of C. gigas at the protein level. Future studies on the functions of the differentially expressed proteins will help to obtain a more in-depth understanding of bivalve metamorphosis. PMID- 26247881 TI - Lymph Node Metastases and Prognosis in Left Upper Division Non-Small Cell Lung Cancers: The Impact of Interlobar Lymph Node Metastasis. AB - BACKGROUND: Left upper division segmentectomy is one of the major pulmonary procedures; however, it is sometimes difficult to completely dissect interlobar lymph nodes. We attempted to clarify the prognostic importance of hilar and mediastinal nodes, especially of interlobar lymph nodes, in patients with primary non-small cell lung cancer (NSCLC) located in the left upper division. METHODS: We retrospectively studied patients with primary left upper lobe NSCLC undergoing surgical pulmonary resection (at least lobectomy) with radical lymphadenectomy. The representative evaluation of therapeutic value from the lymph node dissection was determined using Sasako's method. This analysis was calculated by multiplying the frequency of metastasis to the station and the 5-year survival rate of the patients with metastasis to the station. RESULTS: We enrolled 417 patients (237 men, 180 women). Tumors were located in the lingular lobe and at the upper division of left upper lobe in 69 and 348 patients, respectively. The pathological nodal statuses were pN0 in 263 patients, pN1 in 70 patients, and pN2 in 84 patients. Lymph nodes #11 and #7 were significantly correlated with differences in node involvement in patients with left upper lobe NSCLC. Among those with left upper division NSCLC, the 5-year overall survival in pN1 was 31.5% for #10, 39.3% for #11, and 50.4% for #12U. The involvement of node #11 was 1.89-fold higher in the anterior segment than that in the apicoposterior segment. The therapeutic index of estimated benefit from lymph node dissection for #11 was 3.38, #4L was 1.93, and the aortopulmonary window was 4.86 in primary left upper division NSCLC. CONCLUSIONS: Interlobar node involvement is not rare in left upper division NSCLC, occurring in >20% cases. Furthermore, dissection of interlobar nodes was found to be beneficial in patients with left upper division NSCLC. PMID- 26247882 TI - Tradeoffs of warm adaptation in aquatic ectotherms: Live fast, die young? AB - In the face of a changing climate, questions regarding sub-lethal effects of elevated habitat temperature on the physiology of ectotherms remain unanswered. In particular, long-term responses of ectotherms to the warming trend in tropical regions are unknown, and understudied due to the difficulties in specimen and community traceability. In freshwater lakes employed as cooling reservoirs for power plants, increased physiological stress from high water temperature can potentially alter the community structure of fishes. We employ this highly tractable system to assess how thermal regimes can alter the physiology and ecology of aquatic species. We documented a significantly reduced lifespan, growth performance, and a shift in the age structure towards younger individuals in the thermally- impacted Coffeen Lake population of bluegill (Lepomis macrochirus), compared to a non-impacted control group (Lake Mattoon). Average age calculated for the Lake Mattoon population was 2.42 years, whereas the average age of bluegill from Coffeen Lake was only 0.96 years, and average specimen mass in Lake Mattoon was more than six times that of Coffeen Lake. During laboratory cross-acclimation studies of bluegill from Lake Mattoon at 17.5 and 35.0 degrees C, citrate synthase (CS) activity obtained from white muscle was regulated through acclimation, whereas cold-acclimated specimens exhibited twice the activity at 25 degrees C, if compared to CS activity values from warm acclimated specimens. This study raises the questions about the causal relationships between physiological performance and habitat temperature, in particular how thresholds in an organism's physiology may modulate their community structure, and consequently their ecological success. PMID- 26247883 TI - A Genome Scale Screen for Mutants with Delayed Exit from Mitosis: Ire1 Independent Induction of Autophagy Integrates ER Homeostasis into Mitotic Lifespan. AB - Proliferating eukaryotic cells undergo a finite number of cell divisions before irreversibly exiting mitosis. Yet pathways that normally limit the number of cell divisions remain poorly characterized. Here we describe a screen of a collection of 3762 single gene mutants in the yeast Saccharomyces cerevisiae, accounting for 2/3 of annotated yeast ORFs, to search for mutants that undergo an atypically high number of cell divisions. Many of the potential longevity genes map to cellular processes not previously implicated in mitotic senescence, suggesting that regulatory mechanisms governing mitotic exit may be broader than currently anticipated. We focused on an ER-Golgi gene cluster isolated in this screen to determine how these ubiquitous organelles integrate into mitotic longevity. We report that a chronic increase in ER protein load signals an expansion in the assembly of autophagosomes in an Ire1-independent manner, accelerates trafficking of high molecular weight protein aggregates from the cytoplasm to the vacuoles, and leads to a profound enhancement of daughter cell production. We demonstrate that this catabolic network is evolutionarily conserved, as it also extends reproductive lifespan in the nematode Caenorhabditis elegans. Our data provide evidence that catabolism of protein aggregates, a natural byproduct of high protein synthesis and turn over in dividing cells, is among the drivers of mitotic longevity in eukaryotes. PMID- 26247884 TI - Automatic Adaptation to Fast Input Changes in a Time-Invariant Neural Circuit. AB - Neurons must faithfully encode signals that can vary over many orders of magnitude despite having only limited dynamic ranges. For a correlated signal, this dynamic range constraint can be relieved by subtracting away components of the signal that can be predicted from the past, a strategy known as predictive coding, that relies on learning the input statistics. However, the statistics of input natural signals can also vary over very short time scales e.g., following saccades across a visual scene. To maintain a reduced transmission cost to signals with rapidly varying statistics, neuronal circuits implementing predictive coding must also rapidly adapt their properties. Experimentally, in different sensory modalities, sensory neurons have shown such adaptations within 100 ms of an input change. Here, we show first that linear neurons connected in a feedback inhibitory circuit can implement predictive coding. We then show that adding a rectification nonlinearity to such a feedback inhibitory circuit allows it to automatically adapt and approximate the performance of an optimal linear predictive coding network, over a wide range of inputs, while keeping its underlying temporal and synaptic properties unchanged. We demonstrate that the resulting changes to the linearized temporal filters of this nonlinear network match the fast adaptations observed experimentally in different sensory modalities, in different vertebrate species. Therefore, the nonlinear feedback inhibitory network can provide automatic adaptation to fast varying signals, maintaining the dynamic range necessary for accurate neuronal transmission of natural inputs. PMID- 26247885 TI - Genomic landscape of salivary gland tumors. AB - Effective treatment options for advanced salivary gland tumors are lacking. To better understand these tumors, we report their genomic landscape. We studied the molecular aberrations in 117 patients with salivary gland tumors that were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine, Cambridge, MA) using next-generation sequencing (182 or 236 genes), and analyzed by N-of-One, Inc. (Lexington, MA). There were 354 total aberrations, with 240 distinct aberrations identified in this patient population. Only 10 individuals (8.5%) had a molecular portfolio that was identical to any other patient (with four different portfolios amongst the ten patients). The most common abnormalities involved the TP53 gene (36/117 [30.8% of patients]), cyclin pathway (CCND1, CDK4/6 or CDKN2A/B) (31/117 [26.5%]) and PI3K pathway (PIK3CA, PIK3R1, PTEN or AKT1/3) (28/117 [23.9%]). In multivariate analysis, statistically significant co-existing aberrations were observed as follows: TP53 and ERBB2 (p = 0.01), cyclin pathway and MDM2 (p = 0.03), and PI3K pathway and HRAS (p = 0.0001). We were able to identify possible cognate targeted therapies in most of the patients (107/117 [91.5%]), including FDA-approved drugs in 80/117 [68.4%]. In conclusion, salivary gland tumors were characterized by multiple distinct aberrations that mostly differed from patient to patient. Significant associations between aberrations in TP53 and ERBB2, the cyclin pathway and MDM2, and HRAS and the PI3K pathway were identified. Most patients had actionable alterations. These results provide a framework for tailored combinations of matched therapies. PMID- 26247886 TI - Easy Access to Supramolecular Gels of the Nonsteroidal Anti-inflammatory Drug Diflunisal: Synthesis, Characterization, and Plausible Biomedical Applications. AB - By exploiting salt formation, a new series of primary ammonium monocarboxylate salts of a nonsteroidal anti-inflammatory drug, namely, diflunisal, was synthesized. The majority of the salts thus synthesized turned out to be good gelators of various solvents, including the solvents (e.g., methyl salicylate and pure water) typically used for topical gel formulation. Single-crystal X-ray diffraction studies of a few gelator and nongelator salts in the series revealed details of the hydrogen-bonding networks present in the salts. Furthermore, one such gelator salt, namely, the diflunisal salt of serinol, was found to be biocompatible (MTT assay), and its anti-inflammatory (PGE2 assay) response turned out to be as good as that of the parent drug, which is indicative of its potential in biomedical applications. PMID- 26247887 TI - What is a vertebrate pigment cell? AB - On the basis of discussions emerging from a workshop and discussions at the 7th meeting of the European Society for Pigment Cell Research in Geneva in 2012, this manuscript outlines useful criteria for defining the bona fide pigment cells as a functional entity of the vertebrate body plan and differentiating them from 'pigmented' cells in general. It also proposes a nomenclature for various types of pigment cells of vertebrates. PMID- 26247890 TI - Graphenol defects induced blue emission enhancement in chemically reduced graphene quantum dots. AB - In this work, few layer graphene quantum dots (GQDs) with a size of 3-5 nm are purposely treated with highly concentrated aqueous NaBH4 solutions to obtain the reduced graphene quantum dots (rGQDs). Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS) and Raman spectroscopy demonstrate that the number of carbonyl groups decreases but -OH related defects increase during chemical reduction. Green and weak emissions of original GQDs originate from carrier recombination in the disorder-induced localized state (mainly including carbonyl and carboxyl and epoxy groups). As the reduction degree increases, the photoluminescence (PL) quantum efficiency of GQDs increases dramatically from 2.6% to 10.1%. In the meantime, the PL peak position blue shifts rapidly, and full width at half maximum (FWHM) becomes narrower. Thus we can infer that graphenol topological defects (hydroxyl functionalized graphene) are gradually formed during reduction. Besides, graphenol defect related PL features a longer fluorescence lifetime, excitation wavelength dependence but less pH sensitivity. PMID- 26247889 TI - Temporal patterns of rat behaviour in the central platform of the elevated plus maze. Comparative analysis between male subjects of strains with different basal levels of emotionality. AB - We have analyzed the temporal patterns of behaviour of male rats of the Wistar and DA/Han strains on the central platform of the elevated plus maze. The ethogram encompassed 10 behavioural elements. Durations, frequencies and latencies showed quantitative differences as to walking and sniffing activities. Wistar rats displayed significantly lower latency and significantly higher durations and frequencies of walking activities. DA/Han rats showed a significant increase of sniffing duration. In addition, DA/Han rats showed a significantly higher amount of time spent in the central platform. Multivariate T-pattern analysis revealed differences in the temporal organization of behaviour of the two rat strains. DA/Han rats showed (a) higher behavioural complexity and variability and (b) a significantly higher mean number of T-patterns than Wistar rats. Taken together, T-pattern analysis of behaviour in the centre of the elevated plus maze can noticeably improve the detection of subtle features of anxiety related behaviour. We suggest that T-pattern analysis could be used as sensitive tool to test the action of anxiolytic and anxiogenic manipulations. PMID- 26247891 TI - Current perspectives on the dynamics of antibiotic resistance in different reservoirs. AB - Antibiotic resistance consists of a dynamic web. In this review, we describe the path by which different antibiotic residues and antibiotic resistance genes disseminate among relevant reservoirs (human, animal, and environmental settings), evaluating how these events contribute to the current scenario of antibiotic resistance. The relationship between the spread of resistance and the contribution of different genetic elements and events is revisited, exploring examples of the processes by which successful mobile resistance genes spread across different niches. The importance of classic and next generation molecular approaches, as well as action plans and policies which might aid in the fight against antibiotic resistance, are also reviewed. PMID- 26247888 TI - alpha-Synuclein and nonhuman primate models of Parkinson's disease. AB - Accumulation of alpha-synuclein (alpha-syn) leading to the formation of insoluble intracellular aggregates named Lewy bodies is proposed to have a significant role in Parkinson's disease (PD) pathology. Nonhuman primate (NHP) models of PD have proven essential for understanding the neurobiological basis of the disease and for the preclinical evaluation of first-in-class and invasive therapies. In addition to neurotoxin, aging and intracerebral gene transfer models, a new generation of models using inoculations of alpha-syn formulations, as well as transgenic methods is emerging. Understanding of their advantages and limitations will be essential when choosing a platform to evaluate alpha-syn-related pathology and interpreting the test results of new treatments targeting alpha-syn aggregation. In this review we aim to provide insight on this issue by critically analyzing the differences in endogenous alpha-syn, as well as alpha-syn pathology in PD and PD NHP models. PMID- 26247892 TI - Controlled delivery of SDF-1alpha and IGF-1: CXCR4(+) cell recruitment and functional skeletal muscle recovery. AB - Therapeutic delivery of regeneration-promoting biological factors directly to the site of injury has demonstrated its efficacy in various injury models. Several reports describe improved tissue regeneration following local injection of tissue specific growth factors, cytokines and chemokines. Evidence exists that combined cytokine/growth factor treatment is superior for optimizing tissue repair by targeting different aspects of the regeneration response. The purpose of this study was to evaluate the therapeutic potential of the controlled delivery of stromal cell-derived factor-1alpha (SDF-1alpha) alone or in combination with insulin-like growth factor-I (SDF-1alpha/IGF-I) for the treatment of tourniquet induced ischemia/reperfusion injury (TK-I/R) of skeletal muscle. We hypothesized that SDF-1alpha will promote sustained stem cell recruitment to the site of muscle injury, while IGF-I will induce progenitor cell differentiation to effectively restore muscle contractile function after TK-I/R injury while concurrently reducing apoptosis. Utilizing a novel poly-ethylene glycol PEGylated fibrin gel matrix (PEG-Fib), we incorporated SDF-1alpha alone (PEG-Fib/SDF 1alpha) or in combination with IGF-I (PEG-Fib/SDF-1alpha/IGF-I) for controlled release at the site of acute muscle injury. Despite enhanced cell recruitment and revascularization of the regenerating muscle after SDF-1alpha treatment, functional analysis showed no benefit from PEG-Fib/SDF-1alpha therapy, while dual delivery of PEG-Fib/SDF-1alpha/IGF-I resulted in IGF-I-mediated improvement of maximal force recovery and SDF-1alpha-driven in vivo neovasculogenesis. Histological data supported functional data, as well as highlighted the important differences in the regeneration process among treatment groups. This study provides evidence that while revascularization may be necessary for maximizing muscle force recovery, without modulation of other effects of inflammation it is insufficient. PMID- 26247893 TI - Brief Report: Sexual Risk Behaviors of HIV Seroconverters in the US Army, 2012 2014. AB - The United States (US) Army implemented a comprehensive HIV characterization program in 2012 following repeal of the Don't Ask, Don't Tell policy banning openly homosexual individuals from serving in the US military. Program staff administered a standardized case report form to soldiers newly diagnosed with HIV from 2012 to 2014 in compliance with new program requirements. The case report form documented sociodemographic, sexual, and other risk behavior information elicited from US Army regulation-mandated epidemiologic interviews at initial HIV notification. A majority of HIV-infected soldiers were male and of black/African American racial origin. In the HIV risk period, male soldiers commonly reported male-male sexual contact, civilian partners, online partner-seeking, unprotected anal sex, and expressed surprise at having a positive HIV result. Don't Ask, Don't Tell repeal allows for risk screening and reduction interventions targeting a newly identifiable risk category in the US Army. At-risk populations need to be identified and assessed for possible unmet health needs. PMID- 26247894 TI - Implementation and Operational Research: Risk Factors of Loss to Follow-up Among HIV-Positive Pediatric Patients in Dar es Salaam, Tanzania. AB - OBJECTIVE: To identify risk factors for loss to follow-up (LTFU) in an HIV infected pediatric population in Dar es Salaam, Tanzania, between 2004 and 2011. DESIGN: Longitudinal analysis of 6236 HIV-infected children. METHODS: We conducted a prospective cohort study of 6236 pediatric patients enrolled in care and treatment in Dar es Salaam from October 2004 to September 2011. LTFU was defined as missing a clinic visit for >90 days for patients on ART and for >180 days for patients in care and monitoring. The relationship of baseline and time varying characteristics to the risk of LTFU was examined using a Cox proportional hazards model. RESULTS: A total of 2130 children (34%) were LTFU over a median follow-up of 16.7 months (interquartile range, 3.4-36.9). Factors independently associated with a higher risk of LTFU were age <=2 years (relative risk [RR] = 1.59, 95% CI: 1.40 to 1.80), diarrhea at enrollment (RR = 1.20, 95% CI: 1.03 to 1.41), a low mid-upper arm circumference for age (RR = 1.20, CI: 1.05 to 1.37), eating protein-rich foods <=3 times a week (RR = 1.39, 95% CI: 1.05 to 1.90), taking cotrimoxazole (RR = 1.39, 95% CI: 1.06 to 1.81), initiating onto antiretrovirals (RR = 1.37, 95% CI: 1.17 to 1.61), receiving treatment at a hospital instead of a local facility (RR = 1.39, 95% CI: 1.06 to 1.41), and starting treatment in 2006 or later (RR = 1.10, 95% CI: 1.04 to 1.16). CONCLUSIONS: Health workers should be aware of pediatric patients who are at a greatest risk of LTFU, such as younger and undernourished patients, so that they can proactively counsel families about the importance of visit adherence. Findings support decentralization of HIV care to local facilities as opposed to hospitals. PMID- 26247896 TI - New insights: animal-borne cameras and accelerometers reveal the secret lives of cryptic species. AB - Logging cameras and accelerometers have opened our eyes to the secret lives of many enigmatic species. Here some of the new opportunities provided by this technology are reviewed. Recent discoveries are highlighted including the observation of selective feeding on energy-rich parts of prey. As such, biologging cameras provide new opportunities for consideration of selective feeding within the same sort of theoretical framework (marginal value theory/optimal foraging) that exploitation of prey patches has been examined. A recent study with the world's largest bony fish, the ocean sunfish (Mola mola), is highlighted where animal-borne cameras allowed the ground-truthing of data sets collected with depth recorders and accelerometers. This synergistic use of a range of biologging approaches will help drive an holistic understanding of the free-living behaviour of a range of species. PMID- 26247895 TI - Understanding HIV Care Provider Attitudes Regarding Intentions to Prescribe PrEP. AB - INTRODUCTION: Preexposure prophylaxis (PrEP) is a promising approach to reducing HIV incidence. So, garnering the support of HIV providers, who are most familiar with antiretrovirals and likely to encounter patients in HIV serodiscordant relationships, to scale-up PrEP implementation is essential. We sought to determine whether certain subgroups of HIV providers were more likely to intend to prescribe PrEP. METHODS: Surveys were administered to HIV providers in Miami, Florida and Washington, District of Columbia. Composite scores were developed to measure PrEP knowledge, experience, and likelihood of prescribing. Latent class analysis was used to stratify provider attitudes toward PrEP. RESULTS: Among 142 HIV providers, 73.2% had cared for more than 20 HIV-infected patients in the previous 3 months; 17% had ever prescribed PrEP. Latent class analysis identified 2 classes of providers (entropy, 0.904); class 1 (n = 95) found PrEP less effective and perceived barriers to prescribing it; class 2 (n = 47) perceived PrEP as moderately effective and perceived fewer barriers to prescribing it. Compared with class 2, class 1 had significantly less experience with PrEP delivery (t(22.7) = 2.88, P = 0.009) and was significantly less likely to intend to prescribe to patients with multiple sex partners (20% vs. 43%, P = 0.04) and those with a drug use history (7% vs. 24%, P = 0.001). CONCLUSIONS: Although most HIV providers found PrEP to be effective, those considering it less effective had limited knowledge and experience with PrEP and had lesser intentions to prescribe. Provider training regarding whom should receive PrEP and addressing potential barriers to PrEP provision are needed if this HIV prevention method is to be optimized. PMID- 26247897 TI - Ecotoxicity of neutral red (dye) and its environmental applications. AB - Neutral red (NR) is a synthetic phenazine with promising prospect in environmental biotechnology as an electron shuttle. Recently, NR injections into coal seam associated groundwater in Australia (final dissolved NR concentration: 8 uM +/- 0.2) were shown to increase methanogenesis up to ten-fold. However, information about NR toxicity to ecological receptors is sorely lacking. The main aim of this study was to investigate the concentration dependent toxicity of NR in microorganisms and plants. Acute toxicity of NR was determined by the modified MicrotoxTM assay. Microbial viability was determined using Escherichia coli and Bacillus subtilis. Germination and early growth of plants was studied using Lactuca sativa, Daucus carota, Allium cepa and an Australian native Themeda triandra. Lastly, mutagenicity of the coal seam associated groundwater was assessed using the Ames test. The EC50 of acute NR toxicity was determined to be 0.11 mM. The EC50 of microbial viability was between 1 and 7.1mM NR. Among the concentrations tested, only 0.01, 0.10 and 100mM of NR significantly affected (p<0.001) germination of L. sativa. The EC50 for root elongation in seeds was between 1.2 and 35.5mM NR. Interestingly, root elongation in seeds was significantly stimulated (p<0.001) between 0.25 and 10mM NR, showing a hormetic effect. A significant increase in mutagenicity was only observed in one of the three wells tested. The results suggest that the average dissolved NR concentration (8 uM +/- 0.2) deployed in the field trial at Lithgow State Coal Mine, Australia, appears not to negatively impact the ecological receptors tested in this study. PMID- 26247898 TI - Uptake and toxicity of glyphosate in the lichen Xanthoria parietina (L.) Th. Fr. AB - This study investigated if treatment of the lichen Xanthoria parietina (L.) Th. Fr. with glyphosate caused uptake of this herbicide as well as physiological alterations. Samples were treated with Glifene SL(r), a common commercial glyphosate-based herbicide, at the lowest recommended doses (3.6g/L) as well as with doses slightly higher than the highest suggested (36 g/L). The results clearly showed glyphosate uptake in X. parietina proportionally to the dose provided. Adverse physiological effects were evident on the photosynthetic apparatus (photosynthetic efficiency, chlorophyll a content, chlorophyll degradation) as well as on the fungal respiration rates and cell membrane integrity (ergosterol content, dehydrogenase activity) already after 24h from treatment, also at the low application dose. It is concluded that lichens are suitable organisms for monitoring unwanted biological effects from the application of glyphosate-based herbicides, as well as for detecting the accumulation of this compound in the biota, thus screening for its environmental fate. PMID- 26247899 TI - SMAD2 Mutations Are Associated with Arterial Aneurysms and Dissections. AB - We report three families with arterial aneurysms and dissections in which variants predicted to be pathogenic were identified in SMAD2. Moreover, one variant occurred de novo in a proband with unaffected parents. SMAD2 is a strong candidate gene for arterial aneurysms and dissections given its role in the TGF beta signaling pathway. Furthermore, although SMAD2 and SMAD3 probably have functionally distinct roles in cell signaling, they are structurally very similar. Our findings indicate that SMAD2 mutations are associated with arterial aneurysms and dissections and are in accordance with the observation that patients with pathogenic variants in genes encoding proteins involved in the TGF beta signaling pathway exhibit arterial aneurysms and dissections as key features. PMID- 26247900 TI - The changing landscape of respiratory syncytial virus. AB - Recognition of the acute and chronic burden of respiratory syncytial virus (RSV) lower respiratory tract infections (LRTI) sparked a wave of initiatives to develop preventive and therapeutic products against the pathogen in recent years. RSV is a leading cause of hospitalization in infants in industrialized and developing countries, has been causally linked to recurrent wheezing during childhood, associated with pediatric asthma, and is an important cause of mortality in the first months of life in the developing world. Significant changes in the epidemiology, clinical manifestations, and severe consequences of LRTI may emerge in the next decade with the advent of novel preventive strategies against RSV. This manuscript outlines some of these changes and discusses potential scenarios based on the current literature and experiences with other pathogens. PMID- 26247903 TI - About ISSX. PMID- 26247905 TI - 19th North American ISSX and 29th JSSX Meeting 19-23 October 2014 San Francisco, California, USA. PMID- 26247901 TI - Impact of the 13-valent pneumococcal conjugate vaccine (pcv13) on invasive pneumococcal disease and carriage in Alaska. AB - BACKGROUND: Alaska Native (AN) children have experienced high rates of invasive pneumococcal disease (IPD). In March 2010, PCV13 was introduced statewide in Alaska. We evaluated the impact of PCV13 on IPD in children and adults, 45 months after introduction. METHODS: Pneumococcal sterile site isolates, reported through state-wide surveillance, were serotyped using standard methods. We defined a pre PCV13 time period 2005-2008 and post-PCV13 time period April 2010-December 2013; excluding Jan 2009-March 2010 because PCV13 was introduced pre-licensure in one high-risk region in 2009. RESULTS: Among Alaska children <5 years, PCV13 serotypes comprised 65% of IPD in the pre-PCV13 period and 26% in the PCV13 period. Among all Alaska children <5 years, IPD rates decreased from 60.9 (pre) to 25.4 (post) per 100,000/year (P<0.001); PCV13 serotype IPD decreased from 37.7 to 6.4 (P<0.001). Among AN children <5 years, IPD rates decreased from 149.2 to 60.8 (P<0.001); PCV13 serotype IPD decreased from 87.0 to 17.4 (P<0.001); non PCV13 serotype IPD did not change significantly. Among persons 5-17 and >=45 years, the post-vaccine IPD rate was similar to the baseline period, but declined in persons 18-44 years (39%, P<0.001); this decline was similar in AN and non-AN persons (38%, P=0.016, 43%, P=0.014, respectively). CONCLUSIONS: Forty-five months after PCV13 introduction, overall IPD and PCV13-serotype IPD rates had decreased 58% and 83%, respectively, in Alaska children <5 years of age when compared with 2005-2008. We observed evidence of indirect effect among adults with a 39% reduction in IPD among persons 18-44 years. PMID- 26247906 TI - Upcoming ISSX Meetings. PMID- 26247907 TI - Abstracts from the 19th North American ISSX and 29th JSSX Meeting. PMID- 26247908 TI - Investigating Correlates of Suicide Among Male Youth: Questioning the Close Affinity Between Suicide Attempts and Deaths. AB - This study was based on a sample of male high school students who completed National Longitudinal Adolescent Health Surveys in 1994, 1995, and 2001. We studied these students prospectively, comparing those who later died by suicide (n = 21) with those who were still living (n = 10,101). We employed chi-square and analysis of variance tests for statistical significance between suicide decedents and living respondents. Results showed suicide decedents were more likely to have experienced the suicide loss of another family member, to have been expelled from school, to have engaged in more delinquent actions including fighting, and to have greater involvement with the criminal justice system. Although one might have expected suicide casualties to have exhibited a greater amount of suicidal thoughts, attempts, and higher incidences of suicidality among their friends, our analyses did not find that these factors were associated with actual suicides. Should these findings be replicated, this would point to a need to refine youth suicide risk assessments. Collecting life histories, as well as identifying patterns of delinquency and fighting, may serve as more potentially fruitful means for assessing genuine suicide risk than some traditional risk assessment methods.z. PMID- 26247909 TI - Does major depression affect risk for adolescent obesity? AB - OBJECTIVE: The purpose of this paper is to reexamine the association between major depression and obesity in adolescents, testing the hypothesis that body image mediates this association. This is the first paper to examine this question using DSM-IV diagnosis of depression and data from a two-wave cohort of adolescents. METHODS: Participants were 4175 youths 11-17 years of age sampled from the community who were followed up a year later (n=3134). Major depression was assessed using DSM-IV diagnostic criteria. Body image was measured with perceived weight. Obesity was defined as BMI >=95th percentile using measured height and weight. RESULTS: When we examined a model which included obesity, perceived weight, major depression and covariates, there was no association between major depression at baseline and obesity at follow-up. We found no independent association between major depression and body weight. LIMITATIONS: The study was limited in that it is not a national sample, BMI was the only measure of adiposity, perceived weight was the only measure of body image, and there were no data on lifetime trajectories of depression, obesity, or body image. CONCLUSIONS: If there is an etiologic link between major depression and body weight among adolescents, it most likely operates through processes involving components of body image, since controlling for body image eliminated the association between depression and obesity. Clinically, addressing body image in depressed patients who are obese may improve outcomes. PMID- 26247910 TI - Effect of electroconvulsive therapy on gray matter volume in major depressive disorder. AB - BACKGROUND: Although the clinical efficacy of electroconvulsive therapy (ECT) is well established, the underlying mechanisms of action remain elusive. The aim of this study was to elucidate structural changes of the brain following ECT in patients with major depressive disorder (MDD). METHOD: Fifteen patients with MDD underwent magnetic resonance imaging scanning before and after ECT. Their gray matter volumes were compared between pre- and post-ECT. RESULTS: There were significant volume increases after ECT in the bilateral medial temporal cortices, inferior temporal cortices, and right anterior cingulate. Further, the increase ratio was correlated with the clinical improvement measured by the Hamilton Depression Rating scale. LIMITATION: All subjects were treated with antidepressants that could have a neurotoxic or neuroprotective effect on the brain. CONCLUSIONS: We found that there were significant increases of gray matter volume in medial temporal lobes following ECT, suggesting that a neurotrophic effect of ECT could play a role in its therapeutic effect. PMID- 26247911 TI - Correlates of residual fatigue in patients with major depressive disorder: The role of psychotropic medication. AB - OBJECTIVE: Fatigue is not only a core symptom of major depressive disorder (MDD), but also a common residual symptom. We determined the sociodemographic, clinical, and pharmacologic factors that were associated with fatigue in patients with remission or partial remission of MDD. METHODS: Data was derived from a randomized controlled trial of acupuncture in 137 MDD patients with residual symptoms. Fatigue was measured by Multidimensional Fatigue Inventory (MFI-20). Self-report and clinician-rated scales were used to assess psychopathology. 17 item Hamilton Depression Rating Scale (HDRS17) score<=7 denoted MDD remission. RESULTS: Participants' average HDRS17 score was 10.5; 29.2% were in remission. The average MFI-20 score was 71.8; 83.2% had severe fatigue, defined as MFI-20 score>=60. Fifty-two of 137 participants (38%) were using sedating psychotropic medications. Antidepressant dosage ranged from 1-90mg fluoxetine equivalent and sedatives/hypnotics from 1-60mg diazepam equivalent. There were significant correlations between MFI-20 score and HDRS17 depression and anxiety subscores, Hospital Anxiety and Depression Scale (HADS) depression and anxiety subscores, and Pain Catastrophizing Scale score, but insomnia and daytime sleepiness, sociodemographics, current medical conditions, and psychotropic medication use were not significant correlates. Upon multiple regression, HADS and HDRS17 depression scores independently predicted MFI-20 score. In remission and partial remission subgroups, HADS depression score was an independent predictor. LIMITATION: Participants were recruited from specialty psychiatric units; hence the findings may not be applicable in non-specialized settings. CONCLUSION: Fatigue was predicted by depression severity in remitted or partially remitted MDD. Psychotropic medication and higher dosage were not associated with greater fatigue. PMID- 26247912 TI - Associations between the timing of childhood adversity and adulthood suicidal behavior: A nationally-representative cohort. AB - BACKGROUND: Although childhood adversities (CAs) are known to be associated with later suicidal behavior, it is uncertain whether the timing of specific CAs may influence this association. METHODS: We analyzed nationally representative data for 9205 participants from the Korean Welfare Panel Study. Four different CAs (parental death, parental divorce, suspension of school education and being raised in a relative's house due to financial strain) were assessed and were categorized as early childhood and adolescent onset. Lifetime experiences of suicidal behaviors along with the age of the first time experience were recorded. Cox regression was used. RESULTS: After adjusting for age, sex, and childhood socioeconomic status, parental death before the age of 12 was associated with adulthood suicidal behavior (ideation HR 1.35, 95% CI 1.13, 1.61; attempt HR 1.60, 95% CI 1.02, 2.52), while suspension of school due to financial strain was associated with suicidal behavior when it occurred at adolescence (ideation HR 1.48, 95% CI 1.22, 1.79; plan HR 1.69, 95% CI 1.16, 2.48). When we also adjusted for adulthood SES, which is a potential mediator, there was no significant change except that the association between early parental death and suicidal attempt became non-significant (HR: 1.43, 95% CI: 0.92, 2.26). LIMITATIONS: Experience of CA was assessed retrospectively, and the assessment of suicidal attempt was not specifically defined. There could be selection bias due to loss to the follow-up. CONCLUSIONS: There may be a critical period for the effect of CA on later suicidal behavior depending on the characteristics of CA. PMID- 26247913 TI - Training mental health professionals in suicide practice guideline adherence: Cost-effectiveness analysis alongside a randomized controlled trial. AB - BACKGROUND: There is a lack of information on the cost-effectiveness of suicide prevention interventions. The current study examines the cost-effectiveness of a multifaceted structured intervention aiming to improve adherence to the national suicide practice guideline in comparison with usual implementation. METHODS: In the intervention condition, professionals of psychiatric departments were trained using an e-learning supported Train-the-Trainer program. Newly admitted suicidal patients were assessed as soon as their department was trained and at 3 months follow-up. The primary outcome was improvement in suicide ideation. Missing cost and effect data were imputed using multiple imputation. Cost-effectiveness planes were plotted, and cost-effectiveness acceptability curves were estimated. RESULTS: For the total group of suicidal patients (n=566), no effect of the intervention on suicide ideation or costs was found. For a subgroup of depressed suicidal patients (n=154, intervention=75, control=79), mean level of suicide ideation decreased with 2.7 extra points in the intervention condition, but this was not statistically significant. For this subgroup, the intervention may be considered cost-effective in comparison with usual implementation if society is willing to pay>=? 6100 per unit of effect on the suicide ideation scale extra. LIMITATIONS: Considering the cost outcomes, we had almost no cases that were complete, and heavily relied on statistical techniques to impute the missing data. Also, diagnoses were not derived from structured clinical interviews. CONCLUSIONS: We presented the first randomized trial (trial registration: The Netherlands Trial Register (NTR3092 www.trialregister.nl)) on cost-effectiveness of a suicide practice guideline implementation in mental health care. The intervention might be considered cost-effective for depressed suicidal patients if society is willing to make substantial investments. PMID- 26247914 TI - Differentiating suicide attempters from suicide ideators using the Integrated Motivational-Volitional model of suicidal behaviour. AB - BACKGROUND: Suicidal behaviour is a significant public health concern, yet little is known about the factors that enable or impede behavioural enactment (engaging in a suicide attempt). AIMS: Drawing on the Integrated Motivational-Volitional (IMV) Model of Suicidal Behaviour (2011), this study examined the factors associated with having thoughts of suicide (ideation) versus those associated with suicide enaction (attempts). Within a multivariate context, it was predicted that the factors associated with ideation formation (motivational factors) would be distinct from those factors which governed behavioural enaction (volitional moderators). METHOD: Healthy adults (N=1, 288) completed an anonymous self-report survey. Analyses compared three groups: suicide attempters (n=230), suicide ideators (n=583), and those without any suicide history (n=475). RESULTS: Suicide attempters differed from suicide ideators on all volitional factors (fearlessness about death, impulsivity, and exposure to suicidal behaviour), with the exception of discomfort tolerance. Compared to ideators, attempters were more likely to have a family member and close friend who had self-injured or attempted suicide, and were more impulsive and fearless about death. Conversely, the two suicide groups did not differ on any of the variables (motivational factors) associated with the development of thoughts of death by suicide. LIMITATIONS: This is a cross-sectional study based on self-report measures. CONCLUSIONS: Further research efforts to distinguish between suicide ideators and suicide attempters is crucial to inform the development of intervention and treatment approaches. PMID- 26247915 TI - Strategy of total synthesis based on the use of Rh-catalyzed stereoselective 1,4 addition. AB - In 1998, Hayashi and Miyaura reported the first asymmetric conjugate addition of aryl- and alkenyl-boronic acids to alpha,beta-unsaturated ketones using chiral rhodium complexes as catalysts. During the last decade, this reaction has been developed quickly and the enantioselectivity was significantly improved with the emergence of new phosphine ligands. In addition to the methodological work, this reaction was applied as a key step in the total synthesis of natural compounds. The purpose of this paper focuses on examples of the use of this reaction to prepare elaborated chiral molecules with high diastereoselectivies and/or enantioselectivities. PMID- 26247916 TI - Pd-Catalyzed Ag(I)-Promoted C3-Arylation of Pyrido[1,2-a]pyrimidin-4-ones with Bromo/Iodo-Arenes. AB - A regioselective Ag(I)-promoted Pd-catalyzed C3-H activation-arylation of pyrido[1,2-a]pyrimidin-4-ones with bromo/iodo-(hetero)arenes under aqueous conditions has been developed. It affords an efficient access to pharmaceutically important versatile 3-aryl-pyrido[1,2-a]pyrimidin-4-ones. Interestingly, the arylation undergoes via a pathway with an unusual feature involving the formation of cationic arylpalladium species promoted by halo-sequestering Ag salts enabling concerted C3-palladation-deprotonation, as explored by relevant experiments and spectroscopic studies. The present approach is step economical, good yielding, and compatible with various functionalities and applicable to a wide range of starting materials. PMID- 26247917 TI - Concerns about aging and caregiving among middle-aged and older lesbian and gay adults. AB - OBJECTIVES: Despite the increasing number of lesbian and gay older adults, research geared towards health and well-being of this population is limited. Many lesbian and gay seniors experience health disparities and are at risk for poor health outcomes. The aims of this study were to gather in-depth information on the concerns of lesbian and gay elders with respect to aging and care needs. METHOD: The sample included 124 gay men and lesbian women aged 50+ years. Data were gathered via focus groups and questionnaires. The focus groups addressed: (1) concerns about aging in the LGBT community, (2) barriers to needed support and services, (3) concerns about caregiving and (4) needed programs for lesbian and gay seniors. RESULTS: Concerns expressed about aging included: lack of financial security, lack of family or social support, fears about the lack of someone to provide needed care, and discrimination in healthcare or service communities. Participants also indicated concerns about being alone and vulnerable and a need for resources and support programs, specifically for lesbian and gay older adults and for lesbian and gay caregivers. CONCLUSIONS: These findings suggest needed areas of support and programs for older gay men and lesbian women. They also suggest that healthcare professionals might need more training regarding the particular needs and concerns of this community. PMID- 26247918 TI - Tamoxifen Chemoprevention--End of the Road? PMID- 26247919 TI - The wide-ranging clinical implications of the short telomere syndromes. AB - There is an increasing number of inherited disorders in which excessive telomere shortening underlies the molecular defect, with dyskeratosis congenita (DC) being the archetypal short telomere syndrome. DC is classically described as a mucocutaneous triad of oral leukoplakia, nail dystrophy and abnormal skin pigmentation. However, excessive telomere shortening can affect almost any organ system, so the clinical manifestations are protean, including developmental delay, cerebellar hypoplasia, exudative retinopathy, aplastic anaemia, acute myeloid leukaemia, idiopathic pulmonary fibrosis, idiopathic hepatic cirrhosis, head and neck cancer and dental abnormalities, and may be multi-systemic. Undiagnosed patients may be seen by essentially any medical subspecialist. Correct diagnosis is important to ensure appropriate management, and for initiating investigations to identify affected family members. Treatment is often supportive, with transplantation offering cure for pulmonary fibrosis or bone marrow failure. Higher rates of mortality and morbidity with transplantation often require regimen alterations, underscoring the need for correct diagnosis. Short telomeres result from mutations in genes essential for telomere maintenance (e.g. genes encoding subunits of the telomerase enzyme complex). Disease severity reflects not only the severity of the defect, but also the inheritance of short telomeres, giving rise to incomplete penetrance and genetic anticipation. Attendees of the inaugural Australian Short Telomere Syndrome Conference were updated on the current scientific and clinical understanding of these disorders, and discussed the best approach for management of these patients in the Australian context. This review will include recommendations from the conference and aims to increase awareness of short telomere disorders. PMID- 26247921 TI - Nuclear Translocation of p65 is Controlled by Sec6 via the Degradation of IkappaBalpha. AB - Nuclear factor-kappaB (NF-kappaB) is an inducible transcription factor that mediates immune and inflammatory responses. NF-kappaB pathways are also involved in cell adhesion, differentiation, proliferation, autophagy, senescence, and protection against apoptosis. The deregulation of NF-kappaB activity is found in a number of disease states, including cancer, arthritis, chronic inflammation, asthma, neurodegenerative diseases, and heart disease. The 90 kDa ribosomal S6 kinase (p90RSK) family, which is serine/threonine kinases, is phosphorylated by extracellular signal-regulated kinase1/2 (ERK1/2) and is related to NF-kappaB pathways. Our previous studies revealed that Sec6, a component of the exocyst complex, plays specific roles in cell-cell adhesion and cell cycle arrest. However, the mechanism by which Sec6 regulates the NF-kappaB signaling pathway is unknown. We demonstrated that Sec6 knockdown inhibited the degradation of IkappaBalpha and delayed the nucleus-cytoplasm translocation of p65 in HeLa cells transfected with Sec6 siRNAs after treatment with tumor necrosis factor alpha (TNF-alpha). Furthermore, the binding of p65 and cAMP response element binding protein (CREB) binding protein (CBP) or p300 decreased and NF-kappaB related genes which were inhibitors of NF-kappaB alpha (IkappaBalpha), A20, B cell lymphoma protein 2 (Bcl-2), and monocyte chemoattractant protein-1 (MCP-1) were low in cells transfected with Sec6 siRNAs in response to TNF-alpha stimulation. Sec6 knockdown decreased the expression of p90RSKs and the phosphorylation of ERK or p90RSK1 at Ser380 or IkappaBalpha at Ser32. The present study suggests that Sec6 regulates NF-kappaB transcriptional activity via the control of the phosphorylation of IkappaBalpha, p90RSK1, and ERK. PMID- 26247920 TI - Deuterium oxide dilution and body composition in overweight and obese schoolchildren aged 6-9 years. AB - OBJECTIVE: To correlate different methods of body composition assessment in overweight or obese schoolchildren, using deuterium oxide (D2O) dilution as a reference. METHODS: Percentage of total body water (%TBW), fat free mass (%FFM), and body fat (%BF) were assessed by D2O and tetrapolar electrical bioimpedance analysis (BIA) in 54 obese and overweight students aged 6-9 years. Skinfold thickness (ST), body mass index (BMI), conicity index (CI), waist circumference (WC), waist-to-height ratio (WHtR), and waist-to-hip (WHR) ratio were also used. RESULTS: Mean values for body composition were 38.4%+/-8.4% BF, 44.9%+/-6.1% TBW and 61.6%+/-8.4% FFM. There was no significant difference in body weight, body fat mass (FM), TBW, and FFM between genders. Regarding D2O, ST underestimated %BF, and overestimated %FFM in both genders (p<0.05). BIA overestimated %TBW in the group as a whole and in males (p<0.05). The only positive and strong correlations occurred in females regarding the WC (sigma=0.679), CI (r=0.634), and WHtR (r=0.666). CONCLUSIONS: In this sample of obese and overweight children, there were strong correlations between body composition measured by D2O and some indices and anthropometric indicators in females, but there was no positive and strong correlation of fat tissue with the indices/indicators at all ages and in both genders. PMID- 26247922 TI - A digital microfluidic device with integrated nanostructured microelectrodes for electrochemical immunoassays. AB - Nanostructured microelectrodes (NMEs) are three-dimensional electrodes that have superb sensitivity for electroanalysis. Here we report the integration of NMEs with the versatile fluid-handling system digital microfluidics (DMF), for eventual application to distributed diagnostics outside of the laboratory. In the new methods reported here, indium tin oxide DMF top plates were modified to include Au NMEs as well as counter and pseudoreference electrodes. The new system was observed to outperform planar sensing electrodes of the type that are typically integrated with DMF. A rubella virus (RV) IgG immunoassay was developed to evaluate the diagnostic potential for the new system, relying on magnetic microparticles coated with RV particles and analysis by differential pulse voltammetry. The limit of detection of the assay (0.07 IU mL(-1)) was >100* below the World Health Organization defined cut-off for rubella immunity. The sensitivity of the integrated device and its small size suggest future utility for distributed diagnostics. PMID- 26247923 TI - New Rare Sinapoyl Acylated Flavonoid Glycosides Obtained from the Seeds of Lepidium apetalum Willd. AB - Seven new rare sinapoyl acylated flavonoid glycosides, apetalumosides A1 (1), B8 (2), B9 (3), B10 (4), B11 (5), B12 (6), and C1 (7) were isolated from the seeds of Lepidium apetalum Willd. Their structures were elucidated by chemical and spectroscopic methods. PMID- 26247924 TI - A Database of Force-Field Parameters, Dynamics, and Properties of Antimicrobial Compounds. AB - We present an on-line database of all-atom force-field parameters and molecular properties of compounds with antimicrobial activity (mostly antibiotics and some beta-lactamase inhibitors). For each compound, we provide the General Amber Force Field parameters for the major species at physiological pH, together with an analysis of properties of interest as extracted from us-long molecular dynamics simulations in explicit water solution. The properties include number and population of structural clusters, molecular flexibility, hydrophobic and hydrophilic molecular surfaces, the statistics of intraand inter-molecular H bonds, as well as structural and dynamical properties of solvent molecules within first and second solvation shells. In addition, the database contains several key molecular parameters, such as energy of the frontier molecular orbitals, vibrational properties, rotational constants, atomic partial charges and electric dipole moment, computed by Density Functional Theory. The present database (to our knowledge the first extensive one including dynamical properties) is part of a wider project aiming to build-up a database containing structural, physico chemical and dynamical properties of medicinal compounds using different force field parameters with increasing level of complexity and reliability. The database is freely accessible at http://www.dsf.unica.it/translocation/db/. PMID- 26247925 TI - Palladium-Catalyzed One-Pot Approach to 3-(Diarylmethylene)oxindoles from Propiolamidoaryl Triflate. AB - 3-(Diarylmethylene)oxindoles have been synthesized from propiolamidoaryl triflate utilizing a palladium-catalyzed one-pot reaction consisting of three successive reactions: Sonogashira, Heck, and Suzuki-Miyaura. This method allows for the production of a complex skeleton of 3-(diarylmethylene)oxindole from propiolamidoaryl triflate using a commercially available aryl iodide and arylboronic acid in a simple and efficient way with moderate yield and stereoselectivity. PMID- 26247926 TI - Comparative Immunogenicity of a Cytotoxic T Cell Epitope Delivered by Penetratin and TAT Cell Penetrating Peptides. AB - Cell penetrating peptides (CPP), including the TAT peptide from the human immunodeficiency virus transactivator of transcription (HIV-TAT) protein and penetratin from Drosophila Antennapedia homeodomain protein, translocate various cargos including peptides and proteins across cellular barriers. This mode of delivery has been harnessed by our group and others to deliver antigenic proteins or peptides into the cytoplasm of antigen processing cells (APC) such as monocyte derived dendritic cells (MoDC). Antigens or T cell epitopes delivered by CPP into APC in vivo generate antigen-specific cytotoxic T cell and helper T cell responses in mice. Furthermore, mice immunised with these peptides or proteins are protected from a tumour challenge. The functional properties of CPP are dependent on the various cargos being delivered and the target cell type. Despite several studies demonstrating superior immunogenicity of TAT and Antp-based immunogens, none has compared the immunogenicity of antigens delivered by TAT and Antp CPP. In the current study we demonstrate that a cytotoxic T cell epitope from the mucin 1 (MUC1) tumour associated antigen, when delivered by TAT or Antp, generates identical immune responses in mice resulting in specific MUC1 T cell responses as measured by in vivo CTL assays, IFNgamma ELISpot assays and prophylactic tumour protection. PMID- 26247927 TI - Nanostructures for the Inhibition of Viral Infections. AB - Multivalent interactions are omnipresent in biology and confer biological systems with dramatically enhanced affinities towards different receptors. Such multivalent binding interactions have lately been considered for the development of new therapeutic strategies against bacterial and viral infections. Multivalent polymers, dendrimers, and liposomes have successfully targeted pathogenic interactions. While a high synthetic effort was often needed for the development of such therapeutics, the integration of multiple ligands onto nanostructures turned to be a viable alternative. Particles modified with multiple ligands have the additional advantage of creating a high local concentration of binding molecules. This review article will summarize the different nanoparticle-based approaches currently available for the treatment of viral infections. PMID- 26247928 TI - Mosquitocidal and Oviposition Repellent Activities of the Extracts of Seaweed Bryopsis pennata on Aedes aegypti and Aedes albopictus. AB - The ever-increasing threat from infectious diseases and the development of insecticide resistance in mosquito populations drive the global search for new natural insecticides. The aims of this study were to evaluate the mosquitocidal activity of the extracts of seaweed Bryopsis pennata against dengue vectors Aedes aegypti and Aedes albopictus, and determine the seaweed's toxic effect on brine shrimp nauplii (as a non-target organism). In addition, the chemical compositions of the active larvicidal extract and fraction were analyzed by using liquid chromatography-mass spectrometry (LC-MS). Chloroform extract exhibited strong ovicidal activity (with LC50 values of 229.3 and 250.5 ug/mL) and larvicidal activity against Ae. aegypti and Ae. albopictus. The larvicidal potential of chloroform extract was further ascertained when its A7 fraction exhibited strong toxic effect against Ae. aegypti (LC50 = 4.7 ug/mL) and Ae. albopictus (LC50 = 5.3 ug/mL). LC-MS analysis of the chloroform extract gave a tentative identification of 13 compounds; Bis-(3-oxoundecyl) tetrasulfide was identified as the major compound in A7 fraction. Methanol extract showed strong repellent effect against female oviposition, along with weak adulticidal activity against mosquito and weak toxicity against brine shrimp nauplii. The mosquitocidal results of B. pennata suggest further investigation for the development of effective insecticide. PMID- 26247929 TI - The Efficacy and Underlying Mechanism of Sulfone Derivatives Containing 1,3,4 oxadiazole on Citrus Canker. AB - The objectives of the current study were to isolate and identify the pathogen responsible for citrus canker and investigate the efficacy of sulfone derivatives containing 1,3,4-oxadiazole moiety on controlling citrus canker caused by Xanthomonas citri subsp. citri (Xcc) under in vitro and field conditions. In an in vitro study, we tested eight sulfone derivatives against Xcc and the results demonstrated that compound 3 exhibited the best antibacterial activity against Xcc, with a half-maximal effective concentration (EC50) value of 1.23 MUg/mL, which was even better than those of commercial bactericides Kocide 3000 (58.21 MUg/mL) and Thiodiazole copper (77.04 MUg/mL), respectively. Meanwhile, under field experiments, compound 3 treatments demonstrated the highest ability to reduce the disease of citrus canker in leaves and fruits in two different places relative to an untreated control as well as the commercial bactericides Kocide 3000 and Thiodiazole copper. Meanwhile, compound 3 could stimulate the increase in peroxidase (POD), polyphenol oxidase (PPO), and phenylalanine ammonia lyase (PAL) activities in the navel orange leaves, causing marked enhancement of plant resistance against citrus canker. Moreover, compound 3 could damage the cell membranes, destruct the biofilm formation, inhibit the production of extracellular polysaccharide (EPS), and affect the cell membrane permeability to restrain the growth of the bacteria. PMID- 26247930 TI - Colloidal Stability & Conformational Changes in beta-Lactoglobulin: Unfolding to Self-Assembly. AB - A detailed understanding of the mechanism of unfolding, aggregation, and associated rheological changes is developed in this study for beta-Lactoglobulin at different pH values through concomitant measurements utilizing dynamic light scattering (DLS), optical microrheology, Raman spectroscopy, and differential scanning calorimetry (DSC). The diffusion interaction parameter kD emerges as an accurate predictor of colloidal stability for this protein consistent with observed aggregation trends and rheology. Drastic aggregation and gelation were observed at pH 5.5. Under this condition, the protein's secondary and tertiary structures changed simultaneously. At higher pH (7.0 and 8.5), oligomerizaton with no gel formation occurred. For these solutions, tertiary structure and secondary structure transitions were sequential. The low frequency Raman data, which is a good indicator of hydrogen bonding and structuring in water, has been shown to exhibit a strong correlation with the rheological evolution with temperature. This study has, for the first time, demonstrated that this low frequency Raman data, in conjunction with the DSC endotherm, can be been utilized to deconvolve protein unfolding and aggregation/gelation. These findings can have important implications for the development of protein-based biotherapeutics, where the formulation viscosity, aggregation, and stability strongly affects efficacy or in foods where protein structuring is critical for functional and sensory performance. PMID- 26247931 TI - BAMBI Promotes C2C12 Myogenic Differentiation by Enhancing Wnt/beta-Catenin Signaling. AB - Bone morphogenic protein and activin membrane-bound inhibitor (BAMBI) is regarded as an essential regulator of cell proliferation and differentiation that represses transforming growth factor-beta and enhances Wnt/beta-catenin signaling in various cell types. However, its role in skeletal muscle remains largely unknown. In the current study, we found that the expression level of BAMBI peaked in the early differentiation phase of the C2C12 rodent myoblast cell line. Knockdown of BAMBI via siRNA inhibited C2C12 differentiation, indicated by repressed MyoD, MyoG, and MyHC expression as well as reductions in the differentiation and fusion indices. BAMBI knockdown reduced the activity of Wnt/beta-catenin signaling, as characterized by the decreased nuclear translocation of beta-catenin and the lowered transcription of Axin2, which is a well-documented target gene of the Wnt/beta-catenin signaling pathway. Furthermore, treatment with LiCl, an activator of Wnt/beta-catenin signaling, rescued the reduction in C2C12 differentiation caused by BAMBI siRNA. Taken together, our data suggest that BAMBI is required for normal C2C12 differentiation, and that its role in myogenesis is mediated by the Wnt/beta catenin pathway. PMID- 26247932 TI - Hepatitis B Virus Infection, MicroRNAs and Liver Disease. AB - Hepatitis B virus (HBV) attacks the liver and can cause both acute as well as chronic liver diseases which might lead to liver cirrhosis and hepatocellular carcinoma. Regardless of the availability of a vaccine and numerous treatment options, HBV is a major cause of morbidity and mortality across the world. Recently,microRNAs (miRNAs) have emerged as important modulators of gene function. Studies on the role of miRNA in the regulation of hepatitis B virus gene expression have been the focus of modern antiviral research. miRNAs can regulate viral replication and pathogenesis in a number of different ways, which includefacilitation, direct or indirect inhibition, activation of immune response, epigenetic modulation, etc. Nevertheless, these mechanisms can appropriately be used with a diagnosticand/or therapeutic approach. The present review is an attempt to classify specific miRNAs that are reported to be associated with various aspects of hepatitis B biology, in order to precisely present the participation of individual miRNAs in multiple aspects relating to HBV. PMID- 26247933 TI - Mitochondrial Mechanisms in Septic Cardiomyopathy. AB - Sepsis is the manifestation of the immune and inflammatory response to infection that may ultimately result in multi organ failure. Despite the therapeutic strategies that have been used up to now, sepsis and septic shock remain a leading cause of death in critically ill patients. Myocardial dysfunction is a well-described complication of severe sepsis, also referred to as septic cardiomyopathy, which may progress to right and left ventricular pump failure. Many substances and mechanisms seem to be involved in myocardial dysfunction in sepsis, including toxins, cytokines, nitric oxide, complement activation, apoptosis and energy metabolic derangements. Nevertheless, the precise underlying molecular mechanisms as well as their significance in the pathogenesis of septic cardiomyopathy remain incompletely understood. A well-investigated abnormality in septic cardiomyopathy is mitochondrial dysfunction, which likely contributes to cardiac dysfunction by causing myocardial energy depletion. A number of mechanisms have been proposed to cause mitochondrial dysfunction in septic cardiomyopathy, although it remains controversially discussed whether some mechanisms impair mitochondrial function or serve to restore mitochondrial function. The purpose of this review is to discuss mitochondrial mechanisms that may causally contribute to mitochondrial dysfunction and/or may represent adaptive responses to mitochondrial dysfunction in septic cardiomyopathy. PMID- 26247934 TI - Ovine Hair Follicle Stem Cells Derived from Single Vibrissae Reconstitute Haired Skin. AB - Hair follicle stem cells (HFSCs) possess fascinating self-renewal capacity and multipotency, which play important roles in mammalian hair growth and skin wound repair. Although HFSCs from other mammalian species have been obtained, the characteristics of ovine HFSCs, as well as the methods to isolate them have not been well addressed. Here, we report an efficient strategy to obtain multipotent ovine HFSCs. Through microdissection and organ culture, we obtained keratinocytes that grew from the bulge area of vibrissa hair follicles, and even abundant keratinocytes were harvested from a single hair follicle. These bulge-derived keratinocytes are highly positive for Krt15, Krt14, Tp63, Krt19 and Itga6; in addition to their strong proliferation abilities in vitro, these keratinocytes formed new epidermis, hair follicles and sebaceous glands in skin reconstitution experiments, showing that these are HFSCs from the bulge outer root sheath. Taken together, we developed an efficient in vitro system to enrich ovine HFSCs, providing enough HFSCs for the investigations about the ovine hair cycle, aiming to promote wool production in the future. PMID- 26247935 TI - 2,6-Bis(1,4,7,10-tetraazacyclododecan-1-ylmethyl)pyridine and Its Benzene Analog as Nonmetallic Cleaving Agents of RNA Phosphodiester Linkages. AB - 2,6-Bis(1,4,7,10-tetraazacyclododecan-1-ylmethyl)pyridine (11a) and 1,3 bis(1,4,7,10-tetraazacyclododecan-1-ylmethyl)benzene (11b) have been shown to accelerate at 50 mmol.L-1 concentration both the cleavage and mutual isomerization of uridylyl-3',5'-uridine and uridylyl-2',5'-uridine by up to two orders of magnitude. The catalytically active ionic forms are the tri- (in the case of 11b) tetra- and pentacations. The pyridine nitrogen is not critical for efficient catalysis, since the activity of 11b is even slightly higher than that of 11a. On the other hand, protonation of the pyridine nitrogen still makes 11a approximately four times more efficient as a catalyst, but only for the cleavage reaction. Interestingly, the respective reactions of adenylyl-3',5'-adenosine were not accelerated, suggesting that the catalysis is base moiety selective. PMID- 26247936 TI - Composition, Cytotoxic and Antimicrobial Activities of Satureja intermedia C.A.Mey Essential Oil. AB - In this study, the essential oil (EO) constituents from the aerial parts of Satureja intermedia C.A.Mey were detected by GC and GC/MS. The antimicrobial activity of EO on oral pathogens and its cytotoxicity to human cancer cells were determined by the microbroth dilution method and the crystal violet staining method, respectively. Thirty-nine compounds were identified and the main EO constituents were gamma-terpinene (37.1%), thymol (30.2%), p-cymene (16.2%), limonene (3.9%), alpha-terpinene (3.3%), myrcene (2.5%), germacrene B (1.4%), elemicine (1.1%) and carvacrol (0.5%). The S. intermedia EO showed a concentration-dependent decrease in viability of Hep-G2 (hepatocellular carcinoma) and MCF-7 (breast adenocarcinoma) human cancer cell lines (p < 0.05). Antimicrobial screening of S. intermedia EO demonstrated slight antibacterial and antifungal activities against Streptococcus mutants, S. salivarius, Enterococcus faecalis, Staphylococcus aureus, Candida albicans and C. glabrata. Further preclinical studies are needed to assess the efficacy and safety of S. intermedia EO as a new promising anticancer agent. PMID- 26247937 TI - Renal Transcriptome Analysis of Programmed Hypertension Induced by Maternal Nutritional Insults. AB - Maternal nutrition can affect development, leading to long-term effects on the health of offspring. The most common outcome is programmed hypertension. We examined whether alterations in renal transcriptome are responsible for generating programmed hypertension among four different models using next generation RNA sequencing (NGS) technology. Pregnant Sprague-Dawley rats received 50% caloric restriction (CR), intraperitoneal injection of 45 mg/kg streptozotocin, 60% high-fructose (HF) diet, or 1% NaCl in drinking water to conduct CR, diabetes, HF, or high-salt models, respectively. All four models induced programmed hypertension in adult male offspring. We observed 16 shared genes in a two-week-old kidney among four different models. The identified differential expressed genes (DEGs) that are related to the regulation of blood pressure included Adrb3, Alb, Apoe, Calca, Kng1, Adm2, Guca2b, Hba2, Hba-a2, and Ppara. The peroxisome proliferator-activated receptor (PPAR) signaling pathway and glutathione metabolism pathway were shared by the CR, diabetes, and HF models. Conclusively, a variety of maternal nutritional insults induced the same phenotype-programmed hypertension with differential alterations of renal transcriptome in adult male offspring. The roles of DEGs identified by the NGS in this study deserve further clarification to develop ideal maternal dietary interventions and thus spare the next generations from the burden of hypertension. PMID- 26247938 TI - Direct Injection of CRISPR/Cas9-Related mRNA into Cytoplasm of Parthenogenetically Activated Porcine Oocytes Causes Frequent Mosaicism for Indel Mutations. AB - Some reports demonstrated successful genome editing in pigs by one-step zygote microinjection of mRNA of CRISPR/Cas9-related components. Given the relatively long gestation periods and the high cost of housing, the establishment of a single blastocyst-based assay for rapid optimization of the above system is required. As a proof-of-concept, we attempted to disrupt a gene (GGTA1) encoding the alpha-1,3-galactosyltransferase that synthesizes the alpha-Gal epitope using parthenogenetically activated porcine oocytes. The lack of alpha-Gal epitope expression can be monitored by staining with fluorescently labeled isolectin BS-I B4 (IB4), which binds specifically to the alpha-Gal epitope. When oocytes were injected with guide RNA specific to GGTA1 together with enhanced green fluorescent protein (EGFP) and human Cas9 mRNAs, 65% (24/37) of the developing blastocysts exhibited green fluorescence, although almost all (96%, 23/24) showed a mosaic fluorescent pattern. Staining with IB4 revealed that the green fluorescent area often had a reduced binding activity to IB4. Of the 16 samples tested, six (five fluorescent and one non-fluorescent blastocysts) had indel mutations, suggesting a correlation between EGFP expression and mutation induction. Furthermore, it is suggested that zygote microinjection of mRNAs might lead to the production of piglets with cells harboring various mutation types. PMID- 26247939 TI - The Involvement of Mutual Inhibition of ERK and mTOR in PLCgamma1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes. AB - The issue of whether ERK activation determines matrix synthesis or degradation in osteoarthritis (OA) pathogenesis currently remains controversial. Our previous study shows that PLCgamma1 and mTOR are involved in the matrix metabolism of OA cartilage. Investigating the interplays of PLCgamma1, mTOR and ERK in matrix degradation of OA will facilitate future attempts to manipulate ERK in OA prevention and therapy. Here, cultured human normal chondrocytes and OA chondrocytes were treated with different inhibitors or transfected with expression vectors, respectively. The levels of ERK, p-ERK, PLCgamma1, p PLCgamma1, mTOR, p-mTOR and MMP-13 were then evaluated by Western blotting analysis. The results manifested that the expression level of ERK in human OA chondrocytes was lower than that in human normal articular chondrocytes, and the up-regulation of ERK could promote matrix synthesis, including the decrease in MMP-13 level and the increase in Aggrecan level in human OA chondrocytes. Furthermore, the PLCgamma1/ERK axis and a mutual inhibition of mTOR and ERK were observed in human OA chondrocytes. Interestingly, activated ERK had no inhibitory effect on MMP-13 expression in PLCgamma1-transformed OA chondrocytes. Combined with our previous study, the non-effective state of ERK activation by PLCgamma1 on MMP-13 may be partly attributed to the inhibition of the PLCgamma1/mTOR axis on the PLCgamma1/ERK axis. Therefore, the study indicates that the mutual inhibition of ERK and mTOR is involved in PLCgamma1-mediated MMP-13 expression in human OA chondrocytes, with important implication for the understanding of OA pathogenesis as well as for its prevention and therapy. PMID- 26247940 TI - A Pilot Study of the Photoprotective Effects of Strawberry-Based Cosmetic Formulations on Human Dermal Fibroblasts. AB - Strawberry polyphenols have been extensively studied over the last two decades for their beneficial properties. Recently, their possible use in ameliorating skin conditions has also been proposed; however, their role in preventing UVA induced damage in cosmetic formulation has not yet been investigated. Skin is constantly exposed to several environmental stressors, such as UVA radiation, that induce oxidative stress, inflammation and cell death via the production of reactive oxygen species (ROS). In the present study, we assessed the potential photoprotective capacity of different strawberry-based formulations, enriched with nanoparticles of Coenzyme Q10 and with sun protection factor 10 (SPF10), in human dermal fibroblasts (HuDe) exposed to UVA radiation. We confirmed that strawberries are a very rich source of polyphenols, anthocyanins and vitamins, and possess high total antioxidant capacity. We also showed that strawberry extracts (25 MUg/mL-1 mg/mL) exert a noticeable photoprotection in HuDe, increasing cell viability in a dose-dependent way, and that these effects are potentiated by the presence of CoQ10red (100 MUg/mL). We have demonstrated for the first time that the topical use of strawberry extract may provide good photoprotection, even if more in-depth studies are strongly encouraged in order to evaluate the cellular and molecular effects of strawberry protection. PMID- 26247941 TI - Involvement of Ethylene in the Latex Metabolism and Tapping Panel Dryness of Hevea brasiliensis. AB - Ethephon, an ethylene releaser, is used to stimulate latex production in Hevea brasiliensis. Ethylene induces many functions in latex cells including the production of reactive oxygen species (ROS). The accumulation of ROS is responsible for the coagulation of rubber particles in latex cells, resulting in the partial or complete stoppage of latex flow. This study set out to assess biochemical and histological changes as well as changes in gene expression in latex and phloem tissues from trees grown under various harvesting systems. The Tapping Panel Dryness (TPD) susceptibility of Hevea clones was found to be related to some biochemical parameters, such as low sucrose and high inorganic phosphorus contents. A high tapping frequency and ethephon stimulation induced early TPD occurrence in a high latex metabolism clone and late occurrence in a low latex metabolism clone. TPD-affected trees had smaller number of laticifer vessels compared to healthy trees, suggesting a modification of cambial activity. The differential transcript abundance was observed for twenty-seven candidate genes related to TPD occurrence in latex and phloem tissues for ROS-scavenging, ethylene biosynthesis and signalling genes. The predicted function for some Ethylene Response Factor genes suggested that these candidate genes should play an important role in regulating susceptibility to TPD. PMID- 26247942 TI - Membrane Affinity of Platensimycin and Its Dialkylamine Analogs. AB - Membrane permeability is a desired property in drug design, but there have been difficulties in quantifying the direct drug partitioning into native membranes. Platensimycin (PL) is a new promising antibiotic whose biosynthetic production is costly. Six dialkylamine analogs of PL were synthesized with identical pharmacophores but different side chains; five of them were found inactive. To address the possibility that their activity is limited by the permeation step, we calculated polarity, measured surface activity and the ability to insert into the phospholipid monolayers. The partitioning of PL and the analogs into the cytoplasmic membrane of E. coli was assessed by activation curve shifts of a re engineered mechanosensitive channel, MscS, in patch-clamp experiments. Despite predicted differences in polarity, the affinities to lipid monolayers and native membranes were comparable for most of the analogs. For PL and the di-myrtenyl analog QD-11, both carrying bulky sidechains, the affinity for the native membrane was lower than for monolayers (half-membranes), signifying that intercalation must overcome the lateral pressure of the bilayer. We conclude that the biological activity among the studied PL analogs is unlikely to be limited by their membrane permeability. We also discuss the capacity of endogenous tension activated channels to detect asymmetric partitioning of exogenous substances into the native bacterial membrane and the different contributions to the thermodynamic force which drives permeation. PMID- 26247943 TI - Conformational Motions and Functionally Key Residues for Vitamin B12 Transporter BtuCD-BtuF Revealed by Elastic Network Model with a Function-Related Internal Coordinate. AB - BtuCD-BtuF from Escherichia coli is a binding protein-dependent adenosine triphosphate (ATP)-binding cassette (ABC) transporter system that uses the energy of ATP hydrolysis to transmit vitamin B12 across cellular membranes. Experimental studies have showed that during the transport cycle, the transporter undergoes conformational transitions between the "inward-facing" and "outward-facing" states, which results in the open-closed motions of the cytoplasmic gate of the transport channel. The opening-closing of the channel gate play critical roles for the function of the transporter, which enables the substrate vitamin B12 to be translocated into the cell. In the present work, the extent of opening of the cytoplasmic gate was chosen as a function-related internal coordinate. Then the mean-square fluctuation of the internal coordinate, as well as the cross correlation between the displacement of the internal coordinate and the movement of each residue in the protein, were calculated based on the normal mode analysis of the elastic network model to analyze the function-related motions encoded in the structure of the system. In addition, the key residues important for the functional motions of the transporter were predicted by using a perturbation method. In order to facilitate the calculations, the internal coordinate was introduced as one of the axes of the coordinate space and the conventional Cartesian coordinate space was transformed into the internal/Cartesian space with linear approximation. All the calculations were carried out in this internal/Cartesian space. Our method can successfully identify the functional motions and key residues for the transporter BtuCD-BtuF, which are well consistent with the experimental observations. PMID- 26247944 TI - Combined Screening for Early Detection of Pre-Eclampsia. AB - Although the precise pathophysiology of pre-eclampsia remains unknown, this condition continues to be a major cause of maternal and fetal mortality. Early prediction of pre-eclampsia would allow for timely initiation of preventive therapy. A combination of biophysical and biochemical markers are superior to other tests for early prediction of the development of pre-eclampsia. Apart from the use of parameters in first-trimester aneuploidy screening, cell-free fetal DNA quantification is emerging as a promising marker for prediction of pre eclampsia. This article reviews the current research of the most important strategies for prediction of pre-eclampsia, including the use of maternal risk factors, mean maternal arterial pressure, ultrasound parameters, and biomarkers. PMID- 26247945 TI - Effect of Heavy Metals in Plants of the Genus Brassica. AB - Several species from the Brassica genus are very important agricultural crops in different parts of the world and are also known to be heavy metal accumulators. There have been a large number of studies regarding the tolerance, uptake and defense mechanism in several of these species, notably Brassica juncea and B. napus, against the stress induced by heavy metals. Numerous studies have also been published about the capacity of these species to be used for phytoremediation purposes but with mixed results. This review will focus on the latest developments in the study of the uptake capacity, oxidative damage and biochemical and physiological tolerance and defense mechanisms to heavy metal toxicity on six economically important species: B. juncea, B. napus, B. oleracea, B. carinata, B. rapa and B. nigra. PMID- 26247946 TI - Experimental and Theoretical Investigations on the Supermolecular Structure of Isoliquiritigenin and 6-O-alpha-D-Maltosyl-beta-cyclodextrin Inclusion Complex. AB - Isoliquiritigenin (ILTG) possesses many pharmacological properties. However, its poor solubility and stability in water hinders its wide applications. The solubility of bioactive compounds can often be enhanced through preparation and delivery of various cyclodextrin (CD) inclusion complexes. The 6-O-alpha-D maltosyl-beta-CD (G2-beta-CD), as one of the newest developments of CDs, has high aqueous solubility and low toxicity, especially stable inclusion characteristics with bioactive compounds. In this work, we for the first time construct and characterize the supermolecular structure of ILTG/G2-beta-CD by scanning electron microscopy (SEM), ultraviolet-visible spectroscopy (UV), Fourier transform infrared spectroscopy (FT-IR), and X-ray diffractometry (XRD). The solubility of ILTG in water at 25 degrees C rises from 0.003 to 0.717 mg/mL by the encapsulation with G2-beta-CD. Our experimental observations on the presence of the ILTG/G2-beta-CD inclusion complex are further supported by the ONIOM(our Own N-layer Integrated Orbital molecular Mechanics)-based QM/MM (Quantum Mechanics/Molecular Mechanics) calculations, typically substantiating these supermolecular characteristics, such as detailed structural assignments, preferred binding orientations, selectivity, solvent effects, interaction energies and forces of the ILTG/G2-beta-CD inclusion complex. Our results have elucidated how ILTG interacts with G2-beta-CD, demonstrating the primary host guest interactions between ILTG and G2-beta-CD, characterized by hydrogen bonds, hydrophobic interactions, electrostatic forces, and conformational effects, are favored for the formation of the ILTG/G2-beta-CD inclusion. PMID- 26247947 TI - An Arduino-Based Resonant Cradle Design with Infant Cries Recognition. AB - This paper proposes a resonant electric cradle design with infant cries recognition, employing an Arduino UNO as the core processor. For most commercially available electric cradles, the drive motor is closely combined with the bearing on the top, resulting in a lot of energy consumption. In this proposal, a ball bearing design was adopted and the driving force is under the cradle to increase the distance from the object to fulcrum and torque. The sensors are designed to detect the oscillation state, and then the force is driven at the critical time to achieve the maximum output response while saving energy according to the principle of resonance. As for the driving forces, the winding power and motors are carefully placed under the cradle. The sensors, including the three-axis accelerometer and infrared sensor, are tested and applied under swinging amplitude control. In addition, infant cry recognition technology was incorporated in the design to further develop its functionality, which is a rare feature in this kind of hardware. The proposed nonlinear operator of fundamental frequency (f0) analysis is able to identify different types of infant cries. In conclusion, this paper proposes an energy-saving electric cradle with infant cries recognition and the experimental results demonstrate the effectiveness of this approach. PMID- 26247948 TI - Monitoring of Weekly Sleep Pattern Variations at Home with a Contactless Biomotion Sensor. AB - Many people find that their sleep is restricted or disturbed by social obligations, including work. Sleep phase delays can affect an individual's circadian rhythms on the following day and cause daytime sleepiness and/or poor performance. In this study, to examine weekly variations in sleep patterns, we analyzed sleep data for seven-day periods (from Sunday to Saturday) that had been collected from 2914 subjects (aged 20-79 years) over a total of 24,899 subject weeks using contactless biomotion sensors. On the weekend, the subjects' mean sleep midpoint, bedtime, and wake-up time were delayed by 40, 26 and 53 min, respectively, compared with those seen on weekdays. In addition, on weekdays, the mean difference between the maximum and median sleep midpoint ranged from 35 to 47 min among the subjects in their 20 s-70 s. The weekend delay and weekday variation in the subjects' sleep patterns tended to decrease with age. This study detected sleep pattern disturbances on both weekdays and weekends. The serial changes in weekday bedtimes detected in this study suggest that sleep habits are influenced by changes in the temporal patterns of social activities/duties. We need further study the advantages of getting extra sleep and the disadvantages of sleep pattern disturbances in daily lifestyle. PMID- 26247949 TI - Multiple-Layer Visibility Propagation-Based Synthetic Aperture Imaging through Occlusion. AB - Heavy occlusions in cluttered scenes impose significant challenges to many computer vision applications. Recent light field imaging systems provide new see through capabilities through synthetic aperture imaging (SAI) to overcome the occlusion problem. Existing synthetic aperture imaging methods, however, emulate focusing at a specific depth layer, but are incapable of producing an all-in focus see-through image. Alternative in-painting algorithms can generate visually plausible results, but cannot guarantee the correctness of the results. In this paper, we present a novel depth-free all-in-focus SAI technique based on light field visibility analysis. Specifically, we partition the scene into multiple visibility layers to directly deal with layer-wise occlusion and apply an optimization framework to propagate the visibility information between multiple layers. On each layer, visibility and optimal focus depth estimation is formulated as a multiple-label energy minimization problem. The layer-wise energy integrates all of the visibility masks from its previous layers, multi-view intensity consistency and depth smoothness constraint together. We compare our method with state-of-the-art solutions, and extensive experimental results demonstrate the effectiveness and superiority of our approach. PMID- 26247950 TI - Extrinsic Calibration of Camera Networks Using a Sphere. AB - In this paper, we propose a novel extrinsic calibration method for camera networks using a sphere as the calibration object. First of all, we propose an easy and accurate method to estimate the 3D positions of the sphere center w.r.t. the local camera coordinate system. Then, we propose to use orthogonal procrustes analysis to pairwise estimate the initial camera relative extrinsic parameters based on the aforementioned estimation of 3D positions. Finally, an optimization routine is applied to jointly refine the extrinsic parameters for all cameras. Compared to existing sphere-based 3D position estimators which need to trace and analyse the outline of the sphere projection in the image, the proposed method requires only very simple image processing: estimating the area and the center of mass of the sphere projection. Our results demonstrate that we can get a more accurate estimate of the extrinsic parameters compared to other sphere-based methods. While existing state-of-the-art calibration methods use point like features and epipolar geometry, the proposed method uses the sphere-based 3D position estimate. This results in simpler computations and a more flexible and accurate calibration method. Experimental results show that the proposed approach is accurate, robust, flexible and easy to use. PMID- 26247951 TI - Daily Quantity of Infant Leg Movement: Wearable Sensor Algorithm and Relationship to Walking Onset. AB - BACKGROUND: Normative values are lacking for daily quantity of infant leg movements. This is critical for understanding the relationship between the quantity of leg movements and onset of independent walking, and will begin to inform early therapy intervention for infants at risk for developmental delay. METHODS: We used wearable inertial movement sensors to record full-day leg movement activity from 12 infants with typical development, ages 1-12 months. Each infant was tested three times across 5 months, and followed until the onset of independent walking. We developed and validated an algorithm to identify infant-produced leg movements. RESULTS: Infants moved their legs tens of thousands of times per day. There was a significant effect of leg movement quantity on walking onset. Infants who moved their legs more walked later than infants who moved their legs less, even when adjusting for age, developmental level or percentile length. We will need a much larger sample to adequately capture and describe the effect of movement experience on developmental rate. Our algorithm defines a leg movement in a specific way (each pause or change in direction is counted as a new movement), and further assessment of movement characteristics are necessary before we can fully understand and interpret our finding that infants who moved their legs more walked later than infants who moved their legs less. CONCLUSIONS: We have shown that typically-developing infants produce thousands of leg movements in a typical day, and that this can be accurately captured in the home environment using wearable sensors. In our small sample we can identify there is an effect of leg movement quantity on walking onset, however we cannot fully explain it. PMID- 26247952 TI - Raman Spectroscopy of Optically Trapped Single Biological Micro-Particles. AB - The combination of optical trapping with Raman spectroscopy provides a powerful method for the study, characterization, and identification of biological micro particles. In essence, optical trapping helps to overcome the limitation imposed by the relative inefficiency of the Raman scattering process. This allows Raman spectroscopy to be applied to individual biological particles in air and in liquid, providing the potential for particle identification with high specificity, longitudinal studies of changes in particle composition, and characterization of the heterogeneity of individual particles in a population. In this review, we introduce the techniques used to integrate Raman spectroscopy with optical trapping in order to study individual biological particles in liquid and air. We then provide an overview of some of the most promising applications of this technique, highlighting the unique types of measurements enabled by the combination of Raman spectroscopy with optical trapping. Finally, we present a brief discussion of future research directions in the field. PMID- 26247953 TI - Effects of Meteorological Conditions on PM2.5 Concentrations in Nagasaki, Japan. AB - The fine particulate matter (PM2.5) problem has attracted much scientific and public attention, due to its effects on visibility, human health, and global climate. There are three factors that have important effect on PM2.5 mass concentration: domestic pollutant emission sources, external sources outside of the country, and the meteorological conditions. Nagasaki is a coastal prefecture located at the westernmost part of Japan, which is an ideal location to study pollutants from long range transport and correlation between PM2.5 and meteorological conditions. In this paper, PM2.5 concentration data and meteorological data were obtained during 1 January 2013~31 December 2013. The spatial distribution depicts that the western part of the study area has the most serious PM2.5 pollution. The correlation analysis results between PM2.5 concentration and meteorological data showed that temperature had a negative, and precipitation had a positive, correlation with PM2.5. There was a threshold in the correlations between humidity and wind speed and PM2.5. The correlation was positive or negative depending on the meteorological variable values, if these were lower or higher than the threshold. From the relationship with wind direction, it can be depicted that the west wind might bring the most pollutants to Nagasaki. PMID- 26247954 TI - Whole-Genome Analysis of a Novel Fish Reovirus (MsReV) Discloses Aquareovirus Genomic Structure Relationship with Host in Saline Environments. AB - Aquareoviruses are serious pathogens of aquatic animals. Here, genome characterization and functional gene analysis of a novel aquareovirus, largemouth bass Micropterus salmoides reovirus (MsReV), was described. It comprises 11 dsRNA segments (S1-S11) covering 24,024 bp, and encodes 12 putative proteins including the inclusion forming-related protein NS87 and the fusion-associated small transmembrane (FAST) protein NS22. The function of NS22 was confirmed by expression in fish cells. Subsequently, MsReV was compared with two representative aquareoviruses, saltwater fish turbot Scophthalmus maximus reovirus (SMReV) and freshwater fish grass carp reovirus strain 109 (GCReV-109). MsReV NS87 and NS22 genes have the same structure and function with those of SMReV, whereas GCReV-109 is either missing the coiled-coil region in NS79 or the gene-encoding NS22. Significant similarities are also revealed among equivalent genome segments between MsReV and SMReV, but a difference is found between MsReV and GCReV-109. Furthermore, phylogenetic analysis showed that 13 aquareoviruses could be divided into freshwater and saline environments subgroups, and MsReV was closely related to SMReV in saline environments. Consequently, these viruses from hosts in saline environments have more genomic structural similarities than the viruses from hosts in freshwater. This is the first study of the relationships between aquareovirus genomic structure and their host environments. PMID- 26247955 TI - Papillomavirus Infectious Pathways: A Comparison of Systems. AB - The HPV viral lifecycle is tightly linked to the host cell differentiation, causing difficulty in growing virions in culture. A system that bypasses the need for differentiating epithelium has allowed for generation of recombinant particles, such as virus-like particles (VLPs), pseudovirions (PsV), and quasivirions (QV). Much of the research looking at the HPV life cycle, infectivity, and structure has been generated utilizing recombinant particles. While recombinant particles have proven to be invaluable, allowing for a rapid progression of the HPV field, there are some significant differences between recombinant particles and native virions and very few comparative studies using native virions to confirm results are done. This review serves to address the conflicting data in the HPV field regarding native virions and recombinant particles. PMID- 26247956 TI - Translational Control of the HIV Unspliced Genomic RNA. AB - Post-transcriptional control in both HIV-1 and HIV-2 is a highly regulated process that commences in the nucleus of the host infected cell and finishes by the expression of viral proteins in the cytoplasm. Expression of the unspliced genomic RNA is particularly controlled at the level of RNA splicing, export, and translation. It appears increasingly obvious that all these steps are interconnected and they result in the building of a viral ribonucleoprotein complex (RNP) that must be efficiently translated in the cytosolic compartment. This review summarizes our knowledge about the genesis, localization, and expression of this viral RNP. PMID- 26247957 TI - Vpu Protein: The Viroporin Encoded by HIV-1. AB - Viral protein U (Vpu) is a lentiviral viroporin encoded by human immunodeficiency virus type 1 (HIV-1) and some simian immunodeficiency virus (SIV) strains. This small protein of 81 amino acids contains a single transmembrane domain that allows for supramolecular organization via homoligomerization or interaction with other proteins. The topology and trafficking of Vpu through subcellular compartments result in pleiotropic effects in host cells. Notwithstanding the high variability of its amino acid sequence, the functionality of Vpu is well conserved in pandemic virus isolates. This review outlines our current knowledge on the interactions of Vpu with the host cell. The regulation of cellular physiology by Vpu and the validity of this viroporin as a therapeutic target are also discussed. PMID- 26247958 TI - Neurosurgical Techniques for Disruption of the Blood-Brain Barrier for Glioblastoma Treatment. AB - The blood-brain barrier remains a main hurdle to drug delivery to the brain. The prognosis of glioblastoma remains grim despite current multimodal medical management. We review neurosurgical technologies that disrupt the blood-brain barrier (BBB). We will review superselective intra-arterial mannitol infusion, focused ultrasound, laser interstitial thermotherapy, and non-thermal irreversible electroporation (NTIRE). These technologies can lead to transient BBB and blood-brain tumor barrier disruption and allow for the potential of more effective local drug delivery. Animal studies and preliminary clinical trials show promise for achieving this goal. PMID- 26247959 TI - Influence of Differing Analgesic Formulations of Aspirin on Pharmacokinetic Parameters. AB - Aspirin has been used therapeutically for over 100 years. As the originator and an important marketer of aspirin-containing products, Bayer's clinical trial database contains numerous reports of the pharmacokinetics of various aspirin formulations. These include evaluations of plain tablets, effervescent tablets, granules, chewable tablets, and fast-release tablets. This publication seeks to expand upon the available pharmacokinetic information concerning aspirin formulations. In the pre-systemic circulation, acetylsalicylic acid (ASA) is rapidly converted into its main active metabolite, salicylic acid (SA). Therefore, both substances are measured in plasma and reported in the results. The 500 mg strength of each formulation was chosen for analysis as this is the most commonly used for analgesia. A total of 22 studies were included in the analysis. All formulations of 500 mg aspirin result in comparable plasma exposure to ASA and SA as evidenced by AUC. Tablets and dry granules provide a consistently lower Cmax compared to effervescent, granules in suspension and fast release tablets. Effervescent tablets, fast release tablets, and granules in suspension provide a consistently lower median Tmax compared to dry granules and tablets for both ASA and SA. This report reinforces the importance of formulation differences and their impact on pharmacokinetic parameters. PMID- 26247960 TI - The Pattern of Fatty Acids Displaced by EPA and DHA Following 12 Months Supplementation Varies between Blood Cell and Plasma Fractions. AB - Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are increased in plasma lipids and blood cell membranes in response to supplementation. Whilst arachidonic acid (AA) is correspondingly decreased, the effect on other fatty acids (FA) is less well described and there may be site-specific differences. In response to 12 months EPA + DHA supplementation in doses equivalent to 0-4 portions of oily fish/week (1 portion: 3.27 g EPA+DHA) multinomial regression analysis was used to identify important FA changes for plasma phosphatidylcholine (PC), cholesteryl ester (CE) and triglyceride (TAG) and for blood mononuclear cells (MNC), red blood cells (RBC) and platelets (PLAT). Dose-dependent increases in EPA + DHA were matched by decreases in several n-6 polyunsaturated fatty acids (PUFA) in PC, CE, RBC and PLAT, but were predominantly compensated for by oleic acid in TAG. Changes were observed for all FA classes in MNC. Consequently the n 6:n-3 PUFA ratio was reduced in a dose-dependent manner in all pools after 12 months (37%-64% of placebo in the four portions group). We conclude that the profile of the FA decreased in exchange for the increase in EPA + DHA following supplementation differs by FA pool with implications for understanding the impact of n-3 PUFA on blood lipid and blood cell biology. PMID- 26247961 TI - Partial Enteral Nutrition Preserves Elements of Gut Barrier Function, Including Innate Immunity, Intestinal Alkaline Phosphatase (IAP) Level, and Intestinal Microbiota in Mice. AB - Lack of enteral nutrition (EN) during parenteral nutrition (PN) leads to higher incidence of infection because of gut barrier dysfunction. However, the effects of partial EN on intestina linnate immunity, intestinal alkaline phosphatase (IAP) and microbiota remain unclear. The mice were randomized into six groups to receive either standard chow or isocaloric and isonitrogenous nutritional support with variable partial EN to PN ratios. Five days later, the mice were sacrificed and tissue samples were collected. Bacterial translocation, the levels of lysozyme, mucin 2 (MUC2), and IAP were analyzed. The composition of intestinal microbiota was analyzed by 16S rRNA pyrosequencing. Compared with chow, total parenteral nutrition (TPN) resulted in a dysfunctional mucosal barrier, as evidenced by increased bacterial translocation (p < 0.05), loss of lysozyme, MUC2, and IAP, and changes in the gut microbiota (p < 0.001). Administration of 20% EN supplemented with PN significantly increased the concentrations of lysozyme, MUC2, IAP, and the mRNA levels of lysozyme and MUC2 (p < 0.001). The percentages of Bacteroidetes and Tenericutes were significantly lower in the 20% EN group than in the TPN group (p < 0.001). These changes were accompanied by maintained barrier function in bacterial culture (p < 0.05). Supplementation of PN with 20% EN preserves gut barrier function, by way of maintaining innate immunity, IAP and intestinal microbiota. PMID- 26247962 TI - Rice Bran Protein Hydrolysates Improve Insulin Resistance and Decrease Pro inflammatory Cytokine Gene Expression in Rats Fed a High Carbohydrate-High Fat Diet. AB - A high carbohydrate-high fat (HCHF) diet causes insulin resistance (IR) and metabolic syndrome (MS). Rice bran has been demonstrated to have anti dyslipidemic and anti-atherogenic properties in an obese mouse model. In the present study, we investigated the beneficial effects of rice bran protein hydrolysates (RBP) in HCHF-induced MS rats. After 12 weeks on this diet, the HCHF fed group was divided into four subgroups, which were orally administered RBP 100 or 500 mg/kg, pioglitazone 10 mg/kg, or tap water for a further 6 weeks. Compared with normal diet control group, the MS rats had elevated levels of blood glucose, lipid, insulin, and HOMA-IR. Treatment with RBP significantly alleviated all those changes and restored insulin sensitivity. Additionally, RBP treatment increased adiponectin and suppressed leptin levels. Expression of Ppar-gamma mRNA in adipose tissues was significantly increased whereas expression of lipogenic genes Srebf1 and Fasn was significantly decreased. Levels of mRNA of proinflammatory cytokines, Il-6, Tnf-alpha, Nos-2 and Mcp-1 were significantly decreased. In conclusion, the present findings support the consumption of RBP as a functional food to improve insulin resistance and to prevent the development of metabolic syndrome. PMID- 26247963 TI - Using Short Dietary Questions to Develop Indicators of Dietary Behaviour for Use in Surveys Exploring Attitudinal and/or Behavioural Aspects of Dietary Choices. AB - For countries where nutrition surveys are infrequent, there is a need to have some measure of healthful eating to plan and evaluate interventions. This study shows how it is possible to develop healthful eating indicators based on dietary guidelines from a cross sectional population survey. Adults 18 to 64 years answered questions about the type and amount of foods eaten the previous day, including fruit, vegetables, cereals, dairy, fish or meat and fluids. Scores were based on serves and types of food according to an established method. Factor analysis indicated two factors, confirmed by structural equation modeling: a recommended food healthful eating indicator (RF_HEI) and a discretionary food healthful eating indicator (DF_HEI). Both yield mean scores similar to an established dietary index validated against nutrient intake. Significant associations for the RF_HEI were education, income, ability to save, and attitude toward diet; and for the DF_HEI, gender, not living alone, living in a socially disadvantaged area, and attitude toward diet. The results confirm that short dietary questions can be used to develop healthful eating indicators against dietary recommendations. This will enable the exploration of dietary behaviours for "at risk" groups, such as those with excess weight, leading to more relevant interventions for populations. PMID- 26247964 TI - Correlations between Poor Micronutrition in Family Members and Potential Risk Factors for Poor Diet in Children and Adolescents Using Korean National Health and Nutrition Examination Survey Data. AB - Based on data from the 2010-2011 Korean National Health and Nutrition Examination Survey, we investigated correlations between micronutrients in the diet of family members and the possible risk factors for children and adolescents consuming an inadequate diet. We examined two-generation households with children aged 2-18 years. The quality of the family diet with regard to the following nine nutrients (protein, calcium, phosphorous, iron, vitamin A, vitamin B1, vitamin B2, niacin, and vitamin C) was assessed based on the Index of Nutritional Quality. Correlations between quality of diet and selected variables were analyzed using the Statistical Analysis for Genetic Epidemiology software, and those between diet quality and potential risk factors for poor diet in offspring were analyzed using multinomial logistic regression. Overall, calcium was the most commonly under-consumed micronutrient. More than half of sons and daughters showed insufficient vitamin A, vitamin C, and iron intake, and both mothers and fathers showed insufficiency with respect to vitamin A, vitamin B2, and vitamin C. The correlation between a poor diet in parents and that in offspring was 0.17 (p < 0.0001), and this correlation coefficient was higher between mothers and offspring than between fathers and offspring. Additionally, eating breakfast provided a significant protective effect against the risk of poor nutrition in offspring, even after adjusting for covariates. Our results add to evidence indicating that children should be encouraged to eat breakfast to improve the quality of their diet. PMID- 26247965 TI - Evaluation of the Relative Validity of the Short Diet Questionnaire for Assessing Usual Consumption Frequencies of Selected Nutrients and Foods. AB - A 36-item Short Diet Questionnaire (SDQ) was developed to assess usual consumption frequencies of foods providing fats, fibre, calcium, vitamin D, in addition to fruits and vegetables. It was pretested among 30 community-dwelling participants from the Quebec Longitudinal Study on Nutrition and Successful Aging, "NuAge" (n = 1793, 52.4% women), recruited in three age groups (70 +/- 2 years; 75 +/- 2 years; 80 +/- 2 years). Following revision, the SDQ was administered to 527 NuAge participants (55% female), distributed among the three age groups, both sexes and languages (French, English) prior to the second of three non-consecutive 24 h diet recalls (24HR) and validated relative to the mean of three 24HR. Full data were available for 396 participants. Most SDQ nutrients and fruit and vegetable servings were lower than 24HR estimates (p < 0.05) except calcium, vitamin D, and saturated and trans fats. Spearman correlations between the SDQ and 24HR were modest and significant (p < 0.01), ranging from 0.19 (cholesterol) to 0.45 (fruits and vegetables). Cross-classification into quartiles showed 33% of items were jointly classified into identical quartiles of the distribution, 73% into identical and contiguous quartiles, and only 7% were frankly misclassified. The SDQ is a reasonably accurate, rapid approach for ranking usual frequencies of selected nutrients and foods. Further testing is needed in a broader age range. PMID- 26247966 TI - Postprandial Effect of a High-Fat Meal on Endotoxemia in Arab Women with and without Insulin-Resistance-Related Diseases. AB - This study determined the effects of a high-fat meal on circulating endotoxin and cardiometabolic indices in adult Arab women. The cohort consisted of 92 consenting Saudi women (18 non-diabetic (ND)) control subjects; Age 24.4 +/- 7.9 year; body mass index (BMI) 22.2 +/- 2.2 Kg/m2), 24 overweight/obese (referred to as overweight-plus (overweight+)) subjects (Age 32.0 +/- 7.8 year; BMI 28.5 +/- 1.5 Kg/m2) and 50 type 2 diabetes mellitus (T2DM) patients (Age 41.5 +/- 6.2 year; BMI 35.2 +/- 7.7 Kg/m2). All were given a high-fat meal (standardized meal: 75 g fat, 5 g carbohydrate, 6 g protein) after an overnight fast of 12-14 h. Anthropometrics were obtained and fasting blood glucose, lipids, and endotoxin were serially measured for four consecutive postprandial hours. Endotoxin levels were significantly elevated prior to a high-fat meal in the overweight+ and T2DM than the controls (p < 0.05). Furthermore, the postprandial cardiometabolic changes led to a more detrimental risk profile in T2DM subjects than other groups, with serial changes most notable in glucose, triglycerides, high density lipoprotein-cholesterol (HDL-cholesterol), and insulin levels (p-values < 0.05). The same single meal given to subjects with different metabolic states had varying impacts on cardiometabolic health. Endotoxemia is exacerbated by a high fat meal in Arab subjects with T2DM, accompanied by a parallel increase in cardiometabolic risk profile, suggesting disparity in disease pathogenesis of those with or without T2DM through the altered cardiometabolic risk profile rather than variance in metabolic endotoxinaemia with a high-fat meal. PMID- 26247967 TI - Red Blood Cell Docosapentaenoic Acid (DPA n-3) is Inversely Associated with Triglycerides and C-reactive Protein (CRP) in Healthy Adults and Dose-Dependently Increases Following n-3 Fatty Acid Supplementation. AB - The role of the long-chain omega-3 (n-3) fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in lipid metabolism and inflammation has been extensively studied; however, little is known about the relationship between docosapentaenoic acid (DPA, 22:5 n-3) and inflammation and triglycerides (TG). We evaluated whether n-3 DPA content of red blood cells (RBC) was associated with markers of inflammation (interleukin-6 (IL-6), tumor necrosis factor alpha (TNF alpha), and C-reactive protein (CRP) and fasting TG prior to n-3 supplementation in two studies (Study 1: n = 115, aged 20-44 years, body mass index (BMI) 20-30 kg/m2, TG = 34-176 mg/dL; Study 2: n = 28, aged 22-65 years, BMI 24-37 kg/m2, TG = 141-339 mg/dL). We also characterized the dose-response effects of n-3 fatty acid supplementation on RBC n-3 DPA after five months of supplementation with fish oil (Study 1: 0, 300, 600, 900, and 1800 mg/day EPA + DHA) and eight weeks of prescription n-3 ethyl esters (Study 2: 0, 850, and 3400 mg/day EPA + DHA). In Study 1, RBC n-3 DPA was inversely correlated with CRP (R2 = 36%, p < 0.001) and with fasting TG (r = -0.30, p = 0.001). The latter finding was replicated in Study 2 (r = -0.33, p = 0.04). In both studies, n-3 supplementation significantly increased RBC n-3 DPA dose-dependently. Relative increases were greater for Study 1, with increases of 29%-61% vs. 14%-26% for Study 2. The associations between RBC n-3 DPA, CRP, and fasting TG may have important implications for the prevention of atherosclerosis and chronic inflammatory diseases and warrant further study. PMID- 26247968 TI - Modification of Docosahexaenoic Acid Composition of Milk from Nursing Women Who Received Alpha Linolenic Acid from Chia Oil during Gestation and Nursing. AB - alpha-Linolenic acid (ALA) is the precursor of docosahexaenoic acid (DHA) in humans, which is fundamental for brain and visual function. Western diet provides low ALA and DHA, which is reflected in low DHA in maternal milk. Chia oil extracted from chia (Salvia hispanica L.), a plant native to some Latin American countries, is high in ALA (up to 60%) and thereby is an alternative to provide ALA with the aim to reduce DHA deficits. We evaluated the modification of the fatty acid profile of milk obtained from Chilean mothers who received chia oil during gestation and nursing. Forty healthy pregnant women (22-35 years old) tabulated for food consumption, were randomly separated into two groups: a control group with normal feeding (n = 21) and a chia group (n = 19), which received 16 mL chia oil daily from the third trimester of pregnancy until the first six months of nursing. The fatty acid profile of erythrocyte phospholipids, measured at six months of pregnancy, at time of delivery and at six months of nursing, and the fatty acid profile of the milk collected during the first six months of nursing were assessed by gas-chromatography. The chia group, compared to the control group, showed (i) a significant increase in ALA ingestion and a significant reduction of linoleic acid (LA) ingestion, no showing modification of arachidonic acid (AA), eicosapentaenoic acid (EPA) and DHA; (ii) a significant increase of erythrocyte ALA and EPA and a reduction of LA. AA and DHA were not modified; (iii) a increased milk content of ALA during the six months of nursing, whereas LA showed a decrease. AA and EPA were not modified, however DHA increased only during the first three months of nursing. Consumption of chia oil during the last trimester of pregnancy and the first three months of nursing transiently increases the milk content of DHA. PMID- 26247969 TI - Folate Deficiency Could Restrain Decidual Angiogenesis in Pregnant Mice. AB - The mechanism of birth defects induced by folate deficiency was focused on mainly in fetal development. Little is known about the effect of folate deficiency on the maternal uterus, especially on decidual angiogenesis after implantation which establishes vessel networks to support embryo development. The aim of this study was to investigate the effects of folate deficiency on decidual angiogenesis. Serum folate levels were measured by electrochemiluminescence. The status of decidual angiogenesis was examined by cluster designation 34 (CD34) immunohistochemistry and the expression of angiogenic factors, including vascular endothelial growth factor A (VEGFA), placental growth factor (PLGF), and VEGF receptor 2 (VEGFR2) were also tested. Serum levels of homocysteine (Hcy), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), progesterone (P4), and estradiol (E2) were detected by Enzyme-linked immunosorbent assay. The folate-deficient mice had a lower folate level and a higher Hcy level. Folate deficiency restrained decidual angiogenesis with significant abnormalities in vascular density and the enlargement and elongation of the vascular sinus. It also showed a reduction in the expressions of VEGFA, VEGFR2, and PLGF. In addition, the serum levels of P4, E2, LH, and PRL were reduced in folate-deficient mice, and the expression of progesterone receptor (PR) and estrogen receptor alpha (ERalpha) were abnormal. These results indicated that folate deficiency could impaire decidual angiogenesis and it may be related to the vasculotoxic properties of Hcy and the imbalance of the reproductive hormone. PMID- 26247970 TI - Ferulic Acid Alleviates Changes in a Rat Model of Metabolic Syndrome Induced by High-Carbohydrate, High-Fat Diet. AB - Metabolic syndrome is a cluster of metabolic abnormalities characterized by obesity, insulin resistance, hypertension and dyslipidemia. Ferulic acid (FA) is the major phenolic compound found in rice oil and various fruits and vegetables. In this study, we examined the beneficial effects of FA in minimizing insulin resistance, vascular dysfunction and remodeling in a rat model of high carbohydrate, high-fat diet-induced metabolic changes, which is regarded as an analogue of metabolic syndrome (MS) in man. Male Sprague-Dawley rats were fed a high carbohydrate, high fat (HCHF) diet and 15% fructose in drinking water for 16 weeks, where control rats were fed with standard chow diet and tap water. FA (30 or 60 mg/kg) was orally administered to the HCHF and control rats during the last six weeks of the study. We observed that FA significantly improved insulin sensitivity and lipid profiles, and reduced elevated blood pressure, compared to untreated controls (p < 0.05). Moreover, FA also improved vascular function and prevented vascular remodeling of mesenteric arteries. The effects of FA in HCHF induced MS may be realized through suppression of oxidative stress by down regulation of p47phox, increased nitric oxide (NO) bioavailability with up regulation of endothelial nitric oxide synthase (eNOS) and suppression of tumor necrosis factor-alpha (TNF-alpha). Our results suggest that supplementation of FA may have health benefits by minimizing the cardiovascular complications of MS and alleviating its symptoms. PMID- 26247971 TI - Vitamin D and Inflammatory Cytokines in Healthy and Preeclamptic Pregnancies. AB - Preeclampsia is a pregnancy disease characterized by hypertension and proteinuria. Among several disorders, the imbalance of inflammatory cytokines and the alteration of vitamin D metabolism have been reported in preeclampsia. The effects of calcitriol upon inflammatory cytokines has been demonstrated. In healthy pregnant women there is a shift toward a Th2 cytokine profile, which is necessary for an adequate pregnancy outcome. As compared with normal pregnancy, high pro-inflammatory and low anti-inflammatory cytokine levels have been observed in preeclamptic women. Preeclampsia has been associated with low calcitriol levels and vitamin D deficiency is correlated with a higher risk of the development of this disease. It has been demonstrated that placenta is a source as well as the target of calcitriol and cytokines and placental dysfunction has been associated with preeclampsia. Therefore, the present manuscript includes a review about serum calcitriol levels in non-pregnant, pregnant, and preeclamptic women as well as a review on the fetoplacental vitamin D metabolism in healthy and preeclamptic pregnancies. In addition, circulating and fetoplacental inflammatory cytokines in healthy and preeclamptic pregnancies are reviewed. Finally, the effects of calcitriol upon placental pro-inflammatory cytokines are also explored. In conclusion, maternal and placental calcitriol levels are low in preeclampsia which may explain, at least in part, high pro inflammatory cytokine levels in this disease. PMID- 26247972 TI - Behavioral Symptoms after Breast Cancer Treatment: A Biobehavioral Approach. AB - Being diagnosed and treated for breast cancer is emotionally and physically challenging. Breast cancer is the most commonly diagnosed cancer and the second leading cause of death for women in the United States. Accordingly, women with a breast cancer history are the largest group of female cancer survivors. Psychological stress substantially augments adverse autonomic, endocrine, and immune discharge, including enhanced production of proinflammatory cytokines. Importantly, inflammation is a key biological mechanism underlying the symptom cluster of pain, depression, fatigue, and sleep disturbances; there is also good evidence that inflammation contributes to breast cancer recurrence. Stress may exert direct effects on psychological and physiological risk processes. In this review, we take a biobehavioral approach to understanding predictors and mechanisms underlying somatic symptoms in breast cancer survivors. PMID- 26247973 TI - Corticotropin Releasing Factor Binding Protein and CRF2 Receptors in the Ventral Tegmental Area: Modulation of Ethanol Binge Drinking in C57BL/6J Mice. AB - BACKGROUND: Most studies with corticotropin releasing factor (CRF) and ethanol (EtOH) consumption have focused on CRF type 1 (CRF1 ) receptors; less is known about other components of the CRF system, such as the CRF type 2 (CRF2 ) receptors and the CRF binding protein (CRFBP). In humans, several nucleotide polymorphisms in the CRFBP gene have been associated with EtOH abuse. METHODS: The role of the CRFBP within the ventral tegmental area (VTA) and the central nucleus of the amygdala (CeA) was investigated in C57BL/6J mice exposed to an EtOH binge drinking paradigm (drinking in the dark [DID]), or to a dependence producing drinking protocol (2-bottle choice, intermittent access to alcohol [IAA]) for 4 weeks. Potential interactions between VTA CRFBP and CRF2 receptors on EtOH binge drinking were also assessed. Mice were microinjected with the CRFBP antagonist CRF fragment 6-33 (CRF6-33 ) into the VTA or CeA, or with the CRF2 antagonist astressin-2B (A2B) alone or in combination with CRF6-33 into the VTA, and had access to 20% (w/v) EtOH for 4 hours (DID). Separate cohorts of mice received vehicle and doses of CRF6-33 into the VTA or CeA and had access to EtOH/water for 24 hours (IAA). Blood EtOH concentrations (BECs) were measured, and signs of withdrawal by handling-induced convulsions were determined. RESULTS: Intra-VTA CRF6-33 and A2B reduced EtOH intake dose dependently in mice during DID. Furthermore, a combination of a subeffective dose of CRF6-33 and a lower dose of A2B promoted additive effects in attenuating EtOH binge drinking. Intra VTA CRF6-33 did not affect EtOH consumption in mice given IAA, and intra-CeA CRF6 33 did not change alcohol consumption in both models of drinking. DID and IAA promoted pharmacologically relevant BECs; however, only mice given IAA exhibited convulsive events during withdrawal. CONCLUSIONS: These findings suggest that VTA CRFBP is involved in the initial stages of escalated EtOH drinking by mechanisms that may involve CRF2 receptors. PMID- 26247974 TI - Scenedesmus-based treatment of nitrogen and phosphorus from effluent of anaerobic digester and bio-oil production. AB - In this study, a microalgae-based technology was employed to treat wastewater and produce biodiesel at the same time. A local isolate Scenedesmus sp. was found to be a well suited species, particularly for an effluent from anaerobic digester (AD) containing low carbon but high nutrients (NH3-N=273mgL(-1), total P=58.75mgL(-1)). This algae-based treatment was quite effective: nutrient removal efficiencies were over 99.19% for nitrogen and 98.01% for phosphorus. Regarding the biodiesel production, FAME contents of Scenedesmus sp. were found to be relatively low (8.74% (w/w)), but overall FAME productivity was comparatively high (0.03gL(-1)d(-1)) due to its high biomass productivity (0.37gL(-1)d(-1)). FAMEs were satisfactory to the several standards for the biodiesel quality. The Scenedesmus-based technology may serve as a promising option for the treatment of nutrient-rich wastewater and especially so for the AD effluent. PMID- 26247975 TI - Efficient anaerobic transformation of raw wheat straw by a robust cow rumen derived microbial consortium. AB - A rumen-derived microbial consortium was enriched on raw wheat straw as sole carbon source in a sequential batch-reactor (SBR) process under strict mesophilic anaerobic conditions. After five cycles of enrichment the procedure enabled to select a stable and efficient lignocellulolytic microbial consortium, mainly constituted by members of Firmicutes and Bacteroidetes phyla. The enriched community, designed rumen-wheat straw-derived consortium (RWS) efficiently hydrolyzed lignocellulosic biomass, degrading 55.5% w/w of raw wheat straw over 15days at 35 degrees C and accumulating carboxylates as main products. Cellulolytic and hemicellulolytic activities, mainly detected on the cell bound fraction, were produced in the earlier steps of degradation, their production being correlated with the maximal lignocellulose degradation rates. Overall, these results demonstrate the potential of RWS to convert unpretreated lignocellulosic substrates into useful chemicals. PMID- 26247977 TI - The value of peer review. PMID- 26247976 TI - Inhibitory effects of furan derivatives and phenolic compounds on dark hydrogen fermentation. AB - The inhibitory effects of furan derivatives [i.e. furfural and 5 hydroxymethylfurfural (5-HMF)] and phenolic compounds (i.e. vanillin and syringaldehyde) on dark hydrogen fermentation from glucose were comparatively evaluated. Phenolic compounds exhibited stronger inhibition on hydrogen production and glucose consumption than furan derivatives under the same 15mM concentration. Furan derivatives were completely degraded after 72h fermentation, while over 55% of phenolic compounds remained unconverted after 108h fermentation. The inhibition coefficients of vanillin (14.05) and syringaldehyde (11.21) were higher than those of 5-HMF (4.35) and furfural (0.64). Vanillin exhibited the maximum decrease of hydrogen yield (17%). The consumed reducing power by inhibitors reduction from R-CHO to RCH2OH was a possible reason contributed to the decreased hydrogen yield. Vanillin exhibited the maximum delay of peak times of hydrogen production rate and glucose consumption. Soluble metabolites and carbon conversion efficiency decreased with inhibitors addition, which were consistent with hydrogen production. PMID- 26247978 TI - Physical activity and health in Brazil: research, surveillance and policies. PMID- 26247979 TI - Maternal smoking during pregnancy and birth defects in children: a systematic review with meta-analysis. AB - This systematic review aimed to investigate the association between maternal smoking during pregnancy and birth defects in children. We performed an electronic search of observational studies in the databases ovid MEDLINE (1950 to April 2010), LILACS and SciELO. We included 188 studies with a total of 13,564,914 participants (192,655 cases). Significant positive associations were found between maternal smoking and birth defects in the following body systems: cardiovascular (OR: 1.11; 95%CI: 1.03-1.19), digestive (OR: 1.18; 95%CI: 1.07 1.30), musculoskeletal (OR: 1.27; 95%CI: 1.16-1.39) and face and neck (OR: 1.28; 95%CI: 1.19-1.37). The strength of association between maternal smoking and birth defects measured by the OR (95%CI) is significantly related to the amount of cigarettes smoked daily (chi2 = 12.1; df = 2; p = 0.002). In conclusion, maternal smoking during pregnancy is associated with congenital malformations in children and this association is dose-dependent. PMID- 26247980 TI - [We have never been Flexnerians: Anisio Teixeira and higher education in health in Brazil]. AB - The aim of the current article is to explore central features of Anisio Teixeira's "thought-action" approach in order to help overcome the current crisis in health personnel training. First, the article summarizes Teixeira's life and work, assessing his institutional legacy and its impact on the historical scenario in Brazil's educational system. Second, it discusses his model for a People's University, promoted and implemented twice in Brazil's recent history, but crushed by harsh political repression. Third, the article assesses the potential contribution of Teixeira's work to the current political and pedagogical debates on professional and academic training in health, focusing on similarities with Flexnerian models for university reform. Finally, it raises the hypothesis that the conceptual and pragmatic convergence between Abraham Flexner and Anisio Teixeira allows understanding the absence or invisibility of Teixeira's thinking in the academic literature on Health Education, in the institutional discourse, or in human resources training practices in Brazil. PMID- 26247981 TI - [Comments on the paper by Almeida Filho]. PMID- 26247982 TI - [Thematic space]. PMID- 26247983 TI - [Thematic space]. PMID- 26247984 TI - [The author replies]. PMID- 26247985 TI - [Health in the post-2015 United Nations Development Agenda]. AB - This paper evaluates health as a Sustainable Development Goal (SDG) in the context of the Post-2015 Development Agenda, between 2012 and 2014. Health was part of the debate since the Millennium Summit and the MDGs (2000), and it also appears in the documents discussing the Post-2015 Agenda, from the Rio+20 to the Open Working Group (OWG), whose report was submitted to the General Assembly of the United Nations (UNGA) 2014-2015, and in the Global Consultation on Health and the High-Level Panel of Eminent Persons reports. The Authors concluded that the treatment of health in all these documents is uniform. They point out that the scope of the health-related SDG is very comprehensive, but its targets are conceptually fragmented and reduced. They advocate their change as to include not only the idea of social determinants of health, but also targets in the field of public health, which were not included in the proposal of the OWG. They also warn that the global and national governance systems need to be reformed and advocate more participation of the civil society, which can influence diplomacy, which, in turn, will be responsible for the agreement signed at the UNGA in 2015. PMID- 26247986 TI - Assessing ethical and social issues of transtelephonic electrocardiography (TTEGG) in Chile. AB - The aim of this study was to focus on the ethical and social issues derived from the implementation of transtelephonic electrocardiography (TTECG) in the public healthcare sector in Chile, studying patients and healthcare providers' acceptance and expectations concerning: (a) TTECG effectiveness and safety; and (b) data protection issues, such as confidentiality, privacy and security. For this purpose, we developed two psychosocial surveys; the first was addressed to patients receiving transtelephonic electrocardiogram (either in the emergency services of hospitals or in distant primary care services) and the second one aimed at healthcare providers involved in either administering and/or interpreting it. Results included: (a) major acceptability of TTECG in terms of safety and security; (b) privacy and confidentiality of the patients were considered to be well protected; and (c) the patient-doctor relationship was not affected by this device. PMID- 26247987 TI - Factors associated with undernourishment among people 20 years old or over with HIV/AIDS, attending public health services in the Sao Paulo municipality, Brazil. AB - The study evaluated the nutritional status of 629 people living with HIV/AIDS attended at 12 specialized services of Sao Paulo's Municipal Health Department, Brazil. Data were obtained from medical records and through interviews during nutritional consultation. We used the classification criteria established by World Health Organization to assess malnourished individuals, a BMI < 18.5kg/m2. The prevalence of malnutrition in people with AIDS is 3.12 times that observed among people with HIV, and among people with co-infection it is 3.41 times that obtained among people without co-infection. This indicates how these conditions can harm the maintenance of the nutritional status, and shows that they demand a comprehensive understanding of the mechanisms involved in this phenomenon, as well as the development of strategies to improve the health care of individuals at nutritional risk. PMID- 26247988 TI - [Prevalence of cytological atypia and high-risk human papillomavirus infection in Panara indigenous women in Central Brazil]. AB - The aim of this study was to analyze the prevalence of cytological atypia and human papillomavirus infection in Panara indigenous women in 2006-2007. This was a cross-sectional observational study with data obtained from vaginal cervical samples for Pap smear and hybrid capture, colposcopy, and biopsy. The study included 86 females 12 years or older with a history of sexual activity. 10.7% of the women were diagnosed with cytological atypia and 28.6% were infected with high-risk HPV genotypes, which were more common among young women (mean = 25.6 years). Of these, 41.7% were positive for high-risk HPV genotypes 16 and/or 18 and/or 45, and the majority (58.3%) for other high-risk HPV genotypes. The study concludes that this group of indigenous women constitutes a special population, susceptible to develop precursor lesions for cervical cancer and vulnerable to STDs. Preventive measures are required, such as systematic cervical cancer screening and HPV immunization. PMID- 26247989 TI - [Patterns in the use of outpatient care in Brazil by patients treated through the Brazilian Unified National Health System, private health insurance, and out-of pocket medical care]. AB - Indicators of supply, access, and use of healthcare are helpful for characterizing services, planning activities, and organizing demand. This study describes patterns of use of outpatient care and the associations with demographic and socioeconomic factors, morbidity, population size of the municipality and region, and administrative and financial classification of the provider. This was a population-based cross-sectional study with a sample of 12,402 Brazilian adults from 20 to 59 years of age living in urban areas of 100 municipalities from five regions. Prevalence of outpatient care in the three months prior to the interview was 34.6%. The Brazilian Unified National Health System (SUS) accounted for more than half (53.6%) of the cases, health insurance was used by 34% of the sample, and out-of-pocket services 12.4%, regardless of region, population size, and morbidity profile. Patterns of use of health services remain socially determined, resulting from the supply, demographic and socioeconomic characteristics, and health profile of users. PMID- 26247990 TI - [Experiences with primary care associated to health, socio-demographics and use of services in children and adolescents]. AB - This study aimed to evaluate user experiences with primary care for children and adolescents according to health, socio-demographic characteristics, and use of healthcare services. The 2006 Catalan Health Interview Survey studied a representative sample of the population aged 0 to 14 (n = 2,200). Parents reported their experiences with primary care through 17 items from the Primary Care Assessment Tool. Multivariate models were fitted to estimate prevalence ratios (PR) of scoring low on experiences with primary care by health, use of services, and socio-demographic variables. A low first contact-accessibility score was associated with declared chronic conditions. Immigrant parents declared a poor experience with several primary care functions. A low score on first contact-accessibility, continuity of care, and cultural competence was less likely when children had double healthcare coverage and more likely when they had visited emergency services. Improvement of some aspects of primary care services may reduce both use of emergency services and inequity in this area. PMID- 26247991 TI - [Use of evaluation by primary healthcare managers: a case study in southern Brazil]. AB - This article reports on a meta-evaluation, focused on utilization, in a state in southern Brazil. This was a single case study with primary data collection using semi-structured interviews with health department administrators and staff. Content analysis used categories defined in the evaluation matrix: political and organizational context and implementation of evaluation. The political and organizational context revealed weaknesses in the items on experience, evaluation team, and time and space for reflection. Technical autonomy was verified in the State and in one municipality. In the implementation of evaluation, evaluative quality met the established criteria, but there was no prior definition of the uses and users of evaluation. One report referred to use for planning actions and political use. The study concluded that evaluation produced important information for stakeholders, with the political and organizational context as the principal limiting factor for use. PMID- 26247992 TI - [Pulmonary tuberculosis among residents of municipalities in Mato Grosso do Sul State, Brazil, bordering on Paraguay and Bolivia]. AB - This study analyzed the epidemiological profile of pulmonary tuberculosis from 2007 to 2010 in municipalities (counties) in Mato Grosso do Sul State, Brazil, that border on Paraguay and Bolivia. In the border region, the incidence rate (49.1/100,000 inhabitants), mortality rate (4.0/100,000 inhabitants), and treatment dropout rate (11.3%) were 1.6, 1.8, and 1.5 times higher than in the non-border region. Among indigenous individuals in the border region, the rates for incidence (253.4/100,000 inhabitants), mortality (11.6/100,000 inhabitants), and HIV/TB co-infection (1.9/100,000 inhabitants) were 6.4, 3.2, and 1.9 times higher than in non-indigenous individuals in this region. Living in the border regions was inversely associated with HIV/TB co-infection. Indigenous ethnicity was associated statistically with not abandoning TB treatment. The study concludes that the population residing in these municipalities along the border is exposed to high risk of pulmonary TB and TB mortality and treatment dropout, thus requiring special health surveillance interventions. PMID- 26247993 TI - [The evaluation of health programs and services in Brazil as a space for knowledge and practice]. AB - This social and historical study drew on Bourdieu's genetic sociology to analyze the establishment and development of a specialized space for the production of knowledge and practices in health evaluation in Brazil. The study analyzed the trajectories of 28 researchers and policymakers and the historical conditions that allowed establishing this space, using in-depth interviews, document analysis, and a literature review. The resulting material was analyzed according to Bourdieu's concepts of field, habitus, and capital. The results point to the constitution of a sub-space for evaluation within Public Health, resulting from interaction between actors from the administrative and scientific fields, respectively, represented by management institutions in the Brazilian Unified National Health System at its various levels and research groups affiliated with public universities. No common habitus was found between the interviewees and the inherent issues and disputes in this sub-space. PMID- 26247994 TI - [Physical activity in staff workers at Centers for Psychosocial Care in southern Brazil: temporal trends]. AB - The aim of the study was to analyze temporal trends of physical activity among staff workers in Centers for Psychosocial Care and associated factors in southern Brazil from 2006 to 2011. This cross-sectional study was part of the Evaluation of Centers for Psychosocial Care in Southern Brazil/CAPSUL. Physical and mental health variables were collected using the Self-Report Questionnaire (SRQ-20), and physical activity was measured with the International Physical Activity Questionnaire (IPAQ). Participation included 435 staff workers in 2006 and 546 in 2011. Total prevalence rates were: physical activity (>= 150 minutes/week) 23.2% in 2006 and 17.6% in 2011 and minor psychiatric disorders 11% and 8.4%. There was no statistically significant difference in physical activity between men and women. In 2006, individuals with less schooling (p = 0.03) and lower income (p = 0.01) showed higher levels of physical activity. In 2011, staff workers in larger cities showed higher levels of physical activity (p = 0.02). Interventions are needed to promote physical activity in this population, especially among staff workers at Centers for Psychosocial Care in smaller municipalities. PMID- 26247995 TI - [Femoral fractures in elderly Brazilians: a spatial and temporal analysis from 2008 to 2012]. AB - Fractures in the elderly (>= 60 years) have a major public health impact and take a heavy social and economic toll. This article aimed to describe spatial and time trends in femoral fractures among elderly men and women in all regions of Brazil. Bayesian descriptive analyses of spatial and time series were performed on data obtained from the Hospital Information System of the Brazilian Unified National Health System, using Poisson regression for femoral fractures in individuals 60 years of age or older from 2008 to 2012. There were more than 181,000 femoral fractures during this period, predominantly in women, without important spatial correlations or temporal differences. Despite the lack of temporal and spatial correlations, the number of femoral fractures in elderly Brazilians was high, with heavy financial and social costs. Public health policies are urgently needed to control predisposing factors for femoral fractures in elderly Brazilians. PMID- 26247996 TI - Dietary patterns of Brazilian adolescents: results of the Brazilian National School-Based Health Survey (PeNSE). AB - The objectives of this study were to identify dietary patterns in Brazilian adolescents, describe their distributions in Brazil's State capitals and Federal District, and analyze the correlations with the Municipal Human Development Index (HDI-M). The study analyzed a sample of 60,954 ninth-graders from public and private schools who participated in the National School-Based Health Survey (PeNSE) in 2009. Cluster analysis was used to characterize dietary patterns. Three patterns were identified: healthy (27.7%), unhealthy (34.6%), and mixed (37.7%). Adolescents in the country's Southeast, South, and Central West regions showed a higher proportion of the healthy eating pattern. HDI-M showed a positive correlation with the healthy pattern and a negative correlation with the mixed pattern. The identification of different dietary patterns within and between regions and according to HDI-M highlights the need for better knowledge of each local context in terms of both the magnitude of events and the examination of determinants within these different realities. PMID- 26247997 TI - Reliability of screening tests for health-related problems among low-income elderly. AB - Screening tests for health problems can identify elderly people who should undergo the Comprehensive Geriatric Assessment, enabling the planning of actions to prevent disability. The aim of this study was to analyze the inter-rater reliability (IRR) of self-assessment questions (SAQ) and performance tests (PT) recommended in Brazil, in a sample of low-income elderly people, through an exploratory study performed with 165 elderly assessed by two professionals on different days. IRR was evaluated using the intraclass correlation coefficient (ICC) for continuous variables and the kappa statistic for categorical ones. The IRR for the PT (muscle strength, mobility body mass index, vision) was excellent and presented ICC values greater than 0.75. By contrast, the IRR for SAQ (urinary incontinence, self-perceived health and hearing impairment) was intermediate. Only the fall-related item presented a good IRR. In this study single SAQ had poor reliability when compared to PT, suggesting the necessity of revision of subjective self-assessment items with low reproducibility before implementation. PMID- 26247998 TI - Supporting the use of research evidence in the Americas through an online "one stop shop": the EVIPNet VHL. AB - Since the release of the 'World Report on Knowledge for Better Health' in 2004, a transformation has occurred in the field of health policy and systems research that has brought with it an increased emphasis on supporting the use of research evidence in the policy process. There has been an identified need for comprehensive online "one-stop shops" that facilitate the timely retrieval of research evidence in the policy process. This report highlights the EVIPNet VHL, a recently established project that was developed to meet the need for online repositories of relevant evidence to support knowledge translation efforts in the Americas, which can help contribute to strengthening health systems in the region. PMID- 26247999 TI - Evidence for clock genes circadian rhythms in human full-term placenta. AB - Biological rhythms are driven by endogenous biological clocks; in mammals, the master clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. This master pacemaker can synchronize other peripheral oscillators in several tissues such as some involved in endocrine or reproductive functions. The presence of an endogenous placental clock has received little attention. In fact, there are no studies in human full-term placentas. To test the existence of an endogenous pacemaker in this tissue we have studied the expression of circadian locomoter output cycles kaput (Clock), brain and muscle arnt-like (Bmal)1, period (Per)2, and cryptochrome (Cry)1 mRNAs at 00, 04, 08, 12, 16, and 20 hours by qPCR. The four clock genes studied are expressed in full-term human placenta. The results obtained allow us to suggest that a peripheral oscillator exists in human placenta. Data were analyzed using Fourier series where only the Clock and Bmal1 expression shows a circadian rhythm. PMID- 26248000 TI - Complete sequence and polymorphisms of female Ruditapes philippinarum (Mollusca: Bivalvia) mitochondria genome. AB - Mitogenome of female Ruditapes philippinarum organism was sequenced, and genomic variation and phylogeny were examined in this study. Length of the mitogenome was 22 089 bp showing 94.28% of sequence identity with previously reported sequence. Total 707 single nucleotide polymorphisms, SNPs, were detected and 50 residues were non-synonymous SNPs among the 202 SNPs in protein-coding genes. Deleted genomic fragments with of 265 bp and 322 bp were observed in non-coding regions, ND2 to ND4L and ND4L to tRNA(Ile), respectively. Phylogenic analysis confirmed that used organisms were female R. philippinarum, and the species has closer evolutionary distance with genus Paphia rather than genus Meretrix. Our finding will be help to set an insight for population and evolutionary genomics of Veneroida clams as well as application to marine industry. PMID- 26248001 TI - Reciprocal Relations Between Student-Teacher Relationship and Children's Behavioral Problems: Moderation by Child-Care Group Size. AB - In this Norwegian study, bidirectional relations between children's behavior problems and child-teacher conflict and closeness were examined, and the possibility of moderation of these associations by child-care group size was tested. Eight hundred and nineteen 4-year-old children were followed up in first grade. Results revealed reciprocal effects linking child-teacher conflict and behavior problems. Effects of child-teacher closeness on later behavior problems were moderated by group size: For children in small groups only (i.e., <= 15 children), greater closeness predicted reduced behavior problems in first grade. In consequence, stability of behavior problems was greater in larger than in smaller groups. Results are discussed in light of regulatory mechanisms and social learning theory, with possible implications for organization of child care. PMID- 26248002 TI - Surgery and hemostasis. AB - PURPOSE OF REVIEW: Blood coagulation exists to halt excessive blood loss. It is paradoxical that surgery and trauma simultaneously represent major risk factors for both hemorrhagic and thrombotic complications. A summary of the available evidence used to guide contemporary approaches to perioperative care will be reviewed. RECENT FINDINGS: Although the advent of factor-specific products has safely allowed for intervention on patients with congenital hemostatic defects, the presence of an increasingly complex surgical population (chronic liver disease, traumatic injuries, and requirements for chronic anticoagulation) has renewed concerns about hemorrhagic risks. However, the past three decades of clinical sciences have supported a re-emphasis on the prevention of venous thromboembolism (VTE), a major cause of morbidity and mortality in hospitalized surgical patients. There is now an abundance of data confirming the robust risk:benefit ratio of antithrombotic prophylaxis in the vast majority of surgical patients, regardless of their medical comorbidities. SUMMARY: Perioperative hemorrhage is a natural risk of any surgical intervention and deserves careful evaluation and prompt intervention. However, in order to support ongoing efforts in the prevention of medical errors, the application of evidence-based guidelines for the prophylaxis of VTE in surgical patients must become a standard part of daily practice. PMID- 26248003 TI - Dissecting the genetic determinants of hemostasis and thrombosis. AB - PURPOSE OF REVIEW: New DNA genotyping and sequencing technologies have facilitated the rapid advancement in our knowledge of human genomic variation and a search for the heritable determinants of complex genetic traits. This review highlights findings from recent genetic studies of complex traits primarily related to venous thromboembolism and provides tools to understand and interpret genome-wide association studies and next-generation sequencing studies. RECENT FINDINGS: Genome-wide studies of venous thromboembolic disease and the variation of the protein components of the hemostatic system have been reported. The results of these studies have suggested that variants in a diverse set of known and new genes contribute to the heritability of these traits, but that many of the genetic determinants of these traits still remain undiscovered. SUMMARY: Next generation sequencing studies and functional studies of the gene loci that contribute to hemostatic traits are currently underway. Future studies that explore the role of rare genetic variants, regulatory elements of the genome and gene-gene interactions will be required for a more complete understanding of the genetic control of the hemostatic system and for the application of this knowledge to the care of patients with disorders of thrombosis and hemostasis. PMID- 26248005 TI - Establishing best practise in the application of expert review of mutagenicity under ICH M7. AB - The ICH M7 guidelines for the assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals allows for the consideration of in silico predictions in place of in vitro studies. This represents a significant advance in the acceptance of (Q)SAR models and has resulted from positive interactions between modellers, regulatory agencies and industry with a shared purpose of developing effective processes to minimise risk. This paper discusses key scientific principles that should be applied when evaluating in silico predictions with a focus on accuracy and scientific rigour that will support a consistent and practical route to regulatory submission. PMID- 26248006 TI - A population genomics insight into the Mediterranean origins of wine yeast domestication. AB - The domestication of the wine yeast Saccharomyces cerevisiae is thought to be contemporary with the development and expansion of viticulture along the Mediterranean basin. Until now, the unavailability of wild lineages prevented the identification of the closest wild relatives of wine yeasts. Here, we enlarge the collection of natural lineages and employ whole-genome data of oak-associated wild isolates to study a balanced number of anthropic and natural S. cerevisiae strains. We identified industrial variants and new geographically delimited populations, including a novel Mediterranean oak population. This population is the closest relative of the wine lineage as shown by a weak population structure and further supported by genomewide population analyses. A coalescent model considering partial isolation with asymmetrical migration, mostly from the wild group into the Wine group, and population growth, was found to be best supported by the data. Importantly, divergence time estimates between the two populations agree with historical evidence for winemaking. We show that three horizontally transmitted regions, previously described to contain genes relevant to wine fermentation, are present in the Wine group but not in the Mediterranean oak group. This represents a major discontinuity between the two populations and is likely to denote a domestication fingerprint in wine yeasts. Taken together, these results indicate that Mediterranean oaks harbour the wild genetic stock of domesticated wine yeasts. PMID- 26248008 TI - Antioxidant Gallic Acid-Functionalized Biodegradable in Situ Gelling Copolymers for Cytoprotective Antiglaucoma Drug Delivery Systems. AB - In clinical ophthalmology, oxidative stress has been proposed as the initiating cause of ocular hypertension, which is one of the risk factors for glaucomatous damage and disease progression. In an attempt to improve the therapeutic efficacy of intracamerally administered pilocarpine, herein, a cytoprotective antiglaucoma drug delivery system composed of antioxidant gallic acid (GA)-functionalized gelatin-g-poly(N-isopropylacrylamide) (GN) biodegradable in situ gelling copolymer was developed for the first time. Analyses by UV-vis and Fourier transform infrared spectroscopies showed the formation of biopolymer-antioxidant covalent linkages in GNGA structures through a radical reaction in the presence of water-soluble redox initiators. The synthesized GNGA polymers with strong free radical scavenging effectiveness exhibited appropriate phase transition temperature and degradation rate as injectable bioerodible depots for minimally invasive pilocarpine delivery to the ocular anterior chamber. During the 2-week in vitro study, the sustained releases of sufficient amounts of pilocarpine for a therapeutic action in alleviating ocular hypertension could be achieved under physiological conditions. Results of cell viability, intracellular reactive oxygen species level, and intracellular calcium concentration indicated that the incorporation of antioxidant GA into GN structure can enhance cytoprotective effects of carrier materials against hydrogen peroxide-induced oxidative stress in lens epithelial cultures. Effective pharmacological responses (i.e., reduction of intraocular pressure and preservation of corneal endothelial cell morphology and density) in rabbits receiving intracameral GNGA injections containing pilocarpine were evidenced by clinical observations. The findings of in vivo studies also support the hypothesis that the GNGA carriers are more advantageous over their GN counterparts for the improvement of total antioxidant status in glaucomatous eyes with chronic ocular hypertension. The synthesized multifunctional molecules may be further used as potential polymer therapeutics for intraocular delivery of bioactive agents. PMID- 26248007 TI - Gout Is a Chronic Inflammatory Disease in Which High Levels of Interleukin-8 (CXCL8), Myeloid-Related Protein 8/Myeloid-Related Protein 14 Complex, and an Altered Proteome Are Associated With Diabetes Mellitus and Cardiovascular Disease. AB - OBJECTIVE: The frequent association of gout with metabolic syndrome and cardiovascular disease (CVD) suggests that it has a systemic component. Our objective was to study whether circulating proinflammatory cytokines are associated with comorbidities in gout patients. METHODS: We studied 330 gout patients from 3 independent cohorts and compared them with 144 healthy individuals and 276 disease controls. We measured circulating levels of interleukin-8 (IL-8)/CXCL8, IL-1beta, IL-6, IL-10, IL-12, and tumor necrosis factor, after which we performed proteome-wide analysis in a selection of samples to identify proteins that were possibly prognostic for the development of comorbidities. Replication analysis was performed specifically for myeloid related protein 8 (MRP-8)/MRP-14 complex. RESULTS: Compared to healthy controls and disease control patients, patients with gouty arthritis (n = 48) had significantly higher mean levels of CXCL8 (P < 0.001), while other cytokines were almost undetectable. Similarly, patients with intercritical gout showed high levels of CXCL8. CXCL8 was independently associated with diabetes mellitus in patients with intercritical gout (P < 0.0001). Proteome-wide analysis in gouty arthritis (n = 18) and intercritical gout (n = 39) revealed MRP-8 and MRP-14 as the proteins with the greatest differential expression between low and high levels of CXCL8 and also showed a positive correlation of MRP8/MRP14 complex with CXCL8 levels (R(2) = 0.49, P < 0.001). These findings were replicated in an independent cohort. The proteome of gout patients with high levels of CXCL8 was associated with diabetes mellitus (odds ratio 16.5 [95% confidence interval 2.8 96.6]) and CVD (odds ratio 3.9 [95% confidence interval 1.0-15.3]). CONCLUSION: Circulating levels of CXCL8 are increased during both the acute and intercritical phases of gout, and they coincide with a specific circulating proteome that is associated with risk of diabetes mellitus and CVD. Further research focused on the roles of CXCL8 and MRP8/MRP14 complex in patients with gout is warranted. PMID- 26248009 TI - The current state of cancer genetic counseling access and availability. AB - PURPOSE: Genetic risk assessment and counseling by a qualified genetics professional are recommended to ensure high-quality care for individuals at risk of hereditary cancer. Timely access to genetic services provided by a genetic counselor (GC) is essential, especially in cases where genetic testing results may affect impending surgical decisions. METHODS: A survey of GCs who specialize in cancer genetics was performed to assess service delivery models and ability to accommodate urgent cases. RESULTS: Over half of all respondents indicated that urgent patients can be seen for consultation the same day or within 1-2 business days, and almost all respondents indicated that urgent cases can be seen within 1 week. Most respondents indicated that urgent cases are seen by a GC only with no physician involved. CONCLUSIONS: The results of this survey of GCs demonstrate that timely access to cancer genetic counseling by GCs in an urgent setting is available.Genet Med 18 4, 410-412. PMID- 26248011 TI - [Social networking, health, humanism and euthanasia]. PMID- 26248010 TI - Maternal uniparental disomy of chromosome 20: a novel imprinting disorder of growth failure. AB - PURPOSE: Maternal uniparental disomy of chromosome 20 (UPD(20)mat) has been reported in only four patients, three of whom also had mosaicism for complete or partial trisomy of chromosome 20. We sought to evaluate the clinical significance of isolated UPD(20)mat in eight individuals. METHODS: We evaluated phenotypic and genomic findings of a series of eight new patients with UPD(20)mat. RESULTS: All eight individuals with UPD(20)mat had intrauterine growth restriction, short stature, and prominent feeding difficulties with failure to thrive. As a common feature, they often required gastric tube feeds. Genomic data in most patients are indicative of UPD as a result of trisomy rescue after meiosis II nondisjunction. CONCLUSION: We describe the first natural history of the disorder and the results of therapeutic interventions, including the frequent requirement of direct gastric feedings only during the first few years of life, and propose that growth hormone supplementation is probably safe and effective for this condition. We suggest that UPD(20)mat can be regarded as a new imprinting disorder and its identification requires specialized molecular testing, which should be performed in patients with early-onset idiopathic isolated growth failure.Genet Med 18 4, 309-315. PMID- 26248013 TI - Fungi That Infect Insects: Altering Host Behavior and Beyond. PMID- 26248012 TI - Characterising Upper Limb Movements in Huntington's Disease and the Impact of Restricted Visual Cues. AB - BACKGROUND: Voluntary motor deficits are a common feature in Huntington's disease (HD), characterised by movement slowing and performance inaccuracies. This deficit may be exacerbated when visual cues are restricted. OBJECTIVE: To characterize the upper limb motor profile in HD with various levels of difficulty, with and without visual targets. METHODS: Nine premanifest HD (pre HD), nine early symptomatic HD (symp-HD) and nine matched controls completed a motor task incorporating Fitts' law, a model of human movement enabling the quantification of movement timing, via the manipulation of task difficulty (i.e., target size, and distance between targets). The task required participants to make reciprocal movements under cued and blind conditions. Dwell times (time stationary between movements), speed, accuracy and variability of movements were compared between groups. RESULTS: Symp-HD showed significantly prolonged and less consistent movement times, compared with controls and pre-HD. Furthermore, movement planning and online control were significantly impaired in symp-HD, compared with controls and pre-HD, evidenced by prolonged dwell times and deceleration times. Speed and accuracy were comparable across groups, suggesting that group differences observed in movement time, variability, dwell time and deceleration time were evident over and above simple performance measures. The presence of cues resulted in greater movement time variability in symp-HD, compared with pre-HD and controls, suggesting that the deficit in movement consistency manifested only in response to targeted movements. CONCLUSIONS: Collectively, these findings provide evidence of a deficiency in both motor planning, particularly in relation to movement timing and online control, which became exacerbated as a function of task difficulty during symp-HD stages. These variables may provide a more sensitive measure of motor dysfunction than speed and/or accuracy alone in symp-HD. PMID- 26248015 TI - Sex differences in retention after a visual or a spatial discrimination learning task in brood parasitic shiny cowbirds. AB - Females of avian brood parasites, like the shiny cowbird (Molothrus bonariensis), locate host nests and on subsequent days return to parasitize them. This ecological pressure for remembering the precise location of multiple host nests may have selected for superior spatial memory abilities. We tested the hypothesis that shiny cowbirds show sex differences in spatial memory abilities associated with sex differences in host nest searching behavior and relative hippocampus volume. We evaluated sex differences during acquisition, reversal and retention after extinction in a visual and a spatial discrimination learning task. Contrary to our prediction, females did not outperform males in the spatial task in either the acquisition or the reversal phases. Similarly, there were no sex differences in either phase in the visual task. During extinction, in both tasks the retention of females was significantly higher than expected by chance up to 50 days after the last rewarded session (~85-90% of the trials with correct responses), but the performance of males at that time did not differ than that expected by chance. This last result shows a long-term memory capacity of female shiny cowbirds, which were able to remember information learned using either spatial or visual cues after a long retention interval. PMID- 26248014 TI - Structure and orientation of antibiotic peptide alamethicin in phospholipid bilayers as revealed by chemical shift oscillation analysis of solid state nuclear magnetic resonance and molecular dynamics simulation. AB - The structure, topology and orientation of membrane-bound antibiotic alamethicin were studied using solid state nuclear magnetic resonance (NMR) spectroscopy. (13)C chemical shift interaction was observed in [1-(13)C]-labeled alamethicin. The isotropic chemical shift values indicated that alamethicin forms a helical structure in the entire region. The chemical shift anisotropy of the carbonyl carbon of isotopically labeled alamethicin was also analyzed with the assumption that alamethicin molecules rotate rapidly about the bilayer normal of the phospholipid bilayers. It is considered that the adjacent peptide planes form an angle of 100 degrees or 120 degrees when it forms alpha-helix or 310-helix, respectively. These properties lead to an oscillation of the chemical shift anisotropy with respect to the phase angle of the peptide plane. Anisotropic data were acquired for the 4 and 7 sites of the N- and C-termini, respectively. The results indicated that the helical axes for the N- and C-termini were tilted 17 degrees and 32 degrees to the bilayer normal, respectively. The chemical shift oscillation curves indicate that the N- and C-termini form the alpha-helix and 310-helix, respectively. The C-terminal 310-helix of alamethicin in the bilayer was experimentally observed and the unique bending structure of alamethicin was further confirmed by measuring the internuclear distances of [1-(13)C] and [(15)N] doubly-labeled alamethicin. Molecular dynamics simulation of alamethicin embedded into dimyristoyl phophatidylcholine (DMPC) bilayers indicates that the helical axes for alpha-helical N- and 310-helical C-termini are tilted 12 degrees and 32 degrees to the bilayer normal, respectively, which is in good agreement with the solid state NMR results. PMID- 26248016 TI - Promoting Perioperative Metabolic and Nutritional Care. AB - Surgery represents a major stressor that disrupts homeostasis and can lead to loss of body cell mass. Integrated, multidisciplinary medical strategies, including enhanced recovery programs and perioperative nutrition support, can mitigate the surgically induced metabolic response, promoting optimal patient recovery following major surgery. Clinical therapies should identify those who are poorly nourished before surgery and aim to attenuate catabolism while preserving the processes that promote recovery and immunoprotection after surgery. This review will address the impact of surgery on intermediary metabolism and describe the clinical consequences that ensue. It will also focus on the role of perioperative nutrition, including preoperative nutrition risk, carbohydrate loading, and early initiation of oral feeding (centered on macronutrients) in modulating surgical stress, as well as highlight the contribution of the anesthesiologist to nutritional care. Emerging therapeutic concepts such as preoperative glycemic control and prehabilitation will be discussed. PMID- 26248017 TI - Perioperative Corneal Transplant Wound Dehiscence. PMID- 26248019 TI - Decisions about Limiting Treatment in Cancer Patients: A Systematic Review and Clinical Ethical Analysis of Reported Variables. AB - BACKGROUND: Survey research indicates that decisions about the provision and limitation of treatment near the end of life in patients with cancer vary considerably. OBJECTIVES: The study objectives were to review the evidence on variables associated with explicit decisions about limitation of treatment in patients with cancer and to critically appraise the factors from a clinical ethics perspective. METHODS: A search was conducted of studies published in EMBASE, CINAHL, PsycINFO, Assia, Current Contents Medicine, Belit, and Euroethics before February 5, 2014. Eligible studies reported data on explicit treatment limitation in patients with cancer and included a statistical analysis on possibly associated factors. Information on study participants, types of limited treatment, and variables associated with limiting treatment were extracted by two researchers independently. Data synthesis was performed jointly by researchers from oncology, medical ethics, and social sciences. RESULTS: The search yielded 897 publications, of which 7 were relevant for this review. Factors significantly associated with decisions about limitation of treatment could be distinguished in three categories: first, sociodemographic variables such as the ethnic background of patients; second, health- or treatment-related variables including a lack of capacity in patients with cancer; and third, patients' preferences and the role of relatives in decisions about limitation of treatment. Limitations to this study are that the studies lacked a predefined hypothesis and they all had been conducted in Western countries. CONCLUSION: The identified variables raise ethical issues with regards to possible influence of value judgments underlying decisions about limitation of treatment in end-of-life care. PMID- 26248018 TI - Novel Inhibitory Effect of a Lysophosphatidic Acid 2 Agonist on Allergen-Driven Airway Inflammation. AB - Lysophosphatidic acid (LPA) is a pleiotropic lipid signaling molecule associated with asthma pathobiology. LPA elicits its effects by binding to at least six known cell surface G protein-coupled receptors (LPA1-6) that are expressed in the lung in a cell type-specific manner. LPA2 in particular has emerged as an attractive therapeutic target in asthma because it appears to transduce inhibitory or cell-protective signals. We studied a novel and specific small molecule LPA2 agonist (2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2 yl)butylsulfamoyl] benzoic acid [DBIBB]) in a mouse model of house dust mite induced allergic airway inflammation. Mice injected with DBIBB developed significantly less airway and lung inflammation compared with vehicle-treated controls. Levels of lung Th2 cytokines were also significantly attenuated by DBIBB. We conclude that pharmacologic activation of LPA2 attenuates Th2-driven allergic airway inflammation in a mouse model of asthma. Targeting LPA receptor signaling holds therapeutic promise in allergic asthma. PMID- 26248020 TI - Right and left vagus nerves regulate breathing by multiplicative interaction. AB - Although it has been recognized for more than a century, we still do not know how the two vagus nerves interact to produce Hering-Breuer reflex. In the current study, we tested the hypothesis that the vagus nerves interact via a multiplicative effect. We examined the Hering-Breuer reflex before and after unilateral (first) and then bilateral (second) vagotomies in the mouse. The lung is mostly innervated homolaterally. Since the right and left lung formed 68.2 and 31.8% of total lung weight, if the interaction is mediated by an additive mechanism, unilateral vagotomy would remove the reflex effects by 68.2 and 31.8%, respectively. Instead, unilateral vagotomy removed 85.4 +/- 6.0% (>68.2%) or 52.8 +/- 3.7% (>31.8%) of the reflex effects on respiratory rate (n=9, P<0.05); and removed 79.1 +/- 4.5% (>68.2%) or 59.3 +/- 9.1% (>31.8%) of the effect on expiratory pause induced by lung inflation (n=12, P<0.05). Since the first vagotomy removes more reflex effect than the second vagotomy, we conclude that the two vagus nerves exert their Hering-Breuer reflex effects by a multiplicative effect. PMID- 26248021 TI - Evaluation of the treatment performance of lab-scaled vertical flow constructed wetlands in removal of organic compounds, color and nutrients in azo dye containing wastewater. AB - The objective of this study is to examine the treatment performance of vertical flow intermittent feeding constructed wetland (VFCW) in removal of organic pollution, nutrients and color in azo-dye containing wastewater. The systems consisted of PVC reactors, some filling materials such as gravel, sand and zeolite and wetland plants including Typha angustifolia and Canna indica. The average treatment efficiency of the systems for COD, color, sulphate, NH4-N, and PO4-P were in the range of 57-63%, 94-99%, 44-48%, 39-44%, and 84-88%, respectively among the VFCW reactors. It is concluded that VFCW reactor system can effectively be used in the treatment of dye-rich wastewater, especially for the removal of color and in the reduction of COD. Biofilm formation and cleavage of azo bonds could be observed by SEM and FTIR results, respectively. Almost similar NH4-N and PO4-P removal were obtained in all reactors by using same amount of zeolite media. PMID- 26248022 TI - Orientation of the intercostal muscle fibers in the human rib cage. PMID- 26248023 TI - Mechanostability of the Single-Electron-Transfer Complexes of Anabaena Ferredoxin NADP(+) Reductase. AB - The complexes formed between the flavoenzyme ferredoxin-NADP(+) reductase (FNR; NADP(+) =nicotinamide adenine dinucleotide phosphate) and its redox protein partners, ferredoxin (Fd) and flavodoxin (Fld), have been analysed by using dynamic force spectroscopy through AFM. A strategy is developed to immobilise proteins on a substrate and AFM tip to optimise the recognition ability. The differences in the recognition efficiency regarding a random attachment procedure, together with nanomechanical results, show two binding models for these systems. The interaction of the reductase with the natural electron donor, Fd, is threefold stronger and its lifetime is longer and more specific than that with the substitute under iron-deficient conditions, Fld. The higher bond probability and two possible dissociation pathways in Fld binding to FNR are probably due to the nature of this complex, which is closer to a dynamic ensemble model. This is in contrast with the one-step dissociation kinetics that has been observed and a specific interaction described for the FNR:Fd complex. PMID- 26248024 TI - Epidermal growth factor receptor imaging in human head and neck cancer xenografts. AB - Molecular imaging of specific biomarkers can have prognostic, predictive or monitoring value in head and neck squamous cell carcinoma (HNSCC). The epidermal growth factor receptor (EGFR) is involved in various radiation resistance mechanisms as it steers the pathways related to DNA damage repair, proliferation, hypoxia and apoptosis. Radiolabeled labeled F(ab')2 fragments of the EGFR antibody cetuximab can be applied for non-invasive imaging of this receptor. Preclinical studies have shown that radioresistant tumors had a higher tracer uptake after irradiation, probably due to upregulation of membranous EGFR, thereby increasing target availability possibly as a compensation mechanism. Tumors with increased EGFR availability were also more responsive to the EGFR inhibitor cetuximab. Potentially, radionuclide imaging of the EGFR can be applied for monitoring treatment regimens in clinical practice. PMID- 26248025 TI - External validation of a normal tissue complication probability model for radiation-induced hypothyroidism in an independent cohort. AB - BACKGROUND: A normal tissue complication probability (NTCP) model for radiation induced hypothyroidism (RIHT) was previously derived in patients with squamous cell carcinoma of the head and neck (HNSCC) discerning thyroid volume (Vthyroid), mean thyroid dose (Dmean), and latency as predictive factors. The purpose of this study was to test the performance of this model in an independent cohort of patients receiving primary radiotherapy (RT) for HNSCC. MATERIAL AND METHODS: A validation cohort of 198 patients with HNSCC was included after plasma thyrotropin (TSH) assessment. RIHT was defined as TSH > 4.0 mU/l from blood samples obtained during follow-up. A new mixture NTCP model was developed from the validation cohort after multivariable analysis. Due to only one follow-up TSH assessment in the validation cohort, the time factor derived from the original cohort was fixed in a mixture model and applied for the NTCP validation. Association between model predictions of the initial model and observed clinical outcome in the validation cohort was investigated by applying the previous model (Vthyroid, Dmean and time) on the new cohort and comparing it to the clinical outcome. RESULTS: Both Dmean and Vthyroid were confirmed as significant risk factors for RIHT in the validation cohort, odds ratio (OR) 1.19 (1.1-1.37) and OR 0.75 (0.57-0.9), respectively. A small difference in overall probability of RIHT was observed between the cohorts, further analysis indicated this to be related to less frequent blood tests in the validation cohort relative to the original cohort. However, Pearson's correlation coefficients between model and clinical outcome were high: r = 0.97 estimated by the original model versus the original cohort, and r = 0.97 estimated by the original model versus the new cohort. CONCLUSION: Dmean and Vthyroid were significant predictors of RIHT in both cohorts. The original NTCP model demonstrated external validity owing to high Pearson's correlation coefficients between estimated and observed incidence rates of RIHT in the original as well as in the validation cohort. This model may facilitate clinically relevant estimations of RIHT after RT to the neck. PMID- 26248026 TI - In Vitro Method To Assess Soil Arsenic Metabolism by Human Gut Microbiota: Arsenic Speciation and Distribution. AB - Arsenic (As) speciation and distribution are two important factors in assessing human health risk from As-contaminated soil. In this study, we used the combination of physiologically based extraction test (PBET) and Simulator of Human Intestinal Microbial Ecosystem (SHIME) to determine soil As metabolism by human gut microbiota. The results showed that the percentage of soil arsenate [As(V)] transformation reached 22.1-38.2%, while that of arsenite [As(III)] attained 66.5-92.0%; 30.1-56.4% of As(V) transformed was attached to the soil solid phase. In comparison to sequential extraction results, almost all amorphous Fe/Al-oxide-bound As was liberated in the colon phase. An X-ray absorption near edge structure (XANES) showed that the As(III) percentage in the soil solid phase reached 16.6-26.9% and reached 73.4% (soil 1) in the colon phase. Additionally, plenty of As(III) and different extents of methylation were also observed in colon extraction solution. As bioaccessibility in the colon phase was 1.8-2.8 times that in the small intestinal phase. Our results indicated that human gut microbiota increased As bioaccessibility, and large amounts of As(III) were adsorbed onto the soil solid phase as a result of microbial reduction. Determining As speciation and distribution in extraction solution and soil solid phases will allow for an accurate assessment of the risk to human health upon soil As exposure. PMID- 26248027 TI - Blood Glucose Homeostasis in the Course of Partial Pancreatectomy--Evidence for Surgically Reversible Diabetes Induced by Cholestasis. AB - BACKGROUND AND AIM: Partial pancreatic resection is accompanied not only by a reduction in the islet cell mass but also by a variety of other factors that are likely to interfere with glucose metabolism. The aim of this work was to characterize the patient dynamics of blood glucose homeostasis during the course of partial pancreatic resection and to specify the associated clinico pathological variables. METHODS: In total, 84 individuals undergoing elective partial pancreatic resection were consecutively recruited into this observational trial. The individuals were assigned based on their fasting glucose or oral glucose tolerance testing results into one of the following groups: (I) deteriorated, (II) stable or (III) improved glucose homeostasis three months after surgery. Co-variables associated with blood glucose dynamics were identified. RESULTS: Of the 84 participants, 25 (30%) displayed a normal oGTT, 17 (20%) showed impaired glucose tolerance, and 10 (12%) exhibited pathological glucose tolerance. Elevated fasting glucose was present in 32 (38%) individuals before partial pancreatic resection. Three months after partial pancreatic resection, 14 (17%) patients deteriorated, 16 (19%) improved, and 54 (64%) retained stable glucose homeostasis. Stability and improvement was associated with tumor resection and postoperative normalization of recently diagnosed glucose dysregulation, preoperatively elevated tumor markers and markers for common bile duct obstruction, acute pancreatitis and liver cell damage. Improvement was linked to preoperatively elevated insulin resistance, which normalized after resection and was accompanied by a decrease in fasting- and glucose-stimulated insulin secretion. CONCLUSIONS: Surgically reversible blood glucose dysregulation diagnosed concomitantly with a (peri-) pancreatic tumor appears secondary to compromised liver function due to tumor compression of the common bile duct and the subsequent increase in insulin resistance. It can be categorized as "cholestasis-induced diabetes" and thereby distinguished from other forms of hyperglycemic disorders. PMID- 26248028 TI - Efficacy of Two Common Methods of Application of Residual Insecticide for Controlling the Asian Tiger Mosquito, Aedes albopictus (Skuse), in Urban Areas. AB - After its first introduction in the 1980's the Asian tiger mosquito, Aedes albopictus (Skuse), has spread throughout Southern Europe. Ae. albopictus is considered an epidemiologically important vector for the transmission of many viral pathogens such as the yellow fever virus, dengue fever and Chikungunya fever, as well as several filarial nematodes such as Dirofilaria immitis or D. repens. It is therefore crucial to develop measures to reduce the risks of disease transmission by controlling the vector populations. The aim of the study was to compare the efficacy of two application techniques (mist vs. stretcher sprayer) and two insecticides (Etox based on the nonester pyrethroid Etofenprox vs. Microsin based on the pyrethroid type II Cypermetrin) in controlling adult tiger mosquito populations in highly populated areas. To test the effect of the two treatments pre- and post-treatment human landing rate counts were conducted for two years. After one day from the treatment we observed a 100% population decrease in mosquito abundance with both application methods and both insecticides. However, seven and 14 days after the application the stretcher sprayer showed larger population reductions than the mist sprayer. No effect of insecticide type after one day and 14 days was found, while Etox caused slightly higher population reduction than Microsin after seven days. Emergency measures to locally reduce the vector populations should adopt adulticide treatments using stretcher sprayers. However, more research is still needed to evaluate the potential negative effects of adulticide applications on non-target organisms. PMID- 26248030 TI - Differentiation of coccidiostats-containing feed additives by mid and near infrared microscopy. AB - Coccidiostats belong to the group of feed additives authorised within the European Union exclusively for specific preparations. These preparations not only contain one or more coccidiostats as active substance(s) but also various ingredients such as the carrier, which are included in the European legislation authorising the product. In order to allow the full traceability of the use of feed additives and to check for compliance with legal provisions, there is a strong need for analytical methods that enable the rapid characterisation of these products. This paper describes the applicability of non-destructive techniques such as mid infrared (MIR) and near infrared (NIR) microscopy supported by multivariate analysis for the characterisation of coccidiostats containing feed additives. The application of these methods demonstrated that different feed additives could be distinguished from each other even when containing the same active substance. The use of chemometrics turned out to be crucial especially in cases where the differentiation of spectra by visual inspection was very difficult. PMID- 26248029 TI - Synergistic Activity of the Plant Defensin HsAFP1 and Caspofungin against Candida albicans Biofilms and Planktonic Cultures. AB - Plant defensins are small, cysteine-rich peptides with antifungal activity against a broad range of yeast and fungi. In this study we investigated the antibiofilm activity of a plant defensin from coral bells (Heuchera sanguinea), i.e. HsAFP1. To this end, HsAFP1 was heterologously produced using Pichia pastoris as a host. The recombinant peptide rHsAFP1 showed a similar antifungal activity against the plant pathogen Fusarium culmorum as native HsAFP1 purified from seeds. NMR analysis revealed that rHsAFP1 consists of an alpha-helix and a triple-stranded antiparallel beta-sheet stabilised by four intramolecular disulfide bonds. We found that rHsAFP1 can inhibit growth of the human pathogen Candida albicans as well as prevent C. albicans biofilm formation with a BIC50 (i.e. the minimum rHsAFP1 concentration required to inhibit biofilm formation by 50% as compared to control treatment) of 11.00 +/- 1.70 MUM. As such, this is the first report of a plant defensin exhibiting inhibitory activity against fungal biofilms. We further analysed the potential of rHsAFP1 to increase the activity of the conventional antimycotics caspofungin and amphotericin B towards C. albicans. Synergistic effects were observed between rHsAFP1 and these compounds against both planktonic C. albicans cells and biofilms. Most notably, concentrations of rHsAFP1 as low as 0.53 MUM resulted in a synergistic activity with caspofungin against pre-grown C. albicans biofilms. rHsAFP1 was found non toxic towards human HepG2 cells up to 40 MUM, thereby supporting the lack of a general cytotoxic activity as previously reported for HsAFP1. A structure function study with 24-mer synthetic peptides spanning the entire HsAFP1 sequence revealed the importance of the gamma-core and its adjacent regions for HsAFP1 antibiofilm activity. These findings point towards broad applications of rHsAFP1 and its derivatives in the field of antifungal and antibiofilm drug development. PMID- 26248032 TI - Real-time visual determination of the flux of hydrogen sulphide using a hollow channel paper electrode. AB - A novel 3D microfluidic paper-based turn-on electrochemiluminescence origami cyto device with hollow channels is developed and applied for real-time visual determination of H2S released from multiple cancer cells for the first time. PMID- 26248031 TI - Nutlin-3a: A Potential Therapeutic Opportunity for TP53 Wild-Type Ovarian Carcinomas. AB - Epithelial ovarian cancer is a diverse molecular and clinical disease, yet standard treatment is the same for all subtypes. TP53 mutations represent a node of divergence in epithelial ovarian cancer histologic subtypes and may represent a therapeutic opportunity in subtypes expressing wild type, including most low grade ovarian serous carcinomas, ovarian clear cell carcinomas and ovarian endometrioid carcinomas, which represent approximately 25% of all epithelial ovarian cancer. We therefore sought to investigate Nutlin-3a--a therapeutic which inhibits MDM2, activates wild-type p53, and induces apoptosis--as a therapeutic compound for TP53 wild-type ovarian carcinomas. Fifteen epithelial ovarian cancer cell lines of varying histologic subtypes were treated with Nutlin-3a with determination of IC50 values. Western Blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) analyses quantified MDM2, p53, and p21 expression after Nutlin-3a treatment. DNA from 15 cell lines was then sequenced for TP53 mutations in exons 2-11 including intron-exon boundaries. Responses to Nutlin-3a were dependent upon TP53 mutation status. By qRT-PCR and WB, levels of MDM2 and p21 were upregulated in wild-type TP53 sensitive cell lines, and p21 induction was reduced or absent in mutant cell lines. Annexin V assays demonstrated apoptosis in sensitive cell lines treated with Nutlin-3a. Thus, Nutlin-3a could be a potential therapeutic agent for ovarian carcinomas expressing wild-type TP53 and warrants further investigation. PMID- 26248033 TI - Photosensitizer-Loaded pH-Responsive Hollow Gold Nanospheres for Single Light Induced Photothermal/Photodynamic Therapy. AB - Novel photoinduced triple-response antitumor therapeutic system based on hollow gold nanospheres (HAuNS), pH (low) insertion peptide (pHLIP), and Chlorin e6 (Ce6), was reported for the first time. The system was able to intracellularly deliver the nanocarriers by the transmembrane ability of pHLIP at the condition of pH 6.2. Ce6 and pHLIP were then released from the surface of the carriers due to the weakening electrostatic interaction with HAuNS under the photoirradiation. Herein, HAuNS performed two different functions: (1) as a nanocarrier because of the excellent loading capability; (2) experienced the photothermal therapy (PTT) effect as a photothermal coupling agent (PTCA), thus enhancing the photodynamic therapy (PDT) effect of Ce6. PMID- 26248034 TI - The effect of lifestyle modification and glycemic control on the efficiency of sildenafil citrate in patients with erectile dysfunction due to type-2 diabetes mellitus. AB - OBJECTIVES: We evaluated the effect of lifestyle modifications and glycemic control on the efficiency of sildenafil citrate in patients with type-2 diabetes (T2DM) and erectile dysfunction (ED). METHODS: Eighty-three men with ED due to T2DM were included in the study. The Group 1 (n = 41) patients received lifestyle modifications (diet and exercise), and medical treatment for intensive glycemic control. In Group 2 (n = 42), in addition to the intensive glycemic control, the patients were given sildenafil citrate(r) 100 mg for 2-3 per weeks. The changes in ED were compared between the two groups after three months of treatment. RESULTS: The mean age was 54.9 +/- 9.1 (26-75) years. An increase in the IIEF-5 scores was observed in 23 of 41 patients in Group 1 (44.2%) and 29 of 42 in Group 2 (55.8%). When the changes of the IIEF-5 scores were evaluated, the mean increase was 2.5 in Group 1, and 5.0 in Group 2 (p = 0.012). The mean IIEF changes according to the duration of diabetes were 4.8 in <5 years, 3.6 in 5-10 years and 1.6 in >10 years (p = 0.021). CONCLUSIONS: Glycemic control and lifestyle changes are not solely adequate for a better sexual function in ED due to diabetes, and sildenafil citrate should be used additionally. PMID- 26248035 TI - CO2-Responsive Pillar[5]arene-Based Molecular Recognition in Water: Establishment and Application in Gas-Controlled Self-Assembly and Release. AB - Here we developed a novel CO2-responsive pillararene-based molecular recognition motif established from a water-soluble pillar[5]arene and an anionic surfactant, sodium dodecyl sulfonate (SDS). The inclusion complex acted as a supramolecular amphiphile and self-assembled into spherical bilayer vesicles as confirmed by DLS, SEM, and TEM experiments. These vesicles were disrupted upon bubbling N2 or adding much more SDS to eliminate the inclusion complex. The assembly and disassembly of vesicles were successfully employed in gas and surfactant triggered releases of calcein, a water-soluble dye. PMID- 26248036 TI - Sleep Architecture in Partially Acclimatized Lowlanders and Native Tibetans at 3800 Meter Altitude: What Are the Differences? AB - It is not well known whether high altitude acclimatization could help lowlanders improve their sleep architecture as well as Native Tibetans. In order to address this, we investigated the structural differences in sleep between Native Tibetans and partially acclimatized lowlanders and examined the association between sleep architecture and subjective sleep quality. Partially acclimatized soldiers from lowlands and Native Tibetan soldiers stationed at Shangri-La (3800 m) were surveyed using the Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Scale (HAMA), and Hamilton Depression Rating Scale (HAMD). The sleep architecture of those without anxiety (as determined by HAMA>14) and/or depression (HAMD>20) was analyzed using polysomnography and the results were compared between the two groups. One hundred sixty-five male soldiers, including 55 Native Tibetans, were included in the study. After partial acclimatization, lowlanders still exhibited differences in sleep architecture as compared to Native Tibetans, as indicated by a higher PSQI score (8.14+/-2.37 vs. 3.90+/-2.85, p<0.001), shorter non-rapid eye movement (non-REM) sleep (458.68+/-112.63 vs. 501+/-37.82 min, P=0.03), lower nocturnal arterial oxygen saturation (Spo2; mean 91.39+/-1.24 vs. 92.71+/-2.12%, p=0.03), and increased times of Spo2 reduction from 89% to 85% (median 48 vs.17, p=0.04) than Native Tibetans. Sleep onset latency (beta=0.08, 95%CI: 0.01 to 0.15), non-REM latency (beta=0.011, 95%CI 0.001 to 0.02), mean Spo2 (beta=-0.79, 95%CI: -1.35 to -0.23) and time in stage 3+4 sleep (beta=-0.014, 95%CI: -0.001 to -0.028) were slightly associated with the PSQI score. Partially acclimatized lowlanders experienced less time in non-REM sleep and had lower arterial oxygen saturation than Native Tibetans at an altitude of 3800 m. The main independent contributors to poor sleep quality are hypoxemia, difficulty in sleep induction, and time in deep sleep. PMID- 26248037 TI - A Diabetic Emergency One Million Feet Long: Disparities and Burdens of Illness among Diabetic Foot Ulcer Cases within Emergency Departments in the United States, 2006-2010. AB - OBJECTIVES: To evaluate the magnitude and impact of diabetic foot ulcers (DFUs) in emergency department (ED) settings from 2006-2010 in the United States (US). METHODS: This cross-sectional study utilized Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) National Emergency Department Sample (NEDS) discharge records of ED cases among persons >=18 years with any-listed diagnosis of DFUs. Multivariable analyses were conducted for clinical outcomes of patient disposition from the ED and economic outcomes of charges and lengths of stay based upon patient demographic and socioeconomic factors, hospital characteristics, and comorbid disease states. RESULTS: Overall, 1,019,861 cases of diabetic foot complications presented to EDs in the US from 2006-2010, comprising 1.9% of the 54.2 million total diabetes cases. The mean patient age was 62.5 years and 59.4% were men. The national bill was $1.9 billion per year in the ED and $8.78 billion per year (US$ 2014) including inpatient charges among the 81.2% of cases that were admitted. Clinical outcomes included mortality in 2.0%, sepsis in 9.6% of cases and amputation in 10.5% (major-minor amputation ratio of 0.46). Multivariable analyses found that those residing in non-urban locations were associated with +51.3%, +14.9%, and +41.4% higher odds of major amputation, minor amputation, and inpatient death, respectively (p<0.05). Medicaid beneficiaries incurred +21.1% and +25.1% higher odds for major or minor amputations, respectively, than Medicare patients (p<0.05). Persons within the lowest income quartile regions were associated with a +38.5% higher odds of major amputation (p<0.05) versus the highest income regions. CONCLUSION: Diabetic foot complications exact a substantial clinical and economic toll in acute care settings, particularly among the rural and working poor. Clear opportunities exist to reduce costs and improve outcomes for this systematically neglected condition by establishing effective practice paradigms for screening, prevention, and coordinated care. PMID- 26248038 TI - Disentangling Membrane Dynamics and Cell Migration; Differential Influences of F actin and Cell-Matrix Adhesions. AB - Cell migration is heavily interconnected with plasma membrane protrusion and retraction (collectively termed "membrane dynamics"). This makes it difficult to distinguish regulatory mechanisms that differentially influence migration and membrane dynamics. Yet such distinctions may be valuable given evidence that cancer cell invasion in 3D may be better predicted by 2D membrane dynamics than by 2D cell migration, implying a degree of functional independence between these processes. Here, we applied multi-scale single cell imaging and a systematic statistical approach to disentangle regulatory associations underlying either migration or membrane dynamics. This revealed preferential correlations between membrane dynamics and F-actin features, contrasting with an enrichment of links between cell migration and adhesion complex properties. These correlative linkages were often non-linear and therefore context-dependent, strengthening or weakening with spontaneous heterogeneity in cell behavior. More broadly, we observed that slow moving cells tend to increase in area, while fast moving cells tend to shrink, and that the size of dynamic membrane domains is independent of cell area. Overall, we define macromolecular features preferentially associated with either cell migration or membrane dynamics, enabling more specific interrogation and targeting of these processes in future. PMID- 26248039 TI - Additional diterpenes from Physcomitrella patens synthesized by copalyl diphosphate/kaurene synthase (PpCPS/KS). AB - The bifunctional diterpene synthase, copalyl diphosphate/kaurene synthase from the moss Physcomitrella patens (PpCPS/KS), catalyses the formation of at least four diterpenes, including ent-beyerene, ent-sandaracopimaradiene, ent-kaur-16 ene, and 16-hydroxy-ent-kaurene. The enzymatic activity has been confirmed through generation of a targeted PpCPS/KS knock-out mutant in P. patens via homologous recombination, through transient expression of PpCPS/KS in Nicotiana benthamiana, and expression of PpCPS/KS in E. coli. GC-MS analysis of the knock out mutant shows that it lacks the diterpenoids, supporting that all are products of PpCPS/KS as observed in N. benthamiana and E. coli. These results provide additional knowledge of the mechanism of this bifunctional diterpene synthase, and are in line with proposed reaction mechanisms in kaurene biosynthesis. PMID- 26248041 TI - Graphene-Based Fibers: A Review. AB - Motivated by their unique structure and excellent properties, significant progress has been made in recent years in the development of graphene-based fibers (GBFs). Potential applications of GBFs can be found, for instance, in conducting wires, energy storage and conversion devices, actuators, field emitters, solid-phase microextraction, springs, and catalysis. In contrast to graphene-based aerogels (GBAs) and membranes (GBMs), GBFs demonstrate remarkable mechanical and electrical properties and can be bent, knotted, or woven into flexible electronic textiles. In this review, the state-of-the-art of GBFs is summarized, focusing on their synthesis, performance, and applications. Future directions of GBF research are also proposed. PMID- 26248040 TI - Memantine-associated corneal endothelial dysfunction. PMID- 26248042 TI - Calcineurin Undergoes a Conformational Switch Evoked via Peptidyl-Prolyl Isomerization. AB - A limited repertoire of PPP family of serine/threonine phosphatases with a highly conserved catalytic domain acts on thousands of protein targets to orchestrate myriad central biological roles. A major structural reorganization of human calcineurin, a ubiquitous Ser/Thr PPP regulated by calcium and calmodulin and targeted by immunosuppressant drugs cyclosporin A and FK506, is unveiled here. The new conformation involves trans- to cis-isomerization of proline in the SAPNY sequence, highly conserved across PPPs, and remodels the main regulatory site where NFATc transcription factors bind. Transitions between cis- and trans conformations may involve peptidyl prolyl isomerases such as cyclophilin A and FKBP12, which are known to physically interact with and modulate calcineurin even in the absence of immunosuppressant drugs. Alternative conformations in PPPs provide a new perspective on interactions with substrates and other protein partners and may foster development of more specific inhibitors as drug candidates. PMID- 26248043 TI - Preparation of novel fluorescent DNA bio-dots and their application for biothiols and glutathione reductase activity detection. AB - A new class of fluorescent bio-dots have been successfully prepared by hydrothermal treatment of poly-cytosine DNA at low temperature down to 80 degrees C. The inter-molecule interaction of aromatic cytosine bases forms sp(2) carbon-like centers as the luminescence centers or chromophores. In the presence of Ag(+), the formation of C-Ag(+)-C base pairs results in the destroying of the luminescence centers and thus the fluorescence (FL) quenching of the bio-dots. However, with the addition of biothiols, Ag(+) prefers to react with biothiols to form the Ag(+)-S bond, hence a restoration of FL emission can be observed. Moreover, by employing the classic glutathione reductase (GR) catalyzed enzymatic reaction, this concept can be readily applied to the selective quantification of oxidized glutathione (GSSG) as well as the activity of GR with a very robust, simple, and rapid procedure. It is worth looking forward to design DNAs with a specific function to prepare fluorescent bio-dots for simple biological applications. PMID- 26248045 TI - Quantification of mouse in vivo whole-body vibration amplitude from motion-blur using x-ray imaging. AB - Musculoskeletal effects of whole-body vibration on animals and humans have become an intensely studied topic recently, due to the potential of applying this method as a non-pharmacological therapy for strengthening bones. It is relatively easy to quantify the transmission of whole-body mechanical vibration through the human skeletal system using accelerometers. However, this is not the case for small animal pre-clinical studies because currently available accelerometers have a large mass, relative to the mass of the animals, which causes the accelerometers themselves to affect the way vibration is transmitted. Additionally, live animals do not typically remain motionless for long periods, unless they are anesthetized, and they are required to maintain a static standing posture during these studies. These challenges provide the motivation for the development of a method to quantify vibrational transmission in small animals. We present a novel imaging technique to quantify whole-body vibration transmission in small animals using 280 MUm diameter tungsten carbide beads implanted into the hind limbs of mice. Employing time-exposure digital x-ray imaging, vibrational amplitude is quantified based on the blurring of the implanted beads caused by the vibrational motion. Our in vivo results have shown this technique is capable of measuring vibration amplitudes as small as 0.1 mm, with precision as small as +/-10 MUm, allowing us to distinguish differences in the transmitted vibration at different locations on the hindlimbs of mice. PMID- 26248044 TI - Production of a Shigella sonnei Vaccine Based on Generalized Modules for Membrane Antigens (GMMA), 1790GAHB. AB - Recently, we developed a high yield production process for outer membrane particles from genetically modified bacteria, called Generalized Modules of Membrane Antigens (GMMA), and the corresponding simple two step filtration purification, enabling economic manufacture of these particles for use as vaccines. Using a Shigella sonnei strain that was genetically modified to produce penta-acylated lipopolysaccharide (LPS) with reduced endotoxicity and to maintain the virulence plasmid encoding for the immunodominant O antigen component of the LPS, scale up of the process to GMP pilot scale was straightforward and gave high yields of GMMA with required purity and consistent results. GMMA were formulated with Alhydrogel and were highly immunogenic in mice and rabbits. In mice, a single immunization containing 29 ng protein and 1.75 ng of O antigen elicited substantial anti-LPS antibody levels. As GMMA contain LPS and lipoproteins, assessing potential reactogenicity was a key aspect of vaccine development. In an in vitro monocyte activation test, GMMA from the production strain showed a 600 fold lower stimulatory activity than GMMA with unmodified LPS. Two in vivo tests confirmed the low potential for reactogenicity. We established a modified rabbit pyrogenicity test based on the European Pharmacopoeia pyrogens method but using intramuscular administration of the full human dose (100 MUg of protein). The vaccine elicited an average temperature rise of 0.5 degrees C within four hours after administration, which was considered acceptable and showed that the test is able to detect a pyrogenic response. Furthermore, a repeat dose toxicology study in rabbits using intramuscular (100 MUg/dose), intranasal (80 MUg/dose), and intradermal (10 MUg/dose) administration routes showed good tolerability of the vaccine by all routes and supported its suitability for use in humans. The S. sonnei GMMA vaccine is now in Phase 1 dose-escalation clinical trials. PMID- 26248046 TI - Differential regulation of monocytic expression of leukotriene and lipoxin receptors. AB - INTRODUCTION: Lipoxygenase pathway yields both pro-inflammatory leukotrienes and pro-resolving lipoxins. The aim of the present study was to determine the effects of T-lymphocytes and pro-inflammatory stimuli on the expression levels of the lipoxin FPR2/ALX receptor, and the leukotriene BLT1 receptor in monocytes and macrophages, and to characterize LXA4-induced effects on pro-inflammatory mediators. METHODS: Human macrophages were co-cultured with activated CD4(+) cells. THP-1 cells were stimulated with different cytokines, LXA4 and supernatant from activated CD4(+) cells. mRNA was extracted for qPCR experiments and protein was analyzed by flow cytometry. RESULTS: Co-culture of macrophages with activated CD4(+) cells or their supernatants up-regulated macrophage FPR2/ALX expression but did not alter BLT1 receptor expression. Monocyte stimulation with IFN-gamma up-regulated FPR2/ALX mRNA and protein levels, whereas BLT1 mRNA was down regulated. Finally, LXA4 decreased mRNA levels of MMP-9, CXCL16, IL-1beta, and IL 8 in THP-1 cells. CONCLUSION: The present study shows that pro-inflammatory stimuli lead to FPR2/ALX expression. LXA4 induces an anti-inflammatory response, which could participate in the resolution of inflammation. PMID- 26248047 TI - The effect of quinidine, a strong P-glycoprotein inhibitor, on the pharmacokinetics and central nervous system distribution of naloxegol. AB - Naloxegol is a PEGylated, oral, peripherally acting MU-opioid receptor antagonist approved in the United States for treatment of opioid-induced constipation in patients with noncancer pain. Naloxegol is metabolized by CYP3A, and its properties as a substrate for the P-glycoprotein (PGP) transporter limit its central nervous system (CNS) permeability. This double-blind, randomized, 2-part, crossover study in healthy volunteers evaluated the effect of quinidine (600 mg PO), a CYP3A/PGP transporter inhibitor, on the pharmacokinetics and CNS distribution of naloxegol (25 mg PO). In addition, the effects of quinidine on morphine (5 mg/70 kg IV)-induced miosis and exposure to naloxegol were assessed. Coadministration of quinidine and naloxegol increased naloxegol's AUC 1.4-fold and Cmax 2.5-fold but did not antagonize morphine-induced miosis, suggesting that PGP inhibition does not increase the CNS penetration of naloxegol. Naloxegol pharmacokinetics was unaltered by coadministration of morphine and either quinidine or placebo; conversely, pharmacokinetics of morphine and its metabolites (in the presence of quinidine) were unaltered by coadministration of naloxegol. Naloxegol was safe and well tolerated, alone or in combination with quinidine, morphine, or both. The observed increase in exposure to naloxegol in the presence of quinidine is primarily attributed to quinidine's properties as a weak CYP3A inhibitor. PMID- 26248048 TI - A Partial Least-Squares Analysis of Health-Related Quality-of-Life Outcomes After Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Individuals who have aneurysmal subarachnoid hemorrhages (SAHs) experience decreased health-related qualities of life (HRQoLs) that persist after the primary insult. OBJECTIVE: To identify clinical variables that concurrently associate with HRQoL outcomes by using a partial least-squares approach, which has the distinct advantage of explaining multidimensional variance where predictor variables may be highly collinear. METHODS: Data collected from the CONSCIOUS-1 trial was used to extract 29 clinical variables including SAH presentation, hospital procedures, and demographic information in addition to 5 HRQoL outcome variables for 256 individuals. A partial least-squares analysis was performed by calculating a heterogeneous correlation matrix and applying singular value decomposition to determine components that best represent the correlations between the 2 sets of variables. Bootstrapping was used to estimate statistical significance. RESULTS: The first 2 components accounting for 81.6% and 7.8% of the total variance revealed significant associations between clinical predictors and HRQoL outcomes. The first component identified associations between disability in self-care with longer durations of critical care stay, invasive intracranial monitoring, ventricular drain time, poorer clinical grade on presentation, greater amounts of cerebral spinal fluid drainage, and a history of hypertension. The second component identified associations between disability due to pain and discomfort as well as anxiety and depression with greater body mass index, abnormal heart rate, longer durations of deep sedation and critical care, and higher World Federation of Neurosurgical Societies and Hijdra scores. CONCLUSION: By applying a data-driven, multivariate approach, we identified robust associations between SAH clinical presentations and HRQoL outcomes. ABBREVIATIONS: EQ-VAS, EuroQoL visual analog scaleHRQoL, health-related quality of lifeICU, intensive care unitIVH, intraventricular hemorrhagePLS, partial least squaresSAH, subarachnoid hemorrhageSVD, singular value decompositionWFNS, World Federation of Neurosurgical Societies. PMID- 26248049 TI - Folate Receptor-Beta Has Limited Value for Fluorescent Imaging in Ovarian, Breast and Colorectal Cancer. AB - AIMS: Tumor-specific targeted imaging is rapidly evolving in cancer diagnosis. The folate receptor alpha (FR-alpha) has already been identified as a suitable target for cancer therapy and imaging. FR-alpha is present on ~40% of human cancers. FR-beta is known to be expressed on several hematologic malignancies and on activated macrophages, but little is known about FR-beta expression in solid tumors. Additional or simultaneous expression of FR-beta could help extend the indications for folate-based drugs and imaging agents. In this study, the expression pattern of FR-beta is evaluated in ovarian, breast and colorectal cancer. METHODS: FR-beta expression was analyzed by semi-quantitative scoring of immunohistochemical staining on tissue microarrays (TMAs) of 339 ovarian cancer patients, 418 breast cancer patients, on 20 slides of colorectal cancer samples and on 25 samples of diverticulitis. RESULTS: FR-beta expression was seen in 21% of ovarian cancer samples, 9% of breast cancer samples, and 55% of colorectal cancer samples. Expression was weak or moderate. Of the diverticulitis samples, 80% were positive for FR-beta expression in macrophages. FR-beta status neither correlated to known disease-related variables, nor showed association with overall survival and progression free survival in ovarian and breast cancer. In breast cancer, negative axillary status was significantly correlated to FR-beta expression (p=0.022). CONCLUSIONS: FR-beta expression was low or absent in the majority of ovarian, breast and colorectal tumor samples. From the present study we conclude that the low FR-beta expression in ovarian and breast tumor tissue indicates limited practical use of this receptor in diagnostic imaging and therapeutic purposes. Due to weak expression, FR-beta is not regarded as a suitable target in colorectal cancer. PMID- 26248050 TI - Chimeric RNA Oligonucleotides with Triazole and Phosphate Linkages: Synthesis and RNA Interference. AB - Chimeric RNA oligonucleotides with an artificial triazole linker were synthesized using solution-phase click chemistry and solid-phase automated synthesis. Scalable synthesis methods for jointing units for the chimeric structure have been developed, and after click-coupling of the jointing units with triazole linkers, a series of chimeric oligonucleotides was prepared by utilizing the well established phosphoramidite method for the elongation. The series of chimeric 21 mer oligonucleotides that possessed the triazole linker at different strands and positions allowed for a screening study of the RNA interference to clarify the preference of the triazole modifications in small-interfering RNA molecules. PMID- 26248052 TI - Responsible Use of Pop Culture and Communication in the Face of Ebola Virus. PMID- 26248051 TI - Lithium Modulates Autophagy in Esophageal and Colorectal Cancer Cells and Enhances the Efficacy of Therapeutic Agents In Vitro and In Vivo. AB - Many epithelial cancers, particularly gastrointestinal tract cancers, remain poor prognosis diseases, due to resistance to cytotoxic therapy and local or metastatic recurrence. We have previously shown that apoptosis incompetent esophageal cancer cells induce autophagy in response to chemotherapeutic agents and this can facilitate their recovery. However, known pharmacological inhibitors of autophagy could not enhance cytotoxicity. In this study, we have examined two well known, clinically approved autophagy inducers, rapamycin and lithium, for their effects on chemosensitivity in apoptosis incompetent cancer cells. Both lithium and rapamycin were shown to induce autophagosomes in esophageal and colorectal cancer cells by western blot analysis of LC3 isoforms, morphology and FACS quantitation of Cyto-ID or mCherry-GFP-LC3. Analysis of autophagic flux indicates inefficient autophagosome processing in lithium treated cells, whereas rapamycin treated cells showed efficient flux. Viability and recovery was assessed by clonogenic assays. When combined with the chemotherapeutic agent 5 fluorouracil, rapamycin was protective. In contrast, lithium showed strong enhancement of non-apoptotic cell death. The combination of lithium with 5 fluorouracil or oxaliplatin was then tested in the syngenic mouse (balb/c) colorectal cancer model--CT26. When either chemotherapeutic agent was combined with lithium a significant reduction in tumor volume was achieved. In addition, survival was dramatically increased in the combination group (p < 0.0001), with > 50% of animals achieving long term cure without re-occurrence (> 1 year tumor free). Thus, combination treatment with lithium can substantially improve the efficacy of chemotherapeutic agents in apoptosis deficient cancer cells. Induction of compromised autophagy may contribute to this cytotoxicity. PMID- 26248054 TI - Evaluation of the updated RIDA(r)QUICK (Version N1402) immunochromatographic assay for the detection of norovirus in clinical specimens. AB - The sensitivity and specificity of the R-Biopharm RIDA((r))QUICK (N1402) immunochromatography assay for norovirus detection was examined using fecal material from Australian gastroenteritis incidents. The study involved the analysis of 3 groups of specimens; group 1 comprised 100 norovirus open reading frame (ORF) 1 RT-PCR positive specimens; group 2 comprised 100 ORF 1 RT-PCR norovirus negative specimens and group 3 comprised 12 specimens containing common gastroenteritis viruses other than norovirus. The RIDA((r))QUICK (N1402) assay detected both GI and GII norovirus and had an overall sensitivity of 87%. Genotype analysis of the capsid region of the genome (ORF 2) indicated the RIDA((r))QUICK (N1402) assay could detect a range of genotypes including GI.1, GI.2, GI.3, GI.4, GI.5, GII.3, GII.4 (including variants GII.4 (2009-like), GII.4 (2012), GII.4 (2012-like) and GII.4 (unknown)), GII.6, GII.13 and GII.21. The assay had good sensitivity for both GI and GII norovirus. The assay had a specificity of 97% and did not cross react with a number of common fecal viruses. However, one of eight rotavirus positive, norovirus negative specimens gave a positive result; rotavirus cannot be taken as the cause of such a false positive but cannot be excluded either. The kit was quick and easy to use and would be valuable in point-of-care testing. PMID- 26248053 TI - Informatics for RNA Sequencing: A Web Resource for Analysis on the Cloud. AB - Massively parallel RNA sequencing (RNA-seq) has rapidly become the assay of choice for interrogating RNA transcript abundance and diversity. This article provides a detailed introduction to fundamental RNA-seq molecular biology and informatics concepts. We make available open-access RNA-seq tutorials that cover cloud computing, tool installation, relevant file formats, reference genomes, transcriptome annotations, quality-control strategies, expression, differential expression, and alternative splicing analysis methods. These tutorials and additional training resources are accompanied by complete analysis pipelines and test datasets made available without encumbrance at www.rnaseq.wiki. PMID- 26248055 TI - Multiplex real-time RT-PCR for the simultaneous detection and quantification of GI, GII and GIV noroviruses. AB - Noroviruses are important causes of acute gastroenteritis and are classified into six genogroups with GI, GII and GIV containing human pathogens. This high genetic diversity represents a significant challenge for diagnostic assay development. Genogroup specific monoplex and multiplex real time RT-PCR assays are widely used for the detection of GI and GII noroviruses. On the other hand, GIV norovirus detection is not part of routine laboratory diagnosis. This study describes the development and evaluation of a one tube, real time RT-PCR assay for the simultaneous detection and quantification of GI, GII and GIV noroviruses, including both GIV.1 (human) and GIV.2 (animal) strains. Assay performance was evaluated on a panel of norovirus positive clinical samples by comparison of monoplex and multiplex standard curves and Ct values. The multiplex assay demonstrated equal sensitivity and specificity to the monoplex assays and was able to detect all GI, GII and GIV noroviruses with Ct values equal to that of the monoplex assays. The multiplex assay described in this study will be instrumental for the better understanding of GIV norovirus epidemiology, including their possible zoonotic nature. PMID- 26248056 TI - Direct evidence of Fe(V) and Fe(IV) intermediates during reduction of Fe(VI) to Fe(III): a nuclear forward scattering of synchrotron radiation approach. AB - Identification of unstable high-valent iron species in electron transfer reactions of ferrate(VI) (Fe(VI)O4(2-), Fe(VI)) has been an important challenge in advancing the understanding of the oxidative mechanisms of ferrates. This paper presents the first example of distinguishing various phases differing in the valence state of iron in the solid state reduction of Fe(VI) to Fe(III) oxides at 235 degrees C using hyperfine parameters, isomer shift and hyperfine magnetic field, obtained from nuclear forward scattering of synchrotron radiation (NFS). The NFS technique enables a fast data accumulation resulting in high time resolution of in situ experiments. The results suggest a reaction mechanism, involving Fe(V) and Fe(IV) species, in the thermal decomposition of K2FeO4 to KFeO2. The present study opens up an approach to exploring the unambiguous identification of Fe(VI), Fe(V), Fe(IV), and Fe(III) in electron-transfer reaction mechanisms of ferrates in solid and aqueous phase systems. PMID- 26248057 TI - Oxidative stress, mitochondrial damage and diabetic retinopathy. AB - Diabetes has emerged as an epidemic of the 21st century, and retinopathy remains the leading cause of blindness in young adults and the mechanism of this blinding disease remains evasive. Diabetes-induced metabolic abnormalities have been identified, but a causal relationship between any specific abnormality and the development of this multi-factorial disease is unclear. Reactive oxygen species (ROS) are increased and the antioxidant defense system is compromised. Increased ROS result in retinal metabolic abnormalities, and these metabolic abnormalities can also produce ROS. Sustained exposure to ROS damages the mitochondria and compromises the electron transport system (ETC), and, ultimately, the mitochondrial DNA (mtDNA) is damaged. Damaged mtDNA impairs its transcription, and the vicious cycle of ROS continues to propagate. Many genes important in generation and neutralization of ROS are also epigenetically modified further increasing ROS, and the futile cycle continues to fuel in. Antioxidants have generated beneficial effects in ameliorating retinopathy in diabetic rodents, but limited clinical studies have not been encouraging. With the ongoing use of antioxidants for other chronic diseases, there is a need for a controlled trial to recognize their potential in ameliorating the development of this devastating disease. PMID- 26248059 TI - Comparison of central venous catheterization techniques in pediatric patients: needle vs angiocath. AB - BACKGROUND: A needle or an angiocath has been generally used as a route for inserting a guide wire during central venous catheterization. We compared the needle with the angiocath for ultrasound-guided central venous catheterization in pediatric patients concerning accuracy and easiness. METHODS: One hundred and thirty-two patients aged between 1 day and 5 years were randomized into the needle and the angiocath groups. The study was separately carried out in two age groups: newborns vs infants and children. The primary outcome was time to successful insertion of the guide wire. Secondary outcomes including other time variables (time to 1st successful puncture of the vein, time between 1st successful puncture of the vein and successful insertion of the guide wire, total time to successful central venous catheterization), frequency variables (number of the puncture attempts, number of the guide wire insertion attempts), success rates (1st successful puncture rate, 1st successful guide wire insertion rate), and complications. RESULTS: There were no statistically significant differences in time and frequency variables, success rates, and complications between both the age groups. Time to 1st successful puncture of the vein (36.8 +/- 31.7 vs 19.8 +/- 27.1 s; 95% CI of mean difference 2.2-31.8; P = 0.03) and number of puncture attempts (1.6 +/- 0.7 vs 1.3 +/- 0.8; P = 0.02) were significantly greater in newborns with the needle, whereas with the angiocath, the number of puncture attempts was larger in newborns than in infants and children (1.7 +/- 1.2 vs 1.2 +/- 0.7; P = 0.02). CONCLUSION: The angiocath showed no superiority over the needle for ultrasound-guided central venous catheterization in pediatric patients. Regardless of the needle or the angiocath, puncture of the vein was more difficult in newborns than in infants and children. PMID- 26248060 TI - A Lesion in the Parotid Gland. PMID- 26248058 TI - Age-related changes in the proteostasis network in the brain of the naked mole rat: Implications promoting healthy longevity. AB - The naked mole-rat (NMR) is the longest-lived rodent and possesses several exceptional traits: marked cancer resistance, negligible senescence, prolonged genomic integrity, pronounced proteostasis, and a sustained health span. The underlying molecular mechanisms that contribute to these extraordinary attributes are currently under investigation to gain insights that may conceivably promote and extend human health span and lifespan. The ubiquitin-proteasome and autophagy lysosomal systems play a vital role in eliminating cellular detritus to maintain proteostasis and have been previously shown to be more robust in NMRs when compared with shorter-lived rodents. Using a 2-D PAGE proteomics approach, differential expression and phosphorylation levels of proteins involved in proteostasis networks were evaluated in the brains of NMRs in an age-dependent manner. We identified 9 proteins with significantly altered levels and/or phosphorylation states that have key roles involved in proteostasis networks. To further investigate the possible role that autophagy may play in maintaining cellular proteostasis, we examined aspects of the PI3K/Akt/mammalian target of rapamycin (mTOR) axis as well as levels of Beclin-1, LC3-I, and LC3-II in the brain of the NMR as a function of age. Together, these results show that NMRs maintain high levels of autophagy throughout the majority of their lifespan and may contribute to the extraordinary health span of these rodents. The potential of augmenting human health span via activating the proteostasis network will require further studies. PMID- 26248061 TI - Multivalent DNA recognition by self-assembled clusters: deciphering structural effects by fragments screening and evaluation as siRNA vectors. AB - The identification of low-molecular-weight clusters that effectively complex oligonucleotides of therapeutic interest is of great importance for applications in gene delivery. We recently reported the use of self-assembly processes based on chemoselective ligation in order to generate biomolecular clusters for the multivalent recognition of DNA. Herein, we exploit the modularity of this methodology to perform a one-pot fragments screening of scaffolds and binding groups. Structural parameters affecting DNA binding were observed and hits have been identified by fluorescence displacement and gel electrophoresis assays. Finally, we evaluated the potential of these systems for siRNA transfection. One biomolecular cluster was found to effectively complex and transport a 21-mer siRNA inside MCF7 human breast cancer cells, resulting in a significant knockdown of the target gene. PMID- 26248062 TI - Synthesis of Functionalized Phenanthrenes via Regioselective Oxidative Radical Cyclization. AB - The majority of Sn-mediated cyclizations are reductive and, thus, cannot give a fully conjugated product. This is a limitation in the application of Sn-mediated radical cascades for the preparation of fully conjugated molecules. In this work, we report an oxidatively terminated Bu3Sn-mediated cyclization of an alkyne where AIBN, the commonly used initiator, takes on a new function as an oxidative agent. Sn-mediated radical transformation of biphenyl aryl acetylenes into functionalized phenanthrenyl stannanes can be initiated via two potentially equilibrating vinyl radicals, one of which can be trapped by the fast 6 endoclosure at the biphenyl moiety in good to excellent yields. The efficient preparation of Sn-substituted phenanthrenes opens access to convenient building blocks for the construction of larger polyaromatics. PMID- 26248063 TI - CD44 Influences Fibroblast Behaviors Via Modulation of Cell-Cell and Cell-Matrix Interactions, Affecting Survivin and Hippo Pathways. AB - CD44 has been studied in a wide variety of cell types, in a diverse array of cell behaviors and in a diverse range of signaling pathways. We now document a role for CD44 in mediating fibroblast behaviors via regulation of N-cadherin, extracellular matrix expression, Survivin and the Hippo pathway. Here, we report our findings on the roles of CD44 in modulating proliferation, apoptosis, migration and invasion of murine wild-type (WT-FB) and CD44 knockout dermal fibroblasts (CD44KO-FB). As we have documented in microvascular endothelial cells lacking CD44, we found persistent increased proliferation, reduced activation of cleaved caspase 3, increased initial attachment, but decreased strength of cell attachment in high cell density, post confluent CD44KO-FB cultures. Additionally, we found that siRNA knock-down of CD44 mimicked the behaviors of CD44KO-FB, restoring the decreases in N-cadherin, collagen type I, fibronectin, Survivin, nuclear fractions of YAP and phospho-YAP and decreased levels of cleaved caspase 3 to the levels observed in CD44KO-FB. Interestingly, plating CD44KO-FB on collagen type I or fibronectin resulted in significant decreases in secondary proliferation rates compared to plating cells on non-coated dishes, consistent with increased cell adhesion compared to their effects on WT-FB. Lastly, siRNA knockdown of CD44 in WT-FB resulted in increased fibroblast migration compared to WT-FB, albeit at reduced rates compared to CD44KO-FB. These results are consistent with CD44's pivotal role in modulating several diverse behaviors important for adhesion, proliferation, apoptosis, migration and invasion during development, growth, repair, maintenance and regression of a wide variety of mesenchymal tissues. PMID- 26248064 TI - High prevalence and infection levels of Nosema ceranae in bumblebees Bombus atratus and Bombus bellicosus from Uruguay. AB - Nosema ceranae is one of the most prevalent pathogens in Apis mellifera and has recently been found in multiple host species including several species of bumblebees. Prevalence and infection intensity of N. ceranae was determined in two species of native bumblebees from Uruguay. Nosema ceranae was the only microsporidia identified and mean prevalence was 72% in Bombus atratus and 63% in Bombus bellicosus, values much higher than those reported elsewhere. The presence of this pathogen in bumblebees may be threatening not only for bumblebee populations, but also to the rest of the native pollinator community and to honeybees. PMID- 26248065 TI - An array microhabitat system for high throughput studies of microalgal growth under controlled nutrient gradients. AB - Microalgae have been increasingly recognized in the fields of environmental and biomedical engineering because of its use as base materials for biofuels or biomedical products, and also the urgent needs to control harmful algal blooms protecting water resources worldwide. Central to the theme is the growth rate of microalgae under the influences of various environmental cues including nutrients, pH, oxygen tension and light intensity. Current microalgal culture systems, e.g. raceway ponds or chemostats, are not designed for system parameter optimizations of cell growth. In this article, we present the development of an array microfluidic system for high throughput studies of microalgal growth under well defined environmental conditions. The microfluidic platform consists of an array of microhabitats flanked by two parallel side channels, all of which are patterned in a thin agarose gel membrane. The unique feature of the device is that each microhabitat is physically confined suitable for both motile and non motile cell culture, and at the same time, the device is transparent and can be perfused through the two side channels amendable for precise environmental control of photosynthetic microorganisms. This microfluidic system is used to study the growth kinetics of a model microalgal strain, Chlamydomonas reinhardtii (C. reinhardtii), under ammonium (NH4Cl) concentration gradients. Experimental results show that C. reinhardtii follows Monod growth kinetics with a half saturation constant of 1.2 +/- 0.3 MUM. This microfluidic platform provides a fast (~50 fold speed increase), cost effective (less reagents and human intervention) and quantitative technique for microalgal growth studies, in contrast to the current chemostat or batch cell culture system. It can be easily extended to investigate growth kinetics of other microorganisms under either single or co-culture setting. PMID- 26248066 TI - Behavioural assessment of pain in commercial turkeys (Meleagris gallopavo) with foot pad dermatitis. AB - Two experiments were conducted to investigate the differences in susceptibility to foot pad dermatitis (FPD) of two medium-heavy lines of turkeys, and whether FPD is painful, by detailed analysis of behaviour in birds with and without analgesic treatment (betamethasone). Turkeys housed on dry litter in the first experiment generally had more frequent bouts of different behaviours that were of shorter duration than birds on wet litter. T-patterns (behavioural sequences) were more frequent, varied and complex on dry than on wet litter. Betamethasone injected birds of line B, but not breed A, had shorter resting and longer standing durations on wet litter than saline-injected birds. In the second experiment, turkeys on wet litter given saline stood less and rested more than all other treatment groups, suggesting that they experienced pain that was alleviated in birds receiving betamethasone. Turkeys on dry litter had more frequent, varied and complex patterns of behaviour than turkeys on wet litter and birds kept on intermediate litter wetness. Betamethasone provision increased pattern variety regardless of litter treatment. Turkeys with low FPD scores transferred to wet litter and given saline injections had a longer total duration of resting and shorter duration of standing compared to betamethasone-treated birds. Low FPD birds transferred to wet litter had a similar number of patterns and total pattern occurrence as high FPD birds transferred to dry litter. Betamethasone increased pattern variety and frequency compared to saline injections whereas overall pattern complexity was similar. It was concluded that wet litter affects the behaviour of turkey poults independently of FPD and that betamethasone may also change the behaviour of turkeys. There was some evidence from analgesic treatment and T-pattern analyses that FPD was painful. However, there was no evidence of differences in susceptibility to FPD of the two commercial hybrids. PMID- 26248067 TI - Variably lytic infection dynamics of large Bacteroidetes podovirus phi38:1 against two Cellulophaga baltica host strains. AB - Bacterial viruses (phages) influence global biogeochemical cycles by modulating bacterial mortality, metabolic output and evolution. However, our understanding of phage infections is limited by few methods and environmentally relevant model systems. Prior work showed that Cellulophaga baltica phage phi38:1 infects its original host lytically, and an alternative host either delayed lytically or lysogenically. Here we investigate these infections through traditional and marker-based approaches, and introduce geneELISA for high-throughput examination of phage-host interactions. All methods confirmed the lytic, original host infection (70-80 min latent period; approximately eight phages produced per cell), but alternative host assays were more challenging. A 4.5 h experiment detected no phage production by plaque assay, whereas phageFISH and geneELISA revealed phage genome replication and a latent period >= 150 min. Longer experiments (26 h) suggested an 11 h latent period and a burst size of 871 by plaque assay, whereas phageFISH identified cell lysis starting at < 5 h and lasting to 11 h, but for only 7% to 21.5% of infected cells, respectively, and with ~ 39 phages produced per cell. These findings help resolve the nature of the alternative host infection as delayed lytic and offer solutions to methodological challenges for studying inefficient phage-host interactions. PMID- 26248068 TI - The significance of clean and dirty animals for bacterial dynamics along the beef chain. AB - This study investigated the bacterial dynamics along the beef chain for clean and dirty cattle in the slaughter and processing lines, using classic quantitative methods and molecular analyses. In addition, the Norwegian national guidelines for Good Hygiene Practices in Norway were evaluated. In these guidelines, cattle presented for slaughter are categorised according to hide cleanliness, resulting in separate processing lines for meat from very dirty animals and reduced prices to farmers. The study was conducted in two commercial abattoirs in Norway. Two groups were compared; 40 visually clean cattle and 40 visually dirty cattle presented for slaughter, with 20 from each group at each abattoir. The same animals were sampled at five sampling sites: hides, carcass surfaces after dehiding, just before chilling, after chilling, and meat trimmings. Meat trimmings were sampled in only one abattoir. Three hundred and sixty samples were collected by swabbing 100 cm(2) of the brisket area at the first four sampling sites, and sampling 200 g of meat trimmings at the fifth site. The results showed that the hides of dirty cattle had more Enterobacteriaceae and higher Aerobic Plate Counts (APC) than visually clean cattle (P<0.05), however there was no significant difference for Escherichia coli. For the other sampling sites, there were no differences between the dirty and the clean group. An effect of chilling/drying of the carcass surfaces was demonstrated by the significant reduction in the number of carcasses on which E. coli and Enterobacteriaceae were detected; from 11% and 39% before chilling to 1% and 16% after chilling, respectively. Enterobacteriaceae and E. coli were detected in only three and one of the meat trimming samples, respectively. Amplification and sequencing of the 16S rRNA gene from 643 Enterobacteriaceae colonies derived from 107 samples demonstrated that Escherichia/Shigella were dominant within this family on the hides. However, after dehiding, after grading, and after chilling, the genera Citrobacter and Enterobacter dominated. The meat trimmings were dominated by the genera Kluyvera, Hafnia, and unclassified Enterobacteriaceae. The relative proportions of Escherichia/Shigella were higher for dirty animals than for clean animals, and were higher on hides than from sampling sites further down the chain (P<0.05). The minor differences in contamination on carcass surfaces and meat trimmings between clean and dirty cattle indicate that separate processing lines in Norwegian abattoirs seem to be unnecessary. PMID- 26248069 TI - Search for Antiprotozoal Activity in Herbal Medicinal Preparations; New Natural Leads against Neglected Tropical Diseases. AB - Sleeping sickness, Chagas disease, Leishmaniasis, and Malaria are infectious diseases caused by unicellular eukaryotic parasites ("protozoans"). The three first mentioned are classified as Neglected Tropical Diseases (NTDs) by the World Health Organization and together threaten more than one billion lives worldwide. Due to the lack of research interest and the high increase of resistance against the existing treatments, the search for effective and safe new therapies is urgently required. In view of the large tradition of natural products as sources against infectious diseases [1,2], the aim of the present study is to investigate the potential of legally approved and marketed herbal medicinal products (HMPs) as antiprotozoal agents. Fifty-eight extracts from 53 HMPs on the German market were tested by a Multiple-Target-Screening (MTS) against parasites of the genera Leishmania, Trypanosoma, and Plasmodium. Sixteen HMPs showed in vitro activity against at least one of the pathogens (IC50 < 10 ug/mL). Six extracts from preparations of Salvia, Valeriana, Hypericum, Silybum, Arnica, and Curcuma exhibited high activity (IC50 < 2.5 ug/mL). They were analytically characterized by UHPLC/ESI-QqTOF-MSMS and the activity-guided fractionation of the extracts with the aim to isolate and identify the active compounds is in progress. PMID- 26248070 TI - Synthesis and Herbicidal Activity of New Hydrazide and Hydrazonoyl Derivatives. AB - Three new hydrazide and five new hydrazonoyl derivatives were synthesized. The chemical structures of these compounds were confirmed by 1H-NMR, IR spectroscopy and elemental analysis. The prepared compounds were tested for their activity to inhibit photosynthetic electron transport in spinach chloroplasts and growth of the green algae Chlorella vulgaris. IC50 values of these compounds varied in wide range, from a strong to no inhibitory effect. EPR spectroscopy showed that the active compounds interfered with intermediates Z*/D*, which are localized on the donor side of photosystem II. Fluorescence spectroscopy suggested that the mechanism of inhibitory action of the prepared compounds possibly involves interactions with aromatic amino acids present in photosynthetic proteins. PMID- 26248071 TI - Graphene-Based Nanomaterials as Efficient Peroxidase Mimetic Catalysts for Biosensing Applications: An Overview. AB - "Artificial enzymes", a term coined by Breslow for enzyme mimics is an exciting and promising branch of biomimetic chemistry aiming to imitate the general and essential principles of natural enzymes using a variety of alternative materials including heterogeneous catalysts. Peroxidase enzymes represent a large family of oxidoreductases that typically catalyze biological reactions with high substrate affinity and specificity under relatively mild conditions and thus offer a wide range of practical applications in many areas of science. The increasing understanding of general principles as well as intrinsic drawbacks such as low operational stability, high cost, difficulty in purification and storage, and sensitivity of catalytic activity towards atmospheric conditions of peroxidases has triggered a dynamic field in nanotechnology, biochemical, and material science that aims at joining the better of three worlds by combining the concept adapted from nature with the processability of catalytically active graphene based nanomaterials (G-NMs) as excellent peroxidase mimetic catalysts. This comprehensive review discusses an up-to-date synthesis, kinetics, mechanisms, and biosensing applications of a variety of G-NMs that have been explored as promising catalysts to mimic natural peroxidases. PMID- 26248072 TI - Synthesis of Radiation Curable Palm Oil-Based Epoxy Acrylate: NMR and FTIR Spectroscopic Investigations. AB - Over the past few decades, there has been an increasing demand for bio-based polymers and resins in industrial applications, due to their potential lower cost and environmental impact compared with petroleum-based counterparts. The present research concerns the synthesis of epoxidized palm oil acrylate (EPOLA) from an epoxidized palm oil product (EPOP) as environmentally friendly material. EPOP was acrylated by acrylic acid via a ring opening reaction. The kinetics of the acrylation reaction were monitored throughout the reaction course and the acid value of the reaction mixture reached 10 mg KOH/g after 16 h, indicating the consumption of the acrylic acid. The obtained epoxy acrylate was investigated intensively by means of FTIR and NMR spectroscopy, and the results revealed that the ring opening reaction was completed successfully with an acrylation yield about 82%. The UV free radical polymerization of EPOLA was carried out using two types of photoinitiators. The radiation curing behavior was determined by following the conversion of the acrylate groups. The cross-linking density and the hardness of the cured EPOLA films were measured to evaluate the effect of the photoinitiator on the solid film characteristics, besides, the thermal and mechanical properties were also evaluated. PMID- 26248073 TI - Isolation, Characterization, Crystal Structure Elucidation of Two Flavanones and Simultaneous RP-HPLC Determination of Five Major Compounds from Syzygium campanulatum Korth. AB - Two flavanones named (2S)-7-Hydroxy-5-methoxy-6,8-dimethyl flavanone (1), (S)-5,7 dihydroxy-6,8-dimethyl-flavanone (2), along with known chalcone, namely, (E) 2',4'- dihydroxy-6'-methoxy-3',5'-dimethylchalcone (3) and two triterpenoids, namely, betulinic and ursolic acids (4 and 5), were isolated from the leaves of Syzygium campanulatum Korth (Myrtaceae). The structures of compounds (1 and 2) were determined on the basis of UV-visible, FTIR, NMR spectroscopies and LC-EIMS analytical techniques. Furthermore, new, simple, precise, selective, accurate, highly sensitive, efficient and reproducible RP-HPLC method was developed and validated for the quantitative analysis of the compounds (1-5) from S. campanulatum plants of five different age. RP-HPLC method was validated in terms of specificity, linearity (r2 <= 0.999), precision (2.0% RSD), and recoveries (94.4%-105%). The LOD and LOQ of these compounds ranged from 0.13-0.38 and 0.10 2.23 MUg.mL-1, OPEN ACCESS respectively. Anti-proliferative activity of isolated flavanones (1 and 2) and standardized extract of S. campanulatum was evaluated on human colon cancer (HCT 116) cell line. Compounds (1 and 2) and extract revealed potent and dose-dependent activity with IC50 67.6, 132.9 and 93.4 MUg.mL-1, respectively. To the best of our knowledge, this is the first study on isolation, characterization, X-ray crystallographic analysis of compounds (1 and 2) and simultaneous RP-HPLC determination of five major compounds (1-5) from different age of S. campanulatum plants. PMID- 26248074 TI - UCP2 Modulates Cardioprotective Effects of Ru360 in Isolated Cardiomyocytes during Ischemia. AB - INTRODUCTION: Ruthenium 360 (Ru360) has been shown to induce cardioprotective mechanisms in perfused hearts. The agent is a specific blocker of the main cardiac mitochondrial uptake mechanism, the mitochondrial calcium uniporter (MCU). UCP2, a mitochondrial membrane protein, which influences cardiac ROS formation was reported to interact with the MCU. METHODS: To prove whether Ru360 affects ischemic cell injury on the singular cell level, cell viability (CV) in isolated cardiomyocytes from wild type mice (WT) was measured in a model of pelleting hypoxia (PH). To explore a possible influence of UCP2 on cellular survival, as well as on Ru360 function, cardiomyocytes from UCP2-/- mice were investigated. RESULTS: During PH, Ru360 significantly improved CV in WT cardiomyocytes (Control 26.32% +/- 1.58% vs. PH 13.60% +/- 1.20% vs. PH+Ru360 19.98% +/- 0.98%, n = 6; p < 0.05). No differences in the rate of apoptosis were observed in UCP2-/- vs. WT. In UCP2-/- cardiomyocytes, Ru360 reduced the rate of cell death. However, the effect was less pronounced compared to WT cardiomyocytes. CONCLUSION: Ru360 significantly reduces hypoxic cell injury by preventing single cell apoptosis in WT cardiomyoctes. UCP2 does not affect cell survival in hypoxic cardiomyocytes, but it might modulate cardioprotective effects of Ru360 during ischemia. PMID- 26248075 TI - Fucoxanthinol, Metabolite of Fucoxanthin, Improves Obesity-Induced Inflammation in Adipocyte Cells. AB - Fucoxanthin (Fx) is a marine carotenoid found in edible brown seaweeds. We previously reported that dietary Fx metabolite into fucoxanthinol (FxOH), attenuates the weight gain of white adipose tissue of diabetic/obese KK-Ay mice. In this study, to evaluate anti-diabetic effects of Fx, we investigated improving the effect of insulin resistance on the diabetic model of KK-Ay mice. Furthermore, preventing the effect of FxOH on low-grade chronic inflammation related to oxidative stress was evaluated on 3T3-L1 adipocyte cells and a RAW264.7 macrophage cell co-culture system. A diet containing 0.1% Fx was fed to diabetic model KK-Ay mice for three weeks, then glucose tolerance was observed. Fx diet significantly improved glucose tolerance compared with the control diet group. In in vitro studies, FxOH showed suppressed tumor necrosis factor-alpha (TNF-alpha), and monocyte chemotactic protein-1 (MCP-1) mRNA expression and protein levels in a co-culture of adipocyte and macrophage cells. These findings suggest that Fx ameliorates glucose tolerance in the diabetic model mice. Furthermore, FxOH, a metabolite of Fx, suppresses low-grade chronic inflammation in adipocyte cells. PMID- 26248076 TI - Characterization of Humoral Responses Induced by an H7N9 Influenza Virus-Like Particle Vaccine in BALB/C Mice. AB - In April 2013, human infections with a novel avian influenza (H7N9) virus emerged in China. It has caused serious concerns for public health throughout the world. However, there is presently no effective treatment, and an A (H7N9) H7 subtype influenza vaccine is not available. Vaccination with virus-like particles (VLPs) has showed considerable promise for many other subtype influenza viruses. To produce H7N9 VLPs, full length, unmodified hemagglutinin (HA), neuraminidase (NA), and matrix1 (M1) genes from the A/Wuxi/1/2013(H7N9) were cloned into a pCDNA5.1 FRT vector. By co-transfection, VLPs containing HA, NA, and M1 were secreted by 293T cells. VLPs were purified by ultracentrifugation and injected into mice by the intramuscular route. In animal experiments, humoral and cellular immunoresponse were all triggered by H7N9 VLPs. High levels of specific antibodies and the isotypes of IgG were detected by ELISA. Anamnestic cellular immune responses were examined by detecting specific cytotoxic T cell for IFN Upsilon production in ELISPOT assay. The hemagglutination-inhibition (HAI) against the homologous virus was more than 1:64, and cross-reactive HAI titers against the heterologous virus (H1N1 and H3N2) were more than 1:16. Moreover, VLPs immunized mice showed a rapid increase of neutralizing antibodies, with neutralizing antibody titers more than 1:8, which increased four-fold against PBS immunized mice in week four. By week six, the mice had high neutralization ability against the given strain and held a potent homologous virus neutralizing capacity. Thus, VLPs represent a potential strategy for the development of a safe and effective vaccine against novel avian influenza (H7N9) virus. PMID- 26248077 TI - Molecular Cloning and Functional Studies of Two Kazal-Type Serine Protease Inhibitors Specifically Expressed by Nasonia vitripennis Venom Apparatus. AB - Two cDNA sequences of Kazal-type serine protease inhibitors (KSPIs) in Nasonia vitripennis, NvKSPI-1 and NvKSPI-2, were characterized and their open reading frames (ORFs) were 198 and 264 bp, respectively. Both NvKSPI-1 and NvKSPI-2 contained a typical Kazal-type domain. Real-time quantitative PCR (RT-qPCR) results revealed that NvKSPI-1 and NvKSPI-2 mRNAs were mostly detected specifically in the venom apparatus, while they were expressed at lower levels in the ovary and much lower levels in other tissues tested. In the venom apparatus, both NvKSPI-1 and NvKSPI-2 transcripts were highly expressed on the fourth day post eclosion and then declined gradually. The NvKSPI-1 and NvKSPI-2 genes were recombinantly expressed utilizing a pGEX-4T-2 vector, and the recombinant products fused with glutathione S-transferase were purified. Inhibition of recombinant GST-NvKSPI-1 and GST-NvKSPI-2 to three serine protease inhibitors (trypsin, chymotrypsin, and proteinase K) were tested and results showed that only NvKSPI-1 could inhibit the activity of trypsin. Meanwhile, we evaluated the influence of the recombinant GST-NvKSPI-1 and GST-NvKSPI-2 on the phenoloxidase (PO) activity and prophenoloxidase (PPO) activation of hemolymph from a host pupa, Musca domestica. Results showed PPO activation in host hemolymph was inhibited by both recombinant proteins; however, there was no significant inhibition on the PO activity. Our results suggested that NvKSPI-1 and NvKSPI-2 could inhibit PPO activation in host hemolymph and trypsin activity in vitro. PMID- 26248078 TI - Cross-Excitation in Peripheral Sensory Ganglia Associated with Pain Transmission. AB - Despite the absence of synaptic contacts, cross-excitation of neurons in sensory ganglia during signal transmission is considered to be chemically mediated and appears increased in chronic pain states. In this study, we modulated neurotransmitter release in sensory neurons by direct application of type A botulinum neurotoxin (BoNT/A) to sensory ganglia in an animal model of neuropathic pain and evaluated the effect of this treatment on nocifensive. Unilateral sciatic nerve entrapment (SNE) reduced the ipsilateral hindpaw withdrawal threshold to mechanical stimulation and reduced hindpaw withdrawal latency to thermal stimulation. Direct application of BoNT/A to the ipsilateral L4 dorsal root ganglion (DRG) was localized in the cell bodies of the DRG and reversed the SNE-induced decreases in withdrawal thresholds within 2 days of BoNT/A administration. Results from this study suggest that neurotransmitter release within sensory ganglia is involved in the regulation of pain-related signal transmission. PMID- 26248081 TI - Early Adolescent Alcohol Use: Are Sipping and Drinking Distinct? AB - BACKGROUND: Sipping alcohol is common during early adolescence, but research has ignored the distinction between sipping and drinking whole alcohol beverages, conflating the 2, or else simply classifying "sippers" as abstainers. Research has not addressed whether sippers are different to drinkers, in relation to variables known to be associated with adolescent alcohol consumption, or considered whether sipping and drinking behaviors may have quite different associations. METHODS: Parent-child dyads (N = 1,823) were recruited in 3 states from Australian grade 7 classes. Multinomial logistic analyses compared adolescents who had only had a sip/taste of alcohol (sippers) with adolescents who had consumed at least a whole drink (drinkers) in the past 6 months. The multivariate model assessed a broad range of demographics, parenting practices, peer influences, and adolescent externalizing and internalizing behaviors, and controlled for school clustering. RESULTS: Compared to drinkers, sippers were less likely to come from 1-parent households (odds ratio [OR] = 0.59, 95% confidence interval [CI]: 0.35 to 0.98); less likely to come from low socioeconomic status (SES) households (OR = 0.54, 95% CI: 0.31 to 0.94); more likely to come from families where parents provide stricter alcohol-specific rules (OR = 1.21, 95% CI: 1.11 to 1.32), stricter monitoring of the child's activities (OR = 1.10, 95% CI: 1.04 to 1.16), more consistent parenting practices (OR = 1.13, 95% CI: 1.05 to 1.23), and more positive family relationships (OR = 1.56, 95% CI: 1.02 to 2.43); and report having fewer substance-using peers (OR = 0.80, 95% CI: 0.70 to 0.91) and greater peer disapproval of any substance use (OR = 1.30, 95% CI: 1.19 to 1.42). After adjustment for confounders, the associations with household composition and SES were no longer significant, but the familial and peer associations remained significant in the multivariate analysis, chi(2) (40) = 1,493.06, p < 0.001. CONCLUSIONS: Sipping alcohol has different associations with known predictors of adolescent alcohol use than drinking whole beverages, and sipping may be a distinct or separable behavior. Future research should better define quantities of early consumption and assess the relationship between early sipping and drinking on long-term outcomes separately. PMID- 26248080 TI - Extracellular Vesicles from Ovarian Carcinoma Cells Display Specific Glycosignatures. AB - Cells release vesicles to the extracellular environment with characteristic nucleic acid, protein, lipid, and glycan composition. Here we have isolated and characterized extracellular vesicles (EVs) and total cell membranes (MBs) from ovarian carcinoma OVMz cells. EVs were enriched in specific markers, including Tsg101, CD63, CD9, annexin-I, and MBs contained markers of cellular membrane compartments, including calnexin, GRASP65, GS28, LAMP-1, and L1CAM. The glycoprotein galectin-3 binding protein (LGALS3BP) was strongly enriched in EVs and it contained sialylated complex N-glycans. Lectin blotting with a panel of lectins showed that EVs had specific glycosignatures relative to MBs. Furthermore, the presence of glycoproteins bearing complex N-glycans with alpha2,3-linked sialic acid, fucose, bisecting-GlcNAc and LacdiNAc structures, and O-glycans with the T-antigen were detected. The inhibition of N-glycosylation processing from high mannose to complex glycans using kifunensine caused changes in the composition of EVs and induced a decrease of several glycoproteins. In conclusion, the results showed that glycosignatures of EVs were specific and altered glycosylation within the cell affected the composition and/or dynamics of EVs release. Furthermore, the identified glycosignatures of EVs could provide novel biomarkers for ovarian cancer. PMID- 26248082 TI - On the origins of the linear no-threshold (LNT) dogma by means of untruths, artful dodges and blind faith. AB - This paper is an historical assessment of how prominent radiation geneticists in the United States during the 1940s and 1950s successfully worked to build acceptance for the linear no-threshold (LNT) dose-response model in risk assessment, significantly impacting environmental, occupational and medical exposure standards and practices to the present time. Detailed documentation indicates that actions taken in support of this policy revolution were ideologically driven and deliberately and deceptively misleading; that scientific records were artfully misrepresented; and that people and organizations in positions of public trust failed to perform the duties expected of them. Key activities are described and the roles of specific individuals are documented. These actions culminated in a 1956 report by a Genetics Panel of the U.S. National Academy of Sciences (NAS) on Biological Effects of Atomic Radiation (BEAR). In this report the Genetics Panel recommended that a linear dose response model be adopted for the purpose of risk assessment, a recommendation that was rapidly and widely promulgated. The paper argues that current international cancer risk assessment policies are based on fraudulent actions of the U.S. NAS BEAR I Committee, Genetics Panel and on the uncritical, unquestioning and blind faith acceptance by regulatory agencies and the scientific community. PMID- 26248083 TI - Application of radioisotope XRF and thermoluminescence (TL) dating in investigation of pottery from Tell AL-Kasra archaeological site, Syria. AB - Statistical analysis based on chemical composition, using radioisotope X-ray fluorescence, have been applied on 39 ancient pottery fragments coming from the excavation at Tell Al-Kasra archaeological site, Syria. Three groups were defined by applying Cluster and Factor analysis statistical methods. Thermoluminescence (TL) dating was investigated on three sherds taken from the bathroom (hammam) on the site. Multiple aliquot additive dose (MAAD) was used to estimate the paleodose value, and the gamma spectrometry was used to estimate the dose rate. The average age was found to be 715+/-36 year. PMID- 26248084 TI - Reliability of the peak-analysis results in gamma-ray spectrometry for high relative peak-area uncertainties. AB - When measurement results with values near the decision threshold are being considered, a relative uncertainty of 60% is expected. Since such measurement results can be reported, the performance of the peak-analysing software for gamma ray spectra needs to be examined for peaks that have a large relative uncertainty. The investigation was performed on a series of spectra measured with a HPGe detector under identical counting conditions. It was found that under a limit value of the relative peak area uncertainty the peak-analysis results are reliable with respect to both the peak location and the peak area evaluation. At relative uncertainties exceeding this uncertainty, the probability of type-II errors increases and a systematic influence on the peak area occurs, which originates in fluctuations of the continuous background in the vicinity of the peak. For the counting conditions used in this investigation, the limit relative uncertainty is about 35%, and whereas a systematic influence can be taken into account by a correction factor, the frequency of the type-II errors can only be reduced at the expense of increasing the frequency of the type-I errors. PMID- 26248079 TI - Interactions between Autophagy and Bacterial Toxins: Targets for Therapy? AB - Autophagy is a physiological process involved in defense mechanisms for clearing intracellular bacteria. The autophagic pathway is finely regulated and bacterial toxins interact with this process in a complex manner. Bacterial toxins also interact significantly with many biochemical processes. Evaluations of the effects of bacterial toxins, such as endotoxins, pore-forming toxins and adenylate cyclases, on autophagy could support the development of new strategies for counteracting bacterial pathogenicity. Treatment strategies could focus on drugs that enhance autophagic processes to improve the clearance of intracellular bacteria. However, further in vivo studies are required to decipher the upregulation of autophagy and potential side effects limiting such approaches. The capacity of autophagy activation strategies to improve the outcome of antibiotic treatment should be investigated in the future. PMID- 26248085 TI - Synthesis optimization of 2-(4-N-[11C]methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB), beta-amyloid PET imaging tracer for Alzheimer's disease diagnosis. AB - [11C]PIB is the most used amyloid plaques-specific positron-emitting radiotracers. The radiosynthesis of this compound, carried out by methylation of its precursor with [11C]methyl triflate in 2-butanone, has been improved optimizing the initial concentration and the purification method. Two HPLC methods were compared: good radiochemical yields, specific activities, and chemical purity above 98% were achieved by using as eluant acetonitrile/citrate and formulation in 10% ethanol. PMID- 26248086 TI - Analysis of dysplasia in patients with Barrett's esophagus based on expression pattern of 90 genes. AB - BACKGROUND & AIMS: Diagnoses of dysplasia, based on histologic analyses, dictate management decisions for patients with Barrett's esophagus (BE). However, there is much intra- and inter-observer variation in identification of dysplasia particularly low-grade dysplasia. We aimed to identify a biomarker that could be used to assign patients with low-grade dysplasia to a low- or high-risk group. METHODS: We performed a stringent histologic assessment of 150 frozen esophageal tissues samples collected from 4 centers in the United Kingdom (from 2000 through 2006). The following samples with homogeneous diagnoses were selected for gene expression profiling: 28 from patients with nondysplastic BE, 10 with low-grade dysplasia, 13 with high-grade dysplasia (HGD), and 8 from patients with esophageal adenocarcinoma. A leave-one-out cross-validation analysis was used identify a gene expression signature associated with HGD vs nondysplastic BE. Functional pathways associated with gene signature sets were identified using the MetaCore analysis. Gene expression signature sets were validated using gene expression data on BE and esophageal adenocarcinoma accessed through National Center for Biotechnology Information Gene Expression Omnibus, as well as a separate set of samples (n = 169) collected from patients who underwent endoscopy in the United Kingdom or the Netherlands and analyzed histologically. RESULTS: We identified an expression pattern of 90 genes that could separate nondysplastic BE tissues from those with HGD (P < .0001). Genes in a pathway regulated by retinoic acid-regulated nuclear protein made the largest contribution to this gene set (P < .0001); the transcription factor MYC regulated at least 30% of genes within the signature (P < .0001). In the National Center for Biotechnology Information Gene Expression Omnibus validation set, the signature separated nondysplastic BE samples from esophageal adenocarcinoma samples (P = .0012). In the UK and Netherlands validation cohort, the signature identified dysplastic tissues with an area under the curve value of 0.87 (95% confidence interval: 0.82-0.93). Of samples with low-grade dysplasia (LGD), 64% were considered high risk according to the 90-gene signature; these patients had a higher rate of disease progression than those with a signature categorized as low risk (P = .047). CONCLUSIONS: We identified an expression pattern of 90 genes in esophageal tissues of patients with BE that was associated with low- or high-risk for disease progression. This pattern might be used in combination with histologic analysis of biopsy samples to stratify patients for treatment. It would be most beneficial for analysis of patients without definitive evidence of HGD but for whom early endoscopic intervention is warranted. PMID- 26248087 TI - Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with hepatitis C virus genotype 3 infection and treatment-experienced patients with cirrhosis and hepatitis C virus genotype 2 infection. AB - BACKGROUND & AIMS: We conducted an open-label, randomized, phase 3 trial to determine the efficacy and safety of sofosbuvir and ribavirin, with and without peginterferon-alfa, in treatment-experienced patients with cirrhosis and hepatitis C virus (HCV) genotype 2 infection and treatment-naive or treatment experienced patients with HCV genotype 3 infection. METHODS: The study was conducted at 80 sites in Europe, North America, Australia, and New Zealand Patients were randomly assigned (1:1:1) to groups given sofosbuvir and ribavirin for 16 weeks (n = 196); sofosbuvir and ribavirin for 24 weeks (n = 199); or sofosbuvir, peginterferon-alfa, and ribavirin for 12 weeks (n = 197). The primary end point was the percentage of patients with HCV RNA <15 IU/mL 12 weeks after stopping therapy (sustained virologic response [SVR12]). From October 2013 until April 2014, we enrolled and treated 592 patients-48 with genotype 2 HCV and compensated cirrhosis who had not achieved SVR with previous treatments and 544 with genotype 3 HCV (279 treatment-naive and 265 previously treated). Overall, 219 patients (37%) had compensated cirrhosis. The last post-treatment week 12 patient visit was in January 2015. RESULTS: Rates of SVR12 among patients with genotype 2 HCV were 87% and 100%, for those receiving 16 and 24 weeks of sofosbuvir and ribavirin, respectively, and 94% for those receiving sofosbuvir, peginterferon, and ribavirin for 12 weeks. Rates of SVR12 among patients with genotype 3 HCV were 71% and 84% in those receiving 16 and 24 weeks of sofosbuvir and ribavirin, respectively, and 93% in those receiving sofosbuvir, peginterferon, and ribavirin. On-treatment virologic failure occurred in 3 patients with HCV genotype 3a receiving sofosbuvir and ribavirin for 24 weeks. The most common adverse events were fatigue, headache, insomnia, and nausea. Overall, 1% of patients discontinued treatment due to adverse events. CONCLUSIONS: Among patients with genotype 3 HCV infection, including a large proportion of treatment-experienced patients with cirrhosis, the combination of sofosbuvir, peginterferon, and ribavirin for 12 weeks produces high rates of SVR. Treatment-experienced patients with cirrhosis and genotype 2 HCV infection had high rates of SVR in all groups. EudraCT ID 2013-002641-11. PMID- 26248090 TI - We must pay more attention to record linkage quality. PMID- 26248089 TI - MicroRNA-124 reduces the pentose phosphate pathway and proliferation by targeting PRPS1 and RPIA mRNAs in human colorectal cancer cells. AB - BACKGROUND & AIMS: Cancer cells alter glucose metabolism to support their uncontrolled proliferation. Changes in microRNAs (miRNAs) have been associated with colorectal cancer (CRC) development and progression, but it is not clear whether they regulate metabolism in CRC cells. We aimed to identify miRNAs that alter glucose metabolism in CRC cells and to determine their effects on tumor development. METHODS: CRC tissues and matched nontumor tissues were collected from 78 patients for messenger RNA (mRNA) analysis and from 112 patients for immunohistochemical analysis at the Fudan University Shanghai Cancer Center from 2005 through 2007. We integrated data on 100 miRNAs previously identified as potential regulators of glucose metabolism in a high-throughput screen with data on 66 miRNAs that often are deregulated in CRC cells. miRNAs with the potential to regulate glucose metabolism in CRC cells were blocked with mimics, and effects on lactate production were measured in CRC cell lines. miRNAs and their targets were overexpressed from lentivirals in CRC cell lines (LoVo and HCT-116) or knocked down with small interfering RNAs. The cells were analyzed in proliferation and colony formation assays and for growth as xenograft tumors in mice. RESULTS: We identified 3 miRNAs that significantly inhibited lactate production in 3 CRC cell lines; miR124-3p (miR124) had the strongest effect. By using complementary DNA microarray analyses, we identified 67 mRNAs that were reduced in CRC cell lines that overexpressed miR124; the mRNAs encoding phosphoribosyl pyrophosphate synthetase 1 (PRPS1) and ribose-5-phosphate isomerase-A (RPIA) were found to be direct targets of miR124. Knockdown of PRPS1 and RPIA, as well as overexpression of miR124, each reduced glucose consumption and adenosine triphosphate in level CRC cells. Conversely, overexpression of PRPS1 or RPIA restored glycometabolism to these cells. RPIA and PRPS1 contribute to nucleotide metabolism and supply precursors for DNA and RNA biosynthesis. CRC cells that overexpressed miR124 or with knockdown of RPIA or PRPS1 had reduced DNA synthesis and proliferation, whereas cells incubated with an inhibitor of miR124 had significantly increased DNA synthesis and proliferation and formed more colonies. LoVo cells that overexpressed miR124 formed smaller xenograft tumors that controlled cells in mice, and had lower levels of PRPS1 and RPIA mRNA and protein. Compared with normal colorectal tissues, levels of miR124 were reduced significantly in CRC tissues from patients, whereas levels of PRPS1 and RPIA increased, which was associated with reduced patient survival times. CONCLUSIONS: miR124 inhibits DNA synthesis and proliferation by reducing levels of pentose phosphate pathway enzymes in CRC cells. Expression of miR124 and its targets correlate with survival times and might be used in prognosis. PMID- 26248088 TI - Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome. AB - BACKGROUND & AIMS: African Americans (AAs) have the highest incidence of and mortality resulting from colorectal cancer (CRC) in the United States. Few data are available on genetic and nongenetic risk factors for CRC among AAs. Little is known about cancer risks and mutations in mismatch repair (MMR) genes in AAs with the most common inherited CRC condition, Lynch syndrome. We aimed to characterize phenotype, mutation spectrum, and risk of CRC in AAs with Lynch syndrome. METHODS: We performed a retrospective study of AAs with mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) using databases from 13 US referral centers. We analyzed data on personal and family histories of cancer. Modified segregation analysis conditioned on ascertainment criteria was used to estimate age- and sex specific CRC cumulative risk, studying members of the mutation-carrying families. RESULTS: We identified 51 AA families with deleterious mutations that disrupt function of the MMR gene product: 31 in MLH1 (61%), 11 in MSH2 (21%), 3 in MSH6 (6%), and 6 in PMS2 (12%); 8 mutations were detected in more than 1 individual, and 11 have not been previously reported. In the 920 members of the 51 families with deleterious mutations, the cumulative risks of CRC at 80 years of age were estimated to be 36.2% (95% confidence interval [CI], 10.5%-83.9%) for men and 29.7% (95% CI, 8.31%-76.1%) for women. CRC risk was significantly higher among individuals with mutations in MLH1 or MSH2 (hazard ratio, 13.9; 95% CI, 3.44 56.5). CONCLUSIONS: We estimate the cumulative risk for CRC in AAs with MMR gene mutations to be similar to that of individuals of European descent with Lynch syndrome. Two-thirds of mutations were found in MLH1, some of which were found in multiple individuals and some that have not been previously reported. Differences in mutation spectrum are likely to reflect the genetic diversity of this population. PMID- 26248091 TI - [Private health expenditures in Brazil]. PMID- 26248092 TI - [Review of food policy approaches: from food security to food sovereignty (2000 2013)]. AB - Food policies have attracted special interest due to the global food crisis in 2008 and promotion of the Millennium Development Goals, leading to approaches by different fields. This thematic review aims to describe the main theoretical and methodological approaches to food security and food sovereignty policies. A search was performed in databases of scientific journals from 2000 to 2013. 320 complete articles were selected from a total of 2,699. After reading the articles to apply the inclusion criteria, 55 items were maintained for analysis. In conclusion, with the predominance of food security as a guiding policy, food sovereignty has emerged as a critical response to be included in designing and researching food policies. Food policies are essential for achieving public health goals. Public health should thus take a leading role in linking and orienting such policies. PMID- 26248093 TI - [Vitamin and mineral supplements: regulation, consumption, and health implications]. AB - Micronutrient supplementation to reduce nutritional deficiencies has grown in recent years due to changes in the population's dietary patterns. Widespread preoccupation with health, ease in marketing vitamin and mineral supplements, and strong advertising appeal have encouraged increasing consumption of these products, thereby posing health risks. The current study addresses legislation, consumption, and health risks related to vitamin and mineral supplements in Brazil. The Brazilian legislation on dietary supplements is complex. Studies on their consumption by the Brazilian population are limited, and inappropriate use due to gaps in knowledge poses a potential health risk to the population. The study concludes that public policies are needed to raise awareness on this topic among the general public, health professionals, and sales personnel. PMID- 26248094 TI - The "Healthy Habits, Healthy Girls" randomized controlled trial for girls: study design, protocol, and baseline results. AB - The purpose of this article is to describe the study design, protocol, and baseline results of the "Healthy Habits, Healthy Girls" program. The intervention is being evaluated through a randomized controlled trial in 10 public schools in the city of Sao Paulo, Brazil. Data on the following variables were collected and assessed at baseline and will be reevaluated at 7 and 12 months: body mass index, waist circumference, dietary intake, nutrition, physical activity, social cognitive mediators, physical activity level, sedentary behaviors, self-rated physical status, and overall self-esteem. According to the baseline results, 32.4% and 23.4% of girls were overweight in the intervention and control groups, respectively, and in both groups a higher percentage failed to meet daily recommendations for moderate and vigorous physical activity and maximum screen time (TV, computer, mobile devices). There were no significant differences between the groups for most of the variables, except age (p = 0.000) and waist circumference (p = 0.014). The study showed a gap in the Brazilian literature on protocols for randomized controlled trials to prevent obesity among youth. The current study may thus be an important initial contribution to the field. PMID- 26248095 TI - [Translation and adaptation of a questionnaire to assess patient safety in primary health care]. AB - The objective of this study was to describe the translation and adaptation of the questionnaire used in the Primary Care International Study of Medical Errors (PCISME) for application in primary health care in a local health district in Rio de Janeiro State, Brazil. The process included organization of an expert panel that adapted the questionnaire using a modified Delphi method. The adapted instrument can help produce specific information on primary health care and strengthen initiatives to improve patient safety in Brazil. PMID- 26248097 TI - [Inequality in Brazilian women's access to medicines for chronic diseases]. AB - This study aimed to assess the prevalence of access to continuous prescription drugs for a group of chronic diseases and to investigate the existence of socioeconomic inequalities in access. The data are from the Brazilian National Demographic and Health Survey on Women and Children (2006), with a sample of 15,575 women 15 to 49 years of age. Among these women, 7,717 were diagnosed with a chronic disease that required acquiring medicine and were considered eligible for the study. The dependent variable was defined as the diagnosis of a chronic disease and the need to obtain medication for treatment. Multivariate analysis used Poisson regression. Higher access was associated with residence in a rural area, having one or two chronic diseases, and higher socioeconomic status. Prevalence of access to medication was high, but the analysis revealed socioeconomic inequality in access to medicines in favor of the wealthy, while identifying the most vulnerable groups as the poorest and those with more chronic diseases. PMID- 26248096 TI - Neonatal ventilatory support and respiratory diseases in children up to six years of age: the 2004 Pelotas (Brazil) Birth Cohort study. AB - The study's objective was to evaluate the association between neonatal ventilatory support and the subsequent occurrence of respiratory diseases in children up to six years of age. This was a population-based birth cohort study. The main exposure was ventilatory support at birth, defined as the use of nasal continuous positive airway pressure (NCPAP) and/or mechanical ventilation (MV) for more than three hours from the time of hospitalization at birth until the first 28 days of life. Outcomes were: chest wheezing in the twelve months prior to the follow-up interview, medical diagnosis of asthma any time in the child's life, and occurrence of pneumonia up to six years of age. Crude and adjusted analyses for potential confounding variables were performed using Poisson regression. 3,624 children were analyzed. NCPAP plus MV or MV alone was associated with higher frequency of medical diagnosis of asthma, even after adjusting for maternal and child characteristics (PR = 2.24; 95%CI: 1.27-3.99). The results highlight medium-term respiratory complications associated with neonatal ventilatory support. PMID- 26248098 TI - [Constraints and opportunities for inter-sector health promotion initiatives: a case study]. AB - This article analyzes the implementation of inter-sector initiatives linked to the Family Grant, Family Health, and School Health Programs in the Manguinhos neighborhood in the North Zone of Rio de Janeiro, Brazil. The study was conducted in 2010 and 2011 and included document review, local observation, and 25 interviews with program managers, professionals, and staff. This was an exploratory case study using a qualitative approach that identified constraints and opportunities for inter-sector health experiences, contributing to the debate on the effectiveness of health promotion and poverty relief programs. PMID- 26248099 TI - Changes in perinatal health in two birth cohorts (1997/1998 and 2010) in Sao Luis, Maranhao State, Brazil. AB - The objective of this study was to analyze changes in perinatal health in two birth cohorts started in 1997/1998 and 2010, respectively, in Sao Luis, Maranhao State, Brazil. A total of 2,493 live born infants were included in 1997/1998 and 5,166 in 2010. Low birth weight (LBW) rate did not change (8.5% in 1997/1998 and 8.6% in 2010). Preterm birth (PTB) rate also remained stable (13.2% in 1997/1998 and 13% in 2010). Teenage deliveries and births to single mothers decreased. Maternal schooling and prenatal care coverage increased. Intrauterine growth restriction (IUGR) decreased from 13.3% to 10.6% (p < 0.001). The perinatal mortality rate decreased from 36.6 to 20.7 per 1,000 (p < 0.001) and the infant mortality rate (IMR) dropped from 28.5 to 12.8 per 1,000 (p < 0.001). The cesarean rate increased from 34.1% to 47.5% (p < 0.001). In conclusion, despite favorable changes in socio-demographic, behavioral, and health service factors and decreasing rates of IUGR and perinatal and infant mortality, LBW and PTB remained stable, while the cesarean rate increased. PMID- 26248100 TI - [Functionality and disability in old age: to stay still or not to stay still]. AB - The goals of this study were to identify how community-dwelling elderly deal with the prospect of disability/functionality and to understand how the sociocultural context modulates this process. The study adopted a qualitative approach in which the signs, meanings, and actions model was used in the data collection and analysis. The study interviewed 57 elders ranging from 61 to 96 years of age and enrolled in the six primary health units in Bambui, Minas Gerais State, Brazil. "To stay still or not to stay still" is the underlying question in functioning and disability in old age. However, staying still is not a matter of individual choice, because the answer depends on the elder's financial, intellectual, and subjective resources and available social support. Staying still also implies a concept of old age inexorably associated with disability, leaving the elderly resigned to their condition; when difficulties increase, their only choice is to "wait for death". Health teams need to interfere in this concept, providing care to older people during their recovery and until the end of life. PMID- 26248101 TI - [Live longer and better? Estimates of healthy life expectancy in the Brazilian population]. AB - This study analyzed differences in healthy life expectancy in the elderly based on three health dimensions in Brazil from 1998 to 2008: disability-free life expectancy, healthy life expectancy based on self-rated health, and chronic disease-free life expectancy. The Sullivan method was used, combining life tables from the Brazilian Institute of Geography and Statistics (IBGE) and interval estimates of the prevalence of functional disability, self-rated health, and chronic diseases according to the Brazilian National Household Sample Survey (PNAD, 1998 and 2008). Besides the increase in life expectancy, the study showed significant and similar increases in disability-free life expectancy and healthy life expectancy based on self-rated health at almost all ages. Women had higher life expectancies than men, but expected to live longer with poor health, regardless of the indicator used to measure health. Although the studies measured health differently (making comparisons difficult), women showed a consistent disadvantage in healthy life expectancy. PMID- 26248102 TI - Reliability of cause of death coding: an international comparison. AB - This study evaluates the agreement of nosologic coding of cardiovascular causes of death between a Chilean coder and one in the United States, in a stratified random sample of death certificates of persons aged >= 60, issued in 2008 in the Valparaiso and Metropolitan regions, Chile. All causes of death were converted to ICD-10 codes in parallel by both coders. Concordance was analyzed with inter coder agreement and Cohen's kappa coefficient by level of specification ICD-10 code for the underlying cause and the total causes of death coding. Inter-coder agreement was 76.4% for all causes of death and 80.6% for the underlying cause (agreement at the four-digit level), with differences by the level of specification of the ICD-10 code, by line of the death certificate, and by number of causes of death per certificate. Cohen's kappa coefficient was 0.76 (95%CI: 0.68-0.84) for the underlying cause and 0.75 (95%CI: 0.74-0.77) for the total causes of death. In conclusion, causes of death coding and inter-coder agreement for cardiovascular diseases in two regions of Chile are comparable to an external benchmark and with reports from other countries. PMID- 26248103 TI - [Community health workers' knowledge on tuberculosis, control measures, and directly observed therapy]. AB - This study assessed community health workers' (CHW) knowledge on tuberculosis (TB), TB control measures, and directly observed therapy (DOT) in Belo Horizonte, Minas Gerais State, Brazil. This was a cross-sectional study that applied a questionnaire in a random and representative sample of 489 CHW. The overall proportion of correct answers was 74.6%. The mean proportions of correct answers in the domains for TB, TB control measures, and DOT were 81%, 84.1%, and 59.4%, respectively. The study showed knowledge gaps in the identification of patients with pulmonary TB, the target public for DOT, and adequate technique for treatment supervision. Better knowledge was associated with time working as a CHW (OR = 2.3) and follow-up of cases in the 12 months prior to the interview (OR = 1.7). The study provided new scientific data on level of knowledge among CHW concerning DOT and can support strategies to improve TB control activities. PMID- 26248104 TI - [Street Outreach Offices: visibility, invisibility, and enhanced visibility]. AB - This article discusses care for street people from a socio-anthropological perspective, using participant observation conducted with a team from a street outreach project. Based on observations, street people are historically viewed as marginal and rarely obtain access to health services, thus making them invisible to the Brazilian Unified National Health System. Brazil's National Policy for the Homeless provides for their access to health care, but such care is not always guaranteed in practice, because health services and professionals have little experience in dealing with homeless persons. The study concludes that enhanced visibility is needed to ensure care for people living on the street, establishing a therapeutic bond that deconstructs stigmatizing practice. PMID- 26248105 TI - Hemodialysis services: are public policies turned to guaranteeing the access? AB - The increasing incidence of chronic renal failure in Brazil and the consequential expansion of hemodialysis as a choice for treatment in final stage have to be taken into account to guarantee access to those in need. The ecological study conducted in Mato Grosso do Sul State, Brazil, in 2012, using data from the Brazilian Health Informatics Department (DATASUS) and from the analysis of medical records in 12 clinics, identified and mapped patients on hemodialysis, the distance they travelled and the estimated number of patients. The prevalence of hemodialysis patients in Mato Grosso do Sul State, about 55 per 100,000 inhabitants, is similar to the national average. The analyses indicated concentration of patients in counties with clinics and also geographical gaps that generate displacement of over 100km for more than 16% of patients. The results point to the necessity of strengthening public policies that consider, for decision-making, the decentralization of service, the expansion of home care and the follow-up education for professionals. PMID- 26248106 TI - [Strategies by civil society organizations for access to breast cancer drugs in the Brazilian Unified National Health System]. AB - This study aims to identify and analyze strategies by civil society organizations working with breast cancer (CSOs) on access to drugs in Brazilian Unified National Health System (SUS) and the main social actors. A qualitative approach used the snowball technique, semi-structured interviews, and participant observation. Thematic analysis was based on the following categories: access to drugs for breast cancer treatment, relationship between CSOs and government, relationship between CSOs and the pharmaceutical industry, and other strategies used by CSOs. The results showed that civil society organizations have influenced access to drugs for breast cancer in the SUS and that their main strategies have focused on pressuring government at all levels. Meanwhile, the pharmaceutical industry sponsors some CSOs in order to strengthen them and expand its own market. The main difficulties in access to such drugs involve insufficient services, unequal treatment, and inclusion of technology in the SUS. PMID- 26248107 TI - Time to death in a prospective cohort of 252 patients treated for fracture of the proximal femur in a major hospital in Portugal. AB - The objectives were to analyze one-year survival and mortality predictors in patients with fracture of the proximal femur (low/moderate trauma). A prospective cohort was formed by inviting all patients hospitalized in the Orthopedic Ward of the second largest hospital in Portugal (May 2008-April 2009). Survival was assessed at 3, 6, 9, and 12 months after fracture and related to demographic factors, lifestyle, and clinical history, as well as to data from medical records (fracture type, surgery date, surgical treatment, and preoperative risk). Of the 340 patients hospitalized, 252 were included (78.9% women). Mortality at 3, 6, 9, and 12 months was 21.2%, 25%, 28.8%, and 34.6% for men and 7.8%, 13.5%, 19.2%, and 21.4% for women, respectively. Predictors of death were male gender (HR = 2.54; 95%CI: 1.40-4.58), ASA score III/IV vs. I/II (HR = 1.95; 95%CI: 1.10-3.47), age (HR = 1.06; 95%CI: 1.03-1.10), and delay in days to surgery (HR = 1.07; 95%CI: 1.03-1.12). Factors related to death were mainly related to patients' characteristics at admission. PMID- 26248108 TI - [Human Development Index and secondary prevention of breast and cervical cancer: an ecological study]. AB - This ecological study assessed mammography and Papanicolaou test (Pap smear) screening rates and their association with the Human Development Index (HDI) in Brazilian state capitals and Federal District in 2011, based on VIGITEL telephone survey data. More than 70% of women had a mammogram some time in life in all the state capitals, while the Pap smear rates any time in life and in the previous three years fell short of the 80% target in most state capitals. There was a strong positive correlation between HDI and the test rates (r = 0.52 and 0.66 for mammogram any time in life and in the previous two years and r = 0.66 and 0.71 for Pap smear any time in life and in the previous three years, respectively). Prevalence ratio (PR) for mammogram in the previous two years was 1.06 (95%CI: 1.01-1.10) and PR for Pap smear in the previous three years was 1.07 (IC95%: 1.04 1.10). The promotion of public health policies that encourage Brazil's urban economic and social development should help increase coverage for these tests. PMID- 26248109 TI - Burden of disease in Brazil and its regions, 2008. AB - The current study estimated DALY (disability-adjusted life years), an indicator of burden of disease, for Brazil in 2008. The North and Northeast regions showed higher burden of disease. Chronic noncommunicable diseases predominated in all regions of the country, especially cardiovascular diseases, mental disorders (particularly depression), diabetes, and chronic obstructive pulmonary disease. The study also showed a high burden of homicides and traffic accidents. Brazil's epidemiological profile appears even more complex when one considers the non negligible burden of communicable diseases, maternal and perinatal conditions, and nutritional deficiencies. The analyses allowed a more detailed understanding of the Brazilian's population's health status, underscoring the need for crosscutting actions beyond specific health sector policies and greater attention to the quality of information on morbidity and mortality. PMID- 26248110 TI - Comparison of serum creatinine levels in different color/race categories in a Brazilian population. AB - Serum creatinine (sCr) is usually higher among black people in the United States due to increased muscle mass, justifying the addition of race adjustment in creatinine-based formulas to estimate glomerular filtration rate (eGFR). We aimed to assess if sCr levels are different in low-income communities in Brazil according to their race. A total of 1,303 participants were enrolled (58% females, 50+/-14 years-old, 33% self-defined as white, 41% as mixed race, and 26% as black). No significant differences in sCr were found between racial groups and no influence of race on sCr was seen in the linear regression analysis. The eGFR, calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula with no race adjustment, was no different between whites, mixed race and blacks. However, using such adjustment, eGFR for mixed race and black individuals was significantly higher than for whites (p < 0.001). In conclusion, no significant differences in sCr levels were found between racial groups, raising doubts as to whether race adjustment in eGFR formula should be used in that population. PMID- 26248111 TI - Racial and ethnic-related differences in obesity and the migration factor. PMID- 26248114 TI - Genotypic Diversity of Methicillin-Resistant Coagulase-Negative Staphylococci Isolated from Inpatients and Outpatients. AB - We investigated the prevalence of methicillin-resistant coagulase-negative staphylococci (MRCoNS) isolated from hospitalized patients and outpatients (OP). Out of 350 staphylococcal isolates collected from three hospitals, 190 were coagulase-negative staphylococci (CoNS). These isolates were subjected to antimicrobial susceptibility tests, detection of mecA, and pulsed-field gel electrophoresis (PFGE) typing. Among the 190 isolated CoNS, Staphylococcus epidermidis (47.3%) and Staphylococcus haemolyticus (44.2%) were the most prevalent species. Other CoNS species that were isolated were Staphylococcus saprophyticus (2.1%), Staphylococcus warneri (2.1%), Staphylococcus simulans (1.6%), Staphylococcus capitis (1.1%), Staphylococcus schleiferi (1.1%), and Staphylococcus hominis (0.5%). The rate of resistance to methicillin was 60% with 58 (50%) S. epidermidis and 55 (49%) S. haemolyticus. The rate of resistance to 13 antibiotics tested with the lowest and highest to chloramphenicol and penicillin, respectively. High clonal diversity with different PFGE patterns was obtained for methicillin-resistant S. epidermidis and S. haemolyticus by 32 and 31 types, respectively. Our results indicated that the dissemination of MRCoNS is widespread in Tehran. The majority of these isolates showed distinct genotyping patterns. At the same time, the common patterns were found among the MRCoNS obtained from outpatient and inpatient isolates, suggestive of an epidemiological link. PMID- 26248115 TI - Acute and Chronic Effects of Tantric Yoga Practice on Distress Index. AB - OBJECTIVES: To evaluate the acute and chronic effects of yoga practice. DESIGN: Quantitative study using a one-group pre-posttest design. SETTING: Visao Futuro Institute, Porangaba, Sao Paulo, Brazil. PARTICIPANTS: 22 volunteers (7 men and 15 women). INTERVENTION: Six weeks of a tantric yoga program (TYP), 50 minutes per session, held twice a week from 8 a.m. to 9 a.m. The local ethics committee approved the protocol. OUTCOME MEASURES: Data were collected in the first week and at the end of the sixth week of TYP. Salivary cortisol concentration (SCC) was used to measure physiology of distress and to analyze the short- and long term effects of TYP. Psychological distress was evaluated by applying a specific perceived stress questionnaire (PSQ). Results (mean+/-standard deviation) were analyzed by Wilcoxon test (p<0.05). RESULTS: SCC decreased 24% after the first (0.66+/-0.20 MUg/dL versus 0.50+/-0.13 MUg/dL) and last (1.01+/-0.37 versus 0.76+/-0.31 MUg/dL) sessions, showing the short-term effect of yoga. Long-term effects were analyzed by daily rhythm of cortisol production. In the beginning, volunteers showed altered SCC during the day, with nighttime values (0.42+/-0.28) higher than those at noon (0.30+/-0.06). After the TYP, SCC was higher in the morning (1.01+/-0.37) and decreased during the day, with lower values before sleep (0.30+/-0.13). The TYP was also efficient to reduce PSQ scores (0.45+/-0.13 versus 0.39+/-0.07). Specifically, the irritability, tension, and fatigue domains on the PSQ decreased (0.60+/-0.20 versus 0.46+/-0.13), as did the fear and anxiety domains (0.54+/-0.30 versus 0.30+/-0.20). CONCLUSION: Over the short term, TYP led to the decrease of cortisol production. Over the long term, TYP induced higher cortisol production in the morning and lower production in the evening. Those effects contributed to the physical and mental well-being of the participants. PMID- 26248116 TI - Relationship between serum vitamin D levels and angiographic severity and extent of coronary artery disease. AB - BACKGROUND: Vitamin D is known for its effect in calcium and bone homeostasis. There is an increasing evidence for health benefits accomplished by activated vitamin D that go beyond these classical functions. Previous studies have suggested that lower vitamin D levels are associated with increased cardiovascular disease risk. Therefore, we aimed to evaluate relationship between vitamin D levels and extent and severity of coronary artery disease. MATERIALS AND METHODS: A total of 746 patients in whom coronary angiography was performed between August 2012 and July 2013 were enrolled in this study. Serum vitamin D levels were measured, and patients were grouped according to their serum vitamin D levels (vitamin D <20 ng/mL (n = 602) Group 1 versus >20 ng/dL (n = 144) Group 2). Gensini score system was used to evaluate the association between serum vitamin D levels and severity and extent of coronary artery disease. RESULTS: There was no significant difference between the groups in terms of baseline characteristics and demographic characteristics. Mean serum vitamin D levels of all patient cohort was 15.54 +/- 7.46 ng/mL. Group 1 and Group 2 had an average serum vitamin D levels of 12.6 +/- 3.3 ng/mL and 27.5 +/- 7.8 ng/mL, respectively. Gensini score for all cohort was 26.25 +/- 34.32. Group 1 had an average Gensini score of 26.4 +/- 35.7; on the other hand, Gensini score was 25.5 +/- 27.5 in Group 2 (P = 0.097). CONCLUSIONS: This study failed to demonstrate significant relationship between serum vitamin D levels and the severity and extent of coronary artery disease. Further studies with more participation and homogenous groups with comparable individual and environmental features are needed to evaluate the association of serum vitamin D levels and cardiovascular diseases. PMID- 26248117 TI - Epidemiology of hepatitis C virus in HIV-infected patients. AB - PURPOSE OF REVIEW: This review will give an update on the prevalence of HIV/hepatitis C virus (HCV) coinfection, and describe recent trends in all-cause and cause-specific mortality. The focus is mainly on patients followed in clinics in high-income countries and their heterogeneity in terms of risk factors and clinical outcomes. RECENT FINDINGS: In countries that have introduced comprehensive preventive strategies for injection drug users, the prevalence of HIV/HCV coinfection has declined. Compared with HIV monoinfected patients, the mortality among HCV-coinfected patients remains markedly increased because of multiple risk factors, in particular among drug users. The spectrum of causes of death among coinfected has recently been described in large cohort studies. Around a quarter of all deaths were liver related, and the incidence has decreased in Western Europe and stabilized in Eastern Europe where AIDS remains the dominant cause of death. In North America, the incidence of end-stage liver disease has not decreased despite improvements in HIV care. HCV treatment seems to have had little effect thus far on mortality at the population level. SUMMARY: Despite a decreasing prevalence of HIV/HCV coinfection in many countries, coinfection remains an important clinical problem that requires a multidisciplinary approach including direct-acting antivirals for those at risk of liver-related death. PMID- 26248118 TI - Natural history of liver disease and effect of hepatitis C virus on HIV disease progression. AB - PURPOSE OF REVIEW: Due to high prevalence rates, the hepatitis C virus (HCV) and the HIV cause two viral infections of global importance. Shared routes of transmission lead to a high number of dually infected individuals especially in specific populations such as intravenous drug users or people from highly endemic regions for both viruses. Treatment progress made in the field of HIV in the past three decades diminished the number of HIV patients who die from opportunistic infections and enabled a rise of HCV-associated liver disease in the HIV-HCV coinfected population. RECENT FINDINGS: An HIV-HCV coinfection is mainly characterized by a faster progression to liver cirrhosis that may lead to hepatic decompensation or the development of hepatocellular carcinoma (HCC). The treatment of HIV with highly active antiretroviral therapy (HAART) may only partly reverse this effect by the restoration of the immune system. Although no clear deleterious effect of HCV on the course of HIV infection is described, an increased HIV-associated and non-HIV-associated mortality has been described in patients not cured from their HCV infection. SUMMARY: In this article, we review the latest knowledge on the natural course of HCV in the HIV-infected population, the role of HIV treatment, and the possible effects of HCV on HIV disease progression. PMID- 26248119 TI - Current guidelines and prioritizing treatment of hepatitis C virus in HIV infected patients. AB - PURPOSE OF REVIEW: Coinfection with hepatitis C virus (HCV) and HIV is a significant public health problem worldwide. The broad spectrum antivirals interferon-alpha (IFN) and ribavirin (RBV) have lower sustained virologic response rates in HIV-HCV coinfection compared with HCV monoinfection, with significant associated toxicities and prolonged treatment courses. The recent availability of direct acting antivirals (DAA) has transformed the treatment of HCV, with the opportunity of cure available for most patients with much more tolerable regimens. These regimens are now being studied in HIV-HCV coinfection. RECENT FINDINGS: DAA-based regimens for HIV-HCV coinfection have shown excellent efficacy, with cure rates similar to HCV monoinfection. Either in combination with IFN and RBV, or in 'IFN-free' regimens, cure rates of over 90% are the goal for all HIV-HCV-infected individuals. Data are excellent in genotype 1 infection, but further data on genotype 2-6 are required. These regimens have been shown to be cost-effective in HCV monoinfection, and are likely to be cost-effective in HIV-HCV coinfection. Nonetheless they remain expensive. Recent guidelines have identified coinfected patients as a group for prioritization for treatment, regardless of fibrosis stage. Earlier treatment of those likely to transmit HCV is also recommended. SUMMARY: With the use of DAA, HCV infection in HIV should be curable for most patients, and HIV-infected patients should be prioritized for treatment. The optimal treatment regimens for some genotypes have yet to be determined. The significant cost of DAA-containing regimens is likely to significantly impair their widespread use for the short to medium term, even in well resourced settings, and those with more advanced liver disease are likely to access them first. PMID- 26248120 TI - Direct-acting antiviral-based therapy for acute hepatitis C coinfection. AB - PURPOSE OF REVIEW: Modern interferon (IFN)-free, and potentially also ribavirin free, combinations consisting of two or three direct-acting antivirals (DAAs) are highly efficacious in treating chronic hepatitis C virus (HCV) infection with treatment durations being much shorter and with much more favorable toxicity profiles. With the acute HCV (AHC) epidemic among men who have sex with men (MSM) still ongoing, the question remains should we be using DAAs in the acute phase of the infection? RECENT FINDINGS: To date, none of the currently available DAAs has been licensed for use in the setting of AHC infection. Thus, the current gold standard of treatment still is a combination of pegylated interferon (pegIFN) and weight-adapted ribavirin (RBV). However, with less patients being treated in the acute phase, the current epidemic of AHC in HIV-positive MSM will continue. SUMMARY: A decision to treat AHC with pegIFN and RBV can currently only be made on an individual basis in an open discussion between patient and physician which will need to weigh up the risk and benefits of a rather toxic and lengthy treatment now versus the likely available options in the chronic phase. Therefore, studies with IFN-free DAA combinations remain of great urgency to further evaluate the role of DAAs in the treatment of AHC. PMID- 26248121 TI - Direct-acting antiviral-based therapy for chronic hepatitis C virus in HIV infected patients. AB - PURPOSE OF REVIEW: The aim of this review was to detail the current therapies and treatments for chronic hepatitis C virus in coinfected patients, focusing on HCV antiviral agents currently used in practice today or scheduled to enter the open market soon. RECENT FINDINGS: Several direct-acting antiviral (DAA) combinations show high sustained virologic response (SVR) rates in HIV/HCV-coinfected patients, which are often close to those observed in HCV-monoinfected patients. Most recommendations regarding treatment stem from trials with coinfected patients. However, data are lacking for some aspects of HCV-treatment in coinfection, so extrapolations must be made from data obtained predominately from monoinfected patients. SUMMARY: HIV/HCV-coinfected patients, who, not too long ago, had inferior outcomes in capturing SVR, now enjoy similar fates as the monoinfected patients. They should thus be prioritized for treatment, since HCV and liver disease have become major causes of morbidity and mortality in this population. However, potential drug-drug interactions between antiretroviral agents and DAAs have to be systematically anticipated before initiating HCV therapy. PMID- 26248122 TI - Key drug-drug interactions with direct-acting antiviral in HIV-HCV coinfection. AB - PURPOSE OF REVIEW: We reviewed the most recent data on pharmacokinetic interactions between hepatitis C direct-acting antiviral (DAA) agents and HIV antiretrovirals (ARVs). RECENT FINDINGS: Drug interactions between DAAs and HIV ARVs are extrapolated from phase 1 drug-drug interaction (DDI) studies in healthy volunteers. Safety and efficacy data of DAA-ARV combinations are largely limited to the drug combinations permitted in phase 2 and 3 HIV-HCV coinfection trials. Paritapervir/ritonavir with ombitasvir and dasabuvir (3D) should not be coadministered with efavirenz, etravirine, elvitegravir/cobicistat or with additional doses of ritonavir. Atazanavir, darunavir and rilpivirine require cautious monitoring when used with 3D. The combination of sofosbuvir and ledipasvir can be safely used with most ARVs, but there is a risk of hyperbilirubinaemia with atazanavir. Tenofovir exposure is significantly increased when used with sofosbuvir-ledipasvir and a boosted protease inhibitor or emtricitabine/efavirenz, and therefore should be used with cautious monitoring for renal toxicity only when alternative therapy is not possible. Daclatasvir requires dosage modification with atazanavir, efavirenz and cobicistat. The coadministration of simeprevir with efavirenz, etravirine or ritonavir-boosted and cobicistat-boosted regimens is not recommended. SUMMARY: The safety and efficacy of HCV therapy in HIV-HCV coinfection is now comparable with HCV monoinfection, but drug interactions need to be carefully considered before instituting therapy to minimize potential harm. Real-world data are required to further assess the clinical implications of some DDIs. PMID- 26248123 TI - Beyond cure: preventing and managing the complications of end-stage liver disease. AB - PURPOSE OF REVIEW: The aim of this review was to define the implication of hepatitis C virus (HCV) eradication in patients with cirrhosis. RECENT FINDINGS: Sustained virologic response (SVR) is associated with a favourable outcome in patients with cirrhosis especially in the presence of regression of cirrhosis but also with extrahepatic outcomes regarding health-related quality of life, risk of diabetes, risk of cardiovascular diseases and control of HIV replication by antiretroviral therapy. In patients with decompensated cirrhosis identifying the point of no return where viral eradication is not followed by clinical improvement is extremely relevant. A strict follow-up is needed in order to early diagnose HCC and signs of liver dysfunction, even after SVR, not only in patients with histological diagnosis of cirrhosis but also in those with advanced disease identified by liver stiffness measurements or by noninvasive methods. SUMMARY: Eradication of HCV is associated with regression or 'freezing' of cirrhosis even if it is still unknown the point of no return where this has no benefit for the patient. Nevertheless, in patients with cirrhosis, follow-up should be pursued after eradication of HCV. In addition, HCV eradication has several extrahepatic benefits. PMID- 26248125 TI - Resistance to direct-acting antiviral agents: clinical utility and significance. AB - PURPOSE OF REVIEW: This article examines the dynamics and factors underlying hepatitis C virus (HCV) resistance, along with their impact on daily clinical management of HCV-infected patients. RECENT FINDINGS: Across available treatment regimens, GT-3 is the most difficult-to-cure genotype, but also genotype-1a may show lower success-rates compared with genotype-1b. Natural resistance to NS3, NS5A and NS5B inhibitors may contribute to treatment failures. The Q80K NS3 protease mutation affects sensibility to simeprevir + peg-interferon/ribavirin combinations. It reaches up to 48% prevalence in genotype-1a in some studies (but it is lower in other). Resistant variants (particularly in NS5A) developed at failure can persist, in a substantial proportion of patients, even 3 years after treatment-discontinuation, potentially affecting readministration of the same direct-acting antiviral agent (DAA)-class. This will become an issue for those patients failing all-oral regimens with multiple-resistant viruses. SUMMARY: Recent data support the importance of an accurate genotype and genotype-1 subtype (1a/1b) assignment prior therapy. Resistance testing at baseline has no clear indication so far in clinical practice for all-DAA regimens selection, while it remains a valuable option at the retreatment of patients who failed DAA containing regimens, provided that data are generated to inform treatment decisions based on the results of resistance testing. In this context, long-term RAVs persistence after failure should be taken into account. PMID- 26248124 TI - The hepatitis C virus epidemics in key populations (including people who inject drugs, prisoners and MSM): the use of direct-acting antivirals as treatment for prevention. AB - PURPOSE OF REVIEW: The burden of hepatitis C virus (HCV) is high among people who inject drugs (PWID) and prisoners, and increasing among HIV-infected MSM, who are key populations for HCV transmission in high-income countries and may also play a role in many in low- and middle-income countries. There is an increasing interest in the use of HCV antiviral treatment for prevention in these populations. RECENT FINDINGS: Numerous theoretical modelling studies have explored the potential impact of HCV treatment for prevention among PWID in a range of global settings, generally finding that modest and achievable levels of HCV treatment, especially with interferon-free direct-acting antiviral therapy (IFN-free DAAs), could substantially reduce HCV chronic prevalence among PWID within the next 10-20 years. In addition, modelling studies have shown HCV testing and treatment in prison (including prevention benefits) could be cost-effective if continuity of care is ensured, or HCV treatments are shortened with DAAs. Modelling work among HIV-infected MSM has shown that further HCV treatment scale-up is likely required despite high treatment rates in this population. However, no empirical studies have explored whether HCV treatment can reduce HCV prevalence and prevent onwards transmission among those at risk of transmission. SUMMARY: HCV treatment for key populations such as PWID, prisoners and MSM could become an important HCV prevention intervention, especially in the IFN-free DAA era. However, there is an urgent need to test these hypotheses through empirical studies. PMID- 26248126 TI - Characterization of Metallosupramolecular Polymers by Top-Down Multidimensional Mass Spectrometry Methods. AB - Top-down multidimensional mass spectrometry, interfacing electrospray ionization (ESI) with ion mobility mass spectrometry (IM-MS), and energy resolved (gradient) tandem mass spectrometry (gMS(2) ) are employed to characterize the stoichiometries, architectures, and intrinsic stabilities of coordinatively bound supramolecular polymers containing terpyridine functionalized ligands. As a soft ionization method, ESI prevents or minimizes unwanted assembly destruction. The IM dimension affords separation of the supramolecular ions by charge and collision cross-section (a function of size and shape). The mobility separated ions are subsequently identified by their mass-to-charge-ratios and isotope patterns in the orthogonal MS dimension. Finally, the gMS(2) dimension reveals bond breaking proclivities and disintegration pathways of the assemblies. The described methodology does not require high sample purity due to the dispersive nature of the IM and MS steps. Its utility is demonstrated with the comprehensive analysis of bisterpyridine-based metallomacrocycle mixtures and a tristerpyridine based complex with 3-D nanosphere-like architecture. PMID- 26248127 TI - Editorial: Nanotoxicology and Nanomedicine: A special issue of the Food and Chemical Toxicology. PMID- 26248128 TI - Integrating neurocritical care approaches into neonatology: should all infants be treated equitably? AB - To improve the neurologic outcomes for infants with brain injury, neonatal providers are increasingly implementing neurocritical care approaches into clinical practice. Term infants with brain injury have been principal beneficiaries of neurologically-integrated care models to date, as evidenced by the widespread adoption of therapeutic hypothermia protocols for hypoxic-ischemic encephalopathy. Innovative therapeutic and diagnostic support for very low birth weight infants with brain injury has lagged behind. Given that concern for significant future neurodevelopmental impairment can lead to decisions to withdraw life supportive care at any gestational age, providing families with accurate prognostic information is essential for all infants. Current variable application of multidisciplinary neurocritical care approaches to infants at different gestational ages may be ethically problematic and reflect distinct perceptions of brain injury for infants born extremely premature. PMID- 26248129 TI - Infant formula and neurocognitive outcomes: impact of study end-point selection. AB - OBJECTIVES: Assessing validity and reliability of end points used in docosahexanoic and arachidonic acids (DHA and ARA) infant formula supplementation trials as an example for addressing the impact of end-point selection and critical need for well-defined, reliable and validated clinical outcome assessments for neurocognitive assessment in neonates and infants. STUDY DESIGN: We searched eight electronic databases and reviewed all randomized, controlled human trials using DHA/ARA supplements with neurodevelopment clinical outcomes. We systematically evaluated the validity and reliability of end-point measures based on the criteria for studying nutritional additives recommended by the Institute of Medicine, criteria described in the Food and Drug Administration guidance for clinical outcome assessment, development and literature review. RESULTS: We identified 29 articles that met the selection criteria. The end points that were used for neurodevelopment measures in 23 out of 29 original short-term studies included the Bayley Scale of Infant Development (BSID)-I and II (n=12), Brunet-Lezine test (n=2), videotape infant's movements (n=1), record time to milestones including sitting, crawling, standing and walking (n=1), problem-solving test (n=2), brainstem auditory-evoked potential (n=1), Touwen examination (n=1), Fagan test of infant intelligence (n=2) and visual habituation protocol (n=1). None of these end points have a long-term predictive property for neurocognitive assessment. Compared with standard infant formula, the beneficial effects of DHA/ARA supplementation on neurodevelopment were reported in 2 out of 12 studies using BSID vs 8 out of 11 studies using other end-point measures. In addition, 6 out of 29 long-term follow-up studies used the end points including Stanford-Binet IQ test (n=1), Wechsler Preschool and Primary Scale of Intelligence (n=4) and Bracken Basic Concept Scale (n=1), which are generally scales of intellectual ability and typically do not change substantively in the short term. None of these long-term follow-up studies demonstrated beneficial effects of DHA/ARA supplementation on neurodevelopment. CONCLUSION: The choice of end-point measures affects the outcomes of DHA/ARA-supplemented infant formula trials. Available data are currently inadequate to conclude that DHA/ARA supplementation has a clinically meaningful beneficial effect upon neurological development. Although BSID is validated to assess early developmental delays, it is not designed to predict long-term neurocognitive outcome. A well-defined, valid and reliable clinical outcome assessment that measures neurocognitive function in neonates and infants is essential to provide the scientific evidence required for future clinical trials. PMID- 26248130 TI - The association of congenital heart disease with necrotizing enterocolitis in preterm infants: a birth cohort study. AB - OBJECTIVE: To test the hypothesis that congenital heart disease (CHD) in preterm infants with severe CHD (cyanotic or left-sided obstructive lesions, or congestive heart failure) is independently associated with necrotizing enterocolitis (NEC, stage II or greater). STUDY DESIGN: Single-institution retrospective birth cohort of preterm infants with gestational age 23(0/7) to 34(6/7) weeks delivered between 1 January 2002 and 31 December 2011, excluding infants who received comfort care. Patients were classified into severe CHD, mild CHD and control groups. RESULTS: Among 4678 infants, 170 (3.6%) had CHD and 118 (2.5%) developed NEC. The risk for NEC increased with severe CHD (adjusted relative risk (RR)=3.72; 95% confidence interval (CI)=1.37 to 10.10) but not with mild CHD (RR=0.65; CI=0.27 to 1.55). CONCLUSION: In this cohort, severe but not mild CHD was independently associated with increased risk for NEC. This finding, if confirmed by other studies, may help identify patients at risk for NEC. PMID- 26248131 TI - Home care practices for preterm and term infants after hospital discharge in Massachusetts, 2007 to 2010. AB - OBJECTIVE: The objective of this study was to compare the prevalence of home care practices in very to moderately preterm (VPT), late preterm (LPT) and term infants born in Massachusetts. STUDY DESIGN: Using 2007 to 2010 Massachusetts Pregnancy Risk Assessment Monitoring System data, births were categorized by gestational age (VPT: 23 to 33 weeks; LPT: 34 to 36 weeks; term: 37 to 42 weeks). Home care practices included breastfeeding initiation and continuation, and infant sleep practices (supine sleep position, sleeping in a crib, cosleeping in an adult bed). We developed multivariate models to examine the association of infant sleep practices and breastfeeding with preterm status, controlling for maternal sociodemographic characteristics. RESULTS: Supine sleep position was more prevalent among term infants compared with VPT and LPT infants (77.1%, 71.5%, 64.4%; P=0.02). In the adjusted model, LPT infants were less likely to be placed in supine sleep position compared with term infants (adjusted prevalence ratio=0.86; 95% confidence interval: 0.75 to 0.97). Breastfeeding initiation and continuation did not differ among preterm and term groups. Nearly 16% of VPT and 18% of LPT and term infants were not sleeping in cribs and 14% of LPT and term infants were cosleeping on an adult bed. CONCLUSION: Compared with term infants, LPT infants were less likely to be placed in supine sleep position after hospital discharge. A significant percent of preterm and term infants were cosleeping on an adult bed. Hospitals may consider improving their safe sleep education, particularly to mothers of LPT infants. PMID- 26248133 TI - Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization. PMID- 26248132 TI - Providing meaningful care for families experiencing stillbirth: a meta-synthesis of qualitative evidence. AB - OBJECTIVE: The objective of this study was to explore the meaningfulness of non pharmacological care experienced by families throughout the experience of stillbirth from diagnosis onwards. STUDY DESIGN: A comprehensive systematic review was conducted. Multiple sources were searched for relevant studies including gray literature. Studies were included if they reported the experiences of families with the care they received throughout the experience of stillbirth, from diagnosis onwards. Studies were assessed for methodological quality prior to inclusion. Qualitative findings were extracted from included studies and pooled using a meta-aggregative approach. This paper reports the results of one meta synthesis from the systematic review. RESULTS: Ten qualitative studies of moderate to high quality informed this meta-synthesis. The meta-aggregative synthesis included 69 findings that informed the development of 10 categories and one final, synthesized finding. Emerging themes that underpinned the meaningfulness of care provided to parents experiencing stillbirth included: information provision, the need for emotional support and appropriate maternity ward environments and systems. CONCLUSION: The results of this meta-synthesis revealed the elements of care that were experienced as meaningful from the perspective of parents who had experienced stillbirth. Exploration of these elements has provided important detail to underpin a growing understanding of how parents experience care and what may help or hinder parents' experience of distress, anxiety and grief throughout the experience of stillbirth. PMID- 26248134 TI - Autoantibodies in dilated cardiomyopathy induce vascular endothelial growth factor expression in cardiomyocytes. AB - BACKGROUND: Autoantibodies have been identified as major predisposing factors for dilated cardiomyopathy (DCM). Patients with DCM show elevated serum levels of vascular endothelial growth factor (VEGF) whose source is unknown. Besides its well-investigated effects on angiogenesis, evidence is present that VEGF signaling is additionally involved in fibroblast proliferation and cardiomyocyte hypertrophy, hence in cardiac remodeling. Whether autoimmune effects in DCM impact cardiac VEGF signaling needs to be elucidated. METHODS: Five DCM patients were treated by the immunoadsorption (IA) therapy on five consecutive days. The eluents from the IA columns were collected and prepared for cell culture. Cardiomyocytes from neonatal rats (NRCM) were incubated with increasing DCM immunoglobulin-G (IgG) concentrations for 48 h. Polyclonal IgG (Venimmun N), which was used to restore IgG plasma levels in DCM patients after the IA therapy was additionally used for control cell culture purposes. RESULTS: Elevated serum levels of VEGF decreased significantly after IA (Serum VEGF (ng/ml); DCM pre-IA: 45 +/- 9.1 vs. DCM post-IA: 29 +/- 6.7; P < 0.05). In cell culture, pretreatment of NRCM by DCM-IgG induced VEGF expression in a time and dose dependent manner. Biologically active VEGF that was secreted by NRCM significantly increased BNP mRNA levels in control cardiomyocytes and induced cell-proliferation of cultured cardiac fibroblast (Fibroblast proliferation; NRCM medium/HC-IgG: 1 +/- 0.0 vs. NRCM medium/DCM-IgG 100 ng/ml: 5.6 +/- 0.9; P < 0.05). CONCLUSION: The present study extends the knowledge about the possible link between autoimmune signaling in DCM and VEGF induction. Whether this observation plays a considerable role in cardiac remodeling during DCM development needs to be further elucidated. PMID- 26248135 TI - Elevation of urinary methylmolonic acid induces the suppression of megalin mediated endocytotic cycles during vitamin B12 deficiency. AB - Megalin is a scavenger receptor that serves in the endocytosis of a highly diverse group of ligands that includes Vitamin B12. We found an accumulation of megalin closed to apical region in renal proximal tubule cells of Vitamin B12 deficient rats. Interestingly, Vitamin B12 levels also controlled resorption of renal retinol binding protein. Using L2 yolk sac cells, megalin localized to the submembrane compartment by methylmalonic acid (MMA), which accumulates during vitamin B12 deficiency. In addition, MMA inhibited megalin-mediated endocytosis via YWTD repeats motif in an ectodomain of megalin. Therefore, megalin endocytosis may be regulated by MMA. PMID- 26248136 TI - BRAF activated non-coding RNA (BANCR) promoting gastric cancer cells proliferation via regulation of NF-kappaB1. AB - BACKGROUND AND OBJECTIVE: Long non-coding RNA, BANCR, has been demonstrated to contribute to the proliferation and migration of tumors. However, its molecular mechanism underlying gastric cancer is still unknown. In present study, we investigated whether BANCR was involved in the development of gastric cancer cells via regulation of NF-kappaB1. METHODS: Human gastric cancer tissues were isolated as well as human gastric cell lines MGC803 and BGC823 were cultured to investigate the role of BANCR in gastric cancer. RESULTS: BANCR expression was significantly up-regulated in gastric tumor tissues and gastric cell lines. Down regulation of BANCR inhibited gastric cancer cell growth and promoted cell apoptosis, and it also contributed to a significant decrease of NF-kappaB1 (P50/105) expression and 3'UTR of NF-kappaB1 activity. Overexpression of NF kappaB1 reversed the effect of BANCR on cancer cell growth and apoptosis. MiroRNA 9 (miR-9) targeted NF-kappaB1, and miR-9 inhibitor also reversed the effects of BANCR on gastric cancer cell growth and apoptosis. CONCLUSION: BANCR was highly expressed both in gastric tumor tissues and in cancer cells. NF-kappaB1 and miR-9 were involved in the role of BANCR in gastric cancer cell growth and apoptosis. PMID- 26248137 TI - Multimerization of ERBB2/HER2 specific aptamer leads to improved receptor binding. AB - Aptamers represent a promising new treatment modality for cancer. Specificity and high affinity are two parameters that characterize aptamers. In this work, we elucidated physicochemical parameters of an ERBB2/HER2 specific aptamer and determined an optimal multimerization state, leading to higher binding and improved avidity. We applied biochemical, immunochemical and biophysical methodologies to characterize binding behaviors of multimerized versions of an ERBB2/HER2 specific aptamer and demonstrate structural integrity. Finally, we show that the trimeric ERBB2/HER2 specific aptamer instigates no immunogenic response in vivo. In summary, the set of methodologies we employed establishes a way to enhance activity of a model HER2-aptamer. PMID- 26248138 TI - What is Old is New Again: Introducing a New Section on Person-Centered Care. PMID- 26248139 TI - National Priorities for Dementia Care: Perspectives of Individuals Living with Dementia and Their Care Partners. AB - The current article reports the consensus recommendations from individuals living with dementia and their care partners on priorities for public policy and research funding, which were found using a nationwide, Delphi study. A modified snowball sample was used. Listservs, personal contacts, and advocacy groups were asked to distribute the survey. Paper versions were provided upon request. In Rounds 1 and 2 of the study, 388 and 301 responses, respectively, were received. Borda counts produced a ranked order consensus of priorities. Research ranked third, after the need for caregiver support and resources for the provision of long-term care. Education and training in person-centered practices for all care partners was also a high priority. Responses indicated that research funding should be expanded beyond its current emphasis on cure. Policymakers should reconsider the current priorities of the National Alzheimer's Project Act to better address the long-term needs of individuals living with dementia and their care partners. PMID- 26248140 TI - Evaluating an Online Cognitive Training Platform for Older Adults: User Experience and Implementation Requirements. AB - Decline of cognitive function is a part of aging. However, intensive cognitive training can improve important cognitive functions, such as attention and working memory. Because existing systems are not older adult-friendly and are usually not based on scientific evidence, an online platform was developed for cognitive training with information and communication features and evaluated in an 8-week field test. In a randomized clinical trial with 80 older adults, findings from log data analysis and questionnaires revealed a good use of the online platform. Communication or assistive features were not used often. Good usability ratings were given to the cognitive exercises. Subjective improvements of cognitive functions due to the training were reported. The current article presents concrete requirements and recommendations for deploying cognitive training software in older adult residential homes. PMID- 26248142 TI - The Language of Delirium: Keywords for Identifying Delirium from Medical Records. AB - Electronic medical records (EMRs) offer the opportunity to streamline the search for patients with possible delirium. The purpose of the current study was to identify words and phrases commonly noted in charts of patients with delirium. The current study included 67 patients (nested within a cohort study of 300 patients) ages 70 and older undergoing major elective surgery with evidence of confusion in their medical charts. Eight keywords or phrases had positive predictive values of 60% to 100% for delirium. Keywords were charted more often in nursing notes than physician notes. A brief list of keywords may serve as a building block for a methodology to screen for possible delirium from charts, with particular attention to nursing notes, for research and real-time clinical decision making. PMID- 26248143 TI - Inpatient Pulmonary Rehabilitation Program in a Long-Term Care Facility: Short Term Outcomes and Patient Satisfaction. AB - The purpose of the current study was to evaluate short-term outcomes of inpatient pulmonary rehabilitation (IPR) programs for older patients with chronic obstructive pulmonary disease (COPD). IPR comprises medical management, exercise, nutrition counseling, and coping skills education programs, among other interventions. The current study used a pretest-posttest design with 21 participants evenly split by gender between the ages of 46 and 95. Effects of IPR on functional tolerance exercise capacity and perceived dyspnea on exertion level had a statistically significant difference by the end of the program. Scores for health-related quality of life and subscales of symptoms, impact, and activity in participants younger than 65 were not statistically significant, whereas St. George's Respiratory Questionnaire scores for participants older than 65 showed a statistically significant improvement. Results showed that early IPR is an effective intervention for the management of symptoms of COPD in older adults recovering from a COPD exacerbation. PMID- 26248144 TI - Hot-melt extrusion of sugar-starch-pellets. AB - Sugar-starch-pellets (syn. sugar spheres) are usually manufactured through fluidized bed granulation or wet extrusion techniques. This paper introduces hot melt extrusion (HME) as an alternative method to manufacture sugar-starch pellets. A twin-screw extruder coupled with a Leistritz Micro Pelletizer (LMP) cutting machine was utilized for the extrusion of different types (normal-, waxy , and high-amlyose) of corn starch, blended with varying amounts of sucrose. Pellets were characterized for their physicochemical properties including crystallinity, particle size distribution, tensile strength, and swelling expansion. Furthermore, the influence of sugar content and humidity on the product was investigated. Both sucrose and water lowered the Tg of the starch system allowing a convenient extrusion process. Mechanical strength and swelling behavior could be associated with varying amylose and amylopectin. X-ray powder diffractometric (XRPD) peaks of increasing sucrose contents appeared above 30%. This signified the oversaturation of the extruded starch matrix system with sucrose. Otherwise, had the dissolved sucrose been embedded into the molten starch matrix, no crystalline peak could have been recognized. The replacement of starch with sucrose reduced the starch pellets' swelling effect, which resulted in less sectional expansion (SEI) and changed the surface appearance. Further, a nearly equal tensile strength could be detected for sugar spheres with more than 40% sucrose. This observation stands in good relation with the analyzed values of the commercial pellets. Both techniques (fluidized bed and HME) allowed a high yield of spherical pellets (less friability) for further layering processes. Thermal influence on the sugar-starch system is still an obstacle to be controlled. PMID- 26248145 TI - Inverse gas chromatography a tool to follow physicochemical modifications of pharmaceutical solids: Crystal habit and particles size surface effects. AB - Powders are complex systems and so pharmaceutical solids are not the exception. Nowadays, pharmaceutical ingredients must comply with well-defined draconian specifications imposing narrow particle size range, control on the mean particle size, crystalline structure, crystal habits aspect and surface properties of powders, among others. The different facets, physical forms, defects and/or impurities of the solid will alter its interaction properties. A powerful way of studying surface properties is based on the adsorption of an organic or water vapor on a powder. Inverse gas chromatography (IGC) appears as a useful method to characterize the surface properties of divided solids. The aim of this work is to study the sensitivity of IGC, in Henry's domain, in order to detect the impact of size and morphology in surface energy of two crystalline forms of an excipient, d mannitol. Surface energy analyses using IGC have shown that the alpha form is the most energetically active form. To study size and shape influence on polymorphism, pure alpha and beta mannitol samples were cryomilled (CM) and/or spray dried (SD). All forms showed an increase of the surface energy after treatment, with a higher influence for beta samples (gammas(d) of 40-62 mJ m(-2)) than for alpha mannitol samples (gammas(d) of 75-86 mJ m(-2)). Surface heterogeneity analysis in Henry's domain showed a more heterogeneous beta-CM sample (62-52 mJ m(-2)). Moreover, despite its spherical shape and quite homogeneous size distribution, beta-SD mannitol samples showed a slightly heterogeneous surface (57-52 mJ m(-2)) also higher than the recrystallized beta pure sample (~40 mJ m(-2)). PMID- 26248146 TI - Meeting commentary--"Parkinson's disease: From patient to product". AB - A meeting organised by the Academy of Pharmaceutical Sciences (APSGB) Age-Related Medicines Focus Group took place on the 19th of May 2015, in GlaxoSmithKline Ware, UK [*]. The meeting was the first of a planned series of disease specific meetings organised by APSGB. It was attended by a number of experts involved with the treatment and development of drugs for the older adult, including clinicians, pharmacists, academics, regulators and representatives from industry. The event created the platform to discuss the provision of medicines for the treatment of Parkinson's disease (PD) from a pharmaceutical sciences perspective. 'Medications are something you prescribe: something that gives me my life back' (A PD sufferer). PMID- 26248147 TI - Long-distance detection of alpha-radioactivity: Method and device. AB - Negatively charged ions from the alpha particle tracks are detected by the discharge wire counter opened to the air. Ion clusters are transferred from the particle tracks to the detector volume by an air flux. It allows a remote detection of very low concentrations of alpha particles. In contrast to the existing long-range alpha particle detection technique this method employs a detector working in a counting mode using a gas discharge method with an open-air proportional counter that provides sharp selectivity and accuracy of measurements. The device allows to detect alpha contamination over large surface areas, including places hard to reach, using different nozzles such as the tube nozzle or disc nozzle. The basic parameters of the device are: detection distance -0.5 m; time of detection--10 s; the sensitivity per unit area--0.05 Bq/cm(2). Also the auto-calibration technique and results are presented. That allows using the device under different ambient conditions by making an automatic recalibration. PMID- 26248148 TI - Physiological Background of Differences in Quantitative Diffusion-Weighted Magnetic Resonance Imaging Between Acute Malignant and Benign Vertebral Body Fractures: Correlation of Apparent Diffusion Coefficient With Quantitative Perfusion Magnetic Resonance Imaging Using the 2-Compartment Exchange Model. AB - OBJECTIVE: To test the hypothesis that apparent diffusion coefficient (ADC) in vertebral bone marrow of benign and malignant fractures is related to the volume of the interstitial space, determined with dynamic contrast-enhanced (DCE) magnetic resonance imaging. METHODS: Patients with acute benign (n = 24) and malignant (n = 19) vertebral body fractures were examined at 1.5 T. A diffusion weighted single-shot turbo-spin-echo sequence (b = 100 to 600 s/mm) and DCE turbo FLASH sequence were evaluated. Regions of interest were manually selected for each fracture. Apparent diffusion coefficient was determined with a monoexponential decay model. The DCE magnetic resonance imaging concentration time curves were analyzed using a 2-compartment tracer-kinetic model. RESULTS: Apparent diffusion coefficient showed a significant positive correlation with interstitial volume in the whole study population (Pearson r = 0.66, P < 0.001), as well as in the malignant (Pearson r = 0.64, P = 0.004) and benign (Pearson r = 0.52, P = 0.01) subgroup. A significant correlation between ADC and the permeability-surface area product could be observed when analyzing the whole study population (Spearman rs = 0.40, P = 0.008), but not when separately examining the subgroups. Plasma flow showed a significant correlation with ADC in benign fractures (Pearson r = 0.23, P = 0.03). Plasma volume did not show significant correlations with ADC. CONCLUSIONS: The results support the hypothesis that the ADC of a lesion is inversely correlated to its cellularity. This explains previous observations that ADC is reduced in more malignant lesions. PMID- 26248149 TI - Magnetic Resonance Imaging Findings of Intrahepatic Bile Duct Adenoma: A Report of 4 Cases. AB - Intrahepatic bile duct adenoma (BDA) is a rare type of benign hepatic lesions. In this study, 4 cases of BDA diagnosed from surgical resection pathology were examined. Their clinical and magnetic resonance imaging (MRI) data were retrospectively analyzed. The 4 cases (1 men and 3 women) were aged 21 to 55 years without obvious clinical symptoms. Three were identified through routine examination. Three had a history of chronic hepatitis B virus infection. Two cases were accompanied by hepatocellular carcinoma, and one had a higher level of alpha-fetoprotein. The MRI images of BDA all manifested as peripheral hepatic nodules with abnormal signals. The diameters of the lesions in the 4 cases were 7.7 to 17.0 mm. The MRI images showed slight hypointensity on T1WI and slight hyperintensity on T2WI in all cases, and they showed slight hyperintensity in 2 cases and hyperintensity in 2 cases on diffusion-weighted imaging. Dynamic contrast-enhanced MRI scans show hyperintensity in the arterial phase and slight hyperintensity in the late stage in 3 cases. The other case shows hyperintensity in the arterial and portal phases and isointensity at the delayed phase. During follow-up, 3 cases were recurrence-free. The other case was complicated by the reoccurrence of HCC. In general, BDA shows specific MRI characteristics, and peripheral hepatic nodules show slight hypointensity on T1WI and slight hyperintensity on T2WI. Dynamic contrast-enhanced MRI scans showed obvious enhancement in the arterial phase and continuous enhancement at the late stage. PMID- 26248150 TI - Delivering the Saline Chaser Via a Spiral Flow-Generating Tube Improves Arterial Enhancement for Computed Tomography Angiography of the Lower Extremities. AB - RATIONALE AND OBJECTIVES: We delivered the saline chaser via a spiral flow generating tube or a conventional connecting tube and compared arterial enhancement at computed tomography angiography (CTA) of the lower extremities. MATERIALS AND METHODS: We randomly assigned 100 patients whose ankle bronchial pressure index or clinical symptoms were suspect of peripheral arterial disease to a spiral flow-generating tube (protocol A) or a conventional connecting-tube protocol (protocol B) and performed CTA of the lower extremities. The test bolus was delivered under protocol A or B, and the CT numbers recorded for each protocol were compared. Two radiological technologists visually evaluated the descending genicular artery. RESULTS: In the test injection, the median CT number for the popliteal artery was significantly higher with protocol A than B (204.5 HU vs. 170.5 HU, P = 0.03). For CTA of the lower extremities, the median CT number for the popliteal artery at the level of the patella was 436.1 HU (range, 259-608 HU) under protocol A; with protocol B, it was 382.9 HU (range, 244-564 HU) (P = 0.02). The visual score assigned in the descending genicular artery was statistically significantly higher under protocol A than B (P = 0.03). CONCLUSIONS: Use of the spiral flow-generating tube increased the effect of the saline chaser and significantly improved arterial enhancement from the abdominal aorta to the arteries of the foot at CTA of the lower extremities. PMID- 26248151 TI - Does the Degree of Perihepatitis Have Any Relevance to the Severity of the Manifestations of Pelvic Inflammatory Disease on Multidetector Computed Tomography? AB - PURPOSE: This study aimed to evaluate the relationship between the degree of perihepatitis and the severity of pelvic inflammatory disease (PID) on multidetector computed tomography (MDCT). METHODS: A total of 177 women with PID who underwent biphasic abdominal computed tomography (CT) scans were enrolled. Two reviewers retrospectively reviewed the CT scans with consensus and subjectively categorized the severity of PID into 4 grades (normal, mild, moderate, and severe). Another reviewer independently assigned the extent (grades 0 to 4) and the depth (grades 0 to 4) of hepatic surface enhancement in terms of the degree of perihepatitis. Relationships between the degree of perihepatitis and the CT severity as well as each CT manifestation of PID were evaluated using the chi test or a cumulative logistic regression analysis. RESULTS: Of the 177 patients, 99 (55.9%) showed hepatic surface enhancement. The severity of PID on MDCT was significantly related with the degree of perihepatitis (all P < 0.001). Salpingitis, oophoritis, pelvic fat haziness, complicated ascites, and omental/mesenteric fat infiltration were significantly related with the degree of perihepatitis (all P < 0.05). Among these variables, omental/mesenteric fat infiltration (odds ratio = 10.9) and salpingitis (odds ratio = 6.0) were the CT manifestations that were most associated with the presence of perihepatitis in PID. CONCLUSIONS: The degree of perihepatitis seems to show a relationship with the severity of PID on MDCT. Omental/mesenteric fat infiltration and salpingitis can be strongly related with perihepatitis in PID. PMID- 26248152 TI - Procedure Oriented Torsional Anatomy of the Forearm for Spasticity Injection. AB - : This is the second in a series of articles related to the concept of "torsional" anatomy. The objective of this article is to provide musculoskeletal ultrasound (MSKUS) anatomy of the forearm in the position of hemispastic flexion as a reference relevant to needle procedures. METHODS: The MSKUS images were obtained in a healthy human subject. Marker dots were placed over common injection sites in the forearm for spasticity. The MSKUS probe was centered over each dot to obtain a cross-sectional view. A pair of MSKUS images was recorded for each site: the first in anatomic neutral and second in hemiparetic spastic position. The images were compared side to side. In addition, a video recording was made at each site to track the movement of the muscles and nerves during internal rotation. RESULTS: The pronator teres (PT) rotated medially and the brachialis and biceps tendon rotated in view. In addition, the median nerve became more superficial. The flexor carpi radialis rotated medially and was replaced by PT and the median nerve. The flexor carpi ulnaris and flexor digitorum profundus rotated medially and were replaced by the flexor carpi radialis, PT and median nerve. The flexor digitorum superficialis was replaced by the brachioradialis, extensor carpi radialis brevis, and radial nerve. The brachioradialis was replaced by the extensor carpi radialis brevis and extensor digitorum communis. DISCUSSION: Intended muscle targets rotate out of view and injection range. These are replaced by other muscles and nerves that could inadvertently be injected. This potentially could result in both increased complications and decreased efficacy of the procedure. CONCLUSIONS: It is hoped that this series of images will increase the accuracy and safety of needle placement for spasticity injections in the forearm. PMID- 26248153 TI - Review of Commonly Used Serum Tumor Markers and Their Relevance for Image Interpretation. AB - Serum tumor markers are firmly entrenched as one of the primary tools in an oncologist's armamentarium. They can be implemented in a broad range of applications from diagnostic assistance, assessing prognosis, or guiding therapeutic decisions. However, tumor markers also have limitations, which significantly impact how they should be used. Radiologists should be familiar with the following most prevalent tumor markers, which will all be discussed here: prostate-specific antigen (prostate), carcinoembryonic antigen (colon), alpha-fetoprotein (hepatocellular and testicular), carbohydrate antigen 19.9 (pancreas), cancer antigen 125 (ovarian), human chorionic gonadotropin/lactic dehydrogenase (testicular), and chromogranin A (neuroendocrine). This knowledge should avoid needless intervention, enhance image interpretation, and ultimately provide optimal patient care. PMID- 26248154 TI - Preprocedure and Postprocedure Predictive Values of Serum beta2-Microglobulin for Contrast-Induced Nephropathy in Patients Undergoing Coronary Computed Tomography Angiography: A Comparison With Creatinine-Based Parameters and Cystatin C. AB - OBJECTIVE: This study aimed to investigate the values of serum beta2 microglobulin to predict contrast-induced nephropathy (CIN) before and early after coronary computed tomography angiography (CCTA), comparing with creatinine based parameters and cystatin C. METHODS: A total of 424 patients were enrolled. Serum beta2-microglobulin, cystatin C, and creatinine were measured at 0, 24, and 48 hours of CCTA. Contrast-induced nephropathy was defined as an elevation of serum creatinine level by 25% or higher or 0.5 mg/dL or greater from baseline within 48 hours. The estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease study equation. Receiver operating characteristic curves and multivariate logistic regression analysis were used to detect the efficiency of biomarkers in predicting CIN. RESULTS: Fifty-two subjects (12.26%) developed CIN. Before CCTA, CIN was predicted by both baseline beta2-microglobulin (area under the receiver operating characteristic curve [AUC], 0.791; P < 0.001) and cystatin C (AUC, 0.781; P < 0.001), whereas creatinine and eGFR were not predictive. After CCTA, CIN was predicted by both the absolute post-CCTA levels of beta2-microglobulin, cystatin C, creatinine, and eGFR (AUC, 0.842 vs 0.961 vs 0.691 vs 0.688 at 24 hours, P < 0.001; and 0.937 vs 1.000 vs 0.908 vs 0.898 at 48 hours, P < 0.001) and their relative changes (Delta) to baseline (AUC, 0.677 vs 0.846 vs 0.850 vs 0.844 at 24 hours, P < 0.001; and 0.731 vs 0.968 vs 0.984 vs 0.966 at 48 hours, P < 0.001). Multivariate regression analysis confirmed that baseline beta2-microglobulin (odds ratio, 2.137; 95% confidence interval, 1.805-3.109; P < 0.001) and cystatin C (odds ratio, 1.873; 95% confidence interval, 1.667-2.341; P = 0.003) were independent predictors for CIN. CONCLUSIONS: Serum beta2-microglobulin, with values superior to creatinine-based parameters and similar with cystatin C, was a useful biomarker for the prediction of CIN at pre-CCTA and early post-CCTA. PMID- 26248155 TI - Evaluation of Acute Abdominal Pain in the Emergency Setting Using Computed Tomography Without Oral Contrast in Patients With Body Mass Index Greater Than 25. AB - PURPOSE: To evaluate the rate of delayed or missed diagnoses and need for additional computed tomography (CT) imaging in emergency department patients with abdominal pain who are imaged without oral contrast. MATERIALS AND METHODS: The institutional review board approved this Health Insurance Portability and Accountability Act-compliant retrospective study; informed consent was waived. All consecutive adult patients with body mass index greater than 25 undergoing a CT abdomen/pelvis with intravenous contrast and without oral contrast with nontraumatic acute abdominal pain during a 16-month period at our academic tertiary care center were included. Medical records were reviewed, imaging findings on admission CT, use of repeat CT examinations within 4 weeks of the original examination, and clinical outcomes were recorded. In patients undergoing repeat imaging, an investigator determined whether repeat imaging was influenced by the lack of oral contrast on the original examination. As the most common cause of bowel-related positive CT scans, an analysis of acute appendicitis was performed. RESULTS: Of the 1992 patients included in this study, 4 patients (0.2%) underwent repeat CT studies directly related to the absence of oral contrast on the original examination. Of the 1992 CT scans, 1193(59.8%) were interpreted as negative, none of which required surgery or direct intervention. In patients with acute appendicitis, there was a sensitivity of CT in this patient population of 100% with a specificity of 99.5%. CONCLUSIONS: In patients with body mass index greater than 25 presenting to the ED with acute abdominal pain, CT examinations can be acquired without oral contrast without compromising the clinical efficacy of CT. PMID- 26248156 TI - Anatomic variations of the branches of the aortic arch in a Peruvian population. AB - PURPOSE: Previous publications from two countries in South America found one anatomical variation not previously reported in the rest of the world, which in turn give some clues with regard to a racial difference. The objective of the present study is to describe variations in the anatomical distribution of the branches of the aortic arch in a Peruvian population. OBJECTIVE: To describe variations in the anatomical distribution of the branches of the aortic arch in a Peruvian population. METHODS: A descriptive study of patients who underwent a tomography angiography of the aorta was performed. We analyzed the reports that showed the description of the variations of the branches of the aortic arch based on the eight types currently described in the literature. RESULTS: From 361 analyzed reports, 282 patients (78.12%) had a normal aortic arch configuration (type I; aortic arch gives rise to the brachiocephalic trunk, left common carotid and left subclavian arteries); followed by type II (left common carotid artery as a branch of the aorta) with 41 patients (11.36%); and type IX (common ostium for the brachiocephalic trunk and the left common carotid artery) with 25 patients (6.93%). The latter and two other types are new variations. CONCLUSION: Aortic Arch Type I, Type II and Type IX were the most frequent variations in this Peruvian study. Additionally, we also found two more new types that have not been previously described in the literature. Further investigation regarding these variations is needed in order to assess a racial factor in South America and possible relationships with clinical or surgical events. PMID- 26248157 TI - Transgenic Rabbits Expressing Ovine PrP Are Susceptible to Scrapie. AB - Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases affecting a wide range of mammalian species. They are caused by prions, a proteinaceous pathogen essentially composed of PrPSc, an abnormal isoform of the host encoded cellular prion protein PrPC. Constrained steric interactions between PrPSc and PrPC are thought to provide prions with species specificity, and to control cross-species transmission into other host populations, including humans. Transgenetic expression of foreign PrP genes has been successfully and widely used to overcome the recognized resistance of mouse to foreign TSE sources. Rabbit is one of the species that exhibit a pronounced resistance to TSEs. Most attempts to infect experimentally rabbit have failed, except after inoculation with cell-free generated rabbit prions. To gain insights on the molecular determinants of the relative resistance of rabbits to prions, we generated transgenic rabbits expressing the susceptible V136R154Q171 allele of the ovine PRNP gene on a rabbit wild type PRNP New Zealand background and assessed their experimental susceptibility to scrapie prions. All transgenic animals developed a typical TSE 6-8 months after intracerebral inoculation, whereas wild type rabbits remained healthy more than 700 days after inoculation. Despite the endogenous presence of rabbit PrPC, only ovine PrPSc was detectable in the brains of diseased animals. Collectively these data indicate that the low susceptibility of rabbits to prion infection is not enciphered within their non PrP genetic background. PMID- 26248158 TI - The Evolution of the Secreted Regulatory Protein Progranulin. AB - Progranulin is a secreted growth factor that is active in tumorigenesis, wound repair, and inflammation. Haploinsufficiency of the human progranulin gene, GRN, causes frontotemporal dementia. Progranulins are composed of chains of cysteine rich granulin modules. Modules may be released from progranulin by proteolysis as 6kDa granulin polypeptides. Both intact progranulin and some of the granulin polypeptides are biologically active. The granulin module occurs in certain plant proteases and progranulins are present in early diverging metazoan clades such as the sponges, indicating their ancient evolutionary origin. There is only one Grn gene in mammalian genomes. More gene-rich Grn families occur in teleost fish with between 3 and 6 members per species including short-form Grns that have no tetrapod counterparts. Our goals are to elucidate progranulin and granulin module evolution by investigating (i): the origins of metazoan progranulins (ii): the evolutionary relationships between the single Grn of tetrapods and the multiple Grn genes of fish (iii): the evolution of granulin module architectures of vertebrate progranulins (iv): the conservation of mammalian granulin polypeptide sequences and how the conserved granulin amino acid sequences map to the known three dimensional structures of granulin modules. We report that progranulin-like proteins are present in unicellular eukaryotes that are closely related to metazoa suggesting that progranulin is among the earliest extracellular regulatory proteins still employed by multicellular animals. From the genomes of the elephant shark and coelacanth we identified contemporary representatives of a precursor for short-from Grn genes of ray-finned fish that is lost in tetrapods. In vertebrate Grns pathways of exon duplication resulted in a conserved module architecture at the amino-terminus that is frequently accompanied by an unusual pattern of tandem nearly identical module repeats near the carboxyl-terminus. Polypeptide sequence conservation of mammalian granulin modules identified potential structure-activity relationships that may be informative in designing progranulin based therapeutics. PMID- 26248160 TI - Combined Flux Chamber and Genomics Approach Links Nitrous Acid Emissions to Ammonia Oxidizing Bacteria and Archaea in Urban and Agricultural Soil. AB - Nitrous acid (HONO) is a photochemical source of hydroxyl radical and nitric oxide in the atmosphere that stems from abiotic and biogenic processes, including the activity of ammonia-oxidizing soil microbes. HONO fluxes were measured from agricultural and urban soil in mesocosm studies aimed at characterizing biogenic sources and linking them to indigenous microbial consortia. Fluxes of HONO from agricultural and urban soil were suppressed by addition of a nitrification inhibitor and enhanced by amendment with ammonium (NH4(+)), with peaks at 19 and 8 ng m(-2) s(-1), respectively. In addition, both agricultural and urban soils were observed to convert (15)NH4(+) to HO(15)NO. Genomic surveys of soil samples revealed that 1.5-6% of total expressed 16S rRNA sequences detected belonged to known ammonia oxidizing bacteria and archaea. Peak fluxes of HONO were directly related to the abundance of ammonia-oxidizer sequences, which in turn depended on soil pH. Peak HONO fluxes under fertilized conditions are comparable in magnitude to fluxes reported during field campaigns. The results suggest that biogenic HONO emissions will be important in soil environments that exhibit high nitrification rates (e.g., agricultural soil) although the widespread occurrence of ammonia oxidizers implies that biogenic HONO emissions are also possible in the urban and remote environment. PMID- 26248159 TI - Activation of Calpain-2 by Mediators in Pulmonary Vascular Remodeling of Pulmonary Arterial Hypertension. AB - Calpain mediates collagen synthesis and cell proliferation and plays an important role in pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). In the present study, we investigated whether and how calpain is activated by PAH mediators in pulmonary artery smooth muscle cells (PASMCs). These data show that smooth muscle-specific knockout of calpain attenuated and knockout of calpastatin potentiated pulmonary vascular remodeling and pulmonary hypertension. Treatment of PASMCs with the PAH mediators platelet-derived growth factor (PDGF), serotonin, H2O2, endothelin-1, and IL-6 caused significant increases in calpain activity, cell proliferation, and collagen-I protein level without changes in protein levels of calpain-1 and -2. The calcium chelator 1,2-bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA/AM) did not affect calpain activation, but the extracellular signal regulated kinase (ERK) 1/2 inhibitor PD98059 and knocking down of calpain-2 prevented calpain activation in PAH mediator-treated PASMCs. Mass spectrometry data showed that the phosphorylation of calpain-2 at serine (Ser) 50 was increased and the phosphorylation of calpain-2 at Ser369 was decreased in PDGF treated PASMCs. The PDGF-induced increase in Ser50 phosphorylation of calpain-2 was prevented by PD98059, whereas dephosphorylation of calpain-2 at Ser369 was blocked by the protein phosphatase 2A inhibitor fostriecin. Furthermore, smooth muscle of pulmonary arteries in PAH animal models and patients with PAH showed higher levels of phospho-Ser50-calpain-2 (P-Ser50) and lower levels of phospho Ser369-calpain-2 (P-Ser369). These data support that calpain modulates pulmonary vascular remodeling in PAH. PAH mediator-induced activation of calpain is caused by ERK1/2-dependent phosphorylation of calpain-2 at Ser50 and protein phosphatase 2A-dependent dephosphorylation of calpain-2 at Ser369 in pulmonary vascular remodeling of PAH. PMID- 26248161 TI - A rare combination: congenital factor VII deficiency with Chiari malformation. AB - Congenital factor (VII) deficiency is a rare bleeding disorder. We present a patient with congenital FVII deficiency and congenital hydrocephalus who underwent a ventriculoperitoneal shunt operation and needed no prophylaxis after the procedure. PMID- 26248164 TI - Enhanced remediation of chlorpyrifos by ryegrass (Lolium multiflorum) and a chlorpyrifos degrading bacterial endophyte Mezorhizobium sp. HN3. AB - For effective remediation of contaminants, plant-endophyte partnership is a promising field to be explored. Generally endophytic bacteria assist their host plant by withstanding the stress induced by the contaminants. The objective of this study was to explore the suitability of plant-bacterial partnership for chlorpyrifos (CP) remediation using ryegrass and a CP degrading endophyte, Mesorhizobium sp. HN3 which belongs to plant growth promoting rhizobia. The inoculated yfp-tagged Mesorhizobium sp. HN3 efficiently colonized in the rhizosphere, enhanced plant growth and degradation of CP and its metabolite 3,5,6 trichloro-2-pyridinol (TCP). Significantly lower CP residues were observed in the roots and shoots of plants vegetated in inoculated soil which might be attributed to the efficient root colonization of HN3yfp. These results suggest the involvement of Mesorhizobium sp. HN3yfp in CP degradation inside the roots and rhizosphere of plants and further emphasize on the effectiveness of endophytic bacteria in stimulating the remediation of pesticide contaminants. This is the first report which demonstrates the efficacy of bacterial endophyte for degradation of CP residues taken up by the plant and enhanced remediation of chlorpyrifos contaminated soil. PMID- 26248166 TI - Ultrasonic assessment of diagonal stiffness coefficients in children cortical bone. PMID- 26248165 TI - A radiopaque electrospun scaffold for engineering fibrous musculoskeletal tissues: Scaffold characterization and in vivo applications. AB - Tissue engineering strategies have emerged in response to the growing prevalence of chronic musculoskeletal conditions, with many of these regenerative methods currently being evaluated in translational animal models. Engineered replacements for fibrous tissues such as the meniscus, annulus fibrosus, tendons, and ligaments are subjected to challenging physiologic loads, and are difficult to track in vivo using standard techniques. The diagnosis and treatment of musculoskeletal conditions depends heavily on radiographic assessment, and a number of currently available implants utilize radiopaque markers to facilitate in vivo imaging. In this study, we developed a nanofibrous scaffold in which individual fibers included radiopaque nanoparticles. Inclusion of radiopaque particles increased the tensile modulus of the scaffold and imparted radiation attenuation within the range of cortical bone. When scaffolds were seeded with bovine mesenchymal stem cells in vitro, there was no change in cell proliferation and no evidence of promiscuous conversion to an osteogenic phenotype. Scaffolds were implanted ex vivo in a model of a meniscal tear in a bovine joint and in vivo in a model of total disc replacement in the rat coccygeal spine (tail), and were visualized via fluoroscopy and microcomputed tomography. In the disc replacement model, histological analysis at 4 weeks showed that the scaffold was biocompatible and supported the deposition of fibrous tissue in vivo. Nanofibrous scaffolds that include radiopaque nanoparticles provide a biocompatible template with sufficient radiopacity for in vivo visualization in both small and large animal models. This radiopacity may facilitate image-guided implantation and non invasive long-term evaluation of scaffold location and performance. STATEMENT OF SIGNIFICANCE: The healing capacity of fibrous musculoskeletal tissues is limited, and injury or degeneration of these tissues compromises the standard of living of millions in the US. Tissue engineering repair strategies for the intervertebral disc, meniscus, tendon and ligament have progressed from in vitro to in vivo evaluation using a variety of animal models, and the clinical application of these technologies is imminent. The composition of most scaffold materials however does not allow for visualization by methods available to clinicians (e.g., radiography), and thus it is not possible to assess their performance in situ. In this work, we describe a radiopaque nanofibrous scaffold that can be visualized radiographically in both small and large animal models and serve as a framework for the development of an engineered fibrous tissue. PMID- 26248167 TI - Model development of healthy-lifestyle behaviors for rural Muslim Indonesians with hypertension: A qualitative study. AB - Hypertension is a significant health issue in Indonesia. Health professionals in a rural district of West Java identified hypertension as a priority health issue. In this study, we describe healthy-lifestyle behaviors as perceived by the district's middle-aged Muslims with hypertension. A qualitative case-study design was used. Twelve married couples, directly or indirectly impacted by hypertension, and who visited community health centers, were purposively recruited. Semistructured interviews provided data that were systematically analyzed for categories and subcategories. Categories of healthy-lifestyle behaviors currently practiced were eating behavior, physical activity, resting, not smoking, managing stress, seeking health information, seeking health care, caring other people, and fulfilling an obligation to God. Categories of reasons for practicing healthy-lifestyle behaviors were behavioral beliefs, competence, religious support, prior experience, social support, and health system support. Categories for not practicing healthy-lifestyle behaviors were personal, social, and environmental barriers. To achieve healthy-lifestyle behavior changes, it is essential for rural middle-aged Muslim individuals to be supported by reinforcing their positive reasons and to address their negative reasons to practice healthy lifestyle behaviors. PMID- 26248168 TI - Influence of Partial Denitrification and Mixotrophic Growth of NOB on Microbial Distribution in Aerobic Granular Sludge. AB - In aerobic granular sludge (AGS), the growth of nitrite oxidizing bacteria (NOB) can be uncoupled from the nitrite supply of ammonia oxidizing bacteria (AOB). Besides, unlike for conventional activated sludge, Nitrobacter was found to be the dominant NOB and not Nitrospira. To explain these experimental observations, two possible pathways have been put forward in literature. The first one involves the availability of additional nitrite from partial denitrification (nitrite loop) and the second one consists of mixotrophic growth of Nitrobacter in the presence of acetate (ping-pong). In this contribution, mathematical models were set up to assess the possibility of these pathways to explain the reported observations. Simulation results revealed that both pathways influenced the nitrifier distribution in the granules. The nitrite-loop pathway led to an elevated NOB/AOB ratio, while mixotrophic growth of Nitrobacter guaranteed their predominance among the NOB population. Besides, mixotrophic growth of Nitrobacter could lead to NO emission from AGS. An increasing temperature and/or a decreasing oxygen concentration led to an elevated NOB/AOB ratio and increased NO emissions. PMID- 26248169 TI - Compensations for Weight Loss in Successful and Unsuccessful Dieters. AB - OBJECTIVES: To explore for the presence of behavioral compensation for weight loss in successful and unsuccessful dieters. METHODS: Successful dieters (women maintaining a weight loss >= 10% body weight for >= 1 year) and unsuccessful dieters (women who had lost and regained >= 10% body weight) were compared to age and BMI-matched controls for measures obtained from self-report surveys, an online dietary recall, indirect calorimetry, a submaximal treadmill test, and accelerometry. RESULTS: Compared to their controls, successful dieters reported lower carbohydrate intake, greater protein intake, greater eating restraint, and more vigorous intensity physical activity. Accelerometry data reflected more moderate-to-vigorous intensity physical activity, but more energy expenditure over-report in successful dieters than their comparators. Unsuccessful dieters were indistinguishable from their controls. CONCLUSIONS: Successful dieters show behavioral vigilance but over-report total daily energy expenditure, whereas unsuccessful dieters do not demonstrate measurable compensations in health behavior. PMID- 26248170 TI - Evaluations of Validity and Reliability of a Transtheoretical Model for Sedentary Behavior among College Students. AB - OBJECTIVE: To evaluate the measurement properties of the Transtheoretical Model (TTM) questionnaire for sedentary behaviors among college students and to examine the validity and reliability of the developed TTM questionnaire. METHODS: Overall, 225 college students were recruited. For the 2-week test-retest reliability, a random sub-sample (N = 108) of the participants was used. RESULTS: Statistically significant differences were found across the stages on the tests of concurrent (chi(2) = 25.0, p < .001) and construct (p < .01) validity. In addition, the internal consistency reliability (Cronbach alphas from .73 to .88) and test-retest reliability (intra-class correlation coefficients ranging from .80 to .94) were high for the questionnaires. CONCLUSIONS: These results demonstrate high validity and reliability of the TTM questionnaire when applied to sedentary behavior. PMID- 26248171 TI - Effects of a Sexual Risk Reduction Program for African-American Adolescents on Social Cognitive Antecedents of Behavior Change. AB - OBJECTIVES: To identify social cognitive outcomes relevant to a specific adolescent sexual risk reduction intervention, and to examine the program's impact on these. METHODS: A randomized control trial involving 763 adolescents (recruited during 2012-2014) who were randomly assigned to either an 8-session general health intervention (control) or an 8-session sexual risk reduction intervention (treatment). Seven social cognitive outcomes were identified and assessed post-program using ordinary least squares regression. RESULTS: Post program, the treatment group exhibited greater knowledge, self-efficacy, attitudes, and intentions related to safer sex practices. No differences in attitudes toward abstinence, peer norms, or perceived vulnerability. CONCLUSIONS: Results are promising, though insignificant results may diminish the program's behavioral impact. More research is needed to determine the extent to which outcomes are related to short and long term risk behaviors. PMID- 26248172 TI - Sleep-related Cognitions Mediate the Impact of Neuroticism on Insomnia. AB - OBJECTIVES: Our study aimed to explore how neuroticism and neuroticism-related traits as well as sleep-related cognitions (dysfunctional beliefs and subjective quality of sleep) influence the emergence of insomnia using a mediational model. METHODS: A cross-sectional study was conducted in which 159 insomniac patients paired with 159 normal sleepers in sex and age (N = 318) completed an online questionnaire. RESULTS: At the global level, dysfunctional beliefs and poor subjective quality of sleep mediated the neuroticism-insomnia path; at the trait specific level, these variables mediated the anxiety-insomnia path and partially mediated the effects of vulnerability and self-consciousness on insomnia; some other relations were essentially indirect effects (between depression and insomnia). CONCLUSIONS: These findings extend our understanding of how neuroticism is a predisposing factor of insomnia. This knowledge could be helpful to shape prevention and intervention programs to treat insomnia. PMID- 26248173 TI - A Survey of Texas Health Educators' Family Health History-based Practice. AB - OBJECTIVES: To examine Texas health educators' practice of providing family health history (FHH)-based services, alongside factors shaping their practice. METHODS: A theoretical model of factors influencing health educators' FHH-based practice was developed and tested through structural equation modeling. (Master) Certified Health Education Specialists (N = 228; 40.93%) in Texas completed a baseline survey immediately before online or workshop FHH training. RESULTS: Participants incorporated FHH into their practice at low rates (on average=37.10%). Our model fit the data adequately based on the overall model chi square test and model-fit-indices (ie, chi(2) [df = 21]=27.20; p = .16; RMSEA=0.04; SRMR=0.05; CFI=0.97). Intention, self-efficacy, attitudes, and knowledge were associated with practice. CONCLUSIONS: Training health educators to incorporate FHH into their practice is needed. Our theoretical model suggests intervention points for future training. PMID- 26248174 TI - HCV Screening Behaviors and Infection Status among Vietnamese Americans. AB - OBJECTIVES: The aim of this study was to identify socio-economic and acculturation factors associated with hepatitis C (HCV) screening and infection among US Vietnamese Americans. METHODS: Participants were recruited from 7 Vietnamese community-based organizations in Pennsylvania and New Jersey. The analysis ultimately included 309 participants who participated in a HCV education intervention program. RESULTS: Overall, 82.5% (255 of 309) intervention participants completed HCV screening over the 6 months prior to the post intervention assessment. In multivariate-adjusted analysis, participants who lived in Vietnam for 40 years versus 20 years were more likely to receive HCV screening; unemployed individuals were less likely to receive HCV screening than employed people. Among screened participants, 7.5% had HCV infection. CONCLUSIONS: These findings will guide future culturally and linguistically appropriate interventions to reduce HCV infection and HCV-related liver cancer. PMID- 26248175 TI - Initial Validation of the Pleasure and Health Behavior Inventory - A Measure of Motivation to Engage in Health-damaging Behavior to Overcome Deficient Pleasure. AB - OBJECTIVES: To validate the Pleasure and Health Behavior Inventory (PHBI) - a novel 7-item self-report measure of motivation to engage in addictive, health damaging behaviors (ie, substance use, gambling, casual sex, overeating) to overcome deficient pleasure. METHODS: In a cross-sectional analysis of daily cigarette smokers (N = 206), we examined the PHBI's internal consistency, factor structure, and convergent validity with smoking-related characteristics, alcohol and drug use, BMI and other factors. RESULTS: The PHBI had adequate internal consistency and a largely unifactorial structure. The PHBI composite, which amalgamates motivation to engage in several types of unhealthy behaviors for pleasure, positively correlated with unhealthy behaviors. Individual PHBI items were associated with corresponding behavior-specific outcomes. CONCLUSIONS: The PHBI may be useful for understanding the psychological underpinnings of health damaging behavior. PMID- 26248176 TI - Hookah and Alcohol Use among Young Adult Hookah Smokers: A Mixed Methods Study. AB - OBJECTIVES: Hookah tobacco smoking has grown steadily in popularity among young adults in the United States. Little attention has been given to the relationship between hookah smoking and another behavior that is common among young adults - alcohol use. The purpose of this study was to examine hookah and alcohol use among young adults. METHODS: Forty young adult hookah smokers (55% female) participated in focus group sessions on hookah use beliefs and a brief survey examining hookah and alcohol use including drinking alcohol before, during, or after smoking hookah. RESULTS: Quotes from the focus groups indicated that alcohol use may promote hookah use among individuals who have little or no hookah smoking experience. Alcohol use, binge drinking, and alcohol use before, during, and after hookah use were common among the participants regardless of legal drinking age status. Nearly half of the participants preferred to drink alcohol while smoking hookah due to the improved physical and social effects they associated with combining the 2 behaviors. CONCLUSIONS: For some young adult hookah smokers, alcohol appears to enhance the hookah smoking experience and may play a role in hookah smoking initiation. Future research and interventions should address the association between hookah and alcohol use. PMID- 26248177 TI - Tobacco Use among Minnesota Adults, 2014. AB - OBJECTIVES: The changing landscape of tobacco including the introduction of new products such as smokeless tobaccos and electronic delivery devices has highlighted the need for continued surveillance of tobacco use. METHODS: Minnesota has conducted an in-depth surveillance of adult tobacco use since 1999. For the fifth in the series, conducted in 2014, 9304 telephone interviews were completed. RESULTS: The 2014 prevalence of cigarette smoking (14.4%) continues a downward trend that remains lower than the national smoking prevalence (17.3%). Among all Minnesota adults, use prevalence of other tobacco products was as follows: e-cigarettes 5.9%, all smokeless tobaccos 3.6%, cigars 3.0%, water pipe 1.4%, and regular pipe 0.7%. Among individuals who have never smoked cigarettes, smokeless tobacco was the most common product used (2.0%), nearly twice the prevalence of e-cigarette use (1.2%). Former smokers were equally likely to use smokeless tobacco (4.9%) or e-cigarettes (4.8%). Among smokers, 27.3% reported current use of e-cigarettes. CONCLUSION: In the past 15 years, cigarette smoking prevalence in Minnesota has dropped by an average of 0.51 percentage points annually, and prevalence could drop to less than 5% by 2034. PMID- 26248178 TI - Arab-American Hookah Smokers: Initiation, and Pros and Cons of Hookah Use. AB - OBJECTIVES: To examine initiation, pros and cons of hookah tobacco smoking among Arab Americans. METHODS: In this descriptive cross-sectional study, we recruited a community-based convenience sample of 458 adult Arab-American hookah smokers, mean age 28.4 years, who completed self-administered questionnaires. RESULTS: Irrespective of sex, most participants initiated hookah tobacco use by young adulthood in private homes or hookah lounges influenced by friends and family. Women initiated hookah use later than men. Ever dual smokers (hookah smokers who ever smoked a cigarette) initiated hookah use later than cigarettes; however, early hookah initiators < 18 years initiated hookah and cigarettes concurrently. Participants enjoyed the flavors of hookah tobacco, and complained about coughing, dizziness, and headaches. CONCLUSIONS: Early and late initiation of hookah tobacco use warrant prevention programs targeting the youth and older adults in communities, colleges, and middle and high schools that include health education campaigns, and encouragement of voluntary smokefree home rules. Tobacco control policies aimed to prevent initiation of hookah use should include regulation of hookah tobacco flavors, and should target the physical environments in neighborhoods, especially around schools and colleges, to reduce the proliferation of hookah lounges. Dual hookah tobacco and cigarette use warrant continuous monitoring. PMID- 26248179 TI - Supporting Healthy Lifestyles among Adolescent Girls: Mentors' Perceptions of the 'Go Girls!' Program. AB - OBJECTIVE: The aim of this study was to investigate perceptions of a healthy lifestyle program for adolescent girls, entitled Go Girls!, from the perspective of program mentors. Mentors were queried with regard to program processes and attributes as well as changes in the adolescent girls' behaviors and cognitions as a result of participation in the program. METHODS: Data were collected through semi-structured interviews with 9 Go Girls! mentors. RESULTS: Seven themes inductively emerged from the data with descriptive categories that related to positive appraisals of the program, perceptions of the program mandate, experience with the program, suggested program adaptations, challenges in program delivery, characteristics of mentorship, and changes in attitudes and behaviors. CONCLUSIONS: Findings from this study provide preliminary support for the feasibility and enjoyment of delivering the Go Girls! group-based mentoring program as well as observations related to program effectiveness and potential areas for improvement. PMID- 26248180 TI - Regulatory Focus, Proximity to Goal Weight, and Weight Loss Maintenance. AB - OBJECTIVES: Regulatory focus theory proposes 2 self-regulatory orientations: promotion focus - related to achieving aspirations and positive outcomes - and prevention focus - related to fulfilling responsibilities and preventing negative outcomes. The investigation examined whether regulatory focus and proximity to goal weight moderated the effectiveness of a weight-loss maintenance intervention. METHODS: Participants who lost >=10% of their weight were assigned to guided or self-directed treatments and completed regulatory focus and weight goal measures. RESULTS: Across treatment groups, people who were more promotion focused had better 2-year maintenance rates (defined as regain <25%) than people who were less promotion-focused, especially if far from their goal weight (.59 versus .44). In the guided group, people who were more prevention-focused had better maintenance rates than people who were less prevention-focused if closer to their goal weight (.69 versus .42), but poorer maintenance rates if farther from their goal (.36 versus .72). In the self-directed group, prevention focus was unrelated to maintenance. CONCLUSIONS: Regulatory focus and proximity to goal weight moderated intervention effectiveness. Maintenance may be enhanced by tailoring treatments to regulatory focus and goal weight (eg, prevention-focused people far from their goals may need extra weight-loss support before focusing on maintenance). PMID- 26248181 TI - Reactions to Cigarette Taxes and Related Messaging: Is the South Different? AB - OBJECTIVES: Given the lag in tobacco control policies in the southeastern US, we examined differences in reactions to tobacco taxes and related messaging among Southeasterners vs. non-Southeasterners. METHODS: In 2013, a cross-sectional online survey using quota-based sampling was conducted assessing tobacco use, attitudes/knowledge regarding tobacco taxation, and reactions to related messaging (health, youth prevention, economic impact, individual rights/responsibility, morality/religion, hospitality). RESULTS: Of 2501 participants, 36.7% were past 30-day smokers; 26.7% were Southeasterners. Compared to others, Southeasterners more likely believed that their state was in the bottom 20 states in tobacco taxes (p < .001) and less likely reported that their taxes were too high (p < .001). Regression analysis indicated that correlates of opposition to increased taxes included being older, having less education, being an infrequent church-attender, and being a current smoker (p's < .001); being a Southeasterner was not associated. Compared to others, Southeasterners were more likely to find pro-tobacco tax messages related to prevention and hospitality as more persuasive (p < .05) and anti-tobacco tax messaging related to the unfairness of tobacco taxes to smokers (p = .050) less persuasive. CONCLUSIONS: Given that Southeasterners are receptive to increased taxation, other factors must contribute to lagging policy and must be addressed. PMID- 26248182 TI - Global Health Professions Student Survey (GHPSS) in Tobacco Control in China. AB - OBJECTIVES: To examine the prevalence of smoking, second-hand smoke exposure, and attitudes toward tobacco control and cessation training among university students in China. METHODS: We administered the Global Health Professions Student Survey (GHPSS) to students from 50 universities offering medical/ health professional (MHP) programs and received 11,954 responses. Non-MHP students, MHP students, and third-year MHP students comprised the sample. Descriptive statistics were calculated for weighted prevalence and 95% confidence intervals. Key factors of interest and attitudes toward medical smoking cessation were examined using logistic regression. RESULTS: Smoking and exposure to second-hand smoke was higher among non-MHP (15.9%, 31.9%) than MHP (7.0%, 21.2%) students. For third year MHP students, the rates were 6.9% and 19.7%, respectively. Students held positive attitudes toward smoking bans in public places and cessation services. However, few received formal training in smoking cessation, and 37.0% agreed that light cigarettes are less harmful to health. Positive attitudes toward cessation services were related to several factors. CONCLUSIONS: This study is the first comprehensive survey of students in China providing direction for building capacity in tobacco control and smoking cessation among students in health professional programs. PMID- 26248183 TI - Assessment of caffeine intake in the Korean population. AB - An improved method for the analysis of caffeine in foods by HPLC was validated by measuring several analytical parameters. The caffeine contents of 1202 products available from Korean markets were analysed. A consumption study was conducted by using data from the Korea National Health and Nutrition Examination Survey (KNHANES), 2010-12, to estimate the caffeine intakes of the Korean population. The mean intakes of caffeine from all sources in the general population and consumers were 67.8 and 102.6 mg day(-1) for all age groups, respectively. The 95th percentile intakes of the general population and consumers were 250.7 and 313.7 mg day(-1), respectively. In those aged 30-49 years, the caffeine intakes of the general population and consumers were highest at 25.5% (101.8 mg kg(-1) day(-1)) and 36.6% (0.9 mg kg(-1) day(-1)), respectively, compared with the maximum recommended daily intake (400 mg day(-1)) for adults. In the general population, the main contributors to the total caffeine intake were carbonated beverage for the younger age groups and coffee for the adults. These data provide a current perspective on caffeine intake in the Korean population. PMID- 26248184 TI - Visible light mediated efficient oxidative benzylic sp(3) C-H to ketone derivatives obtained under mild conditions using O2. AB - A photooxygenation of benzylic sp(3) C-H reaction has been demonstrated using O2 mediated by visible light. This protocol provides a simple and mild route to obtain ketones from benzylic sp(3) C-H bonds. Various benzylic sp(3) C-H bonds can be transformed into the desired ketone derivatives in moderate to good yields. The (18)O2 labelling experiments demonstrated that the oxygen introduced into ketone originated from dioxygen. A plausible mechanism has been proposed accordingly. PMID- 26248185 TI - Inflatable Elastomeric Macroporous Polymers Synthesized from Medium Internal Phase Emulsion Templates. AB - Closed cell elastomeric polydimethylsiloxane (PDMS) based polymerized medium internal phase emulsions (polyMIPEs) containing an aqueous solution of sodium hydrogen carbonate (NaHCO3) have been produced. Via thermal decomposition of NaHCO3, carbon dioxide was released into the polyMIPE structure to act as a blowing agent. When placed into an atmosphere with reduced pressure, these macroporous elastomers expanded to many times their original size, with a maximum expansion of 30 times. This expansion was found to be repeatable and reproducible. The extent of volume expansion was determined primarily by the dispersed phase volume ratio of the emulsion template; polyMIPEs with 60% dispersed phase content produced greater volume expansion ratios than polyMIPEs with 50% dispersed phase. Increasing the concentration of NaHCO3 in the dispersed phase also led to increased expansion due to the greater volume of gas forming within the porous structure of the silicone elastomer. The expansion ratio could be increased by doubling the agitation time during the emulsification process to form the MIPEs, as this decreased the pore wall thickness and hence the elastic restoring force of the porous silicone elastomer. Although MIPEs with 70% dispersed phase could be stabilized and successfully cured, the resultant polyMIPE was mechanically too weak and expanded less than polyMIPEs with a dispersed phase of 60%. It was also possible to cast the liquid emulsion into thin polyMIPE films, which could be expanded in vacuum, demonstrating that these materials have potential for use in self-sealing containers. PMID- 26248186 TI - Enantioselective recognition of menthol by mouse odorant receptors. AB - The olfactory system has a remarkable ability to detect and discriminate a vast variety of odorant molecules. In mammals, hundreds to thousands of odorant receptors (ORs) expressed in olfactory sensory neurons play an essential role in this discrimination. Odorants are recognized by ORs in a combinatorial fashion in which a single odorant activates a particular combination of receptors, leading to its perception as a particular aroma. It is well known that enantiomers emit different aromas in spite of exhibiting otherwise identical chemical properties. To elucidate the molecular basis for the difference, we recorded responses to l- and d-menthol in the mouse olfactory bulb and found that enantiomers elicited similar but overlapping and distinct receptor activation patterns. We then identified l-menthol-specific and d-menthol-biased receptors and performed detailed structure-activity relationship studies, revealing high stereoselectivity of the enantiospecific menthol receptor. The binding site on ORs appears to have evolved to distinguish subtle differences in very similar odorant structures. PMID- 26248187 TI - Molecular Characterization of Natural Hybrids Formed between Five Related Indigenous Clade 6 Phytophthora Species. AB - Most Phytophthora hybrids characterized to date have emerged from nurseries and managed landscapes, most likely generated as a consequence of biological invasions associated with the movement of living plants and germplasm for ornamental, horticultural and agricultural purposes. Presented here is evidence for natural hybridization among a group of five closely related indigenous clade 6 Phytophthora species isolated from waterways and riparian ecosystems in Western Australia. Molecular characterization of hybrids consisted of cloning and sequencing two nuclear genes (ITS and ASF), sequencing of two further nuclear loci (BT and HSP) and of two mitochondrial loci (COI and NADH). Additionally, phenotypic traits including morphology of sporangia and optima and maxima temperatures for growth were also determined. In most cases the nuclear genes were biparentally and in all cases the mtDNA were uniparentally inherited, indicating hybrid formation through sexual crosses. Some isolates bear the molecular signature of three parents suggesting additional hybrid events, although it cannot be determined from the data if these were sequential or simultaneous. These species and their hybrids co-exist in riparian ecosystems and waterways where their ability for rapid asexual proliferation would enable them to rapidly colonize green plant litter. The apparent ease of hybridization could eventually lead to the merging of species through introgression. However, at this point in time, species integrity has been maintained and a more likely scenario is that the hybrids are not stable evolutionary lineages, but rather transient hybrid clones. PMID- 26248188 TI - Chronic Dosing with Membrane Sealant Poloxamer 188 NF Improves Respiratory Dysfunction in Dystrophic Mdx and Mdx/Utrophin-/- Mice. AB - Poloxamer 188 NF (national formulary (NF) grade of P-188) improves cardiac muscle function in the mdx mouse and golden retriever muscular dystrophy models. However in vivo effects on skeletal muscle have not been reported. We postulated that P 188 NF might protect diaphragm muscle membranes from contraction-induced injury in mdx and mdx/utrophin-/- (dko) muscular dystrophy models. In the first study 7 month old mdx mice were treated for 22 weeks with subcutaneous (s.c.) injections of saline or P-188 NF at 3 mg/Kg. In the second, dkos were treated with saline or P-188 NF (1 mg/Kg) for 8 weeks beginning at age 3 weeks. Prednisone was the positive control in both studies. Respiratory function was monitored using unrestrained whole body plethysmography. P-188 NF treatment affected several respiratory parameters including tidal volume/BW and minute volume/BW in mdx mice. In the more severe dko model, P-188 NF (1 mg/Kg) significantly slowed the decline in multiple respiratory parameters compared with saline-treated dko mice. Prednisone's effects were similar to those seen with P-188 NF. Diaphragms from P 188 NF or prednisone treated mdx and dko mice showed signs of muscle fiber protection including less centralized nuclei, less variation in fiber size, greater fiber density, and exhibited a decreased amount of collagen deposition. P 188 NF at 3 mg/Kg s.c. also improved parameters of systolic and diastolic function in mdx mouse hearts. These results suggest that P-188 NF may be useful in treating respiratory and cardiac dysfunction, the leading causes of death in Duchenne muscular dystrophy patients. PMID- 26248190 TI - Hb G-Waimanalo [A1] [alpha64(E13)Asp->Asn; HBA1: c.193 G > A] with Decreased Oxygen Affinity. AB - A clinically asymptomatic 12-year-old girl showed microcytosis in routine examination. Cation exchange high performance liquid chromatography (HPLC), revealed two additional peaks eluting after Hb A and DNA sequencing uncovered a novel heterozygous mutation at codon 64 of the alpha1-globin gene. The hemoglobin (Hb) variant was annotated as Hb G-Waimanalo [A1]. Further analyses demonstrated a decreased oxygen affinity Hb compared to the normal Hb configuration. PMID- 26248189 TI - Pharmacological Profile of Nociceptin/Orphanin FQ Receptors Interacting with G Proteins and beta-Arrestins 2. AB - Nociceptin/orphanin FQ (N/OFQ) controls several biological functions by selectively activating an opioid like receptor named N/OFQ peptide receptor (NOP). Biased agonism is emerging as an important and therapeutically relevant pharmacological concept in the field of G protein coupled receptors including opioids. To evaluate the relevance of this phenomenon in the NOP receptor, we used a bioluminescence resonance energy transfer technology to measure the interactions of the NOP receptor with either G proteins or beta-arrestin 2 in the absence and in presence of increasing concentration of ligands. A large panel of receptor ligands was investigated by comparing their ability to promote or block NOP/G protein and NOP/arrestin interactions. In this study we report a systematic analysis of the functional selectivity of NOP receptor ligands. NOP/G protein interactions (investigated in cell membranes) allowed a precise estimation of both ligand potency and efficacy yielding data highly consistent with the known pharmacological profile of this receptor. The same panel of ligands displayed marked differences in the ability to promote NOP/beta-arrestin 2 interactions (evaluated in whole cells). In particular, full agonists displayed a general lower potency and for some ligands an inverted rank order of potency was noted. Most partial agonists behaved as pure competitive antagonists of receptor/arrestin interaction. Antagonists displayed similar values of potency for NOP/Gbeta1 or NOP/beta-arrestin 2 interaction. Using N/OFQ as reference ligand we computed the bias factors of NOP ligands and a number of agonists with greater efficacy at G protein coupling were identified. PMID- 26248191 TI - Nomenclature Confusion in Deletion Mutations Involving Repetitive Nucleotides: A Lesson from HBB Gene Codon 35 (-C) vs. Codon 36 (-C). PMID- 26248192 TI - Host Specificity in the Honeybee Parasitic Mite, Varroa spp. in Apis mellifera and Apis cerana. AB - The ectoparasitic mite Varroa destructor is a major global threat to the Western honeybee Apis mellifera. This mite was originally a parasite of A. cerana in Asia but managed to spill over into colonies of A. mellifera which had been introduced to this continent for honey production. To date, only two almost clonal types of V. destructor from Korea and Japan have been detected in A. mellifera colonies. However, since both A. mellifera and A. cerana colonies are kept in close proximity throughout Asia, not only new spill overs but also spill backs of highly virulent types may be possible, with unpredictable consequences for both honeybee species. We studied the dispersal and hybridisation potential of Varroa from sympatric colonies of the two hosts in Northern Vietnam and the Philippines using mitochondrial and microsatellite DNA markers. We found a very distinct mtDNA haplotype equally invading both A. mellifera and A. cerana in the Philippines. In contrast, we observed a complete reproductive isolation of various Vietnamese Varroa populations in A. mellifera and A. cerana colonies even if kept in the same apiaries. In light of this variance in host specificity, the adaptation of the mite to its hosts seems to have generated much more genetic diversity than previously recognised and the Varroa species complex may include substantial cryptic speciation. PMID- 26248193 TI - Temporal artery biopsy in giant cell arteritis--reply. PMID- 26248194 TI - Topoisomerase-I PS506 as a Dual Function Cancer Biomarker. AB - Novel biomarkers for cancer diagnosis and therapy selection are urgently needed to facilitate early detection and improve therapy outcomes. We have previously identified a novel phosphorylation site at serine 506 (PS506) on topoisomerase-I (topo-I) and have shown that it is widely expressed in cell lines derived from several cancers, including lung cancer, but is low in cell lines derived from non cancerous tissues. Here we have investigated how PS506 expression in lung tissue specimens correlates with their malignant status. We find that PS506 expression is significantly elevated in malignant tumors of non-small cell lung cancer (NSCLC) compared to adjacent, non-cancerous lung tissue and benign lung tumors. PS506 expression was up to 6-fold higher in malignant specimens than in paired non-malignant tissue. Using the well-characterized NIH/NCI 60-cell line panel, we correlate the most elevated expression levels of PS506 in lung, ovarian, and colon cancer cells lines with increased sensitivity to camptothecin, a plant alkaloid that targets topo-I. This is consistent with our earlier studies in a smaller sampling of cell lines and with our finding that PS506 increases topo-I DNA binding. Two widely used chemotherapeutic drugs for ovarian and colon cancer, topotecan and irinotecan, respectively, are derived from camptothecin. Irinotecan has also displayed efficacy in clinical trials of NSCLC. Our results suggest that elevated PS506 expression may correlate with clinical chemosensitivity to these agents in ovarian, colon, and NSCLC. PS506 may therefore serve as a biomarker for diagnosis or therapy selection. PMID- 26248195 TI - Biomimetic Approach for Ion Channels Based on Surfactant Encapsulated Spherical Porous Metal-Oxide Capsules. AB - Distinguished hybrid clusters with hydrophilic and hydrophobic interiors embedded within cationic surfactant shells are spontaneously inserted into lipid bilayers, showing well-defined ionic conductance behaviors. The transport via the narrow pore gates acting as selectivity filters is controlled by the dehydration energy of the cations. PMID- 26248196 TI - Occupational Exposure to Diesel Particulate Matter in Municipal Household Waste Workers. AB - OBJECTIVE: The purposes of this study were to determine the following: 1) the exposure levels of municipal household waste (MHW) workers to diesel particulate matter (DPM) using elemental carbon (EC), organic carbon (OC), total carbon (TC), black carbon (BC), and fine particulate matter (PM 2.5) as indicators; 2) the correlations among the indicators; 3) the optimal indicator for DPM; and 4) factors that influence personal exposure to DPM. METHODS: A total of 72 workers in five MHW collection companies were assessed over a period of 7 days from June to September 2014. Respirable EC/OC samples were quantified using the thermal optical transmittance method. BC and PM 2.5 were measured using real-time monitors, an aethalometer and a laser photometer. All results were statistically analyzed for occupational and environmental variables to identify the exposure determinants of DPM. RESULTS: The geometric mean of EC, OC, TC, BC and PM 2.5 concentrations were 4.8, 39.6, 44.8, 9.1 and 62.0 MUg/m3, respectively. EC concentrations were significantly correlated with the concentrations of OC, TC and BC, but not with those of PM 2.5. The exposures of the MHW collectors to EC, OC, and TC were higher than those of the drivers (p<0.05). Workers of trucks meeting Euro 3 emission standard had higher exposures to EC, OC, TC and PM 2.5 than those working on Euro 4 trucks (p<0.05). Multiple regression analysis revealed that the job task, European engine emission standard, and average driving speed were the most influential factors in determining worker exposure. CONCLUSIONS: We assessed MHW workers' exposure to DPM using parallel sampling of five possible indicators. Of these five indicators, EC was shown to be the most useful indicator of DPM exposure for MHW workers, and the job task, European emission standard, and average driving speed were the main determinants of EC exposure. PMID- 26248197 TI - Evaluating the Impact of Zimbabwe's Prevention of Mother-to-Child HIV Transmission Program: Population-Level Estimates of HIV-Free Infant Survival Pre Option A. AB - OBJECTIVE: We estimated HIV-free infant survival and mother-to-child HIV transmission (MTCT) rates in Zimbabwe, some of the first community-based estimates from a UNAIDS priority country. METHODS: In 2012 we surveyed mother infant pairs residing in the catchment areas of 157 health facilities randomly selected from 5 of 10 provinces in Zimbabwe. Enrolled infants were born 9-18 months before the survey. We collected questionnaires, blood samples for HIV testing, and verbal autopsies for deceased mothers/infants. Estimates were assessed among i) all HIV-exposed infants, as part of an impact evaluation of Option A of the 2010 WHO guidelines (rolled out in Zimbabwe in 2011), and ii) the subgroup of infants unexposed to Option A. We compared province-level MTCT rates measured among women in the community with MTCT rates measured using program monitoring data from facilities serving those communities. FINDINGS: Among 8568 women with known HIV serostatus, 1107 (12.9%) were HIV-infected. Among all HIV exposed infants, HIV-free infant survival was 90.9% (95% confidence interval (CI): 88.7-92.7) and MTCT was 8.8% (95% CI: 6.9-11.1). Sixty-six percent of HIV exposed infants were still breastfeeding. Among the 762 infants born before Option A was implemented, 90.5% (95% CI: 88.1-92.5) were alive and HIV-uninfected at 9-18 months of age, and 9.1% (95%CI: 7.1-11.7) were HIV-infected. In four provinces, the community-based MTCT rate was higher than the facility-based MTCT rate. In Harare, the community and facility-based rates were 6.0% and 9.1%, respectively. CONCLUSION: By 2012 Zimbabwe had made substantial progress towards the elimination of MTCT. Our HIV-free infant survival and MTCT estimates capture HIV transmissions during pregnancy, delivery and breastfeeding regardless of whether or not mothers accessed health services. These estimates also provide a baseline against which to measure the impact of Option A guidelines (and subsequently Option B+). PMID- 26248198 TI - Detecting and estimating head motion in brain PET acquisitions using raw time-of flight PET data. AB - Head motion during brain PET imaging is not uncommon and can negatively affect image quality. Motion correction techniques typically either use hardware to prospectively measure head motion, or they divide the acquisition into short fixed-frames and then align and combine these to produce a motion free image. The aim of this work was to retrospectively detect when motion occurred in PET data without the use of motion detection hardware, and then align the frames defined by these motion occurrences. We describe two methods that use either principal component analysis or the motion induced spatial displacements over time to detect motion in raw time-of-flight PET data. The points in time of motion then define the temporal boundaries of frames which are reconstructed without attenuation correction, aligned and combined. Phantom and [18F]-Fallypride patient acquisitions were used to validate and evaluate these approaches, which were compared with motion estimation using 60 s fixed-frames. Both methods identified all motion occurrences in phantom data, and unlike the fixed-frame approach did not exhibit intra-frame motion. With patient acquisitions, images corrected with the motion detection methods increased the average image sharpness by the same amount as the fixed-frame approach, but reduced the number of reconstructions and registrations by a factor of 3.4 on average. Detecting head motion in raw PET data alone is possible, allowing retrospective motion estimation of any listmode brain PET acquisition without additional hardware, subsequently decreasing data processing and potentially reducing intra-frame motion. PMID- 26248199 TI - Phytol is lethal for Amacr-deficient mice. AB - alpha-Methylacyl-CoA racemase (Amacr) catalyzes the racemization of the 25-methyl group in C27-intermediates in bile acid synthesis and in methyl-branched fatty acids such as pristanic acid, a metabolite derived from phytol. Consequently, patients with Amacr deficiency accumulate C27-bile acid intermediates, pristanic and phytanic acid and display sensorimotor neuropathy, seizures and relapsing encephalopathy. In contrast to humans, Amacr-deficient mice are clinically symptomless on a standard laboratory diet, but failed to thrive when fed phytol enriched chow. In this study, the effect and the mechanisms behind the development of the phytol-feeding associated disease state in Amacr-deficient mice were investigated. All Amacr-/- mice died within 36weeks on a phytol diet, while wild-type mice survived. Liver failure was the main cause of death accompanied by kidney and brain abnormalities. Histological analysis of liver showed inflammation, fibrotic and necrotic changes, Kupffer cell proliferation and fatty changes in hepatocytes, and serum analysis confirmed the hepatic disease. Pristanic and phytanic acids accumulated in livers of Amacr-/- mice after a phytol diet. Microarray analysis also revealed changes in the expression levels of numerous genes in wild-type mouse livers after two weeks of the phytol diet compared to a control diet. This indicates that detoxification of phytol metabolites in liver is accompanied by activation of multiple pathways at the molecular level and Amacr-/- mice are not able to respond adequately. Phytol causes primary failure in liver leading to death of Amacr-/- mice thus emphasizing the indispensable role of Amacr in detoxification of alpha-methyl branched fatty acids. PMID- 26248200 TI - Climate-smart agriculture and forestry: maintaining plant productivity in a changing world while minimizing production system effects on climate. PMID- 26248201 TI - Responding to pulmonary-related blood transfusion reactions. PMID- 26248202 TI - Differential Effects of Polymer-Surface Decoration on Drug Delivery, Cellular Retention, and Action Mechanisms of Functionalized Mesoporous Silica Nanoparticles. AB - Polymer-surface decoration has been found to be an effective strategy to enhance the biological activities of nanomedicine. Herein, three different types of polymers with a cancer-targeting ligand Arg-Gly-Asp peptide (RGD) have been used to decorate mesoporous silica nanoparticles (MSNs) and the functionalized nanosystems were used as drug carriers of oxaliplatin (OXA). The results showed that polymer-surface decoration of the MSNs nanosystem by poly(ethylene glycol) (PEG) and polyethyleneimine (PEI) significantly enhanced the anticancer efficacy of OXA, which was much higher than that of chitosan (CTS). This effect was closely related to the enhancement of the cellular uptake and cellular drug retention. Moreover, PEI@MSNs-OXA possessed excellent advantages in penetrating ability and inhibitory effects on SW480 spheroids that were used to simulate the in vivo tumor environments. Therefore, this study provides useful information for the rational design of a cancer-targeted MSNs nanosystem with polymer-surface decoration. PMID- 26248203 TI - Co-immunization with tandem repeat heterologous M2 extracellular proteins overcomes strain-specific protection of split vaccine against influenza A virus. AB - Current influenza vaccines are less efficacious against antigenically different influenza A viruses. This study presents an approach to overcome strain-specific protection, using a strategy of co-immunization with seasonal H3N2 split vaccine and yeast-expressed soluble proteins of a tandem repeat containing heterologous influenza M2 ectodomains (M2e5x). Co-immunization with both vaccines in mice was superior to either vaccine alone in inducing cross protection against heterologous H3N2 virus by raising M2e-specific humoral and cellular immune responses toward a T-helper type 1 profile inducing IgG2a isotype antibodies as well as interferon-gamma-producing cells in systemic and mucosal sites. In addition, co-immunization sera were found to confer cross-protection against different subtypes of H1N1 and H5N1 influenza A viruses in naive mice. A mechanistic study provides evidence that activation of dendritic cells by co stimulation with M2e5x and split vaccine was associated with the proliferation of CD4(+) T cells. Our results suggest that a strategy of co-immunization with seasonal split and M2e5x protein vaccines could be a promising approach for overcoming the limitation of strain-specific protection by current influenza vaccination. PMID- 26248204 TI - High Throughput Sequencing of Entamoeba 27nt Small RNA Population Reveals Role in Permanent Gene Silencing But No Effect on Regulating Gene Expression Changes during Stage Conversion, Oxidative, or Heat Shock Stress. AB - The human parasite Entamoeba histolytica has an active RNA interference (RNAi) pathway with an extensive repertoire of 27nt small RNAs that silence genes. However the role of this pathway in regulating amebic biology remains unknown. In this study, we address whether silencing via 27nt small RNAs may be a mechanism for controlling gene expression changes during conversion between the trophozoite and cyst stages of the parasite. We sequenced small RNA libraries generated from trophozoites, early cysts, mature cysts, and excysting cells and mapped them to the E. invadens genome. Our results show that, as in E. histolytica, small RNAs in E. invadens are largely ~27nt in length, have an unusual 5'-polyphosphate structure and mediate gene silencing. However, when comparing the libraries from each developmental time-point we found few changes in the composition of the small RNA populations. Furthermore, genes targeted by small RNAs were permanently silenced with no changes in transcript abundance during development. Thus, the E. invadens 27nt small RNA population does not mediate gene expression changes during development. In order to assess the generalizability of our observations, we examined whether small RNAs may be regulating gene expression changes during stress response in E. histolytica. Comparison of the 27nt small RNA populations from E. histolytica trophozoites from basal conditions, or after heat shock or exposure to oxidative stress showed few differences. Similar to data in E. invadens development, genes targeted by small RNAs were consistently silenced and did not change expression under tested stress conditions. Thus, the biological roles of the 27nt small RNA population in Entamoeba remain elusive. However, as the first characterization of the RNAi pathway in E. invadens these data serve as a useful resource for the study of Entamoeba development and open the door to the development of RNAi-based gene silencing tools in E. invadens. PMID- 26248205 TI - Tuning the charge state of Ag and Au atoms and clusters deposited on oxide surfaces by doping: a DFT study of the adsorption properties of nitrogen- and niobium-doped TiO2 and ZrO2. AB - The charge state of Ag and Au atoms and clusters (Ag4 and Au4, Ag5 and Au5) adsorbed on defective TiO2 anatase(101) and tetragonal ZrO2(101) has been systematically investigated as a function of oxide doping and defectivity using a DFT+U approach. As intrinsic defects, we have considered the presence of oxygen vacancies. As extrinsic defects, substitutional nitrogen- and niobium-doping have been investigated, respectively. Both surface and sub-surface defects and dopants have been considered. Whereas on surfaces with oxygen vacancies or Nb-doping, atoms and clusters may become negatively charged, N-doping always leads to the formation of positively charged adsorbates, independently of the supporting material (TiO2 or ZrO2). This suggests the possibility to tune the electronic properties of supported metal clusters by selective doping of the oxide support, an effect that may result in complete changes in chemical reactivity. PMID- 26248206 TI - Intra-Monozygotic Twin Pair Discordance and Longitudinal Variation of Whole Genome Scale DNA Methylation in Adults. AB - Monozygotic twins share identical genomic DNA and are indistinguishable using conventional genetic markers. Increasing evidence indicates that monozygotic twins are epigenetically distinct, suggesting that a comparison between DNA methylation patterns might be useful to approach this forensic problem. However, the extent of epigenetic discordance between healthy adult monozygotic twins and the stability of CpG loci within the same individual over a short time span at the whole-genome scale are not well understood. Here, we used Infinium HumanMethylation450 Beadchips to compare DNA methylation profiles using blood collected from 10 pairs of monozygotic twins and 8 individuals sampled at 0, 3, 6, and 9 months. Using an effective and unbiased method for calling differentially methylated (DM) CpG sites, we showed that 0.087%-1.530% of the CpG sites exhibit differential methylation in monozygotic twin pairs. We further demonstrated that, on whole-genome level, there has been no significant epigenetic drift within the same individuals for up to 9 months, including one monozygotic twin pair. However, we did identify a subset of CpG sites that vary in DNA methylation over the 9-month period. The magnitude of the intra-pair or longitudinal methylation discordance of the CpG sites inside the CpG islands is greater than those outside the CpG islands. The CpG sites located on shores appear to be more suitable for distinguishing between MZ twins. PMID- 26248207 TI - The transcriptional coactivator Taz regulates proximodistal patterning of the pronephric tubule in zebrafish. AB - The zebrafish pronephric tubule consists of proximal and distal segments and a collecting duct. The proximal segment is subdivided into the neck, proximal convoluted tubule (PCT) and proximal straight tubule (PST) segments. The distal segment consists of the distal-early (DE) and distal-late (DL) segments. How the proximal and distal segments develop along the anteroposterior axis is poorly understood. Here we show that knockdown of taz in zebrafish caused shortening and a significant reduction in the number of principal cells of the PST-DE segment, and proximalization of the pronephric tubule in 24 hpf embryos. RA treatment expanded the pronephric proximal domain in normal embryos as in taz morphants, an effect that was further enhanced upon exposure of taz morphants to RA. The early pronephric defects in 24 hpf taz morphants led to the failure of anterior pronephric tubule migration and convolution, and to PCT dilation and cyst formation in older embryos. In situ hybridization showed weak and transient expression of taz at the bud stage in the intermediate mesoderm, the source of pronephric progenitors. The present findings show that Taz is required in the anteroposterior patterning of the pronephric progenitor domain in the intermediate mesoderm, acting in part by regulating RA signaling in the pronephric progenitor field in the intermediate mesoderm. PMID- 26248208 TI - Quercetin Influences Quorum Sensing in Food Borne Bacteria: In-Vitro and In Silico Evidence. AB - Quorum sensing (QS) plays a vital role in regulating the virulence factor of many food borne pathogens, which causes severe public health risk. Therefore, interrupting the QS signaling pathway may be an attractive strategy to combat microbial infections. In the current study QS inhibitory activity of quercetin and its anti-biofilm property was assessed against food-borne pathogens using a bio-sensor strain. In addition in-silico techniques like molecular docking and molecular dynamics simulation studies were applied to screen the quercetin's potentiality as QS inhibitor. Quercetin (80 MUg/ml) showed the significant reduction in QS-dependent phenotypes like violacein production, biofilm formation, exopolysaccharide (EPS) production, motility and alginate production in a concentration-dependent manner. Synergistic activity of conventional antibiotics with quercetin enhanced the susceptibility of all tested pathogens. Furthermore, Molecular docking analysis revealed that quercetin binds more rigidly with LasR receptor protein than the signaling compound with docking score of -9.17 Kcal/mol. Molecular dynamics simulation predicted that QS inhibitory activity of quercetin occurs through the conformational changes between the receptor and quercetin complex. Above findings suggest that quercetin can act as a competitive inhibitor for signaling compound towards LasR receptor pathway and can serve as a novel QS-based antibacterial/anti-biofilm drug to manage food borne pathogens. PMID- 26248209 TI - Adipose Tissue-Derived Mesenchymal Stromal Cells Protect Mice Infected with Trypanosoma cruzi from Cardiac Damage through Modulation of Anti-parasite Immunity. AB - BACKGROUND: Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), is a complex disease endemic in Central and South America. It has been gathering interest due to increases in non-vectorial forms of transmission, especially in developed countries. The objective of this work was to investigate if adipose tissue-derived mesenchymal stromal cells (ASC) can alter the course of the disease and attenuate pathology in a mouse model of chagasic cardiomyopathy. METHODOLOGY/PRINCIPAL FINDINGS: ASC were injected intraperitoneally at 3 days post-infection (dpi). Tracking by bioluminescence showed that cells remained in the abdominal cavity for up to 9 days after injection and most of them migrated to the abdominal or subcutaneous fat, an early parasite reservoir. ASC injection resulted in a significant reduction in blood parasitemia, which was followed by a decrease in cardiac tissue inflammation, parasitism and fibrosis at 30 dpi. At the same time point, analyses of cytokine release in cells isolated from the heart and exposed to T. cruzi antigens indicated an anti-inflammatory response in ASC-treated animals. In parallel, splenocytes exposed to the same antigens produced a pro-inflammatory response, which is important for the control of parasite replication, in placebo and ASC-treated groups. However, splenocytes from the ASC group released higher levels of IL-10. At 60 dpi, magnetic resonance imaging revealed that right ventricular (RV) dilation was prevented in ASC treated mice. CONCLUSIONS/SIGNIFICANCE: In conclusion, the injection of ASC early after T. cruzi infection prevents RV remodeling through the modulation of immune responses. Lymphoid organ response to the parasite promoted the control of parasite burden, while the heart, a target organ of Chagas disease, was protected from damage due to an improved control of inflammation in ASC-treated mice. PMID- 26248211 TI - A survey of practice patterns in the use of laryngeal mask by pediatric anesthesiologists. AB - BACKGROUND: Laryngeal mask is frequently the airway device of choice in routine general anesthesia for many procedures in children. Several studies have described the use of laryngeal masks in unconventional situations. This survey was undertaken to assess how laryngeal masks are being used by pediatric anesthesiologists. METHOD: The 40-question electronic survey using SurveyMonkeyTM was sent to 2740 members of the Society for Pediatric Anesthesia (SPA). This survey assessed the age, work environment, types of practice, and training levels, as well as clinical situations in which the practitioners use laryngeal masks across different pediatric age groups. RESULTS: Seven hundred and forty three (27.1%) responses were obtained. The use of laryngeal mask increased as the patient age increased in nearly every queried situation. The practitioners routinely utilize laryngeal masks in a variety of challenging scenarios, such as in patients with a recent upper respiratory infection, in the difficult airway, remote locations, and long-duration surgeries. A small percentage of pediatric anesthesiologists use laryngeal masks in laparoscopic surgery and prone position procedures. CONCLUSION: Pediatric anesthesiologists are using laryngeal masks in both routine and challenging/unconventional situations. Although many of the uses for laryngeal masks are not explicitly stated in the manufacturer guidelines, literature and current practice support the use of laryngeal masks in several of these scenarios. PMID- 26248210 TI - The Force at the Tip--Modelling Tension and Proliferation in Sprouting Angiogenesis. AB - Sprouting angiogenesis, where new blood vessels grow from pre-existing ones, is a complex process where biochemical and mechanical signals regulate endothelial cell proliferation and movement. Therefore, a mathematical description of sprouting angiogenesis has to take into consideration biological signals as well as relevant physical processes, in particular the mechanical interplay between adjacent endothelial cells and the extracellular microenvironment. In this work, we introduce the first phase-field continuous model of sprouting angiogenesis capable of predicting sprout morphology as a function of the elastic properties of the tissues and the traction forces exerted by the cells. The model is very compact, only consisting of three coupled partial differential equations, and has the clear advantage of a reduced number of parameters. This model allows us to describe sprout growth as a function of the cell-cell adhesion forces and the traction force exerted by the sprout tip cell. In the absence of proliferation, we observe that the sprout either achieves a maximum length or, when the traction and adhesion are very large, it breaks. Endothelial cell proliferation alters significantly sprout morphology, and we explore how different types of endothelial cell proliferation regulation are able to determine the shape of the growing sprout. The largest region in parameter space with well formed long and straight sprouts is obtained always when the proliferation is triggered by endothelial cell strain and its rate grows with angiogenic factor concentration. We conclude that in this scenario the tip cell has the role of creating a tension in the cells that follow its lead. On those first stalk cells, this tension produces strain and/or empty spaces, inevitably triggering cell proliferation. The new cells occupy the space behind the tip, the tension decreases, and the process restarts. Our results highlight the ability of mathematical models to suggest relevant hypotheses with respect to the role of forces in sprouting, hence underlining the necessary collaboration between modelling and molecular biology techniques to improve the current state-of-the-art. PMID- 26248212 TI - Size-dependent cytotoxicity and genotoxicity of ZnO particles to human lymphoblastoid (WIL2-NS) cells. AB - The relationship between particle size and cytogenotoxicity of ZnO particles was systematically studied in vitro using WIL2-NS human lymphoblastoid cells. Before toxicity measurements, the ZnO particles of three different sizes (26 nm, 78 nm, and 147 nm) were well characterized for their physical and chemical properties to ensure that variations in other properties including surface chemistry and particle shape, which also may influence particle toxicity, were minimal. Cell viability testing showed that increasing cytotoxicity was associated with decreasing particle size. Both the dissolution kinetics of ZnO particles in supplemented cell culture medium and the apparent numbers of ZnO particles internalized by cells were size dependent and showed strong correlation with cytotoxicity. Genotoxicity, as measured by micronucleus formation, was significantly enhanced in the presence of the medium-sized and large-sized particles. The observation that necrosis increased with smaller- sized particles but micronuclei were present to a greater extent with larger- sized particles suggests that different mechanisms of cell damage induction or susceptibilities are operating depending on particle size. PMID- 26248213 TI - Laryngotracheal Cleft Repair in Children With Complex Airway Anomalies. AB - IMPORTANCE: This study provides clinicians with relevant information regarding the surgical outcomes of patients with laryngotracheal cleft in the context of additional airway anomalies. OBJECTIVES: To determine the rates of surgical success in patients who underwent laryngotracheal cleft repair in the context of additional airway anomalies, determine the revision rate for cleft repair, characterize the time to revision among patients who underwent cleft repair, and assess the functional swallowing outcomes after cleft repair. DESIGN, SETTING, AND PARTICIPANTS: A retrospective study was conducted at a quaternary pediatric center of 81 children diagnosed as having laryngotracheal cleft with or without concomitant airway anomalies who underwent laryngotracheal cleft repair between February 1, 2000, and February 28, 2013. Analysis was conducted from October 1, 2012, through March 30, 2013. INTERVENTIONS: Surgical repair of laryngotracheal cleft. MAIN OUTCOMES AND MEASURES: Surgery-specific success, overall surgical success, and revision rate. We defined surgery-specific success as a repair not requiring revision and overall surgical success as absence of a cleft or TEF at the last operative examination, regardless of the number of revisions required. RESULTS: Of 81 patients with laryngotracheal cleft who underwent surgical repair, 48 (59%) had at least 1 additional airway finding; 24 (30%) had tracheomalacia and 21 (26%) had subglottic stenosis. Seventeen patients required a revision of laryngotracheal cleft repair, with a median time to revision of 8.3 months (interquartile range, 4.3-25.1 months). Six patients required a second revision, with a median interval between revisions of 44.2 months (interquartile range, 28.6-53.6 months). The surgery-specific success rate was 77% (37 of 48) in patients with additional airway anomalies and 82% (27 of 33) in those with laryngotracheal clefts alone. The overall surgical success rate was 92% (44 of 48) in patients with additional airway anomalies and 97% (32 of 33) in those with clefts alone. Fourteen (17%) patients demonstrated swallowing dysfunction postoperatively despite closure of the cleft. CONCLUSIONS AND RELEVANCE: Although additional airway findings were common in our cohort of patients with laryngotracheal clefts, these anomalies did not affect surgery-specific or overall surgical success. The overall surgical success rate for those with and without additional airway anomalies was 92% and 97%, respectively. In view of the fact that cleft breakdown after surgical repair is not uncommon and may occur years after the initial repair, we strongly advocate long-term follow-up. Despite successful closure, a significant percentage of children with laryngotracheal cleft will have persistent swallowing dysfunction. PMID- 26248214 TI - Effects of structural modifications on the metal binding, anti-amyloid activity, and cholinesterase inhibitory activity of chalcones. AB - As the number of individuals affected with Alzheimer's disease (AD) increases and the availability of drugs for AD treatment remains limited, the need to develop effective therapeutics for AD becomes more and more pressing. Strategies currently pursued include inhibiting acetylcholinesterase (AChE) and targeting amyloid-beta (Abeta) peptides and metal-Abeta complexes. This work presents the design, synthesis, and biochemical evaluation of a series of chalcones, and assesses the relationship between their structures and their ability to bind metal ions and/or Abeta species, and inhibit AChE/BChE activity. Several chalcones were found to exhibit potent disaggregation of pre-formed N-biotinyl Abeta1-42 (bioAbeta42) aggregates in vitro in the absence and presence of Cu(2+)/Zn(2+), while others were effective at inhibiting the action of AChE. PMID- 26248215 TI - Toll-Like Receptors and Tissue Remodeling: The Pro/Cons Recent Findings. AB - The Toll-like Receptor (TLR) family ensures prompt response towards pathogens, protecting the host against infections, and guarantees a realistic balance between protective and detrimental activities. Multiple regulating mechanisms characterize TLR activity that is not limited to innate and adaptive antimicrobial immune responses, as observed in the inflammatory (either infective, allergic, or autoimmune) responses associated with tissue remodeling. Following the insult and the arise of inflammatory response, tissue remodeling takes place and might develop in fibrosis, depending on microenvironment as a result of imbalanced fibroblasts (FBs) and myofibroblasts (myoFBs) activation/survival. The process is driven by an epithelial-fibroblast-immune cell cross-talk. While the main FB function is the matrix metabolism for tissue homeostasis or repair, the myoFB differentiation represents a crucial step in attempting repair of injury. FBs/myoFBs provide more than structural support at site of injury, synthesizing and/or reacting to different cytokines, growth factors, neuromediators and soluble/lipid mediators. TLR-bearing FBs/myoFBs might contribute at the innate immune level, providing a second line of protection/defense as well as being a target/effector cell of tissue remodeling. TLRs might also interfere with acute inflammation as well as with established fibrosis, triggering structural/functional changes in agreement with the genetic background, the site of lesion, the entity of associated infection, the poor blood circulation or the pharmacological treatments, all together strictly influencing tissue repair/remodeling process. This review will focus on the recent findings on TLRs at launch and long-lasting tissue remodeling process, that strongly suggest TLRs as optional targets for future therapies. PMID- 26248216 TI - Exposure of Human Prostaspheres to Bisphenol A Epigenetically Regulates SNORD Family Noncoding RNAs via Histone Modification. AB - Bisphenol A (BPA) is a ubiquitous endocrine disruptor exerting lifelong effects on gene expression in rodent prostate cancer (PCa) models. Here, we aimed to determine whether epigenetic events mediating the action of BPA on human prostaspheres enriched in epithelial stem-like/progenitor cells is linked to PCa. We performed genome-wide transcriptome and methylome analyses to identify changes in prostaspheres treated with BPA (10 nM, 200 nM, and 1000 nM) or estradiol 17beta (E2) (0.1 nM) for 7 days and validated changes in expression, methylation, and histone marks in parallel-treated prostaspheres. BPA/E2-treatment altered expression of 91 genes but not the methylation status of 485,000 CpG sites in BPA/E2-treated prostaspheres. A panel of 26 genes was found repressed in all treatment groups. Fifteen of them were small nucleolar RNAs with C/D motif (SNORDs), which are noncoding, small nucleolar RNAs known to regulate ribosomal RNA assembly and function. Ten of the most down-regulated SNORDs were further studied. All 10 were confirmed repressed by BPA, but only 3 ratified as E2 repressed. SNORD suppression showed no correlation with methylation status changes in CpG sites in gene regulatory regions. Instead, BPA-induced gene silencing was found to associate with altered recruitments of H3K9me3, H3K4me3, and H3K27me3 to 5'-regulatory/exonic sequences of 5 SNORDs. Expression of 4 out of these 5 SNORDs (SNORD59A, SNORD82, SNORD116, and SNORD117) was shown to be reduced in PCa compared with adjacent normal tissue. This study reveals a novel and unique action of BPA in disrupting expression of PCa-associated SNORDs and a putative mechanism for reprogramming the prostasphere epigenome via histone modification. PMID- 26248217 TI - Phenotypic Characterization of Mice Carrying Homozygous Deletion of KLF11, a Gene in Which Mutations Cause Human Neonatal and MODY VII Diabetes. AB - We have previously shown that amino acid changes in the human Kruppel-Like Factor (KLF) 11 protein is associated with the development of maturity onset diabetes of the young VII, whereas complete inactivation of this pathway by the -331 human insulin mutation causes neonatal diabetes mellitus. Here, we report that Klf11-/- mice have decreased circulating insulin levels, alterations in the control of blood glucose and body weight, as well as serum dyslipidemia, but do not develop diabetes. Functional assays using ex vivo liver tissue sections demonstrate that Klf11-/- mice display increased insulin sensitivity. Genome-wide experiments validated by pathway-specific quantitative PCR arrays reveal that the Klf11-/- phenotype associates to alterations in the regulation of gene networks involved in lipid metabolism, in particular those regulated by peroxisome proliferator activated receptor-gamma. Combined, these results demonstrate that the major phenotype given by the whole-body deletion of Klf11 in mouse is not diabetes but increased insulin sensitivity, likely due to altered transcriptional regulation in target tissues. The absence of diabetes in the Klf11-/- mouse either indicates an interspecies difference for the role of this transcription factor in metabolic homeostasis between mouse and humans, or potentially highlights the fact that other molecular factors can compensate for its absence. Nevertheless, the data of this study, gathered at the whole-organism level, further support a role for KLF11 in metabolic processes like insulin sensitivity, which regulation is critical in several forms of diabetes. PMID- 26248219 TI - Arginine Vasopressin Potentiates the Stimulatory Action of CRH on Pituitary Corticotropes via a Protein Kinase C-Dependent Reduction of the Background TREK-1 Current. AB - The hypothalamic hormone arginine vasopressin (AVP) potentiates the stimulatory action of CRH on ACTH secretion from pituitary corticotropes, but the underlying mechanism is elusive. Using the perforated patch-clamp technique to monitor membrane potentials in mouse corticotropes, we found that AVP triggered a transient hyperpolarization that was followed by a sustained depolarization. The hyperpolarization was caused by intracellular Ca(2+) release that in turn activated the small conductance Ca(2+)-activated K(+) (SK) channels. The depolarization was due to the suppression of background TWIK-related K(+) (TREK) 1 channels. Direct activation of protein kinase C (PKC) reduced the TREK-1 current, whereas PKC inhibition attenuated the AVP-mediated reduction of the TREK 1 current, implicating the involvement of PKC. The addition of CRH (which stimulates the protein kinase A pathway) in the presence of AVP, or vice versa, resulted in further suppression of the TREK-1 current. In corticotropes with buffered cytosolic Ca(2+) concentration ([Ca(2+)]i), AVP evoked a sustained depolarization, and the coapplication of AVP and CRH caused a larger depolarization than that evoked by AVP or CRH alone. In cells with minimal perturbation of [Ca(2+)]i and background TREK-1 channels, CRH evoked a sustained depolarization that was superimposed with action potentials, and the subsequent coapplication of AVP and CRH triggered a transient hyperpolarization that was followed by a larger depolarization. In summary, AVP and CRH have additive effects on the suppression of the TREK-1 current, resulting in a more robust depolarization in corticotropes. We suggest that this mechanism contributes to the potentiating action of AVP on CRH-evoked ACTH secretion. PMID- 26248218 TI - FABP4-Cre Mediated Expression of Constitutively Active ChREBP Protects Against Obesity, Fatty Liver, and Insulin Resistance. AB - Carbohydrate response element binding protein (ChREBP) regulates cellular glucose and lipid homeostasis. Although ChREBP is highly expressed in many key metabolic tissues, the role of ChREBP in most of those tissues and the consequent effects on whole-body glucose and lipid metabolism are not well understood. Therefore, we generated a transgenic mouse that overexpresses a constitutively active ChREBP isoform under the control of the fatty acid binding protein 4-Cre-driven promoter (FaChOX). Weight gain was blunted in male, but not female, FaChOX mice when placed on either a normal chow diet or an obesogenic Western diet. Respiratory exchange ratios were increased in Western diet-fed FaChOX mice, indicating a shift in whole-body substrate use favoring carbohydrate metabolism. Western diet fed FaChOX mice showed improved insulin sensitivity and glucose tolerance in comparison with controls. Hepatic triglyceride content was reduced in Western diet-fed FaChOX mice in comparison with controls, suggesting protection from fatty liver. Epididymal adipose tissue exhibited differential expression of genes involved in differentiation, browning, metabolism, lipid homeostasis, and inflammation between Western diet-fed FaChOX mice and controls. Our findings support a role for ChREBP in modulating adipocyte differentiation and adipose tissue metabolism and inflammation as well as consequent risks for obesity and insulin resistance. PMID- 26248220 TI - Xenoestrogens Ethinyl Estradiol and Zearalenone Cause Precocious Puberty in Female Rats via Central Kisspeptin Signaling. AB - Xenoestrogens from synthetic or natural origin represent an increasing risk of disrupted endocrine functions including the physiological activity of the hypothalamo-pituitary-gonad axis. Ethinyl estradiol (EE2) is a synthetic estrogen used in contraceptive pills, whereas zearalenone (ZEA) is a natural mycoestrogen found with increasing prevalence in various cereal crops. Both EE2 and ZEA are agonists of estrogen receptor-alpha and accelerate puberty. However, the neuroendocrine mechanisms that are responsible for this effect remain unknown. Immature female Wistar rats were treated with EE2 (10 MUg/kg), ZEA (10 mg/kg), or vehicle for 10 days starting from postnatal day 18. As a marker of puberty, the vaginal opening was recorded and neuropeptide and related transcription factor mRNA levels were measured by quantitative real time PCR and in situ hybridization histochemistry. Both ZEA and EE2 accelerated the vaginal opening, increased the uterine weight and the number of antral follicles in the ovary, and resulted in the increased central expression of gnrh. These changes occurred in parallel with an earlier increase of kiss1 mRNA in the anteroventral and rostral periventricular hypothalamus and an increased kisspeptin (KP) fiber density and KP-GnRH appositions in the preoptic area. These changes are compatible with a mechanism in which xenoestrogens overstimulate the developmentally unprepared reproductive system, which results in an advanced vaginal opening and an enlargement of the uterus at the periphery. Within the hypothalamus, ZEA and EE2 directly activate anteroventral and periventricular KP neurons to stimulate GnRH mRNA. However, GnRH and gonadotropin release and ovulation are disrupted due to xenoestrogen-mediated inhibitory KP signaling in the arcuate nucleus. PMID- 26248221 TI - In silico research to assist the investigation of carboxamide derivatives as potent TRPV1 antagonists. AB - The transient receptor potential vanilloid type 1 (TRPV1), a non-selective cation channel, is known for its essential role in the pathogenesis of various pain conditions such as nerve damage induced hyperalgesia, diabetic neuropathy and cancer pain. Therefore, TRPV1 is considered as a promising target for the development of new anti-inflammatory and analgesic drugs. In the present study, a theoretical study on the functionalities of the molecular interactions between 236 active ligands and TRPV1 was carried out, using three-dimensional quantitative structure-activity relationships (3D-QSAR), molecular docking and molecular dynamics (MD) simulation approaches. The ligand-based CoMSIA model (obtained by use of a random division method for splitting the training and test sets) exhibits optimum predictivity (Q(2) = 0.522, R(ncv)(2) = 0.935, R(pred)(2) = 0.839). The results show that the models are useful tools for the prediction of the test sets as well as newly designed structures against TRPV1 activity. In addition, to verify the rationality of the random division method for splitting the dataset, we also used a self-organizing map (SOM) division approach for establishing the QSAR models. Interestingly, the obtained optimal CoMSIA model based on the SOM division exhibits almost the same proper statistical results (Q(2) = 0.521, R(ncv)(2) = 0.929, R(pred)(2) = 0.829) as the random division derived model, proving the reasonability of both division methods for building the models. The contour plots of molecular fields along with docking and MD simulation have identified several key structural requirements responsible for the activity. The present work provides extremely useful guidelines for future structural modifications of this class of compounds towards the development of superior TRPV1 antagonists. The new computational insights presented in this study are expected to be valuable for the guideline and development of new potent TRPV1 antagonists. PMID- 26248222 TI - Footpad dermatitis and pain assessment in turkey poults using analgesia and objective gait analysis. AB - The relationships between litter moisture, footpad dermatitis (FPD) and pain in medium-heavy turkey strains was studied by gait analysis in two medium-heavy with and without analgesia (betamethasone or bupivacaine). The relationship between FPD and litter moisture was linear above a breakpoint of 49% litter moisture, and there were no differences between the two breeds in susceptibility to FPD. Gait analysis showed higher impulse, single support time, stride time and stance time in breed A compared to breed B. Significant interactions between breed, litter and analgesic for impulse, single support time and stride time were associated with higher means for breed A given saline injection on wet litter. Data from betamethasone analgesia in Experiments 1 and 3 were combined for analysis. Peak vertical force was higher in saline- compared to betamethasone-treated birds. Compared to the wet (high FPD) litter treatments, birds on dry (low FPD) litter had greater speed and lower double support time and longer stride length. Turkeys kept on wet litter had a longer stride length compared to dry litter when given saline, whereas in betamethasone-treated birds the means were similar. There were no differences between birds with or without bupivacaine analgesia. Peak vertical force was higher in breed A than B and in birds with a low FPD compared to a high FPD score. It was concluded that breeds A and B did not differ in susceptibility to develop FPD when housed on wet litter but may have natural gait differences. Significant changes in gait parameters were associated with wet litter and with analgesic treatments. The results showed that FPD affected the gait of the turkeys and, combined with evidence of behavioural changes when given analgesia, suggest that footpad lesions are painful. PMID- 26248223 TI - Role of the MoYAK1 protein kinase gene in Magnaporthe oryzae development and pathogenicity. AB - Conidiation and appressorium differentiation are key processes for polycyclic dissemination and infection in many pathogens. Our previous study using DNA microarray led to the discovery of the MoYAK1 gene in Magnaporthe oryzae that is orthologous to YAK1 in Saccharomyces cerevisiae. Although the mechanistic roles of YAK1 in S. cerevisiae have been described, roles of MoYAK1 in M. oryzae, a phytopathogenic fungus responsible for rice blast, remain uncharacterized. Targeted disruption of MoYAK1 results in pleiotropic defects in M. oryzae development and pathogenicity. The DeltaMoyak1 mutant exhibits a severe reduction in aerial hyphal formation and conidiation. Conidia in the DeltaMoyak1 are delayed in germination and demonstrate decreased glycogen content in a conidial age-dependent manner. The expression of hydrophobin-coding genes is dramatically changed in the DeltaMoyak1 mutant, leading to a loss of surface hydrophobicity. Unlike the complete inability of the DeltaMoyak1 mutant to develop appressoria on an inductive surface, the mutant forms appressoria of abnormal morphology in response to exogenous cyclic adenosine-5'-monophosphate and host-driven signals, which are all defective in penetrating host tissues due to abnormalities in glycogen and lipid metabolism, turgor generation and cell wall integrity. These data indicate that MoYAK1 is a protein kinase important for the development and pathogenicity of M. oryzae. PMID- 26248224 TI - Effect of Iodine Intake on p14ARF and p16INK4a Expression in Thyroid Papillary Carcinoma in Rats. AB - BACKGROUND: Iodine intake is related to thyroid disease. This study investigated the effect of the amount of iodine intake on p14ARF and p16INK4a expression of thyroid papillary carcinoma in rats. MATERIAL AND METHODS: A cohort of 240 SD rats were randomly divided into control group, low iodine, normal iodine, and high iodine groups (n=60 per group). We inoculated 2 * 10(5) papillary thyroid carcinoma (PTC) cells on the left side of the thyroid gland. After 6 and 12 weeks, serum thyroid hormone level and urine iodine level were measured in addition to morphological observations of tumor tissues. Expression of p14ARF, p16INK4a was detected by immunohistochemical staining. RESULTS: The expression of p14ARF, p16INK4a, FT3, and FT4 levels in all iodine-treated animals were significantly lower than in the control group, while TSH level was significantly higher (P<0.05). Compared to the normal iodine group, the low and high groups had lower p14ARF and p16INK4a expression, lower FT3 and FT4 levels, higher TSH levels, and heavier tumors (P<0.05). In a further between-group comparison, p14ARF and p16INK4a expression and FT3 and FT4 levels at 12 weeks were lower than at 6 weeks. Expression of p14ARF and p16INK4a were positively correlated with FT3 and FT4, and negatively correlated with TSH and tumor weight. CONCLUSIONS: Low and high iodine diet intake could reduce p14ARF and p16INK4a expressions and promote tumor development. PMID- 26248225 TI - The Use of Open- and Closed-Loop Control During Goal-Directed Force Responses by Children with Heavy Prenatal Alcohol Exposure. AB - BACKGROUND: Many daily functional activities involve goal-directed responses based on open-loop and closed-loop motor control, yet little is known about how children with heavy prenatal alcohol exposure organize and regulate these 2 types of control systems when completing a goal-directed force response. METHODS: Children with (n = 19) or without (n = 23) heavy prenatal alcohol exposure were required to match a target force (25 and 50% of maximum voluntary force) in a specified target time (200, 800, and 2,000 ms). Target force and produced force were visually displayed on a computer monitor. The analog force-time record was parsed into 2 segments: the period beginning from force initiation to the first reversal in force was designated the open-loop phase, and the remainder of the response was the closed-loop phase. RESULTS: Compared to controls, alcohol exposed children produced a significantly shorter duration of open-loop control, a higher open-loop phase rate of force development, a shorter time to reach maximum force during the closed-loop phase, and greater absolute target force error. Increasing target force magnitude did not differentially alter the performance of the clinical group. CONCLUSIONS: The results indicate that alcohol exposed children experience deficits in completing goal-directed force responses that likely stem from an alcohol-related insult to the central nervous system. Therapeutic exercises should be designed to recalibrate internal timing systems and improve visuomotor integration. PMID- 26248226 TI - Response of the common cutworm Spodoptera litura to lead stress: changes in sex ratio, Pb accumulations, midgut cell ultrastructure. AB - When cutworm Spodoptera litura larvae were fed on the diets with different lead (Pb) concentrations for one or five generations, changes in growth and food utilization were recorded; Pb accumulations were detected by Atomic Absorption Spectrophotometer; changes in midgut cell ultrastructure were observed by Transmission Electron Microscopy (TEM). The effects of Pb stress on S. litura growth and food utilization differed significantly between insects of the 1st and 5th generation. The male-female rate of 200mgkg(-1) Pb treatment from the 1st generation and 50mgkg(-1) Pb treatment from the 5th generation was significantly higher than control. No significant difference of Pb accumulations was found in larvae, pupae and adults between the 1st and 5th generation. No significant difference of Pb accumulations in corresponding tissues of larvae was found between male and female. Compared to fat body, hemolymph, head, foregut and hindgut, the highest Pb accumulation was found in migut of larvae exposed to 200mgkg(-1) Pb. TEM showed that expanded intercellular spaces were observed in Pb treated midgut cells. The nuclei were strongly destroyed by Pb stress, evidenced by chromatin condensation and destroyed nuclear envelope. Mitochondria became swollen with some broken cristae after exposure to Pb. Therefore, neither gender nor progeny difference was present in Pb accumulations of S. litura, although effects of Pb stress on S. litura growth and food utilization differed from different generations and genders. Pb accumulations in midgut caused pathological changes in cells ultrastructure, possibly reflected the growth and food utilization of S. litura. PMID- 26248227 TI - Nesfatin-1 as a new positive inotrope in the goldfish (Carassius auratus) heart. AB - The hypothalamic neuropeptide Nesfatin-1 is present in both mammals and teleosts in which it elicits anorexigenic effects. In mammals, Nesfatin-1 acts on the heart by inducing negative inotropism and lusitropism, and cardioprotection against ischemic damages. We evaluated whether in teleosts, Nesfatin-1 also influences cardiac performance. In the goldfish (Carassius auratus), mature, fully processed Nesfatin-1 was detected in brain, gills, intestine and skeletal muscle, but not in the cardiac ventricle. However, on the isolated and perfused working goldfish heart, exogenous Nesfatin-1 induced a positive inotropic effect, revealed by a dose-dependent increase of stroke volume (SV) and stroke work (SW). Positive inotropism was abolished by inhibition of adenylate cyclase (AC; MDL123330A) and cAMP-dependent kinase (PKA; KT5720), suggesting a cAMP/PKA mediated pathway. This was confirmed by the increased cAMP concentrations revealed by ELISA on Nesfatin-1-treated hearts. Perfusion with Diltiazem, Thapsigargin and PD98059 showed the involvement of L-type calcium channels, SERCA2a pumps and ERK1/2, respectively. The role of ERK1/2 and phospholamban in Nesfatin-1-induced cardiostimulation was supported by Western blotting analysis. In conclusion, this is the first report showing that in teleosts, Nesfatin-1 potentiates mechanical cardiac performance, strongly supporting the evolutionary importance of the peptide in the control of the cardiac function of vertebrates. PMID- 26248228 TI - Beta-cell-tropin is associated with short-term stimulation of food intake in chicks. AB - Beta-cell-tropin, a peptide derived from adrenocorticotropic hormone, is an insulin secretagogue. When centrally injected, it increases food intake in rats, but its appetite-associated effects have not been reported in any other species. Thus, the present study was designed to evaluate the effects of central beta-cell tropin on appetite-associated parameters in an alternative vertebrate model, the chick. Central injection of 2 or 4 nmol beta-cell-tropin increased food intake for 60 min. Whole hypothalamus was collected at 60 min post-injection, and real time PCR performed to measure mRNA abundance of agouti-related peptide, corticotropin releasing factor, galanin, melanin concentrating hormone, neuropeptide Y, orexin, prohormone convertase 2, pro-opiomelanocortin, peroxisome proliferator-activated receptor gamma, urotensin 2, and visfatin, not one of which were affected by beta-cell-tropin treatment. Results demonstrate that beta cell-tropin is associated with short-term stimulation of food intake. PMID- 26248229 TI - Overcoming the problem of residual microbial contamination in dental suction units left by conventional disinfection using novel single component suction handpieces in combination with automated flood disinfection. AB - OBJECTIVES: Decontaminating dental chair unit (DCU) suction systems in a convenient, safe and effective manner is problematic. This study aimed to identify and quantify the extent of the problems using 25 DCUs, methodically eliminate these problems and develop an efficient approach for reliable, effective, automated disinfection. METHODS: DCU suction system residual contamination by environmental and human-derived bacteria was evaluated by microbiological culture following standard aspiration disinfection with a quaternary ammonium disinfectant or alternatively, a novel flooding approach to disinfection. Disinfection of multicomponent suction handpieces, assembled and disassembled, was also studied. A prototype manual and a novel automated Suction Tube Cleaning System (STCS) were developed and tested, as were novel single component suction handpieces. RESULTS: Standard aspiration disinfection consistently failed to decontaminate DCU suction systems effectively. Semi confluent bacterial growth (101-500 colony forming units (CFU) per culture plate) was recovered from up to 60% of suction filter housings and from up to 19% of high and 37% of low volume suction hoses. Manual and automated flood disinfection of DCU suction systems reduced this dramatically (ranges for filter cage and high and low volume hoses of 0-22, 0-16 and 0-14CFU/plate, respectively) (P<0.0001). Multicomponent suction handpieces could not be adequately disinfected without prior removal and disassembly. Novel single component handpieces, allowed their effective disinfection in situ using the STCS, which virtually eliminated contamination from the entire suction system. CONCLUSION: Flood disinfection of DCU suction systems and single component handpieces radically improves disinfection efficacy and considerably reduces potential cross-infection and cross-contamination risks. CLINICAL SIGNIFICANCE: DCU suction systems become heavily contaminated during use. Conventional disinfection does not adequately control this. Furthermore, multicomponent suction handpieces cannot be adequately disinfected without disassembly, which is costly in time, staff and resources. The automated STCS DCU suction disinfection system used with single component handpieces provides an effective solution. PMID- 26248230 TI - A Single Molecular Diels-Alder Crosslinker for Achieving Recyclable Cross-Linked Polymers. AB - A triol-functional crosslinker combining the thermoreversible properties of Diels Alder (DA) adducts in one molecule is designed, synthesized, and used as an ideal substitute of a traditional crosslinker to prepare thermal recyclable cross linked polyurethanes with excellent mechanical properties and recyclability in a very simple and efficient way. The recycle property of these materials achieved by the DA/retro-DA reaction at a suitable temperature is verified by differential scanning calorimetry and in situ variable temperature solid-state NMR experiments during the cyclic heating and cooling processes. The thermal recyclability and remending ability of the bulk polyurethanes is demonstrated by three polymer processing methods, including hot-press molding, injection molding, and solution casting. It is notable that all the recycled cross-linked polymers display nearly invariable elongation/stress at break compared to the as-synthesized samples. Further end-group functionalization of this single molecular DA crosslinker provides the potential in preparing a wide range of recyclable cross-linked polymers. PMID- 26248231 TI - Intracellular Uropathogenic E. coli Exploits Host Rab35 for Iron Acquisition and Survival within Urinary Bladder Cells. AB - Recurrent urinary tract infections (UTIs) caused by uropathogenic E. coli (UPEC) are common and morbid infections with limited therapeutic options. Previous studies have demonstrated that persistent intracellular infection of bladder epithelial cells (BEC) by UPEC contributes to recurrent UTI in mouse models of infection. However, the mechanisms employed by UPEC to survive within BEC are incompletely understood. In this study we aimed to understand the role of host vesicular trafficking proteins in the intracellular survival of UPEC. Using a cell culture model of intracellular UPEC infection, we found that the small GTPase Rab35 facilitates UPEC survival in UPEC-containing vacuoles (UCV) within BEC. Rab35 plays a role in endosomal recycling of transferrin receptor (TfR), the key protein responsible for transferrin-mediated cellular iron uptake. UPEC enhance the expression of both Rab35 and TfR and recruit these proteins to the UCV, thereby supplying UPEC with the essential nutrient iron. Accordingly, Rab35 or TfR depleted cells showed significantly lower intracellular iron levels and reduced ability to support UPEC survival. In the absence of Rab35, UPEC are preferentially trafficked to degradative lysosomes and killed. Furthermore, in an in vivo murine model of persistent intracellular infection, Rab35 also colocalizes with intracellular UPEC. We propose a model in which UPEC subverts two different vesicular trafficking pathways (endosomal recycling and degradative lysosomal fusion) by modulating Rab35, thereby simultaneously enhancing iron acquisition and avoiding lysosomal degradation of the UCV within bladder epithelial cells. Our findings reveal a novel survival mechanism of intracellular UPEC and suggest a potential avenue for therapeutic intervention against recurrent UTI. PMID- 26248234 TI - A puppy and case reports in Medwave. PMID- 26248232 TI - The Prognostic Value of C-Reactive Protein Serum Levels in Patients with Uterine Leiomyosarcoma. AB - OBJECTIVE: C-reactive protein (CRP) has previously been shown to serve as a prognostic parameter in women with gynecologic malignancies. Due to the lack of valid prognostic markers for uterine leiomyosarcoma (ULMS) this study set out to investigate the value of pre-treatment CRP serum levels as prognostic parameter. METHODS: Data of women with ULMS were extracted from databases of three Austrian centres for gynaecologic oncology. Pre-treatment CRP serum levels were measured and correlated with clinico-pathological parameters. Univariate and multivariable survival analyses were performed. RESULTS: In total, 53 patients with ULMS were included into the analysis. Mean (SD) CRP serum level was 3.46 mg/dL (3.96). Solely, an association between pre-treatment CRP serum levels and tumor size (p = 0.04) but no other clinic-pathologic parameter such as tumor stage (p = 0.16), or histological grade (p = 0.07), was observed. Univariate and multivariable survival analyses revealed that CRP serum levels (HR 2.7 [1.1-7.2], p = 0.037) and tumor stage (HR 6.1 [1.9-19.5], p = 0.002) were the only independent prognostic factors for overall survival (OS) in patients with ULMS. Patients with high pre-treatment CRP serum levels showed impaired OS compared to women with low levels (5-year-OS rates: 22.6% and 52.3%, p = 0.007). CONCLUSION: High pre treatment CRP serum levels were independently associated with impaired prognosis in women with ULMS and might serve as a prognostic parameter in these patients. PMID- 26248233 TI - Photophysical and antibacterial properties of complex systems based on smectite, a cationic surfactant and methylene blue. AB - Solid or colloidal materials with embedded photosensitizers are promising agents from the medical or environmental perspective, where the direct use of photoactive solutions appears to be problematic. Colloids based on layered silicates of the saponite (Sap) and montmorillonite (Mon) type, including those modified with dodecylammonium cations (C12) and photosensitizer--methylene blue (MB) were studied. Two representatives of bacteria, namely Enterobacter cloacae and Escherichia coli, were selected for this work. A spectral study showed that MB solutions and also colloids with Sap including C12 exhibited the highest photoactivities. The antimicrobial properties of the smectite colloids were not directly linked to the photoactivity of the adsorbed MB cations. They were also influenced by other parameters, such as light vs. dark conditions, the spectrum, power and duration of the light used for the irradiation; growth phases, and the pre-treatment of microorganisms. Both the photoactivity and antimicrobial properties of the colloids were improved upon pre-modification with C12. Significantly higher antimicrobial properties were observed for the colloids based on Mon with MB in the form of molecular aggregates without significant photoactivities. The MB/Mon colloids, both modified and non-modified with C12 cations, exhibited higher antimicrobial effects than pure MB solution. Besides the direct effect of photosensitization, the surface properties of the silicate particles likely played a crucial role in the interactions with microorganisms. PMID- 26248235 TI - Is hormone therapy during climacteric for all? PMID- 26248236 TI - Correlation between Apgar score and hipoxic-ischemic encephalopathy. PMID- 26248238 TI - Birth route in case of cesarean section in a previous pregnancy. PMID- 26248239 TI - Glucagonoma syndrome associated with necrolytic migratory erythema. AB - INTRODUCTION: glucagonoma is a pancreatic neuroendocrine tumor derived from alpha cells of the islets of Langerhans. It is marked by tumoral autonomous production of glucagon and characterized, among other symptoms, by necrolytic migratory erythema, an erythematous circinate lesion with areas of necrosis and sloughing. This is a rare disease with worldwide incidence estimated at 1 case per 20 million people. CASE REPORT: we report a case of glucagonoma associated necrolytic migratory erythema in a male patient, 56 years, with signs of skin lesions mainly on his legs and groin, hyperglycemia and weight loss. Biopsies of the skin lesions were performed and imaging of the abdomen showed a mass of 10 x 9 cm, at the pancreatic region. The patient was subjected to body-caudal pancreatectomy and splenectomy with autotransplant of the spleen in the greater omentum. The histopathologic report indicated a tumor in the pancreatic alpha cells. Immunohistochemistry showed expression of glucagon and chromogranin A in most tumor cells, consistent with the diagnosis of glucagonoma. The patient presented 3 years of outpatient follow-up with no complications. CONCLUSION: the necrolytic migratory erythema is important for the clinical recognition of glucagonoma, and its early diagnosis is essential for a successful curative therapy. PMID- 26248240 TI - Solitary fibrous tumor of the pleura: 3 case reports. AB - INTRODUCTION: solitary fibrous tumor of the pleura (SFTP) is a rare tumor arising from mesenchymatous cells in submesothelial pleural tissue which, unlike mesothelioma, is not related to asbestos or smoking. METHODS: report of four patients who underwent surgical treatment for giant SFTP and review of the pertinent literature. RESULTS: of the four patients operated, two presented symptoms including cough, chest pain and feeling of compression, whereas the other two subjects were asymptomatic. All patients underwent complete surgical resection by wide posterolateral thoracotomy, and surgical specimens removed with minimum bleeding. None of the cases required complementary lobectomy or segmentectomy. All tumors were histologically benign. CONCLUSION: complete resection of the lesion is the treatment of choice in all SFTP cases. Prognosis of the benign lesion is excellent, although close follow-up is necessary. In the rarer, more aggressive forms, treatment may be complemented by adjunctive chemotherapy or radiotherapy, the benefits of which have yet to be confirmed. PMID- 26248241 TI - Adaptation and cross-cultural validation of the Brazilian version of the Warwick Edinburgh mental well-being scale. AB - OBJECTIVE: the Warwick-Edinburgh mental well-being scale (WEMWBS) was designed to assess the level of mental well-being of a population or specific groups. The scale consists of 14 items covering functional psychological aspects, as well as well-being. The final score is calculated by adding up the response of each item, ranging from 1 to 5, obtaining a result from 14 to 70 points. METHODS: the procedure was developed in accordance with the protocol recommended by the World Health Organization covering translation, back translation, semantic equivalence, expert evaluation of the previous steps, pre-test and final version of the instrument. Following, the final version was applied to a sample of 122 individuals and the data were subjected to descriptive statistical analysis, factor analysis, internal consistency and correlation with other validated instruments. RESULTS: we performed the instrument's adaptation to the Portuguese spoken in Brazil, replacing terms to approximate the language to expressions of everyday life. The final version showed similar results to those from the original version, demonstrated by factor analysis, internal consistency (Cronbach's alpha: 0.89) and positive correlation with instruments validated to the Portuguese language. CONCLUSION: the Brazilian version of the WEMWBS proved to be easy to use and understand, showed high internal consistency and construct validity similar to the original instrument. PMID- 26248242 TI - Association of oral contraceptive and metformin did not improve insulin resistance in women with polycystic ovary syndrome. AB - OBJECTIVE: OBJECTIVE: to compare clinical and laboratory parameters in women with polycystic ovary syndrome (PCOS) using metformin or combined oral contraceptive (COC) after 6 months. METHODS: retrospective study analyzing records of patients with PCOS using the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society criteria. The groups were: I-COC (21 tablets, pause of 7 days; n=16); II-metformin (850 mg 12/12h, n=16); III-COC plus metformin (n=9). Body mass index (BMI), acne (% of improvement), modified Ferriman-Gallway index and menstrual cycle index (MCI), luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (TT), androstenedione (A) and homeostasis model assessment: insulin resistance (HOMA-IR) index were assessed Results: isolated use of COC compared to metformin was better regarding to acne, Ferriman index, MCI, LH, TT and A levels. On the other hand, metformin was better in the HOMA-IR index (4.44 and 1.67 respectively, p=0.0007). The association COC plus metformin, compared to metformin alone shows the maintenance of improvement of acne, Ferriman index, MCI, and testosterone levels. The HOMA-IR index remained lower in the metformin alone group (4.19 and 1.67, respectively; p=0,046). The comparison between COC plus metformin and COC alone, in turn, shows no difference in the improvement of acne, Ferriman index, MCI, LH, TT and A levels, indicating that the inclusion of metformin did not lead to additional benefits in these parameters. Still, the HOMA-IR index was similar in both groups (4.19 and 4.44 respectively; p=0.75), showing that the use of metformin associated with COC may not improve insulin resistance as much as it does if used alone. CONCLUSION: our data suggest that the combination of metformin and contraceptive does not improve insulin resistance as observed with metformin alone. PMID- 26248243 TI - Clinical and mammographic profile of patients with breast cancer surgically treated. AB - OBJECTIVE: to analyze the epidemiological, clinical and mammographic profile of women with breast cancer who were treated at the mastology clinic of the University Hospital of Santa Maria and who underwent breast surgery between January 2007 and December 2012. METHODS: this was a cross-sectional study, approved by the Ethics in Research Committee. A review of the patients' medical records was performed. The data were then exported to a software program for statistical analysis, namely Minitab 14.1. RESULTS: the patients' profile indicated that they were mostly born and raised in Santa Maria (respectively 11.1%, n=16, and 26.3%, n=68). They were about 55.6 years old (SD +/- 12.3), white (90.2%, n=213), had already given birth and breastfed their children, were nonsmokers, but also overweight (average BMI of 27 kg/m2). On physical examination of the first medical consultation, these patients, as described in the records: had a palpable mass (81.1%, n=184) measuring over three centimeters, located in the left breast, precisely in the upper outer quadrant (41.4%, n=81). Mammography (39%, n=109) showed that this lump was classified as BIRADS (r) 5 (40%, n=81). On histopathological examination, the lump was diagnosed as an invasive ductal cancer (71.1%, n=191). Surgery was generally a radical mastectomy (84.7%, n=236) with axillary dissection (92.5%, n=222). CONCLUSION: some of the epidemiological, clinical and mammographic features mentioned above resembled those found in the literature reviewed. However, these patients had advanced disease and underwent non conservative surgical procedures. PMID- 26248244 TI - Comparison of feeding habits and physical activity between eutrophic and overweight/obese children and adolescents: a cross sectional study. AB - OBJECTIVE: it is broadly accepted, but little explored, that obese children practice less physical activity and eat more. This study has the objective of comparing feeding habits and physical activity between eutrophic and overweight/obese children and adolescents. METHODS: 126 students with ages ranging from 6 to 18 years were evaluated. Eutrophic and overweight/obese students were compared according to calorie intake, macro and micronutrients, prevalence of physical inactivity and ingestion of micronutrients. RESULTS: differences were observed in the amount of calories ingested per unit of BMI (eutrophic, 97.6, and overweight/obese, 70.5, p=0.0061), as well as in calcium intake (eutrophic, 546.2, and overweight/obese, 440.7, p=0.0366). Both groups presented sedentarism, as well as a high prevalence of micronutrient intake deficiency, especially calcium and vitamins A, E, and C, but with no difference observed between eutrophic and overweight/obese subjects. CONCLUSION: energy and macronutrients consumption, as well as physical activity, were similar between eutrophic and overweight/obese. Calcium intake was lower in the overweight/obese group and the ingestion of vitamin C was lower in the eutrophic group. These results demonstrate the importance of considering all etiologic factors that may lead to obesity, so that new strategies for prevention and control may be added to traditional interventions. PMID- 26248245 TI - Association of family risk and lifestyle/comorbidities in ovarian cancer patients. AB - OBJECTIVES: to analyze factors that might indicate familial predisposition for ovarian cancer in patients diagnosed with this disease. METHODS: in a prospective single center cohort study at the Institute of Cancer of the State of Sao Paulo (ICESP), 51 women diagnosed with ovarian cancer were included. Familial predisposition for ovarian cancer was defined as having a higher than 10% chance of having a BRCA1/2 mutation according to the Manchester scoring system, a validated method to assess the likelihood of mutation detection. Each patient was interviewed with a standardized questionnaire on established risk factors for ovarian cancer and other factors that might influence the risk to develop ovarian cancer. Logistic regression analyses were performed to estimate the impact of the evaluated factors on the likelihood of mutation detection, by calculating odds ratios and 95% confidence intervals. RESULTS: seventeen out of 51 patients had a family history of breast and/or ovarian cancer, four patients had a history of breast or endometrial cancer, 11 were diagnosed before the age of 50, and 12 presented a risk of familial predisposition to ovarian cancer higher than 10%. Patients with comorbidities, such as hypertension, diabetes, hormonal disorders, dyslipidemia and psychiatric conditions, presented a lower chance of having a familial predisposition for ovarian cancer (OR: 0.22; 95% CI: 0.06-0.88; p=0.03). CONCLUSION: in this study, having comorbidities was associated with a lower risk of having a familial predisposition for ovarian cancer. Other factors associated with the risk of ovarian cancer did not have an impact on this predisposition. PMID- 26248246 TI - Predominance of STEMI and severity of coronary artery disease in a cohort of patients hospitalized with acute coronary syndrome: a report from ABC Medical School. AB - INTRODUCTION: acute coronary syndromes (ACS) represent a widely prevalent health issue with high mortality in Brazil and worldwide. The severity of ACS is not known in patients in the city of Sao Bernardo do Campo a municipality contiguous and adjacent to the city of Sao Paulo. OBJECTIVES: to study the profile of coronary disease in patients hospitalized with ACS who underwent coronary angiography in the emergency room between 2012 and 2013. METHODS: this is an observational study that included consecutive patients with ACS admitted to the emergency room of a hospital. Data collection was performed using medical records with the following variables: sex, age, risk factors for cardiovascular disease, coronary angiography. RESULTS: the sample in this period included 131 patients, of which 64.8% were men. The most prevalent diagnosis was ST-elevation myocardial infarction (STEMI) (57.2%) followed by non-ST-elevation myocardial infarction (NSTEMI) (22.1%) and unstable angina (UA) (20.6%). There were no significant differences in the epidemiology and risk factors between the diagnoses, except that heart failure was more prevalent in patients with UA. DISCUSSION: there were no differences between groups regarding the coronaries involved; however, STEMI patients showed similar numbers of multi- and singlevessel lesions, NSTEMI patients showed more multivessel lesions, and UA patients showed more multivessel lesions or lesion-free arteries. Although multivessel lesions were prevalent in all groups, STEMI patients showed a significantly higher number of single-vessel lesions compared with the other acute coronary syndromes. CONCLUSION: the study demonstrated a predominance of STEMI in the studied population, which differs from the usual results in ACS. PMID- 26248247 TI - Trends of 9,416 multidrug-resistant Gram-negative bacteria. AB - OBJECTIVE: a resistance of hospital-acquired bacteria to multiple antibiotics is a major concern worldwide. The objective of this study was to investigate multidrugresistant (MDR) bacteria, clinical specimens, origin of specimen and trends, and correlate these with bacterial sensitivity and consumption of antimicrobials. METHODS: 9,416 bacteria of nosocomial origin were evaluated in a tertiary hospital, from 1999 to 2008. MDR was defined for Gram-negative bacteria (GNB) as resistance to two or more classes/groups of antibiotics. RESULTS: GNB MDR increased by 3.7 times over the study period (p<0.001). Acinetobacter baumannii was the most prevalent (36.2%). Over the study period, there were significant 4.8-fold and 14.6-fold increases for A. baumannii and K. pneumoniae (p<0.001), respectively. Sixty-seven percent of isolates of MDR GNB were isolated in intensive care units. The resistance of A. baumannii to carbapenems increased from 7.4 to 57.5% during the study period and concomitant with an increased consumption. CONCLUSION: that decade showed prevalence of GNB and a gradual increase in MDR GNB. There was an increase in carbapenem resistance of 50.1% during the study. PMID- 26248248 TI - Fast-track protocols in devascularization for cirrhotic portal hypertension. AB - INTRODUCTION/OBJECTIVE: fast-tract surgery (FTS) has been rapidly embraced by surgeons as a mechanism for improving patient care and driving down complications and costs. The aim of this study was to determine if any improvement in outcomes occurred after FTS protocol for selective double portazygous disconnection with preserving vagus (SDPDPV) compared with non-FTS postoperative care. METHODS: patients eligible for SDPDPV in the period January 2012-April 2014 were randomly selected for the FTS group or non-FTS group. A designed protocol was used in the FTS group with emphasis on an interdisciplinary approach. The non-FTS group was treated using previously established standard procedures. The number of postoperative complications, time of functional recovery and duration of hospital stay were recorded. RESULTS: patients in the FTS group (n=59) and non-FTS group (n=57) did not differ in terms of preoperative data and operative details (p>0.05). The FTS procedure led to significantly better control and faster restoration of gastrointestinal functions, food tolerance, rehabilitation and hospital discharge (p<0.05). Postoperative complications, including nausea/vomiting, severe ascites, wound infection, urinary tract infection and pulmonary infection were all significantly lower in the FTS group (p<0.05). According to the postoperative morbidity classification used by Clavien, overall complications and grade I complications were both significantly lower in the FTS group compared with the non-FTS group (p<0.05). CONCLUSION: adopting the FTS protocol helped to recover gastrointestinal functions, to reduce frequency of postoperative complications and to reduce hospital stay. The FTS strategy is safe and effective in improving postoperative outcomes. PMID- 26248249 TI - Evidences in the treatment of idiopathic normal pressure hydrocephalus. AB - INTRODUCTION: idiopathic normal pressure hydrocephalus (INPH) is characterized by gait apraxia, cognitive dysfunction and urinary incontinence. There are two main treatment options: ventriculoperitoneal shunt (VPS) and endoscopic third ventriculostomy (ETV). However, there are doubts about which modality is superior and what type of valve should be applied. We are summarizing the current evidence in INPH treatment. METHODS: an electronic search of the literature was conducted on the Medline, Embase, Scielo and Lilacs databases from 1966 to the present to obtain data published about INPH treatment. RESULTS: the treatment is based on three pillars: conservative, ETV and VPS. The conservative option has fallen into disuse after various studies showing good results after surgical intervention. ETV is an acceptable mode of treatment, but the superiority of VPS has made the latter the gold standard. CONCLUSION: well-designed studies with a high level of appropriate evidence are still scarce, but the current gold standard for treatment of INPH is conducted using VPS. PMID- 26248250 TI - Lonomia obliqua Walker (Lepidoptera: Saturniidae): hemostasis implications. AB - In southern Brazil, since 1989, several cases of accidents produced by unwilling contact with the body of poisonous caterpillars of the moth species Lonomia obliqua Walker, 1855 (Lepidoptera: Saturniidae), were described. L. obliqua caterpillars have gregarious behavior and feed on leaves of host trees during the night, staying grouped in the trunk during the day, which favors the occurrence of accidents with the species. This caterpillar has the body covered with bristles that on contact with the skin of individuals, breaks and release their contents, inoculating the venom into the victim. The basic constitution of the venom is protein and its components produce physiological changes in the victim, which include disturbances in hemostasis. Hemorrhagic syndrome associated with consumption coagulopathy, intravascular hemolysis and acute renal failure are some of the possible clinical manifestations related to poisoning by L. obliqua. Specific laboratory tests for diagnosis of poisoning have not been described previously. The diagnosis of poisoning is made based on the patient's medical history, clinical manifestations, erythrocyte levels, and, primarily, parameters that evaluate blood coagulation. Treatment is performed with the use of supportive care and the administration of specific hyperimmune antivenom. Poisoning can be serious and even fatal. PMID- 26248251 TI - Effects of melatonin and prolactin in reproduction: review of literature. AB - The pineal gland is responsible for producing a hormone called melatonin (MEL), and is accepted as the gland that regulates reproduction in mammals. Prolactin (PRL) also exhibits reproductive activity in animals in response to photoperiod. It is known that the concentrations of PRL are high in the summer and reduced during winter, the opposite of what is seen with melatonin in these seasons. In placental mammals, both prolactin and melatonin affect implantation, which is considered a critical point of pregnancy, since a successful pregnancy requires the development of a synchronous interaction between the endometrium and blastocyst for placental development. It is also known that PRL levels during pregnancy are essential for the maintenance of pregnancy, because this hormone induces the corpus luteum to produce progesterone, in addition to stimulating blastocyst implantation to maintain pregnancy and form the placenta. However, melatonin levels in plasma have also been shown to increase during pregnancy, peaking at the end of this period, which suggests that this hormone plays an important role in the maintenance of pregnancy. Thus, it is clear that treatment with prolactin or melatonin interferes with the processes responsible for the development and maintenance of pregnancy. PMID- 26248252 TI - MicroRNAs, cancer and ionizing radiation: Where are we? AB - The aim of this study is to describe the biogenesis of microRNA, its relations with carcinogenesis, and the correlation between microRNA and ionizing radiation (IR), focusing on radioresponsiveness. It is known that microRNA biogenesis is well established and involves different enzymatic cleavages, resulting in the production of mature microRNA. MicroRNAs are involved in carcinogenesis. Their interaction is related to the genetic and epigenetic changes associated with activation of proto-oncogenes or inactivation of tumor suppressor genes. Several studies have shown that the levels of expression of some microRNAs vary significantly after irradiation. There are evidences that microRNAs can influence cellular response after IR. In addition, microRNAs are related to modulation of the expression of several post-transcriptional targets in DNA damage response pathways, and to the DNA damage repair regulation mechanism. Future studies can clarify a possible clinical use of microRNAs as a new class of radiosensitive agents. PMID- 26248253 TI - Pediatric cancer and Li-Fraumeni/Li-Fraumeni-like syndromes: a review for the pediatrician. AB - INTRODUCTION: cancer is the second leading cause of death in children between the ages of 0 and 14 years, corresponding to approximately 3% of all cases diagnosed in Brazil. A significant percentage (5-10%) of pediatric cancers are associated with hereditary cancer syndromes, including Li-Fraumeni/Li-Fraumeni-like syndromes (LFS/LFL), both of which are caused by TP53 germline mutations. Recent studies have shown that a specific TP53 mutation, known as p.R337H, is present in 1 in 300 newborns in Southern and Southeast Brazil. In addition, a significant percentage of children with LFS/LFL spectrum tumors in the region have a family history compatible with LFS/LFL. OBJECTIVE: to review clinical relevant aspects of LFS/LFL by our multidisciplinary team with focus on pediatric cancer. METHODS: the NCBI (PubMed) and SciELO databases were consulted using the keywords Li Fraumeni syndrome, Li-Fraumeni-like syndrome and pediatric cancer; and all manuscripts published between 1990 and 2014 using these keywords were retrieved and reviewed. CONCLUSION: although LFS/LFL is considered a rare disease, it appears to be substantially more common in certain geographic regions. Recognition of population- specific risks for the syndrome is important for adequate management of hereditary cancer patients and families. In Southern and Southeastern Brazil, LFS/ LFL should be considered in the differential diagnosis of children with cancer, especially if within the spectrum of the syndrome. Due to the complexities of these syndromes, a multidisciplinary approach should be sought for the counseling, diagnosis and management of patients and families affected by these disorders. Pediatricians and pediatric oncologists in areas with high prevalence of hereditary cancer syndromes have a central role in the recognition and proper referral of patients and families to genetic cancer risk evaluation and management programs. PMID- 26248254 TI - Corrections. PMID- 26248255 TI - Fullerene-based materials for solar cell applications: design of novel acceptors for efficient polymer solar cells--a DFT study. AB - Fossil fuel alternatives, such as solar energy, are moving to the forefront in a variety of research fields. Polymer solar cells (PSCs) hold promise for their potential to be used as low-cost and efficient solar energy converters. PSCs have been commonly made from bicontinuous polymer:fullerene composites or so-called bulk heterojunctions. The conjugated polymer donors and the fullerene derivative acceptors are the key materials for high performance PSCs. In the present study, we have performed density functional theory calculations to investigate the electronic structures and magnetic properties of several representative C60 fullerene derivatives, seeking ways to improve their efficiency as acceptors of photovoltaic devices. In our survey, we have successfully correlated the LUMO energy level as well as chemical hardness, hyper-hardness, nucleus-independent chemical shift, and static dipole polarizability of PC60BM-like fullerene derivative acceptors with the experimental open circuit voltage of the photovoltaic device based on the P3HT:fullerene blend. The obtained structure property correlations allow finding the best fullerene acceptor match for the P3HT donor. For this purpose, four new fullerene derivatives are proposed and the output parameters for the corresponding P3HT-based devices are predicted. It is found that the proposed fullerene derivatives exhibit better photovoltaic properties than the traditional PC60BM acceptor. The present study opens the way for manipulating fullerene derivatives and developing promising acceptors for solar cell applications. PMID- 26248256 TI - Targeting the programmed death-1/programmed death-ligand 1 axis in lymphoma. AB - PURPOSE OF REVIEW: The development of 'immune checkpoint inhibitors' or drugs targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has been a stunning success of cancer immunotherapy. This review provides a timely overview of the biology and function of the PD-1 pathway and discusses the rationale for therapeutic inhibition of this pathway in lymphoma. RECENT FINDINGS: Recent studies have evaluated the prevalence and prognostic implications of PD-1, PD-L1/2 expression in various lymphoma subtypes. We present an overview of the clinical trials evaluating pidilizumab, nivolumab, and pembrolizumab in patients with lymphoid malignancies, and highlight some of the more promising agents in this class, currently in development. Finally, we discuss biomarkers that may predict response to therapy in patients with lymphoma across these clinical trials. SUMMARY: A plethora of clinical trials are in progress testing immune checkpoint inhibitors in many subtypes of lymphoma, which will define their role both as a monotherapy and in combination with other biologic agents. PMID- 26248258 TI - Challenge accepted: Human challenge trials for dengue. PMID- 26248259 TI - Going batty: Studying natural reservoirs to inform drug development. PMID- 26248261 TI - Problem of persisters persists, but anti-cancer drugs hold hope. PMID- 26248262 TI - Lung mapping seeks to crack microbial code in cystic fibrosis. PMID- 26248263 TI - Germs and joints: the contribution of the human microbiome to rheumatoid arthritis. PMID- 26248264 TI - Supporting itch: a new role for astrocytes in chronic itch. PMID- 26248265 TI - Progenitor cell engraftment in the lung: at last? PMID- 26248266 TI - Breaking bad blood: beta2-microglobulin as a pro-aging factor in blood. PMID- 26248267 TI - Toward understanding and exploiting tumor heterogeneity. AB - The extent of tumor heterogeneity is an emerging theme that researchers are only beginning to understand. How genetic and epigenetic heterogeneity affects tumor evolution and clinical progression is unknown. The precise nature of the environmental factors that influence this heterogeneity is also yet to be characterized. Nature Medicine, Nature Biotechnology and the Volkswagen Foundation organized a meeting focused on identifying the obstacles that need to be overcome to advance translational research in and tumor heterogeneity. Once these key questions were established, the attendees devised potential solutions. Their ideas are presented here. PMID- 26248269 TI - Application of MR virtual endoscopy in children with hydrocephalus. AB - PURPOSE: To evaluate the performance of MR virtual endoscopy (MRVE) in children with hydrocephalus. MATERIALS AND METHODS: Clinical and imaging data were collected from 15 pediatric patients with hydrocephalus and 15 normal control children. All hydrocephalus patients were confirmed by ventriculoscopy or CT imaging. The cranial 3D-T1 weighted imaging data from fast spoiled gradient echo scan (FSPGR) were transported to working station. VE images of cerebral ventricular cavity were constructed with Navigator software. RESULTS: Cerebral ventricular MRVE can achieve similar results as ventriculoscopy in demonstrating the morphology of ventricular wall or intracavity lesion. In addition, MRVE can observe the lesion from distal end of obstruction, as well as other areas that are inaccessible to ventriculoscopy. MRVE can also reveal the pathological change of ventricular inner wall surface, and help determine patency of the cerebral aqueduct and fourth ventricle outlet. CONCLUSION: MR virtual endoscopy provides a non-invasive diagnostic modality that can be used as a supplemental approach to ventriculoscopy. However, its sensitivity and specificity need to be determined in the large study. PMID- 26248268 TI - The central role of muscle stem cells in regenerative failure with aging. AB - Skeletal muscle mass, function, and repair capacity all progressively decline with aging, restricting mobility, voluntary function, and quality of life. Skeletal muscle repair is facilitated by a population of dedicated muscle stem cells (MuSCs), also known as satellite cells, that reside in anatomically defined niches within muscle tissues. In adult tissues, MuSCs are retained in a quiescent state until they are primed to regenerate damaged muscle through cycles of self renewal divisions. With aging, muscle tissue homeostasis is progressively disrupted and the ability of MuSCs to repair injured muscle markedly declines. Until recently, this decline has been largely attributed to extrinsic age-related alterations in the microenvironment to which MuSCs are exposed. However, as highlighted in this Perspective, recent reports show that MuSCs also progressively undergo cell-intrinsic alterations that profoundly affect stem cell regenerative function with aging. A more comprehensive understanding of the interplay of stem cell-intrinsic and extrinsic factors will set the stage for improving cell therapies capable of restoring tissue homeostasis and enhancing muscle repair in the aged. PMID- 26248270 TI - Intravoxel incoherent imaging of renal fibrosis induced in a murine model of unilateral ureteral obstruction. AB - PURPOSE: To evaluate non-invasive imaging biomarkers for assessing renal fibrosis. DWI is used to assess renal function; intravoxel incoherent motion (IVIM) provides additional measures of perfusion-related diffusion (D*, blood flow; f, perfusion fraction). We aim to determine if reduced ADC seen in renal fibrosis is attributable to perfusion-related diffusion changes or to known reduction in tissue diffusivity (D). MATERIALS AND METHODS: Unilateral ureteral obstruction (UUO) was created in six mice to induce renal fibrosis. DWI was performed the day before and 7 days post-UUO. A range of b-values from 0 to 1200 s/mm(2) were used. IVIM parameters were obtained using region of interests drawn over the renal parenchyma. Histopathological analysis of both kidneys was performed in all mice. Results were analyzed using the paired t-test with P<0.05 considered statistically significant. RESULTS: D and f were significantly lower in the ligated kidneys at Day 7 compared to before ligation and no significant difference was found for D*. Comparing non-ligated and ligated kidneys within the same mouse at Day 7, significantly lower D values were observed in the ligated kidneys, while no significant difference was found for f and D*, although the values of f were generally lower. Histopathological analysis confirmed development of fibrosis and reduction in glomeruli in all the ligated kidneys at Day 7. CONCLUSION: Our study shows that the reduction in ADC seen in renal fibrosis is attributable not only to reduced D as previously encountered but also a decrease in vascularity as assessed by f. Reduction in f is possibly related to a reduction in glomeruli. PMID- 26248271 TI - Susceptibility and size quantification of small human veins from an MRI method. AB - Recently a method called CISSCO (Complex Image Summation around a Spherical or a Cylindrical Object) was introduced for accurately quantifying the susceptibility and the radius of any narrow cylindrical object at any orientation using a typical two-echo gradient echo sequence. This work further optimizes the method for quantifying oxygen saturation in small cerebral veins in the human brain. The revised method is first validated through numerical simulations and then applied to data from phantom and human brain. The effect of phase high pass filtering on the quantified parameters is studied and procedures for mitigating its adverse effects are suggested. Uncertainty of each measurement is estimated from the error propagation method. It is shown that the revised method allows for accurate quantification of both the vessel size and its oxygen saturation even in the case of a low SNR (signal to noise ratio) in the vein. The results are self consistent across different veins within a given subject with a variation of less than 6%. Finally, imaging parameters and some procedures are suggested for accurate susceptibility and radius quantifications of small human veins. PMID- 26248272 TI - Nuclear-Overhauser-enhanced MR imaging of (31)P-containing metabolites: multipoint-Dixon vs. frequency-selective excitation. AB - The purpose of this study is to develop nuclear-Overhauser-enhanced (NOE) [(1)H] (31)P magnetic resonance imaging (MRI) based on 3D fully-balanced steady-state free precession (fbSSFP). Therefore, two implementations of a 3D fbSSFP sequence are compared using frequency-selective excitation (FreqSel) and multipoint-Dixon (MP-Dixon). (31)P-containing model solutions and four healthy volunteers were examined at field strengths of B0=3T and 7T. Maps of the distribution of phosphocreatine (PCr), inorganic phosphate (Pi), and adenosine 5'-triphosphate (ATP) in the human calf were obtained with an isotropic resolution of 1.5cm (1.0cm) in an acquisition time of 5min (10min). NOE-pulses had the highest impact on the PCr acquisitions enhancing the signal up to (82 +/- 13) % at 3T and up to (37 +/- 9) % at 7T. An estimation of the level of PCr in muscle tissue from [(1)H]-(31)P MRI data yielded a mean value of (33 +/- 8) mM. In conclusion, direct [(1)H]-(31)P imaging using FreqSel as well as MP-Dixon is possible in clinically feasible acquisition times. FreqSel should be preferred for measurements where only a single metabolite resonance is considered. MP-Dixon performs better in terms of SNR if a larger spectral width is of interest. PMID- 26248274 TI - Possible practical utility of an enzyme cocktail produced by sludge-degrading microbes for methane and hydrogen production from digested sludge. AB - Digested sludge (DS) is a major waste product of anaerobic digestion of sewage sludge and is resistant to biodegradation. In this study, we examined suitability of the hydrolases produced by DS-degrading fungal strains (DS-hydrolases) for methane and hydrogen fermentation from DS. Although the strains are mesophilic, DS-hydrolases showed strong chitinase and keratinase activity at ~50 degrees C. SDS-PAGE analysis suggested that the strains possess a multienzyme system, which allows the hydrolases of some strains to be stable in a wide range of temperatures. Addition of the DS-hydrolases to a vial-scale anaerobic digester enhanced methane and hydrogen production from DS at pH 9.0 and 5.0, respectively. The hydrogen production was also enhanced by the use of methacrylate ester precipitated DS as a substrate. Further improvement of culture and reaction conditions may make these hydrolases suitable for production of renewable fuels. PMID- 26248273 TI - A deconvolution-based approach to identifying large-scale effective connectivity. AB - Rapid, robust computation of effective connectivity between neural regions is an important next step in characterizing the brain's organization, particularly in the resting state. However, recent work has called into question the value of causal inference computed directly from BOLD, demonstrating that valid inferences require transformation of the BOLD signal into its underlying neural events as necessary for accurate causal inference. In this work we develop an approach for effective connectivity estimation directly from deconvolution-based features and estimates of inter-regional communication lag. We then test, in both simulation as well as whole-brain fMRI BOLD signal, the viability of this approach. Our results show that deconvolution precision and network size play outsized roles in effective connectivity estimation performance. Idealized simulation conditions allow for statistically significant effective connectivity estimation of networks of up to four hundred regions-of-interest (ROIs). Under simulation of realistic recording conditions and deconvolution performance, however, our result indicates that effective connectivity is viable in networks containing up to approximately sixty ROIs. We then validated the ability for the proposed method to reliably detect effective connectivity in whole-brain fMRI signal parcellated into networks of viable size. PMID- 26248275 TI - The implementation of high fermentative 2,3-butanediol production from xylose by simultaneous additions of yeast extract, Na2EDTA, and acetic acid. AB - The effective use of xylose may significantly enhance the feasibility of using lignocellulosic hydrolysate to produce 2,3-butanediol (2,3-BD). Previous difficulties in 2,3-BD production include that the high-concentration xylose cannot be converted completely and the fermentation rate is slow. This study investigated the effects of yeast extract, ethylenediaminetetraacetic acid disodium salt (Na2EDTA), and acetic acid on 2,3-BD production from xylose. The central composite design approach was used to optimize the concentrations of these components. It was found that simultaneous addition of yeast extract, Na2EDTA, and acetic acid could significantly improve 2,3-BD production. The optimal concentrations of yeast extract, Na2EDTA, and acetic acid were 35.2, 1.2, and 4.5 g/L, respectively. The 2,3-BD concentration in the optimized medium reached 39.7 g/L after 48 hours of shake flask fermentation, the highest value ever reported in such a short period. The xylose utilization ratio and the 2,3-BD concentration increased to 99.0% and 42.7 g/L, respectively, after 48 hours of stirred batch fermentation. Furthermore, the 2,3-BD yield was 0.475 g/g, 95.0% of the theoretical maximum value. As the major components of lignocellulosic hydrolysate are glucose, xylose, and acetic acid, the results of this study indicate the possibility of directly using the hydrolysate to effectively produce 2,3-BD. PMID- 26248276 TI - Effectiveness of Valsartan/Amlodipine Single-pill Combination in Hypertensive Patients With Excess Body Weight: Subanalysis of China Status II. AB - Obesity is a major global health concern and is associated with hypertension. However, there is a lack of studies evaluating the effectiveness of valsartan/amlodipine single-pill combination in Chinese hypertensive patients with excess body weight uncontrolled by monotherapy. To evaluate this effectiveness and its association with obese categories, we performed a prespecified subanalysis and a post hoc analysis of patients from China status II study. In this subanalysis, 11,289 and 11,182 patients stratified by body mass index (BMI) and waist circumference (WC), respectively, were included. Significant mean sitting systolic and diastolic blood pressure (BP) reductions from baseline were observed at week 8 across all BMI and WC subgroups (P < 0.001). The percentages of patients achieving BP control were 65.2%, 62.8%, and 64.5% (men 64.5% and women 64.4%) in the overweight, obesity, and abdominal obesity subgroups, respectively. The positive association between BP control and obese categories could only be found in subgroups stratified by BMI other than WC. Our study demonstrated the effectiveness of valsartan/amlodipine single-pill combination in Chinese hypertensive patients with excess body weight uncontrolled by monotherapy, and its effectiveness was better associated with BMI than WC. PMID- 26248277 TI - beta2- and beta1-Adrenoceptor Expression Exhibits a Common Regulatory Pattern With GRK2 and GRK5 in Human and Animal Models of Cardiovascular Diseases. AB - To explore if genic expression of beta(1)- or beta(2)-adrenoceptors (ARs) exhibits a common regulatory pattern with G protein-coupled receptor kinase (GRK) 2, GRK3, or GRK5 expression, we determined messenger RNA levels for these genes in different tissues from human and animal models of cardiovascular disease. We measured genic expression by qRT polymerase chain reaction in the left and right ventricles or peripheral blood mononuclear cells from healthy (n = 21), hypertensive (n = 20), heart failure (n = 24), and heart transplanted patients (n = 17) or in left ventricle, peripheral blood mononuclear cells, and kidney from spontaneously hypertensive rats or L-N-methyl-arginine-induced hypertensive rats and their respective controls (n = 4-5). In diseased versus healthy subjects and rats, parallel changes in messenger RNA levels of GRK2 and beta(2)-AR or GRK5 and beta(1)-AR were observed in each territory. Therefore, without excluding other regulatory mechanisms, the parallelism observed suggests a common regulatory pattern for the beta(1)-AR/GRK5 and beta(2)-AR/GRK2 genes, which is independent of cellular type or pathology. This highlights the need to focus not only on GRKs but also on beta(1)- or beta(2)-AR changes to completely understand the involvement of beta-AR/GRK pathways in cardiovascular diseases. PMID- 26248278 TI - Effects of Long-term Blockade of Vasopressin Receptor Types 1a and 2 on Cardiac and Renal Damage in a Rat Model of Hypertensive Heart Failure. AB - The effects of chronic blockade of vasopressin type 1a receptors (V1aR) and the additive effects of a type 2 receptor (V2R) antagonist on the treatment of hypertension-induced heart failure and renal injury remain to be unknown. In this study, Dahl salt-sensitive hypertensive rats were chronically treated with a vehicle (CONT), a V1aR antagonist (OPC21268; OPC), a V2R antagonist (tolvaptan; TOLV), or a combination of OPC21268 and tolvaptan (OPC/TOLV) from the pre hypertrophic stage (6 weeks). No treatment altered blood pressure during the study. Significant improvements were seen in median survival for the OPC and TOLV, and the OPC/TOLV showed a further improvement in Kaplan-Meier analysis. Echocardiography showed suppressed left ventricular hypertrophy in the OPC and OPC/TOLV at 11 weeks with improved function in all treatment groups by 17 weeks. In all treatment groups, improvements were seen in the following: myocardial histological changes, creatinine clearance, urinary albumin excretion, and renal histopathologic damage. Also, key mRNA levels were suppressed (eg, endothelin-1 and collagen). In conclusion, chronic V1aR blockade ameliorated disease progression in this rat model, with additive benefits from the combination of V1aR and V2R antagonists. It was associated with protection of both myocardial and renal damage, independent of blood pressure. PMID- 26248279 TI - Electrolytic lesions of the bilateral ventrolateral orbital cortex inhibit methamphetamine-associated contextual memory formation in rats. AB - The memories that are formed between rewarding and drug-associated contextual cues have been suggested to contribute to drug addiction relapse. Recent evidence has indicated that the ventrolateral orbital cortex (VLO) plays important roles in reward-based learning and reversal learning. However, whether the VLO is required for methamphetamine-induced contextual memory formation is not well understood. In the present study, a three-phase methamphetamine-induced conditioned place preference (CPP) model was used to investigate the effects of VLO lesions on the formation of drug-associated contextual memories in rats. We found that the VLO lesions themselves elicited no observable effects on place preferences. However, the VLO lesions delayed the acquisition and extinction phases of CPP without affecting the expression level. Furthermore, the VLO lesions did not have an obvious influence on CPP reinstatement. These results indicate that electrolytic lesions of the bilateral ventrolateral orbital cortex can inhibit the formation of methamphetamine-induced contextual memories in rats. Moreover, VLO may not be critically involved in memory storage and retrieval. PMID- 26248281 TI - Association between body levels of trace metals and glaucoma prevalence. AB - IMPORTANCE: Abnormal body levels of essential elements and exposure to toxic trace metals have been postulated to contribute to the pathogenesis of diseases affecting many organ systems, including the eye. OBJECTIVE: To investigate associations between body levels of trace metals and the prevalence of glaucoma in a cross-sectional population-based study. DESIGN, SETTING, AND PARTICIPANTS: Blood or urine metallic element levels and information pertaining to ocular disease were available for 2680 individuals 19 years and older participating in the fourth Korea National Health and Nutrition Examination Survey between January 1, 2008, and December 31, 2009, the second and the third years of the survey (2007-2009). Glaucoma diagnosis was based on criteria established by the International Society of Geographic and Epidemiologic Ophthalmology. Demographic, comorbidity, and health-related behavior information was obtained via interview. Multivariable logistic regression analyses were performed to determine associations between blood and urine trace element levels and the odds of glaucoma diagnosis. All analyses were performed between September 2014 and December 2014. MAIN OUTCOME AND MEASURE: The presence or absence of glaucoma. RESULTS: After adjustment for potential confounders, blood manganese level was negatively associated with the odds of glaucoma diagnosis (odds ratio [OR], 0.44; 95% CI, 0.21-0.92). Blood mercury level was positively associated with glaucoma prevalence (OR, 1.01; 95% CI, 1.00-1.03). No definitive association was identified between blood cadmium or lead levels or urine arsenic level and a diagnosis of glaucoma. CONCLUSIONS AND RELEVANCE: These findings in a cross sectional study of the South Korean population suggest that a lower blood manganese level and a higher blood mercury level are associated with greater odds of glaucoma. For more confidence that trace metals may have a role in the pathogenesis of glaucoma, prospective studies would need to confirm that the presence of such trace metals increases the chance of developing glaucoma. PMID- 26248282 TI - Crosslinking Graphene Oxide into Robust 3D Porous N-Doped Graphene. AB - 3D N-doped graphene crosslinked by covalent bonds is fabricated through thermal treatment of graphene oxide with a nitrogen-contained resin. The material possesses a hierarchical porous architecture, robust mechanical stability, and abundant N-doped properties. As an electrode material for supercapacitors, this multifunctional material exhibits an unprecedented specific capacitance, high rate capability, and excellent long-term cycle stability. PMID- 26248280 TI - Inhibition of Pediatric Glioblastoma Tumor Growth by the Anti-Cancer Agent OKN 007 in Orthotopic Mouse Xenografts. AB - Pediatric glioblastomas (pGBM), although rare, are one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. Here, we describe the use of conventional and advanced in vivo magnetic resonance imaging (MRI) techniques to assess a novel orthotopic xenograft pGBM mouse (IC-3752GBM patient-derived culture) model, and to monitor the effects of the anti-cancer agent OKN-007 as an inhibitor of pGBM tumor growth. Immunohistochemistry support data is also presented for cell proliferation and tumor growth signaling. OKN-007 was found to significantly decrease tumor volumes (p<0.05) and increase animal survival (p<0.05) in all OKN 007-treated mice compared to untreated animals. In a responsive cohort of treated animals, OKN-007 was able to significantly decrease tumor volumes (p<0.0001), increase survival (p<0.001), and increase diffusion (p<0.01) and perfusion rates (p<0.05). OKN-007 also significantly reduced lipid tumor metabolism in responsive animals [(Lip1.3 and Lip0.9)-to-creatine ratio (p<0.05)], as well as significantly decrease tumor cell proliferation (p<0.05) and microvessel density (p<0.05). Furthermore, in relationship to the PDGFRalpha pathway, OKN-007 was able to significantly decrease SULF2 (p<0.05) and PDGFR-alpha (platelet-derived growth factor receptor-alpha) (p<0.05) immunoexpression, and significantly increase decorin expression (p<0.05) in responsive mice. This study indicates that OKN-007 may be an effective anti-cancer agent for some patients with pGBMs by inhibiting cell proliferation and angiogenesis, possibly via the PDGFRalpha pathway, and could be considered as an additional therapy for pediatric brain tumor patients. PMID- 26248283 TI - Elevated Steady State WBC and Platelet Counts Are Associated with Frequent Emergency Room Use in Adults with Sickle Cell Anemia. AB - INTRODUCTION: Sickle cell anemia has many sequelae that result in emergency department (ED) use, but a minority of patients with sickle cell disease are frequent utilizers and make up the majority of ED visits. If patients who are likely to be frequent ED can be identified in steady state, they can be treated with disease modifying agents in an attempt to reduce ED use frequency. We sought to identify steady state markers for frequent ED use. METHODS: We identified all patients with SS/Sbeta0 seen at our facilities in 2012. Health care utilization over the entire year was calculated and ED visit numbers categorized as either 0 1, 2-5, or 6 or more visits a year. Steady state and acutely active laboratory parameters were collected and analyzed using analysis of variance models and odds ratios. RESULTS: 432 adult sickle cell patients were identified, ages 18-87, 54% female, and 38% had been prescribed hydroxyurea. Of the 432 patients,192 had 0-1 visits in the year, 144 had 2-5 visits in the year, and 96 had >6 visits for a total of 2259 visits. Those who had >6 visits accounted for 1750 (77%) of the total visits for the year. When steady state laboratory markers were examined, each additional 50x10(9)/L platelets was associated with 22% greater risk (p < .001); each 1x10(9)/L of WBC was associated with 11% greater risk (p = .003), and each 1g/dL Hb was associated with 23% lower risk (p = .007) of >6 ED visits/year. We did not observe a relationship between baseline HbF, LDH or reticulocyte count with >6 ED visits. CONCLUSION: Patients with elevated white blood cell counts, elevated platelet counts, and low hemoglobin levels exhibited higher risk for frequent ED utilization and could be candidates for early and aggressive therapy with disease modifying agents. PMID- 26248284 TI - MicroRNAs Enhance Keratinocyte Proliferative Capacity in a Stem Cell-Enriched Epithelium. AB - MicroRNAs are critical regulators of stem cell behavior. The miR-103/107 family is preferentially expressed in the stem cell-enriched corneal limbal epithelium and plays an important role in coordinating several intrinsic characteristics of limbal epithelial stem cells. To elucidate further the mechanisms by which miRs 103/107 function in regulating limbal epithelial stem cells, we investigate the global effects of miRs-103/107 on gene expression in an unbiased manner. Using antagomirs-103/107, we knocked down endogenous miRs-103/107 in keratinocytes and conducted an mRNA profiling study. We show that miRs-103/107 target mitogen activated protein kinase kinase kinase 7 (MAP3K7) and thereby negatively regulate the p38/AP-1 pathway, which directs epithelial cells towards a differentiated state. Pharmacological inhibition of p38 increases holoclone colony formation, a measure of proliferative capacity. This suggests that the negative regulation of p38 by miRs-103/107 contributes to enhanced proliferative capacity, which is a hallmark of stem cells. Since miRs-103/107 also promote increased holoclone colony formation by regulating JNK activation through non-canonical Wnt signaling, we believe that this microRNA family preserves "stemness" by mediating the crosstalk between the Wnt/JNK and MAP3K7/p38/AP-1 pathways. PMID- 26248287 TI - Caveat Emptor: What the New IOM Report Does Not Deliver. PMID- 26248286 TI - Damage/Danger Associated Molecular Patterns (DAMPs) Modulate Chlamydia pecorum and C. trachomatis Serovar E Inclusion Development In Vitro. AB - Persistence, more recently termed the chlamydial stress response, is a viable but non-infectious state constituting a divergence from the characteristic chlamydial biphasic developmental cycle. Damage/danger associated molecular patterns (DAMPs) are normal intracellular components or metabolites that, when released from cells, signal cellular damage/lysis. Purine metabolite DAMPs, including extracellular ATP and adenosine, inhibit chlamydial development in a species specific manner. Viral co-infection has been shown to reversibly abrogate Chlamydia inclusion development, suggesting persistence/chlamydial stress. Because viral infection can cause host cell DAMP release, we hypothesized DAMPs may influence chlamydial development. Therefore, we examined the effect of extracellular ATP, adenosine, and cyclic AMP exposure, at 0 and 14 hours post infection, on C. pecorum and C. trachomatis serovar E development. In the absence of de novo host protein synthesis, exposure to DAMPs immediately post or at 14 hours post infection reduced inclusion size; however, the effect was less robust upon 14 hours post infection exposure. Additionally, upon exposure to DAMPs immediately post infection, bacteria per inclusion and subsequent infectivity were reduced in both Chlamydia species. These effects were reversible, and C. pecorum exhibited more pronounced recovery from DAMP exposure. Aberrant bodies, typical in virus-induced chlamydial persistence, were absent upon DAMP exposure. In the presence of de novo host protein synthesis, exposure to DAMPs immediately post infection reduced inclusion size, but only variably modulated chlamydial infectivity. Because chlamydial infection and other infections may increase local DAMP concentrations, DAMPs may influence Chlamydia infection in vivo, particularly in the context of poly-microbial infections. PMID- 26248285 TI - Genome Sequence of Bacillus endophyticus and Analysis of Its Companion Mechanism in the Ketogulonigenium vulgare-Bacillus Strain Consortium. AB - Bacillus strains have been widely used as the companion strain of Ketogulonigenium vulgare in the process of vitamin C fermentation. Different Bacillus strains generate different effects on the growth of K. vulgare and ultimately influence the productivity. First, we identified that Bacillus endophyticus Hbe603 was an appropriate strain to cooperate with K. vulgare and the product conversion rate exceeded 90% in industrial vitamin C fermentation. Here, we report the genome sequencing of the B. endophyticus Hbe603 industrial companion strain and speculate its possible advantage in the consortium. The circular chromosome of B. endophyticus Hbe603 has a size of 4.87 Mb with GC content of 36.64% and has the highest similarity with that of Bacillus megaterium among all the bacteria with complete genomes. By comparing the distribution of COGs with that of Bacillus thuringiensis, Bacillus cereus and B. megaterium, B. endophyticus has less genes related to cell envelope biogenesis and signal transduction mechanisms, and more genes related to carbohydrate transport and metabolism, energy production and conversion, as well as lipid transport and metabolism. Genome-based functional studies revealed the specific capability of B. endophyticus in sporulation, transcription regulation, environmental resistance, membrane transportation, extracellular proteins and nutrients synthesis, which would be beneficial for K. vulgare. In particular, B. endophyticus lacks the Rap-Phr signal cascade system and, in part, spore coat related proteins. In addition, it has specific pathways for vitamin B12 synthesis and sorbitol metabolism. The genome analysis of the industrial B. endophyticus will help us understand its cooperative mechanism in the K. vulgare-Bacillus strain consortium to improve the fermentation of vitamin C. PMID- 26248288 TI - "I Want a New Drug": Exercise as a Pharmacological Therapy. AB - Skeletal muscle can be considered a secretory organ that produces myokines and other humoral factors having autocrine-, paracrine-, and endocrine-like signaling effects throughout the body. Exercise has such profound pharmacological and physiological effects that it should be considered a drug therapy. Exercise has documented benefits for preventing or treating many physical and mental disorders or their sequelae, and it has a potential role in managing adverse effects associated with drug therapies. If exercise were a drug evaluated by the Food and Drug Administration, it might be approved for a large number of therapeutic indications. Exercise can be appropriately prescribed for virtually anyone for primary, secondary, or tertiary prevention of many mental and physical disorders. PMID- 26248291 TI - Walkable school neighborhoods are not playable neighborhoods. AB - The objectives were to determine whether: (1) playability features differed across walkable and non-walkable school neighborhoods, and (2) physical activity differed in children living in walkable and non-walkable school neighborhoods. A total of 3912 grade 6-8 students from 132 school neighborhoods were studied. There was more developed park space in high walkability neighborhoods than low walkability neighborhoods. Other playability features were more preferable in the low (e.g., undeveloped treed and water areas) and moderate (e.g., physical disorder/esthetics) walkability neighborhoods. Children from low walkability neighborhoods were more likely to engage in free-time physical activity outside of school and to achieve recommended levels of moderate-to-vigorous physical activity than were children from high walkability neighborhoods. PMID- 26248290 TI - Effect of Chronic Administration of Low Dose Rapamycin on Development and Immunity in Young Rats. AB - Mammalian target of rapamycin (mTOR) regulates cell growth, cell differentiation and protein synthesis. Rapamycin, an inhibitor of mTOR, has been widely used as an immunosuppressant and anti-cancer drug. Recently, mTOR inhibitors have also been reported to be a potential anti-epileptic drug, which may be effective when used in young patients with genetic epilepsy. Thus, a suitable dose of rapamycin which can maintain the normal function of mTOR and has fewer side effects ideally should be identified. In the present study, we first detected changes in marker proteins of mTOR signaling pathway during development. Then we determined the dose of rapamycin by treating rats of 2 weeks of age with different doses of rapamycin for 3 days and detected its effect on mTOR pathway. Young rats were then treated with a suitable dose of rapamycin for 4 weeks and the effect of rapamycin on mTOR, development and immunity were investigated. We found that the expression of the marker proteins of mTOR pathway was changed during development in brain hippocampus and neocortex. After 3 days of treanent, 0.03 mg/kg rapamycin had no effect on phospho-S6, whereas 0.1, 0.3, 1.0 and 3.0 mg/kg rapamycin inhibited phospho-S6 in a dose-dependent manner. However, only 1.0 mg/kg and 3.0 mg/kg rapamycin inhibited phospho-S6 after 4 weeks treatment of rapamycin. Parallel to this result, rats treated with 0.1 and 0.3 mg/kg rapamycin had no obvious adverse effects, whereas rats treated with 1.0 and 3.0 mg/kg rapamycin showed significant decreases in body, spleen and thymus weight. Additionally, rats treated with 1.0 and 3.0 mg/kg rapamycin exhibited cognitive impairment and anxiety as evident by maze and open field experiments. Furthermore, the content of IL-1beta, IL-2, IFN-gamma, TNF-alpha in serum and cerebral cortex were significantly decreased in 1.0 and 3.0 mg/kg rapamycin treated rats. The expression of DCX was also significantly decreased in 1.0 and 3.0 mg/kg rapamycin-treated rats. However, rats treated with 1.0 mg/kg rapamycin exhibited fewer and milder side effects than those treated with 3.0 mg/kg. In summary, all these data suggest that there is not a rapamycin dose that can inhibit mTOR for epilepsy without causing any side effects, but 1 mg/kg may be the optimal dose for young rats for suppressing mTOR with relatively few side effects. PMID- 26248292 TI - Cystic Lesions of the Jaw in Children: A 15-Year Experience. AB - IMPORTANCE: Pediatric jaw cysts represent a rarely symptomatic clinical entity and are not well addressed in the otolaryngology literature. It is important that otolaryngologists should be familiar with these lesions, which can manifest as jaw swelling or as paranasal sinus abnormalities. OBJECTIVE: To review the clinical presentation, radiologic features, management, and outcomes of jaw cysts in children treated at a single academic institution. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review at a tertiary care children's hospital among patients 16 years and younger who were seen with a cystic jaw lesion. MAIN OUTCOMES AND MEASURES: Medical records were reviewed for data on symptoms, physical examination findings, imaging, pathology, interventions, and outcomes among children who were seen at the Department of Oral and Maxillofacial Surgery or the Department of Otorhinolaryngology-Head and Neck Surgery at the University of Maryland Medical Center between January 1997 and December 2012 and were diagnosed as having a jaw cyst. RESULTS: Fifty-seven patients were identified who were diagnosed as having a true cystic jaw lesion and whose complete medical records were available for review. The most common cystic lesions were keratocystic odontogenic tumors (n = 19) and dentigerous cysts (n = 17). Fifty-six percent (32 of 57) of all cystic lesions were asymptomatic on presentation and were identified by imaging. The second most common presentation was local swelling (n = 15), followed by dental irregularities (n = 6). All patients, except for 1 with an eruption cyst, required surgical intervention, including biopsy, enucleation, curettage, or ostectomy, with reconstruction as indicated. Keratocystic odontogenic tumors tended to require more treatment (median, 2 procedures) for metachronous lesions or recurrence. CONCLUSIONS AND RELEVANCE: Pediatric jaw cysts are unusual, and data are scarce regarding their presentation and management. Many of these cysts are asymptomatic and are identified incidentally on orthopantomography. Keratocystic odontogenic tumors were the most common lesion seen in our series, followed by dentigerous cysts. Surgical intervention is required in most patients with a cystic lesion of the jaw. PMID- 26248293 TI - Cribellate thread production in spiders: Complex processing of nano-fibres into a functional capture thread. AB - Spider silk production has been studied intensively in the last years. However, capture threads of cribellate spiders employ an until now often unnoticed alternative of thread production. This thread in general is highly interesting, as it not only involves a controlled arrangement of three types of threads with one being nano-scale fibres (cribellate fibres), but also a special comb-like structure on the metatarsus of the fourth leg (calamistrum) for its production. We found the cribellate fibres organized as a mat, enclosing two parallel larger fibres (axial fibres) and forming the typical puffy structure of cribellate threads. Mat and axial fibres are punctiform connected to each other between two puffs, presumably by the action of the median spinnerets. However, this connection alone does not lead to the typical puffy shape of a cribellate thread. Removing the calamistrum, we found a functional capture thread still being produced, but the puffy shape of the thread was lost. Therefore, the calamistrum is not necessary for the extraction or combination of fibres, but for further processing of the nano-scale cribellate fibres. Using data from Uloborus plumipes we were able to develop a model of the cribellate thread production, probably universally valid for cribellate spiders. PMID- 26248294 TI - State-of-the-art strategies for targeting protein-protein interactions by small molecule inhibitors. AB - Targeting protein-protein interactions (PPIs) has emerged as a viable approach in modern drug discovery. However, the identification of small molecules enabling us to effectively interrupt their interactions presents significant challenges. In the recent past, significant advances have been made in the development of new biological and chemical strategies to facilitate the discovery process of small molecule PPI inhibitors. This review aims to highlight the state-of-the-art technologies and the achievements made recently in this field. The "hot spots" of PPIs have been proved to be critical for small molecules to bind. Three strategies including screening, designing, and synthetic approaches have been explored for discovering PPI inhibitors by targeting the "hot spots". Although the classic high throughput screening approach can be used, fragment screening, fragment-based drug design and newly improved virtual screening are demonstrated to be more effective in the discovery of PPI inhibitors. In addition to screening approaches, design strategies including anchor-based and small molecule mimetics of secondary structures involved in PPIs have become powerful tools as well. Finally, constructing new chemically spaced libraries with high diversity and complexity is becoming an important area of interest for PPI inhibitors. The successful cases from the recent five year studies are used to illustrate how these approaches are implemented to uncover and optimize small molecule PPI inhibitors and notably some of them have become promising therapeutics. PMID- 26248295 TI - Comparative study of perception and processing of socially or sexually significant odor information in male rats with normal or accelerated senescence using fMRI. AB - Olfaction plays an important role in mammals while aging causes olfactory dysfunction. Here the features of olfactory function in aging male rats were studied. We compared brain activity of regions involved in the perception (olfactory bulbs) and processing (cerebral cortex, hippocampus, hypothalamus) of sexually or socially significant odor stimulus with 11.7 T MR-scanner and odor perception using behavioral tests in 5-month old males with normal (Wistar rats) or accelerated senescence (d-galactose-treated Wistar rats (150 mg/kg/day, i.p., 12 weeks) or OXYS rats with hereditary defined accelerated aging). d-galactose treated Wistar males had altered BOLD-response in the centers processing socially significant odor information and changed patterns of the functional connectivity. We detected no significant changes in the olfactory function of OXYS males probably due to compensatory processes. In saline-treated Wistar rats, the correlation of BOLD-responses to both types of stimuli in the olfactory bulbs and cerebral cortex indicated changes in odor differentiation. Behavioral tests showed no significant differences between groups. However, the time of odor exploration increased in d-galactose-treated males indicating changes in odor recognition. Thus, we first revealed that in animal model of pharmacologically induced aging olfactory dysfunction occurred at the level of the centers processing socially significant odor information while the centers of odor perception (olfactory bulbs) remained unaffected. Alterations observed in Wistar rats chronically treated with saline evidenced the influence of long-term manipulations with experimental animals on olfactory function per se. PMID- 26248297 TI - The phase diagram and radial collapse of an inflated soft tube under twist. AB - When an inflated soft tube such as a cylindrical balloon is twisted, mechanical instability can arise and produces a kink-like radius collapsing in the middle of the tube. Here this phenomenon inspires us to theoretically analyze a standard non-linear model of rubber elasticity for soft tubes. We show that there exists a critical pressure beyond which such instability arises. The critical pressure depends on the elastic properties of the tube material and the geometric dimensions of the thin-walled tube. This general theory covers a large class of soft materials and explains why twist-induced collapsing is observable in soft and thin elastic tubes such as balloons, but not in hard and thick tubes such as water hoses. PMID- 26248296 TI - The change of spatial cognition ability in depression rat model and the possible association with down-regulated protein expression of TRPC6. AB - An increasing number of researches have focused on the cognitive changes in depression patients. Here, we observed impaired cognitive ability in a rat depression model along with down-regulated expression of canonical transient receptor potential 6 (TRPC6) protein. The cognitive defect could be rescued by treatment with hyperforin, which can invoke TRPC6 activation. This study was designed as following: rats were randomly divided into control, stressed and stressed+hyperforin groups. Chronic unpredictable stress combined with isolation rearing was applied on rats for three weeks, except for control group. Morris water maze was applied to evaluate spatial cognitive ability while long-term potentiation (LTP) was recorded to test the synaptic plasticity. Results showed that both spatial cognition and synaptic plasticity were impaired in stress group while improved after hyperforin treatment in stressed+hyperforin group, meanwhile, Western blot assay showed that TRPC6 expression was decreased in stressed group. The histological data also presented the decline of dendritic length, dendritic spine density and the number of excitatory synapses in stress group while they were increased in stressed+hyperforin group. These results suggest that there is a well potential of TRPC6 to become a new target for selecting promising new candidates as antidepressants with therapeutically effect on impaired cognition. PMID- 26248299 TI - One-pot pyrolysis of lithium sulfate and graphene nanoplatelet aggregates: in situ formed Li2S/graphene composite for lithium-sulfur batteries. AB - Lithium sulfide (Li2S) as a cathodic material in Li-S batteries can not only deliver a high theoretical specific capacity of 1166 mA h g(-1), but also is essential for batteries using Li-free anode materials such as silicon and graphite. Various efforts have been made to synthesize a highly efficient Li2S carbon composite; however, the electronically and ionically insulating nature and high melting point of Li2S strongly complicate the synthetic procedures, making it difficult to realize the expected capacity. Herein, a very simple method is proposed to prepare Li2S/graphene composites by one-pot pyrolysis of a mixture of graphene nanoplatelet aggregates (GNAs) and low-cost lithium sulfate (Li2SO4). For the first time, the entire pyrolysis process is clarified by thermogravimetry mass spectrometry, wherein GNAs were found to partly serve as a carbon source to reduce Li2SO4 to Li2S, while the remaining GNAs formed thin graphene sheets as a result of this in situ etching, as a highly conductive host can immobilize the generated Li2S by intimate contact. Consequently, the obtained Li2S/graphene composite, combined with a Li2Sx-insoluble (x = 4-8) electrolyte developed by our group, exhibits excellent electrochemical behavior for Li-S batteries. PMID- 26248298 TI - Temporal and Spatial Distribution of the Microbial Community of Winogradsky Columns. AB - Winogradsky columns are model microbial ecosystems prepared by adding pond sediment to a clear cylinder with additional supplements and incubated with light. Environmental gradients develop within the column creating diverse niches that allow enrichment of specific bacteria. The enrichment culture can be used to study soil and sediment microbial community structure and function. In this study we used a 16S rRNA gene survey to characterize the microbial community dynamics during Winogradsky column development to determine the rate and extent of change from the source sediment community. Over a period of 60 days, the microbial community changed from the founding pond sediment population: Cyanobacteria, Chloroflexi, Nitrospirae, and Planctomycetes increased in relative abundance over time, while most Proteobacteria decreased in relative abundance. A unique, light dependent surface biofilm community formed by 60 days that was less diverse and dominated by a few highly abundant bacteria. 67-72% of the surface community was comprised of highly enriched taxa that were rare in the source pond sediment, including the Cyanobacteria Anabaena, a member of the Gemmatimonadetes phylum, and a member of the Chloroflexi class Anaerolinea. This indicates that rare taxa can become abundant under appropriate environmental conditions and supports the hypothesis that rare taxa serve as a microbial seed bank. We also present preliminary findings that suggest that bacteriophages may be active in the Winogradsky community. The dynamics of certain taxa, most notably the Cyanobacteria, showed a bloom-and-decline pattern, consistent with bacteriophage predation as predicted in the kill-the-winner hypothesis. Time-lapse photography also supported the possibility of bacteriophage activity, revealing a pattern of colony clearance similar to formation of viral plaques. The Winogradsky column, a technique developed early in the history of microbial ecology to enrich soil microbes, may therefore be a useful model system to investigate both microbial and viral ecology. PMID- 26248300 TI - Preparation of a mixed-matrix hydrogel of vorinostat for topical administration on the rats as experimental model. AB - Oral vorinostat has the remarkable curative effect on aggravated and recurrent cutaneous T-cell lymphoma (CTCL), but is accompanied by serious adverse effects. Therefore, oral vorinostat is not applicable to the treatment of early stage CTCL. The aim of this study is to develop a novel vorinostat formulation which is effective for early stage CTCL and free of the serious adverse effects. A mixed matrix hydrogel of vorinostat was prepared and characterized as a potential topical skin delivery system. Moisture retention, swelling behavior, viscosity, real-time morphology and differential scanning calorimeter analysis (DSC) of hydrogel were evaluated to select the solvent, matrix and humectant. The optimal HPMC/HPC ratio, pH, additive, dose and drug loading of vorinostat hydrogel were determined by evaluating the cumulative vorinostat amount of skin retention and transdermal amount of vorinostat through the skin in vitro. The optimal hydrogel presented a low transdermal amount of vorinostat through the skin, suggesting that the hydrogel reduced the amount of vorinostat that was absorbed in the systemic circulation. More importantly, in vivo percutaneous permeation experiments were also performed to evaluate the permeation behavior of vorinostat into the skin. The topical application with a much lower dose showed higher AUC (the cumulative vorinostat amount of skin retention) than oral application and the hydrogel achieved a sustained permeation of vorinostat in the skin for 24h in vivo. It indicated that a higher relative bioavailability for hydrogel was achieved compared with oral vorinostat. Moreover, there was no damage, inflammation or cell swelling of the skin after administration. Thus, the mixed matrix vorinostat hydrogel prepared in this study could deliver vorinostat into local skin more efficiently than oral administration. PMID- 26248301 TI - Inter-laboratory comparison of the in vivo comet assay including three image analysis systems. AB - To compare the extent of potential inter-laboratory variability and the influence of different comet image analysis systems, in vivo comet experiments were conducted using the genotoxicants ethyl methanesulfonate and methyl methanesulfonate. Tissue samples from the same animals were processed and analyzed-including independent slide evaluation by image analysis-in two laboratories with extensive experience in performing the comet assay. The analysis revealed low inter-laboratory experimental variability. Neither the use of different image analysis systems, nor the staining procedure of DNA (propidium iodide vs. SYBR(r) Gold), considerably impacted the results or sensitivity of the assay. In addition, relatively high stability of the staining intensity of propidium iodide-stained slides was found in slides that were refrigerated for over 3 months. In conclusion, following a thoroughly defined protocol and standardized routine procedures ensures that the comet assay is robust and generates comparable results between different laboratories. PMID- 26248302 TI - Autism spectrum disorder (ASD) and its perioperative management. AB - Autism spectrum disorder (ASD) is now diagnosed in more than 1 in 100 children, so it is not surprising that anesthetists are increasingly providing care for children with this diagnosis. The diagnostic classification for ASD has recently changed and our understanding of the causes and management of ASD are also changing rapidly. This review provides a timely update to increase understanding and awareness of the problems that children with ASD experience, and to minimize perioperative problems. Current literature on premedication and the increasing use of alpha-2 agonists such as clonidine and dexmedetomidine as well as the use of old favorites midazolam and ketamine is reviewed. Some simple strategies that will improve care and decrease anxiety, like social stories, the use of tablet computers, other comfort items or games for distraction, and using favorite drinks to disguise the bitter taste of medications, are described. Remember, the parents are their child's expert and will know what agitates and settles them. Talking to them prior to the day of the procedure is ideal. The importance of staff training and having a clinical practice guideline available at every institution cannot be overstated. PMID- 26248303 TI - Separate effects of moisture content and water activity on the hyphal extension of Penicillium rubens on porous media. AB - To prevent indoor fungal growth, understanding the moisture relations of fungi is a key element. Indoor moisture is quantified by the relative humidity (RH). RH controls the water activity of the indoor materials that fungi grow on, a well studied parameter known to limit fungal growth. RH, however, also controls the amount of water present in these materials, the moisture content. The significance of the moisture content of these materials to indoor fungal growth is currently overlooked. In the work reported here, growth experiments with the indoor fungus Penicillium rubens on gypsum substrates were performed to test whether the moisture content influences growth on porous materials. Second, we report the development of a video microscopy method that for the first time quantified hyphal growth on a porous material. It is found that a higher moisture content leads to earlier colonization and higher hyphal extension rates. This is a fundamental step in unravelling the effect of RH on indoor fungal growth. The real-time monitoring of colonization of gypsum provides a new view of growth on indoor surfaces. PMID- 26248304 TI - MicroRNAs in Control of Plant Development. AB - In the long evolutionary history, plant has evolved elaborate regulatory network to control functional gene expression for surviving and thriving, such as transcription factor-regulated transcriptional programming. However, plenty of evidences from the past decade studies demonstrate that the 21-24 nucleotides small RNA molecules, majorly microRNAs (miRNAs) play dominant roles in post transcriptional gene regulation through base pairing with their complementary mRNA targets, especially prefer to target transcription factors in plants. Here, we review current progresses on miRNA-controlled plant development, from miRNA biogenesis dysregulation-caused pleiotropic developmental defects to specific developmental processes, such as SAM regulation, leaf and root system regulation, and plant floral transition. We also summarize some miRNAs that are experimentally proved to greatly affect crop plant productivity and quality. In addition, recent reports show that a single miRNA usually displays multiple regulatory roles, such as organ development, phase transition, and stresses responses. Thus, we infer that miRNA may act as a node molecule to coordinate the balance between plant development and environmental clues, which may shed the light on finding key regulator or regulatory pathway for uncovering the mysterious molecular network. PMID- 26248305 TI - An exploration of the political economy dynamics shaping health worker incentives in three districts in Sierra Leone. AB - The need for evidence-based practice calls for research focussing not only on the effectiveness of interventions and their translation into policies, but also on implementation processes and the factors influencing them, in particular for complex health system policies. In this paper, we use the lens of one of the health system's 'building blocks', human resources for health (HRH), to examine the implementation of official policies on HRH incentives and the emergence of informal practices in three districts of Sierra Leone. Our mixed-methods research draws mostly from 18 key informant interviews at district level. Data are organised using a political economy framework which focuses on the dynamic interactions between structure (context, historical legacies, institutions) and agency (actors, agendas, power relations) to show how these elements affect the HRH incentive practices in each district. It appears that the official policies are re-shaped both by implementation challenges and by informal practices emerging at local level as the result of the district-level dynamics and negotiations between District Health Management Teams (DHMTs) and nongovernmental organisations (NGOs). Emerging informal practices take the form of selective supervision, salary supplementations and per diems paid to health workers, and aim to ensure a better fit between the actors' agendas and the incentive package. Importantly, the negotiations which shape such practices are characterised by a substantial asymmetry of power between DHMTs and NGOs. In conclusion, our findings reveal the influence of NGOs on the HRH incentive package and highlight the need to empower DHMTs to limit the discrepancy between policies defined at central level and practices in the districts, and to reduce inequalities in health worker remuneration across districts. For Sierra Leone, these findings are now more relevant than ever as new players enter the stage at district level, as part of the Ebola response and post-Ebola reconstruction. PMID- 26248306 TI - An exploration of the longer-term impacts of community participation in rural health services design. AB - This article explores what happened, over the longer term, after a community participation exercise to design future rural service delivery models, and considers perceptions of why more follow-up actions did or did not happen. The study, which took place in 2014, revisits three Scottish communities that engaged in a community participation research method (2008-2010) intended to design rural health services. Interviews were conducted with 22 citizens, healthcare practitioners, managers and policymakers all of whom were involved in, or knew about, the original project. Only one direct sustained service change was found - introduction of a volunteer first responder scheme in one community. Sustained changes in knowledge were found. The Health Authority that part-funded development of the community participation method, through the original project, had not adopted the new method. Community members tended to attribute lack of further impact to low participation and methods insufficiently attuned to the social nuances of very small rural communities. Managers tended to blame insufficient embedding in the healthcare system and issues around power over service change and budgets. In the absence of convincing formal community governance mechanisms for health issues, rural health practitioners tended to act as conduits between citizens and the Health Authority. The study provides new knowledge about what happens after community participation and highlights a need for more exploration. PMID- 26248307 TI - Disability prevalence and disability-related employment gaps in the UK 1998-2012: Different trends in different surveys? AB - The persistently low employment rate among disabled individuals has been an enduring concern of governments across developed countries and has been the subject of a succession of policy initiatives, including labour market activation programmes, equality laws and welfare reform. A key indicator of progress is the trend in the disability-related employment gap, the percentage point difference between the employment rate for disabled and non-disabled individuals. Confusingly for the UK, studies undertaken between 1998 and 2012 have simultaneously reported both a widening and a narrowing of the gap. The source of the discrepancy can be found in the choice of survey, the General Household Survey (GHS) or the Labour Force Survey (LFS), although both use a common conception of disability and collect self-reported information from a random sample of households. The literature has analysed these surveys separately from each other and ignored inter-survey differences in findings. The Health Survey for England (HSE), a third national household survey, replicates the GHS questions on disability but has had limited use in this context. This empirical study compares the trends in disability prevalence and the disability-related employment gap across the three surveys using a three-stage harmonisation process. The negative relationship between the prevalence of disability and the employment gap found in cross-section inter-survey comparisons prompts an initial focus on differences in the definition of disability as an explanation of the discrepancy. This is broadened to include differences in survey methods and sample composition. Differences in the trend in disability prevalence and the employment gap remain following harmonisation for definition, survey method and sample composition. It is the LFS, the main policy-influencing and policy assessment survey, which generates outlying results. As such, we cannot be confident that the disability-related employment gap has narrowed in the UK since 1998. PMID- 26248308 TI - Bulimic Behaviors and Early Substance Use: Findings from a Cotwin-Control Study. AB - BACKGROUND: Bulimic behaviors (i.e., binge eating and compensatory behaviors) and substance use frequently co-occur. However, the etiology underlying this association is poorly understood. This study evaluated the association between bulimic behaviors and early substance use, controlling for genetic and shared environmental factors. METHODS: Participants were 3,540 young adult women from the Missouri Adolescent Female Twin Study. A telephone adaptation of the Semi Structured Assessment for the Genetics of Alcoholism interview assessed DSM-IV bulimic behaviors, substance use, and other psychological characteristics. Lifetime bulimic behaviors were examined in twin pairs concordant and discordant for early substance use. Logistic regressions were adjusted for the nonindependence of twin data, zygosity, age, body mass index, early menarche (onset before age 12), and early sex (first consensual sexual intercourse before age 15). RESULTS: In the entire study population, women who reported early use of alcohol or nicotine were more likely to engage in bulimic behaviors after adjusting for covariates. In 53 pairs of monozygotic twins discordant for alcohol experimentation before age 15, the twin who reported early alcohol experimentation had 3.21 (95% confidence interval = 1.54 to 6.67) times higher odds of reporting bulimic behaviors than the cotwin who did not report early alcohol experimentation, even after adjustment for covariates. CONCLUSIONS: Findings suggest that early alcohol experimentation may contribute to the development of bulimic behaviors via mechanisms extending beyond shared vulnerability, including individual-specific environmental experiences or causal pathways. PMID- 26248310 TI - Synthesis and biological evaluation of a novel betulinic acid derivative as an inducer of apoptosis in human colon carcinoma cells (HT-29). AB - A novel family of betulinic acid analogues, carrying a triazole unit at C-3 attached through a linker, was synthesized by the application of azide-alkyne "Click reaction". These were screened for their anticancer activity against different cancer cells and normal human PBMC by MTT assay. Compound 2c [(3S)-3-{2 (4-(hydroxymethyl-1H-1,2,3-triazol-1-yl)acetyloxy}-lup-20(29)-en-28-oic acid] was found as the most potent inhibitor of cell line HT-29 with IC50 value 14.9 MUM. Its role as an inducer of apoptosis was investigated in this cell line by Annexin V/PI binding assay and by following its capability for ROS generation, depolarization of mitochondrial transmembrane potential, activation of caspases, PARP cleavage, nuclear degradation and expression of pro- and anti-apoptotic proteins. It exhibited much higher cytotoxicity than the standard drug 5 fluorouracil but showed negligible cytotoxicity towards normal PBMC. Elevated level of ROS generation, activation of caspase 3 and caspase 9, DNA fragmentation, higher expression of Bax and Bad, lower expression of Bcl2 and Bcl xl, and increased level of Bax/Bcl-xl ratio identified 2c as a promising inducer of apoptosis that follows a mitochondria dependent pathway. Bio-physical studies indicate that compound 2c acts as a minor groove binder to the DNA. PMID- 26248309 TI - Diet-induced obesity and kidney disease - In search of a susceptible mouse model. AB - Obesity and metabolic syndrome are independent risk factors for chronic kidney disease, even without diabetes or hyperglycemia. Here, we compare two mouse models that are susceptible to diet-induced obesity: the relatively renal injury resistant C57BL/6J strain and the DBA2/J strain which is more sensitive to renal injury. Our studies focused on characterizing the effects of high fat diet feeding on renal oxidative stress, albuminuria, fibrosis and podocyte loss/insulin resistance. While the C57BL/6J strain does not develop significant pathological changes in the kidney, at least on lard based diets within the time frame investigated, it does show increased renal iNOS and nitrotyrosine levels and elevated mitochondrial respiration which may be indicative of mitochondrial lipid overfueling. Restricting the high fat diet to decrease adiposity decreased the levels of cellular oxidative stress markers, indicating that adiposity related proinflammatory changes such as increased iNOS levels may trigger similar responses in the kidney. Mitochondrial respiration remained higher, suggesting that eating excess lipids, despite normal adiposity may still lead to renal mitochondrial overfueling. In comparison, DBA/2J mice developed albuminuria on similar diets, signs of fibrosis, oxidative stress, early signs of podocyte loss (evaluated by the markers podocin and WT-1) and podocyte insulin resistance (unable to phosphorylate their glomerular Akt when insulin was given). To summarize, while the C57BL/6J strain is not particularly susceptible to renal disease, changes in its mitochondrial lipid handling combined with the easy availability of transgenic technology may be an advantage to design new knockout models related to mitochondrial lipid metabolism. The DBA/2J model could serve as a basis for studying podocyte insulin resistance and identifying early renal markers in obesity before more severe kidney disease develops. Based on our observations, we encourage further critical evaluation of mouse models for obesity related chronic kidney disease. PMID- 26248311 TI - Preparation of Lanthanide-Polymer Composite Material via Click Chemistry. AB - Covalently attaching lanthanide complexes to the polymer backbone can effectively reduce the clustering of lanthanides and thus become an important strategy to fully unleash their potential. In this Communication, a metal-free click reaction is used for the first time to link a lanthanide complex to the polymer matrix. A diene-bearing copolymer with anthracenylmethyl methacrylate as a monomer and a dienophile-bearing lanthanide complex with 5-maleimido-1,10-phenanthroline as the second ligand are synthesized and coupled together through a Diels-Alder cycloaddition (DA). A comparative investigation demonstrates that the composite material prepared by DA click reaction shows the highest quantum yields in the same lanthanide concentration as compared to materials prepared by widely used "directly doping" and "in situ coordinating lanthanide ions with macromolecular ligand" approaches. This work suggests that the "metal-free" DA click reaction can be a promising tool in the synthesis of high efficient lanthanide functionalized polymeric materials. PMID- 26248312 TI - Influence of practice schedules and attention on skill development and retention. AB - Focus of attention during dual-tasks and practice schedules are important components of motor skill performance and learning; often studied in isolation. The current study required participants to complete a simple key-pressing task under a blocked or random practice schedule. To manipulate attention, participants reported their finger position (i.e., skill-focused attention) or the pitch of an auditory tone (i.e., extraneous attention) while performing two variations of a dual-task key-pressing task. Analyses were conducted at baseline, 10 min and 24h after acquisition. The results revealed that participants in a blocked schedule, extraneous focus condition had significantly faster movement times during retention compared to a blocked schedule, skill focus condition. Furthermore, greatest improvements from baseline to immediate and delayed retention were evident for an extraneous attention compared to the skill-focused attention, regardless of practice schedule. A discussion of the unique benefits an extraneous focus of attention may have on the learning process during dual task conditions is presented. PMID- 26248313 TI - The Obesogenic Quality of the Home Environment: Associations with Diet, Physical Activity, TV Viewing, and BMI in Preschool Children. AB - OBJECTIVES: The home environment is thought to play a key role in early weight trajectories, although direct evidence is limited. There is general agreement that multiple factors exert small individual effects on weight-related outcomes, so use of composite measures could demonstrate stronger effects. This study therefore examined whether composite measures reflecting the 'obesogenic' home environment are associated with diet, physical activity, TV viewing, and BMI in preschool children. METHODS: Families from the Gemini cohort (n = 1096) completed a telephone interview (Home Environment Interview; HEI) when their children were 4 years old. Diet, physical activity, and TV viewing were reported at interview. Child height and weight measurements were taken by the parents (using standard scales and height charts) and reported at interview. Responses to the HEI were standardized and summed to create four composite scores representing the food (sum of 21 variables), activity (sum of 6 variables), media (sum of 5 variables), and overall (food composite/21 + activity composite/6 + media composite/5) home environments. These were categorized into 'obesogenic risk' tertiles. RESULTS: Children in 'higher-risk' food environments consumed less fruit (OR; 95% CI = 0.39; 0.27-0.57) and vegetables (0.47; 0.34-0.64), and more energy-dense snacks (3.48; 2.16-5.62) and sweetened drinks (3.49; 2.10-5.81) than children in 'lower risk' food environments. Children in 'higher-risk' activity environments were less physically active (0.43; 0.32-0.59) than children in 'lower-risk' activity environments. Children in 'higher-risk' media environments watched more TV (3.51; 2.48-4.96) than children in 'lower-risk' media environments. Neither the individual nor the overall composite measures were associated with BMI. CONCLUSIONS: Composite measures of the obesogenic home environment were associated as expected with diet, physical activity, and TV viewing. Associations with BMI were not apparent at this age. PMID- 26248314 TI - gPGA: GPU Accelerated Population Genetics Analyses. AB - BACKGROUND: The isolation with migration (IM) model is important for studies in population genetics and phylogeography. IM program applies the IM model to genetic data drawn from a pair of closely related populations or species based on Markov chain Monte Carlo (MCMC) simulations of gene genealogies. But computational burden of IM program has placed limits on its application. METHODOLOGY: With strong computational power, Graphics Processing Unit (GPU) has been widely used in many fields. In this article, we present an effective implementation of IM program on one GPU based on Compute Unified Device Architecture (CUDA), which we call gPGA. CONCLUSIONS: Compared with IM program, gPGA can achieve up to 52.30X speedup on one GPU. The evaluation results demonstrate that it allows datasets to be analyzed effectively and rapidly for research on divergence population genetics. The software is freely available with source code at https://github.com/chunbaozhou/gPGA. PMID- 26248315 TI - SPARC Controls Melanoma Cell Plasticity through Rac1. AB - Cell transition to a more aggressive mesenchymal-like phenotype is a hallmark of cancer progression that involves different steps and requires tightly regulated cell plasticity. SPARC (Secreted Protein Acidic and Rich in Cysteine) is a matricellular protein that promotes this transition in various malignant cell types, including melanoma cells. We found that suppression of SPARC expression in human melanoma cells compromised cell migration, adhesion, cytoskeleton structure, and cell size. These changes involved the Akt/mTOR pathway. Re expression of SPARC or protein addition restored all the cell features. Suppression of SPARC expression was associated with increased Rac1-GTP levels and its membrane localization. Expression of the dominant negative mutant of Rac1 counteracted almost all the changes observed in SPARC-deficient cells. Overall, these data suggest that most of the SPARC-mediated effects occurred mainly through the blockade of Rac1 activity. PMID- 26248316 TI - Asymptomatic Helminth Infection in Active Tuberculosis Is Associated with Increased Regulatory and Th-2 Responses and a Lower Sputum Smear Positivity. AB - BACKGROUND: The impact of intestinal helminth infection on the clinical presentation and immune response during active tuberculosis (TB) infection is not well characterized. Our aim was to investigate whether asymptomatic intestinal helminth infection alters the clinical signs and symptoms as well as the cell mediated immune responses in patients with active TB. METHODOLOGY: Consecutive, newly diagnosed TB patients and healthy community controls (CCs) were recruited in North-west Ethiopia. TB-score, body mass index and stool samples were analyzed. Cells from HIV-negative TB patients (HIV-/TB) and from CCs were analyzed for regulatory T-cells (Tregs) and cytokine responses using flow cytometry and ELISPOT, respectively. RESULTS: A significantly higher ratio of helminth co-infection was observed in TB patients without HIV (Helm+/HIV-/TB) compared to HIV negative CCs, (40% (121/306) versus 28% (85/306), p = 0.003). Helm+/HIV-/TB patients showed significantly increased IL-5 secreting cells compared to Helm-/HIV-/TB (37 SFU (IQR:13-103) versus 2 SFU (1-50); p = 0.02, n = 30). Likewise, levels of absolute Tregs (9.4 (3.2-16.7) cells/MUl versus 2.4 (1.1 4.0) cells/MUl; p = 0.041) and IL-10 secreting cells (65 SFU (7-196) versus 1 SFU (0-31); p = 0.014) were significantly higher in Helm+/HIV-/TB patients compared to Helm-/HIV-/TB patients. In a multivariate analysis, a lower rate of sputum smear positivity for acid fast bacilli, lower body temperature, and eosinophilia were independently associated with helminth infection in TB patients. CONCLUSIONS: Asymptomatic helminth infection is associated with increased regulatory T-cell and Th2-type responses and a lower rate of sputum smear positivity. Further studies are warranted to investigate the clinical and immunological impact of helminth infection in TB patients. PMID- 26248319 TI - Biotechnological applications of Yarrowia lipolytica: Past, present and future. AB - Non-conventional yeasts have attracted increasing interest due to their biochemical characteristics and potential applications. Yarrowia lipolytica is a non-conventional yeast with specific characteristics and physiology. The potential physiological and metabolic capabilities of Y. lipolytica, which can assimilate many different carbon sources, including typical hydrophilic and hydrophobic materials, are reviewed in this paper. Concerning the uptake and metabolism substrates, this review focuses particularly on low-cost raw materials, such as glycerol. Moreover, this review presents the results of safety studies of Y. lipolytica. Finally, the wide applications of Y. lipolytica, such as functional enzyme production, metabolite synthesis and environmental bioremediation, are reviewed in this paper. Recently, with the development of system biology and synthetic biology, it was concluded that these technologies will provide new opportunities for potential applications of Y. lipolytica in the future. PMID- 26248317 TI - Effect of Low Doses (5-40 cGy) of Gamma-irradiation on Lifespan and Stress related Genes Expression Profile in Drosophila melanogaster. AB - Studying of the effects of low doses of gamma-irradiation is a crucial issue in different areas of interest, from environmental safety and industrial monitoring to aerospace and medicine. The goal of this work is to identify changes of lifespan and expression stress-sensitive genes in Drosophila melanogaster, exposed to low doses of gamma-irradiation (5-40 cGy) on the imaginal stage of development. Although some changes in life extensity in males were identified (the effect of hormesis after the exposure to 5, 10 and 40 cGy) as well as in females (the effect of hormesis after the exposure to 5 and 40 cGy), they were not caused by the organism "physiological" changes. This means that the observed changes in life expectancy are not related to the changes of organism physiological functions after the exposure to low doses of ionizing radiation. The identified changes in gene expression are not dose-dependent, there is not any proportionality between dose and its impact on expression. These results reflect nonlinear effects of low dose radiation and sex-specific radio-resistance of the postmitotic cell state of Drosophila melanogaster imago. PMID- 26248318 TI - AAV-Delivered Antibody Mediates Significant Protective Effects against SIVmac239 Challenge in the Absence of Neutralizing Activity. AB - Long-term delivery of potent broadly-neutralizing antibodies is a promising approach for the prevention of HIV-1 infection. We used AAV vector intramuscularly to deliver anti-SIV monoclonal antibodies (mAbs) in IgG1 form to rhesus monkeys. Persisting levels of delivered mAb as high as 270 MUg/ml were achieved. However, host antibody responses to the delivered antibody were observed in 9 of the 12 monkeys and these appeared to limit the concentration of delivered antibody that could be achieved. This is reflected in the wide range of delivered mAb concentrations that were achieved: 1-270 MUg/ml. Following repeated, marginal dose, intravenous challenge with the difficult-to-neutralize SIVmac239, the six monkeys in the AAV-5L7 IgG1 mAb group showed clear protective effects despite the absence of detectable neutralizing activity against the challenge virus. The protective effects included: lowering of viral load at peak height; lowering of viral load at set point; delay in the time to peak viral load from the time of the infectious virus exposure. All of these effects were statistically significant. In addition, the monkey with the highest level of delivered 5L7 mAb completely resisted six successive SIVmac239 i.v. challenges, including a final challenge with a dose of 10 i.v. infectious units. Our results demonstrate the continued promise of this approach for the prevention of HIV-1 infection in people. However, the problem of anti-antibody responses will need to be understood and overcome for the promise of this approach to be effectively realized. PMID- 26248320 TI - RNAi-mediated downregulation of poplar plasma membrane intrinsic proteins (PIPs) changes plasma membrane proteome composition and affects leaf physiology. AB - Plasma membrane intrinsic proteins (PIPs) are one subfamily of aquaporins that mediate the transmembrane transport of water. To reveal their function in poplar, we generated transgenic poplar plants in which the translation of PIP genes was downregulated by RNA interference investigated these plants with a comprehensive leaf plasma membrane proteome and physiome analysis. First, inhibition of PIP synthesis strongly altered the leaf plasma membrane protein composition. Strikingly, several signaling components and transporters involved in the regulation of stomatal movement were differentially regulated in transgenic poplars. Furthermore, hormonal crosstalk related to abscisic acid, auxin and brassinosteroids was altered, in addition to cell wall biosynthesis/cutinization, the organization of cellular structures and membrane trafficking. A physiological analysis confirmed the proteomic results. The leaves had wider opened stomata and higher net CO2 assimilation and transpiration rates as well as greater mesophyll conductance for CO2 (gm) and leaf hydraulic conductance (Kleaf). Based on these results, we conclude that PIP proteins not only play essential roles in whole leaf water and CO2 flux but have important roles in the regulation of stomatal movement. PMID- 26248321 TI - iCFD: Interpreted Computational Fluid Dynamics - Degeneration of CFD to one dimensional advection-dispersion models using statistical experimental design - The secondary clarifier. AB - The present study aims at using statistically designed computational fluid dynamics (CFD) simulations as numerical experiments for the identification of one dimensional (1-D) advection-dispersion models - computationally light tools, used e.g., as sub-models in systems analysis. The objective is to develop a new 1-D framework, referred to as interpreted CFD (iCFD) models, in which statistical meta-models are used to calculate the pseudo-dispersion coefficient (D) as a function of design and flow boundary conditions. The method - presented in a straightforward and transparent way - is illustrated using the example of a circular secondary settling tank (SST). First, the significant design and flow factors are screened out by applying the statistical method of two-level fractional factorial design of experiments. Second, based on the number of significant factors identified through the factor screening study and system understanding, 50 different sets of design and flow conditions are selected using Latin Hypercube Sampling (LHS). The boundary condition sets are imposed on a 2-D axi-symmetrical CFD simulation model of the SST. In the framework, to degenerate the 2-D model structure, CFD model outputs are approximated by the 1-D model through the calibration of three different model structures for D. Correlation equations for the D parameter then are identified as a function of the selected design and flow boundary conditions (meta-models), and their accuracy is evaluated against D values estimated in each numerical experiment. The evaluation and validation of the iCFD model structure is carried out using scenario simulation results obtained with parameters sampled from the corners of the LHS experimental region. For the studied SST, additional iCFD model development was carried out in terms of (i) assessing different density current sub-models; (ii) implementation of a combined flocculation, hindered, transient and compression settling velocity function; and (iii) assessment of modelling the onset of transient and compression settling. Furthermore, the optimal level of model discretization both in 2-D and 1-D was undertaken. Results suggest that the iCFD model developed for the SST through the proposed methodology is able to predict solid distribution with high accuracy - taking a reasonable computational effort when compared to multi-dimensional numerical experiments, under a wide range of flow and design conditions. iCFD tools could play a crucial role in reliably predicting systems' performance under normal and shock events. PMID- 26248322 TI - Pial artery and subarachnoid width response to apnoea in normal humans. AB - BACKGROUND: Little is known about intracranial pressure (ICP)-cerebral haemodynamic interplay during repetitive apnoea. A recently developed method based on near-infrared transillumination/backscattering sounding (NIR-T/BSS) noninvasively measures changes in pial artery pulsation (cc-TQ) as well as subarachnoid width (sas-TQ) in humans. METHOD: We tested the complex response of the pial artery and subarachnoid width to apnoea using this method. The pial artery and subarachnoid width response to consecutive apnoeas lasting 30, 60 s and maximal breath-hold (91.1 +/- 23.1 s) were studied in 20 healthy volunteers. The cc-TQ and sas-TQ were measured using NIR-T/BSS; cerebral blood flow velocity (CBFV), pulsatility index and resistive index were measured using Doppler ultrasound of the left internal carotid artery; heart rate (HR) and beat-to-beat SBP and DBP blood pressure were recorded using a Finometer; end-tidal CO2 (EtCO2) was measured using a medical gas analyser. RESULTS: Apnoea evoked a multiphasic response in blood pressure, pial artery compliance and ICP. First, SBP declined, which was accompanied by an increase in cc-TQ and sas-TQ. Directly after these changes, SBP exceeded baseline values, which was followed by a decline in cc-TQ and the return of sas-TQ to baseline. During these initial changes, CBFV remained stable. Towards the end of the apnoea, BP, cc-TQ and CBFV increased, whereas pulsatility index, resistive index and sas-TQ declined. Changes in sas-TQ were linked to changes in EtCO2, HR and SBP. CONCLUSION: Apnoea is associated with ICP swings, closely reflecting changes in EtCO2, HR and peripheral BP. The baroreflex influences the pial artery response. PMID- 26248323 TI - Carotid stiffness change over the cardiac cycle by ultrafast ultrasound imaging in healthy volunteers and vascular Ehlers-Danlos syndrome. AB - OBJECTIVES: Arterial stiffness is related to age and collagen properties of the arterial wall and can be indirectly evaluated by the pulse wave velocity (PWV). Ultrafast ultrasound imaging, a unique ultrahigh frame rate technique (>10, 000 images/s), recently emerged enabling direct measurement of carotid PWV and its variation over the cardiac cycle. Our goal was to characterize the carotid diastolic-systolic arterial stiffening using ultrafast ultrasound imaging in healthy individuals and in vascular Ehlers-Danlos syndrome (vEDS), in which collagen type III is defectuous. METHODS: Ultrafast ultrasound imaging was performed on common carotids of 102 healthy individuals and 37 consecutive patients with vEDS. Results are mean +/- standard deviation. RESULTS: Carotid ultrafast ultrasound imaging PWV in healthy individuals was 5.6 +/- 1.2 in early systole and 7.3 +/- 2.0 m/s in end systole, and correlated with age (r = 0.48; P < 0.0001 and r = 0.68; P < 0.0001, respectively). Difference between early and end-systole PWV increased with age independently of blood pressure (r = 0.54; P < 0.0001). In patients with vEDS, ultrafast ultrasound imaging PWV was 6.0 +/- 1.5 in early systole and 6.7 +/- 1.5 m/s in end systole. Carotid stiffness change over the cardiac cycle was lower than in healthy people (0.021 vs. 0.057 m/s per mmHg; P = 0.0035). CONCLUSION: Ultrafast ultrasound imaging can evaluate carotid PWV and its variation over the cardiac cycle. This allowed to demonstrate the age induced increase of the arterial diastolic-systolic stiffening in healthy people and a lower stiffening in vEDS, both characterized by arterial complications. We believe that this easy-to-use technique could offer the opportunity to go beyond the diastolic PWV to better characterize arterial stiffness change with age or other collagen alterations. PMID- 26248324 TI - Inhibitors of dihydroceramide desaturase 1: Therapeutic agents and pharmacological tools to decipher the role of dihydroceramides in cell biology. AB - Dihydroceramide desaturase (Des1) is the last enzyme in the de novo synthesis of ceramides (Cer). It catalyzes the insertion of a double bond into dihydroceramides (dhCer) to convert them to Cer, both of which are further metabolized to more complex (dihydro) sphingolipids. For many years dhCer have received poor attention, mainly due to their supposed lack of biological activity. It was not until about ten years ago that the concept that dhCer might have regulatory roles in biology emerged for the first time. Since then, multiple publications have established that dhCer are implicated in a wide spectrum of biological processes. Physiological and pathophysiological functions of dhCer have been recently reviewed. In this review we will focus on the biochemical features of Des1 and on its inhibition by different compounds with presumably different modes of action. PMID- 26248325 TI - Synthetic lipids and their role in defining macromolecular assemblies. AB - Lipids have a variety of physiological roles, ranging from structural and biophysical contributions to membrane functions to signaling contributions in normal and abnormal physiology. This review highlights some of the contributions made by Robert Bittman to our understanding of lipid assemblies through the production of synthetic lipid analogs in the sterol, sphingolipid, and glycolipid classes. His contributions have included the development of a fluorescent cholesterol analog that shows strong functional analogies to cholesterol that has allowed live imaging of cholesterol distribution in living systems, to stereospecific synthetic approaches to both sphingolipid and glycolipid analogs crucial in defining the structure-activity relationships of lipid biological targets. PMID- 26248326 TI - Ceramide synthases in biomedical research. AB - Sphingolipid metabolism consists of multiple metabolic pathways that converge upon ceramide, one of the key molecules among sphingolipids (SLs). In mammals, ceramide synthesis occurs via N-acylation of sphingoid backbones, dihydrosphingosine (dhSo) or sphingosine (So). The reaction is catalyzed by ceramide synthases (CerS), a family of enzymes with six different isoforms, with each one showing specificity towards a restricted group of acyl-CoAs, thus producing ceramides (Cer) and dihydroceramides (dhCer) with different fatty acid chain lengths. A large body of evidence documents the role of both So and dhSo as bioactive molecules, as well as the involvement of dhCer and Cer in physiological and pathological processes. In particular, the fatty acid composition of Cer has different effects in cell biology and in the onset and progression of different diseases. Therefore, modulation of CerS activity represents an attractive target in biomedical research and in finding new treatment modalities. In this review, we discuss functional, structural and biochemical features of CerS and examine CerS inhibitors that are currently available. PMID- 26248327 TI - Perovskite Sr-Doped LaCrO3 as a New p-Type Transparent Conducting Oxide. AB - Epitaxial La1-x Srx CrO3 deposited on SrTiO3 (001) is shown to be a p-type transparent conducting oxide with competitive figures of merit and a cubic perovskite structure, facilitating integration into oxide electronics. Holes in the Cr 3d t2g bands play a critical role in enhancing p-type conductivity, while transparency to visible light is maintained because low-lying d-d transitions arising from hole doping are dipole forbidden. PMID- 26248328 TI - Associated Risk Factors of STIs and Multiple Sexual Relationships among Youths in Malawi. AB - BACKGROUND: Having unprotected sex with multiple sexual partners (MSP) is the greatest risk factor for human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs) among youths. Young people with MSPs are less likely to use a condom and the greater the risk for STIs. This study examines the associated risk factors of STIs and multiple sexual partnerships among youths aged 15-24 years. DATA AND METHODS: The Malawi Demographic Health Survey 2010 data was used. Out of a sample of 2,987 males and 9,559 females aged 15-24 years, 2,026 males and 6,470 females were considered in the study. Chi square test and logistic regression techniques were performed. Analysis was performed using Statistical Package for Social Sciences (SPSS) version 22. FINDINGS: The results indicate that 1,399 (69.0%) males and 2,290 (35.4%) females reported multiple sexual partnerships (MSP). Within the rural area, females (n = 1779) were more likely to report MSP than males (n = 1082) and within the urban areas, a higher proportion of females (n = 511) still reported MSP, with males (n = 316). About 78% rural females aged 20-24 years, and about 79% rural males aged 15-19 years reported MSP. The likelihood of MSP was higher among females in the poorest households (OR = 1.31), being married (OR = 5.71) and Catholic males (OR = 1.63), who were married (OR = 1.59). Catholic males (OR = 1.82) in the rural areas, who were married (OR = 1.80) and rural females in the northern region (OR = 1.26) were more likely to have MSP. The odds ratios were higher among urban females in the poorest (OR = 3.45) households who were married (OR = 4.22). CONCLUSIONS: Having more than one sexual partner increases the risk of STIs and sexuality education programs should be introduced that emphasize the danger that surrounds MSP. PMID- 26248329 TI - Specialist group therapy for psychological factors associated with firesetting: Evidence of a treatment effect from a non-randomized trial with male prisoners. AB - Despite huge societal costs associated with firesetting, no standardized therapy has been developed to address this hugely damaging behavior. This study reports the evaluation of the first standardized CBT group designed specifically to target deliberate firesetting in male prisoners (the Firesetting Intervention Programme for Prisoners; FIPP). Fifty-four male prisoners who had set a deliberate fire were referred for FIPP treatment by their prison establishment and psychologically assessed at baseline, immediately post treatment, and three months post treatment. Prisoners who were treatment eligible yet resided at prison establishments not identified for FIPP treatment were recruited as Treatment as Usual controls and tested at equivalent time-points. Results showed that FIPP participants improved on one of three primary outcomes (i.e., problematic fire interest and associations with fire), and made some improvement on secondary outcomes (i.e., attitudes towards violence and antisocial attitudes) post treatment relative to controls. Most notable gains were made on the primary outcome of fire interest and associations with fire and individuals who gained in this area tended to self-report more serious firesetting behavior. FIPP participants maintained all key improvements at three-month follow up. These outcomes suggest that specialist CBT should be targeted at those holding the most serious firesetting history. PMID- 26248330 TI - Retention of the Native Epigenome in Purified Mammalian Chromatin. AB - A protocol is presented for the isolation of native mammalian chromatin as fibers of 25-250 nucleosomes under conditions that preserve the natural epigenetic signature. The material is composed almost exclusively of histones and DNA and conforms to the structure expected by electron microscopy. All sequences probed for were retained, indicating that the material is representative of the majority of the genome. DNA methylation marks and histone marks resembled the patterns observed in vivo. Importantly, nucleosome positions also remained largely unchanged, except on CpG islands, where nucleosomes were found to be unstable. The technical challenges of reconstituting biochemical reactions with native mammalian chromatin are discussed. PMID- 26248331 TI - Neuronal Differentiation of Human Mesenchymal Stem Cells Using Exosomes Derived from Differentiating Neuronal Cells. AB - Exosomes deliver functional proteins and genetic materials to neighboring cells, and have potential applications for tissue regeneration. One possible mechanism of exosome-promoted tissue regeneration is through the delivery of microRNA (miRNA). In this study, we hypothesized that exosomes derived from neuronal progenitor cells contain miRNAs that promote neuronal differentiation. We treated mesenchymal stem cells (MSCs) daily with exosomes derived from PC12 cells, a neuronal cell line, for 1 week. After the treatment with PC12-derived exosomes, MSCs developed neuron-like morphology, and gene and protein expressions of neuronal markers were upregulated. Microarray analysis showed that the expression of miR-125b, which is known to play a role in neuronal differentiation of stem cells, was much higher in PC12-derived exosomes than in exosomes from B16-F10 melanoma cells. These results suggest that the delivery of miRNAs contained in PC12-derived exosomes is a possible mechanism explaining the neuronal differentiation of MSC. PMID- 26248332 TI - Molecular Characteristics of Disease-Causing and Commensal Staphylococcus lugdunensis Isolates from 2003 to 2013 at a Tertiary Hospital in Taiwan. AB - OBJECTIVES: Staphylococcus lugdunensis can cause community- and healthcare associated infections. This study investigated the molecular characteristics of S. lugdunensis isolates collected at our hospital and compared the characteristics of the infectious and commensal isolates. METHODS: We collected the S. lugdunensis isolates between 2003 and 2013. The antimicrobial resistance test, SCCmec typing, accessory gene regulator (agr) typing, pulsed-field gel electrophoresis (PFGE), and delta-like hemolysin activity were performed. RESULTS: In total, 118 S. lugdunensis isolates were collected, of which 67 (56.8%) were classified into the infection group and 51 (43.2%) into the commensal group. The oxacillin resistance rate was 36.4%. The most common SCCmec types were SCCmec types V (51.4%) and II (32.6%). In total, 34 pulsotypes were identified. The PFGE typing revealed five clones (pulsotypes A, J, M, N, and P) at our hospital. Pulsotypes A and N caused the spread of high oxacillin resistance. In total, 10.2% (12 of 118) of the isolates lacked delta-like hemolysin activity. Compared with the infection group, the commensal group showed a higher percentage of multiple drug resistance and carried a higher percentage of SCCmec type II (11 of 22, 50% and 3 of 21, 14.3%) and a lower percentage of SCCmec type V (8 of 22, 36.4% and 14 of 21, 66.7%). The commensal group (27 PFGE types) showed higher genetic diversity than did the infection group (20 PFGE types). No difference was observed in the distribution of the five main pulsotypes, agr typing, and the presence of delta-like hemolysin activity between the two groups. CONCLUSIONS: Five main clones were identified at our hospital. The commensal group showed higher genetic diversity, had a higher percentage of multidrug resistance, and carried a higher percentage of SCCmec type II and a lower percentage of SCCmec type V than did the infection group. PMID- 26248333 TI - Combined immunodeficiency in the United States and Kuwait: Comparison of patients' characteristics and molecular diagnosis. AB - AIM: To compare different variables among (S)CID patients diagnosed in the USA and Kuwait. METHODS: Review of patients registered in The US Immune Deficiency Network registry or Kuwait National PID Registry between 2004 and 2014. RESULTS: Totals of 98 and 69 (S)CID patients were registered during the study period in the USIDNET registry and the KNPIDR, respectively. The average annual incidence rate for the period 2004-2014 of (S)CID in children in Kuwait was 13.01/100,000 children, with an estimated occurrence of 1/7500 live births. There were differences between the two countries in the following variables: age at onset and diagnosis, family history of (S)CID, parental consanguinity, and outcome. More than 14% of (S)CID patients from USIDNET registry were diagnosed through newborn screening. CONCLUSIONS: Patients' characteristics and molecular causes of S(CID) are different between USA and Kuwait. NBS for SCID should be started in countries where the incidence of (S)CID is high. PMID- 26248334 TI - The Inner Membrane Protein PilG Interacts with DNA and the Secretin PilQ in Transformation. AB - Expression of type IV pili (Tfp), filamentous appendages emanating from the bacterial surface, is indispensable for efficient neisserial transformation. Tfp pass through the secretin pore consisting of the membrane protein PilQ. PilG is a polytopic membrane protein, conserved in Gram-positive and Gram-negative bacteria, that is required for the biogenesis of neisserial Tfp. PilG null mutants are devoid of pili and non-competent for transformation. Here, recombinant full-length, truncated and mutated variants of meningococcal PilG were overexpressed, purified and characterized. We report that meningococcal PilG directly binds DNA in vitro, detected by both an electromobility shift analysis and a solid phase overlay assay. PilG DNA binding activity was independent of the presence of the consensus DNA uptake sequence. PilG-mediated DNA binding affinity was mapped to the N-terminus and was inactivated by mutation of residues 43 to 45. Notably, reduced meningococcal transformation of DNA in vivo was observed when PilG residues 43 to 45 were substituted by alanine in situ, defining a biologically significant DNA binding domain. N-terminal PilG also interacted with the N-terminal region of PilQ, which previously was shown to bind DNA. Collectively, these data suggest that PilG and PilQ in concert bind DNA during Tfp-mediated transformation. PMID- 26248335 TI - Normal Human Lung Epithelial Cells Inhibit Transforming Growth Factor-beta Induced Myofibroblast Differentiation via Prostaglandin E2. AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with very few effective treatments. The key effector cells in fibrosis are believed to be fibroblasts, which differentiate to a contractile myofibroblast phenotype with enhanced capacity to proliferate and produce extracellular matrix. The role of the lung epithelium in fibrosis is unclear. While there is evidence that the epithelium is disrupted in IPF, it is not known whether this is a cause or a result of the fibroblast pathology. We hypothesized that healthy epithelial cells are required to maintain normal lung homeostasis and can inhibit the activation and differentiation of lung fibroblasts to the myofibroblast phenotype. To investigate this hypothesis, we employed a novel co culture model with primary human lung epithelial cells and fibroblasts to investigate whether epithelial cells inhibit myofibroblast differentiation. MEASUREMENTS AND MAIN RESULTS: In the presence of transforming growth factor (TGF)-beta, fibroblasts co-cultured with epithelial cells expressed significantly less alpha-smooth muscle actin and collagen and showed marked reduction in cell migration, collagen gel contraction, and cell proliferation compared to fibroblasts grown without epithelial cells. Epithelial cells from non-matching tissue origins were capable of inhibiting TGF-beta induced myofibroblast differentiation in lung, keloid and Graves' orbital fibroblasts. TGF-beta promoted production of prostaglandin (PG) E2 in lung epithelial cells, and a PGE2 neutralizing antibody blocked the protective effect of epithelial cell co culture. CONCLUSIONS: We provide the first direct experimental evidence that lung epithelial cells inhibit TGF-beta induced myofibroblast differentiation and pro fibrotic phenotypes in fibroblasts. This effect is not restricted by tissue origin, and is mediated, at least in part, by PGE2. Our data support the hypothesis that the epithelium plays a crucial role in maintaining lung homeostasis, and that damaged and/ or dysfunctional epithelium contributes to the development of fibrosis. PMID- 26248336 TI - Functional Characterization of NAC and MYB Transcription Factors Involved in Regulation of Biomass Production in Switchgrass (Panicum virgatum). AB - Switchgrass is a promising biofuel feedstock due to its high biomass production and low agronomic input requirements. Because the bulk of switchgrass biomass used for biofuel production is lignocellulosic secondary walls, studies on secondary wall biosynthesis and its transcriptional regulation are imperative for designing strategies for genetic improvement of biomass production in switchgrass. Here, we report the identification and functional characterization of a group of switchgrass transcription factors, including several NACs (PvSWNs) and a MYB (PvMYB46A), for their involvement in regulating secondary wall biosynthesis. PvSWNs and PvMYB46A were found to be highly expressed in stems and their expression was closely associated with sclerenchyma cells. Overexpression of PvSWNs and PvMYB46A in Arabidopsis was shown to result in activation of the biosynthetic genes for cellulose, xylan and lignin and ectopic deposition of secondary walls in normally parenchymatous cells. Transactivation and complementation studies demonstrated that PvSWNs were able to activate the SNBE driven GUS reporter gene and effectively rescue the secondary wall defects in the Arabidopsis snd1 nst1 double mutant, indicating that they are functional orthologs of Arabidopsis SWNs. Furthermore, we showed that PvMYB46A could activate the SMRE-driven GUS reporter gene and complement the Arabidopsis myb46 myb83 double mutant, suggesting that it is a functional ortholog of Arabidopsis MYB46/MYB83. Together, these results indicate that PvSWNs and PvMYB46A are transcriptional switches involved in regulating secondary wall biosynthesis, which provides molecular tools for genetic manipulation of biomass production in switchgrass. PMID- 26248337 TI - Inability to sustain intraphagolysosomal killing of Staphylococcus aureus predisposes to bacterial persistence in macrophages. AB - Macrophages are critical effectors of the early innate response to bacteria in tissues. Phagocytosis and killing of bacteria are interrelated functions essential for bacterial clearance but the rate-limiting step when macrophages are challenged with large numbers of the major medical pathogen Staphylococcus aureus is unknown. We show that macrophages have a finite capacity for intracellular killing and fail to match sustained phagocytosis with sustained microbial killing when exposed to large inocula of S. aureus (Newman, SH1000 and USA300 strains). S. aureus ingestion by macrophages is associated with a rapid decline in bacterial viability immediately after phagocytosis. However, not all bacteria are killed in the phagolysosome, and we demonstrate reduced acidification of the phagolysosome, associated with failure of phagolysosomal maturation and reduced activation of cathepsin D. This results in accumulation of viable intracellular bacteria in macrophages. We show macrophages fail to engage apoptosis-associated bacterial killing. Ultittop mately macrophages with viable bacteria undergo cell lysis, and viable bacteria are released and can be internalized by other macrophages. We show that cycles of lysis and reuptake maintain a pool of viable intracellular bacteria over time when killing is overwhelmed and demonstrate intracellular persistence in alveolar macrophages in the lungs in a murine model. PMID- 26248338 TI - Prognostic Nomogram for Patients with Nasopharyngeal Carcinoma after Intensity Modulated Radiotherapy. AB - This study was aimed to define possible predictors of overall survival in nasopharyngeal carcinoma (NPC). Patients were treated with intensity-modulated radiation therapy (IMRT), to establish an effective prognostic nomogram that could provide individualized predictions of treatment outcome in this setting. We reviewed the records of 533 patients with non-metastatic NPC who underwent IMRT with or without concurrent chemotherapy at the Department of Radiation Oncology of Sun Yat-Sen University from 2002 to 2009; none of these patients received induction or adjuvant chemotherapy. These data sets were used to construct a nomogram based on Cox regression. Nomogram performance was determined via a concordance index (C-index) and a calibration curve which was compared with the TNM staging system for NPC. The results were validated in an external cohort of 442 patients from the Department of Radiation Oncology of Wenzhou Medical College who were treated during the same period. Results showed that the greatest influence on survival were primary gross tumor volume, age, tumor stage and nodal stage (2002 Union for International Cancer Control [UICC] staging system), which were selected into the nomogram. The C-index of the nomogram for predicting survival was 0.748 (95%CI, 0.704-0.785), which was statistically higher than that of TNM staging system (0.684, P<0.001). The calibration curve exhibited agreement between nomogram-predicted and the actual observed probabilities for overall survival. In the validation cohort, the nomogram discrimination was superior to the TNM staging system (C-index: 0.768 vs 0.721; P = 0.026). In conclusion, the nomogram proposed in this study resulted in more-accurate prognostic prediction for patients with NPC after IMRT and compared favorably to the TNM staging system; this individualized information will aid in patient counseling and may be used for de-escalation trials in the future. PMID- 26248339 TI - Precocene II, a Trichothecene Production Inhibitor, Binds to Voltage-Dependent Anion Channel and Increases the Superoxide Level in Mitochondria of Fusarium graminearum. AB - Precocene II, a constituent of essential oils, shows antijuvenile hormone activity in insects and inhibits trichothecene production in fungi. We investigated the molecular mechanism by which precocene II inhibits trichothecene production in Fusarium graminearum, the main causal agent of Fusarium head blight and trichothecene contamination in grains. Voltage-dependent anion channel (VDAC), a mitochondrial outer membrane protein, was identified as the precocene II-binding protein by an affinity magnetic bead method. Precocene II increased the superoxide level in mitochondria as well as the amount of oxidized mitochondrial proteins. Ascorbic acid, glutathione, and alpha-tocopherol promoted trichothecene production by the fungus. These antioxidants compensated for the inhibitory activity of precocene II on trichothecene production. These results suggest that the binding of precocene II to VDAC may cause high superoxide levels in mitochondria, which leads to stopping of trichothecene production. PMID- 26248340 TI - Brain Localization and Neurotoxicity Evaluation of Polysorbate 80-Modified Chitosan Nanoparticles in Rats. AB - The toxicity evaluation of inorganic nanoparticles has been reported by an increasing number of studies, but toxicity studies concerned with biodegradable nanoparticles, especially the neurotoxicity evaluation, are still limited. For example, the potential neurotoxicity of Polysorbate 80-modified chitosan nanoparticles (Tween 80-modified chitosan nanoparticles, TmCS-NPs), one of the most widely used brain targeting vehicles, remains unknown. In the present study, TmCS-NPs with a particle size of 240 nm were firstly prepared by ionic cross linking of chitosan with tripolyphosphate. Then, these TmCS-NPs were demonstrated to be entered into the brain and specially deposited in the frontal cortex and cerebellum after systemic injection. Moreover, the concentration of TmCS-NPs in these two regions was found to decrease over time. Although no obvious changes were observed for oxidative stress in the in vivo rat model, the body weight was found to remarkably decreased in a dose-dependent manner after exposure to TmCS NPs for seven days. Besides, apoptosis and necrosis of neurons, slight inflammatory response in the frontal cortex, and decrease of GFAP expression in the cerebellum were also detected in mouse injected with TmCS-NPs. This study is the first report on the sub-brain biodistribution and neurotoxicity studies of TmCS-NPs. Our results provide new insights into the toxicity evaluation of nanoparticles and our findings would help contribute to a better understanding of the neurotoxicity of biodegradable nanomaterials used in pharmaceutics. PMID- 26248342 TI - Extra-articular implant stabilization for locked atlantoaxial fracture subluxation with intrusion on the vertebral artery: a new option in less-invasive C2 fracture repair. PMID- 26248341 TI - Receptor for Advanced Glycation End-Products Signaling Interferes with the Vascular Smooth Muscle Cell Contractile Phenotype and Function. AB - Increased blood glucose concentrations promote reactions between glucose and proteins to form advanced glycation end-products (AGE). Circulating AGE in the blood plasma can activate the receptor for advanced end-products (RAGE), which is present on both endothelial and vascular smooth muscle cells (VSMC). RAGE exhibits a complex signaling that involves small G-proteins and mitogen activated protein kinases (MAPK), which lead to increased nuclear factor kappa B (NF kappaB) activity. While RAGE signaling has been previously addressed in endothelial cells, little is known regarding its impact on the function of VSMC. Therefore, we hypothesized that RAGE signaling leads to alterations in the mechanical and functional properties of VSMC, which could contribute to complications associated with diabetes. We demonstrated that RAGE is expressed and functional in the A7r5 VSMC model, and its activation by AGE significantly increased NF-kappaB activity, which is known to interfere with the contractile phenotype of VSMC. The protein levels of the contraction-related transcription factor myocardin were also decreased by RAGE activation with a concomitant decrease in the mRNA and protein levels of transgelin (SM-22alpha), a regulator of VSMC contraction. Interestingly, we demonstrated that RAGE activation increased the overall cell rigidity, an effect that can be related to an increase in myosin activity. Finally, although RAGE stimulation amplified calcium signaling and slightly myosin activity in VSMC challenged with vasopressin, their contractile capacity was negatively affected. Overall, RAGE activation in VSMC could represent a keystone in the development of vascular diseases associated with diabetes by interfering with the contractile phenotype of VSMC through the modification of their mechanical and functional properties. PMID- 26248343 TI - Virus-host interactions: insights from the replication cycle of the large Paramecium bursaria chlorella virus. AB - The increasing interest in cytoplasmic factories generated by eukaryotic infecting viruses stems from the realization that these highly ordered assemblies may contribute fundamental novel insights to the functional significance of order in cellular biology. Here, we report the formation process and structural features of the cytoplasmic factories of the large dsDNA virus Paramecium bursaria chlorella virus 1 (PBCV-1). By combining diverse imaging techniques, including scanning transmission electron microscopy tomography and focused ion beam technologies, we show that the architecture and mode of formation of PBCV-1 factories are significantly different from those generated by their evolutionary relatives Vaccinia and Mimivirus. Specifically, PBCV-1 factories consist of a network of single membrane bilayers acting as capsid templates in the central region, and viral genomes spread throughout the host cytoplasm but excluded from the membrane-containing sites. In sharp contrast, factories generated by Mimivirus have viral genomes in their core, with membrane biogenesis region located at their periphery. Yet, all viral factories appear to share structural features that are essential for their function. In addition, our studies support the notion that PBCV-1 infection, which was recently reported to result in significant pathological outcomes in humans and mice, proceeds through a bacteriophage-like infection pathway. PMID- 26248344 TI - Erratum for "Long-term Visual Function and Patient Satisfaction After Bilateral Implantation and Combination of Two Similar Multifocal IOLs". PMID- 26248345 TI - Postoperative IOL Axial Movements and Refractive Changes After Femtosecond Laser assisted Cataract Surgery Versus Conventional Phacoemulsification. AB - PURPOSE: To evaluate intraocular lens (IOL) axial movements and refractive changes during a 6-month follow-up period after femtosecond laser-assisted cataract surgery and conventional cataract surgery, investigate the influence of capsulorhexis features on postoperative IOL axial changes, and assess the prediction error for both techniques. METHODS: Eighty eyes of 80 candidates for cataract extraction were randomized into two groups: femtosecond laser (40 eyes) and manual (40 eyes). RESULTS: The overall anterior chamber depth variation was significantly lower in the femtosecond laser group compared to the manual group during follow-up (P<.001). At 30 and 180 days postoperatively, the mean spherical equivalent showed a hyperopic shift (0.09+/-0.28 diopters [D]) in the femtosecond laser group and a myopic shift in the manual group (-0.25+/-0.18 D). Median absolute error was not significantly different between the two groups with standard formulas ranging between 0.29 and 0.64 (Hoffer Q) in the femtosecond laser group and between 0.24 (SRK-T) and 0.55 D (Hoffer Q) in the manual group. There was a significant lower deviation from intended versus achieved capsulotomy/capsulorhexis area in the femtosecond laser group (P<.001) compared to the manual group. The femtosecond laser group showed better IOL centration compared to the manual group at all time periods (P<.001). CONCLUSIONS: Femtosecond laser-assisted cataract surgery was related to a lower overall variability of anterior chamber depth compared to conventional cataract surgery with more stable postoperative refraction. The two techniques did not show significant differences of prediction error. PMID- 26248346 TI - Corneal Power Distribution and Functional Optical Zone Following Small Incision Lenticule Extraction for Myopia. AB - PURPOSE: To evaluate corneal power distribution using the ray tracing method (corneal power) in eyes undergoing small incision lenticule extraction (SMILE) surgery and compare the functional optical zone with two lenticular sizes. METHODS: This retrospective study evaluated 128 patients who underwent SMILE for the correction of myopia and astigmatism with a lenticular diameter of 6.5 mm (the 6.5-mm group) and 6.2 mm (the 6.2-mm group). The data include refraction, correction, and corneal power obtained via a Scheimpflug camera from the pupil center to 8 mm. The surgically induced changes in corneal power (Deltacorneal power) were compared to correction and Deltarefraction. The functional optical zone was defined as the largest ring diameter when the difference between the ring power and the pupil center power was 1.50 diopters or less. The functional optical zone was compared between two lenticular diameter groups. RESULTS: Corneal power distribution was measured by the ray tracing method. In the 6.5-mm group (n=100), Deltacorneal power at 5 mm showed the smallest difference from Deltarefraction and Deltacorneal power at 0 mm exhibited the smallest difference from correction. In the 6.2-mm group (n=28), Deltacorneal power at 2 mm displayed the lowest dissimilarity from Deltarefraction and Deltacorneal power at 4 mm demonstrated the lowest dissimilarity from correction. There was no significant difference between the mean postoperative functional optical zones in either group when their spherical equivalents were matched. CONCLUSIONS: Total corneal refactive power can be used in the evaluation of surgically induced changes following SMILE. A lenticular diameter of 6.2 mm should be recommended for patients with high myopia because there is no functional difference in the optical zone. PMID- 26248347 TI - Central PresbyLASIK for Hyperopia and Presbyopia Using Micro-monovision With the Technolas 217P Platform and SUPRACOR Algorithm. AB - PURPOSE: To analyze the refractive outcomes and satisfaction of presbyopic hyperopes treated with central presbyopicLASIK (presbyLASIK) with induced micro monovision. METHODS: This retrospective study included 74 eyes of 37 patients treated with central presbyLASIK with micro-monovision using the Technolas 217P excimer laser (Technolas Perfect Vision GmbH, Munich, Germany) between June 2011 and March 2014. Study parameters included uncorrected distance visual acuity (UDVA) and uncorrected near visual acuity (UNVA), aberrometry, the central steep zone, and patient satisfaction. RESULTS: Median age was 54.3+/-4 years (range: 46 to 63 years). Mean postoperative spherical equivalent refraction was 0.00+/-0.58 diopters (D) for dominant eyes and -0.51+/-0.54 D for non-dominant eyes. Mean binocular UDVA was 0.01+/-0.10 logMAR (Snellen 20/20) at 6 months and -0.01+/ 0.05 logMAR (Snellen 20/19) at 1 year postoperatively. Mean binocular UNVA was 0.18+/-0.14 logMAR (Parinaud 2) (Jaeger 1) at 6 months and 0.18+/-0.12 logMAR (Parinaud 2) (Jaeger 1) at 1 year postoperatively. At 6 months, 79.31% of patients achieved 20/25 and could read Parinaud 2 (Jaeger 1) binocularly. At 1 year, 84.21% of patients achieved 20/25 and could read Parinaud 2 (Jaeger 1) binocularly. The mean central steep zone was 2.35+/-1.00 D. There were significantly more negative spherical aberration and vertical coma in the central 5 mm postoperatively (P<.05). The re-treatment rate was 6.75%. Eighty-three percent of these patients did not need any glasses for distance and near vision. CONCLUSIONS: This procedure may improve functional near, intermediate, and distance vision in presbyopic patients with low and moderate hyperopia. PMID- 26248348 TI - Implantable Collamer Lens for Myopia: Assessment 12 Years After Implantation. AB - PURPOSE: To evaluate the long-term refractive and visual stability and the risks related to the implantation of Implantable Collamer Lens (ICL; STAAR Surgical, Monrovia, CA) phakic intraocular lens (PIOL) for myopia. METHODS: This retrospective, consecutive, cumulative clinical study was performed in a group of 144 eyes implanted with ICL PIOL for myopia. Only the cases with clinical data available 12 years after the implantation were included in the series. Corrected distance visual acuity (CDVA), uncorrected distance visual acuity, spherical equivalent, refractive astigmatism, endothelial cell density, ICL vaulting, and postoperative complications were analyzed. RESULTS: Mean spherical equivalent refraction was -16.90+/-4.26 diopters (D) preoperatively and -1.77+/-1.93 D 12 years postoperatively. Mean CDVA at the first and last visit were 0.31+/-0.19 logMAR and 0.22+/-0.22 logMAR, respectively (Mann-Whitney U test, P<.001). Twelve years postoperatively, 8.9% of eyes had lost more than two lines of CDVA. The incidence of clinically relevant cataracts (13.88%) was significantly linked to the use of the V3 model ICL (chi-square test, P=.007). During the follow-up period, a significant reduction in PIOL vaulting was observed (Kruskal-Wallis test, P<.05), and the mean endothelial cell density decreased by 19.75%. CONCLUSIONS: The ICL PIOL provided good refractive outcomes and stability in the long term. The incidence of cataracts is low when the latest models of this PIOL are used. PMID- 26248349 TI - Spontaneous Haptic Flexion and Misalignment of a New Microincisional Aspheric Intraocular Lens in the Early Postoperative Period in Two Patients. AB - PURPOSE: To present two cases of spontaneous haptic flexion and misalignment of a new single-piece microincisional aspheric intraocular lens (IOL) following uneventful microincisional phacoemulsification surgery and IOL implantation. METHODS: Case reports. RESULTS: Both patients had decreased visual acuity and significant myopia and astigmatism in their operated eye at the postoperative first month visit. On dilated biomicroscopic examination, flexion of one haptic was observed in both cases. In one of the cases, the misaligned IOL was explanted and a different posterior chamber IOL was implanted. In the other case, the misaligned IOL was repositioned. CONCLUSIONS: Cataract surgeons should be aware of the risk for haptic flexion and misalignment of this new IOL, causing decreased visual acuity and significant refractive error in the early postoperative period. Satisfactory results can be achieved by either IOL exchange or repositioning the IOL. PMID- 26248350 TI - Endophthalmitis Caused by Rhizobium radiobacter After Posterior Chamber Phakic Intraocular Lens Implantation to Correct Myopia. AB - PURPOSE: To describe a 29-year-old man presenting with acute-onset endophthalmitis caused by Rhizobium (formerly Agrobacterium) radiobacter after uneventful implantable collamer lens implantation for myopia. METHODS: Case report. RESULTS: The patient was treated with intravitreal injections of vancomycin and ceftazidime, as well as topical and systemic antibiotics. The patient had a good response with a final visual acuity of 20/50 at the last follow-up visit 25 months postoperatively. CONCLUSIONS: This case represents the first case report of endophthalmitis caused by Rhizobium radiobacter following implantable collamer lens implantation. PMID- 26248351 TI - Surgically Induced Astigmatism. PMID- 26248352 TI - Causes of Explantation of Phakic Intraocular Lenses. PMID- 26248353 TI - Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery. AB - Meropenem serves as a clinically important, broad-spectrum antibiotic. While meropenem is commonly used in obese patients, its pharmacokinetics in this patient group is not well known. Our aim was to characterize the population pharmacokinetics and target attainment in plasma, subcutaneous tissue, and peritoneal fluid for meropenem in morbidly obese patients. Four doses of 1g meropenem were given as 15-min infusions every 8 h to five morbidly obese patients (body mass index [BMI], 47.6 to 62.3 kg/m(2)). After the fourth dose, serial meropenem concentrations were determined in plasma and, via microdialysis, in subcutaneous tissue and peritoneal fluid. All concentrations were analyzed simultaneously via population modeling, and target attainment probabilities predicted via Monte Carlo simulations using the target of unbound meropenem concentrations above the MIC for at least 40% of the dosing interval. For patients with 53 kg fat-free mass, total clearance was 18.7 liters/h and volume of distribution at steady state was 27.6 liters. The concentrations in subcutaneous tissue and peritoneal fluid largely paralleled those in plasma (equilibration half-life, <30 min). The area under the curve (AUC) in subcutaneous tissue divided by the plasma AUC had a mean of 0.721. For peritoneal fluid, this AUC ratio had a mean of 0.943. Target attainment probabilities were >90% after 1 g meropenem every 8 h as a 15-min infusion for MICs of up to 2 mg/liter in plasma and peritoneal fluid and 0.5 mg/liter in subcutaneous tissue. Meropenem pharmacokinetics in plasma and peritoneal fluid of obese patients was predictable, but subcutaneous tissue penetration varied greatly. (This study has been registered at ClinicalTrials.gov under registration no. NCT01407965.). PMID- 26248354 TI - Complete Sequence of a bla(NDM-1)-Harboring Plasmid in an Acinetobacter bereziniae Clinical Strain Isolated in Argentina. PMID- 26248355 TI - In Vitro Activities of Tedizolid and Linezolid against Gram-Positive Cocci Associated with Acute Bacterial Skin and Skin Structure Infections and Pneumonia. AB - Tedizolid is a novel, expanded-spectrum oxazolidinone with potent activity against a wide range of Gram-positive pathogens. A total of 425 isolates of Gram positive bacteria were obtained consecutively from patients with acute bacterial skin and skin structure infections (ABSSSIs) or pneumonia. These isolates included methicillin-susceptible Staphylococcus aureus (MSSA) (n = 100), methicillin-resistant Staphylococcus aureus (MRSA) (n = 100), Streptococcus pyogenes (n = 50), Streptococcus agalactiae (n = 50), Streptococcus anginosus group (n = 75), Enterococcus faecalis (n = 50), and vancomycin-resistant enterococci (VRE) (Enterococcus faecium) (n = 50). The MICs of tedizolid and linezolid were determined by the agar dilution method. Tedizolid exhibited better in vitro activities than linezolid against MSSA (MIC90s, 0.5 versus 2 MUg/ml), MRSA (MIC90s, 0.5 versus 2 MUg/ml), S. pyogenes (MIC90s, 0.5 versus 2 MUg/ml), S. agalactiae (MIC90s, 0.5 versus 2 MUg/ml), Streptococcus anginosus group (MIC90s, 0.5 versus 2 MUg/ml), E. faecalis (MIC90s, 0.5 versus 2 MUg/ml), and VRE (MIC90s, 0.5 versus 2 MUg/ml). The tedizolid MICs against E. faecalis (n = 3) and VRE (n = 2) intermediate to linezolid (MICs, 4 MUg/ml) were 1 MUg/ml and 0.5 MUg/ml, respectively. The tedizolid MIC90s against S. anginosus, S. constellatus, and S. intermedius were 0.5, 1, and 0.5 MUg/ml, respectively, and the rates of susceptibility based on the U.S. FDA MIC interpretive breakpoints to the isolates were 16%, 28%, and 72%, respectively. Tedizolid exhibited 2- to 4-fold better in vitro activities than linezolid against a variety of Gram-positive cocci associated with ABSSSIs and pneumonia. The lower susceptibilities of tedizolid against isolates of S. anginosus and S. constellatus than against those of S. intermedius in Taiwan were noted. PMID- 26248356 TI - Telavancin for Acute Bacterial Skin and Skin Structure Infections, a Post Hoc Analysis of the Phase 3 ATLAS Trials in Light of the 2013 FDA Guidance. AB - Two phase 3 ATLAS trials demonstrated noninferiority of telavancin compared with vancomycin for complicated skin and skin structure infections. Data from these trials were retrospectively evaluated according to 2013 U.S. Food and Drug Administration (FDA) guidance on acute bacterial skin and skin structure infections. This post hoc analysis included patients with lesion sizes of >=75 cm(2) and excluded patients with ulcers or burns (updated all-treated population; n = 1,127). Updated day 3 (early) clinical response was defined as a >=20% reduction in lesion size from baseline and no rescue antibiotic. Updated test-of cure (TOC) clinical response was defined as a >=90% reduction in lesion size, no increase in lesion size since day 3, and no requirement for additional antibiotics or significant surgical procedures. Day 3 (early) clinical responses were achieved in 62.6% and 61.0% of patients receiving telavancin and vancomycin, respectively (difference, 1.7%, with a 95% confidence interval [CI] of -4.0% to 7.4%). Updated TOC visit cure rates were similar for telavancin (68.0%) and vancomycin (63.3%), with a difference of 4.8% (95% CI, -0.7% to 10.3%). Adopting current FDA guidance, this analysis corroborates previous noninferiority findings of the ATLAS trials of telavancin compared with vancomycin. PMID- 26248357 TI - Multicenter, Double-Blind, Randomized, Phase 2 Study Evaluating the Novel Antibiotic Cadazolid in Patients with Clostridium difficile Infection. AB - Cadazolid, a novel fluoroquinolone-oxazolidinone antibiotic, exhibits potent in vitro activity against Clostridium difficile, including the epidemic BI/NAP1/027 strain. This multicenter, randomized, double-blind, active reference group, phase 2 study evaluated the efficacy and safety of oral cadazolid in treatment of adult patients with C. difficile infection (CDI). Eligible patients with first occurrence/first recurrence of CDI were randomized 1:1:1:1 to 250, 500, or 1,000 mg cadazolid twice daily (BID) or oral 125 mg vancomycin four times daily (QID) for 10 days. The primary endpoint was clinical cure at test of cure (48 +/- 24 h after the end of treatment; modified intent-to-treat population), defined as resolution of diarrhea with no further CDI treatment required. Secondary endpoints included recurrence rate, sustained clinical response (clinical cure without recurrence), and time to diarrhea resolution. Of 84 patients enrolled, 20, 22, 20, and 22 received 250, 500, or 1,000 mg cadazolid BID or 125 mg vancomycin QID, respectively. The primary endpoint was achieved in 76.5% (80% confidence interval [CI], 58.4, 89.3), 80.0% (63.9, 91.0), 68.4% (51.1, 82.5), and 68.2% (52.3, 81.3) of patients, respectively. There was no evidence of a cadazolid dosage-dependent response. Each dosage of cadazolid resulted in a lower recurrence rate than with vancomycin (18.2 to 25.0% versus 50%). Consequently, higher sustained clinical response rates were observed with cadazolid (46.7 to 60.0%) than with vancomycin (33.3%). The times to diarrhea resolution were similar for cadazolid and vancomycin. Cadazolid was well tolerated, with no safety signal observed. The results of this phase 2 study support further clinical development of cadazolid. (This study has been registered in the United States at ClinicalTrials.gov under registration no. NCT01222702 and in Europe with the European Medicines Agency under registration no. EUDRA-CT 2010-020941 29.). PMID- 26248358 TI - New Insights Regarding Yeast Survival following Exposure to Liposomal Amphotericin B. AB - In vitro resistance to amphotericin B is an extremely rare event among pathogenic yeasts. However, in vivo response is sometimes reduced, resulting in an unfavorable outcome. Such adverse outcomes might be related to subfungicidal plasma concentrations. We aimed to clarify the mechanisms of liposomal amphotericin B (AMB-L; AmBisome)-induced lesions and the mechanisms responsible for yeast cell recovery following exposure at plasma concentrations. The physiological statuses developing following exposure to AMB-L at simulated plasma concentrations (20 to 0.1 mg/liter) and at a constant concentration (3 mg/liter) were assessed in a 24-h time course assay. Time-kill experiments also were carried out under the same AMB-L treatment conditions. Our results suggest that yeast cells develop compensatory responses related to membrane polarization, metabolic activity, and reactive oxygen species (ROS) production after exposure to high plasma concentrations (20 to 5 mg/liter) during the first 6 h; in the remaining 18 h, when exposed to lower concentrations, cells reveal almost full recovery with no evidence of fungicidal activity. In contrast, whenever cells are exposed to a constant concentration above the MIC, despite initially exhibiting compensatory stress responses, soon afterwards they exhibit membrane depolarization, a decrease of metabolic activity, increasing ROS production, and lastly, programmed cell death and necrosis, resulting in succumbing to AMB-L fungicidal effects. This study may represent a step forward in the support of AMB L use for clinical treatment of invasive fungal infections, since it demonstrates the importance of maintaining levels of AMB-L above the MIC in plasma and tissues to ensure it produces its fungicidal effects. PMID- 26248359 TI - A Novel Y319H Substitution in CYP51C Associated with Azole Resistance in Aspergillus flavus. AB - This study aimed to explore any mutation in the CYP51 gene conferring azole resistance in Aspergillus flavus. Two voriconazole-resistant and 45 voriconazole susceptible isolates were included in the study. Sequence analysis demonstrated a T1025C nucleotide change in CYP51C, resulting in the Y319H amino acid substitution in one resistant isolate. However, the earlier described T788G mutation in CYP51C conferring voriconazole resistance in A. flavus isolates was present in all isolates, irrespective of their susceptibility status. PMID- 26248360 TI - An Antifungal Benzimidazole Derivative Inhibits Ergosterol Biosynthesis and Reveals Novel Sterols. AB - Fungal infections are a leading cause of morbidity and death for hospitalized patients, mainly because they remain difficult to diagnose and to treat. Diseases range from widespread superficial infections such as vulvovaginal infections to life-threatening systemic candidiasis. For systemic mycoses, only a restricted arsenal of antifungal agents is available. Commonly used classes of antifungal compounds include azoles, polyenes, and echinocandins. Due to emerging resistance to standard therapies, significant side effects, and high costs for several antifungals, there is a need for new antifungals in the clinic. In order to expand the arsenal of compounds with antifungal activity, we previously screened a compound library using a cell-based screening assay. A set of novel benzimidazole derivatives, including (S)-2-(1-aminoisobutyl)-1-(3 chlorobenzyl)benzimidazole (EMC120B12), showed high antifungal activity against several species of pathogenic yeasts, including Candida glabrata and Candida krusei (species that are highly resistant to antifungals). In this study, comparative analysis of EMC120B12 versus fluconazole and nocodazole, using transcriptional profiling and sterol analysis, strongly suggested that EMC120B12 targets Erg11p in the ergosterol biosynthesis pathway and not microtubules, like other benzimidazoles. In addition to the marker sterol 14-methylergosta-8,24(28) dien-3beta,6alpha-diol, indicating Erg11p inhibition, related sterols that were hitherto unknown accumulated in the cells during EMC120B12 treatment. The novel sterols have a 3beta,6alpha-diol structure. In addition to the identification of novel sterols, this is the first time that a benzimidazole structure has been shown to result in a block of the ergosterol pathway. PMID- 26248362 TI - Exposure-Response Analyses for Tafenoquine after Administration to Patients with Plasmodium vivax Malaria. AB - Tafenoquine (TQ), a new 8-aminoquinoline with activity against all stages of the Plasmodium vivax life cycle, is being developed for the radical cure of acute P. vivax malaria in combination with chloroquine. The efficacy and exposure data from a pivotal phase 2b dose-ranging study were used to conduct exposure-response analyses for TQ after administration to subjects with P. vivax malaria. TQ exposure (i.e., area under the concentration-time curve [AUC]) and region (Thailand compared to Peru and Brazil) were found to be statistically significant predictors of clinical response based on multivariate logistic regression analyses. After accounting for region/country, the odds of being relapse free at 6 months increased by approximately 51% (95% confidence intervals [CI], 25%, 82%) for each 25-U increase in AUC above the median value of 54.5 MUg . h/ml. TQ exposure was also a significant predictor of the time to relapse of the infection. The final parametric, time-to-event model for the time to relapse, included a Weibull distribution hazard function, AUC, and country as covariates. Based on the model, the risk of relapse decreased by 30% (95% CI, 17% to 42%) for every 25-U increase in AUC. Monte Carlo simulations indicated that the 300-mg dose of TQ would provide an AUC greater than the clinically relevant breakpoint obtained in a classification and regression tree (CART) analysis (56.4 MUg . h/ml) in more than 90% of subjects and consequently result in a high probability of being relapse free at 6 months. This model-based approach was critical in selecting an appropriate phase 3 dose. (This study has been registered at ClinicalTrials.gov under registration no. NCT01376167.). PMID- 26248361 TI - Bactericidal Activity of Ceragenin CSA-13 in Cell Culture and in an Animal Model of Peritoneal Infection. AB - Ceragenins constitute a novel family of cationic antibiotics characterized by a broad spectrum of antimicrobial activities, which have mostly been assessed in vitro. Using a polarized human lung epithelial cell culture system, we evaluated the antibacterial activities of the ceragenin CSA-13 against two strains of Pseudomonas aeruginosa (PAO1 and Xen5). Additionally, the biodistribution and bactericidal activity of a CSA-13-IRDye 800CW derivate were assessed using an animal model of peritoneal infection after PAO1 challenge. In cell culture, CSA 13 bactericidal activities against PAO1 and Xen5 were higher than the activities of the human cathelicidin peptide LL-37. Increased CSA-13 activity was observed in polarized human lung epithelial cell cultures subjected to butyric acid treatment, which is known to increase endogenous LL-37 production. Eight hours after intravenous or intraperitoneal injection, the greatest CSA-13-IRDye 800CW accumulation was observed in mouse liver and kidneys. CSA-13-IRDye 800CW administration resulted in decreased bacterial outgrowth from abdominal fluid collected from animals subjected to intraperitoneal PAO1 infection. These observations indicate that CSA-13 may synergistically interact with antibacterial factors that are naturally present at mucosal surfaces and it maintains its antibacterial activity in the infected abdominal cavity. Cationic lipids such as CSA-13 represent excellent candidates for the development of new antibacterial compounds. PMID- 26248363 TI - Racial Differences in Clostridium difficile Infection Rates Are Attributable to Disparities in Health Care Access. AB - This study confirms previously reported racial differences in Clostridium difficile infection (CDI) rates in the United States and explores the nature of those differences. We conducted a retrospective study using the 2010 Nationwide Inpatient Sample, the largest all-payer database of hospital discharges in the United States. We identified hospital stays most likely to include antibiotic treatment for infections, based on hospital discharge diagnoses, and we examined how CDI rates varied, in an attempt to distinguish between genotypic and environmental racial differences. Logistic regressions for the survey design were used to test hypotheses. Among patients likely to have received antibiotics, white patients had higher CDI rates than black, Hispanic, Asian, and Native American patients (P < 0.0001). CDI rates increased with higher income levels and were higher for hospitalizations paid by private insurance versus those paid by Medicaid or classified as self-pay or free care (P < 0.0001). Among patients admitted from skilled nursing facilities, where racial bias in health care access is less, racial differences in CDI rates disappeared (P = 1.0). Infected patients did not show racial differences in rates of complicated CDI or death (P = 1.0). Although white patients had greater CDI rates than nonwhite patients, racial differences in CDI rates disappeared in a population for which health care access was presumed to be less racially biased. This provides evidence that apparent racial differences in CDI risks may represent health care access disparities, rather than genotypic differences. CDI represents a deviation from the paradigm that increased health care access is associated with less morbidity. PMID- 26248364 TI - Mutations in beta-Lactamase AmpC Increase Resistance of Pseudomonas aeruginosa Isolates to Antipseudomonal Cephalosporins. AB - Mutation-dependent overproduction of intrinsic beta-lactamase AmpC is considered the main cause of resistance of clinical strains of Pseudomonas aeruginosa to antipseudomonal penicillins and cephalosporins. Analysis of 31 AmpC-overproducing clinical isolates exhibiting a greater resistance to ceftazidime than to piperacillin-tazobactam revealed the presence of 17 mutations in the beta lactamase, combined with various polymorphic amino acid substitutions. When overexpressed in AmpC-deficient P. aeruginosa 4098, the genes coding for 20/23 of these AmpC variants were found to confer a higher (2-fold to >64-fold) resistance to ceftazidime and ceftolozane-tazobactam than did the gene from reference strain PAO1. The mutations had variable effects on the MICs of ticarcillin, piperacillin tazobactam, aztreonam, and cefepime. Depending on their location in the AmpC structure and their impact on beta-lactam MICs, they could be assigned to 4 distinct groups. Most of the mutations affecting the omega loop, the R2 domain, and the C-terminal end of the protein were shared with extended-spectrum AmpCs (ESACs) from other Gram-negative species. Interestingly, two new mutations (F121L and P154L) were predicted to enlarge the substrate binding pocket by disrupting the stacking between residues F121 and P154. We also found that the reported ESACs emerged locally in a variety of clones, some of which are epidemic and did not require hypermutability. Taken together, our results show that P. aeruginosa is able to adapt to efficacious beta-lactams, including the newer cephalosporin ceftolozane, through a variety of mutations affecting its intrinsic beta lactamase, AmpC. Data suggest that the rates of ESAC-producing mutants are >=1.5% in the clinical setting. PMID- 26248365 TI - Fluconazole and Voriconazole Resistance in Candida parapsilosis Is Conferred by Gain-of-Function Mutations in MRR1 Transcription Factor Gene. AB - Candida parapsilosis is the second most prevalent fungal agent causing bloodstream infections. Nevertheless, there is little information about the molecular mechanisms underlying azole resistance in this species. Mutations (G1747A, A2619C, and A3191C) in the MRR1 transcription factor gene were identified in fluconazole- and voriconazole-resistant strains. Independent expression of MRR1 genes harboring these mutations showed that G1747A (G583R) and A2619C (K873N) are gain-of-function mutations responsible for azole resistance, the first described in C. parapsilosis. PMID- 26248366 TI - Antimicrobial Susceptibility and SOS-Dependent Increase in Mutation Frequency Are Impacted by Escherichia coli Topoisomerase I C-Terminal Point Mutation. AB - Topoisomerase functions are required in all organisms for many vital cellular processes, including transcription elongation. The C terminus domains (CTD) of Escherichia coli topoisomerase I interact directly with RNA polymerase to remove transcription-driven negative supercoiling behind the RNA polymerase complex. This interaction prevents inhibition of transcription elongation from hypernegative supercoiling and R-loop accumulation. The physiological function of bacterial topoisomerase I in transcription is especially important for a rapid network response to an antibiotic challenge. In this study, Escherichia coli with a topA66 single nucleotide deletion mutation, which results in a frameshift in the TopA CTD, was shown to exhibit increased sensitivity to trimethoprim and quinolone antimicrobials. The topoisomerase I-RNA polymerase interaction and the SOS response to the antimicrobial agents were found to be significantly reduced by this topA66 mutation. Consequently, the mutation frequency measured by rifampin selection following SOS induction was diminished in the topA66 mutant. The increased antibiotic sensitivity for the topA66 mutant can be reversed by the expression of recombinant E. coli topoisomerase I but not by the expression of recombinant Mycobacterium tuberculosis topoisomerase I that has a nonhomologous CTD even though the recombinant M. tuberculosis topoisomerase I can restore most of the plasmid DNA linking number deficiency caused by the topA66 mutation. Direct interactions of E. coli topoisomerase I as part of transcription complexes are likely to be required for the rapid network response to an antibiotic challenge. Inhibitors of bacterial topoisomerase I functions and interactions may sensitize pathogens to antibiotic treatment and limit the mutagenic response. PMID- 26248367 TI - A simple, efficient, and sensitive method for simultaneous detection of anti-HIV drugs atazanavir, ritonavir, and tenofovir by use of liquid chromatography-tandem mass spectrometry. AB - In the treatment of HIV infection, a combination of anti-HIV drugs is commonly used in highly active antiretroviral therapy (HAART). One such combination recommended for clinical therapy consists of the two HIV protease inhibitors atazanavir and ritonavir and the HIV nucleotide reverse transcriptase inhibitor tenofovir. The detection of plasma and cell drug concentrations provides an assessment of actual drug exposure and patient compliance. We thus developed a simple, efficient, and sensitive method to simultaneously extract and detect these three drugs in plasma and peripheral blood mononuclear cells. The use of a liquid-liquid extraction followed by protein precipitation provided a simple process, yielding a high recovery rate for all three drugs in plasma (>92%) and in cells (>86%). The liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was able to detect 0.01, 0.25, and 2.5 pg (2, 50, and 500 pg/ml, respectively) in 5 MUl for atazanavir, ritonavir, and tenofovir, respectively. Validation of the method exhibited high precision and accuracy. This method was subsequently applied to a primate study to determine the concentrations of all three drugs in both plasma and cell samples. This validated method can be useful for an evaluation of drug concentrations in biological samples in an efficient and sensitive manner. PMID- 26248368 TI - Persister Development by Borrelia burgdorferi Populations In Vitro. AB - Doxycycline is an antibiotic commonly used to treat Lyme disease and other bacterial infections. The MIC and minimum bactericidal concentration (MBC) for Borrelia burgdorferi have been investigated by different groups but were experimentally established in this study as a function of input cell density. We demonstrated that B. burgdorferi treated in the stationary phase has a higher probability of regrowth following removal of antibiotic. In addition, we determined experimentally and mathematically that the spirochetes which persist posttreatment do not have a longer lag phase but exhibit a lower growth rate than untreated spirochetes. Finally, we found that treating the spirochetes by pulse dosing did not eliminate growth or reduce the persister population in vitro. From these data, we propose that B. burgdorferi persister development is stochastic and driven by slowed growth. PMID- 26248369 TI - The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir. AB - Malaria and HIV infection are coendemic in a large portion of the world and remain a major cause of morbidity and mortality. Growing resistance of Plasmodium species to existing therapies has increased the need for new therapeutic approaches. The Plasmodium glucose transporter PfHT is known to be essential for parasite growth and survival. We have previously shown that HIV protease inhibitors (PIs) act as antagonists of mammalian glucose transporters. While the PI lopinavir is known to have antimalarial activity, the mechanism of action is unknown. We report here that lopinavir blocks glucose uptake into isolated malaria parasites at therapeutically relevant drug levels. Malaria parasites depend on a constant supply of glucose as their primary source of energy, and decreasing the available concentration of glucose leads to parasite death. We identified the malarial glucose transporter PfHT as a target for inhibition by lopinavir that leads to parasite death. This discovery provides a mechanistic basis for the antimalarial effect of lopinavir and provides a direct target for novel drug design with utility beyond the HIV-infected population. PMID- 26248370 TI - Role of Interleukin-12 in Protection against Pulmonary Infection with Methicillin Resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a common pathogen associated with nosocomial pneumonia and is an increasing threat for severe community-acquired pneumonia. We have now investigated the role of interleukin-12 (IL-12) in protective immunity against lung infection with MRSA. The importance of IL-12 in protection from pulmonary MRSA infection was demonstrated by the finding that IL-12p35-deficient mice had a lower survival rate, higher bacterial burdens in lung and spleen, and decreased expression of interferon gamma (IFN gamma) in the lung compared to wild-type mice. These effects were completely reversed by replacement intranasal therapy with recombinant IL-12. Furthermore, exogenous IL-12 treatment of wild-type mice 24 h before pulmonary challenge with a lethal dose of MRSA significantly improved bacterial clearance and resulted in protection from death. The IL-12-treated mice had increased numbers of lung natural killer (NK) cells and neutrophils and higher levels of IFN-gamma in the lung and serum compared to untreated mice. The major source of IL-12-driven IFN gamma expression in the lung was the NK cell, and the direct target of pulmonary IFN-gamma was the lung macrophage, as shown using mice with a macrophage-specific defect in interferon gamma (IFN-gamma) signaling (MIIG mice). Importantly, combination therapy with linezolid and IL-12 following intranasal MRSA infection significantly increased survival compared to that of mice receiving linezolid or IL-12 alone. These results indicate that IL-12-based immunotherapy may hold promise for treatment of MRSA pneumonia. PMID- 26248371 TI - Modulation of ccrAB Expression and SCCmec Excision by an Inverted Repeat Element and SarS in Methicillin-Resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a notorious human pathogen that can cause a broad spectrum of infections. MRSA strains are resistant to almost the entire family of beta-lactam antibiotics due to the acquisition of staphylococcal cassette chromosome mec (SCCmec). The chromosome cassette recombinases A and B, encoded by ccrAB genes located on SCCmec, play a key role in the excision of SCCmec. Studies have shown that ccrAB genes are expressed in only a minority of cells, suggesting the involvement of a subtle regulatory mechanism in ccrAB expression which has not been uncovered. Here, we found that an inverted repeat (IR) element, existing extensively and conservatively within the ccrAB promoter of different SCCmec types, played a repressive role in ccrAB expression and SCCmec excision in MRSA strain N315. Replacement of the IR sequence led to a significant increase in ccrAB expression and curing of SCCmec from strain N315 cells. In addition, we identified the transcriptional regulator SarS using DNA-affinity chromatography and further demonstrated that SarS can bind to the IR sequence and upregulate ccrAB expression and SCCmec excision. These findings reveal a molecular mechanism regulating ccrAB expression and SCCmec excision and may provide mechanic insights into the lateral transfer of SCCmec and spread of antibiotic resistance in S. aureus. PMID- 26248372 TI - Amikacin Concentrations Predictive of Ototoxicity in Multidrug-Resistant Tuberculosis Patients. AB - Aminoglycosides, such as amikacin, are used to treat multidrug-resistant tuberculosis. However, ototoxicity is a common problem and is monitored using peak and trough amikacin concentrations based on World Health Organization recommendations. Our objective was to identify clinical factors predictive of ototoxicity using an agnostic machine learning method. We used classification and regression tree (CART) analyses to identify clinical factors, including amikacin concentration thresholds that predicted audiometry-confirmed ototoxicity among 28 multidrug-resistant pulmonary tuberculosis patients in Botswana. Amikacin concentrations were measured for all patients. The quantitative relationship between predictive factors and the probability of ototoxicity were then identified using probit analyses. The primary predictors of ototoxicity on CART analyses were cumulative days of therapy, followed by cumulative area under the concentration-time curve (AUC), which improved on the primary predictor by 87%. The area under the receiver operating curve was 0.97 on the test set. Peak and trough were not predictors in any tree. When algorithms were forced to pick peak and trough as primary predictors, the area under the receiver operating curve fell to 0.46. Probit analysis revealed that the probability of ototoxicity increased sharply starting after 6 months of therapy to near maximum at 9 months. A 10% probability of ototoxicity occurred with a threshold cumulative AUC of 87,232 days . mg . h/liter, while that of 20% occurred at 120,000 days . mg . h/liter. Thus, cumulative amikacin AUC and duration of therapy, and not peak and trough concentrations, should be used as the primary decision-making parameters to minimize the likelihood of ototoxicity in multidrug-resistant tuberculosis. PMID- 26248373 TI - The Flavonoid Isoliquiritigenin Reduces Lung Inflammation and Mouse Morbidity during Influenza Virus Infection. AB - The host response to influenza virus infection is characterized by an acute lung inflammatory response in which intense inflammatory cell recruitment, hypercytokinemia, and a high level of oxidative stress are present. The sum of these events contributes to the virus-induced lung damage that leads to high a level of morbidity and mortality in susceptible infected patients. In this context, we identified compounds that can simultaneously reduce the excessive inflammatory response and the viral replication as a strategy to treat influenza virus infection. We investigated the anti-inflammatory and antiviral potential activities of isoliquiritigenin (ILG). Interestingly, we demonstrated that ILG is a potent inhibitor of influenza virus replication in human bronchial epithelial cells (50% effective concentration [EC50] = 24.7 MUM). In addition, our results showed that this molecule inhibits the expression of inflammatory cytokines induced after the infection of cells with influenza virus. We demonstrated that the anti-inflammatory activity of ILG in the context of influenza virus infection is dependent on the activation of the peroxisome proliferator-activated receptor gamma pathway. Interestingly, ILG phosphate (ILG-p)-treated mice displayed decreased lung inflammation as depicted by reduced cytokine gene expression and inflammatory cell recruitment. We also demonstrated that influenza virus-specific CD8(+) effector T cell recruitment was reduced up to 60% in the lungs of mice treated with ILG-p (10 mg/kg) compared to that in saline-treated mice. Finally, we showed that administration of ILG-p reduced lung viral titers and morbidity of mice infected with the PR8/H1N1 virus. PMID- 26248374 TI - Addressing Therapeutic Options for Ebola Virus Infection in Current and Future Outbreaks. AB - Ebola virus can cause severe hemorrhagic disease with high fatality rates. Currently, no specific therapeutic agent or vaccine has been approved for treatment and prevention of Ebola virus infection of humans. Although the number of Ebola cases has fallen in the last few weeks, multiple outbreaks of Ebola virus infection and the likelihood of future exposure highlight the need for development and rapid evaluation of pre- and postexposure treatments. Here, we briefly review the existing and future options for anti-Ebola therapy, based on the data coming from rare clinical reports, studies on animals, and results from in vitro models. We also project the mechanistic hypotheses of several potential drugs against Ebola virus, including small-molecule-based drugs, which are under development and being tested in animal models or in vitro using various cell types. Our paper discusses strategies toward identifying and testing anti-Ebola virus properties of known and medically approved drugs, especially those that can limit the pathological inflammatory response in Ebola patients and thereby provide protection from mortality. We underline the importance of developing combinational therapy for better treatment outcomes for Ebola patients. PMID- 26248375 TI - Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice. AB - Based on a previously derived population pharmacokinetic model, a novel neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (<3 mg/liter) and peak (>24 mg/liter) levels. Second, all observed TDM concentrations were compared with model-predicted concentrations, whereby the results of a normalized prediction distribution error (NPDE) were considered. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (i.e., prescription errors and disease characteristics of outliers) were explored. In 579 neonates (median birth body weight, 2,285 [range, 420 to 4,850] g; postnatal age 2 days [range, 1 to 30 days]; gestational age, 34 weeks [range, 24 to 41 weeks]), 90.5% of the observed early peak levels reached 24 mg/liter, and 60.2% of the trough levels were <3 mg/liter (93.4% <=5 mg/liter). Observations were accurately predicted by the model without bias, which was confirmed by the NPDE. Monte Carlo simulations showed that peak concentrations of >24 mg/liter were reached at steady state in almost all patients. Trough values of <3 mg/liter at steady state were documented in 78% to 100% and 45% to 96% of simulated cases with and without ibuprofen coadministration, respectively; suboptimal trough levels were found in patients with postnatal age <14 days and current weight of >2,000 g. Prospective evaluation of a model-based neonatal amikacin dosing regimen resulted in optimized peak and trough concentrations in almost all patients. Slightly adapted dosing for patient subgroups with suboptimal trough levels was proposed. This model-based approach improves neonatal dosing individualization. PMID- 26248376 TI - Elevated Expression of GlpT and UhpT via FNR Activation Contributes to Increased Fosfomycin Susceptibility in Escherichia coli under Anaerobic Conditions. AB - Because a shortage of new antimicrobial agents is a critical issue at present, and with the spread of multidrug-resistant (MDR) pathogens, the use of fosfomycin to treat infections is being revisited as a "last-resort option." This drug offers a particular benefit in that it is more effective against bacteria growing under oxygen-limited conditions, unlike other commonly used antimicrobials, such as fluoroquinolones and aminoglycosides. In this study, we showed that Escherichia coli strains, including enterohemorrhagic E. coli (EHEC), were more susceptible to fosfomycin when grown anaerobically than when grown aerobically, and we investigated how the activity of this drug was enhanced during anaerobic growth of E. coli. Our quantitative PCR analysis and a transport assay showed that E. coli cells grown under anaerobic conditions had higher levels of expression of glpT and uhpT, encoding proteins that transport fosfomycin into cells with their native substrates, i.e., glycerol-3-phosphate and glucose-6 phosphate, and led to increased intracellular accumulation of the drug. Elevation of expression of these genes during anaerobic growth requires FNR, a global transcriptional regulator that is activated under anaerobic conditions. Purified FNR bound to DNA fragments from regions upstream of glpT and uhpT, suggesting that it is an activator of expression of glpT and uhpT during anaerobic growth. We concluded that the increased antibacterial activity of fosfomycin toward E. coli under anaerobic conditions can be attributed to elevated expression of GlpT and UhpT following activation of FNR, leading to increased uptake of the drug. PMID- 26248377 TI - Effects of Zidovudine Treatment on Heart mRNA Expression and Mitochondrial DNA Copy Number Associated with Alterations in Deoxynucleoside Triphosphate Composition in a Neonatal Rat Model. AB - The prevention of mother-to-child transmission (MTCT) of HIV is a crucial component in HIV therapy. Nucleoside reverse transcriptase inhibitors (NRTIs), primarily 3'-azido-3'-thymidine (AZT [zidovudine]), have been used to treat both mothers and neonates. While AZT is being replaced with less toxic drugs in treating mothers in MTCT prevention, it is still commonly used to treat neonates. Problems related to mitochondrial toxicity and potential mutagenesis associated with AZT treatment have been reported in treated cohorts. Yet little is known concerning the metabolism and potential toxicity of AZT on embryonic and neonatal tissues, especially considering that the enzymes of nucleoside metabolism change dramatically as many tissues convert from hyperplastic to hypertrophic growth during this period. AZT is known to inhibit thymidine phosphorylation and potentially alter deoxynucleoside triphosphate (dNTP) pools in adults. This study examines the effects of AZT on dNTP pools, mRNA expression of deoxynucleoside/deoxynucleotide metabolic enzymes, and mitochondrial DNA levels in a neonatal rat model. Results show that AZT treatment dramatically altered dNTP pools in the first 7 days of life after birth, which normalized to age matched controls in the second and third weeks. Additionally, AZT treatment dramatically increased the mRNA levels of many enzymes involved in deoxynucleotide synthesis and mitochondrial biogenesis during the first week of life, which normalized to age-matched controls by the third week. These results were correlated with depletion of mitochondrial DNA noted in the second week. Taken together, results demonstrated that AZT treatment has a powerful effect on the deoxynucleotide synthesis pathways that may be associated with toxicity and mutagenesis. PMID- 26248378 TI - Pharmacokinetics of Antituberculosis Drugs in HIV-Positive and HIV-Negative Adults in Malawi. AB - Limited data address the impact of HIV coinfection on the pharmacokinetics (PK) of antituberculosis drugs in sub-Saharan Africa. A total of 47 Malawian adults underwent rich pharmacokinetic sampling at 0, 0.5, 1, 2, 3, 4, 6, 8, and 24 h postdose. Of the subjects, 51% were male, their mean age was 34 years, and 65% were HIV-positive with a mean CD4 count of 268 cells/MUl. Antituberculosis drugs were administered as fixed-dose combinations (150 mg rifampin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol) according to recommended weight bands. Plasma drug concentrations were determined by high-performance liquid chromatography (rifampin and pyrazinamide) or liquid chromatography-mass spectrometry (isoniazid and ethambutol). Data were analyzed by noncompartmental methods and analysis of variance of log-transformed summary parameters. The pharmacokinetic parameters were as follows (median [interquartile range]): for rifampin, maximum concentration of drug in plasma (Cmax) of 4.129 MUg/ml (2.474 to 5.596 MUg/ml), area under the curve from 0 to 24 h (AUC0-infinity) of 21.32 MUg/ml . h (13.57 to 28.60 MUg/ml . h), and half-life of 2.45 h (1.86 to 3.08 h); for isoniazid, Cmax of 3.97 MUg/ml (2.979 to 4.544 MUg/ml), AUC0-24 of 22.5 (14.75 to 34.59 MUg/ml . h), and half-life of 3.93 h (3.18 to 4.73 h); for pyrazinamide, Cmax of 34.21 MUg/ml (30.00 to 41.60 MUg/ml), AUC0-24 of 386.6 MUg/ml . h (320.0 to 463.7 MUg/ml . h), and half-life of 6.821 h (5.71 to 8.042 h); and for ethambutol, Cmax of 2.278 MUg/ml (1.694 to 3.098 MUg/ml), AUC0-24 of 20.41 MUg/ml . h (16.18 to 26.27 MUg/ml . h), and half-life of 7.507 (6.517 to 8.696 h). The isoniazid PK data analysis suggested that around two-thirds of the participants were slow acetylators. Dose, weight, and weight-adjusted dose were not significant predictors of PK exposure, probably due to weight-banded dosing. In this first pharmacokinetic study of antituberculosis drugs in Malawian adults, measures of pharmacokinetic exposure were comparable with those of other studies for all first-line drugs except for rifampin, for which the Cmax and AUC0-24 values were notably lower. Contrary to some earlier observations, HIV status did not significantly affect the AUC of any of the drugs. Increasing the dose of rifampin might be beneficial in African adults, irrespective of HIV status. Current co-trimoxazole prophylaxis was associated with an increase in the half life of isoniazid of 41% (P = 0.022). Possible competitive interactions between isoniazid and sulfamethoxazole mediated by the N-acetyltransferase pathway should therefore be explored further. PMID- 26248379 TI - In Vitro and In Vivo Effects of the Bumped Kinase Inhibitor 1294 in the Related Cyst-Forming Apicomplexans Toxoplasma gondii and Neospora caninum. AB - We report on the in vitro effects of the bumped kinase inhibitor 1294 (BKI-1294) in cultures of virulent Neospora caninum isolates Nc-Liverpool (Nc-Liv) and Nc Spain7 and in two strains of Toxoplasma gondii (RH and ME49), all grown in human foreskin fibroblasts. In these parasites, BKI-1294 acted with 50% inhibitory concentrations (IC50s) ranging from 20 nM (T. gondii RH) to 360 nM (N. caninum Nc Liv), and exposure of intracellular stages to 1294 led to the nondisjunction of newly formed tachyzoites, resulting in the formation of multinucleated complexes similar to complexes previously observed in BKI-1294-treated N. caninum beta galactosidase-expressing parasites. However, such complexes were not seen in a transgenic T. gondii strain that expressed CDPK1 harboring a mutation (G to M) in the gatekeeper residue. In T. gondii ME49 and N. caninum Nc-Liv, exposure of cultures to BKI-1294 resulted in the elevated expression of mRNA coding for the bradyzoite marker BAG1. Unlike in bradyzoites, SAG1 expression was not repressed. Immunofluorescence also showed that these multinucleated complexes expressed SAG1 and BAG1 and the monoclonal antibody CC2, which binds to a yet unidentified bradyzoite antigen, also exhibited increased labeling. In a pregnant mouse model, BKI-1294 efficiently inhibited vertical transmission in BALB/c mice experimentally infected with one of the two virulent isolates Nc-Liv or Nc Spain7, demonstrating proof of concept that this compound protected offspring from vertical transmission and disease. The observed deregulated antigen expression effect may enhance the immune response during BKI-1294 therapy and will be the subject of future studies. PMID- 26248380 TI - Antimicrobial Peptide Novicidin Synergizes with Rifampin, Ceftriaxone, and Ceftazidime against Antibiotic-Resistant Enterobacteriaceae In Vitro. AB - The spread of antibiotic resistance among Gram-negative bacteria is a serious clinical threat, and infections with these organisms are a leading cause of mortality worldwide. Traditional novel drug development inevitably leads to the emergence of new resistant strains, rendering the new drugs ineffective. Therefore, reviving the therapeutic potentials of existing antibiotics represents an attractive novel strategy. Novicidin, a novel cationic antimicrobial peptide, is effective against Gram-negative bacteria. Here, we investigated novicidin as a possible antibiotic enhancer. The actions of novicidin in combination with rifampin, ceftriaxone, or ceftazidime were investigated against 94 antibiotic resistant clinical Gram-negative isolates and 7 strains expressing New Delhi metallo-beta-lactamase-1. Using the checkerboard method, novicidin combined with rifampin showed synergy with >70% of the strains, reducing the MICs significantly. The combination of novicidin with ceftriaxone or ceftazidime was synergistic against 89.7% of the ceftriaxone-resistant strains and 94.1% of the ceftazidime-resistant strains. Synergistic interactions were confirmed using time kill studies with multiple strains. Furthermore, novicidin increased the postantibiotic effect when combined with rifampin or ceftriaxone. Membrane depolarization assays revealed that novicidin alters the cytoplasmic membrane potential of Gram-negative bacteria. In vitro toxicology tests showed novicidin to have low hemolytic activity and no detrimental effect on cell cultures. We demonstrated that novicidin strongly rejuvenates the therapeutic potencies of ceftriaxone or ceftazidime against resistant Gram-negative bacteria in vitro. In addition, novicidin boosted the activity of rifampin. This strategy can have major clinical implications in our fight against antibiotic-resistant bacterial infections. PMID- 26248381 TI - Characterization of an Enterobacter cloacae Strain Producing both KPC and NDM Carbapenemases by Whole-Genome Sequencing. AB - A carbapenem-resistant Enterobacter cloacae strain, WCHECl-14653, causing a fatal bloodstream infection, was characterized by genome sequencing and conjugation experiments. The strain carried two carbapenemase genes, blaNDM-1 and blaKPC-2, on separate IncF plasmids. The coexistence of blaNDM-1 and blaKPC-2 conferred slightly higher-level carbapenem resistance compared with that of blaNDM-1 or blaKPC-2 alone, and the coexistence of two IncF plasmids may generate new platforms for spreading carbapenemase genes. PMID- 26248383 TI - Characterization of a Novel Putative Xer-Dependent Integrative Mobile Element Carrying the bla(NMC-A) Carbapenemase Gene, Inserted into the Chromosome of Members of the Enterobacter cloacae Complex. AB - An Enterobacter ludwigii strain was isolated during routine screening of a Japanese patient for carriage of carbapenem-resistant Enterobacteriaceae. PCR analysis revealed the blaNMC-A carbapenemase gene. Whole-genome sequencing revealed that blaNMC-A was inserted in the chromosome and associated with a novel 29.1-kb putative Xer-dependent integrative mobile element, named EludIMEX-1. Bioinformatic analysis identified similar elements in the genomes of an Enterobacter asburiae strain and of other Enterobacter cloacae complex strains, confirming the mobile nature of this element. PMID- 26248382 TI - Key Residues of Outer Membrane Protein OprI Involved in Hexamer Formation and Bacterial Susceptibility to Cationic Antimicrobial Peptides. AB - Antimicrobial peptides (AMPs) are important components of the host innate defense mechanism against invading pathogens. Our previous studies have shown that the outer membrane protein, OprI from Pseudomonas aeruginosa or its homologue, plays a vital role in the susceptibility of Gram-negative bacteria to cationic alpha helical AMPs (Y. M. Lin, S. J. Wu, T. W. Chang, C. F. Wang, C. S. Suen, M. J. Hwang, M. D. Chang, Y. T. Chen, Y. D. Liao, J Biol Chem 285:8985-8994, 2010, http://dx.doi.org/10.1074/jbc.M109.078725; T. W. Chang, Y. M. Lin, C. F. Wang, Y. D. Liao, J Biol Chem 287:418-428, 2012, http://dx.doi.org/10.1074/jbc.M111.290361). Here, we obtained two forms of recombinant OprI: rOprI-F, a hexamer composed of three disulfide-bridged dimers, was active in AMP binding, while rOprI-R, a trimer, was not. All the subunits predominantly consisted of alpha-helices and exhibited rigid structures with a melting point centered around 76 degrees C. Interestingly, OprI tagged with Escherichia coli signal peptide was expressed in a hexamer, which was anchored on the surface of E. coli, possibly through lipid acids added at the N terminus of OprI and involved in the binding and susceptibility to AMP as native P. aeruginosa OprI. Deletion and mutation studies showed that Cys1 and Asp27 played a key role in hexamer formation and AMP binding, respectively. The increase of OprI hydrophobicity upon AMP binding revealed that it undergoes conformational changes for membrane fusion. Our results showed that OprI on bacterial surfaces is responsible for the recruitment and susceptibility to amphipathic alpha helical AMPs and may be used to screen antimicrobials. PMID- 26248384 TI - Detection of a New cfr-Like Gene, cfr(B), in Enterococcus faecium Isolates Recovered from Human Specimens in the United States as Part of the SENTRY Antimicrobial Surveillance Program. AB - Two linezolid-resistant Enterococcus faecium isolates (MICs, 8 MUg/ml) from unique patients of a medical center in New Orleans were included in this study. Isolates were initially investigated for the presence of mutations in the V domain of 23S rRNA genes and L3, L4, and L22 ribosomal proteins, as well as cfr. Isolates were subjected to pulsed-field gel electrophoresis (just one band difference), and one representative strain was submitted to whole-genome sequencing. Gene location was also determined by hybridization, and cfr genes were cloned and expressed in a Staphylococcus aureus background. The two isolates had one out of six 23S rRNA alleles mutated (G2576T), had wild-type L3, L4, and L22 sequences, and were positive for a cfr-like gene. The sequence of the protein encoded by the cfr-like gene was most similar (99.7%) to that found in Peptoclostridium difficile, which shared only 74.9% amino acid identity with the proteins encoded by genes previously identified in staphylococci and non-faecium enterococci and was, therefore, denominated Cfr(B). When expressed in S. aureus, the protein conferred a resistance profile similar to that of Cfr. Two copies of cfr(B) were chromosomally located and embedded in a Tn6218 similar to the cfr carrying transposon described in P. difficile. This study reports the first detection of cfr genes in E. faecium clinical isolates in the United States and characterization of a new cfr variant, cfr(B). cfr(B) has been observed in mobile genetic elements in E. faecium and P. difficile, suggesting potential for dissemination. However, further analysis is necessary to access the resistance levels conferred by cfr(B) when expressed in enterococci. PMID- 26248385 TI - Antimicrobial Susceptibility Profiles of Staphylococcus aureus Isolates Recovered from Humans, Environmental Surfaces, and Companion Animals in Households of Children with Community-Onset Methicillin-Resistant S. aureus Infections. AB - Our objective was to determine the antibiotic susceptibility profiles of Staphylococcus aureus isolates recovered from 110 households of children with community-onset methicillin-resistant S. aureus (MRSA) infections. Cultures were obtained from household members, household objects, and dogs and cats, yielding 1,633 S. aureus isolates. The S. aureus isolates were heterogeneous, although more than half were methicillin resistant. The highest proportion of MRSA was found in bathrooms. The majority of isolates were susceptible to antibiotics prescribed in outpatient settings. PMID- 26248387 TI - Role models and social supports related to adolescent physical activity and overweight/obesity. AB - Positive role models, social and community activities, and school support are protective social factors that promote youth health and well-being. Latino, African-American, Asian, multi-racial, and low-income adolescents are less likely to experience these protective social factors compared to other groups, which may contribute to health disparities. Adolescents who identify a role model, volunteer, participate in organizations outside of school, or experience high levels of teacher or other adult support at school engage in greater physical activity and are more likely to have a healthy weight. Strategies to increase these protective social factors among adolescents could help promote healthy weight and healthy behaviors. PMID- 26248388 TI - Civilian Health and Medical Program of the Uniformed Services (CHAMPUS)/TRICARE: Refills of Maintenance Medications Through Military Treatment Facility Pharmacies or National Mail Order Pharmacy Program. Interim final rule. AB - This interim final rule implements Section 702 (c) of the Carl Levin and Howard P. "Buck" McKeon National Defense Authorization Act for Fiscal Year 2015 which states that beginning October 1, 2015, the pharmacy benefits program shall require eligible covered beneficiaries generally to refill non-generic prescription maintenance medications through military treatment facility pharmacies or the national mail-order pharmacy program. Section 702(c) of the National Defense Authorization Act for Fiscal Year 2015 also terminates the TRICARE For Life Pilot Program on September 30, 2015. The TRICARE For Life Pilot Program described in Section 716 (f) of the National Defense Authorization Act for Fiscal Year 2013, was a pilot program which began in March 2014 requiring TRICARE For Life beneficiaries to refill non-generic prescription maintenance medications through military treatment facility pharmacies or the national mail order pharmacy program. TRICARE for Life beneficiaries are those enrolled in the Medicare wraparound coverage option of the TRICARE program. This interim rule includes procedures to assist beneficiaries in transferring covered prescriptions to the mail order pharmacy program. This regulation is being issued as an interim final rule in order to comply with the express statutory intent that the program begin October 1, 2015. Public comments, however, are invited and will be considered for possible revisions to this rule for the second year of the program. PMID- 26248389 TI - Final Priority and Definitions; Demonstration and Training Program: Career Pathways for Individuals With Disabilities. Final priority and definitions. AB - The Assistant Secretary for Special Education and Rehabilitative Services announces a priority designed to demonstrate promising practices in the use of career pathways to improve employment outcomes for individuals with disabilities. Specifically, this priority will establish model demonstration projects that engage State vocational rehabilitation (VR) agencies in partnerships with other entities to develop and use career pathways to help individuals with disabilities eligible for VR services, including youth with disabilities, acquire necessary marketable skills and recognized postsecondary credentials. The Assistant Secretary may use this priority for competitions in fiscal year (FY) 2015 and later years. PMID- 26248390 TI - Medicare Program; Inpatient Rehabilitation Facility Prospective Payment System for Federal Fiscal Year 2016. Final rule. AB - This final rule updates the prospective payment rates for inpatient rehabilitation facilities (IRFs) for federal fiscal year (FY) 2016 as required by the statute. As required by section 1886(j)(5) of the Act, this rule includes the classification and weighting factors for the IRF PPS's case-mix groups and a description of the methodologies and data used in computing the prospective payment rates for FY 2016. This final rule also finalizes policy changes, including the adoption of an IRF-specific market basket that reflects the cost structures of only IRF providers, a 1-year phase-in of the revised wage index changes, a 3-year phase-out of the rural adjustment for certain IRFs, and revisions and updates to the quality reporting program (QRP). PMID- 26248391 TI - Medicare Program; FY 2016 Hospice Wage Index and Payment Rate Update and Hospice Quality Reporting Requirements. Final rule. AB - This final rule will update the hospice payment rates and the wage index for fiscal year (FY) 2016 (October 1, 2015 through September 30, 2016), including implementing the last year of the phase-out of the wage index budget neutrality adjustment factor (BNAF). Effective on January 1, 2016, this rule also finalizes our proposals to differentiate payments for routine home care (RHC) based on the beneficiary's length of stay and implement a service intensity add-on (SIA) payment for services provided in the last 7 days of a beneficiary's life, if certain criteria are met. In addition, this rule will implement changes to the aggregate cap calculation mandated by the Improving Medicare Post-Acute Care Transformation Act of 2014 (IMPACT Act), align the cap accounting year for both the inpatient cap and the hospice aggregate cap with the federal fiscal year starting in FY 2017, make changes to the hospice quality reporting program, clarify a requirement for diagnosis reporting on the hospice claim, and discuss recent hospice payment reform research and analyses. PMID- 26248392 TI - Foreword to the proceedings of the "Selye Symposium - 2013", held at the Hungarian Academy of Sciences, Budapest, Hungary, May 8, 2013. PMID- 26248393 TI - Looking forward. Women surgeons: challenges; role models; leadership. PMID- 26248394 TI - What's next? The future of Medicare physician payment in the post-SGR era. PMID- 26248395 TI - The American Board of Surgery Maintenance of Certification Program: The first 10 years. PMID- 26248396 TI - The Hartford Consensus III: Implementation of Bleeding Control--If you see something do something. PMID- 26248397 TI - Profiles in surgical research: Dorry L. Segev, MD, PhD, FACS. PMID- 26248398 TI - Quality and Resource Use Reports. PMID- 26248399 TI - The North Dakota RUral Surgery Support Program: Providing surgical services to communities in need. PMID- 26248400 TI - Multimodality treatment considerations in esophageal and gastric cancer: Are we making progress? PMID- 26248401 TI - The College standardizes surgical dressings. PMID- 26248402 TI - TST: The right operation, on the right patient, in the right location. PMID- 26248403 TI - NTDB datapoints: all smoke, no fire. PMID- 26248404 TI - Addressing the source of surgeon burnout. PMID- 26248405 TI - PreOp program applauded. PMID- 26248406 TI - 2015 Leadership program: Leading with influence and overcoming resistance to change. PMID- 26248407 TI - Why are you here? To lead, to advocate, and to connect. PMID- 26248408 TI - 2015 Advocacy program: Attendees learn the power of a unified voice. PMID- 26248409 TI - [The effects of DEHP on morphology and function of progenitor Leydig cell in rat]. AB - OBJECTIVE: To investigate the effects and mechanisms of diethylhexylphthalate (DEHP) on morphology and function of progenitor Leydig cells (PLC) in rats. METHODS: Twenty pregnant SD rats were randomly divided into 4 groups ( n = 5): normal control group, DEHP low dose group , middle dose group, and high dose group, which were treated from postnatal day (PND) 1 to PND 21 of the pubs with DEHP at the doses of 0, 10, 100, 750 mg/(kg . d) in 0.5 ml of corn oil by gavage respectively. At the end of the treatment, the male pups were killed and blood samples were collected for determination of serum testosterone concentration by chemiluminescence method. The body weight, testis weight and anogenital distance (AGD) were measured. The morphology of PLC was observed by light and transmission electron microscopy. The protein expression of steroidogenic acute regulatory protein(StAR) in PLC was determined by immunohistochemistry. The mRNA expression of insulin-like growth factor-I (IGF-I) in the testis was assayed by real-time PCR. RESULTS: Compared with normal control group, the serum testosterone and AGD of male pubs from the middle and high dose groups were declined significantly (P < 0.01), the testis weight and body weight from high dose group were decreased significantly (P < 0.01), while the testis weight increased in the low dose group (P < 0.05). Under light microscope, PLC showed hyperplasia and cluster aggregation in the low dose group and focal hyperplasia in the middle and high dose group. The spermatogenic cells in seminiferous tubules showed decrease, apoptosis and unfix in the high dose group. Under transmission electron microscope, the PLC showed decreased lipid droplets, smooth endoplasmic reticulum and mitochondriae in the treated group. The mRNA expression of IGF-I increased in the low dose group, and the protein expression of StAR decreased in the middle and high dose group. CONCLUSION: Lactating exposure to DEHP may interfere with the synthesis of testosterone of PLC in male pubs, the decrease of StAR and the damage of PLC may be involved in it. PMID- 26248410 TI - [Effects of hydroxyl acetylated curcumin induced sonodynamic therapy on viability, apoptosis and necrosis of THP-1 macrophages]. AB - OBJECTIVE: We aim to investigate the sonodynamic effect induced by hydroxyl acetylated curcumin (HAC) on THP-1 macrophages. METHODS: THP-1 derived macrophages (1 x 10(5) per milliliter) were cultured with HAC at a concentration of 5 ug/mL for 4 h and then exposed to pulse ultrasound treatment (0.5 W/cm2) for 5 min. Six hours later, cell viability analysis was performed with CCK-8 assay, apoptosis and necrosis analysis were detected with Annexin V/PI staining by flow cytometery. RESULTS: The cell viability of THP-1 macrophage decreased significantly in the group treated with the combination of HAC and ultrasound (P < 0.01), and HAC-SDT induced both apoptosis and necrosis in THP-1 macrophages, the apoptotic rate was higher than the necrotic rate with appropriate conditions, the maximum apoptosis/necrosis ratio was detected in sonodynamic therapy (SDT) group (P < 0.01). CONCLUSION: hAC-SDT was effective to induce THP-1 macrophages apoptosis. PMID- 26248411 TI - [Effect of Volatile Oil of Radix Angelicae Sinensis on experimental asthma in rats]. AB - OBJECTIVE: To study the effects of Volatile Oil of Radix Angelicae Sinensis (VOA) on experimental asthma in rat model based on abnormal immune functions of Treg cells. METHODS: After grouping, the asthmatic rats were developed through injecting OVA and AI(OH)3 for sensitization and then administering OVA aerosol for challenge, and the respiratory functions, asthmatic behaviors, IL-10 levels in bronchoalveolar lavage fluid (BALF) (ELISA) and Foxp3 expression (immunohistochemistry) in lung of asthmatic rats were observed. RESULTS: VOA at the doses of 40-160 mg/kg could improve the respiratory functions and the asthmatic behaviors, and upgrade IL-10 levels in BALF and Foxp3 expression in lung of asthmatic rats. CONCLUSION: VOA has some effects of anti-asthma and one of the mechanisms is to improving the lower immune functions of Treg cells. PMID- 26248412 TI - [Effect of reactive oxygen species induced by paraquat on neutrophil apoptosis]. AB - OBJECTIVE: To investigate the effect of paraquat (PQ) on reactive oxygen species (ROS) and neutrophil apoptosis and its possible signal transduction pathways. METHODS: Cultured neutrophils were treated with different concentrations of PQ for 6-24 h. The apoptosis rate of neutrophils and ROS content were determined by flow cytometry. The exoressions of nuclear factor kappa B (NF-kappaB) and Caspase 3 were detected by Western blot. These parameters were checked again after NF kappaB and Caspase 3 antagonist were applied. RESULTS: PQ could boost ROS generation and depress neutrophil apoptosis significantly. At the same time PQ could enhance the expression of NF-kappaB and inhibit the expression of Caspase 3. These effects could be reversed by ROS inhibitor diphenyleneiodonium (DPI) and NF-kappaB inhibitor pyrrolidinedithiocarbamate (PDTC). CONCLUSION: PQ is a potent inducer of ROS and can inhibit neutrophil apoptosis by activating NF-kappaB and surpressing Caspase 3 activity. PMID- 26248413 TI - [Effects of the new compound codonopsis tablets on brain performance capacity of youth at high altitude]. PMID- 26248414 TI - [Effects of polydatin on learning and memory and Cdk5 kinase activity in the hippocampus of rats with chronic alcoholism]. AB - OBJECTIVE: To observe the effects of polydatin on learning and memory and cyclin dependent kinase 5 (Cdk5) kinase activity in the hippocampus of rats with chronic alcoholism. METHODS: Forty rats were randomly divided into 4 groups: control group, chronic alcoholism group, low and high polydatin group. The rat chronic alcoholism model was established by ethanol 3.0 g/(kg . d) (intragastric administration). The abstinence scoring was used to evaluate the rats withdrawal symptoms; cognitive function was measured by Morris water maze experiment; Cdk5 protein expression in the hippocampus was detected by immunofluorescence; Cdk5 kinase activity in the hippocampus was detected by liquid scintillation counting method. RESULTS: The abstinence score, escape latency, Cdk5 kinase activity in chronic alcoholism group rats were significantly higher than those of control group (P < 0.05). The abstinence score, escape latency in high polydatin group rats were significantly lower than those of chronic alcoholism group (P < 0.05); Cdk5 kinase activity in high and low polydatin group rats was significantly lower than that of chronic alcoholism group( P < 0.05); immunofluorescence showed that the Cdk5 positive cells of chronic alcoholism group were significantly increased compared with control group (P < 0.05), and the Cdk5 positive cells of polydatin groups were significantly decreased compared with chronic alcoholism group ( P < 0.05). CONCLUSION: Polydatin-reduced the chronic alcoholism damage may interrelate with regulation of Cdk5 kinase activity. PMID- 26248415 TI - [The protection of scorpion venom derived activity peptide against the change of dynorphin in the early Parkinson's disease rats]. PMID- 26248416 TI - [Effect of Oxymatrine on cardiac function and left ventricular remodeling in rabbits after acute myocardial infarction]. AB - OBJECTIVE: To observe the effect of Oxymatrine on left cardiac function and ventricular remodeling in rabbits after acute myocardial infarction. METHODS: Ligation of the left anterior descending artery was adopted to establish acute myocardial infarction model, forty eight rabbits were randomized into the sham operation group, model group and Oxymatrine group. Eight models were successfully established in each group. the sham operation group and model group were given conventional feed. Oxymatrine were gavage administration 0.5 ml/100 g, once a day, lasted for 4 weeks. Respectively in postoperative week, and three weeks, to observe the Oxymatrine on cardiac output (CO), left ventricular end systolic pressure (LVESP), left ventricular end-diastolic pressure (LVEDP), left indoor pressure change rate peak (dp/dtmax)), and left ventricular cavity internal diameter (D), ventricular weight index (VWI), ventricular weight (VW). RESULTS: Left ventricular anterior wall was from red to deep purple, electrocardiogram showed II guide ST-segment camber up >= 0.25 mv. Postoperative week in Oxymatrine group compared with model group, LVESP increased significantly (P < 0.01), LVEDP decreased obviously (P < 0.01); After three weeks in Oxymatrine group compared with model group, VW, VWI decreased (P < 0.05), D significantly reduced (P < 0.01); LVESP increased significantly (P < 0.01), LVEDP decreased obviously (P <0.01); dp/dt(max), CO increased (P < 0.05). CONCLUSION: After acute myocardial infarction in rabbit Oxymatrine can improve the left ventricular reconstruction parameters, increase cardiac output, and improve cardiac function. PMID- 26248417 TI - [Research on expression of miRNA-21 in the peripheral blood of coronary heart disease and its clinical significance]. AB - OBJECTIVE: To study the expression difference in MicroRNA-21 (miRNA-21) levels of the plasma between the patients with coronary heart disease and the subjects without coronary artery lesions, and its clinical significance. METHODS: Plasma was obtained from the patients with coronary heart disease(trial group,56 cases) and the subjects without coronary artery lesions(control group, 10 cases), patients with coronary disease were divided into angina(AP, 39 cases) and acute myocardial infarction(AMI, 17 cases)subgroup, the contents of miRNA-21 were detected using qRT-PCR method, and the differential expression of miRNA-21 in each group was analyzed. The levels of creatine kinase isoenzyme (CK-MB), high sensitive troponin I(cTnI), B type natriuretic peptide urea (BNP), Gensini, left ventricular ejection fraction (LVEF), integral value of coronary left ventricular end diastole diameter (LV) and homocysteine (HCY) were determined and the correlation between miRNA-21 and these clinical indexes was analyzed. RESULTS: Compared with control group, there was a significant difference in expression of miRNA-21 in patients with angina and AMI (P < 0.05), and miRNA-21 expression in AMI group was much higher than that in AP group. There was statistical significance in CK, CK-MB, cTnI, Genisis integral comparison between AMI group and control group (P < 0.05). The correlation analysis showed that there was a positive correlation between expression of CK, CK-MB, cTnI and the level of circulating miRNA-21 in patients with acute myocardial infarction. And there was a negative correlation between BNP, Gensini integral, LVEF value of coronary artery, LV and circulating miRNA-21. CONCLUSION: miRNA-21 was significantly elevated in acute myocardial infarction subgroup than the control group. The level of miRNA-21 associates with the degree of coronary artery stenosis, and might be a potential marker for the diagnosis of acute myocardial infarction. miRNA-21 may play an important role in protecting myocardium from ischemia/reperfusion injury. PMID- 26248418 TI - [The influences of ultrafiltration and alcohol sedimentation on protective effects of Radix Astragali and Radix Hedyseri against rat's cerebral ischemia]. AB - OBJECTIVE: To investigate the influences of ultrafiltration and alcohol sedimentation on protective effects of Radix Astragali and Radix Hedyseri against rat's cerebral ischemia. METHODS: Using dexamethasone (im.) and ligating common carotid artery, the rat stasis model combined transient cerebral ischemia was established to evaluate the effects of the ultrafiltration and alcohol sedimentation through detecting antioxidant system and other indexes in brain tissue. RESULTS: The results showed that the 6 g/kg water extract(crude drug), ultrafiltration and alcohol sedimentation of Radix Astragali and Radix Hedyseri could upgrade adenosine-triphosphate (ATP), superoxide dismutase (SOD) and catalase (CAT), and degrade malondialdehyde(MDA) and water content of brain tissue in rat stasis model combined transient cerebral ischemia, the water extract and ultrafiltration of them could degrade lactic acid (LD) of brain tissue, and the effects of alcohol sedimentation of Radix Astragali and Radix Hedyseri become weaker than water extract of them. CONCLUSION: The water extract, ultrafiltration and alcohol sedimentation of Radix Astragali and Radix Hedyseri have some protective effects on cerebral ischemia in rats, the effective differences of the extract through the same extraction method are not remarkable, and alcohol precipitation method has obvious influences effect on Radix Astragali and Radix Hedyseri. PMID- 26248419 TI - [Effect of 3-n-butylphthalide pretreatment on expression of the HSP70 after brain ischemia/reperfusion]. AB - OBJECTIVE: To explore the effect of 3-n-butylphthalide pretreatment on the delayed neuronal death(DND) and the expreesion of heat shock protein70 (HSP70) in rat hippocampus after ischemia/ reperfusion. METHODS: All rats were randomly divided into sham group (n = 36), total cerebral ischemia (TCI) group (n = 36), butylphthalide (NBP) group (n = 6), NBP + TCI group( n = 36), quercetin + NBP + TCI group (n = 6), dimethyl sulfoxide (DMSO) + NBP + TCI group (n = 6). The model of total cerebral ischemia/reperfusion was established by blocking vertebral arteries and carotid arteries. In sham group, TCI group and NBP group, the animals were further divided into instantly, 6 h, 12 h, 1 d, 3 d, 5 d groups according to the time interval after sham operation or TCI. Histological changes of the hippocampus were evaluated using thionin staining under light microscope by determining the delayed neuronal death (DND) and the expression of HSP70 was assayed using immunohistochemistry. RESULTS: NBP pretreatment could reduce delayed neuronal death in CA1 of hippocampus induced by TCI-reperfusion injury in rats, and up-regulated the expression of HSP70 in CA1 hippocampus of brain ischemic/reperfusion for 5 days. Quercetin blocked the acquirement of the brain ischemic tolerance induced by NBP preconditioning. CONCLUSION: 3-n-butylphthalide (NBP) prevents the neurons from ischemia/reperfusion injury through upregulating the expression of HSP70. PMID- 26248420 TI - [Effect of light source on microleakage of composite resin]. PMID- 26248421 TI - [Effects of midazolam on hERG K+ channel]. AB - OBJECTIVE: To investigate the effect of midazolam on human ether-a-go-go (hERG) K+ channels exogenously expressed in human embryonic kidney cells (HEK-293) and the underlying molecular mechanisms. METHODS: Whole-cell patch clamp technique was used to record WT, Y652A and F656C hERG K+ current expressed in HEK-293 cells. RESULTS: Midazolam inhibited hERG K+ current in a concentration-dependent manner, the half-maximum block concentrations (IC50) values were (1.31 +/- 0.32) umol/L. The half-activation voltage (V1/2) were (2.32 +/- 0.38) mV for the control and (-1.96 +/- 0.83) mV for 1.0 umol/L midazolam. The half-inactivation voltage (V1/2) was slightly shifted towards negative voltages from (-49.25 +/- 0.69) mV in control to (-57.53 +/- 0.53) mV after 1.0 umol/L midazolam (P < 0.05). Mutations in drug-binding sites (Y652A or F656C) of the hERG channel significantly attenuated the hERG current blockade by midazolam. CONCLUSION: Midazolam can block hERG K+ channel and cause the speed of inactivation faster. Mutations in the drug-binding sites (Y652 or F656) of the hERG channel were found to attenuate hERG current blockage by midazolam. PMID- 26248422 TI - [Protective effects and mechanisms of rich selenium Banqiao codonopsis pilosula on myocardial ischemia/reperfusion injury in rats]. PMID- 26248423 TI - [The significance of quantitative temperature sense thresholds in diagnosis of small fibrous sensory neuropathy in patients with type 2 diabetes]. AB - OBJECTIVE: To evaluate the small fiber function in patients with type 2 diabetes mellitus of the early stage by measuring the sensory threshold with the quantitative temperature testing technology. METHODS: Twenty cases of patients with type 2 diabetes with no neurological deficit (DM group) and twenty age and sex-matched healthy controls underwent the detecting of cold sensory threshold (CST), warm sensory threshold (WST), cold pain threshold (CPT), heat pain threshold (HPT) in both inside of their hands. RESULTS: There was no significant difference in CST, WST, CPT and HPT between left and right inside of hand of the same sample among all the testers. But the four kinds of threshold showed significant difference in the right inside of hand between patients and healthy people ( P < 0.05). In addition, the CST and WST differed significantly in the left inside of hand between the patients and healthy controls while the CPT and HPT showed no significant difference in the left inside of hand between them. Patients group and control group with CST and WST on the left side of the comparison difference was statistically significant (P < 0.05). CONCLUSION: Quantitative analysis of temperature sense threshold can not only reflect increase of the pain threshold value, also can reflect its decrease, i. e. hyperalgesia, which may help to diagnose small fibrous peripheral neuropathy recognition, especially in early diabetic peripheral neuropathy. PMID- 26248424 TI - [Establishment and evaluation of methods for determinating cystic fibrosis transmembrane conductance regulator quantitatively]. AB - OBJECTIVE: To establish and evaluate a BA-ELISA method for the quantitative detection of cystic fibrosis transmembrane conductance regulator (CFTR) protein. METHODS: We deliberately selected three tables of CFTR and made the synthetic peptide be expressed in E. coli, then used the antigen to immunize rabbits to obtain the anti-CFTR polyclonal serum. After that, 96 well plates were coated with the purified antibody against CFTR. The antigen CFTR which was extracted from human sperm was detected by anti-CFTR antibody labeled with biotin, horseradish peroxidase conjugated avidin, and the substrate. The concentrations of two kinds of antibodies and the experiment parameters were optimized. Thereby, the double antibody sandwich BA-ELISA method for the quantitative detection of CFTR protein was established. Furthermore, the reproducibility, specificity and so on were evaluated by clinical specimens of sperm. RESULTS: The optimal concentration of coated anti-CFTR IgG was 4 ug/ml, while the biotin labeled anti CFTR IgG was 10 ug/ml; the optimal blocking buffer was 1% BSA-PBST, the optimal time of the reaction between antigen and antibody was 60 min, the optimal chromogenic time was 15 min, the intra-assay and inter-assay coefficient were 2.16%-9.23% and 2.29%-11.71% respectively; The lowest detectable limit was 0.15 ng/ml; the standard curve had a good linear correlation of R2 = 0.962. CONCLUSION: The BA-ELISA method for the quantitative detection of CTFR protein is successfully established, and it is demonstrated that the method has strong specificity, high sensitivity and good reproducibility. It provides the basis and evidence of the further application of the method. PMID- 26248425 TI - [Effects of long-term Tai Ji Quan exercise on automatic nervous modulation in the elderly]. AB - OBJECTIVE: To examine the effects of long-term Tai Ji Quan (Chinnese Traditional Exercise) on automatic nervous modulation in the elders. METHODS: The 18 subjects from Tai Ji Quan exercise class in Liaoning University of Retired Veteran Cadres were assigned into long-term Tai Ji Quan exercise group including 10 subjects and novice group including 8 subjects. Electrocardiography, respiratory and blood pressure data were collected on the following time points: at rest before Tai Ji Qhuan exercise and 30 min or 60 min after Tai Ji Quan exercise. RESULTS: The subjects at rest state in the long-term Tai Ji Quan exercise group showed higher than the subjects in the novice group in resperitory rate (RR), standard deviations of normal to normal intervals (SDNN), total power (TP), low frequency power (LFP), high frequency power (HFP), normalized high frequency power (nHFP), but lower in LFP/HFP, systolic and diastolic blood pressure, and heart rate. At rest state the respiratory rate of subjects in long-term Tai Ji Quan exercise group was significantly lower than the novices. After Tai Ji Quan exercise, TP, nHFP, LFP/HFP, heart rate and systolic pressure showed significantly changes, and the change level of Tai Ji Quan on these indices was larger in Tai Ji Quan exercise group than that in the novice group. CONCLUSION: Long-term Tai Ji Quan exercise can improve vagal modulations, and tend to reduce the sympathetic modulations. PMID- 26248426 TI - [Research on complexity feature of cardiac reserve mobilization trend under stress conditions]. PMID- 26248427 TI - [Study of anti-aging effect and its mechanism of total saponins of Wu-He Dipsacus asper on skin of mouse-aging model]. AB - OBJECTIVE: To Study the effect of anti-aging and its mechanism of total saponins of Wu-He Dipsacus asper on skin of mice-aging model. METHODS: Forty-eight mice were randomly divided into blank control group, model group, low-Dipsacus group, medium-Dipsacus group, high-Dipsacus group and positive control group( n = 8) . The mouse model of skin aging was established by nape subcutaneous injection of 5% D-galactose (0.025 mL/(g . d)), the mouse of low-Dipsacus group, medium Dipsacus group, high-Dipsacus group were administered with total saponins of Wu He Dipsacus asper (50 ml/(kg . d), 100 mL/(kg . d), 200 mL/(kg . d)), the mice of the positive control group were administered with vitamin E(50 mg/(kg . d)) for 42 d. The content of hydroxyproline (HYP) and lipofuscin (LF) were measured in skin of each group mice, the activity of catalase (CAT) glutathione peroxidase ( GSH-Px) superoxide dismutase (SOD) and the content of malondi- aldehyde (MDA) were determined in serum and skin of each group mice. RESULTS: Compared with blank control group, the content of HYP decreased significantly and the content of LF increased significantly in skin, the activities of CAT, GSH-Px and SOD decreased significantly and the content of MDA increased significantly in serum and skin of model group; Compared with model group, the content of HYP increased significantly and the content of LF decreased significantly in skin, the activities of CAT, GSH-Px and SOD enhanced significantly and the con- tent of MDA decreased significantly in serum and skin of low-Dipsacus group, medium-Dipsacus group, high-Dipsacus group and positive control group; Compared with low-Dipsacus group, the content of HYP increased significantly and the content of LF decreased significantly in skin, the activities of CAT, GSH-Px and SOD enhanced significantly and the content of MDA decreased significantly in serum and skin of high-Dipsacus group and positive control group; The activity of SOD in serum and skin had a significant positive correlation with the content of HYP, and a significant negative correlation with LF in skin. CONCLUSION: Total saponins of Wu-He Dipsacus asper have obvious effect of anti-agng on skin of mouse-aging model , its mechanism is closely related to oxidative damage. PMID- 26248428 TI - [Effects of Jiji decoction on the cognitive function and oxidative stress in mice with vascular dementia induced by cerebral ischemia/reperfusion]. AB - OBJECTIVE: To determine the effects of Jiji decoction (Traditional Chinese Medicine) on the cognitive function and oxidative stress in mice with vascular dementia (VD) induced by cerebral ischemia/reperfusion. METHODS: Thirty-two mice were randomly divided into nonnal group (n = 8), sham group (operation, but no cerebral ischemia/reperfusi6n, n = 8), model group (vascular dementia model induced by cerebral ischemia/reperfusion, n = 8), and Jiji decoction-treated group (vascular dementia model plus treatment with Jiji decoction, n = 8). Fourteen days of treatment after operation, the cognitive behavior was measured in step-through test, spatial probe test and platform test. Afterwards, to assess the levels of oxidative stress, the activity of superoxide dismutase(SOD) and content of malonaldehyde (MDA) in brain of these mice were measured. RESULTS: Data from step-through test indicated that the escaping latency of Jiji decoction treated group was prolonged and the error counts were decreased significantly ( P <0.01) compared with those of model group. Data from spatial probe test indicated that the time of entering darkroom, the time of climbing height and the time of entering bright room in Jiji decoction-treated group were shortened and the counts of climbing height were increased (P < 0.05-0.01) significantly compared with those of model group. Data from platform test showed that the escaping latency of Jiji decoction-treated group was prolonged significantly (P < 0.01) compared with that of model group. Compared with normal and sham group, the activity of SOD was decreased and the content of MDA was increased in model group significantly (P < 0.01). Compared with those of model group, the levels of SOD and MDA in Jiji decoction-treated group were improved significantly (P < 0.01). CONCLUSION: Jiji decoction could improve cognitive function of VD mice. Its mechanism might be related with the inhibition of oxidative stiess in the brain. PMID- 26248429 TI - [Curcumin induces apoptosis by PTEN/PI3K/AKT pathway in EC109 cells]. AB - OBJECTIVE: To study the molecular mechanism of curcumin in human esophageal carcinoma cell line (EC109). METHODS: EC109 cells were cultivated in vitro. When 80%-90% confluence was reached, they were treated with curcumin in different concentrations (15-120 umol/L). The effects on cell proliferation were examined by CCK-8 colorimetry. The ultrastructure of EC109 cells were detected with transmission electron microscope(TEM). The cells apoptosis was observed with laser confocal microscope(LCM) by AnnexinV-FITC/PI double staining. The proteins level of PTEN, AKT, GSK3beta and Caspase 3 were tested by flow cytometry(FCM) . RESULTS: CCK-8 test showed that curcumin could inhibit the proliferation of EC109 cells in a time- and concentration-dependent manner. TEM and LCM examinations indicated that curcumin could make EC109 cells apoptosis. The data of FCM showed that curcumin could increase the expression of PTEN, GSK3beta and Caspase 3, decreased the expression of AKT. CONCLUSION: The effects of curcumin on inhibiting proliferation and promoting apoptosis of EC109 cells were related with increased expression of PTEN and inhibition of PI3K/AKT signaling pathway. PMID- 26248430 TI - [The expression and significance of CD151 in pituitary adenomas]. AB - OBJECTIVE: To investigate the expression and significance of CD151 in pituitary adenomas. METHODS: Thirty-six pituitary adenomas were collected immediately after surgery together with five normal pituitary tissue. Real time-PCR, Western blot and immunohistochemistry analysis were performed to detect the expression of CD151 mRNA and protein in thirty-six pituitary adenomases and five normal pituitary tissues. RESULTS: The expression of CD151 in all pituitary adenomases was observed to be significantly higher than that in normal pituitary tissues by Western blot, real time PCR, and immunohistochemistry analysis (P < 0.01). The expression levels of protein and mRNA in invasive pituitary adenomas were much higher than those in non-invasive pituitary adenomas (P < 0.01). CONCLUSION: The results suggested that the expression of CD151 was closely correlated with malignant degree of pituitary adenomas, which indicated the expression of CD151 was intimately correlated with occurrence and development of pituitary adenomas. Detecting CD151 might be a vital index to predict prognosis of pituitary adenomas. PMID- 26248431 TI - [Establishment of real time PCR for detecting plasma cell free DNA of rats and its significance]. AB - OBJECTIVE: Overtraining is a serious problem in sports, assessed by comprehensive multi-index evaluation, but so far there is still no sensitive, specific monitoring indicator or simple evaluation method to evaluate it. This research established a method for detecting plasma cell free DNA (cfDNA) of rats by real time PCR and discuss edits significance: a new molecular marker of overtraining? METHODS: Twelve male SD rats were randomly divided into control group and overtraining group. The overtraining group rats were undertaken overtraining on a motor-driven treadmill for 5 weeks, while the control group rats kept quiescent. All the rats were drawn blood at pre-and after-5 weeks to detect plasma levels of cfDNA, testosterone (T) and corticosterone (Cort) as well as peroxidation/antioxidation parameters (T-AOC, MDA, SOD, GSH-Px) and creatin kinase (CK). RESULTS: (1) Plasma cfDNA of rat was detected specifically by our real time PCR. (2) Compared with control group rats, the plasma cfDNA of overtraining rats increased obviously (about 5.43 fold). (3) Plasma cfDNA was related to plasma T, Cort, T/C ratio and MDA (correlation coefficent were -0.729, 0.854, -0.655 and 0.720, respectively) rather than plasma T-AOC, GSH-Px, SOD and CK. CONCLUSION: (1) A real time PCR method was established successfully to determine plasma cfDNA of rat. (2) A remarkable raises of plasma levels of cfDNA were found in overtraining rats which were associated with T, Cort and T/C, suggested that plasma cfDNA might be a new molecular marker of overtraining. (3) The increase of plasma cfDNA of overtraining rat might correlate with enhanced oxidative stress induced by overtraining instead of muscle damage. PMID- 26248432 TI - [Experience in typesetting the periodical "Chinese Journal of Applied Physiology (English version)" with InDesign CS6]. PMID- 26248433 TI - [Diagnosis and treatment of pulsatile tinnitus caused by the sigmoid sinus anomalies]. PMID- 26248434 TI - [Treatment and management of tinnitus]. PMID- 26248435 TI - [How to face the challenge of tinnitus for the otologist]. PMID- 26248436 TI - [The thinking of differential diagnosis of tinnitus based on clinical features]. PMID- 26248437 TI - [Application of cognitive theory of emotion in the study of tinnitus]. AB - Tinnitus is a common clinical disorder, which may generate trom a lot of causes, including otological disease and other systemic diseases associated with tinnitus or some factors such as insomnia and emotional cognition. Some studies have found that mood is associated with the occurrence and development of tinnitus and that psychological factors play a role in the occurrence and development of tinnitus in the tinnitus patients with mood disorders. At the same time, the psychological distress and emotional problems caused by tinnitus have drawn more and more attention of clinicians. Based on this, the cognitive theory of emotion can be helpful for evaluating tinnitus, and patients with severe tinnitus can be relieved by biofeedback information in tinnitus management. This article will analyze literature in these disciplines. PMID- 26248439 TI - [Intratympanic therapy in the management of tinnitus]. AB - Tinnitus is a common symptom which often becomes disabling, affecting the emotional and psychosocial dimensions of life. Nowadays, therapies for tinnitus vary greatly, none of which could give a satisfactory therapeutic effect however. Intratympanic therapy allows the generation of high concentration of drugs within the inner ear without systemic side effects. This review aims to introduce the commonly used medications and approaches for intratympanic management of tinnitus. Although different medications have been tested for their effects on tinnitus by intratympanic application, no breakthrough has been achieved so far. Consequently, the clinical use of specific medications for tinnitus has remained limited. A more widespread adoption of intratympanic management requires the development of specific medications for tinnitus, as well as proof of their safety and efficacy. PMID- 26248438 TI - [Social psychological factors causes of acute exacerbation or re-decompensation of clinically significant chronic tinnitus]. AB - OBJECTIVE: To analyze social-psychological causes of acute exacerbation or re decompensation of chronic tinnitus and provide theoretical basis for controlling and preventing tinnitus exacerbation and re-decompensation. METHOD: Systemic audiological tests and tinnitus handicap inventory were performed on 136 chronic tinnitus patients with acuteexacerbation or re-decompensation. For the patients with new hearing loss, a further investigation of living conditions and assessment of social support rating scale were utilized. The patients with relatively definite causes were treated accordingly. RESULT: (1) There were 89 patients complained of new changes of hearing, all of whom could tell the definite time point of tinnitus exacerbation, and 5 of them felt the exacerbation of hearing loss meanwhile. (2) Forty-two patients encountered adverse events on life or working, and tinnitus exacerbation occurred within several weeks to 3 months afterwards. Most of these patients could not tell the definite time point of tinnitus exacerbation or re-decompensation. Five cases of tinnitus exacerbation didn't tell any adverse events on life or working, but showed mood disorders, and the anti-anxiety treatment was effective to them. (3) Forty-seven cases without new hearing loss scored significantly lower in SSRS than healthy adults. CONCLUSION: Emerging hearing loss is the main cause of acute exacerbation of chronic tinnitus. To find it in time and give effective treatment can save newly presented hearing loss, cure or relieve tinnitus. Adverse events in life(or working) and short of social support is another important cause of acute exacerbation of chronic tinnitus or decompensation recurrence, which suggests that social-psychological factors besides of hearing loss should be concerned in diagnosis and treatment of tinnitus. PMID- 26248440 TI - [Analysis of the clinical application effect of tinnitus diagnosis and treatment process]. AB - OBJECTIVE: To investigate the clinical application effects of tinnitus diagnosis and treatment process. METHOD: The 1541 clinic patients with tinnitus were included in the diagnosis and treatment process. The diagnosis was clarified based on comprehensive examinations and tests. According to the characteristics of tinnitus, the patients underwent etiological treatment, drug therapy, masking therapy, sound therapy and psychological therapy, respectively, and the curative effect was evaluated. RESULT: There were 781 patients received etiological treatment, where the effective rate is 86.17%. For 369 cases of acute and subacute tinnitus, the effective rate for low frequency tinnitus is 80.77% (126/156), and that for high frequency is 72.30% (154/213). For 224 cases of chronic compensated tinnitus, the effective rate of masking therapy is 79.63% (86/108), and the effective rate of sound therapy is 79.31% (92/116). For the 124 cases of chronic decompensated tinnitus, the effective rate of sound therapy combined with psychological counseling is 83.06%. CONCLUSION: The utilization of tinnitus diagnosis and treatment process can give the patients of tinnitus with different characteristics satisfactory curative effects, and is suggested to be proposed for clinical application. PMID- 26248441 TI - [Reconsideration of tinnitus diagnosis and treatment]. PMID- 26248442 TI - [The curative effect of cognitive behavior therapy for the treatment of chronic subjective tinnitus]. AB - OBJECTIVE: To explore the efficacy of the cognitive behavior therapy (CBT) for the treatment of chronic subjective tinnitus. METHOD: One hundred and fifty-seven patients were randomly divided into two groups. Sixty-eight patients of the control group were treated by masking therapy; and the other 89 patients of the experimental group were treated by CBT therapy. The score of tinnitus handicap inventory (THI) was utilized to analyze the treatment efficacy in the two groups respectively. RESULT: The effective rate assessed by of THI score in the experimental group was not significantly higher than the control group 2 months after treatment (P > 0.05), but was significantly higher than the control group 6 months and 12 months after treatment (P < 0.05 respectively). CONCLUSION: The CBT therapy contributed to achieve rapid adaptation of tinnitus feeling, which shows great value of further clinical application. PMID- 26248443 TI - [Analysis of characteristics of tinnitus in patients with auditory neuropathy spectrum disorder]. AB - OBJECTIVE: To investigate the characteristics of tinnitus in patients with auditory neuropathy spec- trum disorder (ANSD). METHOD: This study recruited 14 ANSD patients with tinnitus. All the ANSD patients un- derwent detailed history taking, audiological examinations and assessments of tinnitus. This study analyzed the correlation of tinnitus status and hearing loss, and discussed the effects of sex, age, and the course of disease on tinnitus in ANSD patients. RESULT: (1) In the ANSD patients, tinnitus often occurred in 3 years after the onset of hearing loss; (2) Tinnitus was highly prevalent in ANSD patients, and the severity of tinnitus was mostly from mild to moderate; (3) There was no obvious correlation between the subjective grading of tinnitus and hearing loss de- gree, and the impact of curve patterns of hearing loss on the level of tinnitus need much more evidence-based proof; (4) Along with the course extension, the impact of tinnitus on the quality of life was much more obvious; (5) Some risk factors such as noise exposure could be the reasons of aggravating the degree of tinnitus. CONCLUSION: Tinnitus in ANSD patients has its unique clinical features. The study of Tinnitus in ANSD patients can provide clinical basis for further research in ANSD. PMID- 26248444 TI - [The management of facial nerve tumor manifested as facial paralysis]. AB - OBJECTIVE: To heighten the awareness of the facial nerve tumors. METHOD: The clinical data of twenty-three patients complaining of facial paralysis who were diagnosed postoperatively as facial nerve tumors were analyzed. The hearing assessment of all patients was based on pure tone audiometry at the frequency of 0. 5, 1, 2, 4 kHz. Temporal bone high resolution CT scan and temporal bone MRI with gadolinium enhancement were conducted on all patients. Facial nerve function was assessed with the House-Brackmann (HB) grading system. Facial electroneurography (ENoG) was conducted on 20 patients to quantify the degree of nerve degeneration preoperatively. The pathological types of tumor were determined by postoperative pathological reports. RESULT: Nineteen out of 23 cases presented hearing loss (82.6%), 10 cases suffered from tinnitus (43.5%), otalgia (17.4%) affected 4 cases, 3 cases manifested otorrhea (13.0%), and 2 cases presented vertigo (8.7%). Geniculate ganglion was the most commonly involved site (20 cases, 87.0%), followed by tympanic segments (18 cases, 78.3%), pyramid segment (16 cases, 69.6%), mastoid segment (10 cases, 43.5%), labyrinthine segment (9 cases, 39.1%), internal auditory canal segment and parotid gland segment (5 cases, 21.7%, respectively). Twenty-one cases (91.3%) of schwannomas, 1 case (4.3%) of neurofibroma and 1 case (4.3%) of hemangiomas were identified with histopathology postoperatively. The tumors were all completely excised, and the facial nerve function could recovered to HB III at the best after facial nerve repairment. CONCLUSION: Facial nerve tumor is a rare and often misdiagnosed disease which was commonly manifested as facial nerve paralysis. Temporal bone CT and MRI can help to clarify the diagnosis preoperatively. Pure tone audiometry and electroneurography also plays a some certain roles in the diagnosis of facial nerve tumors. The tumors should be completely resected and the surgical approaches were determined based on tumor size, facial nerve function and preoperative auditory function. PMID- 26248445 TI - [Time of salvage treatment on sudden sensorineural hearing loss]. AB - OBJECTIVE: To explore the best time of intratympanic dexamethasone injection to treat sudden sensorineural hearing loss (SSNHL) as salvage therapy so that to improve the curative efficacy on sudden deafness at the utmost. METHOD: A total of 192 patients with SSNHL were included in this study, among whom 63 cases received the systemic steroid therapy throughout the study, while the other ones were treated with systemic steroid as initial treatment and were given intratympanic steroid administration as salvage treatment starting at different time point. The salvage treatment started on the 3rd day after the beginning of the initial treatment for 29 cases, on the 7th day for 38 cases, on the 14th day for 43 cases, and 1 month later for 19 cases. All the patients were followed up for 2 months. RESULT: The recovery rates and total effective rates showed no statistically significant difference between the patients received only systemic steroid therapy and the ones received intratympanic steroid administration on the 3rd, 7th day and 1 month later after the initial treatment. The recovery rate and total effective rate exhibited statistically significant difference between the patients received intratympanic steroid administration since the 14th day after the initial treatment and the ones received only systemic steroid therapy, with the numerical value of P 0. 037 and 0. 034, respectively. CONCLUSION: (1) As an initial management plan, the curative effects. between the intratympanic steroid administration and the systemic steroid therapy were not significantly different. (2) As a salvage treatment, intratympanic steroid was a better choice for patients who have not completely recover from ISSNHL after failure of initial management with systemic steroid only. (3) The best time point of salvage treatment with intratympanic steroid was about 2 weeks after initial management with systemic steroid. PMID- 26248446 TI - [A systematic review of adenoidectomy in the treatment of otitis media with effusion in children]. AB - OBJECTIVE: Systematic reviews and Meta-analysis were conducted to assess the efficacy and security of adenoidectomy for the treatment of otitis media with effusion in children. METHOD: Based on the principles and methods of Cochrane systematic reviews, literature was searched in PubMed, Medline, Elisevier, Ovid, CBM, CNKI, VIP and Wanfang datebases. Randomized controlled trials about treatment of otitis media with effusion in children using adenoidectomy were included. Meta-analysis was performed for the result of homogeneous studies using RevMan 5.2 software. RESULT: Adenoidectomy (combined with myringotomy or puncture) was superior to non-surgical (combined with myringotomy or puncture) treatment in reducing the incidence of acute otitis media and removing the middle ear effusion. Adenoidectomy combined with tympanostomy tube was superior to tympanostomy tube alone in the removal of the middle ear effusion and improvement of hearing level. Three trials described some postoperative complications including haemorrhage, incipient malignant hyperthermia, postoperative pneumonia and velopharyngeal insufficiency. CONCLUSION: Our research shows a benefit of adenoidectomy in the removal of middle ear effusion in children with OME. Adenoidectomy combined with tympanostomy tube was superior to tympanostomy tube alone in improving hearing level. At present, there is no evidence of serious postoperative complications after adenoidectomy. PMID- 26248447 TI - [Ocular complications following surgery of chronic suppurative otitis media]. AB - OBJECTIVE: To investigate the rarely reported ocular complications following surgery of chronic suppurative otitis media (CSOM) and explore the possible mechanisms. METHOD: The clinical data of 4,012 cases of CSOM treated with surgery were analyzed retrospectively, including age, sex, operation time, surgical approach, time of ocular symptoms presentation, duration of ocular symptoms, treatment and prognosis. RESULT: Among the 4,012 cases, 109 patients (2.72%) developed ocular complication, of which 68.81% (75/109) suffered from blurred vision, 24.77% (27/109) presented only erythema on eyelids or mild periorbital edema, 4.59% (5/109) had erythema on eyelids with periorbital edema, and 1.83% (2/109) complained of periorbital ecchymosis and edema. All of these complications recovered themselves without any sequela. CONCLUSION: Ocular complications following surgery of CSOM are rarely reported. Pre-auricular incision and fascia harvesting, turbulence of venous and lymphatic drainage and preseptal cellulitis might be the risk factors. Blurred vision might be associated with eye injury during surgery and the use of anticholinergic agent. PMID- 26248448 TI - [Comparison of anxiety and depression state among patients with different type of vestibular peripheral vertigo]. AB - OBJECTIVE: To investigate and analyze the status of anxiety and depression among patients with four types of peripheral vertigo. METHOD: The clinical data of patients with one of the four types of peripheral vertigo, namely benign paroxysmal positional vertigo (BPPV), vestibular migraine (VM), Meniere's disease (MD), and vestibular neuritis (VN), were collected. Thorough otological and neuro otological examinations were performed on these patients, and their status of anxiety and depression were assessed using self-rating anxiety scale (SAS) and self-rating depression scale (SDS). RESULT: A total of 129 patients with one of the four types of peripheral vertigo(49 cases of BPPV, 37 cases of VM, 28 cases of MD and 15 cases of VN) were included in the study. The scores of SAS and SDS were higher in the patients with VM or MD than those with BPPV or VN (P < 0.05), and the incidence of anxiety (VM = 45.9% MD = 50.0%) and depression (VM = 27.0% MD = 28.6%) were higher in the patients with VM or MD than those with BPPV or VN (P < 0.05). Paired comparisons showed the differences between the incidences of BPPV and MV groups, BPPV and MD groups, and MD and VN groups were statistically significant (P < 0.05). CONCLUSION: Among patients with different types of peripheral vertigo, anxiety/depression is more common in patients with VM or MD. This may be due to the different mechanisms involved in different types of vertigo, as well as differences in the prevention and self-control of the patients against the vertigo. PMID- 26248449 TI - [Clinical analysis of sudden deafness after radiotherapy and chemotherapy in nasopharyngeal carcinoma patients]. AB - OBJECTIVE: To investigate the clinical features and therapeutic effects of sudden deafness after radiotherapy combined with chemotherapy in nasopharyngeal carcinoma patients. METHOD: Clinical data of 42 nasopharyngeal carcinoma patients suffered from sudden deafness after radiotherapy combined with chemotherapy were analyzed retrospectively. Among the 42 patients, 2 showed moderate deafness, 4 presented excessive deafness, 30 suffered from severe deafness, and 6 exhibited profound deafness. The audiogram pattern of 33 patients met with the type of high tone frequencies hearing loss, and that of the rest 9 cases showed hearing loss at all frequencies. All patients received medical therapy combined with hyperbaric oxygen therapy. RESULT: Of all the cases with hearing loss, 2 were cured, 2 showed excellent recovery, 9 came out partial recovery, and 29 showed no response to the treatment. The total effective rate was 30.95%. For the accompanied symptoms, none of the 30 cases of tinnitus were relieved, 3 out of 10 cases of aural fullness were cured, and the 5 cases of dizziness or vertigo were all improved. CONCLUSION: The sudden deafness after radiotherapy combined with chemotherapy in patients with nasopharyngeal carcinoma is closely related to radiotherapy. The hearing loss is serious, and the therapeutic effects are not satisfactory. PMID- 26248450 TI - [The principal component analysis of clinical symptoms in patients with Meniere's disease during acute phase]. AB - OBJECTIVE: To explore the severity index of Meniere's disease during acute phase by a statistical method of principal component analysis (PCA). METHOD: Ninety five patients with Meniere's disease in the acute phase who saw the doctor with 24 hours after onset were included in this study and their clinical data were analyzed retrospectively. The subjective symptoms of hearing loss (X1) and ear stuffy plug (X4) were evaluated by VAS scoring system, and the impact of vertigo (X2) and tinnitus (X3) on the patients were evaluated by DHI and THI score. The principal component analysis (PCA) method was used to analyze the quantified data and construct a synthetic evaluate function of subjective symptoms. RESULT: (1) The quantitative results of subjective symptoms in patients with Meniere's disease were as follow: VAS score (X1) of hearing loss was 0-91 points, with an average of 46.23 +/- 18.80, DHI score (X2) of vertigo was 8-98 points, with an average of 49.66 +/- 15.67, THI score (X3) of tinnitus was 10-100 points, with an average of 47.53 +/- 17.44, and ear VAS score (X4) of stuffy plug feeling was 0 82 points, with an average of 21.55 +/- 27.54. (2) The eigenvalue of principal components Z1, Z2 and Z3 were 1.876, 0.984 and 0.703 respectively, and the variance contribution were 46.898%, 24.592% and 17.574% respectively. (3) The constructed synthetic evaluate function of the disease was as follow: The Meniere's disease severity index f = 0.213ZX1 + 0.398ZX2 + 0.370ZX3 + 0.455ZX4. CONCLUSION: The method of PCA for the subjective evaluation of symptoms in Meniere's disease can be constructed as a model of comprehensive evaluation system, which may provide relatively comprehensive information of clinical original variables included in the four main symptoms, reflecting the severity of the disease. PMID- 26248451 TI - [Evaluation of the effect of early postoperative aural/oral rehabilitation of prelingual deaf children with cochlear implants]. AB - OBJECTIVE: To evaluate the effect of aural/oral rehabilitation in the prelingual deaf children with cochlear implants, analyze the relationship between the age at the time of surgery and the rehabilitation effect, and explore the law of aural/oral rehabilitation in the prelingual deaf children after cochlear implantation. METHOD: Prelingual deaf children with cochlear implants were divided by age into 1.3-2.9 group (17 cases), 3.0-4.9 group(14 cases)and 5.0-7.9 group (26 cases). All the children were evaluated by CAP and SIR questionnaires 3 months, 6 months, 9 months and 12 months after the surgery. RESULT: The scores of CAP and SIR in different age groups were all increased with time after cochlear implantation. The score of CAP in 1.3-2.9 group rose the fastest, which was lowest at the end of the 3rd month and was highest at the end of the 12th month. There were no differences between the CAP scores of 1.3-2.9 group and 5.0-7.9 group in the later test. The score of SIR rose the fastest in 1.3-2.9 group, which was lowest at the end of the 3rd month and highest at the end of the 12th month and rose the slowest in 5.0-7.9 group, which was lower than the other groups at the end of the 12th month. CONCLUSION: Within one year after cochlear implantation, the younger the age, the better the effect of aural/oral rehabilitation. PMID- 26248452 TI - [Meta-analysis of the efficacy of cochlear implantation in deaf patients with inner ear malformation]. AB - OBJECTIVE: Assess and compare the clinical efficacy and safety of cochlear implantation in deaf patients with inner ear malformation and in the ones with normal inner ear structure, so that to clarify whether it is effective to restore hearing for the deaf patients with inner ear malformation. METHOD: The literature with relevant key words were retrieved in the databases including PubMed, YZ365. com, WANFANG data, CMJD, CHKD and CNKI with language limited to Chinese and English. Extracted data included author, year of publication, diagnosis, treatment, et al. The clinical efficacy of cochlear implantation was assessed by the complications, electrode impedance, behavior T-level, hearing abilities and speech discrimination. Meta-analysis was performed using random or fixed effects model according to the heterogeneity of data. RESULT: There were 11 randomized control studies involving 655 patients included in this study. There was no statistically significant difference among the deaf patients in mixed inner ear malformation group, Mondini group and large vestibular aqueduct syndrome group in the aspects of postoperative complications, electrode impedance, behavior T level, hearing abilities and speech discrimination. CONCLUSION: Cochlear implantation could be the way of treatment and rehabilitation for deaf patients with inner ear malformation. Further controlled studies with longer follow-up periods and more multiracial cases included may help to evaluate the efficacy of cochlear implantation for deaf patients with inner ear malformation more reliably. PMID- 26248453 TI - [The study of the pure tone audiometry characteristics and curative effect in sudden hearing loss patients with hypertension]. AB - OBJECTIVE: To investigate the pure tone audiometry characteristics and curative effect in sudden hearing loss patients with hypertension. METHOD: One hundred and fifty-seven inpatients (168 ears) with hypertension suffered from sudden hearing loss were included in this study. We retrospectively analyzed the audiological index of these patients by comparing the pure tone audiometry (PTA) among patients in the aspects of gender, age, affected side, duration of hypertension, with or without inducement, concomitant symptoms and other combined diseases. The hearing threshold at different frequency was also compared, as well as the curative effect among patients with diverse audiological characteristics. RESULT: Of the contemporaneous sudden hearing loss patients (874 cases), the prevalence of hypertension was 17.96%, where the male ones accounted for. 28.69% (103/359) and the female ones accounted for 19.42% (54/278) respectively with statistically significant difference between genders (P < 0.01). The prevalence of hypertension in 34-44 years old group, 45-49 years old group, 60-69 years old group and over 70 years old group was 12.69% (25/197), 22.51% (70/311), 47.62% (40/84), 48.89% (22/45) respectively, which were statistically different (P < 0.01). The number of impaired ears with audiogram configuration characterized by rise type, downslope type, flat type and completely deafness type was 18 (10.71%), 61 (36.31%), 41 (24.40%), and 48 (28.57%), respectively. The decrease of hearing threshold in PTA were increasingly severe as the increasing impaired-frequency, and the difference of the degree of hearing impairment among these three types of frequencies was statistically significant (P < 0.01). The hearing threshold means of each frequency had no significant difference among patients with various gender, age and Cardiovascular Risk Stratification (P > 0.05). The hearing threshold means of each frequency of unilateral hearing loss patients was significantly higher than that of bilateral hearing loss patients (P < 0.05). The hearing threshold means at 125 Hz, 250 Hz, 500 Hz and 1 kHz showed significant difference among patients with different duration of hypertension (P < 0.05). The total effective rate of sudden hearing loss in patients with hypertension was significantly lower than that in the sudden hearing loss patients without hypertension (19.64%, 61.57% respectively, P < 0.01). The total effective rate presented significant difference among patients with different duration of hypertension and different Cardiovascular Risk Stratification (P < 0.05). CONCLUSION: The prevalence of sudden hearing loss in hypertension patients was higher in male than in female, which rose with age and combined disease. The hearing threshold means at mid-frequency and high-frequency were higher than that at low-frequency. The total effective rate of sudden hearing loss was relatively low in patients with hypertension. The longer the duration of hypertension and the higher the Cardiovascular Risk Stratification, the lower the total effective rate. Comprehensive understanding of audiological characteristics and hypertension condition plays a crucial role in type-specific treatment of sudden hearing loss. PMID- 26248454 TI - [Curative effect observation of plasma eardrum perforation homochronous with palatoplasty in the treatment of chronic secretory otitis media]. AB - OBJECTIVE: To investigate the effect of plasma eardrum perforation homochronous with palatoplasty on hearing and tympanic cavity pressure in cleft palate children with secretory otitis media. METHOD: Fifty-six cases of cleft palate children with secretory otitis media were randomly divided into observation group and control group. For the control group, palatoplasty was carried out alone. For the observation group, homochronous with palatoplasty, plasma eardrum perforation was performed with the diameter of the aperture 2-3 mm, which was decided by observing viscosity of tympanum fluid under microscope or otoscope. RESULT: Compared with the simple cleft palate repairing palatoplasty, the perforation in the observation group could keep for 6-8 weeks after the surgery. Followed up 6 months later, the children in observation group improved better in terms of hearing restoration and tympanometry. CONCLUSION: By means of plasma eardrum perforation homochronous with palatoplasty, the children of cleft palate with secretory otitis media could improve hearing and tympanometry in a short period, recovering the function of middle ear. PMID- 26248455 TI - [The expression of corticotropin-releasing factor 1 receptor in hippocampus of rats model of salicylate induced tinnitus]. AB - OBJECTIVE: To observe the expression of corticotropin-releasing factor-1 receptor in hippocampus of rats model of salicylate induced tinnitus. METHOD: Twenty-four rats were randomly divided into three groups, eight for each group. For Group A and Group B, 10% salicylic sodium solution was intraperitoneal injected each day at the dose of 350 mg/kg for 21 days in Group A and 14 days in Group B. Group C received intraperitoneal injection with the same amount of saline solution each day for 14 days. ABR were tested 2 days before, and 2 hours after the first administration and after the last injection. Immunohistochemical test and Western Blot were utilized to detect the expression of CRF1R in hippocampus for each group. RESULT: ABR thresholds tested 2 days before the first administration of the 3 groups showed no statistically significant difference (P > 0.05). At the time point of 2 hours after the first injection, the ABR thresholds of Group A and Group B rose by 25.90 dB SPL and 25.03 dB SPL compared with that before the administration, respectively (P < 0. 01). After the last administration, the ABR thresholds of Group A and Group B rose 34.91 dB SPL and 32.62 dB SPI. compared with that before the administration, respectively (P < 0.01). The ABR thresholds of Group C showed no significant statistical difference at all the tested time points (P > 0.05). Immunohistochemical test and Western Blot revealed that the expression level of CRF1R in the hippocampus was A > B > C (P < 0.05). CONCLUSION: The expression of CRF1R in the hippocampus of salicylate induced tinnitus rat increased with the injection time, illustrating that CRF1R may participate in the mechanism of tinnitus involving the limbic system. PMID- 26248456 TI - [Clinical analysis of nasal sinus myoepithelioma]. PMID- 26248457 TI - [The treatment of 176 cases of auricular pseudocyst by the probe microwave burning]. PMID- 26248458 TI - [Clinical analysis of submental lymph node enlargement after radiotherapy for nasopharyngeal cancer]. PMID- 26248459 TI - [Dentinogenic ghost cell tumor presenting as a giant cyst: a case report]. AB - A 55 year old man complained of a painless mass at the left maxillofacial region. The mass had continuously grown over 10 years. Upon physical examination a cystic mass with size of 5 cm in length with bulging smooth surface was seen on the left maxillofacial region. Computed tomography (CT) scan showed a giant cyst with bone destruction and invasion in the left maxilla, maxillary sinus and nasal cavity. Needle aspiration of the mass yielded 80 milliliter of brown fluid. The excisional biopsy was made which revealed ghost cells and dysplastic dentin that were features of dentinogenic ghost cell tumor. Finally, a dentinogenic ghost cell was diagnosed. PMID- 26248460 TI - [A case of infratemporal fossa abscess cause by facial acupuncture]. AB - The infratemporal fossa abscess is an irregularly shaped cavity, situated below and media to the zygomatic arch. It consists of masseter and nervus vascularis, etc. Comparatively speaking, the low position of the infratemporal fossa has almost freed the patient from dental, nasal,ocular and aural source of pain. So facial acupuncture is more likely to cause the infection. But it is also possible that the patient get cryptogenic infection of maxillofacial cavity, the treatment of which needs further study. PMID- 26248461 TI - [A case report of poorly differentiated thyroid carcinoma with contralateral papillary carcinoma]. AB - A 22-year-old female patient complained of neck discomfort for one week. Examination revealed bilateral neck masses. Color doppler ultrasound showed bilateral thyroid masses,which resulted in two thyroid lobes asymmetry. Bilateral cervical enlarged lymph nodes were not found. Thyroid function was normal. Complete left lobe and subtotal right lobe of thyroid gland were resected. The pathological results showed poorly differentiated carcinoma of left thyroid and papillary carcinoma of right thyroid with bilateral Hashimoto's thyroiditis. The patient received resection of residual thyroid and lymph nodes in another hospital, with no tumor or metastasis found. The patient without radiotherapy or chemotherapy was followed up for 34 months, and no progressive lesions were found. PMID- 26248462 TI - [Ear keloid and clinical research progress]. AB - Keloid refers to the damaged skin due to excessive fibroblast proliferation. Ear is one predilection site. The pathogenesis of ear keloid is not very clear, and the treatment is also varied. Surgery, postoperative radiotherapy and laser treatment, steroid hormones, pressure therapy are the basic treatment methods. Integrated application of a variety of treatments, classification research and new materials using revealed the prospect for the treatment of the disease. This thesis reviews literature about ear keloid in recent 10 years, and introduces this disease and clinical research progress. PMID- 26248463 TI - Rapid mapping of functional cis-acting RNA elements by recovery of virus from a degenerate RNA population: application to genome segment 10 of bluetongue virus. AB - The regulatory elements which control the processes of virus replication and gene expression in the Orbivirus genus are uncharacterized in terms of both their locations within genome segments and their specific functions. The reverse genetics system for the type species, Bluetongue virus, has been used in combination with RNA secondary structure prediction to identify and map the positions of cis-acting regions within genome segment 10. Through the simultaneous introduction of variability at multiple nucleotide positions in the rescue RNA population, the functional contribution of these positions was used to map regions containing cis-acting elements essential for virus viability. Nucleotides that were individually lethal when varied mapped within a region of predicted secondary structure involving base pairing between the 5' and 3' ends of the transcript. An extended region of predicted perfect base pairing located within the 3' untranslated region of the genome segment was also found to be required for virus viability. In contrast to the identification of individually lethal mutations, gross alteration of the composition of this predicted stem region was possible, providing the base-pairing potential between the two strands was maintained, identifying a structural feature predicted to be conserved throughout the Orbivirus genus. The approach of identifying cis-acting sequences through sequencing the recovered virus following the rescue of a degenerate RNA population is broadly applicable to viruses where reverse genetics is available. PMID- 26248464 TI - Impact of epidermal growth factor receptor (EGFR) activating mutations and their targeted treatment in the prognosis of stage IV non-small cell lung cancer (NSCLC) patients harboring liver metastasis. AB - OBJECTIVES: Liver metastases appear in 20-30% of patients diagnosed with non small cell lung cancer (NSCLC) and represent a poor prognosis feature of NSCLC and a possibly more treatment-resistant condition. Potential clinical outcome differences in NSCLC patients with liver metastases harboring molecular alterations in EGFR, KRAS and EML4-ALK genes are still to be determined. This study aims to evaluate the incidence of liver metastasis in a single population and look for potential correlations between EGFR mutations, liver infiltration and clinical outcomes. METHODS: A total of 236 consecutive stage IV NSCLC patients treated at the Clinica Universidad de Navarra were analyzed. RESULTS: At onset, liver metastases were present in 16.9% of patients conferring them a shorter overall survival (OS) compared to those with different metastatic locations excluding liver infiltration (10 vs. 21 months; p = 0.001). Patients with EGFR wild-type tumors receiving standard chemotherapy and showing no liver involvement presented a superior median OS compared to those with liver metastases (23 vs. 13 months; p = 0.001). Conversely, patients with EGFR-mutated tumors treated with EGFR tyrosin-kinase inhibitors (TKI's) presented no significant differences in OS regardless of liver involvement (median OS not reached vs. 25 months; p = 0.81). CONCLUSION: Overall, liver metastases at onset negatively impact OS of NSCLC patients. EGFR TKIs however, may reverse the effects of an initial negative prognosis of liver metastasis in first-line treatment of EGFR mutated NSCLC patients. PMID- 26248465 TI - BioWardrobe: an integrated platform for analysis of epigenomics and transcriptomics data. AB - High-throughput sequencing has revolutionized biology by enhancing our ability to perform genome-wide studies. However, due to lack of bioinformatics expertise, modern technologies are still beyond the capabilities of many laboratories. Herein, we present the BioWardrobe platform, which allows users to store, visualize and analyze epigenomics and transcriptomics data using a biologist friendly web interface, without the need for programming expertise. Predefined pipelines allow users to download data, visualize results on a genome browser, calculate RPKMs (reads per kilobase per million) and identify peaks. Advanced capabilities include differential gene expression and binding analysis, and creation of average tag -density profiles and heatmaps. BioWardrobe can be found at http://biowardrobe.com . PMID- 26248466 TI - Functional role of dimerization and CP190 interacting domains of CTCF protein in Drosophila melanogaster. AB - BACKGROUND: Insulators play a central role in gene regulation, chromosomal architecture and genome function in higher eukaryotes. To learn more about how insulators carry out their diverse functions, we have begun an analysis of the Drosophila CTCF (dCTCF). CTCF is one of the few insulator proteins known to be conserved from flies to man. RESULTS: In the studies reported here we have focused on the identification and characterization of two dCTCF protein interaction modules. The first mediates dCTCF multimerization, while the second mediates dCTCF-CP190 interactions. The multimerization domain maps in the N terminus of the dCTCF protein and likely mediates the formation of tetrameric complexes. The CP190 interaction module encompasses a sequence ~200 amino acids long that spans the C-terminal and mediates interactions with the N-terminal BTB domain of the CP190 protein. Transgene rescue experiments showed that a dCTCF protein lacking sequences critical for CP190 interactions was almost as effective as wild type in rescuing the phenotypic effects of a dCTCF null allele. The mutation did, however, affect CP190 recruitment to specific Drosophila insulator elements and had a modest effect on dCTCF chromatin association. A protein lacking the N-terminal dCTCF multimerization domain incompletely rescued the zygotic and maternal effect lethality of the null and did not rescue the defects in Abd-B regulation evident in surviving adult dCTCF mutant flies. Finally, we show that elimination of maternally contributed dCTCF at the onset of embryogenesis has quite different effects on development and Abd-B regulation than is observed when the homozygous mutant animals develop in the presence of maternally derived dCTCF activity. CONCLUSIONS: Our results indicate that dCTCF CP190 interactions are less critical for the in vivo functions of the dCTCF protein than the N-terminal dCTCF-dCTCF interaction domain. We also show that the phenotypic consequences of dCTCF mutations differ depending upon when and how dCTCF activity is lost. PMID- 26248468 TI - Motor network disruption in essential tremor: a functional and effective connectivity study. AB - Although involvement of the cerebello-thalamo-cortical network has often been suggested in essential tremor, the source of oscillatory activity remains largely unknown. To elucidate mechanisms of tremor generation, it is of crucial importance to study the dynamics within the cerebello-thalamo-cortical network. Using a combination of electromyography and functional magnetic resonance imaging, it is possible to record the peripheral manifestation of tremor simultaneously with brain activity related to tremor generation. Our first aim was to study the intrinsic activity of regions within the cerebello-thalamo cortical network using dynamic causal modelling to estimate effective connectivity driven by the concurrently recorded tremor signal. Our second aim was to objectify how the functional integrity of the cerebello-thalamo-cortical network is affected in essential tremor. We investigated the functional connectivity between cerebellar and cortical motor regions showing activations during a motor task. Twenty-two essential tremor patients and 22 healthy controls were analysed. For the effective connectivity analysis, a network of tremor signal related regions was constructed, consisting of the left primary motor cortex, premotor cortex, supplementary motor area, left thalamus, and right cerebellar motor regions lobule V and lobule VIII. A measure of variation in tremor severity over time, derived from the electromyogram, was included as modulatory input on intrinsic connections and on the extrinsic cerebello-thalamic connections, giving a total of 128 models. Bayesian model selection and random effects Bayesian model averaging were used. Separate seed-based functional connectivity analyses for the left primary motor cortex, left supplementary motor area and right cerebellar lobules IV, V, VI and VIII were performed. We report two novel findings that support an important role for the cerebellar system in the pathophysiology of essential tremor. First, in the effective connectivity analysis, tremor variation during the motor task has an excitatory effect on both the extrinsic connection from cerebellar lobule V to the thalamus, and the intrinsic activity of cerebellar lobule V and thalamus. Second, the functional integrity of the motor network is affected in essential tremor, with a decrease in functional connectivity between cortical and cerebellar motor regions. This decrease in functional connectivity, related to the motor task, correlates with an increase in clinical tremor severity. Interestingly, increased functional connectivity between right cerebellar lobules I-IV and the left thalamus correlates with an increase in clinical tremor severity. In conclusion, our findings suggest that cerebello-dentato-thalamic activity and cerebello-cortical connectivity is disturbed in essential tremor, supporting previous evidence of functional cerebellar changes in essential tremor. PMID- 26248467 TI - Reducing amplification artifacts in high multiplex amplicon sequencing by using molecular barcodes. AB - BACKGROUND: PCR amplicon sequencing has been widely used as a targeted approach for both DNA and RNA sequence analysis. High multiplex PCR has further enabled the enrichment of hundreds of amplicons in one simple reaction. At the same time, the performance of PCR amplicon sequencing can be negatively affected by issues such as high duplicate reads, polymerase artifacts and PCR amplification bias. Recently researchers have made some good progress in addressing these shortcomings by incorporating molecular barcodes into PCR primer design. So far, most work has been demonstrated using one to a few pairs of primers, which limits the size of the region one can analyze. RESULTS: We developed a simple protocol, which enables the use of molecular barcodes in high multiplex PCR with hundreds of amplicons. Using this protocol and reference materials, we demonstrated the applications in accurate variant calling at very low fraction over a large region and in targeted RNA quantification. We also evaluated the protocol's utility in profiling FFPE samples. CONCLUSIONS: We demonstrated the successful implementation of molecular barcodes in high multiplex PCR, with multiplex scale many times higher than earlier work. We showed that the new protocol combines the benefits of both high multiplex PCR and molecular barcodes, i.e. the analysis of a very large region, low DNA input requirement, very good reproducibility and the ability to detect as low as 1% mutations with minimal false positives (FP). PMID- 26248469 TI - Fast-food and full-service restaurant consumption in relation to daily energy and nutrient intakes among US adult cancer survivors, 2003-2012. AB - BACKGROUND: Healthy diet is an essential component in cancer survivorship care planning. Cancer survivors should be particularly prudent regarding their daily food choices, with an aim of ensuring safe consumption, reducing risk of recurrence or other comorbidity, and improving quality of life. OBJECTIVE: We aimed to examine the impacts of fast-food and full-service restaurant consumption on daily energy and nutrient intakes among US adult cancer survivors. METHODS: Nationally representative data of 1308 adult cancer survivors came from the National Health and Nutrition Examination Survey 2003-2012 waves. First difference estimator was adopted to address confounding bias from time-invariant unobservables like personal food/beverage preferences by using within-individual variations in diet and restaurant consumption status between two non-consecutive 24-hour dietary recalls. RESULTS: Fast-food and full-service restaurant consumption, respectively, was associated with an increase in daily total energy intake by 125.97 and 152.26 kcal and sodium intake by 312.47 and 373.75 mg. Fast food consumption was significantly associated with a decrease in daily vitamin A intake by 119.88 ug and vitamin K intake by 30.48 ug, whereas full-service restaurant consumption was associated with an increase in daily fat intake by 8.99 g and omega-6 fatty acid intake by 3.85 g, and a decrease in vitamin D intake by 0.93 ug. Compared with fast-food and full-service restaurant consumption at home, consumption away from home led to further reduced diet quality. CONCLUSIONS: Individualized nutrition counseling and food assistance programs should address cancer survivors' overall dining-out behavior rather than fast-food consumption alone. PMID- 26248471 TI - Domiciliary administration of intravenous albumin in congenital nephrotic syndrome. AB - BACKGROUND: Early management of congenital nephrotic syndrome invariably includes the frequent administration of intravenous human albumin solution. The safety and feasibility of intravenous administration of albumin in the patients' home setting has not previously been reported. CASE-DIAGNOSIS/TREATMENT: We report a series of seven paediatric patients whose parents were trained in the administration of albumin via a central venous catheter at home, with the aim of minimising hospital admission or attendances. We describe the clinical course of these patients and complication rates ascribed to this strategy. CONCLUSIONS: Our results demonstrate that home albumin infusion can be performed safely. PMID- 26248470 TI - Dealing with the incidental finding of secondary variants by the example of SRNS patients undergoing targeted next-generation sequencing. AB - BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is a severe cause of progressive renal disease. Genetic forms of SRNS can present with autosomal recessive or autosomal dominant inheritance. Recent studies have identified mutations in multiple podocyte genes responsible for SRNS. Improved sequencing methods (next-generation sequencing, NGS) now promise rapid mutational testing of SRNS genes. METHODS: In the present study, a simultaneous screening of ten SRNS genes in 37 SRNS patients was performed by NGS. RESULTS: In 38 % of the patients, causative mutations in one SRNS gene were found. In 22 % of the patients, in addition to these mutations, a secondary variant in a different gene was identified. CONCLUSIONS: This high incidence of accumulating sequence variants was unexpected but, although they might have modifier effects, the pathogenic potential of these additional sequence variants seems unclear so far. The example of molecular diagnostics by NGS in SRNS patients shows that these new sequencing technologies might provide further insight into molecular pathogenicity in genetic disorders but will also generate results, which will be difficult to interpret and complicate genetic counseling. Although NGS promises more frequent identification of disease-causing mutations, the identification of causative mutations, the interpretation of incidental findings and possible pitfalls might pose problems, which hopefully will decrease by further experience and elucidation of molecular interactions. PMID- 26248472 TI - Urinary KIM-1 in children undergoing nephrotoxic antineoplastic treatment: a prospective cohort study. AB - BACKGROUND: Acute kidney injury (AKI) is a significant complication in patients with cancer, and nephrotoxic drugs are among the most common causes of AKI. To date, there is no study evaluating the potential role of renal biomarkers in children receiving nephrotoxic chemotherapy. METHODS: A prospective study was conducted in children receiving methotrexate (MTX) or platinum-based treatment. Urinary kidney injury molecule-1 (KIM-1) was measured 24 h after the initiation of the chemotherapy infusion, and serum creatinine (sCr) was measured prior to drug infusion and at 24, 48, 72, and 96 h, 1 and 2 weeks, and 3 months post initiation of treatment. RESULTS: A total of 64 children were evaluated, of whom 21 (32.8%) developed AKI. The majority had AKI stage 1 (n = 12, 57.1%) and only one developed AKI stage 3. Median values of urinary KIM-1 were higher in patients with AKI than in those without AKI [10.7, interquartile range (IQR) 1.6-17.9 vs. 4.3 (IQR 1.3-6.1) ng/mg creatinine; p < 0.01]. Urinary KIM-1 showed good discrimination for AKI in patients receiving nephrotoxic chemotherapy, with an area under the receiver operator characteristic curve for AKI up to 1 week later of 0.82 (95% confidence interval 0.66-0.95). Even when measured only 24 h after drug infusion, urinary KIM-1 still showed good discrimination to predict persistent renal impairment three months later. CONCLUSION: Urinary KIM-1 measured 24 h after the start of drug infusion has the potential to detect early AKI in pediatric patients treated with MTX or platinum-class drugs. PMID- 26248473 TI - Long-term treatment by ACE inhibitors and angiotensin receptor blockers in children with Alport syndrome. AB - BACKGROUND: The aim of this study was to analyze the long-term efficacy and safety of angiotensin-converting enzyme inhibitor (ACEi) and ACEi + angiotensin receptor blocker (ARB) treatments in a cohort of children with Alport syndrome (AS). METHODS: This was a respective review of 79 Chinese children with AS who received ACEi alone or combined ACEi + ARB therapy. RESULTS: The mean age of the pediatric patients with AS at onset of treatment was 8.6 +/- 4.1 (range 1.5-16.3) years. The mean duration of follow-up was 2.5 +/- 1.8 (range 0.5-7.8) years. For analysis, we separated the children into three groups according to proteinuria level before treatment, namely, <25, 25-50, and >=50 mg/kg/day, respectively; after 1 year of treatment the proteinuria had decreased from 11.0 to 9.7 mg/kg/day, from 34.6 to 15.2 mg/kg/day, and from 73.0 to 50.0 mg/kg/day in each group, respectively. Proteinuria decreased significantly during the first 2 years of treatment and was stable from the third to fifth years of treatment. There was no statistically significant difference in the antiproteinuric effect of the ACEi and ACEi + ARB treatments in patients with severe or less severe mutations after 1 year of therapy. Five children stopped the ACEi + ARB treatment due to a decline in creatinine clearance. CONCLUSION: Our findings demonstrate that early and long-term ACEi and ARB treatments in children with AS is efficient and well tolerated. The antiproteinuric effect of ACEi and ARB is of equal value in children with severe and less severe mutations in the COL4An gene. PMID- 26248474 TI - Social functioning and autonomic nervous system sensitivity across vocal and musical emotion in Williams syndrome and autism spectrum disorder. AB - Both Williams syndrome (WS) and autism spectrum disorders (ASD) are associated with unusual auditory phenotypes with respect to processing vocal and musical stimuli, which may be shaped by the atypical social profiles that characterize the syndromes. Autonomic nervous system (ANS) reactivity to vocal and musical emotional stimuli was examined in 12 children with WS, 17 children with ASD, and 20 typically developing (TD) children, and related to their level of social functioning. The results of this small-scale study showed that after controlling for between-group differences in cognitive ability, all groups showed similar emotion identification performance across conditions. Additionally, in ASD, lower autonomic reactivity to human voice, and in TD, to musical emotion, was related to more normal social functioning. Compared to TD, both clinical groups showed increased arousal to vocalizations. A further result highlighted uniquely increased arousal to music in WS, contrasted with a decrease in arousal in ASD and TD. The ASD and WS groups exhibited arousal patterns suggestive of diminished habituation to the auditory stimuli. The results are discussed in the context of the clinical presentation of WS and ASD. PMID- 26248475 TI - A Pharmacist-Physician Intervention Model Using a Computerized Alert System to Reduce High-Risk Medication Use in Elderly Inpatients. AB - BACKGROUND: Prescription is a complex challenge facing clinicians caring for elderly inpatients. Potentially inappropriate medication (PIM) use frequently leads to adverse drug events and geriatric syndromes. Strategies to reduce PIM use are thus urgently needed. OBJECTIVES: The objectives of this study were to assess (1) the applicability of a pharmacist-physician intervention model to reduce the use of high-risk medications; and (2) the clinical relevance of the alerts generated by a computerized alert system (CAS). METHODS: The study was conducted in patients aged 65 years or older admitted to a teaching hospital between April and June 2014. In the intervention model, the pharmacist determined the clinical relevance of the Beers criteria-based CAS alerts, analyzed the patient's pharmacotherapy, and developed a geriatric pharmacotherapeutic plan to be discussed with the treating physician. The main outcome was the change rate, defined as the number of patient-days with a change in at least one medication out of the number of patient-days with a pharmacist intervention. RESULTS: The CAS identified at least one alert in 200 patient-days, i.e., 4.3% of screened patient-days. In 74.5% of those patient-days, at least one alert was judged to be clinically relevant. The change rate was 77.7%. The most frequent changes were drug discontinuation (42.4%) and dose reduction (29.1%). The inpatient geriatric consultation team was involved in only 24% of the hospitalizations with at least one change in medication. CONCLUSION: The intervention model reduced high-risk medication use in older inpatients. Most of the vulnerable inpatients identified by CAS alerts would not have otherwise had a geriatric medication review. PMID- 26248476 TI - Leaf dynamics in growth and reproduction of Xanthium canadense as influenced by stand density. AB - BACKGROUND AND AIMS: Leaf longevity is controlled by the light gradient in the canopy and also by the nitrogen (N) sink strength in the plant. Stand density may influence leaf dynamics through its effects on light gradient and on plant growth and reproduction. This study tests the hypothesis that the control by the light gradient is manifested more in the vegetative period, whereas the opposite is true when the plant becomes reproductive and develops a strong N sink. METHODS: Stands of Xanthium canadense were established at two densities. Emergence, growth and death of every leaf on the main stem and branches, and plant growth and N uptake were determined from germination to full senescence. Mean residence time and dry mass productivity were calculated per leaf number, leaf area, leaf mass and leaf N (collectively termed 'leaf variables') in order to analyse leaf dynamics and its effect on plant growth. KEY RESULTS: Branching and reproductive activities were higher at low than at high density. Overall there was no significant difference in mean residence time of leaf variables between the two stands. However, early leaf cohorts on the main stem had a longer retention time at low density, whereas later cohorts had a longer retention time at high density. Branch leaves emerged earlier and tended to live longer at low than at high density. Leaf efficiencies, defined as carbon export per unit investment of leaf variables, were higher at low density in all leaf variables except for leaf number. CONCLUSIONS: In the vegetative phase of plant growth, the light gradient strongly controls leaf longevity, whereas later the effects of branching and reproductive activities become stronger and over-rule the effect of light environment. As leaf N supports photosynthesis and also works as an N source for plant development, N use is pivotal in linking leaf dynamics with plant growth and reproduction. PMID- 26248477 TI - Fluidic-Based Ion Memristors and Ionic Latches. AB - The formation of a nanoscale anodic silicon oxide layer on silicon electrodes in an aqueous environment leads to fluidic-based ionic memristive devices and ionic latches for large integrated fluidic ion logic circuitry, which can enable massively multiplexed smart biosensor arrays and complex active chemical circuits. PMID- 26248478 TI - Feeding jejunostomy tube placement during resection of gastric cancers. AB - BACKGROUND: Feeding tube placement is common among patients undergoing gastrectomy, and national guidelines currently recommend consideration of a feeding jejunostomy tube (FJT) for all patients undergoing resection for gastric cancer. However, data are limited regarding the safety of FJT placement at the time of gastrectomy for gastric cancer. METHODS: The 2005-2011 American College of Surgeons National Surgical Quality Improvement Program Participant User Files were queried to identify patients who underwent gastrectomy for gastric cancer. Subjects were classified by the concomitant placement of an FJT. Groups were then propensity matched using a 1:1 nearest neighbor algorithm, and outcomes were compared between groups. The primary outcomes of interest were overall 30-d overall complications and mortality. Secondary end points included major complications, surgical site infection, and early reoperation. RESULTS: In total, 2980 subjects underwent gastrectomy for gastric cancer, among whom 715 (24%) also had an FJT placed. Patients who had an FJT placed were more likely to be male (61.6% versus 56.6%, P = 0.02), have recent weight loss (21.0% versus 14.8%, P < 0.01), and have undergone recent chemotherapy (7.9% versus 4.2%, P < 0.01) and radiation therapy (4.2% versus 1.3%, P < 0.01). They were also more likely to have undergone total (compared with partial) gastrectomy (66.6% versus 28.6%, P < 0.01) and have concomitant resection of an adjacent organ (40.4 versus 24.1%, P < 0.01). After adjustment with propensity matching, however, all baseline characteristics and treatment variables were highly similar. Between groups, there were no statistically significant differences in 30-d overall complications (38.8% versus 36.1%, P = 0.32) or mortality (5.8 versus 3.7%, P = 0.08). There were also no differences in major complications, surgical site infection, or early reoperation. Operative time was slightly longer among patients with feeding tubes placed (median, 248 versus 233 min, P = 0.01), but otherwise there were no significant differences in any outcomes between groups. CONCLUSIONS: Concomitant placement of FJT at the time of gastrectomy may result in slightly increased operative times but does not appear to lead to increased perioperative morbidity or mortality. Further investigation is needed to identify the patients most likely to benefit from FJT placement. PMID- 26248479 TI - The impact of public versus private insurance on trauma patients. AB - BACKGROUND: The socioeconomic status has been associated with disparities in the incidence and mortality of traumatic injuries. However, there is a lack of studies on the level of health insurance with regard to various epidemiologic data of traumatic injuries, which this study opted to clarify. MATERIALS AND METHODS: All consecutive 6595 patients admitted to a level one trauma center in 2012 and 2013 were included in this retrospective cohort study. Patients were grouped according to their health insurance status (public versus private extended health care insurance) and compared with regard to several epidemiologic variables, that is, the type of injuries, inhospital outcome, and surgical procedures. RESULTS: Public insurance coverage was significantly more common than private insurance (75% versus 25%). Public insurance was associated with younger age, male sex, transfers to another hospital or mental institution, head concussions, head fractures, and increased mortality. Contrarily, patients with private insurance were more often associated with longer hospital stay, discharge to a rehabilitation clinic, fractures of the proximal humerus, and shoulder dislocations. However, there were no significant differences for the remaining majority of studied variables. CONCLUSIONS: In a trauma setting, the level of insurance does not seem to play a crucial role in most types of injuries and surgical procedures in a country with a high level of obligatory health care coverage. Nonetheless, it appears that publicly insured patients are more commonly younger, males, transferred to another hospital more often, more prone to head trauma, and subject to increased mortality, whereas privately insured patients show longer hospital stays, increased transfers to rehabilitation clinics, and more fractures of the proximal humerus. PMID- 26248480 TI - Isolation and characterisation of a novel trophoblast side-population from first trimester placentae. AB - The placenta is responsible for all nutrient and gas exchange between mother and baby during pregnancy. The differentiation of specialised placental epithelial cells called trophoblasts is essential for placental function, but we understand little about how these populations arise. Mouse trophoblast stem cells have allowed us to understand many of the factors that regulate murine trophoblast lineage development, but the human placenta is anatomically very different from the mouse, and it is imperative to isolate a human trophoblast stem cell to understand human placental development. Here we have developed a novel methodology to isolate a Hoechst side-population of trophoblasts from early gestation placentae and compared their transcriptome to differentiated trophoblast populations (cytotrophoblasts and extravillous trophoblasts) using microarray technology. Side-population trophoblasts clustered as a transcriptomically distinct population but were more closely related to cytotrophoblasts than extravillous trophoblasts. Side-population trophoblasts up regulated a number of genes characteristic of trophectoderm and murine trophoblast stem cells in comparison to cytotrophoblasts or extravillous trophoblasts and could be distinguished from both of these more mature populations by a unique set of 22 up-regulated genes, which were enriched for morphogenesis and organ development and the regulation of growth functions. Cells expressing two of these genes (LAMA2 and COL6A3) were distributed throughout the cytotrophoblast layer at the trophoblast/mesenchymal interface. Comparisons to previously published trophoblast progenitor populations suggest that the side population trophoblasts isolated in this work are a novel human trophoblast population. Future work will determine whether these cells exhibit functional progenitor/stem cell attributes. PMID- 26248481 TI - Pd nanoparticles encapsulated in magnetic carbon nanocages: an efficient nanoenzyme for the selective detection and multicolor imaging of cancer cells. AB - Rapid and simple molecular recognition based techniques for the identification of the subtypes of cancer cells are essential in molecular medicine. However, improving the sensitivity and accuracy of the early diagnosis of this disease remains a major challenge. Herein, we develop a novel approach for the in situ growth of palladium nanoparticles in magnetic carbon nanocages (PdNPs/MCNCs). The confined Pd NPs, which have excellent dispersion in magnetic carbon nanocages, show superior catalytic performance for the cleavage reaction of N-butyl-4 NHAlloc-1,8-naphthalimide (NNPH), thereby producing significant changes in both color (from colorless to jade-green) and fluorescence (from blue to green) through the ICT process. Based on the abovementioned results, a novel sensing platform utilizing the PdNPs/MCNC nanocatalyst as an artificial enzyme and NNPH as a fluorescent and color change reporter molecule for the multicolor imaging and colorimetric detection of cancer cells was developed. We envision that this nanomaterial can be used as a power tool for a wide range of potential applications in biotechnology and medicine. PMID- 26248482 TI - Inverse relationship between cancer and Alzheimer's disease: a systemic review meta-analysis. AB - Alzheimer's disease (AD) and cancer are both prevalent in the elderly. Some epidemiological researches have reported the negative association between AD and cancer, but the results are controversial. The present meta-analysis is aimed to clarify the association between cancer and AD. PubMed, Web of knowledge and the Cochrane library databases were searched for eligible publications. The analysis indicated that history of cancer was associated with a reduced risk of AD (ES 0.62, 95 % CIs 0.53-0.74; p < 0.001), with no significance between-study heterogeneity and publication bias. Similar results were found in subgroup analysis by stratifying variables with education and APOEepsilon4 carriers, years of follow-up and sample size of cases. The negative association was also found in analysis of risk of cancer among patients with AD (ES 0.59, 95 % CIs 0.42-0.82; p = 0.002), but with evidence of between-study heterogeneity and publication bias. In order to identify sources of the heterogeneity, subgroup analysis was performed by stratifying variable with or without education adjusted, sample size of cases and years of follow-up. Negative association was found in all subgroup analysis except in studies with less than 5-year follow-up and with heterogeneity disappeared only in the subgroup analysis stratified with sample size of cases. Our results in the present meta-analysis support the negative association between AD and cancer. But further well-designed perspective studies with strict control of confounding factors are needed to clarify the association between AD and cancer. PMID- 26248484 TI - In vivo magnetic resonance imaging of iron oxide-labeled, intravenous-injected mesenchymal stem cells in kidneys of rabbits with acute ischemic kidney injury: detection and monitoring at 1.5 T. AB - BACKGROUND: Acute kidney injury (AKI) is one of the most important causes of mortality and morbidity worldwide. Mesenchymal stem cells (MSCs) can be used for stem cell-based therapy containing AKI. Magnetic resonance imaging (MRI) is an ideal mean for stem cells tracking by labeling with superparamagnetic iron oxide (SPIO). Therefore, using the iron oxide-labeled mesenchymal stem cells (MSC) to treat the AKI and evaluating migration, distribution, and homing of cells by MRI is an ideal method for cell therapy and cell tracking in vivo. METHODS: In vitro, the MSCs were labeled with 25 MUg/mL for 24 h, and test the labeled efficiency and cells viability. In vitro experiments, magnetic resonance imaging (MRI) measurement of non-labeled and SPIO-labeled MSCs (SPIO-MSCs) was performed in correlation to detectable cells concentrations and detectable time windows. In vivo experiments, MRI evaluation was performed before and after ischemic/reperfusion AKI (N = 14) and intravenous injection of 5 * 10(5) SPIO MSCs (N = 10), PBS (N = 6) up to 8 days using a clinical 1.5 T scanner. Signal intensity of kidneys were measured and tested for statistical significance (unpaired Student's t-test, p < 0.05) in comparison histology (hematoxylin and eosin [H&E], Prussian blue). RESULTS: In vitro, MSCs can be labeled with the SPIO without affecting the viability and labeling efficiency. SPIO-MSCs showed a reduction of signal intensity at T2WI and T2*WI, 5 * 10(4) cells/mL, SPIO-MSCs were the minimum imaging cells concentration using a 1.5 T MR in vitro. In vivo, SPIO-MSCs administration resulted in a T2*WI signal intensity decrease in renal medulla caused by SPIO-MSCs accumulation in contrast to control groups (p < 0.05) up to day 3 after transplantation, but T2*WI low signal intensity region of the renal medulla revealed an decrease at day 5, and no significant differences between SPIO-MSCs and control animals at day 8. CONCLUSION: Our data demonstrate that in vitro and in vivo, cell-tracking and monitoring of kidney distribution of intravenous injected SPIO-MSCs after AKI is feasible in MRI at 1.5 T. PMID- 26248483 TI - Linking insulin with Alzheimer's disease: emergence as type III diabetes. AB - Alzheimer's disease (AD) has characteristic neuropathological abnormalities including regionalized neurodegeneration, neurofibrillary tangles, amyloid beta (Abeta) deposition, activation of pro-apoptotic genes, and oxidative stress. As the brain functions continue to disintegrate, there is a decline in person's cognitive abilities, memory, mood, spontaneity, and socializing behavior. A framework that sequentially interlinks all these phenomenons under one event is lacking. Accumulating evidence has indicated the role of insulin deficiency and insulin resistance as mediators of AD neurodegeneration. Herein, we reviewed the evidence stemming from the development of diabetes agent-induced AD animal model. Striking evidence has attributed loss of insulin receptor-bearing neurons to precede or accompany initial stage of AD. This state seems to progress with AD such that, in the terminal stages, it worsens and becomes global. Oxidative stress, tau hyperphosphorylation, APP-Abeta deposition, and impaired glucose and energy metabolism have all been linked to perturbation in insulin/IGF signaling. We conclude that AD could be referred to as "type 3 diabetes". Moreover, owing to common pathophysiology with diabetes common therapeutic regime could be effective for AD patients. PMID- 26248485 TI - Effect of avocado/soybean unsaponifiables on ligature-induced bone loss and bone repair after ligature removal in rats. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the effects of administration of avocado/soybean unsaponifiable (ASU), a drug that is commonly used in the treatment of rheumatoid arthritis, on ligature-induced bone loss and bone repair after ligature removal in rats. MATERIAL AND METHODS: Eighty-four rats were randomly assigned to four groups of equal size and received a daily gavage of either sterile saline [control (CTR)] or ASU (0.6 mg/kg), starting 7 d before (ASU/-7), on the day of (ASU/0) or 7 d after (ASU/+7) periodontitis induction. Periodontitis was induced by placing silk ligatures into the gingival sulcus of the second maxillary molars for 7 d; after 7 d, the ligatures were removed. Seven rats from each group were sacrificed, 7, 15 or 30 d after ligature removal. Bone resorption was evaluated by histomorphometry and micro-computed tomography (micro-CT). Immunohistochemistry was used to evaluate the expression of TRAP, RANKL and alkaline phosphatase (ALP), and quantitative PCR (qPCR) was used to evaluate the levels of interleukin-1beta (Il1beta), tumor necrosis factor alpha (Tnfalpha), interleukin-6 (Il-6), Rankl and Alp. Statistical analysis was performed using the Shapiro-Wilk test, ANOVA and Tukey's test for normal data, and using the Kruskall-Wallis and Dunnet's tests for non-normal data (p < 0.05). RESULTS: Histomorphometry and micro-CT analysis showed greater bone resorption in the CTR group than in the ASU/0 (15 d) and ASU/+7 (7 and 15 d) groups. The CTR group also presented with a higher expression of TRAP (15 and 30 d) and RANKL (7 and 15 d) compared with ASU/0 and ASU/+7 groups. Similarly, qPCR analysis showed higher levels of Rankl and Il1beta mRNAs, and lower levels of Alp mRNA, in the CTR group compared with all other groups (for all periods). CONCLUSION: ASU exhibited a positive effect on bone repair following ligature-induced periodontitis in rats. PMID- 26248486 TI - Effect of persulfate and persulfate/H2O2 on biodegradability of an anaerobic stabilized landfill leachate. AB - The current study investigated the effects of S2O8(2-) and S2O8(2-)/H2O2 oxidation processes on the biodegradable characteristics of an anaerobic stabilized leachate. Total COD removal efficiency was found to be 46% after S2O8(2-) oxidation (using 4.2 g S2O8(2-)/1g COD0, at pH 7, for 60 min reaction time and at 350 rpm shaking speed), and improved to 81% following S2O8(2-)/H2O2 oxidation process (using 5.88 g S2O8(2-) dosage, 8.63 g H2O2 dosage, at pH 11 and for 120 min reaction time at 350 rpm). Biodegradability in terms of BOD5/COD ratio of the leachate enhanced from 0.09 to 0.1 and to 0.17 following S2O8(2-) and S2O8(2-)/H2O2 oxidation processes, respectively. The fractions of COD were determined before and after each oxidation processes (S2O8(2-) and S2O8(2 )/H2O2). The fraction of biodegradable COD(bi) increased from 36% in raw leachate to 57% and 68% after applying S2O8(2-) and S2O8(2-)/H2O2 oxidation, respectively. As for soluble COD(s), its removal efficiency was 39% and 78% following S2O8(2-) and S2O8(2-)/H2O2 oxidation, respectively. The maximum removal for particulate COD was 94% and was obtained after 120 min of S2O8(2-)/H2O2 oxidation. As a conclusion, S2O8(2-)/H2O2 oxidation could be an efficient method for improving the biodegradability of anaerobic stabilized leachate. PMID- 26248487 TI - Response surface methodology assisted biodiesel production from waste cooking oil using encapsulated mixed enzyme. AB - In the recent scenario, consumption of petroleum fuels has increased to greater height which has led to deforestation and decline in fossil fuels. In order to tackle the perilous situation, alternative fuel has to be generated. Biofuels play a vital role in substituting the diesel fuels as they are renewable and ecofriendly. Biodiesel, often referred to as green fuel, could be a potential replacement as it could be synthesized from varied substrates, advantageous being the microalgae in several ways. The present investigation was dealt with the interesterification of waste cooking oil using immobilised lipase from mixed cultures for biodiesel production. In order to standardize the production for a scale up process, the parameters necessary for interesterification had been optimized using the statistical tool, Central Composite Design - Response Surface Methodology. The optimal conditions required to generate biodiesel were 2 g enzyme load, 1:12 oil to methyl acetate ratio, 60 h reaction time and 35 degrees C temperature, yielding a maximum of 93.61% biodiesel. The immobilised lipase beads remain stable without any changes in their function and structure even after 20 cycles which made this study, less cost intensive. In conclusion, the study revealed that the cooking oil, a residue of many dining centers, left as waste product, can be used as a potential raw material for the production of ecofriendly and cost effective biofuel, the biodiesel. PMID- 26248488 TI - Recovery of essential nutrients from municipal solid waste--Impact of waste management infrastructure and governance aspects. AB - Every year 120-140 million tonnes of bio-waste are generated in Europe, most of which is landfilled, incinerated or stabilized and used as covering material in landfill operation. None of these practices enables the recovery of essential nutrients such as phosphorus (P) and nitrogen (N), which are in great demand for agricultural production. Recovery of these nutrients is a matter of international concern considering the non-renewable nature of P sources and the energy intensive production process required for the synthesis of N fertilizers. The objective of this research is to understand the relation between the municipal solid waste management (MSWM) system, both its the physical components and governance aspects, and the recovery of nutrients in Vitoria-Gasteiz (Basque Country) as a benchmark for European medium-size cities. The analysis shows that the existing physical infrastructure and facilities for bio-waste have high potential for nutrient recovery, 49% for N and 83% for P contained in bio-waste. However, governance aspects of the MSWM system such as legislation and user inclusivity play an important role and decrease the actual nutrient recovery to 3.4% and 7.4% for N and P respectively. PMID- 26248489 TI - Valsartan protects HK-2 cells from contrast media-induced apoptosis by inhibiting endoplasmic reticulum stress. AB - Contrast-induced acute kidney injury (CI-AKI) is associated with increasing in hospital and long-term adverse clinical outcomes in high-risk patients undergoing percutaneous coronary intervention (PCI). Contrast media (CM)-induced renal tubular cell apoptosis is reported to participate in this process by activating endoplasmic reticulum (ER) stress. An angiotensin II type 1 receptor (AT1R) antagonist can alleviate ER stress-induced renal apoptosis in streptozotocin (STZ)-induced diabetic mice and can reduce CM-induced renal apoptosis by reducing oxidative stress and reversing the enhancement of bax mRNA and the reduction of bcl-2 mRNA, but the effect of the AT1R blocker on ER stress in the pathogenesis of CI-AKI is still unknown. In this study, we explored the effect of valsartan on meglumine diatrizoate-induced human renal tubular cell apoptosis by measuring changes in ER stress-related biomarkers. The results showed that meglumine diatrizoate caused significant cell apoptosis by up-regulating the expression of ER stress markers, including glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), CCAAT/enhancer-binding protein-homologous protein (CHOP) and caspase 12, in a time- and dose-dependent manner, which could be alleviated by preincubation with valsartan. In conclusion, valsartan had a potential nephroprotective effect on meglumine diatrizoate-induced renal cell apoptosis by inhibiting ER stress. PMID- 26248490 TI - Co-overexpression of lmbW and metK led to increased lincomycin A production and decreased byproduct lincomycin B content in an industrial strain of Streptomyces lincolnensis. AB - AIMS: To improve lincomycin A production and decrease the content of byproduct lincomycin B in an industrial lincomycin-producing strain. METHODS AND RESULTS: The in silico analysis indicated that LmbW could be involved in propylproline biosynthesis of lincomyin A. In this study, we constructed an lmbW deletion mutant and found that the mutant lost the ability to produce lincomycin A, but increased the accumulation of lincomycin B. The loss of lincomycin A production can be restored by complementing the mutant with the expression of lmbW gene. When lmbW and metK (encoding S-adenosylmethionine synthetase) was co overexpressed, lincomycin A titre was 1744.6 mg l(-1) , a 35.83% improvement over the original strain. Meanwhile, the content of lincomycin B was reduced to 4.41%, a remarkable decrease of 34.76%, compared to that of the original strain. CONCLUSIONS: lmbW encodes a C-methyltransferase involved in the biosynthesis of lincomycin A but not lincomycin B. Co-overexpression of lmbW and metK improved lincomycin A production and decreased the content of lincomycin B. SIGNIFICANCE AND IMPACT OF THE STUDY: The engineered Streptomyces lincolnensis strain shows promising application in the fermentation production of lincomycin A, which may help cut production costs and simplify downstream separation processes. PMID- 26248491 TI - Comparison of abdominal wall morbidity between medial and lateral row-based deep inferior epigastric perforator flap. AB - INTRODUCTION: Although deep inferior epigastric perforator (DIEP) flap is associated with decreased abdominal morbidity, motor nerve damage during flap elevation cannot be ignored. We compared abdominal morbidity after elevation of DIEP flap with lateral row perforators (L-DIEP) and medial row perforators (M DIEP) to determine the perforators associated with less abdominal morbidity. METHODS: Women who underwent breast reconstruction with DIEP flaps (n = 49) were included in this study. Among them, M-DIEP and L-DIEP were harvested in 27 and 22 patients, respectively. Pre- and postoperative trunk flexor muscle ability (at 3 and 6 months after surgery) was measured prospectively in all patients using an isokinetic dynamometer. The patients were also investigated for postoperative pain, stiffness, activity, bulging, and lumbago. RESULTS: At 3 months after surgery, a significant decrease in trunk flexor muscle ability was observed in the patients of the L-DIEP group, but they recovered well after further 3 months. However, the recovery tended to be weak. Similar results were obtained with respect to pain, stiffness, activity, bulging, and lumbago between the two groups at 6 months after surgery. CONCLUSIONS: Dominant perforators for DIEP flap elevation should be chosen by considering flap viability. However, surgeons should be aware that elevation with L-DIEP is associated with a high risk of nerve injury, and may in turn result in short-term decreases in trunk flexor muscle ability. Therefore, precautionary methods should be taken by the surgeons to preserve the motor nerve with atraumatic dissection, especially during elevation with L-DIEP. PMID- 26248492 TI - Lateral platysma resection and resetting as an alternative approach to correct aesthetic neck deformity. PMID- 26248493 TI - Re: 'SeriTM: A surgical scaffold for breast reconstruction or for bacterial ingrowth?'. PMID- 26248494 TI - Oral glucocorticoid pulse therapy for induction of treatment of canine pemphigus foliaceus - a comparative study. AB - BACKGROUND: The management of canine pemphigus foliaceus (PF) often requires long term immunosuppressive treatment that is often associated with unacceptable adverse effects. High-dose glucocorticoid pulse therapy, an alternative protocole used for pemphigus in people, has been shown to provide rapid improvement in dogs with pemphigus foliaceus and vulgaris. OBJECTIVES: To further identify the benefit of pulse therapy for management of canine PF, we compared the outcomes of oral glucocorticoid pulse and traditional therapies during the first 3 months of disease management. ANIMALS: Dogs were allocated based on their oral glucocorticoid regimen during the first 12 weeks of PF management into the 'traditional' (20 dogs) or the 'pulse' (18 dogs) treatment groups. RESULTS: The proportion of dogs achieving complete remission (CR) during the first 12 weeks of treatment was significantly higher for the 'pulse' (61%) than for the 'traditional' group (15%; P = 0.0063). The maximal oral glucocorticoid dosage given to dogs from the 'traditional' group was significantly higher (median: 3.2 mg/kg) than that given between pulses to dogs from the other group (median: 1.1 mg/kg; P < 0.0001). There was no significant difference between groups in the time needed to achieve CR, the proportion of dogs requiring adjuvant immunosuppressive treatment or in the proportion of dogs experiencing severe adverse drug reactions. CONCLUSIONS AND CLINICAL IMPORTANCE: These results suggest several benefits associated with oral glucocorticoid pulse therapy, such as a higher proportion of dogs achieving CR during the first 3 months, a lower average maximal oral glucocorticoid dosage given between pulses and minimal adverse drug events. PMID- 26248495 TI - The Effect of Compression Stockings on Cerebral Desaturation Events in Obese Patients Undergoing Shoulder Arthroscopy in the Beach-Chair Position. AB - PURPOSE: To determine if the use of thigh-high compression stockings could decrease the incidence of cerebral desaturation events (CDEs) in patients with a body mass index (BMI) of 30 kg/m(2) or greater undergoing shoulder arthroscopy in the beach-chair position (BCP). METHODS: Between December 2013 and May 2014, 23 patients aged 18 years or older with a BMI of 30 kg/m(2) or greater undergoing shoulder arthroscopy in the BCP were monitored intraoperatively using near infrared spectroscopy while wearing thigh-high compression stockings. Data obtained on these patients were compared with data from a previous cohort at our institution comprising 24 patients with a BMI of 30 kg/m(2) or greater who underwent elective shoulder arthroscopy in the BCP with the same monitoring but without wearing compression stockings. The incidence of CDEs was identified in each group. RESULTS: The incidence of CDEs in the group with compression stockings was 4% (1 of 23) compared with 18% (7 of 24) in the group without compression stockings (P = .048). There were no statistically significant differences in mean age (53.0 years v 53.3 years, P = .91), mean BMI (34.5 kg/m(2)v 36.2 kg/m(2), P = .21), or various medical comorbidities between the treatment group and control group. There was a significant difference in the operative time between the treatment group (156.6 minutes) and control group (94.1 minutes) (P < .001). CONCLUSIONS: The use of thigh-high compression stockings may decrease the incidence of CDEs in obese patients undergoing shoulder arthroscopy in the BCP. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26248496 TI - Results of Surgical Treatment of Chronic Patellar Tendinosis (Jumper's Knee): A Systematic Review of the Literature. AB - PURPOSE: To review the literature concerning surgical treatment options for chronic patellar tendinosis (jumper's knee), a common problem among athletes. When conservative treatment fails, surgical treatment is required. METHODS: Systematic review of the literature concerning the results of current surgical treatment options for chronic patellar tendinosis. All articles of studies with an evidence level >=IV from January 2000 until February 2015 presenting the surgical outcome after arthroscopic as well as open treatment of chronic patellar tendinosis were included. The literature research of the PubMed database was performed using the following key words: "patellar" and "tendinitis," "tendonitis," "tendinosis" or "tendinopathy"; "inferior patellar pole"; "jumper's knee"; "surgical treatment" and "open" or "arthroscopic patellar tenotomy." RESULTS: A systematic review of the literature was performed especially to point out the effectiveness of arthroscopic treatment of chronic patellar tendinosis. The results revealed good clinical results for arthroscopic as well as open treatment of chronic patellar tendinosis that is refractory to conservative treatment in athletes. An average success rate of 87% was found for the open treatment group and of 91% for the arthroscopic treatment group. However, after open surgery, the mean time of return to the preinjury level of activity is 8 to 12 months, with a certain number of patients/athletes who cannot return to the preinjury level of activity. CONCLUSIONS: Minimally invasive, arthroscopically assisted or all-arthroscopic procedures may lead to a significantly faster return to sporting activities and may, therefore, be the preferred method of surgical treatment. LEVEL OF EVIDENCE: Level IV, systematic review of Level I-IV studies. PMID- 26248497 TI - The evolution of digit form in Gonatodes (Gekkota: Sphaerodactylidae) and its bearing on the transition from frictional to adhesive contact in gekkotans. AB - Although the phenomenon of adhesion in geckos has been intensively studied for over 200 years, our understanding of how the morphological apparatus associated with this arose is less clear. Indeed, whether or not all of the intricate morphological hierarchy that is implicated in the attachment and removal of the adhesive setae originated at the same time is unknown. To explore whether setae may have arisen prior to the other parts of this structural hierarchy, we undertook morphological observations of Gonatodes, an ancestrally padless, sphaerodatyline genus known to exhibit the expression of incipient subdigital pads in some species. Focusing on this geographically and morphologically well circumscribed genus, for which intraspecific relationships are adequately known and ecology is quite well documented, allowed us to deduce trends in digit proportions, shape, scalation, and skeletal structure, and associate these with the micro-ornamentation of the subdigital surfaces. Our findings indicate that in Gonatodes, setae capable of inducing adhesion are present without the modifications of the digital musculotendinous, circulatory and skeletal systems that are generally considered to be necessary for the operation of a functional adhesive apparatus. The acquisition of these latter characteristics (independently in many lineages of gekkotans, and incipiently so in Anolis) may have been preceded by a suite of modifications of the digits that enhanced static clinging in relation to sit-and-wait predation and the ability to take refuge on surfaces unavailable to other taxa. These possibilities await further testing. PMID- 26248498 TI - A Combination of Amino Acids and Caffeine Enhances Sprint Running Capacity in a Hot, Hypoxic Environment. AB - Heat and hypoxia exacerbate central nervous system (CNS) fatigue. We therefore investigated whether essential amino acid (EAA) and caffeine ingestion attenuates CNS fatigue in a simulated team sport-specific running protocol in a hot, hypoxic environment. Subelite male team sport athletes (n = 8) performed a repeat sprint running protocol on a nonmotorized treadmill in an extreme environment on 4 separate occasions. Participants ingested one of four supplements: a double placebo, 3 mg.kg-1 body mass of caffeine + placebo, 2 x 7 g EAA (Musashi Create)+placebo, or caffeine + EAA before each exercise session using a randomized, double-blind crossover design. Electromyography (EMG) activity and quadriceps evoked responses to magnetic stimulation were assessed from the dominant leg at preexercise, halftime, and postexercise. Central activation ratio (CAR) was used to quantify completeness of quadriceps activation. Oxygenation of the prefrontal cortex was measured via near-infrared spectroscopy. Mean sprint work was higher (M = 174 J, 95% CI [23, 324], p < .05, d = 0.30; effect size, likely beneficial) in the caffeine + EAA condition versus EAAs alone. The decline in EMG activity was less (M = 13%, 95% CI [0, 26]; p < .01, d = 0.58, likely beneficial) in caffeine + EAA versus EAA alone. Similarly, the pre- to postexercise decrement in CAR was significantly less (M = -2.7%, 95% CI [0.4, 5.4]; p < .05, d = 0.50, likely beneficial) when caffeine + EAA were ingested compared with placebo. Cerebral oxygenation was lower (M = -5.6%, 95% CI [1.0, 10.1]; p < .01, d = 0.60, very likely beneficial) in the caffeine + EAA condition compared with LNAA alone. Co-ingestion of caffeine and EAA appears to maintain muscle activation and central drive, with a small improvement in running performance. PMID- 26248499 TI - On the study of plant defence and herbivory using comparative approaches: how important are secondary plant compounds. AB - Species comparisons are a cornerstone of biology and there is a long tradition of using the comparative framework to study the ecology and evolution of plant defensive traits. Early comparative studies led to the hypothesis that plant chemistry plays a central role in plant defence, and the evolution of plant secondary chemistry in response to insect herbivory remains a classic example of coevolution. However, recent comparative work has disagreed with this paradigm, reporting little connection between plant secondary chemicals and herbivory across distantly related plant taxa. One conclusion of this new work is that the importance of secondary chemistry in plant defence may have been generally overstated in earlier research. Here, we attempt to reconcile these contradicting viewpoints on the role of plant chemistry in defence by critically evaluating the use and interpretation of species correlations as a means to study defence herbivory relationships. We conclude that the notion that plant primary metabolites (e.g. leaf nitrogen content) are the principal determinants of herbivory (or the target of natural selection by herbivores) is not likely to be correct. Despite the inference of recent community-wide studies of herbivory, strong evidence remains for a prime role of secondary compounds in plant defence against herbivores. PMID- 26248500 TI - Assessment of cytology and mucin 2 in colorectal mucus collected from patients with inflammatory bowel disease: Results of a pilot trial. AB - BACKGROUND AND AIM: Non-invasive diagnosis of colorectal disease remains problematic, fecal biomarkers presenting the only current option. Colorectal mucus is the diagnostically informative element of stool samples, but its separation from stool is difficult. We aimed to: (i) test a novel method of non invasive colorectal mucus sampling in a pilot clinical trial; (ii) evaluate sampling method acceptance by study participants; (iii) characterize the collected material cytologically; and (iv) assess feasibility of quantitative protein analysis in the samples. METHODS: A total of 141 patients with IBD (58), IBS (50), and healthy controls (33) participated in the study. Samples rich in colorectal mucus were self-collected by swabbing the anal area immediately following defecation. Collected samples were examined cytologically and subjected to quantitative analysis for total protein and mucin 2 (MUC2). RESULTS: The novel sampling technique was assessed as "good" or "adequate" by 96% of study participants. A total of 55% of the collected samples were free of fecal contamination. Cytology showed large numbers of well preserved inflammatory cells in IBD cases. Total protein values varied in all groups, being affected by fecal contamination. MUC2 levels were similar among all IBD-free individuals (control and IBS groups) and elevated in IBD patients (p < 0.001). MUC2 measurement applied as a test for IBD detection provided sensitivity = 72.4% and specificity = 86.7%. CONCLUSIONS: A novel non-invasive method for collecting human colorectal mucus has been successfully tested. The method was very well accepted by trial participants. The results have proven high quality of collected samples for both cytological investigation and diagnostic biomarker analysis. PMID- 26248501 TI - Hypoglycaemia in adults with insulin-treated diabetes in the UK: self-reported frequency and effects. AB - AIM: Few real-life studies of non-severe (self-treated) hypoglycaemic events are available. This survey quantified the self-reported frequency of non-severe hypoglycaemia and its effects in adults with insulin-treated diabetes in the UK. METHODS: Adults aged > 15 years with Type 1 diabetes or insulin-treated Type 2 diabetes completed <= 4 weekly questionnaires (7-day recall). Respondents with Type 2 diabetes were grouped by insulin regimen: basal-only, basal-bolus and 'other'. RESULTS: Overall, 1038 respondents (466 with Type 1 diabetes, 572 with Type 2 diabetes) completed 3528 questionnaires. Mean numbers of non-severe events per week were 2.4 (Type 1 diabetes; median = 2) and 0.8 (Type 2 diabetes; median = 0); 23% and 26% of non-severe events occurred at night, respectively. Fatigue and reduced alertness were the commonest issues following events (78% and 51% of respondents, respectively). The effects of nocturnal events persisted longer than those of daytime events: Type 1 diabetes = 10.6 vs. 4.9 h (P = 0.0002); Type 2 diabetes = 15.3 vs. 5.1 h (P < 0.0001). In the week following an event, respondents' blood glucose measurements increased by 4.3 (Type 1 diabetes; 12% increment) and 4.2 (Type 2 diabetes; 21% increment) tests/week. In employed respondents, 20% of events caused work-time loss, more so following nocturnal (vs. daytime) hypoglycaemia: Type 1 diabetes = 2.7 vs. 1.1 h (P = 0.0184); Type 2 diabetes = 2.5 vs. 1.6 h (P = 0.1340). Most respondents rarely/never informed healthcare professionals about events (Type 1 diabetes = 82%, Type 2 diabetes = 69%). CONCLUSIONS: Non-severe hypoglycaemia is common in adults with insulin treated diabetes in the UK, with consequent health-related/economic effects. Communication about non-severe hypoglycaemia is limited and the burden of hypoglycaemia may be underestimated. PMID- 26248503 TI - First Record of an Unusual Incident Between a Finfish--the White Snake Mackerel Thyrsitops lepidopoides (Teleostei, Gempylidae)--and a Surfer. PMID- 26248502 TI - Transcriptome analysis provides insights into the regulatory function of alternative splicing in antiviral immunity in grass carp (Ctenopharyngodon idella). AB - Characterization of the transcriptomic response to infection is an effective approach to understanding the immune mechanisms. Herein we challenged grass carp (Ctenopharyngodon idella) with grass carp reovirus (GCRV) and sequenced four cDNA libraries obtained from head-kidney and spleen by using Illumina Miseq. As a result, we gained a total of 21.52 Gb clean data with 107.96 million reads, and de novo assembled 55,199 unigenes with an average length of 1,470 bp. Comparative transcriptome analysis reveals that 217 unigenes are differentially expressed (fold-change of at least 4) between resistant and susceptible fish in both head kidney and spleen, and of which 36 unigenes were validated by RT-qPCR experiment. The expression profile of immune-related genes demonstrates that the immune response of spleen is more intense than that of head-kidney. Remarkably, 11,811 unigenes contain multiple transcripts, of which 322 unigenes possess notably differentially expressed transcripts between the four transcriptomic datasets. Furthermore, the splicing transcripts of IL-12p40 and IL-1R1 are firstly found to play diverse roles in the antiviral response of fishes. This study provides a complete transcriptome dataset of C. idella, which is valuable for the studies of immune complexity and, moreover, throws light on the regulatory role of AS in antiviral immunity. PMID- 26248504 TI - Novel Paths to Relevance: How Clinical Ethics Committees Promote Ethical Reflection. AB - How may clinical ethics committees (CECs) inspire ethical reflection among healthcare professionals? How may they deal with organizational ethics issues? In recent years, Norwegian CECs have attempted different activites that stretch or go beyond the standard trio of education, consultation, and policy work. We studied the novel activities of Norwegian CECs by examining annual reports and interviewing CEC members. Through qualitative analysis we identified nine categories of novel CEC activities, which we describe by way of examples. In light of the findings, we argue that some novel working methods may be well suited to promote ethical reflection among clinicians, and that the CEC may be a suitable venue for discussing issues of organizational ethics. PMID- 26248505 TI - A phase II study of bortezomib added to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with previously untreated indolent non Hodgkin's lymphoma. AB - Bortezomib-containing combinations are active in non-Hodgkin lymphoma (NHL) although peripheral neuropathy can limit their dose intensity. Based on our phase I findings, we conducted a phase II trial of bortezomib in combination with R CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with a modified dose of vincristine. Patients with untreated indolent NHL received bortezomib (1.6 mg/m(2) ) on days 1 and 8 of a 21-day cycle for up to 8 cycles and R-CHOP with a 1.5 mg cap of vincristine. Patients achieving a complete response (CR) received maintenance rituximab, and remaining patients received maintenance rituximab and bortezomib. The primary endpoint was CR rate; secondary survival analyses were evaluated using the Kaplan-Meier method. Among 29 eligible patients, NHL morphologies included follicular (n = 20), marginal zone (n = 5) and small lymphocytic lymphoma (n = 4). Nineteen patients had CR (66%) and 10 had partial response (34%), yielding a 100% overall response rate. With a median follow-up of 48.7 months, the 4-year progression-free and overall survivals were 83% and 93%. Twenty-two patients experienced peripheral neuropathy of any grade, and two had grade 3 neuropathy. The combination of bortezomib with R-CHOP is effective for indolent NHL, and we plan to evaluate therapies incorporating novel proteasome inhibitors in future studies in NHL. PMID- 26248506 TI - Long-term efficacy and safety of adjunctive extended-release oxcarbazepine (Oxtellar XR(r) ) in adults with partial-onset seizures. AB - OBJECTIVE: To evaluate long-term outcomes of adjunctive therapy with SPN-804 (Oxtellar XR(r) , Supernus Pharmaceuticals), an extended-release tablet formulation of oxcarbazepine (OXC), in adults with refractory partial-onset seizures. METHODS: After completing a 16-week double-blind, placebo-controlled trial of SPN-804 at fixed dosages (1200 or 2400 mg QD), patients entering this open-label extension study were converted in blinded fashion to 1200 mg QD SPN 804 as a target starting dose for long-term treatment. Patients were followed for 1 year, during which SPN-804 dosages could be adjusted up to 2400 mg/day according to clinical response. RESULTS: Of 214 patients, 84% completed 1-year open-label treatment. Median maintenance SPN-804 dosage was 1200 mg; <10% of patients required 2400 mg. Median 28-day seizure frequency reduction from baseline was 59%; seizure frequency was reduced >=50% in 58% of patients; 11% were seizure free >=6 months; and 5% were seizure free >=1 year. SPN-804 was discontinued due to adverse events in 5% (n = 10). Incidences of each of the most common adverse events (dizziness, headache, diplopia, nausea, vomiting, balance disorder, blurred vision) were <=15% during 1-year follow-up and occurred most frequently in patients previously naive to SPN-804. No new safety signals, no clinically significant changes in health status, and no deaths attributable to SPN-804 were observed. CONCLUSION: SPN-804 administered once daily for 1 year was effective as adjunctive therapy in improving seizure control and maintaining therapeutic response in adults with refractory partial-onset seizures. With dosage flexibility, SPN-804 was well tolerated. PMID- 26248507 TI - Editorial Comment to Urethra-sparing high-intensity focused ultrasound for localized prostate cancer: Functional and oncological outcomes. PMID- 26248508 TI - Brain-derived neurotrophic factor inhibits neuromuscular junction maturation mediated by inTracellular Ca(2+) and Ca(2+)/calmodulin-dependent kinase. AB - INTRODUCTION: Brain-derived neurotrophic factor (BDNF) inhibits neuromuscular junction (NMJ) maturation. In this study we investigated the underlying molecular mechanisms of this process. METHODS: We used a patch-clamp technique to measure spontaneous synaptic currents (SSCs) from innervated muscle cells in Xenopus nerve-muscle cocultures. RESULTS: In the presence of Ca(2+)/calmodulin-dependent kinase (CaMK) inhibitor KN93, SSC amplitude (226.3 +/- 26.5 pA), frequency (30.9 +/- 10.1 events/min), and percentage of bell-shaped amplitude distributions (47.1%) were reversed to control levels (286.7 +/- 48.2 pA, 26.2 +/- 5.8 events/min, and 47.1%, respectively). Depletion of intracellular Ca(2+) by BAPTA AM or thapsigargin had similar reversal effects to KN93. In addition, cotreatment with both 2-APB (IP3 receptor inhibitor) and TMB-8 (ryanodine receptor inhibitor) also reversed the inhibitory effects of BDNF, as shown by the physiological parameters. CONCLUSIONS: CaMK mediates the inhibitory effects of BDNF on NMJ maturation. Ca(2+) released from intracellular stores through either IP3 receptors or ryanodine receptors regulates neurotrophic actions on NMJ maturation. PMID- 26248509 TI - Interpersonal Functioning Among Treatment-Seeking Trans Individuals. AB - OBJECTIVES: Trans people have been found to have high levels of depression. In view of the association between interpersonal problems and depression and the importance of interpersonal skills to navigate the transition of trans people, this study aims to investigate the levels of interpersonal problems among treatment-seeking trans men and women and the role of depression in this association. METHOD: A total of 104 patients from a UK gender identity clinic and 104 age- and gender-matched control participants completed self-report measures of interpersonal problems and general psychopathology, including depression. RESULTS: Trans people reported significantly higher scores on global interpersonal problems and on the Inventory of Interpersonal Problems-32 (IIP-32) Hard to be Sociable, Hard to be Supportive, and Hard to be Involved subscales and lower scores on the Too Open subscale. Depression accounted for significant differences on IIP-32 global and the Too Open subscale but not on Hard to be Sociable, Hard to be Supportive, and Hard to be Involved subscales. CONCLUSIONS: Trans individuals present with interpersonal problems, which could potentially increase their vulnerability to mental health problems. Therefore, addressing interpersonal problems may help to prevent the development of depressive symptomatology and facilitate transition. PMID- 26248511 TI - Use of low dose rVSV-ZEBOV: safety issues in a Swiss cohort. PMID- 26248510 TI - The effect of dose on the safety and immunogenicity of the VSV Ebola candidate vaccine: a randomised double-blind, placebo-controlled phase 1/2 trial. AB - BACKGROUND: Safe and effective vaccines against Ebola could prevent or control outbreaks. The safe use of replication-competent vaccines requires a careful dose selection process. We report the first safety and immunogenicity results in volunteers receiving 3 * 10(5) plaque-forming units (pfu) of the recombinant vesicular stomatitis virus-based candidate vaccine expressing the Zaire Ebola virus glycoprotein (rVSV-ZEBOV; low-dose vaccinees) compared with 59 volunteers who had received 1 *10(7) pfu (n=35) or 5 * 10(7) pfu (n=16) of rVSV-ZEBOV (high dose vaccinees) or placebo (n=8) before a safety-driven study hold. METHODS: The Geneva rVSV-ZEBOV study, an investigator-initiated phase 1/2, dose-finding, placebo-controlled, double-blind trial conducted at the University Hospitals of Geneva, Switzerland, enrolled non-pregnant, immunocompetent, and otherwise healthy adults aged 18-65 years. Participants from the low-dose group with no plans to deploy to Ebola-aff5cted regions (non-deployable) were randomised 9:1 in a double-blind fashion using randomly permuted blocks of varying sizes to a single injection of 3 * 10(5) pfu or placebo, whereas deployable participants received single-injection 3 * 10(5) pfu open-label. Primary safety and immunogenicity outcomes were the incidence of adverse events within 14 days of vaccination and day-28 antibody titres, respectively, analysed by intention to treat. After viral oligoarthritis was observed in 11 of the first 51 vaccinees (22%) receiving 10(7) or 5 * 10(7) pfu, 56 participants were given a lower dose (3 * 10(5) pfu, n=51) or placebo (n=5) to assess the effect of dose reduction on safety and immunogenicity. This trial is ongoing with a follow-up period of 12 months; all reported results are from interim databases. This study is registered with ClinicalTrials.gov, number NCT02287480. FINDINGS: Between Jan 5 and Jan 26, 2015, 43 non-deployable participants received low-dose rVSV-ZEBOV (3 * 10(5) pfu) or placebo in a double-blind fashion, whereas 13 deployable participants received 3 * 10(5) pfu open-label. Altogether, in the low-dose group, 51 participants received rVSV-ZEBOV and five received placebo. No serious adverse events occurred. At 3 * 10(5) pfu, early-onset reactogenicity remained frequent (45 [88%] of 51 compared with 50 [98%] of 51 high dose and two [15%] of 13 placebo recipients), but mild. Objective fever was present in one (2%) of 51 low-dose versus 13 (25%) of 51 high-dose vaccinees receiving at least 1 *10(7) pfu (p<0.0001). Subjective fever (p<0.0001), myalgia (p=0.036), and chills (p=0.026) were significantly reduced and their time of onset delayed, reflecting significantly lower viraemia (p<0.0001) and blood monocyte-activation patterns (p=0.0233). Although seropositivity rates remained similarly high (48 [94%] of 51), day-28 EBOV-glycoprotein-binding and neutralising antibody titres were lower in low-dose versus high-dose vaccinees (geometric mean titres 344.5 [95% CI 229.7 516.4] vs 1064.2 [757.6-1495.1]; p<0.0001; and 35.1 [24.7-50.7] vs 127.0 [86.0 187.6]; p<0.0001, respectively). Furthermore, oligoarthritis again occurred on day 10 (median; IQR 9-14) in 13 (25%) of 51 low-dose vaccinees, with maculopapular, vesicular dermatitis, or both in seven (54%) of 13; arthritis was associated with increasing age in low-dose but not high-dose vaccinees. Two vaccinees presented with purpura of the lower legs; histological findings indicated cutaneous vasculitis. The presence of rVSV in synovial fluid and skin lesions confirmed causality. INTERPRETATION: Reducing the dose of rVSV-ZEBOV improved its early tolerability but lowered antibody responses and did not prevent vaccine-induced arthritis, dermatitis, or vasculitis. Like its efficacy, the safety of rVSV-ZEBOV requires further definition in the target populations of Africa. FUNDING: Wellcome Trust through WHO. PMID- 26248512 TI - Calcium Signaling Involvement in Cadmium-Induced Astrocyte Cytotoxicity and Cell Death Through Activation of MAPK and PI3K/Akt Signaling Pathways. AB - Cadmium (Cd), a highly ubiquitous toxic heavy metal, can contaminate the environment, including agricultural soil, water and air, via industrial runoff and other sources of pollution. Cd accumulated in the body via direct exposure or through the food chain results in neurodegeneration and many other diseases. Previous studies on its toxicity in the central nervous system (CNS) focused mainly on neurons. To obtain a more comprehensive understanding of Cd toxicity for the CNS, we investigated how astrocytes respond to acute and chronic Cd exposure and its toxic molecular mechanisms. When primary cultures of cerebral cortical astrocytes incubated with 1-300 MUM CdCl2, morphological changes, LDH release and cell death were observed in a time and dose-dependent manner. Further studies demonstrated that acute and chronic Cd treatment phosphorylated JNK, p38 and Akt to different degrees, while ERK1/2 was only phosphorylated under low doses of Cd (10 MUM) exposure. Inhibition of JNK and PI3K/Akt, but not of p38, could partially protect astrocyte from cytotoxicity in chronic and acute Cd exposure. Moreover, Cd also induced a strong calcium signal, while BAPTA, a specific intracellular calcium (Ca(2+)) chelator, prevented Cd-induced intracellular increase of calcium levels in astrocytes; inhibited the Cd-induced activation of ERK1/2, JNK, p38 and Akt; and also significantly reduced astrocyte cell death. All of these results suggested that the Cd-Ca(2+)-MAPK and PI3K/Akt signaling pathways were involved in Cd-induced toxicity in astrocytes. This toxicity involvement indicates that these pathways may be exploited as a target for the prevention of Cd-induced neurodegenerative diseases. PMID- 26248514 TI - Mitochondrion as a Target for Heart Failure Therapy- Role of Protein Lysine Acetylation. AB - Heart failure is a leading cause of death worldwide. Despite medical advances, the dismal prognosis of heart failure has not been improved. The heart is a high energy-demanding organ. Impairments of cardiac energy metabolism and mitochondrial function are intricately linked to cardiac dysfunction. Mitochondrial dysfunction contributes to impaired myocardial energetics and increased oxidative stress in heart failure, and the opening of mitochondrial permeability transition pore triggers cell death and myocardial remodeling. Therefore, there has been growing interest in targeting mitochondria and metabolism for heart failure therapy. Recent developments suggest that mitochondrial protein lysine acetylation modulates the sensitivity of the heart to stress and hence the propensity to heart failure. This article reviews the role of mitochondrial dysfunction in heart failure, with a special emphasis on the regulation of the nicotinamide adenine dinucleotide (NAD(+)/NADH) ratio and sirtuin-dependent lysine acetylation by mitochondrial function. Strategies for targeting NAD(+)-sensitive mechanisms in order to intervene in protein lysine acetylation and, thereby, improve stress tolerance, are described, and their usefulness in heart failure therapy is discussed. PMID- 26248513 TI - A Combination Supplement of Fructo- and Xylo-Oligosaccharides Significantly Abrogates Oxidative Impairments and Neurotoxicity in Maternal/Fetal Milieu Following Gestational Exposure to Acrylamide in Rat. AB - Prebiotic oligosaccharides are demonstrated to confer a wide spectrum of physiological benefits during pregnancy. In view of this, focused attempts are being directed towards understanding their role as modulators of brain chemistry and behavior. Epidemiological studies have identified that exposure to neurotoxins during prenatal/early life can profoundly impact neurodevelopment/function. In this context, we have tested the hypothesis that a combination of prebiotic supplements during gestation has the propensity to attenuate acrylamide (ACR) induced oxidative impairments, mitochondrial dysfunction and neurotoxicity in maternal and fetal brain of rats. To achieve this, pregnant dams given oral supplements of a combination of fructo- and xylooligosaccharides (FOS + XOS, 3 g/kg/day) during gestation days (GD 0-19) were exposed to ACR (200 ppm in drinking water, GD 6-19). The behavioral analysis revealed that ACR dams fed prebiotics displayed higher exploratory behavior in the open field test. The prenatal evaluation showed that ACR-induced decrements of placental/fetal weights were markedly restored with prebiotic feeding. Prebiotics significantly offset markers of oxidative stress, restored enzymic antioxidants, cholinergic and mitochondrial function in the maternal and fetal brain. Concomitantly, prebiotics restored ACR-induced depletion in the levels of dopamine and gamma-aminobutyric acid in the maternal cortex that positively correlated with cecal bacterial numbers. Collectively, these data suggest that prenatal prebiotic oligosaccharide supplements protect developing brain against oxidative stress-mediated neurotoxicity. While the underlying mechanism/s by which prebiotics abrogate the impact of neurotoxicants in the developing brain merits further studies, we speculate that it may be mediated predominantly through attenuation of oxidative stress and proliferation of enteric microbiota. PMID- 26248515 TI - Roles of Canonical Transient Receptor Potential 6 in Basal [Ca(2+)]i Regulation in Pulmonary Venous Smooth Muscle Cells Under Chronic Hypoxia-Induced Hypertension. PMID- 26248516 TI - The Future of Non-Invasive Angiogenic Therapy Using Acoustic Waves. PMID- 26248517 TI - Pulsatility During Left Ventricular Assist Device Treatment. PMID- 26248518 TI - Psychometric Evaluation of a Self-Report Evidence-Based Practice Tool Using Rasch Analysis. AB - AIMS: This paper reports if estimates of final year nursing students' self-rated abilities in responding to evidence-based practice (EBP) issues is a psychometrically robust measure. BACKGROUND: EBP as it applies to nursing continues to be heralded as a method to improve clinical patient care. Health professionals such as nurses are well positioned to respond to this demand; however, evidence suggests they are not always able to embrace this important foundation of everyday nursing practice. DESIGN: Instrument development. METHODS: The study was a survey set in a large teaching university in Adelaide, South Australia. The evidence-based practice survey was made available to a convenience sample of 471 final year nursing students, with a response rate of 79.6% (n = 375). Rasch analysis was used to critique and develop a scale for future learning based on the conjoint estimates of nursing students' self-efficacy estimates, when meeting the challenges of various EBP of differing complexities. RESULTS: Outcomes confirm that final year nursing students' EBP ability measures can be reliably estimated and a hierarchical scale of learning can be developed for use by beginning registered nurses' in their staff development. LINKING EVIDENCE TO ACTION: Although Australian health and nursing authorities acknowledge the desirability of the nursing workforce in adopting EBP for patient management, elements of this approach remains problematic for nurses. Measures to estimate EBP skills difficulty can be reliably generated to inform EBP education and skills development. PMID- 26248519 TI - Synthesis of low-valent uranium fluorides by C-F bond activation. AB - The uranium(III) alkyl, Tp*2UCH2Ph (Tp* = hydrotris(3,5 dimethylpyrazolyl)borate), activates C-F bonds on a variety of fluorinated substrates. From these reactions two new uranium containing products, Tp*2UF and Tp*2UF2, were isolated and characterized by (1)H, (13)C, (11)B NMR, infrared and electronic absorption spectroscopies, as well as X-ray crystallography. Formation of the uranium(III) or uranium(IV) product was found to be substrate dependent. PMID- 26248520 TI - Sterilization of sterlet Acipenser ruthenus by using knockdown agent, antisense morpholino oligonucleotide, against dead end gene. AB - Sturgeons (chondrostean, acipenseridae) are ancient fish species, widely known for their caviar. Nowadays, most of them are critically endangered. The sterlet (Acipenser ruthenus) is a common Eurasian sturgeon species with a small body size and the fastest reproductive cycle among sturgeons. Such species can be used as a host for surrogate production; application is of value for recovery of critically endangered and huge sturgeon species with an extremely long reproductive cycle. One prerequisite for production of the donor's gametes only is to have a sterile host. Commonly used sterilization techniques in fishes such as triploidization or hybridization do not guarantee sterility in sturgeon. Alternatively, sterilization can be achieved by using a temporary germ cell exclusion-specific gene by a knockdown agent, the antisense morpholino oligonucleotide (MO). The targeted gene for the MO is the dead end gene (dnd) which is a vertebrate specific gene encoding a RNA-binding protein which is crucial for migration and survival of primordial germ cells (PGCs). For this purpose, a dnd homologue of Russian sturgeon (Agdnd), resulting in the same sequence in the start codon region with isolated fragments of sterlet dnd (Ardnd), was used. Reverse transcription polymerase chain reaction confirmed tissue-specific expression of Ardnd only in the gonads of both sexes. Dnd-MO for depletion of PGCs together with fluorescein isothiocyanate (FITC)-biotin-dextran for PGCs labeling was injected into the vegetal region of one- to four-cell-stage sterlet embryos. In the control groups, only FITC was injected to validate the injection method and labeling of PGCs. After optimization of MO concentration together with volume injection, 250-MUM MO was applied for sterilization of sturgeon embryos. Primordial germ cells were detected under a fluorescent stereomicroscope in the genital ridge of the FITC-labeled control group only, whereas no PGCs were present in the body cavities of morphants at 21 days after fertilization. Moreover, the body cavities of MO-treated and nontreated fish were examined by histology and in situ hybridization, showing gonads which had no germ cells in morphants at various stages (60, 150, and 210 days after fertilization). Taken together, these results report the first known and functional method of sturgeon sterilization. PMID- 26248524 TI - Suicidal Smothering by Rubber Latex Gloves and Handkerchief. AB - Asphyxial deaths are common in forensic practice, being sustained by a variety of mechanisms that cause an oxygen deficiency to the brain. Several classification models have been proposed in the literature, the most recent one being that of the International Network for Forensic Research Group (INFOR). This report describes an unusual case of suffocation where the obstruction of the airways was caused by a gag formed of three latex gloves and a handkerchief. The manner of death (differential diagnosis between homicide and suicide) and the different alternatives of classification are discussed. PMID- 26248525 TI - Prognosis of uveal melanoma based on race in 8100 patients: The 2015 Doyne Lecture. AB - A retrospective, nonrandomized, interventional case series of 8100 patients with uveal melanoma were evaluated for melanoma-related metastasis based on patient race. The patient race was Caucasian (n=7918, 98%), Hispanic (n=105, 1%), Asian (n=44, <1%), or African American (n=33, <1%). On the basis of race (Caucasian, Hispanic, Asian, and African American), significant differences were noted in mean age at presentation (58, 48, 44, and 52 years; P<0.001), distance of posterior tumor margin to foveola (5, 5, 6, and 4 mm; P<0.001), distance of posterior tumor margin to optic disc (5, 5, 6, and 4 mm) (P<0.001), tumor base (11, 12, 12, and 13 mm; P<0.001), tumor thickness (5.4, 7.1, 6.5, and 7.5 mm; P<0.001), intraocular hemorrhage (10, 14, 11, and 24%; P=0.02), and rupture of Bruch's membrane (20, 27, 39, and 36%; P=0.001). On the basis of multivariate analysis, the rate of metastasis increased with increasing age (P<0.001), ciliary body location (P<0.001), increasing tumor base (P<0.001), increasing tumor thickness (P<0.001), pigmented tumor (P=0.001), subretinal fluid (P=0.001), intraocular hemorrhage (P=0.045), and extraocular extension (P=0.036). Kaplan Meier estimates of metastasis at 3, 5, and 10 were 8, 15, and 25% in Caucasians; 13, 13, and 13% in Hispanics; 4, 4, and 36% in Asians; and 8, 8, and 8% in African Americans. Compared with Caucasians, despite relative risk for metastasis of 0.31 for African Americans, 0.73 for Hispanics, and 1.42 for Asians, there was no statistical difference in metastasis, or death from uveal melanoma based on race. In summary, uveal melanoma showed similar prognosis for all races. PMID- 26248526 TI - The incidence of unexplained visual loss following removal of silicone oil. AB - PURPOSE: To assess the incidence and clinical features of unexpected visual loss after removal of silicone oil (ROSO). PATIENTS AND METHODS: A retrospective cross sectional observational study of 421 consecutive eyes, which underwent silicone oil removal at one institution over a 2-year period. RESULTS: Fourteen (3.3%) patients, (12 male, mean age of 53.1 years) suffered unexplained visual loss. In these eyes, the mean duration of silicone oil fill was 141 days (range 76-218). The mean loss of visual acuity was 3.7 (range 2-6) Snellen lines (SL) at 1 month, 3.5 (2-6) SL at 3 months and 2.91 (0-6) SL at 6 months. The change from preoperative visual acuity was statistically significant at all visits (P=0.02). Subgroup analysis of 20 fovea-sparing giant retinal tear (GRT) detachments, observed 10 (50%) cases of visual loss after ROSO. Electrodiagnostic testing suggested predominantly macular dysfunction, with optic nerve involvement in one case. Five of the 14 cases had variable recovery of vision. CONCLUSION: There is a 3.3% overall incidence of visual loss following ROSO with a high rate (50%) observed in maculae on GRT detachments. Although recovery of visual acuity is seen in a minority of cases, visual loss after ROSO remains a serious and unexplained concern for vitreoretinal surgeons. PMID- 26248527 TI - Stability of ubiquinol-10 (reduced form of coenzyme Q10 ) in human blood. AB - The ratio of ubiquinol-10 in total coenzyme Q10 (TQ10 ) in human plasma has been proposed as a useful biomarker of oxidative stress. Since ubiquinol-10 is easily oxidized in air, it is necessary to perform suitable processing at medical institutions prior to analysis. To establish stable storage conditions for blood to determine the ubiquinol-10/TQ10 ratios properly, the effects of temperature conditions on the stability of ubiquinol-10 were studied. Blood samples were collected from nine male Japanese volunteers. Changes in ubiquinol-10/TQ10 ratios in blood samples were evaluated under three temperature conditions (room temperature, refrigerated and ice-cooled). Plasma levels of ubiquinol-10 and ubiquinone-10 were determined by an HPLC system with electrochemical detection and the ubiquinol-10/TQ10 ratios were calculated. We found that the ubiquinol 10/TQ10 ratio was stable up to 8 or 4 h when blood samples were stored in refrigerator or ice-cold container, respectively, and its decreases during these periods were <1.0%. We conclude that, in order to evaluate ubiquinol-10/TQ10 ratios, blood samples should be stored in a refrigerator or an ice-cold container, and processed for plasma separation within 4 h. PMID- 26248528 TI - Perceptions of needs related to the practice of self-care for minor illness. AB - AIMS AND OBJECTIVES: The aim of this study was to describe people's perceptions of needs to feel confident in self-care for minor illnesses as well as their perceptions about supporting and obstructing factors in the practice of self care. BACKGROUND: Minor illness constitutes a large part of primary care, and patients' attendance to doctors' appointments for minor illness has been seen to increase future attendance for the same condition. Almost half of the consultations with telenurses result in the provision of self-care advice. DESIGN: A cross-sectional survey. METHOD: Primary data were collected using a questionnaire, and the study participants (n = 315) were randomly selected from the national Swedish address register. RESULTS: Having knowledge and receiving health care advice and reliable information were perceived to be needs in order for participants to feel confident in self-care. Having family or friends to consult with was perceived to be a positive factor influencing confidence in self care, especially for persons under the age of 35. Health care services were perceived to support self-care practice by offering easy access to care, giving information about self-care, and offering increased follow-up after consultations. Lack of knowledge, along with difficulties being away from work, were obstructing factors in the practice of self-care. CONCLUSIONS: Young age was the factor influencing people's perceptions of needs and supporting factors the most. Young age and low knowledge scores about minor illnesses were the two factors that had the most influence on perceived obstructing factors. RELEVANCE TO CLINICAL PRACTICE: Nurses play a major role in the promotion of self-care and in the dissemination of self-care advice. If health care services fail to meet the needs of care-seekers with minor illnesses, patients might turn to out-of hours clinics and emergency departments for help. PMID- 26248529 TI - The depth, duration, and degree of outpatient pediatric polypharmacy in Colorado fee-for-service Medicaid patients. AB - BACKGROUND AND OBJECTIVES: Outpatient pediatric polypharmacy is poorly characterized. Identification of at-risk populations has clinical implications for pharmacy case management programs. We described the degree of exposure to polypharmacy using parameters of depth (concurrent medication count) and duration, reported commonly dispensed medications and exposure to three example potential drug-drug interactions by different depths of polypharmacy, and determined patient characteristics associated with exposure to increased degrees (a function of depth and duration) of polypharmacy. METHODS: Retrospective cohort study of Colorado fee-for-service Medicaid patients aged <18 years with 12 months of continuous enrollment. We calculated depth of polypharmacy using daily concurrent medication counts and duration of polypharmacy using days exposed to a certain depth. Multinomial logistic regression was used to assess patient characteristics associated with different degrees of polypharmacy. RESULTS: Of 242 230 patients, 35% percent were exposed to any depth of polypharmacy, most commonly to anti-infective medications. Patients with higher depth polypharmacy were exposed to less common medications (psychotropic drugs, anticonvulsants, cardiovascular agents, and opioids) and to higher rates of exposure to potential drug-drug interactions. Of 47 972 patients exposed to >=3 concurrent medications, 50% were exposed for <15 days, 25% for 15-38 days, 15% for 39-111 days, and 10% for 112-327 days. High-degree polypharmacy was associated with increasing age, male gender, and presence of a complex chronic condition. CONCLUSIONS: Outpatient pediatric polypharmacy occurs to a substantial degree for a small but vulnerable population of children, who may be candidates for pharmacy case management. We must determine whether increased exposure to high-degree polypharmacy causes harm. PMID- 26248531 TI - Gastric presentation (vasculitis) mimics a gastric cancer as initial symptom in granulomatosis with polyangiitis: a case report and review of the literature. AB - Granulomatosis with polyangiitis (GPA), formerly called Wegener's Granulomatosis, is characterized by necrotizing granulomatous inflammation and belongs to the family of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. The main clinical symptoms of GPA are vasculitis primarily involving upper and lower respiratory tracts, as well as kidneys. Gastrointestinal manifestations of GPA are less common (0-20 %), with gastric presentation mimicking a gastric cancer as an initial symptom. This is a descriptive case report of one patient, together with systematic review of the literature. We described a 31-year-old Chinese woman who presented with complaints of abdominal distention, anorexia for 2 months. Gastroscopy was carried out for three times, and stomach cancer was suspected. However, histopathology of gastric biopsy revealed a chronic inflammation with mucosal ulceration, frequent neutrophils and lymphocytes infiltration, and local granulomatous formation, whereas no sign of stomach carcinoma was observed. In view of the positive cANCA test, a diagnosis of GPA was considered. From the onset of the GPA in the patients, no other organs have been involved in the disease. The patient was successfully treated with corticosteroids and cyclophosphamide. As shown in the report, patients who present only with gastrointestinal manifestations represent challenges to diagnosis. ANCA testing can serve as a decisive diagnostic tool. Although uncommon, GI involvement may be a major feature in GPA, sometimes presenting as gastric tumor-like lesions. Diagnosis should be considered in patients presenting with GI symptoms accompanied by evidence of systemic vasculitis, and ANCA test should be used as a diagnostic measurement to clarify differential diagnosis. PMID- 26248532 TI - Finger stiffness or edema as presenting symptoms of eosinophilic fasciitis. AB - To investigate the clinical features and finger symptoms of eosinophilic fasciitis (EF), we reviewed five patients with EF. The chief complaint was pain, edema and/or stiffness of the extremities. The distal extremities were affected in all patients, and there was also proximal involvement in one patient. One patient had asymmetrical symptoms. All four patients with upper limb involvement had limited range of motion of the wrist joints, and three of them complained of finger symptoms. Two of these three patients showed slight non-pitting edema of the hands, and the other one had subcutaneous induration of the forearm. All four patients with lower limb symptoms had limited range of motion of the ankle joints, and two showed edema or induration of the legs. Inflammatory changes in the joints were not detected in any of the patients. Two patients displayed neither objective induration nor edema, and two patients had muscle tenderness. In conclusion, finger symptoms of patients with EF might be caused by fasciitis of the forearms, which leads to dysfunction of the long finger flexors and extensors as well as slight edema of hands. Limited range of motion of wrist and/or ankle joints indicates sensitively distal muscle dysfunction caused by fasciitis. PMID- 26248533 TI - Bone and bone marrow involvement in sarcoidosis. AB - Bone and bone marrow involvement in sarcoidosis have been infrequently reported. We aimed to describe the clinical features, radiological descriptions, pathological examinations, and outcomes of three patients with osseous sarcoidosis and one patient with bone marrow sarcoidosis seen at our institution. Our case series included fluorodeoxyglucose positron emission tomography descriptions in assessing the whole-body extent of sarcoidosis. In the era of advanced imaging, large bone and axial skeleton sarcoidosis lesions are more common than previously reported. PMID- 26248534 TI - Prevalence of HLA-B27 in Moroccan healthy subjects and patients with ankylosing spondylitis and mapping construction of several factors influencing AS diagnosis by using multiple correspondence analysis. AB - The aim of the present study was to determine the prevalence of human leukocyte antigen HLA-B27 in Moroccan healthy controls and in patients with ankylosing spondylitis (AS), and to analyze the correlation between HLA-B27 and AS in Moroccan patients. The prevalence of HLA-B27 was determined by evaluating the number of HLA-B27-positive samples in 128 healthy subjects and in 53 patients diagnosed with AS according to the ESSG and AMOR criteria. HLA-B27 was determined by the polymerase chain reaction using sequence-specific primers. Multivariate analysis of our data (HLA-B27, age, sex, and family history) for AS and healthy controls was performed by multiple correspondence analysis (MCA). The frequency of HLA-B27 was significantly greater in AS patients (45.3 %) than in healthy controls (4.7 %) [p < 0.0001, OR 16.8, and CI 95 % (5.83-51.03)]. In addition, HLA-B27 was more common in male patients than in female ones (p < 0.05). 100 % of the AS patients reported a family history of AS, whereas only 20 % of the healthy controls reported a family history of AS. The graphical interpretation of MCA showed a significant relation between the presence of HLA-B27 and AS. This study strengthens the link between HLA-B27 and AS and represents a very valuable informative diagnostic tool, especially in regard to male patients who have a family history of AS. PMID- 26248535 TI - Influence of phase correction of late gadolinium enhancement images on scar signal quantification in patients with ischemic and non-ischemic cardiomyopathy. AB - BACKGROUND: Myocardial fibrosis imaging using late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) has been validated as a quantitative predictive marker for response to medical, surgical, and device therapy. To date, all such studies have examined conventional, non-phase corrected magnitude images. However, contemporary practice has rapdily adopted phase-corrected image reconstruction. We sought to investigate the existence of any systematic bias between threshold-based scar quantification performed on conventional magnitude inversion recovery (MIR) and matched phase sensitive inversion recovery (PSIR) images. METHODS: In 80 patients with confirmed ischemic (N = 40), or non-ischemic (n = 40) myocardial fibrosis, and also in a healthy control cohort (N = 40) without fibrosis, myocardial late enhancement was quantified using a Signal Threshold Versus Reference Myocardium technique (STRM) at >=2, >=3, and >=5 SD threshold, and also using the Full Width at Half Maximal (FWHM) technique. This was performed on both MIR and PSIR images and values compared using linear regression and Bland-Altman analyses. RESULTS: Linear regression analysis demonstrated excellent correlation for scar volumes between MIR and PSIR images at all three STRM signal thresholds for the ischemic (N = 40, r = 0.96, 0.95, 0.88 at 2, 3, and 5 SD, p < 0.0001 for all regressions), and non ischemic (N = 40, r = 0.86, 0.89, 0.90 at 2, 3, and 5 SD, p < 0.0001 for all regressions) cohorts. FWHM analysis demonstrated good correlation in the ischemic population (N = 40, r = 0.83, p < 0.0001). Bland-Altman analysis demonstrated a systematic bias with MIR images showing higher values than PSIR for ischemic (3.3 %, 3.9 % and 4.9 % at 2, 3, and 5 SD, respectively), and non-ischemic (9.7 %, 7.4 % and 4.1 % at >=2, >=3, and >=5 SD thresholds, respectively) cohorts. Background myocardial signal measured in the control population demonstrated a similar bias of 4.4 %, 2.6 % and 0.7 % of the LV volume at 2, 3 and 5 SD thresholds, respectively. The bias observed using FWHM analysis was -6.9 %. CONCLUSIONS: Scar quantification using phase corrected (PSIR) images achieves values highly correlated to those obtained on non-corrected (MIR) images. However, a systematic bias exists that appears exaggerated in non-ischemic cohorts. Such bias should be considered when comparing or translating knowledge between MIR- and PSIR-based imaging. PMID- 26248537 TI - Mapping Thalamocortical Functional Connectivity in Chronic and Early Stages of Psychotic Disorders. AB - BACKGROUND: There is considerable evidence that the thalamus is abnormal in psychotic disorders. Resting-state functional magnetic resonance imaging has revealed an intriguing pattern of thalamic dysconnectivity in psychosis characterized by reduced prefrontal cortex (PFC) connectivity and increased somatomotor-thalamic connectivity. However, critical knowledge gaps remain with respect to the onset, anatomical specificity, and clinical correlates of thalamic dysconnectivity in psychosis. METHODS: Resting-state functional magnetic resonance imaging was collected on 105 healthy subjects and 148 individuals with psychosis, including 53 early-stage psychosis patients. Using all 253 subjects, the thalamus was parceled into functional regions of interest (ROIs) on the basis of connectivity with six a priori defined cortical ROIs covering most of the cortical mantle. Functional connectivity between each cortical ROI and its corresponding thalamic ROI was quantified and compared across groups. Significant differences in the ROI-to-ROI analysis were followed up with voxelwise seed-based analyses to further localize thalamic dysconnectivity. RESULTS: ROI analysis revealed reduced PFC-thalamic connectivity and increased somatomotor-thalamic connectivity in both chronic and early-stage psychosis patients. PFC hypoconnectivity and motor cortex hyperconnectivity correlated in patients, suggesting that they result from a common pathophysiological mechanism. Seed based analyses revealed thalamic hypoconnectivity in psychosis localized to dorsolateral PFC, medial PFC, and cerebellar areas of the well-described executive control network. Across all subjects, thalamic connectivity with areas of the fronto-parietal network correlated with cognitive functioning, including verbal learning and memory. CONCLUSIONS: Thalamocortical dysconnectivity is present in both chronic and early stages of psychosis, includes reduced thalamic connectivity with the executive control network, and is related to cognitive impairment. PMID- 26248538 TI - Encapsulation of Mentha Oil in Chitosan Polymer Matrix Alleviates Skin Irritation. AB - Mentha spicata L. var. viridis oil (MVO) is a potent antifungal agent, but its application in the topical treatment is limited due to its irritancy and volatility. It was aimed to develop more efficient, chitosan-incrusted MVO microspheres with reduced volatility and lesser irritancy and to dispense it in the form of ointment. Simple coacervation technique was employed to microencapsulate MVO in chitosan matrix. Morphological properties and polymer cross-linking were characterized by scanning electron microscopy and differential scanning calorimetry, respectively. Optimization was carried out on the basis of entrapment efficiency (EE) using response surface methodology. Well-designed microspheres having smooth surface and spherical shape were observed. EE (81.20%) of optimum batch (R21) was found at 1.62% w/v of cross-linker, 5.4:5 of MVO to chitosan ratio and at 1000 rpm. R21 showed 69.38 +/- 1.29% in vitro MVO release in 12 h and 96.92% retention of MVO in microspheres even after 8 week. Ointments of PEG 4000 and PEG 400 comprising MVO (F1) and R21 (F2) were developed separately. F2 showed comparatively broader zone of growth inhibition (13.33 +/- 1.76-18.67 +/- 0.88 mm) and less irritancy (PII 0.5833, irritation barely perceptible) than that of F1. F2 was able to avoid the direct contact of mild irritant MVO with the skin and to reduce its rapid volatility. Controlled release of MVO helped in lengthening the duration of availability of MVO in agar media and hence improved its therapeutic efficacy. In conclusion, a stable and non irritant formulation with improved therapeutic potential was developed. PMID- 26248536 TI - Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory. AB - BACKGROUND: Prior exposure to stress is a risk factor for developing posttraumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon. METHODS: Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacologic manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior. RESULTS: Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2C receptor (5-HT2CR) activity during memory consolidation were necessary for stress enhancement of fear memory, but neither process affected fear memory in unstressed mice. Additionally, prior stress increased amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also showed that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning. CONCLUSIONS: Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD. PMID- 26248540 TI - C, Cl and H compound-specific isotope analysis to assess natural versus Fe(0) barrier-induced degradation of chlorinated ethenes at a contaminated site. AB - Compound-specific isotopic analysis of multiple elements (C, Cl, H) was tested to better assess the effect of a zero-valent iron-permeable reactive barrier (ZVI PRB) installation at a site contaminated with tetrachloroethene (PCE) and trichloroethene (TCE). The focus was on (1) using (13)C to evaluate natural chlorinated ethene biodegradation and the ZVI-PRB efficiency; (2) using dual element (13)C-(37)Cl isotopic analysis to distinguish biotic from abiotic degradation of cis-dichloroethene (cis-DCE); and (3) using (13)C-(37)Cl-(2)H isotopic analysis of cis-DCE and TCE to elucidate different contaminant sources. Both biodegradation and degradation by ZVI-PRB were indicated by the metabolites that were detected and the (13)C data, with a quantitative estimate of the ZVI PRB efficiency of less than 10% for PCE. Dual element (13)C-(37)Cl isotopic plots confirmed that biodegradation was the main process at the site including the ZVI PRB area. Based on the carbon isotope data, approximately 45% and 71% of PCE and TCE, respectively, were estimated to be removed by biodegradation. (2)H combined with (13)C and (37)Cl seems to have identified two discrete sources contributing to the contaminant plume, indicating the potential of delta(2)H to discriminate whether a compound is of industrial origin, or whether a compound is formed as a daughter product during degradation. PMID- 26248539 TI - Neurochemical characterization of pERK-expressing spinal neurons in histamine induced itch. AB - Acute itch is divided into histamine- and non-histamine-dependent subtypes, and our previous study has shown that activation of ERK signaling in the spinal dorsal horn (SDH) is required selectively for histamine-induced itch sensation. Morphological characteristics of pERK-expressing neurons are required for exploring the mechanism underlying spinal itch sensation. To investigate whether pERK-expressing neurons are supraspinally-projecting neurons, we injected Fluorogold (FG) into the ventrobasal thalamic complex (VB) and parabrachial region, the two major spinal ascending sites in rodents. A small number (1%) of pERK-positive neurons were labeled by FG, suggesting that histamine-induced activation of ERK is primarily located in local SDH neurons. We then examined the co-localization of pERK with Calbindin and Lmx1b, which are expressed by excitatory neurons, and found that more than half (58%) of pERK-positive neurons expressed Lmx1b, but no co-expression with Calbindin was observed. On the other hand, approximately 7% of pERK-positive neurons expressed GAD67, and 27% of them contained Pax2. These results support the idea that pERK-expressing neurons serve as a component of local neuronal circuits for processing itch sensation in the spinal cord. PMID- 26248541 TI - Metadynamics Simulations Rationalise the Conformational Effects Induced by N Methylation of RGD Cyclic Hexapeptides. AB - We combined metadynamics, docking and molecular mechanics/generalised born surface area (MM/GBSA) re-scoring methods to investigate the impact of single and multiple N-methylation on a set of RGD cyclopeptides displaying different affinity for integrin alphaIIbbeta3. We rationalised the conformational effects induced by N-methylation and its interplay with receptor affinity, obtaining good agreement with experimental data. This approach can be exploited before entering time-consuming and expensive synthesis and binding experiments. PMID- 26248542 TI - Eyebrow restoration: the approach, considerations, and technique in follicular unit transplantation. AB - BACKGROUND: Eyebrows serve a key role in eye protection, communication, and self expression. Trends in eyebrow grooming are constantly evolving, often requiring plucking, waxing, or laser hair removal to style. When combined with the natural thinning of the brow with aging, the result can be a sparse or even absent eyebrow hair over time. Follicular unit transplantation provides a means of restoring eyebrow fullness and architecture. With careful attention and augmentation of follicle transfer techniques, a natural end result is possible. PMID- 26248543 TI - A General Access to Propargylic Ethers through Bronsted Acid Catalyzed Alkynylation of Acetals and Ketals with Trifluoroborates . AB - A general Bronsted acid catalyzed methodology for the alkynylation of acetals and ketals with alkynyltrifluoroborate salts has been developed. The reaction proceeds rapidly to afford valuable synthetic building block propargylic ethers in good to excellent yields. Unlike Lewis acid catalyzed transformations of trifluoroborates, this approach does not proceed via unstable organodifluoroborane intermediate. As a result, the developed methodology features excellent functional group tolerance and good atom economy. PMID- 26248544 TI - Prospective separation and transcriptome analyses of cortical projection neurons and interneurons based on lineage tracing by Tbr2 (Eomes)-GFP/Dcx-mRFP reporters. AB - In the cerebral cortex, projection neurons and interneurons work coordinately to establish neural networks for normal cortical functions. While the specific mechanisms that control productions of projection neurons and interneurons are beginning to be revealed, a global characterization of the molecular differences between these two neuron types is crucial for a more comprehensive understanding of their developmental specifications and functions. In this study, using lineage tracing power of combining Tbr2(Eomes)-GFP and Dcx-mRFP reporter mice, we prospectively separated intermediate progenitor cell (IPC)-derived neurons (IPNs) from non-IPC-derived neurons (non-IPNs) of the embryonic cerebral cortex. Molecular characterizations revealed that IPNs and non-IPNs were enriched with projection neurons and interneurons, respectively. Expression profiling documented cell-specific genes including differentially expressed transcriptional regulators that might be involved in cellular specifications, for instance, our data found that SOX1 and SOX2, which were known for important functions in neural stem/progenitor cells, continued to be expressed by interneurons but not by projection neurons. Transcriptome analyses of cortical neurons isolated at different stages of neurogenesis revealed distinct temporal patterns of expression of genes involved in early-born or late-born neuron specification. These data present a resource useful for further investigation of the molecular regulations and functions of projection neurons and interneurons. PMID- 26248545 TI - Applying insecticides through drip irrigation to reduce wireworm (Coleoptera: Elateridae) feeding damage in sweet potato. AB - BACKGROUND: A 2 year field study was conducted at multiple locations to determine whether insecticides or an entomopathogenic nematode, Steinernema carpocapsae Weiser, applied through drip irrigation in sweet potato reduced wireworm damage when compared with the non-treated check and/or insecticides applied conventionally. RESULTS: Wireworm damage was low in 2012, and there were no differences in the proportion of roots damaged or the severity of damage between treatments. In 2013, a preplant-incorporated (PPI) application of chlorpyrifos followed by either bifenthrin, imidacloprid, clothianidin, or oxamyl injected through drip irrigation significantly reduced the proportion of wireworm damage as well as the severity of wireworm damage when compared with the non-treated check. The incidence and severity of wireworm damage in these treatments did not differ significantly from those in the conventional management practice. The PPI application of chlorpyrifos followed by either cyantraniliprole or S. carpocapsae injected through drip irrigation was not significantly different from the non treated check in the proportion of wireworm damage; however, both treatments reduced the severity of wireworm damage compared with the non-treated check. CONCLUSION: Applying insecticides through drip irrigation provides an alternative to conventionally applied insecticides. (c) 2015 Society of Chemical Industry. PMID- 26248547 TI - How Do Cooks Actually Cook Vegetables? A Field Experiment With Low-Income Households. AB - Vegetables in the diet contribute to disease prevention. However, low-income households underconsume fresh vegetables, perhaps because of cost and of unavailability at nearby stores. A third reason may lurk behind those barriers: cooks' unfamiliarity with various and appealing ways to prepare vegetables. To illuminate that possibility and to suggest interventions that could be designed more effectively to boost vegetable consumption, this study took the novel step of providing ample, if temporary, supplies of a fresh vegetable to random sets of clients of food pantries. A week later, telephone interviews obtained details about preparations of meals and snacks that household cooks had made with their unexpected bounty. Among the experiment's 10 vegetables, some were used twice as often as others. Even more striking, cooks practiced a narrow repertoire of preparation methods, dominated by boiling and steaming, across most of the vegetables. Fats and salt were often added to boiled and steamed preparations. Implications are drawn to suggest kinds of recipes-pairings of vegetables and of vegetables with underused means of preparation-that could expand cooks' repertoires and add variety in flavors, appearances of dishes, meal textures, and aromas. PMID- 26248546 TI - Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1. AB - To explore mechanisms of hepatitis C viral (HCV) replication we screened a compound library including licensed drugs. Flunarizine, a diphenylmethylpiperazine used to treat migraine, inhibited HCV cell entry in vitro and in vivo in a genotype-dependent fashion. Analysis of mosaic viruses between susceptible and resistant strains revealed that E1 and E2 glycoproteins confer susceptibility to flunarizine. Time of addition experiments and single particle tracking of HCV demonstrated that flunarizine specifically prevents membrane fusion. Related phenothiazines and pimozide also inhibited HCV infection and preferentially targeted HCV genotype 2 viruses. However, phenothiazines and pimozide exhibited improved genotype coverage including the difficult to treat genotype 3. Flunarizine-resistant HCV carried mutations within the alleged fusion peptide and displayed cross-resistance to these compounds, indicating that these drugs have a common mode of action. CONCLUSION: These observations reveal novel details about HCV membrane fusion; moreover, flunarizine and related compounds represent first-in-class HCV fusion inhibitors that merit consideration for repurposing as a cost-effective component of HCV combination therapies. PMID- 26248548 TI - Worksite Health Program Promoting Changes in Eating Behavior and Health Attitudes. AB - BACKGROUND: The aim of the present study was to evaluate the effectiveness of a worksite multicomponent health promotion intervention on eating behavior and attitudes, changes in body weight, and readiness to make eating behavior changes among workers over a 12-month intervention period. METHOD: A total of 3,095 workers of a logistic company participated in a quasi-experimental comparison group study design. The intervention group received a multicomponent health training. Two of the main elements of the multicomponent intervention were physical exercise training and nutrition counseling/training. During the pilot year, participants completed a survey at baseline and again after 12 months to assess physical activity-, health-, and diet-related factors. RESULTS: Results showed that participants' body weight did not significantly decrease in the intervention group. Mean weight loss in the intervention groups was 0.5 kg (body mass index = 0.1 kg/m(2)). Eating behaviors in the intervention group improved more than in the comparison group. Some positive intervention effects were observed for the cognitive factors (e.g., changes in eating attitudes). Baseline readiness to change eating behavior was significantly improved over time. CONCLUSIONS: We demonstrated initial results of a long-term multicomponent worksite health promotion program with regard to changes in body weight, eating behavior, and attitudes. This evaluation of a 12-month pilot study suggests that a worksite health promotion program may lead to improvements in nutritional health behaviors for a number of workers. An investigation of long-term effects of this multicomponent intervention is strongly recommended. PMID- 26248549 TI - Age-specific performance of careHPV versus Papanicolaou and visual inspection of cervix with acetic acid testing in a primary cervical cancer screening. AB - BACKGROUND: Human papillomavirus (HPV) is recommended as a primary screening tool for cervical screening. Assessment of age-specific performance of newer HPV careHPV DNA testing is important as risk of cervical intraepithelial neoplasia (CIN) varies at different ages. We aim to evaluate careHPV in comparison to Papanicolaou (Pap) test and visual inspection of the cervix with acetic acid (VIA) cervical screening tests for the detection of high-grade CIN. METHODS: The cross sectional study was conducted in a rural population of North India. Ever married women 30-59 years of age were invited for screening by careHPV (self collected vaginal and physician-collected cervical samples), Pap test and VIA. Associations for trend in age for detecting histological-confirmed CINII+ and CINIII+ for each screening test were evaluated. Age-specific association with each screening test was evaluated. RESULTS: Of a total of 7761 women invited, 5032 were screened and analysis was performed on 4658 with all screen test results. No significant (p>0.05) association of age for any screening test in the detection of CINII+ or CINIII+ was observed. For the older age group, cervical HPV (CHPV) showed high sensitivity and specificity for CINII+ detection. Specificity of CHPV or vaginal HPV (VHPV) was equal or higher than Pap in all age groups. CONCLUSIONS: Cervical screening options of CHPV or VHPV, or Pap, performed equally in the younger age group while CHPV might be an option for all ages in the detection of high-grade CIN. PMID- 26248551 TI - One-Step Mask Etching Strategy Toward Ordered Ferroelectric Pb(Zr0.52Ti 0.48)O 3 Nanodot Arrays. AB - In this report, ordered lead zirconate titanate Pb(Zr0.52Ti0.48)O3 (PZT) nanodot arrays were fabricated by an original one-step mask etching route. The one-step mask etching strategy is based on the patterned nanostructure of barrier layer (BL) at the bottom of anodic aluminum oxide (AAO), by a direct transfer of the nanopattern from BL to the pre-deposited PZT film, without introduction of any sacrifice layer and lithography. Therefore, the presented strategy is relatively simple and economical. X-ray diffraction and Raman analysis revealed that the as prepared PZT was in a perovskite phase. Atomic and piezoresponse force microscopy indicated that the PZT nanodot arrays were with both good ordering and well defined ferroelectric properties. Considering its universality on diverse substrates, the present method is a general approach to the high-quality ordered ferroelectric nanodot arrays, which is promising for applications in ultra-high density nonvolatile ferroelectric random access memories (NV-FRAM). PMID- 26248550 TI - Contribution of modifiable risk factors for hypertension and type-2 diabetes in Peruvian resource-limited settings. AB - BACKGROUND: It is important to understand the local burden of non-communicable diseases including within-country heterogeneity. The aim of this study was to characterise hypertension and type-2 diabetes profiles across different Peruvian geographical settings emphasising the assessment of modifiable risk factors. METHODS: Analysis of the CRONICAS Cohort Study baseline assessment was conducted. Cardiometabolic outcomes were blood pressure categories (hypertension, prehypertension, normal) and glucose metabolism disorder status (diabetes, prediabetes, normal). Exposures were study setting and six modifiable factors (smoking, alcohol drinking, leisure time and transport-related physical activity levels, TV watching, fruit/vegetables intake and obesity). Poisson regression models were used to report prevalence ratios (PR). Population attributable risks (PAR) were also estimated. RESULTS: Data from 3238 participants, 48.3% male, mean age 45.3 years, were analysed. Age-standardised (WHO population) prevalence of prehypertension and hypertension was 24% and 16%, whereas for prediabetes and type-2 diabetes it was 18% and 6%, respectively. Outcomes varied according to study setting (p<0.001). In multivariable model, hypertension was higher among daily smokers (PR 1.76), heavy alcohol drinkers (PR 1.61) and the obese (PR 2.06); whereas only obesity (PR 2.26) increased the prevalence of diabetes. PAR showed that obesity was an important determinant for hypertension (15.7%) and type-2 diabetes (23.9%). CONCLUSIONS: There is an evident heterogeneity in the prevalence of and risk factors for hypertension and diabetes within Peru. Prehypertension and prediabetes are highly prevalent across settings. Our results emphasise the need of understanding the epidemiology of cardiometabolic conditions to appropriately implement interventions to tackle the burden of non communicable diseases. PMID- 26248552 TI - Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy. AB - BACKGROUND: Epigenetic variation has been linked to several human diseases. Proliferative diabetic retinopathy (PDR) is a major cause of vision loss in subjects with diabetes. However, studies examining the association between PDR and the genome-wide DNA methylation pattern are lacking. Our aim was to identify epigenetic modifications that associate with and predict PDR in subjects with type 1 diabetes (T1D). METHODS: DNA methylation was analyzed genome-wide in 485,577 sites in blood from cases with PDR (n = 28), controls (n = 30), and in a prospective cohort (n = 7). False discovery rate analysis was used to correct the data for multiple testing. Study participants with T1D diagnosed before 30 years of age and insulin treatment within 1 year from diagnosis were selected based on 1) subjects classified as having PDR (cases) and 2) subjects with T1D who had had diabetes for at least 10 years when blood DNA was sampled and classified as having no/mild diabetic retinopathy also after an 8.7-year follow-up (controls). DNA methylation was also analyzed in a prospective cohort including seven subjects with T1D who had no/mild diabetic retinopathy when blood samples were taken, but who developed PDR within 6.3 years (converters). The retinopathy level was classified by fundus photography. RESULTS: We identified differential DNA methylation of 349 CpG sites representing 233 unique genes including TNF, CHI3L1 (also known as YKL-40), CHN2, GIPR, GLRA1, GPX1, AHRR, and BCOR in cases with PDR compared with controls. The majority of these sites (79 %) showed decreased DNA methylation in cases with PDR. The Natural Killer cell-mediated cytotoxicity pathway was found to be significantly (P = 0.006) enriched among differentially methylated genes in cases with PDR. We also identified differential DNA methylation of 28 CpG sites representing 17 genes (e.g. AHRR, GIPR, GLRA1, and BCOR) with P <0.05 in the prospective cohort, which is more than expected by chance (P = 0.0096). CONCLUSIONS: Subjects with T1D and PDR exhibit altered DNA methylation patterns in blood. Some of these epigenetic changes may predict the development of PDR, suggesting that DNA methylation may be used as a prospective marker of PDR. PMID- 26248553 TI - High nuclear expression of protein arginine methyltransferase-5 is a potentially useful marker to estimate submucosal invasion in endoscopically resected early colorectal carcinoma. AB - Protein arginine methyltransferase-5 (PRMT5), a major type II arginine methyltransferase, is an important epigenetic modifier with oncogene-like properties because of its ability to repress the expression of tumor suppressor genes. We determined the correlations between PRMT5 expression or its cellular localization and malignant progression, with special reference to invasiveness, in colorectal adenomas and early colorectal carcinomas (CRCs). We performed immunohistochemical detection of PRMT5 in 108 endoscopically resected tissue samples (6 adenomas with low-grade dysplasia, 34 adenomas with high-grade dysplasia, 30 intramucosal carcinomas, and 38 submucosal invasive carcinomas). Early CRC (55 of 68, 80.9%) showed more frequent nuclear expression of PRMT5 than adenoma (15 of 40, 37.5%) (P < 0.001). Furthermore, high (strong staining in >= 50% of nuclei) nuclear expression of PRMT5 was more common in submucosal invasive carcinoma (21 of 38, 55.3%) than in intramucosal carcinoma (9 of 30, 30.0%) (P = 0.037). In conclusion, our data suggests that high nuclear expression of PRMT5 is a potentially useful marker for estimating submucosal invasion of early CRC in endoscopically resected specimens. PMID- 26248554 TI - Bipartite structure of the inactive mouse X chromosome. AB - BACKGROUND: In mammals, one of the female X chromosomes and all imprinted genes are expressed exclusively from a single allele in somatic cells. To evaluate structural changes associated with allelic silencing, we have applied a recently developed Hi-C assay that uses DNase I for chromatin fragmentation to mouse F1 hybrid systems. RESULTS: We find radically different conformations for the two female mouse X chromosomes. The inactive X has two superdomains of frequent intrachromosomal contacts separated by a boundary region. Comparison with the recently reported two-superdomain structure of the human inactive X shows that the genomic content of the superdomains differs between species, but part of the boundary region is conserved and located near the Dxz4/DXZ4 locus. In mouse, the boundary region also contains a minisatellite, Ds-TR, and both Dxz4 and Ds-TR appear to be anchored to the nucleolus. Genes that escape X inactivation do not cluster but are located near the periphery of the 3D structure, as are regions enriched in CTCF or RNA polymerase. Fewer short-range intrachromosomal contacts are detected for the inactive alleles of genes subject to X inactivation compared with the active alleles and with genes that escape X inactivation. This pattern is also evident for imprinted genes, in which more chromatin contacts are detected for the expressed allele. CONCLUSIONS: By applying a novel Hi-C method to map allelic chromatin contacts, we discover a specific bipartite organization of the mouse inactive X chromosome that probably plays an important role in maintenance of gene silencing. PMID- 26248555 TI - The impact of chromatin remodelling on cellulase expression in Trichoderma reesei. AB - BACKGROUND: Trichoderma reesei is used for industry-scale production of plant cell wall-degrading enzymes, in particular cellulases, but also xylanases. The expression of the encoding genes was so far primarily investigated on the level of transcriptional regulation by regulatory proteins. Otherwise, the impact of chromatin remodelling on gene expression received hardly any attention. In this study we aimed to learn if the chromatin status changes in context to the applied conditions (repressing/inducing), and if the presence or absence of the essential transactivator, the Xylanase regulator 1 (Xyr1), influences the chromatin packaging. RESULTS: Comparing the results of chromatin accessibility real-time PCR analyses and gene expression studies of the two prominent cellulase-encoding genes, cbh1 and cbh2, we found that the chromatin opens during sophorose-mediated induction compared to D-glucose-conferred repression. In the strain bearing a xyr1 deletion the sophorose mediated induction of gene expression is lost and the chromatin opening is strongly reduced. In all conditions the chromatin got denser when Xyr1 is absent. In the case of the xylanase-encoding genes, xyn1 and xyn2, the result was similar concerning the condition-specific response of the chromatin compaction. However, the difference in chromatin status provoked by the absence of Xyr1 is less pronounced. A more detailed investigation of the DNA accessibility in the cbh1 promoter showed that the deletion of xyr1 changed the in vivo footprinting pattern. In particular, we detected increased hypersensitivity on Xyr1-sites and stronger protection of Cre1-sites. Looking for the players directly causing the observed chromatin remodelling, a whole transcriptome shotgun sequencing revealed that 15 genes encoding putative chromatin remodelers are differentially expressed in response to the applied condition and two amongst them are differentially expressed in the absence of Xyr1. CONCLUSIONS: The regulation of xylanase and cellulase expression in T. reesei is not only restricted to the action of transcription factors but is clearly related to changes in the chromatin packaging. Both the applied condition and the presence of Xyr1 influence chromatin status. PMID- 26248556 TI - Cyanate as an Active Precursor of Ethyl Carbamate Formation in Sugar Cane Spirit. AB - The thermodynamic and kinetic aspects of ethyl carbamate (EC) formation through the reaction between cyanate and ethanol were investigated. The rate constant values for cyanate ion decay and EC formation are (8.0 +/- 0.4) * 10(-5) and (8.9 +/- 0.4) * 10(-5) s(-1), respectively, at 25 degrees C in 48% aqueous ethanolic solution at pH 4.5. Under the investigated experimental conditions, the rate constants are independent of the ethanol and cyanate concentrations but increase as the temperature increases (DeltaH1(?) = 19.4 +/- 1 kcal/mol, DeltaS1(?) = 12.1 +/- 1 cal/K, and DeltaG1(?) = 23.0 +/- 1 kcal/mol) and decrease as the solution pH increases. According to molecular modeling (DFT) that was performed to analyze the reaction mechanism, the isocyanic acid (HNCO) is the active EC precursor. The calculated DeltaG1(?), DeltaH1(?), and DeltaS1(?) values are in very good agreement with the experimental ones. PMID- 26248557 TI - Influence of the Surface Functional Group Density on the Carbon-Nanotube-Induced alpha-Chymotrypsin Structure and Activity Alterations. AB - Because of the special properties of carbon nanotubes (CNTs), their applications have been introduced to many fields. The biosafety of these emerging materials is of high concern concomitantly. Because CNTs may initially bind with proteins in biofluids before they exert biological effects, it is of great importance to understand how the target proteins interact with these exogenous nanomaterials. Here we investigated the interaction between alpha-chymotrypsin (alpha-ChT) and carboxylized multiwalled CNTs in a simulated biophysical environment utilizing the techniques of fluorescence, UV-vis, circular dichroism spectroscopy, zeta potential, atomic force microscopy, and bicinchoninic acid analysis. It was demonstrated that CNTs interacted with alpha-ChT through electrostatic forces, causing a decrement in the alpha-helix and an increment in the beta-sheet content of the protein. The protein fluorescence was quenched in a static mode. The increase in the surface modification density of CNTs enhanced the protein absorption and decreased the enzymatic activity correspondingly. alpha-ChT activity inhibition induced by CNTs with low surface modification density exhibited noncompetitive characteristics; however, a competitive feature was observed when CNTs with high surface modification density interacted with the protein. An increase of the ionic strength in the reaction buffer may help to reduce the interaction between CNTs and alpha-ChT because the high ionic strength may favor the release of the protein from binding on a CNT surface modified with functional groups. Accordingly, the functionalization density on the CNT surface plays an important role in the regulation of their biological effects and is worthy of concern when new modified CNTs are developed. PMID- 26248558 TI - The impact of 10-valent and 13-valent pneumococcal conjugate vaccines on serotype 19A invasive pneumococcal disease. AB - The circulation in the community of pneumococcal serotype 19A, a highly invasive and frequently extremely resistant pneumococcal strain, has increased the focus on methods to control its presence and effect. Two vaccines have been developed: the 10-valent pneumococcal conjugate vaccine (PCV10) and the 13-valent pneumococcal conjugate vaccine (PCV13). Available data indicate that PCV13 is highly effective in reducing the risk of serotype 19A invasive pneumococcal disease (IPD) in both vaccinated children and unvaccinated adults. Positive data have also been published for PCV10 that suggest that the conjugated serotype 19F included in the vaccine could evoke a cross-reactive antibody response with serotype 19A. However, a great number of invasive pneumococcal disease (IPD) cases are associated with serotypes not included in either of the vaccines, and preparation of a vaccine containing all the serotypes is unrealistic. Protein vaccines are the real future to definitively reduce the pneumococcal disease burden. PMID- 26248560 TI - Antipsychotic and Benzodiazepine Drug Changes Affect Acute Falls Risk Differently in the Nursing Home. AB - BACKGROUND: Psychotropic drugs increase the risk of falls, but they are still frequently prescribed to treat behavioral symptoms associated with dementia in the nursing home. We examined whether there is an acute increased risk of falls in the days following a change to an antipsychotic or benzodiazepine drug prescription. METHODS: We collected information on 594 long-stay nursing home residents from two facilities who fell at least once between September 1, 2010 and May 31, 2013. Psychotropic drug changes were ascertained from the facilities' computerized medication administration log. We used the case-crossover design to compare the frequency of antipsychotic and benzodiazepine drug changes during the days before a fall with the frequency of drug changes at more remote times. RESULTS: Mean age was 87.5 years, and 75.1% were female. The risk of falls was higher in the 24 hours following benzodiazepine initiation compared with other times (odds ratio [OR] 3.79, 95% confidence interval [CI] 1.10, 13.00). There was no clear difference in risk following antipsychotic initiation (OR 2.42, CI 0.58, 10.06), but this could be due to the small sample size. Stopping a benzodiazepine was associated with a significantly reduced fall risk (OR 0.26, 95% CI 0.08 0.91). CONCLUSIONS: Benzodiazepines pose an immediate threat to fall risk, whereas it is less clear if antipsychotics also pose an immediate risk. Nursing home staff should be particularly vigilant in the days following the new prescription for a benzodiazepine in an effort to prevent injury. PMID- 26248559 TI - Motoric Cognitive Risk Syndrome Subtypes and Cognitive Profiles. AB - BACKGROUND: The motoric cognitive risk (MCR) syndrome, characterized by slow gait and cognitive complaints, is a simple and easily accessible clinical approach to identify older adults at high risk for transitioning to dementia. This study aims to define subtypes of MCR based on individual quantitative gait variables and to compare their neuropsychological profiles and risk factors as well risk for incident cognitive impairment. METHODS: MCR was diagnosed in 314 community residing, nondemented, older adults aged 65 and older (56% women) based on the presence of cognitive complaints and slow gait velocity (MCRv). Four new subtypes of MCR were defined by substituting slow gait with short stride length (MCRsl), slow swing time (MCRsw), high stride length variability (MCRslv), and high swing time variability (MCRswv). MCR subtypes were not mutually exclusive. RESULTS: A total of 25 participants (8%) met criteria for MCRv, 20 for MCRsl (6.4%), 15 for MCRsw (4.8%), 16 for MCRslv (5.1%), 12 for MCRswv (3.8%), and 266 participants (84.7%) did not meet criteria for any MCR subtype. At baseline, MCRv was associated with deficits in attention and language as well as in overall cognitive status. MCRswv was associated with deficits in all cognitive domains including memory. Obesity and sedentariness were risk factors of MCRv, MCRsl, and MCRsw. MCRv status predicted incident cognitive impairment in global cognition (odds ratio: 3.59, p = .016), whereas MCRswv status predicted incident cognitive impairment in memory (odds ratio: 4.24, p = .048). CONCLUSIONS: MCR subtypes based on individual gait parameters show commonalities and differences in cognitive profiles and risk factors. Future studies should investigate whether the MCR subtypes predict different subtypes of dementia. PMID- 26248562 TI - hapbin: An Efficient Program for Performing Haplotype-Based Scans for Positive Selection in Large Genomic Datasets. AB - Understanding how the genome is shaped by selective processes forms an integral part of modern biology. However, as genomic datasets continue to grow larger it is becoming increasingly difficult to apply traditional statistics for detecting signatures of selection to these cohorts. There is therefore a pressing need for the development of the next generation of computational and analytical tools for detecting signatures of selection in large genomic datasets. Here, we present hapbin, an efficient multithreaded implementation of extended haplotype homzygosity-based statistics for detecting selection, which is up to 3,400 times faster than the current fastest implementations of these algorithms. PMID- 26248561 TI - Interactions of Short-Term and Chronic Treadmill Training With Aging of the Left Ventricle of the Heart. AB - With aging, there is a decline in cardiac function accompanying increasing risk of arrhythmias. These effects are likely to be mechanistically associated with age-associated changes in calcium regulation within cardiac myocytes. Previous studies suggest that lifelong exercise can potentially reduce age-associated changes in the heart. Although exercise itself is associated with changes in cardiac function, little is known about the interactions of aging and exercise with respect to myocyte calcium regulation. To investigate this, adult (12 months) and old (24 months) C57/Bl6 mice were trained using moderate-intensity treadmill running. In response to 10 weeks' training, comparable cardiac hypertrophic responses were observed, although aging independently associated with additional cardiac hypertrophy. Old animals also showed increased L- and T type calcium channels, the sodium-calcium exchange, sarcoendoplasmic reticulum calcium ATPase, and collagen (by 50%, 92%, 66%, 88%, and 113% respectively). Short-term exercise training increased D-type and T-type calcium channels in old animals only, whereas an increase in sodium-calcium exchange was seen only in adult animals. Long-term (12 months) training generally opposed the effects of aging. Significant hypertrophy remained in long-term trained old animals, but levels of sarcoendoplasmic reticulum calcium ATPase, sodium-calcium exchange, and collagen were not significantly different from those found in the adult trained animals. PMID- 26248563 TI - ITS2 Database V: Twice as Much. AB - The internal transcribed spacer 2 (ITS2) is a well-established marker for phylogenetic analyses in eukaryotes. A reliable resource for reference sequences and their secondary structures is the ITS2 database (http://its2.bioapps.biozentrum.uni-wuerzburg.de/). However, the database was last updated in 2011. Here, we present a major update of the underlying data almost doubling the number of entities. This increases the number of taxa represented within all major eukaryotic clades. Moreover, additional data has been added to underrepresented groups and some new groups have been added. The broader coverage across the tree of life improves phylogenetic analyses and the capability of ITS2 as a DNA barcode. PMID- 26248565 TI - Effect of Resistance Training and Various Sources of Protein Supplementation on Body Fat Mass and Metabolic Profile in Sarcopenic Overweight Older Adult Men: A Pilot Study. AB - The decrease in resting energy expenditure (REE) and fat oxidation with aging is associated with an increase in fat mass (FM), and both could be prevented by exercise such as resistance training. Dairy consumption has also been shown to promote FM loss in different subpopulations and to be positively associated with fat oxidation. Therefore, we sought to determine whether resistance exercise combined with dairy supplementation could have an additive impact on FM and energy metabolism, especially in individuals with a deficit in muscle mass. Twenty-six older overweight sarcopenic men (65 +/- 5 years old) were recruited for the study. They participated in 4 months of resistance exercise and were randomized into three groups for postexercise shakes (control, dairy, and nondairy isocaloric and isoprotein supplement with 375 ml and ~280 calories per shake). Body composition was measured by dual X-ray absorptiometry and REE by indirect calorimetry. Fasting glucose, insulin, leptin, inflammatory profile, and blood lipid profile were also measured. Significant decreases were observed with FM only in the dairy supplement group; no changes were observed for any other variables. To conclude, FM may decrease without changes in metabolic parameters during resistance training and dairy supplementation with no caloric restriction without having any impact on metabolic properties. More studies are warranted to explain this significant decrease in FM. PMID- 26248564 TI - The Pseudoautosomal Regions of the U/V Sex Chromosomes of the Brown Alga Ectocarpus Exhibit Unusual Features. AB - The recombining regions of sex chromosomes (pseudoautosomal regions, PARs) are predicted to exhibit unusual features due to their being genetically linked to the nonrecombining, sex-determining region. This phenomenon is expected to occur in both diploid (XY, ZW) and haploid (UV) sexual systems, with slightly different consequences for UV sexual systems because of the absence of masking during the haploid phase (when sex is expressed) and because there is no homozygous sex in these systems. Despite a considerable amount of theoretical work on PAR genetics and evolution, these genomic regions have remained poorly characterized empirically. We show here that although the PARs of the U/V sex chromosomes of the brown alga Ectocarpus recombine at a similar rate to autosomal regions of the genome, they exhibit many genomic features typical of nonrecombining regions. The PARs were enriched in clusters of genes that are preferentially, and often exclusively, expressed during the sporophyte generation of the life cycle, and many of these genes appear to have evolved since the Ectocarpales diverged from other brown algal lineages. A modeling-based approach was used to investigate possible evolutionary mechanisms underlying this enrichment in sporophyte-biased genes. Our results are consistent with the evolution of the PAR in haploid systems being influenced by differential selection pressures in males and females acting on alleles that are advantageous during the sporophyte generation of the life cycle. PMID- 26248566 TI - In vivo endoscopic tissue identification by rapid evaporative ionization mass spectrometry (REIMS). AB - Gastrointestinal cancers are a leading cause of mortality, accounting for 23 % of cancer-related deaths worldwide. In order to improve outcomes from these cancers, novel tissue characterization methods are needed to facilitate accurate diagnosis. Rapid evaporative ionization mass spectrometry (REIMS) is a technique developed for the in vivo classification of human tissue through mass spectrometric analysis of aerosols released during electrosurgical dissection. This ionization technique was further developed by utilizing surface induced dissociation and was integrated with an endoscopic polypectomy snare to allow in vivo analysis of the gastrointestinal tract. We tested the classification performance of this novel endoscopic REIMS method in vivo. It was shown to be capable of differentiating between healthy layers of the intestinal wall, cancer, and adenomatous polyps based on the REIMS fingerprint of each tissue type in vivo. PMID- 26248567 TI - Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. AB - AIMS: There is a significant uncertainty regarding the effect of testosterone replacement therapy (TRT) on cardiovascular (CV) outcomes including myocardial infarction (MI) and stroke. The aim of this study was to examine the relationship between normalization of total testosterone (TT) after TRT and CV events as well as all-cause mortality in patients without previous history of MI and stroke. METHODS AND RESULTS: We retrospectively examined 83 010 male veterans with documented low TT levels. The subjects were categorized into (Gp1: TRT with resulting normalization of TT levels), (Gp2: TRT without normalization of TT levels) and (Gp3: Did not receive TRT). By utilizing propensity score-weighted Cox proportional hazard models, the association of TRT with all-cause mortality, MI, stroke, and a composite endpoint was compared between these groups. The all cause mortality [hazard ratio (HR): 0.44, confidence interval (CI) 0.42-0.46], risk of MI (HR: 0.76, CI 0.63-0.93), and stroke (HR: 0.64, CI 0.43-0.96) were significantly lower in Gp1 (n = 43 931, median age = 66 years, mean follow-up = 6.2 years) vs. Gp3 (n = 13 378, median age = 66 years, mean follow-up = 4.7 years) in propensity-matched cohort. Similarly, the all-cause mortality (HR: 0.53, CI 0.50-0.55), risk of MI (HR: 0.82, CI 0.71-0.95), and stroke (HR: 0.70, CI 0.51-0.96) were significantly lower in Gp1 vs. Gp2 (n = 25 701, median age = 66 years, mean follow-up = 4.6 years). There was no difference in MI or stroke risk between Gp2 and Gp3. CONCLUSION: In this large observational cohort with extended follow-up, normalization of TT levels after TRT was associated with a significant reduction in all-cause mortality, MI, and stroke. PMID- 26248568 TI - Percutaneous closure of patent foramen ovale: an underutilized prevention? AB - Stroke is a devastating event for patients and their families. Paradoxical embolism through a patent foramen ovale (PFO) is a recognized cause of stroke. Percutaneous PFO closure is a simple and safe procedure. The debate on PFO closure is far from settled. This is, in part, due to the fact that the three published randomized controlled trials (RCTs) on PFO closure vs. medical therapy were negative regarding their primary endpoint; however, as-treated and per protocol analyses as well as several meta-analyses report a benefit of PFO closure. In our opinion, PFO closure is underutilized and the results of the three RCTs are not adequately reflected in the current guidelines. PMID- 26248569 TI - Oral dual antiplatelet therapy: what have we learnt from recent trials? AB - International guidelines recommend the use of aspirin treatment immediately and indefinitely in coronary patients. The optimal time to start and the duration of dual antiplatelet therapy (DAPT; aspirin plus a P2Y12 inhibitor) have not been clearly established. Recent clinical trials have provided important new information allowing for evidence-based decisions regarding timing of initiation and duration of DAPT. The benefit-to-risk ratio of DAPT pre-treatment appears to depend on the type of acute coronary syndrome, the time until angiography, and the onset of action of the drug. In stable patients undergoing percutaneous coronary intervention with the latest generation drug-eluting stents, patients should be treated for at least ~6 months. Shorter courses of therapy may be necessary when special conditions occur (e.g. surgery; oral anticoagulation). Longer courses of therapy may be reasonable in patients at low bleeding risk who are tolerating DAPT well. For patients with ACS, prolonged DAPT is beneficial and therefore reasonable as long as the patient is tolerating the therapy. Individualized management of DAPT must be seen as a dynamic prescription with regular re-evaluations of the risk-benefit to the patient according to changes in his/her clinical profile. PMID- 26248571 TI - Long-Term Comparison of Three Types of Aortic St. Jude Medical Mechanical Prosthesis in Japanese Patients. AB - BACKGROUND: The long-term results achieved with aortic St. Jude Medical (SJM) mechanical prostheses in various age groups of Japanese patients have not been previously compared or reported. METHODS AND RESULTS: Since 1981, a total of 240 SJM valves were implanted in 79 patients using the Standard model, in 58 patients with the Hemodynamic Plus model, and in 103 patients with the Regent model for aortic valve replacement (AVR). Follow-up was completed for 2,397 patient-years in 97.5% of the patients, among whom the effect of age was compared, and the subjects were divided into younger (<65 years) and older (>=65 years) groups. Hospital mortality rate was 2.5%. No structural valve deterioration was observed during the follow-up period. In addition, no significant differences were observed in long-term survival between the 3 models. In contrast, significantly better rates of freedom from all-cause death (P<0.0001), valve-related death (P=0.0018) and valve-related morbidity (P=0.0021), including bleeding events (P=0.0007), were observed in the younger group (n=157, 50.6+/-1.0 years old) than in the older group (n=83, 72.5+/-0.7 years old). CONCLUSIONS: All types of SJM valve used for single AVR achieved satisfactory early and long-term results in each age group even 25 years after surgery. When selecting this prosthesis for elderly patients, however, relatively worse performance may be expected compared with that observed in younger patients. PMID- 26248570 TI - Serum amyloid A: high-density lipoproteins interaction and cardiovascular risk. AB - AIMS: High-density lipoproteins (HDLs) are considered as anti-atherogenic. Recent experimental findings suggest that their biological properties can be modified in certain clinical conditions by accumulation of serum amyloid A (SAA). The effect of SAA on the association between HDL-cholesterol (HDL-C) and cardiovascular outcome remains unknown. METHODS AND RESULTS: We examined the association of SAA and HDL-C with mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, which included 3310 patients undergoing coronary angiography. To validate our findings, we analysed 1255 participants of the German Diabetes and Dialysis study (4D) and 4027 participants of the Cooperative Health Research in the Region of Augsburg (KORA) S4 study. In LURIC, SAA concentrations predicted all-cause and cardiovascular mortality. In patients with low SAA, higher HDL-C was associated with lower all-cause and cardiovascular mortality. In contrast, in patients with high SAA, higher HDL-C was associated with increased all-cause and cardiovascular mortality, indicating that SAA indeed modifies the beneficial properties of HDL. We complemented these clinical observations by in vitro experiments, in which SAA impaired vascular functions of HDL. We further derived a formula for the simple calculation of the amount of biologically 'effective' HDL-C based on measured HDL-C and SAA from the LURIC study. In 4D and KORA S4 studies, we found that measured HDL-C was not associated with clinical outcomes, whereas calculated 'effective' HDL-C significantly predicted better outcome. CONCLUSION: The acute-phase protein SAA modifies the biological effects of HDL-C in several clinical conditions. The concomitant measurement of SAA is a simple, useful, and clinically applicable surrogate for the vascular functionality of HDL. PMID- 26248572 TI - Transcatheter Closure of Intracristal Ventricular Septal Defect With Mild Aortic Cusp Prolapse Using Zero Eccentricity Ventricular Septal Defect Occluder. AB - BACKGROUND: Transcatheter closure is a well-established therapy for patients with perimembranous ventricular septal defects (VSDs), but with limited experience in intracristal VSDs (IVSDs) with aortic cusp prolapse (ACP). METHODS AND RESULTS: From 2012 to 2014, we reviewed 38 patients with IVSDs complicated with mild ACP who underwent device closure, and, in light of the findings, assessed the effect of transcatheter intervention on preoperative mild ACP. The zero eccentric VSD occluder was chosen for closure (Shanghai Shape Memory Alloy Ltd, Shanghai, China). The mean defect was 4.8+/-1.6 mm (range, 2-8) as measured by transthoracic echocardiography and the mean device size was 10.1+/-2.1 mm (range, 4-14). Placement of the device was successful in 35 patients (92.1%). In the remaining 3 patients (7.9%), major complications occurred and they were converted to surgical intervention: severe aortic regurgitation (AR) in 2 patients and occluder dislodgement in 1 patient. During the follow-up (median 14.2 months; range, 3-24), no deaths, residual shunt, late-onset AR, heart block, or device failure occurred. CONCLUSIONS: The mid-term prognostic results of high success rate and low complications rate in this study are inspiring. Transcatheter closure of IVSD with mild ACP can be performed safely and effectively as an alternative to surgery in selected patients. PMID- 26248573 TI - Efficacy and Safety of Dabigatran Etexilate vs. Warfarin in Asian RE-LY Patients According to Baseline Renal Function or CHADS2 Score. AB - BACKGROUND: In Asian patients in RE-LY, dabigatran etexilate (DE) was as effective as warfarin, with a significantly lower bleeding risk. We evaluated the relationship between baseline renal function or CHADS2 score and efficacy or safety outcomes in these patients. METHODS AND RESULTS: Asian patients (n=2,782) were categorized according to baseline renal function or CHADS2 score, and efficacy and safety outcomes were analyzed for DE (110 mg and 150 mg b.i.d.) vs. warfarin. There was an increase in the rates of stroke/systemic embolism and major bleeding with worsening renal function and CHADS2 score. For stroke/systemic embolism (primary efficacy endpoint), there was no treatment interaction for dabigatran at either 110 or 150 mg b.i.d. compared with warfarin related to patients' baseline renal function (Pinteraction=0.56 for DE 110 mg and 0.62 for DE 150 mg vs. warfarin) or CHADS2 score (Pinteraction=0.68 for DE 110 mg and 0.31 for DE 150 mg vs. warfarin). For major bleeding, there was no treatment interaction by creatinine clearance category observed for either dose (Pinteraction=0.60 and 0.62 for DE 110 mg and DE 150 mg, respectively). Baseline CHADS2 score had no significant effect on bleeding event rates with DE vs. warfarin. CONCLUSIONS: Bleeding and stroke rates in Asian patients varied according to renal function and CHADS2 score, but the relative benefits of DE over warfarin were preserved when analyzed by subcategories. PMID- 26248574 TI - CO2 controlled flocculation of microalgae using pH responsive cellulose nanocrystals. AB - Cellulose nanocrystals were grafted with imidazole functionalities up to DS 0.06 using a one-pot functionalization strategy. The resulting nanocrystals were shown to have a pH responsive surface charge which was found to be positive below pH 6 and negative above pH 7. These imidazolyl cellulose nanocrystals were tested for flocculation of Chlorella vulgaris using CO2 to induce flocculation. Up to 90% flocculation efficiency was achieved with 200 mg L(-1) dose. Furthermore, the modified cellulose nanocrystals showed good compatibility with the microalgae during cultivation, giving potential for the production of reversible flocculation systems. PMID- 26248575 TI - A luminescent ruthenium(II) complex for light-triggered drug release and live cell imaging. AB - We report a novel ruthenium(II) complex for selective release of the imidazole based drug econazole. While the complex is highly stable and luminescent in the dark, irradiation with green light induces release of one of the econazole ligands, which is accompanied by a turn-off luminescence response and up to a 34 fold increase in cytotoxicity towards tumour cells. PMID- 26248576 TI - Cysteine-Ag Cluster Hydrogel Confirmed by Experimental and Numerical Studies. AB - The native cysteine (Cys)-Ag3 cluster hydrogel is approved for the first time by both experimental and theoretical studies. From the detailed molecular structure and energy information, three factors are found to ensure the self-assembly of Cys and Ag3 , and result in the hydrogel. First, the Ag-S bonds make Cys and Ag3 form Cys-Ag3 -Cys monomer. Second, intermolecular hydrogen bonds between carboxyl groups of adjacent monomer push them self-assembled. Third, more monomer precisely self-assemble to produce the -[Cys-Ag3 -Cys]n multimer, e.g., a single molecular chain with the left-handed helix conformation, via a benign thermodynamic process. These multimers entangle together to form micro-network to trap water and produce hydorgel in situ. The hydrogen bonds of hydrogel are sensitive to thermal and proton stimuli, and the hydrogel presents lysosome targeting properties via fluorescent imaging with biocompatibility. PMID- 26248578 TI - Introduction to Mammalian Genome special issue: Informatics and Integrative Genomics--Part 1. PMID- 26248577 TI - The oncogenic role of GASC1 in chemically induced mouse skin cancer. AB - Gene amplified in squamous cell carcinoma (SCC) 1 (GASC1), also known as KDM4C/JMJD2C, encodes a histone demethylase that specifically demethylates lysine residues (H3K9, H3K36, and H1.4K26) and plays a crucial role in the regulation of gene expression as well as in heterochromatin formation. GASC1 is located at human chromosome 9p23-24, where frequent genomic amplification is observed in human esophageal cancer, and its aberrant expression is detected in a variety of human cancers, such as breast, colon, and prostate. Therefore, it is highly likely that GASC1 contributes to the genesis and/or development of cancer. However, there is a lack of direct evidence of GASC1 having an oncogenic function. In this study, we aimed to clarify the role of GASC1 in the skin SCC carcinogenesis. For this purpose, we generated Gasc1-heterozygous mice (Gasc1+/-) with reduced expression of Gasc1. On the basis of our results, Gasc1+/- mice displayed a significantly lower incidence and multiplicity of both benign and malignant tumors induced by the two-stage skin carcinogenesis protocol than wild type mice. In addition, the volume of carcinoma was significantly lower in Gasc1+/- mice. Consistent with these observations, knocking down of Gasc1 resulted in reduced cell viability of SCC cells in vitro. Our findings clearly demonstrated that GASC1 has an oncogenic role in skin carcinogenesis. PMID- 26248579 TI - [Consideration of guidelines, recommendations and quality indicators for treatment of stroke in the dataset "Emergency Department" of DIVI]. AB - BACKGROUND: The dataset "Emergency Department" of the German Interdisciplinary Association of Critical Care and Emergency Medicine (DIVI) has been developed during several expert meetings. Its goal is an all-encompassing documentation of the early clinical treatment of patients in emergency departments. Using the example of the index disease acute ischemic stroke (stroke), the aim was to analyze how far this approach has been fulfilled. MATERIAL AND METHODS: In this study German, European and US American guidelines were used to analyze the extent of coverage of the datasets on current emergency department guidelines and recommendations from professional societies. In addition, it was examined whether the dataset includes recommended quality indicators (QI) for quality management (QM) and in a third step it was examined to what extent national provisions for billing are included. In each case a differentiation was made whether the respective rationale was primary, i.e. directly apparent or whether it was merely secondarily depicted by expertise. In the evaluation an additional differentiation was made between the level of recommendations and further quality relevant criteria. RESULTS: The modular design of the emergency department dataset comprising 676 data fields is briefly described. A total of 401 individual fields, divided into basic documentation, monitoring and specific neurological documentation of the treatment of stroke patients were considered. For 247 data fields a rationale was found. Partially overlapping, 78.9 % of 214 medical recommendations in 3 guidelines and 85.8 % of the 106 identified quality indicators were primarily covered. Of the 67 requirements for billing of performance of services, 55.5 % are primarily part of the emergency department dataset. Through appropriate expertise and documentation by a board certified neurologist, the results can be improved to almost 100 %. CONCLUSION: The index disease stroke illustrates that the emergency department dataset of the DIVI covers medical guidelines, especially 100 % of the German guidelines with a grade of recommendation. All necessary information to document the specialized stroke treatment procedure in the German diagnosis-related groups (DRG) system is also covered. The dataset is also suitable as a documentation tool of quality management, for example, to participate in the registry of the German Stroke Society (ADSR). Best results are obtained if the dataset is applied by a physician specialized in the treatment of patients with stroke (e.g. board certified neurologist). Finally the results show that changes in medical guidelines and recommendations for quality management as well as billing-relevant content should be implemented in the development of datasets for documentation to avoid duplicate documentation. PMID- 26248580 TI - Appraising the Role of Iron in Brain Aging and Cognition: Promises and Limitations of MRI Methods. AB - Age-related increase in frailty is accompanied by a fundamental shift in cellular iron homeostasis. By promoting oxidative stress, the intracellular accumulation of non-heme iron outside of binding complexes contributes to chronic inflammation and interferes with normal brain metabolism. In the absence of direct non invasive biomarkers of brain oxidative stress, iron accumulation estimated in vivo may serve as its proxy indicator. Hence, developing reliable in vivo measurements of brain iron content via magnetic resonance imaging (MRI) is of significant interest in human neuroscience. To date, by estimating brain iron content through various MRI methods, significant age differences and age-related increases in iron content of the basal ganglia have been revealed across multiple samples. Less consistent are the findings that pertain to the relationship between elevated brain iron content and systemic indices of vascular and metabolic dysfunction. Only a handful of cross-sectional investigations have linked high iron content in various brain regions and poor performance on assorted cognitive tests. The even fewer longitudinal studies indicate that iron accumulation may precede shrinkage of the basal ganglia and thus predict poor maintenance of cognitive functions. This rapidly developing field will benefit from introduction of higher-field MRI scanners, improvement in iron-sensitive and -specific acquisition sequences and post-processing analytic and computational methods, as well as accumulation of data from long-term longitudinal investigations. This review describes the potential advantages and promises of MRI-based assessment of brain iron, summarizes recent findings and highlights the limitations of the current methodology. PMID- 26248582 TI - Brain stimulation improves cognitive control by modulating medial-frontal activity and preSMA-vmPFC functional connectivity. AB - Previous research has demonstrated that brain stimulation can improve inhibitory control. However, the neural mechanisms underlying such artificially induced improvement remain unclear. In this study, by coupling anodal transcranial direct current stimulation (atDCS) with functional MRI, we found that atDCS over preSMA effectively improved stopping speed, which was associated with increased BOLD response in the preSMA and ventromedial prefrontal cortex (vmPFC). Furthermore, such atDCS-induced BOLD increase in vmPFC was positively correlated with participants' improvement in stopping efficiency, and the functional connectivity between preSMA and vmPFC increased during successful stop. These results suggest that the rapid behavioral improvement from preSMA brain stimulation involves modulated medial-frontal activity and preSMA-vmPFC functional connectivity. PMID- 26248583 TI - Efficient human face detection in infancy. AB - Adults detect conspecific faces more efficiently than heterospecific faces; however, the development of this own-species bias (OSB) remains unexplored. We tested whether 6- and 11-month-olds exhibit OSB in their attention to human and animal faces in complex visual displays with high perceptual load (25 images competing for attention). Infants (n = 48) and adults (n = 43) passively viewed arrays containing a face among 24 non-face distractors while we measured their gaze with remote eye tracking. While OSB is typically not observed until about 9 months, we found that, already by 6 months, human faces were more likely to be detected, were detected more quickly (attention capture), and received longer looks (attention holding) than animal faces. These data suggest that 6-month-olds already exhibit OSB in face detection efficiency, consistent with perceptual attunement. This specialization may reflect the biological importance of detecting conspecific faces, a foundational ability for early social interactions. PMID- 26248584 TI - Clinical-Pathological Conference Series from the Medical University of Graz Case No 155: 26-year-old woman in third trimester of pregnancy with epigastric pain and thrombocytopenia. PMID- 26248581 TI - Functional Magnetic Resonance Imaging Methods. AB - Since its inception in 1992, Functional Magnetic Resonance Imaging (fMRI) has become an indispensible tool for studying cognition in both the healthy and dysfunctional brain. FMRI monitors changes in the oxygenation of brain tissue resulting from altered metabolism consequent to a task-based evoked neural response or from spontaneous fluctuations in neural activity in the absence of conscious mentation (the "resting state"). Task-based studies have revealed neural correlates of a large number of important cognitive processes, while fMRI studies performed in the resting state have demonstrated brain-wide networks that result from brain regions with synchronized, apparently spontaneous activity. In this article, we review the methods used to acquire and analyze fMRI signals. PMID- 26248586 TI - Upregulation of centromere protein H is associated with progression of renal cell carcinoma. AB - Centromere protein H (CENPH), one of the essential component of active kinetochore, plays an important role in carcinogenesis of many cancer types. However, its expression signature and prognostic significance of renal cell carcinoma (RCC) are unclear. In the present study, we concluded that the expression of CENPH was prominently upregulated in RCC specimens and three RCC cell lines (ACHN, 786-O and A704). Immunohistochemical analysis revealed that RCCs exhibited higher levels of CENPH expression than normal renal tissues in paraffin-embedded archival specimens. Further statistical analysis suggested the upregulation of CENPH was positively correlated with the Fuhrman grade (P = 0.001), distant metastasis (P = 0.024) and clinical stage (P = 0.014). In addition, the CENPH served as an independent predictor of overall survival of RCC patients in multivariate analysis (P = 0.018). Furthermore, our in vitro assays of RCC cell lines indicated that knockdown of CENPH reduced cell proliferation, inhibited cell growth, and increased cell apoptosis. In conclusion, our data suggest that CENPH is a novel molecule involved in RCC progression, which provides a potential biomarker and therapeutic target. PMID- 26248585 TI - Genetic diversity and temporal dynamics of phytoplankton viruses in East Lake, China. AB - Phytoplankton viruses are important components of aquatic ecosystems. However, their prevalence and genetic diversity in marine and freshwater systems are largely under estimated owing to the immense size of water bodies and limitations in virus discovery techniques. In this study, we conducted a 1-year survey of phytoplankton virus communities by collecting surface water monthly from an inland lake (East Lake) in China between May 2012 and April 2013. We examined four phytoplankton viruses, i.e., myoviruses, podoviruses, siphoviruses, and phycodnaviruses, and seven sets of primers were used to target conserved genes within these four species. In this year-long investigation, a total of 358 different virus-related sequences from four virus families were obtained. All virus families were detected in all months, except for cyanopodoviruses, which were only identified during eight of the 12 months surveyed. Moreover, virus abundance and diversity changed dynamically over time. Phylogenetic analysis revealed that the majority of viral sequences from East Lake, China displayed distinct clustering patterns compared with published sequences. These results supported the existence of a highly diverse and unique phytoplankton virus community in East Lake, China. PMID- 26248587 TI - Mainstem-tributary linkages by mayfly migration help sustain salmonids in a warming river network. AB - Animal migrations can link ecosystems across space. We discovered an aquatic insect that migrates between a river mainstem and its tributaries, and provides an important trophic subsidy for tributary predators. A mayfly, Ephemerella maculata, rears in a warm, sunlit productive river mainstem, then migrates as adults to cool, shaded unproductive tributaries where they oviposit and die. This migration tripled insect flux into a tributary for 1 month in summer. A manipulative field experiment showed that this E. maculata subsidy nearly tripled the growth of the young of the year steelhead trout (Oncorhynchus mykiss) in the recipient tributary over the summer months, and was more important than terrestrial invertebrate subsidies, which have been considered the primary food source for predators in small, forested creeks. By delivering food subsidies from productive but warming river mainstems to cool but food-limited tributaries, aquatic insect migrations could enhance resilience to cool-water predators in warming river networks. PMID- 26248588 TI - Patients with multiple myeloma have excellent long-term outcomes after recovery from dialysis-dependent acute kidney injury. AB - OBJECTIVES: The aim of this study was to report the long-term outcomes in patients with multiple myeloma (MM) who receive dialysis treatment for acute kidney injury (AKI) due to myeloma cast nephropathy and subsequently recover renal function. METHODS: Patients presenting with dialysis-dependent AKI secondary to myeloma cast nephropathy and subsequently recovering independent renal function between January 2005 and December 2012 were included in this study. Both renal and haematological parameters were collected at multiple time points as part of routine clinic practice. Factors associated with renal function and overall survival (OS) were determined. RESULTS: Twenty-four patients fulfilled the criteria for inclusion. Mean age was 62.1 years; 75% were male and 75% were of White ethnicity. The median OS was 64.1 months (95% confidence interval [CI] 34.8-93.3). Twenty-three (95.8%) patients remained dialysis independent until death or end of follow-up; one patient required further haemodialysis treatment during the follow-up period. The independent determinant of worse OS was a known history of chronic kidney disease (CKD) at presentation. Shorter length of time on haemodialysis and higher percentage reduction in clonal serum FLC at day 21 from baseline predicted better excretory renal function (estimated glomerular filtration rate) at 6 months. CONCLUSION: In this series, the large majority of patients with MM and dialysis-dependent AKI secondary to myeloma cast nephropathy who recovered independent renal function had no requirement for further dialysis. Survival following recovery of renal function is good, and early variables are independently associated with survival and future renal function. PMID- 26248589 TI - Gene transcription of pro-inflammatory cytokines and chemokines induced by IL-17A in canine keratinocytes. AB - BACKGROUND: Pro-inflammatory cytokines and chemokines produced by activated keratinocytes play an important role in the pathogenesis of canine atopic dermatitis (AD) as well as human AD. Recent studies suggest that keratinocytes activated by IL-17A are involved in the pathogenesis of human AD. However, the role of IL-17A in canine keratinocytes is poorly understood. HYPOTHESIS/OBJECTIVES: Interleukin-17A would induce the transcription of pro inflammatory cytokines and chemokines in canine keratinocytes. METHODS: The transcription levels of pro-inflammatory cytokines and chemokines were quantified in a canine keratinocyte cell line stimulated with recombinant canine (rc) IL 17A. RESULTS: The transcription of GM-CSF, S100A8, IL-8 and IL-19 in cultured keratinocytes was significantly enhanced at 24 h after stimulation with rcIL-17A. CONCLUSIONS AND CLINICAL IMPORTANCE: Keratinocytes activated by IL-17A have the ability to produce various pro-inflammatory cytokines and chemokines, suggesting that IL-17A may play a central role of the development of Th2-associated inflammation in canine AD. PMID- 26248591 TI - Erratum to: Insulin improves memory and reduces chronic neuroinflammation in the hippocampus of young but not aged brains. PMID- 26248590 TI - Who gains clinical benefit from using insulin pump therapy? A qualitative study of the perceptions and views of health professionals involved in the Relative Effectiveness of Pumps over MDI and Structured Education (REPOSE) trial. AB - AIMS: To explore health professionals' views about insulin pump therapy [continuous subcutaneous insulin infusion (CSII)] and the types of individuals they thought would gain greatest clinical benefit from using this treatment. METHODS: In-depth interviews with staff (n = 18) who delivered the Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE) trial. Data were analysed thematically. RESULTS: Staff perceived insulin pumps as offering a better self-management tool to some individuals due to the drip feed of insulin, the ability to alter basal rates and other advanced features. However, staff also noted that, because of the diversity of features on offer, CSII is a more technically complex therapy to execute than multiple daily injections. For this reason, staff described how, alongside clinical criteria, they had tended to select individuals for CSII in routine clinical practice based on their perceptions about whether they possessed the personal and psychological attributes needed to make optimal use of pump technology. Staff also described how their assumptions about personal and psychological suitability had been challenged by working on the REPOSE trial and observing individuals make effective use of CSII who they would not have recommended for this type of therapy in routine clinical practice. CONCLUSIONS: Our findings add to those studies that highlight the difficulties of using patient characteristics and variables to predict clinical success using CSII. To promote equitable access to CSII, attitudinal barriers and prejudicial assumptions amongst staff about who is able to make effective use of CSII may need to be addressed. PMID- 26248592 TI - Approach for needle insertion into the tibialis posterior: An ultrasonography study. AB - INTRODUCTION: To avoid neurovascular damage by needle electrode insertion into the tibialis posterior, we used ultrasonography to determine the proper insertion point based on anatomic landmarks. METHODS: Using ultrasonography, the safety window, the corrected safety window, and the depth of the tibialis posterior were measured at 4 points (the upper third and midpoint of the tibia using anterior and posterior approaches) in healthy volunteers. RESULTS: The safety window at the midpoint for the posterior approach was significantly larger than at the other points. The corrected safety window could be defined only at the upper third for the anterior approach and at the midpoint for the posterior approach. CONCLUSIONS: Among the 4 points used for needle insertion into the tibialis posterior, the midpoint by the posterior approach may be the most favorable insertion point. The upper third may be better for the anterior approach. PMID- 26248593 TI - Evaluation of the Pharmacokinetics and Renal Excretion of Simeprevir in Subjects with Renal Impairment. AB - BACKGROUND: Simeprevir is a N3/4 protease inhibitor approved for the treatment of hepatitis C virus (HCV) infection. HCV prevalence is higher in patients with chronic kidney disease compared with the general population; safe and efficacious therapies in renal impairment are needed. OBJECTIVES: To evaluate simeprevir renal excretion in healthy subjects and to compare the simeprevir steady-state pharmacokinetics between subjects with severe renal impairment and healthy subjects. METHODS: In the mass balance study, healthy adults received a single 200-mg dose of (14)C-simeprevir; radioactivity in the urine and feces was quantified until concentrations were <2% of the administered dose and seven or more stools were produced. In the pharmacokinetic study, non-HCV-infected adults with severe renal impairment (estimated glomerular filtration rate <=29 mL/min/1.73 m(2)) and matched healthy subjects (estimated glomerular filtration rate >=80 mL/min/1.73 m(2)) received 150 mg simeprevir for 7 days. Pharmacokinetic analysis was performed post-dose on Day 7. RESULTS: (14)C simeprevir recovery from the urine was low (0.009-0.138% of total dose). The minimum plasma concentration, maximum plasma concentration, and area under the plasma concentration-time curve at 24 h were 71, 34, and 62% higher, respectively, in subjects with severe renal impairment compared with healthy subjects. The mean fraction of simeprevir unbound to protein was <0.0001 (all subjects). Most adverse events were grade I or II; one subject with renal impairment who was receiving fenofibrate presented with grade 3 rhabdomyolysis. CONCLUSIONS: Simeprevir plasma concentrations were mildly elevated in subjects with severe renal impairment. The results suggest that simeprevir may be administered without dose adjustment in patients with renal impairment. PMID- 26248596 TI - Latent Fingerprint Development on Thermal Paper Using Traditional Ninhydrin and 1,2-indanedione. AB - Thermal paper poses a significant challenge to latent print development as it tends to change color when traditional fingerprint development formulations are applied to it. In this study, the optimal components of ninhydrin, 1,2 indanedione, 1,8-diazafluoren-9-one (DFO), and 5-methylthioninhydrin (5-MTN) for yielding clear fingerprints on thermal paper were determined by systematically adjusting the relative amounts of the reagents, polar solvents, and the nonpolar diluent petroleum ether, followed by validation on text-printed thermal paper. Specifically, 3.0% ethyl acetate as the polar solvent in petroleum ether was found to be the optimal combination; the optimal dilution ratios of ninhydrin, DFO, and 5-MTN original solutions with petroleum ether were 1 to 2, 11, and 7, respectively. The optimal concentration of 1,2-indanedione in petroleum ether was 0.125 g/L, with a string of 0.5% ethyl acetate in petroleum ether. PMID- 26248595 TI - Armored geckos: A histological investigation of osteoderm development in Tarentola (Phyllodactylidae) and Gekko (Gekkonidae) with comments on their regeneration and inferred function. AB - Osteoderms are bone-rich organs found in the dermis of many scleroglossan lizards sensu lato, but are only known for two genera of gekkotans (geckos): Tarentola and Gekko. Here, we investigate their sequence of appearance, mode of development, structural diversity and ability to regenerate following tail loss. Osteoderms were present in all species of Tarentola sampled (Tarentola annularis, T. mauritanica, T. americana, T. crombei, T. chazaliae) as well as Gekko gecko, but not G. smithii. Gekkotan osteoderms first appear within the integument dorsal to the frontal bone or within the supraocular scales. They then manifest as mineralized structures in other positions across the head. In Tarentola and G. gecko, discontinuous clusters subsequently form dorsal to the pelvis/base of the tail, and then dorsal to the pectoral apparatus. Gekkotan osteoderm formation begins once the dermis is fully formed. Early bone deposition appears to involve populations of fibroblast-like cells, which are gradually replaced by more rounded osteoblasts. In T. annularis and T. mauritanica, an additional skeletal tissue is deposited across the superficial surface of the osteoderm. This tissue is vitreous, avascular, cell-poor, lacks intrinsic collagen, and is herein identified as osteodermine. We also report that following tail loss, both T. annularis and T. mauritanica are capable of regenerating osteoderms, including osteodermine, in the regenerated part of the tail. We propose that osteoderms serve roles in defense against combative prey and intraspecific aggression, along with anti-predation functions. PMID- 26248594 TI - Molecular dynamics and functional studies define a hot spot of crystal contacts essential for PcTx1 inhibition of acid-sensing ion channel 1a. AB - BACKGROUND AND PURPOSE: The spider-venom peptide PcTx1 is the most potent and selective inhibitor of acid-sensing ion channel (ASIC) 1a. It has centrally acting analgesic activity and is neuroprotective in rodent models of ischaemic stroke. Understanding the molecular details of the PcTx1 : ASIC1a interaction should facilitate development of therapeutically useful ASIC1a modulators. Previously, we showed that several key pharmacophore residues of PcTx1 reside in a dynamic beta-hairpin loop; conclusions confirmed by recent crystal structures of the complex formed between PcTx1 and chicken ASIC1 (cASIC1). Numerous peptide : channel contacts were observed in these crystal structures, but it remains unclear which of these are functionally important. EXPERIMENTAL APPROACH: We combined molecular dynamics (MD) simulations of the PcTx1 : cASIC1 complex with mutagenesis of PcTx1 and rat ASIC1a. KEY RESULTS: Crystal structures of the PcTx1 : cASIC1 complex indicated that 15 PcTx1 residues form a total of 57 pairwise intermolecular contacts (<5 A) with 32 channel residues. MD simulations, however, suggested that about half of these interactions do not persist in solution. Mutation to alanine of only eight of 15 PcTx1 contact residues substantially altered ASIC1a inhibition by PcTx1. Our data reveal that many of the peptide channel interactions observed in the PcTx1 : cASIC1 crystal structures are not important for PcTx1 inhibition of rat ASIC1a. CONCLUSIONS AND IMPLICATIONS: We identified the atomic interactions that are critical for PcTx1 inhibition of ASIC1a. Our data highlight the value of combining structural information, MD and functional experiments to obtain detailed insight into the molecular basis of protein : protein interactions. PMID- 26248597 TI - Biofunctionalization of conductive hydrogel coatings to support olfactory ensheathing cells at implantable electrode interfaces. AB - Mechanical discrepancies between conventional platinum (Pt) electrodes and neural tissue often result in scar tissue encapsulation of implanted neural recording and stimulating devices. Olfactory ensheathing cells (OECs) are a supportive glial cell in the olfactory nervous system which can transition through glial scar tissue while supporting the outgrowth of neural processes. It has been proposed that this function can be used to reconnect implanted electrodes with the target neural pathways. Conductive hydrogel (CH) electrode coatings have been proposed as a substrate for supporting OEC survival and proliferation at the device interface. To determine an ideal CH to support OECs, this study explored eight CH variants, with differing biochemical composition, in comparison to a conventional Pt electrodes. All CH variants were based on a biosynthetic hydrogel, consisting of poly(vinyl alcohol) and heparin, through which the conductive polymer (CP) poly(3,4-ethylenedioxythiophene) was electropolymerized. The biochemical composition was varied through incorporation of gelatin and sericin, which were expected to provide cell adherence functionality, supporting attachment, and cell spreading. Combinations of these biomolecules varied from 1 to 3 wt %. The physical, electrical, and biological impact of these molecules on electrode performance was assessed. Cyclic voltammetry and electrochemical impedance spectroscopy demonstrated that the addition of these biological molecules had little significant effect on the coating's ability to safely transfer charge. Cell attachment studies, however, determined that the incorporation of 1 wt % gelatin in the hydrogel was sufficient to significantly increase the attachment of OECs compared to the nonfunctionalized CH. PMID- 26248598 TI - Sex Cord Stromal Tumors: It is Networking-or Not Working. PMID- 26248599 TI - Cortical Stimulation Concurrent With Skilled Motor Training Improves Forelimb Function and Enhances Motor Cortical Reorganization Following Controlled Cortical Impact. AB - BACKGROUND: Electrical and magnetic brain stimulation can improve motor function following stroke in humans, rats, and nonhuman primates, especially when paired with rehabilitative training (RT). Previously, we found in rodent stroke models that epidural electrical cortical stimulation (CS) of the ipsilesional motor cortex (MC) combined with motor RT enhances motor function and motor cortical plasticity. It was unknown whether CS following experimental traumatic brain injury (TBI) would have similar effects. OBJECTIVE: To test the effects of CS combined with motor training after moderate/severe TBI on behavioral outcome and motor cortical organization. METHODS: Following unilateral controlled cortical impact (CCI) over the caudal forelimb area of the MC in adult male rats, forelimb reach training was administered daily for 9 weeks concurrently with subthreshold, 100-Hz monopolar CS or no-stimulation control procedures. The rate and magnitude of behavioral improvements and changes in forelimb movement representations in the injured MC as revealed by intracortical microstimulation were measured. RESULTS: CCI resulted in severe motor impairments persisting throughout the 9 weeks of training in both groups, but CS-treated animals had significantly greater behavioral improvements. CS also increased wrist motor cortical representation, one of the main movements used in the training task, when compared with RT alone. However, the overall recovery level was modest, leaving animals still extremely impaired. CONCLUSIONS: These data suggest that CS may be useful for improving rehabilitation efficacy after TBI but also raise the possibility that the CS parameters that are highly effective following stroke are suboptimal after moderate/severe TBI. PMID- 26248600 TI - Microwave-Assisted Hydrothermal Rapid Synthesis of Amorphous Calcium Phosphate Mesoporous Microspheres Using Adenosine 5'-Diphosphate and Application in pH Responsive Drug Delivery. AB - Herein we report a rapid and green strategy for the preparation of amorphous calcium phosphate mesoporous microspheres (ACP-MSs) using adenosine 5' diphosphate disodium salt (ADP) as an organic phosphorus source by a microwave assisted hydrothermal method. The effects of the pH value, the reaction time, and temperature on the crystal phase and morphology of the product are investigated. The ADP biomolecules used in this strategy play an important role in the formation of ACP-MSs. The as-prepared ACP-MSs are efficient for anticancer drug delivery by using doxorubicin (Dox) as a model drug, and the Dox-loaded ACP-MSs show a high ability to damage cancer cells. Moreover, the ACP-MSs drug delivery system exhibits a pH-responsive drug-release behavior due to the degradation of ACP-MSs at a low pH value, thus, it is promising for applications in pH responsive drug delivery. PMID- 26248601 TI - Detection and genotyping of group A rotaviruses isolated from sewage samples in Monastir, Tunisia between April 2007 and April 2010. AB - AIMS: To ascertain the viral load, the distribution of G and P types of group A rotaviruses (RV-A) in sewage samples and to compare strains in clinical, animal and environmental samples. METHODS AND RESULTS: During our study from April 2007 to April 2010, 518 samples of raw and treated sewage were collected from two biological sewage treatment plants (STPs) located in the Monastir region, Tunisia. RV-A was detected by real-time RT-PCR in 375 (72.4%) sewage samples. According to the quantification results of RV-A, it appears that the viral load in raw and treated sewage of the two STPs was quite similar (P = 0.735). The genotyping of RV-A strains detected in sewage samples showed a great diversity with 10 G types and 8 P types. Most of them were described as common in humans, but we also detected genotypes commonly found in animals. All the genotypes detected in two previous studies performed in our laboratory on clinical and bovine samples were also found in environmental samples. However, some genotypes commonly found in animal were only found in sewage samples. CONCLUSION: The comparison of environmental, clinical and animal data suggests that STPs may convey not only human sewage but also animal wastes, both of them contaminated with numerous RV-A strains which are not efficiently eliminated by the sewage treatment process and may spread to surface waters. SIGNIFICANCE AND IMPACT OF THE STUDY: This work demonstrates the potential release of human and animal RV-A into water sources, representing a public health risk, by inducing gastroenteritis in population, but also by increasing the risk of zoonotic transmission and formation of reassortant viruses which could get a higher infectious potential. Our findings also suggest that monitoring of sewage may provide an additional tool to determine the epidemiology of RV-A circulating in a given community. PMID- 26248602 TI - Updated analysis: central venous access device infection rates in an expanded cohort of paediatric patients with severe haemophilia receiving prophylactic recombinant tissue plasminogen activator. AB - INTRODUCTION: Central venous access devices (CVADs) are used in the care of paediatric haemophilic patients with difficult peripheral access, but their use is limited by complications such as infection. We previously published our experience with monthly recombinant tissue plasminogen activator (r-tPA) administration to CVADs of haemophilic patients as an intervention for infection prophylaxis, which suggested a 10-fold decrease in infection rate compared to published rates without r-tPA. AIM: This study was conducted to assess the CVAD infection rate in an expanded haemophilia cohort receiving r-tPA over an extended period. METHODS: A retrospective review was performed on patients with haemophilia who received monthly r-tPA to CVADs, with data collected from January 1, 2008 to December 31, 2012. The data were merged with the previously reported data set (collected from June 1, 1998 to December 31, 2007). RESULTS: Over the entire observation period, there were 46 350 CVAD days among 32 patients [26 severe factor VIII (FVIII) deficiency, six severe FIX deficiency]. Eight patients received immune tolerance therapy for inhibitors and 24 patients received prophylactic factor administration. No patients were HIV positive. Three infections were observed, with an overall infection rate of 0.06 infections per 1000 CVAD days. CONCLUSIONS: A low CVAD infection rate, similar to that observed in our previous study (0.04 per 1000 CVAD days), was observed in this expanded haemophilia cohort treated with prophylactic r-tPA, supporting the use of monthly r-tPA as CVAD infection prophylaxis in haemophilia patients. PMID- 26248603 TI - Evaluation of the influence of salt processing on pharmacokinetics of psoralen and isopsoralen in Psoralea corylifolia L. AB - A sensitive, specific and rapid ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method has been developed to investigate pharmacokinetic properties of psoralen and isopsoralen, two compounds isolated from raw/salt-processed fruit of Psoralea corylifolia L. UHPLC-MS/MS was used with positive ion electrospray. The mobile phase was composed of acetonitrile and 0.1% formic acid aqueous solution and a gradient elution program at flow rate of 0.3 mL/min was applied. Multiple reaction monitoring mode was used for the quantification of psoralen, isopsoralen ([M + H](+) m/z 187.0 -> m/z 131.0) and scoparone (m/z 207.0 -> m/z 151.1). Scoparone served as an internal standard. The method was fully validated for its sensitivity, selectivity, stability, matrix effect and extraction recovery. The obtained results showed that salt-processed Buguzhi significantly promoted the absorption of psoralen and isopsoralen, and increased the bioavailability of these compounds. PMID- 26248604 TI - Leucine metabolism regulates TRI6 expression and affects deoxynivalenol production and virulence in Fusarium graminearum. AB - TRI6 is a positive regulator of the trichothecene gene cluster and the production of trichothecene mycotoxins [deoxynivalenol (DON)] and acetylated forms such as 15-Acetyl-DON) in the cereal pathogen Fusarium graminearum. As a global transcriptional regulator, TRI6 expression is modulated by nitrogen-limiting conditions, sources of nitrogen and carbon, pH and light. However, the mechanism by which these diverse environmental factors affect TRI6 expression remains underexplored. In our effort to understand how nutrients affect TRI6 regulation, comparative digital expression profiling was performed with a wild-type F. graminearum and a Deltatri6 mutant strain, grown in nutrient-rich conditions. Analysis showed that TRI6 negatively regulates genes of the branched-chain amino acid (BCAA) metabolic pathway. Feeding studies with deletion mutants of MCC, encoding methylcrotonyl-CoA-carboxylase, one of the key enzymes of leucine metabolism, showed that addition of leucine specifically down-regulated TRI6 expression and reduced 15-ADON accumulation. Constitutive expression of TRI6 in the Deltamcc mutant strain restored 15-ADON production. A combination of cellophane breach assays and pathogenicity experiments on wheat demonstrated that disrupting the leucine metabolic pathway significantly reduced disease. These findings suggest a complex interaction between one of the primary metabolic pathways with a global regulator of mycotoxin biosynthesis and virulence in F. graminearum. PMID- 26248605 TI - Efficient Syntheses of Novel Fluoro-Substituted Pentacenes and Azapentacenes: Molecular and Solid-State Properties. AB - Non-symmetrical 6,13-disubstituted pentacenes bearing trifluoromethyl and aryl substituents have been synthesized starting from pentacenequinone. Diazapentacenes with a variety of fluorine substituents were prepared either via a Hartwig-Buchwald aryl amination route or by a SNAr strategy. As a result of a non-symmetric substitution pattern containing electron-donating substituents in combination with electron-accepting fluorine substituents, the synthesized compounds feature distinct molecular dipoles. All compounds are analyzed regarding their optoelectronic properties in solution with special focus on the frontier orbital energies as well as their molecular packing in the crystal structures. The analyses of isolated molecules are complemented by thin-film studies to examine their solid-state properties. A precise comparison between these and the molecular properties gave detailed insights into the exciton binding energies of these compounds, which are explained by means of a simple model considering the molecular packing and polarizabilities. PMID- 26248607 TI - Effects of imidacloprid and clothianidin seed treatments on wheat aphids and their natural enemies on winter wheat. AB - BACKGROUND: Wheat aphid (Hemiptera: Aphididae) is one of the major pests of winter wheat and has posed a significant threat to winter wheat production in China. Although neonicotinoid insecticidal seed treatments have been suggested to be a control method, the season-long efficacy on pests and the impact on their natural enemies are still uncertain. Experiments were conducted to determine the efficacy of imidacloprid and clothianidin on the control of aphids, the number of their natural enemies and the emergence rate and yield of wheat during 2011-2014. RESULTS: Imidacloprid and clothianidin seed treatments had no effect on the emergence rate of winter wheat and could prevent yield losses and wheat aphid infestations throughout the winter wheat growing season. Furthermore, their active ingredients were detected in winter wheat leaves up to 200 days after sowing. Imidacloprid and clothianidin seed treatments had no adverse effects on ladybirds, hoverflies or parasitoids, and instead increased the spider-aphid ratios. CONCLUSION: Wheat seeds treated with imidacloprid and clothianidin were effective against wheat aphids throughout the winter wheat growing season and reduced the yield loss under field conditions. Imidacloprid and clothianidin seed treatments may be an important component of the integrated management of wheat aphids on winter wheat. (c) 2015 Society of Chemical Industry. PMID- 26248606 TI - Infection susceptibility and immune senescence with advancing age replicated in accelerated aging Lmna(Dhe) mice. AB - Aging confers increased susceptibility to common pathogens including influenza A virus. Despite shared vulnerability to infection with advancing age in humans and rodents, the relatively long time required for immune senescence to take hold practically restricts the use of naturally aged mice to investigate aging-induced immunological shifts. Here, we show accelerated aging Lmna(Dhe) mice with spontaneous mutation in the nuclear scaffolding protein, lamin A, replicate infection susceptibility, and substantial immune cell shifts that occur with advancing age. Naturally aged (>= 20 month) and 2- to 3-month-old Lmna(Dhe) mice share near identically increased influenza A susceptibility compared with age matched Lmna(WT) control mice. Increased mortality and higher viral burden after influenza infection in Lmna(Dhe) mice parallel reduced accumulation of lung alveolar macrophage cells, systemic expansion of immune suppressive Foxp3+ regulatory T cells, and skewed immune dominance among viral-specific CD8+T cells similar to the immunological phenotype of naturally aged mice. Thus, aging induced infection susceptibility and immune senescence are replicated in accelerated aging Lmna(Dhe) mice. PMID- 26248608 TI - Large oligomeric complex structures can be computationally assembled by efficiently combining docked interfaces. AB - Macromolecular oligomeric assemblies are involved in many biochemical processes of living organisms. The benefits of such assemblies in crowded cellular environments include increased reaction rates, efficient feedback regulation, cooperativity and protective functions. However, an atom-level structural determination of large assemblies is challenging due to the size of the complex and the difference in binding affinities of the involved proteins. In this study, we propose a novel combinatorial greedy algorithm for assembling large oligomeric complexes from information on the approximate position of interaction interfaces of pairs of monomers in the complex. Prior information on complex symmetry is not required but rather the symmetry is inferred during assembly. We implement an efficient geometric score, the transformation match score, that bypasses the model ranking problems of state-of-the-art scoring functions by scoring the similarity between the inferred dimers of the same monomer simultaneously with different binding partners in a (sub)complex with a set of pregenerated docking poses. We compiled a diverse benchmark set of 308 homo and heteromeric complexes containing 6 to 60 monomers. To explore the applicability of the method, we considered 48 sets of parameters and selected those three sets of parameters, for which the algorithm can correctly reconstruct the maximum number, namely 252 complexes (81.8%) in, at least one of the respective three runs. The crossvalidation coverage, that is, the mean fraction of correctly reconstructed benchmark complexes during crossvalidation, was 78.1%, which demonstrates the ability of the presented method to correctly reconstruct topology of a large variety of biological complexes. PMID- 26248609 TI - The risk of acute liver injury among users of antibiotic medications: a comparison of case-only studies. AB - PURPOSE: The aims of this study were two-fold: (i) to investigate the effect of exposure to antibiotic agents on the risk of acute liver injury using a self controlled case series and case-crossover study and (ii) to compare the results between the case-only studies. METHODS: For the self-controlled case series study relative incidence ratios (IRR) were calculated by dividing the rate of acute liver injury experienced during patients' periods of exposure to antibiotics to patients' rate of events during non-exposed time using conditional Poisson regression. For the case-crossover analysis we calculated Odds Ratios (OR) using conditional logistic regression by comparing exposure during 14- and 30-day risk windows with exposure during control moments. RESULTS: Using the self-controlled case series approach, the IRR was highest during the first 7 days after receipt of a prescription (10.01, 95% CI 6.59-15.18). Omitting post-exposure washout periods lowered the IRR to 7.2. The highest estimate in the case-crossover analysis was found when two 30-day control periods 1 year prior to the 30-day ALI risk period were retained in the analysis: OR = 6.5 (95% CI, 3.95-10.71). The lowest estimate was found when exposure in the 14-day risk period was compared to exposure in four consecutive 14-day control periods immediately prior to the risk period (OR = 3.05, 95% CI, 2.06-4.53). CONCLUSION: An increased relative risk of acute liver injury was consistently observed using both self-controlled case series and case-crossover designs. Case-only designs can be used as a viable alternative study design to study the risk of acute liver injury, albeit with some limitations. PMID- 26248610 TI - Role of nurse practitioners in reducing cardiovascular risk factors: a retrospective cohort study. AB - AIMS AND OBJECTIVES: To determine the impact of nurse practitioners' counselling on reducing cardiovascular risk factors in patients participating in routine preventive check-ups. BACKGROUND: A new model of 'renewed' family practice was introduced in Slovenia as a pilot project in 2011, in which nurse practitioners are included in a team carrying out preventive activities and managing patients with stable chronic diseases. DESIGN: A retrospective cohort study. METHODS: This study was conducted in 16 family medicine practices (eight renewed and eight regular family practices). In each family practice, a systematic sample was selected of registered patients participating in a cardiovascular preventive check-up. Data on sex, age, blood pressure, cholesterol, blood sugar, smoking, level of physical activity and cardiovascular risk were collected. Patients attending renewed family practices received counselling on risk factors from nurse practitioners (test group), and patients attending regular family practices received counselling from family physicians (control group). Data were collected again at least one and no more than five years after the baseline consultation. RESULTS: There were 128 patients in the test group and 129 patients in the control group. At the control visit, the patients counselled by nurse practitioners had significantly lower levels of systolic blood pressure and cholesterol and practiced regular physical activity significantly more often than patients counselled by family physicians. CONCLUSION: Nurse practitioners can be at least as successful as physicians when counselling patients on cardiovascular risk factors during their preventive check-ups. RELEVANCE TO CLINICAL PRACTICE: This study showed that nurse practitioners have an important role in managing patients at the primary care level. PMID- 26248611 TI - Sperm of Galeorhinus galeus (Elasmobranchii, Triakidae) Traverse an Excurrent Duct System Characterized by Pronounced Regionalization: A Scanning Electron and Light Microscopy Study. AB - The transport and subsequent maturation of spermatozoa in the vertebrate excurrent duct require the creation of a series of biochemically defined luminal milieus along the length of the duct. Such specialization is accomplished, among others, by changes in the epididymal histoarchitecture. Here we show that the intratesticular and extratesticular genital ducts of mating Galeorhinus galeus exhibit pronounced regionalization both in terms of epithelial histology and lumen diameter size. Findings also reveal distinct differences in the manner in which the spermatozoa were found in each segment of the duct. Novel scanning electron microscopy evidence is presented showing that the wide lumen ductuli epididymides, which ultimately convey the spermatozoa to the proximal epididymis, show functional specialization as well. The wall of the former consisted of cuboidal ciliated and nonciliated cells whose spatial arrangement in the duct wall resulted in a luminal surface showing lengthy rows of cilia-free areas, with each row bordered on both sides by a single row of cilia. The proximal epididymis comprised several subregions whose epithelial histology varied widely. The distal epididymis and ampulla of the epididymis possessed many fingerlike projections and transverse septa, respectively. As the main storage site for spermatozoa, the ampulla completed the bundling of spermatozoa into spermatozeugmata. These were circular sperm masses in which the heads of the spermatozoa were aligned side by side and embedded in a seminal matrix, while their tails extended outward. These findings of pronounced regionalization differ greatly from the rather uniform epididymal histology seen in some rays. PMID- 26248612 TI - Hepatic stellate cells relay inflammation signaling from sinusoids to parenchyma in mouse models of immune-mediated hepatitis. AB - Hepatic stellate cells (HSCs) constitute the liver sinusoid with Kupffer cells and liver sinusoidal endothelial cells. While the sinusoid functions as the gateway to liver inflammation, whether HSCs contribute to liver inflammation and, if so, how they exert such functions remain elusive. Here, we found that mouse as well as human HSCs expressed DP1 receptor for prostaglandin D2 selectively in the liver. Pharmacological stimulation of DP1 by BW245C, a DP1-selective agonist, suppressed the activation of cultured HSCs by tumor necrosis factor-alpha at least in part through down-regulation of nuclear factor kappa-light-chain enhancer of activated B cells signaling and inhibition of c-Jun N-terminal kinase phosphorylation. DP1 deficiency or BW245C administration in mice significantly enhanced or suppressed concanavalin A (ConA)-induced hepatitis, respectively. ConA injection induced tumor necrosis factor-alpha and interferon-gamma expression in the sinusoid, which was suppressed by administration of BW245C. Coculture of spleen cells and liver nonparenchymal cells showed that ConA first activated spleen cells and that this activation led to activation of nonparenchymal cells to secondarily produce tumor necrosis factor-alpha and interferon-gamma. Microarray analysis revealed ConA-induced expression of endothelin-1, tissue factor, and chemokines in the liver and inducible nitric oxide synthase in hepatocytes, resulting in flow stagnation, leukocyte adherence and migration to the parenchyma, and hepatocyte death. DP1 stimulation inhibits all these events in the liver. Therefore, HSCs mediate amplification of ConA induced liver inflammation in the sinusoid, causing direct and indirect hepatocyte injury, and DP1 stimulation inhibits this HSC activation. CONCLUSIONS: HSCs integrate cytokine-mediated inflammatory responses in the sinusoids and relay them to the liver parenchyma, and these HSC actions are inhibited by DP1 stimulation. PMID- 26248614 TI - Efficiency and durability of hyaluronic acid of different particle sizes as an injectable material for VF augmentation. AB - CONCLUSION: The results of the present investigation suggest that modification of HA could improve efficiency and durability in augmentation laryngoplasty. OBJECTIVES: Injection laryngoplasty (IL) is one of the most suitable options for treatment of glottic insufficiency, which is caused by vocal fold (VF) paralysis, atrophy, or scarring. Hyaluronic acid (HA) is a widely used material for VF injection. This study was intended to evaluate the durability and efficiency of HA of different particle sizes for VF augmentation. METHODS: Three types of HA, Restylane(r), monophasic low-viscosity, and unequal particle-sized middle viscosity HA were injected into the left VF of three groups with eight rabbits each. RESULTS: After 6 and 10 weeks, the injected site was evaluated endoscopically, histologically, radiologically, and functionally. None of the 24 rabbits showed any signs of respiratory distress. Computed tomography (CT) images and endoscopic evaluation revealed sufficient augmented volume of the injected VF in all treated groups 6 weeks after the injection. Histological data at week 10 showed that unequal particle-sized HA did not migrate from its original injection site, while other HAs migrated to the periphery of the arytenoid cartilage. Videokymographic analysis showed more favorable vibrations of unequal particle sized HA injected VF mucosa 10 weeks post-injection, compared to the other treatment groups. PMID- 26248615 TI - Identifying children with excess malaria episodes after adjusting for variation in exposure: identification from a longitudinal study using statistical count models. AB - BACKGROUND: The distribution of Plasmodium falciparum clinical malaria episodes is over-dispersed among children in endemic areas, with more children experiencing multiple clinical episodes than would be expected based on a Poisson distribution. There is consistent evidence for micro-epidemiological variation in exposure to P. falciparum. The aim of the current study was to identify children with excess malaria episodes after controlling for malaria exposure. METHODS: We selected the model that best fit the data out of the models examined and included the following covariates: age, a weighted local prevalence of infection as an index of exposure, and calendar time to predict episodes of malaria on active surveillance malaria data from 2,463 children of under 15 years of age followed for between 5 and 15 years each. Using parameters from the zero-inflated negative binomial model which best fitted our data, we ran 100 simulations of the model based on our population to determine the variation that might be seen due to chance. RESULTS: We identified 212 out of 2,463 children who had a number of clinical episodes above the 95(th) percentile of the simulations run from the model, hereafter referred to as "excess malaria (EM)". We then identified exposure-matched controls with "average numbers of malaria" episodes, and found that the EM group had higher parasite densities when asymptomatically infected or during clinical malaria, and were less likely to be of haemoglobin AS genotype. CONCLUSIONS: Of the models tested, the negative zero-inflated negative binomial distribution with exposure, calendar year, and age acting as independent predictors, fitted the distribution of clinical malaria the best. Despite accounting for these factors, a group of children suffer excess malaria episodes beyond those predicted by the model. An epidemiological framework for identifying these children will allow us to study factors that may explain excess malaria episodes. PMID- 26248613 TI - Current concepts in the pathogenesis and treatment of chronic suppurative otitis media. AB - Otitis media (OM) is an inflammation of the middle ear associated with infection. Despite appropriate therapy, acute OM (AOM) can progress to chronic suppurative OM (CSOM) associated with ear drum perforation and purulent discharge. The effusion prevents the middle ear ossicles from properly relaying sound vibrations from the ear drum to the oval window of the inner ear, causing conductive hearing loss. In addition, the inflammatory mediators generated during CSOM can penetrate into the inner ear through the round window. This can cause the loss of hair cells in the cochlea, leading to sensorineural hearing loss. Pseudomonas aeruginosa and Staphylococcus aureus are the most predominant pathogens that cause CSOM. Although the pathogenesis of AOM is well studied, very limited research is available in relation to CSOM. With the emergence of antibiotic resistance as well as the ototoxicity of antibiotics and the potential risks of surgery, there is an urgent need to develop effective therapeutic strategies against CSOM. This warrants understanding the role of host immunity in CSOM and how the bacteria evade these potent immune responses. Understanding the molecular mechanisms leading to CSOM will help in designing novel treatment modalities against the disease and hence preventing the hearing loss. PMID- 26248616 TI - Hypertension: a cross-sectional study of the role of multimorbidity in blood pressure control. AB - BACKGROUND: Hypertension is the most prevalent cardiovascular long-term condition in the UK and is associated with a high rate of multimorbidity (MM). Multimorbidity increases with age, ethnicity and social deprivation. Previous studies have yielded conflicting findings about the relationship between MM and blood pressure (BP) control. Our aim was to investigate the relationship between multimorbidity and systolic blood pressure (SBP) in patients with hypertension. METHODS: A cross-sectional analysis of anonymised primary care data was performed for a total of 299,180 adult patients of whom 31,676 (10.6 %) had a diagnosis of hypertension. We compared mean SBP in patients with hypertension alone and those with one or more co-morbidities and analysed the effect of type of comorbidity on SBP. We constructed a regression model to identify the determinants of SBP control. RESULTS: The strongest predictor of mean SBP was the number of comorbidities, beta -0.13 (p < 0.05). Other predictors included Afro-Caribbean ethnicity, beta 0.05 (p < 0.05), South Asian ethnicity, beta -0.03 (p < 0.05), age, beta 0.05 (p < 0.05), male gender, beta 0.05 (p < 0.05) and number of hypotensive drugs beta 0.06 (p < 0.05). SBP was lower by a mean of 2.03 mmHg ( 2.22, -1.85) for each additional comorbidity and was lower in MM regardless of the type of morbidity. CONCLUSION: Hypertensive patients with MM had lower SBP than those with hypertension alone; the greater the number of MM, the lower the SBP. We found no evidence that BP control was related to BP targets, medication category or specific co-morbidity. Further research is needed to determine whether consultation rate, "white-coat hypertension" or medication adherence influence BP control in MM. PMID- 26248617 TI - Sex-specific placental differences as a contributor to sex-specific metabolic programming? PMID- 26248618 TI - Brainstem white matter integrity is related to loss of consciousness and postconcussive symptomatology in veterans with chronic mild to moderate traumatic brain injury. AB - We investigated associations between DTI indices of three brainstem white matter tracts, traumatic brain injury (TBI) injury characteristics, and postconcussive symptomatology (PCS) in a well-characterized sample of veterans with history of mild to moderate TBI (mTBI). 58 military veterans (mTBI: n = 38, mean age = 33.2, mean time since injury = 90.9 months; military controls [MC]; n = 20; mean age = 29.4) were administered 3T DTI scans as well as a comprehensive neuropsychiatric evaluation including evaluation of TBI injury characteristics and PCS symptoms (e.g., negative mood, dizziness, balance and coordination difficulties). Tractography was employed by seeding ROIs along 3 brainstem white matter tracts (i.e., medial lemniscus-central tegmentum tract [ML-CTT]; corticospinal tracts [CST], and pontine tegmentum [PT]), and mean DTI values were derived from fractional anisotropic (FA) maps. Results showed that there were no significant difference in FA between the MC and TBI groups across the 3 regions of interest; however, among the TBI group, CST FA was significantly negatively associated with LOC duration. Additionally, lower FA of certain tracts-most especially the PT-was significantly associated with increased PCS symptoms (i.e., more severe vestibular symptoms, poorer physical functioning, and greater levels of fatigue), even after adjusting for PTSD symptoms. Our findings show that, in our sample of veterans with mTBI, tractography-based DTI indices of brainstem white matter tracts of interest are related to the presence and severity of PCS symptoms. Findings are promising as they show linkages between brainstem white matter integrity and injury severity (LOC), and they raise the possibility that the pontine tegmentum in particular may be a useful marker of PCS symptoms. Collectively, these data point to important neurobiological substrates of the chronic and complex constellation of symptoms following the 'signature injury' of our combat-exposed veterans. PMID- 26248620 TI - 'Biohoarding': treasures not seen, stories not told. AB - This article raises the concern that biobanks are failing to realize the expected research and health service outcomes. Rather than biobanking, we have been engaging in 'biohoarding', where building a quantifiable collection of tissue samples is the primary basis of the bio-resource. The root cause of 'biohoarding' is an ideological and motivational confusion as to the purpose for collecting the tissue in the first place. We have lost sight of the knowledge gain that biobanks should generate. The obligation to prevent 'biohoarding' lies not with researchers, funders or managers but with policy makers. PMID- 26248621 TI - Variation in avoidable emergency admissions: multiple case studies of emergency and urgent care systems. AB - OBJECTIVE: To identify factors affecting variation in avoidable emergency admissions that are not usually identified in statistical regression. METHODS: As part of an ethnographic residual analysis, we compared six emergency and urgent care systems in England, interviewing 82 commissioners and providers of key emergency and urgent care services. RESULTS: There was variation between the six cases in how interviewees described three parts of their emergency and urgent care systems. First, interviewees' descriptions revealed variation in the availability of services before patients decided to attend emergency departments. Poor availability of general practice out of hours services in some of the cases reportedly made attendance at emergency departments the easier option for patients. Second, there was variation in how interviewees described patients being dealt with during their emergency department visit in terms of availability of senior review by specialists and in coding practices when patients were at risk of breaching the NHS's 4-hour waiting time target. Third, there was variability in services described as facilitating discharge home from emergency departments. In some cases, emergency department staff described dealing with multiple agencies in multiple localities outside the hospital, making admission the easier option. In other cases, proactive multidisciplinary rapid assessment teams were described as available to avoid admissions. Perceptions of resources available out of hours and the extent of integration between different health services, and between health and social services, also differed by case. CONCLUSIONS: This comparative case study approach identified further factors that may affect avoidable emergency admissions. Initiatives to improve GP out of hours services, make coding more accurately reflect patient experience, increase senior review in emergency departments, offer proactive multidisciplinary admission avoidance teams, improve the availability of out of hours care in the wider emergency and urgent care system, and increase service integration may reduce avoidable admissions. Evaluation of such initiatives would be necessary before wide-scale adoption. PMID- 26248619 TI - Upstream therapeutic strategies of Valsartan and Fluvastatin on Hypertensive patients with non-permanent Atrial Fibrillation (VF-HT-AF): study protocol for a randomized controlled trial. AB - BACKGROUND: Previous studies regarding rhythm control in patients with atrial fibrillation (AF) could not sufficiently demonstrate the efficacy of available anti-arrhythmic drugs. 'Upstream therapy' has emerged as a potential strategy for the prevention and treatment of AF. The use of angiotensin II receptor blockers and statins has been suggested to decrease new-onset AF, but which remains inadequately explored. This study was designed to examine whether valsartan or fluvastatin can reduce the risk of non-permanent AF in patients with hypertension. METHODS/DESIGN: The VF-HT-AF study is a multicenter, randomized, open-label, four-arm parallel group study with comparative evaluation of valsartan and fluvastatin as upstream therapies for the treatment of non permanent AF complicated by hypertension. The primary outcome measure is change in the development of paroxysmal AF into persistent or permanent AF, the development of persistent AF to permanent AF, and change in incidence of overall and persistent AF recurrence, as evaluated by 7-days ambulatory electrocardiograph monitoring (Holter) and patients' diaries during 2 years' follow-up. Secondary outcome measures of this study include the occurrence of: (1) fatal and nonfatal myocardial infarction; (2) heart failure (New York Heart Association stage III or IV); (3) cardiogenic shock; (4) serious bleeding necessitating hospitalization; (5) malignant ventricular arrhythmia; (6) revascularization therapy; (7) radiofrequency catheter ablation of AF; (8) changes of left atrial dimension, as measured by ultrasound echocardiography; (9) stroke; (10) cardiovascular mortality; and (11) all-cause mortality. A total of 1879 patients will be investigated from 15 medical centers throughout China to obtain the relevant information. DISCUSSION: This is the first study in hypertensive patients complicated non-permanent AF in the Chinese population. Results of this study will inform the use of upstream therapies of AF. TRIAL REGISTRATION: chictr.org, ChiCTR-TRC-12002642. PMID- 26248622 TI - Translation and Validation of the De Jong Gierveld Loneliness Scale Among Older Migrants Living in the Netherlands. AB - OBJECTIVES: We validate a translated version of the De Jong Gierveld Loneliness Scale (DJGLS) for use among older migrants from Turkish and Moroccan descent and validate the original Dutch version of the same scale for Surinamese migrants in the Netherlands. METHOD: The data were derived from a population-based cross sectional study among community-dwelling individuals aged 55 and older. In addition to translating the DJGLS for these ethnic groups, several statistical analyses were performed to assess the scale's reliability and validity. RESULTS: The DJGLS proved to be internally consistent and to have adequate convergent validity among all ethnic groups. Latent structure analysis confirmed the two latent factors (emotional and social subscales) in all groups, but also showed that fit was not optimal in most groups. Known groups validity was observed using functional limitations and subjective health as grouping variables. CONCLUSIONS: The results provide sufficient support for use of the translated version of the 11-item DJGLS among Turkish and Moroccan older migrants and use of the Dutch version for Surinamese older migrants as a reliable and valid measure of loneliness. Fit of latent structural models varied between good and poor. Further research is needed to investigate ethnic differences in levels and determinants of loneliness. PMID- 26248623 TI - Occipital Condyle Fractures in Adolescents. AB - BACKGROUND: Occipital condyle fractures are rare injuries of the cranio-cervical junction seen more often in adults than in children. They are best diagnosed with CT of the cranio-cervical junction. Treatment depends on the morphology and stability of the fracture. The aim of the present paper was to present cases of occipital condyle fractures treated at our Department, review the literature, and stress the importance of MRI studies in the diagnostic work-up of these injuries. MATERIAL AND METHODS: Our retrospective study involved a group of 3 female patients (mean age was 16.3 years) with occipital condyle fractures diagnosed/treated at our Department. We assessed the cause and type of fracture, additional damage, available classification systems, treatment methods, outcomes and complications. RESULTS: Mean follow-up period was 16 (10-22) months. We achieved good clinical outcomes (NDI scores) in all the patients. In one patient, a follow-up MRI scan revealed the presence of a clinically silent post-traumatic epidural meningeal cyst at the C2-C6 level, anterior to the spinal cord. CONCLUSIONS: CT of the cranio-cervical junction is the best method of diagnosing occipital condyle fractures. 2. The choice of an appropriate treatment method is decisively based on the assessment of the morphology and stability of the fracture in a CT/MRI scan rather than on the fracture type alone. 3. There is no noticeable difference between the usefulness of the classification system developed by Anderson and Montesano and that according to Tuli et al. 4. In our opinion, the system of occipital condyle fracture classification proposed in 2012 does not seem superior in everyday clinical practice. 5. The use of the halo-vest is a good method of treating unstable occipital condyle fractures. 6. Early diagnosis and appropriate treatment of cranio-cervical junction fractures make it possible for the fracture to heal without severe clinical sequelae. PMID- 26248624 TI - Surgical Treatment in Patients with Spinal Tumors - Differences in Surgical Strategies and Malignancy-Associated Problems. An Analysis of 474 Patients. AB - BACKGROUND: Surgical treatment of spinal tumors, especially metastatic disease, is becoming increasingly popular, and its results are encouraging. However, good knowledge of clinical aspects of tumors and surgical techniques is essential. The aim of this paper was to analyze the problems of and differences in surgical strategies for spinal tumor surgery. MATERIAL AND METHODS: The objectives of this paper were accomplished on the basis of a retrospective evaluation of the surgical records of 474 patients with spinal tumors treated at the Oncological Orthopedics Department in Brzozow in the years 2010-2014. Preoperative and postoperative pain intensity, motor skills and neurological function were evaluated. Surgical strategies, operative approach to the spine, extent of bone resection, methods of filling bone voids and spinal fixation methods were analyzed. RESULTS: Pain intensity, measured with a VAS scale, decreased in most patients (84%). Motor skills, assessed with the Karnofsky score, improved in 67% of patients. Neurological deficits decreased in 36 out of 105 patients. 369 surgeries were performed from a posterior approach with a preference for long segment fixation. Anterior approach surgeries with tumor resection and implantation of a vertebral body prosthesis or cement were performed in 61 patients. 25 patients with upper thoracic spine pathology were operated from a posterolateral approach. The tumors were resected, prostheses or cement were implanted and transepiphyseal fixation of the spine was performed. Dual-approach surgery was performed in 19 patients, of whom two underwent simultaneous procedures. Laminectomy-associated damage to the dura mater was the most common complication. 34 patients were operated on due to infections of the surgical site. Seven patients died in the perioperative period. CONCLUSIONS: 1. Surgical treatment with adjuvant radiotherapy should be a first-line choice for spinal metastases. 2. Qualification for the procedure involves several factors and should be individualized. 3. The surgical strategy for spinal tumors often differs from general principles of spinal surgery. PMID- 26248625 TI - Polish Adaptation of Wrist Evaluation Questionnaires. AB - BACKGROUND: Questionnaires evaluating hand and wrist function are a very useful tool allowing for objective and systematic recording of symptoms reported by the patients. Most questionnaires generally accepted in clinical practice are available in English and need to be appropriately adapted in translation and undergo subsequent validation before they can be used in another culture and language. MATERIAL AND METHODS: The process of translation of the questionnaires was based on the generally accepted guidelines of the International Quality of Life Assessment Project (IQOLA). First, the questionnaires were translated from English into Polish by two independent translators. Then, a joint version of the translation was prepared collectively and translated back into English. Each stage was followed by a written report. The translated questionnaires were then evaluated by a group of patients. We selected 31 patients with wrist problems and asked them to complete the PRWE, Mayo, Michigan and DASH questionnaires twice at intervals of 3-10 days. The results were submitted for statistical analysis. RESULTS: We found a statistically significant (p<0.05) correlation for the two completions of the questionnaires. A comparison of the PRWE and Mayo questionnaires with the DASH questionnaire also showed a statistically significant correlation (p<0.05). CONCLUSION: Our results indicate that the cultural adaptation of the translated questionnaires was successful and that the questionnaires may be used in clinical practice. PMID- 26248626 TI - Evaluation of the Effectiveness of Preoperative Physiotherapy Using the Lysholm Gillquist Scale in Patients Qualified for Surgical Arthroscopic Anterior Cruciate Ligament Reconstruction - Pilot Study. AB - BACKGROUND: Recent years have seen a noticeable increase in the number of people experiencing total damage to the anterior cruciate ligament in the knee joint. The causes are many, but increased sporting activity among people who generally lead a hypokinetic lifestyle is regarded as the most important factor. Researchers are seeking to optimize the surgical treatment and rehabilitation. AIM OF THE STUDY: To evaluate the effectiveness of preoperative physiotherapy according to the Lysholm and Gillquist scale in patients scheduled for arthroscopic anterior cruciate ligament reconstruction. MATERIAL AND METHODS: The study involved a random sample of 30 patients with confirmed complete rupture of anterior cruciate ligament (ACL) qualified for surgical ACL reconstruction. Within this group, an experimental group consisted of 15 patients (mean age 41.0 +/- 7 years) who attended physiotherapy before surgery based on recognized therapeutic models. A control group consisted of 15 patients (mean age 39.0 +/- 9 years). The Lysholm and Gillquist 100-point scale was used for assessment. Student's t test, the Mann-Whitney U test and the Wilcoxon test were used for statistical analysis. The level of statistical significance was set at p < 0.05. RESULTS: The operated knee improved functionally in both the experimental and control group. In the experimental group, the difference was 20 points and was statistically significant at p = 0.000. In the control group, the difference was 6 points, which was also within the limit of statistical significance at p = 0.002. CONCLUSIONS: 1. Patients with total ACL rupture attending a pre-operative rehabilitation program led by a physiotherapist (experimental group) achieved greater improvement in functional status compared with the control group. 2. These results indicate a need to analyze the impact ofpreoperative rehabilitation on the final outcome of patients after complete ACL rupture. PMID- 26248627 TI - The Effectiveness of a Newly Designed Orthosis on Knee Contact Forces in Subjects with Knee Osteoarthritis. AB - BACKGROUND: This study was aimed to assess the effectiveness of a newly designed orthosis on knee contact forces in subjects with knee osteoarthritis (OA). MATERIAL AND METHODS: Five patients with OA participated in the study. All had knee OA on the medial side according to the American College of Rheumatology criteria, medial knee pain and radiographic osteophyte on the medial side of knee joint. The knee joint contact forces were determined by the use of Open Simm software under two conditions, namely, walking with and without the orthosis. RESULTS: There was no significant difference between the mean values of walking speed, stride length and cadence during walking with and without the orthosis. The mean and standard deviation (SD) values of the first and second peaks of the knee joint contact force in a vertical direction were 2.83+/-0.26 and 3.17+/-1.16 N/BW, respectively, compared to 2.54+/-0.22 and 2.54+/-0.958 N/BW in walking with and without the orthosis (p <0.05). CONCLUSION: The results of this study confirmed that the new design of orthosis decreases the joint contact forces, due to reduction in muscle performance needed to stabilize the knee joint. PMID- 26248628 TI - Effect of Single Preoperative Dose of Tranexamic Acid on Blood Loss and Transfusion in Hip Arthroplasty. AB - BACKGROUND: The aim of the study was to assess the effect of a single intravenous dose of tranexamic acid administered before surgery in patients undergoing total cementless hip arthroplasty on: intra-, post-, and perioperative blood lost, the number of patients requiring transfusion, the incidence of thromboembolic complications Material and methods. The study enrolled 124 patients, who were randomly divided into two groups. The experimental group (61 patients) received an intravenous dose of 15 mg/kg of tranexamic acid 20 minutes before the skin incision, while the control group (63 patients) did not receive this drug. We analysed intraoperative blood loss (volume of blood in the aspirator), postoperative blood loss (volume of blood drained), total perioperative blood loss, and the number of patients requiring transfusion as well as the number of thromboembolic complications in both groups. RESULTS: In the experimental group, mean intraoperative blood loss was significantly lower at 216 ml compared to 408.5 ml in the control group (p=0.00421). Postoperative blood loss on the first postoperative day was also lower in the experimental group (246.3 ml) as compared with the control group (358 ml, p=0.000097). Estimated perioperative blood loss in the experimental group was lower as well, reaching 779 ml, vs. 1315.5 ml in the control group (p=0.00567). The percentage of patients requiring transfusion in the experimental group (3.27%) was significantly lower than in the control group (22.22%) (p=0.00166). The use of tranexamic acid did not influence the number of thromboembolic complications (p=0.3075). CONCLUSIONS: 1. The administration of 15 mg/kg of tranexamic acid 20 minutes before surgery decreases the need for postoperative transfusion of allogeneic blood due to a significant reduction in intra-, post-, and perioperative blood loss. 2. Seeing that this method does not increase the number of thromboembolic complications and is simple and inexpensive, it should be considered worthy of recommendation in total cementless hip arthroplasty. PMID- 26248629 TI - A Retrospective Analysis of Bacteriological Studies of Surgical Site Infections in a Monoprofile, Multidepartmental Orthopedic Hospital. AB - BACKGROUND: Despite improvements in surgical techniques, aseptics and prevention of infections, hospital surgical site infections (SSI) still remain one of the main reasons for failure in therapeutic musculoskeletal surgery. This study aimed to conduct a retrospective analysis of microbiological examinations and determine pathogen sensitivity to antibiotics as the basis for selecting methods for preventing and treating complicating infections. MATERIAL AND METHODS: The study is a retrospective analysis of bacteriological tests performed in the departments of the Public Clinical Hospital of the Medical Centre of Postgraduate Education in Otwock. Importantly, our monoprofile hospital specialising in musculoskeletal pathology is a reference centre, admitting patients from the entire country. Often these are patients transferred from Intensive Care Units at other hospitals with internally infected local emergencies (infections with local, complex, multidrug resistant bacterial flora). Bacteriological mapping of the hospital covered the period from 2009 to 2013 to indicate so called "strategic departments" demonstrating the most complex multidrug-resistant bacterial flora. Surgical site infections were managed by surgery with targeted antibiotic therapy. RESULTS: Analysis of patients' profiles revealed that SSIs detected across hospital departments in SPSK CMKP in Otwock mostly came from other medical centers where patients were initially hospitalized. The Osteomyelitis Department and the Department of Pelvic Pathology and Traumatology were identified as "strategic departments". CONCLUSIONS: 1. The analysis indicated that methicillin sensitive Staphylococcus aureus (MSSA) was the most common pathogen responsible for complicating infections in our hospital. 2. The percentage of bacterial resistance to methicillin signifi -cantly increased in patients with multi-organ injuries who had previously been hospitalized at other centres. 3. Credible prevention and diagnosis of inflammatory risk factors in the preoperative period was of key importance in reducing the percentage of complicating infections. PMID- 26248630 TI - Analysis of Risk Factors for Periprosthetic Joint Infection in Clinical Data. AB - BACKGROUND: Progress in orthopaedics has now made it possible to improve the functional status of damaged hip joints with hip arthroplasty and eliminate the associated pain. The constantly growing number of hip replacement procedures is, however, associated with a proportional rise in the number of subsequent surgery related complications. The most important complication is septic loosening of the implant. The treatment of septic complications is often ineffective and recovery becomes impossible. In that setting, an awareness of the risk factors of septic complications and an ability to prevent periprosthetic joint infection (PJI) are becoming necessary. AIM: The aim of the study was to analyse the risk factors of PJI as an essential element of the prophylaxis of septic complications. MATERIAL AND METHODS: We analysed the data of 142 patients treated for PJI at the Ward of Bone and Joint Infections, Department of Orthopaedics, Medical Centre of Postgraduate Education in Otwock, between 2008 and 2010. Their medical records were analysed retrospectively. The diagnosis was evidence-based, relying on case histories, physical examination and accessory investigations, including imaging studies and biochemical and microbiological testing. RESULTS: The analysis of clinical data served to identify factors that appeared repetitively in the patients with PJI treated at the Ward. Those elements constitute the combination of risk factors for PIJ. CONCLUSIONS: 1. An awareness of risk factors for septic complications and their early elimination are necessary in daily orthopaedic care. 2. The pre-surgery checklist is a very effective tool to eliminate the most common risk factors of PJI. PMID- 26248631 TI - Pathological Subtrochanteric Femoral Fracture Due to Extensive Arterio-venous Malformation. A Case Study. AB - Despite the case of a 19-year-old male with a pathological subtrochanteric left femoral fracture in the course of an extensive arteriovenous malformation of the left thigh. The arteriovenous malformation was diagnosed when the patient was 16 years old. He has undergone several embolization procedures. The fracture was caused by a fall from the patient's own height. Before the patient was qualified for surgery of the fracture, a left lower limb angiography confirmed the presence of extensive pathological vascularity (arteriovenous malformation), and an embolization procedure was performed on the branches and trunk of the left deep femoral artery, several vessels branching off of the proximal and distal segment of the superficial femoral artery and one branch of the internal iliac artery. That was followed by internal stabilization of the left femur with a Targon PF intramedullary nail, resulting in an optimal therapeutic effect with a relatively low blood loss. This case presents a rare clinical problem that constitutes a significant therapeutic challenge. PMID- 26248632 TI - An in Silico Analysis of Ankle Joint Loads in Secondary Ankle Osteoarthritis. Case Study. AB - Secondary, post-traumatic, degenerative lesions of the ankle joint remain a serious clinical challenge. This paper presents the case of a 66-year-old patient with secondary, post-traumatic ankle osteoarthritis and subchondral cysts. The use of rapid computer modelling FEM 2D enabled optimization of surgical treatment. A FEM 2D model of biomechanical changes in bones may help in streamlining treatment as well as improve our understanding of the pathomechanism of osteoarthritis. PMID- 26248633 TI - European Organizations of Physical and Rehabilitation Medicine. AB - Physical and Rehabilitation Medicine (PRM) is a basic medical specialty officially recognized in Europe since 1962. This article briefly presents the significance, attainments and tasks recently undertaken by the leading structures responsible for international harmonization and management of the specialty within healthcare systems in Europe and for scientific development: the Section and Board of the European Union of Medical Specialists (UEMS-PRM), European Academy of Rehabilitation Medicine (AEMR) and European Society of PRM (ESPRM). The concept of rehabilitation according to the biopsychosocial model of functioning recently promoted by the World Health Organization (WHO) closely follows the assumptions of the Polish Model of Rehabilitation, formulated in the 1960's and approved by the WHO in 1970. Since its accession to the European Union in 2004, Poland has been gradually increasing active participation in the European structures of PRM. PMID- 26248634 TI - Measurement of preoperative lobar lung function with computed tomography ventilation imaging: progress towards rapid stratification of lung cancer lobectomy patients with abnormal lung function. AB - OBJECTIVES: In lung cancer preoperative evaluation, functional lung imaging is commonly used to assess lobar function. Computed tomography ventilation (CT-V) imaging is an emerging lung function imaging modality. We compared CT-V imaging assessment of lobar function and its prediction of postoperative lung function to that achieved by (i) positron emission tomography ventilation (PET-V) imaging and (ii) the standard anatomical segment counting (ASC) method. We hypothesized (i) that CT-V and PET-V have similar relative lobar function and (ii) that functional imaging and anatomic assessment (ASC) yield different predicted postoperative (ppo) lung function and therefore could change clinical management. METHODS: In this proof-of-concept study, 11 patients were subjected to pulmonary function tests, CT-V and PET-V imaging. The Bland-Altman plot, Pearson's correlation and linear regression analysis were used to assess the agreement between the CT-V-, PET-V- and ASC-based quantification of lobar function and in the ppo lung function. RESULTS: CT-V and PET-V imaging demonstrated strong correlations in quantifying relative lobar function (r = 0.96; P < 0.001). A Wilcoxon-signed rank test showed no significant difference in the lobar function estimates between the two imaging modalities (P = 0.83). The Bland-Altman plot also showed no significant differences. The correlation between ASC-based lobar function estimates with ventilation imaging was low, r < 0.45; however, the predictions of postoperative lung function correlated strongly between all three methods. CONCLUSIONS: The assessment of lobar function from CT-V imaging correlated strongly with PET-V imaging, but had low correlations with ASC. CT-V imaging may be a useful alternative method in preoperative evaluation for lung cancer patients. PMID- 26248635 TI - Mode of delivery and birthweight among teenage and adult primigravida Saudi women: A retrospective comparative study. AB - AIM: The aim of this study was to determine the mode of delivery and birthweight among teenagers in comparison to adult pregnant Saudi women. MATERIAL AND METHODS: This was a retrospective comparative study. We included all primigravid teenage girls aged 19 years or younger and adult women aged 20-29 years with singleton term normal pregnancies who delivered at Hail Maternity Hospital during 1 January-31 December 2013. RESULTS: Incidence of vaginal delivery among teenagers was higher than that in adults, at 105 (80.2%) and 588 (70.5%), respectively. There was a lower incidence of vacuum extraction and cesarean section among the teenage group compared to the adult group (1 [0.8%] vs 25 [3.0%], and 25 [19.1%] vs 221 [26.5%], respectively [P > 0.05]). Incidence of low birthweight among the teenage group was higher than that in adults (28 [21.4%] and 84 [10.1%], respectively [P < 0.05]). CONCLUSION: Our study concluded that teenage pregnancy is associated with a high risk of low birthweight (P < 0.05). Adult mothers experienced more cesarean section and vacuum extraction deliveries (P > 0.05). Adequate antenatal care, community education and raising awareness might decrease the number of teenage pregnancies, which was 13.6% in our study. PMID- 26248636 TI - Comparative efficacy of non-steroidal anti-inflammatory drugs in ankylosing spondylitis: a Bayesian network meta-analysis of clinical trials. AB - OBJECTIVE: To compare the efficacy of 20 non-steroidal anti-inflammatory drugs (NSAIDs) in the short-term treatment of ankylosing spondylitis (AS). METHODS: We performed a systematic literature review of randomised controlled trials of NSAIDs in patients with active AS. We included trials that reported efficacy at 2 12 weeks. Efficacy outcomes were the change in pain score and change in the duration of morning stiffness. We also examined the number of adverse events. We used Bayesian network meta-analysis to compare effects directly and indirectly between drugs. RESULTS: We included 26 trials (66 treatment arms) of 20 NSAIDs with 3410 participants in the network meta-analysis. Fifty-eight per cent of trials had fewer than 50 participants. All 20 NSAIDs reduced pain more than placebo (standardised mean difference ranging from -0.65 to -2.2), with 15 NSAIDs significantly better than placebo. Etoricoxib was superior to celecoxib, ketoprofen and tenoxicam in pain reduction, but no other interdrug comparisons were significant. There were no significant differences among NSAIDs in decreases in the duration of morning stiffness or the likelihood of adverse events. Adverse events were uncommon in these short-term studies. In 16 trials that used NSAIDs at full doses, etoricoxib was superior to all but two other NSAIDs in pain reduction. CONCLUSIONS: Etoricoxib was more effective in reducing pain in AS than some other NSAIDs, but there was otherwise insufficient evidence to conclude that any particular NSAID was more effective in the treatment of AS. Comparisons were limited by small studies. PMID- 26248637 TI - The accuracy of osteoporotic fracture risk prediction tools: a systematic review and meta-analysis. AB - OBJECTIVES: To identify and synthesise the best available evidence on the accuracy of the currently available tools for predicting fracture risk. METHODS: We systematically searched PubMed MEDLINE, Embase and Cochrane databases to 2014. Two reviewers independently selected articles, collected data from studies, and carried out a hand search of the references of the included studies. The Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS) checklist was used, and the primary outcome was the area under the curve (AUC) and 95% CIs, obtained from receiver operating characteristic (ROC) analyses. We excluded tools if they had not been externally validated or were designed for specific disease populations. Random effects meta-analyses were performed with the selected tools. RESULTS: Forty-five studies met inclusion criteria, corresponding to 13 different tools. Only three tools had been tested more than once in a population-based setting: FRAX (26 studies in 9 countries), GARVAN (6 studies in 3 countries) and QFracture (3 studies in the UK, 1 also including Irish participants). Twenty studies with these three tools were included in a total of 17 meta-analyses (for hip or major osteoporotic fractures; men or women; with or without bone mineral density). CONCLUSIONS: Most of the 13 tools are feasible in clinical practice. FRAX has the largest number of externally validated and independent studies. The overall accuracy of the different tools is satisfactory (>0.70), with QFracture reaching 0.89 (95% CI 0.88 to 0.89). Significant methodological limitations were observed in many studies, suggesting caution when comparing tools based solely on the AUC. PMID- 26248638 TI - Long-term effects of secukinumab on MRI findings in relation to clinical efficacy in subjects with active ankylosing spondylitis: an observational study. AB - INTRODUCTION: A 28-week study suggested efficacy of the anti-interleukin-17A monoclonal antibody secukinumab in active ankylosing spondylitis (AS). MRI assessed inflammation was reduced at weeks 6, 28. OBJECTIVE: To analyse the longer-term effects of secukinumab on MRI inflammatory and non-inflammatory spinal lesions in relation to its clinical efficacy in subjects with active AS. METHODS: Spinal MRI results (baseline, week 94) for 13 subjects with AS initially treated with secukinumab 2*10 mg/kg intravenously (n=10) or placebo (n=3) and receiving a secukinumab maintenance dose of 3 mg/kg IV every 4 weeks up to week 94 were evaluated by the Berlin score; inflammatory/non-inflammatory (fatty) changes were assessed at vertebral edges (VEs). Results were compared with clinical outcomes. RESULTS: Most of the 13 subjects assessed at week 94 had sustained clinical responses: 8 (62%) achieved Assessment of SpondyloArthritis international Society 20% (ASAS20), including 6 (46%) achieving ASAS40 responses, corresponding to 75% and 83% reductions in the Berlin score, respectively. In the 10 subjects treated with secukinumab throughout the study period, 79/91 (87%) inflammatory VEs at baseline resolved by week 94; new fatty lesions occurred in 39/796 (4.9%) of VEs; 87/124 (70%) VEs with fatty lesions at baseline remained unchanged; 30% were no longer visible. CONCLUSIONS: In this pilot study, secukinumab treatment up to 2 years yielded sustained clinical improvement accompanied by regression of spinal inflammation. The impact of secukinumab on the development of fatty changes and bone formation in AS will be assessed in larger trials. TRIAL REGISTRATION NUMBER: This study is registered with ClinicalTrials.gov, number NCT00809159. PMID- 26248639 TI - The role of carrier ligands of platinum(II) anticancer complexes in the protein recognition of Pt-DNA adducts. AB - In order to systematically investigate the influence of carrier ligands on the interaction of Pt-DNA adducts with damage recognition proteins, a series of DNA probes containing 1,2-GG platinum compound crosslinks using cisplatin, oxaliplatin, (S,S-DACH)PtCl2 and (cis-1,4-DACH)PtCl2 (kiteplatin) has been constructed. These complexes share similar DNA binding properties although they exhibit quite different cytotoxicity. It is revealed that HMGB1 (high-mobility group protein B1) was the most commonly found protein that recognizes all Pt(II) DNA probes and prefers cisplatin-DNA probes more than the others. Interestingly, an important component of the replication protein A complex, RPA2, was found to bind to kiteplatin much more tightly than other proteins. These results may be important for the interpretation of the roles of carrier ligands in platinum(II) based anticancer complexes. PMID- 26248642 TI - A Self-Assembled DNA Origami-Gold Nanorod Complex for Cancer Theranostics. AB - A self-assembled DNA origami (DO)-gold nanorod (GNR) complex, which is a dual functional nanotheranostics constructed by decorating GNRs onto the surface of DNA origami, is demonstrated. After 24 h incubation of two structured DO-GNR complexes with human MCF7 breast cancer cells, significant enhancement of cell uptake is achieved compared to bare GNRs by two-photon luminescence imaging. Particularly, the triangle shaped DO-GNR complex exhibits optimal cellular accumulation. Compared to GNRs, improved photothermolysis against tumor cells is accomplished for the triangle DO-GNR complex by two-photon laser or NIR laser irradiation. Moreover, the DO-GNR complex exhibits enhanced antitumor efficacy compared with bare GNRs in nude mice bearing breast tumor xenografts. The results demonstrate that the DO-GNR complex can achieve optimal two-photon cell imaging and photothermal effect, suggesting a promising candidate for cancer diagnosis and therapy both in vitro and in vivo. PMID- 26248643 TI - A Gallium-Substituted Distibene and an Antimony-Analogue Bicyclo[1.1.0]butane: Synthesis and Solid-State Structures. AB - RGa {R=HC[C(Me)N(2,6-iPr2C6H3)]2} reacts with Sb(NMe2)3 with insertion into the Sb-N bond and elimination of RGa(NMe2)2 (2), yielding the Ga-substituted distibene R(Me2N)GaSb=SbGa(NMe2 )R (1). Thermolysis of 1 proceeded with elimination of RGa and 2 and subsequent formation of the bicyclo[1.1.0]butane analogue [R(Me2N)Ga]2Sb4 (3). PMID- 26248644 TI - Dual regulating effect of Ningdong granule on extracellular dopamine content of two kinds of Tourette's syndrome rat models. AB - Tourette's syndrome (TS) is an inherited chronic neuropsychiatric disorder characterized by involuntary stereotyped motor and phonic behaviors called tics. Its pathogenesis is still unclear and its treatment remains limited. Our previous basic and clinical studies have shown that traditional Chinese medicine (TCM) preparation Ningdong granule (NDG) is effective for the treatment of TS with little side effects. In the current study, two TS rat models (Apomorphine (Apo)- and 3,3'-iminodipropionitrile (IDPN)-induced) were used to explore the dual regulating effects and mechanisms of NDG on extracellular DA concentration. We found that NDG could regulate the extracellular DA concentration dually: it could make a gradual recovery in extracellular DA content from both an up-regulated level in Apo-induced rats and down-regulated level in IDPN-induced rats measured by high-performance liquid chromatography (HPLC). The protein expression of DA transporter (DAT) was measured by Western blot and the result showed that NDG could elevate DAT expression when DA release was up-regulated and could decrease DAT expression when extracellular DA concentration was down-regulated. The main mechanism of the dual regulating effect of NDG on extracellular DA release might be related to DAT protein expression in TS, through which the released DA is re uptaken into nerve terminals. Taken together, compared with conventional single target anti-tics drugs such as haloperidol (Hal), NDG with the dual regulating effect would be more significant for TS treatment. PMID- 26248645 TI - The hybrid nanostructure of MnCo2O4.5 nanoneedle/carbon aerogel for symmetric supercapacitors with high energy density. AB - Current applications of carbon-based supercapacitors are limited by their low energy density. One promising strategy to enhance the energy density is to couple metal oxides with carbon materials. In this study, a porous MnCo2O4.5 nanoneedle/carbon aerogel hybrid nanostructure was synthesized by assembling MnCo2O4.5 nanoneedle arrays on the surface of channel walls of hierarchical porous carbon aerogels derived from chitosan for the supercapacitor application. The synthetic process of the hybrid nanostructure involves two steps, i.e. the growth of Mn-Co precursors on carbon aerogel by a hydrothermal process and the conversion of the precursor into MnCo2O4.5 nanoneedles by calcination. The carbon aerogel exhibits a high electrical conductivity, high specific surface area and porous structure, ensuring high electrochemical performance of the hybrid nanostructure when coupled with the porous MnCo2O4.5 nanoneedles. The symmetric supercapacitor using the MnCo2O4.5 nanoneedle/carbon aerogel hybrid nanostructure as the active electrode material exhibits a high energy density of about 84.3 Wh kg(-1) at a power density of 600 W kg(-1). The voltage window is as high as 1.5 V in neutral aqueous electrolytes. Due to the unique nanostructure of the electrodes, the capacitance retention reaches 86% over 5000 cycles. PMID- 26248646 TI - Convergence in insulin resistance between very severely obese and lean women at the end of pregnancy. AB - AIMS: Disrupted intermediary metabolism may contribute to the adverse pregnancy outcomes in women with very severe obesity. Our aim was to study metabolism in such pregnancies. METHODS: We recruited a longitudinal cohort of very severely obese (n = 190) and lean (n = 118) glucose-tolerant women for anthropometric and metabolic measurements at early, mid and late gestation and postpartum. In case control studies of very severely obese and lean women we measured glucose and glycerol turnover during low- and high-dose hyperinsulinaemic-euglycaemic clamps (HEC) at early and late pregnancy and in non-pregnant women (each n = 6-9) and body fat distribution by MRI in late pregnancy (n = 10/group). RESULTS: Although greater glucose, insulin, NEFA and insulin resistance (HOMA-IR), and greater weight and % fat mass (FM) was observed in very severely obese vs lean participants, the degree of worsening was attenuated in the very severely obese individuals with advancing gestation, with no difference in triacylglycerol (TG) concentrations between very severely obese and lean women at term. Enhanced glycerol production was observed in early pregnancy only in very severely obese individuals, with similar intrahepatic FM in very severely obese vs lean women by late gestation. Offspring from obese mothers were heavier (p = 0.04). CONCLUSIONS/INTERPRETATION: Pregnancies complicated by obesity demonstrate attenuation in weight gain and insulin resistance compared with pregnancies in lean women. Increased glycerol production is confined to obese women in early pregnancy and obese and lean individuals have similar intrahepatic FM by term. When targeting maternal metabolism to treat adverse pregnancy outcomes, therapeutic intervention may be most effective applied early in pregnancy. PMID- 26248647 TI - The new biology of diabetes. AB - Until recently, type 2 diabetes was seen as a disease caused by an impaired ability of insulin to promote the uptake and utilisation of glucose. Work on forkhead box protein O (FOXO) transcription factors revealed new aspects of insulin action that have led us to articulate a liver- and beta cell-centric narrative of diabetes pathophysiology and treatment. FOXO integrate a surprisingly diverse subset of biological functions to promote metabolic flexibility. In the liver, they controls the glucokinase/glucose-6-phosphatase switch and bile acid pool composition, directing carbons to glucose or lipid utilisation, thus providing a unifying mechanism for the two abnormalities of the diabetic liver: excessive glucose production and increased lipid synthesis and secretion. Moreover, FOXO are necessary to maintain beta cell differentiation, and diabetes development is associated with a gradual loss of FOXO function that brings about beta cell dedifferentiation. We proposed that dedifferentiation is the main cause of beta cell failure and conversion into non-beta endocrine cells, and that treatment should restore beta cell differentiation. Our studies investigating these proposals have revealed new dimensions to the pathophysiology of diabetes that can be leveraged to design new therapies. PMID- 26248648 TI - Tumor-Derived Cell Lines as Molecular Models of Cancer Pharmacogenomics. AB - Compared with normal cells, tumor cells have undergone an array of genetic and epigenetic alterations. Often, these changes underlie cancer development, progression, and drug resistance, so the utility of model systems rests on their ability to recapitulate the genomic aberrations observed in primary tumors. Tumor derived cell lines have long been used to study the underlying biologic processes in cancer, as well as screening platforms for discovering and evaluating the efficacy of anticancer therapeutics. Multiple -omic measurements across more than a thousand cancer cell lines have been produced following advances in high throughput technologies and multigroup collaborative projects. These data complement the large, international cancer genomic sequencing efforts to characterize patient tumors, such as The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). Given the scope and scale of data that have been generated, researchers are now in a position to evaluate the similarities and differences that exist in genomic features between cell lines and patient samples. As pharmacogenomics models, cell lines offer the advantages of being easily grown, relatively inexpensive, and amenable to high-throughput testing of therapeutic agents. Data generated from cell lines can then be used to link cellular drug response to genomic features, where the ultimate goal is to build predictive signatures of patient outcome. This review highlights the recent work that has compared -omic profiles of cell lines with primary tumors, and discusses the advantages and disadvantages of cancer cell lines as pharmacogenomic models of anticancer therapies. PMID- 26248649 TI - miR-200c Targets CDK2 and Suppresses Tumorigenesis in Renal Cell Carcinoma. AB - miRNA expression profiles are widely investigated in the major cancers, but their specific roles and functions in cancers have not yet to be fully elucidated. In this study, miRNA expression profiles were determined in clear cell renal cell carcinomas (ccRCC) and in matched normal kidney tissues by using a miRNA microarray platform which covers a total of 851 human miRNAs. Differential expression of 74 miRNAs were identified between ccRCC specimens and their matched adjacent noncancerous tissues, of which 30 were significantly upregulated in ccRCCs, and the other 44 were downregulated (fold change >= 2, P < 0.05). Interestingly, miR-200c was commonly downregulated in ccRCC specimens and ccRCC cell lines with significant functional consequences. Growth curve and FACS assay indicated that overexpression of miR-200c suppressed cell growth and induced cell cycle arrest at G0-G1 phases in SN12-PM6 and 786-O cells. Furthermore, miR-200c could suppress in vivo tumor growth of SN12-PM6 cells in mice. Bioinformatics exposed cyclin-dependent kinase 2 (CDK2) as a potential target of miR-200c, which was validated using a luciferase reporter assay. Mechanistic investigations revealed that miR-200c was directly responsible for suppressing the expression of CDK2 in ccRCC cell lines and xenografts. Taken together, miR-200c plays an antioncogenic role in ccRCC, through controlling cell growth and cell-cycle progression by downregulating the G1-S regulator CDK2. IMPLICATIONS: miR-200c exerts its novel antioncogenic function in renal cell carcinoma by controlling CDK2-dependent cell growth and cell-cycle progression. PMID- 26248650 TI - Efficacy of elemental diet on prevention for chemoradiotherapy-induced oral mucositis in patients with oral squamous cell carcinoma. AB - PURPOSE: Oral mucositis induced by radiation or chemoradiation can compromise the quality of life of oral squamous cell carcinoma (OSCC) patients. The present study was designed to evaluate the preventive effects of elemental diet (ED), Elental(r), on radiotherapy- or chemoradiotherapy-induced mucositis in OSCC patients. PATIENTS AND METHODS: Seventy-four patients who underwent radiation (60 70 Gy) with/without chemotherapy [S-1, cisplatin (CDDP), CDDP plus S-1] were enrolled in this retrospective study; 37 had received Elental(r) during treatment (Elental(r) group) and 37 had not (control group). Factors related to alleviation of oral mucositis were identified by multivariate logistic regression analysis. Rates of completion of chemoradiation treatments were compared between Elental(r) and control groups according to the treatment regimen. The comparison of the nutritional status between groups was also performed. RESULTS: Multivariate analysis indicated that the administration of Elental(r) and no combined chemotherapy (radiation alone) were significant factors associated with the degree of oral mucositis, i.e., most of the patients who consumed Elental(r) suffered from a lower degree of mucositis compared to the control group. Elental(r) was associated with a significantly improved rate of completion of chemoradiation (no interruption). There was no significant difference between Elental(r) group and control group in terms of mean change of body weight or total protein and albumin levels in blood serum before and after (chemo)radiation. CONCLUSIONS: The present study indicates that Elental(r) is effective for ameliorating oral mucositis induced by (chemo)radiation in OSCC patients. Elental(r) was also associated with improved completion rates of (chemo)radiotherapy. PMID- 26248651 TI - Evaluating the efficacy of a self-guided Web-based CBT intervention for reducing cancer-distress: a randomised controlled trial. AB - PURPOSE: This study evaluated the efficacy of a self-guided Web-based cognitive behaviour therapy (CBT) intervention compared to an attention control in improving cancer-related distress, health-related quality of life (HRQOL), and maladaptive coping, among people recently diagnosed with cancer. METHODS: Sixty individuals with cancer diagnosed in the previous 6 months and receiving treatment with curative intent were randomised to receive either the 6-week intervention Cancer Coping Online (CCO: n = 30) or the 6-week Web-based attention control (n = 30). Outcome measures, including cancer distress (the Posttraumatic Stress Scale - Self-Report), general distress (Depression Anxiety Stress Scale), quality of life (EORTC QLQ-C30), and coping (mini-MAC), were administered at baseline, immediately post-intervention, and at 3 and 6 months post-intervention. RESULTS: Significant main effects for time were found for cancer distress, global QOL, physical function, role function, social function, and anxious preoccupation. Post hoc between-group comparisons showed CCO participants had statistically significantly higher physical functioning compared to controls at 3 months of follow-up (d = -0.52, p = 0.02). Furthermore, compared to controls, post hoc comparisons found moderate between-group effect sizes favouring CCO post intervention for cancer distress (d = 0.43) and anxious preoccupation (d = 0.38), and at 6 months of follow-up for global QOL (d = -0.43). CONCLUSIONS: These results provide preliminary support for the potential efficacy of a self-guided Web-based CBT programme in improving aspects of HRQOL, cancer-related distress, and anxious preoccupation after cancer diagnosis. This paper provides justification for, and will help inform the development of, subsequent larger multi-site studies. PMID- 26248652 TI - MC11C4: a pilot randomized, placebo-controlled, double-blind study of venlafaxine to prevent oxaliplatin-induced neuropathy. AB - PURPOSE: Previous pilot data suggested that venlafaxine could prevent acute and chronic oxaliplatin-related neuropathy. The purpose of this randomized, placebo controlled, double-blinded pilot study was to obtain additional data to support conducting a phase III trial to test the use of venlafaxine to prevent oxaliplatin neurotoxicity. METHODS: Fifty patients, scheduled to undergo oxaliplatin-based therapy (FOLFOX) for stages II-III (67%) or stage IV (33%) colon cancer, were randomized to receive venlafaxine extended release (37.5 mg) or placebo, twice daily, through their last dose of oxaliplatin and then titrated off. Neurotoxicity was evaluated via several patient- and physician-reported measures, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20) instrument. RESULTS: Baseline patient characteristics were equivalent for the two arms, with a median age of 60 years. There was a trend toward benefit for the venlafaxine arm, when evaluated by the oxaliplatin specific neuropathy scale and by acute neuropathy measures of throat discomfort and discomfort swallowing cold liquids, the latter only for the first two oxaliplatin doses. These trends were outweighed by a lack of any such trends in all other measurements including the following: (1) the CIPN20 sensory subscale (P = 0.55, primary endpoint), physician-completed NCI CTCAE assessment, or cumulative administered oxaliplatin doses (median 716 vs 631 mg for placebo and venlafaxine, respectively, P = 0.34). CONCLUSIONS: The present study neither supports the use of venlafaxine for preventing oxaliplatin-induced neuropathy in clinical practice nor the initiation of a phase III trial to investigate venlafaxine in this setting. PMID- 26248653 TI - Phase II evaluation of S-adenosyl-L-methionine (SAMe) for the treatment of hot flashes. AB - PURPOSE: Hot flashes are a significant source of symptom burden that negatively impacts quality of life (QOL). For women who have contraindications to, or are unwilling to consider, estrogens or antidepressants for bothersome hot flashes, there are limited effective pharmacologic or complementary and alternative medicines. METHODS: This single-arm phase II trial studied the efficacy of S adenosyl-L-methionine (SAMe) for the treatment of hot flashes. Eligible women were required to have reported >=14 hot flashes per week for >=1 month. The patients were treated with SAMe at a dose of 400 mg twice daily to evaluate whether a reduction in hot flash score appeared to be better than the historical placebo response of approximately 25%. The women kept a daily hot flash diary during a baseline week and then daily during weeks 2-7. The primary endpoint was the change from baseline to week 7 in hot flash score and hot flash frequency. Secondary endpoints included toxicity analyses and the effect of SAMe on QOL. RESULTS: From October 28, 2010 to January 30, 2012, 43 women were treated with SAMe. The decrease in mean percent of baseline hot flash score and frequency was 35.4 and 32.6%, respectively. When compared to the historical placebo response of 25%, the effect of SAMe on hot flash score was not statistically significant (p = 0.09). Treatment was well tolerated with expected grade 1/2 gastrointestinal toxicity and no negative effect on QOL. CONCLUSIONS: The use of SAMe does not appear to significantly reduce hot flashes more than would be expected with a placebo. PMID- 26248654 TI - A new once-a-day fentanyl citrate patch (Fentos Tape) could be a new treatment option in patients with end-of-dose failure using a 72-h transdermal fentanyl matrix patch. AB - PURPOSE: The recommended dosing interval for transdermal fentanyl is every 72 h. However, some patients will have "end-of-dose failure," which may be seen as an increase of episodes of severe pain flares at the third day after application of the patch. A new once-a-day fentanyl patch was developed in Japan since 2010. This study aimed to assess the efficacy of the once-a-day fentanyl citrate patch for patients with cancer-related pain receiving the 72-h transdermal fentanyl not lasting 72 h. METHODS: We performed a cross-sectional retrospective analysis of 445 inpatients with the 72-h transdermal fentanyl at Higashi Sapporo Hospital. We could switch to the once-a-day fentanyl citrate patch if patients reported inadequate pain relief beyond 48 h after application of the 72-h transdermal fentanyl. Patients recorded baseline scores for background pain intensity (PI) and the frequency of use of daily rescue medication for breakthrough cancer pain (BTcP). RESULTS: Of all patients, 10.1% showed the increase in PI of 30% or more baseline PI on the third day after application of the 72-h transdermal fentanyl. Of patients, 84.4% were converted from equivalent dose of the 72-h transdermal fentanyl to the once-a-day fentanyl citrate patch. On the third day after switching, 60.5% of patients showed a reduction of more than 30% from baseline PI. Switching to the once-a-day fentanyl citrate patch significantly reduced the mean frequency of daily rescue dose for BTcP. CONCLUSIONS: A once-a-day fentanyl citrate patch provided stable pain control. Its use may be considered as the dominant strategy for patients receiving a 72-h transdermal fentanyl not lasting 72 h. PMID- 26248655 TI - Low-level laser therapy prevents severe oral mucositis in patients submitted to hematopoietic stem cell transplantation: a randomized clinical trial. AB - PURPOSE: The purpose of this study is to evaluate the effectiveness of low-level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic stem cell transplantation. METHODS: This is a randomized, parallel, superiority trial including 35 patients divided into the following: laser (n = 17) and sham (n = 18). The variables assessed were oral mucositis (grade 2 of the World Health Organization oral toxicity scale), severe oral mucositis (grade 3 or 4), and pain (according to a visual analogue scale). In the laser group, a InGaAlP laser, wavelength of 650 nm, power 100 mW, energy per point of 2 J, time 20 s by point, extremity fiber optic 0.028 cm(2), and energy density 70 J/cm(2), was used, applied the first day of conditioning until D + 5, while the sham group received simulated laser over the same period. RESULTS: No statistically significant difference was found in the incidence of oral mucositis (p = 0.146). Severe mucositis was found in 40% of the patients (14/35), 3 in the intervention group (17.65%) and 11 in the sham group (61.11%) (p = 0.015). The cumulative probability of survival with respect to the development of severe oral mucositis was >0.6 for the intervention group and 0 for the control group (p = 0.0397). On the day on which pain was considered the worst, patients in the sham group were more likely to classify their pain as severe compared to those in the laser group (p = 0.041). CONCLUSION: Low-level laser therapy proved effective for the prevention of severe oral mucositis and intense oral pain in patients submitted to hematopoietic stem cell transplantation. PMID- 26248656 TI - Pharmacologically inhibiting GluR2 internalization alleviates neuropathic pain. AB - Neuropathic pain is of serious clinical concern and only about half of patients achieve partial relief with currently-available treatments, so it is critical to find new drugs for this condition. Recently, the cellsurface trafficking of pain related receptors has been suggested as an important mechanism underlying persistent neuropathic pain. Here, we used the short peptide GluA2-3y, which specifically inhibits the GluA2-dependent endocytosis of alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid receptors, and tested its anti-nociceptive effect in the periaqueductal grey (PAG) of intact rats and rats with neuropathic pain. Intra-PAG injection of 0.15, 1.5, 7.5, and 15 pmol of GluA2-3y induced dose dependent increases in hindpaw withdrawal latencies to noxious thermal and mechanical stimuli in intact rats, suggesting that GluA2 cell-surface trafficking in the PAG is involved in pain modulation. Furthermore, GluA2-3y had much stronger anti-nociceptive effects in rats with neuropathic pain induced by sciatic nerve ligation. Interestingly, the intra-PAG injection of 15 pmol GluA2 3y had an analgesic effect similar to 10 MUg (35 nmol) morphine in rats with neuropathic pain. Taken together, our results suggested that GluA2 trafficking in the PAG plays a critical role in pain modulation, and inhibiting GluA2 endocytosis with GluA2-3y has potent analgesic effects in rats with neuropathic pain. These findings strongly support the recent hypothesis that targeting receptor trafficking could be a new strategy for the treatment of neuropathic pain. PMID- 26248657 TI - Heat shock protein 90 inhibition abrogates TLR4-mediated NF-kappaB activity and reduces renal ischemia-reperfusion injury. AB - Renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury. Toll-like receptor 4 (TLR4) mediates sterile inflammation following renal IRI. Heat shock protein 90 (Hsp90) inhibition is a potential strategy to reduce IRI, and AT13387 is a novel Hsp90 inhibitor with low toxicity. This study assessed if pre-treatment with AT13387 could reduce renal IRI and established if the mechanism of protection involved a reduction in inflammatory signalling. Mice were pre-treated with AT13387 prior to renal IRI. 24 h later, renal function was determined by serum creatinine, kidney damage by tubular necrosis score, renal TLR4 expression by PCR and inflammation by cytokine array. In vitro, human embryonic kidney cells were co-transfected to express TLR4 and a secreted alkaline phosphatase NF-kappaB reporter. Cells were pre-treated with AT13387 and exposed to endotoxin-free hyaluronan to stimulate sterile TLR4-specific NF-kappaB inflammatory activation. Following renal IRI, AT13387 significantly reduced serum creatinine, tubular necrosis, TLR4 expression and NF-kappaB-dependent chemokines. In vitro, AT13387-treatment resulted in breakdown of IkappaB kinase, which abolished TLR4-mediated NF-kappaB activation by hyaluronan. AT13387 is a new agent with translational potential that reduces renal IRI. The mechanism of protection may involve breakdown of IkappaB kinase and repression of TLR4 mediated NF-kappaB inflammatory activity. PMID- 26248658 TI - Abiogenic Syntheses of Lipoamino Acids and Lipopeptides and their Prebiotic Significance. AB - Researchers have formed peptide bonds under a variety of presumed prebiotic conditions. Here it is proposed that these same conditions would have also formed amide bonds between fatty acids and amino acids, producing phosphate-free amphipathic lipoamino acids and lipopeptides. These compounds are known to form vesicles and are ubiquitous in living organisms. They could represent molecules that provided protection by membranes as well as possibilities for proto-life metabolism . It is here demonstrated that when a fatty acid is heated with various amino acids, optimally in the presence of suitable salts or minerals, lipoamino acids are formed. Magnesium and potassium carbonates as well as iron (II) sulfide are found to be particularly useful in these reactions. In this manner N-lauroylglycine, N-lauroylalanine, N-stearoylalanine and several other lipoamino acids have been synthesized. Similarly, when glycylglycine was heated with lauric acid in the presence of magnesium carbonate, the lipopeptide N lauroylglycylglycine was formed. Such compounds are proposed to have been critical precursors to the development of life. PMID- 26248659 TI - Perceived weight status and risk of weight gain across life in US and UK adults. AB - BACKGROUND: Correctly identifying oneself as being overweight is presumed to be a prerequisite to successful weight management. The present research examined the effect that perceiving oneself as being 'overweight' has on risk of future weight gain in US and UK adults. METHODS: Data from three longitudinal studies; US National Longitudinal Study of Adolescent Health (Add Health) 2001/2002 2008/2009, UK National Child Development Study (NCDS) 1981-2002/2004, and Midlife in the United States (MIDUS) 1995/1996-2004/2005, were used to examine the impact of perceiving oneself as being overweight on weight gain across adulthood in over 14 000 US and UK adults. RESULTS: Participants who perceived their weight status as being overweight were at an increased risk of subsequent weight gain. This effect was observed irrespective of weight status at baseline and whether weight status perceptions were accurate or inaccurate. In the MIDUS sample, perceiving oneself as being overweight was associated with overeating in response to stress and this mediated the relationship between perceived overweight and weight gain. CONCLUSIONS: Perceiving oneself as being 'overweight' is counter-intuitively associated with an increased risk of future weight gain among US and UK adults. PMID- 26248660 TI - Large adipocytes function as antigen-presenting cells to activate CD4(+) T cells via upregulating MHCII in obesity. AB - BACKGROUND/OBJECTIVES: Although obesity is associated with low-grade inflammation and metabolic disorders, clinical studies suggested some obese people were metabolically healthy with smaller adipocyte size compared with metabolically abnormal obese (MAO). This indicated adipocyte size may be an important predictor underlay the distinction between MAO and metabolically healthy obese. As recent study has shown that adipocytes expressed class II major histocompatibility complex (MHCII), which functioned as APCs during obesity. However, the relationship between adipocyte hypertrophy and MHCII expression was not involved. Here we hypothesize that hypertrophic adipocytes could be associated with upregulating MHCII to influence adipose tissue metabolism. METHODS: Adipocytes were sorted by fluorescence-activated cell sorting (FACS) according to the cell size from MAO mice. The activation of MHCII, T cells and related signaling molecules were examined by FACS, ELISA and western blotting. 3T3-L1 cell line and primary adipocytes were used to examine the effect of free fatty acids (FFA) on adipocytes enlargement and MHCII expression. RESULTS: MAO mice had a significant increase in adipocytes size and FFA concentration. The large adipocytes from both obese and non-obese mice expressed higher levels of MHCII than small adipocytes. Importantly, large adipocytes from obese mice stimulated CD4(+) T cells to secrete more interferon (IFN)-gamma. Furthermore, the activation of the JNK-STAT1 pathway was involved in upregulation of MHCII in large adipocytes. In vitro FFA treatment promoted adipocyte hypertrophy and expression of MHCII-associated genes. CONCLUSIONS: This study demonstrates that large adipocytes highly express MHCII and function as APC to stimulate IFN-gamma-expressing CD4(+) T cells, in which FFA may have important roles before IFN-gamma elevated. These findings suggest that adipocyte hypertrophy, rather than overall obesity, is the major contributor to adipose tissue inflammation and insulin resistance. PMID- 26248661 TI - The relation between internet use and overweight among adolescents: a longitudinal study in Switzerland. AB - OBJECTIVE: This longitudinal study aimed to investigate the characteristics and predictive risk factors of overweight among adolescents. The hypothesis was that baseline overweight predicted most overweight over time compared to other factors, especially excessive internet use. SUBJECTS: A sample of 621 youths were followed from age 14 (T0 Spring 2012) to age 16 (T1 Spring 2014) in Switzerland. Participants were divided into two groups according to their weight at the final assessment: overweight and non-overweight. At T0, participants reported demographic, health, substance use and internet use data. A logistic regression was performed to assess the explanatory variables of overweight at T1. Data are presented as adjusted odds ratios (aORs) with 95% confidence interval. RESULTS: The 2-year evolution showed a net BMI increase of 4.8%. Overweight adolescents were significantly more likely to be male, to live in an urban area, to be on a diet and to report using the internet more than 2 h per day on weekends at T0. However, with the addition of baseline overweight, only the excessive use of internet on weekends remained as an explanatory variable. An adolescent who was already overweight at T0 had a more than 20-fold risk (aOR 21.04) of being overweight 2 years later. Moreover, among adolescents becoming overweight between T0 and T1, internet use did not show any significant effect. CONCLUSION: The risk of being overweight is mostly influenced by weight status at baseline compared to excessive internet use. Thus, our results do not confirm the negative effect of internet on healthier activities. Internet use could at most reinforce an already existing risk of being overweight. PMID- 26248662 TI - Job strain and risk of obesity: should we discriminate mental and physical strain? PMID- 26248663 TI - Online repetitive transcranial magnetic stimulation (TMS) to the parietal operculum disrupts haptic memory for grasping. AB - The parietal operculum (OP) contains haptic memory on the geometry of objects that is readily transferrable to the motor cortex but a causal role of OP in memory-guided grasping is only speculative. We explored this issue by using online high-frequency repetitive transcranial magnetic stimulation (rTMS). The experimental task was performed by blindfolded participants acting on objects of variable size. Trials consisted in three phases: haptic exploration of an object, delay, and reach-grasp movement onto the explored object. Motor performance was evaluated by the kinematics of finger aperture. Online rTMS was applied to the left OP region separately in each of the three phases of the task. The results showed that rTMS altered grip aperture only when applied in the delay phase to the OP. In a second experiment a haptic discriminative (match-to-sample) task was carried out on objects similar to those used in the first experiment. Online rTMS was applied to the left OP. No psychophysical effects were induced by rTMS on the detection of explicit haptic object size. We conclude that neural activity in the OP region is necessary for proficient memory-guided haptic grasping. The function of OP seems to be critical while maintaining the haptic memory trace and less so while encoding it or retrieving it. PMID- 26248664 TI - Comment on 'A justification for less restrictive guidelines on the use of metformin in stable chronic renal failure'. PMID- 26248665 TI - L-type lectin receptor kinases in Nicotiana benthamiana and tomato and their role in Phytophthora resistance. AB - Membrane-bound receptors play crucial roles as sentinels of plant immunity against a large variety of invading microbes. One class of receptors known to be involved in self/non-self-surveillance and plant resistance comprises the L-type lectin receptor kinases (LecRKs). Previously, we reported that several Arabidopsis LecRKs play a role in resistance to Phytophthora pathogens. In this study, we determined whether homologues of these LecRKs from the Solanaceous plants Nicotiana benthamiana and tomato (Solanum lycopersicum) play similar roles in defence against Phytophthora. In genome-wide screenings, a total of 38 (Nb)LecRKs were identified in N. benthamiana and 22 (Sl)LecRKs in tomato, each consisting of both a lectin and a kinase domain. Phylogenetic analysis revealed that, in contrast to Arabidopsis, which has a LecRK family comprising nine clades, Solanaceous species have just five of these nine clades (i.e. IV, VI, VII, VIII, and IX), plus four additional clades that lack Arabidopsis homologues. Several of the Solanaceous LecRKs were selected for functional analysis using virus-induced gene silencing. Infection assays with Phytophthora capsici and Phytophthora infestans on LecRK-silenced plants revealed that N. benthamiana and tomato homologues in clade IX play a role in Phytophthora resistance similar to the two Arabidopsis LecRKs in this clade, suggesting conserved functions of clade IX LecRKs across different plant families. This study provides a first insight into the diversity of Solanaceous LecRKs and their role in plant immunity, and shows the potential of LecRKs for Phytophthora resistance breeding. PMID- 26248666 TI - Long and short photoperiod buds in hybrid aspen share structural development and expression patterns of marker genes. AB - Tree architecture develops over time through the collective activity of apical and axillary meristems. Although the capacity of both meristems to form buds is crucial for perennial life, a comparative analysis is lacking. As shown here for hybrid aspen, axillary meristems engage in an elaborate process of axillary bud (AXB) formation, while apical dominance prevents outgrowth of branches. Development ceased when AXBs had formed an embryonic shoot (ES) with a predictable number of embryonic leaves at the bud maturation point (BMP). Under short days, terminal buds (TBs) formed an ES similar to that of AXBs, and both the TB and young AXBs above the BMP established dormancy. Quantitative PCR and in situ hybridizations showed that this shared ability and structural similarity was reflected at the molecular level. TBs and AXBs similarly regulated expression of meristem-specific and bud/branching-related genes, including CENTRORADIALIS-LIKE1 (CENL1), BRANCHED1 (BRC1), BRC2, and the strigolactone biosynthesis gene MORE AXILLARY BRANCHES1 (MAX1). Below the BMP, AXBs maintained high CENL1 expression at the rib meristem, suggesting that it serves to maintain poise for growth. In support of this, decapitation initiated outgrowth of CENL1-expressing AXBs, but not of dormant AXBs that had switched CENL1 off. This singles out CENL1 as a rib meristem marker for para-dormancy. BRC1 and MAX1 genes, which may counterbalance CENL1, were down-regulated in decapitation-activated AXBs. The results showed that removal of apical dominance shifted AXB gene expression toward that of apices, while developing TBs adopted the expression pattern of para-dormant AXBs. Bud development thus follows a shared developmental pattern at terminal and axillary positions, despite being triggered by short days and apical dominance, respectively. PMID- 26248667 TI - Xanthomonas campestris cell-cell signalling molecule DSF (diffusible signal factor) elicits innate immunity in plants and is suppressed by the exopolysaccharide xanthan. AB - Several secreted and surface-associated conserved microbial molecules are recognized by the host to mount the defence response. One such evolutionarily well-conserved bacterial process is the production of cell-cell signalling molecules which regulate production of multiple virulence functions by a process known as quorum sensing. Here it is shown that a bacterial fatty acid cell-cell signalling molecule, DSF (diffusible signal factor), elicits innate immunity in plants. The DSF family of signalling molecules are highly conserved among many phytopathogenic bacteria belonging to the genus Xanthomonas as well as in opportunistic animal pathogens. Using Arabidopsis, Nicotiana benthamiana, and rice as model systems, it is shown that DSF induces a hypersensitivity reaction (HR)-like response, programmed cell death, the accumulation of autofluorescent compounds, hydrogen peroxide production, and the expression of the PATHOGENESIS RELATED1 (PR-1) gene. Furthermore, production of the DSF signalling molecule in Pseudomonas syringae, a non-DSF-producing plant pathogen, induces the innate immune response in the N. benthamiana host plant and also affects pathogen growth. By pre- and co-inoculation of DSF, it was demonstrated that the DSF induced plant defence reduces disease severity and pathogen growth in the host plant. In this study, it was further demonstrated that wild-type Xanthomonas campestris suppresses the DSF-induced innate immunity by secreting xanthan, the main component of extracellular polysaccharide. The results indicate that plants have evolved to recognize a widely conserved bacterial communication system and may have played a role in the co-evolution of host recognition of the pathogen and the communication machinery. PMID- 26248669 TI - Symptomatic retethering of the spinal cord in postoperative lipomyelomeningocele patients: a meta-analysis. AB - BACKGROUND: Timing of surgical treatment for tethered cord syndrome due to a lipomyelomeningocele (LMM) has been controversial. The purpose of this study was to evaluate populations of patients treated surgically for LMM in a meta-analysis in order to better understand how outcomes differ based on follow-up time, symptomatology, and LMM classification. METHODS: An extensive search on PubMed and Google Scholar was performed for LMM and surgical outcomes to identify case series of patients for inclusion in this analysis. Patients were sorted based upon symptomatology prior to surgery and Chapman's LMM classification, where possible. Deterioration rates were determined by symptomatic retethering of the spinal cord that led to repeat surgery. RESULTS: Of 608 (19 %) patients, 115 were included in the study experienced deterioration leading to repeat surgery. Symptomatic and asymptomatic patients did not experience significantly different rates of deterioration after surgical untethering. There was a significant positive linear correlation between follow-up time of studies and percentage of patients deteriorating with an increase of 3.3 % per year of follow-up. Transitional LMM had a significantly higher rate of deterioration compared to the caudal type along with the entire patient pool. CONCLUSIONS: Outcomes of primary surgical treatment in regard to late deterioration are not significantly affected by patient symptomatology. Patient deterioration increases linearly over time. Additional studies should be performed to adequately determine the natural history of asymptomatic patients that are treated conservatively for LMM. PMID- 26248668 TI - Determinants in HIV-2 Env and tetherin required for functional interaction. AB - BACKGROUND: The interferon-inducible factor BST-2/tetherin blocks the release of nascent virions from the surface of infected cells for certain enveloped virus families. The primate lentiviruses have evolved several counteracting mechanisms which, in the case of HIV-2, is a function of its Env protein. We sought to further understand the features of the Env protein and tetherin that are important for this interaction, and to evaluate the selective pressure on HIV-2 to maintain such an activity. RESULTS: By examining Env mutants with changes in the ectodomain of the protein (virus ROD14) or the cytoplasmic tail (substitution Y707A) that render the proteins unable to counteract tetherin, we determined that an interaction between Env and tetherin is important for this activity. Furthermore, this Env-tetherin interaction required an alanine face in the tetherin ectodomain, although insertion of this domain into an artificial tetherin-like protein was not sufficient to confer sensitivity to the HIV-2 Env. The replication of virus carrying the ROD14 substitutions was significantly slower than the matched wild-type virus, but it acquired second-site mutations during passaging in the cytoplasmic tail of Env which restored the ability of the protein to both bind to and counteract tetherin. CONCLUSIONS: These results shed light on the interaction between HIV-2 and tetherin, suggesting a physical interaction that maps to the ectodomains of both proteins and indicating a strong selection pressure to maintain an anti-tetherin activity in the HIV-2 Env. PMID- 26248670 TI - Signs and symptoms of pediatric brain tumors and diagnostic value of preoperative EEG. AB - In pediatric patients, brain tumors have been estimated to be the cause for seizures in only 0.2-0.3% of cases, whereas seizures occurred in about 13% of pediatric brain tumor patients at presentation. This survey was conducted to analyze EEG findings in pediatric tumor patients over the past 14 years to evaluate the diagnostic value of preoperative EEG for diagnosis of brain tumors. Surface EEG was obtained in awake patients using the international 10- to 20 electrode placement in all pediatric patients with intracranial neoplasms between 2000 and 2013 at the University Hospital of Leipzig except for those who needed emergency operative treatment. One hundred forty-two pediatric patients with 80 infratentorial and 62 supratentorial tumors (WHO grades I-II: 91 patients; WHO grades III-IV: 46 patients). Symptomatic hydrocephalus was found in 37. Sensitivity and specificity of ophthalmologic examination for predicting hydrocephalus was 0.39 and 0.72. Preoperative EEG has been conducted in 116 patients, showing normal activity in 54 patients (47%). Out of 62 pathologic EEGs, 40 indicated correctly to the site of the lesion, 15 were pathologic despite of infratentorial location of the tumor. Nineteen patients had a history of seizures of which six had normal EEGs. Sensitivity for and specificity of EEG examination for symptomatic epilepsy was 0.68 and 0.7. Conclusion Preoperative routine EEG provides no additional value in the diagnostic algorithm of pediatric train tumors. The low specificity and sensitivity of EEG (even in patients with clinical seizures as primary symptom of a brain tumor) underline that EEG does not contribute to diagnosis and a normal EEG might even delay correct diagnosis. PMID- 26248671 TI - Pre-operative embolization of a choroid plexus carcinoma: review of the vascular anatomy. AB - AIM: The purpose of this case is to highlight the benefits of preoperative embolization as well as to review the vascular anatomy that needs to be recognized in order to perform pre-operative embolization of choroid plexus tumors. METHOD: We achieve this by presenting the case of a 12-month-old female who had symptoms of raised intracranial pressure. MRI demonstrated a large vividly enhancing mass centered within the atria of the right lateral ventricle associated with hydrocephalus in keeping with a choroid plexus tumor. RESULT: Enlarged anterior and posterior choroidal arteries supplying the tumor were noted on the MRI scan. Pre-operative embolization was performed with NBCA glue via the anterior and posterior choroidal arteries. Subsequently, total surgical resection was achieved with only 200 cc of blood loss. Pathology confirmed a choroid plexus carcinoma. CONCLUSION: Pre-operative embolization can be useful in minimizing blood loss during excision of choroid plexus tumors. It is important to understand the anatomy of the anterior and posterior choroidal arteries to perform embolization of these tumors safely. PMID- 26248672 TI - Arterial spin-labeling perfusion imaging of childhood meningitis: a case series. AB - INTRODUCTION: Conventional magnetic resonance imaging (MRI), which is mainly used to detect complications, is ineffective in determining the neurological status of patients with meningitis. Hemodynamic change in the brain may be more indicative of the neurological status but few imaging studies have verified this. Arterial spin-labeling (ASL) perfusion, a noninvasive MR method requiring no contrast agent injection, can be used to measure cerebral blood flow (CBF). CASE REPORTS: We describe three pediatric patients with meningitis, who all showed regions of increased CBF on perfusion imaging. One patient, presenting with headache and conscious disturbance, had CBF changes in the frontal, temporal, and occipital regions. The other two patients, presenting with hallucinations, memory deficits, and seizures, had CBF changes in the frontal and temporal regions. CONCLUSION: ASL perfusion imaging may be helpful in assessing patients with meningitis, demonstrating CBF changes more strongly correlating with the neurological status, and detecting active brain abnormalities. PMID- 26248673 TI - Complications of transoral and transnasal odontoidectomy: a comprehensive review. AB - BACKGROUND: Odontoidectomy has been considered an effective way to treat anterior cervicomedullary compression in patients presenting with craniocervical joint anomalies. The transoral and transnasal routes have been described for anterior decompression surgery. However, to date, a comprehensive review of the complications from this procedure is lacking in the extant medical literature. Therefore, herein, we review this specific literature as a resource for surgeons. METHODS: A comprehensive review of the literature via online search engines was performed. CONCLUSION: The most reported complications for odontoidectomy are CSF leakage, postoperative craniocervical instability, velopharyngeal insufficiency, wound dehiscence, pulmonary issues, meningitis, and death. To our knowledge, this is the first comprehensive review of complications of odontoidectomy. Increased awareness of the more common complications associated with this procedure may help in the care of patients in the future. PMID- 26248674 TI - Shunt revision requirements after posthemorrhagic hydrocephalus of prematurity: insight into the time course of shunt dependency. AB - PURPOSE: Intraventricular hemorrhage (IVH) is a common affliction of preterm infants and often results in posthemorrhagic hydrocephalus (PHH). These patients typically eventually require permanent CSF diversion and are presumed to be indefinitely shunt-dependent. To date, however, there has been no study of long term shunt revision requirements in patients with PHH. METHODS: We analyzed retrospectively collected data for 89 preterm patients diagnosed with grades III and IV IVH and PHH at our institution from 1998 to 2011. RESULTS: Sixty-nine out of 89 patients (77.5%) underwent ventriculoperitoneal (VP) shunt placement, and 33 (47.8%) required at least one shunt revision and 18 (26.1%) required multiple revisions. The mean +/- standard deviation follow-up time for shunted patients was 5.0 +/- 3.3 years. The majority of early failures were due to proximal catheter malfunction, while later failures were mostly due to distal catheter problems. There was a significant difference in the number of patients requiring revisions in the first 3 years following initial VP shunt insertion compared after 3 years, with 28 revisions versus 10 (p < 0.004). In 8 out of 10 patients who underwent shunt revisions after 3 years, evidence of obstructive hydrocephalus was found on imaging either in the form of an isolated fourth ventricular cyst or aqueductal stenosis. CONCLUSIONS: Our results suggest that in a distinct subset of patients with PHH, obstructive hydrocephalus may develop, resulting in long-term dependence on CSF diversion. Further study on the factors associated with long-term shunt dependence and revision requirements within the PHH group is warranted. PMID- 26248675 TI - An Ebola vaccine: first results and promising opportunities. PMID- 26248677 TI - Photosynthetic innovation broadens the niche within a single species. AB - Adaptation to changing environments often requires novel traits, but how such traits directly affect the ecological niche remains poorly understood. Multiple plant lineages have evolved C4 photosynthesis, a combination of anatomical and biochemical novelties predicted to increase productivity in warm and arid conditions. Here, we infer the dispersal history across geographical and environmental space in the only known species with both C4 and non-C4 genotypes, the grass Alloteropsis semialata. While non-C4 individuals remained confined to a limited geographic area and restricted ecological conditions, C4 individuals dispersed across three continents and into an expanded range of environments, encompassing the ancestral one. This first intraspecific investigation of C4 evolutionary ecology shows that, in otherwise similar plants, C4 photosynthesis does not shift the ecological niche, but broadens it, allowing dispersal into diverse conditions and over long distances. Over macroevolutionary timescales, this immediate effect can be blurred by subsequent specialisation towards more extreme niches. PMID- 26248676 TI - Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. AB - BACKGROUND: A recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising Ebola vaccine candidate. We report the results of an interim analysis of a trial of rVSV-ZEBOV in Guinea, west Africa. METHODS: For this open-label, cluster-randomised ring vaccination trial, suspected cases of Ebola virus disease in Basse-Guinee (Guinea, west Africa) were independently ascertained by Ebola response teams as part of a national surveillance system. After laboratory confirmation of a new case, clusters of all contacts and contacts of contacts were defined and randomly allocated 1:1 to immediate vaccination or delayed (21 days later) vaccination with rVSV-ZEBOV (one dose of 2 * 10(7) plaque-forming units, administered intramuscularly in the deltoid muscle). Adults (age >=18 years) who were not pregnant or breastfeeding were eligible for vaccination. Block randomisation was used, with randomly varying blocks, stratified by location (urban vs rural) and size of rings (<=20 vs >20 individuals). The study is open label and masking of participants and field teams to the time of vaccination is not possible, but Ebola response teams and laboratory workers were unaware of allocation to immediate or delayed vaccination. Taking into account the incubation period of the virus of about 10 days, the prespecified primary outcome was laboratory-confirmed Ebola virus disease with onset of symptoms at least 10 days after randomisation. The primary analysis was per protocol and compared the incidence of Ebola virus disease in eligible and vaccinated individuals in immediate vaccination clusters with the incidence in eligible individuals in delayed vaccination clusters. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193. FINDINGS: Between April 1, 2015, and July 20, 2015, 90 clusters, with a total population of 7651 people were included in the planned interim analysis. 48 of these clusters (4123 people) were randomly assigned to immediate vaccination with rVSV-ZEBOV, and 42 clusters (3528 people) were randomly assigned to delayed vaccination with rVSV-ZEBOV. In the immediate vaccination group, there were no cases of Ebola virus disease with symptom onset at least 10 days after randomisation, whereas in the delayed vaccination group there were 16 cases of Ebola virus disease from seven clusters, showing a vaccine efficacy of 100% (95% CI 74.7-100.0; p=0.0036). No new cases of Ebola virus disease were diagnosed in vaccinees from the immediate or delayed groups from 6 days post-vaccination. At the cluster level, with the inclusion of all eligible adults, vaccine effectiveness was 75.1% (95% CI -7.1 to 94.2; p=0.1791), and 76.3% (95% CI -15.5 to 95.1; p=0.3351) with the inclusion of everyone (eligible or not eligible for vaccination). 43 serious adverse events were reported; one serious adverse event was judged to be causally related to vaccination (a febrile episode in a vaccinated participant, which resolved without sequelae). Assessment of serious adverse events is ongoing. INTERPRETATION: The results of this interim analysis indicate that rVSV-ZEBOV might be highly efficacious and safe in preventing Ebola virus disease, and is most likely effective at the population level when delivered during an Ebola virus disease outbreak via a ring vaccination strategy. FUNDING: WHO, with support from the Wellcome Trust (UK); Medecins Sans Frontieres; the Norwegian Ministry of Foreign Affairs through the Research Council of Norway; and the Canadian Government through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre, and Department of Foreign Affairs, Trade and Development. PMID- 26248679 TI - Detection of attempted movement from the EEG during neuromuscular block: proof of principle study in awake volunteers. AB - Brain-Computer Interfaces (BCIs) have the potential to detect intraoperative awareness during general anaesthesia. Traditionally, BCI research is aimed at establishing or improving communication and control for patients with permanent paralysis. Patients experiencing intraoperative awareness also lack the means to communicate after administration of a neuromuscular blocker, but may attempt to move. This study evaluates the principle of detecting attempted movements from the electroencephalogram (EEG) during local temporary neuromuscular blockade. EEG was obtained from four healthy volunteers making 3-second hand movements, both before and after local administration of rocuronium in one isolated forearm. Using offline classification analysis we investigated whether the attempted movements the participants made during paralysis could be distinguished from the periods when they did not move or attempt to move. Attempted movement trials were correctly identified in 81 (68-94)% (mean (95% CI)) and 84 (74-93)% of the cases using 30 and 9 EEG channels, respectively. Similar accuracies were obtained when training the classifier on the participants' actual movements. These results provide proof of the principle that a BCI can detect movement attempts during neuromuscular blockade. Based on this, in the future a BCI may serve as a communication channel between a patient under general anaesthesia and the anaesthesiologist. PMID- 26248681 TI - Benefit of Anticoagulation Therapy in Hyperthyroidism-Related Atrial Fibrillation. AB - BACKGROUND: Existing data on the risk of ischemic stroke in hyperthyroidism related atrial fibrillation (AF) and the impact of long-term anticoagulation in these patients, particularly those with self-limiting AF, remain inconclusive. HYPOTHESIS: Risk of stroke in hyperthyroidism-related AF is the same as nonhyperthyroid counterparts. METHODS: This was a single-center observational study of 9727 Chinese patients with nonvalvular AF from July 1997 to December 2011. Patients with AF diagnosed concomitantly with hyperthyroidism were identified. Primary and secondary endpoints were defined as hospitalization with ischemic stroke and intracranial hemorrhage in the first 2 years. Patient characteristics, duration of AF, and choice of antithrombotic therapy were recorded. Self-limiting AF was defined as <7 days' duration. RESULTS: Out of 9727 patients, 642 (6.6%) had concomitant hyperthyroidism and AF at diagnosis. For stroke prevention, 136 and 243 patients (21.1% and 37.9%) were prescribed warfarin and aspirin, respectively, whereas the remaining patients (41.0%) received no therapy. Ischemic stroke occurred in 50 patients (7.8%), and no patient developed hemorrhagic stroke. Patients with CHA2 DS2 -VASc of 0 did not develop stroke. Warfarin effectively reduced the incidence of stroke compared with aspirin or no therapy in patients with CHA2 DS2 -VASc >=1 and non-self limiting AF, but not in those with self-limiting AF or CHA2 DS2 -VASc of 0. Presence of hyperthyroidism did not confer additional risk of ischemic stroke compared with nonhyperthyroid AF. CONCLUSIONS: Patients with hyperthyroidism related AF are at high risk of stroke (3.9% per year). Warfarin confers stroke prevention in patients with CHA2 DS2 -VASc >=1 and non-self-limiting AF. Overall stroke risk was lower in hyperthyroid non-self-limiting AF patients compared with nonhyperthyroid counterparts. PMID- 26248680 TI - Different downstream signalling of CCK1 receptors regulates distinct functions of CCK in pancreatic beta cells. AB - BACKGROUND AND PURPOSE: Cholecystokinin (CCK) is secreted by intestinal I cells and regulates important metabolic functions. In pancreatic islets, CCK controls beta cell functions primarily through CCK1 receptors, but the signalling pathways downstream of these receptors in pancreatic beta cells are not well defined. EXPERIMENTAL APPROACH: Apoptosis in pancreatic beta cell apoptosis was evaluated using Hoechst-33342 staining, TUNEL assays and Annexin-V-FITC/PI staining. Insulin secretion and second messenger production were monitored using ELISAs. Protein and phospho-protein levels were determined by Western blotting. A glucose tolerance test was carried out to examine the functions of CCK-8s in streptozotocin-induced diabetic mice. KEY RESULTS: The sulfated carboxy-terminal octapeptide CCK26-33 amide (CCK-8s) activated CCK1 receptors and induced accumulation of both IP3 and cAMP. Whereas Gq -PLC-IP3 signalling was required for the CCK-8s-induced insulin secretion under low-glucose conditions, Gs PKA/Epac signalling contributed more strongly to the CCK-8s-mediated insulin secretion in high-glucose conditions. CCK-8s also promoted formation of the CCK1 receptor/beta-arrestin-1 complex in pancreatic beta cells. Using beta-arrestin-1 knockout mice, we demonstrated that beta-arrestin-1 is a key mediator of both CCK 8s-mediated insulin secretion and of its the protective effect against apoptosis in pancreatic beta cells. The anti-apoptotic effects of beta-arrestin-1 occurred through cytoplasmic late-phase ERK activation, which activates the 90-kDa ribosomal S6 kinase-phospho-Bcl-2-family protein pathway. CONCLUSIONS AND IMPLICATIONS: Knowledge of different CCK1 receptor-activated downstream signalling pathways in the regulation of distinct functions of pancreatic beta cells could be used to identify biased CCK1 receptor ligands for the development of new anti-diabetic drugs. PMID- 26248683 TI - Re: Laparoscopic Mitrofanoff procedure in children: Critical analysis of difficulties and benefits. Blanc T, Muller C, Pons M, Pashootan P, Paye-Jaouen A, El Ghoneimi A. J Pediatr Urol 2015;11, 28.e1-8. PMID- 26248682 TI - Proinflammatory genotype is associated with the frailty phenotype in the English Longitudinal Study of Ageing. AB - BACKGROUND: Frailty is a state of increased vulnerability to poor resolution of homeostasis after a stressor event, which increases the risk of adverse outcomes including falls, disability and death. The underlying pathophysiological pathways of frailty are not known but the hypothalamic-pituitary-adrenal axis and heightened chronic systemic inflammation appear to be major contributors. METHODS: We used the English Longitudinal Study of Ageing dataset of 3160 individuals over the age of 50 and assessed their frailty status according to the Fried-criteria. We selected single nucleotide polymorphisms in genes involved in the steroid hormone or inflammatory pathways and performed linear association analysis using age and sex as covariates. To support the biological plausibility of any genetic associations, we selected biomarker levels for further analyses to act as potential endophenotypes of our chosen genetic loci. RESULTS: The strongest association with frailty was observed in the Tumor Necrosis Factor (TNF) (rs1800629, P = 0.001198, beta = 0.0894) and the Protein Tyrosine Phosphatase, Receptor type, J (PTPRJ) (rs1566729, P = 0.001372, beta = 0.09397) genes. Rs1800629 was significantly associated with decreased levels of high density lipoprotein (HDL) (P = 0.00949) and cholesterol levels (P = 0.00315), whereas rs1566729 was associated with increased levels of HDL (P = 0.01943). After correcting for multiple testing none of the associations remained significant. CONCLUSIONS: We provide potential evidence for the involvement of a multifunctional proinflammatory cytokine gene (TNF) in the frailty phenotype. The implication of this gene is further supported by association with the endophenotype biomarker results. PMID- 26248684 TI - Re: Laparoscopic Mitrofanoff procedure in children, surgery alone is not effective for the treatment of bladder dysfunction. PMID- 26248685 TI - The GOLD ReGISTry: a Global, Prospective, Observational Registry Collecting Longitudinal Data on Patients with Advanced and Localised Gastrointestinal Stromal Tumours. AB - BACKGROUND: Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal sarcomas. This global, prospective registry followed patients with advanced or localised GIST (2007-2011). METHODS: Current and evolving diagnostics, treatments and outcome measures in patients with GIST were assessed. Eligible patients were diagnosed with advanced or localised GIST within 15months of registry entry. No treatment plan was prescribed, and no visit schedule was mandated. Treating physicians recorded patient information, including tumour response, diagnostic methods, medications, surgeries performed, mutation status and adverse events leading to dose/medication changes. Survival outcomes were estimated using the Kaplan-Meier method. Other data were analysed using descriptive statistics. RESULTS: The registry included 1663 patients (advanced GIST, n=1095; localised GIST, n=537). Medications (e.g. tyrosine kinase inhibitor use and dosing), disease progression or recurrence and physician assessment of response to treatment in registry patients were consistent with controlled trials and prevailing clinical recommendations. In advanced GIST, estimated 30-month progression-free survival (PFS) (59.8%) and overall survival (OS) (82.7%) were higher than results from previously reported trials (~40% and ~70%, respectively). Consistent with treatment guidelines, the most common initial treatments were imatinib for advanced GIST, and complete surgical resection for localised GIST. Computed tomography scans were the most common imaging technique used at diagnosis and follow-up. Mutation analysis was performed at diagnosis in only 15.3% and 14.5% of patients with advanced and localised GIST, respectively. CONCLUSIONS: In this real-world GIST registry, patients with advanced GIST were treated with imatinib and patients with localised GIST received surgical resection, in accordance with prevailing clinical recommendations. PMID- 26248686 TI - Novel and known genetic variants for male breast cancer risk at 8q24.21, 9p21.3, 11q13.3 and 14q24.1: results from a multicenter study in Italy. AB - Increasing evidence indicates that common genetic variants may contribute to the heritable risk of breast cancer (BC). In this study, we investigated whether single nucleotide polymorphisms (SNPs), within the 8q24.21 multi-cancer susceptibility region and within BC-associated loci widespread in the genome, may influence the risk of BC in men, and whether they may be associated with specific clinical-pathologic characteristics of male BC (MBC). In the frame of the ongoing Italian Multicenter Study on MBC, we performed a case-control study on 386 MBC cases, including 50 BRCA1/2 mutation carriers, and 1105 healthy male controls, including 197 unaffected BRCA1/2 mutation carriers. All 1491 subjects were genotyped by Sequenom iPLEX technology for a total of 29 susceptibility SNPs. By logistic regression models, we found a significant association with MBC risk for five SNPs: rs1562430 (p=0.002) and rs445114 (p=0.026) both within the 8q24.21 region; rs1011970/9p21.3 (p=0.011), rs614367/11q13.3 (p=0.016) and rs1314913/14q24.1 (p<0.0001). Differences in the distribution of rs614367/11q13.3 genotypes according to oestrogen receptor (ER) status (p=0.006), and of rs1011970/9p21.3 genotypes according to human epidermal growth factor receptor 2 (HER2) status (p=0.002) emerged. Association of rs1011970/9p21.3 risk genotype with HER2+MBC was confirmed by a multivariate analysis. rs1314913/14q24.1 was associated with increased MBC risk in analyses restricted to male BRCA1/2 mutation carriers (p=0.041). In conclusion, we provided the first evidence that the 8q24.21 region is associated with MBC risk. Furthermore, we showed that the SNPs rs1562430/8q24.21 and rs1314913/14q24.1 strongly influence BC risk in men and suggested that the SNP rs1314913/14q24.1 may act as a risk modifier locus in male BRCA1/2 mutation carriers. PMID- 26248687 TI - Debunking the pyramidal mind: A plea for synergy between reason and emotion. PMID- 26248688 TI - The Role of Allostery in the Termination of Second Messenger Signaling. PMID- 26248689 TI - A genome-wide survey reveals abundant rice blast R genes in resistant cultivars. AB - Plant resistance genes (R genes) harbor tremendous allelic diversity, constituting a robust immune system effective against microbial pathogens. Nevertheless, few functional R genes have been identified for even the best studied pathosystems. Does this limited repertoire reflect specificity, with most R genes having been defeated by former pests, or do plants harbor a rich diversity of functional R genes, the composite behavior of which is yet to be characterized? Here, we survey 332 NBS-LRR genes cloned from five resistant Oryza sativa (rice) cultivars for their ability to confer recognition of 12 rice blast isolates when transformed into susceptible cultivars. Our survey reveals that 48.5% of the 132 NBS-LRR loci tested contain functional rice blast R genes, with most R genes deriving from multi-copy clades containing especially diversified loci. Each R gene recognized, on average, 2.42 of the 12 isolates screened. The abundant R genes identified in resistant genomes provide extraordinary redundancy in the ability of host genotypes to recognize particular isolates. If the same is true for other pathogens, many extant NBS-LRR genes retain functionality. Our success at identifying rice blast R genes also validates a highly efficient cloning and screening strategy. PMID- 26248690 TI - Paraneoplastic neurological syndrome due to burned-out testicular tumor showing hot cross-bun sign. AB - BACKGROUND: Paraneoplastic neurological syndromes (PNS) are rare remote effect of cancer. The antibodies and tumors associated with PNS have been well described, but there are still many clinically suspected cases in which no tumor or antibody can be identified. This is the first report of PNS showing hot cross-bun sign and caused by exceptionally rare underlying malignancy, such as burned-out testicular tumor. CASE PRESENTATION: A 42-year-old man presented subacute progression of hearing loss and cerebellar ataxia. Cerebrospinal fluid showed continuous inflammation and magnetic resonance imaging (MRI) revealed cerebellar atrophy and hot cross-bun sign. Resection of tumors improved both laboratory findings and neurological signs and their pathology was seminoma. CONCLUSION: Seminoma can cause PNS showing 8th cranial nerve palsy, cerebellar, and brainstem atrophy with hot cross-bun sign on MRI study. Extensive screening for onconeural antibodies was negative and thereby suggested that unknown antibodies worked for both antitumor immunity and induction of PNS. PMID- 26248692 TI - Anti-dengue virus serotype 2 activity and mode of action of a novel peptide. AB - AIM: To identify a novel antiviral peptide against dengue virus serotype 2 (DENV 2) by screening a phage display peptide library and to evaluate its in vitro antiviral activity and mode of action. METHODS AND RESULTS: A phage display peptide library was biopanned against purified DENV-2 and resulted in the identification and selection of a peptide (peptide gg-ww) for further investigation. ELISA was performed, and peptide gg-ww was shown to possess the highest binding affinity against DENV-2. Thus, peptide gg-ww was synthesized for cytotoxicity and antiviral assays. Virus plaque reduction assay, real-time PCR and immunofluorescence assay were used to investigate the inhibitory effect of peptide gg-ww on DENV-2 infection in Vero cells. Three different assays (pre-, simultaneous and post-treatments assays) were performed to investigate the peptide's mode of action. Results indicated that peptide gg-ww possessed strong antiviral activity with a ~96% inhibition rate, which was achieved at 250 MUmol l(-1) . Viral replication was inhibited during a simultaneous treatment assay, indicating that the entry of the virus was impeded by this peptide. CONCLUSIONS: Peptide gg-ww displayed antiviral action against DENV-2 by targeting an early stage of viral replication (i.e. during viral entry). SIGNIFICANCE AND IMPACT OF THE STUDY: Peptide gg-ww may represent a new therapeutic candidate for the treatment of DENV infections and is a potential candidate to be developed as a peptide drug. PMID- 26248691 TI - Accuracy of diagnosis codes to identify febrile young infants using administrative data. AB - BACKGROUND: Administrative data can be used to determine optimal management of febrile infants and aid clinical practice guideline development. OBJECTIVE: Determine the most accurate International Classification of Diseases, Ninth Revision (ICD-9) diagnosis coding strategies for identification of febrile infants. DESIGN: Retrospective cross-sectional study. SETTING: Eight emergency departments in the Pediatric Health Information System. PATIENTS: Infants aged <90 days evaluated between July 1, 2012 and June 30, 2013 were randomly selected for medical record review from 1 of 4 ICD-9 diagnosis code groups: (1) discharge diagnosis of fever, (2) admission diagnosis of fever without discharge diagnosis of fever, (3) discharge diagnosis of serious infection without diagnosis of fever, and (4) no diagnosis of fever or serious infection. EXPOSURE: The ICD-9 diagnosis code groups were compared in 4 case-identification algorithms to a reference standard of fever >=100.4 degrees F documented in the medical record. MEASUREMENTS: Algorithm predictive accuracy was measured using sensitivity, specificity, and negative and positive predictive values. RESULTS: Among 1790 medical records reviewed, 766 (42.8%) infants had fever. Discharge diagnosis of fever demonstrated high specificity (98.2%, 95% confidence interval [CI]: 97.8 98.6) but low sensitivity (53.2%, 95% CI: 50.0-56.4). A case-identification algorithm of admission or discharge diagnosis of fever exhibited higher sensitivity (71.1%, 95% CI: 68.2-74.0), similar specificity (97.7%, 95% CI: 97.3 98.1), and the highest positive predictive value (86.9%, 95% CI: 84.5-89.3). CONCLUSIONS: A case-identification strategy that includes admission or discharge diagnosis of fever should be considered for febrile infant studies using administrative data, though underclassification of patients is a potential limitation. PMID- 26248693 TI - Spin Crossover and Valence Tautomerism in Neutral Homoleptic Iron Complexes of Bis(pyridylimino)isoindolines. AB - Homoleptic iron complexes of six bis(pyridylimino)isoindoline (bpi) ligands with different substituents (H, Me, Et, tBu, OMe, NMe2) at the 4-positions of the pyridine moieties have been prepared and studied with regard to temperature dependent spin and redox states by a combination of (57)Fe Mossbauer spectroscopy, SQUID magnetometry, single-crystal X-ray diffraction analysis, X band EPR, and (1)H NMR spectroscopy. While the H-, methyl-, and ethyl-substituted complexes remain in a pure high-spin state irrespective of the temperature, the 4 tert-butyl-substituted derivative shows spin-crossover behavior. The methoxy- and dimethylamino-substituted compounds were found to easily undergo oxidation. In the crystalline state, valence tautomeric behavior was observed for the methoxy derivative as a thermally activated charge-transfer transition, accompanied by a spin crossover above 200 K. The valence tautomerism leads to a chelate with one of the bpi ligands as a dianion radical L(2-.) and with an effective spin of S=2. PMID- 26248694 TI - [The Family and Communitary Medicine goes to University]. PMID- 26248695 TI - Assessment of pharmacokinetic interaction between piracetam and l-carnitine in healthy subjects. AB - A rapid, sensitive and specific method for quantifying piracetam in human plasma using Piracetam d-8 as the internal standard (IS) is described. The analyte and the IS were extracted from plasma by one-step precipitation of protein using an acetonitrile (100%). The extracts were analyzed by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS/MS). The method had a chromatographic run time of 3.8 min and a linear calibration curve over the range 0.5-50 ug/mL (r > 0.99). This LC-MS-MS procedure was used to assess the bioavailability of two piracetam formulations: piracetam + l-carnitine (Piracar(r); 270/330 mg tablet) and piracetam (Nootropil(r); 800 mg tablet) in healthy volunteers of both sexes. The geometric means with corresponding 90% confidence interval (CI) for test/reference percentage ratios were 88.49% (90% CI = 81.19 - 96.46) for peak concentration/dose and 102.55% (90% CI = 100.62 - 104.51) for AUCinf /dose. The limit of quantitation of 0.5 ug/mL is well suited for pharmacokinetic studies in healthy volunteers. It was concluded that piracetam (Piracar(r); 270/330 mg tablet) has a bioavailability equivalent to the piracetam (Nootropil(r); 800 mg tablet) formulation with regard to both the rate and the extent of absorption. PMID- 26248696 TI - Treatment of Childhood T-Cell Lymphoblastic Lymphoma-Long-Term Results of the SFOP LMT96 Trial. AB - PURPOSE: Outcome of T-cell lymphoblastic lymphoma (T-LBL) in children is around 75-85% of event-free survival. The role of early intensification to improve outcome while using short infusions of high dose methotrexate (HDMTX) and shorter maintenance treatment was addressed by the French Society of Pediatric Oncology (SFOP) group. METHODS: From 1997 through 2003, 79 children (52 males; median age 10.5 years) were prospectively registered into the SFOP LMT 96 trial. The LMT96 protocol, with elements from the protocol of the Berlin-Frankfurt-Munster (BFM) Group included four main modifications: (a) 10 courses of HD-MTX (3 g/m(2) ) delivered over the first 44 weeks; (b) early intensification with cyclophosphamide together with the first course of HD-MTX; (c) a maintenance phase that included 6 monthly intensified chemotherapy pulses; and (d) treatment duration of 18 months for stages I-III. RESULTS: Eighty-nine percent of patients had an initial mediastinal involvement. With a median follow-up of 87 months, the 5-year event-free survival was 85% and overall survival 89%. Nine patients relapsed, eight during treatment. The early intensification did not change the pattern of relapses. Only 58% of patients experienced grade 3-4 neutropenia during the induction phase, 13% patients experienced grade 3 and 4 mucositis, and 5% patients experienced diabetes. The early intensification did not delay phases of chemotherapy. CONCLUSIONS: Early intensification in treatment for T-LBL in children is manageable. Three-hour infusion of HD-MTX did not jeopardize patient outcome. Our results are comparable with those of other international protocols in spite of shorter maintenance treatment for stages I-III. PMID- 26248697 TI - A Study of Myometrial Growth and Development. AB - STUDY OBJECTIVE: To evaluate myometrial growth and development. DESIGN: Thirty five autopsy uteri, ranging from 10 weeks' gestation to age 18 years, acquired over 3 decades from 2 hospitals, were studied based on specimen availability, photographed for documentation, and reviewed at the end of the study. Most were embedded in toto, with 1 block and 1 slide per case. Some were immunostained for actin, CD10, MIB-1, and/or trichrome stain for collagen and muscle. Myometrial thickness was measured by ocular micrometry when sections were nontangential and analyzed by paired-sample t tests and bivariate linear regression. SETTING: Two university-affiliated hospitals. RESULTS: From 20 to 34 weeks, lateral wall corpus thickness increased 6-fold, with a 4- to 6-fold perinatal burst of growth (P < .01) and a drop in thickness after the neonatal period (P = .013). The corpus was thicker than the dome (P < .01) but less thick than the lower uterine segment (P = .087). The lower uterine segment was fully muscular in the second trimester, becoming more fibrous near term. Intramural, subserosal, and inframucosal myometaplasia were observed, as primitive stromal cells turned into muscle cells. Myometrial proliferation was brisk in the second trimester but greatly diminished in the perinatal period. Pressure effects from myometrial tone were observed during development. There was a pubertal burst of inframucosal myometaplasia. CONCLUSIONS: Myometaplasia accounted for most myometrial growth, especially in the perinatal and pubertal bursts of growth. Pressure effects, related to myometrial tone, appeared to affect myometrial development. True endocervix, with a fibrous wall and mucinous epithelium, appeared late in development. PMID- 26248698 TI - Reconstruction for Type IV Radial Polydactyly. AB - Type IV radial polydactyly represents a thumb with an extra proximal and distal phalanx. Assessment of the thumb for surgical reconstruction includes observing thumb function, evaluating thumb size and stability, and assessing the first web space. Reconstruction includes excision of the smaller thumb, typically the radial thumb, and re-creating thumb stability and alignment by addressing tendon insertion and joint orientation. Although surgical results are satisfying and complications are uncommon, additional surgical intervention may be required over time owing to thumb malalignment or instability. PMID- 26248700 TI - Dermoscopy of Darier's disease. PMID- 26248699 TI - Impact of Joint Position and Joint Morphology on Assessment of Thumb Metacarpophalangeal Joint Radial Collateral Ligament Integrity. AB - PURPOSE: A 2-part biomechanical study was constructed to test the hypothesis that coronal morphology of the thumb metacarpophalangeal joint impacts the assessment of instability in the context of radial collateral ligament (RCL) injury. METHODS: Fourteen cadaveric thumbs were disarticulated at the carpometacarpal joint. Four observers measured the radius of curvature of the metacarpal (MC) heads. In a custom jig, a micrometer was used to measure the RCL length as each thumb was put through a flexion and/or extension arc under a 200 g ulnar deviation load. Strain was calculated at maximal hyperextension, 0 degrees , 15 degrees , 30 degrees , 45 degrees , and maximal flexion. Radial instability was measured with a goniometer under 45 N stress. The RCL was then divided and measurements were repeated. Analysis of variance and Pearson correlation metrics were used. RESULTS: The RCL strain notably increased from 0 degrees to 30 degrees and 45 degrees of flexion. With an intact RCL, the radial deviation was 15 degrees at 0 degrees of flexion, 18 degrees at 15 degrees , 17 degrees at 30 degrees , 16 degrees at 45 degrees , and 14 degrees at maximal flexion. With a divided RCL, instability was greatest at 30 degrees of flexion with 31 degrees of deviation. The mean radius of curvature of the MC head was 19 +/- 4 mm. Radial instability was inversely correlated with the radius of curvature to a considerable degree only in divided RCL specimens, and only at 0 degrees and 15 degrees of flexion. CONCLUSIONS: The RCL contributes most to the radial stability of the joint at flexion positions greater than 30 degrees . The results suggest that flatter MC heads contribute to stability when the RCL is ruptured and the joint is tested at 0 degrees to 15 degrees of metacarpophalangeal flexion. CLINICAL RELEVANCE: The thumb MC joint should be examined for RCL instability in at least 30 degrees of flexion. PMID- 26248701 TI - Crystalline fibrillar gel formation in aqueous surfactant-antioxidant system. AB - Cetyltrimethylammonium bromide (CTAB) is a well-known cationic surfactant capable to micellize into diverse morphologies in aqueous medium. We observed the formation of an opaque gel state from aqueous CTAB solution in the presence of the aromatic additive, para-coumaric acid (PCA). Optical microscopic images revealed the presence of large fibrils in the system at room temperature. Gel nature of the fibrils was confirmed by rheological measurements. Presence of interstitial water in the fibrils was recognized with Raman spectroscopy. On heating the sample above 30 ( degrees ) C, the fibrillar gel state changes to a transparent liquid state with Newtonian flow properties. Dynamic light scattering study hinted the presence of small micelles in the solution above 30 ( degrees ) C. Thus the system showed a temperature-dependent structural transition from opaque water-swollen gel to transparent micellar liquid. The formation of water swollen fibrillar network is attributed to surfactant-additive intermolecular interactions in aqueous medium. Transition to micelle phase above 30 ( degrees ) C is related to Kraft transition which is observed at significantly lower temperature for CTAB in the absence of PCA. The structural features of PCA play a key role in promoting fibrillar network formation and elevating the Kraft transition in aqueous solution of CTAB. PMID- 26248704 TI - Retroperitoneal catecholamine-producing ganglioneuroma with a birth history of monozygotic twins who both suffered from neuroblastoma during their childhoods: a case report with genome analysis. PMID- 26248703 TI - Topology of desiccation crack patterns in clay and invariance of crack interface area with thickness. AB - We study the crack patterns developed on desiccating films of suspensions of three different clays-bentonite, halloysite nanoclay and laponite on a glass substrate. Varying the thickness of the layer, h gives the following new and interesting results: i) We can identify a critical thickness h c for bentonite and halloysite, above which isolated cracks join each other to form a fully connected network. ii) A topological analysis involving the Euler number is shown to be useful for characterising the patterns. iii) We find, further, that the total vertical surface area of the clay A v, which has opened up due to cracking, and the total area of the glass substrate A s, exposed by the hierarchical sequence of cracks are constant, independent of the layer thickness for a certain range of h. These results are shown to be consistent with a simple energy conservation argument, neglecting dissipative losses. Finally we show that if the crack pattern is viewed at successively finer resolution, the total cumulative area of cracks visible at a certain resolution scales with the layer thickness. PMID- 26248705 TI - CT and MRI findings and follow-up after massive nitrobenzene ingestion. A case report. PMID- 26248702 TI - Computational study of remodeling in a nucleosomal array. AB - Chromatin remodeling complexes utilize the energy of ATP hydrolysis to change the packing state of chromatin, e.g. by catalysing the sliding of nucleosomes along DNA. Here we present simple models to describe experimental data of changes in DNA accessibility along a synthetic, repetitive array of nucleosomes during remodeling by the ACF enzyme or its isolated ATPase subunit, ISWI. We find substantial qualitative differences between the remodeling activities of ISWI and ACF. To understand better the observed behavior for the ACF remodeler, we study more microscopic models of nucleosomal arrays. PMID- 26248706 TI - [Laboratory coagulation tests in patients treated by direct oral anticoagulants (DOACs)]. AB - Routine clotting time assays (Prothrombin Time/INR, activated Partial Thromboplastin Time [aPTT]) are prolonged at variable extent by direct oral anticoagulants (DOAC), according to the assay, the reagent and the type of DOAC. These assays are not reliable for monitoring the intensity of treatment and the measurement of the plasma level of the DOAC is usually not required. At high concentrations, DOAC interfere with the routine clotting assays, making them difficult to interpret. In critical situations such as major bleeding or urgent invasive procedure, the measurement of DOAC level and its kinetics are simple and useful to manage the patient. PMID- 26248707 TI - [Hypertensive emergencies and urgencies]. AB - Hypertension is a common disease, the most common chronic disease. Hypertensive emergency is much less frequent and only affects 1 to 2 % of all hypertensive patients. The true hypertensive emergency is characterized by the serious damage of one hypertensive target organ and requires an urgent intravenous treatment. Isolated blood pressure elevation should not be regarded as a hypertensive emergency if there is no target organ damage, even if the blood pressure is very high. These situations of "false hypertensive emergency", or hypertensive urgencies, often requires an immediate treatment, but oral. Signs of visceral pain of true hypertensive emergency often are a poor general condition, severe headache, decreased visual acuity, neurological deficit of ischemic or hemorrhagic cause, confusion, dyspnea with orthopnoea revealing heart failure, angina, chest pain revealing an aortic dissection, proteinuria, acute renal failure or eclampsia. True hypertensive emergencies include several entities, namely: severe hypertension, malignant hypertension and accelerated hypertension. If malignant hypertension is not treated, the prognosis is poor with 50 % death risk in the following year. PMID- 26248708 TI - [Treatable neurometabolic diseases. Association with schizophrenia spectrum disorders]. AB - Schizophrenia spectrum disorders are presented on 1% of subjects over general population. Organic pathologies prevalence in schizophrenia spectrum patients is not well determined, and it is probably underestimated. In the present update review, we are going to highlight seven treatable neurometabolic diseases (NMD) associated to sub-clinic neurological symptoms. It is not infrequent to witness the absence of any clinical neurological signs going along with the NMD. Psychiatric symptoms may be the only clinical alarm that can guide physicians to an acute diagnosis. This is why it is a challenging pathology, defying our clinical accuracy as psychiatrist or any other practitioners confronted to this population. Hereby we are going to expose a literature review and comprehensive tables in order to present in a glance the essential clinical features of disorders of homocysteine metabolism, urea cycle disorders, Niemann-Pick disease type C, acute porphyria, cerebrotendinous-xanthomatosis. These conditions are sensible to major improvement strongly correlated to the accuracy of diagnosis. Literature analysis led us to propose a comprehensive list of atypical psychiatric symptoms including highly predominant visual hallucinations, compared to auditory ones, as well as confusion, catatonia or progressive cognitive decline. We highlight the importance of considering antipsychotic treatment resistance as a crucial sign leading to suspect an organic factor beneath the psychiatric features. PMID- 26248709 TI - [Cardiovascular risk in ankylosing spondylitis]. AB - An increased cardiovascular risk has been consistently reported in inflammatory rheumatic diseases. An important number of studies found the same higher cardiovascular risk in rheumatoid arthritis and systemic lupus erythematosus. On the contrary, the presence of this increase cardiac risk is less documented in ankylosing spondylitis (AS) with some contradictory information in the studies. This review aims to report the current data in 2014 on the high cardiovascular risk in AS, the prevalence of cardiovascular risk factors in this rheumatic disease, the cardiovascular effects of treatment and the guidelines for cardiovascular risk management. PMID- 26248710 TI - Host genetic resistance to root-knot nematodes, Meloidogyne spp., in Solanaceae: from genes to the field. AB - Root-knot nematodes (RKNs) heavily damage most solanaceous crops worldwide. Fortunately, major resistance genes are available in a number of plant species, and their use provides a safe and economically relevant strategy for RKN control. From a structural point of view, these genes often harbour NBS-LRR motifs (i.e. a nucleotide binding site and a leucine rich repeat region near the carboxy terminus) and are organised in syntenic clusters in solanaceous genomes. Their introgression from wild to cultivated plants remains a challenge for breeders, although facilitated by marker-assisted selection. As shown with other pathosystems, the genetic background into which the resistance genes are introgressed is of prime importance to both the expression of the resistance and its durability, as exemplified by the recent discovery of quantitative trait loci conferring quantitative resistance to RKNs in pepper. The deployment of resistance genes at a large scale may result in the emergence and spread of virulent nematode populations able to overcome them, as already reported in tomato and pepper. Therefore, careful management of the resistance genes available in solanaceous crops is crucial to avoid significant reduction in the duration of RKN genetic control in the field. From that perspective, only rational management combining breeding and cultivation practices will allow the design and implementation of innovative, sustainable crop production systems that protect the resistance genes and maintain their durability. PMID- 26248712 TI - Estimated herd prevalence and sequence types of Coxiella burnetii in bulk tank milk samples from commercial dairies in Indiana. AB - BACKGROUND: Coxiella burnetii is the etiologic agent of Q fever, a zoonotic disease causing influenza-like illness, pregnancy loss, cardiovascular disease and chronic fatigue syndrome in people. C. burnetii is considered to be enzootic in ruminants, but clinical signs of infection do not always manifest. National studies have documented the presence of C. burnetii in dairy herds in Indiana. This represents an opportunity to better characterize the distribution and prevalence of C. burnetii infection at the state scale, allowing evaluation of the need for surveillance and response planning to occur at this level. A cross sectional study was conducted to estimate the herd prevalence of C. burnetii in commercial cattle dairies in Indiana and characterize the strains of C. burnetii within these dairies. RESULTS: Bulk tank milk samples were collected between June and August of 2011 by the Indiana State Board of Animal Health (ISBOAH). A total of 316 of these samples were tested for the IS1111 transposon of C. burnetii using quantitative real time polymerase chain reaction (PCR). Single nucleotide polymorphism (SNP) genotyping was used to identify the multispacer sequence genotypes (ST) present in samples where the IS1111 transposon was identified. The geographic distribution of dairies testing positive for C. burnetii DNA and the identified STs were also evaluated. The estimated overall herd prevalence for C. burnetii DNA was 61.1 % (95 % CI 55.6-66.3 %). The highest estimated regional prevalence was 70.2 % in the Central region of Indiana. An ST was identifiable in 74 of the positive 178 samples (41.6 %) and none of the 10 negative samples tested. Of these samples, 71 (95.9 %) were identified as ST20, 2 (2.7 %) as ST8 and a combination of ST20 and ST8 was identified in a single sample. CONCLUSIONS: C. burnetii is present in dairy herds throughout Indiana. Indiana follows national trends with ST20 most commonly identified. The presence of multiple STs in a single bulk tank sample indicates that multiple strains of C. burnetii can circulate within a herd. This supports potential transmission of C. burnetii between goats and cattle, presenting the potential for a switch in the dominant genotype found in a given species. PMID- 26248713 TI - Synthesis and Analgesic Activity of Annelated Xanthine Derivatives in Experimental Models in Rodents. AB - A series of annelated derivatives of xanthine were synthesized and assayed as potential analgesic agents. All synthesized xanthine derivatives were tested in the writhing test and hot-plate test. The pharmacological assays demonstrated that all the compounds prepared, without exception, displayed a significant activity in the mouse writhing assay. The analgesic action of the most active compounds, expressed as ED50 was found to be 1.4-4.3 times more potent than that of acetylsalicylic acid used as the reference compound. However, only some of the compounds demonstrated analgesic activity in the hot-plate test. The analgesic effect of some compounds is probably related to their agonistic, antagonistic, or partial agonistic activity at the adenosine receptors. PMID- 26248714 TI - Classification and regression tree analysis vs. multivariable linear and logistic regression methods as statistical tools for studying haemophilia. AB - INTRODUCTION: Haemophilia is a rare genetic haemorrhagic disease characterized by partial or complete deficiency of coagulation factor VIII, for haemophilia A, or IX, for haemophilia B. As in any other medical research domain, the field of haemophilia research is increasingly concerned with finding factors associated with binary or continuous outcomes through multivariable models. Traditional models include multiple logistic regressions, for binary outcomes, and multiple linear regressions for continuous outcomes. Yet these regression models are at times difficult to implement, especially for non-statisticians, and can be difficult to interpret. AIMS: The present paper sought to didactically explain how, why, and when to use classification and regression tree (CART) analysis for haemophilia research. MATERIALS & METHODS: The CART method is non-parametric and non-linear, based on the repeated partitioning of a sample into subgroups based on a certain criterion. Breiman developed this method in 1984. Classification trees (CTs) are used to analyse categorical outcomes and regression trees (RTs) to analyse continuous ones. RESULTS: The CART methodology has become increasingly popular in the medical field, yet only a few examples of studies using this methodology specifically in haemophilia have to date been published. Two examples using CART analysis and previously published in this field are didactically explained in details. CONCLUSION: There is increasing interest in using CART analysis in the health domain, primarily due to its ease of implementation, use, and interpretation, thus facilitating medical decision-making. This method should be promoted for analysing continuous or categorical outcomes in haemophilia, when applicable. PMID- 26248715 TI - Smartphone Image Acquisition During Postmortem Monocular Indirect Ophthalmoscopy. AB - The medical usefulness of smartphones continues to evolve as third-party applications exploit and expand on the smartphones' interface and capabilities. This technical report describes smartphone still-image capture techniques and video-sequence recording capabilities during postmortem monocular indirect ophthalmoscopy. Using these devices and techniques, practitioners can create photographic documentation of fundal findings, clinically and at autopsy, without the expense of a retinal camera. Smartphone image acquisition of fundal abnormalities can promote ophthalmological telemedicine--especially in regions or countries with limited resources--and facilitate prompt, accurate, and unbiased documentation of retinal hemorrhages in infants and young children. PMID- 26248716 TI - Introduction: Uremic Toxicity - State of the Art 2014. PMID- 26248717 TI - The Saga of Two Centuries of Urea: Nontoxic Toxin or Vice Versa? AB - In the early 1700s, a substance ultimately identified as urea was reported for the first time in urine. About a century later, in 1828, synthesis of this organic compound was achieved, thus giving rise to modern organic chemistry. In parallel, physicians showed that urine comes from the kidneys and contains large amounts of urea, which is produced outside of the kidneys, establishing the humoral approach of renal physiology. Urea was the first uremic retention solute to be identified and it has been used as a marker of renal disease ever since. However, progress in the knowledge of urea metabolism has shown that it is susceptible to many extrarenal variations and, therefore, it cannot be a reliable marker of renal function. It reflects protein intake in the stable patient and has been used to assess nutrition and dialysis efficacy in renal patients. Although it has been studied for almost 200 years, its toxicity has been largely debated. An indirect toxicity occurring through carbamylation of lysine residues is now well established and some evidence from recent work also supports direct toxicity of urea, offering additional rationale for interventional prevention of uremic complications. PMID- 26248711 TI - Effect of cotrimoxazole prophylaxis on the incidence of malaria in HIV-infected children in 2012, in Abidjan, Cote d'Ivoire: a prospective cohort study. AB - BACKGROUND: Cotrimoxazole prophylaxis has an antimalarial effect which could have an additional protective effect against malaria in HIV-infected children on antiretroviral therapy (ART). We measured the incidence and associated factors of malaria in HIV-infected children on ART and/or cotrimoxazole in Abidjan, Cote d'Ivoire. METHODS: All HIV-infected children <16 years, followed-up in the IeDEA West-African paediatric cohort (pWADA) in Abidjan, were prospectively included from May to August 2012, the rainy season. Children presenting signs suggesting malaria had a thick blood smear and were classified as confirmed or probable malaria. We calculated incidence density rates (IR) per 100 child-years (CY). Risk factors were assessed using a Poisson regression model. RESULTS: Overall, 1117 children were included, of whom 89 % were ART-treated and 67 % received cotrimoxazole. Overall, there were 51 malaria events occurring in 48 children: 28 confirmed and 23 probable; 94 % were uncomplicated malaria. The overall IR of malaria (confirmed and probable) was 18.3/100 CY (95 % CI: 13.3-23.4), varying from 4.2/100 CY (95 % CI: 1.1-7.3) in children on ART and cotrimoxazole to 57.3/100 CY (95 % CI: 7.1-107.6) for those receiving no treatment at all. In univariate analysis, age < 5 years was significantly associated with a 2-fold IR of malaria compared to age >10 years (incidence rate ratio [IRR] = 2.18, 95 % CI: 1.04-4.58). Adjusted for severe immunodeficiency, cotrimoxazole reduced significantly the IR of first malarial episode (adjusted IRR [aIRR] = 0.13, 95 % CI: 0.02-0.69 and aIRR = 0.05, 95 % CI:0.02-0.18 in those off and on ART respectively). Severe immunodeficiency increased significantly the malaria IR (aIRR = 4.03, 95 % CI: 1.55-10.47). When considering the IR of confirmed malaria only, this varied from 2.4/100 CY (95 % CI: 0.0-4.8) in children on ART and cotrimoxazole to 34.4/100 CY (95 % CI: 0.0-73.3) for those receiving no treatment at all. In adjusted analyses, the IR of malaria in children on both cotrimoxazole and ART was significantly reduced (aIRR = 0.05, 95 % CI: 0.01-0.24) compared to those receiving no treatment at all. CONCLUSIONS: Cotrimoxazole prophylaxis was strongly protective against the incidence of malaria when associated with ART in HIV-infected children. Thus, these drugs should be provided as widely and durably as possible in all HIV-infected children <5 years of age. PMID- 26248718 TI - Subjective sleep quality and postconcussion symptoms following mild traumatic brain injury. AB - PRIMARY OBJECTIVE: The goal of this investigation is to examine the prevalence of poor subjective sleep in patients with a history of mild traumatic brain injury (mTBI) and examine the relationship between subjective sleep quality and postconcussive symptoms (PCS), above and beyond the typical demographic and psychological distress variables. RESEARCH DESIGN: Individuals with a history of mTBI completed online questionnaires. Regression analysis was utilized to determine if subjective sleep quality would predict PCS severity, above and beyond demographic variables and psychological distress. METHODS AND PROCEDURES: Individuals with a history of mTBI (n = 158) completed surveys online. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and PCS with the Neurobehavioral Symptom Inventory (NSI). Demographic information was collected and psychological distress was measured using the Brief Symptom Inventory-18 (BSI-18). MAIN OUTCOMES AND RESULTS: In this sample, 92% of patients with mTBI reported poor sleep. Sleep quality significantly accounted for the variance in PCS, above and beyond demographics, time since injury and psychological distress (p < 0.001), although only a small amount of the variance in PCS was explained. CONCLUSIONS: Results indicate that poor subjective sleep quality is a significant problem in those with mTBI. While sleep is associated with PCS severity, psychological distress is a more potent predictor. PMID- 26248719 TI - Psychosis, psychedelic substance misuse and head injury: A case report and 23 year follow-up. AB - BACKGROUND: This study describes the case of a 57 year old gentleman with a previous severe brain injury who developed a severe psychotic disorder 19 years after the injury. This appears to have been precipitated by heavy psychedelic substance use, including cannabis, salvia divinorum, ketamine, LSD, cocaine and DMT amongst others. The psychosis remained in the absence of drug intoxication and was associated with prominent apathy, lack of concern and abulia. CASE STUDY: This study discusses the heavy psychedelic substance misuse possibly potentiating a transition to psychosis in this individual. Little work has been undertaken in this area as substance misuse has traditionally been an exclusion criteria for investigating psychosis in this patient group. CONCLUSIONS: It is suggested that psychedelic substance misuse should be investigated as a risk factor for psychotic illness in patients with brain injury, as this case clearly suggests. PMID- 26248720 TI - Pilot feasibility of an mHealth system for conducting ecological momentary assessment of mood-related symptoms following traumatic brain injury. AB - OBJECTIVE: This study assessed pilot feasibility and validity of a mobile health (mHealth) system for tracking mood-related symptoms after traumatic brain injury (TBI). DESIGN: A prospective, repeated measures design was used to assess compliance with daily ecological momentary assessments (EMA) conducted via a smartphone application over an 8-week period. METHODS: An mHealth system was developed specifically for individuals with TBI and utilized previously validated tools for depressive and anxiety symptoms (Patient Health Questionnaire-9, Generalized Anxiety Disorder-7). Feasibility was assessed in 20 community dwelling adults with TBI via an assessment of compliance, satisfaction and usability of the smartphone applications. The authors also developed and implemented a clinical patient safety management mechanism for those endorsing suicidality. RESULTS: Participants correctly completed 73.4% of all scheduled assessments, demonstrating good compliance. Daily assessments took <2 minutes to complete. Participants reported high satisfaction with smartphone applications (6.3 of 7) and found them easy to use (6.2 of 7). Comparison of assessments obtained via telephone-based interview and EMA demonstrated high correlations (r = 0.81-0.97), supporting the validity of conducting these assessments via smartphone application in this population. CONCLUSIONS: EMA conducted via smartphone demonstrates initial feasibility among adults with TBI and presents numerous opportunities for long-term monitoring of mood-related symptoms in real world settings. PMID- 26248721 TI - Return-to-work challenges following a work-related mild TBI: The injured worker perspective. AB - PRIMARY OBJECTIVE: To explore how individuals with work-related mild traumatic brain injury (wrMTBI) experience return-to-work (RTW) processes when returning to the workplace where the injury occurred. DESIGN: RTW experiences were explored using in-depth interviews and an inductive analytic approach. Qualitative analysis guided by the research question moved through phases of line-by-line and thematic coding through which categories and the interaction between categories emerged. PARTICIPANTS: Twelve workers diagnosed with a wrMTBI reported on their RTW experiences following wrMTBIs that occurred 3-5 years prior to the time of the interview. MAIN OUTCOMES AND RESULTS: Participants perceived employer and workers' compensation factors as profoundly influencing their RTW experiences. Participants consistently reported that employers and workers' compensation representatives had an inadequate understanding of wrMTBI sequelae. Six of 12 participants were re-injured following their wrMTBI, with three of these injuries occurring at work. CONCLUSION: Employers, co-workers and workers' compensation representatives should be aware of wrMTBI sequelae so injured workers can receive appropriate supports and both stigmatization and re-injury can be mitigated. Greater attention to the structural and social elements of workplace and compensation environments could inform strategies to break down barriers to successful return-to-work following a wrMTBI. PMID- 26248722 TI - Optimization of affinity capillary electrophoresis for routine investigations of protein-metal ion interactions. AB - To facilitate the implementation of affinity capillary electrophoresis into routine binding screening studies of proteins with metal ions, method acceleration, transfer and precision improvement were investigated. Affinity capillary electrophoresis was accelerated by using shorter capillaries, employing lower sample concentrations and smaller injection volumes. Intra- and inter instrument method transfers were investigated considering the temperature setting of the capillary cooling system. For intra-instrument method transfer, similar results were obtained when transferring a method from a long (62 cm) to a short (31 cm) capillary. The analysis time was reduced from 9 to 4 min. In case of inter-instrument method transfer, interaction results showed small variation on the capillary electrophoresis instrument with inefficient capillary cooling system. Binding measurement precision was enhanced by slightly pushing the sample above the beginning of the capillary. Changing the buffer vials after each 30 runs and employing extra flushing after each 60 subsequent runs further enhanced the precision. The use of 0.1 molar ethylenediaminetetraacetic acid in the rinsing solution successfully desorbs the remaining metal ions from the capillary wall. Excellent precision for apparent mobility ratio measurements was achieved for different protein-metal ion interactions (relative standard deviation of 0.16 0.89%, 15 series, 12 runs for each). PMID- 26248723 TI - Inside the Black Box: The Case Review Process of an Elder Abuse Forensic Center. AB - OBJECTIVE: Preliminary evidence suggests that elder abuse forensic centers improve victim welfare by increasing necessary prosecutions and conservatorships and reducing the recurrence of protective service referrals. Center team members gather information and make decisions designed to protect clients and their assets, yet the collective process of how these case reviews are conducted remains unexamined. The purpose of this study is to present a model describing the interprofessional approach of investigation and response to financial exploitation (FE), a frequent and complex type of abuse of vulnerable adults. METHODS: To develop an understanding of the case review process at the Los Angeles County Elder Abuse Forensic Center (Center), a quasi-Delphi field study approach was used involving direct observations of meetings, surveying team members, and review from the Center's Advisory Council. The goal of this iterative analysis was to understand the case review process for suspected FE in Los Angeles County. RESULTS: A process map of key forensic center elements was developed that may be useful for replication in other settings. The process map includes: (a) multidisciplinary data collection, (b) key decisions for consideration, and (c) strategic actions utilized by an interprofessional team focused on elder justice. DISCUSSION: Elder justice relies on a complex system of providers. Elder abuse forensic centers provide a process designed to efficiently address client safety, client welfare, and protection of assets. Study findings provide a process map that may help other communities replicate an established multidisciplinary team, one experienced with justice system outcomes designed to protect FE victims. PMID- 26248724 TI - Severe hepatotoxicity associated with asunaprevir and daclatasvir in chronic hepatitis C. PMID- 26248725 TI - Topological and sequence information predict that foldons organize a partially overlapped and hierarchical structure. AB - It has been suggested that proteins have substructures, called foldons, which can cooperatively fold into the native structure. However, several prior investigations define foldons in various ways, citing different foldon characteristics, thereby making the concept of a foldon ambiguous. In this study, we perform a Go model simulation and analyze the characteristics of substructures that cooperatively fold into the native-like structure. Although some results do not agree well with the experimental evidence due to the simplicity of our coarse grained model, our results strongly suggest that cooperatively folding units sometimes organize a partially overlapped and hierarchical structure. This view makes us easy to interpret some different proposal about the foldon as a difference of the hierarchical structure. On the basis of this finding, we present a new method to assign foldons and their hierarchy, using structural and sequence information. The results show that the foldons assigned by our method correspond to the intermediate structures identified by some experimental techniques. The new method makes it easy to predict whether a protein folds sequentially into the native structure or whether some foldons fold into the native structure in parallel. PMID- 26248726 TI - The Health Of Patients' Eyes (HOPE) Glaucoma study. The effectiveness of a 'glaucoma personal record' for newly diagnosed glaucoma patients: study protocol for a randomised controlled trial. AB - BACKGROUND: Glaucoma involves progressive optic nerve fibre loss, subsequently leading to irreversible and disabling visual field defects. In Europe, the prevalence of glaucoma is approximately 2.2 % of all people aged over 40 years; this equates to 12 million people. Glaucoma patients require regular lifelong follow-up, contributing to a large financial and resource burden for the National Health Service (NHS) in the UK. This study aims to determine whether providing newly diagnosed glaucoma patients with a personalised client-held eye health summary ('glaucoma personal record'), improves patients' knowledge of their glaucoma condition. A potential long-term benefit could be improved self management and henceforth a slower rate of deterioration. METHODS/DESIGN: HOPE Glaucoma is a 3-year, prospective, parallel-group, pragmatic, single-centred, randomised controlled trial. An anticipated 122 adults, newly diagnosed with glaucoma (including ocular hypertension, suspected glaucoma and/or chronic open angle glaucoma) will be recruited from a nurse-led ophthalmology outpatient clinic at a medium-sized NHS Trust. Participants will be randomly allocated to receive standard clinical care (control arm) or standard care plus a glaucoma personal record, detailing the current state of their condition (interventional arm). Participant assessments are designed to test whether provision of a glaucoma personal record 1) improves patient knowledge of glaucoma and 2) contributes to improvements in clinical outcomes, i.e. delay of visual field loss. The primary outcome measure is better client knowledge of glaucoma at the 9 12 month follow-up visit. Secondary outcome measures include the rate of visual field loss and patient-reported outcome measures on visual function (National Eye Institute VFQ - 25) measured at baseline, 9-12 months, 24 months and 36 months. Estimating a 20 % drop-out rate, the study will have 90 % power to detect a mean two-point difference in glaucoma knowledge score between groups at 5 % significance - based on two-sided Mann-Whitney U test. DISCUSSION: If a glaucoma personal record is found to significantly improve glaucoma patients' knowledge of their condition, this intervention could potentially provide a low-cost, straightforward tool to educate and engage glaucoma patients. Subsequently, this could have the potential to increase patient self-management and therefore allow glaucoma patients to prolong their sight functionality for longer. TRIAL REGISTRATION: ISRCTN41306818 , registered on 22 August 2013. PMID- 26248727 TI - Seduction of Finding Universality in Sputtering Yields Due to Cluster Bombardment of Solids. AB - Universal descriptions are appealing because they simplify the description of different (but similar) physical systems, allow the determination of general properties, and have practical applications. Recently, the concept of universality has been applied to the dependence of the sputtering (ejection) yield due to energetic cluster bombardment versus the energy of the incident cluster. It was observed that the spread in data points can be reduced if the yield Y and initial projectile cluster kinetic energy E are expressed in quantities scaled by the number of cluster atoms n, that is, Y/n versus E/n. The convergence of the data points is, however, not perfect, especially when the results for molecular and atomic solids are compared. In addition, the physics underlying the apparent universal dependence in not fully understood. For the study presented in this Account, we performed molecular dynamics simulations of Arn cluster bombardment of molecular (benzene, octane, and beta-carotene) and atomic (Ag) solids in order to address the physical basis of the apparent universal dependence. We have demonstrated that the convergence of the data points between molecular and atomic solids can be improved if the binding energy of the solid U0 is included and the dependence is presented as Y/(E/U0) versus (E/U0)/n. As a material property, the quantity U0 is defined per the basic unit of material, which is an atom for atomic solids and a molecule for molecular solids. Analogously, the quantity Y is given in atoms and molecules, respectively. The simulations show that, for almost 3 orders of magnitude variation of (E/U0)/n, there are obvious similarities in the ejection mechanisms between the molecular and atomic solids, thus supporting the concept of universality. For large (E/U0)/n values, the mechanism of ejection is the fluid flow from a cone-shaped volume. This regime of (E/U0)/n is generally accessed experimentally by clusters with hundreds of atoms and results in the largest yields. For molecular systems, a large fraction of the total energy E is consumed by internal excitation and molecular fragmentation, which are energy loss channels not present in atomic solids. For small (E/U0)/n values, the cluster deforms the surface and the ejection occurs from a ring-shaped ridge of the forming crater rim. This regime of (E/U0)/n is generally accessed experimentally by clusters with thousands of atoms and results in the smallest yields. For the molecular systems, there is little or no molecular fragmentation. The simulations indicate, however, that the representation which includes U0 as the only material property cannot be completely universal, because there are other material properties which influence the sputtering efficiency. Furthermore, neither the Y/n nor Y/(E/U0) representation includes the energy loss physics associated with molecular fragmentation in the high (E/U0)/n regime. The analysis of the universal concept implies for practical applications that if the objective of the experiment is large material removal, then the high energy per cluster atom regime is applicable. If the objective is little or no molecular fragmentation in organic materials, then the low energy per atom regime is appropriate. PMID- 26248728 TI - Hypertension and Estrogen Deficiency Augment Aneurysmal Remodeling in the Rabbit Circle of Willis in Response to Carotid Ligation. AB - Increased cerebral blood flow has been shown to induce pathological structural changes in the Circle of Willis (CoW) in experimental models. Previously, we reported flow-induced aneurysm-like remodeling in the CoW secondary to flow redistribution after bilateral common carotid artery (CCA) ligation in rabbits. In the current study, we tested the hypothesis that loading rabbits with biological risk factors for vascular disease would increase flow-induced aneurysmal remodeling in the CoW. In the same series as the previously-reported bilateral CCA-ligation-alone (n = 6) and sham surgery (n = 3) groups, eight additional female rabbits (the experimental group in this study) were subjected to two risk factors for intracranial aneurysm (hypertension and estrogen deficiency) and then bilateral CCA ligation. Upon euthanasia at 6 months, vascular corrosion casts of the CoW were created and analyzed by scanning electron microscopy for morphological changes and aneurysmal damage. In rabbits with hypertension and estrogen deficiency, arterial caliber increased throughout the CoW, similar to rabbits with CCA ligation alone. However, aneurysmal remodeling (i.e., local bulging) in the CoW was significantly greater than in CCA ligation-only rabbits and was more widespread, presenting in regions that did not show aneurysmal changes after CCA ligation alone. Furthermore, hypertension and estrogen deficiency caused greater increases in vessel length and tortuosity. These results suggest that hypertension and estrogen deficiency make the CoW more vulnerable to flow-induced aneurysmal remodeling and tortuosity. We propose they do so by lowering the tolerance of vascular tissue to hemodynamic forces caused by CCA ligation, thus lowering the threshold necessary to incite vascular damage. PMID- 26248729 TI - Changes in health-related quality of life in older patients one year after an intensive care unit stay. AB - AIMS AND OBJECTIVES: This study investigates health-related quality of life in older patients, over one year following an intensive care unit stay. BACKGROUND: Health-related quality of life is an important outcome when assessing long-term effectiveness of intensive care treatment, and to assist patients, their relatives and healthcare professionals in making treatment decisions. DESIGN: Prospective non-randomised longitudinal study. METHODS: The Short Form Health Survey 36 was administered 1 week after an intensive care stay (retrospective baseline), and after six months and 12 months to the study population and to an age-matched comparison group at recruitment (baseline), and after six months and 12 months. Demographic data, admission diagnosis, length of stay, severity of illness, pain, anxiety, agitation, and intratracheal suctioning, turning and intubation were recorded. Recruitment period: December 2008 to April 2011. RESULTS: Health-related quality of life of the older patients was significantly lower than the comparison group, both before and after the intensive care unit stay, and showed great individual variability. Within group scores, however, were stable over the year. Both physical and mental health scores were lower for the older patients. Renal failure, cardiac surgery and illness severity were associated with lower physical health scores. Cardiovascular illness, intratracheal suctioning and turning were associated with lower mental health scores. CONCLUSIONS: Health-related quality of life was lower in older patients than in the age-matched group but remained stable over one year. RELEVANCE TO CLINICAL PRACTICE: Older patients with severe illnesses, acute renal failure or who have had cardiac surgery, need additional support after hospital discharge due to functional restrictions. Discharge planning should ensure that this support would be provided. Special attention should be given to develop and use methods to reduce distress during routine intensive care interventions such as intratracheal suctioning or turning. PMID- 26248730 TI - Heterogeneous behavior of metalloproteins toward metal ion binding and selectivity: insights from molecular dynamics studies. AB - About one-third of the existing proteins require metal ions as cofactors for their catalytic activities and structural complexities. While many of them bind only to a specific metal, others bind to multiple (different) metal ions. However, the exact mechanism of their metal preference has not been deduced to clarity. In this study, we used molecular dynamics (MD) simulations to investigate whether a cognate metal (bound to the structure) can be replaced with other similar metal ions. We have chosen seven different proteins (phospholipase A2, sucrose phosphatase, pyrazinamidase, cysteine dioxygenase (CDO), plastocyanin, monoclonal anti-CD4 antibody Q425, and synaptotagmin 1 C2B domain) bound to seven different divalent metal ions (Ca(2+), Mg(2+), Zn(2+), Fe(2+), Cu(2+), Ba(2+), and Sr(2+), respectively). In total, 49 MD simulations each of 50 ns were performed and each trajectory was analyzed independently. Results demonstrate that in some cases, cognate metal ions can be exchanged with similar metal ions. On the contrary, some proteins show binding affinity specifically to their cognate metal ions. Surprisingly, two proteins CDO and plastocyanin which are known to bind Fe(2+) and Cu(2+), respectively, do not exhibit binding affinity to any metal ion. Furthermore, the study reveals that in some cases, the active site topology remains rigid even without cognate metals, whereas, some require them for their active site stability. Thus, it will be interesting to experimentally verify the accuracy of these observations obtained computationally. Moreover, the study can help in designing novel active sites for proteins to sequester metal ions particularly of toxic nature. PMID- 26248731 TI - Trans Fatty Acid Levels in Foods and Intakes among Population Aged 3 Years and above in Beijing and Guangzhou Cities, China. AB - OBJECTIVE: To understand the dietary intake levels of trans fatty acids (TFA) in a Chinese population and establish a basis for health risk assessment of trans fatty acids. METHODS: The TFA contents data of 2613 food items and food consumption data of 10,533 people aged 3 years and above in two large cities in China were matched and a simple assessment method was used to estimate the distribution of dietary TFA intake. RESULTS: The mean content of TFA was highest in margarine (1.68 +/- 0.83 g/100g), followed by chocolate and candy (0.89 +/- 2.68 g/100g), edible vegetable oils (0.86 +/- 0.82 g/100g), milk (0.83 +/- 1.56 g/100g), and bakery foods (0.41 +/- 0.91 g/100g). TFA intake accounted for 0.34%, 0.30%, 0.32%, and 0.29% of the total energy intake in the 3-6, 7-12, 13-17, and ?18 year age groups, respectively. Of the populations studied, 0.42% demonstrated TFA intakes (as percentage of energy intake) greater than 1%. The main sources of dietary TFA intake were edible vegetable oils, milk, mutton, and beef, and baked foods, which accounted for 49.8%, 16.56%, 12.21%, and 8.87%, respectively. CONCLUSION: The current intake of TFA among people in two cities did not appear to be of major health concern regarding the threshold of TFA intake as the percentage of total energy recommended by the World Health Organization. Because most TFA were derived from industrially processed foods, the government should reinforce nutrition labeling and regulate food producers to further reduce TFA in food and to provide scientific instruction for consumers to make sound choices. PMID- 26248732 TI - Negative Association of Domestic Activity and Active Commuting with Metabolic Syndrome in a Chinese Population Aged 35-64 Years. AB - OBJECTIVE: To understand the associations of physical activity domains with metabolic syndrome among a middle-aged Chinese population. METHODS: In all, 3326 professional adults aged 35-64 years from Beijing and Zhejiang province were recruited with a cluster random sampling method. The Global Physical Activity Questionnaire was modified, and the recommended Asia-Pacific cut-offs of waist circumstance were introduced into the criteria for metabolic syndrome from the Adult Treatment Panel III. A binary logistic regression model was applied to examine the association of all physical activity domains with the risk of the syndrome. RESULTS: Participants who engaged in domestic activity for ?1176 MET min/week had a 41.6% less chance of having metabolic syndrome [odds ratio (OR), 0.584; 95% confidence interval (CI), 0.480-0.710] than those without this activity. In adjusted models, adults who actively commuted for ?33 MET-min/week but <528 MET-min/week had a 25% less chance of having the syndrome (OR, 0.750; 95% CI, 0.582-0.966) than those who did not. No interaction was detected between the two domains of activity and the syndrome. CONCLUSION: This study highlighted the independently negative association of traffic and house activity with the prevalence of the syndrome in this sample with a generally low level of moderate activity. PMID- 26248733 TI - Ocular Trauma in a Rural Population of North China: The Handan Eye Study. AB - OBJECTIVE: To determine the prevalence of ocular trauma and the proportion of blindness and visual impairment due to trauma in a rural population in northern China. METHODS: The Handan Eye Study is a population-based cross-sectional study that surveyed 6830 Chinese people aged 30+ years from 13 randomly selected villages in Yongnian County, city of Handan, Hebei Province, in July, 2006. All participants underwent a standardized interview and extensive examinations. A structured questionnaire was used to collect information on ocular trauma. RESULTS: Of the 5837 participants who filled out the questionnaire, 124 subjects [2.1%; 95% confidence interval (CI), 1.8%-2.5%] reported a history of ocular trauma in either eye, including 19 (0.3%) persons reporting trauma in both eyes. Men were more likely to have an eye injury than women [odds ratio (OR), 3.3; 2.2 4.9]. In multiple logistic regression models, ocular trauma was significantly more frequent among normotensive participants when compared with hypertensive participants (hypertensive vs. normotensive: OR, 0.6; 0.4-0.9) and among participants who had a history of falls (OR, 2.4; 1.2-4.8). The proportion of unilateral visual impairment and unilateral blindness due to trauma were 10.5% (13 subjects) and 21.0% (26 subjects), respectively. CONCLUSION: Our study reports the prevalence of severe ocular trauma among adults in rural China, revealing a high proportion of blindness and visual impairment due to trauma. These findings suggest the need for educational strategies to increase eye health awareness in this rural population with focus on providing at least appropriate first aid care to reduce blindness due to trauma. PMID- 26248734 TI - MAGI3 Suppresses Glioma Cell Proliferation via Upregulation of PTEN Expression. AB - OBJECTIVE: To investigate the role and molecular mechanism of membrane-associated guanylate kinase inverted 3 (MAGI3) in glioma cell proliferation. METHODS: The expression levels of MAGI3 and PTEN were assessed in glioma samples by Western blotting. MAGI3 was stably transfected into C6 glioma cells to obtain C6-MAGI3 cells. Then, the proliferation, the expression levels of MAGI3 and PTEN, and Akt phosphorylation were evaluated in C6 and C6-MAGI3 cells. Xenograft tumor models were established by subcutaneous injection of C6 and C6-MAGI3 cells into nude mice, and the growth rates of xenografts in the mice were compared. The potential role of MAGI3 expression in PI3K/Akt signaling activation was further investigated by examining the correlation between MAGI3 expression and the expression of PI3K/Akt signaling downstream target genes in a glioma dataset using gene set enrichment analysis (GSEA). RESULTS: Expression levels of MAGI3 and PTEN were significantly downregulated in gliomas. Overexpression of MAGI3 in the glioma C6 cell line upregulated PTEN protein expression, inhibited the phosphorylation of Akt, and suppressed cell proliferation. MAGI3 overexpression also inhibited the growth of C6 glioma tumor xenografts in nude mice. Analysis based on the GEO database confirmed the negative correlation between activation of PI3K/Akt pathway and MAGI3 mRNA levels in human glioma samples. CONCLUSION: The loss of MAGI3 expression in glioma may enhance the proliferation of glioma cells via downregulation of PTEN expression, leading to the activation of the PI3K/Akt pathway. MAGI3 is a potential glioma suppressor. PMID- 26248735 TI - Association between Low-density Lipoprotein Receptor-related Protein 5 Polymorphisms and Type 2 Diabetes Mellitus in Han Chinese: a Case-control Study. AB - OBJECTIVE: To investigate the association between low-density lipoprotein receptor-related protein 5 (LRP5) variants (rs12363572 and rs4930588) and type 2 diabetes mellitus (T2DM) in Han Chinese. METHODS: A total of 1842 T2DM cases (507 newly diagnosed cases and 1335 previously diagnosed cases) and 7777 controls were included in this case-control study. PCR-RFLP was conducted to detect the genotype of the two single nucleotide polymorphisms (SNPs). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to describe the strength of the association by logistic regression. RESULTS: In the study subjects, neither rs12363572 nor rs4930588 was significantly associated with T2DM, even after adjusting for relevant covariates. When stratified by body mass index (BMI), the two SNPs were also not associated with T2DM. Among the 3 common haplotypes, only haplotype TT was associated with reduced risk of T2DM (OR 0.820, 95% CI 0.732 0.919). In addition, rs12363572 was associated with BMI (P<0.001) and rs4930588 was associated with triglyceride levels (P=0.043) in 507 newly diagnosed T2DM cases but not in healthy controls. CONCLUSION: No LRP5 variant was found to be associated with T2DM in Han Chinese, but haplotype TT was found to be associated with T2DM. PMID- 26248736 TI - Phylogenetic and Molecular Analysis of an H7N7 Avian Influenza Virus Isolated in East Dongting Lake in 2012. AB - OBJECTIVE: In March 2012, an H7N7 subtype avian influenza virus (AIV) named A/wild goose/Dongting/PC0360/2012 (H7N7) (DT/PC0360) was recovered from a wild goose in East Dongting Lake. We performed whole-genome sequencing of the isolate, and analyzed the phylogenetic and molecular characterization. METHODS: RNA was extracted from environment samples (including fecal samples from wild bird or domestic ducks, and water samples) for detecting the presence of Influenza A Virus targeting Matrix gene, using realtime RT-PCR assay. The positive samples were performed virus isolation with embryonated eggs. The subtype of the isolates were identified by RT-PCR assay with the H1-H16 and N1-N9 primer set. The whole genome sequencing of isolates were performed. Phylogenetic and molecular characterizations of the eight genes of the isolates were analyzed. RESULTS: Our results suggested that all the eight gene segments of DT/PC0360 belonged to the Eurasian gene pool, and the HA gene were belonged to distinct sublineage with H7N9 AIV which caused outbreaks in Mainland China in 2013. The hemagglutinin cleavage site of HA of DT/PC0360 showed characterization of low pathogenic avian influenza virus. CONCLUSION: Strengthening the surveillance of AIVs of wild waterfowl and poultry in this region is vital for our knowledge of the ecology and mechanism of transmission to prevent an influenza pandemic. PMID- 26248737 TI - Nonlinear Reduction in Risk for Type 2 Diabetes by Magnesium Intake: An Updated Meta-Analysis of Prospective Cohort Studies. AB - Observational studies between magnesium int- ake and risk of type 2 diabetes yielded inconsistent results. We conducted a system literature search of PubMed database through March 2015 for prospective cohort studies of magnesium intake and type 2 diabetes risk. Study-specific results were pooled in a random-effects model. Subgroup and sensitivity analysis were performed to assess the potential sources of heterogeneity and the robustness of the pooled estimation. Generalized least squares trend estimation was used to investigate the dose-response relationship. A total of 15 papers with 19 analyses were identified with 539,735 participants and 25,252 incident diabetes cases. Magnesium intake was associated with a significant lower risk of type 2 diabetes (RR: 0.77; 95% CI: 0.71-0.82) for the highest compared with lowest category. This association was not significantly modified by the pre-specified study characteristics. In the dose response analysis, a magnesium intake increment of 100 mg/day was associated with a 16% reduction in type 2 diabetes risk (RR: 0.84; 95% CI: 0.80-0.88). A nonlinear relationship existed between magnesium intake and type 2 diabetes (P nonlinearity=0.003). This meta-analysis further verified a protective effect of magnesium intake on type 2 diabetes in a nonlinear dose-response manner. PMID- 26248738 TI - A Case-control Study of Environmental Risk Factors for Nonsyndromic Cleft of the Lip and/or Palate in Xuzhou, China. AB - In this study, we sought to determine the association between environmental factors and nonsyndromic cleft of the lip and/or palate (NSCLP) to understand the etiology of the disease. A total of 200 NSCLP cases and 327 controls were recruited at the Maternal and Child Health Hospital of Xuzhou City. We conducted face-to-face interviews with the mothers of both cases and controls. The factors increasing the risk of NSCLP were a positive family history [odds ratio (OR)=56.74], pesticide exposure (OR=8.90), and indoor decoration pollution (OR=4.32). On the other hand, the factors decreasing the risk of NSCLP were a high education level (OR=0.22) and supplementation of folic acid (OR=0.23) and multivitamins (OR=0.16). Positive family history, pesticide exposure, and indoor decoration pollution are associated with the risk of NSCLP. In contrast, high education level and folic acid and multivitamin supplementation are protective factors against NSCLP. PMID- 26248739 TI - The Epidemiological Characteristics of Beijing Lineage Mycobacterium tuberculosis from a National Referral Center in China. AB - Our study was to investigate the epidemiological characteristics of M.tuberculosis from a national tuberculosis referral center in China. All strains isolated from TB patients, were genotyped by the RD105 deletion, 8 and 51 SNP loci and VNTR. The high differentiation SNPs of modern Beijing strains were analyzed for protein function and structure. 413 M. tuberculosis were included. Of 379 Beijing lineage M. tuberculosis, 'modern' and 'ancient' strains respectively represented 85.5% (324/379) and 14.5% (55/379). Rv2494 (V48A) and Rv0245 (S103F) were confirmed as high differentiation SNPs associated with modern strains. In a word, Modern Beijing lineage M.tuberculosis was dominant and the structural models suggested that modern sub-lineage may more easily survive in 'extreme' host condition. PMID- 26248740 TI - Transcriptional Factor Snail Mediates Epithelial-Mesenchymal Transition in Human Bronchial Epithelial Cells Induced by Silica. AB - Epithelial-mesenchymal transition (EMT) plays an important role in fibrotic diseases. We have previously showed that silica induces EMT in human bronchial epithelial cells (BECs); however, the underlying mechanism of silica-induced EMT is poorly understood. In the present study, we investigated the role of Snail in silica-induced EMT in human BECs in vitro. Human BECs were treated with silica at various concentrations and incubation times. Then MTT assay, western blot, electrophoretic mobility shift assay (EMSA), and small interfering RNA (siRNA) transfection were performed. We found that silica increased the expression and DNA binding activity of Snail in human BECs. SNAI siRNA inhibited the silica induced expression of Snail. Moreover, SNAI siRNA upregulated the expression of epithelial marker E-cadherin, but attenuated the expression of mesenchymal marker alpha-smooth muscle actin and vimentin in silica-stimulated cells. These results suggest that Snail mediates the silica-induced EMT in human BECs. PMID- 26248741 TI - Basal Autophagy Is Required for Herpes simplex Virus-2 Infection. AB - Autophagy is a conserved catabolic process of the cell, which plays an important role in regulating plethora of infections. The role of autophagy in Herpes simplex virus-2 (HSV-2) infection is unknown. Here, we found that HSV-2 does not allow induction of an autophagic response to infection, but maintains basal autophagy levels mostly unchanged during productive infection. Thus, we investigated the importance of basal autophagy for HSV-2 infection, using pharmacological autophagy suppression or cells genetically deficient in an autophagy-essential gene (ATG5). Interference with basal autophagy flux in cells significantly reduced viral replication and diminished the infection. These results indicate that basal autophagy plays an indispensable role required for a productive infection. Importantly, this study draws a sharp distinction between induced and basal autophagy, where the former acts as a viral clearance mechanism abrogating infection, while the latter supports infection. PMID- 26248742 TI - The influence of propoxyphene withdrawal on opioid use in veterans. AB - PURPOSE: Our aim is to determine if propoxyphene withdrawal from the US market was associated with opioid continuation, continued chronic opioid use, and secondary propoxyphene-related adverse events (emergency department visits, opioid-related events, and acetaminophen toxicity). METHODS: Medical service use and pharmacy data from 19/11/08 to 19/11/11 were collected from the national Veterans Healthcare Administration healthcare databases. A quasi-experimental pre post retrospective cohort design utilizing a historical comparison group provided the study framework. Logistic regression controlling for baseline covariates was used to estimate the effect of propoxyphene withdrawal. RESULTS: There were 24,328 subjects (policy affected n = 10,747; comparison n = 13,581) meeting inclusion criteria. In the policy-affected cohort, 10.6% of users ceased using opioids, and 26.6% stopped chronic opioid use compared with 3.8% and 13.5% in the historical comparison cohort, respectively. Those in the policy-affected cohort were 2.7 (95%CI: 2.5-2.8) and 3.2 (95%CI: 2.9-3.6) times more likely than those in the historical comparison cohort to discontinue chronic opioid and any opioid use, respectively. Changes in adverse events and Emergency Department (ED) visits were not different between policy-affected and historical comparison cohorts (p > 0.05). CONCLUSIONS: The withdrawal of propoxyphene-containing products resulted in rapid and virtually complete elimination in propoxyphene prescribing in the veterans population; however, nearly 90% of regular users of propoxyphene switched to an alternate opioid, and three quarters continued to use opioids chronically. PMID- 26248743 TI - The influence of low molecular weight heparin medication on plasma DNA in pregnant women. PMID- 26248744 TI - TegadermTM for prevention of intraoperative tooth aspiration. PMID- 26248746 TI - Enzyme Relaxes Cortex of Mitotic Cells. AB - At the end of mitosis, the stiff actomyosin cortex at a cell's poles has to soften so that the cell can elongate and divide. The enzyme PP1, which sits on the kinetochores during metaphase and anaphase, spurs the polar cortex to relax. Polar relaxation is particularly important for cancer cells, and inhibiting it might rein in their division. PMID- 26248745 TI - Personal hand gel for improved hand hygiene compliance on the regional anesthesia team. AB - PURPOSE: Hand hygiene reduces healthcare-associated infections, and several recent publications have examined hand hygiene in the perioperative period. Our institution's policy is to perform hand hygiene before and after patient contact. However, observation suggests poor compliance. This is a retrospective review of a quality improvement database showing the effect of personal gel dispensers on perioperative hand hygiene compliance on a regional anesthesia team. METHODS: Healthcare providers assigned to the Acute Pain Service were observed for compliance with hand hygiene policy during a quality improvement initiative. Provider type and compliance were prospectively recorded in a database. Team members were then given a personal gel dispensing device and again observed for compliance. We have retrospectively reviewed this database to determine the effects of this intervention. RESULTS: Of the 307 encounters observed, 146 were prior to implementing personal gel dispensers. Compliance was 34%. Pre- and post patient contact compliances were 23 and 43%, respectively. For 161 encounters after individual gel dispensers were provided, compliance was 63%. Pre- and post patient contact compliances were 53 and 72%, respectively. Improvement in overall compliance from 34 to 63% was significant. CONCLUSION: On the Acute Pain Service, compliance with hand hygiene policy improves when individual sanitation gel dispensing devices are worn on the person. PMID- 26248752 TI - Liquid Biopsies Track DNA Changes in Tumors. PMID- 26248753 TI - Outpatient-based injection laryngoplasty for the management of unilateral vocal fold paralysis - clinical outcomes from a UK centre. AB - OBJECTIVE: To assess voice outcomes in patients undergoing vocal fold injection (VFI) augmentation laryngoplasty in a clinic-based setting. METHODS: A prospective study of patients with unilateral vocal cord palsy undergoing Radiesse((r)) vocal cord augmentation. We used the ten-item voice handicap index (VHI-10) as a postal survey before and after the intervention. RESULTS: A total of 43 patients were referred to our ENT clinic from June 2011 to October 2014 with unilateral vocal cord palsy. The majority were referred from the oncology department with mediastinal tumours. Fifteen patients died of malignant disease. Twenty-one patients responded to our survey. VHI-10 scores were analysed using one-way analysis of variance (anova), and the results suggest a sustained improvement before and after the intervention (pre-injection versus 3 months post injection P < 0.01; pre-injection versus 6 months post-injection P < 0.033). CONCLUSION: This is the largest case series of patients who had a local anaesthetic vocal cord injection with calcium hydroxylapaptite using the trans thyrohyoid approach. Early data would suggest that the results are similar to injections performed under general anaesthesia when performed by an experienced laryngologist. VFI in a clinic-based (awake) setting has the distinct advantage of providing instant feedback of vocal fold closure and voice outcome during the procedure, avoiding general anaesthesia with its inherent risks and cost and also the limitations of difficult exposure. PMID- 26248754 TI - Tolerability of Vidaza (azacitidine) subcutaneous administration using a maximum volume of 3 ml per injection. AB - The azacitidine (Vidaza(r)) product monograph indicates that doses greater than 4 ml should be divided equally into two syringes and injected into different sites. Although 2 ml is a more commonly used maximum volume for subcutaneous injections, there is a lack of evidence to support the use of any given maximum volume with azacitidine. Applying the status quo of 2 ml to azacitidine results in patients receiving 3-4 injections per visit. This prospective study evaluated the frequency and type of injection site reactions when the maximum subcutaneous injection volume was increased from 2 to 3 ml per injection site. Among 30 patients, 309 doses were administered, and injection site reactions were noted in 92.9% of all doses, with the majority (82.2%) being grade 1; only 10.7% of doses resulted in grade 2 reactions, and there were no grade 3 or 4 reactions. There was no increase in frequency or severity of injection site reactions when the maximum volume was increased to 3 ml. The median number of injections that patients received per visit decreased from 3 to 2 after the volume was increased, and there was a statistically significant reduction in the incidence of pain. Decreasing the number of injections also facilitates ease of rotation of injection sites and decreases pharmacy preparation time. This is the first time that injection site reaction data relating to injection volume have been reported for azacitidine. PMID- 26248755 TI - Assessment of Idiopathic Scoliosis Patients' Satisfaction with Thoracolumbar Brace Treatment. AB - BACKGROUND: Bracing is the most efficient non-surgical method of treatment for idiopathic scoliosis patients with 25-45 degrees curvature according to Cobb. The aim of the present study was to assess compliance of idiopathic scoliosis patients with medical instructions concerning the time patients should spend wearing orthopedic braces, patients' self-perceived health status and problems occurring in patients with idiopathic scoliosis. MATERIAL AND METHODS: A total of 51 patients aged between 9 to 18 years (84% females) treated for adolescent idiopathic scoliosis with a thoracolumbar brace were asked to complete a survey titled ''The profile of quality of life with spine deformity". Survey data were subjected to statistical analysis. RESULTS: Mean brace-wearing compliance among the patients was about 70% of the required time of 23 h/day. The vast majority of patients - 48 (94%) -were satisfied with the treatment method and the results. Pain of about 4 pts (VAS scale) was reported by 18 patients. Excoriations occurred in 70% of the patients. We did not find a significant correlation between the time of brace-wearing per day vs. pain (p=0.18) and excoriations (p=0.36). CONCLUSIONS: 1. Increasing the number of brace-wearing hours per day does not interfere with the socioeconomic relations and does not affect the child's sleep quality. 2. High awareness of the faulty posture is an important factor improving patients' assessment of the progress and methods of treatment. 3. The number of brace-wearing hours per day does not correlate with pain and epidermal injury; appropriate fitting of the brace to a given patient is of key importance here. PMID- 26248756 TI - Shoulder Hemiarthroplasty for Trauma: does a Tuberosity Friendly Prosthesis Improve Outcome? AB - BACKGROUND: Reported outcomes of shoulder hemiarthroplasty for proximal humeral fractures have been poor due to tuberosity non-union or rotator cuff disruption. Newer designs provide features to allow secure tuberosity apposition and stabilisation. To evaluate the outcomes of a shoulder hemiarthroplasty system with "tuberosity friendly" features in the treatment of multi-fragmentary proximal humeral fractures. MATERIAL AND METHODS: An analysis of 12 patients undergoing Exactech Equinoxe hemiarthroplasty for proximal humeral fractures over a two year period. Radiological and clinical outcomes were assessed. RESULTS: Twelve patients, aged 55 to 84, were examined. Median follow up was 20 months (range 7 to 31). Although tuberosity reduction remained and the tuberosities united radiologically in all cases, 5 patients went on to develop superior migration of the humeral head. The median Oxford shoulder score was 25.7 out of 48 (range 11 to 43). CONCLUSIONS: 1. A trauma hemiarthroplasty system combined with good surgical technique can ensure tuberosity fixation and subsequent union. 2. Superior migration of the prosthesis can still occur due to rotator cuff disruption. 3. The use of reverse shoulder arthroplasty may be more appropriate in elderly patients with multi-fragmentary proximal humeral fractures. PMID- 26248757 TI - Impact of Body Mass Index (BMI) on Early Outcomes of Total Knee Arthroplasty. AB - BACKGROUND: The aim of the study was to evaluate the impact of BMI on the early outcomes of total knee arthroplasty in patients with primary osteoarthritis of the knee. MATERIAL AND METHODS: The study involved a group of 59 patients who were examined twice. Patients were divided into 3 groups on the basis of their BMI (G1: BMI < 29.99 kg/m2; G2: BMI 30.00-34.99 kg/m2; G3: BMI > 35.00 kg/m2). A 10-point visual analogue scale (VAS) was used to assess the severity of pain in the affected knee joint (pre- and post-surgery). The WOMAC questionnaire was used to assess the functional status of the patient. RESULTS: The highest values of a correlation index (r) were observed for the correlations between the BMI and WOMAC questionnaire scores for pain (r = 0.55), the level of physical activity (r = 0.47) and the total score (r = 0.56). CONCLUSIONS: 1. Increased body weight and a high BMI (above 35.00 kg/m2) influence the level of pain severity in the operated knee joint and physical activity of the patient after the surgery. 2. The results indicate the need for further evaluation of BMI as a prognostic factor in the planning of physiotherapy in patients treated for idiopathic osteoarthritis of the knee joint after total knee arthroplasty. PMID- 26248758 TI - Comparative Analysis of Clinical Outcomes of Tibial Plateau Fractures and Computed Tomography Examinations. AB - BACKGROUND: The aim of the study was to evaluate the outcomes of treatment of tibial plateau fractures. Based on CT examination, we set out to determine what factors were associated with a poor functional outcome. MATERIAL AND METHODS: The study involved 13 patients after surgery for tibial plateau fracture by locking plate osteosynthesis. CT studies using a MARS application were performed. The presence of subchondral defects was evaluated, including their area and depth. The reduction and widening of the tibial plateau were measured. The study data were correlated with the clinical outcome: pain according to a VAS scale, knee joint range of motion and the subjective IKDC score. RESULTS: Bone defects were observed in the majority of patients. On the basis of surface reconstruction, it was possible to accurately evaluate the articular step-off of the tibial plateau, which closely correlated with the range of motion and the subjective IKDC score (p <0.05). A correlation was also observed between widening of the lateral condyle and the IKDC score and pain level in the VAS scale (p<0.05). CONCLUSIONS: 1. Articular step-off and widening of the lateral condyle strongly correlates with the clinical outcome of tibial plateau fracture treatment. 2. The presence and extent of subchondral bone defects in the tibial plateau are related to knee pain in patients but have no effect on the range of motion and the IKDC score. 3. Bone graft remodeling cannot be fully assessed despite the use of MARS in CT imaging. PMID- 26248759 TI - Ankle Arthrodesis Using the Ilizarov Technique in Difficult Situations - a Prospective Study with Mid-to Long-term Follow up. AB - BACKGROUND: Although various operative techniques are available for ankle arthrodesis, it is not rare to see orthopaedic surgeons facing difficult situations with ankles that cannot be reliably treated by any conventional methods other than the Ilizarov technique. This study was conducted to measure the outcome in such patients using the Ilizarov Ring fixator. MATERIAL AND METHODS: Sixteen patients (average age 47.5 years) had primary or revision unilateral ankle arthrodesis using the Ilizarov technique. Among the 16 patients the pathology included severe difficult posttraumatic arthritis with diabetes mellitus (n=7), failed arthrodesis with internal fixation (n=4), difficult post septic arthritis (n=3) and 1 case each of rheumatoid arthritis and post-polio residual palsy with instability. The primary outcome was bony union and ankle alignment. The clinical results were further evaluated according to the American Orthopaedic Foot and Ankle Society scoring (AOFAS) System at 6 months and yearly till final follow-up. RESULTS: All ankles achieved arthrodesis at an average of 14 weeks (range 12-18 weeks). The average duration of follow-up was 5.7 years (range 4- 10 years). No major complication was seen except for 5 cases of superficial pin track infections, wound dehiscence in 1 patient and chronic discharging sinus in 1 patient. The average AOFAS score improved from an average of 35.25 (range 20- 44) points pre-operatively to an average of 78.37 (range 72 89) points at final follow-up. CONCLUSION: Ankle arthrodesis using Ilizarov technique shows a high fusion rate with no major complications and operative failures even in difficult and complicated situations. PMID- 26248760 TI - Long Term Follow-up of Subcutaneous Achilles Tendon Lengthening in the Treatment of Spastic Equinus Foot in Patients with Cerebral Palsy. AB - BACKGROUND: Spastic equinus foot is among the most common deformities in patients with cerebral palsy. The optimal therapy of this condition is yet to be determined. Despite a considerable volume of literature concerned with the subject of cerebral palsy, there is still a need for studies focusing on long term follow-up after corrective procedures. The study aimed to evaluate the long term effects of subcutaneous Achilles tendon lengthening in the treatment of spastic equinus foot. MATERIAL AND METHODS: A total of 100 patients after Hooke's or White's isolated subcutaneous lengthening of the Achilles tendon were invited to participate in the retrospective assessment. Of the above number, 53 patients reported for an examination (76 feet). The average follow-up time was 10.09 years. To enable a more accurate determination of the risk of recurrence, the patients were divided into two groups according to whether they had been operated before or after reaching the age of 8 years. All patients were able to walk and suffered from the spastic type of cerebral palsy. RESULTS: The average age of patients at the time of the Achilles tendon lengthening procedure was 7 years. The follow-up time ranged from 3 to 17 years (an average of 10.09 years). The degree of equinus foot contracture before the surgery was from -5 to -60 degrees (an average of -17.53 degrees). Recurrence of the deformity was reported in 43.42% of the patients. Recurrences were more common in those with hemiplegic cerebral palsy. CONCLUSIONS: 1. Subcutaneous Achilles tendon lengthening is not associated with a risk of serious complications, while providing good long-term therapeutic outcomes as well as very good cosmetic and functional effects. 2. Subcutaneous Achilles tendon lengthening minimises the costs and time of patients' hospitalisation and uses a relatively simple operative technique. PMID- 26248761 TI - Long-term Results of Operative Treatment of Calcaneal Fractures. AB - BACKGROUND: This paper presents the long-term results of surgical treatment of intra-articular calcaneal fractures, including subjective evaluation, orthopaedic examination and radiographic evaluation. MATERIAL AND METHODS: A total of 126 patients with 135 calcaneal fractures were treated surgically at the Department of Traumatology of the Military Medical Institute in Warsaw between 2008 and 2012. The analysis involves 73 patients (53 persons were lost to follow-up), including 45 men (61.6%). The mean age of the patients was 46.2 years (18-77 years). Based on imaging studies, patients required specific surgical techniques: the minimally invasive Westhues method involving fixation with a bundle of K wires or open reduction and internal fixation with a plate and screws. The outcomes of the surgical treatment of calcaneal fractures were assessed on the basis of a subjective evaluation and orthopaedic and radiographic examinations. Statistical analysis was performed using Microsoft Excel. RESULTS: Based on the Creighton-Nebraska scores, in the group of patients treated with a bundle of K wires (minimally invasive Westhues method), there were 12 excellent results (42.8%), 5 good (17.9%), 6 satisfactory (21.4%) and 5 poor (17.9%). In the group of patients treated with a plate and screws, excellent and good results (58.1%) prevailed in Sanders type II fractures. Most of the poor results were recorded in patients with type IV fractures. In general, radiographic results were better than functional and subjective evaluation. A statistically significant relationship between the subjective outcome of treatment and patient age was found (p <0.001). The least satisfying results were found for patients younger than 39 years of age. CONCLUSIONS: 1. The key to success in the surgical treatment of calcaneal fractures is appropriate restoration of Bohler's angle 2. A good or excellent radiographic outcome did not always coincide with good functional results and good subjective evaluation 3. The poorer subjective scores in younger patients resulted from their inability to return to pre-injury activity levels. PMID- 26248762 TI - Translation, Cultural Adaptation and Validation of Polish Version of Foot and Ankle Outcomes Questionnaire. AB - BACKGROUND: The Polish orthopaedic literature lacks a tool to measure patient reported treatment outcomes in the foot and ankle. MATERIAL AND METHODS: The translation and cultural adaptation of the Foot and Ankle Outcomes Questionnaire was performed in accordance with relevant guidelines. The Polish version of the questionnaire was tested to check its test retest reliability, internal consistency and construct validity. RESULT: The Polish version of the questionnaire was prepared. Testing of the questionnaire revealed acceptable test retest reliability, internal consistency and construct validity. CONCLUSION: The translation, cultural adaptation and testing of the Polish version of patient related outcome measuring tool for the foot and ankle is described. PMID- 26248763 TI - Severe Thoraco-lumbar Kyphoscoliosis Associated with Osteoporosis in Siblings - Case study. AB - The incidence of scoliosis among patients with certain systemic diseases is much higher than in the general population. Moreover, the onset of the scoliosis is in early childhood before the age of 5 and the deformity reaches extreme values. We present the clinical course of two siblings with multiple musculoskeletal deformities, osteoporosis, severe kyphoscolisis and an undiagnosed systemic disease. The onset of scoliosis was in the first months of life of both children, with a marked progression about the 8th month of life. Due to lower limb deformities, ambulation was delayed until the 5th year of life in the male sibling, and the girl remains non-ambulant. Both children had osteoporosis, which caused numerous fractures of the upper and lower limbs. Due to progression of the spinal deformity the boy underwent a posterior hemispondylodesis with instrumentation at the age of 7. The girl also underwent surgery at the age of 7, but instrumentation could not be placed successfully due to inadequate bone quality. The last follow-up to date has been at the age of 12 years for the female patient and 20 years for the male patient. The spinal deformity in the female has not progressed during the last 2-3 years. She has been on bisphosphonate therapy for two years and no new fractures have been noted. The male patient has undergone multiple surgeries for lower limb deformities and is an independent walker. His scoliosis remains stable, but a minor progression of kyphosis has been noted in the last year. The history of the two patients shows that not all early-onset deformities can be effectively treated and that osteoporosis is a crucial obstacle to this treatment. PMID- 26248764 TI - Franciszek Neugebauer's Ichnograms as a Pioneering Diagnostic Method in Orthopedics in the 19th Century. AB - The aim of this paper is to present an original orthopedic diagnostic method from the late 19th century developed by Franciszek Neugebauer, a distinguished Polish physician. His technique of detecting skeletal abnormalities was an excellent coping method in the time before the first diagnostic imaging method - x-ray imaging - had been invented. PMID- 26248765 TI - [The Use of Pedobarographic Examination to Biomechanical Evaluation of Foot and Ankle Joint in Adult - Own Experience]. AB - A non-invasive method, that can be used to describe the underfoot pressure distribution during stance and gait, is pedobarography. This examination helps to describe biomechanics of foot and ankle. It has been used to diagnose foot disorders, assess the disease progression, monitor the progress of rehabilitation and also evaluate the effectivness of undergone surgical treatment. In this article we describe chosen issues of pedobarographic examination in diagnostics and treatment of foot and ankle in adults. We base on our own experience (about 10 thousand examinations) and review of literature. In our opinion, pedobarography should be used in diagnostics and treatment of foot and ankle more often and widely than now. PMID- 26248767 TI - Presentation of the 2015 ASP Distinguished Service Award to John Janovy Jr. PMID- 26248766 TI - Health behaviors, quality of life, and psychosocial health among survivors of adolescent and young adult cancers. AB - PURPOSE: Survivors of adolescent and young adult (AYA) cancer may engage in unhealthy lifestyles (e.g., smoking), potentially heightening their risk for long term health problems. We assessed health behaviors and constructs including quality of life (QOL) and psychosocial well-being among survivors of AYA cancer compared to the general population. METHODS: We used 2009 Behavioral Risk Factor Surveillance System data to evaluate health behaviors for survivors of AYA cancer compared to AYAs without cancer. Multivariable regressions assessed health behaviors (smoking, binge drinking, physical inactivity, and low fruit/vegetable intake) by sex and age between AYA survivors and controls, and among survivors to determine the effects of demographic, QOL, psychosocial, and cancer factors on behaviors. RESULTS: A greater proportion of female survivors of AYA cancer smoked than controls (currently aged 20-39: 27 vs. 14.3%, respectively; currently aged 40-64: 29.3 vs. 18.4%, respectively). Generally, survivors and controls were non adherent to national health behavior guidelines. Uninsured survivors were at greater risk of smoking vs. insured (females, Relative Risk (RR) = 1.64, 95% confidence interval (CI) 1.43-1.90; males, RR = 2.62, 95% CI 1.71-4.02). Poor social/emotional support was associated with smoking (RR = 1.26, 95% CI 1.07 1.48) among female survivors and was associated with low fruit/vegetable intake among male (RR = 1.12, 95% CI 1.01-1.23) and female (RR= 1.12, 95% CI 1.05-1.19) survivors. Female survivors >10 years from diagnosis had higher risk of smoking (RR = 1.26-1.91, all p < 0.01) than survivors 5-10 years from diagnosis. CONCLUSIONS: Unhealthy lifestyle behaviors are common in survivors of AYA cancer. IMPLICATIONS FOR CANCER SURVIVORS: AYA survivors require health behavior support. PMID- 26248768 TI - Affinity purification in target identification: the specificity challenge. AB - Since phenotype-based screening directly evaluates capability of small molecules for modulating biology in actual biological systems, it has become an important discover modality in modern pharmaceutical sciences. However, in order to fully elucidate the molecular mechanism underlying the bioactivity of small molecules, identification of their biological targets is an indispensable step. Among the many target identification strategies developed during the past several decades, affinity purification remains to be one of the most important and powerful approaches, as it can directly reveal the physical interactions between small molecules and their biomolecular targets. However, due to the complexity of the proteome and the diversity of small molecule-protein interactions, affinity purification faces the specificity challenge: how to identify the true specific targets from the non-specific background? Focusing on this challenge, in this review, we briefly introduce the history and background of affinity purification, and then we discussed the major technological developments aiming to address this challenge. We have summarized these approaches in two categories: noise reduction and comparative distinction. This review also highlights the importance of choosing an integrated approach combining multiple methods to achieving success in target identification. PMID- 26248769 TI - Adolescent/Youth Reproductive Mobile Access and Delivery Initiative for Love and Life Outcomes (ARMADILLO) Study: formative protocol for mHealth platform development and piloting. AB - BACKGROUND: There is a high unmet need for sexual and reproductive health (SRH) information and services among youth (ages 15-24) worldwide (MacQuarrie KLD. Unmet Need for Family Planning among Young Women: Levels and Trends 2014). With the proliferation of mobile technology, and its popularity with this age group, mobile phones offer a novel and accessible platform for a discreet, on-demand service providing SRH information. The Adolescent/Youth Reproductive Mobile Access and Delivery Initiative for Love and Life Outcomes (ARMADILLO) formative study will inform the development of an intervention, which will use the popular channel of SMS (text messages) to deliver SRH information on-demand to youth. METHODS/DESIGN: Following the development of potential SMS message content in partnership with SRH technical experts and youth, formative research activities will take place over two phases. Phase 1 will use focus group discussions (FGDs) with youth and parents/caregivers to develop and test the appropriateness and acceptability of the SMS messages. Phase 2 will consist of 'peer piloting', where youth participants will complete an SRH outcome-focused pretest, be introduced to the system and then have three weeks to interact with the system and share it with friends. Participants will then return to complete the SRH post-test and participate in an in-depth interview about their own and their peers' opinions and experiences using ARMADILLO. DISCUSSION: The ARMADILLO formative stage will culminate in the finalization of country-specific ARMADILLO messaging. Reach and impact of ARMADILLO will be measured at later stages. We anticipate that the complete ARMADILLO platform will be scalable, with the potential for national level adoption. PMID- 26248770 TI - A versatile and efficient synthesis of bithiophene-based dicarboxaldehydes from a common synthon. AB - Bithiophene dicarboxaldehydes are promising electron-rich building blocks for the development of arylene vinylene-based organic semiconductors, but their use has been limited due to their synthetic inaccessibility. To facilitate the facile synthesis of these compounds we have prepared a novel functional bithiophene, namely 2,2'-(3,3'-dibromo-[2,2'-bithiophene]-5,5'-diyl)bis(5,5-dimethyl-1,3 dioxane) in two high yielding steps from 3,3',5,5'-tetrabromo-2,2'-bithiophene. This synthon is readily transformed into variety of bithiophene-based dicarboxaldehydes, also in high yields. The use of these functional molecules in the synthesis of arylene vinylene-linked donor-acceptor copolymers is demonstrated by the synthesis of two copolymers with electron deficient benzobisazoles. PMID- 26248771 TI - A new label-free strategy for a highly efficient chemiluminescence immunoassay. AB - A new label-free chemiluminescence (CL) immunoassay method is proposed for the cheap, convenient and sensitive detection of proteins through the co immobilization of a capture antibody and horseradish peroxidase on a sensing interface. The specific immunoreaction on the interface effectively inhibits the enzymatic CL reaction, thus causing a decrease in CL signals. PMID- 26248773 TI - The burden of human influenza in Malaysia. AB - Seasonal and pandemic influenza causes considerable morbidity and mortality globally, but the burden of disease is understudied and underreported in developing countries such as Malaysia. Before considering the cost-effectiveness of introducing interventions such as vaccines to control influenza, it is imperative to determine clinical and socioeconomic impact of the disease. This review summarises the main available literature on human influenza in Malaysia, the possible reasons for the lack of study and awareness of influenza, and important knowledge gaps for future study. PMID- 26248774 TI - Outcome of chemotherapy counseling by pharmacists on psychological effects and self esteem among oncology patients in a Government Hospital in Malaysia. AB - INTRODUCTION: Chemotherapy is the most common form of treatment among cancer patients. It is also known to cause many physical and psychological side-effects. OBJECTIVE: This study developed, implemented and evaluated the outcome of a chemotherapy counseling module among oncology patients by pharmacists based on their psychological effects (depression, anxiety) and selfesteem. METHODS: A randomized, single blind, placebo controlled study was conducted among 162 patients undergoing chemotherapy in a government hospital in Malaysia. INTERVENTION: Counseling sessions were conducted using the 'Managing Patients on Chemotherapy' module for oncology patients undergoing chemotherapy at each treatment cycle. OUTCOME: The outcome of repetitive chemotherapy counseling using the module was determined at baseline, first follow-up, second follow-up and third follow-up. RESULTS: The findings revealed that there was significant improvement in the intervention group as compared to the control group with large effect size on depression (p = 0.001, partial eta(2) = 0.394), anxiety (p = 0.001, partial eta(2) = 0.232) and self-esteem (p = 0.001, partial eta(2) = 0.541). CONCLUSION: Repetitive counseling using the 'Managing Patients on Chemotherapy' module was found to be effective in improving psychological effects and self-esteem among patients undergoing chemotherapy. PMID- 26248775 TI - Audit on management of eclampsia at Sultan Abdul Halim Hospital. AB - INTRODUCTION: Maternal mortality and morbidity from eclampsia continues to be seen around the globe. Local Key Performance Index on recurrence of eclamptic fits did not meet targets, thus this raised the issue whether the care provided adhered to the standard management for eclampsia. METHODS: This clinical audit was conducted to assess and improve the quality of the service being offered to patient, particularly in managing eclampsia cases. It was conducted according to the audit cycle. It begins with the development of 12 standardized criteria for eclampsia management. First audit was conducted by retrospectively reviewing eclampsia cases from year 2008 till 2012. Strategies for changes were formulated and implemented following the results of the first audit. Second audit was conducted six months after the changes. RESULTS: The overall incidence rate of eclampsia was 9.17 per 10,000 deliveries. A first seizure occurred during the antepartum period in 52.9% of cases (n=27), intrapartum in 24% (n=11) and postpartum in 21% of cases (n=13). Suboptimal care was mainly on delay of activation of Red Alert system and no treatment for uncontrolled blood pressure. Several strategies were implemented, mainly on improving working knowledge of the staffs and reengineering hospital Red Alert system. Positive achievements observed during the second audit, shown by a reduction in the number of patients with recurrence eclamptic fits and perinatal mortality rate. CONCLUSION: Conducting an audit is essential to evaluate local performance against the standardized criteria. Improvement can be achieved with inexpensive solutions and attainable within a short period of time. PMID- 26248772 TI - G-protein genomic association with normal variation in gray matter density. AB - While detecting genetic variations underlying brain structures helps reveal mechanisms of neural disorders, high data dimensionality poses a major challenge for imaging genomic association studies. In this work, we present the application of a recently proposed approach, parallel independent component analysis with reference (pICA-R), to investigate genomic factors potentially regulating gray matter variation in a healthy population. This approach simultaneously assesses many variables for an aggregate effect and helps to elicit particular features in the data. We applied pICA-R to analyze gray matter density (GMD) images (274,131 voxels) in conjunction with single nucleotide polymorphism (SNP) data (666,019 markers) collected from 1,256 healthy individuals of the Brain Imaging Genetics (BIG) study. Guided by a genetic reference derived from the gene GNA14, pICA-R identified a significant SNP-GMD association (r=-0.16, P=2.34*10(-8)), implying that subjects with specific genotypes have lower localized GMD. The identified components were then projected to an independent dataset from the Mind Clinical Imaging Consortium (MCIC) including 89 healthy individuals, and the obtained loadings again yielded a significant SNP-GMD association (r=-0.25, P=0.02). The imaging component reflected GMD variations in frontal, precuneus, and cingulate regions. The SNP component was enriched in genes with neuronal functions, including synaptic plasticity, axon guidance, molecular signal transduction via PKA and CREB, highlighting the GRM1, PRKCH, GNA12, and CAMK2B genes. Collectively, our findings suggest that GNA12 and GNA14 play a key role in the genetic architecture underlying normal GMD variation in frontal and parietal regions. PMID- 26248776 TI - Factors influencing late stage of breast cancer at presentation in a district Hospital - Segamat Hospital, Johor. AB - INTRODUCTION: In Malaysia, late stage presentation of breast cancer (stage III or IV) has been a healthcare problem that varies geographically throughout the country. This study aims to understand the factors influencing late stage of breast cancer at presentation among Malaysian women in Segamat Hospital, Johor, which is a district hospital. METHODS: A retrospective descriptive study was conducted on secondary data of all newly diagnosed breast cancer women from 1st August 2011 to 28th February 2014. Secondary data includes age, ethnicity, marital status, family history, education level, occupation, presenting symptom, duration of symptom, tumour size, tumour pathology, tumour grading, oestrogen, progesterone and HER-2 receptor status were collected and analysed using SPSS version 20.0.0. RESULT: In total, data from 52 women was analysed and two women were excluded for incompleteness as these women defaulted. Late stage at presentation was 59.6% of all new cases (17.3% stage III and 42.3% stage IV). The commonest age group of all women diagnosed with breast cancer was in the 5th decade. Majority of them were Malay, married and housewives with no family history of breast cancer. The statistically significant factors associated with late stage at presentation include Malay ethnicity (p=0.019), presenting symptoms other than breast lump (p=0.047), and duration of breast lump more than 3 months (p=0.009). DISCUSSION/CONCLUSION: The study demonstrated presentation at late stage of breast cancer is a major health concern among Malaysian women in district hospital. This may be attributed to different sociocultural beliefs, strong belief in complementary and alternative medicine, lack of awareness, and difficult accessibility to healthcare services. PMID- 26248777 TI - Bacterial pathogens and antibiotic resistance patterns in children with urinary tract infection in a Malaysian tertiary hospital. AB - INTRODUCTION: Urinary tract infection (UTI) is a common bacterial infection affecting children and therefore, prompt recognition and accurate antimicrobial management are vital to prevent kidney damage. This study aims to determine the bacterial pathogens and their patterns of antimicrobial resistance in children presenting with UTI. METHODS: A retrospective study of 721 cases, involving children between the ages of 1-day old to 13 years old with culture-proven UTI in Selayang Hospital, Malaysia between January 2007 and December 2011. The bacterial pathogens and antibiotic resistance patterns in the total population, prophylaxis and no prophylaxis groups were studied. RESULTS: The 3 most common organisms isolated in the total population were E.Coli (41.6%), Klebsiella spp. (21.2%) and Enterococcus spp. (11.0%). With regards to the antibiotic resistance, E.Coli resistance rates to ampicillin, cefuroxime and gentamicin were 67.7%, 15.3% and 7.3% respectively. Ampicillin-resistance was also highest in Klebsiella spp. (84.3%), Enterococcus spp. (15.5%) and Proteus spp. (55.5%). CONCLUSION: E.coli remains to be the leading bacterial pathogen causing UTI in children, with ampicillin-resistance occurring in more than half of these cases. Therefore, accurate choice of antibiotics is important to ensure optimal outcome. In our study, cefuroxime and gentamicin have lower antibiotic resistance rates and can be used in the treatment of UTI in children. PMID- 26248778 TI - Role of high resolution ultrasound in ulnar nerve neuropathy. AB - AIM: This study was conducted to measure the cross sectional area (CSA) of the ulnar nerve (UN) in the cubital tunnel and to evaluate the role of high resolution ultrasonography in the diagnosis of ulnar nerve neuropathy (UNN). MATERIALS AND METHODS: This was a cross sectional study with 64 arms from 32 patients (34 neuropathic, 30 nonneuropathic). Diagnosis was confirmed by nerve conduction study and electromyography. The ulnar nerves were evaluated with 15MHz small footprint linear array transducer. The ulnar nerve CSA was measured at three levels with arm extended: at medial epicondyle (ME), 5cm proximal and 5cm distal to ME. Results from the neuropathic and nonneuropathic arms were compared. Independent T-tests and Pearson correlation tests were used. P value of less than 0.05 was considered significant. RESULTS: Mean CSA values for the UN at levels 5cm proximal to ME, ME and 5cm distal to ME were 0.055, 0.109, 0.045 cm(2) respectively in the neuropathic group and 0.049, 0.075, 0.042 cm2 respectively in the non-neuropathic group. The CSA of the UN at the ME level was significantly larger in the neuropathic group, with p value of 0.005. However, there was no statistical difference between the groups at 5cm proximal and distal to the ME, with p values of 0.10 and 0.35 respectively. CONCLUSION: There is significant difference in CSA values of the UN at ME between the neuropathic and non neuropathic groups with mean CSA value above the predetermined 0.10cm(2) cut-off point. High-resolution ultrasonography is therefore useful to diagnose and follow up cases of elbow UNN. PMID- 26248779 TI - Knowledge, attitude and practice among healthcare staffs in the Emergency Department, Hospital Universiti Sains Malaysia towards Rape Victims In One Stop Crisis Centre (OSCC). AB - INTRODUCTION: Aimed at providing integrated multi-level crisis intervention to women experiencing violence such as rape, One Stop Crisis Centre (OSCC) in Malaysia is often located in the emergency department. Hence, it is imperative that emergency department healthcare providers possess adequate knowledge and acceptable attitudes and practices to ensure the smooth running of an efficient OSCC work process. METHOD: To study the knowledge, attitude and practice of rape management in OSCC among four groups of healthcare providers in the emergency department [i.e., the emergency medicine doctors (EDs), the staff nurses (SNs), the medical assistants (MAs) and the hospital attendants (HAs)], a selfadministered questionnaire in the form of Likert scale was conducted from January to October 2013. Correct or favourable responses were scored appropriately. RESULTS: Out of the 159 participants invited, 110 responded (69.2% response rate). As all data sets in the Knowledge, Attitude and Practice sections are non-parametric, Kruskal- Wallis test was performed. Homogeneity of variance was verified using non-parametric Levene test. In all three sections, there are statistically significant differences in scores obtained among the four groups of healthcare providers with H(3) = 16.0, p<0.001 for Knowledge, H(3) = 27.1, p<0.001 for Attitude and H(3) = 15.8, p<0.001 for Practice sections. Generally, the SNs obtained the highest mean rank score in the knowledge and practice sections but the EDs obtained the highest mean rank score in the attitude section. Some of the responses implied that our healthcare providers have the victim-blaming tendency that can negatively impact the victims. CONCLUSION: Healthcare providers must not only have adequate knowledge but also the non judgemental attitude towards victims in OSCC. PMID- 26248780 TI - A tale of two construct validation analysis: Rasch model and exploratory factor analysis approach for Three-Factor Eating Questionnaire (TFEQ-R21) among Malaysian male workers. AB - INTRODUCTION: This study aims for construct validation using two approaches, i.e., exploratory factor analysis and Rasch Model. METHODS: A cross sectional of 313 male workers from multiple worksites had completed self-administered Malay translated version of Three-Factor Eating Questionnaire- R21. Data quality was assessed by misfit person criteria, dimensionality, summary statistic, item measure and rating (partial credit) scale followed by exploratory factor analysis and internal consistency reliability assessment. RESULTS: The dual approaches of construct validation analysis were complement to each other. Rasch analysis supported the theoretical constructs of three eating behaviour dimensions among respondents. In contrary to exploratory factor analysis, it did show presence of a newfound factor (?=0.04) came up from the separation of the cognitive restrain and uncontrolled eating however, the correlation between the two respective sub factors were fair (r=0.39) and weak (r= -0.08). Both analyses had detected three problematic items but those items were psychometrically fit for used for current study setting. The data had adequate psychometric properties. Cronbach's alpha for cognitive restraint, uncontrolled eating and emotional eating were 0.66, 0.79 and 0.87 respectively. Rating scale quality was conformed to standard criteria. CONCLUSION: Malay version TFEQ-R21 with promising psychometric properties and valid measures for eating behaviour dimensions among male workers aged between 20 to 60 years old is now available. Further development should focus on the items in relation to Malaysian cultural adaptation before its use for daily practice in future setting. PMID- 26248781 TI - Clinical profile, morbidity and outcome of adult patients with psoriasis at a district hospital in Northern Malaysia. AB - INTRODUCTION: Psoriasis is a common, chronic, relapsing, immune-mediated inflammatory disease. Our objective is to review the clinical profile, co morbidities, and outcome of patients with psoriasis. METHODS: This is a cross sectional study of outpatient psoriasis patients attending the dermatology clinic, Hospital Sultan Abdul Halim (HSAH) between January 2012 and June 2014. Data collection was based on Malaysian Psoriasis Registry. RESULTS: Among 296 patients with psoriasis, Malays were the most common 175 (59.1%), followed by Indians 82 (27.7%), Chinese 37 (12.5%) and others 2 (0.6%). Male to female ratio was 1.2:1. More than half (54.7%) of the patients had early onset disease (age 40 or less). Only 26 patients (8.8%) have positive family history. The most common clinical presentation was chronic plaque psoriasis (89.9%), followed by erythrodermic psoriasis (4.7%), guttate psoriasis (3.0%) and pustular psoriasis (1.7%). Twenty eight percent had nail involvement while arthropathy was seen only in 14.7%. Common triggers were sunlight (46.0%), stress (31.1%), trauma (5.4%), food (4.0%), pregnancy (4.0%), and upper respiratory tract infections (2.7%). Co morbidities observed include ischaemic heart disease (7.1%), hypertension (26.7%), dyslipidemia (17.6%), and diabetes mellitus (22.0%). All patients were on topical medications. About 6.8% of the patients were treated with phototherapy. One third of patients (35.5%) were given systemic therapy. Out of these, 84 patients (80.0%) were on methotrexate while only 16 (15.2%) on acitretin. None was on cyclosporine or biologic. In term of disease severity, 41.7% of patients had BSA >10% and 31.4% patients had DLQI > 10. CONCLUSION: Our patients show a similar clinical profile and outcome as our Malaysian psoriasis population. However they tend to have a more severe disease. There is a need for a more effective targeted therapy for a better outcome. PMID- 26248782 TI - Clinical presentation and microorganisms sensitivity profile for diabetic foot ulcers: a pilot study. AB - INTRODUCTION: Patients suffering from diabetes mellitus (DM) frequently present with infected diabetic foot ulcers (DFU). This study was done to record the anatomical site and the grade of ulcers according to Wagner's classification and to culture the microorganisms from the ulcers and determine their antibiotic sensitivity. MATERIALS AND METHODS: Prospective study was conducted on 77 diabetic patients who were admitted with DFU from June until December 2011. Patients with end stage renal failure, those who had previous vascular surgery on the involved limb, or hyperbaric oxygen or maggot therapy for the ulcers, or had unrelated skin diseases around the involved foot were excluded from the study. Specimens for culture were obtained by a sterile swab stick or tissue sample was taken from the wound with sterile surgical instruments. RESULTS: Wagner's grade III and IV ulcers were most common. Majority of the ulcers involved toes (48%). Gram negative microorganisms were predominantly isolated (71.1%). Gram positive microorganisms were less frequently cultured (27.7%). Fungus was cultured from one sample (1.2%). Gram negative microorganisms were sensitive to aminoglycosides, cephalosporins or beta-lactamase inhibitors. More than 40% were resistant to ampicillin. Gram positive microorganisms were sensitive to cloxacillin. MRSA were sensitive to vancomycin. CONCLUSION: Empirical use of antibiotics should be curtailed to prevent development of drug resistant strains of microorganisms and MRSA. We suggest use of antiseptic solutions to clean the ulcers until antibiotic sensitivity report is available. Results of our altered treatment regimen we plan to publish in a later study. PMID- 26248783 TI - The effectiveness of psychological interventions among tinnitus sufferers: A review. AB - INTRODUCTION: The aim of this article was to review the types of psychological interventions for patients with tinnitus, professionals involved in giving the intervention, the effectiveness of each method of interventions and comparisons with non-psychological approaches in treating tinnitus. MATERIALS AND METHODS: PubMed database searched. RESULTS: Twenty one articles that employed randomized controlled trials design were included. Cognitive behavioural therapy (CBT) was the most common intervention conducted by the researchers. Clinical psychologists and trainee psychologists were the most professionals involved in the therapy. The length of therapy ranged from six weeks to three months. DISCUSSION: Psychological interventions were more effective in reducing psychological impacts of tinnitus than non-psychological interventions such as the use of tinnitus maskers. Nevertheless, the combination of the treatments yielded more superior outcomes. CONCLUSION: A simplified version of psychological intervention that can be implemented by other clinical professionals should be developed to treat tinnitus holistically to overcome the shortage number of clinical psychologists. PMID- 26248784 TI - A case of ear canal black pigment foreign body mimicking a melanoma. AB - Melanoma of the ear canal is extremely rare; due to its hidden area, most would present late in their history. We present the first case reported, of a black pigment foreign body mimicking a melanoma in the external auditory canal. A 14 year old Chinese male presented with right sided otalgia and itch. Otoscopic examination revealed an irregular black naevus in the right auditory canal. An intraoperative excision showed a black pigment foreign body giant cell reaction. Clinicians should be aware of the possibility of a foreign body granuloma of the ear canal that might mimic a melanoma. PMID- 26248785 TI - Individualised second line anti-tuberculous therapy for an extensively resistant pulmonary tuberculosis (XDR PTB) in East Malaysia. AB - Clinical experience with extensively Drug Resistant tuberculosis (XDR-TB) has not been reported in Malaysia before. We describe the clinical characteristics, risk factors, progress and therapeutic regimen for a healthcare worker with XDR-TB, who had failed therapy for multidrug resistant TB (MDR TB) in our institution. This case illustrates the risk of TB among healthcare workers in high TB-burden settings, the importance of obtaining upfront culture and susceptibility results in all new TB cases, the problem of acquired drug resistance developing during MDR-TB treatment, the challenges associated with XDR-TB treatment regimens, the value of surgical resection in refractory cases, and the major quality of life impact this disease can have on young, economically productive individuals. PMID- 26248786 TI - Post hysterectomy intravenous leiomyomatosis: multimodality imaging appearances. AB - No abstract available. PMID- 26248787 TI - Reappraisal of bovril as a source of arginine in the arginine stimulation test for growth hormone deficiency. AB - The purpose of this case study is to report the use of oral Bovril (a food supplement which contains arginine) as an alternative test for growth hormone stimulation test. We performed oral Bovril test in 3 patients -- one with suspected growth hormone deficiency in whom insulin tolerance test could not be performed (subject A), one sex-matched control (subject B), and one with confirmed growth hormone deficiency (subject C). 14g/m(2) of oral Bovril was mixed with 150ml of warm water and was given to all three subjects. Blood for growth hormone was taken at baseline, and every 30 minutes till 150 minutes after ingestion of oral Bovril. The ingestion of oral Bovril showed a positive response in subjects A and B, with highest growth hormone levels of 28.4mIU/L and 42.0mIU/L respectively at 150 minutes. Subject C had suppressed growth hormone throughout the test. Oral Bovril is readily available and is a safe alternative for standard growth hormone stimulation test. PMID- 26248788 TI - Preliminary Assessment of Cyanobacteria Diversity and Toxic Potential in Ten Freshwater Lakes in Selangor, Malaysia. AB - Toxic cyanobacteria blooms are increasing in magnitude and frequency worldwide. However, this issue has not been adequately addressed in Malaysia. Therefore, this study aims to better understand eutrophication levels, cyanobacteria diversity, and microcystin concentrations in ten Malaysian freshwater lakes. The results revealed that most lakes were eutrophic, with total phosphorus and total chlorophyll-a concentrations ranging from 15 to 4270 ug L(-1) and 1.1 to 903.1 ug L(-1), respectively. Cyanobacteria were detected in all lakes, and identified as Microcystis spp., Planktothrix spp., Phormidium spp., Oscillatoria spp., and Lyngbya spp. Microcystis spp. was the most commonly observed and most abundant cyanobacteria recorded. Semi-quantitative microcystin analysis indicated the presence of microcystin in all lakes. These findings illustrate the potential health risk of cyanobacteria in Malaysia freshwater lakes, thus magnifying the importance of cyanobacteria monitoring and management in Malaysian waterways. PMID- 26248790 TI - Ca2+ signaling at membrane contact sites. PMID- 26248789 TI - Effectiveness of the Kids in Control of Food (KICk-OFF) structured education course for 11-16 year olds with Type 1 diabetes. AB - AIM: To assess the effect of a 5-day structured education course (Kids in Control of Food; KICk-OFF) on biomedical and psychological outcomes in young people with Type 1 diabetes. METHODS: This was a cluster-randomized trial involving 31 UK paediatric centres. Participants were recruited prior to stratified centre randomization. Intervention centres delivered KICk-OFF courses, whereas control centres delivered usual care. Participants were 11-16 years of age and had Type 1 diabetes for at least one year. The KICk-OFF course was delivered by trained educators to eight participants per course. Glycaemic control and quality of life were measured at baseline, 6, 12 and 24 months. Secondary outcomes were hypoglycaemia, ketoacidosis, fear of hypoglycaemia and diabetes self-efficacy. RESULTS: Three hundred and ninety-six participants provided baseline data (199 intervention and 197 control). At 6 and 12 months the intervention group showed significantly improved total generic quality of life scores compared with controls (baseline: 80 vs. 82; 6 months: 82 vs. 82; P = 0.04). Across the whole intervention group mean HbA1c levels were not significantly different from controls; baseline HbA1c mean (95% confidence interval), 78 mmol/mol (75-81) vs. 76 mmol/mol (74-79) [9.3% (9-9.6%) vs. 9.1% (8.9-9.4%); 24 months: 77 mmol/mol (74-79) vs. 78 mmol/mol (75-81) (9.2% (8.9-9.4%) vs. 9.3% (9-9.6%)], adjusted mean difference, -2.0 mmol/mol (6.5-2.5) [2.3% (-2.7% to 2.4%)], P = 0.38. CONCLUSIONS: Attending a KICk-OFF course was associated with significantly improved total quality of life scores within 6 months. Glycaemic control, as measured by HbA1c , was no different at 24 months. (Clinical Trial Registry No: ISRCTN3704268). PMID- 26248791 TI - Preincubation with green tea polyphenol extract is beneficial for attenuating sperm injury caused by freezing-thawing in swine. AB - Polyphenols (PFs) extracted from green tea, known to be potent anti-oxidants, have been reported to be effective in increasing the motility and viability of mammalian sperm, preserved in a liquid form. Therefore, we tested whether PFs might also be effective for maintaining the integrity of frozen-thawed boar spermatozoa. Ejaculates, collected from Clawn miniature pigs, were diluted in a semen extender containing various amounts of PFs (0, 0.01, 0.05, 0.1 and 0.2% w/v) and then stored at 15 degrees C overnight. The semen samples were processed, using the straw freezing procedure, and then frozen in liquid nitrogen. After rapid thawing at 40 degrees C, the spermatozoa were subjected to several assays to evaluate semen quality. Spermatozoa frozen in a medium containing 0.01% w/v PFs exhibited significantly (P < 0.05) higher degrees of post-thawed viability and acrosomal integrity than those stored in the absence of PFs. However, no change in the mitochondrial activity was noted between the two groups. The inclusion of 0.01% PFs in the semen extender was significantly (P < 0.05) effective in increasing both the rates of monospermic oocyte formation and of blastocyst formation. These findings indicate that preincubation with the semen extender, containing 0.01% PFs prior to freezing, exerts a protective effect on boar sperm by preventing injuries associated with freezing-thawing. PMID- 26248792 TI - Treatment of perforated colon carcinomas-outcomes of radical surgery. AB - PURPOSE: When patients present with a perforation of a colon cancer (CC), this situation increases the challenge to treat them properly. The question arises how to deal with these patients adequately, more restrictively or the same way as with elective cases. METHODS: Between January 1995 and December 2009, 52 patients with perforated CC and 1206 nonperforated CC were documented in the Erlangen Registry of Colorectal Carcinomas (ERCRC). All these patients underwent radical resection of the primary including systematic lymph node dissection with CME. The median follow-up period was 68 months. RESULTS: The median age of the patients in the perforated CC group was significantly higher than in the nonperforated CC group (p = 0.010). Significantly, more patients with perforated CC were classified in ASA categories 3 and 4 (p = 0.014). Hartmann procedures were performed significantly more frequently with perforation than with the nonperforated ones (p < 0.001). If an anastomosis was performed, the leakage rate of primary anastomoses did not differ (p = 1.0). Cancer-related survival was significantly lower with perforated cancer (difference 12.8 percentage points) and by 9.6 percentage points for observed survival, if postoperative mortality was excluded. CONCLUSIONS: Perforated CC patients should be treated basically following the same oncologic demands, which are CME for colonic cancer including multivisceral resections, if needed. This strategy can only be performed if high quality surgery is available, permanently. PMID- 26248793 TI - Incidence and risk factors for rectovaginal fistula after low anterior resection for rectal cancer. AB - BACKGROUND: The rectovaginal fistula (RVF) is a rare complication after low anterior resection (LAR) for rectal cancer. The aim of this study was to evaluate the risk factors for RVF after LAR for rectal cancer. METHODS: This was a retrospective multi-institution study of 371 female rectal cancer patients who underwent LAR with anastomosis between January 2007 and December 2011. Patient-, tumor-, and surgery-related variables were examined by univariate and multivariate analyses. RESULTS: The overall RVF rate was 3.0 % (11/371). The RVF was diagnosed on median postoperative day 83 (15-766). In 81.8 % (9/11) of the patients, the diagnosis of RVF was made after hospital discharge. Multivariate analysis identified prognostic nutritional index (PNI; odds ratio (OR) 6.97; 95 % confidence interval (CI) 1.47-33.08; P = 0.015), preoperative chemotherapy (OR 27.31; CI 3.49-213.62; P = 0.002), tumor size (OR 5.90; CI 1.04-33.47; P = 0.045), intraoperative bleeding (OR 13.91; CI 1.34-144.42; P = 0.027), and lateral lymph node dissection (OR 4.92; CI 1.02-23.63; P = 0.045) as independent risk factors for RVF after LAR. CONCLUSIONS: Risk factors of RVF were PNI (<45), preoperative chemotherapy, tumor size (? 50 mm), intraoperative bleeding (? 200 ml), and lateral lymph node dissection. Before an operation, obtaining the information about these risk factors is of great importance in LAR for rectal cancer. PMID- 26248794 TI - Persistent anal and pelvic floor pain after PPH and STARR: surgical management of the fixed scar staple line. AB - BACKGROUND: Persistent anal pain (PAP) after stapled procedures, be it hemorrhoidopexy (PPH) or stapled transanal rectal resection (STARR) may be hardly resolved by medical therapy. The typical objective finding in these patients is the staple line characterized by fixed scar to underlying layers. METHODS: A total of 21 consecutive patients were operated for PAP after stapled procedure. The scarred staple line was excised and detached from layers below, the mucosal continuity reconstructed by single stitches. From January 2003 to December 2013 1500 patients underwent stapled procedure. Of these patients treated in our unit, 9 (0.6 %) were operated for chronic anal pain and 12 were referred to our center from other hospitals. RESULTS: Fifteen (71.4 %) patients resolved and do not take any drugs for pain; an overall of 85.7 % (18/21) improved their clinical status. Mean time between the beginning of symptoms and the operation was 4.27 months (range 1-18 months). We divided the patients into three groups: before 3 months, between 3 and 6 months and after 6 months from the beginning of symptoms to the operation. The best results were in the first group with 100 % pain relief and satisfactory functional results. CONCLUSIONS: The relief of PAP after stapled procedure, in which we recognize a scarred and fixed staple line, depends by the early recognition of this typical finding. The authors suggest the surgical treatment not later than 3-6 months after the onset of symptoms to achieve the best results. PMID- 26248795 TI - Fatty Acid Binding Proteins Expressed at the Human Blood-Brain Barrier Bind Drugs in an Isoform-Specific Manner. AB - PURPOSE: To examine the expression of fatty acid binding proteins (FABPs) at the human blood-brain barrier (BBB) and to assess their ability to bind lipophilic drugs. METHODS: mRNA and protein expression of FABP subtypes in immortalized human brain endothelial (hCMEC/D3) cells were examined by RT-qPCR and Western blot, respectively. FABPs that were found in hCMEC/D3 cells (hFABPs) were recombinantly expressed and purified from Escherichia coli C41(DE3) cells. Drug binding to these hFABPs was assessed using a fluorescence assay, which measured the ability of a panel of lipophilic drugs to displace the fluorescent probe compound 1-anilinonaphthalene-8-sulfonic acid (ANS). RESULTS: hFABP3, 4 and 5 were expressed in hCMEC/D3 cells at the mRNA and protein level. The competitive ANS displacement assay demonstrated that, in general, glitazones preferentially bound to hFABP5 (Ki: 1.0-28 MUM) and fibrates and fenamates preferentially bound to hFABP4 (Ki: 0.100-17 MUM). In general, lipophilic drugs appeared to show weaker affinities for hFABP3 relative to hFABP4 and hFABP5. No clear correlation was observed between the molecular structure or physicochemical properties of the drugs and their ability to displace ANS from hFABP3, 4 and 5. CONCLUSIONS: hFABP3, 4 and 5 are expressed at the human BBB and bind differentially to a diverse range of lipophilic drugs. The unique expression and binding patterns of hFABPs at the BBB may therefore influence drug disposition into the brain. PMID- 26248796 TI - Co-evolution in a landrace meta-population: two closely related pathogens interacting with the same host can lead to different adaptive outcomes. AB - We examined the local adaptation patterns in a system comprising several interconnected heterogeneous plant populations from which populations of two phylogenetically closely related pathogens were also sampled. The host is Hordeum vulgare (cultivated barley); the pathogens are Pyrenophora teres f. teres (net form) and Pyrenophora teres f. maculata (spot form), the causal agents of barley net blotch. We integrated two approaches, the comparison between the population structures of the host and the pathogens, and a cross-inoculation test. We demonstrated that two closely related pathogens with very similar niche specialisation and life-styles can give rise to different co-evolutionary outcomes on the same host. Indeed, we detected local adaptation for the net form of the pathogen but not for the spot form. We also provided evidence that an a priori well-known resistance quantitative-trait-locus on barley chromosome 6H is involved in the co-evolutionary 'arms race' between the plant and the net-form pathogen. Moreover, data suggested latitudinal clines of host resistance and that different ecological conditions can result in differential selective pressures at different sites. Our data are of interest for on-farm conservation of plant genetic resources, as also in establishing efficient breeding programs and strategies for deployment of resistance genes of P. teres. PMID- 26248797 TI - The Methylsulfonyloxyl Radical, CH3SO3. AB - The methylsulfonyloxyl radical, CH3SO3, one of the key intermediates in the atmospheric oxidation of dimethyl sulfide (DMS), was generated by flash pyrolysis of CH3SO2OOSO2CH3 and subsequently isolated in solid noble-gas matrices. The radical has been characterized by UV/Vis and IR spectroscopy and its tautomerization to CH2SO3H observed upon irradiation with light of lambda>=360 nm. PMID- 26248798 TI - Developmental reversals in recognition memory in children and adults. AB - Older members of a given species typically exhibit superior learning and memory abilities relative to younger members, however, the developmental difference does not always occur in this younger-to-older direction. Developmental reversals are thought to reflect adaptive responses to the unique challenges imposed by the infant's niche. In humans, identification of developmental reversals has largely been precluded because infants, children, and adults are rarely tested using the same experimental procedures. Here, we adapted the visual recognition memory task and tested 3-year-olds and adults using one set of child-oriented stimuli and one set of adult-orientated stimuli. When tested immediately, children and adults exhibited recognition memory for both stimuli. When tested after a 1-week delay, children exhibited recognition memory for the child-oriented stimuli, but not for the adult-oriented stimuli and adults exhibited recognition memory for the adult oriented stimuli, but not for the child-oriented stimuli. These data have important implications for current theories of memory development. PMID- 26248800 TI - Different axes of environmental variation explain the presence vs. extent of cooperative nest founding associations in Polistes paper wasps. AB - Ecological constraints on independent breeding are recognised as major drivers of cooperative breeding across diverse lineages. How the prevalence and degree of cooperative breeding relates to ecological variation remains unresolved. Using a large data set of cooperative nesting in Polistes wasps we demonstrate that different aspects of cooperative breeding are likely to be driven by different aspects of climate. Whether or not a species forms cooperative groups is associated with greater short-term temperature fluctuations. In contrast, the number of cooperative foundresses increases in more benign environments with warmer, wetter conditions. The same data set reveals that intraspecific responses to climate variation do not mirror genus-wide trends and instead are highly heterogeneous among species. Collectively these data suggest that the ecological drivers that lead to the origin or loss of cooperation are different from those that influence the extent of its expression within populations. PMID- 26248801 TI - The Cost of Improving Hip Replacement Follow-Up in the UK. PMID- 26248803 TI - Synergistic activation of quorum sensing in Vibrio harveyi. AB - Autoinducer-2 (AI-2) has been suggested to serve as a ubiquitous quorum sensing (QS) signal that mediates intra- and interspecies cross-talk between bacteria. To add tools for the study of its function in bacterial communication, we present a new and an improved synthetic route to AI-2 and aromatic analogues. We used this strategy to prepare naphthyl-DPD, and observed remarkably high synergistic activity at low nanomolar concentrations for this analogue in Vibrio harveyi. PMID- 26248802 TI - Boronic acid-containing aminopyridine- and aminopyrimidinecarboxamide CXCR1/2 antagonists: Optimization of aqueous solubility and oral bioavailability. AB - The chemokine receptors CXCR1 and CXCR2 are important pharmaceutical targets due to their key roles in inflammatory diseases and cancer progression. We have previously identified 2-[5-(4-fluoro-phenylcarbamoyl)-pyridin-2-ylsulfanylmethyl] phenylboronic acid (SX-517) and 6-(2-boronic acid-5-trifluoromethoxy benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide (SX-576) as potent non competitive boronic acid-containing CXCR1/2 antagonists. Herein we report the synthesis and evaluation of aminopyridine and aminopyrimidine analogs of SX-517 and SX-576, identifying (2-{(benzyl)[(5-boronic acid-2-pyridyl)methyl]amino}-5 pyrimidinyl)(4-fluorophenylamino)formaldehyde as a potent chemokine antagonist with improved aqueous solubility and oral bioavailability. PMID- 26248804 TI - Total synthesis of cordatanine, structural reassignment of drymaritin, and anti inflammatory activity of synthetic precursors. AB - In this study, cordatanine, with a canthin-6-one skeleton, was totally synthesized in four steps via a Pictet-Spengler reaction using tryptamine and methyl glyoxylate with a total yield of 8%. The NMR spectra of synthesized cordatanine compared well with those of drymaritin isolated by Hsieh et al., confirming the need to revise the original structural assignment. In addition, kumujian A, a synthetic intermediate, showed significant anti-inflammatory effects, inhibiting both superoxide anion generation (IC50 4.87 MUg/mL) and elastase release (IC50 6.29 MUg/mL). PMID- 26248805 TI - Isolation and structure elucidation of bioactive compounds from the roots of the Tunisian Ononis angustissima L. AB - A phytochemical investigation of the roots of Ononis angustissima L. (Fabaceae) offered to the bio-guided isolation of new isoflavone 3-(4-(glucopyranosyloxy)-5 hydroxy-2-methoxyphenyl)-7-hydroxy-4H-chromen-4-one 1, together with nine known compounds, ononin 2, formononetin 3, (+)-puerol A-2'-O-beta-D-glucose 4, (-) puerol B-2'-O-beta-D-glucopyranose ((-)-sophoraside A) 5, (+)-puerol A 6, (-) trifolirhizin 7, (-)-trifolirhizin-6'-O-malonate 8, (-)-maackiain 9 and (-) medicarpin 10. Compounds 2-10 were isolated and identified for the first time in Ononis angustissima. We investigated antioxidant capacities of isolated molecules and results showed that compound 6 exhibited the highest antioxidant activity with IC50 values of 19.53 MUg/mL, 28.29 MUg/mL and 38.53 MUg/mL by DPPH radical, ABTS radical cation and reducing power assay, respectively, and an interesting IC50 (20.45 MUg/mL) of 1 against DPPH. In addition, the neuroprotective activity of six isolated molecules (4-7, 9, 10) were evaluated. Following the exposure of PC12 cells to Abeta25-35, compounds 9 and 10 triggered a significant increase of cell viability and in a dose dependent manner. PMID- 26248806 TI - Age and growth of the tiger shark Galeocerdo cuvier off the east coast of Australia. AB - Total lengths (L(T)) at age and growth rates for south-west Pacific Galeocerdo cuvier were estimated from vertebral growth-band counts of 202 sagitally sectioned centra from 112 females (71-430 cm L(T)), 79 males (72-351 cm L(T)) and 11 of unknown sex. Captive growth data were also examined to complement vertebral age estimations. The sexes combined modelled growth coefficient (k = 0.08) was smaller than previously reported for G. cuvier populations elsewhere. Split-band and narrow banding patterns were identified as potential sources of age underestimation in this species. PMID- 26248807 TI - Transdisciplinary care in the emergency department: A qualitative analysis. AB - In response to increasing demands some emergency departments have introduced transdisciplinary care coordination teams. Such teams comprise staff from multiple disciplines who are trained to perform roles outside their usual scope of practice. This study aimed to critically evaluate the patient, carer and ED staff perceptions of the transdisciplinary model of care in an emergency department in a Melbourne metropolitan hospital. The evaluation of the transdisciplinary team involved interviews with patients and carers who have received the transdisciplinary team services, and focus groups with emergency nursing and transdisciplinary team staff. Analysis of the data revealed that the transdisciplinary model provided an essential service, where staff members were capable of delivering care across all disciplines. The ability to perform comprehensive patient assessments ensured safe discharge, with follow-up services in place. The existence of this team was seen to free up time for the emergency nursing staff, enabling them to see other patients, and improving department efficiency while providing quality care and increasing staff satisfaction. This study identified several important factors which contributed to the success of the transdisciplinary team, which was well integrated into the larger emergency department team. PMID- 26248808 TI - Historic cohort study on mode of delivery of a macrosomic baby: the women's point of view. AB - INTRODUCTION: A historic cohort study was conducted to evaluate satisfaction with childbirth of a macrosomic baby according to mode of delivery. MATERIAL AND METHODS: All 559 nulliparous women who delivered a neonate weighing >4000 g between 2008 and 2012 were included. The degree of women's satisfaction with childbirth after elective cesarean, vaginal delivery or cesarean during labor was assessed using a five-level scale. Immediate neonatal and maternal outcomes were retrieved from clinical records. Long-term maternal outcomes were evaluated using four questionnaires on urinary incontinence, anal incontinence, and sexual functioning. RESULTS: Ninety-nine women underwent elective cesarean, whereas 460 attempted a vaginal delivery. In the latter group, 276 women delivered vaginally, whereas 184 underwent a cesarean during labor. Long-term outcomes were assessed in 273 women (49%; elective cesarean, n = 55; vaginal delivery, n = 135; cesarean in labor, n = 83) after a mean 3-year follow up. The proportion of long-term stress or mixed urinary incontinence was, respectively, 8%, 34%, and 12%, whereas that of anal incontinence was 7%, 19%, and 6%. Sexual functioning was similar in the three groups. No major neonatal complications were observed. When pooling the vaginal delivery and the cesarean in labor groups, the likelihood of being satisfied with childbirth was 63% in the "attempted vaginal delivery" group and 85% in the elective cesarean group (adjusted risk ratio, 0.72; 95% CI 0.61-0.84). CONCLUSIONS: About one-third of women attempting a vaginal delivery of a macrosomic baby, would choose an elective cesarean if they could turn back time. PMID- 26248809 TI - INDUCER OF CBF EXPRESSION 1 integrates cold signals into FLOWERING LOCUS C mediated flowering pathways in Arabidopsis. AB - Plants constantly monitor changes in photoperiod and temperature throughout the year to synchronize flowering with optimal environmental conditions. In the temperate zones, both photoperiod and temperature fluctuate in a somewhat predictable manner through the seasons, although a transient shift to low temperature is also encountered during changing seasons, such as early spring. Although low temperatures are known to delay flowering by inducing the floral repressor FLOWERING LOCUS C (FLC), it is not fully understood how temperature signals are coordinated with photoperiodic signals in the timing of seasonal flowering. Here, we show that the cold signaling activator INDUCER OF CBF EXPRESSION 1 (ICE1), FLC and the floral promoter SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1) constitute an elaborate signaling network that integrates cold signals into flowering pathways. The cold-activated ICE1 directly induces the gene encoding FLC, which represses SOC1 expression, resulting in delayed flowering. In contrast, under floral promotive conditions, SOC1 inhibits the binding of ICE1 to the promoters of the FLC gene, inducing flowering with a reduction of freezing tolerance. These observations indicate that the ICE1-FLC SOC1 signaling network contributes to the fine-tuning of flowering during changing seasons. PMID- 26248810 TI - An unusual presentation of lymphoma in a patient with rheumatoid arthritis in remission. PMID- 26248811 TI - Increased risk of cardiovascular disease in giant cell arteritis: a general population-based study. AB - OBJECTIVE: To determine the risk of newly recorded myocardial infarction (MI) and stroke among incident GCA cases compared with controls from the general population. We also evaluated time trends during follow-up. METHODS: We conducted a matched cohort study (1996-2010) of all patients with incident GCA from the province of British Columbia, Canada. We estimated incidence rates of MI and stroke according to GCA disease duration. We calculated hazard ratios (HRs), adjusting for potential confounders. RESULTS: Among 809 individuals with GCA (mean age 75.9 years, 75.8% female), 83 developed MI and 60 developed stroke, with corresponding incidence rates of 38.1 and 26.4/1000 person-years, respectively. Compared with non-GCA cases, the age-, sex- and entry time-matched HRs were 2.75 (95% CI 2.16, 3.50) for MI and 2.21 (95% CI 1.68, 2.91) for stroke. When other covariates were adjusted for, the corresponding HRs were 1.77 (95% CI 1.29, 2.43) and 2.04 (95% CI 1.43, 2.93). The age-, sex- and entry time-matched HRs for MI and stroke were highest during the first year after GCA diagnosis [4.76 (95% CI 3.29, 6.88) and 3.20 (95% CI 2.11, 4.87), respectively]. CONCLUSION: These findings provide general population-based evidence that GCA patients are at a substantially increased risk of cardiovascular disease. Increased monitoring for this potentially fatal outcome and its modifiable risk factors is warranted for GCA patients. PMID- 26248812 TI - Periodontal pathogens participate in synovitis in patients with rheumatoid arthritis in clinical remission: a retrospective case-control study. AB - OBJECTIVE: The objective of this study was to investigate the role of periodontal pathogens in RA in remission. METHODS: Twenty-one patients with active RA and 70 patients in clinical remission, including 48 patients with synovitis [US power Doppler (USPD)(+) group] and 22 patients without synovitis [USPD(-) group] were clinically assessed by US. CRP, ESR, haemoglobin, MMP-3, RF and ACPA were measured. Antibody titres against four types of periodontal pathogen [Aggregatibacter actinomycetemcomitans, Eikenella corrodens (Ec), Porphyromonas gingivalis and Prevotella intermedia (Pi)] were analysed using ELISA. RESULTS: Musculoskeletal US examination showed that 68.6% of patients with RA in clinical remission exhibited synovitis. CRP, ESR, haemoglobin, MMP-3 and RF levels in both the USPD(+) and USPD(-) groups were clearly lower compared with the RA group in non-remission. The IgG serum antibody titre against Ec in the non-remission RA(+) group was significantly greater than that in the USPD(+) group, and the IgG antibody titre against Pi in the non-remission RA and USPD(+) groups was greater than in the USPD(-) group. CONCLUSION: More than half of RA patients in remission showed persistent synovitis. This synovitis may be associated with periodontal disease-causing Pi. Thus, treating periodontal disease should also be considered in order to achieve more profound remission of RA. PMID- 26248813 TI - Changes in IGF-I, urinary free cortisol and adipokines during dronabinol therapy in anorexia nervosa: Results from a randomised, controlled trial. AB - OBJECTIVE: Anorexia nervosa (AN) is characterised by complex neuroendocrine disturbances due to severe underweight, physical hyperactivity and purging behaviour. Cannabinoid agonists are used to palliate cachexia of various causes, but their interactions with the hormonal systems that are involved in energy metabolism have not been previously described in humans. Therefore we found it of interest to assess interactions between the synthetic cannabinoid agonist dronabinol and insulin-like growth factor I (IGF-I), urinary free cortisol (UFC) and adipokines in patients with chronic AN. DESIGN: This was a prospective, double-blind randomised crossover study, conducted at a specialised care centre for eating disorders. The results are based on twenty-four adult women with chronic AN, who completed the study. The participants received dronabinol (oral capsules, 5mg daily) and matching placebo over four weeks, separated by a four week washout period. Bioactive IGF was determined by a cell-based bioassay, whereas total IGF-I, IGFBP-2 and -3 and the two adipokines leptin and adiponectines were measured by immunoassays. The UFC excretion was determined by mass spectrometry. RESULTS: As previously reported, dronabinol treatment caused a small, yet significant increase in BMI as compared to placebo (+0.23 kg/m(2); P = 0.04). This modest weight gain predicted a corresponding increase in bioactive IGF-I, while the amount of daily energy expenditure due to physical activity had a comparable but opposite effect. Nevertheless, neither IGF-I, bioactive IGF nor the IGFBPs levels changed significantly during dronabinol intervention as compared to placebo. Adiponectin also remained unaffected by the weight gain, whereas plasma leptin showed a transient increase at three weeks (P < 0.05). UFC levels were decreased during dronabinol intervention. CONCLUSION: Our results showed that low-dosage therapy with the synthetic cannabinoid agonist dronabinol affected neither the concentration nor the activity of the circulating IGF-system in women with severe and chronic AN. However, our results suggest that such treatment may alleviate the increased hypothalamic-pituitary-adrenal axis activity seen in these patients. PMID- 26248814 TI - Cell extraction combined with off-line HPLC for screening active compounds from Coptis chinensis. AB - Cell membrane chromatography is a useful tool for screening active compounds from natural products. As the reason of separation mechanism, traditional cell membrane chromatography could not be used for screening the active compounds absorbed through the cell membrane and influencing the cell signal transduction pathway. In this work, we establish a new method named cell extraction combined with off-line HPLC for screening the compounds penetrating the cell membrane. This is the first time 3 T3-L1 adipocyte culture has been combined with HPLC technology. Compared with other cell membrane chromatography methods, there is good resolution and no further analysis by other chromatographic steps is required. On co-incubating crude extracts of Coptis chinensis with cells and analyzing the compounds extracted by the cells, active compounds such as berberine were detected. Glucose consumption tests showed that berberine could increase glucose consumption by insulin-resistant 3 T3-L1 adipocytes. The levels of intracellular berberine correlated with its activity. The results indicate that the developed method could be an alternative method for screening active compounds from natural products. PMID- 26248815 TI - Enterovirus71 virus-like particles produced from insect cells and purified by multistep chromatography elicit strong humoral immune responses in mice. AB - AIMS: The study aims to develop a novel multistep chromatographic purification process for human enterovirus71 virus-like particles (VLPs) produced from insect cells (Sf9) infected with recombinant baculovirus. METHODS AND RESULTS: Sf9 cells were maintained in the Wave Bioreactor system 20/50, and harvested when the viability decreased to 75% after infected with Bac-P1-3CD at the multiplicity of infection (MOI) of 1. After sonication and centrifugation, EV71 VLPs were purified with Capto(TM) Core 700, Capto(TM) adhere and Capto(TM) butyl. The purity was then determined by SDS-PAGE, Western blotting and high-performance liquid chromatography (HPLC), while the diameter of purified EV71 VLPs was analysed by Dynamic Light Scattering (DLS) and Transmission electron microscopy (TEM). Immunization of BALB/c mice and serum collection were performed after contamination analysis, and neutralization antibodies were then analysed by pseudovirus-based microneutralization assay. Results showed that these purified EV71 VLPs can be successfully purified with ~31.52% yield and >95% purity. They could elicit stronger neutralization antibodies in mice compared with those produced from formalin-inactivated EV71 virus. CONCLUSIONS: Our results demonstrated that EV71 VLPs can be purified with the multistep chromatographic protocol. SIGNIFICANCE AND IMPACT OF THE STUDY: This work presents a novel multistep chromatographic technique, an effective way of purifying EV71 VLPs with high purity. This purification process can thus serve as foundation for further development of industrial-scale production process of EV71 VLP vaccine candidates. PMID- 26248817 TI - Epidemiology of pseudoexfoliation syndrome: Demystifying legends and looking to the future. PMID- 26248818 TI - Synthesis of Bifunctional Azobenzene Glycoconjugates for Cysteine-Based Photosensitive Cross-Linking with Bioactive Peptides. AB - Azobenzene linker molecules can be utilized to control peptide/protein function when they are ligated to appropriately spaced amino acid side chains of the peptide. This is because the photochemical E/Z isomerization of the azobenzene N=N double bond allows to switch peptide conformation between folded and unfolded. In this context, we have introduced carbohydrate-functionalized azobenzene derivatives in order to advance the biocompatible properties of azobenzene peptide linkers. Chloroacetamide-functionalized and O-allylated carbohydrate derivatives were synthesized and conjugated with azobenzene to achieve new bifunctional cross-linkers, in order to allow ligation to cysteine side chains by nucleophilic substitution or thiol-ene reaction, respectively. The photochromic properties of the new linker glycoconjugates were determined and first ligation reactions performed. PMID- 26248819 TI - Tolerance evaluation of overdosed dietary levels of 25-hydroxyvitamin D3 in growing piglets. AB - Forty-eight, cross-bred (GL * LW * P) piglets were used in a 42-day tolerance trial to assess the effects of feeding diets supplemented with vitamin D or increasing levels of 25-hydroxyvitamin D3 (25-OH-D3 ). Six-week-old piglets (24 castrate males, 24 females) were used. Two replicate groups of 6 piglets were randomized by weight and allocated to four dietary treatments. The control group (T1) was supplemented with 50 MUg vitamin D3 /kg feed. The experimental groups received 25-OH-D3 at the recommended dose (T2: 50 MUg/kg = 1x), at 250 MUg/kg (T3: 5x) or at 500 MUg/kg (T4: 10x) respectively. Feed intake and daily weight gain were measured weekly, and the animals were examined by a veterinarian daily. After 42 days, body mass, blood, urine, bone and tissue samples were analysed and a pathology examination conducted. Dietary treatments had no significant effect on final body mass or daily weight gain. The 25-OH-D3 plasma concentration in T1 was 17 +/- 3 ng/ml (mean +/- SD) while the respective values of the experimental groups were significantly increased in T2, T3 and T4. Tissue concentrations of 25 OH-D3 were higher in liver and muscle for T3 and T4 and in skin for T4 than in T1. However, neither gross pathology nor histology, nor blood and urine characteristics, nor bone parameters were affected by dietary treatments. Weight of organs as well as dry matter, ash and calcium content of kidneys remained unaffected by dietary 25-OH-D3 intake. Furthermore, no changes were observed for general indicators of health. The results of this study demonstrated that feeding piglets with 25-OH-D3 at 5 or 10 times the recommended level had no adverse effects on any of the biological parameters measured. It was concluded that 25-OH D3 can be regarded as a supplement with a very high safety margin when used at the recommended level. PMID- 26248820 TI - Stopping antiplatelet medication before coronary artery bypass graft surgery: is there an optimal timing to minimize bleeding? AB - OBJECTIVES: As the indication for antiplatelet medication expands, patients may be exposed to an increased risk of excessive blood loss when cardiac surgery is required. The optimal timing to stop acetylsalicylic acid (ASA) or ASA combined with clopidogrel (ASA+Clo) before surgery is the subject of controversy. METHODS: A total of 1065 patients were selected from a prospective randomized study on the effect of a fibrin sealant application in coronary artery bypass graft surgery [Fibrin sealant Induced Blood Exposure Reduction study; REGISTRATION NUMBER: NTR1386 (http://www.trialregister.nl)], and divided into three groups according to the use of antiplatelet medication within 10 days prior to surgery: (i) ASA only (n = 662), (ii) ASA+Clo (n = 290) or (iii) no antiplatelet medication (n = 113). To investigate if an optimal stop day could be established, we fitted a series of multiple linear regression models, one for each preoperative day (running from Day -10 up to -1). The specific day corresponding to the best fitting model (highest adjusted R(2), with blood loss in the first 48 h postoperatively as the dependent variable) was considered as the best estimate for the optimal stop day. Bootstrap analysis (1000 times) was performed to calculate the corresponding confidence interval. Furthermore, major adverse cardiovascular and cerebral events (MACCE) were evaluated. RESULTS: We could not estimate an optimal stop day for patients using ASA or ASA+Clo prior to their operation. Last use of ASA on Day -2 or earlier significantly decreased the percentage of patients receiving platelet transfusions compared with continuation until surgery (7 vs 13% for Day -1, P = 0.007). In patients using ASA+Clo, this percentage was reduced from 41 to 10 (P < 0.001). There was no association between stop day and the occurrence of MACCE. CONCLUSIONS: There is no clinically relevant effect on blood loss indicating an optimal stop day for ASA alone or in combination with Clo. Last use on Day -2 resulted in the reduction of percentage of patients receiving platelet transfusions, especially in the ASA+Clo group. PMID- 26248821 TI - Perioperative and mid-term results of endovascular management of complicated type B aortic dissection using a proximal thoracic endoprosthesis and selective distal bare stenting. AB - OBJECTIVES: To present results of endovascular treatment of complicated type B aortic dissection. METHODS: Patients with acutely complicated type B aortic dissection extending from the left sub-clavian artery to the abdominal aorta were treated. The strategy involved the placement of a covered endoprosthesis to seal the primary entry tear and, in cases where malperfusion persisted, distal extension with uncovered stents, to enhance true lumen (TL) expansion and reperfusion of the ischaemic arterial branches originating from the TL. RESULTS: Thirty-five patients were included. Mean age was 63.1 (37-79) years and malperfusion syndrome occurred in 71.4%. Average aortic coverage with endoprostheses was 220.6 mm (136-355 mm). In 17 cases (48.5%), distal extension with uncovered stents was necessary. Thirty-day major morbidity was 28.5%, and mortality 2.8%. At follow-up (25.6 +/- 19.5 months; 4-73 months), overall mortality was 15.2%, and aortic mortality 12.1%. Additional aortic intervention was necessary in 18.2%. Although patients undergoing distal extension with bare metal stents suffered most often from preoperative malperfusion, no significant differences were noted in the 30-day and follow-up clinical results. Follow-up angio-computed tomography showed complete thrombosis of the false lumen in the proximal half of the thoracic aorta in 76.4%. Patients treated with bare stents had significantly larger aortic TL sizes, at the different abdominal aorta levels. CONCLUSIONS: In patients with complicated type B aortic dissection, tailored elongation with uncovered stents is a safe treatment of persistent malperfusion. Although the results presented are encouraging, randomized data and a longer follow-up are required to confirm benefits and complications of this strategy. PMID- 26248822 TI - Short intra-aortic balloon pump in a swine model of myocardial ischaemia: a proof of-concept study. AB - OBJECTIVES: This proof-of-concept study examined the haemodynamic performance as well as the coronary and visceral organ perfusion using a new short balloon for intra-aortic counterpulsation (IABP) in a swine model of myocardial ischaemia. METHODS: Eighteen healthy pigs underwent 120-min ligation of the left anterior descending coronary artery followed by 6 h of reperfusion, and they were randomly assigned into 3 groups undergoing IABP implantation with a 35-ml short balloon (n = 6), a 40-ml short balloon (n = 6) or no IABP implantation (controls, n = 6). Haemodynamics, and visceral and coronary flows were measured at baseline (t0), at 2 h of ischaemia (t1) and every hour thereafter until 6 h of reperfusion (from tR1 to tR6), respectively. RESULTS: Mesenteric and renal flows increased significantly at tR1 only in the IABP groups (all, P < 0.001) and were significantly higher than controls throughout the reperfusion periods (P < 0.001). Coronary systolic and diastolic blood flows increased only at tR1 in the IABP groups (all, P < 0.001) but were higher than controls at tR1-tR6. The IABP was associated with enhanced haemodynamics compared with controls. No difference was detected using different balloon volumes (all, P > 0.05). CONCLUSIONS: The new short balloon significantly increased visceral flow, enhanced haemodynamics and improved coronary circulation during reperfusion following myocardial ischaemia in our experimental model. PMID- 26248823 TI - Forecasting the use of elderly care: a static micro-simulation model. AB - This paper describes a model suitable for forecasting the use of publicly funded long-term elderly care, taking into account both ageing and changes in the health status of the population. In addition, the impact of socioeconomic factors on care use is included in the forecasts. The model is also suitable for the simulation of possible implications of some specific policy measures. The model is a static micro-simulation model, consisting of an explanatory model and a population model. The explanatory model statistically relates care use to individual characteristics. The population model mimics the composition of the population at future points in time. The forecasts of care use are driven by changes in the composition of the population in terms of relevant characteristics instead of dynamics at the individual level. The results show that a further 37 % increase in the use of elderly care (from 7 to 9 % of the Dutch 30-plus population) between 2008 and 2030 can be expected due to a further ageing of the population. However, the use of care is expected to increase less than if it were based on the increasing number of elderly only (+70 %), due to decreasing disability levels and increasing levels of education. As an application of the model, we simulated the effects of restricting access to residential care to elderly people with severe physical disabilities. The result was a lower growth of residential care use (32 % instead of 57 %), but a somewhat faster growth in the use of home care (35 % instead of 32 %). PMID- 26248824 TI - Quality of the surface sediments of the northern coast of the Gulf of Finland, Baltic Sea. AB - The Gulf of Finland is a shallow sea where a multitude of activities compete of space. Many of the activities include reworking of the sea floor. The gulf is known to have been rather largely contaminated by heavy metals during the last century, and although indications of recovery have been reported, it is crucial to know the levels of sea floor sediment contamination before any decisions of activities are taken by the authorities. In order to predict sediment toxicity the sediment concentrations acquired during a study from 2001 to 2004 are compared to Canadian sediment quality guidelines (SQG: s), which reveal that in the majority of the subsamples the metals and arsenic exceed the threshold levels of the used SQG: s, some exceed also the probable effect level. As, Cd, Hg, and especially Zn concentrations occur at unacceptably high levels in the coastal Gulf of Finland sediments. PMID- 26248825 TI - Intrinsic bioremediation potential of a chronically polluted marine coastal area. AB - A microbiological survey of the Priolo Bay (eastern coast of Sicily, Ionian Sea), a chronically polluted marine coastal area, was carried out in order to discern its intrinsic bioremediation potential. Microbiological analysis, 16S rDNA-based DGGE fingerprinting and PLFAs analysis were performed on seawater and sediment samples from six stations on two transects. Higher diversity and variability among stations was detected by DGGE in sediment than in water samples although seawater revealed higher diversity of culturable hydrocarbon-degrading bacteria. The most polluted sediment hosted higher total bacterial diversity and higher abundance and diversity of culturable HC degraders. Alkane- and PAH-degrading bacteria were isolated from all stations and assigned to Alcanivorax, Marinobacter, Thalassospira, Alteromonas and Oleibacter (first isolation from the Mediterranean area). High total microbial diversity associated to a large selection of HC degraders is believed to contribute to natural attenuation of the area, provided that new contaminant contributions are avoided. PMID- 26248826 TI - Using a Contradictory Approach to Treat a Wound Induced by Hematoma in a Patient With Antiphospholipid Antibody Syndrome Using Negative Pressure Wound Therapy: Lessons Learnt. AB - A 48-year-old woman with antiphospholipid syndrome (APS) had multiple skin necrosis caused by massive bleeding and hematoma collection at the right lower leg, left thigh, and abdomen. During the first month, we did surgical debridement every 2 to 3 days with meticulous coagulation and applied negative pressure wound therapy (NPWT). Then as the base showed initial granulation, we changed the NPWT every 4 days. NPWT was used with lower pressure and cyclic mode (-40 to -75 mm Hg) to minimize trauma and to reduce the possibility of bleeding from the wounds. After 2 months of NPWT treatment, all the wounds eventually healed with secondary intension despite the patient's condition with diabetes, hemodialysis, anticoagulant use, and corticosteroid therapy. This report supports the idea that if accompanied by conservative debridement with meticulous bleeding control, application of NPWT in low pressures and close monitoring of the patient, NPWT is possible to use even in wounds of patients with risk for bleeding. PMID- 26248827 TI - Hidradenitis Suppurativa and Wound Management. AB - Hidradenitis suppurativa (HS) is a chronic, burdensome, debilitating disease of the hair follicle. It presents with recurrent painful inflamed and noninflamed lesions usually in specific body areas such as axillary, inguinal, perineal, and genital areas. It is associated with a large range of other diseases and conditions, such as obesity, arthropathy, inflammatory bowel diseases, and sqaumous cell carcinoma. Medical therapy may be systemic or topical, mainly based on antibiotics, retinoids, hormones and immunosuppressive drugs, including biological therapies. Surgical and laser therapies may be a valid therapeutic approach in order to treat locally recurring lesions. The aim of this article is to review the wound healing options after skin excision and laser treatments, with a focus on lesions left to heal by secondary intention, analyzing the efficacy of moist wound dressings, negative pressure wound therapy, bioactive dressings, such as platelet-rich plasma gel and hylarunoic acid scaffold, or autologous keratinocyte suspension in platelet concentrate and skin-grafting tecniques. PMID- 26248829 TI - Restoring confidence in research integrity. PMID- 26248828 TI - Can We Stop Antibiotic Therapy When Signs and Symptoms Have Resolved in Diabetic Foot Infection Patients? AB - The study aimed to investigate whether we can stop antibiotic therapy when signs and symptoms have resolved in diabetic foot infection (DFI) patients with different grades of peripheral arterial disease (PAD) and those without PAD, and to determine whether the severity of PAD and infection has an effect on antibiotic therapy duration. A prospective randomized controlled trial of DFI patients was carried out. Patients were randomized into 2 groups when signs and symptoms had resolved: continuing antibiotics group (CAG) and discontinuing antibiotics group (DAG). The recurrence and clinical outcomes were recorded. The recurrence rate of mild infection with mild/moderate PAD was similar in the 2 groups. Compared with CAG, the recurrence rate of mild infection with severe PAD was higher in DAG (P = .030), also for moderate/severe infection with PAD (mild/moderate [P = .032]; severe [P = .008]). No difference was found in the 2 groups (either mild or moderate/severe) for those without PAD. The clinical outcomes of mild infection in patients were similar in the 2 groups. For moderate/severe infection, the healing rate was higher (73.3% vs 48.3%), and the rate of minor/major amputation and death was lower (23.8% vs 49.4%; 6.9% vs 20.7%; 2.0% vs 13.8%) in the CAG. When the clinical signs and symptoms of infection have resolved, it might be appropriate to stop antibiotics for DFI patients without PAD, and also for patients with mild infection with mild/moderate PAD. For patients with mild infection with severe PAD and moderate/severe infection with PAD, we should perhaps continue antibiotic treatment. Continuing antibiotic therapy could improve clinical outcomes for patients with moderate/severe infection. PMID- 26248830 TI - N-of-1 trials in oncology. PMID- 26248831 TI - Strengthening the oncology nurse workforce in low-income and middle-income countries. PMID- 26248833 TI - Medopad. PMID- 26248834 TI - Bollywood's cancer: disconnect between reel and real oncology. PMID- 26248836 TI - Surgery versus SABR for resectable non-small-cell lung cancer. PMID- 26248837 TI - Surgery versus SABR for resectable non-small-cell lung cancer. PMID- 26248838 TI - Surgery versus SABR for resectable non-small-cell lung cancer. PMID- 26248839 TI - Surgery versus SABR for resectable non-small-cell lung cancer. PMID- 26248840 TI - Surgery versus SABR for resectable non-small-cell lung cancer. PMID- 26248841 TI - Surgery versus SABR for resectable non-small-cell lung cancer - Authors' reply. PMID- 26248842 TI - Breast cancer risk in women with PALB2 mutations in different populations. PMID- 26248843 TI - Relapse models for clear cell renal carcinoma. PMID- 26248844 TI - Relapse models for clear cell renal carcinoma - Authors' reply. PMID- 26248845 TI - Correction to Lancet Oncol 2011; 12: 625. PMID- 26248846 TI - Barriers to overcome for effective cancer control in Africa. AB - Cancer control in Africa is complicated due to large differences in cancer incidence between countries caused by differences in exposure to known risk factors. For example, substantial differences are seen when selected cancers in north Africa are compared with those in sub-Saharan Africa. In the future, population growth and demographic shifts are likely to have profound effects on the prevalence of cancer across the continent. Likewise, many factors outside of health care such as language differences, conflict, and poverty can affect cancer control efforts. Although cooperation in cancer control efforts is desirable, differences in cultural and geopolitical factors that characterise African countries and their populations, together with the sheer size of the continent, present unique challenges to effective cancer control. This Series paper discusses factors related to the size, diversity, and conditions within Africa that present barriers to optimal collaboration in cancer control efforts across the continent. PMID- 26248847 TI - Corruption in health-care systems and its effect on cancer care in Africa. AB - At the government, hospital, and health-care provider level, corruption plays a major role in health-care systems in Africa. The returns on health investments of international financial institutions, health organisations, and donors might be very low when mismanagement and dysfunctional structures of health-care systems are not addressed. More funding might even aggravate corruption. We discuss corruption and its effects on cancer care within the African health-care system in a sociocultural context. The contribution of high-income countries in stimulating corruption is also described. Corrupt African governments cannot be expected to take the initiative to eradicate corruption. Therefore, international financial institutions, health organisations, and financial donors should use their power to demand policy reforms of health-care systems in Africa troubled by the issue of corruption. These modifications will ameliorate the access and quality of cancer care for patients across the continent, and ultimately improve the outcome of health care to all patients. PMID- 26248848 TI - Capacity building for oncology programmes in sub-Saharan Africa: the Rwanda experience. AB - Despite an estimated 456,000 deaths caused by cancer in sub-Saharan Africa in 2012 and a cancer burden that is predicted to double by 2030, the region accounts for only 0.3% of worldwide medical expenditure for cancer. Challenges to cancer care in sub-Saharan Africa include a shortage of clinicians and training programmes, weak healthcare infrastructure, and inadequate supplies. Since 2011, Rwanda has developed a national cancer programme by designing comprehensive, integrated frameworks of care, building local human resource capacity through partnerships, and delivering equitable, rights-based care. In the 2 years since the inauguration of Rwanda's first cancer centre, more than 2500 patients have been enrolled, including patients from every district in Rwanda. Based on Rwanda's national cancer programme development, we suggest principles that could guide other nations in the development of similar cancer programmes. PMID- 26248849 TI - Establishment of a cancer surveillance programme: the South African experience. AB - Cancer is projected to become a leading cause of morbidity and mortality in low income and middle-income countries in the future. However, cancer incidence in South Africa is largely under-reported because of a lack of nationwide cancer surveillance networks. We describe present cancer surveillance activities in South Africa, and use the International Agency for Research on Cancer framework to propose the development of four population-based cancer registries in South Africa. These registries will represent the ethnic and geographical diversity of the country. We also provide an update on a cancer surveillance pilot programme in the Ekurhuleni Metropolitan District, and the successes and challenges in the implementation of the IARC framework in a local context. We examine the development of a comprehensive cancer surveillance system in a middle-income country, which might serve to assist other countries in establishing population based cancer registries in a resource-constrained environment. PMID- 26248850 TI - Rfx2 is required for spermatogenesis in the mouse. AB - RFX transcription factors are key regulators of ciliogenesis in vertebrates. In Xenopus and zebrafish embryos, knockdown of Rfx2 causes defects in neural tube closure and in left-right axis patterning. To determine the essential role of the Rfx2 gene in mammalian development, we generated Rfx2-deficient mice using an embryonic stem cell clone containing a lacZ gene trap reporter inserted into the first intron of the Rfx2 gene. We found that the Rfx2 lacZ reporter is expressed in ciliated tissues during mouse development including the node, the floor plate and the dorsal neural tube. However, mice homozygous for the Rfx2 gene trap mutation did not have defects in neural tube closure or in organ situs. The gene trap insertion appears to create a null allele as Rfx2 mRNA was not detected in Rfx2gt/gt embryos. Although Rfx2-deficient mice do not have an obvious embryonic phenotype, we found that Rfx2gt/gt males are infertile because of a defect in spermatid maturation at or before the round and elongating spermatid stage. Our results indicate that Rfx2 is not essential for embryonic development in the mouse but is required for spermatogenesis. genesis 53:604-611, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26248851 TI - Update: Rationale and design of the Sodium Lowering In Dialysate (SoLID) trial: a randomised controlled trial of low versus standard dialysate sodium concentration during hemodialysis for regression of left ventricular mass. AB - After the publication of our paper Dunlop et al. "Rationale and design of the Sodium Lowering In Dialysate (SoLID) trial: a randomised controlled trial of low versus standard dialysate sodium concentration during hemodialysis for regression of left ventricular mass", we became aware of further data correlating left ventricular (LV) mass index at baseline and their corresponding mass at 12 months, using cardiac magnetic resonance imaging (MRI) in patients on hemodialysis. The original published sample size for the SoLID trial of 118 was a conservative estimate, calculated using analysis of covariance and a within person Pearson's correlation for LV mass index of 0.75. New data communicated to the SoLID trial group has resulted in re-calcuation of the sample size, based upon a within person Pearson's correlation of 0.8 but otherwise unchanged assumptions. As a result, the SoLID trial will now recruit 96 participants. PMID- 26248852 TI - Analysis of Longitudinal Outcome Data with Missing Values in Total Knee Arthroplasty. AB - We sought to determine the influence of missing data on the statistical results, and to determine which statistical method is most appropriate for the analysis of longitudinal outcome data of TKA with missing values among repeated measures ANOVA, generalized estimating equation (GEE) and mixed effects model repeated measures (MMRM). Data sets with missing values were generated with different proportion of missing data, sample size and missing-data generation mechanism. Each data set was analyzed with three statistical methods. The influence of missing data was greater with higher proportion of missing data and smaller sample size. MMRM tended to show least changes in the statistics. When missing values were generated by 'missing not at random' mechanism, no statistical methods could fully avoid deviations in the results. PMID- 26248853 TI - Genome-scale metabolic model of Rhodococcus jostii RHA1 (iMT1174) to study the accumulation of storage compounds during nitrogen-limited condition. AB - BACKGROUND: Rhodococcus jostii RHA1 growing on different substrates is capable of accumulating simultaneously three types of carbon storage compounds: glycogen, polyhydroxyalkanoates (PHA), and triacylglycerols (TAG). Under nitrogen-limited (N-limited) condition, the level of storage increases as is commonly observed for other bacteria. The proportion of each storage compound changes with substrate, but it remains unclear what modelling approach should be adopted to predict the relative composition of the mixture of the storage compounds. We analyzed the growth of R. jostii RHA1 under N-limited conditions using a genome-scale metabolic modelling approach to determine which global metabolic objective function could be used for the prediction. RESULTS: The R. jostii RHA1 model (iMT1174) produced during this study contains 1,243 balanced metabolites, 1,935 unique reactions, and 1,174 open reading frames (ORFs). Seven objective functions used with flux balance analysis (FBA) were compared for their capacity to predict the mixture of storage compounds accumulated after the sudden onset of N limitation. Predictive abilities were determined using a Bayesian approach. Experimental data on storage accumulation mixture (glycogen, polyhydroxyalkanoates, and triacylglycerols) were obtained for batch cultures grown on glucose or acetate. The best FBA simulation results were obtained using a novel objective function for the N-limited condition which combined the maximization of the storage fluxes and the minimization of metabolic adjustments (MOMA) with the preceding non-limited conditions (max storage + environmental MOMA). The FBA solutions for the non-limited growth conditions were simply constrained by the objective function of growth rate maximization. Measurement of central metabolic fluxes by (13)C-labelling experiments of amino acids further supported the application of the environmental MOMA principle in the context of changing environment. Finally, it was found that the quantitative predictions of the storage mixture during N-limited storage accumulation were fairly sensitive to the biomass composition, as expected. CONCLUSIONS: The genome-scale metabolic model analysis of R. jostii RHA1 cultures suggested that the intracellular reaction flux profile immediately after the onset of N-limited condition are impacted by the values of the same fluxes during the period of non-limited growth. PHA turned out to be the main storage pool of the mixture in R. jostii RHA1. PMID- 26248854 TI - Untreated Congenital Adrenal Hyperplasia with 17-alpha Hydroxylase/17,20-Lyase Deficiency Presenting as Massive Adrenocortical Tumor. AB - Congenital adrenal hyperplasia (CAH) with 17alpha-hydroxylase/17,20-lyase deficiency is usually characterized by hypertension and primary amenorrhea, sexual infantilism in women, and pseudohermaphroditism in men. hypertension, and sexual infantilism in women and pseudohermaphroditism in men. In rare cases, a huge adrenal gland tumor can present as a clinical manifestation in untreated CAH. Adrenal cortical adenoma is an even more rare phenotype in CAH with 17alpha hydroxylase/17,20-lyase deficiency. A 36-year-old female presented with hypertension and abdominal pain caused by a huge adrenal mass. Due to mass size and symptoms, left adrenalectomy was performed. After adrenalectomy, blood pressure remained high. Based on hormonal and genetic evaluation, the patient was diagnosed as CAH with 17alpha-hydroxylase/17,20-lyase deficiency. The possibility of a tumorous change in the adrenal gland due to untreated CAH should be considered. It is important that untreated CAH not be misdiagnosed as primary adrenal tumor as these conditions require different treatments. Adequate suppression of adrenocorticotropic hormone (ACTH) in CAH is also important to treat and to prevent the tumorous changes in the adrenal gland. Herein, we report a case of untreated CAH with 17alpha-hydroxylase/17,20-lyase deficiency presenting with large adrenal cortical adenoma and discuss the progression of adrenal gland hyperplasia due to inappropriate suppression of ACTH secretion. PMID- 26248855 TI - Bilateral Adrenocortical Masses Producing Aldosterone and Cortisol Independently. AB - A 31-year-old woman was referred to our hospital with symptoms of hypertension and bilateral adrenocortical masses with no feature of Cushing syndrome. The serum aldosterone/renin ratio was elevated and the saline loading test showed no suppression of the plasma aldosterone level, consistent with a diagnosis of primary hyperaldosteronism. Overnight and low-dose dexamethasone suppression tests showed no suppression of serum cortisol, indicating a secondary diagnosis of subclinical Cushing syndrome. Adrenal vein sampling during the low-dose dexamethasone suppression test demonstrated excess secretion of cortisol from the left adrenal mass. A partial right adrenalectomy was performed, resulting in normalization of blood pressure, hypokalemia, and high aldosterone level, implying that the right adrenal mass was the main cause of the hyperaldosteronism. A total adrenalectomy for the left adrenal mass was later performed, resulting in a normalization of cortisol level. The final diagnosis was bilateral adrenocortical adenomas, which were secreting aldosterone and cortisol independently. This case is the first report of a concurrent cortisol producing left adrenal adenoma and an aldosterone-producing right adrenal adenoma in Korea, as demonstrated by adrenal vein sampling and sequential removal of adrenal masses. PMID- 26248856 TI - Limited Diagnostic Utility of Plasma Adrenocorticotropic Hormone for Differentiation between Adrenal Cushing Syndrome and Cushing Disease. AB - BACKGROUND: Measurement of the plasma adrenocorticotropic hormone (ACTH) level has been recommended as the first diagnostic test for differentiating between ACTH-independent Cushing syndrome (CS) and ACTH-dependent CS. When plasma ACTH values are inconclusive, a differential diagnosis of CS can be made based upon measurement of the serum dehydroepiandrosterone sulfate (DHEA-S) level and results of the high-dose dexamethasone suppression test (HDST). The aim of this study was to assess the utility of plasma ACTH to differentiate adrenal CS from Cushing' disease (CD) and compare it with that of the HDST results and serum DHEA S level. METHODS: We performed a retrospective, multicenter study from January 2000 to May 2012 involving 92 patients with endogenous CS. The levels of plasma ACTH, serum cortisol, 24-hour urine free cortisol (UFC) after the HDST, and serum DHEA-S were measured. RESULTS: Fifty-seven patients had adrenal CS and 35 patients had CD. The area under the curve of plasma ACTH, serum DHEA-S, percentage suppression of serum cortisol, and UFC after HDST were 0.954, 0.841, 0.950, and 0.997, respectively (all P<0.001). The cut-off values for plasma ACTH, percentage suppression of serum cortisol, and UFC after HDST were 5.3 pmol/L, 33.3%, and 61.6%, respectively. The sensitivity and specificity of plasma ACTH measurement were 84.2% and 94.3%, those of serum cortisol were 95.8% and 90.6%, and those of UFC after the HDST were 97.9% and 96.7%, respectively. CONCLUSION: Significant overlap in plasma ACTH levels was seen between patients with adrenal CS and those with CD. The HDST may be useful in differentiating between these forms of the disease, especially when the plasma ACTH level alone is not conclusive. PMID- 26248857 TI - Plasma Adiponectin Levels in Elderly Patients with Prediabetes. AB - BACKGROUND: The significance of adiponectin levels in elderly individuals with prediabetes has yet to be determined. Thus, the present study was performed to evaluate the relationships between adiponectin levels and anthropometric variables, body composition parameters, insulin sensitivity, and lipid profiles in elderly prediabetic patients. METHODS: The present study included 120 subjects with prediabetes who were >65 years of age and were selected from among 1,993 subjects enrolled in the Korea Rural Genomic Cohort Study. All subjects underwent a 75 g oral glucose tolerance test and tests for measurement of insulin sensitivity. All diagnoses of prediabetes satisfied the criteria of the American Diabetes Association. RESULTS: Plasma adiponectin levels were lower in elderly prediabetic subjects than elderly subjects with normal glucose tolerance (P<0.01) as well as in elderly prediabetic patients with metabolic syndrome (MetS) than in those without MetS (P<0.02). When the subjects were categorized into two groups according to plasma adiponectin levels, the waist-to-hip ratio and 2-hour insulin levels were significantly lower in individuals with high plasma adiponectin levels than in those with low plasma adiponectin levels. Additionally, the plasma adiponectin levels of elderly prediabetic subject were inversely correlated with body mass index (BMI), waist circumference (WC), waist-to-hip ratio, visceral fat, visceral fat ratio, and 2-hour insulin levels. CONCLUSION: The present findings demonstrated that the major factors correlated with adiponectin levels in elderly prediabetic subjects were BMI, WC, waist-to-hip ratio, visceral fat, visceral fat ratio, and 2-hour insulin levels. PMID- 26248858 TI - Weight Changes in Patients with Differentiated Thyroid Carcinoma during Postoperative Long-Term Follow-up under Thyroid Stimulating Hormone Suppression. AB - BACKGROUND: There are limited data about whether patients who receive initial treatment for differentiated thyroid cancer (DTC) gain or lose weight during long term follow-up under thyroid stimulating hormone (TSH) suppression. This study was aimed to evaluate whether DTC patients under TSH suppression experience long term weight gain after initial treatment. We also examined the impact of the radioactive iodine ablation therapy (RAIT) preparation method on changes of weight, comparing thyroid hormone withdrawal (THW) and recombinant human TSH (rhTSH). METHODS: We retrospectively reviewed 700 DTC patients who underwent a total thyroidectomy followed by either RAIT and levothyroxine (T4) replacement or T4 replacement alone. The control group included 350 age-matched patients with benign thyroid nodules followed during same period. Anthropometric data were measured at baseline, 1 to 2 years, and 3 to 4 years after thyroidectomy. Comparisons were made between weight and body mass index (BMI) at baseline and follow-up. RESULTS: Significant gains in weight and BMI were observed 3 to 4 years after initial treatment for female DTC but not in male patients. These gains among female DTC patients were also significant compared to age-matched control. Women in the THW group gained a significant amount of weight and BMI compared to baseline, while there was no increase in weight or BMI in the rhTSH group. There were no changes in weight and BMI in men according to RAIT preparation methods. CONCLUSION: Female DTC patients showed significant gains in weight and BMI during long-term follow-up after initial treatment. These changes were seen only in patients who underwent THW for RAIT. PMID- 26248859 TI - Attenuation of streptozotocin-induced pancreatic beta cell death in transgenic fat-1 mice via autophagy activation. AB - BACKGROUND: The incidence of diabetes has rapidly increased due to changes in eating habits. Inflammatory factors and beta (beta) cell dysfunction due to high fat diets aggravate chronic diseases and their complications. However, omega-3 dietary fats have anti-inflammatory effects, and the involvement of autophagy in the etiology of diabetes has been reported. Therefore, we examined the protective effects of autophagy on diabetes using fat-1 transgenic mice with omega-3 self synthesis capability. METHODS: Streptozotocin (STZ) administration induced beta cell dysfunction in mice; blood glucose levels and water consumption were subsequently measured. Using hematoxylin and eosin (H&E) and Masson's trichrome staining, we quantitatively assessed STZ-induced changes in the number, mass, and fibrosis of pancreatic islets in fat-1 and control mice. We identified the microtubule-associated protein 1A/1B light chain 3-immunoreactive puncta in beta cells and quantified p62 levels in the pancreas of fat-1 and control mice. RESULTS: STZ-induced diabetic phenotypes, including hyperglycemia and polydipsia, were attenuated in fat-1 mice. Histological determination using H&E and Masson's trichrome staining revealed the protective effects of the fat-1 mutation on cell death and the scarring of pancreatic islets after STZ injection. In the beta cells of control mice, autophagy was abruptly activated after STZ treatment. Basal autophagy levels were elevated in fat-1 mice beta cells, and this persisted after STZ treatment. Together with autophagosome detection, these results revealed that n-3 PUFA enrichment might partly prevent the STZ-related pancreatic islet damage by upregulating the basal activity of autophagy and improving autophagic flux disturbance. CONCLUSION: Fat-1 transgenic mice with a n-3 PUFA self-synthesis capability exert protective effects against STZ-induced beta cell death by activating autophagy in beta cells. PMID- 26248860 TI - Factors Associated with Glycemic Variability in Patients with Type 2 Diabetes: Focus on Oral Hypoglycemic Agents and Cardiovascular Risk Factors. AB - BACKGROUND: The role of glycemic variability (GV) in development of cardiovascular diseases remains controversial, and factors that determine glucose fluctuation in patients with diabetes are unknown. We investigated relationships between GV indices, kinds of oral hypoglycemic agents (OHAs), and cardiovascular risk factors in patients with type 2 diabetes mellitus (T2DM). METHODS: We analyzed 209 patients with T2DM. The GV index (standard deviation [SD] and mean absolute glucose change [MAG]) were calculated from 7-point self-monitoring of blood glucose profiles. The patients were classified into four groups according to whether they take OHAs known as GV-lowering (A) and GV-increasing (B): 1 (A only), 2 (neither), 3 (both A and B), and 4 (B only). The 10-year risk for atherosclerotic cardiovascular disease (ASCVD) was calculated using the Pooled Cohort Equations. RESULTS: GV indices were significantly higher in patients taking sulfonylureas (SUs), but lower in those taking dipeptidyl peptidase-4 inhibitors. In hierarchical regression analysis, the use of SUs remained independent correlates of the SD (gamma=0.209, P=0.009) and MAG (gamma=0.214, P=0.011). In four OHA groups, GV indices increased progressively from group 1 to group 4. However, these did not differ according to quartiles of 10-year ASCVD risk. CONCLUSION: GV indices correlated significantly with the use of OHAs, particularly SU, and differed significantly according to combination of OHAs. However, cardiovascular risk factors and 10-year ASCVD risk were not related to GV indices. These findings suggest that GV is largely determined by properties of OHAs and not to cardiovascular complications in patients with T2DM. PMID- 26248862 TI - Subclinical Hypothyroidism and Cardiovascular Disease. AB - Subclinical hypothyroidism (SCH) is a common disorder that is characterized by elevated thyroid-stimulating hormone levels in conjunction with free thyroxine concentrations within the normal reference range. Thyroid hormones are known to affect the heart and vasculature and, as a result, the impact of SCH on the cardiovascular (CV) system has recently become an important topic of research. Strong evidence points to a link between SCH and CV risk factors such as alterations in blood pressure, lipid levels, and atherosclerosis. Additionally, accumulating evidence indicates that SCH is associated with metabolic syndrome and heart failure. The present review proposes that SCH may be a potentially modifiable risk factor of CV disease and mortality. However, large-scale clinical trials with appropriate power investigating the risks and benefits of SCH treatment are required to determine whether these benefits can be achieved with levothyroxine therapy. PMID- 26248861 TI - Connecting Myokines and Metabolism. AB - Skeletal muscle is the largest organ of the body in non-obese individuals and is now considered to be an endocrine organ. Hormones (myokines) secreted by skeletal muscle mediate communications between muscle and liver, adipose tissue, brain, and other organs. Myokines affect muscle mass and myofiber switching, and have profound effects on glucose and lipid metabolism and inflammation, thus contributing to energy homeostasis and the pathogenesis of obesity, diabetes, and other diseases. In this review, we summarize recent findings on the biology of myokines and provide an assessment of their potential as therapeutic targets. PMID- 26248863 TI - Extraocular sebaceous carcinoma in association with a clonal seborrheic keratosis: Dermoscopic features. PMID- 26248864 TI - Decreased theta power at encoding and cognitive mapping deficits in elderly individuals during a spatial memory task. AB - The purpose of this study was to investigate the role of theta activity in cognitive mapping, and to determine whether age-associated decreased theta power may account for navigational difficulties in elderly individuals. Cerebral activity was recorded using electroencephalograph in young and older individuals performing a spatial memory task that required the creation of cognitive maps. Power spectra were computed in the frontal and parietal regions and correlated with recognition performance. We found that accuracy of cognitive mapping was positively correlated with left frontal theta activity during encoding in young adults but not in older individuals. Compared with young adults, older participants were impaired in the creation of cognitive maps and showed reduced theta and alpha activity at encoding. These results suggest that encoding processes are impaired in older individual, which may explain age-related cognitive mapping deficits. PMID- 26248865 TI - Inhibition of aberrant complement activation by a dimer of acetylsalicylic acid. AB - We here report synthesis for the first time of the acetyl salicylic acid dimer 5,5'-methylenebis(2-acetoxybenzoic acid) (DAS). DAS inhibits aberrant complement activation by selectively blocking factor D of the alternative complement pathway and C9 of the membrane attack complex. We have previously identified aurin tricarboxylic and its oligomers as promising agents in this regard. DAS is much more potent, inhibiting erythrocyte hemolysis by complement-activated serum with an IC50 in the 100-170 nanomolar range. There are numerous conditions where self damage from the complement system has been implicated in the pathology, including such chronic degenerative diseases of aging as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and age-related macular degeneration. Consequently, there is a high priority for the discovery and development of agents that can successfully treat such conditions. DAS holds considerable promise for being such an agent. PMID- 26248867 TI - A Practical Guide for the Formulation of Propositions in the Bayesian Approach to DNA Evidence Interpretation in an Adversarial Environment. AB - The interpretation of complex DNA profiles is facilitated by a Bayesian approach. This approach requires the development of a pair of propositions: one aligned to the prosecution case and one to the defense case. This note explores the issue of proposition setting in an adversarial environment by a series of examples. A set of guidelines generalize how to formulate propositions when there is a single person of interest and when there are multiple individuals of interest. Additional explanations cover how to handle multiple defense propositions, relatives, and the transition from subsource level to activity level propositions. The propositions depend on case information and the allegations of each of the parties. The prosecution proposition is usually known. The authors suggest that a sensible proposition is selected for the defense that is consistent with their stance, if available, and consistent with a realistic defense if their position is not known. PMID- 26248866 TI - Matrix metalloproteinase 9-mediated intracerebral hemorrhage induced by cerebral amyloid angiopathy. AB - Cerebral amyloid angiopathy (CAA), the deposition of amyloid-beta in cerebrovascular walls, is the most common cause of lobar hemorrhagic stroke. Previous studies show that cerebrovascular amyloid-beta induces expression and activation of matrix metalloproteinase 9 (MMP-9) in cerebral vessels of amyloid precursor protein transgenic mice. Here, we extended these findings and evaluated MMP-9 expression in postmortem brain tissues of human CAA cases. MMP-9 colocalized with CAA, correlated with the severity of the vascular pathology, and was detected in proximity to microbleeds. We characterized a novel assay using longitudinal multiphoton microscopy and a novel tracer to visualize and quantify the magnitude and kinetics of hemorrhages in three dimensions in living mouse brains. We demonstrated that topical application of recombinant MMP-9 resulted in a time- and dose-dependent cerebral hemorrhage. Amyloid precursor protein mice with significant CAA developed more extensive hemorrhages which also appeared sooner after exposure to MMP-9. Our data suggest an important role for MMP-9 in development of hemorrhages in the setting of CAA. Inhibition of MMP-9 may present a preventive strategy for CAA-associated hemorrhage. PMID- 26248868 TI - Evolutionary stasis in pollen morphogenesis due to natural selection. AB - The contribution of developmental constraints and selective forces to the determination of evolutionary patterns is an important and unsolved question. We test whether the long-term evolutionary stasis observed for pollen morphogenesis (microsporogenesis) in eudicots is due to developmental constraints or to selection on a morphological trait shaped by microsporogenesis: the equatorial aperture pattern. Most eudicots have three equatorial apertures but several taxa have independently lost the equatorial pattern and have microsporogenesis decoupled from aperture pattern determination. If selection on the equatorial pattern limits variation, we expect to see increased variation in microsporogenesis in the nonequatorial clades. Variation of microsporogenesis was studied using phylogenetic comparative analyses in 83 species dispersed throughout eudicots including species with and without equatorial apertures. The species that have lost the equatorial pattern have highly variable microsporogenesis at the intra-individual and inter-specific levels regardless of their pollen morphology, whereas microsporogenesis remains stable in species with the equatorial pattern. The observed burst of variation upon loss of equatorial apertures shows that there are no strong developmental constraints precluding variation in microsporogenesis, and that the stasis is likely to be due principally to selective pressure acting on pollen morphogenesis because of its implication in the determination of the equatorial aperture pattern. PMID- 26248870 TI - Internal target volume for post-hysterectomy vaginal recurrences of cervical cancers during image-guided radiotherapy. AB - OBJECTIVE: The outcome of post-surgical recurrences of cervical cancer may be improved through radiation dose escalation, which hinges on accurate identification and treatment of the target. The present study quantifies target motion during course of image-guided radiotherapy (IGRT) for vault cancers. METHODS: All patients underwent planning CT simulation after bladder-filling protocol. A daily pre-treatment megavoltage CT was performed. All translations and rotations were recorded. Post-registration displacement of gross tumour volume (GTV) and centre of mass (COM) of GTV was independently recorded by two observers for fractions one to seven. Day 1 image sets served as reference images against which the displacements of COM were measured. We calculated the displacements of common volume (CV) and encompassing volume (EV) of GTV for both the observers. RESULTS: A total of 90 image data sets of 15 patients were available for evaluation. Individual patient GTV and average GTV by both the observers were comparable. The average shifts for EV were 2.4 mm [standard deviation (SD) +/-1.2] in the mediolateral, 4.2 mm (SD +/-2.8) in the anteroposterior and 4.0 mm (SD +/-2.1) in superoinferior directions. Similarly, the average shifts for CV were 1.9 mm (SD +/-0.6) in the mediolateral, 3.7 mm (SD +/-2.7) in the anteroposterior and 4.4 mm (SD +/-2.7) in superoinferior directions. Using Stroom's/van Herk's formula, the minimum recommended margins would be 4.5/5.2, 8.2/9.4 and 7.3/8.3 mm, respectively, for lateral, anteroposterior and superoinferior directions. CONCLUSION: Differential directional internal margin is recommended in patients undergoing IGRT for post surgical recurrence of cervical cancers. ADVANCES IN KNOWLEDGE: Internal organ motion of vault cancers can be accounted for by a directional margin to the gross tumour. PMID- 26248869 TI - Associations between school- and household-level water, sanitation and hygiene conditions and soil-transmitted helminth infection among Kenyan school children. AB - BACKGROUND: Soil-transmitted helminths, a class of parasitic intestinal worms, are pervasive in many low-income settings. Infection among children can lead to poor nutritional outcomes, anaemia, and reduced cognition. Mass treatment, typically administered through schools, with yearly or biannual drugs is inexpensive and can reduce worm burden, but reinfection can occur rapidly. Access to and use of sanitation facilities and proper hygiene can reduce infection, but rigorous data are scarce. Among school-age children, infection can occur at home or at school, but little is known about the relative importance of WASH in transmission in these two settings. METHODS: We explored the relationships between school and household water, sanitation, and hygiene conditions and behaviours during the baseline of a large-scale mass drug administration programme in Kenya. We assessed several WASH measures to quantify the exposure of school children, and developed theory and empirically-based parsimonious models. RESULTS: Results suggest mixed impacts of household and school WASH on prevalence and intensity of infection. WASH risk factors differed across individual worm species, which is expected given the different mechanisms of infection. CONCLUSIONS: No trend of the relative importance of school versus household-level WASH emerged, though some factors, like water supply were more strongly related to lower infection, which suggests it is important in supporting other school practices, such as hand-washing and keeping school toilets clean. PMID- 26248871 TI - The future of nanosized radiation enhancers. AB - Radiotherapy has a universal and predictable mode of action, that is, a physical mode of action consisting of the deposit of a dose of energy in tissues. Tumour cell damage is proportional to the energy dose. However, the main limitation of radiotherapy is the lack of spatial control of the deposition of energy, that is, it penetrates the healthy tissues, damages them and renders unfeasible delivery of an efficient energy dose when tumours are close to important anatomical structures. True nanosized radiation enhancers may represent a disruptive approach to broaden the therapeutic window of radiation therapy. They offer the possibility of entering tumour cells and depositing high amounts of energy in the tumour only when exposed to ionizing radiations (on/off activity). They may unlock the potential of radiation therapy by rendering the introduction of a greater energy dose, exactly within the tumour structure without passing through surrounding tissues feasible. Several nanosized radiation enhancers have been studied in in vitro and in vivo models with positive results. One agent has received the authorization to conduct clinical trials for human use. Opportunities to improve outcomes for patients receiving radiotherapy, to create new standards of care and to offer solutions to new patient populations are looked over here. PMID- 26248873 TI - Simultaneous determination of four trace estrogens in feces, leachate, tap and groundwater using solid-liquid extraction/auto solid-phase extraction and high performance liquid chromatography with fluorescence detection. AB - A simple and selective high-performance liquid chromatography method coupled with fluorescence detection was developed for the simultaneous measurement of trace levels of four estrogens (estrone, estradiol, estriol and 17alpha-ethynyl estradiol) in environmental matrices. For feces samples, solid-liquid extraction was applied with a 1:1 v/v mixture of acetonitrile and ethyl acetate as the extraction solvent. For liquid samples (e.g., leachate and groundwater), hydrophobic/lipophilic balanced automated solid-phase extraction disks were selected due to their high recoveries compared to conventional C18 disks. Chromatographic separations were performed on a reversed-phase C18 column gradient-eluted with a 45:55 v/v mixture of acetonitrile and water. The detection limits were down to 1.1 * 10(-2) (estrone), 4.11 * 10(-4) (estradiol), 5.2 * 10( 3) (estriol) and 7.18 * 10(-3) MUg/L (17alpha-ethynyl estradiol) at excitation/emission wavelengths of 288/310 nm, with recoveries in the range of 96.9 +/- 3.2-105.4 +/- 3.2% (n = 3). The method was successfully applied to determine estrogens in feces and water samples collected at livestock farms and a major river in Northeast China. We observed relatively high abundance and widespread distribution of all four estrogens in our sample collections, implying the urgency for a comprehensive and intricate investigation of estrogenic fate and contamination in our researched area. PMID- 26248872 TI - Nanoparticles and clinically applicable cell tracking. AB - In vivo cell tracking has emerged as a much sought after tool for design and monitoring of cell-based treatment strategies. Various techniques are available for pre-clinical animal studies, from which much has been learned and still can be learned. However, there is also a need for clinically translatable techniques. Central to in vivo cell imaging is labelling of cells with agents that can give rise to signals in vivo, that can be detected and measured non-invasively. The current imaging technology of choice for clinical translation is MRI in combination with labelling of cells with magnetic agents. The main challenge encountered during the cell labelling procedure is to efficiently incorporate the label into the cell, such that the labelled cells can be imaged at high sensitivity for prolonged periods of time, without the labelling process affecting the functionality of the cells. In this respect, nanoparticles offer attractive features since their structure and chemical properties can be modified to facilitate cellular incorporation and because they can carry a high payload of the relevant label into cells. While these technologies have already been applied in clinical trials and have increased the understanding of cell-based therapy mechanism, many challenges are still faced. PMID- 26248876 TI - The current role of orthoses in treating haemophilic arthropathy. AB - INTRODUCTION: Haemophilic arthropathy (HA) is an inevitable consequence of repeated haemarthroses in people with haemophilia, and principally affects their ankles, knees and elbows. It is advisable that haematological treatment be complemented with rehabilitation therapy and surgery. Orthoses are devices that are used within the framework of rehabilitation, in order to change the functional or structural characteristics of the neuromusculoskeletal system. MATERIALS AND METHODS: This article reviews the design, the materials and characteristics of orthoses and the indications for the various orthoses used in HA. Ankle, knee, elbow orthoses, insoles, footwear modifications and orthopedic shoes are discussed. RESULTS: Orthoses can control or prevent joint movement, stabilise a specific joint or relieve the load or stress on it. These devices must be prescribed by a physician within the framework of rehabilitation. Recommendations for the proper selection and use of orthoses are highly complex. DISCUSSION: To maximise the benefits of this mode of therapy, a profound understanding of anatomy and biomechanics is crucial, as is an understanding of the devices available for the various joints that may be affected by HA (ankles feet, knees, elbows). CONCLUSIONS: Orthotic devices can reduce pain and improve quality of life of people with HA, delaying surgery in many cases. PMID- 26248874 TI - Olive Oil-derived Oleocanthal as Potent Inhibitor of Mammalian Target of Rapamycin: Biological Evaluation and Molecular Modeling Studies. AB - The established anticancer and neuroprotective properties of oleocanthal combined with the reported role of mammalian target of rapamycin (mTOR) in cancer and Alzheimer's disease development encouraged us to examine the possibility that oleocanthal inhibits mTOR. To validate this hypothesis, we docked oleocanthal into the adenosine triphosphate binding pocket of a close mTOR protein homologue, namely, PI3K-gamma. Apparently, oleocanthal shared nine out of ten critical binding interactions with a potent dual PIK3-gamma/mTOR natural inhibitor. Subsequent experimental validation indicated that oleocanthal indeed inhibited the enzymatic activity of mTOR with an IC50 value of 708 nM. Oleocanthal inhibits the growth of several breast cancer cell lines at low micromolar concentration in a dose-dependent manner. Oleocanthal treatment caused a marked downregulation of phosphorylated mTOR in metastatic breast cancer cell line (MDA-MB-231). These results strongly indicate that mTOR inhibition is at least one of the factors of the reported anticancer and neuroprotective properties of oleocanthal. PMID- 26248877 TI - Cone-shell Raman spectroscopy (CSRS) for depth-sensitive measurements in layered tissue. AB - We report the development of a depth-sensitive Raman spectroscopy system using the configuration of cone-shell excitation and cone detection. The system uses a 785 nm diode laser and three identical axicons for Raman excitation of the target sample in the form of a hollow conic section. The Raman scattered light from the sample, passed through the same (but solid) conic section, is collected for detection. Apart from its ability of probing larger depths (~ few mm), an important attraction of the system is that the probing depths can be varied by simply varying the separation between axicons in the excitation arm. Furthermore, no adjustment is required in the sample arm, which is a significant advantage for noncontact, depth-sensitive measurement. Evaluation of the performance of the developed setup on nonbiological phantom and biological tissue sample demonstrated its ability to recover Raman spectra of layers located at depths of ~2-3 mm beneath the surface. PMID- 26248879 TI - Quality of physical health care among patients with personality disorder. AB - OBJECTIVE: To investigate the assessment and treatment of physical health in patients with personality disorder and compare this to the care received in schizophrenia. METHOD: We collected data from a random sample of 246 patients with personality disorder on monitoring and intervention for seven key aspects of physical health. We compared the results with those from a random sample with schizophrenia. RESULTS: In our sample, 160 (65%) people had the diagnosis of emotionally unstable personality disorder. In total, 104 (42.3%) people with personality disorder were being prescribed antipsychotic medication; 23 (9.3%) participants had all seven aspects of physical health recorded. Alcohol was most frequently recorded (76%); BMI (38.6%), blood glucose (25.2%) and blood cholesterol (20.7%) were less likely to be recorded. Interventions were not given to all those requiring them. Compared to people with schizophrenia, a lower proportion had evidence of assessment of smoking, illicit drug use, blood glucose and blood lipid levels. Smoking cessation advice was more likely to be offered to people with schizophrenia (difference = 29.4%, 95% CI = 12.5 to 44.7). CONCLUSION: Physical health is under-assessed and under-treated in patients with personality disorder. Medical staff must do more to help tackle increased morbidity among this group. PMID- 26248878 TI - Decellularized human liver as a natural 3D-scaffold for liver bioengineering and transplantation. AB - Liver synthetic and metabolic function can only be optimised by the growth of cells within a supportive liver matrix. This can be achieved by the utilisation of decellularised human liver tissue. Here we demonstrate complete decellularization of whole human liver and lobes to form an extracellular matrix scaffold with a preserved architecture. Decellularized human liver cubic scaffolds were repopulated for up to 21 days using human cell lines hepatic stellate cells (LX2), hepatocellular carcinoma (Sk-Hep-1) and hepatoblastoma (HepG2), with excellent viability, motility and proliferation and remodelling of the extracellular matrix. Biocompatibility was demonstrated by either omental or subcutaneous xenotransplantation of liver scaffold cubes (5 * 5 * 5 mm) into immune competent mice resulting in absent foreign body responses. We demonstrate decellularization of human liver and repopulation with derived human liver cells. This is a key advance in bioartificial liver development. PMID- 26248881 TI - Reply. PMID- 26248880 TI - Decrease expression and clinicopathological significance of miR-148a with poor survival in hepatocellular carcinoma tissues. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, mainly due to its high rates of postoperative recurrence and metastasis. Please remove, it currently ranks as the third most common cause of cancer-related deaths. MiRNAs are a set of small, single-stranded, non-coding RNA molecules that negatively regulate gene expression at the post-transcriptional level. In this study, we demonstrated the down-regulation of miR-148a in HCC and non-cancerous tissues using qRT-PCR. METHODS: Ninety six HCC samples and their noncancerous normal liver tissues were collected. Total mRNA including miRNA was extracted, and miR-148a expression was determined using qRT-PCR. Furthermore, the correlation between the miR-148a expression and clinicopathological parameters was investigated. RESULTS: The result showed that reduction of miR-148a expression was associated with TNM stage, metastasis, and number of tumor nodes. Multivariate Cox proportional hazards model analysis showed that low expression of miR-148a was independently associated with recurrence of HCC in the current study. Moreover, our result showed that lower expression in tumor tissues in comparison with corresponding normal control tissues. CONCLUSION: Down-regulation of miR-148a is related to HCC carcinogenesis and deterioration of HCC. MicroRNA 148a may act as a suppressor miRNA of HCC, and it is therefore a potential prognostic biomarker for HCC patients. PMID- 26248882 TI - Realising skilled companionship in nursing: a utopian idea or difficult challenge? AB - AIMS AND OBJECTIVES: The question being considered in this discussion article is whether nurses' practice can be usefully characterised in terms of skilled companionship. BACKGROUND: A nurse's role might be characterised as one of a 'skilled companion,' a concept that brings together the scientific and moral basis of nursing practice. It is this focus on integrating both 'skill' and 'companionship' characteristics of nurses' practice that largely determines their effectiveness as care providers and their specific contribution to health care outcomes. METHODS: Discursive article that invites readers to explore and arrive at a more comprehensive understanding of nurses' daily practice, one from an ethical perspective that is based on empirical data from the study of patients' caring experiences, nurses' caring experiences and nurses' ethical practice in daily care. CONCLUSIONS: Research in this era of health care highlights an important dilemma that the nursing profession is confronted with daily: realising nurses' role as a skilled companion in an environment where this concept of nursing care is discouraged, or even thwarted. Although the ethical dimension is explicitly and universally recognised as a core dimension of nursing care, research clearly highlights nurses' difficulties in translating this element into daily practice. Most disturbing in these findings is that both patients and nurses feel compelled to reach a compromise to 'survive' in this often-chaotic caring environment. RELEVANCE TO CLINICAL PRACTICE: It appears today that nurses' intrinsic strengths and potential are largely underutilised in daily practice. More than ever, the nursing profession is challenged to reflect on the future position, aspirations and responsibilities of nurses, to make clear choices, and to act accordingly. Viewing and implementing the nurse's role as one of a skilled companion promise better health care delivery in a postmodern world. PMID- 26248883 TI - Drugs and ventricular repolarization in a general population: the Rotterdam Study. AB - PURPOSE: Prolonged ventricular repolarization (measured as heart-rate corrected QT (QTc) prolongation or JT-interval prolongation) is a risk factor for ventricular arrhythmias and can be drug-induced. Drugs can be classified as having known or possible QTc-prolonging properties. Regulatory agencies recommend avoiding concomitant use of multiple QTc-prolonging drugs, but evidence is lacking to what degree ventricular repolarization is influenced by concomitant use of these drugs. METHODS: Within a population-based cohort of persons aged 45 years and older, with up to five electrocardiograms recorded per participant between 1991 and 2010, we used generalised estimating equations to study the association between concomitant use of multiple QTc-prolonging drugs and repolarization duration. RESULTS: The study population consisted of 13 009 participants with 26 908 electrocardiograms. With the addition of a second or third QTc-prolonging drug there was no substantial increase in QTc and JT interval and no increased risk of a prolonged QTc interval, compared to use of one QTc-prolonging drug. There was a large difference between the effect of one known or one possible QTc-prolonging drugs on QTc interval: 15 ms for known, and 3 ms for possible QTc-prolonging drugs. CONCLUSIONS: In this study, the added prolongation in users of two or three QTc-prolonging drugs on QTc was small. There was a large difference in QTc prolongation between known and possible QTc prolonging drugs. Further research in larger or high-risk populations is needed to establish whether it is safe to use multiple QTc-prolonging drugs concomitantly to prevent that the current advice might unnecessarily withhold beneficial drugs from patients. PMID- 26248884 TI - Aero-optimum hovering kinematics. AB - Hovering flight for flapping wing vehicles requires rapid and relatively complex reciprocating movement of a wing relative to a stationary surrounding fluid. This note develops a compact analytical aero-kinematic model that can be used for optimization of flapping wing kinematics against aerodynamic criteria of effectiveness (maximum lift) and efficiency (minimum power for a given amount of lift). It can also be used to make predictions of required flapping frequency for a given geometry and basic aerodynamic parameters. The kinematic treatment is based on a consolidation of an existing formulation that allows explicit derivation of flapping velocity for complex motions whereas the aerodynamic model is based on existing quasi-steady analysis. The combined aero-kinematic model provides novel explicit analytical expressions for both lift and power of a hovering wing in a compact form that enables exploration of a rich kinematic design space. Good agreement is found between model predictions of flapping frequency and observed results for a number of insects and optimal hovering kinematics identified using the model are consistent with results from studies using higher order computational models. For efficient flight, the flapping angle should vary using a triangular profile in time leading to a constant velocity flapping motion, whereas for maximum effectiveness the shape of variation should be sinusoidal. For both cases the wing pitching motion should be rectangular such that pitch change at stroke reversal is as rapid as possible. PMID- 26248885 TI - A polarizable empirical force field for molecular dynamics simulation of liquid hydrocarbons. AB - Electronic polarizability is usually treated implicitly in molecular simulations, which may lead to imprecise or even erroneous molecular behavior in spatially electronically inhomogeneous regions of systems such as proteins, membranes, interfaces between compounds, or mixtures of solvents. The majority of available molecular force fields and molecular dynamics simulation software packages does not account explicitly for electronic polarization. Even the simplest charge-on spring (COS) models have only been developed for few types of molecules. In this work, we report a polarizable COS model for cyclohexane, as this molecule is a widely used solvent, and for linear alkanes, which are also used as solvents, and are the precursors of lipids, amino acid side chains, carbohydrates, or nucleic acid backbones. The model is an extension of a nonpolarizable united-atom model for alkanes that had been calibrated against experimental values of the density, the heat of vaporization and the Gibbs free energy of hydration for each alkane. The latter quantity was used to calibrate the parameters governing the interaction of the polarizable alkanes with water. Subsequently, the model was tested for other structural, thermodynamic, dielectric, and dynamic properties such as trans/gauche ratios, excess free energy, static dielectric permittivity, and self-diffusion. A good agreement with the experimental data for a large set of properties for each considered system was obtained, resulting in a transferable set of polarizable force-field parameters for CH2, CH3, and CH4 moieties. PMID- 26248886 TI - Computational modeling of extracellular dopamine kinetics suggests low probability of neurotransmitter release. AB - Dopamine in the striatum signals the saliency of current environmental input and is involved in learned formation of appropriate responses. The regular baseline firing rate of dopaminergic neurons suggests that baseline dopamine is essential for proper brain function. The first goal of the study was to estimate the likelihood of full exocytotic dopamine release associated with each firing event under baseline conditions. A computer model of extracellular space associated with a single varicosity was developed using the program MCell to estimate kinetics of extracellular dopamine. Because the literature provides multiple kinetic values for dopamine uptake depending on the system tested, simulations were run using different kinetic parameters. With all sets of kinetic parameters evaluated, at most, 25% of a single vesicle per varicosity would need to be released per firing event to maintain a 5-10 nM extracellular dopamine concentration, the level reported by multiple microdialysis experiments. The second goal was to estimate the fraction of total amount of stored dopamine released during a highly stimulated condition. This was done using the same model system to simulate published measurements of extracellular dopamine following electrical stimulation of striatal slices in vitro. The results suggest the amount of dopamine release induced by a single electrical stimulation may be as large as the contents of two vesicles per varicosity. We conclude that dopamine release probability at any particular varicosity is low. This suggests that factors capable of increasing release probability could have a powerful effect on sculpting dopamine signals. PMID- 26248887 TI - Solution-processed new porphyrin-based small molecules as electron donors for highly efficient organic photovoltaics. AB - A series of unsymmetrical pi-conjugated small molecules have been constructed from meso-alkyl substituted porphyrins as the central unit and 3-ethylrhodanine as the terminal group. Using PC71BM as an acceptor, and these small molecules as electron donors in solution-processed bulk-heterojunction solar cells, a high power conversion efficiency of 6.49% has been achieved. PMID- 26248888 TI - Re-evaluating the role of Doppler ultrasonography in patients presenting with scrotal pain. AB - AIM: To describe our experience of all patients presenting to a tertiary referral centre over a 5-year time period with acute scrotum and to investigate the role of Doppler ultrasonography (DUS) for investigating this group of patients. METHOD: A retrospective analysis was performed on all patients presenting to the emergency department (ED) of a level 1 trauma centre with acute scrotum from 2009 to 2014 inclusive. Inclusion criteria included all patients who underwent an investigatory DUS and/or emergency scrotal exploration. Recorded patient demographics included age, presenting symptoms, duration of symptoms and relevant examination findings. RESULT: Three-hundred and twelve patients were included with a mean age of 15 years (range 1 day-40 years). In total, 106 patients underwent immediate scrotal exploration, and testicular torsion (TT) was found in 30 % (n = 32/106). Two-hundred and twenty-two patients were initially investigated with DUS and 16 (7.2 %) proceeded to scrotal exploration. Of this sub-group, 2/16 presented with a history <24 h and exploration was negative for TT. In comparison, 14/16 presented with a history >24 h, and DUS findings were consistent with TT. No patients with a normal DUS represented to the ED after discharge. CONCLUSION: DUS may prevent unnecessary scrotal exploration in patients presenting with acute scrotal pain and is useful for diagnosing TT in patients presenting with symptoms >24 h. PMID- 26248889 TI - Persistent rotavirus diarrhea post-transplant in a novel JAK3-SCID patient after vaccination. PMID- 26248890 TI - Effects of Developmental Temperature on Gametocysts and Oocysts of Two Species of Gregarines Blabericola migrator and Blabericola cubensis (Apicomplexa: Eugregarinida: Blabericolidae) Parasitizing Blaberid Cockroaches (Dictyoptera: Blaberidae). AB - Abiotic environmental conditions, especially temperature and humidity, have profound effects on the growth and development of gregarines, but these effects remain largely undocumented. Quantifying the effects of environmental conditions on the growth and development of exogenous gregarine ontogenetic stages is an important first step in understanding the transmission, population dynamics, and environmental persistence of gregarine infection. In this study, we examined the effect of 6 environmental temperatures (10, 18, 22, 27, 35, and 40 C) at constant humidity (0 mmHg vapor pressure deficit) on gametocyst development and oocyst viability in 2 gregarine species: Blabericola migrator and Blabericola cubensis parasitizing the Tiger-striped Hissing Cockroach, Princisia vanwaerebecki, and the Discoid Cockroach, Blaberus discoidalis, respectively. Temperature has a significant effect on gametocyst development and oocyst viability for both gregarine species. Gametocyst development for both gregarine species displays a similar threshold response to environmental temperature: 10 and 40 C represent extremes outside their developmental range, but within these extremes, the relationship between gametocyst development and temperature is weakly direct. Dehiscence increased with temperature from 68% at 18 C to 93% at 22 C and remained at that level through 35 C. Developmental temperature also has a meaningful but inverse effect on oocyst viability of both B. migrator and B. cubensis. For both species, oocyst viability is highest at 18 and 22 C and is significantly reduced at 27 and 35 C. Thus oocyst production and sporozoite viability are linked but environmentally independent phenomena. Overall, there is an acceptable developmental temperature zone for B. migrator and B. cubensis that ranges from 18 to 27 C, but production of viable sporozoites is greatest in a relatively narrow zone around 22 C. Prior studies have postulated that mechanisms that concentrate oocysts and hosts, such as host behavior or host microhabitat preference, increase the host-oocyst encounter rate and thus transmission. This study indicates that abiotic influences on gametocyst development may also lead to heterogeneous oocyst distributions in the environment and increase the likelihood of host-oocyst encounters. PMID- 26248891 TI - Evolution of anuran brains: disentangling ecological and phylogenetic sources of variation. AB - Variation in ecological selection pressures has been implicated to explain variation in brain size and architecture in fishes, birds and mammals, but little is known in this respect about amphibians. Likewise, the relative importance of constraint vs. mosaic hypotheses of brain evolution in explaining variation in brain size and architecture remains contentious. Using phylogenetic comparative methods, we studied interspecific variation in brain size and size of different brain parts among 43 Chinese anuran frogs and explored how much of this variation was explainable by variation in ecological factors (viz. habitat type, diet and predation risk). We also evaluated which of the two above-mentioned hypotheses best explains the observed patterns. Although variation in brain size explained on average 80.5% of the variation in size of different brain parts (supporting the constraint hypothesis), none of the three ecological factors were found to explain variation in overall brain size. However, habitat and diet type explained a significant amount of variation in telencephalon size, as well in three composite measures of brain architecture. Likewise, predation risk explained a significant amount of variation in bulbus olfactorius and optic tecta size. Our results show that evolution of anuran brain accommodates features compatible with both constraint (viz. strong allometry among brain parts) and mosaic (viz. independent size changes in response to ecological factors in certain brain parts) models of brain size evolution. PMID- 26248892 TI - Explaining the mobility of retinal in activated rhodopsin and opsin. AB - Rhodopsin, the mammalian dim light photoreceptor, is the canonical model for G protein-coupled receptors. Activation of rhodopsin occurs when the covalently bound inverse agonist, retinal, absorbs a photon and undergoes an 11-cis to all trans isomerization. Two critical components of the visual cycle occur with the (1) hydrolytic release of all-trans retinaldehyde and subsequent (2) uptake of 11 cis retinaldehyde to reform the Schiff base linkage in the apoprotein opsin. Two pores on the surface of opsin are connected via the retinal channel, as discovered upon solution of the X-ray crystal structure (Park et al., Nature, 2008), and could serve as potential entryways for uptake and release. Using molecular dynamics simulations, we examined the behavior of rhodopsin in the Meta II conformation (active) under Meta-I conditions (inactive), and discovered that the retinal binding pocket is flexible enough to allow a 180 degrees rotation along the long axis of the retinal polyene chain. This result reconciles a discrepancy between the known polyene chain orientation from crystallographic and spectroscopic studies and opens the door for further investigation into the intermolecular interactions between the retinal ligand and the apoprotein opsin. Subsequent docking studies of both isomers of retinal into the opsin channel were then conducted to identify the mechanism for uptake and release. Our results suggest that retinal undergoes unidirectional uptake through Pore A and release through Pore B, and that aromatic sidechain interactions play a key role in stabilizing retinal within the opsin channel. These findings are significant in developing our understanding of the retinoid cycle and how ligand-receptor interactions in rhodopsin relate to G protein-coupled receptor activation. PMID- 26248894 TI - CD34 immunohistochemistry in bone marrow biopsies for early response assessment in acute myeloid leukemia. AB - INTRODUCTION: Acute myeloid leukemia is a heterogenous disease with respect to prognosis. Early response assessment has an established role as predictor of remission rate, and overall and disease-free survival. Assessment of blast percentage on bone marrow aspirate smears at this stage has its own limitations. MATERIALS AND METHOD: In this study, a total of 100 AML cases that were positive for CD34 at the time of diagnosis were included in the study. Blast percentage obtained in bone marrow aspirate smears by morphology was compared with that obtained in bone marrow biopsy using CD34 immunohistochemistry. RESULTS: Bone marrow aspirate and biopsy were discordant in 19% of the cases. In 15% of the cases, bone marrow aspirate blast count was <= 5% and bone marrow biopsy blast percentage was >5%. CONCLUSION: Early response assessment plays an important role in management of acute myeloid leukemia. In patients with CD34-positive blasts, the CD34 IHC can improve the detection of residual blasts on Day 14 bone marrow biopsy in comparison with morphological assessment of blast percentage in bone marrow aspirate. PMID- 26248895 TI - GNAS mutations are not detected in parosteal and low-grade central osteosarcomas. AB - Parosteal osteosarcoma, low-grade central osteosarcoma, and fibrous dysplasia share similar histological features that may pose a diagnostic challenge. The detection of GNAS mutations in primary bone tumors has been useful in clinical practice for diagnosing fibrous dysplasia. However, the recent report of GNAS mutations being detected in a significant proportion of parosteal osteosarcoma challenges the specificity of this mutation. As the number of cases reported in this study was small we set out to determine if these results could be reproduced. We studied 97 formalin-fixed paraffin-embedded low-grade osteosarcomas from 90 patients including 62 parosteal osteosarcomas, of which MDM2 amplification was detected in 79%, 11 periosteal osteosarcomas and 24 low grade central osteosarcoma samples. The mutational status of GNAS was analyzed in codons p.R201, p.Q227, and other less common GNAS alterations by bidirectional Sanger sequencing and/or next generation sequencing using the Life Technologies Ion Torrent platform. GNAS mutations were not detected in any of the low-grade osteosarcomas from which informative DNA was extracted. Our findings therefore support prior observations that GNAS mutations are highly specific for fibrous dysplasia and occur rarely, if ever, in parosteal and other low-grade osteosarcomas. PMID- 26248896 TI - Metanephric adenoma: the utility of immunohistochemical and cytogenetic analyses in differential diagnosis, including solid variant papillary renal cell carcinoma and epithelial-predominant nephroblastoma. AB - Metanephric adenoma is a benign renal neoplasm that overlaps in morphology with the solid variant of papillary renal cell carcinoma and epithelial-predominant nephroblastoma. To aid in resolving this differential diagnosis, we investigated the utility of immunohistochemical and molecular analyses in distinguishing between these entities; the first study, to our knowledge, to use a combined approach in analyzing all three tumors. We analyzed 37 tumors originally diagnosed as metanephric adenomas (2 of which we reclassified as papillary renal cell carcinomas), 13 solid variant papillary renal cell carcinomas, and 20 epithelial-predominant nephroblastomas using a combination of immunohistochemistry and fluorescence in situ hybridization (FISH) assessing for trisomy of chromosomes 7 and 17 and loss of Y. Immunohistochemical staining was performed for CK7, AMACR, WT1, and CD57. The combination of CK7-, AMACR-, WT1+, and CD57+ was considered characteristic of metanephric adenoma. Most of the tumors originally diagnosed as metanephric adenomas (31/37) showed the expected staining pattern of metanephric adenoma (CK7-, AMACR-, WT1+, and CD57+). Of the six tumors with discordant immunophenotype, two tumors were reclassified as papillary renal cell carcinoma after cytogenetic workup. It is recommended that all adult cases histologically resembling metanephric adenoma have WT1, CD57, CK7, and AMACR immunohistochemical staining performed. If the staining pattern is characteristic for metanephric adenoma (CK7-, AMACR-, WT1+, and CD57+, including membranous staining), then no other diagnostic tests are indicated. However, if there is a different immunostaining pattern, then we recommend FISH analysis. PMID- 26248898 TI - Reaction monitoring using online vs tube NMR spectroscopy: seriously different results. AB - We report findings from the qualitative evaluation of nuclear magnetic resonance (NMR) reaction monitoring techniques of how each relates to the kinetic profile of a reaction process. The study highlights key reaction rate differences observed between the various NMR reaction monitoring methods investigated: online NMR, static NMR tubes, and periodic inversion of NMR tubes. The analysis of three reaction processes reveals that rates derived from NMR analysis are highly dependent on monitoring method. These findings indicate that users must be aware of the effect of their monitoring method upon the kinetic rate data derived from NMR analysis. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26248899 TI - Dissociated neural effects of cortisol depending on threat escapability. AB - Evolution has provided us with a highly flexible neuroendocrine threat system which, depending on threat imminence, switches between active escape and passive freezing. Cortisol, the "stress-hormone", is thought to play an important role in both fear behaviors, but the exact mechanisms are not understood. Using pharmacological functional magnetic resonance imaging we investigated how cortisol modulates the brain's fear systems when humans are under virtual predator attack. We show dissociated neural effects of cortisol depending on whether escape from threat is possible. During inescapable threat cortisol reduces fear-related midbrain activity, whereas in anticipation of active escape cortisol boosts activity in the frontal salience network (insula and anterior cingulate cortex), which is involved in autonomic control, visceral perception and motivated action. Our findings suggest that cortisol adjusts the human neural threat system from passive fear to active escape, which illuminates the hormone's crucial role in the adaptive flexibility of fear behaviors. PMID- 26248897 TI - Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy. AB - Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in a variety of human neoplasms. The prognostic significance of survivin expression in diffuse large B-cell lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is unclear. We used standard immunohistochemistry methods to quantify survivin expression in 463 patients with de novo diffuse large B-cell lymphoma who received the R-CHOP. Of the 463 patients, 269 (58%) had survivin overexpression with a cutoff of >25%, associated with an International Prognostic Index score of >2 (P=0.015), disease in >=2 extranodal sites (P=0.011), and a high Ki-67 index (P<0.0001). Among patients with activated B cell-like disease, the overall survival rate of survivin-positive patients was significantly lower than that of survivin-negative patients (P=0.033); multivariate analysis confirmed that in these patients, survivin overexpression was an independent prognostic factor for survival. Among patients with wild-type p53 overexpression, the overall survival and progression free survival rates of the survivin-positive group were significantly lower than those of the survivin-negative group (P=0.035 and P=0.04 respectively). In STAT3 positive patients, survivin overexpression was associated with significantly better survival. Among patients with activated B cell-like disease, survivin positive compared with survivin-negative groups had significantly different gene expression signatures, including genes involved in mitosis or tumor cell proliferation. Our results indicate that survivin is an independent prognostic factor for poor outcome in patients with activated B cell-like disease treated with the R-CHOP regimen, and patients with survivin-positive activated B cell like diffuse large B-cell lymphoma seem to benefit less from this treatment and may require additional novel agents. PMID- 26248901 TI - Decreased rates of operant food self-administration are associated with reward deficits in high-fat feeding mice. AB - PURPOSE: Highly palatable foods behave as appetitive reinforcers and tend to be consumed compulsively. Nevertheless, the motivation for this kind of diets in experimental diet-induced obesity models has not been well established. Our hypothesis is that obesity caused by a regular consumption of high-fat diet (HFD) occurs concomitantly with the inhibition of food reward. The ultimate goal of our study was to further analyze the extent to which the perception of food as an appetitive reinforcer is a necessary condition for obesity. METHODS: We have evaluated the influence of HFD on operant food self-administration (FSA) during a whole light-dark (12-12-h) cycle in mice that consumed HFD either during 1, 4 or 8 weeks. The study has been complemented by a two-bottle free-choice assay between tap water and sweetened drinks. RESULTS: These data show that both 4- and 8-week HFD treatments induced a significant decrease in operant FSA rate. Moreover, HFD impaired the sweetened-conditioned flavor preference in the two bottle choice assay. CONCLUSION: Our results, showing a reduction in how hard an animal is willing to work for food reinforcers, provide evidence that chronic consumption of HFD negatively contributes to the incentive motivation to acquire food/drink reinforcers. We demonstrate that energy homeostasis imbalance triggered by HFD is associated with the inhibition of hedonic feeding. PMID- 26248902 TI - Taxonomic revision and molecular phylogeny of Gymnocorymbus Eigenmann, 1908 (Teleostei, Characiformes, Characidae). AB - Characidae, one of the most diverse families of Characiformes and one of the largest clades of fishes in the world, has a complex taxonomic background, with one issue being the placement of various genera, including Gymnocorymbus. Herein, we generate the first molecular phylogeny for the genus using three nuclear and two mitochondrial loci and review the systematics of Gymnocorymbus. This genus includes the black tetra, a well-known and popular species among aquarists. Molecular phylogeny strongly supports the monophyly of Gymnocorymbus, with this hypothesis corroborated by the presence of three morphological synapomorphies. Of the six previously known nominal species of Gymnocorymbus, three are considered valid herein: Gymnocorymbus bondi from the Rio Orinoco basin, Gymnocorymbus ternetzi from the Rio Paraguay basin, and Gymnocorymbus thayeri from the Corantijn and Amazon basin and rivers of northeastern Brazil. A fourth species, Gymnocorymbus flaviolimai sp. n., is described from the Rio Madeira, Amazon basin. Lectotypes are designated for G. ternetzi and G. thayeri. Our results support previous hypotheses of the alignment of Gymnocorymbus close to the subfamily Stethaprioninae and also support the sister relationship between G. ternetzi and G. thayeri, and of that clade as sister to G. bondi. PMID- 26248903 TI - Merluccius tasmanicus Matallanas & Lloris 2006 is a junior synonym of M. australis (Hutton 1872) (Gadiformes: Merluciidae) based on morphological and molecular data. AB - The high intraspecific variation among and the conservative external morphology of Merluccius spp. have resulted in serious identification difficulties. Four hundred and twenty fresh and preserved specimens of Merluccius were analyzed, including the type series of Merluccius australis, M. tasmanicus and M. hubbsi; specimens of M. hubbsi from Argentina, Brazil and Uruguay, and individuals of M. australis from Argentina and New Zealand were examined. The nomenclatural status of the type specimens of M. australis is discussed and the designation of a lectotype and a paralectotype is proposed. The comparative study of morphology, meristic, traditional and landmark-based morphometry, both external and internal, and through DNA-based Barcoding molecular tools demonstrates that Merluccius tasmanicus is a junior synonym of Merluccius australis. Meristic and morphometric characters of types of M. tasmanicus completely overlap those of M. australis, whereas M. hubbsi show fewer scales along the lateral line, total vertebrae, second dorsal and anal-fin rays. A trend of a longer snout and wider head in M. australis and M. tasmanicus, and larger eyes and longer pelvic fins, in M. hubbsi was observed. While discriminant characters were found in the internal elements (hyomandibula, urohyal and sagitta otolith) between M. hubbsi and M. australis, none were observed between M. australis and those reported for M. tasmanicus. DNA barcoding analyses found no evidence of the existence of other species of Merluccius besides M. hubbsi and M. australis. PMID- 26248904 TI - The water mite genus Procorticacarus K.O. Viets in Australasia (Acari: Hydrachnidia, Hygrobatidae). AB - The following new species are described: Procorticacarus curtipalpis, P. kosciuszko, P. nasutus, P. neocaledonicus, P. neoprasadi, P. paulaae, P. quadriscutatus, P. queenslandicus, P. septentrionalis and P. wenlockensis. The male of Procorticacarus australicus is described for the first time. Many new records are reported for Australia, with the first records of the genus from South Australia, Western Australia and the Northern Territory. Moreover, the genus is for the first time reported from New Caledonia. A key is given for all Australian species of the genus. PMID- 26248905 TI - Taxonomic studies on Dolichothrips (Thysanoptera: Phlaeothripinae), pollinators of Macaranga trees in Southeast Asia (Euphorbiaceae). AB - Five new species associated with the inflorescences of Macaranga trees are described in the Asian genus Dolichothrips Karny. Four of these, chikakoae, eriae, fialae and utae, are from the Malaysian region where they are involved in the pollination of these trees. The fifth, franae, is described from the Hawaiian Islands but is probably introduced from Southeast Asia, and this species appears also to be a pollinator of its host plant. In contrast, little is known of the biology of the many species of Dolichothrips from India. However, D. indicus (Hood) is here interpreted as a variable, polyphagous and widespread species around the tropics, with D. nesius Stannard and D. pumilus Priesner placed as new synonyms. D. reuteri (Karny) from Australia, is also not restricted to Macaranga, and D. flavipes (Moulton) from Taiwan is here considered a new synonym of reuteri. An identification key is provided to 15 species of this genus, but this excludes five species for which specimens were not available. D. citricrurus Moulton, described from Ethiopia, is transferred to Apelaunothrips Karny. PMID- 26248906 TI - Tachornithoglyphus gen. nov.--a new genus of nidicolous Pyroglyphidae (Acariformes: Astigmata). AB - Tachornithoglyphus gen. nov. (Acariformes: Pyroglyphidae) is established for Tachornithoglyphus tachornis (Cruz, Cuervo and Dusbabek, 1984), comb. nov. (transferred from Guatemalichus), collected from nests of the Antillean palm swift, Tachornis phoenicobia (Apodiformes: Apodidae) in Cuba. The new genus differs from the other four genera of the subfamily Guatemalichinae, Guatemalichus Fain and Wharton, 1970, Pottocola Fain, 1971, Fainoglyphus Atyeo and Gaud, 1977, and Capitonocoptes Fain and Gaud, 1984, mainly by having the length of solenidion sigma1 of genu I less than one-third that of the segment (vs. solenidion sigma1I at least half as long as genu I), by the absence of famulus epsilon on tarsus I (vs. present), and by coxal apodemes Ia separated from each other and contiguous to the lateral parts of the epigynal arch (vs. posterior tips of apodemes Ia fused to each other and with the median part of the epigynal arch, or separated and contiguous to or fused with the median part of the epigynal arch). A detailed redescription of adults and tritonymphs of T. tachornis is provided. PMID- 26248907 TI - A review of the genus Palaeagrotis with description of a new species from South Mongolia (Lepidoptera, Noctuidae). AB - A small Central Asian Noctuidae genus Palaeagrotis Hampson, 1907 is revised. One new species, P. adrienneae Volynkin, Gyulai & Behounek, sp. n. is described from South Mongolia. The lectotypes of Hadena inops Lederer, 1853 and Heterographa sibirica Staudinger, 1896 are designated. The adults, and the male and female genitalia are illustrated. PMID- 26248908 TI - Review of the Mexican species of Erythmelus (Hymenoptera: Mymaridae), with description of two new species. AB - The Mexican species of Erythmelus Enock (Hymenoptera: Mymaridae) are revised. A key to females of 13 species is provided in both English and Spanish. Two new taxa are described--E. maya Guzman-Larralde & Triapitsyn, sp. n. and E. tigres Guzman-Larralde & Triapitsyn, sp. n. Six species are newly recorded from Mexico- E. angustatus Ogloblin, E. cingulatus Ogloblin, E. clavatus Ogloblin, E. gracilis (Howard), E. nanus Dozier, and E. noeli (Dozier), besides new geographic records for E. miridiphagus Dozier, E. picinus (Girault), E. psallidis Gahan, and E. rex (Girault) which were previously known from the country. PMID- 26248909 TI - Description and biology of Euborellia arcanum sp. nov., an alien earwig occupying greenhouses in Germany and Austria (Dermaptera: Anisolabididae). AB - Greenhouses in botanical or zoological gardens are home to dozens of species of invertebrates that were introduced alongside plants or potting soil. Our study presents the description of an alien species of earwig, Euborellia arcanum sp. nov., found in tropical greenhouses in Leipzig and Potsdam (Germany) and in Vienna (Austria), including information about its biology in breeding culture. The species was most likely introduced into Europe by way of plants or plant matter from Florida, but the region of its natural habitat is unknown. The sequence of the mitochondrial gene cytochrome c oxidase subunit I (COI) was also evaluated and added to GenBank as a DNA barcode for further identification. PMID- 26248911 TI - On the family-group ranks of katydids (Orthoptera, Tettigoniidae). AB - The purpose of this note is to propose minor modifications to recent changes in the classification of katydids, to preserve the stability of the family Tettigoniidae as including all katydids. This concept has been used in the majority of references since it was established long ago (Krauss 1902), with comparatively few exceptions, where all katydid subfamilies were treated as families in superfamily Tettigonioidea. PMID- 26248910 TI - Description of a new species of Fannia Robineau-Desvoidy, 1830 (Diptera: Fanniidae) and distribution records of the genus from the Caucasus Mountains. AB - A new species, Fannia caucasica sp. nov., is described from localities in Georgia and Armenia between 1600 and 2200 m. In addition, previous literature on the genus Fannia Robineau-Desvoidy, 1830 in the Caucasus Mountains is reviewed, and records are given for 15 species from Armenia and Georgia, of which nine are new records for Armenia and seven are new records for Georgia. PMID- 26248912 TI - Phylogeny of Protopolybia Ducke, 1905 and taxonomic revision of the Protopolybia exigua species-group (Hymenoptera: Vespidae, Polistinae), with description of four new species. AB - A first phylogenetic hypothesis is proposed for Protopolybia Ducke, 1905 based on cladistic analysis of 31 species. New evidence in support of monophyly of the genus is presented. A revision of the Protopolybia exigua species-group is also presented. Protopolybia diligens (Smith, 1857), stat. resurr. is revalidated. Four new species are described: P. collombiana Santos, Silveira & Carpenter, sp. nov., P. clypeata Santos, Silveira & Carpenter, sp. nov., P. similis Santos, Silveira & Carpenter, sp. nov., and P. potiguara Santos, Silveira & Carpenter, sp. nov. Protopolybia holoxantha (Ducke, 1904) and P. rubrithorax Bequaert, 1944 are redescribed. New synonymy is proposed for P. bituberculata Silveira & Carpenter, 1995 =Polybia nana Cameron, 1912 (nom. praeocc., nec de Saussure 1863), syn. nov. New records and description of the male genitalia are provided for some of the species of the P. exigua species-group. PMID- 26248913 TI - The Orbiniidae (Annelida: Polychaeta) of Pacific Costa Rica. AB - Seven species of Orbiniidae are described from the Pacific coast of Costa Rica including two new species. Leodamas hamatus n. sp., a commonly occurring species on the coast of Pacific Costa Rica, is described from 11-18 m in the Gulf of Nicoya and Bahia Culebra. This species is unusual in that the neuropodial uncini differ morphologically from anterior to posterior in the thorax. Scoloplos cryptospinigerus n. sp. is described from 18-22 m in the Gulf of Nicoya and has only a few short, toothed spines amidst numerous capillary setae in most of the thoracic neuropodia. This arrangement of thoracic neurosetae is unusual and has been seen only in one other described species of Scoloplos from Australia. PMID- 26248914 TI - Revision of the Australian species of Aka White, 1879 (Fulgoromorpha: Cixiidae) with the description of a new genus. AB - The Australian species of the genus Aka White are revised. Seven new species are described: A. balma sp. nov., A. dobsonensis sp. nov., A. gwana sp. nov., A. issidopsis sp. nov., A. kuraka sp. nov., A. pirri sp. nov., A. sorellensis sp. nov. Adding to those the 5 species solely occurring in New Zealand, we have a total number of 14 species in Aka. The types of A. hardyi Muir, 1931 and part of the type series including the holotype of A. tasmani Muir, 1931 are declared lost. However, based on the original descriptions and the remaining type material, these species have been matched with new material examined and are redescribed in this paper. Neotypes are designated for A. hardyi and A. tasmani. A new monotypic genus Yanganaka gen. nov. is described from Australia. Based on characters such as the general shape of the body as well as a forked frontal carina it appears to be closely related to Aka and the New Zealand genus Chathamaka Lariviere, 1999. Yanganaka ariecornia sp. nov. is described and illustrated. An identification key to differentiate between the two genera occurring in Australia, Aka and Yanganaka, is provided. Information on how to distinguish Chathamaka from the latter two genera, as well as a key to identify all Australian species of Aka is presented. Host plant associations are discussed which support the hypothesis that Aka is a Gondwanan relict. PMID- 26248915 TI - A new subgenus and two new species of oribatid mites of the genus Neoribates (Acari, Oribatida, Parakalummidae) from the Philippines. AB - The oribatid mite family Parakalummidae (Oribatida, Oripodoidea) is recorded for the first time from the Philippines. A new subgenus of the genus Neoribates, N. (Pseudoneoribates) subgen. nov., is proposed and two new species, N. (Ps.) negrosensis sp. nov. and N. (Ps.) kontschani sp. nov., are described. The new subgenus differs from the other subgenera and genera of Parakalummidae by the morphology and structure of prolamellae, which are smoothly fused to lamellae basally and curving backwards in medio-anterior parts. An identification key to all known subgenera of Neoribates is given. Neoribates (N.) corticis (Ewing, 1913) combined in the subgenus Neoribates (Parakalumma): N. (Par.) corticis comb. nov.. PMID- 26248916 TI - New Aderidae (Coleoptera: Tenebrionoidea) from Baltic and Bitterfeld amber. AB - Nine extinct species and one genus of aderid beetles (Coleoptera: Tenebrionoidea: Aderidae) are described from Baltic and Bitterfeld amber from Germany, Russia (Kaliningrad), Poland, and Denmark. These new species include: Escalerosia igori sp. nov., Picemelinus irinae sp. nov., Vanonus ulmerigicus sp. nov., Vanonus aestiorum sp. nov., Cnopus kraxtepellenensis sp. nov., and four species from the extinct genus Palaeocnopus gen. nov.: P. densipunctatus sp. nov., P. saeticornis sp. nov., P. glabricornis sp. nov., and P. mara sp. nov. A key to the species of Palaeocnopus in amber is provided. The newly described taxa of these ant-like leaf beetles are photographed, illustrated, and compared with extinct and related extant representatives of the genera. PMID- 26248917 TI - A new caruncle-bearing Limnonectes (Anura: Dicroglossidae) from northeastern Thailand. AB - A new species of the dicroglossid frog genus Limnonectes is described from Ubon Ratchathani Province, northeastern Thailand. Limnonectes lauhachindai sp. nov. differs from its congeners by having males with a low-profiled, U-shaped caruncle with free posterior margin that completely occupies, but does not extend beyond, the interobital region. The new species is most closely related to L. gyldenstolpei and L. dabanus. Its description brings the total number of caruncle bearing species of Limnonectes to five. PMID- 26248918 TI - A new species of Larimichthys from Terengganu, east coast of Peninsular Malaysia (Perciformes: Sciaenidae). AB - A new species of Larimichthys from Terengganu, east coast of Peninsular Malaysia is described from specimens collected from the fish landing port at Pulau Kambing, Kuala Terengganu. Larimichthys terengganui can be readily distinguished from other species of the genus by having an equally short pair of ventral limbs at the end of the gas bladder appendages, which do not extend lateral-ventrally to the lower half of the body wall, and fewer dorsal soft rays (29-32 vs. 31-36) and vertebrae (24 vs. 25-28). Larimichthys terengganui can be distinguished from L. polyactis and L. crocea by having a gill raker at the angle of first gill arch shorter than the gill filament. Furthermore, the second anal spine in L. terengganui is equal or slightly shorter than eye diameter (vs. shorter in L. polyactis); L. terengganui has 8-9 anal soft rays (vs. only 7 in L. pamoides). Snout length of L. terengganui is greater than eye diameter, whereas in L. crocea the snout is shorter than eye diameter. A key to species of Larimichthys is provided. All obtained specimens of the species were recorded from Terengganu waters, east coast of Peninsular Malaysia. PMID- 26248919 TI - Taxonomic notes on the crab spider genera Stephanopoides and Isaloides (Araneae: Thomisidae: Stephanopinae). AB - According to current catalogues, two species are allocated to the genus Parastephanops F. O. Pickard-Cambridge, 1900. The examination of the type of Parastephanops cognatus (O. Pickard-Cambridge, 1892) (type-species of Parastephanops) has revealed the presence of a high cephalic region, legs with dark metatarsus and apex of tibia, and triangular epigynum with median ridge, all diagnostic features of Stephanopoides Keyserling, 1880. However, the female of P. echinatus (Banks, 1914) has a low cephalic region, a median ocular quadrangle longer than wide and a large atrium of the epigynum, which are diagnostic features of Isaloides F. O. Pickard-Cambridge, 1900. Thus, Parastephanops is synonymized with Stephanopoides and its two species, P. cognatus and P. echinatus, are redescribed, illustrated and assigned to Stephanopoides and Isaloides, respectively. We also propose that Pyresthesis berlandi Caporiacco, 1947 is a junior synonym of Stephanopoides simoni Keyserling, 1880 based on shape and arrangement of the epigynal plate, copulatory ducts and spermathecae. PMID- 26248920 TI - A new species of Amanahyphes Salles & Molineri, 2006 (Ephemeroptera: Leptohyphidae) from Bahia, Brazil. AB - A new species of the previously monotypic genus Amanahyphes Salles & Molineri, 2006 is described based on the male imago, egg and nymph from the state of Bahia, Brazil. Characters and illustrations to distinguish Amanahyphes bahiensis sp. nov. from A. saguassu and all other species in Leptohyphidae are provided. Amanahyphes bahiensis sp. nov. is diagnosed as follows: in the male imago, forewing shaded slightly with brownish at basal third and penes basally fused, distally with diverging lobes, and with a short spine-like projection at midlength on lateral margin; in the nymph, femoral spines long, slender and acuminate, tarsal claws with 10-11 marginal denticles and 2+3 subapical submarginal denticles, gill formula 3/2/2/2. Geographic records of both species are amended and indicated on a map. PMID- 26248921 TI - A new species of Simopelta (Hymenoptera: Formicidae: Ponerinae) from Brazil and Costa Rica. AB - The genus Simopelta consists of 21 described species restricted to Central America and South America. The present study describes a new cryptobiotic species, Simopelta anomma sp. nov.. The new species is blind, possesses a 3 segmented antennal club, and has the midtibia with several stout setae, a combination of characters unique within the genus. Moreover, some traits of this species require broadening the definition of the genus. The discovery of S. anomma sp. nov. suggests that many undiscovered species, some of which may be important for understanding ant evolution, remain hidden below ground in Neotropical rainforests. PMID- 26248922 TI - Additional new species of the genus Pterodichopetala (Phaneropteridae: Phaneropterinae) from Northeastern Mexico. AB - Four new Species of the genus Pterodichopetala from Northeastern Mexico are described: P. monternach n. sp., P. tuliensis n. sp., P. geovanyi n. sp., and P. robertoi n. sp. Information on distribution and ecology is provided. PMID- 26248923 TI - Selected species of the family Diastylidae (Cumacea, Peracarida, Crustacea) from the deep-sea of the NW Pacific. AB - New species of the genera Diastylis, Divacuma and Leptostylis are described. Also a new species of the genus Pseudoleptostyloides, known from the Atlantic, is described for the NW Pacific. Additional information is given on Leptostyloides quadridentata. PMID- 26248924 TI - Pizacris: a new genus and two new species of Luzarinae cricket close to Guabamima de Mello, 1992 and Mellopsis Mews & Sperber, 2010 (Orthoptera: Grylloidea: Luzarinae). AB - Here we describe a new genus and two new species of Luzarinae crickets (Grylloidea, Phalangopsidae) from the Brazilian Atlantic Forest of Espirito Santo, Minas Gerais and Rio de Janeiro States (Brazil). We describe Pizacris Souza-Dias & Desutter-Grandcolas, n. gen., transfer the species Mellopsis zefai Mews & Sperber, 2010 to P. zefai (Mews & Sperber, 2010) n. comb., redescribe this species based in topotypes and, since the type series is lost, designate a neotype. We also describe the second species of this genus, P. carioca Desutter Grandcolas & Souza-Dias n. gen., n. sp. The new genus is characterized by the dark brown uniform coloration with strikingly white joints 4 and 5 of maxillary palpi, reduced FWs, without stridulatory file and, mainly, the absence of the pseudepiphallic arms in male phallic complex. We provide a brief discussion about the morphology of male genitalia in Pizacris Souza-Dias & Desutter-Grandcolas, n. gen. and related genera, Guabamima de Mello, 1992 and Mellopsis Mews & Sperber, 2010. We also provide an identification key for these genera and notes about the reproductive behavior of P. zefai (Mews & Sperber, 2010) n. comb. PMID- 26248925 TI - A new species of the stingless bee Trichotrigona (Hymenoptera: Apidae, Meliponini). AB - Trichotrigona camargoiana sp. nov. from Candeias do Jamari, Rondonia, Brazil is described and illustrated, along with nesting and behavior, as the second species of the rare and unusual genus Trichotrigona Camargo & Moure, 1983. The new species differs from T. extranea Camargo & Moure, 1983 by having plumose setae on the face and mesepisterna, wing setae predominantly yellow and black metatibia. The diagnosis for Trichotrigona is updated. As believed for T. extranea, T. camargoiana sp. nov. apparently does not store food and is a cleptobiotic social bee associated with Frieseomelitta. PMID- 26248926 TI - Vansoestia caribensis gen. nov., sp. nov.: first report of the family Ianthellidae (Verongida, Demospongiae) in the Caribbean. AB - A thin fiber-less sponge from Caribbean reefs (Bocas del Toro, Panama) with close genetic affinities (based on 18S and 28S nuclear ribosomal RNA gene sequences) to large fan-shaped fiber-bearing sponges (Ianthella and Anomoianthella) from the Indo-Pacific Ocean is here presented. We describe its overall external morphology, histological features, and ultrastructure. Its genetic distance from the only previously known fiber-less verongid genus, Hexadella, prompted the need to erect a new genus to classify this species. This novel species constitutes the first record for a member of the family Ianthellidae in the Caribbean. The characterization of the family Ianthellidae (sensu Cook and Bergquist, 2000) is here modified by: i) highlighting the cavernous nature of the choanosome, with many lacunae and channels reported for all genera included in the family; ii) extending the family distribution to the Caribbean; and iii) adding a fourth genus to the group of verongids with eurypylous chambers. The possession of a cellularized cortex (10-300 um in thickness) is here proposed as a potential synapomorphic character of the Ianthella-Anomoianthella-Vansoestia clade. The main issues regarding the suprageneric classification of verongids are discussed. PMID- 26248927 TI - Two new species of lizards of the genus Stenocercus (Iguania, Tropiduridae) from central Peru. AB - We describe two new species of Stenocercus from the Andes of central Peru (Departamento Ancash): Stenocercus amydrorhytus sp. nov. from elevations between 2810 and 3075 m and S. johaberfellneri sp. nov. from elevations between 3120 and 3200 m. Stenocercus amydrorhytus is most similar to S. ivitus, S. chrysopygus, S. melanopygus, S. modestus, S. orientalis, and S. stigmosus from which it differs in having a combination of 44-52 vertebral scales, 42-47 scales around midbody, 18-21 gulars, and 23-26 subdigital lamellae under fourth toe, the lateral nuchals less than half the size of dorsal nuchals, predominantly smooth dorsal head scales, a poorly developed oblique neck fold with a shallow or no mite pocket underneath, a uniformly gray venter in preservative in the only known adult male, and a tail length less than 70% of total length. Stenocercus johaberfellneri is most similar to S. latebrosus and S. ornatissimus from which it differs in having a combination of 47-53 vertebral scales, 46-53 scales around midbody, the presence of a postfemoral pocket in adult males, a throat pattern of bold black streaks or reticulations in adult males, a dusky or grayish venter in preservative without black spots or reticulations, and lateral nuchals less than half the size of dorsal ones. PMID- 26248928 TI - New taxa of southern African Sesiini (Lepidoptera: Sesiidae). AB - Two new genera of Sesiini from southern Africa, each comprising only a single species are described and figured: Microsesia nana, new gen., new sp. (holotype in TMPS) and Coccophila, new gen., with Coccophila pythes (Druce, 1899), new comb. (holotype in BMNH). Bionomical data for Coccophila pythes are given for the first time. PMID- 26248930 TI - A further note on the scientific name of Bullocks' Oriole. PMID- 26248929 TI - Description of the first species of Scambus Hartig (Hymenoptera, Ichneumonidae) from Peru, with a key to the Neotropical species. AB - In this work we describe and illustrate two new species of Scambus from the Peruvian Andes and the Andean-Amazonian interface: S. amazonicus Gomez sp. n., and S. incanus Gomez sp. n. These are the first Scambus species described from Peru. In addition, we provide an identification key to the Neotropical species of the genus. PMID- 26248931 TI - Redescription of Eidophasia tauricella Staudinger, 1880 (Lepidoptera, Plutellidae) with first description of the female genitalia. AB - Eidophasia tauricella Staudinger, 1880 is redescribed with a photo of the type specimen. The female genitalia are described for the first time. PMID- 26248932 TI - New substitute name for the genus Mistaria Medler, 1988 (Hemiptera: Fulgoromorpha: Flatidae). PMID- 26248933 TI - Descriptions of twelve new species of ochyroceratids (Araneae, Ochyroceratidae) from mainland Ecuador. AB - Twelve new species in three different genera from the spider family Ochyroceratidae are described from mainland Ecuador: Speocera bioforestae sp. n., Speocera violacea sp. n., Speocera musgo sp. n., Ochyrocera rinocerotos sp. n., Ochyrocera callaina sp. n., Ochyrocera italoi sp. n., Ochyrocera minotaure sp. n., Ochyrocera losrios sp. n., Ochyrocera zabaleta sp. n., Ochyrocera otonga sp. n., Ochyrocera cashcatotoras sp. n. and Psiloochyrocera tortilis sp. n. Speocera machadoi Gertsch 1977 is transferred to Ochyrocera. PMID- 26248934 TI - Two new species of the genus Vosmaeropsis Dendy, 1892 (Porifera, Calcarea), with comments on the distribution of V. sericata (Ridley, 1881) along the Southwestern Atlantic Ocean. AB - Two new species of the genus Vosmaeropsis are described: V. recruta sp. nov. and V. complanatispinifera sp. nov., both from the Brazilian coast. These species possess arrow-shaped large diactines in their skeletons, which are being described for the first time in Vosmaeropsis. In addition, the latter species presents another remarkable character: the apical actines of its atrial tetractines is flattened and provided with spines. Vosmaeropsis complanastispinifera sp. nov. is being proposed based on the re-analysis of specimens that in the past were assigned to V. sericata. Thus, with the reallocation of these specimens to the newly described species, the current distribution range of V. sericata does not include the Brazilian northeastern coast. Vosmaeropsis now comprises 23 species. Most of them present an endemic pattern of distribution, but the genus is widely distributed in tropical and temperate regions around the world. PMID- 26248935 TI - Passalidae (Coleoptera: Scarabaeoidea) of the Greater and Lesser Antilles. AB - We present a synthesis of the state of knowledge concerning the species of Passalidae (Coleoptera) of the West Indies and we present a key to the species. The recently described genus Antillanax Boucher renders the subgenus Passalus (Pertinax) Kaup paraphyletic, therefore we place Antillanax in synonymy with Passalus (Pertinax) and we propose a new combination for Passalus (Pertinax) doesburgi (Boucher). The island richest in species is Hispaniola, with five species, three of them endemic. Excluding Trinidad and Tobago, the passalid fauna of the West Indies comprises 13 species; this is low richness, but with high endemism (50%), especially for the Greater Antilles. PMID- 26248936 TI - Records of Naididae and Lumbriculidae (Clitellata) from Tibet, China, with description of a new species of Nais. AB - The Tibetan Plateau is considered to have a unique fauna of fish and invertebrates. However, little taxonomic work has been conducted on the aquatic Oligochaeta of Tibet, China. Based on the surveys of rivers and lakes in this region between 2010 and 2011, we recorded 25 species of oligochaetes belonging to 2 families and 15 genera. This paper provides an overview of the species composition of different waterbodies, the description of one new species, Nais longidentata sp. n., and re-descriptions of four previously described species. Hitherto, 30 species of aquatic oligochaetes have been recorded from Tibet. The oligochaete fauna is similar to that of the Holarctic, but has several endemic elements. PMID- 26248937 TI - New species and new records of Tingidae (Hemiptera: Heteroptera) from Vietnam. AB - Tingidae (Hemiptera: Heteroptera) collected in Vietnam by several institutions between 1958 and 2013 continue to yield new information about tropical diversity in this family of insects. Herein, thirty-seven species are newly recorded for Vietnam, and four are described as new to science. Comments on their affinities and distribution are provided, highlighting the biological richness of a rapidly developing country with human impacts. PMID- 26248938 TI - New species of Thinophilus Wahlberg (Diptera: Dolichopodidae) from mangroves in southern China (Shenzhen). AB - Three species of Thinophilus Wahlberg are recorded from mangroves near Shenzhen (China). Two species new to science are described and illustrated: T. dongae sp. nov. and T. zhuae sp. nov. In addition, Thinophilus lamellaris Zhu, Yang & Masunaga originally described from Hainan (China) is reported here. Females of this species are described for the first time and variability in male characters is given. These three species plus 6 additional Thinophilus and three Nanothinophilus species from South China Sea mangroves were COI barcoded and compared to species known from the northern part of the South China Sea. PMID- 26248939 TI - Saurida lessepsianus a new species of lizardfish (Pisces: Synodontidae) from the Red Sea and Mediterranean Sea, with a key to Saurida species in the Red Sea. AB - Saurida lessepsianus n. sp., a lizardfish (Aulopiformes: Synodontidae) from the Red Sea and Mediterranean Sea, previously misidentified as S. undosquamis (Richardson) and more recently as S. macrolepis Tanaka, is described as a new species. It is characterised by the following combination of characters: dorsal fin with 11-12 rays; pectoral fins with 13-15 rays; lateral-line scales 47-51; transverse scale rows above lateral line 41/2, below lateral line 51/2; pectoral fins moderately long (extending to between just before or just beyond a line from origin of pelvic fins to origin of dorsal fin); 2 rows of teeth on outer palatines; 0-2 teeth on vomer; tongue with 3-6 rows of teeth posteriorly; caudal peduncle slightly compressed (depth a little more than width); upper margin of caudal fin with row of 3-8 (usually 6 or 7) small black spots; stomach pale grey to blackish anteriorly; intestine whitish. The species is common in the Red Sea and as a result of Lessepsian migration through the Suez Canal, it is now widely distributed in the eastern Mediterranean. The taxonomic status of two other Red Sea nominal species, Saurus badimottah Ruppell [= Saurida tumbil (Bloch)] and Saurida sinaitica Dollfus in Gruvel (a nomen nudum), is clarified. A key is provided for the species of Saurida in the Red Sea. PMID- 26248940 TI - Caprella suprapiscis sp. nov. (Crustacea: Amphipoda: Caprellidae) from the Pacific coast of Mexico. AB - A new species of caprellid, Caprella suprapiscis sp. nov., is described based on several specimens collected from Bahia Chamela, Jalisco, Mexico. All specimens were found in association with the scorpionfish Scorpaena mystes. Caprellids are set on the dorsal surface of fishes. The species is distinguished by head with a short dorsal projection, eyes distinctive, body slender and smooth, peduncular articles of antenna 1 not setose, antenna 2 with swimming setae, gnathopod 2 with three ventral projections in males. The species is close to C. californica, C. mercedesae, and C. scaura for a sharp spine on the forehead but can be distinguished by gnathopod 2 finely setose, and basis of gnathopod 2 shorter. PMID- 26248941 TI - A new genus of the tribe Parahiraciini (Hemiptera: Fulgoromorpha: Issidae) from Hainan Island. AB - A new issid genus in the tribe Parahiraciini (Hemiptera: Fulgoromorpha: Issidae) is erected for Fortunia jianfenglingensis Chen, Zhang et Chang, 2014 (China: Hainan). Male of the species is described and illustrated for the first time. A key for the 15 genera of Parahiraciini is provided. Morphological peculiarity and phylogenetic position of the new genus and the distribution of the tribe Parahiraciini are briefly discussed. PMID- 26248942 TI - Revision of the Tephritis maccus species group (Diptera: Tephritidae) with description of a new species from Iran. AB - The maccus species group of the genus Tephritis Latreille 1804 is revised. The maccus group contains five species with a radiate wing pattern, cell r without or with only one large hyaline spot or indentation on the anterior wing margin, and the aculeus moderately broad, sharply narrowing and pointed at the very apex. The included species are: Tephritis azari Mohamadzade Namin & Korneyev, Tephritis gharalii sp. nov., Tephritis maccus Hering, Tephritis sophus and Tephritis urelliosomima Korneyev & Dirlbek. PMID- 26248943 TI - ARNO A. LISE, CYNARA C. KESSTER & ESTEVAM L. CRUZ DA SILVA (2015) Revision of the orb-weaving spider genus Verrucosa McCook, 1888 (Araneae, Araneidae). Zootaxa, 3921 (1), 1-105. PMID- 26248944 TI - Phosphatase inhibition prevents the activity-dependent trafficking of GABAA receptors during status epilepticus in the young animal. AB - OBJECTIVES: To determine if the activity-dependent trafficking of gamma2 subunit containing gamma-aminobutyric acid type A receptors (GABAA Rs) that has been observed in older animals and posited to contribute to benzodiazepine pharmacoresistance during status epilepticus (SE) is age-dependent, and to evaluate whether blockade of protein phosphatases can inhibit or reverse the activity-dependent plasticity of these receptors. METHODS: The efficacy and potency of diazepam 0.2-10 mg/kg administered 3 or 60 min after the onset of a lithium/pilocarpine-induced seizure in postnatal day 15-16 rats was evaluated using video-electroencephalography (EEG) recordings. The surface expression of gamma2 subunit-containing GABAA Rs was assessed using a biotinylation assay, and GABAA R-mediated miniature inhibitory postsynaptic currents (mIPSCs) were recorded using whole-cell patch-clamp recording techniques from dentate granule cells in hippocampal slices acutely obtained 60 min after seizure onset (SE treated). The effect of the protein phosphatase inhibitors FK506 and okadaic acid (OA) on the surface expression of these receptors was determined in organotypic slice cultures exposed to high potassium and N-methyl-d-aspartate (NMDA) or in SE treated slices. RESULTS: Diazepam terminated seizures of 3 min but not 60 min duration, even at the highest dose. In the SE-treated slices, the surface expression of gamma2 subunit-containing GABAA Rs was reduced and the amplitude of the mIPSCs was diminished. Inhibition of protein phosphatases prevented the activity-induced reduction of the gamma2 subunit-containing GABAA Rs in organotypic slice cultures. Furthermore, treatment of SE-treated slices with FK506 or OA restored the surface expression of the gamma2 subunit-containing GABAA Rs and the mIPSC amplitude. SIGNIFICANCE: This study demonstrates that the plasticity of gamma2 subunit-containing GABAA Rs associated with the development of benzodiazepine resistance in young and adult animals is similar. The findings of this study suggest that the mechanisms regulating the activity-dependent trafficking of GABAA Rs during SE can be targeted to develop novel adjunctive therapy for the treatment of benzodiazepine-refractory SE. PMID- 26248945 TI - MRP1 and P-glycoprotein expression assays would be useful in the additional detection of treatment non-responders in CML patients without ABL1 mutation. AB - We evaluated the ability of the rhodamine-123 efflux assay, multidrug resistance associated protein-1 (MRP1) expression assay and P-glycoprotein (Pgp) expression assay to discriminate chronic myelogenous leukemia (CML) patients who had failed treatment or were at risk of failure. Each assay was performed in blood samples from CML patients (n=224) treated with tyrosine kinase inhibitors, taken at diagnosis (n=14) and follow-up (n=210). Patient samples were categorized as optimal response (n=120), suboptimal response (n=54), and treatment failure (n=36). Treatment-failed patients had a significantly higher MRP1 expression (5.24% vs. 3.54%, P=0.006) and Pgp expression (5.25% vs. 3.48%, P=0.005) than responders. Both MRP1 (%) and Pgp (%) were highly specific (95.2% and 94.5%) and relatively accurate (83.0% and 82.5%) in the detection of treatment non responders. Of treatment-failed patients, 41.2% had a positive result in at least one assay and of these patients without ABL1 kinase domain mutation, 51.9% were positive in at least one assay. However, the rhodamine-123 efflux assay failed to discriminate two patient groups. Thus, both MRP1 and Pgp expression assays could be useful for additional identification of treatment non-responders in CML patients without ABL1 mutation. PMID- 26248946 TI - Silencing of miR-21 sensitizes CML CD34+ stem/progenitor cells to imatinib induced apoptosis by blocking PI3K/AKT pathway. AB - BCR-ABL tyrosine kinase inhibitor imatinib fails to eradicate leukemia stem cells (LSCs), the underlying mechanisms maintaining CML LSCs remain poorly understood. Here, we showed that transient inhibition of miR-21 by antagomiR-21 markedly increased imatinib-induced apoptosis in CML, but not normal CD34+ stem/progenitor cells. Furthermore, PI3K inhibitors also significantly sensitized CML CD34+ cells to imatinib-induced apoptosis. MiR-21 or PI3K inhibitor in combination with imatinib treatment significantly decreased AKT phosphorylation and c-Myc expression than either agent did alone, but did not affect Bim and Bcl-6 expresssion. These findings indicate that miR-21 is required for maintaining the imatinib-resistant phenotype of CML CD34+ cells through PI3K/AKT signaling pathway, thus providing the basis for a promising therapeutic approach to eliminate CML LSCs. PMID- 26248947 TI - Satellite cells isolated from skeletal muscle will proliferate faster in WENS yellow feather chicks. AB - This study was conducted to evaluate the differential proliferation ability of satellite cells (SCs) derived from pectoral muscles (PM) with different fiber characteristics and further to explore the underlying molecular mechanism. WENS Yellow Feather Chicks (WYFC) were chosen as the animal model, with White Plymouth Rock Chicks (WPRC) as a comparison. The results showed that WPRC had higher body and pectoral muscle weight than WYFC at 4 days old (P < 0.05). However, WYFC showed greater fiber numbers/mm(2) but smaller fiber cross-sectional area compared with WPRC in PM (P < 0.05). SCs derived from PM of WYFC had a faster proliferation rate but smaller cell size compared with that from PM of WPRC (P < 0.05). The percentage of cell population in G2/M phase and the messenger RNA abundance of TSC1 (P = 0.08), Rheb (P = 0.07) and target of rapamycin (TOR, P = 0.06) in WYFC were higher than that in WPRC. In conclusion, our results demonstrated that SCs isolated from PM of WYFC had faster proliferation rate but smaller cell size than that in WPRC. The higher SC proliferation in WYFC may be due to higher gene expression of TOR signaling pathway than in WPRC, and the larger cell size of WPRC may be due to higher insulin-like growth factor-1 expression than in WYFC. PMID- 26248948 TI - An experimental viewpoint on the information depth of EBSD. AB - This article contains a critical review of the literature concerning the information depth of electron backscatter diffraction (EBSD) and a viewpoint on the topic is formulated. EBSD is applied to a crystal partially covered by a wedge of amorphous glass. EBSD-patterns of decreasing quality are obtained from a crystal covered by an increasingly thick layer of glass. The location of the last indexable EBSD-patterns is compared to the last discernible contrast in SEM micrographs obtained from the same crystal using accelerating voltages of 2-20 kV. It is concluded that the information depth of EBSD is at least as large as that of an SEM-micrograph obtained with a voltage of 4 kV from a non-tilted sample. Concepts of the information depth and experimental approaches are discussed. PMID- 26248950 TI - Time-of-day variation of visuo-spatial attention. AB - Time-of-day variation of visuo-spatial attention in relation to body temperature and subjective arousal was assessed. At five different times of day, alertness, covert, and overt orienting of attention were assessed in fifteen healthy subjects. Based on previous studies reporting a tight coupling of alerting and orienting the present study investigates potential attentional asymmetries induced by diurnal variations of arousal. Both covert and overt orienting of attention improved in the course of the day. However, no asymmetries between left and right visual hemifields could be detected. Covert orienting additionally covaried with body temperature, indicating a quite close relation between the attentional arousal and orienting system. Conversely, overt orienting only improved due to repeated testing but did not correlate with body temperature suggesting a partial independence of both modes of attentional orienting. It can be assumed that due to limited diurnal variations of arousal in the participants and practice effects caused by repeated testing, no attentional asymmetries could be provoked. PMID- 26248949 TI - Microfluidic Chip-LC/MS-based Glycomic Analysis Revealed Distinct N-glycan Profile of Rat Serum. AB - The rat is an important alternative for studying human pathology owing to certain similarities to humans. Glycomic studies on rat serum have revealed that variations in the N-glycans of glycoproteins correlated with disease progression, which is consistent with the findings in human serum. Therefore, we comprehensively characterized the rat serum N-glycome using microfluidic chip-LC ESI-QTOF MS and MS/MS techniques. In total, 282 N-glycans, including isomers, were identified. This study is the first to present comprehensive profiling of N glycans containing O-acetylated sialic acid, among which 27 N-glycans are novel. In addition, the co-existence of N-acetylneuraminic acid (NeuAc) and N glycolylneuraminic acid (NeuGc) in a single N-glycan ('mixed' N-glycan) was detected and represents a new type of N-glycan in rat serum. The existence of O acetylated sialic acid is the characteristic feature of rat serum that distinguishes it from mouse and human sera. Comparisons between the rat, mouse, and human serum glycomes revealed that the rat glycome is more similar to that of human sera than to that of mouse sera. Our findings highlight the similarities between the glycomic profile of rat and human sera and provided important selection criteria for choosing an appropriate animal model for pathological and pharmacological studies. PMID- 26248951 TI - Growth of High-Quality, Thickness-Reduced Zeolite Membranes towards N2 /CH4 Separation Using High-Aspect-Ratio Seeds. AB - Greatly improved zeolite membranes were prepared by using high-aspect-ratio zeolite seeds. Slice-shaped seeds with a high aspect ratio (AR) facilitated growth of thinner continuous SAPO-34 membranes of much higher quality. These membranes showed N2 permeances as high as (2.87+/-0.15)*10(-7) mol m(-2) s(-1) Pa(-1) at 22 degrees C while maintaining a decent N2 /CH4 selectivity (9-11.2 for equimolar mixture). On the basis of these thinner high-quality SAPO-34 membranes, fine-tuning the local crystal structure by incorporating more silicon further increased the N2 permeance by 1.4 times without sacrificing the N2 /CH4 selectivity. We expect that application of large AR zeolite seeds might be a viable strategy to grow thin high-quality zeolite membranes. In addition, fine tuning of the crystal structure by changing the crystal composition might be a feasible way for further improving the separating performance of high-quality zeolite membranes. PMID- 26248952 TI - Understanding medical errors and adverse events in ICU patients. PMID- 26248953 TI - ICUs after surgery, mortality, and the Will Rogers effect. PMID- 26248954 TI - Integrating macroecological metrics and community taxonomic structure. AB - We extend macroecological theory based on the maximum entropy principle from species level to higher taxonomic categories, thereby predicting distributions of species richness across genera or families and the dependence of abundance and metabolic rate distributions on taxonomic tree structure. Predictions agree with qualitative trends reported in studies on hyper-dominance in tropical tree species, mammalian body size distributions and patterns of rarity in worldwide plant communities. Predicted distributions of species richness over genera or families for birds, arthropods, plants and microorganisms are in excellent agreement with data. Data from an intertidal invertebrate community, but not from a dispersal-limited forest, are in excellent agreement with a predicted new relationship between body size and abundance. Successful predictions of the original species level theory are unmodified in the extended theory. By integrating macroecology and taxonomic tree structure, maximum entropy may point the way towards a unified framework for understanding phylogenetic community structure. PMID- 26248955 TI - Ombitasvir/paritaprevir/r, dasabuvir and ribavirin for cirrhotic HCV patients with thrombocytopaenia and hypoalbuminaemia. AB - BACKGROUND & AIMS: Thrombocytopaenia and hypoalbuminaemia are surrogate markers for portal hypertension and hepatic synthetic dysfunction respectively. Patients infected with hepatitis C virus (HCV) with these surrogates have reduced likelihood of sustained virologic response and increased risk for hepatic decompensation or death when treated with peginterferon/ribavirin plus either telaprevir or boceprevir. METHODS: We conducted a post-hoc analysis of the TURQUOISE-II clinical trial in patients with cirrhosis to examine the impact of these surrogates on efficacy and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin. RESULTS: Of 380 genotype 1-infected patients in TURQUOISE-II, 104 had either a platelet count <100 * 10(9)/L or albumin <3.5 g/dl. Sustained virologic response rates were 89 and 97% in patients with thrombocytopaenia, and 84 and 89% in patients with hypoalbuminaemia after 12 and 24 weeks of ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin respectively. These rates were similar to those observed in the overall study population (92 and 97% for 12 and 24 weeks). HCV genotype 1a-infected patients with thrombocytopaenia or hypoalbuminaemia had higher response rates when treated for 24 weeks, whereas only 1 of 35 genotype 1b patients did not achieve a sustained virologic response. Adverse event rates and discontinuations because of adverse events were low. CONCLUSIONS: The findings of these analyses support the use of ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin in these subpopulations with cirrhosis. Genotype 1a-infected patients with indicators of portal hypertension may benefit from a 24-week treatment duration. PMID- 26248956 TI - I am AmeriBritSouthAfrican-Zambian: Multidimensional remote acculturation and well-being among urban Zambian adolescents. AB - One impact of globalisation is that adolescents today are frequently exposed to the values, attitudes and norms of other nations without leaving their own backyards. This may lead to remote acculturation-cultural and psychological changes experienced by non-migrant individuals having indirect and/or intermittent contact with a geographically separate culture. Using quantitative and qualitative data, we examined multidimensional remote acculturation among 83 urban Zambian adolescents who are routinely exposed to U.S., U.K. and South African cultures through traditional and social media and materials/goods. Cluster analyses showed 2 distinct groups of adolescents. "Traditional Zambians, TZs" (55.4%) were significantly more oriented towards Zambian culture and reported a higher level of obligation to their families and greater interdependent self-construal compared with "Westernised Multicultural Zambians, WMZs" (44.6%), who were more oriented towards U.S., U.K. and South African cultures. Furthermore, remote acculturation predicted somewhat lower life satisfaction among WMZs. These results demonstrate that individuals' behaviours, values and identity may be influenced by multiple geographically distant cultures simultaneously and may be associated with psychological costs. PMID- 26248957 TI - Benefits of glucocorticoids in non-ambulant boys/men with Duchenne muscular dystrophy: A multicentric longitudinal study using the Performance of Upper Limb test. AB - The aim of this study was to establish the possible effect of glucocorticoid treatment on upper limb function in a cohort of 91 non-ambulant DMD boys and adults of age between 11 and 26 years. All 91 were assessed using the Performance of Upper Limb test. Forty-eight were still on glucocorticoid after loss of ambulation, 25 stopped steroids at the time they lost ambulation and 18 were GC naive or had steroids while ambulant for less than a year. At baseline the total scores ranged between 0 and 74 (mean 41.20). The mean total scores were 47.92 in the glucocorticoid group, 36 in those who stopped at loss of ambulation and 30.5 in the naive group (p < 0.001). The 12-month changes ranged between -20 and 4 (mean -4.4). The mean changes were -3.79 in the glucocorticoid group, -5.52 in those who stopped at loss of ambulation and -4.44 in the naive group. This was more obvious in the patients between 12 and 18 years and at shoulder and elbow levels. Our findings suggest that continuing glucocorticoids throughout teenage years and adulthood after loss of ambulation appears to have a beneficial effect on upper limb function. PMID- 26248958 TI - Atypical nuclear abnormalities in a patient with Brody disease. AB - Brody disease was first described as a benign pseudo-myotonic disorder with muscular stiffness, which increased with exercise. Biochemical and genetic studies have pointed out its close relationship to a functional defect of the fast-twitch sarcoplasmic reticulum Ca(++) ATPase pump (SERCA1) encoded by the ATP2A1 gene located on chromosome 16. The histopathological features in this form of myopathy were generally described as non-specific, i.e. moderate degree of type 2 fibre atrophy and excess of internal nuclei. We here present the clinical and histopathological features of a patient with Brody disease over a 19-year follow-up period. This patient had two heterozygous ATP2A1 mutations and complained about muscle stiffness immediately after effort. He had suffered from this since early childhood and exhibited clinical symptoms mimicking myotonia. Histological, ultrastructural and cytogenetic analyses revealed morphologically abnormal nuclei with polyploidy. In this report, we discuss the possible links between the consequences of the genetic abnormality and the peculiar aspect of the nuclei. PMID- 26248959 TI - Seasonal prevalence and determinants of food insecurity in Iqaluit, Nunavut. AB - BACKGROUND: Food insecurity is an ongoing problem in the Canadian Arctic. Although most studies have focused on smaller communities, little is known about food insecurity in larger centres. OBJECTIVES: This study aimed to estimate the prevalence of food insecurity during 2 different seasons in Iqaluit, the territorial capital of Nunavut, as well as identify associated risk factors. DESIGNS: A modified United States Department of Agriculture Food Security Survey was applied to 532 randomly selected households in September 2012 and 523 in May 2013. Chi-square tests and multivariable logistic regression were used to examine potential associations between food security and 9 risk factors identified in the literature. RESULTS: In September 2012, 28.7% of surveyed households in Iqaluit were food insecure, a rate 3 times higher than the national average, but lower than smaller Inuit communities in Nunavut. Prevalence of food insecurity in September 2012 was not significantly different in May 2013 (27.2%). When aggregating results from Inuit households from both seasons (May and September), food insecurity was associated with poor quality housing and reliance on income support (p<0.01). Unemployment and younger age of the person in charge of food preparation were also significantly associated with food insecurity. In contrast to previous research among Arctic communities, gender and consumption of country food were not positively associated with food security. These results are consistent with research describing high food insecurity across the Canadian Arctic. CONCLUSION: The factors associated with food insecurity in Iqaluit differed from those identified in smaller communities, suggesting that experiences with, and processes of, food insecurity may differ between small communities and larger commercial centres. These results suggest that country food consumption, traditional knowledge and sharing networks may play a less important role in larger Inuit communities. PMID- 26248961 TI - F12-46C/T polymorphism as modifier of the clinical phenotype of hereditary angioedema. AB - The factors influencing the heterogeneous clinical manifestation of hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) represent one of the oldest unsolved problems of the disease. Considering that factor XII (FXII) levels may affect bradykinin production, we investigated the contribution of the functional promoter polymorphism F12-46C/T in disease phenotype. We studied 258 C1-INH-HAE patients from 113 European families, and we explored possible associations of F12 46C/T with clinical features and the SERPING1 mutational status. Given that our cohort consisted of related subjects, we implemented generalized estimating equations (GEEs), an extension of the generalized linear model accounting for the within-subject correlation. F12-46C/T carriers exhibited a significantly delayed disease onset (P < 0.001) and did not need long-term treatment (P = 0.02). In a GEE linear regression model, the presence of F12-46C/T was significantly associated with a 7-year delay in disease onset (P < 0.0001) regardless of SERPING1 mutational status. It is concluded that F12-46C/T carriage acts as an independent modifier of C1-INH-HAE severity. PMID- 26248962 TI - Rheology of Rice Flour Dough with Gum Arabic: Small and Large-Deformation Studies, Sensory Assessment and Modeling. AB - The absence of gluten protein makes the rice flour doughs difficult to handle when flattened/sheeted products are to be prepared. The rheological, sensory and microstructural changes in rice flour doughs having gum Arabic (0% to 5%, w/w) and moisture contents (44% to 50%) were studied for improving the dough handling characteristics. Rheological parameters like storage modulus (G') and complex viscosity (eta*) decreased with an increase in moisture content while loss angle (delta) increased. A power-law type equation was suitable to relate angular frequency (omega) with G', G", and eta* (0.814 <= r <= 0.999, P <= 0.01). An increase in gum and moisture contents increased delta from 6.9 degrees to 15.5 degrees but decreased the energy required for compression/flattening. The 6 element spring-dashpot model was suitable (r >= 0.991, P <= 0.01) for creep curves. The sensory panel had the opinion that dough with a low to moderate hardness between 3 and 4, and stickiness of <= 3.5 was suitable for the purpose of flattening in relation to the preparation of sheeted/flattened products; the appropriate condition for dough formulation was with the moisture and gum contents of 47.0% to 47.9% and 1.55% to 2.25%, respectively to offer the desirability index between 0.50 and 0.52. The microstructure of the rice flour dough in the absence of gum Arabic appeared to possess loosely bound flour particles. The presence of gum provided a coating on flour particles to yield dough having good cohesive microstructure. PMID- 26248960 TI - Basal Protein Expression Is Associated With Worse Outcome and Trastuzamab Resistance in HER2+ Invasive Breast Cancer. AB - BACKGROUND: We investigated the effect of basal protein expression on trastuzamab response in patients with HER2-positive (HER2(+)) breast cancer who received trastuzamab (T) and in HER2(+) breast cancer cell lines. PATIENTS AND METHODS: Expression of cytokeratin (CK) 5/6, CK14, and epidermal growth factor receptor (EGFR) was evaluated after immunohistochemical staining in paraffin-embedded tissue of 97 patients with stage I to III HER2(+) breast cancer treated with chemotherapy/T. Groups with and without basal protein expression were compared with respect to clinicopathologic parameters and survival. We treated 4 cell lines (2 basal-HER2 [HCC1569, HCC1954] and 2 nonbasal HER2 [BT474, SKBR3]) each with vehicle, T 20 MUg/mL, paclitaxel 0.01 MUM (P), and T with P (T + P). Cell viability was assessed and HER2 pathway suppression was compared between groups using immunoblot analysis. Mammosphere formation was used to assess breast cancer stem cell properties. RESULTS: EGFR expression was significantly associated with cancer-specific survival (CSS) (P = .05). CK5/6 expression strongly correlated with overall and disease-free survival, and CSS (P = .03, P = .04, and P = .03, respectively). Statistical significance was maintained for EGFR and CK5/6 after adjustment for covariates. CK14 was not associated with survival. All cell lines expressed similar levels of HER2. T and P alone inhibited proliferation of nonbasal cell lines; T + P had an additive cytotoxic effect. Basal cells were resistant to T, P inhibited proliferation, but T + P had no additive cytotoxic effect on cell growth in basal cells. Immunoblot analysis showed a significant decrease in phosphorylated Akt levels after treatment with T or T + P in nonbasal cells but not in basal cells. Akt blockade suppressed growth of basal and nonbasal HER2(+) cells. Furthermore, basal HER2 cell lines had increased mammosphere formation, which suggests increased stem cell properties compared with nonbasal HER2 cell lines. CONCLUSION: CK5/6 and EGFR expression are predictive of worse prognosis in HER2(+) breast cancer patients treated with T. Basal HER2 breast cancer cell lines are resistant to trastuzamab, which is mediated through the Akt pathway; AKT inhibition abrogates this resistance. Basal HER2 cell lines also have increased stem cell properties, which might play a role in the resistance pathway. PMID- 26248963 TI - Preoperative 4D CT Localization of Nonlocalizing Parathyroid Adenomas by Ultrasound and SPECT-CT. AB - OBJECTIVE: To evaluate 4-dimensional (4D) computed tomography (CT) for the localization of parathyroid adenomas previously considered nonlocalizing on ultrasound and single-photon emission CT with CT scanning (SPECT-CT). To measure radiation exposure associated with 4D-CT and compared it with SPECT-CT. STUDY DESIGN: Case series with chart review. SETTING: University tertiary hospital. SUBJECTS AND METHODS: Nineteen adults with primary hyperparathyroidism who underwent preoperative 4D CT from November 2013 through July 2014 after nonlocalizing preoperative ultrasound and technetium-99m SPECT-CT scans. Sensitivity, specificity, predictive values, and accuracy of 4D CT were evaluated. RESULTS: Nineteen patients (16 women and 3 men) were included with a mean age of 66 years (range, 39-80 years). Mean preoperative parathyroid hormone level was 108.5 pg/mL (range, 59.3-220.9 pg/mL), and mean weight of the excised gland was 350 mg (range, 83-797 mg). 4D CT sensitivity and specificity for localization to the patient's correct side of the neck were 84.2% and 81.8%, respectively; accuracy was 82.9%. The sensitivity for localizing adenomas to the correct quadrant was 76.5% and 91.5%, respectively; accuracy was 88.2%. 4D CT radiation exposure was significantly less than the radiation associated with SPECT-CT (13.8 vs 18.4 mSv, P = 0.04). CONCLUSION: 4D CT localizes parathyroid adenomas with relatively high sensitivity and specificity and allows for the localization of some adenomas not observed on other sestamibi-based scans. 4D CT was also associated with less radiation exposure when compared with SPECT-CT based on our study protocol. 4D CT may be considered as first- or second-line imaging for localizing parathyroid adenomas in the setting of primary hyperparathyroidism. PMID- 26248964 TI - Granulocytic Sarcoma of the Frontal Sinuses. PMID- 26248965 TI - The physician and the world of technology. PMID- 26248966 TI - Prevalence of oral and oropharyngeal human papillomavirus infection in Brazilian population studies: a systematic review. AB - INTRODUCTION: Human papillomavirus has been associated with head and neck squamous cell carcinoma. However, there is no conclusive evidence on the prevalence of oral or pharyngeal infection by human papillomavirus in the Brazilian population. OBJECTIVE: To determine the rate of human papillomavirus infection in the Brazilian population. METHODS: Systematic review of published articles. Medline, The Cochrane Library, Embase, Lilacs (Latin American and Caribbean Health Sciences) and Scielo electronic databases were searched. The search included published articles up to December 2014 in Portuguese, Spanish and English. A wide search strategy was employed in order to avoid publication biases and to assess studies dealing only with oral and/or oropharyngeal human papillomavirus infections in the Brazilian population. RESULTS: A total of 42 articles included 4066 enrolled patients. It was observed that oral or oropharyngeal human papillomavirus infections were identified in 738 patients (18.2%; IC 95 17.6-18.8), varying between 0.0% and 91.9%. The prevalences of oral or oropharyngeal human papillomavirus infections were respectively 6.2%, 44.6%, 44.4%, 27.4%, 38.5% and 11.9% for healthy people, those with benign oral lesions, pre-malignant lesions, oral or oropharyngeal squamous cell carcinoma, risk groups (patients with genital human papillomavirus lesions or infected partners) and immunocompromised patients. The risk of human papillomavirus infection was estimated for each subgroup and it was evident that, when compared to the healthy population, the risk of human papillomavirus infection was approximately 1.5-9.0 times higher, especially in patients with an immunodeficiency, oral lesions and squamous cell carcinoma. The rates of the most well-known oncogenic types (human papillomavirus 16 and/or 18) also show this increased risk. CONCLUSIONS: Globally, the Brazilian healthy population has a very low oral human papillomavirus infection rate. Other groups, such as at-risk patients or their partners, immunocompromised patients, people with oral lesions and patients with oral cavity or oropharyngeal squamous cell carcinoma have a high risk of human papillomavirus infection. PMID- 26248967 TI - Variables with prognostic value in the onset of idiopathic sudden sensorineural hearing loss. AB - INTRODUCTION: The establishment of an individualized prognostic evaluation in patients with a diagnosis of idiopathic sudden sensorineural hearing loss (ISSHL) remains a difficult and imprecise task, due mostly to the variety of etiologies. Determining which variables have prognostic value in the initial assessment of the patient would be extremely useful in clinical practice. OBJECTIVE: To establish which variables identifiable at the onset of idiopathic sudden sensorineural hearing loss have prognostic value in the final hearing recovery. METHODS: Prospective, longitudinal cohort study. Patients with ISSHL followed by the Department of Otology-Neurotology of a quaternary hospital were included. The following variables were evaluated and correlated with final hearing recovery: age, gender, vertigo, tinnitus, initial degree of hearing loss, contralateral ear hearing, and elapsed time to treatment. RESULTS: 127 patients with ISSHL were evaluated. Rates of absolute and relative recovery were 23.6dB and 37.2% respectively. Complete hearing improvement was observed in 15.7% patients; 27.6% demonstrated significant improvement and improvement was noted in 57.5%. CONCLUSION: During the onset of ISSHL, the following variables were correlated with a worse prognosis: dizziness, profound hearing loss, impaired hearing in the contralateral ear, and delay to start treatment. Tinnitus at the onset of ISSHL correlated with a better prognosis. PMID- 26248968 TI - Chemical and cytological analysis of cerebral spinal fluid after intrathecal injection of hypodense fluorescein. AB - INTRODUCTION: Intrathecal fluorescein has been effective for topographic diagnosis of rhinoliquorrhea. Nonetheless, there are no reports on the study of cerebral spinal fluid (CSF) after use of intrathecal fluorescein. OBJECTIVE: A prospective study attempting to evaluate CSF through chemical and cytological analysis, after injection of fluorescein. METHODS: Prospective analysis of 24 samples of CSF after intrathecal injection of fluorescein for topographic diagnosis of CSF fistulae, collected at the time of puncture and after 24 and 48h, divided by cellularity: Group 1, up to five cells, and Group 2, with more than five cells. RESULTS: The yellow-greenish color of CSF remained after 48h in 36%, evidencing permanence of fluorescein. No changes in protein and glucose levels were observed between 0-24h and 0-48h. In group 2, an increase in cell count was observed between 24h and 48h (p=0.019). In both groups, there was an increase of neutrophils between 0 and 48h (p=0.048) and a decrease between 24 and 48h (p=0.05). CONCLUSION: Intrathecal fluorescein provoked discreet meningeal reactions, such as an increase of cells between 24 and 48h and an increase of neutrophils at 24h, with a subsequent decrease at 48h with no correlation with symptomatology. PMID- 26248969 TI - Effect of contralateral stimulation on acoustic reflectance measurements. AB - INTRODUCTION: Acoustic reflectance is an important tool in the assessment of middle ear afflictions, and the method is considered advantageous in relation to tympanometry. There has been a growing interest in the study of contralateral acoustic stimulation and its effect on the activation of the efferent auditory pathway. Studies have shown that the introduction of simultaneous stimulation in the contralateral ear generates alterations in auditory response patterns. OBJECTIVE: To investigate the influence of contralateral stimulation on acoustic reflectance measurements. METHODS: Case study of 30 subjects with normal hearing, of both genders, aged 18-30 years. The test and retest acoustic reflectance was conducted in the frequency range 200-6000Hz. The procedure was repeated with the simultaneous presence of contralateral white noise at 30dBNS. RESULTS: The analysis of the conditions of test, retest, and test with contralateral noise showed statistical difference at the frequency of 2kHz (p=0.011 and p=0.002 in test and retest, respectively) in the right ear. CONCLUSION: The activation of the auditory efferent pathways through contralateral acoustic stimulation produces alterations in response patterns of acoustic reflectance, increasing sound reflection and modifying middle ear acoustical energy transfer. PMID- 26248970 TI - Factors influencing the development of otitis media among Sicilian children affected by upper respiratory tract infections. AB - INTRODUCTION: Upper respiratory tract infection is a nonspecific term used to describe an acute infection involving the nose, paranasal sinuses, pharynx and larynx. Upper respiratory tract infections in children are often associated with Eustachian tube dysfunction and complicated by otitis media, an inflammatory process within the middle ear. Environmental, epidemiologic and familial risk factors for otitis media (such as sex, socioeconomic and educational factors, smoke exposure, allergy or duration of breastfeeding) have been previously reported, but actually no data about their diffusion among Sicilian children with upper respiratory tract infections are available. OBJECTIVE: To investigate the main risk factors for otitis media and their prevalence in Sicilian children with and without upper respiratory tract infections. METHODS: A case-control study of 204 children with upper respiratory tract infections who developed otitis media during a 3 weeks monitoring period and 204 age and sex-matched healthy controls. Seventeen epidemiologically relevant features were inventoried by means of standardized questionnaires and skin tests were performed. Univariate analysis and multivariate logistic regression analysis were used to examine the association between risk factors and occurrence of otitis media. RESULTS: Otitis media resulted strongly associated to large families, low parental educational attainment, schooling within the third years of life (p<0.05); children were more susceptible to develop otitis media in the presence of asthma, cough, laryngopharyngeal reflux disease, snoring and apnea (p<0.05). Allergy and urban localization increased the risk of otitis media in children exposed to smoke respectively of 166% and 277% (p<0.05); the joint effect of asthma and presence of pets in allergic population increased the risk of recurrence of 11%, while allergy, cough and runny nose together increased this risk of 74%. CONCLUSIONS: Upper respiratory tract infections and otitis media are common childhood diseases strongly associated with low parental educational attainment (p=0.0001), exposure to smoke (p=0.0001), indoor exposure to mold (p=0.0001), laryngopharyngeal reflux disease (p=0.0002) and the lack of breast-feeding (p=0.0014); an increased risk of otitis media recurrences was observed in the presence of allergy, persistent cough and runny nose (p=0.0001). The modification of the identified risk factors for otitis media should be recommended to realize a correct primary care intervention. PMID- 26248972 TI - Reply "Vaginal rejuvenation": comparative effectiveness studies are needed. PMID- 26248971 TI - Anti-inflammatory effect of certain dimethoxy flavones. AB - OBJECTIVE: The aim of the present study was to evaluate the anti-inflammatory effect of four dimethoxy flavone derivatives; 7,2'-dimethoxy flavone, 7,3' dimethoxy flavone, 7,4'-dimethoxy flavone and 7,8,-dimethoxy flavone and to investigate the possible cellular mechanisms involved. MATERIALS AND METHODS: The acute anti-inflammatory effect of dimethoxy flavones was investigated by carrageenan induced hind paw oedema in rats. Further, the effect of dimethoxy flavones on certain mediators of pain and inflammation like cyclooxygenases (COX 1 and COX-2), pro-inflammatory cytokines (IL-1beta and TNF-alpha) and free radical scavenging activity (NO and LPO) were investigated by using in vitro tests. RESULTS: The investigated dimethoxy flavones produced a significant, dose and time dependent reduction of carrageenan induced paw oedema in rats with a maximum inhibition of 52.4% observed for 7,4'-dimethoxy flavone. Although, the test compounds inhibited both the isoforms of cyclooxygenase, a higher degree of inhibition on COX-2 was evident. A concentration dependent inhibition of other inflammatory cytokines like tumor necrosis factor-alpha and interleukin-1beta was identified in the present study. 7,4'-dimethoxy flavone was found to be maximally effective in inhibiting nitrite ion free radical generation and 7,8-dimethoxy flavone was more active in inhibiting lipid peroxidation than the other compounds. CONCLUSION: The results of the present study reveal the anti inflammatory action of the investigated dimethoxy flavones. Inhibition of cyclooxygenases, cytokines and reactive oxygen species, observed in subsequent experiments may be suggested as possible mechanisms involved in the action of these compounds. PMID- 26248973 TI - Evaluation of adipocytokines and traditional cardiometabolic risk factors in young male cancer survivors: an age-matched control study. AB - BACKGROUND: Life expectancy of cancer survivors has doubled in the past four decades; however, death due to cardiovascular disease is more prevalent in survivors than the general population. OBJECTIVE, DESIGN AND METHODS: We evaluated novel and traditional cardiometabolic risk factors in young male cancer survivors in a cross-sectional study of male cancer survivors aged 25-45 years compared with age-matched noncancer controls. Demographic and anthropometric data were recorded and biochemical and hormonal parameters assayed from fasting blood samples in 176 survivors and 213 controls (lipids were measured in all survivors and 97 controls). RESULTS: Compared with controls, survivors had significantly higher body mass index, adipocytokines, insulin resistance, total cholesterol and triglyceride levels and lower free androgen index (FAI). Handgrip strength, smoking, alcohol consumption, free oestrogen index, insulin-like growth factor 1 and high-density lipoprotein cholesterol levels did not differ between cancer survivors and controls. Risk factors were analysed simultaneously using stepwise multivariable logistic regression, and this showed that high leptin: adiponectin ratio (odds ratio = 2.63; 95% confidence interval: 1.34-5.15; P = 0.005), hypercholesterolaemia (odds ratio = 1.85; 95%CI: 1.08-3.17; P = 0.025) and low FAI (odds ratio = 2.01; 95% confidence interval: 1.07-3.79; P = 0.030) were independently more common in survivors. The odds ratio in survivors for having at least two of these three risk factors rose to 6.58 (95% confidence interval: 3.30 13.12; P < 0.001). Among survivors, risk factors were not different between cancer therapies but worse in survivors who had radiotherapy involving the testes (hyperleptinaemia and insulin resistance) or age at diagnosis above group median (hypertriglyceridaemia and hypercholesterolaemia). CONCLUSIONS: A high leptin: adiponectin ratio, hypercholesterolaemia and low FAI are observed in young male cancer survivors, especially those who received radiotherapy involving the testes or were diagnosed at a later age. In view of their youth and known increased risk of cardiovascular death, treatment strategies are required to address this cardiovascular risk. PMID- 26248974 TI - What Triggers Anger in Everyday Life? Links to the Intensity, Control, and Regulation of These Emotions, and Personality Traits. AB - Why do people experience anger? Most of our knowledge on anger-triggering events is based on the study of reactions at a single time point in a person's life. Little research has examined how people experience anger in their daily life over time. In this study, we conducted a comprehensive examination of the situational determinants of anger over the course of 3 weeks. Using daily diary methodology, people (N = 173; 2,342 anger episodes) reported their most intense daily anger and, with an open-ended format, described the trigger. Participants also answered questions on anger intensity, control, and regulatory strategies, along with baseline personality trait measures. Using an iterative coding system, five anger trigger categories emerged: other people, psychological and physical distress, intrapersonal demands, environment, and diffuse/undifferentiated/unknown. Compared with other triggers, when anger was provoked by other people or when the source was unknown, there was a stronger positive association with anger intensity and lack of control. Personality traits (i.e., anger, mindfulness, psychological need satisfaction, the Big Five) showed few links to the experience and regulation of daily anger. Although aversive events often spur anger, the correlates and consequences of anger differ depending on the source of aversion; personality traits offer minimal value in predicting anger in daily life. PMID- 26248976 TI - Drug-drug interaction between isavuconazole and tacrolimus: a case report indicating the need for tacrolimus drug-level monitoring. AB - WHAT IS KNOWN AND OBJECTIVE: Despite the known significant drug-drug interaction between isavuconazole and tacrolimus, there are no recommendations on dose adjustment when these drugs are given concomitantly. We report on a patient with a mediastinal Aspergillus fumigatus infection resistant to posaconazole and describe how she was successfully managed with tacrolimus therapeutic drug-level monitoring. CASE SUMMARY: Our patient presented with a mediastial Aspergillus fumigatus infection, 2 years after lung transplantation. A. fumigatus was resistant to posaconazole, and the patient had intolerance to voriconazole shown by elevated transaminases. The patient was given isavuconazole with drug-level monitoring. She was managed successfully with no adverse events. Tacrolimus concentration continued to increase after more than 2 weeks of therapy and required a further reduction to 72% of the usual dose to maintain the target concentrations over a 8-week period. WHAT IS NEW AND CONCLUSION: When isavuconazole is given to patients on tacrolimus, the dose of the latter will need considerable reduction. We would suggest an initial 50% reduction and recommend close weekly monitoring of tacrolimus concentration. Further dose decreases of 25-50% may be required. PMID- 26248975 TI - Intracranial fibrosarcoma treated with adjuvant radiation and temozolomide: Report of a case and review of all published cases. AB - INTRODUCTION: Fibrosarcoma is a rare brain tumour with 33 cases reported so far. However, there is no clear consensus about the nature of the disease and treatment as well as outcome. METHODS: A MEDLINE search was carried out using MESH terms like intracranial fibrosarcoma, intraspinal fibrosarcoma, fibrosarcoma meninges and fibrosarcoma brain. A total of 22 case reports and series reporting a total of 33 cases were identified. We here also report a case treated in our institute with adjuvant radiation and concurrent and maintenance temozolomide. RESULTS: The age of presentation ranged from 2months to 75years (Median=17years). The gender ratio was found to be M:F of 1.75-1. Treatment modalities were described for 17 cases. Surgery was part of treatment in all cases while radiation was a part of treatment in 59% of cases (n=10) and chemotherapy in 29% cases (n=5). Survival data were available only for 8 cases and ranged from 1day to 8years (Median=15.5months). CONCLUSION: Fibrosarcoma is a rare disease with dismal prognosis. Surgery remains the cornerstone of therapy. Radiation confers long term disease control and survival. Chemotherapy needs to be evaluated for these tumours to improve survival. PMID- 26248977 TI - Bifidobacterium longum BBMN68-specific modulated dendritic cells alleviate allergic responses to bovine beta-lactoglobulin in mice. AB - AIMS: This study was designed to demonstrate the protective effects of Bifidobacterium longum BBMN68-specific modulated dendritic cells (DCs) on allergic inflammation in beta-lactoglobulin (BLG)-sensitized mice. METHODS AND RESULTS: BALB/c mice were sensitized to BLG in accordance with a model of food allergy protocol and given oral BBMN68 daily. BBMN68 was found to significantly reduce BLG-specific hypersensitivity reactions by suppressing the aberrant balance of Th1/Th2 responses with increasing the number of CD4+CD25+Foxp3+ Treg cells in mesenteric lymph nodes (MLN) by 48.1%. The level of CD103+DCs was up regulated by 136.7 and 56.2% in payer's patches and MLN, respectively, in response to the lower expression levels of cell-surface molecules (CD86 and MHC II) induced by BBMN68 supplementation. The CD11c+DCs isolated from BBMN68 mice showed 45.6% more Foxp3+ expression in vitro. CONCLUSIONS: These data suggest that BBMN68-specific induction of CD11c+CD103+DCs and semi-mature DCs reduce BLG allergic reactions. SIGNIFICANCE AND IMPACT OF THE STUDY: These data confirm that BBMN68 may be a suitable therapeutic approach to the alleviation of food allergies, and BBMN68-specific induction of CD11c+CD103+DCs and semi-mature DCs are associated with this protection. PMID- 26248978 TI - Epithelial atrophy in oral submucous fibrosis is mediated by copper (II) and arecoline of areca nut. AB - Exposure of oral cavity to areca nut is associated with several pathological conditions including oral submucous fibrosis (OSF). Histopathologically OSF is characterized by epithelial atrophy, chronic inflammation, juxtaepithelial hyalinization, leading to fibrosis of submucosal tissue and affects 0.5% of the population in the Indian subcontinent. As the molecular mechanisms leading to atrophied epithelium and fibrosis are poorly understood, we studied areca nut actions on human keratinocyte and gingival fibroblast cells. Areca nut water extract (ANW) was cytotoxic to epithelial cells and had a pro-proliferative effect on fibroblasts. This opposite effect of ANW on epithelial and fibroblast cells was intriguing but reflects the OSF histopathology such as epithelial atrophy and proliferation of fibroblasts. We demonstrate that the pro proliferative effects of ANW on fibroblasts are dependent on insulin-like growth factor signalling while the cytotoxic effects on keratinocytes are dependent on the generation of reactive oxygen species. Treatment of keratinocytes with arecoline which is a component of ANW along with copper resulted in enhanced cytotoxicity which becomes comparable to IC(50) of ANW. Furthermore, studies using cyclic voltammetry, mass spectrometry and plasmid cleavage assay suggested that the presence of arecoline increases oxidation reduction potential of copper leading to enhanced cleavage of DNA which could generate an apoptotic response. Terminal deoxynucleotidyl transferase dUTP Nick End Labeling assay and Ki-67 index of OSF tissue sections suggested epithelial apoptosis, which could be responsible for the atrophy of OSF epithelium. PMID- 26248979 TI - [Politic scandal and civic role of health professionals]. PMID- 26248980 TI - Chirality Transfer in Gold(I)-Catalysed Direct Allylic Etherifications of Unactivated Alcohols: Experimental and Computational Study. AB - Gold(I)-catalysed direct allylic etherifications have been successfully carried out with chirality transfer to yield enantioenriched, gamma-substituted secondary allylic ethers. Our investigations include a full substrate-scope screen to ascertain substituent effects on the regioselectivity, stereoselectivity and efficiency of chirality transfer, as well as control experiments to elucidate the mechanistic subtleties of the chirality-transfer process. Crucially, addition of molecular sieves was found to be necessary to ensure efficient and general chirality transfer. Computational studies suggest that the efficiency of chirality transfer is linked to the aggregation of the alcohol nucleophile around the reactive pi-bound Au-allylic ether complex. With a single alcohol nucleophile, a high degree of chirality transfer is predicted. However, if three alcohols are present, alternative proton transfer chain mechanisms that erode the efficiency of chirality transfer become competitive. PMID- 26248981 TI - Second-Generation Linkage Maps for the Pacific Oyster Crassostrea gigas Reveal Errors in Assembly of Genome Scaffolds. AB - The Pacific oyster Crassostrea gigas, a widely cultivated marine bivalve mollusc, is becoming a genetically and genomically enabled model for highly fecund marine metazoans with complex life-histories. A genome sequence is available for the Pacific oyster, as are first-generation, low-density, linkage and gene-centromere maps mostly constructed from microsatellite DNA makers. Here, higher density, second-generation, linkage maps are constructed from more than 1100 coding (exonic) single-nucleotide polymorphisms (SNPs), as well as 66 previously mapped microsatellite DNA markers, all typed in five families of Pacific oysters (nearly 172,000 genotypes). The map comprises 10 linkage groups, as expected, has an average total length of 588 cM, an average marker-spacing of 1.0 cM, and covers 86% of a genome estimated to be 616 cM. All but seven of the mapped SNPs map to 618 genome scaffolds; 260 scaffolds contain two or more mapped SNPs, but for 100 of these scaffolds (38.5%), the contained SNPs map to different linkage groups, suggesting widespread errors in scaffold assemblies. The 100 misassembled scaffolds are significantly longer than those that map to a single linkage group. On the genetic maps, marker orders and intermarker distances vary across families and mapping methods, owing to an abundance of markers segregating from only one parent, to widespread distortions of segregation ratios caused by early mortality, as previously observed for oysters, and to genotyping errors. Maps made from framework markers provide stronger support for marker orders and reasonable map lengths and are used to produce a consensus high-density linkage map containing 656 markers. PMID- 26248982 TI - Genome-Wide Linkage Analysis Identifies Loci for Physical Appearance Traits in Chickens. AB - Physical appearance traits, such as feather-crested head, comb size and type, beard, wattles size, and feathered feet, are used to distinguish between breeds of chicken and also may be associated with economic traits. In this study, a genome-wide linkage analysis was used to identify candidate regions and genes for physical appearance traits and to potentially provide further knowledge of the molecular mechanisms that underlie these traits. The linkage analysis was conducted with an F2 population derived from Beijing-You chickens and a commercial broiler line. Single-nucleotide polymorphisms were analyzed using the Illumina 60K Chicken SNP Beadchip. The data were used to map quantitative trait loci and genes for six physical appearance traits. A 10-cM/0.51-Mb region (0.0 10.0 cM/0.00-0.51 Mb) with 1% genome-wide significant level on LGE22C19W28_E50C23 linkage group (LGE22) for crest trait was identified, which is likely very closely linked to the HOXC8. A QTL with 5% chromosome-wide significant level for comb weight, which partly overlaps with a region identified in a previous study, was identified at 74 cM/25.55 Mb on chicken (Gallus gallus; GG) chromosome 3 (i.e., GGA3). For beard and wattles traits, an identical region 11 cM/2.23 Mb (0.0-11.0 cM/0.00-2.23 Mb) including WNT3 and GH genes on GGA27 was identified. Two QTL with 1% genome-wide significant level for feathered feet trait, one 9 cM/2.80-Mb (48.0-57.0/13.40-16.20 Mb) region on GGA13, and another 12-cM/1.45-Mb (41.0-53.0 cM/11.37-12.82 Mb) region on GGA15 were identified. These candidate regions and genes provide important genetic information for the physical appearance traits in chicken. PMID- 26248983 TI - GC-Content of Synonymous Codons Profoundly Influences Amino Acid Usage. AB - Amino acids typically are encoded by multiple synonymous codons that are not used with the same frequency. Codon usage bias has drawn considerable attention, and several explanations have been offered, including variation in GC-content between species. Focusing on a simple parameter-combined GC proportion of all the synonymous codons for a particular amino acid, termed GCsyn-we try to deepen our understanding of the relationship between GC-content and amino acid/codon usage in more details. We analyzed 65 widely distributed representative species and found a close association between GCsyn, GC-content, and amino acids usage. The overall usages of the four amino acids with the greatest GCsyn and the five amino acids with the lowest GCsyn both vary with the regional GC-content, whereas the usage of the remaining 11 amino acids with intermediate GCsyn is less variable. More interesting, we discovered that codon usage frequencies are nearly constant in regions with similar GC-content. We further quantified the effects of regional GC-content variation (low to high) on amino acid usage and found that GC-content determines the usage variation of amino acids, especially those with extremely high GCsyn, which accounts for 76.7% of the changed GC-content for those regions. Our results suggest that GCsyn correlates with GC-content and has impact on codon/amino acid usage. These findings suggest a novel approach to understanding the role of codon and amino acid usage in shaping genomic architecture and evolutionary patterns of organisms. PMID- 26248984 TI - A Tool Set for the Genome-Wide Analysis of Neurospora crassa by RT-PCR. AB - Neurospora crassa is an important model organism for filamentous fungi as well as for circadian biology and photobiology. Although the community-accumulated tool set for the molecular analysis of Neurospora is extensive, two components are missing: (1) dependable reference genes whose level of expression are relatively constant across light/dark cycles and as a function of time of day and (2) a catalog of primers specifically designed for real-time PCR (RT-PCR). To address the first of these we have identified genes that are optimal for use as reference genes in RT-PCR across a wide range of expression levels; the mRNA/transcripts from these genes have potential for use as reference noncycling transcripts outside of Neurospora. In addition, we have generated a genome-wide set of RT-PCR primers, thereby streamlining the analysis of gene expression. In validation studies these primers successfully identified target mRNAs arising from 70% (34 of 49) of all tested genes and from all (28) of the moderately to highly expressed tested genes. PMID- 26248985 TI - Fibroblasts Rendered Antifibrotic, Antiapoptotic, and Angiogenic by Priming With Cardiosphere-Derived Extracellular Membrane Vesicles. AB - BACKGROUND: Cardiosphere-derived cells mediate therapeutic regeneration in patients after myocardial infarction and are undergoing further clinical testing for cardiomyopathy. The beneficial effects of cardiosphere-derived cells are mediated by the secretion of exosomes and possibly other extracellular membrane vesicles (EMVs). OBJECTIVES: This study sought to investigate the effect of cardiosphere-derived EMVs (CSp-EMVs) on fibroblasts in vitro and tested whether priming with CSp-EMVs could confer salutary properties on fibroblasts in vivo. METHODS: CSp-EMVs were isolated from serum-free media conditioned for 3 days by cardiospheres. Dermal fibroblasts were primed with CSp-EMVs for 24 h followed by exosomal micro-ribonucleic acid profiling. In vivo, we injected CSp-EMV-primed or -unprimed dermal fibroblasts (or CSp-EMVs) in a chronic rat model of myocardial infarction and defined the functional and structural consequences. RESULTS: CSp EMVs amplified their own biological signals: exposure of "inert" fibroblasts to CSp-EMVs rendered the fibroblasts therapeutic. Intramyocardially injected CSp-EMV primed (but not unprimed) fibroblasts increased global pump function and vessel density while reducing scar mass. CSp-EMV priming caused fibroblasts to secrete much higher levels of stromal-cell-derived factor 1 and vascular endothelial growth factor and dramatically changed the micro-ribonucleic acid profile of fibroblast-secreted EMVs in vitro. The priming was followed by significant angiogenic and cardioprotective effects. CONCLUSIONS: CSp-EMVs alter fibroblast phenotype and secretome in a salutary positive-feedback loop. The phenotypic conversion of inert cells to therapeutically active cells reveals a novel mechanism for amplification of exosome bioactivity. PMID- 26248986 TI - Exosomes Explosion for Cardiac Resuscitation. PMID- 26248987 TI - Use and Outcomes of Triple Therapy Among Older Patients With Acute Myocardial Infarction and Atrial Fibrillation. AB - BACKGROUND: Antithrombotic therapy for acute myocardial infarction (MI) with atrial fibrillation (AF) among higher risk older patients treated with percutaneous coronary intervention (PCI) remains unclear. OBJECTIVES: This study sought to determine appropriate antithrombotic therapy for acute MI patients with AF treated with PCI. METHODS: We examined 4,959 patients >=65 years of age with acute MI and AF who underwent coronary stenting (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines). The primary effectiveness outcome was 2-year major adverse cardiac events (MACE) comprising death, readmission for MI, or stroke; the primary safety outcome was bleeding readmission. Outcomes with dual antiplatelet therapy (DAPT) or triple therapy (DAPT plus warfarin) were compared using Cox proportional hazard modeling with inverse probability-weighted propensity adjustment. RESULTS: Among 4,959 patients, 27.6% (n = 1,370) were discharged on triple therapy. Relative to DAPT, patients on triple therapy had a similar risk of MACE (adjusted hazard ratio [HR]: 0.99 [95% confidence interval (CI): 0.86 to 1.16]) but significantly greater risk of bleeding requiring hospitalization (adjusted HR: 1.61 [95% CI: 1.31 to 1.97]) and greater risk of intracranial hemorrhage (adjusted HR: 2.04 [95% CI: 1.25 to 3.34]). Of 1,591 Medicare Part D patients, 90-day post-discharge warfarin persistence among patients discharged on warfarin was 93.2% (n = 412). Results of 90-day landmark analyses comparing triple therapy versus DAPT in patients persistently on warfarin versus those not discharged on warfarin who had not filled a warfarin prescription were similar to our primary findings. CONCLUSIONS: Approximately 1 in 4 older AF patients undergoing PCI for MI were discharged on triple therapy. Those receiving triple therapy versus DAPT had higher rates of major bleeding without a measurable difference in composite MI, death, or stroke. PMID- 26248988 TI - Triple Therapy...Can We Replace More With Better? PMID- 26248989 TI - Identification of Typical Left Bundle Branch Block Contraction by Strain Echocardiography Is Additive to Electrocardiography in Prediction of Long-Term Outcome After Cardiac Resynchronization Therapy. AB - BACKGROUND: Current guidelines suggest that patients with left bundle branch block (LBBB) be treated with cardiac resynchronization therapy (CRT); however, one-third do not have a significant activation delay, which can result in nonresponse. By identifying characteristic opposing wall contraction, 2 dimensional strain echocardiography (2DSE) may detect true LBBB activation. OBJECTIVES: This study sought to investigate whether the absence of a typical LBBB mechanical activation pattern by 2DSE was associated with unfavorable long term outcome and if this is additive to electrocardiographic (ECG) morphology and duration. METHODS: From 2 centers, 208 CRT candidates (New York Heart Association classes II to IV, ejection fraction <=35%, QRS duration >=120 ms) with LBBB by ECG were prospectively included. Before CRT implantation, longitudinal strain in the apical 4-chamber view determined whether typical LBBB contraction was present. The pre-defined outcome was freedom from death, left ventricular assist device, or heart transplantation over 4 years. RESULTS: Two-thirds of patients (63%) had a typical LBBB contraction pattern. During 4 years, 48 patients (23%) reached the primary endpoint. Absence of a typical LBBB contraction was independently associated with increased risk of adverse outcome after adjustment for ischemic heart disease and QRS width (hazard ratio [HR]: 3.1; 95% CI: 1.64 to 5.88; p < 0.005). Adding pattern assessment to a risk prediction model including QRS duration and ischemic heart disease significantly improved the net reclassification index to 0.14 (p = 0.04) and improved the C-statistics (0.63 [95% CI: 0.54 to 0.72] vs. 0.71 [95% CI: 0.63 to 0.80]; p = 0.02). Use of strict LBBB ECG criteria was not independently associated with outcome in the multivariate model (HR: 1.72; 95% CI: 0.89 to 3.33; p = 0.11. Assessment of LBBB contraction pattern was superior to time-to-peak indexes of dyssynchrony (p < 0.01 for all). CONCLUSIONS: Contraction pattern assessment to identify true LBBB activation provided important prognostic information in CRT candidates. PMID- 26248990 TI - Will the Real Left Bundle Branch Block Please Stand Up? PMID- 26248991 TI - Life Expectancy and Years of Potential Life Lost After Acute Myocardial Infarction by Sex and Race: A Cohort-Based Study of Medicare Beneficiaries. AB - BACKGROUND: Most studies of sex and race differences after acute myocardial infarction (AMI) have not taken into account differences in life expectancy in the general population. Years of potential life lost (YPLL) is a metric that takes into account the burden of disease and can be compared by sex and race. OBJECTIVES: This study sought to determine sex and race differences in long-term survival after AMI using life expectancy and YPLL to account for differences in population-based life expectancy. METHODS: Using data from the Cooperative Cardiovascular Project, a prospective cohort study of Medicare beneficiaries hospitalized for AMI between 1994 and 1995 (N = 146,743), we calculated life expectancy and YPLL using Cox proportional hazards regression with extrapolation using exponential models. RESULTS: Of the 146,743 patients with AMI, 48.1% were women and 6.4% were black; the average age was 75.9 years. Post-AMI life expectancy estimates were similar for men and women of the same race but lower for black patients than white patients. On average, women lost 10.5% (SE 0.3%) more of their expected life than men, and black patients lost 6.2% (SE 0.6%) more of their expected life than white patients. After adjustment, women still lost an average of 7.8% (0.3%) more of their expected life than men, but black race became associated with a survival advantage, suggesting that racial differences in YPLL were largely explained by differences in clinical presentation and treatment between black and white patients. CONCLUSIONS: Women and black patients lost more years of life after AMI, on average, than men and white patients, an effect that was not explained in women by clinical or treatment differences. PMID- 26248992 TI - Life Expectancy and Years of Potential Life Lost: Useful Outcome Measures in Cardiovascular Medicine? PMID- 26248993 TI - Prognostic Role of Serum Chloride Levels in Acute Decompensated Heart Failure. AB - BACKGROUND: Acute decompensated heart failure (ADHF) can be complicated by electrolyte abnormalities, but the major focus has been concentrated on the clinical significance of serum sodium levels. OBJECTIVES: This study sought to determine the prognostic significance of serum chloride levels in relation to serum sodium levels in patients with ADHF. METHODS: We reviewed 1,318 consecutive patients with chronic heart failure admitted for ADHF to the Cleveland Clinic between July 2008 and December 2013. We also validated our findings in an independent ADHF cohort from the University of Pennsylvania (n = 876). RESULTS: Admission serum chloride levels during hospitalization for ADHF were independently and inversely associated with long-term mortality (hazard ratio [HR] per unit change: 0.94; 95% confidence interval [CI]: 0.92 to 0.95; p < 0.001). After multivariable risk adjustment, admission chloride levels remained independently associated with mortality (HR per unit change: 0.93; 95% CI: 0.90 to 0.97; p < 0.001) in contrast to admission sodium levels, which were no longer significant (p > 0.05). Results were similar in the validation cohort in unadjusted (HR per unit change for mortality risk within 1 year: 0.93; 95% CI: 0.91 to 0.95; p < 0.001) and multivariable risk-adjusted analysis (HR per unit change for mortality risk within 1 year: 0.95; 95% CI: 0.92 to 0.99; p = 0.01). CONCLUSIONS: These observations in a contemporary advanced ADHF cohort suggest that serum chloride levels at admission are independently and inversely associated with mortality. The prognostic value of serum sodium in ADHF was diminished compared with chloride. PMID- 26248994 TI - The Role of Sodium and Chloride in Heart Failure: Does It Take Two to Tango? PMID- 26248995 TI - Filling the Feedback Gap in Cardiovascular Education. PMID- 26248996 TI - Pacemaker Quantified Physical Activity Predicts All-Cause Mortality. PMID- 26248997 TI - Severity of Metabolic Syndrome as a Predictor of Cardiovascular Disease Between Childhood and Adulthood: The Princeton Lipid Research Cohort Study. PMID- 26248998 TI - Vulnerable Plaque: Absence of Evidence or Evidence of Absence. PMID- 26248999 TI - Reply: Vulnerable Plaque: Absence of Evidence or Evidence of Absence. PMID- 26249000 TI - Musculoskeletal Pain and Cancer Risk of Staff Working With Fluoroscopically Guided Procedures. PMID- 26249001 TI - Reply: Musculoskeletal Pain and Cancer Risk of Staff Working With Fluoroscopically Guided Procedures. PMID- 26249003 TI - Energy requirements for growth of pubertal female Saanen goats. AB - Previous research on energy requirements of female Saanen goats, using the factorial approach, has not considered the specific requirements for maintenance and growth during the pubertal phase. Thus, the purpose of this study was to estimate energy requirements for maintenance (Trial 1) and growth (Trial 2) of non-pregnant and non-lactating female Saanen goats at the pubertal phase from 30 to 45 kg. In Trial 1, the net energy requirements for maintenance (NEm ) were estimated using 18 female Saanen goats randomly assigned to three levels of intake: ad libitum, and 70% and 40% of ad libitum intake. These animals were pair fed in six slaughter groups, each consisting of one animal for each level of intake. In Trial 2, the net energy requirements for growth (NEg ) were estimated using 18 female Saanen goats, which were fed ad libitum and slaughtered at targeted BW of 30, 38 and 45 kg. The NEm was 52 kcal/kg(0.75) of BW. The NEg increased from 3.5 to 4.7 Mcal/kg of BW gain as BW increased from 30 to 45 kg. Our results suggest that the guidelines of the major feeding systems for the entire growth phase may not be adequate for females at pubertal phase. PMID- 26249002 TI - Altered CELF1 binding to target transcripts in malignant T cells. AB - The RNA-binding protein, CELF1, binds to a regulatory sequence known as the GU rich element (GRE) and controls a network of mRNA transcripts that regulate cellular activation, proliferation, and apoptosis. We performed immunoprecipitation using an anti-CELF1 antibody, followed by identification of copurified transcripts using microarrays. We found that CELF1 is bound to a distinct set of target transcripts in the H9 and Jurkat malignant T-cell lines, compared with primary human T cells. CELF1 was not phosphorylated in resting normal T cells, but in malignant T cells, phosphorylation of CELF1 correlated with its inability to bind to GRE-containing mRNAs that served as CELF1 targets in normal T cells. Lack of binding by CELF1 to these mRNAs in malignant T cells correlated with stabilization and increased expression of these transcripts. Several of these GRE-containing transcripts that encode regulators of cell growth were also stabilized and up-regulated in primary tumor cells from patients with T cell acute lymphoblastic leukemia. Interestingly, transcripts encoding numerous suppressors of cell proliferation that served as targets of CELF1 in malignant T cells, but not normal T cells, exhibited accelerated degradation and reduced expression in malignant compared with normal T cells, consistent with the known function of CELF1 to mediate degradation of bound transcripts. Overall, CELF1 dysfunction in malignant T cells led to the up-regulation of a subset of GRE containing transcripts that promote cell growth and down-regulation of another subset that suppress cell growth, producing a net effect that would drive a malignant phenotype. PMID- 26249004 TI - New concepts for ICD-classification of common mental disorders from the perspective of general medical practice. AB - BACKGROUND: This study aimed at obtaining views of Austrian general practitioners (GPs) regarding the appropriateness of the proposed new ICD11-PHC classifications 'anxious depression', 'bodily stress syndrome' and 'health anxiety'and on the usefulness of their diagnostic criteria in the general medical setting. METHODS: This qualitative study used a focus group method for data collection. RESULTS: There was general support for the additional new concept of anxious depression. When asked to choose between diagnostic criteria of bodily stress syndrome, that listed somatic symptoms in each of four bodily systems, or to use a simpler definition, most participants favoured the simpler approach. Health anxiety was thought to be a concept that overlapped with bodily stress syndrome, but several participants saw advantages in nevertheless distinguishing the two concepts. CONCLUSIONS: The three new concepts were considered as appropriate and useful for the general medical setting, with a general view supporting the simpler definition of bodily stress syndrome. PMID- 26249005 TI - [Pasteur's rabies vaccination: 130 years ago successfully started in Vienna, however officially rejected]. AB - The Viennese surgeon Emerich Ullmann who was trained in rabies vaccination by Pasteur personally started his activity in Vienna on 28.6.1886 vaccinating persons of Austria-Hungary been bitten by rabid animals. Whereas Prof. v.Frisch of the other surgical clinic who also had visited Pasteur carried out animal experiments which urged him to disapprove Pasteur's human rabies vaccination. Ullmann vaccinated with great success but soon there appeared obstructions in Viennese medical journals and hateful discussions in the Austrian Parliament against Pasteur and Ullmann. These facts blocked the necessary financial subvention of Ullmann's self financed vaccinations and resulted in their interruption. After a mass infection of rabies in the Bukowina in 1891 the Supreme Sanitary Board formed an Epidemiologic Committee which recommended the establishment of a vaccination unit in an Austrian hospital. In July 1894 the Vaccination Unit was opened in the Viennese hospital Rudolfstiftung, where Emerich Ullmann carried out the rabies vaccinations. PMID- 26249006 TI - [Can psychopathy be detected psychophysiologically?]. AB - The aim of the present study was to determine whether pupillometry was able to identify and differentiate psychopathic personality traits in criminally responsible mentally disordered offenders (S 21/2 StGB). Psychopathic disorder has not only behavioral, but also psychophysiological correlates, which may be evaluated by pupillometry. This might make it possible to diagnose psychopathy by means of a non-invasive method and in a further step to adapt therapeutic measures accordingly. Psychopathic behavior and personality traits were identified by means of the Hare Psychopathy Checklist-Revised (PCL-R) and offenders were divided into 4 groups with PCL-R scores of 0-10, 11-20, 21-30 and 31-40, respectively. Pupillometry makes it possible to objectively measure amplitudes of pupillary oscillations, which may serve as an indicator of central nervous activation/deactivation. The study at hand showed that the higher the PCL R values, the smaller the amplitudes. Thus, it can be concluded that central nervous activation decreases with higher PCL-R values and psychopathy is associated with central nervous deactivation. PMID- 26249007 TI - [Respiratory allergies in children and adolescents: the role of component resolved diagnosis and specific immunotherapy]. AB - Respiratory allergies of children and adolescents are an important issue in allergology. In parallel to increasing prevalence rates also research has rapidly been developing for the last 10 years. Today we can better understand complex systems to improve our diagnostic and therapeutic accuracy. In addition to medical history, skin-prick-testing and analysis of specific IgE to allergen extracts, component resolved diagnosis has gained importance in the last years. While being increasingly helpful in the diagnosis of insect-venom and food allergies, component-based diagnosis can also improve the management of patients with respiratory allergies. Concerning different therapeutic approaches like allergen-avoidance or symptomatic therapy, specific immunotherapy (SIT) is one of the most interesting therapy-options, as it is still the only causal therapy available. After reasonable patient-selection and the selection of the right allergen and product, SIT has a very good risk/benefit-ration and can induce long term immuno-tolerance to specific allergens. PMID- 26249008 TI - Metabolically Healthy Obesity and Carotid Intima-Media Thickness: Effects of Cardiorespiratory Fitness. AB - OBJECTIVE: To test the hypothesis that cardiorespiratory fitness modifies the association between metabolically healthy obesity (MHO) phenotype and carotid intima-media thickness. PATIENTS AND METHODS: We evaluated 3838 men (mean age, 51 +/- 6 years) who participated in the general health examination program at Samsung Medical Center, Seoul, South Korea, between January 2, 2008, and December 31, 2008. Participants were divided into 4 groups on the basis of body habitus and metabolic health status using the Asia-Pacific criteria. On the basis of Asian criteria, MHO was defined as body mass index greater than or equal to 25 kg/m(2) with less than 3 metabolic abnormalities. Cardiorespiratory fitness (fitness) was directly measured by using peak oxygen uptake and divided into unfit (lower tertile of fitness) and fit (middle and upper tertiles of fitness) categories on the basis of age-specific peak oxygen uptake percentiles. The prevalence of subclinical carotid atherosclerosis was defined as a mean carotid intima-media thickness greater than the 75th percentile. RESULTS: Compared with metabolically healthy normal weight (MHNW), MHO was associated with a higher prevalence of subclinical carotid atherosclerosis (odds ratio, 1.39; 95% CI, 1.12 1.72) after adjusting for potential confounding variables. Using multivariate logistic regression analysis, we found that the MHO unfit group had 2.00 times (95% CI, 1.48-2.73) and the metabolically unhealthy obesity unfit group had 1.84 times (95% CI, 1.26-2.67) higher risk of subclinical carotid atherosclerosis as compared with the MHNW fit group (reference group). However, MHO fit (OR, 1.25; 95% CI, 0.97-1.62) and metabolically unhealthy obesity fit (OR, 1.31; 95% CI, 0.90-1.92) groups had odds ratios for subclinical carotid atherosclerosis similar to those of the MHNW fit group. CONCLUSION: Metabolically healthy obesity was associated with a higher prevalence of subclinical carotid atherosclerosis, but this association was attenuated by increasing levels of cardiorespiratory fitness. PMID- 26249009 TI - Prognostic Value of Model for End-Stage Liver Disease Score Measurements on a Daily Basis in Critically Ill Patients With Cirrhosis. AB - OBJECTIVE: To determine whether daily measurement of Model for End-Stage Liver Disease (MELD) score adds prognostic value to the initial MELD score in predicting mortality among patients with cirrhosis admitted to the intensive care unit (ICU). METHODS: We included 830 consecutive patients with cirrhosis admitted to a tertiary care ICU from January 1, 2003, through December 31, 2013, who had MELD scores on admission day 1 (MELD-D1). Daily MELD score during the first 7 days of ICU admission were retrospectively abstracted. The performances of MELD D1 to MELD-D7 and changes in MELD score on consecutive days (Delta-MELD) in predicting 90-day mortality were determined using logistic regression. RESULTS: MELD-D1 was an independent predictor of mortality (adjusted odds ratio, 1.07; 95% CI, 1.05-1.10; P<.001), with an area under the receiver operating characteristic curve (AUC) of 0.72. MELD-D2 to MELD-D7 yielded comparable performance to MELD-D1 with an approximately 10% increase in risk of death per each incremental unit of MELD score (odds ratios, 1.09-1.11; P<.001; AUCs, 0.68-0.72). Delta-MELD-D2 to Delta-MELD-D7 were not independently associated with mortality (P=.69, P=.42, P=.81, P=.94, P=.83 and P=.28, respectively) and did not increase the predictive performance (AUCs) when combined with MELD-D2 to MELD-D7. CONCLUSION: Repeating MELD score assessment during the first 7 days after ICU admission does not improve the ability of the initial MELD score for predicting 90-day mortality among patients with cirrhosis. Our finding does not support the practice of routine daily measurement of the MELD score. PMID- 26249010 TI - ICOS regulates the pool of group 2 innate lymphoid cells under homeostatic and inflammatory conditions in mice. AB - Group 2 innate lymphoid cells (ILC2s) are innate effectors playing an important role in the defense against helminthic infections and in the pathogenesis of allergic inflammation. Cytokines have been identified as the major stimuli driving ILC2 activation and expansion. Conversely, it is unclear whether costimulatory molecules contribute to regulation of ILC2 functions. ILC2s display high expression of inducible T-cell costimulator (ICOS), which belongs to the CD28 superfamily, and which has been shown to control late effector T-cell functions, and is of utmost importance for the humoral immune response. However, the biological function of ICOS expression on ILC2s is unknown. Here, we show that ICOS signaling in mice regulates ILC2 homeostasis independently of T cells and B cells, by promoting proliferation and accumulation of mature ILC2s in lung and intestine. In a model of IL-33-induced airway inflammation, ICOS controls ILC2 activation and eosinophil infiltration in the lung. Our data identify a role of ICOS in innate immunity and indicate that not only cytokines, but also costimulatory pathways such as those involving ICOS, can contribute to regulate the ILC2 pool. Thus, ICOS costimulation blockade, which is currently under clinical evaluation for inhibiting the humoral immune response, could also target innate inflammatory circuits. PMID- 26249011 TI - Leukocyte Telomere Length and Risks of Incident Coronary Heart Disease and Mortality in a Racially Diverse Population of Postmenopausal Women. AB - OBJECTIVE: Telomeres are regions at the ends of chromosomes that maintain chromosomal structural integrity and genomic stability. In studies of mainly older, white populations, shorter leukocyte telomere length (LTL) is associated with cardiometabolic risk factors and increased risks of mortality and coronary heart disease (CHD). On average, African Americans (AfAm) have longer LTL than whites, but the LTL-CHD relationship in AfAm is unknown. We investigated the relationship of LTL with CHD and mortality among AfAm. APPROACH AND RESULTS: Using a case-cohort design, 1525 postmenopausal women (667 AfAm and 858 whites) from the Women's Health Initiative had LTL measured in baseline blood samples by Southern blotting. CHD or mortality hazards ratios were estimated using race stratified and risk factor-adjusted Cox proportional hazards models. There were 367 incident CHD (226 mortality) events in whites, whereas AfAm experienced 269 incident CHD (216 mortality) events during median follow-up of 13 years. Shorter LTL was associated with older age, current smoking, and white race/ethnicity. In whites, each 1 kilobase decrease in LTL was associated with 50% increased hazard of CHD, hazard ratio=1.50 (95% confidence interval, 1.08-2.10), P=0.017. There was no association between CHD and LTL in AfAm. White women with shorter LTL had higher risks of mortality. In contrast, shorter LTL was weakly associated with decreased mortality hazard in AfAm. CONCLUSIONS: As one of the largest prospective studies of LTL associations with incident CHD and mortality in a racially diverse sample, our study suggests differences in LTL associations with CHD and mortality between white and AfAm postmenopausal women. PMID- 26249012 TI - Specific induction of cranial placode cells from Xenopus ectoderm by modulating the levels of BMP, Wnt, and FGF signaling. AB - The neural-epidermal boundary tissues include the neural crest and preplacodal ectoderm (PPE) as primordial constituents. The PPE region is essential for the development of various sensory and endocrine organs, such as the anterior lobe of the pituitary, olfactory epithelium, lens, trigeminal ganglion, and otic vesicles. During gastrulation, a neural region is induced in ectodermal cells that interacts with mesendodermal tissue and responds to several secreted factors. Among them, inhibition of bone morphogenetic protein (BMP) in the presumptive neuroectoderm is essential for the induction of neural regions, and formation of a Wnt and fibroblast growth factor (FGF) signaling gradient along the midline determines anterior-posterior patterning. In this study, we attempted to specifically induce PPE cells from undifferentiated Xenopus cells by regulating BMP, Wnt, and FGF signaling. We showed that the proper level of BMP inhibition with an injection of truncated BMP receptor or treatment with a chemical antagonist triggered the expression of PPE genes. In addition, by varying the amount of injected chordin, we optimized specific expression of the PPE genes. PPE gene expression is increased by adding an appropriate dose of an FGF receptor antagonist. Furthermore, co-injection with either wnt8 or the Wnt inhibitor dkk-1 altered the expression levels of several region-specific genes according to the injected dose. We specifically induced PPE cell differentiation in animal cap cells from early-stage Xenopus embryos by modulating BMP, Wnt, and FGF signaling. This is not the first research on placode induction, but our simple method could potentially be applied to mammalian stem cell systems. PMID- 26249013 TI - Case reports of adjuvant combination therapy in severe acne vulgaris with chemical peeling using glycolic acid and iontophoresis. PMID- 26249015 TI - Model-data synthesis for the next generation of forest free-air CO2 enrichment (FACE) experiments. AB - The first generation of forest free-air CO2 enrichment (FACE) experiments has successfully provided deeper understanding about how forests respond to an increasing CO2 concentration in the atmosphere. Located in aggrading stands in the temperate zone, they have provided a strong foundation for testing critical assumptions in terrestrial biosphere models that are being used to project future interactions between forest productivity and the atmosphere, despite the limited inference space of these experiments with regards to the range of global ecosystems. Now, a new generation of FACE experiments in mature forests in different biomes and over a wide range of climate space and biodiversity will significantly expand the inference space. These new experiments are: EucFACE in a mature Eucalyptus stand on highly weathered soil in subtropical Australia; AmazonFACE in a highly diverse, primary rainforest in Brazil; BIFoR-FACE in a 150 yr-old deciduous woodland stand in central England; and SwedFACE proposed in a hemiboreal, Pinus sylvestris stand in Sweden. We now have a unique opportunity to initiate a model-data interaction as an integral part of experimental design and to address a set of cross-site science questions on topics including responses of mature forests; interactions with temperature, water stress, and phosphorus limitation; and the influence of biodiversity. PMID- 26249014 TI - Off-Clamp Renal Tumourectomy by Retroperitoneoscopy in Posterior Renal Tumours of Medium Complexity (Padua score 8-9). AB - BACKGROUND: The guidelines recommend partial surgery for T1 renal tumours. Various aspects of this surgery have evolved in recent years, including the clamping method and duration, enucleation, the retroperitoneoscopic approach and the use of 3mm ports. We present our initial series on laparoscopic renal tumourectomy by retroperitoneoscopy (LRTR) and analyse our learning curve and use of 3-mm instrumentation. MATERIAL AND METHODS: From January 2011 to January 2015, we performed LRTR on 50 patients with posterior or convex T1 renal tumours. After 10 cases, the technique changed to off-clamp, and 11 cases were subsequently performed with 3mm instrumentation. RESULTS: The mean tumour size was 34.36 mm (14-62), with a mean PADUA score of 8.42 (5-12). The mean operative time was 163.1 minutes (75-300), and the mean warm ischaemia time was 4.21 minutes (0-28). The main renal artery was not clamped in 41 (82%) patients, and no vessel (zero ischaemia) was clamped in 39 (78%) patients. Seven cases had positive margins (6 focal). Eleven LRTRs were performed with 3mm instrumentation, with shorter surgical times, less intraoperative bleeding and shorter hospital stays. CONCLUSIONS: Retroperitoneoscopy coupled with enucleation enables the extirpation without clamping of posterior renal tumours, with a relatively short learning curve. The 3-mm material enables the technique to be performed, although in our experience it has resulted in a higher rate of positive surgical margins. PMID- 26249017 TI - Method development for the determination of 24S-hydroxycholesterol in human plasma without derivatization by high-performance liquid chromatography with tandem mass spectrometry in atmospheric pressure chemical ionization mode. AB - We developed a highly sensitive and specific high-performance liquid chromatography with tandem mass spectrometry method with an atmospheric pressure chemical ionization interface to determine 24S-hydroxycholesterol, a major metabolite of cholesterol formed by cytochrome P450 family 46A1, in human plasma without any derivatization step. Phosphate buffered saline including 1% Tween 80 was used as the surrogate matrix for preparation of calibration curves and quality control samples. The saponification process to convert esterified 24S hydroxycholesterol to free sterols was optimized, followed by liquid-liquid extraction using hexane. Chromatographic separation of 24S-hydroxycholesterol from other isobaric endogenous oxysterols was successfully achieved with gradient mobile phase comprised of 0.1% propionic acid and acetonitrile using L-column2 ODS (2 MUm, 2.1 mm id * 150 mm). This assay was capable of determining 24S hydroxycholesterol in human plasma (200 MUL) ranging from 1 to 100 ng/mL with acceptable intra- and inter-day precision and accuracy. The potential risk of in vitro formation of 24S-hydroxycholesterol by oxidation from endogenous cholesterol in human plasma was found to be negligible. The stability of 24S hydroxycholesterol in relevant solvents and human plasma was confirmed. This method was successfully applied to quantify the plasma concentrations of 24S hydroxycholesterol in male and female volunteers. PMID- 26249016 TI - Cross-sectional association of volume, blood pressures, and aortic stiffness with left ventricular mass in incident hemodialysis patients: the Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) study. AB - BACKGROUND: Higher left ventricular mass (LV) strongly predicts cardiovascular mortality in hemodialysis patients. Although several parameters of preload and afterload have been associated with higher LV mass, whether these parameters independently predict LV mass, remains unclear. METHODS: This study examined a cohort of 391 adults with incident hemodialysis enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study. The main exposures were systolic and diastolic blood pressure (BP), pulse pressure, arterial stiffness by pulse wave velocity (PWV), volume status estimated by pulmonary pressures using echocardiogram and intradialytic weight gain. The primary outcome was baseline left ventricular mass index (LVMI). RESULTS: Each systolic, diastolic blood, and pulse pressure measurement was significantly associated with LVMI by linear regression regardless of dialysis unit BP or non dialysis day BP measurements. Adjusting for cardiovascular confounders, every 10 mmHg increase in systolic or diastolic BP was significantly associated with higher LVMI (SBP beta = 7.26, 95 % CI: 4.30, 10.23; DBP beta = 10.05, 95 % CI: 5.06, 15.04), and increased pulse pressure was also associated with higher LVMI (beta = 0.71, 95 % CI: 0.29, 1.13). Intradialytic weight gain was also associated with higher LVMI but attenuated effects after adjustment (beta = 3.25, 95 % CI: 0.67, 5.83). PWV and pulmonary pressures were not associated with LVMI after multivariable adjustment (beta = 0.19, 95 % CI: -1.14, 1.79; and beta = 0.10, 95 % CI: -0.51, 0.70, respectively). Simultaneously adjusting for all main exposures demonstrated that higher BP was independently associated with higher LVMI (SBP beta = 5.64, 95 % CI: 2.78, 8.49; DBP beta = 7.29, 95 % CI: 2.26, 12.31, for every 10 mmHg increase in BP). CONCLUSIONS: Among a younger and incident hemodialysis population, higher systolic, diastolic, or pulse pressure, regardless of timing with dialysis, is most associated with higher LV mass. Future studies should consider the use of various BP measures in examining the impact of BP on LVM and cardiovascular disease. Findings from such studies could suggest that high BP should be more aggressively treated to promote LVH regression in incident hemodialysis patients. PMID- 26249019 TI - Beneficial effects of omega-3 fatty acids and vitamin B12 supplementation on brain docosahexaenoic acid, brain derived neurotrophic factor, and cognitive performance in the second-generation Wistar rats. AB - In vegetarian population, vitamin B12 deficiency coexists with suboptimal levels of omega-3 fatty acids. Studies indicate a need for supplementation/fortification of vitamin B12 and omega-3 fatty acids to reduce the risk of brain disorders. We have described the effects of vitamin B12 and omega-3 fatty acid supplementation on brain development in F1 generation animals. The current study investigates the effects of vitamin B12 and omega-3 fatty acids supplementation on brain function and cognition. Pregnant Wistar rats were assigned the following groups: control, vitamin B12 deficient (BD), vitamin B12 deficient + omega-3 fatty acid (BDO), vitamin B12 supplemented (BS), vitamin B12 supplemented + omega-3 fatty acid (BSO). The same diets were continued for two generations. BDO group showed higher (P < 0.05) levels of BDNF (brain derived neurotrophic factor) and DHA (docosahexaenoic acid) in the cortex and hippocampus as compared with the BD group. The cognitive performance was also normalized in this group. BS showed comparable levels of DHA, BDNF (protein and mRNA), and CREB mRNA (cAMP response element-binding protein) to that of control group while Tropomyosin receptor kinase mRNA levels were higher. The combined vitamin B12 and omega-3 fatty acid supplementation further enhanced the levels of DHA (P < 0.05) and BDNF (P < 0.05) in the hippocampus and CREB mRNA (P < 0.01) in the cortex as compared with BS group. The cognitive performance of these animals was higher (P < 0.05) as compared with BS group. Our data indicates the beneficial effects of vitamin B12 and omega-3 fatty acid supplementation across two generations on brain development and function. PMID- 26249020 TI - [Are treatments with statins that are considered unsuitable really unsuitable?]. AB - In the Catalonian Institute of health there are 2 well-established circumstances for indicating lipid-lowering drug treatment with statins in the primary prevention of ischaemic heart disease. These are, severe hypercholesterolaemia, with a low density lipoprotein cholesterol equal to or greater than 240mg/dL, or above 130mg/dL when the coronary risk is equal to or greater than 10% at 10 years. There are data that suggest that these 2 criteria are not the only ones used in routine clinical practice, as such that the majority of patients to whom it is indicated, do not meet either of these 2 conditions. This study aims to determine the characteristics of the patients when statins are indicated outside the aforementioned circumstances. It is concluded that around 40% of patients have clinical characteristics that could justify the treatment. The level of suitability could not be established in about 33% of the patients, due to not being able to determine the coronary risk. PMID- 26249018 TI - Delay in treatment intensification increases the risks of cardiovascular events in patients with type 2 diabetes. AB - BACKGROUND: The aim of the study was to evaluate the effect of delay in treatment intensification (IT; clinical inertia) in conjunction with glycaemic burden on the risk of macrovascular events (CVE) in type 2 diabetes (T2DM) patients. METHODS: A retrospective cohort study was carried out using United Kingdom Clinical Practice Research Datalink, including T2DM patients diagnosed from 1990 with follow-up data available until 2012. RESULTS: In the cohort of 105,477 patients mean HbA1c was 8.1% (65 mmol/mol) at diagnosis, 11% had a history of cardiovascular disease, and 7.1% experienced at least one CVE during 5.3 years of median follow-up. In patients with HbA1c consistently above 7/7.5% (53/58 mmol/mol, n = 23,101/11,281) during 2 years post diagnosis, 26/22% never received any IT. Compared to patients with HbA1c <7% (<53 mmol/mol), in patients with HbA1c >=7% (>=53 mmol/mol), a 1 year delay in receiving IT was associated with significantly increased risk of MI, stroke, HF and composite CVE by 67% (HR CI: 1.39, 2.01), 51% (HR CI: 1.25, 1.83), 64% (HR CI: 1.40, 1.91) and 62% (HR CI: 1.46, 1.80) respectively. One year delay in IT in interaction with HbA1c above 7.5% (58 mmol/mol) was also associated with similar increased risk of CVE. CONCLUSIONS: Among patients with newly diagnosed T2DM, 22% remained under poor glycaemic control over 2 years, and 26% never received IT. Delay in IT by 1 year in conjunction with poor glycaemic control significantly increased the risk of MI, HF, stroke and composite CVE. PMID- 26249021 TI - Single molecule localization deep within thick cells; a novel super-resolution microscope. AB - A novel 3D imaging system based on single-molecule localization microscopy is presented to allow high-accuracy drift-free (<0.7 nm lateral; 2.5 nm axial) imaging many microns deep into a cell. When imaging deep within the cell, distortions of the point-spread function result in an inaccurate and very compressed Z distribution. For the system to accurately represent the position of each blink, a series of depth-dependent calibrations are required. The system and its allied methodology are applied to image the ryanodine receptor in the cardiac myocyte. Using the depth-dependent calibration, the receptors deep within the cell are spread over a Z range that is many hundreds of nanometers greater than implied by conventional analysis. We implemented a time domain filter to detect overlapping blinks that were not filtered by a stringent goodness of fit criterion. This filter enabled us to resolve the structure of the individual (30 nm square) receptors giving a result similar to that obtained with electron tomography. PMID- 26249022 TI - A tortuous route to a capable fatherhood: the experience of being a father to a child with severe haemophilia. AB - INTRODUCTION: Haemophilia is a chronic illness that affects the whole family as the child's reactions to the illness occur in interaction with the parents. Limited research has been conducted on how fathers of children with haemophilia experience their life situation. AIM: The aim of this study was to describe the lived experience of being a father to a child with severe haemophilia. METHOD: Individual, qualitative interviews were conducted with 14 fathers of 17 children with severe Haemophilia A. Data were analysed by means of a phenomenological hermeneutic method, including naive reading, structural analysis and comprehensive interpretation. RESULTS: The results revealed that the fathers gradually grew into fatherhood through a process that can be explained in the metaphor, 'A tortuous road to a capable fatherhood'. The fathers experienced sorrow, powerlessness, concern and loss of a regular fatherhood after the child's diagnosis. The loss of an envisaged fatherhood emerged as the greatest sorrow of being a father to a child with haemophilia. When home treatment with factor concentrates functioned without the involvement of Health Care Personal (HCP), the fathers' sense of insufficiency decreased. CONCLUSION: A sense of being a capable father was associated with a sense of independence and control of one's life situation. Support from the Haemophilia Treatment Centre (HTC) in the learning process is essential for both parents of a child with severe haemophilia. Awareness of the fathers' struggle to feel capable is also vital while supporting the family in the first years after diagnosis. PMID- 26249023 TI - DBC1/CCAR2 is involved in the stabilization of androgen receptor and the progression of osteosarcoma. AB - Deleted in breast cancer 1 (DBC1/CCAR2) is a protein of interest because of its diverse roles in tumorigenesis and its possible role as an androgen receptor (AR) co-activator. However, there are limited studies on the role of DBC1 in osteosarcoma. Therefore, we investigated the role of DBC1 and AR and their relationship in osteosarcoma. Immunohistochemical expression of DBC1 and AR was significantly associated with higher clinical stage and higher histologic grade, and predicted shorter survival. Especially, DBC1 expression was an independent prognostic indicator of overall survival (p = 0.005) and relapse-free survival (p = 0.004) by multivariate analysis. In osteosarcoma cell lines, U2OS and SaOS2, the knock down of DBC1 and AR with siRNA significantly reduced cellular proliferation and inhibited proliferation-related signaling. In addition, the knock down of DBC1 and AR decreased the invasion activity and inhibited invasion related signaling of osteosarcoma cells. Interestingly, DBC1 affects the stabilization of AR protein via a mechanism involving the ubiquitination of AR. Proteosome-mediated degradation and poly-ubiquitination of AR were increased with the knock-down of DBC1. In conclusion, this study has shown that DBC1 is involved in the stabilization of AR protein and DBC1-AR pathways might be involved in the progression of osteosarcoma. PMID- 26249024 TI - Cyclospora cayetanensis infection in transplant traveller: a case report of outbreak. AB - BACKGROUND: Cyclospora cayetanensis is a protozoan parasite causing intestinal infections. A prolonged course of infection is often observed in immunocompromised individuals. In Europe, less than 100 cases of C. cayetanensis infection have been reported to date, almost all of which being diagnosed in individuals after travelling abroad. FINDINGS: We described cases of three businessmen who developed acute traveller's diarrhoea after they returned to Poland from Indonesia. One of the travellers was a renal transplant recipient having ongoing immunosuppressive treatment. In each case, acute and prolonged diarrhoea and other intestinal disorders occurred. Oocysts of C. cayetanensis were identified in faecal smears of two of the travellers (one immunosuppressed and one immunocompetent). Diagnosis was confirmed by the successful amplification of parasite DNA (18S rDNA). A co-infection with Blastocystis hominis was identified in the immunocompetent man. CONCLUSIONS: Infection of C. cayetanensis shall be considered as the cause of prolonged acute diarrhoea in immunocompromised patients returning from endemic regions. PMID- 26249025 TI - Validation of hepatitis B virus-related hepatocellular carcinoma prediction models in the era of antiviral therapy. AB - Several risk prediction models have been created to predict hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) occurrence, with promising results. However, their prognostic performances need to be validated in the era of antiviral therapy. From 2006 to 2011, patients with chronic HBV infection were recruited and those with a history of HCC or hepatic decompensation were excluded. At enrollment, liver stiffness (LS) was measured using transient elastography. We assessed the performances of conventional HCC prediction models (CU-HCC, GAG-HCC, REACH-B, and LSM-HCC scores) and the modified REACH-B (mREACH B) score where LS values were incorporated into REACH-B score instead of serum HBV-DNA levels. Of 1,308 subjects analyzed, the median age was 50.0 years (883 men). During the follow-up (median, 75.3 months), HCC developed in 125 (9.6%) patients. mREACH-B score had the highest areas under the receiver operating characteristic curves (AUROCs) for the prediction of HCC development at 3/5 years (0.828/0.806), compared with LSM-HCC (0.777/0.759), GAG-HCC (0.751/0.757), REACH B (0.717/0.699), and CU-HCC (0.698/0.700) scores, respectively, with statistical significances (all P values <0.05 vs. mREACH-B). When serum HBV-DNA levels were excluded from the formula for REACH-B score, AUROCs for HCC development at 3/5 years improved paradoxically (from 0.717/0.699 to 0.757/0.732, respectively). In patients with antiviral therapy (n = 848), mREACH-B score had the better prognostic performances for HCC development at 3/5 years, compared to other prediction models. However, in patients without antiviral therapy (n = 460), it had the prognostic performances comparable to those of other prediction models. CONCLUSIONS: Prognostic performances of mREACH-B score seemed better compared to conventional models. In the era of antiviral therapy, incorporation of serum HBV DNA level should be applied cautiously and individual risks should be assessed effectively based on the fibrotic burden. PMID- 26249026 TI - Nurse perceptions of the Nursing Delirium Screening Scale in two palliative care inpatient units: a focus group study. AB - AIMS AND OBJECTIVES: To explore nurse perceptions of the feasibility of integrating the Nursing Delirium Screening Scale into practice within the inpatient palliative care setting. BACKGROUND: Delirium occurs frequently in palliative care inpatient populations, yet is under-recognised. Exploring feasibility of delirium screening tools in this setting can provide insights into how recognition can be improved. DESIGN: This was a qualitative study using a focus group methodology. METHOD: Four semi-structured focus groups were conducted with 21 nurses working in two Australian palliative care units. Focus groups were digitally recorded and transcribed verbatim. Thematic content analysis was used to analyse the data. RESULTS: Three major themes were identified: (1) Delirium screening using the Nursing Delirium Screening Scale is feasible, but then what? (2) Nuances, ambiguity and clinical complexity; and (3) Implementing structured processes requires firmer foundations. Themes describe how nurses perceived the Nursing Delirium Screening Scale to be an easy and brief screening tool which raised their awareness of delirium. They were largely willing to adopt it into practice, yet had uncertainty and misunderstandings of the tool specifically and delirium screening generally, application in a palliative care context, interventions for delirium and impact of screening on medical practice. CONCLUSION: The Nursing Delirium Screening Scale is feasible for use in a palliative care inpatient setting, but requires investigation of its psychometric properties before routine use in this patient population. RELEVANCE TO CLINICAL PRACTICE: Nurses require understanding of delirium, tailored guidance and a united approach with doctors to support their effective use of a delirium screening tool in the palliative care unit. Delirium practice change in this setting will also require nurses to become more active leaders and collaborators within their interdisciplinary teams. PMID- 26249028 TI - The Total Position Spread in mixed-valence compounds: A study on the H4+ model system. AB - The behavior of the Total Position Spread (TPS) tensor, which is the second moment cumulant of the total position operator, is investigated in the case of a mixed-valence model system. The system consists of two H2 molecules placed at a distance D. If D is larger than about 4 bohr, the singly ionized system shows a mixed-valence character. It is shown that the magnitude of the TPS has a strong peak in the region of the avoided crossing. We believe that the TPS can be a powerful tool to characterize the behavior of the electrons in realistic mixed valence compounds. PMID- 26249027 TI - Correlates of smoking status among women experiencing intimate partner violence: Substance use, posttraumatic stress, and coping. AB - BACKGROUND AND OBJECTIVES: Smoking prevalence among women who experience intimate partner violence (IPV) is two to three times higher than the prevalence among women nationally. Yet, research on cigarette smoking among this population of women is scarce. METHODS: This study examined differences between daily smokers and non-smokers among a sample of 186 IPV-victimized women. Comparing these groups may identify key factors that could inform future research, and ultimately, smoking cessation interventions to improve women's health. RESULTS: Results showed that smokers and non-smokers differed in terms of alcohol and drug use problem severity, posttraumatic stress symptom severity, psychological and physical IPV victimization severity, and severity of use of psychological and physical IPV. Smokers fared worse on all domains where differences emerged. Findings of a logistic regression demonstrated that alcohol problem severity was related to daily smoking status; post hoc analysis revealed that the effect of alcohol problem severity was moderated by the level of Posttraumatic stress disorder (PTSD) avoidance symptom severity. DISCUSSION AND CONCLUSIONS: Findings suggest a sub-population of women experiencing IPV who smoke and incur additional risk for psychiatric symptom severity and maladaptive behaviors. This study suggests the need to examine factors such as IPV and its negative sequelae to inform smoking cessation research for women. SCIENTIFIC SIGNIFICANCE: This study contributes to the scarce literature examining the intersections of PTSD, alcohol and drug use, and smoking. Examining these factors in the context of IPV, which is a highly prevalent problem, is critical to informing future treatment development investigations. PMID- 26249029 TI - Branched-linear polyion complexes at variable charge densities. AB - Structural behavior of complexes formed by a charged and branched copolymer and an oppositely charged and linear polyion was examined by Monte Carlo simulations employing a coarse-grained bead-spring model. The fractional bead charge and the branching density were systematically varied; the former between 0e and 1e and the latter such that both the comb-polymer and the bottle-brush limits were included. The number of beads of the main chain of the branched copolymer and of the linear polyion was always kept constant and equal, and a single side-chain length was used. Our analysis involved characterization of the complex as well as investigation of size, shape, and flexibility of the charged moieties. An interplay between Coulomb interaction and side-chain repulsion governed the structure of the polyion complex. At strong Coulomb interaction, the complexes underwent a gradual transition from a globular structure at low branching density to an extended one at high branching density. As the electrostatic coupling was decreased, the transition was smoothened and shifted to lower branching density, and, eventually, a behavior similar to that found for neutral branched polymer was observed. Structural analogies and dissimilarities with uncharged branched polymers in poor solutions are discussed. PMID- 26249030 TI - Mesoporous silica film-assisted amplified electrochemiluminescence for cancer cell detection. AB - A mesoporous silica film-assisted amplification method is reported for the first time for the sensitive electrochemiluminescence detection of cancer cells. PMID- 26249032 TI - The use of local vancomycin powder in degenerative spine surgery. AB - PURPOSE: Wound infection after spine surgery is a debilitating complication. Local placement of vancomycin powder into the surgical wounds prior to closing of the fascia has been introduced as a method to reduce deep infection rates. METHODS: The infection rates of all the patients who were treated with intra operative local vancomycin between June 2012 and June 2013 were compared to all cases that were not treated with vancomycin between January 2009 and December 2010. Patients for both groups were operated by four senior, fellowship-trained spine surgeons with a combined experience of 55 years of practice at a referral orthopedic center. Patients' charts and microbiology reports were reviewed. RESULTS: 1224 cases were performed with the use of vancomycin. The average age was 56.3 years (SD -13.2; NS). The male to female ratio was 1:1.12 (NS). 2253 cases were performed without the use of vancomycin. The average patient age was 57.1 years (SD 14.5). The male to female ratio was 1:1.14. There were 30 cases of deep infections needing a surgical irrigation and debridement without vancomycin versus 5 when vancomycin was used (P = 0.04). Infections in patients treated with vancomycin were not vancomycin-resistant bacteria. CONCLUSION: In conclusion, the use of vancomycin reduces the rate of deep wound infections and irrigation and debridement procedures after spine surgery in a referral center among surgeons with a high surgical volume. PMID- 26249031 TI - ITPKA expression is a novel prognostic factor in hepatocellular carcinoma. AB - BACKGROUND: Inositol-1,4,5-trisphosphate-3-kinase-A (ITPKA) has recently been found to be implicated in the tumor progression of various cancers. However, the expression and the prognostic value of ITPKA in hepatocellular carcinoma (HCC) remains unexplored. The aim of this study is to investigate the clinical significance of ITPKA expression in HCC. METHODS: We determined the expression level of ITPKA in 135 cases of HCC tissues and the matched adjacent nontumorous tissues by quantitative real-time RT-PCR. The correlation between ITPKA expression and prognosis of HCC patients was further evaluated by univariate and multivariate analysis. Multivariate analysis of the prognostic factors was performed with Cox proportional hazards model. RESULTS: Up-regulation of ITPKA occurred in 48.9% of primary HCCs compared with their nontumor counterparts (P < 0.001). In addition, high expression of ITPKA was significantly associated with vascular invasion (P = 0.001) and TNM stage (P = 0.005). Kaplan-Meier analysis showed that the 5-year overall survival (OS) and relapse-free survival (RFS) rate in the group with high expression of ITPKA is poorer than that in low expression group (32.2 and 26.8% versus 59.2 and 57.7%). Univariate and multivariate analyses revealed that ITPKA was an independent prognostic factor for OS and RFS. Moreover, Stratified analysis revealed that its prognostic significance still existed within the subgroup of patients with early clinical stage (TNM stage I) or normal serum AFP level (<=25 MUg/L). CONCLUSION: Our data indicated that ITPKA expression was significantly up-regulated in HCC and could serve as a potential novel prognostic biomarker for HCC patients after surgery. PMID- 26249033 TI - Thermal and health outcomes of energy efficiency retrofits of homes of older adults. AB - Mitigation of thermal stress and adverse indoor climatic conditions is important to older low-income populations whose age, health, and economic circumstances make them vulnerable to indoor environmental conditions. This research examines whether energy retrofits in affordable housing for older adults can also improve indoor climatic (i.e., temperature, humidity, air infiltration) conditions and whether such improvements correspond with improved health and comfort of residents. An apartment complex for low-income older adults in Phoenix was the study site. In 2010, renovations were undertaken to make it more energy efficient and to replace interior cabinetry, flooring, and paint with materials that had low or no volatile organic compounds (VOCs). Fifty-seven residents from 53 apartment units participated in both baseline (pre-renovation) and 1 year post renovation data collection trials. Environmental measures included temperature, relative humidity, and air infiltration. Health measures included general health, emotional distress, and sleep. Four questions addressed residents' perceptions of temperature quality. Results demonstrated a 19% reduction in energy consumption following the retrofit. In addition, fixed effects statistical models of the panel data showed significant stabilization of unit temperature from pre-retrofit to 1 year post-retrofit. Reductions in an apartment's temperature extremes of 27.2 degrees C (81 degrees F) and above also corresponded with improvement in occupant's reported health over the same time period, although not with occupant's perceptions of thermal comfort. PMID- 26249034 TI - Connecting proximate mechanisms and evolutionary patterns: pituitary gland size and mammalian life history. AB - At the proximate level, hormones are known to play a critical role in influencing the life history of mammals, including humans. The pituitary gland is directly responsible for producing several hormones, including those related to growth and reproduction. Although we have a basic understanding of how hormones affect life history characteristics, we still have little knowledge of this relationship in an evolutionary context. We used data from 129 mammal species representing 14 orders to investigate the relationship between pituitary gland size and life history variation. Because pituitary gland size should be related to hormone production and action, we predicted that species with relatively large pituitaries should be associated with fast life histories, especially increased foetal and post-natal growth rates. Phylogenetic analyses revealed that total pituitary size and the size of the anterior lobe of the pituitary significantly predicted a life history axis that was correlated with several traits including body mass, and foetal and post-natal growth rates. Additional models directly examining the association between relative pituitary size and growth rates produced concordant results. We also found that relative pituitary size variation across mammals was best explained by an Ornstein-Uhlenbeck model of evolution, suggesting an important role of stabilizing selection. Our results support the idea that the size of the pituitary is linked to life history variation through evolutionary time. This pattern is likely due to mediating hormone levels but additional work is needed. We suggest that future investigations incorporating endocrine gland size may be critical for understanding life history evolution. PMID- 26249035 TI - Micrometer-sized network structure of novel DNA-lipid conjugates induced by heat stimulation. AB - We have developed a novel lipid-bearing DNA that forms hairpin modules, including a single RNA monomer; this can be used to create micrometer-sized structures from nanometer-sized building blocks during breakage at the RNA site. In the presence of divalent metal ions and heat stimulation, we observed transition of the self assembly, which results in the formation of a three-dimensional network structure. To our knowledge, this is also the first report of heat-induced micrometer-sized molecular self-assembly of molecules that carry biological information. PMID- 26249036 TI - Biomechanical comparison between hybrid turf ('AirFibr' technology) and natural turf at landing after hurdle jumping in one horse. PMID- 26249037 TI - Solid-state fermentation in multi-well plates to assess pretreatment efficiency of rot fungi on lignocellulose biomass. AB - The potential of fungal pretreatment to improve fermentable sugar yields from wheat straw or Miscanthus was investigated. We assessed 63 fungal strains including 53 white-rot and 10 brown-rot fungi belonging to the Basidiomycota phylum in an original 12 day small-scale solid-state fermentation (SSF) experiment using 24-well plates. This method offers the convenience of one-pot processing of samples from SSF to enzymatic hydrolysis. The comparison of the lignocellulolytic activity profiles of white-rot fungi and brown-rot fungi showed different behaviours. The hierarchical clustering according to glucose and reducing sugars released from each biomass after 72 h enzymatic hydrolysis splits the set of fungal strains into three groups: efficient, no-effect and detrimental effect species. The efficient group contained 17 species belonging to seven white rot genera and one brown-rot genus. The yield of sugar released increased significantly (max. 62%) compared with non-inoculated controls for both substrates. PMID- 26249038 TI - Hyperbranched lysine-arginine copolymer for gene delivery. AB - Based on the reactivity of amine groups and carboxyl groups of L-lysine and L arginine, thermal polymerization of these two natural amino acids results in hyperbranched lysine-arginine copolymers (P-lys-argX, where X refers to the relevant molar ratio of arginine to lysine). Hyperbranched polylysine (P-lys) and two derivatives (P-lys-arg0.10 and P-lys-arg0.20) have been prepared. The arginine-rich hyperbranched polymers can interact with plasmid DNA to form nano sized particles. The polyplexes were physicochemically analyzed by agarose gel electrophoresis, dynamic light scattering, and zeta potential measurements. Furthermore, their transfection efficiency was assessed, employing COS-7, 293T, and HeLa cell lines. It was found that P-lys showed poorly in its ability of condensation with DNA and transfection efficiency. On the other hand, arginine rich products resulted to significant enhancement of its transfection efficiency, which is dependent on the content of arginine in the polymers, and the cell line used. P-lys-arg0.20 exhibited better transfection efficiency under all the condition studied. Besides, P-lys-arg0.20 showed lower toxicity in COS-7 cells. PMID- 26249040 TI - Left Ventricular Lead Placement Targeted at the Latest Activated Site Guided by Electrophysiological Mapping in Coronary Sinus Branches Improves Response to Cardiac Resynchronization Therapy. AB - INTRODUCTION: Electrophysiological mapping (EPM) in coronary sinus (CS) branches is feasible for guiding LV lead placement to the optimal, latest activated site at cardiac resynchronization therapy (CRT) procedures. However, whether this procedure optimizes the response to CRT has not been demonstrated. This study was to evaluate effects of targeting LV lead at the latest activated site guided by EPM during CRT. METHODS: Seventy-six consecutive patients with advanced heart failure who were referred for CRT were divided into mapping (MG) and control groups (CG). In MG, the LV lead, also used as a mapping bipolar electrode, was placed at the latest activated site determined by EPM in CS branches. In CG, conventional CRT procedure was performed. Patients were followed for 6 months after CRT. RESULTS: Baseline characteristics were comparable between the 2 groups. In MG (n = 29), EPM was successfully performed in 85 of 91 CS branches during CRT. A LV lead was successfully placed at the latest activated site guided by EPM in 27 (93.1%) patients. Compared with CG (n = 47), MG had a significantly higher rate (86.2% vs. 63.8%, P = 0.039) of response (>15% reduction in LV end systolic volume) to CRT, a higher percentage of patients with clinical improvement of >=2 NYHA functional classes (72.4% vs. 44.7%, P = 0.032), and a shorter QRS duration (P = 0.004). CONCLUSIONS: LV lead placed at the latest activated site guided by EPM resulted in a significantly greater CRT response, and a shorter QRS duration. PMID- 26249039 TI - Diastereomeric liquid crystal domains at the mesoscale. AB - In many technologies used to achieve separation of enantiomers, chiral selectors are designed to display differential affinity for the two enantiomers of a chiral compound. Such complexes are diastereomeric, differing in structure and free energy for the two enantiomers and enabling chiral discrimination. Here we present evidence for strong diastereomeric interaction effects at the mesoscale, manifested in chiral liquid crystal guest materials confined in a chiral, nanoporous network of semi-crystalline helical nanofilaments. The nanoporous host is itself an assembly of achiral, bent-core liquid crystal molecules that phase separate into a conglomerate of 100 micron-scale, helical nanofilament domains that differ in structure only in the handedness of their homogeneous chirality. With the inclusion of a homochiral guest liquid crystal, these enantiomeric domains become diastereomeric, exhibiting unexpected and markedly different mesoscale structures and orientation transitions producing optical effects in which chirality has a dominant role. PMID- 26249041 TI - Multidimensional NMR spectroscopy in a single scan. AB - Multidimensional NMR has become one of the most widespread spectroscopic tools available to study diverse structural and functional aspects of organic and biomolecules. A main feature of multidimensional NMR is the relatively long acquisition times that these experiments demand. For decades, scientists have been working on a variety of alternatives that would enable NMR to overcome this limitation, and deliver its data in shorter acquisition times. Counting among these methodologies is the so-called ultrafast (UF) NMR approach, which in principle allows one to collect arbitrary multidimensional correlations in a single sub-second transient. By contrast to conventional acquisitions, a main feature of UF NMR is a spatiotemporal manipulation of the spins that imprints the chemical shift and/or J-coupling evolutions being sought, into a spatial pattern. Subsequent gradient-based manipulations enable the reading out of this information and its multidimensional correlation into patterns that are identical to those afforded by conventional techniques. The current review focuses on the fundamental principles of this spatiotemporal UF NMR manipulation, and on a few of the methodological extensions that this form of spectroscopy has undergone during the years. PMID- 26249042 TI - Conformational analysis of large and highly disulfide-stabilized proteins by integrating online electrochemical reduction into an optimized H/D exchange mass spectrometry workflow. AB - Analysis of disulfide-bonded proteins by hydrogen/deuterium exchange mass spectrometry (HDX-MS) requires effective and rapid reduction of disulfide bonds before enzymatic digestion in order to increase sequence coverage. In a conventional HDX-MS workflow, disulfide bonds are reduced chemically by addition of a reducing agent to the quench solution (e.g., tris(2-carboxyethyl)phosphine (TCEP)). The chemical reduction, however, is severely limited under quenched conditions due to a narrow time window as well as low pH and temperature. Here, we demonstrate the real-world applicability of integrating electrochemical reduction into an online HDX-MS workflow. We have optimized the electrochemical reduction efficiency during HDX-MS analysis of two particularly challenging disulfide stabilized proteins: a therapeutic IgG1-antibody and nerve growth factor-beta (NGF). Several different parameters (flow rate and applied square wave potential, as well as the type of labeling and quench buffer) were investigated, and the optimized workflow increased the sequence coverage of NGF from 46% with chemical reduction to 99%, when electrochemical reduction was applied. Additionally, the optimized workflow also enabled a similar high sequence coverage of 96% and 87% for the heavy and light chain of the IgG1 antibody, respectively. The presented results demonstrate the successful electrochemical reduction during HDX-MS analysis of both a small exceptional tightly disulfide-bonded protein (NGF) as well as the largest protein attempted to date (IgG1-antibody). We envision that online electrochemical reduction is poised to decrease the complexity of sample handling and increase the versatility of the HDX-MS technique. PMID- 26249043 TI - RAB2A Polymorphism impacts prefrontal morphology, functional connectivity, and working memory. AB - Calbindin-containing gamma-aminobutyric acid (GABA)ergic interneurons in the prefrontal cortex (PFC) have been found to play an important role in working memory (WM) and their malfunctions have been linked to psychiatric disorders. A recent genome-wide association and expression-SNP study indicated that the RAB2A gene was associated with the density of prefrontal calbindin-positive neurons, suggesting this gene may have a broader influence on prefrontal structure and function. Using multimodal MRI and behavioral tasks, the current study investigated the effect of RAB2A on prefrontal morphology, resting-state functional connectivity, and WM performance in a large sample of healthy Han Chinese subjects. Results showed that the RAB2A AGCAAA haplotype was associated with improved WM accuracy, increased cortical thickness in the left inferior frontal gyrus, and decreased functional connectivity between the left inferior frontal gyrus and the left dorsolateral PFC. Our findings provide consistent evidence supporting the effect of RAB2A on the structure and function of the PFC and related cognitive functions. These results should provide new insights into the neural mechanisms underlying the GABAergic genes' role in WM as well as its dysfunction. PMID- 26249044 TI - Lotus japonicus flowers are defended by a cyanogenic beta-glucosidase with highly restricted expression to essential reproductive organs. AB - Flowers and leaves of Lotus japonicus contain alpha-, beta-, and gamma hydroxynitrile glucoside (HNG) defense compounds, which are bioactivated by beta glucosidase enzymes (BGDs). The alpha-HNGs are referred to as cyanogenic glucosides because their hydrolysis upon tissue disruption leads to release of toxic hydrogen cyanide gas, which can deter herbivore feeding. BGD2 and BGD4 are HNG metabolizing BGD enzymes expressed in leaves. Only BGD2 is able to hydrolyse the alpha-HNGs. Loss of function mutants of BGD2 are acyanogenic in leaves but fully retain cyanogenesis in flowers pointing to the existence of an alternative cyanogenic BGD in flowers. This enzyme, named BGD3, is identified and characterized in this study. Whereas all floral tissues contain alpha-HNGs, only those tissues in which BGD3 is expressed, the keel and the enclosed reproductive organs, are cyanogenic. Biochemical analysis, active site architecture molecular modelling, and the observation that L. japonicus accessions lacking cyanogenic flowers contain a non-functional BGD3 gene, all support the key role of BGD3 in floral cyanogenesis. The nectar of L. japonicus flowers was also found to contain HNGs and additionally their diglycosides. The observed specialisation in HNG based defence in L. japonicus flowers is discussed in the context of balancing the attraction of pollinators with the protection of reproductive structures against herbivores. PMID- 26249045 TI - Alterations of histone modifications at the senescence-associated gene HvS40 in barley during senescence. AB - The barley gene HvS40, encoding a putative regulator of leaf senescence, is strongly induced during leaf senescence. As shown by chromatin immunoprecipitation, euchromatic histone modification H3K9ac is added at promoter close to ATG and coding sequence of HvS40 after onset of senescence. In parallel, level of heterochromatic H3K9me2 decreases at this gene. Bisulfite sequencing revealed no DNA-methylation in this region, but a heavily methylated DNA-island, starting 664 bp upstream from translational start site in both, mature and senescent leaves. A decrease in DNA methylation in senescing leaves could be shown at one specific CpG motif at the end of this methylation island. In addition, global changes in chromatin structure during senescence were analyzed via immunocytology, revealing senescence-associated changes in spatial distribution of heterochromatic H3K9me2 patterns in the nuclei. Our results prove a senescence-specific mechanism, altering histone modification marks at distinct sequences of the senescence-associated gene HvS40 and altering distribution of heterochromatic areas in the nuclei. PMID- 26249047 TI - [ECG in patients with tako tsubo cardiomyopathy]. AB - Takotsubo cardiomyopathy, also known as transient left ventricular ballooning and stress myocardiopathy, has been diagnosed increasingly more over the last decade. The takotsubo syndrome mimics acute myocardial infarction in symptoms and in electrocardiographic findings. There are two major types of takotsubo cardiomyopathy: the classical type with left ventricular apical ballooning and a type with midventricular ballooning. Both types show different electrocardiographic patterns at presentation. The present article describes classical electrocardiographic findings of the acute and subacute phases of takotsubo cardiomyopathy. PMID- 26249046 TI - Functional roles of the pepper RING finger protein gene, CaRING1, in abscisic acid signaling and dehydration tolerance. AB - Plants are constantly exposed to a variety of biotic and abiotic stresses, which include pathogens and conditions of high salinity, low temperature, and drought. Abscisic acid (ABA) is a major plant hormone involved in signal transduction pathways that mediate the defense response of plants to abiotic stress. Previously, we isolated Ring finger protein gene (CaRING1) from pepper (Capsicum annuum), which is associated with resistance to bacterial pathogens, accompanied by hypersensitive cell death. Here, we report a new function of the CaRING1 gene product in the ABA-mediated defense responses of plants to dehydration stress. The expression of the CaRING1 gene was induced in pepper leaves treated with ABA or exposed to dehydration or NaCl. Virus-induced gene silencing of CaRING1 in pepper plants exhibited low degree of ABA-induced stomatal closure and high levels of transpirational water loss in dehydrated leaves. These led to be more vulnerable to dehydration stress in CaRING1-silenced pepper than in the control pepper, accompanied by reduction of ABA-regulated gene expression and low accumulation of ABA and H2O2. In contrast, CaRING1-overexpressing transgenic plants showed enhanced sensitivity to ABA during the seedling growth and establishment. These plants were also more tolerant to dehydration stress than the wild-type plants because of high ABA accumulation, enhanced stomatal closure and increased expression of stress-responsive genes. Together, these results suggest that the CaRING1 acts as positive factor for dehydration tolerance in Arabidopsis by modulating ABA biosynthesis and ABA-mediated stomatal closing and gene expression. PMID- 26249048 TI - [Fragmented QRS. Relevance in clinical practice]. AB - The QRS complex represents the electrical depolarization of ventricular myocardium. In the case of an undisturbed depolarization, the QRS complex has a normal configuration and duration, but abnormal electrical conduction leads to widening of the QRS complex. The block of one of the Tawara branches results in a typical bundle branch block pattern. A QRS complex that cannot be classified as bundle branch block due to an atypical configuration and contains notched R or S waves is called a fragmented QRS. The underlying pathophysiologies are manifold and include myocardial scars induced by ischemic heart disease, myocardial fibrosis due to other diseases, primary cardiac pathologies as well as systemic diseases with cardiac involvement. Pathologies on the cellular level, such as ion channel dysfunctions, also correlate with fragmented QRS. Besides the diagnostic relevance, fragmented QRS is known to have prognostic properties, for example in identifying high risk patients with coronary artery disease, cardiomyopathy, Brugada syndrome and acquired long QT syndrome; however, fragmented QRS may also be detected in ECGs of healthy individuals. PMID- 26249050 TI - An annotated checklist of the Eulophidae (excl. Tetrastichinae (Hymenoptera: Chalcidoidea) of Israel. AB - An annotated checklist of Israeli Eulophidae, excluding Tetrastichinae, is presented based primarily on a total of 757 specimens collected since the 1970s from 70 localities in Israel mostly by Malaise traps, sweeping and rearing from hosts. Altogether, 127 species belonging to 35 genera are recorded, of which 82 species (65%) are newly reported for Israel. Valid names, distribution, and known hosts are given for each species. Two previously reported species are excluded from the fauna and one is considered as doubtful in the country. The most species rich genera are Pediobius, with 14 species, and Elasmus, with 12 species. The most common species, comprising about half of the collected specimens, are Diglyphus isaea (Walker), Neochrysocharis formosus (Westwood), Sympiesis sericeicornis (Nees), Pediobius pyrgo (Walker) and Euderus albitarsis Zetterstedt. Three species are currently known only from Israel, Aulogymnus albipes (Askew), Elasmus aternalis Yefremova & Strakhova and Pediobius thysanopterus Burks. Hosts are reported for 17 species, of which 10 are new records. Most of the species (88%) have a vast area of distribution characterized as Palearctic, Holarctic, or even cosmopolitan. PMID- 26249049 TI - [Brugada ECG]. AB - The Brugada syndrome (BrS) is characterized by a typical electrocardiogram (ECG) pattern of right precordial ST-segment elevation and the cardinal symptoms syncope and sudden cardiac death as clinical correlate of malignant ventricular arrhythmias in young adults without structural heart disease. The diagnosis of a type 1 Brugada-ECG is based on the documentation of a coved-type (>= 0.2 mV) ST elevation followed by a negative T wave. The use of the ECG criteria postulated in the consensus of 2012 is helpful to distinguish between saddleback-type 2 (or type 3) J point/ST elevation and incomplete right bundle branch block. Spontaneous or drug-induced type 1 ST elevation can frequently only be detected in a single right precordial lead (V1 or V2), occurs sometimes together with a type 2 (or type 3) pattern in one and the same 12-lead ECG and can sometimes only be seen in modified right precordial leads. The ST elevation is less pronounced in females. Spontaneous and exercise-induced type 1 ST elevation, fragmented QRS complex, prolonged PR interval (> 200 ms), QRS prolongation in V2 (>= 120 ms) and markers of an increased heterogeneity of ventricular repolarization are associated with an increased arrhythmic risk. The occurrence of spontaneous or dynamic type 1 ST elevation, a macroscopic T wave alternans or pronounced inferior (lateral) J point/ST elevation are signs of acute electrical instability. PMID- 26249051 TI - Discovery of living Potamolepidae (Porifera: Spongillina) from Nearctic freshwater with description of a new genus. AB - We report here the first record of a living Potamolepidae (Cherokeesia n. gen.) from the Nearctic Region and from the northern hemisphere. The new species Cherokeesia armata from southern Appalachians diverges at generic and specific level from all the other known taxa of the family Potamolepidae in its unique combination of diagnostic traits: gemmular theca armed by gemmuloscleres ranging from small strongyle-like spicules to stout, large oxeas; absence of pneumatic layer; spiny oxeas as main skeleton megascleres; irregular, slender pauci- to uni spicular skeletal network. The most similar species belong to the genera Potamophloios and Oncosclera. The circumtropical biogeographic pattern of extant Potamolepidae, previously considered of Gondwanian to Gondwanian-like origin, is enlarged to the Nearctic. The present Tennessee discovery confirms a wider range of the family. An updated species inventory of Nearctic Spongillina, a checklist of the family Potamolepidae at the global level together with a key to the genera of Potamolepidae are also provided. PMID- 26249052 TI - Frigitilla gen. nov., a new genus of Amazonian Mutillidae (Hymenoptera). AB - Mutilla frigidula Cresson, 1902 was transferred to Tobantilla by Williams et al. (2011), based on morphological similarities with females of that genus. Discovery of the male of this species indicated significant morphological differences from Tobantilla. We therefore erect the genus, Frigitilla gen. nov., for Mutilla frigidula. Herein, we describe the male of F. frigidula (Cresson, 1902), comb. nov., associate it with its host (Trypoxylon spp.), and discuss its relations to other mutillid genera. The impact of collecting method and specimen age on the integumental coloration of specimens is discussed, emphasizing the need to diagnose species on consistent structural features rather than differences in color pattern. PMID- 26249053 TI - First description of the soft part anatomy of Ilyocypris ramirezi Cusminsky & Whatley (Crustacea, Ostracoda) from Argentina, South America. AB - The anatomy of the soft parts of Ilyocypris ramirezi Cusminsky & Whatley, 1996 is described and illustrated for the first time, based on findings of this species from water bodies in the shallow areas of the Llancanelo basin, south-west of Mendoza Province, Argentina. This species is common in Quaternary and extant environments of the Pampa and Patagonian regions. Its distribution is now extending in Argentina to the Central-West area, locally named "Cuyo region". Ilyocypris ramirezi is a good environmental indicator and constitutes a useful tool in paleolimnological studies. PMID- 26249054 TI - Three new species of Anacroneuria Klapalek (Plecoptera: Perlidae) from Panama. AB - In Central America, the Plecoptera is represented by the genera Anacroneuria and Perlesta, both from the Perlidae family. A total of 45 species have been reported for the region, of which 16 have been found in Panama, all of the genus Anacroneuria. Three new species for Panama are described in this study: Anacroneuria darien, A. embera, and A. laru. PMID- 26249055 TI - A new genus of the tribe Parahiraciini (Hemiptera: Fulgoroidea: Issidae) from Southern China. AB - A new genus Tetricodissus gen. nov. with one new species Tetricodissus pandlineus sp. nov. from Yunnan Province, China, is described and illustrated in the tribe Parahiraciini of planthopper family Issidae. Fortunia jianfenglingensis Chen, Zhang & Chang, 2014 is transferred into the genus Bardunia Stal, 1863. A key to genera of the tribe Parahiraciini is provided and the taxonomic position of the new genus in Parahiraciini is discussed. PMID- 26249057 TI - Two new species of Pachyseius Berlese (Acari: Pachylaelapidae) from Turkey, with a key to the world species. AB - Two new species of the genus Pachyseius are described from leaf litter in Turkey. Pachyseius destitutus sp. nov. is described based on the female, and P. quadrigeminus sp. nov. is described based on the female and male. These species have some uncommon character states for the genus, such as the absence of dorsal shield seta z1, four pairs of setae on the ventri-anal shield, and a male with a holoventral shield. We provide a key to the world species incorporating new information about the genus. PMID- 26249058 TI - Dentex carpenteri, a new species of deepwater seabream from Western Australia (Pisces: Sparidae). AB - A new species of sparid fish, Dentex carpenteri, is described from nine type specimens collected off Ningaloo Reef near Exmouth, Western Australia. Four valid species of Dentex are currently known in the western Pacific, Dentex abei and D. hypselosomus in the Northern Hemisphere, and D. fourmanoiri and D. spariformis in the Southern Hemisphere. These four species comprise the "Dentex hypselosomus complex". Dentex carpenteri n. sp. is most similar to D. spariformis in overall body form, but differs from D. spariformis in having the posterior margin of the upper jaw not reaching or reaching slightly beyond a vertical at the anterior margin of eye; often with the greater part from the snout to the second infraorbital yellowish; deeper suborbital (9.7-10.9% SL); and a considerably deeper body (vs. posterior margin of upper jaw reaching clearly beyond anterior margin of eye; slight yellow region on snout; suborbital depth shallow (7.6-9.6% SL); and a less deep body in D. spariformis). The mitochondrial 16S ribosomal RNA genes (16S rRNA, 545 bp) of the above five species were analyzed using the Atlantic congener, Dentex macrophthalmus as an out-group, the results clearly indicating that D. carpenteri n. sp. is a valid and distinct species. A key to the "Dentex hypselosomus complex" is provided. The distributional information available for the five species from the western Pacific, including western Australia and the nearby eastern Indian Ocean, are discussed, with the species considered to be allopatric. PMID- 26249056 TI - Larval description of Drusus bosnicus Klapalek 1899 (Trichoptera: Limnephilidae), with distributional, molecular and ecological features. AB - In this study we present morphological, molecular and ecological features of the last instar larvae of Drusus bosnicus with data about distribution of this species in Bosnia and Herzegovina. We also included the most important diagnostic features enabling separation of larvae of D. bosnicus from larvae of the other European Drusinae and Trichoptera species. PMID- 26249059 TI - Synoecnema watinagii (Drilonematoidea: Ungellidae: Synoecneminae), a new nematode species parasitic in earthworms from the Philippines with the first molecular and SEM data for the genus. AB - A new species of the genus Synoecnema-S. watinagii sp. n.-is described and illustrated. The species is characterized by its small size, lack of sexual dimorphism apart from sexual characters, males with pericloacal disk, females with anterior vulva position and lacking an anus, and similar caudal organs in both sexes in the shape of long, deep slits on the surface of the posterior half of body. Sequences of D2-D3 LSU and SSU rDNA and SEM images were obtained for the first time for the genus Synoecnema. Phylogenetic analysis of these sequences supported the validity of the genus and elucidated its relationships within Synoecneminae and Drilonematoidea. The earthworm host was characterized by its CoxI mt DNA sequence. PMID- 26249060 TI - Argentine Hydrellia Robineau-Desvoidy (Diptera, Ephydridae): new species and key to identification. AB - Hydrellia egeriae sp. nov., a new species of Hydrellia from Campana (34 14' 04 S, 58 52' 32 W) and Hurlingham (3435'14 S, 5838'27 W), Buenos Aires province, Argentina is described. A key to the Argentine Hydrellia species is presented. PMID- 26249061 TI - New species of African Plume moths (Lepidoptera, Pterophoridae). AB - This article describes four new Pterophoridae species from Africa (Zambia, Tanzania and the Republic of South African): Platyptilia junkeri Ustjuzhanin & Kovtunovich sp. nov., Pselnophorus huntii Ustjuzhanin & Kovtunovich sp. nov., Pselnophorus tanzanicus Ustjuzhanin & Kovtunovich sp. nov., Merrifieldia aurea Ustjuzhanin & Kovtunovich sp. nov. PMID- 26249062 TI - Classification of the Polytminae (Aves: Trochilidae). PMID- 26249063 TI - The genus Elaphopsocus Roesler (Psocodea: 'Psocoptera': Psocidae) with six new species from Brazil and Colombia. AB - Six new species of Elaphopsocus Roesler from Brazil and Colombia are described and illustrated. Revised generic diagnoses are provided for Elaphopsocoides and Elaphopsocus; based on the structure of the male hypandrium and phallosome three species groups are recognized in Elaphopsocus. PMID- 26249064 TI - Four new species of Tanycarpa (Hymenoptera, Braconidae, Alysiinae) from the Palaearctic Region and new records of species from China. AB - Four new species of Tanycarpa (Hymenoptera, Braconidae, Alysiinae), T. gymnonotum Yao sp. n., T. similis Yao sp. n., T. areolata Yao sp. n., and T. lineata Yao sp. n., are described from the Palaearctic Region of China, and T. chors Belokobylskij is newly recorded from China. Significant range extensions are given for T. bicolor (Nees von Esenbeck), T. gracilicornis (Nees von Esenbeck), and T. mitis Stelfox. A key to the Palaearctic species of Tanycarpa is provided. PMID- 26249065 TI - Contribution to the knowledge of Tenuibaetis Kang & Yang 1994, Nigrobaetis Novikova & Kluge 1987 and Labiobaetis Novikova & Kluge 1987 (Ephemeroptera: Baetidae) from the Western Ghats (India). AB - As part of ongoing exploration of the mayflies of hill streams of southern Western Ghats, we describe two new species: Nigrobaetis paramakalyani Kubendran & Balasubramanian n. sp. and Labiobaetis jacobusi Kubendran & Balasubramanian n. sp. The genus Nigrobaetis is reported for the first time from India. Tenuibaetis frequentus (Muller-Liebenau & Hubbard 1985) n. comb. was also collected in this area and we provide the first description of this species at the imaginal stage. Brief ecological notes of the three species are added. PMID- 26249066 TI - A new subspecies of hutia (Plagiodontia, Capromyidae, Rodentia) from southern Hispaniola. AB - Continued uncertainty persists over the taxonomic status of many threatened Caribbean mammal populations. Recent molecular analysis has identified three genetically isolated allopatric hutia populations on Hispaniola that diverged during the Middle Pleistocene, with observed levels of sequence divergence interpreted as representing subspecies-level differentiation through comparison with genetic data for other capromyids. Subsequent analysis of existing museum specimens has demonstrated biogeographically congruent morphometric differentiation for two of these three populations, Plagiodontia aedium aedium (southwestern population) and P. aedium hylaeum (northern population). We report the first craniodental material for the southeastern Hispaniolan hutia population, and demonstrate that this population can also be differentiated using quantitative morphometric analysis from other Hispaniolan hutia subspecies. The holotype skull of P. aedium aedium, of unknown geographic provenance within Hispaniola, clusters morphometrically with the southwestern population. The southeastern Hispaniolan subspecies is described as Plagiodontia aedium bondi subsp. nov., and is assessed as Endangered under Criterion B1a,biii,v on the IUCN Red List. PMID- 26249067 TI - Uroptychus minutus Benedict, 1902 and a closely related new species (Crustacea: Anomura: Chirostylidae) from the western Atlantic Ocean. AB - A new squat lobster, Uroptychus marissae, is described based upon two specimens taken associated with the antipatharian Tanacetipathes sp. from the northern Gulf of Mexico, at a depth of about 90 m. It closely resembles U. minutus Benedict, 1902, known only from the type material from off Trinidad. The original description is so brief that an opportunity is taken here to redescribe it to help discriminate between the two species. PMID- 26249068 TI - A new species of the genus Acria Stephens, 1834 (Lepidoptera: Depressariidae: Acriinae) from India. AB - A new species, Acria meyricki sp. nov. (Lepidoptera: Depressariidae: Acriinae) occurring on oil palm, is described from India. The status and nomenclature of the genus is reviewed and an annotated checklist of species is given. A key to the seven species known so far from the Indian subcontinent is provided. PMID- 26249069 TI - The male imago of Paramaka incognita Dominguez, Grillet, Nieto, Molineri and Guerrero, 2014 (Ephemeroptera: Leptophlebiidae). AB - The genus Paramaka Savage & Dominguez, 1992 (Ephemeroptera: Leptophlebiidae) is restricted to South America, and it is comprised of four species. The male imago of P. incognita is described for the first time based on material from the state of Roraima in northern Brazil. The male adult differs from other described species of the genus by having the following combination of characteristics: Forewing with costal and subcostal areas basally washed with light yellowish brown; hind wing with base of wing washed with yellowish brown; abdominal terga II-V and VI-IX with lateral margins washed with reddish brown; abdominal sterna VI-VIII with lateral blackish stripes; styliger plate median portion with a pointed, posterior projection that is oriented in a posterior direction; and penes with ventral spines length subequal to length of penes, located on the distal third of the penes. PMID- 26249070 TI - First record of cassava mealybug, Phenacoccus manihoti (Hemiptera: Pseudococcidae), in Malaysia. PMID- 26249071 TI - New record of Paralomis spinosissima Birstein & Vinogradov (Decapoda: Anomura: Lithodidae) from Mar del Plata, Argentina. AB - The lithodid crab Paralomis spinosissima is previously known only in Sub Antarctic waters from South Georgia Island to the Drake Passage. Here we recorded a juvenile male obtained off shores of Mar del Plata (~37 degrees S), Argentina. This new occurrence extends the distribution range of the species over 1300 km northwards in the Atlantic Ocean. PMID- 26249072 TI - Apostolepis parassimilis Lema & Renner, 2012 an objective synonym of A. tertulianobeui Lema, 2004 (Dipsadidae: Elapomorphini). PMID- 26249073 TI - A new Atractides Koch (Acari: Hydrachnidia, Hygrobatidae) species from southwestern Turkey. PMID- 26249074 TI - Rectification of the type locality of Ischnocnema paranaensis (Anura: Brachycephalidae), a missing species of the Atlantic Forest of Brazil. PMID- 26249075 TI - Phylogeny and taxonomic revision of the subgenus Velleius Leach (Coleoptera: Staphylinidae: Staphylininae). AB - The subgenus Velleius Leach, 1819 of the genus Quedius Stephens, 1829 is a small and very distinctive group in the subtribe Quediina (Staphylinidae: Staphylininae) with pectinate antennal segments and larvae living in nests of Vespa species. This paper reviews the taxonomy of all Velleius species and analyzes the phylogeny of this group. Two new species, Quedius (Velleius) sagittalis sp. nov. from Shaanxi, China and Q. (V.) rectilatus sp. nov. from Guangdong, China, are described. Q. (V.) simillimus (Fairmaire,1891) syn. nov. is proposed as a new synonym of Q. (V.) pectinatus (Sharp, 1874). Phylogenetic result shows that all nine Velleius species can be divided into two clades and both have strong tree supports of Bremer/Bootstrap/Jackknife values. PMID- 26249076 TI - To systematics of the mite genus Hoplocheylus (Acariformes: Tarsocheylidae). AB - A new species of the genus Hoplocheylus Atyeo and Baker, 1964 (Acariformes: Heterostigmatina: Tarsocheylidae), H. magnificus sp. nov. is described from the nest of the ant Formica rufa Linnaeus (Hymenoptera: Formicidae) from Kurgan Province, Western Siberia, Russia. A poorly-known species Hoplocheylus sogdianicus Barilo and Sharipov, 1987 is redescribed from the holotype. A key to species of the genus Hoplocheylus is provided. PMID- 26249077 TI - Two new high altitude genera of Camiarini (Coleoptera: Leiodidae: Camiarinae) from Australia and New Zealand. AB - Two new leiodid genera and species, Camisolus ptinoides gen. nov., sp. nov. and Camiarodes nunni gen. nov., sp. nov. are described from southeastern Australia and New Zealand, respectively. Each new species is placed within its own genus on the basis of morphological uniqueness within Camiarini (Camiarinae) based on the presence of an enlarged maxillary palpomere 4 and metanepisternum with a lateral, tongue-like process that overlaps the elytron in repose. A key to the described genera is provided for world Camiarini. The tribe, new to Australia, is otherwise known only from New Zealand (six genera including one new) and southern South America (one genus). Both new genera are found exclusively in high altitude areas. PMID- 26249078 TI - Description of three new troglobiontic species of Cybaeodes (Araneae, Liocranidae) endemic to the Iberian Peninsula. AB - Three new troglobiontic species of the spider genus Cybaeodes Simon endemic to caves in the southeastern Iberian Peninsula are described and illustrated: Cybaeodes indalo sp. n. from Almeria, C. dosaguas sp. n. from Valencia and C. magnus sp. n. from Alacant. The new species confirm the presence of Cybaeodes on the Iberian Peninsula and its wide distribution throughout the Western Mediterranean including Algeria, Tunisia, Italy, France, Spain and the islands of Sardinia, Sicily and Mallorca. A record of C. liocraninus (Simon), from an Iberian cave was probably based on misidentified specimens of C. magnus sp. n. C. liocraninus is known only from Algeria and should be removed from lists of the Iberian fauna. In addition, the three new species are clear candidates for protection: they have highly restricted ranges and show a high degree of adaptation to the subterranean environment. PMID- 26249079 TI - Larval morphology of the hanging-fly Bittacus trapezoideus Huang & Hua (Insecta: Mecoptera: Bittacidae). AB - The first-instar larva of the hanging-fly Bittacus trapezoideus Huang & Hua, 2005 is described using scanning electron microscopy for the first time. The eruciform larva bears three pairs of thoracic legs and eight pairs of abdominal prolegs. Like other species of the family Bittacidae, the larval head is remarkable for bearing a median ocellus frontally and a pair of compound eyes laterally. Each compound eye consists of seven ommatidia. The larval trunk is symmetrically furnished with furcated protuberances. The larva of B. trapezoideus is diagnostic for bearing short brush-shaped setae on dorsal protuberances. In addition, the labial palp possesses nine basiconic sensilla on the apex; the abdomen bears a pair of sensory protuberances beside the protrusible sucker. The function of the furcated protuberances is briefly discussed. PMID- 26249080 TI - The presence of species of Pseudochironomus Malloch 1915 (Diptera: Chironomidae) in watercourses of Chaco Serrano Ecoregion (Argentina, South America). AB - Male imagos of Pseudochironomus viridis (Kieffer) are redescribed, the immature stages are described and figured for the first time. During this study, larva and pupal exuviae associated to P. richardsoni (Malloch) were recorded for the first time for South America. The specimens were collected from a stream and a river in the Pampasic Hills System in the Chaco Serrano ecoregion of Argentina. PMID- 26249081 TI - First record of the orchid bee genus Eufriesea Cockerell (Hymenoptera: Apidae: Euglossini) in the United States. AB - The orchid bee genus Eufriesea Cockerell is documented for the first time from the southwestern United States, extending its apparent range north well beyond its previous tropical/subtropical boundaries. Eufriesea coerulescens (Lepeletier de Saint Fargeau 1841) is recorded from the Guadalupe Mountains of western Texas and southeastern New Mexico, USA. Whether E. coerulescens is resident in the USA, or merely a vagrant from Mexico, remains unclear. Distinctive morphological traits shared with the holotype are enumerated and illustrated. In addition, observations that question the current species concept and distribution of E. coerulescens are provided. PMID- 26249082 TI - Redescription of Argyresthia mirabiella Toll, 1947 (Lepidoptera: Argyresthiidae). PMID- 26249083 TI - The intertidal Fortuyniidae (Acari: Oribatida): new species, morphological diversity, ecology and biogeography. AB - Three new fortuyniid species, Fortuynia longiseta sp. nov., F. maledivensis sp. nov. and Alismobates pseudoreticulatus sp. nov., were found in littoral environments of the Maldives and Singapore and are described based on adult and juvenile morphology. A key is given to all Alismobates and Fortuynia species. The genus Fortuynia shows a homogeneous morphology and this is supposed to be a result of a limited habitat preference shown in this genus. Nearly all species only occur on rocky intertidal shores, except for F. rotunda dwelling in mangrove habitats and F. smiti found in riverine environments. Fortuynia smiti was now also found in a typical littoral habitat in Singapore and hence the remarkably broad ecological range of this species is discussed. The records of further fortuyniid species in the Indo-Pacific affirm that this taxon may be continuously distributed along shores of this geographic region. PMID- 26249084 TI - Discovery of a new species of Caloptilia (Lepidoptera: Gracillariidae) from east and central Africa with its suggested associated host (Gentianales: Rubiaceae) and natural enemies (Hymenoptera: Eulophidae). AB - A new species of the leaf-mining moth genus Caloptilia (Gracillariidae), C. mwamba sp. nov., suggested to be associated with Cremaspora triflora (Thonn.) K.Schum. (Rubiaceae) is described from east and central Africa. The taxonomic relationships of the new species with its congeners from the Oriental and the Palaearctic regions are discussed. Newly obtained taxonomic and biological data are linked with the DNA barcode workbench in BOLD, providing the molecular, machine-readable identification tag of the new species. New distribution and morphological data for two parasitoid species, Afrotroppopsis risbeci Gumovsky, 2007 and Zaommomentedon newbyi (Kerrich, 1969) (Eulophidae), which were found to be associated with C. mwamba sp. nov., are presented. PMID- 26249085 TI - A review of the cicada genus Haphsa Distant from China (Hemiptera: Cicadidae). AB - The cicada genus Haphsa Distant from China was reviewed based on the description of a new species (Haphsa lueta sp. n.) and redescriptions of other three known species which are reported from China for the first time. A key to all known species of Haphsa worldwide is provided. The geographical distribution of the Haphsa species and the availability of Haphsa dianensis Chou, Lei, Li, Lu & Yao, 1997 are discussed. PMID- 26249086 TI - Description of three new species of Eumida Malmgren, 1865 (Phyllodocidae, Annelida) from Southern and Southeastern Brazil. AB - We describe three new species of Eumida from shallow estuarine and shelf bottoms from south and southeastern Brazil as part of a regional survey of the family Phyllodocidae. Previous regional records of Eumida sanguinea (Orsted, 1843) are herein referred to Eumida dracodermica sp. nov. The two species differ in the size of the prostomium, the distribution of micropapillae on the proboscis, and the shape of the dorsal cirri. Eumida macrophthalma sp. nov. has much larger eyes than the other two species described herein. The dorsal cirri on anterior median segments are rounded and on median and posterior segments they are asymmetrical and cordiform, longer than the dorsal cirri in Eumida dracodermica sp. nov. The lanceolate median dorsal cirri in Eumida delicata sp. nov. are only shared with E. ockelmanni Eibye-Jacobsen, 1987. It is also possible to diagnose the three species by their dorsal whitish pigmentation patterns on the first segments of living or well conserved animals. PMID- 26249087 TI - A review of the Canthyporus exilis group, with the description of two new species (Coleoptera: Dytiscidae). AB - Canthyporus namaqualacrimus sp. nov. and Canthyporus pallidus sp. nov. are described from the Namaqualand region of South Africa, both members of the exilis group. A revised key to species of the group is provided, together with details of the external and spermathecal tract morphology of the female of Canthyporus aenigmaticus Bistrom & Nilsson, 2006, a species previously known only from the male holotype. The opportunity is also taken to present new ecological and distributional data on members of the exilis group, most of which are primarily associated with springs and seepage habitats. PMID- 26249088 TI - Cryptic diversity in Australian stick insects (Insecta; Phasmida) uncovered by the DNA barcoding approach. AB - The barcoding approach was applied to analyze 16 Australian morphospecies of the order Phasmida, with the aim to test if it could be suitable as a tool for phasmid species identification and if its discrimination power would allow uncovering of cryptic diversity. Both goals were reached. Eighty-two specimens representing twelve morphospecies (Sipyloidea sp. A, Candovia annulata, Candovia sp. A, Candovia sp. B, Candovia sp. C, Denhama austrocarinata, Xeroderus kirbii, Parapodacanthus hasenpuschorum, Tropidoderus childrenii, Cigarrophasma tessellatum, Acrophylla wuelfingi, Eurycantha calcarata) were correctly recovered as clades through the molecular approach, their sequences forming monophyletic and well-supported clusters. In four instances, Neighbor-Joining tree and barcoding gap analyses supported either a specific (Austrocarausius mercurius, Anchiale briareus) or a subspecific (Anchiale austrotessulata, Extatosoma tiaratum) level of divergence within the analyzed morphospecies. The lack of an appropriate database of homologous coxI sequences prevented more detailed identification of undescribed taxa. PMID- 26249089 TI - The identity of Tachina westermanni Wiedemann, 1819 (Diptera: Calliphoridae or Tachinidae) with a solution to a nomenclatural problem. AB - Tachina westermanni Wiedemann, 1819 was based on four syntypes, two conspecific calliphorids and two conspecific tachinids. Two existing but contradictory lectotype fixations have resulted in confusion as to the correct application of the specific name westermanni Wiedemann. Evidence is presented showing that the lectotype fixation of Townsend in 1931 is valid and assigns westermanni Wiedemann to the Calliphoridae, with Pericallimyia westermanni as the valid binomen. The valid name for the tachinid taxon becomes Brachelia westermanni Robineau Desvoidy, 1830 and a neotype is designated for it in the interests of nomenclatural stability. PMID- 26249090 TI - Synonymy of Cryptopsocus Li with Trichadenotecnum Enderlein (Insecta: Psocodea: 'Psocoptera': Psocidae) and description of three new species. AB - The genus Cryptopsocus Li, 2002 is synonymized with Trichadenotecnum Enderlein, 1909. The type species of Crypto-psocus, T. cynostigmus (Li, 2002) n. comb., is considered to be a close relative of T. marginatum New & Thornton, 1976. These species cannot be assigned to any species group previously established in Trichadenotecnum so that the marginatum species group is here proposed for them. Three new species belonging to this species group are described: T. tigrinum and T. sharkeyi from Thailand and T. sabahense from Sabah, Malaysia. The phylogenetic position of the marginatum group is discussed using morphological data. PMID- 26249091 TI - Description of two new cicada species of the genus Poviliana Boulard (Insecta: Hemiptera, Cicadoidea, Cicadidae) from New Caledonia. AB - Poviliana dayubiikii Delorme sp. nov. and Poviliana montrouzieri Delorme sp. nov. are described from New Caledonia. They are respectively found in mid altitude rain forest on Mont Panie (570 m) and Col des Roussettes (300 m). Male calling songs of the two new species are described from the field recordings. A key to the species of Poviliana is also provided. PMID- 26249092 TI - The atyid shrimps from Lake Lindu, Central Sulawesi, Indonesia with description of two new species (Crustacea: Decapoda: Caridea). AB - The atyid shrimp Caridina linduensis Roux, 1904, has not been reported since its description more than a century ago. We here redescribe and figure this poorly known species based on new material from its type locality, Lake Lindu, Central Sulawesi, Indonesia. Two new species, C. dali sp. nov. and C. kaili sp. nov. are also found in this lake and they are described and illustrated. Compared to C. linduensis, C. dali sp. nov. is distinguished by its relatively shorter rostrum which only overreaches the end of basal segment of antennular peduncle and the fewer teeth on the incisor process of the mandible. Caridina kaili sp. nov. can be separated from C. linduensis by its extremely short rostrum, which reaches almost or just reaches the end of the basal segment of the antennular peduncle, proportionately stouter second pereiopod and larger egg size. The two new species also prefer different habitats; C. linduensis is a true lake inhabitant, C. dali sp. nov. can be found both in the lake itself and associated streams while C. kaili sp. nov. is an obligate stream species. PMID- 26249093 TI - On two new species of the shrimp genus Salmoneus Holthuis, 1955 (Decapoda, Caridea, Alpheidae) from the tropical eastern Pacific. AB - The present study deals two new alpheid shrimp species from the transisthmian Salmoneus ortmanni (Rankin, 1898) complex. Salmoneus alvarezi sp. nov. is described based on materials collected in Bahia Malaga, Colombia, and Punta Morales, Costa Rica, and is closely related to the western Atlantic S. ortmanni and S. wehrtmanni Anker, 2011. Salmoneus malagensis sp. nov. is described based on specimens from Bahia Malaga, Colombia, and beyond any doubts represents the eastern Pacific sister species of the western Atlantic S. carvachoi Anker, 2007. The two new species can be easily distinguished from each other by a number of morphological characters and colouration, and in addition appear to be ecologically separated. All previous records of S. ortmanni from the eastern Pacific are reassigned, some tentatively, to S. alvarezi sp. nov. based on description, illustrations or ecological data. PMID- 26249094 TI - The family Opilioacaridae (Parasitiformes: Opilioacarida) in Mexico, description of two new species and notes on biology and geographical distribution. AB - Two new species of Opilioacaridae from Mexico are described, Neocarus chactemalensis sp. nov. and N. comalensis sp. nov., and new records for N. texanus Chamberlin & Mulaik and N. veracruzensis Vazquez & Klompen are presented. Relative positions of internal structures of the ovipositor, a highly variable character, are described based on comparisons of invaginated and evaginated ovipositors. A study of records of Opilioacaridae in Mexico shows that the group is distributed across a wide range of ecosystems and elevations, from dry, semi desert to wet tropical forest, and coastal plains to the altiplano (>2,000 m). PMID- 26249095 TI - A new species of Leberis Smirnov, 1989 (Cladocera: Chydoridae) from Colombia. AB - A new species of Leberis Smirnov 1989 (Cladocera: Chydoridae) is described based on the material from Cienaga El Convento (Atlantico Department), Cienaga Grande de Santa Marta (Magdalena Department), and Laguna Navio Quebrado (La Guajira Department), Colombia. In the Neotropics, Leberis colombiensis sp. nov. could be confused with L. davidi Richard, 1985. But the former differs from the latter in: (1) smaller size; (2) smaller post-pore distance; (3) gonopore region on male postabdomen un-inflated, not overhanging base of postabdominal claw; (4) shorter postanal portion of male postabdomen. Diversity of the genus worldwide is underestimated yet. We believe that more species of Leberis will be described in the future, i.e. after molecular genetic studies. PMID- 26249096 TI - Redescription of Lusitanipus alternans (Verhoeff, 1893) (Diplopoda, Callipoda, Dorypetalidae) and ecological data on its Laboulbeniales ectoparasites in caves. AB - The Portuguese endemic callipodidan millipede Lusitanipus alternans (Verhoeff, 1893) is redescribed, based on abundant new material collected in caves of central Portugal. The species is illustrated with comprehensive SEM images. The relationships of the genus Lusitanipus Mauries, 1978 to other callipodidan genera of the subfamily Cyphocallipodinae Verhoeff, 1909 are discussed. The major part of the studied material is highly infected with ectoparasitic fungi of the order Laboulbeniales, we also include information about the infection in the subterranean ecosystem. PMID- 26249097 TI - Re-description and first host and biology records of Entedon magnificus (Girault & Dodd) (Hymenoptera, Eulophidae), a natural enemy of Gonipterus weevils (Coleoptera, Curculionidae), a pest of Eucalyptus trees. AB - Entedon magnificus (Girault & Dodd) (Hymenoptera: Eulophidae, Entedoninae) is recorded as a gregarious larval endoparasitoid of Gonipterus weevils (Coleoptera: Curculionidae), significant pests of Eucalyptus trees. Entedon magnificus is re described and illustrated based on females and males from Australia and Tasmania. PMID- 26249098 TI - Description of a new distinctive species of Parabetaeus Coutiere, 1897 (Decapoda: Caridea: Alpheidae) from the Indo-West Pacific. AB - Parabetaeus acanthus sp. nov. is described based on two specimens from Thuwal, Saudi Arabia, and Madang, Papua New Guinea. The new species is unique within the genus in possessing an anteriorly directed, spine-like tooth on the mid-dorsal line of the carapace, posterior to base of the eyes, and in the stylocerite not reaching the mid-length of the first article of the antennular peduncle. The chelipeds of P. acanthus sp. nov. are variable in size and proportions, as well as in the armature on the finger cutting edges. This cheliped polymorphism appears to be typical to all species of the genus. PMID- 26249099 TI - Preliminary diagnoses of three new species of Tasmanian mountain shrimps, Anaspides Thomson, 1894 (Syncarida, Anaspidacea, Anaspididae). PMID- 26249100 TI - JULIANA MOURAO DOS SANTOS RODRIGUES, FELIPE FERRAZ FIGUEIREDO MOREIRA, ISABELLE DA ROCHA SILVA CORDEIRO, MAGALY DOLSAN DE ALMEIDA & JOSE JURBERG (2015) List of the type-specimens of Reduviidae (Hemiptera: Heteroptera) in the Triatomines Collection of the Oswaldo Cruz Institute, Brazil . Zootaxa, 3936(2): 181-206. PMID- 26249101 TI - White matter alterations in patients with MRI-negative temporal lobe epilepsy and their asymptomatic siblings. AB - OBJECTIVE: The identification of "endophenotypes"-measurable variations along the pathways between genes and distal disease state-may help deconstruct focal epilepsies into more sensitive phenomena and improve future efforts to map the genetic underpinnings of the disorder. In this study, we set out to determine if diffusion tensor imaging (DTI)-inferred white matter (WM) alterations represent a suitable structural endophenotype for focal epilepsy. METHODS: We recruited 25 patients with sporadic mesial temporal lobe epilepsy (MTLE) with normal magnetic resonance imaging (MRI) findings, 25 of their gender-matched, asymptomatic siblings, and 60 control subjects. Whole-brain, voxelwise statistics were conducted to identify regions of microstructural degeneration in patients with MTLE and/or their asymptomatic siblings. WM tracts exhibiting evidence of microstructural disruption were then reconstructed using deterministic tractography. Diffusion metrics including fractional anisotropy (FA) and mean diffusivity (MD) were compared across groups using a series of one-way multivariate analyses of covariance (MANCOVAs). RESULTS: Voxelwise statistics revealed significant FA reductions in the corpus callosum (CC), bilateral superior longitudinal fasciculi (SLF), bilateral inferior longitudinal fasciculi (ILF), and left corticospinal tract (CST) in MTLE patients only. MD increases were observed in MTLE patients and their asymptomatic siblings in the left SLF and left CST. Deterministic tractography supported the voxelwise results, revealing significant FA alterations in the left SLF and CST in patients only and significant MD alterations in MTLE patients and their unaffected siblings. The diffusion scalars of MTLE patients and their asymptomatic siblings were highly correlated in the SLF and CST ipsilateral to patients' sides of seizure onset. SIGNIFICANCE: These findings confirm the presence of microstructural WM alterations in patients with MRI-negative MTLE and provide preliminary support for a diffusion-based endophenotype in the disorder. Further studies of narrow sense heritability in larger cohorts of first-degree relatives of MTLE patients are required to confirm these results. PMID- 26249102 TI - Cytological features of complex type fibroadenoma in comparison with non-complex type fibroadenoma. AB - BACKGROUND: To determine the cytomorphological features of complex type fibroadenoma (CFA), we reviewed fine needle aspiration (FNA) cytology with correlation to its histopathology findings, and compared them with non-complex type fibroadenoma (NCFA). METHODS: From excisional biopsy or resected specimens of fibroadenoma (FA) cases treated at our institution from 2004 to 2013, we chose 46 patients who underwent FNA before a diagnosis of FA was established. We histologically re-classified them into two groups: CFA and NCFA. FNA diagnosis was retrospectively re-evaluated from FNA reports. We further re-assessed detailed characteristics of each FNA smears to identify cytomorphological features of CFA. RESULTS: We found that 15 cases fulfilled the diagnostic criteria of CFA, in which 7 (46.7 %) had an FNA diagnosis of "suspicious for malignancy" or "indeterminate" while only 2 NCFA cases had that of "indeterminate" (p = 0.004). FNA smears from CFA cases showed discohesiveness, enlarged nuclei, prominent nucleoli, and fewer myoepithelial cells more often than NCFA. Although no significant difference was noted in patients' age and tumor size between CFA and NCFA, 5 CFA cases (33.3 %) were accompanied by the presence of carcinoma in the same breast or the contralateral breast while no NCFA cases had carcinoma in the breast. CONCLUSIONS: FNA of CFA can lead to erroneous or indeterminate interpretation, due to proliferative and/or hyperplastic changes of ductal epithelium with or without atypia. It is important to recognize the disease entity and characteristic cytomorphological findings of CFA to reach accurate FNA diagnosis of breast lesions. PMID- 26249103 TI - Nipple malposition after nipple-sparing mastectomy and expander-implant reconstruction. AB - BACKGROUND: Nipple malposition after nipple-sparing mastectomy and expander implant reconstruction performed in our institute between 2002 and 2010 was studied retrospectively, targeting breast ptosis and volume. METHODS: The preoperative nipple position relative to the inframammary fold was used as the breast ptosis index. The intraoperative resected breast tissue was measured and used as the volume index. For pre- and postoperative photograph evaluation, the vertical distance of the nipple was defined as the distance from the nipple to the midpoint of the bottoms of the sternocleidomastoid muscle. The vertical distance ratio was defined as the postoperative affected-side/unaffected-side vertical distance to the preoperative one. A correlation analysis was carried out comparing the vertical distance ratios with the preoperative nipple position relative to the inframammary fold and resection tissue weight. RESULTS: A total of 42 cases using the expander-implant method were analyzed. The mean vertical distance ratio was 0.88. There was a comparatively high correlation between the vertical distance ratio and the resection tissue weight (correlation coefficient 0.53, P = 0.0003) and between the vertical distance ratio and the preoperative nipple position relative to the inframammary fold (correlation coefficient 0.37, P = 0.0152). CONCLUSION: In expander-implant reconstruction of a large or ptotic breast, nipple-sparing mastectomy should be performed with the expectation that ancillary procedures will be needed. PMID- 26249105 TI - Nutritional values and antioxidative activities of whole peanuts and peanut skins for ruminant feeds. AB - This study was conducted to investigate the nutritive values of two peanut by products, nonstandardized whole peanuts and peanut skins, along with their effects on microbial growth and fermentation in the rumen, their roughage values, and their antioxidative activities by a digestion trial using four goats. The experimental rations were alfalfa haycube (basal ration), 85% alfalfa with 15% whole peanuts, and 70% alfalfa with 15% whole peanuts and 15% peanut skins. The ether extracts and crude protein in whole peanuts were 47% and 27% on a dry matter basis (DM) both with over 90% of digestibilities, resulting in total digestive nutrients (TDN) of 140%. Peanut skins also had a high energy value with 91% of TDN. Ruminal concentrations of total volatile fatty acids (VFA) and acetic acid decreased in the rations containing the peanut by-products, but the NDF digestibility and ruminal microbial protein estimated from urinary purines was not altered by feeding the peanut by-products. Plasma oxidative stress maker, malondialdehyde, tended to be lower when peanut skins were supplemented. Whole peanuts and peanut skins could be used as high-energy and high-protein diets for ruminants, and peanut skins would be expected as a feed having antioxidant functions. PMID- 26249104 TI - Implementation of the Every Newborn Action Plan: Progress and lessons learned. AB - Progress in reducing newborn mortality has lagged behind progress in reducing maternal and child deaths. The Every Newborn Action Plan (ENAP) was launched in 2014, with the aim of achieving equitable and high-quality coverage of care for all women and newborns through links with other global and national plans and measurement and accountability frameworks. This article aims to assess country progress and the mechanisms in place to support country implementation of the ENAP. A country tracking tool was developed and piloted in October-December 2014 to collect data on the ENAP-related national milestones and implementation barriers in 18 high-burden countries. Simultaneously, a mapping exercise involving 47 semi-structured interviews with partner organizations was carried out to frame the categories of technical support available in countries to support care at and around the time of birth by health system building blocks. Existing literature and reports were assessed to further supplement analysis of country progress. A total of 15 out of 18 high-burden countries have taken concrete actions to advance newborn health; four have developed specific action plans with an additional six in process and a further three strengthening newborn components within existing plans. Eight high-burden countries have a newborn mortality target, but only three have a stillbirth target. The ENAP implementation in countries is well-supported by UN agencies, particularly UNICEF and WHO, as well as multilateral and bilateral agencies, especially in health workforce training. New financial commitments from development partners and the private sector are substantial but tracking of national funding remains a challenge. For interventions with strong evidence, low levels of coverage persists and health information systems require investment and support to improve quality and quantity of data to guide and track progress. Some of the highest burden countries have established newborn health action plans and are scaling up evidence based interventions. Further progress will only be made with attention to context-specific implementation challenges, especially in areas that have been neglected to date such as quality improvement, sustained investment in training and monitoring health worker skills, support to budgeting and health financing, and strengthening of health information systems. PMID- 26249107 TI - Correlation modeling between process condition of sandblasting and surface texture: A multi-scale approach. AB - In the present study, the influence of sandblasting condition (working pressure) on surface texture is modeled, relying on a multi-scale approach and statistical analysis. To improve the correlation modeling between the process condition and surface texture, special effort is made to identification of an optimal parameter set, including 3D roughness parameters, cut-off lengths, filter types and model types. A power law relationship is identified between the pressure and Sdq computed with a cut-off length of 120 um using a low-pass filter. Experimental and theoretical arguments are provided for justification. SCANNING 38:191-201, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26249106 TI - Leishmania infection modulates beta-1 integrin activation and alters the kinetics of monocyte spreading over fibronectin. AB - Contact with Leishmania leads to a decreases in mononuclear phagocyte adherence to connective tissue. In this work, we studied the early stages of bond formation between VLA4 and fibronectin, measured the kinetics of membrane alignment and the monocyte cytoplasm spreading area over a fibronectin-coated surface, and studied the expression of high affinity integrin epitope in uninfected and Leishmania infected human monocytes. Our results show that the initial VLA4-mediated interaction of Leishmania-infected monocyte with a fibronectin-coated surface is preserved, however, the later stage, leukocyte spreading over the substrate is abrogated in Leishmania-infected cells. The median of spreading area was 72 [55 89] MUm(2) for uninfected and 41 [34-51] MUm(2) for Leishmania-infected monocyte. This cytoplasm spread was inhibited using an anti-VLA4 blocking antibody. After the initial contact with the fibronectrin-coated surface, uninfected monocyte quickly spread the cytoplasm at a 15 MUm(2) s(-1) ratio whilst Leishmania infected monocytes only made small contacts at a 5.5 MUm(2) s(-1) ratio. The expression of high affinity epitope by VLA4 (from 39 +/- 21% to 14 +/- 3%); and LFA1 (from 37 +/- 32% to 18 +/- 16%) molecules was reduced in Leishmania-infected monocytes. These changes in phagocyte function may be important for parasite dissemination and distribution of lesions in leishmaniasis. PMID- 26249108 TI - Electrocatalytic Hydrogen Production by an Aluminum(III) Complex: Ligand-Based Proton and Electron Transfer. AB - Environmentally sustainable hydrogen-evolving electrocatalysts are key in a renewable fuel economy, and ligand-based proton and electron transfer could circumvent the need for precious metal ions in electrocatalytic H2 production. Herein, we show that electrocatalytic generation of H2 by a redox-active ligand complex of Al(3+) occurs at -1.16 V vs. SCE (500 mV overpotential). PMID- 26249109 TI - Gut physiology mediates a trade-off between adaptation to malnutrition and susceptibility to food-borne pathogens. AB - The animal gut plays a central role in tackling two common ecological challenges, nutrient shortage and food-borne parasites, the former by efficient digestion and nutrient absorption, the latter by acting as an immune organ and a barrier. It remains unknown whether these functions can be independently optimised by evolution, or whether they interfere with each other. We report that Drosophila melanogaster populations adapted during 160 generations of experimental evolution to chronic larval malnutrition became more susceptible to intestinal infection with the opportunistic bacterial pathogen Pseudomonas entomophila. However, they do not show suppressed immune response or higher bacterial loads. Rather, their increased susceptibility to P. entomophila is largely mediated by an elevated predisposition to loss of intestinal barrier integrity upon infection. These results may reflect a trade-off between the efficiency of nutrient extraction from poor food and the protective function of the gut, in particular its tolerance to pathogen-induced damage. PMID- 26249110 TI - Orthopaedic surgeons' use and knowledge of ionizing radiation during surgical treatment for femoroacetabular impingement. AB - PURPOSE: To better understand how radiograph imaging is currently used throughout perioperative care for femoroacetabular impingement (FAI) and to define surgeon knowledge and perspective on radiation safety when treating FAI. METHODS: An online questionnaire was designed to be completed by hip arthroscopists on the imaging modalities and projections they use during evaluation and treatment of FAI and the associated radiation exposures and safety. A sample of practicing attending orthopaedic surgeons was surveyed via an anonymous survey link emailed to corresponding authors on publications related to FAI. The anonymous survey link was also provided to orthopaedic surgeons at the 2014 Vail Hip Symposium. RESULTS: Ninety-one surgeons completed the survey. Of these participants, 72 surgeons (79.1 %) indicated they use pre-operative radiographs and intra operative spot fluoroscopic images during FAI treatment. Thirty-three surgeons (36.3 %) use pre-operative computed tomography (CT). Twenty-three surgeons (25.3 %) use real-time moving fluoroscopy. A majority of surgeons incorrectly answered multiple-choice questions about which C-arm positions and settings result in the lowest doses of radiation to the surgeon or patient. Eighty-three surgeons (91.2 %) indicated they believe most orthopaedic surgeons need to be more informed about radiation safety. CONCLUSIONS: This study gives a quantitative representation of the imaging modalities and projections utilized during perioperative treatment for FAI. This study also identified a lack of knowledge of radiation safety among orthopaedic surgeons treating patients with FAI and demonstrates the need for greater education. LEVEL OF EVIDENCE: IV. PMID- 26249111 TI - Influence of lateral meniscal posterior root avulsions and the meniscofemoral ligaments on tibiofemoral contact mechanics. AB - PURPOSE: The purpose of this study was to investigate the effect of lateral meniscal posterior root avulsions combined with intact meniscofemoral ligaments (MFLs), deficient MFLs, anterior cruciate ligament (ACL) tears and reconstructions, and root repairs using an established tibiofemoral contact mechanics testing protocol. METHODS: Ten fresh-frozen cadaveric knees were tested with six knee conditions (1: intact; 2: lateral meniscal posterior root avulsion; 3: root avulsion and deficient MFLs; 4: condition 3 with ACL tear; 5: condition 4 with ACL reconstruction; 6: ACL reconstruction with root repair) at five flexion angles (0 degrees , 30 degrees , 45 degrees , 60 degrees , and 90 degrees ), under a 1000-N axial load. Contact area and pressure were measured with Tekscan sensors. RESULTS: Compared to the intact state, condition 2 did not significantly change lateral compartment contact area or pressure. Changes in contact mechanics were greater at increased flexion angles; for condition 3 at 0 degrees and 90 degrees , contact area decreased 37 and 52 % [95 % CI (21-53) and (39-66), respectively] and mean contact pressure increased 55 and 87 % [95 % CI (33-76) and (59-114), respectively]. Root repair with ACL reconstruction was not significantly different from the intact state. CONCLUSIONS: The MFLs protect the lateral compartment from changes in contact mechanics in the setting of a lateral meniscal posterior root avulsion, whereas a combination of lateral meniscal root avulsion and deficient MFLs leads to significant changes. Concurrent ACL reconstruction and lateral meniscal root repair restore mean contact pressure and area to the intact state and are recommended in this combined injury to prevent or slow the development of lateral compartment arthritis. PMID- 26249112 TI - The ESSKA paediatric anterior cruciate ligament monitoring initiative. AB - PURPOSE: To survey and describe the treatment of paediatric anterior cruciate ligament (ACL) injuries performed by orthopaedic surgeons affiliated with the European Society for Sports Traumatology, Knee Surgery and Arthroscopy (ESSKA). METHODS: A closed e-survey was submitted to all registered members and affiliates of ESSKA in July 2013. All recipients were invited to participate in the survey by answering 34 questions online. The list of potential respondents was extracted from the ESSKA office database. RESULTS: Invitation was sent to 2236 ESSKA members and affiliates, and received 491 (22%) unique responses. Among the respondents, 445 (91%) were orthopaedic surgeons, with 354 (72%) stating that they were involved in treatment of paediatric ACL injuries. The main findings were that there are substantial differences with regard to preferred treatment algorithms, surgical techniques and long-term follow-up procedures. The summed estimate of skeletally immature children with ACL injury seen by the responders in 2012 was minimum 1923 individuals, and a minimum of 102 clinically relevant post-operative growth disturbances were registered. CONCLUSION: The present survey documents that the incidences of paediatric ACL injuries and idiopathic growth disturbances may be higher than previously estimated. Treatment algorithms and surgical techniques are highly diverse, and consensus could not be identified. It is worrying that only half the surgeons reported to follow-up children until skeletal maturity after surgical treatment. The results of this survey highlight the importance of international multicentre studies on paediatric ACL treatment and the development of an outcome registry to enable prospective data collections. LEVEL OF EVIDENCE: IV. PMID- 26249113 TI - Spectra, stability and labeling of 1-(5-carboxypentyl)-4-(2-(N-ethyl-carbazole-3 yl) vinyl) pyridinium bromide with a large Stokes shift. AB - Carbazole and its derivatives have been widely utilized as a functional building block in the fabrication of the organic medicine, pesticides, materials, etc., because of their excellent solubility, stability and biological activity. In this paper, 1-(5-carboxypentyl)-4-(2-(N-ethyl-carbazole-3-yl) vinyl) pyridinium bromide with a large Stokes shift was synthesized and characterized by (1)H NMR and MS. The UV/vis absorption and fluorescence spectra in different solvents and at different pH values were investigated preliminarily. The photostability and thermostability were also studied and the results showed that the compound was stable. The compound was also used to label bovine serum albumin (BSA) and calf thymus (ct)DNA. The results showed that the fluorescence intensity is enhanced when labeling with BSA and the binding ability is stronger than ctDNA, making it may be used as a biological probe. PMID- 26249114 TI - The LEGACY Girls Study: Scientists seek answers to girls' future risk of breast cancer. PMID- 26249116 TI - Vegetarian diet associated with lower risk of colorectal cancer. PMID- 26249115 TI - Studies presented at ASCO meeting highlight success with targeted therapies. PMID- 26249118 TI - Psychometric properties of the Social Problem Solving Inventory-Revised Short Form in a South African population. AB - The Social Problem Solving Inventory-Revised Short-Form (SPSI-R:SF) has been used in several countries to identify problem-solving deficits among clinical and general populations in order to guide cognitive-behavioural interventions. Yet, very few studies have evaluated its psychometric properties. Three language versions of the questionnaire were administered to a general population sample comprising 1000 participants (771 English-, 178 Afrikaans- and 101 Xhosa speakers). Of these participants, 210 were randomly selected to establish test retest reliability (70 in each language). Principal component analysis was performed to examine the applicability of the factor structure of the original questionnaire to the South African data. Supplementary psychometric analyses were performed, including internal consistency and test-retest reliability. Collectively, results provide initial evidence of the reliability and validity of the SPSI-R:SF for the assessment of problem solving deficits in South Africa. Further studies that explore how the Afrikaans language version of the SPSI-R:SF can be improved and that establish the predictive validity of scores on the SPSI R:SF are needed. PMID- 26249119 TI - Picking the optimal endocrine adjuvant treatment for pre-menopausal women. AB - Endocrine treatments are key component of the adjuvant strategy for pre menopausal patients with luminal tumors. Treatment options should be based not only upon the risk of relapse and level of endocrine responsiveness, but also on co-morbidities, preferences of the patient and degree of side effects. Tamoxifen should still be considered as an appropriate endocrine therapy in a large group of premenopausal patients (e.g. lower risk patient, presence of co-morbidities, patient preference). However, the results of the SOFT and TEXT trials, evaluating the value of ovarian function suppression (OFS) as well as the role of adjuvant aromatase inhibitor (AI), raised questions about the use of tamoxifen alone in selected higher risk patient. In the SOFT study, premenopausal patients did not benefit from the addition of OFS, but for those women at sufficient risk of recurrence to deserve adjuvant chemotherapy and who maintained pre-menopausal estradiol, the addition of OFS to tamoxifen reduced the risk of recurrence. Moreover, in the TEXT trial, adjuvant treatment with exemestane plus OFS, as compared with tamoxifen plus OFS, significantly improved disease-free survival, breast cancer-free interval and distant disease-free survival, thus representing a new treatment option. Recent available information on endocrine options for younger patients with luminal tumors support the use of tailored endocrine treatments. Issues specific for younger patients related to pregnancies desire, family planning, safety, quality of life and subjective side effects should be a priority in the therapeutic algorithm. PMID- 26249120 TI - Progress in the surgical management of breast cancer: Present and future. AB - Recognition of differing risks of locoregional recurrence (LRR) in breast cancer patients based on estrogen receptor, progesterone receptor, and HER2 status, coupled with a reduction in LRR in patients receiving adjuvant systemic therapy, offers the opportunity to tailor surgical treatment and reduce the morbidity of therapy. New guidelines for margins in breast-conserving therapy of tumor not touching ink and avoidance of axillary dissection in sentinel node positive patients undergoing breast-conserving therapy are examples of this approach which have entered practice. Increased use of neoadjuvant therapy offers the opportunity to identify which patients are responsive to chemotherapy prior to surgery, potentially allowing further tailoring of treatment, and ongoing clinical trials will address the question of the extent of axillary surgery and radiotherapy after neoadjuvant therapy in patients with and without pathologic complete response. PMID- 26249121 TI - Hypofractionated radiotherapy in early breast cancer: Clinical, dosimetric and radio-genomic issues. PMID- 26249122 TI - Is there a place for brachytherapy in the salvage treatment of cervical lymph node metastases of head and neck cancers? AB - PURPOSE: Therapeutic options are limited for unresectable isolated cervical lymph node recurrences. The purpose of the study was to evaluate the feasibility, safety, and efficacy of high-dose-rate (HDR) and pulsed-dose-rate (PDR) brachytherapy (BT) in such cases. METHODS AND MATERIALS: Sixty patients have been analyzed. All them had previously been treated with radical radiotherapy or chemoradiotherapy with or without surgery. PDR-BT and HDR-BT were used in 49 and 11 patients, respectively. In PDR-BT, a dose per pulse of 0.6-0.8 Gy (median 0.7 Gy) was given up to a median total dose of 20 Gy (range, 20-40 Gy). HDR-BT delivered a median total dose of 24 Gy (range, 7-60 Gy) in 3-10 fractions at 3-6 Gy per fraction. RESULTS: The overall survival and lymph node control rates at 1 and 2 years were estimated for 31.7% and 19%, and 41.4% and 27.3%, respectively. Serious late side effects (soft tissue necrosis) were observed in 11.7% of patients. Adverse events occurred statistically more often in patients >59 years (p = 0.02). CONCLUSIONS: HDR-BT and PDR-BT are feasible in previously irradiated patients with isolated regional lymph node metastases of head and neck cancers. The techniques should be considered if surgery is contraindicated. They provide acceptable toxicity and better tumor control than chemotherapy alone. PMID- 26249124 TI - Point: Surgery is the most cost-effective option for prostate cancer needing treatment. PMID- 26249123 TI - Intraoperative breast radiation therapy with image guidance: Findings from CT images obtained in a prospective trial of intraoperative high-dose-rate brachytherapy with CT on rails. AB - PURPOSE: Intraoperative radiation therapy (IORT) is an increasingly popular approach to breast conserving therapy in the treatment of early-stage breast cancer. A drawback to IORT compared with postoperative adjuvant radiation therapy is that it is not performed using image guidance. Our aim was to report on how our institution's unique IORT workflow integrates CT image guidance and how these CT images were used intraoperatively to change applicator positioning. METHODS AND MATERIALS: We retrospectively reviewed the first 29 patients who participated in a prospective clinical trial of breast IORT at our institution. All patients underwent lumpectomy, multicatheter balloon placement, intraoperative CT scan, and high-dose-rate brachytherapy treatment delivery to 12.5 Gy to 1 cm from the balloon surface. This report focuses on the intraoperative CT findings that led to clinical changes, followed by repeat CT for IORT treatment planning. RESULTS: After initial intraoperative CT, 7 patients underwent an additional intraoperative CT scan (24.1%). In 6 patients, the initial intraoperative CT scan identified large air cavities and/or poor tissue conformity. This defect could be improved in all patients with adjustment of the balloon applicator before planning and delivering IORT. Intraoperative CT scan was used in one patient to localize a biopsy clip and aided in excision to negative margin. CONCLUSIONS: In our study, intraoperative CT identifies actionable findings in breast IORT, including residual tumor or errors in applicator positioning, in almost 25% of patients. Clinical results of the described trial will serve to further validate this image-guided approach to IORT. PMID- 26249126 TI - Decomposition Rate and Pattern in Hanging Pigs. AB - Accurate prediction of the postmortem interval requires an understanding of the decomposition process and the factors acting upon it. A controlled experiment, over 60 days at an outdoor site in the northwest of England, used 20 freshly killed pigs (Sus scrofa) as human analogues to study decomposition rate and pattern. Ten pigs were hung off the ground and ten placed on the surface. Observed differences in the decomposition pattern required a new decomposition scoring scale to be produced for the hanging pigs to enable comparisons with the surface pigs. The difference in the rate of decomposition between hanging and surface pigs was statistically significant (p=0.001). Hanging pigs reached advanced decomposition stages sooner, but lagged behind during the early stages. This delay is believed to result from lower variety and quantity of insects, due to restricted beetle access to the aerial carcass, and/or writhing maggots falling from the carcass. PMID- 26249125 TI - Does location of prostate cancer by sextant biopsies predict for relapse after (125)I seed implant brachytherapy? AB - PURPOSE: To report on the importance of cancer location from diagnostic prostate biopsies in predicting biochemical relapse for patients treated with (125)I seed implant brachytherapy as monotherapy for favorable risk disease; specifically, to assess the clinical significance of potentially underdosing the base region of the prostate gland. METHODS AND MATERIALS: Of 1145 consecutive patients, 846 had pretreatment biopsies allowing for sextant analysis and consequent evaluation of biochemical failure tendencies. Biochemical failure was defined as a posttreatment rise in the nadir prostate-specific antigen (PSA) by at least 2 ng/mL. Patient and tumor characteristics, dosimetry, the use of hormone therapy, source strength, and postimplant PSA kinetics were analyzed between sextant subgroups. RESULTS: Sixty-two patients (7.3%) with sextant pathology had biochemical failure. There was no significant difference between the failure locations. There were 528 patients (62.4%) with some element of base involvement (BI), and 318 patients (37.6%) with no evidence of BI. Of the 62 patients with biochemical failure, 42 (67.7%) showed BI on biopsy and 20 (32.3%) had no BI. The 10-year relapse-free survival rate is 88.2% (95% confidence interval: 84.3%, 92.2%) and 92.0% (95% confidence interval: 88.4%, 95.8%) for the BI and no BI groups, respectively (p = 0.17). The mean D90 delivered to the base, midgland, and apex was 140.8 (+/-21.8) Gy, 170.8 (+/-22.5) Gy, and 177.9 (+/-29.5) Gy, respectively, for all patients. CONCLUSIONS: There are no significantly worse outcomes for patients treated with an (125)I seed implant for favorable risk prostate cancer with some element of BI, despite lower doses of radiation delivered to the base region. PMID- 26249127 TI - HIV sexual transmission risks in the context of clinical care: a prospective study of behavioural correlates of HIV suppression in a community sample, Atlanta, GA, USA. AB - INTRODUCTION: Antiretroviral therapy (ART) improves the health of people living with HIV and has the potential to reduce HIV infectiousness, thereby preventing HIV transmission. However, the success of ART for HIV prevention hinges on sustained ART adherence and avoiding sexually transmitted infections (STI). OBJECTIVES: To determine the sexual behaviours and HIV transmission risks of individuals with suppressed and unsuppressed HIV replication (i.e., viral load). METHODS: Assessed HIV sexual transmission risks among individuals with clinically determined suppressed and unsuppressed HIV. Participants were 760 men and 280 women living with HIV in Atlanta, GA, USA, who completed behavioural assessments, 28-daily prospective sexual behaviour diaries, one-month prospective unannounced pill counts for ART adherence, urine screening for illicit drug use and medical record chart abstraction for HIV viral load. RESULTS: Individuals with unsuppressed HIV demonstrated a constellation of behavioural risks for transmitting HIV to uninfected sex partners that included symptoms of STI and substance use. In addition, 15% of participants with suppressed HIV had recent STI symptoms/diagnoses, indicating significant risks for sexual infectiousness despite their HIV suppression in blood plasma. Overall, 38% of participants were at risk for elevated sexual infectiousness and just as many engaged in unprotected sexual intercourse with non-HIV-infected partners. CONCLUSIONS: Implementation strategies for using HIV treatments as HIV prevention requires enhanced behavioural interventions that extend beyond ART to address substance use and sexual health that will otherwise undermine the potential preventive impact of early ART. PMID- 26249128 TI - Relationship of weight status, physical activity and screen time with academic achievement in adolescents. AB - OBJECTIVE: The aim of this study was to examine the relationship of weight status, physical activity and screen time with academic achievement in Chilean adolescents. METHODS: The present cross-sectional study included 395 adolescents. The International Obesity Task Force cut-off points were used to define the weight status. Physical activity was assessed using the Physical Activity Questionnaire for Adolescents and screen time was assessed using several questions about television, videogame and computer use. Academic achievement was measured using the mean of the grades obtained in mathematics and language subjects. RESULTS: In both genders, adolescents with obesity and excessive screen time earned worse grades compared to their non-obese peers and their peers that complied with screen time recommendations. The logistic regression analysis showed that adolescents with obesity, classified with medium-low physical activity and excessive screen time recommendations (excess >=2h/day) are less likely to obtain high academic achievement (boys: OR=0.26; girls: OR=0.23) compared to their non-obese peers, high levels of physical activity and those who comply with the current screen time recommendations. Similar results were observed in adolescents with obesity and classified with medium-low physical activity (boys: OR=0.46; girls: OR=0.33) or excessive screen time (boys: OR=0.35; girls: OR=0.36) compared to adolescents with high levels of physical activity and those who complied with the screen time recommendations, respectively. CONCLUSION: This study shows that when combined, obesity, low-medium levels of physical activity and excessive screen time might be related to poor academic achievement. PMID- 26249129 TI - Self-reported weight perceptions in euthyroid individuals across different levels of free thyroxine and BMI. PMID- 26249130 TI - Incidence and distribution of paravascular lamellar holes and their relationship with macular retinoschisis in highly myopic eyes using spectral-domain oct. AB - The purpose of the study is to determine the incidence and distribution of paravascular lamellar holes (PLH) around retinal vessels in highly myopic eyes and their relationship with macular retinoschisis (MR). We examined 306 eyes of 178 patients with high myopia, performing multiple scans of the posterior pole within the retinal vascular arcades using spectral-domain OCT. Type of staphyloma was determined. PLH were divided into three groups: holes only (group 1), holes extending below vessels (group 2), and holes in an area of paravascular retinoschisis (group 3). OCT showed that 96/306 eyes (31.4 %) had PLH mainly along the infero-temporal arcade (39.9 %). Type V and IX staphylomas had a higher proportion of PLH in the infero-temporal arcade than other staphylomas. Group 3 eyes presented higher rates of myopia and staphyloma. MR was detected in 10/27 eyes (37 %) in Group 3, but only in 2/33 eyes (6.1 %) in Group 1. No MR was found in Group 2. PLH are relatively common in highly myopic eyes and mainly distributed in the inferior temporal arcade. Findings from this descriptive study suggest that distribution of PLH might be related to the type of staphyloma. Further studies are needed to evaluate the relevance of PLH in the pathogenesis of MR. PMID- 26249131 TI - Clinicopathological profile of orbital exenteration: 14 years of experience from a tertiary eye care center in South India. AB - This study aims to describe the clinicopathological features and outcomes of patients who underwent orbital exenteration at a tertiary eye care center in south India. Retrospective chart reviews were performed on all patients undergoing orbital exenteration from January 1999 to December 2012. Parameters recorded include demographic data, clinical presentations, past medical or surgical interventions, exenteration notes, histopathological diagnosis, adjunctive treatment, follow-up examination findings, recurrences, complications, and their management. Orbital exenteration was performed on 119 orbits of 119 patients over a 14-year period. The mean age was 48.9 years (range 1-82 years). The indications were malignancies in 90.7 % (108/119), while 9.3 % (11/119) of cases were exenterated for non-malignant indications. Among the malignancies, the commonest tissue of origin was conjunctiva, noted in 45.4 % (49/108), followed by eyelids (25.9 %, 28/108), orbit (19.4 %, 21/108), and intraocular tissues (9.3 %, 10/108). The commonest malignancies noted in this series were an extensive ocular surface squamous neoplasia (OSSN) (44.4 %, 48/108) and sebaceous gland carcinoma of eyelids with an orbital involvement (18.5 %, 20/108). Extensive fungal granuloma (mucormycosis-4, aspergillosis-4) was the commonest (81.8 %, 9/11) indication among the non-malignant group. All complications were wound related, and none had a recurrence at a mean follow-up of 12.8 months. Extensive orbital involvement with OSSN and SGC were the commonest indications for exenteration. There is a need of creating awareness among general ophthalmologists in specific geographical regions regarding early diagnosis, standardized protocols of management, and appropriate referral. PMID- 26249132 TI - Small differences in age and cataract surgery percentage have a potentially high effect on the corneal endothelial cell density. PMID- 26249133 TI - Trends in cerclage use. AB - INTRODUCTION: The indications of placement of cerclage have recently changed, and so it is important to evaluate how many women are undergoing this procedure. With the recent completion of clinical trials, it is plausible that obstetricians and perinatologists may have become more selective in terms of the best candidates for cerclage. MATERIAL AND METHODS: We conducted a retrospective cohort study of women who underwent cerclage for prevention of preterm birth in the Division of Maternal and Fetal Medicine of Thomas Jefferson University Hospital (Philadelphia, USA) over a 16-year period, from 1998 to 2013. We included women with singleton gestations who had a history-indicated (HIC) or ultrasound indicated cerclage (UIC). Physical examination-indicated cerclage and transabdominal cerclage were excluded. We planned to compare data before and after 2005. RESULTS: From 1998 to 2013, there were 33 353 deliveries, of which 16 871 occurred from 1998 to 2005 and 16 482 from 2006 to 2013. Of all deliveries, 328 women (1.0%) received HIC or UIC, and were therefore included in the analysis. Between 1998-2005 and 2006-2013 there were significant decreases in the overall rate of cerclage (1.4% to 0.6%; p < 0.001), as well as the rate of HIC (0.8% to 0.2%; p < 0.001) and UIC (0.6% to 0.3%; p < 0.001). CONCLUSIONS: During the last 16 years, the overall rate of HIC and UIC cerclage at Thomas Jefferson University Hospital significantly declined from 1.4% to 0.6%; significant decreases were seen for both HIC and UIC. The reason for the lower rate of cerclages may be the recently published evidence. PMID- 26249134 TI - Pancreatic fat and hepato-metabolic features in obese children with nonalcoholic fatty liver disease. PMID- 26249135 TI - The Benefits of Benevolence: Basic Psychological Needs, Beneficence, and the Enhancement of Well-Being. AB - Pro-social behaviors have been associated with enhanced well-being, but what psychological mechanisms explain this connection? Some theories suggest that beneficence-the sense of being able to give-inherently improves well-being, whereas evidence from self-determination theory (Weinstein & Ryan, 2010) shows that increases in well-being are mediated by satisfaction of innate psychological needs for autonomy, competence, and relatedness. Here we simultaneously assess these two explanations. Study 1 (N = 335) used a cross-sectional survey with an Internet sample to develop a measure to assess beneficence satisfaction. The next two cross-sectional Internet-sample studies tested mediators between pro-social behavior and general well-being (Study 2, N = 332) and situational peak moment well-being (Study 3, N = 180). A fourth study (N = 85) used a diary method with university students to assess daily fluctuations in well-being associated with needs and beneficence. It was shown across all studies that both the three psychological needs and beneficence satisfaction mediate the relations between pro-social actions and well-being, with all four factors emerging as independent predictors. Together, these studies underscore the role of autonomy, competence, and relatedness in explaining the well-being benefits of benevolence, and they also point to the independent role of beneficence as a source of human wellness. PMID- 26249136 TI - Differential expression of virulence genes and role of gyrA mutations in quinolone resistant and susceptible strains of Salmonella Weltevreden and Newport isolated from seafood. AB - AIMS: To investigate the differential expression of virulence genes and role of gyrA mutations in quinolone resistant and susceptible strains of Salmonella isolated from seafood. METHODS AND RESULTS: Forty Salmonella isolates from seafood were tested for antibiotic sensitivity. Minimal inhibitory concentration (MIC) was determined and two nalidixic acid-resistant isolates, viz Salmonella Weltevreden (SW9) and Salmonella Newport (SN36) were selected for identifying the mechanism of resistance. SW9 showed mutation in the gyrA gene at codon 83 (Ser to Tyr) while SN36 presented at codon 87 (Asp to Asn). Experimental induction of resistance to a sensitive Salm. Newport (SN71) showed point mutation at codon 87 (Asp to Gly) in the gyrA gene, and was designated SN71R. All the isolates resistant to nalidixic acid had a single mutation at different positions in the gyrA gene. However, induction of resistance to a sensitive Salm. Weltevreden (SW30) was exceptional in that it did not show any mutation in the gyrA region. Use of Phe-Arg-beta-naphthylamide (PAbetaN) also could not reduce MIC below the Clinical and Laboratory Standards Institute guidelines revealing the absence of efflux mediated resistance. Thus, the resistance mechanism in SW30R is unknown. The growth rate of quinolone resistant isolates was slower than the susceptible ones. The resistant isolates showed decreased epithelial cell invasion and intracellular replication. The mRNA expression levels of some of the genes were significantly (P < 0.005) reduced in SN71R compared to the sensitive strain (SN71). CONCLUSIONS: Nalidixic acid-resistant Salmonella strains are associated with lower virulence and pathogenicity than the sensitive strains. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provided valuable information on the difference in the growth, cytotoxicity, infectivity and expression of virulence genes in resistant and susceptible strains. Furthermore, the gyrA mutation was shown to be the main mechanism of quinolone resistance in Salmonella other than the overexpression of efflux pumps or the presence of plasmid mediated quinolone resistance genes. PMID- 26249137 TI - Ectoparasite Burdens of the Damaraland Mole-Rat (Fukomys damarensis) from Southern Africa. AB - Damaraland mole-rats (Fukomys damarensis) of the family Bathyergidae are widely distributed subterranean rodents in sub-Saharan Africa. No parasites have ever been reported for this species and only 1 ectoparasite is described for the entire genus. In the current study ectoparasites were collected from individuals captured at 3 localities in South Africa and Namibia to document the ectoparasite community of F. damarensis, investigate their aggregation patterns, and evaluate the influence of season on ectoparasite burden. A total of 2,071 arthropods from 9 mite taxa and 1 louse species (Eulinognathus hilli) were collected from 293 hosts sampled. Of these, 5 mite species (Androlaelaps scapularis, Androlaelaps capensis, Androlaelaps tauffliebi, Radfordia sp., and unidentified chiggers) and the louse were parasites while the remainder was soil mites. All ectoparasites were highly aggregated and the species richness as well as the prevalence and abundance of 4 of them were significantly greater in summer compared to winter, possibly as a result of seasonal changes in rainfall patterns affecting the ectoparasites, host behavior, or both. PMID- 26249138 TI - Brain PET imaging optimization with time of flight and point spread function modelling. AB - PURPOSE: To assess the influence of reconstruction algorithms and parameters on the PET image quality of brain phantoms in order to optimize reconstruction for clinical PET brain studies in a new generation PET/CT. METHODS: The 3D Hoffman phantom that simulates (18)F-fluorodeoxyglucose (FDG) distribution was imaged in a Siemens Biograph mCT TrueV PET/CT with Time of Flight (TOF) and Point Spread Function (PSF) modelling. Contrast-to-Noise Ratio (CNR), contrast and noise were studied for different reconstruction models: OSEM, OSEM + TOF, OSEM + PSF and OSEM + PSF + TOF. The 2D multi-compartment Hoffman phantom was filled to simulate 4 different tracers' spatial distribution: FDG, (11)C-flumazenil (FMZ), (11)C Methionine (MET) and 6-(18)F-fluoro-l-dopa (FDOPA). The best algorithm for each tracer was selected by visual inspection. The maximization of CNR determined the optimal parameters for each reconstruction. RESULTS: In the 3D Hoffman phantom, both noise and contrast increased with increasing number of iterations and decreased with increasing FWHM. OSEM + PSF + TOF reconstruction was generally superior to other reconstruction models. Visual analysis of the 2D Hoffman brain phantom suggested that OSEM + PSF + TOF is the optimum algorithm for tracers with focal uptake, such as MET or FDOPA, and OSEM + TOF for tracers with diffuse cortical uptake (i.e. FDG and FMZ). Optimization of CNR demonstrated that OSEM + TOF reconstruction must be performed with 2 iterations and a filter FWHM of 3 mm, and OSEM + PSF + TOF reconstruction with 4 iterations and 1 mm FWHM filter. CONCLUSIONS: Optimization of reconstruction algorithm and parameters has been performed to take particular advantage of the last generation PET scanner, recommending specific settings for different brain PET radiotracers. PMID- 26249139 TI - Laparoscopic management of pancreatic pseudocysts: experience at a general hospital in Mexico City. AB - BACKGROUND: Invasive management of pancreatic pseudocysts (PP) is currently indicated in those patients with symptoms or complications. Treatment options are classified as surgical (open and laparoscopic) and non-surgical (endoscopic and radiologic). AIM: To describe the morbidity, mortality, and efficacy in terms of technical and clinical success of the laparoscopic surgical approach in the treatment of patients with PP in the last 3 years at our hospital center. METHODS: We included patients with PP treated with laparoscopic surgery within the time frame of January 2012 and December 2014. The morbidity and mortality associated with the procedure were determined, together with the postoperative results in terms of effectiveness and recurrence. RESULTS: A total of 38 patients were diagnosed with PP within the last 3 years, but only 20 of them had invasive treatment. Laparoscopic surgery was performed on 17 of those patients (mean pseudocyst diameter of 15.3, primary drainage success rate of 94.1%, complication rate of 5.9%, and a 40-month follow-up). CONCLUSIONS: The results obtained with the laparoscopic technique used at our hospital center showed that this approach is feasible, efficacious, and safe. Thus, performed by skilled surgeons, it should be considered a treatment option for patients with PP. PMID- 26249140 TI - Iatrogenic Cushing's syndrome related to the interaction between oral budesonide with fluvoxamine: a case report. AB - WHAT IS KNOWN AND OBJECTIVE: Budesonide, an oral glucocorticoid indicated for the treatment of Crohn's disease, rarely interferes with the hypothalamic-pituitary adrenal axis because more than 80% of it is metabolized by cytochrome P450 enzymes. CASE SUMMARY: A 33-year-old female patient diagnosed with Crohn's disease, treated with oral budesonide, was admitted for Cushingoid symptoms and signs. The onset coincided with the use of fluvoxamine, a serotonin reuptake inhibitor and also a potent inhibitor of cytochrome P450 enzymes that presumably led to budesonide accumulation. WHAT IS NEW AND CONCLUSION: Practitioners should take into consideration the possibility of iatrogenic Cushing's syndrome caused by the association of oral budesonide with a P450 cytochrome inhibitor. PMID- 26249141 TI - Neutral and Cationic Molybdenum Imido Alkylidene N-Heterocyclic Carbene Complexes: Reactivity in Selected Olefin Metathesis Reactions and Immobilization on Silica. AB - The synthesis and single-crystal X-ray structures of the novel molybdenum imido alkylidene N-heterocyclic carbene complexes [Mo(N-2,6 Me2C6H3)(IMesH2)(CHCMe2Ph)(OTf)2] (3), [Mo(N-2,6-Me2C6H3)(IMes)(CHCMe2Ph)(OTf)2] (4), [Mo(N-2,6-Me2C6H3)(IMesH2)(CHCMe2Ph)(OTf){OCH(CF3)2}] (5), [Mo(N-2,6 Me2C6H3)(CH3CN)(IMesH2)(CHCMe2Ph)(OTf)](+)BArF(-) (6), [Mo(N-2,6 Cl2C6H3)(IMesH2)(CHCMe3)(OTf)2] (7) and [Mo(N-2,6-Cl2C6H3)(IMes)(CHCMe3)(OTf)2] (8) are reported (IMesH2=1,3-dimesitylimidazolidin-2-ylidene, IMes=1,3 dimesitylimidazolin-2-ylidene, BArF(-)=tetrakis-[3,5-bis(trifluoromethyl)phenyl] borate, OTf=CF3SO3(-)). Also, silica-immobilized versions I1 and I2 were prepared. Catalysts 3-8, I1 and I2 were used in homo-, cross-, and ring-closing metathesis (RCM) reactions and in the cyclopolymerization of alpha,omega-diynes. In the RCM of alpha,omega-dienes, in the homometathesis of 1-alkenes, and in the ethenolysis of cyclooctene, turnover numbers (TONs) up to 100,000, 210,000 and 30,000, respectively, were achieved. With I1 and I2, virtually Mo-free products were obtained (<3 ppm Mo). With 1,6-hepta- and 1,7-octadiynes, catalysts 3, 4, and 5 allowed for the regioselective cyclopolymerization of 4,4 bis(ethoxycarbonyl)-1,6-heptadiyne, 4,4-bis(hydroxymethyl)-1,6-heptadiyne, 4,4 bis[(3,5-diethoxybenzoyloxy)methyl]-1,6-heptadiyne, 4,4,5,5 tetrakis(ethoxycarbonyl)-1,7-octadiyne, and 1,6-heptadiyne-4-carboxylic acid, underlining the high functional-group tolerance of these novel Group 6 metal alkylidenes. PMID- 26249142 TI - The influences of ambient temperature and crude protein levels on performance and serum biochemical parameters in broilers. AB - This study was undertaken to investigate the effects of ambient temperature, crude protein levels and their interaction on performance and serum biochemical parameters of broiler chickens. A total of 216 Arbor Acre broiler chickens (108 males and 108 females) were used in a 2 * 3 factorial arrangement and randomly reared at two temperatures (normal temperature: 23 degrees C; daily cyclic high temperature: 28-32 degrees C) and fed on three diets with different crude protein levels (153.3, 183.3 or 213.3 g/kg, with constant essential amino acids) from 28 to 42 days of age. Daily cyclic high ambient temperature decreased final body weight, average daily weight gain, average daily feed intake and serum total protein contents (p < 0.001, p < 0.001, p < 0.001, p = 0.008 respectively), but increased feed/gain, mortality, respiratory rate, rectal temperature, serum uric acid contents and serum creatine kinase activity (p = 0.008, p = 0.003, p < 0.0001, p < 0.0001, p < 0.0001, p = 0.003 respectively), irrespective of crude protein levels. At the ambient temperature, reducing crude protein levels resulted in an increase in feed/gain (p < 0.001), but a decrease in serum total protein and uric acid contents. Only serum creatine kinase activity in broiler chickens was interacted by daily cyclic high ambient temperature and dietary crude protein levels (p = 0.003). These results indicated that daily cyclic high ambient temperature had a great effect on performance and serum biochemical parameters in broiler chickens, whereas dietary crude protein levels affected them partially. PMID- 26249143 TI - Periostin down-regulation attenuates the pro-fibrogenic response of hepatic stellate cells induced by TGF-beta1. AB - Liver fibrosis is characterized by an exacerbated accumulation of deposition of the extracellular matrix (ECM), and the activation of hepatic stellate cells (HSC) plays a pivotal role in the development of liver fibrosis. Periostin has been shown to regulate cell adhesion, proliferation, migration and apoptosis; however, the involvement of periostin and its role in transforming growth factor (TGF)-beta1-induced HSC activation remains unclear. We used RT-PCR and Western blot to evaluate the expression level of periostin in hepatic fibrosis tissues and HSCs, respectively. Cell proliferation was determined using the Cell Proliferation ELISA BrdU kit, cell cycle was analysed by flow cytometry. The expression of alpha-smooth muscle actin (alpha-SMA), collagen I, TGF-beta1, p Smad2 and p-Smad3 were determined by western blot. Our study found that periostin was up-regulated in liver fibrotic tissues and activated HSCs. In addition, siRNA periostin suppressed TGF-beta1-induced HSC proliferation. The HSC transfected with siRNA-periostin significantly inhibited TGF-beta1-induced expression levels of alpha-SMA and collagen I. Furthermore, TGF-beta1 stimulated the expression of periostin, and siRNA-periostin attenuated TGF-beta1-induced Smad2/3 activation in HSCs. These results suggest that periostin may function as a novel regulator to modulate HSC activation, potentially by promoting the TGF-beta1/Smad signalling pathway, and propose a strategy to target periostin for the treatment of liver fibrosis. PMID- 26249144 TI - Evaluation of Pathologic Nipple Discharge: What is the Added Diagnostic Value of MRI? AB - PURPOSE: To determine the diagnostic value of magnetic resonance imaging (MRI) for the evaluation of patients with pathologic nipple discharge. METHODS: We performed a retrospective review of women with nipple discharge who underwent breast MRI between January 1, 2004, and December 31, 2013. Radiographic findings, pathology results, and clinical notes were reviewed. Sensitivity, specificity, positive predictive value, and negative predictive value of MRI were calculated. RESULTS: Over a 10-year period, 103 women (mean age 46 years, range 25-72 years) underwent MRI for evaluation of nipple discharge. Ninety-one patients (88 %) underwent surgical excision or had clinical and/or radiographic follow-up at least 2 years after presentation and thus comprise the study population. Eleven (30 %) of 37 patients with MRIs coded as American College of Radiology Breast Imaging-Reporting and Data System (BI-RADS) 4 of 5 were diagnosed with ductal carcinoma in situ (n = 6) or invasive adenocarcinoma (n = 5). Seven (64 %) of 11 patients diagnosed with malignancy had a negative mammographic and sonographic workup. None of the patients with MRIs coded as BI-RADS 1, 2, or 3 was diagnosed with malignancy immediately after presentation or during the 2-year follow-up period. The sensitivity and specificity of MRI for the detection of malignancy were 100 % (11 of 11) and 68 % (54 of 80), respectively. The positive predictive value and negative predictive value were 37 and 100 %, respectively. CONCLUSIONS: MRI is a valuable additional diagnostic tool for the evaluation of pathologic nipple discharge when conventional imaging is negative. A negative MRI in this symptomatic population may obviate the need for duct exploration and excision. PMID- 26249145 TI - [Low atrial rhythm]. PMID- 26249146 TI - [Smoking prevalence and mortality in Spain]. PMID- 26249147 TI - [Non-healing shoulder ulcer and cachexia]. PMID- 26249149 TI - Model organism databases. PMID- 26249148 TI - Progesterone promotes maternal-fetal tolerance by reducing human maternal T-cell polyfunctionality and inducing a specific cytokine profile. AB - Progesterone is a steroid hormone essential for the maintenance of human pregnancy, and its actions are thought to include promoting maternal immune tolerance of the semiallogenic fetus. We report that exposure of maternal T cells to progesterone at physiological doses induced a unique skewing of the cytokine production profile of CD4(+) and CD8(+) T cells, with reductions not only in potentially deleterious IFN-gamma and TNF-alpha production but also in IL-10 and IL-5. Conversely, production of IL-4 was increased. Maternal T cells also became less polyfunctional, focussing cytokine production toward profiles including IL 4. This was accompanied by reduced T-cell proliferation. Using fetal and viral antigen-specific CD8(+) T-cell clones, we confirmed that this as a direct, nonantigen-specific effect. Yet human T cells lacked conventional nuclear progesterone receptors, implicating a membrane progesterone receptor. CD4(+) and CD8(+) T cells responded to progesterone in a dose-dependent manner, with subtle effects at concentrations comparable to those in maternal blood, but profound effects at concentrations similar to those at the maternal-fetal interface. This characterization of how progesterone modulates T-cell function is important in understanding the normal biology of pregnancy and informing the rational use of progesterone therapy in pregnancies at risk of fetal loss. PMID- 26249150 TI - Clarivein(r) mechano-chemical ablation an interim analysis of a randomized controlled trial dose-finding study. AB - OBJECTIVES: The ClariVein(r) system is an endovenous technique that uses mechano chemical ablation to treat incompetent truncal veins. This study was conducted to identify the ideal Polidocanol dosage and form for mechano-chemical ablation in order to occlude the great saphenous vein. When adhering to safe dosage levels, sclerosants with higher concentrations potentially limit the extent of treatment. It has been demonstrated that this problem may be overcome by using Polidocanol as a microfoam. This paper was established on findings of a preliminary analysis. MATERIAL AND METHODS: The initial study was a single-blinded multicenter randomized controlled trial where patients are allocated to three treatment arms. Group 1 consisted of mechano-chemical ablation +2% Polidocanol liquid, group 2: mechano-chemical ablation +3% Polidocanol liquid and group 3: mechano-chemical ablation +1% Polidocanol foam RESULTS: Eighty-seven, 34 males and 53 females (60.9%), mean age 55 years s.d. 16.0 (range 24-84), were enrolled in the study. Treatment length was 30 cm (range 10-30) for 95.2% of the patients. Mean operating time was 16 minutes (range 5-70). The mean saphenofemoral junction diameter (7.7 mm) was similar in all three groups. At 6 weeks post-treatment duplex ultrasound showed that 25 out of 25 = 100%, 27 out of 28 = 96.4% and 13 out of 23 = 56.5% were occluded in the mechano-chemical ablation + 2% Polidocanol liquid, mechano-chemical ablation + 3% Polidocanol liquid and mechano-chemical ablation + 1% Polidocanol microfoam respectively (p < 0.001). However, stricter scrutiny showed that the anatomical success rate defined as occlusion of at least 85% of the treated length to be 88.0%, 85.7% and 30.4% respectively (p < 0.001). CONCLUSION: Mechano-chemical ablation using ClariVein(r) combined with 1% Polidocanol microfoam is significantly less effective and should not be considered as a treatment option of incompetent truncal veins. Further investigation to determine the ideal Polidocanol liquid dosage with mechano chemical ablation is advocated and is being conducted accordingly. PMID- 26249151 TI - Evaluation of nonpermanent inferior vena cava filter placement in patients with deep venous thrombosis after lower extremity fracture: A single-center retrospective study. AB - OBJECTIVE: To investigate nonpermanent inferior vena cava (IVC) filter in the prevention of perioperative pulmonary embolism (PE) in patients of lower extremity and/or pelvic bone fracture with deep vein thrombosis (DVT). METHODS: Lower extremity or pelvic bone fracture patients with lower extremity DVT hospitalized in our hospital from January 2003 to October 2014 were retrospectively analyzed. Data was analyzed for age, gender, position of fracture, position of proximal of thrombosis, indications of placement, complications, retrieval rate, and rate of entrapped filter clot. Patients who underwent IVC filter placement were selected as the filter group. The patients who did not perform IVC filter placement after 2008 and the cases between January 2003 and December 2007 were selected as control group 1 and control group 2, respectively. The incidence of perioperative symptomatic PE and mortality were analyzed. RESULTS: A total of 2763 cases complicated with DVT underwent orthopedic surgery between January 2003 and October 2014. 823 nonpermanent filters were inserted. All filters were successfully deployed with no major complications. After a mean 14.2 days indwelling time, all of temporary filters were removed. Retrieval was attempted in 556 patients with retrievable filters and was successful in 545 (98%); mean indwelling time was 16.3 days. The total retrieval rate was 90%. The incidence of PE in the filter group was significantly lower compared with the two control groups. Among the patients who received chemical anticoagulant therapy, the incidence of PE in filter group, control group 1 and control group 2 were 0.14%, 1.60% and 2.10%, respectively. The incidence of PE in filter group was also significant lower compared with control groups. CONCLUSION: Nonpermanent IVC filter placement seems like to be a safe and effective method for preventing perioperative symptomatic and fatal PE in bone fracture patients with DVT in the present retrospective study. PMID- 26249152 TI - Successful treatment of subcutaneous granuloma annulare with bath-psoralen plus ultraviolet A therapy. PMID- 26249153 TI - A Comparison of Dental Chartings Performed at the Joint POW/MIA Accounting Command Central Identification Laboratory and the Kokura Central Identification Unit on Remains Identified from the Korean War. AB - During the Korean War, the Office of the Quartermaster General's Graves Registration Service (GRS) was responsible for the recovery, processing, identification, and repatriation of US remains. In January 1951, the GRS established a Central Identification Unit (CIU) at Kokura, Japan. At the Kokura CIU, postmortem dental examinations were performed by the dental technicians. Thirty-nine postmortem dental examinations performed at the CIU were compared to the findings documented in the Forensic Odontology Reports written at the JPAC Central Identification Laboratory (CIL). Differences were noted in 20 comparisons (51%). The majority of the discrepancies was considered negligible and would not alter the JPAC decision to disinter a set of unknown remains. Charting discrepancies that were considered significant included the occasional failure of the Kokura technicians to identify teeth with inter-proximal or esthetic restorations and the misidentification of a mechanically prepared tooth (i.e., tooth prepared for a restoration) as a carious surface. PMID- 26249154 TI - [Endometriosis of the appendix]. PMID- 26249155 TI - [Inflammatory pseudotumor of the liver: A propos of a case]. PMID- 26249156 TI - Association between environmental exposure to cadmium and human semen quality. AB - Cadmium (Cd) is a heavy metal with toxicant to reproductive functions. The aim of this study was to explore the effects of environmental exposure to Cd on human semen quality. A total of 587 men from the general population, aged from 20 to 59 years old, and without occupational exposure to Cd were recruited from three provinces in China to participate in the study. The median of serum Cd was 1.9 MUg/L (P25-P75:1.1-2.9). In case Cd was less than or equal to 6.3 MUg/L (P95) and the semen parameters were logarithmically transformed, the inverse associations between Cd and semen volume (-0.03 +/- 0.007), progressive motility (-0.01 +/- 0.004), and sperm morphology (-0.04 +/- 0.004) were found across the whole group, after adjusting for age group, occupation, season of semen sample collection, abstinence intervals, smoking, alcohol drinking, and body mass index. Our findings indicate that higher Cd may reduce the semen volume, progressive motility, and morphology among men without occupational exposure to Cd. PMID- 26249157 TI - Validation of a food frequency questionnaire to determine vitamin D intakes using the method of triads. AB - BACKGROUND: Dietary sources of vitamin D (both natural and fortified) are increasingly contributing to consumers' vitamin D intake and status. Therefore, the present study aimed to validate a vitamin D food frequency questionnaire (FFQ) for the assessment of habitual vitamin D intake. METHODS: A total of 49 apparently healthy consenting adults (aged 18-64 years) from the local community were sampled at the end of winter. Dietary intakes were recorded using a 4-day weighed food record (4d-WFR) and a 17-item FFQ based on foods known to contribute to dietary vitamin D intake. Fasting vitamin D status was quantified by serum 25 hydroxyvitamin D [25(OH)D] using liquid chromatography tandem mass spectrometry. The method of triads was applied using these three measurements to determine the overall validity of the FFQ. RESULTS: Vitamin D intakes from 4d-WFR ranged between 0.42 and 31.65 MUg day(-1), whereas intakes determined from the FFQ ranged from 1.03 to 36.08 MUg day(-1). Serum 25(OH)D concentrations ranged between 12.89 and 279.00 nmol L(-1). The mean (SD) difference between the FFQ and 4d-WFR was +1.62 ( 3.86). There were strong correlations between the vitamin D intake estimated by the FFQ and that from the 4d-WFR (r = 0.562) and also with serum 25(OH)D concentrations (r = 0.567). Vitamin D intake estimated from the 4d WFR was also strongly correlated with serum 25(OH)D concentrations (r = 0.411). The overall validity coefficient calculated using the method of triads was high (0.881). CONCLUSIONS: The vitamin D FFQ has been validated for use in future studies aiming to assess habitual vitamin D intake. PMID- 26249158 TI - Chemometrics for comprehensive analysis of nucleobases, nucleosides, and nucleotides in Siraitiae Fructus by hydrophilic interaction ultra high performance liquid chromatography coupled with triple-quadrupole linear ion-trap tandem mass spectrometry. AB - A rapid and sensitive hydrophilic interaction ultra high performance liquid chromatography coupled with triple-quadrupole linear ion-trap tandem mass spectrometry method was validated for the simultaneous determination of 20 nucleobases, nucleosides, and nucleotides (within 3.5 min), and then was employed to test the functional food of Luo-Han-Guo samples. The analysis showed that the Luo-Han-Guo was rich in guanosine and uridine, but contained trace levels of the other target compounds. Chemometrics methods were employed to identify 40 batches of Luo-Han-Guo samples from different cultivated forms, regions and varieties. Unsupervised hierarchical cluster analysis and principal component analysis were used to classify Luo-Han-Guo samples based on the level of the 20 target compounds, and the supervised learning method of counter propagation artificial neural network was utilized to further separate clusters and validate the established model. As a result, the samples could be clustered into three primary groups, in which correlation with cultivated varieties was observed. The present strategy could be applied to the investigation of other edible plants containing nucleobases, nucleosides, or nucleotides. PMID- 26249163 TI - Migrated venous stent causing severe heart failure: a multimodality imaging approach. PMID- 26249164 TI - Replacement therapy in inherited factor VII deficiency: occurrence of adverse events and relation with surgery. PMID- 26249165 TI - Transplant biopsy beyond light microscopy. AB - Despite its long-standing status as the diagnostic "gold standard", the renal transplant biopsy is limited by a fundamental dependence on descriptive, empirically-derived consensus classification. The recent shift towards personalized medicine has resulted in an increased demand for precise, mechanism based diagnoses, which is not fully met by the contemporary transplantation pathology standard of care. The expectation is that molecular techniques will provide novel pathogenetic insights that will allow for the identification of more accurate diagnostic, prognostic, and therapeutic targets. Here we review the current state of molecular renal transplantation pathology. Despite significant research activity and progress within the field, routine adoption of clinical molecular testing has not yet been achieved. The recent development of novel molecular platforms suitable for use with formalin-fixed paraffin-embedded tissue will offer potential solution for the major barriers to implementation. The recent incorporation of molecular diagnostic criteria into the 2013 Banff classification is a reflection of progress made and future directions in the area of molecular transplantation pathology. Transcripts related to endothelial injury and NK cell activation have consistently been shown to be associated with antibody-mediated rejection. Prospective multicenter validation and implementation of molecular diagnostics for major entities remains an unmet clinical need in transplantation. It is expected that an integrated system of transplantation pathology diagnosis comprising molecular, morphological, serological, and clinical variables will ultimately provide the greatest diagnostic precision. PMID- 26249166 TI - CD73 and AMPD3 deficiency enhance metabolic performance via erythrocyte ATP that decreases hemoglobin oxygen affinity. AB - Erythrocytes are the key target in 5'-AMP induced hypometabolism. To understand how regulation of endogenous erythrocyte AMP levels modulates systemic metabolism, we generated mice deficient in both CD73 and AMPD3, the key catabolic enzymes for extracellular and intra-erythrocyte AMP, respectively. Under physiological conditions, these mice displayed enhanced capacity for physical activity accompanied by significantly higher food and oxygen consumption, compared to wild type mice. Erythrocytes from Ampd3(-/-) mice exhibited higher half-saturation pressure of oxygen (p50) and about 3-fold higher levels of ATP and ADP, while they maintained normal 2,3-bisphosphoglycerate (2,3-BPG), methemoglobin levels and intracellular pH. The affinity of mammalian hemoglobin for oxygen is thought to be regulated primarily by 2,3-BPG levels and pH (the Bohr effect). However, our results show that increased endogenous levels of ATP and ADP, but not AMP, directly increase the p50 value of hemoglobin. Additionally, the rise in erythrocyte p50 directly correlates with an enhanced capability of systemic metabolism. PMID- 26249168 TI - PDE constrained optimization of electrical defibrillation in a 3D ventricular slice geometry. AB - A computational study of an optimal control approach for cardiac defibrillation in a 3D geometry is presented. The cardiac bioelectric activity at the tissue and bath volumes is modeled by the bidomain model equations. The model includes intramural fiber rotation, axially symmetric around the fiber direction, and anisotropic conductivity coefficients, which are extracted from a histological image. The dynamics of the ionic currents are based on the regularized Mitchell Schaeffer model. The controls enter in the form of electrodes, which are placed at the boundary of the bath volume with the goal of dampening undesired arrhythmias. The numerical optimization is based on Newton techniques. We demonstrated the parallel architecture environment for the computation of potentials on multidomains and for the higher order optimization techniques. PMID- 26249167 TI - Sensitivity of various adiposity indices in identifying cardiometabolic diseases in Arab adults. AB - BACKGROUND: Obesity is a recognized risk factor for various cardiometabolic diseases and several indices are used clinically to assess overall cardiometabolic risk. This study aims to determine the sensitivity of six anthropometric indices [Body mass index (BMI), waist, waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), body adiposity index (BAI) and visceral adiposity index (VAI)] in determining diabetes mellitus type 2, coronary heart disease, dyslipidemia, hypertension and metabolic syndrome (MetS) in Saudi adults recruited from two independent cohorts (2008-2009 and 2013-2014). METHODS: A total of 6,821 Saudi adults [2008-2009, N = 3,971 (1,698 males and 2,273 females); 2013-2014, N = 2,850 (926 males and 1,924 females)] aged 18-70 years old were included in this descriptive, cross-sectional study. Anthropometrics were obtained and fasting blood samples analyzed for glucose and lipids. BMI, WHR, WHtR, BAI and VAI were computed mathematically. RESULTS: VAI was the most sensitive index in determining DMT2 (AUC 0.72; p < 0.001) in the 2008-2009 cohort and MetS (AUC = 0.84; p < 0.001) in the 2013-2014 cohort. WHR was most discriminating for CHD in both cohorts (AUC 0.70 and 0.84 for 2008-2009 and 2013 2014, p values <0.001, respectively). WHtR was most sensitive but rather modest in determining hypertension (AUC 0.66; p < 0.001), while waist circumference was most sensitive for dyslipidemia (AUC 0.72; p < 0.001) in the 2008-2009 cohort and MetS (AUC 0.85; p < 0.001) in the 2013-2014 cohort. BAI was the least sensitive adiposity index. CONCLUSION: Sensitivity of adiposity indices regarding cardiometabolic diseases highlight the importance of body fat distribution in determining overall cardiometabolic risk, with indices involving abdominal obesity being more clinically significant than BMI and BAI. The sensitivity of these adiposity indices should be noted in assessing a particular cardiometabolic disease. PMID- 26249169 TI - Emergency nurses' perceptions of sedation management practices for critically ill intubated patients: a qualitative study. AB - AIMS AND OBJECTIVES: The aim of this study was to explore factors influencing practices in assessing, titrating and managing sedation for the critically ill intubated patients, from the perspective of emergency nurses. BACKGROUND: The number of critically ill patients presenting to Australian public Emergency Departments has increased by over 30% since 1980. Emergency nurses are increasingly relied upon to manage sedation of critically ill intubated patients. There is little evidence within international literature relating to how emergency nurses accomplish this. DESIGN: Descriptive qualitative study. METHOD: A purposive sample of 15 experienced emergency nurses participated in semi structured face-to-face interviews. Transcribed data were analysed using thematic analysis. RESULTS: The qualitative analysis yielded five themes: becoming the resuscitation nurse; becoming confident as the resuscitation nurse; communicating about sedation; visual cues and the vanishing act. The safety and quality of sedation experienced by critically ill intubated patients in ED was the responsibility of emergency nurses, yet uncertainties and barriers were evident. CONCLUSION: Patient continuity of care, including optimisation of comfort relies upon the knowledge, skills and expertise of the emergency nurse allocated to the resuscitation area. For most nurses transitioning into the resuscitation nurse role, it represents the first time they will have had contact with patients with highly complex needs and sedation. The use of self-directed clinical workbooks and supervised clinical practice alone may be insufficient to adequately prepare nurses for the spectrum of critically ill sedated patients managed in the resuscitation area; a situation made worse in the presence of poor team communication. RELEVANCE TO CLINICAL PRACTICE: The findings of this study should assist in the development of policy and formal education of emergency nurses transitioning into the resuscitation area and the management of continuous intravenous sedation to critically ill mechanically ventilated patients is required. PMID- 26249170 TI - Cancer-related symptoms predict psychological wellbeing among prostate cancer survivors: results from the PiCTure study. AB - BACKGROUND: Prostate cancer treatments are associated with a range of symptoms and physical side-effects. Cancer can also adversely impact on psychological wellbeing. Because many prostate cancer-related symptoms and side-effects are potentially modifiable, we investigated associations between symptoms and psychological wellbeing among prostate cancer survivors. METHODS: Postal questionnaires were distributed to men diagnosed with prostate cancer 2-18 years previously identified through cancer registries. General and prostate cancer specific symptoms were assessed using the EORTC QLQ-C30 and QLQ-PR25, with higher symptom scores indicating more/worse symptomatology. Psychological wellbeing was assessed by the DASS-21. Associations between symptoms and each outcome were investigated using multivariate logistic regression, controlling for socio demographic and clinical factors. RESULTS: A total 3348 men participated (response rate = 54%). Seventeen percent (95%CI 15.2%-17.9%), 16% (95%CI 15.1% 17.8%) and 11% (95%CI 9.5%-11.8%) of survivors scored in the range for depression, anxiety and distress on the DASS scales, respectively. In multivariate models, risk of depression on the DASS scale was significantly higher in men with higher urinary and androgen deprivation therapy (ADT)-related symptoms, and higher scores for fatigue, insomnia and financial difficulties. Risk of anxiety on the DASS scale was higher in men with higher scores for urinary, bowel and ADT-related symptoms and fatigue, dyspnoea and financial difficulties. Risk of distress on the DASS scale was positively associated with urinary, bowel and ADT-related symptoms, fatigue, insomnia and financial difficulties. CONCLUSIONS: Cancer-related symptoms significantly predict psychological wellbeing among prostate cancer survivors. Greater use of interventions and medications and to alleviate symptoms might improve psychological wellbeing of prostate cancer survivors. PMID- 26249171 TI - Properties of atoms in electronically excited molecules within the formalism of TDDFT. AB - The topological analysis of the electron density for electronic excited states under the formalism of the quantum theory of atoms in molecules using time dependent density functional theory (TDDFT) is presented. Relaxed electron densities for electronic excited states are computed by solving a Z-vector equation which is obtained by means of the Sternheimer interchange method. This is in contrast to previous work in which the electron density for excited states is obtained using DFT instead of TDDFT, that is, through the imposition of molecular occupancies in accordance with the electron configuration of the excited state under consideration. Once the electron density of the excited state is computed, its topological characterization and the properties of the atoms in molecules are obtained in the same manner that for the ground state. The analysis of the low-lying pi->pi* singlet and triplet vertical excitations of CO and C6H6 are used as representative examples of the application of this methodology. Altogether, it is shown how this procedure provides insights on the changes of the electron density following photoexcitation and it is our hope that it will be useful in the study of different photophysical and photochemical processes. PMID- 26249172 TI - E-commerce trade in invasive plants. AB - Biological invasions are a major concern in conservation, especially because global transport of species is still increasing rapidly. Conservationists hope to anticipate and thus prevent future invasions by identifying and regulating potentially invasive species through species risk assessments and international trade regulations. Among many introduction pathways of non-native species, horticulture is a particularly important driver of plant invasions. In recent decades, the horticultural industry expanded globally and changed structurally through the emergence of new distribution channels, including internet trade (e commerce). Using an automated search algorithm, we surveyed, on a daily basis, e commerce trade on 10 major online auction sites (including eBay) of approximately three-fifths of the world's spermatophyte flora. Many recognized invasive plant species (>500 species) (i.e., species associated with ecological or socio economic problems) were traded daily worldwide on the internet. A markedly higher proportion of invasive than non-invasive species were available online. Typically, for a particular plant family, 30-80% of recognized invasive species were detected on an auction site, but only a few percentages of all species in the plant family were detected on a site. Families that were more traded had a higher proportion of invasive species than families that were less traded. For woody species, there was a significant positive relationship between the number of regions where a species was sold and the number of regions where it was invasive. Our results indicate that biosecurity is not effectively regulating online plant trade. In the future, automated monitoring of e-commerce may help prevent the spread of invasive species, provide information on emerging trade connectivity across national borders, and be used in horizon scanning exercises for early detection of new species and their geographic source areas in international trade. PMID- 26249173 TI - CCL5-Mediated Th2 Immune Polarization Promotes Metastasis in Luminal Breast Cancer. AB - The tumor-promoting chemokine CCL5 has been implicated in malignant transformation of breast epithelial cells, with studies to date focusing mainly on basal-type breast cancers. In this study, we investigated the consequences of CCL5 deletion in the MMTV-PyMT transgenic mouse model of luminal breast cancer. In this model, primary tumor burden and pulmonary metastases were reduced significantly in CCL5-deficient subjects, an effect found to be associated with a deficit of Th2 (IL4+CD4+ T) cells. Mechanistic investigations revealed that CCL5 activates CCR3, a highly expressed chemokine receptor on CD4+ T cells, and also boosts Gfi1 expression to promote the differentiation of Th2 cells, which enhance the prometastatic activity of tumor-associated myeloid cells. Clinically, polarization toward this immunosuppressive Th2 phenotype was also evident in patients with advanced luminal breast cancer. Thus, our findings showed that CCL5/CCR3 signaling promotes metastasis by inducing Th2 polarization of CD4+ T cells, with implications for prognosis and immunotherapy of luminal breast cancer. PMID- 26249174 TI - Targeting the miR-221-222/PUMA/BAK/BAX Pathway Abrogates Dexamethasone Resistance in Multiple Myeloma. AB - Despite recent therapeutic advances that have doubled the median survival time of patients with multiple myeloma, intratumor genetic heterogeneity contributes to disease progression and emergence of drug resistance. miRNAs are noncoding small RNAs that play important roles in the regulation of gene expression and have been implicated in cancer progression and drug resistance. We investigated the role of the miR-221-222 family in dexamethasone-induced drug resistance in multiple myeloma using the isogenic cell lines MM1R and MM1S, which represent models of resistance and sensitivity, respectively. Analysis of array comparative genome hybridization data revealed gain of chromosome X regions at band p11.3, wherein the miR-221-222 resides, in resistant MM1R cells but not in sensitive MM1S cells. DNA copy number gains in MM1R cells were associated with increased miR-221-222 expression and downregulation of p53-upregulated modulator of apoptosis (PUMA) as a likely proapoptotic target. We confirmed PUMA mRNA as a direct target of miR 221-222 in MM1S and MM1R cells by both gain-of-function and loss-of-function studies. In addition, miR-221-222 treatment rendered MM1S cells resistant to dexamethasone, whereas anti-miR-221-222 partially restored the dexamethasone sensitivity of MM1R cells. These studies have uncovered a role for miR-221-222 in multiple myeloma drug resistance and suggest a potential therapeutic role for inhibitors of miR-221-222 binding to PUMA mRNA as a means of overcoming dexamethasone resistance in patients. The clinical utility of this approach is predicated on the ability of antisense miR-221-222 to increase survival while reducing tumor burden and is strongly supported by the metastatic propensity of MM1R cells in preclinical mouse xenograft models of multiple myeloma. Moreover, our observation of increased levels of miR-221-222 with decreased PUMA expression in multiple myeloma cells from patients at relapse versus untreated controls suggests an even broader role for miR-221-222 in drug resistance and provides a rationale for the targeting of miR-221-222 as a means of improving patient outcomes. PMID- 26249175 TI - Carbonic Anhydrase Activity Monitored In Vivo by Hyperpolarized 13C-Magnetic Resonance Spectroscopy Demonstrates Its Importance for pH Regulation in Tumors. AB - Carbonic anhydrase buffers tissue pH by catalyzing the rapid interconversion of carbon dioxide (CO2) and bicarbonate (HCO3 (-)). We assessed the functional activity of CAIX in two colorectal tumor models, expressing different levels of the enzyme, by measuring the rate of exchange of hyperpolarized (13)C label between bicarbonate (H(13)CO3(-)) and carbon dioxide ((13)CO2), following injection of hyperpolarized H(13)CO3(-), using (13)C-magnetic resonance spectroscopy ((13)C-MRS) magnetization transfer measurements. (31)P-MRS measurements of the chemical shift of the pH probe, 3-aminopropylphosphonate, and (13)C-MRS measurements of the H(13)CO3(-)/(13)CO2 peak intensity ratio showed that CAIX overexpression lowered extracellular pH in these tumors. However, the (13)C measurements overestimated pH due to incomplete equilibration of the hyperpolarized (13)C label between the H(13)CO3(-) and (13)CO2 pools. Paradoxically, tumors overexpressing CAIX showed lower enzyme activity using magnetization transfer measurements, which can be explained by the more acidic extracellular pH in these tumors and the decreased activity of the enzyme at low pH. This explanation was confirmed by administration of bicarbonate in the drinking water, which elevated tumor extracellular pH and restored enzyme activity to control levels. These results suggest that CAIX expression is increased in hypoxia to compensate for the decrease in its activity produced by a low extracellular pH and supports the hypothesis that a major function of CAIX is to lower the extracellular pH. PMID- 26249176 TI - Heparanase Enhances Tumor Growth and Chemoresistance by Promoting Autophagy. AB - Heparanase is the only enzyme in mammals capable of cleaving heparan sulfate, an activity implicated in tumor inflammation, angiogenesis, and metastasis. Heparanase is secreted as a latent enzyme that is internalized and subjected to proteolytic processing and activation in lysosomes. Its role under normal conditions has yet to be understood. Here, we provide evidence that heparanase resides within autophagosomes, where studies in heparanase-deficient or transgenic mice established its contributions to autophagy. The protumorigenic properties of heparanase were found to be mediated, in part, by its proautophagic function, as demonstrated in tumor xenograft models of human cancer and through use of inhibitors of the lysosome (chloroquine) and heparanase (PG545), both alone and in combination. Notably, heparanase-overexpressing cells were more resistant to stress and chemotherapy in a manner associated with increased autophagy, effects that were reversed by chloroquine treatment. Collectively, our results establish a role for heparanase in modulating autophagy in normal and malignant cells, thereby conferring growth advantages under stress as well as resistance to chemotherapy. Cancer Res; 75(18); 3946-57. (c)2015 AACR. PMID- 26249177 TI - Recommendations for Benchmarking Preclinical Studies of Nanomedicines. AB - Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small-molecule drug therapy for cancer and to achieve both therapeutic and diagnostic functions in the same platform. Preclinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of preclinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of preclinical trials and propose a protocol for benchmarking that we recommend be included in in vivo preclinical studies of drug-delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. PMID- 26249180 TI - Challenges in Improving Health Care by Use of Health Informatics Technology. AB - This chapter discusses the complementary role of Techno-Anthropological methodologies in relation to classical quantitative and qualitative methodologies. The chapter addresses the importance of evidencing the problems in health informatics and how these problems are framed in order to find appropriate solutions. It is the claim that problem based learning approaches (PBL) and inter disciplinary teamwork is paramount in order to meet the current challenges of development and implementation of health informatics in the health care system. The triple aim of providing better health, better care at lower cost on a societal level is complemented by similar aims on an institutional and individual level in order to frame health informatics on a more holistic level. In order to achieve this goal we have to embrace concepts like co-creation and co construction with users and actors. The aim of the chapter is condensed in methodological recommendations for Techno-Anthropological work in health informatics contexts. PMID- 26249181 TI - Using Rapid Ethnography to Support the Design and Implementation of Health Information Technologies. AB - Ethnography is the defining practice - and art - of anthropology. Among health information technology (IT) developers, however, ethnography remains a little used and undervalued mode of inquiry and representation. In this chapter we demonstrate that ethnography can make important contributions to the design and implementation of more user-oriented health IT devices and systems. In particular, we propose 'rapid ethnography' as a pragmatic strategy that draws on classic ethnographic methods, but emphasizes shorter periods of fieldwork and quick turnaround of findings to inform (re)design, programming and implementation efforts. Rapid ethnography is theoretically and empirically situated in science and technology studies' explorations of a) the entanglement of social and technical dimensions of technology use; b) how getting tools to 'work' requires aligning interests across a wide range of human and non-human actors; and c) the ways in which humans and technology transform each other as they interact. We provide two detailed case studies to illustrate the evolution and uses of rapid ethnography at a U.S. academic medical center. By providing deeper insights into the experiences of users, and the contexts and communities in which new tools are introduced, rapid ethnography can serve as a valuable component of Techno Anthropology and health IT innovation. PMID- 26249182 TI - Uncovering Everyday Rhythms and Patterns: Food tracking and new forms of visibility and temporality in health care. AB - This chapter demonstrates how ethnographically-oriented research on emergent technologies, in this case self-tracking technologies, adds to Techno Anthropology's aims of understanding techno-engagements and solving problems that deal with human-technology relations within and beyond health informatics. Everyday techno-relations have been a long-standing research interest in anthropology, underlining the necessity of empirical engagement with the ways in which people and technologies co-construct their daily conditions. By focusing on the uses of a food tracking application, MealLogger, designed for photographing meals and visualizing eating rhythms to share with health care professionals, the chapter details how personal data streams support and challenge health care practices. The interviewed professionals, from doctors to nutritionists, have used food tracking for treating patients with eating disorders, weight problems, and mental health issues. In general terms, self-tracking advances the practices of visually and temporally documenting, retrieving, communicating, and understanding physical and mental processes and, by doing so, it offers a new kind of visual mediation. The professionals point out how a visual food journal opens a window onto everyday life, bypassing customary ways of seeing and treating patients, thereby highlighting how self-tracking practices can aid in escaping the clinical gaze by promoting a new kind of communication through visualization and narration. Health care professionals are also, however, acutely aware of the barriers to adopting self-tracking practices as part of existing patient care. The health care system is neither used to, nor comfortable with, personal data that originates outside the system; it is not seen as evidence and its institutional position remains insecure. PMID- 26249178 TI - A Molecular Portrait of High-Grade Ductal Carcinoma In Situ. AB - Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2(+)) displayed signatures characteristic of activated Treg cells (CD4(+)/CD25(+)/FOXP3(+)) and CTLA4(+)/CD86(+) complexes indicative of a tumor associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer. PMID- 26249183 TI - The British National Formulary: Checking, medicines and clinicians. AB - The British National Formulary underpins the way medical practice is made safe in the UK. Its move from book to digital product has been identified as welcome but with problematic aspects. This chapter describes and investigates the current use of the formulary in order to examine how a rapid, well-targeted project is designed and executed. PMID- 26249184 TI - Patient Centred Systems: Techno-Anthropological reflections on the challenges of 'meaningfully engaging' patients within health informatics research. AB - This chapter explores how Techno-Anthropology can contribute to more explicitly professional and ethically responsible reflections on the socio-technical practices involved in meaningfully engaging patients in health informatics research. The chapter draws on insights from health informatics research projects focused on chronic disease and self-management conducted in Tasmania during the last 10 years. Through these projects the paper explores three topics of relevance to 'meaningful engagement' with patients: (i) Patient Self-Management and Chronic Disease (ii) Patients as Users in Health Informatics research, and, (iii) Evaluations of outcomes in Health and Health Informatics Interventions. Techno-Anthropological reflections are then discussed through the concepts of liminality, polyphony and power. This chapter argues that beyond its contribution to methodology, an important role for Techno-Anthropology in patient centred health informatics research may be its capacity to support new ways of conceptualising and critically reflecting on the construction and mediation of patients' needs, values and perspectives. PMID- 26249185 TI - Tracking Porters: Learning the Craft of Techno-Anthropology. AB - Anthropology attempts to gain insight into people's experiential life-worlds through long-term fieldwork. The quality of anthropological knowledge production, however, does not depend solely on the duration of the stay in the field, but also on a particular way of seeing social situations. The anthropological perspective is grounded in socio-cultural theory and forged by a distinct relativist or contextualist epistemological stance. The point is to understand events, concepts and phenomena from the insiders' point of view and to show how this view relates to the particular social and cultural context. In this chapter, we argue that although anthropology has its specific methodology - including a myriad of ethnographic data-gathering tools, techniques, analytical approaches and theories - it must first and foremost be understood as a craft. Anthropology as craft requires a specific 'anthropological sensibility' that differs from the standardized procedures of normal science. To establish our points we use an example of problem-based project work conducted by a group of Techno-Anthropology students at Aalborg University, we focus on key aspects of this craft and how the students began to learn it: For two weeks the students followed the work of a group of porters. Drawing on anthropological concepts and research strategies the students gained crucial insights about the potential effects of using tracking technologies in the hospital. PMID- 26249186 TI - Part 2. Ethical and Sociotechnical Approaches. PMID- 26249187 TI - Techno-Anthropological Ethics and Health Information Systems Technologies. AB - One of the most important Techno-Anthropological intellectual virtues is the ability to make contextualized ethical judgments of new and emerging technologies. This Techno-Anthropological core competence is especially relevant in Health Information Systems Technologies, which is a field characterized by inherent ethical dilemmas such as the pros and cons of regulation of research databases with sensitive information, or storing and application of tissue and blood samples. In this paper we present a method to make 'proper and quick' ethical estimates in Health Information. The method guides its user to make ethical judgments by splitting the judgment process into four steps: (1) Identification of intended beneficial consequences, potential misuse, unintended side effects and long-term consequences for culture and society. (2) Linkage of intended consequences, misuse, side effects and cultural implications to appropriate ethical values. (3) Identification of ethical dilemmas related to a specific use of the Health Information Systems Technology under assessment. (4) Formulation of appropriate technological and institution design criteria that can transcend the identified ethical dilemmas. The methodology will be applied to a the discussions at a hearing on ethical challenges accompanying research involving health data organized by the Danish Council of Ethics and the case of risk reducing breast cancer surgery based on diagnosed genetic predisposition to breast cancer. PMID- 26249188 TI - Technology in Intersecting Figured Worlds. AB - In this chapter we analyze aspects of how Danish student nurses acquire technological literacy during their clinical internship at a Danish hospital. The argument is supported by several cases from Esbensen's empirical work. We focus on a Techno-Anthropological study of how student nurses learn to engage in technological mediated relations, and discuss how we think the ideas of intersecting worlds help to analyze some of the difficulties, student's experience. PMID- 26249189 TI - Persons and Their Personal Health Records: Augmented Embodiment Meets the Quasi Doctor. AB - The links between a Personal Health Record (PHR) and an Electronic Health Record (EHR) have influences beyond the technical tethering. It should involve an analysis of the relations between users, healthcare professionals and technology. In order to provide fresh perspectives, the postphenomenological relations of embodiment, hermeneutic and alterity are analyzed and developed into augmented embodiment and quasi-doctor terminology. PMID- 26249190 TI - A Model of Tradeoffs for Understanding Health Information Technology Implementation. AB - Implementing health information technology (HIT) is a challenge that frequently results in unintended consequences post implementation. To better manage these consequences we need approaches that can proactively identify issues so we deal with them pre-implementation. It can be suggested that a reason unintended consequences occur is because of trade-offs between people's work practices and pre and post HIT implementation. If we can identify what these trade-offs are we can use them for proactive management of unintended consequences. This paper uses a case study of a perioperative information system and principles of social BPM and qualitative content analysis to develop a model of seven trade-off patterns that can be used to study HIT mediated change. It also discusses the implications of the model on the design and evaluation of HIT. PMID- 26249191 TI - Use of Techno-Anthropologic Approaches in Studying Technology--induced Errors. AB - In this book chapter the authors review several Techno-Anthropologic approaches that can be used to improve the quality and safety of health information technology (HIT) by eliminating or reducing the incidence and occurrence of technology-induced errors. Technology-induced errors arise from interactions between health professionals, patients and/or HIT (i.e., software and hardware) and lead to a medical error. Techno-Anthropologic methods can be used to address these types of medical errors before they occur. In this book chapter they are discussed in the context of: (a) how they can be applied to identifying technology-induced errors and (b) how this information can be used to design and implement safer HIT. Important in this chapter is a review of several methods: traditional ethnography, rapid assessment of clinical information systems, video ethnography and photovoice as they are applied to the discovery of potential (i.e., near misses) and actual (i.e., mistakes) technology-induced errors. PMID- 26249192 TI - Part 3. Users, Participation and Human Factors. PMID- 26249193 TI - Technology and the Ecology of Chronic Illness in Everyday Life. AB - A major challenge in the design of useful technological tools is effectively conceptualizing the context in which users engage the technology. Contextually specific research on activities of patients and their caregivers - and how those activities are supported by social and material arrangements--can result in insights for design of consumer health informatics technologies and infrastructural advancements that can better support patients outside of institutional settings. This chapter describes an ecosystem focused on activity- how activity is shaped by cultural institutions, and the negotiations that arise between actors and institutions. PMID- 26249194 TI - Monitoring Technology Meets Care Work: Challenges of monitoring wet-beds in a nursing home. AB - Monitoring technology, especially sensor-based technology, is increasingly taken into use in care work. Despite the simplicity of these technologies - aimed to automate what appear as mundane monitoring tasks - recent research has identified major challenges primarily related to the technology's ability to meet the complexity of care work. Understanding intersectional challenges between these care technologies and care work is fundamental to improve design and use of health informatics. In this paper we present an analysis of interaction challenges between a wet-sensor at the task of monitoring wet beds at a nursing home. The analysis identifies the multifaceted nature of monitoring work and the intricacy of integrating sensor technology into the complex knowledge system of monitoring work. PMID- 26249195 TI - Techno-Anthropological Sensibilities in Health Informatics: Opportunities and challenges. AB - What kind of knowledges, skills and competences may be required by Techno Anthropology engaging with health informatics? If we understand Techno Anthropology to mean conducting anthropological analyses of the interwoven and mutually shaping relationship between organizing, technologies and actors in healthcare, such engagements and interventions can take many forms: Short-term consultancy work dedicated to achieving specific goals, long-term studies of broad changes in healthcare; management support within hospitals and public healthcare administration; or technology development with vendors of healthcare IT. The opportunities would seem to be manifold. Since the healthcare sector is a heterogeneous mix of interests, political agendas, professions et cetera, there is great merit in having people knowledgeable about this heterogeneity; able to facilitate meetings and processes between the various professions and organizations; and skilled in generating analyses and proposing new solutions. Also, people with insight into how action, technologies and organizing are interwoven and redistribute competences, responsibilities and risks are invaluable: Look at from afar, technologies seem to cause and determine social development, whereas detailed studies reveal that determinants and causes are both technical and social. The challenges include the one of making one's knowledge and skills legitimate and relevant to health informatics. Having a degree from arts or social sciences is not necessarily impressive for people with similar degrees in medicine, computer science, and business administration. Another challenge is to design an engagement with health informatics that will generate insights which often requires time, while also providing quick results for project sponsors or collaborators. The chapter points at three issues that seem to be central foundations for appropriate and quality-driven research and interventions of the 'quick and proper' kind: Modes of engagement; characteristics of the healthcare sector; and medical informatics and work. PMID- 26249196 TI - Techno-Anthropologists as Change Agents: A case in health informatics. AB - Studying technology will often involve studying change - or in the perspective of this chapter should involve not just studying but also actively being involved with change. Your presence and the questions you ask shape the way people think and act and on the other hand their responses and your study of practice change the researchers perspective. For Techno-Anthropologist, this means that asking in specific ways about technology and having a focus on technology in the data collection and fieldwork will (should) influence what they see, the data they collect and their analysis - and also the way the informants think and the way people talk about practice and technology. The Techno-Anthropological researcher should be aware and actively use the potential for change in the empirical study of technology. In this chapter I exemplify and examine how and why change can be embraced and seen as an integral part of Techno-Anthropological studies in Health Informatics and beyond. This statement is supported through reflections on empirical examples, qualitative methods, and ethical and philosophical considerations on research and change. The chapter concludes that Techno Anthropologists should actively consider and engage in the potential for change of the empirical studies of technology. PMID- 26249197 TI - The Smart Floor: How a Public-Private Partnership co-developed a heterogeneous healthcare technology system. AB - Currently, a wide variety of healthcare technologies are being implemented in private homes, hospitals, nursing homes, etc. with the triple aim of improving people's health, improving the quality of care, and reducing costs related to healthcare services. In this chapter, we discuss how different actors in a public private partnership co-developed a heterogeneous system around the Smart Floor to ensure that both new healthcare practices and residents' routines were inscribed into the new healthcare technology. We argue that implementing the Smart Floor was not just a question of buying a technology and integrating it during construction-it required co-development with the healthcare staff. The floor is more than a technology placed under the floor surface in a resident's apartment; rather, it is a heterogeneous network of human and non-human actors communicating with each other. In this chapter, we illustrate how the heterogeneous technological system was co-developed and redesigned during knowledge sharing processes with companies, lead-users, and healthcare staff. We also discuss how care practices have changed as a result of the Smart Floor system. In particular, healthcare staff members no longer feel a need to disturb elderly residents with routine in-person checks. Domesticating the technologies for different groups of actors required not only coordinating communication among sensors, the interface, the portable nurse call (smartphones), and alarms, but also accepting the use of surveillance technology. PMID- 26249198 TI - Video Analysis and Remote Digital Ethnography: Approaches to understanding user perspectives and processes involving healthcare information technology. AB - Innovations in healthcare information systems promise to revolutionize and streamline healthcare processes worldwide. However, the complexity of these systems and the need to better understand issues related to human-computer interaction have slowed progress in this area. In this chapter the authors describe their work in using methods adapted from usability engineering, video ethnography and analysis of digital log files for improving our understanding of complex real-world healthcare interactions between humans and technology. The approaches taken are cost-effective and practical and can provide detailed ethnographic data on issues health professionals and consumers encounter while using systems as well as potential safety problems. The work is important in that it can be used in techno-anthropology to characterize complex user interactions with technologies and also to provide feedback into redesign and optimization of improved healthcare information systems. PMID- 26249199 TI - Clinical Simulation: For what and how can it be used in design and evaluation of health IT. AB - The usability of health information technology (IT) is increasingly recognized as critically important to the development of systems that are both safe to use and acceptable to end-users. The substantial complexity of organizations, work practice and physical environments within the healthcare sector influences the development and application of health IT. When health IT is introduced in local clinical work practices, potential patient safety hazards and insufficient support of work practices need to be examined. Qualitative methods, such as clinical simulation, may be used to support Techno-Anthropologists design and evaluate new technology navigating in the intersection between people and technology and between various interests in forms of experts and stakeholders. This chapter will introduce the reader to clinical simulation, present the general guidelines and recommendation conducting simulations and describe a simulation lab in Copenhagen. Illustrative examples and references to specific projects will be part of the contribution. PMID- 26249200 TI - Application of Human Factors Methods to Design Healthcare Work Systems: Instance of the prevention of Adverse Drug Events. AB - Human Factors (HF) methods are increasingly needed to support the design of new technologies in order to avoid that introducing those technologies into healthcare work systems induces use errors with potentially catastrophic consequences for the patients. This chapter illustrates the application of HF methods in developing two health technologies aiming at securing the hospital medication management process. Lessons learned from this project highlight the importance of (i) analyzing the work system in which the technology is intended to be implemented, (ii) involving end users in the design process and (iii) the intermediation role of HF between end users and scientific/technical experts. PMID- 26249201 TI - Mapping Health Outcome and Costs when Coordinating Local Information System Redesign. AB - As costs for healthcare are rising in society, information systems are often seen as enablers of new cost-saving healthcare processes. But an on-going deployment of a wide range of new kinds of systems requires close attention to interoperability between new and legacy systems. Another challenge is to assure that the healthcare professions are given realistic opportunities to play an active part in designing the new ways of working that the new, integrated systems are designed to support. We argue that a feasible way to approach such a user participation in design of work processes and systems is to extend well known user-survey and strategy-mapping methods with the new value-based healthcare approach which invites health professionals to participate in strategic assessments of health outcome and costs along the care chain in which they work. We also argue that such a combination of practical research methods resonates well with Techno-Anthropology's foregrounding of ethical considerations to inform the interdisciplinary cross-fertilization of interactional competencies in health informatics research. PMID- 26249205 TI - The effect of IFN-gamma and TGF-beta in the functional activity of mononuclear cells in the presence of Entamoeba histolytica. AB - BACKGROUND: Entamoeba histolytica (E. histolytica) causes amoebiasis, which is a disease with significant morbidity and mortality. Phagocytic cells and cytokines appear to be important in amoebiasis, but very little is known about the influence of these cells and cytokines in protozoan infections. The aim of this study was to analyse the supernatant of cultures of mononuclear (MN) cells with E. histolytica to determine: 1) the levels of the cytokines IFN-gamma and TGF beta, and 2) the amoebicidal activity of MN cells after incubation with cytokines. METHODS: Blood samples were collected from 30 volunteer donors. The cytokine concentrations in MN cells culture supernatants, superoxide release, leukophagocytosis, amoebicide activity, intracellular calcium release and apoptosis were analysed. RESULTS: The IFN-gamma concentrations were 6.22 +/- 0.36 and TGF-beta concentrations were 17.01 +/- 2.21 in cells-trophozoite culture supernatants. MN cells, independently of cytokines, in the presence of amoeba increase the superoxide release. In the absence of cytokines, the ingestion of MN cells by amoebae was higher. In the presence of IFN- gamma or TGF- beta, a lower ingestion of MN cells was observed by amoebae. MN cells treated with cytokines exhibited higher amoebicide and apoptosis indexes. The incubation of cytokines increased the intracellular calcium release by MN cells. CONCLUSIONS: These results suggest that cytokines play a beneficial role for the host by activating MN cells against E. histolytica. The increased death of amoebae during the leukophagocytosis suggests that both cytokines (IFN-gamma and TGF-beta) can modulate the functional activity of MN cells and that these cytokines probably are important in the control of amoebic infections. PMID- 26249207 TI - Understanding the UCST-type transition of P(AAm-co-AN) in H2O and D2O: dramatic effects of solvent isotopes. AB - The UCST-type transition of poly(acrylamide-co-acrylonitrile) (P(AAm-co-AN)) (molar fraction of AN: 13.3%; PDI = 3.2) in H2O and D2O is explored and compared by applying turbidity, DLS as well as FTIR measurements. The transition temperature of P(AAm-co-AN) in D2O is observed to be almost 10 degrees C higher than that in H2O at the same concentration, demonstrating a dramatic solvent isotope effect. Such a phenomenon could be rooted from a stronger interaction among polymer chains in D2O than in H2O, as indicated from DLS results. It is also observed in second-derivative analysis of FTIR spectra in the nu(C=O) region, where all C=O groups participate in the formation of inter-/intra-chain hydrogen bonds (C=O...H-N) in D2O while there is still part of relatively "free" C=O groups in H2O. Moreover, we find in the temperature-dependent FTIR spectra that C=N groups exhibit hydrating behavior while C=O groups present increased inter-/intra-molecular hydrogen bonding interaction (C=O...H-N) upon cooling, revealing the later process to be the driving force of the UCST-type transition. PMID- 26249206 TI - Effect of exenatide, insulin and pioglitazone on bone metabolism in patients with newly diagnosed type 2 diabetes. AB - AIM: Preclinical studies suggested that insulin, incretin and thiazolidinediones had effect on regulation of bone metabolism. But clinical evidence is limited. We assessed the effects of these antihyperglycemic agents on bone metabolism in patients with newly diagnosed type 2 diabetes. METHODS: The present study was a two-center, randomized, parallel-group clinical trial. Sixty-two newly diagnosed and drug-naive patients with type 2 diabetes were randomized to exenatide (EXE, n = 20), mixed protamine zinc recombinant human insulin lispro injection (25R; INS, n = 21) or pioglitazone (PIO, n = 21) group for a 24-week treatment. Glycosylated hemoglobin A1c (HbA1c), body weight, body mineral density (BMD) and fasting serum concentration of bone turnover markers including osteocalcin (OC), C-telopeptide of type I collagen (CTX) and tartrate-resistant alkaline phosphatase 5b (TRAcP5b) were assessed at baseline and week 24. RESULTS: Baseline characteristics were similar among groups. At week 24, HbA1c improved in all patients (EXE:-2.4 +/- 0.3 %, INS:-2.4 +/- 0.3 %, PIO:-2.0 +/- 0.2 %; p > 0.05 among groups). Patients treated with exenatide lost body weight remarkably (-4.7 +/- 0.8 kg). In spite of the amelioration of glucose control, no significant improvement of OC, CTX or TRAcP5b was observed at week 24 (EXE: OC -0.619 +/- 0.728 ng/ml, CTX 0.147 +/- 0.046 ng/ml, TRAcP5b 0.302 +/- 0.149 U/L;INS: OC 0.637 +/- 0.787 ng/ml, CTX 0.012 +/- 0.074 ng/ml, TRAcP5b 0.124 +/- 0.395 U/L; PIO: OC -0.150 +/- 0.691 ng/ml, CTX 0.073 +/- 0.094 ng/ml, TRAcP5b 0.586 +/- 0.183 U/L; p > 0.05), as well as BMD measurement, regardless of the treatments. CONCLUSIONS: Twenty-four-week treatment with exenatide, insulin and pioglitazone improved glucose control in patients with newly diagnosed type 2 diabetes, but had no impact on bone turnover markers or BMD. PMID- 26249208 TI - Effect of double conical abutment screw on implant preload. AB - OBJECTIVE: This study compared the loosening torque of experimental double conical abutment screws to that of conventional conical abutment screws and flat head screws in implants with internal connections before and after mechanical loading. MATERIAL AND METHODS: Eighty implant-screw-abutment assemblies were divided into four groups: flat-head screw (Xive S), conical screw (Straumann), conical screw (Nobel Biocare), and double conical screw (RTB). Abutments were tightened to a torque of 30 Ncm. After 10 min, they were retightened and loosening torque was measured. The same abutments were then retightened with new screws to a torque of 30 Ncm and, again, retightened after 10 min. They were then mechanically loaded for 3 000 000 cycles, and loosening torque was again measured. Data were collected, and an exploratory analysis was performed. RESULTS: Comparisons before mechanical cycling showed significant differences between groups. After mechanical cycling, only the comparisons of Straumann and Nobel Biocare showed no significant differences. Considering the same group before and after mechanical cycling, all comparisons showed significant differences. CONCLUSION: The shape of the abutment screw head significantly influenced loosening torque: Double conical-head screws showed significantly higher loosening torque values than conical-head screws. Conical-head screws showed higher loosening torque values than conventional flat-head screws before and after loading. PMID- 26249209 TI - Regional identification of mechanical properties in arteries. PMID- 26249210 TI - Colour pattern homology and evolution in Vanessa butterflies (Nymphalidae: Nymphalini): eyespot characters. AB - Ocelli are serially repeated colour patterns on the wings of many butterflies. Eyespots are elaborate ocelli that function in predator avoidance and deterrence as well as in mate choice. A phylogenetic approach was used to study ocelli and eyespot evolution in Vanessa butterflies, a genus exhibiting diverse phenotypes among these serial homologs. Forty-four morphological characters based on eyespot number, arrangement, shape and the number of elements in each eyespot were defined and scored. Ocelli from eight wing cells on the dorsal and ventral surfaces of the forewing and hindwing were evaluated. The evolution of these characters was traced over a phylogeny of Vanessa based on 7750 DNA base pairs from 10 genes. Our reconstruction predicts that the ancestral Vanessa had 5 serially arranged ocelli on all four wing surfaces. The ancestral state on the dorsal forewing and ventral hindwing was ocelli arranged in two heterogeneous groups. On the dorsal hindwing, the ancestral state was either homogenous or ocelli arranged in two heterogeneous groups. On the ventral forewing, we determined that the ancestral state was organized into three heterogeneous groups. In Vanessa, almost all ocelli are individuated and capable of independent evolution relative to other colour patterns except for the ocelli in cells -1 and 0 on the dorsal and ventral forewings, which appear to be constrained to evolve in parallel. The genus Vanessa is a good model system for the study of serial homology and the interaction of selective forces with developmental architecture to produce diversity in butterfly colour patterns. PMID- 26249211 TI - A semi-automated method to assess intraepidermal nerve fibre density in human skin biopsies. AB - AIMS: Evaluation of intraepidermal nerve fibres (IENFs) in skin biopsies is used in the diagnosis of small-fibre neuropathies. The number of IENFs is assessed manually under a microscope, with an inter-rater variability of ~25%. Unless the images are digitized, there is no documentation. Our aim was to develop a method for standardized semi-automated quantification (SAQ) and documentation of IENF density. METHODS AND RESULTS: We analysed samples from four different university centres that were immunostained according to local protocols. Images were acquired through the Z-plane with a whole slide scanner. orbit image analysis software was used to create an analysable image and develop a reliable algorithm for IENF detection. Rebuilt images revealed well-contrasted nerves, allowing detection of IENFs (automated). The software presented the detected nerves for confirmation by the operator (manual). As compared with the conventional microscopy count, the SAQ achieved correlation coefficients of 0.99 and 0.96 and interfacility variabilities of 19% and 23%, respectively. We found better reproducibility with fluorescence-stained specimens than with bright-field images. CONCLUSIONS: The new semi-automated method has high experimenter independent reproducibility when based on nerve detection by fluorescence and is easy to perform, even by untrained users. The IENF counting is electronically well documented. PMID- 26249212 TI - A steep-slope transistor based on abrupt electronic phase transition. AB - Collective interactions in functional materials can enable novel macroscopic properties like insulator-to-metal transitions. While implementing such materials into field-effect-transistor technology can potentially augment current state-of the-art devices by providing unique routes to overcome their conventional limits, attempts to harness the insulator-to-metal transition for high-performance transistors have experienced little success. Here, we demonstrate a pathway for harnessing the abrupt resistivity transformation across the insulator-to-metal transition in vanadium dioxide (VO2), to design a hybrid-phase-transition field effect transistor that exhibits gate controlled steep ('sub-kT/q') and reversible switching at room temperature. The transistor design, wherein VO2 is implemented in series with the field-effect transistor's source rather than into the channel, exploits negative differential resistance induced across the VO2 to create an internal amplifier that facilitates enhanced performance over a conventional field-effect transistor. Our approach enables low-voltage complementary n-type and p-type transistor operation as demonstrated here, and is applicable to other insulator-to-metal transition materials, offering tantalizing possibilities for energy-efficient logic and memory applications. PMID- 26249214 TI - Atrioventricular Nodal Reentrant Tachycardia in Implantable Cardioverter Defibrillators: Diagnosis and Troubleshooting. AB - Inappropriate therapies are frequent in patients with implantable cardioverter defibrillators (ICDs) and are associated with adverse outcomes, including increased mortality. Atrioventricular nodal reentrant tachycardia (AVNRT) is the most common reentrant supraventricular tachycardia (SVT) and a cause of inappropriate therapies in these patients. In the present article we review the problem of AVNRT in ICD patients with a focus on diagnosis and the available algorithms to improve arrhythmia discrimination and prevent inappropriate shocks. PMID- 26249213 TI - Synthesis of dual-functional targeting probes for cancer theranostics based on iron oxide nanoparticles coated by centipede-like polymer connected with pH responsive anticancer drug. AB - A tumor-targeted and pH-responsive drug release system based on superparamagnetic iron oxide nanoparticles (IONPs) coated by poly(ethylene glycol) (PEG) and dodecylamine (DDA)-modified polyitaconic acid (PIA) connecting with bortezomib (BTZ) (PIA-PEG-DDA-BTZ@IOs) has been constructed and characterized. The anticancer drug BTZ was first conjugated using dopamine as the linker via catechol borate ester bond, which is acid cleavable and used as an ideal pH responsive drug release system. The IONPs were then coated by PIA-PEG-DDA-BTZ to form micelles with good biocompatibility. The conjugates were further designed to target liver cancer cells overexpressing vascular endothelial growth factor (VEGF) by the targeting molecule anti-vascular endothelial growth factor (anti VEGF). The magnetic resonance imaging showed that the targeting capability of IONPs-anti-VEGF conjugates to Hep G2 cells was more significant than that of non anti-VEGF IONPs. From the above, this kind of novel dual-functional targeting probe could provide a new idea for the diagnosis and treatment of cancer. PMID- 26249215 TI - CD109 is a novel marker for squamous cell/adenosquamous carcinomas of the gallbladder. AB - Gallbladder cancer is the most common biliary tract malignancy with the worst overall prognosis. CD109 is a co-receptor of TGF-beta1 and suppresses TGF-beta signaling. In this study, CD109 protein expression in three subtypes of gallbladder cancer was examined by immunohistochemistry on human tissue samples and tissue microarrays. We found that CD109 is specifically expressed in malignant squamous cells in squamous cell carcinomas (86.7%) and adenosquamous carcinomas (91.7%), but not in adenocarcinomas or normal gallbladder tissues. Thus, CD109 may be a potential pathology marker for gallbladder squamous cell/adenosquamous carcinomas. PMID- 26249216 TI - NMR studies of dilithiostyrenes: aggregation, NMR parameters, and DFT calculations for (E)-1-Lithio-2-(o-lithiophenyl)-1-trimethylsilylethene. AB - The dilithio compound (E)-1-lithio-2-(o-lithiophenyl)-1-trimethylsilylethene (5) was synthesized from 2-trimethylsilylbenzo-[b]tellurophene (6) with lithium-6 and a detailed analysis of its 1 H, 6 Li, 13 C, and 29 Si NMR spectra showed 5 to form a dimer 52 in tetrahydrofuran and diethylether, while addition of tetramethylethylenediamine stabilizes a monomer 51 . A monomer-dimer equilibrium exists with K at 230 K = 1.25 and DeltaG230o = -0.43 kJ mol-1 . Homonuclear 6 Li,6 Li coupling of 0.25 +/- 0.07 Hz in the dimer was detected by a 1D-6 Li,6 Li INADEQUATE experiment, and scalar 6 Li,13 C coupling constants were obtained from 13 C satellites in the 6 Li spectrum, from 13 C multiplet simulation and 6 Li,13 C-HMQC spectra. In addition, structures and coupling constants of 51 and 52 were calculated by density functional theory (DFT) methods. It was found that the magnitude of the 6 Li,13 C spin-spin interactions shows an inverse correlation with the C-Li bond lengths. The intra-aggregate exchange in the dimer, caused by 180 degrees rotation of one monomer unit within the solvent cage, was studied by 6 Li DNMR and line shape analysis and yielded DeltaG298? = 60 +/- 3 kJ mol-1 ; DeltaH? = 84 +/- 3 kJ mol-1 ; DeltaS? = 80 +/- 3 J mol-1 K-1 for this process. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26249217 TI - Visual and fluorescent detection of tyrosinase activity by using a dual-emission ratiometric fluorescence probe. AB - In this work, we designed a dual-emission ratiometric fluorescence probe by hybridizing two differently colored quantum dots (QDs), which possess a built-in correction that eliminates the environmental effects and increases sensor accuracy. Red emissive QDs were embedded in the silica nanoparticle as reference while the green emissive QDs were covalently linked to the silica nanoparticle surface to form ratiometric fluorescence probes (RF-QDs). Dopamine (DA) was then conjugated to the surface of RF-QDs via covalent bonding. The ratiometric fluorescence probe functionalized with dopamine (DA) was highly reactive toward tyrosinase (TYR), which can catalyze the oxidization of DA to dopamine quinine and therefore quenched the fluorescence of the green QDs on the surface of ratiometric fluorescence probe. With the addition of different amounts of TYR, the ratiometric fluorescence intensity of the probe continually varied, leading to color changes from yellow-green to red. So the ratiometric fluorescence probe could be utilized for sensitive and selective detection of TYR activity. There was a good linear relationship between the ratiometric fluorescence intensity and TYR concentration in the range of 0.05-5.0 MUg mL(-1), with the detection limit of 0.02 MUg mL(-1). Significantly, the ratiometric fluorescence probe has been used to fabricate paper-based test strips for visual detection of TYR activity, which validates the potential on-site application. PMID- 26249218 TI - Region-specific disturbed iron distribution in early idiopathic Parkinson's disease measured by quantitative susceptibility mapping. AB - In Parkinson's disease (PD), iron elevation in specific brain regions as well as selective loss of dopaminergic neurons is a major pathologic feature. A reliable quantitative measure of iron deposition is a potential biomarker for PD and may contribute to the investigation of iron-mediated PD. The primary purpose of this study is to assess iron variations in multiple deep grey matter nuclei in early PD with a novel MRI technique, quantitative susceptibility mapping (QSM). The inter-group differences of susceptibility and R2* value in deep grey matter nuclei, namely head of caudate nucleus (CN), putamen (PUT), global pallidus (GP), substantia nigra (SN), and red nucleus (RN), and the correlations between regional iron deposition and the clinical features were explored in forty-four early PD patients and 35 gender and age-matched healthy controls. Susceptibility values were found to be elevated within bilateral SN and RN contralateral to the most affected limb in early PD compared with healthy controls (HCs). The finding of increased susceptibility in bilateral SN is consistent with work on a subgroup of patients at the earliest clinical detectable state (Hoehn and Yahr [1967]: Neurology 17:427-442; Stage I). However, increased R2* values were only seen within SN contralateral to the most affected limb in the PD group when compared with controls. Furthermore, bilateral SN magnetic susceptibility positively correlated with disease duration and UPDRS-III scores in early PD. This finding supports the potential value of QSM as a non-invasive quantitative biomarker of early PD. PMID- 26249219 TI - Impact of Different Salts in Soaking Water on the Cooking Time, Texture and Physical Parameters of Cowpeas. AB - The characteristics of modern life has led consumers to seek convenience and speed in food preparation, but storage, which is often prolonged, can result in grain hardening, leading to higher energy consumption during preparation, grain with increased hardness is often discarded. Due to the increasing global demand for grain, the use of alternative techniques aimed at reducing grain waste is necessary. Therefore, we studied a method that meets consumer demand and results in better use of harvested grain. The beans studied were cowpea beans (Vigna unguiculata) of the BRS Guariba cultivar after 1 and 12 months of storage. Sodium chloride (NaCl), potassium chloride (KCl) and sodium bicarbonate (NaHCO3) were added to soaking water at different concentrations as a way to reduce cooking time. These beans were placed in soaking water for 12 h at 3 concentrations (0, 1.0 and 2.5%). The cowpeas soaked in water containing NaHCO3 presented the highest hydration coefficient, which increased with the salt concentration; these beans also had decreased hardness, chewiness and cooking time. PMID- 26249220 TI - Physiological Effects Associated with Quinoa Consumption and Implications for Research Involving Humans: a Review. AB - Quinoa is a pseudo-grain consumed as a dietary staple in South America. In recent years, consumer demand for quinoa in the developed world has grown steadily. Its perceived health benefits have been cited as a driving force behind this trend, but there are very few human studies investigating the impact of quinoa consumption. The aim of this review was to identify physiological effects of quinoa consumption with potential for human health. A critical evaluation of animal model studies was conducted. The quality of identified studies was assessed using a methodological quality assessment tool and summative conclusions were drawn to guide the direction of future human research. The majority of studies were of fair quality. Purported physiological effects of quinoa consumption included decreased weight gain, improved lipid profile and improved capacity to respond to oxidative stress. These physiological effects were attributed to the presence of saponins, protein and 20-hydroxyecdysone in the quinoa seed. The implications of these findings are that human studies should investigate the impact of quinoa consumption on weight gain and lipid levels. The role of quinoa as an antioxidant is still unclear and requires further elucidation in animal models. PMID- 26249221 TI - Increased Galectin-9 Concentration and Number of CD4+Foxp3high+Cells in Bronchoalveolar Lavage Fluid of Patients with Cryptogenic Organizing Pneumonia. AB - PURPOSE: Galectin-9 (Gal-9) is a beta-galactoside-binding protein that exhibits various biological reactions, such as chemoattraction, cell aggregation, and apoptosis. Recent studies demonstrated that Gal-9 has a role as an immunomodulator in excessive immunological reactions by expanded regulatory T cells (Tregs). We examined the role of Gal-9 in the pathogenesis of one of the major idiopathic interstitial pneumonias, cryptogenic organizing pneumonia (COP) as compared with idiopathic pulmonary fibrosis (IPF). METHODS: Gal-9, transforming growth factor-beta1, and interleukin (IL)-10 levels in the bronchoalveolar lavage fluid (BALF) of patients with COP and IPF were estimated by enzyme-linked immunosorbent assay. Forkhead box protein 3 (Foxp3) expressing Tregs were evaluated by flow cytometry. The effect of Gal-9 on interactions between human lung fibroblast cells and hyarulonan was assessed in vitro. RESULTS: Gal-9 and IL-10 levels in the BALF were significantly higher in patients with COP than in patients with IPF. The number of CD4+Foxp3high+cells was significantly higher in the BALF of patients with COP than in those with IPF. Gal 9 levels significantly correlated with the absolute number of CD4+CD25+Foxp3+cells or CD4+Foxp3high+cells, but not with the absolute number of CD4+CD25+Foxp3-cells, in the BALF of patients with COP. Gal-9 suppressed the CD44 dependent interaction of human lung fibroblast cells with hyarulonan in a dose dependent manner. CONCLUSIONS: Our findings suggest that increased Gal-9 levels in the lung have a protective role against lung inflammation and fibrosis in patients with COP through the induction of Tregs in the lung and CD44-dependent inhibitory effects on lung fibroblast cells. PMID- 26249222 TI - Mitochondria sequence mapping strategies and practicability of mitochondria variant detection from exome and RNA sequencing data. AB - The rapid progress in high-throughput sequencing has significantly enriched our capacity for studying the mitochondrial DNA (mtDNA). In addition to performing specific mitochondrial targeted sequencing, an increasingly popular alternative approach is using the off-target reads from exome sequencing to infer mtDNA variants, including single nucleotide polymorphisms (SNPs) and heteroplasmy. However, the effectiveness and practicality of this approach have not been tested. Recently, RNAseq data have also been suggested as a good source for alternative data mining, but whether mitochondrial variants can be detected from RNAseq data has not been validated. We designed a study to evaluate the practicability of mtDNA variant detection using exome and RNA sequencing data. Five breast cancer cell lines were sequenced through mitochondrial targeted, exome, and RNA sequencing. Mitochondrial targeted sequencing was used as the gold standard to compute the validation and false discovery rates of SNP and heteroplasmy detection in exome and RNAseq data. We found that exome and RNA sequencing can accurately detect mitochondrial SNPs. However, the lower false discovery rate makes exome sequencing a better choice for heteroplasmy detection than RNAseq. Furthermore, we examined three alignment strategies and found that aligning reads directly to the mitochondrial reference genome or aligning reads to the nuclear and mitochondrial references genomes simultaneously produced the best results, and that aligning to the nuclear genome first and afterwards to the mitochondrial genome performed poorly. In conclusion, our study provides important guidelines for future studies that intend to use either exome sequencing or RNAseq data to infer mitochondrial SNPs and heteroplasmy. PMID- 26249224 TI - Problems, challenges and promises: perspectives on precision medicine. AB - The 'precision medicine (systems medicine)' concept promises to achieve a shift to future healthcare systems with a more proactive and predictive approach to medicine, where the emphasis is on disease prevention rather than the treatment of symptoms. The individualization of treatment for each patient will be at the centre of this approach, with all of a patient's medical data being computationally integrated and accessible. Precision medicine is being rapidly embraced by biomedical researchers, pioneering clinicians and scientific funding programmes in both the European Union (EU) and USA. Precision medicine is a key component of both Horizon 2020 (the EU Framework Programme for Research and Innovation) and the White House's Precision Medicine Initiative. Precision medicine promises to revolutionize patient care and treatment decisions. However, the participants in precision medicine are faced with a considerable central challenge. Greater volumes of data from a wider variety of sources are being generated and analysed than ever before; yet, this heterogeneous information must be integrated and incorporated into personalized predictive models, the output of which must be intelligible to non-computationally trained clinicians. Drawing primarily from the field of 'oncology', this article will introduce key concepts and challenges of precision medicine and some of the approaches currently being implemented to overcome these challenges. Finally, this article also covers the criticisms of precision medicine overpromising on its potential to transform patient care. PMID- 26249223 TI - Reasoning over genetic variance information in cause-and-effect models of neurodegenerative diseases. AB - The work we present here is based on the recent extension of the syntax of the Biological Expression Language (BEL), which now allows for the representation of genetic variation information in cause-and-effect models. In our article, we describe, how genetic variation information can be used to identify candidate disease mechanisms in diseases with complex aetiology such as Alzheimer's disease and Parkinson's disease. In those diseases, we have to assume that many genetic variants contribute moderately to the overall dysregulation that in the case of neurodegenerative diseases has such a long incubation time until the first clinical symptoms are detectable. Owing to the multilevel nature of dysregulation events, systems biomedicine modelling approaches need to combine mechanistic information from various levels, including gene expression, microRNA (miRNA) expression, protein-protein interaction, genetic variation and pathway. OpenBEL, the open source version of BEL, has recently been extended to match this requirement, and we demonstrate in our article, how candidate mechanisms for early dysregulation events in Alzheimer's disease can be identified based on an integrative mining approach that identifies 'chains of causation' that include single nucleotide polymorphism information in BEL models. PMID- 26249225 TI - A revision of ant-mimicking spiders of the family Corinnidae (Araneae) in the Western Pacific. AB - The Corinnidae of the western Pacific are revised. The formerly sparassid genus Anchognatha Thorell, 1881, and the gnaphosid genus Battalus Karsch, 1878, are transferred to the Castianeirinae. The Corinninae include only the introduced Creugas gulosus Thorell, 1878 and Medmassa christae sp. nov. from the northern Torres Strait islands. Medmassa pallipes (L. Koch, 1873) and Medmassa pusilla Simon, 1896 are newly synonymised with Creugas gulosus. The Castianeirinae from the Western Pacific including Australia includes Battalus Karsch, 1878, Copa Simon, 1886, Leichhardteus Raven & Baehr, 2013, Nyssus Walckenaer, 1805, Poecilipta Simon, 1897, and eight new genera: Disnyssus gen. nov., Iridonyssus gen. nov., Kolora gen. nov., Leptopicia gen. nov., Melanesotypus gen. nov., Nucastia gen. nov., Ozcopa gen. nov. and Ticopa gen. nov. Battalus includes B. adamparsonsi sp. nov., B. baehrae sp. nov., B. bidgemia sp. nov., B. byrneae sp. nov., B. diadens sp. nov., B. helenstarkae sp. nov., B. microspinosus sp. nov., B. rugosus sp. nov., B. spinipes Karsch, 1878, B. wallum sp. nov., B. zuytdorp sp. nov. and B. semiflavus (Simon, 1896), new combination (transferred from Medmassa). Copa, an otherwise African and Sri Lankan genus, includes C. kabana sp. nov. Disnyssus gen. nov. includes D. helenmirrenae sp. nov. and D. judidenchae sp. nov. Iridonyssus gen. nov. includes I. auripilosus sp. nov., I. formicans sp. nov., I. kohouti sp. nov. and I. leucostaurus sp. nov. Kolora gen. nov. includes K. cushingae sp. nov., K. cooloola sp. nov. and K. lynneae sp. nov., and K. sauverubens (Simon, 1896) new combination (transferred from Corinnomma Karsch, 1880). Leichhardteus includes Leichhardteus yagan sp. nov., Leichhardteus evschlingeri sp. nov., Leichhardteus strzelecki sp. nov., as well as eight recently described species. Leptopicia gen. nov. includes only Methesis bimaculata (Simon, 1896) new combination (transferred from Methesis Simon, 1896). Melanesotypus guadal gen. et sp. nov. is described from the Solomon Islands. Nucastia gen. nov., includes N. culburra sp. nov., N. eneabba sp. nov., N. muncoonie sp. nov., N. supunnoides sp. nov. and N. virewoods sp. nov.; Medmassa fusca Hogg, 1900 is transferred to Nucastia but is considered a nomen dubium. The genera Anchognatha and Supunna Simon, 1897 are junior synonyms of Nyssus, which includes Supunna albopunctatus (Hogg, 1896), Anchognatha avida Thorell, 1881, Nyssus coloripes Walckenaer, 1805, N. emu sp. nov., Agroeca insularis L. Koch, 1873 (from Fiji and the Solomon Islands), N. jaredwarden sp. nov., N. jonraveni sp. nov., N. loureedi sp. nov., N. luteofinis sp. nov., N. paradoxus sp. nov., N. pseudomaculatus sp. nov., N. robertsi sp. nov., N. semifuscus sp. nov., N. wendyae sp. nov. and N. yuggera sp. nov. Supunna funerea (Simon, 1896) and Supunna albomaculata (Rainbow, 1902) are junior synonyms of Nyssus albopunctatus; Supunna picta (L. Koch, 1873) and Storena auripes Rainbow, 1916 are junior synonyms of Nyssus coloripes Walckenaer, 1805. Ozcopa gen. nov. includes O. chiunei sp. nov., O. colloffi sp. nov., O. margotandersenae sp. nov., O. mcdonaldi sp. nov., O. monteithi sp. nov. and O. zborowskii sp. nov. Poecilipta includes P. carnarvon sp. nov., P. contorqua sp. nov., P. davidi sp. nov., P. elvis sp. nov., P. formiciforme (Rainbow, 1904) comb. nov. (transferred from Corinnomma), P. gloverae sp. nov., P. harveyi sp. nov., P. kgari sp. nov., P. samueli sp. nov., P. janthina Simon, 1896, P. kohouti sp. nov., P. lugubris sp. nov., P. marengo sp. nov., P. metallica sp. nov., P. micaelae sp. nov., P. qunats sp. nov., P. rawlinsonae sp. nov., P. ruthae Santana & Raven, sp. nov., P. smaragdinea (Simon, 1909) new combination (transferred from Supunna), P. tinda sp. nov., P. venusta Rainbow, 1904, P. waldockae sp. nov., P. wallacei sp. nov., P. yambuna sp. nov., and P. zbigniewi sp. nov. Ticopa gen. nov. includes T. australis sp. nov., T. carnarvon sp. nov., T. chinchilla sp. nov., T. dingo sp. nov., T. hudsoni sp. nov., and T. longbottomi sp. nov. For comparative purposes, males of the South-east Asian Corinnomma severum (Thorell, 1881) (the type species) and C. javanum Simon, 1905 are figured and supplementary notes provided. Liocranum australiensis L. Koch, 1873 is transferred from Medmassa to Miturga where it is a nomen dubium. One hundred and eight species are treated in this work, of which 77 are new, 21 existing species are recognised; five existing genera are recognised, two are placed in synonymy, eight new genera are added; and one species is transferred to Miturgidae and another is listed as a nomen dubium. The Australian corinnid fauna includes 14 genera and 97 species. PMID- 26249226 TI - A Cerebellar Framework for Predictive Coding and Homeostatic Regulation in Depressive Disorder. AB - Depressive disorder is associated with abnormalities in the processing of reward and punishment signals and disturbances in homeostatic regulation. These abnormalities are proposed to impair error minimization routines for reducing uncertainty. Several lines of research point towards a role of the cerebellum in reward- and punishment-related predictive coding and homeostatic regulatory function in depressive disorder. Available functional and anatomical evidence suggests that in addition to the cortico-limbic networks, the cerebellum is part of the dysfunctional brain circuit in depressive disorder as well. It is proposed that impaired cerebellar function contributes to abnormalities in predictive coding and homeostatic dysregulation in depressive disorder. Further research on the role of the cerebellum in depressive disorder may further extend our knowledge on the functional and neural mechanisms of depressive disorder and development of novel antidepressant treatments strategies targeting the cerebellum. PMID- 26249227 TI - Uptake of milk with and without solid feed during the monogastric phase: Effect on fibrolytic and methanogenic microorganisms in the gastrointestinal tract of calves. AB - Microbial communities are affected by diet and play a role in the successful transition from milk to a solid diet. The response of microorganisms in the gastrointestinal tract of Holstein bull calves to the uptake of milk with solid feed (control treatment; CT), or milk without solid feed (milk-only treatment; MT) during the first 3 weeks of life was investigated. Samples were collected from the rumen (fluid and tissue), abomasum (fluid), cecum (fluid and tissue) and feces at 7, 14 and 20 days of age. Calf weight was higher on days 14 and 20 in the MT than the CT. In the rumen at 14 days, the fibrolytic bacteria Fibrobacter succinogenes and Prevotella ruminicola increased in the CT and Ruminococcus flavefaciens increased in the MT. This suggests that R. flavefaciens is not strictly fibrolytic and that it might use milk as a substrate or other microbial species might supply a substrate. Diet affected methanogens, but this may have been due to an indirect effect via an association with Geobacter spp. or other syntrophic partners. The treatments also affected microorganisms in the abomasum, cecum and feces. Our results contribute to an understanding of diet, microbes in the gastrointestinal tract and weaning. PMID- 26249228 TI - Slip pulse and resonance of the Kathmandu basin during the 2015 Gorkha earthquake, Nepal. AB - Detailed geodetic imaging of earthquake ruptures enhances our understanding of earthquake physics and associated ground shaking. The 25 April 2015 moment magnitude 7.8 earthquake in Gorkha, Nepal was the first large continental megathrust rupture to have occurred beneath a high-rate (5-hertz) Global Positioning System (GPS) network. We used GPS and interferometric synthetic aperture radar data to model the earthquake rupture as a slip pulse ~20 kilometers in width, ~6 seconds in duration, and with a peak sliding velocity of 1.1 meters per second, which propagated toward the Kathmandu basin at ~3.3 kilometers per second over ~140 kilometers. The smooth slip onset, indicating a large (~5-meter) slip-weakening distance, caused moderate ground shaking at high frequencies (>1 hertz; peak ground acceleration, ~16% of Earth's gravity) and minimized damage to vernacular dwellings. Whole-basin resonance at a period of 4 to 5 seconds caused the collapse of tall structures, including cultural artifacts. PMID- 26249229 TI - A self-interfering clock as a "which path" witness. AB - In Einstein's general theory of relativity, time depends locally on gravity; in standard quantum theory, time is global-all clocks "tick" uniformly. We demonstrate a new tool for investigating time in the overlap of these two theories: a self-interfering clock, comprising two atomic spin states. We prepare the clock in a spatial superposition of quantum wave packets, which evolve coherently along two paths into a stable interference pattern. If we make the clock wave packets "tick" at different rates, to simulate a gravitational time lag, the clock time along each path yields "which path" information, degrading the pattern's visibility. In contrast, in standard interferometry, time cannot yield "which path" information. This proof-of-principle experiment may have implications for the study of time and general relativity and their impact on fundamental effects such as decoherence and the emergence of a classical world. PMID- 26249231 TI - EBOLA VACCINE. VSV-EBOV rapidly protects macaques against infection with the 2014/15 Ebola virus outbreak strain. AB - The latest Ebola virus (EBOV) epidemic spread rapidly through Guinea, Sierra Leone, and Liberia, creating a global public health crisis and accelerating the assessment of experimental therapeutics and vaccines in clinical trials. One of those vaccines is based on recombinant vesicular stomatitis virus expressing the EBOV glycoprotein (VSV-EBOV), a live-attenuated vector with marked preclinical efficacy. Here, we provide the preclinical proof that VSV-EBOV completely protects macaques against lethal challenge with the West African EBOV-Makona strain. Complete and partial protection was achieved with a single dose given as late as 7 and 3 days before challenge, respectively. This indicates that VSV-EBOV may protect humans against EBOV infections in West Africa with relatively short time to immunity, promoting its use for immediate public health responses. PMID- 26249232 TI - Safety, Tolerability, and Pharmacokinetic Profile of the Novel Translocator Protein 18 kDa Antagonist ONO-2952 in Healthy Volunteers. AB - PURPOSE: To investigate safety, tolerability, and pharmacokinetic properties of single and multiple doses of novel translocator protein 18 kDa antagonist ONO 2952 in healthy subjects. METHODS: Double-blind, placebo-controlled single (SAD) and multiple (MAD) dose escalation studies were conducted. Healthy men and women aged 18 to 55 years inclusive and without history of psychiatric disorders were eligible. Forty-eight volunteers received single doses of ONO-2952 (3, 10, 30, 100, 200, or 400 mg) or placebo under fasted conditions (SAD study), and 36 received ONO-2952 (30, 60, or 100 mg/d) or placebo for 21 consecutive days under fed conditions (MAD study). ONO-2952 10 and 200 mg were administered under fasted and fed conditions in the SAD study to investigate the effect of food on the absorption of ONO-2952. Safety assessments included adverse events, vital signs, 12-lead ECGs, and clinical laboratory evaluations. Plasma and urine pharmacokinetic profiles of ONO-2952 were determined. FINDINGS: Across both studies, mean age ranged from 29.8 to 39.8 years, most participants were white, and the proportion of female volunteers was 52%. No treatment or dose-related trends in adverse events were observed. The most frequent adverse events were headache and presyncope (n = 2 each [SAD study]) and constipation and headache (n = 3 each [MAD study]). All headache and constipation episodes were possibly related to the study drug. Plasma ONO-2952 concentrations peaked 2.5 to 3.5 hours (SAD study) and 3.0 to 4.0 hours (MAD study) postdose. ONO-2952 systemic exposure increased less than dose proportionally under fasted conditions. Fed conditions significantly increased exposure compared with fasted conditions: geometric mean ratios of Cmax (90% CIs) were 229% (176-299 [10 mg]) and 778% (623-971 [200 mg]), and AUClast were 159% (131-192 [10 mg]) and 382% (288-506 [200 mg]). In the MAD study, the systemic exposure of ONO-2952 increased in a slightly greater than dose-proportional manner. Geometric mean accumulation ratios (95% CI) of AUC24 were 2.50 (2.09-2.98 [30 mg]), 2.23 (1.85-2.68 [60 mg]), and 2.73 (2.10-3.55 [100 mg]); and Cmax were 1.65 (1.43-1.90 [30 mg]), 1.56 (1.31-1.85 [60 mg]), and 1.85 (1.38-2.49 [100 mg]). IMPLICATIONS: ONO-2952 was safe and well tolerated in these early clinical studies investigating safety, tolerability, and pharmacokinetic properties of single and multiple doses. ONO-2952 systemic exposure increased in a less than dose-proportional manner under fasted conditions and in a slightly greater than dose-proportional manner under fed conditions. These results support the progression of ONO-2952 to further studies in humans. SAD study: ClinicalTials.gov identifier: NCT01364441. MAD study: ClinicalTrials.gov identifier: NCT01489345. PMID- 26249233 TI - Outcome of Donor Cats After Unilateral Nephrectomy as Part of a Clinical Kidney Transplant Program. AB - OBJECTIVE: To compare 1) complications between 2 ureteral harvest techniques (ureteral papilla harvest [UPH] and ureteral transection [UT]); 2) to investigate the prevalence of kidney failure in a population of kidney donors; and 3) to evaluate owner satisfaction with commercially sourced cats adopted after kidney donation. STUDY DESIGN: Retrospective case series. ANIMALS: Cats (n = 72) that had unilateral nephrectomy for kidney donation. METHODS: Medical records were reviewed and information on short- and long-term complications and evidence of kidney failure was recorded. Clients were interviewed by telephone to ascertain their satisfaction with the adopted donor cats as pets. RESULTS: Seventy-two cats had unilateral nephrectomy. Forty-two owners were able to be contacted for survey data. Twenty-eight cats had complete medical records including serum BUN, creatinine, and urine specific gravity. For these 28 cats, mean age at nephrectomy was 1.9 years (median, 1.1 years; range, 0.5-9.3 years) and mean age at follow-up was 6.8 years (median, 5.1 years; range, 1.0-18.7 years). There was no difference in major or minor complication rates between UPH and UT techniques. Kidney failure occurred in 17.8% of cats. All owners were satisfied with the adopted donor cats, which were obtained from commercial facilities. CONCLUSIONS: UPH is a safe technique in cats being used for kidney donation. Commercially sourced cats make suitable pets after kidney donation. The prevalence of kidney failure in the donor population appears to be higher than that in the general population, but definitive conclusions cannot be made based on this study. Further, prospective study is needed to identify the true prevalence of kidney failure in cats after unilateral nephrectomy. PMID- 26249230 TI - Global diversity, population stratification, and selection of human copy-number variation. AB - In order to explore the diversity and selective signatures of duplication and deletion human copy-number variants (CNVs), we sequenced 236 individuals from 125 distinct human populations. We observed that duplications exhibit fundamentally different population genetic and selective signatures than deletions and are more likely to be stratified between human populations. Through reconstruction of the ancestral human genome, we identify megabases of DNA lost in different human lineages and pinpoint large duplications that introgressed from the extinct Denisova lineage now found at high frequency exclusively in Oceanic populations. We find that the proportion of CNV base pairs to single-nucleotide-variant base pairs is greater among non-Africans than it is among African populations, but we conclude that this difference is likely due to unique aspects of non-African population history as opposed to differences in CNV load. PMID- 26249234 TI - Tunable emission, energy transfer and charge compensation in SrMoO4:Sm(3+),Tb(3+),Na(+) phosphor. AB - A series of SrMoO4:Sm(3+),Tb(3+),Na(+) phosphors was synthesized using a high temperature solid-state reaction method in air. On excitation at 290 nm, SrMoO4:Sm(3+),Tb(3+) phosphor emitted light that varied systematically from green to reddish-orange on changing the Sm(3+) and Tb(3+) ion concentrations. The emission intensities of SrMoO4:Sm(3+) and SrMoO4:Sm(3+),Tb(3+) phosphors were increased two to four times due to charge compensation when Na(+) was added as a charge compensator. The luminescence mechanism and energy transfer could be explained using energy-level diagrams of the MoO4(2-) group, Sm(3+) and Tb(3+) ions. SrMoO4:Sm(3+),Tb(3+),Na(+) could be used as reddish-orange phosphor in white light-emitting diodes (LEDs) based on an ~ 405 nm near-UV LED chip. This research is helpful in adjusting and improving the luminescence properties of other phosphors. PMID- 26249235 TI - Robotic versus laparoscopic sacrocolpopexy for treatment of prolapse of the apical segment of the vagina: a systematic review and meta-analysis. AB - INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse shows an increasing prevalence (3-50 %). The gold standard treatment for apical prolapse is sacrocolpopexy, which can be performed via minimal access (conventional laparoscopy or robotic surgery) or open sacrocolpopexy. The objective is to appraise the effectiveness and safety of robotic surgery compared with laparoscopic sacropexy in the treatment of apical prolapse. METHODS: Keywords were searched in: CINAHL, MEDLINE, CENTRAL, Cochrane MDSG Trials Register, Cochrane Library, Current Controlled Trials, ClinicalTrials.gov, WHO International Trials Registry Platform search portal, LILACS, and Google Scholar. A hand-search was also performed from IUJ and JMIG. Randomised and non-randomised controlled trials evaluating all women who underwent robotic sacropexy (RSC) or laparoscopic sacropexy (LSC) were included. A data extraction tool was used for data collection. RSC was compared with LSC. Narrative analysis and meta-analysis (RevMan) were conducted where appropriate. RESULTS: Nine papers compared RSC with LSC, involving 1,157 subjects. No significant difference was found between approaches for anatomical outcomes, mortality, hospital stay (MD: -0.72/95 % CI 1.72, 0.28], p = 0.16), and postoperative quality of life. However, robotic sacropexy had more postoperative pain and longer operating times, although fewer overall complications when performed concomitantly with hysterectomy (OR 0.35; 95 % CI 0.19-0.64). CONCLUSIONS: Robotic sacropexy was related to more postoperative pain and longer operating times. However, no significant differences were found regarding anatomical outcomes, mortality, hospital stay or postoperative quality of life. Cautious interpretation of results is advised because of the risk of bias caused by the inclusion of non-randomised studies. More research comparing RSC with LSC is mandatory, particularly draw conclusions regarding estimated blood loss and complication rate. PMID- 26249236 TI - Laparoscopic versus open sacrocolpopexy for treatment of prolapse of the apical segment of the vagina: a systematic review and meta-analysis. AB - INTRODUCTION: Pelvic organ prolapse is showing an increasing prevalence (3 - 50%). The gold standard treatment of apical prolapse is sacrocolpopexy which can be performed via minimal access (laparoscopy or robotics) or open approaches. The aim of this review was to appraise the effectiveness of minimal access surgery versus the open approach in the treatment of apical prolapse. METHODS: Keywords were searched in: CINAHL, MEDLINE, CENTRAL, Cochrane MDSG Trials Register, Cochrane Library, Current Controlled Trials, ClinicalTrials.gov, WHO International Trials Registry Platform search portal, LILACS, and Google Scholar databases. Data up to 31 April 2014 were considered. Randomized and nonrandomized controlled trials evaluating all women who underwent minimally invasive sacropexy (MISC) and open sacropexy (OSC) were included. A data extraction tool was used for data collection. MISC was compared with OSC using narrative analysis and meta analysis (RevMan) where appropriate. RESULTS: MISC and OSC were compared in 12 studies involving 4,757 participants. MISC and OSC were equally effective in terms of point-C POP-Q measurements and recurrence rate. MISC was associated with a lower transfusion rate (odds ratio 0.41, 95% CI 0.20 - 0.83), shorter length of hospital stay (mean difference -1.57 days, 95% CI -1.91 - -1.23 days), and less blood loss (mean difference -113.27 mL, 95% CI -163.67 - -62.87 mL) but a longer operating time (mean difference 87.47, 95% CI 58.60 - 116.34, p < 0.0001). CONCLUSIONS: MISC showed similar anatomic results to OSC with a lower transfusion rate, shorter length of hospital stay and less blood loss. The rate of other complications was similar between the approaches. Cautious interpretation of results is advised due to risk of bias caused by the inclusion of nonrandomized studies. PMID- 26249237 TI - The association between different measures of pelvic floor muscle function and female pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: We aimed to compare palpatory and translabial ultrasound (TLUS) measurements of pelvic floor muscle (PFM) function with symptoms and signs of female pelvic organ prolapse (FPOP) to determine a possible association. METHODS: We analysed data from 726 women with a mean age of 56 (SD 13.7, range 18-88) years, seen for symptoms of pelvic floor dysfunction between August 2011 and April 2013. The examination included a standardised interview and clinical assessment of FPOP with Pelvic Organ Prolapse Quantification (POP-Q) measurements, Modified Oxford Scale (MOS) grading and 4D TLUS. RESULTS: Symptoms of prolapse were reported in 51.4% (373 out of 726) with a mean bother score of 5.8 (SD 2.91, range 0-10). A clinically significant POP (Incontinence Society [ICS]-POP-Q stage >= 2) in any compartment was diagnosed in 77.1%. Mean MOS was 2.4 (SD 1.1, range 0-5). Significant POP on TLUS was seen in 54.6% (389 out of 712). TLUS volumes at rest and on maximal PFM contraction were analysed on a desktop PC, to assess the degree of bladder neck (BN) cranioventral shift and levator antero-posterior (AP) diameter reduction, blinded against other data. Mean cranioventral BN shift was 7.11 (SD 4.36, range 0.32-25.32) mm and mean levator AP diameter reduction was 8.6 (SD 4.8, range 0.3-31.3) mm. MOS was strongly associated with subjective and objective POP (P <= 0.001), whereas this was not true for TLUS measurements of tissue displacement. CONCLUSION: The MOS seems to be a more valid measure of PFM function than sonographically determined BN displacement or reduction of hiatal AP diameter observed on PFM contraction. PMID- 26249238 TI - Martius graft for TOT extrusion: a case series. AB - INTRODUCTION: The management of mid-urethral tape extrusion is inconsistent. We believe that we present here the first case series detailing the use of the Martius graft for trans-obturator tape (TOT) extrusion. METHODS: Five women had a Martius graft for TOT extrusion. Data were obtained retrospectively from case notes and a review postoperatively to investigate the results in the short and intermediate term. RESULTS: All extrusions were greater than 1 cm in diameter and situated between the midline and the lateral vaginal sulcus. In 3 women the tape extrusion was discovered at 6-12 weeks postoperatively and 2 presented with symptoms again after 12 months. Following the Martius graft, there was no ipsilateral recurrence of tape extrusion or exposure. Postoperatively, 2 women received oral antibiotics. Two women developed de novo sexual problems, which had resolved at follow-up. CONCLUSIONS: It is promising that all the tape extrusions were successfully treated with a Martius Graft, thus preserving tape function. There was a high incidence of minor complications initially, but there was minimal long-term morbidity and no cosmetic dissatisfaction. We believe that testing this proposition in a larger case series will provide better evidence. PMID- 26249239 TI - Biocatalytic Feedback-Driven Temporal Programming of Self-Regulating Peptide Hydrogels. AB - Switchable self-assemblies respond to external stimuli with a transition between near-equilibrium states. Although being a key to present-day advanced materials, these systems respond rather passively, and do not display autonomous dynamics. For autonomous behavior, approaches must be found to orchestrate the time domain of self-assemblies, which would lead to new generations of dynamic and self regulating materials. Herein, we demonstrate catalytic control of the time domain of pH-responsive peptide hydrogelators in a closed system. We program transient acidic pH states by combining a fast acidic activator with the slow, enzymatic, feedback-driven generation of a base (dormant deactivator). This transient state can be programmed over orders of magnitude in time. It is coupled to dipeptides to create autonomously self-regulating, dynamic gels with programmed lifetimes, which are used for fluidic guidance, burst release, and self-erasing rapid prototyping. PMID- 26249240 TI - Inter-/Intra-observer Reliability of Hand Assessment Using Skin Detail: A Count based Method. AB - Skin detail of the hand is used in photographic comparisons, yet its reliability has not been evaluated. This study examines a count-based method for documenting skin features. In Part I, 14 individuals counted skin features on 40 color images of the hand, three of which were repeated. An average correlation value of 0.557 was obtained for interobserver assessment; values ranged from 0.545 to 0.832 for intra-observer assessment. The variation in correlation values for hands suggests that there are certain distinguishing characteristics that increase reliability. In Part II, 17 examiners assessed 20 nonrepeated grayscale images of hands by circling skin features. An average correlation value of 0.674 was obtained, but visual assessment of examiner markings suggested some examiners grouped features whereas others viewed them individually. The results suggest further research is warranted, some hands may be more suitable for comparisons, and a standardized method for examining skin features is needed. PMID- 26249241 TI - Risk stratification in patients with advanced-stage breast cancer by pretreatment [(18) F]FDG PET/CT. AB - BACKGROUND: The objective of the current study was to investigate the prognostic value of pretreatment [(18) F] fluorodeoxyglucose position emission tomography/computed tomography ([(18) F]FDG PET/CT) in patients with advanced stage breast cancer. METHODS: Pretreatment PET/CT scans from 240 consecutive patients with American Joint Committee on Cancer stage III or stage IV BC were analyzed retrospectively. Clinicopathological factors and metabolic parameters of the primary tumor including maximum standardized uptake value (SUVmax ), metabolic tumor volume, and total lesion glycolysis (TLG) with a range of thresholds were compared to predict progression-free survival (PFS) and overall survival (OS) using a time-dependent receiver operating characteristic curve and Cox proportional hazards regression analyses. RESULTS: SUVmax with a cutoff value of 6.0, TLG30% with a cutoff value of 158 g, and phenotype associated with PFS and OS were analyzed using multivariate analysis. The mean TLG30% of primary tumors for patients with stage III and stage IV disease was 405 g and 750 g (P = .010), respectively. Patients with triple-negative breast cancer or a TLG30% >158 g or with both were categorized as being at high risk, and those with non-triple negative breast cancer and a primary tumor with a TLG30% <=158 g were defined as low risk. The 5-year PFS rates for stage III disease among patients with low-risk versus high-risk BC were 85% and 67.5%, respectively. For patients with stage IV disease, the 5-year PFS rates were 45% and 9%, respectively, for patients with low-risk versus high-risk disease. Patients with stage III and high-risk BC had OS rates that were similar to those for patients with stage IV and low-risk BC (P = .552). CONCLUSIONS: The TLG30% from pretreatment PET/CT was found to independently correlate with survival outcomes and appears to be able to effectively stratify both patients with stage III and those with stage IV BC. PMID- 26249242 TI - The Use of Hebbian Cell Assemblies for Nonlinear Computation. AB - When learning a complex task our nervous system self-organizes large groups of neurons into coherent dynamic activity patterns. During this, a network with multiple, simultaneously active, and computationally powerful cell assemblies is created. How such ordered structures are formed while preserving a rich diversity of neural dynamics needed for computation is still unknown. Here we show that the combination of synaptic plasticity with the slower process of synaptic scaling achieves (i) the formation of cell assemblies and (ii) enhances the diversity of neural dynamics facilitating the learning of complex calculations. Due to synaptic scaling the dynamics of different cell assemblies do not interfere with each other. As a consequence, this type of self-organization allows executing a difficult, six degrees of freedom, manipulation task with a robot where assemblies need to learn computing complex non-linear transforms and - for execution - must cooperate with each other without interference. This mechanism, thus, permits the self-organization of computationally powerful sub-structures in dynamic networks for behavior control. PMID- 26249243 TI - PCR-based prevalence of a fatal reovirus of the blue crab, Callinectes sapidus (Rathbun) along the northern Atlantic coast of the USA. AB - There is a need for more information on the relationship between diseases and fluctuations of wild populations of marine animals. In the case of Callinectes sapidus reovirus 1 (CsRV1, also known as RLV), there is a lack of baseline information on range, prevalence and outbreaks, from which to develop an understanding of population-level impacts. An RT-qPCR assay was developed that is capable of detecting 10 copies of the CsRV1 genome. In collaboration with state, federal and academic partners, blue crabs were collected from sites throughout the north-eastern United States to assess the northern range of this pathogen. In addition, archived crab samples from the Chesapeake Bay were assessed for CsRV1 by RT-qPCR and histology. PCR-based assessments indicate that CsRV1 was present at all but one site. Prevalence of CsRV1 as assessed by RT-qPCR was highly variable between locations, and CsRV1 prevalence varied between years at a given location. Mean CsRV1 prevalence as assessed by RT-qPCR was >15% each year, and peak prevalence was 79%. The wide geographic range and highly variable prevalence of CsRV1 indicate that more study is needed to understand CsRV1 dynamics and the role the virus plays in blue crab natural mortality. PMID- 26249244 TI - MGMT inactivation and clinical response in newly diagnosed GBM patients treated with Gliadel. AB - We examined the relationship between the O(6)-methylguanine-methyltransferase (MGMT) methylation status and clinical outcomes in newly diagnosed glioblastoma multiforme (GBM) patients who were treated with Gliadel wafers (Eisai, Tokyo, Japan). MGMT promoter methylation has been associated with increased survival among patients with GBM who are treated with various alkylating agents. MGMT promoter methylation, in DNA from 122 of 160 newly diagnosed GBM patients treated with Gliadel, was determined by a quantitative methylation-specific polymerase chain reaction, and was correlated with overall survival (OS) and recurrence-free survival (RFS). The MGMT promoter was methylated in 40 (32.7%) of 122 patients. The median OS was 13.5 months (95% confidence interval [CI] 11.0-14.5) and RFS was 9.4 months (95% CI 7.8-10.2). After adjusting for age, Karnofsky performance score, extent of resection, temozolomide (TMZ) and radiation therapy (RT), the newly diagnosed GBM patients with MGMT methylation had a 15% reduced mortality risk, compared to patients with unmethylated MGMT (hazard ratio 0.85; 95% CI 0.56 1.31; p=0.46). The patients aged over 70 years with MGMT methylation had a significantly longer median OS of 13.5 months, compared to 7.6 months in patients with unmethylated MGMT (p=0.027). A significant difference was also found in older patients, with a median RFS of 13.1 versus 7.6 months for methylated and unmethylated MGMT groups, respectively (p=0.01). Methylation of the MGMT promoter in newly diagnosed GBM patients treated with Gliadel, RT and TMZ, was associated with significantly improved OS compared to the unmethylated population. In elderly patients, methylation of the MGMT promoter was associated with significantly better OS and RFS. PMID- 26249245 TI - Awake craniotomy using electromagnetic navigation technology without rigid pin fixation. AB - We report our institutional experience using an electromagnetic navigation system, without rigid head fixation, for awake craniotomy patients. The StealthStation(r) S7 AxiEMTM navigation system (Medtronic, Inc.) was used for this technique. Detailed preoperative clinical and neuropsychological evaluations, patient education and contrast-enhanced MRI (thickness 1.5mm) were performed for each patient. The AxiEM Mobile Emitter was typically placed in a holder, which was mounted to the operating room table, and a non-invasive patient tracker was used as the patient reference device. A monitored conscious sedation technique was used in all awake craniotomy patients, and the AxiEM Navigation Pointer was used for navigation during the procedure. This offers the same accuracy as optical navigation, but without head pin fixation or interference with intraoperative neurophysiological techniques and surgical instruments. The application of the electromagnetic neuronavigation technology without rigid head fixation during an awake craniotomy is accurate, and offers superior patient comfort. It is recommended as an effective adjunctive technique for the conduct of awake surgery. PMID- 26249246 TI - Merosin-deficient congenital muscular dystrophy: A novel homozygous mutation in the laminin-2 gene. AB - Merosin deficient congenital muscular dystrophy (MDC1A) is an autosomal recessive disorder characterized by mutations in the LAMA2 gene at chromosome 6q22-23. This gene spans 65 exons and encodes the alpha2 chain subunit of laminin-2. A variety of deletions, missense, nonsense and splice site mutations have been described in the LAMA2 gene, with resultant MDC1A. We describe a novel LAMA2 homozygous sequence variant in a Samoan patient with MDC1A and confirm its pathogenic effect with merosin immunohistochemistry on skeletal muscle biopsy. The likely effect of the sequence variant is modeled using in silico analysis. PMID- 26249247 TI - Cognitive neuroscience goes social. PMID- 26249248 TI - Planning for Travel With Children in the Modern World. PMID- 26249249 TI - Political consumer behaviour among university students in Brazil and Germany: The role of contextual features and core political values. AB - This study investigates the relationship between political consumerism and core political values (CPVs) among university students in Brazil (N = 414) and Germany (N = 222). Despite the prerequisite to endorse values that are compatible with political consumerism, contextual features of one's immediate environment might affect overall levels of political consumerism. Our results show that political consumerism is significantly associated with higher income in Brazil (but not in Germany). After controlling for income, political consumerism was practised more frequently in Germany than in Brazil, in urban compared with rural areas, and was not dependent on gender. The urban-rural split was stronger in Brazil than in Germany. These results confirm our hypothesis that contextual features are associated with political consumerism. Furthermore, the political value Equality positively predicted political consumerism in both countries. In contrast, Traditional Morality and support of Free Enterprise negatively predicted political consumerism, although the effect sizes of these relationships were only small. These results suggest that political consumerism among university students is widespread in Germany but not in Brazil. Interestingly, regardless of its low prevalence in Brazil, political consumerism is positively associated with the CPV of Equality among university students in both countries. PMID- 26249250 TI - Lithium toxicity in a neonate owing to false elevation of blood lithium levels caused by contamination in a lithium heparin container: case report and review of the literature. AB - Lithium toxicity in a neonate can occur owing to antenatal exposure as a result of maternal treatment for psychiatric illnesses. False elevation of lithium levels has been reported in the paediatric population when the sample was mistakenly collected in a lithium heparin container. A term, male infant was born to a mother who was on lithium treatment for a psychiatric illness. On day 1, the infant was jittery, had a poor suck with difficulties in establishing feeds. Blood taken from the infant approximately 8 hours after birth demonstrated a lithium level of 4.9 mmol/L (adult toxic level w1.5 mmol/L). However, the sample for lithium levels was sent in a lithium heparin container and the probability of false elevation was considered. He was closely monitored in the neonatal intensive care unit and his hydration was optimised with intravenous fluids. Clinically, he remained well and commenced feeding, and his jitteriness had decreased the following day. A repeat blood lithium level, collected in a gel container, was only 0.4 mmol/L. The initially raised lithium level was owing to contamination from the lithium heparin container. PMID- 26249252 TI - Place of Death: Trends Over the Course of a Decade: A Population-Based Study of Death Certificates From the Years 2001 and 2011. AB - BACKGROUND: In Germany, data on place of death is recorded from death certificates, but not further analyzed. Consequently, hardly any information is available at the population level regarding the distribution of place of death (e.g. home, hospital, palliative care unit, nursing home, hospice). METHODS: We carried out a descriptive statistical analysis of the registered places of death in evaluated death certificates from selected areas of Westphalia-Lippe for the years 2001 and 2011. Factors affecting the place of death were determined with binary multivariate regression. RESULTS: We analyzed 24 009 death certificates (11 585 for 2001 and 12 424 for 2011). The distribution of places of death for the overall population was as follows (2001 vs. 2011): at home, 27.5% vs. 23.0% (p<0.001); in the hospital, 57.6% vs. 51.2% (p<0.001); on a palliative care unit, 0.0% vs. 1.0%, in a care or nursing home, 12.2% vs. 19.0% (p<0.001); in a hospice, 2.0% vs. 4.6% (p<0.001); elsewhere, 0.6% vs. 0.6% (p = 0.985); not indicated, 0.1% vs. 0.6% (p<0.001). Independent factors affecting the place of death were age, sex, place of residence, and the presence of cancer or of dementia. CONCLUSION: Most people in Germany die in institutions; the most common place of death is still the hospital, where more than half of all deaths take place. Only one death in four occurs at home. There is a marked secular trend away from dying at home or in the hospital, in favor of dying in a care or nursing home; death in palliative care units and hospices is also becoming more common. PMID- 26249253 TI - Platelet Transfusion and Hemorrhage. PMID- 26249251 TI - Indications for and Risks of Elective Cesarean Section. AB - BACKGROUND: Rates of cesarean section have risen around the world in recent years. Accordingly, much effort is being made worldwide to understand this trend and to counteract it effectively. A number of factors have been found to make it more likely that a cesarean section will be chosen, but the risks cannot yet be clearly defined. METHODS: This review is based on pertinent publications that were retrieved by a selective search in the PubMed, Scopus, and DIMDI databases, as well as on media communications, analyses by the German Federal Statistical Office, and guidelines of the Association of Scientific Medical Societies in Germany (AWMF). RESULTS: The increased rates of cesarean section are thought to be due mainly to changed risk profiles both for expectant mothers and for their yet unborn children, as well as an increase in cesarean section by maternal request. In 1991, 15.3% of all newborn babies in Germany were delivered by cesarean section; by 2012, the corresponding figure was 31.7%, despite the fact that a medical indication was present in less than 10% of all cases. This development may perhaps be explained by an increasing tendency toward risk avoidance, by risk-adapted obstetric practice, and increasing media attention. The intraoperative and postoperative risks of cesarean section must be considered, along with complications potentially affecting subsequent pregnancies. CONCLUSION: Scientific advances, social and cultural changes, and medicolegal considerations seem to be the main reasons for the increased acceptibility of cesarean sections. Cesarean section is, however, associated with increased risks to both mother and child. It should only be performed when it is clearly advantageous. PMID- 26249254 TI - Exemption: Promyelocytic Leukemia. PMID- 26249255 TI - In Reply. PMID- 26249256 TI - Transfusion of Packed Red Cells: Indications, Triggers and Adverse Events. AB - BACKGROUND: About four million units of packed red cells are transfused in Germany every year. The safety of blood transfusions is further improved by modern production methods and molecular diagnostic techniques. METHODS: This review is based on selected publications,including the German guidelines and regulations and the German Transfusion Act. RESULTS: Packed red blood cells are transfused to prevent tissue hypoxia. As the clinical manifestations of anemia are nonspecific, the indication for transfusion is based on surrogate parameters, such as the hemoglobin (Hb) concentration, in addition to clinical criteria. For patients with unimpaired cardiopulmonary and vascular function, transfusion is generally indicated at hemoglobin values of 6 g/dL (3.7 mmol/L) or less. Randomized controlled trials have shown that a restrictive transfusion strategy (trigger: Hb 7-8 g/dL) in certain patient groups is as effective as a more liberal strategy (trigger: Hb about 10 g/dL). The most frequent causes for transfusion errors are lack of informed consent, lack of identity checking and/or AB0 identity testing, and the drawing of blood samples in unlabelled tubes. CONCLUSION: Overtransfusion, undertransfusion, as well as other transfusion errors can be markedly reduced by means of appropriate organizational measures and training. PMID- 26249257 TI - Post-operative infection of endoscopic submucosal dissection of early colorectal neoplasms: a case-controlled study using a Japanese database. AB - WHAT IS KNOWN AND OBJECTIVE: Endoscopic submucosal dissection of early colorectal neoplasms (ESD-ECN) is known to be an operation with risk of contamination, possibly requiring pre-operative antimicrobial prophylaxis for the prevention of post-operative infection. However, an evaluation of the need for pre-operative antimicrobial prophylaxis for ESD-ECN has yet to be reported. The objective of this study was to determine whether pre-operative antimicrobial prophylaxis is associated with a reduced incidence of post-operative infection following ESD ECN. METHODS: The present retrospective case-controlled study utilized a database built from the medical records of 14 university hospitals throughout Japan. Patients who were admitted and discharged from the hospital from April 2012 to October 2013 and who had undergone ESD-ECN were included in the study. Patients who had been undergone any other operation during their course of hospitalization, and patients who were prescribed antimicrobial agents for reasons other than post-operative infection or for prophylaxis were excluded. Characteristics of the study population, pre-operative antimicrobial prophylaxis and antimicrobial therapy for post-operative infection were investigated. In addition, we compared the characteristics of patients with post-operative infection (PI) and those with no post-operative infection (NPI). Univariate analyses were used to estimate the odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS AND DISCUSSION: We obtained the records of 522 patients who had undergone ESD-ECN from the database. After application of exclusion criteria, 421 patients were enrolled. The post-operative infection rate was 1.2%. Peritonitis was found most to be the most common post-operative infection (44%). Pre operative antimicrobial prophylaxis was used for 314 patients (75%), with a median duration of 3.0 (range 1-11) days. Cefotiam was most frequently prescribed for pre-operative antimicrobial prophylaxis (56%). Antimicrobial therapies were started 1-10 days after ESD-ECN for a duration of 1-14 days. Pre-operative antimicrobial prophylaxis was not associated with post-operative infection rate, with an OR (95% CI) of 0.73 (0.08-6.61). However, digestive tract perforation was shown to be associated with post-operative infection and had an OR (95% CI) of 17.1 (1.66-176.45). WHAT IS NEW AND CONCLUSION: Post-operative infection is an exceedingly rare event following ESD-ECN. Pre-operative antimicrobial prophylaxis had no significant effect on post-operative infection following ESD-ECN and thus may be unnecessary. Instead, prevention of digestive tract perforation may be more critical for the decrease in post-operative infections. PMID- 26249259 TI - Personality Correlates of Midlife Cardiometabolic Risk: The Explanatory Role of Higher-Order Factors of the Five-Factor Model. AB - Varying associations are reported between Five-Factor Model (FFM) personality traits and cardiovascular disease risk. Here, we further examine dispositional correlates of cardiometabolic risk within a hierarchical model of personality that proposes higher-order traits of Stability (shared variance of Agreeableness, Conscientiousness, inverse Neuroticism) and Plasticity (Extraversion, Openness), and we test hypothesized mediation via biological and behavioral factors. In an observational study of 856 community volunteers aged 30-54 years (46% male, 86% Caucasian), latent variable FFM traits (using multiple-informant reports) and aggregated cardiometabolic risk (indicators: insulin resistance, dyslipidemia, blood pressure, adiposity) were estimated using confirmatory factor analysis (CFA). The cardiometabolic factor was regressed on each personality factor or higher-order trait. Cross-sectional indirect effects via systemic inflammation, cardiac autonomic control, and physical activity were tested. CFA models confirmed the Stability "meta-trait," but not Plasticity. Lower Stability was associated with heightened cardiometabolic risk. This association was accounted for by inflammation, autonomic function, and physical activity. Among FFM traits, only Openness was associated with risk over and above Stability, and, unlike Stability, this relationship was unexplained by the intervening variables. A Stability meta-trait covaries with midlife cardiometabolic risk, and this association is accounted for by three candidate biological and behavioral factors. PMID- 26249260 TI - A mutation in TRPV4 results in altered chondrocyte calcium signaling in severe metatropic dysplasia. AB - Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is a polymodal modulated non-selective cation channel required for normal development and maintenance of bone and cartilage. Heterozygous mutations of this channel cause a variety of channelopathies, including metatropic dysplasia (MD). We analyzed the effect of a novel TRPV4 mutation c.2398G>A, p.Gly800Asp on intracellular calcium ([Ca(2+) ]i ) regulation in chondrocytes and compared this response to chondrocytes with a frequently observed mutation, c.2396C>T, p.Pro799Leu. We observed temperature-dependent [Ca(2+) ]i oscillations in both intact and MD chondrocytes however, MD mutations exhibited increased peak magnitudes of [Ca(2+) ]i during oscillations. We also found increased baseline [Ca(2+) ]i in MD primary cells, as well as increased [Ca(2+) ]i response to either hypotonic swelling or the TRVP4-specific agonist, GSK1016790A. Oscillations and stimulation responses were blocked with the TRPV4-specific antagonist, GSK205. Analysis of [Ca(2+) ]i response kinetics showed that MD chondrocytes had increased frequency of temperature-sensitive oscillations, and the magnitude and duration of [Ca(2+) ]i responses to given stimuli. Duration of the response of the p.Gly800Asp mutation to stimulation was greater than for the p.Pro799Leu mutation. These experiments show that this region of the channel is essential for proper [Ca(2+) ]i regulation. These studies of primary cells from patients show how both mutant and WT TRPV4 channels regulate cartilage and bone development. (c) 2015 Wiley Periodicals, Inc. PMID- 26249261 TI - Brief Report: Patterns of Eye Movements in Face to Face Conversation are Associated with Autistic Traits: Evidence from a Student Sample. AB - The current study investigated whether the amount of autistic traits shown by an individual is associated with viewing behaviour during a face-to-face interaction. The eye movements of 36 neurotypical university students were recorded using a mobile eye-tracking device. High amounts of autistic traits were neither associated with reduced looking to the social partner overall, nor with reduced looking to the face. However, individuals who were high in autistic traits exhibited reduced visual exploration during the face-to-face interaction overall, as demonstrated by shorter and less frequent saccades. Visual exploration was not related to social anxiety. This study suggests that there are systematic individual differences in visual exploration during social interactions and these are related to amount of autistic traits. PMID- 26249262 TI - Acute kidney injury after orthotopic liver transplantation using living donor versus deceased donor grafts: A propensity score-matched analysis. PMID- 26249263 TI - Impact of obstetric factors on outcome of extremely preterm births in Sweden: prospective population-based observational study (EXPRESS). AB - INTRODUCTION: A population-based observational study investigated the contribution of obstetric factors to the survival and postnatal development of extremely preterm infants. MATERIAL AND METHODS: Mortality up to 1 year and neurodevelopment at 2.5 years (Bayley-III test, cerebral palsy, vision, hearing) were evaluated in infants born before 27 weeks of gestation in Sweden 2004-2007 (n = 1011), using logistic regression analyses of risk factors. RESULTS: Of 844 fetuses alive at admission, 8.4% died in utero before labor, 7.8% died intrapartum. Of 707 live-born infants, 15% died within 24 h, 70% survived >=365 days, 64% were assessed at 2.5 years. The risk of death within 24 h after birth decreased with gestational age [odds ratio (OR) 0.3; 95% CI 0.2-0.4], antenatal corticosteroids (OR 0.3; 95% CI 0.1-0.6), and cesarean section (OR 0.4; 95% CI 0.2-0.9); it increased with multiple birth (OR 3.0; 95% CI 1.5-6.0), vaginal breech delivery (OR 2.3; 95% CI 1.0-5.1), 5-min Apgar score <4 (OR 50.4; 95% CI 28.2-90.2), and birth at a level II hospital (OR 2.6; 95% CI 1.2-5.3). The risk of death between 1 and 365 days remained significantly decreased for gestational age and corticosteroids. The risk of mental developmental delay at 2.5 years decreased with gestational age, birthweight and fetal growth; it increased with vaginal breech delivery (OR 2.0; 95% CI 1.2-7.4), male gender, low Apgar score and high Clinical Risk Index for Babies score. CONCLUSION: Several obstetric factors, including abdominal delivery, influenced the risk of death within the first day of life, but not later. Antenatal corticosteroids and gestational age decreased the mortality up to 1 year. Mental developmental delay was related to vaginal breech delivery. PMID- 26249264 TI - QT interval prolongation associated with low magnesium in chronic alcoholics. AB - BACKGROUND: Alcoholism is a psychoactive drug-dependence with high prevalence throughout the world. Alcoholism has already been shown to be associated with electrical heart disorders, such as QT interval prolongation. Long QT, rare among healthy individuals (0.0017-0.31%), can trigger tachyarrhythmias and sudden death and might be caused by alcohol consumption itself and the resulting hypomagnesaemia. METHODS: This case-control study assessed active alcoholics and alcoholics who have been abstinent for at least seven days to compare changes in electrocardiographic, clinical and laboratory analyses among groups. RESULTS: A total of 166 alcoholics were evaluated, of which 62 were active and 104 abstinent alcoholics. Long QT was more prevalent among active alcoholics compared to abstinent alcoholics (16% vs. 2%, respectively, odds ratio (OR) 9.81, p=0.011), as was hypomagnesaemia (23% vs. 10%, OR 3.11, p=0.013). Serum magnesium levels were inversely proportional to the length of the corrected QT interval among active alcoholics (beta=-35.1ms, p=0.005). CONCLUSIONS: Active chronic alcoholics exhibited a higher association of long QT and hypomagnesaemia. Low serum magnesium levels were predictive of QT interval prolongation. Because the above changes potentially trigger fatal arrhythmias, it is of fundamental importance to consider the diagnostic possibility by routinely requesting electrocardiograms and serum magnesium level assessment during the treatment of chronic alcoholic patients. PMID- 26249266 TI - Impaired learning from errors in cannabis users: Dorsal anterior cingulate cortex and hippocampus hypoactivity. AB - BACKGROUND: The chronic use of cannabis has been associated with error processing dysfunction, in particular, hypoactivity in the dorsal anterior cingulate cortex (dACC) during the processing of cognitive errors. Given the role of such activity in influencing post-error adaptive behaviour, we hypothesised that chronic cannabis users would have significantly poorer learning from errors. METHODS: Fifteen chronic cannabis users (four females, mean age=22.40 years, SD=4.29) and 15 control participants (two females, mean age=23.27 years, SD=3.67) were administered a paired associate learning task that enabled participants to learn from their errors, during fMRI data collection. RESULTS: Compared with controls, chronic cannabis users showed (i) a lower recall error-correction rate and (ii) hypoactivity in the dACC and left hippocampus during the processing of error related feedback and re-encoding of the correct response. The difference in error related dACC activation between cannabis users and healthy controls varied as a function of error type, with the control group showing a significantly greater difference between corrected and repeated errors than the cannabis group. CONCLUSIONS: The present results suggest that chronic cannabis users have poorer learning from errors, with the failure to adapt performance associated with hypoactivity in error-related dACC and hippocampal regions. The findings highlight a consequence of performance monitoring dysfunction in drug abuse and the potential consequence this cognitive impairment has for the symptom of failing to learn from negative feedback seen in cannabis and other forms of dependence. PMID- 26249265 TI - Cortical thinness and volume differences associated with marijuana abuse in emerging adults. AB - BACKGROUND: The prevalence of marijuana (MJ) use among youth and its legalization for medical or recreational use has intensified public health endeavors of understanding MJ effects on brain structure and function. Studies indicate that MJ use is related to impaired cognitive performance, and altered functional brain activation and chemistry in adolescents and adults, but MJ effects on brain morphology in emerging adults are less understood. METHODS: Fifteen MJ users (age 21.8+/-3.6, 2 females) and 15 non-user (NU) participants (age 22.3+/-3.5, 2 females) were included, demographically matched on age, education and alcohol use. High-resolution structural MR images were acquired at 3Tesla. Cortical thickness (CT) and volumetric analyses were performed using Freesurfer. A priori regions of interest (ROI) included orbitofrontal and cingulate cortices, amygdala, hippocampus and thalamus. RESULTS: Whole brain CT analysis did not result in significant group differences in a priori ROIs but revealed MJ users had significantly less CT (i.e., thinness) in right fusiform gyrus (rFG) compared to NU (p<0.05). Thalamic volume was significantly smaller in MJ users compared to NU (right, p=0.05; left, p=0.01) and associated with greater non-planning (p<0.01) and overall impulsivity (p=0.04). There were no other group differences. CONCLUSIONS: RFG cortical thinness and smaller thalamic volume in emerging adults is associated with MJ abuse. Furthermore, smaller thalamic volume associated with greater impulsivity contributes to growing evidence that the thalamus is neurobiologically perturbed by MJ use. Collectively, altered thalamic and rFG structural integrity may interfere with their known roles in regulating visuoperceptual and object information processing. PMID- 26249267 TI - IL-33 promotes innate IFN-gamma production and modulates dendritic cell response in LCMV-induced hepatitis in mice. AB - Recent studies have revealed IL-33 as a key factor in promoting antiviral T-cell responses. However, it is less clear as to how IL-33 regulates innate immunity. In this study, we infected wild-type (WT) and IL-33(-/-) mice with lymphocytic choriomeningitis virus and demonstrated an essential role of infection-induced IL 33 expression for robust innate IFN-gamma production in the liver. We first show that IL-33 deficiency resulted in a marked reduction in the number of IFN gamma(+) gammadelta T and NK cells, but an increase in that of IL-17(+) gammadelta T cells at 16 h postinfection. Recombinant IL-33 (rIL-33) treatment could reverse such deficiency via increasing IFN-gamma-producing gammadelta T and NK cells, and inhibiting IL-17(+) gammadelta T cells. We also found that rIL-33 induced type 2 innate lymphoid cells were not involved in T-cell responses and liver injury, since the adoptive transfer of type 2 innate lymphoid cells neither affected the IFN-gamma and TNF-alpha production in T cells, nor liver transferase levels in lymphocytic choriomeningitis virus infected mice. Interestingly, we found that while IL-33 was not required for costimulatory molecule expression, it was critical for DC proliferation and cytokine production. Together, this study highlights an essential role of IL-33 in regulating innate IFN-gamma-production and DC function during viral hepatitis. PMID- 26249269 TI - Design of BODIPY Dyes as Photosensitisers in Multicomponent Catalyst Systems for Light-Driven Hydrogen Production. AB - A study of visible-light-driven hydrogen production using a multicomponent system consisting of different boron dipyrromethene (BODIPY) dyes, triethylamine and [{Pd(PPh3)Cl2}2] from THF/water mixtures is presented. A trio of meso-mesityl BODIPY dyes display the best activities and long-term stabilities of more than ten days with the 2,6-diiodo derivative showing the best performance. PMID- 26249270 TI - [How life passes by, and how years fly]. PMID- 26249268 TI - Central role of neutrophil in the pathogenesis of severe acute pancreatitis. AB - Severe acute pancreatitis (SAP) is an acute abdominal disease with the strong systemic inflammatory response, and rapidly progresses from a local pancreatic damage into multiple organ dysfunction. For many decades, the contributions of neutrophils to the pathology of SAP were traditionally thought to be the chemokine and cytokine cascades that accompany inflammation. In this review, we focus mainly on those recently recognized aspects of neutrophils in SAP processes. First, emerging evidence suggests that therapeutic interventions targeting neutrophils significantly lower tissue damage and protect against the occurrence of pancreatitis. Second, trypsin activation promotes the initial neutrophils recruitment into local pancreas, and subsequently neutrophils infiltration in turn triggers trypsin production. Finally, neutrophils have the unique ability to release neutrophil extracellular traps even in the absence of pathogens. PMID- 26249271 TI - Chiasmatic cavernoma haemorrhage: To treat or not to treat? Concerning a clinical case. AB - We present the case of a 43-year-old man with acute visual loss due to an optic chiasm cavernoma. Our clinical and imaging findings quickly led us to this diagnosis. As a clinical improvement spontaneously occurred soon after the initial diagnosis, we decided not to perform any surgical treatment. The visual evolution was satisfactory and, to date after a 36-months follow-up, no clinical worsening has been reported. We present this clinical case regarding our approach, primarily a close follow-up, as well as a review of the literature. PMID- 26249272 TI - Minimally invasive transmuscular approach for the treatment of benign intradural extramedullary spinal cord tumours: Technical note and results. AB - BACKGROUND: Minimally invasive surgery has expanded over the past two decades and was initially used for the treatment of lumbar disc herniation. Later, this approach was used to treat other spine pathologies, as well as to perform spinal fusion and extended spinal decompression. In this study, we report our experience regarding the use of a minimal surgical approach in the treatment of intradural extramedullary spinal cord tumours. METHODS: Between January 2008 and July 2013, 18 patients with an intradural extramedullary tumour were included in the study (13 thoracic, 4 lumbar and one cervical tumours). The mean age was 59 years. We operated on 11 meningiomas, 6 neurinomas and one ependymoma. All patients underwent minimally invasive surgery using a tubular retractor system to perform a hemilaminectomy in order to access the spinal canal. Fifteen patients had a neurological deficit and 7 suffered from radicular pain prior to surgery. RESULTS: Gross completed resection was performed in all patients. Mean time of surgery was 95 min. Blood loss was less than 200 cc. Fifteen patients out of 18 were able to get up the day after surgery. Mean hospital stay was 6 days. There were no complications. CONCLUSION: A minimal surgical approach using a tubular retractor permits an effective resection of intradural extramedullary tumours. This procedure may be a useful tool to decrease the risk of secondary spine instability and postoperative kyphosis, and could also be used for spinal junctions and in fragile patients. PMID- 26249273 TI - [Intra cranial meningiomas and long term use of cyproterone acetate with a conventional dose in women. A report of two cases of tumor decrease after treatment withdrawal]. AB - The action of synthetic progestogens, prescribed at a conventional dose in women, for a meningioma, is still poorly understood, and could be related to progesterone receptors. We report two cases illustrating multiple meningiomas with stabilization or tumor reduction after withdrawal of cyproterone acetate originally prescribed for a long term period. We also review the influence of synthetic progestogens on meningiomas, particularly the impact of treatment withdrawal. PMID- 26249274 TI - [In utero surgery of myelomeningocele in France]. PMID- 26249275 TI - [Surgical anatomy of spinal cord tumors]. AB - In this article, we respectively describe the morphology of the spinal cord, spinal meningeal layers, main fiber tracts, and both arterial and venous distribution in order to explain signs of spinal cord compression. We will then describe a surgical technique for spinal cord tumor removal. PMID- 26249276 TI - First detection of papillomaviruses and polyomaviruses in swimming pool waters: unrecognized recreational water-related pathogens? AB - AIMS: Viral outbreaks associated with swimming pools have been described worldwide. The objective of this study was to examine the extent of viral contamination in indoor and outdoor swimming pools. METHODS AND RESULTS: Pools were examined for the presence of human enteric viruses (adenovirus, norovirus and enterovirus) and nonenteric viruses (papillomavirus and polyomavirus-BK, JC, KI, WU and Merkel cell). Bacteriological parameters were also evaluated. The analysed pool waters met microbiological quality standards. Enteric viruses were not detected. On the other hand, papillomaviruses (HPV8, 12, 23, 25, 120 and unclassified HPVs) and polyomaviruses (JC and Merkel cell polyomaviruses) were detected in 9/14 samples (64%). The number of HPV DNA copies in pool waters, measured by quantitative Real-time PCR, ranged from 1.27E+04 to 1.13E+05/10L. CONCLUSION: Results show that a variety of nonenteric viruses may be discharged in pool waters by various secretions and excretions from infected individuals or asymptomatic carriers. SIGNIFICANCE AND IMPACT OF THE STUDY: To the best of our knowledge, this is the first report on human papillomaviruses and polyomaviruses in swimming pools. The likelihood that these viruses can be transmitted by recreational activities deserves to be explored in future studies. PMID- 26249277 TI - On the road. PMID- 26249278 TI - Efficacy and challenges of in-home telepsychotherapy. PMID- 26249279 TI - Medication for ADHD and accidental injury. PMID- 26249280 TI - Bipolar disorder and anxiety: a comorbidity needing better treatments. PMID- 26249281 TI - Does cigarette smoking cause psychosis? PMID- 26249282 TI - Alcohol-related brain damage in older people. PMID- 26249283 TI - The need for sustainable psychiatry. PMID- 26249284 TI - Brain disease model of addiction: why is it so controversial? PMID- 26249286 TI - Corrections. PMID- 26249285 TI - Mental health mainstreamed in new UN disaster framework. PMID- 26249287 TI - Corrections. PMID- 26249288 TI - Variation in mortality risk of people released from prison. PMID- 26249289 TI - Variation in mortality risk of people released from prison - Authors' reply. PMID- 26249290 TI - Giving up the disease model. PMID- 26249292 TI - Louis Appleby: "We need a progressive alternative to prison". PMID- 26249293 TI - Growing Better Lives: peace, quiet, and yurts. PMID- 26249294 TI - Everyday compassion. PMID- 26249295 TI - Dark arts. PMID- 26249296 TI - Deeper than words. PMID- 26249297 TI - Freak show. PMID- 26249298 TI - Canned art. PMID- 26249299 TI - Wellbeing matters. PMID- 26249300 TI - Psychotherapy for depression in older veterans via telemedicine: a randomised, open-label, non-inferiority trial. AB - BACKGROUND: Many older adults with major depression, particularly veterans, do not have access to evidence-based psychotherapy. Telemedicine could increase access to best-practice care for older adults facing barriers of mobility, stigma, and geographical isolation. We aimed to establish non-inferiority of behavioural activation therapy for major depression delivered via telemedicine to same-room care in largely male, older adult veterans. METHODS: In this randomised, controlled, open-label, non-inferiority trial, we recruited veterans (aged >=58 years) meeting DSM-IV criteria for major depressive disorder from the Ralph H Johnson Veterans Affairs Medical Center and four associated community outpatient-based clinics in the USA. We excluded actively psychotic or demented people, those with both suicidal ideation and clear intent, and those with substance dependence. The study coordinator randomly assigned participants (1:1; block size 2-6; stratified by race; computer-generated randomisation sequence by RGK) to eight sessions of behavioural activation for depression either via telemedicine or in the same room. The primary outcome was treatment response according to the Geriatric Depression Scale (GDS) and Beck Depression Inventory (BDI; defined as a 50% reduction in symptoms from baseline at 12 months), and Structured Clinical Interview for DSM-IV, clinician version (defined as no longer being diagnosed with major depressive disorder at 12 months follow-up), in the per-protocol population (those who completed at least four treatment sessions and for whom all outcome measurements were done). Those assessing outcomes were masked. The non-inferiority margin was 15%. This trial is registered with ClinicalTrials.gov, number NCT00324701. FINDINGS: Between April 1, 2007, and July 31, 2011, we screened 780 patients, and the study coordinator randomly assigned participants to either telemedicine (120 [50%]) or same-room treatment (121 [50%]). We included 100 (83%) patients in the per-protocol analysis in the telemedicine group and 104 (86%) in the same-room group. Treatment response according to GDS did not differ significantly between the telemedicine (22 [22.45%, 90% CI 15.52-29.38] patients) and same-room (21 [20.39%, 90% CI 13.86 26.92]) groups, with an absolute difference of 2.06% (90% CI -7.46 to 11.58). Response according to BDI also did not differ significantly (telemedicine 19 [24.05%, 90% CI 16.14-31.96] patients; same room 19 [23.17%, 90% CI 15.51 30.83]), with an absolute difference of 0.88% (90% CI -10.13 to 11.89). Response on the Structured Clinical Interview for DSM-IV, clinician version, also did not differ significantly (39 [43.33%, 90% CI 34.74-51.93] patients in the telemedicine group and 46 [48.42%, 90% CI 39.99-56.85] in the same-room group), with a difference of -5.09% (-17.13 to 6.95; p=0.487). Results from the intention to-treat population were similar. MEM analyses showed that no significant differences existed between treatment trajectories over time for BDI and GDS. The criteria for non-inferiority were met. We did not note any adverse events. INTERPRETATION: Telemedicine-delivered psychotherapy for older adults with major depression is not inferior to same-room treatment. This finding shows that evidence-based psychotherapy can be delivered, without modification, via home based telemedicine, and that this method can be used to overcome barriers to care associated with distance from and difficulty with attendance at in-person sessions in older adults. FUNDING: US Department of Veterans Affairs. PMID- 26249301 TI - Effect of drugs on the risk of injuries in children with attention deficit hyperactivity disorder: a prospective cohort study. AB - BACKGROUND: Injuries represent the largest disease burden and most common cause of death in children. Attention deficit hyperactivity disorder (ADHD) is associated with increased mortality, with accidents being the most common cause of death in ADHD. However, it is not known whether pharmacological treatment has any modifying effect on the risk of injuries in children and adolescents with ADHD. METHODS: Using Danish national registers, we followed a cohort of 710 120 individuals, including 4557 individuals diagnosed with ADHD before age 10 years. Using a quasi-experimental, difference-in-difference design, we estimated the odds ratios (ORs) for injuries and the mean change in prevalence rates of injuries and emergency ward visits before and after treatment, with matched untreated children with ADHD at the same age serving as controls. FINDINGS: Children with ADHD were more likely to sustain injuries, compared with children without ADHD, at age 10 years (adjusted OR=1.29, 95% CI 1.22-1.37) and at age 12 years (adjusted OR=1.30, 1.23-1.37). From age 5 to 10 years, the prevalence of injuries in children with ADHD who were treated with ADHD drugs decreased from 19% to 14%, compared with a prevalence of about 17% in non-treated children with ADHD. This corresponded to an adjusted difference-in-difference reduction in prevalence of injuries at age 10 years of 31.5% (8.2-54.8) and 43.5% (18.1-69.0) at age 12 years due to treatment. Pharmacological treatment also reduced the prevalence of emergency ward visits at age 10 years (28.2%, 6.3-50.1) and age 12 years (45.7%, 25.8-65.7). INTERPRETATION: Children with ADHD had an increased risk of injuries compared with other children. Treatment with ADHD drugs reduced the risk of injuries by up to 43% and emergency ward visits by up to 45% in children with ADHD. Taken together with previous findings of accidents being the most common cause of death in individuals with ADHD, these results are of major public health importance. FUNDING: The Lundbeck Foundation, the Danish Council for Independent Research, Centre For Integrated Register-based Research at Aarhus University, the Region of Southern Denmark Research Foundation, and Worzner's Foundation. PMID- 26249302 TI - Lifetime prevalence of anxiety disorders in people with bipolar disorder: a systematic review and meta-analysis. AB - BACKGROUND: Anxiety disorders are increasingly recognised as an important determinant of outcomes in patients with bipolar disorder. However, a reliable estimate of their prevalence is still missing, because the published prevalence of anxiety disorders in individuals with bipolar disorder varies widely. In this study, we aimed to quantify the lifetime prevalence of anxiety disorders in individuals with bipolar disorder and compare it with rates in people without the disorder. METHODS: We searched the Web of Knowledge and Medline (through the PubMed interface) for articles published in any language from the database inception dates up until June 1, 2014, using a combination of the word "bipolar" and search terms for anxiety disorders. We included studies that reported original data about the lifetime prevalence of DSM-III and DSM-IV anxiety disorders in adults with bipolar disorder that recruited participants irrespective of comorbidities and that used a validated diagnostic interview to establish the diagnoses of bipolar disorder and at least one anxiety disorder. We excluded studies that reported only the current prevalence or if we were unable to establish whether they described current or lifetime prevalence, and those with discrepancies in the data that could not be resolved by contacting the authors. We did a random-effects meta-analysis of lifetime prevalence of DSM-III and DSM-IV anxiety disorders in adults with bipolar disorder, in which we quantified the lifetime prevalence of any anxiety disorder in people with bipolar disorder. We compared this prevalence in people with bipolar I disorder versus those with bipolar II disorder, and in people with bipolar disorder versus population controls. FINDINGS: Data from 40 studies, including 14 914 individuals from North America, Europe, Australia, South America, and Asia, indicate that the lifetime prevalence of anxiety disorders in individuals with bipolar disorder is 45% (95% CI 40-51). Direct comparison in five samples with a total of 1378 individuals with bipolar disorder and 56 812 population controls without bipolar disorder indicates a three-fold increase (risk ratio [RR] 3.22 [95% CI 2.41 4.29]; p<0.0001) in the prevalence of anxiety disorders in those with bipolar disorder. 13 studies that included both individuals with bipolar I disorder (n=4270) and those with bipolar II disorder (n=1939) showed no difference in the lifetime prevalence of anxiety disorders between these subtypes (RR 1.07 [95% CI 0.96-1.20]; p=0.223). We noted significant heterogeneity among included studies that was not accounted for by reported differences in study characteristics. INTERPRETATION: People with bipolar disorder are at increased risk of anxiety disorders compared with those without bipolar disorder; nearly one in two has an anxiety disorder in their lifetime. Anxiety disorders should therefore be assessed alongside the mood symptoms in patients with bipolar disorder. FUNDING: Capital Health Research Fund. PMID- 26249304 TI - Mental health starts with physical health: current status and future directions of non-pharmacological interventions to improve physical health in first-episode psychosis. AB - People with psychotic disorders have reduced life expectancy compared with the general population. This difference is primarily due to increased prevalence of cardiovascular disease associated with antipsychotic drugs and with modifiable risk factors, including weight gain, low exercise, poor diet, and high prevalence of cigarette smoking. We review non-pharmacological interventions for physical health behaviour in patients with chronic and first-episode psychosis. Our findings suggest that weight loss and attenuation of weight gain are achievable but limited and might not persist beyond the end of an intervention. Evidence for smoking cessation interventions is scarce. The case for early intervention to prevent deterioration of physical health is strong. We propose a framework for development of interventions, which addresses three main factors largely absent in previous research: (1) examination of aetiological factors related to poor physical health, (2) theory-driven interventions that target aetiological factors, and (3) assessment of feasibility. PMID- 26249305 TI - The serotonin transporter in psychiatric disorders: insights from PET imaging. AB - Over the past 20 years, psychotropics affecting the serotonergic system have been used extensively in the treatment of psychiatric disorders. Molecular imaging, in particular PET, has allowed for elucidation of the essential contribution of the serotonin transporter to the pathophysiology of various psychiatric disorders and their treatment. We review studies that use PET to measure cerebral serotonin transporter activity in psychiatric disorders, focusing on major depressive disorder and antidepressant treatment. We also discuss opportunities and limitations in the application of this neuroimaging method in clinical practice. Although results from individual studies diverge, meta-analysis indicates a trend towards reduced serotonin transporter availability in patients with major depressive disorder. Inconsistencies in results might suggest symptom heterogeneity in major depressive disorder and might therefore be relevant for stratification of patients into clinical subsets. PET has enabled the elucidation of mechanisms of response to selective serotonin reuptake inhibitors (SSRIs) and hence provides a basis for rational pharmacological treatment of major depressive disorder. Such imaging studies have also suggested that the pattern of serotonin transporter binding before treatment might predict response to antidepressant treatment, which could potentially be clinically useful in the future. Additionally, this Review discusses PET studies investigating the serotonin transporter in anxiety, obsessive-compulsive disorder, and eating disorders. Few studies have shown changes in serotonin transporter activity in schizophrenia and attention deficit hyperactivity disorder. By showing the scarcity of data in these psychiatric disorders, we highlight the potential for further investigation in this field. PMID- 26249303 TI - Does tobacco use cause psychosis? Systematic review and meta-analysis. AB - BACKGROUND: Although the association between psychotic illness and cigarette smoking is well known, the reasons are unclear why people with psychosis are more likely to smoke than are the general population. We aimed to test several hypotheses. First, that daily tobacco use is associated with an increased risk of psychotic illness in both case-control and prospective studies. Second, that smoking is associated with an earlier age at onset of psychotic illness. Finally, that an earlier age at initiation of smoking is associated with an increased risk of psychosis. We also aimed to derive an estimate of the prevalence of smoking in patients presenting with their first episode of psychosis. METHODS: We searched Embase, Medline, and PsycINFO and selected observational studies in which rates of smoking were reported in people with psychotic disorders, compared with controls. We calculated the weighted mean difference for age at onset of psychosis and age at initiation of smoking. For categorical outcomes, we calculated odds ratios from cross-sectional studies and risk ratios from prospective studies. FINDINGS: Of 3717 citations retrieved, 61 studies comprising 72 samples met inclusion criteria. The overall sample included 14 555 tobacco users and 273 162 non-users. The prevalence of smoking in patients presenting with their first episode of psychosis was 0.57 (95% CI 0.52-0.62; p<0.0001). In case-control studies, the overall odds ratio for the first episode of psychosis in smokers versus non-smokers was 3.22 (95% CI 1.63-6.33), with some evidence of publication bias (Egger's test p=0.018, Begg's test p=0.007). For prospective studies, we calculated an overall relative risk of new psychotic disorders in daily smokers versus non-smokers of 2.18 (95% CI 1.23-3.85). Daily smokers developed psychotic illness at an earlier age than did non-smokers (weighted mean difference -1.04 years, 95% CI -1.82 to -0.26). Those with psychosis started smoking at a non-significantly earlier age than did healthy controls (-0.44 years, 95% CI -1.21 to 0.34). INTERPRETATION: Daily tobacco use is associated with increased risk of psychosis and an earlier age at onset of psychotic illness. The possibility of a causal link between tobacco use and psychosis merits further examination. FUNDING: NIHR Maudsley Biomedical Research Centre. PMID- 26249307 TI - France's forensic psychiatry provision: the long and winding road. PMID- 26249306 TI - What can triumphs and tribulations from drug research in Alzheimer's disease tell us about the development of psychotropic drugs in general? AB - Drug development for psychiatric disorders has almost ground to a halt. Some newer drugs are better tolerated or safer than older ones, but none is more effective. Years of failure in preventing or delaying the onset of illness, ameliorating symptoms, lowering suicide rates, or improving quality of life has put the commercial investments that had previously funded drug development at risk. To promote the development of psychiatric drugs with greater efficacy, we need to improve the way we bring potentially beneficial drugs to market. We need to acknowledge, as has been done in other specialties, that people differ in their response to drugs. Psychiatric drug research needs to be grounded in a better understanding of molecular brain mechanisms, neural circuits, and their relations to clinical disease. With this understanding, drugs need to be more precisely directed at specific brain targets. In psychiatric drug development, government, industry, regulatory bodies, and academia should realign to ensure medical science is used in the best interests of patients. PMID- 26249308 TI - The mental health of HIV-positive adolescents. PMID- 26249309 TI - Case of primary cutaneous adenoid cystic carcinoma: Expression of c-KIT and activation of its downstream signaling molecules. PMID- 26249310 TI - Small-peptide signals that control root nodule number, development, and symbiosis. AB - Many legumes have the capacity to enter into a symbiotic association with soil bacteria generically called 'rhizobia' that results in the formation of new lateral organs on roots called nodules within which the rhizobia fix atmospheric nitrogen (N). Up to 200 million tonnes of N per annum is fixed by this association. Therefore, this symbiosis plays an integral role in the N cycle and is exploited in agriculture to support the sustainable fixation of N for cropping and animal production in developing and developed nations. Root nodulation is an expendable developmental process and competency for nodulation is coupled to low N conditions. Both nodule initiation and development is suppressed under high-N conditions. Although root nodule formation enables sufficient N to be fixed for legumes to grow under N-deficient conditions, the carbon cost is high and nodule number is tightly regulated by local and systemic mechanisms. How legumes co ordinate nodule formation with the other main organs of nutrient acquisition, lateral roots, is not fully understood. Independent mechanisms appear to regulate lateral roots and nodules under low- and high-N regimes. Recently, several signalling peptides have been implicated in the local and systemic regulation of nodule and lateral root formation. Other peptide classes control the symbiotic interaction of rhizobia with the host. This review focuses on the roles played by signalling peptides during the early stages of root nodule formation, in the control of nodule number, and in the establishment of symbiosis. Here, we highlight the latest findings and the gaps in our understanding of these processes. PMID- 26249311 TI - When Children are the Least Vulnerable to False Memories: A True Report or a Case of Autosuggestion? AB - In this case report, a legal case revolving around the reliability of statements given by a 6-year-old girl is described. She claimed to have witnessed her mother being murdered by her father. Two psychological experts provided diametrically opposed opinions about the reliability of her statements. One expert, a clinician, opined that the girl's statements were based on autosuggestion whereas the other expert, a memory researcher, stated that autosuggestion was unlikely to have played a role. This case and the analysis of the experts' opinions illustrate what may happen when experts in court are unaware of the recent literature on (false) memory. That is, recent studies show that autosuggestion is less likely to occur in young children than in older children and adults. The current case stresses the importance and implications of relying on memory experts in cases concerning the reliability of eyewitness statements. PMID- 26249312 TI - Photoisomerization of Trans Ortho-, Meta-, Para-Nitro Diarylbutadienes: A Case of Regioselectivity. AB - A series of ortho-, meta- and para-substituted trans-nitro aryl (phenyl and pyridyl) butadienes have been synthesized and characterized. The effect of substitution and positional selectivity on their fluorescence and photoisomerization were systematically investigated. Among all dienes, meta- and para-nitro phenyl-substituted derivatives exhibit remarkable solvatochromic emission shifts due to intramolecular charge transfer. On the other hand, ortho derivatives undergo regioselective isomerization upon photoexcitation in contrast to inefficient isomerization of para and meta nitro-substituted dienes. Single crystal X-ray analysis revealed existence of intramolecular hydrogen bonding between the nitro group and the hydrogen of the proximal double bond. This restricts the rotation of the proximal double bond thereby allowing regioselective isomerization. The observations were also supported by NMR spectroscopic studies. PMID- 26249313 TI - [Trends in ambulatory surgical procedures in Catalonia (Spain), 2001-2011]. AB - OBJECTIVE: To analyse the trend in ambulatory surgery procedures in Catalonia (Spain) hospitals with regard to the activity in inpatient care units and structural resources in surgery. METHODS: A descriptive study was performed using data from the Statistics of Health Facilities with Inpatient Care of the Health Department of the Catalan Government from 2001 to 2011. Data from acute care hospitals were analysed and were classified in public and private hospitals. DISCUSSION: The percentage of ambulatory surgical procedures increased by 63.2% and the percentage of inpatient surgery decreased by 23.5% (this trend was more pronounced in public hospitals). This result coincided with a decrease of structural resources in surgery (beds and operating rooms) and with an improvement in inpatient surgical activity (a decrease in the mean length of stay and bed occupancy rate in all hospitals). Structural surgery resources were optimized and efficiency was improved in surgery inpatient care units. PMID- 26249314 TI - Broiler responses to digestible threonine at different ages: a neural networks approach. AB - Three experiments were conducted with broiler chickens to evaluate the effects of digestible threonine (DThr) and crude protein (CP) on their performance at three different phases of age: 1-14, 15-28 and 29-42 days. The measured traits included the following: average daily gain (ADG), feed intake (FI), feed conversion ratio (FCR), carcass crude protein (CCP), body lipid (BL), feather weight gain (FWG), protein deposited in feather (FCP), carcass plus feather protein (CFCP), carcass Thr deposition (CDThr) and nitrogen excretion (NE). A dilution technique was used to create seven diets (with eight replicates) increasing the DThr content from 1.5 to 10 g/kg of diet for phase 1, 1.3-8.9 g/kg of diet for phase 2, and 1.2-8.2 g/kg of diet for phase 3. Data measured were imported into neural networks (NNs) to: (i) predict the measured traits in response to DThr and CP, (ii) rank the importance of DThr and CP on these traits through sensitivity analysis and (iii) find the optimal levels of DThr and CP that lead to the desired (maximum or minimum) responses. For each trait investigated, 50 different random groups of data were generated using a bootstrapping method. These 50 data groups were then used to develop 50 separate NNs which were subsequently combined to construct the final ensemble NN model. In general, accuracy of the models constructed was acceptable, although models of high (ADG, FCR, CFCP, BL, DThr and NE; 0.64 <= R(2) <= 0.99) and low (CCP, FWG and FCP; 0.26 <= R(2) <= 0.79) accuracy were obtained. All models developed showed the greatest sensitivity to DThr. This may be explained by the dilution technique diet preparation used in these experiments. Optimization results showed decreases in optimal values of DThr and CP with increasing age for all traits. The highest level of DThr was suggested for minimum BL, followed by minimum FCR, maximum ADG, maximum CFCP, minimum NE and maximum CCP respectively. Results showed that the optimal values of DThr for minimum FCR in phases 1-3 were 8.5, 7.4 and 6.4 g/kg of diet, while these values for maximum ADG were 8.2, 7.2 and 6.4 g/kg of diet respectively. PMID- 26249315 TI - Paracoccus aquimaris sp. nov., isolated from seawater. AB - A Gram-stain negative, motile and short rod-shaped bacterial strain, designated KF89(T), was isolated from seawater of Tong-Yeong, South of Korea. Growth occurred between 10 and 35 degrees C (optimum 32 degrees C) and at pH 6.0-9.0 (optimum pH 7.0) and at 0-7 % NaCl (optimum at 2 % NaCl). The 16S rRNA gene sequence identified it as a member of the genus Paracoccus that belongs to the phylum Proteobacteria. Based on the 16S rRNA gene sequence, the highest degree of gene sequence similarities were shared with Paracoccus homiensis DD-R11(T) (97.3 %), P. zeaxanthinifaciens ATCC21588(T) (97.1 %), P. rhizosphaerae CC-CCM15-8(T) (96.9 %), P. beibuensis JLT1284 (96.9 %) and P. aestuarii B7(T) (96.6 %). Strain KF89(T) contained Ubiquinone-10 as the major respiratory quinone, and the polar lipid profile included phosphatidylglycerol, phosphatidylcholine, diphosphatidylglycerol and an unidentified aminolipid. The major fatty acid of strain KF89(T) is C18:1 omega7c and the DNA G+C content is 57 mol%. Strain KF89(T) showed a DNA-DNA relatedness with P. homiensis KACC 11518(T) of 49 %. Based on phylogenetic and phenotypic analyses, strain KF89(T) is clearly shown to be a novel member of the genus Paracoccus. The type strain is Paracoccus aquimaris KF89(T) (=KEMB 3-508(T) = JCM 19892(T)). PMID- 26249316 TI - The association between portion size, nutrient intake and gestational weight gain: a secondary analysis in the WATCH study 2006/7. AB - BACKGROUND: Excessive gestational weight gain (GWG) is associated with adverse maternal-child health outcomes. Managing energy intake and GWG versus optimising nutrient intake can be challenging. The present study aimed to examine the relationships between dietary portion size, GWG and nutrient intakes during pregnancy. It is hypothesised that, after adjustment for potential confounders, portion size would be positively associated with both GWG and nutrient intakes during pregnancy. METHODS: Prospective data were obtained for 179 Australian women from the Women and Their Children's Health Study. A validated food frequency questionnaire was used at 18-24 and 36-40 weeks of gestation to quantify diet and portion size during the previous 3 months of pregnancy. Nutrient intakes were compared with Australian Nutrient Reference Values (NRVs). GWG was measured up to 36 weeks and compared with the Institute of Medicine weight gain recommendations (WtAdh). RESULTS: In multivariate regression models, portion size factor (PSF) was positively associated with GWG in women with high socio-economic status (SES; beta = 0.20, P = 0.04) and those with an overweight/obese pre-pregnancy body mass index (BMI) (beta = 0.28, P = 0.04). PSF uniquely accounted for 8.2% and 3.7% of the variability in GWG for women with high SES and overweight/obese pre-pregnancy BMIs, respectively. Nutrient intakes and PSF were similar regardless of WtAdh. Women achieved NRVs for calcium and zinc in all PSF categories. Most of the women with large PSF still failed to achieve the NRVs for folate (95.7%), iron (89.6%) and fibre (85.5%). CONCLUSIONS: All women require advice on quality food choices during pregnancy to optimise health outcomes. Targeting portion size alone is insufficient to manage GWG but may prove to be a valuable tool in pregnant women of high SES and/or those who are overweight/obese pre-pregnancy. PMID- 26249317 TI - Comparison of binding behavior for molecularly imprinted polymers prepared by hierarchical imprinting or Pickering emulsion polymerization. AB - The aim of this study was the evaluation of the binding performances and selectivity of molecularly imprinted beads prepared toward several penicillins (i) by hierarchical bulk polymerization in the pores of template-grafted silica microbeads (hMIPs) and (ii) by Pickering emulsion polymerization in the presence of template-decorated silica nanobeads (pMIPs). 6-Aminopenicillanic acid was chosen as the common fragmental mimic template. Both approaches produced micron sized polymeric beads with good recognition properties toward the target ligands whereas the selectivity pattern appeared quite different. The polymer prepared by the Pickering emulsion approach showed binding properties similar to imprinted beads prepared by hierarchical approach. Equilibrium binding constants changed their values from 0.1-0.2 * 10(6) (hMIPs) to 0.2-0.6 * 10(6) M(-1) (pMIPs), while the binding site densities changed from 3.7-4.8 (hMIPs) to 0.3-0.55 MUmol/g (pMIPs). Compared to the hierarchical polymerization, Pickering emulsion polymerization represents a more practical approach when a template mimic needs to be used. PMID- 26249321 TI - Nitrogen losses, uptake and abundance of ammonia oxidizers in soil under mineral and organo-mineral fertilization regimes. AB - BACKGROUND: A laboratory incubation experiment and greenhouse studies investigated the impact of organo-mineral (OM) fertilization as an alternative practice to conventional mineral (M) fertilization on nitrogen (N) uptake and losses in perennial ryegrass (Lolium perenne) as well as on soil microbial biomass and ammonia oxidizers. RESULTS: While no significant difference in plant productivity and ammonia emissions between treatments could be detected, an increase in soil total N content and an average 17.9% decrease in nitrates leached were observed in OM fertilization compared with M fertilization. The microbial community responded differentially to treatments, suggesting that the organic matter fraction of the OM fertilizer might have influenced N immobilization in the microbial biomass in the short-medium term. Furthermore, nitrate contents in fertilized soils were significantly related to bacterial but not archaeal amoA gene copies, whereas in non-fertilized soils a significant relationship between soil nitrates and archaeal but not bacterial amoA copies was found. CONCLUSION: The application of OM fertilizer to soil maintained sufficient productivity and in turn increased N use efficiency and noticeably reduced N losses. Furthermore, in this experiment, ammonia-oxidizing bacteria drove nitrification when an N source was added to the soil, whereas ammonia-oxidizing archaea were responsible for ammonia oxidation in non-fertilized soil. (c) 2015 Society of Chemical Industry. PMID- 26249322 TI - Identification of aqueous pollen extracts using surface enhanced Raman scattering (SERS) and pattern recognition methods. AB - Aqueous pollen extracts of varying taxonomic relations were analyzed with surface enhanced Raman scattering (SERS) by using gold nanoparticles in aqueous suspensions as SERS substrate. This enables a selective vibrational characterization of the pollen water soluble fraction (mostly cellular components) devoid of the spectral contributions from the insoluble sporopollenin outer layer. The spectra of the pollen extracts are species-specific, and the chemical fingerprints can be exploited to achieve a classification that can distinguish between different species of the same genus. In the simple experimental procedure, several thousands of spectra per species are generated. Using an artificial neural network (ANN), it is demonstrated that analysis of the intrinsic biochemical information of the pollen cells in the SERS data enables the identification of pollen from different plant species at high accuracy. The ANN extracts the taxonomically-relevant information from the data in spite of high intra-species spectral variation caused by signal fluctuations and preparation specifics. The results show that SERS can be used for the reliable characterization and identification of pollen samples. They have implications for improved investigation of pollen physiology and for allergy warning. PMID- 26249323 TI - Bilateral upper limb compartment syndrome induced by strenuous exercise in a patient with haemophilia A and a low titre inhibitor. PMID- 26249324 TI - RNA-Seq-Based Transcriptome Analysis of Changes in Gene Expression Linked to Human Pregnancy Outcome After In Vitro Fertilization-Embryo Transfer. AB - To promote the pregnancy rate of in vitro fertilization-embryo transfer (IVF-ET), we proposed to examine the differentially expressed gene during pregnancy success and failure. We used high-sequencing technology to characterize and compare the gene expression profiles of pregnancy success and pregnancy failure patients during 3 different stages: before IVF-ET (stage I), after ovarian stimulation (stage II), and day 15 after embryo transfer (stage III). Selected data from RNA sequencing experiments were validated by quantitative real-time polymerase chain reaction (qRT-PCR). A total of 282, 208, and 372 genes in stages I, II, and III, respectively, were differentially expressed between pregnancy success and pregnancy failure, respectively. Through confirmation with qRT-PCR, compared to pregnancy failure, we demonstrated much lower level of major histocompatibility complex, human leukocyte antigen class I A, and an much higher level of human leukocyte antigen, class II DQ alpha1 (HLA-DQA1) in pregnancy success, although the HLA-DQA1 decreased with development duration of pregnancy. Interleukin 1beta increased with the development duration of pregnancy in pregnancy failure group and was much higher than that in pregnancy success group. Hemoglobin delta decreased with the development duration of pregnancy in pregnancy failure women and maintained in a lower level in stage I and II but dramatically increased to a much higher level in stage III in pregnancy success women. Minichromosome maintenance complex component 4 significantly increased in stage III in pregnancy failure but not in pregnancy success women. The altered expression of genes implicated in immune response and inflammation, oocyte meiosis, rhythmic process, and so on. Therefore, the current results provide a strong basis for future research to expound the molecular mechanism coping with pregnancy outcome. PMID- 26249325 TI - Improving battery safety by reducing the formation of Li dendrites with the use of amorphous silicon polymer anodes. AB - To provide safe lithium-ion batteries (LIBs) at low cost, battery materials which lead to reduced Li dendrite formation are needed. The currently used anode materials have low redox voltages that are very close to the redox potential for the formation of Li metal, which leads to severe short circuiting. Herein, we report that when the three-dimensional amorphous silicon polymers poly(methylsilyne) and poly(phenylsilyne) are used as anode materials, dendritic Li formation on the anode surface is avoided up to a practical current density of 10 mA.g(-1) at 5 degrees C. Equally as significant, poly(methylsilyne) and poly(phenylsilyne) are capable of reacting with 0.45 and 0.9 Li atoms per formula unit, respectively, at an average voltage of approximately 1.0 V, affording reversible capacities of 244 mAh.g(-1) and 180 mAh.g(-1). Moreover, noteworthy is the fact that polysilynes are suitable for practical applications because they can be prepared through a simple and low-cost process and are easy to handle. PMID- 26249327 TI - Numerical simulation of electrocardiograms for full cardiac cycles in healthy and pathological conditions. AB - This work is dedicated to the simulation of full cycles of the electrical activity of the heart and the corresponding body surface potential. The model is based on a realistic torso and heart anatomy, including ventricles and atria. One of the specificities of our approach is to model the atria as a surface, which is the kind of data typically provided by medical imaging for thin volumes. The bidomain equations are considered in their usual formulation in the ventricles, and in a surface formulation on the atria. Two ionic models are used: the Courtemanche-Ramirez-Nattel model on the atria and the 'minimal model for human ventricular action potentials' by Bueno-Orovio, Cherry, and Fenton in the ventricles. The heart is weakly coupled to the torso by a Robin boundary condition based on a resistor-capacitor transmission condition. Various electrocardiograms (ECGs) are simulated in healthy and pathological conditions (left and right bundle branch blocks, Bachmann's bundle block, and Wolff Parkinson-White syndrome). To assess the numerical ECGs, we use several qualitative and quantitative criteria found in the medical literature. Our simulator can also be used to generate the signals measured by a vest of electrodes. This capability is illustrated at the end of the article. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26249326 TI - Noncoding RNAs and chronic inflammation: Micro-managing the fire within. AB - Inflammatory responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled chronic inflammation can occur. Chronic inflammation is now recognized as a contributing factor to many age-associated diseases including metabolic disorders, arthritis, neurodegeneration, and cardiovascular disease. Due to the connection between chronic inflammation and these diseases, it is essential to understand underlying mechanisms behind this process. In this review, factors that contribute to chronic inflammation are discussed. Further, we emphasize the emerging roles of microRNAs (miRNAs) and other noncoding RNAs (ncRNA) in regulating chronic inflammatory states, making them important future diagnostic markers and therapeutic targets. PMID- 26249328 TI - Synthesis of Evidence to Characterize National Measles and Rubella Exposure and Immunization Histories. AB - Population immunity depends on the dynamic levels of immunization coverage that countries achieve over time and any transmission of viruses that occur within the population that induce immunity. In the context of developing a dynamic transmission model for measles and rubella to support analyses of future immunization policy options, we assessed the model inputs required to reproduce past behavior and to provide some confidence about model performance at the national level. We reviewed the data available from the World Health Organization (WHO) and existing measles and rubella literature for evidence of historical reported routine and supplemental immunization activities and reported cases and outbreaks. We constructed model input profiles for 180 WHO member states and three other areas to support disease transmission model development and calibration. The profiles demonstrate the significant variability in immunization strategies used historically by regions and member states and the epidemiological implications of these historical choices. The profiles provide a historical perspective on measles and rubella immunization globally at the national level, and they may help immunization program managers identify existing immunity and/or knowledge gaps. PMID- 26249329 TI - A potential impact of nursing characteristics prior to in-hospital cardiac arrest: a self-reported study. PMID- 26249330 TI - Psychological interventions for distress in adults undergoing haematopoietic stem cell transplantation: a systematic review with meta-analysis. AB - OBJECTIVES: To investigate the characteristics, methodology, quality, and efficacy of psychological interventions for distress in adult patients undergoing haematopoietic stem cell transplantation (HSCT). METHODS: A systematic review of relevant studies was conducted using six databases with supplementary hand searching. Included studies employed an experimental or quasi-experimental design, interventions included at least one psychological component, and outcomes involved psychological distress in affective terms. Data were abstracted, and study quality was assessed using Cochrane Foundation criteria amended to include confounder and common factors control. Data were examined and synthesised using a narrative approach and meta-analysis. RESULTS: Eleven articles for nine interventions met the inclusion criteria out of 11,741 abstracts. The studies varied in quality, general, intervention, and methodological characteristics while findings were mixed. Interventions tended to show better efficacy when incorporating a major psychological component involving cognitive behavioural or emotional processing methods with substantial interventionist input. However, this was also associated with methodological limitations and threats to internal validity such as poor confounder and common factors control. A meta-analysis yielded a small but significant pooled effect size estimate in favour of interventions with inconsequential heterogeneity. Risk of bias remained a concern. CONCLUSIONS: Psychological interventions may provide some benefit in alleviating distress in HSCT but conclusions remain tentative in light of methodological limitations and risk of bias. Further research is needed to evidence the individual contribution of intervention components and mechanism of change together with improving intervention efficiency and methodological quality. PMID- 26249331 TI - The Costs and Valuation of Health Impacts of Measles and Rubella Risk Management Policies. AB - National and global health policymakers require good information about the costs and benefits of their investments in measles and rubella immunization programs. Building on our review of the existing measles and rubella health economics literature, we develop inputs for use in regional and global models of the expected future benefits and costs of vaccination, treatment, surveillance, and other global coordination activities. Given diversity in the world and limited data, we characterize the costs for countries according to the 2013 World Bank income levels using 2013 U.S. dollars (2013$US). We estimate that routine immunization and supplemental immunization activities will cost governments and donors over 2013$US 2.3 billion per year for the foreseeable future, with high income countries accounting for 55% of the costs, to vaccinate global birth cohorts of approximately 134 million surviving infants and to protect the global population of over 7 billion people. We find significantly higher costs and health consequences of measles or rubella disease than with vaccine use, with the expected disability-adjusted life year (DALY) loss for case of disease generally at least 100 times the loss per vaccine dose. To support estimates of the economic benefits of investments in measles and/or rubella elimination or control, we characterize the probabilities of various sequelae of measles and rubella infections and vaccine adverse events, the DALY inputs for health outcomes, and the associated treatment costs. Managing measles and rubella to achieve the existing and future regional measles and rubella goals and the objectives of the Global Vaccine Action Plan will require an ongoing commitment of financial resources that will prevent adverse health outcomes and save the associated treatment costs. PMID- 26249332 TI - Weighing the evidence: obesity, metabolic syndrome, and the risk of chronic kidney disease. AB - Evaluating effect of obesity per se and the metabolic syndrome as a whole on the risk of developing chronic kidney disease (CKD) is key factor in developing a comprehensive public health approach to reduce morbidity and healthcare resource consumption. While there is considerable evidence to support increased risk of CKD in obese individuals and those with the metabolic syndrome, this relationship may be influenced by several factors. These include confounding variables, anthropometric measures, the end-point studied (e.g. development of early stage CKD, progression to end-stage renal disease or mortality), and the complex interrelationship between the various components of the metabolic syndrome. The study by Cao et al. in the current issue of BMC nephrology examines the impact of obesity on CKD risk in people with and without co-existing metabolic syndrome. The findings of this large, prospective study illustrate a clear correlation between increased body mass index (BMI) and risk of CKD regardless of whether or not there is co-existing metabolic syndrome. While the presence of the metabolic syndrome confers some additional risk of CKD in overweight and obese individuals, its effect is relatively modest and accounts for only 26 % of the risk associated with increased BMI. We discuss the complex epidemiological and methodological context in which these important findings should be understood, and their implications for public health and for individual patients and healthcare practitioners. PMID- 26249333 TI - Optimizing Implementation of Obesity Prevention Programs: A Qualitative Investigation Within a Large-Scale Randomized Controlled Trial. AB - PURPOSE: The prevalence of obesity in rural and remote areas is elevated in comparison to urban populations, highlighting the need for interventions targeting obesity prevention in these settings. Implementing evidence-based obesity prevention programs is challenging. This study aimed to investigate factors influencing the implementation of obesity prevention programs, including adoption, program delivery, community uptake, and continuation, specifically within rural settings. METHODS: Nested within a large-scale randomized controlled trial, a qualitative exploratory approach was adopted, with purposive sampling techniques utilized, to recruit stakeholders from 41 small rural towns in Australia. In-depth semistructured interviews were conducted with clinical health professionals, health service managers, and local government employees. Open coding was completed independently by 2 investigators and thematic analysis undertaken. FINDINGS: In-depth interviews revealed that obesity prevention programs were valued by the rural workforce. Program implementation is influenced by interrelated factors across: (1) contextual factors and (2) organizational capacity. Key recommendations to manage the challenges of implementing evidence based programs focused on reducing program delivery costs, aided by the provision of a suite of implementation and evaluation resources. Informing the scale-up of future prevention programs, stakeholders highlighted the need to build local rural capacity through developing supportive university partnerships, generating local program ownership and promoting active feedback to all program partners. CONCLUSION: We demonstrate that the rural workforce places a high value on obesity prevention programs. Our results inform the future scale-up of obesity prevention programs, providing an improved understanding of strategies to optimize implementation of evidence-based prevention programs. PMID- 26249334 TI - LEGOs(r) and legacies of centrioles and centrosomes. PMID- 26249335 TI - Enhanced production of Ca2+-polymalate (PMA) with high molecular mass by Aureobasidium pullulans var. pullulans MCW. AB - BACKGROUND: Polymalic acid (PMA) has many applications in food and medical industries. However, so far it has not been commercially produced by fermentation. Therefore, it is very important how to develop an economical process for a large scale production of PMA by one step fermentation. RESULTS: After over 200 strains of Aureobasidium spp. isolated from the mangrove systems in the South of China were screened for their ability to produce Ca(2+) polymalate (PMA), it was found that Aureobasidium pullulans var. pullulans MCW strain among them could produce high level of Ca(2+)-PMA. The medium containing only 140.0 g/L glucose, 65.0 g/L CaCO3 and 7.5 g/L corn steep liquor was found to be the most suitable for Ca(2+)-PMA production. Then, 121.3 g/L of Ca(2+)-PMA was produced by A. pullulans var. pullulans MCW strain within 120 h at flask level. During 10-L batch fermentation, 152.52 g/L of Ca(2+)-PMA in the culture and 8.6 g/L of cell dry weight were obtained within 96 h, leaving 4.5 g/L of reducing sugar in the fermented medium. After purification of the Ca(2+)-PMA from the culture and acid hydrolysis of the purified Ca(2+)-PMA, HPLC analysis showed that A. pullulans var. pullulans MCW strain produced only one main component of Ca(2+) PMA and the hydrolysate of the purified Ca(2+)-PMA was mainly composed of L-malic acid. Mw (the apparent molecular weight) of the purified PMA was 2.054 * 10(5) (g/moL) and the purified PMA was estimated to be composed of 1784 L-malic acids. CONCLUSIONS: It was found that A. pullulans var. pullulans MCW strain obtained in this study could yield 152.52 g/L of Ca(2+)-PMA within the short time, the produced PMA had the highest molecular weight and the medium for production of Ca(2+)- PMA by this yeast was very simple. PMID- 26249336 TI - Recent Advances in Imaging of the Axial Skeleton in Spondyloarthritis for Diagnosis, Assessment of Treatment Effect, and Prognostication. AB - In the last few years, many studies have investigated the role of imaging for improved diagnosis, assessment of treatment effects, and determining prognosis in patients with axial spondyloarthritis (SpA). Recent research has primarily focused on the utility of magnetic resonance imaging (MRI) for improved diagnosis of patients with non-radiographic axial SpA, and in particular on the classification utility of the MRI criteria as defined by the Assessment of Spondyloarthritis International Society (ASAS). New and more sensitive methods for evaluation of MRI of the sacroiliac joints have been developed and have provided insight into effects of treatment on structural progression and the interrelationships between different lesions visualized by MRI. This review gives an overview of the recent advances in imaging of the axial skeleton in axial SpA from a clinical perspective. PMID- 26249337 TI - Lower prevalence of Lynch syndrome in colorectal cancer patients in a Japanese hospital-based population. AB - PURPOSE: The aim of this study was to investigate the prevalence of Lynch syndrome among Japanese patients with surgically resected colorectal cancer at a single institution. METHODS: Of 616 colorectal cancer patients who underwent surgical operation in our institution from January 2005 to August 2010, immunohistochemistry analyses for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) and microsatellite instability (MSI) testing for surgically resected, formalin-fixed paraffin-embedded colorectal cancer specimens from 138 colorectal cancer patients under 60 years of age were undertaken. Hypermethylation of the MLH1 promoter and BRAF mutation were analyzed where necessary. RESULTS: Seven patients were identified as candidates for genetic testing by mismatch repair protein loss (n = 7) or MSI-H (n = 6). Methylation of MLH1 was detected in one case. Three patients were diagnosed with Lynch syndrome, comprising 2.2 % of the total colorectal cancer patients younger than 60 years of age. CONCLUSION: The prevalence of Lynch syndrome among hospital-based diagnosed cancer patients may therefore be lower than expected in Japan compared with Western populations. PMID- 26249338 TI - Correction: chromatic response of polydiacetylene vesicle induced by the permeation of methotrexate. PMID- 26249339 TI - Peripheral blood derived mononuclear cells enhance osteoarthritic human chondrocyte migration. AB - INTRODUCTION: A major problem in cartilage repair is the lack of chondrogenic cells migrating from healthy tissue into defects. Cartilage is essentially avascular and therefore its healing is not considered to involve mononuclear cells. Peripheral blood derived mononuclear cells (PBMC) offer a readily available autologous cell source for clinical use and therefore this study was designed to evaluate the effects of PBMCs on chondrocytes and cartilage. METHODS: Human primary chondrocytes and cartilage tissue explants were taken from patients undergoing total knee replacement (n = 17). Peripheral blood samples were obtained from healthy volunteers (n = 12) and mononuclear cells were isolated by density-gradient centrifugation. Cell migration and chemokinetic potential were measured using a scratch assay, xCELLigence and CyQuant assay. PCR array and quantitative PCR was used to evaluate mRNA expression of 87 cell motility and/or chondrogenic genes. RESULTS: The chondrocyte migration rate was 2.6 times higher at 3 hour time point (p < 0.0001) and total number of migrating chondrocytes was 9.7 times higher (p < 0.0001) after three day indirect PBMC stimulus and 8.2 times higher (p < 0.0001) after three day direct co-culture with PBMCs. A cartilage explant model confirmed that PBMCs also exert a chemokinetic role on ex vivo tissue. PBMC stimulation was found to significantly upregulate the mRNA levels of 2 chondrogenic genes; collagen type II (COL2A1 600-fold, p < 0.0001) and SRY box 9 (SOX9 30-fold, p < 0.0001) and the mRNA levels of 7 genes central in cell motility and migration were differentially regulated by 24h PBMC stimulation. CONCLUSION: The results support the concept that PBMC treatment enhances chondrocyte migration without suppressing the chondrogenic phenotype possibly via mechanistic pathways involving MMP9 and IGF1. In the future, peripheral blood mononuclear cells could be used as an autologous point-ofcare treatment to attract native chondrocytes from the diseased tissue to aid in cartilage repair. PMID- 26249340 TI - Structural evidence for asymmetric ligand binding to transthyretin. AB - Human transthyretin (TTR) represents a notable example of an amyloidogenic protein, and several compounds that are able to stabilize its native state have been proposed as effective drugs in the therapy of TTR amyloidosis. The two thyroxine (T4) binding sites present in the TTR tetramer display negative binding cooperativity. Here, structures of TTR in complex with three natural polyphenols (pterostilbene, quercetin and apigenin) have been determined, in which this asymmetry manifests itself as the presence of a main binding site with clear ligand occupancy and related electron density and a second minor site with a much lower ligand occupancy. The results of an analysis of the structural differences between the two binding sites are consistent with such a binding asymmetry. The different ability of TTR ligands to saturate the two T4 binding sites of the tetrameric protein can be ascribed to the different affinity of ligands for the weaker binding site. In comparison, the high-affinity ligand tafamidis, co crystallized under the same experimental conditions, was able to fully saturate the two T4 binding sites. This asymmetry is characterized by the presence of small but significant differences in the conformation of the cavity of the two binding sites. Molecular-dynamics simulations suggest the presence of even larger differences in solution. Competition binding assays carried out in solution revealed the presence of a preferential binding site in TTR for the polyphenols pterostilbene and quercetin that was different from the preferential binding site for T4. The TTR binding asymmetry could possibly be exploited for the therapy of TTR amyloidosis by using a cocktail of two drugs, each of which exhibits preferential binding for a distinct binding site, thus favouring saturation of the tetrameric protein and consequently its stabilization. PMID- 26249341 TI - Structural basis of Deerpox virus-mediated inhibition of apoptosis. AB - Apoptosis is a key innate defence mechanism to eliminate virally infected cells. To counteract premature host-cell apoptosis, poxviruses have evolved numerous molecular strategies, including the use of Bcl-2 proteins, to ensure their own survival. Here, it is reported that the Deerpox virus inhibitor of apoptosis, DPV022, only engages a highly restricted set of death-inducing Bcl-2 proteins, including Bim, Bax and Bak, with modest affinities. Structural analysis reveals that DPV022 adopts a Bcl-2 fold with a dimeric domain-swapped topology and binds pro-death Bcl-2 proteins via two conserved ligand-binding grooves found on opposite sides of the dimer. Structures of DPV022 bound to Bim, Bak and Bax BH3 domains reveal that a partial obstruction of the binding groove is likely to be responsible for the modest affinities of DPV022 for BH3 domains. These findings reveal that domain-swapped dimeric Bcl-2 folds are not unusual and may be found more widely in viruses. Furthermore, the modest affinities of DPV022 for pro death Bcl-2 proteins suggest that two distinct classes of anti-apoptotic viral Bcl-2 proteins exist: those that are monomeric and tightly bind a range of death inducing Bcl-2 proteins, and others such as DPV022 that are dimeric and only bind a very limited number of death-inducing Bcl-2 proteins with modest affinities. PMID- 26249343 TI - Structural and adhesive properties of the long polar fimbriae protein LpfD from adherent-invasive Escherichia coli. AB - Crohn's disease (CD) is an inflammatory bowel disease characterized by an exaggerated immune response to commensal microbiota in the intestines of patients. Metagenomic studies have identified specific bacterial species and strains with increased prevalence in CD patients, amongst which is the adherent invasive Escherichia coli (AIEC) strain LF82. AIEC strains express long polar fimbriae (LPF), which are known to target Peyer's patches in a mouse CD model. Here, the recombinant production of a soluble, self-complemented construct of the LpfD protein of E. coli LF82 is reported and it is demonstrated that it forms the adhesive tip subunit of LPF. The LpfD crystal reveals an N-terminal adhesin domain and a C-terminal pilin domain that connects the adhesin to the minor pilus subunit LpfE. Surface topology and sequence conservation in the adhesin domain hint at a putative receptor-binding pocket as found in the Klebsiella pneumoniae MrkD and E. coli F17-G (GafD) adhesins. Immunohistostaining of murine intestinal tissue sections revealed that LpfD specifically binds to the intestinal mucosa and submucosa. LpfD binding was found to be resistant to treatment with O- or N glycosidases, but was lost in collagenase-treated tissue sections, indicating the possible involvement of an intestinal matrix-associated protein as the LpfD receptor. LpfD strongly adhered to isolated fibronectin in an in vitro assay, and showed lower levels of binding to collagen V and laminin and no binding to collagens I, III and IV. PMID- 26249342 TI - Detection of trans-cis flips and peptide-plane flips in protein structures. AB - A coordinate-based method is presented to detect peptide bonds that need correction either by a peptide-plane flip or by a trans-cis inversion of the peptide bond. When applied to the whole Protein Data Bank, the method predicts 4617 trans-cis flips and many thousands of hitherto unknown peptide-plane flips. A few examples are highlighted for which a correction of the peptide-plane geometry leads to a correction of the understanding of the structure-function relation. All data, including 1088 manually validated cases, are freely available and the method is available from a web server, a web-service interface and through WHAT_CHECK. PMID- 26249344 TI - Defined PEG smears as an alternative approach to enhance the search for crystallization conditions and crystal-quality improvement in reduced screens. AB - The quest for an optimal limited set of effective crystallization conditions remains a challenge in macromolecular crystallography, an issue that is complicated by the large number of chemicals which have been deemed to be suitable for promoting crystal growth. The lack of rational approaches towards the selection of successful chemical space and representative combinations has led to significant overlapping conditions, which are currently present in a multitude of commercially available crystallization screens. Here, an alternative approach to the sampling of widely used PEG precipitants is suggested through the use of PEG smears, which are mixtures of different PEGs with a requirement of either neutral or cooperatively positive effects of each component on crystal growth. Four newly defined smears were classified by molecular-weight groups and enabled the preservation of specific properties related to different polymer sizes. These smears not only allowed a wide coverage of properties of these polymers, but also reduced PEG variables, enabling greater sampling of other parameters such as buffers and additives. The efficiency of the smear-based screens was evaluated on more than 220 diverse recombinant human proteins, which overall revealed a good initial crystallization success rate of nearly 50%. In addition, in several cases successful crystallizations were only obtained using PEG smears, while various commercial screens failed to yield crystals. The defined smears therefore offer an alternative approach towards PEG sampling, which will benefit the design of crystallization screens sampling a wide chemical space of this key precipitant. PMID- 26249345 TI - Structures of substrate- and nucleotide-bound propionate kinase from Salmonella typhimurium: substrate specificity and phosphate-transfer mechanism. AB - Kinases are ubiquitous enzymes that are pivotal to many biochemical processes. There are contrasting views on the phosphoryl-transfer mechanism in propionate kinase, an enzyme that reversibly transfers a phosphoryl group from propionyl phosphate to ADP in the final step of non-oxidative catabolism of L-threonine to propionate. Here, X-ray crystal structures of propionate- and nucleotide-bound Salmonella typhimurium propionate kinase are reported at 1.8-2.0 A resolution. Although the mode of nucleotide binding is comparable to those of other members of the ASKHA superfamily, propionate is bound at a distinct site deeper in the hydrophobic pocket defining the active site. The propionate carboxyl is at a distance of ~ 5 A from the gamma-phosphate of the nucleotide, supporting a direct in-line transfer mechanism. The phosphoryl-transfer reaction is likely to occur via an associative SN2-like transition state that involves a pentagonal bipyramidal structure with the axial positions occupied by the nucleophile of the substrate and the O atom between the beta- and the gamma-phosphates, respectively. The proximity of the strictly conserved His175 and Arg236 to the carboxyl group of the propionate and the gamma-phosphate of ATP suggests their involvement in catalysis. Moreover, ligand binding does not induce global domain movement as reported in some other members of the ASKHA superfamily. Instead, residues Arg86, Asp143 and Pro116-Leu117-His118 that define the active-site pocket move towards the substrate and expel water molecules from the active site. The role of Ala88, previously proposed to be the residue determining substrate specificity, was examined by determining the crystal structures of the propionate bound Ala88 mutants A88V and A88G. Kinetic analysis and structural data are consistent with a significant role of Ala88 in substrate-specificity determination. The active-site pocket-defining residues Arg86, Asp143 and the Pro116-Leu117-His118 segment are also likely to contribute to substrate specificity. PMID- 26249346 TI - The quaternary structure of the eukaryotic DNA replication proteins Sld7 and Sld3. AB - The initiation of eukaryotic chromosomal DNA replication requires the formation of an active replicative helicase at the replication origins of chromosomes. Yeast Sld3 and its metazoan counterpart treslin are the hub proteins mediating protein associations critical for formation of the helicase. The Sld7 protein interacts with Sld3, and the complex formed is thought to regulate the function of Sld3. Although Sld7 is a non-essential DNA replication protein that is found in only a limited range of yeasts, its depletion slowed the growth of cells and caused a delay in the S phase. Recently, the Mdm2-binding protein was found to bind to treslin in humans, and its depletion causes defects in cells similar to the depletion of Sld7 in yeast, suggesting their functional relatedness and importance during the initiation step of DNA replication. Here, the crystal structure of Sld7 in complex with Sld3 is presented. Sld7 comprises two structural domains. The N-terminal domain of Sld7 binds to Sld3, and the C terminal domains connect two Sld7 molecules in an antiparallel manner. The quaternary structure of the Sld3-Sld7 complex shown from the crystal structures appears to be suitable to activate two helicase molecules loaded onto replication origins in a head-to-head manner. PMID- 26249347 TI - Predicting X-ray diffuse scattering from translation-libration-screw structural ensembles. AB - Identifying the intramolecular motions of proteins and nucleic acids is a major challenge in macromolecular X-ray crystallography. Because Bragg diffraction describes the average positional distribution of crystalline atoms with imperfect precision, the resulting electron density can be compatible with multiple models of motion. Diffuse X-ray scattering can reduce this degeneracy by reporting on correlated atomic displacements. Although recent technological advances are increasing the potential to accurately measure diffuse scattering, computational modeling and validation tools are still needed to quantify the agreement between experimental data and different parameterizations of crystalline disorder. A new tool, phenix.diffuse, addresses this need by employing Guinier's equation to calculate diffuse scattering from Protein Data Bank (PDB)-formatted structural ensembles. As an example case, phenix.diffuse is applied to translation-libration screw (TLS) refinement, which models rigid-body displacement for segments of the macromolecule. To enable the calculation of diffuse scattering from TLS-refined structures, phenix.tls_as_xyz builds multi-model PDB files that sample the underlying T, L and S tensors. In the glycerophosphodiesterase GpdQ, alternative TLS-group partitioning and different motional correlations between groups yield markedly dissimilar diffuse scattering maps with distinct implications for molecular mechanism and allostery. These methods demonstrate how, in principle, X ray diffuse scattering could extend macromolecular structural refinement, validation and analysis. PMID- 26249348 TI - From deep TLS validation to ensembles of atomic models built from elemental motions. AB - The translation-libration-screw model first introduced by Cruickshank, Schomaker and Trueblood describes the concerted motions of atomic groups. Using TLS models can improve the agreement between calculated and experimental diffraction data. Because the T, L and S matrices describe a combination of atomic vibrations and librations, TLS models can also potentially shed light on molecular mechanisms involving correlated motions. However, this use of TLS models in mechanistic studies is hampered by the difficulties in translating the results of refinement into molecular movement or a structural ensemble. To convert the matrices into a constituent molecular movement, the matrix elements must satisfy several conditions. Refining the T, L and S matrix elements as independent parameters without taking these conditions into account may result in matrices that do not represent concerted molecular movements. Here, a mathematical framework and the computational tools to analyze TLS matrices, resulting in either explicit decomposition into descriptions of the underlying motions or a report of broken conditions, are described. The description of valid underlying motions can then be output as a structural ensemble. All methods are implemented as part of the PHENIX project. PMID- 26249349 TI - A binding hotspot in Trypanosoma cruzi histidyl-tRNA synthetase revealed by fragment-based crystallographic cocktail screens. AB - American trypanosomiasis, commonly known as Chagas disease, is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. The chronic form of the infection often causes debilitating morbidity and mortality. However, the current treatment for the disease is typically inadequate owing to drug toxicity and poor efficacy, necessitating a continual effort to discover and develop new antiparasitic therapeutic agents. The structure of T. cruzi histidyl tRNA synthetase (HisRS), a validated drug target, has previously been reported. Based on this structure and those of human cytosolic HisRS, opportunities for the development of specific inhibitors were identified. Here, efforts are reported to identify small molecules that bind to T. cruzi HisRS through fragment-based crystallographic screening in order to arrive at chemical starting points for the development of specific inhibitors. T. cruzi HisRS was soaked into 68 different cocktails from the Medical Structural Genomics of Pathogenic Protozoa (MSGPP) fragment library and diffraction data were collected to identify bound fragments after soaking. A total of 15 fragments were identified, all bound to the same site on the protein, revealing a fragment-binding hotspot adjacent to the ATP binding pocket. On the basis of the initial hits, the design of reactive fragments targeting the hotspot which would be simultaneously covalently linked to a cysteine residue present only in trypanosomatid HisRS was initiated. Inhibition of T. cruzi HisRS was observed with the resultant reactive fragments and the anticipated binding mode was confirmed crystallographically. These results form a platform for the development of future generations of selective inhibitors for trypanosomatid HisRS. PMID- 26249350 TI - Structure of the green fluorescent protein NowGFP with an anionic tryptophan based chromophore. AB - A green-emitting fluorescent variant, NowGFP, with a tryptophan-based chromophore (Thr65-Trp66-Gly67) was recently developed from the cyan mCerulean by introducing 18 point mutations. NowGFP is characterized by bright green fluorescence at physiological and higher pH and by weak cyan fluorescence at low pH. Illumination with blue light induces irreversible photoconversion of NowGFP from a green emitting to a cyan-emitting form. Here, the X-ray structures of intact NowGFP at pH 9.0 and pH 4.8 and of its photoconverted variant, NowGFP_conv, are reported at 1.35, 1.18 and 2.5 A resolution, respectively. The structure of NowGFP at pH 9.0 suggests the anionic state of Trp66 of the chromophore to be the primary cause of its green fluorescence. At both examined pH values Trp66 predominantly adopted a cis conformation; only ~ 20% of the trans conformation was observed at pH 4.8. It was shown that Lys61, which adopts two distinct pH-dependent conformations, is a key residue playing a central role in chromophore ionization. At high pH the side chain of Lys61 forms two hydrogen bonds, one to the indole N atom of Trp66 and the other to the carboxyl group of the catalytic Glu222, enabling an indirect noncovalent connection between them that in turn promotes Trp66 deprotonation. At low pH, the side chain of Lys61 is directed away from Trp66 and forms a hydrogen bond to Gln207. It has been shown that photoconversion of NowGFP is accompanied by decomposition of Lys61, with a predominant cleavage of its side chain at the C(gamma)-C(delta) bond. Lys61, Glu222, Thr203 and Ser205 form a local hydrogen bond network connected to the indole ring of the chromophore Trp66; mutation of any of these residues dramatically affects the spectral properties of NowGFP. On the other hand, an Ala150Val replacement in the vicinity of the chromophore indole ring resulted in a new advanced variant with a 2.5-fold improved photostability. PMID- 26249351 TI - An unexpected reactivity of the P460 cofactor in hydroxylamine oxidoreductase. AB - Hydroxylamine oxidoreductases (HAOs) contain a unique haem cofactor called P460 that consists of a profoundly ruffled c-type haem with two covalent bonds between the haem porphyrin and a conserved tyrosine. This cofactor is exceptional in that it abstracts electrons from a ligand bound to the haem iron, whereas other haems involved in redox chemistry usually inject electrons into their ligands. The effects of the tyrosine cross-links and of the haem ruffling on the chemistry of this cofactor have been investigated theoretically but are not yet clear. A new crystal structure of an HAO from Candidatus Kuenenia stuttgartiensis, a model organism for anaerobic ammonium oxidation, now shows that its P460 cofactor has yet another unexpected reactivity: when ethylene glycol was used as a cryoprotectant, the 1.8 A resolution electron-density maps showed additional density which could be interpreted as an ethylene glycol molecule covalently bound to the C16 atom of the haem ring, opposite the covalent links to the conserved tyrosine. Possible causes for this unexpected reactivity are discussed. PMID- 26249352 TI - The first crystal structure of a glycoside hydrolase family 17 beta-1,3 glucanosyltransferase displays a unique catalytic cleft. AB - beta-1,3-Glucanosyltransferase (EC 2.4.1.-) plays an important role in the formation of branched glucans, as well as in cell-wall assembly and rearrangement in fungi and yeasts. The crystal structures of a novel glycoside hydrolase (GH) family 17 beta-1,3-glucanosyltransferase from Rhizomucor miehei (RmBgt17A) and the complexes of its active-site mutant (E189A) with two substrates were solved at resolutions of 1.30, 2.30 and 2.27 A, respectively. The overall structure of RmBgt17A had the characteristic (beta/alpha)8 TIM-barrel fold. The structures of RmBgt17A and other GH family 17 members were compared: it was found that a conserved subdomain located in the region near helix alpha6 and part of the catalytic cleft in other GH family 17 members was absent in RmBgt17A. Instead, four amino-acid residues exposed to the surface of the enzyme (Tyr135, Tyr136, Glu158 and His172) were found in the reducing terminus of subsite +2 of RmBgt17A, hindering access to the catalytic cleft. This distinct region of RmBgt17A makes its catalytic cleft shorter than those of other reported GH family 17 enzymes. The complex structures also illustrated that RmBgt17A can only provide subsites 3 to +2. This structural evidence provides a clear explanation of the catalytic mode of RmBgt17A, in which laminaribiose is released from the reducing end of linear beta-1,3-glucan and the remaining glucan is transferred to the end of another beta-1,3-glucan acceptor. The first crystal structure of a GH family 17 beta-1,3-glucanosyltransferase may be useful in studies of the catalytic mechanism of GH family 17 proteins, and provides a basis for further enzymatic engineering or antifungal drug screening. PMID- 26249354 TI - Structure of shikimate kinase, an in vivo essential metabolic enzyme in the nosocomial pathogen Acinetobacter baumannii, in complex with shikimate. AB - Acinetobacter baumannii is an opportunistic Gram-negative pathogen that is an important cause of healthcare-associated infections exhibiting high mortality rates. Clinical isolates of multidrug-resistant (MDR) and extremely drug resistant (XDR) A. baumannii strains are increasingly being observed. Compounding this concern is the dearth of new antibacterial agents in late-stage development that are effective against MDR and XDR A. baumannii. As part of an effort to address these concerns, two genes (aroA and aroC) of the shikimate pathway have previously been determined to be essential for the growth and survival of A. baumannii during host infection (i.e. to be essential in vivo). This study expands upon these results by demonstrating that the A. baumannii aroK gene, encoding shikimate kinase (SK), is also essential in vivo in a rat soft-tissue infection model. The crystal structure of A. baumannii SK in complex with the substrate shikimate and a sulfate ion that mimics the binding interactions expected for the beta-phosphate of ATP was then determined to 1.91 A resolution and the enzyme kinetics were characterized. The flexible shikimate-binding domain and LID region are compared with the analogous regions in other SK crystal structures. The impact of structural differences and sequence divergence between SKs from pathogenic bacteria that may influence antibiotic-development efforts is discussed. PMID- 26249353 TI - Three-dimensional structure of the human breast cancer resistance protein (BCRP/ABCG2) in an inward-facing conformation. AB - ABCG2 is an efflux drug transporter that plays an important role in drug resistance and drug disposition. In this study, the first three-dimensional structure of human full-length ABCG2 analysed by electron crystallography from two-dimensional crystals in the absence of nucleotides and transported substrates is reported at 2 nm resolution. In this state, ABCG2 forms a symmetric homodimer with a noncrystallographic twofold axis perpendicular to the two-dimensional crystal plane, as confirmed by subtomogram averaging. This configuration suggests an inward-facing configuration similar to murine ABCB1, with the nucleotide binding domains (NBDs) widely separated from each other. In the three-dimensional map, densities representing the long cytoplasmic extensions from the transmembrane domains that connect the NBDs are clearly visible. The structural data have allowed the atomic model of ABCG2 to be refined, in which the two arms of the V-shaped ABCG2 homodimeric complex are in a more closed and narrower conformation. The structural data and the refined model of ABCG2 are compatible with the biochemical analysis of the previously published mutagenesis studies, providing novel insight into the structure and function of the transporter. PMID- 26249355 TI - Structural and biophysical characterization of the alpha-carbonic anhydrase from the gammaproteobacterium Thiomicrospira crunogena XCL-2: insights into engineering thermostable enzymes for CO2 sequestration. AB - Biocatalytic CO2 sequestration to reduce greenhouse-gas emissions from industrial processes is an active area of research. Carbonic anhydrases (CAs) are attractive enzymes for this process. However, the most active CAs display limited thermal and pH stability, making them less than ideal. As a result, there is an ongoing effort to engineer and/or find a thermostable CA to fulfill these needs. Here, the kinetic and thermal characterization is presented of an alpha-CA recently discovered in the mesophilic hydrothermal vent-isolate extremophile Thiomicrospira crunogena XCL-2 (TcruCA), which has a significantly higher thermostability compared with human CA II (melting temperature of 71.9 degrees C versus 59.5 degrees C, respectively) but with a tenfold decrease in the catalytic efficiency. The X-ray crystallographic structure of the dimeric TcruCA shows that it has a highly conserved yet compact structure compared with other alpha-CAs. In addition, TcruCA contains an intramolecular disulfide bond that stabilizes the enzyme. These features are thought to contribute significantly to the thermostability and pH stability of the enzyme and may be exploited to engineer alpha-CAs for applications in industrial CO2 sequestration. PMID- 26249356 TI - Fully automatic characterization and data collection from crystals of biological macromolecules. AB - Considerable effort is dedicated to evaluating macromolecular crystals at synchrotron sources, even for well established and robust systems. Much of this work is repetitive, and the time spent could be better invested in the interpretation of the results. In order to decrease the need for manual intervention in the most repetitive steps of structural biology projects, initial screening and data collection, a fully automatic system has been developed to mount, locate, centre to the optimal diffraction volume, characterize and, if possible, collect data from multiple cryocooled crystals. Using the capabilities of pixel-array detectors, the system is as fast as a human operator, taking an average of 6 min per sample depending on the sample size and the level of characterization required. Using a fast X-ray-based routine, samples are located and centred systematically at the position of highest diffraction signal and important parameters for sample characterization, such as flux, beam size and crystal volume, are automatically taken into account, ensuring the calculation of optimal data-collection strategies. The system is now in operation at the new ESRF beamline MASSIF-1 and has been used by both industrial and academic users for many different sample types, including crystals of less than 20 um in the smallest dimension. To date, over 8000 samples have been evaluated on MASSIF-1 without any human intervention. PMID- 26249357 TI - Structure of the DNA-binding domain of the response regulator SaeR from Staphylococcus aureus. AB - The SaeR/S two-component regulatory system is essential for controlling the expression of many virulence factors in Staphylococcus aureus. SaeR, a member of the OmpR/PhoB family, is a response regulator with an N-terminal regulatory domain and a C-terminal DNA-binding domain. In order to elucidate how SaeR binds to the promoter regions of target genes, the crystal structure of the DNA-binding domain of SaeR (SaeR(DBD)) was solved at 2.5 A resolution. The structure reveals that SaeR(DBD) exists as a monomer and has the canonical winged helix-turn-helix module. EMSA experiments suggested that full-length SaeR can bind to the P1 promoter and that the binding affinity is higher than that of its C-terminal DNA binding domain. Five key residues on the winged helix-turn-helix module were verified to be important for binding to the P1 promoter in vitro and for the physiological function of SaeR in vivo. PMID- 26249358 TI - Combining 'dry' co-crystallization and in situ diffraction to facilitate ligand screening by X-ray crystallography. AB - X-ray crystallography is an established technique for ligand screening in fragment-based drug-design projects, but the required manual handling steps - soaking crystals with ligand and the subsequent harvesting - are tedious and limit the throughput of the process. Here, an alternative approach is reported: crystallization plates are pre-coated with potential binders prior to protein crystallization and X-ray diffraction is performed directly 'in situ' (or in plate). Its performance is demonstrated on distinct and relevant therapeutic targets currently being studied for ligand screening by X-ray crystallography using either a bending-magnet beamline or a rotating-anode generator. The possibility of using DMSO stock solutions of the ligands to be coated opens up a route to screening most chemical libraries. PMID- 26249360 TI - LIFR functions as a metastasis suppressor in hepatocellular carcinoma by negatively regulating phosphoinositide 3-kinase/AKT pathway. AB - Hepatocellular carcinoma (HCC) is one of the leading causes for cancer related mortality worldwide. Poor prognosis of HCC patients is mainly due to frequent metastasis and recurrence. Deregulation of metastasis suppressors in malignant cells plays critical roles during cancer metastasis. Thus, novel metastasis suppressors are urgently needed to be uncovered to shed new light on molecular mechanisms driving HCC metastasis. In the present study, decreased expression of leukemia inhibitory factor receptor (LIFR) was demonstrated in HCC, and its expression levels were even lower in HCC with metastasis. Downregulated LIFR expression predicted poor prognosis in HCC patients. LIFR was an independent and significant risk factor for their recurrence and survival. Silencing LIFR resulted in forced metastasis of HCC cells, whereas ectopic overexpression of LIFR attenuated migration and invasion of HCC cells in vitro and in vivo. Moreover, LIFR knockdown could activate phosphoinositide 3-kinase/V-akt Murine Thymoma Viral Oncogene Homolog (PI3K/AKT) signaling through enhancing phosphorylation of Janus kinase 1 (JAK1), which successively promoted matrix metalloproteinase 13 (MMP13) expression and HCC metastasis. Combination of LIFR and p-AKT or MMP13 was a more powerful predictor of poor prognosis for HCC patients. Together, these findings conclude that LIFR functions as a novel metastasis suppressor in HCC and may serve as a prognostic biomarker for HCC patients. PMID- 26249359 TI - Disruptive viability selection on a black plumage trait associated with dominance. AB - Traits used in communication, such as colour signals, are expected to have positive consequences for reproductive success, but their associations with survival are little understood. Previous studies have mainly investigated linear relationships between signals and survival, but both hump-shaped and U-shaped relationships can also be predicted, depending on the main costs involved in trait expression. Furthermore, few studies have taken the plasticity of signals into account in viability selection analyses. The relationship between signal expression and survival is of particular interest in melanin-based traits, because their main costs are still debated. Here, we first determined the main factors explaining variability in a melanin-based trait linked to dominance: the bib size of a colonial bird, the sociable weaver Philetairus socius. We then used these analyses to obtain a measure representative of the individual mean expression of bib size. Finally, we used capture-recapture models to study how survival varied in relation to bib size. Variation in bib size was strongly affected by year and moderately affected by age, body condition and colony size. In addition, individuals bearing small and large bibs had higher survival than those with intermediate bibs, and this U-shaped relationship between survival and bib size appeared to be more pronounced in some years than others. These results constitute a rare example of disruptive viability selection, and point towards the potential importance of social costs incurred by the dominance signalling function of badges of status. PMID- 26249361 TI - In vivo behavior of hydroxyapatite/beta-TCP/collagen scaffold in animal model. Histological, histomorphometrical, radiological, and SEM analysis at 15, 30, and 60 days. AB - OBJECTIVE: The aim of this study was to fabricate and characterize HA/beta TCP/collagen ceramic scaffolds of different composition ratios and compare their physical and In vivo mechanical behavior. MATERIALS AND METHODS: Three groups of twenty samples each one of calcium-phosphate ceramic scaffold cylindrical implants (6 +/- 0.01 mm in diameter and 2 +/- 0.01 mm in length) were studied with varying wt % HA/wt % TCP/wt % Collagen composition: Group A: 40/30/30; Group B: 50/20/30; Group C: 60/20/20. A fourth group, Group D (unfilled critical size defect), acted as control. Three times of work were established 15, 30, and 60 days. Characterization, histological, histomorphometric, SEM, and radiological analysis were performed. RESULTS: Micrographs obtained on the different composites are comparable, it is possible observe that the materials revealed a microporous morphology formed by aggregated nanoparticles independently of the composition of the composite. BIC values for the three materials, with Group A showing best BIC at 15, 30, and 60 days (43.12 +/- 0.14; 52.49 +/- 1.08 and 67.23% +/- 0.34) (with closer contact observed) than Group B (38.84 +/- 1.32; 47.64 +/- 1.21 and 54.87 +/- 0.32), followed by Group C (28.92 +/- 2.41; 35.94 +/ 1.92 and 48.53 +/- 0.31). CONCLUSIONS: The influence of time on the biological behavior of biomaterials studied has been demonstrated by varying the percentage of bone-implant contact and bone formation to obtain the best results at 60 days. PMID- 26249362 TI - Evaluation of bone remodeling around single dental implants of different lengths: a mechanobiological numerical simulation and validation using clinical data. AB - Algorithmic models have been proposed to explain adaptive behavior of bone to loading; however, these models have not been applied to explain the biomechanics of short dental implants. Purpose of present study was to simulate bone remodeling around single implants of different lengths using mechanoregulatory tissue differentiation model derived from the Stanford theory, using finite elements analysis (FEA) and to validate the theoretical prediction with the clinical findings of crestal bone loss. Loading cycles were applied on 7-, 10-, or 13-mm-long dental implants to simulate daily mastication and bone remodeling was assessed by changes in the strain energy density of bone after a 3, 6, and 12 months of function. Moreover, clinical findings of marginal bone loss in 45 patients rehabilitated with same implant designs used in the simulation (n = 15) were computed to validate the theoretical results. FEA analysis showed that although the bone density values reduced over time in the cortical bone for all groups, bone remodeling was independent of implant length. Clinical data showed a similar pattern of bone resorption compared with the data generated from mathematical analyses, independent of implant length. The results of this study showed that the mechanoregulatory tissue model could be employed in monitoring the morphological changes in bone that is subjected to biomechanical loads. In addition, the implant length did not influence the bone remodeling around single dental implants during the first year of loading. PMID- 26249363 TI - Coupling of individual quantum emitters to channel plasmons. AB - Efficient light-matter interaction lies at the heart of many emerging technologies that seek on-chip integration of solid-state photonic systems. Plasmonic waveguides, which guide the radiation in the form of strongly confined surface plasmon-polariton modes, represent a promising solution to manipulate single photons in coplanar architectures with unprecedented small footprints. Here we demonstrate coupling of the emission from a single quantum emitter to the channel plasmon polaritons supported by a V-groove plasmonic waveguide. Extensive theoretical simulations enable us to determine the position and orientation of the quantum emitter for optimum coupling. Concomitantly with these predictions, we demonstrate experimentally that 42% of a single nitrogen-vacancy centre emission efficiently couples into the supported modes of the V-groove. This work paves the way towards practical realization of efficient and long distance transfer of energy for integrated solid-state quantum systems. PMID- 26249364 TI - Conformational studies of dammarane-type triterpenoids using computational and NMR spectroscopic methods. AB - Natural triterpenoids are of great interest to researchers of various fields as they possess diverse physicochemical and biological properties. In medicinal chemistry, detailed information about the chemical structures of bioactive triterpenoids often helps find new lead compounds. Herein, the low-energy structures of (20S)-protopanaxadiol and (20S)-protopanaxatriol, the aglycones of various triterpenoid saponins found in Panax ginseng, and their (20R)-epimers have been predicted by the geometry optimization of the conformers extracted from molecular dynamics simulations with the self-consistent-charge density functional tight-binding method. By performing quantum mechanical calculations on the low energy conformers, we have estimated the NMR chemical shifts of the compounds, which display good agreement with the most recently reported experimental values within an expected range of errors. Our results indicate that theoretical estimation of the NMR parameters of a relatively large molecule with a molecular mass of 500 is feasible. PMID- 26249365 TI - Metabolomics of cocaine: implications in toxicity. AB - Cocaine is the most commonly used illicit drug among those seeking care in Emergency Departments or drug detoxification centers. Cocaine, chemically known as benzoylmethylecgonine, is a naturally occurring substance found in the leaves of the Erythroxylum coca plant. The pharmacokinetics of cocaine is dependent on multiple factors, such as physical/chemical form, route of administration, genetics and concurrent consumption of alcohol. This review aims to discuss metabolomics of cocaine, namely by presenting all known metabolites of cocaine and their roles in the cocaine-mediated toxic effects. PMID- 26249366 TI - Mismatch extension of DNA polymerases and high-accuracy single nucleotide polymorphism diagnostics by gold nanoparticle-improved isothermal amplification. AB - Sequence mismatches may induce nonspecific extension reaction, causing false results for SNP diagnostics. Herein, we systematically investigated the impact of various 3'-terminal mismatches on isothermal amplification catalyzed by representative DNA polymerases. Despite their diverse efficiencies depending on types of mismatch and kinds of DNA polymerase, all 12 kinds of single 3'-terminal mismatches induced the extension reaction. Generally, only several mismatches (primer-template, C-C, G-A, A-G, and A-A) present an observable inhibitory effect on the amplification reaction, whereas other mismatches trigger amplified signals as high as those of Watson-Crick pairs. The related mechanism was deeply discussed, and a primer-design guideline for specific SNP analysis was summarized. Furthermore, we found that the addition of appropriate gold nanoparticles (AuNPs) can significantly inhibit mismatch extension and enhance the amplification specificity. Also the high-accuracy SNP analysis of human blood genomic DNA has been demonstrated by AuNPs-improved isothermal amplification, the result of which was verified by sequencing (the gold standard method for SNP assay). Collectively, this work provides mechanistic insight into mismatch behavior and achieves accurate SNP diagnostics, holding great potential for the application in molecular diagnostics and personalized medicine. PMID- 26249367 TI - Diverse Fibrosis Architecture and Premature Stimulation Facilitate Initiation of Reentrant Activity Following Chronic Atrial Fibrillation. AB - INTRODUCTION: Patients with paroxysmal atrial fibrillation (AF) often transition between sinus rhythm and AF. For AF to initiate there must be both a trigger and a substrate that facilitates reentrant activity. This trigger is often caused by a premature atrial contraction or focal activations within the atrium. We hypothesize that specific architectures of fibrosis alter local conduction to enable AF. METHODS AND RESULTS: Control goats (n = 13) and goats in chronic AF (for an average of 6 months, n = 6) had a high-density electrode plaque placed on the LA appendage. Conduction patterns following a premature atrial contraction, caused by an electrical stimulation, were quantified to determine regions of conduction slowing. These regions were compared to architecture, either diffuse fibrosis or regions of obstructive fibrosis, and overall fibrosis levels as determined by histology from the mapped region. The chronic AF goats had more obstructive fibrosis than the controls (17.5 +/- 8.0 fibers/mm(2) vs. 8.6 +/- 3.0 fibers/mm(2)). Conduction velocity of the AF goats was significantly slowed compared to the control goats in the transverse direction (0.40 +/- 0.04 m/s vs. 0.53 +/- 0.15 m/s) but not in the longitudinal direction (0.70 +/- 0.27 m/s vs. 0.76 +/- 0.18 m/s). CONCLUSIONS: AF-induced atrial remodeling leads to increased obstructive fibrosis and conduction velocity slowing transverse to fiber orientation following premature stimuli. The decrease in conduction velocity causes a decrease in the cardiac wavelength, and increases the likelihood of reentry and AF onset. PMID- 26249369 TI - Differential functional brain network connectivity during visceral interoception as revealed by independent component analysis of fMRI TIME-series. AB - Influential theories of brain-viscera interactions propose a central role for interoception in basic motivational and affective feeling states. Recent neuroimaging studies have underlined the insula, anterior cingulate, and ventral prefrontal cortices as the neural correlates of interoception. However, the relationships between these distributed brain regions remain unclear. In this study, we used spatial independent component analysis (ICA) and functional network connectivity (FNC) approaches to investigate time course correlations across the brain regions during visceral interoception. Functional magnetic resonance imaging (fMRI) was performed in thirteen healthy females who underwent viscerosensory stimulation of bladder as a representative internal organ at different prefill levels, i.e., no prefill, low prefill (100 ml saline), and high prefill (individually adapted to the sensations of persistent strong desire to void), and with different infusion temperatures, i.e., body warm (~37 degrees C) or ice cold (4-8 degrees C) saline solution. During Increased distention pressure on the viscera, the insula, striatum, anterior cingulate, ventromedial prefrontal cortex, amygdalo-hippocampus, thalamus, brainstem, and cerebellar components showed increased activation. A second group of components encompassing the insula and anterior cingulate, dorsolateral prefrontal and posterior parietal cortices and temporal-parietal junction showed increased activity with innocuous temperature stimulation of bladder mucosa. Significant differences in the FNC were found between the insula and amygdalo-hippocampus, the insula and ventromedial prefrontal cortex, and the ventromedial prefrontal cortex and temporal-parietal junction as the distention pressure on the viscera increased. These results provide new insight into the supraspinal processing of visceral interoception originating from an internal organ. PMID- 26249370 TI - Association between interleukin 8-251 T/A and +781 C/T polymorphisms and glioma risk. AB - BACKGROUND: Gliomas are aggressive tumors of the central nervous system that rely on production of growth factors for tumor progression. Interleukin 8 (IL-8) is up regulated in gliomas to promote angiogenesis and proliferation. The aim of this study was to evaluate the association of the IL-8 -251 T/A and +781 C/T polymorphisms and glioma risk. METHODS: We enrolled 300 glioma patients and 300 age- and gender-matched healthy controls. A prospective hospital-based case control design and logistic regression analysis were utilized. The IL-8 gene polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Glioma patients had a significantly higher frequency of IL-8 -251 AA genotype [odds ratio (OR) =1.91, 95% confidence interval (CI) = 1.22, 3.00; P = 0.005] and IL-8 -251 A allele (OR =1.36, 95% CI = 1.08, 1.70; P = 0.009) than controls. When stratified by the grade of glioma, patients with WHO IV glioma had a significantly higher frequency of IL-8 -251 AA genotype (OR =1.56, 95% CI = 1.01, 2.39; P = 0.04). CONCLUSIONS: To the best of our knowledge, this is the first report in the literature that the IL-8 -251 AA genotype and A allele were at a higher risk for glioma. PMID- 26249372 TI - Revisional studies on the Luciolinae fireflies of Asia (Coleoptera: Lampyridae): 1. The genus Pyrophanes Olivier with two new species. 2. Four new species of Pteroptyx Olivier and 3. A new genus Inflata Boontop, with redescription of Luciola indica (Motsch.) as Inflata indica comb. nov. AB - The Luciolinae firefly genus Pyrophanes is redescribed and a key is provided for 7 species, viz. appendiculata Olivier, beccarii Olivier, quadrimaculata Olivier, semilimbata (Olivier) and similis Olivier, with Py. elongata Ballantyne sp. nov. and Py. similisimma Ballantyne sp. nov. described as new. Macropterous females associated for several species have 2 pairs of broad bursa plates. Following an enlarged phylogenetic analysis of morphological characters, an expanded generic description of Pteroptyx Olivier now accommodates four new species with metafemoral combs. Three of these have an entire light organ in ventrite 7 but are without the generic hallmark of deflexed elytral apices in the male. The first species of Pteroptyx to possess these features are Pt. sayangia Ballantyne sp. nov., Pt. galbina Jusoh sp. nov. and Pt. surabayia Ballantyne sp. nov. Based on a single unusual specimen Pt. gombakia Ballantyne sp. nov. is here described with deflexed elytral apices and bipartite light organ in ventrite 7, but with exceptional incurving lobes along the posterior margin of ventrite 7, which is a characteristic of Pyrophanes. The description of Luciola testacea Motschulsky is discussed and many morphological characters of its type specimen are correctly outlined. Its place as the type for Pteroptyx is addressed. Inflata gen. nov. Boontop is erected for specimens of Luciola indica Motschulsky as Inflata indica (Motsch.) comb. nov., and is described from males and reliably associated females. Discussion overviews the present situation regarding Luciolinae taxonomy of southeast Asian and the Australopacific regions. PMID- 26249371 TI - Two different immunostaining patterns of beta-amyloid precursor protein (APP) may distinguish traumatic from nontraumatic axonal injury. AB - Immunostaining for beta-amyloid precursor protein (APP) is recognized as an effective tool for detecting traumatic axonal injury, but it also detects axonal injury due to ischemic or other metabolic causes. Previously, we reported two different patterns of APP staining: labeled axons oriented along with white matter bundles (pattern 1) and labeled axons scattered irregularly (pattern 2) (Hayashi et al. (Leg Med (Tokyo) 11:S171-173, 2009). In this study, we investigated whether these two patterns are consistent with patterns of trauma and hypoxic brain damage, respectively. Sections of the corpus callosum from 44 cases of blunt head injury and equivalent control tissue were immunostained for APP. APP was detected in injured axons such as axonal bulbs and varicose axons in 24 of the 44 cases of head injuries that also survived for three or more hours after injury. In 21 of the 24 APP-positive cases, pattern 1 alone was observed in 14 cases, pattern 2 alone was not observed in any cases, and both patterns 1 and 2 were detected in 7 cases. APP-labeled injured axons were detected in 3 of the 44 control cases, all of which were pattern 2. These results suggest that pattern 1 indicates traumatic axonal injury, while pattern 2 results from hypoxic insult. These patterns may be useful to differentiate between traumatic and nontraumatic axonal injuries. PMID- 26249373 TI - Spathius Nees, 1818 (Hymenoptera: Braconidae, Doryctinae) from China with a key to species. AB - One hundred and twenty-nine Chinese species of Spathius Nees, 1819 are recognized, of which thirty-five species are described as new to science: S. aciculatus sp. nov., S. albithorax sp. nov., S. angustalatus sp. nov., S. aspratiloides sp. nov., S. basalis sp. nov., S. beatoides sp. nov., S. cephalus sp. nov., S. clavator sp. nov., S. daweiensis sp. nov., S. ferrugineus sp. nov., S. flavicorpus sp. nov., S. gutianensis sp. nov., S. hainanicola sp. nov., S. longulator sp. nov., S. macrurus sp. nov., S. moscoides sp. nov., S. nehebrus sp. nov., S. neleiformis sp. nov., S. parallelus sp. nov., S. parimbecillus sp. nov., S. proximoscus sp. nov., S. pseudaphareus sp. nov., S. pseudido sp. nov., S. pseudocritolaus sp. nov., S. quasiasander sp. nov., S. rectangulus sp. nov., S. rugosivertex sp. nov., S. spinosus sp. nov., S. striolatiformis sp. nov., S. subcyparissus sp. nov., S. suberymanthus sp. nov., S. tanae sp. nov., S. virgulatus sp. nov., S. wuae sp. nov., and S. xui sp. nov. Twenty-eight species are recorded from China for the first time: S. amoenus Belokobylskij, 1998; S. capys Nixon, 1943; S. cavus Belokobylskij, 1998; S. cyparissus Nixon, 1943; S. depressithorax Belokobylskij, 1998; S. fasciatus Walker, 1874; S. femoralis (Westwood, 1882); S. galinae Belokobylskij et Strazanac, 2012; S. habui Belokobylskij et Maeto, 2009; S. hephaestus Nixon, 1943; S. hikoensis Belokobylskij, 1998; S. ibarakius Belokobylskij et Maeto, 2009; S. ishigakus Belokobylskij 2009; S. konishii Belokobylskij, 2009; S. kunashiri Belokobylskij, 1998; S. leschii Belokobylskij, 1998; S. longipetiolus Belokobylskij et Maeto, 2009; S. melpomene Nixon, 1943; S. nixoni Belokobylskij et Maeto, 2009; S. paramoenus Belokobylskij et Maeto, 2009; S. parochus Belokobylskij et Maeto, 2009; S. piperis Wilkinson, 1931; S. planus Belokobylskij, 1998; S. pseudaspersus Belokobylskij, 2009; S. pumilio Belokobylskij, 2009; S. rubidus (Rossi, 1794); S. testaceitarsis (Cameron, 1908), and S. vladimiri Belokobylskij, 1998. The following new synonyms are proposed: S. crebristriatus Chao, 1978 and S. mundus Chao, 1978 with S. araeceri Nixon, 1943; S. tanycoleosus Shi et Chen, 2004 with S. exarator Chao, 1978; S. fukienensis Chao, 1957 with S. japonicus Watanabe, 1937; S. changbaishanensis Chen et Shi, 2004 with S. oriens Belokobylskij, 1998 (stat. nov.); S. applanatus Chen et Shi, 2004 with S. phymatodis Fischer, 1966; S. bellus Chao, 1957 and S. agrili Yang, 2005 with S. sinicus Chao, 1957; S. lunganjiding Chao, 1977 and S. shennongensis Chen et Shi, 2004 with S. verustus Chao, 1977. The records of S. brevicaudis Ratzeburg, S. esakii Watanabe, S. ruficeps (Smith) and S. labdacus Nixon in China are considered as invalid. PMID- 26249374 TI - The black flies (Diptera: Simuliidae) from Thua Thien Hue and Lam Dong Provinces, Vietnam. AB - Surveys of pupae and larvae of black flies (Diptera: Simuliidae) were carried out in Thua Thien Hue Province of central Vietnam, and Lam Dong Province of southern Vietnam in 2014. A total of 26 species belonging to the genus Simulium were collected, consisting of eight known species, one newly recorded species, and 17 new species (of which three species of the subgenus Nevermannia were described in 2014). The remaining 14 new species (nine of the subgenus Gomphostilbia and five of the subgenus Simulium) are described here based on females, males, pupae and mature larvae. The total number of species of black flies in Vietnam is now 46. Keys to identify all 26 species recorded from the two provinces of Vietnam are given for females, males, pupae and mature larvae. PMID- 26249377 TI - Preface and Constitution of the Asian Society of Ichthyologists. PMID- 26249378 TI - Catalogue of the type specimens in the fish collection of the National Zoological Museum, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. AB - A checklist of type specimens housed in the National Zoological Museum, Institute of Zoology, Chinese Academy of Sciences, Beijing, is presented for research and scientific communication. Included are 80 holotypes, 1 lectotype, 1 neotype, 402 paratypes and 17 syntypes of 99 species belonging to 28 families and 12 orders. With 60 species, Cypriniformes has the largest representation. All of the specimens were collected in China and neighboring countries in the past 90 years. PMID- 26249379 TI - Glyptothorax mibangi, a new species of catfish (Teleostei: Sisoridae) from the Tisa River, Arunachal Pradesh, northeast India. AB - Glyptothorax mibangi, a new sisorid catfish, is described from the Tisa River of Arunachal Pradesh, India. The new species can be distinguished from its congeners in the Ganga-Brahmaputra and Barak-Surma-Meghna basins by the following combination of characters: an obtuse leaf-shaped thoracic adhesive apparatus with a spindle-shaped median depression, skin ridges present over the entire apparatus including the depressed region; ventral surface of pectoral spine and first pelvic-fin ray non-plaited; slender body with depth of 10.4-13.5% SL; caudal peduncle shallow with depth 6.8-8.3% SL; snout long with length 52.9-58.6% HL; and 2+7 gill rakers on the first branchial arch. PMID- 26249380 TI - Two new species of shovel-jaw carp Onychostoma (Teleostei: Cyprinidae) from southern Vietnam. AB - Two new species of large shovel-jaw carps in the genus Onychostoma are described from the upper Krong No and middle Dong Nai drainages of the Langbiang Plateau in southern Vietnam. These new species are known from streams in montane mixed pine and evergreen forests between 140 and 1112 m. Their populations are isolated in the headwaters of the upper Sre Pok River of the Mekong basin and in the middle of the Dong Nai basin. Both species are differentiated from their congeners by a combination of the following characters: transverse mouth opening width greater than head width, 14-17 predorsal scales, caudal-peduncle length 3.9-4.2 times in SL, no barbels in adults and juveniles, a strong serrated last simple ray of the dorsal fin, and small eye diameter (20.3-21.5% HL). Onychostoma krongnoensis sp. nov. is differentiated from Onychostoma dongnaiensis sp. nov. by body depth (4.0 vs. 3.2 times in SL), predorsal scale number (14-17 vs. 14-15), dorsal-fin length (4.5 vs. 4.2 times in SL), caudal-peduncle length (3.9 vs. 4.2 times in SL), colour in life (dark vs. bright), and by mitochondrial DNA (0.2% sequence divergence). Molecular evidence indicates that both species are members of Onychostoma and are distinct from all congeners sampled (uncorrected sequence divergences at the 16S rRNA gene of >2.0% for all Onychostoma for which homologous 16S rRNA sequences are available). PMID- 26249381 TI - Cyprinid fishes of the genus Neolissochilus in Peninsular Malaysia. AB - Meristic, morphometric and distributional patterns of cyprinid fishes of the genus Neolissochilus found in Peninsular Malaysia are presented. Based on the current concept of Neolissochilus, only two species are present: N. soroides and N. hendersoni. Neolissochilus hendersoni differs from N. soroides by having lower scale and gill raker counts. Neolissochilus soroides has three mouth types (normal with a rounded snout, snout with a truncate edge, and lobe with a comparatively thick lower lip). A PCA of log-transformed measurements did not reveal significant differences between N. hendersoni and N. soroides, or between any of the morphotypes of N. soroides; however, a CVA of log-transformed measurements successfully classified 87.1% of all specimens. Removing body size by running a CVA on all of the principal components except PC1 (which was correlated with length) only slightly decreased the successful classification rate to 86.1%. Differences in morphometrics were as great between the three morphotypes of N. soroides as between any of the morphotypes and N. hendersoni suggesting that the morphotypes should be examined in greater detail with genetic tools. The PCA of morphometrics revealed separate clouds for N. hendersoni and N. soroides, but no differences between the N. soroides morphotypes. This study revealed that N. hendersoni is recorded for the first time in the mainland area of Peninsular Malaysia. Other nominal species of Neolissochilus reported to occur in the river systems of Peninsular Malaysia are discussed. Lissochilus tweediei Herre in Herre & Myers 1937 and Tor soro Bishop 1973 are synonyms of Neolissochilus soroides. PMID- 26249382 TI - A new species of highland loach, Schistura sirindhornae, from the upper Chao Phraya River basin, Thailand (Pisces: Ostariophysi: Nemacheilidae). AB - Schistura sirindhornae, a new species of nemacheilid, is described from the Nan River basin in northern Thailand. It is distinguished from all other species of Schistura in having overlapping scales on the entire body similar to scales of balitorids, transparent scales on the belly and thorax, a lateral-line canal that is similar to that of most cyprinids and balitorids in being present across the entire lateral-line surface of the scale instead of being represented only by a pore. It also has a unique color pattern of irregular brown bars on the back and side of the faint yellow-orange body, a bright triangular orange mark on the occiput, an orange crown-shaped mark between the eyes, an uninterrupted black mark along the base of the dorsal fin, a crescent-shaped bar on the base of the caudal fin, and bright iridescent orange areas on the upper and lower extremities of the caudal-fin base. Schistura sirindhornae is known only from the upper Nan River drainage, Nan Province, Thailand. PMID- 26249383 TI - Psilorhynchus kaladanensis, a new species (Teleostei: Psilorhynchidae) from Mizoram, northeastern India. AB - Psilorhynchus kaladanensis, a new psilorhynchid, is described from the Kaladan basin of Mizoram, India. The new species is diagnosed by having the following combination of characters: caudal fin with small but distinct dark brown triangular spot at mid-base, slightly elongated dark mark near base of lower lobe, indistinct V-shaped vertical bar across center, dark brown oblique bar across fin anterior to center; absence of scales on mid-ventral region between pectoral fins; anteriormost branchiostegal ray greatly reduced in length; 32-33 total vertebrae; 30-32 lateral-line scales; caudal fin with 10+9 principal rays. PMID- 26249384 TI - Aperioptus pictorius Richardson 1848 is a senior synonym of Acanthopsoides molobrion Siebert 1991, and Aperioptus is a senior synonym of Acanthopsoides Fowler 1934 (Cypriniformes: Cobitidae). AB - Aperioptus pictorius was described by Richardson in 1848 with limited textual information but with an illustration sufficient to confirm the species as one currently recognized as Acanthopsoides molobrion making Aperioptus a senior synonym of Acanthopsoides Fowler 1934 and A. pictorius a senior synonym of Acanthopsoides molobrion Siebert 1991. Species to be recognized in Aperioptus in addition to A. molobrion are A. gracilis (Fowler 1934), A. gracilentus (Smith 1945), A. delphax (Siebert 1991), A. hapalias (Siebert 1991), and A. robertsi (Siebert 1991). Aperioptus also is a senior synonym of Neacanthopsis Smith 1945, type species Neacanthopsis gracilentus. PMID- 26249385 TI - Genetic identification and structure of Clarias batrachus (Linnaeus, 1758) from Southeast Asia using a mitochondrial DNA marker. AB - A phylogenetic tree and median-joining network based on cytochrome b sequence data revealed clades consistent with morphological differences and geographical distribution of Clarias batrachus (Linnaeus, 1758) in Southeast Asia. AMOVA analysis for variation was significant among populations (P<0.05) and was in agreement with morphological differences. Pairwise differences were significant between Java and Brunei/Borneo, Brunei/Borneo and west Malaysia, and Java and west Malaysia samples (P < 0.05). Closest relationships were found between samples from Brunei/Borneo and Java, and between west Malaysia and Laos-Sumatra. Nine haplotypes were unique to geographical regions. The Java species had high haplotype (1.000 +/- 0.126) but low nucleotide (0.017) diversities, suggesting a population bottleneck followed by expansion. However, SSD and Hri (P=0.5) did not support demographic expansion. Instead, purifying selection where mutations occur and accumulate at silent sites is a more acceptable explanation. PMID- 26249386 TI - Revalidation and redescription of Brachymystax tsinlingensis Li, 1966 (Salmoniformes: Salmonidae) from China. AB - Brachymystax tsinlingensis Li, 1966 is revalidated and redescribed. It can be distinguished from all congeners by the following combination of characteristics: no spots on operculum; gill rakers 15-20; lateral-line scales 98-116; pyloric caeca 60-71. Unique morphological characters and genetic divergence of this species are discussed. This species has a limited distribution in several streams of the middle part of the Qinling Mountains in China. Methods for management and protection of B. tsinlingensis need to be re-evaluated. PMID- 26249387 TI - Revision of the hillstream lizard loaches, genus Balitoropsis (Cypriniformes: Balitoridae). AB - The genus Balitoropsis Smith 1945 consists of two species, B. zollingeri (Bleeker 1853) and B. ophiolepis (Bleeker 1853). Homaloptera maxinae Fowler 1937, Balitoropsis bartschi Smith 1945, and Homaloptera nigra Alfred 1969 are junior synonyms of B. zollingeri. Balitoropsis zollingeri has been reported from Thailand, Laos, Cambodia, Malay Peninsula, Sumatra, Java, and Borneo, and B. ophiolepis is known from Sumatra, Java, and Borneo. PMID- 26249388 TI - Metzia parva, a new cyprinid species (Teleostei: Cypriniformes) from south China. AB - A new species of a small cyprinid fish, Metzia parva sp. nov., is described here based on specimens collected from a tributary of Hongshui-He River in the Pearl River basin at Anyang Town, Du'an County, Guangxi Province, south China. It differs from congeners in having a smaller body with a standard length of 48.3 57.7 mm (vs. 58.3-151.4 mm in other species); a complete lateral line (although some specimens show interruptions on the ventral margin above the anal-fin); 12 14 branched anal-fin rays (vs. 10-11 or 15-20); 10 branched pectoral-fin rays (vs. 11-16); 6 branched pelvic-fin rays (vs. 7-9); a longer caudal peduncle (17.8 21.7% vs. 14.8-17.4% SL); a shorter preanal length (60.9-66.0% vs. 69.0-73.0% SL) and an obviously larger interorbital width (28.4-33.0% vs. 20.2-24.7% of head length). While Metzia parva shares a lateral black stripe from the gill opening to the caudal-fin base with M. formosae, the new species can be distinguished from M. formosae by a deeper head (16.4-19.2% vs. 13.3-15.7% SL) and a longer anal fin (15.4-18.9% vs. 10.0-13.6% SL) in addition to the diagnostic characters above. Kimura's 2-parameter genetic distance between the two species is 6.6% for the barcoding region of the mitochondrial COI gene and 7.3% across the complete mitochondrial genome. PMID- 26249389 TI - A review of the genus Discomyza (Diptera: Ephydridae) from Afrotropical, Australasian/Oceanian and Oriental Regions. AB - Tropical Old World species of the genus Discomyza are redescribed, including male terminalia, photographs of heads and wings. One new species Discomyza fagomoga sp. nov. is described from D. R. Congo, Ethiopia, Kenya and Uganda. Two new synonyms are proposed: Discomyza obscuricornis Canzoneri and Rampini, 1996 = D. dolichocerus Cresson, 1944 and D. intermedia Canzoneri and Meneghini, 1969 = D. eritrea Cresson, 1939. A key to all species is provided. Relationships among species of Discomyza are suggested. PMID- 26249390 TI - Description of four new species of Hypaeus Simon and redescription of H. taczanowskii Mello-Leitao (Araneae: Salticidae: Amycinae). AB - Four new species of Hypaeus Simon are described from the Brazilian Amazon, all based on both sexes: H. tridactylus sp. nov. and H. femoratus sp. nov. from Juruti, Para, and H. poseidon sp. nov. and H. terraemediae sp. nov. from Sao Felix do Xingu, Para. Additionally, Asaracus pauciaculeis Caporiacco, 1947 is transferred from Mago O.P.-Cambridge, resulting in Hypaeus pauciaculeis comb. nov. Both sexes of H. taczanowskii (Mello-Leitao, 1948), the type species of Hypaeus, are redescribed for comparisons. PMID- 26249391 TI - An additional record of Kyphosus vaigiensis (Quoy & Gaimard, 1825) (Osteichthyes, Kyphosidae) from Sicily clarifies the confused situation of the Mediterranean kyphosids. AB - The lowfin chub, Kyphosus vaigiensis, is reported for the first time off Favignana Island, Sicily, central Mediterranean Sea. The specimen was identified on the basis of morphometric and meristic characters as well as mitochondrial DNA sequences (COI and 16S-rDNA). Two, perhaps three, Kyphosus species-K. bigibbus, K. sectatrix and K. vaigiensis-have been occasionally recorded in the Mediterranean. These species occur both in the Atlantic and Indo-Pacific regions but it is likely they entered the Mediterranean through the Strait of Gibraltar. However, it is unclear whether they have established reproductive native populations in the Mediterranean. PMID- 26249393 TI - Review of the family Veliidae in Romania (Hemiptera: Heteroptera: Gerromorpha). AB - A critical review of the family Veliidae (Hemiptera: Heteroptera: Gerromorpha) in Romania is provided. In total, two genera and eight species (Microvelia Westwood, 1834-3 species, Velia Latreille, 1804-5 species) are known from the country. Microvelia buenoi Drake, 1920 and Velia serbica Tamanini, 1951 are recorded for the first time from Romania. The occurrence of V. affinis filippii Tamanini, 1947 and V. mancinii mancinii Tamanini, 1947 is confirmed by additional records. Based on proven or suspected misidentifications, V. currens (Fabricius, 1794) and V. rivulorum (Fabricius, 1775) are excluded from the Romanian fauna. A checklist of the Veliidae of Romania and updated distribution maps are provided. Biogeographical aspects of the fauna are summarized. PMID- 26249392 TI - A study of the type series of Nautilus pompilius Linnaeus, 1758 (Mollusca, Cephalopoda, Nautilida). AB - Few animals are treasured by zoologists more than Nautilus, and Nautilus pompilius Linnaeus, 1758, the type species of the genus, in particular. However, the type series of this species has not been studied in great detail. According to the rules of zoological nomenclature the type series consists of all the specimens included by the author in the new nominal taxon at the time of description (whether directly or by bibliographic reference), and any evidence, published or unpublished, may be taken into account to determine what specimens are included. The type series of Nautilus pompilius includes specimens in the Linnean Society of London, the University Museum in Uppsala, and specimens figured by pre-Linnaean authors indicated by reference by Linnaeus (1758). One specimen in London and four specimens in Uppsala, which are still extant, are likely to have been known to Linnaeus at the time when he prepared the 10th Edition of Systema Naturae (Linnaeus 1758), although none of these specimens was specifically mentioned by him. Even though it is widely believed that Linnaeus (1767) designated as lectotype a specimen figured by Rumphius (1705) in his D'Amboinsche Rariteitkamer, referred to in the Systema Naturae, this presumed lectotypification is not valid because Linnaeus did not explicitly indicate that any particular specimen was considered to be the type of the species. Later lectotype designations of Rumphius' illustrations are invalid because they show three different specimens. It seems that the best approach, given the quality of the material and the lack of clarity as to its type status, would be to apply to the ICZN asking to set aside all previous type fixations and designate a neotype, preferably a DNA sequenced specimen of known provenance. PMID- 26249394 TI - Neotropical Physoderinae revisited, with description of a new, sexually dimorphic species of Leptophysoderes Weirauch (Hemiptera: Reduviidae). AB - The small reduviid subfamily Physoderinae has the greatest species diversity in the Oriental region and Madagascar. Only the two monotypic genera Cryptophysoderes Wygodzinsky and Maldonado and Leptophysoderes Weirauch are currently known from the Neotropical region. We here describe and document a new, sexually dimorphic species of Physoderinae, Leptophysoderes sarapiqui sp. nov. from Costa Rica. The generic diagnosis of Leptophysoderes is modified to accommodate the new species. Females and immatures of Leptophysoderes are documented for the first time. PMID- 26249395 TI - SILVIO FELIPE BARBOSA LIMA & CARMEN REGINA PARISOTTO GUIMARAES (2015) New bathyal Anachis (Neogastropoda: Buccinoidea: Columbellidae) from the Southwestern Atlantic, and the designation of a lectotype for A. stricta (Watson, 1882). Zootaxa, 3949(3): 445-450. PMID- 26249396 TI - New Conopid records from the Afrotropical Region (Diptera). Part 1: Paramyopa Krober, Pseudoconops Camras, Stylogaster Macquart, Thecophora Rondani, and Zodion Latreille. AB - New records of 38 species of the Conopid genera Paramyopa Krober, 1916a, Pseudoconops Camras, 1962b, Stylogaster Macquart, 1835, Thecophora Rondani, 1845, and Zodion Latreille, 1797 are presented from the Afrotropical Region. Stylogaster angolensis spec. nov. (Angola), Stylogaster cryptica spec. nov. (Ethiopia), Stylogaster fianarantsoensis spec. nov. (Madagascar), Stylogaster ivindoensis spec. nov. (Gabon), Stylogaster malaisei spec. nov. (Madagascar), Stylogaster occulta spec. nov. (Democratic Republic of Congo, Burundi), Stylogaster rwenzoriensis spec. nov. (Democratic Republic of Congo), Stylogaster tanzaniensis spec. nov. (Tanzania), Thecophora clementsi spec. nov. (Madagascar), Thecophora freidbergi spec. nov. (Kenya), Thecophora nigrifrons spec. nov. (Kenya, Cameroon), Thecophora obsoleta spec. nov. (Madagascar), and Thecophora submetallica spec. nov. (Madagascar) are new to science. A neotype is designated for Thecophora pilosa (Krober, 1916). Thecophora africana (Brunetti, 1925), Thecophora flavicornis (Krober, 1936), and Thecophora ruwenzori (Camras, 1962) are new junior synonyms of Thecophora pilosa; Paramyopa schultzei (Bezzi, 1908) is a new junior synonym of Paramyopa oestracea (Loew, 1863) (syn. nov.). Stylogaster nitidula Krober, 1936 is interpretated as a nomen dubium (stat. rev.). PMID- 26249397 TI - Digitate and capitate soft corals (Cnidaria: Octocorallia: Alcyoniidae) from Western Australia with reports on new species and new Australian geographical records. AB - We report on digitate and capitate Octocorallia within the genera Parasphaerasclera McFadden & Ofwegen, 2013, Eleutherobia Putter, 1900, Sphaerasclera McFadden & Ofwegen, 2013, and Paraminabea Williams & Alderslade, 1999 from tropical Western Australian waters. Three new species (Parasphaerasclera kimberleyensis, Eleutherobia australiensis, Eleutherobia imaharai) are described, with a discussion of their taxonomic placement in the light of a recent treatment of the genus Eleutherobia and related taxa by McFadden & Ofwegen (2013). In addition, range extensions for three species are reported, Parasphaerasclera grayi (Thomson & Dean, 1931) known from Indonesia and the Pacific Ocean, Eleutherobia somaliensis Verseveldt & Bayer, 1988 from Somalia, and Eleutherobia splendens (Thomson & Dean, 1931) recorded from Indonesia and the Philippines. Additionally, one new Australian geographical record (Sphaerasclera flammicerebra) (Williams, 2003) with a known distribution from Palau to Mauritius, has been included. We complement morphological taxonomy with molecular data (mtMutS, 28S rDNA) to analyse and clarify phylogenetic placement of these species. The mitochondrial mtMutS phylogeny supported Eleutherobia, Paraminabea, Parasphaerasclera and Sphaerasclera as distinct monophyletic genera. Phylogenetic analyses based on 28S rDNA lacked resolution and were largely unresolved. Additionally, the molecular data corroborated our proposed morphological hypothesis of the placement of the new species P. kimberleyensis sp. nov. with no anthocodial armature in the genus Parasphaerasclera, and the assignment of the new species, E. australiensis sp. nov. and E. imaharai sp. nov., with distinct polyps sclerites in the genus Eleutherobia. PMID- 26249398 TI - Lineage divergence in Odorrana graminea complex (Anura: Ranidae: Odorrana). AB - The confusing and unstable taxonomy of Odorrana livida (Rana livida) since its first record has made it a focal frog complex for systematics. In China, four species, Odorrana nebulosa, O. graminea, O. sinica, O. leporipes, were described to closely resemble O. livida or O. chloronota based on their morphological similarities, accompanied by much taxonomic confusion because of ambiguities in the wide distribution and morphological variations. Currently O. graminea is being used as the name of a provisional monotypic species group to include all the populations in China that closely resemble O. livida or O. chloronota. Here, we conducted a range-wide molecular phylogeographic analysis of the large green odorous frog (Odorrana graminea) complex across the majority of its range in China, based on 2780 bp DNA sequences of three mitochondrial genes (12S, 16S, ND2) in 107 samples from 20 sites. Our data recognized three distinct phylogeographic lineages of the Odorrana graminea (lato sensu) complex in China, and they together with a Thailand lineage formed a monophyletic group. Among the four lineages within O. graminea complex, the average genetic distances based on the concatenated sequences of 12S, 16S and ND2 were 7.5-8.8% and those based on 16S rRNA alone were 4.2-5.5%. Furthermore, canonical discriminant functions in morphometric analyses showed significant separations of all the paired lineage comparisons in China. The aforementioned genetic divergence and mismatched phenotypes among the lineages within the Odorrana graminea complex, in addition to their non-overlapping geographic distributions, imply extensive lineage diversification. However, precise taxonomic status of these lineages needs more studies based on adequate type information and more thorough species delimitation based on analysis of differentiation in bioacoustic and nuclear genetic characters especially regarding gene flow and admixture in geographical contact zones. PMID- 26249399 TI - Ultrastructure of the fossula spongiosa and pretarsus in Haematoloecha nigrorufa (Stal) (Hemiptera: Heteroptera: Reduviidae: Ectrichodinae). AB - The ultrastructure of the fossula spongiosa and pretarsus of adult Haematoloecha nigrorufa (Stal) (Heteroptera: Reduviidae: Ectrichodinae) was examined for the first time using scanning electron microscope. The fossula spongiosa of H. nigrorufa is located on the ventral surface of the distal part of the tibia of both the fore- and midlegs. The area of the fossula spongiosa on the female foreleg is approximately 251338.88 MUm(2), while the area of the fossula spongiosa on the male foreleg is markedly smaller, only about 196548.98 MUm(2). For both genders the area of the fossula spongiosa on the foreleg is approximately 1.50 times as large as that on the midleg. Externally, the ventral surface of the fossula spongiosa is covered by a large number of tenent hairs that are evenly interspersed with a few mechanosensory setae. Each tenent hair consists of two parts: a hair shaft and an apical plate. A tenent hair is 22.58 +/- 1.60 MUm in length, 1.90 +/- 0.09 MUm in shaft diameter, and 10.90 +/- 0.63 MUm(2) in apical plate area. Morphologically, the tenent hairs are similar and constitute a nearly uniform hair array on the ventral side of the fossula spongiosa. The density of tenent hairs is about 4.46 +/- 0.35 hairs per 100 MUm(2) and the total number of tenent hairs is more than ten thousand on the fossula spongiosa of the female foreleg. These tenent hairs are presumed to function as adherence during locomotion or prey capture of the assassin bugs. In addition, scanning micrographs and descriptions for the pretarsus are also given. PMID- 26249400 TI - New species and revisions of Pediciidae (Diptera) from the Middle Jurassic of northeastern China and Russia. AB - Two new species of Praearchitipula Kalugina, 1985, P. apprima sp. nov. and P. mirabilis sp. nov., are described and illustrated from the late Middle Jurassic Jiulongshan Formation of Daohugou in eastern Inner Mongolia, China. In addition, we propose to transfer Architipula abnormis Hao & Ren, 2009 (which is from the same locality of Daohugou) from Architipula of Limoniidae to Praearchitipula of Pediciidae: Praearchitipula abnormis (Hao & Ren, 2009) comb. nov. In addition, we propose to transfer Praearchitipula spasskia Kalugina, 1985 to the genus Mesotipula (Limoniidae, Architipulinae). We also suggest treating Praearchitipula lata Kalugina, 1985 as a junior synonym of Praearchitipula notabilis Kalugina, 1985. An emended generic diagnosis of Praearchitipula is provided. PMID- 26249401 TI - VINICIUS DE SOUZA FERREIRA (2015) An annotated catalogue of the type material of Elateroidea Leach, 1815 (Coleoptera) deposited in the Coleoptera collection of the Museum of Zoology of the University of Sao Paulo, Brazil. Zootaxa, 3937(2) 263-310. PMID- 26249402 TI - Review of the fish-parasitic genus Ceratothoa Dana, 1852 (Crustacea: Isopoda: Cymothoidae) from Australia, with description of two new species. AB - The genus Ceratothoa Dana, 1852, is revised for Australian waters. Ceratothoa is represented in Australia by nine species, including two new species: Ceratothoa barracuda sp. nov. described from Cairns and Ceratothoa globulus sp. nov. described from Lord Howe Island. Ceratothoa imbricata Fabricius, 1775 is redescribed, with Ceratothoa trillesi (Avdeev, 1979) and Ceratothoa huttoni Filhol, 1885 placed into junior synonymy; the preferred hosts are species of the genus Trachurus (Carangidae). Ceratothoa banksii (Leach, 1818) is validated and brought out of synonymy with Ceratothoa imbricata; host species are from the families Kyphosidae, Scombridae, Latridae, Carangidae, Mugilidae, Salmonidae, Scatophagidae, Pomatomidae and Hemiramphidae. Species excluded from the Australian fauna are Ceratothoa trigonocephala (Leach, 1818) with an unknown host identity and type locality; and Ceratothoa lineata Miers, 1876a, that here is transferred to the genus Mothocya Costa, 1851, with Mothocya ihi Bruce, 1986 placed into junior synonymy. Ceratothoa contracta (Miers, 1880), the New Zealand Ceratothoa novaezelandiae Filhol, 1885 and the East Pacific Ceratothoa gaudichaudii (Milne Edwards, 1840) are regarded here as species inquirenda. A key to the Australian species of Ceratothoa is presented. PMID- 26249403 TI - A revised checklist of Nepticulidae fossils (Lepidoptera) indicates an Early Cretaceous origin. AB - With phylogenetic knowledge of Lepidoptera rapidly increasing, catalysed by increasingly powerful molecular techniques, the demand for fossil calibration points to estimate an evolutionary timeframe for the order is becoming an increasingly pressing issue. The family Nepticulidae is a species rich, basal branch within the phylogeny of the Lepidoptera, characterized by larval leaf mining habits, and thereby represents a potentially important lineage whose evolutionary history can be established more thoroughly with the potential use of fossil calibration points. Using our experience with extant global Nepticulidae, we discuss a list of characters that may be used to assign fossil leaf mines to Nepticulidae, and suggest useful methods for classifying relevant fossil material. We present a checklist of 79 records of Nepticulidae representing adult and leaf-mine fossils mentioned in literature, often with multiple exemplars constituting a single record. We provide our interpretation of these fossils. Two species now are included in the collective generic name Stigmellites: Stigmellites resupinata (Krassilov, 2008) comb. nov. (from Ophiheliconoma) and Stigmellites almeidae (Martins-Neto, 1989) comb. nov. (from Nepticula). Eleven records are for the first time attributed to Nepticulidae. After discarding several dubious records, including one possibly placing the family at a latest Jurassic position, we conclude that the oldest fossils likely attributable to Nepticulidae are several exemplars representing a variety of species from the Dakota Formation (USA). The relevant strata containing these earliest fossils are now dated at 102 Ma (million years ago) in age, corresponding to the latest Albian Stage of the Early Cretaceous. Integration of all records in the checklist shows that a continuous presence of nepticulid-like leaf mines preserved as compression-impression fossils and by amber entombment of adults have a fossil record extending to the latest Early Cretaceous. PMID- 26249404 TI - The external and internal structures of Amphizoa davidi Lucas (Coleoptera, Amphizoidae), using X-ray phase contrast microtomography. AB - The Chinese endemic water beetle Amphizoa davidi Lucas, is a rare and endangered species belonging to the monotypic family Amphizoidae (Coleoptera: Adephaga). A study of the external and internal structures of A. davidi is here presented, by using X-ray phase contrast tomography and light microscopy. Morphological details and three dimensional (3D) structures of this species are provided: skeletons, muscles, reproductive organs of male and female, nervous system, alimentary canal and pygidial gland. The reproductive organs of females are compared in two different developmental phases (ages): before copulation without mature ovaries and after copulation with mature ovaries. Such detailed 3D tomographic study based on micro-CT technology may promote our understanding of the detailed morphology in Amphizoidae and Coleoptera in general. PMID- 26249405 TI - Taxonomic studies on Oriental Microplitis Foerster (Hymenoptera: Braconidae, Microgastrinae) with description of two new species from South India. AB - The Oriental species of Microplitis Foerster are reviewed. 21 species are recognized from the Oriental region, of which two are described as new, Microplitis narendrani sp. nov. and M. pennatulae sp. nov., and Microplitis carinicollis (Cameron), M. demolitor Wilkinson, M. maculipennis (Szepligeti) and M. similis Lyle are redescribed. Four species, Microplitis areyongensis Austin & Dangerfield, M. bicoloratus Xu & He, M. vitellipedis Li, Tan & Song and M. zhaoi Xu & He are recorded for the first time from the Indian subcontinent. Host records are summarized. An illustrated key to the Oriental species is provided along with a character matrix to aid identification. Distributional pattern in Oriental region, host-parasitoid association and biology of the genus are critically summarized. PMID- 26249406 TI - Spiralothelphusa gibberosa, a new freshwater crab (Brachyura: Gecarcinucidae) from Thrissur district, Kerala, India. AB - A new species of freshwater crab, Spiralothelphusa gibberosa n. sp. is described from rice fields near Kizhoor in Thrissur district of Kerala in southern India. The new species is easily differentiated from its congeners by its first male pleopod (G1), which has a long, less strongly twisted terminal segment and distal portion of subterminal segment in addition to a setose hump on the outer margin of the non-twisted portion. Key to the species of the genus Spiralothelphusa Bott, 1968, is provided. We recognized S. wuellerstorfi (Heller, 1862), as a new record to Maharashtra based on specimens wrongly identified as S. hydrodroma (Herbst, 1794), by Pati & Sharma (2014). PMID- 26249407 TI - A review of the Japanese species of Barycnemis Forster (Hymenoptera: Ichneumonidae: Tersilochinae). AB - Four species of the genus Barycnemis Forster are found to occur in Japan: B. dissimilis (Gravenhorst), B. harpura (Schrank), B. naganoensis sp. nov. and B. tobiasi Khalaim. These are the first records of Barycnemis from this country. All recognized Japanese species belong to the harpura species group. An identification key to four species of Barycnemis occurring in Japan is provided. Barycnemis funiuensis Sheng, 2002 from East China is synonymised with the widely distributed Holarctic species Porizon dissimilis Gravenhorst, 1829 (syn. nov.). PMID- 26249408 TI - Two new species of the cheilostome bryozoan Cheilopora from the Aleutian Islands. AB - Two new species of Cheilopora-C. peristomata and C. elfa-are described from the shallow water around Adak and Amchitka of the Andreanof and Rat island groups of the Aleutian Islands. Zooids of both new species have cormidial peristomes, composed by the distal (originating from neighbouring zooid) and proximal lappets. In contrast to previously described species, the strongly elevated peristomial lappets defining the secondary orifice confer the overall shape of an incomplete circle with deep U-shaped proximolateral pseudosinuses. Depending on angle of view, this gives a campanuliform or trifoliate outline to the secondary orifice, by which the new species differ from congeners. Together with previous discoveries from the Aleutians, these two new Cheilopora species are indicative of incomplete knowledge of the marine biodiversity of the region, including the distinctive character of the bryozoan fauna. There is a need for intensification of taxonomic effort along the island arc. PMID- 26249409 TI - A new species of the genus Duolandrevus (Orthoptera: Gryllidae: Landrevinae) from China. AB - A bark cricket genus Duolandrevus Kirby, 1906 is discussed here. These species are brownish with depressed bodies, with reduced elytra, lack hind wings and live in the bark of dead trees or branches. Duolandrevus are distributed from the south of China and Japan to the Philippines, the Malay Archipelago and New Guinea. Only one species, Duolandrevus hongkongae Otte, 1988, was recorded in China. Here, one additional species, Duolandrevus (Eulandrevus) unguiculatus sp. nov. is described from Southern China. Its description and illustrations and the key to the subgenera of Duolandrevus worldwide are given. PMID- 26249410 TI - VENKATESWARA RAO TOTAKURA & YENUMULA RANGA REDDY (2015) Groundwater cyclopoid copepods of peninsular India, with description of eight new species. Zootaxa, 3945(1): 1-93. PMID- 26249411 TI - An annotated checklist of oribatid mites (Acari: Oribatida) of Iran. AB - Oribatid mites (Acari: Oribatida) are one of the largest and dominating groups of soil inhabitants that play an important role in the formation and fertilization processes of the soils. In the present paper, a list of oribatid mites of Iran (excluding Astigmata) is present based mainly on the collected and identified species and on literature records since 1961. In total, 380 species belonging to 191 genera and 86 families have been recorded and these are listed along with their known geographical distributions and localities in Iran. The following seven species Sellnickochthonius cricoides (Weis-Fogh, 1948), Hypochthoniella minutissima (Berlese, 1904), Nothrus silvestris Nicolet, 1855, Hemileius (Hemileius) initialis (Berlese, 1908), Punctoribates (Punctoribates) punctum (C. L. Koch, 1839), Ceratozetes conjunctus Mihelcic, 1956, Eupelops tardus (C. L. Koch, 1835) and Pelopsis Hall, 1911 are recorded for the first time from Iran. The closing date for publications included in this list was 15 January 2015. PMID- 26249412 TI - A taxonomic review of the polymorphic assassin bug genus Rihirbus Stal (Hemiptera: Reduviidae: Harpactorinae). AB - Two species in the genus Rihirbus Stal are recognized, redescribed and illustrated. The diagnosis of the genus is slightly modified. The deposition information of Miller's type specimens is corrected. Rihirbus trochantericus Stal is newly recorded from Cambodia, Laos, Nepal, Thailand, and Vietnam. A key for the identification of species of Rihirbus is provided. The sexual dimorphism and polymorphism of this genus are briefly noted. PMID- 26249413 TI - A revision of the Elachista dispilella complex (Lepidoptera: Gelechioidea: Elachistidae). AB - The Elachista dispilella group and its subordinate E. dispilella species complex are characterized. Identity of the long confused oldest names applicable for taxa in the E. dispilella complex, i.e., E. dispilella Zeller, E. festucicolella Zeller, and E. distigmatella Frey, is resolved. Elachista dispilella Zeller is the valid name for the species often identified as E. festucicolella, E. steueri Traugott-Olsen, or E. manni Traugott-Olsen. Elachista distigmatella Frey is the valid name for the species regularly identified as E. dispilella. The identity of E. festucicolella Zeller, so far entirely dubious, is clarified. Nineteen species attributable to the E. dispilella complex sensu Traugott-Olsen are recognized. The following new synonymies are proposed: Elachista steueri Traugott-Olsen, 1990, syn. nov.; E. manni Traugott-Olsen, 1990, syn. nov.; E. jaeckhi Traugot Olsen, 1990, syn. nov.; and E. gebzeensis Traugott-Olsen, 1990, syn. nov., are considered synonyms of E. dispilella Zeller, 1839. Elachista klimeschiella Parenti, 2002 is synonymized with E. festucicolella Zeller, 1853; and Elachista purella Sruoga, 2000 with E. levasi Sruoga, 1998, syn. nov. Identification keys for males and females are provided. All species are diagnosed, the lesser known are also redescribed. Four new species are described: Elachista implana Kaila, sp. nov., from Austria; E. ripai Kaila, sp. nov., from Kyrgyzstan; Elachista sitibunda Kaila, sp. nov., from Uzbekistan; and Elachista laterotis Kaila, sp. nov., from Turkey. PMID- 26249414 TI - Review of the species of Pelodiaetodes Moore (Coleoptera: Carabidae: Bembidiini: Anillina) of New Zealand. AB - Four new species of the formerly monotypic genus Pelodiaetodes are described from New Zealand. Three of them: P. constricticollis, sp. n., P. moorei, sp. n., and P. aldermensis, sp. n., occurring on the North Island, are morphologically similar to the type species, P. prominens Moore. The fourth species, P. nunni, sp. n., occurring on the South Island, is morphologically distinct from the nominotypical species group. A new subgenus, Monosetodes, subgen.n., is proposed to accommodate P. nunni within Pelodiaetodes. Redescriptions of the genus and the type species are given based on new morphological data, and a taxonomic key as well as a distribution map for all known species are provided. Some biogeographical aspects of the evolutionary history of Pelodiaetodes and its morphological relatives from Madagascar, Australia and New Zealand are discussed. PMID- 26249415 TI - A new species of dwarf crayfish (Decapoda: Cambaridae) from central Mexico, as supported by morphological and genetic evidence. AB - Dwarf crayfish are a subfamily of freshwater decapods distributed along the southeastern coast of United States and the Central Plateau of Mexico. Recent phylogenetic studies have found that diversity of dwarf crayfish in Mexico could be currently underestimated, and suggested the existence of possible new species for a number of clades for which taxonomic identity was uncertain, including one from Zacapu, a small lake in the Trans-Mexican Volcanic Belt. Here, a congruence criterion between morphological and molecular evidence is used to test if this previously detected clade should be considered as a new species. A set of morphometric variables was taken to characterize variation from this population (including some newly proposed traits possibly valuable for species discrimination) and to compare it statistically to its closest relative, C. chapalanus. Also, additional individuals to those previously sequenced were included using a set of molecular characters, including 5 molecular markers (three mitochondrial and two nuclear fragments) and all extant species described to date from Mexico. Principal Component Analysis, Mann-Whitney paired test and Discriminant Factor Analysis support morphological differentiation of the Zacapu population. Phylogenetic analyses are congruent with morphology and confirm that this population constitutes an exclusive monophyletic clade with high support values. Additionally, genetic Cytochrome Oxidase subunit I (cox1) distance between Zacapu and the closest related species is above the average between species distance in crayfish (ML=3.6%). Congruence between morphology and molecular evidence support the hypothesis that the population from lake Zacapu should be considered a new species, to which the name C. zacapuensis sp. nov. is given and its description provided. With respect to its closest relatives, C. zacapuensis sp. nov. is diagnosed according to the following set of morphological characters: a wider cephalotorax (5.10-5.70 vs. 4.40-4.70), wider abdomen (4.52 4.84 vs. 3.94-4.35) a more robust chela (2.12-2.48 vs. 1.72-1.96) and a shorter merus (3.04-4.20 vs. 4.26-4.71) and mesial process of first pleopod of the form I male reaching distally well beyond the other elements. This study emphasizes the utility of using an integrative framework for species recognition in crayfish. PMID- 26249416 TI - The authorships and dates of the specific nomina Megophrys shuichengensis and Pseudohynobius shuichengensis (Amphibia). AB - Two amphibian species from China are designated by the specific nomen shuichengensis, which refers to the Shuicheng County (26 degrees 34'N, 104 degrees 51'E), south of the city of Liupanshui in the province of Guizhou: Megophrys shuichengensis (Amphibia, Anura) and Pseudohynobius shuichengensis (Amphibia, Urodela). The holotypes (holophoronts) of both species were deposited in Department of Biology of the Liupanshui Teachers Higher College (LTHC below). Both species share the particularity of having been described as new twice, at different dates, in different journals and with different authorships. Although this has been acknowledged for the salamander, it has not yet been so for the frog. PMID- 26249417 TI - CHARLES R. BARTLETT & GERNOT KUNZ (2015) A new genus and species of delphacid planthopper (Hemiptera: Fulgoroidea: Delphacidae) from Central America with a preliminary regional species list. Zootaxa, 3946(4): 510-518. PMID- 26249418 TI - A review of Chilean chiggers (Acari: Trombiculidae), with the description of a new genus and ten new species. AB - A new genus and species of chigger mites, Diaguitacarus choapensis gen. et sp. nov., is described from four lizard species of the genus Liolaemus in Choapa Province of Chile. Eight new chigger species are described from lizards of the genera Liolaemus, Phymaturus (Squamata: Liolaemidae), and Microlophus (Squamata: Tropiduridae), in Arica and Parinacota, Atacama, Coquimbo, Valparaiso, and Biobio Regions: Eutrombicula nerudai sp. nov., Eutrombicula mistrali sp. nov., Eutrombicula picunche sp. nov., Microtrombicula mapuche sp. nov., Parasecia molini sp. nov., Paratrombicula philippii sp. nov., Morelacarus jorgei sp. nov., and Morelacarus camanchaca sp. nov. A new species Proschoengastia antarctica sp. nov., which is described from American mink Neovison vison on Navarino Island (Region of Magallanes and Antartica Chilena), is the most southerly chigger species, found at the distance of about 1000 km from the continent of Antarctica. Whartonacarus chaetosus (Brennan and Jones, 1961) comb. nov., which was described from Peru, is for the first time recorded in Chile (Atacama Region) and on Microlophus atacamensis. A new combination Proschoengastia macrochaeta (Brennan and Jones, 1961) comb. nov. is established. The genus Morelacarus Vercammen Grandjean, 1973 previously known from Mexico and southwestern USA is for the first time recorded in Chile. A review of all previously described Chilean chiggers and a key to Eutrombicula species from Chile are provided. In all, 22 species from 13 genera were recorded in Chile, of which only one species (Whartonacarus chaetosus) is known outside the country. PMID- 26249419 TI - Complete mitochondrial genomes of two Oriental dobsonflies, Neoneuromus tonkinensis (van der Weele) and Nevromus exterior (Navas) (Megaloptera: Corydalidae), and phylogenetic implications of Corydalinae. AB - The complete mitochondrial (mt) genomes of two Oriental endemic dobsonfly species, Neoneuromus tonkinensis (van der Weele) and Nevromus exterior (Navas), were determined and analyzed, which represent the first mt genomes of the genera Neoneuromus van der Weele, 1909 and Nevromus Rambur, 1842. The mt genome of N. tonkinensis is a typical circular DNA of 15776 bp with A+T content being 76.3%, while that of N. exterior is 15763 bp with A+T content being 77.5%. Both mt genomes are composed of 37 genes with an ancestral gene arrangement of the insect mt genome. Eleven of the 13 protein coding genes (PCGs) start with codon ATT and ATG, except for cox1 and nad1 respectively having ATC and ATA as the start codons in the mt genome of N. tonkinensis. Complete termination codons TAG and TAA were found in nine PCGs, while the remaining four genes are supposed to end with a single T. Most tRNAs are folded into the typical clover-leaf structure except for the trnS1 whose dihydrouridine arm is a simple loop. The secondary structure of rrnL consists of five structural domains and 50 helices, while the rrnS includes three domains and 34 helices. In the phylogenomic analysis, both Bayesian inference (BI) and maximum likelihood (ML) approaches, based on sequence data of all 13 PCGs and two rRNA genes of the mt genomes, suggested that Neoneuromus and Nevromus form a monophyletic group, which is the sister group of the lineage including Corydalus and Acanthacorydalis but not the sister group of Acanthacorydalis van der Weele, 1907 as previously reported based on morphological data. PMID- 26249420 TI - Contribution to the taxonomy of Poecilimon bosphoricus species group (Orthoptera: Phaneropteridae): two new species from its core range. AB - The Poecilimon bosphoricus species group, representing the most diverse lineage of the bushcricket genus Poecilimon, has been studied in the Basin of Marmara Sea. Two new species, P. warchalowskae sp. n. and P. canakkale sp. n., are described morphologically and acoustically in comparison to their related taxa of the P. bosphoricus species group. Song type and morphology of the new species suggests that they are related to P. turcicus, P. turciae and P. athos and each of these five species can be distinguished by their specific male cerci. The diagnoses are supplemented with comparative figures of morphology and song. Additionally, a short account is given on the synonymy of P. anatolicus with P. sureyanus. PMID- 26249421 TI - New species and revisions of Pediciidae (Diptera) from the Middle Jurassic of northeastern China and Russia. AB - Two new species of Praearchitipula Kalugina, 1985, P. apprima sp. nov. and P. mirabilis sp. nov., are described and illustrated from the late Middle Jurassic Jiulongshan Formation of Daohugou in eastern Inner Mongolia, China. In addition, we propose to transfer Architipula abnormis Hao & Ren, 2009 (which is from the same locality of Daohugou) from Architipula of Limoniidae to Praearchitipula of Pediciidae: Praearchitipula abnormis (Hao & Ren, 2009) comb. nov. In addition, we propose to transfer Praearchitipula spasskia Kalugina, 1985 to the genus Mesotipula (Limoniidae, Architipulinae). We also suggest treating Praearchitipula lata Kalugina, 1985 as a junior synonym of Praearchitipula notabilis Kalugina, 1985. An emended generic diagnosis of Praearchitipula is provided. PMID- 26249422 TI - Two new species of the genus Luzonomyza from CHINA (Diptera, Lauxaniidae). AB - Two species Luzonomyza gaimarii sp. nov. and Luzonomyza hirsuta sp. nov. are described as new to science. A key to separate species of the genus is provided. PMID- 26249423 TI - A note on the new species of the genus Isopsera (Orthoptera: Phaneropteridae: Phaneropterinae) from India. AB - A new species of the genus, Isopsera: Isopsera arcuata Nagar, Mal, Swaminathan sp. nov. (Orthoptera:Phaneropteridae Burmeister, 1838; Phaneropterinae Burmeister, 1838) is described. The holotype (?) was collected from South India: Coimbatore (Tamil Nadu). The geographical location had the following specifications: 12058 N 77035E 930MSL South India. The described species differs from the two closely related species, I. caligula Ingrisch and I. spinosa Ingrisch, based on the structure of the male sub-genital plate, cerci and stridulatory file on the left tegmen. PMID- 26249424 TI - Lectotype designations and taxonomic corrections on species of Lygaeoidea (Hemiptera: Heteroptera) described by Gustav Breddin. AB - Types of selected species of Lygaeoidea (Hemiptera: Heteroptera) described by Gustav Breddin, so far of unknown depository, were re-examined and the taxonomic and nomenclatural problems that existed among those species are discussed and resolved as required. The holotype of Dieuches schultheissi Breddin, 1906 is documented. Lectotypes are designated and documented for the following taxa: Lygaeidae: Aethalotus horni Breddin, 1907; Aspilogeton nubicola Breddin, 1901; Lygaeus hospes Fabricius, 1794 var. celebensis Breddin, 1901; Oxycarenidae: Oxycarenus musculus Breddin, 1907; Rhyparochromidae: Lispochroa blandula Breddin, 1907; Notochilaster teres Breddin, 1907; Dieuches horni Breddin, 1906; D. jacobsoni Breddin, 1906; D. nudipes Breddin, 1906; D. villosulus Breddin, 1906; Poeantius brevicollis Breddin, 1907; Pamera recincta Breddin, 1901; Paromius robustior Breddin, 1907. The following taxonomic changes are proposed: Naphius schultzei (Breddin, 1913), new combination (transferred from Rhyparochromus); Graptostethus verticalis (Dallas, 1852) = Pyrrhobaphus scutellatus Breddin, 1907, new subjective synonym; Naphius schultzei (Breddin, 1913) = Naphius capensis Scudder, 1971, new subjective synonym. PMID- 26249425 TI - Cyrtodactylus rosichonariefi sp. nov. (Squamata: Gekkonidae), a new swamp dwelling bent-toed gecko from Bunguran Island (Great Natuna), Indonesia. AB - Cyrtodactylus rosichonariefi sp. nov. is the second newly described species of Bent-toed gecko from Bunguran Island (Great Natuna), Indonesia. This species occurs in the Sekunyam Forest and is differentiated from all other species of the C. semenanjungensis species group of the Thai-Malay Peninsula by having the following unique combination of characteristics: intermediate size (SVL of adult male holotype 54.6 mm); enlarged femoral scales, no femoral pores, no precloacal groove, enlarged precloacal scales, no precloacal pores; subcaudals not enlarged; and dorsal pattern blotched but lacking paired, dark, semilunar-shaped blotches on upper nape. The new species is the sister species of C. majulah Grismer, Wood & Lim. [Corrected] PMID- 26249426 TI - Dolichopodidae (Diptera) from the Iberian Peninsula, with description of three new species. AB - Faunistic data is given for 43 species of Dolichopodidae from the Iberian Peninsula. Altogether nine species are recorded for the first time from Portugal and six species from Spain. Three species are described as new to science: Chrysotimus meridionalis sp. nov. (Spain, Portugal), Hercostomus ibericus sp. nov. (Spain), and Sciapus negrobovi sp. nov. (Portugal). PMID- 26249427 TI - Risiophlebia guentheri sp. nov. (Odonata, Libellulidae) from southeastern Indochina. AB - Risiophlebia guentheri sp. nov. (holotype: Cambodia, Mondulkiri Province, Dak Dam village environs, a tall grass forest swamp, 12 degrees 25' N 107 degrees 19' E, ~780 m a.s.l., 16 June 2014, RMNH), the second species in its genus, is described from Central Plateau of the Annamese Mountains. The new species is most probably separated from R. dohrni by a 1000-km gap of the range of the genus in Thailand and most of Cambodia. PMID- 26249428 TI - Ticks (Acarina: Ixodida) infesting five reptile species in Sri Lanka with sixteen new host records. AB - The first study on ticks on reptiles of Sri Lanka dates back to Seneviratna (1965) who reported ticks from five reptiles. Later studies were either limited to one reptile (Fernando & Fernando 2012), or captive animals in zoos (Fernando & Randeniaya 2009) and household pets (Nathanael et al. 2004). According to the current classification (Guglielmone et al. 2010), all the tick species previously recorded on reptiles belong to five species of Amblyomma: A. clypeolatum Neumann, A. gervaisi (Lucas), A. pattoni (Neumann), A. trimaculatum (Lucas) and A. varanense (Supino). Some of the species listed by Seneviratna (1965) were either synonyms or invalid in respect to the present classification. For example Amblyomma laeve sensu Warburton (1910) is a junior synonym of A. pattoni and A. gervaisii var. lucasi is considered a junior synonym of A. varanense (Guglielmone et al. 2010; D. Apanaskevich pers. comm.). PMID- 26249429 TI - Nomenclatural issues in the Psammodromus hispanicus (Squamata: Lacertidae) species group. AB - The Psammodromus hispanicus species group has been recently shown to include three lineages that differ in morphology (San-Jose et al. 2012), have largely parapatric range but exhibit little evidence of historical gene flow (Fitze et al. 2011), leading to the recognition of these three lineages as distinct species (Fitze et al. 2012). The eastern species can be unambiguously associated with the nomen Lacerta edwarsiana Duges 1829, as the detailed information in Duges (1829) leaves no doubt that he describes as Lacerta edwarsiana the local member of the P. hispanicus complex, and the type locality is the "bas Languedoc", an area of France equivalent to the lowland parts of the current Languedoc region where the only member of the complex is the eastern lineage. The types of Psammodromus edwarsianus have not been traced as far as I am aware, but given the lack of uncertainty regarding allocation of this nomen to the eastern lineage of the P. hispanicus complex this has no nomenclatural consequence. Two nomenclatural issues remain in this species group however: the aim of this note is to solve them. PMID- 26249430 TI - A revision of the genus Euseboides Gahan, 1893 (Coleoptera: Cerambycidae: Lamiinae), with description of two new species. AB - A taxonomic revision of the genus Euseboides Gahan is presented. Two new species, E. motuoensis sp. nov. and E. reni sp. nov., are described from China; habitus, male terminalia and aedeagus are illustrated. E. gorodinskii and E. tonkinensis are newly recorded from China. The male terminalia and aedeagus of E. gorodinskii, E. matsudai and E. punctatissimus are described for the first time. A new combination, Mimozotale (Parazotale) truncatipennis (Breuning, 1949) comb. nov., is proposed. Euseboides is redescribed and a key to Euseboides species presented. PMID- 26249431 TI - Endemics and adventives: Thysanoptera (Insecta) biodiversity of Norfolk, a tiny Pacific Island. AB - The thrips fauna of Norfolk Island is a curious mix of endemics and adventives, with notable absences that include one major trophic group. A brief introduction is provided to the history of human settlement and its ecological impact on this tiny land mass in the western Pacific Ocean. The Thysanoptera fauna comprises about 20% endemic and almost 50% widespread invasive species, and shows limited faunal relationships to the nearest territories, Australia, New Caledonia and New Zealand. This fauna, comprising 66 species, includes among named species 29 Terebrantia and 33 Tubulifera, with four Tubulifera remaining undescribed. At least 12 species are endemics, of which 10 are mycophagous, and up to 10 further species are possibly native to the island. As with the thrips fauna of most Pacific islands, many species are widespread invasives. However, most of the common thrips of eastern Australia have not been found on Norfolk Island, and the complete absence of leaf-feeding Phlaeothripinae is notable. The following new taxa are described: in the Phlaeothripidae, Buffettithrips rauti gen. et sp. n. and Priesneria akestra sp. n.; and in the Thripidae, Scirtothrips araucariae sp. n. and Thrips merae sp. n. PMID- 26249432 TI - A new species and ten new records of bdelloid rotifers from Korea. AB - We conducted a taxonomic study of bdelloid rotifers collected from various terrestrial habitats, such as mosses, lichens, mushrooms on tree trunks, and leaf litter, at six different locations in Korea. The study yielded 10 new Korean records and a new species, Bradyscela hoonsooi n. sp. Among the 10 new Korean records, nine species are new to Asia, and seven of these are rare species with poorly known distributions. Our study is the first to record Habrotrocha fuscochlaena De Koning outside its type locality. Macrotrachela sonorensis Orstan and Habrotrocha acornis Murray have previously been reported from only two countries. Habrotrocha longula Bryce and Habrotrocha visa Donner are recorded outside Europe for the first time. Habrotrocha flaviformis De Koning has previously been reported from Europe, Brazil and New Zealand. Finally, Philodina grandis Milne has been reported from Eastern and Southern Africa and New Zealand before the present study. Here, we provide a description of the new species and discuss the taxonomy and distribution of the seven rare species. PMID- 26249433 TI - Three new endemic species of Epictia Gray, 1845 (Serpentes: Leptotyphlopidae) from the dry forest of northwestern Peru. AB - Three new blind snake species of the genus Epictia are described based on material collected in the Peruvian Regions Amazonas, Cajamarca and La Libertad. All three species are well differentiated from all congeners based on characteristics of their morphology and coloration. They share 10 scale rows around the middle of the tail and possess two supralabials with the anterior one in broad contact with the supraocular. Epictia septemlineata sp. nov. has 16 subcaudal scales, 257 mid-dorsal scale rows, a yellowish-white rostral, and a black terminal spine. Epictia vanwallachi sp. nov. exhibits 16 subcaudals, 188 mid-dorsal scale rows, a grayish-brown rostral, and a yellow terminal spine. Epictia antoniogarciai sp. nov. features 14-18 subcaudals, 195-208 mid-dorsal scale rows, a bright yellow or yellowish-white rostral, and the terminal spine and terminal portion of the tail yellow. All three species were collected in the interandean dry forest valleys of the Maranon River and its tributaries. This region is an area of endemism and warrants further attention from systematic and conservation biologists. PMID- 26249434 TI - Flexammina islandica gen. nov. sp. nov. and some new phylotypes of monothalamous foraminifera from the coast of Iceland. AB - Monothalamous (single-chambered) foraminifera comprise a poorly known group, the diversity of which is strongly underestimated according to environmental DNA surveys. The gross morphology of monothalamids offers few distinguishing features; their organic-walled or agglutinated tests are often very delicate and make isolation difficult. Here, we use an integrated taxonomic approach, including morphological and molecular analysis, to examine the diversity of monothalamids in a shallow subtidal area on the coast of Iceland. We report nine new phylotypes of single-chambered foraminifera distinguished by SSU rDNA sequences. Among them, we establish a new genus Flexammina and a new species Flexammina islandica, possessing a very pliable, finely agglutinated test capable of extreme shape transformations. According to molecular data, F. islandica belongs to the monothalamid clade M, which also includes the well-known genus Allogromia. In addition, we provide brief descriptions and illustrations of nine other monothalamous foraminifera isolated from the same area. Three of them are closely related to some unidentified environmental sequences and serve as the first microscopic documentation of these anonymous lineages. PMID- 26249435 TI - Phytoseiidae (Acari: Mesostigmata) from rubber tree crops in the State of Bahia, Brazil, with description of two new species. AB - The current study describes the results of a survey of Phytoseiidae mites conducted on a rubber tree plantation in the State of Bahia, Brazil. We present 22 species, two of which are new to science, Amblydromalus insolitus n. sp. Nuvoloni & Lofego, and Typhlodromips paramilus n. sp. Nuvoloni & Lofego, and three new records for this host are presented. The species composition was more related with the records of the northern Brazilian Region, than with that of Southeastern and Midwestern. PMID- 26249436 TI - Two new species of Leptobatopsis Ashmead (Hymenoptera: Ichneumonidae: Banchinae) from South Korea and gynandromorphy in L. nigricapitis. AB - Four species of Leptobatopsis Ashmead are recorded for the first time from South Korea. Among them, L. koreana sp. nov. and L. daedeokensis sp. nov. are newly described. We also report two newly recorded species, L. nigricapitis Chandra & Gupta and L. appendiculata Momoi, from South Korea. In addition, we describe a case of gynandromorphy of L. nigricapitis in a single specimen from South Korea. This specimen presents bilateral asymmetry, with the left half of its habitus displaying male characters and the right half displaying female characters. We also provide a key to Eastern Palaearctic species of Leptobatopsis. PMID- 26249437 TI - Description of a new species of Bothinodroctonus Schedl, 1969 (Coleoptera: Curculionidae, Scolytinae) from Africa. AB - A new species of Bothinodroctonus in the tribe Polygraphini is described from Gambia and Kenya. This is the first representative of the genus in Afrotropical region. A holotype based description contains also the intraspecific variety of the newly described species based on available specimens and differential diagnoses to species within the genus. PMID- 26249438 TI - A new species of Canon Solovyev, 2014 (Lepidoptera: Limacodidae) from Thailand. AB - Canon Solovyev is a small genus belonging to the Parasa-complex of Limacacodidae. It is distributed from northern India to the Malayan Peninsula. The genus previously included two species: C. punica (Herrich-Schaffer) from the Indian region and C. eos Solovyev from Nepal. Canon punica is recorded from China (Yunnan), northern Thailand and Malaysia, but specimens from northern Thailand and probably those from China (Yunnan) represent a new species that is described herein: C. sripanae Pellinen and Solovyev, new species. Externally, C. sripanae is similar to other Canon species, but it differs from punica and eos in hindwing color and male genitalia. The moths studied were collected at UV and mixed lights. Genitalia of the male holotype and a male and female paratypes are figured. Nomenclature of this study is based on Solovyev (2014). PMID- 26249439 TI - Formalizing the names of subfamilies and tribes of ponyfishes (Leiognathidae Gill 1893). AB - Several higher-level clades (subfamilies and tribes) of ponyfishes were introduced and diagnosed without the term "new" following the taxon names and without reference to a type genus. We correct these errors here so that the clade names comply with Articles 16.1 and 16.2, and Recommendation 16A of the Code (ICZN 2000, 4th edition), and may be formally recognized. Diagnoses for all of these clades were presented in Chakrabarty et al. (2011) and their membership updated in Sparks and Chakrabarty (2015). PMID- 26249440 TI - Reassessment of multiple species of Gymnelus (Teleostei: Zoarcidae) in Pacific Arctic and boreal regions. AB - Recently described new nominal species and resurrected species in the eelpout genus Gymnelus Reinhardt 1834 were reassessed for validity using fresh material collected in Pacific Arctic regions and a large body of data from a previous systematic review of the genus. The analysis reported here included both DNA barcodes and morphology. Only two species were validated: G. viridis (Fabricius 1780) and G. hemifasciatus Andriashev 1937. The latter species occurred as two morphotypes for which there is some evidence of difference in ecological preference, but the available environ-mental data are not robust enough to firmly identify or verify ecophenotypes. PMID- 26249441 TI - The Giant Pill-Millipedes of Nepal (Diplopoda, Sphaerotheriida, Zephroniidae). AB - The type of the only species of the order Sphaerotheriida with a record in Nepal, Kophosphaera excavata (Butler, 1874), originally described from Sikkim, is redescribed. The subspecies K. excavata mammifera Attems, 1936 from Sureil, Darjeeling, India, is elevated to species rank, K. mammifera stat. nov.. A species of unclear country of origin ('Himalaya'), Sphaeropoeus montanus Karsch, 1881, is briefly redescribed and transferred to the genus Zephronia, Z. montana (Karsch, 1881) n. comb.. Z. tumida Butler, 1882, an apparently widespread north Indian Zephronia species, is redescribed. Sphaerotheriida specimens collected during several expeditions to Nepal undertaken by Prof. J. Martens in the 1970s and 1980s were examined. The material contained 10 specimens (7 males, 3 females) from seven localities, including three undescribed species, Zephronia nepalensis n. sp., Kophosphaera shivapuri n. sp., and Kophosphaera martensi n. sp., as well as a specimen of Kophosphaera politissima Attems, 1935, type species of the genus and described previously from India. A key to all (now seven) species of Kophosphaera is presented. A brief diagnosis of the Kophosphaera excavata group is provided. While Zephronia seems to be restricted to the eastern part of Nepal, two endemic and two more widespread Kophosphaera species occur also in its central and mid-western part, representing the western-most records of the family Zephroniidae in Asia. The current distribution of the family in Nepal clearly indicates the Zephroniidae as a family adapted to tropical environments. PMID- 26249442 TI - Five species under Dicranomyia (Dicranomyia) mitis (Meigen, 1830) (Diptera, Limoniidae). AB - Five species previously usually treated as Dicranomyia (Dicranomyia) mitis (Meigen, 1830) are redescribed and named with already existing names, viz. D. (D.) mitis [s. str.], D. (D.) affinis (Schummel, 1829), D. (D.) quadra (Meigen, 1838), sp. restit., D. (D.) lutea (Meigen, 1804), and D. (D.) imbecilla Lackschewitz in Lackschewitz & Pagast, 1941, stat. n. All important characters of the wing, male tarsi and male and female terminalia are illustrated. A key to D. (D.) mitis and allies is appended. PMID- 26249443 TI - The assamiids harvestmen (Opiliones: Laniatores: Assamiidae) from Champasak Province, Laos. AB - Three assamiids species are recorded from southern Laos, two of which are new: Paramaracandus dolabratus sp. nov. (male) and Simalurius suzukii sp. nov. (male and female). Mysorea thaiensis Suzuki, 1985, that was previously known only from the type locality in northern Thailand is redescribed here. The family Assamiidae was first recorded from Laos. PMID- 26249444 TI - A new species of the palaemonid shrimp genus Palaemonella Dana, 1852 (Crustacea: Decapoda: Caridea) from Okinawa Island, Ryukyu Islands, Japan. AB - The palaemonid shrimp genus Palaemonella Dana, 1852 is currently represented by 21 formally described species worldwide, of which 17 species are known from the Indo-West Pacific. In this study, a new species, P. okunoi, is described and illustrated on the basis of two ovigerous female specimens collected from coastal waters in Okinawa Island, Ryukyu Islands, Japan, at depths of 5-30 m. The new species closely resembles P. hachijo Okuno, 1999, but the shorter rostrum, more anteriorly located postrostral teeth on the carapace, the presence of a pair of submedian teeth on the fourth thoracic sternite and the less slender pereopods distinguish P. okunoi n. sp. from P. hachijo. The discovery of the present new species raises the number of Japanese species of Palaemonella to eight. An updated key to the Indo-West Pacific species of the genus is presented. PMID- 26249445 TI - Review of the millipede genus Yasudatyla Shear & Tsurusaki, 1995 new to the fauna of Russia, with description of new species from the Kurile Islands (Diplopoda, Chordeumatida, Conotylidae). AB - The diplopod genus Yasudatyla Shear & Tsurusaki, 1995 is new to the fauna of Russia, due to the discovery of Y. kurilensis sp. nov. from Kurile Islands. The genus is currently represented by four species, i.e. Y. yasudai Shear & Tsurusaki, 1995, Y. hidakaensis Shear & Tsurusaki, 1995, Y. shariensis Shear & Tsurusaki, 1995, all from Japan, and Y. kurilensis sp. nov. from the Kurile Islands, Russia, described here. All known species of the genus are keyed, including the new species. PMID- 26249446 TI - New combinations and a new generic synonym in the genus Taeniothrips (Thysanoptera: Thripidae). AB - Reasons are provided for considering Javathrips as a new synonym of Taeniothrips, resulting in the following new combinations: Taeniothrips ciliaris (Reyes) comb.n., Taeniothrips musae (Zhang & Tong) comb.n., and Taeniothrips variegatus (Reyes) comb.n. Also recognised here are the following nomenclatural changes: Taeniothrips grisbrunneus (Feng, Chou & Li) comb.n. (from Megalurothrips), and Yaothrips pediculae Han comb.n. (from Taeniothrips) with Yaothrips shii Mirab balou et al. syn.n. Taeniothrips musae is redescribed and illustrated. PMID- 26249447 TI - Mediporus, a new genus of the leafhopper subfamily Evacanthinae (Hemiptera: Cicadellidae), with a key to genera of the Evacanthini. AB - Mediporus splendens gen. n. and sp. n. is described and illustrated based on specimens from Thailand. In addition, a key to genera of the Evacanthini is provided. PMID- 26249448 TI - Two new species of Medetera Fischer von Waldheim (Diptera, Dolichopodidae) from Russia and Mongolia. AB - Two new species Medetera sakhalinensis Negrobov & Naglis sp. nov. from Russian Far East (Sakhalin) and M. emeljanovi Negrobov & Naglis sp. nov. from Mongolia are described and differential diagnosis are given. PMID- 26249449 TI - Nannophlebia leoboppi sp nov., a new dragonfly species from New Guinea (Odonata: Anisoptera: Libellulidae). AB - Nannophlebia leoboppi sp. nov. is described and figured based on a male specimen collected in the Star Mountains of Central New Guinea. This relatively large representative of its genus is compared with its probable nearest relative, N. antiacantha Lieftinck, 1963, which is also partially figured. The new species brings the total number of Nannophlebia species to 25. PMID- 26249450 TI - A new species of Hyponephele Muschamp, 1915 from Tajikistan (Lepidoptera: Satyridae). AB - Hyponephele Muschamp, 1915 is a Palaearctic genus comprising 39 species (Eckweiler, Bozano, 2011), with most distributed in the Central Asiatic region. During the course of faunistic studies on the butterflies of Tajikistan, a new member of this genus was found; it is described herein as new. It is closely related and sympatric to H. hilaris (Staudinger, 1886) so compared to this one. PMID- 26249451 TI - KNUT ROGNES (2015) Revision of the frog fly genus Caiusa Surcouf, 1920 (Diptera, Calliphoridae), with a note on the identity of Plinthomyia emimelania Rondani, 1875. Zootaxa, 3952(1): 1-80. PMID- 26249452 TI - The identity of Hamilton's Ticto Barb, Pethia ticto (Teleostei: Cyprinidae). AB - While describing the fishes of Ganges, Hamilton described Cyprinus ticto (now allocated to Pethia) from south-eastern parts of Bengal. The unavailability of type material and insufficient diagnostic characters in the original description resulted in ambiguities in the identity of this species. In this paper, we clarify the identity of P. ticto through an integrative-taxonomic approach. Pethia ticto can be distinguished from all other known species of the genus by a combination of characters that includes an abbreviated lateral line with 6-12 pored scales; 23-26 scales in lateral-scale row; 9 predorsal scales; 1/24/1/31/2 4 scales in transverse series; and a pigmentation pattern that includes a small black humeral spot covering the third and fourth lateral-line scales, a prominent spot on the caudal peduncle on the 16th-19th scales of the lateral-line scale row, and two rows of black spots scattered on the dorsal fin. PMID- 26249453 TI - A review of the current state of knowledge of fossil Mantispidae (Insecta: Neuroptera). AB - There are 32 individual specimens of Mantispidae (Insecta: Neuroptera) currently recorded from the fossil record, the oldest of which dates back to the Lower Jurassic. These include 19 described species (in 16 genera), 1 specimen described to genus level and 9 unnamed specimens The specimens have been assigned to the extant subfamilies Drepanicinae (4), Mantispinae (10), Symphrasinae (1), and the extinct subfamily Mesomantispinae (16), with one incertae sedis within Mantispidae. There are currently no known fossil representatives of the subfamily Calomantispinae. Mesithoninae has been removed from Mantispidae and placed back within Berothidae. The species Mesithone carnaria and M. monstruosa, however, are true mantispids and have been removed from Mesithone and placed within a new genus Karataumantispa gen. nov. in the subfamily Mesomantispinae. The current state of knowledge of the fossil record of Mantispidae is reviewed and a key to the genera of Mesomantispinae is provided. PMID- 26249454 TI - Two new species and two new records of Ptecticus Loew (Diptera: Stratiomyidae: Sargiinae) from China. AB - Two species, Ptecticus brevispinus sp. nov. and P. guangxiensis sp. nov., from China are described and illustrated. Additional two species, P. longispinus Rozkosny & Kovac, 2003 and P. melanurus (Walker, 1848), are recorded from China for the first time. A checklist of the known Chinese Ptecticus Loew, 1855 species together with their geographical distribution and a new identification key (19 spp.) are presented. PMID- 26249455 TI - Third contribution to the knowledge of water mites from the Comoros, with the description of two new species (Acari: Hydrachnidia). AB - New records of water mites (Acari: Hydrachnidia) from the Comoros are presented. Two species new to science, Torrenticola comorosensis (Torrenticolidae) and Sterkspruitia comorosensis (Hygrobatidae) are described; the latter species is the second known species of the genus Sterkspruitia Cook, 2003. First records are given for Limnochares crinita Koenike, 1898 and Mamersella thienemanni K. Viets, 1929. Additional measurements, figures and information on the morphology are given for specimens assigned to the Monatractides ventriosus-species complex. PMID- 26249456 TI - Description of a new species of Penicillate Millipede from the genus Monographis (Diplopoda: Polyxenidae) found in Vietnam. AB - A new species of penicillate millipede, from genus Monographis (Diplopoda: Polyxenidae), was collected from Trang Bom and Dinh Quan, within the Dong Nai province, southern Vietnam. Taxonomic characteristics of the genus Monographis Attems, 1907, were used to formally describe this new species. Sensilla of the 6th antennal article and claw structures of Monographis dongnaiensis were compared with those of M. tamoyoensis, M. yunnanensis and M. queenslandicus. Genomic DNA of M. dongnaiensis was compared with the DNA of other species within the genus Monographis. Monographis dongnaiensis is confirmed as the ninth member of the genus Monographis and named Monographis dongnaiensis after the collection site Dong Nai province in Vietnam. PMID- 26249457 TI - Rediscovery and redescription of Leodice laurillardi (Quatrefages, 1866) comb. nov. (Annelida: Eunicidae)-a rare European polychaete or just an overlooked species? AB - The eunicid polychaete, Eunice laurillardi Quatrefages, 1866, originally described from the central Mediterranean, has been discovered on the northern Iberian Peninsula, constituting the first report of the species since its original description. The new specimens are compared with the type collection and the species is redescribed. Furthermore, the species is assigned to the genus Leodice Savigny in Lamarck, 1818, based on information provided by re-examination of type material and the newly collected specimens. A summary of the complex taxonomic history of the species and a discussion of its current status are also provided. PMID- 26249458 TI - Two new species of the genus Anthaxia (Anthaxia Eschscholtz 1829) from China, and notes on the related species (Coleoptera: Buprestidae: Anthaxiini). AB - Anthaxia (Anthaxia) kmoniceki sp. nov. and Anthaxia (Anthaxia) ungulata sp. nov. (China, Sichuan) both belonging to the A. (A.) nitidula Linnaeus, 1758 species group are described, illustrated and compared with the most similar species. A short description of the male and new records of Anthaxia (A.) nitiduliformis Bily, 1995 are given together with the notes on the bionomy of the species-group. PMID- 26249459 TI - Systematic placement of some taxa in the family Galumnidae (Acari, Oribatida). AB - Based on the recent ascertaining studies of type specimens, the new systematic placement for one subgenus and three species of oribatid mites of the family Galumnidae (Acari, Oribatida) are proposed, resulting in the following taxonomic proposals: Pergalumna (Bigalumna) Mahunka & Mahunka-Papp, 2009 stat. nov., P. (B.) rimosa (Mahunka & Mahunka-Papp, 2009) comb. nov., Allogalumna quadrimaculata (Mahunka, 1988) comb. nov. and A. brevisetosa (Bayartogtokh & Weigmann, 2005) comb. nov. The initial taxonomic position of the species, Galumna scripta Balogh & Mahunka, 1966, is supported. Some details on important morphological characters of these species are provided. PMID- 26249460 TI - The genus Danielithosia Dubatolov & Kishida, 2012 (Lepidoptera, Erebidae, Arctiinae) in Cambodia, with description of one new species. AB - Although the arctiine fauna of Cambodia remains poorly known, considerable progress has been made over the last seven years (Bucsek, 2012; Cerny & Pinratana, 2009; Bae et al., 2012; Dubatolov, 2012, 2013; Dubatolov et al., 2012, 2013). The genus Danielithosia (Arctiinae) was established by Dubatolov and Kishida (2012), with the type species Tigrioides aureolata Daniel, 1954 from Fujian, Sichuan, and Zhejiang, China. To date, this genus comprises 11 species in the world, most of which are distributed in the Palaearctic and Oriental Regions (Dubatolov, 2013). The genus Danielithosia can be recognized by the following characters: sacculus with a characteristic broadening subapically; juxta long, with a long sclerotized bifurcated process apically (Dubatolov et al., 2012). In Cambodia, only one species, D. hoenei Dubatolov, 2013, has been reported (Dubatolov, 2013), and we here describe one new species from Cambodia. Terminology in this paper follows Dubatolov et al. (2012), and the specimens used in this study are deposited in the collection of Incheon National University (INU), on indefinite loan from Cambodia. PMID- 26249461 TI - Description of Duttaphrynus atukoralei (Anura: Bufonidae) tadpoles from Sri Lanka. AB - Duttaphrynus atukoralei (Bogert & Senanayake, 1966) is a relatively abundant toad known from Southern and Southeastern Sri Lanka. It occurs from sea level up to ~200 m above sea level (IUCN 2014). For almost half a century since its original description there was no information on its life cycle; the only information available is related to its description and distribution (Dutta & Manamendra Arachchi 1996; Manamendra-Arachchi & Pethiyagoda 2006). PMID- 26249462 TI - One new genus and five new nematode species (Monhysterida, Xyalidae) from Tonga and Kermadec Trenches, Southwest Pacific. AB - Little is known about the diversity and systematics of nematodes in hadal trenches (>6000 m depth). The analysis of core samples recently obtained from Tonga (10810 m) and Kermadec Trenches (8081 m) reveals the presence of a diverse nematode community in these extreme environments, and provides the deepest record for the phylum. Here, one new genus and five new species of the family Xyalidae are described. Lamyronema n. gen. is characterised by a large, tripartite buccal cavity and can be distinguished from other genera with similar buccal cavities mainly by the pharyngeal tissue almost completely surrounding the buccal cavity and by the presence of sub-cephalic setae positioned anteriorly to the amphideal fovea. Lamyronema horizonensis n. gen. n. sp. is characterised by the presence of 16-22 sub-cephalic setae, pronounced sexual dimorphism in the size of the amphideal fovea, and short, straight spicules. Daptonema amphorum n. sp. is characterised by short somatic setae, narrow head region, amphideal fovea relatively far from anterior body extremity, thin gubernaculum without apophyses, and cuticularised prevulvar uterine sac with two conspicuous rims. Manganonema kitasatoi n. sp., M. rowdeni n. sp., and M. majusculum n. sp. share traits that set them apart from other species of the genus, i.e., large body size (1100-2080 um), presence of one pair of short setae posterior to the amphideal fovea, and male reproductive system with two testes. The latter trait necessitates amendments to the genus diagnosis. PMID- 26249463 TI - Cherax (Astaconephrops) gherardii, a new crayfish (Decapoda: Parastacidae) from West Papua, Indonesia. AB - Cherax (Astaconephrops) gherardii n. sp. is a moderate burrowing crayfish endemic to the Ajamaru Lakes of West Papua, Indonesia. This species is one of the crayfish species from this region that are exploited for ornamental purposes. Its commonly used commercial name in the pet trade is "Rainbow Crayfish" or "Blue Moon Crayfish", and its native name is "udang kuku biru". The new species is genetically and morphologically similar to Cherax boesemani, however, both species may be easily distinguished morphologically or by using sequence divergence, which is substantial for considering C. gherardii n. sp. to be a valid species. PMID- 26249464 TI - New and little known digger wasps of the genus Ammophila W. Kirby, 1798 (Hymenoptera: Apoidea: Sphecidae) from Central Asia. AB - Five species of Ammophila are treated. The lectotype of Ammophila separanda F. Morawitz, 1891 is designated and illustrated. The holotype of Ammophila cellularis Gussakovskij, 1930 is redescribed and illustrated. Two new species, Ammophila barkalovi sp. nov. (Kazakhstan) and A. pevtsovi sp. nov. (China), are described and illustrated. The hitherto unknown female of A. vetuberosa Li & Yang, 1994 is described. PMID- 26249465 TI - Stemmiulus brasiliensis n. sp., a new species of millipede from Brazilian iron ore caves (Diplopoda: Stemmiulida: Stemmiulidae). AB - A new species of Stemmiulus Gervais, 1844 is described from Amazonian iron ore caves located in Para State, Brazil. The new species differs from the other Brazilian species by gonopod morphology, especially the angiocoxite and colpocoxite, and for the first pairs of legs of males. A key for the species of Stemmiulus found in Brazil is included. PMID- 26249466 TI - A new species, new synonymy, and notes on Neomacrocoris (Heteroptera: Nepomorpha: Naucoridae). AB - Based on borrowed museum specimens and fresh collections from South Africa, Tanzania, and Uganda, many specimens of Neomacrocoris Montandon have been made available for study. Neomacrocoris liberianus n. sp. is described from Liberia and Sierra Leone based on two museum specimens. Neomacrocoris bondelaufa Sites is synonymized with N. transvaalensis (Distant) and distribution records for N. parviceps Montandon and N. vuga Sites are provided. PMID- 26249467 TI - New records of the genus Clistopyga Gravenhorst, 1829 (Hymenoptera: Ichneumonidae: Pimplinae) from the Oriental region, with description of a new species. AB - A new species, Clystopyga longifemoralis Varga & Reshchikov sp. n., is described and illustrated from Thailand. Clistopyga latifrontalis (Uchida, 1941) is re described and illustrated. Clistopyga nagatomii Kusigemati, 1984 is considered to be a junior synonym of C. sziladyi Kiss, 1959 (syn. nov) and also recorded from India for the first time. PMID- 26249468 TI - Castianeira furva sp. nov. (Araneae, Corinnidae, Castianeirinae), a new polymorphic ground sac spider from the southern Western Ghats of India. AB - The ground-dwelling, ant-mimicking corinnid spider genus Castianeira, with Castianeira rubicunda as type species, was erected by Keyserling (1879). Members of the genus are closely related to the Afrotropical genus Cambalida Simon, 1910 (Haddad 2012a) and are distributed mainly in tropical and temperate regions of the world except for Australia and nearby islands (World Spider Catalog 2015). The genus was revised from the Nearctic Region and south-east Asia (Reiskind 1969 and Deeleman-Reinhold 2001, respectively) and currently includes 126 described species, making it as the largest genus within the family Corinnidae (World Spider Catalog 2015). Even though the genus is rich in species, the validity and placement of majority of the species are still doubtful and questionable. For example, according to Haddad (2012b), many of the Afrotropical species, as well as majority of the species described from India (Haddad, pers. comm.) are misplaced or synonyms of previously described ones (e.g. Haddad 2012a, 2013a). The genus thus will remain as a trash-can until all the species described so far can be revised. PMID- 26249469 TI - Notes on the genus Conanalus Tinkham, 1943 (Orthoptera: Tettigoniidae: Conocephalinae) with one new species from Yunnan, China. AB - The paper describes one new species, i.e. Conanalus bilobus sp. nov., and provides additional information on Conanalus brevicaudus Shi, Mao & Ou, 2008 (including female description for the first time), and Conanalus robustus Shi, Mao & Ou, 2008 from Yunnan, as well as illustrations of important morphological characters of Conanalus axinus Shi, Wang & Fu, 2005. A distribution map of the species of Conanalus from Yunnan, China is presented. The type material is deposited in the Museum of Hebei University. PMID- 26249470 TI - A new species of Oroplexia (Lepidoptera: Noctuidae) from China. AB - The genus Oroplexia Hampson, 1908 comprises some 25 known species. Oroplexia is a south Asiatic, widely distributed genus, displays the highest diversity from the monsoon influenced regions of the Central and Southern Himalaya (Nepal, Myanmar and Vietnam) and Southern China (Sichuan and Yunnan provinces) to India (Hindostan) to the South. PMID- 26249471 TI - Haromyia, a new genus of long-legged flies from Dominica (Diptera: Dolichopodidae). AB - The new micro-dolichopodid genus Haromyia gen. nov. and the type species H. iviei sp. nov. are described from the island of Dominica in the Lesser Antilles. Males and females of Haromyia are distinguished by the large setae on a bulging clypeus, minute size, and wing veins that are nearly straight and evenly diverging from wing base. Haromyia does not fit readily into any contemporary dolichopodid subfamily, although it superficially resembles the Enliniinae and Achalcinae. Haromyia should be regarded as incertae sedis until the dolichopodid subfamilies can be refined, particularly to better incorporate the tropical diversity of this large family. PMID- 26249472 TI - A new species of the genus Meiyingia Holzchuh, 2010 (Coleoptera, Cerambycidae, Cerambycinae) from China. AB - The genus Meiyingia Holzchuh, 2010 presently consists of only one species, Meiyingia paradoxa Holzchuh, 2010 from Henan and Shaanxi, China. The genus is characterized by following characters: Head concave between antennal tubercles; clypeus narrow; frons flattened. Eyes small, finely faceted, divided with two lobes widely separated. Antennae slender; those of males longer than the body, with spines at basal antennomeres; third antennomere longest, eleventh antennomere shorter than previous ones. Pronotum slightly longer than broad. Stridulatory organ without median groove. Elytra soft, membranous and narrowed posteriorly with apex rounded; disc flattened. Legs very short, femora gradually widened, tibiae long; first hind tarsal segment longer than following two combined. Procoxal cavity widely open. Prosternal process very short, narrow and deep. Metacoxal cavity open to mesepimeron. Second to fourth sternites pressed in the middle, sternites remarkably long and densely hairy medially. The first four sternites laterally with greater dent. PMID- 26249473 TI - Redescription of Cateria gerlachi (Kinorhyncha, Cyclorhagida) from Sri Lanka and of C. styx from Brazil, with notes on C. gerlachi from India and C. styx from Chile, and the ground pattern of the genus. AB - Cateria gerlachi is redescribed based on specimens from the west coast of Sri Lanka by light microscopical observations of 57 adult and 47 juvenile specimens and by SEM investigations of 33 adult and 10 juvenile specimens. Cateria styx from Brazil is redescribed from 33 adult and 5 juvenile specimens mounted for light microscopy (original material). The original material of C. gerlachi from India and new material of C. styx from Chile have been studied for comparison. Cateria gerlachi can be distinguished from C. styx by leaf-like cuticular hairs dorsally but not laterally on the tergal plate of segment 1 and on the midsternal plate of segments 1-2 vs scales with a posterior process on the entire tergal plate of segment 1 and on the midsternal plate of segments 1-2 in C. styx, fewer lines of leaf-like hairs of the secondary fringe on segments 2-10 in C. gerlachi, broader scales in the central part of the segments in C. gerlachi, the blunt tube on segment 5 in a lateral accessory vs a lateroventral position in C. styx, the lack of a midlateral spine on segment 11 vs its existence on segment 11 of C. styx, the lack of a protrusible dorsal organ at the border of segments 5 and 6 vs its existence in C. styx and type-5 sensory spots and gland cell outlets present on different segments and positions in the two species. We report and document for species of Cateria detailed morphological data, including variability within populations, a female and a male life-history stage, as well as moulting of an adult stage to another adult stage. In contrast to previous records, C. gerlachi occurs in sandy intertidal habitats not only deeply buried in the sediment but also at the surface. PMID- 26249474 TI - Taxonomy on Quedius euryalus group (Coleoptera: Staphylinidae: Staphylinini: Quediina) from China with description of eight new species. AB - Eight new species of the subgenus Microsaurus Dejean, 1833 of the genus Quedius Stephens, 1829 are described based on specimens collected in China, namely Q. aculeatus sp. nov., Q. acutulus sp. nov., Q. altus sp. nov., Q. capillus sp. nov., Q. perlucidus sp. nov., Q. postangulus sp. nov., Q. subwrasei sp. nov. from Sichuan and Q. arcus sp. nov. from Ningxia. The female of Q. songpanoides Smetana, 2009 is described for the first time. These new species belong to the Quedius euryalus group and the fauna of this species group is thus increased to 53 species. In addition, this paper reviews the taxonomic history of the Quedius euryalus group and reports the sexual dimorphism in the hind wing length, i.e. male with longer hind wings in many species of the Quedius euryalus group. Line drawings and color illustrations of adults and genitalia of the new species and some other ones are provided, along with a key to all the known species of the euryalus group. PMID- 26249475 TI - World reclassification of the Gonatocerus group of genera (Hymenoptera: Mymaridae). AB - The 400+ nominal species of the worldwide genus Gonatocerus Nees are reclassified into 14 genera that are placed in Gonatocerini, which is defined by three putative autapomorphies. A key to the 13 extant genera of Gonatocerini is given, based on females. Five previously described genus-group taxa are recognized: Cosmocomoidea Howard stat. rev. (= ater group, of authors), Gahanopsis Ogloblin stat. rev. (= deficiens group, of authors), Gastrogonatocerus Ogloblin stat. n. (= membraciphagus group, of authors), Gonatocerus (= sulphuripes group, of authors), and Lymaenon Walker stat. rev. (= litoralis group, of authors). One new fossil genus, Archigonatocerus Huber gen. n., with two fossil species, A. balticus Huber sp. n., and A. longivena Huber sp. n. and one fossil species in Gonatocerus, G. janzeni Huber sp. n., are described, all from Baltic amber from the Eocene epoch. Eight new extant genera and 16 new extant species are described and their species keyed: Cosmocomopsis Huber gen. n., with C. flopsis Huber sp. n. and C. mopsis Huber sp. n.; Heptagonatocerus Huber gen. n., with H. madagascarensis Huber sp. n., H. magnificus Huber sp. n., H. parvus Huber sp. n., and H. pulchellus Huber sp. n.; Krateriske Huber gen. n., with K. ecuadorensis Huber sp. n., K. guianensis Huber sp. n., and K. peruensis Huber sp. n.; Octomicromeris Huber gen. n., with O. compacta Huber sp. n. and O. brevis Huber sp. n.; Pro-gonatocerus Huber gen. n., with P. albiclava Huber sp. n. and P. brunneiclava Huber sp. n; Tanyxiphium Huber gen. n., with T. breviovipositor Huber sp. n., T. longissimum Huber sp. n., and T. seychellense Huber sp. n. Yoshimotoana Huber gen. n. (= masneri group, of authors) with one included species and Zeyanus Huber, gen. n. (= asulcifrons group, of authors) with 9 included species. Keys to the species of seven genera: Archigonatocerus, Cosmocomopsis, Heptagonatocerus, Krateriske, Octomicromeris, Progonatocerus, and Tanyxiphium are provided. Information for each nominal species catalogued includes the original reference, kind, sex and depository of primary type, and subsequent references that include relevant previous generic combinations, if applicable. The type locality is given, based on original descriptions or, where necessary, subsequent publications that provide clarification on the collection locality. Two new synonyms are proposed: Gonatocerus similis Gupta & Poorani, 2008, syn. n. under G. bialbifuniculatus Subba Rao, 1989; and Gonatocerus hispaniolus Triapitsyn & Huber, 2010, syn. n. under G. masneri Yoshimoto, 1990. Among the species, 245 new combinations are proposed: 82 in Cosmocomoidea, 1 in Cosmocomopsis, 4 in Gahanopsis, 8 in Gastrogonatocerus, 3 in Gonatocerus, 135 in Lymaenon, 2 in Tanyxiphium, 1 in Yoshimotoana, and 9 in Zeyanus. Revived combinations are proposed for Twelve species: 1 in Cosmocomoidea, 1 in Gahanopsis, 2 in Gonatocerus, and 8 in Lymaenon. The 410 nominal species group names are catalogued under their currently accepted genus and also listed alphabetically in an appendix. A tentative generic phylogeny is proposed. PMID- 26249476 TI - Checklist of the Quill mites (Acariformes: Syringophilidae) of the World. AB - Mites of the family Syringophilidae (Acariformes: Cheyletoidea) are ectoparasites inhabiting the quills of various feather types in many groups of birds. Until now, 334 valid species and 60 genera of quill mites have been described and recorded from 482 bird species (95 families and 24 orders). Currently, the family is divided into 2 subfamilies: Syringophilinae Lavoipierre, 1953 with 260 species grouped in 49 genera, and Picobinae Johnston and Kethley, 1973 with 74 species grouped in 11 genera. Mites of the subfamily Syringophilinae inhabit quills of primaries, secondaries, tertials, rectrices and wing coverts and just occasionally the body feathers; representatives of the subfamily Picobinae live predominantly inside the body feathers. The rapid increase of the knowledge on biodiversity and systematics of quill mites started in end of the 1990s; numerous new descriptions appeared since that time and taxonomic rearrangements make an urgent need to summarize all previous data. We present a complete checklist of the family Syringophilidae of the world including the following data: a species name, author(s), references, a number of first page of description, figure numbers in descriptions, depository of type and non-type materials, host spectrum and geographical distribution. The checklist is additionally provided with the table including bird hosts and associated quill mite species. PMID- 26249477 TI - Revision of the Afrotropical species of Norbanus Walker (Hymenoptera: Pteromalidae). AB - The Afrotropical species of Norbanus Walker, 1843 (Hymenoptera: Pteromalidae) are revised. Four previously described Afrotropical species are recognized as valid and redescribed: N. africanus Subba Rao, 1973, N. garouae (Risbec, 1956) comb. nov. (transferred from Bruchobius Ashmead), N. kitegaensis (Risbec, 1957) and N. seyrigi (Risbec, 1952) comb. nov. (from Habrocytus Thomson). In addition, the Mediterranean species N. tenuicornis Boucek, 1970 is recorded for the first time from the Afrotropical region, and 21 species are described as new: N. aequus sp. nov., N. awi sp. nov., N. brevicephalus sp. nov., N. breviclava sp. nov., N. caloramans sp. nov., N. draco sp. nov., N. erebus sp. nov., N. foritempus sp. nov., N. gibber sp. nov., N. gracilis sp. nov., N. incombo sp. nov., N. ingens sp. nov., N. longissimus sp. nov., N. maliarphae sp. nov., N. mustatai sp. nov., N. pilosus sp. nov., N. pleuralis sp. nov., N. polaszeki sp. nov., N. prinslooi sp. nov., N. rotundus sp. nov., and N. sunabron sp. nov. Three extralimital species from North Africa are included in the key: N. cerasiops (Masi, 1922), N. guyoni (Giraud, 1869), and N. obscurus (Masi, 1922). Lectotypes are designated for N. cerasiops, N. kitegaensis and N. seyrigi. The subgenus Picroscytoides Masi is placed in synonymy with Norbanus s.s. syn. nov. Host records are given for several new species, including some economically important pests of maize, sorghum or rice. PMID- 26249478 TI - Revision of the New World cycad weevils of the subtribe Allocorynina, with description of two new genera and three new subgenera (Coleoptera: Belidae: Oxycoryninae). AB - The taxonomy of the weevils inhabiting male cycad cones in the New World is reviewed. All species belong in a single subtribe, Allocorynina, of the family Belidae, subfamily Oxycoryninae and tribe Oxycorynini and are known to develop only in cones of the cycad genera Dioon and Zamia. Most species of Rhopalotria Chevrolat develop in male cones of Zamia ranging from Mexico, Belize, the Caribbean (Cuba, Isle of Youth, Cayman Islands, Jamaica and the Bahamas) to southern Florida, and one species in those of Dioon spinulosum in Mexico. Rhopalotria consists of three previously described species, two previously described genus-group names (treated herein as subgenera) and four new species described herein: subgenus Allocorynus Sharp with R. calonjei n. sp., R. furfuracea n. sp., R. mollis (Sharp) and R. vovidesi n. sp., and the nominate subgenus Rhopalotria with R. dimidiata Chevrolat, R. meerowi n. sp. and R. slossoni (Schaeffer). The species of Parallocorynus Voss develop only in cones of Dioon in Mexico, and the genus consists of one previously described species, the nominate subgenus and three new subgenera and 11 new species described herein: subgenus Dysicorynus n. subg. with P. andrewsi n. sp. and P. sonorensis n. sp., subgenus Eocorynus n. subg. with P. chemnicki n. sp. and P. schiblii n. sp., subgenus Neocorynus n. subg. with P. iglesiasi n. sp. and P. inexpectatus n. sp., and the nominate subgenus Parallocorynus with P. bicolor (Voss), P. gregoryi n. sp., P. jonesi n. sp., P. norstogi n. sp., P. perezfarrerai n. sp. and P. salasae n. sp. Two new genera are described, Protocorynus with one new species in Honduras, P. bontai, and Notorhopalotria with four new species ranging from Costa Rica to Colombia, N. montgomeryensis, N. panamensis, N. platysoma and N. taylori. Keys to genera, subgenera and species are provided. All of these weevils are believed to be involved in pollination of their host cycads. PMID- 26249479 TI - On the new Afrotropical genus Suffrica with discovery of an abdominal gland and a dual femoral organ (Araneae, Zodariidae). AB - A new genus, Suffrica, is described from Tanzania and Kenya. It contains three new species occurring in the Eastern Arc Mountains and the adjacent Mkomazi Game Reserve: S. exotica, S. chawia and S. gus. They are characterized by a remarkable combination of features which has not been documented in spiders so far: a pair of femoral organs on each leg, a gland on the dorsal side of the abdomen in both sexes and a dorsal abdominal groove in males. A dual femoral organ appears to occur in species of the genus Suffasia Jocque, 1991 and Asceua Thorell, 1887. The discovery of a new African genus close to Suffasia is remarkable since the latter genus is known only from Asia. PMID- 26249480 TI - Seven new species of the genus Physotarsus Townes 1966 (Hymenoptera, Ichneumonidae) from South America. AB - Seven new species of the genus Physotarsus Townes are described and illustrated: P. iquitos Reshchikov and Saaksjarvi sp. n., P. mishanensis Reshchikov and Saaksjarvi sp. n., P. orellanensis Reshchikov and Saaksjarvi sp. n., P. polleti Reshchikov and Saaksjarvi sp. n., P. saltilloensis Reshchikov sp. n., P. tampobata Reshchikov and Saaksjarvi sp. n., and P. tunchi Reshchikov sp. n. The male of P. oculatus Zhaurova, 2009 is described for the first time. An illustrated key for Neotropical species is provided. PMID- 26249481 TI - Four new caponiids species (Araneae, Caponiidae) from the West Indies and redescription of Nops blandus (Bryant). AB - We update the knowledge of the unusual Caponiidae spiders from the West Indies with the description of four new species, and the redescription of Nops blandus (Bryant) including the first description of the female. Specimens previously assigned to N. blandus from Hispaniola and Puerto Rico represents two new species: Nops hispaniola n. sp. and Nops agnarssoni n. sp. respectively; while the distribution of the former is limited to British and U. S. Virgin Islands. The others two new species are Nops finisfurvus n. sp. from British Virgin Islands and Cubanops luquillo n. sp. from Puerto Rico. Female internal genitalia of Nops species are described, photographed and illustrated for the first time. PMID- 26249482 TI - A new genus and species of pterygosomatid mite (Acari: Pterygosomatidae) parasitizing Callopistes maculatus (Squamata: Teiidae) from Chile. AB - A new genus and species Callopistiella atacamensis gen. nov. and sp. nov. (Acariformes: Pterygosomatidae) are described from Callopistes maculatus (Squamata: Teiidae) in Chile. In this species, both sexes are characterized by the hypostome without a velum, the chelicerae proximally globose and very thin distally, ending in a movable digit curved outward, the fixed cheliceral digit reduced to a membranous and sparsely serrate structure, presence of seta 2c, tarsus I with seta ft nude and 2 times longer than solenidion omega2; larvae have solenidion omega1 on tarsus I and tibia I without solenidion phi and moderate hypertrichy present around the genital area. Some biological aspects of this new species are discussed. PMID- 26249483 TI - The tribe Dysoniini part IV: New species of Quiva Hebard, 1927 (Orthoptera: Tettigoniidae: Phaneropterinae) from Brazilian rainforest and some clarifications. AB - Two new species of the genus Quiva: Quiva buhrnheimi n. sp. and Quiva gutjahrae n. sp. from Brazilian Amazon are described. Determinations for distributional data previously published by Sovano & Mendes (2013) are clarified and the synonymy of Ituana dorisae under Q. abacata is confirmed. In this paper, an updated key to subgenus Quiva is provided. PMID- 26249484 TI - Alpheopsis balaeniceps sp. nov., an unusual alpheid shrimp (Decapoda: Caridea) from French Polynesia. AB - Alpheopsis balaeniceps sp. nov. is described based on a single male specimen from Moorea, French Polynesia. The new species is unique within the genus Alpheopsis Coutiere, 1896 in possessing balaeniceps-type setae on the fingers of both chelipeds, being especially well developed on the major chela. Within the family Alpheidae, this feature exists only in some species of the distantly related genus Alpheus Fabricius, 1798, however, only on the minor cheliped. This convergence between Alpheopsis and Alpheus is another example of the remarkable diversity and plasticity of the alpheid chelipeds. PMID- 26249485 TI - The Holarctic genus Aeolothrips (Thysanoptera: Aeolothripidae) from Iran, with description of two new species. AB - Two new species of the genus Aeolothrips are described from northeast of Iran. A. bhattii sp.n. from flowering Caroxylon dendroides is remarkable for its strikingly bicolored body with brown head and last three abdominal segments. A. laurencei sp.n. from flowers of Elaeagnus angustifolia is characterized by its large and dark brown body, all yellow tarsi and fore wings with two brown transverse bands connected posteriorly. PMID- 26249486 TI - Catalogue of genera and their type species in the mite Suborder Uropodina (Acari: Mesostigmata). AB - This paper provides details of 300 genus-group names in the suborder Uropodina, including the superfamilies Microgynioidea, Thinozerconoidea, Uropodoidea, and Diarthrophalloidea. For each name, the information provided includes a reference to the original description of the genus, the type species and its method of designation, and details of nomenclatural and taxonomic anomalies where necessary. Twenty of these names are excluded from use because they are nomina nuda, junior homonyms, or objective junior synonyms. The remaining 280 available names appear to include a very high level of subjective synonymy, which will need to be resolved in a future comprehensive revision of the Uropodina. PMID- 26249487 TI - The hydrozoan fauna (Cnidaria: Hydrozoa) from the peaks of the Ormonde and Gettysburg seamounts (Gorringe Bank, NE Atlantic). AB - Twenty-seven species of hydroids were collected from the peaks (35-42 meters depth) of the Gorringe Bank (NE Atlantic) during the oceanographic campaign 'LusoExpedicao Olympus 2008'. Twenty-one of these species are new for the Gorringe Bank that now has published records for a total of 37 hydroid species. Lafoeina tenuis, Sertularella ellisii and Clytia hemisphaerica were the most abundant hydroid species collected. Results revealed spatial differences in the composition of species assemblages along the summits of the Gorringe, as only 14 of the species sampled were found both in the Ormonde and Gettysburg seamounts. The large density of algae at the peaks of the seamounts sustain a considerable hydrozoan diversity (23 species), but visibly inhibits the establishment of hydroids to the rocky substrates (only 2 species found). All the known hydrozoan species from the peaks of the Gorringe were exclusively collected during summer, thus sampling in other seasons may reveal further hydrozoan diversity due to seasonal patterns of growth of algae and hydroids. Nevertheless, the reasonably high levels of hydrozoan biodiversity demonstrated only from a small portion the summits of the Gorringe, corroborate its seamounts as 'biodiversity hotspots'. In agreement with previous investigations with shallow-water molluscs and sponges, the shallow-water hydroid fauna of the Gorringe revealed greater biogeographical affinities with the Mediterranean and mainland Portugal. This is the first report of Eudendrium armatum outside of the Mediterranean. PMID- 26249488 TI - On the spider genus Thymoites in the Neotropical Region (Araneae, Theridiidae): nine new species, complementary descriptions and new records. AB - The theridiid genus Thymoites Keyserling, 1884 is distributed worldwide. Spiders of this genus are mainly known from the Neotropical Region, but are poorly studied in Brazil. In this paper nine new species of Thymoites are described from Brazil, one from the state of Alagoas: Thymoites murici n. sp.; two from Sao Paulo: T. bocaina n. sp., T. ilhabela n. sp. and T. taiobeiras n. sp. from states of Minas Gerais and Sao Paulo; one from the state of Santa Catarina: Thymoites tabuleiro n. sp.; and, three from state of Rio Grande do Sul: Thymoites cristal n. sp., T. camaqua n. sp. and T. piratini n. sp., all based on males and females; and one from the state of Rio de Janeiro: T. pinheiral n. sp. based on male. The male of Thymoites puer (Mello-Leitao, 1941) and the female of T. melloleitaoni (Bristowe, 1938) are here described and illustrated for the first time. Additionally, new records from Brazil are provided for Thymoites ilvan Levi, 1964 for state of Santa Catarina; T. iritus Levi, 1964 for state of Goias; T. piarco (Levi, 1959) for state of Amazonas; and, T. struthio (Simon, 1895) for Bolivia. PMID- 26249489 TI - Two new species and two detailed chaetotaxy descriptions of Seira (Collembola: Entomobryidae) from Brazil. AB - Two new species, Seira coroatensis sp. nov. and Seira diamantinae sp. nov., from different areas of Caatinga Biome, Northeastern Brazil, are described and illustrated in this paper. Seira coroatensis sp. nov. share some similarities with Seira mendoncae Bellini & Zeppelini and Seira ritae Bellini & Zeppelini, but presents a very distinct pattern of setae on dorsal head and mesothorax. In the other hand, Seira diamantinae sp. nov. is the fifth neotropical species described bearing modified blunt macrosetae on distal manubrium and proximal dens. The detailed dorsal chaetotaxy of S. paraibensis Bellini & Zeppelini and S. glabra Godeiro & Bellini are presented with some notes regarding the original descriptions of the species. PMID- 26249490 TI - A taxonomic revision of the seed-harvester ant genus Pogonomyrmex (Hymenoptera: Formicidae) on Hispaniola. AB - We revise species of seed-harvester ants in the genus Pogonomyrmex (subfamily Myrmicinae) that occur on the Caribbean island of Hispaniola. Three species are recognized: P. aterrimus Wheeler (new status), P. saucius Wheeler and Mann, and P. schmitti Forel. Pogonomyrmex schmitti sublaevigatus Wheeler (= schmitti) and P. schmitti darlingtoni Wheeler (= aterrimus) are synonomized. We also describe the queen of P. aterrimus and P. saucius, and provide information on biology, distribution maps, and a key to workers and queens. PMID- 26249491 TI - Colobognatha millipedes in the Caucasus (Diplopoda: Polyzoniida, Platydesmida, Siphonocryptida). AB - The superorder Colobognatha is represented in the Caucasus by three genera and species, one each in the orders Polyzoniida, Platydesmida and Siphonocryptida. Hirudisoma roseum (Victor, 1839) (Hirudisomatidae, Polyzoniida) is especially widespread, ranging from S Russia, Abkhazia, Georgia (with a neotype designated and described from Kakhetia, E Georgia) and NW Azerbaijan to E Turkey, and also including H. ponticum (Lohmander, 1939) (junior subjective synonym, syn. nov.). Fioria hyrcana Golovatch, 1980 (Andrognathidae, Platydesmida) is endemic to the Hyrcanian parts of the Republic of Azerbaijan and NW Iran along the western and southern coasts of the Caspian Sea. Due to the finding of Hirudicryptus abchasicus sp. nov. (Siphonocryptidae, Siphonocryptida), from a single locality in Abkhazia, NW Caucasus, the order Siphonocryptida is new to the fauna of the region. A key to all four species of the trans-Palaearctic genus Hirudicryptus is given. All three Caucasian species of Colobognatha are described in due detail and abundantly illustrated, and their distributions mapped. PMID- 26249492 TI - Reduvius frommeri, a new species of Reduviidae from the Western United States (Hemiptera: Reduviidae), with a synopsis of the Nearctic species of Reduvius Fabricius. AB - The rate of discovery of new species of Reduviidae (Insecta: Heteroptera) from North America has slowed in the 21st century. This is not surprising, given the conspicuousness and large distribution ranges of many Nearctic assassin bug species that are often collected using general insect collecting techniques. Nevertheless, biodiversity discovery in Nearctic Reduviidae is ongoing. We here describe a new species, Reduvius frommeri, n. sp., from Southern California that is so far only known from a small endemic range in the Sonoran Desert. With about 197 species, the genus Reduvius Fabricius is one of the most speciose genera of Reduviidae. The majority of species occur in arid- and semi-arid areas in the Afrotropical, Oriental, and Palearctic regions and only three species are New World endemics. A fourth species that occurs in the United States, Reduvius personatus Fabricius, is cosmopolitan and has been introduced to the Western Nearctic. The new species of Reduvius stands out amongst the four other Nearctic Reduvius species by the small size and pale body coloration with a contrasting dark head. Image plates documenting habitus and selected morphological details and maps are provided for the five species in the Nearctic. We conclude that efforts to document species diversity and distribution ranges even for conspicuous insects such as assassin bugs in fairly well studied biogeographic regions need to continue. PMID- 26249493 TI - Descriptions of three new species of the genus Cheilosia Meigen from China (Diptera, Syrphidae). AB - Three species of genus Cheilosia (Diptera, Syrphidae: Eristalinae) from China are described as new to science, Cheilosia bullabucca Barkalov & Stahls sp. n., C. lamproptera Barkalov & Stahls sp. n. and C. yunnanensis Barkalov & Stahls sp. n. We provide species descriptions and keys for their identification. The phylogenetic placements of the taxa was estimated based on their morphological characteristics and by analysing the taxa under parsimony using a mtDNA COI sequence dataset including a comprehensive set of Palaearctic previously generated Cheilosia spp. sequences representing all major subgenera. Based on both their morphological affinities and the molecular data. The Chinese taxa were placed in the subgenera Eucartosyrphus (C. bullabucca), Cheilosia s. str. (C. oblonga), Floccocheila (C. versicolor) while C. yunnanensis was not resolved as member of Cheilosia s. str. based on DNA despite sharing morphological characteristics with the subgenus. As the name Cheilosia (Nephocheila) prima Barkalov & Cheng from China is a junior homonym of Cheilosia (Cartosyrphus) prima Hunter, 1896 from the Nearctic region, for the Chinese species the new name Cheilosia (Nephocheila) primaria Barkalov & Stahls nomen nov. is proposed. PMID- 26249494 TI - Three new species of Neuraphes in eastern Qinghai-Tibet Plateau (Coleoptera, Staphylinidae, Scydmaeninae). AB - Three new ant-like stone beetle species: Neuraphes (Pararaphes) sichuanus sp. n., N. (P.) tuyuhun sp. n., and N. (P.) miniqinghaiensis sp. n. are described from Sichuan and Qinghai provinces of China. Another species, close to N. qinghaiensis Jaloszynski, is illustrated, but not formally described because of unclear diagnostic characters. The placement of Neuraphes species that inhabit mountain ranges surrounding Qinghai-Tibet Plateau in the subgenus Pararaphes is discussed and their distribution is summarized. PMID- 26249495 TI - Elmohardyia Rafael (Diptera, Pipunculidae) from northeastern Brazil: new records and description of new species. AB - Eleven species of Elmohardyia are recorded for the first time in northeastern Brazil, the most arid Brazilian region. There are two new records, E. lindneri (Collin) and E. trinidadensis (Hardy), and nine new species, which are here described and illustrated: Elmohardyia cearensis sp. nov.; E. cheliformis sp. nov.; E. distincta sp. nov.; E. formosa sp. nov.; E. limeirai sp. nov.; E. martae sp. nov.; E. potiguar sp. nov.; E. quadricornis sp. nov. and E. rosalinae sp. nov. PMID- 26249496 TI - Gorgonolaureus bicornutus sp. nov (Crustacea: Thecostraca: Ascothoracida) from off South-East Taiwan with notes on morphology and distribution. AB - A new ascothoracidan species, Gorgonolaureus bicornutus sp. nov., has been discovered off south-eastern Taiwan at a depth of 227 m. Five females were found in permanent cysts on the branches of a plexaurid octocoralian alcyonacean (former "gorgonian"), Echinogorgia sp. These specimens are assigned to the genus Gorgonolaureus on account of their having an enlarged and inflated carapace with a long, slit-like aperture, long dorsal thoracic horns, no filamentary appendages associated with the first pair of thoracopods, and rudimentary telsonic spines. Gorgonolaureus bicornutus differs from its congeners in having two long, naked dorsal horns on thoracomeres 2 and 3, the number of seminal receptacles in the thoracopods, and the higher number of stout setae on the fifth antennular segment. The characters that unite the genus Gorgonolaureus are redefined as follows: i) the absence of filamentary appendages associated with the first pair of thoracopods; ii) the possession of 1-3 dorsal horns distributed singly among thoracomeres 1-3; iii) the absence of prominent proximal teeth medially on the mandibles; iv) the possession of short or rudimentary telsonic spines; and v) host preference, with most species infecting octocorals of the suborder Halaxonia (mostly of the family Plexauridae) and never the calcaxonian families Chrysogorgiidae and Isididae. The gorgonian-infecting genera Gorgonolaureus and Isidascus are Tethyan relics that have survived only in the Western Pacific and the Eastern Atlantic, respectively, while their relatives in the genera Cardomanica and Thalassomembracis have disjunct Western Atlantic/Western Pacific distributions, thus exemplifying a major pattern of Tethyan reliction. PMID- 26249497 TI - Descriptions of four kleptoparasitic spiders of the genus Mysmenopsis (Araneae, Mysmenidae) and their potential host spider species in the genus Linothele (Araneae, Dipluridae) from Ecuador. AB - Four new species of the genus Mysmenopsis are described: M. onorei n. sp., M. otonga n. sp., M. fernandoi n. sp. and M. chiquita n. sp. All species were collected in diplurid webs and are therefore assumed to be kleptoparasitic. Five potential host species of the genus Linothele (Dipluridae) that were collected with the symbionts are also described: Linothele yanachanka n. sp., L. pukachumpi n. sp., L. zaia n. sp., L. tsachilas n. sp. and L. quori n. sp. PMID- 26249498 TI - Review of some little-known benthic hydroids (Cnidaria, Hydrozoa) from the Southern Ocean. AB - A number of benthic hydroid species inhabiting the Southern Ocean are insufficiently characterized. A revision of eight little-known Antarctic species of the order Anthoathecata was made, based on the study of type material. Some of the species have not been recorded since their original description a century ago. Four species (Bimeria corynopsis, Bougainvillia macloviana, ?Koellikerina belgicae and Rhizorhagium antarcticum) belong to the family Bougainvilliidae, two species (Hydractinia angusta and H. dendritica) to the family Hydractiniidae, Perarella clavata to the family Cytaeididae and, finally, Rhysia halecii to the family Rhysiidae. For each species a list of synonyms, a description, a discussion on its relationship with other species and its systematic position, and an account of its autecological data are given. All records found in the literature have been checked. PMID- 26249499 TI - Characterization of mitochondrial control region in Merlucciidae: sequence variation and molecular phylogeny. AB - In order to describe the structure and evolution of Merlucciidae and related Gadiformes mitochondrial control region we analysed 470 bp of 31 taxa belonging to 28 different species. The general structure and conserved sequence blocks observed in Gadiformes mitochondrial control region are similar to those present in other teleost fishes. The length of this segment is variable among related species due to the presence of numerous indels at domain I. Domain II is the most conserved region with a high G content. The GTGGG-box is absent in all Merluccius and seven other Gadidae species. Several methods of phylogenetic analyses has revealed the monophyly of Gadiformes, Gadinae and Merlucciidae. Merlucciidae is most closely related to Gadidae. Within Merlucciidae, American and Euroafrican clades show similar levels of differentiation to those within Gadinae where Trisopterus and Micromesistius are sister taxa. Genetic distance values for Merluccius subspecies pairs are less than half of those between species, comparable to intra specific differentiation levels in marine fish species. PMID- 26249500 TI - Re-description of Craspodema reflectans (Nematoda, Cyatholaimidae) using confocal laser scanning microscopy. AB - Craspodema reflectans, erected by Gerlach 1964, is here re-described from some specimens recently found in the Maldivian archipelago and the implication of the new findings for the taxonomy of the Craspodema genus is discussed. Accordingly, an emended diagnosis of Craspodema genus and C. reflectans species are proposed. New data are also provided with the aid of the confocal laser scanning microscopy, using the natural fluorescence of the nematodes. The approach described here lays new foundations for the study of Museum collection material and it may be decisive for capture of new morphological details. PMID- 26249501 TI - Extending the southern range of four shrimps (Crustacea: Decapoda: Stenopodidae, Hippolytidae and Alpheidae) in southwestern Atlantic (27o S) and confirming the presence of Mediterranean Stenopus spinosus Risso, 1827 in Brazil. AB - In subtidal zones, certain shrimp species with cryptic behaviour represent a gap in the biodiversity description in many places in the world. This study extends the southern limit of Stenopus hispidus (Oliver, 1811), Alpheus formosus Gibbes, 1850, Alpheus cf. packardii Kingsley, 1880 and Lysmata ankeri Rhyne & Lin, 2006 to Santa Catarina State-Brazil, 27oS. The results also confirm the new occurrence of Stenopus spinosus Risso, 1827 in Brazilian waters. All specimens were collected by scuba diving from rocky islands between 3 and 25 meters depth. We present for each species certain taxonomic features in colour images that will help to identify these decapods in situ in further monitoring programs. PMID- 26249502 TI - Revision of some ophiuroid records (Echinodermata: Ophiuroidea) from Argentina. AB - The taxonomy of some ophiuroids reported from off Argentina, western Antarctica and the SW Atlantic Ocean is reviewed. The species Amphilepis sanmatiensis, known only from the small holotype, is a synonym of Amphioplus lucyae. This synonymy removes the only reported endemic ophiuroid from Argentina. The species name "Ophiacantha ingrata Koehler, 1923" used for specimens from South Georgia is invalid; the specimens are likely to belong to one of two cryptic species within the O. vivipara complex. Specimens of Amphiura joubini reported from Argentina are re-identified as Amphiura princeps, and specimens of Ophiactis amator from the Antarctic Peninsula are re-identified as Ophiactis asperula. PMID- 26249503 TI - A new genus and new species of family Antedonidae (Echinodermata: Crinoidea) from southern Japan. AB - A new genus and new species of antedonid comatulid is described from southern Japan. Belonometra n. gen. has a unique appearance with ten long arms, numerous cirri, and remarkably long and crowded pinnules. The new genus shares some characters with subfamily Heliometrinae. However, the comparative length of pinnules, which is a diagnostic character to determine subfamily Antedonidae, is different. The subfamily into which the new genus should be placed is unclear. PMID- 26249504 TI - NAOYA OHTSUCHI, TOMOHIKO KAWAMURA & MASATSUNE TAKEDA (2014) Redescription of a poorly known epialtid crab Pugettia pellucens Rathbun, 1932 (Crustacea: Decapoda: Brachyura: Majoidea) and description of a new species from Sagami Bay, Japan. Zootaxa, 3765(6), 557-570. PMID- 26249505 TI - Revision of the genus Caenota Mosely (Trichoptera: Calocidae), with descriptions of 2 new species and the larva of C. nemorosa Neboiss. AB - The caddisfly genus Caenota Mosely 1953 (in Mosely & Kimmins 1953) currently contains 5 species known from eastern Australia. Caenota is distinguished from other Calocidae genera by having adult males with greatly expanded maxillary palpi and a large membranous process associated with the antennal scape. Of the 5 described species, the larvae of only 1 is known. Here, we describe 2 new species, Caenota cudonis sp. nov. and C. equustagna sp. nov., from adult, larval, and pupal material. Also, we describe for the first time the larva of C. nemorosa Neboiss. These descriptions increase the number of Caenota species to 7 and the number of associated and described larvae to 4. This paper also provides descriptions of features associated with the adult head capsule of all described species of Caenota. Each of the known species is considered, with illustrations and re-descriptions of these features given. PMID- 26249506 TI - Contribution to the knowledge of two endemic species of Anatolian Gomphocerinae Fieber, 1853 (Orthoptera: Acrididae). AB - This study focuses on two endemic Anatolian Gomphocerinae Fieber, 1853 species, which are evaluated in terms of nomenclature and taxonomy using biogeographical, morphological, and acoustical data. The original description of Eremippus zeybekoglui is supplemented by the data on new specimens collected from type locality, and the female of this species is described for the first time in this study. Based on the new specimens of Stenobothrus weidneri (Demirsoy, 1977) comb. nov., which were collected at the type locality, the species is transferred from Eremippus Uvarov, 1926 to Stenobothrus Fischer, 1853. Additionally, male calling songs of both species are described for the first time in this study. Also, the biogeography of these species is presented and discussed. PMID- 26249507 TI - New species and new records of Mesoceration Janssens, 1967 from South Africa (Coleoptera, Hydraenidae). AB - Mesoceration Janssens, 1967 is the most speciose genus of Prosthetopinae, most of the 44 described species being restricted to South Africa, and almost all occupying the benthic zone of streams and rivers. Here seven species are described as new: Mesoceration caniplenum sp. nov., M. foggoi sp. nov., M. helmei sp. nov., M. hirsutum sp. nov., M. rugulosum sp. nov., M. sewefonteinense sp. nov. and M. sinclairi sp. nov., bringing the number of known species to 51. All seven new species have been discovered during recent, targeted sampling of South African Hydraenidae. New collection records resulting from this fieldwork are also provided for 27 previously described species, together with ecological notes. PMID- 26249508 TI - Revision of the Orasema festiva species group (Hymenoptera: Chalcidoidea: Eucharitidae). AB - The Neotropical Orasema festiva species group is revised, retaining O. festiva (Fabricius) and O. delicatula (Walker) as valid species, and describing four new species: O. alvarengai n. sp., O. caesariata n. sp., O. erwini n. sp., and O. reburra n. sp. The festiva-group is characterized by features that are unusual or unique in Orasema, including the presence of 8-11 labral digits, a smooth face, and a lateral petiolar carina. The egg of O. caesariata and the first-instar larva of O. delicatula are newly described and found to be similar to other species of Orasema. PMID- 26249509 TI - Hooked from the deep: a rare new species of Taeniogyrus (Holothuroidea, Chiridotidae) from the continental slope of Brazil, southwestern Atlantic. AB - Most species of Taeniogyrus Semper, 1867 are known from shallow water in the Indo Pacific, with other records in Antarctica, Mediterranean Sea, and the Atlantic. A new species of Taeniogyrus is described and illustrated here from the continental slope of Campos Basin, southeast of Brazil. In this species, sigmoid hooks (336 405 um) are much larger than in any other in the genus, bearing a long and conspicuous hook region. Wheels with six spokes (86-169 um), inner margin with 60 125 continuous teeth, are confined to round papillae along each interradius. Polian vesicles are ventral, numerous (15-21), of different sizes, and tubular shaped with a terminal round region. This new species represents the deepest record of the genus Taeniogyrus. It increases to three the number of chiridotids in Brazilian waters, and the number of Taeniogyrus species in the Atlantic. Additionally, Taeniogyrus furcipraeditus (Salvini-Plawen, 1972) from the Mediterranean Sea and Taeniogyrus havelockensis (Rao, 1975) from the Andaman Sea are proposed as new combinations. PMID- 26249510 TI - Description of the first cave dwelling species of the spider genus Trilacuna Tong & Li from Iran (Araneae: Oonopidae). AB - A new species of the hard-bodied oonopid genus Trilacuna Tong & Li is described from a cave in Kohgiluyeh and Boyer-Ahmad Province, southwestern Iran. Trilacuna qarzi sp. nov. is the first troglobiont species known of the genus, and is also the fifth oonopid species to be reported from Iran. Relationships of this new species are briefly discussed in the context of the limits of the genera belonging to the Dysderoides complex. PMID- 26249511 TI - Hyphessobrycon lucenorum (Characiformes: Characidae), a new species from the rio Madeira basin, Rondonia State, Brazil. AB - A new species of characid is described from the upper rio Machado, a tributary of the rio Madeira basin, Rondonia, Brazil. Hyphessobrycon lucenorum can be distinguished from all congeners by the unique combination of the presence of a conspicuous rounded humeral blotch and a broad and diffuse longitudinal stripe. The new species is included within the Hyphessobrycon agulha group. The high number of endemic species of fishes occurring in the headwater tributaries of three river systems (rio Madeira, rio Tapajos, and rio Paraguai) draining the watershed defined by the Chapada dos Parecis is discussed. PMID- 26249512 TI - Skadisotoma, a new genus of Isotomidae (Collembola) from Australia. AB - A new species and genus, Skadisotoma inpericulosa, is described from south eastern Australia. It possesses some characters that are found in Tomoceridae, such as a long cylindrical dens that is medially bent and a mucro with at least six teeth of different sizes and three setae but in other characters it resembles an isotomid. In this it shows similarities to the Boreal genus Mucronia Fjellberg, but differs from it in the possession of spines on the dens and in some chaetotaxic characters. PMID- 26249513 TI - Review of the genus Vertomannus Distant (Hemiptera: Heteroptera: Lygaeoidea: Rhyparochromidae: Ozophorini), with description of two new species. AB - The ozophorine genus Vertomannus Distant, 1903 is reviewed in this paper. Ten species are recognized in the genus, including two new species, Vertomannus parvus sp. nov. and Vertomannus tibetanus sp. nov. The new species are described and illustrated. A key to all known members is included. Diagnosis of the genus, habitus photos, measurements, male genitalia illustrations, additional distributions are also presented. PMID- 26249514 TI - A taxonomic study of the genus Bagdadia Amsel, 1949 from Hainan Island of China (Lepidoptera: Gelechiidae). AB - Five species of the genus Bagdadia Amsel are recognized from Hainan Island of China in this paper, of these, Bagdadia khaoensis (Park & Ponomarenko) comb. nov. is proposed, and it is reported for the first time from this country. One new species, Bagdadia tricornis sp. nov. is described and one possibly new species is discussed but not formally named for lack of material. Adults and genitalia of the new and the unnamed species are illustrated and a key to known species of the genus from China is provided. PMID- 26249515 TI - Reinterpreting features of the advertisement call of Dermatonotus muelleri (Boettger, 1885; Anura, Microhylidae). AB - The advertisement call of Dermatonotus muelleri was originally described by Nelson (1973) in a brief section of a review on the mating calls of the Microhylinae. He used two calls from Sao Leopoldo, state of Minas Gerais, in Brazil to determine that they have i) dominant frequency between 1.500-2.200 kHz (mean 1.854 + 0.216 kHz), and ii) harmonic intervals between 0.140 and 0.150 kHz (0.146 +/- 0.005 kHz). Nelson (1973) based his description on an audiospectrogram produced with high frequency resolution and did not quantify the pulse structure of the calls. More recently, Giaretta and colleagues (2013) expanded on the original description using a larger set of calls recorded from Gurinhat, state of Minas Gerais, in Brazil. They quantified the temporal structure of the call and confirmed that the dominant frequency is around 1.8 kHz. In addition, they identified a secondary low frequency band at 667 Hz. PMID- 26249516 TI - New combinations and changes in the classification of Ceratopogonidae (Diptera, biting midges). AB - This short article contains some necessary taxonomic changes prior to the publication of a chapter on the Ceratopogonidae by the author for the upcoming Manual of Afrotropical Diptera and spearheaded by Ashley Kirk-Spriggs. Some additional placements of three genera to a recently redefined tribe are also included. PMID- 26249517 TI - A review of the genus Antorchis Linton, 1911 (Trematoda: Faustulidae) from Indo Pacific fishes with the description of a new species. AB - Species of the faustulid genus Antorchis Linton, 1911 of the tropical Indo-West Pacific are reviewed. We recognise five species in the region, including a novel form. Antorchis nasonis n. sp. is described from Naso annulatus (Quoy & Gaimard) and N. tonganus (Valenciennes) on the southern Great Barrier Reef (GBR). We interpret specimens reported from Naso hexacanthus (Bleeker) from Japan as the same species. This species appears to be the only faustulid known from acanthurid fishes and differs from all other species in the genus in having the prominent dorsal genital invagination close to the posterior end of the body. In addition, new host and locality records are reported for two described species of Antorchis, A. pomacanthi (Hafeezullah & Siddiqi, 1970) and A. tsushimaensis (Machida, 1971). The wide distribution of A. pomacanthi was further demonstrated by the generation of identical ITS2 rDNA sequences for specimens from Ningaloo Reef off Western Australia, off Lizard and Heron Islands (GBR) and off New Caledonia, localities separated by up to 5,300 km. The host-specificity of the genus is considered. PMID- 26249518 TI - A new genus for Entophilus mirabiledictu Markham & Dworschak, 2005 (Crustacea: Isopoda: Cryptoniscoidea: Entophilidae) with remarks on morphological support for epicaridean superfamilies based on larval characters. AB - A detailed reexamination of male and female Entophilus mirabiledictu Markham & Dworschak, 2005 (an endoparasite of callianassid shrimp), resulted in recognition of seven female and five male characters that separate the species from its sole congener, E. omnitectus Richardson, 1903 (an endoparasite of munidid squat lobsters). These characters show that the two species are so different as to warrant E. mirabiledictu being placed in its own genus within the Entophilidae. Additionally, a review of the morphological features of entophilid cryptoniscus larvae led to the finding that the number of flagellar segments on the second antenna offers morphological support for a recent molecular phylogeny of epicaridean taxa that rearranged the component families within the two recognised superfamilies. This work highlights the power of using larval characters in testing hypotheses on the evolutionary relationships of epicaridean taxa. PMID- 26249519 TI - Two new mite species of the subfamily Harpirhynchinae Dubinin, 1957 (Acariformes: Harpirhynchidae), parasites of the passerine birds (Aves: Passeriformes) in Australia and South Asia. AB - Two new mite species of the subfamily Harpirhynchinae Dubinin, 1957 (Acariformes: Harpirhynchidae) are described from passerine birds (Aves: Passeriformes): Harpirhynchoides artamus n. sp. from Artamus fuscus Vieillot (Artamidae) from an unknown locality in South Asia and Neharpyrhynchus domrowi n. sp. from three host species of the family Meliphagidae, Acanthorhynchus tenuirostris (Latham) (type host) from Australia (New South Walles), Ptiloprora perstriata (De Vis) and Myzomela rosenbergii Schlegel from Papua New Guinea. PMID- 26249520 TI - Peltogasterella sensuru n. sp. (Crustacea: Cirripedia: Rhizocephala) from off Okinawa Island (Ryukyu Archipelago, Japan) with remarks on its single brood externae. AB - Peltogasterella sensuru n. sp. infests Pagurixus hermit crabs inhabiting rocky shores off Okinawa Island (Ryukyu Archipelago, Japan). This species is clearly distinguishable from Peltogasterella gracilis (Boschma, 1927): the stalk emerges from the middle part of the externa in the present species and P. sulcata (Lilljeborg, 1859), while the stalk in P. gracilis emerges from the posterior end of the externae. The new species differs from P. sulcata based on the morphology of the mantle aperture. Peltogasterella sensuru n. sp. repeatedly produces single brood externae that have not been previously observed in species belonging to the suborder Kentrogonida Delage, 1884. We also determined partial sequences of the COI gene and 16S rRNA gene of the new species for use as molecular markers for species identification. PMID- 26249521 TI - Morphological and molecular characterisation of Ditrachybothridium macrocephalum Rees, 1959 (Cestoda: Diphyllidea) from Galeus melastomus Rafinesque in the Western Mediterranean. AB - New morphological, molecular and ecological data for Ditrachybothridium macrocephalum Rees, 1959 (Cestoda: Diphyllidea) are presented and discussed based on specimens recovered from the blackmouth catshark Galeus melastomus Rafinesque (Scyliorhinidae) in the Western Mediterranean. A redescription of the plerocercus of this parasite is provided and new data on immature and mature worms including the first description of the eggs are reported, based on light and scanning electron microscopy observations. Analysis of 28S rDNA (domains D1-D3) sequences from plerocerci, immature and adult specimens revealed that they are conspecific with specimens from the North East Atlantic. Although previous authors considered that museum specimens identified as D. macrocephalum may represent more than one species, examination of type- and voucher material revealed no relevant morphological differences between museum specimens and the present material. Information on infection levels of D. macrocephalum is provided from a large number of host specimens (n = 170). This species was more abundant in juvenile than in adult hosts and on the middle slope than on the upper slope; this may be related to ontogenetic and bathymetric diet shifts of G. melastomus. PMID- 26249522 TI - Proparasitylenchus californicus n. sp. (Tylenchida: Allantonematidae), parasitic in the intertidal rove beetle Tarphiota geniculata (Maklin) (Coleoptera: Staphylinidae) in California, USA. AB - A new nematode species, Proparasitylenchus californicus n. sp., is described from the intertidal rove beetle Tarphiota geniculata (Maklin) (Coleoptera: Staphylinidae) in California, USA. The new species differs from European representatives of the genus by possessing a cleft stylet in both sexes. The parasitic female is ovoviviparous and produces numerous juveniles that moult twice in the beetle host, then exit and moult twice to the adult stage in the environment. After mating, the free-living fertilised females enter a new host. Heavy infections sterilise the beetles. This is the first record of the genus Proparasitylenchus Wachek, 1955 in the New World and the first allantonematid parasite of a marine, intertidal beetle. PMID- 26249523 TI - Stibarokris annae n. sp. from Ciconia maguari (Gmelin) (Ciconiiformes: Ciconiidae), a new species of quill mites (Acariformes: Syringophilidae) exhibiting dimorphism of females. AB - A new quill mite species having dimorphic females Stibarokris annae n. sp. (Acariformes: Syringophilidae) is described from the maguari stork Ciconia maguari (Gmelin) (Ciconiiformes: Ciconiidae) from Uruguay. "S-form" females of S. annae differ from S. phoeniconaias Skoracki & OConnor, 2010 by the hysteronotal shield not reaching setal bases d1 (vs hysteronotal shield bearing setal bases d2 and d1 in S. phoeniconaias), the length ratio of setae ag1:ag2:ag3 1:1-1.4:2-2.4 (vs 1:1:1.2-1.3), the genital setae g1 2-2.5 times as long as g2 (vs g1 1.4-1.8* as long as g2), the fan-like setae of legs III-IV with 15-17 tines (vs with 6-8 tines) and the length of setae f2 (230-255 vs 295-370 um), h1 (25-30 vs 45-55 um), ag1 (125-165 vs 245-285 um) and ag2 (145-180 vs 245-270 um). "C-form" females of S. annae are distinguishable from S. phoeniconaias ("C-form") by the longitudinal branch of the peritremes with 14-16 chambers (vs 12-13 chambers in S. phoeniconaias), the propodonotal shield weakly sclerotised and punctate along its lateral borders (vs well sclerotised and apunctate), the hysteronotal shield represented by an oval area covered by delicate striations (vs distinct hysteronotal shield), genital setae g1 1.5-1.8 times as long as g2 (vs g1 and g2 subequal in length), the fan-like setae p' and p" with 10 tines (vs with 5 tines) and the length of setae ve (120-130 vs 185-195 um), si (120-130 vs 220 um), se (180-200 vs 245-295 um), c1 (180-195 vs 270-285 um), d2 (180-205 vs 265-270 um), d1 (195-205 vs 255-285 um) and e2 (195-215 vs 285-320 um). PMID- 26249524 TI - MR-guided laser interstitial thermal therapy for pediatric drug-resistant lesional epilepsy. AB - OBJECTIVE: To report the feasibility, safety, and clinical outcomes of an exploratory study of MR-guided Laser Interstitial Thermal Therapy (MRgLITT) as a minimally invasive surgical procedure for the ablation of epileptogenic foci in children with drug-resistant, lesional epilepsy. METHODS: Retrospective chart review of all MRgLITT procedures at a single tertiary care center. All procedures were performed using a U.S. Food and Drug Administration (FDA)-cleared surgical laser ablation system (Visualase Thermal Therapy System). Predefined clinical and surgical variables were extracted from archived medical records. RESULTS: Seventeen patients underwent 19 MRgLITT procedures from May 2011 to January 2014. Mean age at seizure onset was 7.1 years (range 0.1-14.8 years). Mean age at surgery was 15.3 years (range 5.9-20.6 years). Surgical substrates were mixed but mainly composed of focal cortical dysplasia (n = 11). Complications occurred in four patients. Average length of hospitalization postsurgery was 1.56 days. Mean follow-up was 16.1 months (n = 16; range 3.5-35.9 months). Engel class I outcome was achieved in seven patients (7/17; 41%), Engel class II in one (1/17; 6%), Engel class III in three (3/17; 18%), and Engel class IV in six (6/17; 35%). Three patients (3/8; 38%) with class I and II outcomes and five patients (5/9; 56%) with class III and IV outcomes had at least one prior resection. Fisher's exact test was not statistically significant for the association between Engel class outcome and previous resection (p = 0.64). SIGNIFICANCE: This study provides descriptive results regarding the use of MRgLITT in a mixed population of pediatric, lesional, drug-resistant epilepsy cases. The ability to classify case-specific outcomes and reduce technical complications is anticipated as experience develops. Further multicenter, prospective studies are required to delineate optimal candidates for MRgLITT, and larger cohorts are needed to more accurately define outcome and complication rates. PMID- 26249525 TI - Complete pathological response induced by sorafenib for advanced hepatocellular carcinoma with multiple lung metastases and venous tumor thrombosis allowing for curative resection. AB - We report the first case of initially unresectable advanced hepatocellular carcinoma (HCC) with portal vein and hepatic venous tumor thrombosis and multiple lung metastases that allowed for curative hepatectomy after multidisciplinary treatment including sorafenib. A 54-year-old male presented with a large HCC in the right liver with tumor thrombosis of the left portal vein and middle hepatic vein (MHV) as well as multiple lung metastases. His serum alpha-fetoprotein level was elevated at 52,347 ng/mL and palliative treatment with sorafenib was initiated. One month later, a significant reduction in the serum AFP level, decrease in the tumor size with recanalization of the portal vein and the absence of lung metastases were noted. Three months after the start of sorafenib treatment, external-beam radiotherapy was performed to treat enlargement of the area of MHV thrombosis, and the thrombosis regressed. Five months after the initiation of sorafenib treatment, central bisegmentectomy associated with removal of the tumor thrombus in the inferior vena cava was performed. A microscopic examination revealed complete necrosis of the tumor. Sorafenib treatment may be a bridge to curative resection in selected patients with initially unresectable advanced HCC, even in cases involving multiple extrahepatic metastases. PMID- 26249526 TI - So-called carcinosarcoma of the duodenum with a chondrosarcomatous component. AB - Carcinosarcoma is a biphasic malignant tumor consisting of both carcinomatous and sarcomatous components, and its occurrence in the duodenum is very rare. In the present report, we describe a case of so-called carcinosarcoma of the duodenum with a chondrosarcomatous component. A 79-year-old man was referred to our hospital because of anorexia, weight loss, and jaundice. A preoperative imaging examination showed a hypovascular mass located in the pancreatic head. Histological examination of specimens obtained through a forceps biopsy revealed anaplastic carcinoma (spindle cell type), and a pancreatoduodenectomy was performed. Histologically, the tumor showed an elevated lesion with a wide base in proximity to duodenal mucosal carcinoma. The tumor was found to be predominantly composed of sarcoma with carcinomatous and chondrosarcomatous components. There was a transitional zone between the carcinomatous and sarcomatous components, and a portion of the sarcomatous component was positive for cytokeratin, and negative for vimentin. As mentioned above, we diagnosed the lesion as so-called carcinosarcoma with a chondrosarcomatous component. PMID- 26249527 TI - Allelic frequencies and association with carcass traits of six genes in local subpopulations of Japanese Black cattle. AB - Marker-assisted selection (MAS) is expected to accelerate the genetic improvement of Japanese Black cattle. However, verification of the effects of the genes for MAS in different subpopulations is required prior to the application of MAS. In this study, we investigated the allelic frequencies and genotypic effects for carcass traits of six genes, which can be used in MAS, in eight local subpopulations. These genes are SCD, FASN and SREBP1, which are associated with the fatty acid composition of meat, and NCAPG, MC1R and F11, which are associated with carcass weight, coat color and blood coagulation abnormality, respectively. The frequencies of desirable alleles of SCD and FASN were relatively high and that of NCAPG was relatively low, and NCAPG was significantly associated with several carcass traits, including carcass weight. The proportions of genotypic variance explained by NCAPG to phenotypic variance were 4.83 for carcass weight. We thus confirmed that NCAPG is a useful marker for selection of carcass traits in these subpopulations. In addition, we found that the desirable alleles of six genes showed no negative effects on carcass traits. Therefore, selection using these genes to improve target traits should not have negative impacts on carcass traits. PMID- 26249528 TI - Comparison of Outcome After Use of Extra-Luminal Rings and Intra-Luminal Stents for Treatment of Tracheal Collapse in Dogs. AB - OBJECTIVE: To report short- and long-term complications and outcomes of dogs treated for tracheal collapse secondary to chondromalacia with extra-luminal rings (ELR) or intra-luminal stents (ILS). STUDY DESIGN: Retrospective cohort. SAMPLE POPULATION: Dogs with naturally occurring tracheal collapse (n = 103). METHODS: Medical records (2002-2012) of dogs diagnosed with tracheal collapse that had treatment with ELR (n = 73) or ILS (30) were reviewed. Demographic information, procedural information, complications, survival time, and subjective outcomes were recorded. Follow-up periods were defined as <730 days (short-term) and >730 days (long-term). RESULTS: Ninety-two percent of dogs undergoing ELR and 100% of dogs undergoing ILS survived to hospital discharge. ELR dogs were significantly younger (P = .009) and significantly fewer had main-stem bronchial collapse (P < .001). After accounting for effects of age and presence of main stem bronchial collapse, there was no significant difference in median survival time between groups. Dogs with main-stem bronchial collapse (regardless of treatment type) had a shorter survival time than dogs without main-stem bronchial collapse. Major complications occurred in ELR (42%) and ILS dogs (43%). CONCLUSIONS: Both ELR and ILS are associated with high complication rates. Younger dogs and dogs without main-stem bronchial collapse had a longer survival time, regardless of treatment. PMID- 26249530 TI - [Longitudinal melanonychia]. PMID- 26249529 TI - Study on the interaction between pelargonidin-3-O-glucoside and bovine serum albumin using spectroscopic, transmission electron microscopy and molecular modeling techniques. AB - The aim of this study is to evaluate the binding behavior between pelargonidin-3 O-glucoside (P3G) and bovine serum albumin (BSA) using multi-spectroscopic, transmission electron microscopy (TEM) and molecular docking methods under physiological conditions. Fluorescence spectroscopy and time-resolved fluorescence showed that the fluorescence of BSA could be quenched remarkably by P3G via a static quenching mechanism, and there is a single class of binding site on BSA. In addition, the thermodynamic functions DeltaH and DeltaS were -21.69 kJ/mol and 24.46 J/mol/K, indicating that an electrostatic interaction was a main acting force. The distance between BSA and P3G was 2.74 nm according to Forster's theory, illustrating that energy transfer occurred. In addition, the secondary structure of BSA changed with a decrease in the alpha-helix content from 66.2% to 64.0% as seen using synchronous fluorescence, UV/vis, circular dichroism and Fourier transform infrared spectroscopies, whereas TEM images showed that P3G led to BSA aggregation and fibrillation. Furthermore, site marker competitive experiments and molecular docking indicated that P3G could bind with subdomain IIA of BSA. The calculated results of the equilibrium fraction showed that the concentration of free P3G in plasma was high enough to be stored and transported from the circulatory system to its target sites to provide therapeutic effects. PMID- 26249531 TI - [Negative pressure therapy: NPT]. AB - Negative pressure therapy or treatment (NPT) is used very frequently in hospitals in both surgical and medical departments. NPT consists of maintaining the wound surface at a pressure below ambient atmospheric pressure by means of a specially designed dressing attached to a depressurisation device as well as a system to drain exudate. NPT has been shown to be beneficial in increasing blood flow, thanks to feedback resulting from the decreased oxygen pressure, angiogenesis and reduction of the wound surface area. The French Health Authority (HAS) has issued recommendations for good use in a specific and limited series of applications. NPT may be used in post-traumatic or post-surgical wounds, burns, and in chronic wounds, such as bedsores and ulcers. It is also effective as an adjuvant treatment for infected wounds. In recent years, various different NPT devices have become commercially available. PMID- 26249532 TI - [Fixed drug eruption induced by leuprorelin]. PMID- 26249533 TI - Thermosensitive Ion Channel Activation in Single Neuronal Cells by Using Surface Engineered Plasmonic Nanoparticles. AB - Controlling cell functions using external photoresponsive nanomaterials has enormous potential for the development of cell-engineering technologies and intractable disease therapies, but the former currently requires genetic modification of the target cells. We present a method using plasma-membrane targeted gold nanorods (pm-AuNRs) prepared with a cationic protein/lipid complex to activate a thermosensitive cation channel, TRPV1, in intact neuronal cells. Highly localized photothermal heat generation mediated by the pm-AuNRs induced Ca(2+) influx solely by TRPV1 activation. In contrast, the use of previously reported cationic AuNRs that are coated with a conventional synthetic polymer also led to photoinduced Ca(2+) influx, but this influx resulted from membrane damage. Our method provides an optogenetic platform without the need for prior genetic engineering of the target cells and might be useful for novel TRPV1 targeted phototherapeutic approaches. PMID- 26249534 TI - Sudden Cardiac Death in a Young Man with Migraine-associated Arrhythmia. AB - A 31-year-old man with migraine-induced syncope and bradycardia with subsequent pacemaker implantation died unexpectedly. Clinically unsuspected cardiac anomalies were found at autopsy including myocardial bridging of the left anterior descending artery and shelf-like coronary artery ostia. Nortriptyline was identified by toxicologic analysis. A review of the autopsy findings, the historical information, and the effects of the possible arrhythmogenic circumstances is undertaken and the potential contributions to the death are discussed. Cardiac arrhythmias have been documented during migraines. Coronary artery bridging has been known to lead to ischemia and infarction, ventricular tachycardia, and sudden death; however, these are very rare sequelae. Congenital coronary artery anomalies have been linked to sudden cardiac death, but only rarely cause death in people younger than 31 years. Migraines and the autopsy findings described have been associated with cardiac arrhythmia and sudden death. Altogether, they led to the unexpected death of this young man. PMID- 26249535 TI - Renal function in survivors of nonsyndromic Wilms tumor treated with unilateral radical nephrectomy. PMID- 26249536 TI - Ultrathin MoS2 Nanosheets with Superior Extreme Pressure Property as Boundary Lubricants. AB - In this paper, a new kind of oil-soluble ultrathin MoS2 nanosheets is prepared through a one-pot process. A superior extreme pressure property, which has not been attained with other nano-additives, is discovered when the nanosheets are used as lubricant additives. The as-synthesized MoS2 nanosheet is only a few atomic layers thick and tens of nanometers wide, and it is surface-modified with oleylamine so it can be well dispersed in oil or lubricant without adscititious dispersants or surfactants. By adding 1 wt% ultrathin MoS2 nanosheets, at the temperature of 120 degrees C, the highest load liquid paraffin can bear is tremendously improved from less than 50 N to more than 2000 N. Based on the tribological tests and analysis of the wear scar, a lubrication mechanism is proposed. It is believed that the good dispersion and the ultrathin shape of the nanosheets ensure that they can enter the contact area of the opposite sliding surfaces and act like a protective film to prevent direct contact and seizure between them. This work enriches the investigation of ultrathin MoS2 and has potential application in the mechanical industry. PMID- 26249537 TI - The influence of area level social deprivation on preoperative disease severity and postoperative outcomes following unicompartmental knee joint replacement. AB - BACKGROUND: This study investigated the effect of socioeconomic deprivation on preoperative disease and outcome following unicompartmental knee replacement (UKR). METHODS: 307 Oxford UKRs implanted between 2008 and 2013 under the care of one surgeon using the same surgical technique were analysed. Deprivation was quantified using the Northern Ireland Multiple Deprivation Measure. Preoperative disease severity and postoperative outcome were measured using the Oxford Knee Score (OKS). RESULTS: There was no difference in preoperative OKS between deprivation groups. Preoperative knee range of motion (ROM) was significantly reduced in more deprived patients with 10 degrees less ROM than least deprived patients. Postoperatively there was no difference in OKS improvement between deprivation groups (p=0.46), with improvements of 19.5 and 21.0 units in the most and least deprived groups respectively. There was no significant association between deprivation and OKS improvement on unadjusted or adjusted analysis. Preoperative OKS, Short Form 12 mental component score and length of stay were significant independent predictors of OKS improvement. A significantly lower proportion of the most deprived group (15%) reported being able to walk an unlimited distance compared to the least deprived group (41%) one year postoperatively. CONCLUSION: More deprived patients can achieve similar improvements in OKS to less deprived patients following UKR. PMID- 26249538 TI - Does 3D orientation account for variation in osteon morphology assessed by 2D histology? AB - The primary microstructural unit of cortical bone, the secondary osteon or Haversian system, is widely assumed to have a cylindrical shape. It is generally accepted that osteons are roughly circular in cross-section and deviations from circularity have been attributed to deviations from longitudinal orientation. To our knowledge this idealized geometric relationship, which assumes osteons are perfect cylinders, has not been rigorously explored. As such, we sought to explore two research questions: (i) Does the orientation of osteons in 3D explain variation in shapes visualized in 2D? (ii) Can differences in osteon 3D orientation explain previously reported age-related differences observed in their 2D cross-sectional shape (e.g. more circular shape and decreased area with age)? To address these questions we utilized a combination of 2D histology to identify osteon shape and superimposed micro-computed tomography data to assess osteon orientation in 3D based upon the osteonal canal. Shape was assessed by the inverse of Aspect Ratio (On.AspR(-1), based on a fitted ellipse) - which ranged from 0 (infinitely elongated shape) to 1 (perfectly circular). A sample (n = 27) of human female anterior femoral cortical bone samples from across the human lifespan (20-87 years) were included in the analysis, which involved 1418 osteons. The overall mean measure of On.AspR(-1) was 0.703 (1.42 Aspect Ratio). Mean osteon orientation was 79.1 degrees (90 degrees being longitudinal). While we anticipated a positive relation between orientation and On.AspR(-1), we found the opposite - a weak negative correlation (with more oblique 3D osteon alignment, the 2D shape became more circular as reflected by increased On.AspR( 1)). When analysis of covariance was performed with age and orientation as covariates, the negative relation with orientation was replaced by a significant relation with age alone. This relation with age accounted for 41% of the variation of On.AspR(-1). The results revealed that osteons, on average, are not circular in cross-section and that 3D orientation cannot account for deviation from circular shape. Osteons thus are strictly speaking not cylinders, as they tend to have elliptical cross-sections. We observed that osteons did become less elliptical in cross-section with age independent of orientation - suggesting this is a real change in morphology. PMID- 26249539 TI - Posterior tibial slope accuracy with patient-specific cutting guides during total knee arthroplasty: A preliminary study of 50 cases. AB - BACKGROUND: Patient-specific cutting guides were recently introduced to facilitate total knee arthroplasty (TKA). Their accuracy in achieving optimal implant alignment remains controversial. The objective of this study was to evaluate postoperative radiographic outcomes of 50 TKA procedures with special attention to posterior tibial slope (PTS), which is difficult to control intraoperatively. We hypothesized that patient-specific cutting guides failed to consistently produce the planned PTS. MATERIAL AND METHODS: The SignatureTM patient-specific cutting guides (Biomet) developed from magnetic resonance imaging data were used in a prospective case-series of 50 TKAs. The target PTS was 2 degrees . Standardised digitised radiographs were obtained postoperatively and evaluated by an independent reader. Reproducibility of the radiographic measurements was assessed on 20 cases. The posterior cortical line of the proximal tibia was chosen as the reference for PTS measurement. Inaccuracy was defined as an at least 2 degrees difference in either direction compared to the target. RESULTS: The implant PTS was within 2 degrees of the target in 72% of knees. In the remaining 28%, PTS was either excessive (n=10; maximum, 9 degrees ) or reversed (n=4; maximum, -6 degrees ). The postoperative hip-knee-ankle angle was 0 degrees +/- 3 degrees in 88% of knees, and the greatest deviation was 9 degrees of varus. CONCLUSION: These findings support our hypothesis that patient specific instrumentation decreases PTS accuracy. They are consistent with recently published data. In contrast, patient-specific instrumentation provided accurate alignment in the coronal plane. PMID- 26249540 TI - The outset of another nitrogenase. PMID- 26249541 TI - Effects of single nucleotide polymorphisms in c-Myc on stable warfarin doses in patients with cardiac valve replacements. AB - AIM: This study aimed to investigate an association between c-Myc SNPs and stable warfarin doses. MATERIALS & METHODS: The influences of genetic polymorphisms on dose requirements were investigated by genotyping ten SNPs in 201 patients with stable warfarin doses; VKORC1 (rs9923231), CYP2C9 (rs1057910), CYP4F2 (rs2108622), GATA4 (rs10090884), c-Myc (rs4645962, rs4645943, rs4645948 and rs4645974) and 8q24 (rs1447295 and rs16901979). RESULTS: Around 44.3% of the overall interindividual variability in warfarin dose requirements was explained by the multivariate regression model; VKORC1 genotype accounted for 26.4%, CYP2C9 genotype for 4.9%, age for 3.4%, c-Myc genotypes for 5.2% (rs4645974 for 2.4% and rs4645943 for 2.8%), CYP4F2 genotype for 2.9% and diuretic use for 1.5%. CONCLUSION: Our results revealed that c-Myc could be a determinant of stable warfarin doses. PMID- 26249542 TI - Fondaparinux vs. enoxaparin in patients with non-ST elevation acute coronary syndromes (NSTE-ACS) treated with percutaneous coronary intervention and tirofiban: an exploratory study in China. AB - WHAT IS KNOWN AND OBJECTIVE: Fondaparinux and enoxaparin are used in patients with acute coronary syndrome (ACS), but their effect in particular populations of patients is not well known. The objective was to explore the difference between fondaparinux and enoxaparin in patients with non-ST elevation ACS (NSTE-ACS) treated with percutaneous coronary intervention (PCI) and tirofiban. METHODS: We prospectively enrolled 461 patients with NSTE-ACS treated with PCI, tirofiban, and either fondaparinux (n = 229) or enoxaparin (n = 232). Death, myocardial infarction, recurrent ischaemia and its composite outcome were assessed. The incidences of major or minor bleeding not related to coronary artery bypass grafting were also evaluated. RESULTS AND DISCUSSION: The rates of death, MI or refractory angina did not differ between the fondaparinux and enoxaparin groups at day 7 (4.40% vs. 4.70%), 30 (7.90% vs. 8.60%) or 180 (9.60% vs. 10.80%). Similarly, there were not statistically significant differences in the rates of major bleeding at day 7 (0.87% vs. 2.16%), 30 (1.31% vs. 2.59%) or 180 (2.18% vs. 3.88%), or in the rates of minor bleeding at day 7 (3.49% vs. 6.47%), 30 (5.68% vs. 9.48%) or 180 (8.30% vs. 13.36%). WHAT IS NEW AND CONCLUSION: In this relatively small study of Chinese patients with NSTE-ACS treated with tirofiban, there was no statistically significant difference in ischaemic or bleeding outcomes with the use of either fondaparinux or enoxaparin. PMID- 26249543 TI - Pharmacokinetic Properties of Single and Repeated Injection of Liposomal Platelet Substitute in a Rat Model of Red Blood Cell Transfusion-Induced Dilutional Thrombocytopenia. AB - A preclinical study of dodecapeptide ((400)HHLGGAKQAGDV(411)) (H12)-(adenosine diphosphate, ADP)-liposomes for use as a synthetic platelet (PLT) substitute under conditions of red blood cell (RBC) transfusion-induced dilutional thrombocytopenia is limited to pharmacological effect. In this study, the pharmacokinetics of H12-(ADP)-liposomes in RBC transfusion-induced dilutional thrombocytopenic rats were evaluated. As evidenced by the use of (14) C, (3) H double-radiolabeled H12-(ADP)-liposomes in which the encapsulated ADP and liposomal membrane were labeled with (14) C and (3) H, respectively, the H12 (ADP)-liposomes remained intact in the blood circulation for up to 3 h after injection, and were mainly distributed to the liver and spleen. The encapsulated ADP was mainly eliminated in the urine, whereas the outer membrane was mainly eliminated in the feces. These successive pharmacokinetic properties of the H12 (ADP)-liposomes in RBC transfusion-induced dilutional thrombocytopenic rats were similar to those in healthy rats, except for the shorter retention time in the circulation. When H12-(ADP)-liposomes were repeatedly injected into RBC transfusion-induced dilutional thrombocytopenic rats at intervals of 5 days at a dose of 10 mg lipids/kg, the second dose of injected H12-(ADP)-liposomes were rapidly cleared from the circulation, namely, via the accelerated blood clearance phenomenon. These novel pharmacokinetic findings provide useful information for the further development of H12-(ADP)-liposomes as a PLT substitute. PMID- 26249544 TI - Craniosynostosis and Noonan syndrome with KRAS mutations: Expanding the phenotype with a case report and review of the literature. AB - Noonan syndrome (NS) is a multiple congenital anomaly syndrome caused by germline mutations in genes coding for components of the Ras-mitogen-activated protein kinase (RAS-MAPK) pathway. Features include short stature, characteristic facies, congenital heart anomalies, and developmental delay. While there is considerable clinical heterogeneity in NS, craniosynostosis is not a common feature of the condition. Here, we report on a 2 month-old girl with Noonan syndrome associated with a de novo mutation in KRAS (p.P34Q) and premature closure of the sagittal suture. We provide a review of the literature of germline KRAS mutations and find that approximately 10% of published cases have craniosynostosis. Our findings expand on the NS phenotype and suggest that germline mutations in the KRAS gene are causally involved in craniosynostosis, supporting the role of the RAS-MAPK pathway as a mediator of aberrant bone growth in cranial sutures. The inclusion of craniosynostosis as a possible phenotype in KRAS-associated Noonan Syndrome has implications in the differential diagnosis and surgical management of individuals with craniosynostosis. PMID- 26249545 TI - Non-surgical treatment of peri-implant mucositis and peri-implantitis at zirconia implants: a prospective case series. AB - OBJECTIVES: To assess the efficacy of non-surgical therapy for the management of peri-implant diseases at a two-piece zirconium implant system. MATERIAL & METHODS: Thirty-four patients with 45 implants participated in this study. Seventeen patients (24 implants) were diagnosed with peri-implant mucositis and received mechanical debridement + local antiseptic therapy using chlorhexidine digluconate (MD + CXH), while 17 patients (21 implants) diagnosed with peri implantitis were assigned to Er:YAG laser therapy. In both groups, post-operative maintenance care included supramucosal plaque removal and local pocket irrigation using CHX. The primary endpoint was defined as disease resolution at 6 months (i.e. absence of bleeding upon probing (BOP) at mucositis sites/absence of BOP and probing pocket depths (PD) >=6 mm at peri-implantitis sites). RESULTS: Resolution of peri-implant mucositis and peri-implantitis was obtained in 9/17 (52.9%) (p = 0.001) and 5/17 (29.4%) (p = 0.02) of the patients respectively. CONCLUSION: Non-surgical treatment of either peri-implant mucositis using MD + CHX or peri-implantitis using ERL at zirconia implants was associated with significant short-term clinical improvements. A complete disease resolution, however, was not achieved in the majority of the patients. PMID- 26249546 TI - Colchicine toxicity in renal patients - Are we paying attention? AB - Colchicine is an approved agent in the management and prophylaxis of gout and familial Mediterranean fever but its therapeutic value is limited by its narrow therapeutic index. Multisystem toxicity is uncommonly reported; and is often associated with renal impairment and/or specific drug interactions. We report two cases of colchicine toxicity marked by severe neuromyopathy in a diabetic with stage 4 chronic kidney disease (CKD) and a renal transplant recipient. Both patients presented with diarrhea, acute on chronic kidney injury and progressive muscle weakness while on colchicine for several weeks or longer. In addition to kidney disease, risk factors for colchicine toxicity included maintenance therapy with simvastatin in the first patient and cyclosporine in the second. Creatine phosphokinase (CPK) was elevated in both cases at presentation and neurophysiologic studies showed a pattern of severe myopathy with axonal sensorimotor neuropathy. The first patient recovered from neurological weakness in a few weeks, but the second patient suffered an extraordinarily protracted and severe neuromuscular disability for a year. The two cases reinforce the need for extra vigilance in prescribing and monitoring colchicine therapy in renal patients with specific attention to drug interactions known to increase the risk of toxicity, thus avoiding such combinations in patients with renal impairment. PMID- 26249547 TI - BK virus-associated nephropathy with hydronephrosis in a patient with AIDS: a case report and literature review. AB - BK virus is ubiquitous worldwide, with infection usually occurring in early childhood. BK virus replicates prolifically under immunosuppressive conditions, causing inflammation along the genitourinary tract and progressing clinically to hemorrhagic cystitis, ureteral stenosis, and tubulointerstitial nephritis. Most BK virusassociated nephropathy occurs in renal allograft patients after kidney transplantation, although some case reports have described BK virus-associated nephropathy in the native kidney, particularly in patients with human immunodeficiency virus infection. Here we present the case of a 49-year-old male with acquired immunodeficiency syndrome (AIDS) and renal dysfunction with hydronephrosis. The renal biopsy showed tubulointerstitial nephritis with lymphoplasmacytic infiltrates and intranuclear inclusions in the tubular epithelium, which are typical findings for BK virus-associated nephropathy. In addition, immunohistochemical staining revealed that the SV40 large T antigen exhibited a nuclear localization in tubular cells. To the best of our knowledge, this is the first case report of BK virus-associated nephropathy combined with hydronephrosis that was diagnosed by biopsy in a patient with AIDS. PMID- 26249548 TI - Fibrillary glomerulonephritis masquerading as rapidly progressive glomerulonephritis with pseudo-linear glomerular basement membrane staining. AB - Fibrillary glomerulonephritis (FGN) is a rare disorder with poor renal prognosis. It is a heterogeneous disease associated with significant risk of end-stage renal disease (ESRD). Its etiology and pathogenesis have not been clearly identified. We report a case of a patient presenting with hypertensive crisis, nephrotic range proteinuria, and rapidly progressive glomerulonephritis (RPGN). The kidney biopsy demonstrates crescentic GN on light microscopy (LM) and strong pseudo linear/globular glomerular basement membrane (GBM) staining for immunoglobulin G on immunofluorescence (IF), suggestive of anti-GBM disease. However, circulating anti-GBM antibodies were negative. Electron microscopy (EM) revealed fibrillary deposits in the GBM, confirming the diagnosis of FGN. Review of the literature revealed very few reported similar cases. It appears that severe hypertension and heavy proteinuria, while uncommon in anti-GBM disease, are consistent findings in RPGN form of FGN. PMID- 26249549 TI - Early supplemented low-protein diet restriction for chronic kidney disease patients in Taiwan - A cost-effectiveness analysis. AB - BACKGROUND: Low-protein diet (LPD) together with supplementation with ketoanalogs (KA) is associated with slower decline of estimated glomerular filtration rate (eGFR) in chronic kidney disease (CKD). We compared potential clinical and economic outcomes of KA supplement initiation at eGFR 15 - 29 mL/min/1.73 m2 vs. eGFR < 15 mL/min/1.73 m2 in CKD patients on LPD from the healthcare payer's perspective. METHODS: Markov model was designed to simulate outcomes of adult patients with eGFR 15 - 29 mL/min/1.73 m2 on two strategies LPD with KA supplementation; watchfulwaiting on LPD alone and KA initiation when eGFR declined to < 15 mL/min/1.73 m2. Medical cost and quality-adjusted life-years (QALYs) were calculated over 10 years. Results The early-initiation group gained higher QALYs (3.926 QALYs vs. 3.787 QALYs) with lower cost (USD 564,637 vs. USD 914,236) (USD 1 = NTD 30) when compared with the watchful-waiting group in base case analysis. Sensitivity analysis indicated that early KA initiation at eGFR at 17 - 29 mL/min/1.73 m2 would be the preferred cost-effective option, if relative reduction of eGFR decline associated with LPD plus KA was > 4%. 10,000 Monte Carlo simulations showed the early-initiation group to be less costly with higher QALYs gained than the watchful-waiting group by USD 343,665 (95% CI 342,139 - 345,191) and 0.160 QALYs (95% CI 0.140 - 0.180), respectively. CONCLUSIONS: Early KA supplementation with LPD in CKD patients appeared to be cost-saving and gained higher QALYs in Taiwan. Acceptance of early supplemented LPD as cost-effective depended upon the reduction of eGFR decline associated with KA plus LPD and eGFR level to initiate KA supplementation. PMID- 26249550 TI - Phenotypic heterogeneity in females with X-linked Alport syndrome. AB - AIMS: X-linked Alport syndrome (AS) is a monogenic inherited disorder of type IV collagen, a structural protein in the kidney and cochlea. Males typically exhibit a severe phenotype with end-stage renal disease (ESRD) and/or deafness by early adulthood. Because of the presence of two X chromosomes, females often have a less severe phenotype and hence the diagnosis of AS is often not considered. Herein, we present a case of an adolescent girl with proteinuria and hematuria in the setting of a strong family history of AL. CASE REPORT: The mother and maternal aunt of the proband had both presented with dipstick positive hematuria and proteinuria at age 8 years. These girls were not evaluated by nephrology until mid-adolescence when they had worsening creatinine levels. Kidney biopsy in the younger sister demonstrated segmental glomerulosclerosis with segmental thinning and lamination of the glomerular basement membrane, consistent with AS. Kidney biopsy in the older sister was performed just prior to the need for renal replacement therapy and showed only global glomerulosclerosis. Both sisters were transplanted by the age of 20 years. Their mother subsequently developed ESRD at age 53 years. With the advent of genetic testing, the proband and her family were brought in for evaluation. It had been assumed this family of AS had autosomal dominant transmission, however, genetic testing of the proband was positive for a splice site mutation of COL4A5 located on the X-chromosome. Sequencing of genes COL4A3, COL4A4, and COL4A6 were negative for mutation. CONCLUSIONS: The current case report demonstrates the importance of considering skewed X-inactivation in females who exhibit signs or symptoms of Xlinked disorders. PMID- 26249551 TI - IgA nephropathy with anti-neutrophil cytoplasmic antibody seropositivity. AB - BACKGROUND: There are few reports of IgA nephropathy (IgAN) with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. METHODS: The authors report the clinical and pathological findings in 14 patients with IgAN and ANCA seropositivity. RESULTS: These retrospective cases consisted of 4 men and 10 women with a mean age of 44.4 +/- 12.7 years. ANCA-positivity was documented by EUROBlot kits and indirect immunofluorescence in all patients. The results of EUROBlot kits were positive in 14 patients (12 MPO-ANCA, 2 PR3-ANCA). Indirect immunofluorescence was positive in 14 patients (12 P-ANCA, 2 C-ANCA). Three of 14 IgAN with ANCA-positive patients showed severe clinical manifestations with crescents involving a mean of 56% glomeruli, including heavy proteinuria (mean 24 hour urine protein: 3.8 g/d), hematuria and acute renal failure (mean creatinine: 4.5 +/- 3.7 mg/dL). The remaining 11 patients with no crescents showed various degrees of proteinuria (mean 24-hour urine protein: 2.4 +/- 2.4 g/d), hematuria and serum creatinine levels (median creatinine: 0.9 (IQR, 0.5 - 1.4) mg/dL). The follow-up period for 10 patients had an average length of 14.0 +/- 11.2 months. Among the three patients with crescents who had been treated with steroids and cyclophosphamide, one patient became dialysis dependent at the time of biopsy and remained on dialysis after treatment, another died of acute heart failure, and the last one showed improvement in renal function after treatment and did not develop end-stage renal disease (ESRD) 26 months after renal biopsy. The remaining 7 patients with no crescents were treated with steroids, cyclophosphamide, renin-angiotensin system inhibitors, and/or Traditional Chinese Medicine; 6 had stabilized or improved renal function and one progressed to ESRD with worsening renal function. CONCLUSIONS: These findings suggest not all ANCAs are involved in the pathology of IgAN. In patients with IgAN and ANCAs, identification of pathogenic vs. non-pathogenic ANCAs is recommended. PMID- 26249552 TI - Keratinized squamous metaplasia of the upper urinary tract resulting in recurrent renal colic. AB - A 60-year-old female with an extensive history of stone disease and shock wave lithotripsy presents with recurrent and increasingly severe renal colic. Work-up reveals obstruction with translucent debris that is found to be composed of keratin. Her history of chronic irritation of the collecting system has resulted in keratinizing squamous metaplasia (KSM) with hyperkeratosis that has sloughed from the upper urinary tract and has become lodged in the ureter. Because of the worsening of her symptoms on conservative management, the patient elected for a nephrectomy and her symptoms have since resolved. KSM of the renal pelvis is a relatively rare phenomenon and most often presents with irritative symptoms. It is thought to result from chronic irritation of the urothelium. KSM has been found to be coincident with squamous cell cancers of the urinary tract, though clear data implicating KSM as a premalignant lesion is lacking. We present a case of recurrent renal colic secondary to sloughing keratin debris from KSM. PMID- 26249554 TI - Should age matter? A new proposal for liver transplantation allocation. PMID- 26249553 TI - Damage to fetal bovine ovarian tissue caused by cryoprotectant exposure and vitrification is mitigated during tissue culture. AB - PURPOSE: The objective of this study is to characterize the impact of exposure to cryoprotectants followed by vitrification on primordial follicle survival and activation using a fetal bovine model. METHODS: In the first study, fetal bovine cortical pieces were exposed to cryoprotectants with or without sucrose and cultured up to 7 days in the presence or absence of insulin. In the second study, cortical pieces were exposed to cryoprotectants with or without sucrose, vitrified, and cultured up to 7 days after warming in the presence or absence of insulin. Viability and morphology of follicles, as well as proliferation and/or DNA repair in ovarian tissue were analyzed. RESULTS: When compared to non-exposed controls, normal follicular morphology was affected in groups exposed to cryoprotectants only immediately post-exposure and after 1 day of culture, but improved by day 3 and did not significantly differ by day 7. Similarly, normal follicular morphology was compromised in vitrified groups after warming and on day 1 compared to controls, but improved by days 3 and 7. Proliferation and/or DNA repair in ovarian tissue was not affected by vitrification in this model. Cryoprotectant exposure and vitrification of ovarian tissue did not impair the activation of primordial follicles in response to insulin, although activation was delayed relative to non-exposed controls. Interestingly, sucrose had no noticeable protective effect. CONCLUSION: Vitrified fetal bovine ovarian tissue has the intrinsic capacity to mitigate the immediate damage to primordial follicles' morphology and retains the capacity to activate. These findings provide a basis for a successful cryopreservation protocol for ovarian cortical tissue in other species including humans. PMID- 26249555 TI - Assisted reproductive technology treatment in women with severe eating disorders: a national cohort study. AB - INTRODUCTION: This national retrospective cohort study investigates the prevalence of women with severe eating disorders in assisted reproductive technology (ART) treatment compared with an age-matched background population without ART treatment. It assesses the frequency distribution of the first and last eating disorder diagnosis before, during, and after ART treatment, and evaluates differences in obstetric outcomes between women with and without a severe eating disorder. MATERIAL AND METHODS: Hospital-diagnosed eating disorders among 42,915 women in the Danish National ART cohort (DANAC), registered during 1994-2009 in the mandatory Psychiatric Central Research Register, were compared with a non-eating disorder ART cohort of 42,644 women and an age-matched background population of 215,290 women without a history of ART treatment for the main outcome measures prevalence of eating disorders, frequency distribution of diagnoses before/during/after ART treatment, as well as ART treatment and obstetric outcomes. RESULTS: In the ART cohort, 271 women (0.63%) had an eating disorder diagnosis compared with 0.73% in the background population (p = 0.025). The prevalence of ovulatory disorder was significantly higher in women with a severe eating disorder compared with the ART cohort without eating disorders. Obstetric outcomes were similar in ART-treated women with and without an eating disorder. CONCLUSION: Women with severe eating disorders were identified in the ART cohort, although significantly less often than in the age-matched background population. Women with severe eating disorders suffered more often from anovulatory infertility than the ART comparison cohort without this disease. Obstetric outcomes appeared reassuring in the ART cohort with eating disorders. PMID- 26249557 TI - Proton-Coupled Electron Transfer Reactions Catalysed by 3 d Metal Complexes. AB - Proton-coupled electron transfer (PCET) reactions are essential for a wide range of natural energy-conversion reactions and recently, the impact of PCET pathways has been exploited in artificial systems, too. The Minireview highlights PCET reactions catalysed by first-row transition-metal complexes, with a focus on the water oxidation, the oxygen reduction, the hydrogen evolution, and the CO2 reduction reaction. Special attention will be paid to systems in which the impact of such pathways is deduced by comparison to systems with "electron-only" transfer pathways. PMID- 26249556 TI - Association of common polymorphisms in the IL2RA gene with type 1 diabetes: evidence of 32,646 individuals from 10 independent studies. AB - Single nucleotide polymorphisms (SNPs) in the interleukin 2 receptor alpha (IL2RA) gene have been suggested to be associated with type 1 diabetes (T1D) susceptibility. However, the results from individual studies are inconsistent. To explore the association of IL2RA polymorphisms with T1D, including rs11594656, rs2104286, rs3118470, rs41295061 and rs706778, a meta-analysis involving 10 independent studies with 19 outcomes was conducted: five studies with a total of 10,572 cases and 12,956 controls were analysed for rs11594656 with T1D risk, three studies with 7300 cases and 8331 controls for rs2104286, three studies with 3880 cases and 5409 controls for rs3118470, five studies with 11,253 cases and 13,834 controls for rs41295061 and three studies with 1896 cases and 1709 controls for rs706778 respectively. Using minor allelic comparison, the five investigated SNPs were all observed to have a significant association with T1D: For rs11594656, fixed effect model (FEM) odds ratio (OR) 0.87, 95% confidence interval (CI) 0.83, 0.91; rs2104286, FEM OR 0.81, 95% CI 0.77, 0.85; rs3118470, FEM OR 1.23, 95% CI 1.16, 1.31; rs41295061, random effect model (REM) OR 0.67, 95% CI 0.60, 0.76 and rs706778 FEM OR 1.20, 95% CI 1.08, 1.33. Similar results were obtained when all the included studies were calculated by a REM. Our meta analysis suggests that all five SNPs in the IL2RA gene are risk factors for T1D risk, and rs11594656, rs2104286 and rs41295061 are the most associated SNPs in the populations investigated. This conclusion warrants confirmation by further studies. PMID- 26249558 TI - Pancreaticoduodenectomy in Florida: do 20-year trends document the salutary benefits of centralization of care? AB - BACKGROUND: Concentration of care has been promoted as fostering superior outcomes. This study was undertaken to determine if the concentration of care is occurring in Florida for a pancreaticoduodenectomy, and if so, is it having a salutary effect. METHODS: The data for a pancreaticoduodenectomy were obtained from the Florida Agency for Health Care Administration for three 3-year periods:1992-1994, 2001-2003, 2010-2012; data were sorted by surgeon volume of pancreaticoduodenectomy during these periods and correlated with post-operative length of stay (LOS), in-hospital mortality and hospital charges (adjusted to 2012 dollars). RESULTS: Relative to 1992-1994, in 2010-2012 46% fewer surgeons performed 115% more pancreaticoduodenectomies with significant reductions in LOS and in-hospital mortality, and higher charges (P < 0.001 for each). From 1992 1994 to 2010-2012 there was an 18-fold increase in the number of pancreaticoduodenectomies by surgeons completing >= 12 per year (n = 45 to n = 806, respectively). During 2010-2012, the more frequently surgeons performed a pancreaticoduodenectomy, the shorter LOS, the lower in-hospital mortality, the greater the likelihood of discharge home and the lower the hospital charges (P < 0.03 for each). CONCLUSIONS: Over the last 20 years, the concentration of care has occurred in Florida with substantially fewer surgeons undertaking many more pancreaticoduodenectomies with dramatic improvements in LOS and in-hospital mortality, albeit with increased hospital charges. PMID- 26249559 TI - Electromechanical response of silk fibroin hydrogel and conductive polycarbazole/silk fibroin hydrogel composites as actuator material. AB - Pure silk fibroin (SF) hydrogel and polycarbazole/silk fibroin (SF/PCZ) hydrogels were fabricated by solvent casting technique to evaluate electromechanical responses, dielectric properties, and cantilever deflection properties as functions of electric field strength, SF concentration, glutaraldehyde concentration, and PCZ concentration in the blends. Electromechanical properties were characterized in oscillatory shear mode at electric field strengths ranging from 0 to 600V/mm and at a temperature of 27 degrees C. For both the pristine SF and SF/PCZ hydrogels, the storage modulus response (DeltaG') and the storage modulus sensitivity (DeltaG'/G'0) increased dramatically with increasing electric field strength. The pristine hydrogel possessed the highest storage modulus sensitivity value of 5.87, a relatively high value when compared with other previously studied electroactive polymers. With the addition of conductive PCZ in SF hydrogel, the storage modulus sensitivity and the relative dielectric constant decreased; the conductive polymer thus provided the softening effect under electric field. In the deflection response, the dielectrophoresis force and deflection distance increased monotonically with electric field strength, where the pure SF hydrogel showed the highest deflection distance and dielectrophoresis force. PMID- 26249560 TI - New generation poly(epsilon-caprolactone)/gel-derived bioactive glass composites for bone tissue engineering: Part I. Material properties. AB - Poly(epsilon-caprolactone) (PCL) based composite films containing 12 and 21vol.% bioactive glass (SBG) microparticles were prepared by solvent casting method. Two gel-derived SBGs of SiO2-CaO-P2O5 system differing in SiO2 and CaO contents were applied (mol%): S2: 80SiO2, 16CaO, 4P2O5 and A2: 40SiO2, 54CaO, 6P2O5. The surfaces of the films in contact with Petri dish and exposed to the gas phase during casting were denoted as GS and AS, respectively. Both surfaces of films were characterised in terms of their morphology, micro- and nano-topography as well as wettability. Also mechanical properties (tensile strength, Young's modulus) and PCL matrix crystallinity (degree of crystallinity, crystal size) were evaluated. Degradation behaviour was examined by incubation of materials in UHQ-water at 37 degrees C for 56weeks. The crystallinity, melting temperature and mass loss of incubated materials and pH changes of water were monitored. Furthermore, proliferation of MG-63 osteoblastic cells by direct contact and cytotoxic effect of obtained materials were investigated. Results showed that opposite surfaces of the same polymer and composite films differ in studied surface parameters. The addition of SBG particles into PCL matrix improves nano- and micro-roughness of both surfaces, enhances the hydrophilicity of GS surfaces (~67 degrees for 21A2-PCL compared to ~78 degrees for pure PCL) and also makes AS surface more hydrophobic (~94 degrees for 21S2-PCL compared to ~86 degrees for pure PCL). The nucleation density of PCL was increased with increasing content of SBG particles, which results in the large number of fine spherulites on composite AS surfaces observed using polarized optical (POM), scanning electron (SEM), and atomic force (AFM) microscopies. Higher content of SBG particles causes a notable increase of Young's modulus (from 0.38GPa for pure PCL, 0.90GPa for 12A2-PCL to 1.31GPa for 21A2-PCL), which also depends on SBG chemical composition. After 56-week degradation test, considerably higher crystallinity increase (Deltachic ~148% for 21S2-PCL, ~81% for 21A2-PCL) and weight loss (~17% for both) were found for composite materials, depending on SBG composition, in contrast to value variations for pure PCL film (Deltachic ~43%, weight loss ~1.6%). Furthermore, it seems that both SBG could neutralize acidic degradation by-products of PCL at later incubation stages. Obtained SBG-PCL composites show excellent biocompatibility, support cell proliferation also may modulate cell response depending on the glass composition. The results indicate the possibility to use different contents and/or chemical compositions of SBG to obtain composite materials with various, but controlled, surface and mechanical properties as well as degradation kinetics. PMID- 26249561 TI - MC3T3-E1 cell response to stainless steel 316L with different surface treatments. AB - In the present study, stainless steel 316L samples with polishing, aluminum oxide blasting, and hydroxyapatite (HA) coating were prepared and characterized through a scanning electron microscope (SEM), optical interferometer (surface roughness, Sq), contact angle, surface composition and phase composition analyses. Osteoblast-like MC3T3-E1 cell adhesion on the samples was investigated by cell morphology using a SEM (4h, 1d, 3d, 7d), and cell proliferation was assessed by MTT method at 1d, 3d, and 7d. In addition, adsorption of bovine serum albumin on the samples was evaluated at 1h. The polished sample was smooth (Sq: 1.8nm), and the blasted and HA coated samples were much rougher (Sq: 3.2MUm and 7.8MUm). Within 1d of incubation, the HA coated samples showed the best cell morphology (e.g., flattened shape and complete spread), but there was no significant difference after 3d and 7d of incubation for all the samples. The absorbance value for the HA coated samples was the highest after 1d and 3d of incubation, indicating better cell viability. However, it reduced to the lowest value at 7d. Protein adsorption on the HA coated samples was the highest at 1h. The results indicate that rough stainless steel surface improves cell adhesion and morphology, and HA coating contributes to superior cell adhesion, but inhibits cell proliferation. PMID- 26249562 TI - A new design of a Nitinol ring-like wire for suturing in deep surgical field. AB - The present work proposes a new suturing procedure based on self-accommodating suture points. Each suture point is made of a commercial NiTi wire hot-shaped in a single loop ring; a standard suture needle is then fixed at one end of the NiTi suture. According to this simple geometry, several NiTi suture stitches have been prepared and tested by tensile test to verify the closing force in comparison to that of commercial sutures. Further experimental tests have also been performed on anatomic samples from animals to verify the handiness of the NiTi suture. Moreover, surface quality of sutures has been carefully investigated via microscopy. Results show that the NiTi suture expresses high stiffness and a good surface quality. In addition, the absence of manual knotting allows for a simple, fast and safe procedure. PMID- 26249563 TI - beta-Tricalcium phosphate/poly(glycerol sebacate) scaffolds with robust mechanical property for bone tissue engineering. AB - Despite good biocompatibility and osteoconductivity, porous beta-TCP scaffolds still lack the structural stability and mechanical robustness, which greatly limit their application in the field of bone regeneration. The hybridization of beta-TCP with conventional synthetic biodegradable PLA and PCL only produced a limited toughening effect due to the plasticity of the polymers in nature. In this study, a beta-TCP/poly(glycerol sebacate) scaffold (beta-TCP/PGS) with well interconnected porous structure and robust mechanical property was prepared. Porous beta-TCP scaffold was first prepared with polyurethane sponge as template and then impregnated into PGS pre-polymer solution with moderate viscosity, followed by in situ heat crosslinking and freezing-drying process. The results indicated that the freezing-drying under vacuum process could further facilitate crosslinking of PGS and formation of Ca(2+)-COO(-) ionic complexing and thus synergistically improved the mechanical strength of the beta-TCP/PGS with in situ heat crosslinking. Particularly, the beta-TCP/PGS with 15% PGS content after heat crosslinking at 130 degrees C and freezing-drying at -50 degrees C under vacuum exhibited an elongation at break of 375+/-25% and a compressive strength of 1.73MPa, 3.7-fold and 200-fold enhancement compared to the beta-TCP, respectively. After the abrupt drop of compressive load, the beta-TCP/PGS scaffolds exhibited a full recovery of their original shape. More importantly, the PGS polymer in the beta-TCP/PGS scaffolds could direct the biomineralization of Ca/P from particulate shape into a nanofiber-interweaved structure. Furthermore, the beta-TCP/PGS scaffolds allowed for cell penetration and proliferation, indicating a good cytobiocompatibility. It is believed that beta TCP/PGS scaffolds have great potential application in rigid tissue regeneration. PMID- 26249564 TI - Influence of Cu-Ti thin film surface properties on antimicrobial activity and viability of living cells. AB - The paper describes properties of thin-film coatings based on copper and titanium. Thin films were prepared by co-sputtering of Cu and Ti targets in argon plasma. Deposited coatings consist of 90at.% of Cu and 10at.% of Ti. Characterization of the film was made on the basis of investigations of microstructure and physicochemical properties of the surface. Methods such as scanning electron microscopy, x-ray microanalysis, x-ray diffraction, x-ray photoelectron spectroscopy, atomic force microscopy, optical profilometry and wettability measurements were used to assess the properties of deposited thin films. An impact of Cu-Ti coating on the growth of selected bacteria and viability of the living cells (line L929, NCTC clone 929) was described in relation to the structure, surface state and wettability of the film. It was found that as-deposited films were amorphous. However, in such surroundings the nanocrystalline grains of 10-15nm and 25-35nm size were present. High surface active area with a roughness of 8.9nm, had an effect on receiving relatively high water contact angle value (74.1 degrees ). Such wettability may promote cell adhesion and result in an increase of the probability of copper ion transfer from the film surface into the cell. Thin films revealed bactericidal and fungicidal effects even in short term-contact. High activity of prepared films was directly related to high amount (ca. 51 %) of copper ions at 1+ state as x-ray photoelectron spectroscopy results have shown. PMID- 26249565 TI - Electrocatalytic boost up of epinephrine and its simultaneous resolution in the presence of serotonin and folic acid at poly(serine)/multi-walled carbon nanotubes composite modified electrode: A voltammetric study. AB - The present paper describes the new strategy for the development of nanosensor based on dropcasting of multi-walled carbon nanotubes (MWCNTs) followed by electropolymerization of serine (ser) onto the glassy carbon electrode (GCE). The developed nanocomposite sensor was abbreviated as poly(ser)/MWCNTs/GCE and was characterized by using electrochemical impedance spectroscopy (EIS) technique. The EIS results confirmed the fast electron transfer rate at the surface of poly(ser)/MWCNTs/GCE. The proposed sensor exhibited good catalytic activity towards the sensing of epinephrine (EP) individually and simultaneously in the presence of serotonin (5-HT) and folic acid (FA) in 0.1M phosphate buffer solution (PBS) at pH7.0. The limit of detection (LOD) and limit of quantification (LOQ) of EP was found to be 6*10(-7)M and 2*10(-6)M respectively. The fabricated sensor showed excellent precision and accuracy with a relative standard deviation (RSD) of 4.86%. The proposed composite sensor was effectively applied towards the determination of EP in human blood serum and pharmaceutical injection sample. PMID- 26249566 TI - Electrospraying technique for the fabrication of metronidazole contained PLGA particles and their release profile. AB - Advanced engineering of materials for the development of drug delivery devices provides scope for novel and versatile strategies for treatment of various diseases. 'Electrospraying' was used to prepare PLGA microparticles and further encapsulate the drug, metronidazole (Met) within the particles to function as a drug delivery system. Two different solvents were utilized for the preparation of drug loaded PLGA particles, whereby the polymeric solution in dichloromethane (DCM) produced particles of bigger sizes than using trifluoroethanol (TFE). Scanning electron microscopy showed the spherical morphology of the particles, with sizes of 3946+/-407nm and 1774+/-167nm, respectively for PLGA-Met(DCM) and PLGA-Met(TFE). The FTIR spectroscopy proved the incorporation of metronidazole in the polymer, but without any specific drug-polymer interaction. The release of the drug from the particles was studied in phosphate buffered saline, where a sustained drug release was obtained for at least 41days. Cytotoxicity evaluation of the drug extract using mesenchymal stem cells (MSCs) showed not hindering the proliferation of MSCs, and the cell phenotype was retained after incubation in the drug containing media. Electrospraying is suggested as a cost-effective and single step process for the preparation of polymeric microparticles for prolonged and controlled release of drug. PMID- 26249567 TI - Biocide immobilized OMMT-carbon dot reduced Cu2O nanohybrid/hyperbranched epoxy nanocomposites: Mechanical, thermal, antimicrobial and optical properties. AB - The present work demonstrated a transparent thermosetting nanocomposite with antimicrobial and photoluminescence attributes. The nanocomposites are fabricated by incorporation of different wt.% (1, 2 and 3) of a biocide immobilized OMMT carbon dot reduced Cu2O nanohybrid (MITH-NH) in the hyperbranched epoxy matrix. MITH-NH is obtained by immobilization of 2-methyl-4-isothiazolin-3-one hydrochloride (MITH) at room temperature using sonication on OMMT-carbon dot reduced Cu2O nanohybid. The nanohybrid is prepared by reduction of cupric acetate using carbon dot as the reducing agent in the presence of OMMT at 70 degrees C. The significant improvements in tensile strength (~2 fold), elongation at break (3 fold), toughness (4 fold) and initial thermal degradation temperature (30 degrees C) of the pristine hyperbranched epoxy system are achieved by incorporation of 3wt.% of MITH-NH in it. The nanocomposites exhibit strong antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumoniae and Pseudomonas aeruginosa bacteria and Candida albicans, a fungus. The nanocomposite also shows significant activity against biofilm formation compared to the pristine thermoset. Further, the nanocomposite films emit different colors on exposure of different wavelengths of UV light. The properties of these nanocomposites are also compared with the same nanohybrid without OMMT. PMID- 26249568 TI - Biomineralization of nanoscale single crystal hydroxyapatite. AB - The chemical and physical characteristics of nanocrystalline hydroxyapatite particles which formed during the subcutaneous implantation of crab shell in Sprague-Dawley rats were studied using selected area electron diffraction (SAED) and high resolution transmission electron microscopy (HRTEM). The initial SAED characterization evidence indicated the presence of an amorphous calcium phosphate phase. The electron dense nanophase particles which formed in the wound healing zone displayed broad diffuse rings which usually indicate a low crystalline order or amorphous phase. High resolution transmission electron microscopy (HRTEM) revealed that these mineralized regions contained discrete single crystal particles less than 5nm in size. Micrographs taken at successively higher magnifications revealed very small nanoparticles with a hexagonal arrangement of ion channels with characteristic spacing of 0.54nm and 0.23nm. This study revealed that single crystal hydroxyapatite nanoparticles consisting of only a few unit cells formed via a biomineralization directed process. PMID- 26249569 TI - Lipid nanocarriers based on natural oils with high activity against oxygen free radicals and tumor cell proliferation. AB - The development of nano-dosage forms of phytochemicals represents a significant progress of the scientific approach in the biomedical research. The aim of this study was to assess the effectiveness of lipid nanocarriers based on natural oils (grape seed oil, fish oil and laurel leaf oil) in counteracting free radicals and combating certain tumor cells. No drug was encapsulated in the nanocarriers. The cytotoxic effect exerted by bioactive nanocarriers against two tumor cells, MDA MB 231 and HeLa cell lines, and two normal cells, L929 and B16 cell lines, was measured using the MTT assay, while oxidative damage was assessed by measuring the total antioxidant activity using chemiluminescence analysis. The best performance was obtained for nanocarriers based on an association of grape seed and laurel leaf oils, with a capacity to scavenge about 98% oxygen free radicals. A dose of nanocarriers of 5mg.mL(-1) has led to a drastic decrease in tumor cell proliferation even in the absence of an antitumor drug (e.g. about 50% viability for MDA-MB 231 cell line and 60% viability for HeLa cell line). A comparative survival profile of normal and tumor cells, which were exposed to an effective dose of 2.5mg.mL(-1) lipid nanocarriers, has revealed a death rate of 20% for normal B16 cells and of 40% death rate for MDA-MB 231 and HeLa tumor cells. The results in this study imply that lipid nanocarriers based on grape seed oil in association with laurel leaf oil could be a candidate to reduce the delivery system toxicity and may significantly improve the therapeutic efficacy of antitumor drugs in clinical applications. PMID- 26249570 TI - Silver deposition on polypyrrole films electrosynthesised onto Nitinol alloy. Corrosion protection and antibacterial activity. AB - The electrosynthesis of polypyrrole films onto Nitinol from sodium salicylate solutions of different concentrations is reported. The morphology and corrosion protection properties of the resulting coatings were examined and they both depend on the sodium salicylate concentration. The immobilisation of silver species in PPy films constituted by hollow rectangular microtubes was studied as a function of the polymer oxidation degree. The highest amount of silver was deposited when the coated electrode was prepolarised at -1.00V (SCE) before silver deposition, suggesting an increase in the amount of non-oxidised segments in the polymer. Finally, the antibacterial activity of the coating against the Gram positive Staphylococcus aureus and Staphylococcus epidermidis bacteria was evaluated. Both strains resulted sensitive to the modified coatings, obtaining a slightly better result against S. aureus. PMID- 26249571 TI - Synthesis of piroxicam loaded novel electrospun biodegradable nanocomposite scaffolds for periodontal regeneration. AB - Development of biodegradable composites having the ability to suppress or eliminate the pathogenic micro-biota or modulate the inflammatory response has attracted great interest in order to limit/repair periodontal tissue destruction. The present report includes the development of non-steroidal anti-inflammatory drug encapsulated novel biodegradable chitosan (CS)/poly(vinyl alcohol) (PVA)/hydroxyapatite (HA) electro-spun (e-spun) composite nanofibrous mats and films and study of the effect of heat treatment on fibers and films morphology. It also describes comparative in-vitro drug release profiles from heat treated and control (non-heat treated) nanofibrous mats and films containing varying concentrations of piroxicam (PX). Electrospinning was used to obtain drug loaded ultrafine fibrous mats. The physical/chemical interactions were evaluated by Fourier Transform Infrared (FT-IR) spectroscopy. The morphology, structure and pore size of the materials were investigated by scanning electron microscopy (SEM). The thermal behavior of the materials was investigated by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Control (not heat treated) and heat treated e-spun fibers mats and films were tested for in vitro drug release studies at physiological pH7.4 and initially, as per requirement burst release patterns were observed from both fibers and films and later sustained release profiles were noted. In vitro cytocompatibility was performed using VERO cell line of epithelial cells and all the synthesized materials were found to be non-cytotoxic. The current observations suggested that these materials are potential candidates for periodontal regeneration. PMID- 26249572 TI - The role of nicotine, cotinine and caffeine on the electrochemical behavior and bacterial colonization to cp-Ti. AB - Although smoking promotes deleterious effect to bone healing, there is a lack of study investigating its role on the implant structure and biofilm growth. We hypothesized that nicotine, cotinine and caffeine would impair the corrosion resistance of commercially-pure titanium (cp-Ti) and would enhance Streptococcus sanguinis biofilm growth. Neither the smoking products nor the caffeine affected the corrosion tendency (P>.05) and the oxide layer resistance (P=.762) of cp-Ti. Lower capacitance values were noted in the presence of nicotine (P=.001) and cotinine (P=.0006). SEM showed no pitting corrosion, and the EDS spectra did not differ among groups. Nicotine (300MUg/mL) induced higher surface roughness (P=.03) and greater surface change of cp-Ti. Nicotine at 3MUg/mL, and cotinine at 0.3 and 3MUg/mL increased the number of viable cells (P<.05). Biofilm exposed to nicotine (0.3, 3 and 30MUg/mL) (P=.025, .030, .040, respectively) and cotinine (3 and 30MUg/mL) (P=.027, .049, respectively) enhanced carbohydrate content. Biofilm biomass and protein content were similar among groups (P>.05). These findings suggest a greater biofilm accumulation in smokers, a risk factor that may lead to peri-implantitis. PMID- 26249573 TI - Preparation of bio-deep eutectic solvent triggered cephalopod shaped silver chloride-DNA hybrid material having antibacterial and bactericidal activity. AB - 2.5% w/w DNA (Salmon testes) was solubilized in a bio-deep eutectic solvent [(bio DES), obtained by the complexation of choline chloride and ethylene glycol at 1:2 molar ratio] containing 1% w/w of silver chloride (AgCl) to yield a AgCl decorated DNA based hybrid material. Concentration dependent formation of AgCl crystals in the DES was observed and upon interaction with DNA it gave formation of a cephalopod shaped hybrid material. DNA was found to maintain its chemical and structural stability in the material. Further, AgCl microstructures were found to have orderly self assembled on the DNA helices indicating the electrostatic interaction between Ag(+) and phosphate side chain of DNA as a driving force for the formation of the material with ordered microstructural distribution of AgCl. Furthermore, the functionalized material exhibited excellent antibacterial and bactericidal activity against both Gram negative and Gram positive pathogenic bacteria. PMID- 26249574 TI - Evaluation of protein immobilization capacity on various carbon nanotube embedded hydrogel biomaterials. AB - This study investigates effective immobilization of proteins, an important procedure in many fields of bioengineering and medicine, using various biomaterials. Gelatin, alginate and chitosan were chosen as polymeric carriers, and applied in both their composites and nanocomposite forms in combination with carbon nanotubes (CNTs). The prepared nano/composite structures were characterized using scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TG) and contact angle analysis (CA). Electrochemical impedance spectroscopy analysis revealed gelatin composites in general to exhibit better immobilization performance relative to the native gelatin which can be attributed to enhanced film morphologies of the composite structures. Moreover, superior immobilization efficiencies were obtained with the addition of carbon nanotubes, due to their conducting and surface enhancement features, especially in the gelatin-chitosan structures due to the presence of structural active groups. PMID- 26249575 TI - Composite ECM-alginate microfibers produced by microfluidics as scaffolds with biomineralization potential. AB - A novel approach to produce artificial bone composites (microfibers) with distinctive features mimicking natural tissue was investigated. Currently proposed inorganic materials (e.g. apatite matrixes) lack self-assembly and thereby limit interactions between cells and the material. The present work investigates the feasibility of creating "bio-inspired materials" specifically designed to overcome certain limitations inherent to current biomaterials. We examined the dimensions, morphology, and constitutive features of a composite hydrogel which combined an alginate based microfiber with a gelatin solution or a particulate form of urinary bladder matrix (UBM). The effectiveness of the composite microfibers to induce and modulate osteoblastic differentiation in three-dimensional (3D) scaffolds without altering the viability and morphological characteristics of the cells was investigated. The present study describes a novel alginate microfiber production method with the use of microfluidics. The microfluidic procedure allowed for precise tuning of microfibers which resulted in enhanced viability and function of embedded cells. PMID- 26249576 TI - Triethyl orthoformate mediated a novel crosslinking method for the preparation of hydrogels for tissue engineering applications: characterization and in vitro cytocompatibility analysis. AB - This paper describes the development of a new crosslinking method for the synthesis of novel hydrogel films from chitosan and PVA for potential use in various biomedical applications. These hydrogel membranes were synthesized by blending different ratios of chitosan (CS) and poly(vinyl alcohol) (PVA) solutions and were crosslinked with 2.5% (w/v) triethyl orthoformate (TEOF) in the presence of 17% (w/v) sulfuric acid. The physical/chemical interactions and the presence of specific functional groups in the synthesized materials were evaluated by Fourier transform infrared (FT-IR) spectroscopy. The morphology, structure and pore size of the materials were investigated by scanning electron microscopy (SEM). Thermal gravimetric analysis (TGA) proved that these crosslinked hydrogel films have good thermal stability which was decreased as the CS ratio was increased. Differential scanning calorimetry (DSC) exhibited that CS and PVA were present in the amorphous form. The solution absorption properties were performed in phosphate buffer saline (PBS) solution of pH7.4. The 20% PVA 80% CS crosslinked hydrogel films showed a greater degree of solution absorption (183%) as compared to other compositions. The hydrogels with greater CS concentration (60% and 80%) demonstrated relatively more porous structure, better cell viability and proliferation and also revealed good blood clotting ability even after crosslinking. Based on the observed facts these hydrogels can be tailored for their potential utilization in wound healing and skin tissue engineering applications. PMID- 26249577 TI - Poly(dopamine) coating of 3D printed poly(lactic acid) scaffolds for bone tissue engineering. AB - 3D printing is a versatile technique to generate large quantities of a wide variety of shapes and sizes of polymer. The aim of this study is to develop functionalized 3D printed poly(lactic acid) (PLA) scaffolds and use a mussel inspired surface coating to regulate cell adhesion, proliferation and differentiation of human adipose-derived stem cells (hADSCs). We prepared PLA 3D scaffolds coated with polydopamine (PDA). The chemical composition and surface properties of PDA/PLA were characterized by XPS. PDA/PLA modulated hADSCs' responses in several ways. Firstly, adhesion and proliferation, and cell cycle of hADSCs cultured on PDA/PLA were significantly enhanced relative to those on PLA. In addition, the collagen I secreted from cells was increased and promoted cell attachment and cell cycle progression were depended on the PDA content. In osteogenesis assay, the ALP activity and osteocalcin of hADSCs cultured on PDA/PLA were significantly higher than seen in those cultured on pure PLA scaffolds. Moreover, hADSCs cultured on PDA/PLA showed up-regulation of the ang-1 and vWF proteins associated with angiogenic differentiation. Our results demonstrate that the bio-inspired coating synthetic PLA polymer can be used as a simple technique to render the surfaces of synthetic scaffolds active, thus enabling them to direct the specific responses of hADSCs. PMID- 26249578 TI - Microwave-assisted fabrication of strontium doped apatite coating on Ti6Al4V. AB - Strontium has been shown to be a beneficial dopant to calcium phosphates when incorporated at nontoxic level. In the present work we studied the possibility of solution derived doping strontium into calcium phosphate coatings on titanium alloy Ti6Al4V based implants by a recently reported microwave-assisted method. By using this method strontium doped calcium phosphate nuclei were deposited to pretreated titanium alloy surface dot by dot to compose a crack-free coating layer. The presence of strontium in solution led to reduced roughness of the coating and finer nucleus size formed. In vitro study found that proliferation and differentiation of osteoblast cells seeded on the coating were influenced by strontium content in coatings, showing an increasing followed by a decreasing behavior with increasing substitution of calcium by strontium. It is suggested that this new microwave-assisted strontium doped calcium phosphate coatings may have great potential in implant modification. PMID- 26249579 TI - Synthesis, characterization, and biodistribution studies of (99m)Tc-labeled SBA 16 mesoporous silica nanoparticles. AB - Along with anti-cancer drug delivery researches, many efforts have been done to develop new tracers for diagnostic applications. Based on advances in molecular imaging, nanoparticles can be used to visualize, characterize and measure biological process at molecular and cellular level. Therefore, the purpose of this study was to synthesize, characterize and radiolabeled mesoporous silica nanoparticles (MSNs) for in vivo applications. The nanoparticles were synthesized, functionalized with 3-aminopropyltriethoxysilane (APTES) and then, anchored with diethylenetriaminepentaacetic acid (DTPA). Particles were physicochemical characterized by elemental analysis (CHN), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), and zeta potential, and were morphologically characterized by scanning electron microscopy (SEM), low-angle X-ray diffraction (XRD) and transmission electron microscopy (TEM) techniques. Results indicate that functionalization process was successfully achieved. Next, functionalized silica nanoparticles were radiolabeled with technetium-99m showing high radiochemical yields and high radiolabeled stability. These findings allow the use of the particles for in vivo applications. Biodistribution and scintigraphic images were carried out in healthy mice in order to determine the fate of the particles. Results from in vivo experiments showed high uptake by liver, as expected due to phagocytosis. However, particles also showed a significant uptake in the lungs, indicated by high lung-to-non-target tissue ratio. In summary, taking into account the great potential of these silica mesoporous structures to carry molecules this platform could be a good strategy for theranostic purposes. PMID- 26249580 TI - Electrospinning of PEGylated polyamidoamine dendrimer fibers. AB - Polyamidoamine (PAMAM) dendrimers have emerged as an important class of nanostructured materials and have found a broad range of applications. There is also an ongoing effort to synthesize higher-complexity structures using PAMAM dendrimers as enabling building blocks. Herein, we report for the first time the fabrication of electrospun nanocomposite fibers composed of dendrimer derivatives, namely PEGylated PAMAM dendrimers, blended with a small amount of high-molecular-weight polyethylene oxide (PEO). Morphological features and mechanical properties of the resulting dendrimer fiber mats were assessed. PMID- 26249581 TI - Physio-chemical and antibacterial characteristics of pressure spun nylon nanofibres embedded with functional silver nanoparticles. AB - A novel and facile approach to prepare hybrid nanoparticle embedded polymer nanofibers using pressurised gyration is presented. Silver nanoparticles and nylon polymer were used in this work. The polymer solution's physical properties, rotating speed and the working pressure had a significant influence on the fibre diameter and the morphology. Fibres in the range of 60-500nm were spun using 10wt.%, 15wt.% and 20wt.% nylon solutions and these bead-free fibres were processed under 0.2MPa and 0.3MPa working pressure and a rotational speed of 36,000rpm. 1-4wt.% of Ag was added to these nylon solutions and in the case of wt.% fibres in the range 50-150nm were prepared using the same conditions of pressurised gyration. Successful incorporation of the Ag nanoparticles in nylon nanofibres was confirmed by using a combination of advanced microscopical techniques and Raman spectrometry was used to study the bonding characteristics of nylon and the Ag nanoparticles. Inductively coupled plasma mass spectroscopy showed a substantial concentration of Ag ions in the nylon fibre matrix which is essential for producing effective antibacterial properties. Antibacterial activity of the Ag-loaded nanofibres shows higher efficacy than nylon nanofibres for Gram-negative Escherichia coli and Pseudomonas aeruginosa microorganisms, and both Ag nanoparticles and the Ag ions were found to be the reason for enhanced cell death in the bacterial solutions. PMID- 26249582 TI - MRI-compatible Nb-60Ta-2Zr alloy for vascular stents: Electrochemical corrosion behavior in simulated plasma solution. AB - Using revised simulated body fluid (r-SBF), the electrochemical corrosion behavior of an Nb-60Ta-2Zr alloy for MRI compatible vascular stents was characterized in vitro. As indicated by XPS analysis, the surface passive oxide film of approximately 1.3nm thickness was identified as a mixture of Nb2O5, Ta2O5 and ZrO2 after immersion in the r-SBF. The Nb-60Ta-2Zr alloy manifests a low corrosion rate and high polarization resistance similar to pure Nb and Ta, as shown by the potentiodynamic polarization curves and EIS. Unlike 316L stainless steel and the L605 Co-Cr alloy, no localized corrosion has been detected. Semiconducting property of passive film on the Nb-60Ta-2Zr alloy was identified as the n-type, with growth mechanism of high-field controlled growth. The excellent corrosion resistance in simulated human blood enviroment renders the Nb 60Ta-2Zr alloy promising as stent candidate material. PMID- 26249583 TI - A novel microwave recipe for an antibiofilm titanium surface. AB - A microwave based method for the surface modification of titanium was demonstrated for biomedical applications. The surfaces were characterized using XRD, HR-SEM and Goniometer. The absence of rutile, anatase and brookite phases and the presence of an amorphous near-native oxide film were confirmed. The microwave oxidized (MWO) surfaces exhibited a significant antibiofilm activity against Escherichia coli and Staphylococcus aureus. In the presence and absence of the water pot, the oxidation times of 60 and 20min demonstrated a high antibiofilm property respectively. The surfaces turned more hydrophobic with increasing oxidation time. The viability of L6 cells remained unaffected on the MWO oxidized surfaces, signifying no loss in biocompatibility. This systematic study presents MWO as a promising technique for solving the biofilm problem faced by the otherwise robust titanium. PMID- 26249584 TI - Functionalized silica nanoparticles as a carrier for Betamethasone Sodium Phosphate: Drug release study and statistical optimization of drug loading by response surface method. AB - Mesoporous silica nanoparticles with a hexagonal structure (SBA-15) were synthesized and modified with (3-aminopropyl) triethoxysilane (APTES), and their performance as a carrier for drug delivery system was studied. Chemical structure and morphology of the synthesized and modified SBA-15 were characterized by SEM, BET, TEM, FT-IR and CHN technique. Betamethasone Sodium Phosphate (BSP) as a water soluble drug was loaded on the mesoporous silica particle for the first time. The response surface method was employed to obtain the optimum conditions for the drug/silica nanoparticle preparation, by using Design-Expert software. The effect of time, pH of preparative media, and drug/silica ratio on the drug loading efficiency was investigated by the software. The maximum loading (33.69%) was achieved under optimized condition (pH: 1.8, time: 3.54 (h) and drug/silica ratio: 1.7). The in vitro release behavior of drug loaded particles under various pH values was evaluated. Finally, the release kinetic of the drug was investigated using the Higuchi and Korsmeyer-Peppas models. Cell culture and cytotoxicity assays revealed the synthesized product doesn't have any cytotoxicity against human bladder cell line 5637. Accordingly, the produced drug loaded nanostructures can be applied via different routes, such as implantation and topical or oral administration. PMID- 26249585 TI - Desorption of 3,3'-diindolylmethane from imprinted particles: An impact of cross linker structure on binding capacity and selectivity. AB - Here, seven cross-linkers (six polar diacrylates or dimethacrylates of different lengths between double bonds, and one aromatic-divinylbenzene) were used to examine the impact of the cross-linker on binding capacity and selectivity of 3,3'-diindolylmethane (DIM) imprinted material. DIM participates in the suppression of viability of human ovarian and human breast cancer cell lines, but has low bioavailability. The investigations of novel imprinted polymer matrices for improvement of DIM release could allow to utilize not only a potency of DIM but also similar alkaloids, which are the important compounds with pharmacological activity. The bulk, thermal radical copolymerization of the cross linkers in the presence of 3,3'-diindolylmethane (the template) and allylamine (the functional monomer) in dimethyl sulfoxide or in carbon tetrachloride (porogens) was carried out. The binding capacities of imprinted and non-imprinted polymers were compared, and two polymers (these were prepared using ethylene glycol dimethacrylate and polyethylene glycol dimethacrylate as the cross linkers) with the highest selectivity and binding capacity were selected to desorption test. The desorption profile of polymer prepared using polyethylene glycol dimethacrylate as the cross-linker revealed sustained release of 3,3' diindolylmethane, and this system was selected for further optimization of the cross-linker amounts. The morphology and structure of the selected particles were analyzed using SEM micrographs, (13)C CP/MAS NMR spectroscopy, and BET measurements. The desorption of 3,3'-diindolylmethane from poly(allylamine-co polyethylene glycol dimethacrylate) particles was in accordance with pseudo second-order kinetics and the simplified Higuchi model indicated the diffusion controlled release of 3,3'-diindolylmethane. PMID- 26249586 TI - Powder metallurgical low-modulus Ti-Mg alloys for biomedical applications. AB - In this work, powder metallurgical (PM) Ti-Mg alloys were prepared using combined techniques of mechanical alloying and spark plasma sintering. The alloys mainly consist of super saturations of Mg in Ti matrix, and some laminar structured Ti- and Mg-rich phases. The PM Ti-Mg alloys contain a homogeneous mixtures of nanocrystalline Mg and Ti phases. The novel microstructures result in unconventional mechanical and biological properties. It has been shown that the PM Ti-Mg alloys have a much lower compression modulus (36-50GPa) compared to other Ti alloys, but still remain a very high compressive strength (1500 1800MPa). In addition, the PM Ti-Mg alloys show good biocompatibility and bioactivity. Mg can dissolve in the simulated body fluids, and induce the formation of the calcium phosphate layer. The compression modulus of PM Ti-Mg alloys decreases with the amount of Mg, while the bioactivity increases. Although the corrosion resistance of Ti-Mg alloys decreases with the content of Mg, the alloys still show good stability in simulated body fluid under electrochemical conditions. The indirect and direct cytotoxicity results show that PM Ti-Mg alloys have a good biocompatibility to NIH-3T3 cells. Therefore, the PM Ti-Mg alloys are promising candidates in biomedical applications. PMID- 26249587 TI - PLGA/alginate composite microspheres for hydrophilic protein delivery. AB - Poly(lactic-co-glycolic acid) (PLGA) microspheres and PLGA/alginate composite microspheres were prepared by a novel double emulsion and solvent evaporation technique and loaded with bovine serum albumin (BSA) or rabbit anti-laminin antibody protein. The addition of alginate and the use of a surfactant during microsphere preparation increased the encapsulation efficiency and reduced the initial burst release of hydrophilic BSA. Confocal laser scanning microcopy (CLSM) of BSA-loaded PLGA/alginate composite microspheres showed that PLGA, alginate, and BSA were distributed throughout the depths of microspheres; no core/shell structure was observed. Scanning electron microscopy revealed that PLGA microspheres erode and degrade more quickly than PLGA/alginate composite microspheres. When loaded with anti-laminin antibody, the function of released antibody was well preserved in both PLGA and PLGA/alginate composite microspheres. The biocompatibility of PLGA and PLGA/alginate microspheres were examined using four types of cultured cell lines, representing different tissue types. Cell survival was variably affected by the inclusion of alginate in composite microspheres, possibly due to the sensitivity of different cell types to excess calcium that may be released from the calcium cross-linked alginate. PMID- 26249588 TI - A novel drug delivery of 5-fluorouracil device based on TiO2/ZnS nanotubes. AB - The structural and electronic properties of titanium oxide nanotubes (TiO2) have attracted considerable attention for the development of therapeutic devices and imaging probes for nanomedicine. However, the fluorescence response of TiO2 has typically been within ultraviolet spectrum. In this study, the surface modification of TiO2 nanotubes with ZnS quantum dots was found to produce a red shift in the ultra violet emission band. The TiO2 nanotubes used in this work were obtained by sol-gel template synthesis. The ZnS quantum dots were deposited onto TiO2 nanotube surface by a micelle-template inducing reaction. The structure and morphology of the resulting hybrid TiO2/ZnS nanotubes were investigated by scanning electron microscopy, transmission electron microscopy and X-ray diffraction techniques. According to the results of fluorescence spectroscopy, pure TiO2 nanotubes exhibited a high emission at 380nm (3.26eV), whereas TiO2/ZnS exhibited an emission at 410nm (3.02eV). The TiO2/ZnS nanotubes demonstrated good bio-imaging ability on sycamore cultured plant cells. The biocompatibility against mammalian cells (Chinese Hamster Ovarian Cells-CHO) suggesting that TiO2/ZnS may also have suitable optical properties for use as biological markers in diagnostic medicine. The drug release characteristic of TiO2/ZnS nanotubes was explored using 5-fluorouracil (5-FU), an anticancer drug used in photodynamic therapy. The results show that the TiO2/ZnS nanotubes are a promising candidate for anticancer drug delivery systems. PMID- 26249589 TI - Analysis of the mechanical and thermal properties of jute and glass fiber as reinforcement epoxy hybrid composites. AB - This work describes the study to investigate and compare the mechanical and thermal properties of raw jute and glass fiber reinforced epoxy hybrid composites. To improve the mechanical properties, jute fiber was hybridized with glass fiber. Epoxy resin, jute and glass fibers were laminated in three weight ratios (69/31/0, 68/25/7 and 64/18/19) respectively to form composites. The tensile, flexural, impact, density, thermal and water absorption tests were carried out using hybrid composite samples. This study shows that the addition of jute fiber and glass fiber in epoxy, increases the density, the impact energy, the tensile strength and the flexural strength, but decreases the loss mass in function of temperature and the water absorption. Morphological analysis was carried out to observe fracture behavior and fiber pull-out of the samples using scanning electron microscope. PMID- 26249590 TI - VIS-NIR spectroscopy as a process analytical technology for compositional characterization of film biopolymers and correlation with their mechanical properties. AB - There is an increasing interest in the use of polysaccharides and proteins for the production of biodegradable films. Visible and near-infrared (VIS-NIR) spectroscopy is a reliable analytical tool for objective analyses of biological sample attributes. The objective is to investigate the potential of VIS-NIR spectroscopy as a process analytical technology for compositional characterization of biodegradable materials and correlation to their mechanical properties. Biofilms were produced by single-screw extrusion with different combinations of polybutylene adipate-co-terephthalate, whole oat flour, glycerol, magnesium stearate, and citric acid. Spectral data were recorded in the range of 400-2498nm at 2nm intervals. Partial least square regression was used to investigate the correlation between spectral information and mechanical properties. Results show that spectral information is influenced by the major constituent components, as they are clustered according to polybutylene adipate co-terephthalate content. Results for regression models using the spectral information as predictor of tensile properties achieved satisfactory results, with coefficients of prediction (R(2)C) of 0.83, 0.88 and 0.92 (calibration models) for elongation, tensile strength, and Young's modulus, respectively. Results corroborate the correlation of NIR spectra with tensile properties, showing that NIR spectroscopy has potential as a rapid analytical technology for non-destructive assessment of the mechanical properties of the films. PMID- 26249592 TI - Microwave assisted synthesis and characterization of magnesium substituted calcium phosphate bioceramics. AB - Hydroxyapatite is used extensively in hard tissue repair due to its biocompatibility and similarity to biological apatite, the mineral component of bone. It differs subtly in composition from biological apatite which contains other ions such as magnesium, zinc, carbonate and silicon (believed to play biological roles). Traditional methods of hydroxyapatite synthesis are time consuming and require strict reaction parameter control. This paper outlines synthesis of magnesium substituted hydroxyapatite using simple microwave irradiation of precipitated suspensions. Microwave irradiation resulted in a drastic decrease in ageing times of amorphous apatitic phases. Time taken to synthesize hydroxyapatite (which remained stable upon heat treatment at 900 degrees C for 1h) reduced twelve folds (to 2h) as compared to traditionally required times. The effects of increasing magnesium concentration in the precursors on particle size, surface area, phase-purity, agglomeration and thermal stability, were observed using scanning electron microscopy, BET surface area analysis, X-ray diffraction and photo acoustic Fourier transform infra-red spectroscopy. Porous agglomerates were obtained after a brief heat-treatment (1h) at 900 degrees C. PMID- 26249591 TI - A self-assembled system for tumor-targeted co-delivery of drug and gene. AB - A new cationic polymer eprosartan-graft-PEI (ESP) containing eprosartan (ES) and polyethylenimine 1.8K was successfully developed and employed as a safe gene vector to assemble a drug (ES) and gene co-delivery complex (ESP/pDNA). Chondroitin sulfate (CS) was then used as a coating polymer to shield the surface charge of ESP/pDNA complexes, as well as a tumor targeting entity to ensure specific delivery of CS/ESP/pDNA complexes. The CS/ESP/pDNA complexes with desirable particle size and zeta potential, exhibited amidase-responsive drug release and CS-mediated endocytosis in vitro. As compared with ESP/pDNA complexes, in vivo imaging results demonstrated decreased reticuloendothelial system uptake and remarkably increased tumor accumulation of CS/ESP/pDNA complexes. All these findings indicated the potential of CS/ESP/pDNA as a promising tumor-targeted drug and gene co-delivery system. PMID- 26249593 TI - Physico-chemical characterization and cytotoxicity evaluation of curcumin loaded in chitosan/chondroitin sulfate nanoparticles. AB - In this study, chitosan (CTS)/chondroitin sulfate (CS) nanoparticles, both pure and curcumin-loaded, were synthesized by ionic gelation. This method is simple and efficient for obtaining nanoparticles with a low polydispersity index (0.151+/-0.03 to 0.563+/-0.07) and hydrodynamic diameter in the range of 175.7+/ 2.5 to 710.2+/-8.9nm, for this study. Samples have a relatively high zeta potential value, a fact that indicates that the colloidal system has good physical and chemical stabilities. The efficiency of the curcumin encapsulation in nanoparticles, which ranged from 62.4+/-0.61% to 68.3+/-0.88%, depends on the pH of the chitosan solution. The release of curcumin from the nanoparticles was enabled by a diffusion mechanism, with fast release in a phosphate buffer solution at pH6.8. The assaying of cell viability by the MTT test showed that the presence of both free curcumin and curcumin in the nanoencapsulated form leads to a statistically significant reduction in the viability of A549 cells, by comparison with the control group. The most significant reductions in cell viability of 41.1% and 60.4% (p<0.0001) were observed after 72h, by using 40MUmol?L(-1) free curcumin and curcumin encapsulated in CTS/CS nanoparticles with the chitosan solution at pH6.0, respectively. PMID- 26249594 TI - Nanocomposite scaffold fabrication by incorporating gold nanoparticles into biodegradable polymer matrix: Synthesis, characterization, and photothermal effect. AB - Nanoparticle incorporation into scaffold materials is a valuable route to deliver various therapeutic agents, such as drug molecules or large biomolecules, proteins (e.g. DNA or RNA) into their targets. In particular, gold nanoparticles (Au NPs) with their low inherent toxicity, tunable stability and high surface area provide unique attributes facilitating new delivery strategies. A biodegradable, photocurable polymer resin, polypropylene fumarate (PPF) along with Au NPs were utilized to synthesize a hybrid nanocomposite resin, directly exploitable in stereolithography (SL) processes. To increase the particles' colloidal stability, the Au NP nanofillers were coated with polyvinyl pyrrolidone (PVP). The resulting resin was used to fabricate a new type of composite scaffold via mask projection excimer laser stereolithography. The thermal properties of the nanocomposite scaffolds were found to be sensitive to the concentration of NPs. The mechanical properties were augmented by the NPs up to 0.16MUM, though further increase in the concentration led to a gradual decrease. Au NP incorporation rendered the biopolymer scaffolds photosensitive, i.e. the presence of Au NPs enhanced the optical absorption of the scaffolds as well, leading to possible localized temperature rise when irradiated with 532nm laser, known as the photothermal effect. PMID- 26249595 TI - Biodegradable hyaluronic acid hydrogels to control release of dexamethasone through aqueous Diels-Alder chemistry for adipose tissue engineering. AB - A robust synthetic strategy of biopolymer-based hydrogels has been developed where hyaluronic acid derivatives reacted through aqueous Diels-Alder chemistry without the involvement of chemical catalysts, allowing for control and sustain release of dexamethasone. To conjugate the hydrogel, furan and maleimide functionalized hyaluronic acid were synthesized, respectively, as well as furan functionalized dexamethasone, for the covalent immobilization. Chemical structure, gelation time, morphologies, swelling kinetics, weight loss, compressive modulus and dexamethasone release of the hydrogel system in PBS at 37 degrees C were studied. The results demonstrated that the aqueous Diels-Alder chemistry provides an extremely selective reaction and proceeds with high efficiency for hydrogel conjugation and covalent immobilization of dexamethasone. Cell culture results showed that the dexamethasone immobilized hydrogel was noncytotoxic and preserved proliferation of entrapped human adipose-derived stem cells. This synthetic approach uniquely allows for the direct fabrication of biologically functionalized gel scaffolds with ideal structures for adipose tissue engineering, which provides a competitive alternative to conventional conjugation techniques such as copper mediated click chemistry. PMID- 26249596 TI - Dye affinity cryogels for plasmid DNA purification. AB - The aim of this study is to prepare megaporous dye-affinity cryogel discs for the purification of plasmid DNA (pDNA) from bacterial lysate. Poly(hydroxyethyl methacrylate) [PHEMA] cryogel discs were produced by free radical polymerization initiated by N,N,N',N'-tetramethylene diamine (TEMED) and ammonium persulfate (APS) redox pair in an ice bath. Cibacron Blue F3GA was used as an affinity ligand (loading amount: 68.9MUmol/g polymer). The amount of pDNA adsorbed onto the PHEMA-Cibacron Blue F3GA cryogel discs first increased and then reached a plateau value (i.e., 32.5mg/g cryogel) at 3.0mg/mL pDNA concentration. Compared with the PHEMA cryogel (0.11mg/g cryogel), the pDNA adsorption capacity of the PHEMA-Cibacron Blue F3GA cryogel (32.4mg/g polymer) was improved significantly due to the Cibacron Blue 3GA immobilization onto the polymeric matrix. pDNA adsorption amount decreased from 11.7mg/g to 1.1mg/g with the increasing of NaCl concentration. The maximum pDNA adsorption was achieved at 4 degrees C. The overall recovery of pDNA was calculated as 90%. The PHEMA-Cibacron Blue F3GA cryogel discs could be used five times without decreasing the pDNA adsorption capacity significantly. The results show that the PHEMA-Cibacron Blue F3GA cryogel discs promise high selectivity for pDNA. PMID- 26249597 TI - Aligned poly(epsilon-caprolactone)/graphene oxide and reduced graphene oxide nanocomposite nanofibers: Morphological, mechanical and structural properties. AB - A number of studies have demonstrated that the mechanical properties of electrospun polymeric nanofibrous scaffolds are enhanced with the incorporation of graphene and its derivatives, thus developing their applications in hard tissue engineering. However, our understanding of the relationship between the microstructure and properties of these fibrous scaffolds and how they are influenced by graphene oxide (GO) and reduced graphene oxide (RGO) loading is much more limited. Thus, in this paper, poly(epsilon-caprolactone) (PCL)/GO and RGO nanocomposite nanofibers containing 0, 0.1, 0.5 and 1wt.% GO and RGO were prepared using an electrospinning technique. With the addition of 0.1wt.% of GO and RGO nanosheets in PCL, the tensile strength of PCL scaffolds increased over ~160 and 304% respectively and elastic modulus increased over 103 and 163% due to the good dispersion of the nanosheets and their interaction with the molecular chains of PCL. These were supported by the parallel increase in relaxation time and molecular orientation of PCL chains at the presence of nanosheets with a loading of 0.1wt.%. The enhancement effect of the nanosheets was weakened with an increase in GO and RGO loading up to 1wt.% in which it is connected to a partial exfoliation of the nanosheets. PMID- 26249598 TI - Auto-fluorescent mesoporous ZnO nanospheres for drug delivery carrier application. AB - The zinc oxide (ZnO) nanostructures are very interesting materials because of their practical bio-applications in various areas such as drug delivery, construction of biomaterial, optical and acoustic devices as well as their bactericidal properties. Herein, we have prepared spheroidal mesoporous auto fluorescent ZnO nanospheres by modified continuous distillation method, showed a blue emission in the concentration of 2mg/ml at 444nm. The auto-fluorescent property of ZnO nanospheres can be used in biomaterials for target sites of tissues/cells, thereby enabling site drug delivery especially in cancer therapy. Initially, the auto-fluorescent property of the ZnO material was characterized by different techniques like PXRD, FESEM with EDAX graph, TEM, ICP-OES, particle sizes, zeta potentials and BET analysis. The mesoporous ZnO nanospheres has attracted well for their crystalline, functionalized and intensified fluorescent properties. The surface of the ZnO nanospheres was porous, spherical and nanometric in size. The synthesized material has enormous potential as a nano drug-carrier. Preliminary studies indicated that the material prepared has an excellent scope for detection and delivery at the site of therapeutic action. PMID- 26249599 TI - Conductive nylon fabric through in situ synthesis of nano-silver: Preparation and characterization. AB - A simple, green and low cost method based on Tollens' reagent is presented to synthesize a nano-conductive silver layer on nylon 6 fabric. The nylon fabric was first treated with potassium permanganate to oxidize fabric surface and thereby, increasing the number of assembled particles on the fabric surface. SEM images indicated distribution of silver nanoparticles on the fabric surface and formation of nanolayer on the fiber surface. EDX and XRD patterns confirmed assembling silver nanoparticles on the nylon fibers. The treated fabrics displayed a very low electrical resistivity i.e. 4.5Omega/sq. Furthermore, the fabric color was indicated by a reflectance spectrophotometer in order to study the effects of the synthesized nanoparticles on the fabric color. It is also indicated that oxidation process has no significant influence on the mechanical properties of the fabric, and nano-treatment revenged the negative effect of oxidation of nylon fabric. Moreover, silver nanoparticles imparted reasonable antibacterial properties to the fabric against Staphylococcus aureus. PMID- 26249600 TI - Ascorbic acid delivered by mesoporous silica nanoparticles induces the differentiation of human embryonic stem cells into cardiomyocytes. AB - Embryonic stem (ES) cells offer the potential to generate all cell types in the body, which provide a promising approach to repair tissue damage or dysfunction. In the past decade, great efforts have been made to induce the differentiation of ES cells into numerous types of cells, such as adipocytes, neurocytes and cardiomyocytes. However, the low differentiated efficiency and successful rate limit the development of induction of the differentiation of stem cells for tissue engineering. Here, we utilize ascorbic acid (AA)-loaded fluorescent TRITC mesoporous silica nanoparticles (TMSN-AA) as a potential tool to induce the differentiation of human ES cells into cardiomyocytes. The treatment of human ES cells by TMSN-AA nanoplex arrests cell cycle at G1 phase and decreases the expression of stemness genes octamer-binding transcription factor 4 (OCT4) and sex determining region Y-box 2 (SOX2), which exhibits more significant induction efficiency of stem cell differentiation than the treatment by AA alone. Furthermore, we have tested the myocardial marker genes cardiac Troponin I (cTnI) and fetal liver kinase 1 (FLK-1), and found these genes are up-regulated by TMSN AA nanoplex. Importantly, this work demonstrates the more efficient induction efficiency of human ES cells differentiation by the nanoparticle-drug formulation. Our studies reveal a novel approach based on MSNs as nanocarriers to induce the differentiation of human ES cells into cardiomyocytes efficiently and feasibly, and offer the potential perspectives for tissue engineering, eventually in clinical applications. PMID- 26249601 TI - Continuous microwave flow synthesis of mesoporous hydroxyapatite. AB - We have successfully used continuous microwave flow synthesis (CMFS) technique for the template free synthesis of mesoporous hydroxyapatite. The continuous microwave flow reactor consisted of a modified 2.45GHz household microwave, peristaltic pumps and a Teflon coil. This cost effective and efficient system was exploited to produce semi-crystalline phase pure nano-sized hydroxyapatite. Effect of microwave power, retention time and the concentration of reactants on the phase purity, degree of crystallinity and surface area of the final product was studied in detail. X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) were used to study the phase purity and composition of the product, while transmission electron microscopy (TEM) was used to study the effect of process parameters on the morphology of hydroxyapatite. The TEM analysis confirmed the formation of spherical particles at low microwave power; however the morphology of the particles changed to mesoporous needle and rod-like structure upon exposing the reaction mixture to higher microwave power and longer retention time inside the microwave. The in-vitro ion dissolution behavior of the as synthesized hydroxyapatite was studied by determining the amount of Ca(2+) ion released in SBF solution. PMID- 26249602 TI - Synthesis, characterization and application of biodegradable crosslinked carboxymethyl chitosan/poly(vinyl alcohol) clay nanocomposites. AB - Crosslinked poly(vinyl alcohol) (PVA)/carboxymethyl chitosan (CMCh) nanocomposites were synthesized using terephthaloyl diisothiocyanate crosslinker, in the presence of montmorillonite (MMT), in different ratios of the two matrices. Characterization of nanocomposites was performed using different analyses. Swelling behavior was studied in different buffered solutions. It was found that formation of crosslinked CMCh/PVA hydrogels increased the swellability. Metal ion adsorption has also been investigated. The results indicated that crosslinked CMCh adsorbs various metal ions much more than non crosslinked CMCh. Antimicrobial activity was examined against Gram positive bacteria, against Gram negative bacteria, and also against fungi. Results indicated that most of these nanocomposites exhibited good antimicrobial potency. Degradation study was carried out in Simulated Body Fluid (SBF) for different time periods in order to find out degradation index (Di). Results showed that weight loss of most of the nanocomposites increased as a function of incubation time. PMID- 26249603 TI - Antimicrobial efficacy of green synthesized drug blended silver nanoparticles against dental caries and periodontal disease causing microorganisms. AB - Development of biologically inspired green synthesis of silver nanoparticles is evolving into an important branch of nano-biotechnology. In the present investigation, we report the green synthesis of silver nanoparticles (AgNPs) employing the leaf extract of Justicia glauca. Water-soluble organics present in the leaf extract are mainly responsible for the reduction of silver nitrate (AgNO3) solution to AgNPs. The AgNPs are 10-20nm in dimensions as determined by TEM images. The antimicrobial activities of green synthesized AgNPs and drug blended AgNPs have been evaluated against the dental caries and periodontal disease causing microorganisms such as Streptococcus mutans, Staphylococcus aureus, Lactobacillus acidophilus, Micrococcus luteus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Candida albicans. The AgNPs and drug blended AgNPs show a significant antibacterial and antifungal activity. Minimum inhibitory concentration (MIC) value of AgNPs determined against the selected dental caries and periodontal disease causing microorganisms are noticeable between the range of 25-75MUg/mL. PMID- 26249604 TI - Microscopic view of osseointegration and functional mechanisms of implant surfaces. AB - Argon ion beam polishing technique was applied to prepare the cross sections of implants feasible for high resolution scanning electron microscope investigation. The interfacial microstructure between newly formed bone and implants with three modified surfaces retrieved after in vivo test using three different animal models was characterized. By this approach it has become possible to directly observe early bone formation, the increase of bone density, and the evolution of bone structure. The two bone growth mechanisms, distant osteogenesis and contact osteogenesis, can also be distinguished. These direct observations give, at microscopic level, a better view of osseointegration and expound the functional mechanisms of various implant surfaces for osseointegration. PMID- 26249605 TI - Structure, mechanical property and corrosion behaviors of (HA+beta-TCP)/Mg-5Sn composite with interpenetrating networks. AB - In this paper, a novel (Hydroxyapatite+beta-tricalcium phosphate)/Mg-5Sn ((HA+beta-TCP)/Mg-5Sn) composite with interpenetrating networks was fabricated by infiltrating Mg-5Sn alloy into porous HA+beta-TCP using suction casting technique. The structure, mechanical property and corrosion behaviors of the composite have been evaluated by means of scanning electron microscopy (SEM), X ray diffraction (XRD), mechanical testing, electrochemical and immersion test. It is shown that the molten Mg-5Sn alloy has infiltrated not only into the pores but also into the struts of the HA+beta-TCP scaffold to forming a compact composite. The microstructure observation also shows that the Mg alloy contacts to the HA+beta-TCP closely, and no reaction layer can be found between Mg-5Sn alloy and scaffold. The ultimate compressive strength of the composite is as high as 176MPa, which is about four fifths of the strength of the Mg-5Sn bulk alloy. The electrochemical and immersion tests indicate that the corrosion resistance of the composite is better than that of the Mg-5Sn bulk alloy. The corrosion products on the composite surface are mainly Mg(OH)2, Ca3(PO4)2 and HA. Appropriate mechanical and corrosion properties of the (HA+beta-TCP)/Mg-5Sn composite indicate its possibility for new bone tissue implant materials. PMID- 26249606 TI - Self-degrading niosomes for encapsulation of hydrophilic and hydrophobic drugs: An efficient carrier for cancer multi-drug delivery. AB - In this study, we have examined the encapsulation and release of hydrophilic and hydrophobic drugs in self-degrading niosomes as a unique method for anticancer therapy. Niosomes were prepared by amphiphilic self-assembly of Tween 80 and cholesterol through film hydration method. Encapsulation studies with two active molecules curcumin and doxorubicin hydrochloride (Dox) showed that curcumin is supposed to accumulate in the shell whereas Dox accumulates in the inner aqueous core of the niosome. Confocal studies indicated that nile red adsorbs preferentially to the head group of the Tween 80 and forms two separate layers in the shell. It was also seen that the niosomes undergo self-degradation in PBS through a sequential process, forming interconnected pores followed by complete collapse after 1week. The release profile shows two phases: i) initial Dox release in the first two days, followed by ii) curcumin release over 7days. Enhanced (synergistic) cytotoxicity was observed for dual-drug loaded niosomes against HeLa cell lines. Thus these niosomes are shown to offer a promising delivery system for hydrophobic and hydrophilic drugs collectively. PMID- 26249607 TI - Preparation of ds-DNA functionalized magnetic nanobaits for screening of bioactive compounds from medicinal plant. AB - A novel magnetic nanocomposite (MNPs@DNA) was synthesized by bonding double strand DNA (ds-DNA) onto Fe3O4 magnetic nanoparticles (MNPs) directly. MNPs@DNA was characterized by cyclic voltammetry (CV), differential pulse voltammetry (DPV), Fourier transform infrared spectroscopy (FT-IR) and thermo-gravimetric analysis (TGA), which indicated that ds-DNA was immobilized onto MNPs. Vibrating sample magnetometer (VSM) analysis indicated that the MNPs@DNA had a high saturation magnetization of 42.97emu/g. A novel method for screening of active compounds from natural sources was developed by employing MNPs@DNA as a nanobait and high-performance liquid chromatography-mass spectrometry as detecting system. Columbamine, palmatine, jateorhizine, epiberberine and berberine were identified as DNA binders from the extract of Rhizoma coptidis. In addition, a comparison of the binding abilities among MNPs with different DNA strand lengths (25, 200 and 1200bp) showed that the shortest one exhibited the highest binding ability. This is the first report on fast chemical characterization of active ingredients in medicinal plant using ds-DNA immobilized on magnetic nano-baits. This method can be used not only for screening of DNA binders from complex herbal matrices, but also for assessing the affinities between a specific ds-DNA and its potential binders. PMID- 26249608 TI - Preparation and biocompatibility evaluation of bioactive glass-forsterite nanocomposite powder for oral bone defects treatment applications. AB - Bone defects which emerge around dental implants are often seen when implants are placed in areas with insufficient alveolar bone, in extraction sockets, or around failing implants. Bone regeneration in above-mentioned defects using of bone grafts or bone substitutes may cure the long-term prognoses of dental implants. Biocompatibility, bioactivity and osteogenic properties are key factors affecting the applications of a bone substitute. This study was aimed at preparation, characterization, biocompatibility and bioactivity evaluation of the bioactive glass-forsterite nanocomposite powder as a desired candidate for oral bone defect treatments. Nanocomposite powders containing 58S bioactive glass and different amounts of forsterite nanopowder were synthesized in situ by sol-gel technique. Characterization of the prepared nanocomposite powders and their cytotoxicity assessment was performed via MTT test. Bioactivity assessment was done by immersing the prepared powder in the simulated body fluid (SBF). Results showed that nanocomposite powders containing forsterite with crystallite size of 20-50nm were successfully fabricated by calcination at 600 degrees C. The prepared bioactive glass-forsterite nanocomposite powders revealed high in vitro biocompatibility; besides, the nanocomposite containing 20wt.% forsterite showed a substantial increase in the cell viability compared with control groups. During immersion in SBF, the formation of apatite layer confirmed the bioactivity of bioactive glass-forsterite nanocomposite powders. According to the results, the fabricated nanocomposite powders can be introduced as a promising candidate for oral bone imperfection treatments and hard tissue mend. PMID- 26249609 TI - Surface characteristics, corrosion and bioactivity of chemically treated biomedical grade NiTi alloy. AB - The surface of NiTi alloy was chemically modified using acidified ferric chloride solution and the characteristics of the alloy surface were studied from the view point of application as a bioimplant. Chemically treated NiTi was also subjected to post treatments by annealing at 400 degrees C and passivation in nitric acid. The surface of NiTi alloy after chemical treatment developed a nanogrid structure with a combination of one dimensional channel and two dimensional network-like patterns. From SEM studies, it was found that the undulations formed after chemical treatment remained unaffected after annealing, while after passivation process the undulated surface was filled with oxides of titanium. XPS analysis revealed that the surface of passivated sample was enriched with oxides of titanium, predominantly TiO2. The influence of post treatment on the corrosion resistance of chemically treated NiTi alloy was monitored using Potentiodynamic Polarization and Electrochemical Impedance Spectroscopy (EIS) in Phosphate Buffered Saline (PBS) solution. In the chemically treated condition, NiTi alloy exhibited poor corrosion resistance due to the instability of the surface. On the other hand, the breakdown potential (0.8V) obtained was highest for the passivated samples compared to other surface treated samples. During anodic polarization, chemically treated samples displayed dissolution phenomenon which was predominantly activation controlled. But after annealing and passivation processes, the behavior of anodic polarization was typical of a diffusion controlled process which confirmed the enhanced passivity of the post treated surfaces. The total resistance, including the porous and barrier layer, was in the range of mega ohms for passivated surfaces, which could be attributed to the decrease in surface nickel content and formation of compact titanium oxide. The passivated sample displayed good bioactivity in terms of hydroxyapatite growth, noticed after 14days immersion in Hanks' solution. PMID- 26249610 TI - A highly sensitive hydrogen peroxide sensor based on (Ag-Au NPs)/poly[o phenylenediamine] modified glassy carbon electrode. AB - Herein, the poly(o-phenylenediamine) decorated with gold-silver nanoparticle (Ag Au NPs) nanocomposite modified glassy carbon was used for the determination of hydrogen peroxide. Electrochemical experiments indicated that the proposed sensor possesses an excellent sensitivity toward the reduction of hydrogen peroxide. The resulting sensor exhibited a good response to hydrogen peroxide over linear range from 0.2 to 60.0MUM with a limit of detection of 0.08MUM, good reproducibility, long-term stability and negligible interference from ascorbic acid, uric acid and dopamine. The proposed sensor was successfully applied to the determination of hydrogen peroxide in human serum sample. PMID- 26249611 TI - Poly(glycidyl methacrylate-co-3-thienylmethylmethacrylate) as an immobilization matrix for microbial glycerol biosensing based on Gluconobacter oxydans. AB - A commercial strain of Gluconobacter oxydans together with a new co-polymer Poly(glycidyl methacrylate-co-3-thienylmethylmethacrylate) (Poly(GMA-co-MTM)), which provides effective immobilization in the continuous flow system, was used in the sensor design. By taking the advantages of the nano-technology, carbon nanotubes (CNTs) were also added to the cell film and the sensitivity of the sensor was increased about 15 times. During the glycerol analysis in the continuous system, it was shown that composite film was not removed from the electrode surface and film elements were not washed out from the system. Glycerol analyses were performed by using batch loaded continuously flow cell at different flow rates of 1, 2, 4, and 6mL/min. The linear range was found as 2-100mM with the detection limit (LOD) of 0.057mM according to S/N=3. The calibration graphs were obtained for Poly(GMA-co-MTM)/G. oxydans and Poly(GMA-co-MTM)/CNT/G. oxydans biofilm electrodes in FIA mode, and sensitivities were found to be 1.50nA/mM and 19.13nA/mM, respectively. In this study, Poly(GMA-co-MTM) was used for the first time as a microbial matrix and was shown to be an effective immobilization agent. PMID- 26249612 TI - Titania nanotube delivery fetal bovine serum for enhancing MC3T3-E1 activity and osteogenic gene expression. AB - Titania nanotube (TNT) delivery of fetal bovine serum (FBS) was conducted on titanium (Ti) to enhance bone tissue repair. Scanning electron microscopy (SEM) and energy dispersive spectrometer (EDS) showed FBS increased the tube wall thickness and decreased the tube diameter. Attenuated total reflectance Fourier transform infrared further confirmed that FBS completely covered the TNT and changed the surface composition. Water contact angle tests showed TNT/FBS possessed hydrophilic properties. Compared to original Ti, the TNT/FBS group had more attached osteoblasts after 2h and enhanced filopodia growth at 0.5h. Significantly, more osteoblasts were also observed on TNT/FBS after 7d culturing. FBS was released steadily from TNT; about 70% of FBS had been released at 3d and 90% at 5d, as shown by the bicinchoninic acid method. TNT/FBS also enhanced subsequent osteoblast differentiation and gene expression; the quantum real-time polymerase chain reaction test showed that TNT/FBS up-regulated alkaline phosphatase and osteocalcin gene expression at 7d and 14d. Therefore, TNT/FBS delivered sustained in situ nutrition and enhanced osteoblast activity and osteogenic gene expression. PMID- 26249613 TI - Simple method to generate and fabricate stochastic porous scaffolds. AB - Considerable effort has been made to generate regular porous structures (RPSs) using function-based methods, although little effort has been made for constructing stochastic porous structures (SPSs) using the same methods. In this short communication, we propose a straightforward method for SPS construction that is simple in terms of methodology and the operations used. Using our method, we can obtain a SPS with functionally graded, heterogeneous and interconnected pores, target pore size and porosity distributions, which are useful for applications in tissue engineering. The resulting SPS models can be directly fabricated using additive manufacturing (AM) techniques. PMID- 26249614 TI - Porcine kidneys as a source of ECM scaffold for kidney regeneration. AB - OBJECTIVE: To produce and examine decellularized kidney scaffolds from porcine as a platform for kidney regeneration research. METHODS: Porcine kidneys were decellularized with sodium dodecyl sulfate solution and Triton X-100 after the blood was rinsed. Then the renal ECM scaffolds were examined for vascular imaging, histology to investigate the vascular patency, degree of decellularization. RESULTS: Renal ECM scaffolds of porcine kidneys were successfully produced. Decellularized renal scaffolds retained intact microarchitecture including the renal vasculature and essential extracellular matrix components. CONCLUSION: We have developed an excellent decellularization method that can be used in large organs. These scaffolds maintain their basic components, and show intact vasculature system. This represents a step toward development of a transplantable organ using tissue engineering techniques. PMID- 26249615 TI - Improved dimensional stability with bioactive glass fibre skeleton in poly(lactide-co-glycolide) porous scaffolds for tissue engineering. AB - Bone tissue engineering requires highly porous three-dimensional (3D) scaffolds with preferable osteoconductive properties, controlled degradation, and good dimensional stability. In this study, highly porous 3D poly(d,l-lactide-co glycolide) (PLGA) - bioactive glass (BG) composites (PLGA/BG) were manufactured by combining highly porous 3D fibrous BG mesh skeleton with porous PLGA in a freeze-drying process. The 3D structure of the scaffolds was investigated as well as in vitro hydrolytic degradation for 10weeks. The effect of BG on the dimensional stability, scaffold composition, pore structure, and degradation behaviour of the scaffolds was evaluated. The composites showed superior pore structure as the BG fibres inhibited shrinkage of the scaffolds. The BG was also shown to buffer the acidic degradation products of PLGA. These results demonstrate the potential of these PLGA/BG composites for bone tissue engineering, but the ability of this kind of PLGA/BG composites to promote bone regeneration will be studied in forthcoming in vivo studies. PMID- 26249616 TI - Metallic zinc exhibits optimal biocompatibility for bioabsorbable endovascular stents. AB - Although corrosion resistant bare metal stents are considered generally effective, their permanent presence in a diseased artery is an increasingly recognized limitation due to the potential for long-term complications. We previously reported that metallic zinc exhibited an ideal biocorrosion rate within murine aortas, thus raising the possibility of zinc as a candidate base material for endovascular stenting applications. This study was undertaken to further assess the arterial biocompatibility of metallic zinc. Metallic zinc wires were punctured and advanced into the rat abdominal aorta lumen for up to 6.5months. This study demonstrated that metallic zinc did not provoke responses that often contribute to restenosis. Low cell densities and neointimal tissue thickness, along with tissue regeneration within the corroding implant, point to optimal biocompatibility of corroding zinc. Furthermore, the lack of progression in neointimal tissue thickness over 6.5months or the presence of smooth muscle cells near the zinc implant suggest that the products of zinc corrosion may suppress the activities of inflammatory and smooth muscle cells. PMID- 26249617 TI - Multifunctional chitosan/polyvinyl pyrrolidone/45S5 Bioglass(r) scaffolds for MC3T3-E1 cell stimulation and drug release. AB - Novel chitosan-polyvinyl pyrrolidone/45S5 Bioglass(r) (CS-PVP/BG) scaffolds were prepared via foam replication and chemical cross-linking techniques. The pristine BG, CS-PVP coated BG and genipin cross-linked CS-PVP/BG (G-CS-PVP/BG) scaffolds were synthesized and characterized in terms of chemical composition, physical structure and morphology respectively. Resistance to enzymatic degradation of the scaffold is improved significantly with the use of genipin cross-linked CS-PVP. The bio-effects of scaffolds on MC3T3-E1 osteoblast-like cells were evaluated by studying cell viability, adhesion and proliferation. The CCK-8 assay shows that cell viability on the resulting G-CS-PVP/BG scaffold is improved obviously after cross-linking of genipin. Cell skeleton images exhibit that well-stretched F actin bundles are obtained on the G-CS-PVP/BG scaffold. SEM results present significant improvement on the cell adhesion and proliferation for cells cultured on the G-CS-PVP/BG scaffold. The drug release performance on the as-synthesized scaffold was studied in a phosphate buffered saline (PBS) solution. Vancomycin is found to be released in burst fashion within 24h from the pristine BG scaffold, however, the release period from the G-CS-PVP/BG scaffold is enhanced to 7days, indicating improved drug release properties of the G-CS-PVP/BG scaffold. Our results suggest that the G-CS-PVP/BG scaffolds possess promising physicochemical properties, sustained drug release capability and good biocompatibility for MC3T3 E1 cells' proliferation and adhesion, suggesting their potential applications in areas such as MC3T3-E1 cell stimulation and bone tissue engineering. PMID- 26249618 TI - Development and characterization of hydroxyapatite/beta-TCP/chitosan composites for tissue engineering applications. AB - Calcium phosphate ceramics that mimic bone composition provide interesting possibilities for the advancement in bone tissue engineering. The present study reports on a chitosan composite reinforced by hydroxyapatite (HA) and beta tricalcium phosphate (beta-TCP) obtained from waste mussel shells and cross linked using tripolyphosphate (TPP). The ratios of the ceramic components in composites were 20/10/70, 30/20/50 and 40/30/30 (HA/beta-TCP/CH, w/w %). Biodegradation rate, structural properties and in-vitro degradation of the bone like composite scaffolds were investigated. The optimum amount of TPP required for composite was 2.5% and glycerol was used as plasticizer at an optimized concentration of 1%. Tripolyphosphate cross-linked chitosan composites were developed by freezing and lyophilisation. The Young's modulus of the scaffolds was increased from 4kPa to 17kPa and the porosity of composites dropped from 85 to 68% by increasing the HA/beta-TCP ratio. After 28days in physiological solution, bone-like composite scaffolds with a higher ratio of HA/beta-TCP (e.g. 40/30/30) showed about 2% lower biodegradation in comparison to scaffolds with a lower ratio of HA/beta-TCP (i.e. 20/10/70). The obtained data suggest that the chitosan based bone-like composites could be potential candidates for biomedical applications. PMID- 26249619 TI - Effect of decellularized tissue powders on a rat model of acute myocardial infarction. AB - Many research groups are currently investigating new treatment modalities for myocardial infarction. Numerous aspects need to be considered for the clinical application of these therapies, such as low cell integration and engraftment rates of cell injection techniques. Decellularized tissues are considered good materials for promoting regeneration of traumatic tissues. The properties of the decellularized tissues are sustained after processing to powder form. In this study, we examined the use of decellularized tissue powder in a rat model of acute myocardial infarction. The decellularized tissue powders, especially liver powder, promoted cell integration and neovascularization both in vitro and in vivo. Decellularized liver powder induced neovascularization in the infarct area, resulting in the suppression of myocardial necrosis. The results of this study suggest that decellularized liver powder has good potential for application as a blood supply material for the treatment of myocardial infarction. PMID- 26249620 TI - Studies on polymer-coated zinc oxide nanoparticles: UV-blocking efficacy and in vivo toxicity. AB - Zinc oxide (ZnO) is explicitly used in sunscreens and cosmetic products; however, its effect in vivo is toxic in some cases. The UV blocking efficacy of ZnO nanoparticles is lost due to photocatalysis. To isolate a lower toxic species of sunblockers, ZnO nanoparticles were synthesized and coated with chitosan - a natural polymer (ZnO-CTS) and polyethylene glycol (PEG) - a synthetic polymer (ZnO-PEG). Coating with CTS and PEG circumvented the photocatalytic activity, increased the stability and improved the UV absorption efficacy. The effect of ZnO, ZnO-CTS and ZnO-PEG nanoparticles in vivo on zebrafish embryo revealed lower deposition of ZnO-CTS and ZnO-PEG nanoparticles atop the eggs compared to ZnO. The survival of zebrafish embryos was always found to be higher in case of ZnO CTS with respect to ZnO-treated ones. PEG coating exhibited better UV attenuation, but, in vivo it induced delayed hatching. Thus, one of the reasons for better survival could be attributed to lower aggregation of ZnO-CTS nanoparticles atop eggs thereby facilitating the breathing of embryos. PMID- 26249621 TI - Electrospun nanofibrous scaffolds of segmented polyurethanes based on PEG, PLLA and PTMC blocks: Physico-chemical properties and morphology. AB - Biocompatible polymeric scaffolds are crucial for successful tissue engineering. Biomedical segmented polyurethanes (SPUs) are an important and versatile class of polymers characterized by a broad spectrum of compositions, molecular architectures, properties and applications. Although SPUs are versatile materials that can be designed by different routes to cover a wide range of properties, they have been infrequently used for the preparation of electrospun nanofibrous scaffolds. This study reports the preparation of new electrospun polyurethane scaffolds. The segmented polyurethanes were synthesized using low molar masses macrodyols (poly(ethylene glycol), poly(l-lactide) and poly(trimethylene carbonate)) and 1,6-hexane diisocyanate and 1,4-butanodiol as isocyanate and chain extensor, respectively. Different electrospinning parameters such as solution properties and processing conditions were evaluated to achieve smooth, uniform bead-free fibers. Electrospun micro/nanofibrous structures with mean fiber diameters ranging from 600nm to 770nm were obtained by varying the processing conditions. They were characterized in terms of thermal and dynamical mechanical properties, swelling degree and morphology. The elastomeric polyurethane scaffolds exhibit interesting properties that could be appropriate as biomimetic matrices for soft tissue engineering applications. PMID- 26249622 TI - Controlled formation of surface hydrophilicity enhanced chitosan film by layer-by layer electro-assembly. AB - Several surface hydrophilicity enhanced chitosan, CS, films were controllably formed by using the layer-by-layer electro-assembly, LBLEA, method with varied voltages. Experimentally, an employed electrostatic generator was employed by taking its anode and cathode electrodes alternatively linking to the CS solution or silicon plate to form two opposite cycles corresponding to the electrostatic force, EF, enhancement or reduction, respectively. Wetting results showed that the water contact angle, thetaW, on those CS film surfaces was gradually reduced with the applied voltage increase, especially by EF reduction, e.g. the thetaW on 0V sample at about 55 degrees and on 4kV EF-reduction formed sample at about 20 degrees . AFM images comparison showed that the LBLEA process can control the surface structure for CS film. ATR-FTIR spectra comparison showed that the EF reduction process would reveal the C-O groups on CS film surface to enhance the hydrophilicity. PMID- 26249623 TI - Modification of the bacterial adhesion of Staphylococcus aureus by antioxidant blooming on polyurethane films. AB - Medical device-related infections are a major problem in hospital. The risk of developing an infection is linked to the bacterial adhesion ability of pathogen strains on the device and their ability to form a biofilm. Here we focused on polymer surfaces exhibiting a blooming of antioxidant (Irganox 3114(r) and Irganox 1076(r)) on their surface. We tried to put into evidence the effect of such a phenomenon on the bacterial adhesion in terms of number of viable cultivable bacteria and bacteria localization on the surface. We showed that the blooming has a tendency to increase the Staphylococcus aureus adhesion phenomenon in part for topographic reasons. PMID- 26249624 TI - Corrosion behavior of Ti-39Nb alloy for dentistry. AB - To increase an orthopedic implant's lifetime, researchers are now concerned on the development of new titanium alloys with suitable mechanical properties (low elastic modulus-high fatigue strength), corrosion resistance and good workability. Corrosion resistance of the newly developed titanium alloys should be comparable with that of pure titanium. The effect of medical preparations containing fluoride ions represents a specific problem related to the use of titanium based materials in dentistry. The aim of this study was to determine the corrosion behavior of beta titanium alloy Ti-39Nb in physiological saline solution and in physiological solution containing fluoride ions. Corrosion behavior was studied using standard electrochemical techniques and X-ray photoelectron spectroscopy. It was found that corrosion properties of the studied alloy were comparable with the properties of titanium grade 2. The passive layer was based on the oxides of titanium and niobium in several oxidation states. Alloying with niobium, which was the important part of the alloy passive layer, resulted in no significant changes of corrosion behavior. In the presence of fluoride ions, the corrosion resistance was higher than the resistance of titanium. PMID- 26249626 TI - Changes induced by UV radiation in the presence of sodium benzoate in films formulated with polyvinyl alcohol and carboxymethyl cellulose. AB - This work was focused on: i) developing single and blend films based on carboxymethyl cellulose (CMC) and polyvinyl alcohol (PVOH) studying their properties, ii) analyzing the interactions between CMC and PVOH and their modifications UV-induced in the presence of sodium benzoate (SB), and iii) evaluating the antimicrobial capacity of blend films containing SB with and without UV treatment. Once the blend films with SB were exposed to UV radiation, they exhibited lower moisture content as well as a greater elongation at break and rougher surfaces compared to those without treatment. Considering oxygen barrier properties, the low values obtained would allow their application as packaging with selective oxygen permeability. Moreover, the characteristics of the amorphous phase of the matrix prevailed with a rearrangement of the structure of the polymer chain, causing a decrease of the crystallinity degree. These results were supported by X-rays and DSC analysis. FT-IR spectra reflected some degree of polymer-polymer interaction at a molecular level in the amorphous regions. The incorporation of sodium benzoate combined with UV treatment in blend films was positive from the microbial point of view because of the growth inhibition of a wide spectrum of microorganisms. From a physicochemical perspective, the UV treatment of films also changed their morphology rendering them more insoluble in water, turning the functionalized blend films into a potential material to be applied as food packaging. PMID- 26249625 TI - Titanium-35niobium alloy as a potential material for biomedical implants: In vitro study. AB - Research on new titanium alloys and different surface topographies aims to improve osseointegration. The objective of this study is to analyze the behavior of osteogenic cells cultivated on porous and dense samples of titanium-niobium alloys, and to compare them with the behavior of such type of cells on commercial pure titanium. Samples prepared using powder metallurgy were characterized using scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), X-ray diffraction (XRD), and metallographic and profilometer analyses. Osteogenic cells from newborn rat calvaria were plated over different groups: dense or porous samples composed of Ti or Ti-35niobium (Nb). Cell adhesion, cell proliferation, MTT assay, cell morphology, protein total content, alkaline phosphatase activity, and mineralization nodules were assessed. Results from XRD and EDS analysis confirmed the presence of Ti and Nb in the test alloy. Metallographic analysis revealed interconnected pores, with pore size ranging from 138 to 150MUm. The profilometer analysis detected the greatest rugosity within the dense alloy samples. In vitro tests revealed similar biocompatibility between Ti-35Nb and Ti; furthermore, it was possible to verify that the association of porous surface topography and the Ti-35Nb alloy positively influenced mineralized matrix formation. We propose that the Ti-35Nb alloy with porous topography constitutes a biocompatible material with great potential for use in biomedical implants. PMID- 26249627 TI - HPLC detection of loss rate and cell migration of HUVECs in a proanthocyanidin cross-linked recombinant human collagen-peptide (RHC)-chitosan scaffold. AB - Porous scaffolds with appropriate pore structure, biocompatibility, mechanical property and processability play an important role in tissue engineering. In this paper, we fabricated a recombinant human collagen-peptide (RHC)-chitosan scaffold cross-linked by premixing 30% proanthocyanidin (PA) in one-step freeze-drying. To remove the residual acetic acid, optimized 0.2M phosphate buffer of pH6.24 with 30% ethanol (PBSE) was selected to neutralize the lyophilized scaffold followed by three times deionized water rinse. Ninhydrin assay was used to characterize the components loss during the fabrication process. To detect the exact RHC loss under optimized neutralization condition, high performance liquid chromatography (HPLC) equipped size exclusion chromatography column was used and the total RHC loss rate through PBSE rinse was 19.5+/-5.08%. Fourier transform infrared spectroscopy (FT-IR) indicated hydrogen bonding among RHC, chitosan and PA, it also presented a probative but not strong hydrophobic interaction between phenyl rings of polyphenols and pyrrolidine rings of proline in RHC. Further, human umbilical vein endothelial cell (HUVEC) viability analyzed by a scanning electron microscope (SEM) and acridine orange/ethidium bromide (AO/EB) fluorescence staining exhibited that this scaffold could not only promote cell proliferation on scaffold surface but also permit cells migration into the scaffold. qRT-PCR exhibited that the optimized scaffold could stimulate angiogenesis associated genes VEGF and CD31 expression. These characterizations indicated that this scaffold can be considered as an ideal candidate for tissue engineering. PMID- 26249629 TI - Overview of PES biocompatible/hemodialysis membranes: PES-blood interactions and modification techniques. AB - Polyethersulfone (PES) based membranes are used for dialysis, but exposure to blood can result in numerous interactions between the blood elements and the membrane. Adsorption and transformation of plasma proteins, activation of blood cells, adherence of platelets and thrombosis reactions against PES membrane can invoke severe blood reactions causing the increase rate of mortality and morbidity of hemodialysis (HD) patients. In order to minimize blood immune response, different biomimetic, zwitterionic, non-ionic, anticoagulant molecules and hydrophilic brushes were immobilized or blended with PES polymers. These additives modified the nature of the membrane, enhanced their biocompatibility and also increased the uremic waste dialysis properties. In this review, current perspectives of the different additives which are used with PES are highlighted in relation with PES membrane-associated blood reactions. The additive's purpose, compatibility, preparation techniques, methods of addition to polymer and influence on the chemistry and performance of hemodialysis membranes are described. PMID- 26249630 TI - Introducing you to Healthcare: The Journal of Delivery Science and Innovation. PMID- 26249628 TI - Lysine-doped polypyrrole/spider silk protein/poly(l-lactic) acid containing nerve growth factor composite fibers for neural application. AB - Lysine-doped polypyrrole (PPy)/regenerated spider silk protein (RSSP)/poly(l lactic) acid (PLLA)/nerve growth factor (NGF) (L-PRPN) composite scaffold was fabricated by co-axial electrospraying and electrospinning. This L-PRPN composite scaffold had a structure of microfibers with a core-shell structure as the stems and nanofibers as branches. Assessment in vitro demonstrated that the L-PRPN composite micro/nano-fibrous scaffold could maintain integrated structure for at least 4months and the pH value of PBS at about 7.28. It had good biocompatibility and cell adhesion and relatively stable conductivity. PC 12 cells cultured on this scaffold, anisotropic cell-neurite-cell-neurite or neurite-neurite sheets were formed after being cultured for 6days. Evaluations in vivo also showed that L-PRPN composite fibrous conduit was effective at bridging 2.0cm sciatic nerve gap in adult rat within 10months. This conduit and electrical stimulation (ES) through it promoted Schwann cell migration and axonal regrowth. PMID- 26249631 TI - Introduction to Healthcare: The Journal of Delivery Science and Innovation. PMID- 26249632 TI - Introduction to Healthcare: The Journal of Delivery Science and Innovation. PMID- 26249633 TI - Making the RCT more useful for innovation with evidence-based evolutionary testing. AB - We propose a new innovation model designed to accelerate the rate of learning from provider payment reform initiatives. Drawing on themes from operations research, we describe a new approach that balances speed and rigor to more quickly build evidence on what works in delivery system redesign. While randomized controlled trials provide "gold standard" evidence on efficacy, traditional RCTs tend to be static and provide information too slowly given the CMMI tagline of "We can't wait." Our approach speaks to broader needs within health financing and delivery reform for testing that while rigorous recognizes the urgency of the challenges we face. PMID- 26249634 TI - Will new care delivery solve the primary care physician shortage?: A call for more rigorous evaluation. AB - Transformations in care delivery and payment models that make care more efficient are leading some to question whether there will really be a shortage of primary care physicians. While it is encouraging to see numerous federal and state policy levers in place to support greater accountability and coordination of care, it is too early to know whether these efforts will change current and future primary care physician workforce needs. More research is needed to inform whether efforts to reduce cost and improve quality of care and population health will help alleviate or further exacerbate expected primary care physician shortages. PMID- 26249635 TI - Commentary on the spread of new payment models. PMID- 26249636 TI - Reliability of utilization measures for primary care physician profiling. AB - BACKGROUND: Given rising health care costs, there has been a renewed interest in using utilization measures to profile physicians. Despite the measures' common use, few studies have examined their reliability and whether they capture true differences among physicians. METHODS: A local health improvement organization in New York State used 2008-2010 claims data to create 11 utilization measures for feedback to primary care physicians (PCP). The sample consists of 2938 PCPs in 1546 practices who serve 853,187 patients. We used these data to measure reliability of these utilization measures using two methods (hierarchical model versus test-retest). For each PCP and each practice, we estimate each utilization measure's reliability, ranging from 0 to 1, with 0 indicating that all differences in utilization are due to random noise and 1 indicating that all differences are due to real variation among physicians. RESULTS: Reliability varies significantly across the measures. For 4 utilization measures (PCP visits, specialty visits, PCP lab tests (blood and urine), and PCP radiology and other tests), reliability was high (mean>0.85) at both the physician and the practice level. For the other 7 measures (professional therapeutic visits, emergency room visits, hospital admissions, readmissions, skilled nursing facility days, skilled home care visits, and custodial home care services), there was lower reliability indicating more substantial measurement error. CONCLUSIONS: The results illustrate that some utilization measures are suitable for PCP and practice profiling while caution should be used when using other utilization measures for efforts such as public reporting or pay-for-performance incentives. PMID- 26249637 TI - Contributors to variation in hospital spending for critically ill patients with sepsis. AB - BACKGROUND: Costs of severe sepsis in the US exceeded $24 billion in 2007. Identifying the relative contributions of patient, hospital, and physician factors to the variation in hospital costs of sepsis could help target efforts to improve the value of care. METHODS: We identified adults with a principal or secondary diagnosis of sepsis who received care between June 1, 2004 and June 30, 2006 at one of the hospitals participating in a multi-institutional database. We constructed a regression model to predict mean hospital costs that included patient characteristics, hospital mission and environment (e.g., teaching status, percentage of low-income patients), hospital fixed costs, and risk-adjusted length of stay, which encompasses hospital throughput, the incidence of complications, and other aspects of physician practice. To determine the contribution to cost variance by each predictor, we calculated the R(2). RESULTS: At 189 hospitals, we identified 40,265 adults with sepsis who met inclusion criteria. The median cost of a hospitalization was $20,216. The model explained 69% of the hospital-level variation in the costs of hospitalization. Of explained variation, differences in patients' ages, comorbidities, and severity accounted for 20%; hospital mission and environment represented 16%; differences in hospital fixed costs, including acquisition costs and overhead, accounted for 19%; and wage index explained an additional 12%. Risk-adjusted length of stay comprised the final one-third of explained variation. CONCLUSION: A large proportion of variation in the cost of caring for critically ill patients with sepsis across hospitals is related to differences in patient characteristics and immutable hospital characteristics, while nearly one-third is the result of differences in risk-adjusted length of stay. IMPLICATIONS: Efforts to reduce spending on the critically ill should aim to understand determinants of practice style but should also focus on hospital throughput, overhead, acquisition, and labor costs. PMID- 26249638 TI - Innovating in health delivery: The Penn medicine innovation tournament. AB - BACKGROUND: Innovation tournaments can drive engagement and value generation by shifting problem-solving towards the end user. In health care, where the frontline workers have the most intimate understanding of patients' experience and the delivery process, encouraging them to generate and develop new approaches is critical to improving health care delivery. PROBLEM: In many health care organizations, senior managers and clinicians retain control of innovation. Frontline workers need to be engaged in the innovation process. GOALS: Penn Medicine launched a system-wide innovation tournament with the goal of improving the patient experience. We set a quantitative goal of receiving 500 ideas and getting at least 1000 employees to participate in the tournament. A secondary goal was to involve various groups of the care process (doctors, nurses, clerical staff, transporters). STRATEGY: The tournament was broken up into three phases. During Phase 1, employees were encouraged to submit ideas. Submissions were judged by an expert panel and crowd sourcing based on their potential to improve patient experience and ability to be implemented within 6 months. During Phase 2, the best 200 ideas were pitched during a series of 5 workshops and ten finalists were selected. During Phase 3, the best 10 ideas were presented to and judged by an audience of about 200 interested employees and a judging panel of 15 administrators. Two winners were selected. RESULTS: A total of 1739 ideas were submitted and over 5000 employees participated in the innovation tournament. Patient convenience/amenities (21%) was the top category of submission, with other popular areas including technology optimization (11%), assistance with navigation within UPHS (10%), and improving patient/family centered care (9%) and care delivery models/transitions (9%). A combination of winning and submitted ideas were implemented. PMID- 26249639 TI - What can the past of pay-for-performance tell us about the future of Value-Based Purchasing in Medicare? AB - The Medicare program has implemented pay-for-performance (P4P), or Value-Based Purchasing, for inpatient care and for Medicare Advantage plans, and plans to implement a program for physicians in 2015. In this paper, we review evidence on the effectiveness of P4P and identify design criteria deemed to be best practice in P4P. We then assess the extent to which Medicare's existing and planned Value Based Purchasing programs align with these best practices. Of the seven identified best practices in P4P program design, the Hospital Value-Based Purchasing program is strongly aligned with two of the best practices, moderately aligned with three, weakly aligned with one, and has unclear alignment with one best practice. The Physician Value-Based Purchasing Modifier is strongly aligned with two of the best practices, moderately aligned with one, weakly aligned with three, and has unclear alignment with one of the best practices. The Medicare Advantage Quality Bonus Program is strongly aligned with four of the best practices, moderately aligned with two, and weakly aligned with one of the best practices. We identify enduring gaps in P4P literature as it relates to Medicare's plans for Value-Based Purchasing and discuss important issues in the future of these implementations in Medicare. PMID- 26249640 TI - Instant replay. AB - With widespread adoption of electronic health records (EHRs) and electronic clinical documentation, health care organizations now have greater faculty to review clinical data and evaluate the efficacy of quality improvement efforts. Unfortunately, I believe there is a fundamental gap between actual health care delivery and what we document in the current EHR systems. This process of capturing the patient encounter, which I'll refer to as transcription, is prone to significant data loss due to inadequate methods of data capture, multiple points of view, and bias and subjectivity in the transcriptional process. Our current EHR, text-based clinical documentation systems are lossy abstractions - one sided accounts of what take place between patients and providers. Our clinical notes contain the breadcrumbs of relationships, conversations, physical exams, and procedures but often lack the ability to capture the form, the emotions, the images, the nonverbal communication, and the actual narrative of interactions between human beings. I believe that a video record, in conjunction with objective transcriptional services and other forms of data capture, may provide a closer approximation to the truth of health care delivery and may be a valuable tool for healthcare improvement. PMID- 26249641 TI - CARD14 gene polymorphism c.C2458T (p.Arg820Trp) is associated with clinical features of psoriasis vulgaris in a Chinese cohort. AB - Genome-wide association studies have found the single nucleotide polymorphism (SNP) c.C2458T, at the caspase recruitment domain family member 14 (CARD14) gene, to be associated with psoriasis. But little is known about the association of c.C2458T and clinical features of psoriasis vulgaris (PsV) in a Chinese cohort. This study was undertaken to further explore the relationship between c.C2458T and risk of psoriasis in southern Chinese subjects and to evaluate the SNP effect on the clinical features of psoriasis. A case-control study was performed involving 345 PsV patients and 206 controls. The variant of c.C2458T was typed using a SNaPshot assay. Statistical analysis was performed using SPSS version 13.0 software. In analysis of the basic situation of the sample, no difference was observed between cases and controls for age and sex. In the frequency distribution of genotypes and alleles in patients and controls, we found no association between the SNP and the risk of PsV. We performed a stratified analysis according to the age of onset, family history and Psoriasis Area and Severity Index (PASI) subphenotypes. We found that the CC genotype was associated significantly with an increased familial history of PsV. The main finding of our study was that the CC genotype was more common in familial cases than in sporadic cases. However, there were no significant differences found in other subphenotypes of age of onset or PASI between patients positive and those negative for a particular phenotype. In conclusion, the SNP c.C2458T may have significant effects on heritability of PsV in our Chinese population. PMID- 26249642 TI - Analysis of mitochondrial mechanical dynamics using a confocal fluorescence microscope with a bent optical fibre. AB - The cells in the cardiovascular system are constantly subjected to mechanical forces created by blood flow and the beating heart. The effect of forces on cells has been extensively investigated, but their effect on cellular organelles such as mitochondria remains unclear. We examined the impact of nano-Newton forces on mitochondria using a bent optical fibre (BOF) with a flat-ended tip (diameter exceeding 2 MUm) and a confocal fluorescence microscope. By indenting a single mitochondrion with the BOF tip, we found that the mitochondrial elastic modulus was proportional to the (-1/2) power of the mitochondrial radius in the 9.6-115 kPa range. We stained the mitochondria with a potential-metric dye (TMRE) and measured the changes in TMRE fluorescence intensity. We confirmed that more active mitochondria exhibit a higher frequency of repetitive transient depolarization. The same trend was observed at forces lower than 50 nN. We further showed that the depolarization frequency of mitochondria decreases under an extremely large force (nearly 100 nN). We conclude that mitochondrial function is affected by physical environmental factors, such as external forces at the nano-Newton level. PMID- 26249643 TI - Gender differences in sleep in older men and women. AB - Sleep disturbances increase with increasing age in both males and females and become fairly common in the older community when compared to their younger counterparts. Even though these sleep disturbances increase with advancing age, there are nevertheless inherent differences in sleep disturbances between males and females. When compared to older men, older women will have a longer sleep latency (number of minutes it takes to fall asleep), more daytime sleepiness, will sleep about 20 min less per day, have less NREM stages 1 and 2 sleep, have more slow-wave sleep, and are more predisposed to REM sleep. Women have at least a 40% increased risk for developing insomnia, are at twice the risk for restless legs syndrome, will have different obstructive sleep apnea symptoms and more partial obstructions during sleep compared to men. They are also less likely to use antidepressants but will metabolize zolpidem 50% slower than men. PMID- 26249644 TI - Standard instruction versus simulation: Educating registered nurses in the early recognition of patient deterioration in paediatric critical care. AB - Identifying and stabilising deterioration in a child with significant clinical compromise is both a challenging and necessary role of the paediatric critical care nurse. Within adult critical care research, high fidelity patient simulation (HFPS) has been shown to positively impact learner outcomes regarding identification and management of a deteriorating patient; however, there is a paucity of evidence examining the use of HFPS in paediatric nursing education. The aim of this study was to investigate the effect of HFPS on nurses' self efficacy and knowledge for recognising and managing paediatric deterioration. Further, participants' perceptions of the learning experiences specific to the identification and management of a deteriorating child were also explored. Registered nurses working in a tertiary-referral paediatric critical care unit were recruited for this quasi-experimental study. Using a pre-test/post-test control-group design, participants were assigned to one of two learning experiences: HFPS or standard instruction. Following the learning experience, nurses were also invited to participate in semi-structured interviews. 30 nurses participated in the study (control n=15, experiment n=15). Participants in the HFPS intervention were most likely to demonstrate an increase in both perceived self-efficacy (p=<0.01) and knowledge (p=<0.01). No statistically significant change was observed in control group scores. The mean difference in self-efficacy gain score between the two groups was 5.67 score units higher for the experiment group compared to the control. HFPS also yielded higher follow-up knowledge scores (p=0.01) compared to standard instruction. Ten nurses participated in semi structured interviews. Thematic analysis of the interview data identified four themes: self-awareness, hands-on learning, teamwork, and maximising learning. The results of this study suggest that HFPS can positively influence nurses' self efficacy and knowledge test scores specific to the recognition and management of paediatric deterioration. PMID- 26249645 TI - Educating registered nursing and healthcare assistant students in community-based supportive care of older adults: A mixed methods study. AB - BACKGROUND: Collaborative education that prepares nursing and healthcare assistant students in supportive care for older adults living at home with advanced chronic illness is an important innovation to prepare the nursing workforce to meet the needs of this growing population. OBJECTIVES: To explore whether a collaborative educational intervention could develop registered nursing and healthcare assistant students' capabilities in supportive care while enhancing care of clients with advanced chronic illness in the community. DESIGN: Mixed method study design. SETTING: A rural college in Canada. PARTICIPANTS: Twenty-one registered nursing and 21 healthcare assistant students completed the collaborative workshop. Eight registered nursing students and 13 healthcare assistant students completed an innovative clinical experience with fifteen clients living with advanced chronic illness. METHODS: Pre and post-test measures of self-perceived competence and knowledge in supportive care were collected at three time points. Semi-structured interviews were conducted to evaluate the innovative clinical placement. RESULTS: Application of Friedman's test indicated statistically significant changes on all self-perceived competence scores for RN and HCA students with two exceptions: the ethical and legal as well as personal and professional issues domains for HCA students. Application of Friedman's test to self-perceived knowledge scores showed statistically significant changes in all but one domain (interprofessional collaboration and communication) for RN students and all but three domains for HCA students (spiritual needs, ethical and legal issues, and inter-professional collaboration and communication). Not all gains were sustained until T-3. The innovative community placement was evaluated positively by clients and students. CONCLUSIONS: Collaborative education for nursing and healthcare assistant students can enhance self-perceived knowledge and competence in supportive care of adults with advanced chronic illness. An innovative clinical experience can maximize reciprocal learning while providing nursing services to a population that is not receiving home-based care. PMID- 26249646 TI - Constitutive changes in pigment concentrations: implications for estimating isoprene emissions using the photochemical reflectance index. AB - The photochemical reflectance index (PRI), through its relationship with light use efficiency (LUE) and xanthophyll cycle activity, has recently been shown to hold potential for tracking isoprene emissions from vegetation. However, both PRI and isoprene emissions can also be influenced by changes in carotenoid pigment concentrations. Xanthophyll cycle activity and changes in carotenoid concentrations operate over different timescales, but the importance of constitutive changes in pigment concentrations for accurately estimating isoprene emissions using PRI is unknown. To clarify the physiological mechanisms behind the PRI-isoprene relationship, the light environment of potted Salix viminalis (osier willow) trees was modified to induce acclimation in photosynthetic rates, phytopigments, isoprene emissions and PRI. Acclimation resulted in differences in pigment concentrations, isoprene emissions and PRI. Constitutive changes in carotenoid concentration were significantly correlated with both isoprene emissions and PRI, suggesting that the relationship between PRI and isoprene emissions is significantly influenced by constitutive pigment changes. Consequently knowledge regarding how isoprene emissions are affected by both longer term changes in total carotenoid concentrations and shorter term dynamic adjustments of LUE is required to facilitate interpretation of PRI for monitoring isoprene emissions. PMID- 26249647 TI - Whey protein gel composites in the diet of goats increased the omega-3 and omega 6 content of milk fat. AB - Previously, feeding whey protein gels containing polyunsaturated fatty acids (PUFA) reduced their rumen biohydrogenation and increased their concentration in milk fat of Holstein cows. Our objective was to test the efficacy of whey protein isolate (WPI) gels produced in a steam tunnel as a method to alter the fatty acid (FA) composition of the milk lipids. Four primiparous Lamancha goats in midlactation were fed three diets in a 3 * 4 Latin square design. The WPI gels were added to a basal concentrate mix that contained one of three lipid sources: (i) 100% soya bean oil (S) to create (WPI/S), (ii) a 1:1 (wt/wt) mixture of S and linseed (L) oil to create (WPI/SL), or (iii) 100% L to create (WPI/L). Periods were 22 days with the first 10 days used as an adjustment phase followed by a 12 day experimental phase. During the adjustment phase, all goats received a rumen available source of lipid, yellow grease, to provide a baseline for milk FA composition. During the experimental phase, each goat received its assigned WPI. Milk FA concentration of C18:2 n-6 and C18:3 n-3 reached 9.3 and 1.64 g/100 g FA, respectively, when goats were fed WPI/S. Feeding WPI/SL increased the C18:2 n-6 and C18:3 n-3 concentration to 6.22 and 4.36 g/100 g FA, and WPI/L increased C18:2 n-6 and C18:3 n-3 to 3.96 and 6.13 g/100 g FA respectively. The adjusted transfer efficiency (%) of C18:3 n-3 to milk FA decreased significantly as dietary C18:3 n-3 intake increased. Adjusted transfer efficiency for C18:2 n-6 did not change with increasing intake of C18:2 n-6. The WPI gels were effective at reducing rumen biohydrogenation of PUFA; however, we observed a change in the proportion increase of C18:3 n-3 in milk FA suggesting possible regulation of n-3 FA to the lactating caprine mammary gland. PMID- 26249648 TI - Erratum to: Lipid Peroxidation-Antioxidant Defense System during Toxic Liver Damage and Its Correction with a Composite Substance Containing Selenium and Arabinogalactan. PMID- 26249649 TI - Pinch grip strength as an alternative assessment to hand grip strength for assessing muscle strength in patients with chronic kidney disease treated by haemodialysis: a prospective audit. AB - BACKGROUND: Muscle weakness and wasting are prevalent in haemodialysis (HD) patients, and substantially increase mortality. Convenient, readily applicable screening tests for routine clinical practice are required. Hand grip strength (HGS) has been validated in HD patients but cannot be readily measured during a HD session. On the other hand, pinch strength (PS) can be measured during a HD session, and we aimed to compare the two methods of assessing muscle strength. METHODS: We measured pinch strength (PS) and hand grip strength (HGS) in 209 adult HD patients. The mean of three measurements was taken. RESULTS: The mean (SD) HGS was 15.3 (7.1) kg, compared to a PS of 2.9 (1.5) kg (P < 0.0001). HGS was weaker in the arteriovenous fistula (AVF) arm than the non-AVF arm [14.01 (6.9) versus 16.4 (7.1) kg (P < 0.001)], as was PS [AVF arm 2.63 (1.30) versus 3.08 (1.65) kg (P < 0.001)]. We found a strong correlation between HGS and PS (r = 0.82, P < 0.001. Comparing HGS and PS, we found a mean difference of 12.08 kg (Bland-Altman analysis), although the absolute difference was smaller with lower HGS. CONCLUSIONS: We found PS to be highly correlated with HGS, and was more convenient for patients because PS could be readily performed during the HD session. PS may provide an easier screening tool for muscle strength than HGS for dialysis patients, although further validation studies are required. PMID- 26249650 TI - Inhibiting sorbent stripping by designing a sorbent-packed porous probe for headspace solid-phase microextraction. AB - To prevent the stripping of coating sorbents in headspace solid-phase microextraction, a porous extraction probe with packed sorbent was introduced by using a porous stainless steel needle tube and homemade sol-gel sorbents. The traditional stainless-steel needle tube was punched by a laser to obtain two rows of holes, which supply a passageway for analyte vapor during extraction and desorption. The sorbent was prepared by a traditional sol-gel method with both poly(ethylene glycol) and hydroxy-terminated silicone oil as coating ingredients. Eight polycyclic aromatic hydrocarbons and six benzene series compounds were used as illustrative semi-volatile and volatile organic compounds in sequence to verify the extraction performance of this porous headspace solid-phase microextraction probe. It was found that the analysis method combining a headspace solid-phase microextraction probe and gas chromatography with mass spectrometry yielded determination coefficients of no less than 0.985 and relative standard deviations of 4.3-12.4%. The porous headspace solid-phase microextraction probe showed no decrease of extraction ability after 200 uses. These results demonstrate that the packed extraction probe with porous structure can be used for headspace solid-phase microextraction. This novel design may overcome both the stripping and breakage problems of the conventional coating fiber. PMID- 26249651 TI - Consumer peach preferences and purchasing behavior: a mixed methods study. AB - BACKGROUND: Peaches (Prunus persica (L.) Stokes) are grown in several regions throughout the USA, are eaten fresh, and used as ingredients in value-added processed products. An Internet survey was conducted to investigate Mid-Atlantic consumers' fresh and processed peach purchasing behaviors, and whether packaging certain numbers of peaches together, providing information about nutritional content, and other factors would increase purchases. Additionally, laboratory based sensory testing was used to better understand peel color, texture, sweetness, sourness, and flavor preferences for cultivars commonly grown in the Mid-Atlantic region. RESULTS: Irrespective of fresh peach consumption frequency, certain value-added products were of interest. For some products, interest in purchasing was higher than reported purchasing behavior. Preference for certain fresh peach characteristics, such as peel color, differed between less frequent fresh peach consumers and those who consumed fresh peaches more often. Of the four peach cultivars included in the sensory test, most were liked; however, there were some cultivar differences pertaining to color, texture, sweetness, tartness, and flavor liking. CONCLUSION: Potential marketing strategies can be developed based on frequency of fresh peach consumption and household demographics. Data can be used to select peaches that best appeal to consumers. (c) 2015 Society of Chemical Industry. PMID- 26249652 TI - The Araguaia River as an Important Biogeographical Divide for Didelphid Marsupials in Central Brazil. AB - The riverine barrier model suggests that rivers play a significant role in separating widespread organisms into isolated populations. In this study, we used a comparative approach to investigate the phylogeography of 6 didelphid marsupial species in central Brazil. Specifically, we evaluate the role of the mid-Araguaia River in differentiating populations and estimate divergence time among lineages to assess the timing of differentiation of these species, using mitochondrial DNA sequence data. The 6 didelphid marsupials revealed different intraspecific genetic patterns and structure. The 3 larger and more generalist species, Didelphis albiventris, Didelphis marsupialis, and Philander opossum, showed connectivity across the Araguaia River. In contrast the genetic structure of the 3 smaller and specialist species, Gracilinanus agilis, Marmosa (Marmosa) murina, and Marmosa (Micoureus) demerarae was shaped by the mid-Araguaia. Moreover, the split of eastern and western bank populations of the 2 latter species is consistent with the age of Araguaia River sediments formation. We hypothesize that the role of the Araguaia as a riverine barrier is linked to the level of ecological specialization among the 6 didelphid species and differences in their ability to cross rivers or disperse through the associated habitat types. PMID- 26249653 TI - Alloantibody developed in a factor XIII A subunit deficient patient during substitution therapy; characterization of the antibody. AB - INTRODUCTION: In factor XIII A subunit (FXIIIA) deficiency, the development of alloantibodies is extremely rare. Only four reports have been published and the antibodies were not characterized. AIM: The aim of this study was to describe the clinical course and the laboratory diagnosis of a FXIII-A deficient patient who developed alloantibodies. METHODS: FXIII activity was assessed with an ammonia release assay. FXIII-A, FXIII B subunit (FXIII-B) and the complex plasma FXIII (FXIII-A2 B2 ) antigens were determined by ELISA. The causative mutation was detected by fluorescent DNA sequencing. The binding of alloantibody to FXIII-A2 and FXIII-A2 B2 was studied by surface plasmon resonance. The cleavage of FXIII-A by thrombin and Ca2+ -induced activation of thrombin-cleaved FXIII were followed by western blotting and activity measurement, respectively. RESULTS: FXIII activity, FXIII-A2 B2 and FXIII-A antigens were below the limit of detection in the patient's plasma. The severe FXIII-A deficiency was due to a novel homozygous mutation resulting in early stop codon (c.127C>T, p.Gln42STOP). The alloantibody bound to FXIII-A2 and FXIII-A2 B2 with equally high affinity (Kd ~10-8 ). It accelerated the elimination of administered FXIII concentrate from the circulation, interfered with thrombin and Ca2+ -induced activation and inhibited FXIII activity. Attempts to eliminate the alloantibody resulted only in transient improvement. Patient developed intracerebral haemorrhage after a minor trauma and died in spite of aggressive replacement therapy with FXIII concentrate. CONCLUSION: The anti-FXIII-A alloantibody caused an unmanageable bleeding complication. The antibody was of combined subtype which accelerated the elimination of FXIII and exerted a multiple inhibitory effect on FXIII activation/activity. PMID- 26249654 TI - Improvement of (R)-3-hydroxybutyric acid secretion during Halomonas sp. KM-1 cultivation with saccharified Japanese cedar by the addition of urea. AB - Japanese cedar (Cryptomeria japonica) is a major species in artificial Japanese forests. The Halomonas sp. KM-1 was recently isolated and found to grow effectively on saccharified Japanese cedar wood, resulting in the intracellular storage of poly-(R)-3-hydroxybutyric acid (PHB) under aerobic conditions. Under microaerobic conditions, the extracellular secretion of (R)-3-hydroxybutyric acid ((R)-3-HB) led to the degradation of intracellular PHB. In this study, the production of PHB and the secretion of (R)-3-HB using saccharified Japanese cedar were much improved in cultures that were grown in the presence of urea. The level of intracellular PHB production after 36 h under aerobic cultivation was 23.6 g l(-1) ; after shifting to microaerobic conditions for 24 h, the (R)-3-HB concentration in the medium reached 21.1 g l(-1) . Thus, KM-1 efficiently utilizes saccharified Japanese cedar to produce PHB and secretes (R)-3-HB, making it a practical candidate for use in the industrial production of (R)-3-HB. SIGNIFICANCE AND IMPACT OF THE STUDY: Japanese cedar is a major species grown in artificial Japanese forests, and its thinning is crucial for the health of artificial forests and the Japanese economy. Halomonas sp. KM-1 grew effectively on saccharified Japanese cedar wood, resulting in intracellular storage of poly (R)-3-hydroxybutyric acid (PHB) under aerobic conditions. Under microaerobic conditions, extracellular secretion of (R)-3-hydroxybutyric acid ((R)-3-HB) caused intracellular PHB degradation. (R)-3-HB is a chiral compound that is useful in the chemical, health food and pharmaceutical industries. The production of PHB and secretion of (R)-3-HB using saccharified wood was dramatically improved, which may positively affect its future industrial production. PMID- 26249655 TI - Statistical Modeling of Fire Occurrence Using Data from the Tohoku, Japan Earthquake and Tsunami. AB - In this article, we develop statistical models to predict the number and geographic distribution of fires caused by earthquake ground motion and tsunami inundation in Japan. Using new, uniquely large, and consistent data sets from the 2011 Tohoku earthquake and tsunami, we fitted three types of models-generalized linear models (GLMs), generalized additive models (GAMs), and boosted regression trees (BRTs). This is the first time the latter two have been used in this application. A simple conceptual framework guided identification of candidate covariates. Models were then compared based on their out-of-sample predictive power, goodness of fit to the data, ease of implementation, and relative importance of the framework concepts. For the ground motion data set, we recommend a Poisson GAM; for the tsunami data set, a negative binomial (NB) GLM or NB GAM. The best models generate out-of-sample predictions of the total number of ignitions in the region within one or two. Prefecture-level prediction errors average approximately three. All models demonstrate predictive power far superior to four from the literature that were also tested. A nonlinear relationship is apparent between ignitions and ground motion, so for GLMs, which assume a linear response-covariate relationship, instrumental intensity was the preferred ground motion covariate because it captures part of that nonlinearity. Measures of commercial exposure were preferred over measures of residential exposure for both ground motion and tsunami ignition models. This may vary in other regions, but nevertheless highlights the value of testing alternative measures for each concept. Models with the best predictive power included two or three covariates. PMID- 26249656 TI - Excessive bleeding predictors after cardiac surgery in adults: integrative review. AB - AIMS AND OBJECTIVES: To integrate literature data on the predictors of excessive bleeding after cardiac surgery in adults. BACKGROUND: Perioperative nursing care requires awareness of the risk factors for excessive bleeding after cardiac surgery to assure vigilance prioritising and early correction of those that are modifiable. DESIGN: Integrative literature review. METHODS: Articles were searched in seven databases. Seventeen studies investigating predictive factors for excessive bleeding after open-heart surgery from 2004-2014 were included. RESULTS: Predictors of excessive bleeding after cardiac surgery were: Patient related: male gender, higher preoperative haemoglobin levels, lower body mass index, diabetes mellitus, impaired left ventricular function, lower amount of prebypass thrombin generation, lower preoperative platelet counts, decreased preoperative platelet aggregation, preoperative platelet inhibition level >20%, preoperative thrombocytopenia and lower preoperative fibrinogen concentration. Procedure-related: the operating surgeon, coronary artery bypass surgery with three or more bypasses, use of the internal mammary artery, duration of surgery, increased cross-clamp time, increased cardiopulmonary bypass time, lower intraoperative core body temperature and bypass-induced haemostatic disorders. Postoperative: fibrinogen levels and metabolic acidosis. CONCLUSIONS: Patient related, procedure-related and postoperative predictors of excessive bleeding after cardiac surgery were identified. RELEVANCE TO CLINICAL PRACTICE: The predictors summarised in this review can be used for risk stratification of excessive bleeding after cardiac surgery. Assessment, documentation and case reporting can be guided by awareness of these factors, so that postoperative vigilance can be prioritised. Timely identification and correction of the modifiable factors can be facilitated. PMID- 26249657 TI - Ploidy manipulation and induction of alternate cleavage patterns through inhibition of centrosome duplication in the early zebrafish embryo. AB - BACKGROUND: Whole genome duplication is a useful genetic tool because it allows immediate and complete genetic homozygosity in gynogenetic offspring. A whole genome duplication method in zebrafish, Heat Shock, involves a heat pulse in the period 13-15 min postfertilization (mpf) to inhibit cytokinesis of the first mitotic cycle. However, Heat Shock produces a relatively low yield of gynogenotes. RESULTS: A heat pulse at a later time point during the first cell cycle (22 mpf, HS2) results in a high (>80%) frequency of embryos exhibiting a precise one-cell division stall during the second cell cycle, inducing whole genome duplication. Coupled with haploid production, HS2 generates viable gynogenetic diploids with yields up to 4 times higher than those achieved through standard Heat Shock. The cell cycle delay also causes blastomere cleavage pattern variations, supporting a role for cytokinesis in spindle orientation during the following cell cycle. CONCLUSIONS: Our studies provide a new tool for whole genome duplication, induced gynogenesis, and cleavage pattern alteration in zebrafish, based on a time period before the initiation of cell division that is sensitive to temperature-mediated interference with centrosome duplication. Targeting of this period may also facilitate genetic and developmental manipulations in other organisms. PMID- 26249658 TI - Multiple CD163(+) adult xanthogranuloma associated with myelodysplastic syndrome. PMID- 26249659 TI - Factors Influencing Mental Health Screening and Treatment Among Women in a Rural South Central Appalachian Primary Care Clinic. AB - PURPOSE: Some of the most significant mental health concerns among US adults are depression, anxiety, substance abuse, and intimate partner violence. These concerns represent an ever-growing portion of the primary care population, especially in rural areas. However, few studies have examined factors influencing screening and treatment of these concerns by primary care providers, particularly in Appalachia. This study explores barriers and facilitators to mental health screening and treatment among women at a rural, primary care clinic in Appalachia. METHODS: Eighteen patients and 4 providers were interviewed face-to face. Thematic analysis was used to identify emergent themes. FINDINGS: Patients identified 3 barriers (stigma, lack of support, and lack of education) and 2 facilitators (integrated care and positive experiences with providers). Providers identified 4 barriers (operational barriers, mental health competence, predicted patient reactions, and patient attitudes) and 3 facilitators (clinic characteristics, provider characteristics, and patient and provider education). Generally, patients focused more on individual and social factors influencing mental health service use, while providers were more aware of training gaps, logistical factors at the clinic, and systemic issues within the larger health care system. Both participant types emphasized specific interpersonal qualities and the importance of integrated services. CONCLUSIONS: Screening and treatment may be influenced by the availability and advertisement of integrated services, institutional support, strong patient-provider relationships, and provider training and experience. For rural south central Appalachia women, limited mental health resources may make these factors even more salient. PMID- 26249660 TI - A case of a choroid plexus papilloma mimicking a hemangioblastoma--letter to the editor. PMID- 26249661 TI - The supraorbital keyhole approach: how I do it. PMID- 26249662 TI - Relative stability and reducibility of CeO2 and Rh/CeO2 species on the surface and in the cavities of gamma-Al2O3: a periodic DFT study. AB - We report the structure and stability of ceria units deposited on the surface of gamma-Al2O3 or incorporated in its cavities, as determined by periodic density functional calculations. Ceria species are modeled as CeO2 or Ce2O4 moieties or as a small nanoparticle, Ce13O26, on the (100) and (001) surfaces of a gamma Al2O3 slab. Among the studied structures the incorporation of Ce(4+) ions in cavities of gamma-Al2O3 is favored with respect to the ions on the surface only in subsurface cavities of the (100) surface. The calculations also suggested that formation of a surface layer of ceria on the (100) alumina surface is preferable compared to three-dimensional moieties. The deposition of a small ceria nanoparticle on (100) and (001) surfaces of gamma-Al2O3 reduces the energy for oxygen vacancy formation to an essentially spontaneous process on the (100) surface, which may be the reason for the experimentally detected large fraction of Ce(3+) ions in the CeO2/gamma-Al2O3 systems. The deposition of a single rhodium atom or RhO unit in some of the structures with a CeO2 unit and Ce13O26 showed that spontaneous electron transfer from rhodium to cerium ion occurs, which results in reduction of Ce(4+) to Ce(3+) and the oxidation of rhodium. Only in the presence of deposited rhodium atoms, the incorporated cerium ions can be reduced to Ce(3+). PMID- 26249663 TI - Acceleration of Monte Carlo simulation of photon migration in complex heterogeneous media using Intel many-integrated core architecture. AB - Over two decades, the Monte Carlo technique has become a gold standard in simulation of light propagation in turbid media, including biotissues. Technological solutions provide further advances of this technique. The Intel Xeon Phi coprocessor is a new type of accelerator for highly parallel general purpose computing, which allows execution of a wide range of applications without substantial code modification. We present a technical approach of porting our previously developed Monte Carlo (MC) code for simulation of light transport in tissues to the Intel Xeon Phi coprocessor. We show that employing the accelerator allows reducing computational time of MC simulation and obtaining simulation speed-up comparable to GPU. We demonstrate the performance of the developed code for simulation of light transport in the human head and determination of the measurement volume in near-infrared spectroscopy brain sensing. PMID- 26249664 TI - From cadavers to clinical practice: the anatomy of lifelong learning. AB - BACKGROUND: Much has been postulated about the perceived deterioration of anatomy knowledge amongst graduates. Little is known about levels of confidence in, and educational needs concerning, clinical anatomy knowledge amongst foundation year doctors. AIMS: To establish foundation year doctors' perceptions of anatomy related to: importance to career, confidence in anatomy knowledge and its application, preferred methods of teaching. Secondarily, to determine impact of an integrated clinical approach to anatomy teaching on foundation year doctors' level of knowledge and confidence in its clinical application of anatomy. METHODS: A course teaching anatomy through common surgeries and related radiology was delivered to foundation year doctors. A pre- and post-course assessment based on anatomy competence score assessed holistic knowledge acquisition. Foundation year doctors' perceptions of anatomy and course satisfaction were measured through questionnaire. RESULTS: Confidence in applying anatomy knowledge was low. The average pre- and post-course assessment score increased from 55% to 81%; 92.86% felt an integrated clinical approach to anatomy teaching improved their confidence on the subject and 58.62% felt it improved their clinical skills. CONCLUSION: This study identified a need for ongoing educational support for foundation year doctors regarding anatomy teaching. An integrated clinical approach to teaching anatomy proved both highly relevant and popular, as well as an effective teaching approach. PMID- 26249665 TI - Association between changes in brain microstructure and cognition in older subjects at increased risk for vascular disease. AB - BACKGROUND: The purpose of this study is to investigate whether changes in brain microstructure, detected by magnetization transfer imaging, are associated with cognition in older subjects at increased risk for vascular disease. METHODS: One hundred ninety three nondemented subjects (105 men, mean age 77 +/- 3 years) from the Prospective Study of Pravastatin in the Elderly at Risk were included. To assess cross-sectional associations between magnetization transfer ratio (MTR) peak height and cognitive test scores, general linear model multivariate analysis was performed. Models were adjusted for age, sex, education level, vascular risk factors, individual white matter lesion volume, and brain atrophy. A repeated measures general linear model was used to investigate whether MTR peak height relates to cognitive test performance at baseline and 3.3-year follow-up. RESULTS: Cross-sectionally, MTR peak height was associated with performance on the STROOP test (unstandardized beta = -0.27, p = 0.045), delayed Picture Word Learning (PWL) test (beta = 0.48, p = 0.007), and the Letter Digit Coding test (beta = 1.1, p = 0.006). Repeated measures general linear model analysis showed that individuals with low MTR peak height at baseline performed worse on the STROOP test compared to subjects with intermediate MTR peak height (mean time to complete the test at baseline and follow-up, lower versus middle tertile of MTR peak height: 61.6 versus 52.7 s, p = 0.019) or compared to subjects with high MTR peak height (p = 0.046). Similarly, low MTR peak height was associated with worse performance on the immediate (lower versus middle tertile, p = 0.023; lower versus higher tertile, p = 0.032) and delayed PWL test (lower versus middle, p = 0.004; lower versus higher, p = 0.012) at baseline and follow-up testing. CONCLUSIONS: MTR peak height is associated with cognitive function in older subjects at increased risk for vascular disease. PMID- 26249666 TI - Remarkable repellency of Ligusticum sinense (Umbelliferae), a herbal alternative against laboratory populations of Anopheles minimus and Aedes aegypti (Diptera: Culicidae). AB - BACKGROUND: For personal protection against mosquito bites, user-friendly natural repellents, particularly from plant origin, are considered as a potential alternative to applications currently based on synthetics such as DEET, the standard chemical repellent. This study was carried out in Thailand to evaluate the repellency of Ligusticum sinense hexane extract (LHE) against laboratory Anopheles minimus and Aedes aegypti, the primary vectors of malaria and dengue fever, respectively. METHODS: Repellent testing of 25% LHE against the two target mosquitoes; An. minimus and Ae. aegypti, was performed and compared to the standard repellent, DEET, with the assistance of six human volunteers of either sex under laboratory conditions. The physical and biological stability of LHE also was determined after keeping it in conditions that varied in temperature and storage time. Finally, LHE was analysed chemically using the qualitative GC/MS technique in order to demonstrate a profile of chemical constituents. RESULTS: Ethanol preparations of LHE, with and without 5% vanillin, demonstrated a remarkably effective performance when compared to DEET in repelling both An. minimus and Ae. aegypti. While 25% LHE alone provided median complete-protection times against An. minimus and Ae. aegypti of 11.5 (9.0-14.0) hours and 6.5 (5.5 9.5) hours, respectively, the addition of 5% vanillin increased those times to 12.5 (9.0-16.0) hours and 11.0 (7.0-13.5) hours, respectively. Correspondingly, vanillin added to 25% DEET also extended the protection times from 11.5 (10.5 15.0) hours to 14.25 (11.0-18.0) hours and 8.0 (5.0-9.5) hours to 8.75 (7.5-11.0) hours against An. minimus and Ae. aegypti, respectively. No local skin reaction such as rash, swelling or irritation was observed during the study period. Although LHE samples kept at ambient temperature (21-35 degrees C), and 45 degrees C for 1, 2 and 3 months, demonstrated similar physical characteristics, such as similar viscosity and a pleasant odour, to those that were fresh and stored at 4 degrees C, their colour changed from light- to dark-brown. Interestingly, repellency against Ae. aegypti of stored LHE was presented for a period of at least 3 months, with insignificantly varied efficacy. Chemical analysis revealed that the main components of LHE were 3-N-butylphthalide (31.46%), 2, 5-dimethylpyridine (21.94%) and linoleic acid (16.41%), constituting 69.81% of all the extract composition. CONCLUSIONS: LHE with proven repellent efficacy, no side effects on the skin, and a rather stable state when kept in varied conditions is considered to be a potential candidate for developing a new natural alternative to DEET, or an additional weapon for integrated vector control when used together with other chemicals/measures. PMID- 26249668 TI - Bioinspired Synthesis of Well-Ordered Layered Organic-Inorganic Nanohybrids: Mimicking the Natural Processing of Nacre by Mineralization of Block Copolymer Templates. AB - The unique mechanical performance of nacre, the pearly internal layer of shells, is highly dependent on its complex morphology. Inspired by the structure of nacre, the fabrication of well-ordered layered inorganic-organic nanohybrids is presented herein. This biomimetic approach includes the use of a block copolymer template, consisting of hydrophobic poly(vinylidene fluoride) (PVDF) lamellae covered with hydrophilic poly(methacrylic acid) (PMAA), to direct silica (SiO2 ) mineralization. The resulting PVDF/PMAA/SiO2 nanohybrid material resembles biogenic nacre with respect to its well-ordered and layered nanostructure, alternating organic-inorganic phases, macromolecular template, and mild processing conditions. PMID- 26249667 TI - MRP8/14 serum levels as a predictor of response to starting and stopping anti-TNF treatment in juvenile idiopathic arthritis. AB - INTRODUCTION: Approximately 30% of juvenile idiopathic arthritis (JIA) patients fail to respond to anti-TNF treatment. When clinical remission is induced, some patients relapse after treatment has been stopped. We tested the predictive value of MRP8/14 serum levels to identify responders to treatment and relapse after discontinuation of therapy. METHODS: Samples from 88 non-systemic JIA patients who started and 26 patients who discontinued TNF-blockers were analyzed. MRP8/14 serum levels were measured by in-house MRP8/14 ELISA and by Buhlmann Calprotectin ELISA at start of anti-TNF treatment, within 6 months after start and at discontinuation of etanercept in clinical remission. Patients were categorized into responders (ACRpedi >= 50 and/or inactive disease) and non-responders (ACRpedi < 50) within six months after start, response was evaluated by change in JADAS-10. Disease activity was assessed within six months after discontinuation. RESULTS: Baseline MRP8/14 levels were higher in responders (median MRP8/14 of 1466 ng/ml (IQR 1045-3170)) compared to non-responders (median MRP8/14 of 812 (IQR 570-1178), p < 0.001). Levels decreased after start of treatment only in responders (p < 0.001). Change in JADAS-10 was correlated with baseline MRP8/14 levels (Spearman's rho 0.361, p = 0.001). Patients who flared within 6 months after treatment discontinuation had higher MRP8/14 levels (p = 0.031, median 1025 ng/ml (IQR 588-1288)) compared to patients with stable remission (505 ng/ml (IQR 346-778)). Results were confirmed by Buhlmann ELISA with high reproducibility but different overall levels. CONCLUSION: High levels of baseline MRP8/14 are associated with good response to anti-TNF treatment, whereas elevated MRP8/14 levels at discontinuation of etanercept are associated with higher chance to flare. PMID- 26249669 TI - Parental perceptions of avoidability of their child's emergency department visit. AB - OBJECTIVES: To identify the factors associated with paediatric emergency department (ED) visits and parental perceptions of the avoidability of their child's ED visit. DESIGN: Cross-sectional study by performing secondary analysis of 2010-2011 Iowa Child and Family Household Health Survey data. SETTING: State wide representative population-based sample of families with at least one child in the state of Iowa in the USA. PATIENTS/PARTICIPANTS: Among the eligible households, 2386 families completed the survey, yielding a cooperation rate of 80%. EXPOSURE/INTERVENTION: Presence of a medical home. MAIN OUTCOME MEASURES: Child visiting an ED in the past year; parents believing that ED care could have been provided in a primary-care setting. RESULTS: Among children who needed medical care in the past year, 26% visited an ED. Younger children, non-Hispanic black children, non-Hispanic others, children whose parents were not married, children who were from food-insecure households and had poorer health status were more likely to visit an ED. Having a medical home was not associated with ED visits (OR=0.80, 95% CI 0.61 to 1.04), even after stratifying by the child's health status. About 69% of parents who took their child to an ED agreed that ED care could have been provided in a primary-care setting. Parents of children with public insurance, those who were not referred to the ED and those who could not get routine care appointments were more likely to report a primary-care preventable ED visit. CONCLUSIONS: The majority of parents believed that paediatric ED visits could be avoided if adequate primary-care alternatives were available. Expanding access to primary care could lead to a reduction in avoidable ED visits by children. PMID- 26249670 TI - Porphyromonas gingivalis biofilm formation in different titanium surfaces, an in vitro study. AB - OBJECTIVE: The aim of this work was to evaluate the biofilm formation of Porphyromonas gingivalis on disks of titanium (Ti) grade 4 (G4) and Ti-6Al-4V alloy grade 5 (G5) with different surface topographies. MATERIALS AND METHODS: Porphyromonas gingivalis ATCC 33277 was used to develop an in vitro mature biofilm on a total of 96 disk-shaped specimens of laser-treated (L), sandblasted (S), and machined (M) surfaces of Ti G4 and Ti G5. Surface roughness (Ra) and the wettability contact angle (WCA) were measured to characterize the surface of the specimens. The bacterial biofilm was evaluated by biomass quantification, bacterial viability, visualization of the biofilm extracellular matrix, and bacterial cell count. Data were analyzed using one-way ANOVA and Holm-Sidak tests and expressed as mean +/- standard deviation. RESULTS: The Ra for the L group was 0.10 (+/-0.07) MUm inside the craters and 0.40 (+/-0.08) MUm in the area surrounding the craters resulting the smoothest (P < 0.05) in respect to the S group (1.30 +/- 0.61 MUm) and the M group (0.75 +/- 0.23 MUm). The L group showed a higher WCA than S and M groups for both G4 (109.9 degrees +/- 6.6) and G5 (104.2 degrees +/- 5.9) materials (P < 0.05). The L group displayed both the less P. gingivalis bacterial biomass (0.38 +/- 0.01 for G4; 0.62 +/- 0.02 for G5) that was significant in respect to G4-S (P < 0.001), G4-M (P < 0.001), and G5-M (P = 0.001) and the less total cell number (215 +/- 18 for G4 and 244 +/- 9 for G5) than S and M groups for both G4 and G5 materials (P < 0.01). CONCLUSION: Within the limits of the present study, the results showed that G4-L appears to be significantly efficient in the reduction of the P. gingivalis biofilm formation. PMID- 26249672 TI - Electrophilic N-Trifluoromethylation of N-H Ketimines. AB - A direct N-trifluoromethylation method has been developed by the use of the in situ generated [ArICF3](+) species as the electrophilic trifluoromethyl source. Upon treatment of N-H ketimines with Ruppert-Prakash reagent in the presence of PhI(OAc)2 and KF, or with Togni's reagent II catalyzed by copper salt, N trifluoromethylated imine products were obtained in moderate to good yields. PMID- 26249671 TI - Effects of raltegravir combined with tenofovir/emtricitabine on body shape, bone density, and lipids in African-Americans initiating HIV therapy. AB - BACKGROUND: Raltegravir (RAL) plus tenofovir/emtricitabine (TDF/FTC) is a recommended initial antiretroviral regimen. A substantial proportion of persons diagnosed with HIV infection and starting antiretrovirals in the U.S. are African American (AA); however, the effects of this regimen on metabolic parameters have largely been studied in white patients. METHODS: Single-arm, open-label study of untreated AA HIV-infected patients administered RAL with TDF/FTC for 104 weeks. Changes in fasting lipids, insulin resistance, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT), limb and trunk fat, and bone mineral density (BMD) were assessed at weeks 56 and 104. RESULTS: Thirty (85% men) participants were included. Median entry characteristics included age of 38 years, CD4 323 cells/mm3, HIV RNA level 29,245 copies/ml, and body mass index 28.1 kg/m2. At 56 and 104 weeks, significant increases in VAT, trunk fat, limb fat, and overall fat were observed. Bone mineral density decreased by 1.5% by week 104.There were no significant changes in non-HDL-cholesterol, fasting triglycerides, or insulin resistance. A median CD4 cell count increase of 318 cells/mm3 (IQR 179, 403; full range 40, 749) (P<0.001) was observed. Assuming missing=failure, 78 and 70% had HIV RNA levels<40 copies/ml at weeks 56 and 104, respectively. There were no treatment-related discontinuations and no new antiretroviral resistance mutations were detected. CONCLUSIONS: In this cohort of AAs, initiation of RAL with TDF/FTC was associated with significant general increases in fat. Significant changes in lipids or insulin resistance were not observed and there was a small decline in BMD. Therapy was well tolerated and effective. These results are consistent with findings of studies of initial antiretroviral therapy in racially diverse cohorts and inform treatment selection for AA patients starting therapy for HIV infection. PMID- 26249673 TI - Nanometre-scale probing of spin waves using single-electron spins. AB - Pushing the frontiers of condensed-matter magnetism requires the development of tools that provide real-space, few-nanometre-scale probing of correlated-electron magnetic excitations under ambient conditions. Here we present a practical approach to meet this challenge, using magnetometry based on single nitrogen vacancy centres in diamond. We focus on spin-wave excitations in a ferromagnetic microdisc, and demonstrate local, quantitative and phase-sensitive detection of the spin-wave magnetic field at ~50 nm from the disc. We map the magnetic-field dependence of spin-wave excitations by detecting the associated local reduction in the disc's longitudinal magnetization. In addition, we characterize the spin noise spectrum by nitrogen-vacancy spin relaxometry, finding excellent agreement with a general analytical description of the stray fields produced by spin-spin correlations in a 2D magnetic system. These complementary measurement modalities pave the way towards imaging the local excitations of systems such as ferromagnets and antiferromagnets, skyrmions, atomically assembled quantum magnets, and spin ice. PMID- 26249674 TI - Optimal breastfeeding practices and infant and child mortality: a systematic review and meta-analysis. AB - AIM: To synthesise the evidence for effects of optimal breastfeeding on all-cause and infection-related mortality in infants and children aged 0-23 months. METHODS: We conducted a systematic review to compare the effect of predominant, partial or nonbreastfeeding versus exclusive breastfeeding on mortality rates in the first six months of life and effect of no versus any breastfeeding on mortality rates between 6 and 23 months of age. A systematic literature search was conducted in PubMed, Cochrane CENTRAL and CABI. RESULTS: The risk of all cause mortality was higher in predominantly (RR 1.5), partially (RR 4.8) and nonbreastfed (RR14.4) infants compared to exclusively breastfed infants 0-5 months of age. Children 6-11 and 12-23 months of age who were not breastfed had 1.8- and 2.0-fold higher risk of mortality, respectively, when compared to those who were breastfed. Risk of infection-related mortality in 0-5 months was higher in predominantly (RR 1.7), partially (RR 4.56) and nonbreastfed (RR 8.66) infants compared to exclusive breastfed infants. The risk was twofold higher in nonbreastfed children when compared to breastfed children aged 6-23 months. CONCLUSION: The findings underscore the importance of optimal breastfeeding practices during infancy and early childhood. PMID- 26249675 TI - Bleb-related infection revisited: a literature review. AB - Bleb-related infection (BRI) is one of the serious complications of glaucoma filtering surgery. This literature review is aimed at the evaluation of recent studies related to BRI. The review presented and discussed risk factors, and clinical and laboratory diagnosis emphasizing advances in diagnostic techniques to detect and distinguish the disease as well as to initiate immediate intensive antibacterial treatment. Clinical features of recognized prognostic factors of visual outcome were also presented. The studies showed that the prognosis of blebitis is usually good, unless infection has progressed to endophthalmitis that would signify a poorer prognosis. Despite prompt and intensive treatment of patients with bleb-related endophthalmitis, the outcomes remain unsatisfactory especially with virulent organisms and low initial visual acuity. It has been recommended that early detection and treatment of risk factors and thorough patient education are indispensable in ensuring best prognosis in post trabeculectomy patients. PMID- 26249676 TI - Genetic underpinnings of left superior temporal gyrus thickness in patients with schizophrenia. AB - OBJECTIVES: Schizophrenia is a highly disabling psychiatric disorder with a heterogeneous phenotypic appearance. We aimed to further the understanding of some of the underlying genetics of schizophrenia, using left superior temporal gyrus (STG) grey matter thickness reduction as an endophenoptype in a genome-wide association (GWA) study. METHODS: Structural magnetic resonance imaging (MRI) and genetic data of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia were used to analyse the interaction effects between 1,067,955 single nucleotide polymorphisms (SNPs) and disease status on left STG thickness in 126 healthy controls and 113 patients with schizophrenia. We next used a pathway approach to detect underlying pathophysiological pathways that may be related to schizophrenia. RESULTS: No SNP by diagnosis interaction effect reached genome-wide significance (5 * 10-8) in our GWA study, but 10 SNPs reached P-values less than 10-6. The most prominent pathways included those involved in insulin, calcium, PI3K-Akt and MAPK signalling. CONCLUSIONS: Our strongest findings in the GWA study and pathway analysis point towards an involvement of glucose metabolism in left STG thickness reduction in patients with schizophrenia only. These results are in line with recently published studies, which showed an increased prevalence of psychosis among patients with metabolic syndrome-related illnesses including diabetes. PMID- 26249677 TI - In vivo protein crystallization in combination with highly brilliant radiation sources offers novel opportunities for the structural analysis of post translationally modified eukaryotic proteins. AB - During the last decade, the number of three-dimensional structures solved by X ray crystallography has increased dramatically. By 2014, it had crossed the landmark of 100 000 biomolecular structures deposited in the Protein Data Bank. This tremendous increase in successfully crystallized proteins is primarily owing to improvements in cloning strategies, the automation of the crystallization process and new innovative approaches to monitor crystallization. However, these improvements are mainly restricted to soluble proteins, while the crystallization and structural analysis of membrane proteins or proteins that undergo major post translational modifications remains challenging. In addition, the need for relatively large crystals for conventional X-ray crystallography usually prevents the analysis of dynamic processes within cells. Thus, the advent of high brilliance synchrotron and X-ray free-electron laser (XFEL) sources and the establishment of serial crystallography (SFX) have opened new avenues in structural analysis using crystals that were formerly unusable. The successful structure elucidation of cathepsin B, accomplished by the use of microcrystals obtained by in vivo crystallization in baculovirus-infected Sf9 insect cells, clearly proved that crystals grown intracellularly are very well suited for X-ray analysis. Here, methods by which in vivo crystals can be obtained, isolated and used for structural analysis by novel highly brilliant XFEL and synchrotron radiation sources are summarized and discussed. PMID- 26249678 TI - Structure of human collapsin response mediator protein 1: a possible role of its C-terminal tail. AB - Collapsin response mediator protein 1 (CRMP-1) is the first identified member of the CRMP family and is crucial for both the mediation of neuronal differentiation and in suppressing the invasion of lung cancer. The crystal structure of full length human CRMP-1 was determined at a resolution of 3 A. Human CRMP-1 comprises a tetrameric assembly; its overall structure is similar to that of mouse CRMP-1, but the measured electron density of the C-terminal residues 488-496 show a randomly coiled link that connects the protomers to each other, within which residues 497-572 are proteolytically susceptible in vivo. Deletion of residues 472-572 by thrombin in vitro not only releases a randomly coiled tail but also transduces observable structural changes of CRMP-1, as revealed by analytical size-exclusive chromatography and circular dichroism spectra. These results indicate a possible alternative role in CRMP dynamics and function. PMID- 26249679 TI - Crystallographic studies of the extracytoplasmic function sigma factor sigma(J) from Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis has multiple sigma factors which enable the bacterium to reprogram its transcriptional machinery under diverse environmental conditions. sigma(J), an extracytoplasmic function sigma factor, is upregulated in late stationary phase cultures and during human macrophage infection. sigma(J) governs the cellular response to hydrogen peroxide-mediated oxidative stress. sigma(J) differs from other canonical sigma factors owing to the presence of a SnoaL_2 domain at the C-terminus. sigma(J) crystals belonged to the tetragonal space group I422, with unit-cell parameters a = b = 133.85, c = 75.08 A. Diffraction data were collected to 2.16 A resolution on the BM14 beamline at the European Synchrotron Radiation Facility (ESRF). PMID- 26249680 TI - Structure of recombinant prolidase from Thermococcus sibiricus in space group P21221. AB - The crystal structure of recombinant prolidase from Thermococcus sibiricus was determined by X-ray diffraction at a resolution of 2.6 A and was found to contain a tetramer in the asymmetric unit. A protein crystal grown in microgravity using the counter-diffusion method was used for X-ray studies. The crystal belonged to space group P21221, with unit-cell parameters a = 97.60, b = 123.72, c = 136.52 A, alpha = beta = gamma = 90 degrees . The structure was refined to an Rcryst of 22.1% and an Rfree of 29.6%. The structure revealed flexible folding of the N terminal domain of the protein as well as high variability in the positions of the bound metal ions. The coordinates of the resulting model were deposited in the Protein Data Bank as entry 4rgz. PMID- 26249681 TI - Purification and crystallographic studies of a putative carbohydrate-binding module from the Ruminococcus flavefaciens FD-1 endoglucanase Cel5A. AB - Ruminant herbivores meet their carbon and energy requirements from a symbiotic relationship with cellulosome-producing anaerobic bacteria that efficiently degrade plant cell-wall polysaccharides. The assembly of carbohydrate-active enzymes (CAZymes) into cellulosomes enhances protein stability and enzyme synergistic interactions. Cellulosomes comprise diverse CAZymes displaying a modular architecture in which a catalytic domain is connected, via linker sequences, to one or more noncatalytic carbohydrate-binding modules (CBMs). CBMs direct the appended catalytic modules to their target substrates, thus facilitating catalysis. The genome of the ruminal cellulolytic bacterium Ruminococcus flavefaciens strain FD-1 contains over 200 modular proteins containing the cellulosomal signature dockerin module. One of these is an endoglucanase Cel5A comprising two family 5 glycoside hydrolase catalytic modules (GH5) flanking an unclassified CBM (termed CBM-Rf2) and a C-terminal dockerin. This novel CBM-Rf2 has been purified and crystallized, and data from cacodylate derivative crystals were processed to 1.02 and 1.29 A resolution. The crystals belonged to the orthorhombic space group P212121. The CBM-Rf2 structure was solved by a single-wavelength anomalous dispersion experiment at the As edge. PMID- 26249682 TI - Molecular cloning, overexpression, purification and crystallographic analysis of a GH43 beta-xylosidase from Bacillus licheniformis. AB - beta-Xylosidases (EC 3.2.1.37) catalyze the hydrolysis of short xylooligosaccharides into xylose, which is an essential step in the complete depolymerization of xylan, the major hemicellulosic polysaccharide of plant cell walls, and has great biotechnological relevance for the production of lignocellulose-based biofuels and the paper industry. In this study, a GH43 beta xylosidase identified from the bacterium Bacillus licheniformis (BlXylA) was cloned into the the pET-28a bacterial expression vector, recombinantly overexpressed in Escherichia coli BL21(DE3) cells and purified to homogeneity by metal-affinity and size-exclusion chromatography. The protein was crystallized in the presence of the organic solvent 2-methyl-2,4-pentanediol and a single crystal diffracted to 2.49 A resolution. The X-ray diffraction data were indexed in the monoclinic space group C2, with unit-cell parameters a = 152.82, b = 41.9, c = 71.79 A, beta = 91.7 degrees . Structural characterization of this enzyme will contribute to a better understanding of the structural requirements for xylooligosaccharide specificity within the GH43 family. PMID- 26249684 TI - Purification and crystallographic analysis of a FAD-dependent halogenase from Streptomyces sp. JCM9888. AB - A new FAD (flavin adenine dinucleotide)-dependent halogenase HalY from Streptomyces sp. JCM9888 was reported to be involved in the regioselective halogenation of adenine. HalY is a variant B FAD-dependent halogenase that is most similar to the halogenase PltA involved in pyoluteorin biosynthesis. This study reports the overexpression and purification of HalY with an N-terminal hexahistidine tag, followed by crystallization experiments and X-ray crystallographic analysis. HalY was purified as a monomer in solution and crystallized to give X-ray diffraction to a resolution of 1.7 A. The crystal belonged to the monoclinic space group P21, with unit-cell parameters a = 41.4, b = 113.4, c = 47.6 A, alpha = gamma = 90, beta = 107.4 degrees , and contained one monomer of HalY in the asymmetric unit, with a calculated Matthews coefficient of 2.3 A(3) Da(-1) and a solvent content of 46%. The structure of the halogenase CndH was used as a search model in molecular replacement to obtain the initial model of HalY. Manual model building and structure refinement of HalY are in progress. PMID- 26249683 TI - Structure of the response regulator ChrA in the haem-sensing two-component system of Corynebacterium diphtheriae. AB - ChrA is a response regulator (RR) in the two-component system involved in regulating the degradation and transport of haem (Fe-porphyrin) in the pathogen Corynebacterium diphtheriae. Here, the crystal structure of full-length ChrA is described at a resolution of 1.8 A. ChrA consists of an N-terminal regulatory domain, a long linker region and a C-terminal DNA-binding domain. A structural comparison of ChrA with other RRs revealed substantial differences in the relative orientation of the two domains and the conformation of the linker region. The structural flexibility of the linker could be an important feature in rearrangement of the domain orientation to create a dimerization interface to bind DNA during haem-sensing signal transduction. PMID- 26249685 TI - Crystallographic analysis of the N-terminal domain of Middle East respiratory syndrome coronavirus nucleocapsid protein. AB - The N-terminal domain of the nucleocapsid protein from Middle East respiratory syndrome coronavirus (MERS-CoV NP-NTD) contains many positively charged residues and has been identified to be responsible for RNA binding during ribonucleocapsid formation by the virus. In this study, the crystallization and crystallographic analysis of MERS-CoV NP-NTD (amino acids 39-165), with a molecular weight of 14.7 kDa, are reported. MERS-CoV NP-NTD was crystallized at 293 K using PEG 3350 as a precipitant and a 94.5% complete native data set was collected from a cooled crystal at 77 K to 2.63 A resolution with an overall Rmerge of 9.6%. The crystals were monoclinic and belonged to space group P21, with unit-cell parameters a = 35.60, b = 109.64, c = 91.99 A, beta = 101.22 degrees . The asymmetric unit contained four MERS-CoV NP-NTD molecules. PMID- 26249686 TI - Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome. AB - Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson-Crick base pairs in the genome. Pathogenic mutations in the MLH1 gene are associated with a predisposition to Lynch and Turcot's syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. The structure shares a high degree of similarity with previously determined prokaryotic MLH1 homologs; however, this structure affords a more accurate platform for the classification of MLH1 variants. PMID- 26249687 TI - The soluble Y115E-Y117E variant of human glutaminyl cyclase is a valid target for X-ray and NMR screening of inhibitors against Alzheimer disease. AB - Recent developments in molecular pathology and genetics have allowed the identification of human glutaminyl cyclase (hQC) among the abnormal proteins involved in many neurodegenerative disorders. Difficulties in obtaining large quantities of pure protein may limit the use of crystallographic screening for drug development on this target. Site-directed mutagenesis experiments have led to the identification of some solvent-exposed residues that are absolutely critical to achieve increased solubility and to avoid precipitation of the enzyme in inclusion bodies when expressed in Escherichia coli. The designed variant Y115E-Y117E has been found to be able to provide large amounts of monodisperse, pure hQC from an E. coli expression system. To validate the use of the artificial construct as a target for large-scale X-ray and NMR screening campaigns in the search for new inhibitors of hQC, the X-ray crystal structures of the hQC Y115E Y117E variant and of its adduct with the inhibitor PBD-150 were determined. PMID- 26249688 TI - Cloning, expression, purification and crystallographic studies of galectin-11 from domestic sheep (Ovis aries). AB - Galectins are an evolutionarily conserved family of proteins that translate glycan recognition into cellular effects. Galectin-11 is a unique member of the galectin family that is only expressed in ruminants such as sheep, goat and cattle and that plays a critical role in several important biological processes, such as reproduction and parasite-mediated innate immune responses. Currently, these two areas are of major importance for the sustainability of ruminant livestock production. Despite the emerging biological significance of galectin 11, no structural information is available. It is expected that structural studies will unravel the functional mechanisms of galectin-11 activity. Here, the expression, purification and crystallization of the ruminant-specific galectin-11 from domestic sheep and the collection of X-ray data to 2.0 A resolution are reported. PMID- 26249689 TI - Phormidium phycoerythrin forms hexamers in crystals: a crystallographic study. AB - The crystallographic analysis of a marine cyanobacterium (Phormidium sp. A09DM) phycoerythrin (PE) that shows distinct sequence features compared with known PE structures from cyanobacteria and red algae is reported. Phormidium PE was crystallized using the sitting-drop vapour-diffusion method with ammonium sulfate as a precipitant. Diffraction data were collected on the protein crystallography beamline at the Indus-2 synchrotron. The crystals diffracted to about 2.1 A resolution at 100 K. The crystals, with an apparent hexagonal morphology, belonged to space group P1, with unit-cell parameters a = 108.3, b = 108.4 A, c = 116.6 A, alpha = 78.94, beta = 82.50, gamma = 60.34 degrees . The molecular replacement solution confirmed the presence of 12 alphabeta monomers in the P1 cell. The Phormidium PE elutes as an (alphabeta)3 trimer of alphabeta monomers from a molecular-sieve column and exists as [(alphabeta)3]2 hexamers in the crystal lattice. Unlike red algal PE proteins, the hexamers of Phormidium PE do not form higher-order structures in the crystals. The existence of only one characteristic visual absorption band at 564 nm suggests the presence of phycoerythrobilin chromophores, and the absence of any other types of bilins, in the Phormidium PE assembly. PMID- 26249690 TI - Structure of alpha-carbonic anhydrase from the human pathogen Helicobacter pylori. AB - The crystal structure of alpha-carbonic anhydrase, an enzyme present in the periplasm of Helicobacter pylori, a bacterium that affects humans and that is responsible for several gastric pathologies, is described. Two enzyme monomers are present in the asymmetric unit of the monoclinic space group P21, forming a dimer in the crystal. Despite the similarity of the enzyme structure to those of orthologues from other species, the H. pylori protein has adopted peculiar features in order to allow the bacterium to survive in the difficult environment of the human stomach. In particular, the crystal structure shows how the bacterium has corrected for the mutation of an essential amino acid important for catalysis using a negative ion from the medium and how it localizes close to the inner membrane in the periplasm. Since carbonic anhydrase is essential for the bacterial colonization of the host, it is a potential target for antibiotic drugs. The definition of the shape of the active-site entrance and cavity constitutes a basis for the design of specific inhibitors. PMID- 26249691 TI - Crystallographic studies of aspartate racemase from Lactobacillus sakei NBRC 15893. AB - Aspartate racemase catalyzes the interconversion between L-aspartate and D aspartate and belongs to the PLP-independent racemases. The enzyme from the lactic acid bacterium Lactobacillus sakei NBRC 15893, isolated from kimoto, is considered to be involved in D-aspartate synthesis during the brewing process of Japanese sake at low temperatures. The enzyme was crystallized at 293 K by the sitting-drop vapour-diffusion method using 25%(v/v) PEG MME 550, 5%(v/v) 2 propanol. The crystal belonged to space group P3121, with unit-cell parameters a = b = 104.68, c = 97.29 A, and diffracted to 2.6 A resolution. Structure determination is under way. PMID- 26249692 TI - Crystallographic analysis of FAD-dependent glucose dehydrogenase. AB - An FAD-dependent glucose dehydrogenase (GDH) from Aspergillus terreus was purified and crystallized at 293 K using the sitting-drop vapour-diffusion method. A data set was collected to a resolution of 1.6 A from a single crystal at 100 K using a rotating-anode X-ray source. The crystal belonged to space group P21, with unit-cell parameters a = 56.56, b = 135.74, c = 74.13 A, beta = 90.37 degrees . The asymmetric unit contained two molecules of GDH. The Matthews coefficient was calculated to be 2.2 A(3) Da(-1) and the solvent content was estimated to be 44%. PMID- 26249693 TI - Structures of Pseudomonas aeruginosa beta-ketoacyl-(acyl-carrier-protein) synthase II (FabF) and a C164Q mutant provide templates for antibacterial drug discovery and identify a buried potassium ion and a ligand-binding site that is an artefact of the crystal form. AB - Bacterial infections remain a serious health concern, in particular causing life threatening infections of hospitalized and immunocompromised patients. The situation is exacerbated by the rise in antibacterial drug resistance, and new treatments are urgently sought. In this endeavour, accurate structures of molecular targets can support early-stage drug discovery. Here, crystal structures, in three distinct forms, of recombinant Pseudomonas aeruginosa beta ketoacyl-(acyl-carrier-protein) synthase II (FabF) are presented. This enzyme, which is involved in fatty-acid biosynthesis, has been validated by genetic and chemical means as an antibiotic target in Gram-positive bacteria and represents a potential target in Gram-negative bacteria. The structures of apo FabF, of a C164Q mutant in which the binding site is altered to resemble the substrate-bound state and of a complex with 3-(benzoylamino)-2-hydroxybenzoic acid are reported. This compound mimics aspects of a known natural product inhibitor, platensimycin, and surprisingly was observed binding outside the active site, interacting with a symmetry-related molecule. An unusual feature is a completely buried potassium binding site that was identified in all three structures. Comparisons suggest that this may represent a conserved structural feature of FabF relevant to fold stability. The new structures provide templates for structure-based ligand design and, together with the protocols and reagents, may underpin a target-based drug discovery project for urgently needed antibacterials. PMID- 26249694 TI - Overproduction, crystallization and X-ray diffraction data analysis of ectoine synthase from the cold-adapted marine bacterium Sphingopyxis alaskensis. AB - Ectoine biosynthetic genes (ectABC) are widely distributed in bacteria. Microorganisms that carry them make copious amounts of ectoine as a cell protectant in response to high-osmolarity challenges. Ectoine synthase (EctC; EC 4.2.1.108) is the key enzyme for the production of this compatible solute and mediates the last step of ectoine biosynthesis. It catalyzes the ring closure of the cyclic ectoine molecule. A codon-optimized version of ectC from Sphingopyxis alaskensis (Sa) was used for overproduction of SaEctC protein carrying a Strep tag II peptide at its carboxy-terminus. The recombinant SaEctC-Strep-tag II protein was purified to near-homogeneity from Escherichia coli cell extracts by affinity chromatography. Size-exclusion chromatography revealed that it is a dimer in solution. The SaEctC-Strep-tag II protein was crystallized using the sitting-drop vapour-diffusion method and crystals that diffracted to 1.0 A resolution were obtained. PMID- 26249695 TI - Crystallographic analysis of NosA, which catalyzes terminal amide formation in the biosynthesis of nosiheptide. AB - Nosiheptide is a member of the thiopeptide family of antibiotics which demonstrates potent activities against various bacterial pathogens. The formation of its C-terminal amide is catalysed by NosA in an unusual strategy for maturating certain thiopeptides by processing precursor peptides featuring a serine extension. Here, a recombinant C-terminally truncated selenomethionine derivatized NosA1-111 variant from Streptomyces actuosus consisting of residues 1 111, named SeMet NosA1-111, was crystallized using the sitting-drop vapour diffusion method. Diffraction data were collected to 2.40 A resolution using synchrotron radiation. The crystals belonged to the primitive cubic space group P4132, with unit-cell parameters a = b = c = 143.3 A. Assuming the presence of three molecules in the asymmetric unit, the calculated Matthews coefficient was 3.94 A(3) Da(-1) and the corresponding solvent content was 40.3%. PMID- 26249696 TI - Crystallographic studies of SarV, a global regulator from Staphylococcus aureus. AB - SarV, a member of the SarA protein family, is a global transcriptional regulator which has been reported to be involved in the regulation of autolysis in Staphylococcus aureus. In this study, SarV from S. aureus was successfully cloned, expressed, purified and crystallized. X-ray diffraction data were collected to 2.10 A resolution. The crystals of SarV belonged to the monoclinic space group P21, with unit-cell parameters a = 36.40, b = 119.64, c = 66.80 A, alpha = gamma = 90, beta = 98.75 degrees . The Matthews coefficient and the solvent content were estimated to be 2.57 A(3) Da(-1) and 52%, respectively, suggesting the presence of four molecules in the asymmetric unit. The results of size-exclusion chromatography (SEC) indicated that S. aureus SarV exists as a homodimer in solution. Unfortunately, the structure cannot be solved by molecular replacement because of the low sequence identity of S. aureus SarV to known structures. Further phase determination by selenomethionine single-wavelength anomalous dispersion (SAD) and the heavy-atom method is in progress. PMID- 26249697 TI - Crystal structure analysis of c4763, a uropathogenic Escherichia coli-specific protein. AB - Urinary-tract infections (UTIs), which are some of the most common infectious diseases in humans, can cause sepsis and death without proper treatment. Therefore, it is necessary to understand their pathogenicity for proper diagnosis and therapeutics. Uropathogenic Escherichia coli, the major causative agents of UTIs, contain several genes that are absent in nonpathogenic strains and are therefore considered to be relevant to UTI pathogenicity. c4763 is one of the uropathogenic E. coli-specific proteins, but its function is unknown. To investigate the function of c4763 and its possible role in UTI pathogenicity, its crystal structure was determined at a resolution of 1.45 A by a multiple wavelength anomalous diffraction method. c4763 is a homodimer with 129 residues in one subunit that contains a GGCT-like domain with five alpha-helices and seven beta-strands. c4763 shows structural similarity to the C-terminal domain of allophanate hydrolase from Kluyveromyces lactis, which is involved in the degradation of urea. These results suggest that c4763 might be involved in the utilization of urea, which is necessary for bacterial survival in the urinary tract. Further biochemical and physiological investigation will elucidate its functional relevance in UTIs. PMID- 26249698 TI - Structure of human Roquin-2 and its complex with constitutive-decay element RNA. AB - Roquin mediates mRNA degradation by recognizing the constitutive-decay element (CDE) in the 3' untranslated region of the target gene followed by recruitment of the deadenylation machinery. Deficiency or dysfunction of Roquin has been associated with autoimmunity and inflammation. To establish the structural basis for the recognition of CDE RNA by Roquin, the crystal structure of the ROQ domain of human Roquin-2 was determined in ligand-free and CDE-derived RNA-bound forms. The ROQ domain of Roquin-2 folded into a winged-helix structure in which the wing region showed structural flexibility and acted as a lid for RNA binding. The CDE RNA, forming a stem-loop structure, bound to the positively charged surface of the ROQ domain and was mainly recognized via direct interactions with the phosphate backbone in the 5' half of the stem-loop and its triloop and via indirect water-mediated interactions. Structural comparison with Roquin-1 revealed conserved features of the RNA-binding mode. Therefore, it is suggested that the Roquin proteins function redundantly in mRNA degradation. PMID- 26249699 TI - Structure of BbKI, a disulfide-free plasma kallikrein inhibitor. AB - A serine protease inhibitor from Bauhinia bauhinioides (BbKI) belongs to the Kunitz family of plant inhibitors, which are common in plant seeds. BbKI does not contain any disulfides, unlike most other members of this family. It is a potent inhibitor of plasma kallikrein, in addition to other serine proteases, and thus exhibits antithrombotic activity. A high-resolution crystal structure of recombinantly expressed BbKI was determined (at 1.4 A resolution) and was compared with the structures of other members of the family. Modeling of a complex of BbKI with plasma kallikrein indicates that changes in the local structure of the reactive loop that includes the specificity-determining Arg64 are necessary in order to explain the tight binding. An R64A mutant of BbKI was found to be a weaker inhibitor of plasma kallikrein, but was much more potent against plasmin, suggesting that this mutant may be useful for preventing the breakup of fibrin and maintaining clot stability, thus preventing excessive bleeding. PMID- 26249700 TI - Crystallographic analysis of RsmA, a ribosomal RNA small subunit methyltransferase A from Staphylococcus aureus. AB - RsmA, a ribosomal RNA small subunit methyltransferase from Staphylococcus aureus, catalyzes the N(6) methylation of adenine in 16S rRNA. In this study, RsmA from Staphylococcus aureus was cloned, expressed, purified and crystallized. The crystal belonged to space group C2, with unit-cell parameters a = 84.38, b = 157.76, c = 96.50 A, beta = 95.04 degrees . X-ray diffraction data were collected to a resolution of 3.2 A. The self-rotation function and the Matthews coefficient suggested the presence of two molecules in the asymmetric unit. PMID- 26249701 TI - Structure of GTP-specific succinyl-CoA synthetase in complex with CoA. AB - Pig GTP-specific succinyl-CoA synthetase is an alphabeta-heterodimer. The crystal structure of the complex with the substrate CoA was determined at 2.1 A resolution. The structure shows CoA bound to the amino-terminal domain of the alpha-subunit, with the free thiol extending from the adenine portion into the site where the catalytic histidine residue resides. PMID- 26249702 TI - Crystallization, neutron data collection, initial structure refinement and analysis of a xyloglucan heptamer bound to an engineered carbohydrate-binding module from xylanase. AB - Carbohydrate-binding modules (CBMs) are discrete parts of carbohydrate hydrolyzing enzymes that bind specific types of carbohydrates. Ultra high resolution X-ray crystallographic studies of CBMs have helped to decipher the basis for specificity in carbohydrate-protein interactions. However, additional studies are needed to better understand which structural determinants confer which carbohydrate-binding properties. To address these issues, neutron crystallographic studies were initiated on one experimentally engineered CBM derived from a xylanase, X-2 L110F, a protein that is able to bind several different plant carbohydrates such as xylan, beta-glucan and xyloglucan. This protein evolved from a CBM present in xylanase Xyn10A of Rhodothermus marinus. The protein was complexed with a branched xyloglucan heptasaccharide. Large single crystals of hydrogenous protein (~1.6 mm(3)) were grown at room temperature and subjected to H/D exchange. Both neutron and X-ray diffraction data sets were collected to 1.6 A resolution. Joint neutron and X-ray refinement using phenix.refine showed significant density for residues involved in carbohydrate binding and revealed the details of a hydrogen-bonded water network around the binding site. This is the first report of a neutron structure of a CBM and will add to the understanding of protein-carbohydrate binding interactions. PMID- 26249703 TI - Expression, purification, crystallization and X-ray crystallographic analysis of the periplasmic binding protein VatD from Vibrio vulnificus M2799. AB - Vibrio vulnificus is a halophilic marine microorganism which causes gastroenteritis and primary septicaemia in humans. An important factor that determines the survival of V. vulnificus in the human body is its ability to acquire iron. VatD is a periplasmic siderophore-binding protein from V. vulnificus M2799. The current study reports the expression, purification and crystallization of VatD. Crystals of both apo VatD and a VatD-desferrioxamine B Fe(3+) (VatD-FOB) complex were obtained. The crystal of apo VatD belonged to space group P6422, while the crystal of the VatD-FOB complex belonged to space group P21. The difference in the two crystal forms could be caused by the binding of FOB to VatD. PMID- 26249704 TI - Crystallographic analysis of archaeal ribosomal protein L11. AB - Ribosomal protein L11 is an important part of the GTPase-associated centre in ribosomes of all organisms. L11 is a highly conserved two-domain ribosomal protein. The C-terminal domain of L11 is an RNA-binding domain that binds to a fragment of 23S rRNA and stabilizes its structure. The complex between L11 and 23S rRNA is involved in the GTPase activity of the translation elongation and release factors. Bacterial and archaeal L11-rRNA complexes are targets for peptide antibiotics of the thiazole class. To date, there is no complete structure of archaeal L11 owing to the mobility of the N-terminal domain of the protein. Here, the crystallization and X-ray analysis of the ribosomal protein L11 from Methanococcus jannaschii are reported. Crystals of the native protein and its selenomethionine derivative belonged to the orthorhombic space group I222 and were suitable for structural studies. Native and single-wavelength anomalous dispersion data sets have been collected and determination of the structure is in progress. PMID- 26249705 TI - High-resolution crystal structure of cAMP-dependent protein kinase from Cricetulus griseus. AB - Protein kinases (PKs) are dynamic regulators of numerous cellular processes. Their phosphorylation activity is determined by the conserved kinase core structure, which is maintained by the interaction and dynamics with associated domains or interacting proteins. The prototype enzyme for investigations to understand the activity and regulation of PKs is the catalytic subunit of cAMP dependent protein kinase (PKAc). Major effects of functional regulation and ligand binding are driven by only minor structural modulations in protein-protein interactions. In order to resolve such minor structural differences, very high resolution structures are required. Here, the high-resolution X-ray structure of PKAc from Cricetulus griseus is reported. PMID- 26249706 TI - Structure of GUN4 from Chlamydomonas reinhardtii. AB - The genomes uncoupled 4 (GUN4) protein stimulates chlorophyll biosynthesis by increasing the activity of Mg-chelatase, the enzyme that inserts magnesium into protoporphyrin IX (PPIX) in the chlorophyll biosynthesis pathway. One of the roles of GUN4 is in binding PPIX and Mg-PPIX. In eukaryotes, GUN4 also participates in plastid-to-nucleus signalling, although the mechanism for this is unclear. Here, the first crystal structure of a eukaryotic GUN4, from Chlamydomonas reinhardtii, is presented. The structure is in broad agreement with those of previously solved cyanobacterial structures. Most interestingly, conformational divergence is restricted to several loops which cover the porphyrin-binding cleft. The conformational dynamics suggested by this ensemble of structures lend support to the understanding of how GUN4 binds PPIX or Mg PPIX. PMID- 26249710 TI - Double deprivation: a phenomenological study into the experience of being a carer during a mental health crisis. AB - AIM: To explore carers' experience of caring during a mental health crisis. BACKGROUND: Community mental health care including crisis care relies increasingly on carers. The relationship between carers and professionals is at times fraught due to issues of what constitutes a crisis, confidentiality and a perception of lack of empathy. The caring experience can lead carers to feel isolated and neglected. DESIGN: A qualitative study with a phenomenological approach. Eight carers participated and were interviewed individually using a semi-structured approach. METHOD: Analysis used the Interpretive Phenomenological Analysis method including transcribing of interviews, initial noting, searching for connections and patterns across the transcripts and cases. The themes were checked with the participants for their views on the emerging themes. The data were collected from November 2011-May 2012. FINDINGS: Carers experienced 'double deprivation' by not receiving support from professionals and protecting their social network from the trauma of the crisis. The caring in crisis invoked complex feelings of guilt and loyalty which made discussing aggression difficult. Caring was described as a terrifying experience not just because of the aggression but also because of the perception of abandonment by professionals. CONCLUSION: The experience was an overwhelmingly negative one with a wish for acknowledgement of the crisis and support from mental health services. For most of the participants the caring during crisis was traumatic which left the carer feeling isolated and unsupported. The study should be used to help educate professionals on the complexities of caring during a crisis. PMID- 26249712 TI - Taxonomic revision of Plesianthidium Cameron (Apoidea: Megachilidae: Anthidiini), an endemic southern African bee genus. AB - The southern African bee genus Plesianthidium Cameron is revised. It comprises twelve species. Two new species are described: Plesianthidium (Spinanthidium) richtersveldense sp. nov. (Namibia and South Africa) and P. (S.) namaquaense sp. nov. (South Africa). Two species, Plesianthidium calvini (Cockerell, 1932) and P. rufocaudatum (Friese, 1909), are reinstated as valid species. Keys for the identification of the species of Plesianthidium are given. PMID- 26249716 TI - A review of the genus Spanagonicus Berg (Hemiptera: Miridae: Phylinae: Nasocorini) with the description of novel antennal characters, the description of a new species from Central America, and a key to currently known taxa. AB - The New World genus Spanagonicus Berg, 1883 is reviewed. A new species, Spanagonicus schusterus sp. nov. is described from Central America. A key to all known species, as well as redescriptions for all species but S. tiquiensis Carvalho & Carpintero (which was unavailable for inspection), are provided. Characterization of the sexual dimorphism, morphology, and possible function of the newly discovered spatulate setae on the ventral surface of male antennae is also discussed. Color digital habitus images and genitalic illustrations are provided for both male and female specimens of Spanagonicus. Scanning electron and transmission electron micrographs of the second antennal segment of male and female specimens of S. albofasciatus are also included. PMID- 26249715 TI - Redescriptions of three species of freshwater crabs from the Democratic Republic of Congo, Central Africa (Brachyura: Potamoidea: Potamonautidae). AB - The taxonomy of three species of freshwater crabs from the Upper Congo River in the Democratic Republic of Congo, Potamonautes congoensis (Rathbun, 1921), P. langi (Rathbun, 1921), and P. stanleyensis (Rathbun, 1921), is revised based on examination of the holotypes. Updated diagnoses, illustrations, and distribution maps are provided for these species, and their conservation status is discussed. PMID- 26249713 TI - Molecular and morphological systematics of Doto Oken, 1851 (Gastropoda: Heterobranchia), with descriptions of five new species and a new genus. AB - The nudibranch family Dotidae has been an extremely challenging group to study taxonomically due to their small body size, lack of distinct internal morphological differences and similar color patterns. This integrative systematic study of the Dotidae encompasses 29 individuals from the north Atlantic and Mediterranean, and 11 from the Indo-Pacific. Two mitochondrial genes, 16S, COI, and a nuclear gene, H3, were sequenced for 31 specimens and Bayesian and RAxML concatenated analyses were run. Dotidae is monophyletic and possesses strong geographic structure. Co-evolution between some of the north Atlantic taxa and their hydroid prey is apparent, thus supporting the hypothesis that speciation may be correlated with prey diversification. This study also supports the notion that the hydroid prey is a reliable indicator for distinguishing between cryptic species. Doto coronata Gmelin, the type species for the genus Doto, is re described and a neotype, collected near Goes, Netherlands, is designated. From the molecular data, D. millbayana, D. dunnei, D. koenneckeri, D. maculata Lemche within the Doto coronata species complex, are confirmed to be distinct from D. coronata. Based on molecular data, specimens previously identified as D. coronata from South Africa are determined to represent a new species. It is described here and named Doto africoronata n. sp. Kabeiro n. gen. is introduced for the clade of elongate individuals from the Indo-Pacific, which diverges by 11.6% or greater in 16S from short-bodied Doto species. These elongate species are sister to all the short-bodied species and possess an enlarged pericardium, elongate cerata, a reproductive system with a pocketed prostate (penial gland), and an external tube like digestive gland, which are absent in short-bodied Doto. Species of Kabeiro described here are: Kabeiro christianae n. sp., Kabeiro rubroreticulata n. sp., and Kabeiro phasmida n. sp. from the Philippines. The Indo-Pacific short-bodied species, Doto greenamyeri n. sp. from Papua New Guinea is also described. PMID- 26249714 TI - Description of the larva of Tetragonoderus (Crossonychus) variegatus Dejean, 1829 (Coleoptera: Carabidae: Cyclosomini) with notes on biology. AB - A late instar of the Tetragonoderus (Crossonychus) variegatus Dejean, 1829 larva is described for the first time, and is compared with its first instar, with the larva of another Tetragonoderus species, and with the larva of one Cyclicus species. Habitus and important structures of the larva are illustrated, as well the adult's membranous wings. Some aspects of the natural history of the larva and adult are also noted. PMID- 26249717 TI - New species and new distribution records of Lestremiinae, Micromyinae and Porricondylinae (Diptera: Cecidomyiidae) in Sweden. AB - The Swedish species of fungivorous Cecidomyiidae have been the subject of comprehensive inventory in recent years (2004-2012). Notwithstanding these efforts,which are unparalleled in the remainder of Europe and the World, a follow up project running over four months (May-August, 2014) revealed the presence in Sweden of an additional 28 species of Lestremiinae, Micromyinae and Porricondylinae. These discoveries, comprising 10 species new to science and 18 species new to the Swedish fauna, are outlined and discussed in terms of taxonomic position and geographical distribution. New species are described and named as follows: Aprionus forshagei, Aprionus gustavssoni, Aprionus karlssonorum, Aprionus lindgrenae, Aprionus magnussoni (all in Micromyinae), Asynapta panzari, Asynapta suzzae, Dicerura peterssoni, Monepidosis tinnerti, and Tetraneuromyia wilksae (all in Porricondylinae). Serratyla acuta (Spungis), originally classified as a Porricondyla, is a new combination. PMID- 26249718 TI - A checklist of the millipedes (Diplopoda) of Cambodia. AB - At the present, the millipede fauna of Cambodia comprises only 19 species from 15 genera, 12 families and 8 orders. These counts certainly represent but a minor fraction of the country's real diversity of Diplopoda even at the ordinal level, let alone at lower ones. Based on the available information from the adjacent parts of China, Thailand, Myanmar, Vietnam and/or Laos, the orders Glomerida, Platydesmida, Polyzoniida, Callipodida and Chordeumatida must occur in Cambodia, maybe also Stemmiulida and Siphonocryptida, but none has been recorded there yet. This shows that a lot more collecting effort is required to amass a representative material of Diplopoda of Cambodia to make it available for study. PMID- 26249721 TI - JHABAR MAL, RAJENDRA NAGAR & R. SWAMINATHAN (2015) Morphological characterization of some representative species of the genus Loxoblemmus (Orthoptera: Gryllidae; Gryllinae; Gryllini) from India. Zootaxa, 3955(3): 329 339. PMID- 26249719 TI - Elasmopus alkhiranensis sp. nov., a new species of amphipod (Senticaudata, Maeridae) from the Persian Gulf. AB - A new species, Elasmopus alkhiranensis allied to E. pectenicrus is described from the Persian Gulf. Recent collections identify this species as having a morphological variation previously unreported in Elasmopus. PMID- 26249720 TI - Rediscovery of Mantellias pubicornis Westwood, 1889, a rare praying mantis from the Amazon (Mantodea, Thespidae, Oligonicinae). AB - Many praying mantis species remain known from type specimens only. The majority of these taxa have vague taxonomic limits, as original descriptions are often very short, making strong emphasis on superficial characters (Rivera 2010). One clear example of this is the Amazonian Mantellias Westwood, 1889, a monotypical genus represented by Mantellias pubicornis Westwood, 1889. PMID- 26249729 TI - Erratum to: Pediatric Reference Values for Tibial Trabecular Bone Mineral Density and Bone Geometry Parameters Using Peripheral Quantitative Computed Tomography. PMID- 26249708 TI - Crystallization and crystallographic analysis of branching enzymes from Cyanothece sp. ATCC 51142. AB - Several cyanobacterial species, including Cyanothece sp. ATCC 51142, remarkably have four isoforms of alpha-glucan branching enzymes (BEs). Based on their primary structures, they are classified into glycoside hydrolase (GH) family 13 (BE1, BE2 and BE3) or family 57 (GH57 BE). In the present study, GH13-type BEs from Cyanothece sp. ATCC 51142 (BE1, BE2 and BE3) have been overexpressed in Escherichia coli and biochemically characterized. The recombinant BE1 was crystallized by the hanging-drop vapour-diffusion method. Crystals of BE1 were obtained at 293 K in the presence of 0.2 M Mg(2+), 7-10%(w/v) ethanol, 0.1 M HEPES-NaOH pH 7.2-7.9. The crystals belonged to the tetragonal space group P41212, with unit-cell parameters a = b = 133.75, c = 185.90 A, and diffracted to beyond 1.85 A resolution. Matthews coefficient calculations suggested that the crystals of BE1 contained two molecules in the asymmetric unit. PMID- 26249725 TI - Acceptability of a Touch Screen Tablet Psychosocial Survey Administered to Radiation Therapy Patients in Japan. AB - BACKGROUND: Studies in western clinical settings suggest that touch screen computer surveys are an acceptable mode of collecting information about cancer patients' wellbeing PURPOSE: We examined the acceptability of a touch screen tablet survey among cancer patients in Japan. METHODS: Eligible patients (n = 262) attending a university hospital radiation therapy (RT) department were invited to complete a touch screen tablet survey about psychosocial communication and care. Survey consent and completion rates, the proportion and characteristics of patients who completed the touch screen survey unassisted, and patient reported acceptability were assessed. RESULTS: Of 158 consenting patients (consent rate 60 % [95 % CI 54, 66 %] of eligible patients), 152 completed the touch screen computer survey (completion rate 58 % [95 % CI 52, 64 %] of eligible patients). The survey was completed without assistance by 74 % (n = 113; 95 % CI 67, 81 %) of respondents. Older age was associated with higher odds of having assistance with survey completion (OR 1.09; 95 % CI 1.04, 1.14 %). Ninety-two percent of patients (95 % CI 86, 96 %) felt that the touch screen survey was easy to use and 95 % (95 % CI 90, 98 %) agreed or strongly agreed that they were comfortable answering the questions. Overall, 65 % (95 % CI 57, 73 %) of respondents would be willing to complete such a survey more than once while waiting for RT treatment. CONCLUSIONS: Although patient self-reported acceptability of the touch screen survey was high, self-administered touch screen tablet surveys may not be entirely appropriate for older cancer patients or possibly for patients with lower educational attainment. PMID- 26249728 TI - Luminescence and energy-transfer properties of color-tunable Ca2Mg0.25Al1.5Si1.25O7:Ce(3+)/Eu(2+)/Tb(3+) phosphors for ultraviolet light emitting diodes. AB - A series of Ca2Mg0.25Al1.5Si1.25O7:Ce(3+)/Eu(2+)/Tb(3+) phosphors was been prepared via a conventional high temperature solid-state reaction and their luminescence properties were studied. The emission spectra of Ca2Mg0.25Al1.5Si1.25O7:Ce(3+),Eu(2+) and Ca2Mg0.25Al1.5Si1.25O7:Ce(3+),Tb(3+) phosphors show not only a band due to Ce(3+) ions (409 nm) but also as a band due to Eu(2+) (520 nm) and Tb(3+) (542 nm) ions. More importantly, the effective energy transfer from Ce(3+) to Eu(2+) and Tb(3+) ions was confirmed and investigated by emission/excitation spectra and luminescent decay behaviors. Furthermore, the energy level scheme and energy transfer mechanism were investigated and were demonstrated to be of resonant type via dipole-dipole (Ce(3+) to Eu(2+)) and dipole-quadrupole (Ce(3+) to Tb(3+)) reactions, respectively. Under excitation at 350 nm, the emitting color could be changed from blue to green by adjusting the relative doping concentration of Ce(3+) and Eu(2+) ions as well as Ce(3+) and Tb(3+) ions. The above results indicate that Ca2Mg0.25Al1.5Si1.25O7:Ce(3+),Eu(2+)/Tb(3+) are promising single-phase blue-to green phosphors for application in phosphor conversion white-light-emitting diodes. PMID- 26249722 TI - In vitro, antithrombotic and bleeding time studies of BMS-654457, a small molecule, reversible and direct inhibitor of factor XIa. AB - BMS-654457 ((+) 3'-(6-carbamimidoyl-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin 2-yl)-4-carbamoyl-5'-(3-methyl-butyrylamino)-biphenyl-2-carboxylic acid) is a small-molecule factor XIa (FXIa) inhibitor. We evaluated the in vitro properties of BMS-654457 and its in vivo activities in rabbit models of electrolytic-induced carotid arterial thrombosis and cuticle bleeding time (BT). Kinetic studies conducted in vitro with a chromogenic substrate demonstrated that BMS-654457 is a reversible and competitive inhibitor for FXIa. BMS-654457 increased activated partial thromboplastin time (aPTT) without changing prothrombin time. It was equipotent in prolonging the plasma aPTT in human and rabbit, and less potent in rat and dog. It did not alter platelet aggregation to ADP, arachidonic acid and collagen. In vivo, BMS-654457 or vehicle was given IV prior to initiation of thrombosis or cuticle transection. Preservation of integrated carotid blood flow over 90 min (iCBF, % control) was used as a marker of antithrombotic efficacy. BMS-654457 at 0.37 mg/kg + 0.27 mg/kg/h produced almost 90 % preservation of iCBF compared to its vehicle (87 +/- 10 and 16 +/- 3 %, respectively, n = 6 per group) and increased BT by 1.2 +/- 0.04-fold (P < 0.05). At a higher dose (1.1 mg/kg + 0.8 mg/kg/h), BMS-654457 increased BT by 1.33 +/- 0.08-fold. This compares favorably to equivalent antithrombotic doses of reference anticoagulants (warfarin and dabigatran) and antiplatelet agents (clopidogrel and prasugrel) which produced four- to six-fold BT increases in the same model. In summary, BMS 654457 was effective in the prevention of arterial thrombosis in rabbits with limited effects on BT. This study supports inhibition of FXIa, with a small molecule, reversible and direct inhibitor as a promising antithrombotic therapy with a wide therapeutic window. PMID- 26249709 TI - Observations on Attenuation of Local Electrogram Amplitude and Circuit Impedance During Atrial Radiofrequency Ablation: An In vivo Investigation Using a Novel Direct Endocardial Visualization Catheter. AB - AIMS: To define the temporal characteristics of atrial lesion growth (lesion surface area), local electrogram amplitude attenuation, and circuit impedance decrement during in vivo radiofrequency (RF) ablation with direct endocardial visualization (DEV). METHODS AND RESULTS: A direct endocardial visualization catheter was used for real-time endoscopic visualization of atrial endocardial surface during RF ablation. Videos of lesion growth (surface area), circuit impedance, and local electrogram amplitude were recorded during ablation in 11 ovine. Fifty-two atrial ablations at 12 W, 14 W, and 16 W power for 30 seconds were analyzed. During 30-second RF ablation, the lesion matured (90% of final lesion dimension) in the first 23.0 +/- 5.8 seconds. The local electrogram amplitude attenuation (80% decrement) and circuit impedance attenuation (20% decrement from initial) occurred 13.8 +/- 8.2 seconds and 13.1 +/- 7.9 seconds, respectively, before lesion maturity in a significant proportion of 30 second atrial ablations. CONCLUSION: The DEV observations suggest that in smooth atrial surface ablations with significant local electrogram and impedance decrement in the first 10 seconds, further extension of ablation for 10-15 seconds could deliver optimal surface dimensions; however, real-time measurement of depth was not possible. PMID- 26249723 TI - Metachronous tubulovillous and tubular adenomas of the anal canal. AB - Anal canal adenoma is an extremely rare disease that has the potential to transform into a malignant tumor. We herein presented a rare case of metachronous multiple adenomas of the anal canal. A 48-year-old woman underwent total colonoscopy following a positive fecal blood test. A 9-mm villous polyp arising from the posterior wall of the anal canal was removed by snare polypectomy. Histologically, the tumor was tubulovillous adenoma with high-grade dysplasia and the cut end was negative for tumor cells. Six years later, an elevated lesion, macroscopically five millimeters in size, was detected in the left wall of the anal canal in a follow-up colonoscopy. Local excision of the tumor was performed, and the lesion was pathologically confirmed to be tubular adenoma with high-grade dysplasia limited to the mucosa. The patient is currently alive without any evidence of recurrence for six months after surgery. Although she had a past history of cervical cancer, the multiple tumors arising in the anal canal were unlikely to be related to human papilloma virus infection. Our case report underscores the importance of careful observations throughout colonoscopy to detect precancerous lesions, particularly in anatomically narrow segments. PMID- 26249733 TI - Increased Submacular Choroidal Thickness in Active, Isolated, Extramacular Toxoplasmosis. PMID- 26249726 TI - The relevance of somatosensory auras in refractory temporal lobe epilepsies. AB - The purpose of this study is to look at the prevalence, characteristics, and prognostic value of somatosensory auras (SSAs) in patients who have undergone temporal lobe epilepsy (TLE) surgery to treat drug-resistant focal epilepsy. We retrospectively reviewed all patients with drug-resistant epilepsy who underwent TLE surgery at Cleveland Clinic between 2005 and 2010 (n = 333) to study the prevalence, characteristics, and prognostic implications of SSA in the context of TLE surgery. Analyses were performed using two seizure outcome definitions: complete seizure freedom and Engel classification. Of the 333 patients, 26 (7.8%) had SSA. Almost half (12 patients) had unilateral sensory symptoms, whereas the rest had bilateral symptoms. Tingling and numbness were the most frequently reported sensations. Compared to their non-SSA counterparts, patients with SSA had the same clinical and imaging characteristics, but had a higher rate of breakthrough seizures (p = 0.03), although most (54%) were still able to achieve Engel class of I (p = 0.02). Based on our results we would encourage detailed presurgical testing, which may include an invasive evaluation to analyze the extent of the epileptogenic zone in patients with SSA and suspected TLE. PMID- 26249734 TI - Scavenger Species-typical Alteration to Bone: Using Bite Mark Dimensions to Identify Scavengers. AB - Scavenger-induced alteration to bone occurs while scavengers access soft tissue and during the scattering and re-scavenging of skeletal remains. Using bite mark, dimensional data to assist in the more accurate identification of a scavenger can improve interpretations of trauma and enhance search and recovery methods. This study analyzed bite marks produced on both dry and fresh surface deposited remains by wild and captive red fox (Vulpes vulpes) and Eurasian badger (Meles meles), as well as domestic dog (Canis familiaris). The bite marks produced by foxes were distinguishable from those made by badgers and dogs based on ranges of mean length and breadth of pits. The dimensional data of bite marks produced by badgers and dogs were less discernible. Bone modifications vary due to a variety of factors which must be considered, such as scavenger species-typical scavenging behavior, scavenger species' dentition, condition and deposition of remains, and environmental factors. PMID- 26249707 TI - Structural analysis of Clostridium acetobutylicum ATCC 824 glycoside hydrolase from CAZy family GH105. AB - Clostridium acetobutylicum ATCC 824 gene CA_C0359 encodes a putative unsaturated rhamnogalacturonyl hydrolase (URH) with distant amino-acid sequence homology to YteR of Bacillus subtilis strain 168. YteR, like other URHs, has core structural homology to unsaturated glucuronyl hydrolases, but hydrolyzes the unsaturated disaccharide derivative of rhamnogalacturonan I. The crystal structure of the recombinant CA_C0359 protein was solved to 1.6 A resolution by molecular replacement using the phase information of the previously reported structure of YteR (PDB entry 1nc5) from Bacillus subtilis strain 168. The YteR-like protein is a six-alpha-hairpin barrel with two beta-sheet strands and a small helix overlaying the end of the hairpins next to the active site. The protein has low primary protein sequence identity to YteR but is structurally similar. The two tertiary structures align with a root-mean-square deviation of 1.4 A and contain a highly conserved active pocket. There is a conserved aspartic acid residue in both structures, which has been shown to be important for hydration of the C=C bond during the release of unsaturated galacturonic acid by YteR. A surface electrostatic potential comparison of CA_C0359 and proteins from CAZy families GH88 and GH105 reveals the make-up of the active site to be a combination of the unsaturated rhamnogalacturonyl hydrolase and the unsaturated glucuronyl hydrolase from Bacillus subtilis strain 168. Structural and electrostatic comparisons suggests that the protein may have a slightly different substrate specificity from that of YteR. PMID- 26249727 TI - Influence of co-culture with denuded oocytes during in vitro maturation on fertilization and developmental competence of cumulus-enclosed porcine oocytes in a defined system. AB - Co-culture of cumulus-oocyte complexes (COCs) with denuded oocytes (DOs) during in vitro maturation (IVM) was reported to improve the developmental competence of oocytes via oocyte-secreted factors in cattle. The aim of the present study was to investigate if addition of DOs during IVM can improve in vitro fertilization (IVF) and in vitro culture (IVC) results for oocytes in a defined in vitro production system in pigs. The maturation medium was porcine oocyte medium supplemented with gonadotropins, dbcAMP and beta-mercaptoethanol. Cumulus-oocyte complexes were matured without DOs or with DOs in different ratios (9 COC, 9 COC+16 DO and 9 COC+36 DO). Consequently; oocytes were subjected to IVF as intact COCs or after denudation to examine if DO addition during IVM would affect cumulus or oocyte properties. After fertilization, penetration and normal fertilization rates of zygotes were not different between all tested groups irrespective of denudation before IVF. When zygotes were cultured for 6 days, no difference could be observed between all treatment groups in cleavage rate, blastocyst rate and cell number per blastocyst. In conclusion, irrespective of the ratio, co-culture with DOs during IVM did not improve fertilization parameters and embryo development of cumulus-enclosed porcine oocytes in a defined system. PMID- 26249732 TI - Lower Macular Pigment Optical Density in Foveal-Involved Glaucoma. AB - PURPOSE: To evaluate the relationship between macular pigment optical density (MPOD) and structural parameters of the macula and optic nerve head in glaucomatous eyes. DESIGN: A cross-sectional analysis of the baseline data collected during the Macular Pigment and Glaucoma Trial (ISRCTN registry number: 56985060). PARTICIPANTS: Eighty-eight subjects (48 male, 40 female) with a diagnosis of open-angle glaucoma and a median age of 67 years (interquartile range, 13; range, 36-84 years) were enrolled in this trial. METHODS: The MPOD at 0.25 degrees , 0.5 degrees , and 1 degrees retinal eccentricity was measured using a customized heterochromatic flicker photometry technique. Glaucoma-related structural parameters were captured using RTVue Fourier-domain optical coherence tomography (FD-OCT). Statistical significance was set at P < 0.01, and P values ranging from 0.01 to 0.05 were considered borderline significant. MAIN OUTCOME MEASURES: The MPOD and its relationship to the macula and optic nerve head topography in glaucomatous eyes. RESULTS: The MPOD peaked centrally at 0.25 degrees of retinal eccentricity (mean +/- standard deviation, 0.23+/-0.14) and decreased at more peripheral eccentricities. For the overall group, borderline significant correlations were observed between MPOD and a range of topographic measures, including inferior peripapillary retinal nerve fiber layer (RNFL) thickness, inferior ganglion cell complex (GCC) thickness, foveal inner retinal thickness, cup-to-disc area ratio, and optic disc rim area. Glaucomatous eyes with GCC loss involving the foveal zone on FD-OCT imaging (n = 52) had lower MPOD at 0.25 degrees , 0.5 degrees , and 1 degrees of retinal eccentricity compared with those without foveal GCC involvement (P < 0.001, for all). Those with foveal GCC loss also had greater glaucoma severity, and this was evident by lower GCC and RNFL thickness, greater cup-to-disc area ratio, and lower optic disc rim area (P < 0.001 for all). CONCLUSIONS: Our observations indicate that MPOD is lower in glaucomatous eyes with foveal GCC involvement relative to those without foveal involvement. A longitudinal evaluation of MPOD and structural change among patients with glaucoma is required to elucidate the nature of any causal relationship that might exist between MPOD and foveal damage in glaucoma. PMID- 26249735 TI - Reply to price and value in cancer care. PMID- 26249731 TI - Assessment of Durability of Online and Multisensory Learning Using an Ophthalmology Model. AB - PURPOSE: To explore the impact of online learning and multisensory small-group teaching on acquisition and retention of specialty knowledge and diagnostic skills during a third-year family medicine rotation. DESIGN: Exploratory, observational, longitudinal, and multiple-skill measures. PARTICIPANTS: Two medical school classes (n = 199) at a public medical school in California. METHODS: Students engaged in online self-study, small-group interactive diagnostic sessions, picture identification of critical pathologic features, and funduscopic simulator examinations. The authors compared performance on testing immediately after online learning with testing at end-rotation, as well as picture identification versus simulator diagnostic ability in students with (n = 94) and without (n = 105) practice tracing contours on whiteboard projections of those same slides depicting fundus pathologic features of common systemic diseases. MAIN OUTCOMES MEASURES: Picture identification, accuracy of funduscopic descriptions, online module post-tests, and end-rotation tests. RESULTS: Proprioceptive reinforcement of fundus pattern recognition significantly reduced the need for remediation for misdiagnosing optic disc edema during end-rotation funduscopic simulator testing, but it had no effect on fundus pattern recognition or diagnostic ability overall. Near-perfect immediate online post-test scores contrasted sharply with poor end-rotation scores on an in-house test (average, 59.4%). Rotation timing was not a factor because the patterns remained consistent throughout the academic school year. CONCLUSIONS: Neither multisensory teaching nor online self-study significantly improved retention of ophthalmic knowledge and diagnostic skills by the end of a month-long third-year rotation. Timing such training closer to internship when application is imminent may enhance students' appreciation for its value and perhaps may improve retention. Pulsed quizzes over time also may be necessary to motivate students to retain the knowledge gained. PMID- 26249730 TI - Photopsias: A Key to Diagnosis. AB - PURPOSE: To assess the character and cause of photopsias in vitreoretinal patients. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 169 consecutive patients (217 eyes) with vitreoretinal disease presenting with a history of photopsias. METHODS: A total of 217 eyes with photopsias in 169 patients were evaluated. Photopsia assessment included (1) laterality (unilateral, bilateral but not simultaneous, bilateral, and simultaneous); (2) morphology (flash, zig zag, strobe, scintillating scotoma, twinkling, other); (3) color (white, silver, yellow, combination, other); (4) location (temporal, central, other); (5) duration (quick, prolonged, constant, other); (6) frequency; (7) diurnal appearance (day, night, both); (8) stimuli (turning head or eyes, hypoglycemia, hyperglycemia, other); and (9) associated systemic or ocular signs and symptoms (headache, numbness, weakness, vertigo, syncope, diplopia, hypotension, floaters, other). MAIN OUTCOME MEASURES: Clinical photopsia features correlated with the causes of photopsias. RESULTS: Thirty-two photopsia causes were identified. The top 16 included posterior vitreous detachment (PVD) in 39.7% of eyes; retinal tear in 8.9% of eyes; neovascular age-related macular degeneration (AMD) in 7.9% of eyes; rhegmatogenous retinal detachment (RRD) in 7.5% of eyes; classic and ophthalmic migraine in 6.5% of eyes; hypoglycemia in 2.8% of eyes; vertebrobasilar insufficiency in 2.8% of eyes; non-AMD choroidal neovascularization in 2.3% of eyes; retinitis pigmentosa in 1.9% of eyes; severe cough in 1.9% of eyes; central serous chorioretinopathy in 1.4% of eyes; intraocular lens reflections in 0.9% of eyes; blue field entoptic phenomenon in 0.9% of eyes; Charles Bonnet syndrome in 0.9% of eyes; digitalis in 0.9% of eyes; and metastatic adenocarcinoma to the brain in 0.9% of eyes. The photopsias associated with PVD are typically quick (96%), with lightning/flash morphology (96%), white (87%), temporally located (86%), associated with new-onset floaters (85%), preferentially seen in dark (90%) rather than lighted environments (29%), and often initiated by head/eye movements (60%). Retinal detachment had a similar profile, but with more nontemporal photopsias (40%) (P = 0.01). The photopsias from neovascular AMD are more centrally located (83%), quick and repetitive (79%), seen in light (73%) and dark (63%) environments, have no inciting stimuli (84%), and are more likely to be nonwhite (40%). CONCLUSIONS: A pointed history for photopsias can reveal a cause that may not initially seem apparent. Thus, the history can play a key role in management decisions. PMID- 26249711 TI - Occupational noise exposure and hearing: a systematic review. AB - PURPOSE: To give a systematic review of the development of noise-induced hearing loss (NIHL) in working life. METHODS: A literature search in MEDLINE, Embase, Web of Science, Scopus, and Health and Safety Abstracts, with appropriate keywords on noise in the workplace and health, revealed 22,413 articles which were screened by six researchers. A total of 698 articles were reviewed in full text and scored with a checklist, and 187 articles were found to be relevant and of sufficient quality for further analysis. RESULTS: Occupational noise exposure causes between 7 and 21 % of the hearing loss among workers, lowest in the industrialized countries, where the incidence is going down, and highest in the developing countries. It is difficult to distinguish between NIHL and age-related hearing loss at an individual level. Most of the hearing loss is age related. Men lose hearing more than women do. Heredity also plays a part. Socioeconomic position, ethnicity and other factors, such as smoking, high blood pressure, diabetes, vibration and chemical substances, may also affect hearing. The use of firearms may be harmful to hearing, whereas most other sources of leisure-time noise seem to be less important. Impulse noise seems to be more deleterious to hearing than continuous noise. Occupational groups at high risk of NIHL are the military, construction workers, agriculture and others with high noise exposure. CONCLUSION: The prevalence of NIHL is declining in most industrialized countries, probably due to preventive measures. Hearing loss is mainly related to increasing age. PMID- 26249724 TI - Leisure-Time Physical Activity and Sedentary Behavior and Their Cross-Sectional Associations with Excessive Daytime Sleepiness in the French SU.VI.MAX-2 Study. AB - BACKGROUND: The potential benefit of physical activity in terms of decreasing excessive daytime sleepiness (EDS) prevalence is unclear, especially in aging adults. PURPOSE: We aimed to elucidate the associations among physical activity, sedentariness, and EDS in middle-aged and older adults. METHODS: We conducted a cross-sectional analysis using data from a subsample of participants in the SU.VI.MAX-2 observational study (2007-2009; N = 4179; mean age = 61.9 years). EDS was defined as a score >10 on the Epworth Sleepiness Scale. Leisure-time physical activity and different types of sedentary behavior were assessed with the Modifiable Activity Questionnaire. The associations were examined with multivariable logistic regression models. RESULTS: In the adjusted multivariable model, total leisure-time physical activity (modeled in quartiles, Q) was significantly, inversely associated with EDS (odds ratios (OR)Q4 vs Q1 = 0.70, 95 % confidence interval (CI) = 0.54-0.89). The association persisted in analyses restricted to individuals not taking sleep medication (ORQ4 vs Q1 = 0.72, 95 % CI = 0.54-0.95). In turn, time spent watching television and time spent reading appeared protective against EDS (ORQ4 vs Q1 = 0.73, 95 % CI = 0.57-0.94; ORQ4 vs Q1 = 0.76, 95 % CI = 0.60-0.97, respectively), whereas time spent on a computer appeared to confer an increased risk for EDS (ORQ4 vs Q1 = 1.30, 95 % CI = 1.05 1.62). When physical activity and sedentariness were modeled jointly, using WHO recommendation-based cutoffs for high/low levels, no significant associations were observed in the fully adjusted models. CONCLUSIONS: The findings reinforce public health recommendations promoting behavior modification and specifically moderate-intensity exercise in middle-aged and older adults. The association of high physical activity/low sedentariness with EDS, which was not supported by the data, merits further investigation before firm conclusions could be drawn. PMID- 26249736 TI - Malva verticillata seed extracts upregulate the Wnt pathway in human dermal papilla cells. AB - OBJECTIVE: Mesenchymal-epithelial interactions are important in controlling hair growth and the hair cycle. The beta-catenin pathway of dermal papilla cells (DPCs) plays a pivotal role in morphogenesis and normal regeneration of hair follicles. Deletion of beta-catenin in the dermal papilla reduces proliferation of the hair follicle progenitor cells that generate the hair shaft and induces an early onset of the catagen phase. In this study, a modulator of the Wnt/beta catenin activity was studied in oriental herb extracts on cultured human DPCs. METHODS: The effect of Malva verticillata (M. verticillata) seeds on human DPCs was investigated by a Wnt/beta-catenin reporter activity assay system (beta catenin-TCF/LEF reporter gene) and cell proliferation analysis. The synthesis of the factors related to hair growth and cycling was measured at both the mRNA and the protein level by semi-quantitative PCR and Western blot analysis, respectively. RESULTS: An extract from M. verticillata seeds increased Wnt reporter activity in a concentration-dependent manner and also led to increased beta-catenin levels in cultured human DPCs. Myristoleic acid, identified as an effective compound of M. verticillata seeds, stimulated the proliferation of DPCs in a dose-dependent manner and increased transcription levels of the downstream targets: IGF-1, KGF, VEGF and HGF. Myristoleic acid also enhanced the phosphorylation of MAPKs (Akt and p38). CONCLUSION: Overall, the data suggest that this extract of M. verticillata seeds could be a good candidate for treating hair loss by modulating the Wnt/beta-catenin pathway in DPCs. PMID- 26249738 TI - Spiritual Treatment for Depression in Brazil: An Experience From Spiritism. AB - BACKGROUND: Spiritism has been strongly connected with mental health in Brazil. However, there is a lack of descriptions of spiritual treatment provided by thousands of Brazilian Spiritist centers. The present study aims to describe the spiritual care for depression provided by one large Spiritist center in Sao Paulo, Brazil. METHODS: This is a descriptive study carried out in 2012 at "Sao Paulo Spiritist Federation." Authors visited the "spiritual intervention sections," observed the therapies provided, listened to the "spirits' communication," and interviewed two patients. RESULTS: The assistance consists on a 90-min "Spiritual healing" session which includes educational lectures, "disobsession" (spirit release therapy), "passe" (laying on of hands) and person advice. Both patients had remitted depression when they were interviewed. CONCLUSIONS: Further studies would be necessary to report other religious/spiritual treatments in order to improve our understanding of the available practices used by patients and optimize the integration of conventional care with spiritual treatments. PMID- 26249739 TI - Cochrane Commentary: Probiotics For Prevention of Acute Upper Respiratory Infection. AB - BACKGROUND: Probiotics may improve a person's health by regulating their immune function. Some trials have shown that probiotic strains can prevent respiratory infections. Even though the previous version of our review showed benefits of probiotics for acute upper respiratory tract infections (URTIs), several new studies have been published. OBJECTIVES: To assess the effectiveness and safety of probiotics (any specified strain or dose), compared with placebo, in the prevention of acute URTIs in people of all ages, who are at risk of acute URTIs. SEARCH METHODS: We searched CENTRAL (2014, Issue 6), MEDLINE (1950 to July week 3, 2014), EMBASE (1974 to July 2014), Web of Science (1900 to July 2014), the Chinese Biomedical Literature Database, which includes the China Biological Medicine Database (from 1978 to July 2014), the Chinese Medicine Popular Science Literature Database (from 2000 to July 2014) and the Masters Degree Dissertation of Beijing Union Medical College Database (from 1981 to July 2014). We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for completed and ongoing trials on 31 July 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing probiotics with placebo to prevent acute URTIs. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility and quality of trials, and extracted data using the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included 13 RCTs, although we could only extract data to meta-analyze 12 trials, which involved 3720 participants including children, adults (aged around 40 years) and older people. We found that probiotics were better than placebo when measuring the number of participants experiencing episodes of acute URTI [at least one episode: odds ratio (OR): 0.53; 95% CI = 0.37-0.76, P < .001, low quality evidence; at least three episodes: OR: 0.53; 95% CI = 0.36-0.80, P = .002, low quality evidence]; the mean duration of an episode of acute URTI [mean difference (MD): 1.89; 95% CI = -2.03 to -1.75, P < .001, low quality evidence]; reduced antibiotic prescription rates for acute URTIs (OR: 0.65; 95% CI = 0.45-0.94, moderate quality evidence) and cold-related school absence (OR: 0.10; 95% CI = 0.02-0.47, very low quality evidence). Probiotics and placebo were similar when measuring the rate ratio of episodes of acute URTI (rate ratio: 0.83; 95% CI = 0.66-1.05, P = .12, very low quality evidence) and adverse events (OR: 0.88; 95% CI = 0.65-1.19, P = .40, low quality evidence). Side effects of probiotics were minor and gastrointestinal symptoms were the most common. We found that some subgroups had a high level of heterogeneity when we conducted pooled analyses and the evidence level was low or very low quality. AUTHORS' CONCLUSIONS: Probiotics were better than placebo in reducing the number of participants experiencing episodes of acute URTI, the mean duration of an episode of acute URTI, antibiotic use and cold-related school absence. This indicates that probiotics may be more beneficial than placebo for preventing acute URTIs. However, the quality of the evidence was low or very low. PMID- 26249740 TI - Troubled Waters: Building a Bridge to a Restorative Water Future Healthcare's Role in Our Water Future. PMID- 26249741 TI - Health anxiety and depression in patients with fibromyalgia syndrome. AB - OBJECTIVES: To investigate health anxiety and depressive symptoms in patients with fibromyalgia syndrome (FMS). METHODS: Patients with FMS and healthy control subjects were recruited. All participants completed the Health Anxiety Inventory Short Form (HAI-SF) and Beck Depression Inventory (BDI). Pain was assessed in patients with FMS using the Fibromyalgia Impact Questionnaire (FIQ) and Visual Analogue Scale (VAS). RESULTS: This study involved 95 patients with FMS (15 male) and 95 healthy controls (17 male). Mean +/- SD HAI-SF and BDI scores were significantly higher in patients with FMS = than in controls=. HAI-SF scores were 23.50 +/- 10.78 and 9.38 +/- 4.24 respectively; BDI scores were 18.64 +/- 10.11 and 6.21 +/- 4.05 respectively. There were highly significant correlations between FIQ and HAI-SF, FIQ and BDI, and HAI-SF and BDI. CONCLUSIONS: Patients with FMS had significantly higher HAI-SF and BDI scores than healthy controls. Psychiatric support is essential for patients with FMS. Treatment should include biological, psychological and social approaches. PMID- 26249749 TI - The tick Ixodes uriae (Acari: Ixodidae): Hosts, geographical distribution, and vector roles. AB - The seabird tick Ixodes uriae White 1852, has the most extensive geographical distribution of all tick species, including Afrotropical, Australasian, Nearctic, Neotropical and Palearctic Zoogeographic Regions. Additionally, this tick species parasitizes a wide range of seabirds and constitutes a host for several viral and bacterial agents. Considering the current biological knowledge about this tick species, in this article we list localities, hosts, tick-borne microorganisms and viruses transmitted by I. uriae described in the literature and include new geographical records. PMID- 26249742 TI - Polymorphism rs4263535 in GABRA1 intron 4 was related to deeper sedation by intravenous midazolam. AB - OBJECTIVE: To evaluate whether polymorphisms in the gamma-aminobutyric acid A receptor alpha1 subunit (GABRA1) gene influence sleep induction time, bispectral index score (BIS) during sleep induction and the total dose of midazolam required to reach a Ramsay Sedation Assessment Scale (RSAS) score of 4. METHODS: Patients scheduled for elective orthopaedic surgery were enrolled. All patients received initial doses of 0.02 mg/kg intravenous midazolam. If the RSAS score did not reach 4, an additional 1-mg dose of midazolam was administered. Results were compared among groups of patients with five single-nucleotide polymorphisms (SNPs) in GABRA1: rs4263535, rs980791, rs6556562, rs998754 and rs2279020. RESULTS: A total of 104 patients were evaluated. Polymorphism rs4263535 was associated with the lowest BIS during sedation induction. Multinomial logistic regression analysis demonstrated that polymorphism rs4263535 was significantly associated with the total dose of midazolam required for sedation induction. CONCLUSIONS: Polymorphism rs4263535 in GABRA1 intron 4 was associated with deeper sedation by intravenous midazolam. Patients with the A/A rs4263535 genotype required a smaller dose of midazolam. PMID- 26249744 TI - Study of suitability of Fricke-gel-layer dosimeters for in-air measurements to characterise epithermal/thermal neutron beams for NCT. AB - The reliability of Fricke gel dosimeters in form of layers for measurements aimed at the characterization of epithermal neutron beams has been studied. By means of dosimeters of different isotopic composition (standard, containing (10)B or prepared with heavy water) placed against the collimator exit, the spatial distribution of gamma and fast neutron doses and of thermal neutron fluence are attained. In order to investigate the accuracy of the results obtained with in air measurements, suitable MC simulations have been developed and experimental measurements have been performed utilizing Fricke gel dosimeters, thermoluminescence detectors and activation foils. The studies were related to the epithermal beam designed for BNCT irradiations at the research reactor LVR-15 (Rez). The results of calculation and measurements have revealed good consistency of gamma dose and fast neutron 2D distributions obtained with gel dosimeters in form of layers. In contrast, noticeable modification of thermal neutron fluence is caused by the neutron moderation produced by the dosimeter material. Fricke gel dosimeters in thin cylinders, with diameter not greater than 3mm, have proved to give good results for thermal neutron profiling. For greater accuracy of all results, a better knowledge of the dependence of gel dosimeter sensitivity on radiation LET is needed. PMID- 26249737 TI - Growth differentiation factor-15: a p53- and demethylation-upregulating gene represses cell proliferation, invasion, and tumorigenesis in bladder carcinoma cells. AB - Growth differentiation factor-15 (GDF15), a member of the TGF-beta superfamily, affects tumor biology of certain cancers, but remains poorly understood in bladder cancer cells. This study determined the expression, regulation, function, and potential downstream target genes of GDF15 in bladder carcinoma cells. The transitional papilloma carcionoma cells (RT4) expressed higher levels of GDF15 as compared with the bladder carcinoma cells (HT1376 and T24). Treatments of recombinant human GDF15 (rhGDF15) reduced the proliferations of HT1376 and T24 cells. Expression of GDF15 was upregulated via DNA demethylation and p53. The cell proliferation, invasion, and tumorigenesis were reduced in ectopic overexpression of GDF15, while enhanced in GDF15 knockdown. The expressions of mammary serine protease inhibitor (MASPIN) and N-myc downstream-regulated family genes (NDRG1, NDRG2, and NDRG3) were upregulated by GDF15 overexpressions and rhGDF15 treatments in bladder carcinoma cells. GDF15 knockdown induced epithelial mesenchymal transition (EMT) and F-actin polarization in HT1376 cells. Our results suggest that enhanced expressions of MASPIN and N-myc downstream regulated family genes and the modulation of EMT may account for the inhibitory functions of GDF15 in the cell proliferation, invasion, and tumorigenesis of bladder carcinoma cells. The GDF15 should be considered as a tumor suppressor in human bladder carcinoma cells. PMID- 26249745 TI - Prompt gamma and neutron detection in BNCT utilizing a CdTe detector. AB - In this work, a novel sensor technology based on CdTe detectors was tested for prompt gamma and neutron detection using boronated targets in (epi)thermal neutron beam at FiR1 research reactor in Espoo, Finland. Dedicated neutron filter structures were omitted to enable simultaneous measurement of both gamma and neutron radiation at low reactor power (2.5 kW). Spectra were collected and analyzed in four different setups in order to study the feasibility of the detector to measure 478 keV prompt gamma photons released from the neutron capture reaction of boron-10. The detector proved to have the required sensitivity to detect and separate the signals from both boron neutron and cadmium neutron capture reactions, which makes it a promising candidate for monitoring the spatial and temporal development of in vivo boron distribution in boron neutron capture therapy. PMID- 26249748 TI - Assessment of high-sensitive methods for the detection of EGFR mutations in circulating free tumor DNA from NSCLC patients. AB - AIM: We assessed the ability of the Therascreen((r)) kit (plasma-Therascreen) and of a peptide nucleic acids (PNA)-clamp approach to detect EGFR mutations in plasma-derived circulating-free tumor DNA (cftDNA) from non-small-cell lung cancer patients. MATERIALS & METHODS: cftDNA from 96 patients was analyzed for exon 19 deletions and the p.L858R mutation, using both plasma-Therascreen and PNA clamp-based assays. RESULTS: None of the 70 EGFR wild-type patients showed EGFR mutations in cftDNA with both techniques (specificity: 100%). In 17/26 EGFR mutant patients, plasma-Therascreen analysis confirmed the mutation identified in the primary tumor (analytical sensitivity: 65.4%). Similar results were obtained with the PNA-clamp method. CONCLUSION: Both approaches were specific and sensitive for EGFR mutational analysis of cftDNA in non-small-cell lung cancer patients. PMID- 26249750 TI - Survey on the Implementation of Preconception Care in Shanghai, China. AB - BACKGROUND: Recently, the Chinese government has promoted preconception care (PCC) to prevent birth defects. The objective of this study was to evaluate the implementation of PCC in Shanghai, China, following a 3-year municipal project providing 'Free Pre-pregnancy Health Evaluation Services' to 20 000 residents. METHODS: A retrospective questionnaire survey was undertaken among 12 309 pregnant women and 8997 of their partners during their initial prenatal visit in six hospitals with the most births in Shanghai. RESULTS: A total of 90% (n = 11 113) of the women and 87% (n = 7856) of the men were aware of PCC, and 40% (n = 4890) of the women and 35% (n = 3185) of the men had previously participated in PCC. Logistic regression showed that PCC participants were more likely to have a planned pregnancy, receive support from their partner for PCC services, were older, and have higher educational attainment and higher household incomes. Regardless of gender, there were significant differences between the participating and non-participating groups in terms of prepregnancy changes in lifestyle and behaviour, such as folic acid supplementation, smoking cessation (for men only), avoiding passive smoking, abstaining from alcohol/drugs, and rubella/hepatitis B immunity. CONCLUSIONS: The government-led efforts proved to be effective in promoting PCC participation and positive lifestyle and behavioural changes in couples of childbearing age. Future efforts should target couples who are young, poorly educated, and/or from low-income families. Strategies must ensure that the couples' knowledge of and positive attitudes toward PCC are translated into their practical participation in PCC. PMID- 26249753 TI - The assessment of the influence of vertical incisions on the aesthetic outcome of the Miller class I and II recession treatment: a split-mouth study. AB - AIM: The aim of this study was to compare the clinical and aesthetic parameters following a connective tissue graft (CTG) combined with the modified coronally advanced flap (MCAF), or the coronally advanced flap combined with vertical incisions (CAF) in the treatment of Miller class I and II recessions. MATERIALS AND METHODS: Twenty patients with 99 recessions were treated in a split-mouth study model. The MCAF with CTG was used on the right side, while the CAF with CTG was applied on the left side. The clinical and aesthetic evaluation was executed. RESULTS: The mean root coverage on the MCAF side was 90.52% 1 year post operatively, whereas on the CAF side was 91.77%. A complete root coverage (CRC) was achieved in 78.43% of gingival defects treated with the MCAF and 83.33% defects treated with the CAF. The average RES after the MCAF was 7.98 +/- 1.88 and after the CAF was 8.37 +/- 1.81. There was no significant difference in the CRC and RES values or their variables between the two techniques. CONCLUSIONS: MCAF with CTG and CAF with CTG allow obtaining satisfactory and comparable root coverage as well as an aesthetic outcome without the negative effect of vertical incisions on the appearance of soft tissue. PMID- 26249751 TI - A New Approach for Quantitative Determination of gamma-Cyclodextrin in Aqueous Solutions: Application in Aggregate Determinations and Solubility in Hydrocortisone/gamma-Cyclodextrin Inclusion Complex. AB - Fast and simple high-pressure liquid chromatographic (HPLC) method with charged aerosol detector (CAD) was developed for quantitation of gamma-cyclodextrin (gammaCD) in aqueous solutions. The chromatographic system consisted of a C18 column (i.e., the stationary phase) and an aqueous mobile phase containing 7% (v/v) methanol. Calibration curve was obtained over the gammaCD concentration range of 0.005%-1% (w/v). The limit of detection and quantitation of gammaCD were 0.0001% and 0.0002% (w/v), respectively. Formation of gammaCD aggregates in aqueous solution and their critical aggregation concentration (cac) were determined by both conventional dynamic light scattering method and permeation method using HPLC-CAD for quantitative determination of gammaCD. The cac of gammaCD was determined to be 0.95% (w/v) and the amount of gammaCD self aggregates increased with increasing gammaCD concentrations. Also, the developed HPLC-CAD method was used to determine the gammaCD phase-solubility profile in an aqueous hydrocortisone (HC)/gammaCD complexation medium. The maximum concentration of dissolved gammaCD and HC was determined to be 1.47% and 0.31% (w/v), respectively. The membrane permeation method was shown to be a reliable method for determination of metastable gammaCD aggregates. The HPLC-CAD method was successfully applied for quantitative determination of gammaCD in aqueous solutions during permeation and phase-solubility studies. PMID- 26249752 TI - National down syndrome patient database: Insights from the development of a multi center registry study. AB - The Down Syndrome Study Group (DSSG) was founded in 2012 as a voluntary, collaborative effort with the goal of supporting evidenced-based health care guidelines for individuals with Down syndrome (DS). Since then, 5 DS specialty clinics have collected prospective, longitudinal data on medical conditions that co-occur with DS. Data were entered by clinical staff or trained designees into the National Down Syndrome Patient Database, which we created using REDCap software. In our pilot year, we enrolled 663 participants across the U.S., ages 36 days to 70 years, from multiple racial and ethnic backgrounds. Here we report: (i) the demographic distribution of participants enrolled, (ii) a detailed account of our database infrastructure, and (iii) lessons learned during our pilot year to assist future researchers with similar goals for other patient populations. PMID- 26249746 TI - A critical view on microplastic quantification in aquatic organisms. AB - Microplastics, plastic particles and fragments smaller than 5mm, are ubiquitous in the marine environment. Ingestion and accumulation of microplastics have previously been demonstrated for diverse marine species ranging from zooplankton to bivalves and fish, implying the potential for microplastics to accumulate in the marine food web. In this way, microplastics can potentially impact food safety and human health. Although a few methods to quantify microplastics in biota have been described, no comparison and/or intercalibration of these techniques have been performed. Here we conducted a literature review on all available extraction and quantification methods. Two of these methods, involving wet acid destruction, were used to evaluate the presence of microplastics in field-collected mussels (Mytilus galloprovincialis) from three different "hotspot" locations in Europe (Po estuary, Italy; Tagus estuary, Portugal; Ebro estuary, Spain). An average of 0.18+/-0.14 total microplastics g(-1) w.w. for the Acid mix Method and 0.12+/-0.04 total microplastics g(-1) w.w. for the Nitric acid Method was established. Additionally, in a pilot study an average load of 0.13+/-0.14 total microplastics g(-1) w.w. was recorded in commercial mussels (Mytilus edulis and M. galloprovincialis) from five European countries (France, Italy, Denmark, Spain and The Netherlands). A detailed analysis and comparison of methods indicated the need for further research to develop a standardised operating protocol for microplastic quantification and monitoring. PMID- 26249755 TI - Clinical human hepatocyte transplantation: Current status and challenges. PMID- 26249759 TI - Combination of Cyanine Behaviour and Giant Hyperpolarisability in Novel Merocyanine Dyes: Beyond the Bond Length Alternation (BLA) Paradigm. AB - Merocyanine dyes that exhibit antithetic cyanine-like behaviour and giant first order hyperpolarisability (beta) values have been designed. These cyanine-type dyes open up an intriguing route towards molecular-based electro-optic materials as well as new second-harmonic generation dyes for imaging. PMID- 26249743 TI - How the embryo makes a limb: determination, polarity and identity. AB - The vertebrate limb with its complex anatomy develops from a small bud of undifferentiated mesoderm cells encased in ectoderm. The bud has its own intrinsic polarity and can develop autonomously into a limb without reference to the rest of the embryo. In this review, recent advances are integrated with classical embryology, carried out mainly in chick embryos, to present an overview of how the embryo makes a limb bud. We will focus on how mesoderm cells in precise locations in the embryo become determined to form a limb and express the key transcription factors Tbx4 (leg/hindlimb) or Tbx5 (wing/forelimb). These Tbx transcription factors have equivalent functions in the control of bud formation by initiating a signalling cascade involving Wnts and fibroblast growth factors (FGFs) and by regulating recruitment of mesenchymal cells from the coelomic epithelium into the bud. The mesoderm that will form limb buds and the polarity of the buds is determined with respect to both antero-posterior and dorso-ventral axes of the body. The position in which a bud develops along the antero-posterior axis of the body will also determine its identity - wing/forelimb or leg/hindlimb. Hox gene activity, under the influence of retinoic acid signalling, is directly linked with the initiation of Tbx5 gene expression in the region along the antero-posterior axis of the body that will form wings/forelimbs and determines antero-posterior polarity of the buds. In contrast, Tbx4 expression in the regions that will form legs/hindlimbs is regulated by the homeoprotein Pitx1 and there is no evidence that Hox genes determine antero-posterior polarity of the buds. Bone morphogenetic protein (BMP) signalling determines the region along the dorso-ventral axis of the body in which both wings/forelimbs and legs/hindlimbs develop and dorso-ventral polarity of the buds. The polarity of the buds leads to the establishment of signalling regions - the dorsal and ventral ectoderm, producing Wnts and BMPs, respectively, the apical ectodermal ridge producing fibroblast growth factors and the polarizing region, Sonic hedgehog (Shh). These signals are the same in both wings/forelimbs and legs/hindlimbs and control growth and pattern formation by providing the mesoderm cells of the limb bud as it develops with positional information. The precise anatomy of the limb depends on the mesoderm cells in the developing bud interpreting positional information according to their identity - determined by Pitx1 in hindlimbs - and genotype. The competence to form a limb extends along the entire antero-posterior axis of the trunk - with Hox gene activity inhibiting the formation of forelimbs in the interlimb region - and also along the dorso ventral axis. PMID- 26249757 TI - Virtual reconstruction of the Neanderthal Amud 1 cranium. AB - OBJECTIVES: We describe a new computer reconstruction to obtain complete anatomical information of the ecto- and endocranium from the imperfectly preserved skull of the Neanderthal Amud 1. MATERIALS AND METHODS: Data were obtained from computed tomography scans of the fossil cranium. Adhesive and plaster were then virtually removed from the original specimen, and the fragments comprising the fossil cranium were separated. These fragments were then mathematically reassembled based on the smoothness of the joints. Both sides of the cranium were reassembled separately, and then aligned based on bilateral symmetry and the distance between the mandibular fossae obtained from the associated mandible. The position of the isolated maxilla was determined based on the position of the mandible that was anatomically articulated to the mandibular fossae. To restore missing basicranial and damaged endocranial regions, the cranium of Forbes' Quarry 1 was warped onto that of La Chapelle-aux-Saints 1, and the resulting composite Neanderthal cranium was then warped onto the reconstructed Amud 1 by an iterative thin-plate spline deformation. RESULTS: Comparison of the computer reconstruction with the original indicated that the newly reconstructed Amud 1 cranium was slightly shorter and wider in the anteroposterior and mediolateral directions, respectively, suggesting that it was relatively more brachycephalic. The endocranial volume was estimated to be 1,736 cm3 , which was quite similar to the original estimated value of 1,740 cm3 . DISCUSSION: This new computer reconstruction enables not only measurement of new cranial metrics, but also inclusion of the Amud 1 specimen in three-dimensional geometric morphometric analyses that were previously difficult due to its incompleteness. Am J Phys Anthropol 158:185-197, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26249754 TI - Accuracy of inhaled agent usage displays of automated target control anesthesia machines. AB - Automated low flow anesthesia machines report how much inhaled anesthetic agent has been used for each anesthetic. We compared these reported values with the amount of agent that had disappeared by weighing the vaporizer/injectors before and after each anesthetic. The vaporizers/injectors of the Aisys, Zeus and FLOW-i were weighed with a high precision weighing scale before and after anesthesia with either desflurane in O2/air or sevoflurane in O2/N2O. These values were compared with the values reported by the cumulative agent use display tools of the respective anesthesia machines using a linear curve fit. Twenty-five measurements were performed in each group, except for the sevoflurane data with the Aisys that were available from another study (87 pairs). We also determined the amount lost by inserting and removing the vaporizers/injectors or by performing a machine checkout, corrected the measured amounts for these artifacts and repeated the linear fits. The average amount of sevoflurane and desflurane wasted by inserting and removing the cassette for the Aisys, Zeus, and FLOW-i were 0.21, 0.12, and 0.04 mL and 0.12, 0.61, and 1.13 mL liquid agent, respectively. The average amount of sevoflurane and desflurane wasted by the machine checkout with the Aisys, Zeus, and FLOW-i were 1.78, 0.21, and 1.67 mL and 2.39, 0.67, and 4.19 mL, respectively. Performance error of the displayed amount of agent use remained within 10 % of the weighed amount, expect for amounts less than 3 mL sevofurane with the FLOW-i and less than 20 mL desflurane with the Aisys and FLOW-i. Cumulative agent usage displayed by the Aisys, Zeus, and FLOW-i is within 10 % of the measured consumption, except for low consumption cases (<3 mL sevoflurane, <20 mL desflurane). The differences may be due to either measurement error or cumulative agent display error. The current results can help the researchers decide whether the displayed amounts are accurate enough for their study purposes. The extent to which these discrepancies differ between different units of the same machine remains unstudied. PMID- 26249762 TI - A mission-driven organization. PMID- 26249764 TI - Inhibition of chemokine receptor CCR2 reduces sarcoma cell transendothelial migration and metastasis to the lungs. PMID- 26249756 TI - TLR4 stimulation and corticosteroid interactively induce osteonecrosis of the femoral head in rat. AB - We previously reported that a toll-like receptor 4 signaling contributes to the development of osteonecrosis of the femoral head. Also, oxidative stress is suggested to be one of the possible pathogenesis of osteonecrosis of the femoral head. A recent study showed that toll-like receptor 4 signaling leads to oxidative stress. The aim of the present study was to evaluate whether toll-like receptor 4 stimulation and subsequent corticosteroid treatment lead to the development of osteonecrosis of the femoral head in rat, and oxidative stress is associated with it. Male Wistar rats were randomly divided into four treatment groups: Saline + Saline, Saline + Methylprednisolone, Lipopolysaccharide + Saline, Lipopolysaccharide + Methylprednisolone. Osteonecrosis of the femoral head at 14 days after the treatment was observed in 1 of 10 Lipopolysaccharide + Saline, and 5 of 10 Lipopolysaccharide + Methylprednisolone treated rats. However, it was not observed at all in the Saline + Saline and Saline + Methylprednisolone treated groups. Glutathione peroxidase activity in the liver at 1 day after the treatment was significantly increased when treated with lipopolysaccharide. However, methylprednisolone treatment reduced the activity. On the other hand, glutathione peroxidase activity in the femur did not change in any intergroup. In conclusion, the present study showed that toll-like receptor 4 stimulation by lipopolysaccharide administration strengthen incidence of corticosteroid-induced osteonecrosis of the femoral head, however, concomitant oxidative stress via toll-like receptor 4 signaling may not contribute to the development of osteonecrosis of the femoral head in rats. PMID- 26249747 TI - Innate immunity against Leishmania infections. AB - Leishmaniasis is a major health problem that affects more than 300 million people throughout the world. The morbidity associated with the disease causes serious economic burden in Leishmania endemic regions. Despite the morbidity and economic burden associated with Leishmaniasis, this disease rarely gets noticed and is still categorized under neglected tropical diseases. The lack of research combined with the ability of Leishmania to evade immune recognition has rendered our efforts to design therapeutic treatments or vaccines challenging. Herein, we review the literature on Leishmania from innate immune perspective and discuss potential problems as well as solutions and future directions that could aid in identifying novel therapeutic targets to eliminate this parasite. PMID- 26249763 TI - Relevance of subcellular localization of extracellular signal-regulated kinase 1/2 (ERK1/2) for cisplatin resistance. PMID- 26249761 TI - Practical use of povidone-iodine antiseptic in the maintenance of oral health and in the prevention and treatment of common oropharyngeal infections. AB - AIMS: To better inform medical practitioners on the role of antiseptics in oropharyngeal health and disease, this article focuses on povidone-iodine (PVP I), an established and widely-available antiseptic agent. METHODOLOGY: Review of the anti-infective profile, efficacy and safety of PVP-I in managing common upper respiratory tract infections such as the common cold, influenza and tonsillo pharyngitis, as well as oral complications resulting from cancer treatment (oral mucositis), and dental conditions (periodontitis, caries). RESULTS: Antiseptics with broad-spectrum anti-infective activity and low resistance potential offer an attractive option in both infection control and prevention. While there is some evidence of benefit of antiseptics in a variety of clinical settings that include dental and oral hygiene, dermatology, oncology, and pulmonology, there appears to be discordance between the evidence-base and practice. This is especially apparent in the management and prevention of oropharyngeal infections, for which the use of antiseptics varies considerably between clinical practices, and is in marked contrast to their dermal application, where they are extensively used as both a prophylaxis and a treatment of skin and wound infections, thus minimising the use of antibiotics. CONCLUSION: The link between oral and oropharyngeal health status and susceptibility to infection has long been recognised. The high rates of antibiotic misuse and subsequent development of bacterial resistance (e.g. increasing vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA)) in large parts of the world, especially across Asia Pacific, highlight the need for identifying alternative antimicrobials that would minimise the use of these medications. This, together with recent large-scale outbreaks of, for example, avian and swine influenza virus, further underline the importance of an increasing armamentarium for infection prevention and control. PMID- 26249760 TI - Review of heart failure treatment in type 2 diabetes patients: It's at least as effective as in non-diabetic patients! AB - Our society is currently facing an epidemic of diabetes and heart failure. Historically, certain cardiology treatments, mainly beta-blockers, have been considered 'dangerous' in diabetic patients, but the time has come for personalized medicine to be applied in the field of cardiology, especially in heart failure (HF). To determine whether HF treatment should be individualized according to diabetes status, this review of the available randomized evidence was carried out, with special emphasis on treatment-effect modification in relation to diabetes. Based on a large body of evidence in the literature, our review concludes that HF treatment should be the same for diabetic and non diabetic patients. In concurrence, international guidelines now strongly advocate the use of HF drugs, including beta-blockers, in diabetic HF patients. The benefit of HF treatment is at least as favourable in such patients as in non diabetic patients on a relative basis. Given the higher risk of events in diabetics, this could translate to an even greater absolute impact of HF treatment in these patients, which should further encourage caregivers to more aggressively manage HF in diabetic patients. To this end, non-cardiologists, including general practitioners and endocrinologists/diabetologists who treat diabetic HF patients, should be considered part of the HF drug optimalization process, including the referral of patients to specialized centres for possible implantable cardiac defibrillators and/or cardiac resynchronization indication assessment. PMID- 26249768 TI - A new era of patient- and family-centered innovation in healthcare. PMID- 26249769 TI - Healthcare: Serving the Patient. PMID- 26249772 TI - The EFECT framework for interprofessional education in the patient centered medical home. AB - The very nature of the Patient-Centered Medical Home (PCMH) necessitates new instructional models that prepare learners for the roles they will have to assume in these transformed primary care practices. In this manuscript we describe a new instructional framework that seeks to blend the goals of patient-centered care and inter-professional education, and can be implemented in existing training environments while practice transformation continues to proceed. We propose a 5 step process, the EFECT framework, which is simultaneously a sequence of tasks for effective patient care and a guide for the learners and faculty in teaching and evaluating that care delivery. These steps include: (1) Eliciting a patient centered narrative, (2) Facilitating an inter-professional team discussion, (3) Evaluating clinical evidence, (4) Creating a shared care plan, and (5) Tracking outcomes. We then report preliminary descriptive outcomes from the first EFECT pilot. Our proposed framework supports learners' abilities to construct a patient centered narrative from multiple professional perspectives as the basis for developing an evidence-based, integrated care plan between the patient and the inter-professional care team and deliberately following up on outcomes. We present this framework to stimulate a process for creating new curricula and evaluative tools to measure and promote learner functioning in medical home environments. PMID- 26249767 TI - Once-daily dosing of levocabastine has comparable efficacy to twice-daily dosing in the treatment of allergic rhinitis assessed in an allergen challenge chamber. AB - OBJECTIVES: To test the hypothesis that intranasal levocabastine (LEVO) may provide benefits as a oncedaily treatment in allergic rhinitis (AR), this non inferiority study compared the effect at steady state of once- and twice-daily dosing with LEVO on allergen-induced nasal symptoms in AR patients. METHODS: This was a randomized, double-blind, three-way cross over study evaluating the effects of repeat doses of LEVO 200 ug once-daily, LEVO 200 ug twice-daily (total dose 400 ug) and placebo, all via intranasal spray, in 78 AR patients. The primary endpoint was weighted mean total nasal symptom score (TNSS) during a 4-hour allergen exposure in the Environmental Exposure Chamber measured at trough pharmacokinetic levels either 12 (LEVO twice-daily) or 24 (LEVO once-daily) hours post-dose. RESULTS: After 7 days dosing, the difference in weighted mean TNSS (0 4 hours) following LEVO once-daily versus twice-daily was 0.23 units (95% CI 0.36, 0.82), demonstrating noninferiority between the two LEVO dosing regimens by meeting the pre-specified criterion of an upper limit of 95% CI<1.0. Both dosing regimens of LEVO resulted in a statistically significant reduction in mean TNSS compared with placebo (adjusted mean difference from placebo: LEVO once-daily: 1.12 (95% CI -1.71, -0.53); LEVO twice-daily: -1.35 (-1.94, -0.76)), meeting the pre-specified criterion for superiority (upper limit of 95% CI<0). All treatments were well-tolerated. CONCLUSIONS: The results of this study support the hypothesis that at steady state LEVO 200 ug taken once-daily provides similar benefit to LEVO 200 ug dosed twice-daily. PMID- 26249771 TI - The evolving role of health services researchers in a transforming healthcare system. PMID- 26249774 TI - Patient-centered innovation: The VA approach. PMID- 26249765 TI - Pharmacokinetics and bioavailability in healthy Chinese volunteers of a novel rabeprazole sterile powder formulation for injection. AB - Rabeprazole sterile powder for injection (RSPI) is a new formulation, compared with rabeprazole enteric coated tablets. The aim of this study was to evaluate the pharmacokinetic properties and bioavailability of RSPI in healthy Chinese volunteers. Pharmacokinetic studies included an ascending single dose of 10, 20, 40 mg, and a multiple doses of 20 mg. A bioavailability study was evaluated following a single dose of 20 mg between RSPI and Pariet(r) Pharmacokinetic parameters of rabeprazole given in each treatment period were calculated using non-compartmental analysis. In the PK study, after a single intravenous dose of 10, 20, and 40 mg, the main pharmacokinetic parameters for rabeprazole were as follows: Cmax 566.88, 897.23, 2,171.6 ng/mL; AUClast/794.31, 1,122.76, 2,446.85 ng*h/mL, respectively. After multiple doses of 20 mg, the main pharmacokinetic parameters for rabeprazole were Cmax 991.90 ng/mL, AUClast 1,261.08 ng*h/mL. In the BA study, after a single oral dose of Pariet(r) 20 mg, the main pharmacokinetic parameters for rabeprazole were Cmax 582.74 ng/mL, AUClast 1,135.5 ng*h/mL. RSPI produced a less-than-proportional increase in exposure with increasing dose in healthy subjects. The accumulation ratio was 1.0, suggesting RSPI displayed no accumulation after repeated administration. The bioavailability of RSPI was increased by ~ 11% as measured by AUClast compared with Pariet(r) after a single oral administration. PMID- 26249770 TI - Patients as customers: Applying service industry lessons to health care. PMID- 26249773 TI - How it's done: Keys to implementation of delivery system reform. AB - The vision of Obamacare - including the expansion of health care coverage to millions more Americans - rests in no small part on the reduction of health care waste and the spread of cheaper, more sustainable models of health care delivery. Though this will require thoughtful policy, powerful payment incentives and innovative new models of care delivery, it will also require all health care industry stakeholders to execute rapid, large-scale change in practice much more effectively. This paper offers nine strategies for more successfully managing this transformative change. PMID- 26249775 TI - Paying for value: What's next? PMID- 26249776 TI - The new tools: What 21st century education can teach us. AB - This article explores the shifting education paradigm that leverages videos and massive online open courses (MOOCs) and the implication of these developments for the patient-doctor encounter. This essay argues that medicine can learn from the rapid evolution of online video learning techniques to empower both patients and clinicians. Video technology is a powerful tool for the patient and physician and has the potential to significantly improve the delivery of care in an increasingly complex health care system. PMID- 26249758 TI - RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection. AB - Acute cellular rejection (ACR) is the adverse response of the recipient's immune system against the allogeneic graft. Using human surveillance endomyocardial biopsies (EMBs) manifesting ACR and murine allogeneic grafts, we profiled implicated microRNAs (miRs) and mRNAs. MiR profiling showed that miR-21, -142-3p, -142-5p, -146a, -146b, -155, -222, -223, and -494 increased during ACR in humans and mice, whereas miR-149-5p decreased. mRNA profiling revealed 70 common differentially regulated transcripts, all involved in immune signaling and immune related diseases. Interestingly, 33 of 70 transcripts function downstream of IL-6 and its transcription factor spleen focus forming virus proviral integration oncogene (SPI1), an established target of miR-155, the most upregulated miR in human EMBs manifesting rejection. In a mouse model of cardiac transplantation, miR-155 absence and pharmacological inhibition attenuated ACR, demonstrating the causal involvement and therapeutic potential of miRs. Finally, we corroborated our miR signature in acute cellular renal allograft rejection, suggesting a nonorgan specific signature of acute rejection. We concluded that miR and mRNA profiling in human and murine ACR revealed the shared significant dysregulation of immune genes. Inflammatory miRs, for example miR-155, and transcripts, in particular those related to the IL-6 pathway, are promising therapeutic targets to prevent acute allograft rejection. PMID- 26249778 TI - HALE and hearty: Toward more meaningful health measurement in the clinical setting. PMID- 26249777 TI - Patient-centered financial incentives for health: Can employers get change for their dollars? AB - While employer-sponsored financial incentives for healthy behaviors have demonstrated the potential to promote short-term employee behavior change, the effectiveness of such incentives in promoting long-term health behavior change has often been disappointing. This paucity of sustained change could be explained by the many factors that shape employees' health behaviors, only some of which may be influenced by incentives. We discuss how employer-sponsored incentives for healthy behaviors could become more patient-centered, and thus perhaps more effective, by integrating insights from self-determination theory and health behavior theories, targeting employees' capacity for change, and using tailoring. PMID- 26249766 TI - Ibuprofen lysinate, quicker and less variable: relative bioavailability compared to ibuprofen base in a pediatric suspension dosage form. AB - OBJECTIVES: To assess and compare the bioavailability of ibuprofen enantiomers (R and S) of two different pediatric suspensions: the first one with ibuprofen lysinate (Algidrin(r) Pediatrico, FARDI S.A., Barcelona, Spain) and the second one with ibuprofen base (Dalsy(r), Abbott Laboratories S.A., Madrid, Spain). METHODS: A randomized, open-label, single-dose, balanced, crossover study under fasting conditions was performed at the CIM-Sant Pau. 24 healthy volunteers received a single dose of ibuprofen lysinate (AlgidrinA(r) PediA!trico, FARDI S.A.) and ibuprofen base (Dalsy(r), Abbott Laboratories S.A.) equivalent to 400 mg of ibuprofen. 18 blood samples were drawn and ibuprofen enantiomer plasma concentrations were determined using an enantioselective analytical method. An analysis of variance (ANOVA) model was used, and the 90% confidence intervals (CI) were calculated; further analyses were made regarding rate of absorption and variability. RESULTS: The pharmacokinetic parameters (Algidrin(r) Pediatrico vs. Dalsy(r) (Mean+/-SD)) were: S-enantiomer: Cmax=22.39+/-5.33 vs. 19.97+/-3.19 MUg/mL; AUC0t=74.83+/-16.69 vs. 74.64+/-14.80 MUg*h/mL, and AUC0infinity=77.46+/ 19.33 vs. 76.98+/-17.13 MUg*h/mL; and for R-enantiomer: Cmax=21.74+/-3.76 vs. 15.20+/-2.03 MUg/mL; AUC0t=57.55+/-10.17 vs. 46.13+/-9.61 MUg*h/mL, and AUC0infinity value was 58.49+/-10.57 vs. 47.03+/-10.02 MUg*h/mL. The tmax (Median) for S-enantiomer (active) were: 0.5 vs. 1.33 hours (p=0.001) and for R enantiomer: 0.5 vs. 1.0 hours (p=0.004). Ibuprofen pharmacokinetic values may vary under fed state and in pediatric population. CONCLUSIONS: While S-ibuprofen shows a similar bioavailability for AUC0t, AUC0infinity, and Cmax, R-ibuprofen shows suprabioavailability for the lysinate formulation. The rate of absorption of the ibuprofen lysinate suspension is quicker and less variable than that of the ibuprofen base reference suspension and it exhibits a shorter tmax, which is of particular interest for achieving a rapid and homogeneous analgesic and antipyretic effect. PMID- 26249787 TI - Snapshots from the State Innovation Models initiative. PMID- 26249782 TI - Measuring the value of process improvement initiatives in a preoperative assessment center using time-driven activity-based costing. AB - BACKGROUND: The value and impact of process improvement initiatives are difficult to quantify. We describe the use of time-driven activity-based costing (TDABC) in a clinical setting to quantify the value of process improvements in terms of cost, time and personnel resources. PROBLEM: Difficulty in identifying and measuring the cost savings of process improvement initiatives in a Preoperative Assessment Center (PAC). GOALS: Use TDABC to measure the value of process improvement initiatives that reduce the costs of performing a preoperative assessment while maintaining the quality of the assessment. STRATEGY: Apply the principles of TDABC in a PAC to measure the value, from baseline, of two phases of performance improvement initiatives and determine the impact of each implementation in terms of cost, time and efficiency. RESULTS: Through two rounds of performance improvements, we quantified an overall reduction in time spent by patient and personnel of 33% that resulted in a 46% reduction in the costs of providing care in the center. The performance improvements resulted in a 17% decrease in the total number of full time equivalents (FTE's) needed to staff the center and a 19% increase in the numbers of patients assessed in the center. Quality of care, as assessed by the rate of cancellations on the day of surgery, was not adversely impacted by the process improvements. PMID- 26249781 TI - A novel community-based delivery model to combat cancer disparities. PMID- 26249779 TI - Experience-based design for integrating the patient care experience into healthcare improvement: Identifying a set of reliable emotion words. AB - BACKGROUND: Experience-based design is an emerging method used to capture the emotional content of patient and family member healthcare experiences, and can serve as the foundation for patient-centered healthcare improvement. However, a core tool-the experience-based design questionnaire-requires words with consistent emotional meaning. Our objective was to identify and evaluate an emotion word set reliably categorized across the demographic spectrum as expressing positive, negative, or neutral emotions for experience-based design improvement work. METHODS: We surveyed 407 patients, family members, and healthcare workers in 2011. Participants designated each of 67 potential emotion words as positive, neutral, or negative based on their emotional perception of the word. Overall agreement was assessed using the kappa statistic. Words were selected for retention in the final emotion word set based on 80% simple agreement on classification of meaning across subgroups. RESULTS: The participants were 47.9% (195/407) patients, 19.4% (33/407) family members and 32.7% (133/407) healthcare staff. Overall agreement adjusted for chance was moderate (k=0.55). However, agreement for positive (k=0.69) and negative emotions (k=0.68) was substantially higher, while agreement in the neutral category was low (k=0.11). There were 20 positive, 1 neutral, and 14 negative words retained for the final experience-based design emotion word set. CONCLUSIONS: We identified a reliable set of emotion words for experience questionnaires to serve as the foundation for patient-centered, experience-based redesign of healthcare. IMPLICATIONS: Incorporation of patient and family member perspectives in healthcare requires reliable tools to capture the emotional content of care touch points. PMID- 26249785 TI - Interview with Harvey V. Fineberg, MD, PhD. PMID- 26249783 TI - Interview with Donald M. Berwick, MD, MPP. PMID- 26249784 TI - Interview with Carolyn M. Clancy, MD. PMID- 26249780 TI - Paying physician group practices for quality: A statewide quasi-experiment. AB - This article presents the results of a unique quasi-experiment of the effects of a large-scale pay-for-performance (P4P) program implemented by a leading health insurer in Washington state during 2001-2007. The authors received external funding to provide an objective impact evaluation of the program. The program was unique in several respects: (1) It was designed dynamically, with two discrete intervention periods-one in which payment incentives were based on relative performance (the "contest" period) and a second in which payment incentives were based on absolute performance compared to achievable benchmarks. (2) The program was designed in collaboration with large multispecialty group practices, with an explicit run-in period to test the quality metrics. Public reporting of the quality scorecard for all participating medical groups was introduced 1 year before the quality incentive payment program's inception, and continued throughout 2002-2007. (3) The program was implemented in stages with distinct medical groups. A control group of comparable group practices also was assembled, and difference-in-differences methodology was applied to estimate program effects. Case mix measures were included in all multivariate analyses. The regression design permitted a contrast of intervention effects between the "contest" approach in the sub-period of 2003-2004 and the absolute standard, "achievable benchmarks of care" approach in sub-period 2005-2007. Most of the statistically significant quality incentive program coefficients were small and negative (opposite to program intent). A consistent pattern of differential intervention impact in the sub-periods did not emerge. Cumulatively, the probit regression estimates indicate that neither the quality scorecard nor the quality incentive payment program had a significant positive effect on general clinical quality. Based on key informant interviews with medical leaders, practicing physicians, and administrators of the participating groups, the authors conclude that several factors likely combined to dampen program effects: (1) modest size of the incentive; (2) use of rewards only, rather than a balance of rewards and penalties; (3) targeting incentive payments to the group, thus potentially weakening incentive effects at the individual level. PMID- 26249789 TI - A general model for resolution of digital holographic microscopy. AB - For digital holographic microscopic imaging, the resolution in the reconstructed image is one of the most important parameters. To optimize the lateral resolution, a general model for the resolution of digital holographic microscopy (DHM) is proposed in this work, in which the effects of the sizes of each pixel, total area of the charge coupled device (CCD) and the microscopic objective lens are taken into account. Comparison between our model and others was carried out by calculating the point spread function (PSF) of DHM at different reconstruction distances and with different fill factors. It is shown that the effect of fill factors on the resolution of DHM becomes significant when the reconstruction distance is long. For high resolution DHM imaging the influence of fill factors must be taken into account when estimating the resolution of the reconstructed image. Furthermore, It is also demonstrated that the sidelobe of PSF can be cut effectively choosing appropriate values of the fill factors. Finally, the reconstructions of polyethylene microspheres have been implemented to demonstrate the theoretical analysis. These results obtained are helpful for estimation of the resolution and design of the DHM systems. PMID- 26249790 TI - Vitamin D in colorectal cancer: should we follow the flow? PMID- 26249796 TI - Protein Structure. PMID- 26249794 TI - Novel scalable and monolithically integrated extracorporeal gas exchange device. AB - A novel extracorporeal gas exchange device (EGED) is developed, implemented and characterized. The aim hereby is to overcome drawbacks of state-of-the-art devices and of state-of-science approaches, like their labor intensive fabrication and their low volume density of the gas exchange area, respectively. As a consequence of the stacked setup of alternating layers of the blood compartment and the ventilation gas compartment, the developed EGED allows for double sided gas exchange. Furthermore, it enables an adaption to the diversity of medical requirements by scaling the amount of layers. The developed fabrication chain is used to fabricate leakage-free evaluation models and allows for a transition to automated fabrication. The EGED is completely fabricated in polydimethylsiloxane (PDMS) and features diffusion membranes, which are separating the compartments, with a mean thickness of 90 MUm. With the evaluation models and oxygen as ventilation gas an oxygen transfer of 60 ml/lblood (25 ml/(min m(2))) and a carbon dioxide transfer of 70 ml/lblood (30 ml/(min m(2))) are achieved. The linear scalability of the concept as well as the functionality of the EGED with air as ventilation gas is shown. PMID- 26249807 TI - Importance of Reaction Kinetics and Oxygen Crossover in aprotic Li-O2 Batteries Based on a Dimethyl Sulfoxide Electrolyte. AB - Although still in their embryonic state, aprotic rechargeable Li-O2 batteries have, theoretically, the capabilities of reaching higher specific energy densities than Li-ion batteries. There are, however, significant drawbacks that must be addressed to allow stable electrochemical performance; these will ultimately be solved by a deeper understanding of the chemical and electrochemical processes occurring during battery operations. We report a study on the electrochemical and chemical stability of Li-O2 batteries comprising Au coated carbon cathodes, a dimethyl sulfoxide (DMSO)-based electrolyte and Li metal negative electrodes. The use of the aforementioned Au-coated cathodes in combination with a 1 M lithium bis(trifluoromethane)sulfonimide (LiTFSI)-DMSO electrolyte guarantees very good cycling stability (>300 cycles) by minimizing eventual side reactions. The main drawbacks arise from the high reactivity of the Li metal electrode when in contact with the O2 -saturated DMSO-based electrolyte. PMID- 26249805 TI - ALK7 protects against pathological cardiac hypertrophy in mice. AB - AIMS: Activin receptor-like kinase 7 (ALK7), one of the type I transforming growth factor-beta receptors, is expressed in various tissues, including the heart. However, the participation of ALK7 in the regulation of cardiac hypertrophy has not yet been studied. Here, we sought to determine the regulatory role and underlying mechanisms of ALK7 in cardiac hypertrophy. METHODS AND RESULTS: We performed aortic banding (AB) in ALK7-knockout mice, cardiac-specific ALK7-transgenic mice, and the wild-type littermates of these mice. Cardiac hypertrophy was evaluated using pathological analysis, echocardiographic measurement, haemodynamic measurement, and molecular analysis. Our results revealed that ALK7 disruption led to an aggravated cardiac hypertrophic response that was accompanied by increased cardiac fibrosis and reduced contractile function, whereas cardiac-specific ALK7 overexpression exhibited the opposite phenotype in response to pressure overload. Similarly, ALK7 protected against angiotensin II-induced cardiomyocyte hypertrophy in vitro. Mechanistically, we demonstrated that ALK7-dependent cardioprotection was mediated largely through inhibition of the MEK-ERK1/2 signalling pathway. CONCLUSION: Our data suggest that ALK7 acts as a novel regulator of pathological cardiac hypertrophy via the negative regulation of MEK-ERK1/2 signalling and may serve as a potential therapeutic target for pathological cardiac hypertrophy. PMID- 26249795 TI - A nested case-control study on dietary fat consumption and the risk for gallstone disease. AB - BACKGROUND: Gallstone disease (GD) incidence and prevalence rates differ between populations. Diet and lifestyle may be involved in GD development. To our knowledge, no study to date has evaluated quantitative data on diet when studying the relationship between fat consumption levels and GD in an Argentinean population. The present study aimed to assess the association between dietary fat intake and GD. METHODS: A nested case-control study design was applied. Data were taken from subjects who participated in a previous cross-sectional study carried out in a random sample of asymptomatic people in Rosario, Argentina. Participants underwent a personal interview, and current weight and height, ancestor's ethnicity, and socio-economic status were recorded. Applying a food-frequency questionnaire and a food photography atlas, quantitative dietary data were estimated by combining the intake frequency, portion size and food composition. Logistic regression analysis was used to compute odds ratios and 95% confidence intervals adjusted by age, sex, ancestor's ethnicity, body mass index and daily total energy intake as potential confounders. RESULTS: In total, 114 patients were studied (49 cases and 65 controls), without any statistically significant differences for age, sex, socio-economic status, body mass index and ancestry. The mean energy intake was higher in cases than in controls, and significant differences were found for dietary fat consumption. Obese or overweight people have a higher GD risk than subjects with normal weight. Increased GD risks were associated with high intakes of energy, total fat, and saturated and monounsaturated fatty acids. CONCLUSIONS: According to our results, total fat, saturated and monounsaturated fatty acids high intakes are associated with increased GD risk. PMID- 26249793 TI - Rapamycin, a specific inhibitor of the target of rapamycin complex 1, disrupts intestinal barrier integrity in broiler chicks. AB - To uncover the molecular mechanisms underlying the intestinal barrier integrity, this study determined whether the rapamycin (RAPA)-sensitive target of rapamycin complex 1 (TORC1) pathway was involved in this process. Three groups of 4-day-old male chicks were randomly subjected to one of the following treatments for 6 days: high-dose RAPA [a specific inhibitor of TORC1; an intraperitoneal injection of 1.0 mg/kg body weight (BW), once daily at 09:00 hours], low-dose RAPA (0.4 mg/kg BW) and RAPA vehicle (control). Results showed that the RAPA treatment increased mortality, while decreasing villus height (p < 0.01), claudin 1 expression, content of immunoglobulin A (IgA), extent of TORC1 phosphorylation (p < 0.05), ratio of villus height to crypt depth (p < 0.01), and population of IgA positive B cells in intestinal mucosa, particularly for the jejunum. Some aspects of these responses were dose dependent and appeared to result from weight loss. Together, RAPA exerts the expected inhibition of small intestinal development and IgA production in birds, suggesting the important role of TORC1 in gut barrier integrity. PMID- 26249808 TI - ARResT/AssignSubsets: a novel application for robust subclassification of chronic lymphocytic leukemia based on B cell receptor IG stereotypy. AB - MOTIVATION: An ever-increasing body of evidence supports the importance of B cell receptor immunoglobulin (BcR IG) sequence restriction, alias stereotypy, in chronic lymphocytic leukemia (CLL). This phenomenon accounts for ~30% of studied cases, one in eight of which belong to major subsets, and extends beyond restricted sequence patterns to shared biologic and clinical characteristics and, generally, outcome. Thus, the robust assignment of new cases to major CLL subsets is a critical, and yet unmet, requirement. RESULTS: We introduce a novel application, ARResT/AssignSubsets, which enables the robust assignment of BcR IG sequences from CLL patients to major stereotyped subsets. ARResT/AssignSubsets uniquely combines expert immunogenetic sequence annotation from IMGT/V-QUEST with curation to safeguard quality, statistical modeling of sequence features from more than 7500 CLL patients, and results from multiple perspectives to allow for both objective and subjective assessment. We validated our approach on the learning set, and evaluated its real-world applicability on a new representative dataset comprising 459 sequences from a single institution. AVAILABILITY AND IMPLEMENTATION: ARResT/AssignSubsets is freely available on the web at http://bat.infspire.org/arrest/assignsubsets/ CONTACT: nikos.darzentas@gmail.com. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26249788 TI - Salmonella Typhimurium strain expressing OprF-OprI protects mice against fatal infection by Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa poses a major threat to human health and to the mink industry. Thus, development of vaccines that elicit robust humoral and cellular immunity against P. aeruginosa is greatly needed. In this study, a recombinant attenuated Salmonella vaccine (RASV) that expresses the outer membrane proteins fusion OprF190-342 -OprI21-83 (F1I2) from P. aeruginosa was constructed and the potency of this vaccine candidate assessed by measuring F1I2-specific humoral immune responses upon vaccination through s.c. or oral routes. S.C. administration achieved higher serum IgG titers and IgA titers in the intestine and induced stronger F1I2-specific IgG and IgA titers in lung homogenate than did oral administration, which resulted in low IgG titers and no local IgA production. High titers of IFN-gamma, IL-4, and T-lymphocyte subsets induced a mixed Th1/Th2 response in mice immunized s.c., indicating elicitation of cellular immunity. Importantly, when immunized mice were challenged with P. aeruginosa by the intranasal route 30 days after the initial immunization, s.c. vaccination achieved 77.78% protection, in contrast to 41.18% via oral administration and 66.67% via Escherichia coli-expressed F1I2 (His-F1I2) vaccination. These results indicate that s.c. vaccination provides a better protective response against P. aeruginosa infection than do oral administration and the His-F1I2 vaccine. PMID- 26249806 TI - Comparison of bioactivities and phenolic composition of Choerospondias axillaris peels and fleshes. AB - BACKGROUND: Choerospondias axillaris is both an edible and medicinal fruit. It has a growing popularity and economic importance due to its nutritive value and medicinal effects, but comprehensive information on the chemical composition and bioactivity of its fruits is still lacking. Therefore the aim of this study was to investigate the antioxidant, antimicrobial and antiproliferative effects and chemical composition of peel polyphenolic (PP) and flesh polyphenolic (FP) extracts from C. axillaris. RESULTS: The phenolics and flavonoids of peel were significantly higher than those of flesh. Ultra-performance liquid chromatography (UPLC) and ultra-performance liquid chromatography/electrospray ionization quadrupole time-of-flight-mass spectrometry (UPLC/ESI-QTOF-MS(2) ) analysis revealed that (+)-catechin and oligomeric procyanidins were the most abundant compounds in PP and FP. Both extracts exhibited strong ferric-reducing antioxidant power, total antioxidant activity and 2,2-diphenyl-1-picrylhydrazyl radical (DPPH(*) )-scavenging ability. PP showed a significantly higher antimicrobial effect against tested strains than that of FP, in a dose-dependent manner. Furthermore, both extracts inhibited the growth of HepG2 and Caco-2 cells in a dose- and time-dependent manner, with IC50 values of 39.31 and 47.49 ug mL( 1) to HepG2 cells and 101.90 and 102.61 ug mL(-1) to Caco-2 cells respectively. CONCLUSION: This is the first detailed report on the chemical composition and bioactivities of C. axillaris fruits. (c) 2015 Society of Chemical Industry. PMID- 26249792 TI - Temporomandibular disorder or not? A case report. AB - OBJECTIVES: The purpose of this case study is to show the need for a good differential diagnosis of suspected temporomandibular disorder (TMD) with otologic symptoms. METHODS/RESULTS: This study is a clinical case referring to a patient seeking treatment for pain in the right maxilla. The usual Medical History for diagnosis of a TMD was applied. Anamnesis revealed the patient had had a right maxillary pain for one month, a slight hearing loss and dizziness for the past five to six months, and two implants placed in the upper jaw two years previously. Clinical examination showed right temporomandibular joint (TMJ) clicking and tenderness in the lateral pterygoid muscles and in the right masseter muscle. Temporomandibular disorder and orofacial pain were diagnosed, and the appropriate treatment was initiated. In addition, a cranial magnetic resonance imaging (MRI) evaluation was requested and revealed acoustic neuroma. CONCLUSION: The coexistence of TMD with otovestibular symptoms suggests the need for a cranial MRI evaluation, especially if the dental or TMD treatment has not been positive. PMID- 26249810 TI - NRGsuite: a PyMOL plugin to perform docking simulations in real time using FlexAID. AB - Ligand protein docking simulations play a fundamental role in understanding molecular recognition. Herein we introduce the NRGsuite, a PyMOL plugin that permits the detection of surface cavities in proteins, their refinements, calculation of volume and use, individually or jointly, as target binding-sites for docking simulations with FlexAID. The NRGsuite offers the users control over a large number of important parameters in docking simulations including the assignment of flexible side-chains and definition of geometric constraints. Furthermore, the NRGsuite permits the visualization of the docking simulation in real time. The NRGsuite give access to powerful docking simulations that can be used in structure-guided drug design as well as an educational tool. The NRGsuite is implemented in Python and C/C++ with an easy to use package installer. The NRGsuite is available for Windows, Linux and MacOS. AVAILABILITY AND IMPLEMENTATION: http://bcb.med.usherbrooke.ca/flexaid. CONTACT: rafael.najmanovich@usherbroke.ca. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26249791 TI - Impact of diet and nutraceutical supplementation on inflammation in elderly people. Results from the RISTOMED study, an open-label randomized control trial. AB - BACKGROUND & AIMS: Eating habits may influence the life span and the quality of ageing process by modulating inflammation. The RISTOMED project was developed to provide a personalized and balanced diet, enriched with or without nutraceutical compounds, to decrease and prevent inflammageing, oxidative stress and gut microbiota alteration in healthy elderly people. This paper focused on the effect on inflammation and metabolism markers after 56 days of RISTOMED diet alone or supplementation with three nutraceutical compounds. METHODS: A cohort of 125 healthy elderly subjects was recruited and randomized into 4 arms (Arm A, RISTOMED diet; Arm B, RISTOMED diet plus VSL#3 probiotic blend; Arm C, RISTOMED diet plus AISA d-Limonene; Arm D, RISTOMED diet plus Argan oil). Inflammatory and metabolism parameters as well as the ratio between Clostridium cluster IV and Bifidobacteria (CL/B) were collected before and after 56 days of dietary intervention, and their evolution compared among the arms. Moreover, participants were subdivided according to their baseline inflammatory parameters (erythrocytes sedimentation rate (ESR), C-Reactive Protein, fibrinogen, Tumor Necrosis Factor alfa (TNF-alpha), and Interleukin 6) in two clusters with low or medium-high level of inflammation. The evolution of the measured parameters was then examined separately in each cluster. RESULTS: Overall, RISTOMED diet alone or with each nutraceutical supplementation significantly decreased ESR. RISTOMED diet supplemented with d-Limonene resulted in a decrease in fibrinogen, glucose, insulin levels and HOMA-IR. The most beneficial effects were observed in subjects with a medium-high inflammatory status who received RISTOMED diet with AISA d Limonene supplementation. Moreover, RISTOMED diet associated with VSL#3 probiotic blend induced a decrease in the CL/B ratio. CONCLUSIONS: Overall, this study emphasizes the beneficial anti-inflammageing effect of RISTOMED diet supplemented with nutraceuticals to control the inflammatory status of elderly individuals. PMID- 26249809 TI - ASSIsT: an automatic SNP scoring tool for in- and outbreeding species. AB - ASSIsT (Automatic SNP ScorIng Tool) is a user-friendly customized pipeline for efficient calling and filtering of SNPs from Illumina Infinium arrays, specifically devised for custom genotyping arrays. Illumina has developed an integrated software for SNP data visualization and inspection called GenomeStudio (GS). ASSIsT builds on GS-derived data and identifies those markers that follow a bi-allelic genetic model and show reliable genotype calls. Moreover, ASSIsT re edits SNP calls with null alleles or additional SNPs in the probe annealing site. ASSIsT can be employed in the analysis of different population types such as full sib families and mating schemes used in the plant kingdom (backcross, F1, F2), and unrelated individuals. The final result can be directly exported in the format required by the most common software for genetic mapping and marker-trait association analysis. ASSIsT is developed in Python and runs in Windows and Linux. AVAILABILITY AND IMPLEMENTATION: The software, example data sets and tutorials are freely available at http://compbiotoolbox.fmach.it/assist/. CONTACT: eric.vandeweg@wur.nl. PMID- 26249811 TI - SurvCurv database and online survival analysis platform update. AB - Understanding the biology of ageing is an important and complex challenge. Survival experiments are one of the primary approaches for measuring changes in ageing. Here, we present a major update to SurvCurv, a database and online resource for survival data in animals. As well as a substantial increase in data and additions to existing graphical and statistical survival analysis features, SurvCurv now includes extended mathematical mortality modelling functions and survival density plots for more advanced representation of groups of survival cohorts. AVAILABILITY AND IMPLEMENTATION: The database is freely available at https://www.ebi.ac.uk/thornton-srv/databases/SurvCurv/. All data are published under the Creative Commons Attribution License. CONTACT: matthias.ziehm@ebi.ac.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26249812 TI - Strategies to improve the performance of rare variant association studies by optimizing the selection of controls. AB - MOTIVATION: When analyzing a case group of patients with ultra-rare disorders the ethnicities are often diverse and the data quality might vary. The population substructure in the case group as well as the heterogeneous data quality can cause substantial inflation of test statistics and result in spurious associations in case-control studies if not properly adjusted for. Existing techniques to correct for confounding effects were especially developed for common variants and are not applicable to rare variants. RESULTS: We analyzed strategies to select suitable controls for cases that are based on similarity metrics that vary in their weighting schemes. We simulated different disease entities on real exome data and show that a similarity-based selection scheme can help to reduce false positive associations and to optimize the performance of the statistical tests. Especially when data quality as well as ethnicities vary a lot in the case group, a matching approach that puts more weight on rare variants shows the best performance. We reanalyzed collections of unrelated patients with Kabuki make-up syndrome, Hyperphosphatasia with Mental Retardation syndrome and Catel-Manzke syndrome for which the disease genes were recently described. We show that rare variant association tests are more sensitive and specific in identifying the disease gene than intersection filters and should thus be considered as a favorable approach in analyzing even small patient cohorts. AVAILABILITY AND IMPLEMENTATION: Datasets used in our analysis are available at ftp://ftp.1000genomes.ebi.ac.uk./vol1/ftp/ CONTACT: : peter.krawitz@charite.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26249804 TI - Jagged1 intracellular domain-mediated inhibition of Notch1 signalling regulates cardiac homeostasis in the postnatal heart. AB - AIMS: Notch1 signalling in the heart is mainly activated via expression of Jagged1 on the surface of cardiomyocytes. Notch controls cardiomyocyte proliferation and differentiation in the developing heart and regulates cardiac remodelling in the stressed adult heart. Besides canonical Notch receptor activation in signal-receiving cells, Notch ligands can also activate Notch receptor-independent responses in signal-sending cells via release of their intracellular domain. We evaluated therefore the importance of Jagged1 (J1) intracellular domain (ICD)-mediated pathways in the postnatal heart. METHODS AND RESULTS: In cardiomyocytes, Jagged1 releases J1ICD, which then translocates into the nucleus and down-regulates Notch transcriptional activity. To study the importance of J1ICD in cardiac homeostasis, we generated transgenic mice expressing a tamoxifen-inducible form of J1ICD, specifically in cardiomyocytes. Using this model, we demonstrate that J1ICD-mediated Notch inhibition diminishes proliferation in the neonatal cardiomyocyte population and promotes maturation. In the neonatal heart, a response via Wnt and Akt pathway activation is elicited as an attempt to compensate for the deficit in cardiomyocyte number resulting from J1ICD activation. In the stressed adult heart, J1ICD activation results in a dramatic reduction of the number of Notch signalling cardiomyocytes, blunts the hypertrophic response, and reduces the number of apoptotic cardiomyocytes. Consistently, this occurs concomitantly with a significant down-regulation of the phosphorylation of the Akt effectors ribosomal S6 protein (S6) and eukaryotic initiation factor 4E binding protein1 (4EBP1) controlling protein synthesis. CONCLUSIONS: Altogether, these data demonstrate the importance of J1ICD in the modulation of physiological and pathological hypertrophy, and reveal the existence of a novel pathway regulating cardiac homeostasis. PMID- 26249816 TI - Linear-No-Threshold Default Assumptions for Noncancer and Nongenotoxic Cancer Risks: A Mathematical and Biological Critique. AB - To improve U.S. Environmental Protection Agency (EPA) dose-response (DR) assessments for noncarcinogens and for nonlinear mode of action (MOA) carcinogens, the 2009 NRC Science and Decisions Panel recommended that the adjustment-factor approach traditionally applied to these endpoints should be replaced by a new default assumption that both endpoints have linear-no-threshold (LNT) population-wide DR relationships. The panel claimed this new approach is warranted because population DR is LNT when any new dose adds to a background dose that explains background levels of risk, and/or when there is substantial interindividual heterogeneity in susceptibility in the exposed human population. Mathematically, however, the first claim is either false or effectively meaningless and the second claim is false. Any dose-and population-response relationship that is statistically consistent with an LNT relationship may instead be an additive mixture of just two quasi-threshold DR relationships, which jointly exhibit low-dose S-shaped, quasi-threshold nonlinearity just below the lower end of the observed "linear" dose range. In this case, LNT extrapolation would necessarily overestimate increased risk by increasingly large relative magnitudes at diminishing values of above-background dose. The fact that chemically-induced apoptotic cell death occurs by unambiguously nonlinear, quasi threshold DR mechanisms is apparent from recent data concerning this quintessential toxicity endpoint. The 2009 NRC Science and Decisions Panel claims and recommendations that default LNT assumptions be applied to DR assessment for noncarcinogens and nonlinear MOA carcinogens are therefore not justified either mathematically or biologically. PMID- 26249813 TI - A statistical approach to virtual cellular experiments: improved causal discovery using accumulation IDA (aIDA). AB - MOTIVATION: We address the following question: Does inhibition of the expression of a gene X in a cellular assay affect the expression of another gene Y? Rather than inhibiting gene X experimentally, we aim at answering this question computationally using as the only input observational gene expression data. Recently, a new statistical algorithm called Intervention calculus when the Directed acyclic graph is Absent (IDA), has been proposed for this problem. For several biological systems, IDA has been shown to outcompete regression-based methods with respect to the number of true positives versus the number of false positives for the top 5000 predicted effects. Further improvements in the performance of IDA have been realized by stability selection, a resampling method wrapped around IDA that enhances the discovery of true causal effects. Nevertheless, the rate of false positive and false negative predictions is still unsatisfactorily high. RESULTS: We introduce a new resampling approach for causal discovery called accumulation IDA (aIDA). We show that aIDA improves the performance of causal discoveries compared to existing variants of IDA on both simulated and real yeast data. The higher reliability of top causal effect predictions achieved by aIDA promises to increase the rate of success of wet lab intervention experiments for functional studies. AVAILABILITY AND IMPLEMENTATION: R code for aIDA is available in the Supplementary material. CONTACT: franziska.taruttis@ur.de, julia.engelmann@ur.de. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26249820 TI - Range separated hybrids of pair coupled cluster doubles and density functionals. AB - Pair coupled cluster doubles (pCCD) is a size-consistent, size-extensive, low cost simplification of CCD that has been shown to be able to describe static correlation without breaking symmetry. We combine pCCD with Kohn-Sham functionals of the density and the local pair density in order to incorporate dynamic correlation in pCCD while maintaining its low cost. Double counting is eliminated by splitting the (interelectron) Coulomb operator into complementary short- and long-range parts, and evaluating the two-body energy with pCCD in the long-range and with density functionals in the short-range. This simultaneously suppresses self-interaction in the Hartree-exchange term of the functionals. Generalizations including a fraction of wavefunction two-body energy in the short-range are also derived and studied. The improvement of our pCCD+DFT hybrids over pCCD is demonstrated in calculations on benchmarks where both types of correlation are important. PMID- 26249821 TI - LAMP proteins account for the maturation delay during the establishment of the Coxiella burnetii-containing vacuole. AB - The obligate intracellular pathogen Coxiella burnetii replicates in a large phagolysosomal-like vacuole. Currently, both host and bacterial factors required for creating this replicative parasitophorous C. burnetii-containing vacuole (PV) are poorly defined. Here, we assessed the contributions of the most abundant proteins of the lysosomal membrane, LAMP-1 and LAMP-2, to the establishment and maintenance of the PV. Whereas these proteins were not critical for uptake of C. burnetii, they influenced the intracellular replication of C. burnetii. In LAMP 1/2 double-deficient fibroblasts as well as in LAMP-1/2 knock-down cells, C. burnetii establishes a significantly smaller, yet faster maturing vacuole, which harboured more bacteria. The accelerated maturation of PVs in LAMP double deficient fibroblasts, which was partially or fully reversed by ectopic expression of LAMP-1 or LAMP-2, respectively, was characterized by an increased fusion rate with endosomes, lysosomes and bead-containing phagosomes, but not by different fusion kinetics with autophagy vesicles. These findings establish that LAMP proteins are critical for the maturation delay of PVs. Unexpectedly, neither the creation of the spacious vacuole nor the delay in maturation was found to be prerequisites for the intracellular replication of C. burnetii. PMID- 26249814 TI - LoopIng: a template-based tool for predicting the structure of protein loops. AB - MOTIVATION: Predicting the structure of protein loops is very challenging, mainly because they are not necessarily subject to strong evolutionary pressure. This implies that, unlike the rest of the protein, standard homology modeling techniques are not very effective in modeling their structure. However, loops are often involved in protein function, hence inferring their structure is important for predicting protein structure as well as function. RESULTS: We describe a method, LoopIng, based on the Random Forest automated learning technique, which, given a target loop, selects a structural template for it from a database of loop candidates. Compared to the most recently available methods, LoopIng is able to achieve similar accuracy for short loops (4-10 residues) and significant enhancements for long loops (11-20 residues). The quality of the predictions is robust to errors that unavoidably affect the stem regions when these are modeled. The method returns a confidence score for the predicted template loops and has the advantage of being very fast (on average: 1 min/loop). AVAILABILITY AND IMPLEMENTATION: www.biocomputing.it/looping. CONTACT: anna.tramontano@uniroma1.it. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26249815 TI - cgmisc: enhanced genome-wide association analyses and visualization. AB - High-throughput genotyping and sequencing technologies facilitate studies of complex genetic traits and provide new research opportunities. The increasing popularity of genome-wide association studies (GWAS) leads to the discovery of new associated loci and a better understanding of the genetic architecture underlying not only diseases, but also other monogenic and complex phenotypes. Several softwares are available for performing GWAS analyses, R environment being one of them. RESULTS: We present cgmisc, an R package that enables enhanced data analysis and visualization of results from GWAS. The package contains several utilities and modules that complement and enhance the functionality of the existing software. It also provides several tools for advanced visualization of genomic data and utilizes the power of the R language to aid in preparation of publication-quality figures. Some of the package functions are specific for the domestic dog (Canis familiaris) data. AVAILABILITY AND IMPLEMENTATION: The package is operating system-independent and is available from: https://github.com/cgmisc-team/cgmisc CONTACT: marcin.kierczak@imbim.uu.se. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26249817 TI - Role of the Lebanese family caregivers in cardiac self-care: a collective approach. AB - AIMS AND OBJECTIVES: The purpose of this study was to explore perceptions of cardiac self-care among Lebanese family caregivers of cardiac patients. The specific aims were to describe the cultural context of cardiac care-giving in Lebanon and to explore the roles of family caregivers in enhancing self-care practices in patients with cardiac diseases. BACKGROUND: The role of family caregivers in Lebanon, a country in the Middle East, is assumed to extend beyond care-giving to making decisions on behalf of the patient and assuming responsibility for patient care. To date, there has been no study done to empirically validate this impression. DESIGN: The design of the study is qualitative descriptive that used semi-structured individual interviews with family caregivers of Lebanese cardiac patients. METHOD: Thirteen family caregivers of cardiac patients were recruited from a referral medical centre in Lebanon. The participants were designated by their patients and interviewed in a place of their choice. RESULTS: One overarching and three themes emerged from data analysis describing roles of family care givers in cardiac self-care. The overarching theme was: Family caregivers of Lebanese cardiac patients were unfamiliar with the term, concept and meaning of Self-Care. The moral and emotional duty to care for the family member stemmed from obligation and responsibility towards patients (theme I). Interdependent care (theme II) between cardiac patients and their families emerged as a significant cultural role. Family members play multiple supportive roles in care-giving namely emotional, informational and instrumental role (theme III). CONCLUSION: In this study, family caregiver role is shown to be based in the sense of obligation and duty towards the sick family member who collectively provide different types of supportive care. RELEVANCE TO CLINICAL PRACTICE: Nurses have to give significant importance to the family caregiver role as an integral part of any culturally sensitive patient/family intervention. PMID- 26249819 TI - Virulence and antimicrobial resistance of Enterococcus faecium isolated from water samples. AB - The aim of this study was to determine the incidence of Enterococcus species and six virulence factors of Enterococcus faecium which were isolated from surface water and wells. Fifteen different water samples, which were used for drinking as well as agricultural irrigation, were collected from nine private wells and surface water from six rivers located at the east of Tehran. The Ent. faecium isolates were tested for their resistance to 10 antibiotics and their virulence factors were detected using multiplex PCR for esp, acm, gelE, asa1, cylA and hyl genes. The most predominant species in 315 isolates were Ent. faecium (n = 118) followed by Enterococcus galinarom (n = 110), Enterococcus mundeti (n = 18), Enterococcus hirea (n = 37) and Enterococcus casselifelavus (n = 32). The resistance rates were observed in 41.5, 27.1, 12.7, 6.8 and 1.7% isolates for tetracycline, erythromycin, ampicillin, ciprofloxacin and chloramphenicol respectively. None of the Ent. faecium isolates were resistant to vancomycin, teicoplanin, linezolid, gentamicin and quinuspristin-dalfopristin. Virulence determinant was found in 84.7, 33.9, 16.1 and 2.5% of isolates for acm, asa1, esp, cylA respectively. None of the isolates carried hyl and gelE gene. The presence of virulence factors and antibiotic resistance indicated that water might be an important source of dissemination of virulent enterococci. SIGNIFICANCE AND IMPACT OF THE STUDY: Contamination of drinking or recreational water by human or animal faecal waste is a major public health threat. In this study, we determine the incidence of Enterococcus species and six virulence factors of Enterococcus faecium which were isolated from surface water and wells. Results from this study suggest that the presence of Ent. faecium in natural and well waters was found to be significant in rural areas of Tehran. Resistant to erythromycin among Ent. faecium was relatively high and the incidence of acm and asa1 among our isolates was common overall. PMID- 26249818 TI - Wntless spatially regulates bone development through beta-catenin-dependent and independent mechanisms. AB - BACKGROUND: Canonical and noncanonical Wnt signaling pathways both play pivotal roles in bone development. Wntless/GPR177 is a chaperone protein that is required for secretion of all Wnt ligands. We previously showed that deletion of Wntless within mature osteoblasts severely impaired postnatal bone homeostasis. RESULTS: In this study, we systemically evaluated how deletion of Wntless in different stages of osteochondral differentiation affected embryonic bone development, by crossing Wntless (Wls)-flox/flox mice with strains expressing cre recombinase behind the following promoters: Osteocalcin, Collagen 2a1, or Dermo1. Ex vivo uCT and whole-mount skeletal staining were performed to examine skeletal mineralization. Histology and immunohistochemistry were used to evaluate cellular differentiation and alterations in Wnt signaling. In this work, we found that Wntless regulated chondrogenesis and osteogenesis through both canonical and noncanonical Wnt signaling. CONCLUSIONS: These findings provide more insight into the requirements of different Wnt-secretion cell types critical for skeletal development. PMID- 26249825 TI - Long-term changes in quality of life after endoscopic resection of sinonasal and skull-base tumors. AB - BACKGROUND: Minimally invasive endoscopic resection (MIER) has emerged as the new standard for surgical treatment of sinonasal and skull-base tumors. The objective of the present study was to evaluate quality of life (QOL) 2 years after MIER. METHODS: Prospective 20-item Sino-Nasal Outcome Test (SNOT-20) data was accrued on 104 patients over 4 years. The study cohort included 72 patients with sinonasal malignancy, while 32 patients with inverted papilloma (IP) served as controls. RESULTS: The overall and rhinologic subdomain SNOT-20 scores for cancer patients did not statistically improve at 2 years (p = 0.12). They had statistically significant improvement in the psychological subdomain scores at 1 year (p = 0.03) and 2 years (p = 0.03). Similarly, the sleep subdomain scores improved at 1 year (p = 0.04) and 2 years (p = 0.03). In contrast, IP patients had statistically significant improvement in overall SNOT-20 (p = 0.01), rhinologic (p = 0.01), and sleep (p = 0.05) subdomain scores at 6 months, which remained stable at 2 years. Analysis of various factors demonstrated that history of prior smoking adversely affected QOL scores in cancer patients, with higher total SNOT-20 scores than nonsmokers (p = 0.01). Smokers also had higher psychological (p = 0.04), sleep (p = 0.01), and ear/facial (p = 0.001) domain scores than nonsmokers at 2 years. CONCLUSION: The long-term effects of MIER for sinus cancer showed improved psychological and sleep scores at both 1 year and 2 years. Unfortunately, rhinologic QOL did not statistically improve at any of the measured time points. History of smoking was noted to be the most important predictor of QOL 2 years after MIER for sinonasal malignancy. PMID- 26249824 TI - Low-Field Magnetic Resonance Imaging and Multislice Computed Tomography for the Detection of Cervical Syringomyelia in Dogs. AB - BACKGROUND: Syringomyelia (SM) is defined as the presence of fluid-containing cavities within the parenchyma of the spinal cord. Sagittal magnetic resonance (MR) images have been described as the preferred technique for visualizing SM in dogs and humans. OBJECTIVE: To investigate whether computed tomography (CT) can be used to diagnose SM. ANIMALS: Thirty-two client-owned dogs referred for investigation of the cervical spine on magnetic resonance imaging (MRI) and CT. METHODS: Two reviewers retrospectively analyzed sagittal and transverse T1 weighted spin echo (T1WSE) MR images and CT images from each dog for the presence of SM and, if SM was present, the width (mm, syrinx width [SW]) was measured. The results were analyzed statistically. RESULTS: For the presence of SM there was a moderate interobserver agreement for MR (81%, kappa = 0.54) and almost perfect agreement for CT (94%, kappa = 0.87). There was a moderate intramodality agreement for both observers (observer 1 81%, kappa = 0.59; observer 2 81%, kappa = 0.57). For measurement of SW the repeatability was the best on the midsagittal T1WSE images (95% repeatability coefficient <0.52 mm) and the reproducibility was the best on midsagittal images in both modalities (95% limits of agreement -0.55 0.45; P = 0.002). CONCLUSION AND CLINICAL IMPORTANCE: Both techniques can be used to detect SM. Midsagittal MR and CT images are best used for measuring SW. Computed tomography can be used as a diagnostic tool for SM when MRI is not available, but CT cannot replace MRI as the standard screening technique for the detection of SM in Cavalier King Charles Spaniel for breeding purposes. PMID- 26249823 TI - Predominance of hepatitis C virus Q80K among NS3 baseline-resistance-associated amino acid variants in direct-antiviral-agent-naive patients with chronic hepatitis: single-centre experience. AB - In the era of direct-acting antiviral agents (DAAs), hepatitis C virus (HCV) genotyping tests at baseline are controversial. The HCV NS3-Q80K polymorphism is associated with resistance to the recently approved NS3 inhibitor simeprevir (SMV) when combined with PEG-interferon and ribavirin (PEG-IFN/RBV) and alternative therapy should be considered for patients with baseline Q80K. The aim of this study was to provide an estimate of Q80K prevalence at baseline in a study group of 205 DAA-naive patients (21% of them with HIV coinfection) using NS3 full-population direct sequencing to detect resistance-associated amino acid variants (RAVs). NS3 RAVs were identified in 56 patients (27.3%). Q80K was the most frequently reported one (41%), in both HIV/HCV-coinfected and HCV monoinfected patients, but it was only detectable in cases of HCV-subtype 1a infection. Therefore, in clinical practice, an NS3-Q80K genotyping test prior to simeprevir plus PEG-IFN/RBV treatment is highly recommended. PMID- 26249822 TI - Importance of molecular typing in confirmation of the source of a national hepatitis A virus outbreak in Norway and the detection of a related cluster in Germany. AB - In March 2014, after an increase of notifications of domestically acquired hepatitis A virus infections, an outbreak investigation was launched in Norway. Sequenced-based typing results showed that these cases were associated with a strain that was identical to one causing an ongoing multinational outbreak in Europe linked to frozen mixed berries. Thirty-three confirmed cases with the outbreak strain were notified in Norway from November 2013 to June 2014. Epidemiological evidence and trace-back investigations linked the outbreak to the consumption of a berry mix cake. Identification of the hepatitis A virus outbreak strain in berries from one of the implicated cakes confirmed the cake to be the source. Subsequently, a cluster in Germany linked to the cake was also identified. PMID- 26249831 TI - Outpatient transcervical microwave myolysis assisted by transabdominal ultrasonic guidance for menorrhagia caused by submucosal myomas. AB - PURPOSE: The aim of this paper was to evaluate the effectiveness in day clinics of microwave endometrial ablation (MEA) on transcervical microwave myolysis for patients with menorrhagia caused by submucosal myomas. MATERIALS AND METHODS: Thirty-five outpatients (average age 44.8 +/- 5.2 years (mean +/- SD), range 34 58) with a single submucosal myoma that was 4-7 cm (5.5 +/- 2.1 cm) in size underwent MEA with trans-cervical microwave myolysis using a specifically developed transabdominal ultrasound probe attachment for transcervical puncture. Primary outcomes were the changes in the blood haemoglobin level and the volume of myoma before and after the treatment. Secondary outcomes were the improvement in menorrhagia and satisfaction after the operation, assessed by visual analogue scale (VAS). RESULTS: The mean operation time was 27.9 +/- 13.6 min. The myomas had shrunk by 56.2% at 3 months and 72.5% at >=6 months after the operation. Blood haemoglobin levels had increased significantly at 3 months (10.2 +/- 2.0 vs. 12.7 +/- 1.2, p < 0.001). The average VAS assessment of menstrual bleeding had decreased to 1.7 +/- 1.7 at 3 months after the operation (preoperative VAS = 10). The average VAS score for feelings of satisfaction 3 months after the operation was 9.8 +/- 0.5 (full score = 10). CONCLUSIONS: MEA with transcervical microwave myolysis is a feasible and effective procedure in a day surgery clinic for menorrhagia caused by submucosal myomas. The procedure may be an alternative to hysterectomy for menorrhagia caused by submucosal myomas in women during the perimenopausal period. PMID- 26249827 TI - Are licensed canine parvovirus (CPV2 and CPV2b) vaccines able to elicit protection against CPV2c subtype in puppies?: A systematic review of controlled clinical trials. AB - Severe gastroenteritis caused by canine parvovirus type 2 (CPV2) is a serious life-threatening disease in puppies less than 4-months of age. The emergence of new variants has provoked some concern about the cross-protection elicited by licensed canine parvovirus modified-live type 2 (CPV2) and type 2b (CPV2b) vaccines against the most recent subtype CPV2c. A systematic review was carried out to assess the efficacy of commercial vaccines. We conducted a literature search of Pub Med/MEDLINE from January 1990 to May 2014. This was supplemented by hand-searching of related citations and searches in Google/Google Scholar. Controlled clinical trials in which vaccinated puppies were challenged with CPV2c virus were evaluated. Reporting of outcome measures and results for vaccine efficacy were critically appraised through a variety of clinical signs, serological tests, virus shedding and the ability to overcome maternally derived antibodies (MDA) titres. Six controlled clinical trials were included in the review. In most cases, the results of the selected studies reported benefits in terms of clinical signs, serological tests and virus shedding. However, MDA interference was not considered or evaluated in 5 of the selected trials. No accurate definitions of baseline healthy status and/or clinical outcomes were provided. Methods of randomization, allocation concealment and blinding were usually poorly reported. As a result of the limited number of included studies matching the inclusion criteria, the small sample sizes, short follow-up and the methodological limitations observed, it was not possible to reach a final conclusion regarding the cross-protection of licensed CPV2 and CPV2b vaccines against the subtype 2c in puppies. Further and specifically designed trials are required in order to elucidate whether cross-protection is acquired from licensed CPV vaccines. PMID- 26249826 TI - A Therapeutic Approach to Psychogenic Nonepileptic Seizures. AB - OPINION STATEMENT: The diagnosis of psychogenic nonepileptic seizures (PNES) is usually made in the seizure monitoring unit (SMU; also commonly named the epilepsy monitoring unit) after PNES are recorded on video-EEG. The diagnosis should be discussed with the patient thoroughly. The discussion should focus on how the diagnosis was reached and that the diagnosis is real and treatable. When the diagnosis is communicated well, some patients may improve significantly without further interventions. Next, a psychiatric evaluation should be completed, ideally before discharge from the SMU. After discharge, the patient should undergo cognitive behavioral therapy (CBT), the only treatment for PNES that is supported by high-quality evidence. Other therapies, including psychodynamic therapy and different types of group therapy can be considered in some patients, although high-level evidence to support their use is lacking. Some patients may benefit from selective serotonin-reuptake inhibitors (SSRIs), especially when psychiatric comorbidities are present. This should be considered on a case-by-case basis. PMID- 26249828 TI - The nasopharyngeal microbiota of feedlot cattle that develop bovine respiratory disease. AB - Bovine respiratory disease is the major cause of morbidity and mortality in feedlot cattle. The objective of this study was to compare the nasopharyngeal bacterial microbiota of healthy cattle and cattle treated for BRD in a commercial feedlot setting using a high-density 16S rRNA gene microarray (Phylochip). Samples were taken from both groups of animals (n=5) at feedlot entry (day 0) and >=60 days after placement. Cattle diagnosed with BRD had significantly less bacterial diversity and fewer OTUs in their nasopharynx at both sampling times. The predominant phyla in both groups were Proteobacteria and Firmicutes. The relative abundance of the phylum Actinobacteria was lower in cattle treated for BRD. At the family-level there was a greater relative abundance (P<0.05) of Micrococcaceae (day 0 only), Lachnospiraceae (>=60 days), Lactobacillaceae (day 0), and Bacillaceae (day 0) in healthy cattle compared to BRD-affected cattle. The community structure of the BRD-affected and healthy cattle were also significantly different from each other at both sampling times as measured using unweighted UniFrac distances. All entry samples of cattle diagnosed with BRD had 16S rRNA gene sequences representative of the BRD-associated bacteria Mannheimia haemolytica or Pasteurella multocida, although 3/5 healthy cattle were also positive for M. haemolytica at this time point. The results also indicate that the bovine nasopharyngeal microbiota is relatively unstable during the first 60 days in the feedlot. PMID- 26249830 TI - A new device for improving dental implants anchorage: a histological and micro computed tomography study in the rabbit. AB - OBJECTIVE: In the present study, a new healing cap that could generate a pulsed electromagnetic field (PEMF) around titanium implants to stimulate peri-implant osteogenesis was tested in the rabbit model. MATERIALS AND METHODS: A total of 22 implants were inserted in the proximal tibial metaphysis of 22 rabbits. A healing cap containing the active device was inserted in half of the implants (11 test implants); an "empty" healing cap was inserted in the other ones (11 control implants). The animals were euthanized after 2 and 4 weeks, and the samples were processed for micro-computed tomography and histology. The peri-implant volume was divided into coronal (where the PEMF was the strongest) and apical regions. RESULTS: Most of the effects of the tested device were confined to the coronal region. Two weeks post-implantation, test implants showed a significant 56% higher trabecular bone fraction (BV/TV), associated with enhanced trabecular number (Tb.N, +37%) and connectivity density (Conn.D, +73%) as compared to the control group; at 4 weeks, the PEMF induced a 69% increase in BV/TV and 34% increase of Tb.N. There was no difference in the trabecular thickness (Tb.Th) at either time point. Furthermore, we observed a 48% higher bone-to-implant contact (BIC) in the test implants vs. controls after 2 weeks; this increase tended to remain stable until the fourth week. Mature trabecular and woven bone were observed in direct contact with the implant surface with no gaps or connective tissue at the bone-implant interface. CONCLUSIONS: These results indicate that the PEMF device stimulated early bone formation around dental implants resulting in higher peri-implant BIC and bone mass already after 2 weeks which suggests an acceleration of the osseointegration process by more than three times. PMID- 26249829 TI - Dual Location Dual Reduction/Photoresponsive Block Copolymer Micelles: Disassembly and Synergistic Release. AB - Self-assembled micellar systems designed with multiple stimuli-responsive degradation have been considered as effective candidates for polymer-based delivery systems exhibiting enhanced/controlled release. However, most conventional approaches involve the incorporation of single, dual, or multiple cleavable linkages positioned at single locations, as in hydrophobic cores or at core/corona interfaces. Herein, a novel dual location dual reduction and photoresponsive block copolymer containing a disulfide linkage at the block junction and pendant o-nitrobenzyl thioether (NBS) groups in the hydrophobic methacrylate block (PEG-ss-PhvM) are reported, which are synthesized by a combination of controlled radical polymerization and facile coupling reaction. The amphiphilic design of the PEG-ss-PhvM enables the formation of self-assembled micellar aggregates with disulfides at the core/corona interfaces and pendant photocleavable NBS groups in the hydrophobic cores. The dual cleavable linkages respond to each stimulus (GSH or light), exhibiting enhanced release; further to a combination of dual locational stimuli, promoting synergistic release at dual locations. PMID- 26249833 TI - Super-resolution photoacoustic imaging through a scattering wall. AB - The use of wavefront shaping to compensate for scattering has brought a renewed interest as a potential solution to imaging through scattering walls. A key to the practicality of any imaging through scattering technique is the capability to focus light without direct access behind the scattering wall. Here we address this problem using photoacoustic feedback for wavefront optimization. By combining the spatially non-uniform sensitivity of the ultrasound transducer to the generated photoacoustic waves with an evolutionary competition among optical modes, the speckle field develops a single, high intensity focus significantly smaller than the acoustic focus used for feedback. Notably, this method is not limited by the size of the absorber to form a sub-acoustic optical focus. We demonstrate imaging behind a scattering medium using two different imaging modalities with up to ten times improvement in signal-to-noise ratio and five to six times sub-acoustic resolution. PMID- 26249839 TI - Psychometric properties of Antonovsky's 29-item Sense of Coherence scale in research on older home-dwelling Norwegians. AB - AIM: The aim of this study was to test the homogeneity and construct validity of the Sense of Coherence 29-item scale (SOC-29) among older home-dwelling Norwegians. METHODS: A postal questionnaire, consisting of background variables, five health-related questions, the SOC-29, and three other instruments measuring mental health, self-care ability, and risk for undernutrition, was sent to 6033 home-dwelling older people (65+ years) in southern Norway. A total of 2069 participants were included. Homogeneity was assessed with Cronbach's alpha coefficient and item-to-total correlations. The construct validity was assessed with "the known-groups technique," a linear stepwise regression analysis with SOC score serving as the dependent variable and with confirmatory factor analysis. RESULTS: With a Cronbach's alpha coefficient of 0.91 and statistically significant item-to-total correlations, the SOC-29 was found to be homogeneous. Construct validity was supported because the SOC-29 could separate known groups with expected high and low scores. The factors that could predict SOC were mental health, self-care ability, feeling lonely, being active, and chronic disease or handicap. Evidence of construct validity was displayed in a confirmatory factor analysis that confirmed SOC-29 as one theoretical construct with the three dimensions, comprehensibility, manageability, and meaningfulness. CONCLUSIONS: The Norwegian version of the SOC-29 is a reliable and valid instrument for use in research among older people. The results confirm that SOC has a particularly strong relationship with mental health and self-care ability. PMID- 26249837 TI - An investigation into inter- and intragenomic variations of graphic genomic signatures. AB - BACKGROUND: Motivated by the general need to identify and classify species based on molecular evidence, genome comparisons have been proposed that are based on measuring mostly Euclidean distances between Chaos Game Representation (CGR) patterns of genomic DNA sequences. RESULTS: We provide, on an extensive dataset and using several different distances, confirmation of the hypothesis that CGR patterns are preserved along a genomic DNA sequence, and are different for DNA sequences originating from genomes of different species. This finding lends support to the theory that CGRs of genomic sequences can act as graphic genomic signatures. In particular, we compare the CGR patterns of over five hundred different 150,000 bp genomic sequences spanning one complete chromosome from each of six organisms, representing all kingdoms of life: H. sapiens (Animalia; chromosome 21), S. cerevisiae (Fungi; chromosome 4), A. thaliana (Plantae; chromosome 1), P. falciparum (Protista; chromosome 14), E. coli (Bacteria - full genome), and P. furiosus (Archaea - full genome). To maximize the diversity within each species, we also analyze the interrelationships within a set of over five hundred 150,000 bp genomic sequences sampled from the entire aforementioned genomes. Lastly, we provide some preliminary evidence of this method's ability to classify genomic DNA sequences at lower taxonomic levels by comparing sequences sampled from the entire genome of H. sapiens (class Mammalia, order Primates) and of M. musculus (class Mammalia, order Rodentia), for a total length of approximately 174 million basepairs analyzed. We compute pairwise distances between CGRs of these genomic sequences using six different distances, and construct Molecular Distance Maps, which visualize all sequences as points in a two-dimensional or three-dimensional space, to simultaneously display their interrelationships. CONCLUSION: Our analysis confirms, for this dataset, that CGR patterns of DNA sequences from the same genome are in general quantitatively similar, while being different for DNA sequences from genomes of different species. Our assessment of the performance of the six distances analyzed uses three different quality measures and suggests that several distances outperform the Euclidean distance, which has so far been almost exclusively used for such studies. PMID- 26249836 TI - Establishment of a decision tree model for diagnosis of early rheumatoid arthritis by proteomic fingerprinting. AB - AIM: The objective of this study was to identify proteomic biomarkers specific for rheumatoid arthritis (RA) by matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MALDI-TOF-MS) in combination with weak cationic exchange (WCX) magnetic beads. METHODS: Serum samples from 50 patients with RA and 110 disease controls (50 SLE and 60 SS) and 51 healthy individuals were analyzed. The samples were randomly divided into a training set or test set to develop a diagnostic model for RA. RESULTS: A total of 83 protein peaks were identified to be related with RA, in which four of the peaks with mass-charge ratio (m/z) at 8133.85, 5844.60, 13 541.3 and 14 029.0 were selected to establish a model for diagnosis of RA. This classification model could separate patients with RA from diseased and healthy controls with sensitivity of 84.0% and specificity of 92.5%, and its accuracy was confirmed in the blind testing set with high sensitivity and specificity of 80.0% and 93.3%, respectively. CONCLUSIONS: This study suggested that potential serum biomarkers for RA diagnosis could be discovered by MALDI-TOF-MS. The classification tree model set up in this study might be used as a novel diagnostic tool for RA. PMID- 26249834 TI - Glucose-6-phosphate dehydrogenase deficiency among malaria patients of Honduras: a descriptive study of archival blood samples. AB - BACKGROUND: The frequency of deficient variants of glucose-6-phosphate dehydrogenase (G6PDd) is particularly high in areas where malaria is endemic. The administration of antirelapse drugs, such as primaquine, has the potential to trigger an oxidative event in G6PD-deficient individuals. According to Honduras' national scheme, malaria treatment requires the administration of chloroquine and primaquine for both Plasmodium vivax and Plasmodium falciparum infections. The present study aimed at investigating for the first time in Honduras the frequency of the two most common G6PDd variants. METHODS: This was a descriptive study utilizing 398 archival DNA samples of patients that had been diagnosed with malaria due to P. vivax, P. falciparum, or both. The most common allelic variants of G6PD: G6PD A+(376G) and G6PD A-(376G/202A) were assessed by two molecular methods (PCR-RFLP and a commercial kit). RESULTS: The overall frequency of G6PD deficient genotypes was 16.08%. The frequency of the "African" genotype A- (Class III) was 11.9% (4.1% A- hemizygous males; 1.5% homozygous A- females; and 6.3% heterozygous A- females). A high frequency of G6PDd alleles was observed in samples from malaria patients residing in endemic regions of Northern Honduras. One case of Santamaria mutation (376G/542T) was detected. CONCLUSIONS: Compared to other studies in the Americas, as well as to data from predictive models, the present study identified a higher-than expected frequency of genotype A- in Honduras. Considering that the national standard of malaria treatment in the country includes primaquine, further research is necessary to ascertain the risk of PQ-triggered haemolytic reactions in sectors of the population more likely to carry G6PD mutations. Additionally, consideration should be given to utilizing point of care technologies to detect this genetic disorder prior administration of 8-aminoquinoline drugs, either primaquine or any new drug available in the near future. PMID- 26249838 TI - Evaluating the predictive ability of childhood body mass index classification systems for overweight and obesity at 18 years. AB - AIM: To evaluate the performance of three childhood body mass index classification systems defining weight status at age 10, for predicting overweight and obesity at 18 years, according to the World Health Organization adult body mass index classification. METHODS: Weight and height of 4235 Swedish girls and boys were measured both at around ages 10 and 18 years. Predictive ability of the extended International Obesity Task Force body mass index cut-offs (2012), the World Health Organization body mass index-for-age (2007) and a Swedish body mass index reference (2001) were assessed for sensitivity and specificity. RESULTS: For predicting overweight including obesity at 18 years, the World Health Organization 2007 and the Swedish body mass index reference 2001 had similar sensitivity, 68% and 71%. The International Obesity Task Force 2012 had a significantly lower sensitivity, 53%. Specificity was 82-91% and highest for International Obesity Task Force 2012. For predicting obesity, the sensitivity for International Obesity Task Force 2012 was 29%, significantly lower than for the other two, 63% and 70%. Specificity was 94-100%, and highest for International Obesity Task Force 2012. CONCLUSIONS: In situations when optimal screening sensitivity is required for identifying as many high-risk children as possible, the World Health Organization 2007 and the Swedish body mass index reference 2001 performed better than the International Obesity Task Force 2012. However, it is important to keep in mind that the International Obesity Task Force 2012 will identify the fewest false positives. PMID- 26249835 TI - Alcohol during pregnancy worsens acute respiratory infections in children. AB - AIM: This study explored whether alcohol consumption during pregnancy increased the risk of life-threatening respiratory infections in children. METHODS: We prospectively evaluated children under the age of two years admitted to hospitals in Buenos Aires, Argentina, with severe acute respiratory infections during the winters of 2011 and 2012. Information on maternal alcohol consumption during the third trimester of pregnancy was collected using standardised questionnaires and categorised as never, low if it was once a week and high if it was equal or more than once a week. RESULTS: Of the 3423 children hospitalised with acute respiratory infection, 2089 (63.7%) had respiratory syncytial virus (RSV). Alcohol consumption during the last trimester was reported by 398 mothers (12.4%) and categorised as low (n = 210, 6.5%) or high (n = 188, 5.9%). A greater effect on life-threatening respiratory infection, defined as oxygen saturation of or up to 87%, was observed with higher alcohol intake due to all viruses and specifically RSV in the logistic regression analyses. Alcohol consumption was strongly associated with life-threatening disease, particularly in boys whose adjusted odds ratio rose from 3.67 to 13.52 when their mothers drank alcohol. CONCLUSION: Alcohol consumption during pregnancy was associated with life threatening respiratory infections in boys. PMID- 26249832 TI - Gestational weight gain information: seeking and sources among pregnant women. AB - BACKGROUND: Promoting healthy gestational weight gain (GWG) is important for preventing obstetric and perinatal morbidity, along with obesity in both mother and child. Provision of GWG guidelines by health professionals predicts women meeting GWG guidelines. Research concerning women's GWG information sources is limited. This study assessed pregnant women's sources of GWG information and how, where and which women seek GWG information. METHODS: Consecutive women (n = 1032) received a mailed questionnaire after their first antenatal visit to a public maternity hospital in Melbourne, Australia. Recalled provision of GWG guidelines by doctors and midwives, recalled provided GWG goals, and the obtaining of GWG information and information sources were assessed. RESULTS: Participants (n = 368; 35.7% response) averaged 32.5 years of age and 20.8 weeks gestation, with 33.7% speaking a language other than English. One in ten women recalled receiving GWG guidelines from doctors or midwives, of which half were consistent with Institute of Medicine guidelines. More than half the women (55.4%) had actively sought GWG information. Nulliparous (OR 7.07, 95% CI = 3.91-12.81) and obese (OR 1.96, 95% CI = 1.05-3.65) women were more likely to seek information. Underweight (OR 0.29, 95% CI = 0.09-0.97) women and those working part time (OR 0.52, 95% CI = 0.28-0.97) were less likely to seek information. Most frequently reported GWG sources included the internet (82.7%), books (55.4%) and friends (51.5%). The single most important sources were identified as the internet (32.8%), general practitioners (16.9%) and books (14.9%). CONCLUSION: More than half of women were seeking GWG guidance and were more likely to consult non-clinician sources. The small numbers given GWG targets, and the dominance of non-clinical information sources, reinforces that an important opportunity to provide evidence based advice and guidance in the antenatal care setting is currently being missed. PMID- 26249841 TI - Early liraglutide treatment improves beta-cell function in patients with type 2 diabetes: a retrospective cohort study. AB - Preclinical studies on liraglutide have suggested related improvements in beta cell function. Therefore, we investigated these effects in patients with type 2 diabetes (T2D) using the glucagon stimulation test (GST). We conducted a retrospective cohort study of 73 insulin-treated patients with T2D who had their treatment switched to liraglutide monotherapy. Their beta-cell function was measured using a 1-mg intravenous GST at baseline and 24 weeks after treatment. The effect of liraglutide treatment on beta-cell function was assessed by the change in the area under the curve (AUC) of serum C-peptide immunoreactivity during the GST (AUC-CPR). The AUC-CPR increased after 24 weeks of liraglutide treatment (9.80 +/- 0.55 ng/mL?min to 11.50 +/- 0.52 ng/mL?min, p = 0.001). In the univariate and adjusted multivariate regression analyses, a negative relationship between the change in the AUC-CPR and T2D duration was noted (beta = -0.22, 95% confidence interval [CI] = -0.35 to -0.09, R(2) = 0.14, p = 0.001 and beta = -0.20, 95% CI = -0.34 to -0.05, R2 = 0.23, p = 0.008, respectively). In the analysis using T2D duration tertiles, early liraglutide treatment (T2D duration <=10 years) significantly improved the AUC-CPR (<4 years: +2.56 +/- 0.73 ng/mL?min, p = 0.002; 4-10 years: +2.60 +/- 0.56 ng/mL?min, p < 0.001), whereas late liraglutide treatment did not (>10 years: -0.33 +/- 1.15 ng/mL?min, p = 0.78). We conclude that early liraglutide treatment potentially improves beta cell function and subsequently glycemic control in patients with T2D, preventing further diabetic complications. PMID- 26249842 TI - Deciphering the Molecular Basis of Functional Divergence in AMPylating Enzymes by Molecular Dynamics Simulations and Structure Guided Phylogeny. AB - The Fic domain was recently shown to catalyze AMPylation-the transfer of AMP from ATP to hydroxyl side chains of diverse eukaryotic proteins, ranging from RhoGTPases to chaperon BiP. We have carried out a series of explicit solvent molecular dynamics (MD) simulations up to 1 MUs duration on the apo, holo, and substrate/product bound IbpA Fic domain (IbpAFic2). Simulations on holo-IbpAFic2 revealed that binding of Mg(2+) to alpha and beta phosphates is crucial for preserving catalytically important contacts involving ATP. Comparative analysis of the MD trajectories demonstrated how binding of ATP allosterically induces conformational changes in the distal switch II binding region of Fic domains thereby aiding in substrate recognition. Our simulations have also identified crucial aromatic-aromatic interactions which stabilize the orientation of the catalytic histidine for inline nucleophilic attack during AMPylation, thus providing a structural basis for the evolutionary conservation of these aromatic residue pairs in Fic domains. On the basis of analysis of interacting interface residue pairs that persist over the microsecond trajectory, we identified a tetrapeptide stretch involved in substrate recognition. The structure-based genome-wide search revealed a distinct conservation pattern for this segment in different Fic subfamilies, further supporting its proposed role in substrate recognition. In addition, combined use of simulations and phylogenetic analysis has helped in the discovery of a new subfamily of Fic proteins that harbor a conserved Lys/Arg in place of the inhibitory Glu of the regulatory helix. We propose the novel possibility of auto-enhancement of AMPylation activity in this new subfamily via the movement of regulatory helix, in contrast to auto inhibition seen in most Fic proteins. PMID- 26249846 TI - Complexity and dynamics of switched human balance control during quiet standing. AB - In this paper, we use a combination of numerical simulations, time series analysis, and complexity measures to investigate the dynamics of switched systems with noise, which are often used as models of human balance control during quiet standing. We link the results with complexity measures found in experimental data of human sway motion during quiet standing. The control model ensuring balance, which we use, is based on an act-and-wait control concept, that is, a human controller is switched on when a certain sway angle is reached. Otherwise, there is no active control present. Given a time series data, we determine how does it look a typical pattern of control strategy in our model system. We detect the switched nonlinearity in the system using a frequency analysis method in the absence of noise. We also analyse the effect of time delay on the existence of limit cycles in the system in the absence of noise. We perform the entropy and detrended fluctuation analyses in view of linking the switchings (and the dead zone) with the occurrences of complexity in the model system in the presence of noise. Finally, we perform the entropy and detrended fluctuation analyses on experimental data and link the results with numerical findings in our model example. PMID- 26249843 TI - Use of concept mapping to characterize relationships among implementation strategies and assess their feasibility and importance: results from the Expert Recommendations for Implementing Change (ERIC) study. AB - BACKGROUND: Poor terminological consistency for core concepts in implementation science has been widely noted as an obstacle to effective meta-analyses. This inconsistency is also a barrier for those seeking guidance from the research literature when developing and planning implementation initiatives. The Expert Recommendations for Implementing Change (ERIC) study aims to address one area of terminological inconsistency: discrete implementation strategies involving one process or action used to support a practice change. The present report is on the second stage of the ERIC project that focuses on providing initial validation of the compilation of 73 implementation strategies that were identified in the first phase. FINDINGS: Purposive sampling was used to recruit a panel of experts in implementation science and clinical practice (N = 35). These key stakeholders used concept mapping sorting and rating activities to place the 73 implementation strategies into similar groups and to rate each strategy's relative importance and feasibility. Multidimensional scaling analysis provided a quantitative representation of the relationships among the strategies, all but one of which were found to be conceptually distinct from the others. Hierarchical cluster analysis supported organizing the 73 strategies into 9 categories. The ratings data reflect those strategies identified as the most important and feasible. CONCLUSIONS: This study provides initial validation of the implementation strategies within the ERIC compilation as being conceptually distinct. The categorization and strategy ratings of importance and feasibility may facilitate the search for, and selection of, strategies that are best suited for implementation efforts in a particular setting. PMID- 26249852 TI - Epsilon Waves Aid in the Prognosis and Risk Stratification of Patients With ARVC/D. PMID- 26249844 TI - Factors that influence the non-technical skills performance of scrub nurses: a prospective study. AB - AIM: To identify and describe the factors that impact on the performance of scrub nurses' non-technical skills performance during the intra-operative phase of surgery. BACKGROUND: Non-technical skills have been identified as important precursors to errors in the operating room. However, few studies have investigated factors influencing non-technical skills of scrub nurses. DESIGN: Prospective observational study. METHODS: Structured observations were performed on a sample of 182 surgical procedures across eight specialities by two trained observers from August 2012-April 2013 at two hospital sites. Participants were purposively selected scrub nurses. Bivariate correlations and a multiple linear regression model were used to identify associations among length of surgery, patients' acuity using the American Society of Anesthesiologists classification system, team familiarity, number of occasions scout nurses leave the operating room, change of scout nurse and the outcome, the non-technical skills performance of scrub nurses. RESULTS: Patient acuity and team familiarity were the strongest predictors of scrub nurses' non-technical skills performance at hospital site A. There were no correlations between the predictors and the performance of scrub nurses at hospital site B. CONCLUSION: A dedicated surgical team and patient acuity potentially influence the performance of scrub nurses' non-technical skills. Familiarity with team members foster advanced planning, thus minimizing distractions and interruptions that impact on scrub nurses' performance. Development of interventions aimed at improving non-technical skills has the potential to make a substantial difference and enhance patient care. PMID- 26249840 TI - Guanylin-Guanylyl cyclase-C signaling in macrophages regulates mesenteric fat inflammation induced by high-fat diet. AB - Guanylin (Gn), a bioactive peptide, and its receptor, guanylyl cyclase-C (GC-C), are primarily present in the intestine and maintain homeostasis in body fluids. Recently, rats whose macrophages overexpress Gn and GC-C were found to be resistant to diet-induced obesity. Considering that obesity is strongly related to a chronic inflammatory state in white adipose tissues, it is possible that Gn GC-C macrophages contribute to the regulation of inflammation. In the present study, we investigated the inflammatory state of mesenteric fat in rats transgenic for both Gn and GC-C (double-transgenic [dTg] rats) by evaluating the levels of cyclic guanosine monophosphate (cGMP), a second messenger of Gn-GC-C, cGMP-dependent protein kinase (PKG), and phosphorylated vasodilator-stimulated phosphoprotein (VASP), a target protein of PKG. The levels of cGMP in dTg rats was higher than in WT rats fed the same diet. Although there were no significant differences in levels of PKG and phosphorylated VASP between WT and dTg rats fed a standard diet (STD), these levels in dTg rats fed a high fat diet (HFD) were markedly increased compared with levels in HFD WT rats. Furthermore, mRNA levels of proinflammatory factors in mesenteric fat were lower in HFD dTg rats than in HFD WT rats and were similar to levels in STD WT and dTg rats. These results indicate that the Gn-GC-C system in macrophages regulates the cGMP-PKG-VASP pathway and controls obesity through the downregulation of proinflammatory factors. PMID- 26249845 TI - Acute or chronic use of lacosamide does not alter its distribution between serum and cerebrospinal fluid. AB - OBJECTIVE: The site of action for antiepileptic drugs (AEDs) is within the brain; however, cerebrospinal fluid (CSF) concentration is highly variable. Lacosamide (LCM) is approved by the U.S. Food and Drug Administration (FDA) for treatment of partial-onset seizures in adults, and has linear pharmacokinetics in serum. Penetration across the blood-brain barrier (BBB) is unknown. This study aims to provide additional insights into the pharmacokinetics of LCM. METHODS: Thirty adults undergoing craniotomy for treatment of intractable epilepsy or brain tumor were recruited and were either taking LCM long term (group 1, n = 15), or were LCM naive, receiving LCM as prophylaxis for surgery (group 2, n = 15). All patients received one intravenous (IV) dose (15 min infusion) immediately prior to craniotomy. CSF and arterial blood were collected simultaneously following craniotomy. LCM concentrations were measured in serum and CSF. RESULTS: LCM concentration differences between groups 1 and 2 for both CSF and serum were statistically significant (p <= 0.0005), but there was no statistically significant difference in CSF/serum ratios (group 1 = 0.726 +/- 0.231; group 2 = 0.556 +/-0.241; p = 0.0585). LCM concentration in serum correlated positively with CSF concentration in group 1 (Pearson r = 0.8527, p < 0.0001). The time interval between the end of dose delivery and sample collection correlated positively with the CSF/serum ratio for the drug-naive group (Pearson r = 0.6525; p = 0.0084). Treatment with other AEDs did not affect LCM distribution between serum and CSF. SIGNIFICANCE: Although chronic dosing resulted in higher LCM concentrations in serum and CSF compared to drug-naive patients, the CSF/serum ratio was not affected by LCM pretreatment. These data suggest that LCM serum concentration may reliably predict CSF concentration. PMID- 26249847 TI - Incomplete coexistence systems and international food trade impacts. AB - Trade disruptions have been both common and costly for the few GM crops that are produced and marketed. We use a range of adoption studies (compiled by Smyth et al. in Handbook on Agriculture, Biotechnology and Development, Edward Elgar Publishing Ltd, Cheltenham, 2014a), regulatory data and production and trade data to quantify the scale for low level presence incidents. To gain a full perspective on the potential scale of this problem in coming years, we use a combination of recent GM trait commercialization studies and corporate pipeline analysis to identify which traits are planned for which products and the countries in which the technology is likely to be commercialized. Their potential impact will be a result of the intended markets, the regulatory process (especially asynchronous decisions) and the scale and scope of trade in those products. Finally, the article examines the potential for some existing trade and industry institutions to manage the inherent risks of uncertain markets and market impacts. PMID- 26249850 TI - Price and value in cancer care. PMID- 26249848 TI - Enantiomeric separation of 1,3-dimethylamylamine by capillary electrophoresis with indirect UV detection using a dual-selector system. AB - The CE method employing an indirect UV detection for the enantioseparation of 1,3 dimethylamylamine (DMAA), widely used in various preworkout and dietary supplements labeled as a constituent of geranium extract has been developed. The dual-selector system consisting of negatively charged sulfated alpha-CD (1.1% w/v) and sulfated beta-CD (0.2% w/v) in 5 mM phosphate/Tris buffer (pH 3.0) containing the addition of 10 mM benzyltriethylammonium chloride (BTEAC) as the chromophoric additive was used for the enantiomeric separation of DMAA stereoisomers with the LODs in the range of 7.82-9.24 MUg/mL. The method was partly validated and applied for the determination of the stereoisomeric composition of DMAA in commercial dietary supplements to verify the potential natural origin of DMAA. PMID- 26249851 TI - Majority of drug-related problems identified during medication review are not associated with STOPP/START criteria. AB - PURPOSE: STOPP and START criteria identify potential inappropriate prescribing and potential prescribing omissions. It is unknown whether STOPP/START criteria identify all drug-related problems. This study aims to determine to what extent STOPP/START correspond to drug-related problems (DRPs) identified during a full clinical medication review. METHODS: In 13 Dutch community pharmacies, 457 community-dwelling patients aged >=65 years and using >=5 drugs, received a full clinical medication review. Community pharmacists identified potential DRPs and recommendations by implicit criteria. After completion, all identified DRPs and recommendations were compared with STOPP and START criteria by investigators. RESULTS: The total number of potential DRPs identified by community pharmacists was 1656 in 457 patients (mean 3.6 per patient). Eighty-one percent of DRPs were not associated with STOPP/START criteria. The percentage of START criteria present in identified DRPs was higher than the percentage of STOPP criteria (13 vs. 5.7%, p < 0.01). The implementation rate for recommendations associated with STOPP criteria was higher compared to recommendations associated with START criteria (56 vs. 39%, p < 0.01). Both implementation rates of STOPP and START recommendations were lower compared to recommendations not associated with STOPP/START criteria (66%, p = 0.047 and p < 0.001, respectively). CONCLUSIONS: This study shows that the majority of drug-related problems of community-dwelling older patients was not associated with STOPP/START criteria. These findings suggest that application of STOPP/START criteria in full clinical medication review should preferably be combined with implicit criteria. PMID- 26249855 TI - New data on Apteroloma (Coleoptera: Agyrtidae) of central Asia and the Himalayas with a new synonymy. AB - The distribution of Apteroloma anglorossicum (Semenov, 1890), A. harmandi (Portevin, 1903) and A. sillemi Jeannel, 1935 in central Asia and along the Himalayas is summarized, and the collecting circumstances and ecology of all three species from Gilgit District, Pakistan are described in detail. Revised diagnoses of all three species are provided, habitus and important morphological structures are illustrated, and available types have been examined. Apteroloma jankovskii Semenov and Znojko in Semenov, 1932 is confirmed as junior subjective synonym of A. anglorossicum. Apteroloma heinzi Schawaller, 1991 is newly treated as a junior subjective synonym of A. harmandi. PMID- 26249856 TI - New species of Trimma (Actinopterygii, Gobiidae) from Indonesia, with comments on head papillae nomenclature. AB - Three new species of the gobiid Trimma are described from Indonesian waters, and a partially reformulated nomenclature for the cephalic sensory papillae of members of this genus is provided. Trimma aturirii possesses two dark oblique stripes on either side of the pupil (blue, edged with red in life, dark brown in preservative), the lower of which continues posteriorly across the dorsal margin of the opercle, with the dorsal half of the body red and the ventral half abruptly white in life. The species has a narrow bony interorbital (<=50% pupil width), a moderate interorbital trench with a slight groove posterodorsal to the eye, no scales on the cheek, opercle or in the predorsal midline, no elongate spines in the first dorsal fin, 9-10 dorsal and 9 anal fin rays, 17-18 (7-11 branched) pectoral fin rays and an unbranched fifth pelvic fin ray. Trimma kardium has a pair of tapering oval red spots which join anteriorly over the anterior region of the hyoid arches, forming an approximate heart-shaped marking on the ventral surface of the head. It has a narrow bony interorbital (<=40% pupil width), a moderate interorbital trench with a slight groove posterodorsal to the eye, 17-18 unbranched pectoral fin rays, 1-5 cycloid scales in the predorsal midline confined to about the middle third of the nape, and a single row of 1-3 cycloid scales along the upper border of the opercle. Trimma trioculatum has a large (slightly greater than pupil diameter in width) round, black, ocellated spot in the first dorsal fin between spines 1 and 5, a second, much smaller black or dark red spot just posterior to the spine of the second dorsal fin and above the basal stripe, a yellow body with a dark purplish or gray head with two distinct red bars across the cheek, no round spots of any colour on the nape, opercle or cheek, a small dark (preserved) or white (alive) spot on the upper pectoral fin base, a narrow bony interorbital (<70% pupil diameter), no elongate spines in the first dorsal fin, 15-16 pectoral fin rays with the middle 4-8 rays branched, a fifth pelvic fin ray with a single dichotomous branch, and 16-17 total gill rakers on the first gill arch. PMID- 26249859 TI - New taxa and new records in Cerambycidae (Coleoptera) from the state of Bahia (Brazil) and notes on Meridiotroctes (Acanthoderini). AB - Twelve new species and two new genera are described from Bahia (Brazil): Ectenessa aurantiaca (Ectenessini); Stizocera lingafelteri (Elaphidiini); Raglicia monnei (Graciliini), new genus and species; Tobipuranga aspera (Heteropsini); Cicatrion unicolor, and Pygmodeon obscurum (Neoibidionini); Neophygopoda agdae (Rhinotragini); Arapari bellus (Trachyderini), new genus and species; Meridiotroctes obliquus (Acanthoderini); Melzerella inopinata (Aerenicini); Ceiupaba poranga, and Desmiphora (Desmiphora) nascimentoi (Desmiphorini). Notes on Meridiotroctes Martins & Galileo, 2007 and Cosmisoma brullei (Mulsant, 1862) are provided. Forty-eight species are recorded for the first time for Bahia (Brazil) including four species which are recorded for the first time for Brazil. PMID- 26249854 TI - Unsuspected difficulty using a laryngeal mask airway and a video laryngoscope due to unanticipated congenital pharyngeal bands. PMID- 26249857 TI - A review of the subfamily Rogadinae (Hymenoptera: Braconidae) from Iran. AB - Specimens of the subfamily Rogadinae (Hymenoptera: Braconidae) were collected in northern Iran during 2010-2011 with a series of Malaise traps. Twelve species belonging to three genera (Aleiodes Wesmael, 1838, Heterogamus Wesmael, 1838 and Clinocentrus Haliday, 1833) were identified, with one genus (Heterogamus) and seven species new for the fauna of Iran. An updated checklist of the genera and species of the subfamily Rogadinae is included. A total of 26 species belonging to four genera are listed for Iran after correction for misidentifications. A key to the genera and the species of Rogadinae known from Iran is provided. PMID- 26249862 TI - New Species of the Spider Genus Cheiracanthium from Continental Africa
(Araneae: Eutichuridae). AB - Eleven new species of Cheiracanthium, C. boendense sp. nov. (Democratic Republic of Congo), C. falcis sp. nov. (Gabon), C. foordi sp. nov. (South Africa), C. ghanaense sp. nov. (Ghana), C. kabalense sp. nov. (Uganda), C. kakamega sp. nov. (Kenya), C. kakumense sp. nov. (Democratic Republic of Congo, Ivory Coast, Ghana), C. lukiense sp. nov. (Democratic Republic of Congo), C. mayombense sp. nov. (Democratic Republic of Congo), C. shilabira sp. nov. (Democratic Republic of Congo, Kenya) and C. tanzanense sp. nov. (Tanzania) are described. Males of C. punctipedellum Caporiacco, 1949, C. sansibaricum Strand, 1907 and C. schenkeli Caporiacco, 1949 are described for the first time. PMID- 26249858 TI - A fifth species of the genus Euparkerella (Griffths, 1959), the advertisement calls of E. robusta Izecksohn, 1988 and E. tridactyla Izecksohn, 1988, and a key for the Euparkerella species (Anura: Brachycephaloidea: Craugastoridae). AB - A new species of the anuran genus Euparkerella is described from a rainforest area in the state of Rio de Janeiro, southeastern Brazil. Morphologically, the species resembles E. brasiliensis and E. cochranae, but differs from them in acoustic features. Relative to its congeners, the new species is characterized by: (1) medium size; (2) slender body; (3) narrow head; (4) long Finger IV, Toes I and V; (5) tubercles of the hand and foot protuberant; (6) duration of advertisement call longer than three seconds; (7) pulse-section rate slower than two sections/second; and (8) exhibiting pulse clusters. The advertisement calls of E. robusta and E. tridactyla are described and a key based on morphological and acoustic characters is presented for species in the genus. PMID- 26249860 TI - Penghou, a new genus of flea beetles from China (Coleoptera: Chrysomelidae: Galerucinae: Alticini). AB - A new genus (Penghou) with a single new species (P. yulongshan) from Yunnan Province in China is described and illustrated. It is compared to Hespera Weise, Hesperomorpha Ogloblin, Laotzeus Chen, Luperomorpha Weise, Mandarella Duvivier, Omeiana Chen, Stenoluperus Ogloblin and Taiwanohespera Kimoto. PMID- 26249863 TI - Review of the buccal-attaching fish parasite genus Glossobius Schioedte & Meinert, 1883 (Crustacea: Isopoda: Cymothoidae). AB - Two species of Glossobius Schioedte & Meinert, 1883 are known from Australia: Glossobius anctus Bruce & Bowman, 1989 and Glossobius impressus (Say, 1818), the latter recorded here for the first time from Australia and southern Africa. Glossobius ogasawarensis Nunomura, 1994 is here placed in synonymy with Glossobius auritus Bovallius, 1885; whereas Glossobius crassa (Dana, 1853) is removed from synonymy with G. auritus and placed into nomen dubium. Glossobius arimae Nunomura, 2001 is transferred to the genus Ceratothoa Dana, 1852. A key to the species of Glossobius is presented. PMID- 26249861 TI - Pseudacanthicus pitanga: a new species of Ancistrini (Siluriformes: Loricariidae: Hypostominae) from rio Tocantins Basin, North Brazil. AB - The genus Pseudacanthicus comprises five valid species distributed in the Amazon, Guyana and Suriname basins: P. serratus, P. fordii, P. histrix, P. spinosus and P. leopardus. A new species of Pseudacanthicus from the Tocantins river basin is described. The new species is distinguished from its congeners by the following combination of characters: presence of dark blotches anostomosing to form continuous zigzag bands alongside longitudinal keels; absence of blotches on ventral surface of body; faint blotches on head; all fins with orange to red color on unbranched ray and sometimes on subsequent branched rays; and sphenotic and sixth infraorbital not in contact. Brief comments on the phylogeny of the genus, ornamental fisheries activities, threats and conservation of the new species are also provided. PMID- 26249866 TI - A new Cephennium of Kyrgyzstan, with notes on subgenera and distribution (Coleoptera, Staphylinidae, Scydmaeninae). AB - Cephennium chirgisianum sp. n. of western Kyrgyzstan is described. This is the easternmost known locality where this predominantly western European genus occurs. This new species is not placed in any subgenus, and problems with subgeneric diagnoses and systematics of Cephennium are discussed. The distribution of Cephennium is summarized and possible dispersal routes or areas where this genus can be expected to occur are indicated. PMID- 26249864 TI - A revision of the genus Morophagoides Petersen (Lepidoptera, Tineidae)
from Japan. AB - Taxonomy of the Japanese species of the genus Morophagoides Petersen, 1957 is revised. Previously four species, namely Morophagoides ussuriensis (Caradja, 1920), M. moriutii Robinson, 1986, M. occidentalis Osada, Yoshimatsu, Sakai and Hirowatari, 2014 and M. meridianus Osada, Yoshimatsu, Sakai and Hirowatari, 2014 were recognized for the Japanese fauna. In the present study, four new species, M. breviculus sp. nov., M. robinsoni sp. nov., M. aquilonis sp. nov. and M. yakuensis sp. nov., from Japan are described based on adult characters. The potential synapomorphy of this widely distributed genus is proposed. In addition, the distribution pattern of the genus in Japan is discussed. PMID- 26249849 TI - Development and initial testing of the Penn Parkinson's Daily Activities Questionnaire. AB - OBJECTIVE: The aim of this work was to describe the development and psychometric analysis of the Penn Parkinson's Daily Activities Questionnaire. The questionnaire is an item response theory-based tool for rating cognitive instrumental activities of daily living in PD. METHODS: Candidate items for the Penn Parkinson's Daily Activities Questionnaire were developed through literature review and focus groups of patients and knowledgeable informants. Item selection and calibration of item-response theory parameters were performed using responses from a cohort of PD patients and knowledgeable informants (n = 388). In independent cohorts of PD patients and knowledgeable informants, assessments of test-retest reliability (n = 50), and construct validity (n = 68) of the questionnaire were subsequently performed. Construct validity was assessed by correlating questionnaire scores with measures of motor function, cognition, an existing activities of daily living measure, and directly observed daily function. RESULTS: Fifty items were retained in the final questionnaire item bank. Items were excluded owing to redundancy, difficult reading level, and when item-response theory parameters could not be calculated. Test-retest reliability was high (intraclass correlation coefficient = 0.97; P < 0.001). The questionnaire correlated strongly with cognition (r = 0.68; P < 0.001) and directly observed daily function (r = 0.87; P < 0.001), but not with motor impairment (r = 0.08; P = 0.53). The questionnaire score accurately discriminated between PD patients with and without dementia (receiver operating characteristic curve = 0.91; 95% confidence interval: 0.85-0.97). CONCLUSIONS: The Penn Parkinson's Daily Activities Questionnaire shows strong evidence of reliability and validity. Item response theory-based psychometric analysis suggests that this questionnaire can discriminate across a range of daily functions. PMID- 26249853 TI - Protective effect of hydrogen sulfide on TNF-alpha and IFN-gamma-induced injury of intestinal epithelial barrier function in Caco-2 monolayers. AB - BACKGROUND AND AIM: Studies have verified the protective effect of Hydrogen Sulfide (H2S) on gastric ulcer and ulcerative colitis, but the mechanisms are not fully illustrated. In this study, the possible protective effect of H2S on TNF alpha/IFN-gamma induced barrier dysfunction was investigated in Caco-2 cell monolayers. METHOD: The barrier function of Caco-2 monolayers was evaluated by measuring trans-epithelial electrical resistance (TEER) and FITC-Dextran 4 kDa (FD-4) trans-membrane flux. ZO-1 and Occludin were chosen as markers of the localization of tight junction (TJ) proteins for immunofluorescence. The expression of MLCK and phosphorylation level of myosin light chain (MLC) were measured by immunoblotting. The activation of NF-kB p65 was analyzed by EMSA and immunofluorescence. RESULTS: NaHS at 500 uM significantly attenuated TNF alpha/IFN-gamma-indueced Caco-2 monolayer barrier injury. The increased expression of MLCK and increased phosphorylation level of MLC induced by TNF alpha/IFN-gamma was also inhibited significantly by NaHS. Additionally, NaHS inhibited TNF-alpha/IFN-gamma induced activation and nuclear translocation of NF kB p65. CONCLUSION: The present study reveals the protective effect of H2S on TNF alpha and IFN-gamma-induced injury of intestinal epithelial barrier function in Caco-2 monolayers and suggests that the suppression of MLCK-P-MLC signaling mediated by NF-kB P65 might be one of the mechanisms underlying the protective effect of H2S. PMID- 26249865 TI - Retroculus acherontos, a new species of cichlid fish (Teleostei) from the Rio Tocantins basin. AB - Retroculus acherontos is described from the Rio Tocantins basin, Brazil. It is distinguished from all congeners by the presence of a nuchal hump in large specimens, an irregular black blotch located on the middle of the anterior soft dorsal-fin rays, fewer pectoral-fin rays (15-16), a deeper body, a convex ventral profile, a more transversely convex ventral surface of the body, and by chest scales similar in size to the scales on the side. An expanded diagnosis for the genus Retroculus is provided. PMID- 26249868 TI - Gender of the genus Botrylloides Milne Edwards (1841) [Tunicata: Ascidiacea]. AB - Milne Edwards (1841) introduced Botrylloides listing species with both feminine and neuter word endings. The International Code on Zoological Nomenclature, however, indicates that generic names ending -oides should be masculine unless the introducing author unambiguously indicated a different gender. The resulting uncertainty has caused prolonged confusion over the correct gender of Botrylloides. It is here affirmed that Milne Edwards did not provide a clear indication of gender and the general rule of the International Code applies: Botrylloides has masculine gender. The type species is B. rotifer Milne Edwards (its ending corrected from the feminine B. rotifera). PMID- 26249867 TI - First record of the subfamily Anoplophilinae (Orthoptera: Rhaphidophoridae) from Russia with description of a new species of the genus Alpinanoplophilus Ishikawa, 1993. AB - The subfamily Anoplophilinae (Rhaphidophopridae) is recorded from Russia for the first time. Alpinanoplophilus kurilensis Storozhenko, sp. nov. is described from Kunashir Island. The holotype of the new species is deposited in the Zoological Institute of Russian Academy of Science (St. Petersburg, Russia). A revised key to the species of the genus Alpinanoplophilus Ishikawa, 1993 is provided. PMID- 26249874 TI - Lost in the middle of the sea, found in the back of the shelf: A new giant species of Trachylepis (Squamata: Scincidae) from Tinhosa Grande islet, Gulf of Guinea. AB - A new species of Trachylepis is described from Tinhosa Grande islet, Sao Tome e Principe, Gulf of Guinea. Tinhosa Grande islet is a small (20.5 ha), isolated desert islet used by several bird communities as a nesting place. The new species is distinguished from its congeners by its color pattern, size and lepidosis. Due to its limited geographical distribution the new species appears to be one of the most vulnerable vertebrate species on the planet. In this study we provide a brief discussion on the natural history of the new species, as well as conservation concerns and suggestions. PMID- 26249875 TI - New data on Himalayan Lesteva Latreille, 1797 (Coleoptera: Staphylinidae: Omaliinae) with description of a new species from Nepal. AB - Lesteva (s.str.) hartmanni sp. n. (Nepal: Gandaki Province, Manaslu Mts.), L. (s.str.) brevipennis Cameron, 1941 and L. (s.str.) torrentum Cameron, 1924 are (re-) described and illustrated. New records of L. (s.str.) championi Lohse, 1982, L. (s.str.) jaegeri Shavrin, 2012 and a modified identification key to the species of Lesteva Latreille, 1797 of Nepal are provided. L. brevipennis is recorded from Pakistan for the first time. PMID- 26249870 TI - Earthworms from Matsu, Taiwan with descriptions of new species of the genera Amynthas (Oligochaeta: Megascolecidae) and Drawida (Oligochaeta: Moniligastridae). AB - In 2012, we conducted earthworm surveys in Matsu Islands, and described five new species of the genera Amynthas and Metaphire and reported two new records, Desmogaster sinensis Gates, 1930 and Ocnerodrilus occidentalis Eisen, 1878. This paper describes three new species, one of them with two new subspecies, Amynthas nanganensis nanganensis sp. nov. et ssp. nov. and Amynthas nanganensis beiganensis ssp. nov., Drawida beiganica sp. nov. and Drawida dongyinica sp. nov., provides a new record of Drawida koreana Kobayashi, 1938 from the remaining specimens collected in the surveys, reports DNA barcodes (the 5' end sequences of the mitochondrial cytochrome c oxidase subunit 1 gene) from type specimens and further reference specimens of the new species, and lists a total of 27 earthworm species and subspecies found from Matsu Islands. Pheretimoid earthworms made up 66.7% of the total number of the species, with Metaphire matsuensis Shen, 2014 and Metaphire californica (Kinberg, 1867) the most dominant. Our findings indicate that the earthworm fauna of Matsu Islands is more closely related to that of warm temperate China than to Taiwan or tropical southern China. PMID- 26249872 TI - Contribution to the eyed Sinella from China: two new species and additional reports on nine known species (Collembola: Entomobryidae). AB - Two new 1+1 eyed species of Sinella Brook, 1882, S. uniseta sp. nov. and S. abietis sp. nov., are described from China. New collection records are reported for nine known species: S. qufuensis Chen & Christiansen, 1993, S. quinocula Chen & Christiansen, 1993, S. affluens Chen & Christiansen, 1993, S. wui Wang & Christiansen, 2000, S. umesaoi Yosii, 1940, S. gei Pan, Zhang & Shi, 2012, S. sunae Pan, Zhang & Shi, 2012, S. gracilis Zhang, 2013 and S. transoculata Pan & Yuan, 2013. Additions to original description, such as clypeal chaetae, chaetae along cephalic groove, and S-chaetotaxy, are provided for above known species. A key to the eyed species of Sinella from China is given. PMID- 26249871 TI - New data on the genus Platypalpus (Diptera: Hybotidae) from the Caucasus with description of seven new species. AB - Currently, 47 species of the genus Platypalpus are known from the Caucasus including fourteen species recorded herein for the first time: P. albicornis (Zetterstedt, 1842), P. baldensis (Strobl, 1899), P. caroli Grootaert, 1987, P. ciliaris (Fallen, 1816), P. clarandus (Collin, 1926), P. collini (Chvala, 1966), P. cothurnatus Macquart, 1827, P. infectus (Collin, 1926), P. longicornis (Meigen, 1822), P. luteicornis (Meigen, 1838), P. nigrinus (Meigen, 1822), P. pseudociliaris (Strobl, 1910), P. ruficornis (von Roser, 1840), and P. smirnovi Kovalev, 1978. In addition, seven new species are described: P. akhunensis sp. nov. (Russia: Krasnodarskiy Territory), P. kintrishiensis sp. nov. (Georgia), P. lantsovi sp. nov. (Georgia), P. pseudosilvahumidus sp. nov. (Russia: Krasnodarskiy Territory, Karachay-Cherkessia), P. sinevi sp. nov. (Russia: Karachay-Cherkessia), P. subcaucasicus sp. nov. (Russia: Krasnodarskiy Territory, Dagestan) and P. teberdaensis sp. nov. (Russia: Karachay-Cherkessia). A key to species of Platypalpus from the Caucasus is presented for the first time. PMID- 26249878 TI - Three new species of the genus Quedius (subgenus Microsaurus) from China (Coleoptera: Staphylinidae: Staphylinini: Quediina). AB - Three new species of the subgenus Microsaurus Dejean, 1833 of the genus Quedius Stephens, 1829 are described based on specimens collected from China: Q. (Microsaurus) bilobus sp. nov. and Q. (Microsaurus) varius sp. nov. from Sichuan, and Q. (Microsaurus) cornutus sp. nov. from Yunnan. Line drawings and color illustrations of adults and genitalia of the new species are provided. PMID- 26249873 TI - Description of the newly-hatched juvenile of Aegla perobae (Crustacea: Decapoda: Aeglidae). AB - The present paper contains the complete description of the external morphology of the first juvenile stage of Aegla perobae analysed through light microscopy (LM) and scanning electron microscopy (SEM). Newly-hatched juveniles were obtained from ovigerous females kept under laboratory conditions. Hatching is asynchronous, taking 2-4 days for all juveniles of a single brood to hatch. Average carapace dimensions are 1.54 mm wide and 1.69 mm long (rostrum excluded). Morphology of the carapace, of the cephalothoracic appendages (antennule, antenna, mandible, maxillule, maxilla, maxillipeds, and pereopods), of the pleon, and of the tail fan (telson plus uropods) are described in detail. Aegla perobae juveniles can be readily differentiate from the first juveniles of other aeglids species described so far by the upwardly curved condition of the distal region of the rostrum and the distinct groove along the orbital sinus produced the elevated free in this area. Pleopods 2-5 are present as rudimentary digitiform buds. Rudimentary pleopods are still present in adult males of the species, a trait not yet described in freshwater aeglids. This curious condition is compared and discussed in the light of the current knowledge of early postembryonic developmental patterns found in other anomurans. PMID- 26249876 TI - A new species and new records of Arrhopalitidae (Collembola: Symphypleona) from the Republic of Moldova. AB - Eight species of the family Arrhopalitidae Stach, 1956 are listed from the Republic of Moldova. A new species, Arrhopalites prutensis sp. nov. is described. It belongs to the diversus group of species with 3, 2, 1, 1 anterior setae on dens, possesses neosminthuroid seta on the furca base region-a character rarely noted for the family. The new species is closely related to A. baccettii Dallai, 1969 and A. antonioi Giuga & Jordana, 2013 described from Sicily. Five species of the family are firstly recorded for the country. PMID- 26249869 TI - A revision of the Indian species of Oligosita Walker (Hymenoptera: Trichogrammatidae). AB - The Indian species of the genus Oligosita Walker, 1851 (Hymenoptera: Trichogrammatidae) are revised. One new species, Oligosita aseta Begum & Anis, sp. nov., is described based on specimens collected from Kerala, India. A key to the 16 Indian species of the genus is also given. PMID- 26249877 TI - New records of stink bugs (Hemiptera: Pentatomidae) from Colombia. AB - New records of genera and species of stink bugs (Hemiptera: Pentatomidae) from Colombia are provided. Two genera are new records for South America: Alathetus and Schraderiellus. Fifteen genera are new record for Colombia: Agaclitus, Boea, Ceratozygum, Euthyrhynchus, Eritrachys, Doesburguedessa, Lopadusa, Marmessulus, Paralincus, Patanius, Peromatus, Phalaecus, Phoeacia, Rio, and Tyrannocoris. Forty-nine species from five subfamiles are recorded for the first time in Colombia. Asopinae: Coryzorhaphis carneolus Erichson, Coryzorhaphis superba Breddin, Euthyrhynchus floridanus (Linnaeus), Podisus sagitta Fabricius, Stiretrus anchorago (Fabricius), Stiretrus cinctellus Germar, Tylospilus peruvianus Horvath, Tyrannocoris nigriceps Thomas. Cyrtocorinae: Ceratozygum horridum (Germar). Discocephalinae: Agaclitus dromedarius Stal, Antiteuchus melanoleucus (Westwood), Antiteuchus sepulcralis (Fabricius), Dinocoris gibbosus (Fallou), Dinocoris variolosus (Linnaeus), Discocephalessa terminalis (Walker), Dryptocephala crenata Ruckes, Dryptocephala dentifrons (Latreille), Eurystethus ovalis Ruckes, Paralcippus dimidiatus (Ruckes), Alathetus rufitarsus Dallas, Eritrachys bituberculata Ruckes, Paralincus bimaculatus (Ruckes), Schraderiellus cinctus (Ruckes), Xynocoris recavus (Garbelotto & Campos). Edessinae: Brachystethus cribus (Fabricius), Brachystethus tricolor Bolivar, Doesburguedessa elongatispina Fernandes and Lopadusa fuscopunctata (Distant). Pentatominae: Banasa fulgida Thomas, Banasa paraexpallescens Thomas, Dichelops divisus (Walker), Dichelops nigrum Bergroth, Euschistus carbonerus Rolston, Mormidea bovilla (Distant), Mormidea triangularis (Walker), Murgantia bifasciata Herrich Schaeffer, Murgantia violascens (Westwood), Oebalus pugnax (Fabricius), Oebalus ypsilon-griseus (DeGeer), Odmalea concolor (Walker), Patanius vittatus Rolston, Proxys albopunctulatus (Palisot), Proxys punctulatus (Palisot), Rhyncholepta grandicallosa Bergroth, Rio insularis Ruckes, Roferta marginalis (Herrich Schaffer), Serdia concolor Ruckes, Sibaria armata (Dallas) and Taurocerus achilles (Stal). These new records for Colombia are importanst for the understanding of the distributional range of the genera and species involved. PMID- 26249879 TI - Late-instar larva of Scydmaenus (Parallomicrus) rufus Muller & Kunze (Coleoptera: Staphylinidae, Scydmaeninae). AB - The late-instar (most likely the last instar) larva of Scydmaenus (Parallomicrus) rufus is described. A comparative study with other known larvae of Scydmaenus (belonging to Scydmaenus s. str. and the subgenus Cholerus) is carried out and it is concluded that while the general body form and some characters are shared by immature Parallomicrus and Cholerus, there are nevertheless features present in Parallomicrus and Scydmaenus s. str. that are absent in Cholerus. A subcylindrical and strongly elongated body differentiates immature Parallomicrus from Scydmaenus s. str., while the following characters, present in Parallomicrus, are not known in Cholerus: a pair of long lateral setae on head capsule, four (and not five) pairs of dorsoanterior setae on the nasale, more than 10 teeth on the anteroventral margin of nasale instead of five only, three (and not two) solenidia on the antennomere III, three (and not two) pairs of labial setae, slightly (and not strongly) elongate abdominal segment IX, and abdominal segment X not constricted near base. PMID- 26249880 TI - A nearly cryptic Scorpionfly, Panorpa cryptica n. sp. (Mecoptera: Panorpidae) from North America. AB - The first nearly cryptic species of scorpionfly from the United States, Panorpa cryptica Bicha and Schiff, n. sp., is described from northern Georgia, southwestern North Carolina and northwestern South Carolina. This insect was initially differentiated from the very similar Panorpa nebulosa Westwood by its unique cytochrome oxidase subunit I (COI) mitochondrial DNA. Habitat details, distribution, and biology are described. PMID- 26249881 TI - An annotated catalogue of the Iranian Alysiinae (Hymenoptera: Braconidae). AB - In the present study, a catalogue of the Iranian Alysiinae (Hymenoptera: Braconidae) is given. It is based on a detailed study of all available published data. In total 78 species from 15 genera including Alloea Haliday, 1833 (1 species), Angelovia Zaykov, 1980 (1 species), Aphaereta Foerster, 1862 (2 species), Aspilota Foerster, 1862 (2 species), Chorebus Haliday, 1833 (42 species), Coelinidea Viereck, 1913 (2 species), Coloneura Foerster, 1862 (1 species), Dacnusa Haliday, 1833 (10 species), Dinotrema Foerster, 1862 (5 species), Idiasta Foerster, 1862 (1 species), Orthostigma Ratzeburg, 1844 (3 species), Phaenocarpa Foerster, 1862 (1 species), Protodacnusa Griffiths, 1964 (2 species), Pseudopezomachus Mantero, 1905 (2 species), and Synaldis Foerster, 1862 (3 species) are reported in this catalogue. Two species are new records for Iran: Coelinidea elegans (Curtis, 1829) and Dacnusa (Pachysema) aterrima Thomson, 1895. Also, a faunistic list with distribution data and host records is provided. PMID- 26249885 TI - New national and state records of Neotropical Staphylinidae (Insecta: Coleoptera). AB - Eighteen new national records of nine species of Osoriinae (Staphylinidae) are added for 10 Neotropical countries. Additionally, 17 species of three subfamilies are first recorded from ten States of Mexico. The distributional patterns of the studied species are commented and the congruence with species of different families of Coleoptera and Odonata previously analyzed is discussed. Finally, we conclude that some of these patterns can be proposed as hypothesis of primary biogeographic homology. PMID- 26249882 TI - Review of the genus Lesteva Latreille, 1797 of Central Asia (Coleoptera: Staphylinidae: Omaliinae: Anthophagini). AB - A taxonomic review of the genus Lesteva Latreille, 1797 of the Central Asia is presented. The type material of the following species was revised: L. bucharica Fauvel, 1900, L. fasciata Luze, 1903, L. nova Bernhauer, 1902, L. transcaspica Bernhauer, 1935 and L. turkestanica Luze, 1904. Lectotypes for L. bucharica and L. turkestanica, a lectotype and paralectotype for L. transcaspica are designated. One species is described as new: L. (s.str.) schuelkei sp. n. (Tajikistan, NW Pamir: Peter-I Mts. and Hissar Mts.). Three synonyms are proposed: L. (s.str.) fasciata=L. (s.str.) turkestanica, syn n.=L. (s.str.) transcaspica, syn. n., L. nova=L. (s.str.) aculeata Shavrin, 2010, syn. n. Three species are redescribed: L. (s.str.) bucharica, L. (s.str.) fasciata and L. (s.str.) nova. All species are illustrated and their distribution mapped. A key to species known from Central Asia, as well as new provincial records for L. (s.str.) barsevskisi Shavrin, 2010, L. (s.str.) bucharica and L. (s.str.) fasciata are provided. PMID- 26249884 TI - Three new Sinopoda species (Araneae: Sparassidae) from southern China. AB - Three new species of the huntsman spider genus Sinopoda Jager, 1999, collected from Sichuan Province and Chongqing Municipality, P. R. China, are described: Sinopoda cochlearia sp. nov. (male, female), S. globosa sp. nov. (male, female) and S. longiducta sp. nov. (male, female). All three new species were collected from native forest by hand. PMID- 26249888 TI - Austrodontella monticola sp. nov., a new species of Collembola from montane New Zealand. AB - Collembola were collected from soil in the alpine belt (1600-1900 m a.s.l.) of the Southern Alps of New Zealand. A list of species found is provided. Austrodontella monticola sp. nov., the third species of a Odontellidae genus with a southern distribution is described. The other two species in the genus occur in southern Australia and in the Indian Ocean sector of the Subantarctic respectively. Notes on A. trispina (Womersley, 1935), the type species of the genus, are provided. PMID- 26249883 TI - Redescription of Argizala brasiliensis Walker, 1869 (Orthoptera: Grylloidea: Trigonidiidae: Nemobiinae: Pteronemobiini) and consideration of its morphological proximity to other Pteronemobiini Nearctic genera. AB - Although male crickets provide more informative characters for the delimitation of species and genera, many taxonomic descriptions are based only on females. This is the case for Argizala Walker, 1869 and its two valid species, A. brasiliensis Walker, 1869 and A. hebardi Rehn, 1915. We provide herein a redescription of A. brasiliensis based on a male collected in the Pampa Biome, Capao do Leao municipality, Rio Grande do Sul State, Brazil. We present photographs of epitype and male genitalia, and discuss the diagnostic features of the genus and its morphological proximity to other Pteronemobiini Nearctic genera. PMID- 26249886 TI - Two new earthworm species (Oligochaeta: Annelida) of the Caribbean region of Colombia. AB - Two new earthworm species are described, Periscolex malibu sp. nov. (Rhinodrilidae) and Righiodrilus lebrijae sp. nov. (Glossoscolecidae). They were found in relicts of tropical dry forests surrounding wetlands in the southern department of Cesar, located near the Caribbean coast of Colombia. Periscolex malibu sp. nov. is close to P. fuhrmanni Michaelsen, 1913 by the position of both clitellum and tubercula pubertatis, but differs in the extension of the clitellum and in the presence of five pairs of spermathecae. Righiodrilus lebrijae sp. nov is close to R. paolettii Righi, 1984a by the extension of the clitellum, but differs in the extension of the tubercula pubertatis, the extension of the seminal vesicles, the position of the male pores, the arrangements of setae, and the shape of the spermathecae. PMID- 26249890 TI - A new species of Busoniomimus Maldonado-Capriles (Hemiptera: Cicadellidae: Idiocerinae) from Malaysia with a key to species of the genus. AB - A new species, Busoniomimus umbellatus sp. nov. is described and illustrated from Malaysia. In addition the female of B. hainanensis Zhang & Li is described from China. A key is provided to males of this genus. PMID- 26249891 TI - Flatseta, a new genus of Dikraneurini (Hemiptera: Cicadellidae: Typhlocybinae) from China, with description of a new species. AB - Flatseta gen. n. described and illustrated based on type species F. scimitara sp. n. from China and placed in the typhlocybine tribe Dikraneurini. The new genus is unique among known Typhlocybinae in having modified setae distributed over the male pygofer appendage. Detailed morphological descriptions and illustration of the new genus are provided. PMID- 26249887 TI - Synopsis of the genus Neoeutrypanus Monne, 1977 (Coleoptera, Cerambycidae, Lamiinae), with the description of two new species. AB - Two new species of Neoeutrypanus Monne, 1977 are described: N. llanero sp. nov. from Colombia (Meta Department), and N. dentatus sp. nov. from Bolivia (La Paz Department). A key to species of Neoeutrypanus is provided and new distributional data for N. decorus (Bates, 1881) and N. mutilatus (Germar, 1824) are given. PMID- 26249889 TI - Description of Sangeeta sinuomacula sp. nov. (Hemiptera: Cicadellidae: Megophthalminae: Agalliini) from Yunnan Province of Southwest China. AB - A new species, Sangeeta sinuomacula Li, Dai & Li sp. nov., of tribe Agalliini of subfamily Megophthalminae (Hemiptera: Cicadellidae) is described and illustrated from Yunnnan Province of Southwest China. The new species is easily distinguished from other Sangeeta species by the aedeagal shaft with a pair of slender processes instead of lamelliform lateral expansions. A key to Sangeeta species and updated checklist with distribution are provided. PMID- 26249894 TI - Uca (Xeruca), a new subgenus for the Taiwanese fiddler crab Uca formosensis Rathbun, 1921 (Crustacea: Decapoda: Ocypodidae), based on morphological and molecular evidence. AB - The fiddler crab Uca formosensis Rathbun, 1921 (Crustacea: Decapoda: Ocypodidae), restricted to the western part of Taiwan and the offshore Penghu (Pescadores) Islands in the Taiwan Strait, has been placed under the subgenus Uca (Gelasimus) Latreille, 1817 (= Uca (Thalassuca) Crane, 1975) based on only less than a dozen specimens, but later suggested under the subgenus Tubuca Bott, 1973 because the similarity of external morphology. A suite of characters of carapace, major cheliped, gastric mill, male first gonopod, and chela handedness, as well as the phylogenic relationships (mitochondrial 16S rDNA and cytochrome oxidase subunit I, and nuclear 28S rDNA), nevertheless support this species belongs to its own subgenus. A new subgenus Uca (Xeruca) subgen. nov. is herein established for U. formosensis. PMID- 26249897 TI - A review of the genus Pulcheria Alpheraky, 1887 with description of a new
species from southeastern Kazakhstan (Lepidoptera, Noctuidae). AB - A small Central Asian genus Pulcheria Alpheraky, 1887 is revised. One new species, P. kasymkhani Volynkin & Matov, sp. n. is described from southeastern Kazakhstan (Almaty region). The lectotype for P. catomelas Alpheraky, 1887 and the neotype for P. cinescens Draudt, 1938 are designated. The adults, male and female genitalia are illustrated. PMID- 26249893 TI - Redescription of "Amaurobius" rufipes Taczanowski, 1874 (Araneae: Corinnidae) with notes of Amaurobius species described from French Guyana. PMID- 26249895 TI - Two new species of the genus Pararrhynchium de Saussure (Hymenoptera: Vespidae: Eumeninae) from northern Vietnam. AB - Two new species of the genus Pararrhynchium are described and figured: P. striatum sp. nov. (northern Vietnam: Hoa Binh, Ha Tinh and Thai Nguyen) and P. concavum sp. nov. (northern Vietnam: Cao Bang). A key to all known species of the genus is provided. PMID- 26249892 TI - Oniticellus (Liatongus) boucomonti Balthasar, 1932 (Coleoptera: Scarabaeidae: Scarabaeinae: Oniticellini)--clarification of its taxonomic status by lectotype designation. PMID- 26249904 TI - Description of a new species of Leiopathes (Antipatharia: Leiopathidae) from the Hawaiian Islands. AB - The Hawaiian antipatharian coral previously identified as Leiopathes glaberrima (Esper, 1792) and Leiopathes sp. is described using polyp morphology, skeletal spine morphology and in situ photographs, and assigned the new name of Leiopathes annosa sp. nov. The species is characterized by tall (1 m or more), fan-shaped colonies, with thick, sometimes overlapping branches, and tissues that are colored bright orange when alive. Skeletal spines are smooth, hemispherical, often times multi-lobed, and typically 75 MUm tall, but range between 30-225 MUm. Polyps are of variable size (0.88-3.35 mm) and arranged on all sides of the corallum on thicker branches, and uniserially on terminal branches. Leiopathes annosa sp. nov differs from all other nominal species of Leiopathes by having a generally flabellate corallum with thick branches and conspicuous skeletal spines that are multi-lobed and hemispherical. The biogeographical distribution of species within the monogeneric family Leiopathidae is presented and discussed. PMID- 26249900 TI - Redescription of three Hippasa species from China (Araneae: Lycosidae), with a proposed species group-division and diagnosis. AB - The genus Hippasa is a group of web-weaving lycosids, whose web is funnel-like, quite similar to those of the Agelenidae. In this paper, based on published papers and specimens from China, we diagnose and discuss the composition of this genus. Two species groups are recognised, the Hippasa greenalliae-group (12 species and a subspecies) mainly from Asia and the Hippasa partita-group (17 species), which is distributed in both South Asia and Africa. In China, there are three Hippasa species: H. holmerae Thorell, 1895, H. lingxianensis Yin & Wang, 1980 (revalidated) and H. lycosina Pocock, 1900. The Japanese species, H. babai Tanikawa, 2007 is newly synonymised with H. lingxianensis. Two Hippasa species, H. agelenoides (Simon, 1884) and H. greenalliae (Blackwall, 1867) have never been found in China. Morphological illustrations, photos and redescriptions of H. holmerae, H. lingxianensis and H. lycosina are provided, based on Chinese specimens. PMID- 26249899 TI - New species of Gelechiidae (Lepidoptera) from Ukraine. AB - Chrysoesthia halimionella, sp. n., Megacraspedus uzunsyrtus, sp. n., Aristotelia confusella, sp. n., and Dirhinosia interposita, sp. n., are described from Ukraine. Adults and genitalia of the new species are illustrated and compared with related species. PMID- 26249905 TI - A new Polychrysia (Lepidoptera, Noctuidae, Plusiinae) species from China. AB - The genus Polychrysia is comprised of seven species separated into three species groups. Six of the seven species are distributed in the Palaearctic region and one of these six species has a Holarctic distribution. The genus has been discussed in detail in monographs by Goater et al. (2003) and Ronkay et al. (2008). A new species of Polychrysia was discovered during an expedition studying the nocturnal fauna of China's Sichuan Province in August, 2014 and is described here. PMID- 26249901 TI - Review of the genus Sobrala Dworakowska (Hemiptera: Cicadellidae: Typhlocybinae: Alebrini) with description of four new species and a new record from China. AB - The genus Sobrala Dworakowska is reported for the first time in China and a key to known species of the genus is provided. Four new species, Sobrala acanthophylla, S. dactylina, S. lamellaris and S. quadrilatera spp. nov. from China are described and illustrated. PMID- 26249902 TI - A range extension of a deep-sea barnacle of the genus Aurivillialepas (Cirripedia, Scalpellomorpha), a Macaronesian and amphitropical refugial genus having Mesozoic affinities. AB - The scalpellomorph barnacle, Aurivillialepas calycula (Aurivillius, 1898), previously known only from Macaronesia, is reported from Banco de Galicia, off the NW corner of the Iberian Peninsula. One of the two specimens was attached to the scleractinian coral, Madrepora oculata Linnaeus, 1758. Since such pedunculate barnacles are little known, the potentially hermaphroditic specimens and its complemental male are illustrated photographically, and a key to the genus Aurivillialepas is provided. The genus, together with Scillaelepas Seguenza, 1876 and Gruvelialepas Newman, 1980, has long been considered to constitute a natural group of scalpellomorphs within the Calanticidae, and therefore the Scillaelepadinae subfam. nov. is proposed to accommodate them. Biogeographical aspects of these deep-sea barnacles support the hypothesis that not only the islands but the banks and guyots of Macaronesia constitute refugia for ancient as well as more recent forms, some of which may stem back to the late Mesozoic. PMID- 26249909 TI - Additional records of the laomediid mud-shrimp genus Naushonia Kingsley, 1897 (Crustacea: Decapoda: Gebiidea), with a revised identification key. AB - Six species of the peculiar mud-shrimp genus Naushonia Kingsley, 1897 (Laomediidae) from various localities in the world are treated in this study: N. carinata Dworschak, Marin & Anker, 2006 (newly recorded from Japan); N. japonica Komai, 2004 (second record since the original description); N. lactoalbida Berggren, 1992 (newly recorded from Papua New Guinea); N. portoricensis (Rathbun, 1901) (newly recorded from the French Antilles); N. serratipalma Komai & Anker, 2010 (newly recorded from Saudi Arabia); and N. draconis Anker, 2014 (newly recorded from Cuba). A detailed description and new illustrations are provided for N. portoricensis, a species for which a modern description was hitherto unavailable. Gill formula was re-examined in all six species. Colour photographs of living or fresh specimens are provided for most species. A revised key to all known species of Naushonia is presented, a eliminating misinterpretation of an important character in previous keys. PMID- 26249896 TI - The genus Xestoleberis (Ostracoda: Xestoleberididae) in the Northern, Northeastern and Eastern regions of the Brazilian continental shelf. AB - The analysis of 359 samples from three regions of the Brazilian continental shelf (Northern, Northeastern and Eastern) resulted in the recognition of six species of the genus Xestoleberis. One of these species was already described, X. umbonata Whatley et al. 1998, four species are new and herein described, X. inesae sp. nov., X. amazonica sp. nov., X. subtriangularis sp. nov. and X. virilis sp. nov., and one was maintained in open nomenclature, Xestoleberis sp. The species X. inesae sp. nov. is widely distributed in the study area, occurring in all mentioned regions, while X. amazonica sp. nov. is restricted to the Northern region. Xestoleberis subtriangularis sp. nov., X. virilis sp. nov. and Xestoleberis sp. occur in the Northeastern and Eastern regions. Xestoleberis umbonata was recorded in this study only in the southernmost part of the Eastern region. PMID- 26249903 TI - Genus Leptoiulus Verhoeff, 1894 new to the fauna of the Asian part of Russia, with description of a new species from the Altai and its comparison with the European Leptoiulus trilineatus (C.L. Koch, 1847) (Diplopoda, Julida, Julidae). AB - The diplopod genus Leptoiulus Verhoeff, 1894 is new to the fauna of the Asian part of Russia, due to the discovery of L. tigirek sp. nov. from the south western part of the Altai Province, Siberia. A description of the new species and information on its habitats, numbers and locomotor activity as well as comparison with the European Leptoiulus trilineatus (C.L. Koch, 1847) are presented. PMID- 26249910 TI - Niphargus (Crustacea: Amphipoda) species in Hungary: literature review, current taxonomy and the updated distribution of valid taxa. AB - Research of the Hungarian Niphargus species is a rather neglected field. This is due to the growing distance between the level of knowledge about Hungarian species and the elaboration determined by the international publications, which had caused a hardly negotiable inconvenience in the judgment of the state of the Hungarian species. The clarification of species in questionable positions could be the starting point of further inland research. During our work, the species with Hungarian distributions were assigned based on the literature's data, and were evaluated with morphological examinations of the specimens collected by us from their type localities and other habitats. Considering the validity of the species we created three categories. Eight of the 20 species proved to be invalid or non-inland species, three remain in an uncertain taxonomic state, while nine are classifiable into the 'valid Hungarian species' category. During the 43 samplings in 27 localities we added new distributional data for seven species. PMID- 26249906 TI - A new species of Cephalocyclus (Coleoptera: Scarabaeidae: Aphodiinae) from Mexico. AB - Cephalocyclus moroni new species (Coleoptera: Scarabaeidae: Aphodiinae) from humid forest in the mountains of Manantlan, Jalisco, Mexico is described and illustrated. It is similar to Cephalocyclus ordonezi Dellacasa, Dellacasa, & Gordon, 2007 and Cephalocyclus stebnickae Deloya & Ibanez-Bernal, 2000, both from Mexico. PMID- 26249907 TI - Cicadidae types (Hemiptera-Cicadomorpha) housed at the Museo de La Plata entomological collection (Argentina). AB - A catalog of the 161 type specimens of species of Hemiptera Cicadidae housed in the collection of the Entomology Division of the Museo de La Plata is presented. This collection represents 52 species grouped in 19 genera. For each species the original and current names, bibliographic references, type category, number of specimens, gender, Museo de La Plata code numbers, and transcription of data from labels (country, province, locality, date of collection, collector's name, and hosts) are given. Information about the state of preservation of the specimens in each series and photographs of each type species are also provided. PMID- 26249898 TI - The genus Campylomma Reuter, 1878 (Hemiptera: Heteroptera: Miridae:
Phylinae): two new synonyms and discussion of the diagnosis. AB - The diagnostic characters of the phyline plant bug genus Campylomma Reuter, 1878 are discussed based on examination of Western Palearctic species. Nigrocapillocoris Wagner, 1973 is synonymized with Campylomma and Campylomma celatum Wagner, 1969 is synonymized with C. annulicorne (Signoret, 1865). Illustrations of the male genitalia, photographs of the dorsal habitus, micrographs of selected structures are given for discussed species and a redescription of C. ochraceum (Scott, 1872) comb. nov. is provided. PMID- 26249912 TI - Wallacellus is Euwallacea: molecular phylogenetics settles generic relationships (Coleoptera: Curculionidae: Scolytinae: Xyleborini). AB - Euwallacea Hopkins and Wallacellus Hulcr & Cognato are ambrosia beetle genera within the tribe Xyleborini (Coleoptera: Curculionidae: Scolytinae). Several species have recently received attention due to their establishment in non-native regions with serious ecological and economic consequences. To clarify generic placement of these species, we tested reciprocal monophyly of the two genera and the placement of several species using molecular phylogenetics. We sequenced, or re-used published sequences of, three markers (COI mtDNA, 28S nuclear rDNA and ArgK single-copy nuclear) from representatives of Euwallacea, Wallacellus, the Ambrosiodmus clade, and the clade containing Xyleborus s. str., and inferred their relationships with a Bayesian approach. We also tested explicit alternative topologies, and examined taxonomic utility of characters used for the delimitation of the genera. All species of Euwallacea, Wallacellus, and two species of Xyleborus were monophyletic with high phylogenetic support. Based on the analysis and shared morphological characters, we transferred the following species to Euwallacea: Xyleborus declivispinatus (Schedl), Wallacellus piceus (Motschulsky), Xyleborus posticus (Eichhoff), Wallacellus similis (Ferrari), and Wallacellus striatulus (Browne). The genus Wallacellus was made a junior synonym of Euwallacea and morphological diagnosis of Euwallacea was updated. The results demonstrated that Euwallacea has a pantropical distribution. PMID- 26249911 TI - A new species of Hemiphyllodactylus Bleeker, 1860 (Squamata: Gekkonidae) from western Yunnan, China. AB - A new species of the genus Hemiphyllodactylus is described from mountainous area of Changning County, Yunnan Province, China. Hemiphyllodactylus changningensis sp. nov. is distinguished from all other congeners by morphology and a significant genetic divergence of greater than 17% (ND2 gene). The new species from Changning is characterized by the following features: a maximum SVL of 40.1 mm in males and 43.8 mm in females; 11-15 dorsal scale rows; 6-8 ventral scale rows; a forefoot lamellar formula of 3-3/4-3/4-3; a hindfoot lamellar formula of 3-4-4-4 or 3-3-3-3; precloacal and femoral pore series continuous; cloacal spurs present in both sexes; dark dorsal transverse blotches; dark postorbital stripe; a brown postsacral mark bearing anteriorly projecting arms; and unpigmented caecum and gonads. The new species occurs also in Longyang District of Baoshan City, Yunnan Province, China. PMID- 26249908 TI - One century after: a reappraisal of the gnathos (sensu Pierce, 1914)
in Larentiinae (Lepidoptera: Geometridae). AB - One century ago, F.N. Pierce in his well-known monograph on the genitalia of Geometridae (Lepidoptera), divided the family into two major subdivisions, the Gnathoi and the Agnathoi, depending on the presence or absence of the gnathos in males. In his study, Pierce assigned the Larentiinae to the Agnathoi based on the apparent absence of the gnathos in this subfamily. A re-examination of the male genitalic characters of numerous larentiine species representing 14 different tribes provided, contrary to Pierce's results, evidence for the presence of the gnathos in Larentiinae. Illustrations of the gnathos (or its remnants) in male genitalia of selected species are provided and the value of the uncus and gnathos for inferring phylogenetic relationships is discussed. PMID- 26249914 TI - A review of the genus Parorthocladius Thienemann, 1935 (Diptera: Chironomidae: Orthocladiinae) from the Russian Far East. AB - Three new species of the genus Parorthocladius Thienemann, P. lazovskiensis sp. nov., P. plolabius sp. nov., and P. tyurkini sp. nov. from the Russian Far East are described and figured. Descriptions of pupae and larvae of one indeterminate species, Parorthocladius sp. 1, are also presented. Keys to determination of adult males, pupae and fourth instar larvae of Far-Eastern species Parorthocladius are provided. PMID- 26249913 TI - A new species of Domene Fauvel, 1873 (Coleoptera: Staphylinidae: Paederinae) from a granitic cavity in Serra da Estrela (Portugal). AB - A new species of the genus Domene Fauvel, 1873-D. viriatoi n. sp.-is described from a granitic natural cavity in Serra da Estrela, Portugal. This subterranean species is diagnosed and compared with closely related species from the Iberian endemic subgenus Lathromene Koch, 1938. The external morphology and male genitalia are illustrated and information on the species' ecology is presented. A dichotomic key to the Lathromene species based on the male genitalia is provided. The need to protect the habitat of this species from human disturbance is commented on. PMID- 26249918 TI - An example of the importance of labels and fieldbooks in scientific collections: A freshwater sponge misunderstood for a marine new genus and species. AB - The demosponge genus Crelloxea Hechtel, 1983 was created to allocate a single species, Crelloxea spinosa Hechtel, 1983, described based on specimens collected by Jacques Laborel in northeastern Brazil in 1964 and deposited at the Porifera Collection of the Yale Peabody Museum. The genus Crelloxea was originally defined as "Crellidae with dermal and interstitial acanthoxeas and acanthostrongyles, with skeletal oxea and without microscleres or echinators" (Hechtel, 1983). Crelloxea was allocated in the marine sponge family Crellidae (Order Poecilosclerida), which is characterized by a tangential crust of spined ectosomal spicules (oxeas, anisoxeas or styles), a choanosomal plumose skeleton of smooth tornotes, sometimes a basal skeleton of acanthostyles erect on the substrate, microscleres usually arcuate chelae or absent, and surface with areolated pore fields (van Soest, 2002). Nowadays, Crelloxea is considered a junior synonym of Crella (Grayella) Carter, 1869 (van Soest, 2002; van Soest et al., 2015). PMID- 26249915 TI - The first record of a species of Perlidae from Jiangsu Province, China: a new species of Neoperla (Plecoptera: Perlidae). AB - A new species of Neoperla (Plecoptera, Perlidae), N. jiangsuensis Chen & Du from Jiangsu Province, China, is described and illustrated. Neoperla jiangsuensis is characterized by the aedeagal sac with two C-shaped rows of large stout spines laterally, a patch of small spines, and with an apical double ear-shaped membranous lobes. The new species is the first recorded species of Perlidae known from the eastern coastal province of Jiangsu, China. PMID- 26249917 TI - Range extension and sexual dimorphism in Megabatrus caviceps Lobl (Coleoptera, Staphylinidae, Pselaphinae). AB - Megabatrus caviceps Lobl, originally described from Kuatun, Fou-kien (= Guadun, Fujian), eastern China, is recorded from the Nanling Nature Reserve, Guangdong, southern China, ca. 550 km SW from the type locality. The female of this species is discovered and described for the first time. For comparative purposes, male diagnostic characters of M. caviceps are figured and supplementary description is provided. Some new data on this species' biology are given. PMID- 26249919 TI - Revision of Chinese Dilaridae (Insecta: Neuroptera) (Part III): Species of the genus Dilar Rambur from the southern part of mainland China. AB - A revision of species of the genus Dilar Rambur, 1838, from the southern part of mainland China is presented. Twenty species are recorded in this region, with 12 species described as new to science. Dilar spectabilis Zhang, Liu, H. Aspock & U. Aspock, 2014, is recorded in this region for the first time. The other seven valid species previously recorded in this region are re-described. Dilar wangi Yang, 1992, is herein treated as a junior synonym of Dilar montanus Yang, 1992. A key to all species of the genus Dilar so far recorded from China is provided. PMID- 26249922 TI - A review of the biology and literature of the Gulf Coast Toad (Incilius nebulifer), native to Mexico and the United States. AB - The Gulf Coast Toad (Incilius nebulifer) is an abundant and widespread species within its range in the United States and Mexico, so it appears on many faunal checklists and is considered in diverse kinds of research. We review the basic biology, distribution, and published history of this species, identifying only those records and publications referable to I. nebulifer, to help researchers identify published works pertaining to I. nebulfer rather than I. valliceps, with which it formerly was considered to be conspecific. PMID- 26249916 TI - Taxonomy of Fulgoraecia melanoleuca (Fletcher, 1939), (Lepidoptera: Epipyropidae) in India, a biological control agent of Pyrilla perpusilla (Walker) (Hemiptera: Lophopidae). AB - The parasitic lepidopteran insect, Fulgoraecia melanoleuca (Fletcher) has been reported as an ectoparasitoid of Pyrilla perpusilla (Walker) from the Indian subcontinent. For the first time, the complete morphology, field biology, egg laying behavior, larval pupal, and adult morphology, including male and female gentialic features, are described and illustrated. PMID- 26249928 TI - The genus Sciara Meigen (Diptera, Sciaridae) in New Caledonia, with the description of two new species. AB - The genus Sciara Meigen includes two species in New Caledonia, both newly described: Sciara insulana sp. n. and S. turgidula sp. n. The species are diagnosed and figured. PMID- 26249921 TI - Nematodes of amphibians from Java, Indonesia, with a description of
new species, Meteterakis wonosoboensis n. sp. (Nematoda : Heterakoidea). AB - During a survey on the parasites of amphibians of Indonesia, toads (30 Bufo melanostictus) and 246 frogs (213 Fejervarya cancrivora, 11 F. limnocharis, 22 Rana macrodon from West Java and 68 F. cancrivora from Central Java) were examined for parasitic nematodes. Three species of nematodes were found and described, i.e. Meteterakis wonosoboensis n. sp. from Fejervaria cancrivora; Meteterakis japonica from Bufo melanostictus, F. cancrivora and F. limnocharis; and Chabaudus sp. from F. cancrivora, F. limnocharis and Rana macrodon. Meteterakis wonosoboensis n. sp. is distinguished from other species of the genus by the length and shape of spicules, the number of caudal papillae, the presence of gubernaculum in male and the presence of vulval flap in female. Bufo melanostictus and Java are recorded as new host and locality for M. japonica, respectively. PMID- 26249926 TI - On the Eocene age of Limodromus Motschulsky, 1850, with description of
L. hoffeinsorum sp. n. from Baltic Amber (Coleoptera: Carabidae: Platynini). AB - The first platynine ground beetle, Limodromus hoffeinsorum sp. n., is described from Baltic amber at species level. The fossil species is considered the sister taxon of the modern species group of L. assimilis (Paykull, 1790). However, it was adapted to warmer climate conditions. The habitat of the new species is assumed similar to that of the modern L. klausnitzeri Schmidt, 2005, which represents a more basal branch of Limodromus and which occurs in the mountains of northern Vietnam. PMID- 26249920 TI - A new species of Mesochaetopterus (Annelida, Chaetopteridae) from Hong Kong, with comments on the phylogeny of the family. AB - We described a new species, Mesochaetopterus tingkokensis, based on 14 specimens collected from an intertidal area in Hong Kong. This species is large (body length of complete specimens 17.9-24.1 cm), with 9, 2 and 36-41 chaetigers in region A, B and C, respectively. It belongs to a small group of Mesochaetopterus species with an expanded wing-shaped notopodia in chaetiger B2. The new species can be distinguished from other Mesochaetopterus species in this group by having a pair of palps with two longitudinal stripes formed by suture-like discontinuous orange bands, more teeth in the uncini of region B and C neuropodia, and presence of a bundle of simple chaetae in region C notopodia. Comparison with other chaetopterids based on partial cytochrome oxidase I (COI), 18S and 28S rRNA gene sequences confirmed the placement of M. tingkokensis n. sp.within Mesochaetopterus and its distinction from other members of this genus with the available DNA sequences. The phylogenetic tree base on COI showed that Mesochaetopterus and Chaetopterus are paraphyletic, but that based on concatenated data, 18S and 28S showed they are monophyletic with low supporting values. PMID- 26249923 TI - A new species of monadal coral snake of the genus Micrurus (Serpentes, Elapidae) from western Amazon. AB - We described a new species of monadal coral snake of the genus Micrurus from the region of Tabatinga and Leticia, along the boundaries of Brazil, Colombia, and Peru. The new species can be distinguished from the other congeners by the combination of the following characters: absence of a pale nuchal collar; black cephalic-cap extending from rostral to firstdorsal scale and enclosing white tipped prefrontal scales; upper half of first to four supralabials and postoculars black; tricolor body coloration, with 27-31 black rings bordered by narrower white rings and 27-31 red rings; tail coloration similar to body, with alternating black rings bordered by irregular narrow white rings, red rings of the same width as the black rings; ventral scales 205-225; subcaudal scales 39 47. PMID- 26249929 TI - A new species of the shore-fly genus Notiphila Fallen, 1810 (Diptera: Ephydridae) from Indonesia. AB - A new shore-fly species, Notiphila oksanae sp.n. from Indonesia is described. The new species is similar to the Oriental species Notiphila thaica Krivosheina, 2010 in having many brown stripes on the thorax and in presurstyli broad in lateral view, but differs in 2 facial setae of subequal length, the absence of brown band on anepisternum and the presence of dark band on hind tibia. A key to the presently known Australasian/Oceanian species of the genus Notiphila Fallen, 1810 is given. PMID- 26249925 TI - Potter wasps of the genus Eumenes Latreille, 1802 (Hymenoptera: Vespidae: Eumeninae) from Vietnam, with description of a new species and key to species. AB - Seven species of the genus Eumenes Latreille, 1802 are recorded from Vietnam. A new species, E. gibbosus Nguyen, sp. nov. is described and figured. Eumenes atrophicus (Fabricius, 1798), E. inconspicuus Smith, 1858, E. labiatus sinicus Giordani Soika, 1941, and E. rubronotatus Perez, 1905 are newly recorded from Vietnam. A key to species is given. PMID- 26249927 TI - Description of a new species of Sinocaulus Fairmaire from China (Coleoptera: Dascillidae). AB - A new species of the genus Sinocaulus Fairmaire, 1878, S. truncatus sp. nov., is described from Guizhou, China. Based on the strongly protuberant eyes, the new species is similar to S. omiensis Jin, Slipinski & Pang, 2013 from Sichuan, but differs from that species in the truncate phallobase of the aedeagus and ventral lobes slightly shorter than dorsal lobe. Distributional data and a key to all four species of Sinocaulus are provided. PMID- 26249931 TI - Cytotaxonomy of the Simuliidae (Diptera): a systematic and bibliographic conspectus. AB - An annotated compilation of all chromosomal works (cytoconspectus) on the Simuliidae is presented, covering 577 species including 541 formally named species-24.8% of the world's extant nominal species-and 36 formally unnamed species. The first published record of polytene chromosomes in a simuliid appeared in 1919, followed by an imposing body of chromosomal research, most notably since 1956. The bibliography assembled here includes 653 works containing novel chromosomal information on the Simuliidae. Cytotaxonomy of the Simuliidae began in 1951 in the Canadian laboratory of Klaus Rothfels and subsequently expanded worldwide. Although chromosomal study has been uneven across species, it has provided a rich database of the genetics of natural populations and much of the foundation for the modern taxonomy and systematics of the family. After peaking in the late 1980s, cytotaxonomic productivity became more sporadic as the molecular movement gained popularity, despite the potential that an integrated chromosomal and molecular approach holds. PMID- 26249924 TI - A new species of Simulium (Gomphostilbia) (Diptera: Simuliidae) from South India, with keys to Indian members of the subgenus Gomphostilbia. AB - A new black fly species, Simulium (Gomphostilbia) cauveryense sp. n., is described based on adult female, adult male, pupal and larval specimens collected from Kushalanagar, Karnataka, South India. This new species is placed in the decuplum subgroup of the batoense species-group within the subgenus Gomphostilbia. Keys to the species of the subgenus Gomphostilbia reported from India are provided for females, males, pupae and mature larvae. PMID- 26249933 TI - Types of true bugs (Insecta, Hemiptera, Heteroptera) deposited in the Museo de La Plata, Argentina. AB - A checklist of Heteroptera type specimens deposited in the collection of Division Entomologia, Museo de La Plata. It harbours type material of 1153 species belonging to 37 families (Enicocephalidae, Schizopteridae, Gerridae, Veliidae, Hydrometridae, Naucoridae, Belostomatidae, Nepidae, Corixidae, Notonectidae, Pleidae, Saldidae, Cimicidae, Polyctenidae, Nabidae, Miridae, Tingidae, Vianaididae, Thaumastocoridae, Reduviidae, Aradidae, Alydidae, Coreidae, Rhopalidae, Berytidae, Blissidae, Lygaeidae, Oxycarenidae, Rhyparochromidae, Idiostolidae, Largidae, Pyrrhocoridae, Anthocoridae, Cydnidae, Pentatomidae, Scutelleridae, Thyreocoridae), represented by 207 holotypes, 26 allotypes, 578 paratypes, 1 lectotype, 1 paralectotype and 340 syntypes. For each taxon providing update information on valid names, categories of types, and locality. PMID- 26249930 TI - Neosataria, replacement name for Sataria Annandale, 1920 (Mollusca: Gastropoda: Bithyniidae), preoccupied by Sataria Roewer, 1915 (Arachnida: Opiliones: Sclerosomatidae). AB - The family Bithyniidae is represented in tropical Asia by the following genera, Bithynia, Digonistoma, Mysorella, Parabithynia, Emmericiopsis, Hydrobioides, Parafossarulus, Pseudovivipara, Sataria and Wattebladia (Dudgeon 1999; Pyron & Brown 2015). PMID- 26249936 TI - The Lasioseius phytoseioides species group (Acari: Blattisociidae): new characterisation, description of a new species, complementary notes on seven described species and a taxonomic key for the group. AB - The Lasioseius phytoseioides species group was first characterised over 50 years ago. Two species of this group, Lasioseius chaudhrii (Wu & Wang) and Lasioseius parberlesei Bhattacharyya, have been considered potentially effective as biological control agents of pest mites of the family Tarsonemidae on rice (Oryza sativa L.) in Asia. A new characterisation of the species group is presented, taking into account a new species here described, Lasioseius piracicabensis Moraes & Perez-Madruga n. sp., as well as other species mostly described since the first characterisation of the group. The main characteristics of the included species are the reduced number of dorsal idiosomal setae, including the absence of j1 and z1; antiaxial surface of fixed cheliceral digit with a subterminal pointed process; and males with broad lateral expansion of the peritrematic shield in the region between coxae II-III, bearing a pore and a lyrifissure. Complementary notes are presented for Lasioseius annandalei Bhattacharyya & Bhattacharyya, Lasioseius chaudhrii (Wu & Wang), Lasioseius parberlesei Bhattacharyya, L. phytoseioides Chant, Lasioseius punjabensis Bhattacharyya & Sanyal, Lasioseius terrestris Menon & Ghai and Lasioseius youcefi Athias-Henriot. New synonymies are proposed and possible misidentifications in the literature are discussed. A dichotomous key is presented to help the identification of the species of the group, and the distribution of the species is summarised. PMID- 26249935 TI - Taxonomic review of the genus Hypomicrogaster Ashmead (Hymenoptera: Braconidae: Microgastrinae), with descriptions of 40 new species. AB - A taxonomic review of the genus Hypomicrogaster Ashmead is presented with the redescription and redelimitation of the already named species Hypomicrogaster ecus Nixon, H. imitator (Ashmead), H. tydeus Nixon and H. zonaria (Say). The review also implies eleven new synonymies, and a new combination for the species H. areolaris (Blanchard). Also, the present revision identified 40 new Hypomicrogaster species: Hypomicrogaster aodous n. sp., H. aplebis n. sp., H. cernus n. sp., H. crocinus n. sp., H. daktulios n. sp., H. deltis n. sp., H. duo n. sp., H. epipagis n. sp., H. espera n. sp., H. evrys n. sp., H. guille n. sp., H. hektos n. sp., H. hupsos n. sp., H. ingensis n. sp., H. insolitus n. sp., H. inversalis n. sp., H. koinos n. sp., H. largus n. sp., H. laxus n. sp., H. linearis n. sp., H. lineatus n. sp., H. luisi n. sp., H. masoni n. sp., H. mesos n. sp., H. mikrosus n. sp., H. multus n. sp., H. pectinatus n. sp., H. plagios n. sp., H. pollex n. sp., H. rugosus n. sp., H. scindus n. sp., H. sicingens n. sp., H. sicpollex n. sp., H. sicscindus n. sp., H. siderion n. sp., H. spatulae n. sp., H. specialis n. sp., H. tantillus n. sp., H. tetra n. sp., H. zan n. sp. The Hypomicrogaster species are using as hosts 11 families of Lepidoptera, and 52 confirmed lepidopteran species feeding on 34 families of plants. Additionally, a fully illustrated key to all known described species of Hypomicrogaster is presented. PMID- 26249939 TI - Two new species of the genus Goniurosaurus (Squamata: Sauria: Eublepharidae) from southern China. AB - Two new species of large geckos in the genus Goniurosaurus are described based on specimens collected from karst areas of Guangxi Zhuang Autonomous Region, southern China: Goniurosaurus kadoorieorum sp. nov. and Goniurosaurus kwangsiensis sp. nov. Data on natural history of the new species are provided, as well as discussions on the current conservation status of Goniurosaurus species in southern China. Due to the popularity of this genus as novelty pets, and recurring cases of scientific descriptions driving herpetofauna to near extinction by commercial collectors, we do not disclose the collecting localities of these restricted-range species in this publication. However, such information has been presented to relevant government agencies, and is available upon request by fellow scientists. PMID- 26249932 TI - Systematic review of diplommatinid land snails (Caenogastropoda, Diplommatinidae) endemic to the Palau Islands. (2) Taxonomic revision of Hungerfordia species with low axial ribs. AB - Hungerfordia Beddome, 1889 is a terrestrial caenogastropod genus of the family Diplommatinidae endemic to the Palau (Belau) islands. Hungerfordia is radiated within the Palau islands and exhibits substantial morphological diversity. In this paper, the taxonomy of Hungerfordia species with low axial ribs is revised. Hungerfordia polymorpha (Crosse, 1866), H. inflatula (Crosse, 1866), H. crassilabris crassilabris (Beddome, 1889), H. lutea lutea (Beddome, 1889), H. ringens ringens (Crosse, 1866), H. pyramis pyramis (Crosse, 1866), and H. aurea (Beddome, 1889) are redescribed based on the syntypes and newly collected materials. The following new taxa are described: H. aspera sp. nov., H. basodonta sp. nov., H. microbasodonta sp. nov., H. rudicostata sp. nov., H. unisulcata sp. nov., H. longissima sp. nov., H. eurystoma sp. nov., H. crenata sp. nov., H. crassilabris tridentata subsp. nov., H. crassilabris attenuata subsp. nov., H. lutea hemilaevis subsp. nov., H. loxodonta sp. nov., H. omphaloptyx sp. nov., H. robiginosa sp. nov., H. angaurensis sp. nov., H. ringens rotundata subsp. nov., H. ringens ventrinodus subsp. nov., H. pyramis pteroma subsp. nov., H. spinoscapula sp. nov. PMID- 26249934 TI - Nomenclatural Studies Toward a World List of Diptera Genus-Group Names. Part IV: Charles Henry Tyler Townsend. AB - The Diptera genus-group names of Charles Henry Tyler Townsend are reviewed and annotated. A total of 1506 available genus-group names in 12 families of Diptera are listed alphabetically for each name, giving author, year and page of original publication, originally included species, type species and method of fixation, current status of the name, family placement, and a list of any emendations of it that have been found in the literature. Remarks are given to clarify nomenclatural and/or taxonomic information. In addition, an index to all the species-group names of Diptera proposed by Townsend (1595, of which 1574 are available names) is given with bibliographic reference (year and page) to each original citation. An appendix with a full bibliography of almost 650 papers written by Townsend is presented with accurate dates of publication. Two new replacement names are proposed for preoccupied genus-group names and both are named to honor our good friend and colleague, James E. O'Hara, for his decades of work on tachinids: Oharamyia Evenhuis, Pont & Whitmore, n. name, for Lindigia Townsend, 1931 [Tachinidae] (preoccupied by Karsten, 1858); Jimimyia Evenhuis, Pont & Whitmore, n. name, for Siphonopsis Townsend, 1916 [Tachinidae] (preoccupied by Agassiz, 1846). Earlier dates of availability are found for the following: Eucnephalia Townsend, 1892 [Tachinidae]; Gabanimyia Townsend, 1914 [Tachinidae]; Incamyia Townsend, 1912 [Tachinidae]; Muscopteryx Townsend, 1892 [Tachinidae]; Philippolophosia Townsend, 1927 [Tachinidae]; Pseudokea Townsend, 1927 [Tachinidae]. Corrected or clarified included species and/or corrected or clarified type-species and methods of typification are given for: Alitophasia Townsend, 1934 [Tachinidae]; Almugmyia Townsend, 1911 [Tachinidae]; Arachnidomyia Townsend, 1934 [Sarcophagidae]; Austenina Townsend, 1921 [Glossinidae]; Austrohartigia Townsend, 1937 [Sarcophagidae]; Awatia Townsend, 1921 [Muscidae]; Azygobothria Townsend, 1911 [Tachinidae]; Brachymasicera Townsend, 1911 [Tachinidae]; Calocarcelia Townsend, 1927 [Tachinidae]; Cnephalodes Townsend, 1911 [Tachinidae]; Cyacyrtoneura Townsend, 1931 [Muscidae]; Cyrtoneuropsis Townsend, 1931 [Muscidae]; Cyrtosoma Brauer & Bergenstamm, 1893 [Tachinidae]; Epiphyllophila Townsend, 1927 [Tachinidae]; Eucalodexia Townsend, 1892 [Tachinidae]; Eumesembrina Townsend, 1908 [Muscidae]; Eumyobia Townsend, 1911 [Tachinidae]; Eusisyropa Townsend, 1908 [Tachinidae]; Gabanimyia Townsend, 1914 [Tachinidae]; Galactomyia Townsend, 1908 [Tachinidae]; Girschneria Townsend, 1919 [Tachinidae]; Gymnochaetopsis Townsend, 1914 [Tachinidae]; Himantostomopsis Townsend, 1921 [Tachinidae]; Incamyia Townsend, 1912 [Tachinidae]; Lithoexorista Townsend, 1921 [Tachinidae]; Muscopteryx Townsend, 1892 [Tachinidae]; Myocuphocera Townsend, 1931 [Tachinidae]; Myxexoristops Townsend, 1911 [Tachinidae]; Neojurinia Townsend, 1914 [Tachinidae]; Newsteadina Townsend, 1921 [Glossinidae]; Ommasicera Townsend, 1911 [Tachinidae]; Ophirion Townsend, 1911 [Tachinidae]; Ophiriodexia Townsend, 1911 [Tachinidae]; Ophiriosturmia Townsend, 1911 [Tachinidae]; Opsozelia Townsend, 1919 [Tachinidae]; Paleotachina Townsend, 1921 [Tachinidae]; Palexorista Townsend, 1921 [Tachinidae]; Phasiatacta Townsend, 1911 [Tachinidae]; Philippolophosia Townsend, 1927 [Tachinidae]; Phrissopolia Townsend, 1908 [Tachinidae]; Pseudokea Townsend, 1927 [Tachinidae]; Pygocalcager Townsend, 1935 [Tachinidae]; Trichobius Townsend, 1891 [Hippoboscidae]; Villeneuvia Townsend, 1921 [Tachinidae]; Zonoepalpus Townsend, 1927 [Tachinidae]; Zygosturmia Townsend, 1911 [Tachinidae]. The following names previously treated as available are shown to be unavailable.-Genera: Denatella Townsend, 1931, n. stat. [Calliphoridae]; Epseudocyptera Townsend, 1927, n. stat. [Tachinidae]; Eustomatodexia Townsend, 1892, n. stat. [Tachinidae].-Species: Epseudocyptera epalpata Townsend, 1927, n. stat. [Tachinidae]; Eustomatodexia insulensis Townsend, 1892, n. stat. [Tachinidae]. The following genus-group names, not listed in previous regional catalogs, are treated here: Arabisca Townsend, 1935 [Sarcophagidae]; Eupeleteria Townsend, 1908 [Tachinidae]; Macropatelloa Townsend, 1931 [Tachinidae]; Neohypostena Townsend, 1915 [Tachinidae]; Neometapodia Townsend, 1892 [Sarcophagidae]; Tricyclopsis Townsend, 1916 [Calliphoridae]; Trongia Townsend, 1916 [Calliphoridae]. Previous First Reviser actions for multiple original spellings that were overlooked by other workers are given for the following: Genus-group names-Microchaetona Townsend, 1919 [Tachinidae]; Neopodomyia Townsend, 1927 [Tachinidae]; Opsophytopsis Townsend, 1918 [Sarcophagidae]; Prohypotachina Townsend, 1933 [Tachinidae]; Rhinomyodes Townsend, 1933 [Tachinidae]; Servilliodes Townsend, 1926 [Tachinidae]; Tephromyiella Townsend, 1918 [Sarcophagidae]; Thelairochaetona Townsend, 1919 [Tachinidae]; Xanthopteromyia Townsend, 1926 [Tachinidae]. Species-group names Brachybelvosia brasiliensis Townsend, 1927 [Tachinidae]; Neocraspedothrix nova Townsend, 1927 [Tachinidae]. The following nominal genera enter into new synonymies: Bathytheresia Townsend, 1915 under Billaea Robineau-Desvoidy, 1830, n. syn. [Tachinidae]; Brachycoma Brauer & Bergenstamm, 1889 under Brachicoma Rondani, 1856, n. syn. [Sarcophagidae]; Chaetolyga Brauer, 1880 under Carcelia Robineau-Desvoidy, 1830, n. syn. [Tachinidae]; Chaetoprosopa Marschall, 1873 under Choeteprosopa Macquart, 1851, n. syn. [Tachinidae]; Chlororhynchomyia Senior-White, Aubertin & Smart, 1940 under Metallea Wulp, 1880, n. syn. [Rhiniidae]; Chrysomyia Macquart, 1835 under Chrysomya Robineau-Desvoidy, 1830, n. syn. [Calliphoridae]; Echinomyia Fischer von Waldheim, 1808 under Echinomya Latreille, 1805, n. syn. [Tachinidae]; Euhypochaetopsis Townsend, 1928 under Campylocheta Rondani, 1859, n. syn. [Tachinidae]; Graphomyia Macquart, 1834 under Graphomya Robineau-Desvoidy, 1830, n. syn. [Muscidae]; Kurintjimyia Townsend, 1926 under Tachina Meigen, 1803, n. syn. [Tachinidae]; Labidigaster Macquart, 1844 under Labigastera Macquart, 1834, n. syn. [Tachinidae]; Mellanactia Guimaraes, 1971 under Oxynops Townsend, 1912, n. syn. [Tachinidae]; Ochromia Townsend, 1935 under Bengalia Robineau-Desvoidy, 1830, n. syn. [Tachinidae]; Pachyrrhina Osten Sacken, 1881 under Nephrotoma Meigen, 1803, n. syn. [Tipulidae]; Procraspedothrix Townsend, 1932 under Phytomyptera Rondani, 1844, n. syn. [Tachinidae]; Pseudogymnosoma Townsend, 1918 under Neomyia Walker, 1859, n. syn. [Muscidae]; Pseudoservillia Townsend, 1916 under Tachina Meigen, 1803, n. syn. [Tachinidae]; Rhymosia Mik, 1886 under Rymosia Winnertz, 1863, n. syn. [Mycetophilidae]; Rhynchomyia Macquart, 1835 under Rhyncomya Robineau-Desvoidy, 1830, n. syn. [Rhiniidae]; Servillioides Townsend, 1926 under Tachina Meigen, 1803, n. syn. [Tachinidae]; Servilliopsis Townsend, 1916 under Tachina Meigen, 1803, n. syn. [Tachinidae]; Stephanostoma Cole, 1923 under Bercaea Robineau Desvoidy, 1863, n. syn. [Sarcophagidae]; Stomatorhinia Townsend, 1935 under Stomorhina Rondani, 1861, n. syn. [Rhiniidae]; Toxorrhina Osten Sacken, 1869 under Toxorhina Loew, 1850, n. syn. [Limoniidae]; Trichoneura Townsend, 1935 under Stevenia Robineau-Desvoidy, 1830, n. syn. [Rhinophoridae]; Trichopticus Schnabl, 1889 under Thricops Rondani, 1856, n. syn. [Muscidae]; Tricyclopsis Townsend, 1916 under Paracalliphora Townsend, 1916, n. syn. [Calliphoridae]. PMID- 26249937 TI - Key to the Ophiodes (Squamata: Sauria: Diploglossidae) of Paraguay with the description of a new species. AB - Ophiodes is a South American genus of legless diploglossid lizards. Four species have been formally described: O. intermedius, O. vertebralis, O. striatus, and O. fragilis; three additional species were described but not officially named in an unpublished dissertation. These species are referred to as Ophiodes sp. "1", Ophiodes sp. "2", and Ophiodes sp. "3". We recognize five species of Ophiodes in Paraguay, one widespread (O. intermedius) and four known from only one or two localities (O. fragilis, O. striatus, O. sp. "3", and an undescribed species, described herein). The new species described represents the fifth Paraguayan species and the eighth member of the genus. It is distinguished by a combination of the following characters: a high number of middorsal scales between occipital and cloacal opening (>165), 29 scale rows around midbody, the posterior limbs 4 scales long, and vertical black bars on the face absent. PMID- 26249942 TI - A contribution to the systematics of Australasian Tanytarsini (Diptera: Chironomidae): first descriptions from New Caledonia. AB - First specific records of chironomids of the tribe Tanytarsini from New Caledonia based on detailed descriptions of new species are presented. Cladotanytarsus (Cladotanytarsus) stylifer sp. nov. and its closest relatives, i.a. Cladotanytarsus (C.) isigacedeus (Sasa et Suzuki, 2000), comb. nov., known from males bearing extraordinarily elongate hypopygial anal points are diagnosed. Paratanytarsus mirificus sp. nov. is described as adult male with unique structure of its hypopygium and shortened antennae. Diagnostic description of Tanytarsus fuscithorax Skuse, 1889 is also complemented. PMID- 26249938 TI - A new goatfish of the genus Upeneus (Mullidae) from Lombok, Indonesia and first verified record of U. asymmetricus for the Indian Ocean. AB - Upeneus lombok n. sp. is described from two specimens collected off Lombok, Indonesia, at depths of 54-76 m, and one subadult specimen from the local fish market at Tanjung Luar, Lombok. Four specimens of U. asymmetricus were collected at the same fish market representing the first record of the species since its description from two Philippine Islands in 1954. These two species are compared in detail and with five congeneric species that all share a 7-spined dorsal fin and a high gill-raker count. Upeneus lombok n. sp. differs from all other congeners in having a short snout (snout length 9.0-9.6% SL) combined with a low anal fin (anal-fin height 12-13% SL in adults, 15% in single subadult). The newly recorded U. asymmetricus specimens differ from their types only slightly and all eight specimens together differ from all congeneric species in the combination of 7 dorsal spines, 12-14 pectoral fin rays, 26-28 total gill rakers, short pectoral fins (pectoral-fin length 18-21% SL) and short jaws (upper jaw length 8.7-11% SL). In both species the caudal-fin colour patterns of fresh fish are of diagnostic significance, the only exception being a close similarity between Upeneus lombok n.sp., U. saiab, and U. seychellensis. Additional comparisons with 14 Upeneus species which overlap in distribution or occur in nearby areas are also made. Needs for further taxonomic exploration of the Indonesian-Philippine region and for enhanced attention to the economic and ecological importance of Upeneus species are discussed. PMID- 26249945 TI - First record of Stephanidae (Hymenoptera, Stephanoidea) for the fauna of Egypt. AB - The family Stephanidae (Hymenoptera, Stephanoidea) is recorded for the first time for the Egyptian fauna, with one species, Foenatopus bisignatus Aguiar & Jennings, 2010. A single specimen was collected among Acacia raddiana trees infested with Agrilus roscidus Kiesenwetter (Coleoptera, Buprestidae), which represents a likely new host record. PMID- 26249946 TI - Taxonomy of European Damaeidae VIII. Contribution to classification of genus Damaeus C. L. Koch, 1835, with a review of Adamaeus Norton, 1978 and Paradamaeus Bulanova-Zachvatkina, 1957 and redescription of three species. AB - Adamaeus Norton, 1978 and Paradamaeus Bulanova-Zachvatkina, 1957, two subgenera of genus Damaeus C. L. Koch, 1835, are reviewed on the basis of the redescription of their type species. Subgenus Eudamaeus Perez-Inigo, 1987 and genus Tectodamaeus Aoki, 1984 are reviewed and their relation to Damaeus is discussed. Damaeus firmus Kunst, 1957 is redescribed and placed into the nominate subgenus. Damaeus helveticus (Schweizer, 1956) n.comb. is redescribed and placed into the nominate subgenus, its synonymy with Damaeus (Adamaeus) onustus C.L.Koch, 1844 is rejected. Damaeus alpinus (Schweizer, 1956) n.comb. is redescribed and placed into the nominate subgenus. Lectotypes and paralectotypes of Damaeus firmus Kunst, 1957; Damaeus helveticus (Schweizer, 1956) and Damaeus alpinus (Schweizer, 1956) are indicated. Based on published reviews and redescriptions, new diagnoses for Tectodamaeus Aoki, 1984, Damaeus C. L. Koch, 1835 and its subgenera are proposed, and a list of all known European species of Damaeus C. L. Koch, 1835 is provided. Tectodamaeus longus Xie & Yang, 2009 is newly combined to Damaeus as D. longus (Xie & Yang, 2009) n.comb. PMID- 26249941 TI - The systematics and independent evolution of cave ecomorphology in distantly related clades of Bent-toed Geckos (Genus Cyrtodactylus Gray, 1827) from the Mekong Delta and islands in the Gulf of Thailand. AB - An integrative taxonomic analysis of the distantly related Cyrtodactylus condorensis and intermedius species complexes of the Mekong Delta revealed that C. paradoxus is a junior synonym of C. condorensis and that C. thochuensis is a junior synonym of C. leegrismeri. Additionally, the analysis revealed that a cave dwelling ecomorpholgy has evolved independently early on in the evolution of both complexes (represented by C. hontreensis in the intermedius complex and C. grismeri and C. eisenmani in the condorensis complex) and cave ecomorphs exist in sympatry-but not syntopy-with general scansorial ecomorphs. Multiple, recent, cyclical, glacioeustatic driven changes in sea levels across the Sunda Shelf are hypothesized to account for the evolution and distribution of the widely separated, conspecific insular populations of C. condorensis and C. leegrismeri. The independent evolution of cave ecomorphology is proposed to have been driven by competition avoidance. Habitat islands across the Mekong Delta are an important source of endemism and in need of protection. PMID- 26249944 TI - A new apterous genus of Carventinae (Hemiptera: Aradidae) from China. AB - A new apterous aradid, Paramorphocoris henanensis Bai & Heiss Cai, gen. et sp. nov., from China is described and illustrated, including the diagnostic morphological features of the new taxon. PMID- 26249940 TI - Fourteen new species, one new genus, and eleven new country or state records for New World Lamiinae (Coleoptera, Cerambycidae). AB - Fourteen new species and one new genus are described from the New World in Lamiinae (Coleoptera: Cerambycidae): Bisaltes (Bisaltes) lingafelteri sp. nov., Trestonia skelleyi sp. nov. and Psapharochrus langeri sp. nov. from Bolivia; Eupogonius azteca sp. nov., Aegomorphus mexicanus sp. nov., Lamacoscylus albatus sp. nov., Lamacoscylus obscurus sp. nov. and Piruanycha wappesi sp. nov. from Mexico; Dolichestola egeri sp. nov. and Wappesellus cavus gen. nov., sp. nov. from Brazil (Rondonia); Scleronotus virgatus sp. nov. from Venezuela; Oreodera casariae sp. nov. from Panama; Alampyris bicolor sp. nov. from Costa Rica; and Emphytoeciosoma flava sp. nov. from Peru. Additionally, eleven new country/state records are established in Lamiinae: three for Peru; three for Bolivia; one for Mexico; one for Uruguay; and two for Brazil (Rondonia) (state records). Bisaltes (Bisaltes) lingafelteri, Eupogonius azteca, Aegomorphus mexicanus, Lamacoscylus albatus, Lamacoscylus obscurus, Piruanycha wappesi, Scleronotus virgatus, Alampyris bicolor, Emphytoeciosoma flava and Wappesellus are included in new or known keys. PMID- 26249943 TI - Rhopalomma stefaniae gen. et sp. n., the first ommatid beetle from the Upper Jurassic in Australia (Coleoptera: Archostemata: Ommatidae). AB - The first Upper Jurassic fossil of the family Ommatidae (Coleoptera: Archostemata) from Australia is described and illustrated from a single specimen discovered at the Talbragar Fish Bed. Rhopalomma stefaniae gen. et sp. n. is classified in Ommatidae based on the length and insertion of the antennae, the tuberculate cuticle, the pattern of elytral striae, the complete epipleura and the presence of scutellary strioles. Due to the lack of preservation of crucial characters, Rhopalomma cannot be assigned to a subfamily and is therefore classified as Ommatidae incertae sedis. Rhopalomma fills an important gap in the fossil record of the family, indicating that Ommatidae occurred in Australia from the Lower Jurassic to the present day. Australia is the only place in the world where this family is found in both the fossil record and the living fauna. PMID- 26249947 TI - A new epigean harvestman of the genus Guerrobunus (Laniatores: Phalangodidae), from Hidalgo, Mexico, with taxonomic notes about the genus. AB - The fifth species of the genus Guerrobunus, Guerrobunus barralesi sp. nov. is described from specimens collected in Hidalgo, Mexico. This species represents the first eastern record from the country and unlike other species of the genus, is completely epigean. Guerrobunus barralesi sp. nov. is compared with the most similar species, Guerrobunus minutus, which also has well developed and pigmented eyes. Finally, external morphology, including male genitalia, taxonomy of the genus, and familial assignment into the family Phalangodidae are discussed. PMID- 26249949 TI - Phylogeny of the genus Willemia (Collembola: Hypogastruridae) and biogeography of the W. buddenbrocki-group with description of a new species from Ivory Coast (western Africa). AB - Willemia tondoh sp. nov. from the Ivory Coast (western Africa) is described and illustrated. The new species is the 14th in the buddenbrocki-group and is defined with two large globular sensilla placed in a cavity and covered in part by tegumental fold on antennal segment IV, 7 chaetae on antennal segment I, postantennal organ with 9 vesicles, s-chaetae subcylindrical and acuminate on abdominal terga and chaetae a1 absent on abdominal sternum IV. A phylogeny for all the 46 species of the genus Willemia is proposed. Based on the phylogentic framework, the biogeography of the buddenbrocki-group is discussed. An identification key for all 46 known species of the genus is provided. PMID- 26249948 TI - A taxonomic revision of the Neotropical spider genus Xiruana Brescovit 1997 (Araneae: Anyphaenidae, Anyphaeninae). AB - The genus Xiruana Brescovit, 1997 is currently composed of four South American species: X. gracilipes (Keyserling) from Brazil, Bolivia and Argentina, X. affinis (Mello-Leitao) from Brazil, X. hirsuta (Mello-Leitao) from Venezuela, Brazil, Paraguay, Argentina and Uruguay, and X. tetraseta (Mello-Leitao) from Venezuela, Brazil and Paraguay. Of these, the last three are redescribed in this paper, including the first description of the females of X. hirsuta and X. tetraseta. Additionally, we describe thirteen new species: Xiruana pocone n. sp. from Brazil, Paraguay and Argentina; X. bifida n. sp. from Brazil and Paraguay; X. aymara n. sp. from Bolivia; X. cocha n. sp. from Peru; X. fiebrigi n. sp. from Paraguay, and X. ajuricaba n. sp., X. tribarrense n. sp., X. guaia n. sp., X. jaboticabal n. sp., X. minacu n. sp., X. tapirape n. sp., X. lusitania n. sp., X. silarae n. sp., all endemic to Brazil. The known geographical distribution of all species here presented is mapped. PMID- 26249950 TI - Description of a new genus, Auritibicen gen. nov., of Cryptotympanini Hemiptera: Cicadidae) with redescriptions of Auritibicen pekinensis (Haupt, 1924) comb. nov. and Auritibicen slocumi (Chen, 1943) comb. nov. from China and a key to the species of Auritibicen. AB - A new genus, Auritibicen gen. nov., is erected for the former members of Lyristes Horvath, 1926 (= Tibicen Latreille, 1825) from eastern Asia, designating Tibicen intermedia Mori, 1931 as the type species. Morphological comparisons are made among Auritibicen, Lyristes, and the American Tibicen species. Auritibicen pekinensis (Haupt, 1924) comb. nov. and Auritibicen slocumi (Chen, 1943) comb. nov. from China are redescribed. Morphological comparisons are made among closely related species, A. pekinensis, A. slocumi, Auritibicen intermedius (Mori, 1931) comb. nov., and Auritibicen kyushyuensis (Kato, 1926) comb. nov. A key to the species of the genus Auritibicen gen. nov. is provided. PMID- 26249951 TI - First record of a living species of the genus Janulum (Class Demospongiae) in the Southern Hemisphere. AB - A new species of the enigmatic sponge genus Janulum de Laubenfels, 1936 was discovered recently on the Louisville Seamount Chain, in International Waters to the east of New Zealand; two small specimens were found encrusting the interstices of the stony coral Solenosmilia variabilis Duncan at a depth of 1200 1600 m. Janulum imago sp. nov., is described and compared with the genus type J. spinispiculum (Carter, 1876) from the North Atlantic. Janulum was also recorded from the Late Eocene Oamaru Diatomite of southern New Zealand in 1892, but was misidentified as genus Plocamia Schmidt (Order Poecilosclerida Topsent, Family Microcionidae Carter). Fossil species Janulum princeps sp. nov. is also described herein and represents the first record of this North Atlantic-Arctic Ocean genus in the Southern Hemisphere. The validity of J. filholi (Topsent, 1890), the second and only other North Atlantic species currently assigned to Janulum, is considered in the context of J. spinispiculum and the new species J. imago sp. nov. PMID- 26249952 TI - Thumb-pads up-a new species of thick-thumbed bat from Sumatra (Chiroptera: Vespertilionidae: Glischropus). AB - To date, three species of the genus Glischropus are recognized from the Indomalayan zoogeographic region-G. bucephalus from the Indochinese subregion, G. tylopus from the Sundaic subregion (Peninsular Thailand and Malaysia, Borneo, Sumatra, Moluccas) and G. javanus, restricted to Java. The investigation of the holotype and three topotype specimens of G. batjanus supported the view that the name was previously correctly regarded as the junior subjective synonym of G. tylopus. During review of material recently collected in southwestern Sumatra, Indonesia, one specimen of a yet undescribed species of Thick-thumbed bat was identified. G. aquilus n. sp. markedly differs from its congeners by its dark brown pelage, nearly black ear and tragus, and in skull proportions. The phylogenetic analysis based on cytb sequences also supports the specific distinctness of G. aquilus n. sp. Its discovery brings the count to 88 species of bats known from Sumatra. PMID- 26249953 TI - The description of a new species Polymastigos javaensis n.sp. (Annelida: Capitellidae) from the Segara Anakan mangroves, Central Java, Indonesia. AB - A new species, Polymastigos javaensis n. sp., is described from sandy clay sediment (0-30 cm depth) of the Segara Anakan mangroves. The species is described based on the distribution of capillaries and hooks, and the form of the prostomium, thorax, abdomen, lateral organs, genital pores, branchiae and pygidium. Methyl green staining pattern was applied to examine the similarity between the material of this study and Green's material. Polymastigos javaensis n. sp. is the second species belonging to the genus Polymastigos, after P. reishi Green, 2002. It differs from P. reishi in the form of abdominal segments and hooks, and the methyl green staining pattern. A key to distinguish the two species is provided in this paper. PMID- 26249954 TI - A new species of the cardinalfish genus Jaydia (Teleostei: Apogonidae) from the Philippines. AB - Jaydia erythrophthalma n. sp. is described from specimens collected during two recent biodiversity surveys along the east and west coasts of Luzon, Philippines. It is characterized by a first dorsal fin with eight spines, serrated posterior and crenulated ventral preopercular edges, reddish orange iris and two series of brown spots tinged in orange on the upper part of the body. PMID- 26249955 TI - Note on Kurzia (Kurzia) latissima (Kurz, 1875) (Branchiopoda: Anomopoda: Chydoridae) from India. AB - Members of the chydorid genus Kurzia Dybowski & Grochowski, 1894 (Branchiopoda: Anomopoda) are typically known from the Holarctic and the Neotropics (Rajapaska & Fernando 1986; Hudec 2000; Elmoor-Loureiro 2002; Kotov, 2004). One representative of the sub genus Kurzia, Kurzia (Kurzia) latissima (Kurz 1875) has been reported from India, in the Oriental Zone. These reports either have unreliable or no illustrations (Rane, 1983; Michael & Sharma 1988; Padhye & Dumont 2015). Recently, Chatterjee et al. (2013) have stated that records of K. latissima from India appear morphologically similar to K. latissima s.str. but have not elaborated on it. The aim of this correspondence is to present an initial diagnosis and provide illustrations of a Kurzia latissima-like population from the Northern Western Ghats, Maharashtra Province, India, along with comments on its distribution. PMID- 26249956 TI - Nomenclatural corrections to Australian species of Cricotopus (Wulp) (Diptera; Chironomidae). AB - Our attention has been drawn to lapsi and errors in a recent publication in this journal concerning Cricotopus Wulp (Diptera: Chironomidae) (Drayson et al., 2015). PMID- 26249957 TI - The Elachista dispunctella (Duponchel) complex (Lepidoptera, Elachistidae) revisited, with exceptional level of synonymy. AB - The E. dispunctella and E. triseriatella complexes sensu Traugott-Olsen are merged. The newly delineated E. dispunctella complex is re-defined and diagnosed. Until now, a total of 64 species has been assigned to this species complex. The taxonomy of the constituent species has been obscure owing to their identities based on unvalidated traits, in particular subtle differences on branching points of forewing veins. The taxonomy of the E. dispunctella complex is revised on the basis of new material, new and reevaluated information obtained from morphology and biology, as well as from the standard barcode region of COI, with at least partial barcode data derived from 194 recently collected specimens and 33 holotypes. As a result, the number of species considered valid is markedly reduced, with only 19 species now recognized. The following 43 new synonymies are established: Elachista dispunctella (Duponchel, 1843) = E. cahorsensis Traugott Olsen, 1992, syn. nov., E. imbi Traugott-Olsen, 1992, syn. nov., E. karsholti Traugott-Olsen, 1992, syn. nov., E. mannella Traugott-Olsen, 1992, syn. nov., E. multipunctella Traugott-Olsen, 1992, syn. nov., E. pocopunctella Traugott-Olsen, 1992, syn. nov., E. povolnyi Traugott-Olsen, 1992, syn. nov., E. punctella Traugott-Olsen, 1992, syn. nov., E. hallini Traugott-Olsen, 1992, syn. nov., E. intrigella Traugott-Olsen, 1992, syn. nov., E. skulei Traugott-Olsen, 1992 and E. nielspederi Traugott-Olsen, 1992, syn. nov.; E. tribertiella Traugott-Olsen, 1985 = E. toveella Traugott-Olsen, 1985, syn. nov., E. baldizzonella Traugott-Olsen, 1985, syn. nov., E. veletaella Traugott-Olsen, 1992, syn. nov., E. bazaella Traugott-Olsen, 1992, syn. nov. and E. louiseae Traugott-Olsen, 1992, syn. nov.; E. parvula Parenti, 1978 = E. minusculella Traugott-Olsen, 1992, syn. nov. and E. blancella Traugott-Olsen, 1992, syn. nov.; E. maboulella Chretien, 1915 = E. catalunella Traugott-Olsen, 1992, syn. nov., E. gerdmaritella Traugott-Olsen, 1992, syn. nov. and E. gielisi Traugott-Olsen, 1992, syn. nov.; E. glaseri Traugott-Olsen, 1992 = E. rikkeae Traugott-Olsen, 1992, syn. nov., E. totanaensis Traugott-Olsen, 1992, syn. nov., E. olemartini Traugott-Olsen, 1992, syn. nov., E. bengtssoni Traugott-Olsen, 1992, syn. nov., E. senecai Traugott-Olsen, 1992, syn. nov., E. wadielhiraensis Traugott-Olsen, 1992, syn. nov., E. rissaniensis Traugott-Olsen, 1992, syn. nov. and E. michelseni Traugott-Olsen, 1992, syn. nov.; E. hispanica Traugott-Olsen, 1992 = E. vivesi Traugott-Olsen, 1992, syn. nov., E. cuencaensis Traugott-Olsen, 1992, syn. nov., E. vanderwolfi Traugott Olsen, 1992, syn. nov., E. amparoae Traugott-Olsen, 1992, syn. nov., E. varensis Traugott-Olsen, 1992, syn. nov., E. luqueti Traugott-Olsen, 1992, syn. nov., E. occidentella Traugott-Olsen, 1992, syn. nov. and E. clintoni Traugott-Olsen, 1992, syn. nov.; E. berndtiella Traugott-Olsen, 1985 = E. casascoensis Traugott Olsen, 1992, syn. nov.; E. triseriatella Stainton, 1854 = E. contisella Chretien, 1922, syn. nov., E. gregori Traugott-Olsen, 1988, syn. nov., and E. lerauti Traugott-Olsen, 1992, syn. nov.; E. elsaella Traugott-Olsen, 1988 = E. svenssoni Traugott-Olsen, 1988, syn. nov.; E. galactitella (Eversmann, 1844) = E. madridensis Traugott-Olsen, 1992, syn. nov. E. deresyensis Traugott-Olsen, 1988 is resurrected as a valid species, stat. rev. Evidence from DNA barcodes suggests that there may exist further species, but in the absence of distinct morphological differences, they are not formally described as new. PMID- 26249958 TI - Two new species of Dracoderes (Kinorhyncha: Dracoderidae) from the Ryukyu Islands, Japan, with a molecular phylogeny of the genus. AB - Two new species, Dracoderes snufkini sp. nov. and Dracoderes toyoshioae sp. nov., are described from Okinawa, southern Japan. Diagnostic characters of D. snufkini include: lateroventral tubules on segments 2 and 5; a thick, plump middorsal spine on segments 2 and 9; thick plump paradorsal spines on segments 3-8, alternately laterally displaced; and a ventral primary pectinate fringe on segment 1, with long, wide conspicuous tips. Diagnostic characters of Dracoderes toyoshioae include: a middorsal subcuticular structure on segment 1; paradorsal subcuticular structures on segments 2-9, alternately laterally displaced; paradorsal acicular spines arising from subcuticular structures, at least on segment 5; ventrolateral acicular spines on segment 1; lateral accessory tubules on segment 2; lateral accessory subcuticular structures on segments 2-7; lateroventral tubules on segment 5; and lateroventral subcuticular structures on segments 2-10. Molecular phylogenetic analyses based on 18S rRNA, 28S rRNA and mitochondrial COI sequences indicate that D. abei and D. nidhug are more closely related to one another than either is to D. snufkini or D. toyoshioae. PMID- 26249959 TI - The land crabs of the Discoplax longipes A. Milne-Edwards, 1867 species group, with description of a new species from Guam (Crustacea: Decapoda: Brachyura: Gecarcinidae). AB - Specimens of the gecarcinid land crab Discoplax longipes A. Milne-Edwards, 1867, from the western Pacific, can be separated into two distinct groups on the basis of DNA (mitochondrial 16S rDNA and cytochrome oxidase subunit I) and structure of the male first gonopod. On the basis of this data, the material that occurs from the Loyalty Islands to French Polynesia is shown to be D. longipes s. str., whereas specimens from Guam are here referred to a new pseudocryptic species, D. michalis n. sp. The two species are described and figured; and a revised key to the long-legged Discoplax species is provided. PMID- 26249960 TI - New species of Blaesodactylus (Squamata: Gekkonidae) from Tsingy karstic outcrops in Ankarana National Park, northern Madagascar. AB - We describe a new gecko of the genus Blaesodactylus from a karstic outcrop in deciduous dry forest of Ankarana National Park, northern Madagascar. Blaesodactylus microtuberculatus sp. nov., the fifth recognized species of Blaesodactylus, is distinguished from all other congeners, B. ambonihazo, B. antongilensis, B. boivini and B. sakalava by a combination of small, homogeneous gular granules, unspotted venter and lack of tubercles on distal part of original tail. Mitochondrial (ND2 and ND4) and nuclear (RAG-1) DNA identify a consistent divergence between B. microtuberculatus and its allotopic sister species B. boivini. We highlight habitat partitioning in these allotopic congeners where Blaesodactylus microtuberculatus inhabits karstic outcrops in Tsingy massif, and B. boivini dwells on tree trunks in deciduous dry forest. PMID- 26249961 TI - Further records of species of Gennadas (Crustacea, Decapoda, Dendrobranchiata, Benthesicymidae) in the Mexican Pacific. AB - Additional material of species of Gennadas was collected off western Mexico during the TALUD survey aboard the R/V "El Puma". Gennadas sordidus was by far the most common species collected and only a few specimens of the other three species, G. incertus, G. propinquus and G. scutatus, were obtained. New and previous records indicate that Gennadas sordidus is widely distributed along the west coast of Mexico, although there is only one record for it south of the Gulf of California. In this study it was collected in as many as 35 localities, both in the Gulf of California and off the west coast of Southern Baja California. Numbers of specimens also confirmed that it is the dominant species of Gennadas in the area. Gennadas incertus was found in six samples, all from off the west coast of northern Baja California. The other two species occurred each in two samples only, with sampling localities widely spread along the Baja California Peninsula. Compared with the rest of the eastern Pacific, the diversity of Gennadas in Mexican waters is intermediate (6 species) vs. 9 in Chile and 4 in the NW Pacific. PMID- 26249962 TI - Notes on the Australian Anacaenini (Coleoptera: Hydrophilidae): description of male of Phelea breviceps Hansen and unravelling the identity of Crenitis neogallica Gentili. AB - The holotype and additional specimens of the Tasmanian endemic Phelea breviceps Hansen, 1999, and the holotype of Crenitis neogallica Gentili, 1996 were examined in order to explore their generic and tribal placement. The morphology of Phelea is illustrated in detail, its male genitalia are described for the first time, and it is confirmed as a member of Anacaenini, sharing numerous characters with Crenitis Bedel, 1881 and the New Zealand endemic Horelophus walkeri Orchymont, 1913. Crenitis neogallica is removed from Anacaenini and transferred to the rygmodine genus Pseudohydrobius Blackburn, 1898 (as Pseudohydrobius neogallicus (Gentili, 1996) comb. nov.) and its holotype is illustrated. The genus Crenitis is hence removed from the Australian fauna. PMID- 26249963 TI - Two new species of the Neotropical spider genus Umuara Brescovit (Araneae, Anyphaenidae, Anyphaeninae) from Brazil. AB - Two new species of the genus Umuara are described from Brazil: Umuara freddyi, from the states of Bahia, Minas Gerais and Sao Paulo and Umuara xingo, from the states of Ceara, Paraiba, Sergipe, Bahia, Espirito Santo, and Rio de Janeiro. PMID- 26249964 TI - Margaiostus sundukovi sp. nov., the first record of the genus in the Palaearctic region (Coleoptera: Elateridae). AB - The genus Margaiostus Stibick, 1978, previously known from North and South America, is recorded for the first time in the fauna of the Palaearctic region. M. sundukovi sp. nov. is described from the Far East of Russia. The position of this species within the genus and the distribution of Margaiostus are discussed. PMID- 26249965 TI - Description of a new species of Odonaspis Leonardi (Hemiptera: Coccomorpha: Diaspididae) from Australia. AB - The adult female of Odonaspis bouldersensis Ben-Dov, new species, collected in the Boulders National Park, Queensland, Australia, off a species of Poaceae, is described. PMID- 26249966 TI - Synonymy in the armoured scale insect genus Unaspis MacGillivray (Hemiptera: Coccomorpha: Diaspididae). AB - In recent years, an undescribed species of Unaspis MacGillivray (Hemiptera: Coccomorpha: Diaspididae) has become a damaging pest on the fruit crop Lansium domesticum Correa (family Meliaceae) in the Philippines. PMID- 26249967 TI - Checklist of nematode parasites of amphibians from Argentina. AB - This review includes information about 47 taxa of nematode parasites reported from 34 species of Argentinean amphibians, all belonging to order Anura (33 native species and 1 introduced species). Thirty four nematode species have been reported as adults and 13 species were reported as larvae (10 taxa) or juveniles (3 taxa). Two species, Cosmocerca parva and C. podicipinus (Cosmocercidae), collected as adults, are the most commonly occurring adult nematodes in Argentinean amphibians; each of them parasitize 14 amphibian species. The bufonid Rhinella schneideri and the leptodactylid Leptodactylus bufonius present the highest species richness of parasitic nematodes (9 species); followed by Rhinella fernandezae, R. arenarum and Leptodactylus chaquensis, each of which is parasitized by 8 nematode species. Mean species richenss was highest for the family Bufonidae (4.5+/-3.4; range: 1-9); followed by the Leptodactylidae (3.5+/ 2.8; range: 1-9). Data on hosts, geographical distribution, site of infection, location of deposited materials, and information about life cycles are provided. This is the first compilation of information on nematode parasites of amphibians in Argentina. PMID- 26249968 TI - Two new species of Rhagovelia (Hemiptera: Heteroptera: Veliidae) from Costa Rica, with a key and new records from the country. AB - Rhagovelia danpolhemi sp. nov., from the Caribbean Slope of Costa Rica and R. springerae sp. nov., from the northern portion of the country, are described, illustrated, compared with similar species, and included in a key to species recorded from the country. Rhagovelia calopa Drake & Harris, R. spinosa Gould, and R. tantilla Drake & Harris are recorded for the first time from Costa Rica. New provincial records are provided for R. acuminata Bacon, R. angustipes Uhler, R. armata (Burmeister), R. bisignata Bacon, R. crassipes Champion, R. elegans Uhler, R. femoralis Champion, R. solida Bacon, R. spinigera Champion, R. tenuipes Champion, and R. uncinata Champion. Additional distributional information is given for these species and for R. formosa Bacon and R. scabra Bacon. PMID- 26249969 TI - A new species of Allobates (Anura: Aromobatidae) from Parque Nacional da Amazonia, Para State, Brazil. AB - We describe the fourth species of nurse-frog genus Allobates occurring in the southeastern Brazilian Amazonia. The new species is sympatric with Allobates femoralis, Allobates masniger and Allobates magnussoni, and inhabits the margins of streams in forested areas within Parque Nacional da Amazonia, on the western bank of the Tapajos River. Snout-to-vent length ranges between 14.9-16.1 mm among males and 15.6-16.5 mm among females. The species is distinguished by the light brown background color of dorsum, with irregular dark brown blotches appearing from eye level to the urostyle region. In life, ventral surfaces of males are golden yellow on throat and chest, and white to yellow on abdomen. Ventral surfaces of females are predominantly white, except for light yellow on chin. The dark brown lateral band has a diffuse lower edge ventrolaterally. Dorsal surface of thigh is cream, with a longitudinal dark brown band extending dorsally from vent to knee. Tail musculature of tadpoles is robust, bifurcating dorsally over the body and reaching about two-thirds of the body length. Advertisement calls consist predominantly of continuous pairs of notes, but other note arrangements are also emitted. Notes have ascending frequency modulation and average peak frequency ranging between 5.3-5.9 kHz. First and second notes of the same note pair are similar in amplitude, duration and frequency spectrum. Successive note pairs are split by approximately regular silent intervals (0.30-0.49 s). The species lays its eggs inside rolled or folded dead leaves on the leaf litter. Egg capsules and jelly nests are opaque. PMID- 26249970 TI - Cambarus (Jugicambarus) pauleyi, a new species of crayfish (Decapoda: Cambaridae) endemic to southcentral West Virginia, USA, with a re-description of Cambarus (J.) dubius. AB - Cambarus (Jugicambarus) dubius Faxon, 1884 is a polychromatic montane burrowing crayfish with a long, turbulent taxonomic history since its original description by Walter Faxon in 1884. Over the years, many distinct color phases have been identified, with the majority of these being confined to a specific geographic or physiographic region in the central and southern Appalachians. Previous investigations of this species (e.g., Dewees 1972) were unable to discover consistent morphological differences among the various groups, and thus were unable to clarify what has long been considered a species complex. Due to lingering taxonomic issues, we herein re-describe, delimit and restrict the concept of C. dubius. We also describe a new species, Cambarus (Jugicambarus) pauleyi, from the same complex, which can be identified through the use of geographic distribution, coloration, and distinct morphological characters. Cambarus dubius sensu stricto, as defined here, is restricted to the "typical form" which has an overall orang-ish color pattern on the dorsal and lateral sides, with cream ventrally. The distribution of C. dubius s.s. is limited to the central and northern portions of the Allegheny Mountains and high elevations of the Appalachian Plateau in central West Virginia, western Maryland, and southcentral Pennsylvania. In contrast, C. pauleyi is endemic to high elevation wetlands (>700 m) in the Meadow and Greenbrier River basins in Greenbrier and Monroe counties, West Virginia. Cambarus pauleyi can be differentiated from C. dubius s.s. by 1) its blue dorsal coloration compared to the orange coloration of C. dubius s.s., 2) its large (palm depth/(palm length) ratio, and 3) its smaller (rostral width)/(rostral length) ratio. Cambarus pauleyi can be separated from other peripatric populations of C. dubius sensu lato that occur in the Meadow and Greenbrier River drainage by its 1) blue coloration compared to the orange and black coloration of the latter, 2) the smaller (palm depth)/(palm length) ratio in C. pauleyi, and 3) the deeply excavated rostrum of C. dubius compared to the moderately excavated rostrum of C. pauleyi. Cambarus pauleyi can be easily differentiated from both taxa by the presence of two subpalmer tubercles. Both C. dubius s.s and peripatric C. dubius lack subpalmer tubercles. Cambarus pauleyi has an extremely narrow geographic distribution and has possibly experienced a significant range reduction due to the conversion of wetlands into pastures, and should be considered "Endangered" according to American Fisheries Society listing criteria (Taylor et al. 2007). PMID- 26249971 TI - New data on Belippo and Myrmarachne of Kenya (Araneae: Salticidae: Myrmarachninae). AB - Basing on the collection of Ake Holm, we provide new data on African Myrmarachninae from Kenya: Belippo elgonensis sp. n. (?) and B. terribilis sp. n. (?) are described, as well as the previously unknown female of Myrmarachne giltayi. Belippo calcarata, B. milloti and M. dundoensis are recorded from Kenya for the first time and new records for Myrmarachne kiboschensis, M. lawrencei and M. marshalli are given. PMID- 26249972 TI - A new species of Imantodes Dumeril, 1853 (Serpentes, Dipsadidae) from the Eastern Cordillera of Colombia. AB - We describe a new species of Imantodes, morphologically similar to I. chocoensis, from the Eastern Cordillera of Colombia. This new species is distinguished from all congeners by the following combination of morphological characters: smooth dorsal scale rows 17/17/15; apical pits absent; infralabials 12-13; ventrals 227 236; subcaudals 147-148; presence of loreal scale; cloacal plate divided; dark temporal stripe on the suture between the lower edge of temporal scales and upper region of supralabials; dorsum of body light brown with dark brown transversal streaks, weakly evident in lateral view; hemipenis in situ extending to the level of 11th subcaudal and reaches the 10th subcaudal when everted; hemipenis with sulcus spermaticus expanded at the base of capitulum and extending distally. Additionally, we discuss the lateral expansion of the sulcus spermaticus in the new species, similar to that of species of Leptodeira. PMID- 26249973 TI - A new species of Dysmicoccus damaging lavender in French Provence (Hemiptera, Sternorrhyncha, Pseudococcidae). AB - Une nouvelle espece de Dysmicoccus nuisible a la lavande en Provence (France) (Hemiptera, Sternorrhyncha, Pseudococcidae). Dysmicoccus lavandulae Germain, Matile-Ferrero & Williams n. sp. est decrite et illustree. Ses sequences ADN sont presentees. L'espece vit sur Lavandula x intermedia cultivee pour la production d'essence de lavande en Provence. La liste des especes de pseudococcines vivant sur les lavandes spontanees en France est dressee. Le statut des 2 genres voisins Trionymus Berg et Dysmicoccus Ferris est discute. PMID- 26249974 TI - Review of Hydrometra gracilenta Horvath, 1899 (Hemiptera: Heteroptera: Hydrometridae) in Italy, with notes on its general distribution. AB - An annotated review of the known Italian distribution of Hydrometra gracilenta Horvath, 1899 is provided, plus unpublished data including a new record which increases the previously known range of the species in Italy. An updated map shows the currently known distribution of the taxon in Italy. An overlooked nomenclatural change is discussed, and the date of description for the genus Hydrometra Lateille is corrected from 1796 to 1797. The presence of H. gracilenta is excluded from Egypt, Sudan, and Rwanda. PMID- 26249975 TI - New species and notes on Microveliinae from northern South America (Hemiptera: Heteroptera: Veliidae). AB - Euvelia mazzucconiae sp. nov., from northern Colombia is described, illustrated, and included in an updated identification key to the species of the genus. A map with the known geographical distribution of the species of Euvelia is presented. Additionally, two species from Colombia previously placed in the genus Paravelia are transferred to Microvelia and a species of the latter genus is synonymized, such that Paravelia acantha Padilla-Gil, 2013 = Microvelia acantha (Padilla-Gil, 2013) comb. nov., Paravelia fanera Padilla-Gil, 2013 = Microvelia fanera (Padilla Gil, 2013) comb. nov., and Microvelia amrishi Makhan 2014 = Microvelia mimula White 1879 syn. nov. PMID- 26249976 TI - External morphology and oral cavity of the tadpole of Trachycephalus atlas Bokermann, 1966 (Amphibia, Anura, Hylidae). AB - The Neotropical genus Trachycephalus Tschudi currently comprises 14 species distributed in lowlands of Mexico, Central and South America east of the Andes, south until northern Argentina (Frost 2014) and throughout Brazil (IUCN 2014). Seven species of the genus have tadpoles formerly described: T. coriaceus (Peters) (Schiesari & Moreira 1996; Lescure et al. 1996), T. cunauaru Gordo, Toledo, Suarez, Kawashita-Ribeiro, Avila, Morais & Nunes (Grillitsch 1992 as Phrynohyas resinifictrix according to Gordo et al. 2013), T. jordani (Stejneger & Test) (McDiarmid & Altig 1989-1990), T. mesophaeus (Hensel) (Lutz 1973; Carvalho e-Silva et al. 2002; Prado et al. 2003), T. nigromaculatus Tschudi (Wogel et al. 2000), T. resinifictrix (Goeldi) (Hero 1990; Schiesari et al. 1996), and T. typhonius (Linnaeus) (Pyburn 1967; Duellman 1970; Schiesari et al. 1996). The oral cavity is described only for T. cunauaru (Grillitsch 1992), T. resinifictrix (Schiesari et al. 1996), and T. typhonius (Schiesari et al. 1996; Fabrezi & Vera 1997). PMID- 26249977 TI - Catalogue of distribution of lizards (Reptilia: Squamata) from the Brazilian Amazonia. II. Gekkonidae, Phyllodactylidae, Sphaerodactylidae. AB - I present distribution data of all geckos (Gekkonidae, Phyllodactylidae and Sphaerodactylidae) known from the Brazilian Amazonia, totaling 19 species, belonging to nine genera. This represents six more taxa than previously reported for these families. Data were based on the direct examination of 23,094 specimens deposited in three North American and eight Brazilian museums. Most species (68.4%) are endemic to the Amazonia; non-endemic species are mainly associated with open dry (semideciduous) forest or open vegetation (savanna) enclaves in Amazonia. As a whole, three taxa are widespread in Amazonia, two are restricted to eastern Amazonia, two to western Amazonia, three to northern Amazonia (either widespread or restriced to parts of the Guiana region), one to southern Amazonia, one to southwestern Amazonia, and three to the southern peripheral portion of Amazonia. Additionally, four species have unique distributions and four species have a distribution that is congruent with one of the areas of endemism recognized for other organisms (birds and primates), of which two occur in the area of endemism of Guiana, one in Inambari, and one in Tapajos. PMID- 26249978 TI - New species and records of cunaxid mites (Acari: Cunaxidae) from soil in Southern Brazil. AB - Neocunaxoides promatae sp. nov., Bonzia flechtmanni sp. nov. and Dactyloscirus multiscutus sp. nov. are described from soil and leaf litter in Atlantic rainforest and Atlantic Araucaria forest in natural environments in Sao Francisco de Paula municipality, Rio Grande do Sul State, Brazil. In addition, the species Pulaeus quadrisolenidius Castro & Den Heyer 2009 and Lupaeus lectus Castro & Den Heyer (2009) are registered for the first time in this State. PMID- 26249979 TI - New species of the Afrotropical spider genus Cheiramiona Lotz & Dippenaar Schoeman (Araneae: Eutichuridae). AB - Twenty-three new species of the Afrotropical sac spider genus Cheiramiona Lotz & Dippenaar-Schoeman, 1999 are described: C. baviaan sp. nov. (?, South Africa), C. boschrandensis sp. nov. (?, South Africa), C. debeeri sp. nov. (?, South Africa), C. haddadi sp. nov. (?, South Africa), C. hlathikulu sp. nov. (?, South Africa), C. hogsbackensis sp. nov. (?, ?, South Africa), C. ibayaensis sp. nov. (?, Tanzania), C. jakobsbaaiensis sp. nov. (?, South Africa), C. kirkspriggsi sp. nov. (?, ?, South Africa), C. kivuensis sp. nov. (?, ?, Democratic Republic of Congo & Rwanda), C. lamorali sp. nov. (?, Namibia), C. lindae sp. nov. (?, South Africa), C. malawiensis sp. nov. (?, ?, Malawi), C. mkhambathi sp. nov. (?, ?, South Africa), C. mohalensis sp. nov. (?, Lesotho), C. musosaensis sp. nov. (?, Democratic Republic of Congo), C. nyungwensis sp. nov. (?, Rwanda), C. plaatbosensis sp. nov. (?, ?, South Africa), C. qachasneki sp. nov. (?, South Africa), C. robinae sp. nov. (?, South Africa), C. saniensis sp. nov. (?, ?, South Africa), C. tembensis sp. nov. (?, South Africa) and C. upperbyensis sp. nov. (?, South Africa). The females of C. lajuma Lotz, 2002 and C. mlawula Lotz, 2002 are described for the first time. PMID- 26249980 TI - Tersilochinae of Western Amazonia (Hymenoptera: Ichneumonidae). Genus Stethantyx Townes, part 2. AB - In this paper we describe four new species of Stethantyx Townes (Ichneumonidae: Tersilochinae) from Ecuador and Peru characterized by the fore wing with first and second abscissae of radius meeting at right angle: S. erwini Khalaim & Saaksjarvi, sp. nov., S. radiata Khalaim & Saaksjarvi, sp. nov., S. rufispa Khalaim & Bordera, sp. nov. and S. undulata Khalaim & Saaksjarvi, sp. nov. Second part of the key to species of Stethantyx occurring in Western Amazonia is given. Additionally, S. altamira Khalaim & Broad and S. aprica Khalaim & Broad are recorded from South America for the first time, and new data on distribution of S. alajuela Khalaim & Broad, S. amazonica Khalaim & Saaksjarvi, S. heredia Kha laim & Broad, S. orellana Khalaim & Saaksjarvi, S. sinuata Khalaim & Saaksjarvi and S. trepida Khalaim & Saaksjarvi in South America are provided. Male of S. orellana is recorded for the first time. PMID- 26249981 TI - Review of the genus Sekaliporus Watts, 1997 with description of a new species from northern Australia (Coleoptera: Dytiscidae, Hydroporinae). AB - Sekaliporus davidi sp. n. is described from northern Australia. It is the second species in the genus. It occurs from the Kimberley region in the northwest of Western Australia to north-eastern Queensland. The new species is morphologically similar to S. kriegi Watts, 1997 described from the Kakadu area in the Northern Territory but well characterized by its constantly larger size, six yellowish markings on elytra, the different form of the apical triangular spine of elytra, and the form of the median lobe. Sekaliporus davidi sp. n. is a lotic species from intermittent creeks and slow flowing rivers and their residual pools. Important species characters (median lobes, parameres and colour patterns) of the two species are figured, and notes on their habitats and distribution are given. Both species are capable of flight and were also collected at light. PMID- 26249982 TI - A new contribution to the knowledge of Neotropical Eumeninae (Hymenoptera, Vespidae). AB - A new species, Pirhosigma sulcata Ferreira & Hermes, sp. nov. is described from the Brazilian Amazon; the male of Pararhaphidoglossa gibbiventris Giordani Soika, 1978 is described for the first time. Pseudodynerus carpenteri Hermes & Melo, 2008 is newly recorded from Brazil. New collecting data are reported for Pseudodynerus griseus (Fox, 1902) and P. subapicalis (Fox, 1902). PMID- 26249983 TI - Notes on Hexapodidae (Crustacea, Brachyura) from Indonesia and Malaysia, with description of a new species of Mariaplax Rahayu & Ng, 2014, from Lombok, Indonesia. AB - The male of Hexapinus latipes (De Haan, 1835), so far known only from female specimens, is described based on the material reported by De Man (1888) as "Hexapus sexpes". Material referred to "Hexapus sexpes" by Tesch (1918) is shown instead to belong to Hexapinus simplex Rahayu & Ng, 2014, and Hexapinus latus Rahayu & Ng, 2014, while his "Hexaplax megalops Doflein, 1904" belongs to Hexaplax aurantium Rahayu & Ng, 2014. A new species, Mariaplax aspera n. sp., is described from a female collected in Lombok, Indonesia. This new species most closely resembles M. narusei Rahayu & Ng, 2014, described from Japan, but differs by its relatively narrower carapace, shorter ambulatory legs, tuberculated third maxillipeds, and shorter telson. PMID- 26249984 TI - A new species of Velarifictorus (Pseudocoiblemmus) from Thailand (Gryllidae; Gryllinae; Modicogryllini) with key to species. AB - One new species of Velarifictorus (Pseudocoiblemmus) is described from Thailand: Velarifictorus (Pseudocoiblemmus) bilobus sp. n. A key to all known species of Velarifictorus (Pseudocoiblemmus) is provided. PMID- 26249985 TI - Note on Rondibilis similis (Coleoptera: Cerambycidae: Lamiinae). AB - Eryssamena was erected by Bates (1884) based on three species E. saperdina, E. acuta and E. spinidorsis, which Breuning (1977) recognised to be the same species: Eryssamena saperdina Bates, 1884. Although Eryssamena had been accepted as an independent genus for a long time, Kusama & Takakuwa (1984) and Hashimoto (2008) considered it as a subgenus of Rondibilis Thomson, 1857. Holzschuh (2003) treated Eryssamena as a synonym of the nominotypical subgenus. Ohbayashi & Niisato (2007) and Lobl & Smetana (2010) considered Eryssamena as a synonym of Rondibilis.We have found that the Laotian Eryssamena similis Breuning, 1965 is a secondary homonym of Rondibilis similis Gahan, 1907. According to the Art 57.3.1 of ICZN (International Commission on Zoological Nomenclature, 1999), we hereby propose the replacement name Rondibilis subquadrinotata nom. n. for Eryssamena similis Breuning, 1965. The lectotype and a paralectotype are designated for Rondibilis similis Gahan, 1907. PMID- 26249986 TI - A new species of Xystonotus Wolcott, 1900 (Acari, Hydrachnidia, Mideopsidae) from bromeliad phytotelmata in Brazilian Atlantic rainforest. AB - The rosette architecture of some bromeliad species traps water and organic matter from the canopy in leaf axils (forming phytotelmata) and harbors many species of invertebrate animals (Frank & Lounibos 2009). Some water mites are adapted to live in phytotelmata; typically recorded from water-filled tree holes, bromeliad tanks, and a range of plant axils. Karl Viets (1939) was the first acarologist who discovered Micruracaropsis phytotelmaticola (Viets, 1939) in the water contained in the leaf bases of epiphytic Bromeliaceae in Surinam. Later on, Orghidan et al. (1977) described Arrenurus bromeliacearum Orghidan, Gruia & Vina Bayes, 1977 from phytotelmata in Cuba. Orghidan & Gruia (1987) reported Arrenurus andrewfieldi Orghidan & Gruia, 1983 from phytotelmata of epiphytic bromeliad Vriesea platynema in Venezuela. Smith & Harvey (1989) described Arrenurus kitchingi Smith & Harvey, 1989 from water-filled tree holes in Queensland, Australia. The same authors (Smith & Harvey 1989) also reported that members of genus Thyopsis occur in water-filled tree holes in Ohio, USA. Rosso de Ferradas & Fernandez (2001) reported two Arrenurus species from water accumulated in Guzmania mucronata (Bromeliaceae) in Venezuela, A. andrewfieldi Orghidan & Gruia, 1983 and A. caquetiorum Rosso de Ferradas & Fernandez, 2001. PMID- 26249987 TI - Checklist, distribution, and a new record of Nepomorphan water bugs (Hemiptera: Heteroptera) in northern Tunisia. AB - We report on the results of a survey of the Nepomorpha of northern Tunisia, and list twenty-three species belonging to twelve genera and seven families: Nepidae, Ochteridae, Corixidae, Micronectidae, Naucoridae, Notonectidae, and Pleidae. These records are based on intensive field surveys during the year 2013 and examination of the entomological collections of the National Museum Natural History of Paris. Ranatra linearis (Linnaeus, 1758) is recorded for the first time from Tunisia. The occurrence of Sigara (Halicorixa) stagnalis stagnalis (Leach, 1817) in Tunisia is confirmed. A preliminary checklist of the Nepomorpha of Northern Tunisia and updated distribution maps for all species treated are provided for further studies. PMID- 26249988 TI - A new record of Chironomus (Chironomus) acidophilus Keyl (Diptera, Chironomidae) from the Uzon volcanic caldera (Kronotsky Reserve, Kamchatka Peninsula, Russia), its karyotype, ecology and biology. AB - Morphology, cytology, ecology and biology of Holarctic Chironomus (Chironomus) acidophilus Keyl, 1960 (Diptera, Chironomidae) was examined from material collected in the geothermal Vosmerka Lake (pH=2.0-2.5). An illustrated redescription of C. acidophilus is given on the basis of adult males reared from field-collected pupae, and of simultaneously collected larvae. Additional larvae belonging to the pseudothummi-complex were identified as C. acidophilus on the basis of their karyotype. The karyotype of C. acidophilus (2n=8) and detailed mapping of the 4 chromosome arms A, E, D and F are provided. The population of C. acidophilus from Kamchatka was found to be karyologically monomorphic. Information on distribution and ecology of C. acidophilus from Vosmerka Lake (total mineralization 1583.5 mg/l) is also given. Chironomus acidophilus is the only species of aquatic insects recorded in this lake. Lack of competition and a richness of food resources contribute to the high abundance (35161 ind./m2) and biomass (11.342 g/m2) of the larvae of C. acidophilus in Vosmerka Lake. PMID- 26249989 TI - Further records and descriptions of the plant bug subfamily Phylinae (Hemiptera: Heteroptera: Miridae) from Thailand. AB - Eleven new species of the plant bug subfamily Phylinae are described: Campylomma koraticola, C. nanna, C. pimai, C. salaciella, Cleotomiris levigatus, Cl. sakaeratensis, Cl. similissimus, Decomia anthophila, Malaysiamiris nigrescens, Rubrocuneocoris anandros and Sejanus adustopaca. In addition, Campylomma chitwanensis, which described originally from southeastern Nepal, is confirmed in Thailand and diagnosed, and the female is documented for the first time as well. Photographic images of live individuals are figured for most new species, and those for C. chitwanensis and Decomia taksini are presented for the first time. An annotated checklist of all currently known taxa including new distributional records, also from neighboring Cambodia, Laos and Myanmar, is provided. Some additional photographic images are also presented for little known taxa. The genus Artchawakomius Yasunaga of the tribe Hallodapini is proposed to place in Leucophoropterini. And furthermore, a Chinese species, Rubrocuneocoris lanceus Li & Liu, is transferred to Atractotomoidea Yasunaga. PMID- 26249990 TI - Biodiversity of freshwater sponges (Porifera: Spongillina) from northeast Brazil: new species and notes on systematics. AB - Systematics and distribution of freshwater sponges is still poorly understood worldwide. This may be due to the scarcity of records, and the limited information about morphological traits used for taxonomy. Brazil has reportedly high species richness in the Neotropical Region; however, this diversity is likely to be significantly underestimated given that there are still many unexplored and poorly sampled areas, mainly in the north and northeast regions. We present here new locality records and taxonomic notes on three families and ten species of freshwater Porifera from northeast Brazil: Metaniidae (1), Potamolepidae (2) and Spongillidae (7). A new species of freshwater sponge is described here (Ephydatia caatingae sp.nov.). Additional notes on the systematics and biogeography of most of these species are also presented. PMID- 26249991 TI - Three new species of Stictane Hampson, 1900 (Erebidae, Arctiinae) from Cambodia, with Checklist of Stictane. AB - Genus Stictane Hampson is reviewed in Cambodia, with seven species treated. Of them, S. cambodiensis Bae & Bayarsaikhan, n. sp., S. khmerensis Bae & Bayarsaikhan, n. sp., and S. bokorensis Bayarsaikhan & Bae, n. sp. are described as new to science. S. pectinata Holloway, 2001, S. mlcochi Bucsek, 2012, and S. fuscus Bucsek, 2014, are newly recorded from Cambodia. Up to now unknown female of S. fuscus, is firstly described. The following three species are newly combined: S. munda (de Joannis, 1928) comb. nov.; S. paucilinea (de Joannis, 1928) comb. nov.; and S. umbrimedia (de Joannis, 1928) comb. nov. Illustrations of adults and genitalia are provided, with a checklist of the genus Stictane. PMID- 26249992 TI - The nymph of Gilliesia Peters & Edmunds, 1970 (Ephemeroptera: Leptophlebiidae), with description of a new species from Thailand. AB - The new species Gilliesia ratchaburiensis sp. nov. is described based on male and female imagos (some of them reared from nymphal stages), nymphs and eggs collected in western Thailand. The nymph of Gilliesia, which is described for the first time, has bifid gills, a dense patch of setae on the ventral side of the glossae, no posterolateral spines on abdominal segment VIII, maxillary palpi 3 segmented and very reduced maxillary canines. Compared to congeners, the male imagos of the new species have penis lobes more straight and with the apical portion bent laterally but not ventrally, and female abdominal sternum 9 with a U shaped, deep, median cleft. Phylogenetically, Gilliesia seems to be more similar to Dipterophlebiodes than to Habrophlebiodes and other Leptophlebiinae. The present finding in Thailand expands the distribution of Gilliesia in tropical Southeast Asia. PMID- 26249993 TI - The phallic structures in Gryllotalpidae (Orthoptera: Gryllotalpoidea), and its generic implications. AB - A nomenclature for phallic structures of members of the family Gryllotalpidae is proposed. Genital structures of the main genera of mole crickets are described, discussing the relationships among subfamilies and their generic delimitation. A key is provided for separation of genera based on genitalia structure. Finally, parthenogenesis in genus Gryllotalpella is recorded for the first time. PMID- 26249994 TI - Description of two new species of Pheles Herrich-Schaffer, [1853] and notes on the taxonomic position of two species hitherto included in the genus (Riodinidae: Riodininae). AB - Two new species of Pheles Herrich-Schaffer, [1853], Pheles plaumanni Dolibaina & Dias sp. nov. and Pheles obscura C. Mielke, Dolibaina & Dias sp. nov. are described from southern Brazil. Through the comparative study of the morphology of the head, labial palpus and the genitalia two species are removed from Pheles and the following new combinations are proposed: Pachythone bicolor (Godman & Salvin, 1886) comb. nov. and Melanis caatingensis (Callaghan & Nobre, 2014) comb. nov. The species studied are pictured and details of the head and genitalia are illustrated. PMID- 26249995 TI - Styela cearense n. sp. (Ascidiacea: Styelidae) from the Northeastern Brazilian Coast. AB - The species Styela cearense n. sp. is described from material collected in shallow waters at the Ceara State, Northeastern Brazil. Discussion includes several other species with one gonad on each side of the body, and a tabular key is provided. A set of important anatomical features and their intraspecific variability within the genus is considered, including the number of branchial and stomach folds, the presence of endocarps, and anal border shape. PMID- 26249996 TI - Uca cryptica Naderloo, Turkay & Chen, 2010 (Crustacea: Brachyura:
Ocypodidae) is no longer cryptic. AB - Uca cryptica Naderloo, Turkay & Chen, 2010, was originally described from four male specimens found in museum collections without any information regarding the site of collection. We present the first recorded field observations of this species and new morphological features. Specimens were observed and collected in the Wakatobi National Park, on the island of Kaledupa, Sulawesi Tenggara, Indonesia. Colouration of both males and females is described and ecology and distribution are noted. Uca cryptica has been seen coexisting with nine other species; one of the highest recorded numbers of Uca species living in sympatry. PMID- 26249997 TI - On the generic placement of the narrow-range endemic 'Helix' arguineguinensis Seddon & Aparicio, 1998 from Gran Canaria (Canary Islands). AB - The nominal taxon 'Helix' arguineguinensis Seddon & Aparicio, 1998 is a narrow range endemic from Gran Canaria (Canary Islands, Spain) known only from few localities in the vicinity of Arguineguin in the south-western part of the island (Mousson, 1874; Wollaston, 1878; Seddon & Aparicio, 1998). The narrow range of the taxon and potential threats to its habitat as a consequence of ongoing urbanisation of the area justify its classification in the category 'critically endangered' of the International Union for Conservation of Nature (IUCN) as proposed by Cuttelod et al. (2011). The species has tentatively been included in the genus Xerotricha Monterosato, 1892 (Bank et al., 2002) or classified as possibly belonging to Monilearia Mousson, 1872 on the basis of general shell morphology (Ibanez et al., 2006). The genus Monilearia is believed to be closely related to the genera Cochlicella Ferussac, 1821 in Ferussac, 1821-1822 Prietocella Schileyko & Menkhorst, 1997 and Obelus Hartmann, 1842 in Hartmann (1840-1844) because it shares with these taxa the presence of a vaginal appendage with a peculiar morphology similar to the generalized penial appendix of orthurethran gastropods as described by Schileyko (1984) (Fig. 1). Schileyko (1972) introduced Cochlicellinae as a subfamily of the Hygromiidae. The phylogenetic affinity of this family-level taxon has been variously interpreted (Nordsieck, 1987, 1993; Schileyko, 1991; Schileyko & Menkhorst, 1997; Steinke et al., 2004; Manganelli et al., 2005; Wade et al., 2006, 2007), but recent molecular analyses of Palearctic Helicoidea by Razkin et al. (2015) have lend support to the hypothesis that it represents a tribe (Cochlicellini) within the family Geomitridae as newly delimited by these authors. Diagnostic for the genera in Cochlicellini are details of the anatomy of the vaginal appendage consisting in all anatomically known species of a tubular, comparatively wide section (A1) inserting into the vagina opposite of the insertion point of the penis. Attached apically to the A1 section, the A2 section follows, which may be developed as a curved, finger-like portion ending in a blind sac (Obelus), a rudimentary sac (Cochlicella), or as one (Monilearia) or two to four (Prietocella) propulsory organs with narrow central ducts (Fig. 1B-E, see also Ibanez et al., 2003). The thin tubular A4 section (reduced in Prietocella) inserts laterally of the blind sac (Obelus and Cochlicella) or apically into the propulsory organ (Monilearia) ending distally (in relation to the insertion point of the organ into the vagina) in unbranched or branched glands (A5 section), the latter inserting directly into the propulsory organs in Prietocella (Fig. 1). If the homology with the reconstructed penial appendix of orthurethran gastropods with the appendage of Cochlicellini (in which then the A3 section is reduced) is really justified or if it represents a highly derived state of the dart apparatus of other Palearctic Helicoidea is beyond the scope of this short note, but for ease of comparison the nomenclature of the sections is retained here. PMID- 26249998 TI - Australian Marsh Beetles (Coleoptera: Scirtidae). 7. Genus Nothocyphon, new genus. AB - The new genus Nothocyphon (type species: Helodes (Cyphon ?) lindensis Blackburn, 1892) is proposed for small Contacyphon-like Australian beetles. The included species exhibit a generalized body structure, lacking the derived character expressions of related genera. Male tergite 9 is very weakly developed, membranous and bare. This is derived but as a reduction only weakly supports the monophyly of Nothocyphon.The new genus includes 39 species, with 37 newly described herein: Nothocyphon alces, n. sp., N. amita, n. sp., N. amphora, n. sp., N. armatus, n. sp., N. armstrongi, n. sp., N. auritus, n. sp., N. banksiae, n. sp., N. biserratus, n. sp., N. brevihamatus, n. sp., N. crux, n. sp., N. denticulatus, n. sp., N. donnabuangi, n. sp., N. esau, n. sp., N. frater (Blackburn), n. comb., N. horridus, n. sp., N. imitator, n. sp., N. isolaeregis, n. sp., N. lanceolatus, n. sp., N. lindensis (Blackburn), n. comb., N. multidentatus, n. sp., N. naso, n. sp., N. nungatta, n. sp., N. pacificus, n. sp., N. patruelis, n. sp., N. platyphallus, n. sp., N. plicatus, n. sp., N. radula, n. sp., N. sarcophilus, n. sp., N. scutiger, n. sp., N. serratipenis, n. sp., N. signatus, n. sp., N. soror, n. sp., N. taeniatus, n. sp., N. taurus, n. sp., N. thylacinus, n. sp., N. triangulum, n. sp., N. vandiemeni, n. sp., N. wattsi, n. sp., N. ypsilon, n. sp.Lectotypes are designated for N. frater (Blackburn) and N. lindensis (Blackburn). All species are redescribed or described, and illustrated. Several informal species groups are recognized, and identification keys to males are provided. PMID- 26249999 TI - On the validity of some species names of South American longhorn beetles (Coleoptera, Cerambycidae). AB - In this work, we propose the following taxonomic acts: in Elaphidiini, Ambonus variatus (Newman, 1841) is transferred to Centrocerum Chevrolat, 1861 and has as new junior synonyms Elaphidion elegans Chevrolat, 1861 and E. elegans var. hirsutum, var. jocosum, and var. puberulum, all names proposed by Chevrolat in 1861 as varieties and deemed here as available. In Acanthocinini, Leptostylus neivai Melzer, 1930 is raised from synonymy with L. ovalis Bates, 1863 based on morphological and distributional data. In Acanthoderini, a new synonymy is proposed between Acanthoderes leucogaeus Erichson, 1847 and A. virescens Fuchs, 1962, while in Anisocerini, Tetrasarus lineatus Brethes, 1920 (described in Acanthoderini) is here considered a junior synonym of Caciomorpha genalis (Aurivillius, 1908). PMID- 26250000 TI - Fiddling with the proof: the Magpie Fiddler Ray is a colour pattern variant of the common Southern Fiddler Ray (Rhinobatidae: Trygonorrhina). AB - The Magpie Fiddler ray, Trygonorrhina melaleuca Scott 1954, is presently South Australia's (SA) rarest fish, represented by only three museum specimens collected near Adelaide over the past 60 years and listed as Endangered in the IUCN Red List of Threatened Species. However, there is some doubt as to whether the Magpie Fiddler Ray is a different species from the widespread and common Southern Fiddler Ray, Trygonorrhina dumerilii (Castelnau 1873), resulting in two very contrasting scenarios for marine conservation. If the Magpie Fiddler Ray is a black and white patterned variant of the Southern Fiddler Ray then it will be removed from the Red List and appear as a synonym of T. dumerilii. Conversely, if it proves to be a different species then it remains SA's rarest fish species and highly data deficient. We analysed mtDNA and the largest ever nuclear gene dataset (>4,000 loci) applied to chondrichthyan species level systematics from the most recently collected Magpie Fiddler Ray specimens and a geographically representative selection of Southern Fiddler Rays to determine the species status of this enigmatic ray. We found that the Magpie Fiddler Rays share a mitochondrial haplotype with 23 Southern Fiddler Rays and are not differentiated from 35 Southern Fiddler Rays at more than 4000 SNPs derived from DArTseq data. The morphological trait values that are putatively diagnostic for the Magpie Fiddler Ray fall within the range of variation observed among Southern Fiddler Rays. Our analyses are consistent with the notion that the Magpie Fiddler Ray is a rare colour and pattern variant of the widespread and abundant Southern Fiddler Ray. We also identified two hybrids between the Eastern and Southern Fiddler Rays, only the third time that hybrids have been identified in nature in chondrichthyans. Our results provide critical guidance in the assessment of its conservation status and an ending to a 60 year old conundrum for marine conservation. PMID- 26250001 TI - Lectotype designations of Cerambycidae (Coleoptera) described by E. F. Germar in 1824 and J. C. Klug in 1825 and a new synonymy. AB - Lectotype designation are provided for five species described by Germar: Cerambyx (Lissonotus) gagatinus Germar, 1824, Callichroma rufiventre Germar, 1824, Cerambyx lyciformis Germar, 1824, Rhinotragus dorsiger Germar, 1824, Callidium (Clytus) bisignatus Germar, 1824 and seven described by Klug: Stenopterus crinitus Klug, 1825, Stenopterus hirtipes Klug, 1825, Molorchus scoparius Klug, 1825, Stenopterus albicans Klug, 1825, Cerambyx phtisicus Klug, 1825, Cerambyx perforatus Klug, 1825 and Cerambyx tabidus Klug, 1825. New synonymy proposed: Cerambyx (Lissonotus) gagatinus Germar, 1824 (presently in the genus Rachidion, Cerambycinae, Trachyderini) = Prionus ornatus Dalman, 1823 (presently in the genus Poekilosoma, Prioninae, Anacolini). PMID- 26250002 TI - Type specimens of Heteroptera (Insecta: Hemiptera) collected from North Korea and adjacent regions deposited at Insect Collections of Chungnam National University (CNU) in Daejeon, Republic of Korea. AB - A list of type specimens of Heteroptera (Insecta: Hemiptera) collected from North Korea (mostly by the late Dr. Michail Josifov, Sofia, Bulgaria) acquired earlier by E. Heiss, now donated to and deposited in the insect collections of Chungnam National University (CNU), Deajeon, Korea, is presented. A total of 31 holotypes and 694 paratypes of 41 species and 1 subspecies in 6 families and 9 subfamilies are presented: Miridae (Deraeocorinae, Mirinae, Orthotylinae, Phylinae), Tingidae (Tinginae), Piesmatidae (Piesmatinae), Berytidae (Metacanthinae), Cymidae (Cyminae), Pentatomidae (Asopinae). PMID- 26250003 TI - Monomia calla, a new species of swimming crab (Decapoda, Portunidae)
from Madagascar and the Philippines. AB - A new species of portunid crab (Brachyura: Portunidae) from southern Madagascar and central Philippines is described. Monomia calla sp. nov. is most similar in morphology to M. lecromi (Moosa, 1996) from the Chesterfield Islands in the southwestern Pacific Ocean, and M. rubromarginata (Lanchester, 1900) from the South China Sea, Singapore, Malay Archipelago and the northern half of Australia. The new species can be easily distinguished from all congeners by the distinctive morphology of the male first gonopod. The number of species of the Indo-West Pacific genus Monomia now stands at 12. PMID- 26250004 TI - Armatophallus gen. n., a new genus of gelechiid moths (Lepidoptera, Gelechiidae) from the Afrotropical and Oriental regions. AB - Armatophallus, gen. n., is established for six species: A. exoenota (Meyrick, 1918), comb. n. (ex Gelechia) (= Gelechia xylophaea Meyrick, 1921, syn. n.); A. crudescens (Meyrick, 1920), comb. n. (ex Gelechia); A. kuehnei, sp. n. (Rwanda); A. akagericus, sp. n. (Rwanda); A. hackeri, sp. n. (Yemen, Ethiopia); and A. indicus, sp. n. (India). The systematic position of the new genus is briefly discussed. A key to the species is given based on external characters and the genitalia of both sexes. Adults and genitalia of all species are illustrated. PMID- 26250005 TI - The tadpole of Scinax melanodactylus (Lourenco, Luna & Pombal Jr, 2014) (Amphibia, Anura, Hylidae). AB - Scinax melanodactylus is a small treefrog distributed within the Tropical Atlantic morphoclimatic domain (see Ab'Saber 1977 for South American morphoclimatic domains), from northern Espirito Santo state to Sergipe state in Brazil (Lourenco et al. 2014). The species is usually found inhabiting herbaceous and shrubby xerophytic vegetation (e.g. terrestrial tank-bromeliads) from sandy plains of beach ridges known in Brazil as Restingas (see Rocha et al. 2007 for a Restinga definition), and also the edge of forest areas with temporary ponds and/or permanent lakes and streams near these environments (Bastazini et al. 2007, as Scinax agilis; Lourenco et al. 2014). Scinax melanodactylus is currently placed in the S. catharinae species group (Lourenco et al. 2014), which in turn is included in the S. catharinae clade (sensu Faivovich et al. 2005). The S. catharinae clade is currently comprised of 46 species, 33 placed in the catharinae group and 13 in the perpusillus group (Faivovich et al. 2010, Silva & Alves-da-Silva 2011, Lourenco et al. 2014, Frost 2015). From these, 32 species have tadpoles with external morphology and oral disc formerly described. Here, we describe the external morphology, oral disc and color patterns of the previously unknown tadpole of S. melanodactylus. PMID- 26250006 TI - Colydodes flavisetis sp. nov. (Coleoptera, Zopheridae, Colydiinae), new species from southeastern Brazil with an updated key to the species of the genus. AB - The species Colydodes flavisetis sp. nov. from southeastern Brazil, at the Biological Station of Boraceia, Salesopolis, Sao Paulo, is described and illustrated, raising Colydodes diversity from 7 to 8 known species. An updated key to the species of the genus is given. PMID- 26250007 TI - A new Zoropsis species from China, with notes on Zoropsis pekingensis Schenkel, 1953 (Araneae, Zoropsidae). AB - The family Zoropsidae is currently represented by 15 genera and 87 species (World Spider Catalog 2015). Zoropsids are medium to large size spiders, with a narrow, bipartite cribellum and calamistrum; eight eyes in two rows, anterior eye row nearly straight, posterior row strongly recurved; median furrow longitudinal; toothed chelicerae; tibiae and metatarsi I, II equipped with several pairs of ventral spines; metatarsi and tarsi bearing scopulae; two tarsal claws (Bosselaers 2002). They are often collected from houses, under stones or in leaf litter in forest. PMID- 26250008 TI - Australian Marsh Beetles (Coleoptera: Scirtidae). 8. The new genera
Cygnocyphon, Eximiocyphon, Paracyphon, Leptocyphon, Tectocyphon,
and additions to Contacyphon de Gozis, Nanocyphon Zwick and Eurycyphon Watts. AB - New monotypic genera proposed are: Cygnocyphon ibex n. gen., n. sp., Eximiocyphon excisus n. gen., n. sp., and Paracyphon avicularis n. gen., n. sp. Also proposed are the new genera Leptocyphon n. gen., with L. furcalonga, n. sp. and L. quadricornutus, n. sp., Tectocyphon n. gen., with T. microphallus n. sp., T. hirsutus n. sp., and T. victoriae n. sp. The diagnosis of genus Eurycyphon Watts is amended, E. fulvus Watts and E. aquilus Watts are partly redescribed. New species are: Eurycyphon barringtoni n. sp., E. castaneus n. sp., E. falcatus n. sp., E. parvus n. sp., E. perlatus n. sp., E. thunguttii, n. sp., E. tomweiri n. sp., and E. tricornis n. sp. Species of Nanocyphon are discussed and N. tasmanicus n. sp. is described. Contacyphon forcipatus n. sp. is described and an apparently introduced population of the European Contacyphon putonii Gozis is reported from West Australia. For comparison with some of the new taxa the redescription of Pseudomicrocara orientalis Armstrong, type species of the genus, is supplemented. PMID- 26250009 TI - Tardigrades of Sweden; an updated check-list. AB - Tardigrades occur worldwide and in a variety of ecosystems and habitats representing an important component of the micrometazoan biodiversity. Several studies documenting the occurrence of tardigrades in Sweden have been published since the first reports in early 1900, but no comprehensive summary of these studies have been published. We compiled the available information on recorded tardigrades from Sweden, using material from published studies and museum and university collections. In total, our review document 101 species of tardigrades that have been recorded from Sweden (an updated checklist of tardigrades from Sweden will be available online), of which 14 species are new records for the country. The highest number of species was recorded in the northernmost province of Lappland and the more southern provinces of Uppland and Skane, while much lower species numbers are reported from the middle part of Sweden. This pattern probably represents biased sampling activities of biologists rather than real differences in biodiversity of tardigrades. In view of the few studies that have been made on tardigrade biodiversity in Sweden, the relatively high number of tardigrade species recorded, representing almost a tenth of the species recorded worldwide, indicates that many more species remain to be found. In this respect, more studies of the marine ecosystems along the Swedish west coast and the long Baltic Sea coastline would be of particular interest. PMID- 26250010 TI - Description of the tadpoles of two endemic frogs: the Phu Luang cascade frog Odorrana aureola (Anura: Ranidae) and the Isan big-headed frog Limnonectes isanensis (Anura: Dicroglossidae) from northeastern Thailand. AB - We describe the external morphology of the tadpoles of two frogs endemic to Thailand: the Phu Luang cascade frog (Odorrana aureola) and the Isan big headed frog (Limnonectes isanensis) from the type localities in the Phu Luang Wildlife Sanctuary, Loei Province, northeastern Thailand. Morphological and genetic characters (16S rRNA) were used to identify specimen and match tadpoles to the adults. Detailed descriptions of external morphology and coloration in life are provided for both species. We provide a brief discussion of the ecology of these tadpoles and a comparison to previously published data from tadpoles of closely related taxa. Additionally, we provide evidence for the utility of larval morphology in resolving the taxonomic puzzles presented by cryptic species complexes. PMID- 26250011 TI - Four new species of Moneuptychia (Lepidoptera: Satyrinae: Euptychiina) from Brazil. AB - This paper describes four new species of Moneuptychia as follows: M. montana Freitas, M. vitellina Freitas & Barbosa, M. pervagata Freitas, Siewert & Mielke and M. wahlbergi Freitas, Barbosa, Siewert & Mielke from south and southeastern Brazil. Details are presented on the morphology of adults of all species, and immature stages for two species, and we discuss the taxonomy and identification of the genus Moneuptychia. The mitochondrial CoxI "barcode" region was used for exploring the utility of this DNA marker to identify these species, giving strong support for all new species. PMID- 26250012 TI - On the taxonomic state of water mite taxa (Acari: Hydrachnidia) described from the Palaearctic, part 3, Hygrobatoidea and Arrenuroidea with new faunistic data. AB - Following revision of material from museum collections and recent field work, new taxonomic and faunistic data are given for several representatives of the water mite superfamilies Hygrobatoidea and Arrenuroidea. PMID- 26250013 TI - Note on the genus Neacanista Gressitt, 1940 (Coleoptera: Cerambycidae: Lamiinae: Acanthocinini). AB - Taxonomic notes on the genus Neacanista Gressitt are presented. Hoploranomimus Breuning, 1959 and Paracanthocinus Breuning, 1965a are recognized as new synonyms of Neacanista Gressitt, 1940. Discussions regarding the type locality of Neacanista harmandi (Pic, 1939) and the taxonomic status of Neacanista shirakii (Mitono, 1943) are provided. A key to Neacanista species is presented. PMID- 26250014 TI - Review of the genus Qinshuiacris (Orthoptera: Acrididae) from China with proposal of Caryanda viridis-species group and description of a new species. AB - Based on an examination of type and additional material, Qinshuiacris viridis Zheng & Mao, 1996 and some allied species in the genus Caryanda are reviewed. Q. viridis Zheng & Mao, 1996 is transferred to Caryanda as a new combination: C. viridis (Zheng & Mao, 1996) comb. nov.. The female of C. viridis is described for the first time and sixty-two topotypes are designated. The genus Qinshuiacris Zheng & Mao, 1996 is synonymized with Caryanda Stal, 1878 because of the transfer of the type species. C. yini Mao & Ren, 2006 is proposed as a new junior synonym of C. dehongensis Mao, Xu & Yang, 2003. A new species, C. eshana Mao sp. nov., is also described and illustrated. Additionally, the conception of the Caryanda viridis-species group is proposed to contain the four allied species with falciform cerci: C. albomaculata Mao, Ren & Ou, 2007, C. dehongensis Mao, Xu & Yang, 2003, C. eshana Mao sp. nov., and C. viridis (Zheng & Mao, 1996) comb. nov.. A key to the species of C. viridis-species group is provided. Type specimens are deposited in the Biological Science Museum, Dali University (BMDU), Yunnan Province, China, in the Institute of Zoology, Shaanxi Normal University (IZSNU), Shaanxi Province, China and in the Institute of Zoology, Chinese Academy of Sciences, Beijing, China (IZCAS). PMID- 26250015 TI - Description of immatures of Berosus decolor Knisch, 1924 (Coleoptera: Hydrophilidae: Berosini), with emphasis on chaetotaxy and morphometry. AB - The preimaginal stages of Berosus decolor Knisch, 1924 are described for the first time, including illustrations of the egg case and all larval instars. Larval morphology of this species is studied emphasizing chaetotaxic and morphometric analyses. The egg case lacks a mast and contains 2-3 eggs; all larval instars are characterized by the following features: presence of 6 teeth on anterior margin of nasale; left epistomal lobe carrying 14-16 strong and curved setae (gFR2); seta FR1 elongate, inserted posteriorly to seta PA7; pore FR14 absent; parietale with spinulae in the area between setae PA5 and PA12; mandibles asymmetrical; seta MN1 minute; first antenommere with a digitiform projection on distal inner margin; antennal sensilla AN8 and AN9 absent; maxillary sensilla MX10 hair-like, MX11 and MX16 with an intermediate shape between hair-like and spine-like; labial sensilla LA4 and LA15 absent; seta LA2 present, minute; abdomen with 7 pairs of tracheal gills. The morphology of the egg cases and larvae within the genus Berosus are compared and discussed. PMID- 26250016 TI - A new fossil species of the genus Coptodera Dejean, 1825 (Coleoptera: Carabidae: Lebiinae) from Baltic amber. AB - In this paper a new species of fossil ground-beetle, Coptodera elektra n. sp. (Coleoptera: Carabidae) preserved in a piece of Baltic amber (Eocene) is described and the paleobiology of the species is studied. This new species represents the first known fossil record for the genus, as well as the first record of its presence in Europe. PMID- 26250017 TI - The tadpole of the Lake Oku clawed frog Xenopus longipes (Anura; Pipidae). AB - Xenopus longipes Loumont and Kobel, 1991 is an aquatic polyploid frog endemic to the high altitude crater lake, Lake Oku in North West region, Cameroon (Loumont & Kobel 1991). The tadpole of X. longipes is currently undescribed. So far, only dead tadpoles have been found at Lake Oku during regular monitoring since 2008 (Doherty-Bone et al. 2013), with specimens too decomposed to make adequate descriptions. Captive breeding provides one opportunity to obtain fresh specimens for description. PMID- 26250018 TI - Systematics and morphology of Potamotrygon orbignyi (Castelnau, 1855) and allied forms (Chondrichthyes: Myliobatiformes: Potamotrygonidae). AB - The Neotropical freshwater stingray Potamotrygom orbignyi (Castelnau, 1855), and other similar "reticulated" species occurring in northern South American basins, were submitted to a thorough taxonomic analysis based on an extensive external and internal morphological study. The identity of P. orbignyi and the taxonomic status of the related nominal species Potamotrygon dumerilii (Castelnau, 1855), Potamotrygon reticulata (Gunther, 1880), and Potamotrygon humerosa Garman, 1913, are defined. Taxonomic and morphological analyses revealed that P. reticulata and P. dumerilii fall within the range of variation found in P. orbignyi and were consequently treated as junior synonyms, corroborating previous works. The extensive variation in coloration observed in P. orbignyi could not be divided into consistent morphotypes; P. orbignyi is therefore a widespread species in the upper, mid and lower Amazonas basin, the Orinoco drainage, and in rivers of Suriname and the Guianas. Additionally, P. humerosa and Potamotrygon marinae Deynat, 2007 were found to present characters that support their validity, and are redescribed based on newly collected material. Potamotrygon humerosa occurs predominantly in the mid and lower Amazonas River and in lower reaches of many of its affluents, whereas P. marinae is known only from French Guiana and Suriname. Characters that proved valuable as diagnostic indicators, either in combination or as derived features, are primarily from coloration, dermal denticles and spines (morphology, development and distribution), meristic features (e.g. numbers of tooth rows, vertebrae and mesopterygial radials), morphometric proportions (e.g. snout length, tail width at base and length), and size at sexual maturity. PMID- 26250019 TI - Catalogue of distribution of lizards (Reptilia: Squamata) from the Brazilian Amazonia. I. Dactyloidae, Hoplocercidae, Iguanidae, Leiosauridae, Polychrotidae, Tropiduridae. AB - I present distribution data of all Dactyloidae, Hoplocercidae, Iguanidae, Leiosauridae, Polychrotidae and Tropiduridae lizards known from the Brazilian Amazonia, totaling 40 species-level taxa, belonging to 11 genera. This represents four more species-level taxa than previously reported for these families. Data were based on the direct examination of 41,243 specimens deposited in three North American and eight Brazilian musea, including the main collections harboring Amazonian material. Most species (62.5%) are endemic to the Amazonia; non-endemic species are mainly associated with open dry (semideciduous) forest or open vegetation (savanna) enclaves in Amazonia, with a few exceptions. As a whole, seven taxa are widespread in Amazonia, one is restricted to eastern Amazonia, three to western Amazonia, five to northern Amazonia (either in part of it or widespread in the Guiana region), two to northwestern Amazonia, one to southern Amazonia, nine to southwestern Amazonia, and seven to the southern peripheral portion of Amazonia. Five species have unique distributions and five species have a distribution that is congruent with one of the areas of endemism (AE) recognized for other organisms (birds and primates). The first herpetological gazetteer for the Brazilian Amazonia with about 3,600 georeferenced localities was also produced. PMID- 26250020 TI - An annotated catalogue of the Buprestidae of Iran (Coleoptera: Buprestoidea). AB - An annotated taxonomic catalogue of the jewel beetles (Coleoptera: Buprestidae) of Iran is given. Original descriptions and recent revisionary or catalogue data are included along with the distribution, both within and outside of Iran, ecological data and host plant associations, junior synonyms, and comments. A complete bibliography completes the catalogue. In total 428 species and 52 subspecies of jewel beetles belonging to 6 subfamilies (Julodinae, Polycestinae, Galbellinae, Chrysochroinae, Buprestinae, and Agrilinae), 20 tribes, and 38 genera are known from Iran including doubtful records and 4 nomina nuda. It is likely that the number of jewel beetle species from Iran will be between 460-480 and possibly even more species. PMID- 26250021 TI - Revision of the Simulium (Simulium) melanopus species-group (Diptera: Simuliidae) in Sabah, Malaysia. AB - Species of the Simulium (Simulium) melanopus species-group in Sabah are taxonomically revised by examining type specimens of S. (S.) crassimanum S. (S.) laterale, and S. (S.) nigripilosum, all described from females by Edwards in 1933, and newly collected samples from the vicinity of Mt. Kinabalu. The females of these three species are redescribed, and their males and pupae are described for the first time based on adults reared from pupae. Simulium (S.) liewi Takaoka, 2007 and S. (S.) kinabaluense Smart & Clifford, 1969 are synonymized with S. (S.) crassimanum and S. (S.) laterale, respectively. Simulium (S.) cheedhangi Takaoka, Sofian-Azirun & Ya'cob, 2015 is newly recorded from Sabah. Two new related species, S. (S.) lardizabalae and S. (S.) timpohonense, are described from males reared from pupae. Keys to identify eight species of the S. melanopus species-group in Sabah are provided for females, males, pupae and mature larvae. PMID- 26250022 TI - Taxonomic study of Central Asian species of the genus Macropsis Lewis, 1836 (Homoptera: Auchenorrhyncha: Cicadellidae: Macropsinae). III: Descriptions of two new willow-dwelling species, new synonym, annotated check-list, and key to species. AB - Macropsis milkoi Tishetshkin sp. n. from West Tien Shan, Alay and Hissar-Darvaz Mts. (Kyrgyzstan and Tajikistan) and Macropsis anufrievi Tishetshkin sp. n. from Hissar-Darvaz Mts. (Tajikistan) are described. M. elaeagni Emelyanov, 1964 = M. cyanescens Dubovskiy, 1966 syn. n. is redescribed and illustrated based on the material from Central Asia. Annotated check list and key to 30 Macropsis species from Uzbekistan, Kyrgyzstan, Tajikistan and the mountains of Southern Kazakhstan are given. PMID- 26250023 TI - Feather mites of the genus Passeroptes Fain (Acariformes: Dermationidae) from passerines (Aves: Passeriformes) of China. AB - Five new species of the feather mite genus Passeroptes (Acariformes: Dermationidae) are recorded from birds of the order Passeriformes in China: P. lioparis sp. nov. from Chrysotus chrysotis (Blyth) (Paradoxornithidae); P. motacillae sp. nov. from Motacilla cinerea Tunstall (Motacillidae); P. cyanodermae sp. nov. from Cyanoderma ruficeps Blyth (Timaliidae); P. periparus sp. nov. from Periparus ater (Linnaeus) (Paridae); P. aegithalos sp. nov. from Aegithalos iouschistos bonvaloti (Oustalet) (Aegithalidae). PMID- 26250024 TI - A revision of the genus Ora Clark, 1865 (Coleoptera: Scirtidae) in Argentina (part II)-redescriptions, updated distributions and a key to species. AB - This second part of the revision of the Argentine species of Ora Clark, 1865 provides detailed redescriptions, habitus photos, illustrations of male and female genitalia for eight species, an identification key and updated distributions for all the species. A lectotype is hereby designated for Ora bruchi Pic, 1928. Scirtes brevenotatus v. mediolineatus Pic, 1928 and S. brevenotatus wagneri Pic, 1928 are here raised to species level and transferred to Ora. The females of Ora atroapicalis, O. depressa, O. mediolineata, O. platensis, O. semibrunnea and O. wagneri are described. Ora bivittata Pic, 1922 is newly recorded from Argentina and several provincial records are added to the geographical range of early known species. Eleven species of Ora are now recognized to occur in Argentina: O. atroapicalis Pic, 1928, O. bivittata Pic, 1922, O. brevieminentia Libonatti, 2014, O. bruchi Pic, 1928, O. depressa (Fabricius, 1801), O. mediolineata (Pic, 1928) comb. n., O. megadepressa Libonatti, 2014, O. platensis Brethes, 1925, O. semibrunnea Pic, 1922, O. sigmoidea Libonatti, 2014 and O. wagneri (Pic, 1928) comb. n. PMID- 26250025 TI - Checklist of the species of Neoechinorhynchus (Acanthocephala: Neoechinorhynchidae) in fishes and turtles in Middle-America, and their delimitation based on sequences of the 28S rDNA. AB - Among the acanthocephalans, Neoechinorhynchus is one of the most speciose genera, with 116 described species distributed worldwide. The adults of Neoechinorhynchus are found in the intestine of freshwater and brackish water fish, as well as in freshwater turtles. In this study, a checklist of the congeneric species of Neoechinorhynchus occurring in Middle-American fish and turtles is presented. The checklist contains the records established in all published accounts, as well as novel data from survey work conducted in the region comprising Neotropical areas of Mexico, as well as some localities in Central America. The species delimitation criteria used to discriminate among species is based on molecular data. In the last years, a large database derived from sequences of the D2 + D3 domains of the large subunit of rDNA (28S) was generated for 262 specimens corresponding to nine species of Neoechinorhynchus. This molecular marker has shown to be useful in establishing species limits within Neoechinorhynchus and in resolving phylogenetic relationships at species level. Based on our results, the domains D2 + D3 of the 28S rDNA could be considered as potential DNA barcodes to complement mitochondrial DNA to discriminate among acanthocephalan species. PMID- 26250026 TI - A new species and additional records of the genus Collyria Schiodte, 1839 (Hymenoptera, Ichneumonidae) from Turkey. AB - A new species, Collyria pronotalis Yurtcan and Kolarov sp. n. (Hymenoptera, Ichneumonidae, Collyriinae), from Turkey is described and illustrated. A key for identification of the species of Collyria Schiodte, 1839 is provided. Moreover, additional records are reported for Collyria coxator (Villers, 1789) from Turkey. PMID- 26250027 TI - Molecular phylogeny of the butterfly tribe Satyrini (Nymphalidae: Satyrinae) with emphasis on the utility of ribosomal mitochondrial genes 16s rDNA and nuclear 28s rDNA. AB - The tribe Satyrini is one of the most diverse groups of butterflies, but no robust phylogenetic hypothesis for this group has been achieved. Two rarely used 16s and 28s ribosomal and another seven protein-coding genes were used to reconstruct the phylogeny of the Satyrini, with further aim to evaluate the informativeness of the ribosomal genes. Our maximum parsimony (MP), maximum likelihood (ML) and Bayesian inference (BI) analyses consistently recovered three well-supported clades for the eleven sampled subtribes of Satyrini: clade I includes Eritina and Coenonymphina, being sister to the clade II + clade III; clade II contains Parargina, Mycalesina and Lethina, and the other six subtribes constitute clade III. The placements of the taxonomically unstable Davidina Oberthur and geographically restricted Paroeneis Moore in Satyrina are confirmed for the first time based on molecular evidence. The close relationships of Callerebia Butler, Loxerebia Watkins and Argestina Riley are well-supported. We suggest that Rhaphicera Butler belongs to Lethina. The partitioned Bremer support (PBS) values of MP analysis show that the 16s rDNA contributes well to the nodes representing all the taxa from subtribe to species levels, and the 28s rDNA is informative at the subtribe level. Furthermore, our ML analyses show that the ribosomal genes 16s rDNA and 28s rDNA are informative, because most node support values are lower in the ML tree after the removal of them than that in ML tree constructed based on the full nine-gene dataset. This indicates that some other ribosomal genes should be tentatively used through combining with traditionally used protein-coding genes in further analysis on phylogeny of Satyrini, providing that proper representatives are sampled. PMID- 26250028 TI - Theclini butterflies from Weixi, China, with description of two new species (Lepidoptera: Lycaenidae). AB - Thirteen species belonging to nine genera of the tribe Theclini are recorded from Weixi county, Yunnan province, China. Among which Noseozephyrus Koiwaya and Shirozuozephyrus kirbariensis machimurai Koiwaya are reported as a new record genus and a new record species for China, respectively, and two new species, Noseozephyrus lisus sp. n. and Shirozuozephyrus fibonacci sp. n., are described. All the species and their male genitalia are illustrated. A key for the genus of Shirozuozephyrus is provided. PMID- 26250029 TI - Coastal Talitridae (Amphipoda: Talitroidea) from north-western Australia to Darwin with a revision of the genus Cochinorchestia Lowry & Peart, 2010. AB - Three species of coastal talitrids are reported from north-western Western Australia: Australorchestia tantabiddyensis sp. nov., from Tantabiddy Rockholes Cave, Cape Range National Park; Talorchestia dampieri sp. nov. from Roebuck Bay, Broome and Cygnet Bay, King Sound; and Tropicorchestia derbyensis gen. et sp. nov. from Derby, King Sound. Five species are reported from west of Darwin, Northern Territory: Cochinorchestia lindsayae sp. nov.; Cochinorchestia metcalfeae sp. nov.; Floresorchestia limicola (Haswell, 1880); Microrchestia ntensis sp. nov.; and Tropicorchestia glasbyi sp. nov. The genus Cochinorchestia Lowry & Peart, 2010 is revised: Orchestia notabilis of Griffiths, 1973 is assigned to the new species Cochinorchestia morrumbene sp. nov. from Mozambique; Orchestia sp. of Ledoyer, 1979 is assigned to the new species Cochinorchestia poka sp. nov. from Ambon, eastern Indonesia; and Orchestia notabilis of Ledoyer 1986 is assigned to the new species Cochinorchestia tulear sp. nov. from south western Madagascar. Microrchestia sp. of Bussarawich 1985 appears to be an undescribed species of Cochinorchestia from Thailand. We introduce the term virgula dentata to describe the highly modified tip of antenna 2 in talitrid amphipods and propose a theory for the age and current distribution of the family. PMID- 26250031 TI - Molecular phylogenetics, diversification, and systematics of Tibicen Latreille 1825 and allied cicadas of the tribe Cryptotympanini, with three new genera and emphasis on species from the USA and Canada
(Hemiptera: Auchenorrhyncha: Cicadidae). AB - North America has a diverse cicada fauna with multiple genera from all three Cicadidae subfamilies, yet molecular phylogenetic analyses have been completed only for the well-studied periodical cicadas (Magicicada Davis). The genus Tibicen Latreille, a large group of charismatic species, is in need of such work because morphological patterns suggest multiple groups with complicated relationships to other genera in the tribe Cryptotympanini. In this paper we present a molecular phylogenetic analysis, based on mitochondrial and nuclear DNA, of 35 of the 38 extant USA species and subspecies of the genus Tibicen together with their North American tribal allies (Cornuplura Davis, Cacama Davis), selected Tibicen species from Eurasia, and representatives of other Eurasian and Pacific cryptotympanine genera. This tree shows that Tibicen contains several well-supported clades, one predominating in eastern and central North America and related to Cryptotympana Stal and Raiateana Boulard, another in western North America related to Cacama and Cornuplura, and at least two clades in Eurasia. We also present a morphological cladistic analysis of Tibicen and its close allies based on 27 characters. Character states identified in the cladistic analysis define three new genera, two for North American taxa (Hadoa gen. n. and Neotibicen gen. n.) including several Mexican species, and one for Asian species (Subsolanus gen. n.). Using relaxed molecular clocks and literature-derived mtDNA rate estimates, we estimate the timeframe of diversification of Tibicen clades and find that intergeneric divergence has occurred since the late Eocene, with most extant species within the former Tibicen originating after the mid-Miocene. We review patterns of ecology, behavior, and geography among Tibicen clades in light of the phylogenetic results and note that the study of these insects is still in its early stages. Some Mexican species formerly placed in Tibicen are here transferred to Diceroprocta, following refinement of the definition of that genus. PMID- 26250030 TI - A new insular species of Rock Gecko (Cnemaspis Boulenger) from Pulau Langkawi, Kedah, Peninsular Malaysia. AB - A new, diminutive species of Rock Gecko Cnemaspis mahsuriae sp. nov. of the affinis group, is described from Gunung Raya on Pulau Langkawi, Kedah, Peninsular Malaysia and is differentiated from all other species in the affinis group by having a unique combination of characters including a maximum SVL of 36.6 mm; keeled subtibials and ventrals; 21-24 paravertebral tubercles; no tubercles in the lateral caudal furrows; caudal tubercles not encircling tail; no precloacal pores; 23-26 subdigital lamellae on the fourth toe; no white ocelli in the shoulder region; no yellow postscapular band; and faint yellow bars on the flanks. Cnemaspis mahsuriae sp. nov. is a forest-dwelling species living in close sympatry or paraptry with the insular endemic C. roticanai Grismer & Chan. The Langkawi Archipelago harbors a unique mix of Malaysian and Indochinese taxa and the frequency of new discoveries from this group of islands is increasing. PMID- 26250032 TI - A survey of East Palaearctic Lycosidae (Araneae). 11. Two new genera from the Acantholycosa complex. AB - Two new genera of wolf spiders belonging to Pardosinae, Gulocosa gen. n. and Melecosa gen. n., are erected to accommodate Gulocosa eskovi sp. n. (? ?, Khabarovsk Province, Russia) and Sibirocosa alpina Marusik, Azarkina & Koponen, 2004, respectively. A new combination was also established: Melecosa alpina (Marusik, Azarkina & Koponen, 2004) comb. n. (ex. Sibirocosa). Polytomous and dichotomous keys are provided for the Palearctic Pardosinae genera. PMID- 26250033 TI - New genus and species names for the Eocene lizard Cadurcogekko rugosus Auge, 2005. AB - Cadurcogekko rugosus Auge, 2005 was described as a gekkotan lizard from the Eocene of France. A revision of the material has revealed that the holotype, a nearly complete dentary, actually belongs to a scincid lizard, for which we erect the new genus Gekkomimus. The rest of material originally referred to C. rugosus is of undoubted gekkotan nature and is included in the new species Cadurcogekko verus, with the exception of a partial left dentary belonging to the iguanid lizard Cadurciguana hoffstetteri. PMID- 26250034 TI - Bicoloratum Dai and Li, a new synonym of the leafhopper genus Scaphoideus Uhler (Hemiptera, Cicadellidae, Deltocephalinae),
with description of two new species. AB - Bicoloratum Dai and Li, 2011 is considered to be a junior synonym of Scaphoideus Uhler, 1889 based on study of specimens of two new species, one of which is morphologically very similar to the type species of Bicoloratum, B. pintungisis Dai and Li 2011. Three valid species now included within the genus Scaphoideus are: S. dinghuensis sp. nov., S. taishanensis sp. nov. and S. pingtungisis (Dai and Li, 2011) n. comb. The detailed morphology of the two new species is described, and photographs of their external habitus and male and female genitalia are also given. PMID- 26250035 TI - Garra robertsi, a new cyprinid (Cypriniformes: Cyprinidae) fish species from Borneo. AB - Garra robertsi is described from specimens collected from the Sungai Bongan and Tempassuk rivers in Sabah, Borneo. The species is differentiated from G. borneensis, its only congener on the island of Borneo, in having five (versus four) transverse scale rows above lateral line, the first branched dorsal-fin ray extending beyond the posterior-most extent of any other part of the dorsal fin when depressed (versus not extending posteriorly beyond last ray when depressed), breast with deeply embedded scales (versus exposed scales), fewer tubercles on snout, thin (versus thick) anteromedial fold on the lower lip, absence (versus presence) of a lateral stripe, absence (versus presence) of a stark, contrasting black stripe on lower caudal-fin rays, and other pigmentation characteristics. PMID- 26250036 TI - Zopherobatrus gen. n. (Coleoptera: Staphylinidae: Pselaphinae), a new troglobitic batrisine from southwestern China. AB - A new genus and new species of the pselaphine tribe Batrisini, Zopherobatrus tianmingyii Yin & Li gen. et sp. n., is described based on material collected from a cave in Guizhou, southwestern China. The new taxon exhibits a typical suite of morphological adaptations to life in caves, and represents a third genus of the cave-inhabiting Pselaphinae in China. PMID- 26250037 TI - A redescription of the ant mimicking spider Myrmecium gounellei (Araneae: Corinnidae, Castianeirinae), with notes on the genus. AB - Myrmecium Latreille, 1824 is a relatively large genus of Castianeirinae with 16 species, distributed exclusively in the Neotropics (WSC 2015). Although this genus is rather well known as a good example of ant mimicking spiders, its taxonomy is very poorly studied. Two of its species are described based on unknown sex; one species is described based on a juvenile; eight species are known based on a single sex: for seven, only females are known, and for one, only a male is known (Platnick 2014). Eleven species are known from a single record, and two species were never illustrated. The latest taxonomic paper dealing with Myrmecium was published more than 60 years ago by Camargo (1953). Although both sexes are known for six species of Myrmecium, the male palp and female epigyne are illustrated for three species only. The male palp is relatively well illustrated for the type species of the genus, M. rufum Latreille, 1824 (Camargo 1953). Somatic characters are illustrated also only for M. rufum (Simon 1897). PMID- 26250038 TI - Observations on the Biology of Afrotropical Hesperiidae (Lepidoptera). Part 8. Hesperiinae incertae sedis: Dracaena Feeders. AB - The Afrotropical genera Gamia and Artitropa are only known to feed on species of Dracaena (Asparagaceae), and together with Leona lissa Evans, which may require a new genus, they are the only Afrotropical Hesperiidae that feed on this unusual host genus. We present partial life histories of two species of Gamia, 22 taxa of Artitropa (of at least 12 species, and including several undescribed taxa), and notes on the life history of L. lissa. Based on life history information, Gamia and Artitropa are considered likely to form a monophyletic group, probably most closely related to some of the palm-feeding genera currently placed incertae sedis, but formerly in Evans' 1937 Ploetzia group of genera. Notes on natural enemies of A. erinnys (Trimen) and A. milleri Evans are included. PMID- 26250039 TI - An annotated checklist of Acanthocephala from Australian fish. AB - Thirty one genera, comprising 58 named species, 15 undetermined species and nine species known only as cystacanths from paratenic fish hosts were found infesting 144 marine, esturine and freshwater species of fish from Australian and Australian Antarctic waters. Host habitats are given and the distribution and records of the acanthocephalans are given. A key to these parasites at the generic level is provided. PMID- 26250040 TI - Two new species of Cyrtodactylus (Squamata: Gekkonidae) from the karst forest of Hoa Binh Province, Vietnam. AB - We describe two new species of the genus Cyrtodactylus on the basis of a new reptile collection from the limestone karst forest of Hoa Binh Province, northwestern Vietnam. Cyrtodactylus otai sp. nov. from Hang Kia-Pa Co Nature Reserve and Cyrtodactylus bobrovi sp. nov. from Ngoc Son-Ngo Luong Nature Reserve can be distinguished from each other and from their congeners by their genetic distinction and morphological differences in number of precloacal pores, femoral scales, ventral scales, lamellae, subcaudals and dorsal tubercle arrangement, as well as in size and color pattern. In phylogenetic analyses, both new species are nested in a clade containing taxa from northwestern and northcentral Vietnam and northern Laos, i.e., C. bichnganae and C. cf. martini from northwestern Vietnam, C. puhuensis from northcentral Vietnam, and C. spelaeus, C. vilaphongi, and C. wayakonei from northern Laos. PMID- 26250041 TI - Four new species of the Indo-Burmese genus Badis from West Bengal, India (Actinopterygii: Perciformes: Badidae). AB - Four new species of Badis are described from West Bengal, India. Badis andrewraoi, new species, is diagnosed by a combination of characters which include absence of a black caudal-fin margin, absence of a conspicuous dark blotch on pectoral-fin base, absence of cleithral and opercular blotches, absence of a blotch on the dorsolateral aspect of the caudal peduncle, absence of an ocellus on the caudal-fin base, presence of a conspicuous median black caudal peduncle blotch, a medially broader posterior-most bar, displaying as a partially absorbed second median caudal peduncle blotch, presence of an additional bar anteriorly, and vertical bars restricted to lower half of body and never forming large blocks. Badis autumnum, new species, is diagnosed by a combination of characters which include two autapomorphies: presence of a blotch above the base of the opercular spine, and of a conspicuous dark blotch on pectoral-fin base. Additionally, it presents a black caudal-fin margin, outlining entire fin, absence of a cleithral blotch, absence of a blotch on the dorsolateral aspect of the caudal peduncle, absence of an ocellus on the caudal-fin base, presence of a conspicuous median black caudal peduncle blotch, a medially broader posterior most bar, displaying as a partially absorbed second median caudal peduncle blotch, and presence of an additional bar anteriorly. Badis kyanos, new species, is diagnosed by a combination of characters which include absence of a conspicuous dark blotch on pectoral-fin base, absence of cleithral and opercular blotches, absence of a blotch on the dorsolateral aspect of the caudal peduncle, absence of an ocellus on the caudal-fin base, presence of a conspicuous median black caudal peduncle blotch, a medially broader posterior-most bar, displaying as a partially absorbed second median caudal peduncle blotch, presence of an additional bar anteriorly, its vertical bars forming large, fragmented black blocks dorsolaterally and ventrolaterally, and a unique stress colouration consisting of a dark grey body, metallic dark blue operculum, flanks almost entirely devoid of bars, large, fragmented black blocks dorsolaterally, and absence of a black caudal-fin margin. Based on similarities in colour pattern and biometrics they are deduced to be closely related and form a new species group, which we herein define. The three species are divergent and diagnosable from each other and represent valid evolutionary species. The fourth species represents a cryptic unit that was heretofore unrecognised and considered as the most widespread species of the genus, B. badis. We describe this lineage as Badis soraya, new species, and find it belongs to the B. badis species group. It can be diagnosed by a combination of characters which include absence of opercular blotches, absence of a blotch on the dorsolateral aspect of the caudal peduncle, absence of an ocellus on the caudal-fin base, presence of a cleithral blotch, presence of a small oval black blotch medially on caudal peduncle, interorbital width 6.3-8.8 % SL, dorsal-fin spines XIV-XVI, scales in lateral row 25-27, and vertebrae number 27. PMID- 26250042 TI - A new species of the ghost shrimp genus Lepidophthalmus (Crustacea: Decapoda: Axiidea) from the southwestern Gulf of Mexico. AB - A new species of Lepidophthalmus lacking a ventral median sclerite on the second abdominal somite is described from coastal waters of the southwestern Gulf of Mexico. Lepidophthalmus statoni sp. nov., originally recognized only as a unique population in allozyme studies, is sympatric with the ventrally plated species Lepidophthalmus manningi Felder & Staton, 2000, but more closely resembles Lepidophthalmus louisianensis (Schmitt, 1935) from the northern and northwestern Gulf of Mexico. Apparently restricted to intertidal and shallow subtidal tropical waters, the new species is known to range from western Campeche to middle-upper reaches of Veracruz, Mexico. As many members of the genus, it commonly inhabits euryhaline inlets, estuaries, and protected shorelines, including richly organic muddy to clayey sands and sandy muds adjacent to shoreline vegetation. Coloration is documented and discussed as a tool to facilitate field identifications, as are morphological characters. PMID- 26250043 TI - Taxonomic notes on the genus Satyrium Scudder, 1876 (Lepidoptera, Lycaenidae) of Afghanistan with description of two new taxa. AB - A new species and a new subspecies of Satyrium Scudder, 1876 (subfamily Theclinae, tribe Eumaeini) from the subgenera Superflua Strand, 1910 and Armenia Dubatolov & Korshunov, 1984 respectively are described from Bamyan Province, Central Afghanistan-S. (S.) skrylniki sp. n. and S. (A.) hyrcanica bamiana ssp. n. The new species of Superflua belongs to the Iranian complex of species. It inhabits the territory of Afghanistan, being isolated from two other species of the subgenus known from the territory in question. The new subspecies of Armenia is also found in isolation both from the nominate subspecies and two Middle and Central Asian subspecies. Both findings clarify some aspects of zoogeography of the Central Afghanistan mountains. PMID- 26250044 TI - Talorchestia qeshm sp. nov., a new talitrid amphipod from the Persian Gulf (Amphipoda, Talitridae). AB - A new talitrid amphipod species, Talorchestia qeshm sp. nov., is described from Qeshm Island in the south-eastern Persian Gulf. This is the westernmost confirmed record for Talorchestia and places the genus firmly in the western Indian Ocean. PMID- 26250045 TI - Four new species of Cerambycidae (Coleoptera) from Bolivia and Brazil. AB - Four new species of Cerambycidae are described: Sphaerion iuasanga (Elaphidiini), Glypthaga arena, Hypsioma albosericea (Onciderini) from Bolivia (Santa Cruz), and Hesycha jataiensis (Onciderini) from Brazil. PMID- 26250046 TI - Cymbiodyta lishizheni sp. nov., the second species of the genus from China. AB - The water scavenger beetle genus Cymbiodyta Bedel contains 30 species (Jia & Short 2010, Short & Fikacek 2011), most of which are distributed in North America. Only one species (Cymbiodyta orientalis Jia & Short, 2010) has been described since the worldwide revision of the genus by Smetana (1974). This taxon was the second species of the genus known from the Old World and the first species known from the Oriental Region. Subsequently, Jia (2014) described the male of C. orientalis Jia & Short and provided photographs of the aedeagus. PMID- 26250047 TI - Perceived moral responsibility for attitude-based discrimination. AB - This research investigated judgements of moral responsibility for attitude-based discrimination, testing whether a wrongdoer's mental states - awareness and foresight - are central determinants of culpability. Participants read about and judged a target person who was described as consciously egalitarian, but harbouring negative attitudes that lead him to treat African Americans unfairly. Two studies showed that participants ascribed greater moral responsibility for discrimination when the target was aware of having negative attitudes than when he was unaware. Surprisingly, moral judgements were equally harsh towards a target who was explicitly aware that his bias could influence his behaviour as a target who was not. To explain this result, a second study showed that the path from awareness to moral responsibility was mediated by perceptions that the target had an obligation to foresee his discriminatory behaviour, but not by perceptions of the target's actual foresight. These results suggest that bias awareness influences moral judgements of those who engage in attitude-based discrimination because it obligates them to foresee harmful consequences. The current findings demonstrate that moral judges consider not just descriptive facts, but also normative standards regarding a wrongdoer's mental states. PMID- 26250048 TI - Analysis of the volumetric relationship among human ocular, orbital and fronto occipital cortical morphology. AB - Recent research on the visual system has focused on investigating the relationship among eye (ocular), orbital, and visual cortical anatomy in humans. This issue is relevant in evolutionary and medical fields. In terms of evolution, only in modern humans and Neandertals are the orbits positioned beneath the frontal lobes, with consequent structural constraints. In terms of medicine, such constraints can be associated with minor deformation of the eye, vision defects, and patterns of integration among these features, and in association with the frontal lobes, are important to consider in reconstructive surgery. Further study is therefore necessary to establish how these variables are related, and to what extent ocular size is associated with orbital and cerebral cortical volumes. Relationships among these anatomical components were investigated using magnetic resonance images from a large sample of 83 individuals, which also included each subject's body height, age, sex, and uncorrected visual acuity score. Occipital and frontal gyri volumes were calculated using two different cortical parcellation tools in order to provide a better understanding of how the eye and orbit vary in relation to visual cortical gyri, and frontal cortical gyri which are not directly related to visual processing. Results indicated that ocular and orbital volumes were weakly correlated, and that eye volume explains only a small proportion of the variance in orbital volume. Ocular and orbital volumes were also found to be equally and, in most cases, more highly correlated with five frontal lobe gyri than with occipital lobe gyri associated with V1, V2, and V3 of the visual cortex. Additionally, after accounting for age and sex variation, the relationship between ocular and total visual cortical volume was no longer statistically significant, but remained significantly related to total frontal lobe volume. The relationship between orbital and visual cortical volumes remained significant for a number of occipital lobe gyri even after accounting for these cofactors, but was again found to be more highly correlated with the frontal cortex than with the occipital cortex. These results indicate that eye volume explains only a small amount of variation in orbital and visual cortical volume, and that the eye and orbit are generally more structurally associated with the frontal lobes than they are functionally associated with the visual cortex of the occipital lobes. Results also demonstrate that these components of the visual system are highly complex and influenced by a multitude of factors in humans. PMID- 26250049 TI - Clinical medication review in Australia: A systematic review. AB - BACKGROUND: Clinical medication review (CMR) is a structured and collaborative service aimed at identifying and resolving medication-related problems (MRPs). This is the first systematic review of CMR research in Australia. OBJECTIVE: To systematically review the processes and outcomes of CMR in community-settings in Australia. METHODS: MEDLINE, EMBASE, International Pharmaceutical Abstracts (IPA), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library and the grey literature were searched from 2000 to February 2015. All study designs were considered. Data extraction and quality assessment were performed independently by two investigators. RESULTS: Nine controlled studies, 34 observational and uncontrolled studies, 11 qualitative studies (focus groups and interviews) and nine survey studies were included. The CMRs resulted in identification of MRPs (n = 15 studies, mean 3.6 MPRs per CMR) and improved adherence (n = 3). Reductions in numbers of medications prescribed (n = 3 studies), hospitalizations (n = 3), potentially inappropriate prescribing (n = 3) and costs (n = 6) were demonstrated. Comparisons to a control group, predominately non-recipients of CMR, were made in eleven of 43 studies. Evidence supports additional models that promote interprofessional collaboration and timely referral following hospital discharge. Qualitative research identified low awareness of CMR among eligible non-recipients, while benefits were perceived to outweigh barriers to implementation. Underserved populations include indigenous and culturally and linguistically diverse people, recipients of palliative care, those recently discharged from hospital, people with poor medication adherence, those in rural and remote areas, older males, and younger people with long-term, persistent or serious health problems. CONCLUSION: The available evidence suggests CMR is beneficial in improving the quality use of medications and health outcomes. However, lack of comparator groups in many observational studies limited the strength of conclusions in relation to the impact on clinical outcomes. Addressing access gaps for underserved populations, implementing additional referral pathways, and facilitating greater collaboration between the health professionals represent opportunities for further improvement. PMID- 26250050 TI - First Miocene rodent from Lebanon provides the 'missing link' between Asian and African gundis (Rodentia: Ctenodactylidae). AB - Ctenodactylinae (gundis) is a clade of rodents that experienced, in Miocene time, their greatest diversification and widest distribution. They expanded from the Far East, their area of origin, to Africa, which they entered from what would become the Arabian Peninsula. Questions concerning the origin of African Ctenodactylinae persist essentially because of a poor fossil record from the Miocene of Afro-Arabia. However, recent excavations in the Late Miocene of Lebanon have yielded a key taxon for our understanding of these issues. Proafricanomys libanensis nov. gen. nov. sp. shares a variety of dental characters with both the most primitive and derived members of the subfamily. A cladistic analysis demonstrates that this species is the sister taxon to a clade encompassing all but one of the African ctenodactylines, plus a southern European species of obvious African extraction. As such, Proafricanomys provides the 'missing link' between the Asian and African gundis. PMID- 26250051 TI - Cardiovascular and heart failure safety profile of vildagliptin: a meta-analysis of 17 000 patients. AB - AIMS: To report the cardiovascular (CV) safety profile and heart failure (HF) risk of vildagliptin from a large pool of studies, including trials in high-risk patients with type 2 diabetes mellitus (T2DM), such as those with congestive HF and/or moderate/severe renal impairment. METHODS: We conducted a retrospective meta-analysis of prospectively adjudicated CV events. Patient-level data were pooled from 40 double-blind, randomized controlled phase III and IV vildagliptin studies. The primary endpoint was occurrence of major adverse CV events (MACEs; myocardial infarction, stroke and CV death). Assessments of the individual MACE components and HF events (requiring hospitalization or new onset) were secondary endpoints. The risk ratio (RR) of vildagliptin (50 mg once- and twice-daily combined) versus comparators (placebo and all non-vildagliptin treatments) was calculated using the Mantel-Haenszel (M-H) method. RESULTS: Of the 17 446 patients, 9599 received vildagliptin (9251.4 subject-years of exposure) and 7847 received comparators (7317.0 subject-years of exposure). The mean age of the patients was 57 years, body mass index 30.5 kg/m(2) (nearly 50% obese), glycated haemoglobin concentration 8.1% and T2DM duration 5.5 years. A MACE occurred in 83 (0.86%) vildagliptin-treated patients and 85 (1.20%) comparator-treated patients, with an M-H RR of 0.82 [95% confidence interval (CI) 0.61-1.11]. Similar RRs were observed for the individual events. Confirmed HF events were reported in 41 (0.43%) vildagliptin-treated patients and 32 (0.45%) comparator-treated patients, with an M-H RR 1.08 (95% CI 0.68-1.70). CONCLUSIONS: This large meta-analysis indicates that vildagliptin is not associated with an increased risk of adjudicated MACEs relative to comparators. Moreover, this analysis did not find a significant increased risk of HF in vildagliptin-treated patients. PMID- 26250052 TI - A Concentrated Hydrochloric Acid-based Method for Complete Recovery of DNA from Bone. AB - The successful extraction of DNA from historical or ancient animal bone is important for the analysis of discriminating genetic markers. Methods used currently rely on the digestion of bone with EDTA and proteinase K, followed by purification with phenol/chloroform and silica bed binding. We have developed a simple concentrated hydrochloric acid-based method that precludes the use of phenol/chloroform purification and can lead to a several-fold increase in DNA yield when compared to other commonly used methods. Concentrated hydrochloric acid was shown to dissolve most of the undigested bone and allowed the efficient recovery of DNA fragments <100 bases in length. This method should prove useful for the recovery of DNAs from highly degraded animal bone, such as that found in historical or ancient samples. PMID- 26250053 TI - Macrophages decide between regeneration and fibrosis in muscle. AB - Defective muscle regeneration is usually accompanied by excessive matrix accumulation (fibrosis). A recent study reveals how this fibrotic process is prevented to allow successful regeneration, through a timely interplay between macrophages and fibro/adipogenic progenitor cells. This has biomedical relevance for fibrotic muscular dystrophies. PMID- 26250054 TI - SOX2 anophthalmia syndrome and dental anomalies. AB - SOX2 anophthalmia syndrome is an uncommon autosomal dominant syndrome caused by mutations in the SOX2 gene and clinically characterized by severe eye malformations (anophthalmia/microphthalmia) and extraocular anomalies mainly involving brain, esophagus, and genitalia. In this work, a patient with the SOX2 anophthalmia syndrome and exhibiting a novel dental anomaly is described. SOX2 genotyping in this patient revealed an apparently de novo c.70del20 deletion, a commonly reported SOX2 mutation. A review of the phenotypic variation observed in patients carrying the recurrent SOX2 c.70del20 mutation is presented. Although dental anomalies are uncommonly reported in the SOX2 anophthalmia syndrome, we suggest that a dental examination should be performed in patients with SOX2 mutations. PMID- 26250055 TI - Impact of IL28B, ITPA and PNPLA3 genetic variants on therapeutic outcome and progression of hepatitis C virus infection. AB - Chronic HCV infection comprises a broad spectrum of liver disease, ranging from no or minimal activity to active hepatitis that in time may progress to severe liver fibrosis, cirrhosis and hepatocellular carcinoma if left untreated. This review describes the impact of genetic variants of interleukin 28B (IL28B; also known as interferon-lambda 3), inosine triphosphate pyrophosphatase (ITPA) and patatin-like phospholipase domain-containing 3 (PNPLA3) on therapeutic outcome and liver disease severity in HCV-infected patients. PMID- 26250056 TI - Coronary Heart Disease and Stroke in Adults Born Preterm - The Helsinki Birth Cohort Study. AB - BACKGROUND: Adults born preterm have increased risk factors for cardiovascular disease. We studied the cumulative incidence of manifest coronary heart disease (CHD) and stroke in adults born preterm. METHODS: We studied 19 015 people born in Helsinki, Finland, during 1924-44. Of them, 137 (0.7%) were born early (<34 weeks) and 1006 (5.3%) late preterm (34 to <37 weeks). We ascertained CHD and stroke from the National Hospital Discharge and Death Registers and estimated hazard ratios (HRs) by Cox regression. RESULTS: A total of 3027 subjects (15.9%) had CHD and 1805 (9.5%) stroke. HRs for CHD were 1.17 (95% confidence interval 0.83, 1.65) for early and 0.99 (0.85, 1.14) for late preterm. For stroke, they were 0.84 (0.50, 1.39) and 0.86 (0.71, 1.06). HRs were little changed when adjusted for childhood and adult socio-economic position and birthweight for gestation standard deviation score. They were similar for first-ever events before or after 65 years, for haemorrhagic and thrombotic stroke, and for men and women, except that the HR for CHD for women born early preterm was 1.98 (1.18, 3.30). CONCLUSIONS: We found no increased risk of CHD or stroke up to old age in people born preterm, although women born early preterm had a higher rate of CHD. There is a discrepancy between increased risk factors in younger generations born preterm and little or no increase in manifest disease in older age. Uncovering reasons underlying this discrepancy may give important insights into the prevention of cardiovascular disease. PMID- 26250057 TI - Development of a Fluorescence-Linked Immunosorbent Assay for Baicalin. AB - Previously, we developed an indirect competitive enzyme-linked immunosorbent assay (icELISA) for baicalin (BAL) and used this assay to investigate the pharmacokinetics of BAL in mice. In this study, an anti-BAL monoclonal antibody (MAb) was purified by the caprylic acid method and then labelled with fluorescein isothiocyanate (FITC). Subsequently, an indirect competitive fluorescence-linked immunosorbent assay (icFLISA) was developed to detect baicalin (BAL) using FITC labelled anti-BAL MAbs. Characterization of the assay demonstrated an effective BAL measurement range of 6.4 ng/mL to 500 MUg/mL (R(2) = 0.997). The relative standard deviations (RSDs) for both intra-assay and inter-assay repeatability and precision were below 10 %. This icFLISA for BAL is simple, rapid and sensitive, with a 390-fold larger linear range and a 2-fold lower limit of detection (LOD) compared with the previously developed icELISA. We observed a strong correlation between the results determined by the icFLISA and icELISA methods. Overall, this study provides a useful method for detecting BAL in medicines, enabling in vivo visualization research. PMID- 26250058 TI - Permethylated-beta-Cyclodextrin Capped CdTe Quantum Dot and its Sensitive Fluorescence Analysis of Malachite Green. AB - In the present work, the CdTe quantum dots were covalently conjugated with permethylated-beta-cyclodextrin (OMe-beta-CD) using 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide hydrochloride as cross-linking reagent. The obtained functional quantum dots (OMe-beta-CD/QDs) showed highly luminescent, water solubility and photostability as well as good inclusion ability to malachite green. A sensitive fluorescence method was developed for the analysis of malachite green in different samples. The good linearity was 2.0 * 10(-7)-1.0 * 10(-5) mol/L and the limit of detect was 1.7 * 10(-8) mol/L. The recoveries for three environmental water samples were 92.0-108.2 % with relative standard deviation (RSD) of 0.24-1.87 %, while the recovery for the fish sample was 94.3 % with RSD of 1.04 %. The results showed that the present method was sensitive and convenient to determine malachite green in complex samples. Graphical Abstract The analytical mechanism of OMe-beta-CD/QDs and its linear response to MG. PMID- 26250060 TI - Is progression of periodontitis relevantly influenced by systemic antibiotics? A clinical randomized trial. AB - AIM: We investigated the long-term impact of adjunctive systemic antibiotics on periodontal disease progression. Periodontal therapy is frequently supplemented by systemic antibiotics, although its impact on the course of disease is still unclear. MATERIAL & METHODS: This prospective, randomized, double-blind, placebo controlled multi-centre trial comprising patients suffering from moderate to severe periodontitis evaluated the impact of rational adjunctive use of systemic amoxicillin 500 mg plus metronidazole 400 mg (3x/day, 7 days) on attachment loss. The primary outcome was the percentage of sites showing further attachment loss (PSAL) >=1.3 mm after the 27.5 months observation period. Standardized therapy comprised mechanical debridement in conjunction with antibiotics or placebo administration, and maintenance therapy at 3 months intervals. RESULTS: From 506 participating patients, 406 were included in the intention to treat analysis. Median PSAL observed in placebo group was 7.8% compared to 5.3% in antibiotics group (Q25 4.7%/Q75 14.1%; Q25 3.1%/Q75 9.9%; p < 0.001 respectively). CONCLUSIONS: Both treatments were effective in preventing disease progression. Compared to placebo, the prescription of empiric adjunctive systemic antibiotics showed a small absolute, although statistically significant, additional reduction in further attachment loss. Therapists should consider the patient's overall risk for periodontal disease when deciding for or against adjunctive antibiotics prescription. PMID- 26250061 TI - Advancing Symptom Science Through Use of Common Data Elements. AB - BACKGROUND: Use of common data elements (CDEs), conceptually defined as variables that are operationalized and measured in identical ways across studies, enables comparison of data across studies in ways that would otherwise be impossible. Although healthcare researchers are increasingly using CDEs, there has been little systematic use of CDEs for symptom science. CDEs are especially important in symptom science because people experience common symptoms across a broad range of health and developmental states, and symptom management interventions may have common outcomes across populations. PURPOSES: The purposes of this article are to (a) recommend best practices for the use of CDEs for symptom science within and across centers; (b) evaluate the benefits and challenges associated with the use of CDEs for symptom science; (c) propose CDEs to be used in symptom science to serve as the basis for this emerging science; and (d) suggest implications and recommendations for future research and dissemination of CDEs for symptom science. DESIGN: The National Institute of Nursing Research (NINR)-supported P20 and P30 Center directors applied published best practices, expert advice, and the literature to identify CDEs to be used across the centers to measure pain, sleep, fatigue, and affective and cognitive symptoms. FINDINGS: We generated a minimum set of CDEs to measure symptoms. CONCLUSIONS: The CDEs identified through this process will be used across the NINR Centers and will facilitate comparison of symptoms across studies. We expect that additional symptom CDEs will be added and the list will be refined in future work. CLINICAL RELEVANCE: Symptoms are an important focus of nursing care. Use of CDEs will facilitate research that will lead to better ways to assist people to manage their symptoms. PMID- 26250062 TI - Elevated marrow inflammatory cells and osteoclasts in subchondral osteosclerosis in human knee osteoarthritis. AB - Subchondral osteosclerosis, characterized by an increase of hypomineralized bone material, is a pathological hallmark of osteoarthritis. The cellular components in the subchondral marrow compartment that participate in this aberrant bone remodeling process remain to be elucidated. This study assessed the presence of marrow inflammatory cells and their relative abundance between nonsclerotic and sclerotic tissues in knee osteoarthritis. Bone samples from osteoarthritic knee tibial plateaus were stratified for histological analyses using computed tomography osteoabsorptiometry. Immunohistological analysis revealed the presence of CD20 (B-lymphocyte) and CD68 (macrophage), but not CD3 (T-lymphocyte) immunoreactive mononuclear cells in subchondral marrow tissues and their relative abundance was significantly increased in sclerotic compared with nonsclerotic bone samples. Multinucleated osteoclasts that stained positive for CD68 and tartrate-resistant acid phosphatase, predominantly associated with CD34-positive blood vessels and their abundance was strongly increased in sclerotic samples. Bone-specific alkaline phosphatase activity in outgrowth osteoblasts was induced by conditioned medium from nonsclerotic, but not sclerotic, bone pieces. These results suggest that an interaction between bone-resident cells and marrow inflammatory cells might play a role in aberrant bone remodeling leading to subchondral osteosclerosis. Elevated osteoclast activity in sclerotic bone suggests that bone formation and resorption activities are increased, yet uncoupled, in human knee osteoarthritis. PMID- 26250063 TI - Evaluating noninvasive markers of nonhuman primate immune activation and inflammation. AB - OBJECTIVES: Health, disease, and immune function are key areas of research in studies of ecology and evolution, but work on free-ranging primates has been inhibited by a lack of direct noninvasive measures of condition. Here, we evaluate the potential usefulness of noninvasive measurement of three biomarkers, the acute-phase proteins C-reactive protein (CRP) and haptoglobin, and neopterin, a by-product of macrophage activity. MATERIALS AND METHODS: We took advantage of veterinary checks on captive rhesus (24) and long-tailed (3) macaques at the German Primate Center (DPZ) to analyze serum marker measures, before measuring concentrations in feces and urine, and evaluating relationships between matched serum, urine, and fecal concentrations. In a second study, we monitored excretion of these markers in response to simian immunodeficiency virus (SIV) infection and surgical tissue trauma, undertaken for a separate study. RESULTS: We found that each biomarker could be measured in each matrix. Serum and urinary concentrations of neopterin were strongly and significantly correlated, but neither haptoglobin nor CRP concentrations in excreta proxied circulating serum concentrations. Our infection study confirmed that urinary neopterin, in particular, is a reliable marker of viral infection in macaques, but also indicated the potential of urinary and fecal CRP and haptoglobin as indicators of inflammation. DISCUSSION: We highlight the potential of noninvasive markers of immune function, especially of urinary neopterin, which correlates strongly with serum neopterin, and is highly responsive to infection. PMID- 26250064 TI - A humanized version of Foxp2 does not affect ultrasonic vocalization in adult mice. AB - The transcription factor FOXP2 has been linked to severe speech and language impairments in humans. An analysis of the evolution of the FOXP2 gene has identified two amino acid substitutions that became fixed after the split of the human and chimpanzee lineages. Studying the functional consequences of these two substitutions in the endogenous Foxp2 gene of mice showed alterations in dopamine levels, striatal synaptic plasticity, neuronal morphology and cortico-striatal dependent learning. In addition, ultrasonic vocalizations (USVs) of pups had a significantly lower average pitch than control littermates. To which degree adult USVs would be affected in mice carrying the 'humanized' Foxp2 variant remained unclear. In this study, we analyzed USVs of 68 adult male mice uttered during repeated courtship encounters with different females. Mice carrying the Foxp2(hum/hum) allele did not differ significantly in the number of call elements, their element structure or in their element composition from control littermates. We conclude that neither the structure nor the usage of USVs in adult mice is affected by the two amino acid substitutions that occurred in FOXP2 during human evolution. The reported effect for pup vocalization thus appears to be transient. These results are in line with accumulating evidence that mouse USVs are hardly influenced by vocal learning. Hence, the function and evolution of genes that are necessary, but not sufficient for vocal learning in humans, must be either studied at a different phenotypic level in mice or in other organisms. PMID- 26250065 TI - Formal Gold-to-Gold Transmetalation of an Alkynyl Group Mediated by Palladium: A Bisalkynyl Gold Complex as a Ligand to Palladium. AB - The reaction of [Au(C=C-n-Bu)]n with [Pd(eta(3) -allyl)Cl(PPh3 )] results in a ligand and alkynyl rearrangement, and leads to the heterometallic complex [Pd(eta(3) -allyl){Au(C=C-n-Bu)2 }]2 (3) with an unprecedented bridging bisalkynyl-gold ligand coordinated to palladium. This is a formal gold-to-gold transmetalation that occurs through reversible alkynyl transmetalations between gold and palladium. PMID- 26250066 TI - Influence of contextual task constraints on preferred stride parameters and their variabilities during human walking. AB - Walking is not always a free and unencumbered task. Everyday activities such as walking in pairs, in groups, or on structured walkways can limit the acceptable gait patterns, leading to motor behavior that differs from that observed in more self-selected gait. Such different contexts may lead to gait performance different than observed in typical laboratory experiments, for example, during treadmill walking. We sought to systematically measure the impact of such task constraints by comparing gait parameters and their variability during walking in different conditions over-ground, and on a treadmill. We reconstructed foot motion from foot-mounted inertial sensors, and characterized forward, lateral and angular foot placement while subjects walked over-ground in a straight hallway and on a treadmill. Over-ground walking was performed in three variations: with no constraints (self-selected, SS); while deliberately varying walking speed (self-varied, SV); and while following a toy pace car programmed to vary speed (externally-varied, EV). We expected that these conditions would exhibit a statistically similar relationship between stride length and speed, and between stride length and stride period. We also expected treadmill walking (TM) would differ in two ways: first, that variability in stride length and stride period would conform to a constant-speed constraint opposite in slope from the normal relationship; and second, that stride length would decrease, leading to combinations of stride length and speed not observed in over-ground conditions. Results showed that all over-ground conditions used similar stride length-speed relationships, and that variability in treadmill walking conformed to a constant speed constraint line, as expected. Decreased stride length was observed in both TM and EV conditions, suggesting adaptations due to heightened awareness or to prepare for unexpected changes or problems. We also evaluated stride variability in constrained and unconstrained tasks. We observed that in treadmill walking, lateral variability decreased while forward variability increased, and the normally-observed correlation between wider foot placement and external foot rotation was eliminated. Preferred stride parameters and their variability appear significantly influenced by the context and constraints of the walking task. PMID- 26250067 TI - Brexpiprazole for schizophrenia and as adjunct for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antipsychotic - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? AB - OBJECTIVE: To describe the efficacy, tolerability and safety of brexpiprazole for the treatment of schizophrenia and as adjunct for major depressive disorder (MDD). DATA SOURCES: The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms 'brexpiprazole' OR 'OPC-34712', and by also querying the EMBASE (Elsevier) commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labelling provided additional information. STUDY SELECTION: All available clinical reports of studies were identified. DATA EXTRACTION: Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information. DATA SYNTHESIS: Brexpiprazole is a new dopamine D2 receptor partial agonist that received approval for the treatment of schizophrenia and for adjunctive use for the treatment of MDD based on a clinical trial development programme that included two pivotal Phase III trials of brexpiprazole monotherapy in acute schizophrenia, and two pivotal Phase III trials of adjunctive brexpiprazole in acute MDD in patients who demonstrated inadequate response to standard antidepressant therapy. In addition, results from a 52-week relapse prevention/maintenance randomised placebo-controlled withdrawal study in patients with schizophrenia are available. In these trials, brexpiprazole was administered once daily and titrated to target doses. The recommended dose for the treatment of schizophrenia is 2-4 mg/day and that for MDD, 2 mg/day. Pooling together all the available data for the recommended target dose of brexpiprazole for acute schizophrenia from the above studies, the percentage of responders is 45.5% vs. 31.0% for placebo, yielding a NNT of 7 (95% CI 5-12). In the relapse prevention/maintenance trial, significantly fewer patients relapsed in the brexpiprazole group compared with placebo (13.5% vs. 38.5%), resulting in a NNT of 4 (95% CI 3-8). When the results for brexpiprazole 1, 2 and 3 mg from the two Phase III MDD trials are pooled together, 23.2% of the patients receiving brexpiprazole were responders, vs. 14.5% for placebo, yielding a NNT of 12 (95% CI 8-26). Brexpiprazole was well tolerated - for schizophrenia, discontinuation rates because of an adverse event (AE) were overall lower for patients receiving brexpiprazole vs. placebo, and for MDD a total of 3% of brexpiprazole-treated patients and 1% of placebo-treated patients discontinued because of AEs, resulting in a NNH of 53 (95% CI 30-235). Although the most commonly encountered AE noted in product labelling was akathisia (5.5% in the acute schizophrenia trials and 8.6% in the MDD trials), differences from placebo were small, generating a non-significant NNH of 112 for patients with schizophrenia and a modest NNH of 15 (95% CI 11-23) for patients with MDD. Short term weight gain appears modest; however, more outliers with an increase of >= 7% of body weight were evident in open-label 52-week safety studies. Effects on glucose and lipids were small. Minimal effects on prolactin were observed, and no clinically relevant effects on the ECG QT interval were evident. CONCLUSIONS: Clinical trials of brexpiprazole support its efficacy at the recommended target dose of 2-4 mg/day for the treatment of schizophrenia, and at the recommended target dose of 2 mg/day as adjunct to antidepressant medication for the treatment of MDD. Head-to-head comparisons with other available agents among patients with schizophrenia and MDD in the 'real world' are needed. PMID- 26250068 TI - Capacity Consultation and Contextual Complexities: Depression, Decisions, and Deliberation. PMID- 26250069 TI - Louse-borne relapsing fever (Borrelia recurrentis) in asylum seekers from Eritrea, the Netherlands, July 2015. AB - Two patients from Eritrea, recently arrived in the Netherlands, presented with fever and were investigated for malaria. Bloodfilms showed spirochetes but no blood parasites. Louse-borne relapsing fever caused by Borrelia recurrentis was diagnosed. Treatment was complicated by severe Jarisch-Herxheimer reactions in both patients. Physicians should be aware of the possibility of B. recurrentis infection in migrant populations who travel under crowded conditions, especially after passing through endemic areas such as Ethiopia and neighbouring countries. PMID- 26250070 TI - Outbreak of Salmonella Enteritidis phage type 13a infection in Sweden linked to imported dried-vegetable spice mixes, December 2014 to July 2015. AB - From 24 December to 24 July 2015, 174 cases were reported in a nationwide salmonellosis outbreak in Sweden: 108 cases were connected to a single restaurant. A spice mix, containing dried vegetables from the restaurant tested positive for the outbreak strain. Additional spice mixes with similar content from different suppliers also tested positive. The outbreak investigation suggests there could be a risk of contaminated products being also on the market in other countries. PMID- 26250071 TI - Future directions for the European influenza reference laboratory network in influenza surveillance. AB - By defining strategic objectives for the network of influenza laboratories that have national influenza centre status or national function within European Union Member States, Iceland and Norway, it is possible to align their priorities in undertaking virological surveillance of influenza. This will help maintain and develop the network to meet and adapt to new challenges over the next 3-5 years and underpin a longer-term strategy over 5-10 years. We analysed the key activities undertaken by influenza reference laboratories in Europe and categorised them into a framework of four key strategic objectives areas: enhancing laboratory capability, ensuring laboratory capacity, providing emergency response and translating laboratory data into information for public health action. We make recommendations on the priority areas for future development. PMID- 26250074 TI - Predicting the effects of copper on local population decline of 2 marine organisms, cobia fish and whiteleg shrimp, based on avoidance response. AB - The present study focuses on avoidance response to predict population decline of the marine fish Rachycentron canadum (cobia) and larvae of the estuarine shrimp Litopenaeus vannamei (whiteleg shrimp). Avoidance of approximately 60% was recorded for the cobia fry exposed to 1.0 mg Cu/L, 1.60 mg Cu/L, and 1.80 mg Cu/L. For the shrimp larvae, avoidance was approximately 80% for all Cu concentrations. The population decline of cobia fry was conditioned by avoidance in lower concentrations. However, in higher concentrations mortality begins to play an important role. The displacement toward uncontaminated habitats might determine shrimp population decline. A Cu-contaminated environment can determine the habitat selection of both species and, therefore, their local population decline. PMID- 26250075 TI - Capturing and displaying microscopic images used in medical diagnostics and forensic science using 4K video resolution - an application in higher education. AB - To analyze, interpret and evaluate microscopic images, used in medical diagnostics and forensic science, video images for educational purposes were made with a very high resolution of 4096 * 2160 pixels (4K), which is four times as many pixels as High-Definition Video (1920 * 1080 pixels). The unprecedented high resolution makes it possible to see details that remain invisible to any other video format. The images of the specimens (blood cells, tissue sections, hair, fibre, etc.) are recorded using a 4K video camera which is attached to a light microscope. After processing, this resulted in very sharp and highly detailed images. This material was then used in education for classroom discussion. Spoken explanation by experts in the field of medical diagnostics and forensic science was also added to the high-resolution video images to make it suitable for self study. PMID- 26250076 TI - Child oral health-related quality of life and early childhood caries: a non inferiority randomized control trial. AB - BACKGROUND: The aim of this study was to compare changes in child oral health related quality of life (COHRQoL) after treatment for early childhood caries (ECC) using two alternative treatment approaches. METHODS: A randomized control trial with random allocation of parent/child dyads with ECC to test (minimum intervention) or control (standard care). Participating parents completed the Early Childhood Oral Health Impact Scale (ECOHIS) at baseline and follow-up. Changes in ECOHIS scores and extent of COHRQoL impacts between and within groups were tested using the chi-squared statistic for groups, Wilcoxon's rank-sum test, and matched-pairs signed-rank test. RESULTS: Two hundred and fifty-four children were randomized (test = 127; control = 127). At baseline, mean ECOHIS score 11.1, sd 8.2; mean age = 3.8 years, sd 0.90; mean dmft = 4.9, sd 4.0; and 59% male. After a mean interval of 11.4 months, 210 children were followed-up and returned a completed questionnaire (test = 111; control = 99). There was no significant difference in COHRQoL changes between test and control. For all the children combined, there were significantly fewer impacts at follow-up in the child and family domains and the total ECOHIS, Wilcoxon signed-rank test, p < 0.05. CONCLUSIONS: COHRQoL improved with primary dental care for ECC, and there was no statistically significant difference between test and control in the extent of the improvement. PMID- 26250073 TI - The immunogenetics of primary biliary cirrhosis: A comprehensive review. AB - Primary biliary cirrhosis (PBC), a classic autoimmune liver disease, is characterised by a progressive T cell predominant lymphocytic cholangitis, and a serologic pattern of reactivity in the form of specific anti-mitochondrial antibodies (AMA). CD4+ T cells are particularly implicated by PBC's cytokine signature, the presence of CD4+ T cells specific to mitochondrial auto-antigens, the expression of MHC II on injured biliary epithelial cells, and PBC's coincidence with other similar T cell mediated autoimmune conditions. CD4+ T cells are also central to current animal models of PBC, and their transfer typically also transfers disease. The importance of genetic risk to developing PBC is evidenced by a much higher concordance rate in monozygotic than dizygotic twins, increased AMA rates in asymptomatic relatives, and disproportionate rates of disease in siblings of PBC patients, PBC family members and certain genetically defined populations. Recently, high-throughput genetic studies have greatly expanded our understanding of the gene variants underpinning risk for PBC development, so linking genetics and immunology. Here we summarize genetic association data that has emerged from large scale genome-wide association studies and discuss the evidence for the potential functional significance of the individual genes and pathways identified; we particularly highlight associations in the IL-12-STAT4-Th1 pathway. HLA associations and epigenetic effects are specifically considered and individual variants are linked to clinical phenotypes where data exist. We also consider why there is a gap between calculated genetic risk and clinical data: so-called missing heritability, and how immunogenetic observations are being translated to novel therapies. Ultimately whilst genetic risk factors will only account for a proportion of disease risk, ongoing efforts to refine associations and understand biologic links to disease pathways are hoped to drive more rational therapy for patients. PMID- 26250077 TI - Screening genes associated with myocardial infarction and transverse aortic constriction using a combined analysis of miRNA and mRNA microarray. AB - Myocardial infarction (MI) and transverse aortic constriction (TAC) are two models of cardiac hypertrophy. To study mechanisms of MI and TAC, GSE415 and GSE14267 were downloaded from Gene Expression Omnibus. GSE415 included left ventricle (LV) and intraventricular septum samples from mice that underwent MI, TAC or sham operation. GSE14267 included normal and MI samples from non transgenic mice. Differentially expressed genes (DEGs) and microRNAs (miRNAs) were screened using limma package. Functional enrichment analysis was performed for DEGs using DAVID. Common DEGs of different groups were conducted for protein protein interaction (PPI) analysis using STRING and visualized in PPI network by Cytoscape. Furthermore, targets were predicted for differentially expressed miRNAs using TarMir database. Totally, 277 DEGs, 31 common DEGs (e.g. SFRP2), 6 differentially expressed miRNAs (e.g. mmu-miR-448) and 1 miRNA-mRNA pair (mmu-miR 448->SIM2) were screened out. DEGs were significantly enriched in biological processes related to muscle development and ion transportation. In the PPI network for common DEGs, LOX (degree=7), POSTN (degree=5), SPARC (degree=4) and TIMP1 (degree=3) were with higher degrees. In addition, they might function by interacting with each other (e.g. LOX-TIMP1, LOX-POSTN, SPARC-TIMP1 and SPARC POSTN). In conclusion, LOX, POSTN, SPARC, TIMP1 and SFRP2 might affect MI and TAC.3. PMID- 26250078 TI - Effect of traditional processing methods on the beta-carotene, ascorbic acid and trypsin inhibitor content of orange-fleshed sweet potato for production of amala in Nigeria. AB - BACKGROUND: The aim of the work was to study the effect of traditional processing methods on the beta-carotene, ascorbic acid and trypsin inhibitor contents of orange-fleshed sweet potato amala. The most common sweet potato in Nigeria is white or yellow fleshed, which is very low in provitamin A. However, efforts are underway to promote orange-fleshed sweet potato to improve provitamin A intake. This paper describes how orange-fleshed sweet potato slices were traditionally processed into amala, which is increasingly consumed in Nigeria. RESULTS: The study revealed that both the cold and hot fermentation methods resulted in increased vitamin A levels and lower vitamin C levels in orange-fleshed sweet potato. Further processing to make amala resulted in a fall in both vitamin A and C content. The study found an increase in trypsin inhibitor activity following the cold-water fermentation and a decrease following the hot-water fermentation compared to raw orange-fleshed sweet potato. Trypsin inhibitor activity in amala produced using both the cold and hot methods was below detectable levels. CONCLUSION: The results indicate that amala produced from traditionally fermented orange-fleshed sweet potato could be a good source of vitamins A and C for the rural poor and that the processing removes any potential negative effects of trypsin inhibitors. (c) 2015 Society of Chemical Industry. PMID- 26250079 TI - Health information technology and Healthcare. PMID- 26250080 TI - Introduction. PMID- 26250081 TI - Supporting HITECH implementation and assessing lessons for the future: The role of program evaluation. AB - In addition to supporting the adoption and use of health IT, HITECH also included funds to support independent national program evaluation activities. The main challenges of evaluating health IT programs of the breadth and scale of the HITECH programs are the importance of context in the implementation and impact of the programs, the complexity and heterogeneity of the interventions, and the unpredictable nature of the innovative practices spurred by HITECH. The lessons learned include the importance of tailoring evaluation activities to each phase of implementation, flexible mixed methods, and continuous formative evaluation. PMID- 26250082 TI - Accelerating change: Fostering innovation in healthcare delivery at academic medical centers. AB - Academic medical centers (AMCs) have the potential to be leaders in the era of healthcare delivery reform, but most have yet to display a commitment to delivery innovation on par with their commitment to basic research. Several institutional factors impede delivery innovation including the paucity of adequate training in design and implementation of new delivery models and the lack of established pathways for academic career advancement outside of research. This paper proposes two initiatives to jumpstart disruptive innovation at AMCs: an institutional "innovation incubator" program and a clinician-innovator career track coupled with innovation training programs. PMID- 26250083 TI - Doubling down: Lessons learned from building a new electronic health record as part of primary care practice redesign. AB - Iora Health is a primary care delivery company creating de novo primary care practices with the mission of restoring humanity to health care. To support our very different and evolving model of team-based primary care we realized we needed to build our own electronic health record (EHR). This perspective shares four key lessons from the software development process: the tight relationship between delivery innovation and software development, the benefits of Agile development, the value of having the clinicians at all levels as part of the software development team, and different ways to think about clinical information. PMID- 26250084 TI - Physician leadership in changing times. AB - Today, hospitals and physicians are reorganizing themselves in novel ways to take advantage of payment incentives that reward shared accountability for the total health care experience. These delivery system changes will take place with our without physician leadership. To optimize change on behalf of patients, physicians must play a conscious role in shaping future health care delivery organizations. As physician leaders of three of the nation's largest integrated health care delivery systems - Kaiser Permanente, Virginia Mason Medical Center, and the Mayo Clinic Health System - we call on physicians to view leadership and the development of leaders as key aspects of their role as patient advocates. PMID- 26250085 TI - Worth a thousand words: Integrating clinical photographs into an electronic medical record. AB - Technological advances have made clinical photographs ubiquitous but the tremendous value of images is often burdened by concerns that are both legitimate and unsubstantiated. Compliant photos dramatically improve patient value and should be encouraged after adequate institutional preparation. As healthcare networks continue to transition to electronic medical records, clinicians and administrators should outline reasonable policies to integrate photos safely. PMID- 26250086 TI - Health information exchange among U.S. hospitals: who's in, who's out, and why? AB - BACKGROUND: A key goal of the 2009 HITECH Act is to ensure broad electronic exchange of clinical data among providers. We sought to assess whether current policy efforts, many of which are being developed by states, appear to be tackling key barriers to hospital participation in health information exchange (HIE). METHODS: We used the most recent national data from the American Hospital Association's IT Supplement to assess U.S. hospital participation in HIE and how participation varies by state. We then examined whether HIE is being pursued by all types of hospitals, or whether specific types of hospitals are not yet engaged. We focused on for-profit hospitals, those with smaller market share, and those in more competitive markets. RESULTS: We found that 30% of U.S. hospitals engaged in health information exchange with unaffiliated providers. There was large variation in state-level participation, with some states achieving more than 70% participation (Rhode Island, Delaware and Vermont) and others with minimal participation. In markets where exchange occurred, for-profit hospitals were far less likely to engage in HIE than non-profit hospitals (OR=0.17; p<0.001). Hospitals with a larger market share were more likely to engage in exchange (OR=2.05 for hospitals in the highest relative to the lowest quartile of market share; p<0.001), as were hospitals in less competitive markets (OR=2.15 for hospitals in the most relative to least concentrated market quartile; p=0.04). CONCLUSIONS: Despite an uptick in hospital HIE participation since the start of HITECH, the majority of hospitals still do not engage in HIE and there is large state-to-state variation. Specific types of hospitals appear to feel that they are better off not engaging in HIE. IMPLICATIONS: Stronger policies and incentives may be needed to convince organizations to share their data electronically. Pursuing these is critical to ensuring that the highly anticipated quality and efficiency gains from our large national investment in health information technology are realized. PMID- 26250087 TI - EHR adopters vs. non-adopters: Impacts of, barriers to, and federal initiatives for EHR adoption. AB - While adoption of electronic health record (EHR) systems has grown rapidly, little is known about physicians' perspectives on its adoption and use. Nationally representative survey data from 2011 are used to compare the perspectives of physicians who have adopted EHRs with those that have yet to do so across three key areas: the impact of EHRs on clinical care, practice efficiency and operations; barriers to EHR adoption; and factors that influence physicians to adopt EHRs. Despite significant differences in perspectives between adopters and non-adopters, the majority of physicians perceive that EHR use yields overall clinical benefits, more efficient practices and financial benefits. Purchase cost and productivity loss are the greatest barriers to EHR adoption among both adopters and non-adopters; although non-adopters have significantly higher rates of reporting these as barriers. Financial incentives and penalties, technical assistance, and the capability for electronic health information exchange are factors with the greatest influence on EHR adoption among all physicians. However, a substantially higher proportion of non-adopters regard various national health IT policies, and in particular, financial incentives or penalties as a major influence in their decision to adopt an EHR system. Contrasting these perspectives provides a window into how national policies have shaped adoption thus far; and how these policies may shape adoption in the near future. PMID- 26250088 TI - The effect of health information technology implementation in Veterans Health Administration hospitals on patient outcomes. AB - BACKGROUND: The impact of health information technology (HIT) in hospitals is dependent in large part on how it is used by nurses. This study examines the impact of HIT on the quality of care in hospitals in the Veterans Health Administration (VA), focusing on nurse-sensitive outcomes from 1995 to 2005. METHODS: Data were obtained from VA databases and original data collection. Fixed effects Poisson regression was used, with the dependent variables measured using the Agency for Healthcare Research and Quality Inpatient Quality Indicators and Patient Safety Indicators software. Dummy variables indicated when each facility began and completed implementation of each type of HIT. Other explanatory variables included hospital volume, patient characteristics, nurse characteristics, and a quadratic time trend. RESULTS: The start of computerized patient record implementation was associated with significantly lower mortality for two diagnoses but significantly higher pressure ulcer rates, and full implementation was associated with significantly more hospital-acquired infections. The start of bar-code medication administration implementation was linked to significantly lower mortality for one diagnosis, but full implementation was not linked to any change in patient outcomes. CONCLUSIONS: The commencement of HIT implementation had mixed effects on patient outcomes, and the completion of implementation had little or no effect on outcomes. IMPLICATIONS: This longitudinal study provides little support for the perception of VA staff and leaders that HIT has improved mortality rates or nurse-sensitive patient outcomes. Future research should examine patient outcomes associated with specific care processes affected by HIT. PMID- 26250089 TI - Meaningful use: Floor or ceiling? AB - BACKGROUND: In 2011, federal incentive payments for meaningful use of electronic health records (EHRs) began. This study evaluates the impact of the program on hospitals and EHR vendors, identifying how it affects EHR planning and development. Specifically, it assesses whether vendors and Chief Information Officers (CIOs) are viewing the meaningful use requirements as a floor - the minimally acceptable level of implementation, upon which development continues - or as a ceiling - the upper-bound on EHR development and implementation. METHODS: The study combines interviews with EHR vendors and hospital CIOs with EHR adoption data from American Hospital Association surveys. Results from interviews with 17 hospital and system CIOs (representing 144 individual acute-care hospitals) and 8 EHR development executives (representing two-thirds of installations) are detailed. Furthermore, it compares adoption of two key EHR functions, BCMA and CPOE, which are treated differently under stage 1 of the incentive program. RESULTS: Three key findings emerge from the study. First, meaningful use requirements can serve as either a floor or a ceiling, depending on the abilities of institutions implementing EHRs. Second, the increasing focus on achieving meaningful use across both hospitals and vendors risks missing the forest of health care system change through the trees of meeting discrete requirements. Third, while the meaningful use incentive program has accelerated the development and implementation of some key functions, it has also slowed development of others. CONCLUSIONS: Policy makers should craft subsequent stages of the incentive program to ensure smaller facilities and additional features necessary for health care system change are not left behind. PMID- 26250090 TI - A mobile health infrastructure to support underserved patients with chronic disease. AB - BACKGROUND: Chronic diseases are the global leading cause of death, but the US health system is poorly designed to support patients with chronic disease. Underserved patients report high rates of cell phone use and interest in using mobile technology for health care. A mobile health infrastructure may help transform health care delivery for underserved patients with chronic disease. PROBLEM: This study assessed the feasibility of integrating mobile health infrastructure with clinical information systems and the electronic medical record (EMR) to support patients with chronic disease through automated, bidirectional text messaging. GOALS: Three priority areas of chronic disease management were targeted. Existing self-management support was expanded, and new support for laboratory test scheduling and medication management was created. STRATEGY: Adult patients (n=135) with diabetes selected preferred content and scheduling for self-management message prompts. Outreach messages were sent to patients overdue for laboratory tests and medications. Manual review of pharmacy and laboratory outreach data was conducted for quality assurance. Focus groups were held to solicit patient perspectives. RESULTS: Patients sent over 6500 response messages with response rates of 53.7% (blood sugar), 48.8% (step counts), and 31.9% (blood pressure). Laboratory data integration was achieved, but pharmacy data gaps required ongoing manual review. Focus group participants reported improved self-management and information awareness. IMPLICATIONS: HIT was used to address dependency on visit-bound disease management in a novel, low cost way. Use of a mobile health infrastructure was feasible. Text messaging solutions may mitigate barriers to access and enhance support for patients with chronic disease. PMID- 26250091 TI - When scaling prevention means scaling demand: Voluntary medical male circumcision in Nyanza Province, Kenya. PMID- 26250092 TI - Kenya's voluntary male medical circumcision program: Translatable lessons for both domestic and international programs. AB - As a case of translating a healthcare intervention from randomized controlled trial to public health program, Kenya's voluntary male medical circumcision (VMMC) program offers an example of demand generation through active engagement with the population and reducing barriers to uptake. It illustrates various means by which the Kenyan leadership focused on demand generation which have value both domestically and internationally to healthcare leaders. Community and public engagement must start early and continue focused on key stakeholders and spokespersons. Barriers including cost, time, culture, and personal preference must be identified and addressed. This engagement and overall program must constantly be re-evaluated and shaped iteratively based on data. PMID- 26250093 TI - Interview with Aneesh Chopra, M.P.P. PMID- 26250094 TI - Interview with John Toussaint, MD. PMID- 26250095 TI - Comparative effectiveness research: Evidence, medicine, and policy. PMID- 26250096 TI - Neuronal map reveals the highly regionalized pattern of the juvenile central nervous system of the ascidian Ciona intestinalis. AB - BACKGROUND: The dorsally located central nervous system (CNS) is an important hallmark of chordates. Among chordates, tunicate ascidians change their CNS remarkably by means of a metamorphosis from a highly regionalized larval CNS to an oval-shaped juvenile CNS without prominent morphological features. The neuronal organization of the CNS of ascidian tadpole larvae has been well described, but that in the CNS of postmetamorphosis juveniles has not been characterized well. RESULTS: We investigated the number of neural cells, the number and position of differentiated neurons, and their axonal trajectories in the juvenile CNS of the ascidian Ciona intestinalis. The cell bodies of cholinergic, glutamatergic, and GABAergic/glycinergic neurons exhibited different localization patterns along the anterior-posterior axis in the juvenile CNS. Cholinergic neurons extended their axons toward the oral, atrial and body wall muscles and pharyngeal gill to regulate muscle contraction and ciliary movement. CONCLUSIONS: Unlike its featureless shape, the juvenile CNS is highly patterned along the anterior-posterior axis. This patterning may be necessary for exerting multiple roles in the regulation of adult tissues distributed throughout the body. This basic information of the juvenile CNS of Ciona will allow in-depth studies of molecular mechanisms underlying the reconstruction of the CNS during ascidian metamorphosis. PMID- 26250097 TI - Newly Emerged Porcine Deltacoronavirus Associated With Diarrhoea in Swine in China: Identification, Prevalence and Full-Length Genome Sequence Analysis. AB - To identify and characterize aetiologic agent(s) associated with an outbreak of a severe diarrhoea in piglets in Jiangxi, China, in March 2015, a nested reverse transcription-polymerase chain reaction (RT-PCR) for the detection of porcine deltacoronavirus (PDCoV) was developed. A survey based on the nested RT-PCR established indicated that the monoinfection of PDCoV (33.71%) and coinfection of PDCoV (19.66%) with porcine epidemic diarrhoea virus (PEDV) were common in diarrhoeal pigs in Jiangxi, China. A high prevalence of PDCoV (58.33%) in diarrhoeal samples which were PEDV negative was observed. The complete genome sequence of a representative PDCoV strain, PDCoV/CHJXNI2/2015, was determined. Phylogenetic analysis of complete genome and S protein sequences of PDCoV/CHJXNI2/2015 demonstrated that it was most closely related to Hong Kong and US PDCoVs. To our knowledge, this is the first report on the identification, prevalence, complete genome sequencing and molecular characterizations of PDCoV in diarrhoeal samples in pigs in China. PMID- 26250098 TI - Rare earth element-enriched yeast improved egg production and egg quality in laying hens in the late period of peak egg production. AB - The objective of this study was to determine the effects of rare earth element enriched yeast (RY) on egg production, coefficient of total tract apparent digestibility (CTTAD), egg quality, excreta gas emission and excreta microbiota of laying hens. A total of 216 ISA brown laying hens of 52 weeks of age were used in a 5-week feeding trial and data were collected every week. Birds were randomly allotted to three dietary treatments each with six replicates and 12 hens per replicate. Each cage (38 cm width * 50 cm length * 40 cm height) contained one hen. Treatments consisted of corn-soya bean meal-based diet supplemented with 0, 500 or 1000 mg/kg of RY. From weeks 55 to 56, inclusion of RY linearly increased (p < 0.05) egg production. The CTTAD of nitrogen was increased (linear, p < 0.05) with increasing dietary level of RY. In week 55, yolk height and Haugh units were increased linearly (p < 0.05) with increasing dietary RY content. However, no significant effects were observed in terms of excreta emissions and excreta microbiota in laying hens. In conclusion, dietary supplementation with RY improved egg production and CTTAD of nitrogen and slightly improved egg quality in laying hens of the late period of peak egg production. PMID- 26250100 TI - Editorial overview: Cell organelles: Organelle communication: new means and new views. PMID- 26250099 TI - Insights into colour-tuning of chlorophyll optical response in green plants. AB - First-principles calculations within the framework of real-space time-dependent density functional theory have been performed for the complete chlorophyll (Chl) network of the light-harvesting complex from green plants, LHC-II. A local-dipole analysis method developed for this work has made possible the studies of the optical response of individual Chl molecules subjected to the influence of the remainder of the chromophore network. The spectra calculated using our real-space TDDFT method agree with previous suggestions that weak interaction with the protein microenvironment should produce only minor changes in the absorption spectrum of Chl chromophores in LHC-II. In addition, relative shifting of Chl absorption energies leads the stromal and lumenal sides of LHC-II to absorb in slightly different parts of the visible spectrum providing greater coverage of the available light frequencies. The site-specific alterations in Chl excitation energies support the existence of intrinsic energy transfer pathways within the LHC-II complex. PMID- 26250101 TI - Successful displacement of a traumatic submacular hemorrhage in a 13-year-old boy treated by vitrectomy, subretinal injection of tissue plasminogen activator and intravitreal air tamponade: a case report. AB - BACKGROUND: The natural course of submacular hemorrhage resulting from traumatic choroidal rupture generally has a poor outcome unless treated. The intravitreal injection of gas only or gas with recombinant tissue plasminogen activator (rt PA) has been reported to be effective, but has also been reported to induce severe complications such as retinal detachment and vitreous hemorrhage. Recently, we reported a safe and effective procedure for treating submacular hemorrhage due to polypoidal choroidal vasculopathy (PCV) with a low dose of rt PA. Here we report the application of this procedure to a case of traumatic submacular hemorrhage in a 13-year-old boy, which achieved a good visual outcome. CASE PRESENTATION: A 13-year-old Japanese boy presented with a thick submacular hemorrhage in his left eye as a result of blunt trauma from being hit by a sinker. Best-corrected visual acuity (BCVA) was assessed as only able to perceive hand motions. We carried out a vitrectomy, subretinal injection of 4,000 IU rt-PA (6.9 MUg) and air tamponade. The day after surgery, most of the submacular hemorrhage had moved to the inferior periphery. One month after the surgery, we observed cataract formation, thin remnants of the submacular hemorrhage and juxtafoveal choroidal rupture. We carried out cataract surgery and injected bevacizumab intravitreally to prevent the development of choroidal neovascularization. Two months after the second surgery, the submacular hemorrhage had totally disappeared and the patient had a BCVA of 20/40. CONCLUSION: Vitrectomy, subretinal injection of rt-PA, and intravitreal air tamponade may be a promising strategy for treating traumatic submacular hemorrhage in young patients. PMID- 26250102 TI - Interventions for idiopathic intracranial hypertension. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) has an estimated incidence of one to three people per 100,000 people per year, and occurs most commonly in obese, young women. IIH is associated with severe morbidity, notably due to a significant threat to sight and severe headache. Several different management options have been proposed. Conservative measures centre on weight loss. Pharmacological therapy includes use of diuretics. Refractory and sight threatening cases demand surgical intervention, most often in the form of cerebrospinal fluid (CSF) diversion or optic nerve sheath fenestration. Other treatments include venous sinus stenting and bariatric surgery. OBJECTIVES: To assess the effects of any intervention for IIH in any patient group. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015 Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2015), EMBASE (January 1980 to July 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 22 July 2015. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) in which any intervention was compared to placebo, or to another form of treatment, for people with a clinical diagnosis of IIH. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the search results for trials to be included in the review. We resolved any discrepancies by third party decision. MAIN RESULTS: We identified two completed RCTs (enrolling a total of 211 participants and conducted in the UK and US) and two ongoing trials that met the inclusion criteria. Both completed trials compared acetazolamide to placebo, in conjunction with a weight loss intervention in both groups. Attrition bias was a problem in both trials with high loss to follow-up, in one study this loss to follow-up occurred particularly in the acetazolamide arm. One trial was unmasked and we judged it to be at risk of performance and detection bias.In these studies, change in visual acuity was similar in the treatment and control groups as measured by logMAR acuity. In one study people in the acetalomazide group had a similar change in logMAR acuity compared to the placebo group between baseline and 12 months in the right eye (MD 0.04 logMAR, 95% CI -0.08 to 0.16) and left eye (MD 0.03 logMAR, 95% CI -0.09 to 0.15). In the other study people in the acetalomazide group had a similar change in vision over six months compared with people in the placebo group (mean difference in change in letters read was 0.01 (95% CI -1.45 to 1.46). One study reported no cases of visual loss in 21 people treated with acetalomazide compared to 2/20 cases in the placebo group (odds ratio 0.17, 95% CI 0.01, 3.82).The prespecified outcome for this review was reduction in CSF pressure to normal levels which was not reported by the two trials. One trial reported that, in a subsample of 85 participants who agreed to lumbar puncture at 6 months, people in the acetalomazide group on average had a greater reduction in CSF pressure (MD 59.9 mmH(2)O, 95% CI -96.4, -23.4).In one study, people in the acetalozamide group on average experienced a greater reduction in papilloedema as assessed by fundus photographs MD -0.70 (95% CI -1.00 to -0.40) and by clinical grading MD 0.91 (95% CI -1.27 to -0.54) between baseline and six months in the study eye.Headache was recorded as present/absent in one study at 12 months (OR 0.42, 95% CI 0.12,1.41, 41 participants). Both studies reported headache on visual analogue scales (different ones) but results were inconclusive (MD for change in headache score measured on 10-point visual analogue scale at 12 months was 1.0 ( 1.80, 3.70, 41 participants) and MD for change in headache score on a 6 point scale measured at 6 months was -0.45 (-3.5,2.6, number of participants unclear).In one study, a similar proportion of people in the acetalomazide group were in remission (however, the trial authors did not state their definition of this term) at 12 months compared to the placebo group. However, the 95% CIs were wide and there is considerable uncertainty as to the effect (OR 1.13 (95% CI 0.32 to 3.90, 41 participants).In one study of 185 participants, people in the acetalomazide group had an increased risk of decreased CO2, diarrhoea, dysgeusia, fatigue, nausea, paresthesia, tinnitus and vomiting compared to people in the placebo group. In general, the estimates of effect were uncertain with wide 95% CIs. Adverse effects were not reported in the other study.One study reported that quality of life was better in acetazolamide-treated patients based on the visual quality of life (VFQ-25) (MD 6.35, 95% CI 2.22 to 10.47) and the physical (MD 3.02, 95% CI 0.34 to 5.70) and mental (MD 3.45, 95% CI 0.35 to 6.55) components of the 36-Item Short Form Health Survey tool at six months. Costs were not reported in either study.We judged the evidence to be low certainty (GRADE) downgrading for imprecision and risk of bias. AUTHORS' CONCLUSIONS: Although the two included RCTs showed modest benefits for acetazolamide for some outcomes, there is insufficient evidence to recommend or reject the efficacy of this intervention, or any other treatments currently available, for treating people with IIH. Further high-quality RCTs are required in order to adequately assess the effect of acetazolamide therapy in people with IIH. PMID- 26250103 TI - Anti-vascular endothelial growth factor for prevention of postoperative vitreous cavity haemorrhage after vitrectomy for proliferative diabetic retinopathy. AB - BACKGROUND: Postoperative vitreous cavity haemorrhage (POVCH) is a significant complication following vitrectomy for proliferative diabetic retinopathy (PDR). It delays visual recovery and can make further treatment difficult if the view of the fundus is significantly obscured. A number of interventions to reduce the incidence of POVCH have been proposed, including the perioperative use of anti vascular endothelial growth factor (anti-VEGF). Anti-VEGFs reduce vascular proliferation and the vascularity of neovascular tissue, which is often the source of bleeding following vitrectomy. OBJECTIVES: This updated review aimed to summarise the effects of anti-VEGF use to reduce the occurrence of POVCH after vitrectomy surgery for PDR. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015, Issue 4), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to May 2015), PubMed (January 1966 to May 2015), EMBASE (January 1980 to May 2015), Latin American and Caribbean Health Sciences (LILACS) (January 1982 to May 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 26 May 2015. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) and quasi-RCTs that looked at the use of anti VEGFs and the incidence of POVCH in people undergoing vitrectomy for PDR. DATA COLLECTION AND ANALYSIS: Both review authors independently assessed and extracted the data. We used standard methodological procedures expected by Cochrane.The primary outcomes of the review were the incidence of early and late POVCH following perioperative anti-VEGF administration. Secondary outcomes included best-corrected visual acuity at six months following surgery, the incidence of vitreous cavity washout or revision vitrectomy at six months, adverse effects of intervention (cataract, iris rubeosis and rubeotic glaucoma, retinal detachment, increased inflammation and systemic side effects), quality of life measures performed at least six months following vitrectomy, and density of POVCH. MAIN RESULTS: The current review included 12 RCTs that looked at the pre- or intraoperative use of intravitreal bevacizumab to prevent postoperative vitreous haemorrhage during pars plana vitrectomy for complications of PDR. The studies were conducted in a variety of countries (three from Iran, two from Italy, two from Egypt, and the remaining from South Korea, USA, Mexico, Pakistan, and Japan). The inclusion criteria for entry into the studies were standard complications of proliferative retinopathy: non-clearing vitreous haemorrhage, tractional retinal detachment involving the macula, or combined tractional rhegmatogenous detachment. The included studies randomised a total of 654 eyes. The average age of the participants was 54 years.We identified methodological issues in all included studies. Risk of bias was highest for masking of participants and investigators (four studies were an 'open label' design), and a number of studies were unclear when describing randomisation methods and sequence allocation.Participants receiving intravitreal bevacizumab in addition to pars plana vitrectomy were less likely to experience early POVCH (grade 2) compared to people undergoing pars plana vitrectomy alone (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.08 to 0.96, 2 studies, 144 eyes, high-quality evidence). This corresponds to an absolute effect of 130 fewer people (95% CI 167 fewer to 7 fewer) with early POVCH per 1000 people when treated with intravitreal bevacizumab. We saw similar results for all grades of POVCH (RR 0.35, 95% CI 0.23 to 0.53, 9 studies, 512 eyes) and when excluding cases where assessment of outcome was impossible due to presence of silicone oil (RR 0.34, 95% CI 0.19 to 0.60, 6 studies, 302 eyes).The effect of pre- or intraoperative intravitreal bevacizumab on the incidence of late postoperative haemorrhage was uncertain (RR 0.72, 95% CI 0.30 to 1.72, 3 studies, 196 eyes, low-quality evidence). The absolute effect was 55 fewer people (95% CI 138 fewer to 143 more) with late POVCH per 1000 people when treated with intravitreal bevacizumab. This outcome was rarer and was only reported in a few studies. We are currently unable to provide an estimate of the effect of intravitreal bevacizumab on postoperative visual acuity due to significant study heterogeneity.No local or systemic complications of intravitreal bevacizumab were reported by the RCTs. The risk of postoperative retinal detachment was lower in the participants treated with pre- or intraoperative bevacizumab (RR 0.46, 95% CI 0.19 to 1.08, 7 studies, 372 participants, low-quality evidence); the absolute effect was 49 fewer people (95% CI:73 fewer to 8 more) with postoperative retinal detachment per 1000 people when treated with intravitreal bevacizumab. AUTHORS' CONCLUSIONS: The use of pre- or intraoperative bevacizumab lowers the incidence of early POVCH. The reported complications from its use appear to be low. Futher randomised studies that look at other anti-VEGF medications are ongoing and will strengthen the current review findings, giving both surgeons and patients evidence to guide treatment choices in the management of proliferative retinopathy. PMID- 26250104 TI - Effects of total fat intake on body weight. AB - BACKGROUND: In order to prevent overweight and obesity in the general population we need to understand the relationship between the proportion of energy from fat and resulting weight and body fatness in the general population. OBJECTIVES: To assess the effects of proportion of energy intake from fat on measures of weight and body fatness (including obesity, waist circumference and body mass index) in people not aiming to lose weight, using all appropriate randomised controlled trials (RCTs) and cohort studies in adults, children and young people SEARCH METHODS: We searched CENTRAL to March 2014 and MEDLINE, EMBASE and CINAHL to November 2014. We did not limit the search by language. We also checked the references of relevant reviews. SELECTION CRITERIA: Trials fulfilled the following criteria: 1) randomised intervention trial, 2) included children (aged >= 24 months), young people or adults, 3) randomised to a lower fat versus usual or moderate fat diet, without the intention to reduce weight in any participants, 4) not multifactorial and 5) assessed a measure of weight or body fatness after at least six months. We also included cohort studies in children, young people and adults that assessed the proportion of energy from fat at baseline and assessed the relationship with body weight or fatness after at least one year. We duplicated inclusion decisions and resolved disagreement by discussion or referral to a third party. DATA COLLECTION AND ANALYSIS: We extracted data on the population, intervention, control and outcome measures in duplicate. We extracted measures of weight and body fatness independently in duplicate at all available time points. We performed random-effects meta-analyses, meta-regression, subgrouping, sensitivity and funnel plot analyses. MAIN RESULTS: We included 32 RCTs (approximately 54,000 participants) and 30 sets of analyses of 25 cohorts. There is consistent evidence from RCTs in adults of a small weight-reducing effect of eating a smaller proportion of energy from fat; this was seen in almost all included studies and was highly resistant to sensitivity analyses. The effect of eating less fat (compared with usual diet) is a mean weight reduction of 1.5 kg (95% confidence interval (CI) -2.0 to -1.1 kg), but greater weight loss results from greater fat reductions. The size of the effect on weight does not alter over time and is mirrored by reductions in body mass index (BMI) (-0.5 kg/m(2), 95% CI -0.7 to -0.3) and waist circumference (-0.3 cm, 95% CI -0.6 to 0.02). Included cohort studies in children and adults most often do not suggest any relationship between total fat intake and later measures of weight, body fatness or change in body fatness. However, there was a suggestion that lower fat intake was associated with smaller increases in weight in middle-aged but not elderly adults, and in change in BMI in the highest validity child cohort. AUTHORS' CONCLUSIONS: Trials where participants were randomised to a lower fat intake versus usual or moderate fat intake, but with no intention to reduce weight, showed a consistent, stable but small effect of low fat intake on body fatness: slightly lower weight, BMI and waist circumference compared with controls. Greater fat reduction and lower baseline fat intake were both associated with greater reductions in weight. This effect of reducing total fat was not consistently reflected in cohort studies assessing the relationship between total fat intake and later measures of body fatness or change in body fatness in studies of children, young people or adults. PMID- 26250105 TI - The association between septal deviation and the presence of a maxillary accessory ostium. AB - BACKGROUND: The etiology and the effects of the maxillary accessory ostium (MAO) are not well understood. The aim of this study is to investigate the association between septal deviation (SD) and the presence of an MAO. METHODS: Paranasal computed tomography (CT) scans of 1104 adult patients were studied retrospectively. Patients with chronic sinusitis, acute sinusitis, nasal polyposis, allergic rhinitis, paranasal sinus tumors, septal perforation, and unilateral or bilateral maxillary sinus hypoplasia/aplasia, as well as patients who had previously had nasal surgery or a history of nasal trauma, were not included in the study. Eight-hundred and seven patients were found to meet the criteria and were included in the study. CT scans were examined to note the presence of SD and MAO and the side of both diseases. RESULTS: A total of 807 patients were evaluated. SD and MAO were detected in 572 (70.9%) and 299 (37.1%) patients, respectively. A statistically significant relationship was found between the presence of SD and MAO, regardless of side of the disease (p = 0.002). The side of MAO showed a significant correlation with the direction of SD (p < 0.001). CONCLUSION: Our results revealed a link between SD and MAO. This relationship was correlated with the side of occurrence of the disease. PMID- 26250106 TI - Potential interaction between zinc ions and a cyclodextrin-based diclofenac formulation. AB - Complexes of diclofenac sodium (DF-Na) with hydroxypropyl betacyclodextrin (HPbetaCD) were prepared by co-evaporation in a 1:1 ratio and characterized in light of previously reported data. Phase solubility diagrams were obtained for DF Na with HPbetaCD in the presence and absence of zinc ions. Dissolution profiles were obtained for DF-Na and its HPbetaCD complex at acidic (pH 1.2) as well as in phosphate buffer (pH 6.8), in the presence and absence of zinc. HPbetaCD, as expected, was shown to improve the dissolution of DF-Na in acidic medium but not in phosphate buffer (pH 6.8). The presence of zinc ions decreased the in vitro dissolution of DF-HPbetaCD complex in acidic medium (pH 1.2) but not in phosphate buffer (pH 6.8). It was confirmed that the precipitate that was formed by zinc ions in the presence of HPbetaCD and DF-Na contained no cyclodextrin and most likely it was a mixture of the complexes: DF2-Zn and DF-Zn with some molecules of water. In vivo experiments on rats have shown that HPbetaCD has no statistically significant effect on absorption or bioavailability of DF-Na in spite of the observed improvement of its in vitro dissolution by HPbetaCD. Moreover, zinc ions were shown to decrease the absorption rate of DF-Na in rats model but did neither significantly alter the absorption nor bioavailability of DF-HPbetaCD complex. The zinc induced precipitates of DF were shown to have significantly different crystalline properties when HPbetaCD was present. Therefore, the pharmaceutical details of a DF-Na preparation should be considered when designing the formulation and predicting possible interaction between DF-Na (or other potential NSAIDs) and zinc metal. PMID- 26250107 TI - Experimental superposition of orders of quantum gates. AB - Quantum computers achieve a speed-up by placing quantum bits (qubits) in superpositions of different states. However, it has recently been appreciated that quantum mechanics also allows one to 'superimpose different operations'. Furthermore, it has been shown that using a qubit to coherently control the gate order allows one to accomplish a task--determining if two gates commute or anti commute--with fewer gate uses than any known quantum algorithm. Here we experimentally demonstrate this advantage, in a photonic context, using a second qubit to control the order in which two gates are applied to a first qubit. We create the required superposition of gate orders by using additional degrees of freedom of the photons encoding our qubits. The new resource we exploit can be interpreted as a superposition of causal orders, and could allow quantum algorithms to be implemented with an efficiency unlikely to be achieved on a fixed-gate-order quantum computer. PMID- 26250108 TI - Selection and identification of oleaginous yeast isolated from soil, animal feed and ruminal fluid for use as feed supplement in dairy cattle. AB - The purpose of this study was to select oleaginous yeast for microbial lipid production. Sixty-four yeast isolates were obtained from soil (GSY1-12), animal feeds (FDY1-21), and ruminal fluid (RMY1-31) using yeast extract peptone dextrose (YPD) agar. The cultivation of these isolates on nitrogen limited-medium revealed that GSY2 to GSY6, GSY10, FDY2, FDY12 and FDY14 accumulated lipid over 20% of dry biomass. Therefore, they were preliminarily classified as oleaginous yeast. In subsequent experiment, an 8 * 3 factorial in completely randomized design was conducted to examine the effect of eight oleaginous yeast strains and three nitrogen sources (peptone, (NH4 )2 SO4 , urea) on lipid accumulation when using molasses as substrate. The result illustrated that only GSY3 and GSY10 accumulated lipid over 20% of biomass when using peptone or (NH4 )2 SO4 but urea did not. However, GSY10 gave higher biomass and lipid yield than GSY3 (P < 0.05). Identification of GSY10 using 26S rDNA illustrated that GSY10 belongs to Trichosporon asahii. Fatty acid profiles of this strain contained unsaturated fats up to 62.5% of which oleic acid (C18:1 ) was predominant. In conclusion, T. asahii GSY10 was the most promising oleaginous yeast for microbial lipid production from molasses. SIGNIFICANCE AND IMPACT OF THE STUDY: This study illustrated the ability of T. asahii GSY10 to utilize molasses and (NH4 )2 SO4 for synthesizing and accumulating cellular lipid of which oleic acid (C18:1 ) was predominant. This yeast would be used for microbial lipid production used as feed supplement in dairy cattle. PMID- 26250109 TI - The FMRP/GRK4 mRNA interaction uncovers a new mode of binding of the Fragile X mental retardation protein in cerebellum. AB - Fragile X syndrome (FXS), the most common form of inherited intellectual disability, is caused by the silencing of the FMR1 gene encoding an RNA-binding protein (FMRP) mainly involved in translational control. We characterized the interaction between FMRP and the mRNA of GRK4, a member of the guanine nucleotide binding protein (G protein)-coupled receptor kinase super-family, both in vitro and in vivo. While the mRNA level of GRK4 is unchanged in the absence or in the presence of FMRP in different regions of the brain, GRK4 protein level is increased in Fmr1-null cerebellum, suggesting that FMRP negatively modulates the expression of GRK4 at the translational level in this brain region. The C terminal region of FMRP interacts with a domain of GRK4 mRNA, that we called G4RIF, that is folded in four stem loops. The SL1 stem loop of G4RIF is protected by FMRP and is part of the S1/S2 sub-domain that directs translation repression of a reporter mRNA by FMRP. These data confirm the role of the G4RIF/FMRP complex in translational regulation. Considering the role of GRK4 in GABAB receptors desensitization, our results suggest that an increased GRK4 levels in FXS might contribute to cerebellum-dependent phenotypes through a deregulated desensitization of GABAB receptors. PMID- 26250110 TI - Loss of EZH2 results in precocious mammary gland development and activation of STAT5-dependent genes. AB - Establishment and differentiation of mammary alveoli during pregnancy are controlled by prolactin through the transcription factors STAT5A and STAT5B (STAT5), which also regulate temporal activation of mammary signature genes. This study addressed the question whether the methyltransferase and transcriptional co activator EZH2 controls the differentiation clock of mammary epithelium. Ablation of Ezh2 from mammary stem cells resulted in precocious differentiation of alveolar epithelium during pregnancy and the activation of mammary-specific STAT5 target genes. This coincided with enhanced occupancy of these loci by STAT5, EZH1 and RNA Pol II. Limited activation of differentiation-specific genes was observed in mammary epithelium lacking both EZH2 and STAT5, suggesting a modulating but not mandatory role for STAT5. Loss of EZH2 did not result in overt changes in genome-wide and gene-specific H3K27me3 profiles, suggesting compensation through enhanced EZH1 recruitment. Differentiated mammary epithelia did not form in the combined absence of EZH1 and EZH2. Transplantation experiments failed to demonstrate a role for EZH2 in the activity of mammary stem and progenitor cells. In summary, while EZH1 and EZH2 serve redundant functions in the establishment of H3K27me3 marks and the formation of mammary alveoli, the presence of EZH2 is required to control progressive differentiation of milk secreting epithelium during pregnancy. PMID- 26250111 TI - High speed BLASTN: an accelerated MegaBLAST search tool. AB - Sequence alignment is a long standing problem in bioinformatics. The Basic Local Alignment Search Tool (BLAST) is one of the most popular and fundamental alignment tools. The explosive growth of biological sequences calls for speedup of sequence alignment tools such as BLAST. To this end, we develop high speed BLASTN (HS-BLASTN), a parallel and fast nucleotide database search tool that accelerates MegaBLAST--the default module of NCBI-BLASTN. HS-BLASTN builds a new lookup table using the FMD-index of the database and employs an accurate and effective seeding method to find short stretches of identities (called seeds) between the query and the database. HS-BLASTN produces the same alignment results as MegaBLAST and its computational speed is much faster than MegaBLAST. Specifically, our experiments conducted on a 12-core server show that HS-BLASTN can be 22 times faster than MegaBLAST and exhibits better parallel performance than MegaBLAST. HS-BLASTN is written in C++ and the related source code is available at https://github.com/chenying2016/queries under the GPLv3 license. PMID- 26250112 TI - Site specific replacements of a single loop nucleoside with a dibenzyl linker may switch the activity of TBA from anticoagulant to antiproliferative. AB - Many antiproliferative G-quadruplexes (G4s) arise from the folding of GT-rich strands. Among these, the Thrombin Binding Aptamer (TBA), as a rare example, adopts a monomolecular well-defined G4 structure. Nevertheless, the potential anticancer properties of TBA are severely hampered by its anticoagulant action and, consequently, no related studies have appeared so far in the literature. We wish to report here that suitable chemical modifications in the TBA sequence can preserve its antiproliferative over anticoagulant activity. Particularly, we replaced one residue of the TT or TGT loops with a dibenzyl linker to develop seven new quadruplex-forming TBA based sequences (TBA-bs), which were studied for their structural (CD, CD melting, 1D NMR) and biological (fibrinogen, PT and MTT assays) properties. The three-dimensional structures of the TBA-bs modified at T13 (TBA-bs13) or T12 (TBA-bs12), the former endowed with selective antiproliferative activity, and the latter acting as potently as TBA in both coagulation and MTT assays, were further studied by 2D NMR restrained molecular mechanics. The comparative structural analyses indicated that neither the stability, nor the topology of the G4s, but the different localization of the two benzene rings of the linker was responsible for the loss of the antithrombin activity for TBA-bs13. PMID- 26250113 TI - A conserved Polepsilon binding module in Ctf18-RFC is required for S-phase checkpoint activation downstream of Mec1. AB - Defects during chromosome replication in eukaryotes activate a signaling pathway called the S-phase checkpoint, which produces a multifaceted response that preserves genome integrity at stalled DNA replication forks. Work with budding yeast showed that the 'alternative clamp loader' known as Ctf18-RFC acts by an unknown mechanism to activate the checkpoint kinase Rad53, which then mediates much of the checkpoint response. Here we show that budding yeast Ctf18-RFC associates with DNA polymerase epsilon, via an evolutionarily conserved 'Pol epsilon binding module' in Ctf18-RFC that is produced by interaction of the carboxyl terminus of Ctf18 with the Ctf8 and Dcc1 subunits. Mutations at the end of Ctf18 disrupt the integrity of the Pol epsilon binding module and block the S phase checkpoint pathway, downstream of the Mec1 kinase that is the budding yeast orthologue of mammalian ATR. Similar defects in checkpoint activation are produced by mutations that displace Pol epsilon from the replisome. These findings indicate that the association of Ctf18-RFC with Pol epsilon at defective replication forks is a key step in activation of the S-phase checkpoint. PMID- 26250114 TI - Rationally evolving tRNAPyl for efficient incorporation of noncanonical amino acids. AB - Genetic encoding of noncanonical amino acids (ncAAs) into proteins is a powerful approach to study protein functions. Pyrrolysyl-tRNA synthetase (PylRS), a polyspecific aminoacyl-tRNA synthetase in wide use, has facilitated incorporation of a large number of different ncAAs into proteins to date. To make this process more efficient, we rationally evolved tRNA(Pyl) to create tRNA(Pyl-opt) with six nucleotide changes. This improved tRNA was tested as substrate for wild-type PylRS as well as three characterized PylRS variants (N(epsilon)-acetyllysyl-tRNA synthetase [AcKRS], 3-iodo-phenylalanyl-tRNA synthetase [IFRS], a broad specific PylRS variant [PylRS-AA]) to incorporate ncAAs at UAG codons in super-folder green fluorescence protein (sfGFP). tRNA(Pyl-opt) facilitated a 5-fold increase in AcK incorporation into two positions of sfGFP simultaneously. In addition, AcK incorporation into two target proteins (Escherichia coli malate dehydrogenase and human histone H3) caused homogenous acetylation at multiple lysine residues in high yield. Using tRNA(Pyl-opt) with PylRS and various PylRS variants facilitated efficient incorporation of six other ncAAs into sfGFP. Kinetic analyses revealed that the mutations in tRNA(Pyl-opt) had no significant effect on the catalytic efficiency and substrate binding of PylRS enzymes. Thus tRNA(Pyl-opt) should be an excellent replacement of wild-type tRNA(Pyl) for future ncAA incorporation by PylRS enzymes. PMID- 26250116 TI - Free energy landscape and transition pathways from Watson-Crick to Hoogsteen base pairing in free duplex DNA. AB - Houghton (HG) base pairing plays a central role in the DNA binding of proteins and small ligands. Probing detailed transition mechanism from Watson-Crick (WC) to HG base pair (bp) formation in duplex DNAs is of fundamental importance in terms of revealing intrinsic functions of double helical DNAs beyond their sequence determined functions. We investigated a free energy landscape of a free B-DNA with an adenosine-thymine (A-T) rich sequence to probe its conformational transition pathways from WC to HG base pairing. The free energy landscape was computed with a state-of-art two-dimensional umbrella molecular dynamics simulation at the all-atom level. The present simulation showed that in an isolated duplex DNA, the spontaneous transition from WC to HG bp takes place via multiple pathways. Notably, base flipping into the major and minor grooves was found to play an important role in forming these multiple transition pathways. This finding suggests that naked B-DNA under normal conditions has an inherent ability to form HG bps via spontaneous base opening events. PMID- 26250117 TI - Simultaneous measurement of passage through the restriction point and MCM loading in single cells. AB - Passage through the Retinoblastoma protein (RB1)-dependent restriction point and the loading of minichromosome maintenance proteins (MCMs) are two crucial events in G1-phase that help maintain genome integrity. Deregulation of these processes can cause uncontrolled proliferation and cancer development. Both events have been extensively characterized individually, but their relative timing and inter dependence remain less clear. Here, we describe a novel method to simultaneously measure MCM loading and passage through the restriction point. We exploit that the RB1 protein is anchored in G1-phase but is released when hyper-phosphorylated at the restriction point. After extracting cells with salt and detergent before fixation we can simultaneously measure, by flow cytometry, the loading of MCMs onto chromatin and RB1 binding to determine the order of the two events in individual cells. We have used this method to examine the relative timing of the two events in human cells. Whereas in BJ fibroblasts released from G0-phase MCM loading started mainly after the restriction point, in a significant fraction of exponentially growing BJ and U2OS osteosarcoma cells MCMs were loaded in G1-phase with RB1 anchored, demonstrating that MCM loading can also start before the restriction point. These results were supported by measurements in synchronized U2OS cells. PMID- 26250115 TI - FUS/TLS contributes to replication-dependent histone gene expression by interaction with U7 snRNPs and histone-specific transcription factors. AB - Replication-dependent histone genes are up-regulated during the G1/S phase transition to meet the requirement for histones to package the newly synthesized DNA. In mammalian cells, this increment is achieved by enhanced transcription and 3' end processing. The non-polyadenylated histone mRNA 3' ends are generated by a unique mechanism involving the U7 small ribonucleoprotein (U7 snRNP). By using affinity purification methods to enrich U7 snRNA, we identified FUS/TLS as a novel U7 snRNP interacting protein. Both U7 snRNA and histone transcripts can be precipitated by FUS antibodies predominantly in the S phase of the cell cycle. Moreover, FUS depletion leads to decreased levels of correctly processed histone mRNAs and increased levels of extended transcripts. Interestingly, FUS antibodies also co-immunoprecipitate histone transcriptional activator NPAT and transcriptional repressor hnRNP UL1 in different phases of the cell cycle. We further show that FUS binds to histone genes in S phase, promotes the recruitment of RNA polymerase II and is important for the activity of histone gene promoters. Thus, FUS may serve as a linking factor that positively regulates histone gene transcription and 3' end processing by interacting with the U7 snRNP and other factors involved in replication-dependent histone gene expression. PMID- 26250119 TI - Effect of insecticide-treated bed net usage on under-five mortality in northern Ghana. AB - BACKGROUND: Although under-five mortality rate seems to be declining in Ghana, the northern part of the country has higher levels of under-five mortality vis-a vis the national rates. This research examines the correlates of the high under five mortality among children in the northern part of Ghana, with emphasis on the usage of insecticide-treated bed net (ITN), as recommended by the World Health Organization. METHODS: A total of 3,839 under-five children sourced from the Ghana Demographic and Health Survey--was used for this study. Univariate descriptive statistics was employed to describe the variables used for the empirical estimation. The maximum likelihood estimation technique was used to estimate a logit model in other to determine the effect of insecticide treated bed net usage on under-five mortality. RESULTS: Insecticide-treated bed net usage among children enhances their survival rates. Thus, under-five mortality among children who sleep under treated bed nets is about 18.8% lower than among children who do not sleep under treated bed nets. While health facility delivery was found to reduce to reduce under-five mortality, child bearing among older women is detrimental to the survival of the child. CONCLUSIONS: The study, therefore, recommends that policies targeting reduction in under-five mortality in northern Ghana should consider not mere availability of ITNs in the household, but advocate the usage of these treated nets. The study recommends to the Ministry of Health to extend their services to unreached rural communities to encourage health facility delivery to reduce under-five mortality. PMID- 26250118 TI - Evaluation of rheumatoid factor and anti-citrullinated peptide antibodies in relation to rheumatological manifestations in patients with leprosy from Southern Brazil. AB - BACKGROUND: Leprosy patients may present several osteoarticular complaints, which require further evaluation of inflammatory diseases, such as rheumatoid arthritis (RA). Therefore, an adequate clinical assessment in addition to testing for rheumatoid factors (RF) and anticyclic citrullinated peptide antibodies (anti CCP), can be useful in order to establish the correct diagnosis. METHOD: In this study, the relation of RF and anti-CCP with rheumatological manifestations was evaluated in 97 leprosy patients from Southern Brazil. The results were compared to RA patients and healthy controls from the same geographical area and ethnic background. RESULTS: Neuropathy was observed in 71.1% and arthritis in 35.1% of the leprosy patients. A high frequency of RF positivity was observed among the leprosy patients (41.2%, 40/97), with RF immunoglobulin A (IgA) significantly associated with arthritis (OR = 7.9, 95% CI = 1.5-40.6 P = 0.008). Anti-CCP was observed in 9.3% (9/97) of the patients, with anti-CCP2 being the most frequent subtype. Only 4.1% (4/97) of the patients were RF and anti-CCP concomitantly positive. RF IgM showed a significant association with leprosy when compared to healthy controls (P < 0.0001) whereas for anti-CCP2 no significant results were observed (P = 0.0585). However, both biomarkers showed a strong association with RA when compared to leprosy in patients from the same geographical area and ethnic background (anti-CCP2 OR = 38.6; 95% CI = 16.49-90.26; P < 0.0001 and RF IgM OR = 4.51; 95% CI = 2.62-7.77; P < 0.0001). CONCLUSION: Due to the similarity of some rheumatological manifestations in leprosy with other inflammatory diseases, such as RA, clinical and laboratorial evaluation of affected patients must be carefully assessed in order to achieve proper diagnosis and treatment. PMID- 26250120 TI - Nitrile Oxide-Norbornene Cycloaddition as a Bioorthogonal Crosslinking Reaction for the Preparation of Hydrogels. AB - This communication describes the first application of cycloaddition between an in situ generated nitrile oxide with norbornene leading to a polymer crosslinking reaction for the preparation of poly(ethylene glycol) hydrogels under physiological conditions. Hydrogels with high water content and robust physical strength are readily formed within 2-5 min by a simple two-solution mixing method which allows 3D encapsulation of neuronal cells. This bioorthogonal crosslinking reaction provides a simple yet highly effective method for preparation of hydrogels to be used in bioengineering. PMID- 26250122 TI - Itching sensation and neuronal sensitivity of the skin. AB - BACKGROUND: Sensitive skin is a universal term in the field of cosmetology. In addition, the development and demand for sensitive skin cosmetics is increasing. However, there is no appropriate method for detecting sensitive skin. METHODS: We analyzed the relationship between the frequency of response at each sensation (stinging, burning, and itching) during a lactic acid sting test and the current perception threshold (CPT) value of each frequency. To reconfirm this relationship, we analyzed differences of the CPT value (5 Hz) between the itch responder and non-itch responder groups. RESULTS: There is a significant correlation between itch sensation and CPT values of 5 Hz. The itch responder group showed significantly lower sensory perception value of 5 Hz than the non itch responder group. CONCLUSION: The CPT value (5 Hz) can be used for scanning for itching sensations when a cosmetic or its ingredients possibly cause the sensation. PMID- 26250121 TI - Evaluation of the Cortisol-to-ACTH Ratio in Dogs with Hypoadrenocorticism, Dogs with Diseases Mimicking Hypoadrenocorticism and in Healthy Dogs. AB - BACKGROUND: The adrenocorticotropic hormone (ACTH) stimulation test is the gold standard for diagnosing hypoadrenocorticism (HA) in dogs. However, problems with the availability of synthetic ACTH (tetracosactrin/cosyntropin) and increased costs have prompted the need for alternative methods. OBJECTIVES: To prospectively evaluate the cortisol-to-ACTH ratio (CAR) as a screening test for diagnosing canine HA. ANIMALS: Twenty three dogs with newly diagnosed HA; 79 dogs with diseases mimicking HA; 30 healthy dogs. METHODS: Plasma ACTH and baseline cortisol concentrations were measured before i.v. administration of 5 MUg/kg ACTH in all dogs. CAR was calculated and the diagnostic performance of ACTH, baseline cortisol, CAR and sodium-to-potassium ratios (SPRs) was assessed based on receiver operating characteristics (ROC) curves calculating the area under the ROC curve. RESULTS: The CAR was significantly lower in dogs with HA compared to that in healthy dogs and in those with diseases mimicking HA (P < .0001). There was an overlap between HA dogs and those with HA mimicking diseases, but CAR still was the best parameter for diagnosing HA (ROC AUC 0.998), followed by the ACTH concentration (ROC AUC 0.97), baseline cortisol concentration (ROC AUC 0.96), and SPR (ROC AUC 0.86). With a CAR of >0.01 the diagnostic sensitivity and specificity were 100% and 99%, respectively. CONCLUSION AND CLINICAL IMPORTANCE: Calculation of the CAR is a useful screening test for diagnosing primary HA. As a consequence of the observed overlap between the groups, however, misdiagnosis cannot be completely excluded. Moreover, additional studies are needed to evaluate the diagnostic reliability of CAR in more dogs with secondary HA. PMID- 26250123 TI - Epigenetic silencing of NDRG2 promotes colorectal cancer proliferation and invasion. AB - BACKGROUND: Genome-wide methylation arrays have revealed aberrant methylation of N-Myc downstream-regulated gene 2 (NDRG2) promoter in colorectal cancer (CRC). This study investigated the role of NDRG2 in colorectal carcinogenesis. METHODS: The aberrant promoter methylation, mRNA, and protein expression of NDRG2 were evaluated in 27 pairs of human CRC and adjacent normal tissues and seven human CRC-derived cell-lines. After stable NDRG2 over-expressed RKO and DLD-1 human CRC cell-lines were constructed, in vitro functional assays, including colony formation, cell viability, proliferation, invasion and migration assays, and in vivo xenograft models were performed. RESULTS: The promoter of NDRG2 was methylated in 89% human CRC tissue compared to adjacent normal colonic mucosa (7.4%; P < 0.001). High-level methylation of NDRG2 promoter was more prevalent in proximal CRC (P = 0.022) and advanced T stage (P = 0.039). NDRG2 mRNA and protein expression was down-regulated in 89% and 100% human CRC tissue, respectively. In human CRC cell-lines, the promoter of NDRG2 was methylated aberrantly and mRNA, and protein expression of NDRG2 was down-regulated. NDRG2 mRNA expression was reactivated by 5-aza-2'-deoxycytidine. Colony formation of NDRG2 over-expressing RKO cells was inhibited (P = 0.012), as was the viability, proliferation, and invasion of NDRG2 over-expressing DLD-1 cells (P < 0.001, P = 0.003, and P = 0.044, respectively). Tumor volume in xenograft mice transplanted with NDRG2 over expressing RKO and DLD-1 cells was smaller than that in controls (P = 0.002 and P = 0.001, respectively). CONCLUSIONS: Epigenetic silencing of NDRG2 induces proliferation and invasion of CRC and may be associated with proximal CRC and advanced T stage. NDRG2 methylation might serve as novel biomarker of CRC. PMID- 26250124 TI - [Pancreatic cancer precursor lesions]. PMID- 26250125 TI - [Chronic pancreatitis is a risk factor of pancreatic cancer]. PMID- 26250127 TI - [Familial pancreatic cancer]. PMID- 26250126 TI - [IPMN and pancreatic cyst as high risk of pancreatic cancer]. PMID- 26250128 TI - [The strategy of pancreatic cancer for early detection]. PMID- 26250129 TI - [Characteristics of group A patients according to the ABC classification for gastric cancer risk screening]. AB - In the ABC classification for gastric cancer risk screening, group A (Helicobacter pylori infection-negative, pepsinogen [PG]-negative) patients are assumed to be at low risk, but some patients do have atrophic gastritis and H. pylori infection. This study aimed to identify the characteristics of group A patients. Healthy adults in Yamagata City who underwent barium radiography and ABC classification participated in the survey. Patient radiographs were randomly interspersed and reviewed by two gastroenterologists who were blinded to the H. pylori and PG statuses. Group A patients (n=1462) was subclassified as follows: atrophic gastritis group, 21.5%; intermediate group, 15.7%; and no atrophic gastritis group, 62.8%. Elderly subjects and those with H. pylori antibody titers of 3.0-9.9U/ml should be carefully evaluated while interpreting the results of the ABC classification for gastric cancer risk screening. PMID- 26250130 TI - [Long-term survival of a patient with stage IV basaloid squamous carcinoma of the esophagus with lung metastases following combined modality therapy]. AB - A 72-year-old man visited our hospital because of dysphagia and weight loss. He was diagnosed by endoscopy with advanced (stage IV) basaloid squamous carcinoma of the thoracic esophagus. CT and CT-guided tumor biopsy revealed two lung metastases in the right upper and lower lobes, with diameters of 8 and 5 mm, respectively. The primary lesion disappeared after concurrent chemoradiotherapy consisting of 5-FU, cisplatin, and 60-Gy irradiation, which was administered for palliation of obstructive and hemorrhagic symptoms. Subsequently, eight cycles of chemotherapy were administered, resulting in a reduction in size of the metastases. However, multiple cycles of chemotherapy caused prolonged toxicity, and the metastases slightly enlarged during chemotherapy-free periods. Since the number of metastases did not change, stereotactic body radiotherapy was performed, which resulted in disappearance of the lung metastases. Five years following initial diagnosis, the patient has been doing well, with no signs of disease recurrence. PMID- 26250131 TI - [A case of undifferentiated gastric cancer that recurred with portal vein tumor thrombus]. AB - A 69-year-old man with a malignant tumor of the stomach underwent distal gastrectomy with partial resection of the abdominal wall, transverse colon, and lateral segment of the liver. Based on a detailed pathological examination of the resected specimen, a diagnosis of undifferentiated gastric cancer was established. Six months after the operation, during postoperative adjuvant chemotherapy with S-1, diagnostic imaging, including CT and positron emission tomography (PET), revealed a portal vein tumor thrombus and diffusely spreading metastases in the posterior segment of the liver. Despite chemotherapy with S 1/CDDP, the metastatic tumors continued to grow rapidly. The patient died 10 months after the operation. On autopsy, the portal vein tumor thrombus was observed to be composed of undifferentiated cancer cells invading into the liver parenchyma through hepatic sinusoids, with the metastatic tumors replacing 60% or more of the entire liver. PMID- 26250132 TI - [A case of polyp-type ampullary carcinoma-in-adenoma within the ampullary channel, displaying an intraductal growth pattern]. AB - A 70-year-old woman with jaundice was referred to our hospital. Obstructive jaundice caused by common bile duct (CBD) stones was diagnosed based on the results of blood tests, abdominal computed tomography, and endoscopic retrograde cholangiopancreatography. We attempted to remove the CBD stones endoscopically. After endoscopic sphincterotomy, a polypoid lesion was exposed at the ampulla of Vater. Histological examination of a biopsy specimen from the ampullary lesion revealed a tubular adenoma, and the patient underwent pylorus-preserving pancreatoduodenectomy. Pathological examination of the resected specimen revealed a polyp-type ampullary carcinoma-in-adenoma arising from the ampullary channel. Herein, we report a rare case of polyp-type ampullary carcinoma-in-adenoma displaying an intraductal growth pattern. PMID- 26250133 TI - [A case of liver abscess due to Streptococcus anginosus infection secondary to a dental extraction]. AB - A 74-year-old man was referred to our hospital because of a high fever. He had undergone a dental extraction about 1 month prior to admission because of apical periodontitis. Imaging study revealed liver abscess lesions. Infection with Streptococcus anginosus was confirmed using both stab and blood culture. An adequate selection of antibiotics was administered, and a good outcome was obtained. There have been no case reports of liver abscess caused by intraoral commensal flora related to dental extraction in healthy adults. This case shows that liver abscesses can occur secondary to dental extractions, even in healthy adults. PMID- 26250134 TI - [Two cases of acute hepatitis E infected with descendant strains of hepatitis E virus genotype 3 strain isolated from swine herd in Miyazaki Prefecture 12 years ago - one case had acute facial paralysis]. AB - We experienced two cases of acute hepatitis E in Miyazaki Prefecture in the same period. The patients were unknown to each other and did not have any clear causes or common risk factors of hepatitis E virus (HEV) infection. Nucleotide sequences of the HEV isolates revealed that the two isolates were closely related but with different HEV genotype 3 strains. The two cases appeared to be infected from unknown and different sources. Molecular phylogenetic analysis indicated that the strains were probably descendants of the strains which had been isolated from swine herd in Miyazaki Prefecture 12 years previously. This result indicates that the strains persisted in pig farms, in wild life, or in the natural environment in this region. The source should be identified, and efforts should be made to prevent of the spread of the infection. One of the cases had acute facial paralysis, which might be an extra-hepatic manifestation of HEV infection. PMID- 26250135 TI - Deliberate ROS production and auxin synergistically trigger the asymmetrical division generating the subsidiary cells in Zea mays stomatal complexes. AB - Subsidiary cell generation in Poaceae is an outstanding example of local intercellular stimulation. An inductive stimulus emanates from the guard cell mother cells (GMCs) towards their laterally adjacent subsidiary cell mother cells (SMCs) and triggers the asymmetrical division of the latter. Indole-3-acetic acid (IAA) immunolocalization in Zea mays protoderm confirmed that the GMCs function as local sources of auxin and revealed that auxin is polarly accumulated between GMCs and SMCs in a timely-dependent manner. Besides, staining techniques showed that reactive oxygen species (ROS) exhibit a closely similar, also time dependent, pattern of appearance suggesting ROS implication in subsidiary cell formation. This phenomenon was further investigated by using the specific NADPH oxidase inhibitor diphenylene iodonium, the ROS scavenger N-acetyl-cysteine, menadione which leads to ROS overproduction, and H2O2. Treatments with diphenylene iodonium, N-acetyl-cysteine, and menadione specifically blocked SMC polarization and asymmetrical division. In contrast, H2O2 promoted the establishment of SMC polarity and subsequently subsidiary cell formation in "younger" protodermal areas. Surprisingly, H2O2 favored the asymmetrical division of the intervening cells of the stomatal rows leading to the creation of extra apical subsidiary cells. Moreover, H2O2 altered IAA localization, whereas synthetic auxin analogue 1-napthaleneacetic acid enhanced ROS accumulation. Combined treatments with ROS modulators along with 1-napthaleneacetic acid or 2,3,5-triiodobenzoic acid, an auxin efflux inhibitor, confirmed the crosstalk between ROS and auxin functioning during subsidiary cell generation. Collectively, our results demonstrate that ROS are critical partners of auxin during development of Z. mays stomatal complexes. The interplay between auxin and ROS seems to be spatially and temporarily regulated. PMID- 26250136 TI - CORR Insights: Patients Undergoing Total Shoulder Arthroplasty on the Dominant Extremity Attain Greater Postoperative ROM. PMID- 26250137 TI - Factors Associated With Reoperation After Fixation of Displaced Olecranon Fractures. AB - BACKGROUND: Surgery for fixation of olecranon fractures is associated with reoperation, mostly for implant removal. A study of a large cohort of patients treated by many different surgeons allows us to determine if specific techniques or implants are associated with a higher rate of reoperation. QUESTIONS/PURPOSES: After open reduction and internal fixation of isolated olecranon fractures, what factors are associated with (1) reoperation and (2) implant removal? METHODS: Three hundred ninety-two adult patients who had operative treatment of a displaced olecranon fracture not associated with other fractures, dislocation, or subluxation at two area hospitals between January 2002 and May 2014 were analyzed to determine factors associated with reoperation. One hundred thirty-eight (35%) patients had plate and screw fixation and 254 (65%) tension band wiring. Nearly 100% of patients with displaced olecranon fractures are currently treated operatively at our hospitals. All patients were followed for at least four months. Two hundred three of the 392 (52%) patients were followed for one year or more. Ninety-nine patients (25%) had a second operation, 92 (93%) at least in part for implant removal (12 for wire migration [3% of all fractures, 12% of reoperations]). We considered patient-related, fracture-related, and implant related endpoints as possible factors associated with reoperation. With a total sample size of 99 reoperations, an alpha of 0.05, and an effect size of 0.3, we had 87% power. RESULTS: Reoperation was less common in men (36 [36%], women: 63 [64%]; adjusted odds ratio, 0.32; 95% confidence interval, 0.18-0.56; p < 0.001) and older patients (adjusted odds ratio, 0.75; 95% confidence interval, 0.65 0.87; p < 0.001). Similarly, request for implant removal was less in men (33 [36%], women: 59 [64%], adjusted odds ratio, 0.31; 95% confidence interval, 0.18 0.56; p < 0.001) and older patients (adjusted odds ratio, 0.75; 95% confidence interval, 0.65-0.87; p < 0.001). CONCLUSIONS: Patients who have operative fixation of a fracture of the olecranon can be counseled that most patients keep their implants, that only 3% experience implant migration, and that technical factors such as the type or configuration of an implant seem less important than personal factors in determining who requests a second surgery for implant removal. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 26250138 TI - Orthopaedic Healthcare Worldwide: The Role of Standardization in Improving Outcomes. PMID- 26250140 TI - Atomistic Characterization of the First Step of Calcium Pump Activation Associated with Proton Countertransport. AB - The calcium pump [sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA)] transports Ca(2+) from the cytosol to the SR lumen at the expense of ATP hydrolysis and proton countertransport, thus playing a central role in Ca(2+) homeostasis and muscle contractility. Proton countertransport via deprotonation of transport site residue Glu309 is a critical first step in SERCA activation because it accelerates the E2-E1 structural transition. Previous studies have suggested that flipping of Glu309 toward the cytosol constitutes the primary mechanism for Glu309 deprotonation, but no conclusive data to support this hypothesis have been published. Therefore, we performed three independent 1 MUs molecular dynamics simulations of the E2 state protonated at transport site residues Glu309, Glu771, and Glu908. Structural analysis and pKa calculations showed that Glu309 deprotonation occurs by an inward-to-outward side-chain transition. We also found that Glu309 deprotonation and proton countertransport occur through transient (~113 ps) water wires connecting Glu309 with the cytosol. Although both mechanisms are operational, we found that transient water wire formation, and not Glu309 flipping, is the primary mechanism for Glu309 deprotonation and translocation of protons to the cytosol. The outward-to-inward transition of protonated Glu309 and the presence of water wires suggest that protons from the cytosol might be passively transported to the lumen via Glu309. However, structural analysis indicates that passive SR proton leakage into the lumen unlikely occurs through Glu309 in the E2 state. These findings provide a time resolved visualization of the first step in the molecular mechanism of SERCA activation and proton transport across the SR. PMID- 26250141 TI - Prevalence of depressive symptoms and suicidal thoughts among elderly persons in rural Bangladesh. AB - BACKGROUND: Depression, if broadly defined, is the commonest late-life mental disorder. We examined the distribution of depressive symptoms and suicidal thoughts, across age, sex, literacy, and marital status, among elderly individuals residing in rural Bangladesh and participating in a population-based study on health and aging. METHODS: Prevalence figures of depressive symptoms were assessed with SRQ20 (n = 625), and possible social network and economic associations were examined. Morbidity accounts of depressive symptoms and suicidal thoughts were examined for a subsample that also underwent complete medical examination (n = 471). RESULTS: We selected for analyses the items that corresponded to DSM-IV criteria and constructed a dichotomous variable. The prevalence was 45%, and most pronounced among the oldest women (70%). The overall prevalence of suicidal thoughts was 23%. Being a woman, illiterate or single were all risk factors for depressive symptoms and suicidal thoughts. These associations remained unaccounted for by the social network and economic variables. Co-residing with a child and having a high quality of contact were protective of both depressive symptoms and suicidal thoughts. The main findings were replicated in the subsample, where it was found that morbidities were also associated with the outcomes, independently of the four main predictors. CONCLUSIONS: Prevalence figures for depressive symptoms among elderly in rural Bangladesh are high. Demographic, social network, and morbidity factors are independently associated with both depressive symptoms and suicidal thoughts. This is the first study to report prevalence figures for depressive symptoms in this population. PMID- 26250139 TI - Is Arthroscopic Bone Graft and Fixation for Scaphoid Nonunions Effective? AB - BACKGROUND: Arthroscopic management of scaphoid nonunions has been advanced as a less invasive technique that allows evaluation of associated intrinsic and extrinsic ligamentous injuries; however, few studies have documented the effectiveness of arthroscopic treatment of scaphoid nonunions and which intraarticular pathologies coexist with scaphoid nonunions. QUESTIONS/PURPOSES: (1) What are the outcomes of arthroscopic management of scaphoid nonunions as assessed by the proportion of patients achieving osseous union, visual analog scale (VAS) pain score, grip strength, range of motion, Mayo Wrist Score (MWS), and Disabilities of the Arm, Shoulder and Hand (DASH) score? (2) What complications are associated with arthroscopic scaphoid nonunion management? (3) What forms of intraarticular pathology are associated with scaphoid nonunions? METHODS: Between 2008 and 2012, we treated 80 patients surgically for scaphoid nonunions. Of those, 45 (56%) had arthroscopic management. During that time, our general indications for using an arthroscopic approach over an open approach were symptomatic scaphoid nonunions without necrosis of the proximal fragment, severe deformities, or arthritis. Of the patients treated arthroscopically, 33 (73%) were available for followup at least 2 years later. There were five distal third, 19 middle third, and nine proximal third fractures. The mean followup was 33 months (range, 24-60 months). Union was determined by CT taken at 8 to 10 weeks after operation with bridging trabecula at nonunion site. VAS pain scores, grip strength, active flexion-extension angle, MWS, and DASH scores were obtained preoperatively and at each followup visit. The coexisting intraarticular pathologies and complications were also recorded. RESULTS: Thirty-two (97%) scaphoid nonunions healed successfully. At the last followup, the mean VAS pain score decreased (preoperative: mean 4.5 [SD 1.8], postoperative: mean 0.6 [SD 0.8], mean difference: 3.9 [95% confidence interval {CI}, 3.2-4.6], p < 0.001) and the mean active flexion-extension angle increased (preoperative: mean 100 degrees [SD 26], postoperative: mean 109 degrees [SD 16], mean difference: 9 degrees [95% CI, 2-16], p = 0.017). The mean grip strength increased (preoperative: mean 35 kg of force [SD 8], postoperative: mean 50 kg of force [SD 10], mean difference: 15 kg of force [95% CI, 11-19], p < 0.001). The mean MWS increased (preoperative: mean 56 [SD 23], postoperative: mean 89 [SD 8], mean difference: 33 [95% CI, 26-41], p < 0.001) and the mean DASH score decreased (preoperative: mean 25 [SD 18], postoperative: mean 4 [SD 3], mean difference: 21 [95% CI, 15-28], p < 0.001). There were no operation-related complications and no progression of arthritis at the last followup. Seventeen patients had coexisting intraarticular pathology, including nine triangular fibrocartilage complex tears (seven traumatic and two degenerative), 17 intrinsic ligament tears (nine scapholunate interosseous ligament tears and eight lunotriquetral interosseous ligament tears), and five mild radioscaphoid degenerative changes. CONCLUSIONS: Arthroscopic management of scaphoid nonunions without severe deformities or arthritis was effective in this small series. Although intraarticular pathologies such as triangular fibrocartilage complex tears and intrinsic ligament injuries commonly coexisted with scaphoid nonunions, patients generally achieved good results. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26250142 TI - Comparison of data mining and allometric model in estimation of tree biomass. AB - BACKGROUND: The traditional method used to estimate tree biomass is allometry. In this method, models are tested and equations fitted by regression usually applying ordinary least squares, though other analogous methods are also used for this purpose. Due to the nature of tree biomass data, the assumptions of regression are not always accomplished, bringing uncertainties to the inferences. This article demonstrates that the Data Mining (DM) technique can be used as an alternative to traditional regression approach to estimate tree biomass in the Atlantic Forest, providing better results than allometry, and demonstrating simplicity, versatility and flexibility to apply to a wide range of conditions. RESULTS: Various DM approaches were examined regarding distance, number of neighbors and weighting, by using 180 trees coming from environmental restoration plantations in the Atlantic Forest biome. The best results were attained using the Chebishev distance, 1/d weighting and 5 neighbors. Increasing number of neighbors did not improve estimates. We also analyze the effect of the size of data set and number of variables in the results. The complete data set and the maximum number of predicting variables provided the best fitting. We compare DM to Schumacher-Hall model and the results showed a gain of up to 16.5% in reduction of the standard error of estimate. CONCLUSION: It was concluded that Data Mining can provide accurate estimates of tree biomass and can be successfully used for this purpose in environmental restoration plantations in the Atlantic Forest. This technique provides lower standard error of estimate than the Schumacher-Hall model and has the advantage of not requiring some statistical assumptions as do the regression models. Flexibility, versatility and simplicity are attributes of DM that corroborates its great potential for similar applications. PMID- 26250143 TI - Valproate modulates glucose metabolism in patients with epilepsy after first exposure. AB - Valproate (VPA) treatment has been reported to be associated with weight gain and metabolic changes, such as hyperinsulinemia. The question of whether hyperinsulinemia and other metabolic changes are consequences of increased weight, or are instead direct results of VPA treatment, remains a matter of debate. The aim of the current study was to explore the influence of VPA treatment on glucose and insulin levels during the oral glucose tolerance test (OGTT) directly following the first intravenous (IV) administration. Sixteen patients (18-46 years old) with newly diagnosed epilepsy underwent an OGTT with 75 g glucose prior to the start of VPA treatment, as well as directly following the first IV VPA administration. We observed that plasma glucose levels during the 120 min of OGTT session following infusion of VPA were significantly lower than those measured during OGTT without VPA treatment (mean +/- standard deviation [SD] 4.28 +/- 0.94 mmol/l vs. 4.75 +/- 1.09 mmol/l respectively, p = 0.038). However, blood concentrations of insulin and C-peptide did not differ significantly between the two measurements. This is the first study to show a potential acute glucose-lowering effect of VPA during OGTT in patients with newly diagnosed epilepsy. PMID- 26250146 TI - Association between morningness/eveningness, addiction severity and psychiatric disorders among individuals with addictions. AB - Studies have shown that Evening-Type (ET) subjects used more stimulating and sedative substances, and presented more psychiatric disorders than Morning-Type (MT) subject. However, there is a lack of data on the chronotype of patients with addiction. The aim of our study was to describe chronotype and associated factors in a sample of outpatients beginning treatment for addiction. Subjects were assessed with the Morningness-Eveningness questionnaire of Horne & Ostberg, the Addiction Severity Index and the Mini International Neuropsychiatric Interview. In the 333 subjects with an addiction, 20% were MT and 32% were ET. When comparing ET to MT, multivariate analysis showed that ET was significantly associated with poly-problematic addiction, non-substance addictions, cannabis addiction, and mood disorders, but not with severity of addiction. MT was associated with antisocial personality disorder. Results suggested that chronotype was associated with specific addiction pattern and psychiatric disorders. PMID- 26250148 TI - Nurses' perceptions of transgressive behaviour in care relationships: a qualitative study. AB - AIM: To acquire insight into the onset and meaning of transgressive behaviour from the perspective of nurses. BACKGROUND: Patient aggression towards healthcare providers occurs frequently. Nurses in particular are at risk of encountering aggressive or transgressive behaviour due to the nature, duration and intensity of relationships with patients. This study analysed nurse perspectives with regard to the onset and meaning of transgressive patient behaviour in a general hospital setting. DESIGN: Qualitative research according to the grounded theory method. METHODS: Data were collected in 2011 through individual interviews with 18 nurses who were selected using purposive and theoretical sampling. FINDINGS: Findings revealed that various nurse-patient interactions can result in episodes of transgressive behaviour, depending on the interplay of determining and regulating factors which have been identified at the patient, nurse and ward level. Experiences of transgressive behaviour are influenced by degree of control nurses experience over the provision of care; the degree of patient acceptance of organizational and ward rules, the degree of gratitude and recognition expressed by the patient and the extent of patient regard for the nurse as a person. Factors affecting transgressive experiences were a trusting relationship between patient and nurse; the extent to which patient perspectives are understood; methods of managing transgressive behaviour; and the influence of the team, head nurse and ward culture and habits. CONCLUSIONS: The results of this study can support the development of nurses' coping ability and self-confidence to mitigate or prevent experiences of transgressive behaviour. PMID- 26250145 TI - Tumor size is a major determinant of prognosis of resected stage I hepatocellular carcinoma. AB - PURPOSE: The current American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC) includes all solitary tumors without vascular invasion as stage I, regardless of tumor size. The aim of this study is to determine the prognostic significance of tumor size in stage I HCC patients. METHODS: A total of 230 stage I primary HCCs were selected retrospectively. Based on univariate and multivariate analyses, clinical and pathological factors correlated with 5-year disease-free survival (DFS) and 5-year overall survival (OS) were determined. RESULTS: Univariate and multivariate analyses showed significant correlations of low serum alpha-fetoprotein levels (<=20 ng/ml), small tumor size (<=3 cm), wide resection margin (>= 1 cm), and absence of cirrhotic liver with better DFS, while smaller tumor size, and wide resection margin with better OS. Of all the parameters, tumor size is the most statistically significant markers for DFS and OS. Interestingly, liver cirrhosis exerted prognostic significance in patients with small-size tumors, while resection margin exerted prognostic significance in patients with large-size tumors. CONCLUSIONS: Our results indicated that tumor size is the most important determinant of DFS and OS in resected primary stage I HCC patients. Therefore, we advocate redefining solitary tumors of <=3 cm as T1a disease and tumors >3 cm as T1b disease. This stratification of stage I HCC patients could aid in the determination of prognosis and the development of superior protocols for patient management. However, further analysis of big registry cohorts is needed to establish a common consensus. PMID- 26250155 TI - Higher detectability method for the analysis of nucleosides, putative tumor biomarkers, in blood serum samples by CE-UV with reversed EOF. AB - The development and validation of methodologies for the analysis of biological samples is of outcome importance in order to obtain trustworthy results. This work reports a novel CE-UV method for the assessment of nucleosides, putative tumor biomarkers, in blood serum. The separation of seven nucleosides within c.a. 20 min has been achieved with: BGE 30 mmol/L borate at pH 9.90, 50 mmol/L CTAB, and 10% methanol; V = -10 kV; T = 20 degrees C; and capillary dimensions of 56 cm * 50 MUm. The sample plug was concentrated by a modified large volume sample stacking strategy that provided better detectability. Validation showed that the method is suitable for bioanalytical purposes and initial applications in serum samples from healthy subjects are also presented. Finally, statistical methods were applied to verify the effect of characteristics such as age, smoking habits, and alcohol consumption on nucleoside concentrations in blood serum. Univariate statistical analysis tests emphasized the need for age matching, which was confirmed by PCA-DA and PLS-DA. Cancer history in the nearby family may also interfere in nucleoside levels in blood serum, since adenosine concentrations were statistically higher for volunteers who declared having diseased relatives. PMID- 26250150 TI - Piglet preweaning mortality in a commercial swine herd in Thailand. AB - In the modern swine industry, the number of piglets born alive per litter is dramatically increasing due to genetic improvement of litter traits. However, knowledge on post-partum management is inadequate to reduce piglet preweaning mortality. The present study aimed to investigate piglet preweaning mortality in a commercial swine herd in Thailand in relation to the number of littermate pigs and piglet birth weight. Data included 11,154 litters from 3574 sows farrowed from January 2009 to December 2012. Littermate pig was defined as the number of piglets after cross-fostering. Number of littermate pigs was classified as 1-7, 8 10, 11-12, and 13-15 piglets per litter. Mean birth weight of the piglets was classified as low (<1.30 kg), medium (1.30-1.79 kg), and high (>=1.80 kg). Piglet preweaning mortality was calculated, logged transformed, and analyzed by general linear mixed models. On average, piglet preweaning mortality was 14.5 % (median = 10.0 %). Piglet preweaning mortality in the litter with 13-15 littermate pigs (24.1 %) was significantly higher than the litter with 1-7 (11.9 %, P < 0.001), 8 10 (11.8 %, P < 0.001), and 11-12 (14.6 %, P < 0.001) littermate pigs. The litters with a low piglet birth weight had a higher piglet preweaning mortality rate (18.8 %) than the litters with a medium (15.7 %, P < 0.001) and a high piglet birth weight (12.1 %, P < 0.001). In conclusion, to reduce piglet preweaning mortality in commercial swine herds, special care needs to be taken in litters with more than 13 littermate pigs and with piglets with birth weight below 1.30 kg. PMID- 26250151 TI - Climatic factors associated with reproductive performance in English Berkshire pigs and crossbred pigs between Landrace and Large White raised in a subtropical climate region of Japan. AB - Our objective was to characterize Berkshire female pigs associated with climatic factors by examining the interactions between two pig groups (pure English Berkshire females and crossbred females between Landrace and Large White) for reproductive performance in a humid subtropical zone. We analyzed 63,227 first service records of 11,992 females in 12 herds. Climate data were obtained from four weather stations located close to the herds. Mean daily maximum temperatures (Tmax) and daily average relative humidity (ARH) for different time periods around servicing and farrowing of each female were coordinated with that female's reproductive performance data. Multilevel mixed-effects models were applied to the data. There were two-way interactions between the pig groups and either Tmax or ARH for weaning-to-first-mating interval (WMI) and number of total pigs born (TPB; P < 0.05). The WMI in Berkshire sows increased by 0.64 days as Tmax increased from 20 to 30 degrees C (P < 0.05), whereas in crossbred sows it only increased by 0.09 days over the same Tmax range. In contrast, WMI in Berkshire sows only increased by 0.01 days as ARH increased from 60 to 80 % (P < 0.05), whereas in crossbred sows it increased by 0.32 days. In Berkshire females, TPB decreased by 0.3 pigs as Tmax increased from 20 to 30 degrees C (P < 0.05), whereas that in crossbred females decreased by 0.4 pigs (P < 0.05). Therefore, we recommend producers apply advanced cooling systems for Berkshire females. PMID- 26250147 TI - Development and validation of the Dimensional Anhedonia Rating Scale (DARS) in a community sample and individuals with major depression. AB - Anhedonia, a core symptom of Major Depressive Disorder (MDD), is predictive of antidepressant non-response. In contrast to the definition of anhedonia as a "loss of pleasure", neuropsychological studies provide evidence for multiple facets of hedonic function. The aim of the current study was to develop and validate the Dimensional Anhedonia Rating Scale (DARS), a dynamic scale that measures desire, motivation, effort and consummatory pleasure across hedonic domains. Following item selection procedures and reliability testing using data from community participants (N=229) (Study 1), the 17-item scale was validated in an online study with community participants (N=150) (Study 2). The DARS was also validated in unipolar or bipolar depressed patients (n=52) and controls (n=50) (Study 3). Principal components analysis of the 17-item DARS revealed a 4 component structure mapping onto the domains of anhedonia: hobbies, food/drink, social activities, and sensory experience. Reliability of the DARS subscales was high across studies (Cronbach's alpha=0.75-0.92). The DARS also demonstrated good convergent and divergent validity. Hierarchical regression analysis revealed the DARS showed additional utility over the Snaith-Hamilton Pleasure Scale (SHAPS) in predicting reward function and distinguishing MDD subgroups. These studies provide support for the reliability and validity of the DARS. PMID- 26250154 TI - Modulation of Cytokine Production by the Dydrogesterone Metabolite Dihydrodydrogesterone. AB - PROBLEM: Previous studies have shown that dydrogesterone, the orally administered progestogen, upregulates the production of Th2 cytokines and downregulates Th1 cytokine production. This study was designed to ascertain whether dihydrodydrogesterone (DHD), the major metabolite of dydrogesterone, is similarly capable of modulating cytokine production by peripheral blood mononuclear cells (PBMC) from women with a history of unexplained recurrent miscarriage. METHOD OF STUDY: Mitogen-stimulated PBMC from women with unexplained recurrent miscarriage were exposed to progesterone or dydrogesterone or DHD, and the levels of pro inflammatory (IFN-gamma, TNF-alpha) and anti-inflammatory (IL-4, IL-10, IL-13) cytokines were estimated by ELISA. To ascertain whether DHD mediates its effects via the progesterone receptor, RU486, a progesterone agonist, was added to cultures along with mitogen and DHD. RESULTS: The metabolite DHD, like its parent molecule dydrogesterone, suppresses the production of the pro-inflammatory cytokines IFN- gamma and TNF-alpha and upregulates the production of the anti inflammatory cytokine IL-4. The progesterone antagonist RU486 reverses the effect of DHD, suggesting that this molecule mediates its cytokine-modulating effect via the progesterone receptor. CONCLUSION: Dihydrodydrogesterone retains the immunomodulatory effects of the progestogen dydrogesterone by bringing about a shift in cytokine production profiles that might be conducive to the success of pregnancy. PMID- 26250149 TI - Photoluminescence properties of a new orange-red-emitting Sm(3+)-La3SbO7 phosphor. AB - The antimonate compound La3SbO7 has high chemical stability, lattice stiffness and thermal stability. Orange-red-emitting antimonate-based phosphors La3SbO7:xSm(3+) (x = 0.02, 0.05, 0.08, 0.10, 0.15, 0.20 and 0.25) were synthesized. The phase structure and photoluminescence properties of these phosphors were investigated. The emission spectrum obtained on excitation at 407 nm contained exclusively the characteristic emissions of Sm(3+) at 568, 608, 654 and 716 nm, which correspond to the transitions from (4)G5/2 to (6)H5/2, (6)H7/2, (6)H9/2 and (6)H11/2 of Sm(3+), respectively. The strongest emission was located at 608 nm due to the (4)G5/2->(6)H7/2 transition of Sm(3+), generating bright orange-red light. The critical quenching concentration of Sm(3+) in La3SbO7:Sm(3+) phosphor was determined as 10% and the energy transfer between Sm(3+) was found to be through an exchange interaction. The International Commission on Illumination chromaticity coordinates of the La3SbO7:0.10Sm(3+) phosphors are located in the orange-red region. The La3SbO7:Sm(3+) phosphors may be potentially used as red phosphors for white light-emitting diodes. PMID- 26250161 TI - Plectorhinchus caeruleonothus, a new species of sweetlips (Perciformes:
Haemulidae) from northern Australia and the resurrection of P. unicolor (Macleay, 1883), species previously confused with P. schotaf (Forsskal, 1775). AB - Two distinct haemulid fishes from Australia and the Indo-Australian Archipelago respectively have long been confused with Plectorhinchus schotaf (Forsskal, 1775). Plectorhinchus caeruleonothus sp. nov. is described from 17 specimens collected off western and far northern Australia, between the Monte Bello Islands, Western Australia and Torres Strait, Queensland. It has also been confirmed outside this range by photographs taken at Ningaloo Reef and Exmouth Gulf, Western Australia, and at Claremont Isles and Lizard Island, Queensland. The new species is unique among the genus in having a combination of dorsal-fin rays XII, 18-20, lateral-line scales 56-61, gill rakers 7-9 on the upper limb and 18-20 on the lower limb of the first arch, nostrils minute, and fresh colouration in adults including body uniformly grey, cheek, opercles and posterior margin of the opercular membrane uniformly blue-grey, and rim of orbit and upper edge of maxilla dusky yellow. In contrast to its closest congeners, the juveniles have a distinctive pattern of narrow creamish-white to pale grey stripes on a dark grey to chocolate brown background on the head and body, and oblique dark stripes progressing with growth to spots on the caudal fin. Plectorhinchus unicolor (Macleay, 1883) from Japan to northern Australia is resurrected from the synonomy of P. schotaf and redescribed on the basis of the holotype and 24 non-type specimens. Plectorhinchus unicolor is most similar to P. schotaf, but can be distinguished by fresh colouration, modal dorsal and pectoral-fin ray counts and DNA barcoding. Plectorhinchus schotaf appears to be restricted to the region from southeast Africa to the Arabian Sea, including the Red Sea and Persian Gulf. Plectorhinchus griseus (Cuvier in Cuvier & Valenciennes, 1830) from Indian and Sri Lankan Seas has previously been treated as a junior synonym of P. schotaf, but in accordance with Smith (1962), is here confirmed as a valid species, readily distinguished from the latter by a concavity in the lateral profile of the snout in adults, deep body and high soft dorsal-fin ray count. Comparison of the CO1 genetic marker utilised in DNA barcoding also resulted in significant genetic divergences between the new species, P. unicolor and their closest sampled congeners. Some behavioural observations are also presented for the species treated, including aggressive interactions between individuals of the new species, the likes of which have not previously been recorded among species of Plectorhinchus. PMID- 26250160 TI - The phylogeny of mole crickets (Orthoptera: Gryllotalpoidea: Gryllotalpidae). AB - The monophyly and phylogenetic relationships of the family Gryllotalpidae were researched. Twenty-six in-group taxa, representing all known genera of Gryllotalpidae were included in a cladistic analysis, based on 89, morphological characters (including genital characters of the males). The different analyses of the resulting data matrix supported the monophyly of Scapteriscinae and Gryllotalpinae and its internal group. Subfamilies, tribes and genera of Gryllotalpidae are fully diagnosed, illustrated and keys to their identification are provided. Four tribes are established (Indioscaptorini n. trib. (Scapteriscinae), Triamescaptorini n. trib., Gryllotalpellini n. trib. and Neocurtillini n. trib. (Gryllotalpinae)) and two other are fully delimited (Scapteriscini stat. rev. and Gryllotalpini stat. rev.). Two new genera are described (Neoscapteriscus n. gen. and Leptocurtilla n. gen.) and as well as seven new species: Gryllotalpella rehni n. sp., G. tindalei n. sp., G. lawrencei n. sp., Neocurtilla ingrischi n. sp., N. townsendi n. sp., Leptocurtilla juanmanueli n. sp. and L. chopardi n. sp. The following nomenclatural changes were made: All species previously placed in Scapteriscus s.l. are transferred to the new genus Neoscapteriscus, except Scapteriscus oxydactilus and S. headsi that are still placed in Scapteriscus, Gryllotalpa chilensis reinst. stat. and Leptocurtilla maranona, n. comb. Finally, previous contributions about the phylogenetic relationships of molecrickets are contrasted with the results of this research. PMID- 26250156 TI - Coronaviruses Detected in Brazilian Wild Birds Reveal Close Evolutionary Relationships with Beta- and Deltacoronaviruses Isolated From Mammals. AB - This study showed that the most of the coronaviruses (CoVs) detected in Brazilian wild birds clustered with the mouse hepatitis virus A59 strain, belonging to the BetaCoV group. Furthermore, CoV detected in two different bird species, Amazona vinacea and Brotogeris tirica, clustered with a CoV isolated from Sparrow (SpaCoV HKU17) belonging to a monophyletic group related with the CoVs isolated from swines (PorCoV HKU15), both belonging to the DeltaCoV genus, previously unreported in South America. Considering the risk of inter-species host switching and further adaptation to new hosts, detection in bird species of CoVs closely related to mammal CoVs should warn for the potential emergence of new threatening viruses. PMID- 26250162 TI - Two new species of the millipede family Blaniulidae (Diplopoda, Julida) from caves in central and southeastern Europe. AB - Two new species, one each of the previously monotypic genera Cibiniulus Verhoeff, 1927, and Thassoblaniulus Mauries, 1985, are described from caves in Slovakia and Albania, respectively: C. slovacus Antic, Mock & Enghoff, sp. n. and T. radjai Antic & Enghoff sp. n. Brief discussions on relationships with congeners and on the taxonomic position of the genera Cibiniulus and Thassoblaniulus within Blaniulidae are presented, as well as a distribution map for both genera. PMID- 26250163 TI - Review of species of the Old World genus Doryctophasmus Enderlein, 1912 (Hymenoptera: Braconidae: Doryctinae). AB - The Old World doryctine wasp genus Doryctophasmus Enderlein, 1912 is reviewed. Two new species, D. beninus sp. nov. and D. madagascarus sp. nov., are described and illustrated from the Afrotropical region. The illustrated redescriptions of D. ferrugineiceps Enderlein, 1912, D. ferrugineus (Granger, 1949) and D. rubrotestaceus (Granger, 1949) are provided. Lectotypes of Doryctes ferrugineus Granger 1949 and D. rubrotestaceus Granger 1949 are designated. A key for determination of six know species of Doryctophasmus is given. PMID- 26250167 TI - A new species of the genus Sphedanolestes Stal 1866 (Hemiptera: Reduviidae: Harpactorinae) from China, with a key to Chinese species. AB - A new harpactorine bug, Sphedanolestes zhengi sp. nov., is described and illustrated based on specimens collected from southwestern China. A key to 17 Chinese species of the genus, including the new species, is provided. The bionomics of the new species is briefly noted. PMID- 26250164 TI - Description of two final stadium platystictid larvae from Borneo, including that of Drepanosticta ?attala Lieftinck, identified using DNA barcoding (Odonata: Zygoptera: Platystictidae). AB - The final stadium larva of Drepanosticta ?attala Lieftinck, is described and illustrated based on a single male specimen collected at Kuala Belalong Field Studies Centre, Brunei. The larva was identified by matching the mitochondrial marker COI with that of known adult specimens. The larva presented a good match with both D. attala and D. barbatula Lieftinck in this gene, but as adults of only the former species had been collected at the locality, it is presumed more likely to be that species. Another, unidentified platystictid larva, Platystictidae A, collected at the same general locality is also described. The two larvae show significant differences from each other and from D. sundana Kruger, the only other Oriental region member of the family for which larval morphology is known. The three species are also compared with the larvae of the Neotropical genus Palaemnema, which they closely resemble, despite being currently placed in different subfamilies. Based on this known material, Oriental and Neotropical forms differ significantly in details of mandibular morphology, especially the armature of the molar field. PMID- 26250152 TI - Effects of different forms of white lupin (Lupinus albus) grain supplementation on feed intake, digestibility, growth performance and carcass characteristics of Washera sheep fed Rhodes grass (Chloris gayana) hay-based diets. AB - Protein is the major limiting nutrient in feeding ruminants especially in dryland areas. Thus, looking for locally available protein sources such as white lupin (Lupinus albus) grain is commendable. The objective of this experiment was to determine effects of supplementation of different forms of white lupin grain (WLG) on feed and nutrient intake, digestibility, growth and carcass characteristics. Twenty-five yearling male Washera sheep with initial body weight (BW) of 16.26 +/- 1.41 kg (mean +/- SD) were used. Animals were blocked into five based on their initial BW and were randomly assigned to one of the following five dietary treatments: Rhodes grass (Chloris gayana) hay (RGH) alone (T1) or supplemented with 300 g (on dry matter (DM) basis) raw WLG (T2) or raw soaked and dehulled WLG (T3) or roasted WLG (T4) or raw soaked WLG (T5). Supplementation with WLG significantly improved total DM and nutrient intake (P < 0.001), nutrient digestibility (P < 0.01), and average daily gain (ADG) and feed conversion efficiency (FCE) (P < 0.001). Carcass quality parameters were significantly (P < 0.001) higher for supplemented sheep. However, the difference in carcass quality parameters among supplemented groups was not significant (P > 0.05). It is concluded that roasting white lupin grain can lead to a better feed and nutrient intake and consequently better carcass quality. White lupin grain can be recommended not only for maintenance but also for optimum performance of ruminants. PMID- 26250159 TI - Perceived barriers to reporting adverse drug events in hospitals: a qualitative study using theoretical domains framework approach. AB - BACKGROUND: Adverse drug events (ADEs) are a major source of morbidity and mortality, estimated as the forth to sixth cause of annual deaths in the USA. Spontaneous reporting of suspected ADEs by health care professionals to a national pharmacovigilance system is recognized as a useful method to detect and reduce harm from medicines; however, underreporting is a major drawback. Understanding the barriers to ADE reporting and thereafter design of interventions to increase ADE reporting requires a systematic approach and use of theory. Since multiple theories in behavior change exist that may have conceptually overlapping constructs, a group of experts suggested an integrative framework called theoretical domains framework (TDF). This approach considers a set of 12 domains, came from 33 theories and 128 constructs, covering the main factors influencing practitioner behavior and barriers to behavior change. The aim of this study is to apply TDF approach to establish an evidence-based understanding of barriers associated with ADE reporting among nurses and pharmacists. METHODS: A total of three focus group discussions were conducted; among them two consisted of nurses and one involved pharmacists. Discussions were guided by questions designed based on TDF. Transcriptions of discussions were then thematically analyzed, and detected barriers to reporting ADEs were categorized based on extracted themes. RESULTS: A total of 34 nurses and pharmacists attended the group discussions. Six domains were identified to be relevant to barriers of ADE reporting in hospitals. These domains included "Knowledge," "Skills," "Beliefs about consequences," "Motivation and goals (intention)," "Social influences (norms)," and "Environmental constraints." We detected several barriers to ADE reporting, such as lack of knowledge of what should be reported, fear of punishment and criticism, lack of time, lack of teamwork, and lack of active support by hospital managements and other colleagues. Based on detected barriers, "Cognitive and behavioral factors," "Motivational factors and teamwork," in addition to "Organizational processes and resources" could be targeted in designing appropriate interventions. CONCLUSIONS: Detection of barriers to reporting ADEs is necessary to design appropriate interventions. The TDF is a comprehensive approach that enables us to better understand barriers to behavior change in reporting ADEs. PMID- 26250165 TI - Four new species of the genus Agrilus Curtis, 1825 from Ecuador (Coleoptera, Buprestidae). AB - Agrilus delsinnei n. sp., Agrilus yanzatzanus n. sp., Agrilus touroultinus n. sp, Agrilus quito n. sp. from Ecuador are described. PMID- 26250153 TI - Preventative role of interleukin-17 producing regulatory T helper type 17 (Treg 17) cells in type 1 diabetes in non-obese diabetic mice. AB - T helper type 17 (Th17) cells have been shown to be pathogenic in autoimmune diseases; however, their role in type 1 diabetes (T1D) remains inconclusive. We have found that Th17 differentiation of CD4(+) T cells from BDC2.5 T cell receptor transgenic non-obese diabetic (NOD) mice can be driven by interleukin (IL)-23+IL-6 to produce large amounts of IL-22, and these cells induce T1D in young NOD mice upon adoptive transfer. Conversely, polarizing these cells with transforming growth factor (TGF)-beta+IL-6 led to non-diabetogenic regulatory Th17 (Treg 17) cells that express high levels of aryl hydrocarbon receptor (AhR) and IL-10 but produced much reduced levels of IL-22. The diabetogenic potential of these Th17 subsets was assessed by adoptive transfer studies in young NOD mice and not NOD.severe combined immunodeficient (SCID) mice to prevent possible transdifferentiation of these cells in vivo. Based upon our results, we suggest that both pathogenic Th17 cells and non-pathogenic regulatory Treg 17 cells can be generated from CD4(+) T cells under appropriate polarization conditions. This may explain the contradictory role of Th17 cells in T1D. The IL-17 producing Treg 17 cells offer a novel regulatory T cell population for the modulation of autoimmunity. PMID- 26250168 TI - Andean region: a shapefile of Morrone's (2015) biogeographical regionalisation. AB - Morrone's (2015) biogeographic regionalisation of the Andean region is based on the distributional ranges of terrestrial plants and animals. It is the most comprehensive and methodologically supported biogeographical scheme for the region to date. The Andean region comprises one transition zone (the South American transition zone), three subregions (Central Chilean, Subantarctic and Patagonian) and 15 provinces (Morrone, 2015). PMID- 26250170 TI - Review of the genus Ceratovacuna (Hemiptera: Aphididae) with descriptions of five new species from China. AB - The genus Ceratovacuna Zehntner, 1897 (Hemiptera: Aphididae: Hormaphidinae) is reviewed for the first time in China, with the descriptions of five new species, C. angusticorna Qiao sp. n., C. beijingensis Qiao sp. n., C. imperata Qiao sp. n., C. multiglandula Qiao sp. n., C. separata Qiao sp. n. and four new records for China, C. graminum (van der Goot, 1917), C. keduensis Noordam, 1991, C. panici (van der Goot, 1917) and C. uscare (Tao, 1964). The molecular analyses based on COI and Cytb sequences both supported the status of these new species. PMID- 26250169 TI - New species of Anchastus LeConte, 1853 from South America (Elateridae, Elaterinae, Ampedini, Physorhinina). AB - Seven new species of Anchastus LeConte, 1853 are described: A. brunneifinibus sp. nov. (Bolivia), A. cuiabanus sp. nov. (Brazil), A. flavonigrothoracicum sp. nov. (Bolivia), A. rubrithoracicum sp. nov. (Brazil, Bolivia), A. thoracoferrugineus sp. nov. (Bolivia), A. transverseplagiatus sp. nov. (Bolivia) and A. uniplagipennis sp. nov. (Bolivia). The female genitalia of A. boulardi Chassain, 2010 is described and three species are redescribed: A. moratus (Candeze, 1863) (Mexico, Guyana, Brazil, Bolivia), A. quadrimaculatus Candeze, 1889 (Guyana, Brazil, Bolivia) and A. unitinctus Candeze, 1889 (Brazil). New records for A. touroulti Chassain, 2010 are presented. A provisional identification key for South American species is provided. PMID- 26250166 TI - A new species of the genus Sovia (Lepidoptera: Hesperiidae) from Qinling-Daba Mountains of China. AB - In this paper, a new species Sovia lii spec. nov. is described from Qinling-Daba Mountains in S. Gansu province and S. Shaanxi province, W. China. Variability of wing pattern, differences with its similar congeners and some biological information of this new taxon are introduced. External variability of Sovia lucasii, which is discovered from Shaanxi for the first time and is sympatric with the new species there, is illustrated and discussed. A brief analysis of the distributional pattern of the genus Sovia is provided. A key to the genus is given. PMID- 26250144 TI - Surgeon perspectives on the use and effects of neoadjuvant chemoradiation in the treatment of rectal cancer: a comprehensive review of the literature. AB - BACKGROUND: Despite screening initiatives, rectal cancer remains one of the most prevalent malignancies diagnosed in patients worldwide with a high mortality. The introduction of neoadjuvant therapy has resulted in a paradigm shift in the treatment and outcomes of rectal cancer. Surgeons play an intricate role in the pre-operative, operative, and post-operative management of these patients. PURPOSE: The purpose of this comprehensive literature review was to summarize the evolution of the use chemotherapy and radiation and the process of differentiation into specific neoadjuvant chemoradiation protocols in the treatment of locally advanced rectal cancer. This will provide a concise summary for practicing surgeons of the current evidence for neoadjuvant chemoradiation as well as the various implications of therapy on operative outcomes. CONCLUSION: The initial benefit of adjuvant therapy in the treatment of rectal cancer patients became evident with prospective studies demonstrating improvements in various oncologic survival outcomes. Due to the improved compliance and reduced toxicity, as well as the potential for tumor down-staging and sphincter preservation, neoadjuvant approaches became the preferred method of administering chemotherapy and radiation. Furthermore, a subgroup of patients has been shown to present with complete clinical response to neoadjuvant therapy. This has resulted in the development of the non-operative "watch and wait" approach, which has initiated discussions on changing the interval from the completion of neoadjuvant therapy to surgical resection. The continued development of the multidisciplinary approach will only further improve our ability to provide patients with the best possible oncologic outcomes. PMID- 26250173 TI - Two new species of Agonopterix (Depressariidae, Lepidoptera) from Europe. AB - The species Agonopterix tripunctaria sp. nov. and Agonopterix medelichensis sp. nov. are described. A. tripunctaria, previously misidentified as Agonopterix nodiflorella (Milliere, 1866), was recognized as specifically different by the distinctive male genitalia. 19 specimens have been examined, DNA-barcoding yielded full 658 bp fragment of COI from two specimens and a 639 bp sequence from a third, confirming the impression of a rather isolated species. Specimens from Italy, Slovenia, Croatia and Greece had been checked, among them one reared from Ferulago campestris. A. medelichensis was misidentified as Agonopterix rotundella (Douglas, 1846) in NHMV; its male genitalia are erroneously depicted as A. rotundella in Hannemann (1953) and (1995). 20 specimens have been examined, from one a 555 bp fragment of COI was obtained, confirming that it is not closely related to A. rotundella. Specimens from Austria, Italy, Hungary, Slovakia, Croatia and Greece have been checked, among them one reared from Trinia glauca, which had been misidentified as A. hippomarathri. A report of A. rotundella from Russia also belongs to this species. PMID- 26250171 TI - Revision of the Amphilius jacksonii complex (Siluriformes: Amphiliidae), with the descriptions of five new species. AB - The Amphilius jacksonii complex is revised, and five new species are described: A. ruziziensis n. sp. from the Ruzizi River drainage and northeastern tributaries of Lake Tanganyika; A. pedunculus n. sp. from the Malagarasi River drainage, Lake Rukwa basin, and upper Great Ruaha River drainage, Rufiji basin; A. frieli n. sp. from the upper Congo basin; A. crassus n. sp. from the Rufiji and Wami basins; and A. lujani n. sp. from the Lake Kyogo drainage, northeastern tributaries of Lake Victoria, and the Lake Manyara basin. PMID- 26250177 TI - A remarkable new species of Chalcosyrphus Curran from the Oriental Region (Diptera: Syrphidae). AB - Chalcosyrphus blanki sp. nov. is described from material collected in China, Thailand and Burma. The new species is outstanding because of its size and metallic blue coloration. It is remarkable that only a few specimens have been found so far, all from different countries and only with Malaise traps. The species was only collected at altitudes above 2500 m. It fits very well in the genus Chalcosyrphus, but cannot be placed in any existing subgenus. PMID- 26250174 TI - The Afrotropical genera of Psychodini: Redefinition of the tribe, first Afrotropical record of Perithreticus Vaillant, 1973 and description of Soeliella gen. nov. (Diptera: Psychodidae: Psychodinae). AB - Psychodini is redefined based on morphological characters and newly recognized homologies in the male genitalia. It is hypothesised that the ground-plan aedeagus of Psychodini consists of a symmetrical bipartite aedeagus flanked by paired, symmetrical parameres; which in many lineages have become asymmetrical via the differentiation of phallomeres and parameres and/or via reduction of one paramere. The Afrotropical genera of Psychodini are reviewed and a key for their identification is provided. Perithreticus Vaillant, 1973 is recorded from Tanzania based on the new species Perithreticus anderseni sp. nov. The genus is redefined, characterised by an elongate symmetrical aedeagus with paired subtriangular parameres, and a broad M-shaped epiproct with a concave anterior margin. Soeliella gen. nov. is described to include Soeliella platypenis sp. nov.; characterised by the presence of paired subtriangular parameres and the distiphallic elements broadly fused into a spatulate plate. Rhipidopsychoda Vaillant, 1991 is raised from synonymy based on novel character interpretations. Rhipidopsychoda boettgeri (Wagner, 1979) comb. nov. is redescribed and a key to the world species is presented. The species Psychoda bilobata Quate, 1957 and Psychoda trilobata Quate, 1957, Psychoda morogorica Wagner & Andersen, 2007 and Philosepedon triangularis Eaton, 1913 are of dubious generic placement and need revision. PMID- 26250175 TI - An annotated list of the type specimens of Tortricidae (Lepidoptera) in the collection of Zoological Institute, St. Petersburg, Russia. 1. Types of species described by O. Bremer, A. M. Djakonov, N. G. Erschoff, and A. M. Gerasimov. AB - The primary types of 15 tortricid species described by O. Bremer, A. M. Djakonov, N. G. Erschoff, and A. M. Gerasimov deposited in the collection of Zoological Institute in St. Petersburg, Russia (ZISP) are listed and discussed. Lectotypes are designated for eight of these: Lazotaenia [sic.] aurichalcana Bremer, 1864; Ptycholoma plumbeolana Bremer, 1864; Tortrix euxina Djakonov, 1929; Diceratura rhodograpta Djakonov, 1929; Penthina enervana Erschoff, 1877; Tortrix (Idiographis) excentricana Erschoff, 1877; Conchylis nomadana Erschoff, 1874; Cochylis pistrinana Erschoff, 1877. Descriptions of the labels and photographs of adults are given for each species. Type specimens of two other species presumed to be deposited in ZISP, Bactra griseana Djakonov, 1929 and Lazotaenia [sic.] quinquemaculana Bremer, 1864, were not found in the collection and presumably are lost. PMID- 26250158 TI - MicroRNA-638 inhibits cell proliferation by targeting phospholipase D1 in human gastric carcinoma. AB - MicroRNAs (miRNAs) are a type of small non-coding RNAs that are often play important roles in carcinogenesis, but the carcinogenic mechanism of miRNAs is still unclear. This study will investigate the function and the mechanism of miR 638 in carcinoma (GC). The expression of miR-638 in GC and the DNA copy number of miR-638 were detected by real-time PCR. The effect of miR-638 on cell proliferation was measured by counting kit-8 assay. Different assays, including bioinformatics algorithms (TargetScan and miRanda), luciferase report assay and Western blotting, were used to identify the target gene of miR-638 in GC. The expression of miR-638 target gene in clinical CRC tissues was also validated by immunohistochemical assay. From this research, we found that miR-638 was downregulated in GC tissues compared with corresponding noncancerous tissues (NCTs), and the DNA copy number of miR-638 was lower in GC than NCTs, which may induce the corresponding downregulation of miR-638 in GC. Ectopic expression of miR-638 inhibited GC cell growth in vitro. Subsequently, we identified that PLD1 is the target gene of miR-638 in GC, and silencing PLD1 expression phenocopied the inhibitory effect of miR-638 on GC cell proliferation. Furthermore, we observed that PLD1 was overexpressed in GC tissues, and high expression of PLD1 in GC predicted poor overall survival. In summary, we revealed that miR-638 functions as a tumor suppressor in GC through inhibiting PLD1. PMID- 26250157 TI - Reestablishment of the inactive X chromosome to the ground state through cell fusion-induced reprogramming. AB - The restricted gene expression pattern of a differentiated cell can be reversed by fusion of the somatic cell with a more developmentally potent cell type, such as an embryonic stem (ES) cell. During this reprogramming process, somatic cells obtain most of the characteristics of pluripotent cells. Reactivation of an inactive X chromosome (Xi) is an important epigenetic marker confirming the pluripotent reprogramming of somatic cells. Female somatic cells contain one active X chromosome (Xa) and one Xi, and following the fusion of these cells with male ES cells, the Xi becomes activated, resulting in XaXaXaY fusion hybrid cells. To monitor Xi reactivation, transgenic female neural stem cells (fNSCs) carrying a green fluorescent protein (GFP) reporter gene expressed on the Xa (X GFP), but not on the Xi, were used for reprogramming. XaXi(GFP) NSCs, whose GFP reporter was silenced, were fused with HM1 ES cells (XY) to induce pluripotent reprogramming. The Xi(GFP) of NSCs were found to be activated on day 4 post fusion, indicating reactivation of the Xi. Hybrid cells showed pluripotent cell specific characteristics cells including inactivation of the NSC marker Nestin, DNA demethylation of Oct4, DNA methylation of Nestin, and reactivation of the Xi. Following differentiation of the (GFP-positive) hybrid cells through embryoid body formation, the proportion of GFP-negative cells was found to be approximately 26 %, indicating that there was random inactivation of one of the three Xas. Here, we showed that the Xi of somatic cells is reprogrammed to the Xa state and that cellular differentiation occurs randomly, i.e., regardless of the Xa or Xi state, indicating that the memory of the Xi of somatic cells has been erased and reset to the ground state (i.e., inner cell mass-like state), indicating that random X-chromosome inactivation occurs upon differentiation. PMID- 26250176 TI - Epipsylla millettiae sp. nov. (Hemiptera: Psylloidea), a new psyllid from China associated with Millettia pachyloba (Fabaceae) with comments on Epipsylla including the redescription of E. hainanana. AB - The small genus Epipsylla is diagnosed (adults and immatures), a checklist is given for its constituent species and the phylogenetic relationships of the genus are briefly discussed. E. millettiae sp. nov., associated with Millettia pachyloba from South China is described, diagnosed and illustrated. It differs from other described Epipsylla species in the very narrow paramere. E. hainanana Yang & Li is redescribed, and additional details are provided of the male and female terminalia. Following new synonymies are proposed: Epipsylla guangxiana Yang & Li, 1983, = E. whitfordiodendritis Yang & Li, 1983, syn. nov. and Epipsylla mucunae Yang & Li, 1984, = E. ruiliana Yang & Li, 1984, syn. nov., E. yunnanica Yang & Li, 1984, syn. nov. PMID- 26250172 TI - Mudworm Polydora lingshuiensis sp. n is a new species that inhabits both shell burrows and mudtubes. AB - A new polydorin species, Polydora lingshuiensis sp. n., which is found not only in burrows of pearl oyster shells (shell-boring type) but also in mudtubes on the surface of pearl oyster cages (tube-dwelling type), is described with the use of light microscopy, scanning electron microscopy, and molecular phylogeny. Morphological and molecular distinctions between P. lingshuiensis and other related species reveal that P. lingshuiensis is a valid new species. The reproduction characteristic that the eggs of P. lingshuiensis are gathered together in one hollow cylinder is another piece of evidence confirming that it is indeed a valid new species. Sequence comparisons based on nuclear 18S rDNA, 28S rDNA, and mitochondrial 16S rDNA show that strains of the shell-boring type possess as high as 99.9% to 100% sequence identity relative to those of the tube dwelling type. This finding evidently indicates that these species types are conspecific. We also find that a comparison of mitochondrial 16S rDNA sequences can provide a higher resolution of polydorin species than those of the nuclear 18S rDNA because the former has a higher interspecific/intraspecific difference ratio. Phylogenetic analyses based on 18S rDNA sequences indicate that all P. lingshuiensis samples group together to forming a sister clade to Polydora uncinata and thus fall within Polydora aura/P. uncinata clade. PMID- 26250180 TI - Badis laspiophilus, a new miniature addition to the ichthyofauna of West Bengal, north-eastern India, with observations on its ecology and preliminary notes on its ethology (Actinopterygii: Perciformes: Badidae). AB - Badis laspiophilus is described from the Torsa River drainage, West Bengal, India. It can be distinguished from congeners by a combination of characters which include a small size (15.7-21.0 mm SL), 14-16 circumpeduncular row scales, interorbital width 6.7-8.9% SL, upper and lower jaws 8.2-9.2 and 10.2-13.4% SL, respectively, presence of two dorsal-fin blotches and a single round blotch on the anal fin, and absence of cleithral, opercle and dorsolateral caudal peduncle blotches. Its benthic ecology is discussed and the Badis singenensis species group is diagnosed, of which B. laspiophilus and B. singenensis are considered members. PMID- 26250183 TI - Review of the genus Trichoboscis Meyrick, with descriptions of three new species (Lepidoptera, Lecithoceridae). AB - Trichoboscis Meyrick belongs to the subfamily Lecithocerinae of Lecithoceridae. It is a small, poorly known genus, comprising two known species described from India. In this study, three new species are described: T. multispina Park & Wang, sp. nov. and T. phliuensis Park & Wang, sp. nov. from Thailand, and T. cultriformis Park & Wang, sp. nov. from China. Images of adults and genitalia are provided, along with a key to all the described species in the genus. PMID- 26250182 TI - A taxonomic revision of the Quadrideres simplicipes species-group (Coleoptera: Tenebrionidae: Pedinini), including description of a new species from Tanzania. AB - The taxonomic and distributional data concerning the representatives of the Quadrideres simplicipes species-group is revised. Selinus parallelus Ancey, 1877, considered by some previous authors as incertae sedis Platynotina species, is transferred to the genus Quadrideres. Q. ruandanus Koch, 1956 is proposed as a synonym of S. parallelus. Lectotypes for Selinus parallelus, S. simplicipes Gebien, 1910, Q. robynsi Koch, 1956 and Q. ruandanus are designated to fix the taxonomic status of these species. Q. kazimierzi sp. nov. is described as a new species. An identification key is provided to all known species of the Q. simplicipes species-group. This paper brings the total species number within the genus Quadrideres to 20. PMID- 26250179 TI - A new species of spectacularly coloured flat lizard Platysaurus (Squamata: Cordylidae: Platysaurinae) from southern Africa. AB - We describe a new species of flat lizard (Platysaurus attenboroughi sp. nov.) from the Richtersveld of the Northern Cape Province of South Africa and the Fish River Canyon region of southern Namibia. This species was formerly confused with P. capensis from the Kamiesberg region of Namaqualand, South Africa. Genetic analysis based on one mtDNA and two nDNA loci found Platysaurus attenboroughi sp. nov. to be genetically divergent from P. capensis and these species can also be differentiated by a number of scalation characters, coloration and their allopatric distributions. To stabilize the taxonomy the type locality of Platysaurus capensis A. Smith 1844 is restricted to the Kamiesberg region, Namaqualand, Northern Cape Province, South Africa. PMID- 26250178 TI - Molecular and morphological data support recognition of a new genus of New World direct-developing frog (Anura: Terrarana) from an under-sampled region of South America. AB - We describe a new genus of New World direct-developing frog (Terrarana) from the northern Andes of Venezuela and adjacent Colombia. Tachiramantis gen. nov. includes three species formerly placed in the large genus Pristimantis. Molecular phylogenetic analysis of data from five nuclear and mitochondrial genes shows that Tachiramantis is not part of Pristimantis or any other named genus in its family (Craugastoridae or Strabomantidae). Morphological evidence further supports the distinctiveness of Tachiramantis, which has several aspects of skull morphology that are rare or absent in Pristimantis and synapomorphic for Tachiramantis, including frontoparietal-prootic fusion and degree of vomer development. The terminal phalanges, which narrow greatly before expanding at the tips, may represent an additional morphological synapomorphy. One species, T. prolixodiscus, also displays a fenestra between the posterior portions of the frontoparietals, a character state otherwise present in only 1 of 98 other sampled terraranan species. We use mapped ranges of most New World direct developing frogs to show that Tachiramantis occurs in a geographic region that had been under-sampled in previous molecular studies of New World direct developing frogs. Other under-sampled regions are identified in western Peru, Colombia, and northern Central America; these regions should provide fruitful target taxa for future phylogenetic studies. PMID- 26250181 TI - Descriptions of three new species of Glossogobius (Teleostei: Gobiidae) from New Guinea. AB - Three new species of Glossogobius are described from New Guinea. Glossogobius multipapillus, n. sp. from northeastern New Guinea has a lobed mental fraenum and a distinctive papilla pattern unlike any other species in the genus. Glossogobius sentaniensis, n. sp. is described from Lake Sentani. The species is similar to Glossogobius aureus and G. koragensis differing in head pores and large dark spots on the body. Glossogobius macrocephalus n. sp. from Lake Tebera and surrounding rivers has a lobed mental fraenum and differs from other species in the Glossogobius celebius group in the combination of having a large head, head pore, fin-ray and predorsal scale counts. PMID- 26250184 TI - Male description and intraspecific variations of Cyrtopsis t-sigillata (Orthoptera: Tettigoniidae: Meconematinae). AB - The paper describes the male of Cyrtopsis t-sigillata Liu, Zhou & Bi, 2010 for the first time, and discusses individual variations in the species. It provides the photos of important morphological features, and offers a distribution map about the genus Cyrtopsis Bey-Bienko, 1962. The examined material is deposited in the Museum of Hebei University. Morphological images were acquired using Leica M205 A digital imaging system. PMID- 26250185 TI - Illustrated larval key to lepidopteran pests of rice in Malaysia. AB - Here we provide an illustrated key to lepidopteran larvae that occur as pests on rice (Oryza) in Malaysia. We are unaware of a published key for this region for this vital commercial crop, and hence provide one based on easily observable features that could be useful for identification, early detection, and pest management by specialists and non-specialists alike (see discussion in Mukerji & Singh 1951, Sri et al. 2010, Timm et al. 2007, Tillmon et al. 2000, Wagener et al. 2004). PMID- 26250186 TI - A new name for the deep-sea chiton Leptochiton clarki Sigwart & Sirenko non Berry (Lepidopleurida: Leptochitonidae). AB - Recently we described several new species of chitons living in deep water deposits of sunken wood in the southwest Pacific (Sigwart & Sirenko 2012). Among these, one species, Leptochiton clarki Sigwart & Sirenko, 2012, is homonymous with a fossil taxon of the same genus: Leptochiton clarki Berry, 1922. Herein, we replace this homonym with a new name according to International Code of Zoological Nomenclature (ICZN 1999: Art. 57.2). PMID- 26250189 TI - Revision of the genus Dohrniphora Dahl (Diptera: Phoridae) from China. AB - The Chinese species of Dohrniphora are revised, with 27 recognised species from both Oriental and Palaearctic China. The following 14 species are described as new to science: D. rectangularis sp. nov., D. capillais sp. nov., D. proxima sp. nov., D. longisetalis sp. nov., D. infrequens sp. nov., D. dentiretusa sp. nov., D. aspinula sp. nov., D. separata sp. nov., D. microtrichina sp. nov., D. dilatata sp. nov., D. disparilis sp. nov., D. carinata sp. nov., D. cespitula sp. nov., D. triangula sp. nov. D. microspinosa Shen & Liu, 2009 is regarded as a junior subjective synonym of D. prescherweberae Liu, 2001 and D. rectilinearis Liu, 2001 is a junior subjective synonym of D. malaysiae Green, 1997. Most known species were re-identified, re-described and illustrated. A revised key to Chinese male species is presented. PMID- 26250187 TI - Cycadophila, a new genus (Coleoptera: Erotylidae: Pharaxonothinae) inhabiting Cycas debaoensis (Cycadaceae) in Asia. AB - Asian species assigned to Pharaxonotha Reitter formed a separate clade from New World species of the genus and are distinguished on the basis of morphology and analysis of 16S rRNA gene sequences. Cycadophila, new genus, is described based on a consideration of four Asian species in comparison with New World Pharaxonotha. This new genus includes two new species (Cycadophila debaonica new species and Cycadophila fupingensis new species) and two previously described species (Cycadophila nigra (Gorham) new combination and Cycadophila yunnanensis (Grouvelle) new combination). These latter two may represent species complexes. Lectotypes are designated for Thallis nigra Gorham and Pharaxonotha yunnanensis Grouvelle. Larvae of C. debaonica and C. fupingensis are described based on individuals collected on the cones of Cycas debaoensis Y. C. Zhong & C. J. Chen (Cycadaceae), a cycad native to Guangxi and Yunnan provinces, China. PMID- 26250190 TI - Size-defined morphotypes in Zoanthus (Hexacorallia: Zoantharia) populations on shores in KwaZulu-Natal, South Africa. AB - Colonial zoanthids are a conspicuous feature of the subtropical rocky intertidal in KwaZulu-Natal but those of the genus Zoanthus have a confused taxonomy with 10, difficult to separate, nominal species described from the region. This paper presents an analysis of polyp size, measured as mean diameter determined photographically from the number of polyps occupying an area of 6 * 4 cm(2). The results, based on diameter frequency of 127 samples from five shores, indicate three populations (morphotypes) with means of 4.3 (SD +/-0.53), 5.7 (SD +/-0.70) and 8.4 (SD +/-0.58) mm occurring in the approximate abundance ratios of 10:5:1, possibly corresponding to Zoanthus sansibaricus, Z. natalensis and Z. lawrencei. The underlying assumptions with regard to population structure (the number, size and degree of fragmentation of clones) and the normality of data are discussed, as are trans-oceanic larval dispersal, recruitment, and genetic connectivity. The essential, traditional species description in Zoanthus, using internal morphology, on its own may be an inadequate discriminator of species. The status of the few possibly valid species is discussed in relation to the present results and recent studies based on the application of molecular genetics. Thorough studies of the population structure (genets and ramets) and a taxonomic approach based on the combined use of morphology, genetic methods and statistically robust, quantitative morphometrics are proposed as a potential way forward. PMID- 26250191 TI - Description of Trischistoma abharensis n. sp. (Nematoda: Trischistomatidae) and first record of Tripylella intermedia (Butschli, 1873) Brzeski & Winiszewska Slipinska, 1993 (Nematoda: Tripylidae) from Iran. AB - Two populations of the genera Trischistoma and Tripylella were recovered from the rhizosphere of grapevines and mosses growing on alder trees in Zanjan and Guilan provinces, respectively, Iran. The nematodes were identified as Trischistoma abharensis n. sp. and Tripylella intermedia, respectively. Trischistoma abharensis n. sp. is characterized by having females with body length 1069-1322 MUm, presence of sparse somatic setae on the sublateral body, absence of ventromedian cervical setae, a distinct dorsal tooth directed anteriorly, absence of post-vulval uterine sac, and tail with one pair of subdorsal caudal setae. Males were not found. Tripylella intermedia is characterised by having females with body length 905-990 MUm, annulated cuticle, stoma with two chambers: with dorsal tooth lying in posterior buccal chamber, and one large subventral and one small subventral tooth, respectively lying in posterior and anterior buccal chambers, cardiac glands large, composed of six fused cells, and tail 121-155 MUm long, ventrally bent, anterior half broad, then suddenly narrowing, with posterior half tapered narrowly and cylindrically. The phylogenetic relationships of both species were analysed using sequences of the partial small subunit (SSU) and D2/D3 expansion segments of large subunit (partial LSU) of ribosomal RNA genes and are discussed. PMID- 26250188 TI - Morphological and molecular review of the Gekko diversity of Laos with descriptions of three new species. AB - A review of the taxonomy, phylogeny, zoogeography, and ecology of the genus Gekko in Laos is provided based on morphological and molecular datasets. Three new species, which are both morphologically distinctive and molecularly divergent from described congeners, are described from Khammouane Province, central Laos: two members of the G. japonicus group, Gekko bonkowskii sp. nov. and Gekko sengchanthavongi sp. nov., and another member of the G. petricolus group, Gekko boehmei sp. nov. Gekko bonkowskii sp. nov. is closely related to the recently described G. thakekensis, which also occurs in Khammouane Province. Gekko sengchanthavongi sp. nov. is supported as a sister taxon to G. scientiadventura and Gekko boehmei sp. nov. is recovered as a sister species to G. petricolus. In addition, a key to the currently recognized members of the genus Gekko from Laos is provided. PMID- 26250196 TI - Description of three new species of Moenkhausia (Teleostei, Characiformes, Characidae) with the definition of the Moenkhausia jamesi species complex. AB - From the examination of extensive comparative material currently identified as M. jamesi we verified that there are, at least, three new species under this name. These, along with M. jamesi and M. justae, form what we herein called the M. jamesi species complex, by sharing the following group of characters: a short maxilla, with its distal margin not exceeding anterior third of the second infraorbital; first through third teeth of the inner row of premaxilla and first and second dentary teeth with cusps arranged in a pronounced arch, humeral spot positioned between the fourth and seventh scales of the lateral line and extending up to four scale rows above the lateral line and one scale row below the lateral line, and a vertically oval to round spot at the base of the caudal fin rays. Moenkhausia ischyognatha sp. n., from Rio Xingu basin, differs from the other species of the complex by its lower head depth. Moenkhausia alesis sp. n., from the river system Tocantins-Araguaia, differs from M. jamesi, M. ischyognatha, and M. sthenosthoma by the number of scale rows above the lateral line. Moenkhausia sthenosthoma sp. n., from the Rio Madeira basin, differs from M. jamesi by the number of scale rows between the lateral line and the midventral scale series. Moenkhausia justae can be diagnosed from the other species of the complex by having a tri to pentacuspidate tooth on the maxilla. PMID- 26250195 TI - The different meanings of the nomen Amphibia: a correction. AB - I recently published a survey of the different meanings of the nomen Amphibia in taxonomic publications since 1758 (Dubois 2015). The 'meaning' of a nomen in zoological nomenclature depends on the system used for the allocation of nomina to taxa, and several such systems can be used (see e.g. Dubois 2006a-b). In the paper at stake, I used the 'orostensional nomenclatural system' (OONS) for class series nomenclature. In this system, a class-series nomen-i.e., a nomen above the rank superfamily, therefore one whose taxonomic allocation is not regulated by the Code (Anonymous 1999)-applies, in a given classification, to the most inclusive class-series taxon that includes all its originally expressly included nominal genera (conucleogenera) and excludes all its originally expressly excluded nominal genera (alienogenera)-if such a taxon indeed exists in this classification. However, if one a least of the alienogenera is now part of the most inclusive taxon including all the conucleogenera, the nomen cannot be taxonomically allocated and qualifies as an anaptonym in the classification used as reference (Dubois 2006a-b, 2011), although it may not be so under another taxonomic frame. PMID- 26250194 TI - Discovery of the genus Loeblites Franz (Coleoptera: Staphylinidae: Scydmaeninae) in China, with description of a new species. AB - Loeblites chinesis sp. n. (Scydmaeninae: Cyrtoscydmini) from Yunnan, southern China is described, and its important diagnostic characters are illustrated. This species represents the first record of Loeblites in China. A single female of Loeblites from Tengchong, Yunnan is also recorded. It is similar to Loeblites mastigicornis from Thailand in general habitus and form of the spermatheca, but the identity of this species remains unconfirmed until males are found. PMID- 26250199 TI - The riffle beetles (Coleoptera: Elmidae) of the Eocene Baltic amber: Heterelmis groehni sp. nov. and Heterlimnius samlandicus (Bollow, 1940) comb. nov. AB - The Eocene elmid beetles known from Baltic amber so far are reviewed, and their natural environment is discussed. Palaeoriohelmis samlandica Bollow, 1940 is re described based on examination of the holotype. The genus Palaeoriohelmis Bollow, 1940 is synonymized with Heterlimnius Hinton, 1935, and Palaeoriohelmis samlandica is transferred to Heterlimnius (H. samlandicus comb. nov.). Heterelmis groehni sp. nov. is described and illustrated. Elmadulescens rugosus Peris, Maier & Sanchez-Garcia, 2015 from Cretaceous Spanish amber is removed from Elmidae. PMID- 26250193 TI - A new species of Telenomus Haliday (Hymenoptera: Platygastridae) egg parasitoid of Parides ascanius (Cramer) (Lepidoptera: Papilionidae), a threatened species from Brazil. AB - Telenomus parides Loiacono et Margaria sp. nov., is described and illustrated based on specimens reared from the eggs of Parides ascanius (Cramer). Parides ascanius is a threatened papilionid, which is endemic to the restingas of the Atlantic Forest of Rio de Janeiro, Brazil. The new Telenomus species is gregarious endoparasitoid and belongs to the Telenomus californicus species complex. PMID- 26250203 TI - A review of the genus Aalatettix with the description of a new species from China (Orthoptera: Tetrigidae). AB - A new species, i.e., Aalatettix nyalamensis sp. nov. is described from the Xizang Autonomous Region of China. All seven known species of genus, including A. nyalamensis sp. nov., were reviewed and a key to species of the genus Aalatettix is given. Type specimens are deposited in the Institute of Zoology, Shaanxi Normal University. PMID- 26250192 TI - New species of Cerambycinae from the Neotropical Region, and nomen novum for Anelaphus maculatus Galileo, Martins, and Santos-Silva, 2014 (Elaphidiini). AB - Six new species and one new genus are described: Criodion spinosum sp. nov. (Cerambycini), from Bolivia; Eburodacrys wappesi sp. nov. and Eburodacrys skillmani sp. nov. (Eburiini), from Bolivia; Eupempelus rileyorum sp. nov. (Heteropsini) from Panama; Sphalloeme mexicana sp. nov. (Oemini), from Mexico; Wappesoeme camiri sp. nov., new genus (Oemini), from Bolivia. Wappesoeme, Eburodacrys wappesi, E. skillmani, Eupempelus rileyorum, and Criodion spinosum are included in previously published keys. Anelaphus erakyra nomen novum for A. maculatus Galileo et al., 2014 is established. PMID- 26250202 TI - Clidicus chinensis n. sp. from Hainan, the first species of the Mastigitae from China (Coleoptera: Staphylinidae: Scydmaeninae). AB - The first species of the mastigite genus Clidicus Laporte (Coleoptera: Staphylinidae: Scydmaeninae) from China is described, under the name of Clidicus chinensis n. sp. The type material has been collected in Jianfengling (Hainan prov.); the habitus, aedeagus and spermatheca of the new species are illustrated. PMID- 26250201 TI - Four new species of Astenus (Eurysunius) Dejean, 1833 from Western Anatolia, Turkey (Coleoptera: Staphylinidae, Paederinae). AB - Four new species of Astenus (Eurysunius) Dejean (Staphylinidae: Paederinae) are described from Western Anatolia, Turkey, and illustrated: Astenus gusarovi sp. n. (Cokelez Mountain, Denizli province), A. orgeli sp. n. (Imambaba Tepesi, Aydin province and Bozdaglar, Izmir province), A. kumlutasi sp. n. (Akdaglar, Kutahya province and Murat Mountain, Usak province) and A. honazicus sp. n. (Honaz Mountain, Denizli province). Additional records and updated distributions are provided for A. occiduus Assing, A. sultanicus Assing, and A. sandiklicus Anlas. Distributions of Eurysunius species in Western Turkey are mapped. PMID- 26250206 TI - The Linsenmaier Chrysididae collection housed in the Natur-Museum Luzern (Switzerland) and the main results of the related GBIF Hymenoptera Project (Insecta). AB - Historical notes on Walter Linsenmaier, his entomological career and his Chrysididae collection are given. The purpose of this article is to supply the main results obtained during the GBIF digitalization project and the subsequent reorganization of the Chrysididae collection housed in the Natur-Museum Luzern (Switzerland); we also provide the complete list of the 720 taxa described by the Swiss author (species-group and genus-group names). Observations on the type material is given. A new synonymy (valid name is first) is proposed for: C. consanguinea Mocsary, 1889 = C. consanguinea iberica Linsenmaier, 1959, syn. nov.; C. pyrophana Dahlbom, 1854 = C. pyrophana var. orionea Linsenmaier, 1951, syn. nov.; Hedychridium elegantulum du Buysson, 1887 = H. hybridum Linsenmaier, 1959, syn. nov.; H. perpunctatum Balthasar, 1953 = H. insequosum Linsenmaier, 1959, syn. nov.; Euchroeus (Pseudospinolia) incrassatus (Spinola, 1838) = E. (P.) humboldti jerichoensis Linsenmaier, 1959, syn. nov. A new replacement name Chrysis vulcanica Rosa, nom. nov. is proposed for Chrysis brevicollis Linsenmaier, 1987, nom praeocc., nec Mocsary, 1899. The lectotype of Chrysis auriceps Linsenmaier, 1959 is designated. PMID- 26250198 TI - Re-evaluation of Tellervotrema katadara (Kuramochi, 2001) Kuramochi, 2009 (Opecoelidae: Plagioporinae) and supplementary morphological data for T. beringi (Mamaev, 1965) Gibson & Bray, 1982 with new host and locality. AB - The trematode genus Tellervotrema Gibson & Bray, 1982 was erected for Podocotyle like species that parasitize archybenthal macrourid fishes (also known as grenadiers or rattails) and that possess no vitelline follicles dorsal to the ceca but do have a symmetrical pair of isolated groups of vitelline follicles in the posterior forebody. Tellervotrema katadara (Kuramochi, 2001) Kuramochi, 2009 is resurrected as a valid species based on an examination and re-description of holotype and paratype specimens collected from the intestine of the bathygadine macrourid Gadomus colletti Jordan & Gilbert from 518-582 m depth in Tosa Bay, off the Pacific coast of southern Japan. Tellervotrema beringi (Mamaev, 1965) Gibson & Bray, 1982 is re-described from specimens originally identified as T. katadara, collected from the intestine of the longfin grenadier, Coryphaenoides longifilis Gunther, and found at 1,196 m depth off the Pacific coast of the Tohoku region, northern Honshu, Japan. New host and locality records for T. beringi are presented along with a brief listing of museums housing type and voucher specimens of the three species now recognized in Tellervotrema. A comprehensive listing is given of all parasites reported from the two macrourid species relevant to this study and a key is presented for members of Tellervotrema. Finally, we hypothesize that the life cycles for T. beringi and T. katadara in the deep waters of the North Pacific Ocean off Japan most likely include a gastropod as a first intermediate host, one or more of a variety of invertebrates (amphipods, decapods, mysids) and/or finfish as second intermediate hosts, and the grenadiers, C. longifilis and G. colletti, as definitive hosts, respectively. PMID- 26250207 TI - Taxonomic revision of the Dichotomius speciosus (Waterhouse, 1891) species group (Coleoptera: Scarabaeidae: Scarabaeinae). AB - The Dichotomius speciosus species group, endemic to the highlands of the Brazilian Atlantic Forest and included in the subgenus Luederwaldtinia is taxonomically revised. Dichotomius alvarengai new species and D. malyi new species are described. Dichotomius bucki is here considered to be a new synonym of D. opalescens, for which a lectotype is designated. The group, as well as its species, is diagnosed. A taxonomic key, illustrations and discussions on systematics and conservation of the group are provided. PMID- 26250197 TI - Molecular phylogenetic position of endangered Wilfredomys within Sigmodontinae (Cricetidae) based on mitochondrial and nuclear DNA sequences and comments on Wiedomyini. AB - Wilfredomys, a monotypic genus of endangered sigmodontine rats, was historically related to the tribe Thomasomyini or considered "incertae sedis". Given no molecular data is available for Wilfredomys, the phylogenetic position of this taxon is uncertain in relation to modern, molecular hypotheses of sigmodontine relationships. We investigate the phylogeny of Wilfredomys to provide a hypothesis of its position within Sigmodontinae based on nuclear and mitochondrial DNA sequences. Bayesian and maximum likelihood phylogenetic analyses recovered Wilfredomys oenax as sister to Wiedomys pyrrhorhinos, and Wie. cerradensis fell out sister to this clade. At the genus level, Phaenomys is sister to Wilfredomys + Wiedomys, forming a novel and well-supported sigmodontine clade. Our results suggest that tribe Wiedomyini should encompass Wilfredomys in addition to Wiedomys and Cholomys, thus the hypothesis that Wiedomys is paraphyletic should be investigated further. Another plausible classification scheme consistent with our results would be to expand Wiedomyini to encompass the clade composed of Phaenomys + Wilfredomys + Wiedomys. Last, our recovery of an "Atlantic clade" composed of lineages restricted to eastern South America supports the idea that this region has likely played an important role in sigmodontine diversification. PMID- 26250204 TI - On the genus Sunius Curtis, 1829 of Turkey II. Two new micropterous species and additional records from Western Anatolia (Coleoptera: Staphylinidae: Paederinae). AB - Two new species of the genus Sunius Curtis, 1829 are described from Denizli province of Western Anatolia and illustrated: Sunius yagmuri sp. n. from Akkaya Hill and Sunius golgeliensis sp.n. from Golgeli Mountains. Additional records of five species of Sunius are reported. A total of 32 species are now known from Turkey, 28 of them are endemic. PMID- 26250205 TI - The authorship of Neolissochilus soro (Cypriniformes: Cyprinidae): a correction to Khaironizam et al. (2015). AB - In a meristic, morphometric and distributional study of Neolissochilus from Peninsular Malaysia, Khaironizam et al. (2015) subsumed Lissochilus tweediei Herre in Herre & Myers 1937 and a taxon they called "Tor soro Bishop 1973" into the synonymy of N. soroides (Duncker 1904) based on data collected from museum specimens. However, "Bishop 1973" is not the correct author citation for Tor soro. Instead, Tor (now placed in Neolissochilus) soro was originally described as Barbus soro by Valenciennes in Cuvier & Valenciennes (1842:191). Since "Tor soro Bishop 1973" is not a valid name/author combination, Neolissochilus soro, as treated by Khaironizam et al. (2015), cannot be considered a junior synonym of N. soroides. PMID- 26250208 TI - A new genus and species of Tarsonemidae (Acari: Heterostigmata) from the Atlantic Forest, Brazil. AB - Kaliszewskia ochoai gen. nov., sp. nov. (Tarsonemidae: Tarsoneminae: Tarsonemini) is described from adult females, collected on Blepharocalix salicifolius (Kunth) O.Berg and Plinia sp. (Myrtaceae), from the Atlantic Forest in Brazil. PMID- 26250209 TI - First record of the genus Hephathus Ribaut (Hemiptera: Cicadellidae: Macropsinae) from China. AB - The genus Hephathus with its species Hephathus freyi (Fieber, 1868) is recorded for the first time from China. A new species Hephathus dilatatus is described and illustrated. An updated species checklist with distribution of the genus Hephathus is also provided. PMID- 26250200 TI - Pumiliofossorum: A new genus of Scotobiini (Coleoptera: Tenebrionidae) with two new species from Peru, and a revised key for the genera of the tribe. AB - A new genus, Pumiliofossorum Silvestro & Giraldo gen. nov. (Tenebrioninae: Scotobiini) and two new Peruvian species, Pumiliofossorum moche Silvestro & Flores sp. nov. and P. sechurae Giraldo & Flores sp. nov. are described and illustrated. Distributional data, habitat records, photographs, and SEM images are included. A revised key for the six genera of Scotobiini is provided. Morphology of the newly described genus is discussed in reference to the other genera of Scotobiini. Dome-shaped placoid sensoria are imaged for the first time in Scotobiini. PMID- 26250210 TI - A new species of Aspidoras Ihering (Siluriformes: Callichthyidae: Corydoradinae) from the Rio Xingu Basin, Para, Brazil. AB - A new species of Aspidoras is described from an unnamed stream in the Rio Xingu Basin, Castelo de Sonhos municipality, Para State, representing the northernmost record of the genus along the edge of the Brazilian Shield in the Amazon Basin. Aspidoras marianae is easily distinguished from all congeners in having minute odontode-bearing platelets scattered over the surface of the snout region, minute platelets between the parieto-supraoccipital process and the nuchal plate, and other shared features related to color pattern, morphometrics, meristics and morphological data. Comments about exclusive and shared features are presented. PMID- 26250212 TI - A new species of the genus Oxyporus Fabricius (Coleoptera: Staphylinidae: Oxyporinae) in Yunnan, China. AB - Oxyporus (Oxyporus) bingshengae sp. nov. in Yunnan, China, is described. Color images of the habitus and aedeagus of the new species are included. A key to the species of Oxyporus of Yunnan is provided. PMID- 26250213 TI - Neotype designations and nomenclatural actions for Apionidae described by Johann Ludwig Christian Carl Gravenhorst in 1807 (Coleoptera, Curculionoidea). AB - In accordance with the International Code of Zoological Nomenclature with the express purpose of clarifying the systematic status of some species, neotypes are designated for Apion atratum Gravenhorst, 1807, Apion chloris Gravenhorst, 1807, Apion longirostre Gravenhorst, 1807 and Apion pilosellum Gravenhorst, 1807. Three new synonymies are proposed: Perapion hydrolapathi (Marsham, 1802) = Apion atratum Gravenhorst, 1807, syn. n., Ischnopterapion virens (Herbst, 1797) = Apion chloris Gravenhorst, 1807, syn. n. and Eutrichapion vorax (Herbst, 1797) = Apion longirostre Gravenhorst, 1807, syn. n. The junior primary homonym Apion atratum Wagner, 1908 (non Gravenhorst, 1807) is replaced by Pseudopiezotrachelus gravenhorsti nom. n. PMID- 26250211 TI - Leleshusia, a new replacement name for Granulina Leleshus, 1975 (Anthozoa: Heliolitoidea) nec Jousseaume, 1888 (Gastropoda: Neogastropoda: Marginellidae). AB - The genus Granulina (type species Plasmoporella granulosa Bondarenko, 1958, by original designation) was established by Leleshus (1975: 7) for a distinctive heliolitoid genus from the Upper Ordovician of Kazakhstan and Tajikistan. However, the name Granulina Jousseaume, 1888 (p. 191), which designates a genus of a living molluscs (Gastropoda: Neogastropoda: Marginellidae: Granulininae), has priority over the fossil generic name, which is its junior homonym. PMID- 26250216 TI - The fauna of the family Bombycidae sensu lato (Insecta, Lepidoptera, Bombycoidea) from Mainland China, Taiwan and Hainan Islands. AB - Seventy-seven species of family Bombycidae s. lat., belonging to 25 genera in three subfamilies, that have been recorded from China are listed and described, with illustrations of the adults, preimaginal stages (if available), and their genitalia. Keys to subfamilies and genera are provided. Two new genera and four new species are described, two subgenera are raised to generic status, seven new combinations are made, and one genus and six species are newly recorded from China. The new taxa are as follows: Rotunda Wang, X. & Zolotuhin, gen. nov., Comparmustilia Wang, X. & Zolotuhin, gen. nov., Triuncina daii Wang, X. & Zolotuhin, sp. nov., Triuncina xiongi Wang, X. & Zolotuhin, sp. nov., Gnathocinara boi Wang, X. & Zolotuhin, sp. nov. and Promustilia yajiangensis Wang, X. & Zolotuhin, sp. nov. The taxa newly recorded for China are: Sesquiluna Forbes, 1955; Trilocha friedeli Dierl, 1978; Bivincula kalikotei Dierl, 1978; Sesquiluna forbesi Zolotuhin & Witt, 2009; Mustilizans lepusa Zolotuhin, 2007; Smerkata brechlini (Zolotuhin, 2007) and Mustilia castanea Moore, 1879. The seven new combinations are: Rotunda rotundapex (Miyata & Kishida, 1990), comb. nov., Triuncina nitida (Chu & Wang, L.Y., 1993), comb. nov., Gunda sesostris (Vuillot, 1893), comb. nov., Smerkata fusca (Kishida, 1993), comb. nov., Comparmustilia sphingiformis (Moore, 1879), comb. nov., Comparmustilia semiravida (Yang, 1995), comb. nov., Comparmustilia gerontica (West, 1932), comb. nov.. The two subgenera raised to generic level are: Promustilia Zolotuhin, 2007, stat. nov. and Smerkata Zolotuhin, 2007, stat. nov.. The distributions of the species in China were determined and distributional maps provided. All type specimens of the new species described here are deposited in the College of Plant Protection, Hunan Agricultural University, China (HUNAU); Department of Entomology, South China Agricultural University, China (SCAU); Kyushu University Museum, Kyushu University, Japan (KUM), and Entomological Museum Thomas J. Witt, Munich, Germany (MWM). PMID- 26250220 TI - Three new genera of Schizopteridae from Australia with description of six new species (Hemiptera: Heteroptera: Schizopteridae). AB - From Australia, three new schizopterid genera are described for six new species. The three new genera and Pachyplagioides Gross, 1951 share a declivent head with well-developed internal postocciptal region and a 3-segmented labium with bulbous base. The new genera and species are Parvodeceptor infrequens gen. n., sp. n., Dextritubus cucullatus gen. n., sp. n., D. acucullatus gen. n., sp. n., D. nubis gen. n., sp. n., Carinatala septentrionalis gen. n., sp. n. and C. meridiana gen. n., sp. n. Their description brings to near completion the known generic diversity of Australian Schizopteridae. Parvodeceptor has superficially hypselsomatine facies and may have affinity with the African Humpatanannus Wygodzinsky 1950. Dextritubus has accessory male genitalia reminiscent of Semangananus Stys, 1974 and Vilhenannus Wygodzinsky, 1950. Carinatala has dentate male fore and mid claws, not previously recorded in the family, and an unusual inflatable, spiculate vesica reminiscent of Dundonannus Wygodzinsky 1950. The retention of the internal postocciptal region in several schizopterid genera and lack of its correlation with declivent versus porrect head condition is outlined. PMID- 26250214 TI - CURRENT STATUS OF KNOWLEDGE OF SPHINGIDAE LATREILLE, 1802 (LEPIDOPTERA: BOMBYCOIDEA) IN COLOMBIA. AB - A list of species and a photographic catalog of moths of the family Sphingidae reported for Colombia is presented. Following examination of 1463 specimens deposited in major entomological collections of Colombia, and a review of the literature, 188 species are reported for the country, of which 19 species and Phryxus genus are reported for the first time for Colombia. The genus Xylophanes has the most species recorded and also the most geographical records. The Andean region has the highest number of records. A diagnosis of each subfamily and genus, comments on the biology of many of the reported species and dichotomous keys are also presented. PMID- 26250217 TI - A catalogue of the Chrysididae (Insecta, Hymenoptera) types deposited in the Zoological Museum, Moscow Lomonosov State University, Russia. AB - A critical and annotated catalogue of 52 types of Chrysididae belonging to 32 species deposited in the Zoological Museum of Moscow Lomonosov State University is given. The lectotypes of Chrysis sabulosa Radoszkowski, 1877 and Ellampus (Philoctetes) fedtschenkoi Semenov, 1932 are designated. New synonyms are proposed for (valid name first): Omalus imbecillus (Mocsary, 1889) = Ellampus kozhevnikovi Semenov, 1932, syn. nov., and Chrysis speciosa Radoszkowski, 1877 = C. fulvicornis Mocsary, 1889, syn. nov. The status of Hedychridium erschovi (Radoszkowski, 1877), stat. resurr. is revalidated. PMID- 26250218 TI - Hypandrium as a key character in resolving species-level taxonomy on the example of Perisama oppelii (Latreille) (Lepidoptera: Nymphalidae, Biblidinae). AB - A detailed comparative study of the subspecies of Perisama oppelii (Latreille, [1809]) is carried out. Ten out of eleven subspecies are illustrated, including the females of P. o. bleuzeni Attal & Crosson du Cormier, 1996 and P. o. cristal Attal & Crosson du Cormier, 1996 for the first time. Male genitalia of P. o. amalia Oberthur, 1916, P. o. bleuzeni, P. o. cristal, P. o. erebina Oberthur, 1916, P. o. oppelii (Latreille, [1809]), P. o. viridinota Butler, 1873, and P. o. xanthica (Hewitson, 1868), as well as female genitalia of P. o. bleuzeni, P. o. cristal and P. o. oppelii are also presented for the first time. Based on the characters of hypandrium, a separate specific status is proposed for P. bleuzeni stat. n. Taxonomical value of the hypandrium is evaluated. The co-evolution of male and female genitalia is discussed. PMID- 26250215 TI - A revision of the fish genus Oxyurichthys (Gobioidei: Gobiidae) with descriptions of four new species. AB - The widespread tropical gobionelline fish genus Oxyurichthys is monophyletic due to its species sharing two characters considered derived within the Stenogobius Group of the Gobionellinae (Gobioidei: Gobiidae), a transversely broadened (spatulate) third neural spine that is usually bifid, and no preopercular cephalic lateralis canal. It is most closely related to Oligolepis, also of the Indo-west Pacific, and Ctenogobius, an Atlantic-eastern Pacific genus. Sixteen valid species of Oxyurichthys are redescribed and illustrated and four new species are described, O. limophilus from the western Indian Ocean, O. rapa from French Polynesia, and O. chinensis and O. zeta from the western Pacific. Nineteen species share two additional synapomorphies, a rounded fleshy tongue and a palatine lacking an elongate posterior strut, and form the sister group to the plesiomorphous Oxyurichthys keiensis, known from South Africa and Madagascar. One species, O. stigmalophius, occurs in the western Atlantic. There are no records of this genus from the continental eastern Pacific or the eastern Atlantic. Previous accounts from the Gulf of Guinea region of West Africa are references to Gobionellus occidentalis. Many Oxyurichthys species are limited to shallow estuarine and coastal waters with bottom substrates of silt or other fine sediments, but several are known from depths exceeding 10 m and are often collected by trawling. PMID- 26250221 TI - Revision of the Urophora xanthippe species group, with description of new species (Diptera: Tephritidae). AB - The xanthippe group of species of the genus Urophora Robineau-Desvoidy, 1830 is revised and keyed. It contains seven species with a yellow area on the scutum medial to the notopleuron: Urophora bakhtiari new species (from flowerheads of Cousinia archibaldii), Urophora dirlbeki new species (from flowerheads of Onopordum acanthium), U. iani Korneyev & Merz 1998, U. impicta (Hering 1942) (= Urophora hermonis Freidberg 1974, new synonym), U. kasachstanica (Richter 1964), U. stalker Korneyev 1985, and U. xanthippe (Munro 1934). All the species are described, illustrated and keyed. PMID- 26250225 TI - A new species of Isocossus Roepke, 1957 (Lepidoptera: Cossidae) from Vietnam, including a world catalogue of the genus. AB - Isocossus zolotuhini Yakovlev sp. nov. is described from central Vietnam. PMID- 26250224 TI - Orientozeuzera martinii sp. nov., a new species of Carpenter-Moths (Lepidoptera: Cossidae) from Borneo. AB - Orientozeuzera martinii Yakovlev & Witt sp. nov. is described from Borneo Island (Trus Madi). PMID- 26250219 TI - The Cossidae (Lepidoptera) of Afghanistan with description of three new species and special notes on the fauna of Bande-Amir National Park. AB - The annotated list of Cossidae of Afghanistan consists of 44 species in 17 genera from the four subfamilies Catoptinae, Cossinae, Zeuzerinae, and Mehariinae. Three new species are described: Cossulus habibae Yakovlev, Pljustch, Skrylnik & Pak, sp. nov., Semagystia bamiani Yakovlev, Pljustch, Skrylnik & Pak, sp. nov., Phragmacossia bandeamiri Yakovlev, Pljustch, Skrylnik & Pak, sp. nov.; all from Band-e-Amir National Park in Bamian Province. Three species (Dervishiya cadambae (Moore, 1865), Semagystia cossoides (Graeser, 1892), Phragmacossia territa (Staudinger, 1879)) are reported for the first time from Afghanistan. A brief biogeographical analysis of the Cossidae of Afghanistan is given. PMID- 26250222 TI - Lepadichthys bilineatus, a new species of clingfish from Oman (Teleostei: Gobiesocidae), with a redescription of Lepadichthys erythraeus Briggs and Link from the Red Sea. AB - Lepadichthys bilineatus is described as a new species of gobiesocid fish from a single specimen, 23.5 mm in standard length, collected from 1.5 m in a tidepool on the southeastern coast of Oman. It is distinct from other Lepadichthys species in having the following combination of characters: dorsal-fin rays 16; anal-fin rays 13; pectoral-fin rays 23; principal caudal-fin rays 10; gill rakers 10 on second and third arch; head large, its length 3.1 in SL; body depth 8.0 in SL; disc single; disc length 6.6 in SL; disc width 6.5 in SL; color in alcohol uniform tan; color when fresh: body grayish blue, grading to brownish red posteriorly; head dark brown dorsally, abruptly pale yellowish below eye, with two whitish lines extending posteriorly and slightly ventrally from eye. Lepadichthys erythraeus, a species thus far known only from the Red Sea , is redescribed based on additional diagnostic characteristics and color photos. PMID- 26250223 TI - Endemic Lake Baikal sponges from deep water. 1: Potential cryptic speciation and discovery of living species known only from fossils. AB - We revealed new deep-water species and cryptic speciation within freshwater sponges of the endemic family Lubomirskiidae (Porifera; Demospongiae; Spongillina) based on molecular and spicule morphology analyses of ITS and CO1 mtDNA. Lubomirskiidae contains a group of closely related species which are a dominant component of the benthos in Lake Baikal, the world's deepest and most ancient lake. Spicule morphology was similar between two Recent samples and species only known previously from fossils in Late Pliocene (3.2-2.8 mya) sediments. Despite the morphological similarity with the cosmopolitan family Spongillidae, molecular analysis of ITS sequences has reliably assigned these species to Lubomirskiidae. This not only indicates that species identification of freshwater fossil sponge spicules should be made with caution, but also suggests that the structure of megascleres may not be a reliable character for interpretations of paleoclimatic reconstructions for the Baikal region. Our results do not support the current classification of Lubomirskiidae into its morphologically defined genera and species, suggesting a strong discrepancy between molecular and morphological variation in Baikalian sponges. This present contribution is the first part of a study on the phylogenetic relationships of the Lake Baikal deep water sponge fauna. PMID- 26250226 TI - A new species of Isoceras Turati, 1924 (Lepidoptera: Cossidae) from Armenia. AB - Isoceras shevnini Yakovlev sp. nov. is described from Armenia. PMID- 26250227 TI - Taxonomy of the subgenus Quedius (Raphirus) Stephens (Coleoptera: Staphylinidae: Staphylinini: Quediina) with descriptions of four new species from China. AB - Four new species of the subgenus Raphirus Stephens, 1829 of the genus Quedius Stephens, 1829 (Coleoptera: Staphylinidae: Staphylinini: Quediina) are described based on specimens collected from China: Q. (Raphirus) hubeiensis sp. nov. from Hubei, Q. (Raphirus) ningxiaensis sp. nov. from Ningxia, Q. (Raphirus) spissus sp. nov. from Sichuan, and Q. (Raphirus) tenuiculus sp. nov. from Fujian. The females of Q. (Raphirus) oros Smetana, 2011 and Q. (Raphirus) shunichii Smetana, 2010 are described for the first time. Q. (Raphirus) kuiro Smetana, 1988 is recorded for the first time from China. Line drawings and color illustrations of adults and genitalia of all these species and some other ones are provided. PMID- 26250228 TI - Acteonidae, Bullinidae and Ringiculidae (Gastropoda: Heterobranchia) from the Plio-Pleistocene of the Philippines. AB - Twenty-three species of Acteonidae, Bullinidae and Ringiculidae are documented from the so-called "Cabarruyan" fauna from the Plio-Pleistocene of Pangasinan, the Philippines. There are eleven species of Acteonidae, one species of Bullinidae and eleven species of Ringiculidae. Seven species are described here as new, these are: Bathyacteon valdesi nov. spec., Bullina virgoides nov. spec., Ringicula bella nov. spec., R. circumscripta nov. spec., R. caelestis nov. spec., R. opima nov. spec. and Microglyphis angulata nov. spec.. The presence of Acteonidae and Bullinidae indicates that polychaete worms were also present. PMID- 26250229 TI - The Cephenniini of China. VI. New species and new records of Cephennodes Reitter from Hainan, Guangxi and Guangdong (Coleoptera: Staphylinidae: Scydmaeninae). AB - Five new Chinese species of Cephennodes (s. str.) are described: C. bicavatus sp. n. (Guangdong), C. pseudobos sp. n. (Guangxi), C. huapingensis sp. n. (Guangxi), C. elevatus sp. n. (Guangxi), and C. gaozhaianus sp. n. (Guangxi). Cephennodes qiongdaoanus Jaloszynski and C. capricornis Jaloszynski are recorded for new localities in the provinces of Guangxi and Hainan, respectively. Diagnostic characters of all hitherto known representatives of the Cephennodes taurus, Cephennodes bos and Cephennodes impressifrons species groups are compiled. PMID- 26250233 TI - A new blind snake (Serpentes: Typhlopidae) from an endangered habitat in south eastern Queensland, Australia. AB - A new species of blind snake is described from south-eastern Queensland, eastern Australia. Anilios insperatus sp. nov. differs from all of its congeners in having:16 scales around the body; 442 paravertebral scales; snout slightly trilobed from above and bluntly angular in profile; small, inconspicuous eyes, located within the ocular scale at its junction with the preocular and the supraocular scales; and uniform light colouration. The unique specimen was collected from pasture that was formally Queensland regional ecosystem 12.8.24, a eucalypt dominated ecosystem currently listed as endangered. The site is less than 100 km from Queensland's capital, Brisbane. Given the locality, habitat and absence of additional specimens, the species is probably of conservation concern. PMID- 26250234 TI - Taxonomy of the Alloraphes-Stenichnaphes-Parastenichnaphes complex: Stenichnodes complicates the picture (Coleoptera: Staphylinidae: Scydmaeninae). AB - Examination of the holotype of the type species of Stenichnodes Franz revealed that morphological structures of this Afrotropical genus are nearly identical with those of later described Oriental Parastenichnaphes Franz. Consequently, Parastenichnaphes is reduced to a subgenus of Stenichnodes, resulting in Stenichnodes (Parastenichnaphes) sumatrensis Franz, comb. n. and Stenichnodes (Parastenichnaphes) ceylonensis Franz, comb. n. The subgenus Parastenichnaphes differs from Stenichnodes s. str. in notosternal sutures of the prothorax complete (and not obliterated anteriorly), subtriangular (and not very narrow and carinate) prosternal process and absence of lateral metaventral carinae. Stenichnodes and its type species are redescribed. PMID- 26250232 TI - Description of four new species of brachypterous Encyrtidae (Hymenoptera: Chalcidoidea) from India. AB - Four new brachypterous species of Encyrtidae (Hymenoptera: Chalcidoidea) are described. These are: Astymachus eximius Hayat, sp. nov., Ixodiphagus aethes Hayat, sp. nov., Monstranusia brachyptera Hayat, sp. nov., Ooencyrtus notialis Hayat, sp. nov. Brachyptery in the genera Astymachus Howard and Monstranusia Trjapitzin is reported for the first time. PMID- 26250235 TI - A new Polymixis (Lepidoptera, Noctuidae) species from China. AB - A new Polymixis Hubner species from China's Yunnan and Sichuan Provinces is described and distribution data for Polymixis albiorbis Hreblay & Ronkay, 1998 is provided. The type specimen of Polymixis albirena (Boursin, 1944) and the Polymixis magnirena (Alpheraky, 1892) holotype's genitalia are illustrated. PMID- 26250230 TI - New species and records of Neopronematus (Acari: Iolinidae) from Iran with a key to world species. AB - In this paper, Neopronematus kamalii Darbemamieh and Hajiqanbar sp. nov. (Acari: Prostigmata: Iolinidae), collected from apricot leaves in Kermanshah province, Iran, is described and illustrated. Also, the following species were collected and identified from Kermanshah province, Iran: Neopronematus rapidus (Kuznetzov, 1972), Neopronematus solani Laniecka and Kazmierski, 2013; Neopronematus sepasgosariani Sadeghi, Laniecka and Kazmierski, 2012; Neopronematus lundqvisti Sadeghi, Laniecka and Kazmierski, 2012; and Neopronematus neglectus (Kuznetzov, 1972). Some information about the genus, morphologically close species, remarks and a key to Neopronematus species of the world are given as well. PMID- 26250231 TI - A new species of the genus Liuixalus (Anura: Rhacophoridae) from southern China. AB - A new tree frog species of the genus Liuixalus was described from Heishiding Nature Reserve, Guangdong Province, China based on a combination of morphological characters and molecular phylogenetic analyses. Liuixalus feii sp. nov. is distinguished from its congeners by a combination of following characters: small size (SVL 16.2-17.6 mm in adult males and 18.0-18.7 mm in adult females); snout obtusely pointed; tympanum distinct, about half size of eye diameter; nostril closer to eye than to the tip of snout; fingers free of webbing; toe III longer than toe V; toes weakly webbed; tibiotarsal articulation reaching the naris or loreal; dorsal skin smooth and scattered with fine granulars; a subtle longitudinal median ridge present on dorsum; weak skin folds present on dorsal surface of body and thighs; supratympanic fold distinct and curved; ventral surface dull white with more or less irregular dark spots; iris bicolored. The new species appears to be forest-dependent and to date has only been found on the forest floor in primary forests at elevations between 350-800 m. Based on our molecular analyses, we consider Liuixalus catbaensis as a junior synonym of L. calcarius. Thus, with the description of the new species, the genus Liuixalus hitherto contains five recognized species, four of which are endemic to China. PMID- 26250236 TI - Nemopsis mianzani n. sp. (Hydrozoa, Bougainvilliidae), a new hydromedusa from central Chile. AB - The genus Nemopsis, a bougainvillid hydrozoan with a dominant medusa phase, currently includes three species (Nemopsis bachei, N. dofleini and N. hexacanalis), all characterized by the presence of a pair of club-shaped tentacles in the median portion of the marginal bulbs. In this paper, we describe a fourth species, based on the medusa collected off Dichato, central Chilean coast. PMID- 26250237 TI - Description of Laccomimus gen. n. and eleven new species from the Neotropical region (Coleoptera, Dytiscidae, Laccophilinae). AB - A new genus of laccophiline diving beetles, Laccomimus gen. n., is here described on the basis of a large number of specimens from various collections formerly misidentified as members of the Neotropical genus Laccodytes Regimbart, 1895. Except for similar size, however, the new genus is not closely related to Laccodytes. Instead, it seems to be sister to the Oriental genus Laccosternus Brancucci, 1983, both sharing a similar body size and shape, characters of the female genital structures, and shape of the prosternal process. Twelve species are recognised within Laccomimus, all new to science except Laccomimus pumilio (LeConte, 1878) comb. n., the type species. The new species are: Laccomimus alvarengi sp. n., L. amazonas sp. n., L. bolivari sp. n., L. bordoni sp. n., L. distinctus sp. n., L. improvidus sp. n., L. malkini sp. n., L. spangleri sp. n., L. spinosus sp. n., L. variegatus sp. n., L. youngi sp. n. The distribution of the new genus includes most of the Neotropics, with one species, L. pumilio, reaching Florida, USA. Each taxon is described and illustrated and a key for their identification is provided. Laccomimus is a widespread and relatively common genus in tropical America, the species of which have a wide distributional range, except for a few confined to more restricted areas. In spite of this, Laccomimus is a very uniform genus in body shape, size and colouration, and in most cases identification of the species is possible only after examination of the male genitalia. A key to distinguish genera of the tribe Laccophilini is also presented. PMID- 26250238 TI - The discovery of the genus Protodacnusa Griffiths, 1964 (Hymenoptera: Braconidae, Alysiinae) in China, with descriptions of six new species. AB - The genus Protodacnusa Griffiths, 1964 (Braconidae: Alysiinae: Dacnusini) is newly recorded from China with six new species being described, namely Protodacnusa defectivus sp. nov., P. dimorphus sp. nov., P. helanensis sp. nov., P. longicaudatus sp. nov., P. magnidentis sp. nov. and P. nigra sp. nov. A key to the species of Protodacnusa worldwide is provided. PMID- 26250239 TI - Phylogenetic relationships of the gray-toad agama, Phrynocephalus scutellatus (Olivier, 1807), species complex from Iran. AB - The gray toad agama, Phrynocephalus scutellatus (Olivier, 1807) species complex is confined to the Iranian plateau, and forms one of the most widespread, but rarely studied species of the family Agamidae. It represents a complex with many local populations inhabiting a variety of habitats, and exhibiting considerable morphological, genetic and ecological variations. We analyzed sequences of the mitochondrial ND2 gene and tRNA-Trp and tRNA-Ala derived from 89 geographically distant populations. The sequences data strongly support a basal separation of the populations of southeastern-south--central Iran from those occurring in the North. The subsequent radiation, fragmentation, and evolution of these major assemblages have led to four discernible geographical lineages in Iran: southeastern--south-central, west-central, east-northeastern and Khaf. The southeastern--south-central radiation is the earliest lineage and Khaf lineage is probably related to the Afghan plateau. Separation of northern clades from each other can be explained by the presence of large deserts in central Iran. Due to the lack of sufficient geological information, the divergence between the northern and southern clades cannot be explained by the present data. PMID- 26250240 TI - Crinoids of the stalked family Hyocrinidae (Echinodermata) collected by the USNS Eltanin in the Southern Ocean. AB - Rare species only known from one or a few specimens, mainly collected from abyssal and hadal zones in the Southern Ocean are represented in a collection of stalked crinoids attributed to the family Hyocrinidae (Crinoidea, Echinodermata). The species studied here include Belyaevicrinus latipinnulus Mironov & Sorokina, 1998, Feracrinus heinzelleri Bohn, 2012, Ptilocrinus brucei Vaney, 1908 and Thalassocrinus clausus Mironov & Sorokina, 1998. This collection, mainly collected during the 1960s USNS Eltanin cruises, is housed at the Smithsonian Institution National Museum of Natural History in Washington DC. A detailed study of this material using SEM observations of ossicle articular facets and pinnule architecture allows the emendation of species diagnoses, and a better description of intraspecific variation and of changes in characters through ontogeny. Geographical and depth range extension of species are reported. A gonad with submature ovocytes of 100-150 um was exceptionally preserved at the base of a genital pinnule of P. brucei. This species likely has a lecithotrophic larval development. PMID- 26250241 TI - A new genus and a new species of Sminthuridae (Collembola: Symphypleona) from Atlantic Forest of Brazil. AB - Sminthuridae comprises approximately 240 species distributed worldwide. In Brazil it is represented only by 11 species and four genera. Herein we describe a new genus and species of subfamily Sminthurinae from Atlantic Forest of Rio Grande do Norte State, Northeastern Brazil. The new described genus is similar to Gisinurus, Songhaica, Dietersminthurus and Soqotrasminthurus, especially in its unguis shape, with open cavity; but differs from all other genera of Sminthuridae by the presence of a single pretarsal chaeta in anterior side, smooth mucronal edges and a unique head chaetotaxy. PMID- 26250242 TI - A new species of Losdolobus Platnick & Brescovit 1994 (Araneae: Orsolobidae) from Argentina with notes on its ecology and distribution. AB - A new species of Losdolobus, L. nelsoni sp. nov., is described based on females and males collected from grasslands in the mountains of southern Buenos Aires province, Argentina. Additionally, the phenology of this new species is presented and some aspects of the biogeography and distribution of the genus are discussed. PMID- 26250243 TI - Macrocnemis gracilis, a new genus and species of Idiocnemidinae (Zygoptera: Platycnemididae) from Papua New Guinea. AB - A new genus and species belonging to the damselfly subfamily Idiocnemidinae from Papua New Guinea, Macrocnemis gracilis gen. nov. sp. nov. is described and illustrated. It is the largest known member of the Papuan idiocnemidine radiation, and its affinities to existing genera remain unclear. The new taxon is currently known with certainty only from small streams flowing through mid montane rainforest in the Hindenburg Range of Papua New Guinea's rugged central cordillera. PMID- 26250244 TI - Chileotrecha romero (Kraus, 1966) comb. nov. and Pseudocleobis patagonicus (Roewer, 1934) comb. nov. transferral from Mummuciidae to Ammotrechidae (Arachnida, Solifugae). AB - The solifuge species Mummucina romero Kraus, 1966, from Chile, and Mummucia patagonica Roewer, 1934, from Argentina, are here transferred from Mummuciidae Roewer, 1934 to Ammotrechidae Roewer, 1934. Chileotrecha romero (Kraus, 1966) comb. nov. and Pseudocleobis patagonicus (Roewer, 1934) comb. nov. are proposed. Comments on their morphology are made and previous distributional records are discussed. Pseudocleobis patagonicus is proposed as a nomen dubium. In addition, we confirm that female and immature specimens of the family Mummuciidae, just like males, can be reliably recognized based on features that had been suggested by Maury (1984). PMID- 26250245 TI - A new species from the genus Gorochovitettix (Tetrigidae: Metrodorinae) from Thailand. AB - A new species of pygmy grasshopper from the genus Gorochovitettix is described: Gorochovitettix khaosung sp. n. from Sakaerat Biosphere Reserve, Thailand. This represents the second species from the genus and the first record of the genus outside Vietnam. PMID- 26250246 TI - Concordance between molecular and morphology-based phylogenies of Korean Enhydrosoma (Copepoda: Harpacticoida: Cletodidae) highlights important synapomorphies and homoplasies in this genus globally. AB - Three new species of Enhydrosoma Boeck, 1873 are described from Korea, all found in muddy sediments in the sublittoral zone. They also all have a bifurcate rostrum, just like the type species of this genus, E. curticauda Boeck, 1872, and one recently described Korean representative, E. coreana Kim, Trebukova, Lee & Karanovic, 2014. These five species share a number of other morphological features, and mostly differ in details of integumental relief, caudal rami shape, and ornamentation of the male antennula. We aim to compare molecular and morphology-based phylogenies obtained for four Korean species of Enhydrosoma and two other members of the family Cletodidae: Geehydrosoma intermedia (Chislenko, 1978) from Korea and Russia and Stylicletodes sp. from Korea. Similar studies in other animal groups have helped to reevaluate the suitability of morphological characters for reconstructing phylogenetic relationships and taxonomic revisions, and the genus Enhydrosoma is considered to be polyphyletic and in urgent need of revision. We use partial sequences of the mtCOI gene for our molecular phylogeny and 32 non-additive characters for our morphology-based phylogeny. High congruence between all cladograms suggests that reconstructing phylogenetic relationships in this group of harpacticoids may be straight-forward, but highlights as homoplastic some morphological characters previously considered important for defining supraspecific taxa in this family. On the other hand, some characters previously overlooked in species descriptions show a significant phylogenetic signal. Even though there is no doubt about the monophyly of the Korean Enhydrosoma, their high average pairwise maximum likelihood distances suggest only a remote relationship, and explain their sympatry and/or parapatry. Weak bootstrap support for our basal nodes in molecular phylogenies shows limitations of a single-gene approach, and probably cannot be resolved without a wider taxon and character sampling. Wider taxon sampling will also be necessary to improve bootstrap values of basal nodes in morphology-based cladograms. PMID- 26250247 TI - More than a century old 'Platycleis Kraussi case' finally resolved (Tettigoniidae: Platycleidini). AB - In this paper we deal with a not well known orthopteran species described from Croatia--Krauss' bush-cricket, Platycleis kraussi Padewieth, 1900 with unknown type series. After systematic field studies the species was found only three kilometres from Padewieth's locus typicus, in Francikovac near Senj (Croatia). It was found to be the same as Bicolorana kuntzeni (Ramme, 1931), thus B. kuntzeni (Ramme, 1931) syn. nov. became a synonym of Bicolorana kraussi (Padewieth, 1900) comb. nov. which is moved into genus Bicolorana Zeuner, 1941. Since the type was lost a neotype of B. kraussi is designated and deposited in the Naturalis Biodiversity Center (Leiden, the Netherlands). Historical review of this species' taxonomy is given. An improved description is presented showing some variability of certain morphological characters. The morphology, morphometrics and bioacoustic data of the species are compared with those of the closely related B. bicolor (Philippi, 1830) and Modestana modesta (Fieber, 1853). Vichetia helleri syn. nov. is regarded a synonym of Bicolorana bicolor. The literature and new distribution data are gathered and presented. PMID- 26250248 TI - Phytoseiid mites (Acari: Phytoseiidae) from Patagonia and Tierra del Fuego. AB - Predatory phytoseiid mites have been intensively studied and surveyed in the last decades because of their economic importance as biocontrol agents of agricultural pests. However, many regions of the world remain unexplored and the diversity of the family worldwide is still fragmentary. Up to date no phytoseiid species have been collected in the southernmost part of the Earth down to latitude 45o S. In this study Phytoseiidae were sampled from native vegetation in southern Argentina and Chile in the regions of Patagonia and Tierra del Fuego Island. Thirteen species were collected, five of which were previously described and eight, Chileseius australis n. sp., Neoseiulus mapuche n. sp., Typhlodromips valdivianus n. sp., T. fissuratus n. sp., Amblyseius grandiporus n. sp., A. caliginosus n. sp., Typhlodromus (Anthoseius) anomalos n. sp. and Metaseiulus parabrevicollis n. sp. are proposed as new to science and are described and diagnosed. PMID- 26250249 TI - Brounea, a new genus (Coleoptera: Staphylinidae: Pselaphinae) from New Zealand, with descriptions of nine new species. AB - A new genus and nine new species of New Zealand endemic pselaphine staphylinid beetles belonging to the supertribe Faronitae are described: Brounea Park & Carlton, gen. nov. (type species: Sagola setiventris Broun, 1915); B. yoonhoi Park & Carlton, sp. nov., B. chorui Park & Carlton, sp. nov., B. sungryongi Park & Carlton, sp. nov., B. mijeongae Park & Carlton sp. nov., B. seongmoi Park & Carlton sp. nov., B. daehyuni Park & Carlton sp. nov., B. mangamukaensis Park & Carlton sp. nov., B. sunjaei Park & Carlton sp. nov., and B. seungili Park & Carlton sp. nov. Two species, S. setiventris and S. tenuis Broun, 1886, are transferred to the genus Brounea. A key to species, habitus photographs, and line drawings of diagnostic characters are provided. PMID- 26250250 TI - Taxonomic notes on Acanthomegabunus Tsurusaki, Tchemeris & Logunov 2000 (Arachnida: Opiliones: Phalangiidae), with a description of the new species A. altaicus sp. n. from the Altai Mountains of Russia and NE Kazakhstan. AB - The genus Acanthomegabunus Tsurusaki, Tchemeris & Logunov 2000 is diagnosed and redescribed. A key to species is presented. A new species, Acanthomegabunus altaicus sp. n. from the Altai Mountains of Russia and NE Kazakhstan is diagnosed, described and figured; its distribution is mapped, along with new records of A.sibiricus Tsurusaki, Tchemeris & Logunov 2000. PMID- 26250251 TI - Why is Pseudosphromenus cupanus (Teleostei: Osphronemidae) reported from Bangladesh, Indonesia, Malaysia, Myanmar, and Pakistan? AB - The native distribution of the small labyrinth fish species Pseudosphromenus cupanus includes southern India and Sri Lanka. According to literature it has a range including also Pakistan, Bangladesh, Myanmar, Malaysia, and Indonesia (Sumatra) but there are no voucher specimens or reliable observations from those areas. The distribution record of P. cupanus was inflated partly by including P. dayi as a synonym. Pseudosphronemus dayi is native to the Western Ghats in India, but the origin of the aquarium importation in 1907 was reported as both Cochin (=Kochi) and Malacca (=Malaysia), the latter locality obviously in error. The basis for the Sumatra record is an obviously mislabeled sample of P. dayi from Pulau Weh close to Sumatra. The basis for reporting the species from Pakistan, Myanmar or Bangladesh could not be located. Misidentified museum specimens from Myanmar and Pakistan identified as P. cupanus were never published on. Pseudosphromenus cupanus has been considered recently to be extinct in Bangladesh, but in fact it never occurred there. PMID- 26250252 TI - Review of the genus Arboridia Zachvatkin (Hemiptera: Cicadellidae: Typhlocybinae), with description of two new species from China. AB - The genus Arboridia Zachvatkin is reviewed, including two new species Arboridia cincta sp.nov. and Arboridia ochracea sp.nov., from Henan province, China. A detailed morphological description and illustrations of the two new species are provided. A key to all known species from China is given. PMID- 26250253 TI - Two new endemic Hawai'ian Lepidoptera: a new species of Pseudoschrankia (Erebidae) from O'ahu, and a new species of Thyrocopa (Xyloryctidae) from Moloka'i. AB - Two new endemic Hawai'ian Lepidoptera species are herein described. The first, Pseudoschrankia brevipalpis sp. nov., is a pollinator of the rare endemic plant Schiedea kaalae Wawra. The second, Thyrocopa keliae sp. nov., is endemic to Moloka'i island. Observations of undescribed parasitic mites that attack Hawai'ian Lepidoptera are presented as well. PMID- 26250254 TI - On the identity of Syntermes noiroti Krishna et al. 2013 (Isoptera: Termitidae: Syntermitinae). AB - Syntermes emersoni Grasse & Noirot 1949 is an available name of uncertain taxonomic status. It was published in a paper about the nest and biology of the African termite Sphaerotermes sphaerothorax (Sjostedt 1911), with a brief description and a few illustrations (Grasse & Noirot 1949). The description is limited to the following words: "les mandibles du Syntermes emersoni n. sp. resemblent passablement a celles d'un Sphaerotermes mais sont plus grandes" [the mandibles of Syntermes emersoni n. sp. resemble those of Sphaerotermes but are larger]. Specimens examined by the authors and the localities from which they were collected are not mentioned. Although brief and limited, this description satisfies the requirements of availability (ICZN 1999, articles 10-12). Besides the inadequate description, the name is a junior primary homonym of Syntermes emersoni Snyder 1924 and cannot be used as valid. PMID- 26250255 TI - Eriophyoid mite fauna (Acari: Trombidiformes: Eriophyoidea) of Turkey: new species, new distribution reports and an updated catalogue. AB - More than one hundred species of Eriophyoidea have been recorded hitherto from Turkey. Within the last decade, a large plant survey was carried out in order to investigate the eriophyoid fauna present in Turkey, with particular emphasis on species affecting weeds and ornamental plants. In addition, the Turkish literature has been examined for previous records of eriophyoid mites. New species, Paraphytoptus intybi n. sp. on common cichory, Cichorium intybus (Compositae) and Phytoptus albae n. sp. on white poplar, Populus alba (Salicaceae), are described and illustrated herein. In addition, a further 31 species were found to be new records for the eriophyoid fauna of Turkey with Aceria calaceris, Phyllocoptes didelphis and Vasates immigrans being new reports for the Palaearctic region. All known eriophyoid species records from Turkey appearing in papers published up until March 2013 are listed in this catalogue along with remarks and information on their current distribution in Turkey and taxonomic status. PMID- 26250256 TI - Revision of the genus Oxytelus Gravenhorst (Staphylinidae: Oxytelinae) in Southeast Asia. AB - Oxytelus species are widespread over all continents except Antarctica. Southeast Asia is one of the biodiversity hotspots in the world. In this paper, we review the Oxytelus species currently known from Southeast Asia. Seven species are described as new to science: O. castaneus sp. nov. (Vietnam), O. finitimus sp. nov. (Laos), O. grandiculus sp. nov. (Malaysia, Indonesia, and Thailand), O. insulanus sp. nov. (Malaysia and Indonesia), O. lompobatangensis sp. nov. and O. poecilopterus sp. nov. (Indonesia), and O. sublividus sp. nov. (Vietnam and Laos). Seven new synonymies are proposed: O. ruptus Fauvel = O. sublucidus Cameron, O. lucens Bernhauer = O. malaisei Scheerpeltz, O. puncticeps Kraatz = O. (Anotylus) micantoides Scheerpeltz, O. subferrugineus Cameron = O. kedirianus Cameron, O. megaceros Fauvel = O. kalisi Bernhauer, O. subincisus Cameron = O. fruhstorferi Cameron, O. antennalis Fauvel = O. cheesmani Bernhauer. Lectotypes are designated for the following names: O. armiger Fauvel, O. bellicosus Fauvel, O. discalis Cameron, O. gigantulus Fauvel, O. ginyuenensis Bernhauer, O. javanus Cameron, O. kalisi Bernhauer, O. kedirianus Cameron, O. lucens Bernhauer, O. lucidulus Cameron, O. mandibularis Cameron, O. megaceros Fauvel, O. nilgiriensis Cameron, O. subferrugineus Cameron, O. subincisus Cameron, O. sublucidus Cameron, O. subsculptus Cameron, O. antennalis Fauvel (New Caledonia, New Guinea and Australia), O. cheesmani Bernhauer (New Hebrides), O. cheesmanianus Cameron (Papua New Guinea), O. hingstoni Cameron (India), and O. tibetanus Bernhauer (China). The species O. (Anotylus) transversipennis Scheerpeltz is transferred to the genus Anotylus. Other than the new species, nine previously known species are redescribed, a key to 30 species and line drawings or color photographs of 42 species are provided. Thus, a total of 30 species are recorded from Southeast Asia. PMID- 26250257 TI - Reassessment and division of the genus Agraecia Audinet-Serville (Orthoptera: Tettigoniidae: Conocephalinae: Agraeciini). AB - Agraecia Audinet-Serville, the type-genus of Agraeciini, comprises fifteen species names: thirteen used for extant species, one junior synonym, and one fossil. The species are morphologically very dissimilar, and were collected and described from different localities of the world. The genus was reassessed based on recently collected specimens from Brazil and Argentina as well as museum specimens. Based on morphological characteristics we re-delimit Agraecia sensu novo, keeping only two of the previously assigned species: A. punctata Saint Fargeau & Audinet-Serville and A. dorsalis Karny. The subtribe Agraeciina subtrib. nov. is defined, which include Agraecia s. nov. and three new genera (Iaratrox Chamorro-Rengifo & Lopes-Andrade gen. nov., Starkonsa Chamorro-Rengifo & Lopes-Andrade gen. nov., and Yvelinula Chamorro-Rengifo & Lopes-Andrade gen. nov.). Three additional genera treated here, Parasubria Karny, Ragoniella Chamorro-Rengifo & Lopes-Andrade gen. nov., Redtenbachus Chamorro-Rengifo & Lopes Andrade gen. nov. and Sylvainhugiella Chamorro-Rengifo & Lopes-Andrade gen. nov. currently remain unclassified inside Agraeciini. We desig-nate a neotype and describe the female and male for A. punctata. Bertoniella Rehn is proposed as a junior synonym of Agraecia, and Parasubria ziczac Karny as syn. nov. of Parasubria vittipes (Redtenbacher) comb. nov. The fossil species is transferred to Senexefigia? Chamorro-Rengifo & Lopes-Andrade gen. nov. We also describe two new species of Iaratrox gen. nov., I. brasilienses Chamorro-Rengifo & Lopes Andrade sp. nov. and I. longicornia Chamorro-Rengifo & Lopes-Andrade sp. nov. The holotype of Agraecia fallax Karny nomen dubium seems to be lost and the syntypes of Agraecia festae Griffini are currently unavailable for examination, therefore, these two species are treated as incertae sedis, and should probably be transferred. A key to the studied genera is provided, as well as a key to species of Agraecia s. nov. and Iaratrox gen. nov. The calling songs of Parasubria vittipes (Redtenbacher) comb. nov. and Ragoniella pulchella (Hebard) comb. nov. are described. Numerous morphological details and some natural history aspects are discussed. PMID- 26250258 TI - Review of Amaeana Hartman, 1959 (Annelida, Terebelliformia, Polycirridae), with descriptions of seven new species. AB - Prior to the present study, seven species of Amaeana were known, A. accraensis (Augener, 1918), A. antipoda (Augener, 1926), A. apheles (Hutchings, 1974), A. colei (McIntosh, 1926), A. occidentalis (Hartman, 1944), A. trilobata (Sars, 1863), which is the type-species, and A. yirrarn Hutchings, 1997. Except for A. colei and A. antipoda, for which types could not be located, type material or material from the type localities of all these species was examined and re descriptions are provided; also, a lectotype is designated for A. trilobata, while A. colei and A. antipoda are considered as nomen nuda. In addition, seven new species are described, one from Brazil, A. brasiliensis sp. nov., another from Taiwan, A. hsiehae sp. nov., and five from Australia, A. angulus sp. nov., A. breviachaeta sp. nov., A. crassispinulata sp. nov., A. dampierensis sp. nov., and A. ellobophora sp. nov. A discussion on the most important characters to distinguish between the species of Amaeana is provided, together with a comparative table and a key to all currently known species. PMID- 26250259 TI - Danio annulosus, a new species of chain Danio from the Shuvolong Falls in Bangladesh (Teleostei: Cyprinidae: Danioninae). AB - Danio annulosus, new species, is described from a small pool below the Shuvolong Falls in the Kaptai Lake system in Bangladesh. It shares with chain danios (D. assamila, D. dangila, D. catenatus, D. concatenatus, and D. sysphigmatus) a colour pattern consisting of series of dark rings with light interspaces along the side, complete lateral line, 14 circumpeduncular scales, a produced first ray in the pectoral fin, and a black humeral spot. It differs from other chain danios in possessing much shorter pectoral and pelvic fins, and a humeral spot that is slightly wider than deep instead of round or deeper than wide. The mitochondrial cytochrome c oxidase subunit I (COI) sequence separates D. annulosus from the most similar species, D. catenatus by a p-distance of 3.4%. Although recorded from only a single locality, Danio annulosus is expected to have a wider distribution in the Karnafuli River drainage. PMID- 26250260 TI - Morphology and taxonomy of deutonymphs of the genus Unionicola Haldeman, 1842 (Acari, Hydrachnidia, Unionicolidae) in Russia. AB - This study presents a detailed taxonomic review of water mite deutonymphs of the genus Unionicola Haldeman, 1842 (Hygrobatoidea: Unionicolidae) found in the fauna of Russia during the long-term survey period of 1979-2013. The review includes descriptions and illustrations of 14 Unionicola species found in this country: U. aculeata (Koenike, 1890), U. arcuata (Wolcott, 1898), U. bonzi (Claparede, 1869), U. hankoi Szalay, 1927, U. intermedia (Koenike, 1882), U. japonensis Viets, 1933, U. inusitata Koenike, 1914, U. tricuspis (Koenike, 1895), U. crassipes (Muller, 1776), U. gracilipalpis (Viets, 1908), U. markovensis Tuzovskij, 1990, U. minor (Soar, 1900), U. rossica Tuzovskij & Semenchenko, 2015, U. ypsilophora (Bonz, 1783). Key to all species based on deutonymphs is presented. PMID- 26250261 TI - A new species of Andean frog of the genus Bryophryne from southern Peru Anura: Craugastoridae) and its phylogenetic position, with notes on the diversity of the genus. AB - We describe a new species of terrestrial frog of the genus Bryophryne (Anura: Craugastoridae) from the wet puna and elfin forests of the Amazonian versant of the Andes. The new species seems to be restricted to high altitude environments at elevations between 3506-3651 m in the area now protected by Megantoni National Sanctuary and Manu National Park (Distrito de Echarate, Provincia La Convencion, Departamento Cusco, Peru). The new species is characterized by lacking vomerine processes of vomers, by having tympanic annulus and tympanic membrane not evident through the skin, smooth dorsal skin with scattered warts, conspicuous dorsolateral, middorsal, and occipital folds, warty flanks, areolate skin on ventral surfaces of the body, and by lacking finger and toe fringes and basal web on feet. In life, specimens have bright and highly variable dorsal coloration that ranges from olive-green to red with variable combinations of red or orange marks (red or orange in the green form and olive-green in the red form). Molecular phylogenetic analyses of mitochondrial and nuclear DNA place the new species within the genus Bryophryne and as sister group of B. cophites. Bryophryne bustamantei, also sequenced for this study, is found as the sister group of the clade formed by B. cophites and the new species. Bryophryne is found as sister group of Psychrophrynella in maximum likelihood analyses and as the sister group of a large clade of holoadenines in parsimony analyses. The genus Bryophryne now contains nine species, all of them distributed along the Cordillera Oriental of the Peruvian Andes, southeast of the Apurimac River valley. PMID- 26250262 TI - Diagnoses for Nubensia, n. gen. (Diptera, Chironomidae, Chironomini), with the first full descriptions of the adult female and larva of N. nubens (Edwards, 1929). AB - A new genus, Nubensia Spies, is proposed for N. nubens (Edwards, 1929), n. comb., based on morphological evaluation of both adult sexes, the pupa and larva. The material studied includes name-bearing syntype specimens and the first reared associations linking three life stages for individual members of this species. The larva represents a unique morphotype previously described incompletely only from studies of subfossil chironomid remains. The problems with placement of the species in any previously established genus are discussed in detail, and various related issues in taxonomy and nomenclature are commented on. The verified distribution of N. nubens ranges from the British Isles and central Europe to the western Mediterranean, including northern Africa, with possible extensions to Turkey and central Asia. Larvae have been found on mostly coarse, variously covered substrates near the shores of lakes and banks of slowly flowing running waters, under both oligotrophic and eutrophic conditions. PMID- 26250263 TI - Discovery of Cryptophasa Lewin, 1805 (Lepidoptera: Xyloryctidae) from Indonesia with the descriptions of three new species. AB - Three new species of Cryptophasa Lewin, 1805 are described from eastern Indonesia: C. watungi Sutrisno & Suwito, 2015 sp. nov., C. kwerbaensis Sutrisno & Suwito, 2015 sp. nov., and C. choliki Sutrisno & Suwito, 2015 sp. nov. Each species is described based on adult external and genital characters. The potential apomorphic character in male genitalia of Cryptophasa, the shape of the uncus, is discussed. PMID- 26250265 TI - The genus Conocephalus Thunberg (Orthoptera: Tettigoniidae: Conocephalinae) in Hainan, China with description of one new species. AB - This paper reports four species of the genus Conocephalus from Hainan, China, including Conocephalus (Xiphidion) hainanensis sp. nov. and two new records: C. (Anisoptera) maculatus (Le Guillou, 1841) and C. (Conocephalus) bambusanus Ingrisch, 1990. PMID- 26250264 TI - Bryconops munduruku (Characiformes: Characidae), a new species of fish from the lower Tapajos River basin, Brazil. AB - A new species of Bryconops is described from a right tributary of the lower Tapajos River, State of Para, Brazil. Bryconops munduruku, sp. nov., differs from its congeners, except B. inpai and B. piracolina, by having a black adipose fin (vs. adipose fin hyaline in alcohol) and, except B. inpai, by possessing two humeral blotches (vs. lack of humeral blotch or only one humeral blotch). Bryconops munduruku differs from B. inpai by having a uniform color pattern on the posterior portion of the side of the body (vs. a dark stripe extending posteriorly from the half of the anal-fin base onto the base of the middle caudal fin rays). It differs further from B. inpai and B. piracolina by the presence of a black adipose fin that is hyaline along its base (vs. entirely black adipose fin in B. inpai and B. piracolina). The new species is allocated in the subgenus Creatochanes by having a maxillary bone with one to three teeth on both sides, and its posterior extension reaching the junction of second and third infraorbital bones. PMID- 26250266 TI - Discovery of a new species of Formosatettix Tinkham, 1937 (Orthoptera, Tetrigoidea, Tetrigidae) from China. AB - A new species of the genus Formosatettix Tinkham, 1937, namely Formosatettix xiai sp. n. is described and illustrated. The new species is allied to Formosatettix wulaoshanensis Zheng & Xu, 2010, but differs from the latter by the apex of pronotum reaching distal 2/3 of hind femur, width of frontal ridge equal to that of basal segment of antennae, length of a segment of antennae in the middle 3 times its width, lower margin of fore and mid femora straight, pronotum dorsally with one black spot on each side. The new species is also allied to Formosatettix tianmushanensis Zheng & Li, 2001, but the apex of pronotum reaching distal 2/3 of hind femur, the width of frontal ridge equal to that of basal antennal segment, length of upper ovipositor valve 3 times its width, length of a segment in the middle of antennae 5.0 times its width and pronotum dorsally with one black spot on each side. The type specimens are deposited in the College of Life Sciences, Hebei University, Baoding, Hebei, China. PMID- 26250267 TI - Phlebotomine sand flies (Diptera: Psychodidae) of Chiapas collected near the Guatemala border, with additions to the fauna of Mexico and a new subgenus name. AB - Collections from four localities, two of the High Plateau and two of the Eastern Mountains Municipality of Chiapas, near the border with Guatemala, included 26 species with four new species records for Mexico: Lutzomyia (Helcocyrtomyia) hartmanni (Fairchild & Hertig, 1957), Dampfomyia (Coromyia) disneyi (Williams, 1987), Psychodopygus bispinosus (Fairchild & Hertig, 1951), and Psychodopygus corossoniensis (LePont & Pajot, 1978). These records represent an updated total of 50 species in Mexico, 48 of which are extant species and the remaining two fossils. The name Xiphopsathyromyia n. n. is proposed in substitution of Xiphomyia Artemiev, 1991, a homonym of Xiphomyia Townsend, 1917, a genus of Tachinidae (Diptera). PMID- 26250268 TI - Revision of the genus Lepidoblepharis (Reptilia: Squamata: Sphaerodactylidae) in Central America, with the description of three new species. AB - Based on morphological and molecular data, we describe three new species of the genus Lepidoblepharis with granular dorsals from Panama (Lepidoblepharis emberawoundule sp. nov., Lepidoblepharis rufigularis sp. nov., and Lepidoblepharis victormartinezi sp. nov.). The results of our molecular analyses confirm the existence of five deeply differentiated genealogical lineages among Panamanian Lepidoblepharis. We present detailed descriptions of their morphology, including some new valuable scalation characters (ventral and subfemoral escutcheon) and hemipenes, as well as comparisons with the other two species of the genus known to occur in Panama (L. sanctaemartae and L. xanthostigma) and their South American congeners. Last, we provide an updated identification key for the genus Lepidoblepharis in Central America. PMID- 26250269 TI - A new skink (Scincidae: Liburnascincus) from rocky habitat on Cape York, northeast Australia. AB - The genus Liburnascincus is composed of saxicoline skinks restricted to northeast Australia. This small radiation consists of one widespread species, L. mundivensis, found in a variety of rocky habitats in eastern Queensland, and two localized species, L. coensis and L. scirtetis, restricted to granite boulder habitats on Cape York Peninsula, in north Queensland. Here we describe a fourth species, L. artemis sp. nov., from the Bamboo Range, a low rocky range on Cape York. As for other Liburnascincus, the new species is a saxicoline skink that is active on boulder surfaces primarily early and late in the day. Liburnascincus artemis sp. nov. is most similar to L. mundivensis but can be diagnosed based on longer limbs, higher toe and finger lamellae counts, lower midbody scale count, and other aspects of morphology, scalation and colour pattern. Liburnascincus artemis sp. nov. is currently known from a very small area but further surveys will likely extend the range. It is geographically separated from L. mundivensis to the south by unsuitable habitat in the Laura region, but it may abut the range of L. coensis to the north. Despite a small distribution, L. artemis sp. nov. occurs at high density at the known sites and appears to be currently secure. In this paper we also discuss the distributions and biogeography of Liburnascincus more broadly. PMID- 26250270 TI - New species in the family Ctenidae Keyserling, 1877 from high altitude habitats in Myanmar, with the first case of penetration of the female's cuticle by a male in the RTA-clade (Arachnida: Araneae: Ctenidae). AB - Specimens of the spider genera Ctenus Walckenaer, 1805 and Anahita Karsch, 1879 from Myanmar were investigated. Three species are described as new to science: Anahita popa spec. nov. (female; Mt Popa), Ctenus natmataung spec. nov. (male, female; Mt Victoria) and C. pingu spec. nov. (male, female; Mt Victoria). The female of C. cladarus Jager, 2012 is described for the first time. Males of C. natmataung spec. nov. possess an easily breakable tip of their RTA. Two cases are reported where this part was clinging to the epigyne and a pointed appendix had penetrated the female's cuticle. This is the first such case reported within the RTA-clade. All three Ctenus spp. have very similar copulatory organs and are interpreted as a product of relatively recent speciation events. According to their elevational zonation, the driving factor for this speciation could be different climatic conditions at different elevations. PMID- 26250271 TI - Taxonomic study on the leafhopper genus Cofana Melichar (Hemiptera: Cicadellidae: Cicadellinae) from China, with description of two new species. AB - A review of the genus Cofana Melichar from China is presented. Ten species are recorded, of which two species are new: C. cheni sp. nov. and C. nii sp. nov. The type specimens of the new species are deposited in the Institute of Entomology, Guizhou University, Guiyang, China (GUGC). In this paper, C. bidentata Krishnankutty & Viraktamath, 2008 is placed as junior synonym of C. yasumatsui Young, 1979. A key of all Chinese species of the genus is provided. PMID- 26250272 TI - Two new species of Palapedia Ng, 1993 (Crustacea, Decapoda, Brachyura,
Xanthidae) from the Persian Gulf. AB - Two new species of Palapedia Ng, 1993, are described based on material collected from Abu-Musa Island, Persian Gulf during the present study, from Bahrain by the 1937/38 Danish Expedition, and from the Saudi Arabian coast of the Persian Gulf by Michael Apel in 1992-1995. Palapedia persica n. sp. is distinguishable from its congeners by having distinctly large denticles on the upper margin of the palm and fingers of the chelae and anterior margin of the ambulatory dactyli, and by the markedly sickle-shaped dactylus of the ambulatory legs. Palapedia apeli n. sp. is similar to P. valentini Ng, 1993, and P. nitida (Stimpson, 1858), by having relatively smooth appendages. PMID- 26250273 TI - A new cheilostome bryozoan genus, Abditoporella (Hippoporidridae), from the eastern Pacific. AB - Abditoporella dimorpha n. gen. et n. sp. is described from the Pacific coast of Mexico. It was previously misidentified as Odontoporella adpressa (Busk). Abditoporella seems to be morphologically related to Hagiosynodos Bishop & Hayward, 1989 in having a similar orifice and pseudoporous frontal shield, but is distinguished by having dimorphic zooids. A second species, Hippopodinella turrita Osburn, is reassigned to the new genus as Abditoporella turrita n. comb. Abditoporella is included in the Hippoporidridae. PMID- 26250274 TI - Description of Ascidia paulayi sp. nov. (Phlebobranchia: Ascidiidae) from French Polynesia, with a discussion about the Ascidia sydneiensis Stimpson, 1855 group. AB - In the last decade, new surveys were made in French Polynesia as part of the Moorea Biocode project to improve the knowledge about the regional fauna. Here we describe Ascidia paulayi sp. nov., a new species of Ascidiidae. Due its similarity with A. sydneiensis, a discussion about the species of this group complements the study. PMID- 26250275 TI - A new record of Larnaca Walker, 1869 (Orthoptera: Gryllacrididae: Gryllacridinae) from China with description of a new species. AB - In the paper, Larnaca is recorded from the Chinese fauna for the first time. A single new species, Larnaca (Larnaca) emarginata Bian, Guo & Shi, sp. nov., is described. This extends the distribution of the genus Larnaca from Lao Cai prov., Vietnam to Yunnan prov. in southwestern China. PMID- 26250276 TI - A new species of the genus Hahnia (Araneae: Hahniidae) from South China. AB - The spider genus Hahnia C.L. Koch 1841, which includes 94 species in the world (World Spider Catalog 2015), is the largest group of the comb-tailed spider family, Hahniidae Bertkau 1878. However, this genus appears to be polyphyletic. For example, H. xinjiangensis Wang & Liang 1989 (Wang & Liang 1989: 52, figs 1-6) and H. talei (Gertsch 1934) (Gertsch 1934: 13, figs 5-8, 27-28) exhibit patterns of their copulatory organs that differ from those of the type species H. pusilla C.L. Koch 1841 and other allied species, H. helveola Simon 1875 and H. ononidum Simon 1875 etc. (Almquist 2005: figs 258a-e, 261a-e, 262a-f). Hahnia s. str. has an equidistant tracheal spiracle between the epigastric furrow and the base of spinnerets, a hook-like patellar apophysis, a long and curved tibial apophysis, a threadlike embolus, a membranous median apophysis and a retrolateral cymbial furrow and tube-like and curved copulatory ducts and two epigynal bursae (spermathecae and subspermathecae, see Zhang et al. 2011). PMID- 26250277 TI - Central Asian mountain Rhithrogenini (Ephemeroptera: Heptageniidae) with pointed and ephemeropteroid claws in the winged stages. AB - Among mountain species of Heptageniidae from Central Asia, six species belonging to the taxa Cinygmula McDunnough 1933, Himalogena Kluge 2004 and Caucasiron Kluge 1997 have all claws of the winged stages (subimago and imago) pointed. In this area Cinygmula is represented by two species: C. hutchinsoni (Traver 1939) (with pointed claws) and C. joosti Braasch 1977 (with the more typical ephemeropteroid claws); for both species all stages of both sexes associated by rearing are redescribed. The Central Asian mountain taxon Himalogena includes seven species: Rhithrogena (Himalogena) tianshanica Brodsky 1930, Rh. (H.) pamirica sp. n., Rh. (H.) carnivora sp. n., Rh. (H.) semicarnivora sp. n., Rh. (H.) stackelbergi Sinitshenkova 1973, Rh. (H.) gunti sp. n. and Rh. (H.) nepalensis Braasch 1984; for five of them, all stages of both sexes associated by rearing are redescribed; Rh. (H.) semicarnivora is known as male imagoes reared from larvae; Rh. (H.) nepalensis formerly known only as larvae, is redescribed based on an anomalous female imago (with gynandromorphism caused by helminth in abdomen) reared from the larval stage. Among these species, Rh. (H.) tianshanica, Rh. (H.) pamirica, Rh. (H.) carnivora and Rh. (H.) semicarnivora have mandibles and the labrum modified for carnivorism, while the other three species have the usual Rhithrogena mouth apparatus. Imagoes and subimagoes of Rh. (H.) pamirica, Rh. (H.) carnivora, Rh. (H.) gunti and Rh. (H.) nepalensis, have both claws of each leg pointed, while the other species have ephemeropteroid claws. Corrections to the description of Rh. minima Sinitshenkova 1973 claw denticulation and to original figure references are given. The taxon Ironopsis/g1 is represented by two species in the Central Asian mountains: Epeorus (Caucasiron) guttatus (Braasch & Soldan 1979) (with pointed claws) and Epeorus (Ironopsis) rheophilus (Brodsky 1930) (with ephemeropteroid claws); for both species all stages of both sexes associated by rearing are redescribed. The character distribution patterns of pointed and ephemeropteroid claws within mayfly phylogeny leads one to assume that both types of claws repeatedly change back and forth within Ephemeroptera. However, within Heptageniidae, those species whose winged stages have pointed claws have overlapping ranges of distribution limited to high mountain systems of Central Asia; their larvae inhabit the same biotopes (stones in rapid streams), have the same habitat and can come into contact with one another when they aggregate on a stone. These observations allow for a hypothesis that explains the repeated change to pointed claws from ephemeropteroid claws among various Heptageniidae species via horizontal transfer of some hereditary factor during the evolutionary history of each of those species with the peculiar claw morphology. PMID- 26250278 TI - Molecular phylogeny of Niphargus boskovici (Crustacea: Amphipoda) reveals a new species from epikarst. AB - We describe a new species of an amphipod Niphargus zagorae sp. n. and redescribe its nearest relative and morphologically similar species N. boskovici S. Karaman, 1952. We present the geographic distributions of both species, morphological diagnoses and infer their phylogenetic position within the genus based on COI, 28S and H3 markers. PMID- 26250279 TI - Periclimenes macrorhynchia sp. nov., a new hydrozoan-associated pontoniine shrimp (Crustacea, Decapoda, Palaemonidae) from North East Kalimantan, Indonesia. AB - A new species of pontoniine shrimp belonging to the 'Periclimenes obscurus species group' is described from the Berau Islands, North East Kalimantan, Indonesia. Specimens were obtained from aglaopheniid hydrozoans of the genus Macrorhynchia. The new species is here described and figured. Its affinities with related species are discussed and a DNA-barcode is provided. PMID- 26250280 TI - Subsphaerolaimus minor sp. n. and Micromicron cephalatum Cobb, 1920 (Nematoda) from the Yen River Estuary of Vietnam. AB - Two nematode species found in Yen River Estuary of Vietnam are described and illustrated. Subsphaerolaimus minor sp. n. is similar to S. lamasus Gerlach, 1956, but differs from it in the shorter body, comparatively shorter pharynx and shorter cephalic setae. A pictorial key for determination of valid species in the genus Subsphaerolaimus Lorenzen, 1978 is given. Micromicron cephalatum Cobb, 1920 is redescribed and reillustrated based on numerous males and females. The genus Micromicron Cobb, 1920 is confirmed as a valid genus with type and only species, M. cephalatum Cobb, 1920. PMID- 26250281 TI - Uktena riparia n. gen., n. sp. (Annelida, Clitellata, Lumbriculidae), a new spermatophore-producing oligochaete. AB - Uktena riparia n. gen., n. sp. has been collected in hyporheic habitats at several sites in North Carolina, southeastern USA. The genus is defined by unusual characters related to reproductive structures, including the formation of encapsulated spermatophores for sperm transfer and large bundles of genital chaetae, both previously unknown in the Lumbriculidae. The simultaneous occurrence of both spermatophores and spermathecae is rare in the microdrile oligochaetes. Uktena spermatophores appear more similar to those reported in leeches than to those in other microdrile oligochaete families. Possible synapomorphies associating Uktena with the genera Kincaidiana and Guestphalinus include a filiform, ringed proboscis, a forward shift of reproductive organs relative to the usual position in the family, and spermathecae in the atrial segment. The new species adds to the already diverse, endemic lumbriculid fauna of the North Carolina Sandhills ecoregion. PMID- 26250282 TI - Sometimes two arms are enough--an unusual life-stage in brittle stars (Echinodermata: Ophiuroidea). AB - Off West Africa (Angola-Morocco), benthos samples were collected in the years 2005-2012. These contained 124 specimens of brittle stars with two long arms and three extremely short or absent arms and an elongated, narrow disc. These unusual brittle stars, as well as 33 specimens with five fully developed arms, were identified as Amphiura ungulata. The specimens with unequal arms were juvenile stages, whereas adults had five equal arms. The large number of specimens with unequal arms suggests that this condition is not the result of damage and regeneration, but a normal growth pattern in this species. This study documents the morphology by SEM, amends the species description, and discusses possible explanations for the evolution of this condition. Although brittle star species with unequal arm growth have been reported, this is an extreme case that was unknown before this study. PMID- 26250283 TI - Karyosystematics of Triatoma rubrofasciata (De Geer, 1773) (Hemiptera: Reduviidae: Triatominae). AB - Triatoma rubrofasciata (De Geer) is the first species of triatomine described, and little is known on its vector biology. Studies are restricted to starvation resistance, interspecific morphometric variability, morphometry of testis follicles, coloration of the testicular peritoneal sheath, ultrastructure of the male accessory glands, phylogeny and cytogenetics. Thus, this study aims to address the karyosystematics of T. rubrofasciata and the possible events related to karyotype evolution of this species. Four adult males were analyzed cytogenetically. The analysis of meiotic metaphases of T. rubrofasciata allowed to confirm the karyotype of species, out more, 2n = 25 (22A + X1X2Y). This number is very important for taxonomic and evolutionary inferences on the species, because of the 88 triatomine species with described karyotype, only T. rubrofasciata exhibits 25 chromosomes. Based on the hypothesis of the karyotype 2n = 22 (20A + XY) as ancestral for triatomines, we propose three evolutionary hypotheses for the emergence of the karyotype of T rubrofasciata, all supported by agmatoploidy events (fission). Basically the hypotheses are 1) fission for a pair of autosomes, resulting in 22 autosomes and later fission of sex chromosome X; 2) fission of pair of autosomes and the sex chromosome X concomitantly; 3) fission of sex chromosome X and subsequently fission of pair of autosomes. Thus, this study highlights for the first time the importance of the number of chromosomes of T. rubrofasciata as characteristic diagnosis in Triatominae subfamily and describes three evolutionary hypotheses that possibly led the emergence of karyotype of this insect of global importance. PMID- 26250284 TI - A new species of Huarpea Pate, 1947 from Colombia and redescription of H. wagneriella (du Buysson, 1904) (Hymenoptera: Sapygidae). AB - Huarpea colombiana sp. nov. from Colombia (Meta) is described and illustrated. This is the first record of the family Sapygidae for Colombia and northern South America. Huarpea wagneriella (du Buysson, 1904) is redescribed. An updated key to Neotropical genera and species of Sapygidae is given. PMID- 26250285 TI - New records of Anacroneuria Klapalek, 1909 (Plecoptera: Perlidae) for Central America. AB - The perlid genus Anacroneuria is the most widely distributed stonefly occurring in the Neotropics. Regional studies of this genus were made early in the last century, whereas local taxonomic and distributional studies have recently increased. In this study, we provide new Central American records for four species of Anacroneuria. Anacroneuria choco Stark & Bersosa 2006, A. costana (Navas 1924), A. hacha Stark 1998, and A. laru Gutierrez-Fonseca 2015 are newly reported including new range extensions. PMID- 26250286 TI - Redescription of the advertisement call of Physalaemus albifrons (Spix, 1824) (Amphibia, Anura, Leptodactylidae). AB - The genus Physalaemus Fitzinger, 1826 is composed by 46 species occurring from north to southern South America, east of the Andes (Frost 2015). Physalaemus albifrons is morphologically differentiated from the other species mainly due to the presence of a second tarsal tubercle located nearly the tibio-tarsal articulation (Bokermann 1966). Physalaemus albifrons occurs in Brazil from north of the State of Maranhao through the states of Piaui, Ceara, Bahia, Paraiba, Pernambuco, and Alagoas, being its more austral occurrence in the State of Minas Gerais (Frost 2015). The advertisement call of P. albifrons was described by Bokermann (1966); however, the description needs improvement by applying new technologies, which we provide herein. PMID- 26250288 TI - A checklist of the deep sea fishes of the Levant Sea, Mediterranean Sea. AB - We list sixty five fish species collected at depths greater than 500 m in the Levant Basin, including 10 depth records. The Levantine bathyal ichthyofauna is characterized by its eurybathy, with an upper bathymetric boundary that permitted penetration of the shallow Gibraltar and Siculo-Tunisian sills, and a much lower bathymetric boundary than recorded for conspecifics elsewhere. The opportunistic and resilient ichthyofauna re-colonized recently the deep-sea following the last anoxic event (~ 6 kyr), forming assemblages notably distinct from those in the western Mediterranean. The exploration and production of deep seabed hydrocarbons have raised the specter of severe direct impacts to the deep habitats. There is an urgent need for documenting the full extent of deep-sea biodiversity, and for providing information for the development of competent and pragmatic management plans and effective conservation policies. PMID- 26250287 TI - New taxonomic and distributional information on hermit crabs (Crustacea: Anomura: Paguroidea) from the Gulf of Mexico, Caribbean Sea, and Atlantic coast of South America. AB - A collection of Paguroidea recently obtained during deep-water expeditions along the coast of Brazil, forms the basis of this report. Of the 14 species reported from Brazil, 11 represent range extensions to the south, and one, Michelopagurus atlanticus (Bouvier, 1922), is a first record for the western Atlantic. The specimens were compared with types and western Atlantic materials deposited in various major museums. A diagnosis and illustrations are presented for each of seven species found to be poorly or insufficiently known. New material and information is reported for two additional species that occur in Brazil but not found in the recent deep-water collections: Clibanarius symmetricus (Randall, 1840) and Mixtopagurus paradoxus A. Milne-Edwards, 1880. Remarkable and unique color photographs of live or fresh specimens of Allodardanus bredini Haig & Provenzano, 1965, Bathynarius anomalus (A. Milne-Edwards & Bouvier, 1893), Pylopagurus discoidalis (A. Milne-Edwards, 1880), Paguristes spinipes A. Milne Edwards, 1880, Parapagurus pilosimanus Smith, 1876, and P. alaminos Lemaitre, 1986, are presented. A review of published records and museum collections of the terrestrial Coenobita clypeatus (Fabricius, 1787), has shown that the southern range limit of this species does not extend beyond the southern Caribbean and Trinidad and Tobago, and thus does not occur on the Brazilian coast as previously believed. A distribution map of C. clypeatus is provided based on specimens in the collections of the National Museum of Natural History, Smithsonian Institution. New distribution records in the Gulf of Mexico and southern Caribbean, and morphological information, are included for Pagurus rotundimanus Wass, 1963, a species originally described from the Florida Keys but rarely reported since. Relevant remarks on the taxonomy, morphology, and distribution of all these species are included. The revised list of Paguroidea known from Brazil is updated, and now includes a total of 62 species in the families Pylochelidae (1), Diogenidae (27), Paguridae (28), and Parapaguridae (6). A synopsis of primary taxonomic works on western Atlantic Paguroidea is also presented. PMID- 26250289 TI - Two new stygobiotic copepod species from the Tibesti area (Northern Chad) and a re-description of Pilocamptus schroederi (van Douwe, 1915). AB - Between 4th and 18th March 2014, an international group of biologists carried out a hydrobiological expedition to the Ounianga-Tibesti area of northern Chad (Africa). The Tibesti is a desert volcanic area, intersected by the beds of ancient rivers which were active in the Tertiary. In deep canyons there are small water bodies (gueltas/aguelmans), fed by rain and spring water. They are rich in zooplankton, benthos, and even fish, but their groundwater fauna has previously been unknown. Groundwater samples collected in the vicinity of one guelta contained Syncarida, Isopoda, and Copepoda. Among the latter, two new species were recognised, Haplocyclops (H.) henrii sp. nov. and Parastenocaris joi sp. nov., together with a third species, Pilocamptus schroederi (van Douwe, 1915), previously known only from the littoral zone and wet mosses of Lake Victoria. The Tibesti area is thus the third known location of P. schroederi. All these species have a Gondwanaland distribution and are probably relicts of the Tertiary fauna, formerly widespread in the Sahara. Together with descriptions of two new species, a detailed re-description of P. schroederi is presented, along with remarks on their ecology. PMID- 26250290 TI - New species records of Suwallia Ricker, 1943 (Plecoptera: Chloroperlidae) from China, with description of the nymph of S. decolorata Zhiltzova & Levanidova, 1978. AB - Two species of the chloroperlid genus Suwallia, S. decolorata Zhiltzova & Levanidova, 1978 and S. talalajensis Zhiltzova, 1976 are reported for the first time from the Inner Mongolia Autonomous Region of China. The habitus and diagnostic features of these two species including aedeagal structures are illustrated with color images. Additional descriptions and taxonomic notes are provided. The nymph of S. decolorata is described. PMID- 26250291 TI - Three new species of Horismenus Walker (Hymenoptera: Eulophidae) associated with seed pods of Pithecellobium dulce (Fabaceae). AB - Horismenus abnormicaulis sp. nov., H. patensis sp. nov. and H. zuleidae sp. nov. (Hymenoptera: Eulophidae), all authored by Pikart, Costa & Hansson, are described from material obtained from seed pods of Pithecellobium dulce (Roxb.) Benth. (Fabaceae) collected in Northeastern Brazil. The seed pods were infested with larvae of Coleoptera (Chrysomelidae (Bruchinae) and Curculionidae). The associations of the Horismenus species and the beetle larvae have not been established. Morphological similarities between these new species and previously described species with host known suggest that H. patensis and H. zuleidae are primary parasitoids of Bruchinae, whereas H. abnormicaulis may act as a hyperparasitoid on other Horismenus species. The three species are compared with similar species of Horismenus. PMID- 26250292 TI - A new species of Synagapetus from Spain with a key for the identification of the Iberian and Pyrenean species (Trichoptera: Glossosomatidae). AB - A new species of the caddisfly genus Synagapetus from central Spain is described and figured: Synagapetus vettonicus sp. n. Males of the new species are close to S. placidus and S. marlierorum, but the new species is well characterized by a combination of genitalic characteristics, especially those concerning the shape of the superior and inferior appendages. Additionally we provide a taxonomic key to the Iberian and Pyrenean species, in order to make the identification of this complex group of species easier. PMID- 26250293 TI - Rhigognostis erysiphaea (Meyrick, 1938) comb. nov. (Lepidoptera, Plutellidae), with description of male and female genitalia. AB - A new combination, Rhigognostis erysiphaea (Meyrick, 1938) is proposed. The species is re-described with a photo of the type specimen. The male and female genitalia are described and illustrated for the first time. PMID- 26250294 TI - A case of mything teeth: on the presence of vomerine and palatine teeth in the Pomacanthidae (Teleostei). AB - The presence or absence of teeth on the vomer and palatoquadrate bones has a long history in fish systematics. Dentition of these bones is often consistent across families, and is often included in keys to families and family diagnoses. The angelfish family Pomacanthidae has been almost consistently diagnosed as lacking both vomerine and palatine teeth (e.g., Gunther 1860; Day 1875; Jordan & Fowler 1902; Herre & Montalban 1927; Fowler & Bean 1929; Pyle 2001, 2003; McEachran & Fechhelm 2005); the only exceptions I am aware of are Munro (1967) and Jones and Kumeran (1980) who note that vomerine teeth may be present or absent in pomacanthids, Blum (1988) who alludes to vomerine teeth being present in the family, and Lindberg and Krasyukova (1971) who note that weak vomerine teeth may be present in species of Chaetodontoplus Bleeker. I am aware of no accounts that mention palatine teeth in pomacanthids. During a survey of pomacanthid skeletal preparations for a study of relationships of pomacanthids to other fishes (Gill & Leis in prep.), I noticed that species of the genus Pomacanthus Lacepede, type genus of the family, consistently have a narrow band of villiform teeth on the vomer and a small patch of villiform teeth on the anterior part of the palatines (Figure 1). A broader survey of pomacanthids (25 species, including representatives of all but one of the major clades given in Gaither et al. 2014; the missing clade consists of "Apolemichthys" arcuatus, "Centropyge" colini and "C." narcosis, for which the name Desmoholacanthus Fowler is available) revealed that these bones are otherwise edentate in the family (although only two species of Chaetodontoplus were examined). PMID- 26250295 TI - The identity of Accipiter cirrocephalus rosselianus Mayr, 1940. AB - Mayr (1940) described the subspecies Accipiter cirrocephalus rosselianus of the Collared Sparrowhawk from two specimens in juvenile (first-year) plumage collected on Rossel (Yela) Island, in the Louisiade Archipelago off southeast New Guinea. They are still the only specimens of this form known from the Louisiade Archipelago, and were taken in March 1898 and December 1915 by the renowned Rothschild collector Albert S. Meek, who sexed them as males. Mayr (l.c.) presumed their specific identity and stated that rosselianus differed from juveniles of its sister subspecies, A. c. papuanus Rothschild & Hartert, 1913 of mainland New Guinea, in the bolder, browner chevroning of the ventrum, darker dorsal plumage with broad rufous feather edging, and distinctively large size. The large size of the specimens, in fact, raises the question of missexing, because they approach female papuanus in wing (Mayr l.c.). Nevertheless, the collector Meek was careful and experienced in sexing birds (Mayr l.c.) and had recorded both specimens as males on separate occasions. In accord with data presented below, it is evident that the specimens were correctly sexed as males. PMID- 26250296 TI - P. USTJUZHANIN, V. KOVTUNOVICH & A. USTJUZHANINA (2015) New species of African Plume moths (Lepidoptera, Pterophoridae). Zootaxa, 3957 (1): 137-142. PMID- 26250299 TI - Foreword. PMID- 26250300 TI - Antonbruunia sociabilis sp. nov. (Annelida: Antonbruunidae) associated with the chemosynthetic deep-sea bivalve Thyasira scotiae Oliver & Drewery, 2014, and a re examination of the systematic affinities of Antonbruunidae. AB - Antonbruunia sociabilis sp. nov., an abundant endosymbiont of Thyasira scotiae from a putative sulphidic 'seep' in the Hatton-Rockall Basin (1187-1200 m), North East Atlantic Ocean, is described. The new species is compared with A. viridis and A. gerdesi from the West Indian Ocean and South-East Pacific Ocean respectively. The three species can be distinguished using a suite of morphological characters, and are associated with geographically separated chemosynthetic bivalve molluscs from different families (Thyasiridae, Lucinidae, Vesicomyidae) living in sediments at different depths. New morphological features are recognized for Antonbruunia and a re-assessment of its systematic affinities indicates a close relationship with the Pilargidae. Previous suggestions of an affiliation with the Nautiliniellidae, recently incorporated into the Calamyzinae (Chrysopetalidae), were not supported. The apparent morphological similarities between the two groups are indicative of convergence related to their shared relationships with chemosynthetic bivalves. The first molecular analyses of Antonbruunia (16S and 18S rDNA) clearly indicate that a close relationship to Pilargidae (represented by Ancistrosyllis sp. and Sigambra sp.) is more likely than an affinity to Calamyzinae (represented by Calamyzas amphictenicola, Natushima sp., and Vigtorniella sp.). PMID- 26250301 TI - New Sericosura (Pycnogonida:Ammotheidae) from deep-sea hydrothermal vents in the Southern Ocean. AB - Three new species of Sericosura (Pycnogonida: Ammotheidae) are described from recently discovered hydrothermal vents in the East Scotia Ridge, Southern Ocean: Sericosura bamberi sp. nov., S. dimorpha sp. nov. and S. curva sp. nov. The eleven species known to date in the genus Sericosura are all inhabitants of chemosynthetic environments in different oceans around the world. Morphology and preliminary DNA data from the COI locus suggest the East Scotia Ridge pycnogonids have relatively close evolutionary affinities with species known from the East Pacific Rise and the Mid-Atlantic Ridge. This finding highlights the importance of Sericosura as a characteristic taxon of hydrothermal vents and the great potential of this genus for global scale ecological and evolutionary studies of hydrothermal vents fauna. The use of pycnogonid DNA data combined with recent models explaining biogeographic provinces along the mid-ocean ridge system should prove extremely useful to understanding the patterns of diversification of endemic fauna from chemosynthetic environments and from the deep-sea in general. PMID- 26250302 TI - A reassessment of the pycnogonid genus Cheilopallene (Arthropoda, Callipallenidae) with description of a new species from Papua New Guinea. AB - The genus Cheilopallene is reviewed. Three species are assigned to species incertae sedis pending further analysis. Specimens from Lizard Island, Queensland, previously identified as C. nodulosa are reassigned to C. brevichela. Suspected sexual dimorphism represented by the presence of a chelifore scape node in female C. nodulosa is supported by the finding of the same dimorphism in C. brevichela and in a new species from Milne Bay, Papua New Guinea. It is likely that the presence of a chelifore scape node is a diagnostic character of all females in the genus Cheilopallene. An amended diagnosis is provided. PMID- 26250303 TI - Cheilopallene ogasawarensis, a New Species of Shallow-Water Pycnogonid (Arthropoda: Pycnogonida) from the Ogasawara (Bonin) Islands, Japan, Northwest Pacific. AB - A new species of pycnogonid recorded from the shallow waters of Ogasawara (Bonin) Island, Japan, Cheilopallene ogasawarensis n. sp. is described, illustrated and compared with similar species. Cheilopallene ogasawarensis is only the third pycnogonid species recorded from these islands. Morphological characters clearly distinguish the new species from its geographically closest congener C. nodulosa Hong and Kim, 1987, also recorded from Japanese waters. PMID- 26250304 TI - A new species of Pycnogonum Brunnich, 1764 (Arthropoda, Pycnogonida) from Flemish Cap (Northwest Atlantic Ocean). AB - A new pycnogonid species of the genus Pycnogonum is described from Flemish Cap (Northwest Atlantic Ocean) at 1453-1462 m depth. Pycnogonum bamberi sp. nov. is compared with its congeners, from which it can be distinguished by the combination of a glans-shaped proboscis, the low, transverse ridges that lie on the dorsodistal surfaces of the first coxae and femora of all legs and the distinctive conical tubercle on the mid-dorsal surface of the fourth segment of the trunk. PMID- 26250305 TI - A re-description of Discoconchoecia elegans (Sars, 1865) (Ostracoda: Halocyprididae) from high latitudes in the North Atlantic. AB - Discoconchoecia elegans (Sars, 1865) is one of the most frequently recorded species of halocyprid ostracods and specimens are collected in abundance from various latitudes throughout the world oceans. This species is often dominant or subdominant member of the mesopelagic assemblages. However, its body size varies substantially with latitude, posing the question as to whether D. elegans is either a single, highly variable species, or a complex of cryptic and sibling species. Evaluation of the hypothesis that D. elegans is a complex of species requires comparison between the type material and specimens collected from different latitudes. The inadequacy of the original description from the type locality, off the Lofoten Islands (NW Norway), combined with a lack of the type material is preventing critical rating. In this paper Discoconchoecia elegans is redescribed from specimens collected from an area close to Svalbard, using detailed drawings, morphometric measurements of all limbs, and SEM photographs, and it is compared with specimens collected from an area close to the species type locality. The individuals from those two localities show no significant differences, probably because the hydrographic conditions are similar between the two sites. PMID- 26250306 TI - A new species of Waldeckia from the Austral Isles, Society Islands (Amphipoda, Lysianassoidea, Lysianassidae, Waldeckiinae). AB - A new species of the scavenging lysianassid amphipod genus Waldeckia, W. bamberi sp. nov., is described from the Austral Isles, Society Isles, the first record of Waldeckia on the Pacific Plate. PMID- 26250307 TI - A new amphipod Nicippe rogeri sp. nov. (Crustacea, Pardaliscidae) from New Zealand's deep sea. AB - The amphipod family Pardaliscidae has a worldwide distribution and is considered to be especially common in the deep sea. This is the first record of the genus Nicippe in New Zealand waters and a new species, N. rogeri sp. nov is described in honour of Dr. Roger Bamber. This brings the number of species in the genus Nicippe worldwide to four. The new species is described in detail and a key to the four species of Nicippe is provided. PMID- 26250308 TI - A revision of the genus Paracallisoma Chevreux, 1903 (Crustacea: Amphipoda: Scopelocheiridae: Paracallisominae) with a redescription of the type species of the genus Paracallisoma and the description of two new genera and two new species from the Atlantic Ocean. AB - The genus Paracallisoma (Crustacea: Amphipoda) is revised and the type species, Paracallisoma alberti is redescribed based on holotype material supplemented with new material from the region of the type locality. This revision results in the establishment of two new genera, Pseudocallisoma gen. nov. and Haptocallisoma gen. nov., and the description of a new species of Haptocallisoma and a new species of Paracallisoma from the North Atlantic Ocean. An account of all known species within the three genera is given and updated keys to the genera and species are provided. PMID- 26250309 TI - Platycuma bamberconfabulor sp. nov. (Crustacea: Cumacea: Nannastacidae) from Antarctica, with a note on the gut of Platycuma. AB - Platycuma bamberconfabulor sp. nov. is based on a specimen from the Ross Sea. The species can be distinguished from the other species in the genus through the combination of a laterally expanded and somewhat dorsoventrally flattened carapace, anterior margin of the carapace excavate in dorsal view, uropod peduncles less than twice as long as pleonite 6, and subequal pleonites 4 and 5. PMID- 26250310 TI - Indoapseudes bamberi sp. nov. (Crustacea: Tanaidacea: Pagurapseudidae: Hodometricinae) from Iriomote Island, Ryukyu Islands, southwestern Japan. AB - We describe Indoapseudes bamberi sp. nov., based on a specimen from Funaura Bay, Iriomote Island, Japan. This species can be distinguished from its five congeners by having the combination of the antenna with a squama and pereopods 1 and 2 with one dorsal spine on the basis. We also determined part of the nucleotide sequence for the cytochrome c oxidase subunit I (COI) gene in I. bamberi, and present a key to Indoapseudes species. PMID- 26250311 TI - The first pagurapseudid species (Peracarida: Tanaidacea) from New Zealand with remarks on paguridean (Decapoda: Paguridea) and pagurapseudid convergence and competition. AB - A new species of pagurapseudid, Macrolabrum maui, is described from the lower eulittoral rocky shore on the East Coast of the North Island, New Zealand. It is similar to M. haikung from Bass Strait, Australia and M. distonyx from New Caledonia. Males and females show little dimorphism. Typical of the subfamily Pagurapseudinae, M. maui inhabits shells of micro-molluscs such as the gastropods Eatoniella, Merelina, and Pisinna. A dichotomous key to the species of Macrolabrum is given. Possible competition for micro-mollusc shells between small pagurideans, notably their glaucothoe stage, and pagurapseudids is considered based on their convergent morphologies and on body sizes. PMID- 26250312 TI - Cacoheterotanais rogerbamberi, a new genus and species of leptocheliid Tanaidacea (Crustacea: Peracarida) from shelf-waters of the Gulf of Mexico. AB - A new leptocheliid tanaidacean, Cacoheterotanais rogerbamberi gen. et sp. n., is described from the Continental Shelf of the eastern Gulf of Mexico at depths ranging from 10 to 30 m. The new monotypic genus and species is distinguished from the other genera within the Pseudonototanais complex, or genus-group, (Cocotanais, Heterotanais, Makassaritanais, Ogleus, and Pseudonototanais) by a combination of characters, including the (1) male antennule with three peduncular and three flagella articles, (2) male and female both having three articles in the uropodal endopod, (3) basis of the female maxilliped with three pairs of long distal setae, and (4) differences in the morphology, setation and shape of the male cheliped. A key and table are presented to further distinguish C. rogerbamberi from the genera and species within the Pseudonototanais complex. PMID- 26250313 TI - A new species of heterochelous tanaidacean Tanaissus (Paratanaoidea: Tanaissuidae) from the north-west Iberian Peninsula. AB - A new species of tanaidomorph, Tanaissus bamberi, is described from the north western region of the Iberian Peninsula. Its most remarkable character is the presence of morphologically different right and left chelae in the males. The species occurs sympatrically with T. lilljeborgi, mainly in intertidal and subtidal sediments of medium to muddy sands typical of fully marine and estuarine salinities. PMID- 26250314 TI - First record of Tanaidacea (Crustacea) from a deep-sea coral reef in the Gulf of Guinea. AB - Four undescribed species of Tanaidacea were discovered during a baseline monitoring program conducted off the coast of Ghana. The specimens came from a deep-water reef largely composed of the ahermatypic coral, Lophelia pertusa. The tanaidacean material was collected during November 2012 onboard the RV Dr Fridtjof Nansen using a van Veen grab in depths of between 375 and 386 m. Three of the new species described herein are tanaidomorphans belonging to the genera Bathyleptochelia (Leptocheliidae), Pseudotanais (Pseudotanaidae) and Cryptocopoides (Cryptocopidae). The fourth species, an apseudomorphan, belongs to Calozodion (Metapseudidae), a genus hitherto known only from shallow waters (<200 m). This report constitutes the first records of tanaidaceans from a deep-sea Lophelia reef. PMID- 26250315 TI - Rediagnosis of Callianideidae and its genera (Crustacea: Decapoda: Axiidea), and description of a new species of Heardaxius Sakai, 2011. AB - Callianideidae and Thomassiniidae, two families of Axiidea, are synonymised and Callianideidae diagnosed. The six genera, Callianidea H. Milne Edwards, 1837, Crosniera Kensley & Heard, 1991, Mictaxius Kensley & Heard, 1991, Heardaxius Sakai, 2011, Paracallianidea Sakai, 1992 and Thomassinia de Saint Laurent, 1979 are diagnosed and all species listed. Garyia Sakai, 2011 is synonymised with Thomassinia. A key to genera is provided. A new species Heardaxius rogerbamberi is described from Papua New Guinea. Thomassinia aimsae Poore, 1997 is newly recorded from Papua New Guinea. PMID- 26250316 TI - Two new species of Munidopsis (Crustacea: Anomura: Munidopsidae) from the Kermadec and Louisville ridge systems off New Zealand. AB - Two new species of Munidopsis are described from the wider New Zealand region. Munidopsis bamberi sp. nov. is described from the Havre Trough adjacent to the Kermadec Volcanic Arc north-east of the New Zealand continental shelf, and is named in honour of Roger Bamber for his contributions to arthropod taxonomy and systematics. The second species is M. sculpo sp. nov. from Forde Seamount on the Louisville Ridge east of New Zealand. This brings the number of Munidopsis species known in New Zealand waters to 17 and a key to the New Zealand species is provided. PMID- 26250317 TI - Deep-water Thyasiridae (Mollusca: Bivalvia) from the Oman Margin, Arabian Sea, new species and examples of endemism and cosmopolitanism. AB - Seven species of Thyasiridae are reported from the Oman Margin of the Arabian Sea at depths between 688 m and 3356 m. Hypoxic conditions exist at depths between 400 and 1200 m and three species are restricted to this zone and to the Arabian Sea. Leptaxinus indusarium has also been recorded from the Indus Fan and Channelaxinus investigatoris from off Sri Lanka. A new species Thyasira anassa sp. nov. is described from the hypoxic zone. Another four species are recorded from the abyssal zone where oxygen levels are typical for the deep ocean. Here another new species is described, Parathyasira bamberi sp. nov. but the other species could not be conclusively identified because of close affinity with populations from other oceans. Deep water Atlantic species Axinulus croulinensis and Mendicula ferruginosa are apparently present in the abyssal Indian Ocean while another thyasirid shell is very close to Channelaxinus excavatus from the Eastern Pacific and C. perplicata from the Atlantic. Accompanying these abyssal thyasirids were other bivalve species, Deminucula atacellana, Limopsis pelagica and Bentharca asperula that cannot be distinguished by morphology from their Atlantic populations. It is concluded that using morphology alone that the abyssal species may well be cosmopolitan in distribution. PMID- 26250318 TI - New Prototrochus species of sea cucumber from Australia (Echinodermata: Holothuroidea: Synaptida: Myriotrochidae). AB - The case put by Alexey Smirnov in 2012 is accepted and the order name Synaptida Cuenot is adopted in place of Apodida Brandt. Two new Myriotrochidae Theel species from the continental slope of Australia are described: Prototrochus robbinsae sp. nov. and Prototrochus roniae sp. nov. A key to the six Australasian species of Prototrochus Beljaev & Mironov and a distribution and depth map are provided. PMID- 26250319 TI - New taeniogyrinid species of sea cucumber from the Weddell Sea (Echinodermata: Holothuroidea: Synaptida). AB - The case put by Alexei Smirnov in 2012 is accepted and the order name Synaptida Cuenot is adopted in place of Apodida Brandt. Two new Synaptida species are described for the Weddell Sea in Antarctica with single author O'Loughlin: Sigmodota magdarogera sp. nov. and Taeniogyrus bamberi sp. nov.. A specimen of Sigmodota magnibacula (Massin & Heterier) is described. A key is provided for the genera and species of Taeniogyrinae that occur south of the Antarctic Convergence. PMID- 26250320 TI - Dryinidae of the Eastern Palaearctic region (Hymenoptera: Chrysidoidea). AB - An updated revision of Eastern Palaearctic Dryinidae is presented. Six subfamilies, 17 genera and 160 species are treated. Descriptions, geographic distribution, known hosts, natural enemies and type material of each species are presented, together with illustrations of the main morphological characters and keys to the subfamilies, genera and species. Complete lists of references concerning the Eastern Palaearctic Dryinidae and their hosts are given. The lectotype is designated for Anteon flaviscapus Jansson, 1950. A new combination is proposed for Mirodryinus olmii (Moczar, 1983), comb. nov. (from Radiimancus Moczar). The following new records are reported: Aphelopus prolatus Mita & Olmi, 2014 and Gonatopus formicicolus Richards, 1939 from Sweden; Aphelopus querceus Olmi, 1984, Aphelopus serratus Richards, 1939 and Anteon reticulatum Kieffer, 1905 from Bulgaria; Gonatopus nigricans (R. Perkins, 1905) from Solomon Islands; Haplogonatopus oratorius (Westwood, 1833) from Germany and Sweden. PMID- 26250321 TI - A revision and phylogenetic analysis of the spider genus Oxysoma Nicolet (Araneae: Anyphaenidae, Amaurobioidinae). AB - We review the spider genus Oxysoma Nicolet, with most of its species endemic from the southern temperate forests in Chile and Argentina, and present a phylogenetic analysis including seven species, of which three are newly described in this study (O. macrocuspis new species, O. kuni new species, and O. losruiles new species, all from Chile), together with other 107 representatives of Anyphaenidae. New geographical records and distribution maps are provided for all species, with illustrations and reviewed diagnoses for the genus and the four previously known species (O. punctatum Nicolet, O. saccatum (Tullgren), O. longiventre (Nicolet) and O. itambezinho Ramirez). The phylogenetic analysis using cladistic methods is based on 264 previously defined characters plus one character that arises from this study. The three new species are closely related with Oxysoma longiventre, and this four species compose what we define as the Oxysoma longiventre species group. The phylogenetic analysis did not retrieve the monophyly of Oxysoma, which should be reevaluated in the future, together with the genus Tasata. PMID- 26250322 TI - Revision of the Neotropical species of the caddisfly genus Wormaldia McLachlan (Trichoptera: Philopotamidae). AB - Wormaldia McLachlan 1865 is the 2nd largest genus in the family Philopotamidae (Trichoptera) after Chimarra Stephens 1829 and is diverse and widely distributed, with ca. 175 extant species in all biogeographic regions except the Australasian. In this monograph, 14 previously described species are recognized for the Neotropical region: W. alicia Bueno-Soria, Santiago-Fragoso, & Barba-Alvarez 2005 [Mexico]; W. arizonensis (Ling 1938) [Mexico, USA]; W. cornuta Bueno-Soria & Holzenthal1986 [Mexico]; W. dampfi Ross & King 1956 [Mexico, Nicaragua]; W. dorsata Ross & King 1956 [Mexico]; W. endonima Ross & King 1956 [Mexico]; W. esperonis Ross & King 1956 [Mexico]; W. insignis (Martynov 1912) [Peru]; W. luma Bueno-Soria & Holzenthal 1986 [Mexico]; W. matagalpa Flint 1995 [Costa Rica, Guatemala, Nicaragua]; W. palma Flint 1991 [Colombia]; W. planae Ross & King 1956 [southwestern USA, Mexico, Caribbean, Central America, and northern South America]; W. prolixa Flint 1991[Colombia]; and W. tarasca Bueno-Soria & Holzenthal 1986 [Mexico]. Also, 36 additional Neotropical species are newly diagnosed, described, and illustrated: W. andrea [Ecuador]; W. anhelitus [Central America]; W. araujoi [Ecuador]; W. aymara [Bolivia]; W. barbai [Mexico]; W. bolivari [Venezuela]; W. boteroi [Colombia]; W. buenorum [Mexico]; W. calderonae [Mexico]; W. chrismark [Panama]; W. contrerasi [Panama]; W. dachiardiorum [Colombia]; W. eberhardi [Panama]; W. flinti [Bolivia, Panama]; W. francovilla [Panama]; W. fredycarol [Costa Rica, Panama]; W. gallardoi [Costa Rica, Panama]; W. gonzalezae [Venezuela]; W. hedamafera [Costa Rica, Nicaragua]; W. imberti [Costa Rica]; W. inca [Peru]; W. isela [Mexico]; W. juarox [Costa Rica]; W. lauglo [Panama]; W. machadorum [Costa Rica, Panama]; W. maesi [Nicaragua]; W. menchuae [Guatemala]; W. monsonorum [Costa Rica]; W. navarroae [Mexico]; W. paprockevi [Costa Rica]; W. saboriorum [Panama]; W. tocajoma [Costa Rica]; W. trondi [Costa Rica, Panama]; W. tupacamara [Bolivia]; W. zunigae [Colombia]; and W. zunigarceorum [Costa Rica, Panama]. In addition, the species W. arcopa Denning 1966 from Panama is considered a junior subjective synonym of W. planae. Furthermore, new distribution records for the Neotropical region for several species are given. Diagnoses, redescriptions, and illustrations of the male genitalia of the other 14 described Neotropical species in the genus are also presented. Illustrations of the forewing and hind wing of 19 species are also given. A structural terminology for male tergum X is proposed. Finally, a key for identification of males of all Neotropical species is provided. PMID- 26250323 TI - The genus Loimia Malmgren, 1866 (Annelida: Terebellidae) off the Brazilian coast, with description of three new species and notes on some morphological characters of the genus. AB - Three new species of Loimia were collected along the Brazilian coast, during some independent projects, from shallow to deep waters off the continental slope. These species are L. megaoculata sp. nov., L. armata sp. nov., and L. brasiliensis sp. nov., all herein described and compared with the morphologically most similar congeners. Loimia megaoculata sp. nov., is characterized by having large, dark eyespots, progressively smaller from dorso-laterally towards lateral basal part of prostomium; lobes of segment 1 are distally rounded, roughly circular, barely reaching mid-length of upper lip; uncini have up to 6-7 teeth, including basal-most tooth. Loimia armata sp. nov., lacks eyespots; stout lobes of segment 1 nearly reach level of upper lip; uncini have up to 7-8 teeth, including basal-most tooth. Loimia brasiliensis sp. nov., has two narrow rows of eyespots; lobes of segment 1 are thin, reaching mid-length of upper lip; uncini have 5-6 teeth, including basal-most tooth. We provide a brief discussion on the main morphological characters useful for the taxonomy of this genus, such as presence of eyespots, and morphology of lobes of segments 1 and 3, of mid-ventral pads and neurochaetae. Up to now only two species had been recorded from Brazil, namely L. grubei and L. medusa, both doubtful records, as discussed along this paper. PMID- 26250324 TI - Review of Nexosa Diakonoff in Vietnam, with a new species and a new subspecies, and transfer to the tribe Archipini (Lepidoptera: Tortricidae: Tortricinae: Archipini). AB - The species of Nexosa Diakonoff, 1977 in Vietnam are reviewed: Nexosa hexaphala (Meyrick); Nexosa hexaphala tamdaoana Heppner & Bae, n. subsp.; and Nexosa tonkinensis Heppner & Bae, n. sp. The genus is transferred to the tribe Archipini (Tortricidae: Tortricinae). PMID- 26250325 TI - On some sea cucumbers (Echinodermata: Holothuroidea) from off the south and west coasts of South Africa collected by the South African Environmental and Observation Network (SAEON). AB - Twenty four specimens of holothuroids recently received from the South African Environmental and Observation Network (SAEON), collected from off the south and west coasts of South Africa, are herein recorded and/or described. The specimens comprise eight nominal and one indeterminate species and represent both shallow water and deep-sea forms, distributed from Plettenberg Bay to just north of Lambert's Bay in the Western Cape Province. There are no new species but two new records for the South African region and extensions of horizontal and bathymetric distributions of the other species. Additions to the South African fauna are Zygothuria lactea (Theel, 1886) and Synallactes cf. challengeri (Theel, 1886). The paper also contains the first definite record of Thyone venusta Selenka, 1868, originally described from the Red Sea. Distribution ranges of the following species have been altered Synallactes viridilimus Cherbonnier, 1952; S. mollis Cherbonnier, 1952 and Psuedostichopus langeae Thandar, 2009. PMID- 26250326 TI - New species and records of Burmagomphus Williamson, 1907 (Odonata, Gomphidae) from China. AB - Four new species of Burmagomphus Williamson, 1907 are described from Southwestern China: B. apricus sp. nov. from Xishuangbanna National Nature Reserve, Menglun Town, Xishuangbanna Dai Autonomous Prefecture, Yunnan Province; B. magnus sp. nov. from Huayudong, Nanxi Town, Hekou County, Hani-Yi Autonomous Prefecture of Honghe, Yunnan Province, B. dentatus sp. nov. from Zhangjiang River in Xiaoqikong scenic spot, altitude 400 m, Libo County, Guizhou Province, and B. latescens sp. nov. from Sifangjing, Mengding Town, Gengma County, Lincang City, Yunnan Province. New records of Burmagomphus spp. in China are provided, with B. asahinai and B. williamsoni williamsoni for the first time reported from China. A revised checklist of Burmagomhus spp. of China is provided which includes 14 species. A doubtful record of B. arboreus and relations of the newly described species are discussed. All types are deposited in the Collection of Aquatic Animals, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan City, Hubei Province, China. PMID- 26250327 TI - Systematic status of Fejervarya ((Amphibia, Anura, Dicroglossidae) from South and SE Asia with the description of a new species from the Western Ghats of Peninsular India. AB - We carried out a large-scale phylogenetic analysis of fejervaryan (dicroglossid frogs with 'Fejervaryan lines' on the ventral side of the body) frogs, distributed in South and SE Asia, using published and newly generated sequences of unidentified individuals from the northern Western Ghats. The results corroborate the presence of a larger fejervaryan clade with a sister relationship to a clade composed of Sphaerotheca. Two sister clades could be discerned within the lager fejervaryan clade. The unidentified individuals formed a monophyletic group and showed a strong support for a sister relationship with Minervarya sahyadris. The species was found to be highly divergent (16S rRNA-4% and tyr-1%) from its sister lineage Minervarya sahyadris, and the clade composed of these two lineages were found to be deeply nested within the larger clade of Fejervarya. Based on this, the genus Minervarya Dubois, Ohler and Biju, 2001 is synonymized under the genus Fejervarya Bolkay, 1915. The unidentified lineage is recognized, based on phylogenetic position, genetic divergence and morphological divergence, as a distinct species and named here as Fejervarya gomantaki sp. nov. The presence of rictal glands was observed to be a synapomorphic character shared by the nested clade members, Fejervarya sahyadris and Fejervarya gomantaki sp. nov. Based on the presence of rictal gland and small size, Minervarya chilapata, a species from a lowland region in the Eastern Himalayas, is synonymized under Fejervarya and evidence for morphological separation from the new species, Fejervarya gomantaki sp. nov. is provided. For fejervaryan frogs, three generic names (Frost, 2015) are currently in use for two phylogenetic subclades; the genus Fejervarya Bolkay, 1915 for species distributed in South East Asia; the genus Zakerana Howlader, 2011 for species distributed in South Asia and the genus Minervarya Dubois, Ohler and Biju, 2001 nested within the 'Zakerana clade'. In the phylogenetic analysis Minervarya sahyadris and the new species described herein as Fejervarya gomantaki sp. nov. are nested within the 'Zakerana clade'. If the 'Zakerana clade' for the fejervaryan frogs distributed in South Asia is assigned a generic status, the nomen 'Minervarya' should be used as per the principle of priority of the ICZN Code. Taking into consideration the overlapping distribution ranges of members of the sister clades within the larger fejervaryan clade and the absence of distinct morphological characteristics, we also synonymize the genus Zakerana Howlader, 2011, a name assigned to one of the sister clades with members predominantly distributed in South Asia, under the genus Fejervarya Bolkay, 1915. We discuss the need for additional sampling to identify additional taxa and determine the geographical ranges of the members of the sister clades within Fejervarya to resolve taxonomy within this group. [Corrected] PMID- 26250328 TI - Three new species of the genus Trachelas (Araneae: Trachelidae) from an oak forest inside the Mesoamerican biodiversity hotspot in Mexico. AB - Three new species of the spider genus Trachelas L. Koch, 1872 are described and included in the speciosus group based on the following features: embolus as a separate sclerite from the tegulum with no basal coils, legs with a conspicuous fringe of long trichobothria and narrow copulatory ducts coiled irregularly. The new species described are: T. crassus sp. n., T. ductonuda sp. n. and T. odoreus sp. n. A total of 46 specimens were collected in an oak forest near Pico de Orizaba Volcano, Mexico. Most individuals were collected on low vegetation using beating trays and direct collecting at night. Additional images are available at www.unamfcaracnolab.com. PMID- 26250329 TI - Description of two new species related to Pterostichus (Aphaonus) arcanoides Lorenz, 1998 from the West Transcaucasia (Coleoptera: Carabidae: Pterostichini). AB - Two new carabid beetle species, Pterostichus (Aphaonus) mariamae sp. nov. and Pterostichus (Aphaonus) svetlanae sp. nov., related to an enigmatic mountainous representative of the subgenus Aphaonus, P. (Aphaonus) arcanoides Lorenz, 1998, are described from the Abkhazian midlands (Tsebelda Plateau and Mtsara district). Discriminative features of the new species in the subgenus are briefly discussed. PMID- 26250330 TI - New species of Hippopleurifera (Bryozoa, Cheilostomata) from the Miocene Pirabas Formation, Para state, Brazil. AB - The Pirabas Formation in Brazil has been studied for many years and a great diversity of animal groups (in particular fishes, molluscs and echinoderms) have been described from there, whereas the Bryozoa have scarcely been mentioned. New samples, collected specifically to focus on bryozoans, have shown that the diversity in this formation is higher than previously thought. Here we describe two new species belonging to the cheilostomate genus Hippopleurifera--H. barbosae sp. nov. and H. confusa sp. nov. Both species were collected at Atalaia Beach, northeastern Para state, which boasts some of the best marine Cenozoic fossil outcrops in Brazil. After accounting for all described species, plus the two new species and four generic reassignments (new combinations) described herein, some 29 Hippopleurifera species are now known. Most of these are fossils from Europe or the USA, but a handful are known from the Recent Mediterranean, Caribbean and Indo-West Pacific. PMID- 26250331 TI - Three new species of Megaselia Rondani (Diptera, Phoridae) from mailand China. AB - Three new species, Megaselia cornipalpis sp. nov., M. lacunitarsalis sp. nov. and M. trimacula sp. nov. are described and illustrated from mainland China. A checklist of species of genus Megaselia recorded from mainland China is provided. PMID- 26250332 TI - Compsocommosis new genus, with a new species in Vietnam, and Transfer of Mictocommosis to Archipini (Lepidoptera: Tortricidae: Tortricinae: Archipini). AB - Compsocommosis, n. gen. (Tortricidae: Tortricinae: Archipini), is described, with one new species from Vietnam, Compsocommosis vietnamensis Heppner & Bae, n. sp. The new genus is related to the Asian genus Mictocommosis, and both are placed in the tribe Archipini. PMID- 26250334 TI - Spatial scale and movement behaviour traits control the impacts of habitat fragmentation on individual fitness. AB - Habitat fragmentation, that is the breaking apart of habitat, can occur at multiple spatial scales at the same time, as a result of different land uses. Individuals of most species spend different amounts of times moving in different modes, during which they cover different distances and experience different fitness impacts. The scale at which fragmentation occurs interacts with the distance that individuals move in a particular mode to affect an individual's ability to find habitat. However, there is little knowledge of the fitness consequences of different scales of fragmentation for individuals with different traits of movement behaviour. This is critical to understand the mechanisms of persistence of different species in fragmented landscapes. The aim of this study was to quantify the impacts of habitat fragmentation at different scales on the fitness components (reproduction and survival) of individuals with different traits of movement behaviour. We developed a demographic model of individuals that adopt short and tortuous movements within foraging areas (foraging mode) and long and straight movements between foraging areas (searching mode). We considered individuals that adopt different movement modes with varying frequencies, inherently move different searching distances and experience different risks of mortality during searching. We then applied the model within a spatially explicit simulation framework where we varied simultaneously the degree of fragmentation within (fine scale) and between foraging areas (coarse scale). Fine-scale fragmentation had a greater impact on reproduction and survival than coarse-scale fragmentation, for those individuals with a low searching propensity. The impact of fine-scale fragmentation on reproduction and survival interacted with the impact of coarse-scale fragmentation on reproduction and survival, to affect the fitness of individuals with a high searching propensity, large inherent searching distances and high searching mortality rates. Habitat selection strongly mitigated the impact of the scale at which fragmentation occurred on individual fitness. Our findings suggest that the land use to target with conservation actions to reduce fragmentation, such as financial schemes that promote re-vegetation or retention of standing vegetation, depends on the scale at which fragmentation occurs and the movement behaviour traits of the species of conservation concern. PMID- 26250333 TI - Recommendations for the Design and Analysis of Treatment Trials for Alcohol Use Disorders. AB - BACKGROUND: Over the past 60 years, the view that "alcoholism" is a disease for which the only acceptable goal of treatment is abstinence has given way to the recognition that alcohol use disorders (AUDs) occur on a continuum of severity, for which a variety of treatment options are appropriate. However, because the available treatments for AUDs are not effective for everyone, more research is needed to develop novel and more efficacious treatments to address the range of AUD severity in diverse populations. Here we offer recommendations for the design and analysis of alcohol treatment trials, with a specific focus on the careful conduct of randomized clinical trials of medications and nonpharmacological interventions for AUDs. METHODS: This paper provides a narrative review of the quality of published clinical trials and recommendations for the optimal design and analysis of treatment trials for AUDs. RESULTS: Despite considerable improvements in the design of alcohol clinical trials over the past 2 decades, many studies of AUD treatments have used faulty design features and statistical methods that are known to produce biased estimates of treatment efficacy. CONCLUSIONS: The published statistical and methodological literatures provide clear guidance on methods to improve clinical trial design and analysis. Consistent use of state-of-the-art design features and analytic approaches will enhance the internal and external validity of treatment trials for AUDs across the spectrum of severity. The ultimate result of this attention to methodological rigor is that better treatment options will be identified for patients with an AUD. PMID- 26250336 TI - Bone status of acetylcholinesterase-knockout mice. AB - Acetylcholinesterase (AChE) hydrolyzes acetylcholine (ACh) to acetate and choline and thereby terminates nerve impulse transmission. ACh is also expressed in bone tissue and enhances here proliferation and differentiation of osteoblasts, which makes it interesting to investigate effects of AChE deficiency on bone. To our knowledge, this is the first study that analyzed bone of heterozygous acetylcholinesterase-knockout (AChE-KO) mice. Tibia, femur, thoracic and lumbar vertebrae of 16-week-old female heterozygous AChE-KO mice and their corresponding wildtypes (WT) were analyzed using real-time RT-PCR, dual-energy X-ray absorptiometry, biomechanics, micro-computed tomography, histology and histomorphometry. Our data revealed that heterozygous AChE-KO did not cause negative effects upon bone parameters analyzed. In contrast, the number of osteoclasts per perimeter was significantly reduced in lumbar vertebrae. In addition, we found a significant decrease in trabecular perimeter of lumbar vertebrae and cortical area fraction (Ct.Ar/Tt.Ar) in the mid-diaphysis of femurs of AChE-KO mice compared to their WT. Therefore, presumably a local homozygous knockout of AChE or AChE-inhibitor administration might be beneficial for bone formation due to ACh accumulation. However, many other bone parameters analyzed did not differ statistically significantly between AChE-KO and WT mice. That might be reasoned by the compensating effect of butyrylcholinesterase (BChE). PMID- 26250335 TI - miR-367 promotes proliferation and stem-like traits in medulloblastoma cells. AB - In medulloblastoma, abnormal expression of pluripotency factors such as LIN28 and OCT4 has been correlated with poor patient survival. The miR-302/367 cluster has also been shown to control self-renewal and pluripotency in human embryonic stem cells and induced pluripotent stem cells, but there is limited, mostly correlational, information about these pluripotency-related miRNA in cancer. We evaluated whether aberrant expression of such miRNA could affect tumor cell behavior and stem-like traits, thereby contributing to the aggressiveness of medulloblastoma cells. Basal expression of primary and mature forms of miR-367 were detected in four human medulloblastoma cell lines and expression of the latter was found to be upregulated upon enforced expression of OCT4A. Transient overexpression of miR-367 significantly enhanced tumor features typically correlated with poor prognosis; namely, cell proliferation, 3-D tumor spheroid cell invasion and the ability to generate neurosphere-like structures enriched in CD133 expressing cells. A concurrent downregulation of the miR-367 cancer-related targets RYR3, ITGAV and RAB23, was also detected in miR-367-overexpressing cells. Overall, these findings support the pro-oncogenic activity of miR-367 in medulloblastoma and reveal a possible mechanism contributing to tumor aggressiveness, which could be further explored to improve patient stratification and treatment of this important type of pediatric brain cancer. PMID- 26250337 TI - Germanium-Vacancy Single Color Centers in Diamond. AB - Atomic-sized fluorescent defects in diamond are widely recognized as a promising solid state platform for quantum cryptography and quantum information processing. For these applications, single photon sources with a high intensity and reproducible fabrication methods are required. In this study, we report a novel color center in diamond, composed of a germanium (Ge) and a vacancy (V) and named the GeV center, which has a sharp and strong photoluminescence band with a zero phonon line at 602 nm at room temperature. We demonstrate this new color center works as a single photon source. Both ion implantation and chemical vapor deposition techniques enabled fabrication of GeV centers in diamond. A first principles calculation revealed the atomic crystal structure and energy levels of the GeV center. PMID- 26250338 TI - Genome-wide identification and in silico characterisation of microRNAs, their targets and processing pathway genes in Phaseolus vulgaris L. AB - Common bean (Phaseolus vulgaris L., Fabaceae) is a globally important staple crop, which is an important source of calories, protein and essential micronutrients. At the genomic level little is known regarding the small non coding RNAs within the common bean genome. One of the most important classes of such small non-coding RNAs is microRNAs (miRNAs), which control mRNA and protein expression levels in many eukaryotes. Computational methods have been applied to identify putative miRNAs in the genomes of different organisms. In this study, our objective was to comprehensively identify and characterise miRNAs from the genome and transcriptome of P. vulgaris, including both mature and precursor miRNA forms. We also sought to identify the putative proteins involved in miRNA processing and the likely target genes of common bean miRNAs. We identified 221 mature miRNAs and 136 precursor miRNAs distributed across 52 different miRNA families in the P. vulgaris genome. Amongst these, we distinguished 129 novel mature miRNAs and 123 miRNA precursors belonging to 24 different miRNA families. We also identified 31 proteins predicted to participate in the miRNA-processing pathway in P. vulgaris. Finally, we also identified 483 predicted miRNA targets, including many which corroborate results from other species, suggesting that miRNA regulatory systems are evolutionarily conserved and important for plant development. Our results expand the study of miRNAs and their target genes in common bean, and provide new opportunities to understand their roles in the biology of this important staple crop. PMID- 26250339 TI - Restoration of Obliterated Numbers on 40NiCrMo4 Steel by Etching Method: Metallurgical and Statistical Approaches. AB - The restoration of obliterated serial numbers is a problem of common occurrence in the forensic field. Among several restoration techniques, chemical etching is the most frequently used. The present research is aimed at studying the restoration of serial numbers, stamped on 40NiCrMo4 steel plates, by means of chemical etching. Microstructural characterization was firstly carried out to study the plastically deformed regions surrounding the marks. The obliteration was performed by controlled removals of material at increasing depths of erasure, and five etching reagents were considered to analyze their sensitivity and effectiveness. Experimental results revealed that Fry's reagent was the most sensitive, able to restore erased marks up to 60 MUm under the depth of the imprint. The reagent comprising 25 mL HNO3 and 75 mL H2O provided good results, recovering the major numbers of characters. A descriptive statistical analysis was conducted to study the operator's influence on the recovered marks' identification. PMID- 26250340 TI - Response to Heedman et al.: Variation at presentation among colon cancer patients with metastases: a population-based study. PMID- 26250341 TI - Elevated Troponin Levels in Patients Without Acute Coronary Syndrome: What is the Real Diagnosis? Response. PMID- 26250342 TI - Mosaic partial deletion of PTPN12 in a child with interrupted aortic arch type A. AB - Congenital heart malformations, including those of the great vessels, are among the most common human birth defects. The goal of this study was to identify the significance of a de novo mosaic PTPN12 partial deletion identified in a newborn with an interrupted aortic arch type A, ventricular septal defect, and pyloric stenosis. PTPN12, a downstream target of the RAS pathway, has a known role in endothelial cell adhesion and migration. Neither genetic nor genomic variants in PTPN12 have been described in a human patient; therefore, we evaluated the effect of ptpn12 in a mouse conditional knockout and zebrafish knockdown model to determine the significance of a loss in gene expression. Observed loss of ptpn12 expression in zebrafish resulted in abnormal branchial arch and tail vasculature patterns, with reduced blood flow throughout the animal. This phenotype was supported by anomalous vasculature in a conditional Ptpn12 mouse knockout. Given the novel co-occurrence of interrupted aortic arch type A, ventricular septal defect, and partial deletion of PTPN12 in the patient, as well as vascular phenotypes in Ptpn12 mouse and ptpn12 zebrafish models, it is likely that PTPN12 has a significant role in cardiovascular development and vessel formation during human embryonic development. Furthermore, the partial deletion of PTPN12 lead to interrupted aortic arch type A in this child and may represent a novel condition caused by a null mutation in the RAS pathway. PMID- 26250343 TI - SOST polymorphisms and response to alendronate treatment in postmenopausal Chinese women with osteoporosis. AB - AIM: To investigate the association between SOST gene polymorphisms and response to alendronate treatment. MATERIALS & METHODS: 639 Chinese postmenopausal women with osteoporosis or osteopenia received alendronate treatment. Polymorphisms of SOST were analyzed. Bone mineral density (BMD), serum ALP and beta-CTX levels were measured. The correlation of SOST polymorphisms with changes of BMD and bone biomarkers after treatment was analyzed. RESULTS: rs1234612 and rs851054 polymorphisms were correlated to baseline lumbar spine BMD (p < 0.05). After 12 months of treatment rs1234612 and rs865429 polymorphisms were correlated to BMD changes at the lumbar spine (p < 0.05) or femoral neck (p < 0.05), respectively. CONCLUSION: The polymorphisms of SOST are genetic factors affecting bone health and response to alendronate in Chinese postmenopausal women. PMID- 26250344 TI - Relationship between serum response factor and androgen receptor in prostate cancer. AB - BACKGROUND: Serum response factor (SRF) is an important transcription factor in castrate-resistant prostate cancer (CRPC). Since CRPC is associated with androgen receptor (AR) hypersensitivity, we investigated the relationship between SRF and AR. MATERIALS AND METHODS: Transcriptional activity was assessed by luciferase assay. Cell proliferation was measured by MTT and flow cytometry. Protein expression in patients was assessed by immunohistochemistry. RESULTS: To investigate AR involvement in SRF response to androgen, AR expression was down regulated using siRNA. This resulted in the abrogation of SRF induction post-DHT. Moreover, DHT stimulation failed to induce SRF transcriptional activity in AR negative PC346 DCC cells, which was only restored following AR over-expression. Next, SRF expression was down-regulated by siRNA, resulting in AR increased transcriptional activity in castrate-resistant LNCaP Abl cells but not in the parental LNCaP. This negative feedback loop in the resistant cells was confirmed by immunohistochemistry which showed a negative correlation between AR and SRF expression in CRPC bone metastases and a positive correlation in androgen-naive prostatectomies. Cell proliferation was next assessed following SRF inhibition, demonstrating that SRF inhibition is more effective than AR inhibition in castrate-resistant cells. CONCLUSION: Our data support SRF as a promising therapeutic target in combination with current treatments. PMID- 26250345 TI - Severe intestinal malabsorption associated with olmesartan: a French nationwide observational cohort study. AB - OBJECTIVES: Severe sprue-like enteropathy associated with olmesartan has been reported, but there has been no demonstration of an increased risk by epidemiological studies. AIM: To assess, in a nationwide patient cohort, the risk of hospitalisation for intestinal malabsorption associated with olmesartan compared with other angiotensin receptor blockers (ARB) and ACE inhibitors (ACEIs). DESIGN: From the French National Health Insurance claim database, all adult patients initiating ARB or ACEI between 1 January 2007 and 31 December 2012 with no prior hospitalisation for intestinal malabsorption, no serology testing for coeliac disease and no prescription for a gluten-free diet product were included. Incidence of hospitalisation with a discharge diagnosis of intestinal malabsorption was the primary endpoint. RESULTS: 4 546 680 patients (9 010 303 person-years) were included, and 218 events observed. Compared with ACEI, the adjusted rate ratio of hospitalisation with a discharge diagnosis of intestinal malabsorption was 2.49 (95% CI 1.73 to 3.57, p<0.0001) in olmesartan users. This adjusted rate ratio was 0.76 (95% CI 0.39 to 1.49, p=0.43) for treatment duration shorter than 1 year, 3.66 (95% CI 1.84 to 7.29, p<0.001) between 1 and 2 years and 10.65 (95% CI 5.05 to 22.46, p<0.0001) beyond 2 years of exposure. Median length of hospital stay for intestinal malabsorption was longer in the olmesartan group than in the other groups (p=0.02). Compared with ACEI, the adjusted rate ratio of hospitalisation for coeliac disease was 4.39 (95% CI 2.77 to 6.96, p<0.0001) in olmesartan users and increased with treatment duration. CONCLUSIONS: Olmesartan is associated with an increased risk of hospitalisation for intestinal malabsorption and coeliac disease. PMID- 26250346 TI - What limits performance during whole-body incremental exercise to exhaustion in humans? AB - To determine the mechanisms causing task failure during incremental exercise to exhaustion (IE), sprint performance (10 s all-out isokinetic) and muscle metabolites were measured before (control) and immediately after IE in normoxia (P(IO2) 143 mmHg) and hypoxia (P(IO2): 73 mmHg) in 22 men (22 +/- 3 years). After IE, subjects recovered for either 10 or 60 s, with open circulation or bilateral leg occlusion (300 mmHg) in random order. This was followed by a 10 s sprint with open circulation. Post-IE peak power output (W(peak)) was higher than the power output reached at exhaustion during IE (P < 0.05). After 10 and 60 s recovery in normoxia, W(peak) was reduced by 38 +/- 9 and 22 +/- 10% without occlusion, and 61 +/- 8 and 47 +/- 10% with occlusion (P < 0.05). Following 10 s occlusion, W(peak) was 20% higher in hypoxia than normoxia (P < 0.05), despite similar muscle lactate accumulation ([La]) and phosphocreatine and ATP reduction. Sprint performance and anaerobic ATP resynthesis were greater after 60 s compared with 10 s occlusions, despite the higher [La] and [H(+)] after 60 s compared with 10 s occlusion recovery (P < 0.05). The mean rate of ATP turnover during the 60 s occlusion was 0.180 +/- 0.133 mmol (kg wet wt)(-1) s(-1), i.e. equivalent to 32% of leg peak O2 uptake (the energy expended by the ion pumps). A greater degree of recovery is achieved, however, without occlusion. In conclusion, during incremental exercise task failure is not due to metabolite accumulation or lack of energy resources. Anaerobic metabolism, despite the accumulation of lactate and H(+), facilitates early recovery even in anoxia. This points to central mechanisms as the principal determinants of task failure both in normoxia and hypoxia, with lower peripheral contribution in hypoxia. PMID- 26250347 TI - Review of Spinal Muscular Atrophy (SMA) for Prenatal and Pediatric Genetic Counselors. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular condition with degeneration of the anterior horn cells in the spinal column. Five SMA subtypes exist with classification dependent upon the motor milestones achieved. Study of the SMN1 (survival motor neuron) and SMN2 genes as well as the concepts of the "2 + 0" carriers, gene conversion, de novo mutations and intragenic mutations allow for a better understanding of SMA. Detailing the carrier and diagnostic testing options further deepens the genetic counselor's knowledge of SMA. A review of care guidelines and research options is included as this information gives a patient a well-rounded view of SMA. Although SMA is most commonly associated with the SMN1 gene, a number of spinal muscular atrophies not caused by genetic changes in this gene may be included as differential diagnoses until confirmatory testing can be completed. SMA is a complex condition requiring a detailed knowledge on the genetic counselor's part in order to explain the disorder to the patient with clarity thus facilitating increased communication and decision making guidance with the patient. PMID- 26250348 TI - Exploration of Male Attitudes on Partnerships and Sexuality with Female BRCA1/2 Mutation Carriers. AB - Women with BRCA mutations are inundated with decisions about managing cancer risks and childbearing considerations. Decisions become more complicated when women face disclosing their mutation and risk-reduction options to a romantic partner. This study identifies the concerns and perspectives of male romantic partners regarding these unique decisions. Twenty-five male participants completed an online survey posted to cancer support group message boards. Participants reported relationship changes regarding intimacy levels (n = 9), attraction (n = 2), and communication (n = 22) after mutation disclosure. Participants whose partners had not undergone prophylactic mastectomy (n = 14) reported concerns regarding sexual relations (n = 5), post-surgical appearance (n = 2), post-surgical attraction (n = 5), and health/lifespan (n = 9). Participants did not express attitude changes toward childbearing. While mutation disclosure conversations and surgical options are concerns for many BRCA mutation carriers in relationships, male partners share these concerns. Aspects of the relationship may change, but male study participants continued to support their partners. This information can benefit female BRCA mutation carriers, their current or future partners, and genetic counselors working with this particular population. PMID- 26250349 TI - Accuracy of transvaginal ultrasound for diagnosis of deep endometriosis in uterosacral ligaments, rectovaginal septum, vagina and bladder: systematic review and meta-analysis. AB - OBJECTIVE: To review the diagnostic accuracy of transvaginal ultrasound (TVS) in the preoperative detection of endometriosis in the uterosacral ligaments (USL), rectovaginal septum (RVS), vagina and bladder in patients with clinical suspicion of deep infiltrating endometriosis (DIE). METHODS: An extensive search was performed in MEDLINE (PubMed) and EMBASE for studies published between January 1989 and December 2014. Studies were considered eligible if they reported on the use of TVS for the preoperative detection of endometriosis in the USL, RVS, vagina and bladder in women with clinical suspicion of DIE using the surgical data as a reference standard. Study quality was assessed using the PRISMA guidelines and QUADAS-2 tool. RESULTS: Of the 801 citations identified, 11 studies (n = 1583) were considered eligible and were included in the meta analysis. For detection of endometriosis in the USL, the overall pooled sensitivity and specificity of TVS were 53% (95%CI, 35-70%) and 93% (95%CI, 83 97%), respectively. The pretest probability of USL endometriosis was 54%, which increased to 90% when suspicion of endometriosis was present after TVS examination. For detection of endometriosis in the RVS, the overall pooled sensitivity and specificity were 49% (95%CI, 36-62%) and 98% (95%CI, 95-99%), respectively. The pretest probability of RVS endometriosis was 24%, which increased to 89% when suspicion of endometriosis was present after TVS examination. For detection of vaginal endometriosis, the overall pooled sensitivity and specificity were 58% (95%CI, 40-74%) and 96% (95%CI, 87-99%), respectively. The pretest probability of vaginal endometriosis was 17%, which increased to 76% when suspicion of endometriosis was present after TVS assessment. Substantial heterogeneity was found for sensitivity and specificity for all these locations. For detection of bladder endometriosis, the overall pooled sensitivity and specificity were 62% (95%CI, 40-80%) and 100% (95%CI, 97 100%), respectively. Moderate heterogeneity was found for sensitivity and specificity for bladder endometriosis. The pretest probability of bladder endometriosis was 5%, which increased to 92% when suspicion of endometriosis was present after TVS assessment. CONCLUSION: Overall diagnostic performance of TVS for detecting DIE in uterosacral ligaments, rectovaginal septum, vagina and bladder is fair with high specificity. PMID- 26250351 TI - Advancing the Rigour and Integrity of Our Science: The Registered Reports Initiative. PMID- 26250350 TI - OARSI osteoarthritis cartilage histopathology assessment system: A biomechanical evaluation in the human knee. AB - The study compared the OARSI osteoarthritis cartilage histopathology assessment system with the biomechanical quality of human in vivo cartilage samples. In a prospective cohort study, 84 patients (100 knees) with varus deformity of the knee were included between May, 2010 and January, 2012. Osteochondral samples underwent biomechanical and histologic analysis. The dynamic modulus significantly (p < 0.001) decreased with each advancing grade of degeneration from OARSI Grade 0 (surface intact) to OARSI Grade 4 (erosion). For the aggregate modulus, there were significant (p < 0.001) differences between OARSI Grade 0 and OARSI Grade 1 as well as between OARSI Grade 1 and OARSI Grade 2. From OARSI Grade 2 to OARSI Grade 5, no differences in aggregate modulus occurred. The new OARSI grading system provides useful information about the functional properties of cartilage. There is a significant difference in cartilage stiffness between samples with intact surface and no signs of degeneration (OARSI Grade 0) and samples with intact surface and early signs of arthritis (OARSI Grade 1). Surgeons performing joint preserving procedures have to be aware that in knees with an intact cartilage surface (OARSI Grade 0/1), significant differences in the biomechanical properties may exist. PMID- 26250352 TI - Psychological Capital and Well-being. PMID- 26250353 TI - Anterior Resection for Rectal Cancer and Visceral Blood Flow: An Explorative Study. AB - BACKGROUND AND AIMS: Impaired blood perfusion may be implicated in anastomotic leakage after anterior resection for rectal cancer. We investigated whether high ligation of the inferior mesenteric artery or total mesorectal excision compromises visceral blood flow in the colonic limb and the rectal stump, respectively. MATERIAL AND METHODS: A prospective cohort study was conducted in a university hospital setting. We used Laser Doppler flowmetry to evaluate the impact of level of tie on colonic limb perfusion and the extent of the mesorectal excision on the rectal blood flow. In the rectum, different quadrants were also assessed. The Mann-Whitney U test was used to compare mean blood flow ratios between groups. RESULTS: Some 23 patients were recruited in a convenience sample during a period in 2012-2013. The mean blood flow ratio was not decreased after high tie compared to low tie surgery (1.71 vs 1.19; p = 0.28). Total mesorectal excision reduced the mean blood flow ratio in the rectum, as compared with partial mesorectal excision (0.76 vs 1.28; p = 0.14). This was especially pronounced in the posterior aspect of the rectum (0.66 vs 1.68; p = 0.02). CONCLUSION: High tie ligation did not seem to decrease colonic limb perfusion, while total mesorectal excision may decrease rectal blood flow. The posterior quadrant of the rectum might be particularly vulnerable to the dissection involved in total mesorectal excision. PMID- 26250354 TI - Implementation of Endoscopic Submucosal Dissection for Gastric Lesions in Norway. AB - BACKGROUND AND AIMS: Endoscopic submucosal dissection is a minimal invasive method for an en bloc resection of dysplasia or early cancer in the stomach. It was developed in Japan in the 1990s, but thus far has not been widely adopted in Western countries. The aim of this study is to report from the introductory phase of gastric endoscopic submucosal dissection in a small-volume Scandinavian center. MATERIAL AND METHODS: The 15 first patients operated on with endoscopic submucosal dissection in the stomach at the University Hospital of North Norway were consecutively registered in a prospective database and evaluated as a quality assurance study. The indications for the procedures were diagnostic or therapeutic. RESULTS: Three patients had benign lesions, three had low-grade dysplasia, five had high-grade dysplasia, two had neuroendocrine tumors, and two had early gastric cancers (T1b). The R0 resection rate was 83%. One neuroendocrine tumor was directed to surgery. No recurrences have been detected after the median of 6 months, and with the exception of one delayed bleeding being treated endoscopically, no serious complications occurred. Two perforations were perioperatively closed with clips. CONCLUSION: This is the first report on gastric endoscopic submucosal dissection in Scandinavia. Preliminary results from an introductory phase indicate that endoscopic submucosal dissection for dysplasia or early gastric cancer may be conducted safely and with acceptable results even in a small-volume center, assuming that surgeons and gastroenterologists in a region direct cases to one individual who can learn this skill. PMID- 26250355 TI - Dysphagia is not a Valuable Indicator of Tumor Response after Preoperative Chemotherapy for R0 Resected Patients with Adenocarcinoma of the Gastroesophageal Junction. AB - BACKGROUND: Monitoring treatment response to preoperative chemotherapy is of utmost importance to avoid treatment toxicity, especially in non-responding patients. Currently, no reliable methods exist for tumor response assessment after preoperative chemotherapy. Therefore, the aim of this study was to evaluate dysphagia as a predictor of tumor response after preoperative chemotherapy and as a predictor of recurrence and survival. METHODS: Patients with adenocarcinoma of the gastroesophageal junction, treated between 2010 and 2012, were retrospectively reviewed. Dysphagia scores (Mellow-Pinkas) were obtained before and after three cycles of perioperative chemotherapy together with clinicopathological patient characteristics. A clinical response was defined as improvement of dysphagia by at least 1 score from the baseline. The tumor response was defined as down staging of T-stage from initial computer tomography (CT) scan (cT-stage) to pathologic staging of surgical specimen (pT-stage). Patients were followed until death or censored on June 27th, 2014. RESULTS: Of the 110 included patients, 59.1% had improvement of dysphagia after three cycles of perioperative chemotherapy, and 31.8% had a chemotherapy-induced tumor response after radical resection of tumor. Improvement of dysphagia was not correlated with the tumor response in the multivariate analysis (p = 0.23). Moreover, the presence of dysphagia was not correlated with recurrence (p = 0.92) or survival (p = 0.94) in the multivariate analysis. CONCLUSION: In our study, improvement of dysphagia was not valid for tumor response evaluation after preoperative chemotherapy and was not correlated with the tumor response. The presence of dysphagia does not seem to be a predictor of recurrence or survival. PMID- 26250356 TI - Dietary practices in ancient populations from northern Chile during the transition to agriculture (Tarapaca region, 1000 BC-AD 900). AB - OBJECTIVE: The goal of this research is to understand the relevance of diet diversity during the transition to agriculture, in ancient populations from northern Chile, especially considering the significance of marine resources and crops in a lesser degree. METHODS: A total of 14 human individuals were sampled from the Tarapaca 40 cemetery. Both bone and tooth samples were collected. Samples were studied from bone/dentine collagen for carbon and nitrogen isotopic analysis; and bone/enamel apatite for carbon isotope analysis. Inferential statistical analyses were performed in order to compare Tarapaca 40 stable carbon and nitrogen isotope values with other Formative and Late Intermediate Period groups. A nonparametrical hypothesis Kruskal-Wallis test was used. RESULTS: The results show that the individuals from Tarapaca 40 are intermediate to the values observed for terrestrial and marine fauna as well as C3 and C4 plants. CONCLUSIONS: A gradual transition to crop consumption, especially maize, is suggested. This complemented the earlier hunter-gatherer tradition of marine resources and wild fruit consumption. Contrarily to the predictions made by some archaeologists, the results obtained for northern Chile contrast with the classical perspective of a "Neolithic Revolution" in which transition to agriculture occurred more abruptly and linearly. PMID- 26250357 TI - Antidepressant-like effects and basal immobility depend on age and serotonin transporter genotype. AB - Monoamine uptake inhibitors are common treatments for depression; however, the therapeutic efficacy of these drugs varies widely. Two factors that are commonly linked to clinical outcome are age and serotonin transporter (SERT) genotype. Mouse models provide powerful tools to study consequences of age and genotype on antidepressant-like efficacy; however, to date, systematic studies of this nature are lacking. Here, we used the tail suspension test (TST), a preclinical assay for antidepressant efficacy, to gain insight into age and SERT genotype dependency of immobility time in the TST under control conditions (saline injection) and in response to the tricyclic antidepressant, desipramine (DMI). Immobility after saline injection in juvenile, adolescent, adult, mature adult and middle-aged mice (postnatal days 21, 28, 90, 210 and 300, respectively) significantly increased with age; however, the rate of increase was slower for SERT null (-/-) mice than for wild-type (+/+) or heterozygote (+/-) mice. Desipramine reduced immobility across ages and SERT genotypes. Middle-aged, but not adult, SERT(-/-) mice were significantly more sensitive to DMI than age matched SERT(+/+) or SERT(+/-) mice. Desipramine was less potent in middle-aged SERT(+/+) and SERT(+/-) mice than in adult SERT(+/+) or SERT(+/-) mice. Regardless of age, DMI's maximal effects were greater in SERT(-/-) mice than in SERT(+/+) or SERT(+/-) mice. These results show that immobility time in the TST varies as a function of age and SERT genotype, underscoring the utility of the TST as a potential model to examine age- and SERT genotype-dependent influences on antidepressant response. PMID- 26250358 TI - Assembly of a Complex Branched Oligosaccharide by Combining Fluorous-Supported Synthesis and Stereoselective Glycosylations using Anomeric Sulfonium Ions. AB - There is an urgent need to develop reliable strategies for the rapid assembly of complex oligosaccharides. This paper presents a set of strategically selected orthogonal protecting groups, glycosyl donors modified by a (S) phenylthiomethylbenzyl ether at C-2, and a glycosyl acceptor containing a fluorous tag, which makes it possible to rapidly prepare complex branched oligosaccharides of biological importance. The C-2 auxiliary controlled the 1,2 cis anomeric selectivity of the various galactosylations. The orthogonal protecting groups, 2-naphthylmethyl ether (Nap) and levulinic ester (Lev), made it possible to generate glycosyl acceptors and allowed the installation of a crowded branching point. After the glycosylations, the chiral auxiliary could be removed using acidic conditions, which was compatible with the presence of the orthogonal protecting groups Lev and Nap, thereby allowing the efficient installation of 1,2-linked glycosides. The light fluorous tag made it possible to purify the compounds by a simple filtration method using silica gel modified by fluorocarbons. The set of building blocks was successfully employed for the preparation of the carbohydrate moiety of the GPI anchor of Trypanosoma brucei, which is a parasite that causes sleeping sickness in humans and similar diseases in domestic animals. PMID- 26250360 TI - Chitosan crosslinked microparticles with encapsulated polyphenols: Water sorption and release properties. AB - Chitosan-glutaraldehyde microparticles were produced by emulsion crosslinking method to be used as drug delivery system for polyphenols from Thymus serpyllum L. aqueous extract. The effect of preparation conditions, chitosan concentration (1.5-3% w/v), and glutaraldehyde/chitosan (GA/Ch) mass ratio (0.15-1.20) on water and polyphenols transport properties was investigated. Swelling ratio of dry particles (68-230 um) in water ranged from 280% to 530%, depending on the formulation. The decrease in swelling was observed with increased GA/Ch mass ratio (i.e. crosslinking degree) at the same chitosan concentration, or with increased chitosan concentration at the same GA/Ch mass ratio. The increase in GA/Ch mass ratio was also manifested by increased particle compactness i.e. decreased size and reduced surface roughness. The sorption capacity for polyphenols seems to be a complex interplay of swelling behaviour and interactions chitosan-glutaraldehyde-polyphenols identified by Fourier transmission infrared analysis. An increase in crystallinity of chitosan was observed upon crosslinking with glutaraldehyde and encapsulation of polyphenols, as observed by X-ray diffraction analysis. The results obtained from release kinetics of selected polyphenolic compounds (caffeic acid, rosmarinic acid, total flavonoids, and total phenol content) showed that polyphenols were released at a lower amount (2-4 times) in water, but more rapidly (45-120 min) in comparison with the release in gastric followed by intestinal simulated fluid (SGF-SIF) (120 240 min). The experimental results of the time-dependent swelling in water and polyphenols release in both, water and SGF-SIF, were analyzed with several mathematical models. The results depicted Fickian diffusion as the water transport mechanism. In the case of polyphenols, only empirical Weibull model could be suggested for describing release kinetics. PMID- 26250359 TI - Characterization of subgroups of heart failure patients with preserved ejection fraction with possible implications for prognosis and treatment response. AB - BACKGROUND: Patients with heart failure and preserved ejection fraction (HFpEF) have a poor prognosis, and no therapies have been proven to improve outcomes. It has been proposed that heart failure, including HFpEF, represents overlapping syndromes that may have different prognoses. We present an exploratory study of patients enrolled in the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE) using latent class analysis (LCA) with validation using the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved study to identify HFpEF subgroups. METHODS AND RESULTS: In total, 4113 HFpEF patients randomized to irbesartan or placebo were characterized according to 11 clinical features. The HFpEF subgroups were identified using LCA. Event-free survival and effect of irbesartan on the composite of all-cause mortality and cardiovascular hospitalization were determined for each subgroup. Subgroup definitions were applied to 3203 patients enrolled in CHARM-Preserved to validate observations regarding prognosis and treatment response. Six subgroups were identified with significant differences in event-free survival (P < 0.001). Clinical profiles and prognoses of the six subgroups were similar in CHARM-Preserved. The two subgroups with the worst event free survival in both studies were characterized by a high prevalence of obesity, hyperlipidaemia, diabetes mellitus, anaemia, and renal insufficiency (Subgroup C) and by female predominance, advanced age, lower body mass index, and high rates of atrial fibrillation, valvular disease, renal insufficiency, and anaemia (Subgroup F). CONCLUSION: Using a data-driven approach, we identified HFpEF subgroups with significantly different prognoses. Further development of this approach for characterizing HFpEF subgroups is warranted. PMID- 26250362 TI - Microscopy of nanoparticulate dispersions. AB - We present a critical review of the common methods for determining the dispersion state of nanoparticulate samples particularly in liquid media, including the determination of particle size and morphology; particle size distributions and polydispersity and equilibrium particle structure and chemistry. We highlight the potential contributions of both scanning probe and electron microscopies in this analysis which is of benefit in understanding nanoparticulate formulations and their behaviour applied across a very wide range of technologies and industry sectors. PMID- 26250361 TI - Application of diffusive gradients in thin films and core centrifugation methods to determine inorganic mercury and monomethylmercury profiles in sediment porewater. AB - A diffusive gradient in thin films (DGT) is an in situ sampling technique for the quantitative analysis of contaminant concentrations that is based on the diffusion and adsorption of contaminants on to resin gels. In the present study, a DGT technique was applied to measure total mercury (Hg) and monomethylmercury (MMHg) concentrations in lake and coastal sediment porewaters and compare them with those from ex situ sediment centrifugation. To calculate the total Hg and MMHg concentrations in porewater using the DGT method, the diffusion coefficients of Hg species in a diffusive gel medium was first determined, and then total Hg and MMHg depth profiles were measured using the experimentally determined diffusion coefficients. Using the diffusion coefficients for artificial lake and estuarine waters containing inorganic salts, rather than those for lake and estuarine waters containing Suwannee River humic acid (~5 mg C L(-1) ), the DGT method demonstrated similar Hg and MMHg profiles to those using the centrifugation method. Based on the need for fine vertical resolution and high metal concentrations to be collected, DGT is suggested to be a reliable method for determining Hg(II) and MMHg depth profiles in sediment porewater. PMID- 26250363 TI - External cooling efficiently controls intraosseous temperature rise caused by drilling in a drilling guide system: an in vitro study. AB - The purpose of this study was to measure the rise in intraosseous temperature caused by drilling through a drilling guide system. We compared the rise in temperature generated, and the number of increases of more than 10 degrees C, between drills that had been cooled with saline at room temperature (25 degrees C) and those that had not been cooled, for every step of the drilling sequence. Cortical layers of bovine ribs were used as specimens, and they were drilled through 3-dimensional printed surgical guides. Heat was measured with an infrared thermometer. The significance of differences was assessed with either a two sample t test or Welch's test, depending on the variances. The mean rises (number of times that the temperature rose above 10 degrees C) for each group of measurements were: for the 2mm drill, 4.8 degrees C (0/48) when cooled and 7.0 degrees C (8/48) when not cooled; with the 2.5mm drill, 5.2 degrees C (1/48) when cooled and 8.5 degrees C (17/48) when not cooled (2 mm canal); with the 3 mm drill, 3.3 degrees C when cooled (0/48) and 8.5 degrees C (18/24) when not cooled (2.5 mm canal); and with the 3.5 mm drill, 4.8 degrees C when cooled (0/24) and 9.4 degrees C when not cooled (10/23) (3 mm canal). The temperature rose significantly less with cooling at every step of the drilling sequence (p<0.001). We conclude that external cooling can maintain the intraosseous temperature within the safe range while drilling through an implant guide system, whereas drilling without irrigation can lead to temperatures that exceed the acceptable limit. PMID- 26250364 TI - Rapidly-growing buccal mass in a 6-month-old infant. AB - Lipoblastoma and lipoblastomatosis are rare benign tumours of fetal-embryonal adipocytes that usually present in young children, which is why they are not often included in the differential diagnosis of soft tissue lesions in infants. We describe a case of a 6-month-old infant with an intraoral buccal lipoblastoma. PMID- 26250365 TI - Films based on protein isolated from croaker (Micropogonias furnieri) and palm oil. AB - BACKGROUND: The microstructure and the physical, mechanical, barrier and thermal properties of films based on different concentrations of protein isolated from croaker waste (CPI) and palm oil (PO) were analyzed. Films were elaborated by a casting technique using 2, 3 and 4 g CPI 100 g(-1) of a filmogenic solution and 0, 10 and 20 g of PO 100 g(-1) CPI. RESULT: Microstructure of the film surfaces of CPI with PO showed no presence of lipid droplets dispersed in the filmogenic matrix, although a rough surface was present. Films with 3% and 4% CPI and 20% PO had the lowest rates of water vapor permeability. When there was an addition of PO to the reduced tensile strength of the films, regardless of the concentration of CPI, this addition reduced the elongation of films with 3% and 4% CPI; however, it did not influence films with 2% CPI, which did not differ from the control film (0% OP). Thermal analysis revealed that films with the highest PO percentage had a lower initial weight loss when compared with other films, due to higher hydrophobicity. CONCLUSION: The use of protein isolate obtained from fish residues of low commercial value and palm oil is viable for the production of biodegradable films because the latter constitute good barrier properties and thermal stability. (c) 2015 Society of Chemical Industry. PMID- 26250366 TI - Primary intraocular synovial sarcoma in the post retinal detachment operative state. AB - Synovial sarcoma generally arises in the deep soft tissue, although it has been described at virtually every anatomic site except in the eyeball. We report the case of a 48-year-old woman who had a history of retinal detachment surgery and who had undergone vitrectomy and the insertion of a solid silicon explant 24 years previously. She reported a visual field defect. Funduscopy and MRI revealed a tumour just behind the iris in the left eyeball, and enucleation was performed. Microscopic examination of the tumour revealed uniform spindle cells in a fascicular arrangement with frequent mitotic figures. Immunohistochemistry showed that the tumour was positive for TLE1 and epithelial membrane antigen and fluorescent in situ hybridisation revealed that the tumour had a rearrangement of the SYT gene. Reverse transcription (RT)-PCR confirmed the presence of a SYT-SSX2 fusion transcript. On the basis of these histomorphological and molecular features, the diagnosis of poorly differentiated synovial sarcoma was rendered. PMID- 26250367 TI - Acute myeloid leukaemia with t(8;21)(q22;q22.3) and loss of the X chromosome. AB - Cytogenetic abnormalities occur in approximately 60% of newly diagnosed patients with acute myeloid leukaemia (AML) and are useful in the risk stratification of AML. Translocation between chromosomes 8 and 21-t(8;21)-(q22;q22.3), which carries a favourable prognosis, is found in approximately 5% to 10% of all patients with AML. Additional chromosomal abnormalities have been described in patients with AML with t(8;21), which may impact on the favourable prognosis. We report a patient who had AML with t(8;21)(q22;q22.3) and loss of the X chromosome. PMID- 26250368 TI - Acute compartment syndrome of the thigh in a rugby player. AB - In the absence of obvious trauma, diagnosis of acute compartment syndrome (ACS) of the thigh can easily be delayed, as disproportional pain is not always present. We present a case of ACS of the anterior right thigh compartment in a healthy, semiprofessional rugby player with normal coagulation, who sustained a seemingly innocuous blow during a rugby match. Following early surgical fasciotomy, he returned to his preinjury playing standards within 12 months. Our literature review suggests that high muscle mass, young, athletic males participating in a contact sport are mostly at risk of developing ACS of the thigh. PMID- 26250369 TI - Hibernoma larynx with large multinodular goitre: unusual airway challenge. AB - A 56-year-old man presented with a 6-month history of progressively increasing neck swelling, dysphagia and hoarseness of voice. CT scan revealed multi-nodular goitre and also showed a lesion in the supraglottis. It also showed another lesion in the supraglottis. Fine-needle aspiration cytology of thyroid revealed follicular cells. Routine flexible laryngoscopy was performed to evaluate vocal cord function; however, we found a smooth well-defined lesion just above the glottis, obstructing the direct view of the vocal cords, and an endangered airway. A provisional diagnosis of a laryngeal cyst was made. With all necessary precautions intubation was performed with a bougie and a reinforced endotracheal tube was inserted. Total thyroidectomy was performed first. With direct suspension laryngoscopy an attempt was made to deliver the laryngeal lesion, however, the lesion could not be removed. A suprahyoid lateral pharyngotomy was performed to deliver the lesion. Histopathology of the lesion revealed hibernoma. PMID- 26250370 TI - Out, damned spot.... PMID- 26250372 TI - An introduction to quality improvement and delivery science. PMID- 26250371 TI - Allergic bronchopulmonary aspergillosis in an adult with Kartagener syndrome. AB - Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disorder resulting from immune responses directed against inhaled Aspergillus fumigatus antigens. It manifests with poorly controlled asthma, fleeting pulmonary opacities and structural lung damage in the form of bronchiectasis. Initially defined in individuals suffering from bronchial asthma and cystic fibrosis, it has also been described in patients with other structural lung disorders such as chronic obstructive pulmonary disease, pulmonary tuberculosis, idiopathic bronchiectasis and others. Kartagener syndrome is a manifestation of primary ciliary dyskinesia characterised by the presence of dextrocardia, bronchiectasis and chronic sinusitis. We report a case of ABPA in an adult suffering from Kartagener syndrome. We also performed a systematic review of the literature on the association between Kartagener syndrome and ABPA. PMID- 26250373 TI - Improving the value of healthcare delivery using publicly available performance data in Wisconsin and California. AB - The healthcare industry must change in order to provide higher quality care and lower costs for patients; one method to improve both cost and quality used in Wisconsin and California is leveraging publicly reported claims and costs data. Wisconsin has been building comprehensive, publicly available clinical and administrative data sets: the Wisconsin Collaborative for Healthcare Quality (WCHQ) established in 2003 and the Wisconsin Health Information Organization (WHIO) established in 2009. The WCHQ and the WHIO allow physician groups to compare themselves with one another on cost and quality across 920 distinct episode treatment groups (ETGs). The ETGs include all components of care for a specific disease during a defined period. Since 2002 California has developed public reporting of quality data for physician groups and health plans through its Integrated Healthcare Association (IHA) and since 2008 its Right Care Initiative (RCI). In both states these data are used to identify best practices and opportunities for improvement, enhance care outcomes, and increase value for patients. PMID- 26250374 TI - Fostering innovation in medicine: A conceptual framework for medical centers. PMID- 26250375 TI - Structuring the patient-physician encounter: Joint creation of an actionable roadmap to health. AB - The patient's experiences and costs related to their care are largely dictated by each patient-physician interaction along the continuum of care. However, the amount of time that a physician spends with a patient creating a medical action plan is highly variable and often not related to the severity or complexity of the patient's condition. Adding a structured process to guide and inform patient physician encounters, including outlining expectations and follow-up by both sides is needed. Addressing these barriers to the physician-patient relationship would reduce variation in care, minimize unnecessary trial and error tactics and instead focus on predicted cost effective actions. PMID- 26250376 TI - The Zigzagging zeitgeist of health services research: Rapidly changing priorities in the field. PMID- 26250377 TI - Electronic health records and technical assistance to improve quality of primary care: Lessons for regional extension centers. AB - BACKGROUND: In 2009, the American Recovery and Reinvestment Act apportioned $643 million for a Health Information Technology Extension Program, which established Regional Extension Centers (RECs) to support the implementation and use of electronic health records (EHRs). PROBLEM: Little is known, however, about how RECs should assist in EHR implementation and how they should structure ongoing support. GOALS: The purpose of this paper is to describe physicians' experiences with the Primary Care Information Project (PCIP), an REC run by the New York City Department of Health and Mental Hygiene. STRATEGY: We interviewed 17 physicians enrolled in PCIP to understand the role of the EHRon quality of care and their experience with technical assistance from PCIP. RESULTS: All physicians stated that they felt that the EHR improved the quality of care they delivered to their patients particularly because it helped them track patients. All the physicians found technical assistance helpful but most wanted ongoing assistance months or years after they adopted the EHR. PMID- 26250378 TI - Case study: Delivery and payment reform in congestive heart failure at two large academic centers. AB - To help support implementation of aligning clinical redesign with payment reforms in practices and institutions throughout the country, we present two cases from Duke University Health System ("Duke") and University of Colorado Hospital ("Colorado"). The studies provide practical solutions for not only implementing clinical redesign, but also an understanding of how those clinical innovations can be aligned with alternative payment models. The cases will explore the following questions: What challenges or problems encouraged the organization to redesign CHF care? How did the organization select and then align care innovations with payment reforms, including bundled payments and shared savings? What did the organization identify as key success factors and/or challenges? How did these changes impact the organization's clinical outcomes or financial position? Finally, what lessons would the organization share with others attempting to implement similar strategies? PMID- 26250379 TI - A potential new data source for assessing the impacts of health reform: Evaluating the Gallup-Healthways Well-Being Index. AB - BACKGROUND: Existing national health-related surveys take several months or years to become available. The Affordable Care Act will bring rapid changes to the health care system in 2014. We analyzed the Gallup-Healthways' Well-Being Index (WBI) in order to assess its ability to provide real-time estimates of the impact of the ACA on key health-related outcomes. METHODS: We compared the Gallup Healthways WBI to established surveys on demographics, health insurance, access to care, and health. Data sources were the Gallup-Healthways WBI, the Current Population Survey, the American Community Survey, the Medical Expenditure Panel Survey, the National Health Interview Survey, and the Behavioral Risk Factor Surveillance System. Demographic measures included age, race/ethnicity, education, and income. Insurance outcomes were coverage rates by type, state, and year. Access measures included having a usual source of care and experiencing cost-related delays in care. Health measures were self-reported health and history of specific diagnoses. RESULTS: Most differences across surveys were statistically significant (p<0.05) due to large sample sizes, so our analysis focused on the absolute magnitude of differences. The Gallup-Healthways WBI post weighted sample was similar in age, race/ethnicity, and education to other surveys, though the Gallup-Healthways WBI sample is slightly older, has fewer minorities, and is more highly educated than in other national surveys. In addition, income was more frequently missing. The Gallup-Healthways WBI produced similar national, state, and time-trend estimates on uninsured rates, but far lower rates of public coverage. Access to care and health status were similar in the Gallup-Healthways WBI and other surveys. CONCLUSIONS: The Gallup-Healthways WBI is a valuable complement to existing data sources for health services research. The Gallup-Healthways WBI estimates for uninsured rates and access to care were similar to established national surveys and may allow for rapid estimates of the ACA's impact on the uninsured in 2014. Estimates of insurance type are less comparable, particularly for public coverage, which likely limits the utility of the Gallup-Healthways WBI for analyzing changes in particular types of coverage. PMID- 26250380 TI - An exploration of management practices in hospitals. AB - BACKGROUND: Management practices, including, for example, "Lean" methodologies originally developed at Toyota, may represent one mechanism for improving healthcare performance. METHODS: We surveyed 597 nurse managers at cardiac units to score management on the basis of poor, average, or high performance on 18 practices across 4 dimensions (Lean operations, performance measurement, targets, and employee incentives). We assessed the relationship of management scores to hospital characteristics (size, non-profit status) and market level variables. RESULTS: Our findings provide concrete examples of the high degree of management proficiency of some hospitals, as well as wide variation in management practices. Although the exact ways in which these tools have been implemented vary across hospitals, we identified multiple examples of units that use standardization in their care, track performance on a frequent basis and display data in a visual manner, and set aggressive goals and communicate them clearly to their staff. Regression models indicate that higher management scores are associated with hospitals in more competitive markets, teaching hospitals, and hospitals with a higher net income from patient services (p<0.05). CONCLUSIONS: High quality management practices have been successfully adopted by some hospitals in the US, but the ways in which these practices have been implemented may vary, reflecting the specific context or environment of the hospital. The adoption of modern management practices may be driven in part by market pressure. IMPLICATIONS: An improved understanding of key management practices may assist researchers and policy-makers in identifying mutable hospital characteristics that can drive efficiency, safety, and quality. PMID- 26250381 TI - Effects of implementing a protocol for arterial blood gas use on ordering practices and diagnostic yield. AB - BACKGROUND: The arterial blood gas (ABG) is a valuable and commonly used laboratory test. This prospective cohort study examined the variability of ABG ordering through the implementation of an evidence-based protocol. METHODS: The study consisted of two 6-week periods. The protocol consisted of evidence-based and consensus opinion based indications for ABGs. In the first phase (initial 6 weeks), respiratory therapists recorded the indications for ABGs ordered by clinicians. In the second phase, all medical and surgical physicians were trained on the clinical rationale behind the protocol and were instructed to write the indication for each ABG with the order. Rates of ABGs/patient/day were measured in aggregate and per indication. Multivariate regression was used for adjusted comparisons between indications within the protocol. RESULTS: After protocol implementation, there was a significant decrease in ABGs from 2158 to 1674 (p=0.001), and after adjusting for daily census, there was a significant decrease from 35.3 ABGs/100 patients/day to 26.5 ABGs/100 patients/day (p<0.001), with no change in mortality or demographic characteristics between the populations. The percent of ABGs with normal range values for pH, PaCO2, and PaO2 decreased from 13.3% to 9.6% after implementation (p<0.001). Multivariate analysis revealed a 14% decrease in daily ABGs (p=0.001), a 15% decrease in weaning trial ABGs (p=0.039), and a 15% increase in ABGs ordered following a change in minute ventilation (p=0.004). Cost minimization analysis estimated annual institutional savings to be $87,565. CONCLUSIONS: Implementation of an evidence based protocol for ABG use resulted in fewer ABGs/patient/day largely from reduction of routine, daily ABGs. Ordering patterns for ABGs appeared to shift towards more clinically appropriate/relevant indications. LEVEL OF EVIDENCE: 2b. PMID- 26250382 TI - The use of participatory action research to design a patient-centered community health worker care transitions intervention. AB - BACKGROUND: Policymakers, patients and clinicians are increasingly eager to foster patient involvement in health care innovation. Our objective was to use participatory action research with high-risk hospitalized patients to design a post-hospital transition intervention. METHODS: We conducted qualitative interviews with sixty-five low-income, recently hospitalized patients exploring their perceptions of barriers to post-hospital recovery and ideas for improvement. We then used a modified grounded theory approach to design an intervention that would address each barrier using patients' suggestions. RESULTS: Five key themes were translated into design elements. First, patients wished to establish a relationship with healthcare personnel to whom they could relate. The intervention was provided by an empathic community health worker (CHW) who established rapport during hospitalization. Second, patients suggested tailoring support to their needs and goals. CHWs and patients designed individualized action plans for achieving their goals for recovery. Third, patient goals were misaligned with those of the inpatient team. CHW facilitated patient-provider discharge communication to align goals. Fourth, patients lacked post-discharge support for predominantly psychosocial or financial issues that undermined recovery. CHWs provided support tailored to patient needs. Finally, patients faced numerous barriers in obtaining post-hospital primary care. CHWs helped patients to obtain timely care with a suitable provider. CONCLUSIONS: Low income hospitalized patients voiced needs and suggestions that were directly translated into the design of a scalable patient-centered CHW intervention. IMPLICATIONS: The approach of using participatory action research to tightly mapping patient input into intervention design is rapid and systematic strategy for operationalizing patient involvement in innovation. PMID- 26250383 TI - Flexible implementation and integration of new team members to support patient centered care. AB - BACKGROUND: Central to the patient-centered medical home model are high functioning interdisciplinary teams, which aim to improve care coordination and patient self-management of chronic conditions. We examined the facilitators and barriers of implementing a primary care team redesign intended to augment physician-medical assistant dyads by adding two new care team members - registered nurse care managers [NCM] and patient health coaches [PHC]. METHODS: To assess respondents' experiences of role integration, 22 key informant interviews were conducted of primary care physicians, NCMs, PHCs, and medical assistants at pilot practices (n=5). Additionally, a clinician and staff survey of 400 respondents was conducted at pilot and non-pilot (n=28) practices to contextualize the redesign results. RESULTS: Respondent experiences differed due to flexible protocols in program implementation, intended to allow each care team's approach to be site specific. Three sites struggled in developing processes that best used each new member, often due to poor comprehension of the member's scope. Successful practices (n=2) reported increased team communication and functioning as a result of high physician engagement and local leadership facilitation. CONCLUSIONS: Flexible implementation protocols gave practice stakeholders significant discretion to integrate new care team roles to best fit local needs. The flexibility, however, created ambiguous expectations of the redesign, resulting in inconsistent implementation of key features of the intended redesign in some practices. IMPLICATIONS: When implementing primary care teams across practice networks, standardized scope of practice of personnel, common quality improvement priorities, and shared performance metrics may be helpful in disseminating effective redesign strategies. PMID- 26250384 TI - Interview with Sean Duffy, CEO of Omada Health. PMID- 26250385 TI - Interview with Nirav Shah, M.D., M.P.H. PMID- 26250386 TI - Macroevolutionary developmental biology: Embryos, fossils, and phylogenies. AB - The field of evolutionary developmental biology is broadly focused on identifying the genetic and developmental mechanisms underlying morphological diversity. Connecting the genotype with the phenotype means that evo-devo research often considers a wide range of evidence, from genetics and morphology to fossils. In this commentary, we provide an overview and framework for integrating fossil ontogenetic data with developmental data using phylogenetic comparative methods to test macroevolutionary hypotheses. We survey the vertebrate fossil record of preserved embryos and discuss how phylogenetic comparative methods can integrate data from developmental genetics and paleontology. Fossil embryos provide limited, yet critical, developmental data from deep time. They help constrain when developmental innovations first appeared during the history of life and also reveal the order in which related morphologies evolved. Phylogenetic comparative methods provide a powerful statistical approach that allows evo-devo researchers to infer the presence of nonpreserved developmental traits in fossil species and to detect discordant evolutionary patterns and processes across levels of biological organization. PMID- 26250391 TI - Genomic Characterization of a New PRCV Variant, United States, 2014. PMID- 26250392 TI - Deleterious BRCA1/2 mutations in an urban population of Black women. AB - Information on the prevalence of deleterious BRCA1 and BRCA2 (BRCA1/2) mutations in clinic-based populations of Black women is limited. In order to address this gap, we performed a retrospective study to determine the prevalence of deleterious BRCA1/2 mutations, predictors of having a mutation, and acceptance of risk-reducing surgeries in Black women. In an urban unselected clinic-based population, we evaluated 211 self-identified Black women who underwent genetic counseling for hereditary breast-ovarian cancer syndrome. BRCA1/2 mutations were identified in 13.4% of the participants who received genetic testing. Younger age at diagnosis, higher BRCAPRO score, significant family history, and diagnosis of triple-negative breast cancer were associated with identification of a BRCA1/2 mutation. Of the affected patients found to have a deleterious mutation, almost half underwent prophylactic measures. In our study population, 1 in 7 Black women who underwent genetic testing harbored a deleterious BRCA1/2 mutation independent of age at diagnosis or family history. PMID- 26250394 TI - Supported and inserted monomeric niobium oxide species on/in silica: a molecular picture. AB - The geometry, energetic, and spectroscopic properties of molecular structures of silica-supported niobium oxide catalysts are studied using periodic density functional calculations (DFT) and compared with experimental data. The calculations are done for Nb oxide species inserted or grafted in/on an amorphous hydroxylated silica surface. Different positions of the Nb atom/atoms in the silica structure have been investigated. By means of DFT calculations the geometry and the degree of hydration of Nb oxide species with oxidation state +5 have been studied. The local Nb geometry depends on different parameters such as the number of Nb-O-Si groups vs. Nb-O-H groups, the formation of H bonds and the distance between Nb atoms. The interaction between the oxide and silanol groups occurs by formation of Si-O-Nb bonds with chemically and thermally stable Bronsted and Lewis acid sites. UV-Vis, reflection absorption infrared vibrational spectra (RAIRS) as well as various thermodynamic properties have also been investigated in order to get a better insight into the system studied and to provide support to possible experimental studies. PMID- 26250393 TI - Breast cancer survival in African-American women by hormone receptor subtypes. AB - Breast cancer accounts for over 200,000 annual cases among women in the United States, and is the second leading cause of cancer-related deaths. However, few studies have investigated the association between breast cancer subtype and survival among African-American women. We analyzed cancer-related deaths among African-American women using data obtained from the SEER database linked to the 2000 U.S. census data. We examined distribution of baseline socio-demographic and clinical characteristics by breast cancer subtypes and used Cox proportional hazard models to determine associations between breast cancer subtypes and cancer related mortality, adjusting for age, socio-economic status, stage at diagnosis, and treatment. Among 19,836 female breast cancer cases, 54.4% were diagnosed with the HER2-/HR+ subtype, with the majority of those cases occurring among women ages 55 and older. However, after adjusting for age, stage, and treatment type (surgery, radiation, or no radiation and/or cancer-directed surgery), TNBC (HR 2.34; 95% CI 1.95-2.81) and HER2+/HR- (HR 1.39, 95% CI 1.08-1.79) cases had significantly higher hazards of cancer-related deaths compared with HER2+/HR+ cases. Adjusting for socio-economic status did not significantly alter these associations. African-American women with TNBC were more likely to have a cancer related death than African-American women with other breast cancer subtypes. This association remained after adjustments for age, stage, treatment, and socio economic status. Further studies are needed to identify subtype-specific risk and prognostic factors aimed at better informing prevention efforts for all women. PMID- 26250395 TI - The effect of 48-hour fasting on taurine status in healthy adult dogs. AB - Low circulating taurine concentrations may be a risk factor for dilated cardiomyopathy (DCM) in dogs. Circulating taurine is typically measured in the clinic 4-5 h after feeding, largely because the impact of later sampling is not known. The objective of this study was to measure taurine in the blood during a 48-h fast in 12 healthy adult Labrador Retrievers to refine sampling methodology for determination of taurine status. Plasma and whole blood (WB) taurine concentrations did not fall to levels indicative of clinical deficiency throughout fasting; WB was the more reliable indicator of taurine status. This study shows that blood samples can be taken for assessment of taurine status any time up to 48 h after ingestion of a meal in healthy adult dogs. PMID- 26250396 TI - RNASeq in C. elegans Following Manganese Exposure. AB - Manganese is a metal that is required for optimal biological functioning of organisms. Absorption, cellular import and export, and excretion of manganese are all tightly regulated. While some genes involved in regulation, such as DMT-1 and ferroportin, are known, it is presumed that many more are involved and as yet unknown. Excessive exposure to manganese, usually in industrial settings such as mining or welding, can lead to neurotoxicity and a condition known as manganism that closely resembles Parkinson's disease. Elucidating transcriptional changes following manganese exposure could lead to the development of biomarkers for exposure. This unit presents a protocol for RNA sequencing in the worm Caenorhabditis elegans to assay for transcriptional changes following exposure to manganese. This protocol is adaptable to any environmental exposure in C. elegans. The protocol results in counts of gene transcripts in control versus exposed conditions and a ranked list of differentially expressed genes for further study. PMID- 26250397 TI - Pre-Plated Cell Lines for ADMETox Applications in the Pharmaceutical Industry. AB - Membrane transporters significantly modulate membrane permeability of endobiotics and xenobiotics, such as bile acids and drugs, respectively. Various in vitro methods have been established for both ATP-binding cassette (ABC) transporters to examine cellular efflux and uptake, and for solute carriers (SLC) to examine cellular uptake of substrates. Cell-based systems are the models of choice to test drug-transporter interactions as well as drug-drug interactions for research and regulatory purposes, albeit, for low passive permeability substrates of ABC transporters, vesicular uptake assays are also recommended. Commercially available pre-plated cells (e.g., immortalized or transfected) offer a useful alternative to in-house cell culture. Three main methods are known to manufacture pre-plated cultures: regular culture medium with vacuum seal, cryopreserved delivery, and the solid shipping media technology. The regular culture medium and the solid shipping media technologies provide ready-to-use models for end users. Models expressing a broad selection of transporters are available in pre-plated formats for absorption, distribution, metabolism, excretion, and toxicity (ADMETox) studies. Conversely, the application and utility of pre-plated cultures coupled with personal experiences have not been extensively covered in published research papers or reviews, despite availability and significant use of pre plated products in the pharmaceutical industry. In this overview, we will briefly describe: 1) in vitro tools commonly used for ADMETox testing; 2) methods employed in manufacturing, shipment and preparation of pre-plated cell lines; 3) cell-membrane barrier models currently available in pre-plated format to reproduce passage restriction of physiological barriers to certain compounds; and 4) recommended pre-plated cell lines overexpressing uptake transporters for ADMETox applications. PMID- 26250398 TI - Measuring Mitochondrial Membrane Potential with a Tetraphenylphosphonium Selective Electrode. AB - Mitochondrial bioenergetics is based on the generation of the protonmotive force by the electron transport chain. The protonmotive force is used by mitochondria for different critical aspects of its normal function, ranging from calcium accumulation to the synthesis of ATP. The transmembrane electric potential (DeltaPsi) is the major component of the protonmotive force and is also the main responsible for ATP synthesis by mitochondrial ATP synthase. Although several methods can be used to measure the DeltaPsi, the use of the tetraphenylphosphonium cation (TPP(+))-selective electrode is still a method of election due to its sensitivity. The method is based on the accumulation of TPP(+) by energized mitochondria, which develop a negative charge in the matrix due to the ejection of protons. This unit describes how to build a custom-made TPP(+)-selective electrode and how to establish the necessary set-up to follow DeltaPsi fluctuations in isolated mitochondrial fractions. PMID- 26250399 TI - Alkaline Comet Assay for Assessing DNA Damage in Individual Cells. AB - Single-cell gel electrophoresis, commonly called a comet assay, is a simple and sensitive method for assessing DNA damage at the single-cell level. It is an important technique in genetic toxicological studies. The comet assay performed under alkaline conditions (pH >13) is considered the optimal version for identifying agents with genotoxic activity. The alkaline comet assay is capable of detecting DNA double-strand breaks, single-strand breaks, alkali-labile sites, DNA-DNA/DNA-protein cross-linking, and incomplete excision repair sites. The inclusion of digestion of lesion-specific DNA repair enzymes in the procedure allows the detection of various DNA base alterations, such as oxidative base damage. This unit describes alkaline comet assay procedures for assessing DNA strand breaks and oxidative base alterations. These methods can be applied in a variety of cells from in vitro and in vivo experiments, as well as human studies. PMID- 26250400 TI - Determination of Metabolic Stability Using Cryopreserved Hepatocytes from Rainbow Trout (Oncorhynchus mykiss). AB - Trout provide a relatively easy source of hepatocytes that can be cryopreserved and used for a range of applications including toxicity testing and determination of intrinsic clearance. Standard protocols for isolating, cryopreserving, and thawing rainbow trout hepatocytes are described, along with procedures for using fresh or cryopreserved hepatocytes to assess metabolic stability of xenobiotics in fish by means of a substrate depletion approach. Variations on these methods, troubleshooting tips, and directions for use of extrapolation factors to express results in terms of in vivo intrinsic clearance are included. These protocols have been developed for rainbow trout, but can be adapted to other fish species with appropriate considerations. PMID- 26250401 TI - Can serum white birch (Betula verrucosa) pollen antigen (Bet v 1) immunoglobulin E measurement distinguish between sensitization and allergy? AB - BACKGROUND: In clinical practice, it is fundamental to distinguish between sensitization and allergy, mainly with respect to polysensitized patients. The aim of this study was to evaluate whether serum immunoglobulin E (IgE) to white birch (Betula verrucosa) pollen antigen (Bet v 1) assessment might be able to differentiate simple sensitization from true allergy. METHODS: In total, 197 subjects (100 females; mean age 44.9 years) with serum Bet v 1 IgE positivity and history of nasal symptoms were evaluated. Subjects were subdivided in 2 groups: allergic and sensitized. RESULTS: Allergic patients were 58.4% of the total; they had higher serum Bet v 1 IgE levels than sensitized subjects (p < 0.001). A serum IgE to Bet v 1 value >8.94 kilo units of allergen per liter (kUA/L) was able to differentiate between sensitization and allergy (area under the receiver operating characteristic curve [AUC] = 0.76; diagnostic odds ratio, ie, degree of agreement between health status and dichotomized IgE levels [DOR] = 6.5). Gender and season when the blood was drawn influenced IgE levels. CONCLUSION: Serum Bet v 1 IgE measurement may be able to differentiate sensitization from allergy in subjects with sensitization to Betulaceae pollen allergens. Thus, Bet v 1 IgE measurement should be considered a useful step in the management of patients with allergic rhinitis due to Betulaceae pollen allergens. PMID- 26250402 TI - Dental age assessment on panoramic radiographs in a Swiss population: a validation study of two prediction models. AB - OBJECTIVES: Dental age assessment methods are widely used for age estimation. This study aimed to analyse the accuracy of a meta-analysis method to estimate dental age in Swiss individuals and to detect potential limitations of the method. Precision of repeated tooth staging using Demirjian's classification on maxillary and mandibular teeth was also assessed. METHODS: Panoramic radiographs of 50 Swiss white healthy children were analysed. Developing teeth on the left maxilla and mandible and all third permanent molars were staged following Demirjian's classification. Dental age was calculated for each subject, using a random effects model and a fixed effect model, and compared with chronological age. RESULTS: The mean error of the dental age ranged between -3 and +1 months for both the calculation models. Dental age calculated with the fixed effect model overestimated the age of the subjects (average + 0.10 y, ranging from -1.95 y to +2.16 y) compared with their chronological age, whereas the random effects model underestimated the age (average -0.32 y, ranging from -2.24 y to +1.61 y). CONCLUSIONS: Demirjian's method allowed a precise repeated staging of maxillary and mandibular developing teeth. For both calculation models, dental age correlated well, on average, with chronological age of Swiss subjects younger than 12 years. The random effects model showed a better accuracy for these subjects than the fixed effect model. However, both models underestimated the chronological age in subjects older than 12 years. PMID- 26250404 TI - Fatigue in chronic hepatitis C infection: Understanding patients' experience from a cognitive-behavioural perspective. AB - OBJECTIVES: Fatigue is a leading concern of patients with chronic hepatitis C virus (HCV) infection. Despite its clinical significance, fatigue in HCV is poorly understood and therefore invariably under-treated. A cognitive-behavioural approach offers a framework to understand and treat fatigue, but the characteristics of fatigue in chronic HCV infection have not been documented from a cognitive-behavioural perspective. This study captured the common and unique aspects of fatigue from a cognitive-behavioural perspective in individuals with HCV infection and clinically significant fatigue. DESIGN: Cross-sectional, qualitative using a critical realism approach. METHODS: Fourteen individuals (64% women; age >18 years) participated in semi-structured interviews. The interviews documented the features, course, and perceived antecedents of fatigue; fatigue specific cognitions; fatigue management behaviours; and the functional impact of fatigue. RESULTS: Participants' descriptions included the aspects of fatigue that have been targets of cognitive-behavioural therapy in other medical conditions, including attributing fatigue to the illness; expectation of chronicity; low control; and fatigue-driven coping. There were also components of fatigue experience that appear to be unique characteristics of fatigue related to HCV, including predominantly physical fatigue; high acceptance of fatigue; and liver protective diet as a fatigue management behaviour. CONCLUSIONS: This was the first study to document the experience of fatigue in chronic HCV infection in a cognitive-behavioural framework. The findings suggest that the cognitive behavioural approach can be applied to fatigue in chronic HCV infection. This would open an avenue to alleviate fatigue and thus improve the primary patient reported outcome of the disease. STATEMENT OF CONTRIBUTION: What is already known on this subject? Fatigue is a key patient-reported outcome measure of chronic hepatitis C virus (HCV) infection. Fatigue management is not part of the standard care, because fatigue is poorly characterized in this population. What does this study add? A cognitive-behavioural approach can be applied to understand fatigue in HCV infection. Identified aspects of fatigue (antecedents, consequences, cognitions, behaviours) that can be treatment targets. Cognitive-behavioural therapy would open a new treatment avenue to alleviate fatigue in HCV infection. PMID- 26250403 TI - Superhydrophobic-like tunable droplet bouncing on slippery liquid interfaces. AB - Droplet impacting on solid or liquid interfaces is a ubiquitous phenomenon in nature. Although complete rebound of droplets is widely observed on superhydrophobic surfaces, the bouncing of droplets on liquid is usually vulnerable due to easy collapse of entrapped air pocket underneath the impinging droplet. Here, we report a superhydrophobic-like bouncing regime on thin liquid film, characterized by the contact time, the spreading dynamics, and the restitution coefficient independent of underlying liquid film. Through experimental exploration and theoretical analysis, we demonstrate that the manifestation of such a superhydrophobic-like bouncing necessitates an intricate interplay between the Weber number, the thickness and viscosity of liquid film. Such insights allow us to tune the droplet behaviours in a well-controlled fashion. We anticipate that the combination of superhydrophobic-like bouncing with inherent advantages of emerging slippery liquid interfaces will find a wide range of applications. PMID- 26250405 TI - Biodegradation of pentachloronitrobenzene by Arthrobacter nicotianae DH19. AB - A pentachloronitrobenzene (PCNB)-degrading bacterial strain was identified as Arthrobacter nicotianae based on morphological, physiological and biochemical tests, and 16S rRNA gene sequences analysis. The strain could grow on mineral salt medium (MSM) containing PCNB as the sole carbon source. Under optimal conditions (pH 6.85, 30 degrees C and inoculum biomass amount of 1.45 g l(-1) ), more than 90% residues of PCNB were degraded by strain DH19 within 7 days. Strain DH19 could efficiently degrade dichlorodiphenyl trichloroethane, hexachlorocyclohexane, cypermethrin and cyhalothrin. Metabolites from PCNB degradation were identified by using gas chromatography (GC) coupled with triple quadrupole mass spectrometry. A possible degradation pathway for PCNB was deduced. This is the first report of PCNB-degrading strain DH19 isolated from the rhizospheric soil. Therefore, strain DH19 could potentially be employed in bioremediation of PCNB. SIGNIFICANCE AND IMPACT OF THE STUDY: The degradation of pentachloronitrobenzene (PCNB) by an individual bacterial strain is being reported for the first time. The efficient PCNB-degrading strain DH19 was isolated from ginseng rhizosphere soil and identified as Arthrobacter nicotianae. The strain could utilize PCNB as the sole carbon source for growth and degradation. In addition, strain DH19 could efficiently degrade dichlorodiphenyl trichloroethane, hexachlorocyclohexane, cypermethrin and cyhalothrin. Five metabolites from PCNB degradation were identified, and a possible degradation pathway was deduced. The results suggest that A. nicotianae DH19 has great potential for the bioremediation of PCNB-contaminated environments. PMID- 26250406 TI - Developing a clinical development paradigm for translation of a mammaglobin-A DNA vaccine. PMID- 26250407 TI - Production of anti-CD3/28 expanded CD4+ T lymphocytes from HIV-infected patients with different degrees of disease progression. AB - AIMS: CD4+ T lymphocytes from HIV-infected patients with different degrees of disease progression based on CD4 count were expanded in vitro using anti-CD3/28 coated beads. MATERIALS & METHODS: Purified CD4+ T lymphocytes from healthy subjects and patients were expanded for 3 weeks. Moreover, the improvement of cell expansion by IL-2 supplementation was also determined. RESULTS: Expanded CD4+ T lymphocytes from patients had lower fold expansion when compared with healthy subjects. Furthermore, patients with high CD4 counts had higher fold expansion than patients with low CD4 count, and IL-2 supplementation further increased cell expansion. CONCLUSIONS: Anti-CD3/28 activation failed to potently induce expansion of CD4+ T lymphocytes from patients. However, the cell expansion could be improved by IL-2 supplementation. PMID- 26250408 TI - Palmoplantar pustular psoriasis induced by adalimumab: a case report and literature review. AB - TNF-alpha inhibitors (anti-TNF-alpha) are agents increasingly used in the treatment of rheumatic diseases resistant to classical disease-modifying treatment and they provide significant improvement of disease activity. However, these agents have many cutaneous side effects including psoriasis. Numerous reports of the induction or worsening of psoriasis in patients treated with TNF antagonists indicate that this is not a rare phenomenon. In this study, we present a patient with ankylosing spondylitis who developed palmoplantar pustular psoriasis after receiving anti-TNF-alpha therapy for 4 months. PMID- 26250409 TI - Recombinant replacement therapy for hereditary angioedema due to C1 inhibitor deficiency. AB - Hereditary angioedema is a rare genetic condition transmitted as an autosomal dominant trait and characterized most commonly by the production of either inadequate or nonfunctioning C1 esterase inhibitor (C1-INH), a blood protein that regulates proteases in the complement, fibrinolytic and contact systems. Patients with hereditary angioedema suffer from episodic, unpredictable manifestations of edema affecting multiple anatomical locations, including the GI tract, facial tissue, the upper airway, oropharynx, urogenital region and/or the arms and legs. A rational approach to treatment is replacement of C1-INH protein, to normalize the levels of C1-INH activity and halt the progression of the biochemical activation processes underlying the edema formation. Ruconest is a highly purified recombinant human C1-INH. This article will focus on the results of ten clinical studies demonstrating the efficacy and safety of Ruconest((r)) (Pharming Group NV, Leiden, the Netherlands), which is now approved for use in Europe, Israel and the USA. PMID- 26250411 TI - How can we develop universal H5N1 vaccines. AB - Influenza outbreaks by highly pathogenic avian influenza viruses, such as H5N1, have caused significant morbidity and mortality in poultry and mammals. Though the risk of community-level spread of highly pathogenic avian influenza (HPAI) remains to be low since the transmission of influenza virus from animals to humans is not common, HPAI may acquire changes in receptor-binding specificity that lead to human to human transmission. Cases of sporadic infection in humans have been increasing every year and the continuous spread has posed a threat to animal and human health. Vaccination remains to be the most effective strategy to prevent and control the spread of influenza viruses. Other than conventional inactivated whole virus vaccine, several vaccine strategies have been adopted in order to universally defend against H5N1s infection, including subunit vaccine, viral vector-based vaccine, chimeric epitope vaccine strains and HA stalk-based vaccine. PMID- 26250412 TI - Programmed death-1 & its ligands: promising targets for cancer immunotherapy. AB - Novel strategies for cancer treatment involving blockade of immune inhibitors have shown significant progress toward understanding the molecular mechanism of tumor immune evasion. The preclinical findings and clinical responses associated with programmed death-1 (PD-1) and PD-ligand pathway blockade seem promising, making these targets highly sought for cancer immunotherapy. In fact, the anti-PD 1 antibodies, pembrolizumab and nivolumab, were recently approved by the US FDA for the treatment of unresectable and metastatic melanoma resistant to anticytotoxic T-lymphocyte antigen-4 antibody (ipilimumab) and BRAF inhibitor. Here, we discuss strategies of combining PD-1/PD-ligand interaction inhibitors with other immune checkpoint modulators and standard-of-care therapy to break immune tolerance and induce a potent antitumor activity, which is currently a research area of key scientific pursuit. PMID- 26250410 TI - Preventing stem cell transplantation-associated viral infections using T-cell therapy. AB - Hematopoietic stem cell transplantation is the treatment of choice for many hematologic malignancies and genetic diseases. However, viral infections continue to account for substantial post-transplant morbidity and mortality. While antiviral drugs are available against some viruses, they are associated with significant side effects and are frequently ineffective. This review focuses on the immunotherapeutic strategies that have been used to prevent and treat infections over the past 20 years and outlines different refinements that have been introduced with the goal of moving this therapy beyond specialized academic centers. PMID- 26250413 TI - Cyclosporine use in hematopoietic stem cell transplantation: pharmacokinetic approach. AB - Cyclosporine is one of the most vital agents in the process of successful allogeneic hematopoietic stem cell transplantation. Despite a long history and worldwide extent of cyclosporine use for prevention of graft versus host disease, currently there are lots of uncertainties about its optimal method of application to reach the best clinical outcome. A major portion of this problem stems from complicated cyclosporine pharmacokinetics. Study of cyclosporine pharmacokinetic behavior can significantly help recognition of its effectiveness and consequently, optimization of dosing, administration, monitoring and management of adverse effects. In this review, highly accredited but sparse scientific data are gathered in order to provide a better insight for preparation of practice guidelines and directing future studies for allogeneic hematopoietic cell recipients. PMID- 26250414 TI - Panitumumab for the treatment of metastatic colorectal cancer: a review. AB - In recent years, the treatment of metastatic colorectal cancer (mCRC) has evolved significantly with the increase of new therapeutic options, leading to an improved median survival for these patients. In particular, the identification of molecular targets in tumor cells has led to the introduction of biological drugs for the treatment of mCRC. Panitumumab is a fully human monoclonal antibody that binds the EGF receptor of tumor cells and inhibits downstream cell signaling with antitumor effect on inhibition of tumor growth. Its use has been approved by randomized clinical trials as monotherapy in chemorefractory patients or combined with chemotherapy in the treatment of RAS wild-type mCRC, where it demonstrated a significant improvement in survival and response rate. The purpose of this review is to analyze the use and efficacy profile of panitumumab, particularly focusing on recently reported data on its use, and future perspectives in patients with mCRC. PMID- 26250415 TI - Postoperative anatomical and functional outcomes of different stages of high myopia macular hole. AB - BACKGROUND: Recently it was suggested that high myopia macular holes (HMMH) and macular holes accompanied by retinal detachment occur in the advanced stages of myopia traction maculopathy (MTM), while macular retinoschisis, shallow retinal detachment without holes, and lamellar macular holes occur in the early stages of MTM. Complete vitreous cortex removal associated with internal limiting membrane peeling is now widely used to treat HMMH. However, it remains uncertain at what HMMH stage patients would benefit most from surgical intervention. Our study was aimed to evaluate the postoperative anatomical changes and functional outcomes of high myopia macular holes (HMMH). METHODS: Patients were retrospectively collected between March 2009 and August 2011. Before and 1st, 3rd, and 9th month after 23G pars plana vitrectomy, all patients underwent a complete ophthalmologic examination, spectral domain optical coherence tomography (SD-OCT) and MP-1. At each follow-up, best-corrected visual acuity (BCVA), photoreceptor inner and outer segments (IS/OS) defects, and retinal sensitivity (RS) were investigated. According to different preoperative macular hole morphologies, patients were divided into three groups: Group 1, macular hole with epiretinal membrane (ERM) traction and macular retinoschisis; Group 2, full-thickness macular hole (FTMH); Group 3, FTMH with subretinal fluid. RESULTS: 43 eyes from 43 patients met the inclusion criteria. The mean age was 60 years. BCVA and RS were significantly improved after vitrectomy; the mean IS/OS defect was significantly reduced. At 9 postoperative months, 11 of 43 (25.6 %) eyes achieved IS/OS junction integrity; 9 of these 11 (81.8 %) eyes belonged to Group 1, 2 (18.2 %) belonged to Group 2. CONCLUSIONS: Pars plana vitrectomy combined with ILM peeling and gas tamponade results in limited functional outcomes in patients with HMMH. The appearance of subretinal fluid indicates a worse prognosis for surgical intervention. PMID- 26250416 TI - Chest circumference and sitting height among children and adolescents from Lhasa, tibet compared to other high altitude populations. AB - OBJECTIVES: The adaptation of human beings to a high altitude environment during growth has been reported in several populations but is less known for Tibetans. The objective of this study was to investigate similarities and differences of Tibetans in patterns and characteristics of physical growth and development in comparison to other high altitude populations. METHODS: We measured the stature, weight, chest circumference and sitting height of 2,813 healthy children and adolescents aged 6- to 21-year-old living at 3,658-4,500 m in Tibet, China, and compared them with published data from other high altitude populations. Eligible participants must have been born and raised in Tibet, and both their parents' families have to be Tibetan for at least the past three generations. RESULTS: The physical growth and development of children and adolescents in Tibet and the Andes followed similar patterns, such as delayed growth, short stature and sitting height, and large chest dimensions. Relative to stature, Tibetan sitting heights are similar to Andeans, but chest circumferences are smaller. CONCLUSIONS: Findings from this study reinforce the conclusion that Tibetan and Andean populations have adapted differently to high altitude hypoxia. The physical features of each population may result from unique adaptation to hypoxia, as well as socio-ecological factors, such as poor nutrition. PMID- 26250417 TI - Co-administration of N-Acetylcysteine and Acetaminophen Efficiently Blocks Acetaminophen Toxicity. AB - Preclinical Research Although acetaminophen (APAP) is an effective analgesic and anti-pyretic, APAP overdose is the most frequent cause of serious, often lethal, drug-induced hepatotoxicity. Administration of N-acetyl cysteine (NAC) within 8 hours of APAP overdose effectively mitigates APAP-induced hepatotoxicity. Thus, preventing APAP toxicity before it occurs by formulating APAP with NAC is logical and, as we show here in a mouse model, is effective in preventing APAP toxicity. Thus, toxic oral APAP doses sufficient to cause severe widespread liver damage do not cause significant damage when administered concurrently with equal amounts of NAC, that is, in the NAC-APAP treated animals, hepatic transaminases increase only marginally and liver architecture remains fully intact. Thus, we conclude that concomitant oral dosing with APAP and NAC can provide a convenient and effective way of preventing toxicity associated with large dosage of APAP. From a public health perspective, these findings support the concept that a co formulation of APAP plus NAC is a viable over-the-counter (OTC) alternative to the current practice of providing APAP OTC and treating APAP toxicity if/when it occurs. In essence, our findings indicate that replacing the current OTC APAP with a safe and functional APAP/NAC formulation could prevent the accidental and intentional APAP toxicity that occurs today. PMID- 26250418 TI - Insights into mechanisms of central nervous system myelination using zebrafish. AB - Myelin is the multi-layered membrane that surrounds most axons and is produced by oligodendrocytes in the central nervous system (CNS). In addition to its important role in enabling rapid nerve conduction, it has become clear in recent years that myelin plays additional vital roles in CNS function. Myelinating oligodendrocytes provide metabolic support to axons and active myelination is even involved in regulating forms of learning and memory formation. However, there are still large gaps in our understanding of how myelination by oligodendrocytes is regulated. The small tropical zebrafish has become an increasingly popular model organism to investigate many aspects of nervous system formation, function, and regeneration. This is mainly due to two approaches for which the zebrafish is an ideally suited vertebrate model--(1) in vivo live cell imaging using vital dyes and genetically encoded reporters, and (2) gene and target discovery using unbiased screens. This review summarizes how the use of zebrafish has helped understand mechanisms of oligodendrocyte behavior and myelination in vivo and discusses the potential use of zebrafish to shed light on important future questions relating to myelination in the context of CNS development, function and repair. PMID- 26250419 TI - Effect of feeding greater amounts of dietary energy for a short-term with or without eCG injection on reproductive performance, serum metabolites and hormones in ewes. AB - This study was conducted to compare the effect of transient high-energy diet in a short-term period with or without eCG injection on ovarian follicle development, twining rate, serum metabolites and hormones in ewes. A total of 45 estrous cyclic Naeini ewes were randomly assigned to three experimental groups: 1-Control (control), 2-High energy short-term feeding (HE), and 3-high energy short-term feeding + eCG injection (HEe). Ewes were housed in individual pens with free access to feed and water. The stage of the estrous cycle of all ewes was synchronized by insertion of intravaginal progesterone sponges. Focus feeding started from 4 days before until 1 day after sponge removal. Follicle development was monitored from 4 days before until 1 day after sponge removal and blood samples were taken during this time. Results showed that ewes fed high energy diets (HE and HEe) had greater (P < 0.05) large follicle numbers compared with the control group. Feeding high energy diets increased (P < 0.05) serum glucose, cholesterol and insulin, but had lesser (P < 0.05) serum urea nitrogen concentrations near the time of ovulation. After the start of experiment, ewes fed high energy diets had less (P < 0.05) serum estradiol. However, 1 day after sponge removal, serum estradiol in HE and HEe groups increased (P < 0.05). It was concluded that short-term (6-day) changes in amount of dietary energy with or without eCG injection increased twin births and had beneficial effects on the blood metabolites and hormone concentrations in Naeini ewes. PMID- 26250420 TI - An in vitro test bench reproducing coronary blood flow signals. AB - BACKGROUND: It is a known fact that blood flow pattern and more specifically the pulsatile time variation of shear stress on the vascular wall play a key role in atherogenesis. The paper presents the conception, the building and the control of a new in vitro test bench that mimics the pulsatile flows behavior based on in vivo measurements. METHODS: An in vitro cardiovascular simulator is alimented with in vivo constraints upstream and provided with further post-processing analysis downstream in order to mimic the pulsatile in vivo blood flow quantities. This real-time controlled system is designed to perform real pulsatile in vivo blood flow signals to study endothelial cells' behavior under near physiological environment. The system is based on an internal model controller and a proportional-integral controller that controls a linear motor with customized piston pump, two proportional-integral controllers that control the mean flow rate and temperature of the medium. This configuration enables to mimic any resulting blood flow rate patterns between 40 and 700 ml/min. In order to feed the system with reliable periodic flow quantities in vivo measurements were performed. Data from five patients (1 female, 4 males; ages 44-63) were filtered and post-processed using the Newtonian Womersley's solution. These resulting flow signals were compared with 2D axisymmetric, numerical simulation using a Carreau non-Newtonian model to validate the approximation of a Newtonian behavior. RESULTS: This in vitro test bench reproduces the measured flow rate time evolution and the complexity of in vivo hemodynamic signals within the accuracy of the relative error below 5%. CONCLUSIONS: This post-processing method is compatible with any real complex in vivo signal and demonstrates the heterogeneity of pulsatile patterns in coronary arteries among of different patients. The comparison between analytical and numerical solution demonstrate the fair quality of the Newtonian Womersley's approximation. Therefore, Womersley's solution was used to calculate input flow rate for the in vitro test bench. PMID- 26250421 TI - Genotype of UGT1A1 and phenotype correlation between Crigler-Najjar syndrome type II and Gilbert syndrome. AB - BACKGROUND AND AIMS: Hereditary unconjugated hyperbilirubinemias, Crigler-Najjar syndrome type I, Crigler-Najjar syndrome type II (CN-2), and Gilbert syndrome (GS) all result from mutations of the bilirubin uridine 5'-diphosphate (UDP) glucuronosyltransferase gene (UGT1A1). Often, to distinguish between CN-2 and GS is difficult because the borderline of the two syndromes is unclear. We analyzed the genotypes and phenotypes of 163 Japanese patients with CN-2 or GS. METHODS: Japanese patients (99 males and 64 females) with unconjugated hyperbilirubinemia were analyzed. Their serum bilirubin concentrations varied from 1.2 to 22.2 mg/dL (20 to 379 MUM). Genetic analysis of UGT1A1 was performed by PCR-amplified direct sequencing. Association between serum bilirubin concentrations and genotypes group (typical CN-2, intermediate group, and typical GS) was studied. RESULTS: Most patients had biallelic mutations of UGT1A1. Moreover, many of them (78.5%) had multiple mutations. The mutation in typical CN-2 was a homozygous double missense mutation of p.[G71R:Y486D]. In typical GS group, four prevalent genotypes were detected: homozygous UGT1A1*28, UGT1A1*6/UGT1A1*28, and homozygous UGT1A1*6, and UGT1A1*27/UGT1A1*28. In the intermediate group, three genotypes, p.[G71R:Y486D]/UGT1A1*7, p.[G71R:Y486D]/UGT1A1*6, and homozygous UGT1A1*7, were detected. Serum bilirubin concentrations of typical CN-2, intermediate group, and typical GS are respectively 12.9 +/- 5.1, 5.2 +/- 2.2, and 2.8 +/- 1.1 mg/dL. Serum bilirubin concentration among the three groups is statistically different (P < 0.0001). CONCLUSIONS: The serum bilirubin concentration varied continuously from GS to CN-2 depending on genotypes. Because of the combination of the mutations and polymorphisms, many patients showed intermediate serum bilirubin concentration between two syndromes. Clinically, it is difficult to distinguish clearly between the two syndromes. PMID- 26250422 TI - Utilization of Stearic acid Extracted from Olive Pomace for Production of Triazoles, Thiadiazoles and Thiadiazines Derivatives of Potential Biological Activities. AB - Olive Pomace was firstly dried, then pomace olive oil was extracted, and the obtained oil was hydrolyzed to produce glycerol and mixture of fatty acids. Fatty acids mixture was separated, this mixture was then cooled, where the all saturated fatty acids were solidified, and then they were filtered off. These saturated fatty acids were identified by GC mass after esterification, and were identified as stearic, palmitic and myristic acids. Stearic acid was extracted using supercritical CO2 extractor. The stearic acid was confirmed by means of GC mass after its esterification, and it was used as starting material for preparation of a variety of heterocyclic compounds, which were then tested for their antimicrobial activities. Thus the long-chain fatty acid hydrazide (2) was prepared from the corresponding long-chain fatty ester with hydrazine hydrate. Reacting 2 with phenyl isothiocyanate afforded the corresponding thiosemicarbazide 4. The later 4 underwent intramolecular cyclization in basic medium, and gave the s-triazole derivative 5, which was methylated and afforded 3 heptadecanyl-5-(methylthio)-4-phenyl-4H-1,3,4-triazole (7), which was then treated with hydrazine hydrate and afforded the corresponding 1-(5-heptadecanyl-4 phenyl-4H-1,2,4-triazol-3-yl) hydrazine (8).On the other hand, thiosemicarbazide 4 underwent intramolecular cyclization in acid medium and afforded the corresponding thiadiazole derivative 6.Treatment of thiosemicarbazide 4 with ethyl chloro(arylhydrazono) acetate derivatives 9a-b, furnished a single product 13 (Scheme 6). Similarly, when the thiosemicarbazide 4 was treated with the phenylcarbamoylarylhydrazonyl chloride 10a-c, it afforded (3-Aryl-N-5 (phenylcarbamoyl)-1,3,4-thiadiazol-2(3H)-ylidene)octadecanehydrazide 15a-c (Scheme 7). Also the reaction of thiosemicarbazide 4 with 2-oxo-N arylpropanehydrazonoyl chlorides 11a-c and N-phenylbenzohydrazonoyl chloride 11d gave the corresponding thiadiazole derivatives 16a-d as shown in Scheme 8. A solution of thiosemicarbazide 4 was treated with the haloketones 17a-c, afforded the thiadiazine derivatives 20a-c, as shown in Scheme 9. Analogously, the thiosemicarbazide 4 was reacted with alpha-haloketones 21a-b and afforded the corresponding products 22a-b (Scheme 9). The structure elucidation of all synthesized compounds is based on the elemental analysis and spectral data (IR, 1H NMR, 13C NMR and MS). PMID- 26250423 TI - Fucoxanthin Derivatives: Synthesis and their Chemical Properties. AB - Novel fucoxanthin derivatives that could change the size of mixed micelles were synthesized. The mixed micelles under consideration consist of a bile acid and some additives. To change the affinity against a bile acid, we designed the synthesis of a fucoxanthin-lithocholic acid complex. Lithocholic acid is one of the bile acids. The 3-OH on lithocholic acid was protected by a levulinyl group, and the protected lithocholic acid was selectively coupled via an ester linkage to the 3-OH on fucoxanthin to obtain levulinyl-protected lithocholyl fucoxanthin (LevLF). The levulinyl group was then selectively deprotected using hydrazine to obtain a lithocholyl fucoxanthin (LF). The average sizes of the micelles that contained these compounds (fucoxanthin, LevLF, and LF) with a bile acid (sodium taurocholate) were measured. The LevLF induced larger micelles than fucoxanthin or LF. Interestingly, the addition of 1-oleoyl-rac-glycerol induced a more efficient change in the micelle size. The large micelles grew larger, and the small micelles became smaller. Triple-mixed micelles with LevLF, sodium taurocholate, and 1-oleoyl-rac-glycerol formed the largest micelle with a diameter of 68 nm. On the other hand, triple-mixed micelles using LF, sodium taurocholate, and 1-oleoyl-rac-glycerol made the smallest micelles with diameters as low as 12 nm. We also investigated the hydrolysis of these compounds with enzymes (esterase from porcine liver, lipase from porcine pancreas, and cholesterol esterase from Pseudomonas sp.). The ester linkage between the lithocholic acid and fucoxanthin of LevLF was hydrolyzed with cholesterol esterase. In addition, the intestinal absorption was examined with Caco-2 cells, and no advantageous change in absorption efficiency was observed by chemically modifying the fucoxanthin unless different micelles sizes and increasing hydrophobicity are induced. PMID- 26250424 TI - Oat (Avena sativa L.): Oil and Nutriment Compounds Valorization for Potential Use in Industrial Applications. AB - Oat is a promising plant for the future. It is edible and beneficial thanks to its nutritional, medicinal and pharmaceutical uses and, hence, recognized to be useful for a healthier world. The assessment of the vital functions of oat components is important for industries requiring correct health labelling, valid during the shelf life of any product. Oil, enzymes and other biomolecules of nutraceutic or dietary usage from oats would be valorized for this purpose. Although oats have a unique and versatile composition including antioxidants and biomolecules indispensable for health, they are undervalued in comparison with other staple cereals such as wheat, barley and rice. Furthermore, oats, apart from maize, comprise a high oil content used for a wide range of beneficial purposes. In addition, they contain beta glucan that has proven to be very helpful in reducing blood cholesterol levels and other cardiovascular diseases risks. In fact, there is diversity in the composition and content of the beneficial oat components within their genotypes and the different environmental conditions and, thus, oats are amenable to be enhanced by agronomic practices and genetic approaches. PMID- 26250425 TI - Spontaneous Emulsification of Triolein Induced by Mixed Micellar Solutions of Sodium Polyoxyethylene Alkyl Ether Sulfate and Dodecyldimethyl Amine Oxide. AB - A new mechanism of spontaneous emulsification without any salts or co-solvents is described, and is related to the dilatational behavior. Spontaneous emulsification can reduce the time required to remove oily soils from hard surfaces and enhance the detergency, because this type of emulsification requires no external mechanical work. In this paper, we focused on triolein, the main component of food oils and human sebum soil, and tried to induce spontaneous emulsification by using mixed micellar solutions of sodium polyoxyethylene alkyl ether sulfate and N, N-dimethyldodecylamine oxide (AES/DDAO). We characterized the dilatation of the oil/water interface using dynamic interfacial tension and elasticity measurements. This study confirmed that the degree of spontaneous emulsification can be enhanced by controlling the molar ratio of DDAO to AES. This enhancement can be attributed to an increased rate of decrease in the dynamic interfacial tension (i.e., a decreased interface dilatational elasticity), allowing for much greater suppression of the Marangoni effect. Further, we determined that one of the reasons for the decrease in the interface dilatational elasticity is the increasing number of micelles near the oil drop interface, which results from a decrease in the electrostatic repulsion between the micelles and the drop interface. Therefore, controlling the molar ratio of a mixed anionic/amphoteric surfactant solution is an effective way to induce spontaneous emulsification in the absence of salts or co-solvents. PMID- 26250426 TI - Micelle-Vesicle Transition by Cleavage of Disulfide Spacer Chain for Gemini Surfactant in Didodecyldimethylammonium Chloride Aqueous Solutions. AB - We examined the "micelle-vesicle transition" through the mixing effect of single tailed thiol surfactants produced by the cleavage of gemini surfactants, [C12H25N(CH3)2CH2CH2SSCH2CH2N(CH3)2C12H25] 2Cl (C12SSC12), which have a disulfide bond in the spacer chain. Phase diagrams of C12H25N(CH3)2CH2CH2SHCl didodecyldimethylammonium chloride (C12SH-DDAC) and C12SSC12-DDAC were determined by conductivity and pyrene fluorescence probe methods. The aggregate diameters were evaluated by dynamic light scattering (DLS). The critical vesicle concentration (CVC) was confirmed by the abrupt increase in the intensity of light scattering with excitation at 335 nm. Vesicle formation was confined to the DDAC-rich region of the C12SSC12-DDAC system, while the vesicle formation region for the C12SH-DDAC system spread out with the addition of dithiothreitol (DTT) to C12SSC12-DDAC. This implies that single-tailed surfactants can induce a more favorable environment for molecular packing of the vesicular surface. The micelle vesicle transition occurs with disulfide spacer chain cleavage of gemini surfactants at a particular specific concentration range. PMID- 26250427 TI - Effect of Three-spot Seahorse Petroleum Ether Extract on Lipopolysaccharide Induced Macrophage RAW264.7 Inflammatory Cytokine Nitric Oxide and Composition Analysis. AB - Three-Spot seahorse is a traditional medicine in Asian countries. However, the alcohol extract is largely unknown for its anti-inflammatory activity. This study aimed at elucidating fraction of potent anti-inflammatory activity of seahorse. A systematic solvent extraction method of liquid-liquid fractionation of ethanol crude extract gave four fractions petroleum ether (PE), and ethyl acetate (EtOAc), water saturated butanol (n-BuOH), water (H2O). In this study, PE extract was selected for further study after preliminary screening test, and was connected to silica column chromatography and eluted with different polarity of mobile phases, and obtained four active fractions (Fr I, Fr II, Fr III, Fr IV). Effect of separated fractions on inflammation was investigated in lipopolysaccharide (LPS) stimulated murine RAW264.7 cells in vitro. The result shows that seahorse extract was capable of inhibiting the production of nitric oxide (NO) significantly in a dose dependent manner and exhibited no notable cytotoxicity on cell viability. IC50 of fraction IV was 36.31 MUg/mL, indicating that separated fraction possessed potent NO inhibitory activity against LPS induced inflammatory response, thus, demonstrated its in vitro anti-inflammatory potentiality, it may be at least partially explained by the presence of anti inflammation active substances, phenolic compounds, phospholipids and polyunsaturated fatty acids, especially phospholipids and polyunsaturated fatty acids. It could be suggested that seahorse lipid-soluble components could be used in functional food and anti-inflammatory drug preparations. PMID- 26250428 TI - Volatile Compounds with Characteristic Odor of Essential Oil from Magnolia obovata Leaves by Hydrodistillation and Solvent-assisted Flavor Evaporation. AB - The present study focuses on the volatile compounds with characteristic odor of essential oil from the leaves of Magnolia obovata by hydrodistillation (HD) and solvent-assisted flavor evaporation (SAFE) method. Eighty-seven compounds, representing 98.0% of the total oil, were identified using HD. The major compounds of HD oil were (E)-beta-caryophyllene (23.7%), alpha-humulene (11.6%), geraniol (9.1%), and borneol (7.0%). In SAFE oil, fifty-eight compounds, representing 99.7% of the total oil, were identified. The main compounds of SAFE oil were (E)-beta-caryophyllene (48.9%), alpha-humulene (15.7%), and bicyclogermacrene (4.2%). In this study, we newly identified eighty-five compounds of the oils from M. obovata leaves. These oils were also subjected to aroma evaluation by gas chromatography-olfactometry (GC-O) and aroma extract dilution analysis (AEDA). As a result, twenty-four (HD) and twenty-five (SAFE) aroma-active compounds were detected. (E)-beta-Caryophyllene, alpha-humulene, linalool, geraniol, 1,8-cineole, and bicyclogermacrene were found to impart the characteristic odor of M. obovata leaves. These results imply that the oils of M. obovata leaves must be investigated further to clarify their potential application in the food and pharmaceutical industries. PMID- 26250429 TI - Isopeptidase activity of human transglutaminase 2: disconnection from transamidation and characterization by kinetic parameters. AB - Transglutaminase 2 (TG2) is a multifunctional protein with diverse catalytic activities and biological roles. Its best studied function is the Ca(2+) dependent transamidase activity leading to formation of gamma-glutamyl-epsilon lysine isopeptide crosslinks between proteins and gamma-glutamyl-amine derivatives. TG2 has a poorly studied isopeptidase activity cleaving these bonds. We have developed and characterised TG2 mutants which are significantly deficient in transamidase activity while have normal or increased isopeptidase activity (W332F) and vice versa (W278F). The W332F mutation led to significant changes of both the K m and the V max kinetic parameters of the isopeptidase reaction of TG2 while its calcium and GTP sensitivity was similar to the wild-type enzyme. The W278F mutation resulted in six times elevated amine incorporating transamidase activity demonstrating the regulatory significance of W278 and W332 in TG2 and that mutations can change opposed activities located at the same active site. The further application of our results in cellular systems may help to understand TG2 driven physiological and pathological processes better and lead to novel therapeutic approaches where an increased amount of crosslinked proteins correlates with the manifestation of degenerative disorders. PMID- 26250430 TI - Selenium and Iodine Levels in Subjects with Kashin-Beck Disease: a Meta-analysis. AB - Kashin-Beck disease (KBD) is an endemic, degenerative osteoarthropathy, and particularly seen in China. A deficiency of selenium and iodine is implicated as the main etiological factor for KBD. This meta-analysis aimed to evaluate the differences in the selenium and iodine levels between patients with KBD and healthy individuals. Eligible articles published before March 6, 2015 were searched from four electronic databases. Data extraction and quality assessment of included studies were performed by two independent reviewers. Results were summarized as standardized mean difference (SMD) with 95 % confidence intervals (CIs). Cohen's d test was used to estimate the difference of the effect size between patients with KBD and healthy controls. A total of 26 cross-sectional studies were included in the meta-analysis. The pooled SMD showed that the whole blood selenium (Cohen's d = 4.39, P < 0.001), serum selenium (Cohen's d = 2.42, P = 0.015), hair selenium (Cohen's d = 5.46, P < 0.001), and urinary selenium (Cohen's d = 4.16, P < 0.001) levels were significantly lower in patients with KBD than that in healthy controls. There was no significant difference of plasma selenium (Cohen's d = 0.08, P = 0.936) and urinary iodine (Cohen's d = 0.33, P = 0.744) levels between subjects with KBD and healthy controls. In conclusion, the levels of selenium, but not iodine were significantly lower in subjects with KBD than that in healthy controls. Selenium deficiency might be associated with the risk of KBD. PMID- 26250431 TI - Iron Oxide Based Nanoparticles for Multimodal Imaging and Magnetoresponsive Therapy. PMID- 26250432 TI - The evolution of epilepsy surgery between 1991 and 2011 in nine major epilepsy centers across the United States, Germany, and Australia. AB - OBJECTIVE: Epilepsy surgery is the most effective treatment for select patients with drug-resistant epilepsy. In this article, we aim to provide an accurate understanding of the current epidemiologic characteristics of this intervention, as this knowledge is critical for guiding educational, academic, and resource priorities. METHODS: We profile the practice of epilepsy surgery between 1991 and 2011 in nine major epilepsy surgery centers in the United States, Germany, and Australia. Clinical, imaging, surgical, and histopathologic data were derived from the surgical databases at various centers. RESULTS: Although five of the centers performed their highest number of surgeries for mesial temporal sclerosis (MTS) in 1991, and three had their highest number of MTS surgeries in 2001, only one center achieved its peak number of MTS surgeries in 2011. The most productive year for MTS surgeries varied then by center; overall, the nine centers surveyed performed 48% (95% confidence interval [CI] -27.3% to -67.4%) fewer such surgeries in 2011 compared to either 1991 or 2001, whichever was higher. There was a parallel increase in the performance of surgery for nonlesional epilepsy. Further analysis of 5/9 centers showed a yearly increase of 0.6 +/- 0.07% in the performance of invasive electroencephalography (EEG) without subsequent resections. Overall, although MTS was the main surgical substrate in 1991 and 2001 (proportion of total surgeries in study centers ranging from 33.3% to 70.2%); it occupied only 33.6% of all resections in 2011 in the context of an overall stable total surgical volume. SIGNIFICANCE: These findings highlight the major aspects of the evolution of epilepsy surgery across the past two decades in a sample of well-established epilepsy surgery centers, and the critical current challenges of this treatment option in addressing complex epilepsy cases requiring detailed evaluations. Possible causes and implications of these findings are discussed. PMID- 26250433 TI - TRPV4 activation at the physiological temperature is a critical determinant of neuronal excitability and behavior. AB - For homeothermic animals, constant body temperature is an important determinant of brain function. It is well established that changes in brain temperature dynamically influence hippocampal activity. We previously reported that the thermosensor TRPV4 (activated above 34 degrees C) is activated at the physiological temperature in hippocampal neurons and controls neuronal excitability in vitro. Here, we examined if TRPV4 regulates neuronal excitability through its activation at the physiological temperature in vivo. We found that TRPV4-deficient (TRPV4KO) mice exhibit reduced depression-like and social behaviors compared to wild-type (WT) mice, and the number of c-fos positive cells in the dentate gyrus was significantly reduced upon the depression-like behaviors. We measured resting membrane potentials (RMPs) in the hippocampal granule cells from slice preparations at 35 degrees C and found that TRPV4 positive neurons significantly depolarized the RMPs through TRPV4 activation at the physiological temperature. The depolarization increased the spike numbers depending on the enhancement of TRPV4 activation. We also found that theta frequency electroencephalogram (EEG) activities in TRPV4KO mice during wake periods were significantly reduced compared with those in WT mice. Taken together, we report for the first time that TRPV4 activation at the physiological temperature is important to regulate neuronal excitability and behaviors in mammals. PMID- 26250434 TI - Histologic versus clinical remission in proliferative lupus nephritis. AB - Background: Treatment response in lupus nephritis (LN) is defined clinically, without consideration of renal histology. Few studies have systematically examined histologic responses to induction therapy. In LN patients who underwent protocol kidney biopsies after induction immunosuppression, we describe the renal histology of the second biopsy and correlate histologic activity and damage with short- and long-term kidney outcomes. Methods: Patients with suspected LN were biopsied for diagnosis (Biopsy 1), and those with proliferative LN were rebiopsied after induction (Biopsy 2). Histologic activity and damage at each biopsy were calculated as the National Institutes of Health activity and chronicity indices. Complete and partial renal responses after induction and after long-term follow-up were determined clinically. Results: One-third of patients who achieved a complete clinical response after induction had persistently high histologic activity, and 62% of patients who had complete histologic remission on rebiopsy were still clinically active. Chronic renal damage increased after induction even in complete clinical responders. Chronicity at Biopsy 2 associated with long-term kidney function and development of chronic kidney disease. Conclusions: Early clinical and histologic outcomes are discordant in proliferative LN, and neither correlates with long-term renal outcome. The kidney accrues chronic damage rapidly and despite clinical response in LN. Preservation of kidney function may require therapeutic targeting of both chronic damage and inflammation during LN induction treatment. PMID- 26250436 TI - Surgical techniques and outcomes of cochlear implantation in patients with radiographic findings consistent with X-linked deafness. AB - OBJECTIVES: X-linked deafness is a potential etiology of sensorineural hearing loss characterized by bulbous dilatation of the fundus of the internal auditory canal (IAC) and the absence of the bony plates separating the basal turn of the cochlea and IAC. These malformations predispose patients to IAC insertion during cochlear implantation (CI). Our objective is to describe the surgical technique, audiometric and speech performance outcomes in a group of patients with this unique cochlear malformation. METHODS: A retrospective chart review was performed of all patients at a tertiary care facility who underwent CI between January 2006 and July 2011. RESULTS: A total of five patients were identified with radiographic findings characteristic of X-linked deafness, specifically a deficient modiolous, absent lamina cribrosa and bulbous IAC. A modified cochleostomy was utilized to ensure electrode insertion within the scala tympani avoiding the IAC. In each case, fluoroscopy was utilized to visual electrode progression during insertion and complete insertion was accomplished. All patients demonstrated improved speech performance following implantation. CONCLUSIONS: Utilizing the techniques described, patients with these unique radiographic findings consistent with X-linked deafness may successfully undergo CI with excellent potential for auditory rehabilitation. PMID- 26250435 TI - A randomized trial of iron isomaltoside 1000 versus oral iron in non-dialysis dependent chronic kidney disease patients with anaemia. AB - BACKGROUND: Iron deficiency anaemia is common in patients with non-dialysis dependent chronic kidney disease (NDD-CKD) and is often treated with oral or intravenous (IV) iron therapy. This trial compared the efficacy and safety of IV iron isomaltoside 1000 (Monofer(r)) and oral iron in NDD-CKD patients with renal related anaemia. METHODS: The trial was a Phase III open-label, comparative, multicentre, non-inferiority trial conducted in 351 iron-deficient NDD-CKD patients, randomized 2:1 to either iron isomaltoside 1000 (Group A) or iron sulphate administered as 100 mg elemental oral iron twice daily (200 mg daily) for 8 weeks (Group B). The patients in Group A were randomized into A1 (infusion of max. 1000 mg single doses over 15 min) and A2 (bolus injections of 500 mg over 2 min). A modified Ganzoni formula was used to calculate IV iron need. The primary end point was change in haemoglobin concentrations from baseline to Week 4. RESULTS: Iron isomaltoside 1000 was both non-inferior to oral iron at Week 4 (P < 0.001) and sustained a superior increase in haemoglobin from Week 3 until the end of the study at Week 8 (P = 0.009 at Week 3). The haemoglobin response was more pronounced with iron isomaltoside 1000 doses >=1000 mg (P < 0.05). Serum ferritin and transferrin saturation concentrations were also significantly increased with IV iron. Adverse drug reactions were observed in 10.5% in the iron isomaltoside 1000 group and 10.3% in the oral iron group. More patients treated with oral iron sulphate withdrew from the study due to adverse events (4.3 versus 0.9%, P = 0.2). CONCLUSIONS: Iron isomaltoside 1000 was more efficacious than oral iron for increase in haemoglobin and proved to be well tolerated at the tested dose levels in NDD-CKD patients. PMID- 26250437 TI - The development of the vanderbilt pediatric dizziness handicap inventory for patient caregivers (DHI-PC). AB - PURPOSE: The purpose of the present investigation was to develop a psychometrically sound dizziness disability/handicap outcome measure for use with a pediatric population between 5 and 12 years of age. METHODS: Items comprising Phase 1 of the DHI-PC were created based on reports from parents, providers and patients. This version was administered to the caregivers (mean age 31.6 years, sd 5 years, 74 female) of 86 pediatric patients (mean age 9 years, sd=2.83 years, 45 female). The caregiver's responses to each item were limited to "yes" (scored as 4 points), "sometimes" (scored as 2 points) or "no" (scored as zero points). RESULTS: A factor analysis for Phase 1 of the scale showed there to be a single factor (eigenvalue of 11.51) that explained 29% of the total variance. The results of Cronbach's alpha analysis enabled us to eliminate 15 items reducing the scale to 25 items (i.e. Phase 2 of the DHI-PC). Following elimination of the items with low item-total coefficients, the second phase of the DHI-PC was administered to 56 legal guardians (mean patient age 8 years, sd 4.65 years, 37 female). The analysis of this data again showed there to be a single factor (eigenvalue of 8.30) that explained 33% of the variance. Four items demonstrated item-total correlations less than 0.40. The final version of the DHI-PC has 21 items and a maximum score of 84%. Short-term test-retest reliability (i.e. three week interval between test and retest) of this DHI-PC was assessed for a subset of 10 patients (caregivers, mean age 38 years, sd=7 years, 10 female). The results indicated the short-term, test-retest reliability to be strong (r=0.98, p<=0.001). CONCLUSION: The DHI-PC represents a new tool for assessing the impact of pediatric dizziness on the patient (as viewed through the perspective of the caregiver). This tool may be incorporated into the comprehensive evaluation of children suffering from dizziness. PMID- 26250438 TI - Causes, costs, and risk factors for unplanned return visits after adenotonsillectomy in children. AB - OBJECTIVE: To review the causes, costs, and risk factors for unplanned return visits and readmissions after pediatric adenotonsillectomy (T&A). METHODS: Review of administrative database of outpatient adenotonsillectomy performed at any facility within a vertically integrated health care system in the Intermountain West on children age 1-18 years old between 1998 and 2012. Data reviewed included demographic variables, diagnosis associated with return visit and costs associated with return visits. RESULTS: Data from 39,906 children aged 1-18 years old were reviewed. A total of 2499 (6.3%) children had unplanned return visits. The most common reasons for return visits were bleeding (2.3%), dehydration, (2.3%) and throat pain (1.2%). After multivariate analysis, the main risk factors for any type of return visits were Medicaid insurance (OR=1.64 95% CI 1.47-1.84), Hispanic race (OR=1.36 95% CI 1.13-1.64), and increased severity of illness (SOI) (OR=11.29 95% CI 2.69-47.4 for SOI=3). The only factor associated with increased odds of requiring an inpatient admission on return visit was length of time spent in PACU (p<0.001). A linear relationship was also observed between the child's age and the risk of post-tonsillectomy hemorrhage. CONCLUSION: Children with increased severity of illness, those insured with Medicaid, and children of Hispanic ethnicity should be targeted with increased education and interventions in order to reduce unplanned visits after T&A. Further studies on post tonsillectomy complications should include evaluating the effect of surgical technique and post-operative pain management on all complications and not solely post-tonsillectomy hemorrhage. PMID- 26250439 TI - The formation of human auricular cartilage from microtic tissue: An in vivo study. AB - OBJECTIVES: This study aimed to isolate, culture-expand and characterize the chondrocytes isolated from microtic cartilage and evaluate its potential as a cell source for ear cartilage reconstruction. Specific attention was to construct the auricular cartilage tissue by using fibrin as scaffold. STUDY DESIGN: Cell culture experiment with the use of microtic chondrocytes. DESIGN: Cell culture experiment with the use of microtic chondrocytes. METHODS: After ear reconstructive surgery at the Universiti Kebangsaan Malaysia Medical Center, chondrocytes were isolated from microtic cartilage. Chondrocytes isolated from the tissue were cultured expanded until passage 4 (P4). Upon confluency at P4, chondrocytes were harvested and tissue engineered constructs were made with human plasma polymerized to fibrin. Constructs formed later is implanted at the dorsal part of nude mice for 8 weeks, followed by post-implantation evaluation with histology staining (Hematoxylin and Eosin (H&E) and Safranin O), immunohistochemistry and RT-PCR for chondrogenic associated genes expression level. RESULTS: Under gross assessment, the construct after 8 weeks of implantation showed similar physical characteristics that of cartilage. Histological staining showed abundant lacunae cells embedded in extracellular matrix similar to that of native cartilage. Safranin O staining showed positive staining which indicates the presence of proteoglycan-rich matrix. Immunohistochemistry analysis showed the strong positive staining for collagen type II, the specific collagen type in the cartilage. Gene expression quantification showed no significant differences in the expression of chondrogenic gene used which is collagen type I, collagen type II, aggrecan core protein (ACP), elastin and sox9 genes when compared to construct formed from normal auricular tissue. CONCLUSION: Chondrocytes isolated from microtia cartilage has the potential to be used as an alternative cell source for external ear reconstruction in future clinical application. PMID- 26250440 TI - Longitudinal performance of spoken word perception in Mandarin pediatric cochlear implant users. AB - OBJECTIVE: The objective of the present study was to investigate the longitudinal performance on open-set word perception in Mandarin children with cochlear implants (CIs). METHODS: Prospective cohort study. One hundred and five prelingually deaf children implanted with CIs participated in the study. The Standard-Chinese Version of Monosyllabic Lexical Neighborhood Test (LNT) and Multisyllabic Lexical Neighborhood Test (MLNT) were used as open-set word perception evaluation tools. Evaluations were administrated at 6, 12, 24, 36, 48, 60, 72, and 84 months post CI stimulation, respectively. RESULTS: (1) Spoken word perception performance of congenitally deaf children with CIs improved significantly over time. (2) The fastest improvement occurred in the first 36 months after initial activation, then the improvement slowed down and the final peak score of 81.7% correct was achieved at 72 months after initial activation. (3) Early implanted children exhibited better longitudinal performance. (4) Lexical factors affected consistently in each evaluation session. For lexically harder words, such as monosyllabic hard words, there was substantial room for improvement even after long-term use of CI. CONCLUSIONS: (1) CI continuously provided significant benefits in word perception to children with severe/profound sensorineural hearing loss. (2) Age at implantation and Mandarin lexical factor affected longitudinal performance significantly. PMID- 26250441 TI - Casting a look at pediatric plastic bronchitis. AB - OBJECTIVES: To review clinical presentations and management strategies for children with plastic bronchitis. METHODS: Retrospective chart review. RESULTS: Seven patients required rigid bronchoscopy to remove bronchial casts over a 17 year study period. Mean age at presentation was 60 months. Mean follow-up was 53 months. Co-morbidities included: congenital heart disease (n=3), chronic pulmonary disorders (n=2) and sickle cell disease (n=1). 4 patients required multiple bronchoscopies for recurrent casts. Adjunctive topical therapies were administered in all 7 patients, without complication. Rigid bronchoscopy for cast removal was performed in 2 patients who were on extra-corporal membrane oxygenation (ECMO), using special precautions to safeguard the ECMO catheters. CONCLUSIONS: Bronchial casts in children may present acutely or sub-acutely. Recurrent casts are unusual; however, in combination with severe cardiac disease may lead to mortality. Adjunctive topical therapies are still under investigation. Special safeguards for ECMO catheters are imperative. This case series complements and adds to the International Plastic Bronchitis Registry. PMID- 26250442 TI - Possible role of a dysregulation of the endogenous opioid system in antisocial personality disorder. AB - Around half the inmates in prison institutions have antisocial personality disorder (ASPD). A recent theory has proposed that a dysfunction of the endogenous opioid system (EOS) underlies the neurobiology of borderline personality disorder (BPD). In the present theoretical paper, based on a comprehensive database and hand search of the relevant literature, this hypothesis is extended to ASPD, which may be the predominant expression of EOS dysfunction in men, while the same pathology underlies BPD in women. According to evidence from human and animal studies, the problematic behaviours of persons with antisocial, callous, or psychopathic traits may be seen as desperate, unconscious attempts to stimulate their deficient EOS, which plays a key role in brain reward circuits. If the needs of this system are not being met, the affected persons experience dysphoric mood, discomfort, or irritability, and strive to increase binding of endogenous opioids to receptors by using the rewarding effects of aggression by exertion of physical or manipulative power on others, by abusing alcohol or substances that have the reward system as target, by creating an "endorphin rush" by self-harm, by increasing the frequency of their sexual contacts, or by impulsive actions and sensation seeking. Symptoms associated with ASPD can be treated with opioid antagonists like naltrexone, naloxone, or nalmefene. PMID- 26250443 TI - Confident difference criterion: a new Bayesian differentially expressed gene selection algorithm with applications. AB - BACKGROUND: Recently, the Bayesian method becomes more popular for analyzing high dimensional gene expression data as it allows us to borrow information across different genes and provides powerful estimators for evaluating gene expression levels. It is crucial to develop a simple but efficient gene selection algorithm for detecting differentially expressed (DE) genes based on the Bayesian estimators. RESULTS: In this paper, by extending the two-criterion idea of Chen et al. (Chen M-H, Ibrahim JG, Chi Y-Y. A new class of mixture models for differential gene expression in DNA microarray data. J Stat Plan Inference. 2008;138:387-404), we propose two new gene selection algorithms for general Bayesian models and name these new methods as the confident difference criterion methods. One is based on the standardized differences between two mean expression values among genes; the other adds the differences between two variances to it. The proposed confident difference criterion methods first evaluate the posterior probability of a gene having different gene expressions between competitive samples and then declare a gene to be DE if the posterior probability is large. The theoretical connection between the proposed first method based on the means and the Bayes factor approach proposed by Yu et al. (Yu F, Chen M-H, Kuo L. Detecting differentially expressed genes using alibrated Bayes factors. Statistica Sinica. 2008;18:783-802) is established under the normal-normal-model with equal variances between two samples. The empirical performance of the proposed methods is examined and compared to those of several existing methods via several simulations. The results from these simulation studies show that the proposed confident difference criterion methods outperform the existing methods when comparing gene expressions across different conditions for both microarray studies and sequence-based high-throughput studies. A real dataset is used to further demonstrate the proposed methodology. In the real data application, the confident difference criterion methods successfully identified more clinically important DE genes than the other methods. CONCLUSION: The confident difference criterion method proposed in this paper provides a new efficient approach for both microarray studies and sequence-based high-throughput studies to identify differentially expressed genes. PMID- 26250444 TI - Multivariate Markov models for the conditional probability of toxicity in phase II trials. AB - In addition to getting a preliminary assessment of efficacy, phase II trials can also help to determine dose(s) that have an acceptable toxicity profile over repeated cycles as well as identify subgroups with particularly poor toxicity profiles. Correct modeling of the dose-toxicity relationship in patients receiving multiple cycles of the same dose in oncology trials is crucial. A major challenge lies in taking advantage of the conditional nature of data collection, that is each cycle is observed conditional on having no previous toxicities on earlier cycles. We develop a novel and parsimonious model for the probability of toxicity during a kth cycle of therapy, conditional on not seeing toxicity in any of the k-1 previous cycles using a Markov model, hereafter we refer to these probabilities as conditional probabilities of toxicity. Our model allows the conditional probability of toxicity to depend on randomized dose group, cumulative dose from prior cycles, a measure of how consistently a patient responds to the same dose exposure and individual risk factors influencing the ability to tolerate the treatment regimen. Simulations studying finite sample properties of the model are given. Finally, the approach is demonstrated in a phase II trial studying two dose levels of ifosfamide plus doxorubicin and granulocyte colony-stimulating factor in soft tissue sarcoma patients over four cycles. The Markov model provides correct estimates of the probabilities of toxicity in finite sample simulations. It also correctly models the data from the phase II clinical trial, and identifies particularly high cumulative toxicity in females. PMID- 26250445 TI - Magnetic core/shell Fe3O4/Au nanoparticles for studies of quinolones binding to protein by fluorescence spectroscopy. AB - Magnetic core/shell Fe3O4/Au nanoparticles were used in the determination of drug binding to bovine serum albumin (BSA) using a fluorescence spectroscopic method. The binding constants and number of binding sites for protein with drugs were calculated using the Scatchard equation. Because of their superparamagnetic and biocompatible characteristics, magnetic core/shell Fe3O4/Au nanoparticles served as carrier proteins for fixing proteins. After binding of the protein to a drug, the magnetic core/shell Fe3O4/Au nanoparticles-protein-drug complex was separated from the free drug using an applied magnetic field. The free drug concentration was obtained directly by fluorescence spectrometry and the proteins did not influence the drug determination. So, the achieved number of binding sites should be reliable. The binding constant and site number for ciprofloxacin (CPFX) binding to BSA were 2.055 * 10(5) L/mol and 31.7, and the corresponding values for norfloxacin (NOR) binding to BSA were 1.383 * 10(5) L/mol and 38.8. Based on the achieved results, a suitable method was proposed for the determination of binding constants and the site number for molecular interactions. The method was especially suitable for studies on the interactions of serum albumin with the active ingredients of Chinese medicine. PMID- 26250447 TI - Promising Targets for the Treatment of Neurodegenerative Diseases. AB - Genetics and pathology have proven to be an effective combination to identify an evolving and deepening landscape of pathways and potential therapeutic targets in neurodegenerative diseases. Initially this landscape appeared to be populated with distinct therapeutic targets but with potentially overlapping mechanisms in each neurodegenerative disease. Our understanding has expanded to recognize that multiple pathologies are common in neurodegenerative disease, and that there is considerable overlap in pathways and targets driving neurodegenerative diseases. This potentially opens the way for future treatments to be indicated by tissue pathology and genetic basis rather than clinical phenotype. The potential to treat neurodegenerative disease by addressing underlying pathophysiology is still in the early days and challenges remain, especially the likely need to address pathologies early in disease. This will require redefinition of diagnosis and the tools to enable earlier diagnosis. PMID- 26250446 TI - The RNA-binding properties and domain of Rice stripe virus nucleocapsid protein. AB - The nucleocapsid protein (NP) of rice stripe virus (RSV) encapsidates viral genomic RNAs to form virion. The binding of NP with RNA is essential for the formation of virus particle. In this study, the binding specificity of RSV NP to RNA and the domains within the NP that mediate this interaction were investigated by gel electrophoretic mobility shift assays and Northwestern blot analysis. The results demonstrated that RSV NP was able to bind to all synthetic RNAs and DNAs without sequence specificity. Using a series of truncated NPs expressed in E. coli and synthetic peptides, we mapped the RNA-binding domain of NP to the central region from amino acid residues 201-232. Further alanine substitution analysis revealed that Lys(206), Lys(207), Lys(220), and Tyr(221) in the RNA binding domain were essential for NP to bind with RNA. PMID- 26250449 TI - Triazine herbicide imprinted monolithic column for capillary electrochromatography. AB - Trietazine was selectively separated from aqueous solution containing the competitor molecule cyanazine, which is similar in size and shape to the template molecule. Structural features of the molecularly imprinted column were figured out by SEM. The influence of the mobile-phase composition, applied electrical field, and pH of the mobile phase on the recognition of trietazine by the imprinted monolithic polymer has been evaluated, and the imprint effect in the trietazine-imprinted monolithic polymer was demonstrated by an imprinting factor. The optimized monolithic column resulted in separation of trietazine from a structurally related competitor molecule, cyanazine. In addition, fast separation was obtained within 6 min by applying higher electrical field, with the electrophoretic mobility of 2.97 * 10(-8) m(2) V(-1) s(-1) at pH 11.0. PMID- 26250448 TI - FLAIR Vascular Hyperintensity is a Surrogate of Collateral Flow and Leukoaraiosis in Patients With Acute Stroke Due to Proximal Artery Occlusion. AB - BACKGROUND: Fluid attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH) is a novel radiographic marker detected in acute ischemic stroke (AIS) patients, which is linked to slow blood flow and potentially salvageable brain tissue. Poor leptomeningeal collateral status in AIS patients with proximal artery occlusion (PAO) is associated with larger final infarct and worse clinical outcomes, which are also affected by severity of white matter hyperintensity (WMH). We sought to evaluate FVH utility as a marker of acute collateral vessel status and its association with WMH burden in AIS patients. METHODS: Consecutive AIS patients with PAO on baseline CT angiography (CTA) were retrospectively selected from a prospectively derived database. FVH was graded by its location, degree, and score on admission MRI obtained immediately after intravenous tissue plasminogen activator administration. Leptomeningeal collateral flow grade was ranked on admission CTA. WMH volume (WMHV) was assessed using a validated volumetric protocol. Relationship between FVH, collateral flow grade, and WMHV were analyzed. RESULTS: Among 39 patients (mean age 70.5 +/- 12.7 years; 56% women, mean National Institutes of Health Stroke Scale score 17.2 (+/- 4.4)), median WMHV was 6.0 cm(3). FVH score and collateral flow grade were significantly correlated (Spearman's rho = .41, P = .009). In a univariate regression model, FVH degree was inversely associated with WMHV (beta = -.33, P = .04). CONCLUSIONS: FVH score detected on acute MRI can be used as a surrogate of collateral flow grade in AIS patients. FVH degree is inversely associated with WMHV, possibly signifying diffuse disease of cerebral vasculature in patients with severe leukoaraiosis. PMID- 26250450 TI - Responses to Cd Stress in Two Noccaea Species (Noccaea praecox and Noccaea caerulescens) Originating from Two Contaminated Sites in Mezica, Slovenia and Redlschlag, Austria. AB - The two Noccaea species-Noccaea praecox originating from Mezica, Slovenia (Me) (Pb, Zn, Cd pollution) and Noccaea caerulescens from Redlschlag, Austria (Re) (high levels of Ni, Cr, Mg)-were studied to compare Cd accumulation and tolerance. After 120 days of plant cultivation in Cd-contaminated soil (90 mg Cd kg(-1) soil), gas-exchange parameters (e.g. net photosynthetic rate, transpiration rate, stomatal conductance, and intercellular CO2 concentration), fatty acids, and selected macro- and microelements were determined in addition to N utilization by plants. The comparison between ecotypes showed that Cd stress resulted in similar changes in gas-exchange parameters. Contrasting responses of plants to Cd contamination were confirmed by the macro- and microelement contents and fatty acid and amino acid metabolism. Significantly higher accumulations of Cd and strong decreases in the levels of K, Ca, Na, and Fe were observed in the Me plants in contrast to the Re plants. The higher Re plant ability to take in some cations is a result of selective pressure due to contamination. Different ion uptake by plants affected the activities of metalloenzymes. Significant increases in the glutamic acid/proline ratio resulted from higher adaption of the Me in contrast to the Re plants. PMID- 26250451 TI - Maternal Transfer of Bisphenol A During Nursing Causes Sperm Impairment in Male Offspring. AB - The health effects of environmental chemicals on animals and humans are of growing concern. Human epidemiological and animal study data indicate that reproductive disorders and diseases begin early during prenatal and postnatal development. An increase of human male reproductive disturbance in the past several decades was associated to chemicals called endocrine disruptors (ED). Bisphenol A (BPA) is a ubiquitous organic environmental contaminant with ED activity. This study verified the effect of BPA exposure via breast milk during the lactation (early postnatal) period in male mice. Dams were exposed to oral BPA (300, 900, and 3000 ug/kg/BW/day) during the breastfeeding period (21 days). BPA at all concentrations significantly impaired sperm parameters in adult mice (8 months old), but mitochondrial functionality was more affected at BPA 3000. The acrosome membrane parameter was affected by BPA concentrations from 900 to 3000, and DNA integrity showed pronounced impairment at BPA 900 and 3000. BPA 3000 treatment also induced testicular degeneration and complete aplasia in some seminiferous tubules. Testicular oxidative damage was observed, and the total antioxidant capacity was impaired in BPA 900 and 3000 treatment groups. Taken together, the present study demonstrated long-term adverse effects of BPA in male mice, including reduced sperm quality, antioxidant capacity, and changes in testicular tissue. Our results clearly demonstrate the danger of BPA transferred via lactation on sperm quality registered even after a long time-elapsed from exposure to this harmful chemical. PMID- 26250452 TI - Inorganic Contaminants, Nutrient Reserves and Molt Intensity in Autumn Migrant Red-Necked Grebes (Podiceps grisegena) at Georgian Bay. AB - Red-necked grebes (Podiceps grisegena) are piscivorous waterbirds that breed on freshwater lakes in northwestern Canada and stop-over at the Great Lakes during autumn migration to molt feathers and replenish lipid and protein reserves. The objectives of this study were to (1) describe concentrations of, and correlations among, inorganic contaminants in a sample of autumn migrant red-necked grebes from the Great Lakes, (2) compare concentrations of inorganic contaminants to those in autumn migrant common loons from Schummer et al. (Arch Environ Contam Toxicol 62:704, 2011a), (3) evaluate if the inorganic elements are negatively associated with lipid and protein reserves, and (4) determine if nutrient reserves and molt intensity were correlated. None of the 14 contaminants analyzed were above threshold levels known to cause acute health problems in piscivorous birds. Body masses of plucked birds were within the normal reported range. Lipid reserves varied positively with hepatic concentrations of arsenic, copper, iron, nickel, lead, and selenium and negatively with mercury and magnesium. Protein reserves variety negatively with hepatic concentrations of arsenic, calcium, nickel, lead, and zinc and positively with aluminum, cadmium, and iron. A negative correlation was observed between chest molt and lipid reserves but not between nutrient reserves and other feather tracts. The relationships between lipid reserves and both mercury and selenium were consistent with current research on other piscivorous waterbirds at the Great Lakes and justify continued work to determine interactions of these contaminants in waterbirds that breed, stage, and winter in the region. PMID- 26250453 TI - Symmetric and asymmetric expansion of molars using a Burstone-type transpalatal arch. Biomechanical and clinical analysis. AB - OBJECTIVES: A transpalatal arch (TPA) directly connecting the maxillary first molars can be used in passive (for stabilization) and active (for molar or segment movement) modes. Activation may be symmetric or asymmetric. This study was performed to analyze the effectiveness of TPAs for transverse expansion treatment by measuring both the force systems they deliver and the clinical tooth movements thus achieved. MATERIALS AND METHODS: Ten patients (six with symmetric and four with asymmetric transverse discrepancies) were treated using a TPA made of titanium-molybdenum alloy (TMA) and fitted with 0.032" * 0.032" Burstone lingual brackets. The force systems exerted by these TPAs and the resultant tooth movements were first simulated and measured inside the orthodontic measurement and simulation system (OMSS). All TPAs, whether used in the symmetric or asymmetric activation mode, were adjusted to an expansive force of 4 N. After a treatment of 12 weeks, their effectiveness was analyzed by comparing the clinical tooth movements to the movements simulated in the OMSS. RESULTS: Clinically, the symmetric treatments resulted in a mean correction of 4.5 +/- 1.0 mm and a mean of buccal crown tipping of 10.1 degrees , compared to 9.6 degrees for the movements simulated in the OMSS. The four cases of unilateral crossbite were treated with an asymmetrically activated TPA (including a force on one side and a combination of force and negative torque on the other side). The intended unilateral expansion was achieved in all four cases. Vertical side effects were acceptably small in both the symmetric and the asymmetric treatment cases. The tooth movements could be implemented as planned in all 10 patients, whereby in 5 patients complete correction of the occlusal width discrepancy was achieved by the end of the 12-week treatment. CONCLUSION: Given this combination of good efficacy and minor side effects, the TMA/TPA appliance may be recommended as a suitable approach to correct transverse discrepancies. Recommendations expressed in previous studies for the use of Burstone-type TMA/TPA in these situations is confirmed by our study. PMID- 26250454 TI - Effects of different orthodontic primers on enamel demineralization around orthodontic brackets. AB - AIM: The purpose of this work is to evaluate the effectiveness of one self etching and two filled orthodontic primers on enamel demineralization around orthodontic brackets. METHODS: Brackets were bonded to 84 bovine teeth and the vestibular enamel surfaces covered with acid-resistant nail varnish exposing 1 mm of space on each side of the bracket base. The teeth were allocated to four groups, using either Transbond XT conventional primer on etched enamel (group 1), Transbond Plus Self-Etching Primer on untreated enamel (group 2), Pro Seal filled resin primer on etched enamel (group 3), or Opal Seal filled resin primer on etched enamel (group 4). Each tooth was subjected to 15,000 strokes of brushing followed by exposure to an acid challenge. Calcium-ion release from each sample was calculated using atomic absorption spectrophotometry. Data were analyzed using one-way ANOVA and a post hoc Tukey test. Differences were considered statistically significant at p <= 0.05. RESULTS: Statistically significant differences were observed between the four groups (p < 0.001). No significant difference was found between the controls (group 1) and the Opal Seal group. Higher calcium release was observed in the Pro Seal group and the self-etching primer group compared to the controls. The highest calcium release was recorded in the self-etching primer group. CONCLUSION: Filled sealants may not have a protective effect against enamel demineralization. Transbond Plus Self-Etching Primer should be used cautiously, considering the risk of demineralization involved in its application. PMID- 26250455 TI - Optical 3D scans for orthodontic diagnostics performed on full-arch impressions. Completeness of surface structure representation. AB - OBJECTIVE: The purpose of this work was to evaluate the completeness of surface structure representation offered by full-arch impression scans in different situations of tooth (mal)alignment and whether this completeness could be improved by performing rescans on the same impressions reduced sequentially to different levels of gingival height and by adding extra single scans to the number of single scans recommended by the manufacturer. METHODS: Three pairs of full-arch resin models were used as reference, characterized either by normal occlusion, by anterior diastematic protrusion (and edentulous spaces in the lower posterior segments), or by anterior crowding. An alginate impression of each arch was taken and digitized with a structured-light scanner, followed by three rescans with the impression cut back to 10, 5, and 1 mm of gingival height. Both the initial scan and the rescans were performed both with 19 basic single scans and with 10 extra single scans. Each impression scan was analyzed for quantitative completeness relative to its homologous direct scan of the original resin model. In addition, the topography of voids in the resultant digital model was assessed by visual inspection. RESULTS: Compared to the homologous reference scans of the original resin models, completeness of the original impression scans -in the absence of both gingival cutback and extra single scans--was 97.23 +/- 0.066% in the maxilla or 95.72 +/- 0.070% in the mandible with normal occlusion, 91.11 +/- 0.132% or 96.07 +/- 0.109% in the arches with anterior diastematic protrusion, and 98.24 +/- 0.085% or 93.39 +/- 0.146% in those with anterior crowding. Gingival cutback and extra single scans were found to improve these values up to 100.35 +/- 0.066% or 99.53 +/- 0.070% in the arches with normal occlusion, 91.77 +/- 0.132% or 97.95 +/- 0.109% in those with anterior diastematic protrusion, and 98.59 +/- 0.085% or 98.96 +/- 0.146% in those with anterior crowding. CONCLUSION: In strictly quantitative terms, the impression scans did capture relatively large percentages of the total surface. However, the topographic examinations revealed that regions essential for orthodontic model analysis were missing. The malocclusion models were particularly affected. Thus, impression scans performed with structured-light scanners cannot replace scans of positive casts for diagnostic use in orthodontics. PMID- 26250456 TI - Identification of a stable reference area for superimposing mandibular digital models. AB - PURPOSE: The purpose of this retrospective study was to assess the stability of buccal and lingual alveolar bone surfaces for superimposing three-dimensional (3D) digital models of dental casts. MATERIALS AND METHODS: The pre- and posttreatment dental casts and lateral cephalometric radiographs were obtained from 10 adult patients who had undergone orthodontic treatment entailing the extraction of four premolars. Five of them had bilateral mandibular tori and the other 5 patients had no torus. Dental casts were scanned with a three-dimensional (3D) surface scanning system and 3D digital models were reconstructed using 3D reverse modeling software. The pre- and posttreatment digital models were superimposed on the following reference areas by the best-fit method: Area 1, bilateral lingual surfaces of the alveolar process of the posterior teeth; Area 2, the lingual alveolar surface of the anterior and posterior teeth; Area 3, bilateral surfaces of the posterior teeth's buccal and lingual alveolar surfaces; Area 4, bilateral mandibular tori. The horizontal and vertical movements of the mandibular central incisors and first molars were measured on cephalometric radiographs and on the 3D digital models. RESULTS: In the 5 patients without a mandibular torus, the median differences between cephalograms and 3D digital models ranged from 0.8-1.9 mm and the maximum differences from 1.5-10.0 mm. The median and maximum differences between cephalograms and 3D digital models superimposed on Area 2 were greater than those superimposed on Areas 1 and 3. In the patients with mandibular tori, the median differences between cephalograms and 3D digital models were under 1.0 mm, the maximum difference being 0.7 mm. CONCLUSION: The buccal and lingual alveolar surface near the dentition seems to be inappropriate as a reference area for superimposing 3D mandibular digital models of patients without a mandibular torus. Mandibular tori in adult patients are stable structures which can be used as reference areas for the superimposition of 3D mandibular digital models. PMID- 26250457 TI - Engineered cytotoxic T lymphocytes with AFP-specific TCR gene for adoptive immunotherapy in hepatocellular carcinoma. AB - Alpha-fetoprotein (AFP) is overexpressed in hepatocellular carcinoma (HCC) and could serve as a tumor-associated antigen (TAA) and potential target for adoptive immunotherapy. However, low frequency and severe functional impairment of AFP specific T cells in vivo hamper adoptive infusion. TAA-specific T cell receptor (TCR) gene transfer could be an efficient and reliable alternation to generate AFP-specific cytotoxic T lymphocytes (CTLs). Autologous dendritic cells (DC) pulsed with AFP158-166 peptides were used to stimulate AFP-specific CTLs. TCR alpha/beta chain genes of AFP-specific CTLs were cloned and linked by 2A peptide to form full-length TCR coding sequence synthesized into a lentiviral vector. Nonspecific activated T cells were engineered by lentivirus infection. Transgenetic CTLs were evaluated for transfection efficiency, expression of AFP158-166-specific TCR, interferon (IFN)-gamma secretion, and specific cytotoxicity toward AFP+ HCC cells in vitro and in vivo. Flow cytometry revealed the AFP158-166-MHC-Pentamer positive transgenetic CTLs was 9.86 %. The number of IFN-gamma secretion T cells and the specific cytotoxicity toward HpeG2 in vitro and in tumor-bearing NOD/SCID mice were significantly raised in transgenetic CTLs than that of AFP158-166-specific CTLs obtained by peptide-pulsed DCs or control group. TCR gene transfer is a promising strategy to generate AFP158-166-specific CTLs for the treatment of HCC. PMID- 26250458 TI - The critical role of HMGA2 in regulation of EMT in epithelial ovarian carcinomas. AB - The high mobility group A2 (HMGA2), an oncofetal protein, was shown to play a role in tumor development and progression. However, the molecular and clinical role of HMGA2 in epithelial ovarian carcinomas (EOCs) is still unknown. In the present study, EOC cell line SKOV3 was subjected to in vitro assays. Here, our findings showed that HMGA2 was highly expressed in EOC cell line SKOV3. HMGA2 knockdown promoted cell apoptosis and the cleavage of caspase 3, and decreased the B cell lymphoma 2 (Bcl-2)/Bax ratio in SKOV3. Functionally, HMGA2 knockdown resulted in reduction of SKOV3 cell migration and invasion. Mechanically, HMGA2 knockdown affected the occurrence of EMT by increasing E-cadherin gene and protein expression and decreasing the gene and protein expression of N-cadherin, slug, and vimentin. At the same time, HMGA2 also repressed the expression of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9), which was consistent with the decreased invasion capacity. In conclusion, HMGA2 is associated with migration and invasiveness and regulates the progression of EMT in the development of EOC, and HMGA2 gene and protein may be a novel therapeutic target against EOC in the clinical practice. PMID- 26250459 TI - RND1 is up-regulated in esophageal squamous cell carcinoma and promotes the growth and migration of cancer cells. AB - RND1 is reported to control the dynamics of cytoskeleton, cell growth, and survival, and dysregulation of RND1 is involved in the tumorigenesis. However, its expression and functions in the esophageal squamous cell carcinoma (ESCC) are unknown. In the present study, it was found that the expression of RND1 was up regulated in ESCC tissues compared with the adjacent normal tissues. Forced expression of RND1 promoted the growth and migration of ESCC cells, while knocking down the expression of RND1 inhibited the growth, migration, and metastasis of ESCC cells. Molecular mechanism studies showed that RND1 activated ERK signaling. In summary, our study suggested that RND1 plays an important role in the progression of ESCC, and RND1 might be a promising target for the treatment of ESCC. PMID- 26250460 TI - CP-31398 inhibits the growth of p53-mutated liver cancer cells in vitro and in vivo. AB - The tumor suppressor p53 is one of the most frequently mutated genes in hepatocellular carcinoma (HCC). Previous studies demonstrated that CP-31398 restored the native conformation of mutant p53 and trans-activated p53 downstream genes in tumor cells. However, the research on the application of CP-31398 to liver cancer has not been reported. Here, we investigated the effects of CP-31398 on the phenotype of HCC cells carrying p53 mutation. The effects of CP-31398 on the characteristic of p53-mutated HCC cells were evaluated through analyzing cell cycle, cell apoptosis, cell proliferation, and the expression of p53 downstream genes. In tumor xenografts developed by PLC/PRF/5 cells, the inhibition of tumor growth by CP-31398 was analyzed through gross morphology, growth curve, and the expression of p53-related genes. Firstly, we demonstrated that CP-31398 inhibited the growth of p53-mutated liver cancer cells in a dose-dependent and p53 dependent manner. Then, further study showed that CP-31398 re-activated wild-type p53 function in p53-mutated HCC cells, which resulted in inhibitive response of cell proliferation and an induction of cell-cycle arrest and apoptosis. Finally, in vivo data confirmed that CP-31398 blocked the growth of xenografts tumors through transactivation of p53-responsive downstream molecules. Our results demonstrated that CP-31398 induced desired phenotypic change of p53-mutated HCC cells in vitro and in vivo, which revealed that CP-31398 would be developed as a therapeutic candidate for HCC carrying p53 mutation. PMID- 26250461 TI - G6PD downregulation triggered growth inhibition and induced apoptosis by regulating STAT3 signaling pathway in esophageal squamous cell carcinoma. AB - There is growing evidence that glucose-6-phosphate dehydrogenase (G6PD) is tightly associated with development and progression of many human tumors. However, its precise molecular mechanisms in esophageal squamous cell carcinoma (ESCC) remain unknown. In the current study, we found that G6PD messenger RNA (mRNA) and protein levels in ESCC cell lines (Eca109, EC1, and EC9706 cells) were significantly higher than that in normal esophageal epithelial cell line Het-1A (P < 0.05) and specific small interfering RNA (siRNA) against G6PD significantly reduced the levels of G6PD mRNA and protein in EC1 cells with highest G6PD levels (P < 0.05). Further investigation revealed that G6PD depletion contributed to the growth suppression in EC1 cells in vitro and EC1 cells xenografted nude mice in vivo, which was associated with the reduces of tumor weight and Ki-67 proliferation index, triggered cell cycle arrest at G0/G1 phase coupled with obvious decreases of cyclin D1 and CDK4 protein levels, and induced cell apoptosis accompanied by the increases of caspase-3 activity and Bax protein expression as well as the decrease of Bcl-2 protein expression in EC1 cells. More importantly, G6PD depletion significantly reduced the level of p-STAT3 protein but did not alter total STAT3 protein level. Taken altogether, our data presented herein suggest that G6PD may function as an important regulator in development and progression of ESCC by manipulating STAT3 signaling pathway and thus may be an underlying molecular target for therapy of the patients with ESCC. PMID- 26250462 TI - Concurrent effects of ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp genetic polymorphisms with risk of cancer, clinical output, and response to treatment with imatinib mesylate in patients with chronic myeloid leukemia. AB - There are a paucity and contradicted data about the impact of concurrent heredity of polymorphic genes and risk of chronic myeloid leukemia (CML). In the present study, the concurrent effects of three polymorphisms affecting the integrity of DNA consist of ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp on development of chronic myeloid leukemia were studied. Furthermore, the role of these polymorphisms in clinical and laboratory outcomes of patients was evaluated. In this case-control study, 70 CML patients and 140 healthy individuals were enrolled in the study. The clinical features of patients such as phase of disease and response to treatment and laboratory data before and after treatment with imatinib mesylate were collected. ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp single nucleotide polymorphisms were evaluated by restriction fragment length polymorphism-polymerase chain reaction. The T allele of ABCB1 C3435T, T allele of XRCC1 Arg194Trp, and C allele of ABCG2 C421A polymorphisms were significantly higher in patients than controls. TT genotype of ABCB1 and TT genotype of XRCC1 were associated with higher risk of chronic myeloid leukemia development. CC421 ABCG2/TT3435 ABCB1 and CC421 ABCG2/TT27157 XRCC1 were also correlated with a higher risk of CML. Patients with C allele of ABCB1 had poor cytogenetic response, and correlation of CC421 ABCG2/TT3435 ABCB1 diplotype with accelerated phase of CML was significant. Patients with CC421 ABCG2/TT3435 ABCB1 and CC421 ABCG2/TT27157 XRCC1 diplotypes might be at higher risk to rapid and severe development of CML and have weaker response to treatments with imatinib. PMID- 26250463 TI - The adaptor protein CrkII regulates IGF-1-induced biological behaviors of pancreatic ductal adenocarcinoma. AB - Recently, the adaptor protein CrkII has been proved to function in initiating signals for proliferation and invasion in some malignancies. However, the specific mechanisms underlying insulin-like growth factor 1 (IGF-1)-CrkII signaling-induced proliferation of pancreatic ductal adenocarcinoma (PDAC) were not unraveled. In this work, PDAC tissues and cell lines were subjected to in vitro and in vivo assays. Our findings showed that CrkII was abundantly expressed in PDAC tissues and closely correlated with tumor-node-metastasis (TNM) stage and invasion. When cells were subjected to si-CrkII, si-CrkII inhibited IGF-1 mediated PDAC cell growth. In vitro, we demonstrated the upregulation of CrkII, p Erk1/2, and p-Akt occurring in IGF-1-treated PDAC cells. Conversely, si-CrkII affected upregulation of CrkII, p-Erk1/2, and p-Akt. In addition, cell cycle and in vivo assay identified that knockdown of CrkII inhibited the entry of G1 into S phase and the increase of PDAC tumor weight. In conclusion, CrkII mediates IGF-1 signaling and further balanced PDAC biological behaviors via Erk1/2 and Akt pathway, which indicates that CrkII gene and protein may act as an effective target for the treatment of PDAC. PMID- 26250464 TI - Original Protocol Using Computed Tomographic Angiography for Diagnosis of Brain Death: A Better Alternative to Standard Two-Phase Technique? AB - BACKGROUND The application of computed tomographic angiography (CTA) for the diagnosis of brain death (BD) is limited because of the low sensitivity of the commonly used two-phase method consisting of assessing arterial and venous opacification at the 60th second after contrast injection. The hypothesis was that a reduction in the scanning delay might increase the sensitivity of the test. Therefore, an original technique using CTA was introduced and compared with catheter angiography as a reference. MATERIAL AND METHODS In a prospective multicenter trial, 84 clinically brain-dead patients were examined using CTA and catheter angiography. The sensitivities of original CTA technique, involving an arterial assessment at the 25th second and a venous assessment at the 40th second, and the standard CTA, involving an arterial and venous assessment at the 60th second, were compared to catheter angiography. RESULTS Catheter angiography results were consistent with the clinical diagnosis of BD in all cases. In comparison to catheter angiography, the sensitivity of original CTA technique was 0.93 (95%CI, 0.85-0.97; p<0.001) and 0.57 (95%CI, 0.46-0.68; p<0.001) for the standard protocol. The differences were statistically significant (p=0.03 for original CTA and p<0.001 for standard CTA). Decompressive craniectomy predisposes to a false-negative CTA result with a relative risk of 3.29 (95% CI, 1.76-5.81; p<0.001). CONCLUSIONS Our original technique using CTA for the assessment of the cerebral arteries during the arterial phase and the deep cerebral veins with a delay of 15 seconds is a highly sensitive test for the diagnosis of BD. This method may be a better alternative to the commonly used technique. PMID- 26250465 TI - Neural Firing in the Prefrontal Cortex During Alcohol Intake in Alcohol Preferring "P" Versus Wistar Rats. AB - BACKGROUND: Neural activity within the prefrontal cortex (PFC) is altered by alcohol and alcohol-associated stimuli and is mediated by genetic susceptibility to alcoholism. However, very little is known about how genetic risk of excessive drinking might mediate neural firing in the PFC during alcohol consumption. METHODS: To determine how genetic risk influences alcohol seeking, intake, and neural activity, a Pavlovian alcohol consumption task was used-the 2-Way Cued Access Protocol (2CAP). Alcohol-preferring "P" rats and relatives of their (heterogeneous) founding Wistar population were used for these studies. After acquisition of 2CAP, extinction of responding for alcohol was evaluated by substituting water for alcohol. Following these experiments, in vivo electrophysiological recordings were obtained during 2CAP from the PFC in a separate cohort of Wistar and P rats implanted with moveable tetrode microdrives. RESULTS: P and Wistar rats increased daily alcohol seeking and intake with P rats consuming roughly twice as much alcohol as Wistar. Both rat populations decreased seeking behavior during extinction. However, P rats displayed persistent increases in seeking after controlling for intake versus Wistar. Higher firing rates (FRs) were observed in P rats prior to 2CAP and throughout alcohol and water consumption compared with Wistars that were matched for alcohol-drinking history. Differences in FR were driven, in part, by a larger percentage of neurons in P rats versus Wistars that increased FR compared with those that decreased, or did not change. CONCLUSIONS: These data provide additional evidence of increased alcohol consumption and persistent alcohol seeking in P versus Wistar rats. Differences in PFC neural firing observed in P rats prior to drinking could be heritable and/or related to an enhanced response to alcohol associated contextual cues. FR differences observed during alcohol drinking might be related to an augmented sensitivity of PFC neurons to orally consumed alcohol. PMID- 26250466 TI - Lotic cyprinid communities can be structured as nest webs and predicted by the stress-gradient hypothesis. AB - Little is known about how positive biotic interactions structure animal communities. Nest association is a common reproductive facilitation in which associate species spawn in nests constructed by host species. Nest-associative behaviour is nearly obligate for some species, but facultative for others; this can complicate interaction network topology. Nest web diagrams can be used to depict interactions in nesting-structured communities and generate predictions about those interactions, but have thus far only been applied to cavity-nesting vertebrate communities. Likewise, the stress-gradient hypothesis (SGH) predicts that prevalent biotic interactions shift from competition to facilitation as abiotic and biotic stress increase; this model has been hardly applied to animal communities. Here, both of these models were applied to nest-associative fish communities and extended in novel ways to broaden their applicability. A nest web was constructed using spawning observations over 3 years in several streams in south-western Virginia, USA. Structural equation modelling (SEM) was then implemented through an information-theoretic framework to identify the most plausible nest web topology in stream fish communities at 45 sites in the New River basin of the central Appalachian Mountains, USA. To test the SGH, the per nest reproductive success of 'strong' (nearly obligate) nest associates was used to represent interaction importance. Eigenvectors were extracted from a principal coordinate analysis (PCoA) of proportional species abundances to represent community structure. Both of these metrics were regressed on physical stress, a combination of catchment-scale agricultural land use and stream size (representing spatiotemporal habitat variability). Seventy-one per cent of SEM model evidence supported a parsimonious interaction topology in which strong associates rely on a single host (Nocomis), but not other species. PCoA identified a gradient of community structure dominated by Nocomis and associates, to communities dominated by other reproductive groups. Both metrics of interaction importance responded positively to physical stress. This study demonstrates that nest webs can be useful in a variety of systems and that SEM can be a quantitative extension of this framework. Likewise, the SGH can be used to understand positive interactions in animal communities and can be extended to predict proportional representation of facilitating and beneficiary species in communities. PMID- 26250467 TI - Human papillomavirus type 16 E7 oncoprotein mediates CCNA1 promoter methylation. AB - Human papillomavirus (HPV) oncoproteins drive distinctive promoter methylation patterns in cancer. However, the underlying mechanism remains to be elucidated. Cyclin A1 (CCNA1) promoter methylation is strongly associated with HPV-associated cancer. CCNA1 methylation is found in HPV-associated cervical cancers, as well as in head and neck squamous cell cancer. Numerous pieces of evidence suggest that E7 may drive CCNA1 methylation. First, the CCNA1 promoter is methylated in HPV positive epithelial lesions after transformation. Second, the CCNA1 promoter is methylated at a high level when HPV is integrated into the human genome. Finally, E7 has been shown to interact with DNA methyltransferase 1 (Dnmt1). Here, we sought to determine the mechanism by which E7 increases methylation in cervical cancer by using CCNA1 as a gene model. We investigated whether E7 induces CCNA1 promoter methylation, resulting in the loss of expression. Using both E7 knockdown and overexpression approaches in SiHa and C33a cells, our data showed that CCNA1 promoter methylation decreases with a corresponding increase in expression in E7 siRNA-transfected cells. By contrast, CCNA1 promoter methylation was augmented with a corresponding reduction in expression in E7-overexpressing cells. To confirm whether the binding of the E7-Dnmt1 complex to the CCNA1 promoter induced methylation and loss of expression, ChIP assays were carried out in E7-, del CR3-E7 and vector control-overexpressing C33a cells. The data showed that E7 induced CCNA1 methylation by forming a complex with Dnmt1 at the CCNA1 promoter, resulting in the subsequent reduction of expression in cancers. It is interesting to further explore the genome-wide mechanism of E7 oncoprotein mediated DNA methylation. PMID- 26250468 TI - Telomere length and telomerase activity in non-small cell lung cancer prognosis: clinical usefulness of a specific telomere status. AB - BACKGROUND: Considering previous data and the need to incorporate new biomarkers for the prognosis of solid tumours into the clinic, our aim in this work consists of evaluating the potential clinical use of telomeres and telomerase in non-small cell lung cancer (NSCLC). METHODS: Telomere status was established by determination of telomere length using the Terminal Restriction Fragment length method, and telomerase activity by the Telomeric Repeat Amplification Protocol in 142 NSCLCs and their corresponding control samples, obtained from patients submitted to surgery. Group-oriented curves for disease-free survival were calculated according to the Kaplan-Meier method considering telomere length, T/N ratio (telomere length in tumour to control tissue) and telomerase activity. RESULTS: Overall, tumours had significantly shorter telomeres compared with telomeres in control tissues (P = 0.027). More than 80 % of NSCLCs displayed telomerase activity. Regarding prognosis studies, patients whose tumours showed a mean telomere length (MTL) <7.29 Kb or T/N ratio <0.97 showed a significantly poor clinical evolution (P = 0.034 and P = 0.040, respectively). As result of a Cox multivariate analysis including pathologic state and lymph node dissemination, the MTL and T/N ratio emerged as independent significant prognostic factors. CONCLUSIONS: Telomerase activity was identified as a marker of poor prognosis. The novel finding of this study is the independent prognosis role of a specific telomere status in NSCLC patients. According to our results, telomere function may emerge as a useful molecular tool that allow to select groups of NSCLC patients with different clinical evolution, in order to establish personalized therapy protocols. PMID- 26250470 TI - Response to 'Postoperative analgesia with continuous wound infusion of local anaesthesia vs saline: a double-blind randomized, controlled trial in colorectal surgery'. PMID- 26250471 TI - A New Approach for Copy-Move Detection Based on Improved Weber Local Descriptor. AB - One of the most common image tampering techniques is copy-move; in this technique, one or more parts of the image are copied and pasted in another area of the image. Recently, various methods have been proposed for copy-move detection; however, many of these techniques are not robust to additional changes like geometric transformation, and they are failed to be useful for detecting small copied areas. In this paper, a new method based on point descriptors which are derived from the integration of textural feature-based Weber law and statistical features of the image is presented. In this proposed approach, modified multiscale version of Weber local descriptor is presented to make the method robust versus geometric transformation and detect small copied areas. The results of the experiments showed that our method can detect small copied areas and copy-move tampered images which are influenced by rotation, scaling, noise addition, compression, blurring, and mirroring. PMID- 26250469 TI - Sex hormones have pervasive effects on thymic epithelial cells. AB - The goal of our study was to evaluate at the systems-level, the effect of sex hormones on thymic epithelial cells (TECs). To this end, we sequenced the transcriptome of cortical and medullary TECs (cTECs and mTECs) from three groups of 6 month-old mice: males, females and males castrated at four weeks of age. In parallel, we analyzed variations in the size of TEC subsets in those three groups between 1 and 12 months of age. We report that sex hormones have pervasive effects on the transcriptome of TECs. These effects were exquisitely TEC-subset specific. Sexual dimorphism was particularly conspicuous in cTECs. Male cTECs displayed low proliferation rates that correlated with low expression of Foxn1 and its main targets. Furthermore, male cTECs expressed relatively low levels of genes instrumental in thymocyte expansion (e.g., Dll4) and positive selection (Psmb11 and Ctsl). Nevertheless, cTECs were more abundant in males than females. Accumulation of cTECs in males correlated with differential expression of genes regulating cell survival in cTECs and cell differentiation in mTECs. The sexual dimorphism of TECs highlighted here may be mechanistically linked to the well recognized sex differences in susceptibility to infections and autoimmune diseases. PMID- 26250472 TI - Dysspondyloenchondromatosis (DSC) associated with COL2A1 mutation: Clinical and radiological overlap with spondyloepimetaphyseal dysplasia-Strudwick type (SEMD S). AB - Dysspondyloenchondromatosis (DSC) is a rare skeletal dysplasia characterized by enchondroma-like lesions and anisospondyly. The former leads to discrepancies in limb length, and the latter, to progressive kyphoscoliosis. Two recent cases have highlighted the genetic heterogeneity of DSC, one demonstrating the presence and, the other, the absence of a COL2A1 mutation. This may have important clinical implications, for example, screening for complications including atlanto-axial instability associated with type II collagenopathies, as well as long-term patient management. We report on a case with radiographic features of DSC with overlap into the type II collagenopathy spondyloepimetaphyseal dysplasia, Strudwick type, who was found to carry a novel heterozygous mutation in the COL2A1 gene. Testing for COL2A1 mutations should be performed in all patients with radiological features of DSC. Further research is needed to identify the underlying molecular cause in cases where no COL2A1 mutation is identified. PMID- 26250473 TI - Effects of transcranial direct current stimulation upon attention and visuoperceptual function in Lewy body dementia: a preliminary study. AB - BACKGROUND: Individuals with Lewy body dementia (LBD) typically exhibit impairments in attentional and executive function. Current pharmacological treatments have limited efficacy, with associated side effects. Transcranial direct current stimulation (tDCS) may represent an alternative treatment, as cognitive improvements have been demonstrated in healthy individuals. However, no studies to date have assessed the feasibility of tDCS in an LBD population. The aim of this preliminary study, therefore, was to assess the tolerability of tDCS, as well as its effects upon attentional and visuoperceptual performance, in LBD patients. METHODS: Thirteen participants completed attentional (simple reaction time, choice reaction time, and digit vigilance) and forced-choice visuoperceptual (angle and motion perception) tasks before and after one 20-min session of active tDCS (0.08 mA/cm2). The anodal electrode was applied to the left dorsolateral prefrontal cortex and the cathodal electrode was applied to the right deltoid. Attentional (task accuracy and reaction time to correct answers) and visuoperceptual (task accuracy and difficulty) outcome measures were compared using paired t-tests. RESULTS: All participants tolerated stimulation and did not report any side effects during or immediately after stimulation. Post-stimulation improvements were observed in the choice reaction time (increased percentage of correct answers; p = 0.01) and digit vigilance (reduced mean reaction time to correct answers; p = 0.02) attention tasks. Visuoperceptual task performance did not improve (all p-values > 0.05). CONCLUSIONS: Attentional, but not visuoperceptual, improvements were observed following stimulation in LBD patients. Larger-scale, placebo-controlled trials are needed to confirm whether tDCS is a useful treatment option for attentional deficits in LBD. PMID- 26250475 TI - Robotic general surgery: The current status and a look into the future. PMID- 26250474 TI - Prospective study of DNA methylation at LINE-1 and Alu in peripheral blood and the risk of prostate cancer. AB - BACKGROUND: Evidence suggests that global blood DNA methylation levels may be associated with the risk of various cancers, but no studies have evaluated this relationship for prostate cancer. METHODS: We used pyrosequencing to quantify DNA methylation levels at the long interspersed nuclear element 1 (LINE-1) and Alu repetitive elements in pre-diagnostic blood samples from 694 prostate cancer cases and 703 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We evaluated prostate cancer risk associated with the mean methylation level for each element using logistic regression, adjusting for potential confounders. RESULTS: We did not observe a significant association with prostate cancer for LINE-1 [odds ratio (OR) for the highest compared to the lowest quartile = 1.01, 95% confidence interval (CI): 0.73-1.39, Ptrend = 0.99] or Alu (OR = 0.94, 95% CI: 0.68-1.29, Ptrend = 0.69) methylation levels overall. However, for Alu, we observed that higher DNA methylation levels were associated with a significant increased risk for those diagnosed 4 or more years after blood draw (OR = 2.26, 95% CI: 1.27-4.00, Ptrend = 4.4 * 10(-3) ). In contrast, there was no association for those diagnosed 2 (OR = 1.13, 95% CI: 0.67-1.90, Ptrend = 0.64) or 3 years after draw (OR = 1.22, 95% CI: 0.71-2.07, Ptrend = 0.32), and a decreased risk for those diagnosed less than 2 years after draw (OR = 0.40, 95% CI: 0.25-0.65, Ptrend = 3.8 * 10(-5) ; Pheterogeneity = 5.3 * 10(-6) ). CONCLUSIONS: Although LINE-1 DNA methylation levels were not associated with prostate cancer, we observed an association for Alu that varied by time from blood draw to diagnosis. Our study suggests that elevated Alu blood DNA methylation levels several years before diagnosis may be associated with an increased prostate cancer risk. PMID- 26250476 TI - Human Poisoning Through Atypical Routes of Exposure. AB - There are over 2 million human exposure cases reported to United States poison centers annually. Much of the data involves exposure through ingestion, dermal contact, inhalation, ocular, or parenteral routes. There is limited data characterizing exposure via atypical routes. We conducted a retrospective review of the California Poison Control System Database for a 24-month period from January 2012 to December 2013 for poison exposure that occurred through the otic, vaginal, or rectal route. There were a total of 634 cases involving single-route and single-substance atypical poison exposure. There were 287 (45%) cases of otic exposure, 190 (30.0%) cases of vaginal exposure, and 157 (25%) cases of rectal exposure. Five hundred forty (85%) of the cases were unintentional. Gasoline exposure through the otic route occurred in 83 (13.1%) cases, followed by hydrogen peroxide (4.7%), acetaminophen (3.8%), and miconazole (2.7%). Adverse effects occurred in 336 (53%) cases. No deaths were reported. The most common treatment was observation only, occurring in 396 (62.4%) cases. The majority of the cases did not warrant hospital evaluation (73.5%). This is the first retrospective characterization study of atypical routes of poison exposure. These results may provide education to providers and the public regarding risks of exposure to substances through atypical routes. PMID- 26250477 TI - Effect of gallium aluminium arsenide diode laser therapy on Porphyromonas gingivalis in chronic periodontitis: a randomized controlled trial. AB - OBJECTIVES: The aim of this randomized, controlled trial was to evaluate the effects of 685-nm gallium aluminium arsenide (GaAlAs) diode laser therapy (1.6 J cm-2 ) as an adjunct to scaling and root planing in the treatment of chronic periodontitis. METHODS: Thirty-two patients aged 35-60 years old who had chronic periodontitis met the eligibility criteria. They were randomly assigned to two equal groups: scaling and root planing were performed in the SRP group, while scaling, root planing and laser irradiation of periodontal pockets were performed in the SRP + DL group. Subgingival plaque samples were subjected to polymerase chain reaction (PCR) to detect P. gingivalis-colonized sites, and common clinical indices were evaluated before and 2 months after treatment. Clinical examination included gingival index (GI), plaque index (PI), probing depth (PD), clinical attachment level (CAL) and gingival bleeding index (GBI), all of which were recorded. RESULTS: Data from 30 patients [19 women and 11 men; mean age, 48.4 (5.4) years old] were analysed. There were statistically significant improvements in GI, PD, CAL and GBI for the SRP + DL group compared to SRP group but no significant difference in PI between the groups. Additionally, the percentage of P. gingivalis-positive sites in the SRP + DL group decreased from 80% (12/15) to 20% (3/15) after laser irradiation (P < 0.05). No significant changes were noted in the SRP group. CONCLUSION: GaAlAs diode laser irradiation of diseased periodontal pockets at 685 nm and 1.6 J cm-2 seemed to be an effective adjuvant to mechanical instrumentation to treat chronic periodontitis. PMID- 26250478 TI - Incidence of temporomandibular joint clicking in adolescents with and without unilateral posterior cross-bite: a 10-year follow-up study. AB - Among different malocclusions, posterior cross-bite is thought to have a strong impact on the correct functioning of the masticatory system. The association between unilateral posterior cross-bite (UPCB) and temporomandibular joint (TMJ) clicking, however, remains still controversial. The aim of this study was to investigate whether the presence of UCPB during early adolescence increases the risk of reporting TMJ clicking after a long-term follow-up. A longitudinal survey design was carried out in a group of 12-year-old young adolescents, who were examined at baseline for TMJ clicking sounds and unilateral posterior cross-bite. After 10 years, 519 subjects could be reached by a telephone survey. Standardised questions were used to collect self-reported TMJ sounds and to determine whether participants had received an orthodontic treatment. Logistic regression analysis revealed a significant association between unilateral posterior cross-bite and subjectively reported TMJ clicking (odds ratio = 6.0; 95% confidence limits = 3.4 10.8; P < 0.0001). The incidence of TMJ clicking was 12%. At a ten-year follow up, self-reports of TMJ clicking were significantly associated with the presence of UPCB at baseline, but not with the report of having received an orthodontic treatment. Within the limitation of this study, the presence of unilateral posterior cross-bite in young adolescents may increase the risk of reporting TMJ sounds at a 10-year follow-up. The provision of an orthodontic treatment, however, does not appear to reduce the risk of reporting TMJ sounds. PMID- 26250479 TI - The 4H syndrome due to RNF216 mutation. PMID- 26250480 TI - Cervical length at mid-gestation in screening for preterm birth in twin pregnancy. AB - OBJECTIVE: Short cervical length (CL) in mid-gestation is considered predictive of spontaneous preterm birth (PTB). The medical literature suggests 20 mm as the cut-off for high risk in twin pregnancies. Our objective was to assess the predictive value of CL for spontaneous PTB < 32 weeks' gestation in twin pregnancies and to calculate the cut-off point with the best sensitivity and specificity. METHODS: This was a single-center retrospective cohort study of women in whom CL had been measured by transvaginal ultrasound at 18-23 weeks' gestation. Pregnancies complicated by twin-to-twin transfusion syndrome, those requiring intrauterine therapy or those with indicated PTB were excluded. The predictive value of CL for PTB < 32 weeks was assessed. The distribution of CL measurements and the optimal cut-off in patients with PTB were calculated and logistic regression analysis was performed to assess the association between pregnancy characteristics and PTB. RESULTS: A total of 940 twin pregnancies were included. CL showed an area under the receiver-operating characteristics curve of 0.65 (95% CI, 0.58-0.71) for the prediction of PTB < 32 weeks. The optimal cut off value for predicting PTB was 36 mm (sensitivity, 64.1%; specificity, 62.8%; positive predictive value, 13.5%; negative predictive value, 95.1%; accuracy, 62.9%). The relative risk of PTB with CL <= 36 mm was 2.35 (95% CI, 1.53-3.60; P < 0.001). After adjusting for confounders in logistic regression analysis, only CL (adjusted odds ratio (aOR), 0.94 (95% CI, 0.90-0.99); P = 0.03), and not monochorionicity (aOR 4.14 (95% CI, 0.89-19.25); P = 0.07), was independently associated with PTB. More than one-third (36%) of PTB cases delivering < 32 weeks had a normal CL in mid-gestation. This proportion rose to 85% when considering the 20-mm cut-off suggested by the medical literature. CONCLUSIONS: This study shows that, despite the weak independent association, CL assessed in mid gestation is a poor predictor of PTB < 32 weeks' gestation in asymptomatic twin pregnancies. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26250481 TI - Dermestid Dermatitis in a 2-Year-Old Girl: Case Report and Review of the Literature. AB - Dermatitis from contact with carpet, larder, and hide beetles (family Dermestidae) is a seemingly uncommon or underrecognized hypersensitivity reaction to the specialized hairs on the larvae of certain dermestid beetles. The erythematous papulovesicular dermatitis that may result from such contact can be mistakenly construed as evidence of bites of bedbugs or other arthropods or infestation with scabies mites or can be the basis for a diagnosis of delusory parasitosis. We present a case of dermestid dermatitis in a 2-year-old girl and provide a review of the current literature. PMID- 26250482 TI - Toward intrinsically colored peptides: Synthesis and investigation of the spectral properties of methylated azatryptophans in tryptophan-cage mutants. AB - Tryptophan has been taken as the basic scaffold for a chromophore whose indole residue can be further functionalized by the introduction of endocyclic nitrogen atoms or by N-methylation. When compared with exocyclic modifications, modifying tryptophan in an endocyclic fashion (through atomic substitution) should not perturb the steric profile of the amino acid side chain to such a large extent as that of an exocyclic modification, while simultaneously modulating the polarity, hydrogen-bonding ability, and spectral properties of the amino acid. Of particular interest is that the spectral properties can be tailored such that the chromophore can be monitored at wavelengths that exceed natural protein fluorescence. Ideally, the optimum excitation wavelength should be between 300 and 350 nm, and the emission wavelength should be >=500 nm such that no cross excitation/fluorescence occurs. Here, we report the synthesis of amino acid labels that exhibit large red shifts in their fluorescence profiles and their use in peptides. PMID- 26250483 TI - Metabolism-Guided Bowel Resection: Potential Role and Accuracy of Instant Capillary Lactates to Identify the Optimal Resection Site. AB - BACKGROUND: Strip-based handheld devices can measure lactatemia on capillary blood obtained by needle puncturing. We aimed to assess the kinetic of bowel capillary lactates, metabolomics profiling, and mitochondria respiratory rate in a prolonged model of bowel hypoperfusion. MATERIALS AND METHODS: In 6 pigs, a 3- to 4-cm ischemic segment was created in 6 small bowel loops (total = 36 loops) by clamping the vascular supply, for a duration of 1 to 6 hours. Hourly, 5 blood samples were obtained by puncturing the serosa, and lactates were measured using a handheld analyzer. Samples were made at the following regions of interest (ROIs): center of the ischemic area (1), proximal and distal clinical margins of resection (2a-2b), and vascularized zones (3a-3b). Every hour, surgical biopsies of ROIs were sampled. Activity of bowel mitochondria complexes was measured after 1, 3, and 5 hours of ischemia. Quantification of metabolites was performed on all samples (total N = 180). RESULTS: Capillary lactates were significantly higher at ROI 1 versus ROI 3ab at all time points. After 1 hour lactates at the margins were significantly higher than those at vascularized areas (P = .0095), showing a mismatch between visual assessment and actual perfusion status. From 2 to 6 hours, there was no difference in lactates between ROIs 2a-2b and 3a-3b. Maximal tissue respiration decreased significantly after 1 hour (ROI 1 vs ROI 3ab). Seven metabolites (lactate, glucose, aspartate, choline, creatine, taurine, and tyrosine) expressed significantly different evolutions between ROIs. CONCLUSIONS: Capillary lactates could help precisely estimate local bowel perfusion status. PMID- 26250484 TI - Chronic treatment with Sildenafil has no effect on folliculogenesis or fertility in C57BL/6 and C57BL/6 knockout for iNOS mice. AB - Sildenafil is an important phosphodiesterase inhibitor used to treat a range of diseases, including cardiovascular disease, prostatic hyperplasia and pulmonary hypertension. Its main mechanism of action is the inhibition of phosphodiesterase 5, leading to increased intracellular cyclic guanosine 3',5'-monophosphate. This second messenger plays an interesting role in the reproductive tract. The aim of the present study was to evaluate the effect of Sildenafil on folliculogenesis and fertility in mice. To do so, C57BL/6 wild-type mice and inducible nitric oxide synthase knockout (iNOS(-/-)) mice were treated with Sildenafil, and reproductive variables were evaluated. The treated and control animals underwent estrous cycle and fertility assay. Lipid profile, serum nitric oxide levels and the expression of endothelial nitric oxide synthase, inducible nitric oxide synthase and guanylate cyclase were evaluated. Additionally, ovaries were submitted to histological and morphological analysis. The findings demonstrated that chronic treatment with Sildenafil had no effect on folliculogenesis or fertility in C57BL/6 mice, suggesting that this drug can be safely used by women of childbearing age. PMID- 26250485 TI - Classification of fruits based on anthocyanin types and relevance to their health effects. AB - Anthocyanins are a group of water-soluble pigments that confer the blue, purple, and red color to many fruits. Anthocyanin-rich fruits can be divided into three groups based on the types of aglycones of their anthocyanins: pelargonidin group, cyanidin/peonidin group, and multiple anthocyanidins group. Some fruits contain a major anthocyanin type and can serve as useful research tools. Cyanidin glycosides and peonidin glycosides can be metabolically converted to each other by methylation and demethylation. Both cyanidin and peonidin glycosides can be metabolized to protocatechuic acid and vanillic acid. Pelargonidin-3-glucoside is metabolized to 4-hydroxybenoic acid. On the other hand, phenolic acid metabolites of delphinidin, malvidin, and petunidin glycosides are unstable and can be further fragmented into smaller molecules. A literature review indicates berries with higher cyanidin content, such as black raspberries, chokeberries, and bilberries are more likely to produce an antiinflammatory effect. This observation seems to be consistent with the hypothesis that one or more stable phenolic acid metabolites contribute to the antiinflammatory effects of anthocyanin-rich fruits. More studies are needed before we can conclude that fruits rich in cyanidin, peonidin, or pelargonidin glycosides have better antiinflammatory effects. Additionally, fruit polyphenols other than anthocyanins could contribute to their antiinflammatory effects. Furthermore, blueberries could exert their health effects with other mechanisms such as improving intestinal microbiota composition. In summary, this classification system can facilitate our understanding of the absorption and metabolic processes of anthocyanins and the health effects of different fruits. PMID- 26250486 TI - Effects of selenium supplementation on glucose homeostasis, inflammation, and oxidative stress in gestational diabetes: Randomized, double-blind, placebo controlled trial. AB - OBJECTIVE: To our knowledge, no reports are available indicating the effects of selenium supplementation on metabolic parameters, inflammatory factors, and oxidative stress in gestational diabetes mellitus (GDM). The aim of this study was to assess the effects of selenium supplementation on metabolic status in pregnant women with GDM who were not on oral hypoglycemic agents. METHODS: This randomized, double-blind, placebo-controlled clinical trial was performed with 70 women with GDM. Patients were randomly assigned to receive either 200 MUg selenium supplements as tablet (n = 35) or placebo (n = 35) for 6 wk from weeks 24 to 28 of gestation. Fasting plasma samples were taken at study baseline and after 6 wk of intervention to quantify related variables. RESULTS: Selenium supplementation, compared with placebo, resulted in a significant reduction in fasting plasma glucose (-10.5 +/- 11.9 versus +4.5 +/- 12.9 mg/dL; P < 0.001), serum insulin levels (-1.98 +/- 11.25 versus +5.26 +/- 9.33 MUIU/mL; P = 0.005), homeostasis model of assessment (HOMA)-insulin resistance (-0.84 +/- 2.76 versus +1.47 +/- 2.46; P < 0.001) and a significant increase in quantitative insulin sensitivity check index (+0.008 +/- 0.03 versus -0.01 +/- 0.01; P = 0.009). Additionally, a significant decrease in serum high-sensitivity C-reactive protein (hs-CRP) levels (-791.8 +/- 2271.8 versus +500.5 +/- 2563.3 ng/mL; P = 0.02) was seen after the administration of selenium supplements compared with placebo. Additionally, we observed a significant elevation in plasma glutathione (+52.14 +/- 58.31 versus -39.93 +/- 153.52 MUmol/L; P = 0.002) and a significant reduction in plasma malondialdehyde levels (-0.01 +/- 0.36 versus +0.67 +/- 1.90 MUmol/L; P = 0.04) after consumption of selenium supplements compared with placebo. We did not find any significant effect of taking selenium supplements on HOMA beta-cell function, lipid profiles, plasma nitric oxide, or total antioxidant capacity concentrations. CONCLUSION: Selenium supplementation in pregnant women with GDM demonstrated beneficial effects on glucose metabolism, hs CRP levels, and biomarkers of oxidative stress. PMID- 26250487 TI - Nutritional counseling improves quality of life and preserves body weight in systemic immunoglobulin light-chain (AL) amyloidosis. AB - OBJECTIVE: Malnutrition is associated with mortality and impaired quality of life (QoL) in systemic immunoglobulin light-chain (AL) amyloidosis. The aim of this study was to determine whether nutritional counseling is beneficial to patients with AL. METHODS: In this intervention study (ClinicalTrials.gov Identifier: NCT02055534), 144 treatment-naive outpatients with AL were randomized to usual care (UC; n = 72) and nutritional counseling (NC; n = 72). RESULTS: In the randomized population, although patients in the NC group maintained a stable body weight (weight loss [WL] = 0.6 kg; 95% confidence interval [CI], -1.0 to 2.1; P = 0.214), those in the UC group demonstrated a significant decrease (WL = 2.1 kg; 95% CI, 0.2-4.1; P = 0.003). However, the difference in weight between groups was not significant (mean WL difference = 1.6 kg; 95% CI, -0.7 to 3.9; P = 0.179). Patients in the NC group demonstrated more satisfactory energy intake (>=75% of estimated requirements, odds ratio, 2.18; 95% CI, 1.04-4.57; P = 0.048) and a significant increase in the mental component summary of QoL (Short form-36) at 12 mo (mean difference, 8.1; 95% CI, 2.3-13.9; P = 0.007), which was restored to a mean score of 53 (95% CI, 50-53), over the healthy population norms. NC was also associated with better survival (crude hazard ratio, 0.57; 95% CI, 0.35-0.94; P = 0.028). CONCLUSIONS: In outpatients with AL, NC was helpful in preserving body weight, effective in improving mental QoL, and associated with better survival. PMID- 26250488 TI - Magnetic Alignment of Microelements Containing Cultured Neuronal Networks for High-Throughput Screening. AB - High-throughput screening (HTS) on neurons presents unique difficulties because they are postmitotic, limited in supply, and challenging to harvest from animals or generate from stem cells. These limitations have hindered neurological drug discovery, leaving an unmet need to develop cost-effective technology for HTS using neurons. Traditional screening methods use up to 20,000 neurons per well in 384-well plates. To increase throughput, we use "microraft" arrays, consisting of 1600 square, releasable, paramagnetic, polystyrene microelements (microrafts), each providing a culture surface for 500-700 neurons. These microrafts can be detached from the array and transferred to 384-well plates for HTS; however, they must be centered within wells for automated imaging. Here, we developed a magnet array plate, compatible with HTS fluid-handling systems, to center microrafts within wells. We used finite element analysis to select an effective size of the magnets and confirmed that adjacent magnetic fields do not interfere. We then experimentally tested the plate's centering ability and found a centering efficiency of 100%, compared with 4.35% using a flat magnet. We concluded that microrafts could be centered after settling randomly within the well, overcoming friction, and confirmed these results by centering microrafts containing hippocampal neurons cultured for 8 days. PMID- 26250489 TI - Group visits in the pediatric heart transplant outpatient clinic. AB - The "GVM" has emerged as an alternative to traditional individualized appointments in the ambulatory care setting. We hypothesized that group visits could successfully be utilized in a PHtx clinic. Seven patients, ages 1-18 yr old, and their families participated in a total of 11 group visits in lieu of individualized appointments. Patients were divided into two groups based on whether they were greater or less than one yr post-transplant. Patient/provider satisfaction, medication adherence, and content retention were ascertained via questionnaires and free-response tests. Total clinic throughput time, including per-patient clinic utilization time, was compared to historical data. Six of seven patients completed the study with one dropout. Overall satisfaction ratings were 3.98 of 4 with all patients reporting that they would "strongly recommend" group visits to others. Health information retention tests demonstrated improvement between pre- and post-tests in eight of nine (89%) of the group visits. Overall clinic utilization decreased by nearly 50% while providing 70 min of face-to-face time with the provider. Medication adherence neared 100% for all patients. The GVM can be successfully applied to the PHtx population with high patient and provider satisfaction, more face-to-face time, excellent content retention, and greatly improved clinic efficiency. PMID- 26250490 TI - End-of-life care in oxygen-dependent COPD and cancer: a national population-based study. PMID- 26250491 TI - Impact of HIV infection and smoking on lung immunity and related disorders. AB - HIV-infected persons not only have higher rates of smoking than the general population, but are also unusually vulnerable to the associated adverse health effects, both infective and noninfective in origin. Indeed, in the setting of well-organised care and availability of highly active antiretroviral therapy, HIV infected smokers lose more life-years to smoking than to HIV infection per se, presenting a major challenge to healthcare providers. Not surprisingly, the respiratory system is particularly susceptible to the damaging interactive chronic inflammatory and immunosuppressive effects of HIV and smoking, intensifying the risk of the development of opportunistic infections, as well as lung cancer and obstructive lung disorders. The impact of smoking on the immunopathogenesis and frequencies of these respiratory conditions in the setting of HIV infection, as well as on the efficacy of antiretroviral therapy, represent the primary focus of this review. PMID- 26250492 TI - Increased respiratory symptoms in COPD patients living in the vicinity of livestock farms. AB - Several studies have investigated the effect of livestock farm emissions on the respiratory health of local residents, but results are inconsistent. This study aims to explore associations between the presence of livestock farms and respiratory health in an area of high-density livestock farming in the Netherlands. We focused especially on associations between farm exposures and respiratory symptoms within subgroups of potentially susceptible patients with a pre-existing lung disease.In total, 14 875 adults (response rate 53.4%) completed a questionnaire concerning respiratory health, smoking habits and personal characteristics. Different indicators of livestock farm exposures relative to the home address were computed using a geographic information system.Prevalence of chronic obstructive pulmonary disease (COPD) and asthma was lower among residents living within 100 m of a farm (OR 0.47, 95% CI 0.24-0.91 and OR 0.65, 95% CI 0.45 0.93, respectively). However, >11 farms in 1000 m compared to fewer than four farms in 1000 m (fourth quartile versus first quartile) was associated with wheezing among COPD patients (OR 1.71, 95% CI 1.01-2.89). Using general practitioners' electronic medical records, we demonstrated that selection bias did not affect the observed associations.Our data suggest a protective effect of livestock farm emissions on the respiratory health of residents. Nonetheless, COPD patients living near livestock farms reported more respiratory symptoms, suggesting an increased risk of exacerbations. PMID- 26250493 TI - Unravelling the complexity of COPD by microRNAs: it's a small world after all. AB - Chronic obstructive pulmonary disease (COPD) is a progressive lung disease and is currently the fourth leading cause of death worldwide. Chronic inflammation and repair processes in the small airways are characteristic of COPD. Despite extensive efforts from researchers and industry, there is still no cure for COPD, hence an urgent need for new therapeutic alternatives. MicroRNAs are such an option; they are small noncoding RNAs involved in gene regulation. Their importance has been shown with respect to maintaining the balance between health and disease. Although previous reviews have discussed the expression of microRNAs related to lung disease, a detailed discussion regarding the function of differential miRNA expression in the pathogenesis of COPD is lacking.In this review we link the expression of microRNAs to different features of COPD and explain their importance in the pathogenesis of this disease. We further discuss their potential to contribute to the development of future therapeutic strategies. PMID- 26250494 TI - New potential diagnostic biomarkers for pulmonary hypertension. AB - This study aimed to determine whether the vascular endothelial growth factor (VEGF) family members soluble VEGF receptor 1 (also called soluble fms-like tyrosine kinase 1 (sFlt-1)) and placental growth factor (PlGF) could be used as biomarkers for pulmonary hypertension (PH). Consecutive patients undergoing right heart catheterisation were enrolled (those with mean pulmonary arterial pressure >=25 mmHg were classed as having PH; those with mean pulmonary arterial pressure <25 mmHg acted as non-PH controls). Plasma from the time of PH diagnosis was analysed for PlGF and sFlt-1 using enzyme immunoassays. In total, 247 patients with PH were enrolled: 62 with idiopathic pulmonary arterial hypertension (IPAH), 14 with associated pulmonary arterial hypertension (APAH), 21 with collagen vascular disease (CVD), 26 with pulmonary venous hypertension, 67 with lung disease-associated PH and 57 with chronic thromboembolic PH. The non-PH control group consisted of 40 patients. sFlt-1 plasma levels were significantly higher in patients with IPAH, APAH, CVD and lung disease-associated PH versus controls; PlGF levels were significantly higher in all PH groups versus controls. The combination of sFlt-1 and PlGF resulted in a sensitivity of 83.7% with specificity of 100% for pulmonary arterial hypertension. There was no association between sFlt-1 or PlGF and haemodynamic parameters, 6-min walking distance or survival. In summary, PlGF and sFlt-1 are promising diagnostic biomarkers for PH. PMID- 26250495 TI - Pulmonary hypertension in idiopathic pulmonary fibrosis with mild-to-moderate restriction. AB - The clinical course of pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) is not known except in advanced disease.488 subjects in a placebo controlled study of ambrisentan in IPF with mild-moderate restriction in lung volume, underwent right heart catheterisation (RHC) at baseline and 117 subjects (24%) had repeated haemodynamic measurements at 48 weeks. The subjects were categorised into a) World Health Organization (WHO) Group 3 PH (PH associated with pulmonary disease), n=68 (14%); b) WHO Group 2 PH (PH associated with left sided cardiac disease), n=25 (5%); c) no PH but elevated pulmonary artery wedge pressure (PAWP), n=21 (4%); and d) no PH but without elevation of PAWP, n=374 (77%). The WHO Group 3 PH subjects had a lower diffusion capacity, 6MWD and oxygen saturation compared to the subjects with no PH. There was no significant change in mean pulmonary arterial pressure with ambrisenten or placebo after 12 months. Subjects with IPF associated with WHO Group 3 PH had impaired gas exchange and exercise capacity compared to patients without PH. An additional 9% of the subjects had haemodynamic evidence of subclinical left-ventricular dysfunction. Pulmonary artery pressures remained stable over 1 year in the majority of the cohort. PMID- 26250496 TI - Time trends in surgery for lung cancer in France from 2005 to 2012: a nationwide study. AB - The aim of this study was to assess the evolution of survival in patients treated surgically for non-small cell lung cancer (NSCLC) between 2005 and 2012.From January 2005 to December 2012, 34 006 patients underwent pulmonary resection for NSCLC and were included in the French national database Epithor. Patients' characteristics, procedures and survival were analysed. Survival according to the management was evaluated for each 2-year period separately: 2005-2006, 2007-2008, 2009-2010 and 2011-2012.The proportions of early-stage cancers and adenocarcinomas increased significantly over the periods. 3-year overall survival (OS) increased significantly from 80.5% for the first period to 81.4% for the last period. For the periods 2005-2006 and 2007-2008, 3-year OS was lower after segmentectomy than after lobectomy (77 and 73% versus 82 and 83%, respectively). For the periods 2009-2010 and 2011-2012, 3-year OS in the two sub-groups was similar. OS after bi-lobectomy or pneumonectomy was lower than after lobectomy for all periods analysed. Systematic nodal dissection increased OS for all periods. Chemotherapy but not radiotherapy improved OS in the first 12 postoperative months for all periods.Changes in histological type and stage linked to advances in surgical and medical practices since 2005 led to an increase in OS in patients with surgical-stage NSCLC. PMID- 26250497 TI - Biomarkers for risk of developing active tuberculosis in contacts of TB patients: a prospective cohort study. AB - Identifying those Mycobacterium tuberculosis latent-infected individuals most at risk of developing active tuberculosis (TB) using routine clinical and laboratory tests remains a huge challenge in TB control efforts. We conducted a prospective longitudinal study of clinical and laboratory markers associated with the risk of developing active TB in contacts with latent M. tuberculosis infection.HIV negative household contacts (n=296) of pulmonary TB patients underwent monitoring of clinical features, full blood cell counts, tuberculin skin text (TST) and chest radiography performed regularly during 18 months of follow-up. Paired statistical tests, a Kaplan-Meier analysis and Cox proportional hazard modelling were performed on variables between contacts progressing or not progressing to active TB.The appearance of TB disease symptoms in contacts was significantly associated with an elevated peripheral percentage of blood monocytes (adjusted hazard ratio (aHR) 6.25, 95% CI 1.63-23.95; p<0.01), a >=14 mm TST response (aHR 5.72, 95% CI 1.22-26.80; p=0.03) and an increased monocyte:lymphocyte ratio (aHR 4.97, 95% CI 1.3-18.99; p=0.03). Among contacts having TST >=14 mm, a strong association with risk of progression to TB was found with an elevated blood monocyte percentage (aHR 8.46, 95% CI 1.74-41.22; p<0.01).Elevated percentage of peripheral blood monocytes plus an elevated TST response are potential biomarkers for identifying contacts of TB patients at highest risk of developing active TB. PMID- 26250498 TI - Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence. AB - Chronic obstructive pulmonary disease (COPD) is punctuated by episodes of infection-driven acute exacerbations. Despite the life-threatening nature of these exacerbations, the underlying mechanisms remain unclear, although a high number of neutrophils in the lungs of COPD patients is known to correlate with poor prognosis. Interleukin (IL)-22 is a cytokine that plays a pivotal role in lung antimicrobial defence and tissue protection. We hypothesised that neutrophils secrete proteases that may have adverse effects in COPD, by altering the IL-22 receptor (IL-22R)-dependent signalling.Using in vitro and in vivo approaches as well as reverse transcriptase quantitative PCR, flow cytometry and/or Western blotting techniques, we first showed that pathogens such as the influenza virus promote IL-22R expression in human bronchial epithelial cells, whereas Pseudomonas aeruginosa, bacterial lipopolysaccharide or cigarette smoke do not. Most importantly, neutrophil proteases cleave IL-22R and impair IL-22 dependent immune signalling and expression of antimicrobial effectors such as beta-defensin-2. This proteolysis resulted in the release of a soluble fragment of IL-22R, which was detectable both in cellular and animal models as well as in sputa from COPD patients with acute exacerbations.Hence, our study reveals an unsuspected regulation by the proteolytic action of neutrophil enzymes of IL-22 dependent lung host response. This process probably enhances pathogen replication, and ultimately COPD exacerbations. PMID- 26250499 TI - Molecular and clinical diseasome of comorbidities in exacerbated COPD patients. AB - The frequent occurrence of comorbidities in patients with chronic obstructive pulmonary disease (COPD) suggests that they may share pathobiological processes and/or risk factors.To explore these possibilities we compared the clinical diseasome and the molecular diseasome of 5447 COPD patients hospitalised because of an exacerbation of the disease. The clinical diseasome is a network representation of the relationships between diseases, in which diseases are connected if they co-occur more than expected at random; in the molecular diseasome, diseases are linked if they share associated genes or interaction between proteins.The results showed that about half of the disease pairs identified in the clinical diseasome had a biological counterpart in the molecular diseasome, particularly those related to inflammation and vascular tone regulation. Interestingly, the clinical diseasome of these patients appears independent of age, cumulative smoking exposure or severity of airflow limitation.These results support the existence of shared molecular mechanisms among comorbidities in COPD. PMID- 26250500 TI - Simultaneous in vivo comparison of water-filled and air-filled pressure measurement catheters: Implications for good urodynamic practice. AB - AIMS: This study aimed to evaluate whether the pressure readings obtained from air-filled catheters (AFCs) are the same as the readings from simultaneously inserted water-filled catheters (WFCs). It also aimed to make any possible recommendations for the use of AFCs to conform to International Continence Society (ICS) Good Urodynamic Practices (GUP). METHODS: Female patients undergoing urodynamic studies in a single center had water-filled and air-filled catheters simultaneously measuring abdominal and intravesical pressure during filling with saline and during voiding. The pressures recorded by each system at each event during the test were compared using paired t-test and Bland-Altman analyses. RESULTS: 62 patients were recruited, of whom 51 had pressures that could be compared during filling, and 23 during voiding. On average, the pressures measured by the two systems were not significantly different during filling and at maximum flow, but the values for a given patient were found to differ by up to 10 cmH2 O. CONCLUSIONS: This study shows that AFCs and WFCs cannot be assumed to register equal values of pressure. It has further shown that even when the pdet readings are compared with their value at the start of a test, a divergence of values of up to 10 cmH2 O remains. If AFCs are used, care must be taken to compensate for any pdet variations that occur during patient movement. Before AFCs are adopted, new normal values for resting pressures need to be developed to allow good quality AFC pressure readings to be made. Neurourol. Urodynam. 35:926-933, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26250501 TI - The effects of muffins enriched with sour cherry pomace on acceptability, glycemic response, satiety and energy intake: a randomized crossover trial. AB - BACKGROUND: Sour cherry pomace (CP), a by-product obtained during fruit processing, was used to replace wheat flour in a muffin formula. The influence of the most sensory acceptable muffins on glycemic response, appetite sensation, and energy intake during subsequent meal in a randomized crossover trial was studied. RESULTS: It is acceptable to incorporate up to 30% CP into muffin formulas. With CP-treated muffins glucose responses were significantly lower at 30, 45, and 60 min intervals, and the incremental peak glucose was 0.40 and 0.60 mmol L(-1) lower than for plain muffins (PM). The CP-enriched muffins showed an incremental area under the blood glucose response curve values lower than that of PM. 20% CP and 30% CP resulted in improved satiety and induced a lower energy intake at a test meal ingested 3 h later (-13.7%; -15.1%) as compared to PM, respectively. CONCLUSION: CP may be a good functional ingredient for bakery products that assists in managing glucose levels, satiety, and subsequent energy intake in healthy individuals. (c) 2015 Society of Chemical Industry. PMID- 26250502 TI - Synthesis and pharmacological evaluation of glycosides of resveratrol, pterostilbene, and piceatannol. AB - To enhance their water solubility and pharmacological activities, the stilbenes resveratrol, pterostilbene, and piceatannol were glycosylated to their monoglucosides (beta-glucosides) and diglycosides (beta-maltosides) by cultured cells and cyclodextrin glucanotransferase (CGTase). Cultured cells of Phytolacca americana and glucosyltransferase (PaGT) were capable of glucosylation of resveratrol to its 3- and 4'-beta-glucosides. Pterostilbene was slightly transformed into its 4'-beta-glucoside by P. americana cells. Piceatannol was readily converted into piceatannol 4'-beta-glucoside, with the highest yield among the three substrates. The 3- and 4'-beta-glucosides of resveratrol were subjected to further glycosylation by CGTase to give 3- and 4'-beta-maltoside derivatives. The inhibitory action of resveratrol and pterostilbene toward histamine release induced with compound 48/80 from rat peritoneal mast cells was improved by beta-glucosylation and/or beta-maltosylation (i.e., the inhibitory activity for histamine release of the 3- and 4'-beta-glucosides of resveratrol, the 3- and 4'-beta-maltosides of resveratrol, and the 4'-beta-glucoside of pterostilbene was higher than that of the corresponding aglycones, resveratrol and pterostilbene, respectively). In addition, the phosphodiesterase (PDE) inhibitory activity of resveratrol and pterostilbene was enhanced by beta glucosylation and/or beta-maltosylation (i.e., the PDE inhibitory activities of the 3- and 4'-beta-glucosides of resveratrol, the 4'-beta-maltoside of resveratrol, and the 4'-beta-glucoside of pterostilbene were higher than those of the corresponding aglycones, resveratrol and pterostilbene, respectively). PMID- 26250503 TI - Academic Medical Centers as digital health catalysts. AB - Emerging digital technologies offer enormous potential to improve quality, reduce cost, and increase patient-centeredness in healthcare. Academic Medical Centers (AMCs) play a key role in advancing medical care through cutting-edge medical research, yet traditional models for invention, validation and commercialization at AMCs have been designed around biomedical initiatives, and are less well suited for new digital health technologies. Recently, two large bi-coastal Academic Medical Centers, the University of California, San Francisco (UCSF) through the Center for Digital Health Innovation (CDHI) and Partners Healthcare through the Center for Connected Health (CCH) have launched centers focused on digital health innovation. These centers show great promise but are also subject to significant financial, organizational, and visionary challenges. We explore these AMC initiatives, which share the following characteristics: a focus on academic research methodology; integration of digital technology in educational programming; evolving models to support "clinician innovators"; strategic academic-industry collaboration and emergence of novel revenue models. PMID- 26250504 TI - Aligning emergency care with the triple aim: Opportunities and future directions after healthcare reform. AB - The Triple Aim of better health, better care, and lower costs has become a fundamental framework for understanding the need for broad health care reform and describing health care value. While the framework is not specific to any clinical setting, this article focuses on the alignment between the framework and Emergency Department (ED) care. The paper explores where emergency care is naturally aligned with each Aim, as well as current barriers which must be addressed to meet the full vision of the Triple Aim. We propose a vision of EDs serving as a nexus for care coordination optimally consistent with the Triple Aim and the requirements for such a role. These requirements include: (1) substantial integration in coordinated care models; (2) development of reliable and actionable data on ED quality, population health, and cost outcomes; (3) specific initiatives to control and optimize ED utilization; and (4) payment models which preserve surge and disaster response capacity. PMID- 26250505 TI - Post-acute referral patterns for hospitals and implications for bundled payment initiatives. AB - BACKGROUND: Under new bundled payment models, hospitals are financially responsible for post-acute care delivered by providers such as skilled nursing facilities (SNFs) and home health agencies (HHAs). The hope is that hospitals will use post-acute care more prudently and better coordinate care with post acute providers. However, little is known about existing patterns in hospitals' referrals to post-acute providers. METHODS: Post-acute provider referrals were identified using SNF and HHA claims within 14 days following hospital discharge. Hospital post-acute care network size and concentration were estimated across hospital types and regions. The 2008 Medicare Provider Analysis and Review claims for acute hospitals and SNFs, and the 100% HHA Standard Analytic Files were used. RESULTS: The mean post-acute care network size for U.S. hospitals included 57.9 providers with 37.5 SNFs and 23.4 HHAs. The majority of these providers (65.7% of SNFs, 60.9% of HHAs) accounted for 1 percent or less of a hospital's referrals and classified as "low-volume". Other post-acute providers we classified as routine. The mean network size for routine providers was greater for larger hospitals, teaching hospitals and in regions with higher per capita post-acute care spending. CONCLUSIONS: The average hospital works with over 50 different post-acute providers. Moreover, the size of post-acute care networks varies considerably geographically and by hospital characteristics. These results provide context on the complex task hospitals will face in coordinating care with post-acute providers and cutting costs under new bundled payment models. PMID- 26250506 TI - Assessing variation in utilization for acute myocardial infarction in New York State. AB - BACKGROUND: Wide variations exist in healthcare expenditures, though most prior studies have assessed aggregate utilization. We sought to examine healthcare utilization variation in New York State by assessing hospitals in peer groups of similar capabilities. METHODS: Using charge data in New York State from the 2008 Statewide Planning and Research Cooperative System (SPARCS) and cost-to-charge ratios at the cost-center level drawn from Institutional Cost Reports, we calculated total, routine, and ancillary costs for patients discharged with an acute myocardial infarction (AMI) diagnosis in 2008. We assessed the correlation of these cost data to Hospital Referral Region (HRR) Medicare reimbursement data from the 2007 Dartmouth Atlas of Health Care. After describing hospital level cost variability, we examined characteristics associated with higher costs within peer groups of similar cardiac care capabilities. RESULTS: We found greater costs in hospitals providing the highest level of cardiovascular services, with cardiac surgery capable hospitals and non-invasive hospitals having total costs of $21,166 and $9268 per AMI discharge, and ancillary costs of $12,006 and $4167 per AMI discharge, respectively. Substantial variability in utilization existed in all levels of hospitals and across individual departmental cost centers. The two factors most frequently associated with higher total and ancillary costs across peer groups were patient case mix index and major or minor teaching status. CONCLUSIONS: Significant variation in cost per AMI discharge exists even within peer groups of hospitals with similar cardiac care capabilities. IMPLICATIONS: These findings support measurement and analysis at the hospital level to further understand the reasons for variation in utilization. PMID- 26250507 TI - The impact of electronic health record implementation on emergency physician efficiency and patient throughput. AB - BACKGROUND: In emergency departments (EDs), the implementation of electronic health records (EHRs) has the potential to impact the rapid assessment and management of life threatening conditions. In order to quantify this impact, we studied the implementation of EHRs in the EDs of a two hospital system. METHODS: using a prospective pre-post study design, patient processing metrics were collected for each ED physician at two hospitals for 7 months prior and 10 months post-EHR implementation. Metrics included median patient workup time, median length of stay, and the composite outcome indicator "processing time." RESULTS: median processing time increased immediately post-implementation and then returned to, and surpassed, the baseline level over 10 months. Overall, we see significant decreases in processing time as the number of patients treated increases. CONCLUSIONS: implementation of new EHRs into the ED setting can be expected to cause an initial decrease in efficiency. With adaptation, efficiency should return to baseline levels and may eventually surpass them. IMPLICATIONS: while EDs can expect long term gains from the implementation of EHRs, they should be prepared for initial decreases in efficiency and take preparatory measures to avert adverse effects on the quality of patient care. PMID- 26250508 TI - Using a mentoring approach to implement an inpatient glycemic control program in United States hospitals. AB - BACKGROUND: establishing an inpatient glycemic control program is challenging, requires years of work, significant education and coordination of medical, nursing, dietary, and pharmacy staff, and support from administration and Performance Improvement departments. We undertook a 2 year quality improvement project assisting 10 medical centers (academic and community) across the US to implement inpatient glycemic control programs. METHODS: the project was comprised of 3 interventions. (1) One day site visit with a faculty team (MD and CDE) to meet with key personnel, identify deficiencies and barriers to change, set site specific goals and develop strategies and timelines for performance improvement. (2) Three webinar follow-up sessions. (3) Web site for educational resources. Updates, challenges, and accomplishments for each site were reviewed at the time of each webinar and progress measured at the completion of the project with an evaluation questionnaire. RESULTS: as a result of our intervention, institutions revised and simplified formularies and insulin order sets (with CHO counting options); implemented glucometrics and CDE monitoring of inpatient glucoses (assisting providers with orders); added new protocols for DKA and perinatal treatment; and implemented nursing, physician and patient education initiatives. Changes were institution specific, fitting the local needs and cultures. As to the extent to which Institution's goals were satisfied: 2 reported "completely", 4 "mostly," 3 "partially," and 1 "marginally". Institutions continue to move toward fulfilling their goals. CONCLUSIONS: an individualized, structured, performance improvement approach with expert faculty mentors can help facilitate change in an institution dedicated to implementing an inpatient glycemic control program. PMID- 26250509 TI - Interview with David Blumenthal, MD, MPP. PMID- 26250510 TI - Interview with Patrick Conway, MD, MSc. PMID- 26250512 TI - Boron nitride zigzag nanoribbons: optimal thermoelectric systems. AB - Conventional and spin related thermoelectric effects in zigzag boron nitride nanoribbons are studied theoretically within the Density Functional Theory (DFT) approach. Nanoribbons with edges passivated with hydrogen, as well as those with bare edges are analyzed. It is shown that one spin channel in the nanoribbons of 0HB-0HN and 2HB-1HN types becomes nonconductive slightly above the Fermi level, and therefore such nanoribbons reveal remarkable spin related thermoelectric phenomena and are promising materials for thermoelectric nanodevices. Thermoelectricity in BN nanoribbons of other types is less efficient and therefore these materials are less interesting for applications. PMID- 26250511 TI - Parental experiences of early postnatal discharge: A meta-synthesis. AB - OBJECTIVE: the aim of this study was to investigate new parents' experiences of early postnatal discharge. DESIGN: a meta-synthesis including 10 qualitative studies was conducted using Noblit and Hare's method of meta-synthesis development. SETTING: qualitative studies performed in western countries from 2003-2013 were included. PARTICIPANTS: the 10 included studies involved 237 mothers and fathers, first time parents as well as multiparous. FINDINGS: we identified four overlapping and mutually dependent themes reflecting the new parents' experiences of early postnatal discharge: Feeling and taking responsibility; A time of insecurity; Being together as a family; and Striving to be confident. The mothers' and fathers' experiences of responsibility, security and confidence in their parental role, were positively influenced by having the opportunity to be together as a family, receiving postnatal care that included both parents, having influence on time of discharge, and getting individualised and available support focused on developing and recognising their own experiences of taking care of the baby. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: the new parents' experiences of early discharge and becoming a parent were closely related. Feeling secure and confident in the parental role was positively or negatively influenced by the organisation of early discharge. This underscores the importance of the way health professionals support new mothers and fathers at early postnatal discharge. PMID- 26250513 TI - Structural insights on complement activation. AB - The proteolytic cleavage of C3 to generate C3b is the central and most important step in the activation of complement, a major component of innate immunity. The comparison of the crystal structures of C3 and C3b illustrates large conformational changes during the transition from C3 to C3b. Exposure of a reactive thio-ester group allows C3b to bind covalently to surfaces such as pathogens or apoptotic cellular debris. The displacement of the thio-ester containing domain (TED) exposes hidden surfaces that mediate the interaction with complement factor B to assemble the C3-convertase of the alternative pathway (AP). In addition, the displacement of the TED and its interaction with the macroglobulin 1 (MG1) domain generates an extended surface in C3b where the complement regulators factor H (FH), decay accelerating factor (DAF), membrane cofactor protein (MCP) and complement receptor 1 (CR1) can bind, mediating accelerated decay of the AP C3-convertase and proteolytic inactivation of C3b. In the last few years, evidence has accumulated revealing that the structure of C3b in solution is significantly more flexible than anticipated. We review our current knowledge on C3b structural flexibility to propose a general model where the TED can display a collection of conformations around the MG ring, as well as a few specialized positions where the TED is held in one of several fixed locations. Importantly, this conformational heterogeneity in C3b impacts complement regulation by affecting the interaction with regulators. PMID- 26250514 TI - Exercise improves adipose function and inflammation and ameliorates fatty liver disease in obese diabetic mice. AB - OBJECTIVE: Adipose inflammation and dysfunction underlie metabolic obesity. Exercise improves glycemic control and metabolic indices, but effects on adipose function and inflammation are less clear. Accordingly, it was hypothesized that exercise improves adipose morphometry to reduce adipose inflammation in hyperphagic obese mice. METHODS: Alms1 mutant foz/foz mice housed in pairs were fed an atherogenic or chow diet; half the cages were fitted with a computer monitored wheel for voluntary exercise. Insulin-induced AKT-phosphorylation, adipocyte size distribution, and inflammatory recruitment were studied in visceral versus subcutaneous depots, and severity of fatty liver disease was determined. RESULTS: Exercise prevented obesity and diabetes development in chow fed foz/foz mice and delayed their onset in atherogenic-fed counterparts. Insulin stimulated phospho-AKT levels in muscle were improved with exercise, but not in adipose or liver. Exercise suppressed adipose inflammatory recruitment, particularly in visceral adipose, associated with an increased number of small adipocyte subpopulations, and enhanced expression of beige adipocyte factor PRDM16 in subcutaneous fat. In atherogenic-fed foz/foz mice liver, exercise suppressed development of nonalcoholic steatohepatitis and related liver fibrosis. CONCLUSIONS: Exercise confers metabo-protective effects in atherogenic fed hyperphagic mice by preventing early onset of obesity and diabetes in association with enhanced muscle insulin sensitivity, improved adipose morphometry, and suppressed adipose and liver inflammation. PMID- 26250515 TI - History of uterine leiomyomata and incidence of breast cancer. AB - PURPOSE: Uterine leiomyomata (UL), benign tumors of the myometrium, are influenced by sex steroid hormones. A history of UL diagnosis has been associated with a higher risk of uterine malignancies. The relation between UL and breast cancer, another hormonally responsive cancer, has not been studied. METHODS: We investigated the association between self-reported physician-diagnosed UL and incidence of breast cancer in the Black Women's Health Study, a prospective cohort study. We followed 57,747 participants without a history of breast cancer from 1995 to 2013. UL diagnoses were reported at baseline and biennially. Breast cancer was reported on biennial questionnaires and confirmed by pathology data from medical records or cancer registries. Cox regression was used to derive incidence rate ratios (IRRs) and 95 % confidence intervals (CI) and adjust for potential confounders. RESULTS: There were 2,276 incident cases of breast cancer (1,699 invasive, 394 in situ, and 183 unknown) during 879,672 person-years of follow-up. The multivariable IRR for the overall association between history of UL and breast cancer incidence was 0.99 (95 % CI 0.90-1.08), with similar results for ER + (IRR = 1.03) and ER - breast cancer (IRR = 1.05). IRRs for early diagnosis of UL (before age 30) were slightly above 1.0, with IRRs of 1.14 (95 % CI 0.99-1.31) for overall breast cancer, 1.14 (95 % CI 0.93-1.40) for ER + breast cancer, and 1.20 (95 % CI 0.89-1.61) for ER - breast cancer. IRRs for early diagnosis of UL were elevated for breast cancer diagnosed before 40 years of age (IRR = 1.39, 95 % CI 0.97-1.99) and premenopausal breast cancer (IRR = 1.26, 95 % CI 1.01-1.58). No consistent patterns in risk were observed across estrogen receptor subtypes, and IRRs did not differ appreciably within strata of BMI, female hormone use, mammography recency, or family history of breast cancer. CONCLUSIONS: The present study of US black women suggests that a history of UL diagnosis is unrelated to the incidence of breast cancer overall. The positive associations observed for early diagnosed UL with breast cancer before age 40 and with premenopausal breast cancer require confirmation in future studies. PMID- 26250518 TI - Synthesis, characterization and evaluation of tinidazole-loaded mPEG-PDLLA (10/90) in situ gel forming system for periodontitis treatment. AB - Traditional in situ gel forming systems are potential applications for parenteral administration but always accompanied with burst release. To overcome this limitation, the tinidazole (TNZ)-loaded in situ gel forming system using a diblock copolymer, monomethoxy poly(ethylene glycol)-block-poly(d,l-lactide) (mPEG-PDLLA), was designed. The formulation of the mPEG-PDLLA-based TNZ in situ gel forming system contained 5% (w/w) TNZ, 0.4% glycerol, 5 ml N-methyl pyrrolidone (NMP) and 35% (w/w) mPEG-PDLLA. The in situ gel forming system showed sustained TNZ release over 192 h with low burst effect (around 7% in the first 8 h) in the in vitro release study. Additionally, in vivo studies were performed on rabbits with ligature-induced periodontitis, and the concentration of TNZ in the gingival crevicular fluid (GCF) as well as the pharmacokinetic parameters was calculated and the pharmacological effect of TNZ-loaded in situ gel forming (mPEG PDLLA)-based system was found effective. Finally, histological studies revealed that the gel was a safe formulation with low irritation. The desirable drug release kinetics combined with the excellent in vivo characteristics highlight the potential of the gel in the treatment of periodontitis. Therefore, these results confirmed that the TNZ-loaded in situ gel forming mPEG-PDLLA-based system could reduce burst release of TNZ and act as a sustained-release and injectable drug depot for periodontitis treatment. PMID- 26250516 TI - Association of diabetes and cancer mortality in American Indians: the Strong Heart Study. AB - PURPOSE: The metabolic abnormalities that accompany diabetes mellitus are associated with an increased risk of many cancers. These associations, however, have not been well studied in American Indian populations, which experience a high prevalence of diabetes. The Strong Heart Study is a population-based, prospective cohort study with extensive characterization of diabetes status. METHODS: Among a total cohort of 4,419 participants who were followed for up to 20 years, 430 cancer deaths were identified. RESULTS: After adjusting for sex, age, education, smoking status, drinking status, and body mass index, participants with diabetes at baseline showed an increased risk of gastric (HR 4.09; 95% CI 1.42-11.79), hepatocellular (HR 2.94; 95% CI 1.17-7.40), and prostate cancer mortality (HR 3.10; 95% CI 1.22-7.94). Further adjustment for arsenic exposure showed a significantly increased risk of all-cause cancer mortality with diabetes (HR 1.27; 95% CI 1.03-1.58). Insulin resistance among participants without diabetes at baseline was associated with hepatocellular cancer mortality (HR 4.70; 95% CI 1.55-14.26). CONCLUSIONS: Diabetes mellitus, and/or insulin resistance among those without diabetes, is a risk factor for gastric, hepatocellular, and prostate cancer in these American Indian communities, although relatively small sample size suggests cautious interpretation. Additional research is needed to evaluate the role of diabetes and obesity on cancer incidence in American Indian communities as well as the importance of diabetes prevention and control in reducing the burden of cancer incidence and mortality in the study population. PMID- 26250517 TI - Mesenchymal fibroblast growth factor receptor signaling regulates palatal shelf elevation during secondary palate formation. AB - BACKGROUND: Palatal shelf elevation is an essential morphogenetic process during secondary palate closure and failure or delay of palatal shelf elevation is a common cause of cleft palate, one of the most common birth defects in humans. Here, we studied the role of mesenchymal fibroblast growth factor receptor (FGFR) signaling during palate development by conditional inactivation of Fgfrs using a mesenchyme-specific Dermo1-Cre driver. RESULTS: We showed that Fgfr1 is expressed throughout the palatal mesenchyme and Fgfr2 is expressed in the medial aspect of the posterior palatal mesenchyme overlapping with Fgfr1. Mesenchyme-specific disruption of Fgfr1 and Fgfr2 affected palatal shelf elevation and resulted in cleft palate. We further showed that both Fgfr1 and Fgfr2 are expressed in mesenchymal tissues of the mandibular process but display distinct expression patterns. Loss of mesenchymal FGFR signaling reduced mandibular ossification and lower jaw growth resulting in abnormal tongue insertion in the oral-nasal cavity. CONCLUSIONS: We propose a model to explain how redundant Fgfr1 and Fgfr2 expression in the palatal and mandibular mesenchyme regulates shelf medial wall protrusion and growth of the mandible to coordinate the craniofacial tissue movements that are required for palatal shelf elevation. PMID- 26250519 TI - Sustained protein release from hydrogel microparticles using layer-by-layer (LbL) technology. AB - CONTEXT AND OBJECTIVES: Since most of developed therapeutic proteins are intended to treat chronic diseases, patients are prescribed multiple injections for long time periods, and therefore, sustained release formulations are much needed. However, challenges facing these formulations are quite significant. In this context, a model protein, lysozyme (Lys), was loaded on hydrogel microparticles (beads) and the ability of layer-by-layer (LbL) coating to control Lys release and maintain its activity over a one-month period was investigated. METHODS: LbL coating was composed of chondroitin sulfate as a negatively charged polyelectrolyte and a biocompatible, hydrolytically degradable poly beta aminoester as a positively charged polyelectrolyte. Loading distribution was monitored by fluorescence imaging, and followed by depositing a series of LbL coatings of different thicknesses. Release of Lys from these formulations was studied and activity of released fraction was determined. RESULTS: Lys was loaded effectively on hydrogel beads achieving about 9 mg protein/100 mg wet spheres. LbL coating was proven successful by monitoring the zeta potential of the beads, which was reversed after the addition of each layer. In vitro release studies showed sustained release profiles that depend on the thickness of the deposited coat, with t50 extended from 4.9 to 143.9 h. More importantly, released Lys possessed a high degree of biological activity during the course of release maintaining at least 72% of initial activity. CONCLUSIONS: Successful loading of Lys and extension of its release while maintaining a considerable degree of activity might make this formulation suitable for use with other active therapeutic proteins. PMID- 26250520 TI - Low luminance deficit and night vision symptoms in intermediate age-related macular degeneration. AB - BACKGROUND/AIMS: To determine the relationship between self-reported visual difficulties under low luminance conditions (night vision symptoms) and visual function measures in intermediate age-related macular degeneration (AMD). METHODS: One hundred participants with bilateral intermediate AMD were examined in a prospective cross-sectional study with visual function measures including best-corrected visual acuity (BCVA), low luminance visual acuity (LLVA) and microperimetry in both eyes. A 10-item Night Vision Questionnaire (NVQ-10) was then used to determine the degree of self-reported night vision symptoms experienced by each participant. For analyses, low luminance deficit (LLD) was derived as the difference between LLVA and BCVA, and microperimetric mean sensitivity (MS; all points) and central sensitivity (CS; points within the central 1 degrees ) were determined. Rasch analysis was used to estimate the person measure of night vision symptoms, and its relationship with visual function parameters was determined. RESULTS: NVQ-10 person measures were significantly associated with LLD (beta coefficient=0.067, 95% CI 0.005 to 0.130, p=0.034), but not BCVA, LLVA, microperimetric MS or CS (p>=0.090). Participants with the highest degree of self-reported night vision symptoms (fourth quartile of person measure) had significantly worse LLD than those with the least difficulty (first quartile of person measure; p=0.019). CONCLUSIONS: In individuals with bilateral intermediate AMD, LLD was associated with self reported night vision symptoms, suggesting that this measure may better capture the visual difficulties experienced by these individuals under low luminance conditions than the conventional measure of photopic visual acuity. PMID- 26250521 TI - Heat stress effects on livestock: molecular, cellular and metabolic aspects, a review. AB - Elevated ambient temperatures affect animal production and welfare. Animal's reduced production performances during heat stress were traditionally thought to result from the decreased feed intake. However, it has recently been shown that heat stress disturbs the steady state concentrations of free radicals, resulting in both cellular and mitochondrial oxidative damage. Indeed, heat stress reorganizes the use of the body resources including fat, protein and energy. Heat stress reduces the metabolic rates and alters post-absorptive metabolism, regardless of the decreased feed intake. Consequently, growth, production, reproduction and health are not priorities any more in the metabolism of heat stressed animals. The drastic effects of heat stress depend on its duration and severity. This review clearly describes about biochemical, cellular and metabolic changes that occur during thermal stress in farm animals. PMID- 26250522 TI - Lutein protects against ischemia/reperfusion injury in rat skeletal muscle by modulating oxidative stress and inflammation. AB - BACKGROUND: Lutein is an antioxidant compound with potential biological effects. The present study investigated the protective role of Lutein against I/R injury in skeletal muscle. METHODS: Animals were divided into three groups. Group I - sham operated; Group II- IR injury- Hind limb ischemia was induced by clamping the common femoral artery and vein. After 4 h of ischemia, the clamp was removed and the animals underwent 2 h of reperfusion. Group III-Lutein + IR injury- Rats with Lutein treatment received intraperitoneal injection 1 h before reperfusion. The skeletal tissues were analyzed for oxidative stress parameters (reactive oxygen species, protein carbonylation and sulfhydryls, lipid peroxidation). Antioxidant status was determined by evaluating Nrf-2 levels and antioxidant enzyme activities. The inflammatory mechanism was determined through NF-kappaB and COX-2 expressions. Pro-inflammatory cytokines were determined by ELISA. RESULTS: The results showed that Lutein treatment significantly decreased the oxidative stress by reducing reactive oxygen species, protein carbonylation and sulphydryls, lipid peroxidation. Further, the levels of Nrf-2 and antioxidant status was significantly declined during IR injury compared to sham operated rats. Lutein treatment reduced the oxidative stress by enhancing Nrf-2 levels and antioxidant status. Skeletal IR injury enhanced the inflammatory signaling by up regulating NF-kappaB, COX-2 and various pro-inflammatory cytokines. NF-kappaB, COX-2 expressions were down regulated by Lutein treatment. CONCLUSION: The study shows that Lutein protects against skeletal IR injury by down regulating oxidative stress and inflammatory mechanisms. PMID- 26250523 TI - Thymosin alpha1 plus routine treatment inhibit inflammatory reaction and improve the quality of life in AECOPD patients. AB - CONTEXT: Thymosin alpha1 (Talpha1) is considered to be a promising immunomodulatory drug and could balance immunity and tolerance in immune tolerance and autoimmunity. OBJECTIVE: To explore the efficacy of Talpha1 plus routine complex treatment in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: Eighty-four AECOPD patients were enrolled and randomized into an experimental group and a control group. All patients received the routine treatment. Additionally, the experimental group received subcutaneous injections of Talpha1 while the control group received placebo. Four weeks later, the curative effect of treatment and immune function of both groups were analyzed. RESULTS: Partial pressures of oxygen (PaO2), PaCO2, and pulmonary function of the experimental group improved after treatment compared to that recorded prior to treatment and that observed for the control group (p < 0.01, both). The CD4(+) T cell count, serum interferon (IFN)-gamma levels, and the ratios of CD4(+)/CD8(+) and IFN-gamma/interleukin (IL)-4 increased in both groups (p < 0.01), while the CD8(+) T cell count and levels of IL-4, IL-8, and leukotrienes B4 (LTB4) decreased as expected (p < 0.01). Meanwhile, the above-mentioned indices of the experimental group improved significantly compared to the indices of the control group (p < 0.05 or 0.01). CONCLUSIONS: Talpha1 plus routine treatment could improve the immune function of AECOPD patients and inhibit the inflammatory reaction, thus reducing the recurrence of chronic obstructive pulmonary disease (COPD). PMID- 26250524 TI - Full-length coding sequences of three major histocompatibility complex class I related chain A alleles, MICA*019, MICA*027 and MICA*045, identified by sequence based typing in Chinese individuals. AB - Full-length coding sequences of three major histocompatibility complex class I related chain A alleles, MICA*019, MICA*027 and MICA*045. PMID- 26250525 TI - Molecular metal-Nx centres in porous carbon for electrocatalytic hydrogen evolution. AB - Replacement of precious platinum with efficient and low-cost catalysts for electrocatalytic hydrogen evolution at low overpotentials holds tremendous promise for clean energy devices. Here we report a novel type of robust cobalt nitrogen/carbon catalyst for the hydrogen evolution reaction (HER) that is prepared by the pyrolysis of cobalt-N4 macrocycles or cobalt/o-phenylenediamine composites and using silica colloids as a hard template. We identify the well dispersed molecular CoNx sites on the carbon support as the active sites responsible for the HER. The CoNx/C catalyst exhibits extremely high turnover frequencies per cobalt site in acids, for example, 0.39 and 6.5 s(-1) at an overpotential of 100 and 200 mV, respectively, which are higher than those reported for other scalable non-precious metal HER catalysts. Our results suggest the great promise of developing new families of non-precious metal HER catalysts based on the controlled conversion of homogeneous metal complexes into solid state carbon catalysts via economically scalable protocols. PMID- 26250526 TI - A fluorescein-labeled AmpC beta-lactamase allows rapid characterization of beta lactamase inhibitors by real-time fluorescence monitoring of the beta-lactamase inhibitor interactions. AB - Rapid emergence of class C beta-lactamases has urged an immediate need for developing class C beta-lactamase specific inhibitors for effective clinical treatment. To facilitate the development of effective class C beta-lactamase inhibitors, we propose a new approach for a rapid analysis of the interaction of AmpC beta-lactamase and its inhibitors using our recently developed V211Cf fluorescent beta-lactamase biosensor during drug screening. Since the fluorescein of V211Cf can report the local environment change in the active site of AmpC beta lactamase, fluorescence responses of V211Cf toward its substrates/inhibitors can provide real-time traces of the dynamic change of the interaction of the beta lactamase with its substrates/inhibitors. In this study, we found that V211Cf displayed distinct fluorescence signal patterns toward different kinds of inhibitors (including clavulanic acid, sulbactam, tazobactam and 2 thiopheneboronic acid) due to the differences in their interactions with beta lactamase. V211Cf not only enables a high throughput screening for inhibitors but can also provide a rapid preliminary indication on the inhibitor's potency and stability to beta-lactamase's hydrolytic action as well as how the inhibitors interact with the target enzyme, thereby speeding up the drug discovery and development cycle of class C beta-lactamase inhibitors. PMID- 26250527 TI - Expression profile of ADAM10 and ADAM17 in allergic rhinitis. AB - BACKGROUND: A disintegrin and metalloprotease (ADAM) is a multifunctional gene family that contributes to the homeostasis of the extracellular matrix, transduction of specific intracellular signals, organogenesis, inflammation, tissue remodeling, adhesion, and cell migration. ADAM17 is the best characterized sheddase, with widespread putative substrates, including various inflammatory modulators. ADAM10 is the most similar ADAM to ADAM17 in terms of both protein sequence and the structural properties of their catalytic domains. The objective of this work was to assess the expression of ADAM10 and ADAM17 in allergic rhinitis to gain insight into their respective roles. METHODS: The expression of ADAM10 and ADAM17 was investigated in the nasal mucosa under allergic and nonallergic conditions. Tissue samples were evaluated by reverse-transcription polymerase chain reaction (RT-PCR) and Western blotting, and data were analyzed semiquantitatively with densitometry. RESULTS: The ADAM17 messenger RNA (mRNA) level was significantly (p < 0.001) lower in the allergic nasal mucosa than in the nonallergic nasal mucosa, whereas the ADAM10 mRNA level was significantly (p < 0.001) lower in the nonallergic nasal mucosa. The ADAM17 protein levels were also significantly (p < 0.001) lower in the allergic nasal mucosa, whereas the ADAM10 protein levels were lower in the nonallergic nasal mucosa (p = 0.002). CONCLUSION: Decreased expression of ADAM17 and increased expression of ADAM10 may contribute to the development of allergic rhinitis through unknown pathways. We suggest that understanding the expression profile of ADAM17 and ADAM10 might help to elucidate the mechanism of allergic rhinitis. PMID- 26250528 TI - Isolation and characterization of L-valine-degrading Candida maltosa DLPU-zpb for D-valine preparation from DL-valine. AB - To develop a practical process for D-valine preparation from DL-valine, L-valine was used as a sole source of carbon and nitrogen in basal minimal medium to isolate L-valine-degrading micro-organisms. A yeast strain DLPU-zpb was obtained, which showed asymmetric degrading activity against DL-valine. Based on the morphology, physiological and biochemical characteristics, and 26S rDNA D1/D2 domain sequence, strain DLPU-zpb was identified as Candida maltosa. The cells of this strain were used as a biocatalyst for eliminating the L-isomer from DL valine. The L-isomer was completely degraded within 72 h under the conditions of 30 degrees C, pH control at 6.0, 200 rev min(-1) and 50 g l(-1) DL-valine. The strain DLPU-zpb degraded L-valine effectively but not D-valine, and thus D-valine could be easily isolated from the resultant reaction mixture, which provides a new method for D-valine preparation from DL-valine. SIGNIFICANCE AND IMPACT OF THE STUDY: D-valine is an important raw material for medicines and its demand is increasing year by year. Several approaches for D-valine preparation have been reported, but none of them are likely to provide product at low cost. A newly isolated L-valine-degrading yeast strain Candida maltosa DLPU-zpb was described, which showed asymmetric degrading activity against DL-valine. Thus, a new and practical process for D-valine preparation from DL-valine could be developed. This is the first report of the asymmetric degrading ability of C. maltosa against DL-valine and D-valine preparation from DL-valine. PMID- 26250530 TI - A new computer-tomography-based method of sex estimation: Development of Turkish population-specific standards. AB - The identification of victims involved in mass fatality incidents has become an increasingly important issue nowadays, and identification of unknown individuals is an important aspect in criminal cases and Disaster Victim Identification scenarios. Therefore, the sex estimation is one of the most important biological attributes towards establishing personal identity. In addition, several studies have demonstrated that metric sex determination methods of the skeleton are population-specific due to variation in size and patterns of sexual dimorphism. Unfortunately, the modern Turkish population still lacks wide and representative population standards for identification. Previous research has shown that modern technologies, such as CT scanning appear to offer promising means for the establishment of new standards for contemporary populations. The main aim of this project is to examine the application of measurements taken from the femur in order to assess sex, as well as to contribute to the establishment of discriminant function equations for the Turkish population for forensic applications. The sample population was composed of CT images taken from 200 adult hospital patients. The images of the femora were segmented from the surrounding bones to ensure correct usage of landmarks as accurately as possible. The 3D reconstructions were then created using the volume-rendering function in OsiriX (v.5.6.). Thirteen measurements were acquired using a 3D viewer and were located and marked on each of the CT reconstructed femora. Thirteen anthropometric parameters were measured and analysed by basic descriptive statistics and discriminant analysis methods using the SPSS 21.0 software package. The intra-observer variation was assessed by obtaining the inter-cross correlation coefficient in order to evaluate the accuracy of the linear measurements taken. The accuracy of sex prediction ranged from 63.5 to 88% with single variables. In stepwise analysis, Epicondylar Breadth, Femur Vertical Diameter of Neck and Medial Lateral Subtrochanteric Diameter were found to be the most discriminating variables providing an accuracy of 91%. Ultimately, it is envisaged that this research study will produce data and interpretations that will inform on and improve standards of sex estimation from postcranial osteometric landmarks. Additionally, this research will consider how this data provides value for a developing discipline of forensic anthropology and how it integrates within the existing systems of criminal investigation and Disaster Victim Identification practices in Turkey. PMID- 26250531 TI - Foreign service special care opportunity in SCDA. AB - : A foreign service clinic in Guatemala caring for patients with special needs was initiated by joining SCDA efforts with the Open Wide Foundation. The trip included five SCDA members: two AEGD residents and three support staff. Open Wide participants included the Executive Director, the Clinical Director in Guatemala, as well as two dentists, dental support staff, and Guatemalan dental students. Two physician anesthesiologists provided general anesthesia. Care adjuncts included general anesthesia, oral sedation, and medical stabilization. LESSONS LEARNED: (1) Conducting a dental clinic for patients with special needs is possible and relatively easy to accomplish, given a partnership with a foundation that agrees with and facilitates this service; (2) advance planning is required to maximize the service provided; (3) committed and flexible team members can accomplish a significant amount of care in a short period of time; and (4) limited but invaluable training of in-country healthcare providers is possible. The Special Care Dentistry Association is long known for service and care delivery to patients with special needs by its members, and for its advocacy and organizational support for these activities. A foreign service opportunity in Guatemala, Central America, was sought out by members of the SCDA to further the outreach efforts of the organization, give members clinical experience in a foreign setting, and train in-country providers to deliver care to patients with special needs. This was the first effort by SCDA members to host a clinic to deliver care specifically to patients with special needs outside of North America. PMID- 26250529 TI - Astrocyte reactivity after brain injury-: The role of galectins 1 and 3. AB - Astrocytes react to brain injury in a heterogeneous manner with only a subset resuming proliferation and acquiring stem cell properties in vitro. In order to identify novel regulators of this subset, we performed genomewide expression analysis of reactive astrocytes isolated 5 days after stab wound injury from the gray matter of adult mouse cerebral cortex. The expression pattern was compared with astrocytes from intact cortex and adult neural stem cells (NSCs) isolated from the subependymal zone (SEZ). These comparisons revealed a set of genes expressed at higher levels in both endogenous NSCs and reactive astrocytes, including two lectins-Galectins 1 and 3. These results and the pattern of Galectin expression in the lesioned brain led us to examine the functional significance of these lectins in brains of mice lacking Galectins 1 and 3. Following stab wound injury, astrocyte reactivity including glial fibrillary acidic protein expression, proliferation and neurosphere-forming capacity were found significantly reduced in mutant animals. This phenotype could be recapitulated in vitro and was fully rescued by addition of Galectin 3, but not of Galectin 1. Thus, Galectins 1 and 3 play key roles in regulating the proliferative and NSC potential of a subset of reactive astrocytes. PMID- 26250534 TI - Are 7-Fr caliber pancreatic stents more effective than 5-Fr stents in the endoscopic resolution of pancreatic fistulas? PMID- 26250532 TI - Patterns and prognostic value of lymph node dissection for resected perihilar cholangiocarcinoma. AB - BACKGROUND AND AIM: Lymph node metastasis is a major prognostic factor for perihilar cholangiocarcinoma (PHC). However, prognostic significance of extent of node dissection, lymph node ratio (LNR), and number and location of positive nodes remain unclear. We aimed to evaluate whether node status, LNR, or number or location of positive nodes are independent factors for staging in PHC and to determine the minimum requirements for node examination. METHODS: The Surveillance, Epidemiology, and End Results database was used to identify 1116 resected PHCs from 1998 to 2008. The correlation between nodal status and survival was analyzed retrospectively. RESULTS: Lymph node metastasis occurred in 43.4% patients and was an independent predictor for overall survival and cancer specific survival. No survival benefit was observed for an increasing number of node retrieval in node-positive patients. However, in node-negative patients, >=13 node dissection was of more survival benefit than 3 <= total lymph node count (TLNC) <= 12 and TLNC < 3 (5-year overall survival: 52.8% vs 39.7% vs 26.3%, P = 0.001; 5-year cancer-specific survival: 60.6% vs 46.3% vs 30.0%, P = 0.001). No difference in survival between patients with regional and distant node involvement was found. Survival for patients with greater than three positive nodes was significantly worse than that for those with three or less (relative ratio: 1.466, P = 0.001). And patients with LNR > 0.27 also had unfavorable prognosis (relative ratio: 1.376, P = 0.001). CONCLUSIONS: We determined that to adequately assess nodal status of this life-threatening disease, 13 or more nodes retrieval should be considered. Number of positive nodes and LNR rather than location of metastatic nodes may be defined as parameters for staging of PHC. PMID- 26250533 TI - Overweight status of the primary caregivers of orphan and vulnerable children in 3 Southern African countries: a cross sectional study. AB - BACKGROUND: Africa is facing a nutritional transition where underweight and overweight coexist. Although the majority of programs for orphan and vulnerable children (OVC) focus on undernourishment, the association between OVC primary caregiving and the caregivers' overweight status remains unclear. We investigated the association between OVC primary caregiving status with women's overweight status in Namibia, Swaziland and Zambia. METHODS: Demographic Health Survey (DHS) cross-sectional data collected during 2006-2007 were analyzed using weighted marginal means and logistic regressions. We analyzed data from 20-49 year old women in Namibia (N 6638), Swaziland (N 2875), and Zambia (N 4497). RESULTS: The overweight prevalence of the primary caregivers of OVC ranged from 27.0% (Namibia) to 61.3% (Swaziland). In Namibia, OVC primary caregivers were just as likely or even less likely to be overweight than other primary caregivers. In Swaziland and Zambia, OVC primary caregivers were just as likely or more likely to be overweight than other primary caregivers. In Swaziland and Zambia, OVC primary caregivers were more likely to be overweight than non-primary caregivers living with OVC (Swaziland AOR = 1.56, Zambia AOR = 2.62) and non-primary caregivers not living with OVC (Swaziland AOR = 1.92, Zambia AOR = 1.94). Namibian OVC caregivers were less likely to be overweight than non-caregivers not living with an OVC only in certain age groups (21-29 and 41-49 years old). CONCLUSIONS: African public health systems/OVC programs may face an overweight epidemic alongside existing HIV/AIDS, tuberculosis and malaria epidemics. Future studies/interventions to curb overweight should consider OVC caregiving status and address country-level differences. PMID- 26250535 TI - Lower Barthel Index Is Associated with Higher Risk of Hospitalization-Requiring Pneumonia in Long-Term Care Facilities. AB - Pneumonia is an important infectious entity that affects residents in long-term care facilities (LTCFs), whereas hospitalization-requiring pneumonia (HRP) represents a more critical patient condition with worse outcomes. The evidence addressing the association between Barthel index and risk of HRP among LTCF residents is lacking. A multicenter, retrospective cohort study was conducted in three LTCFs enrolling adult patients who resided for 3 months or more and ever underwent Barthel index evaluation within a study period of January 1 to December 31, 2010. The endpoint was HRP after enrollment. A total of 299 patients (169 women; age, 79.0 +/- 12.2 years) were enrolled and categorized into HRP Group (n = 68; 36 women; age, 79.1 +/- 11.3 years) and Non-HRP Group (n = 231; 133 women; age, 79.0 +/- 12.4 years) by the endpoint. The patients in HRP Group had significantly lower Barthel index (8.6 versus 25.8 points, p < 0.001) but higher proportion of chronic obstructive pulmonary disease (13.2% versus 3.9%, p = 0.004). By the multivariate analysis of logistic regression, we found that lower Barthel index (odds ratio (OR), 0.967; p < 0.001), existence of chronic obstructive pulmonary disease (OR, 4.192; p = 0.015), and feeding route (percutaneous endoscopic gastrostomy comparing with oral feeding; OR, 0.177; p = 0.012) were independently associated with HRP. In conclusion, a lower Barthel index is significantly associated with the occurrence of pneumonia that requires hospitalization in long-term care residents. Barthel index is a useful and reliable tool for risk evaluation in this population. PMID- 26250536 TI - Successful Treatment of TAFRO Syndrome, a Variant of Multicentric Castleman's Disease, with Cyclosporine A: Possible Pathogenetic Contribution of Interleukin 2. AB - Multicentric Castleman's disease is a systemic inflammatory disorder characterized by lymphadenopathy and excessive interleukin-6 production. A unique clinicopathologic variant of multicentric Castleman's disease, TAFRO (i.e., thrombocytopenia, anasarca, fever, renal failure or reticulin fibrosis, and organomegaly) syndrome, was recently proposed in Japan. Despite the successful use of anti-interleukin-6 therapy in some patients with TAFRO syndrome, not all patients achieve remission. The pathophysiological etiology of and suitable therapeutic strategies for this variant have not been established. Here, we present our experience of a unique case of TAFRO syndrome in a 78-year-old woman whose symptoms responded differently to several therapies. Tocilizumab, an anti interleukin-6 receptor antibody, successfully induced remission of fever and lymphadenopathy. However, severe thrombocytopenia persisted and she developed anasarca, ascites, and pleural effusion shortly thereafter. Rituximab, an anti CD20 antibody, and glucocorticoid therapy provided no symptom relief. In contrast, cyclosporine A, an immunosuppressive agent that blocks T cell function by inhibiting interleukin-2, yielded immediate improvements in systemic fluid retention and a gradual increase in platelet count, with complete resolution of disease symptoms. Excessive serum interleukin-2, when used as an anti-cancer agent, has been reported to cause side effects such as fluid retention, thrombocytopenia, and renal failure. Our case was unique because the anti interleukin-2 therapy successfully improved symptoms that were not relieved with anti-interleukin-6 therapy. The present report therefore provides insight into the possible role of interleukin-2, in addition to interleukin-6, in TAFRO syndrome. This report will certainly help to clarify the pathogenesis of and optimal treatment strategies for TAFRO syndrome. PMID- 26250537 TI - Systemic Immune-inflammation Index, Based on Platelet Counts and Neutrophil Lymphocyte Ratio, Is Useful for Predicting Prognosis in Small Cell Lung Cancer. AB - Small cell lung cancer (SCLC) is an aggressive disease characterized by rapid growth and metastases. It has been recognized that the inflammation of the microenvironment plays a critical role in the development of malignancies. However, little is known about the role of multiple inflammatory and hematological markers in the prognosis of SCLC. The aim of this study was to determine the clinical significance of pre-treatment inflammation-based scores and characteristics as prognostic indicators for the survival of SCLC patients. A retrospective analysis of 919 SCLC cases was performed. Patients' characteristics and hematologic tests data at initial diagnosis were collected. The univariate analysis of all SCLC patients indicated that favorable prognostic factors were age ? 70 years, non-smokers, good performance status, limited disease and response to treatment. Moreover, univariate analysis of inflammation-based scores and other blood parameters showed that neutrophil-lymphocyte ratio >= 5, platelet lymphocyte ratio >= 250, systemic immune-inflammation index (SII) >= 1,600 * 10(9)/L, prognostic nutritional index (albumin + 5 * lymphocyte) < 45, and elevated serum lactate dehydrogenase (LDH) predicted poor prognosis in SCLC patients. SII represents the score that is calculated as follows: platelet count * neutrophil count/lymphocyte count. In the multivariate analysis, SII, together with serum LDH, stage and response to therapy, were associated with overall survival (OS). This study demonstrated that the combination of platelet count and neutrophil-lymphocyte ratio could help to predict poor prognosis in SCLC. Our findings will facilitate the understanding of survival differences in SCLC patients in clinical practice. PMID- 26250540 TI - Pathophysiological insights of methylglyoxal induced type-2 diabetes. AB - Diabetes mellitus is a metabolic disorder constituting a major health problem whose prevalence has gradually increased worldwide over the past few decades. Type 2 diabetes mellitus (T2DM) remains more complex and heterogeneous and arises as a combination of insulin resistance and inadequate functional beta-cell mass and comprises about 90% of all diabetic cases. Appropriate experimental animal models are essential for understanding the molecular basis, pathogenesis of complications, and the utility of therapeutic agents to abrogate this multifaceted disorder. Currently, animal models for T2DM are obtained as spontaneously developed diabetes or diabetes induced by chemicals or dietary manipulations or through surgical or genetic methods. The currently used diabetogenic agents have certain limitations. Recently, methylglyoxal (MG), a highly reactive compound derived mainly from glucose and fructose metabolism has been implicated in diabetic complications. MG is a major precursor of the advanced glycation end product (AGE) and promotes impaired functions of insulin signaling, GLUT transporters, anion channels, kinases, and endothelial cells and is finally involved in apoptosis. Recent array of literature also cited that higher concentrations of MG causes rapid depolarization, elevated intracellular Ca(2+) concentration, and acidification in pancreatic beta-cells. This review henceforth highlights the mechanism of action of MG and its implications in the pathophysiology of experimental diabetes. PMID- 26250538 TI - Synthetic promoters in planta. AB - MAIN CONCLUSION: This paper reviews the importance, prospective and development of synthetic promoters reported in planta. A review of the synthetic promoters developed in planta would help researchers utilize the available resources and design new promoters to benefit fundamental research and agricultural applications. The demand for promoters for the improvement and application of transgenic techniques in research and agricultural production is increasing. Native/naturally occurring promoters have some limitations in terms of their induction conditions, transcription efficiency and size. The strength and specificity of native promoter can be tailored by manipulating its 'cis architecture' by the use of several recombinant DNA technologies. Newly derived chimeric promoters with specific attributes are emerging as an efficient tool for plant molecular biology. In the last three decades, synthetic promoters have been used to regulate plant gene expression. To better understand synthetic promoters, in this article, we reviewed promoter structure, the scope of cis-engineering, strategies for their development, their importance in plant biology and the total number of such promoters (188) developed in planta to date; we then categorized them under different functional regimes as biotic stress-inducible, abiotic stress-inducible, light-responsive, chemical-inducible, hormone-inducible, constitutive and tissue-specific. Furthermore, we identified a set of 36 synthetic promoters that control multiple types of expression in planta. Additionally, we illustrated the differences between native and synthetic promoters and among different synthetic promoter in each group, especially in terms of efficiency and induction conditions. As a prospective of this review, the use of ideal synthetic promoters is one of the prime requirements for generating transgenic plants suitable for promoting sustainable agriculture and plant molecular farming. PMID- 26250539 TI - Cultured Mesenchymal Stem Cells Stimulate an Immune Response by Providing Immune Cells with Toll-Like Receptor 2 Ligand. AB - Mesenchymal stem cells (MSCs) serve as supporting and regulatory cells, by providing tissues with multiple factors and are also known for their immunosuppressive capabilities. Our laboratory had previously shown that MSCs expressed toll-like receptor (TLR) 2 and are activated by its ligand Pam3Cys. TLR2 is an important component of the innate immune system, as it recognizes bacterial lipopeptides, thus priming a pro-inflammatory immune response. This study showed that Pam3Cys attached extensively to cells of both wild-type and TLR2 deficient cultured MSCs, thus, independently of TLR2. The TLR2 independent binding occurred through the adsorption of the palmitoyl moieties of Pam3Cys. It was further showed that Pam3Cys was transferred from cultured MSCs to immune cells. Moreover, Pam3Cys provided to the immune cells induced a pro-inflammatory response in vitro and in vivo. Overall, it is demonstrated herein that a TLR2 ligand bound to MSCs also through a TLR2 independent mechanism. Furthermore, the ligand incorporated by MSCs is subsequently released to stimulate an immune response both in vitro and in vivo. It is thus suggested that during bacterial infection, stromal cells may retain a reservoir of the TLR2 ligands, in a long term manner, and release them slowly to maintain an immune response. PMID- 26250541 TI - Objective and subjective sleep during pregnancy: links with depressive and anxiety symptoms. AB - The aims of this paper are to study the associations between objective and subjective sleep in pregnant women, to examine which specific aspects of women's sleep are associated with depressive and anxiety symptoms and to test the moderating role of depressive and anxiety symptoms in the relations between objective and subjective sleep. The sample included 148 pregnant women. Objective sleep was measured by actigraphy for five nights at the participants' home, and subjective sleep was measured with the Pittsburgh sleep quality index. Depressive symptoms were assessed with the Edinburgh postnatal depression scale and anxiety symptoms with the Beck anxiety inventory. Significant associations were found between the subjective sleep measures and the depressive and anxiety scores, but there were no significant associations between actigraphic sleep measures and the depressive and anxiety scores. Depressive and anxiety scores emerged as significant moderators of the links between objective and subjective sleep. The findings suggest that emotional distress (i.e., depressive and anxiety symptoms severity) during pregnancy is associated with subjective sleep disturbances but not with objective sleep disturbances. Importantly, only among women with higher levels of emotional distress was subjective sleep quality associated with objective sleep quality. These findings may suggest that women with higher levels of emotional distress are not necessarily biased in their perception of sleep quality. However, they may perceive fragmented sleep as more detrimental to their wellbeing. PMID- 26250542 TI - Cognitive remediation for older community-dwelling individuals with schizophrenia: a pilot and feasibility study. AB - OBJECTIVE: Cognitive deficits are among the strongest predictors of function in individuals with schizophrenia. This relationship continues to be strong as these individuals grow older into their eight decade. Cognitive remediation (CR) improves cognition in individuals with schizophrenia. This study aims at assessing the feasibility and potential effect of CR in patients with schizophrenia 60 years of age or older. METHODS: We adapted a CR protocol involving restorative and strategy-based methods over four cohorts of older outpatients with schizophrenia to target cognitive deficits associated with aging and schizophrenia. CR was provided in eight, 2-h weekly didactic sessions and online at-home exercises. Computerized drill and practice exercises were used with bridging to activities of daily life. Computer exercise selection and difficulty level parameters optimized adherence. Progression individually determined difficulty levels. We modified computer laboratory ergonomics to accommodate mobility needs. Participants were assessed at baseline and end-of study using clinical and cognitive assessments. RESULTS: Twenty-two participants enrolled: 18 (mean [SD] age: 69.8 [5.3]) completed CR. Mean (SD) global cognition T score from the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery was 27.7 (10) at baseline and 28.8 (9.7) at the completion of the study. These means are over 2 SD below the norms. The change in global cognition was not statistically significant (paired t(17) = 1.18, p = 0.25). CONCLUSIONS: Our pilot study suggests that CR is well tolerated by most older outpatients with schizophrenia. Future studies need to assess whether increasing the frequency or the number of CR sessions leads to significant improvement in cognition. PMID- 26250543 TI - Bayesian outbreak detection in the presence of reporting delays. AB - One use of infectious disease surveillance systems is the statistical aberration detection performed on time series of counts resulting from the aggregation of individual case reports. However, inherent reporting delays in such surveillance systems make the considered time series incomplete, which can be an impediment to the timely detection and thus to the containment of emerging outbreaks. In this work, we synthesize the outbreak detection algorithms of Noufaily et al. (2013) and Manitz and Hohle (2013) while additionally addressing right truncation caused by reporting delays. We do so by considering the resulting time series as an incomplete two-way contingency table which we model using negative binomial regression. Our approach is defined in a Bayesian setting allowing a direct inclusion of all sources of uncertainty in the derivation of whether an observed case count is to be considered an aberration. The proposed algorithm is evaluated both on simulated data and on the time series of Salmonella Newport cases in Germany in 2011. Altogether, our method aims at allowing timely aberration detection in the presence of reporting delays and hence underlines the need for statistical modeling to address complications of reporting systems. An implementation of the proposed method is made available in the R package surveillance as the function "bodaDelay". PMID- 26250544 TI - Ecotoxic heavy metals transformation by bacteria and fungi in aquatic ecosystem. AB - Water is the most important and vital molecule of our planet and covers 75% of earth surface. But it is getting polluted due to high industrial growth. The heavy metals produced by industrial activities are recurrently added to it and considered as dangerous pollutants. Increasing concentration of toxic heavy metals (Pb(2+), Cd(2+), Hg(2+), Ni(2+)) in water is a severe threat for human. Heavy metal contaminated water is highly carcinogenic and poisonous at even relatively low concentrations. When they discharged in water bodies, they dissolve in the water and are distributed in the food chain. Bacteria and fungi are efficient microbes that frequently transform heavy metals and remove toxicity. The application of bacteria and fungi may offer cost benefit in water treatment plants for heavy metal transformation and directly related to public health and environmental safety issues. The heavy metals transformation rate in water is also dependent on the enzymatic capability of microorganisms. By transforming toxic heavy metals microbes sustain aquatic and terrestrial life. Therefore the application of microbiological biomass for heavy metal transformation and removal from aquatic ecosystem is highly significant and striking. This paper reviews the microbial transformation of heavy metal, microbe metal interaction and different approaches for microbial heavy metal remediation from water bodies. PMID- 26250545 TI - CitB is required for full virulence of Xanthomonas oryzae pv. oryzae. AB - To identify novel virulence associated genes in Xanthomonas oryzae pv. oryzae (Xoo), a Xoo isolate (XooIR42), obtained from north of Iran, was selected to generate a mini-Tn5 transposon mutation library. One mutant (XooM176) that indicated reduced virulence on rice plants, while grew similar to wild type was selected. This mutant had an insertion in a coding region with 96% amino acid identity to a response regulator of Xoo KACC10331, citB (Xoo_RS12710). Genome analysis of Xoo KACC10331 indicated several genes including a flagelin protein (FlgL) and a chemotaxis protein (Xoo_RS12720) which were identified as virulence genes 4297 and 1403 nucleotides from the citB, respectively. The swarming motility, resistance to hydrogen peroxide, induced a hypersensitive response, in planta growth and pathogenicity were reduced in XooM176 mutant compared to that of wild-type. A plasmid containing the full citB gene of Xoo KACC10331was sufficient to complement the XooM176 mutant for lesion formation and resistance to hydrogen peroxide. We therefore propose that Xoo requires CitB for full pathogenicity in rice plants and also for protection against oxidative stress. PMID- 26250546 TI - Biological technologies for the removal of sulfur containing compounds from waste streams: bioreactors and microbial characteristics. AB - Waste gases containing sulfur compounds, such as hydrogen sulfide, sulfur dioxide, thioethers, and mercaptan, produced and emitted from industrial processes, wastewater treatment, and landfill waste may cause undesirable issues in adjacent areas and contribute to atmospheric pollution. Their control has been an area of concern and research for many years. As alternative to conventional physicochemical air pollution control technologies, biological treatment processes which can transform sulfur compounds to harmless products by microbial activity, have gained in popularity due to their efficiency, cost-effectiveness and environmental acceptability. This paper provides an overview of the current biological techniques used for the treatment of air streams contaminated with sulfur compounds as well as the advances made in the past year. The discussion focuses on bioreactor configuration and design, mechanism of operation, insights into the overall biological treatment process, and the characterization of the microbial species present in bioreactors, their populations and their interactions with the environment. Some bioreactor case studies are also introduced. Finally, the perspectives on future research and development needs in this research area were also highlighted. PMID- 26250547 TI - Within-lake heterogeneity of environmental factors structuring bacterial community composition in Lake Dongting, China. AB - Within-lake heterogeneity of bacterial community composition (BCC) was investigated in the large and shallow regulating Lake Dongting. Samples were collected at 13 sites located in different areas of the lake. PCR-denaturing gradient gel electrophoresis (DGGE) and redundancy analysis (RDA) were used for revealing spatial distribution of BCC and the relationships between BCC and environmental variables. The DGGE banding patterns revealed a remarkable spatial heterogeneity which was closely related to their geographical positions. RDA result demonstrated that TP and TN, as well as Secchi depth, were the three most influential factors, responsible for a major part of the observed variation in BCC. Total bacterial abundances were significantly higher in Eastern Dongting due to high TP and suspended solids. In conclusion, bacterial community diversity in Lake Dongting was mainly shaped by within-lake heterogeneity of nutrient and transparency. PMID- 26250549 TI - CenC, a multidomain thermostable GH9 processive endoglucanase from Clostridium thermocellum: cloning, characterization and saccharification studies. AB - The growing demands of bioenergy has led to the emphasis on novel cellulases to improve efficiency of biodegradation process of plant biomass. Therefore, a thermostable cellulolytic gene (CenC) with 3675 bp was cloned from Clostridium thermocellum and over-expressed in Escherichia coli strain BL21 CodonPlus. It was attested that CenC belongs to glycoside hydrolase family 9 (GH9) with four binding domains, a processive endoglucanase. CenC was purified to homogeneity, producing a single band on SDS-PAGE corresponding to 137.11 kDa, by purification steps of heat treatment combined with ion-exchange chromatography. Purified enzyme displayed optimal activity at pH 6.0 and 70 degrees C. CenC had a half life of 24 min at 74 degrees C, was stable up to 2 h at 60 degrees C and over a pH range of 5.5-7.5. Enzyme showed high affinity towards various substrates and processively released cellobiose from cellulosic substrates. It efficiently hydrolyzed carboxymethyl cellulose (30 U/mg), beta-Glucan Barley (94 U/mg); also showed activity towards p-nitrophenyl-beta-D-cellobioside (18 U/mg), birchwood xylan (19 U/mg), beechwood xylan (17.5 U/mg), avicel (9 U/mg), whatman filter paper (11 U/mg) and laminarin (3.3 U/mg). CenC exhibited Km, Vmax, Kcat, Vmax Km( 1) and Kcat Km(-1) of 7.14 mM, 52.4 umol mg(-1) min(-1), 632.85 s(-1), 7.34 min( 1) and 88.63, respectively used CMC as substrate. Recombinant CenC saccharified pretreated wheat straw and bagasse to 5.12 and 7.31%, respectively at pH 7.0 and 45 degrees C after 2 h incubation. Its thermostability, high catalytic efficiency and independence of inhibitors make CenC enzyme an appropriate candidate for industrial applications and cost-effective saccharification process. PMID- 26250550 TI - A selective determination of copper ions in water samples based on the fluorescence quenching of thiol-capped CdTe quantum dots. AB - CdTe quantum dots (QDs) capped with different stabilizers, i.e. thioglycolic acid (TGA), 3-mercaptopropionic acid (MPA) and glutathione (GSH) were investigated as fluorescent probes for the determination of Cu(2+). The stabilizer was shown to play an important role in both the sensitivity and selectivity for the determination of Cu(2+). TGA-capped CdTe QDs showed the highest sensitivity, followed by the MPA and GSH-capped CdTe QDs, respectively. The TGA- and MPA capped CdTe QDs were not selective for Cu(2+) that was affected by Ag(+). The GSH capped CdTe QDs were insensitive to Ag(+) and were used to determine Cu(2+) in water samples. Under optimal conditions, quenching of the fluorescence intensity (F0/F) increased linearly with the concentration of Cu(2+) over a range of 0.10 4.0 ug/mL and the detection limit was 0.06 ug/mL. The developed method was successfully applied to the determination of Cu(2+) in water samples. Good recoveries of 93-104%, with a relative standard deviation of < 6% demonstrated that the developed simple method was accurate and reliable. The quenching mechanisms were also described. PMID- 26250548 TI - Arbuscular mycorrhizal fungi in phytoremediation of contaminated areas by trace elements: mechanisms and major benefits of their applications. AB - In recent decades, the concentration of trace elements has increased in soil and water, mainly by industrialization and urbanization. Recovery of contaminated areas is generally complex. In that respect, microorganisms can be of vital importance by making significant contributions towards the establishment of plants and the stabilization of impacted areas. Among the available strategies for environmental recovery, bioremediation and phytoremediation outstand. Arbuscular mycorrhizal fungi (AMF) are considered the most important type of mycorrhizae for phytoremediation. AMF have broad occurrence in contaminated soils, and evidences suggest they improve plant tolerance to excess of certain trace elements. In this review, the use of AMF in phytoremediation and mechanisms involved in their trace element tolerance are discussed. Additionally, we present some techniques used to study the retention of trace elements by AMF, as well as a summary of studies showing major benefits of AMF for phytoremediation. PMID- 26250551 TI - How should ethnicity-related information be included on drug labels? Considerations based on comparison of multiregional clinical trial data on the label between Japan and the United States. AB - Clinical data on various ethnicities collected in multiregional clinical trials (MRCTs) have increased in regulatory review for drug approval. However, how such data should be included on the drug labels has not been discussed. We compared information related to ethnicities on the labels of drugs that were approved in both Japan and the United States, and discussed the issues to be considered for providing better information to healthcare professionals in this era of globalized drug development. PMID- 26250553 TI - Combination of two-dimensional gel electrophoresis and a fluorescent carboxyfluorescein-diacetate-labeled cisplatin analogue allows the identification of intracellular cisplatin-protein adducts. AB - Cisplatin is one of the most widely used anticancer agents, but a major problem for successful chemotherapy is the development of drug resistance of tumor cells against cisplatin. Resistance to cisplatin is a multifactorial problem. A method to detect and identify intracellular cisplatin-protein adducts was developed using a fluorescent carboxyfluorescein-diacetate-labeled cisplatin analogue (CFDA cisplatin), 2DE, and ESI-MS/MS. We identified several CFDA-cisplatin-protein adducts including members of the protein disulfide isomerase family (PDI). These are the first results of the detection of intracellular CFDA-cisplatin-protein adducts, which may help to understand the resistance mechanism of cisplatin. PMID- 26250552 TI - Identification of a blood-borne miRNA signature of synovial sarcoma. AB - BACKGROUND: Synovial sarcoma account for approximately 10 % of all soft-tissue tumors and occur most frequently in young adults. A specific translocation in this sarcoma induces fusion of the SYT gene on chromosome 18 to the SSX genes on chromosome X, leading to proliferation of the tumor cells. The need for non invasive biomarkers indicating recurrence and activity of this disease has sparked research into short non-coding RNA known as microRNA (miRNA). METHODS: Blood samples of patients with active synovial sarcoma and of synovial sarcoma patients in complete remission as well as of healthy donors and patients with active leiomyosarcoma, MPNST, Ewing sarcoma and liposarcoma were collected. Whole blood RNA was extracted and samples of patients with active synovial sarcoma and of healthy donors were analyzed using an Affymetrix GeneChip miRNA Array v. 4.0. qRT-PCR was carried out to confirm a panel of miRNAs which where differentially expressed in the miRNA array. This miRNA-panel was further evaluated in patients with synovial sarcoma in complete remission and patients with active leiomyosarcoma, MPNST, Ewing sarcoma and liposarcoma as well as in an independent cohort of synovial sarcoma patients. RESULTS: Unsupervised hierarchical clustering of the miRNA arrays separated patients with active synovial sarcoma from healthy controls. A panel of seven miRNAs (miR-99a-5p, miR-146b-5p, miR-148b 3p, miR-195-5p, miR-223-3p, miR-500b-3p and miR-505-3p) was further validated by qRT-PCR to be significantly upregulated in synovial sarcoma patients. Moreover, most of the analyzed miRNAs were shown to be significantly upregulated in synovial sarcoma patients compared to leiomyosarcoma, MPNST, Ewing sarcoma and liposarcoma patients. Validation of the miRNA panel in an independent cohort of synovial sarcoma patients confirmed higher expression levels compared to healthy controls and patients in complete remission. CONCLUSION: Our results have identified a specific whole blood miRNA signature that may serve as an independent biomarker for the diagnosis of local recurrence or distant metastasis of synovial sarcoma. It even distinguishes synovial sarcoma from other sarcoma subtypes, thus potentially serving as a specific biomarker for synovial sarcoma. PMID- 26250554 TI - Vascular Reactivity Maps in Patients with Gliomas Using Breath-Holding BOLD fMRI. AB - BACKGROUND AND PURPOSE: To evaluate whether breath-holding (BH) blood oxygenation level-dependent (BOLD) fMRI can quantify differences in vascular reactivity (VR), as there is a need for improved contrast mechanisms in gliomas. METHODS: 16 patients (gliomas, grade II = 5, III = 2, IV = 9) were evaluated using the BH paradigm: 4-second single deep breath followed by 16 seconds of BH and 40 seconds of regular breathing for five cycles. VR was defined as the difference in BOLD signal between the minimal signal seen at the end of the deep breath and maximal signal seen at the end of BH (peak-to-trough). VR was measured for every voxel and compared for gray versus white matter and tumor versus normal contralateral brain. VR maps were compared to the areas of enhancement and FLAIR/T2 abnormality. RESULTS: VR was significantly lower in normal white matter than gray matter (P < .05) and in tumors compared to the normal, contralateral brain (P < 0.002). The area of abnormal VR (1103 +/- 659 mm2) was significantly greater (P = .019) than the enhancement (543 +/- 530 mm2), but significantly smaller (P = .0011) than the FLAIR abnormality (2363 +/- 1232 mm2). However, the variability in the areas of gadolinium contrast enhancement versus VR abnormality indicates that the contrast mechanism elicited by BH (caused by abnormal arteriolar smooth muscles) appears to be fundamentally different from the contrast mechanism of gadolinium enhancement (caused by the presence of "leaky" gap junctions). CONCLUSIONS: BH maps based on peak-to-trough can be used to characterize VR in brain tumors. VR maps in brain tumor patients appear to be caused by a different mechanism than gadolinium enhancement. PMID- 26250555 TI - Hoffmann's disease: MR imaging of hypothyroid myopathy. AB - Hoffmann's syndrome is a hypothyroid myopathy presenting as muscle stiffness and hypertrophy. It is a rare complication of hypothyroidism. MRI features of this syndrome have seldom been described in the literature. We present a case of Hoffmann's syndrome in a 34-year-old man who underwent lower extremity contrast enhanced MRI. MRI can demonstrate the hypertrophic configuration, T2 hyperintensity, and enhancement of the involved muscles in Hoffmann's syndrome. Along with clinical, laboratory, and electromyography findings, MRI may be helpful in distinguishing between inflammatory myopathy, myonecrosis, subacute muscle denervation, and infectious myositis. PMID- 26250556 TI - The reliability of dual-energy X-ray absorptiometry measurements of bone mineral density in the metatarsals. AB - OBJECTIVE: To investigate the reliability of a simple, efficient technique for measuring bone mineral density (BMD) in the metatarsals using dual-energy X-ray absorptiometry (DXA). MATERIALS AND METHODS: BMD of the right foot of 32 trained male distance runners was measured using a DXA scanner with the foot in the plantar position. Separate regions of interest (ROI) were used to assess the BMD of each metatarsal shaft (1st-5th) for each participant. ROI analysis was repeated by the same investigator to determine within-scan intra-rater reliability and by a different investigator to determine within-scan inter-rater reliability. Repeat DXA scans were undertaken for ten participants to assess between-scan intra-rater reliability. RESULTS: Assessment of BMD was consistently most reliable for the first metatarsal across all domains of reliability assessed (intra-class correlation coefficient [ICC] >=0.97; coefficient of variation [CV] <=1.5%; limits of agreement [LOA] <=4.2%). Reasonable levels of intra-rater reliability were also achieved for the second and fifth metatarsals (ICC >=0.90; CV <=4.2%; LOA <=11.9%). Poorer levels of reliability were demonstrated for the third (ICC >=0.64; CV <=8.2%; LOA <=23.6%) and fourth metatarsals (ICC >=0.67; CV <=9.6%; LOA <=27.5%). BMD was greatest in the first and second metatarsals (P < 0.01). CONCLUSION: Reliable measurements of BMD were achieved for the first, second and fifth metatarsals. PMID- 26250557 TI - Flow Diverter Stents for the Treatment of Anterior Cerebral Artery Aneurysms: Safety and Effectiveness. AB - BACKGROUND AND PURPOSE: Flow diverter stents (FDSs) are increasingly used for the treatment of intracranial aneurysms. Initially developed for the management of giant and large aneurysms, their indications have progressively expanded. The purpose of our study was to evaluate the safety and effectiveness of FDSs for the treatment of anterior cerebral artery (ACA) aneurysms. MATERIALS AND METHODS: Among the 94 consecutive patients treated for 100 intracranial aneurysms by means of FDSs in our institution from October 2010 to January 2015, eight aneurysms (8 %) in seven patients were located on the ACA. Three aneurysms were located on the A1 segment, three aneurysms on the anterior communicating artery (ACom) and two on the A2-A3 junction. In three cases, FDS was used for angiographic recurrence after coiling. Five patients were treated with a Pipeline embolization device, one with a NeuroEndograft and the last one with a Silk FDS. RESULTS: Treatment was feasible in all cases. No technical difficulty was reported. No acute or delayed clinical complication was recorded. Modified Rankin Scale was 0 for six patients and one for one patient. Mean angiographic follow-up was 9.7 +/- 3.9 months (range 6-15). Total exclusion was observed in five aneurysms (71.4 %) and neck remnant in two (28.6 %) cases. One patient refused the control DSA. CONCLUSION: Our series shows the safety and effectiveness of FDSs for the treatment of ACA aneurysms. PMID- 26250558 TI - InteMAP: Integrated metagenomic assembly pipeline for NGS short reads. AB - BACKGROUND: Next-generation sequencing (NGS) has greatly facilitated metagenomic analysis but also raised new challenges for metagenomic DNA sequence assembly, owing to its high-throughput nature and extremely short reads generated by sequencers such as Illumina. To date, how to generate a high-quality draft assembly for metagenomic sequencing projects has not been fully addressed. RESULTS: We conducted a comprehensive assessment on state-of-the-art de novo assemblers and revealed that the performance of each assembler depends critically on the sequencing depth. To address this problem, we developed a pipeline named InteMAP to integrate three assemblers, ABySS, IDBA-UD and CABOG, which were found to complement each other in assembling metagenomic sequences. Making a decision of which assembling approaches to use according to the sequencing coverage estimation algorithm for each short read, the pipeline presents an automatic platform suitable to assemble real metagenomic NGS data with uneven coverage distribution of sequencing depth. By comparing the performance of InteMAP with current assemblers on both synthetic and real NGS metagenomic data, we demonstrated that InteMAP achieves better performance with a longer total contig length and higher contiguity, and contains more genes than others. CONCLUSIONS: We developed a de novo pipeline, named InteMAP, that integrates existing tools for metagenomics assembly. The pipeline outperforms previous assembly methods on metagenomic assembly by providing a longer total contig length, a higher contiguity and covering more genes. InteMAP, therefore, could potentially be a useful tool for the research community of metagenomics. PMID- 26250559 TI - Identification and Structural Characterization of Naturally-Occurring Broad Spectrum Cyclic Antibiotics Isolated from Paenibacillus. AB - The rise of antimicrobial resistance necessitates the discovery and/or production of novel antibiotics. Isolated strains of Paenibacillus alvei were previously shown to exhibit antimicrobial activity against a number of pathogens, such as E. coli, Salmonella, and methicillin-resistant Staphylococcus aureus (MRSA). The responsible antimicrobial compounds were isolated from these Paenibacillus strains and a combination of low and high resolution mass spectrometry with multiple-stage tandem mass spectrometry was used for identification. A group of closely related cyclic lipopeptides was identified, differing primarily by fatty acid chain length and one of two possible amino acid substitutions. Variation in the fatty acid length resulted in mass differences of 14 Da and yielded groups of related MS(n) spectra. Despite the inherent complexity of MS/MS spectra of cyclic compounds, straightforward analysis of these spectra was accomplished by determining differences in complementary product ion series between compounds that differ in molecular weight by 14 Da. The primary peptide sequence assignment was confirmed through genome mining; the combination of these analytical tools represents a workflow that can be used for the identification of complex antibiotics. The compounds also share amino acid sequence similarity to a previously identified broad-spectrum antibiotic isolated from Paenibacillus. The presence of such a wide distribution of related compounds produced by the same organism represents a novel class of broad-spectrum antibiotic compounds. PMID- 26250560 TI - Perspective in infertility: the ovarian stem cells. AB - Infertility is a medical and social condition that affects millions of women worldwide and is today considered so far as a new disease. A considerable progress has been recently pursued in the field of the reproductive medicine and the infertility treatment may account for novel and modern procedures such as in vitro oocyte fertilization, egg donation, pregnancy surrogacy and preimplantation diagnosis. However, great interest has lately been reserved to the ovarian stem cells (OSCs) whose existence in woman ovaries has been proven. OSCs are thus suitable for developmental studies in infertility and in other clinical applications as endocrine derangements due to premature ovarian failure, or for infertility treatment after cancer chemotherapies, as well as in restoring the hormonal balance in postmenopausal age. PMID- 26250561 TI - Response to Overcoming the Barrier to Implementing Authentic Research Experiences through Faculty Mentorship: The ASCB Mentoring in Active Learning and Teaching (MALT) Program Is Designed to Facilitate Vision and Change-Inspired Teaching Practices. PMID- 26250562 TI - Modeling Sources of Teaching Self-Efficacy for Science, Technology, Engineering, and Mathematics Graduate Teaching Assistants. AB - Graduate teaching assistants (GTAs) in science, technology, engineering, and mathematics (STEM) have a large impact on undergraduate instruction but are often poorly prepared to teach. Teaching self-efficacy, an instructor's belief in his or her ability to teach specific student populations a specific subject, is an important predictor of teaching skill and student achievement. A model of sources of teaching self-efficacy is developed from the GTA literature. This model indicates that teaching experience, departmental teaching climate (including peer and supervisor relationships), and GTA professional development (PD) can act as sources of teaching self-efficacy. The model is pilot tested with 128 GTAs from nine different STEM departments at a midsized research university. Structural equation modeling reveals that K-12 teaching experience, hours and perceived quality of GTA PD, and perception of the departmental facilitating environment are significant factors that explain 32% of the variance in the teaching self efficacy of STEM GTAs. This model highlights the important contributions of the departmental environment and GTA PD in the development of teaching self-efficacy for STEM GTAs. PMID- 26250563 TI - The Undergraduate Research Student Self-Assessment (URSSA): Validation for Use in Program Evaluation. AB - This article examines the validity of the Undergraduate Research Student Self Assessment (URSSA), a survey used to evaluate undergraduate research (UR) programs. The underlying structure of the survey was assessed with confirmatory factor analysis; also examined were correlations between different average scores, score reliability, and matches between numerical and textual item responses. The study found that four components of the survey represent separate but related constructs for cognitive skills and affective learning gains derived from the UR experience. Average scores from item blocks formed reliable but moderate to highly correlated composite measures. Additionally, some questions about student learning gains (meant to assess individual learning) correlated to ratings of satisfaction with external aspects of the research experience. The pattern of correlation among individual items suggests that items asking students to rate external aspects of their environment were more like satisfaction ratings than items that directly ask about student skills attainment. Finally, survey items asking about student aspirations to attend graduate school in science reflected inflated estimates of the proportions of students who had actually decided on graduate education after their UR experiences. Recommendations for revisions to the survey include clarified item wording and increasing discrimination between item blocks through reorganization. PMID- 26250564 TI - Critical Analysis of Primary Literature in a Master's-Level Class: Effects on Self-Efficacy and Science-Process Skills. AB - The ability to think analytically and creatively is crucial for success in the modern workforce, particularly for graduate students, who often aim to become physicians or researchers. Analysis of the primary literature provides an excellent opportunity to practice these skills. We describe a course that includes a structured analysis of four research papers from diverse fields of biology and group exercises in proposing experiments that would follow up on these papers. To facilitate a critical approach to primary literature, we included a paper with questionable data interpretation and two papers investigating the same biological question yet reaching opposite conclusions. We report a significant increase in students' self-efficacy in analyzing data from research papers, evaluating authors' conclusions, and designing experiments. Using our science-process skills test, we observe a statistically significant increase in students' ability to propose an experiment that matches the goal of investigation. We also detect gains in interpretation of controls and quantitative analysis of data. No statistically significant changes were observed in questions that tested the skills of interpretation, inference, and evaluation. PMID- 26250566 TI - Circulating U2 small nuclear RNA fragments as a novel diagnostic biomarker for primary central nervous system lymphoma. AB - BACKGROUND: Primary central nervous system lymphomas (PCNSLs) are highly aggressive tumors. Chemotherapy has improved prognosis significantly; however, early diagnosis is crucial for effective treatment. Presently, the diagnosis of PCNSL depends on histopathology of tumor biopsies. We have previously demonstrated differential expression of microRNAs in cerebrospinal fluid (CSF) samples from patients with PCNSL. Based on promising findings about circulating U2 small nuclear RNA fragments (RNU2-1f) as novel blood-based biomarkers for pancreatic, colorectal, and lung cancer, we investigated RNU2-1f in the CSF of PCNSL patients. METHODS: CSF was collected from patients with PCNSL (n = 72) and control patients with various neurologic disorders (n = 47). Sequential CSF samples were collected from 9 PCNSL patients. RNU2-1f levels were measured by real-time polymerase chain reaction. RESULTS: Measurement of RNU2-1f levels in CSF enabled the differentiation of patients with PCNSL from controls with an area under the curve (AUC) of 0.909 with a sensitivity of 68.1% and a specificity of 91.4%. The diagnostic accuracy was further improved by combined determination of RNU2-1f and miR-21, resulting in AUC of 0.987 with a sensitivity of 91.7% and a specificity of 95.7%. In consecutive measurements of RNU2-1f, which were performed in 9 patients at different stages of the disease course, RNU2-1f CSF levels paralleled the course of the disease. CONCLUSIONS: Our data suggest that the measurement of RNU2-1f detected in CSF can be used as a diagnostic marker and also as a possible marker for treatment monitoring. These promising results need to be evaluated within a larger patient cohort. PMID- 26250567 TI - Edge effects and geometric constraints: a landscape-level empirical test. AB - Edge effects are pervasive in landscapes yet their causal mechanisms are still poorly understood. Traditionally, edge effects have been attributed to differences in habitat quality along the edge-interior gradient of habitat patches, under the assumption that no edge effects would occur if habitat quality was uniform. This assumption was questioned recently after the recognition that geometric constraints tend to reduce population abundances near the edges of habitat patches, the so-called geometric edge effect (GEE). Here, we present the first empirical, landscape-level evaluation of the importance of the GEE in shaping abundance patterns in fragmented landscapes. Using a data set on the distribution of small mammals across 18 forest fragments, we assessed whether the incorporation of the GEE into the analysis changes the interpretation of edge effects and the degree to which predictions based on the GEE match observed responses. Quantitative predictions were generated for each fragment using simulations that took into account home range, density and matrix use for each species. The incorporation of the GEE into the analysis changed substantially the interpretation of overall observed edge responses at the landscape scale. Observed abundances alone would lead to the conclusion that the small mammals as a group have no consistent preference for forest edges or interiors and that the black-eared opossum Didelphis aurita (a numerically dominant species in the community) has on average a preference for forest interiors. In contrast, incorporation of the GEE suggested that the small mammal community as a whole has a preference for forest edges, whereas D. aurita has no preference for forest edges or interiors. Unexplained variance in edge responses was reduced by the incorporation of GEE, but remained large, varying greatly on a fragment-by fragment basis. This study demonstrates how to model and incorporate the GEE in analyses of edge effects and that this incorporation is necessary to properly interpret edge effects in landscapes. It also suggests that geometric constraints alone are unlikely to explain the variability in edge responses of a same species among different areas, highlighting the need to incorporate other ecological factors into explanatory models of edge effects. PMID- 26250565 TI - Consensus recommendations for a standardized Brain Tumor Imaging Protocol in clinical trials. AB - A recent joint meeting was held on January 30, 2014, with the US Food and Drug Administration (FDA), National Cancer Institute (NCI), clinical scientists, imaging experts, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocate groups to discuss imaging endpoints for clinical trials in glioblastoma. This workshop developed a set of priorities and action items including the creation of a standardized MRI protocol for multicenter studies. The current document outlines consensus recommendations for a standardized Brain Tumor Imaging Protocol (BTIP), along with the scientific and practical justifications for these recommendations, resulting from a series of discussions between various experts involved in aspects of neuro-oncology neuroimaging for clinical trials. The minimum recommended sequences include: (i) parameter-matched precontrast and postcontrast inversion recovery-prepared, isotropic 3D T1-weighted gradient-recalled echo; (ii) axial 2D T2-weighted turbo spin-echo acquired after contrast injection and before postcontrast 3D T1 weighted images to control timing of images after contrast administration; (iii) precontrast, axial 2D T2-weighted fluid-attenuated inversion recovery; and (iv) precontrast, axial 2D, 3-directional diffusion-weighted images. Recommended ranges of sequence parameters are provided for both 1.5 T and 3 T MR systems. PMID- 26250569 TI - A Case of Late Implantable Cardiac Device Infection with Aspergillus in an Immunocompetent Host. AB - BACKGROUND: With the increasing use of cardiac implantable electronic devices (CIED), there has been an associated increase in rate of complications. Infection accounts for about 1% of these, of which only a handful were reported secondary to Aspergillus fumigatus. All of these were seen in chronically-ill patients with several co-morbid conditions within a few years of implantation. None have been reported in an otherwise immunocompetent patient at 7 years after CIED implantation. CASE REPORT: A 67-year-old woman with symptomatic sick sinus syndrome required a pacemaker 15 years ago with subsequent revision 7 years prior due to battery depletion. She now presented with a left pectoral non-tender mass that developed over several weeks. She denied history of recent fever, trauma, or infection. An elective pacemaker revision and pocket exploration led to the drainage of 150 cc of serosanguineous discharge from the pocket. She received peri-procedural prophylaxis with Vancomycin, but later, wound cultures grew Aspergillus fumigatus. She underwent complete removal of the pacemaker system along with a 6-week course of voriconazole and is doing well. CONCLUSIONS: Even though Staphylococcus aureus causes most CIED infections, there should be a suspicion for fungal organisms, especially in culture-negative infections, in immunocompromised states like diabetes mellitus or with minimal improvement on antibiotics. If not treated appropriately, aspergillosis may have catastrophic outcomes, including endocarditis, often leading to death. Appropriate treatment should include immediate initiation of antifungals and removal of the CIED. It is still unclear why an immunocompetent patient developed aspergillosis, but appropriate management helped avoid a grave outcome. PMID- 26250568 TI - Magnolol inhibits growth of gallbladder cancer cells through the p53 pathway. AB - Magnolol, the major active compound found in Magnolia officinalis has a wide range of clinical applications due to its anti-inflammation and anti-oxidation effects. This study investigated the effects of magnolol on the growth of human gallbladder carcinoma (GBC) cell lines. The results indicated that magnolol could significantly inhibit the growth of GBC cell lines in a dose- and time-dependent manner. Magnolol also blocked cell cycle progression at G0 /G1 phase and induced mitochondrial-related apoptosis by upregulating p53 and p21 protein levels and by downregulating cyclin D1, CDC25A, and Cdk2 protein levels. When cells were pretreated with a p53 inhibitor (pifithrin-a), followed by magnolol treatment, pifithrin-a blocked magnolol-induced apoptosis and G0 /G1 arrest. In vivo, magnolol suppressed tumor growth and activated the same mechanisms as were activated in vitro. In conclusion, our study is the first to report that magnolol has an inhibitory effect on the growth of GBC cells and that this compound may have potential as a novel therapeutic agent for the treatment of GBC. PMID- 26250570 TI - Banding for type IA endoleak after endovascular abdominal aortic repair: An underexposed treatment option. AB - More challenging abdominal aortic aneurysms with unfavorable proximal aortic neck anatomy are treated with endovascular means. As a consequence, proximal inadequate sealing may result in type IA endoleak, which in turn can lead to abdominal aortic aneurysm progression or rupture. The presence of type IA endoleak is an indication for secondary interventions. External aortic banding can be a good option to solve a type IA endoleak, but is underreported in literature; we present two cases and review literature. PMID- 26250572 TI - Osteoclast Deficiency Contributes to Temporomandibular Joint Ankylosed Bone Mass Formation. AB - Ankylosed bone mass in temporomandibular joint ankylosis (TMJA) is an important factor affecting mouth-opening limitation. However, the mechanism underlying the occurrence of ankylosed bone mass remains unknown. Research has shown that osteoblasts and osteoclasts maintain balance in bone remodeling. Thus, we hypothesized that aberrant osteoclastogenesis and osteogenesis may be involved in the occurrence of ankylosed bone mass in TMJA. In this study, we characterized the osteogenesis of bone marrow stem cells and the osteoclastogenesis of myelomonocyte in clinical specimens of TMJA and normal controls. Results showed that, compared with control bone marrow stem cells, TMJA bone marrow stem cells had lower proliferative and osteogenic capacities. The number of osteoclasts in the ankylosed bone mass group dramatically decreased, and myelomonocyte osteoclastogenic potential was impaired. The RANKL/OPG ratio of the ankylosed bone mass group was lower than that of the control group. Thus, our study suggests that osteoclast deficiency may be an important factor affecting bone mass ankylosis. PMID- 26250571 TI - Effects of Exendin-4 on bone marrow mesenchymal stem cell proliferation, migration and apoptosis in vitro. AB - Mesenchymal stem cells (MSC) are regarded as an attractive source of therapeutic stem cells for myocardial infarction. However, their limited self-renewal capacity, low migration capacity and poor viability after transplantation hamper the clinical use of MSC; thus, a strategy to enhance the biological functions of MSC is required. Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, exerts cell-protective effects on many types of cells. However, little information is available regarding the influence of Ex-4 on MSC. In our study, MSC were isolated from bone marrow and cultured in vitro. After treatment with Ex 4, MSC displayed a higher proliferative capacity, increased C-X-C motif receptor 4 (CXCR4) expression and an enhanced migration response. Moreover, in H2O2 induced apoptosis, Ex-4 preserved mitochondrial function through scavenging ROS and balancing the expression of anti- and pro-apoptotic proteins, leading to the inhibition of the mitochondria-dependent cell death pathways and increased cell survival. Moreover, higher phospho-Akt (p-Akt) expression was observed after Ex-4 intervention. However, blockade of the PI3K/Akt pathway with inhibitors suppressed the above cytoprotective effects of Ex-4, suggesting that the PI3K/Akt pathway is partly responsible for Ex-4-mediated MSC growth, mobilization and survival. These findings provide an attractive method of maximizing the effectiveness of MSC-based therapies in clinical applications. PMID- 26250573 TI - Rigorous tests of gene-environment interactions in a lab study of the oxytocin receptor gene (OXTR), alcohol exposure, and aggression. AB - Naturalistic studies of gene-environment interactions (G X E) have been plagued by several limitations, including difficulty isolating specific environmental risk factors from other correlated aspects of the environment, gene-environment correlation (rGE ), and the use of a single genetic variant to represent the influence of a gene. We present results from 235 Finnish young men in two lab studies of aggression and alcohol challenge that attempt to redress these limitations of the extant G X E literature. Specifically, we use a latent variable modeling approach in an attempt to more fully account for genetic variation across the oxytocin receptor gene (OXTR) and to robustly test its main effects on aggression and its interaction with alcohol exposure. We also modeled aggression as a latent variable comprising various indices, including the average and maximum levels of aggression, the earliest trial on which aggression was expressed, and the proportion of trials on which the minimum and maximum levels of aggression were expressed. The best fitting model for the genetic variation across OXTR included six factors derived from an exploratory factor analysis, roughly corresponding to six haplotype blocks. Aggression levels were higher on trials in which participants were administered alcohol, won, or were provoked. There was a significant main effect of OXTR on aggression across studies after controlling for covariates. The interaction of OXTR and alcohol was also significant across studies, such that OXTR had stronger effects on aggression in the alcohol administration condition. (c) 2015 Wiley Periodicals, Inc. PMID- 26250574 TI - The G protein-coupled estrogen receptor 1 (GPER-1) contributes to the proliferation and survival of mantle cell lymphoma cells. PMID- 26250575 TI - Impact of mutational status on pregnancy outcome in patients with essential thrombocytemia. PMID- 26250576 TI - Characteristics and management of rash following lenalidomide and rituximab in patients with untreated indolent non-Hodgkin lymphoma. PMID- 26250577 TI - DNMT3A mutations occur early or late in patients with myeloproliferative neoplasms and mutation order influences phenotype. PMID- 26250578 TI - TIGIT-positive circulating follicular helper T cells display robust B-cell help functions: potential role in sickle cell alloimmunization. AB - T follicular helper cells are the main CD4(+) T cells specialized in supporting B cell responses, but their role in driving transfusion-associated alloimmunization is not fully characterized. Reports of T follicular helper subsets displaying various markers and functional activities underscore the need for better characterization/identification of markers with defined functions. Here we show that a previously unidentified subset of human circulating T follicular helper cells expressing TIGIT, the T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains, exhibit strong B-cell help functions. Compared to the subset lacking the receptor, T follicular helper cells expressing this receptor up-regulated co-stimulatory molecules and produced higher levels of interleukins (IL-21 and IL-4) critical for promoting B-cell activation/differentiation. Furthermore, this subset was more efficient at inducing the differentiation of B cells into plasmablasts and promoting immunoglobulin G production. Blocking antibodies abrogated the B-cell help properties of receptor-expressing T follicular helper cells, consistent with the key role of this molecule in T follicular helper-associated responses. Importantly, in chronically transfused patients with sickle cell anemia, we identified functional differences of this subset between alloimmunized and non alloimmunized patients. Altogether, these studies suggest that expression of the T-cell immunoreceptor with Ig and immunoreceptor tyro-sine-based inhibitory domains not only represents a novel circulating T follicular helper biomarker, but is also functional and promotes strong B-cell help and ensuing immunoglobulin G production. These findings open the way to defining new diagnostic and therapeutic strategies in modulating humoral responses in alloimmunization, and possibly vaccination, autoimmunity and immune deficiencies. PMID- 26250579 TI - Better allele-level matching improves transplant-related mortality after double cord blood transplantation. AB - Cord blood transplant requires less stringent human leukocyte antigen matching than unrelated donors. In 133 patients with hematologic malignancies who engrafted after double cord blood transplantation with a dominant unit, we studied the effect of high resolution testing at 4 loci (-A, -B, -C, -DRB1) for its impact on 2-year transplant-related mortality. Ten percent of the dominant cord blood units were matched at 7-8/8 alleles using HLA-A, -B, -C, and -DRB1; 25% were matched at 6/8, 40% at 5/8, and 25% at 4/8 or less allele. High resolution typing at 4 loci showed that there was no 2-year transplant-related mortality in 7-8/8 matched patients. Patients with 5-6/8 matched dominant cord blood units had 2-year transplant-related mortality of 39% while patients with 4/8 or less matched units had 60%. Multivariate regression analyses confirmed the independent effect of high resolution typing on the outcome when adjusted for age, diagnosis, CD34(+) cell dose infused, graft manipulation and cord to cord matching. The worst prognostic group included patients aged over 32 years with 4/8 or less matched cord blood units compared with patients who were either younger than 32 years old independent of allele-level matching, or aged over 32 years but with 5-6/8 matched cord blood units (Hazard Ratio 2.2; 95% confidence interval: 1.3-3.7; P<0.001). Patients with 7-8/8 matched units remained the group with the best prognosis. Our data suggest that high resolution typing at 4 loci and selecting cord blood units matched at at least 5/8 alleles may reduce transplant-related mortality after double cord blood transplantation. PMID- 26250580 TI - Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. AB - Patients with refractory or relapsed and refractory multiple myeloma who no longer receive benefit from novel agents have limited treatment options and short expected survival. del(17p) and t(4;14) are correlated with shortened survival. The phase 3 MM-003 trial demonstrated significant progression-free and overall survival benefits from treatment with pomalidomide plus low-dose dexamethasone compared to high-dose dexamethasone among patients in whom bortezomib and lenalidomide treatment had failed. At an updated median follow-up of 15.4 months, the progression-free survival was 4.0 versus 1.9 months (HR, 0.50; P<0.001), and median overall survival was 13.1 versus 8.1 months (HR, 0.72; P=0.009). Pomalidomide plus low-dose dexamethasone, compared with high-dose dexamethasone, improved progression-free survival in patients with del(17p) (4.6 versus 1.1 months; HR, 0.34; P <0.001), t(4;14) (2.8 versus 1.9 months; HR, 0.49; P=0.028), and in standard-risk patients (4.2 versus 2.3 months; HR, 0.55; P<0.001). Although the majority of patients treated with high-dose dexamethasone took pomalidomide after discontinuation, the overall survival of patients treated with pomalidomide plus low-dose dexamethasone or high-dose dexamethasone was 12.6 versus 7.7 months (HR, 0.45; P=0.008) in patients with del(17p), 7.5 versus 4.9 months (HR, 1.12; P=0.761) in those with t(4;14), and 14.0 versus 9.0 months (HR, 0.85; P=0.380) in standard-risk subjects. The overall response rate was higher in patients treated with pomalidomide plus low-dose dexamethasone than in those treated with high-dose dexamethasone both among standard-risk patients (35.2% versus 9.7%) and those with del(17p) (31.8% versus 4.3%), whereas it was similar in patients with t(4;14) (15.9% versus 13.3%). The safety of pomalidomide plus low-dose dexamethasone was consistent with initial reports. In conclusion, pomalidomide plus low-dose dexamethasone is efficacious in patients with relapsed/refractory multiple myeloma and del(17p) and/or t(4;14). This study is registered at ClinicalTrials.gov as NCT01311687 and with EudraCT as 2010-019820 30. PMID- 26250582 TI - Coordination Properties of Perfluoroethyl- and Perfluorophenyl-Substituted Phosphonous acids, R(f)P(OH)2. AB - Phosphinic acids, R(f)P(O)(OH)H (R(f)=CF3, C2F5, C6F5), turned out to be excellent preligands for the coordination of phosphonous acids, R(f)P(OH)2. Addition of C2F5P(O)(OH)H to solid PtCl2 under different reaction conditions allows the isolation and full characterization of the mononuclear complexes [ClPt{P(C2F5)(OH)O}{P(C2F5)(OH)2}2] and [Pt{P(C2F5)(OH)O}2{P(C2F5)(OH)2}] containing hydrogen-bridged [R(f)P(OH)O](-) and R(f)P(OH)2 units. Further deprotonation of [Pt{P(C2F5)(OH)O}2{P(C2F5)(OH)2}2] leads to the formation of the dianionic platinate, [Pt{P(C2F5)(OH)O}4](2-), revealing four intramolecular hydrogen bridges. With PdCl2 the dinuclear complex [Pd2(MU Cl)2{[P(C2F5)(OH)O]2H}2] was isolated and characterized. The Cl(-) free complex [Pd{P(C2F5)(OH)O}2{P(C2F5)(OH)2}2] was also prepared and deprotonated to the dianionic palladate, [Pd{P(C2F5)(OH)O}4](2-). Both compounds were characterized by NMR spectroscopy, IR spectroscopy, and X-ray analyses. In addition, the C6F5 derivatives [ClPt{P(C6F5)(OH)O}{P(C6F5)(OH)2}2] and [Pd2(MU Cl)2{[P(C6F5)(OH)O]2H}2] as well as the CF3 derivative [Pd2(MU-Cl)2 {[P(CF3)(OH)O]2H}2] were synthesized and fully characterized. Phosphonous acid complexes are inert towards air and moisture and can be stored for several months without decomposition. The catalytic activity of the palladium complexes in the Suzuki cross-coupling reaction between 1-bromo-3-fluorobenzene and phenyl boronic acid was demonstrated. PMID- 26250581 TI - Risks and benefits of sex-mismatched hematopoietic cell transplantation differ according to conditioning strategy. AB - Sex-mismatched hematopoietic cell transplantation is linked to increased graft versus-host disease and mortality in myeloablative conditioning. Here we evaluated outcomes of 1,041 adult transplant recipients at two centers between 2006 and 2013 and investigated how the effect of sex-mismatching differed in myeloablative, reduced-intensity, and non-myeloablative total lymphoid irradiation with anti-thymocyte globulin conditioning. Among patients who underwent myeloablative conditioning, male recipients with female donors had increased chronic graft-versus-host disease (hazard ratio 1.83, P<0.01), increased non-relapse mortality (hazard ratio 1.84, P=0.022) and inferior overall survival (hazard ratio 1.59, P=0.018). In contrast, among patients who received reduced-intensity conditioning, male recipients with female donors had increased acute graft-versus-host disease (hazard ratio 1.96, P<0.01) but no difference in non-relapse mortality or overall survival. Among the patients who underwent total lymphoid irradiation with anti-thymocyte globulin, male recipients with female donors showed no increase in graft-versus-host disease or non-relapse mortality. Notably, only in the cohort receiving total lymphoid irradiation with anti thymocyte globulin were male recipients with female donors significantly associated with reduced relapse (hazard ratio 0.64, P<0.01), and allo-antibody responses against H-Y antigens were predictive of reduced relapse. In the cohort given total lymphoid irradiation with anti-thymocyte globulin, the graft-versus leukemia effect resulted in superior overall survival in recipients of sex mismatched grafts (HR 0.69, P=0.037). In addition, only in the cohort treated with total lymphoid irradiation with anti-thymocyte globulin were female recipients with male donors associated with reduced relapse (hazard ratio 0.59, P<0.01) and superior survival (hazard ratio 0.61, P=0.014) compared with sex matched pairs. We conclude that the risks and benefits of sex-mismatched transplants appear to differ according to conditioning strategy and this could affect donor selection. PMID- 26250584 TI - Fetal hydrocephalus and neonatal stroke as the first presentation of protein C deficiency. AB - Severe protein C-deficiency is a rare heritable thrombophilia of the newborn. Infants with biallelic PROC mutations present purpura fulminans and intracranial thromboembolism, while the prenatal onset of mutated heterozygotes remains unclear. We herewith present the first case of fetal ventriculomegaly and neonatal stroke associated with heterozygous PROC mutation. The infant was born to a healthy mother at 38 gestational weeks. The fetal growth had been normal, but the routine ultrasound screening had indicated mild hydrocephalus at 28 weeks of gestation. He developed convulsions two days after birth. Computed tomography of the brain revealed multiple hemorrhagic infarctions and ventriculomegaly. Dissociated levels of the plasma activity between protein C (21%) and protein S (42%) reached to determine the heterozygote of PROC c.574_576delAAG, a common thrombophilic predisposition in Asian ancestries. PC-mutant heterozygotes may have a limited high risk of cerebral thromboembolism during the perinatal course. PMID- 26250585 TI - Evaluating the role of treatment-related toxicities in the challenges facing targeted therapies for advanced hepatocellular carcinoma. AB - Advanced hepatocellular carcinoma (aHCC) is a complex disease beset by underlying liver dysfunction and high molecular heterogeneity. Sorafenib, introduced in 2007, is considered the standard systemic therapy for aHCC, yet only a minority of patients show objective evidence of a response radiologically, and median overall survival is still under 1 year. Other targeted drugs for the treatment of aHCC have failed to reach their primary endpoints of improved/non-inferior overall survival in comparison with sorafenib in recent phase 3 trials. Toxicity was a significant problem, raising the question as to whether outcomes in aHCC trials are being hindered by high levels of adverse events (AEs), particularly in populations with underlying cirrhosis. This is true of six recently failed phase 3 studies involving sunitinib, erlotinib, linifanib, brivanib (two trials), and everolimus, as well as ongoing phase 2 and 3 trials of other drugs that work through similar molecular pathways. This article reviews these drugs' toxicities, with a focus on AEs as a reason for their failure in phase 3 trials of patients with aHCC. We also review completed and ongoing phase 3 studies of combination therapies with sorafenib, as well as toxicities of many of the targeted agents in aHCC, including geographic/ethnic differences, measures of toxicity, and strategies to improve management. PMID- 26250586 TI - miR-34c-3p functions as a tumour suppressor by inhibiting eIF4E expression in non small cell lung cancer. AB - OBJECTIVES: MicroRNAs (miRNAs) are small non-coding RNAs that post transcriptionally regulate gene expression and mediate diverse physiological processes. In this study, we investigated functions of miRNA miR-34c-3p in non small cell lung cancer (NSCLC). MATERIALS AND METHODS: miR-34c-3p expression was evaluated by qPCR. Cell viability was examined by MTT and proliferation by cell cycle analysis. Cell migration and invasion were tested using Transwells with/without Matrigel coating. Western blot analysis was performed for eIF4E, c Myc, Cyclin D1, survivin and Mcl-1 protein expression. RESULTS: miR-34c-3p expression was significantly reduced in tissues and serum samples from NSCLC patients and in NSCLC cell lines A549, H460, H23, H157 and H1299. Overexpression of miR-34c-3p in A549 and H157 cells reduced cell proliferation, migration and invasion, whereas transfection with miR-34c-3p inhibitor (miR-34c-3p-in) produced opposite effects. Target analysis using algorithms miRanda, TargetScan and DIANA identified eIF4E as a potential target of miR-34c-3p. Luciferase assay using the eIF4E 3'-UTR reporter carrying a putative miR-34c-3p target sequence revealed eIF4E to be a specific target of miR-34c-3p. Overexpression of miR-34c-3p in NSCLS cell lines led to significant reduction in mRNA and protein levels of eIF4E, whereas inhibition of miR-34c-3p resulted in significant increase in eIf4e protein levels, confirming eIF4E to be a direct target of miR-34c-3p in NSCLS. Overexpression of eIF4E in A549 cells promoted cell proliferation, migration and invasion, which were partially reversed by miR-34c-3p. CONCLUSION: miR-34c-3p directly targeted eIF4E and reduced miR-34c-3p expression in NSCLC, promoting cell cycle progression, proliferation, migration and invasion. PMID- 26250587 TI - Robust finite-time chaos synchronization of uncertain permanent magnet synchronous motors. AB - In this paper, a robust finite-time chaos synchronization scheme is proposed for two uncertain third-order permanent magnet synchronous motors (PMSMs). The whole synchronization error system is divided into two cascaded subsystems: a first order subsystem and a second-order subsystem. For the first subsystem, we design a finite-time controller based on the finite-time Lyapunov stability theory. Then, according to the backstepping idea and the adding a power integrator technique, a second finite-time controller is constructed recursively for the second subsystem. No exogenous forces are required in the controllers design but only the direct-axis (d-axis) and the quadrature-axis (q-axis) stator voltages are used as manipulated variables. Comparative simulations are provided to show the effectiveness and superior performance of the proposed method. PMID- 26250588 TI - L1 adaptive control of uncertain gear transmission servo systems with deadzone nonlinearity. AB - This paper deals with the adaptive control problem of Gear Transmission Servo (GTS) systems in the presence of unknown deadzone nonlinearity and viscous friction. A global differential homeomorphism based on a novel differentiable deadzone model is proposed first. Since there exist both matched and unmatched state-dependent unknown nonlinearities, a full-state feedback L1 adaptive controller is constructed to achieve uniformly bounded transient response in addition to steady-state performance. Finally, simulation results are included to show the elimination of limit cycles, in addition to demonstrating the main results in this paper. PMID- 26250590 TI - Abstracts of the 2nd Prostate Cancer World Congress, Australia, 17-21 August 2015. PMID- 26250589 TI - Welcome for PCWC BJUI supplement A global perspective from the Prostate Cancer World Congress. PMID- 26250592 TI - Corrigendum. PMID- 26250591 TI - Patients with pyoderma gangrenosum - analyses of the German DRG data from 2012. AB - Pyoderma gangrenosum (PG) is a rarely diagnosed non-infectious neutrophil ulcerative dermatosis with only limited knowledge on the underlying auto inflammatory process. To unravel common cofactors and comorbidities in patients with PG we analysed Diagnosis Related Groups (DRG) cases of all inpatients diagnosed with PG in German hospitals in 2012. We received data of 1227 inpatient cases having PG as primary diagnosis and 985 inpatient cases with PG as secondary diagnosis. The ratio of women to men was 2:1, and the most often registered age was 75-79 years. Common comorbidities were arterial hypertension (50.3%), non insulin-dependent diabetes mellitus (25.1%) and dysfunction of lipid metabolism (10.8%). In sum, 94.8% of the patients suffered from aspects of metabolic syndrome. Other comorbidities were Crohn's disease (4.5%), ulcerative colitis (4.2%), chronic polyarthritis (5.2%), monoclonal gammopathy or myelodysplastic syndrome (2.5%), leukaemia (1.1%) and lymphoma (0.4%). DRG data do not reflect individual patients, but rather patient cases. We described the worldwide largest PG population and confirmed a wide range of potentially relevant and partly not yet described cofactors and comorbidities such as metabolic syndrome. PMID- 26250593 TI - Use of Transparent Film Dressing for Dermoscopy of Mucosal Lesions. AB - Genital and mucosal nevi are not uncommonly encountered in children. These type of nevi highlight challenges in performing a thorough dermoscopic examination. Contact dermoscopy can provide additional information about a nevus that non contact dermoscopy cannot. We propose applying a sterile transparent film dressing over the dermatoscope to act as a waterproof barrier that is also impermeable to bacteria and viruses. This provides a sanitary way to evaluate nevi in genital skin as well as on other mucosal surfaces. PMID- 26250594 TI - Inclusion of mPRISM potential for polymer-induced protein interactions enables modeling of second osmotic virial coefficients in aqueous polymer-salt solutions. AB - The downstream processing of therapeutic proteins is a challenging task. Key information needed to estimate applicable workup strategies (e.g. crystallization) are the interactions of the proteins with other components in solution. This information can be deduced from the second osmotic virial coefficient B22 , measurable by static light scattering. Thermodynamic models are very valuable for predicting B22 data for different process conditions and thus decrease the experimental effort. Available B22 models consider aqueous salt solutions but fail for the prediction of B22 if an additional polymer is present in solution. This is due to the fact that depending on the polymer concentration protein-protein interactions are not rectified as assumed within these models. In this work, we developed an extension of the xDLVO model to predict B22 data of proteins in aqueous polymer-salt solutions. To show the broad applicability of the model, lysozyme, gamma-globulin and D-xylose ketol isomerase in aqueous salt solution containing polyethylene glycol were considered. For all proteins considered, the modified xDLVO model was able to predict the experimentally observed non-monotonical course in B22 data with high accuracy. When used in an early stage in process development, the model will contribute to an efficient and cost effective downstream processing development. PMID- 26250595 TI - Recovery of Missing Persons in Cyprus: Heavy Equipment Methods and Techniques for Complex Well Excavations. AB - This technical note presents the methods and techniques developed by the Bi communal Forensic Team (BCFT) of the Committee on Missing Persons in Cyprus (CMP) used to excavate and exhume the remains of missing persons, many of whom were buried in deep wells at sites across the island of Cyprus during the conflict period of the 1960s and 1970s. A total of 493 Turkish Cypriots and 1508 Greek Cypriots were officially reported missing by the two communities as a result of the conflict. Since the team's formation, in 2005, the BCFT has excavated 114 wells, resulting in the recovery of 195 missing individuals from 35 of these well excavations. The standard excavation approach used by the BCFT, especially for deep well recovery, consists of "ramp," "pocket," and "pool" components. These excavation features enable CMP archaeologists to excavate deep wells safely and efficiently while simultaneously permitting time for thorough documentation and unimpeded recovery of human remains. The team uses three variants of this approach to cope with the variety of geological, physical, and hydrological contexts faced in Cyprus' wells, including hard and soft landforms, the presence or absence of water, and limitations imposed by surrounding infrastructure. The "terracing", "double-ramp", and "single-ramp" variations are detailed with respect to the environmental contexts which prescribe their use. The BCFT's general procedures for human remains recovery and standard well safety protocols conclude the article. PMID- 26250596 TI - An Apprenticeship Rotation Teaches Chief Residents Nontechnical Skills and ACGME Core Competencies. AB - BACKGROUND: Traditionally, surgical training has used an apprenticeship model but has more recently moved to a service-based model, with groups of residents working with groups of attending surgeons. We developed an apprenticeship rotation to enhance one-on-one interaction between chief residents and selected faculty. We hypothesized that the apprenticeship rotation would be effective for teaching nontechnical skills (NTS) and core competencies. MATERIALS AND METHODS: An apprenticeship rotation was created at a university-based surgery residency in which each chief resident selected a single attending surgeon with whom to work exclusively with for a 4-week period. Emphasis was placed on teaching intraoperative NTS as well as the 4 difficult-to-teach Accreditation Council for Graduate Medical Education core competencies (DCC): Interpersonal and Communication Skills, Practice-Based Learning and Improvement, Professionalism, and Systems-Based Practice. Participants were surveyed afterwards about their rotation using a 5-point Likert scale. A Wilcoxon signed rank test was used to compare differences depending on data distribution. RESULTS: All (13/13) the chief residents and 67% (8/12) faculty completed the survey. Overall, 85% of residents and 87.5% of faculty would recommend the rotation to other residents/faculty members. Both residents and faculty reported improvement in trainees' technical skills and NTS. Residents reported improvement in all 4 DCC, particularly, Practice-Based Learning and Improvement, Professionalism, and Interpersonal and Communication Skills. CONCLUSION: The apprenticeship rotation is an effective means of teaching residents both NTS and DCC essential for independent practice. Consideration should be given to introducing this program into surgical curricula nationally. PMID- 26250597 TI - Anthocyanin-rich extracts from blackberry, wild blueberry, strawberry, and chokeberry: antioxidant activity and inhibitory effect on oleic acid-induced hepatic steatosis in vitro. AB - BACKGROUND: Limited information is available regarding the relationship between the chemical structures and inhibitory effects of anthocyanin (ACN) on triglyceride (TG) overaccumulation. Thus this study investigated the antioxidant activity and inhibitory effect of blackberry, wild blueberry, strawberry, and chokeberry ACN-rich extracts, with different structural characteristics, on oleic acid-induced hepatic steatosis in vitro. Four major ACNs from these berries, with different aglycones, namely cyanidin-3-glucoside (Cy-3-glu), delphinidin-3 glucoside, pelargonidin-3-glucoside, and malvidin-3-glucoside, were also investigated. RESULTS: Blackberry ACN-rich extract exhibited the most significant inhibitory effect on TG clearance (30.5% +/- 3.4%) and reactive oxygen species generation. TG clearance was significantly correlated with total phenolic content (r = 0.991, P < 0.05) and oxygen radical absorbance capacity value (r = 0.961, P < 0.05). Furthermore, Cy-3-glu showed the highest inhibitory effect on intracellular TG overaccumulation, with a maximum TG clearance of 61.3% at 40 ug mL(-1) . CONCLUSION: Our findings suggest that the inhibitory effects of different ACNs on oleic acid-induced hepatic steatosis significantly vary. Cy-3 glu, which contains the ortho hydroxyl group in its B ring, possibly confers the protective effects of antioxidants and inhibits TG accumulation in HepG2 cells. (c) 2015 Society of Chemical Industry. PMID- 26250600 TI - Cervical arterial dissection: An overview and implications for manipulative therapy practice. AB - INTRODUCTION: Cervical arterial dissection (CAD) is a common cause of stroke in young people under 55 years. It can occur spontaneously or subsequent to minor trauma or infection. The incidence is difficult to determine accurately as not all CAD progress to stroke. CAD is the most catastrophic adverse event associated with cervical manipulative therapy but it is rare. Early features of CAD can mimic a painful musculoskeletal presentation and a patient may present for treatment of neck pain and headache with a dissection in progress. Whether the manipulative technique is responsible for dissection or whether the diagnosis of CAD has been missed is unclear. Identification of individuals at risk, or early recognition of CAD could help expedite medical intervention and avoid inappropriate treatment. PURPOSE: The aims of this masterclass are to outline current research into the pathophysiology, aetiology and clinical presentation of CAD, to place the risk in context in a manipulative therapy setting and to discuss its possible clinical recognition. IMPLICATIONS: For those patients presenting with recent onset, moderate to severe unusual headache or neck pain, clinicians should perform a careful history, in particular questioning about recent exposure to head/neck trauma or neck strain. Cardiovascular factors may not be particularly useful indicators of risk of dissection. Clinicians should also be alert to reports of transient neurological dysfunction such as visual disturbance and balance deficits, arm paraesthesia and speech deficits, as these may be subtle. If clinicians suspect arterial dissection is in progress patients should be urgently referred for medical evaluation. PMID- 26250601 TI - Multiple scattering of an acoustic wave from a network of cylindrical rods encased in a solid viscoelastic medium. AB - In this paper, the multiple scattering of normally and obliquely incident acoustic waves from a network of cylindrical rods embedded in a viscoelastic medium is investigated. The cylinders can be either isotropic or transversely isotropic. This problem has applications in studying the interaction of ultrasonic waves with composite materials in ultrasonic nondestructive testing. By extending the classical theory of scattering from a single cylinder, the multiple scattering equations are derived incorporating all three kinds of longitudinal, horizontally polarized shear and vertically polarized shear waves in a viscoelastic matrix. The spatial angle of the incident wave is arbitrarily chosen and the backscattered waves can be found in any point of the space. In the proposed method, there are no restrictions on the number of cylinders and/or on the order of scattering. Therefore, the method is capable of handling any order of scattering from any number of cylinders. To experimentally validate the numerical results, a number of experiments are conducted on steel cylinders embedded in a polymeric matrix. The scattered waves from the cylinders are received and their corresponding form functions are obtained. By comparing the numerical and experimental results, a good agreement is observed. PMID- 26250598 TI - Gene-Stress-Epigenetic Regulation of FKBP5: Clinical and Translational Implications. AB - Stress responses and related outcomes vary markedly across individuals. Elucidating the molecular underpinnings of this variability is of great relevance for developing individualized prevention strategies and treatments for stress related disorders. An important modulator of stress responses is the FK506 binding protein 51 (FKBP5/FKBP51). FKBP5 acts as a co-chaperone that modulates not only glucocorticoid receptor activity in response to stressors but also a multitude of other cellular processes in both the brain and periphery. Notably, the FKBP5 gene is regulated via complex interactions among environmental stressors, FKBP5 genetic variants, and epigenetic modifications of glucocorticoid responsive genomic sites. These interactions can result in FKBP5 disinhibition that has been shown to contribute to a number of aberrant phenotypes in both rodents and humans. Consequently, FKBP5 blockade may hold promise as treatment intervention for stress-related disorders, and recently developed selective FKBP5 blockers show encouraging results in vitro and in rodent models. Although risk for stress-related disorders is conferred by multiple environmental and genetic factors, the findings related to FKBP5 illustrate how a deeper understanding of the molecular and systemic mechanisms underlying specific gene-environment interactions may provide insights into the pathogenesis of stress-related disorders. PMID- 26250599 TI - The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming. AB - Adversity experienced during gestation is a predictor of lifetime neuropsychiatric disease susceptibility. Specifically, maternal stress during pregnancy predisposes offspring to sex-biased neurodevelopmental disorders, including schizophrenia, attention deficit/hyperactivity disorder, and autism spectrum disorders. Animal models have demonstrated disease-relevant endophenotypes in prenatally stressed offspring and have provided unique insight into potential programmatic mechanisms. The placenta has a critical role in the deleterious and sex-specific effects of maternal stress and other fetal exposures on the developing brain. Stress-induced perturbations of the maternal milieu are conveyed to the embryo via the placenta, the maternal-fetal intermediary responsible for maintaining intrauterine homeostasis. Disruption of vital placental functions can have a significant impact on fetal development, including the brain, outcomes that are largely sex-specific. Here we review the novel involvement of the placenta in the transmission of the maternal adverse environment and effects on the developing brain. PMID- 26250602 TI - Controversies in orbital reconstruction-III. Biomaterials for orbital reconstruction: a review with clinical recommendations. AB - The goal of orbital reconstruction is to repair trauma defects, to correct the position of the eye anatomically, avoiding enophthalmos, and to restore ocular function. For the reconstruction of (trauma) defects, many surgeons recommend materials that can be bent into an anatomical shape and that possess the properties of radiopacity and long-term stability. However, apart from these desired properties, the ideal material for orbital reconstruction remains controversial. Autologous bone is often mentioned as the 'gold standard,' likely because of its mechanical properties, revascularization potential, and its adaptation to the orbital tissue with minimal acute and chronic immune reactivity. However, autologous bone can show unpredictable resorption rates and suboptimal volume correction. In recent years, an increasing interest in the use of alloplasts for orbital reconstruction has become apparent in the literature. Modern technological advantages, such as preoperative planning, navigation, and perioperative imaging, can be beneficial in the decision to choose a certain implant. The aim of this review is to give a comprehensive overview of the advantages and disadvantages of materials used to reconstruct traumatic orbital defects and to provide a practical, evidence-based, complexity-driven set of guidelines. PMID- 26250603 TI - Surgical accuracy of three-dimensional virtual planning: a pilot study of bimaxillary orthognathic procedures including maxillary segmentation. AB - This retrospective study evaluated the precision and positional accuracy of different orthognathic procedures following virtual surgical planning in 30 patients. To date, no studies of three-dimensional virtual surgical planning have evaluated the influence of segmentation on positional accuracy and transverse expansion. Furthermore, only a few have evaluated the precision and accuracy of genioplasty in placement of the chin segment. The virtual surgical plan was compared with the postsurgical outcome by using three linear and three rotational measurements. The influence of maxillary segmentation was analyzed in both superior and inferior maxillary repositioning. In addition, transverse surgical expansion was compared with the postsurgical expansion obtained. An overall, high degree of linear accuracy between planned and postsurgical outcomes was found, but with a large standard deviation. Rotational difference showed an increase in pitch, mainly affecting the maxilla. Segmentation had no significant influence on maxillary placement. However, a posterior movement was observed in inferior maxillary repositioning. A lack of transverse expansion was observed in the segmented maxilla independent of the degree of expansion. PMID- 26250604 TI - New Italian lesbian, gay and bisexual psychotherapy guidelines: A review. AB - Although homosexuality was depathologized in the last century and the majority of mental health professionals consider it to be a normal variant of human sexuality, some psychologists and psychiatrists still have negative attitudes toward lesbian, gay and bisexual (LGB) clients. Sometimes they provide interventions aimed at changing sexual orientation through 'reparative' or 'conversion' therapies. At other times their interventions are influenced by anti gay prejudices or simply by lack of knowledge about sexual minorities. This paper argues for the need for appropriate treatment guidelines aimed at providing bias free, respectful, and effective interventions given that Italian health associations have delayed providing them. Some of the main guidelines recently approved by the Consiglio Nazionale dell'Ordine degli Psicologi (National Council of the Italian Association of Psychologists) are presented. Issues addressed include differences between gender and sexual orientation, minority stress, including perceived stigma and internalized stigma, homophobic bullying, coming out, and resilience. Respectful listening to LGB and questioning clients, affirming their identities and fostering a sense of resilience are essential requirements for all mental health professionals wishing to provide effective interventions in a society where sexual minorities are subjected to discrimination throughout their entire life cycle. PMID- 26250605 TI - Highly electron-poor Buchwald-type ligand: application for Pd-catalysed direct arylation of thiophene derivatives and theoretical consideration of the secondary Pd(0)-arene interaction. AB - Highly electron-poor SPhos ligands bearing either 2,6-bis(trifluoromethyl)-4 pyridyl (BFPy) or 3,5-(CF3)2C6H3 groups were synthesised. The former ligand highly accelerated the Pd-catalysed direct arylation of 2-propylthiophene, 2 methylthiophene or benzo[b]thiophene with only 1 mol% of the catalyst. This high catalytic activity can be attributed to a combination of electronic properties and the secondary Pd-arene interaction of BFPySPhos. The secondary interactions of SPhos, PhSPhos and BFPySPhos were optimised at the oniom(mp2/lanl2dz : b3lyp/lanl2dz) level and were further evaluated using the NBO method by DFT at the M06-2X/6-31G(d) level with LanL2DZ + ECP. The deletion energy analysis showed that the transfer of electrons from Pd to aromatic ring is the dominating factor for the secondary Pd-arene interaction of SPhos-Pd(0) complexes. Although an electron-poor BFPySPhos does not particularly favour this type of interaction, this interaction is still substantial enough to sufficiently stabilise the BFPySPhos-Pd complex. PMID- 26250606 TI - Synergistic anticancer efficacy of MEK inhibition and dual PI3K/mTOR inhibition in castration-resistant prostate cancer. AB - BACKGROUND: PTEN deletion, mutation or reduced expression occurs in 63% of metastatic prostate tumors, resulting in the activation of PI3K and its downstream targets, AKT and mTOR. Inhibition of the PI3K pathway results in upregulation of the MAPK pathway. Therefore, co-administration of inhibitors of both pathways, GSK2126458 as a dual PI3K/mTOR inhibitor, and AZD6244 as a MEK inhibitor, is able to overcome resistance and increase anti-tumor efficacy. METHODS: PC3, DU145, LNCaP, and CRPC patient-derived cells were used to assess apoptosis upon exposure to the drug combination. The human DU145 and PC3 tumor xenograft mouse model was employed to evaluate in vivo efficacy. CellTiter Glo(r) luminescent assay, annexin V-FITC apoptosis detection, cell cycle analysis, Western blotting and immunohistochemistry were conducted. Statistical evaluation of the results was performed by one-way ANOVA. RESULTS: The combination of GSK2126458 and AZD6244 inhibited the growth of DU145 and PC3 prostate cancer cells in vitro and in vivo. GSK2126458 decreased phospho-AKT while increasing phospho-ERK and AZD6244 decreased phospho-ERK efficiently while increasing phospho-AKT. The combination of GSK2126458 and AZD6244 decreased both phospho-AKT and phospho-ERK effectively in vitro and in vivo. The combination treatment synergistically induced annexin V-positive cells, sub-G1 cells, and cleavage of caspase-9, caspase-3 and poly-ADP ribose polymerase (PARP) in DU145 cells in vitro. Moreover, the combination decreased the level of Ki-67, and increased TUNEL-positive cells and cleaved caspase-3 in DU145 xenograft tumors implanted in mice. In addition, this combination treatment inhibited both the PI3K and MEK pathway primary in cultures from CRPC patients harboring PTEN loss, leading to synergistic anti-tumor effect. CONCLUSIONS: The combination of GSK2126458 and AZD6244 blocks both the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways simultaneously and is an effective strategy for the treatment of CRPCs. PMID- 26250607 TI - Multi-institutional study of risk factors for perioperative morbidity following transnasal endoscopic pituitary adenoma surgery. AB - BACKGROUND: The goal of this study was to identify preoperative risk factors associated with increased perioperative morbidity after endoscopic pituitary surgery. METHODS: A retrospective review of patients undergoing endoscopic pituitary adenoma surgery between 2002 and 2014 at 6 international centers was performed. Standard demographic and comorbidity data, as well as information regarding tumor extent and treatment were collected. Logistic regression was used to examine risk factors for the following 30-day outcomes: systemic complications, intracranial complications, postoperative cerebrospinal fluid (CSF) leaks, length of hospital stay, readmission, and reoperation. RESULTS: Data was collected on 982 patients with a mean age of 52 years. The median body mass index (BMI) for all patients was 30.9 kg/m(2) with 56% female. The median hospital stay was 5 days and 23.8% of patients suffered a postoperative adverse event. Systemic complications occurred in 3.2% of patients and intraventricular extension was a risk factor (odds ratio [OR] 8.9). Intracranial complications occurred in 7.3% of patients and risk factors included previous radiation (OR 8.6) and intraventricular extension (OR 7.9). Reoperation occurred in 6.5% of patients and intraventricular extension (OR 7.3) and age (<40 years, OR 3.5; 40 to 64 years, OR 3.2) were risk factors. Postoperative CSF leaks occurred in 5.5% of patients and risk factors included female gender (OR 2.4), BMI >= 30 (OR 2.1), age (<40 years, OR 5.3; 40 to 64 years, OR, 7.9), and intraventricular extension (OR, 9.5). CONCLUSION: Postoperative endoscopic pituitary adenoma surgery complications are associated with tumors with intraventricular extension, preoperative radiation, as well as common patient comorbidities. Identification of these factors may permit implementation of strategies to reduce postoperative complications. PMID- 26250608 TI - Communicative interactions between visually impaired mothers and their sighted children: analysis of gaze, facial expressions, voice and physical contacts. AB - BACKGROUND: Social and emotional development of infants and young children is largely based on the communicative interaction with their mother, or principal caretaker (Trevarthen ). The main modalities implied in this early communication are voice, facial expressions and gaze (Stern ). This study aims at analysing early mother-child interactions in the case of visually impaired mothers who do not have access to their children's gaze and facial expressions. METHODS: Spontaneous play interactions between seven visually impaired mothers and their sighted children aged between 6 months and 3 years were filmed. These dyads were compared with a control group of sighted mothers and children analysing four modalities of communication and interaction regulation: gaze, physical contacts, verbal productions and facial expressions. RESULTS: The visually impaired mothers' facial expressions differed from the ones of sighted mothers mainly with respect to forehead movements, leading to an impoverishment of conveyed meaning. Regarding the other communicative modalities, results suggest that visually impaired mothers and their children use compensatory strategies to guaranty harmonic interaction despite the mother's impairment: whereas gaze results the main factor of interaction regulation in sighted dyads, physical contacts and verbal productions assume a prevalent role in dyads with visually impaired mothers. Moreover, visually impaired mother's children seem to be able to differentiate between their mother and sighted interaction partners, adapting differential modes of communication. CONCLUSIONS: The results of this study show that, in spite of the obvious differences in the modes of communication, visual impairment does not prevent a harmonious interaction with the child. PMID- 26250609 TI - Acculturation and Self-Rated Mental Health Among Latino and Asian Immigrants in the United States: A Latent Class Analysis. AB - This study assesses variations in acculturation experiences by identifying distinct acculturation classes, and investigates the role of these acculturation classes for self-rated mental health among Latino and Asian immigrants in the United States. Using 2002-2003 the National Latino and Asian American Study, Latent Class Analysis is used to capture variations in immigrant classes (recent arrivals, separated, bicultural and assimilated), and OLS regressions are used to assess the link between acculturation classes and self-rated mental health. For both Latinos and Asians, bicultural immigrants reported the best mental health, and separated immigrants and recent arrivals reported the worst mental health. The findings also reveal group differences in acculturation classes, whereby Latino immigrants were more likely to be in the separated class and recent arrivals class relative to Asian immigrants. While there was not a significant group difference in self-rated mental health at the bivariate level, controlling for acculturation classes revealed that Latinos report better self-rated mental health than Asians. Thus, Latino immigrants would actually have better self-rated mental health than their Asian counterparts if they were not more likely to be represented in less acculturated classes (separated class and recent arrivals) and/or as likely to be in the bicultural class as their Asian counterparts. Together the findings underscore the nuanced and complex nature of the acculturation process, highlighting the importance of race differences in this process, and demonstrate the role of acculturation classes for immigrant group differences in self-rated mental health. PMID- 26250610 TI - HIV Risk Behaviors Among Latina Women Tested for HIV in Florida by Country of Birth, 2012. AB - Latina women in the United States (US) are disproportionately affected by human immunodeficiency virus (HIV) infection. Data are limited on the risk differences in HIV among Latinas by country of birth. This paper describes the risk behaviors among Latina women tested for HIV at public sites in Florida. Multivariate logistic regression was used to assess the demographic characteristics associated with the report of specific risk behaviors. Results indicate that foreign-born Latina women were 54 % less likely to report partner risk [95 % confidence interval (CI) 0.40, 0.54] than US-born Latina women. Reported risk behaviors varied by race/ethnicity, US-born versus foreign-born status, and by Latina country of origin. Knowledge of these differences can aid in targeting HIV prevention messaging, program decision-making, and allocation of resources, corresponding to the central approach of High Impact Prevention and the National HIV/AIDS Strategy. PMID- 26250611 TI - Optimal full matching for survival outcomes: a method that merits more widespread use. AB - Matching on the propensity score is a commonly used analytic method for estimating the effects of treatments on outcomes. Commonly used propensity score matching methods include nearest neighbor matching and nearest neighbor caliper matching. Rosenbaum (1991) proposed an optimal full matching approach, in which matched strata are formed consisting of either one treated subject and at least one control subject or one control subject and at least one treated subject. Full matching has been used rarely in the applied literature. Furthermore, its performance for use with survival outcomes has not been rigorously evaluated. We propose a method to use full matching to estimate the effect of treatment on the hazard of the occurrence of the outcome. An extensive set of Monte Carlo simulations were conducted to examine the performance of optimal full matching with survival analysis. Its performance was compared with that of nearest neighbor matching, nearest neighbor caliper matching, and inverse probability of treatment weighting using the propensity score. Full matching has superior performance compared with that of the two other matching algorithms and had comparable performance with that of inverse probability of treatment weighting using the propensity score. We illustrate the application of full matching with survival outcomes to estimate the effect of statin prescribing at hospital discharge on the hazard of post-discharge mortality in a large cohort of patients who were discharged from hospital with a diagnosis of acute myocardial infarction. Optimal full matching merits more widespread adoption in medical and epidemiological research. (c) 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID- 26250612 TI - Patterning of anteroposterior body axis displayed in the expression of Hox genes in sea cucumber Apostichopus japonicus. AB - The presence of an anteroposterior body axis is a fundamental feature of bilateria. Within this group, echinoderms have secondarily evolved pentameral symmetric body plans. Although all echinoderms present bilaterally symmetric larval stages, they dramatically rearrange their body axis and develop a pentaradial body plan during metamorphosis. Therefore, the location of their anteroposterior body axis in adult forms remains a contentious issue. Unlike other echinoderms, sea cucumbers present an obvious anteroposterior axis not rearranged during metamorphosis, thus representing an interesting group to study their anteroposterior axis patterning. Hox genes are known to play a broadly conserved role in anteroposterior axis patterning in deuterostomes. Here, we report the expression patterns of Hox genes from early development to pentactula stage in sea cucumber. In early larval stages, five Hox genes (AjHox1, AjHox7, AjHox8, AjHox11/13a, and AjHox11/13b) were expressed sequentially along the archenteron, suggesting that the role of anteroposterior patterning of the Hox genes is conserved in bilateral larvae of echinoderms. In doliolaria and pentactula stages, eight Hox genes (AjHox1, AjHox5, AjHox7, AjHox8, AjHox9/10, AjHox11/13a, AjHox11/13b, and AjHox11/13c) were expressed sequentially along the digestive tract, following a similar expression pattern to that found in the visceral mesoderm of other bilateria. Unlike other echinoderms, pentameral expression patterns of AjHox genes were not observed in sea cucumber. Altogether, we concluded that AjHox genes are involved in the patterning of the digestive tract in both larvae and metamorphosis of sea cucumbers. In addition, the anteroposterior axis in sea cucumbers might be patterned like that of other bilateria. PMID- 26250613 TI - Growth characteristics underlying the lack of a chin in pigs: a histomorphometric study. AB - OBJECTIVES: Despite similar mandibular growth to that of humans, pigs lack a chin projection as shown in most humans. To understand whether this divergence is contributed to differences in local symphyseal growth, this project characterized bone modeling activities at the symphyseal surfaces of juvenile pigs. MATERIAL AND METHODS: Symphyseal specimens from two age groups (4- and 6-month-old, n = 10) were processed into histological sections with and without decalcification, which were assessed for surface mineral apposition and bone resorption, respectively. In a blinded fashion, measurements of four parameters (MAR: mineral apposition rate, MAZ: mineral apposition zone, ES/BS: eroded surface and OC.N/BS: osteoclast number) were obtained and tested by a multivariate two-way mixed-model analyses of variance (manova) for the differences between symphyseal regions and ages. RESULTS: Qualitatively, pig symphyseal labial and lingual surfaces were horizontally oriented and characterized by mineral apposition and bone resorption, respectively. Quantitatively, labial mineral apposition tended to be greater rostrally than caudally at 4 months, which became greater caudally than rostrally at 6 months (region/age interactions: p = 0.127 for MAR, p = 0.012 for MAZ). Lingual bone resorption tended to be greater caudally than rostrally, but only ES/BS measurements were significant (p = 0.039) regardless of age, while OC.N/BS measurements varied with ages and regions (age/region interaction, p = 0.087). CONCLUSIONS: Insufficient differential in symphyseal surface modeling between the labial-caudal and labial-rostral regions contributes to the lack of chin projection in the pig. PMID- 26250614 TI - [Documentation Time and Effort and Associated Resources for Patients with Primary Breast Cancer from Diagnosis to End of Follow-Up - Results of a Multicentre Validation]. AB - INTRODUCTION: Tumour documentation is essential for quality assurance of oncological therapies and as a source of reliable information about the in- and outpatient care. The documentation effort and the associated resource consumption were analysed for the example of breast cancer. MATERIAL AND METHODS: The different steps in the care of patients with primary breast cancer in a standardised disease situation were defined from initial diagnosis to the end of the follow-up. After the pilot phase, a multicentre validation (n=7 centres) was performed with the support of the Federal Ministry of Health. The documentation time points were horizontally collected and analysed with regard to amount, duration and personnel expenses. RESULTS: 57% of the documentation costs are caused by the physicians. Regarding the different centres, documentation costs were calculated between ? 352.82 and ? 1 084.08 per patient from diagnosis to completion of aftercare. Non-certified centres had a reduced documentation effort and thus lower costs. CONCLUSIONS: The results demonstrate the need for a reduction of the documentation effort - particularly for physicians - the most expensive profession in the health system. A quality improvement is expected from the certification with its special requirements. In this context, there is a justified demand for an adequate remuneration of the documentation effort for certified centres. Furthermore, it is necessary to reduce the number of variables for quality assurance and to define them centrally. A comprehensive multi disciplinary documentation should be achieved. Investments in a single data set and interface enhancements of existing documentation systems should be realised. PMID- 26250615 TI - Heat-killed Lactobacillus spp. cells enhance survivals of Caenorhabditis elegans against Salmonella and Yersinia infections. AB - This study examined the effect of feeding heat-killed Lactobacillus cells on the survival of Caenorhabditis elegans nematodes after Salmonella Typhimurium and Yersinia enterocolitica infection. The feeding of heat-killed Lactobacillus plantarum 133 (LP133) and Lactobacillus fermentum 21 (LP21) cells to nematodes was shown to significantly increase the survival rate as well as stimulate the expression of pmk-1 gene that key factor for C. elegans immunity upon infection compared with control nematodes that were only fed Escherichia coli OP50 (OP50) cells. These results suggest that heat-killed LP133 and LF21 cells exert preventive or protective effects against the Gram-negative bacteria Salm. Typhimurium and Y. enterocolitica. To better understand the mechanisms underlying the LF21-mediated and LP133-mediated protection against bacterial infection in nematodes, transcriptional profiling was performed for each experimental group. These experiments showed that genes related to energy generation and ageing, regulators of insulin/IGF-1-like signalling, DAF genes, oxidation and reduction processes, the defence response and/or the innate immune response, and neurological processes were upregulated in nematodes that had been fed heat killed Lactobacillus cells compared with nematodes that had been fed E. coli cells. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, the feeding of heat killed Lactobacillus bacteria to Caenorhabditis elegans nematodes was shown to decrease infection by Gram-negative bacteria and increase the host lifespan. C. elegans has a small, well-organized genome and is an excellent in vivo model organism; thus, these results will potentially shed light on important Lactobacillus-host interactions. PMID- 26250616 TI - Improving preclinical models of HIV microbicide efficacy. AB - Despite potent in vitro efficacy, most topical microbicides fail to effectively prevent HIV transmission. One reason for clinical failure may be that current microbicide testing does not reflect the environment encountered during sexual virus transmission. We discuss how preclinical microbicide development could be improved by more closely mimicking real-life conditions. PMID- 26250618 TI - Trunk fat and persistent organic pollutants. PMID- 26250617 TI - Domain-Specific Activation of Death-Associated Intracellular Signalling Cascades by the Cellular Prion Protein in Neuroblastoma Cells. AB - The biological functions of the cellular prion protein remain poorly understood. In fact, numerous studies have aimed to determine specific functions for the different protein domains. Studies of cellular prion protein (PrP(C)) domains through in vivo expression of molecules carrying internal deletions in a mouse Prnp null background have provided helpful data on the implication of the protein in signalling cascades in affected neurons. Nevertheless, understanding of the mechanisms underlying the neurotoxicity induced by these PrP(C) deleted forms is far from complete. To better define the neurotoxic or neuroprotective potential of PrP(C) N-terminal domains, and to overcome the heterogeneity of results due to the lack of a standardized model, we used neuroblastoma cells to analyse the effects of overexpressing PrP(C) deleted forms. Results indicate that PrP(C) N terminal deleted forms were properly processed through the secretory pathway. However, PrPDeltaF35 and PrPDeltaCD mutants led to death by different mechanisms sharing loss of alpha-cleavage and activation of caspase-3. Our data suggest that both gain-of-function and loss-of-function pathogenic mechanisms may be associated with N-terminal domains and may therefore contribute to neurotoxicity in prion disease. Dissecting the molecular response induced by PrPDeltaF35 may be the key to unravelling the physiological and pathological functions of the prion protein. PMID- 26250619 TI - Hypothyroidism modifies morphometry and thyroid-hormone receptor expression in periurethral muscles of female rabbits. AB - AIM: To evaluate the morphometry and thyroid-hormone receptor (TR) expression in pelvic (pubococcygeus, Pcm) and perineal (bulbospongiosus, Bsm) muscles of control and hypothyroid female rabbits. METHODS: Hypothyroidism was induced administering 0.02% methimazole in the drinking water for one month. Hematoxylin eosin stained muscle sections were used to evaluate the fiber cross-sectional area (CSA) and the number of peripheral myonuclei per fiber. Immunohistochemistry was used to calculate the proportion of TR immunoreactive nuclei per fiber. Significant differences were considered at a P <= 0.05. RESULTS: As compared to control rabbits, hypothyroidism increased the averaged fiber CSA and the myonuclei per fiber in the Bsm. Although the myonuclei number per fiber was also increased in the Pcm, the effect concerning the fiber CSA was only observed in a fraction of the Pcm fibers. Both TRalpha and TRbeta were similarly expressed in the Pcm and Bsm. Hypothyroidism increased the expression of the TRalpha in the Bsm. Meanwhile, the expression of TR isoforms in the Pcm was not altered. CONCLUSION: Our findings support that the TR signaling is directly involved in morphometrical changes induced by hypothyroidism in the Pcm and Bsm. The effect of hypothyroidism on the Pcm and Bsm could be related to the different type of fiber and metabolism that these muscles have. Neurourol. Urodynam. 35:895-901, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26250620 TI - Melatonin reduces obesity and restores adipokine patterns and metabolism in obese (ob/ob) mice. AB - The increasing incidence of obesity, leading to metabolic complications, is now recognized as a major public health problem. The adipocytes are not merely energy storing cells, but they play crucial roles in the development of the so-called metabolic syndrome due to the adipocyte-derived bioactive factors such as adipokines, cytokines, and growth factors. The dysregulated production and secretion of adipokines seen in obesity is linked to the pathogenesis of the metabolic disease processes. In this study, we hypothesized that dietary melatonin administration would support an anti-inflammatory response and play an important role in energy metabolism in subcutaneous and visceral adipose tissues of obese mice and so may counteract some of the disruptive effects of obesity. Lean and obese mice (ob/ob) received melatonin or vehicle in drinking water for 8 weeks. Thereafter, they were evaluated for morphologic alteration, inflammatory cell infiltration, and the adipokine patterns in visceral and subcutaneous white fat depots. In obese mice treated with vehicle, we observed a significant increase in fat depots, inflammation, and a dysregulation of the adipokine network. In particular, we measured a significant reduction of adiponectin and an increase of tumor necrosis factor alpha, resistin, and visfatin in adipose tissue deposits. These changes were partially reversed when melatonin was supplemented to obese mice. Melatonin supplementation by regulating inflammatory infiltration ameliorates obesity-induced adipokine alteration, whereas melatonin administration in lean mice was unaffected. Thus, it is likely that melatonin would be provided in supplement form to control some of the disruptive effects on the basis of obesity pathogenic process. PMID- 26250621 TI - A low cost training phantom model for radio-guided localization techniques in occult breast lesions. AB - Radio-guided localization (RGL) for identifying occult breast lesions has been widely accepted as an alternative technique to other localization methods, including those using wire guidance. An appropriate phantom model would be an invaluable tool for practitioners interested in learning the technique of RGL prior to clinical application. The aim of this study was to devise an inexpensive and reproducible training phantom model for RGL. We developed a simple RGL phantom model imitating an occult breast lesion from inexpensive supplies including a pimento olive, a green pea and a turkey breast. The phantom was constructed for a total cost of less than $20 and prepared in approximately 10 min. After the first model's construction, we constructed approximately 25 additional models and demonstrated that the model design was easily reproducible. The RGL phantom is a time- and cost-effective model that accurately simulates the RGL technique for non-palpable breast lesions. Future studies are warranted to further validate this model as an effective teaching tool. PMID- 26250622 TI - Regional distribution of serotonergic receptors: a systems neuroscience perspective on the downstream effects of the multimodal-acting antidepressant vortioxetine on excitatory and inhibitory neurotransmission. AB - Previous work from this laboratory hypothesized that the multimodal antidepressant vortioxetine enhances cognitive function through a complex mechanism, using serotonergic (5-hydroxytryptamine, 5-HT) receptor actions to modulate gamma-butyric acid (GABA) and glutamate neurotransmission in key brain regions like the prefrontal cortex (PFC) and hippocampus. However, serotonergic receptors have circumscribed expression patterns, and therefore vortioxetine's effects on GABA and glutamate neurotransmission will probably be regionally selective. In this article, we attempt to develop a conceptual framework in which the effects of 5-HT, selective serotonin reuptake inhibitors (SSRIs), and vortioxetine on GABA and glutamate neurotransmission can be understood in the PFC and striatum-2 regions with roles in cognition and substantially different 5-HT receptor expression patterns. Thus, we review the anatomy of the neuronal microcircuitry in the PFC and striatum, anatomical data on 5-HT receptor expression within these microcircuits, and electrophysiological evidence on the effects of 5-HT on the behavior of each cell type. This analysis suggests that 5 HT and SSRIs will have markedly different effects within the PFC, where they will induce mixed effects on GABA and glutamate neurotransmission, compared to the striatum, where they will enhance GABAergic interneuron activity and drive down the activity of medium spiny neurons. Vortioxetine is expected to reduce GABAergic interneuron activity in the PFC and concomitantly increase cortical pyramidal neuron firing. However in the striatum, vortioxetine is expected to increase activity at GABAergic interneurons and have mixed excitatory and inhibitory effects in medium spiny neurons. Thus the conceptual framework developed here suggests that vortioxetine will have regionally selective effects on GABA and glutamate neurotransmission. PMID- 26250623 TI - Imaging methods for analyzing body composition in human obesity and cardiometabolic disease. AB - Advances in the technological qualities of imaging modalities for assessing human body composition have been stimulated by accumulating evidence that individual components of body composition have significant influences on chronic disease onset, disease progression, treatment response, and health outcomes. Importantly, imaging modalities have provided a systematic method for differentiating phenotypes of body composition that diverge from what is considered normal, that is, having low bone mass (osteopenia/osteoporosis), low muscle mass (sarcopenia), high fat mass (obesity), or high fat with low muscle mass (sarcopenic obesity). Moreover, advances over the past three decades in the sensitivity and quality of imaging not just to discern the amount and distribution of adipose and lean tissue but also to differentiate layers or depots within tissues and cells is enhancing our understanding of distinct mechanistic, metabolic, and functional roles of body composition within human phenotypes. In this review, we focus on advances in imaging technologies that show great promise for future investigation of human body composition and how they are being used to address the pandemic of obesity, metabolic syndrome, and diabetes. PMID- 26250624 TI - The tumor suppressor p53 guides GluA1 homeostasis through Nedd4-2 during chronic elevation of neuronal activity. AB - Chronic activity perturbation in neurons can trigger homeostatic mechanisms to restore the baseline function. Although the importance and dysregulation of neuronal activity homeostasis has been implicated in neurological disorders such as epilepsy, the complete signaling by which chronic changes in neuronal activity initiate the homeostatic mechanisms is unclear. We report here that the tumor suppressor p53 and its signaling are involved in neuronal activity homeostasis. Upon chronic elevation of neuronal activity in primary cortical neuron cultures, the ubiquitin E3 ligase, murine double minute- 2 (Mdm2), is phosphorylated by the kinase Akt. Phosphorylated Mdm2 triggers the degradation of p53 and subsequent induction of a p53 target gene, neural precursor cell expressed developmentally down-regulated gene 4-like (Nedd4-2). Nedd4-2 encodes another ubiquitin E3 ligase. We identified glutamate receptor subunit 1 (GluA1), subunit of alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors as a novel substrate of Nedd4-2. The regulation of GluA1 level is known to be crucial for neuronal activity homeostasis. We confirmed that, by pharmacologically inhibiting Mdm2 mediated p53 degradation or genetically reducing Nedd4-2 in a mouse model, the GluA1 ubiquitination and down-regulation induced by chronically elevated neuronal activity are both attenuated. Our findings demonstrate the first direct function of p53 in neuronal homeostasis and elucidate a new mechanism by which cortical neurons respond to chronic activity perturbation. PMID- 26250626 TI - Complicated choices, navigating transitions: Improving patient-centered care for adolescents and young adults. PMID- 26250625 TI - Sox10ER(T2) CreER(T2) mice enable tracing of distinct neural crest cell populations. AB - BACKGROUND: Neural crest cells play an important role in craniofacial morphogenesis and many other developmental processes. The formation of neural crest cells (NCCs) in vivo is a highly dynamic process and remains to be fully understood. RESULTS: To investigate the spatiotemporal patterning of NCCs in vivo, we have generated Sox10ER(T2) CreER(T2) (SECE) mice, a transgenic line driving inducible Cre expression in NCCs. Inducing Cre activity at different stages triggered reporter expression in distinct NCC populations in SECE; R26R mice. By optimizing the timing and dosage of tamoxifen administration, we controlled Cre expression specifically in cranial NCCs. Using this approach, we demonstrate an important role for PDGFRalpha in cranial NCCs mitosis within the mandibular processes. Further reducing Cre activity within the cranial NCCs of SECE; R26R embryos revealed that SECE labels preferentially progenitors of medial nasal process (MNP) rather than the lateral nasal process (LNP), before their formation from the frontonasal prominence (FNP). CONCLUSIONS: Our results indicate that NCCs are formed sequentially from rostral to caudal regions along the neural tube. These findings also suggest that NCCs within the FNP become specified regionally and genetically before they divide into MNP and LNP. PMID- 26250627 TI - Relationship-centered care: A new paradigm for population health management. AB - At the center of population health management services are the relationships between the patient and their care providers. The spread of relationship-centered care has resulted from the need to develop and nurture these relationships. As a model of coordinated and team-based care, relationship-based care is able to strengthen population health management. This paper explores why relationship centered care is fundamental to population health management, describes compatibilities with patient-centered care and discusses examples of early applications of this paradigm. Using our experience in a population health management organization, we describe applications and lessons learned using this paradigm. PMID- 26250628 TI - Evaluation of readiness to transfer to adult healthcare: What about the well adolescent? AB - BACKGROUND: Understanding readiness to transfer from pediatric to adult healthcare is important for all youth; however, research and implementation guidelines in this area have emphasized youth seen in pediatric subspecialty settings. The purpose of this study was to develop an approach for evaluating transition readiness in a primary care setting, collect pilot data that examined the transition readiness of teens in that program, and implement assessments as part of clinical care. METHOD: Forty boys and girls aged 12-22 were recruited from an adolescent medicine outpatient program in a large children's hospital. The first 10 adolescents provided responses to questions and participated in cognitive interviewing. Questions changed minimally and responses from all 40 participants were combined. After the study visit, a researcher compared participant responses to electronic medical records and coded responses for accuracy. The survey consisted of 41 transition readiness items from previously published measures. RESULTS: The research team was able to develop a tool to assess transition readiness within a clinical setting. When administered to participants from that program, participants demonstrated poor transition readiness. Modifications were made based on participant feedback and implementation in the clinical setting. Clinicians were successful with administering transition readiness assessments. CONCLUSIONS: It appears that even in youth who are generally well, transition readiness is low. Transition readiness assessments can be implemented in the primary care setting, and have been useful for guiding clinical care. Additional barriers and next steps will be discussed. PMID- 26250629 TI - Time spent with patients by physicians, nurse practitioners, and physician assistants in community health centers, 2006-2010. AB - BACKGROUND: As health systems struggle to meet access, cost and quality goals in the setting of increased demand, nurse practitioners (NPs) and physician assistants (PAs) are expected to help meet the need for care. The amount of time spent with each patient can affect the clinical productivity, quality of care, and satisfaction of patients and clinicians. This paper compares time spent per patient in community health centers by whether the provider is a physician, NP, or PA. METHODS: This paper uses National Ambulatory Medical Care Survey (NAMCS) Community Health Center (CHC) data from 2006-2010. The NAMCS CHC strata is a national sample of CHCs, providers within CHCs, and patient visits to CHCs. Provider characteristics and variables related to time spent with patients across provider types were compared using t tests and chi square tests of association. Multivariate linear regression analysis was used to compare time spent with patients, controlling for patient and visit characteristics. RESULTS: There were no differences in the number of visits by provider type, but PAs saw patients for a slightly larger portion of the week (3.8 days) than did physicians (3.5 days, p<0.05) or NPs (3.4 days, p<0.05). There were no statistical differences in the mean time spent per patient in the crude and adjusted analyses. CONCLUSIONS: Time spent per patient in CHCs is similar for physicians, NPs and PAs. This information may be useful to planners concerned with health system capacity and cost efficiency, and has implications for patient and provider satisfaction. PMID- 26250630 TI - Association of medical home team-based care functions and perceived improvements in patient-centered care at VHA primary care clinics. AB - INTRODUCTION: Team-based care is central to the patient-centered medical home (PCMH), but most PCMH evaluations measure team structure exclusively. We assessed team-based care in terms of team structure, process and effectiveness, and the association with improvements in teams' abilities to deliver patient-centered care. MATERIAL AND METHODS: We fielded a cross-sectional survey among 913 VA primary care clinics implementing a PCMH model in 2012. The dependent variable was clinic-level respondent-reported improvements in delivery of patient-centered care. Independent variables included three sets of measures: (1) team structure, (2) team process, and (3) team effectiveness. We adjusted for clinic workload and patient comorbidity. RESULTS: 4819 surveys were returned (25% estimated response rate). The highest ratings were for team structure (median of 89% of respondents being assigned to a teamlet, i.e., a PCP working with the same clinical associate, nurse care manager and clerk) and lowest for team process (median of 10% of respondents reporting the lowest level of stress/chaos). In multivariable regression, perceived improvements in patient-centered care were most strongly associated with participatory decision making (beta=32, P<0.0001) and history of change in the clinic (beta=18, P=0008) (both team processes). A stressful/chaotic clinic environment was associated with higher barriers to patient centered care (beta=0.16-0.34, P=<0.0001), and lower improvements in patient-centered care (beta=-0.19, P=0.001). CONCLUSIONS: Team process and effectiveness measures, often omitted from PCMH evaluations, had stronger associations with perceived improvements in patient-centered care than team structure measures. IMPLICATIONS: Team process and effectiveness measures may facilitate synthesis of evaluation findings and help identify positive outlier clinics. PMID- 26250631 TI - Implementing a patient centered medical home in the Veterans health administration: Perspectives of primary care providers. AB - Implementation of a patient centered medical home challenges primary care providers to change their scheduling practices to enhance patient access to care as well as to learn how to use performance metrics as part of a self-reflective practice redesign culture. As medical homes become more commonplace, health care administrators and primary care providers alike are eager to identify barriers to implementation. The objective of this study was to identify non-technological barriers to medical home implementation from the perspective of primary care providers. We conducted qualitative interviews with providers implementing the medical home model in Department of Veterans Affairs clinics-the most comprehensive rollout to date. Primary care providers reported favorable attitudes towards the model but discussed the importance of data infrastructure for practice redesign and panel management. Respondents emphasized the need for administrative leadership to support practice redesign by facilitating time for panel management and recognizing providers who utilize non-face-to-face ways of delivering clinical care. Health care systems considering adoption of the medical home model should ensure that they support both technological capacities and vertically aligned expectations for provider performance. PMID- 26250632 TI - The cost-effectiveness of patient decision aids: A systematic review. AB - The Affordable Care Act includes provisions to encourage patient-centered care through the use of shared decision making (SDM) and patient decision aids (PtDA). PtDAs are tools that can help encourage SDM by providing information about competing treatment options and elucidating patients' values and preferences. Implementing PtDAs into routine practice may incur additional costs through training or increases in physician time. Prominent commentaries have proposed that these costs might be offset if patients choose less expensive options than their providers. However, the cost-effectiveness of PtDAs to date is unclear. The aim of this study was to review the economic evidence from PtDA trials. Our search identified 5347 articles, with 29 included following full-text review. Only one economic evaluation of a PtDA has been completed, which found a PtDA to be cost-saving in women with menorrhagia. Other studies included in the review indicated that PtDAs will likely increase up-front costs, but in some contexts may reduce short-term costs by reducing the uptake of invasive treatments, such as elective surgery. Few studies comprehensively captured long-term costs or measured benefits in a manner conducive to economic evaluation (QALYs or general health utilities). Our review suggests that policy makers currently have insufficient economic evidence to appropriately consider their investments in PtDAs. PMID- 26250633 TI - Opening the ICU doors. AB - Family member presence may contribute to the healing of hospitalized patients, but may also be in conflict with the perceived needs of delivering intensive care. We detail our experience with "opening the doors" of the intensive care unit (ICU), allowing family members to be present and participate in the care of loved ones without restriction. "Opening the doors" challenged the traditions, legacy and sense of professional entitlement that were a part of ICU culture and generated considerable initial resistance among nurses and physicians. We describe our "opening the doors" transformation to more patient- and family centered care in four steps: (1) enlist support of administrative and local leaders; (2) create a collective aim; (3) test on a small scale, and (4) scale up after initial successes. Preparing ICU staff so that they are comfortable with more "on stage" time (i.e., greater family presence) was critical to our success. "Opening the doors" now serves as a guiding vision to organizing the ICU's work. PMID- 26250634 TI - Use of patient ethnography to support quality improvement in benign prostatic hyperplasia. AB - BACKGROUND: Patient-centeredness is a primary aim of quality improvement (QI) but optimal strategies to achieve that goal remain elusive. Benign prostatic hyperplasia (BPH) is one of the commonest urologic diagnoses and significantly affects quality of life. Patient ethnography is an emerging qualitative method of observation and dynamic interviews to understand the context through which the patient experiences care. We implemented patient ethnography to support our QI infrastructure and improve patient-centeredness in BPH. PROBLEM: Little is known about how to measure whether processes of care are patient-centered. We did not know whether the care processes our patients experienced provided value from their perspective. GOALS: We sought to discover previously unrecognized components of care that patients perceived to be of low value. Our primary goal was to develop QI initiatives that targeted low-value themes identified in the ethnography. Our secondary goal was a rapid rollout of three targeted initiatives. STRATEGY: We used a 4-step patient ethnography: (1) created detailed process maps to define phases of care, (2) interviewed patients, (3) synthesized transcript data in focus groups using the Crawford Slip method, and (4) targeted undesirable components of care for QI. Semi-structured interviews with seven representative patients identified low-value themes. Focus groups, comprised of primary care physicians, case coordinators, nurses, and urologists, evaluated the interview transcripts and generated improvement opportunities prioritized based on feasibility, patient value, scalability, and innovation. We used affinity mapping and priority matrix techniques to prioritize QI opportunities. RESULTS: We identified five low-value themes from the patient interviews and developed corresponding QI opportunities. These included issues surrounding the referral and consultation process as well as postoperative care, especially home urinary catheter maintenance. Six months after completing the ethnography three of five targeted improvement opportunities had been implemented. PMID- 26250635 TI - Re-designing primary care: Implementation of patient-aligned care teams. AB - BACKGROUND: Primary care is the foundation of the Department of Veterans Affairs (VA) health care, but transformation efforts are necessary to meet the needs of Veterans and provide patient-centered care (PCC). PROBLEM: The need to transform the VA from a problem/disease-based provider-driven system to a patient-centered, patient-driven health care system. GOALS: Our project objective was to describe the implementation of the Patient-Aligned Care Team (PACT) model in the current Department of Veterans Affairs (VA) health care environment and to identify barriers and facilitators to implementing a new model of care that could apply more broadly to the implementation of large-scale changes in other large integrated health care systems. STRATEGY: We sought to learn through in-depth interviews with leaders and key informants at several stages of the PACT process, including planning, implementing, modifying where needed, and maintenance. RESULTS: The PACT model offers PCC that is managed with high quality, safety, and effectiveness; provides optimal access; and integrates the Veterans' voice to respect their preferences, needs, and values toward achieving optimal health and well-being. IMPLICATIONS: This transformation in VA provides insight into the barriers and facilitators to implementing large-scale change in an integrated health care system. Implementation of a new model of care across a large integrated health care system requires continuous and highly visible engagement from leadership and staff, distribution of resources across initiatives, and alignment of program goals and performance measures, these lessons. PMID- 26250636 TI - Collaboration between a US Academic Institution and International Ministry of Health to develop a culturally appropriate palliative care navigation curriculum. AB - Implementation lessons: (1) The development and testing of a culturally appropriate palliative care navigation curriculum for countries facing high cancer and non-communicable diseases burden requires collaboration with the local Ministry of Health. (2) Lay volunteers from non-governmental and faith-based organizations are potential candidates to provide patient navigation services. PMID- 26250637 TI - Flipping primary health care: A personal story. AB - There is considerable interest in ideas borrowed from education about "flipping the classroom" and how they might be applied to "flipping" aspects of health care to reach the Triple Aim of improved health outcomes, improved experience of care, and reduced costs. There are few real-life case studies of "flipping health care" in practice at the individual patient level. This article describes the experience of one of the authors as he experienced having to "flip" his primary health care. We describe seven inverted practices in his care, report outcomes of this experiment, describe the enabling factors, and derive lessons for patient centered primary care redesign. PMID- 26250638 TI - Interview with Frank Williams. PMID- 26250639 TI - Interview with Bob Kocher, M.D. PMID- 26250641 TI - Identification of a new HLA-A allele: A*02:512. AB - A*02:512 differs from A*02:01:01:01 by one nucleotide at nt 506. PMID- 26250642 TI - Early decrement of serum carbohydrate antigen 19-9 predicts favorable outcome in advanced pancreatic cancer. AB - BACKGROUND AND AIM: The role of carbohydrate antigen 19-9 (CA 19-9) for predicting treatment outcome in pancreatic ductal adenocarcinoma (PDAC) remains to be elucidated. This study was aimed to determine the correlation between early decrement in CA 19-9 concentration and prognosis of advanced PDAC after chemotherapy. METHODS: All patients confirmed with locally advanced or metastatic PDAC who received initial systemic chemotherapy for at least two cycles in our institution between January 2012 and December 2013 were included. Serum CA 19-9 concentrations at baseline and 8 weeks after the initiation of chemotherapy were obtained. Correlation between CA 19-9 decrement and survival outcomes (time to progression [TTP] and overall survival [OS]) were evaluated. RESULTS: A total of 183 patients with initially elevated CA 19-9 were included. OS and TTP was significantly longer for patients whose serum CA 19-9 concentration decreased more than 10% from baseline (n = 103), than that for patients whose serum CA 19-9 was not decreased (n = 80) (423 vs 155 days, P < 0.001 for OS and 222 vs 75 days, P < 0.001 for TTP). In multivariate analysis, CA 19-9 decrement more than 10% from baseline was still a significant factor for longer OS (hazard ratio for progression 0.275 [0.184-0.412], P < 0.001) and TTP (0.322 [0.219-0.473], P < 0.001) in both stage III and IV. CONCLUSIONS: The early decrement of CA 19-9 after the initiation of chemotherapy was an independent factor related with better survival outcomes in unresectable PDAC. PMID- 26250644 TI - A Novel Selective PPARalpha Modulator. PMID- 26250643 TI - Neuroinflammation in the peripheral nerve: Cause, modulator, or bystander in peripheral neuropathies? AB - The role of innate and adaptive inflammation as a primary driver or modifier of neuropathy in premorbidly normal nerves, and as a critical player in amplifying neuropathies of other known causes (e.g., genetic, metabolic) is incompletely understood and under-researched, despite unmet clinical need. Also, cellular and humoral components of the adaptive and innate immune system are substantial disease modifying agents in the context of neuropathies and, at least in some neuropathies, there is an identified tight interrelationship between both compartments of the immune system. Additionally, the quadruple relationship between Schwann cell, axon, macrophage, and endoneurial fibroblast, with their diverse membrane bound and soluble signalling systems, forms a distinct focus for investigation in nerve diseases with inflammation secondary to Schwann cell mutations and possibly others. Identification of key immunological effector pathways that amplify neuropathic features and associated clinical symptomatology including pain should lead to realistic and timely possibilities for translatable therapeutic interventions using existing immunomodulators, alongside the development of novel therapeutic targets. PMID- 26250645 TI - Therapy for hemangiomas of blue rubber bleb nevus syndrome in the small intestine with single balloon endoscopy. PMID- 26250646 TI - Nanodomain Formation of Ganglioside GM1 in Lipid Membrane: Effects of Cholera Toxin-Mediated Cross-Linking. AB - Cross-linking of specific lipid components by proteins mediates transmembrane signaling and material transport. In this work, we conducted coarse-grained simulation to investigate the interactions of binding units of chorela toxin (CTB) with mixed ganglioside GM1 and dipalmitoylphosphatidylcholine (DPPC) lipid bilayer membrane. We determine that the binding of CTB pentamers cross-links GM1 molecules into protein-sized nanodomains that have distinct lipid order compared with the bulk. The toxin in the nanodomain partially penetrates into the membrane. The local disordering can also transmit across the membrane via lipid coupling. Comparison simulations on CTB binding to a membrane that is composed of various lipid components demonstrate that several factors are responsible for the nanodomain formation: (a) the negatively charged headgroup of a GM1 receptor is responsible for the multivalent binding; (b) the head groups being full of hydrogen-bonding donors and receptors stabilize the GM1 cluster itself and ensure the toxin binding with high affinity; and PMID- 26250647 TI - U.S. Shale Gas versus China's Coal as Chemical Feedstock. PMID- 26250648 TI - Journey in Orthopedic Science. PMID- 26250649 TI - Metal implant removal: benefits and drawbacks--a patient survey. AB - BACKGROUND: Hardware removals are among the most commonly performed surgical procedures worldwide. Current literature offers little data concerning postoperative patient satisfaction. The purpose of our study was to evaluate the patients' point of view on implant removal. METHODS: We surveyed patients of a German level one trauma center, who underwent hardware removal in 2009 and 2010, with regard to their personal experiences on implant removal. Exclusively, data obtained out of the survey were analyzed. RESULTS: In 332 patients surveyed, most hardware removals were performed at the ankle joint (21%) followed by the wrist (15%). The most frequent indication was a doctor's recommendation (68%), followed by pain (31%) and impaired function (31%). Patient reported complication rate of implant removal was 10%. Importantly, after implant removal because of pain or impaired function patients reported an improvement in function (72%) as well as decreased pain (96%). 96% of all responding patients and 66% of the patients who suffered from subsequent complications would opt for surgical implant removal again. CONCLUSION: In summary, despite the challenging and frequently troublesome nature of surgical hardware removal our data contradicts the widely held view that implant removal is often without a positive effect on the patients. These findings may influence the surgeons' attitude towards implant removal and their day-to-day routine in patient counseling. PMID- 26250650 TI - Delirium, how does it end? Mortality as an outcome in older medical inpatients. AB - OBJECTIVES: Delirium is associated with poor outcomes. Previous research in delirium and mortality gave rather inconclusive results. This study aims to find out the rates of mortality at 1 year and the factors associated with it in a cohort of hospitalized older patients. METHOD: Prospective, observational, longitudinal study. All acute medical admissions 70 years of age and above were approached within 72 h of admission. Exclusion criteria are as follows: severe aphasia; intubation; severe sensory problems; and non-English speakers. Patients eligible for inclusion were assessed four times, twice weekly during admission. Delirium was defined using the Confusion Assessment Method. RESULTS: Two hundred patients were recruited. The mean age was 81.13 years (SD = 6.45; minimum 70 and maximum 100 years old), of which 100 (50%) participants were women. One hundred fifty-four (77%) patients never developed delirium during hospitalization. The overall rate of delirium was 23%. A total of 55 (27.5%) patients died during the 1-year follow-up. Although at 1-year follow-up, more people with delirium died (chi(2) = 9.873, df:1, p = 0.002), survival analysis after controlling for other variables showed that mortality was independent of delirium and that severity of illness, longer hospital stay and cognition were significant risk factors for mortality. CONCLUSION: Although the sample size precludes drawing any definite conclusion, the findings of this study suggest that delirium is not an important risk factor for subsequent mortality. Perhaps delirium and cognitive impairment share common pathophysiological pathways that are related to mortality and in which the currently used methods cannot detect. PMID- 26250651 TI - Short-run effects of job loss on health conditions, health insurance, and health care utilization. AB - Job loss in the United States is associated with reductions in income and long term increases in mortality rates. This paper examines the short-run changes in health, health care access, and health care utilization after job loss that lead to these long-term effects. Using a sample with more than 10,000 individual job losses and longitudinal data on a wide variety of health-related outcomes, we show that job loss results in worse self-reported health, activity limitations, and worse mental health, but is not associated with statistically significant increases in a variety of specific chronic conditions. Among the full sample of workers, we see reductions in insurance coverage, but little evidence of reductions in health care utilization after job loss. Among the subset of displaced workers with chronic conditions and those for whom the lost job was their primary source of insurance we do see reductions in doctor's visits and prescription drug usage. PMID- 26250652 TI - Reproductive System of Brown-throated Sloth (Bradypus variegatus, Schinz 1825, Pilosa, Xenarthra): Anatomy and Histology. AB - In recent years, habitat degradation led to the decline of some populations of brown-throated sloth. The aim of this study was to describe morphological features of the female reproductive system of the species. The oval ovaries were partially surrounded by ovarian bursa. An external cortex and an inner medulla were present. Corpora lutea and corpora albicans together with follicles at various stages of development each with a single oocyte were found in the cortex. Uterine tubes were tortuous, tubular, travelled around the perimeter of the ovary and possessed a folded mucosa with ciliated pseudostratified epithelium. Uterus was simplex, with no horns and divided into three parts: a pear-shaped cranial segment and a long caudal uterine segment (both forming the body of the uterus) and two cervices. Uterus presented three layers: mucosa, lined by pseudostratified epithelium, muscular and serosa. The cervices connected the uterus to the urogenital sinus, a distensible cavity with longitudinal mucosal folds lined by transitional epithelium that extended from the external urethral orifice and the external uterine ostia to the vulva, which was lined by a keratinized stratified squamous epithelium. Brown-throated sloth presented a bipartite clitoris with paired crura, bodies and glandes. The presence of a double cervix and a bipartite clitoris was unique features of the species. PMID- 26250654 TI - Antimicrobial susceptibility of Escherichia coli in uncomplicated cystitis in the emergency department: is the hospital antibiogram an effective treatment guide? AB - OBJECTIVES: The objective was to compare the rates of antimicrobial susceptibility in strains of Escherichia coli isolated from uncomplicated cystitis cases presenting to the emergency department (ED) of a tertiary care center to those reported on that institution's hospital-wide antibiogram. The hypothesis was that cases of uncomplicated cystitis presenting to the ED will exhibit higher antimicrobial susceptibility than is reported by the hospital-wide antibiogram. METHODS: A retrospective chart review of patients who were diagnosed with uncomplicated cystitis in the ED of a large, academic tertiary care center was conducted. Due to an error in the implementation of a new electronic medical record system at this institution in 2009, all urine samples with any abnormality were reflexively sent for culture. The authors were then able to review and record the antibiotic susceptibility patterns of all cultures that grew E. coli. Exclusion criteria included fever, subsequent hospital admission, treatment of suspected pyelonephritis, receiving current cystitis treatment, male sex, indwelling catheters, recent surgery or hospitalization, or asymptomatic for cystitis. Culture isolate antimicrobial susceptibility was then compared with the hospital-wide antibiogram of the same period. Empiric treatment regimens were also recorded as secondary data. RESULTS: Greater susceptibility to trimethoprim sulfamethoxazole (TMP-SMX; 80% vs. 71%), cefazolin (97% vs. 87%), and ciprofloxacin (89% vs. 73%) was found in our population than was published in the hospital antibiogram. These differences were shown to be statistically significant using Fisher's exact test (p < 0.05). A very high sensitivity to nitrofurantoin (99%), similar to the hospital antibiogram (98%), was also found. Also noted was a high rate of antimicrobial susceptibility when specific empiric treatment was initiated with TMP-SMX or ciprofloxacin: 92 and 89%, respectively. CONCLUSIONS: The greater susceptibility of E. coli to TMP-SMX, cefazolin, and ciprofloxacin observed in this population supports the hypothesis that antimicrobial susceptibility rates in uncomplicated cystitis presenting to the ED are greater than those reported in the hospital-wide antibiogram. This could affect treatment guidelines by confirming that antimicrobials currently recommended for use in uncomplicated cystitis are more effective in this setting than currently reported by the hospital-wide antibiogram. PMID- 26250653 TI - P-Glycoprotein, not BCRP, Limits the Brain Uptake of [(18)F]Mefway in Rodent Brain. AB - PURPOSE: The aim of this study was to determine whether the brain uptake of [(18)F]Mefway is influenced by the action of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) in rodents. PROCEDURES: [(18)F]Mefway was applied to rats pharmacologically inhibited with tariquidar (TQD) and to genetically disrupted mice. RESULTS: Pretreatment of TQD results in 160% higher hippocampal uptake compared with control rats. In genetically disrupted mice, a maximal brain uptake value of 3.2 SUV in the triple knockout mice (tKO, Mdr1a/b(( /-))Bcrp1((-/-))) was comparable to that of the double knockout mice (dKO, Mdr1a/b((-/-))) and 2-fold those of the wild-type and Bcrp1((-/-)) knockout mice. The differences of binding values were statistically insignificant between control and experimental groups. The brain-to-plasma ratios for tKO mice were also two to five times higher than those for other groups. CONCLUSIONS: [(18)F]Mefway is modulated by P-gp, and not by Bcrp in rodents. PMID- 26250655 TI - Studies on the synthesis, characterization, human serum albumin binding and biological activity of single chain surfactant-cobalt(III) complexes. AB - The interaction of surfactant-cobalt(III) complexes [Co(bpy)(dien)TA](ClO4)3 . 3H2O (1) and [Co(dien)(phen)TA](ClO4)3 . 4H2O (2), where bpy = 2,2'-bipyridine, dien = diethylenetriamine, phen = 1,10-phenanthroline and TA = tetradecylamine with human serum albumin (HSA) under physiological conditions was analyzed using steady state, synchronous, 3D fluorescence, UV/visabsorption and circular dichroism spectroscopic techniques. The results show that these complexes cause the fluorescence quenching of HSA through a static mechanism. The binding constant (Kb ) and number of binding-sites (n) were obtained at different temperatures. The corresponding thermodynamic parameters (?G degrees , ?H degrees and ?S degrees ) and Ea were also obtained. According to Forster's non-radiation energy transfer theory, the binding distance (r) between the complexes and HSA were calculated. The results of synchronous and 3D fluorescence spectroscopy indicate that the binding process has changed considerably the polarity around the fluorophores, along with changes in the conformation of the protein. The antimicrobial and anticancer activities of the complexes were tested and the results show that the complexes have good activities against pathogenic microorganisms and cancer cells. PMID- 26250656 TI - Does conditional approval for new oncology drugs in Europe lead to differences in health technology assessment decisions? AB - An early access pathway of conditional approval for potentially beneficial medicines is available within the European regulatory framework. However, marketing authorization does not necessarily result in recommendations for public funding by health technology assessment (HTA) agencies. As conditional approval goes along with less than complete data on benefits and risks of a treatment option for a high medical need, this raises the question how HTA decision-making is affected by these uncertainties. PMID- 26250658 TI - The next century of ecology. PMID- 26250660 TI - INFECTIOUS DISEASES. Unusual Ebola vaccine study pays off in Guinea. PMID- 26250662 TI - ASTROPHYSICS. Catching cosmic rays where they live. PMID- 26250661 TI - CONSERVATION BIOLOGY. Monarchs pose a puzzle. PMID- 26250657 TI - Coupled folding and binding with 2D Window-Exchange Umbrella Sampling. AB - Intrinsically disordered regions of proteins can gain structure by binding to a partner. This process, of coupled folding and binding (CFaB), is a fundamental part of many important biological processes. Structure-based models have proven themselves capable of revealing fundamental aspects of how CFaB occurs, however, typical methods to enhance the sampling of these transitions, such as replica exchange, do not adequately sample the transition state region of this extremely rare process. Here, we use a variant of Umbrella Sampling to enforce sampling of the transition states of CFaB of HdeA monomers at neutral pH, an extremely rare process that occurs over timescales ranging from seconds to hours. Using high resolution sampling in the transition state region, we cluster states along the principal transition path to obtain a detailed description of coupled binding and folding for the HdeA dimer, revealing new insight into the ensemble of states that are accessible to client recognition. We then demonstrate that exchanges between umbrella sampling windows, as done in previous work, significantly improve relaxation in variables orthogonal to the restraints used. Altogether, these results show that Window-Exchange Umbrella Sampling is a promising approach for systems that exhibit flexible binding, and can reveal transition state ensembles of these systems in high detail. (c) 2015 Wiley Periodicals, Inc. PMID- 26250663 TI - OCEAN SCIENCE. Brazil looks to project scientific power on the Atlantic. PMID- 26250664 TI - RESEARCH FACILITIES. The dimming of NEON. PMID- 26250665 TI - The brain's identity crisis. PMID- 26250666 TI - Boom & bust in the Great White North. PMID- 26250667 TI - Don't mess with the bears. PMID- 26250669 TI - WATER. Water security: Gray or green? PMID- 26250668 TI - BIOLOGICAL ADHESIVES. Positive charges and underwater adhesion. PMID- 26250670 TI - WATER. Manage water in a green way. PMID- 26250671 TI - WATER. Built infrastructure is essential. PMID- 26250672 TI - PHYSICS. Plasmons at the interface. PMID- 26250673 TI - NATURAL HAZARDS. Building land with a rising sea. PMID- 26250674 TI - OPTOGENETICS. Expanding the optogenetics toolkit. PMID- 26250675 TI - MARINE SCIENCE. Deepwater Horizon, 5 years on. PMID- 26250676 TI - Selling First Nations down the river. PMID- 26250677 TI - Animal telemetry: Tagging effects. PMID- 26250678 TI - Animal telemetry: Follow the insects. PMID- 26250679 TI - PALEOECOLOGY. Abrupt warming events drove Late Pleistocene Holarctic megafaunal turnover. AB - The mechanisms of Late Pleistocene megafauna extinctions remain fiercely contested, with human impact or climate change cited as principal drivers. We compared ancient DNA and radiocarbon data from 31 detailed time series of regional megafaunal extinctions and replacements over the past 56,000 years with standard and new combined records of Northern Hemisphere climate in the Late Pleistocene. Unexpectedly, rapid climate changes associated with interstadial warming events are strongly associated with the regional replacement or extinction of major genetic clades or species of megafauna. The presence of many cryptic biotic transitions before the Pleistocene/Holocene boundary revealed by ancient DNA confirms the importance of climate change in megafaunal population extinctions and suggests that metapopulation structures necessary to survive such repeated and rapid climatic shifts were susceptible to human impacts. PMID- 26250680 TI - DEVICE TECHNOLOGY. Phase patterning for ohmic homojunction contact in MoTe2. AB - Artificial van der Waals heterostructures with two-dimensional (2D) atomic crystals are promising as an active channel or as a buffer contact layer for next generation devices. However, genuine 2D heterostructure devices remain limited because of impurity-involved transfer process and metastable and inhomogeneous heterostructure formation. We used laser-induced phase patterning, a polymorph engineering, to fabricate an ohmic heterophase homojunction between semiconducting hexagonal (2H) and metallic monoclinic (1T') molybdenum ditelluride (MoTe2) that is stable up to 300 degrees C and increases the carrier mobility of the MoTe2 transistor by a factor of about 50, while retaining a high on/off current ratio of 10(6). In situ scanning transmission electron microscopy results combined with theoretical calculations reveal that the Te vacancy triggers the local phase transition in MoTe2, achieving a true 2D device with an ohmic contact. PMID- 26250681 TI - BIOLOGICAL ADHESIVES. Adaptive synergy between catechol and lysine promotes wet adhesion by surface salt displacement. AB - In physiological fluids and seawater, adhesion of synthetic polymers to solid surfaces is severely limited by high salt, pH, and hydration, yet these conditions have not deterred the evolution of effective adhesion by mussels. Mussel foot proteins provide insights about adhesive adaptations: Notably, the abundance and proximity of catecholic Dopa (3,4-dihydroxyphenylalanine) and lysine residues hint at a synergistic interplay in adhesion. Certain siderophores bacterial iron chelators-consist of paired catechol and lysine functionalities, thereby providing a convenient experimental platform to explore molecular synergies in bioadhesion. These siderophores and synthetic analogs exhibit robust adhesion energies (E(ad) >=-15 millijoules per square meter) to mica in saline pH 3.5 to 7.5 and resist oxidation. The adjacent catechol-lysine placement provides a "one-two punch," whereby lysine evicts hydrated cations from the mineral surface, allowing catechol binding to underlying oxides. PMID- 26250682 TI - CHARGE TRANSFER. Efficient hot-electron transfer by a plasmon-induced interfacial charge-transfer transition. AB - Plasmon-induced hot-electron transfer from metal nanostructures is a potential new paradigm for solar energy conversion; however, the reported efficiencies of devices based on this concept are often low because of the loss of hot electrons via ultrafast electron-electron scattering. We propose a pathway, called the plasmon-induced interfacial charge-transfer transition (PICTT), that enables the decay of a plasmon by directly exciting an electron from the metal to a strongly coupled acceptor. We demonstrated this concept in cadmium selenide nanorods with gold tips, in which the gold plasmon was strongly damped by cadmium selenide through interfacial electron transfer. The quantum efficiency of the PICTT process was high (>24%), independent of excitation photon energy over a ~1 electron volt range, and dependent on the excitation polarization. PMID- 26250683 TI - STATISTICS. The reusable holdout: Preserving validity in adaptive data analysis. AB - Misapplication of statistical data analysis is a common cause of spurious discoveries in scientific research. Existing approaches to ensuring the validity of inferences drawn from data assume a fixed procedure to be performed, selected before the data are examined. In common practice, however, data analysis is an intrinsically adaptive process, with new analyses generated on the basis of data exploration, as well as the results of previous analyses on the same data. We demonstrate a new approach for addressing the challenges of adaptivity based on insights from privacy-preserving data analysis. As an application, we show how to safely reuse a holdout data set many times to validate the results of adaptively chosen analyses. PMID- 26250684 TI - ENVIRONMENTAL SCIENCE. Profiling risk and sustainability in coastal deltas of the world. AB - Deltas are highly sensitive to increasing risks arising from local human activities, land subsidence, regional water management, global sea-level rise, and climate extremes. We quantified changing flood risk due to extreme events using an integrated set of global environmental, geophysical, and social indicators. Although risks are distributed across all levels of economic development, wealthy countries effectively limit their present-day threat by gross domestic product-enabled infrastructure and coastal defense investments. In an energy-constrained future, such protections will probably prove to be unsustainable, raising relative risks by four to eight times in the Mississippi and Rhine deltas and by one-and-a-half to four times in the Chao Phraya and Yangtze deltas. The current emphasis on short-term solutions for the world's deltas will greatly constrain options for designing sustainable solutions in the long term. PMID- 26250685 TI - TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. AB - Cytoplasmic aggregation of TDP-43, accompanied by its nuclear clearance, is a key common pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, a limited understanding of this RNA-binding protein (RBP) impedes the clarification of pathogenic mechanisms underlying TDP-43 proteinopathy. In contrast to RBPs that regulate splicing of conserved exons, we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity. When TDP-43 was depleted from mouse embryonic stem cells, these cryptic exons were spliced into messenger RNAs, often disrupting their translation and promoting nonsense-mediated decay. Moreover, enforced repression of cryptic exons prevented cell death in TDP-43-deficient cells. Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy. PMID- 26250686 TI - Biology, wet and dry. PMID- 26250687 TI - NEURODEGENERATION. Alzheimer's and Parkinson's diseases: The prion concept in relation to assembled Abeta, tau, and alpha-synuclein. AB - The pathological assembly of Abeta, tau, and alpha-synuclein is at the heart of Alzheimer's and Parkinson's diseases. Extracellular deposits of Abeta and intraneuronal tau inclusions define Alzheimer's disease, whereas intracellular inclusions of alpha-synuclein make up the Lewy pathology of Parkinson's disease. Most cases of disease are sporadic, but some are inherited in a dominant manner. Mutations frequently occur in the genes encoding Abeta, tau, and alpha-synuclein. Overexpression of these mutant proteins can give rise to disease-associated phenotypes. Protein assembly begins in specific regions of the brain during the process of Alzheimer's and Parkinson's diseases, from where it spreads to other areas. PMID- 26250688 TI - Terson's Syndrome: Diagnostic Comparison of Ocular Sonography and CT. AB - BACKGROUND AND PURPOSE: To assess the accuracy of ocular B-mode sonography and of standard head computed tomography (CT) as screening tools for intraocular hemorrhages related to subarachnoid hemorrhage (SAH). METHODS: 46 patients with spontaneous SAH were examined using ocular B-mode sonography and underwent funduscopy as gold standard for detection of ocular hemorrhages (OH). Additionally, all head CT scans done during the hospital stay of the study population were rated by a neuroradiologist for the presence of OH. RESULTS: Funduscopy revealed vitreous and/or preretinal hemorrhages in ten eyes and retinal hemorrhages in nine eyes. In comparison with funduscopy, ocular sonography showed a sensitivity and specificity for the detection of vitreous and/or preretinal hemorrhages of 100%, while identification of retinal hemorrhages was less reliable with a sensitivity/specificity of 44%/100%. Standard head CT showed a lower sensitivity/specificity of 60%/96% for vitreous and/or preretinal hemorrhages, and 32%/95% for the diagnosis of any ocular bleeding. CONCLUSION: Ocular sonography identifies SAH-related preretinal and vitreous hemorrhages with high accuracy and is superior to standard head CT. It may be considered as new and useful bedside diagnostic tool for routine clinical care of patients with SAH. PMID- 26250689 TI - The prognostic value of baseline (18)F-FDG PET/CT in steroid-naive large-vessel vasculitis: introduction of volume-based parameters. AB - PURPOSE: The aim of this study was to analyse if the result of a baseline (18)F fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan, in large vessel vasculitis (LVV) patients, is able to predict the course of the disease, not only in terms of presence/absence of final complications but also in terms of favourable/complicated progress (response to steroid therapy, time to steroid suspension, relapses, etc.). METHODS: A total of 46 consecutive patients, who underwent (18)F-FDG PET/CT between May 2010 and March 2013 for fever of unknown origin (FUO) or suspected vasculitis (before starting corticosteroid therapy), were enrolled. The diagnosis of LVV was confirmed in 17 patients. Considering follow-up results, positive LVV patients were divided into two groups, one characterized by favourable (nine) and the other by complicated progress (eight), on the basis of presence/absence of vascular complications, presence/absence of at least another positive PET/CT during follow-up and impossibility to comply with the tapering schedule of the steroid due to biochemical/symptomatic relapse. Vessel uptake in subjects of the two groups was compared in terms of intensity and extension. To evaluate the extent of active disease, we introduced two volume based parameters: "volume of increased uptake" (VIU) and "total lesion glycolysis" (TLG). The threshold used to calculate VIU on vessel walls was obtained by the "vessel to liver" ratio by means of receiver-operating characteristic analysis and was set at 0.92 * liver maximum standardized uptake value in each patient. RESULTS: Measures of tracer uptake intensity were significantly higher in patients with complicated progress compared to those with a favourable one (p < 0.05). Measures of disease extension were even more significant and TLG emerged as the best parameter to separate the two groups of patients (p = 0.01). CONCLUSION: This pilot study shows that, in LVV patients, the combined evaluation of the intensity and the extension of FDG vessel uptake at diagnosis can predict the clinical course of the disease, separating patients with favourable or complicated progress. PMID- 26250690 TI - The value of SPECT/CT in carpal boss. AB - PURPOSE: To assess the value of SPECT/CT in patients with carpal boss (CB). METHODS: In 24 wrists with CB (18 right-sided, 6 left-sided) in 21 patients, planar images and SPECT/CT images were obtained. Three patients had bilateral CB. The grade of uptake (0 absent, 1 low, 2 moderate, 3 high) on planar imaging and SPECT/CT was assessed and compared with CT findings, clinical symptoms and follow up findings. RESULTS: CB affected carpometacarpal joint II in 4 wrists, carpometacarpal joint III in 17 wrists and both carpometacarpal joints II and III in 3 wrists. Of the 24 CB, 12 (50 %) were active (i.e. increased radionuclide uptake) on planar images and 18 (75 %) on SPECT/CT images. Of the 17 symptomatic CB, 10 (59 %) were active on planar images and 14 (82 %) were active (mean grade 1.9, range 1 - 3) on SPECT/CT images. Of the 7 asymptomatic CB, 2 were active on planar images and 4 were active (mean grade 1.25, range 1 - 2) on SPECT/CT images. CT alone showed CB in all patients and an accessory ossicle (os styloideum) in 8 wrists. MR imaging was available in 7 patients and positive for CB in 5 (sensitivity 71 %). Plain radiographs were available in 17 patients and positive in 10 (59 %). Therapeutic infiltration of the CB was performed in 9 patients, and resection of the CB in 7 patients. CONCLUSION: SPECT/CT provides important morphological and metabolic information for the clinical assessment of CB, but because SPECT/CT tends to overestimate the clinical importance of CB, we recommend that planar images should still be obtained. PMID- 26250691 TI - [IL-6 dependent GLP-1 secretion during acute inflammation]. PMID- 26250692 TI - Math anxiety: A review of its cognitive consequences, psychophysiological correlates, and brain bases. AB - A decade has passed since the last published review of math anxiety, which was carried out by Ashcraft and Ridley (2005). Given the considerable interest aroused by this topic in recent years and the growing number of publications related to it, the present article aims to provide a full and updated review of the field, ranging from the initial studies of the impact of math anxiety on numerical cognition, to the latest research exploring its electrophysiological correlates and brain bases from a cognitive neuroscience perspective. Finally, this review describes the factors and mechanisms that have been claimed to play a role in the origins and/or maintenance of math anxiety, and it examines in detail the main explanations proposed to account for the negative effects of math anxiety on performance: competition for working memory resources, a deficit in a low-level numerical representation, and inhibition/attentional control deficit. PMID- 26250693 TI - GABRA2 Alcohol Dependence Risk Allele is Associated with Reduced Expression of Chromosome 4p12 GABAA Subunit Genes in Human Neural Cultures. AB - BACKGROUND: Genetic variation in a region of chromosome 4p12 that includes the GABAA subunit gene GABRA2 has been reproducibly associated with alcohol dependence (AD). However, the molecular mechanisms underlying the association are unknown. This study examined correlates of in vitro gene expression of the AD associated GABRA2 rs279858*C-allele in human neural cells using an induced pluripotent stem cell (iPSC) model system. METHODS: We examined mRNA expression of chromosome 4p12 GABAA subunit genes (GABRG1, GABRA2, GABRA4, and GABRB1) in 36 human neural cell lines differentiated from iPSCs using quantitative polymerase chain reaction and next-generation RNA sequencing. mRNA expression in adult human brain was examined using the BrainCloud and BRAINEAC data sets. RESULTS: We found significantly lower levels of GABRA2 mRNA in neural cell cultures derived from rs279858*C-allele carriers. Levels of GABRA2 RNA were correlated with those of the other 3 chromosome 4p12 GABAA genes, but not other neural genes. Cluster analysis based on the relative RNA levels of the 4 chromosome 4p12 GABAA genes identified 2 distinct clusters of cell lines, a low-expression cluster associated with rs279858*C-allele carriers and a high-expression cluster enriched for the rs279858*T/T genotype. In contrast, there was no association of genotype with chromosome 4p12 GABAA gene expression in postmortem adult cortex in either the BrainCloud or BRAINEAC data sets. CONCLUSIONS: AD-associated variation in GABRA2 is associated with differential expression of the entire cluster of GABAA subunit genes on chromosome 4p12 in human iPSC-derived neural cell cultures. The absence of a parallel effect in postmortem human adult brain samples suggests that AD associated genotype effects on GABAA expression, although not present in mature cortex, could have effects on regulation of the chromosome 4p12 GABAA cluster during neural development. PMID- 26250694 TI - Apurinic/apyrimidinic endonuclease 1 regulates angiogenesis in a transforming growth factor beta-dependent manner in human osteosarcoma. AB - Angiogenesis plays an important role in tumor growth and metastasis and has been reported to be inversely correlated with overall survival of osteosarcoma patients. It has been shown that apurinic/apyrimidinic endonuclease 1 (APE1), a dually functional protein possessing both base excision repair and redox activities, is involved in tumor angiogenesis, although these mechanisms are not fully understood. Our previous study showed that the expression of transforming growth factor beta (TGFbeta) was significantly reduced in APE1-deficient osteosarcoma cells. Transforming growth factor beta promotes cancer metastasis through various mechanisms including immunosuppression, angiogenesis, and invasion. In the current study, we initially revealed that APE1, TGFbeta, and microvessel density (MVD) have pairwise correlation in osteosarcoma tissue samples, whereas TGFbeta, tumor size, and MVD were inversely related to the prognosis of the cohort. We found that knocking down APE1 in osteosarcoma cells resulted in TGFbeta downregulation. In addition, APE1-siRNA led to suppression of angiogenesis in vitro based on HUVECs in Transwell and Matrigel tube formation assays. Reduced secretory protein level of TGFbeta of culture medium also resulted in decreased phosphorylation of Smad3 of HUVECs. In a mouse xenograft model, siRNA-mediated silencing of APE1 downregulated TGFbeta expression, tumor size, and MVD. Collectively, the current evidence indicates that APE1 regulates angiogenesis in osteosarcoma by controlling the TGFbeta pathway, suggesting a novel target for anti-angiogenesis therapy in human osteosarcoma. PMID- 26250695 TI - Continuous-Flow Left Ventricular Assist Device Thrombosis: A Danger Foreseen is a Danger Avoided. AB - Left ventricular assist devices (LVAD) are an increasingly implemented therapeutic intervention for patients with end-stage heart failure. A growing body of evidence, however, has shown an elevated risk of device thrombosis, a major complication jeopardizing the patient's post-implantation survival. To date, multiple causative factors for LVAD thrombosis have been identified, such as internal shear stress, device material, infection, and inadequate anticoagulation. Understanding the mechanisms leading to LVAD thrombosis will not only enable device optimization, but also allow for better patient handling, hence improving post-implantation outcome. In this review we highlight the most commonly identified factors leading to LVAD thrombosis and discuss their mechanisms. PMID- 26250696 TI - Normal ranges of left ventricular strain in children: a meta-analysis. AB - AIMS: The definition of normal values of two-dimensional speckle-tracking echocardiography derived left ventricular (LV) deformation parameters, is of critical importance for the routine application of this modality in children. The objectives of this study were to perform a meta-analysis of normal ranges for longitudinal, circumferential and radial strain/strain rate values and to identify confounders that may contribute to differences in reported measures. METHODS AND RESULTS: A systematic search was conducted. Studies describing normal healthy subjects and observational studies that used control groups as a comparison were included. Data were combined using a random-effect model. Effects of demographic, clinical and equipment variables were assessed through meta regression. The search identified 1,192 subjects form 28 articles. Longitudinal strain (LS) normal mean values varied from -12.9 to -26.5 (mean, -20.5; 95% CI, 20.0 to -21.0). Normal mean values of circumferential strain (CS) varied from 10.5 to -27.0 (mean, -22.06; 95% CI, -21.5 to -22.5). Radial strain (RS) normal mean values varied from 24.9 to 62.1 (mean, 45.4; 95% CI, 43.0 to 47.8). Meta regression showed LV end diastolic diameter as a significant determinant of variation for LS. Longitudinal systolic strain rate (LSRs) was significantly determined by the age and RS by the type of vendor used. CONCLUSION: Variations among different normal ranges were dependent on the vendor used, LV end-diastolic diameter and age. Vendor-independent software for analyzing myocardial deformation in children, using images from different vendors would be the ideal solution for strain measurements or else using the same system for patient's follow up. PMID- 26250697 TI - Alternative reproductive tactics in female striped mice: heavier females are more likely to breed solitarily than communally. AB - Alternative reproductive tactics (ARTs) are discrete reproductive phenotypes governed by decision rules called strategies. ARTs are fixed for life in species with alternative strategies, while tactic expression is plastic in species with a single strategy. ARTs have been investigated in males of many species, but few studies have tested whether the same theoretical framework applies in females. Female striped mice (Rhabdomys pumilio) employ three ARTs: communal breeders give birth in a nest shared with female kin and a breeding male and show allo-parental care; returners give birth away from the shared nest and later return to it; and solitary breeders give birth away from the shared nest and do not return to the group. Here, studying free-living female striped mice over six breeding seasons, we tested whether ARTs arise from alternative strategies or a single strategy. We also asked to what extent stochastic extrinsic factors explain whether individuals become solitary rather than group living. Females switched tactics, consistent with a single strategy, so we tested whether this represented a mixed or conditional single strategy. Only the latter predicts differences between ARTs in traits indicating competitive ability, such as body mass or age, before individuals adopt a tactic. We weighed females at conception when they were still group living to eliminate potential confounding effects of gestation and subsequent social tactic (solitary versus group living) on body mass. Females that went on to use a solitary ART were heavier than those that became communal breeders and returners, in support of a conditional strategy. Solitary breeders also arose through extrinsic factors (mortality of all adult female group members). They weighed less than females that became solitary while relatives were alive, but did not differ in body mass from communal breeders and returners. We conclude that ART theory applies to both sexes, with female striped mice following a conditional single strategy. Future studies should consider the possibility that phenotypes that superficially resemble evolved tactics might also arise through non-adaptive extrinsic causes. PMID- 26250698 TI - Strategies for genotype imputation in composite beef cattle. AB - BACKGROUND: Genotype imputation has been used to increase genomic information, allow more animals in genome-wide analyses, and reduce genotyping costs. In Brazilian beef cattle production, many animals are resulting from crossbreeding and such an event may alter linkage disequilibrium patterns. Thus, the challenge is to obtain accurately imputed genotypes in crossbred animals. The objective of this study was to evaluate the best fitting and most accurate imputation strategy on the MA genetic group (the progeny of a Charolais sire mated with crossbred Canchim X Zebu cows) and Canchim cattle. The data set contained 400 animals (born between 1999 and 2005) genotyped with the Illumina BovineHD panel. Imputation accuracy of genotypes from the Illumina-Bovine3K (3K), Illumina-BovineLD (6K), GeneSeek-Genomic-Profiler (GGP) BeefLD (GGP9K), GGP-IndicusLD (GGP20Ki), Illumina BovineSNP50 (50K), GGP-IndicusHD (GGP75Ki), and GGP-BeefHD (GGP80K) to Illumina BovineHD (HD) SNP panels were investigated. Seven scenarios for reference and target populations were tested; the animals were grouped according with birth year (S1), genetic groups (S2 and S3), genetic groups and birth year (S4 and S5), gender (S6), and gender and birth year (S7). Analyses were performed using FImpute and BEAGLE software and computation run-time was recorded. Genotype imputation accuracy was measured by concordance rate (CR) and allelic R square (R(2)). RESULTS: The highest imputation accuracy scenario consisted of a reference population with males and females and a target population with young females. Among the SNP panels in the tested scenarios, from the 50K, GGP75Ki and GGP80K were the most adequate to impute to HD in Canchim cattle. FImpute reduced computation run-time to impute genotypes from 20 to 100 times when compared to BEAGLE. CONCLUSION: The genotyping panels possessing at least 50 thousands markers are suitable for genotype imputation to HD with acceptable accuracy. The FImpute algorithm demonstrated a higher efficiency of imputed markers, especially in lower density panels. These considerations may assist to increase genotypic information, reduce genotyping costs, and aid in genomic selection evaluations in crossbred animals. PMID- 26250699 TI - Examining the safety of respiratory and intravenous inoculation of Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus in a mouse model. AB - Bdellovibrio spp. and Micavibrio spp. are Gram-negative predators that feed on other Gram-negative bacteria, making predatory bacteria potential alternatives to antibiotics for treating multi-drug resistant infections. While the ability of predatory bacteria to control bacterial infections in vitro is well documented, the in vivo effect of predators on a living host has yet to be extensively examined. In this study, respiratory and intravenous inoculations were used to determine the effects of predatory bacteria in mice. We found no reduction in mouse viability after intranasal or intravenous inoculation of B. bacteriovorus 109J, HD100 or M. aeruginosavorus. Introducing predators into the respiratory tract of mice provoked a modest inflammatory response at 1 hour post-exposure, but was not sustained at 24 hours, as measured by RT-qPCR and ELISA. Intravenous injection caused an increase of IL-6 in the kidney and spleen, TNF in the liver and CXCL-1/KC in the blood at 3 hours post-exposure, returning to baseline levels by 18 hours. Histological analysis of tissues showed no pathological changes due to predatory bacteria. Furthermore, qPCR detected predators were cleared from the host quickly and efficiently. This work addresses some of the safety concerns regarding the potential use of predatory bacteria as a live antibiotic. PMID- 26250701 TI - A Novel Cathode Material for Cathodic Dehalogenation of 1,1-Dibromo Cyclopropane Derivatives. AB - Leaded bronze turned out to be an excellent cathode material for the dehalogenation reaction of cyclopropanes without affecting the strained molecular entity. With this particular alloy, beneficial properties of lead cathodes are conserved, whereas the corrosion of cathode is efficiently suppressed. The solvent in the electrolyte determines whether a complete debromination reaction is achieved or if the process can be selectively stopped at the monobromo cyclopropane intermediate. The electroorganic conversion tolerates a variety of functional groups and can be conducted at rather complex substrates like cyclosporine A. This approach allows the sustainable preparation of cyclopropane derivatives. PMID- 26250700 TI - Airway management by physician-staffed Helicopter Emergency Medical Services - a prospective, multicentre, observational study of 2,327 patients. AB - BACKGROUND: Despite numerous studies on prehospital airway management, results are difficult to compare due to inconsistent or heterogeneous data. The objective of this study was to assess advanced airway management from international physician-staffed helicopter emergency medical services. METHODS: We collected airway data from 21 helicopter emergency medical services in Australia, England, Finland, Hungary, Norway and Switzerland over a 12-month period. A uniform Utstein-style airway template was used for collecting data. RESULTS: The participating services attended 14,703 patients on primary missions during the study period, and 2,327 (16 %) required advanced prehospital airway interventions. Of these, tracheal intubation was attempted in 92 % of the cases. The rest were managed with supraglottic airway devices (5 %), bag-valve-mask ventilation (2 %) or continuous positive airway pressure (0.2 %). Intubation failure rates were 14.5 % (first-attempt) and 1.2 % (overall). Cardiac arrest patients showed significantly higher first-attempt intubation failure rates (odds ratio: 2.0; 95 % CI: 1.5-2.6; p < 0.001) compared to non-cardiac arrest patients. Complications were recorded in 13 %, with recognised oesophageal intubation being the most frequent (25 % of all patients with complications). For non-cardiac arrest patients, important risk predictors for first-attempt failure were patient age (a non-linear association) and administration of sedatives (reduced failure risk). The patient's sex, provider's intubation experience, trauma type (patient category), indication for airway intervention and use of neuromuscular blocking agents were not risk factors for first-attempt intubation failure. CONCLUSIONS: Advanced airway management in physician-staffed prehospital services was performed frequently, with high intubation success rates and low complication rates overall. However, cardiac arrest patients showed significantly higher first attempt failure rates compared to non-cardiac arrest patients. All failed intubations were handled successfully with a rescue device or surgical airway. TRIAL REGISTRATION: STUDY REGISTRATION: www.clinicaltrials.gov NCT01502111 . Registered 22 December 2011. PMID- 26250703 TI - [Vaccination: The dangerous lies of an "anti-vaccine" petition]. PMID- 26250704 TI - Spatiotemporal Expression of Poly(rC)-Binding Protein PCBP2 Modulates Schwann Cell Proliferation After Sciatic Nerve Injury. AB - Poly(C)-binding proteins (PCBPs), also known as RNA-binding proteins, interact in a sequence-specific fashion with single-stranded poly(C). It was reported that PCBP2 contributed to gastric cancer proliferation and survival through miR-34a, and knockdown of PCBP2 inhibited glioma proliferation through inhibition of cell cycle progression. In addition, PCBP2 might play a critical role in the regulation of cortical neurons apoptosis induced by hypoxia or ischemia. Because of the essential role of PCBP2 in nervous system and cell growth, we investigated the spatiotemporal expression of PCBP2 in a rat sciatic nerve crush (SNC) model. We detected the upregulated expression of PCBP2 in Schwann cell after SNC. Besides, the peak expression of PCBP2 was in parallel with proliferation cell nuclear antigen. In vitro, we observed increased expression of PCBP2 during the process of TNF-alpha-induced Schwann cell proliferation. Specially, PCBP2 specific siRNA-transfected Schwann cell showed significantly decreased ability for proliferation. Together, all these data indicated that the change of PCBP2 protein expression was associated with Schwann cell proliferation after the trauma of the peripheral nervous system. PMID- 26250705 TI - Distress, concerns and unmet needs in survivors of head and neck cancer: a cross sectional survey. AB - The aim of this study was to identify the distress, unmet needs and concerns of head and neck cancer (HNC) survivors in the first 5 years after treatment. Two hundred and eighty HNC survivors from three Scottish health boards responded to a cross-sectional postal survey in 2011. Questionnaires included the Distress Thermometer, Patient Concerns Inventory (PCI) and an adapted version of the PCI to measure unmet needs. One-third of the survivors had moderate or severe levels of distress, and 74% had at least one unmet need. The most common concerns and unmet needs included oral and eating problems, fear of recurrence and fatigue. Multivariate analysis revealed that being younger, out of work (not retired), ever having had a feeding tube fitted, having a greater number of comorbidities and living alone were associated with higher levels of distress, concerns and unmet needs. The diversity of concerns and unmet needs identified in this study highlights the importance of holistic needs assessment as part of follow-up care for HNC survivors with tailoring of support for particular concerns. Specific information resources and self-management strategies are required to help HNC survivors with the practical and functional consequences of HNC treatment. PMID- 26250706 TI - Are area-level and individual-level socioeconomic factors associated with self rated health in adult urban citizens? Evidence from Slovak and Dutch cities. AB - Background: Evidence shows that living in disadvantaged areas is associated with poor health. This may be due to the socioeconomic (SE) characteristics of both these residents and the areas where they live. Evidence regarding this on Central European (CE) countries is scarce. Our aim was to assess whether the prevalence of poor self-rated health (SRH) was higher in deprived urban areas, whether this can be explained by individual SE status (SES) and whether this differed between Slovakia and the Netherlands per age group. We examined the association of urban level data and individual-level SE factors from different urban areas in different countries (Slovakia, the Netherlands) using comparable urban health indicators and area indicators. We also obtained unique data from the EU-FP7 EURO URHIS 2 project. Multilevel logistic regression showed that poor SRH was associated with area deprivation in both countries. Regarding age by country, poor SRH occurred more frequently in the more deprived areas for the younger age group (<=64) in the Netherlands but for the older age group (>=65 years) in Slovakia. Moreover, Slovak citizens reported poor SRH significantly more often than Dutch residents. Individual SES was significantly associated with poor SRH in both age groups and both countries for most area-level SE measures. Individual SES is associated with SRH more strongly than area deprivation. Therefore, it is important to account for relative deprivation at an individual level when considering health-enhancing activities. Moreover, the effect of urban-area deprivation seems to differ between CE and WE countries. PMID- 26250707 TI - Alcohol-induced morbidity and mortality by occupation: a population-based follow up study of working Finns. AB - BACKGROUND: To justify alcohol-related health promotion programs and target them at the correct workplaces, it is important to identify occupations with increased risk of severe health outcomes caused by alcohol. METHODS: Data on hospital admissions (854,555 men and 801,653 women) from the Finnish health care register and data on deaths from Statistics Finland from 1 January 2001 to 31 December 2004 were merged with information from the 2000 population census. We assessed the age- and education-adjusted relationship between occupation and the sum of hospitalizations and death primarily caused by alcohol, using Cox proportional hazards regression. We also estimated the fraction of incidence of severe alcohol induced health outcomes that are attributable to factors related to one's occupation (population attributable fraction). RESULTS: Most of the cases were men (80%), middle-aged and usually had no more than a secondary level of education. When the reference was professionals, who were at the lowest risk, those at increased risk were mostly manual workers in craft work, construction and service. However, we also found several non-manual occupations at a high risk. According to population attributable fraction, the proportion of severe alcohol-induced health outcomes would have been 31% lower among men and 20% lower among women if all occupational groups had been at the same risk as professionals. CONCLUSIONS: We detected considerable occupational differences in alcohol-induced morbidity and mortality among a nationally representative working population. This indicates a need for alcohol-focused health promotion programs in these high-risk occupations. PMID- 26250708 TI - Advocacy: the silence of Europe's public health associations is deafening. PMID- 26250709 TI - Elderly from lower socioeconomic groups are more vulnerable to mental health problems, but area deprivation does not contribute: a comparison between Slovak and Dutch cities. AB - Background: Little is known about factors associated with mental health problems (MHP) of the elderly in socioeconomically deprived neighbourhoods, and comparisons between Central European and Western European countries on this topic are lacking. We examined whether MHP occurred more frequently in deprived neighbourhoods and among deprived people. Next, we examined whether the association of MHP with area deprivation differed by country and whether this could be explained by the socioeconomic (SE) characteristics of the residents. We obtained data on non-institutionalized residents aged 65 years and above from the EU-FP7: EURO-URHIS 2 project from Slovak ( N = 665, response rate 44.0%) and Dutch cities ( N = 795, response rate 50.2%). An elevated score on General Health Questionnaire-12 (>=2) indicated MHP. Education and household income with financial strain were used as measures of individual SE status. We employed multilevel logistic regression. Overall rates of MHP were significantly higher in Slovakia (40.6%) than in the Netherlands (30.6%). The neighbourhood unemployment rate was not associated with the mental health of elderly in either country. Rates of MHP were significantly higher among elderly with low and medium income [odds ratio (OR) = 1.75, 95% confidence interval (CI) = 1.16-2.62; OR = 1.64, 95% CI = 1.12-2.41, respectively] and financial strain (OR = 2.26, 95% CI = 1.56 3.28) when compared with those with high income and no strain, respectively. Individual-level SE characteristics explained differences between the two countries. The risk of MHP among the elderly is associated with their individual level SE position but not with neighbourhood deprivation in both Slovakia and the Netherlands. PMID- 26250711 TI - 'A ring in the heart'. Blood cyst. PMID- 26250712 TI - Can a trochanter stabilising plate prevent lateral wall fractures in AO/OTA 31-A2 pertrochanteric fractures with critical thin femoral lateral walls? PMID- 26250713 TI - The role of CT in diagnosis and treatment of distal tibial fractures with intra articular involvement in children. AB - AIM: Distal tibial fractures with intra-articular involvement during childhood are injuries with potentially severe complications if not treated promptly. Daily clinical practice indicates that sole use of plain radiographs may lead to misdiagnosis and subsequent erroneous selection of suitable treatment. The role of computed tomography (CT) in the classification and treatment decision of these injuries is unclear. This study aims to determine whether CT evaluation is required in the management of these fractures. PATIENTS AND METHODS: We assessed 64 distal tibial fractures with intra-articular involvement on two separate occasions in a blinded study, in order to classify the fracture and decide the appropriate treatment approach. In the first part of the study, plain radiographs were evaluated in order to diagnose the type of the fracture and select the appropriate treatment. In the second part, CT scans were performed in the same patients in order to re-evaluate diagnosis and treatment. The study included fractures prior to physeal closure (Salter-Harris III and IV fractures, n=32) as well as transitional fractures (J. Tillaux and triplane fractures, n=32). RESULTS: According to plain radiographs, 31 patients were diagnosed with SH III fracture, 8 with SH IV, 9 with J. Tillaux and 16 with triplane fracture. Surgical treatment was decided in 18 patients and non-surgical in 46. After CT scan evaluation, 20 patients were diagnosed with SH III, 12 with SH IV, 9 with J. Tillaux, and 23 with triplane fracture. In this occasion the number of patients referred for surgical treatment raised to 42 leaving only 22 patients to be treated conservatively. CONCLUSIONS: Computed tomography lead to changes in fracture classification and treatment decision. Treatment decision changed for 24 patients after CT evaluation. Treatment decision in patients with SH III and IV did not change significantly opposed to patients with transitional fractures, where CT scan had major impact on treatment decision. Despite the irradiation of immature skeleton and higher cost containment, this study indicates that patients with transitional distal tibial fractures as well as patients with displaced SH III and IV fractures must undergo CT examination in order to make accurate diagnosis and select the appropriate treatment. PMID- 26250714 TI - Methods to assess area and volume of wounds - a systematic review. AB - Wound measurement is important in monitoring the healing process of chronic wounds and in evaluating the effect of treatment. The objective of this systematic review was to evaluate evidence from the literature on accuracy, agreement, reliability and feasibility of wound measurement techniques described since 1994. Studies were identified by searching the electronic databases PubMed, Embase and Cochrane Library. Of the 12 013 studies identified, 43 were included in the review. A total of 30 papers evaluated techniques for measuring wound area and 13 evaluated techniques for measuring wound volume. The six approaches for measuring wound area were simple ruler method (10 papers), mathematical models (5 papers), manual planimetry (10 papers), digital planimetry (16 papers), stereophotogrammetry (2 papers) and digital imaging method (20 papers). Of these studies, 10 evaluated accuracy, 15 agreement, 17 reliability and 25 mentioned feasibility. The number of wounds examined in the studies was highly variable (n = 3-260). Studies evaluating techniques for measuring wound volume included between 1 and 50 wounds and evaluated accuracy (4 studies), agreement (6 studies), reliability (8 studies) and feasibility (12 studies). Digital planimetry and digital imaging were considered the most accurate and reliable methods for area measurement, particularly in larger and irregularly shaped wounds. None of the three-dimensional technologies have so far had a major impact, because of their low accuracy, high cost and complexity in handling the system set-up. PMID- 26250715 TI - Moral Absolutism, Self-Deception, and Moral Self-Concept in Men Who Commit Intimate Partner Violence: A Comparative Study With an Opposite Sample. AB - The objective of this study is to show compatible data with the idea that men who commit intimate partner violence are uninhibited about the moral consequences of their behaviors, probably because they feel certainty about the rightness of their moral values and they strongly deceive themselves to maintain a good moral self-concept, and thus a good level of well-being. To do that, we compare their scores with those obtained by an opposite sample regarding the use of violence, made up of professional male psychologists who work in the social field trying to teach others alternative strategies to violence. PMID- 26250716 TI - Responding Effectively to Women Experiencing Severe Abuse: Identifying Key Components of a British Advocacy Intervention. AB - This article presents key findings from a multisite evaluation of Independent Domestic Violence Advisor (IDVA) services--a form of intervention targeted specifically at women experiencing severe domestic abuse. Results highlight the complex lives of women accessing these services and the efforts of IDVAs to connect women with multiple community resources. Women remaining engaged with services reported positive safety outcomes. Frequency of contact with an IDVA and the number of community resources accessed were positively associated with the odds of achieving safety. These findings suggest this intervention is a promising strategy for tackling severe and complex cases of domestic abuse. PMID- 26250717 TI - A tale of two theorems: Comment on "Universal scaling for the dilemma strength in evolutionary games" by Z. Wang et al. PMID- 26250718 TI - Exome and genome sequencing: a revolution for the discovery and diagnosis of monogenic disorders. AB - Massively parallel DNA sequencing has revolutionized analyses of human genetic variation. From having been out of reach for individual research groups and even more so for clinical diagnostic laboratories until recently, it is now possible to analyse complete human genomes within reasonable time frames and at a reasonable cost using technologies that are becoming increasingly available. This represents a huge advance in our ability to provide correct diagnoses for patients with rare inherited disorders and their families. This paradigm shift is especially dramatic within the area of monogenic disorders. Not only can rapid and safe diagnostics of virtually all known single-gene defects now be established, but novel causes of disease in previously unsolved cases can also be identified, illuminating novel pathways important for normal physiology. This greatly increases the capability not only to improve management of rare disorders, but also to improve understanding of pathogenetic mechanisms relevant for common, complex diseases. PMID- 26250719 TI - The Impact of a Nurse-Led Home Visitation Program on Hypertension Self-Management among Older Community-Dwelling Koreans. AB - OBJECTIVES: To examine the impact of a nurse-led home visitation program for hypertension self-management among older community-dwelling Koreans. DESIGN AND SAMPLE: As part of a larger community-based home visitation project aimed at behavioral change in this vulnerable population, a single group pre- and posttest design was used. MEASURES: Visiting nurses affiliated to public health center assisted vulnerable elders with hypertension self-management tailored according to their health problems through home visits for a period of 2-4 months. RESULTS: A total of 13,452 hypertensive persons over the age of 65 completed the intervention. All outcomes were significantly improved and included hypertension knowledge, blood pressure monitoring, dietary management, medication adherence, and self-confidence in hypertension self-management (p < .001). Changes in hypertension knowledge, medication adherence, and self-confidence varied by gender with women showing greater knowledge improvement than men but less improvement in medication adherence and confidence in hypertension self management. There was a marginal interaction effect for gender and age on dietary management (F = 3.55, p = .063), with men (>=75 years) showing greater improvement than their female counterparts after the intervention. CONCLUSIONS: This nurse-led home visitation intervention can be helpful in self-management skill building among hypertensive Korean elders. The program may improve medication adherence and health-promoting behavioral changes. PMID- 26250720 TI - 4-Alkylated Silver-N-Heterocyclic Carbene (NHC) Complexes with Cytotoxic Effects in Leukemia Cells. AB - Computational chemistry has shown that backbone-alkylated imidazoles ought to be efficient ligands for transition metal catalysts with improved carbene-to-metal donation. In this work, such alkylated imidazoles were synthesized and complexed with silver(I) by means of an eight/nine-step synthetic pathway we devised to access a new class of biologically active silver complexes. The synthesis involves selective iodination of the imidazole backbone, followed by Sonogashira coupling to replace the backbone iodine. The installed alkyne moiety is then subjected to reductive hydrogenation with Pearlman's catalyst. The imidazole N1 atom is arylated by the palladium-catalyzed Buchwald N-arylation method. The imidazole N3 position was then methylated with methyl iodine, whereupon the synthesis was terminated by complexation of the imidazolium salt with silver(I) oxide. The synthetic pathway provided an overall yield of ~20 %. The resulting complexes were tested in vitro against HL60 and MOLM-13 leukemic cells, two human derived cell lines that model acute myeloid leukemia. The most active compounds exhibiting low IC50 values of 14 and 27 MUM, against HL60 and MOLM-13 cells, respectively. The imidazole side chain was found to be essential for high cytotoxicity, as the imidazole complex bearing a C7 side chain at the 4-position was four- to sixfold more potent than the corresponding imidazole elaborated with a methyl group. PMID- 26250721 TI - Fatal Penetrating Injuries Sustained by High-pressure Water Jet Unit. AB - The high-pressure water jet unit is a generator of frequent burst of water jets. The water jet reaches very high speeds and is able to cause wounds similar to those of high-velocity projectiles. In the presented case, unusual fatal injuries sustained by water jet are presented. Operating with the unit, an untrained worker accidentally activated a high-pressure water jet unit, and the extremely high pressure of water liberated the jet unit from his hand and whirled it around him. A jet stream of water ran across his body and caused fatal penetrating injuries in the femoral region. The edges of the wound were mainly sharp with contusion rings on the skin beyond the edges. Exploring the inside of the canals during the autopsy, the left femoral artery and vein were found to be completely transected. The resemblance to a firearm entry wound and the severity of the internal injury make it a noteworthy entity. PMID- 26250722 TI - Influence of Zonisamide on the LTP-like Effect Induced by Quadripulse Transcranial Magnetic Stimulation (QPS). PMID- 26250723 TI - Emulsion stability and properties of fish gelatin-based films as affected by palm oil and surfactants. AB - BACKGROUND: Gelatin films exhibit the poor water vapour barrier properties. The use of palm oil, which is abundant and available in Thailand, can be a means to lower water vapour migration. To disperse oil in film-forming dispersion (FFD), a surfactant along with appropriate homogenization is required. The study aimed to investigate the influence of palm oil level and surfactants in the absence or presence of glycerol on characteristics of FFD and resulting gelatin films. RESULTS: Similar oil droplet sizes, both d32 and d43 values, of FFD containing soy lecithin were observed, regardless of palm oil level used (P > 0.05). FFD with Tween-20 had larger droplet size as the levels of oil increased (P < 0.05). After 12 h storage, slight increases in d32 and d43 were noticeable in all FFD samples. When the films were determined, lower water vapour permeability (WVP) and tensile strength (TS) but higher elongation at break (EAB) were obtained as palm oil level increased (P < 0.05), regardless of glycerol and surfactant used. Films without glycerol had lower WVP and EAB with higher TS than those containing 300 g kg(-1) glycerol (P < 0.05). No differences in WVP and mechanical properties were found between films containing both surfactants (P > 0.05). CONCLUSION: FFD containing 500 or 750 g kg(-1) palm oil using soy lecithin as a surfactant in the presence of 300 g kg(-1) glycerol had the enhanced homogeneity and stability of oil droplets. The resulting gelatin film had the improved water vapour barrier properties. (c) 2015 Society of Chemical Industry. PMID- 26250724 TI - Magnesium: The Disregarded Cation. PMID- 26250725 TI - Dysmagnesemia in Hospitalized Patients: Prevalence and Prognostic Importance. AB - OBJECTIVE: To examine the prevalence of serum magnesium (Mg) alterations and outcomes in hospitalized patients. PATIENTS AND METHODS: All admissions to Mayo Clinic in Rochester, Minnesota, from January 1, 2009, through December 31, 2013 (288,120 patients), were screened. Admission Mg from each unique patient and relevant clinical data were extracted from the institutional electronic database. RESULTS: After excluding patients aged less than 18 years, those without Mg measurement, and readmission episodes, a total of 65,974 patients were studied. Magnesium levels of 2.1 mg/dL or higher were found in 20,777 patients (31.5%), and levels less than 1.7 mg/dL were noted in 13,320 (20.2%). Hypomagnesemia was common in patients with hematologic/oncological disorders, and hypermagnesemia was common in those with cardiovascular disease. The lowest hospital mortality, assessed by restricted cubic spline and percentage death, occurred in patients with Mg levels between 1.7 and 1.89 mg/dL. An Mg level of less than 1.7 mg/dL was independently associated with an increased risk of hospital mortality after adjusting for all variables except the admission diagnosis; risk for longer hospital stay and being discharged to a care facility were increased in the fully adjusted model. An elevated Mg level of 2.3 mg/dL or higher was a predictor for all adverse outcomes. The magnitude of Mg elevations in patients with levels of 2.3 mg/dL or higher (N=7908) was associated with worse hospital mortality in a dose-response manner. In patients with cardiovascular diseases, Mg levels of 1.5 to 1.69 mg/dL and 2.3 mg/dL or higher both independently predicted poor outcomes including hospital mortality. CONCLUSION: Dysmagnesemia in hospitalized patients is common, with hypermagnesemia being most prevalent. Compared with hypomagnesemia, hypermagnesemia is a stronger predictor for poor outcomes. Magnesium supplementation for patients without Mg deficiency should be avoided in the absence of randomized controlled trials documenting a benefit. PMID- 26250726 TI - Risk of Acute Kidney Injury, Dialysis, and Mortality in Patients With Chronic Kidney Disease After Intravenous Contrast Material Exposure. AB - OBJECTIVE: To examine the effect of intravenous iodinated contrast material administration on the subsequent development of acute kidney injury (AKI), emergent dialysis, and short-term mortality using a propensity score-adjusted analysis of computed tomographic scan recipients with chronic kidney disease (CKD). PATIENTS AND METHODS: In this institutional review board-approved retrospective study, all patients with CKD who received a contrast-enhanced (contrast group) or unenhanced (noncontrast group) computed tomographic scan from January 1, 2000, to August 1, 2013 were identified. Patients were subdivided into CKD stage III (baseline estimated glomerular filtration rate, 30-59 mL/min per 1.73 m(2)) and CKD stage IV-V (baseline estimated glomerular filtration rate, <30 mL/min per 1.73 m(2)) subgroups and separately underwent propensity score generation, stratification, and 1:1 matching. Rates of AKI, 30-day emergent dialysis, and mortality were compared between contrast and noncontrast groups. Sensitivity analyses examining only patients with stable prescan serum creatinine levels and incorporating intravenous fluid administration at the time of the CT scan into the model were also performed. RESULTS: A total of 6902 patients (4496 CKD stage III, matched: 1220 contrast and 1220 noncontrast; 2086 CKD stage IV-V, matched: 491 contrast and 491 noncontrast) were included in the study. After propensity score adjustment, rates of AKI, emergent dialysis, and mortality were not significantly higher in the contrast group than in the noncontrast group in either CKD subgroup (CKD stage III: OR, 0.65-1.00; P<.001-.99 and CKD stage IV-V: OR, 0.93-2.33; P=.22-.99). Both sensitivity analyses revealed similar results. CONCLUSION: Intravenous contrast material administration was not associated with an increased risk of AKI, emergent dialysis, and short-term mortality in a cohort of patients with diminished renal function. PMID- 26250727 TI - Treatment of Immunoglobulin Light Chain Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement. AB - Immunoglobulin light chain amyloidosis (AL amyloidosis) has an incidence of approximately 1 case per 100,000 person-years in Western countries. The rarity of the condition not only poses a challenge for making a prompt diagnosis but also makes evidenced decision making about treatment even more challenging. Physicians caring for patients with AL amyloidosis have been borrowing and customizing the therapies used for patients with multiple myeloma with varying degrees of success. One of the biggest failings in the science of the treatment of AL amyloidosis is the paucity of prospective trials, especially phase 3 trials. Herein, we present an extensive review of the literature with an aim of making recommendations in the context of the best evidence and expert opinion. PMID- 26250728 TI - What Clinicians Should Know Alphabout Spontaneous Coronary Artery Dissection. AB - Spontaneous coronary artery dissection (SCAD) is an important cause of acute coronary syndrome and sudden death in young persons, particularly women. Associated conditions include fibromuscular dysplasia, peripartum status, and episodes of extreme emotion or exercise. Because of heightened awareness and improved diagnostic accuracy, it is increasingly important for clinicians to understand SCAD. Moreover, short-term and long-term management strategies diverge from typical strategies for atherosclerotic disease. In this Concise Review, we aim to highlight the key points about SCAD, including presentation, diagnosis, associated conditions, and short-term and long-term management. PMID- 26250729 TI - 88-Year-Old Man With Mental Status Changes and Vesicular Lesions. PMID- 26250731 TI - Non-Hodgkin Lymphoma: Diagnosis and Treatment. AB - Non-Hodgkin lymphomas are lymphoid malignant neoplasms with diverse biological and clinical behavior. Patients typically present with persistent painless lymphadenopathy, but some patients may present with constitutional symptoms or with involvement of organs other than the lymphoid and hematopoietic system. An accurate diagnosis, careful staging of the disease, and identification of adverse prognostic factors form the basis of treatment selection. Patients commonly receive chemoimmunotherapy as initial treatment, and radiation therapy may be added if patients have early-stage disease. Most patients respond well to treatment, but relapses are frequent and additional therapies including stem cell transplant are often needed. Because many subtypes of lymphoma remain incurable with current management strategies, clinical trials are in progress to identify novel therapies with promising activity in this disease. PMID- 26250730 TI - Alternative Splicing of G Protein-Coupled Receptors: Relevance to Pain Management. AB - Drugs that target G protein-coupled receptors (GPCRs) represent the primary treatment strategy for patients with acute and chronic pain; however, there is substantial individual variability in both the efficacy and adverse effects associated with these drugs. Variability in drug responses is due, in part, to individuals' diversity in alternative splicing of pain-relevant GPCRs. G protein coupled receptor alternative splice variants often exhibit distinct tissue distribution patterns, drug-binding properties, and signaling characteristics that may impact disease pathology as well as the extent and direction of analgesic effects. We review the importance of GPCRs and their known splice variants to the management of pain. PMID- 26250732 TI - Does Pain Lead to Tachycardia? Revisiting the Association Between Self-reported Pain and Heart Rate in a National Sample of Urgent Emergency Department Visits. PMID- 26250733 TI - Complicated and Advanced Atherosclerosis in a Young Woman With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Success and Challenges of BCR/ABL1-Targeted Cancer Therapy. PMID- 26250734 TI - Accumulated Short Bouts of Physical Activity Are Associated With Reduced Premature All-Cause Mortality: Implications for Physician Promotion of Physical Activity and Revision of Current US Government Physical Activity Guidelines. PMID- 26250735 TI - Pulmonary Infarction Manifesting as a Cavitary Lesion. PMID- 26250736 TI - 58-Year-Old Woman With Melena. PMID- 26250737 TI - Max Perutz and the Structure of Hemoglobin. PMID- 26250740 TI - Cell death: Tumour suppressor p53 helps phagocytes clean up. PMID- 26250739 TI - Immunopathology of multiple sclerosis. AB - Two decades of clinical experience with immunomodulatory treatments for multiple sclerosis point to distinct immunological pathways that drive disease relapses and progression. In light of this, we discuss our current understanding of multiple sclerosis immunopathology, evaluate long-standing hypotheses regarding the role of the immune system in the disease and delineate key questions that are still unanswered. Recent and anticipated advances in the field of immunology, and the increasing recognition of inflammation as an important component of neurodegeneration, are shaping our conceptualization of disease pathophysiology, and we explore the potential implications for improved healthcare provision to patients in the future. PMID- 26250741 TI - Elevated C-reactive protein and late-onset bipolar disorder in 78 809 individuals from the general population. AB - BACKGROUND: No prospective studies have examined the role of C-reactive protein (CRP) in late-onset bipolar disorder. AIMS: We tested the hypothesis that elevated levels of CRP are associated cross-sectionally and prospectively with late-onset bipolar disorder, and that such an association possibly is causal. METHOD: We performed cross-sectional and prospective analyses with a median follow-up time of 5.9 years (interquartile range: 4.4-7.6) in 78 809 individuals from the general population, and used genetic variants influencing CRP levels to perform a Mendelian randomisation study. RESULTS: Elevated levels of CRP were associated both cross-sectionally and prospectively with late-onset bipolar disorder. When CRP was on a continuous scale, a doubling in CRP yielded an observational odds ratio for late-onset bipolar disorder of 1.28 (1.08-1.52) with a corresponding causal odds ratio of 4.66 (0.89-24.3). CONCLUSION: Elevated CRP is associated with increased risk of late-onset bipolar disorder in the general population which was supported by the genetic analysis. PMID- 26250742 TI - Evaluation of a cognitive psychophysiological model for management of tic disorders: an open trial. AB - BACKGROUND: Tic disorders, in particular chronic tic disorder and Tourette syndrome, affect about 1% of the population. The current treatment of choice is pharmacological or behavioural, addressing tics or the premonitory urges preceding tic onset. AIMS: The current study reports an open trial evaluating the effectiveness of a cognitive psychophysiological treatment addressing Tourette specific sensorimotor activation processes rather than the tic. METHOD: Forty nine people with Tourette syndrome and 36 people with chronic tics completed 10 weeks of individual cognitive psychophysiological therapy. Outcome measures included two tic severity scales and psychosocial measures. RESULTS: Post treatment both groups had significantly improved on the tic scales with strong effect sizes across tic locations and complex and simple tics, maintained at 6 month follow-up with further change in perfectionism and self-esteem. CONCLUSIONS: The cognitive psychophysiological approach targeting underlying sensorimotor processes rather than tics in Tourette's and chronic tic disorder reduced symptoms with a large effect size. PMID- 26250743 TI - The influence of personality disorder on outcome in adolescent self-harm. AB - BACKGROUND: Little is currently known about the presence and impact of personality disorder in adolescents who self-harm. AIMS: To evaluate personality disorder in repeated self-harm in adolescence and its impact on self-harm psychopathology and adaptation outcomes over 1 year. METHOD: A clinical referral sample (n = 366) of adolescents presenting with repeated self-harm aged 12-17 years, as part of a randomised controlled trial (Assessment of Treatment in Suicidal Teenagers study, ASSIST). Personality disorder was assessed using the Structured Clinical Interview for DSM-IV Axis II (SCID-II). One-year outcomes included frequency and severity of repeat self-harm, self-reported suicidality, mood and functional impairment. RESULTS: About 60% of the referred adolescents showed one or more forms of personality disorder. Personality disorder was associated with significantly greater severity of self-harm, overall psychopathology and impairment. There was a complex association with treatment adherence. Personality disorder predicted worse 1-year outcomes in relation to self-harm frequency and severity, as well as impairment, suicidality and depressive symptoms. CONCLUSIONS: Personality disorder can be reliably measured in adolescence and showed high prevalence in this clinical self-harm sample. Controlling for other variables, it showed a strong independent association with self-harm severity at referral and predicted adherence to treatment and clinical outcomes (independent of treatment) over 1 year. Consideration of personality disorder diagnosis is indicated in the assessment and management of adolescents who repeatedly self-harm. PMID- 26250744 TI - Cognitive and neurophysiological markers of ADHD persistence and remission. AB - BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) persists in around two-thirds of individuals in adolescence and early adulthood. AIMS: To examine the cognitive and neurophysiological processes underlying the persistence or remission of ADHD. METHOD: Follow-up data were obtained from 110 young people with childhood ADHD and 169 controls on cognitive, electroencephalogram frequency, event-related potential (ERP) and actigraph movement measures after 6 years. RESULTS: ADHD persisters differed from remitters on preparation-vigilance measures (contingent negative variation, delta activity, reaction time variability and omission errors), IQ and actigraph count, but not on executive control measures of inhibition or working memory (nogo-P3 amplitudes, commission errors and digit span backwards). CONCLUSIONS: Preparation-vigilance measures were markers of remission, improving concurrently with ADHD symptoms, whereas executive control measures were not sensitive to ADHD persistence/remission. For IQ, the present and previous results combined suggest a role in moderating ADHD outcome. These findings fit with previously identified aetiological separation of the cognitive impairments in ADHD. The strongest candidates for the development of non-pharmacological interventions involving cognitive training and neurofeedback are the preparation-vigilance processes that were markers of ADHD remission. PMID- 26250745 TI - Acceptance and commitment therapy as a web-based intervention for depressive symptoms: randomised controlled trial. AB - BACKGROUND: Depression is a highly prevalent disorder, causing a large burden of disease and substantial economic costs. Web-based self-help interventions seem promising in promoting mental health. AIMS: To compare the efficacy of a guided web-based intervention based on acceptance and commitment therapy (ACT) with an active control (expressive writing) and a waiting-list control condition (Netherlands Trial Register NTR1296). METHOD: Adults with depressive symptoms from the general population were randomised to ACT (n = 82), expressive writing (n = 67) or waiting-list control (n = 87). The main outcome was reduction in depressive symptoms assessed with the Center for Epidemiological Studies - Depression scale. RESULTS: Significant reductions in depressive symptoms were found following the ACT intervention, compared with the control group (Cohen's d = 0.56) and the expressive writing intervention (d = 0.36). The effects were sustained at 6-month and 12-month follow-up. CONCLUSIONS: Acceptance and commitment therapy as a web-based public mental health intervention for adults with depressive symptoms can be effective and applicable. PMID- 26250746 TI - Prognostic Significance of the Renal Resistive Index After Renal Artery Revascularization in the Context of Flash Pulmonary Edema. AB - PURPOSE: To evaluate the prognostic value of the renal resistive index (Ri) after renal artery revascularization in the context of flash pulmonary edema. METHODS: Between 2000 and 2008, 43 patients (mean age 72.1+/-10.9 years; 23 women) underwent renal artery angioplasty/stenting in the context of flash pulmonary edema. Intrarenal Ri was assessed using duplex ultrasound. The majority (97.7%) of patients had hypertension, and nearly half (46.5%) had diabetes mellitus. For this retrospective analysis, the patients were divided into 2 groups according to the median Ri (<0.8 and >=0.8) of the population. A Cox proportional hazards model was used to identify predictors of all-cause mortality (primary endpoint) and rehospitalization for heart failure; the results are presented as the hazard ratio (HR) and 95% confidence interval (CI). The mean follow-up was 49.8+/-30.6 months. RESULTS: There was no difference between the groups regarding clinical characteristics. A high Ri was associated with the risk of all-cause death (HR 2.54, 95% CI 1.15 to 5.60, p=0.021). This relationship was still statistically significant after adjustment for age, gender, diabetes, glomerular filtration rate, and treatment with a renin-angiotensin system inhibitor (HR 1.74, 95%CI 1.08 to 2.81, p=0.032). A high Ri was also associated with cardiovascular death in unadjusted and adjusted analyses. In contrast, a high Ri was not associated with the risk of rehospitalization for heart failure. CONCLUSION: After renal artery revascularization for flash pulmonary edema, a high intrarenal Ri is independently associated with all-cause mortality. Determination of the intrarenal Ri after this procedure may be useful for identifying at-risk patients. PMID- 26250747 TI - Drug-Eluting Balloon Therapy for Femoropopliteal Occlusive Disease: Predictors of Outcome With a Special Emphasis on Calcium. AB - PURPOSE: To assess the association of patient, lesion, and procedure variables, including calcification, with late lumen loss (LLL) after use of drug-eluting balloon (DEB) therapy in patients with femoropopliteal arterial disease. METHODS: In this retrospective study, 91 patients (mean age 72.0+/-8.62 years; 50 men) were analyzed at 6 months after DEB treatment. Lesions were located in the superficial femoral artery (SFA, n=68) and popliteal artery (n=23). Lesion calcification was graded by a core laboratory using 2 published scoring indices: the peripheral artery calcification scoring system and a grading system based on circumference (arc) and length of calcium. RESULTS: The median LLL after 6 months was 0.2 mm (interquartile range -0.5, 1.14) overall and varied significantly across lesions with differing severity of calcification (p=0.042). However, LLL did not differ based on calcium location (intimal, medial, or mixed) or calcium length (p=0.351 and p=0.258, respectively). Additional predictors of LLL after DEB treatment included diabetes (p=0.034), coronary artery disease (p=0.024), and prior intervention (p=0.013). Interestingly, the severity of residual stenosis after the intervention did not have any impact on the LLL during follow-up (Spearman r = -0.238). CONCLUSION: Severity of lesion calcification is associated with LLL after treatment with DEB. One possible approach to overcome this limitation might be plaque modification or removal prior to DEB usage. Nevertheless, clinical data that support this hypothesis are currently lacking. PMID- 26250748 TI - A Comparison of Clinical Outcomes for Diabetic and Nondiabetic Patients Following Directional Atherectomy in the DEFINITIVE LE Claudicant Cohort. AB - PURPOSE: To report a subset analysis that evaluated the hypothesis that directional atherectomy for peripheral artery disease in diabetic claudicants has noninferior primary patency at 12 months compared with nondiabetic claudicants. METHODS: DEFINITIVE LE, a US/European multicenter study, assessed the effectiveness of directional atherectomy using SilverHawk/TurboHawk systems for treatment of peripheral artery disease in the superficial femoral, popliteal, and infrapopliteal arteries. Of the 800 patients enrolled in the study, only the 598 claudicant patients (mean age 69.5+/-10.4 years; 336 men) who were classified at baseline as Rutherford category 1-3 were eligible for this subset analysis. Of these, 46.8% (280/598) had diabetes. Follow-up to 12 months included duplex ultrasound examination, functional assessments, and adverse event evaluations. Independent angiographic and duplex ultrasound core laboratories assessed primary patency and secondary endpoints; a clinical events committee adjudicated adverse events. RESULTS: Although diabetics had significantly more baseline comorbidities, 12-month primary patency (77.0%) was no different than for nondiabetics (77.9%; superiority p=0.98; noninferiority p<0.001) across all anatomic territories treated. Freedom from clinically driven target lesion revascularization was no different between diabetics (83.8%) and nondiabetics (87.5%) overall (p=0.19) or by lesion locations. Secondary clinical outcomes (Rutherford category, ankle-brachial index, and walking impairment) improved at 12 months for both diabetics and nondiabetics. CONCLUSION: Noninferior 12-month patency rates demonstrate that directional atherectomy is an effective treatment in diabetic as well as nondiabetic claudicants. Directional atherectomy remains an attractive treatment option, improving luminal diameters without stents, which preserves future treatment options for both diabetic and nondiabetic patients with progressive, diffuse vascular disease. PMID- 26250749 TI - Mechanisms of enterohepatic fibroblast growth factor 15/19 signaling in health and disease. AB - The gut-derived hormone fibroblast growth factor 15/19 (FGF15/19) is an emerging versatile regulator of various metabolic pathways. As such, FGF15/19 has been implicated in homeostatic control of bile acid, carbohydrate and lipid metabolism in multiple target organs including the liver, adipose tissue and brain. In line with this, growing evidence suggests that dysregulation of FGF15/19 contributes to a number of metabolic and bile acid-associated disorders such as fatty liver disease, Type 2 diabetes and different gastrointestinal dysfunctions. In this review we summarize the current knowledge on the organ-specific functions of FGF15/19 and address their underlying molecular mechanisms. Moreover, recent advances in the characterization of factors that control the release of the hormone in the gut will be discussed and linked to the current view of how alterations of FGF15/19 signaling may contribute to disease development. Finally, the suitability of FGF15/19 as a potential therapeutic target will be critically reviewed. PMID- 26250750 TI - The concurrent validity of three computerized methods of muscle activity onset detection. AB - Although the visual (VIS) method for muscle activation onset detection has been the gold standard, this method has been criticized because of its moderate reproducibility and for being laborious. The simple threshold (STH), approximated generalized likelihood-step (AGL-step), and k-means (KM) algorithms are more repeatable and less laborious but require validation for gait speeds encountered in clinical research. We, therefore, assessed the intra-rater reliability of the VIS method and the concurrent validity of the algorithms against the VIS for 3 gait speeds. We recruited 10 healthy young adults (4 male, 6 female; mean age=28.5+/-4.2). Participants completed 10 walking trials each at 3 speeds. Electromyographic data from 1 gait cycle (GC) were collected from 6 right lower extremity muscles during each trial. We used custom Labview programs to determine muscle activity onset for all 4 methods. Repeatability coefficients for the VIS method ranged from 12.51% to 45.08% of the GC, depending on the muscle. The AGL step algorithm agreed best with the VIS method (root mean squared error (RMSE) 0.86-6.95% of GC) followed by the STH (1.19-15.6% of GC) and KM (4.6-16.9% of GC) methods. A single rater demonstrated large errors (RMSE 8-23% of GC) between VIS assessments. Based on this study's parameters, the AGL-step agreed best with the VIS method and may be an alternative to the VIS. PMID- 26250751 TI - Substantial Receptor-induced Structural Rearrangement of Rotavirus VP8*: Potential Implications for Cross-Species Infection. AB - Rotavirus-cell binding is the essential first step in rotavirus infection. This binding is a major determinant of rotavirus tropism, as host cell invasion is necessary to initiate infection. Initial rotavirus-cell interactions are mediated by carbohydrate-recognizing domain VP8* of the rotavirus capsid spike protein VP4. Here, we report the first observation of significant structural rearrangement of VP8* from human and animal rotavirus strains upon glycan receptor binding. The structural adaptability of rotavirus VP8* delivers important insights into how human and animal rotaviruses utilize the wider range of cellular glycans identified as VP8* binding partners. Furthermore, our studies on rotaviruses with atypical genetic makeup provide information expected to be critical for understanding the mechanisms of animal rotavirus gene emergence in humans and support implementation of epidemiologic surveillance of animal reservoirs as well as future vaccination schemes. PMID- 26250753 TI - High priority for hepatitis C screening in safety net hospitals: Results from a prospective cohort of 4582 hospitalized baby boomers. AB - Low-income populations are disproportionately affected by hepatitis C virus (HCV) infection. Thus, implementing baby boomer screening (born 1945-1965) for HCV may be a high priority for safety net hospitals. We report the prevalence and predictors of HCV infection and advanced fibrosis or cirrhosis based on the Fibrosis-4 score plus imaging for a baby boomer cohort admitted to a safety net hospital over a 21-month interval with >9 months of follow-up. Anti-HCV antibody testing was performed for 4582, or 90%, of all never-screened patients, of whom 312 (6.7%) tested positive. Adjusted odds ratios of testing anti-HCV-positive were 2.66 for men versus women (P<0.001), 1.25 for uninsured versus insured (P=0.06), 0.70 for Hispanics versus non-Hispanic whites (P=0.005), and 0.93 per year of age (P<0.001). Among 287 patients tested for HCV RNA (91% of all anti-HCV positive cases), 175 (61%) were viremic (3.8% overall prevalence in cohort), which was 5% less likely per year of age (P<0.03). Noninvasive staging of 148 (84.6%) chronic HCV patients identified advanced fibrosis or cirrhosis in 50 (33.8%), with higher adjusted odds ratios of 3.21 for Hispanics versus non Hispanic whites/Asians (P=0.02) and 1.18 per year of age (P=0.001). Other factors associated with significantly higher adjusted odds ratios of advanced fibrosis or cirrhosis were alcohol abuse/dependence, obesity, and being uninsured. CONCLUSION: In this low-income, hospitalized cohort, 4% of 4582 screened baby boomers were diagnosed with chronic HCV, nearly twice the rate in the community; one-third had noninvasive testing that indicated advanced fibrosis or cirrhosis, which was significantly more likely for Hispanics, those of older age, those with obesity, those with alcohol abuse/dependence, and those who lacked insurance. PMID- 26250754 TI - Longevity and effectiveness of aluminum addition to reduce sediment phosphorus release and restore lake water quality. AB - 114 lakes treated with aluminum (Al) salts to reduce internal phosphorus (P) loading were analyzed to identify factors driving longevity of post-treatment water quality improvements. Lakes varied greatly in morphology, applied Al dose, and other factors that may have affected overall treatment effectiveness. Treatment longevity based on declines in epilimnetic total P (TP) concentration averaged 11 years for all lakes (range of 0-45 years). When longevity estimates were used for lakes with improved conditions through the end of measurements, average longevity increased to 15 years. Significant differences in treatment longevity between deeper, stratified lakes (mean 21 years) and shallow, polymictic lakes (mean 5.7 years) were detected, indicating factors related to lake morphology are important for treatment success. A decision tree developed using a partition model suggested Al dose, Osgood index (OI, a morphological index), and watershed to lake area ratio (related to hydraulic residence time, WA:LA) were the most important variables determining treatment longevity. Multiple linear regression showed that Al dose, WA:LA, and OI explained 47, 32 and 3% respectively of the variation in treatment longevity. Other variables (too data limited to include in the analysis) also appeared to be of importance, including sediment P content to Al dose ratios and the presence of benthic feeding fish in shallow, polymictic lakes. PMID- 26250755 TI - Analysis of the La:P ratio in lake sediments - Vertical and spatial distribution assessed by a multiple-core survey. AB - In recent years, lanthanum modified bentonite has been increasingly applied to eutrophic lakes with the aim of converting potentially bio-available forms of phosphorus in sediments into biologically unavailable forms. In many of these applications, however, no attempts have been made to assess the efficiency and efficacy of the measure in terms of its effect on the sediment. In this study, we collected sediment cores from a heavily eutrophied lake that has previously been treated with lanthanum modified clay. This restoration method is based on the strong ionic bond formed between lanthanum and phosphate which results in the formation of LaPO4 (Rhabdophane) in the sediment. In order to determine the changes that had occurred in the sediments as a result of the addition of the clay, we measured the vertical distribution of lanthanum in the collected cores, calculated La:P ratios of the different sediment layers and used the ratios to determine whether or not the applied dosage was sufficient. By means of the geostatistical method of kriging these values were transferred into maps of different depth intervals to visualize the results. The results indicate that the La:P ratio may be a useful tool which allows lake managers to measure the vertical distribution of lanthanum in sediments following treatments and determine whether or not dosages are sufficient to permanently render sediment phosphorus biologically unavailable. The method may also provide a basis on which to decide whether or not smaller reapplications are needed and can be used to control the dispersion of the material. PMID- 26250756 TI - Validation and adaptation of rapid neurodevelopmental assessment instrument for infants in Guatemala. AB - BACKGROUND: Timely detection of neurodevelopmental impairments in children can prompt referral for critical services that may prevent permanent disability. However, screening of impairments is a significant challenge in low-resource countries. We adapted and validated the rapid neurodevelopmental assessment (RNDA) instrument developed in Bangladesh to assess impairment in nine domains: primitive reflexes, gross and fine motor development, vision, hearing, speech, cognition, behaviour and seizures. METHODS: We conducted a cross-sectional study of 77 infants (0-12 months) in rural Guatemala in July 2012 and July 2013. We assessed inter-rater reliability and predictive validity between the 27-item RNDA and the 325-item Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) and concurrent validity based on chronic malnutrition, a condition associated with neurodevelopmental impairments. For both RNDA and BSID-III, standardized scores below 80 were defined as borderline impairment. RESULTS: Children came from rural households (92%), were born to indigenous women of Mayan descent (73%) and had moderate or severe growth stunting (43%). Inter-rater reliability for eight RNDA domains was of moderate to high reliability (weighted kappa coefficients, 0.49-0.99). Children screened positive for impairment in fine motor (17%) and gross motor (14%) domains using the RNDA. The RNDA had good concurrent ability; infants who were growth stunted had higher mean levels of impairment in gross motor, speech and cognition domains (all p < 0.001). The RNDA took 20-30 min to complete compared with 45-60 min for BSID-III. CONCLUSIONS: Wide-scale implementation of a simple, valid and reliable screening tool like the RNDA by community health workers would facilitate early screening and referral of infants at-risk for neurodevelopmental impairment. PMID- 26250757 TI - Trainee Occupational Therapists Scoring the Barthel ADL. AB - Within medical applications there are two main types of information design; paper based and digital information [1]. As technology is constantly changing, information within healthcare management and delivery is continually being transitioned from traditional paper documents to digital and online resources. Activity of Daily Living (ADL) charts are still predominantly paper based and are therefore prone to "human error" [2]. In light of this, an investigation has taken place into the design for reducing the amount of human error, between a paper based ADL, specifically the Barthel Index, and the same ADL created digitally. The digital ADL was developed as an online platform as this offers the best method of data capture for a large group of participants all together [3]. The aim of the study was to evaluate the usability of the Barthel Index ADL in paper format and then reproduce the same ADL digitally. This paper presents the findings of a study involving 26 participants who were familiar with ADL charts, and used three scenarios requiring them to complete both a paper ADL and a digital ADL. An evaluation was undertaken to ascertain if there were any 'human errors' in completing the paper ADL and also to find similarities/differences through using the digital ADL. The results from the study indicated that 22/26 participants agreed that the digital ADL was better, if not the same as a paper based ADL. Further results indicated that participants rate highly the added benefit of the digital ADL being easy to use and also that calculation of assessment scores were performed automatically. Statistically the digital BI offered a 100 % correction rate in the total calculation, in comparison to the paper based BI where it is more common for users to make mathematical calculation errors. Therefore in order to minimise handwriting and calculation errors, the digital BI proved superior than the traditional paper based method. PMID- 26250758 TI - Recursive partitioning analysis of prognostic factors in post-transplant lymphoproliferative disorders (PTLD): a 120 case single institution series. AB - The post-transplant lymphoproliferative disorders (PTLD) comprise a heterogeneous group of lymphocytic and plasma cell proliferations occurring in recipients of tissue allografts in the setting of immunosuppression. We describe our experience of 120 patients with PTLD seen between 1990 and 2009, one of the largest series reported by a single institution. Post-transplant lymphoproliferative disorders characteristics were analysed with regard to paediatric and adult patients, and with regard to the decade of diagnosis, 1990-1999 (pre-rituximab era) versus 2000 2009 (the rituximab era). We present a new prognostic score using the recursive partitioning model, consisting of the Eastern Cooperative Oncology Group (ECOG) score (0-1 vs. 2-4), age [paediatrics (<16 years old), adults (16-60 years old) and elderly (>60 years old)] and CD20 status (positive vs negative); separating patients into 4 risk categories based on overall survival. Low-risk included paediatric patients with ECOG score of 0-1; intermediate-low-risk included adults aged 16-60 years with an ECOG score of 0-1; intermediate-high-risk included elderly patients with an ECOG score 0-1 or paediatric patients and adults aged 16 60 years with an ECOG score of 2-4 and CD20 positive; high-risk group included patients of any age with an ECOG score of 2-4 and CD20 negative, and elderly patients with an ECOG score of 2-4 with CD20-positive PTLD. PMID- 26250759 TI - Planning future studies based on the precision of network meta-analysis results. AB - When there are multiple competing interventions for a healthcare problem, the design of new studies could be based on the entire network of evidence as reflected in a network meta-analysis. There is a practical need to answer how many (if any) studies are needed, of which design (i.e., which treatments to compare), and with what sample size to infer conclusively about the relative treatment effects of a set of target or all competing treatments and their relative ranking. We consider the precision in the results obtained from network meta-analysis: the precision of the joint distribution of the estimated basic parameters of the model and the precision in the treatment ranking. We quantify the precision in the estimated effects by considering their variance-covariance matrix and estimate the precision in ranking by quantifying the dissimilarity of the density functions of summary effect estimates. Then, based on a desirable improvement in precision, we calculate the required sample size for each possible study design and number of study arms, and we present visual tools that can help trialists select the optimal study design. We use a published network of interventions for the treatment of hepatocellular carcinoma to illustrate the suggested methodology. The presented methodology can aid investigators making informed and evidence-based decisions about planning new studies. PMID- 26250760 TI - A case report of sporadic hemiplegic migraine associated cerebral hypoperfusion: comparison of arterial spin labeling and dynamic susceptibility contrast perfusion MR imaging. AB - The pathogenesis of sporadic hemiplegic migraine remains unclear, and perfusion weighted magnetic resonance imaging (PWI) has been used for characterization of hemodynamic changes in migraine aura. We report a case of sporadic hemiplegic migraine in which magnetic resonance perfusion imaging showed left cerebral hypoperfusion. Dynamic susceptibility contrast (DSC) perfusion maps showed hypoperfusion with posterior predominance in the left cerebral hemisphere. Findings with arterial spin labeling (ASL) perfusion correlated well with DSC perfusion findings. CONCLUSION: With unique advantages compared with DSC PWI, ASL has significant potential in the evaluation of the patients with sporadic hemiplegic migraine. WHAT IS KNOWN: Sporadic hemiplegic migraine is a rare variety of migraine defined by migraine attacks, which include the presence of motor weakness/hemiparesis during the aura phase and where no first- or second degree relative (parent, sibling, or child) has identical attacks. WHAT IS NEW: Reports on imaging abnormalities described in sporadic hemiplegic migraine are sparse. To our knowledge, this is the first report to describe arterial spin labeling (ASL) perfusion abnormalities in patients with sporadic hemiplegic migraine, as compared with dynamic susceptibility contrast perfusion-weighted magnetic resonance imaging (PWI). PMID- 26250761 TI - Improving survey data on pregnancy-related deaths in low-and middle-income countries: a validation study in Senegal. AB - OBJECTIVE: In low- and middle-income countries (LMICs), siblings' survival histories (SSH) are often used to estimate maternal mortality, but SSH data on causes of death at reproductive ages have seldom been validated. We compared the accuracy of two SSH instruments: the standard questionnaire used during the demographic and health surveys (DHS) and the siblings' survival calendar (SSC), a new questionnaire designed to improve survey reports of deaths among women of reproductive ages. METHODS: We recruited 1189 respondents in a SSH survey in Niakhar, Senegal. Mortality records from a health and demographic surveillance system (HDSS) constituted the reference data set. Respondents were randomly assigned to an interview with the DHS or SSC questionnaires. A total of 164 respondents had a sister who died at reproductive ages over the past 15 years before the survey according to the HDSS. RESULTS: The DHS questionnaire led to selective omissions of deaths: DHS respondents were significantly more likely to report their sister's death if she had died of pregnancy-related causes than if she had died of other causes (96.4% vs. 70.9%, P < 0.007). Among reported deaths, both questionnaires had high sensitivity (>90%) in recording pregnancy-related deaths. But the DHS questionnaire had significantly lower specificity than the SSC (79.5% vs. 95.0%, P = 0.015). The DHS questionnaire overestimated the proportion of deaths due to pregnancy-related causes, whereas the SSC yielded unbiased estimates of this parameter. CONCLUSION: Statistical models informed by SSH data collected using the DHS questionnaire might exaggerate maternal mortality in Senegal and similar settings. A new questionnaire, the SSC, could permit better tracking progress towards the reduction in maternal mortality. PMID- 26250763 TI - Translating the look AHEAD trial into action. PMID- 26250762 TI - Improvement of liver function parameters in advanced HCV-associated liver cirrhosis by IFN-free antiviral therapies. AB - BACKGROUND: Successful antiviral treatment of decompensated hepatitis B with HBV polymerase inhibitors is associated with improvement of liver function. To what extent liver function also improves in cirrhotic patients with chronic hepatitis C receiving novel interferon-free (IFN-free) therapies is unknown. AIM: To study liver function in cirrhotic HCV patients receiving IFN-free therapies. METHODS: We here studied 80 consecutive patients with advanced HCV associated liver cirrhosis including 34 patients (43%) with Child B/C cirrhosis and 42 patients (53%) with platelet counts of <90.000/MUL receiving different combinations of direct acting antivirals without interferon [sofosbuvir/ribavirin (n = 56), sofosbuvir/simeprevir +/- ribavirin (n = 15) and sofosbuvir/daclatasvir +/- ribavirin (n = 9)]. The majority of patients was infected with HCV genotype 1 (n = 50); HCV genotypes 2, 3 and 4 were present in 4, 24 and 2 patients, respectively. RESULTS: Liver function parameters including albumin, bilirubin, cholinesterase and prothrombin time all improved in the majority of patients during antiviral therapy irrespectively of the underlying HCV genotype, however, with different kinetics. MELD scores improved until post-treatment week 12 in 44% of the patients but worsened in 15%. A sustained virological response was achieved in 63% of the patients. HCV RNA relapse led to moderate ALT increases in 15/23 patients but was not associated with hepatic decompensations. CONCLUSION: This real-world single centre study showed that interferon-free treatment of hepatitis C patients with advanced liver cirrhosis restores liver function, and may thereby reduce the need for liver transplantations. PMID- 26250764 TI - SOX4 is a potential prognostic factor in human cancers: a systematic review and meta-analysis. AB - OBJECTIVE: The aim of the this study was to analyze the status of sex-determining region Y-related high-mobility group box 4 (SOX4) expression in varied human cancers and its correlation with overall survival in patients with human cancers. METHODS: To observe initially the expression status of SOX4 in twenty kinds of human cancers at protein database (The Human Protein Atlas). We systematically and carefully searched the studies from electronic databases and seriously identified according to eligibility criteria. The correlation between SOX4 expression and overall survival in human cancers was evaluated through Review Manager. RESULTS: We found that SOX4 expression was significantly positive in most types of human cancer tissues, and the positive rate of SOX4 expression was about 78 % in overall cancer tissues. Furthermore, a total of 10 studies which included 1348 cancer patients were included in the final analysis. Meta-analysis showed that SOX4 overexpression was correlated with a poor overall survival and the pooled hazard ratio (HR), and corresponding 95 % confidence interval (CI) was 1.67 (95 % CI 1.01-2.78). From subgroup analyses, we present evidence that SOX4 overexpression was an unfavorable prognostic factor for colorectal cancer patients' recurrence-free survival and gastric cancer patients' overall survival, and the pooled HRs (95 % CI) were 1.73 (95 % CI 1.04-2.88) and 3.74 (95 % CI 1.04 13.45), respectively. CONCLUSIONS: In summary, SOX4 is a potential prognostic biomarker in human cancers. PMID- 26250765 TI - Response to chemotherapy estimates by FDG PET is an important prognostic factor in patients with Ewing sarcoma. AB - BACKGROUND: Response to chemotherapy is a prognostic factor in patients with Ewing sarcoma (ES); the role of FDG PET to predict response in these patients has not been thoroughly investigated. We evaluated the diagnostic accuracy and the potential of FDG PET to predict response to chemotherapy (CHT). MATERIALS AND METHODS: We analyzed data of 50 patients with ES (median age 12.6 years). All patients were treated with neoadjuvant CHT, and underwent surgery for local control. All patients had (18)F-FDG PET/CT at diagnosis and after induction CHT, prior to local control. We compared response assessed by histopathology with FDG PET using standard uptake values (SUVs). RESULTS: Median SUV at diagnosis (SUV I) was 5 (range 1.2-17), and median SUV after neoadjuvant chemotherapy (SUV II) was 1.8 (range 0-8.4). Median SUV II/I ratio was 0.3 (range 0-1). SUV at diagnosis was significantly lower in patients with good histological response than in patients with poor histological response (median 3.8 vs. 7.2, p 0.02). We found a significant correlation between SUV II and outcome; the positive predictive value of an SUV II <= 2.5 for favorable response was 84.21 %, and the median SUV II was significantly higher in patients with disease progression (2.3 vs. 1.6, p = 0.04). In multivariate analysis, necrosis and SUV II were significant predictors of outcome. CONCLUSIONS: (18)F-FDG PET demonstrates high diagnostic accuracy for response to initial chemotherapy in patients with ES and it correlates with outcome. The role of FDG PET in predicting response and outcome should be further investigated. PMID- 26250767 TI - Dr Roy Patterson. PMID- 26250766 TI - The impact of prostate gland dimension in genitourinary toxicity after definitive prostate cancer treatment with moderate hypofractionation and volumetric modulated arc radiation therapy. AB - PURPOSE: To analyze clinical-dosimetric predictors of genitourinary (GU) toxicity in a cohort of prostate cancer (PC) patients treated with moderate hypofractionation and simultaneous integrated boost (SIB) using volumetric modulated arc therapy (VMAT) technique. MATERIALS AND METHODS: 60 patients were selected. Patients were stratified into low (43 %), intermediate (30 %) and high risk (27 %) groups. Low-risk patients received 73.5 Gy to PTV1; intermediate-risk received 73.5 Gy to PTV1 and 60 Gy to PTV2; high-risk received 73.5 Gy to PTV1, 60 Gy to PTV2, and 54 Gy to PTV3. All patients were treated in 30 fractions. Androgen deprivation therapy (ADT) was prescribed upfront in intermediate and high-risk categories. Toxicity was scored according to Common Terminology Criteria for Adverse Events v4.0 scoring system. RESULTS: Median follow-up was 30 months (range 16-36 months). GU acute toxicity was recorded as followS: G0 = 16/60 (27 %), G1 = 18/60 (30 %); G2 = 26/60 (43 %). GU late toxicity was recorded as follows: G0 = 20/60 (34 %); G1 = 29/60 (48 %); G2 = 11/56 (18 %). The risk of acute G2 GU toxicity was three times higher for prostate volume >=80 cc. In 60 % of the patients with a prostate volume >=80 cc, the first 3 weeks are at particular risk for toxicity onset. In the late setting, no statistical significance was found between GU toxicity and prostate gland dimension. CONCLUSION: Prostate volume >=80 cc resulted a predictive factor of acute G2 GU toxicity, in moderate hypofractionation and volumetric modulated arc radiation therapy for definitive PC. PMID- 26250768 TI - Peripheral T-cell lymphoma: a challenging mimicker of angioedema and urticaria. PMID- 26250769 TI - The nose, upper airway, and obstructive sleep apnea. PMID- 26250770 TI - Sputum high mobility group box-1 in asthmatic children: a noninvasive sensitive biomarker reflecting disease status. AB - BACKGROUND: The monitoring of asthma is based mainly on clinical history, physical examination, and lung function test evaluation. To improve knowledge of the disease, new biomarkers of airway inflammation, including high mobility group box-1 (HMGB1), are being developed. OBJECTIVE: To evaluate sputum HMGB1 levels in children with stable, off-therapy, allergic asthma and to evaluate the relation between HMGB1 levels and lung function parameters. METHODS: Fifty children with asthma (28 boys and 22 girls, median age 11.56 +/- 1.41 years) and 44 healthy children (22 boys and 22 girls, median age 11.07 +/- 2.12 years) were enrolled. Sputum HMGB1 was assessed in the cohort study. Lung function (predicted percentage of forced expiratory volume in 1 second [FEV1%] and forced expiratory flow between 25% and 75% [FEF25%-75%]), serum total IgE levels, and asthma severity by validated Global Initiative for Asthma criteria were recorded. RESULTS: Sputum HMGB1 levels were higher in children with asthma than in healthy controls (100.68 +/- 10.03 vs 9.60 +/- 3.76 ng/mL, P < .0001). Sputum HMGB1 levels also were positively related to total IgE levels in children with asthma (r = 0.6567, P < .0001). An inverse and strict correlation between sputum HMGB1 levels and pulmonary function indices also were observed in children with mild (FEV1%, r = -0.86544, P < .0001; FEF25%-75%, r = -0.53948, P < .05), moderate (FEV1%, r = -0.99548, P < .0001; FEF25%-75%, r = -0.48668, P < .05), and severe (FEV1%, r = -0.90191, P < .0001; FEF25%-75%, r = -0.66777, P < .05) asthma. CONCLUSION: The present study provides evidence that sputum HMGB1 is a sensitive biomarker of allergic asthma in children because it was increased and correlated directly with asthma severity and inversely with lung function indices. PMID- 26250771 TI - No hypothalamic-pituitary-adrenal function effect with beclomethasone dipropionate nasal aerosol, based on 24-hour serum cortisol in pediatric allergic rhinitis. AB - BACKGROUND: Intranasal corticosteroids are the mainstay of allergic rhinitis (AR) treatment. Their potential to suppress the hypothalamic-pituitary-adrenal axis should be evaluated, especially after long-term daily use in children. OBJECTIVE: To evaluate the effects of treatment with non-aqueous beclomethasone dipropionate (BDP) nasal aerosol on hypothalamic-pituitary-adrenal axis function in children with perennial AR. METHODS: In this double-blinded, placebo-controlled, parallel group study, patients (6-11 years old) with perennial AR were randomized (2:1) to BDP nasal aerosol at 80 MUg/day (n = 67) or placebo (n = 32). The primary end point was change from baseline in 24-hour serum cortisol (SC) weighted mean for BDP nasal aerosol and placebo after 6 weeks of treatment, which was analyzed in the per-protocol population. RESULTS: The per-protocol population included 97 patients (BDP nasal aerosol, n = 66; placebo, n = 31). Baseline geometric mean SC weighted mean values were similar in the 80-MUg/day BDP nasal aerosol and placebo groups (5.97 and 6.47 MUg/dL, respectively). After 6 weeks' treatment, geometric mean values were 6.19 and 7.13 MUg/dL, respectively, with no decrease from baseline in either group. Geometric mean SC ratio of BDP nasal aerosol at 80 MUg/day to placebo was 0.91 (95% confidence interval 0.81-1.03), indicating predefined noninferiority. SC concentration-time profiles were similar for the placebo and 80-MUg/day BDP nasal aerosol groups at baseline and week 6. BDP nasal aerosol at 80 MUg/day was generally well tolerated. CONCLUSION: In pediatric patients with perennial AR, 24-hour SC profiles were comparable for BDP nasal aerosol and placebo, indicating that once-daily BDP nasal aerosol treatment did not significantly affect hypothalamic-pituitary-adrenal axis function. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01697956. PMID- 26250772 TI - Allergic reaction to chlorpheniramine maleate. PMID- 26250773 TI - Mental health and behavior of food-allergic adolescents compared to a healthy matched sample. PMID- 26250774 TI - Allergen of the month--mucor. PMID- 26250776 TI - Spatial Reference Memory is Associated with Modulation of Theta-Gamma Coupling in the Dentate Gyrus. AB - Spatial reference memory in rodents represents a unique opportunity to study brain mechanisms responsible for encoding, storage and retrieval of a memory. Even though its reliance on hippocampal networks has long been established, the precise computations performed by different hippocampal subfields during spatial learning are still not clear. To study the evolution of electrophysiological activity in the CA1-dentate gyrus axis of the dorsal hippocampus over an iterative spatial learning paradigm, we recorded local field potentials in behaving mice using a newly designed appetitive version of the Barnes maze. We first showed that theta and gamma oscillations as well as theta-gamma coupling are differentially modulated in particular hippocampal subfields during the task. In addition, we show that dentate gyrus networks, but not CA1 networks, exhibit a transient learning-dependent increase in theta-gamma coupling specifically at the vicinity of the target area in the maze. In contrast to previous immediate early gene studies, our results point to a long-lasting involvement of dentate networks in navigational memory in the Barnes maze. Based on these findings, we propose that theta-gamma coupling might represent a mechanism by which hippocampal areas compute relevant information. PMID- 26250777 TI - Perturbation of Posterior Inferior Temporal Cortical Activity Impairs Coarse Orientation Discrimination. AB - It is reasonable to assume that the discrimination of simple visual stimuli depends on the activity of early visual cortical neurons, because simple visual features are supposedly coded in these areas whereas more complex features are coded in late visual areas. Recently, we showed that training monkeys in a coarse orientation discrimination task modified the response properties of single neurons in the posterior inferior temporal (PIT) cortex, a late visual area. Here, we examined the contribution of PIT to coarse orientation discrimination using causal perturbation methods. Electrical stimulation (ES) of PIT with currents of at least 100 uA impaired coarse orientation discrimination in monkeys. The performance deterioration did not exclusively reflect a general impairment to perform a difficult perceptual task. However, high current (650 uA) but not low-current (100 uA) ES also impaired fine color discrimination. ES of temporal regions dorsal or anterior to PIT produced less impairment of coarse orientation discrimination than ES of PIT. Injections of the GABA agonist muscimol into PIT also impaired performance. These data suggest that the late cortical area PIT is part of the network that supports coarse orientation discrimination of a simple grating stimulus, at least after extensive training in this task at threshold. PMID- 26250775 TI - Mutation of the Dyslexia-Associated Gene Dcdc2 Enhances Glutamatergic Synaptic Transmission Between Layer 4 Neurons in Mouse Neocortex. AB - Variants in DCDC2 have been associated with reading disability in humans, and targeted mutation of Dcdc2 in mice causes impairments in both learning and sensory processing. In this study, we sought to determine whether Dcdc2 mutation affects functional synaptic circuitry in neocortex. We found mutation in Dcdc2 resulted in elevated spontaneous and evoked glutamate release from neurons in somatosensory cortex. The probability of release was decreased to wild-type level by acute application of N-methyl-d-aspartate receptor (NMDAR) antagonists when postsynaptic NMDARs were blocked by intracellular MK-801, and could not be explained by elevated ambient glutamate, suggesting altered, nonpostsynaptic NMDAR activation in the mutants. In addition, we determined that the increased excitatory transmission was present at layer 4-layer 4 but not thalamocortical connections in Dcdc2 mutants, and larger evoked synaptic release appeared to enhance the NMDAR-mediated effect. These results demonstrate an NMDAR activation gated, increased functional excitatory connectivity between layer 4 lateral connections in somatosensory neocortex of the mutants, providing support for potential changes in cortical connectivity and activation resulting from mutation of dyslexia candidate gene Dcdc2. PMID- 26250778 TI - Genetic Effects on Fine-Grained Human Cortical Regionalization. AB - Various brain structural and functional features such as cytoarchitecture, topographic mapping, gyral/sulcal anatomy, and anatomical and functional connectivity have been used in human brain parcellation. However, the fine grained intrinsic genetic architecture of the cortex remains unknown. In the present study, we parcellated specific regions of the cortex into subregions based on genetic correlations (i.e., shared genetic influences) between the surface area of each pair of cortical locations within the seed region. The genetic correlations were estimated by comparing the correlations of the surface area between monozygotic and dizygotic twins using bivariate twin models. Our genetic subdivisions of diverse brain regions were reproducible across 2 independent datasets and corresponded closely to fine-grained functional specializations. Furthermore, subregional genetic correlation profiles were generally consistent with functional connectivity patterns. Our findings indicate that the magnitude of the genetic covariance in brain anatomy could be used to delineate the boundaries of functional subregions of the brain and may be of value in the next generation human brain atlas. PMID- 26250780 TI - Effect of concomitant single incision vaginal surgery on mid urethral sling success. AB - AIMS: The aim of this study was to assess medium-term outcomes of the single anterior vaginal wall incision technique with concomitant mid-urethral sling (MUS) procedure. METHODS: Patients suffering from stress urinary incontinence and who desired surgical correction for their incontinence were divided into two groups according to MUS surgery alone or MUS surgery with anterior vaginal wall surgery. Concomitant surgery was performed via single large anterior vaginal wall incision. Primary outcome was treatment success 12 months after surgery. Urodynamic and baseline factors that may be associated with surgery failure were analyzed. RESULTS: Single incision anterior colporrhaphy with MUS was performed in 180 patients, 62 patients underwent only MUS procedure. Success rate was 87.1% in sling surgery alone and 83.9% in single incision concomitant surgery group (P = 0.5). Detrusor overactivity (DO) was present on UDS in 23 of 37 women (62.2%) with MUS failure, 81 of 205 women (39.7%) with no stress test positivity with the cough stress test (P < 0.05). Total continence rate in patients who underwent vaginal hysterectomy was 60.6% (P < 0.001). CONCLUSION: Concurrent cystocele repair with MUS operations through a single anterior wall incision is a safe and effective method for SUI. This study demonstrated an increased risk of surgery failure for those who underwent a concurrent hysterectomy for pelvic organ prolapse. Neurourol. Urodynam. 35:995-999, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26250779 TI - Laser-Evoked Vertex Potentials Predict Defensive Motor Actions. AB - The vertex potential is the largest response that can be recorded in the electroencephalogram of an awake, healthy human. It is elicited by sudden and intense stimuli, and is composed by a negative-positive deflection. The stimulus properties that determine the vertex potential amplitude have been well characterized. Nonetheless, its functional significance remains elusive. The dominant interpretation is that it reflects neural activities related to the detection of salient stimuli. However, given that threatening stimuli elicit both vertex potentials and defensive movements, we hypothesized that the vertex potential is related to the execution of defensive actions. Here, we directly compared the salience and motoric interpretations by investigating the relationship between the amplitude of laser-evoked potentials (LEPs) and the response time of movements with different defensive values. First, we show that a larger LEP negative wave (N2 wave) predicts faster motor response times. Second, this prediction is significantly stronger when the motor response is defensive in nature. Third, the relation between the N2 wave and motor response time depends not only on the kinematic form of the movement, but also on whether that kinematic form serves as a functional defense of the body. Therefore, the N2 wave of the LEP encodes key defensive reactions to threats. PMID- 26250782 TI - Radiotherapy associated with improved survival for high-grade sarcoma of the extremity. AB - BACKGROUND: The impact of radiotherapy on local control in limb-preserving surgery for high-risk sarcoma has been well studied. However, the impact of the use and timing of radiation therapy on survival is unclear. METHODS: From 1988 to 2010, patients with Stage III extremity sarcoma were identified within the SEER registry and cohorts were created using propensity score matching between irradiated and non-irradiated groups. RESULTS: A total of 2,606 patients were identified, with a median age of 59 years a majority were white (81%), male (54%), received radiotherapy (78%), and had lower extremity (80%) sarcomas. The most common subtype was fibrohistiocytic (29.8%). Patients treated with radiotherapy were younger (57.2 vs. 60.3 years) and differed in subtype compared to those untreated. The matched cohorts were better balanced for all factors. Radiation therapy was associated with a 5% 5-year survival advantage on univariate analysis for both the unmatched (P = 0.002) and matched cohorts (P = 0.01). On multivariate analysis radiotherapy was associated with a 20% and 30% survival advantage for the matched and unmatched cohorts, respectively (P <= 0.02). The timing of radiotherapy did not affect survival. CONCLUSIONS: Radiotherapy, regardless of the timing, is associated with improved survival in high-risk sarcoma. PMID- 26250781 TI - Kidney Function and Fracture Risk: The Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: People with end-stage renal disease are at high risk for bone fracture. Less is known about fracture risk in milder chronic kidney disease and whether chronic kidney disease-associated fracture risk varies by sex or assessment with alternative kidney markers. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 10,955 participants from the Atherosclerosis Risk in Communities (ARIC) Study followed up from 1996 to 2011. PREDICTOR: Kidney function as assessed by creatinine-based estimated glomerular filtration rate (eGFRcr), urine albumin-creatinine ratio, and alternative filtration markers. OUTCOMES: Fracture-related hospitalizations determined by diagnostic code. MEASUREMENTS: Baseline kidney markers; hospitalizations identified by self-report during annual telephone contact and active surveillance of local hospital discharge lists. RESULTS: Mean age of participants was 63 years, 56% were women, and 22% were black. During a median follow-up of 13 years, there were 722 incident fracture-related hospitalizations. Older age, female sex, and white race were associated with higher risk for fracture (P<0.001). The relationship between eGFRcr and fracture risk was nonlinear: <60mL/min/1.73m(2), lower eGFRcr was associated with higher fracture risk (adjusted HR per 10mL/min/1.73m(2) lower, 1.24; 95% CI, 1.05-1.47); there was no statistically significant association for >=60mL/min/1.73m(2) in the primary analysis. In contrast, there was a graded association between other markers of kidney function and subsequent fracture, including albumin-creatinine ratio (HR per doubling, 1.10; 95% CI, 1.06-1.14), cystatin C-based eGFR (HR per 1-SD decrease, 1.15; 95% CI, 1.06-1.25), and 1/beta2-microglobulin (HR per 1-SD decrease, 1.26, 95% CI, 1.15-1.37). LIMITATIONS: No bone mineral density assessment; one-time measurement of kidney function. CONCLUSIONS: Both low eGFR and higher albuminuria were significant risk factors for fracture in this community-based population. The shape of the association in the upper ranges of eGFR varied by the filtration marker used in estimation. PMID- 26250783 TI - Functional Correlates of Midline Brain Volume Loss in Chronic Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is associated with long-term changes in daily life functioning, yet the neuroanatomical correlates of these changes are poorly understood. This study related outcome assessed across several domains to brain structure derived from quantitative magnetic resonance imaging (MRI). Sixty individuals spanning a wide range of TBI severity participated 1-year post-injury as part of the Toronto TBI study. Volumetric data over 38 brain regions were derived from high resolution T1-weighted MRI scans. Functioning was assessed with a battery of self- and significant-other rated measures. Multivariate analysis (partial least squares) was used to identify shared variance between the neuroimaging and outcome measures. TBI was associated with item endorsement on outcome questionnaires without strong evidence for severity or focal lesion effects. Prefrontal midline, cingulate, medial temporal, right inferior parietal and basal ganglia/thalamic volumes were associated with measures of initiative, energization, and physical complaints. In the chronic stage of TBI, self initiation, energization, and physical complaints related to a specific pattern of volume loss in midline and lateral regions known to be involved in motivation, apathy, and attention. These results suggest that crucial functional changes in chronic TBI may be associated with volume loss in established midline-frontal and attentional circuits. PMID- 26250785 TI - miR-144-3p exerts anti-tumor effects in glioblastoma by targeting c-Met. AB - The study aimed to explore the specific function and mechanism of miR-144-3p in glioblastoma (GBM) cells with different phosphatase and tensin homolog (PTEN) phenotypes. We demonstrated that the miR-144-3p level was significantly down regulated in glioma compared with the non-neoplastic brain tissues, and decreased with ascending grades. The loss of miR-144-3p effectively predicted the decreased overall survival in glioma patients. Interestingly, the expression of MET was up regulated and inversely associated with miR-144-3p level in glioma tissues. Next, we certified that miR-144-3p specifically bound to MET 3'-untranslated region (3' UTR) and inhibited its expression. miR-144-3p potently repressed GBM cell proliferation and invasion via suppressing MET in vitro and in vivo. In addition, our results showed no difference in malignancy inhibition induced by miR-144-3p in GBM cells with different PTEN phenotypes. miR-144-3p inhibited several survival signaling pathways by targeting MET independent of PTEN status in GBM cells. Over-expression of miR-144-3p inhibited survival capability and increased apoptosis, resulting in enhancement of radiation and temozolomide sensitivity. Our data provide new insights into the potential application of miR-144-3p in GBM therapy by targeting MET and then inhibiting the downstream signaling. PMID- 26250786 TI - The White Diet is preferred, better tolerated, and non-inferior to a clear-fluid diet for bowel preparation: A randomized controlled trial. AB - BACKGROUND AND AIM: Dietary restrictions contribute to the unpleasantness of bowel preparation for colonoscopy. We compare the effectiveness and tolerability of a low residue diet of white-colored foods ("White Diet") with a clear-fluid diet the day prior to colonoscopy in an endoscopist-blinded randomized non inferiority trial. METHODS: Adults undergoing outpatient colonoscopy were randomized with stratification by procedure timing to a White Diet or clear-fluid diet. All received a 2-L polyethylene glycol lavage solution with ascorbate, sodium sulfate, and electrolytes, the day-before for morning and as a split-dose for afternoon procedures. The primary end-point was successful bowel preparation (A or B on the Harefield Cleansing Scale). Regimen tolerance/acceptance was assessed by questionnaire. An intention-to-treat analysis with a predefined non inferiority margin of 15% was used to compare efficacy. RESULTS: A total of 226 patients (average age 52 years, 51% male) were randomized (111 clear diet, 115 White Diet). Bowel preparation was successful in 91% on the clear-fluid diet vs 84.4% on the White Diet, difference being -6.6% (lower one sided 95% CI -13.8%), with no difference according to diet. The split-dose regimen (in 55%) had a higher success rate than day-before regimen (96% vs 80%, p < 0.001). The White Diet was preferred with less hunger and interference with daily activities (p < 0.001). Procedural/withdrawal time and polyp/adenoma detection were similar between groups. CONCLUSIONS: The White Diet was preferred and better tolerated by patients without detriment to the success of bowel preparation or colonoscopy performance, especially with the split-dose regimen. PMID- 26250784 TI - Family interventions to improve diabetes outcomes for adults. AB - Diabetes self-care is a critical aspect of disease management for adults with diabetes. Since family members can play a vital role in a patient's disease management, involving them in self-care interventions may positively influence patients' diabetes outcomes. We systematically reviewed family-based interventions for adults with diabetes published from 1994 to 2014 and assessed their impact on patients' diabetes outcomes and the extent of family involvement. We found 26 studies describing family-based diabetes interventions for adults. Interventions were conducted across a range of patient populations and settings. The degree of family involvement varied across studies. We found evidence for improvement in patients' self-efficacy, perceived social support, diabetes knowledge, and diabetes self-care across the studies. Owing to the heterogeneity of the study designs, types of interventions, reporting of outcomes, and family involvement, it is difficult to determine how family participation in diabetes interventions may affect patients' clinical outcomes. Future studies should clearly describe the role of family in the intervention, assess quality and extent of family participation, and compare patient outcomes with and without family involvement. PMID- 26250787 TI - Genomic full-length sequence of two HLA-A alleles, A*02:07:01 and A*02:10, identified by cloning and sequencing. AB - We report the sequences of 5' promoter and 3' untranslated region (UTR) of A*02:07:01 and A*02:10 for the first time. PMID- 26250788 TI - TMEM119 marks a subset of microglia in the human brain. AB - Microglia are resident myeloid cells of the central nervous system (CNS), activated in the brains of various neurological diseases. Microglia are ontogenetically and functionally distinct from monocyte-derived macrophages that infiltrate the CNS under pathological conditions. However, a lack of specific markers that distinguish resident microglia from circulating blood-derived macrophages in human brain tissues hampers accurate evaluation of microglial contributions to the human brain pathology. By comparative analysis of five comprehensive microglial transcriptome datasets, we identified an evolutionarily conserved protein TMEM119 as the most promising candidate for human microglial markers. TMEM119 was expressed on immortalized human microglia, in which the expression levels were not elevated by exposure to lipopolysaccharide, IFNgamma, IL-4, IL-13 or TGFbeta1. Notably, TMEM119 immunoreactivity was expressed exclusively on a subset of Iba1(+) CD68(+) microglia with ramified and amoeboid morphologies in the brains of neurodegenerative diseases, such as Alzheimer's disease (AD), whereas Iba1(+) CD68(+) infiltrating macrophages do not express TMEM119 in demyelinating lesions of multiple sclerosis and necrotic lesions of cerebral infarction. TMEM119 mRNA levels were elevated in AD brains, although the protein levels were not significantly different between AD and non-AD cases by western blot and morphometric analyses. TMEM119-positive microglia did not consistently express polarized markers for M1 (CD80) or M2 (CD163, CD209) in AD brains. These results suggest that TMEM119 serves as a reliable microglial marker that discriminates resident microglia from blood-derived macrophages in the human brain. PMID- 26250789 TI - [3 + 2] Cycloaddition/Oxidative Aromatization Sequence via Photoredox Catalysis: One-Pot Synthesis of Oxazoles from 2H-Azirines and Aldehydes. AB - A novel [3 + 2] cycloaddition/oxidative aromatization sequence via visible light induced photoredox catalysis is disclosed. It provides a general synthetic route to 2,4,5-trisubstituted oxazoles from easily accessible 2H-azirines and aldehydes under mild reaction conditions. The potential of this strategy was further demonstrated by the rapid synthesis of a cyclooxygenase-2 inhibitor as well as the success of employing electron-deficient alkenes and imines as the reaction partners. PMID- 26250790 TI - Experience with anidulafungin in patients with allogeneic hematopoietic stem cell transplantation and graft-versus-host disease. AB - BACKGROUND: It is well known that both acute and chronic graft-versus-host disease (GVHD) are associated with invasive fungal disease (IFD). Because the galactomannan antigen diagnostic test has low specificity and sensitivity outside of the neutropenic period, many institutions use posaconazole or voriconazole for IFD prophylaxis during GVHD treatment. Moreover, several factors, mainly hepatic impairment, can limit the use of extended spectrum azoles, both in prophylaxis or treatment. METHODS: We retrospectively analyzed 25 patients with allogeneic hematopoietic stem cell transplantation (HSCT) and GVHD - grade III-IV acute GHVD (n = 15), progressive chronic GVHD (n = 7), and "overlap" GVHD (n = 3) - who received intravenous anidulafungin (200 mg on day 1, followed by 100 mg once daily). If necessary, anidulafungin treatment was followed by oral administration of 200 mg voriconazole twice a day or 200 mg posaconazole 3 times daily until patients were considered not at risk for IFD. RESULTS: Twenty-one patients (85%) received anidulafungin as prophylaxis and 5 patients (15%) received it as treatment. Median duration of intravenous anidulafungin administration was 8 days (range 6-17). Seven patients (28%) presented mild adverse effects, with no significant interactions with calcineurin inhibitors. Sequentially, 4 patients received voriconazole and 6 posaconazole. Two patients (8%) developed IFD after anidulafungin withdrawal: 1 with Candida albicans and the other with Mucor, 8 and 5 days after withdrawal, respectively. CONCLUSIONS: Our results are of interest owing to the absence of data in the literature on anidulafungin use in HSCT patients with GVHD, and suggest that anidulafungin, because of its spectrum, pharmacological profile, low toxicity, and absence of interactions with immunosuppressants, could be a drug of choice in this setting. PMID- 26250791 TI - Prevalence of Children's Mental Health Problems and the Effectiveness of Population-Level Family Interventions. AB - The prevalence of mental health problems among children and adolescents is of growing importance. Intervening in children's mental health early in life has been shown to be more effective than trying to resolve these problems when children are older. With respect to prevention activities in community settings, the prevalence of problems should be estimated, and the required level of services should be delivered. The prevalence of children's mental health disorders has been reported for many countries. Preventive intervention has emphasized optimizing the environment. Because parents are the primary influence on their children's development, considerable attention has been placed on the development of parent training to strengthen parenting skills. However, a public health approach is necessary to confirm that the benefits of parent-training interventions lead to an impact at the societal level. This literature review clarifies that the prevalence of mental health problems is measured at the national level in many countries and that population-level parenting interventions can lower the prevalence of mental health problems among children in the community. PMID- 26250792 TI - Association of Body Mass Index and Mortality in Japanese Diabetic Men and Women Based on Self-Reports: The Japan Collaborative Cohort (JACC) Study. AB - BACKGROUND: The association between body mass index (BMI) and mortality among Asian diabetic people, especially with respect to the obesity paradox (ie, higher BMI is associated with lower mortality risk), remains unresolved. METHODS: We followed a cohort of 3851 self-reported Japanese diabetics (2115 men and 1736 women) in the Japan Collaborative Cohort Study from 1988-1990 through 2009. Individuals were aged 40 to 79 years and free from a history of cardiovascular disease, cancer, renal disease, or tuberculosis. BMI was grouped into the following four categories: <20.0, 20.0-22.9, 23.0-24.9, and >=25.0 kg/m2. RESULTS: During 54 707 person-years of follow-up, 1457 deaths from all causes, 445 from cardiovascular disease, 421 from cancer, 43 from renal disease, and 148 from infectious disease were documented. Mortality from all causes, cardiovascular disease, cancer, and renal disease showed L-shaped associations with BMI. Compared to diabetics with BMI of 20.0-22.9 kg/m2, those with BMIs of 23.0-24.9 kg/m2 and >=25.0 kg/m2 had lower risks of mortality from infectious disease (i.e., obesity paradox). The multivariable HRs for mortality from infectious disease were 0.50 (95% confidence interval, 0.31-0.81) and 0.51 (95% confidence interval, 0.32-0.82) among participants with BMIs of 23.0-24.9 kg/m2 and >=25.0 kg/m2, respectively. Similar results were observed after stratification by smoking status and age and exclusion of early deaths. CONCLUSIONS: We observed L-shaped associations between BMI and mortality from all causes, cardiovascular disease, cancer, and renal disease, while the association between BMI and mortality from infectious disease manifested the obesity paradox. PMID- 26250793 TI - Re: Effect of Individual Omega-3 Fatty Acids on the Risk of Prostate Cancer: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies. PMID- 26250794 TI - Evaluation of oral prophylaxis during and after intensity-modulated radiotherapy due to head and neck cancer--a retrospective study. AB - OBJECTIVES: The aim of this study was to retrospectively analyze the influence of a prophylaxis protocol of head and neck tumor (HNT) patients during and after intensity-modulated radiotherapy (IMRT). MATERIAL AND METHOD: In this 5-year retrospective study (2009-2013), 70 (m 55, f 15; age range 28-8 years; median 58.7 years) out of 248 HNT patients of the Clinic of Cranio-Maxillofacial and Oral Surgery at the University of Zurich, Switzerland, fulfilled the inclusion criteria. Parameters of investigation were the salivary flow rates, possible dental foci and the dental status, oral side effects of radiotherapy, the prophylaxis protocol, and patient's compliance to this protocol. The following time points before during and after IMRT (6 weeks) were analyzed: prior to IMRT, 2-4 weeks, 6 weeks and 3, 6, and 12 months after the onset of radiotherapy. RESULT: Unstimulated salivary flow rate, pH value of unstimulated salivary, and stimulated salivary flow rate showed a significant reduction over time (p < 0.001). One year after IMRT, both unstimulated and stimulated salivary flow showed a statistically significant lower salivary flow. The number of caries affected sites per patient was significantly higher for patients with low compliance to the prophylaxis protocol (mean: low compliance 1.36, high compliance 0.26). Almost 75% of the evaluated patients suffered immediate gustatory change, and 47.1% showed signs of radiostomatitis through IMRT. CONCLUSIONS: High compliance to the prophylaxis protocol during and after radiotherapy is a key factor for the reduction of radiation side effects on dental hard tissue. CLINICAL RELEVANCE: High compliance to a monitored prophylaxis program is crucial for patients after head and neck surgery. PMID- 26250795 TI - Long-term results after treatment of extensive odontogenic cysts of the jaws: a review. AB - AIM: The aim was to perform a literature review concerning long-term results after treatment of extensive cysts of the jaws. METHODS: The following databases were searched: MEDLINE, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, The Cochrane Library, and EMBASE. Case reports and abstracts were excluded. RESULTS: Three hundred fifty-six articles were found, of which 30 were included. Only the minority of the studies reported long-term results. Most authors did not distinguish between temporary complications and permanent deficiencies (incomplete bone healing, permanent sensory deficits). CONCLUSION: Based on this review, it is recommended to consider primary decompression or marsupialization +/- later definitive surgery for the treatment of extensive jaw cysts in order to achieve satisfying clinical results. CLINICAL RELEVANCE: Complications (occurring within the first 6 months postoperatively, e.g., infection) and remaining deficits (after a minimum of 6 months and not changing over time, e.g., bony or sensory deficit) should be clearly separated from each other. Knowledge of permanent deficits and bone healing after different therapeutic approaches is important for decision making. Patients should be informed not only about complications but also about the risk of permanent deficits for each method. PMID- 26250796 TI - Regenerative endodontic procedure of an infected immature permanent human tooth: an immunohistological study. AB - OBJECTIVES: An immunohistological study of an infected immature permanent human tooth after a regenerative endodontic procedure (REP) was conducted in order to determine the histologic outcome of this procedure. Besides observed signs of angiogenesis and neurogenesis, repair and/or regeneration of the pulp-dentin complex was also investigated. MATERIALS AND METHODS: A REP was performed on tooth 45 of a 10-year-old girl. Eleven months post-treatment, the tooth had to be removed for orthodontic reasons. The following investigations were performed: immunohistology and radiographic quantification of root development. After hematoxylin-eosin (HE) staining, the following immunomarkers were selected: neurofilament (NF), pan cytokeratin (PK), osteocalcin (OC), and CD34. RESULTS: The REP resulted in clinical and radiographic healing of the periradicular lesion and quantifiable root development. The HE staining matches with the medical imaging post-REP: underneath the mineral trioxide aggregate a calcified bridge with cell inclusions, connective pulp-like tissue (PLT) with blood vessels, osteodentin against the root canal walls, on the root surface cementum (Ce), and periodontal ligament (PDL). The PDL was PK(+). The blood vessels in the PLT and PDL were CD34(+). The Ce, osteodentin, and stromal cells in the PLT were OC(+). The neurovascular bundles in the PLT were NF(+). CONCLUSIONS: Immunohistologically, REP of this infected immature permanent tooth resulted in an intracanalar connective tissue with a regulated physiology, but not pulp tissue. CLINICAL RELEVANCE: REP of an immature permanent infected tooth may heal the periapical infection and may result in a combination of regeneration and repair of the pulp-dentin complex. PMID- 26250797 TI - Amyloid-associated depression and ApoE4 allele: longitudinal follow-up for the development of Alzheimer's disease. AB - BACKGROUND: Amyloid-associated depression is associated with cognitive impairment cross sectionally. This follow-up study was to determine the relationship between amyloid-associated depression and the development of Alzheimer's disease (AD). METHODS: Two hundred and twenty three subjects who did not have dementia at baseline were given a repeat cognitive evaluation for incident AD. Depression was defined by having a Center for Epidemiological Studies Depression (CES-D) score >= 16, and non-amyloid vs. amyloid-associated depression by having a low vs. high plasma amyloid-beta peptide 40 (Abeta40)/Abeta42 ratio. Apolipoprotein E (ApoE) genotype was determined, and antidepressant usage was documented. RESULTS: Fifteen subjects developed AD (7%) after an average follow-up time of 6.2 years. While none of those with non-amyloid depression developed AD, 9% of those with amyloid-associated depression developed AD. Further, among those with amyloid associated depression, ApoE4 carriers tended to have a higher risk of AD than ApoE4 non-carriers (40% vs. 4%, p = 0.06). In contrast, 8% of those who did not have depression at baseline developed AD, but ApoE4 carriers and non-carriers did not show a difference in the AD risk. After adjusting for age, the interaction between ApoE4 and amyloid-associated depression (beta = +0.113, SE = 0.047, P = 0.02) and the interaction between ApoE4 and antidepressant use (beta = +0.174, SE = 0.064, P = 0.007) were associated with the AD risk. CONCLUSIONS: Amyloid associated depression may be prodromal depression of AD especially in the presence of ApoE4. Future studies with a larger cohort and a longer follow-up are warranted to further confirm this conclusion. PMID- 26250798 TI - Distribution of Neurotensin and Somatostatin-28 (1-12) in the Minipig Brainstem. AB - Using an indirect immunoperoxidase technique, an in depth study has been carried out for the first time on the distribution of fibres and cell bodies containing neurotensin and somatostatin-28 (1-12) (SOM) in the minipig brainstem. The animals used were not treated with colchicine. The distribution of neurotensin- and SOM-immunoreactive fibres was seen to be quite similar and was moderate in the minipig brainstem: a close anatomical relationship between both neuropeptides was observed. The distribution of cell bodies containing neurotensin or SOM was quite different and restricted. Cell bodies containing neurotensin were found in four brainstem nuclei: nucleus centralis raphae, nucleus dorsalis raphae, in the pars centralis of the nucleus tractus spinalis nervi trigemini and in the nucleus ventralis raphae. Cell bodies containing SOM were found in six nuclei/regions of the brainstem: nucleus ambiguus, nucleus dorsalis motorius nervi vagus, formatio reticularis, nucleus parabrachialis medialis, nucleus reticularis lateralis and nucleus ventralis raphae. According to the observed anatomical distribution of the immunoreactive structures containing neurotensin or SOM, the peptides could be involved in sleep-waking, nociceptive, gustatory, motor, respiratory and autonomic mechanisms. PMID- 26250799 TI - Investigations on the effects of Cu(2+) on the structure and function of human serum albumin. AB - Human serum albumin (HSA) is the most prominent protein in blood plasma with important physiological functions. Although copper is an essential metal for all organisms, the massive utilization of copper has led to concerns regarding its potential health impact. To better understand the potential toxicity and toxic mechanisms of Cu(2+), it is of vital importance to characterize the interaction of Cu(2+) with HSA. The effect of Cu(2+) on the structure and function of HSA in vitro were investigated by biophysical methods including fluorescence techniques, circular dichroism (CD), time-resolved measurements, isothermal titration calorimetry (ITC), molecular simulations and esterase activity assay. Multi spectroscopic measurements proved that Cu(2+) quenched the intrinsic fluorescence of HSA in a dynamic process accompanied by the formation of complex and alteration of secondary structure. But the Cu(2+) had minimal effect on the backbone and secondary structure of HSA at relatively low concentrations. The ITC results indicated Cu(2+) interacted with HSA spontaneously through hydrophobic forces with approximately 1 thermodynamic identical binding sites at 298 K. The esterase activity of HSA was inhibited obviously at the concentration of 8 * 10( 5) M. However, molecular simulation showed that Cu(2+) mainly interacted with the amino acid residues Asp (451) by the electrostatic force. Thus, we speculated the interaction between Cu(2+) and HSA might induce microenvironment of the active site (Arg 410). This study has provided a novel idea to explore the biological toxicity of Cu(2+) at the molecular level. PMID- 26250801 TI - Angiogenesis Revisited: An Overlooked Role of Endothelial Cell Metabolism in Vessel Sprouting. AB - During vessel sprouting, endothelial "tip" cells migrate at the forefront, while the endothelial "stalk" cells elongate the sprout; endothelial "phalanx" cells line quiescent vessels. Tip and stalk cells can dynamically switch phenotypes under the control of VEGF and Notch signaling. Novel findings now show that in addition to signaling cascades, metabolism coregulates the formation of the new vasculature. Recent studies demonstrated that ECs rely primarily on glycolysis for ATP production, that glycolysis is further enhanced in angiogenic ECs, and that the key glycolytic regulator PFKFB3 codetermines angiogenesis by controlling the balance of tip versus stalk cells and promoting a migratory tip cell phenotype. On the other hand, FAO regulates endothelial stalk cell proliferation by providing carbon sources for biosynthetic processes, more particularly for de novo nucleotide synthesis for DNA replication. Here, we overview the current understanding of the various metabolic pathways in ECs and their impact on vessel formation in health and disease. PMID- 26250800 TI - Assess the expression of ubiquitin specific protease USP2a for bladder cancer diagnosis. AB - BACKGROUND: Given that a deubiquitinating enzyme, ubiquitin-specific protease 2a (USP2a), regulates ubiquitination, trafficking, and degradation of EGFR, which plays a critical role in bladder cancer, in this study, we aimed to quantify the USP2a gene expression, and to determine the possibility that USP2a can be used for bladder cancer diagnosis. METHODS: Using two independent cohorts (cohort 1, n = 339 in total; cohort 2, n = 140 in total) consisting of human bladder tissues from BC patients and normal controls, we analyzed the gene expression levels of USP2a. A quantitative real-time PCR amplification was performed using a Rotor Gene 6000 instrument to quantify the expression of USP2a mRNA. RESULTS: A comparison of 305 bladder cancers and 34 age-matched controls showed an 81.4% reduction in USP2a expression in bladder cancers as compared to normal bladder tissues (p < 0.001). In the independent cohort consisting of 140 BC tissues and matched adjacent normal bladder tissues, the levels of USP2a in the specimens of BC patients were reduced by 86.9% as compared to matched surrounding normal specimens from the same patients (p < 0.001). Furthermore, there was 36.3% reduction of USP2a gene expression in muscle invasive bladder cancer (MIBC, n = 121), compared to non muscle invasive bladder cancer (NMIBC, n = 184) (p = 0.004). Lastly, USP2a mRNA expression was significantly reduced in higher stages of MIBC patients (p = 0.024), but not in NMIBC patients. CONCLUSIONS: Our findings suggest that USP2a mRNA may be considered as a diagnostic marker candidate for bladder cancer, in particular, to stratify MIBC patients with a more invasive phenotype. PMID- 26250802 TI - How far is arterial spin labeling MRI from a clinical reality? Insights from arterial spin labeling comparative studies in Alzheimer's disease and other neurological disorders. PMID- 26250803 TI - Assessment of hypoxic subvolumes in laryngeal cancer with (18)F fluoroazomycinarabinoside ((18)F-FAZA)-PET/CT scanning and immunohistochemistry. AB - BACKGROUND AND PURPOSE: (18)F-fluoroazomycinarabinoside ((18)F-FAZA) is a promising hypoxia radiopharmaceutical agent with outstanding biokinetic parameters. We aimed to determine the accuracy of (18)F-FAZA-PET/CT scan in detecting hypoxic regions within the tumor using immunohistochemical markers in a pilot study. PATIENTS AND METHODS: Eleven patients with primary or recurrent laryngeal squamous cell carcinoma were indicated for total laryngectomy (TLE). Patients underwent (18)F-FAZA-PET/CT scan before TLE. Hypoxic regions inside the laryngeal tumor were determined. After TLE, regions with high uptake on (18)F FAZA-PET scan were selected for immunohistochemical examination for exogenous (pimonidazole) and endogenous (HIF1alpha, CA-IX and GLUT-1) hypoxia markers. To assess the accuracy of (18)F-FAZA-PET scanning, radiopharmacon accumulation was related with immunohistochemical expression of hypoxia markers. RESULTS: Inter- and intratumoral heterogeneity of tumor hypoxia was observed on (18)F-FAZA-PET scan. Nine of the eleven tumors were hypoxic with (18)F-FAZA-PET. Hypoxia could also be detected with pimonidazole, HIF1alpha, CA-IX and GLUT-1 expression in some tumors. No clear association was observed between (18)F-FAZA uptake and hypoxia markers. CONCLUSIONS: This pilot study could not prove the accuracy of (18)F-FAZA-PET in determining hypoxic subvolumes in laryngeal cancer. Further study is required to investigate the benefit of (18)F-FAZA-PET imaging in radiotherapy planning. PMID- 26250804 TI - No imagination effect on boundary extension. AB - Boundary extension (BE) occurs when people falsely remember perceiving beyond the edges of a presented scene. Theorists argue that BE occurs because people mistakenly attribute information they have generated to the study stimulus-that is, they make a source memory error. Inspired by this idea, in six experiments we tested whether scene details resulting from explicit imagination would be misremembered as actual visual perceptions, resulting in increased BE as compared with standard instructions. In four experiments, undergraduates completed a BE task with separate study and test blocks; in two further experiments, undergraduates completed a trial-by-trial BE task (N = 290). Half of the participants elaborated on the study pictures (imagined smells and sounds, or what was to the left and right of the scene, or what a photographer would see by zooming in or out). Robust BE was found in all experiments, but none of the elaborations modified the size of BE; therefore, BE is not to be affected by explicit elaboration and may be related to spatial rather than visual imagery ability. PMID- 26250805 TI - Categorical and associative relations increase false memory relative to purely associative relations. AB - The goal of the present study was to examine the contributions of associative strength and similarity in terms of shared features to the production of false memories in the Deese/Roediger-McDermott list-learning paradigm. Whereas the activation/monitoring account suggests that false memories are driven by automatic associative activation from list items to nonpresented lures, combined with errors in source monitoring, other accounts (e.g., fuzzy trace theory, global-matching models) emphasize the importance of semantic-level similarity, and thus predict that shared features between list and lure items will increase false memory. Participants studied lists of nine items related to a nonpresented lure. Half of the lists consisted of items that were associated but did not share features with the lure, and the other half included items that were equally associated but also shared features with the lure (in many cases, these were taxonomically related items). The two types of lists were carefully matched in terms of a variety of lexical and semantic factors, and the same lures were used across list types. In two experiments, false recognition of the critical lures was greater following the study of lists that shared features with the critical lure, suggesting that similarity at a categorical or taxonomic level contributes to false memory above and beyond associative strength. We refer to this phenomenon as a "feature boost" that reflects additive effects of shared meaning and association strength and is generally consistent with accounts of false memory that have emphasized thematic or feature-level similarity among studied and nonstudied representations. PMID- 26250806 TI - Strategy in Regulatory Decision-Making for Management of Progressive Multifocal Leukoencephalopathy. AB - Progressive multifocal leukoencephalopathy (PML) has been observed after the use of several medicines, including monoclonal antibodies. As these drugs play important roles in the therapeutic armamentarium, it is important to address the challenges that this severe adverse reaction poses to the safe use of medicines. Considering the need for consistent outcomes of regulatory decisions, the European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) used PML as an example to develop a systematic approach to labeling and risk minimization. PMID- 26250807 TI - Mesenchymal stromal cells inhibit murine syngeneic anti-tumor immune responses by attenuating inflammation and reorganizing the tumor microenvironment. AB - The potential of mesenchymal stromal cells (MSCs) to inhibit anti-tumor immunity is becoming increasingly well recognized, but the precise steps affected by these cells during the development of an anti-tumor immune response remain incompletely understood. Here, we examined how MSCs affect the steps required to mount an effective anti-tumor immune response following administration of adenovirus Fas ligand (Ad-FasL) in the Lewis lung carcinoma (LL3) model. Administration of bone marrow-derived MSCs with LL3 cells accelerated tumor growth significantly. MSCs inhibited the inflammation induced by Ad-FasL in the primary tumors, precluding their rejection; MSCs also reduced the consequent expansion of tumor-specific T cells in the treated hosts. When immune T cells were transferred to adoptive recipients, MSCs impaired, but did not completely abrogate the ability of these T cells to promote elimination of secondary tumors. This impairment was associated with a modest reduction in tumor-infiltrating T cells, with a significant reduction in tumor-infiltrating macrophages, and with a reorganization of the stromal environment. Our data indicate that MSCs in the tumor environment reduce the efficacy of immunotherapy by creating a functional and anatomic barrier that impairs inflammation, T cell priming and expansion, and T cell function-including recruitment of effector cells. PMID- 26250808 TI - Effect of vinegar residue compost amendments on cucumber growth and Fusarium wilt. AB - Fusarium wilt of cucumber caused by Fusarium oxysporum f. sp. cucumerinum J. H. Owen is one of the major destructive soilborne diseases and results in considerable yield losses. Methyl bromide was once the most effective disease control method but has been confirmed as harmful to the environment. Using suppressive media as biological controls to assist crop growth is becoming popular. In this study, Fusarium wilt of cucumber was successfully controlled by a newly identified suppressive media: vinegar residue compost-amended media (vinegar residue compost mixed with peat and vermiculite in a 6:3:1 ratio (v/v) vinegar residue substrate (VRS). Greenhouse experiments were carried out to evaluate the effect of VRS on the growth of cucumber seedlings and disease suppression. The control was peat/vermiculite (2:1, v/v). To identify the mixed media most suitable for the growth of plants and their suppressiveness indicators, we evaluated the biological characteristics of cucumber, the physicochemical and biochemical properties of the growth media, and the enzyme activities. Total organic C (C(org)), microbial biomass C (C(mic)), basal respiration (R(mic)), and enzyme (catalase, invertase, urease, proteinase, phosphatase, beta-glucosidase, and hydrolysis of fluorescein diacetate) activities increased significantly after vinegar waste compost amendment. The compost media also showed a significantly positive effect on the growth of cucumber seedlings and the suppression of the disease severity index (DSI, 38% reduction). The cucumber rhizosphere population of F. oxysporum f. sp. cucumerinum (FOC) was significantly lower in VRS than in the control. These results demonstrate convincingly that vinegar residue compost-amended media has a beneficial effect on cucumber growth and could be applied as a method for biological control of cucumber Fusarium wilt. PMID- 26250809 TI - The potential of autochthonous microbial culture encapsulation in a confined environment for phenol biodegradation. AB - Olive mill wastewater (OMWW) is claimed to be one of the most polluting effluents produced by agro-food industries, providing high contaminants load that encase cytotoxic agents such as phenolic and polyphenolic compounds. Therefore, a significant and continuous stress episode is induced once the mixed liquor of the wastewater treatment plants (WWTP's) is being exposed to OMWW. The use of bio augmentation treatment procedures can be useful to eliminate or reduce such stress episodes. In this study, we have estimated the use of autochthonous biomass implementation within small bioreactor platform (SBP) particles as a bio augmentation method to challenge against WWTPs stress episodes. Our results showed that SBP particles significantly reduced the presence of various phenolics: tannic, gallic and caffeic acid in a synthetic medium and in crude OMWW matrix. Moreover, the SBP particles succeeded to biodegrade a very high concentration of phenol blend (3000 mg L(-1)). Our findings indicated that the presence of the SBP microfiltration membrane has reduced the phenol biodegradation rate by 50 % compared to the same suspended culture. Despite the observed reduction in biodegradation rate, encapsulation in a confined environment can offer significant values such as overcoming the grazing forcers and dilution, thus achieving a long-term sufficient biomass. The potential for reducing stress episodes caused by cytotoxic agents through bio-augmentation treatment procedure using the SBP technology is discussed. PMID- 26250811 TI - Characterisation of CIME, an experimental chamber for simulating interactions between materials of the cultural heritage and the environment. AB - An approach consisting in combining in situ and laboratory experiments is often favoured for investigating the mechanisms involved in the weathering of the materials of the cultural heritage. However, the realistic simulation in the laboratory of the environmental conditions ruling the interactions of atmospheric compounds with materials is a very complex task. The aim of this work is to characterise CIME, a new chamber specially built to simulate the interactions between materials of the cultural heritage and the environment. The originality of this instrument is that beside the usual climatic parameters (temperature, relative humidity, solar radiation) and gaseous pollutants, it also allows the controlled injection of different types of particulate matter such as terrigenous, marine and anthropogenic. Therefore, varied realistic atmospheric environments (marine or urban) can be easily simulated within CIME. In addition to the technical description of CIME, this paper shows the first results obtained by the impact of gaseous pollutants on non-durable glass, bronze and limestone. The first experiments for the deposition of different particles (calcite, clays, soot and halite) are also presented. PMID- 26250810 TI - The spatial distribution of human exposure to PCBs around a former production site in Slovakia. AB - We evaluated concentrations of 15 PCB congeners in blood serum of 2047 adults, 431 8-9-year old children and 1134 mother-child pairs born in 2001-2003. These subjects were long-standing residents living up to 70 km (to the north) and up to 50 km (to the south) of the former Chemko Strazske PCB production facility in the Michalovce district of Slovakia. We plotted serum concentration against distance from the plant both with and without consideration of the direction of their homes from the site. The decrease in exposure with distance could be described by an exponential function which was dependent on direction and climatic parameters. By kriging we created maps depicting predicted isoconcentration contours for sex- and age-adjusted serum concentration of ?PCBs for the same group of children, adults and mothers. The principle of our risk analysis was to relate serum concentration data, reflecting PCB body burden, using the critical concentrations established by the French Agency for Food, Environmental and Occupational Health & Safety (ANSES 2010) as thresholds below which the probability of effects on health is regarded as negligible. We conclude that 10 years ago, around 200,000 residents were at risk in this densely populated area. Exposure has since decreased but the mechanism for this has not yet been studied. PMID- 26250812 TI - Design of an optimized biomixture for the degradation of carbofuran based on pesticide removal and toxicity reduction of the matrix. AB - Pesticide biopurification systems contain a biologically active matrix (biomixture) responsible for the accelerated elimination of pesticides in wastewaters derived from pest control in crop fields. Biomixtures have been typically prepared using the volumetric composition 50:25:25 (lignocellulosic substrate/humic component/soil); nonetheless, formal composition optimization has not been performed so far. Carbofuran is an insecticide/nematicide of high toxicity widely employed in developing countries. Therefore, the composition of a highly efficient biomixture (composed of coconut fiber, compost, and soil, FCS) for the removal of carbofuran was optimized by means of a central composite design and response surface methodology. The volumetric content of soil and the ratio coconut fiber/compost were used as the design variables. The performance of the biomixture was assayed by considering the elimination of carbofuran, the mineralization of (14)C-carbofuran, and the residual toxicity of the matrix, as response variables. Based on the models, the optimal volumetric composition of the FCS biomixture consists of 45:13:42 (coconut fiber/compost/soil), which resulted in minimal residual toxicity and ~99% carbofuran elimination after 3 days. This optimized biomixture considerably differs from the standard 50:25:25 composition, which remarks the importance of assessing the performance of newly developed biomixtures during the design of biopurification systems. PMID- 26250813 TI - Effect of combined microbes on plant tolerance to Zn-Pb contaminations. AB - The presence and composition of soil microbial communities has been shown to have a large impact on plant-plant interactions and consequently plant diversity and composition. The goal of the present study was to evaluate impact of arbuscular mycorrhizal fungi (AMF) and nitrogen-fixing bacteria, which constitutes an essential link between the soil and the plant's roots. A greenhouse pot experiment was conducted to evaluate the feasibility of using selected microbes to improve Hieracium pilosella and Medicago sativa growth on Zn-Pb-rich site. Results of studies revealed that biomass, the dry mass of shoots and roots, increased significantly when plants were inoculated with mycorrhizal fungi and nitrogen-fixing bacteria. The addition of Azospirillum sp. and Nostoc edaphicum without mycorrhiza suppressed plant growth. Single bacterial inoculation alone does not have a positive effect on M. sativa growth, while co-inoculation with AMF improved plant growth. Plant vitality (expressed by the performance index) was improved by the addition of microbes. However, our results indicated that even dry heat sterilization of the substratum created imbalanced relationships between soil-plant and plants and associated microorganisms. The studies indicated that AMF and N2-fixers can improve revegetation of heavy metal-rich industrial sites, if the selection of interacting symbionts is properly conducted. PMID- 26250814 TI - Phytotoxicity and genotoxicity assessment of imazethapyr herbicide using a battery of bioassays. AB - The imazethapyr herbicide (formulation Verosil((r))) was evaluated for phytotoxicity and genotoxicity using a battery of bioassays: (1) the growth inhibition of the green alga Pseudokirchneriella subcapitata, (2) the root growth and germination of the higher plant Lactuca sativa, (3) the genetic damage using the Salmonella/microsome test, and (4) the aneugenic and clastogenic effects on Allium cepa. The Verosil((r)) formulation was highly toxic to the non-target green alga (median effective concentration (EC50) = 1.05 +/- 0.05 mg active ingredient (a.i.) L(-1)), and concentrations above 10 mg a.i. L(-1) inhibited root elongation in lettuce: relative growth index (RGI) between 0.28 +/- 0.01 and 0.66 +/- 0.10. No genotoxic effect was observed in S almonella typhimurium at 100 mg a.i. L(-1), either with or without the microsomal fraction. However, significant differences in the frequency of chromosomal aberrations in anaphases and telophases (bridges, chromosome fragments, and vagrants) were observed in A. cepa at concentrations between 0.01 and 1 mg a.i. L(-1) with respect to the control. The frequencies of micronuclei showed significant differences with respect to the control at concentrations between 0.001 and 0.1 mg a.i. L(-1). A very high mitotic index (MI = 93.8 +/- 5.8) was observed associated with a high number of cells in the prophase stage at 100 mg a.i. L(-1), indicating cytotoxicity. These results showed that imazethapyr is toxic to the non-target populations in both aquatic and terrestrial ecosystems. This herbicide might also exert clastogenic and aneugenic mitotic damage in higher plants. Therefore, the imazethapyr formulation may constitute an environmental risk to plants. PMID- 26250815 TI - Compost addition reduces porosity and chlordecone transfer in soil microstructure. AB - Chlordecone, an organochlorine insecticide, pollutes soils and contaminates crops and water resources and is biomagnified by food chains. As chlordecone is partly trapped in the soil, one possible alternative to decontamination may be to increase its containment in the soil, thereby reducing its diffusion into the environment. Containing the pesticide in the soil could be achieved by adding compost because the pollutant has an affinity for organic matter. We hypothesized that adding compost would also change soil porosity, as well as transport and containment of the pesticide. We measured the pore features and studied the nanoscale structure to assess the effect of adding compost on soil microstructure. We simulated changes in the transport properties (hydraulic conductivity and diffusion) associated with changes in porosity. During compost incubation, the clay microstructure collapsed due to capillary stresses. Simulated data showed that the hydraulic conductivity and diffusion coefficient were reduced by 95 and 70% in the clay microstructure, respectively. Reduced transport properties affected pesticide mobility and thus helped reduce its transfer from the soil to water and to the crop. We propose that the containment effect is due not only to the high affinity of chlordecone for soil organic matter but also to a trapping mechanism in the soil porosity. PMID- 26250816 TI - Biochar efficiency in pesticides sorption as a function of production variables- a review. AB - Biochar is a stabilized, carbon-rich by-product derived from pyrolysis of biomass. Recently, biochar has received extensive attentions because of its multi functionality for agricultural and environmental applications. Biochar can contribute to sequestration of atmosphere carbon, improvement of soils quality, and mitigation of environmental contaminations. The capability of biochar for specific application is determined by its properties which are predominantly controlled by source material and pyrolysis route variables. The biochar sorption potential is a function of its surface area, pores volume, ash contents, and functional groups. The impacts of each production factors on these characteristics of biochar need to be well-understood to design efficient biochars for pesticides removal. The effects of biomass type on biochar sorptive properties are determined by relative amounts of its lingo-cellulosic compounds, minerals content, particles size, and structure. The highest treatment temperature is the most effective pyrolysis factor in the determination of biochar sorption behavior. The expansion of micro-porosity and surface area and also increase of biochar organic carbon content and hydrophobicity mostly happen by pyrolysis peak temperature rise. These changes make biochar suitable for immobilization of organic contaminants. Heating rate, gas pressure, and reaction retention time after the pyrolysis temperatures are sequentially important pyrolysis variables effective on biochar sorptive properties. This review compiles the available knowledge about the impacts of production variables on biochars sorptive properties and discusses the aging process as the main factor in post-pyrolysis alterations of biochars sorption capacity. The drawbacks of biochar application in the environment are summarized as well in the last section. PMID- 26250817 TI - The function of advanced treatment process in a drinking water treatment plant with organic matter-polluted source water. AB - To understand the relationship between chemical and microbial treatment at each treatment step, as well as the relationship between microbial community structure in biofilms in biofilters and their ecological functions, a drinking water plant with severe organic matter-polluted source water was investigated. The bacterial community dynamics of two drinking water supply systems (traditional and advanced treatment processes) in this plant were studied from the source to the product water. Analysis by 454 pyrosequencing was conducted to characterize the bacterial diversity in each step of the treatment processes. The bacterial communities in these two treatment processes were highly diverse. Proteobacteria, which mainly consisted of beta-proteobacteria, was the dominant phylum. The two treatment processes used in the plant could effectively remove organic pollutants and microbial polution, especially the advanced treatment process. Significant differences in the detection of the major groups were observed in the product water samples in the treatment processes. The treatment processes, particularly the biological pretreatment and O3-biological activated carbon in the advanced treatment process, highly influenced the microbial community composition and the water quality. Some opportunistic pathogens were found in the water. Nitrogen relative microorganisms found in the biofilm of filters may perform an important function on the microbial community composition and water quality improvement. PMID- 26250818 TI - Metal bioaccumulation pattern by Cotylorhiza tuberculata (Cnidaria, Scyphozoa) in the Mar Menor coastal lagoon (SE Spain). AB - Coastal lagoons are ecosystems highly vulnerable to human impacts because of their situation between terrestrial and marine environment. Mar Menor coastal lagoon is one of the largest lagoons of the Mediterranean Sea, placed in SE Spain and subjected to major human impacts, in particular the mining of metal sulphides. As a consequence, metal concentration in water column and sediments of this ecosystem is usually higher than in other areas. For monitoring ecosystem health, the present study has assessed the ability of Cotylorhiza tuberculata for bioaccumulating metals from sea water. Up to 65 individuals were sampled at 8 different sampling stations during the summer of 2012. Although the concentration values for different elements considered were moderate (Pb: 0.04-29.50 ppm, Zn: 2.27-93.44 ppm, Cd: 0-0.67 ppm, As: 0.56-130.31 ppm) by dry weight of the jellyfish tissues (bell and oral arms combined), bioconcentration levels in relation to seawater metal concentration were extremely high. In any case, the use or disposal of these organisms should consider their metal content because of their potential environmental and health implications. PMID- 26250819 TI - Effects of long-term irrigation with untreated municipal wastewater on soil properties and crop quality. AB - Irrigating crops with untreated wastewater leads to elevated concentrations of heavy metals both in soil and cultivated crops. The current study was designed to determine heavy metal (i.e., Pb, Cd, Cr, Cu, Ni, Zn, Hg) accumulation in Konya soils in selected nine sites irrigated with wastewater for over 40 years. Non irrigated soil samples and soil samples irrigated with well water were taken as control samples. Transport of these pollutants to the wheat samples cultivated in the investigated site was also examined. The obtained results reveal that high alkaline properties and clay structure of Konya soil reduce the mobility of contaminants and cause accumulation in the top layer of soil. Intense effect of wastewater irrigation on soil EC was determined. The highest concentrations of Pb, Cr, Cu, Cd, Zn, Ni, and Hg in wastewater irrigated soil were 5.32, 37.1, 31.5, 11.4, 91.5, 134, and 0.34 mg kg(-1), respectively. Wastewater irrigated soils were strongly polluted by means of Cd (8.23-11.6 mg kg(-1)) and moderately to strongly polluted by means of Ni (47.7-134 mg kg(-1)), exceeding Maximum Admissible Concentrations for Trace Elements in Agricultural Soils and Sewage Sludge Regulation limit values of Turkey. Maximum concentrations found for Pb, Cr, Cu, Cd, Zn, and Ni in wastewater irrigated wheat grain were 8.44, 1.30, 9.10, n.d, 29.31, and 0.94 mg kg(-1), respectively. Besides, Hg was not detected in any samples of wheat grain. Based on the regulation of Turkish Food Codex, Pb contamination in wheat samples grown in the sampling site was evidenced. PMID- 26250820 TI - Replacement of mineral fertilizers with anaerobically digested pig slurry in paddy fields: assessment of plant growth and grain quality. AB - Rice cultivation requires large quantities of irrigation water and mineral fertilizers. This provides an opportunity for the recycling of the plant nutrients in anaerobically digested pig slurry, large amounts of which are generated in Chinese pig farms. Hence, to promote the sustainable development of livestock and poultry breeding and rice production, a micro-plot field experiment was carried out to assess whether or not slurry can replace mineral fertilizers in rice paddy production in terms of plant tillering, grain quality, and yields. The results indicate that the total N content of the slurry can serve as an alternative source of N when compared to the control (450 kg ha-1 commercial compound fertilizer (N/P2O5/K2O = 15:15:15) as basal fertilizer, 300 kg ha-1 urea (N% = 46), and 150 kg ha-1 commercial compound fertilizer as top-dressed fertilizer). No negative effects on plant growth or grain yield were observed, although there may be a potential risk due to an increase in grain Cu concentration. The amylose content and gel consistency of the rice grains were enhanced significantly by the use of slurry as a basal fertilizer, but the grain protein and total amino acid contents decreased. The results suggest that anaerobically digested pig slurry can replace mineral fertilizers in rice production when applied as a basal dressing together with urea and commercial compound fertilizer as top-dressed fertilizers. PMID- 26250822 TI - GeauxDock: A novel approach for mixed-resolution ligand docking using a descriptor-based force field. AB - Molecular docking is an important component of computer-aided drug discovery. In this communication, we describe GeauxDock, a new docking approach that builds on the ideas of ligand homology modeling. GeauxDock features a descriptor-based scoring function integrating evolutionary constraints with physics-based energy terms, a mixed-resolution molecular representation of protein-ligand complexes, and an efficient Monte Carlo sampling protocol. To drive docking simulations toward experimental conformations, the scoring function was carefully optimized to produce a correlation between the total pseudoenergy and the native-likeness of binding poses. Indeed, benchmarking calculations demonstrate that GeauxDock has a strong capacity to identify near-native conformations across docking trajectories with the area under receiver operating characteristics of 0.85. By excluding closely related templates, we show that GeauxDock maintains its accuracy at lower levels of homology through the increased contribution from physics-based energy terms compensating for weak evolutionary constraints. GeauxDock is available at http://www.institute.loni.org/lasigma/package/dock/. PMID- 26250821 TI - Incorporating bioavailability into toxicity assessment of Cu-Ni, Cu-Cd, and Ni-Cd mixtures with the extended biotic ligand model and the WHAM-F(tox) approach. AB - There are only a limited number of studies that have developed appropriate models which incorporate bioavailability to estimate mixture toxicity. Here, we explored the applicability of the extended biotic ligand model (BLM) and the WHAM-F(tox) approach for predicting and interpreting mixture toxicity, with the assumption that interactions between metal ions obey the BLM theory. Seedlings of lettuce Lactuca sativa were exposed to metal mixtures (Cu-Ni, Cu-Cd, and Ni-Cd) contained in hydroponic solutions for 4 days. Inhibition to root elongation was the endpoint used to quantify the toxic response. Assuming that metal ions compete with each other for binding at a single biotic ligand, the extended BLM succeeded in predicting toxicity of three mixtures to lettuce, with more than 82% of toxicity variation explained. There were no significant differences in the values of f(mix50) (i.e., the overall amounts of metal ions bound to the biotic ligand inducing 50% effect) for the three mixture combinations, showing the possibility of extrapolating these values to other binary metal combinations. The WHAM-F(tox) approach showed a similar level of precision in estimating mixture toxicity while requiring fewer parameters than the BLM-f(mix) model. External validation of the WHAM-F(tox) approach using literature data showed its applicability for other species and other mixtures. The WHAM-F(tox) model is suitable for delineating mixture effects where the extended BLM also applies. Therefore, in case of lower data availability, we recommend the lower parameterized WHAM-F(tox) as an effective approach to incorporate bioavailability in quantifying mixture toxicity. PMID- 26250823 TI - Evaluation of the influence of the definition of an isolated hip fracture as an exclusion criterion for trauma system benchmarking: a multicenter cohort study. AB - PURPOSE: To assess whether the definition of an IHF used as an exclusion criterion influences the results of trauma center benchmarking. METHODS: We conducted a multicenter retrospective cohort study with data from an integrated Canadian trauma system. The study population included all patients admitted between 1999 and 2010 to any of the 57 adult trauma centers. Seven definitions of IHF based on diagnostic codes, age, mechanism of injury, and secondary injuries, identified in a systematic review, were used. Trauma centers were benchmarked using risk-adjusted mortality estimates generated using the Trauma Risk Adjustment Model. The agreement between benchmarking results generated under different IHF definitions was evaluated with correlation coefficients on adjusted mortality estimates. Correlation coefficients >0.95 were considered to convey acceptable agreement. RESULTS: The study population consisted of 172,872 patients before exclusion of IHF and between 128,094 and 139,588 patients after exclusion. Correlation coefficients between risk-adjusted mortality estimates generated in populations including and excluding IHF varied between 0.86 and 0.90. Correlation coefficients of estimates generated under different definitions of IHF varied between 0.97 and 0.99, even when analyses were restricted to patients aged >=65 years. CONCLUSIONS: Although the exclusion of patients with IHF has an influence on the results of trauma center benchmarking based on mortality, the definition of IHF in terms of diagnostic codes, age, mechanism of injury and secondary injury has no significant impact on benchmarking results. Results suggest that there is no need to obtain formal consensus on the definition of IHF for benchmarking activities. PMID- 26250824 TI - Is Enterobius vermicularis infestation associated with acute appendicitis? AB - PURPOSE: Enterobius vermicularis might be seen in specimens of patients who underwent surgery due to acute appendicitis. There is still debate as to E. vermicularis infestation causes acute appendicitis. The primary aim of this study is to determine the incidence of E. vermicularis infestation, and the secondary aim is to determine the possible role of E. vermicularis in pathogenesis of appendicitis as well as the adequacy of demographic data and laboratory values in predicting infestation preoperatively. METHODS: A retrospective investigation was conducted with all patients who underwent appendectomy due to acute appendicitis in a secondary care center. Patients with E. vermicularis were compared with 24 controls that underwent appendectomy during the same time period. Demographic data, preoperative white blood cell (WBC) count, eosinophil counts, and histopathological findings for both groups were analyzed and compared. RESULTS: Enterobius vermicularis was detected in the appendectomy materials in 9 of 1446 patients (0.62 %). Histopathologically, only one of nine patients had acute appendicitis while the others were diagnosed with lymphoid hyperplasia. There were no statistically significant differences between the groups except WBC count. However, the WBC count was significantly (p < 0.05) lower in the group which was detected E. vermicularis. CONCLUSIONS: Enterobius vermicularis is rarely associated with the histopathological findings of acute appendicitis. Also eosinophil count and elevation of white blood counts are inadequate for predicting preoperative E. vermicularis. PMID- 26250825 TI - ST-segment resolution with bivalirudin versus heparin and routine glycoprotein IIb/IIIa inhibitors started in the ambulance in ST-segment elevation myocardial infarction patients transported for primary percutaneous coronary intervention: The EUROMAX ST-segment resolution substudy. AB - BACKGROUND: Myocardial reperfusion after primary percutaneous coronary intervention (PCI) can be assessed by the extent of post-procedural ST-segment resolution. The European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) trial compared pre-hospital bivalirudin and pre-hospital heparin or enoxaparin with or without GPIIb/IIIa inhibitors (GPIs) in primary PCI. This nested substudy was performed in centres routinely using pre-hospital GPI in order to compare the impact of randomized treatments on ST-resolution after primary PCI. METHODS: Residual cumulative ST-segment deviation on the single one hour post-procedure electrocardiogram (ECG) was assessed by an independent core laboratory and was the primary endpoint. It was calculated that 762 evaluable patients were needed to show non-inferiority (85% power, alpha 2.5%) between randomized treatments. RESULTS: A total of 871 participated with electrocardiographic data available in 824 patients (95%). Residual ST-segment deviation one hour after PCI was 3.8+/ 4.9 mm versus 3.9+/-5.2 mm for bivalirudin and heparin+GPI, respectively ( p=0.0019 for non-inferiority). Overall, there were no differences between randomized treatments in any measures of ST-segment resolution either before or after the index procedure. CONCLUSIONS: Pre-hospital treatment with bivalirudin is non-inferior to pre-hospital heparin + GPI with regard to residual ST-segment deviation or ST-segment resolution, reflecting comparable myocardial reperfusion with the two strategies. PMID- 26250826 TI - Total Synthesis of Antitumor Antibiotic Derhodinosylurdamycin A. AB - The first total synthesis of derhodinosylurdamycin A, an angucycline antitumor antibiotic, has been described. The synthesis features a Hauser annulation followed by pinacol coupling to construct the tetracyclic angular aglycon, a Stille coupling of glycal stannane and tetracyclic aryliodide followed by stereoselective reduction to afford the 2-deoxy beta-C-arylglycoside, and a late stage stereoselective glycosylation for the preparation of derhodinosylurdamycin A. This synthetic strategy should be amenable to the chemical synthesis of analogs of derhodinosylurdamycin A bearing diverse 2-deoxy sugar subunits for structure and activity relationship studies. PMID- 26250827 TI - Phase I/II trial of chemoradiotherapy with concurrent S-1 and cisplatin for clinical stage II/III esophageal carcinoma (JCOG 0604). AB - We carried out a phase I/II trial of chemoradiotherapy concurrent with S-1 and cisplatin to determine the maximum tolerated dose and recommended dose and to evaluate the efficacy and safety of this treatment in patients with esophageal carcinoma. Thoracic esophageal cancer patients with clinical stage II/III disease, excluding T4, were eligible. Chemotherapy consisted of S-1 at a dose of 60-80 mg/m(2) /day on days 1-14, and cisplatin at 75 mg/m(2) on day 1, repeated twice every 4 weeks. Single daily radiation of 50.4 Gy was given in 28 fractions concurrently starting on day 1. Patients achieving an objective response after chemoradiotherapy underwent two additional cycles of chemotherapy. Patient accrual was terminated early due to slow enrolment after 44 patients were accrued. In the phase I part, two of six patients experienced dose-limiting toxicities at each level of S-1 (S-1 60 or 80 mg/m(2) /day). Considering treatment compliance, the recommended dose was determined to be S-1 60 mg/m(2) /day. The complete response rate, the primary endpoint of phase II, was 59.5% (22/37; 90% confidence interval, 44.6-73.1%; weighted threshold, 57.2%; P = 0.46 by the exact binomial test) on central review. In the phase II part, 3-year progression-free survival was 48.4%, with a 3-year overall survival of 61.9%. Grade 3 or 4 toxicity in phase II included leukopenia (57.9%), neutropenia (50%), hyponatremia (28.9%), anorexia (21.1%), anemia (18.4%), thrombocytopenia (18.4%), and febrile neutropenia (2.6%). No treatment-related deaths were observed. Although this combination showed acceptable toxicity and favorable 3-year survival, the study did not meet its primary endpoint. This trial was registered at the UMIN Clinical Trials Registry as UMIN000000710. PMID- 26250828 TI - One nanoprobe, two pathogens: gold nanoprobes multiplexing for point-of-care. AB - BACKGROUND: Gold nanoparticles have been widely employed for biosensing purposes with remarkable efficacy for DNA detection. Amongst the proposed systems, colorimetric strategies based on the remarkable optical properties have provided for simple yet effective sequence discrimination with potential for molecular diagnostics at point of need. These systems may also been used for parallel detection of several targets to provide additional information on diagnostics of pathogens. RESULTS: For the first time, we demonstrate that a single Au-nanoprobe may provide for detection of two distinct targets (pathogens) allowing colorimetric multi-target detection. We demonstrate this concept by using one single gold-nanoprobe capable to detect members of the Mycobacterium tuberculosis complex and Plasmodium sp., the etiologic agents of tuberculosis and malaria, respectively. Following characterisation, the developed gold-nanoprobe allowed detection of either target in individual samples or in samples containing both DNA species with the same efficacy. CONCLUSIONS: Using one single probe via the non-cross-linking colorimetric methodology it is possible to identify multiple targets in one sample in one reaction. This proof-of-concept approach may easily be integrated into sensing platforms allowing for fast and simple multiplexing of Au-nanoprobe based detection at point-of-need. PMID- 26250829 TI - Genetic signatures of adaptation revealed from transcriptome sequencing of Arctic and red foxes. AB - BACKGROUND: The genus Vulpes (true foxes) comprises numerous species that inhabit a wide range of habitats and climatic conditions, including one species, the Arctic fox (Vulpes lagopus) which is adapted to the arctic region. A close relative to the Arctic fox, the red fox (Vulpes vulpes), occurs in subarctic to subtropical habitats. To study the genetic basis of their adaptations to different environments, transcriptome sequences from two Arctic foxes and one red fox individual were generated and analyzed for signatures of positive selection. In addition, the data allowed for a phylogenetic analysis and divergence time estimate between the two fox species. RESULTS: The de novo assembly of reads resulted in more than 160,000 contigs/transcripts per individual. Approximately 17,000 homologous genes were identified using human and the non-redundant databases. Positive selection analyses revealed several genes involved in various metabolic and molecular processes such as energy metabolism, cardiac gene regulation, apoptosis and blood coagulation to be under positive selection in foxes. Branch site tests identified four genes to be under positive selection in the Arctic fox transcriptome, two of which are fat metabolism genes. In the red fox transcriptome eight genes are under positive selection, including molecular process genes, notably genes involved in ATP metabolism. Analysis of the three transcriptomes and five Sanger re-sequenced genes in additional individuals identified a lower genetic variability within Arctic foxes compared to red foxes, which is consistent with distribution range differences and demographic responses to past climatic fluctuations. A phylogenomic analysis estimated that the Arctic and red fox lineages diverged about three million years ago. CONCLUSIONS: Transcriptome data are an economic way to generate genomic resources for evolutionary studies. Despite not representing an entire genome, this transcriptome analysis identified numerous genes that are relevant to arctic adaptation in foxes. Similar to polar bears, fat metabolism seems to play a central role in adaptation of Arctic foxes to the cold climate, as has been identified in the polar bear, another arctic specialist. PMID- 26250830 TI - Long-term quality of life in critically ill patients with acute kidney injury treated with renal replacement therapy: a matched cohort study. AB - INTRODUCTION: Acute kidney injury (AKI) is a common complication in intensive care unit (ICU) patients and is associated with increased morbidity and mortality. We compared long-term outcome and quality of life (QOL) in ICU patients with AKI treated with renal replacement therapy (RRT) with matched non AKI-RRT patients. METHODS: Over 1 year, consecutive adult ICU patients were included in a prospective cohort study. AKI-RRT patients alive at 1 year and 4 years were matched with non-AKI-RRT survivors from the same cohort in a 1:2 (1 year) and 1:1 (4 years) ratio based on gender, age, Acute Physiology and Chronic Health Evaluation II score, and admission category. QOL was assessed by the EuroQoL-5D and the Short Form-36 survey before ICU admission and at 3 months, 1 and 4 years after ICU discharge. RESULTS: Of 1953 patients, 121 (6.2%) had AKI RRT. AKI-RRT hospital survivors (44.6%; N = 54) had a 1-year and 4-year survival rate of 87.0% (N = 47) and 64.8% (N = 35), respectively. Forty-seven 1-year AKI RRT patients were matched with 94 1-year non-AKI-RRT patients. Of 35 4-year survivors, three refused further cooperation, three were lost to follow-up, and one had no control. Finally, 28 4-year AKI-RRT patients were matched with 28 non AKI-RRT patients. During ICU stay, 1-year and 4-year AKI-RRT patients had more organ dysfunction compared to their respective matches (Sequential Organ Failure Assessment scores 7 versus 5, P < 0.001, and 7 versus 4, P < 0.001). Long-term QOL was, however, comparable between both groups but lower than in the general population. QOL decreased at 3 months, improved after 1 and 4 years but remained under baseline level. One and 4 years after ICU discharge, 19.1% and 28.6% of AKI RRT survivors remained RRT-dependent, respectively, and 81.8% and 71% of them were willing to undergo ICU admission again if needed. CONCLUSION: In long-term critically ill AKI-RRT survivors, QOL was comparable to matched long-term critically ill non-AKI-RRT survivors, but lower than in the general population. The majority of AKI-RRT patients wanted to be readmitted to the ICU when needed, despite a higher severity of illness compared to matched non-AKI-RRT patients, and despite the fact that one quarter had persistent dialysis dependency. PMID- 26250831 TI - Hepatocellular Carcinoma in the Setting of Non-cirrhotic Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome: US Experience. AB - BACKGROUND: Type 2 diabetes mellitus, obesity, and the metabolic syndrome (MS) have been growing in prevalence in the USA and are independent risk factors for the development of hepatocellular carcinoma (HCC). Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the MS, with or without nonalcoholic steatohepatitis (NASH) can predispose to HCC in the absence of cirrhosis or advanced fibrosis. Nevertheless, the US literature investigating non cirrhotic HCC in the setting of NAFLD/NASH and MS is lacking. AIM: To describe a retrospective case series of patients who developed HCC without cirrhosis in the setting of NAFLD/NASH or features of the MS. METHODS: We identified NAFLD/NASH associated HCC cases arising in the absence of cirrhosis between January 2010 and September 2012 from a tumor board database at Brooke Army Medical Center (BAMC). RESULTS: Of 44 cases of HCC reviewed, six cases of non-cirrhotic HCC associated with NAFLD/NASH and/or MS were identified. Only one patient underwent partial hepatectomy with curative intent. The other five might have been candidates for potential curative partial hepatectomy or liver transplantation had they been diagnosed earlier. CONCLUSION: Our case series highlights the development of NAFLD/NASH and MS-associated HCC in the absence of cirrhosis in the US population and raises the important question of HCC screening for this at-risk group. PMID- 26250832 TI - Multiple Opportunistic Pathogens, but Not Pre-existing Inflammation, May Be Associated with Necrotizing Enterocolitis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) leads to significant morbidity and mortality in the neonatal intensive care unit. Although current evidence would suggest that bacteria contribute to the pathogenesis of NEC, no single bacterium has yet been identified. AIMS: The aims of this study were to investigate fecal S100A12 concentrations and the intestinal bacterial community in premature infants (24-32 weeks) and investigate any associations between the microbiota and the development of NEC. METHODS: Meconium and feces were collected from premature newborn infants (between 24 and 32 weeks gestation) over the first 4 weeks of life. Fecal S100A12 concentrations were assayed by immunoassay, and samples were subject to 16S rDNA analysis using next-generation sequencing techniques. RESULTS: Fecal samples were collected from four infants that developed NEC and 18 control infants. Prior to developing NEC, fecal S100A12 concentrations were not elevated; however, following NEC diagnosis, concentrations were highly elevated. The fecal bacterial communities of infants with NEC did not differ significantly from control infants. However, potentially pathogenic bacteria were detected in significantly more infants with NEC than in controls (p = 0.0007). CONCLUSION: At birth, fecal S100A12 concentrations were not elevated in premature infants subsequently developing NEC in this cohort. Following NEC diagnosis, S100A12 concentrations were highly elevated, suggesting that this potentially could act as a marker of disease progression. Higher detection rates of potentially pathogenic bacteria in NEC infants suggest that a range of potentially pathogenic bacteria may collectively contribute to NEC pathogenesis. PMID- 26250833 TI - Nutritional Status Improved in Cystic Fibrosis Patients with the G551D Mutation After Treatment with Ivacaftor. AB - BACKGROUND: The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gating mutation G551D prevents sufficient ion transport due to reduced channel open probability. Ivacaftor, an oral CFTR potentiator, increases the channel-open probability. AIM: To further analyze improvements in weight and body mass index (BMI) in two studies of ivacaftor in patients aged >=6 years with CF and the G551D mutation. METHODS: Patients were randomized 1:1 to ivacaftor 150 mg or placebo every 12 h for 48 weeks. Primary end point (lung function) was reported previously. Other outcomes included weight and height measurements and CF Questionnaire-Revised (CFQ-R). RESULTS: Studies included 213 patients (aged <= 20 years, n = 105; aged > 20 years, n = 108). In patients <=20 years, adjusted mean change from baseline to week 48 in body weight was 4.9 versus 2.2 kg (ivacaftor vs. placebo, p = 0.0008). At week 48, change from baseline in mean weight-for-age z-score was 0.29 versus -0.06 (p < 0.0001); change in mean BMI-for-age z-score was 0.26 versus -0.13 (p < 0.0001). In patients >20 years, adjusted mean change from baseline to week 48 in body weight was 2.7 versus -0.2 kg (p = 0.0003). Mean BMI change at week 48 was 0.9 versus -0.1 kg/m(2) (p = 0.0003). There was no linear correlation evident between changes in body weight and improvements in lung function or sweat chloride. Significant CFQ-R improvements were seen in perception of eating, body image, and sense of ability to gain weight. CONCLUSIONS: Nutritional status improved following treatment with ivacaftor for 48 weeks. PMID- 26250834 TI - Effects of Noninvasive Positive-Pressure Ventilation with Different Interfaces in Patients with Hypoxemia after Surgery for Stanford Type A Aortic Dissection. AB - BACKGROUND: Hypoxemia is a severe perioperative complication that can substantially increase intensive care unit and hospital stay and mortality. The aim of this study was to determine the effects of non-invasive positive-pressure ventilation (NIPPV) in patients with hypoxemia after surgery for Stanford type A aortic dissection, and to compare the effects of helmet and mask NIPPV. MATERIAL AND METHODS: We recruited 40 patients who developed hypoxemia within 24 h after extubation after surgery for Stanford type A aortic dissection in the Beijing Anzhen Hospital. The patients were randomly divided into the helmet and mask NIPPV groups. The primary endpoints were blood oxygenation levels at 1 and 6 h after initiation and at the end of the treatment. The secondary endpoint was patient outcome, including mortality; incidence of pulmonary atelectasis, pneumonia, re-intubation, and sepsis; and length of ICU and hospital stays. RESULTS: NIPPV improved oxygenation in both groups. Compared with pretreatment levels, the oxygenation index (PaO2/FiO2), PaO2, PaCO2, and respiratory rate (RR) improved in the initial (0-1 h), maintenance (1-6 h), and end stages of the treatment (P<0.05). Compared with mask ventilation, helmet ventilation better improved pH, PaO2, SpO2, PaO2/FiO2, and decreased PaCO2 in the 3 stages (P<0.05). The incidence of major complications, including flatulence, intolerance, and facial pressure sores, was significantly lower with helmet ventilation. CONCLUSIONS: NIPPV effectively improved oxygenation and reduced PaCO2 in patients who developed hypoxemia soon after extubation following surgery for Stanford type A aortic dissection. Compared with mask NIPPV, helmet NIPPV more rapidly increased PaO2 and reduced PaCO2, increased patient tolerance and comfort, and reduced complications. PMID- 26250835 TI - Autonomous home-care nursing staff are more engaged in their work and less likely to consider leaving the healthcare sector: a questionnaire survey. AB - BACKGROUND: The need for home care is rising in many Western European countries, due to the ageing population and governmental policies to substitute institutional care with home care. At the same time, a general shortage of qualified home-care staff exists or is expected in many countries. It is important to retain existing nursing staff in the healthcare sector to ensure a stable home-care workforce for the future. However, to date there has been little research about the job factors in home care that affect whether staff are considering leaving the healthcare sector. OBJECTIVE: The main purpose of the study was to examine how home-care nursing staff's self-perceived autonomy relates to whether they have considered leaving the healthcare sector and to assess the possible mediating effect of work engagement. DESIGN, SETTING AND PARTICIPANTS: The questionnaire-based, cross-sectional study involved 262 registered nurses and certified nursing assistants employed in Dutch home-care organisations (mean age of 51; 97% female). The respondents were members of the Dutch Nursing Staff Panel, a nationwide group of nursing staff members in various healthcare settings (67% response rate). METHODS: The questionnaire included validated scales concerning self-perceived autonomy and work engagement and a measure for considering pursuing an occupation outside the healthcare sector. Logistic regression and mediation analyses were conducted to test associations between self-perceived autonomy, work engagement and considering leaving the healthcare sector. RESULTS: Nursing staff members in home care who perceive more autonomy are more engaged in their work and less likely to have considered leaving the healthcare sector. The positive association between self-perceived autonomy and considering leaving, found among nursing staff members regardless of their level of education, is mediated by work engagement. CONCLUSION: In developing strategies for retaining nursing staff in home care, employers and policy makers should target their efforts at enhancing nursing staff's autonomy, thereby improving their work engagement. PMID- 26250836 TI - M. tuberculosis Secretory Protein ESAT-6 Induces Metabolic Flux Perturbations to Drive Foamy Macrophage Differentiation. AB - The Foamy Macrophage (FM) differentiation forms a major component of the host dependent survival axis of M. tuberculosis. The FM which are characterized by the intracellular accumulation of lipid bodies (LBs), ensure a privileged existence for the bacilli through ready provision of nutrients and by conferring protection against bactericidal pathways. The mycobacterial secretory protein ESAT-6 has been identified as the molecular mediator of the FM differentiation process although little is known about the mechanism through which it induces this process. In the present study, we show that ESAT-6 induces GLUT-1 mediated enhanced glucose uptake by macrophages which is coupled to metabolic flux perturbations in the glycolytic pathway caused by differential rates of reaction at several steps in the pathway. Two major changes identified were the simultaneous buildup of DHAP (for Triglyceride synthesis) and AcCoA (for synthesis of 3-HB, ligand for the anti-lipolytic GPR109A). We also show that part of the observed effects involve protein- protein interactions between ESAT-6 and the macrophage glycolytic enzymes, Enolase1 and Phosphoglycerate kinase1. PMID- 26250837 TI - Teaching children with autism to respond to conversation partners' interest. AB - Successful conversation requires that the speaker's behavior is sensitive to nonvocal listener responses. We observed children with autism spectrum disorder during conversation probes in which a listener periodically displayed nonvocal cues that she was uninterested in the conversation. We used behavioral skills training to teach conversation skills. First, we taught participants to tact nonvocal listener behavior (interested or uninterested), but this was insufficient to improve responding aimed at regaining listener interest. Participants were then taught to ask a question (Experiments 1 and 2) or change the topic (Experiment 2) when the listener was uninterested. Responding persisted over time and with changes in the stimulus conditions. The behavior change was also deemed socially valid by blind observers. In Experiment 3, participants learned to shift to the other trained response when exposed to extinction. This study illustrates a set of procedures for bringing speaker behavior under control of nonvocal listener cues. PMID- 26250838 TI - The 5Cs of Consultation: Training Medical Students to Communicate Effectively in the Emergency Department. AB - BACKGROUND: Effective communication is critical for health care professionals, particularly in the Emergency Department (ED). However, currently, there is no standardized consultation model that is consistently practiced by physicians or used for training medical graduates. Recently, the 5Cs of Consultation model (Contact, Communicate, Core Question, Collaborate, and Close the Loop) has been studied in Emergency Medicine residents using simulated consultation scenarios. OBJECTIVE: Using an experimental design, we aimed to evaluate the efficacy of the 5Cs consultation model in a novel learner population (medical students) and in a "real time and real world" clinical setting. METHODS: A prospective, randomized, controlled study was conducted at eight large, academic, urban, tertiary-care medical centers (U.S. and Canada). Intervention involved two experimental groups (asynchronous and live training) compared to a baseline control group. All participants placed up to four consult phone calls. A senior physician observed and assessed each call using a preapproved 5Cs checklist and a Global Rating Scale (GRS). RESULTS: Participants who received training (asynchronous or live) scored significantly higher on the 5Cs checklist total and GRS than the control group. Both training methods (asynchronous and live) were equally effective. Importantly, learning gains were sustained as students' 5Cs checklist total and GRS scores remained consistently higher at their second, third, and fourth consult (relative to their first consult). At posttest, all participants reported feeling more confident and competent in relaying patient information. CONCLUSION: Medical students can be trained to use the 5Cs model in a timely, inexpensive, and convenient manner and increase effectiveness of physician consultations originating from the ED. PMID- 26250841 TI - Healthy Nordic diet and cardiovascular disease. PMID- 26250839 TI - Gluteus Maximus Muscle Tear as a Rare Cause of Hip Pain and Sciatica. PMID- 26250842 TI - Adrenal insufficiency induced by megestrol acetate: Report of two cases. PMID- 26250843 TI - Plant-produced viral bovine vaccines: what happened during the last 10 years? AB - Vaccination has proved to be an efficient strategy to deal with viral infections in both human and animal species. However, protection of cattle against viral infections is still a major concern in veterinary science. During the last two decades, the development of efficient plant-based expression strategies for recombinant proteins prompted the application of this methodology for veterinary vaccine purposes. The main goals of viral bovine vaccines are to improve the health and welfare of cattle and increase the production of livestock, in a cost effective manner. This review explores some of the more prominent recent advances in plant-made viral bovine vaccines against foot-and-mouth disease virus (FMDV), bovine rotavirus (BRV), bovine viral diarrhoea virus (BVDV), bluetongue virus (BTV) and bovine papillomavirus (BPV), some of which are considered to be the most important viral causative agents of economic loss in cattle production. PMID- 26250844 TI - The Phenomenon of the Urban Mummy. AB - The environmental mummification of a body in an urban setting is an unusual event. Florida is known for its high temperatures and humidity, which typically result in the rapid putrefaction of bodies. However, under certain circumstances, Florida's climate provides an environment suitable for mummification, typically in isolated areas. We previously reported a case of a homicide/suicide in a residential neighborhood in which the mummified remains were undetected for several years. We have subsequently encountered two additional cases in which mummified bodies were discovered in urban settings. Presented in the historical context of the environmental conditions and postmortem processes involved in mummification, these cases illustrate the particular constellation of human behaviors and scenarios, as well as environmental conditions, which must coincide for this phenomenon to occur and highlight the necessity of the multidisciplinary approach to the medicolegal investigation of such deaths and the determination of the cause and manner of death. PMID- 26250845 TI - A review of 18p deletions. AB - Since 18p- was first described in 1963, much progress has been made in our understanding of this classic deletion condition. We have been able to establish a fairly complete picture of the phenotype when the deletion breakpoint occurs at the centromere, and we are working to establish the phenotypic effects when each gene on 18p is hemizygous. Our aim is to provide genotype-specific anticipatory guidance and recommendations to families with an 18p- diagnosis. In addition, establishing the molecular underpinnings of the condition will potentially suggest targets for molecular treatments. Thus, the next step is to establish the precise effects of specific gene deletions. As we look forward to deepening our understanding of 18p-, our focus will continue to be on the establishment of robust genotype-phenotype correlations and the penetrance of these phenotypes. We will continue to follow our 18p- cohort closely as they age to determine the presence or absence of some of these diagnoses, including spinocerebellar ataxia (SCA), facioscapulohumeral muscular dystrophy (FSHD), and dystonia. We will also continue to refine the critical regions for other phenotypes as we enroll additional (hopefully informative) participants into the research study and as the mechanisms of the genes in these regions are elucidated. Mouse models will also be developed to further our understanding of the effects of hemizygosity as well as to serve as models for treatment development. PMID- 26250846 TI - Abstracts of the 31st Annual Scientific Meeting of the Australasian College for Emergency Medicine, 7-11 December 2014, Melbourne, Australia. PMID- 26250847 TI - The development of statin-based therapy for patients with hepatitis C virus (HCV) infection using human induced pluripotent stem (iPS) cell technology. AB - Human induced pluripotent stem (iPS) cells may transform drug discovery. Here I show an example of the development of statin (HMG-CoA reductase inhibitors)-based therapy for patients with hepatitis C virus (HCV) infection using human iPS cell technology. When Shimada et al. considered the two reports on the antiviral effects of pitavastatin for HCV infection in vitro by Moriguchi et al., they conducted a randomized controlled trial. As a result, a proof-of-concept for the antiviral effect of pitavastatin against HCV infection using human iPS cell technology by Moriguchi et al. was confirmed in the randomized controlled trial by Shimada et al. in 2012. Therefore, above-mentioned a series of studies became to the first to report the clinical application of human iPS cells. Furthermore, here I propose that new clinical research methods using human iPS cell technology will be able to circumvent the limitations of conventional randomized controlled trials (RCTs) for the purpose of personalized medicine in the clinical setting. PMID- 26250848 TI - Relationship between pulp structure breakdown and nutritional value of papaya (Carica papaya) and strawberry (Fragaria x ananassa) nectars using alternative thermal and non-thermal processing techniques. AB - BACKGROUND: Papaya and strawberry contain a wide array of nutrients that contribute to human health; however, availability of these fruits is limited due to their short shelf lives and seasonal nature. In this study, the effect of alternative techniques including ultra high temperature (UHT, 20-135 degrees C, 1-3 s) and irradiation (0-10 kGy) on carotenoid concentration, antioxidant capacity and changes to pulp structure using transmission electron microscopy were determined for papaya and strawberry nectars. RESULTS: UHT had moderate effects on antioxidant capacity, but the greatest overall release of carotenoids from the pulp matrix (34.2%, 6.26%, 8.31%; beta-cryptoxanthin, beta-carotene, and lycopene, respectively). Irradiation resulted in the greatest increase in antioxidant capacity [19.22 to 24.32 umol Trolox equivalents kg(-1) (papaya), 190.51 to 287.68 umol Trolox equivalents kg(-1) (strawberry)], with moderate effects on carotenoid concentration. CONCLUSION: This research demonstrates that decreases in nutrient value and antioxidant capacity can result from processing, but that regeneration of these losses can be seen corresponding to the apparent breakdown of pulp structure. (c) 2015 Society of Chemical Industry. PMID- 26250849 TI - Feasibility Testing of a Protocol to Stop Ineffective Drug and Nondrug Treatments. AB - Ineffective treatments continue to be given to nursing home residents with dementia, and many more treatments are started than stopped. The Track and Trigger Treatment (T(3)) Protocol assists nurses to track responses to new treatments and get ineffective treatments stopped or altered. This preliminary study determined feasibility for end users and examined differences between two randomized groups in assessments, treatment changes, nurse time, and drug costs over 8 weeks. Controlling for number of medical diagnoses, 41 residents in the T(3) group had significantly more treatments stopped than 37 residents in the usual care group. Treatments were most commonly stopped because of ineffectiveness (33%), followed by the problem being resolved (29%), side effects (18%), and a change in goals of care (20%). Assessment quality was a statistically significant mediator, and drug costs were significantly less for the T(3) group. The T(3) processes were rated as useful and easy, with one caveat. PMID- 26250850 TI - Regional anesthesia/analgesia and the risk of cancer recurrence and mortality after prostatectomy: a meta-analysis. AB - AIMS: To determine whether the use neuraxial anesthesia/analgesia is associated with longer biochemical recurrence-free survival (BRFS) and overall survival (OS) after radical prostatectomy. METHODS: Ten studies were included in the meta analysis. A random-effects model was used to estimate the hazard ratios (HRs). RESULTS: The HR for BRFS was 1.02 (95% CI: 0.91-1.15) for all studies and 1.08 (95% CI: 0.91-1.15) for those that included propensity score matching. For OS, the HR across all studies was 0.91 (95% CI: 0.7-1.15) and 0.81 (95% CI: 0.68 0.96; p = 0.016) for those reporting propensity score matching. CONCLUSION: The anesthetic technique used during oncologic prostatectomy surgery is not associated with longer BRFS. By contrast, the use of regional analgesia appears to improve OS. PMID- 26250851 TI - Surfactant protein D suppresses lung cancer progression by downregulation of epidermal growth factor signaling. PMID- 26250852 TI - Examining the neural correlates of emergent equivalence relations in fragile X syndrome. AB - The neural mechanisms underlying the formation of stimulus equivalence relations are poorly understood, particularly in individuals with specific learning impairments. As part of a larger study, we used functional magnetic resonance imaging (fMRI) while participants with fragile X syndrome (FXS), and age- and IQ matched controls with intellectual disability, were required to form new equivalence relations in the scanner. Following intensive training on matching fractions to pie charts (A=B relations) and pie charts to decimals (B=C relations) outside the scanner over a 2-day period, participants were tested on the trained (A=B, B=C) relations, as well as emergent symmetry (i.e., B=A and C=B) and transitivity/equivalence (i.e., A=C and C=A) relations inside the scanner. Eight participants with FXS (6 female, 2 male) and 10 controls, aged 10 23 years, were able to obtain at least 66.7% correct on the trained relations in the scanner and were included in the fMRI analyses. Across both groups, results showed that the emergence of symmetry relations was correlated with increased brain activation in the left inferior parietal lobule, left postcentral gyrus, and left insula, broadly supporting previous investigations of stimulus equivalence research in neurotypical populations. On the test of emergent transitivity/equivalence relations, activation was significantly greater in individuals with FXS compared with controls in the right middle temporal gyrus, left superior frontal gyrus and left precuneus. These data indicate that neural execution was significantly different in individuals with FXS than in age- and IQ matched controls during stimulus equivalence formation. Further research concerning how gene-brain-behavior interactions may influence the emergence of stimulus equivalence in individuals with intellectual disabilities is needed. PMID- 26250853 TI - Giving information about the contraceptive implant using a DVD: is it acceptable and informative? A pilot randomised study. AB - BACKGROUND: To provide standardised information about the contraceptive implant (Nexplanon((r))), a digital video disc (DVD) was developed for use within a sexual and reproductive health (SRH) service in Edinburgh. The aim was to determine if the accuracy of information recalled after watching a DVD was comparable to that following a face-to-face consultation, and if patients found the use of a DVD acceptable. METHODS: Fifty women attending an SRH service abortion clinic considering using Nexplanon for the first time agreed to be randomised to receive information about the implant either by (a) a DVD (n=35) developed using information taken from Faculty of Sexual & Reproductive Healthcare guidance or (b) a face-to-face consultation (n=15). A structured interview was conducted immediately following the DVD/face-to-face consultation and by telephone 3 months later. A small number of participants from each group attended for in-depth interview. RESULTS: Knowledge recall (e.g. expected side effects) immediately following each intervention was similar in both groups. Most of the women who watched the DVD felt it was helpful (89%), easy to understand (94%) and acceptable (69%). Subsequently 76% of participants were contacted successfully at 3 months. The majority of those who had watched the DVD agreed that it had been informative (93%) and would be happy to receive contraceptive information via a DVD in future (93%). CONCLUSIONS: The use of a DVD to provide patient information on Nexplanon is acceptable and informative, and may enhance patient consultations. A large randomised controlled trial may determine if provision of quality standardised information via DVD can improve uptake or continuation rates of long-acting reversible methods of contraception. PMID- 26250854 TI - Shifting abortion care from a hospital to a community sexual and reproductive health care setting. AB - BACKGROUND: Community sexual and reproductive health (SRH) services are well placed to deliver abortion assessment services and early medical abortion (EMA), but comparative data on safety and acceptability from both settings are important for future service planning. METHODS: Retrospective review of computerised records of 1342 women undergoing outpatient EMA (<=9 weeks) in a community SRH or hospital department of gynaecology in the same city, and a self-completed, anonymous survey of 303 women requesting abortion at both sites. Primary outcome was safety in terms of re-attendance rates for a complication related to EMA. Secondary outcomes were telephone contact with each site for an EMA-related concern and satisfaction with information about abortion (defined as score out of 10) received at each site. RESULTS: There was no difference in re-attendance rates to either service for a complication following outpatient EMA (2.7%). A higher proportion of women undergoing EMA at the SRH site made telephone contact compared to women at the hospital site (18.8% vs 10.8%; p=0.033). Women rated both settings highly in terms of information received before abortion (9.2 and 9.6 out of 10) at the hospital and SRH sites, respectively. CONCLUSIONS: This study suggests that provision of outpatient EMA in a community SRH setting is as safe as that delivered from a hospital setting, and that women are similarly satisfied with the information they receive about abortion from each setting. More abortion assessment and outpatient EMA services in Great Britain could shift from hospital to community SRH settings. PMID- 26250855 TI - Minimally Invasive Percutaneous Treatment of Small Renal Tumors with Irreversible Electroporation: A Single-Center Experience. AB - PURPOSE: To evaluate whether irreversible electroporation (IRE) can be used as an ablation technique for small renal tumors (T1a cancers or small benign tumors) and to describe features after ablation on computed tomography (CT) or magnetic resonance (MR) imaging. MATERIALS AND METHODS: In this retrospective study, 20 patients (mean age, 65 y +/- 12.8 y) underwent CT-guided IRE of T1a renal carcinoma (n = 13) or small benign or indeterminate renal masses < 4 cm in size (n = 7). Mean tumor size was 2.2 cm +/- 0.7. The ablation area was verified with contrast-enhanced imaging performed immediately after the procedure to determine technical success. Imaging was performed 6 weeks (20 of 20 patients), 6 months (15 of 20), and 12 months (6 of 20) after ablation. Medical records and CT/MR imaging features of all patients were reviewed for recurrence, symptoms, and complications after treatment. RESULTS: Technical success was achieved in all patients (100%); there were no major procedure-related complications. Minor complications occurred in 7 patients, including self-limiting perinephric hematomas, pain difficult to control, and urinary retention. Mean procedure time was 2.0 hours +/- 0.7. At 6 weeks, 2 patients required salvage therapy because of incomplete ablation. At 6 months, all 15 patients with imaging studies available had no evidence of recurrence. At 1 year, 1 patient (1 of 6) was noted to have experienced recurrence. CT/MR imaging after IRE ablation demonstrated an area of nonenhancement in the treatment zone that involuted over ~6 months. CONCLUSIONS: Renal IRE appears to be a safe treatment for small renal tumors. Tumors treated with IRE demonstrated nonenhancement in the treatment zone with involution on follow-up CT/MR imaging. PMID- 26250856 TI - Long-Term Clinical Outcomes of Infrapopliteal Drug-Eluting Stent Placement for Critical Limb Ischemia in Diabetic Patients. AB - PURPOSE: To evaluate long-term clinical outcomes of infrapopliteal drug-eluting stent (DES) placement in insulin-dependent and non-insulin-dependent diabetic patients with critical limb ischemia (CLI). MATERIALS AND METHODS: A retrospective analysis was performed of all diabetic patients treated with infrapopliteal DES between January 2002 and September 2012. The study's primary outcome measures were patient survival and major amputation-free survival (AFS). Secondary outcome measures included technical success (defined as the creation of a straight line of blood flow to the foot arch with < 30%), identification of independent predictors of primary outcomes, infrapopliteal target limb repeat intervention-free survival, and procedure-related complications. RESULTS: In total, 214 patients with CLI (168 men [78.5%]; mean age, 70 y +/- 9) in 311 limbs, 562 arteries, and 679 lesions were treated. According to Kaplan-Meier analysis, survival rates were 90.8%, 55.5%, and 36.2%, and AFS rates were 94.9%, 90.4%, and 90.4%, respectively, at 1, 5, and 10 years. Target limb repeat intervention-free survival rates were 79.7%, 55.2%, and 49.7%, respectively, at 1, 5, and 10 years. The overall technical success rate was 97.7%. Cox multivariate analysis demonstrated that procedural failure was the only independent predictor of decreased AFS (hazard ratio [HR], 61.3; 95% confidence interval [CI], 13.8-271.9), and statin use was associated with increased survival (HR, 0.55; 95% CI, 0.31-0.98). Coronary disease (HR, 1.9; 95% CI, 1.01-3.54), dialysis (HR, 2.2; 95% CI, 1.21-4.06), and duration of diabetes (HR, 1.5; 95% CI, 1.02-2.34) were identified as independent predictors of decreased survival. Major complications occurred in four of 479 procedures (0.8%). CONCLUSIONS: Infrapopliteal DES placement for the management of CLI in diabetic patients resulted in a 55.5% 5-year survival rate, with a 90.4% AFS at 5 and 10 years and a 50.3% repeat intervention rate at 10 years. Technical failure was associated with reduced AFS, and statin intake was associated with increased survival. PMID- 26250857 TI - The relationships among individual and regional smoking, socioeconomic status, and oral and pharyngeal cancer survival: a mediation analysis. AB - Poorer survival from oral and pharyngeal cancer (OPC) has been reported for populations of lower socioeconomic status (SES), adjusting for risk factors such as patient and clinical characteristics. Beyond these risk factors, higher rates of tobacco use may be a mediator for the observed poorer OPC survival for low SES populations. In this study, we aimed to examine the impact of the relationships among SES, individual smoking status, and living in a region with a higher smoking rate on OPC survival. We obtained Florida Cancer Data System data from 1996 to 2010 and merged the data with US Census data and Behavioral Risk Factor Surveillance System data from 1996 to 2010. We built multivariable survival models to quantify the mediational effect of individual smoking on overall and OPC-specific survival, adjusting for regional smoking, demographics, and clinical characteristics. We found that lower SES, individual smoking, and living in a region with a higher smoking rate were all strongly associated with poorer survival. We estimated that the indirect effect of individual smoking accounted for a large part (ranged from 13.3% to 30.2%) of the total effect of SES on overall and OPC-specific survival. In conclusion, individual and regional smoking are both significant and independent predictors of poor cancer survival. Higher rate of individual smoking is partially responsible for poorer cancer survival in low SES populations. Results of this study provide rationale for considering a multi-level approach that simultaneously targets both individual and contextual factors for future smoking cessation interventions. PMID- 26250858 TI - Defining the local nerve blocks for feline distal thoracic limb surgery: a cadaveric study. AB - OBJECTIVES: Though controversial, onychectomy remains a commonly performed distal thoracic limb surgical procedure in cats. Peripheral nerve block techniques have been proposed in cats undergoing onychectomy but evidence of efficacy is lacking. Preliminary tests of the described technique using cadavers resulted in incomplete staining of nerves. The aim of this study was to develop nerve block methods based on cadaveric dissections and test these methods with cadaveric dye injections. METHODS: Ten pairs of feline thoracic limbs (n = 20) were dissected and superficial branches of the radial nerve (RSbr nn.), median nerve (M n.), dorsal branch of ulnar nerve (UDbr n.), superficial branch of palmar branch of ulnar nerve (UPbrS n.) and deep branch of palmar branch of ulnar nerve (UPbrDp n.) were identified. Based on these dissections, a four-point block was developed and tested using dye injections in another six pairs of feline thoracic limbs (n = 12). Using a 25 G * 5/8 inch needle and 1 ml syringe, 0.07 ml/kg methylene blue was injected at the site of the RSbr nn., 0.04 ml/kg at the injection site of the UDbr n., 0.08 ml/kg at the injection site of the M n. and UPbrS n., and 0.01 ml/kg at the injection site of the UPbrDp n. The length and circumference of each nerve that was stained was measured. RESULTS: Positive staining of all nerves was observed in 12/12 limbs. The lengths stained for RSbr nn., M n., UDbr n., UPbrS n. and UPbrDp n. were 34.9 +/- 5.3, 26.4 +/- 4.8, 29.2 +/- 4.0, 39.1 +/- 4.3 and 17.5 +/- 3.3 mm, respectively. The nerve circumferences stained were 93.8 +/- 15.5, 95.8 +/- 9.7, 100 +/- 0.0, 100 +/- 0.0 and 93.8 +/- 15.5%, respectively. CONCLUSIONS AND RELEVANCE: This described four-point injection method may be an effective perioperative analgesia technique for feline distal thoracic limb procedures. PMID- 26250859 TI - Metformin improves performance in high-intensity exercise, but not anaerobic capacity in healthy male subjects. AB - The aim of this study was to determine the ergogenic effects of metformin in high intensity exercise, as well as its effects on anaerobic capacity, in healthy and physically active men. Ten subjects (mean (+/- standard deviation) maximal oxygen uptake (VO2max ) 38.6 +/- 4.5 mL/kg per min) performed the following tests in a cycle ergometer: (i) an incremental test; (ii) six submaximal constant workload tests at 40%-90% (VO2max ); and (iii) two supramaximal tests (110% (VO2max ). Metformin (500 mg) or placebo was ingested 60 min before the supramaximal test. There were no significant differences between the placebo and metformin groups in terms of maximum accumulated oxygen deficit (2.8 +/- 0.6 vs 3.0 +/- 0.8 L, respectively; P = 0.08), lactate concentrations (7.8 +/- 2.6 vs 7.5 +/- 3.0 mmol/L, respectively; P = 0.75) or O2 consumed in either the last 30 s of exercise (40.4 +/- 4.4 vs 39.9 +/- 4.0 mL/kg per min, respectively; P = 0.35) or the first 110 s of exercise (29.0 +/- 2.5 vs 29.5 +/- 3.0 mL/kg per min, respectively; P = 0.42). Time to exhaustion was significantly higher after metformin than placebo ingestion (191 +/- 33 vs 167 +/- 32 s, respectively; P = 0.001). The fast component of VO2 recovery was higher in the metformin than placebo group (12.71 vs 12.18 mL/kg per min, respectively; P = 0.025). Metformin improved performance and anaerobic alactic contribution during high-intensity exercise, but had no effect on overall anaerobic capacity in healthy subjects. PMID- 26250860 TI - Objectively measured night-to-night sleep variations are associated with body composition in very elderly women. AB - This cross-sectional study examined the association between objectively measured sleep patterns and body composition in very elderly community-dwelling women. Participants included 191 community-dwelling adults aged >= 80 years (mean age: 83.4 +/- 2.6 years; age range: 80-92 years). Sleep and physical activity were monitored via accelerometer (ActiGraph GT3X+) during at least five consecutive 24 h periods. Night-to-night sleep pattern variability across all nights of recording was assessed using standard deviations (SDs). Body composition was assessed using dual-energy X-ray absorptiometry. Simple and multivariable linear regression analyses were performed. The mean number of nights with usable actigraphy data was 7.3 +/- 1.3. On average, participants went to bed at 22:57 hours (SD: 1.11 h) and rose from bed at 6:27 hours (SD: 1.01 h). Night-to-night bedtime, sleep duration and sleep timing mid-point variations correlated slightly with the percentage body fat and percentage lean mass (P < 0.05). Multiple linear regression analysis revealed significant associations of night-to-night bedtime variations and inconsistent sleep-wake patterns with all body composition indices after adjusting for potential confounding factors, including mean nightly sleep duration, self-reported nap duration and daily physical activity. After further adjusting for night-to-night wake time, sleep timing mid-point and sleep duration variations, greater bedtime variability remained associated significantly with all body composition indices except lean/fat mass ratio. Inconsistent sleep-wake patterns were associated independently with an increased fat mass and decreased lean mass among very elderly women. These findings suggest that in most elderly individuals, sleep patterns might be an important modifiable factor associated with obesity and sarcopenia development. PMID- 26250861 TI - Young children remedy second- and third-party ownership violations. AB - When responding to ownership violations, children can focus on the victim's needs, the perpetrator's punishment, or both. Recent studies show that 3- and 5 year-olds are equally likely to respond to second- and third-party violations, and 3-year-olds return objects to their rightful owners. Children's interventions are consistent with justice for victims. PMID- 26250862 TI - Phosphane-ene chemistry: the reactivity of air-stable primary phosphines and their compatibility with the thiol-ene reaction. AB - Air-sensitive and air-stable primary phosphines (RPH2) were compared for their ability to undergo photoinitiated phosphane-ene chemistry with 1-hexene. Despite their increased air-stability, the primary phosphines displayed equal to or greater reactivity when compared to air-sensitive alkyl or aryl analogues. The phosphane-ene reaction was also performed in the presence of 1-octanethiol to determine whether thiol-ene and phosphane-ene chemistries could proceed simultaneously. It was determined that the phosphane-ene process takes precedence over thiol-ene as P-H bond conversion was independent of thiol concentration. Tertiary phosphine (R3P) and some secondary phosphine (R2PH) products were found to react with thiols under experimental conditions to create phosphine-sulfides (P-S), but this chemistry only proceeded at low P-H bond concentrations. These results suggests that hydrogen transfer reactions take precedence over P-S formation and demonstrate the unique relationship between phosphane-ene and thiol ene chemistry. PMID- 26250864 TI - Potential impacts of climate change on flow regime and fish habitat in mountain rivers of the south-western Balkans. AB - The climate change in the Mediterranean area is expected to have significant impacts on the aquatic ecosystems and particular in the mountain rivers and streams that often host important species such as the Salmo farioides, Karaman 1938. These impacts will most possibly affect the habitat availability for various aquatic species resulting to an essential alteration of the water requirements, either for dams or other water abstractions, in order to maintain the essential levels of ecological flow for the rivers. The main scope of this study was to assess potential climate change impacts on the hydrological patterns and typical biota for a south-western Balkan mountain river, the Acheloos. The altered flow regimes under different emission scenarios of the Intergovernmental Panel on Climate Change (IPCC) were estimated using a hydrological model and based on regional climate simulations over the study area. The Indicators of Hydrologic Alteration (IHA) methodology was then used to assess the potential streamflow alterations in the studied river due to predicted climate change conditions. A fish habitat simulation method integrating univariate habitat suitability curves and hydraulic modeling techniques were used to assess the impacts on the relationships between the aquatic biota and hydrological status utilizing a sentinel species, the West Balkan trout. The most prominent effects of the climate change scenarios depict severe flow reductions that are likely to occur especially during the summer flows, changing the duration and depressing the magnitude of the natural low flow conditions. Weighted Usable Area-flow curves indicated the limitation of suitable habitat for the native trout. Finally, this preliminary application highlighted the potential of science-based hydrological and habitat simulation approaches that are relevant to both biological quality elements (fish) and current EU Water policy to serve as efficient tools for the estimation of possible climate change impacts on the south-western Balkan river ecosystems. PMID- 26250863 TI - A review of hydrological and chemical stressors in the Adige catchment and its ecological status. AB - Quantifying the effects of multiple stressors on Alpine freshwater ecosystems is challenging, due to the lack of tailored field campaigns for the contemporaneous measurement of hydrological, chemical and ecological parameters. Conducting exhaustive field campaigns is costly and hence most of the activities so far have been performed addressing specific environmental issues. An accurate analysis of existing information is therefore useful and necessary, to identify stressors that may act in synergy and to design new field campaigns. We present an extended review of available studies and datasets concerning the hydrological, chemical and ecological status of the Adige, which is the second longest river and the third largest river basin in Italy. The most relevant stressors are discussed in the light of the information extracted from a large number of studies. The detailed analysis of these studies identified that hydrological alterations caused by hydropower production are the main source of stress for the freshwater ecosystems in the Adige catchment. However, concurrent effects with other stressors, such as the release of pollutants from waste water treatment plants or from agricultural and industrial activities, have not been explored at depth, so far. A wealth of available studies address a single stressor separately without exploring their concurrent effect. It is concluded that a combination of extended experimental field campaigns, focusing on the coupled effects of multiple stressors, and modeling activities is highly needed in order to quantify the impact of the multifaceted human pressures on freshwater ecosystems in the Adige river. PMID- 26250865 TI - Perfluoroalkyl substances in the Ebro and Guadalquivir river basins (Spain). AB - Mediterranean rivers are characteristically irregular with changes in flow and located in high population density areas. This affects the concentration of pollutants in the aquatic environments. In this study, the occurrence and sources of 21 perfluoroalkyl substances (PFASs) were determined in water, sediment and biota of the Ebro and Guadalquivir river basins (Spain). In water samples, of 21 analytes screened, 11 were found in Ebro and 9 in Guadalquivir. In both basins, the most frequents were PFBA, PFPeA and PFOA. Maximum concentration was detected for PFBA, up to 251.3 ng L(-1) in Ebro and 742.9 ng L(-1) in Guadalquivir. Regarding the sediments, 8 PFASs were detected in the samples from Ebro and 9 in those from Guadalquivir. The PFASs most frequently detected were PFBA, PFPeA, PFOA and PFOS. Maximum concentration in Ebro samples was, in dry weight, for PFOA (32.3 ng g(-1)) and in Guadalquivir samples for PFBA (63.8 ng g(-1)). For biota, 12 PFASs were detected in fish from the Ebro River and only one (PFOS) in that from Guadalquivir. In the Ebro basin, the most frequents were PFBA, PFHxA, PFOA, PFBS, PFOS and PFOSA. Maximum concentration in Ebro samples was, in wet weight, for PFHxA with 1280.2 ng g(-1), and in Guadalquivir samples for PFOS with 79.8 ng g(-1). These compounds were detected in the whole course of the rivers including the upper parts. In some points contamination was due to point sources mostly related to human activities (e.g. ski resorts, military camps, urban areas.). However, there are also some areas clearly affected by diffuse sources as atmospheric deposition. PMID- 26250866 TI - Improved hydrological model parametrization for climate change impact assessment under data scarcity - The potential of field monitoring techniques and geostatistics. AB - According to current climate projections, Mediterranean countries are at high risk for an even pronounced susceptibility to changes in the hydrological budget and extremes. These changes are expected to have severe direct impacts on the management of water resources, agricultural productivity and drinking water supply. Current projections of future hydrological change, based on regional climate model results and subsequent hydrological modeling schemes, are very uncertain and poorly validated. The Rio Mannu di San Sperate Basin, located in Sardinia, Italy, is one test site of the CLIMB project. The Water Simulation Model (WaSiM) was set up to model current and future hydrological conditions. The availability of measured meteorological and hydrological data is poor as it is common for many Mediterranean catchments. In this study we conducted a soil sampling campaign in the Rio Mannu catchment. We tested different deterministic and hybrid geostatistical interpolation methods on soil textures and tested the performance of the applied models. We calculated a new soil texture map based on the best prediction method. The soil model in WaSiM was set up with the improved new soil information. The simulation results were compared to standard soil parametrization. WaSiMs was validated with spatial evapotranspiration rates using the triangle method (Jiang and Islam, 1999). WaSiM was driven with the meteorological forcing taken from 4 different ENSEMBLES climate projections for a reference (1971-2000) and a future (2041-2070) times series. The climate change impact was assessed based on differences between reference and future time series. The simulated results show a reduction of all hydrological quantities in the future in the spring season. Furthermore simulation results reveal an earlier onset of dry conditions in the catchment. We show that a solid soil model setup based on short-term field measurements can improve long-term modeling results, which is especially important in ungauged catchments. PMID- 26250867 TI - Structural, Vibrational and Electronic Properties of Defective Single-Walled Carbon Nanotubes Functionalised with Carboxyl Groups: Theoretical Studies. AB - Covalent sidewall functionalisation of defective zigzag single-walled carbon nanotubes [SWCNTs(10,0)] with COOH groups is investigated by using DFT. Four types of point defects are considered: vacancy (V), divacancy [V2 (5-8-5), V2 (555-777)], adatom (AA) and Stone-Wales (SW). The energetic, structural, electronic and vibrational properties of these systems are analysed. Decreasing reactivity is observed in the following order: AA>V>V2 (555-777)>V2 (5-8-5)>SW. These studies also demonstrate that the position in which a carboxyl group is attached to a defective SWCNT is of primary importance. Saturation of two coordinate carbon atoms in systems with the vacancy V-7 and with the adatom AA 1(2) is 3.5-4 times more energetically favourable than saturation of three coordinate carbon atoms for all studied systems. Vibrational analysis for these two systems shows significant redshifts of the nu(C?O) stretching vibration of 96 and 123 cm-1 compared to that for carboxylated pristine systems. Detailed electronic-structure analysis of the most stable carboxylated systems is also presented. PMID- 26250870 TI - Company Policies on Working Hours and Night Work in Relation to Older Workers' Work Ability and Work Engagement: Results From a Dutch Longitudinal Study with 2 Year Follow-Up. AB - Purpose To longitudinally investigate (1) whether lower work ability and work engagement predict the use of company policies on reduced working hours and exemption from evening/night work among older workers, and (2) whether using such policies subsequently contribute to higher work ability and work engagement. Methods In total 6922 employees (45-64 years) participating in the first three waves of the Study on Transitions in Employment, Ability and Motivation were included. Participants yearly filled out an online questionnaires. Regression analyses were applied to study the influence of baseline work ability and work engagement on the incident use of policies during the first year of follow-up, and the incident use of these policies on work ability and work engagement during the second year of follow-up. Results Employees with a higher work ability were less likely to start using the policy 'reduced working hours' [OR 0.91 (95 % CI 0.83-0.98)]. Starting to use this policy was in turn related to lower work ability 1 year later [B -0.28 (95 % CI -0.47 to -0.08)]. Starting to use the policy 'exemption from evening/night work' was related to higher work engagement 1 year later [B 0.23 (95 % CI 0.07-0.39)]. Conclusions Low work ability precedes the use of some company policies aiming to support sustainable employability of older workers. Further research is needed to explore whether company policies result in a (longstanding) improvement, or reduced deterioration, of older workers' employability. PMID- 26250868 TI - A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance. AB - Patients carrying very rare loss-of-function mutations in interleukin-1 receptor associated kinase 4 (IRAK4), a critical signaling mediator in Toll-like receptor signaling, are severely immunodeficient, highlighting the paramount role of IRAK kinases in innate immunity. We discovered a comparatively frequent coding variant of the enigmatic human IRAK2, L392V (rs3844283), which is found homozygously in ~15% of Caucasians, to be associated with a reduced ability to induce interferon alpha in primary human plasmacytoid dendritic cells in response to hepatitis C virus (HCV). Cytokine production in response to purified Toll-like receptor agonists was also impaired. Additionally, rs3844283 was epidemiologically associated with a chronic course of HCV infection in two independent HCV cohorts and emerged as an independent predictor of chronic HCV disease. Mechanistically, IRAK2 L392V showed intact binding to, but impaired ubiquitination of, tumor necrosis factor receptor-associated factor 6, a vital step in signal transduction. CONCLUSION: Our study highlights IRAK2 and its genetic variants as critical factors and potentially novel biomarkers for human antiviral innate immunity. PMID- 26250871 TI - Erratum to: Development and Validation of a Clinical Prediction Rule of the Return-to-Work Status of Injured Employees in Minnesota. PMID- 26250869 TI - Curcumin suppresses NLRP3 inflammasome activation and protects against LPS induced septic shock. AB - SCOPE: The NLRP3 inflammasome responds to various pathogen-derived factors and danger-associated molecules, mediating IL-1beta maturation, therefore is involved in multiple inflammatory diseases. Curcumin has been shown to possess strong anti inflammatory activity, but the underlying mechanism is not fully understood. Here, we sought to investigate the role and mechanism of curcumin on the inhibition of mature IL-1beta production via the regulation of NLRP3 inflammasome. METHODS AND RESULTS: Curcumin dramatically inhibited the production of mature IL-1beta in LPS-primed macrophages triggered by multiple NLRP3 inflammasome activators, and also reduced the level of cleaved caspase-1 as measured by western blot and ELISA. Curcumin prevented K(+) efflux, the common trigger for NLRP3 inflammasome activation, and attenuated lysosomes disruption and intracellular ROS formation as well. The inhibition of NLRP3 inflammasome by curcumin was in part mediated via the suppression of extracellular regulated protein kinases phosphorylation. Furthermore, administration of curcumin significantly reduced peritoneal IL-1beta and HMGB-1 concentration induced by LPS and improved the survival of mice suffering from lethal endotoxic shock. CONCLUSION: Curcumin potently inhibits the activation of NLRP3 inflammasome which may contribute to its anti-inflammatory activity. Our finding offers a mechanistic basis for the therapeutic potential of curcumin in septic shock and other NLRP3 inflammasome-driven diseases. PMID- 26250872 TI - A randomised controlled study comparing valethamate bromide and placebo in shortening the duration of active labour. AB - The aim of this study is to compare the efficacy and safety of valethamate bromide and placebo against placebo in shortening the duration of active labour. A prospective randomised trial of 158 low-risk women in spontaneous labour was conducted. After evaluation of the patients according to exclusion criteria 30 women were given valethamate bromide (Group 1) and 32 women were given placebo (Group 2). Labour duration was the main outcome measure. The duration of the active phase after starting the treatment was similar in the two groups at 225 and 219 min, respectively. However, differences were not significant between the 2 groups. Side effects such as tachycardia, flushing of the face and dryness of mouth were noted with valethamate bromide administration. In conclusion, valethamate bromide did not significantly shortened the duration of active labour in nulliparous women with a singleton pregnancy at term. PMID- 26250873 TI - Decreased fertility rates in 9639 women diagnosed with inflammatory bowel disease: a United Kingdom population-based cohort study. AB - BACKGROUND: Clinical studies have reported reduced fertility in women with inflammatory bowel disease (IBD). AIM: To compare fertility rates in women with IBD to those in women without IBD and assess whether the relative fertility differed following IBD diagnosis, flares and surgery. METHODS: Women aged 15-44 years in 1990-2010 were identified from a UK primary care database. We estimated overall and age-specific fertility rates by 5-year age bands for women with and without IBD. We used Poisson regression to calculate adjusted fertility rate ratios (AFRR), adjusted for age, smoking and socioeconomic deprivation. RESULTS: There were 46.2 live births per 1000 person-years [95% confidence interval (95% CI); 44.6-47.9] in 9639 women with IBD and 49.3 (95% CI 49.2-49.5) in 2 131 864 without (AFRR: 0.93; 95% CI: 0.89-0.96). Excluding periods of contraception use, the AFRR was 0.99 (95% CI: 0.95-1.03). Before diagnosis, the AFRR for women with ulcerative colitis (UC) was 1.07 (95% CI: 0.99-1.16) and was 0.88 (95% CI: 0.81 0.97) for women with CD. After diagnosis, AFRRs were 0.87 (95% CI: 0.82-0.94) for CD and 0.92 (95% CI: 0.86-1.00) for UC. The fertility rate was lower following flares (AFRR: 0.70; 95% CI: 0.59-0.82) or surgery (AFRR: 0.84; 95% CI: 0.77 0.92). Women with pouch and non-pouch surgery had similar overall fertility though the reduction after surgery was greater for pouches (AFRR: 0.48; 95% CI: 0.23-0.99). CONCLUSIONS: Women with Crohn's disease have marginally lower fertility rates. These rates decreased following flares and surgical interventions. Fertility rates returned almost to normal when women were not prescribed contraception but the reduction following surgical intervention remained. As the lifetime effect of pouch vs. nonpouch surgery on fertility is small, the reduction post-pouch surgery should be interpreted with caution. PMID- 26250874 TI - Mycophenolate mofetil therapy for severe immune thrombocytopenia. AB - Severe immune thrombocytopenia purpura (ITP) presents a clinical challenge. Second-line treatment options are variable without a precise protocol. We present 46 severe ITP patients treated with mycophenolate mofetil (MMF), retrospectively identified from three London teaching hospitals. Data was collected on patient demographics, co-morbidities and previous treatment strategies. Our key interest was whether there was a sustained response in platelet count to MMF. Patients included 27 males and 19 females whose ages ranged from 19 to 93 years old (median 52.5 years). Twenty-nine had primary ITP and 17 had secondary ITP, a third of whom had viral-associated disease. The standard dose of MMF was 1 g/day. Twenty-four patients (52%) responded with 15 (33%) achieving a complete response. No active viral-associated ITP patients demonstrated a response to MMF, although numbers were small (n = 4). We were not able to demonstrate a difference between responders and non-responders based on gender, age, previous therapies or time since diagnosis of ITP. Three of four previously splenectomized patients responded, two achieving complete response. We conclude that MMF is a useful steroid-sparing immunosuppressant to be considered in the second-line or later treatment of ITP. PMID- 26250875 TI - Factors associated with loss to follow-up in women undergoing repair for obstetric fistula in Guinea. AB - OBJECTIVES: To analyse the trend of loss to follow-up over time and identify factors associated with women being lost to follow-up after discharge in three fistula repair hospitals in Guinea. METHODS: This retrospective cohort study used data extracted from medical records of fistula repairs conducted from 1 January 2007 to 30 September 2013. A woman was considered lost to follow-up if she did not return within 4 months post-discharge. Factors associated with loss to follow up were identified using a subsample of the data covering the period 2010-2013. RESULTS: Over the study period, the proportion of loss to follow-up was 21.5% (448/2080) and varied across repair hospitals and over time with an increase from 2% in 2009 to 52% in 2013. After adjusting for other variables in a multivariate logistic regression model, women who underwent surgery at Labe hospital and at Kissidougou hospital were more likely to be lost to follow-up than women operated at Jean Paul II hospital (OR: 50.6; 95% CI: 24.9-102.8) and (OR: 11.5; 95% CI: 6.1-22.0), respectively. Women with their fistula closed at hospital discharge (OR: 3.2; 95% CI: 2.1-4.8) and women admitted for repair in years 2011-2013 showed higher loss to follow-up as compared to 2010. Finally, loss to follow-up increased by 20/00 for each additional kilometre of distance a client lived from the repair hospital (OR: 1.002; 95% CI: 1.001-1.003). CONCLUSION: Reimbursement of transport was the likely reason for change over time of LTFU. Reducing geographical barriers to care for women with fistula could sustain fistula care positive outcomes. PMID- 26250877 TI - [Erratum for: Technique and Results for the Transconjunctival Removal of Orbital Haemangiomas]. PMID- 26250878 TI - The Fitness Effects of Men's Family Investments : A Test of Three Pathways in a Single Population. AB - Men's investments in parenting and long-term reproductive relationships are a hallmark feature of human reproduction and life history. The uniqueness of such male involvement among catarrhines has driven an extensive debate surrounding the selective pressures that led to and maintain such capacities in men. Three major pathways have been proposed through which men's involvement might confer fitness benefits: enhancing child well-being, increasing couple fertility, and decreasing likelihood of partner desertion. Previous research has explored the impact of father involvement on these factors individually, but here we present novel research that explores all three pathways within the same population, the Mayangna/Miskito horticulturalists of Nicaragua. Furthermore, we expand the traditional dichotomous measure of father presence/absence by using a continuous measure of overall male investment, as well as two continuous measures of its subcomponents: direct care and wealth. We find that men's investments are associated with children's growth and possibly with wife's marital satisfaction; however, they are not associated with couple fertility. PMID- 26250879 TI - Optimal linear combination of biomarkers for multi-category diagnosis. AB - The receiver operating characteristic (ROC) curve and the area under the ROC curve have been popularly employed in evaluating the diagnosis accuracy for diseases with binary outcome categories and have been naturally used as the utility measures for finding the 'optimal' linear combination of multiple biomarkers, in the hope to improve the diagnostic accuracy based on each single biomarker. For diseases with more than two outcome categories, the ROC manifold and the hypervolume under the ROC manifold (HUM) have been analogously proposed as diagnostic accuracy measures. However, finding optimal combinations of biomarkers based on the HUM criterion is less easily feasible in computation, especially when the number of disease categories is more than three and the number of biomarkers is large. In this study, we propose two new indices for evaluating the diagnostic accuracy for multi-category diagnosis, which are related to the lower and upper bounds of HUM, and involve only diagnostic accuracies for comparing adjacent pairs of outcome categories. We then propose finding the optimal linear combinations of biomarkers for multi-category diagnosis using the new indices as the criterion functions. Simulations and real data examples show that the optimal linear combinations identified by the new proposal perform quite well in diagnostic accuracy and can be much more efficient in computation than the HUM-based method. PMID- 26250880 TI - Age-related changes in bladder function with altered angiotensin II receptor mechanisms in rats. AB - AIMS: To examine alterations in expression of angiotensin II type 1 receptors (AT1R) which induce organ tissue remodeling, angiotensin II type 2 receptors (AT2R) which protect against it, and related molecules in the bladder of matured rats with bladder dysfunction. METHODS: Female SD rats of three different ages were used: 8 weeks old (8W; n = 5), 9 months old (9M; n = 5), and 15 months old (15M; n = 5). After cystometry, the expression levels of AT1R, connexin43 (Cx43), MAP kinase (MAPK), collagen1, AT2R, PPAR-gamma, adiponectin (Adipo), and adiponectin receptor (Adipo-R) were investigated in the bladder. RESULTS: Pressure threshold, post-void residual volume and the number of non-voiding contractions were significantly increased in 15M versus 8W rats (P < 0.01). Maximum voiding pressure was significantly decreased in 15M versus 8W rats (P < 0.05). There was no significant difference in CMG parameters between 8W and 9M rats. In the bladder, the mRNA expression of AT1R, Cx43, MAPK, collagen 1, AT2R, PPAR-gamma, Adipo, and Adipo-R were significantly higher in 15M than in 8W rats. The relative expression ratio of AT1R protein against AT2R protein in the mucosa and detrusor was significantly increased in 15M versus 8W rats. CONCLUSIONS: These results indicate that matured rats exhibit not only bladder overactivity but also impaired voiding, which are associated with upregulation of AT1R. The upregulation of AT2R also may play a significant role in the suppressing of AT1R induced remodelling. However, because AT1R upregulation is more dominant than AT2R increases, AT2R activation may not be sufficient to suppress AT1R stimulation in matured rats. Neurourol. Urodynam. 35:908-913, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26250876 TI - Process of hepatic metastasis from pancreatic cancer: biology with clinical significance. AB - PURPOSE: Pancreatic cancer shows a remarkable preference for the liver to establish secondary tumors. Selective metastasis to the liver is attributed to the development of potential microenvironment for the survival of pancreatic cancer cells. This review aims to provide a full understanding of the hepatic metastatic process from circulating pancreatic cancer cells to their settlement in the liver, serving as a basic theory for efficient prediction and treatment of metastatic diseases. METHODS: A systematic search of relevant original articles and reviews was performed on PubMed, EMBASE and Cochrane Library for the purpose of this review. RESULTS: Three interrelated phases are delineated as the contributions of the interaction between pancreatic cancer cells and the liver to hepatic metastasis process. Chemotaxis of disseminated pancreatic cancer cells and simultaneous defensive formation of platelets or neutrophils facilitate specific metastasis toward the liver. Remodeling of extracellular matrix and stromal cells in hepatic lobules and angiogenesis induced by proangiogenic factors support the survival and growth of clinical micrometastasis colonizing the liver. The bimodal role of the immune system or prevalence of cancer cells over the immune system makes metastatic progression successfully proceed from micrometastasis to macrometastasis. CONCLUSIONS: Pancreatic cancer is an appropriate research object of cancer metastasis representing more than a straight cascade. If any of the successive or simultaneous phases, especially tumor-induced immunosuppression, is totally disrupted, hepatic metastasis will be temporarily under control or even cancelled forever. To shrink cancers on multiple fronts and prolong survival for patients, novel oral or intravenous anti cancer agents covering one or different phases of metastatic pancreatic cancer are expected to be integrated into innovative strategies on the premise of safety and efficacious biostability. PMID- 26250881 TI - [The interest of electroneuromyography in peripheral facial palsy]. AB - In case of peripheral facial palsy, electroneuromyogram of the facial nerve provides an indication of the nature (myelinic and/or axonal) and severity of nerve damage, thereby facilitating establishment of a prognosis, which is favorable for myelin damage, and guarded for severe axonal damage. The initial examination must be carried out during the second week. In case of severe axonal damage, examination results can be monitored at the third, and more particularly the sixth and the twelfth months. Stable neurophysiological data between the sixth and the twelfth months signal damage stability and open the way to possible palliative surgery. In the event of trigeminal damage, neurophysiological exploration furthers analysis of temporal muscle innervation. ENMG can confirm and precisely indicate peripheral hemifacial spasm. PMID- 26250882 TI - E-Cigarette Uptake Amongst UK Youth: Experimentation, but Little or No Regular Use in Nonsmokers. PMID- 26250883 TI - Is recommending breaks in sedentary behavior effective for improving health related outcomes? PMID- 26250884 TI - Lymph node identification following neoadjuvant therapy in rectal cancer: A stage stratified analysis using the surveillance, epidemiology, and end results (SEER) medicare database. AB - BACKGROUND AND OBJECTIVES: Neoadjuvant chemoradiation (nCRT) for rectal adenocarcinoma reduces lymph node (LN) identification following surgical resection. We sought to evaluate the relationship between LN identification following nCRT and disease-specific survival (DSS), stratified by pathologic stage. METHODS: The SEER-Medicare database (2000-2009) was queried for 1,216 pathologic stage I-III rectal cancer patients who underwent nCRT followed by curative-intent resection. Cox regressions evaluated the association between pathologic stage and DSS for LN cut-points from >=2 up to >=12 LNs. RESULTS: Extent of LN identification did not influence DSS in ypStage I or ypStage III disease; in particular, the 12 LN cut-point was not associated with DSS for ypStage I (HR 1.29, P = 0.51) or ypStage III (HR 1.08, P = 0.42) patients. In ypStage II patients, actuarial survival improved continually with increasing lymph node identification up to >=12 LNs. The 5 LN cut-point was associated with the greatest reduction of risk of cancer death (HR 0.56, P = 0.006), with decreasing magnitudes of survival benefit associated with nodal counts beyond 5 LN. The 12 LN cut-point was not associated with DSS in ypStage II patients (HR 0.67, P = 0.07). CONCLUSION: The association between DSS and LN identification is a dynamic outcome that varies by pathologic stage, with unique prognostic significance for ypStage II patients. PMID- 26250885 TI - Effects of Emotional Facial Expression on Time Perception in Patients with Parkinson's Disease. AB - Previous studies have demonstrated that emotional facial expressions alter temporal judgments. Moreover, while some studies conducted with Parkinson's disease (PD) patients suggest dysfunction in the recognition of emotional facial expression, others have shown a dysfunction in time perception. In the present study, we investigate the magnitude of temporal distortions caused by the presentation of emotional facial expressions (anger, shame, and neutral) in PD patients and controls. Twenty-five older adults with PD and 17 healthy older adults took part in the present study. PD patients were divided into two sub groups, with and without mild cognitive impairment (MCI), based on their neuropsychological performance. Participants were tested with a time bisection task with standard intervals lasting 400 ms and 1600 ms. The effect of facial emotional stimuli on time perception was evident in all participants, yet the effect was greater for PD-MCI patients. Furthermore, PD-MCI patients were more likely to underestimate long and overestimate short temporal intervals than PD non-MCI patients and controls. Temporal impairment in PD-MCI patients seem to be mainly caused by a memory dysfunction. (JINS, 2016, 22, 890-899). PMID- 26250887 TI - Reduction of prostaglandin transporter predicts poor prognosis associated with angiogenesis in gastric adenocarcinoma. AB - BACKGROUND AND AIM: Prostaglandin (PG) E2 promotes gastrointestinal carcinogenesis and tumor progression. The total amount of biologically active PGE2 in tissues is determined by a balance of PG biosynthesis and degradation pathways, which involve the PG transporter (PGT). We investigated PGT in gastric adenocarcinoma by determining its expression pattern and examining associations of PGT with prognosis and tumor angiogenesis. METHODS: PGT expression was determined by immunohistochemistry in advanced gastric adenocarcinoma specimens obtained from 96 patients who underwent surgical resection. Correlations between PGT expression level and clinicopathological factors were statistically analyzed. Angiogenesis in the tumor tissue was evaluated by counting the number of microvessels. The role of PGT in mRNA and protein expression of vascular endothelial growth factor (VEGF) was examined in gastric cancer cells stimulated by PGE2 . RESULTS: Based on multivariate and Kaplan-Meier analyses, negativity for PGT expression was an independent poor prognostic factor. There were more microvessels in PGT-negative tumors than in PGT-positive tumors. Transfection of AGS and MKN7 gastric cancer cells with PGT-specific siRNA led to increased VEGF mRNA and protein expression accompanied by increased PGE2 in the culture media. CONCLUSIONS: PGT expression is an independent predictor of poor survival and is associated with tumor angiogenesis in gastric adenocarcinoma. PMID- 26250886 TI - Neuronal connectivity between habenular glutamate-kisspeptin1 co-expressing neurons and the raphe 5-HT system. AB - The habenula, located on the dorsal thalamic surface, is an emotional and reward processing center. As in the mammalian brain, the zebrafish habenula is divided into dorsal (dHb) and ventral (vHb) subdivisions that project to the interpeduncular nucleus and median raphe (MR) respectively. Previously, we have shown that kisspeptin 1 (Kiss1) expressing in the vHb, regulates the serotonin (5 HT) system in the MR. However, the connectivity between the Kiss1 neurons and the 5-HT system remains unknown. To resolve this issue, we generated a specific antibody against zebrafish Kiss1 receptor (Kiss-R1); using this primary antibody we found intense immunohistochemical labeling in the ventro-anterior corner of the MR (vaMR) but not in 5-HT neurons, suggesting the potential involvement of interneurons in 5-HT modulation by Kiss1. Double-fluorescence labeling showed that the majority of habenular Kiss1 neurons are glutamatergic. In the MR region, Kiss1 fibers were mainly seen in close association with glutamatergic neurons and only scarcely within GABAergic and 5-HT neurons. Our findings indicate that the habenular Kiss1 neurons potentially modulate the 5-HT system primarily through glutamatergic neurotransmission via as yet uncharacterized interneurons. The neuropeptide kisspeptin (Kiss1) play a key role in vertebrate reproduction. We have previously shown modulatory role of habenular Kiss1 in the raphe serotonin (5-HT) systems. This study proposed that the habenular Kiss1 neurons modulate the 5-HT system primarily through glutamatergic neurotransmission, which provides an important insight for understanding of the modulation of 5-HT system by the habenula-raphe pathway. PMID- 26250889 TI - Biochemical and morphological alterations of the extracellular matrix of chicken calcaneal tendon during maturation. AB - The region in tendons that surrounds bone extremities adapts to compression forces, developing a fibrocartilaginous structure. During maturation, changes occur in the amount and organization of macromolecules of the extracellular matrix of tendons, changing the tissue morphology. To study the effect of maturation on tendons, Pedres chickens were sacrificed at 1, 5, and 8 months old and had the calcaneal tendon (CT) divided into proximal region, submitted to tension/compression forces (p), and distal region submitted to tension force (d). Morphological analysis of the p region showed the presence of fibrocartilage in all ages. In the central part of the fibrocartilage, near a diminishment of the metachromasy, there was also a development of a probable fat pad that increased with the maturation. The activity of MMP-2 and MMP-9 was higher at 5 and 8 months old, in both regions, compared with 1-month-old animals. In SDS-PAGE analysis, components with electrophoretic migration similar to decorin and fibromodulin increased with maturation, particularly in the d region. The Western blotting confirmed the increased amount of fibromodulin with maturation. In conclusion, our results show that process of maturation leads to the appearance of a probable fat pad in the center of the fibrocartilage of CT, with a reduced amount of glycosaminoglycans and an increased activity of MMPs. PMID- 26250888 TI - Clinical exome sequencing in neurogenetic and neuropsychiatric disorders. AB - Exome sequencing has recently been elevated to the standard of care for genetic diagnostic testing, particularly for genetically diverse and clinically heterogeneous disorders. This review provides a clinically oriented discussion of the next-generation sequencing technology that makes exome sequencing possible and how such technology is applied to the diagnosis of Mendelian disease, including clinically significant de novo variation, interpretation of variants of uncertain clinical significance, the future potential for genetic assessments of disease risk, and the substantial benefits in diagnostic efficiency. Important caveats are also discussed, including the implications of incidental or secondary findings detected during exome sequencing and the relationship of exome sequencing to other methods of clinical genomic testing, such as chromosomal microarray and genome sequencing. Overall, the widespread adoption and use of exome sequencing in routine clinical practice is expected to improve diagnosis rates and reduce test costs, while leading to improvements in patient outcomes and a renewed emphasis on disease management. PMID- 26250890 TI - Stereolability of chiral ruthenium catalysts with frozen NHC ligand conformations investigated by dynamic-HPLC. AB - The stereolability of chiral Hoveyda-Grubbs II type ruthenium complexes bearing N heterocyclic carbene (NHC) ligands with Syn-phenyl groups on the backbone and Syn or Anti-oriented o-tolyl N-substituents was studied by resorting to dynamic high performance liquid chromatography (D-HPLC). A complete chromatographic picture of the involved stereoisomers (four for Anti- and two for Syn-complexes) was achieved at very low temperatures (-53 degrees C and -40 degrees C respectively), at which the NHC-Ru bond rotations were frozen out. Inspection of the chromatographic profiles recorded at higher temperatures revealed the presence of plateau zones between the couples of either Syn or Anti stereoisomers, attesting to the active interconversion between the eluted species. Such dynamic chromatograms were successfully simulated through procedures based on both theoretical plate and classical stochastic models. The good superimposition achieved between experimental and simulated chromatographic profiles allowed determination of the related isomerization energy barriers (DeltaGisom (#) ), all derived by rotation around the NHC-Ru bond. The obtained diastereomerization barriers between the Anti isomers were found in very good agreement with those previously measured by experimental nuclear magnetic resonance (NMR) and assessed through Density Functional Theory (DFT) calculations. With the same approach, for the first time we also determined the enantiomerization barrier of the Syn isomer. Focused changes to the structure of complex Syn, studied by a molecular modeling approach, were found suitable to strongly reduce the stereolability arising from rotation around the NHC-Ru bond. PMID- 26250891 TI - Determination of Prometryn in Vetiver Grass and Water Using Gas Chromatography Nitrogen Chemiluminescence Detection. AB - Nitrogen chemiluminescence detector (NCD) is a nitrogen-specific detector that responds to ammonia, hydrazine, hydrogen cyanide and nitrogen oxide. A method to analyze the herbicide prometryn in plant and water samples was developed using gas chromatograph (GC) coupled with NCD. Extracts from plant (vetiver grass) and water matrices were analyzed for prometryn using an Agilent 7890A GC coupled with an Agilent 255 NCD in a split injection mode with a ratio of 2 : 1. Separation was carried out at 200 degrees C and combustion at 1,018 degrees C with H2 and O2 following optimized method development conditions. The percent recovery of prometryn in the two different matrices tested ranged from 81 to 107%, with relative standard deviations varying from 0.10 to 3.30% for spiked samples. Detection limit of the proposed method was 0.02 ug mL(-1) and the limit of quantification was 0.06 ug mL(-1). The proposed GC-NCD method was successfully applied to determine prometryn extracted from plant and water samples without potential interference of S-triazine, a pesticide from the same group. PMID- 26250892 TI - Prednisolone does not affect direct-acting antivirals against hepatitis C, but inhibits interferon-alpha production by plasmacytoid dendritic cells. AB - BACKGROUND: Chronic hepatitis C virus (HCV) infection compromises long-term outcomes of liver transplantation. Although glucocorticosteroid-based immunosuppression is commonly used, discussion is ongoing on the effect of prednisolone (Pred) on HCV recurrence and response to antiviral therapy post transplantation. Recently, new drugs (direct-acting antivirals) have been approved for the treatment of HCV, however, it remains unknown whether their antiviral activity is affected by Pred. The aim of this study was to investigate the effects of Pred on the antiviral activity of asunaprevir (Asu), daclatasvir (Dac), ribavirin (RBV), and interferon-alpha (IFN-alpha), and on plasmacytoid dendritic cells (PDCs), the main IFN-alpha-producing immune cells. METHODS: The effects of Pred and antiviral compounds were tested in both a subgenomic and infectious HCV replication model. Furthermore, effects were tested on human PDCs stimulated with a Toll-like receptor-7 ligand. RESULT: Pred did not directly affect HCV replication and did not inhibit the antiviral action of Asu, Dac, RBV, or IFN-alpha. Stimulated PDCs potently suppressed HCV replication. This suppression was reversed by treating PDCs with Pred. Pred significantly decreased IFN-alpha production by PDCs without affecting cell viability. When Asu and Dac were combined with PDCs, a significant cooperative antiviral effect was observed. CONCLUSION: This study shows that Pred acts on the antiviral function of PDCs. Pred does not affect the antiviral action of Asu, Dac, RBV, or IFN-alpha. This implies that there is no contraindication to combine antiviral therapies with Pred in the post-transplantation management of HCV recurrence. PMID- 26250893 TI - High Expression Levels of Trigger Receptor Expressed on Myeloid Cells-1 on Neutrophils Associated with Increased Severity of Acute Pancreatitis in Mice. AB - Triggering receptor expressed on myeloid cells (TREM)-1 expression on neutrophils is associated with inflammation and infection. However, the dynamic changes of the TREM-1 expression on neutrophils have not been clarified in inflammatory acute pancreatitis (AP). The aim of this study was to longitudinally investigate the TREM-1 expression on peripheral blood and peritoneal neutrophils and its relationship with the levels of plasma cytokines and disease severity in a mouse model of AP following injection with varying doses of L-arginine to induce mild AP (MAP) or severe AP (SAP). The results indicated that induction of MAP or SAP was associated with moderate and severe pancreatic tissue damage and varying levels of serum and peritoneal fluid amylase as well as survival rates in mice. In comparison with that in the healthy controls, significantly increased percentages of peripheral blood and peritoneal fluid CD14-TREM-1(+) neutrophils and higher levels of TREM-1 mRNA transcripts in peripheral blood nuclear cells were detected in the MAP and SAP mice, particularly in the SAP mice. Higher levels of plasma tumor necrosis factor (TNF)-alpha and granulocyte-macrophage colony stimulating factor (GM-CSF), but lower levels of plasma interleukin (IL) 10, were detected in the MAP and SAP mice at varying time points post induction. The percentages of peripheral blood CD14-TREM-1(+) neutrophils were correlated positively with the levels of TNF-alpha, GM-CSF, and amylase as well as the pathogenic scores, but negatively with the levels of IL-10 in the AP mice. Therefore, TREM-1(+) neutrophils may participate in the pathogenesis of AP and serve as a biomarker for evaluating the severity of AP. PMID- 26250894 TI - Changes in the expression of collapsin response mediator protein-2 during synaptic plasticity in the mouse hippocampus. AB - We have previously reported that nicotine application to the adult mouse causing long-term potentiation-like facilitation in vivo in the hippocampus can serve as a model of synaptic plasticity. The present study clarifies the involvement of collapsin response mediator protein-2 (CRMP2) in synaptic plasticity. CRMP2 was detected in hippocampal neurons of adult mice. The levels of CRMP2 mRNA and protein were increased 2-24 hr and 4-24 hr, respectively, after application of nicotine (3 mg/kg, i.p.), finally returning to the basal level by 48 hr. Furthermore, the ratio of phosphorylated CRMP2 (pCRMP2) at Thr514 residue, an inactive form, to total CRMP2 levels was not changed during synaptic plasticity expressed by nicotine, indicating an enhanced level of non-pCRMP2. This increase of CRMP2 was inhibited by blockade of nicotinic acetylcholine receptors (nAChRs) and required activation of both alpha4beta2 and alpha7 nAChRs. Although the level of ubiquitinated CRMP2 was increased 8 hr after nicotine treatment, the ratio of ubiquitinated CRMP2 to total CRMP2 protein was similar for nicotine-treated and nontreated mice. This study demonstrates that the expression of CRMP2 increases in hippocampal neurons during synaptic plasticity and that the increment is due mainly to mRNA expression. We propose that CRMP2, particularly non-pCRMP2, could contribute to long-lasting synaptic plasticity. PMID- 26250897 TI - Impact of gadolinium-based contrast agent in the assessment of Crohn's disease activity: Is contrast agent injection necessary? AB - PURPOSE: To determine whether magnetic resonance enterography (MRE) performed without intravenous contrast injection is diagnostically noninferior to conventional contrast-enhanced MRE (CE-MRE) in patients with Crohn's disease (CD). MATERIALS AND METHODS: This was an Institutional Review Board (IRB) approved retrospective study. Ninety-six patients (52 male and 44 female; 47.18 years +/- 13.6) with a diagnosis of CD underwent MRE at 1.5T including T2 weighted single-shot turbo-spin-echo, T2 -weighted spectral fat presaturation with inversion recovery (SPAIR), T1 -weighted balanced fast-field-echo MR sequences, and CE-MRE consisting in T1 -weighted breath-hold THRIVE 3D MRI sequences after administration of gadobenate dimeglumine (0.2 mL/kg of body weight). Unenhanced MRE, CE-MRE, and unenhanced MRE plus CE-MRE were reviewed in separate sessions with blinding by two readers in consensus, and subsequently by two other readers independently considering a subgroup of 20 patients. Crohn's Disease Endoscopic Index of Severity (CDEIS) and/or histologic analysis of the surgical specimen were considered as reference standards for the assessment of inflammatory activity. RESULTS: Patients revealed prevalently active (n = 55 patients) or quiescent CD (n = 41 patients). The agreement between unenhanced MRE vs. CE-MRE in interpreting active bowel inflammation was 96% (123/128 bowel segments; one-sided 95% confidence interval [CI], >94.4%). Unenhanced MRE vs. CE MRE vs. unenhanced MRE plus CE-MRE revealed a diagnostic accuracy of 93% [90/96] vs. 92% [88/96] vs. 97% [93/96] (P > 0.05) in the diagnosis of active CD. Interreader agreement was very good for all variables (kappa value = 0.8-0.9) except for the measurement of the length of disease (kappa value = 0.45). CONCLUSION: Unenhanced MRE was noninferior to CE-MRE in diagnosing active inflammation in patients with CD. PMID- 26250896 TI - Characterization of desmoglein-3 epitope region peptides as synthetic antigens: analysis of their in vitro T cell stimulating efficacy, cytotoxicity, stability, and their conformational features. AB - Desmoglein-3 (Dsg3) adhesion protein is the main target of autoantibodies and autoreactive T cells in Pemphigus vulgaris (PV) autoimmune skin disorder. Several mapping studies of Dsg3 T cell epitope regions were performed, and based on those data, we designed and synthesized four peptide series corresponding to Dsg3 T cell epitope regions. Each peptide series consists of a 17mer full-length peptide (Dsg3/189-205, Dsg3/206-222, Dsg3/342-358, and Dsg3/761-777) and its N-terminally truncated derivatives, resulting in 15 peptides altogether. The peptides were prepared on solid phase and were chemically characterized. In order to establish a structure-activity relationship, the solution conformation of the synthetic peptides has been investigated using electronic circular dichroism spectroscopy. The in vitro T cell stimulating efficacy of the peptides has been determined on peripheral blood mononuclear cells isolated from whole blood of PV patients and also from healthy donors. After 20 h of stimulation, the interferon (IFN)-gamma content of the supernatants was measured by enzyme-linked immunosorbent assay. In the in vitro conditions, peptides were stable and non-cytotoxic. The in vitro IFN gamma production profile of healthy donors and PV patients, induced by peptides as synthetic antigens, was markedly different. The most unambiguous differences were observed after stimulation with 17mer peptide Dsg3/342-358, and three truncated derivatives from two other peptide series, namely, peptides Dsg3/192 205, Dsg3/763-777, and Dsg3/764-777. Comparative analysis of in vitro activity and the capability of oligopeptides to form ordered or unordered secondary structure showed that peptides bearing high solvent sensibility and backbone flexibility were the most capable to distinguish between healthy and PV donors. PMID- 26250895 TI - Child and adolescent psychiatry: which knowledge and skills do primary care physicians need to have? A survey in general practitioners and paediatricians. AB - Primary care physicians (PCPs) play a key role in the initial assessment and management of children and adolescents with mental health problems. However, it is unclear whether current medical education curricula sufficiently equip PCPs for this task. The aim of this study was to investigate, which child and adolescent psychiatry (CAP)-related skills and knowledge PCPs say they require in their daily practice. A questionnaire was generated, employing a modified two step Delphi approach. Besides socio-demographic items, the questionnaire contained 17 CAP-related knowledge items and 13 CAP-related skills items, which had to be rated by importance in daily practice. The questionnaire was distributed to 348 office-based paediatricians and 500 general practitioners (GPs) in Germany. The overall return rate was 51.3% (435/848). Regarding CAP related knowledge, both paediatricians and GPs rated somatoform disorders and obesity as highly important for daily practice. Moreover, paediatricians also deemed regulatory disorders during infancy (e.g. crying, sleep disorders) as important, while GPs assessed knowledge on paediatric depression as relevant. For paediatricians and GPs, the most relevant CAP-related skills were communicating with children and adolescents and their parents. Additionally, paediatricians rated differentiating between non-pathologic and clinically relevant behaviour problems very relevant, while GPs considered basic psychotherapeutic skills essential. The CAP-related knowledge and skills perceived relevant for doctors in primary care differ from the majority of current medical school CAP curricula, which cover mainly typical, epitomic CAP disorders and are predominantly knowledge-oriented. Therefore, medical education in CAP should be amended to reflect the needs of PCPs to improve healthcare for children and adolescents with mental health problems. PMID- 26250898 TI - Bone Ceramic(r) at Implants Installed Immediately into Extraction Sockets in the Molar Region: An Experimental Study in Dogs. AB - PURPOSE: The aim of this paper was to study the healing of 1-1.4 mm wide buccal defects at implants placed immediately into extraction sockets (IPIES) filled with a mixture of synthetic hydroxyapatite (HA) 60% and beta-tricalciumphosphate (TCP) 40% or left with the clot alone and both covered with collagen membranes. MATERIAL AND METHODS: Eight Labrador dogs were used and implants were placed immediately into the extraction sockets of the first molar bilaterally. A mixture of synthetic HA 60% and beta-TCP 40% at the test or the clot alone at the control sites were used to fill the defects. All surgical sites were subsequently covered by a resorbable collagen membrane and a non-submerged healing was allowed. After 4 months, the animals were euthanized, biopsies harvested and processed for histomorphometric analysis. RESULTS: At the time of installation, residual buccal defects occurred that were 1.1 mm and 1.4 mm wide and 3 mm and 4 mm deep at the control and test sites, respectively. After 4 months of healing, the top of the bony crest and the coronal level of osseointegration were located respectively at 0.1 +/- 1.8 mm and 1.5 +/- 1.8 mm at the test, and 0.6 +/- 1.6 mm and 1.2 +/- 0.7 mm at the control sites apically to the implant shoulder. Bone-to-implant contact at the buccal aspect was 34.9 +/- 25.9% and 36.4 +/- 17.3% at the test and control sites, respectively. No statistically significant differences were found between test and control sites for any of the variables analyzed at the buccal aspects. CONCLUSIONS: The use of a mixture of synthetic HA 60% and beta-TCP 40% to fill residual buccal defects 1-1.4 mm wide at IPIES did not improve significantly the results of healing. PMID- 26250899 TI - Plasma macrophage-stimulating protein and hepatocyte growth factor levels are associated with prostate cancer progression. AB - Hepatocyte growth factor (HGF) is a well-known multifunctional growth factor, and evidence has accumulated indicating that the HGF/MET (HGF receptor) signaling axis is involved in the progression of cancer. Macrophage-stimulating protein (MSP) is also known as a growth factor which activates not only macrophages but also cancer cells and osteoclasts through the activation of the specific Receptor d'origine nantais (RON). Pro-HGF and pro-MSP lack biological activity and, therefore, require proteolytic activation for conversion to an active two-chain form by HGF activator (HGFA). Although, there are several studies on HGF/MET signaling with castration-resistant prostate cancer (CRPC) and bone metastasis, reports on plasma protein are rare. In addition, the MSP/RON signaling axis in PC is not well understood. Here, we analyzed associations between PC progression and plasma HGF and MSP levels. We tested plasma samples from 58 patients with PC: 36 with castration-resistant (CR) PC and 22 with pretreatment for PC as control. We used enzyme-linked immunosorbent assay (ELISA) kit to determine plasma levels of HGF, MSP and HGFA, and examined correlations with clinicopathological characteristics such as Gleason grade and bone metastasis. PCR was used to evaluate HGF and MSP-related molecules in PC cell lines. Plasma levels of HGF, MSP and HGFA in the CRPC group were higher than in the control group (HGF: P < 0.001; MSP: P = 0.008; HGFA: P < 0.001). HGF and MSP levels were significantly correlated (P = 0.003). In the CRPC group, plasma HGF and MSP levels and Gleason score were not correlated; however, high plasma MSP level correlated with bone metastasis. (P = 0.016). In cell lines, PC3 expressed significantly more HGF, MET and RON than did LNCaP (P < 0.001), and both cell lines expressed MSP. Plasma concentrations of HGF, MSP and HGFA are significantly elevated in patients with CRPC. Also, as plasma MSP levels are significantly associated with bone metastasis in CRPC patients, MSP may be a candidate for serum marker of bone metastasis. Our results show the importance of the HGF/MET and MSP/RON signaling systems in CRPC. PMID- 26250900 TI - Current thinking on the mechanistic basis of Alzheimer's and implications for drug development. AB - Alzheimer disease (AD) is the most common cause of dementia and is characterized by the aggregation and accumulation of two proteins in the brain, amyloid-beta (Abeta) and tau. Abeta and tau begin to buildup 15-20 years before the clinical onset of AD dementia. Increasing evidence suggests that preventing or decreasing the amount of aggregated forms of both Abeta and tau in the brain can serve as potential disease-modifying treatments for AD. PMID- 26250901 TI - Ruthenium-Catalyzed Straightforward Synthesis of 1,2,3,4-Tetrahydronaphthyridines via Selective Transfer Hydrogenation of Pyridyl Ring with Alcohols. AB - Through a ruthenium-catalyzed selective hydrogen transfer coupling reaction, a novel straightforward synthesis of 1,2,3,4-tetrahydronaphthyridines from o aminopyridyl methanols and alcohols has been developed. The synthetic protocol proceeds in an atom- and step-economic fashion together with the advantages of operational simplicity, broad substrate scope, production of water as the only byproduct, and no need for external reducing reagents such as high pressure H2 gas, offering a highly practical approach for accessing this type of structurally unique products. PMID- 26250902 TI - Challenges in the translation and commercialization of cell therapies. AB - BACKGROUND: Cell therapies are an emerging form of healthcare that offer significant potential to improve the practice of medicine and provide benefits to patients who currently have limited or no treatment options. Ideally, these innovative therapies can complement existing small molecule, biologic and device approaches, forming a so-called fourth pillar of medicine and allowing clinicians to identify the best treatment approach for each patient. Despite this potential, cell therapies are substantially more complex than small molecule or biologic interventions. This complexity poses challenges for scientists and firms developing cell therapies and regulators seeking to oversee this growing area of medicine. RESULTS: In this project, we retrospectively examined the development of seven cell therapies - including three autologous interventions and four allogeneic interventions - with the aim of identifying common challenges hindering attempts to bring new cell therapies to market. We complemented this analysis with a series of qualitative interviews with experts in various aspects of cell therapy. Through our analysis, which included review of extant literature collected from company documents, newspapers, journals, analyst reports and similar sources, and analysis of the qualitative interviews, we identified several common challenges that cell therapy firms must address in both the pre- and post-market stages. Key pre-market challenges included identifying and maintaining stable funding to see firms through lengthy developmental timelines and uncertain regulatory processes. These challenges are not unique to cell therapies, of course, but the novelty of cell-based interventions complicates these efforts compared to small molecule or biologic approaches. The atypical nature of cell therapies also led to post-market difficulties, including challenges navigating the reimbursement process and convincing providers to change their treatment approaches. In addition, scaling up production, distributing cell therapies and managing the costs of production were challenges that started pre-market and continued into the post-market phase. CONCLUSIONS: Our analysis highlights several interrelated challenges hindering the development of cell therapies. Identifying strategies to address these challenges may accelerate the development and increase the impact of novel cell therapies. PMID- 26250903 TI - Hyperdynamic left ventricular ejection fraction in the intensive care unit. AB - INTRODUCTION: Limited information exists on the etiology, prevalence, and significance of hyperdynamic left ventricular ejection fraction (HDLVEF) in the intensive care unit (ICU). Our aim in the present study was to compare characteristics and outcomes of patients with HDLVEF with those of patients with normal left ventricular ejection fraction in the ICU using a large, public, deidentified critical care database. METHODS: We conducted a longitudinal, single center, retrospective cohort study of adult patients who underwent echocardiography during a medical or surgical ICU admission at the Beth Israel Deaconess Medical Center using the Multiparameter Intelligent Monitoring in Intensive Care II database. The final cohort had 2867 patients, of whom 324 had HDLVEF, defined as an ejection fraction >70%. Patients with an ejection fraction <55% were excluded. RESULTS: Compared with critically ill patients with normal left ventricular ejection fraction, the finding of HDLVEF in critically ill patients was associated with female sex, increased age, and the diagnoses of hypertension and cancer. Patients with HDLVEF had increased 28-day mortality compared with those with normal ejection fraction in multivariate logistic regression analysis adjusted for age, sex, Sequential Organ Failure Assessment score, Elixhauser score for comorbidities, vasopressor use, and mechanical ventilation use (odds ratio 1.38, 95% confidence interval 1.039-1.842, p =0.02). CONCLUSIONS: The presence of HDLVEF portended increased 28-day mortality, and may be helpful as a gravity marker for prognosis in patients admitted to the ICU. Further research is warranted to gain a better understanding of how these patients respond to common interventions in the ICU and to determine if pharmacologic modulation of HDLVEF improves outcomes. PMID- 26250904 TI - Anti-Mullerian-Hormone during pregnancy and peripartum using the new Beckman Coulter AMH Gen II Assay. AB - BACKGROUND: AMH levels determined by the conventional AMH assay declined during pregnancy and postpartum. A new Beckman Coulter AMH Gen II assay removes the potentially assay-interfering complement which is activated in pregnancy. The aim of this study was to evaluate if the decline of AMH levels in the serum of pregnant women during the course of pregnancy and peripartum was assay-dependent and thus artificial. METHODS: In this cross-sectional study prepartal blood samples were collected from 62 patients (median age 30.6 years [interquartile range: 25.6 - 34.5]) in the third trimester of pregnancy and again 1-4 days after delivery between 2011 and 2012. In another cohort of 11 patients (median age 34.1 years [interquartile range: 32.6 - 37.8]) blood samples were taken in different trimesters of pregnancy between 1995 and 2001. The conventional and the modified AMH assay were performed in the same patient serum samples. We used the conventional and the modified AMH-Gen-II ELISA (Beckman Coulter, Immunotech, Webster, USA) for the assessment of AMH levels. The Wilcoxon signed rank test was used for determining differences between AMH levels pre- and postpartum. The method of Bland and Altman was applied for analyzing the agreement of both methods for determining AMH levels. RESULTS: AMH values peripartum were lower than those expected in fertile non-pregnant women of comparable age. An overall mean difference of 0.44 ng/ml was observed between the conventional and the modified assay. Measurements with the modified assay showed a significant decline of postpartal levels compared with prepartal levels which is consistent with values obtained using the conventional assay (both p < 0.00001). Compared to the longitudinal measurements of AMH levels determined using the conventional assay, AMH levels obtained using the modified assay suggest a steeper decline of values during the course of pregnancy. CONCLUSION: By comparing the conventional assay for AMH determination with the modified assay the present study confirmed that AMH levels decline during the course of pregnancy and early after delivery. PMID- 26250905 TI - Putative type 1 thymidylate synthase and dihydrofolate reductase as signature genes of a novel Bastille-like group of phages in the subfamily Spounavirinae. AB - BACKGROUND: Spounavirinae viruses have received an increasing interest as tools for the control of harmful bacteria due to their relatively broad host range and strictly virulent phenotype. RESULTS: In this study, we collected and analyzed the complete genome sequences of 61 published phages, either ICTV-classified or candidate members of the Spounavirinae subfamily of the Myoviridae. A set of comparative analyses identified a distinct, recently proposed Bastille-like phage group within the Spounavirinae. More importantly, type 1 thymidylate synthase (TS1) and dihydrofolate reductase (DHFR) genes were shown to be unique for the members of the proposed Bastille-like phage group, and are suitable as molecular markers. We also show that the members of this group encode beta-lactamase and/or sporulation-related SpoIIIE homologs, possibly questioning their suitability as biocontrol agents. CONCLUSIONS: We confirm the creation of a new genus--the "Bastille-like group"--in Spounavirinae, and propose that the presence of TS1- and DHFR-encoding genes could serve as signatures for the new Bastille-like group. In addition, the presence of metallo-beta-lactamase and/or SpoIIIE homologs in all members of Bastille-like group phages makes questionable their suitability for use in biocontrol. PMID- 26250906 TI - In vitro method for the screening and monitoring of estrogen-deficiency osteoporosis by targeting peripheral circulating monocytes. AB - Bone loss occurs insidiously and initially asymptomatically; therefore, osteoporosis is frequently diagnosed only after the first clinical fracture. The aim of this study was to test the hypothesis is that by simply observing the behavior of cultured peripheral monocytes, it might be possible to diagnose altered bone remodeling and, therefore, limit the complications associated with osteoporosis, especially fractures. Monocytes isolated as mononuclear precursors from healthy and ovariectomized rats were cultured both in basal and differentiation medium for up to 3 weeks. Viability and differentiation capability towards the osteoclastic phenotype was checked by light microscopy at early times, whereas differentiation state and synthetic activity (tartrate resistant acid phosphatase (TRAP) staining; phalloidin, fluorescin isothiocynate (FITC) staining, cathepsin K, metalloproteinase 7 and 9, MMP-7 and MMP-9) were measured at 1, 2, and 3 weeks. Compared to their controls, monocytes isolated from ovariectomized rats proliferate and lean toward the osteoclastic phenotype in the absence of differentiating factors. In both culture conditions, osteoclasts from ovariectomized rats showed significantly higher productions of cathepsin K, MMP-7, and MMP-9 than those of cells isolated from healthy rats, steadily over time. These results obtained in an animal osteoporotic model, if confirmed by clinical studies, open up the possibility to assess the presence of an alteration in bone remodeling with a simple in vitro diagnostic test requiring a small blood sample and less than 48 h. This might allow to early select patients with a spontaneous viability and differentiation of monocytes to osteoclasts for further diagnostic techniques. PMID- 26250907 TI - A comparison of melatonin and alpha-lipoic acid in the induction of antioxidant defences in L6 rat skeletal muscle cells. AB - Aging is characterized by a progressive deterioration in physiological functions and metabolic processes. The loss of cells during aging in vital tissues and organs is related to several factors including oxidative stress and inflammation. Skeletal muscle degeneration is common in elderly people; in fact, this tissue is particularly vulnerable to oxidative stress since it requires large amounts of oxygen, and thus, oxidative damage is abundant and accumulates with increasing age. Melatonin (N-acetyl-5-methoxytryptamine) is a highly efficient scavenger of reactive oxygen species and it also exhibits beneficial anti-inflammatory and anti-aging effects. This study investigated the susceptibility of rat L6 skeletal muscle cells to an induced oxidative stress following their exposure to hydrogen peroxide (50 MUM) and evaluating the potential protective effects of pre treatment with melatonin (10 nM) compared to the known beneficial effect of alpha lipoic acid (300 MUM). Hydrogen peroxide-induced obvious oxidative stress; it increased the expression of tumour necrosis factor-alpha and in turn promoted nuclear factor kappa-B and overrode the endogenous defence mechanisms. Conversely, pre-treatment of the hydrogen peroxide-exposed cells to melatonin or alpha-lipoic acid increased endogenous antioxidant enzymes, including superoxide dismutase-2 and heme oxygenase-1; moreover, they ameliorated significantly oxidative stress damage and partially reduced alterations in the muscle cells, which are typical of aging. In conclusion, melatonin was equally effective as alpha-lipoic acid; it exhibited marked antioxidant and anti-aging effects at the level of skeletal muscle in vitro even when it was given in a much lower dose than alpha-lipoic acid. PMID- 26250908 TI - Heparan sulfation is essential for the prevention of cellular senescence. AB - Cellular senescence is considered as an important tumor-suppressive mechanism. Here, we demonstrated that heparan sulfate (HS) prevents cellular senescence by fine-tuning of the fibroblast growth factor receptor (FGFR) signaling pathway. We found that depletion of 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2), a synthetic enzyme of the sulfur donor PAPS, led to premature cell senescence in various cancer cells and in a xenograft tumor mouse model. Sodium chlorate, a metabolic inhibitor of HS sulfation also induced a cellular senescence phenotype. p53 and p21 accumulation was essential for PAPSS2-mediated cellular senescence. Such senescence phenotypes were closely correlated with cell surface HS levels in both cancer cells and human diploid fibroblasts. The determination of the activation of receptors such as FGFR1, Met, and insulin growth factor 1 receptor beta indicated that the augmented FGFR1/AKT signaling was specifically involved in premature senescence in a HS-dependent manner. Thus, blockade of either FGFR1 or AKT prohibited p53 and p21 accumulation and cell fate switched from cellular senescence to apoptosis. In particular, desulfation at the 2-O position in the HS chain contributed to the premature senescence via the augmented FGFR1 signaling. Taken together, we reveal, for the first time, that the proper status of HS is essential for the prevention of cellular senescence. These observations allowed us to hypothesize that the FGF/FGFR signaling system could initiate novel tumor defenses through regulating premature senescence. PMID- 26250909 TI - Ligand-independent requirements of steroid receptors EcR and USP for cell survival. AB - The active form of the Drosophila steroid hormone ecdysone, 20-hydroxyecdysone (20E), binds the heterodimer EcR/USP nuclear receptor to regulate target genes that elicit proliferation, cell death and differentiation during insect development. Although the 20E effects are relatively well known, the physiological relevance of its receptors remains poorly understood. We show here that the prothoracic gland (PG), the major steroid-producing organ of insect larvae, requires EcR and USP to survive in a critical period previous to metamorphosis, and that this requirement is 20E-independent. The cell death induced by the downregulation of these receptors involves the activation of the JNK-encoding basket gene and it can be rescued by upregulating EcR isoforms which are unable to respond to 20E. Also, while PG cell death prevents ecdysone production, blocking hormone synthesis or secretion in normal PG does not lead to cell death, demonstrating further the ecdysone-independent nature of the receptor deprivation cell death. In contrast to PG cells, wing disc or salivary glands cells do not require these receptors for survival, revealing their cell and developmental time specificity. Exploring the potential use of this feature of steroid receptors in cancer, we assayed tumor overgrowth induced by altered yorkie signaling. This overgrowth is suppressed by EcR downregulation in PG, but not in wing disc, cells. The mechanism of all these cell death features is based on the transcriptional regulation of reaper. These novel and context-dependent functional properties for EcR and USP receptors may help to understand the heterogeneous responses to steroid-based therapies in human pathologies. PMID- 26250912 TI - Reference Intervals in Neonatal Hematology. AB - The various blood cell counts of neonates must be interpreted in accordance with high-quality reference intervals based on gestational and postnatal age. Using very large sample sizes, we generated neonatal reference intervals for each element of the complete blood count (CBC). Knowledge of whether a patient has CBC values that are too high (above the upper reference interval) or too low (below the lower reference interval) provides important insights into the specific disorder involved and in many instances suggests a treatment plan. PMID- 26250910 TI - Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization. AB - The MICOS complex (mitochondrial contact site and cristae organizing system) is essential for mitochondrial inner membrane organization and mitochondrial membrane contacts, however, the molecular regulation of MICOS assembly and the physiological functions of MICOS in mammals remain obscure. Here, we report that Mic60/Mitofilin has a critical role in the MICOS assembly, which determines the mitochondrial morphology and mitochondrial DNA (mtDNA) organization. The downregulation of Mic60/Mitofilin or Mic19/CHCHD3 results in instability of other MICOS components, disassembly of MICOS complex and disorganized mitochondrial cristae. We show that there exists direct interaction between Mic60/Mitofilin and Mic19/CHCHD3, which is crucial for their stabilization in mammals. Importantly, we identified that the mitochondrial i-AAA protease Yme1L regulates Mic60/Mitofilin homeostasis. Impaired MICOS assembly causes the formation of 'giant mitochondria' because of dysregulated mitochondrial fusion and fission. Also, mtDNA nucleoids are disorganized and clustered in these giant mitochondria in which mtDNA transcription is attenuated because of remarkable downregulation of some key mtDNA nucleoid-associated proteins. Together, these findings demonstrate that Mic60/Mitofilin homeostasis regulated by Yme1L is central to the MICOS assembly, which is required for maintenance of mitochondrial morphology and organization of mtDNA nucleoids. PMID- 26250913 TI - Neonatal Transfusion Medicine: Five Major Unanswered Research Questions for the Twenty-First Century. AB - Blood component transfusions are important to the care of preterm neonates; however, their use in clinical practice often is not based on high levels of evidence. Five major questions for neonates are discussed: (1) What is the optimal red blood cell (RBC) transfusion threshold? (2) What is the optimal platelet transfusion threshold? (3) Does the storage age of an RBC unit affect outcomes? (4) Does RBC transfusion contribute to the pathogenesis of necrotizing enterocolitis? and (5) Which new practices should be used to prevent transfusion transmitted infections? Although definitive answers to these questions do not exist, future research should help answer them. PMID- 26250911 TI - Erythropoietin and Neonatal Neuroprotection. AB - Certain groups of neonates are at high risk of developing long-term neurodevelopmental impairment and might be considered candidates for neuroprotective interventions. This article explores some of these high-risk groups, relevant mechanisms of brain injury, and specific mechanisms of cellular injury and death. The potential of erythropoietin (Epo) to act as a neuroprotective agent for neonatal brain injury is discussed. Clinical trials of Epo neuroprotection in preterm and term infants are updated. PMID- 26250914 TI - Hemolytic Disorders Causing Severe Neonatal Hyperbilirubinemia. AB - A shortened erythrocyte life span, because of hemolytic disorders, is a common cause of extreme neonatal hyperbilirubinemia. Clinical and laboratory examinations can frequently identify the underlying cause of extreme neonatal hyperbilirubinemia. In this article, several tests, techniques, and approaches have been reviewed, including red blood cell morphology assessment, end-tidal carbon monoxide quantification, eosin-5-maleimide flow cytometry, as well as next generation DNA sequencing using neonatal jaundice panels. PMID- 26250915 TI - Plasma Biomarkers of Oxidative Stress in Neonatal Brain Injury. AB - Perinatal encephalopathy is a leading cause of lifelong disability. Increasing evidence indicates that the pathogenesis of perinatal brain damage is much more complex than originally thought, with multiple pathways involved. An important role of oxidative stress (OS) in the pathogenesis of brain injury is recognized for preterm and term infants. This article examines potential reliable and specific OS biomarkers that can be used in premature and term infants for the early detection and follow-up of the most common neonatal brain injuries, such as hypoxic-ischemic encephalopathy, intraventricular hemorrhage, and periventricular leukomalacia. The next step will be to explore the correlation between brain specific OS biomarkers and functional brain outcomes. PMID- 26250916 TI - Umbilical Cord Blood-An Untapped Resource: Strategies to Decrease Early Red Blood Cell Transfusions and Improve Neonatal Outcomes. AB - Umbilical cord blood is a resource that is available to all neonates. Immediately after delivery of the fetus, cord blood can be used for the direct benefit of the premature infant. Delayed cord clamping and milking of the umbilical cord are 2 methods of transfusing additional fetal blood into the neonate after vaginal or cesarean delivery. Additionally, umbilical cord blood can be utilized for neonatal admission laboratory testing rather than direct neonatal phlebotomy. Together these strategies both increase initial neonatal total blood volume and limit immediate loss through phlebotomy. PMID- 26250917 TI - Darbepoetin Administration in Term and Preterm Neonates. AB - Erythropoiesis-stimulating agents (ESAs) such as erythropoietin have been studied as red cell growth factors in preterm and term infants for more than 20 years. Recent studies have evaluated darbepoetin (Darbe, a long-acting ESA) for both erythropoietic effects and potential neuroprotection. We review clinical trials of Darbe in term and preterm infants, which have reported significant erythropoietic uses and neuroprotective effects. ESAs show great promise in decreasing or eliminating transfusions, and in preventing and treating brain injury in term and preterm infants. PMID- 26250919 TI - Hematologic Aspects of Early and Late-Onset Sepsis in Preterm Infants. AB - This article reviews and updates the state of the art on the hematologic aspects related to neonatal sepsis in preterm neonates in the neonatal intensive care unit and overviews all hematologic changes occurring during neonatal infections and their implications both as diagnostic and prognostic parameters to guide clinicians at the patients' bedside. PMID- 26250918 TI - Immunologic and Hematological Abnormalities in Necrotizing Enterocolitis. AB - Necrotizing enterocolitis (NEC) is a leading cause of mortality in preterm infants. This article reviews the immunologic and hematological abnormalities typically seen in infants with NEC, such as elevated plasma cytokine levels, thrombocytopenia, increased or decreased neutrophil counts, low monocyte counts, and anemia. Some of these findings may provide important diagnostic and prognostic information. PMID- 26250921 TI - Platelet Transfusions in the Neonatal Intensive Care Unit. AB - There is significant world-wide variability in platelet transfusion thresholds used to transfuse thrombocytopenic neonates. A large multicenter randomized controlled trial comparing 2 different platelet transfusion thresholds in neonates is currently ongoing, and should provide data to guide transfusion practice. However, several studies have found that factors other than the degree of thrombocytopenia determine the bleeding risk. Thus, it will be important to develop better tests to assess primary hemostasis and bleeding risk in neonates. PMID- 26250920 TI - Stem Cells: Potential Therapy for Neonatal Injury? AB - Stem cell transplantation (SCT) is an established first-line or adjunctive therapy for a variety of neonatal and adult diseases. New evidence in preclinical models as well as a few human studies show the potential utility of SCT in neuroprotection and in the modulation of inflammatory injury in at risk-neonates. This review briefly summarizes current understanding of human stem cell biology during ontogeny and present recent evidence supporting SCT as a viable approach for postinsult neonatal injury. PMID- 26250922 TI - Neonatal Platelet Function. AB - Similarly to the development of the plasma coagulation system, which matures during the early weeks and months of life, age-dependent mechanisms and developmental changes influence platelet production and function in neonates. Platelet function testing on cord blood and peripheral blood demonstrates a generalized platelet hyporeactivity, during the first days of life. This reactivity reaches normal adult levels between the fifth and ninth day of life. The persistence of hyporeactivity after the tenth day of life might indeed suggest a platelet disorder. PMID- 26250923 TI - Fresh Frozen Plasma Administration in the Neonatal Intensive Care Unit: Evidence Based Guidelines. AB - Neonates receiving fresh frozen plasma (FFP) should do so according to evidence based guidelines so as to reduce inappropriate use of this life-saving and costly blood product and to minimize associated adverse effects. The consensus-based uses of FFP in neonatology involve neonates with active bleeding and associated coagulopathy. However, because of limited and poor-quality evidence, considerable FFP utilization occurs outside these recommendations. In this review, we describe what we conclude are currently the best practices for the use of FFP in neonates, including interpreting neonatal coagulation tests and strategies for reducing unnecessary FFP transfusions. PMID- 26250924 TI - Thrombosis in the Neonatal Intensive Care Unit. AB - Neonates have the highest risk for pathologic thrombosis among pediatric patients. A combination of genetic and acquired risk factors significantly contributes to this risk, with the most important risk factor being the use of central venous catheters. Proper imaging is critical for confirming the diagnosis. Despite a significant number of these events being life- and limb threatening, there is limited evidence on what the appropriate management strategy should be. Evaluation and treatment of any neonate with a clinically significant thrombosis should occur at a tertiary referral center that has proper support. PMID- 26250925 TI - The Expanding Evidence Base to Guide Neonatal Hematology and Transfusion Medicine Practice. Preface. PMID- 26250926 TI - Neonatal Hematology and Transfusion Medicine: What We Can Learn from Pediatric Oncology Groups. PMID- 26250927 TI - Enhanced stability of the model mini-protein in amino acid ionic liquids and their aqueous solutions. AB - Using molecular dynamics simulations, the structure of model mini-protein was thoroughly characterized in the imidazolium-based amino acid ionic liquids and their aqueous solutions. Complete substitution of water by organic cations and anions further results in hindered conformational flexibility of the mini protein. This observation suggests that amino acid-based ionic liquids are able to defend proteins from thermally induced denaturation. We show by means of radial distributions that the mini-protein is efficiently solvated by both solvents due to a good mutual miscibility. Amino acid-based anions prevail in the first coordination sphere of positively charged sites of the mini-protein whereas water molecules prevail in the first coordination sphere of negatively charged sites of the mini-protein. PMID- 26250928 TI - Identifying Deteriorating Patients Through Multidisciplinary Team Training. AB - Multidisciplinary training has improved maternity outcomes when the training has been well attended, regular, in house, used high-fidelity simulators, and integrated teamwork training. If these principles were used in other settings, better clinical care may result. This before-after study sought to establish whether a short multidisciplinary training intervention can improve recognition of the deteriorating patient using an aggregated physiological parameter scoring system (Early Warning Score [EWS]). Nursing, medical, and allied nursing staff participated in an hour-long training session, using real-life scenarios with simple tools and structured debriefing. After training, staff were more likely to calculate EWS scores correctly (68.02% vs 55.12%; risk ratio [RR] = 1.24, 95% confidence interval [CI] = 1.07-1.44), and observations were more likely to be performed at the correct frequency (78.57% vs 68.09%; RR = 1.20, 95% CI = 1.09 1.32). Multidisciplinary training, according to core principles, can lead to more accurate identification of deteriorating patients, with implications for subsequent care and outcome. PMID- 26250929 TI - Off-Label Prescribing: Justified or Not? PMID- 26250930 TI - The VA Medical Foster Home Program, Ambulatory Care Sensitive Conditions, and Avoidable Hospitalizations. AB - This quality control study analyzes whether the Veterans Administration Medical Foster Home (VA MFH) program has been successful in improving access and effectiveness of ambulatory care. Individuals hospitalized for one or more of 22 adult ambulatory care sensitive conditions were identified. Pre and post comparisons of a specified population of participants in the program were conducted to determine rates of avoidable hospitalizations for 6 months prior to and following MFH enrollment. The overall rate of avoidable hospitalizations declined from 18.5 to 14.9 per 100 enrollees following enrollment. The number of bed days used declined by 39%, as did the cost associated with avoidable hospitalizations. Enrollment in the VA MFH program resulted in an overall reduction in the rate of avoidable hospitalizations, resource utilization, and costs. Studies are needed comparing these results with other matched cohorts of nursing home eligible veterans. PMID- 26250931 TI - [Long QT syndrome. History, genetics, clinical symptoms, causes and therapy]. AB - The long QT syndrome is caused by a change in cardiac repolarization due to functional ion channel defects. A differentiation is made between a congenital (cLQTS) and an acquired (aLQTS) form of the disease. The disease results in the name-giving prolongation of the QT interval in the electrocardiogram and represents a predisposition for cardiac arrhythmia and sudden cardiac death. This article summarizes the current knowledge on the history, pathophysiology, clinical symptoms and therapy of cLQTS and aLQTS. This knowledge of pathophysiological features of the symptoms allows the underlying anesthesiological approach for individualized perioperative concepts for patients suffering from LQTS to be derived. PMID- 26250932 TI - Teaching discriminated social approaches to individuals with Angelman syndrome. AB - Angelman syndrome is a neurogenetic disorder characterized by intellectual and developmental disability. Common behavioral characteristics of this disorder include a heightened interest in social interactions and frequent bids to initiate interaction. These bids can be problematic, for instance, when a child attempts to hug strangers in public places. The current study evaluated a discrimination training program to teach 3 boys with Angelman syndrome to discriminate appropriate from inappropriate times to initiate interactions. During baseline, we alternated periods in which attention was delivered following social initiations on a continuous reinforcement schedule with periods in which initiations were placed on extinction. We then implemented discrimination training by presenting a salient discriminative stimulus, prompting the occurrence of initiations, and providing reinforcement during reinforcement periods and withdrawing the stimulus during extinction periods. This resulted in discriminated approaches for each of the 3 participants; these results were replicated across caregivers and extended to the participants' homes. PMID- 26250933 TI - Objective Analysis of Impressed Chisel Toolmarks. AB - Historical and recent challenges to the practice of comparative forensic examination have created a driving force for the formation of objective methods for toolmark identification. In this study, fifty sequentially manufactured chisels were used to create impression toolmarks in lead (500 toolmarks total). An algorithm previously used to statistically separate known matching and nonmatching striated screwdriver marks and quasi-striated plier marks was used to evaluate the chisel marks. Impression toolmarks, a more complex form of toolmark, pose a more difficult test for the algorithm that was originally designed for striated toolmarks. Results show in this instance that the algorithm can separate matching and nonmatching impression marks, providing further validation of the assumption that toolmarks are identifiably unique. PMID- 26250935 TI - Beyond the Binary: Trans-Negotiations in Couple and Family Therapy. AB - Dualistic notions about gender and sexuality have permeated the field of couple and family therapy. These binary constructions have been limiting for everyone, especially those who fall outside the male/female dichotomy. This article examines the impact of these binary notions, especially on transgender and gender creative individuals, couples, and families. Current theory and research in the field as they relate to gender identity, sexuality, and gender minority stress in couples and families are presented. Case examples are used to illustrate affirmative approaches to treatment issues such as coming out, safety, grief and loss, redefining relationships, and social/medical transitions that may arise for transgender or gender nonconforming (TGNC) individuals, couples, and families. PMID- 26250936 TI - Immunohistochemistry 2015: Protein correlates of molecular alterations and predictive testing. PMID- 26250934 TI - CD44 variant 6 is correlated with peritoneal dissemination and poor prognosis in patients with advanced epithelial ovarian cancer. AB - Cancer stem cells (CSCs) drive tumor initiation and metastasis in several types of human cancer. However, the contribution of ovarian CSCs to peritoneal metastasis remains unresolved. The cell adhesion molecule CD44 has been identified as a major marker for CSCs in solid tumors, including epithelial ovarian cancer. CD44 exists as a standard form (CD44s) and also as numerous variant isoforms (CD44v) generated by alternative mRNA splicing. Here we show that disseminated ovarian tumors in the pelvic peritoneum contain highly enriched CD44v6-positive cancer cells, which drive tumor metastasis and are responsible for tumor resistance to chemotherapy. Clinically, an increased number of CD44v6 positive cancer cells in primary tumors was associated with a shortened overall survival in stage III-IV ovarian cancer patients. Furthermore, a subpopulation of CD44v6-positive cancer cells manifested the ability to initiate tumor metastasis in the pelvic peritoneum in an in vivo mouse model, suggesting that CD44v6 positive cells show the potential to serve as metastasis-initiating cells. Thus, the peritoneal disseminated metastasis of epithelial ovarian cancer is initiated by the CD44v6-positive subpopulation, and CD44v6 expression is a biomarker for the clinical outcome of advanced ovarian cancer patients. Given that a distinct subpopulation of CD44v6-positive cancer cells plays a critical role in peritoneal metastasis, definitive treatment should target this subpopulation of CD44v6 positive cells in epithelial ovarian cancer. PMID- 26250937 TI - Lethal and sublethal effects of lufenuron on sugarcane borer Diatraea flavipennella and its parasitoid Cotesia flavipes. AB - The combination of chemical and biological controls is a historic goal of integrated pest management, but has rarely been achieved due to lethal and sublethal impact of insecticides on natural enemies altering their performance. In this context, the susceptibility of the yellow sugarcane borer, Diatraea flavipennella (Lepidoptera: Crambidae), to the insect growth regulator lufenuron and the consequent effects upon its endoparasitoid Cotesia flavipes (Hymenoptera: Braconidae) encountering exposed but surviving larvae were studied. Neonate and 10-day-old larvae were subjected to one of seven concentrations of lufenuron (1.56, 3.12, 6.25, 12.5, 25.0, 50.0 and 100 mg a.i./L). Further, effects of lufenuron to the host larvae and to the parasitoid were assessed using low lethal LC20 and LC50. Lufenuron at concentrations up to 12.5 mg a.i./L allowed partial survival of borer larvae; and concentrations over 12.5 mg a.i./L caused 100 % larval mortality before pupation in both ages. Neonate larvae exhibited lower pupal weights only at concentrations 12.5 mg a.i./L; while 10-day-old larvae treated with the LC50 exhibited delayed development. Egg viability was reduced for adult borers from surviving larvae of both ages treated with low lethal concentrations. The parasitoid C. flavipes successfully parasitized surviving low lethal treated larvae. Among the studied life history characteristics of C. flavipes, only a delayed development was observed. The results showed that lufenuron can be effective against D. flavipennella at concentrations over 25 mg a.i./L, and that surviving larvae can be successfully parasitized by C. flavipes. The insecticide lufenuron and the parasitoid C. flavipes seem to be compatible for sugarcane borer control. PMID- 26250938 TI - Responses of growth and hemolymph quality in juvenile Chinese horseshoe crab Tachypleus tridentatus (Xiphosura) to sublethal tributyltin and cadmium. AB - Responses of growth endpoints and hemolymph constituents in juvenile Chinese horseshoe crab Tachypleus tridentatus under treatments of 0.01 and 0.1 mg/l tributyltin (TBT) and 0.1 and 1 mg/l cadmium (Cd) were examined in a 12-week experiment. A significant decline in final body weight, final prosomal width, percentage of individuals molted and mean molting time was detected under TBT exposures. While morphological abnormalities of the juveniles between TBT treatments and the control were statistically indistinguishable, significantly higher occurrences of carapace erosion and appendage loss were noted under 0.1 and 1 mg/l Cd exposures. Various hemolymph quality indicators, including hemolymph plasma protein level, amebocyte viability and percentage of granular spherical state of amebocytes of the juveniles exposed to TBT or Cd were significantly lower than the control. Such a decrease in hemolymph quality suggested deleterious effects of metal contaminant-induced stressors on the health status of the juveniles even at low exposure levels (i.e., 0.01 mg/l TBT and 0.1 mg/l Cd). Changes of hemolymph parameters in juvenile horseshoe crabs were more sensitive than growth performance as well as morphological abnormalities in response to metal stressors, and can be used as an indicator to reflect habitat conditions and contaminant levels. PMID- 26250939 TI - Serum miRNA expression profile as a prognostic biomarker of stage II/III colorectal adenocarcinoma. AB - We sought to identify a serum miRNA expression profile to improve disease surveillance and to predict post-operative disease recurrence for stage II/III colorectal cancer (CRC) patients. Using the TaqMan Low-Density Array (TLDA), we performed an initial survey to analyze 749 miRNAs in the pooled serum of 20 paired pre- and post-operative CRC patients and 20 matched normal subjects. Using individual RT-qPCR verification in 175 stage II/III CRC patients, we identified that miR-145, miR-106a and miR-17-3p were significantly differentially expressed between pre- and post-operative CRC patients and between pre-operative CRC patients and normal controls (P < 0.0001). The area under the ROC curve (AUC) for the three-miRNA panel was 0.886 (95% CI 0.850-0.921) for discriminating between pre-operative CRC patients and normal subjects and 0.850 (95% CI 0.809-0.891) for discriminating between pre- and post-operative CRC patients. Furthermore, using the Kaplan-Meier method and Cox proportional hazards analysis, we found that miR 17-3p and miR-106a were powerful and independent prognostic indicators and that high levels of these miRNAs were associated with shorter disease-free survival (DFS) (P < 0.0001 for miR-17-3p and P = 0.001 for miR-106a). The present study reveals novel serum-miRNA-based biomarkers for monitoring tumor dynamics as well as for predicting disease recurrence in patients with stage II/III CRC. PMID- 26250940 TI - Molecular structure-function relationship of dietary polyphenols for inhibiting VEGF-induced VEGFR-2 activity. AB - SCOPE: We recently reported potent inhibition of VEGF signalling by two flavanols at sub-micromolar concentrations, mediated by direct binding of the flavanols to VEGF. The aim of this study was to quantify the inhibitory potency and binding affinity of a wide range of dietary polyphenols and determine the structural requirements for VEGF inhibition. METHODS AND RESULTS: The concentration of polyphenol required to cause 50% inhibition (IC50 ) of VEGF-dependent VEGFR-2 activation in HUVECS was determined after pretreating VEGF with polyphenols at various concentations. Binding affinities and binding sites on VEGF were predicted using in-silico modelling. Ellagic acid and 15 flavonoids had IC50 values <=10 MUM while 28 other polyhenols were weak/non-inhibitors. Structural features associated with potent inhibition included 3-galloylation, C-ring C2=C3, total OH, B-ring catechol, C-ring 3-OH of flavonoids. Potency was not associated with polyphenol hydrophobicity. There was a strong correlation between potency of inhibition and binding affinities, and all polyphenols were predicted to bind to a region on VEGF involved in VEGFR-2 binding. CONCLUSION: Specific polyphenols bind directly to a discrete region of VEGF and inhibit VEGF signalling, and this potentially explains the associations between consumption of these polyphenols and CVD risk. PMID- 26250941 TI - Do we have sufficient information to optimally inform regulatory or other policy decisions about medications containing codeine? PMID- 26250942 TI - An investigation of snakebite antivenom usage in Taiwan. AB - BACKGROUND/PURPOSE: Four types of antivenom are used to treat snakebites by the six species of venomous snakes native to Taiwan. Research into antivenom use in Taiwan and its outcomes, as well as the utility of current Taiwan Poison Control Center guidelines for antivenom use, has been limited. We aimed to provide increased understanding by investigating the treatment and outcomes of patients treated for snakebite in Taiwan. METHODS: On the basis of data collected from the 2009 Taiwan National Health Insurance database, patients with snakebites were identified and categorized into two sets of groups according to types of antivenom administered. The relationships between antivenom types, dosage and the variables of antibiotic use, surgical intervention, acute respiratory failure acute, renal failure, antivenom-related allergic reaction, mortality, need for hospital admission, and length of hospitalization were analyzed by multivariate logistic regression and the Kruskal-Wallis test. RESULTS: The majority of patients were successfully treated by administration of 1 vial of antivenom and discharged without complications. However, patients treated for neurotoxic-type venom snakebite required administration of larger doses of antivenom and > 30% required surgical intervention, particularly those treated for Chinese cobra snakebite. Approximately 10% of patients were administered two types of antivenom. CONCLUSION: The results partially support Taiwan Poison Control Center guidelines for treating the hemorrhagic-type venom snakebite. However, deficit in the guidelines for treatment of neurotoxic-type venom snakebite is obvious and new guidelines for treatment of neurotoxic-type venom snakebite and diagnosis should be developed. PMID- 26250943 TI - The importance of understanding: Model space moderates goal specificity effects. AB - The three-space theory of problem solving predicts that the quality of a learner's model and the goal specificity of a task interact on knowledge acquisition. In Experiment 1 participants used a computer simulation of a lever system to learn about torques. They either had to test hypotheses (nonspecific goal), or to produce given values for variables (specific goal). In the good- but not in the poor-model condition they saw torque depicted as an area. Results revealed the predicted interaction. A nonspecific goal only resulted in better learning when a good model of torques was provided. In Experiment 2 participants learned to manipulate the inputs of a system to control its outputs. A nonspecific goal to explore the system helped performance when compared to a specific goal to reach certain values when participants were given a good model, but not when given a poor model that suggested the wrong hypothesis space. Our findings support the three-space theory. They emphasize the importance of understanding for problem solving and stress the need to study underlying processes. PMID- 26250944 TI - A Density Functional Study of the Nonlinear Optical Properties of Edge Functionalized Nonplanar Nanographenes. AB - The atomically precise edge chlorination of nanographenes has recently been reported as a crucial technology of functionalization through which the planar structure and optical properties of nanographenes can be significantly changed. To check the effects of molecular size, geometrical symmetry and edge functionalization of nanographenes on their optical properties, a series of nanographenes is studied in the framework of density functional theory with the B3LYP functional. Our results indicate that edge functionalization remarkably changes the nonlinear optical properties and increases the anisotropy of nanographenes compared to the effects of the molecular size and system geometric symmetry. Furthermore, the nonlinear optical properties of nanographenes can be tuned by precise edge functionalization, which opens a new avenue for using nanographenes as nonlinear optical materials. PMID- 26250945 TI - Reversal Circularly Polarized Luminescence of AIE-Active Chiral Binaphthyl Molecules from Solution to Aggregation. AB - Four aggregation-induced emission (AIE)-active chiral binaphthyl-based molecules, (R/S)-1 and (R/S)-2, were designed and synthesized. Interestingly, all of them can exhibit reversal circularly polarized luminescence (CPL) signals from solution to aggregation, which could be attributed to the different dihedral angle of binaphthyl units from cis-conformation in pure THF solution to trans conformation in THF/water mixtures. PMID- 26250946 TI - Comments on "reflectance confocal microscopy as a useful diagnostic tool for monitoring of skin containing vascularized allograft rejection: A preliminary study on rats". PMID- 26250948 TI - Systematic review of guidelines for management of intermediate hepatocellular carcinoma using the Appraisal of Guidelines Research and Evaluation II instrument. AB - BACKGROUND: Hepatocellular carcinoma is the second leading cause of cancer related mortality worldwide. Multiple guidelines have been developed to assist clinicians in its management. We aimed to explore methodological quality of these guidelines focusing on treatment of intermediate hepatocellular carcinoma by transarterial chemoembolization. METHODS: A systematic search was performed for Clinical Practice Guidelines and Consensus statements for hepatocellular carcinoma management. Guideline quality was appraised using the Appraisal of Guidelines Research and Evaluation II instrument, which rates guideline development processes across 6 domains: 'Scope and purpose', 'Stakeholder involvement', 'Rigour of development', 'Clarity of presentation', 'Applicability' and 'Editorial independence'. Thematic analysis of guidelines was performed to map differences in recommendations. RESULTS: Quality of 21 included guidelines varied widely, but was overall poor with only one guideline passing the 50% mark on all domains. Key recommendations as (contra)indications and technical aspects were inconsistent between guidelines. Aspects on side effects and health economics were mainly neglected. CONCLUSIONS: Methodological quality of guidelines on transarterial chemoembolization in hepatocellular carcinoma management is poor. This results in important discrepancies between guideline recommendations, creating confusion in clinical practice. Incorporation of the Appraisal of Guidelines Research and Evaluation II instrument in guideline development may improve quality of future guidelines by increasing focus on methodological aspects. PMID- 26250949 TI - Adalimumab treatment in intestinal Behcet's disease: Relationship with ectopic mucin 5AC glycoprotein expression and endoscopic improvement. PMID- 26250956 TI - Sensitivity of different measures of frontal plane alignment to medial and lateral joint space narrowing: From the osteoarthritis initiative. AB - OBJECTIVES: To explore cross-sectional relationships between a new radiographic measure of the femorotibial angle (FTA), the hip-knee-ankle angle (HKA), and the goniometry; to quantify sex differences between measures; and to evaluate the sensitivity of these measures to medial and lateral joint space narrowing (JSN). METHODS: Concurrent validity was evaluated in 2123 knees from the osteoarthritis (OA) initiative using Pearson correlation coefficients (r) and Bland-Altman plots (offsets). Diagnostic validity with respect to JSN was evaluated using areas under the receiver-operating characteristic curves (AUC) and standardized mean differences (SMD). Analyses were stratified by sex and JSN. RESULTS: JSN and sex contributed significantly to regression models predicting offsets between measures (p < 0.001), after controlling for age, BMI, and OA severity. There were weak correlations between FTA vs. goniometry (r: 0.16-0.22), and moderate correlations between FTA vs. HKA (r: 0.25-0.53) and HKA vs. goniometry (r: 0.40 0.67). The offset between the new FTA measure and HKA was larger in females than males (p < 0.001). Offsets between radiographic measures and goniometry also varied by sex and JSN (FTA: 2.9 degrees -7.6 degrees ; HKA: 0.5 degrees -2.4 degrees ). AUC (0.74-0.91) and SMD (0.53-3.80) between JSN strata were largest for FTA, whereas diagnostic validity was moderate for HKA (AUC: 0.69-0.80; SMD: 0.43-2.04) and weakest for handheld goniometry (AUC: 0.56-0.63; SMD: 0.07-0.90). CONCLUSIONS: Compared to HKA, goniometry demonstrated poor diagnostic validity with respect to JSN. The new FTA measure, in contrast, represented a reasonable surrogate of radiographic disease severity (JSN). The new FTA measure was skewed in the varus direction when compared to HKA and more so in females. This requires cautious interpretation when measurements are related to previous studies. PMID- 26250957 TI - Diagnosis of Penicillium marneffei infection from a blood film. PMID- 26250958 TI - Radiation effects on the spinal cord: is mitigation in the long run possible? PMID- 26250959 TI - The effect of alpha-lipoic acid (ALA) supplementation on cardiovascular risk factors in men with chronic spinal cord injury: a clinical trial. PMID- 26250960 TI - In situ evaluation of the fruit and oil characteristics of the main Lebanese olive germplasm. AB - BACKGROUND: Very little information is available on the characteristics of the Lebanese olive germplasm. Therefore, the aim of this work was to evaluate the fruit and oil characteristics of the main Lebanese olive varieties (Aayrouni, Abou chawkeh, Baladi, Del and Soury) from two successive crop seasons (2010 2011). RESULTS: All of the genotypes had medium-high oil content in the fruit, indicating their suitability for oil production; Aayrouni had particularly high values. The variety Abou chawkeh also had a high pulp/pit ratio, which is a very desirable trait in table olives. For all the varieties the values of free fatty acids, peroxide values, absorbances in ultraviolet, fatty acid composition, sterol content and composition and erythrodiol + uvaol content of the oils were within the requirements of the International Olive Council's Trade Standard for extra virgin olive oil. The only exception was for the values of Delta-7 stigmastenol in 2011 in Soury and, especially, in Baladi, which were higher than 0.5%. In some cases, stearic and arachidic acids fluctuated around the maximum values allowed. CONCLUSION: The findings of this study provide a first picture of the main characteristics of olives and oils currently produced in Lebanon. (c) 2015 Society of Chemical Industry. PMID- 26250962 TI - Evolved gas composition monitoring by repetitive injection gas chromatography. AB - Performance characteristics and applications of a small volume gas chromatograph oven are described. Heating and cooling properties of the apparatus are evaluated and examples are given illustrating the advantages of greatly reducing the air bath volume surrounding fused silica columns. Fast heating and cooling of the oven permit it to be employed for repetitive injection analyses. By using fast gas chromatography separations to achieve short assay cycle times, the apparatus can be employed for on-line species-specific gas stream composition monitoring when volatile species concentrations vary on time scales of a few minutes or longer. This capability facilitates repeated sampling and fast gas chromatographic separations of volatile product mixtures produced during thermal analyses. Applications of repetitive injection gas chromatography-mass spectrometry evolved gas analyses to monitoring purge gas effluent streams containing volatile acid catalyzed polymer cracking products are described. The influence of thermal analysis and chromatographic experimental parameters on effluent sampling frequency are delineated. PMID- 26250961 TI - Polymorphisms in maternal folate pathway genes interact with arsenic in drinking water to influence risk of myelomeningocele. AB - BACKGROUND: Arsenic induces neural tube defects in many animal models. Additionally, studies have shown that mice with specific genetic defects in folate metabolism and transport are more susceptible to arsenic-induced neural tube defects. We sought to determine whether 14 single-nucleotide polymorphisms in genes involved in folate metabolism modified the effect of exposure to drinking water contaminated with inorganic arsenic and posterior neural tube defect (myelomeningocele) risk. METHODS: Fifty-four mothers of children with myelomeningocele and 55 controls were enrolled through clinical sites in rural Bangladesh in a case-control study of the association between environmental arsenic exposure and risk of myelomeningocele. We assessed participants for level of myelomeningocele, administered questionnaires, conducted biological and environmental sample collection, and performed genotyping. Inductively coupled plasma mass spectrometry was used to measure inorganic arsenic concentration in drinking water. Candidate single-nucleotide polymorphisms were identified through review of the literature. RESULTS: Drinking water inorganic arsenic concentration was associated with increased risk of myelomeningocele for participants with 4 of the 14 studied single-nucleotide polymorphisms in genes involved in folate metabolism: the AA/AG genotype of rs2236225 (MTHFD1), the GG genotype of rs1051266 (SLC19A1), the TT genotype of rs7560488 (DNMT3A), and the GG genotype of rs3740393 (AS3MT) with adjusted odds ratio of 1.13, 1.31, 1.20, and 1.25 for rs2236225, rs1051266, rs7560488, and rs3740393, respectively. CONCLUSION: Our results support the hypothesis that environmental arsenic exposure increases the risk of myelomeningocele by means of interaction with folate metabolic pathways. PMID- 26250963 TI - Fluoroquinolone residues in compost by green enhanced microwave-assisted extraction followed by ultra performance liquid chromatography tandem mass spectrometry. AB - A novel, simple and straightforward method for determination of fluoroquinolones (FQs) in compost has been developed. The procedure entails a low-pressurized microwave-assisted extraction (MAE) carried out by a high performance instrument, in alkaline aqueous solution containing magnesium ions as FQs complexing agent, followed by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS). Ciprofloxacin (CIP), Enrofloxacin (ENR), Levofloxacin (LEV) and Norfloxacin (NOR), four widely used FQ antibiotics, were simultaneously extracted from compost by a single MAE cycle (20min, 135 degrees C). The method was validated in terms of linearity, selectivity, sensitivity and accuracy. Quantitative absolute recovery (70-112%, n=3) and suitable precision (RSD<15%, n=3) were observed, at concentration levels ranging from 25 ng g(-1) to 2500 ng g(-1). Analytes were separated in a 10min chromatographic run and quantified/confirmed in single reaction monitoring (SRM) mode. UPLC coupled to SRM-MS detection allowed to achieve improved sensitivity, and selective detection. Method detection and quantification limits, MDLs and MQLs, were in the range 2.2-3.0 ng g(-1) and 6.6-9.0 ng g(-1), respectively. The high-performance microwave system here used strongly improved the extraction efficiency with respect to a conventional apparatus. The procedure proved to be simpler, less expensive, faster, and more green with respect to the few methods currently described in literature, providing at the same time suitable recovery and reproducibility. The analytical method has been applied to the analysis of actual compost samples, wherein FQs have been quantified at concentrations up to 88 ng g(-1). PMID- 26250964 TI - Diagnostic performance of fluorescent light-emitting diode microscopy for tuberculous lymphadenitis in a high-burden setting. AB - OBJECTIVE: Diagnosis of tuberculous lymphadenitis using fine-needle aspiration cytology is a simple and safe but low-specificity method, whereas conventional smear microscopy has variable sensitivity due to low bacterial load. We evaluated the diagnostic performance of fluorescent light-emitting diode (LED) microscopy on routinely collected fine-needle aspirates from tuberculous lymphadenitis presumptive cases. METHODS: Fine-needle aspirates were collected from patients clinically suspected of having tuberculous lymphadenitis as part of routine diagnosis. Smear preparation was performed from the aspirate and processed for cytology, conventional Ziehl-Neelsen and LED microscopy. The remaining aspirate was processed for culture on Lowenstein-Jensen media. Capilia TB-Neo test was used to differentiate M. tuberculosis complex from non-tuberculous mycobacteria. RESULT: A total of 144 tuberculous lymphadenitis presumptive cases were included. 66.7% (96/144) were positive for M. tuberculosis complex on culture. Only one isolate was identified as non-tuberculous mycobacteria. The detection rates of Ziehl-Neelsen and LED microscopy were 18.8% (27/144) and 34% (49/144), respectively. As compared to culture, sensitivity was 25.0% [95% CI: 16.3-33.7] for Ziehl-Neelsen microscopy and 45.8% [95% CI: 35.9-55.8] for LED microscopy. The specificity was 93.8% [95% CI: 86.9-100] for Ziehl-Neelsen microscopy and 89.6% [95% CI: 80.9-98.2] for LED microscopy. LED microscopy showed a statistically significant increase in sensitivity and similar specificity compared to Ziehl-Neelsen microscopy. Mean reading time of positive slides was 2.62 min/slide for Ziehl-Neelsen and 1.60 min/slide for LED microscopy. Cytology showed sensitivity of 82.3% and specificity of 54.2%. LED microscopy detected TB bacilli in 33.3% of cases cytologically classified as suppurative abscess. CONCLUSION: The LED microscopy for tuberculous lymphadenitis had significantly higher sensitivity and shorter screening time than Ziehl-Neelsen microscopy. Use of LED microscopy among cases classified as suppurative abscess on fine-needle aspirate cytology improves evidence-based diagnosis of presumptive tuberculous lymphadenitis cases. Moreover, LED microscopy could be considered as an alternative approach in settings where fine-needle aspirate cytology is impractical. PMID- 26250965 TI - Long-term dietary habits and interventions in solid-organ transplantation. AB - Diet and nutrition are moving to the forefront of modern primary and preventive care to help address the rising burden of chronic diseases among the general population. Such a movement has yet to occur formally across the field of transplantation. We therefore looked to establish the current base of knowledge regarding diet, nutrition and solid-organ transplantation. A limited number of focused studies looking into the dietary habits of solid-organ transplant patients have been performed and many of the available studies have detailed the nutritional status in the peri-operative period. Frequently described, however, is the heavy incidence of metabolic abnormalities, such as obesity, dyslipidemia and diabetes, occurring after solid-organ transplantation. Optimistically, several studies have noted improvement in several metabolic abnormalities with the use of dietary interventions in the post-transplant period. Despite these positive results, few consensus guidelines for post-transplant diet have been established and nutritional support among transplant programs remains limited. Although there are many hurdles to implementation of detailed dietary recommendations and nutritional support for transplant patients, creating such programs and guidelines could dramatically impact long-term outcomes and burden of chronic metabolic disease for transplant recipients. PMID- 26250967 TI - Elevated IL-5 and IL-13 responses to egg proteins predate the introduction of egg in solid foods in infants with eczema. AB - BACKGROUND: Egg allergy is a leading cause of food allergy in young infants; however, little is known about early allergen-specific T-cell responses which predate the presentation of egg allergy, and if these are altered by early egg exposure. OBJECTIVE: To investigate the early T-cell responses to multiple egg proteins in relation to patterns of egg exposure and subsequent IgE-mediated egg allergy. METHODS: Egg-specific T-cell cytokine responses (IL-5, IL-13, IL-10, IFNgamma and TNFalpha) to ovomucoid (OM), ovalbumin (OVA), conalbumin (CON) and lysozyme (LYS) were measured in infants with eczema at 4 months of age (n = 40), before randomization to receive 'early egg' or a placebo as part of a randomized controlled trial (Australian New Zealand Clinical Trials Registry number 12609000415202) and at 12 months of age (n = 58), when IgE-mediated egg allergy was assessed by skin prick test and food challenge. RESULTS: In 4-month-old infants, who had not directly ingested egg, those who subsequently developed egg allergy already had significantly higher Th2 cytokine responses to multiple egg allergens, particularly elevated IL-13 responses to OVA (P = 0.004), OM (P = 0.012) and LYS (P = 0.003) and elevated IL-5 to the same antigens (P = 0.031, 0.04 and 0.003, respectively). IL-13 responses (to OVA and LYS) and IL-5 responses (to LYS) at 4 months significantly predicted egg allergy at 12 months. All responses significantly declined with age in the egg-allergic infants, and this did not appear to be modified by 'early' introduction of egg. CONCLUSIONS & CLINICAL RELEVANCE: Elevated egg-specific Th2 cytokine responses were established prior to egg ingestion at 4 months and were not significantly altered by introduction of egg. Th2 responses at 4 months of age predicted egg allergy at 12 months, suggesting that this could be used as a biomarker to select infants for early prevention and management strategies. PMID- 26250966 TI - Nutritional Risk Index predicts mortality in hospitalized advanced heart failure patients. AB - BACKGROUND: Hospitalized advanced heart failure (HF) patients are at high risk for malnutrition and death. The Nutritional Risk Index (NRI) is a simple, well validated tool for identifying patients at risk for nutrition-related complications. We hypothesized that, in advanced HF patients from the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial, the NRI would improve risk discrimination for 6-month all-cause mortality. METHODS: We analyzed the 160 ESCAPE index admission survivors with complete follow-up and NRI data, calculated as follows: NRI = (1.519 * discharge serum albumin [in g/dl]) + (41.7 * discharge weight [in kg] / ideal body weight [in kg]); as in previous studies, if discharge weight is greater than ideal body weight (IBW), this ratio was set to 1. The previously developed ESCAPE mortality model includes: age; 6-minute walk distance; cardiopulmonary resuscitation/mechanical ventilation; discharge beta-blocker prescription and diuretic dose; and discharge serum sodium, blood urea nitrogen and brain natriuretic peptide levels. We used Cox proportional hazards modeling for the outcome of 6-month all-cause mortality. RESULTS: Thirty of 160 patients died within 6 months of hospital discharge. The median NRI was 96 (IQR 91 to 102), reflecting mild-to-moderate nutritional risk. The NRI independently predicted 6-month mortality, with adjusted HR 0.60 (95% CI 0.39 to 0.93, p = 0.02) per 10 units, and increased Harrell's c-index from 0.74 to 0.76 when added to the ESCAPE model. Body mass index and NRI at hospital admission did not predict 6-month mortality. The discharge NRI was most helpful in patients with high (>= 20%) predicted mortality by the ESCAPE model, where observed 6-month mortality was 38% in patients with NRI < 100 and 14% in those with NRI > 100 (p = 0.04). CONCLUSIONS: The NRI is a simple tool that can improve mortality risk stratification at hospital discharge in hospitalized patients with advanced HF. PMID- 26250968 TI - Alteration in PI3K/mTOR, MAPK pathways and Her2 expression/amplification is more frequent in uterine serous carcinoma than ovarian serous carcinoma. AB - OBJECTIVES: To compare the molecular profile of a large cohort of uterine papillary serous carcinoma (UPSC) and ovarian serous carcinoma (EOC-S). METHODS: 628 UPSC and 5335 EOC-S tumors were evaluated using a commercial multiplatform profiling service (CARIS Life Sciences, Phoenix, AZ). Specific testing performed included a combination of gene sequencing (Sanger, next generation sequencing), protein expression (IHC) and gene amplification (CISH or FISH). RESULTS: TP53 was the most commonly mutated gene in both UPSC and EOC-S (76% vs. 69%, P = 0.03). UPSC were more likely to have mutation in PIK3CA (29% vs. 2%, P < 0.001), FBXW7 (12% vs. 1%, P < 0.001), KRAS (9% vs. 5%, P < 0.001) PTEN (7% vs. 1%, P < 0.001), and CTNNB1 (2% vs. 0%, P < 0.001) compared to EOC-S. On the other hand, EOC-S were more likely to harbor mutation in BRCA1 (20% vs. 9% P = 0.17) and BRCA2 (18% vs. 6% P = 0.09). HER2 gene amplification (17% vs. 4%, P < 0.001) and Her2/neu expression (10% vs. 2%, P < 0.001) were more frequent in UPSC than EOC-S, respectively. CONCLUSION: UPSC have a distinct mutation profile indicating higher activity of PI3K/AKT/mTOR, and MAPK pathways and Her2 expression/amplification but a trend toward lower frequency of alteration in homologous recombination pathway compared to EOC-S. Targeted PI3K/AKT/mTOR inhibitors should be evaluated in UPSC. PMID- 26250969 TI - Improving our patients' experience in their radiological care. PMID- 26250970 TI - Pot au Feu. PMID- 26250971 TI - How the ACR works: the vital role of the council steering committee: representing our members and setting college policy. PMID- 26250972 TI - Radiology after the Fukushima Disaster: a case report Of Soma General Hospital. PMID- 26250973 TI - The great migration. PMID- 26250974 TI - Minor patients: consent to treatment and access to medical records. PMID- 26250975 TI - Dose length products for the 10 most commonly ordered CT examinations in adults: analysis of three years of the ACR Dose Index Registry. AB - As CT use steadily rises, concern over potential risks of radiation exposure from medical imaging has received increasing attention. Since May 2011, the ACR Dose Index Registry (DIR) has been open for general participation and has been collecting CT radiation dose data from an increasing number of facilities of various types. In this introductory review, we analyze the first three years of ACR DIR data, categorize the 10 most commonly performed CT examinations nationwide, review the variability of the recorded radiation dose indices for each, and take preliminary steps toward identifying possible factors associated with variability in dose indices. We believe that disseminating such information will help prompt informed improvements in standardization of CT protocols with respect to radiation dose. PMID- 26250976 TI - Protocol management and design: current and future best practices. PMID- 26250977 TI - Enhancing structured reporting: improving quality by tailoring the report to the clinical scenario. PMID- 26250978 TI - Last series hold: a feature on fluoroscopy systems with the potential to reduce patient and operator dose. PMID- 26250979 TI - Radiogenomics: what it is and why it is important. AB - In recent years, a new direction in cancer research has emerged that focuses on the relationship between imaging phenotypes and genomics. This direction is referred to as radiogenomics or imaging genomics. The question that subsequently arises is: What is the practical significance of elucidating this relationship in improving cancer patient outcomes. In this article, I address this question. Although I discuss some limitations of the radiogenomic approach, and describe scenarios in which radiogenomic analysis might not be the best choice, I also argue that radiogenomics will play a significant practical role in cancer research. Specifically, I argue that the significance of radiogenomics is largely related to practical limitations of currently available data that often lack complete characterization of the patients and poor integration of individual datasets. Radiogenomics offers a practical way to leverage limited and incomplete data to generate knowledge that might lead to improved decision making, and as a result, improved patient outcomes. PMID- 26250980 TI - Physician rating websites: do radiologists have an online presence? AB - PURPOSE: Given that patient satisfaction and provider transparency intersect on online physician-rating websites, we aimed to assess radiologist representation on these increasingly popular sites. METHODS: From a directory of all Medicare participating physicians, we randomly selected 1,000 self-designated diagnostic radiologists and manually extracted their rating information from five popular online physician-review websites (HealthGrades, Healthcare Reviews, RateMDs, Kudzu, and Yelp). Using automated web "data-scraping" techniques, we separately extracted all radiologist and nonradiologist rating information from a single amenable site (Healthcare Reviews). Rating characteristics were analyzed. RESULTS: Of 1,000 sampled self-designated diagnostic radiologists representing all 50 states, only 197 (19.7%) were profiled on any of the five online physician review websites. Only 24 (2.4%) were rated on two of the sites, and none was profiled on >=3 sites. Of all 6,775 physicians listed on a single electronically interrogated site, only 30 (0.4%) were radiologists. With 28,555 (5.2%) of all 547,849 Medicare-participating physicians identified as diagnostic radiologists, radiologists were thus significantly underrepresented online (P < .0001). Although reviewed radiologists and nonradiologists were rated online by similar numbers of patients (1.13 +/- 0.43 versus 1.03 +/- 0.22, P = .22), radiologists were rated (on a low to high score of 1 to 10) significantly higher than nonradiologists (median 8.5 versus 5, P = .04). CONCLUSIONS: Most diagnostic radiologists are not profiled on common online physician-rating websites, and they are significantly underrepresented compared with nonradiologists. Reviewed radiologists, however, scored favorably. Given the potential for patient satisfaction scores and public domain information to affect referrals and future value-based payments, initiatives to enhance radiologists' online presence are advised. PMID- 26250981 TI - Alpha-Synuclein Fibrils Interact with Dopamine Reducing its Cytotoxicity on PC12 Cells. AB - Aggregated alpha-synuclein (alpha-SYN) is the major component of Lewy bodies and Lewy neurites, two of the pathological hallmarks of Parkinson's disease (PD). Aggregation of alpha-SYN leads to toxic species involved in the degeneration of dopaminergic neurons in the midbrain. Different studies suggest a strong association between the presence of dopamine (DA) and the cell specific degeneration caused by alpha-SYN aggregates in PD. Despite extensive studies on the effect of DA on alpha-SYN fibrillation, it remains unclear how the simultaneous presence of DA and alpha-SYN influences the degeneration of dopaminergic neurons. In this study we show that separate treatments with specific doses of DA or early stage alpha-SYN aggregates (ESAA) are both cytotoxic to PC12 cells. Surprisingly, simultaneous treatment of cells with DA and ESAA significantly decreased this toxicity. This cytotoxicity was further reduced by the presence of heavier particles of alpha-SYN aggregates with more fibrillogenic characteristics. Spectrometric analysis revealed that alpha-SYN fibrils interact with DA even after the sample was dialyzed for 48 h, suggesting a strong interaction. Interestingly, digestion of unprotected N- and C-alpha-SYN fibril terminals by proteinase K did not affect this interaction. Our results suggest that fibrillar forms of alpha-SYN with localized expanded active surfaces may interact with DA and moderate its cytotoxicity. Thus, highlighting the importance of fibrillar proteins in developing clinical approaches for amyloid diseases. PMID- 26250982 TI - Tuning growth cycles of Brassica crops via natural antisense transcripts of BrFLC. AB - Several oilseed and vegetable crops of Brassica are biennials that require a prolonged winter cold for flowering, a process called vernalization. FLOWERING LOCUS C (FLC) is a central repressor of flowering. Here, we report that the overexpression of natural antisense transcripts (NATs) of Brassica rapa FLC (BrFLC) greatly shortens plant growth cycles. In rapid-, medium- and slow-cycling crop types, there are four copies of the BrFLC genes, which show extensive variation in sequences and expression levels. In Bre, a biennial crop type that requires vernalization, five NATs derived from the BrFLC2 locus are rapidly induced under cold conditions, while all four BrFLC genes are gradually down regulated. The transgenic Bre lines overexpressing a long NAT of BrFLC2 do not require vernalization, resulting in a gradient of shortened growth cycles. Among them, a subset of lines both flower and set seeds as early as Yellow sarson, an annual crop type in which all four BrFLC genes have non-sense mutations and are nonfunctional in flowering repression. Our results demonstrate that the growth cycles of biennial crops of Brassica can be altered by changing the expression levels of BrFLC2 NATs. Thus, BrFLC2 NATs and their transgenic lines are useful for the genetic manipulation of crop growth cycles. PMID- 26250983 TI - Activity of the external urethral sphincter evoked by genital stimulation in male rats. AB - AIMS: To determine whether the external urethral sphincter (EUS) fasciculi of male rats respond to the mechanical stimulation of genital structures and to characterize the pattern of the electromyographic (EMG) activity of the three regions of the EUS: the cranial (CrEUS), the medial (MeEUS) and the caudal (CaEUS). METHODS: Electromyographic signals were recorded from the CrEUS, MeEUS and CaEUS regions of the male rat's EUS, before, during and after the mechanical stimulation of the urogenital structures. RESULTS: The CrEUS, MeEUS and CaEUS regions responded when brushing and squeezing the foreskin and glans as well as to penile and prostatic urethral distension. The CaEUS EMG amplitude (P < 0.01) and frequency (P < 0.05) were lower in comparison to the CrEUS and MeEUS responses to the mechanical stimulation. In addition, the CaEUS was characterized by a short or no afterdischarge. In contrast, the CrEUS and MeEUS responded by presenting a long discharge after the penile or prostatic urethral distension. CONCLUSIONS: The activity of the EUS is modulated by both, cutaneous and visceral genitourinary stimuli, with motor units being activated by mechanoreceptors located in the foreskin, glans, bladder, and urethra. The CrEUS, MeEUS and CaEUS have differential EMG patterns, indicating that the EUS consists of three anatomically and functionally different regions. Precise coordination in the muscular activity of these regions may be crucial for the control of male expulsive urethral functions, i.e., during voiding and ejaculation. Neurourol. Urodynam. 35:914-919, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26250984 TI - Indirect study of non-covalent protein complexes by MALDI mass spectrometry: Origins, advantages, and applications of the "intensity-fading" approach. AB - This review article describes the origins, advantages, and application of an indirect approach with which to study protein and other macromolecular complexes and identify the nature and site of interaction interfaces by means of conventional matrix-assisted laser desorption ionization mass spectrometry (MALDI MS). First reported in 1999, it involves the detection of ion depletion or the absence of ions associated with a binding partner or domain in the MALDI mass spectrum of a mixture of interacting components compared to that for an untreated control. Later referred to as intensity-fading in some applications, the method offers numerous advantages over the direct detection of protein and other macromolecule complexes by MALDI-MS and even electrospray ionization (ESI) MS. The origins of this indirect method, its development for use with gel-separated components, validation using companion biochemical assays, and application to a range of protein-antibody and protein-drug complexes are reviewed together with software specifically developed to aid with data interpretation. The sensitivity of the approach for revealing how subtle differences in the structure of the binding partners can be detected by MALDI-MS is also demonstrated. (c) 2015 Wiley Periodicals, Inc. Mass Spec Rev 35:559-573, 2016. PMID- 26250985 TI - Natural prevalence in Cuban populations of the lymnaeid snail Galba cubensis infected with the liver fluke Fasciola hepatica: small values do matter. AB - Natural infections of lymnaeid snails by Fasciola hepatica are of primary importance to study transmission. Also, infected snails in the field can be used to explore the existing compatibility in host-parasite interactions. This paper aimed to describe the infection rate of Galba cubensis populations in fasciolosis transmission areas. Eight sites were sampled in western Cuba and 24 infected snails at six sites were found. The mean prevalence was 2.94% and the maximum value was 11.4%. The intensity of parasite infection was assessed as the number of rediae inside a single snail. High variation within the sites examined was observed, but a maximum of 76 rediae was recovered from one individual. Although the presence of two other trematode families (Schistosomatidae and Paramphistomatidae) was discovered in dissected individuals, no co-infection with F. hepatica was observed. This is the first time a study of natural prevalence of F. hepatica infection is carried out in Cuba, considered a hyper endemic country for bovine fasciolosis. Our results suggest that fasciolosis transmission may occur even when the number of infected snails remains relatively low. PMID- 26250986 TI - A Study of the Demographics of Web-Based Health-Related Social Media Users. AB - BACKGROUND: The rapid spread of Web-based social media in recent years has impacted how patients share health-related information. However, little work has studied the demographics of these users. OBJECTIVE: Our aim was to study the demographics of users who participate in health-related Web-based social outlets to identify possible links to health care disparities. METHODS: We analyze and compare three different types of health-related social outlets: (1) general Web based social networks, Twitter and Google+, (2) drug review websites, and (3) health Web forums. We focus on the following demographic attributes: age, gender, ethnicity, location, and writing level. We build and evaluate domain-specific classifiers to infer missing data where possible. The estimated demographic statistics are compared against various baselines, such as Internet and social networks usage of the population. RESULTS: We found that (1) drug review websites and health Web forums are dominated by female users, (2) the participants of health-related social outlets are generally older with the exception of the 65+ years bracket, (3) blacks are underrepresented in health-related social networks, (4) users in areas with better access to health care participate more in Web based health-related social outlets, and (5) the writing level of users in health related social outlets is significantly lower than the reading level of the population. CONCLUSIONS: We identified interesting and actionable disparities in the participation of various demographic groups to various types of health related social outlets. These disparities are significantly distinct from the disparities in Internet usage or general social outlets participation. PMID- 26250987 TI - Emerging ICT implementation issues in aged care. AB - BACKGROUND: Demand for aged care services continues to soar as a result of an aging population. This increasing demand requires more residential aged care facilities and healthcare workforce. One recommended solution is to keep older people in their homes longer and support their independent life through the use of information and communication technologies (ICT). However, the aged care sector is still in the early stages of adopting ICT. OBJECTIVE: The aim of this study was to identify the key issues that affect the adoption of ICT in the aged care sector. METHODS: A systematic literature review was undertaken and involved four steps. The first two steps aimed to identify and select relevant articles. Data was then extracted from the selected articles and identified issues were analyzed and grouped into three major categories. RESULTS: ICT adoption issues were categorized into different perspectives, representing older people, health professionals and management. Our findings showed that all three groups were mostly concerned with issues around behavior, cost and lack of technical skills. DISCUSSION AND CONCLUSIONS: Findings reported in this study will help decision makers at aged care settings to systematically understand issues related to ICT adoption and thus proactively introduce interventions to improve use of ICT in this sector. On the basis of our findings, we suggest future research focus on the examination of aged care workflow and assessment of return on ICT investment. PMID- 26250988 TI - Protein-truncating variants in moderate-risk breast cancer susceptibility genes: a meta-analysis of high-risk case-control screening studies. AB - Several "moderate-risk breast cancer susceptibility genes" have been conclusively identified. Pathogenic mutations in these genes are thought to cause a two to fivefold increased risk of breast cancer. In light of the current development and use of multigene panel testing, the authors wanted to systematically obtain robust estimates of the cancer risk associated with loss-of-function mutations within these genes. An electronic search was conducted to identify studies that sequenced the full coding regions of ATM, CHEK2, BRIP1, PALB2, NBS1, and RAD50 in a general and gene-targeted approach. Inclusion was restricted to studies that sequenced the germline DNA in both high-risk cases and geographically matched controls. A meta-analysis was then performed on protein-truncating variants (PTVs) identified in the studies for an association with breast cancer risk. A total of 10,209 publications were identified, of which 64 studies comprising a total of 25,418 cases and 52,322 controls in the 6 interrogated genes were eligible under our selection criteria. The pooled odds ratios for PTVs in the susceptibility genes were at least >2.6. Additionally, mutations in these genes have shown geographic and ethnic variation. This comprehensive study emphasizes the fact that caution should be taken when identifying certain genes as moderate susceptibility with the lack of sufficient data, especially with regard to the NBS1, RAD50, and BRIP1 genes. Further data from case-control sequencing studies, and especially family studies, are warranted. PMID- 26250989 TI - Trends in nutritional status and nutrient intakes and correlates of overweight/obesity among rural adult women (>=18-60 years) in India: National Nutrition Monitoring Bureau (NNMB) national surveys. AB - OBJECTIVE: To assess trends in nutrient intakes and nutritional status of rural adult women (>=18-60 years) and the association of sociodemographic characteristics with overweight/obesity. DESIGN: Community-based cross-sectional studies carried out during 1975-79 to 2011-12 by the National Nutrition Monitoring Bureau (NNMB) were used. Anthropometric measurements such as height, weight and waist circumference, carried out during the surveys, were used. Association and logistic regression analyses between sociodemographic characteristics and overweight/obesity and abdominal obesity were conducted using a complex samples procedure. SETTING: Ten NNMB states of India. SUBJECTS: Non pregnant and non-lactating rural women aged >=18-60 years covered during the above periods from ten states in India. RESULTS: The prevalence of chronic energy deficiency has declined from 52 % during 1975-79 to 34 % during 2011-12, while that of overweight/obesity has increased from 7 % to 24 % during the same period. Median intakes of most of the nutrients have increased over the same period, although they were below recommended levels. The chance of overweight/obesity and abdominal obesity was significantly (P<0.01) higher among women aged 40-60 years, those belonging to Christian religion and other backward communities, women living in pucca houses, literate women, women engaged in service and business, and those having higher per capita income. CONCLUSIONS: Prevalence of chronic energy deficiency has declined significantly; however, overweight/obesity has increased during the same period. This increase in overweight/obesity may be attributed to increased consumption of fatty foods, sedentary lifestyle and improved socio-economic status. There is a need to educate the community about regular physical exercise, low intakes of fats and oils, and a balanced diet. PMID- 26250990 TI - Genetic susceptibility to hepatitis E viral infection: An enigmatic virus gives up a secret. PMID- 26250991 TI - Mesoporous-Silica-Functionalized Nanoparticles for Drug Delivery. AB - The ever-growing interest for finding efficient and reliable methods for treatment of diseases has set a precedent for the design and synthesis of new functional hybrid materials, namely porous nanoparticles, for controlled drug delivery. Mesoporous silica nanoparticles (MSNPs) represent one of the most promising nanocarriers for drug delivery as they possess interesting chemical and physical properties, thermal and mechanical stabilities, and are biocompatibile. In particular, their easily functionalizable surface allows a large number of property modifications further improving their efficiency in this field. This Concept article deals with the advances on the novel methods of functionalizing MSNPs, inside or outside the pores, as well as within the walls, to produce efficient and smart drug carriers for therapy. PMID- 26250992 TI - Tandem hydrogenation and condensation of fluorinated alpha,beta-unsaturated ketones with primary amines, catalyzed by nickel. AB - A simple homogeneous catalytic system based on nickel phosphine complexes has been developed for the transfer hydrogenation and condensation of alpha,beta unsaturated ketones to yield saturated ones and saturated imines using primary amines as hydrogen donors. Thus, a wide range of fluorinated 1,5-diaryl-1,4 pentadiene-3-ones were allowed to react with substituted benzylamines in the presence of [(dippe)Ni(MU-H)]2 (dippe = 1,2-bis-(diisopropylphosphino)-ethane) using ethanol as a solvent at 180 degrees C to give the corresponding saturated carbonyl compounds; here hydrogenation of the C[double bond, length as m-dash]C bond was preferred over the C[double bond, length as m-dash]O bond. Under the same reaction conditions but using an excess of benzylamine, a tandem process is then favoured, starting also with the reduction of the C[double bond, length as m dash]C bond followed by a nucleophilic addition of the primary amine to yield valuable saturated imines with good to excellent yields (62%-91%). PMID- 26250994 TI - [Orbital mass in a 23 years old male patient]. PMID- 26250993 TI - [Misdiagnosis of a chronic otitis media]. PMID- 26250995 TI - Effects of esophageal capsaicin instillation on acid induced excitation of secondary peristalsis in humans. AB - BACKGROUND/AIM: Esophageal instillation of capsaicin or hydrochloric acid enhances secondary peristalsis. Our aim was to investigate whether intra esophageal capsaicin infusion can influence symptom perception and physiological alteration of secondary peristalsis subsequent to acid infusion. METHODS: Secondary peristalsis was induced by mid-esophagus injections of air in 18 healthy subjects. Two different sessions including esophageal infusion of hydrochloric acid (0.1 N) following pretreatment with saline or capsaicin containing red pepper sauce were randomly performed at least one week apart. Symptoms of heartburn and secondary peristalsis were determined and compared between each study session. RESULTS: The intensity of heartburn symptom subsequent to acid infusion was significantly reduced after capsaicin infusion as compared with saline infusion (54 +/- 3 vs 61 +/- 3; P = 0.03). Capsaicin infusion significantly increased the threshold volume of secondary peristalsis to rapid air injections subsequent to esophageal acid infusion (8.0 +/- 0.5 mL vs 4.4 +/- 0.3 mL; P < 0.0001). The frequency of secondary peristalsis subsequent to acid infusion was significantly decreased after capsaicin infusion as compared to saline infusion (70% [60-82.5%] vs 80% [70-90%]; P = 0.03). Capsaicin infusion significantly decreased the pressure wave amplitude of secondary peristalsis subsequent to acid infusion during rapid air injections (90.6 +/- 8.7 mmHg vs 111.1 +/- 11.1 mmHg; P = 0.03). CONCLUSIONS: Capsaicin appears to desensitize the esophagus to acid induced excitation of secondary peristalsis in humans, which is probably mediated by rapidly adapting mucosal mechanoreceptors. High capsaicin containing diet might attenuate normal physiological response to abrupt acid reflux by inhibiting secondary peristalsis. PMID- 26250996 TI - Reduction in NPY-positive neurons and dysregulation of excitability in young senescence-accelerated mouse prone 8 (SAMP8) hippocampus precede the onset of cognitive impairment. AB - The senescence-accelerated mouse prone 8 (SAMP8) strain is considered a neurodegeneration model showing age-related cognitive deficits with little physical impairment. Young SAMP8 mice, however, exhibit signs of disturbances in development such as marked hyperactivity and reduced anxiety well before the onset of cognitive impairment. As the key enzyme in local regulation of thyroid hormone (TH) signaling, type 2 deiodinase, was significantly reduced in the SAMP8 hippocampus relative to that of the normally aging SAM-resistant 1 (SAMR1), we used these two strains to compare the development of the hippocampal GABAergic system, which is known to be strongly affected by hypothyroidism. Among GABAergic components, neuronal K+ /Cl- co-transporter 2 was down-regulated in SAMP8 transiently at 2 weeks. Although distribution of total GABAergic neurons was similar in both strains, 22-30% reduction was observed in the neuropeptide Y (NPY)-positive subpopulation of GABAergic neurons in SAMP8. Electrophysiological studies on hippocampal slices obtained at 4 weeks revealed that epileptiform activity, induced by high-frequency stimulation, lasted four times longer in SAMP8 compared with SAMR1, indicating a dysregulation of excitability that may be linked to the behavioral abnormalities of young SAMP8 and to neurodegeneration later on in life. Local attenuation of TH signaling may thus impact the normal development of the GABAergic system. PMID- 26250997 TI - Resveratrol metabolite profiling in clinical nutrition research--from diet to uncovering disease risk biomarkers: epidemiological evidence. AB - Resveratrol is a bioactive plant compound that has drawn scientific and media attention owing to its protective effects against a wide variety of illnesses, including cardiovascular diseases and cancer. In the last two decades, a plethora of preclinical studies have shown these beneficial effects, and some of them have been supported by clinical trials. However, there are few epidemiological studies assessing these relationships, showing mostly inconsistent results among them. This could be partially due to the difficulty of accurately estimating dietary resveratrol exposure. The development of Phenol-Explorer, a database containing resveratrol food-composition data, will facilitate the estimation of resveratrol intake. Moreover, the discovery and validation of a nutritional biomarker of this exposure, urinary resveratrol metabolite profile, will allow a more accurate assessment of dietary resveratrol exposure. Few epidemiological studies have assessed the potential health effects of resveratrol. Resveratrol was not associated with total mortality, cancer, or cardiovascular events, but it was associated with an improvement of serum glucose and triglyceride levels and a decrease in heart rate. Together, these findings suggest a potential cardioprotective effect of resveratrol in epidemiological studies, although the evidence is still scarce. PMID- 26250998 TI - Usefulness of Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol as Predictors of Cardiovascular Disease in Chinese. AB - The predictive effect of non-high-density lipoprotein cholesterol (non-HDL-C) for cardiovascular disease (CVD) in Chinese general population has not been well demonstrated. The aim of our study was to examine the relation between non-HDL-C and CVD and compare the predictive effect of non-HDL-C and low-density lipoprotein cholesterol (LDL-C) for CVD in Chinese population. The baseline examination of 27,020 participants aged 35 to 74 years from the China Cardiovascular Health Study and the China Multicenter Collaborative Study of Cardiovascular Epidemiology was conducted in 1998 to 2001. Follow-up evaluation was conducted in 2007 to 2008 with a response rate of 79.8%. Cox proportional hazards regression models were used to obtain the multivariable-adjusted hazard ratios and 95% confidence intervals (CIs) for CVD. Compared with those with non HDL-C level of <130 mg/dl, multivariable-adjusted hazard ratios of CVD were 1.30 (95% CI 1.04 to 1.62) and 1.93 (95% CI 1.50 to 2.47) in participants with non-HDL C levels of 160 to 189.9 and >=190 mg/dl, respectively. An increase of 30 mg/dl in non-HDL-C level would correspond to 15%, 24%, and 12% increase in risk of CVD, coronary heart disease, and stroke, respectively. Using likelihood ratio tests, non-HDL-C appeared to be a similar predictor for CVD incidence as LDL-C (chi square for non-HDL-C, 18.02, p <0.001; chi-square for LDL-C, 18.90, p <0.001). In conclusion, higher non-HDL-C level is associated with the increased CVD incidence and has a similar effect as LDL-C on predicting CVD risk in Chinese. PMID- 26250999 TI - Hypertrabeculation Is Noncompaction Also in Athletes. PMID- 26251000 TI - Risk Factors and Markers for Acute Myocardial Infarction With Angiographically Normal Coronary Arteries. AB - Myocardial Infarction with normal coronary arteries (MINCA) is common with a prevalence of 1% to 12% of all myocardial infarctions. The pathogenic mechanisms of MINCA are still unknown, but endothelial dysfunction has been suggested as a possible cause. To investigate risk factors and markers for MINCA, we conducted a case-control study. Considering the reported low prevalence of classical risk factors for coronary heart disease (CHD) in some but not all studies, our hypothesis was that endothelial function and intima-media thickness (IMT) were better, respectively lower, than CHD controls. One hundred patients with MINCA fulfilling diagnostic criteria according to the European Society of Cardiology/American Collage of Cardiology/American Heart Association universal definition of myocardial infarction with myocarditis excluded by cardiac magnetic resonance imaging were investigated. Risk factors, endothelial function (EndoPAT), and IMT were compared to gender- and age-matched patients with myocardial infarction and CHD, respectively healthy controls. Smoking, hypertension, impaired glucose tolerance and diabetes mellitus, inflammatory disease, and psychiatric disorders were more common in patients with MINCA than in healthy controls. In contrast to patients with CHD, the lipid profile was antiatherogenic with low low-density lipoprotein and high high-density lipoprotein cholesterol. There were no major differences between the groups regarding endothelial function and IMT that were in the normal range. In conclusion, the present study showed that MINCA was associated with many established cardiovascular risk factors without major differences in atherosclerosis markers. MINCA patients recalled a high prevalence of emotional stress before admission that together with previous psychiatric vulnerability and female gender speaks strongly in favor of Takotsubo syndrome being an important cause of MINCA. PMID- 26251001 TI - Relation of Combined Non-High-Density Lipoprotein Cholesterol and Apolipoprotein B With Atherosclerosis in Adults With Type 1 Diabetes Mellitus. AB - Apolipoprotein B (apoB) and non-high-density lipoprotein cholesterol (non-HDL-C) are cardiovascular disease risk markers, although data in adults with type 1 diabetes mellitus (DM) are limited. We hypothesized that elevated apoB and non HDL-C would be associated with greater odds of coronary artery calcification progression (CACp), a measure of coronary atherosclerosis, than either category alone in adults with type 1 DM. We grouped subjects with type 1 DM (n = 652) into 4 groups: elevated apoB (>=90 mg/dl) and elevated non-HDL-C (>=130 mg/dl), elevated non-HDL-C alone, elevated apoB alone, and normal apoB and non-HDL-C. We used logistic regression to examine the associations between the groups and CACp for a period of 6 years. We performed sensitivity analyses with elevated apoB and non-HDL-C redefined as at or more than the cohort means (91.4 and 119.0 mg/dl, respectively). Subjects with elevated apoB and non-HDL-C had greater odds of CACp compared with those with normal apoB and non-HDL-C (odds ratio 1.90, 95% confidence interval 1.15 to 3.15) and compared with subjects with elevated apoB alone (odds ratio 2.86, 95% confidence interval 1.43 to 5.74) adjusting for age, gender, duration, hemoglobin A1c, and statins. Similar results were obtained with elevated apoB and non-HDL-C defined as at or more than the cohort means. In conclusion, elevated apoB and non-HDL-C carry a greater risk of atherosclerosis than elevated apoB in the absence of elevated non-HDL-C in adults with type 1 DM. These data suggest that apoB and non-HDL-C should be viewed as complementary rather than competitive indexes of cardiovascular disease risk in type 1 DM. PMID- 26251002 TI - Determinants of Time of Recovery of Left Ventricular Function in Patients With Takotsubo Syndrome. PMID- 26251003 TI - Comparison Between Echocardiography and Cardiac Magnetic Resonance Imaging in Predicting Transplant-Free Survival After the Fontan Operation. AB - Adverse outcomes increase in frequency as patients after Fontan operation approach adulthood. Cardiac magnetic resonance (CMR) imaging-derived parameters have been shown to predict death/transplant; however, limited data are available on the usefulness of echocardiography in risk stratification. We conducted a retrospective, single-center review of records of patients after Fontan operation with an echocardiogram and CMR within 1 year of each other. The primary end point was time to all-cause mortality or listing for transplant. Of the 127 eligible patients, there were 12 end points (9%; 10 deaths and 2 listing for transplant). Median age was 16.8 years (interquartile range 12 to 23.1) with a median follow up of 3.8 years (interquartile range 2.6 to 5.7). Among clinical parameters, protein-losing enteropathy had the strongest association with the outcome. Among echocardiographic variables, global circumferential strain showed the strongest association (hazard ratio 1.3 per unit change, 95% confidence interval 1.1 to 1.5, p value 0.001, C-index 0.81), whereas among CMR variables indexed ventricular end-diastolic volume showed the strongest association with the outcome (hazard ratio 1.04 per 10 ml/BSA(1.3) increase in volume, 95% confidence interval 1.02 to 1.06, p value 0.001, C-index 0.82). Cox proportional hazards analysis revealed echocardiography and CMR models to each individually have a higher predictive ability than the clinical model; however, in direct comparison, neither technique was superior. In conclusion, both echocardiography-derived circumferential strain and CMR-derived ventricular end-diastolic volume index are associated with transplant-free survival in patients after Fontan operation. Echocardiography and CMR parameters have higher discriminative ability than clinical variables. Although neither imaging technique is superior in this cohort, both introduce important factors for risk stratification. PMID- 26251004 TI - Automated Computer-Assisted Diagnosis of Obstructive Coronary Artery Disease in Emergency Department Patients Undergoing 256-Slice Coronary Computed Tomography Angiography for Acute Chest Pain. AB - A 256-slice coronary computed tomography angiography (CCTA) is an accurate method for detection and exclusion of obstructive coronary artery disease (OBS-CAD). However, accurate image interpretation requires expertise and may not be available at all hours. The purpose of this study was to evaluate the usefulness of a fully automated computer-assisted diagnosis (COMP-DIAG) tool for exclusion of OBS-CAD in patients in the emergency department (ED) presenting with chest pain. Three hundred sixty-nine patients in ED without known coronary disease underwent 256-slice CCTA as part of the assessment of chest pain of uncertain origin. COMP-DIAG (CorAnalyzer II) automatically reported presence or exclusion of OBS-CAD (>50% stenosis, >=1 vessel). Performance characteristics of COMP-DIAG for exclusion and detection of OBS-CAD were determined using expert reading as the reference standard. Seventeen (5%) studies were unassessable by COMP-DIAG software, and 352 patients (1,056 vessels) were therefore available for analysis. COMP-DIAG identified 33% of assessable studies as having OBS-CAD, but the prevalence of OBS-CAD on CCTA was only 18% (66 of 352 patients) by standard expert reading. However, COMP-DIAG correctly identified 61 of the 66 patients (93%) with OBS-CAD with 21 vessels (2%) with OBS-CAD misclassified as negative. In conclusion, compared to expert reading, automated computer-assisted diagnosis using the CorAnalyzer showed high sensitivity but only moderate specificity for detection of obstructive coronary disease in patients in ED who underwent 256 slice CCTA. The high negative predictive value of this computer-assisted algorithm may be useful in the ED setting. PMID- 26251005 TI - Community-Based Mind-Body Meditative Tai Chi Program and Its Effects on Improvement of Blood Pressure, Weight, Renal Function, Serum Lipoprotein, and Quality of Life in Chinese Adults With Hypertension. AB - Obesity, metabolic syndrome, dyslipidemia, and poor quality of life are common conditions associated with hypertension, and incidence of hypertension is age dependent. However, an effective program to prevent hypertension and to improve biomedical factors and quality of life has not been adequately examined or evaluated in Chinese older adults. This study aims to examine the effectiveness of a Tai Chi program to improve health status in participants with hypertension and its related risk factors such as dyslipidemia, hyperglycemia, and quality of life in older adults in China. A randomized study design was used. At the conclusion of the intervention, 266 patients remained in the study. Blood pressure and biomedical factors were measured according to the World Diabetes Association standard 2002. A standardized quality-of-life measure was used to measure health-related quality of life. It was found that a Tai Chi program to improve hypertension in older adults is effective in reducing blood pressure and body mass index, maintaining normal renal function, and improving physical health of health-related quality of life. It did not improve existing metabolic syndrome levels, lipid level (dyslipidemia) or fasting glucose level (hyperglycemia), to prevent further deterioration of the biomedical risk factors. In conclusion, Tai Chi is effective in managing a number of risk factors associated with hypertension in Chinese older adults. Future research should examine a combination of Tai Chi and nutritional intervention to further reduce the level of biomedical risks. PMID- 26251006 TI - Diagnostic Accuracy of Cardiac Magnetic Resonance Imaging in the Evaluation of Newly Diagnosed Heart Failure With Reduced Left Ventricular Ejection Fraction. AB - The aim of this study was to determine the diagnostic value of cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement (LGE), cine imaging, and resting first-pass perfusion (FPP) in the evaluation for ischemic (IC) versus nonischemic (NIC) cardiomyopathy in new-onset heart failure with reduced (<=40%) left ventricular ejection fraction (HFrEF). A retrospective chart review analysis identified 83 patients from January 2009 to June 2012 referred for CMR imaging evaluation for new-onset HFrEF with coronary angiography performed within 6 months of CMR. The diagnosis of IC was established using Felker criteria on coronary angiography. CMR sequences were evaluated for the presence of patterns suggestive of severe underlying coronary artery disease as the cause of HFrEF (subendocardial and/or transmural LGE, regional wall motion abnormality on cine, regional hypoperfusion defect on resting FPP). Discriminative power was assessed using receiver operator characteristics curve analysis. Coronary angiography identified 36 patients (43%) with IC. Presence of subendocardial and/or transmural LGE alone demonstrated good discriminative power (C-statistic 0.85, 95% confidence interval 0.76 to 0.94) for the diagnosis of IC. The presence of an ischemic pattern on both LGE and cine sequences resulted in a specificity of 87% for the diagnosis of IC, whereas the absence of an ischemic pattern on both LGE and cine sequences resulted in a specificity of 94% for the diagnosis of NIC. Addition of resting FPP on a subset of patients did not improve diagnostic values. In conclusion, CMR has potential value in the diagnostic evaluation of IC versus NIC. PMID- 26251008 TI - The efficacy of propofol on emergence agitation--a meta-analysis of randomized controlled trials. AB - BACKGROUND: Emergence agitation (EA) is a common, post-anesthetic complication in pediatric patients following sevoflurane and desflurane anesthesia. The aim of this meta-analysis was to assess the effects of an adjunctive dose of propofol to reduce the incidence of EA in pediatric patients. METHODS: A comprehensive literature review was conducted to identify clinical trials focusing on the effects of propofol on EA in children under sevoflurane and desflurane anesthesia. The MEDLINE, EMBASE, Wiley Online Library, Web of Science, China National Knowledge Internet databases, and other sources were searched. The data were combined to calculate the pooled relative ratio (RR) or mean difference (MD), and relevant 95% confidence interval (CI). Heterogeneity and potential publication bias were assessed. The required information size was calculated and a Lan-DeMets sequential monitoring boundary was constructed to improve the precision of our findings. RESULTS: Data from 11 studies showed that an adjunctive dose of propofol conveyed a preventive effect on EA, as compared with placebo (RR = 0.56; 95% CI = 0.43-0.74; P < 0.0001). There was no significant difference in the length of stay in the post-anesthesia care unit between groups (MD = 0.25 min; 95% CI = -2.81 to 2.31; P = 0.85). The required information size was 2297 patients and the Lan-DeMets sequential monitoring boundary was crossed. However, most of the included studies had a high risk of bias and non-ignorable inter-study and clinical heterogeneity. CONCLUSION: Future studies on the benefits of adjunct propofol in reducing the incidence of EA are required. PMID- 26251007 TI - Endocytosis of Ubiquitylation-Deficient EGFR Mutants via Clathrin-Coated Pits is Mediated by Ubiquitylation. AB - Signaling by epidermal growth factor receptor (EGFR) is controlled by endocytosis. However, mechanisms of EGFR endocytosis remain poorly understood. Here, we found that the EGFR mutant lacking known ubiquitylation, acetylation and clathrin adaptor AP-2-binding sites (21KRDeltaAP2) was internalized at relatively high rates via the clathrin-dependent pathway in human duodenal adenocarcinoma HuTu-80 cells. RNA interference analysis revealed that this residual internalization is strongly inhibited by depletion of Grb2 and the E2 ubiquitin conjugating enzyme UbcH5b/c, and partially affected by depletion of the E3 ubiquitin ligase Cbl and ubiquitin-binding adaptors, indicating that an ubiquitylation process is involved. Several new ubiquitin conjugation sites were identified by mass spectrometry in the 21KRDeltaAP2 mutant, suggesting that cryptic ubiquitylation may mediate endocytosis of this mutant. Total internal reflection fluorescence microscopy imaging of HuTu-80 cells transfected with labeled ubiquitin adaptor epsin1 demonstrated that the ubiquitylation-deficient EGFR mutant was endocytosed through a limited population of epsin-enriched clathrin-coated pits (CCPs), although with a prolonged CCP lifetime. Native EGFR was recruited with the same efficiency into CCPs containing either AP-2 or epsin1 that were tagged with fluorescent proteins by genome editing of MDA-MD-231 cells. We propose that two redundant mechanisms, ubiquitylation and interaction with AP 2, contribute to EGFR endocytosis via CCPs in a stochastic fashion. PMID- 26251009 TI - Response to Editorial Comments to Varicocele is associated with varicose veins: A population-based case-control study. PMID- 26251010 TI - Carbon Nanotubes Released from an Epoxy-Based Nanocomposite: Quantification and Particle Toxicity. AB - Studies combining both the quantification of free nanoparticle release and the toxicological investigations of the released particles from actual nanoproducts in a real-life exposure scenario are urgently needed, yet very rare. Here, a new measurement method was established to quantify the amount of free-standing and protruding multiwalled carbon nanotubes (MWCNTs) in the respirable fraction of particles abraded from a MWCNT-epoxy nanocomposite. The quantification approach involves the prelabeling of MWCNTs with lead ions, nanocomposite production, abrasion and collection of the inhalable particle fraction, and quantification of free-standing and protruding MWCNTs by measuring the concentration of released lead ions. In vitro toxicity studies for genotoxicity, reactive oxygen species formation, and cell viability were performed using A549 human alveolar epithelial cells and THP-1 monocyte-derived macrophages. The quantification experiment revealed that in the respirable fraction of the abraded particles, approximately 4000 ppm of the MWCNTs were released as exposed MWCNTs (which could contact lung cells upon inhalation) and approximately 40 ppm as free-standing MWCNTs in the worst-case scenario. The release of exposed MWCNTs was lower for nanocomposites containing agglomerated MWCNTs. The toxicity tests revealed that the abraded particles did not induce any acute cytotoxic effects. PMID- 26251012 TI - A novel cysteine-free venom peptide with strong antimicrobial activity against antibiotics-resistant pathogens from the scorpion Opistophthalmus glabrifrons. AB - Antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, pose serious threat to human health. The outbreak of antibiotic-resistant pathogens in recent years emphasizes once again the urgent need for the development of new antimicrobial agents. Here, we discovered a novel antimicrobial peptide from the scorpion Opistophthalmus glabrifrons, which was referred to as Opisin. Opisin consists of 19 amino acid residues without disulfide bridges. It is a cationic, amphipathic, and alpha helical molecule. Protein sequence homology search revealed that Opisin shares 42.1-5.3% sequence identities to the 17/18-mer antimicrobial peptides from scorpions. Antimicrobial assay showed that Opisin is able to potently inhibit the growth of the tested Gram-positive bacteria with the minimal inhibitory concentration (MIC) values of 4.0-10.0 MUM; in contrast, it possesses much lower activity against the tested Gram-negative bacteria and a fungus. It is interesting to see that Opisin is able to strongly inhibit the growth of methicillin- and vancomycin-resistant pathogens with the MICs ranging from 2.0 to 4.0 MUM and from 4.0 to 6.0 MUM, respectively. We found that at a concentration of 5 * MIC, Opisin completely killed all the cultured methicillin-resistant Staphylococcus aureus. These results suggest that Opisin is a promising therapeutic candidate for the treatment of the antibiotic-resistant bacterial infections. PMID- 26251011 TI - Basal brain oxidative and nitrative stress levels are finely regulated by the interplay between superoxide dismutase 2 and p53. AB - Superoxide dismutases (SODs) are the primary reactive oxygen species (ROS) scavenging enzymes of the cell and catalyze the dismutation of superoxide radicals O2- to H2O2 and molecular oxygen (O2). Among the three forms of SOD identified, manganese-containing SOD (MnSOD, SOD2) is a homotetramer located wholly in the mitochondrial matrix. Because of the SOD2 strategic location, it represents the first mechanism of defense against the augmentation of ROS/reactive nitrogen species levels in the mitochondria for preventing further damage. This study seeks to understand the effects that the partial lack (SOD2( /+) ) or the overexpression (TgSOD2) of MnSOD produces on oxidative/nitrative stress basal levels in different brain isolated cellular fractions (i.e., mitochondrial, nuclear, cytosolic) as well as in the whole-brain homogenate. Furthermore, because of the known interaction between SOD2 and p53 protein, this study seeks to clarify the impact that the double mutation has on oxidative/nitrative stress levels in the brain of mice carrying the double mutation (p53(-/-) * SOD2(-/+) and p53(-/-) * TgSOD2). We show that each mutation affects mitochondrial, nuclear, and cytosolic oxidative/nitrative stress basal levels differently, but, overall, no change or reduction of oxidative/nitrative stress levels was found in the whole-brain homogenate. The analysis of well-known antioxidant systems such as thioredoxin-1 and Nrf2/HO-1/BVR-A suggests their potential role in the maintenance of the cellular redox homeostasis in the presence of changes of SOD2 and/or p53 protein levels. PMID- 26251014 TI - Site-Selective Peptide/Protein Cleavage. AB - Site-selective peptide/protein degradation through chemical cleavage methods is an important modification of biologically relevant macromolecules which complements enzymatic hydrolysis. In this review, recent progress in chemical, site-selective peptide bond cleavage is overviewed, with an emphasis on postulated mechanisms and their implications on reactivity, selectivity, and substrate scope. PMID- 26251013 TI - Dual-tasking gait variability and cognition in late-life depression. AB - OBJECTIVES: Studies have demonstrated an association between major depressive disorder (MDD) symptoms and fall risk in older adults, which may be at least partially mediated by executive functioning skills. There have also been observations of increased gait variability associated with fall risk and disease. This preliminary study first sought to understand whether gait variability in the context of dual task cost differs among older adults with MDD, relative to those with no history of psychiatric illness, and second, to identify relationships between gait variability measures and cognitive functioning in the context of MDD. METHODS: We recruited 15 older adults with MDD and 17 non-depressed (ND) community-dwelling older adults. All participants had impaired balance based on unipedal stance time. Assessments included neuropsychological measures and measures of gait variability using an instrumented gait mat (GAITRite(c) ) in the context of dual task relative to single task performance (i.e., dual task cost). RESULTS: The groups did not differ on any gait variability parameters. The MDD group demonstrated poorer performance in the psychomotor speed domain, relative to the ND group, but cognitive functioning between the groups in other domains was equivalent. In MDD, increased variability in stride time, stride velocity, and swing time during dual-tasking were associated with poorer executive functioning and visual memory. In ND, no significant relationships between gait variables and cognitive performance were observed. CONCLUSIONS: Findings suggest that unique cognitive mechanisms underlie mobility problems associated with fall risk in late-life depression. PMID- 26251015 TI - Diffusion-prepared neurography of the brachial plexus with a large field-of-view at 3T. AB - PURPOSE: To study diffusion-prepared neurography optimized for a large field-of view (FOV) to include the neck and both shoulders. In a large FOV poor homogeneity of the magnetic field (B0 ) often leads to poor image quality and possibly to poor diagnostic accuracy. The aim was therefore to find an optimal (combination of) shimming method(s) for diffusion-prepared neurography in a large FOV. MATERIALS AND METHODS: A 3D diffusion-prepared sequence with a large FOV was tested with and without the use of a susceptibility-matched pillow combined with image-based (IB) or standard shimming in six healthy volunteers on a 3T system. B0 , B1 , signal to noise ratio (SNR), and contrast to noise ratio (CNR) were compared between all protocols. Additionally, nerve visibility, fat suppression, artifacts, and overall image quality were ordinally (5-point scale) assessed by two readers. Furthermore, correlations between B0 and B1 (offset and variation) and SNR, CNR, and image quality were explored. RESULTS: The use of the susceptibility-matched pillow led to a 43% reduction of B0 variation over the brachial plexus compared to the situation without a pillow (P < 0.05). The combination of the pillow with IB-shimming and the optimized diffusion-prepared sequence resulted in good nerve visibility, good fat suppression, no artifacts that would hinder clinical diagnosis, and a good overall quality (median scores >=4). Reducing B0 variation was associated with SNR, CNR, and the above-mentioned scored features (P < 0.05). CONCLUSION: The use of a susceptibility-matched pillow in combination with IB-shimming enables robust and high-quality neurography of the complete brachial plexus. PMID- 26251019 TI - Shusterman replies. PMID- 26251016 TI - Recombinant filgrastim (BK0023) pharmacodynamics and pharmacokinetics after single and multiple escalating doses in an equivalence study in healthy men. AB - BACKGROUND AND OBJECTIVES: The new filgrastim formulation, BK0023, whose synthesis method is patented, was tested in a phase I clinical study that was aimed at investigating the pharmacodynamic and pharmacokinetic equivalence and the safety of BK0023 in healthy male subjects. METHODS: Single and multiple escalating doses were administered to healthy male volunteers according to a double-blind, randomised, two-way crossover design. Thirty-two subjects received subcutaneous filgrastim 2.5 ug/kg/day for 7 consecutive days in each period, 36 subjects received 5 ug/kg/day for 7 days in each period, and 22 subjects received 10 ug/kg/day for 5 days. Absolute neutrophil count (ANC) and CD34+ cell count were measured in whole blood as primary and secondary pharmacodynamic parameters. Filgrastim concentrations were measured in serum to calculate the primary pharmacokinetic parameters. RESULTS: The maximum ANC and the area under the curve of the ANC after the first dose and to the end of treatment satisfied the equivalence criterion (95 % confidence intervals within 85-115 or 85-117 % in case of log-transformation). At all three dose regimens, BK0023 was also bioequivalent to the reference product in terms of pharmacokinetic profile of serum filgrastim. The frequency of the treatment-emergent adverse events did not differ significantly between treatments, with the most frequent untoward effects being back and bone pain. CONCLUSIONS: Equivalence could be established using both the baseline-adjusted values and the original unadjusted values. The tested formulation at all three dose regimens was also bioequivalent to the reference product in terms of pharmacokinetic profile. PMID- 26251020 TI - Base-Catalyzed Selective Synthesis of 2-Azabicyclo[3.2.0]hept-2-enes and Sulfonyl Vinyl-Substituted Pyrroles from 3-Aza-1,5-enynes. AB - A base-catalyzed selective cycloisomerization of 3-aza-1,5-enynes is developed. This transformation provides a facile access to highly functionalized 2 azabicyclo[3.2.0]hept-2-enes and sulfonyl vinyl-substituted pyrroles. The chemoselectivity was controlled by the substituent pattern of the substrates. PMID- 26251021 TI - Reference data on muscle volumes of healthy human pelvis and lower extremity muscles: an in vivo magnetic resonance imaging feasibility study. AB - PURPOSE: Muscle volumes are of crucial interest when attempting to analyze individual physical performance and disease- or age-related alterations in muscle morphology. However, very little reference data are available in the literature on pelvis and lower extremity muscle volumes originating from healthy and young individuals. Furthermore, it is of interest if representative muscle volumes, covering large anatomical regions, can be obtained using magnetic resonance imaging (MRI) in a setting similar to the clinical routine. Our objective was therefore to provide encompassing, bilateral, 3-T MRI-based datasets on muscle volumes of the pelvis and the lower limb muscles. METHODS: T1-weighted 3-T MRI records were obtained bilaterally from six young and healthy participants. Three dimensional volumes were compiled from 28 muscles and muscle groups of each participant before the muscle volumes were computed. RESULTS: Muscle volumes were obtained from 28 muscles and muscle groups of the pelvis and lower extremity. Volumes were larger in male than in female participants. Volumes of the dominant and non-dominant sides were similar in both genders. The obtained results were in line with volumetric data obtained from smaller anatomical areas, thus extending the available datasets. CONCLUSIONS: This study provides an encompassing and feasible approach to obtain data on the muscle volumes of pelvic and limb muscles of healthy, young, and physically active individuals. The respective data form a basis to determine effects of therapeutic approaches, progression of diseases, or technical applications like automated segmentation algorithms applied to different populations. PMID- 26251022 TI - The internal anatomy of the inferior vena cava with specific emphasis on the entrance of the renal, gonadal and lumbar veins. AB - Major tributaries such as the renal and adrenal veins have been studied extensively; however, tributaries of the infra-renal segment of the inferior vena cava (IVC) have not been given much attention. Accurate knowledge of the anatomy of these veins is necessary for improved efficacy of surgical interventions in the retroperitoneum. The aim of this study therefore was to provide a comprehensive picture of the internal anatomy of the tributaries of the infra renal segment of the IVC. Dissection of the posterior abdominal wall was performed on 30 formalin-fixed cadavers. Endoscopic study was carried out followed by a midline venotomy on the anterior wall of the isolated IVC, the location and orientation of its tributaries and their ostia were observed and measurements taken. The results showed that while there was great variation in the drainage pattern of the lumbar veins, most lumbar veins had ostia located between L2 and L3 vertebrae irrespective of the location of renal and gonadal tributaries. Valves were found in 81.81 % of gonadal veins, in 56.60 % of all lumbar veins and discrete ostial valves in 14.81 % of renal veins. The location of the tributaries of the IVC was correlated with the vertebral levels. Empirical data regarding their ostio-valvular complexes were established, which put into question widely accepted concept of valveless tributaries. Our results may implicate surgical procedures in and around the retroperitoneal region. PMID- 26251023 TI - Internal carotid artery agenesis associated with a rare collateral pathway: supraclinoid-supraclinoid anastomosis. A case report. AB - Internal carotid artery (ICA) agenesis is an infrequent vascular anomaly, less than 0.01% of the population. Here we report a case of internal carotid agenesis with a rare collateral pathway, via supraclinoid ICA anastomosis to the contralateral supraclinoid ICA. PMID- 26251024 TI - Accessory articulation of elongated anterior transverse process: a rare anatomical variant of the cervical spine depicted with CT and post-processing techniques. AB - There are several described anatomical variants of the cervical spine, ranging from common to extremely rare, which may have different clinical implications. We present the case of an extremely rare anatomical variant of the cervical spine, in a symptomatic patient, consisting of a unilateral accessory articulation between the 5th and 6th cervical vertebrae, due to elongated anterior transverse processes. Our search found only three cases in the English literature describing similar findings to the case here reported. Our case is, to our knowledge, the first report of this anatomical variant imaged with computed tomography including post-processing images (volume rendering technology and multiplanar reformations), which contribute greatly to a better understanding and depiction of the anatomical variant. PMID- 26251025 TI - Excessive substance use among young people consulting family doctors: a cross sectional study. AB - BACKGROUND: Family doctors can only play a role in the prevention of excessive substance use in young people if those affected are seen in the practice. OBJECTIVE: To describe the prevalence of excessive substance use among young people consulting family doctors in a European context. METHODS: As part of a trial of an intervention addressing substance use we collected data from young people consulting 32 family doctors in the French-speaking part of Switzerland. Before the consultation, consecutive patients aged 15-24 years completed a self administered questionnaire on their general health and substance use. Outcomes were excessive alcohol (defined as >=1 episode of binge drinking), excessive cannabis (use >=1/week), regular tobacco (>=1 cigarettes a day) and/or any other substance use in the past 30 days. Prevalence data were computed with 95% confidence intervals (CIs) adjusted for clustering within practices, stratified by age and gender. RESULTS: Between February 2009 and November 2010, 636 patients were eligible. Participation rate was 93.4% (n=594, 53% female). The prevalence of excessive use in the past 30 days was alcohol 44.9% (95% CI: 37.8-52.1), cannabis 11.1% (95% CI: 8.0-14.1), tobacco 23.4% (95% CI: 19.0-28.1) and any other drug 2.6 (95% CI: 1.4-4.2). Excessive use was higher in males than in females. Except for tobacco prevalence of excessive use was only slightly higher in young adults compared to adolescents. CONCLUSION: Excessive substance use is frequent among young people consulting family doctors in a European context. Future research should provide guidance about how to best seize this window of opportunity for prevention and early intervention. PMID- 26251026 TI - Anticoagulant management of atrial fibrillation: the influence of dosing algorithm and recall schedule on time in therapeutic range. AB - BACKGROUND: The quality of anticoagulation management in atrial fibrillation patients is reflected by the concept of time spent in therapeutic range (TTR). In a primary care setting, the implementation of a dose nomogram could help increase the mean TTR among these patients. OBJECTIVE: This study compares the influence of a dose algorithm with an integrated recall on TTR prior to standard care and after the implementation of the protocol. PATIENTS AND METHODS: In a purposive sample of patients with AF, an uncontrolled 'before' and 'after' study design was utilized to measure the effects of the protocol on TTR. Demographic data, TTR levels, frequency of international normalized ratio (INR) within therapeutic range, clinician adherence to dose nomogram and warfarin dose changes were captured from consultations at the anticoagulation clinic. RESULTS: A total of 152 patients with AF were entered into the final analysis. The increment in mean TTR in the 'after' intervention phase (2.9%) was not statistically significant (57.5-60.4%, P=0.252). The increase in the frequency of INR values within therapeutic range in the 'after' intervention phase was significant (50.0-56.0%, P<0.05) but with a very low effect size (r=0.04). CONCLUSIONS: The implementation of a dose nomogram has the potential of reducing unnecessary dose changes for minor fluctuations in INR levels. The findings in this study needs to be confirmed in a future study involving other indications for anticoagulation, various regional primary care clinics and a larger population size. PMID- 26251027 TI - Restarting antidepressant treatment following early discontinuation--a primary care database study. AB - BACKGROUND: Many patients in primary care stop antidepressant treatment after only one prescription, so do not benefit from treatment. Some patients who stop initial antidepressant treatment go on to restart it, but neither the incidence of restarting nor the probability that patients who restart treatment subsequently complete an adequate course of treatment is known. OBJECTIVE: To examine subsequent antidepressant use in patients who discontinued treatment after only one antidepressant prescription. METHODS: We used a primary care database (over 1.2 million records) to study patients who commenced treatment with an eligible antidepressant between April 2007 and March 2008 and who stopped treatment for at least 1 month after the first prescription. We examined their subsequent antidepressant prescriptions to estimate the probability of restarting antidepressant treatment, the likelihood of continuing subsequent treatment and the patient characteristics associated with these. RESULTS: Out of 24817 patients, 6952 (28%) patients discontinued antidepressant treatment after the first prescription. The cumulative probability of restarting treatment after early discontinuation was 8.6% (95% confidence interval [CI] 8.0-9.3) after 1 month off-treatment, and 24.1% (22.9-25.2) after 9 months off-treatment. The probability of those who restarted treatment continuing for 6 months or more was 29.3% (26.5-32.5). CONCLUSIONS: Few patients who stop antidepressant treatment after the first prescription subsequently complete an adequate treatment course within the next year. Initiatives to promote adherence to appropriate antidepressant treatment should begin during the first prescription. PMID- 26251028 TI - High-resolution detection of sustained ventricular and supraventricular tachycardia through FPGA-based fuzzy processing of ECG signal. AB - The paper presents a field-programmable gate array (FPGA)-based fast processing system with 12-channel high-resolution (24 bits) front-end for ECG signal processing. The implemented high-resolution data conversion makes the system suitable for recording of late potentials of the QRS complex in patients prone to sustained ventricular tachycardia. The system accepts ECG signals through 12 channels and then filtered to minimize baseline wander and power-line interference. The filter outputs are connected to 12 delta-sigma ADCs. The whole ADCs work synchronously at 8 kHz sampling frequency, and their output data are transferred to an FPGA that computes online on the digitized sample values in real time and ascertains whether the patient under study suffers from ventricular tachycardia or not. In order to ascertain the QRS complex accurately in the noisy ECG signal, fuzzy entropy of the sample values has been computed and provided as an input to inverse multiquadratic radial basis function neural network. Using the standard CSE ECG database, the algorithm performed highly effectively. The performance of the algorithm in respect of QRS detection with sensitivity of 99.83 % and accuracy of 99.7 % is achieved when tested using single-channel ECG with entropy criteria. The performance of the QRS detection system has been compared and found to be better than most of the QRS detection systems available in the literature. Using the system, 200 patients have been diagnosed with an accuracy of 99 %. PMID- 26251029 TI - S100, bcl2 and myeloperoxid protein expirations during periodontal inflammation. AB - BACKGROUND: Periodontal inflammation is characterized by injuries in collagen, epithelial, bone tissues. The hypotheses to be tested were relationship between the s100, bcl2 and myeloperoxidase in gingival tissues (MPO does affect the level of s100, bcl2). The object of this study was to investigate of s100 expression, bcl2 expression and myeloperoxidase expression in periodontal inflammation. METHODS: 27 patients (giant-cell epulis) and 30 patients (acute and chronic inflammations) were included in the study for s100 expression, bcl2 expression and myeloperoxidase expression by immunohistochemistry and hematoxylin--eosin. RESULTS: Giant-cells in epulis positivity for myeloperoxidase has been observed in 100% However, only 75.31% of giant-cells were positive for bcl2 expression. Acute 98.2%, and chronic 89.28% inflammation was a significant positive for myeloperoxidase. The immunohistochemical findings of s100, bcl 2 and myeloperoxidase in epithelial layers have showed the result of 100%, 82,2%, 100% positive cells in acute and 100%, 78.25%, 100% in chronic process of inflammation respectively. CONCLUSION: The results indicate that the pathogenesis of periodontal inflammation might involve inhibition of cell death, through the overexpression of bcl-2, due to identifying factors myeloperoxidase (result in the DNA damage by the product of catalysis). The highest levels of s100 activity have been found at sites with chronic inflammation. PMID- 26251030 TI - Novel analogs targeting histone deacetylase suppress aggressive thyroid cancer cell growth and induce re-differentiation. AB - To develop novel therapies for aggressive thyroid cancers, we have synthesized a collection of histone deacetylase (HDAC) inhibitor analogs named AB1 to AB13, which have different linkers between a metal chelating group and a hydrophobic cap. The purpose of this study was to screen out the most effective compounds and evaluate the therapeutic efficacy. AB2, AB3 and AB10 demonstrated the lowest half maximal inhibitory concentration (IC50) values in one metastatic follicular and two anaplastic thyroid cancer cell lines. Treatment with each of the three ABs resulted in an increase in apoptosis markers, including cleaved poly adenosine diphosphate ribose polymerase (PARP) and cleaved caspase 3. Additionally, the expression of cell-cycle regulatory proteins p21(WAF1) and p27(Kip1) increased with the treatment of ABs while cyclin D1 decreased. Furthermore, AB2, AB3 and AB10 were able to induce thyrocyte-specific genes in the three thyroid cancer cell lines indicated by increased expression levels of sodium iodide symporter, paired box gene 8, thyroid transcription factor 1 (TTF1), TTF2 and thyroid stimulating hormone receptors. AB2, AB3 and AB10 suppress thyroid cancer cell growth via cell-cycle arrest and apoptosis. They also induce cell re differentiation, which could make aggressive cancer cells more susceptible to radioactive iodine therapy. PMID- 26251031 TI - Expression of p53 synergistically augments caspases-mediated apoptosis induced by replication-competent adenoviruses in pancreatic carcinoma cells. AB - We examined cytotoxicity of replication-competent type 5 adenoviruses (Ad5) in human pancreatic carcinoma cells with a p53-defective genotype. The replication competent Ad5 of which E1A gene was activated by exogenous transcriptional regulatory sequences, derived from the midkine and survivin genes, achieved cytotoxicity to the pancreatic carcinoma. These cells were susceptible to replication-incompetent Ad5 expressing the wild-type p53 gene. We also produced the replication-competent Ad5 bearing the same exogenous regulatory sequences and the type 35 Ad-derived fiber-knob region, and showed that the cytotoxicity was comparable to that of the replication-competent Ad5 prototype. We then investigated possible combinatory effects of the fiber-modified replication competent Ad and Ad5 expressing the wild-type p53 gene, both of which did not interfere respective infections. The combination produced synergistic cytotoxic effects with enhanced cleavages of caspase-3 and PARP molecules, and with increased sub-G1 fractions and annexin V-positive populations although the viral production of the replication-competent Ad was rather suppressed by expressed p53. Pancreatic cells infected with both Ad showed increase of p53 and decrease of MDM2 and p21 levels, compared with those infected with Ad expressing the p53 gene. These data collectively indicated that replication-competent Ad augmented susceptibility of pancreatic cells to apoptosis through upregulated p53 expression. PMID- 26251032 TI - Molecular characterization of an apoptotic strain of Newcastle disease virus isolated from an outbreak in India. AB - Newcastle disease (ND) is a highly contagious disease of poultry. The ND virus (NDV) encodes an error-prone RNA-dependent RNA polymerase which can cause high mutation rate leading to the emergence of its new antigenic variants. Antigenic difference of NDV strains may result in massive outbreak in vaccinated and unvaccinated poultry flocks around the globe. Apart from its pathogenic potential NDV has been explored as an oncolytic agent for a broad range of human cancers. In the present study, we isolated a novel NDV strain from an outbreak in chicken flock from the eastern part of India. Molecular characterization showed the NDV strain to be virulent in nature. The complete genome sequence analysis of the newly isolated strains belongs to genotype XIII. Moreover, the newly isolated strain of NDV showed positive results in various apoptotic assays in human breast cancer cells, MCF-7. The study will be useful to explore the possibility of using a newly isolated strain of NDV for virotherapy. PMID- 26251033 TI - Molecular cloning and expression analysis of adiponectin and its receptors (AdipoR1 and AdipoR2) in the hypothalamus of the Huoyan goose during different stages of the egg-laying cycle. AB - BACKGROUND: Adiponectin and its receptors (AdipoR1 and AdipoR2) are novel endocrine systems that act at various levels to regulate metabolic homeostasis and reproductive processes. We cloned and characterized the cDNA of adiponectin and its receptors from the hypothalamus of the Huoyan goose to reveal the influence of these factors on the process of goose egg-laying. We also determined the mRNA and protein expression profiles during different stages of the egg laying cycle. METHODS: Hypothalamus tissues were obtained from 36 Huoyan geese in the pre-laying, early-laying, peak-laying, and ceased periods. The cDNA sequences of goose adiponectin and its receptors (AdipoR1 and AdipoR2) were cloned and characterized using the 5'-RACE and 3'-RACE methods. Multiple alignments and phylogenetic analyses of the deduced amino acid sequence were conducted using bioinformatics tools. The expression profiles of mRNA and protein in the hypothalamus during the pre-laying, early-laying, peak-laying and ceased periods were examined using real-time PCR (qRT-PCR) and Western blotting techniques. RESULTS: The cDNA of adiponectin, AdipoR1 and AdipoR2 consisted of 738, 1131 and 1161 bp open reading frame encoding 245, 376 and 386 amino acids, respectively. The deduced amino acid sequence of goose adiponectin, as well as AdipoR1 and AdipoR2 showed a closer genetic relationship to the avian species than to other mammal species. The expression level of adiponectin mRNA and protein increased from the pre-laying period to the peak-laying period, reached its peak in the peak-laying period, and then decreased during the ceased period. Conversely, the expression levels of AdipoR1 and AdipoR2 mRNA and protein decreased in the early laying period, peak-laying period, and ceased period compared with the pre-laying period. CONCLUSIONS: This study is the first to obtain full-length cDNA sequences of goose adiponectin and the genes of its receptors from the hypothalamus, and demonstrate that the egg-laying cycle affects the expression of the goose adiponectin system. Our results suggest the potential role of adiponectin as a key neuromodulator of reproductive functions. PMID- 26251034 TI - The molecular landscape of premenopausal breast cancer. AB - INTRODUCTION: Breast cancer in premenopausal women (preM) is frequently associated with worse prognosis compared to that in postmenopausal women (postM), and there is evidence that preM estrogen receptor-positive (ER+) tumors may respond poorly to endocrine therapy. There is, however, a paucity of studies characterizing molecular alterations in premenopausal tumors, a potential avenue for personalizing therapy for this group of women. METHODS: Using TCGA and METABRIC databases, we analyzed gene expression, copy number, methylation, somatic mutation, and reverse-phase protein array data in breast cancers from >2,500 preM and postM women. RESULTS: PreM tumors showed unique gene expression compared to postM tumors, however, this difference was limited to ER+ tumors. ER+ preM tumors showed unique DNA methylation, copy number and somatic mutations. Integrative pathway analysis revealed that preM tumors had elevated integrin/laminin and EGFR signaling, with enrichment for upstream TGFbeta regulation. Finally, preM tumors showed three different gene expression clusters with significantly different outcomes. CONCLUSION: Together these data suggest that ER+ preM tumors have distinct molecular characteristics compared to ER+ postM tumors, particularly with respect to integrin/laminin and EGFR signaling, which may represent therapeutic targets in this subgroup of breast cancers. PMID- 26251036 TI - [Routine fluoroscopic investigations after primary bariatric surgery]. AB - BACKGROUND: Staple line and anastomotic leakages are life-threatening complications after bariatric surgery. Upper gastrointestinal (GI) tract X-ray examination with oral administration of a water-soluble contrast agent can be used to detect leaks. The aim of this study was to evaluate the impact of routine upper GI tract fluoroscopy after primary bariatric surgery. METHODS: Between January 2009 and December 2014 a total of 658 bariatric interventions were carried out of which 442 were primary bariatric operations. Included in this single center study were 307 sleeve gastrectomies and 135 Roux-en-Y gastric bypasses. Up to December 2012 upper GI tract fluoroscopy was performed routinely between the first and third postoperative days and the detection of leakages was evaluated. RESULTS: In the investigation period 8 leakages (2.6 %) after sleeve gastrectomy, 1 anastomotic leakage in gastrojejunostomy and 1 in jejunojejunostomy after Roux-en-Y gastric bypass occurred. All patients developed clinical symptoms, such as abdominal pain, tachycardia or fever. In one case the leakage was detected by upper GI fluoroscopy and in nine cases radiological findings were unremarkable. No leakages were detected in asymptomatic patients. CONCLUSION: Routine upper GI fluoroscopy is not recommended for uneventful postoperative courses after primary bariatric surgery. PMID- 26251037 TI - Practitioner Review: Borderline personality disorder in adolescence--recent conceptualization, intervention, and implications for clinical practice. AB - BACKGROUND: The past decade has seen an unprecedented increase in research activity on personality disorders (PDs) in adolescents. The increase in research activity, in addition to major nosological systems legitimizing the diagnosis of borderline personality disorder (BPD) in adolescents, highlights the need to communicate new research on adolescent personality problems to practitioners. SCOPE: In this review, we provide up-to-date information on the phenomenology, prevalence, associated clinical problems, etiology, and intervention for BPD in adolescents. Our aim was to provide a clinically useful practitioner review and to dispel long-held myths about the validity, diagnostic utility, and treatability of PDs in adolescents. FINDINGS AND CONCLUSION: Alongside providing up-to-date information on the phenomenology, prevalence, and etiology, we also report on associated clinical problems and interventions for adolescent BPD. It is only through early active assessment and identification of youngsters with these problems that a lifetime of personal suffering and health system burden can be reduced or altogether avoided. A variety of evidence-based approaches are now available to treat BPD and related clinical problems in young people. Future research should focus on establishing optimal precision in the diagnostic processes in different treatment settings. PMID- 26251035 TI - Trends in genome dynamics among major orders of insects revealed through variations in protein families. AB - BACKGROUND: Insects belong to a class that accounts for the majority of animals on earth. With over one million identified species, insects display a huge diversity and occupy extreme environments. At present, there are dozens of fully sequenced insect genomes that cover a range of habitats, social behavior and morphologies. In view of such diverse collection of genomes, revealing evolutionary trends and charting functional relationships of proteins remain challenging. RESULTS: We analyzed the relatedness of 17 complete proteomes representative of proteomes from insects including louse, bee, beetle, ants, flies and mosquitoes, as well as an out-group from the crustaceans. The analyzed proteomes mostly represented the orders of Hymenoptera and Diptera. The 287,405 protein sequences from the 18 proteomes were automatically clustered into 20,933 families, including 799 singletons. A comprehensive analysis based on statistical considerations identified the families that were significantly expanded or reduced in any of the studied organisms. Among all the tested species, ants are characterized by an exceptionally high rate of family gain and loss. By assigning annotations to hundreds of species-specific families, the functional diversity among species and between the major clades (Diptera and Hymenoptera) is revealed. We found that many species-specific families are associated with receptor signaling, stress-related functions and proteases. The highest variability among insects associates with the function of transposition and nucleic acids processes (collectively coined TNAP). Specifically, the wasp and ants have an order of magnitude more TNAP families and proteins relative to species that belong to Diptera (mosquitoes and flies). CONCLUSIONS: An unsupervised clustering methodology combined with a comparative functional analysis unveiled proteomic signatures in the major clades of winged insects. We propose that the expansion of TNAP families in Hymenoptera potentially contributes to the accelerated genome dynamics that characterize the wasp and ants. PMID- 26251038 TI - Blow Flies from Forest Fragments Embedded in Different Land Uses: Implications for Selecting Indicators in Forensic Entomology. AB - Given the general expectation that forest loss can alter biodiversity patterns, we hypothesize that blow fly species abundances differ in a gradient of native vegetation cover. This study was conducted in 17 fragments across different landscapes in central Brazil. Different land cover type proportions were used to represent landscape structure. In total, 2334 specimens of nine species of Calliphoridae were collected. We used principal component analysis (PCA) to reduce dimensionality and multicollinearity of the landscape data. The first component explained 70%, and it represented a gradient of forest-pasture land uses. Alien species showed a wide distribution in different fragments with no clear relationship between the abundance values and the scores of PCA axes, whereas native species occurred only in areas with a predominance of forest cover. Our study revealed that certain native species may be sensitive to forest loss at the landscape scale, and they represent a bioindicator in forensic entomology. PMID- 26251040 TI - Benchmarking Outpatient Rehabilitation Clinics Using Functional Status Outcomes. AB - OBJECTIVE: To utilize functional status (FS) outcomes to benchmark outpatient therapy clinics. DATA SOURCES: Outpatient therapy data from clinics using Focus on Therapeutic Outcomes (FOTO) assessments. STUDY DESIGN: Retrospective analysis of 538 clinics, involving 2,040 therapists and 90,392 patients admitted July 2006 June 2008. FS at discharge was modeled using hierarchical regression methods with patients nested within therapists within clinics. Separate models were estimated for all patients, for those with lumbar, and for those with shoulder impairments. All models risk-adjusted for intake FS, age, gender, onset, surgery count, functional comorbidity index, fear-avoidance level, and payer type. Inverse probability weighting adjusted for censoring. DATA COLLECTION METHODS: Functional status was captured using computer adaptive testing at intake and at discharge. PRINCIPAL FINDINGS: Clinic and therapist effects explained 11.6 percent of variation in FS. Clinics ranked in the lowest quartile had significantly different outcomes than those in the highest quartile (p < .01). Clinics ranked similarly in lumbar and shoulder impairments (correlation = 0.54), but some clinics ranked in the highest quintile for one condition and in the lowest for the other. CONCLUSIONS: Benchmarking models based on validated FS measures clearly separated high-quality from low-quality clinics, and they could be used to inform value-based-payment policies. PMID- 26251041 TI - VPS35 pathogenic mutations confer no dominant toxicity but partial loss of function in Drosophila and genetically interact with parkin. AB - Mutations in VPS35 (PARK17) cause autosomal dominant, late onset Parkinson's disease (PD). VPS35 forms a core component of the retromer complex that mediates the retrieval of membrane proteins from endosomes back to either the Golgi or plasma membrane. While aberrant endosomal protein sorting has been linked to several neurodegenerative diseases, the mechanisms by which VPS35 mutations and retromer function contribute to PD pathogenesis are not clear. To address this, we generated transgenic Drosophila that express variant forms of human VPS35 found in PD cases and the corresponding variants of the Drosophila ortholog. We did not find evidence of dominant toxicity from any variant form including the pathogenic D620N mutation, even with aging. However, assessing the ability of Vps35 variants to rescue multiple vps35-mutant phenotypes, we found that the D620N mutation confers a partial loss of function. Recently, VPS35 has been linked to the formation of mitochondria-derived vesicles, which mediate the degradation of mitochondrial proteins and contribute to mitochondrial quality control. This process is also promoted by two other PD-lined genes parkin (PARK2) and PINK1 (PARK6). We demonstrate here that vps35 genetically interacts with parkin but interestingly not with pink1. Strikingly, Vps35 overexpression is able to rescue several parkin-mutant phenotypes. Together these findings provide in vivo evidence that the D620N mutation likely confers pathogenicity through a partial loss of function mechanism and that this may be linked to other known pathogenic mechanisms such as mitochondrial dysfunction. PMID- 26251039 TI - Potential roles of microRNA-29a in the molecular pathophysiology of T-cell acute lymphoblastic leukemia. AB - Recent evidence has shown that deregulated expression of members of the microRNA 29 (miR-29) family may play a critical role in human cancer, including hematological malignancies. However, the roles of miR-29 in the molecular pathophysiology of T-cell acute lymphoblastic leukemia (T-ALL) has not been investigated. Here, we show that lower levels of miR-29a were significantly associated with higher blast counts in the bone marrow and with increased disease free survival in T-ALL patients. Furthermore, miR-29a levels are extremely reduced in T-ALL cells compared to normal T cells. Microarray analysis following introduction of synthetic miR-29a mimics into Jurkat cells revealed the downregulation of several predicted targets (CDK6, PXDN, MCL1, PIK3R1, and CXXC6), including targets with roles in active and passive DNA demethylation (such as DNMT3a, DNMT3b, and members of the TET family and TDG). Restoring miR 29a levels in Jurkat and Molt-4 T-ALL cells led to the demethylation of many genes commonly methylated in T-ALL. Overall, our results suggest that reduced miR 29a levels may contribute to the altered epigenetic status of T-ALL, highlighting its relevance in the physiopathology of this disease. PMID- 26251042 TI - Pathogenic Cx31 is un/misfolded to cause skin abnormality via a Fos/JunB-mediated mechanism. AB - Mutations in connexin-31 (Cx31) are associated with multiple human diseases, including familial erythrokeratodermia variabilis (EKV). The pathogenic mechanism of EKV-associated Cx31 mutants remains largely elusive. Here, we show that EKV pathogenic Cx31 mutants are un/misfolded and temperature sensitive. In Drosophila, expression of pathogenic Cx31, but not wild-type Cx31, causes depigmentation and degeneration of ommatidia that are rescued by expression of either dBip or dHsp70. Ectopic expression of Cx31 in mouse skin results in skin abnormalities resembling human EKV. The affected tissues show remarkable disrupted gap junction formation and significant upregulation of chaperones Bip and Hsp70 as well as AP-1 proteins c-Fos and JunB, in addition to molecular signatures of skin diseases. Consistently, c-Fos, JunB, Bip and Hsp70 are strikingly higher in keratinocytes of EKV patients than their matched control individuals. Furthermore, a druggable AP-1 inhibitory small molecule suppresses skin phenotype and pathological abnormalities of transgenic Cx31 mice. The study suggests that Cx31 mutant proteins are un/misfolded to cause EKV likely via an AP 1-mediated mechanism and identifies a small molecule with therapeutic potential of the disease. PMID- 26251043 TI - Pathogenic LRRK2 mutations, through increased kinase activity, produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression. AB - Lysosomal dysfunction plays a central role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease (PD). Several genes linked to genetic forms of PD, including leucine-rich repeat kinase 2 (LRRK2), functionally converge on the lysosomal system. While mutations in LRRK2 are commonly associated with autosomal-dominant PD, the physiological and pathological functions of this kinase remain poorly understood. Here, we demonstrate that LRRK2 regulates lysosome size, number and function in astrocytes, which endogenously express high levels of LRRK2. Expression of LRRK2 G2019S, the most common pathological mutation, produces enlarged lysosomes and diminishes the lysosomal capacity of these cells. Enlarged lysosomes appears to be a common phenotype associated with pathogenic LRRK2 mutations, as we also observed this effect in cells expressing other LRRK2 mutations; R1441C or Y1699C. The lysosomal defects associated with these mutations are dependent on both the catalytic activity of the kinase and autophosphorylation of LRRK2 at serine 1292. Further, we demonstrate that blocking LRRK2's kinase activity, with the potent and selective inhibitor PF-06447475, rescues the observed defects in lysosomal morphology and function. The present study also establishes that G2019S mutation leads to a reduction in lysosomal pH and increased expression of the lysosomal ATPase ATP13A2, a gene linked to a parkinsonian syndrome (Kufor-Rakeb syndrome), in brain samples from mouse and human LRRK2 G2019S carriers. Together, these results demonstrate that PD-associated LRRK2 mutations perturb lysosome function in a kinase-dependent manner, highlighting the therapeutic promise of LRRK2 kinase inhibitors in the treatment of PD. PMID- 26251044 TI - Increased levels of interleukin-6 exacerbate the dystrophic phenotype in mdx mice. AB - Duchenne muscular dystrophy (DMD) is characterized by progressive lethal muscle degeneration and chronic inflammatory response. The mdx mouse strain has served as the animal model for human DMD. However, while DMD patients undergo extensive necrosis, the affected muscles of adult mdx mice rapidly regenerates and regains structural and functional integrity. The basis for the mild effects observed in mice compared with the lethal consequences in humans remains unknown. In this study, we provide evidence that interleukin-6 (IL-6) is causally linked to the pathogenesis of muscular dystrophy. We report that forced expression of IL-6, in the adult mdx mice, recapitulates the severe phenotypic characteristics of DMD in humans. Increased levels of IL-6 exacerbate the dystrophic muscle phenotype, sustaining inflammatory response and repeated cycles of muscle degeneration and regeneration, leading to exhaustion of satellite cells. The mdx/IL6 mouse closely approximates the human disease and more faithfully recapitulates the disease progression in humans. This study promises to significantly advance our understanding of the pathogenic mechanisms that lead to DMD. PMID- 26251045 TI - Inactive nurses in Taiwan: human capital, intention to return to hospital nursing, and incentives for returning. AB - AIMS: To investigate inactive nurses' human capital, intention to return to hospital nursing and incentives for returning. BACKGROUND: Few studies have discussed the loss of human capital with regard to inactive nurses and how to attract them to return to clinical work. METHOD: Systematic random sampling was used, with 328 subjects completing the mailed questionnaires, resulting in a response rate of 25.4%. RESULTS: Inactive nurses not only had moderate to high human capital (average years of nursing experience was 10.29, with moderate to high levels of nursing professional commitment and nursing competence) and were young. Forty-three percent of subjects reported intending to return to hospital nursing. Sufficient nurse staffing, greater safety in the working environment, and re-entry preparation programmes were incentives for returning. CONCLUSIONS: Recruiting inactive nurses back to hospital work is vital and feasible as inactive nurses had a moderate to high degree of human capital. The most feasible way is offering reasonable working conditions, in particular, providing sufficient staffing, a safe working environment and re-entry preparation programmes. IMPLICATIONS FOR NURSING MANAGEMENT: The findings confirm the human capital of inactive nurses and provide concrete directions for nursing managers to follow when recruiting inactive nurses to hospital nursing. PMID- 26251046 TI - Possible Alternatives to Diagnosis-Based Denominators for Addiction Treatment Quality Measures. AB - Consumers of healthcare quality measures are often unaware of how measured performance may be driven by diagnosing practices rather than the provision of high quality care. Reliance on quality metrics that depend on documented diagnoses can therefore subvert comparisons between clinicians, facilities or systems. In this study, three versions of an alcohol use disorder (AUD) treatment quality measure were calculated: method 1--the usual denominator including all diagnosed patients; method 2--a "population-based" denominator including the entire facility census; and method 3-an epidemiologically-derived denominator comprising the expected prevalence of AUD based on case-mix characteristics and geographic region. Performance rankings under the three specifications were calculated. Changes in percentile rank of up to 30-45% were observed between methods. Therefore, much of the observed between-facility differences on diagnosis-based quality measures may reflect variation in the propensity to diagnose rather than real differences in performance. Stakeholders must decide which of the validity threats produced by these different methods is least worrisome. PMID- 26251047 TI - Surface Buckling and Subsurface Oxygen: Atomistic Insights into the Surface Oxidation of Pt(111). AB - Platinum is a catalyst of choice in scientific investigations and technological applications, which are both often carried out in the presence of oxygen. Thus, a fundamental understanding of platinum's (electro)catalytic behavior requires a detailed knowledge of the structure and degree of oxidation of platinum surfaces in operando. ReaxFF reactive force field calculations of the surface energies for structures with up to one monolayer of oxygen on Pt(111) reveal four stable surface phases characterized by pure adsorbate, high- and low-coverage buckled, and subsurface-oxygen structures, respectively. These structures and temperature programmed desorption (TPD) spectra simulated from them compare favorably with and complement published scanning tunneling microscopy (STM) and TPD experiments. The surface buckling and subsurface oxygen observed here influence the surface oxidation process, and are expected to impact the (electro)catalytic properties of partially oxidized Pt(111) surfaces. PMID- 26251048 TI - HIV care continuum among men who have sex with men and persons who inject drugs in India: barriers to successful engagement. AB - BACKGROUND: We characterize the human immunodeficiency virus (HIV) care continuum for men who have sex with men (MSM) and persons who inject drugs (PWID) across India. METHODS: We recruited 12 022 MSM and 14 481 PWID across 26 Indian cities, using respondent-driven sampling (September 2012 to December 2013). Participants were aged >=18 years and either self-identified as male and reported sex with a man in the prior year (MSM) or reported injection drug use in the prior 2 years (PWID). Correlates of awareness of HIV-positive status were characterized using multilevel logistic regression. RESULTS: A total of 1146 MSM were HIV infected, of whom a median of 30% were aware of their HIV-positive status, 23% were linked to care, 22% were retained before antiretroviral therapy (ART), 16% had started ART, 16% were currently receiving ART, and 10% had suppressed viral loads. There was site variability (awareness range, 0%-90%; suppressed viral load range, 0% 58%). A total of 2906 PWID were HIV infected, of whom a median of 41% were aware, 36% were linked to care, 31% were retained before ART, 20% had started ART, 18% were currently receiving ART, and 15% had suppressed viral loads. Similar site variability was observed (awareness range: 2%-93%; suppressed viral load range: 0%-47%). Factors significantly associated with awareness were region, older age, being married (MSM) or female (PWID), use of other services (PWID), more lifetime sexual partners (MSM), and needle sharing (PWID). Ongoing injection drug use (PWID) and alcohol use (MSM) were associated with lower awareness. CONCLUSIONS: In this large sample, the major barrier to HIV care engagement was awareness of HIV-positive status. Efforts should focus on linking HIV testing to other essential services. CLINICAL TRIALS REGISTRATION: NCT01686750. PMID- 26251049 TI - How next-generation sequencing and multiscale data analysis will transform infectious disease management. AB - Recent reviews have examined the extent to which routine next-generation sequencing (NGS) on clinical specimens will improve the capabilities of clinical microbiology laboratories in the short term, but do not explore integrating NGS with clinical data from electronic medical records (EMRs), immune profiling data, and other rich datasets to create multiscale predictive models. This review introduces a range of "omics" and patient data sources relevant to managing infections and proposes 3 potentially disruptive applications for these data in the clinical workflow. The combined threats of healthcare-associated infections and multidrug-resistant organisms may be addressed by multiscale analysis of NGS and EMR data that is ideally updated and refined over time within each healthcare organization. Such data and analysis should form the cornerstone of future learning health systems for infectious disease. PMID- 26251050 TI - The Brassica epithionitrile 1-cyano-2,3-epithiopropane triggers cell death in human liver cancer cells in vitro. AB - SCOPE: Glucosinolates are secondary metabolites present in Brassica vegetables. Alkenyl glucosinolates are enzymatically degraded forming nitriles or isothiocyanates, but in the presence of epithiospecifier protein, epithionitriles are released. However, studies on the occurrence of epithionitriles in Brassica food and knowledge about their biological effects are scarce. METHODS AND RESULTS: Epithionitrile formation from glucosinolates of seven Brassica vegetables was analyzed using GC-MS and HPLC-DAD. Bioactivity of synthetic and plant-derived 1-cyano-2,3-epithiopropane (CETP) - the predominant epithionitrile in Brassica vegetables - in three human hepatocellular carcinoma (HCC) cell lines and primary murine hepatocytes was also evaluated. The majority of the Brassica vegetables were producers of nitriles or epithionitriles as hydrolysis products and not of isothiocyanates. For example, Brussels sprouts and savoy cabbage contained up to 0.8 MUmol CETP/g vegetable. Using formazan dye assays, concentrations of 380-1500 nM CETP were observed to inhibit the mitochondrial dehydrogenase activity of human HCC cells without impairment of cell growth. At 100-fold higher CETP concentrations, cell death was observed. Presence of plant matrix increased CETP-based toxicity. CONCLUSION: These in vitro data provide no indication that epithionitriles will severely affect human health by Brassica consumption. In contrast to isothiocyanates, no evidence of selective toxicity against HCC cells was found. PMID- 26251051 TI - Pulse Pressure Amplification and Arterial Stiffness in Low-Risk, Uncomplicated Pregnancies. AB - BACKGROUND: Arterial stiffness, a composite indicator of vascular health and predictor of future cardiovascular (CV) disease and events, was assessed in low risk, uncomplicated pregnancies. METHODS: Women with low-risk pregnancy were recruited consecutively (recruitment across the 3 trimesters). Vessel hemodynamics and arterial stiffness were measured every 4 weeks from recruitment until delivery and at 6.5 weeks postpartum. RESULTS: Sixty-three women (maternal age: 32.7 +/- 4.9 years) with low-risk, uncomplicated pregnancy were recruited. Mean arterial pressure (P = .04) and aortic pulse pressure (P = .03) decreased during pregnancy, whereas heart rate gradually increased until delivery (P = .0002) and decreased postpartum (P = .06). Pulse pressure amplification (PPA) and carotid-to-radial pulse wave velocity initially decreased in the second trimester, followed by a steady increase until delivery (P = .01 and P = .04, respectively). Interestingly, PPA sharply decreased postpartum (P = .01). Augmentation index and the subendocardial viability ratio significantly increased postpartum (P = .03 and .02, respectively). CONCLUSION: The PPA increased steadily after the second trimester and was sharply decreased postpartum in low risk, uncomplicated pregnancy. Longer and larger longitudinal studies will evaluate changes in PPA and its potential as a marker of CV risk later in women's life. PMID- 26251052 TI - Predictive Value of Combination of NLR and PLR in the Absence of Medical Treatment. PMID- 26251053 TI - [Detection and treatment of respiratory disorders in obese children: Obstructive sleep apnea syndrome and obesity hypoventilation syndrome]. AB - Pediatric obesity may induce multiple complications, including cardiovascular and metabolic problems in adulthood. It may also cause respiratory disorders, which are not usually the first-intention diagnosis by physicians. The aim of this study was to evaluate how investigations had been performed in obese children referred to Timone Pediatric Hospital. PATIENTS AND METHODS: A retrospective study of children referred to our department for severe non-syndromic obesity was conducted. The clinical features comprised history, anthropometric parameters, dietary habits, acanthosis nigricans, symptoms of obstructive sleep apnea syndrome (OSAS) as well as the paraclinical endocrine markers, blood gases, and sleep recordings. RESULTS: Of 102 patients (mean age, 10.5+/-3.3 years; BMI Z score, 4.52+/-1.5), 29.4% had OSAS symptoms (n=30). Nine had a pathological polysomnography confirming OSAS. Eight of them required ventilation: these children were the most severe with an earlier weight gain (2.17+/-1.2 years vs. 4.0+/-2.2 years; P=0.01) and a higher BMI Z-score (7.2+/-2.3 vs. 4.3+/-1.1; P=0.027). Obesity hypoventilation syndrome (OHS) was diagnosed in 3.9% of these children (n=4). CONCLUSION: Diagnosis of OSAS and OHS, often overlooked in obese children, requires a systematic approach and early clinical detection of respiratory disorders. Better accessibility to sleep respiratory explorations would improve quality of care for these children. PMID- 26251054 TI - [Screening for the risk of allergy and prevention in French maternity units: A survey]. AB - Allergy has been on the rise for half a century and concerns nearly 30% of children; it has now become a real public health problem. The guidelines on prevention of allergy set up by the French Society of Paediatrics (SFP) and the European Society of Paediatric Allergology and Clinical Immunology (ESPACI) are based on screening children at risk through a systematic search of the family history and recommend, for children at risk, exclusive breastfeeding whenever possible or otherwise utilization of hypoallergenic infant formula, which has demonstrated efficacy. The AllerNaiss practice survey assessed the modes of screening and prevention of allergy in French maternity units in 2012. The SFP guidelines are known by 82% of the maternity units that took part in the survey, and the ESPACI guidelines by 55% of them. A screening strategy is in place in 59% of the participating maternity wards, based on local consensus for 36% of them, 13% of the units having a written screening procedure. Screening is based on the search for a history of allergy in first-degree relatives (99%) during pregnancy (51%), in the delivery room (50%), and after delivery (89%). A mode of prevention of the risk of allergy exists in 62% of the maternity units, most often in writing (49%). A hypoallergenic infant formula is prescribed for non-breastfed children in 90% of the units. The survey shows that there is a real need for formalization of allergy risk screening and prevention of allergy in newborns in French maternity units. PMID- 26251055 TI - [Study of reports to the departmental home of disabled children placed in social assistance to children in the Bouches-du-Rhone]. AB - INTRODUCTION: By the end of 2011, 275,000 children in France were included in the Aide sociale a l'enfance (ASE, Child Welfare System). Half of these children were entrusted to public care. There is limited data on these children. The MDPH (Maison departementale des personnes handicapees) is an administrative body assisting in the care of disabled children, through material, financial, and human means. Analyzing MDPH medical records can provide medical information about these children. The aim of this study was to describe the characteristics of children left to the ASE with a record at MDPH in Bouches-du-Rhone. METHODS: We extracted administrative data from two registers, the ASE register and the MDPH register. The MDPH medical files of each patient were analyzed and their medical information was coded: gestational age, deficiencies, and pathologies. RESULTS: In Bouches-du-Rhone, 2965 children were entrusted, 506 (17%) of whom were known by the MDPH: 30.6% of the entrusted children known by MDPH were taken into foster care and 48% were in residential group homes. Half of the MDPH notifications concerned a referral to a school or medico-social institution. By analyzing the medical data, we observed an average of 2.1 deficiencies per child. The types of deficiencies were distributed as follows: 35.9% were psychological deficiencies, 26.4% were speech deficiencies, and 21.6% were intellectual cognitive deficiencies. The most common pathology was mental and behavioral disorder (71% of diagnoses). DISCUSSION: The MDPH notification rate in children entrusted to public care was seven times higher than in the general population. Overall, explaining the relation between child abuse and neglect and disability is difficult. The psychopathology of these children is complex. These results show the importance of specific medical monitoring for these children. PMID- 26251056 TI - [Disseminated BCG disease revealing a partial deficiency in receptor 1 interferon gamma]. AB - We report on a case of disseminated BCGitis with an unusual presentation in a 4 month-old infant revealing a syndrome of Mendelian susceptibility to mycobacteria due to a partial dominant mutation of the interferon gamma receptor 1 gene. PMID- 26251057 TI - Streptococcus mutans copes with heat stress by multiple transcriptional regulons modulating virulence and energy metabolism. AB - Dental caries is closely associated with the virulence of Streptococcus mutans. The virulence expression of S. mutans is linked to its stress adaptation to the changes in the oral environment. In this work we used whole-genome microarrays to profile the dynamic transcriptomic responses of S. mutans during physiological heat stress. In addition, we evaluated the phenotypic changes, including, eDNA release, initial biofilm formation, extracellular polysaccharides generation, acid production/acid tolerance, and ATP turnover of S. mutans during heat stress. There were distinct patterns observed in the way that S. mutans responded to heat stress that included 66 transcription factors for the expression of functional genes being differentially expressed. Especially, response regulators of two component systems (TCSs), the repressors of heat shock proteins and regulators involved in sugar transporting and metabolism co-ordinated to enhance the cell's survival and energy generation against heat stress in S. mutans. PMID- 26251058 TI - Distribution system water age can create premise plumbing corrosion hotspots. AB - Cumulative changes in chemical and biological properties associated with higher "water age" in distribution systems may impact water corrosivity and regulatory compliance with lead and copper action levels. The purpose of this study was to examine the effects of water age and chemistry on corrosivity of various downstream premise plumbing pipe materials and configurations using a combination of controlled laboratory studies and a field survey. Examination of lead pipe, copper pipe with lead solder, and leaded brass materials in a replicated lab rig simulating premise plumbing stagnation events indicated that lead or copper release could increase as much as ~440 % or decrease as much as 98 % relative to water treatment plant effluent. In field studies at five utilities, trends in lead and copper release were highly dependent on circumstance; for example, lead release increased with water age in 13 % of cases and decreased with water age in 33 % of conditions tested. Levels of copper in the distribution system were up to 50 % lower and as much as 30 % higher relative to levels at the treatment plant. In many cases, high-risks of elevated lead and copper did not co-occur, demonstrating that these contaminants will have to be sampled separately to identify "worst case" conditions for human exposure and monitoring. PMID- 26251060 TI - Reconstructing disturbance history for an intensively mined region by time-series analysis of Landsat imagery. AB - Surface mining disturbances have attracted attention globally due to extensive influence on topography, land use, ecosystems, and human populations in mineral rich regions. We analyzed a time series of Landsat satellite imagery to produce a 28-year disturbance history for surface coal mining in a segment of eastern USA's central Appalachian coalfield, southwestern Virginia. The method was developed and applied as a three-step sequence: vegetation index selection, persistent vegetation identification, and mined-land delineation by year of disturbance. The overall classification accuracy and kappa coefficient were 0.9350 and 0.9252, respectively. Most surface coal mines were identified correctly by location and by time of initial disturbance. More than 8 % of southwestern Virginia's >4000 km(2) coalfield area was disturbed by surface coal mining over the 28-year period. Approximately 19.5 % of the Appalachian coalfield surface within the most intensively mined county (Wise County) has been disturbed by mining. Mining disturbances expanded steadily and progressively over the study period. Information generated can be applied to gain further insight concerning mining influences on ecosystems and other essential environmental features. PMID- 26251059 TI - Spatial distribution and ecological risk assessment of trace metals in urban soils in Wuhan, central China. AB - Surface soil samples from 467 sample sites were collected in urban area of Wuhan City in 2013, and total concentrations of five trace metals (Pb, Zn, Cu, Cr, and Cd) were measured. Multivariate and geostatistical analyses showed that concentrations of Pb, Zn, and Cu are higher along Yangtze River in the northern area of Wuhan, gradually decrease from city center to suburbs, and are mainly controlled by anthropogenic activities, while those of Cr and Cd are relatively spatially homogenous and mainly controlled by soil parent materials. Pb, Zn, Cu, and Cd have generally higher concentrations in roadsides, industrial areas, and residential areas than in school areas, greenbelts, and agricultural areas. Areas with higher road and population densities and longer urban construction history usually have higher trace metal concentrations. According to estimated results of the potential ecological risk index and Nemero synthesis pollution index, almost the whole urban area of Wuhan is facing considerable potential ecological risk caused by soil trace metals. These results reveal obvious trends of trace metal pollution, and an important impact of anthropogenic activities on the accumulation of trace metals in soil in Wuhan. Vehicular emission, industrial activities, and household wastes may be the three main sources for trace metal accumulation. Increasing vegetation cover may reduce this threat. It should be pointed out that Cd, which is strongly accumulated in soil, could be the largest soil pollution factor in Wuhan. Effective measures should be taken as soon as possible to deal with Cd enrichment, and other trace metals in soil should also be reduced, so as to protect human health in this important large city. PMID- 26251061 TI - Accumulation of metals in three fish species from the Yaounde Municipal Lake in Cameroon. AB - Metals are dangerous to aquatic organisms and they can bioaccumulate in the food chain and represent risk for humans. In order to appraise their levels in fish species, concentrations of various elements including Na, Mg, K, Ca, Al, Fe, Mn, Cr, Ni, Co, Cd, Cu, Pb, Zn, Ba, and Sr were determined in the muscles and gills of three fish species (Oreochromis niloticus, Sarotherodon galilaeus, and Clarias sp.) which are more fished and consumed in the Yaounde Municipal Lake, Cameroon. According to chemical results of the fish samples analyzed by ICP-AES, the concentrations of metals (mg kg(-1), wet tissues) in those fish tissues varied as follows for the muscle (and gill) Na 1480-3780 (4180-9310), Mg 897-1250 (843 1450), K 9600-18,500 (6020-10,400), Ca 430-3900 (22,200-62,400), Al 8.10-615 (113 951), Fe 12.0-725 (307-1160), Mn 1.61-30.1 (14.3-433), Cr 1.58-267 (0.31-35.4), Ni 0.16-1.85 (1.06-2.82), Co 0.10-0.47 (0.07-0.16), Cd 0.11-0.23 (0.10-0.22), Cu 0.59-5.13 (1.31-5.13), Pb 1.11-5.12 (2.56-5.74), Zn 15.4-47.2 (45.3-69.2), Ba 0.61-51.15 (0.35-83.2), and Sr 2.31-5.74 (2.09-5.75). The results revealed that Na, Ca, Zn, Fe, and Mn were higher concentrated in the gills than in the muscles, while K, Cr, Ni, Co, and Cd were more concentrated in the muscles of the species. In addition, all the elements were bioaccumulated in the fish species and the bioaccumulation factors (BAFs) were decreased in the following order: Cr > Ni > Zn > Al > Ca > Pb > Mn > Ba > K > Fe > Mg > Cu > Na > Sr > Co > Cd. Compared to international standards, Pb, Cd, Cr, Ni, and Zn were over the recommendations of the European Community, WHO, and Norwegian guidance values for human health. Therefore, fishes from the Yaounde Municipal Lake are not advised for human consumption as toxic elements might be taken above the recommended levels. PMID- 26251062 TI - Watershed-scale assessment of background concentrations and guidance values for heavy metals in soils from a semiarid and coastal zone of Brazil. AB - Determining heavy metal background concentrations in soils is fundamental in order to support the monitoring of potentially contaminated areas. This is particularly important to areas submitted to high environmental impact where an intensive and local monitoring is required. To this end, the aim of this study was to establish background concentrations and quality reference values (QRVs) for the heavy metals Cd, Cr, Cu, Fe, Mn, Ni, Pb, Zn, As, and Hg in an environmentally impacted watershed from Brazil. Geochemical associations among Fe, Mn, and trace elements were also assessed to provide an alternative tool for establishing background concentrations. A total of one hundred and four samples comprised twenty-six composite soil samples from areas of native forest or minimal anthropic influence. Samples were digested (USEPA method 3051A), and the metals were determined by ICP-OES, except for As and Hg measured by atomic absorption spectrophotometer. Background concentrations of heavy metals in soils had the following decreasing order: Fe > Mn > Zn > Cr > Pb > Ni > Cu > As > Cd > Hg. These values were usually lower than those observed in the international and national literature. The QRVs for Ipojuca watershed followed the order (mg kg( 1)) Fe (13,020.40) > Mn (91.80) > Zn (30.12) > Cr (15.00) > Pb (13.12) > Cu (3.53) > Ni (3.30) > As (0.51) > Cd (0.08) > Hg (0.04). Significant correlation among Fe, Mn, and heavy metals shows that solubilization by the method 3051A provides a reasonable estimate for predicting background concentrations for Cd, Cr, and Cu as well as Zn, Cr, Cu, and Ni. PMID- 26251063 TI - Exposure of hairdressers to aromatic diamines: an interventional study confirming the protective effect of adequate glove use. AB - OBJECTIVES: Many hairdressers leave their profession due to health problems, including occupational hand eczema, which has been associated with skin exposure to sensitising hair dye components such as paraphenylenediamine (PPD) and paratoluenediamine (PTD). Since the use of protective gloves is advised but without the short-term effect being known, our main goal was to attribute a significant biomarker reduction to adequate glove use, in a real work situation. METHODS: 11 hairdressers were studied over 2 weeks. In the first week, they worked as usual and (re)used their gloves. Thereafter, we intervened to improve glove use during the second week. In both weeks, workplace exposure data were collected through observations, and systemic exposure was quantified by biomonitoring of PPD and PTD. The effect of improved glove use and other exposure determinants was studied through mixed models analysis. RESULTS: We showed that improved glove use significantly reduced mean PTD concentrations from 24.1 before to 4.2 ug/g creatinine after the intervention (n=11, third day postshift). In addition, mean PTD concentrations increased during the first week (14 times elevated after three consecutive shifts), but not during the second week. For PPD, no effect of improved glove use and no accumulation effect were detected. CONCLUSIONS: Our study is the first to deliver evidence for a significant reduction in systemic exposure to PTD through improved glove use. Disposable gloves should never be reused. PTD biomonitoring is shown to be a practical tool to quantify recent dermal exposure to oxidative hair dye components. PMID- 26251064 TI - Work schedule and physical factors in relation to fecundity in nurses. AB - OBJECTIVES: To evaluate the association of work schedule and physical factors with fecundity. METHODS: Women currently employed outside the home and trying to get pregnant (n=1739) in the Nurses' Health Study 3 cohort (2010-2014) were included in this analysis. Work schedule and physical labour were self-reported on the baseline questionnaire, and every 6 months thereafter the women reported the duration of their ongoing pregnancy attempt. Multivariable accelerated failure time models were used to estimate time ratios (TR) and 95% CIs. RESULTS: Among the 1739 women (median age=33 years, 93% Caucasian) the estimated proportions of women not pregnant after 12 and 24 months were 16% and 5%, respectively. None of the various shift work patterns were associated with duration of pregnancy attempt (as a surrogate for fecundity). However, women working >40 h/week had a 20% (95% CI 7 to 35%) longer median duration of pregnancy attempt compared to women working 21-40 h/week (p-trend=0.005). Women whose work entailed heavy lifting or moving (ie, 25+ pounds) >15 times/day also had a longer median duration of pregnancy attempt (adjusted TR=1.49; 95% CI 1.20 to 1.85) compared to women who never lifted or moved heavy loads (p-trend=0.002). The association between heavy moving and lifting and duration of pregnancy attempt was more pronounced among overweight or obese women (body mass index, BMI<25: TR=1.17; 95% CI 0.88 to 1.56; BMI>=25: TR=2.03, 95% CI 1.48 to 2.79; p interaction=0.007). CONCLUSIONS: Working greater than 40 h per week and greater frequency of lifting or moving a heavy load were associated with reduced fecundity in a cohort of nurses planning pregnancy. PMID- 26251066 TI - The value of perioperative antibiotics on the success of oral free flap reconstructions. AB - The subject of the presented study was to monitor and compare problems and outcomes of reconstructive surgery with microvascular free flaps in the head and neck region between groups of patients treated with perioperative antibiotics and a group of patients without antibiotics. Patients requiring oral reconstructive surgery following cancer resections with microvascular free flaps were prospectively evaluated (2007-2012). Antibiotic therapy was started 30 min before the operation and administered for 10 days. Three hundred and fifty patients were included (208 male, 59.4%; 142 female, 40.6%; mean age 59.8 +/- 13.2 years). 330 patients received perioperative antibiotics. Twenty patients (5.7%) who received no antibiotics for specific reasons served as the control group. Wound infections developed in 33 of 122 patients (27%) who received benzylpenicillin, 17 of 88 patients (19.3%) who received amoxicillin combined with sulbactam and 25 of 120 patients (20.8%) who received cefuroxime. Ten patients (50%) who did not receive antibiotics developed wound infections. Receiving no antibiotics or penicillin showed no benefit (P = 0.11). Those receiving cefuroxime showed significantly lower incidence of wound infections (P = 0.034; risk decreased by the factor 2.88). The use of amoxicillin combined with sulbactam showed the lowest rate of wound infections (P = 0.018; risk decreased by the factor 3.46). The use of amoxicillin combined with sulbactam appears to be the most appropriate prophylactic antibiotic followed by cefuroxime in oral microsurgical free flap reconstructions. These data may serve as a guide until a controlled multicenter prospective trial is performed comparing newer antibiotics against current standards. PMID- 26251065 TI - Work-focused cognitive-behavioural therapy and individual job support to increase work participation in common mental disorders: a randomised controlled multicentre trial. AB - OBJECTIVES: Common mental disorders (CMDs) are a major cause of rising disability benefit expenditures. We urgently need evidence on programmes that can increase work participation in CMDs. The aim of this study was to evaluate the effectiveness of work-focused cognitive-behavioural therapy (CBT) and individual job support for people struggling with work participation due to CMDs. METHODS: A randomised controlled multicentre trial (RCT) including 1193 participants was conducted. Participants were on sick leave, at risk of going on sick leave or on long-term benefits. The intervention integrated work-focused CBT with individual job support. The control group received usual care. The main outcome was objectively ascertained work participation at 12 months follow-up, with changes in mental health and health-related quality of life as secondary outcomes. RESULTS: A larger proportion of participants in the intervention group had increased or maintained their work participation at follow-up compared to the control group (44.2% vs 37.2%, p=0.015). The difference remained significant after 18 months (difference 7.8%, p=0.018), and was even stronger for those on long-term benefits (difference 12.2%, p=0.007). The intervention also reduced depression (t=3.23, p<=0.001) and anxiety symptoms (t=2.52, p=0.012) and increased health-related quality of life (t=2.24, p=0.026) more than usual care. CONCLUSIONS: A work-focused CBT and individual job support was more effective than usual care in increasing or maintaining work participation for people with CMDs. The effects were profound for people on long-term benefits. This is the first large-scale RCT to demonstrate an effect of a behavioural intervention on work participation for the large group of workers with CMDs. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, registration number: NCT01146730. PMID- 26251067 TI - SSRIs and risk of suicide attempts in young people - A Danish observational register-based historical cohort study, using propensity score. AB - BACKGROUND: SSRIs are widely used in the treatment of mental illness for both children and adults. Studies have found a slightly increased risk of suicidal thoughts and suicide attempts in young people using SSRIs but SSRIs' impact on risk for suicides in youth is not well-established. AIM: Is there indication that SSRIs might raise risk for suicide attempts in young people? METHODS: We used an observational register-based historical cohort design, a large cohort of all Danish individuals born in 1983-1989 (n = 392,458) and a propensity score approach to analyse the impact from SSRIs on risk for suicide attempts. Every suicide attempt and redeemed prescription of SSRIs was analysed by Cox regression. RESULTS: We found a significant overlap between redeeming a prescription on SSRIs and subsequent suicide attempt. The risk for suicide attempt was highest in the first 3 months after redeeming the first prescription. The hazard ratio for suicide attempts after redeeming a prescription was estimated to 5.23, 95% CI 4.82-5.68. CONCLUSION: We conclude that the risk of suicide attempt is higher for young people in the first months after redeeming their first prescription for SSRIs, compared to non-users. For SSRI users with lower propensity score (fewer risk factors for SSRIs) the risk of suicide attempt is estimated to be highest. Although the design may miss some explicit reason for prescription of SSRIs and SSRIs might be a marker for those in high risk rather than a causal risk factor, we would recommend systematic risk assessment in the period after redeeming the first prescription. PMID- 26251068 TI - Radiomic feature clusters and prognostic signatures specific for Lung and Head & Neck cancer. AB - Radiomics provides a comprehensive quantification of tumor phenotypes by extracting and mining large number of quantitative image features. To reduce the redundancy and compare the prognostic characteristics of radiomic features across cancer types, we investigated cancer-specific radiomic feature clusters in four independent Lung and Head &Neck (H) cancer cohorts (in total 878 patients). Radiomic features were extracted from the pre-treatment computed tomography (CT) images. Consensus clustering resulted in eleven and thirteen stable radiomic feature clusters for Lung and H cancer, respectively. These clusters were validated in independent external validation cohorts using rand statistic (Lung RS = 0.92, p < 0.001, H RS = 0.92, p < 0.001). Our analysis indicated both common as well as cancer-specific clustering and clinical associations of radiomic features. Strongest associations with clinical parameters: Prognosis Lung CI = 0.60 +/- 0.01, Prognosis H CI = 0.68 +/- 0.01; Lung histology AUC = 0.56 +/- 0.03, Lung stage AUC = 0.61 +/- 0.01, H HPV AUC = 0.58 +/- 0.03, H stage AUC = 0.77 +/- 0.02. Full utilization of these cancer-specific characteristics of image features may further improve radiomic biomarkers, providing a non-invasive way of quantifying and monitoring tumor phenotypic characteristics in clinical practice. PMID- 26251070 TI - Degradable poly(apigenin) polymer inhibits tumor cell adhesion to vascular endothelial cells. AB - Cancer and the inflammatory system share a complex intertwined relationship. For instance, in response to an injury or stress, vascular endothelial cells will express cell adhesion molecules as a means of recruiting leukocytes. However, circulating tumor cells (CTCs) have been shown to highjack this expression for the adhesion and invasion during the metastatic cascade. As such, the initiation of endothelial cell inflammation, either by surgical procedures (cancer resection) or chemotherapy can inadvertently increase the metastatic potential of CTCs. Yet, systemic delivery of anti-inflammatories, which weaken the entire immune system, may not be preferred in some treatment settings. In this work, we demonstrate that a long-term releasing flavone-based polymer and subsequent nanoparticle delivery system can inhibit tumor cell adhesion, through the suppression of endothelial cell adhesion molecule expression. The degradation of a this anti-inflammatory polymer provides longer term, localized release profile of active therapeutic drug in nanoparticle form as compared with that of the free drug, permitting more targeted anti-metastatic therapies. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1438-1447, 2016. PMID- 26251069 TI - Issues involved in the phenotypic classification of orofacial clefts ascertained through a state birth defects registry for the North Carolina Cleft Outcomes Study. AB - BACKGROUND: Epidemiologic studies involving birth defects are extremely sensitive to phenotype accuracy and precision. We devised a case review and classification protocol for a project to study school achievement in children with idiopathic, nonsyndromic orofacial clefts to improve the reliability of phenotypic classification from the statewide birth defects registry. METHODS: Surveillance program abstraction data and medical records at the birth or treating hospitals were used when available. Exclusion criteria included: median cleft lip; Tessier cleft; premaxillary agenesis; presence of a recognizable syndrome, phenotype, association, or sequence (other than Robin sequence); clefts with other malformations not considered to be normal or common variants in the newborn; and cases with documented or suspected genetic or teratogenic causes. RESULTS: Of 712 children identified with orofacial clefts, 153 were excluded, leaving 559 nonsyndromic orofacial cleft cases of unknown cause in the final study. These cases were grouped into the following clinically meaningful types: cleft lip with or without cleft alveolus; cleft lip and cleft palate; and cleft palate only. This review and classification process resulted in the elimination of 21.5% of the original cohort of identified cases, with most exclusions being due to suspected syndromic associations. CONCLUSION: Verbatim descriptions of the clinical findings are critical for accurate classification of diagnoses. This review process improved the precision of orofacial cleft phenotype classification for our study. Precision would have been further improved if all of the cases had verbatim descriptions of diagnoses and all medical records could have been reviewed by the classification team. PMID- 26251071 TI - Life-threatening bowel perforation while on thalidomide-based triplet regimen for multiple myeloma: a retrospective case series. PMID- 26251072 TI - From steroid hormones to depressive states and senile dementias: New mechanistic, therapeutical and predictive approaches. AB - The discovery of "neurosteroids" leads to new descriptions and treatments of neuro-pathological pathologies. 3-beta-methoxy-pregnenolone may be used to treat alterations of neuro-traumatisms and cerebral lesions associated with depressive states. Protein FKBP52 is involved in the dysfunction of the tau protein in Alzheimer's disease and senile dementias. In all cases, neuronal microtubules are involved in the mechanism of lesions and their repair. PMID- 26251073 TI - An examination of age-related changes in the control of lexical and sublexical pathways in mapping spelling to sound. AB - The current study investigated the extent to which young and older adults are able to direct attention to distinct processes in mapping spelling onto sound. Young and older adults completed either a speeded pronunciation task (reading aloud words) or regularization task (pronouncing words based on spelling-to-sound correspondences, e.g., pronouncing PINT such that it rhymes with HINT) in order to bias processing of lexical, whole-word information, or sublexical, spelling-to sound mapping, respectively. Both younger and older adults produced reduced word frequency effects and lexicality effects in the regularization task compared to the normal pronunciation task. Importantly, compared to younger adults, older adults produced exaggerated effects of task (i.e., pronunciation vs. regularization) on the observed frequency and lexicality effects. These results highlight both the flexibility of the lexical processing system and changes in the influence of the underlying lexical route due to additional 50 years of reading experience and/or changes in attentional control. PMID- 26251074 TI - A Straightforward Approach to Tetrahydroindolo[3,2-b]carbazoles and 1 Indolyltetrahydrocarbazoles through [3+3] Cyclodimerization of Indole-Derived Cyclopropanes. AB - A rapid new approach to produce biologically relevant bisindoles, namely indolyltetrahydrocarbazoles and indolo[3,2-b]carbazoles, has been developed, based on the Ga(OTf)3 -catalyzed [3+3] cyclodimerization of indole-derived donor acceptor cyclopropanes. Chemoselectivity of the process depends on the location of the three-membered ring at the indole core. PMID- 26251075 TI - Microfluidics enables multiplex evaluation of the same cells for further studies. AB - OBJECTIVE: The continuous discovery of biomarkers and their evolving use for the diagnosis and guidance of therapy for patients with cancer has increased awareness of the need to triage biospecimens properly. On occasion, cytology samples are the only type of biospecimen available for analysis. Often, the current approach for these latter specimens is cytopathology-centric, with cells limited to examination by bright field microscopy. When specimens are paucicellular, there is often insufficient material for ancillary testing. Therefore, a need exists to develop an alternative approach that allows for the multiplexed analysis of cells when they are limited in number. In recent previous publications, we demonstrated that clinically derived cells from tissue are suitable for evaluation in a microfluidic device. In our current endeavour, we seek to expand upon those findings and determine if those same cells can be recovered for further analysis. METHODS: A microfluidic channel was designed, fabricated and tested using cytology specimens generated from tissue specimens. The cytological features of the cells tested were examined prior to entering the channel; they were then compared to similar cells while in the channel, and upon recovery from the channel. Recovery of DNA and proteins were also tested. RESULTS: The morphology of the tested cells was not compromised in either the channel or upon recovery. More importantly, the integrity of the cells remained intact, with the recovery of proteins and high molecular weight DNA possible. CONCLUSIONS: We developed and tested an alternative approach to the processing of cytopathology specimens that enables multiplexed evaluation. Using microfluidics, cytological examination of biopecimens can be performed, but in contrast to existing approaches, the same cells examined can be recovered for downstream analysis. PMID- 26251076 TI - Autophagy protein 5 enhances the function of rat EPCs and promotes EPCs homing and thrombus recanalization via activating AKT. AB - Deep venous thrombosis (DVT) is one of the most common peripheral vascular diseases. The roles of bone marrow-derived endothelial progenitor cells (EPCs) on the recanalization of venous thrombosis has been suggested recently, while the underlying mechanisms are not completely understood. Our objective was to investigate the functions of autophagy protein 5 (ATG5) in rat EPCs and its potential application in DVT. We have found that silencing of ATG5 or pharmacological suppression of ATG5 in rat EPCs reduces both the migration and psudotube formation under hypoxia in vitro. In line, overexpression of ATG5 significantly enhances the EPCs migration and psudotube formation capabilities. More importantly, injection of EPCs that stably express ATG5 increases EPC homing to the ischemic site and promotes thrombus recanalization in a rat DVT model in vivo. Mechanistically, we have shown that ATG5 overexpression enhances psudotube formation via the activation of AKT. These findings suggest that ATG5-AKT signaling plays an essential role in EPC migration and psudotube formation. Regulation of ATG5-AKT signaling may provide a potential novel therapy for DVT. PMID- 26251077 TI - Is Thrombin Time useful for the assessment of dabigatran concentrations? An in vitro and ex vivo study. PMID- 26251078 TI - Non-O blood groups can be a prognostic marker of in-hospital and long-term major adverse cardiovascular events in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - BACKGROUND: Recent studies have suggested ABO blood type locus as an inherited predictor of thrombosis, cardiovascular risk factors, myocardial infarction. However, data is scarce about the impact of non-O blood groups on prognosis in patients with ST-elevation myocardial infarction (STEMI). Therefore, we aimed to evaluate the prognostic importance of non-O blood groups in patients with STEMI undergoing primary percutaneous coronary intervention (pPCI) METHODS: 1835 consecutive patients who were admitted with acute STEMI between 2010 and 2015 were included and followed-up for a median of 35.6months. RESULTS: The prevalence of hyperlipidemia, total cholesterol, LDL, peak CKMB and no-reflow as well as hospitalization duration were higher in patients with non-O blood groups. Gensini score did not differ between groups. During the in-hospital and long-term follow up period, MACE, the prevalence of stent thrombosis, non-fatal MI, and mortality were higher in non-O blood groups. In multivariate logistic regression analysis, non-0 blood groups were demonstrated to be independent predictors of in-hospital (OR:2.085 %CI: 1.328-3.274 p=0.001) and long term MACE (OR:2.257 %CI: 1.325-3.759 p<0.001). Kaplan-Meier analysis according to the long-term MACE free survival revealed a higher occurrence of MACE in non-O blood group compared with O blood group (p<0.001, Chi-square: 22.810). CONCLUSION: Non-O blood groups were determined to be significant prognostic indicators of short- and long-term cardiovascular adverse events and mortality in patients with STEMI undergoing pPCI. In conjunction with other prognostic factors, evaluation of this parameter may improve the risk categorization and tailoring the individual therapy and follow-up in STEMI patient population. PMID- 26251079 TI - Severe, recessive type 1 is a discrete form of von Willebrand disease: the lesson learned from the c.1534-3C>A von Willebrand factor mutation. AB - Type 1 von Willebrand disease (VWD) is transmitted mainly as a dominant trait - especially in forms involving von Willebrand factor (VWF) levels below 20 U/dL - and less frequently as a recessive trait. In the latter case, mutations at heterozygous level may be associated with type 3 carrier status, while mutations at homozygous or compound heterozygous level often coincide with type 3 VWD. Here we present a recessive, severe type 1 form as a distinct type of VWD. Eight patients with severe type 1 VWD belonging to 7 unrelated families were studied. They had VWF levels below 10 U/dL, FVIII higher than 10 U/dL, and a significantly lower than normal platelet VWF content. All patients were homozygous or compound heterozygous for the c.1534-3C>A VWF mutation, that simultaneously induces the skipping of exon 14, the activation of a cryptic splice site, and a normal VWF gene transcription. This means that one of the three different mRNA generated assures the synthesis of normal VWF. The probands' relatives who were heterozygous for the c.1534-3C>A mutation always had low platelet VWF levels, sometimes with circulating VWF levels within normal range. This finding confirms the utility of measuring platelet VWF content to identify an abnormal VWF synthesis. Because the c.1534-3C>A mutation impairs, but does not abolish normal mRNA processing, it may never cause type 3 VWD. We propose a model of severe recessive type 1 VWF defect associated with mutations that sporadically go undetected by the cells' molecular machinery, as the c.1534-3C>A VWF mutation. BULLET POINTS: What is known about this topic? - Type 1 VWD is transmitted mainly as a dominant trait. - Recessive type 1 mutations at homozygous or compound heterozygous level are often associated with type 3 VWD, and at heterozygous level with type 3 VWD carrier status. What does this paper add? - There are quantitative VWF mutations, such as c.1534-3C>A, that impair, but do not abolish normal mRNA processing. - The c.1534-3C>A VWF mutation simultaneously induces the skipping of exon 14, the activation of a cryptic splice site, and a normal VWF gene transcription. - The c.1534-3C>A mutation is the archetype of mutations that cause severe recessive type 1 VWD, but never type 3 VWD. - Recessive, severe type 1 appears to be a distinct form of VWD. PMID- 26251080 TI - Mesothelial/monocytic incidental cardiac excrescences of the heart - a report of three cases. AB - Mesothelial/monocytic incidental cardiac excrescences (MICE) are uncommon pseudotumours and may histologically mimic metastatic adenocarcinoma. They consist of nonneoplastic proliferations of mesothelial cells intermingled with foamy macrophages enmeshed in fibrin. There are only around 40 cases reported in literature, and it is important that the pathologists should be aware of this lesion especially while dealing with cardiac surgery specimens. We report a series of three cases of MICE that were incidentally discovered during valve replacement surgeries. PMID- 26251081 TI - An autopsy report of acute myocardial infarction with hypertrophic obstructive cardiomyopathy-like heart. AB - An 84-year-old woman, who was followed up as hypertrophic obstructive cardiomyopathy (HOCM) in a local hospital, was transferred to our center because of anterior chest pain and diagnosed with acute myocardial infarction (MI). Coronary angiography showed total occlusion of the mid-left anterior descending, and flow was restored after endovascular thrombectomy. An autopsy was performed after she died on hospital day 6. At autopsy, there was no significant stenosis in this vessel and the absence of plaque rupture was confirmed. Likewise, it was unclear asymmetric hypertrophy at autopsy, it could not deny that a sigmoid deformity of the basal septum occurs in elderly patients and can mimic the asymmetric septal hypertrophy of hypertrophic cardiomyopathy. MI was thought to be caused by coronary spasm or squeezing in HOCM-like heart. Therefore, it may be necessary antithrombosis therapy in HOCM-like patients with no history of paroxysmal atrial fibrillation. PMID- 26251082 TI - Differentiation of high-risk stage I and II colon tumors based on evaluation of CAV1 gene expression. AB - BACKGROUND: Several molecular markers are currently being investigated for their prognostic or predictive value in colorectal cancer. One of the genes proposed, as a potential molecular marker in CRC is CAV1. METHODS: The level of CAV1 expression was investigated in low-stage (I and II TNM) colon cancers using Real Time PCR and immunohistochemistry. RESULTS: The level of CAV1 expression increased in tumors characterized by greater depths of invasiveness. The CAV1 expression level detected in tumors with a depth of invasion at stage T4 was significantly higher compared to that in T2 (P = 0.01) and T3 (P = 0.003) lesions. The length of a patient's survival depended on CAV1 expression level; the 10-year survival rate for patients with elevated expression of CAV1 was ~59% compared with 91% for patients with reduced or unchanged expression of CAV1 (P = 0.007). The overall survival rate of patients with T3 + T4 lesions was significantly lower (P = 0.006) for patients with tumor displaying elevated CAV1 expression compared with patients with reduced or unchanged CAV1 expression. CONCLUSIONS: Evaluation of CAV1 expression offers valuable prognostic information for patients with colorectal cancer, and could be used to select patients with stage I or II disease, who are at increased risk of unfavorable outcomes. PMID- 26251084 TI - The effects of different vascular carrier patterns on the angiogenesis and osteogenesis of BMSC-TCP-based tissue-engineered bone in beagle dogs. AB - Bone repair using tissue-engineered bone (TEB) in a large defect or accompanied by a poor recipient vascular bed is a long-standing challenge. Surgical vascular carrier patterns of vascular bundle (VB) and arteriovenous loop (AV loop) have been shown to improve the vascularization and repair capacity of TEB. However, the effects of these different vascular carrier patterns on angiogenesis and osteogenesis in TEB have never been evaluated. Here, TEB was constructed with bone marrow mesenchymal stem cells (BMSCs) and beta-TCP and prevascularized by the VB or AV loop technique in beagle dogs. The vascularization and bone formation in TEB were quantitatively compared using Microfil perfusion, histological examination and CT and micro-CT analyses. The distribution and constitution of the neovasculature were analysed to determine the underlying mechanism of angiogenesis. The results showed that prevascularized TEB generated bone tissue faster and more homogeneously than untreated TEB. The VB technique was found to strike a better balance between bone regeneration and beta-TCP scaffold degradation than the AV loop strategy, which resulted in more vascularization but less bone yield, due to faster degradation of the beta-TCP scaffold. This study indicates that a suitable triangular relationship, composed of bone regeneration, scaffold degradation and vasculature, is critical to TEB construction. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26251086 TI - Falling Cardiovascular Mortality in Heart Failure With Reduced Ejection Fraction and Implications for Clinical Trials. AB - OBJECTIVES: This study examined the trends in the relative contributions of cardiovascular and noncardiovascular mortality to total mortality according to use of beta-blockers in clinical trials of patients with heart failure with reduced ejection fraction (HF-REF). BACKGROUND: With the increasingly widespread use of disease-modifying therapies, particularly beta-blockers, in HF-REF, the proportion of patients dying from cardiovascular causes is likely to be decreasing. METHODS: In a systematic review, 2 investigators independently searched online databases to identify clinical trials including >400 patients with chronic heart failure published between 1986 and 2014 and that adjudicated cause of death. Trials were divided into 3 groups on the basis of the proportion of patients treated with a beta-blocker (<33% [low], 33% to 66% [medium], and >66% [high]). Percentages of total deaths adjudicated as cardiovascular or noncardiovascular were calculated by weighted means and weighted standard deviations. Weighted Student t tests were used to compare results between groups. RESULTS: Sixty-six trials met the inclusion criteria with a total of 136,182 patients and 32,140 deaths. There was a sequential increase in the percentage of noncardiovascular deaths with increasing beta-blocker use from 11.4% of all deaths in trials with low beta-blocker use to 19.1% in those with high beta blocker use (p < 0.001). CONCLUSIONS: In trials of patients with HF-REF, the proportion of deaths adjudicated as cardiovascular has decreased. Cardiovascular mortality, and not all-cause mortality, should be used as an endpoint for trials of new treatments for HF-REF. PMID- 26251085 TI - Human Immunodeficiency Virus and Heart Failure in Low- and Middle-Income Countries. AB - Successful combination therapy for human immunodeficiency virus (HIV) has transformed this disease from a short-lived infection with high mortality to a chronic disease associated with increasing life expectancy. This is true for high as well as low- and middle-income countries. As a result of this increased life expectancy, people living with HIV are now at risk of developing other chronic diseases associated with aging. Heart failure has been common among people living with HIV in the eras of pre- and post- availability of antiretroviral therapy; however, our current understanding of the pathogenesis and approaches to management have not been systematically addressed. HIV may cause heart failure through direct (e.g., viral replication, mitochondrial dysfunction, cardiac autoimmunity, autonomic dysfunction) and indirect (e.g., opportunistic infections, antiretroviral therapy, alcohol abuse, micronutrient deficiency, tobacco use) pathways. In low- and middle-income countries, 2 large observational studies have recently reported clinical characteristics and outcomes in these patients. HIV-associated heart failure remains a common cardiac diagnosis in people living with heart failure, yet a unifying set of diagnostic criteria is lacking. Treatment patterns for heart failure fall short of society guidelines. Although there may be promise in cardiac glycosides for treating heart failure in people living with HIV, clinical studies are needed to validate in vitro findings. Owing to the burden of HIV in low- and middle-income countries and the concurrent rise of traditional cardiovascular risk factors, strategic and concerted efforts in this area are likely to impact the care of people living with HIV around the globe. PMID- 26251087 TI - The Ongoing Evolution of Optimal Clinical Endpoints for Heart Failure Trials. PMID- 26251088 TI - Combined Free Light Chains Are Novel Predictors of Prognosis in Heart Failure. AB - OBJECTIVES: This study investigated the prevalence and potential incremental prognostic value of combined free light chains (cFLCs) in patients recently hospitalized with decompensated heart failure (HF). BACKGROUND: Inflammatory pathways are recognized in the pathogenesis and progression of HF. Free light chain (FLC) elevation is conventionally associated with monoclonal gammopathies, including multiple myeloma. Polyclonal increases in both kappa and lambda FLCs occur in autoimmune and other chronic inflammatory conditions. Recently, a novel assay for measuring kappa and lambda immunoglobulin FLCs together, known as combined free light chain (cFLC) has been developed. METHODS: Six hundred twenty eight patients recently hospitalized with decompensated HF were studied. cFLCs were measured by turbidimetry using an immunoassay. The incremental prognostic value of cFLCs for mortality was evaluated using Cox proportional hazard models including 22 established predictors of outcome in HF. RESULTS: Of 628 patients, 290 (46%) died during a follow-up of 3.2 +/- 1.5 years. Two hundred seventy patients (43%) had elevated cFLCs. There was a clear gradient in the risk of death according to cFLC quartile, with those in the top quartile having an unadjusted risk of mortality more than twice that of those in the lowest quartile (hazard ratio: 2.38; p < 0.0001). After multivariable analysis, cFLC remained an independent predictor of mortality, with an almost 50% higher adjusted risk for those in the top compared with bottom quartile. Older age, lower body mass index, New York Heart Association classification III/IV, previous myocardial infarction, current smoking and B-type natriuretic peptide, bilirubin, high-sensitivity C reactive protein, glycated hemoglobin, and lymphocyte concentrations were also independent predictors of mortality. CONCLUSIONS: cFLCs are an independent predictor of mortality in patients recently hospitalized with decompensated HF. Further work is required to assess the effects of HF therapies on cFLC concentrations and whether or not directly targeting this marker of inflammation improves prognosis for patients with HF. PMID- 26251089 TI - Light Chains and the Failing Heart: Important Mechanistic Link or Fifty Shades of Gray? PMID- 26251090 TI - Elevated Plasma B-Type Natriuretic Peptide Concentrations Directly Inhibit Circulating Neprilysin Activity in Heart Failure. AB - OBJECTIVES: This study sought to hypothesize that elevated B-type natriuretic peptide (BNP) could act as an endogenous neprilysin inhibitor. BACKGROUND: A hallmark of acute decompensated heart failure (ADHF) is the overproduction of natriuretic peptides (NPs) by stretched cardiomyocytes. Various strategies have been developed to potentiate the beneficial effect of the NPs, including the recent use of neprilysin angiotensin receptor inhibitors. Contrary to rodents, human BNP is poorly sensitive to neprilysin degradation while retaining affinity to neprilysin. METHODS: We enrolled 638 patients presenting to the emergency department with acute dyspnea of which 468 had ADHF and 169 had dyspnea of noncardiac origin. We also included 46 patients with stable chronic heart failure (HF) and 10 age-matched healthy subjects. Plasma samples were collected within 4 h after emergency department admission. BNP, neprilysin concentration and activity, and the neprilysin substrate substance P concentration were measured. RESULTS: We found that when plasma BNP rose above 916 pg/ml, neprilysin activity was markedly reduced (p < 0.0001) and stratified 95% of the population into 2 groups: BNP <916 pg/ml/neprilysin activity >= 0.21 nmol/ml/min and BNP >=916 pg/ml/neprilysin activity <0.21 nmol/ml/min with very different prognoses. In vitro, BNP was responsible for neprilysin inhibition. Neprilysin activity was inversely correlated with the concentration of substance P (rho = -0.80; p < 0.0001). CONCLUSIONS: Besides being an effector of the cardiac response to cardiomyocyte stretching in ADHF, elevated plasma BNP is also an endogenous neprilysin inhibitor. A biologically relevant BNP threshold discriminates 2 populations of HF patients with different vasoactive peptide profiles and outcome. If confirmed, this may identify an important threshold for managing HF patients. PMID- 26251091 TI - Neprilysin in Heart Failure: From Oblivion to Center Stage. PMID- 26251092 TI - Prognostic Value and Kinetics of Soluble Neprilysin in Acute Heart Failure: A Pilot Study. AB - OBJECTIVES: This study sought to examine the prognostic value of the soluble form of neprilysin (sNEP) in acute heart failure (AHF) and sNEP kinetics during hospital admission. BACKGROUND: sNEP was recently identified in chronic heart failure (HF) and was associated with cardiovascular outcomes. METHODS: A total of 350 patients (53% women, mean 72.6 +/- 10.7 years of age) were included in the study. Primary endpoints were composites of cardiovascular death or HF hospitalizations at short-term (2 months) and long-term (mean: 1.8 +/- 1.2 years) follow-up. sNEP was measured using an ad hoc-modified enzyme-linked immunosorbent assay, and its prognostic value was assessed using Cox regression analyses. In a subgroup of patients, sNEP was measured both at admission and at discharge (n = 92). RESULTS: Median admission sNEP concentrations were 0.67 ng/ml (Q1 to Q3: 0.37 to 1.29), and sNEP was significantly associated, in age-adjusted Cox regression analyses, with the composite endpoint at short-term (hazard ratio [HR]: 1.29; 95% confidence interval [CI]: 1.04 to 1.61; p = 0.02) and long-term (HR: 1.23; 95% CI: 1.01 to 1.05; p = 0.003) follow-up. In multivariate Cox analyses that included clinical variables and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration, sNEP concentration at admission showed a clear trend toward significance for the composite endpoint at 2 months (HR: 1.22; 95% CI: 0.97 to 1.53; p = 0.09) and remained significant at the end of follow-up (HR: 1.21; 95% CI: 1.04 to 1.40; p = 0.01). At discharge, sNEP levels decreased from 0.70 to 0.52 ng/ml (p = 0.06). CONCLUSIONS: Admission sNEP concentration was associated with short- and long-term outcomes in AHF, and dynamic sNEP concentrations were observed during hospital admission. These preliminary data may be hypothesis-generating for the use of NEP inhibitors in AHF. PMID- 26251093 TI - Neprilysin: Biotarget and Biomarker in Heart Failure. PMID- 26251095 TI - Beta-Blockers in Acute Heart Failure: Do They Cause Harm? PMID- 26251094 TI - Effects of Beta-Blocker Withdrawal in Acute Decompensated Heart Failure: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: This study sought to evaluate the effects of beta-blocker withdrawal in acute decompensated heart failure (ADHF). BACKGROUND: Published reports showed trends for either no harm or increased risk of in-hospital mortality, short-term mortality, and rehospitalization rates in patients admitted for ADHF that discontinued beta-blockers; however, a comprehensive analysis has not been conducted. METHODS: Relevant studies from January 2000 through January 2015 were identified in the PubMed, EMBASE, and COCHRANE electronic databases. Where appropriate data were available, weighted relative risks were estimated using random-effects meta-analysis techniques. RESULTS: Five observational studies and 1 randomized clinical trial (n = 2,704 patients who continued beta-blocker therapy and n = 439 patients who discontinued beta-blocker therapy) that reported the short-term effects of beta-blocker withdrawal in ADHF were included in the analyses. In 2 studies, beta-blocker withdrawal significantly increased risk of in-hospital mortality (risk ratio: 3.72; 95% confidence interval [CI]: 1.51 to 9.14). Short-term mortality (relative risk: 1.61; 95% CI: 1.04 to 2.49; 4 studies) and combined short-term rehospitalization or death (relative risk: 1.59; 95% CI: 1.03 to 2.45; 4 studies) were also significantly increased. CONCLUSIONS: Discontinuation of beta-blockers in patients admitted with ADHF was associated with significantly increased in-hospital mortality, short-term mortality, and the combined endpoint of short-term rehospitalization or mortality. These data suggest beta-blockers should be continued in ADHF patients if their clinical picture allows. PMID- 26251096 TI - The Globalization of Heart Failure Research. PMID- 26251097 TI - Perhexiline, Cardiac Energetics, and Heart Failure: Lessons From the First Law of Thermodynamics. PMID- 26251098 TI - Reply: Perhexiline, Cardiac Energetics, and Heart Failure: Lessons From the First Law of Thermodynamics. PMID- 26251099 TI - CD20-positive primary gastric T-cell lymphoma poorly responding to initial treatment with rituximab plus CHOP, and a literature review. AB - There have been rare reported cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) that co-expressed CD20. A 44-year-old Japanese male was initially misdiagnosed as CD20-positive diffuse large B-cell lymphoma with a background of reactive CD3-positive T-cells in the stomach. After four cycles of R-CHOP [rituximab plus cyclophosphamide (CY), doxorubicin, vincristine, and prednisolone (PSL)], total gastrectomy with regional lymph node dissection was performed due to the poor response to R-CHOP. A final diagnosis of CD20-positive primary gastric PTCL-NOS was made based on the immunohistochemical, flow cytometric, and molecular genetic findings. In the present case, CD20 immunostaining for T-cell lymphoma cells in tumor tissue varied; in a large part, these were strong to weak-positive, and in some parts, absent. We additionally reviewed the literature focusing on CD20-positive PTCL-NOS treated with rituximab. The administration of rituximab has been performed as an initial treatment in 11 cases, including the case reported here. The response was good in cases with high expression of CD20, while it was poor in cases with variable intensity in CD20 staining, which is consistent with our experience in the present case. The efficacy of rituximab may be associated with intensity of CD20 expression in T cells and its homogeneity in the tumor tissue. PMID- 26251100 TI - Model Minority Stereotyping, Perceived Discrimination, and Adjustment Among Adolescents from Asian American Backgrounds. AB - The model minority image is a common and pervasive stereotype that Asian American adolescents must navigate. Using multiwave data from 159 adolescents from Asian American backgrounds (mean age at initial recruitment = 15.03, SD = .92; 60 % female; 74 % US-born), the current study targeted unexplored aspects of the model minority experience in conjunction with more traditionally measured experiences of negative discrimination. When examining normative changes, perceptions of model minority stereotyping increased over the high school years while perceptions of discrimination decreased. Both experiences were not associated with each other, suggesting independent forms of social interactions. Model minority stereotyping generally promoted academic and socioemotional adjustment, whereas discrimination hindered outcomes. Moreover, in terms of academic adjustment, the model minority stereotype appears to protect against the detrimental effect of discrimination. Implications of the complex duality of adolescents' social interactions are discussed. PMID- 26251101 TI - Prosocial Bystander Behavior in Bullying Dynamics: Assessing the Impact of Social Capital. AB - Individuals who observe a bullying event, but are not directly involved as a bully or victim, are referred to as bystanders. Prosocial bystanders are those individuals who actively intervene in bullying dynamics to support the victim and this prosocial behavior often ends the bullying. The current study examines how social capital in the form of social support, community engagement, mental health functioning, and positive school experiences and characteristics is associated with the likelihood of engaging in prosocial bystander behavior in a large sample (N = 5752; 51.03% female) of racially/ethnically diverse rural youth. It was hypothesized that social capital would be associated with an increased likelihood of engaging in prosocial bystander behavior. Following multiple imputation, an ordered logistic regression with robust standard errors was run. The hypothesis was partially supported and results indicated that social capital in the form of friend and teacher support, ethnic identity, religious orientation, and future optimism were significantly associated with an increased likelihood of engaging in prosocial bystander behavior. Contrary to the hypothesis, a decreased rate of self-esteem was significantly associated with an increased likelihood of engaging in prosocial bystander behavior. The findings highlight the importance of positive social relationships and community engagement in increasing prosocial bystander behavior and ultimately decreasing school bullying. Implications were discussed. PMID- 26251102 TI - The Regulatory Status of Genome-edited Crops. AB - Genome editing with engineered nucleases (GEEN) represents a highly specific and efficient tool for crop improvement with the potential to rapidly generate useful novel phenotypes/traits. Genome editing techniques initiate specifically targeted double strand breaks facilitating DNA-repair pathways that lead to base additions or deletions by non-homologous end joining as well as targeted gene replacements or transgene insertions involving homology-directed repair mechanisms. Many of these techniques and the ancillary processes they employ generate phenotypic variation that is indistinguishable from that obtained through natural means or conventional mutagenesis; and therefore, they do not readily fit current definitions of genetically engineered or genetically modified used within most regulatory regimes. Addressing ambiguities regarding the regulatory status of genome editing techniques is critical to their application for development of economically useful crop traits. Continued regulatory focus on the process used, rather than the nature of the novel phenotype developed, results in confusion on the part of regulators, product developers, and the public alike and creates uncertainty as of the use of genome engineering tools for crop improvement. PMID- 26251103 TI - Association of genetic variants in INS (rs689), INSR (rs1799816) and PP1G.G (rs1799999) with type 2 diabetes (T2D): a case-control study in three ethnic groups from North-West India. AB - Genetic contributions towards Type 2 diabetes (T2D) have been assessed through association studies across different world populations with inconsistencies. The majority of the T2D susceptibility loci are common across different races or populations but show ethnicity-specific differences. The pathogenesis of T2D involves genetic variants in the candidate genes. The interactions between the genes involved in insulin signaling and secretory pathways are believed to play an important role in determining an individual's susceptibility towards T2D. Therefore, the present study was initiated to examine the differences, if any, in the contribution of polymorphisms towards T2D susceptibility in the background of different ethnic specifications. The present case-control study included a total of 1216 T2D cases and healthy controls from three ethnic groups (Jat Sikhs, Banias and Brahmins) of North-West India. Polymorphisms were selected on the basis of information available in the literature for INS (rs689), INSR (rs1799816) and PP1G.G (rs1799999) in context to T2D. The genotyping was done using PCR-RFLP method. Statistical analysis was done using SPSS 16.0. The analyses revealed that INS (rs689) polymorphism conferred risk towards T2D susceptibility in all the three ethnic groups whereas INSR (rs1799816) polymorphism conferred risk towards T2D in Brahmins only and PP1G.G (rs1799999) polymorphism indicated T2D risk in Jat Sikhs only. Furthermore, interaction analyses indicated the cumulative role of three genetic variants in modulating T2D susceptibility in the three ethnic groups. In conclusion, our results substantiated the evidences for the role of ethnicity in differential susceptibility to T2D in the background of same genetic variants. PMID- 26251105 TI - Analysis of retinal nerve fibre layer, visual evoked potentials and relative afferent pupillary defect in multiple sclerosis patients. AB - OBJECTIVE: The aim of this study was to analyse retinal nerve fibre layer (RNFL), pattern-reversal visual evoked potentials (pVEPs) and relative afferent pupillary defect (RAPD) changes in multiple sclerosis (MS) patients with the consideration of past optic neuritis (ON). METHODS: Ophthalmological, neurological, OCT, RNFL and pVEP studies were conducted in 59 MS patients. RAPD tests were performed in 47 of them. Control group consisted of 28 healthy volunteers. RESULTS: Abnormal RNFL was found in 59% of cases of eyes with ON and 28% of eyes without ON. In eyes with ON, significantly lower RNFL values were indicated in the temporal and lower quadrants. Elongation of pVEP latency was found in 83% of eyes with ON and 60% of eyes without ON. The average value of pVEP latency was larger and the amplitude was lower in the subgroup of eyes with RNFL at the borderline or below the norm. RAPD was observed only in eyes with ON and with RNFL thinning. No association was found between the RAPD and pVEP parameters. CONCLUSIONS: VEPs were more frequently abnormal than RNFL in MS patients. RNFL damage in eyes without ON may indicate neurodegenerations in CNS of MS patients; it can also be the consequence of subclinical ON. SIGNIFICANCE: An analysis of RNFL and VEP can be useful for evaluating the optic nerve in MS patients. PMID- 26251104 TI - Depression Awareness and Self-Management Through the Internet: Protocol for an Internationally Standardized Approach. AB - BACKGROUND: Depression incurs significant morbidity and confers increased risk of suicide. Many individuals experiencing depression remain untreated due to systemic and personal barriers to care. Guided Internet-based psychotherapeutic programs represent a promising means of overcoming such barriers and increasing the capacity for self-management of depression. However, existing programs tend to be available only in English and can be expensive to access. Furthermore, despite evidence of the effectiveness of a number of Internet-based programs, there is limited evidence regarding both the acceptability of such programs and feasibility of their use, for users and health care professionals. OBJECTIVE: This paper will present the protocol for the development, implementation, and evaluation of the iFightDepression tool, an Internet-based self-management tool. This is a cost-free, multilingual, guided, self-management program for mild to moderate depression cases. METHODS: The Preventing Depression and Improving Awareness through Networking in the European Union consortium undertook a comprehensive systematic review of the available evidence regarding computerized cognitive behavior therapy in addition to a consensus process involving mental health experts and service users to inform the development of the iFightDepression tool. The tool was implemented and evaluated for acceptability and feasibility of its use in a pilot phase in 5 European regions, with recruitment of users occurring through general practitioners and health care professionals who participated in a standardized training program. RESULTS: Targeting mild to moderate depression, the iFightDepression tool is based on cognitive behavioral therapy and addresses behavioral activation (monitoring and planning daily activities), cognitive restructuring (identifying and challenging unhelpful thoughts), sleep regulation, mood monitoring, and healthy lifestyle habits. There is also a tailored version of the tool for young people, incorporating less formal language and additional age-appropriate modules on relationships and social anxiety. The tool is accompanied by a 3-hour training intervention for health care professionals. CONCLUSIONS: It is intended that the iFightDepression tool and associated training for health care professionals will represent a valuable resource for the management of depression that will complement existing resources for health care professionals. It is also intended that the iFightDepression tool and training will represent an additional resource within a multifaceted approach to improving the care of depression and preventing suicidal behavior in Europe. PMID- 26251106 TI - Defining abnormal slow EEG activity in acute ischaemic stroke: Delta/alpha ratio as an optimal QEEG index. AB - OBJECTIVE: Quantitative electroencephalographic (QEEG) indices sensitive to abnormal slow (relative to faster) activity power seem uniquely informative for clinical management of ischaemic stroke (IS), including around acute reperfusion therapies. However these have not been compared between IS and control samples. The primary objective was to identify the QEEG slowing index and threshold value which can most accurately discriminate between IS patients and controls. METHODS: The samples comprised 28 controls (mean age: 70.4; range: 56-84) and 18 patients (mean age: 69.3; range: 51-86). Seven indices were analysed: relative bandpower (delta, theta, alpha, beta), delta/alpha power ratio (DAR), (delta+theta)/(alpha+beta) ratio (DTABR) and QSLOWING. The accuracies of each index for classifying participants (IS or control) were analysed using receiver operating characteristic (ROC) techniques. RESULTS: All indices differed significantly between the samples (p<.001). DAR alone exhibited optimal classifier accuracy, with a threshold of 3.7 demonstrating 100% sensitivity and 100% specificity for discriminating between radiologically-confirmed, acute IS or control. DTABR and relative delta were the next most accurate classifiers. CONCLUSIONS: DAR of 3.7 demonstrated maximal accuracy for classifying all 46 participants as acute IS or control. SIGNIFICANCE: DAR assessment may inform clinical management of IS and perhaps other neurocritical patients. PMID- 26251107 TI - Depressed Spousal Caregivers Have Psychological Stress Unrelated to the Progression of Alzheimer Disease: A 3-Year Follow-Up Report, Kuopio ALSOVA Study. AB - OBJECTIVE: To explore family caregiver (FC) long-term psychological distress after Alzheimer disease (AD) diagnosis in a family member. METHODS: FC (n = 236) and patients with AD were prospectively followed up to 36 months after AD diagnosis. FC psychological distress was evaluated using the General Health Questionnaire (GHQ). Furthermore, caregiver depressive symptoms and sense of coherence, along with AD patient measurements, were measured at baseline and annually. Generalized estimating equation models were applied to study associations of these baseline factors to caregiver GHQ. RESULTS: After 36 months of follow-up, spousal caregivers (SCs) GHQ was significantly higher (P < .001) than in the nonspousal caregivers (NSCs). The difference in GHQ scores was associated by depressive symptoms (P < .001) at baseline, and the depressed SCs have more severe distress than NSCs over the observation period. CONCLUSION: During longitudinal caregiving, spousal and depressed caregivers of patients with AD report higher and increasing psychological stress than nonspousal and nondepressed caregivers. Spousal relationship, caregivers' depressive symptoms, and the severity of patients' neuropsychological symptoms at the time of AD diagnosis predict the trajectory of psychological distress. The current study highlights the need for evaluating AD caregiver mental health and level of coping. PMID- 26251108 TI - Strengths and Limitations of the MoCA for Assessing Cognitive Functioning: Findings From a Large Representative Sample of Irish Older Adults. AB - BACKGROUND: The Montreal Cognitive Assessment (MoCA) is a very widely used test for mild cognitive impairment. Differing recommendations have been made regarding its utility in providing a profile of performance across several cognitive domains. OBJECTIVES: To examine the factor structure of the MoCA in a nationally representative population study of older Irish adults and evaluate its utility in providing domain-specific information. METHODS: A cross-sectional analysis of wave 1 data from the Irish Longitudinal Study on Ageing was undertaken. Data from a subset of 2342 participants assessed using the MoCA were analyzed using both confirmatory factor analytic (CFA) and exploratory factor analytic (EFA) methods. RESULTS: Mean age was 72.64 (range 65 to 98), 53% female. The CFA provided evidence of adequate overall model fit for a previously proposed 6-factor model. In contrast, EFA yielded a 3-factor solution and test items cross-loaded onto a number of factors with no clear pattern of underlying cognitive domains. Using EFA to explore the 6-factor model yielded good fit, but again test items cross loaded onto a number of factors with no clear pattern evident. CONCLUSION: Lack of concordance between the CFA and EFA findings demonstrates that the correspondence between individual tests and their assumed cognitive domains is not robust, reflecting at least in part a current lack of consensus on how core cognitive constructs are defined and on what subcomponents can be subsumed under different cognitive domains. The MoCA should not be viewed as a substitute for more in-depth neuropsychological assessment when domain-specific information is required. PMID- 26251109 TI - Executive Abilities as Reflected by Clock Hand Placement: Frontotemporal Dementia Versus Early-Onset Alzheimer Disease. AB - The clock-drawing test (CDT) is widely used in clinical practice to diagnose and distinguish patients with dementia. It remains unclear, however, whether the CDT can distinguish among the early-onset dementias. Accordingly, we examined the ability of both quantitative and qualitative CDT analyses to distinguish behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer disease (eAD), the 2 most common neurodegenerative dementias with onset <65 years of age. We hypothesized that executive aspects of the CDT would discriminate between these 2 disorders. The study compared 15 patients with bvFTD and 16 patients with eAD on the CDT using 2 different scales and correlated the findings with neuropsychological testing and magnetic resonance imaging. The total CDT scores did not discriminate bvFTD and eAD; however, specific analysis of executive hand placement items successfully distinguished the groups, with eAD exhibiting greater errors than bvFTD. The performance on those executive hand placement items correlated with measures of naming as well as visuospatial and executive function. On tensor-based morphometry of the magnetic resonance images, executive hand placement correlated with right frontal volume. These findings suggest that lower performance on executive hand placement items occurs with involvement of the right dorsolateral frontal-parietal network for executive control in eAD, a network disproportionately affected in AD of early onset. Rather than the total performance on the clock task, the analysis of specific errors, such as executive hand placement, may be useful for early differentiation of eAD, bvFTD, and other conditions. PMID- 26251110 TI - Cognitive and Behavioral Symptoms in ALSFTD: Detection, Differentiation, and Progression. AB - Brief screening tools that detect and differentiate patients with amyotrophic lateral sclerosis and frontotemporal dementia (ALSFTD) from those more subtle cognitive or behavioral symptoms (ALS plus) and motor symptoms only (ALS pure) is pertinent in a clinical setting. The utility of 2 validated and data-driven tests (Mini-Addenbrooke's Cognitive Examination [M-ACE] and Motor Neuron Disease Behavioral Scale [MiND-B]) was investigated in 70 ALS patients (24 ALSFTD, 19 ALS plus, and 27 ALS pure). More than 90% of patients with ALSFTD scored at or below the cutoff on the M-ACE, whereas this was seen in only about 20% of ALS patients without dementia. The MiND-B differentiated between ALS pure and ALS plus diagnostic categories. Rasch modeling of M-ACE and MiND-B items revealed early cognitive (fluency, memory recall) and behavioral (apathy) symptoms in ALSFTD. The combined use of the M-ACE and MiND-B detects patients with ALSFTD, differentiates along the ALS continuum, and offers insight into the progression of nonmotor symptomatology in ALSFTD. PMID- 26251113 TI - World Lung Cancer Day 2015: lung cancer experts seek to improve awareness and confront stigma. PMID- 26251111 TI - Updating the Cognitive Performance Scale. AB - This study presents the first update of the Cognitive Performance Scale (CPS) in 20 years. Its goals are 3-fold: extend category options; characterize how the new scale variant tracks with the Mini-Mental State Examination; and present a series of associative findings. Secondary analysis of data from 3733 older adults from 8 countries was completed. Examination of scale dimensions using older and new items was completed using a forward-entry stepwise regression. The revised scale was validated by examining the scale's distribution with a self-reported dementia diagnosis, functional problems, living status, and distress measures. Cognitive Performance Scale 2 extends the measurement metric from a range of 0 to 6 for the original CPS, to 0 to 8. Relating CPS2 to other measures of function, living status, and distress showed that changes in these external measures correspond with increased challenges in cognitive performance. Cognitive Performance Scale 2 enables repeated assessments, sensitive to detect changes particularly in early levels of cognitive decline. PMID- 26251112 TI - The Effect of Reminiscence Therapy on Cognition, Depression, and Activities of Daily Living for Patients With Alzheimer Disease. AB - The purpose of this study was, conducted with experimental design, to investigate the effect of reminiscence therapy on cognition, depression, activities of daily living of institutionalized mild and moderate Alzheimer patients. The study was conducted with a total of 62 patients (31 intervention group and 31 control group) in four home care in Ankara, Turkey. Study was done between the July 1, 2013 and December 20, 2014. Reminiscence therapy sessions were held with groups consists of 4-5 patients, once a week with 30-35 minute duration for 12 weeks. Standardized Mini Mental Test was used in sample selection. Patients were listed through their mini mental test scores, and randomized as odd numbers to control group and even numbers to intervention group. Data were collected with forms developed by researcher 'Data Sheet' and 'Activities of Daily Living Follow-up Form' as well as scales 'Standardized Mini Mental Test' and 'Geriatric Depression Scale'. Chi-square, Mann Whitney-U test, variance analyses in repeated measures and Bonferroni tests were used for analysis. The increase in mean Standardized Mini Mental Test score and the decrease in mean Geriatric Depression Scale score of the individuals in the intervention group compared to the control group at the end of the reminiscence therapy was statistically significant (P < 0.05). At the end of reminiscence therapy sessions, increase in cognition and decrease in depression were found statistically significant in intervention group. PMID- 26251114 TI - Main animal welfare problems in ruminant livestock during preslaughter operations: a South American view. AB - Animals destined for meat production are usually exposed to many stressful conditions during production and particularly during preslaughter operations. Handling animals on farm, loading into and unloading from vehicles, transportation, passing through livestock markets, fasting, lairage and stunning can all affect their welfare. How badly welfare can be affected will depend on both the intrinsic factors of the specific type of animal involved and the extrinsic factors of the environment where those animals live or are being handled, including the animal handlers. In South America (SA), it has been part of a strategy for improving animal welfare (AW) to address not only ethical aspects, but to emphasize the close relationship existing between handling ruminants preslaughter and the quantity and quality of the meat they produce. This has resulted not only in improvements in AW, but has also brought economic rewards to producers which in turn can lead to higher incomes for them and hence better human welfare. For producers with a high number of animals, considering AW during production and preslaughter operations can determine the possibility of exporting and/or getting better prices for their products. At smallfarmer level, particularly in some less developed countries, where human welfare is impaired, using this strategy together with education has also been relevant. It is important that education and training in AW are done not only considering global knowledge, but also including specific geographical and climatic characteristics of each country and the cultural, religious and socio-economical characteristics of its people; therefore, research within the context of each country or region becomes relevant. The aim of this review was to show the results of research dealing with AW of ruminant livestock in Chile and some other SA countries. Some of the main problems encountered are related to lack of proper infrastructure to handle animals; long distance transport with high stocking densities in the larger countries; long fasting times due to animals passing through livestock markets and dealers; bad handling of animals by untrained personnel in these and other premises; and finally the lack of knowledge and skills by operators in charge of stunning procedures. Interventions at these stages have considered training animal handlers and transporters by showing them the consequences of bad handling with audiovisual material prepared on site. Research results have helped to improve AW and support the development of new legislation or to make changes in the existent legislation related to AW. PMID- 26251115 TI - A Facile Molten-Salt Route for Large-Scale Synthesis of NiFe2O4 Nanoplates with Enhanced Lithium Storage Capability. AB - Binary metal oxides have been deemed as a promising class of electrode materials for high-performance lithium ion batteries owing to their higher conductivity and electrochemical activity than corresponding monometal oxides. Here, NiFe2O4 nanoplates consisting of nanosized building blocks have been successfully fabricated by a facile, large-scale NaCl and KCl molten-salt route, and the changes in the morphology of NiFe2O4 as a function of the molten-salt amount have been systemically investigated. The results indicate that the molten-salt amount mainly influences the diameter and thickness of the NiFe2O4 nanoplates as well as the morphology of the nanosized building blocks. Cyclic voltammetry (CV) and galvanostatic charge-discharge measurements have been conducted to evaluate the lithium storage properties of the NiFe2O4 nanoplates prepared with a Ni(NO3)2/Fe(NO3)3/KCl/NaCl molar ratio of 1:2:20:60. A high reversible capacity of 888 mAh g(-1) is delivered over 100 cycles at a current density of 100 mA g( 1). Even at a current density of 5000 mA g(-1) , the discharge capacity could still reach 173 mAh g(-1). Such excellent electrochemical performances of the NiFe2O4 nanoplates are contributed to the short Li(+) diffusion distance of the nanosized building blocks and the synergetic effect of the Ni(2+) and Fe(3+) ions. PMID- 26251117 TI - New talent: Asia-Pacific. PMID- 26251116 TI - Acetaminophen knocks on death's door and receptor interacting protein 1 kinase answers. PMID- 26251118 TI - Uterine Leiomyoma Stem Cells: Linking Progesterone to Growth. AB - Uterine leiomyomas (fibroids) represent the most common class of benign tumors in women. Multiple leiomyomas usually arise from the uterus of a symptomatic woman. These tumors cause a variety of symptoms, including abnormal uterine bleeding, pelvic pain, bladder or bowel dysfunction, and recurrent pregnancy loss, and are responsible for more than 200,000 hysterectomies in the United States annually. Each leiomyoma seems to arise from the clonal expansion of a single myometrial smooth muscle cell transformed by a mutation. Tumor expansion is sustained by cell proliferation together with the production of large amounts of extracellular matrix. Estrogen and progesterone stimulate the growth of leiomyomas. Estrogen, together with its receptor ERalpha, enables progesterone action via induction of progesterone receptor (PR) expression. Progesterone induces the growth of leiomyoma by regulation of a set of key genes that control proliferation and apoptosis. A distinct cell population with stem-progenitor properties is indispensable for progesterone-dependent growth of leiomyomas. This stem progenitor cell population is deficient in ERalpha and PR and dependent on the much higher levels of these steroid receptors in surrounding mature leiomyoma or myometrial cells. Progesterone sends paracrine signals from these mature cells to stem cells. The WNT/beta-catenin pathway comprises a key component of this paracrine signaling system. The majority of medical treatments currently available for leiomyoma works by inhibiting estrogen or progesterone production or action, but tumors tend to regrow once treatment is stopped. Targeting stem cells and their paracrine interactions with more differentiated cell populations within leiomyoma may lead to the development of more effective therapeutics. PMID- 26251119 TI - Stem Cells in Endometrial Physiology. AB - Human endometrial mucosa is a dynamically remodeling tissue, undergoing cyclical morphologic and functional changes in response to fluctuating sex steroid hormones each menstrual cycle during a woman's reproductive life. Postmenopausal endometrium responds similarly to exogenous estrogen. Cyclical endometrial regeneration also occurs in nonmenstruating rodents, although to a lesser extent. The recent identification of rare populations of endogenous epithelial progenitor cells, mesenchymal stem/stromal cells (MSCs), the side population (SP) cells, and label-retaining cells (LRCs) suggests these stem/progenitor cell populations may play a key role in endometrial regeneration during menstrual and estrus cycles. This review summarizes the identification of epithelial progenitors, MSC, SP, and LRC, and discusses their contribution to endometrial tissue regeneration, maintaining tissue homeostasis, decidualization, and placentation. Markers for human endometrial MSC have been identified, revealing their perivascular location in both the functionalis and basalis layers. These markers also allow their purification from biopsy tissue and menstrual blood. These findings have advanced our understanding of normal endometrial physiology and will provide new insight into endometrial proliferative disorders (endometriosis, endometrial cancer). The ability to prospectively isolate endometrial MSC will enable their utilization in cell-based therapies for reproductive tract pathologies. PMID- 26251120 TI - Wnt Signaling in Stem Cells and Tumor Stem Cells. AB - The Wnt signaling cascade is critically important in stem cell biology, both in homeostatic maintenance and repair and regeneration of tissues and organs, through their respective somatic stem cells (SSCs). However, aberrant Wnt signaling is associated with a wide array of tumor types and Wnt signaling is important in the so-termed cancer stem cell/tumor-initiating cell (CSC/TIC) population. The ability to safely therapeutically target the Wnt signaling pathway offers enormous promise. However, just like the Sword of Damocles, significant risks and concerns regarding targeting such a critical pathway in normal stem cell maintenance and tissue homeostasis remain ever present. With this in mind, we review our current understanding of the role of Wnt signaling in SSCs and CSC/TICs and the potential to pharmacologically manipulate these endogenous stem cell populations (both normal and tumor). PMID- 26251121 TI - Autophagy protects human brain microvascular endothelial cells against methylglyoxal-induced injuries, reproducible in a cerebral ischemic model in diabetic rats. AB - Cerebral microvascular endothelial cells (ECs) are crucial for brain vascular repair and maintenance, but their physiological function may be impaired during ischemic stroke and diabetes. Methylglyoxal (MGO), a reactive dicarbonyl produced during glucose metabolism, could exacerbate ischemia-induced EC injury and dysfunction. We investigated the protective effect of autophagy on cultured human brain microvascular endothelial cells (HBMEC) that underwent MGO treatment. A further study was conducted to explore the underlying mechanisms of the protective effect. Autophagic activity was assessed by evaluating protein levels, using western blot. 3-methyladenine (3-MA), bafilomycin A1, ammonium chloride (AC), Beclin 1 siRNA, and chloroquine (CQ) were used to cause autophagy inhibition. Alarmar blue assay and lactate dehydrogenase release assay were used to evaluate cell viability. Streptozotocin was administered to induce type I diabetes in rats and post-permanent middle cerebral artery occlusion was performed to elicit cerebral ischemia. Blood-brain barrier permeability was also assessed. Our study found that MGO reduced HBMEC cell viability in a concentration- and time-dependent manner, and triggered the responsive autophagy activation. Autophagy inhibitors bafilomycin A1, AC, 3-MA, and BECN1 siRNA exacerbated MGO-induced HBMEC injury. FAK phosphorylation inhibitor PF573228 inhibited MGO-triggered autophagy and enhanced lactate dehydrogenase release. Meanwhile, similar autophagy activation in brain vascular ECs was observed during permanent middle cerebral artery occlusion-induced cerebral ischemia in diabetic rats, while chloroquine-induced autophagy inhibition enhanced blood-brain barrier permeability. Taken together, our study indicates that autophagy triggered by MGO defends HBMEC against injuries. PMID- 26251122 TI - Changing trends in tissue acquisition in malignant pancreatic neoplasms. AB - BACKGROUND AND AIM: To compare the frequency of use, hospital costs, and resource availability between endoscopic ultrasound-guided fine needle aspiration (EUS FNA), percutaneous, and surgical techniques for tissue acquisition in malignant pancreatic neoplasms. METHODS: This is a retrospective claims analysis of Medicare patients undergoing biopsy of malignant pancreatic neoplasms over 5 years (2006-2010). The primary outcome measure was to compare the utilization of EUS, percutaneous techniques, and surgery for performing pancreatic biopsies. The secondary outcome measures were to compare treatment costs and variations in availability of resources between the three techniques over a 1-year period (2010). RESULTS: Over 5 years, the use of EUS-FNA increased by 69.3% (7100 to 12 020) and the use of percutaneous biopsy by 1.8% (4480 to 4560) compared to decrease in surgical biopsy (720 to 420) by 41.7% (P < 0.0001). When compared to percutaneous and surgical biopsies ($9639 and $21 947, respectively) the median hospital cost/claim for EUS-FNA ($1794) was significantly lower (P < 0.0001). More EUS-FNA procedures were performed in urban and teaching hospitals compared to rural and non-teaching hospitals (P < 0.001). CONCLUSIONS: Although EUS-FNA is increasingly performed and is less costly, and the rate of surgical biopsies has declined precipitously, the utilization of percutaneous techniques remains prevalent. Training and education are required to disseminate the use of EUS-FNA outside major teaching institutions or foster referral of patients to EUS centers because of implications for patient care and resource use. PMID- 26251123 TI - Levels of Phthalate Metabolites in Urine of Pregnant Women and Risk of Clinical Pregnancy Loss. AB - Toxicological studies have shown that phthalate esters (PAEs), a class of widely used and environmentally prevalent chemicals, can increase the abortion rate in animals, but epidemiological evidence is scarce. This study aimed to explore the relationship between the urinary concentration of phthalate metabolites and the risk of clinical pregnancy loss. A total of 132 women who underwent clinical pregnancy loss (cases) and 172 healthy pregnant women (controls) were recruited from Beijing, China. Eight phthalate metabolites in urine were determined by ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Five phthalate metabolites, monomethyl phthalate (MMP), monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), and mono(2 ethlyhexyl) phthalate (MEHP), were detected in at least 95% of the urine samples, with the highest median concentration of 51.0 MUg/g of creatinine for MnBP of all participants. The differences in urinary concentrations of phthalate metabolites between cases and controls were evaluated using the Mann-Whitney U test. The concentrations of MEP (median of 18.7 MUg/g of creatinine), MiBP (23.3 MUg/g of creatinine), and MnBP (58.2 MUg/g of creatinine) detected in the cases were significantly higher than those (15.7 MUg/g of creatinine for MEP, 19.4 MUg/g of creatinine for MiBP, and 43.9 MUg/g of creatinine for MnBP) in the controls (p < 0.05). Increasing risks of clinical pregnancy loss were observed from the first to fourth quartiles of the MEP, MiBP, and MnBP concentrations (p < 0.05 for trend). We concluded that exposure to MEP, MiBP, and MnBP was associated with an increased risk of clinical pregnancy loss. PMID- 26251124 TI - Superior Oblique Extraocular Muscle Shape in Superior Oblique Palsy. PMID- 26251125 TI - Choroidal Thickness Changes After Photodynamic Therapy and Recurrence of Chronic Central Serous Chorioretinopathy. PMID- 26251126 TI - The global regulatory landscape regarding micronutrient fortification of condiments and seasonings. AB - Fortification of staple foods has been a successful strategy for combatting micronutrient deficiency. Recently, fortification of condiments and seasonings has been considered as a new approach to mitigate micronutrient deficiencies worldwide. The regulatory environment of already existing programs must be examined to assess their safety, efficacy, and sustainability as this strategy expands globally. The objective of this review is to summarize the global regulatory landscape for the fortification of condiments and seasonings. Presently, legislation regarding the fortification of condiments and seasonings is primarily voluntary and limited to a few nations in Asia. The only dietary vehicles addressed are salt, soy sauce, and fish sauce, and the micronutrients addressed are iron and iodine. A marketing-driven introduction of fortified seasoning powders with iron, and indirectly with iodine, is also gaining popularity in Africa, Central America, and Caribbean countries. It is recommended that legislation regarding food fortification be mandatory in nature and follow established CODEX and World Trade Organization principles as well as World Health Organization/Food and Agriculture Organization of the United Nations fortification guidelines to ensure that these programs are safe, effective, and sustainable. PMID- 26251127 TI - Urethra-sparing high-intensity focused ultrasound for localized prostate cancer: Functional and oncological outcomes. AB - OBJECTIVES: To evaluate longitudinal changes in urinary function and quality of life, and the oncological outcomes of patients treated with urethra-sparing high intensity focused ultrasound for localized prostate cancer. METHODS: Patients with negative findings in the urethra and the anterior urethral zone using transrectal ultrasound-guided targeted biopsies, and magnetic resonance imaging, received urethra-sparing or whole-gland high-intensity focused ultrasound as the primary therapy for localized prostate cancer without transurethral resection of the prostate. Longitudinal changes in urinary function and quality of life, and the oncological outcomes of the patients were analyzed retrospectively. RESULTS: The median follow-up times for urethra-sparing and whole-gland high-intensity focused ultrasound were 36 and 30 months, respectively. Comparing the patients treated with urethra-sparing high-intensity focused ultrasound (n = 45) with those treated with whole-gland high-intensity focused ultrasound (n = 65), there were significant differences in the International Prostate Symptom Score (P = 0.014) at 3 months, International Prostate Symptom Score quality of life (P = 0.033) at 3 months, maximum urinary flow rate (mL/s; at 3 months, P = 0.010; at 6 months, P = 0.038) and residual urine volume (mL; at 3 months, P < 0.0001; at 6 months, P = 0.016; at 12 months, P = 0.028). For quality of life, there were significant differences in Functional Assessment of Cancer Therapy - General (at 3 months, P = 0.022) and Functional Assessment of Cancer Therapy - Prostate (at 3 months, P = 0.028; at 6 months, P = 0.034). There were no significant differences in oncological outcomes regarding negative biopsy rates on follow up (91% vs 92%; P = 0.8) or biochemical disease-free survival rates (86.7% vs 89.2%; P = 0.7). CONCLUSIONS: Urethra-sparing high-intensity focused ultrasound might prevent prolonged bladder outlet obstruction, and could be a treatment option for localized prostate cancer. PMID- 26251128 TI - Occlusal characteristics in 3-year-old children--results of a birth cohort study. AB - BACKGROUND: Aim of this prospective study was to determine prevalence of malocclusion and associated risk factors in 3-year-old Thuringian children. METHODS: Subjects (n = 377) were participants in a regional oral health programme, a birth cohort study with the aim to prevent caries (German Clinical Trials Register DRKS00003438). Children received continuous dental care since birth. Occlusal characteristics (overjet, overbite, anterior open bite, canine relationship and posterior crossbite) were measured at the age of 3 years by one calibrated clinician using a vernier caliper (accuracy 0.1 mm; Munchner Modell 042-751-00, Germany). A regular parent survey was conducted to assess risk factors for development of malocclusion. RESULTS: Three hundred seventy seven children (mean age 3.31 +/- 0.70 years; 52.5% male) were examined. Children had a mean overjet of 2.4 +/- 0.8 mm and the mean overbite was 0.8 +/- 1.2 mm; 58.8 % of the children had a normal overjet <= 3 mm and 88.8% a normal overbite with < [Formula: see text] overlap. Prevalence of malocclusion was 45.2% (10.9% anterior open bite, 41.2% increased overjet >= 3 mm, 40.8% Class II/III canine relationship, 3.4% posterior crossbite). All children who sucked the thumb had a malocclusion. Children who used a pacifier had greater odds of having a malocclusion at age of 3 years than children without pacifier use (OR = 3.36; 95% CI: 1.87-6.05). Malocclusion and dental trauma were associated, but not statistically significant (OR = 1.83; 95% CI: 0.99-3.34; p = 0.062). Malocclusion was not associated with gender, migration background, low socioeconomic status, preterm birth, special health care needs, breathing or dietary patterns (p > 0.05). CONCLUSIONS: Non-nutritive sucking habits were important risk factors for development of a malocclusion in the primary dentition. PMID- 26251129 TI - Genomewide effects of peroxisome proliferator-activated receptor gamma in macrophages and dendritic cells--revealing complexity through systems biology. AB - BACKGROUND: Systems biology approaches have become indispensable tools in biomedical and basic research. These data integrating bioinformatic methods gained prominence after high-throughput technologies became available to investigate complex cellular processes, such as transcriptional regulation and protein-protein interactions, on a scale that had not been studied before. Immunology is one of the medical fields that systems biology impacted profoundly due to the plasticity of cell types involved and the accessibility of a wide range of experimental models. MATERIALS AND METHODS: In this review, we summarize the most important recent genomewide studies exploring the function of peroxisome proliferator-activated receptor gamma in macrophages and dendritic cells. PPARgamma ChIP-seq experiments were performed in adipocytes derived from embryonic stem cells to complement the existing data sets and to provide comparators to macrophage data. Finally, lists of regulated genes generated from such experiments were analysed with bioinformatics and system biology approaches. RESULTS: We show that genomewide studies utilizing high-throughput data acquisition methods made it possible to gain deeper insights into the role of PPARgamma in these immune cell types. We also demonstrate that analysis and visualization of data using network-based approaches can be used to identify novel genes and functions regulated by the receptor. CONCLUSIONS: The example of PPARgamma in macrophages and dendritic cells highlights the crucial importance of systems biology approaches in establishing novel cellular functions for long known signaling pathways. PMID- 26251130 TI - Diffusion-weighted imaging using readout-segmented echo-planar imaging, parallel imaging, and two-dimensional navigator-based reacquisition in detecting acute optic neuritis. AB - PURPOSE: To evaluate the accuracy of diffusion-weighted imaging (DWI) in comparison to contrast-enhanced, fat-suppressed T1 -weighted imaging (CET1WI) in detecting acute optic neuritis (ON). MATERIALS AND METHODS: The clinical data and magnetic resonance imaging (MRI) findings of 42 patients who presented with decreased vision were retrospectively reviewed. Both 3.0T MRI DWI and CET1WI orbital imaging studies were performed. Two neuroradiologists independently evaluated the DWI and CET1WI. The sensitivity, specificity, and accuracy of the DWI and CET1WI were individually calculated using the clinical diagnosis as the reference standard. The interobserver and intraobserver reliability of DWI and CET1WI were assessed by using a weighted Cohen's kappa (kappa) test; a value of P < 0.05 was set as the threshold for statistical significance. RESULTS: Of the 42 patients, 34 patients (41 nerves) had clinically confirmed acute ON, two had ischemic optic neuropathy, and three had chronic recurrent ON. The sensitivities of DWI and CET1WI for acute ON were 82.9-82.9% and 68.3-85.4%, respectively; the specificities were 81.4-83.7% and 79.1-93.0%, respectively; and the accuracies were 82.1-83.3% and 82.1-90.0%, respectively. The interobserver kappa values were 0.596-0.643 and 0.694-0.734 for DWI and CET1WI, respectively; the intraobserver kappa values were 0.809-0.905 and 0.834-0.924 for DWI and CET1WI, respectively (each P < 0.0001). CONCLUSION: Given that its sensitivity and specificity are similar to those of dedicated CET1WI for acute ON, DWI can play an important complementary role in detecting acute ON, especially in atypical ON cases, and can provide a quantitative modality that can be used to evaluate axonal damage in the optic nerves. PMID- 26251131 TI - Use of enzymes to minimize the rheological dough problems caused by high levels of damaged starch in starch-gluten systems. AB - BACKGROUND: During wheat milling, starch granules can experience mechanical damage, producing damaged starch. High levels of damaged starch modify the physicochemical properties of wheat flour, negatively affecting the dough behavior as well as the flour quality and cookie and bread making quality. The aim of this work was to evaluate the effect of alpha-amylase, maltogenic amylase and amyloglucosidase on dough rheology in order to propose alternatives to reduce the issues related to high levels of damaged starch. RESULTS: The dough with a high level of damaged starch became more viscous and resistant to deformations as well as less elastic and extensible. The soluble fraction of the doughs influenced the rheological behavior of the systems. The alpha-amylase and amyloglucosidase reduced the negative effects of high damaged starch contents, improving the dough rheological properties modified by damaged starch. The rheological behavior of dough with the higher damaged-starch content was related to a more open gluten network arrangement as a result of the large size of the swollen damaged starch granules. CONCLUSION: We can conclude that the dough rheological properties of systems with high damaged starch content changed positively as a result of enzyme action, particularly alpha-amylase and amyloglucosidase additions, allowing the use of these amylases and mixtures of them as corrective additives. Little information was reported about amyloglucosidase activity alone or combined with alpha-amylase. The combinations of these two enzymes are promising to minimize the negative effects caused by high levels of damaged starch on product quality. More research needs to be done on bread quality combining these two enzymes. (c) 2015 Society of Chemical Industry. PMID- 26251133 TI - Polymicrogyria: the common endpoint of many different aetiological processes. PMID- 26251132 TI - Tissue repair in osteoradionecrosis using pentoxifylline and tocopherol--report of three cases. AB - PURPOSE: Osteoradionecrosis is a complication of head and neck radiotherapy, with a difficult resolution and no well-established treatment. The disease progression can cause important loss on patient's quality of life after cancer treatment. The options for treatment are limited and include clinical monitoring, prescription, or surgical procedures. As an alternative for bone necrosis treatment, a combination of drugs, pentoxifylline and tocopherol, can be used. Studies have shown that this combination significantly reduces chronic radiotherapy damage. The article reports successful treatment with this prescription protocol. METHODS: We report three cases of patients referred to the Service of Oral and Maxillofacial Surgery at Erasto Gaertner Hospital, in Curitiba, Brazil. They were submitted to radiotherapy for the treatment of malignant head and neck tumors and later developed osteoradionecrosis. They were treated with the combination pentoxifylline and tocopherol. RESULTS: All patients achieved complete remission in less than 1 year, with complete healing of bone exposure and without clinical symptoms. CONCLUSIONS: This results show that this combination of drugs is beneficial in cases of bone necrosis induced by radiation, avoiding more aggressive treatments and reducing morbidity. PMID- 26251136 TI - [Overview]. PMID- 26251134 TI - The HDL receptor SR-BI is associated with human prostate cancer progression and plays a possible role in establishing androgen independence. AB - BACKGROUND: Human prostate cancer represents one of the most frequently diagnosed cancers in men worldwide. Currently, diagnostic methods are insufficient to identify patients at risk for aggressive prostate cancer, which is essential for early treatment. Recent data indicate that elevated cholesterol levels in the plasma are a prerequisite for the progression of prostate cancer. Here, we analyzed clinical prostate cancer samples for the expression of receptors involved in cellular cholesterol uptake. METHODS: We screened mRNA microarray files of prostate cancer samples for alterations in the expression levels of cholesterol transporters. Furthermore, we performed immunohistochemistry analysis on human primary prostate cancer tissue sections derived from patients to investigate the correlation of SR-BI with clinicopathological parameters and the mTOR target pS6. RESULTS: In contrast to LDLR, we identified SR-BI mRNA and protein expression to be induced in high Gleason grade primary prostate cancers. Histologic analysis of prostate biopsies revealed that 53.6 % of all cancer samples and none of the non-cancer samples showed high SR-BI staining intensity. The disease-free survival time was reduced (P = 0.02) in patients expressing high intra-tumor levels of SR-BI. SR-BI mRNA correlated with HSD17B1 and HSD3B1 and SR BI protein staining showed correlation with active ribosomal protein S6 (RS = 0.828, P < 0.00001). CONCLUSIONS: We identified SR-BI to indicate human prostate cancer formation, suggesting that increased levels of SR-BI may be involved in the generation of a castration-resistant phenotype. PMID- 26251135 TI - [Picture in Clinical Hematology]. PMID- 26251137 TI - [Hemoglobinopathies in Japan: characteristics and comparison with those of other ethnic groups]. AB - Abnormalities of hemoglobin (Hb), or hemoglobinopathies, are classified into Hb abnormalities that arise from altered quality induced mainly by amino acid substitution. Furthermore, thalassemia is a quantitative abnormality of normal Hb. Most hemoglobinopathies are inherited disorders. The abnormal Hb known to date comprise more than 210 types in the Japanese population. The rate of thalassemia in Japan is less than that in endemic regions, but the frequencies of beta- and alpha- thalassemias are 1/1,000 and 1/3,500 in the general population, respectively, so not particularly rare. The mutation spectrum is different from that of endemic regions, probably because Japanese have been historically isolated islanders. Japanese hemoglobinopathy generally has minor symptoms, which are different from those in endemic areas where thalassemia exhibits major clinical manifestations. This might be why useful knowledge is obtained in our laboratory which concentrates on detailed observation of clinical data in addition to genetic analysis. We have, in fact, discovered new clinical characteristics and the significance of hemoglobinopathy, especially of minor or intermediate thalassemia. This approach is quite different from that in other countries coping with only the major type. By focusing on this novel approach, we aim to contribute to improving diagnostic technology for patients. PMID- 26251138 TI - [Hereditary red cell membrane disorders in Japan: comparison with other countries]. AB - Red cell membrane disorders are the most common type of inherited hemolytic disorders in the Japanese population. In hereditary spherocytosis (HS), the primary presentation is a loss of membrane surface area, leading to reduced deformability because of defects in the membrane proteins ankyrin, band 3, beta spectrin, alpha spectrin, or protein 4.2 (P4.2). Complete P4.2 deficiencies, which are inherited in an autosomal recessive manner, comprise a unique HS subgroup and are common in Japanese, but rare in other populations. In contrast, the principle presentation in hereditary elliptocytosis (HE) is mechanical weakness of the erythrocyte membrane skeleton due to defects in alpha-spectrin, beta-spectrin, or protein 4.1. Although alpha-spectrin mutations are the most frequent cause of HE in Caucasian, African, and Mediterranean populations, these mutations are rare in the Japanese population, in which P4.1 deficiencies are instead most common. Furthermore, hereditary stomatocytoses (HSt) are disorders of monovalent cation permeability in the red cell membrane. PMID- 26251139 TI - [Glucose-6-phosphate dehydrogenase deficiency in Japan]. AB - In the past 10 years, we have diagnosed congenital hemolytic anemia in 294 patients, approximately 33% of whom were found to have glucose-6-phosphate dehydrogenase (G6PD) deficiency. It is becoming more common for Japanese to marry people of other ethnic origins, such that G6PD deficiency is becoming more prevalent in Japan. Japanese G6PD deficiency tends to be diagnosed in the neonatal period due to severe jaundice, while G6PD-deficient patients with foreign ancestors tend to be diagnosed at the onset of an acute hemolytic crisis before the age of six. It is difficult to predict the clinical course of each patient by G6PD activity, reduced glutathione content, or the presence/absence of severe neonatal jaundice. We propose that both neonatal G6PD screening and systematic analyses of G6PD gene mutations may be useful for personalized management of patients with G6PD-deficient hemolytic anemia. PMID- 26251140 TI - [Autoimmune hemolytic anemia as a paraneoplastic syndrome associated with solid tumors]. AB - Autoimmune hemolytic anemia (AIHA) is a rare paraneoplastic syndrome (PNS) associated with malignant solid tumors. Patients with PNS-AIHA are often refractory to steroid treatment before surgery. The mechanisms underlying PNS AIHA are not well understood. In a recent case report describing a patient with PNS-AIHA, the antibodies had formed against the tumor antigens and cross-reacted with the erythrocyte antigen: band 3. Further study of this case may provide clues to finding novel mechanisms and targets for immunotherapy against AIHA and solid tumors. PMID- 26251141 TI - [Management of pregnancy and delivery in patients with paroxysmal nocturnal hemoglobinuria]. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hemolytic anemia, which generally affects women of childbearing age. PNH hemolysis increases the risk of complications such as thrombosis during pregnancy and the postpartum period. Management of a pregnant woman with PNH remains a challenge due to the high incidence of thrombotic complications and the difficulty of differentiating a PNH crisis from the complications of pregnancy. PNH is associated with an increased rate of premature labor and fetal loss. Eculizumab, a C5 complement inhibitor, is a potential therapeutic option for such patients. This review presents the current strategies for the management of pregnant women with PNH, the cases experienced in our hospital, and the recently proposed remedy guide regarding the management of pregnancy in cases with PNH by the Pregnancy Working Group of The Japan PNH Interest group. PMID- 26251142 TI - [Diagnosis and treatment of microangiopathic hemolytic anemia]. AB - "Microangiopathic hemolytic anemia (MAHA)" is now used to designate any hemolytic anemia related to RBC fragmentation, occurring in association with small vessel disease. In DIC, RBC fragmentation is thought to result from the deposition of fibrin or platelets within the microvasculature. The term "thrombotic microangiopathy (TMA)" is also used to describe syndromes characterized by MAHA, thrombocytopenia, and thrombotic lesions in small blood vessels. The most prominent diagnoses associated with TMA are thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Many different disorders, including preeclampsia, infections, adverse drug reactions, hematopoietic stem cell transplantation, autoimmune diseases, and malignancies, can cause TMA (i.e., secondary TMA). Recently, because the pathogeneses of TTP and HUS have been elucidated, great progress has been made in diagnosis and treatments. However, the pathogenesis of secondary TMA remains unclear. Clinical problems awaiting solution in TMA management include determination of the positioning of rituximab in the treatment sequence of primary TTP, management of Shiga-toxin producing Escherichia coli-HUS complicated by encephalopathy, confirmation of the efficacy and long-term safety of eculizumab in the treatment of atypical HUS, and elucidating the pathogenesis of secondary TMA as well as improving the efficacy of treatment. PMID- 26251143 TI - [Key players in intestinal GVHD]. AB - Acute graft versus host disease (GVHD) is a potentially life threatening complication after allogeneic hematopoietic stem cell transplantation. The gut is one of the most frequently affected organs in GVHD. Intestinal GVHD is often resistant to current therapies for GVHD and greatly affects the nutritional status of patients. Recent advances in understanding the biology of the intestinal immune system have revealed the significance of mechanical and chemical barriers involving the intestinal mucosa and intestinal microflora in the pathophysiology of GVHD. These barriers and flora are tightly regulated by key populations such as intestinal stem cells, Paneth cells, innate lymphoid cells, and macrophages. Recent findings for these key players in the process of intestinal GVHD are reviewed in this article. PMID- 26251144 TI - [Development of Tax-redirected T-cell immunotherapy using TCR gene transduction in patients with ATL]. AB - ATL is an aggressive T-cell malignancy caused by HTLV-1 virus infection. Tax, which is the most important regulatory protein of HTLV-1, is associated with aggressive proliferation of host cells and is also a major target antigen for CD8+ cytotoxic T-cells (CTLs). Recently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has proven effective for ATL, and donor-derived Tax specific CTL might contribute to graft-versus-ATL effects in some recipients who maintained complete remission after allo-HSCT. We, for the first time, analyzed the Tax-specific T-cell receptor (TCR) repertoire, phenotypes and functions of Tax-specific CTLs at single-cell levels in HLA-A24+ ATL patients who underwent allo-HSCT. We found that 1) a particular amino acid sequence motif (PDR) in the CDR3 region of TCR-beta was conserved in different patients and also within the same patient before and after allo-HSCT, and 2) the PDR+ Tax-specific CTL clone selectively expanded in ATL long-term survivors as less-differentiated effector memory CTLs. Actually, the PDR+ CTL showed not only strong binding activity for the Tax-tetramer but also strong killing activity against patients' HTLV-1 infected T-cells without any reaction against normal cells. We are presently evaluating the killing activities of PDR+ TCR-transduced T-cells against Tax in immunodeficient mice, with the aim of developing a new immunotherapy for ATL. PMID- 26251145 TI - [Cytomegalovirus reactivation after allogeneic stem cell transplantation reduces the risk of relapse in patients with acute myeloid leukemia]. AB - Cytomegalovirus (CMV) infection is still a major infectious complication after allogeneic hematopoietic cell transplantation (HCT). Recently, CMV reactivation was reported to be associated with a decreased risk of relapse in patients with acute myeloid leukemia (AML). We herein retrospectively evaluated the impact of early CMV reactivation on the incidence of disease relapse after allo-HCT using the database of the Transplant Registry Unified Management Program (TRUMP) at the JSHCT. Patients who underwent their first allo-HCT from HLA-matched related or unrelated donors between 2000 and 2009, and who survived without disease relapse until day 100 after transplantation, were analyzed. CMV reactivation was associated with a decreased cumulative incidence of relapse among patients with AML, but not in patients with other hematological malignancies in our study. However, this benefit was nullified by the increased rate of non-relapse mortality. The underlying mechanism is unclear, but the immunological reaction against CMV reactivation plays an essential role in this association. Thus, immune augmentation treatment options including vaccination and adoptive T-cell transfer might be useful for taking advantage of the efficacy of CMV reactivation while minimizing the increase in non-relapse mortality. PMID- 26251146 TI - [Structure of human erythrocyte band 3: two-dimensional crystallographic analysis of the membrane domain]. AB - Band 3 (also known as anion exchanger 1, AE1) is one of the most abundant membrane proteins in human erythrocytes. Band 3 has 911 amino acids and consists of two structurally and functionally distinct domains. One is a 40-kDa N-terminal cytoplasmic domain and the other is a 55-kDa C-terminal membrane domain. The cytoplasmic domain maintains red cell shape through interactions with cytoskeletal proteins, such as protein 4.1, protein 4.2, ankyrin, and spectrin. On the other hand, the membrane domain mediates electroneutral exchange of anions, such as bicarbonate and chloride across the erythrocyte membrane. We reported the three-dimensional structure of the outward-open membrane domain of band 3, which was cross-linked between K539 and K851 with H2DIDS, at 7.5 A resolution using cryo-electron crystallography. Although the results showed significantly improved resolution as compared with previous structural analyses, we could not assign all alpha-helices because of low resolution and uncertainty persists regarding the fold of band 3. However, we recognized that band 3 has internal repeats, because the structure exhibited distinctive anti-parallel V shaped motifs, which protrude from the membrane bilayer on both sides. One of the helices in the motif is very long and highly tilted with respect to the normal structure of the bilayer. PMID- 26251147 TI - [Band 3 deficiency as a cause of hereditary spherocytosis]. AB - Band 3 protein accounts for the largest percentage of whole erythrocyte membrane proteins. Abnormalities in this protein are closely associated with pathologies including hereditary spherocytosis (HS), Southeast Asian ovalocytosis and distant renal tubular acidosis. Currently, EMA binding capacity measurement in erythrocytes is the most useful screening test for diagnosing HS. We have also demonstrated reduced EMA binding capacity in patients with HS who have deficiencies of membrane proteins such as ankyrin not directly binding to EMA and who have as yet undetectable abnormalities of membrane proteins. However, even patients with hereditary elliptocytosis, who have a partial spectrin deficiency, were found to show reduced EMA binding capacity. Six of 7 had spherocytic elliptocytosis. Therefore, it is necessary to meticulously diagnose HS by ruling out all other possibilities. PMID- 26251148 TI - [Molecular mechanisms of autoimmune hemolytic anemia]. AB - Autoimmune hemolytic anemia (AIHA) is an acquired immunological disease in which red blood cells (RBCs) are selectively attacked and destroyed (hemolyzed) by autoantibodies produced by the patient's own immune system. Several hypotheses regarding the mechanisms underlying the development of AIHA have been proposed, but the actual pathogenesis remains unclear. Since the major autoantigens in warm AIHA were determined to be Rh protein, band 3 and glycophorin A in 1993, helper T cells (Th1, Th2 and Th17) and regulatory T (Treg) cells specifically reacting to Rh peptides were reported in patients with AIHA. Recently, Th1 responses were found to be suppressed with synthetic peptides that are recognized by the Treg cells, and Th17 cells and interleukin 17 were shown to contribute to the induction and the development of AIHA. This approach to understanding AIHA pathogenesis may provide clues to finding novel targets for immunotherapy against AIHA. PMID- 26251149 TI - [Genetic variants in C5 and poor response to eculizumab]. AB - This review summarizes the presentation entitled "Genetic variants in C5 and poor response to eculizumab" (N Engl J Med. 2014; 370: 632-639), given at Symposium 3 entitled "Basic and clinical topics on red blood cell membrane", during the 76th Annual Meeting of the Japanese Society of Hematology. The molecular basis for the poor response to eculizumab in Japanese patients is unclear. Of 345 Japanese patients with PNH who received eculizumab, 11 showed a poor response. All 11 had a single missense C5 heterozygous mutation, c.2654G->A, which predicts the polymorphism p.Arg885His. The prevalence of this mutation among patients with PNH (3.2%) was similar to that in healthy Japanese people (3.5%). This polymorphism was also identified in a Han Chinese population. Non-mutant and mutant C5 both caused hemolysis in vitro, but only non-mutant C5 bound to and was blocked by eculizumab. In vitro hemolysis due to non-mutant and mutant C5 was completely blocked by N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab. The functional capacity of the C5 polymorphism p. Arg885His, together with its failure to undergo blockade by eculizumab, accounts for the poor response to this agent of patients who carry this mutation. PMID- 26251150 TI - [Genetic analysis of hereditary hematological disorders: overview]. AB - During the past 30 years, our knowledge of congenital/hereditary hematological disorders has dramatically improved due to the identification of their causative genes, which has also provided novel insights into disease pathobiology. More recently, the development of next-generation sequencing (NGS) technologies has provided an unprecedented opportunity to elucidate the genetic basis of rare congenital/hereditary disorders by enabling single nucleotide resolution analysis of patients' genomes. Currently, targeted sequencing, especially whole-exome sequencing (WES), is widely used for analysis of Mendelian disorders. Protein coding exons constitute about 1.3% of the human genome and are predicted to harbor most of the disease-causing mutations. Therefore, much higher sequence coverage of exonic regions can be achieved more effectively with considerably less sequence data as compared with whole-genome sequencing. In addition to the discovery of novel causative genes, NGS have been used for diagnostic purposes in congenital hematological disorders. WES or targeted sequencing of known causative genes could identify the mutations causing diseases more accurately and effectively than traditional Sanger sequencing. Therefore, the widespread use of NGS for clinical diagnosis (clinical sequencing) of congenital/hereditary hematological disorders, namely, clinical sequencing is anticipated in the near future. PMID- 26251151 TI - [Molecular mechanisms underlying the pathology of Diamond-Blackfan anemia]. AB - Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome, characterized by red blood cell aplasia. Macrocytic anemia is a prominent feature of DBA but the disease is also characterized by growth retardation and congenital anomalies that are present in approximately 40% of affected patients. DBA is associated with single, monoallelic, inactivating mutations in ribosomal protein (RP) genes. In DBA, mutations or large deletions in RP genes include RPS7, RPS10, RPS17, RPS19, RPS24, RPS26, RPL5, RPL11, RPL26 and RPL35A. These mutations have been reported in up to 60% of DBA patients. To date, no known pathogenic mutations have been found in the remaining patients. In an effort to identify new mutations responsible for DBA, we performed whole-exome sequencing analysis of 48 patients with no documented mutations/deletions in our first screening and identified a de novo splicing error mutation in RPL27 and a frameshift deletion in RPS27 in sporadic patients with DBA. In vitro knockdown of the gene expression disturbed pre-ribosomal RNA processing. Zebrafish models of rpl27 and rps27 mutations showed impairments of erythrocyte production and tail and/or brain development. In this report, we also discuss current knowledge regarding pathways from the impairment of ribosomal biogenesis to the pathology of DBA. PMID- 26251152 TI - [Current problems in the diagnosis of Philadelphia-negative myeloproliferative neoplasms in Japan]. AB - To investigate the current situation and issues regarding the diagnosis of Philadelphia-negative myeloproliferative neoplasms (MPN) in Japan, we retrospectively analyzed an accumulated cohort consisting of 1,081 patients with suspected MPN. Based on WHO2008 diagnostic criteria, we diagnosed 101 of these patients with polycythemia vera, 179 with essential thrombocythemia, 36 with primary myelofibrosis, 45 with unclassifiable MPN, and 4 with myelodysplastic syndromes. Out of 716 patients, 235 were not diagnosed with MPN despite the detection of a JAK2, CALR, or MPL mutation. Among 156 patients with undefined MPN receiving further follow-up, none underwent bone marrow examination and screening for BCR-ABL1 was not performed in 88 cases. Thus, diagnosis was not possible in these cases due to a lack of essential examinations. Since the prognosis and treatment strategy associated with MPN differ among disease types, in addition to mutation analysis, the importance of bone marrow examination and screening for BCR-ABL1 must be re-recognized. PMID- 26251153 TI - [Hypofibrinogenemia associated with steroid therapy for the patients who developed GVHD after allogeneic stem cell transplantation]. AB - Hypofibrinogenemia (plasma fibrinogen level <150 mg/dl) is occasionally observed after allogeneic hematopoietic stem cell transplantation, and its etiology is often difficult to determine. We herein report that steroids administered for the treatment of graft-versus-host disease (GVHD) are associated with the development of hypofibrinogenemia. We retrospectively analyzed the plasma fibrinogen (Fg) levels in 15 consecutive patients who had been administered 1 mg/kg/day (1 mg/kg group) or 2 mg/kg/day (2 mg/kg group) methylprednisolone for the treatment of Grade II to IV acute GVHD. Hypofibrinogenemia had developed in 8 of the 15 patients (53%) by day 50 after the start of steroid treatment, and was observed in 2 of 6 patients in the 1 mg/kg group and 6 of 9 in the 2 mg/kg group. A significant decrease in the Fg level was observed in the 2 mg/kg group (the median value before starting steroid treatment and that on the 20th day after starting steroid treatment were 506 mg/dl and 180 mg/dl, respectively, P=0.0013). Other possible causes of hypofibrinogenemia, including liver dysfunction or disseminated intravascular coagulation, were confirmed in only 3 patients during the observation period. In conclusion, hypofibrinogenemia commonly occurs in patients treated with steroids, especially those administered 2 mg/kg/day methylprednisolone for the treatment of GVHD. PMID- 26251154 TI - [Successful second cord blood transplantation (CBT) for late graft failure associated with several immune disorders after the initial CBT in a patient with acute myeloid leukemia]. AB - A 64-year-old woman underwent reduced-intensity conditioning cord blood transplantation (RIC-CBT) for refractory acute myeloid leukemia (AML). A 6/6 antigen-level HLA-identical cord blood from a male infant was transfused. After successful engraftment with complete donor chimerism, the patient developed mixed chimera (XX 8.8%) on day 82. Tapering of tacrolimus was started on day 96. Bone marrow chimerism analysis showed a decreasing recipient cell population (XX 2.2%) on day 117 and tacrolimus was discontinued with no clinical signs of GVHD on day 123. However, pancytopenia with agranulocytosis was detected on day 138. She was diagnosed as having secondary graft failure associated with Coombs-positive immune hemolytic anemia and immune thrombocytopenia (ITP). At the same time, the percentage of recipient T cell chimerism in peripheral blood was about 50% and the B cell population showed lambda light chain restriction. On day 180, she received a second RIC-CBT due to lack of improvement of agranulocytosis. A single dose of rituximab was administered on day - 11 before the second CBT to eliminate the activated B cells. Prompt neutrophil engraftment was achieved and both hemolytic anemia and ITP also showed resolution. She is currently well (30 months after the second CBT), showing normal blood cell counts and complete second donor chimerism of marrow cells. PMID- 26251155 TI - A Framework for Inferring Unobserved Multistrain Epidemic Subpopulations Using Synchronization Dynamics. AB - A new method is proposed to infer unobserved epidemic subpopulations by exploiting the synchronization properties of multistrain epidemic models. A model for dengue fever is driven by simulated data from secondary infective populations. Primary infective populations in the driven system synchronize to the correct values from the driver system. Most hospital cases of dengue are secondary infections, so this method provides a way to deduce unobserved primary infection levels. We derive center manifold equations that relate the driven system to the driver system and thus motivate the use of synchronization to predict unobserved primary infectives. Synchronization stability between primary and secondary infections is demonstrated through numerical measurements of conditional Lyapunov exponents and through time series simulations. PMID- 26251156 TI - Incidence of testicular microlithiasis in patients with beta-thalassemia major. AB - We assessed the prevalence of testicular microlithiasis by scrotal ultrasonography in beta-thalassemia major patients older than 10 years and evaluated the association with serum ferritin levels, calcium (Ca), phosphate (Ph), and parathyroid hormone levels (PTH). In this cross-sectional study, 132 male beta-thalassemia major patients from 300 male patients older than 10 years old were randomly evaluated by scrotal ultrasonography. Parathyroid hormone, calcium, phosphate, and serum ferritin levels were also evaluated. All of the patients were urologically asymptomatic. One hundred healthy age-matched subjects were selected as control group. Testicular microlithiasis was found in 16 patients and 1 individual in control group (12.1 vs 1 %; p = 0.003). Testicular microlithiasis was associated with age and high serum ferritin levels, but there was no association between Ca, Ph, and PTH levels; blood transfusion; and oral or subcutaneous iron chelation therapy. Also, there was no significant correlation between hyperparathyroidism, history of viral hepatitis, and splenectomy with testicular microlithiasis. The frequency of testicular microlithiasis in beta thalassemia major patients was higher than previously reported. A correlation was found between testicular microlithiasis with age and serum ferritin levels, so regular and adequate iron chelator therapy (at least 10-12 h per day for 5-6 days a week) is recommended. We suggest a close observation and treatment with iron chelating agents of these patients. Since testicular microlithiasis is occasionally associated with germ cell tumors, clinical and sonographic follow-up is recommended. PMID- 26251157 TI - Clinical and echocardiographic characteristics for differentiating between transthyretin-related and light-chain cardiac amyloidoses. AB - Differential diagnosis between transthyretin (TTR) and immunoglobulin light-chain (AL) cardiac amyloidoses is essential due to significantly different prognoses and therapeutic options. Therefore, clinical characteristics of patients with biopsy-proven cardiac amyloidosis were investigated to differentiate TTR from AL amyloidosis. From September 2006 to May 2014, 46 patients were confirmed to have cardiac amyloidosis (TTR, n = 28; AL, n = 18) in our institute. The median age of patients with TTR amyloidosis was 78 years (range 61-90) with 27 (96 %) males, while that of patients with AL amyloidosis was 66 (range 52-76) with 12 (67 %) males. There were no statistically significant differences in echocardiographic findings regarding left ventricular (LV) systolic function or diastolic dysfunction between the two groups. Interestingly, serum brain natriuretic peptide (BNP) levels in patients with AL amyloidosis were significantly higher than those in TTR amyloidosis patients. In contrast, the LV wall was significantly thicker in patients with TTR amyloidosis than in those with AL amyloidosis. Therefore, the ratio of BNP to LV mass index (LVMI) at presentation in AL amyloidosis patients was significantly higher than that in TTR patients (6.7 vs 2.9, p = 0.0006). A BNP-LVMI ratio of less than 3.5 had a diagnostic sensitivity and specificity for TTR amyloidosis of 71 and 83 %, respectively. One year overall survival was 88.7 % in the patients with TTR amyloidosis and 23.7 % in the patients with AL amyloidosis. Our analysis indicates that the BNP-LVMI ratio, as well as age and sex, may be useful parameters for distinguishing TTR from AL cardiac amyloidosis. PMID- 26251158 TI - Salvage chemotherapy of gemcitabine, dexamethasone, and cisplatin (GDP) for patients with relapsed or refractory peripheral T-cell lymphomas: a consortium for improving survival of lymphoma (CISL) trial. AB - There is no standard salvage chemotherapy for relapsed or refractory peripheral T cell lymphomas (PTCLs). Gemcitabine combined with cisplatin has been known as an effective regimen for lymphoma treatment in the salvage setting. We investigated the efficacy and toxicity of gemcitabine, dexamethasone, and cisplatin (GDP) for relapsed or refractory PTCLs in search of a more effective and less toxic therapy. Patients with relapsed or refractory PTCLs with more than one previous regimen were eligible. Treatment consisted of gemcitabine 1000 mg/m(2) intravenously (i.v.) on days 1 and 8, dexamethasone 40 mg orally on days 1-4, and cisplatin 70 mg/m(2) i.v. on day 1, and then every 21 days. Patients could proceed to autologous stem cell transplantation (ASCT) after four cycles of GDP or receive up to six treatment cycles. Twenty-five eligible patients were evaluated for toxicity and response. The diagnoses of participants included 14 cases of PTCL-not otherwise specified (NOS) (56 %) and four cases of angioimmunoblastic T-cell lymphoma (16 %) among others. The median age of the patients was 59 years (range 20-75 years). After treatments with GDP, which delivered a median of four GDP cycles, there were 12 patients with complete responses (CR; 48 %) and six with partial responses (PR; 24 %). The overall response rate (RR) was 72 %. Four patients preceded to ASCT, and three patients finally achieved CR. The median progression free survival was 9.3 months (95 % confidence interval (CI); 4.1-14.6) with a median follow-up duration of 27.1 months. In a total of 86 cycles of GDP, grade 3 or 4 neutropenia and thrombocytopenia occurred in 16.3 and 12.8 % of cycles, respectively. Three patients (3.3 %) experienced febrile neutropenia. GDP is a highly effective and optimal salvage regimen for relapsed or refractory PTCLs and can be administered with acceptable toxicity. PMID- 26251159 TI - External validation of the Norwegian survival prediction model in trauma after major trauma in Southern Finland. AB - BACKGROUND: The Norwegian Survival Prediction Model in Trauma (NORMIT) is a newly developed outcome prediction model for patients with trauma. We aimed to compare the novel NORMIT to the more commonly used Trauma and Injury Severity Score (TRISS) in Finnish trauma patients. METHODS: We performed a retrospective open cohort study, using the trauma registry of Helsinki university hospital's trauma unit, including severely injured patients (new injury severity score > 15) admitted from 2007 to 2011. We used 30-day in-hospital mortality as the primary outcome, and discharge functional outcome as a secondary outcome of interest. Model performance was evaluated by comparing discrimination (by area under the receiver operating characteristic curve [AUC]), using a re-sample bootstrap technique, and by assessing calibration (GiViTI belt). RESULTS: We identified 1111 patients fulfilling the study inclusion criteria. Overall mortality was 13% (n = 147). NORMIT showed slightly better discrimination for mortality prediction (AUC = 0.83, 95% confidence interval [CI] = 0.80-0.86 vs. AUC = 0.79, 95% CI = 0.75-0.83, P = 0.004) and functional outcome prediction (AUC = 0.78, 95% CI = 0.76-0.82 vs. AUC = 0.75, 95% CI = 0.72-0.78, P < 0.001) than TRISS. Calibration testing revealed poor calibration for both NORMIT and TRISS (P < 0.001), by giving too pessimistic predictions (predicted survival significantly lower than actual survival). CONCLUSION: NORMIT and TRISS showed good discrimination, but poor calibration, in this mixed cohort of severely injured trauma patients from Southern Finland. We found NORMIT to be a feasible alternative to TRISS for trauma patient outcome prediction, but trauma prediction models with improved calibration are needed. PMID- 26251160 TI - Erratum to: Rewriting the blueprint of life by synthetic genomics and genome engineering. PMID- 26251161 TI - Healing of chronic wounds with adjunctive ablative fractional laser resurfacing in two pediatric patients. AB - BACKGROUND AND OBJECTIVES: The development of chronic non-healing wounds is multifactorial and can lead to increased patient morbidity. When traditional wound care methods fail, alternative treatments are needed to prevent chronic ulcer complications. Ablative fractional laser resurfacing (AFR) is an emerging therapy for chronic wounds. We report the successful use of AFR to facilitate the healing of chronic wounds in two pediatric patients. STUDY DESIGN/MATERIALS AND METHODS: This is a case series including two patients with chronic wounds within scars that were treated with a micro-fractionated carbon dioxide (CO2 ) laser in a single pass at a pulse energy of 50 mJ and a treatment density of 5%. One patient had one treatment and the other had two treatments 1 month apart. RESULTS: AFR led to rapid healing of chronic wounds in both pediatric patients. The wounds remained epithelialized after 9 months in one patient and 4 months in the other. There were no complications. CONCLUSIONS: The combination of tolerability and efficacy observed in these cases introduces AFR as a potential promising adjunct to existing treatments for chronic, non-healing wounds in the pediatric population. PMID- 26251162 TI - Intravenous Recombinant Tissue Plasminogen Activator Does Not Impact Mortality in Acute Ischemic Stroke at Any Time Point up to 6 Months: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials. AB - BACKGROUND AND OBJECTIVE: Concerns about the harms of intravenous alteplase (recombinant tissue plasminogen activator) continue to deter physicians from treating patients with acute ischemic stroke with the only drug proven to positively impact outcomes and reduce disability. Recent literature indicates an increase in mortality with alteplase within 7 days, an effect that does not persist from 3 months onwards. The objective of this meta-analysis was to pool mortality estimates from randomized controlled clinical trials (RCTs) at 7 days, 30 days, 90 days, and 6 months after stroke onset. METHODS: PubMed, Embase, Scopus, CENTRAL, and clinicaltrials.gov were searched through to April 2014, using "hedges" for tissue plasminogen activator, acute ischemic stroke, and placebo. Two independent authors abstracted data and assessed study quality. Data were pooled using Dersimonian and Laird's random effects model. RESULTS: Eleven RCTs (n = 6905) were included in the final analysis. Two authors independently performed study selection and data abstraction. There was no publication bias and total variance attributable to heterogeneity was not significant (I(2) < 50%) at any time point. There was no difference in mortality between alteplase and placebo groups at any time point. Trials that randomized patients beyond 3 h (excluded patients within the 3-h window) did not drive the mortality difference seen at any time point. Exclusion sensitivity analysis revealed that exclusion of the NINDS trial rendered the 7-day difference significant towards increased mortality with alteplase. Quality adjustment did not alter the results. CONCLUSION: Intravenous alteplase did not impact mortality in patients with acute ischemic stroke at any of the measured time points up to 6 months (i.e., there was no increase in the risk of death with alteplase). Therefore, intravenous alteplase should be given to all eligible patients with acute ischemic stroke to improve long-term neurologic outcomes. The effects of alteplase on early survival are more complex than previously understood. PMID- 26251164 TI - The Diagnostic Performance of Multifunction Cardiogram (MCG) in Functional Myocardial Ischemia. PMID- 26251163 TI - The impact of surgical excisions on human gastric slow wave conduction, defined by high-resolution electrical mapping and in silico modeling. AB - BACKGROUND: Gastric contractions are coordinated by slow waves, generated by interstitial cells of Cajal (ICC). Gastric surgery affects slow wave conduction, potentially contributing to postoperative gastric dysfunction. However, the impact of gastric cuts on slow waves has not been comprehensively evaluated. This study aimed to define consequences of surgical excisions on gastric slow waves by applying high-resolution (HR) electrical mapping and in silico modeling. METHODS: Patients undergoing gastric stimulator implantation (n = 10) underwent full thickness stapled excisions (25 * 15 mm, distal corpus) for histological evaluation, enabling HR mapping (256 electrodes; 36 cm(2) ) over and adjacent to excisions. A biophysically based in silico model of bidirectionally coupled ICC networks was developed and applied to investigate the underlying conduction mechanisms and importance of excision orientation. KEY RESULTS: Normal gastric slow waves propagated aborally (3.0 +/- 0.2 cpm). Excisions induced complete conduction block and wavelets that rotated around blocks, then propagated rapidly circumferentially distal to the blocks (8.5 +/- 1.2 vs normal 3.6 +/- 0.4 mm/s; p < 0.01). This 'conduction anisotropy' homeostatically restored antegrade propagating gastric wavefronts distal to excisions. Excisions were associated with complex dysrhythmias in five patients: retrograde propagation (3/10), ectopics (3/10), functional blocks (2/10), and collisions (1/10). Simulations demonstrated conduction anisotropy emerged from bidirectional coupling within ICC layers and showed transverse incision length and orientation correlated with the degree of conduction distortion. CONCLUSIONS & INFERENCES: Orienting incisions in the longitudinal gastric axis causes least disruption to electrical conduction and motility. However, if transverse incisions are made, a homeostatic mechanism of gastric conduction anisotropy compensates by restoring aborally propagating wavefronts. Complex dysrhythmias accompanying excisions could modify postoperative recovery in susceptible patients. PMID- 26251165 TI - Bromodeoxyuridine promotes full-chemical induction of mouse pluripotent stem cells. PMID- 26251166 TI - Effect of brachial plexus block-driven vascular access planning on primary distal arteriovenous fistula recruitment and outcomes. AB - OBJECTIVE: Hemodialysis vascular accesses (VAs) are traditionally planned based on the nondominant upper extremity preoperative physical and sonographic vascular findings. Clinical guidelines advocate the use of the most suitably distended vein in the most distal location. Brachial plexus block (BPB), through its sympathectomy-like effect, promotes vasodilation and can thus further optimize vein recruitment and operative strategy. However, studies on its role in driving primary distal autogenous arteriovenous fistula (AVF) placement are limited. We therefore evaluated a traditional approach of clinic-based VA planning against an on-table sonography-guided strategy under BPB. METHODS: This was a prospective observational study involving 110 consecutive end-stage renal disease multiethnic Asian patients referred for primary VA creation under BPB after preoperative venous mapping. Cases were grouped according to whether there was a preset operative plan for radial cephalic (RC) or brachial cephalic (BC) AVF creation based on artery and vein >2 mm and >2.5 mm size criteria respectively (group A) or vein size or length were suboptimal (2-2.5 mm and <5 cm respectively), thus precluding any operative plan till after BPB (group B). Group B also included cases with a preset VA plan but that subsequently underwent an on-table change in operative plan as a result of more favorable distal vein dilation post-BPB. RC AVF recruitment, maturation, and patency rates were compared in the two groups over a 1-year follow up. RESULTS: One hundred RC and BC AVF were available for analysis after excluding brachial AVFs and grafts: 41 in group A and 59 in group B. Twenty one (51%) primary RC AVFs were created according to a preset preoperative plan compared with 37 (63%) based upon on-table planning or plan modification (P > .05). Satisfactory post-BPB forearm vasodilation resulted in 44% of 36 plans for BC being changed to RC AVFs. RC AVF 6-week hemodynamic maturation and 3-month functional maturation in group A vs B were 48% vs 60% and 69% vs 57%, respectively (P > .05). One-year primary and secondary patency rates were 57% vs 50% and 73% vs 87%, respectively (log rank >.05). Outcomes of RC AVFs in group B were not inferior to those of BC AVFs. CONCLUSIONS: On-table BPB driven VA planning and plan modification strategy contribute to considerable AVF recruitment but do not lead to significantly better distal AVF prevalence or outcomes over the traditional approach. An adequately powered randomized controlled study is, however, warranted to better assess the long-term clinical and cost benefits of such a strategy. PMID- 26251167 TI - Cost analysis of vascular readmissions after common vascular procedures. AB - OBJECTIVE: This study analyzed readmissions and their associated hospital costs after common vascular surgeries at a single institution. METHODS: Patients undergoing open or endovascular abdominal aortic aneurysm repair, aortoiliac revascularization, or infrainguinal revascularization, from 2010 through 2012, were retrospectively evaluated. We compared 30- and 90-day readmission rates and costs by procedure group, and we tabulated reasons for readmission and procedures performed during readmission. We used both American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) data and patient records; as NSQIP only captures 30-day data, we retrospectively reviewed patient charts to extend the evaluation to 90 days. Analyses were performed using parametric or nonparametric methods as appropriate. RESULTS: Two hundred nineteen cases were analyzed; the overall rate of index admission survivors experiencing at least one readmission within 30 days was 17% and within 90 days, 27%. Median readmission costs were $10,700, which added 39% to the median index costs of $27,700. Over half of readmissions (55%) included an operation. The most common cause for readmission was related to wound complications, comprising approximately 30% of the entire readmission cohort. Independent drivers of readmission costs were the need for additional surgical procedures, the use of intensive care unit services, and the number of days spent in the hospital above the median. Total 90-day costs were statistically equivalent between open and endovascular procedures when including readmissions. CONCLUSIONS: We found that vascular surgery readmissions occur at a rate of 17% at 30 days and 27% at 90 days. When including the costs of readmission for a wide variety of common vascular cases, there is no significant difference in total costs between endovascular and open procedures at 90 days. PMID- 26251168 TI - Comorbid psychiatric conditions as mediators to predict later social adjustment in youths with autism spectrum disorder. AB - BACKGROUND: Individuals with autism spectrum disorder (ASD) experience long-term social impairment and their comorbid psychiatric conditions negatively impact adaptive functioning. The aims of the study are to investigate whether comorbid psychopathologies, such as anxiety/depression, inattention, hyperactivity/impulsivity, and oppositional behaviors, mediated the link between autistic symptoms and social maladjustment. METHOD: One hundred and twenty-four youths diagnosed with a clinical diagnosis of DSM-IV ASD (mean age, 10.6 +/- 3.3 years) participated in this longitudinal study. They were assessed using semistructured diagnostic interviews on ASD and other psychiatric conditions at recruitment. Follow-up interviews took place approximately 3 years later (37.59 +/- 15 months) while the parents reported to the Social Adjustment Inventory for Children and Adolescents on their children's social adjustment. Mediation models were used to examine the mediating effect of comorbid psychopathologies on social adjustment. RESULTS: Youths with ASD had worse school, peer, and home functions than controls at follow-up assessment. In general, comorbid psychiatric conditions mediated the link between autistic symptoms and different domains of social adjustment, independent of age, sex, and full-scale IQ. Additionally, we found specific mediating effects of anxiety/depression and inattention on school functions; anxiety/depression on peer relationships; and oppositional behaviors on home behaviors. CONCLUSION: Early comorbid psychopathologies may further impair later social adjustment in youths with ASD and an early identification and intervention of these comorbid conditions are suggested. PMID- 26251169 TI - [Acne scars and striae distensae: Effective treatment with medical skin needling]. AB - BACKGROUND: Medical skin needling as a nonablative procedure appears to be a good alternative to conventional surgical treatment options for the treatment of acne scars and striae. OBJECTIVE: The effect of medical skin needling particularly with regard to the treatment of acne scars and striae as an alternative to ablative therapy options is explained. MATERIALS AND METHODS: A summary of recent publications on medical skin needling in terms of skin regeneration in vivo and improving skin quality of patients in vivo in striae is provided. RESULTS: Medical needling shows a positive effect on the healing process of the skin, proven in clinical studies providing positive results in the treatment of striae and acne scars. Thus, PCI is a good alternative to conventional surgical procedures. CONCLUSIONS: The therapeutic strategies are numerous, and even if no single modality results in complete remission of scars, medical skin needling is a safe, easy-to-perform treatment option with very promising results. PMID- 26251170 TI - [Erythematous papules in a 26-year-old man]. PMID- 26251172 TI - Synthesis and Recognition Properties of Enantiomerically Pure Acyclic Cucurbit[n]uril-Type Molecular Containers. AB - Enantiomerically pure acyclic cucurbit[n]uril containers 1 and 2 were synthesized by the condensation of enantiomerically pure aromatic sidewalls 3b and 4b with glycoluril tetramer 5. Containers 1 and 2 are C2-symmetric, feature four arms of the same handedness, and bind to a variety of guests (6-15) in aqueous solution including aliphatic and aromatic ammonium ions, amino acids, dyes, and viologens. The binding constants of hosts 1Ac and 1OH toward selected chiral ammonium ions were measured by (1)H NMR and UV/vis spectroscopy. PMID- 26251173 TI - Mechanism of the Multiple-Electron Oxygen Reduction Reaction in the Presence of the Binuclear Cu(acac)2 Complex. AB - The potential of the electron for the serial oxygen reduction reaction is calculated by DFT in an aqueous solution in the presence and absence of Cu(acac)2 complex. The study provides interesting information about the rational design of complex-semiconductor hybrid photocatalysts and cathodes for polymer electrolyte membrane fuel cells. PMID- 26251171 TI - Effect of 90Sr internal emitter on gene expression in mouse blood. AB - BACKGROUND: The radioactive isotope Strontium-90 ((90)Sr) may be released as a component of fallout from nuclear accidents, or in the event of a radiological incident such as detonation of an improvised nuclear device, and if ingested poses a significant health risk to exposed individuals. In order to better understand the response to (90)Sr, using an easily attainable and standard biodosimetry sample fluid, we analyzed the global transcriptomic response of blood cells in an in vivo model system. RESULTS: We injected C57BL/6 mice with a solution of 90SrCl2 and followed them over a 30-day period. At days 4, 7, 9, 25 and 30, we collected blood and isolated RNA for microarray analyses. These days corresponded to target doses in a range from 1-5 Gy. We investigated changes in mRNA levels using microarrays, and changes in specific microRNA (miRNA) predicted to be involved in the response using qRT-PCR. We identified 8082 differentially expressed genes in the blood of mice exposed to (90)Sr compared with controls. Common biological functions were affected throughout the study, including apoptosis of B and T lymphocytes, and atrophy of lymphoid organs. Cellular functions such as RNA degradation and lipid metabolism were also affected during the study. The broad down regulation of genes observed in our study suggested a potential role for miRNA in gene regulation. We tested candidate miRNAs, mmu-miR 16, mmu-miR-124, mmu-miR-125 and mmu-mir-21; and found that all were induced at the earliest time point, day 4. CONCLUSIONS: Our study is the first to report the transcriptomic response of blood cells to the internal emitter (90)Sr in mouse and a possible role for microRNA in gene regulation after (90)Sr exposure. The most dramatic effect was observed on gene expression related to B-cell development and RNA maintenance. These functions were affected by genes that were down regulated throughout the study, suggesting severely compromised antigen response, which may be a result of the deposition of the radioisotope proximal to the hematopoietic compartment in bone. PMID- 26251174 TI - Reforming Access: Trends in Medicaid Enrollment for New Medicare Beneficiaries, 2008-2011. AB - OBJECTIVE: To evaluate whether aligning the Part D low-income subsidy and Medicaid program enrollment pathways in 2010 increased Medicaid participation among new Medicare beneficiaries. DATA SOURCES: Medicare enrollment records for years 2007-2011. STUDY DESIGN: We used a multinomial logistic model with state fixed effects to examine the annual change in limited and full Medicaid enrollment among new Medicare beneficiaries for 2 years before and after the reforms (2008-2011). DATA EXTRACTION METHODS: We identified new Medicare beneficiaries in the years 2008-2011 and their participation in Medicaid based on Medicare enrollment records. PRINCIPAL FINDINGS: The percentage of beneficiaries enrolling in limited Medicaid at the start of Medicare coverage increased in 2010 by 0.3 percentage points for individuals aging into Medicare and by 1.3 percentage points for those qualifying due to disability (p < .001). There was no significant difference in the size of enrollment increases between states with and without concurrent limited Medicaid eligibility expansions. CONCLUSIONS: Our findings suggest that streamlining financial assistance programs may improve Medicare beneficiaries' access to benefits. PMID- 26251175 TI - Fatal Eurasian Brown Bear Attacks-Two Swedish Fatalities in Modern Times. AB - Fatal bear attacks on humans are uncommon with only one reported case in Sweden since 1902. The bear population is, however, growing and the frequency of confrontations is likely to increase. Case I-A 40-year-old hunter and his dog were found dead near a bear's den. Autopsy showed that a large portion of the face, facial skeleton, and anterior portion of the brain was missing. Autopsy of the bear showed two nonfatal gunshot wounds. Case II-A 61-year-old man and his dog were found dead outside a hunting lodge. Autopsy revealed numerous wounds, including partial evisceration of the intestines. The victim's blood ethanol concentration was 0.27%. These cases confirm the presence of risk factors identified by the Scandinavian Brown Bear Research Project, that is, provocation by a dog, encountering an injured bear, and appearing close to its den. An additional possible factor in case II was ethanol intoxication. PMID- 26251176 TI - Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S (2-carboxypropyl)cysteine excretion. AB - BACKGROUND: Short-chain enoyl-CoA hydratase-ECHS1-catalyses many metabolic pathways, including mitochondrial short-chain fatty acid beta-oxidation and branched-chain amino acid catabolic pathways; however, the metabolic products essential for the diagnosis of ECHS1 deficiency have not yet been determined. The objective of this report is to characterise ECHS1 and a mild form of its deficiency biochemically, and to determine the candidate metabolic product that can be efficiently used for neonatal diagnosis. METHODS: We conducted a detailed clinical, molecular genetics, biochemical and metabolic analysis of sibling patients with ECHS1 deficiency. Moreover, we purified human ECHS1, and determined the substrate specificity of ECHS1 for five substrates via different metabolic pathways. RESULTS: Human ECHS1 catalyses the hydration of five substrates via different metabolic pathways, with the highest specificity for crotonyl-CoA and the lowest specificity for tiglyl-CoA. The patients had relatively high (~7%) residual ECHS1 enzyme activity for crotonyl-CoA and methacrylyl-CoA caused by the compound heterozygous mutations (c.176A>G, (p.N59S) and c.413C>T, (p.A138V)) with normal mitochondrial complex I-IV activities. Affected patients excrete large amounts of N-acetyl-S-(2-carboxypropyl)cysteine, a metabolite of methacrylyl-CoA. CONCLUSIONS: Laboratory data and clinical features demonstrated that the patients have a mild form of ECHS1 deficiency harbouring defective valine catabolic and beta-oxidation pathways. N-Acetyl-S-(2-carboxypropyl) cysteine level was markedly high in the urine of the patients, and therefore, N-acetyl-S-(2 carboxypropyl)cysteine was regarded as a candidate metabolite for the diagnosis of ECHS1 deficiency. This metabolite is not part of current routine metabolic screening protocols, and its inclusion, therefore, holds immense potential in accurate diagnosis. PMID- 26251177 TI - The role of vitamin D in reducing gastrointestinal disease risk and assessment of individual dietary intake needs: Focus on genetic and genomic technologies. AB - With the endogenous formation of vitamin D being significantly curtailed because of public awareness of skin cancer dangers, attention is turning to dietary sources. Cumulative evidence has implicated vitamin D deficiency in increasing susceptibility to various gastrointestinal disorders, including colorectal cancer, inflammatory bowel diseases, diverticulitis, and irritable bowel syndrome. There is also reason to suggest adjunct vitamin D therapy for such diseases. Although there is justification for increasing vitamin D intake overall, optimal intakes will vary among individuals. Genomic technologies have revealed several hundreds of genes associated with vitamin D actions. The nature of these genes emphasizes the potentially negative implications of modulating vitamin D intakes in the absence of complementary human genetic and genomic data, including information on the gut microbiome. However, we are not yet in a position to apply this information. Genomic data (transcriptomics, metabolomics, proteomics, and metagenomics) could provide evidence that vitamin D sufficiency has been achieved. We suggest that there is an increasingly strong case for considering the more widespread use of vitamin D fortified foods and/or dietary supplements to benefit gastrointestinal health. However, intake levels might beneficially be informed by personalized genetic and genomic information, for optimal disease prevention and maintenance of remission. PMID- 26251178 TI - Survivorship Issues in Radiation Oncology. PMID- 26251179 TI - Metabolomics analysis reveals the association between lipid abnormalities and oxidative stress, inflammation, fibrosis, and Nrf2 dysfunction in aristolochic acid-induced nephropathy. AB - Alternative medicines are commonly used for the disease prevention and treatment worldwide. Aristolochic acid (AAI) nephropathy (AAN) is a common and rapidly progressive interstitial nephropathy caused by ingestion of Aristolochia herbal medications. Available data on pathophysiology and molecular mechanisms of AAN are limited and were explored here. SD rats were randomized to AAN and control groups. AAN group was treated with AAI by oral gavage for 12 weeks and observed for additional 12 weeks. Kidneys were processed for histological evaluation, Western blotting, and metabolomics analyses using UPLC-QTOF/HDMS. The concentrations of two phosphatidylcholines, two diglycerides and two acyl carnitines were significantly altered in AAI treated rats at week 4 when renal function and histology were unchanged. Data obtained on weeks 8 to 24 revealed progressive tubulointerstitial fibrosis, inflammation, renal dysfunction, activation of NF-kappaB, TGF-beta, and oxidative pathways, impaired Nrf2 system, and profound changes in lipid metabolites including numerous PC, lysoPC, PE, lysoPE, ceramides and triglycerides. In conclusion, exposure to AAI results in dynamic changes in kidney tissue fatty acid, phospholipid, and glycerolipid metabolisms prior to and after the onset of detectable changes in renal function or histology. These findings point to participation of altered tissue lipid metabolism in the pathogenesis of AAN. PMID- 26251180 TI - Focal adhesion kinase phosphorylates the phosphatase and tensin homolog deleted on chromosome 10 under the control of p110delta phosphoinositide-3 kinase. AB - The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor protein is regulated by various mechanisms that are not fully understood. This includes regulation by Tyr phosphorylation by a mechanism that remains elusive. Here, we show that focal adhesion kinase (FAK) phosphorylates PTEN in vitro, in cell-free systems and in cells. Furthermore, by mass spectrometry, we identified Tyr336 on PTEN as being phosphorylated by FAK. Tyr336 phosphorylation increased phosphatase activity, protein-lipid interaction, and protein stability of PTEN. In cells, including primary mouse macrophages and human cancer cell lines, FAK was found to be negatively regulated by p110delta phosphoinositide-3 kinase (PI3K), whereas the activation of FAK was positively regulated by RhoA-associated kinase (ROCK). Indeed, the phosphorylation of FAK was unexpectedly increased in macrophages derived from mice expressing kinase dead p110delta. Pharmacologic inactivation of RhoA/ROCK reduced the phosphorylation of FAK to normal levels in cells with genetically inactivated p110delta. Likewise, pharmacologic inactivation of FAK reduced the phosphorylation of PTEN in cells expressing kinase-dead p110delta and restored the functional defects of p110delta inactivation, including Akt phosphorylation and cell proliferation. This work identifies FAK as a target of p110delta PI3K that links RhoA with PTEN and establishes for the first time that PTEN is a substrate of FAK-mediated Tyr phosphorylation. PMID- 26251181 TI - Retinal functional alterations in mice lacking intermediate filament proteins glial fibrillary acidic protein and vimentin. AB - Vimentin (Vim) and glial fibrillary acidic protein (GFAP) are important components of the intermediate filament (IF) (or nanofilament) system of astroglial cells. We conducted full-field electroretinogram (ERG) recordings and found that whereas photoreceptor responses (a-wave) were normal in uninjured GFAP(-/-)Vim(-/-) mice, b-wave amplitudes were increased. Moreover, we found that Kir (inward rectifier K(+)) channel protein expression was reduced in the retinas of GFAP(-/-)Vim(-/-) mice and that Kir-mediated current amplitudes were lower in Muller glial cells isolated from these mice. Studies have shown that the IF system, in addition, is involved in the retinal response to injury and that attenuated Muller cell reactivity and reduced photoreceptor cell loss are observed in IF-deficient mice after experimental retinal detachment. We investigated whether the lack of IF proteins would affect cell survival in a retinal ischemia-reperfusion model. We found that although cell loss was induced in both genotypes, the number of surviving cells in the inner retina was lower in IF-deficient mice. Our findings thus show that the inability to produce GFAP and Vim affects normal retinal physiology and that the effect of IF deficiency on retinal cell survival differs, depending on the underlying pathologic condition. PMID- 26251182 TI - Duration of Heart Failure Is an Important Predictor of Outcomes After Mechanical Circulatory Support. AB - BACKGROUND: Heart failure (HF) progression results in worsening functional capacity and end-organ compromise. HF may occur acutely or be associated with a chronic presentation. We hypothesized that the duration of HF affects outcomes after mechanical circulatory support. METHODS AND RESULTS: A total of 10 730 patients registered in Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) who received primary implant of a mechanical circulatory support device were stratified according to the duration of HF symptoms: acute HF (AHF; <=1 month), sub-AHF (1-12 months), and chronic HF (Cr-HF; >= 12 months). AHF patients were younger with a higher proportion of women and white and with a lower prevalence of peripheral vascular disease and history of prior cardiac surgeries. Sixty percent of AHF patients were INTERMACS profile 1 at the time of implantation versus 24% and 13.2% in the sub-AHF and Cr-HF groups, respectively (P=0.0001). Patients with AHF had the highest utilization of biventricular support (14.4%). The estimated survival at 4 years was 58%, 51%, and 45% for the AHF, sub-AHF, and Cr-HF patients (P=0.006). The proportion of patients with AHF who received heart transplantation at 1 year was 29% compared with 22.6% in the patients with Cr-HF. After adjustment for known risk factors of adverse outcome, patients with AHF have a better late phase prognosis compared with patients with Cr-HF (hazard ratio, 0.34; P=0.0003). CONCLUSIONS: The duration of HF before durable mechanical circulatory support implant is an important variable influencing outcome. Patients with AHF had improved survival at 4 years and higher rates of transplantation at 1 year despite higher acuity of presentation. PMID- 26251184 TI - Reproducibility of Echocardiograph-Derived Multilevel Left Ventricular Apical Twist Mechanics. AB - Left ventricular (LV) twist mechanics are routinely assessed via echocardiography in clinical and research trials investigating the function of obliquely oriented myocardial fibers. However, echocardiograph-derived measures of LV twist may be compromised by nonstandardized acquisition of the apical image. This study examined the reproducibility of echocardiograph-derived parameters of apical twist mechanics at multiple levels of the apical myocardium. Two sets of 2D LV parasternal short-axis images were obtained in 30 healthy subjects (24 men; 19-57 year) via echocardiography. Images were acquired immediately distal to the papillary muscles (apical image 1), immediately above the point of LV cavity obliteration at end systole (apical image 3), and midway between apical image 1 and apical image 3 (apical image 2). Repeat scans were performed within 1 hour, and twist mechanics (rotation and rotation rate) were calculated via frame-by frame tracking of natural acoustic echocardiographic markers (speckle tracking). The magnitude of apical rotation increased progressively toward the apex (apical image 1: 4.2 +/- 2.1 degrees , apical image 2: 7.2 +/- 3.9 degrees , apical image 3: 11.8 +/- 4.6 degrees ). apical images 1, 2, and 3 each had moderate to good correlations between repeat scans (ICC: 0.531-0.856). When apical images 1, 2, and 3 were averaged, rotation was 7.7 +/- 2.7 degrees and between-scan correlation was excellent (ICC: 0.910). Similar results were observed for systolic and diastolic rotation rates. Averaging multiple standardized apical images, tending progressively toward the apex, generated the most reproducible rotation indices and may be optimal for the assessment of LV twist mechanics across therapeutic, interventional, and research studies; however, care should be taken given the influence of acquisition level on the magnitude of apical rotation. PMID- 26251183 TI - POLE mutations in families predisposed to cutaneous melanoma. AB - Germline mutations in the exonuclease domain of POLE have been shown to predispose to colorectal cancers and adenomas. POLE is an enzyme involved in DNA repair and chromosomal DNA replication. In order to assess whether such mutations might also predispose to cutaneous melanoma, we interrogated whole-genome and exome data from probands of 34 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, BAP1, TERT, POT1, ACD and TERF2IP. We found a novel germline mutation, POLE p.(Trp347Cys), in a 7-case cutaneous melanoma family. Functional assays in S. pombe showed that this mutation led to an increased DNA mutation rate comparable to that seen with a Pol epsilon mutant with no exonuclease activity. We then performed targeted sequencing of POLE in 1243 cutaneous melanoma cases and found that a further ten probands had novel or rare variants in the exonuclease domain of POLE. Although this frequency is not significantly higher than that in unselected Caucasian controls, we observed multiple cancer types in the melanoma families, suggesting that some germline POLE mutations may predispose to a broad spectrum of cancers, including melanoma. In addition, we found the first mutation outside the exonuclease domain, p.(Gln520Arg), in a family with an extensive history of colorectal cancer. PMID- 26251185 TI - Unhealthy environments, unhealthy consequences: Experienced homonegativity and HIV infection risk among young men who have sex with men. AB - Unfavourable social environments can negatively affect the health of gay, bisexual, and other men who have sex with men (MSM). We described how experienced homonegativity - negative perceptions and treatment that MSM encounter due to their sexual orientations - can increase HIV vulnerability among young MSM. Participants (n = 44) were young MSM diagnosed with HIV infection during January 2006-June 2009. All participants completed questionnaires that assessed experienced homonegativity and related factors (e.g. internalised homonegativity). We focus this analysis on qualitative interviews in which a subset of participants (n = 28) described factors that they perceived to have placed them at risk for HIV infection. Inductive content analysis identified themes within qualitative interviews, and we determined the prevalence of homonegativity and related factors using questionnaires. In qualitative interviews, participants reported that young MSM commonly experienced homonegativity. They described how homonegativity generated internalised homonegativity, HIV stigma, silence around homosexuality, and forced housing displacement. These factors could promote HIV risk. Homonegative experiences were more common among young Black (vs. non-Black) MSM who completed questionnaires. Results illustrate multiple pathways through which experienced homonegativity may increase HIV vulnerability among young MSM. Interventions that target homonegativity might help to reduce the burden of HIV within this population. PMID- 26251186 TI - RNA editing in acute myeloid leukaemia with normal karyotype. PMID- 26251187 TI - Cellobiose dehydrogenase functionalized urinary catheter as novel antibiofilm system. AB - Urinary catheters expose patients to a high risk of acquiring nosocomial infections. To prevent this risk of infection, cellobiose dehydrogenase (CDH), an antimicrobial enzyme able to use various oligosaccharides as electron donors to produce hydrogen peroxide using oxygen as an electron acceptor, was covalently grafted onto plasma-activated urinary polydimethylsiloxane (PDMS) catheter surfaces. Successful immobilization of CDH on PDMS was confirmed by Fourier transformed-infrared spectrometry and production of H2 O2 . The CDH functionalized PDMS surfaces reduced the amount of viable Staphylococcus aureus by 60%, total biomass deposited on the surface by 30% and 70% of biofilm formation. The immobilized CDH was relatively stable in artificial urine over 16 days, retaining 20% of its initial activity. The CDH coated PDMS surface did not affect the growth and physiology of HEK 239 and RAW 264,7 mammalian cells. Therefore this new CDH functionalized catheter system shows great potential for solving the current problems associated with urinary catheters. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1448-1456, 2016. PMID- 26251188 TI - Calcitonin gene-related peptide pre-administration acts as a novel antidepressant in stressed mice. AB - Calcitonin gene-related peptide (CGRP) is a neuropeptide that has potent vasodilator properties and is involved in various behavioral disorders. The relationship between CGRP and depression-like behavior is unclear. In this study, we used chronically stressed mice to investigate whether CGRP is involved in depression-like behavior. Each mouse was exposed to restraint and water immersion stress for 15 days. After stress exposure, mice were assessed using behavioral tests: open field test, forced swim test and sucrose preference test. Serum corticosterone levels, hippocampal proliferation and mRNA expression of neurotrophins were measured. After stress exposure, mice exhibited depression like behavior and decreased CGRP mRNA levels in the hippocampus. Although intracerebroventricular CGRP administration (0.5 nmol) did not alter depression like behavior after 15-day stress exposure, a single CGRP administration into the brain, before the beginning of the 15-day stress exposure, normalized the behavioral dysfunctions and increased nerve growth factor (Ngf) mRNA levels in stressed mice. Furthermore, in the mouse E14 hippocampal cell line, CGRP treatment induced increased expression of Ngf mRNA. The NGF receptor inhibitor K252a inhibited CGRP's antidepressant-like effects in stressed mice. These results suggest that CGRP expression in the mouse hippocampus is associated with depression-like behavior and changes in Ngf mRNA levels. PMID- 26251189 TI - Multi-response optimisation of ultrasound-assisted extraction for recovery of flavonoids from red grape skins using response surface methodology. AB - INTRODUCTION: For the characterisation of grape cultivars, the profile and content of flavonoids are important because these compounds impact grape and wine quality. To determine the correct profile and content of flavonoids, the use of robust, sensitive and reliable methods is necessary. OBJECTIVE: The object of this research is to develop a new ultrasound-assisted extraction (UAE) method for the recovery of flavonoids from grape skins using response surface methodology. METHOD: Optimisation of UAE was performed using a complementary study combining a Box-Behnken experimental design with qualitative analysis by high-performance liquid chromatography. RESULTS: Optimal extraction conditions were obtained using the extraction solvent composed of acetonitrile:water:formic acid (26:73:1, v/v/v) at an extraction temperature of 50 degrees C, an extraction time of 15 min in a single-extraction step and with a solid-to-solvent ratio of 1:80 g/mL. The calculated relative standard deviations for the optimal extraction method were very low, measuring less than 5%. CONCLUSIONS: This study demonstrates that numerous factors have strong effects on the extraction efficiency, including the type of organic modifier and its percentage in the extraction solvent, the number of extraction steps, the solid-to-solvent ratio, the extraction time and temperature and, finally, the particular nature of analyte and their position within the grape skin cell. PMID- 26251190 TI - [Clinical and epidemiological characteristics of neonatal influenza]. PMID- 26251191 TI - [Need for the gender perspective in the Anales de Pediatria yearbook]. PMID- 26251192 TI - Assessment of the lung toxicity of copper oxide nanoparticles: current status. AB - Copper oxide nanoparticles (CuO NPs) are being used in several industrial and commercial products. Inhalation is one of the most significant routes of metal oxide NP exposure. Hence, the toxicity of CuO NPs in lung tissues is of great concern. In vitro studies have indicated that CuO NPs induce cytotoxicity, oxidative stress and genetic toxicity in cultivated human lung cells. Leaching of Cu ions, reactive oxygen species generation and autophagy appear to be the underlying mechanisms of Cu NP toxicity in lung cells. In vivo studies on the lung toxicity of CuO NPs are largely lacking. Some studies have shown that intratracheal instillation of CuO NPs induced oxidative stress, inflammation and neoplastic lesions in rats. This review critically assessed the current findings of the toxicity of CuO NPs in the lung. PMID- 26251193 TI - Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome. AB - OBJECTIVE: Systemic juvenile idiopathic arthritis (JIA) is associated with high levels of interleukin-6 (IL-6) in the serum and synovial fluid, and impairment of natural killer (NK) cell function is often observed. This study was undertaken to evaluate a possible link between these 2 biologic findings and whether they may be associated with the development of macrophage activation syndrome, a condition frequently observed in systemic JIA. METHODS: Splenocytes from wild-type (WT) or IL-6-transgenic (Tg) mice were evaluated for NK cell cytotoxicity using a (51) Cr release assay. Numbers of NK cells and expression of perforin, granzyme B, CD69, and CD107a were evaluated by flow cytometry. Human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were treated with IL-6 and cultured in the presence or absence of tocilizumab (TCZ), an IL-6 receptor blocker. Human polyclonal NK cells from healthy donor PBMCs were evaluated for cell cytotoxicity and expression of perforin, granzyme B, and CD107a. PBMCs harvested from patients with systemic JIA during periods of active or inactive disease were left untreated or treated with IL-6 in combination with soluble IL-6 receptor and analyzed for the expression of perforin and granzyme B. RESULTS: Splenic NK cell cytotoxicity was reduced in IL-6-Tg mice compared to WT mice. Levels of CD69 and CD107a showed no significant differences, whereas expression of perforin and granzyme B was impaired in NK cells from IL-6-Tg mice. Exposure of human peripheral blood NK cells to IL-6 led to reduced expression of perforin and granzyme B. Culturing human polyclonal NK cells in the presence of TCZ significantly increased cell cytotoxicity, and also increased expression of perforin and granzyme B. In patients with systemic JIA, a reduction in IL-6 plasma levels during disease remission correlated with the rescue of perforin and granzyme B expression in NK cells from these patients. CONCLUSION: In both mice and humans, IL-6 down-modulated the cytotoxic activity of NK cells. This decrease was associated with reduced perforin and granzyme B levels in the absence of altered granule exocytosis. PMID- 26251194 TI - Evaluation of the prognostic role of tumour-associated macrophages in newly diagnosed classical Hodgkin lymphoma and correlation with early FDG-PET assessment. AB - In Hodgkin Lymphoma (HL), about 20% of patients still have relapsed/refractory disease and late toxic effects rate continue to rise with time. 'Early FDG-PET' and tissue macrophage infiltration (TAM) emerged as powerful prognostic predictors. The primary endpoint was to investigate the prognostic role of both early FDG-PET and TAM; the secondary endpoint was to test if early FDG-PET positivity could correlate with high TAM score. A cohort of 200 HL patients was analysed. Induction treatment plan consisted of two to six courses of ABVD and, if indicated, involved field radiation therapy. All patients repeated CT scan and FDG-PET after two cycles and after the completion of therapy. TAM in diagnostic specimens was determined by immunohistochemistry with a monoclonal antibody (anti CD68 KP1). Overall, early FDG-PET was negative in 163 patients (81.5%) and positive in 37 patients (18.5%), showing a significant correlation with the achievement of CR (p < 0.0001). After a median follow-up of 40 months, progression free survival (PFS) was significantly better for PET negative patients (p < 0.0001). CD68 expression was low, intermediate or high in 26 (13%), 100 (50%) and 74 (37%) cases, without difference in the distribution between responders and non-responders. PFS analysis showed no significant difference in any score group. TAM score did not show any correlation with early FDG-PET result. This study confirms that early FDG-PET has a high prognostic power, while TAM score does not seem to influence the outcome; in contrast to our original hypothesis, it does not correlate with FDG-PET assessment. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26251195 TI - Identification of key micro-organisms involved in Douchi fermentation by statistical analysis and their use in an experimental fermentation. AB - AIMS: To screen and identify safe micro-organisms used during Douchi fermentation, and verify the feasibility of producing high-quality Douchi using these identified micro-organisms. METHODS AND RESULTS: PCR-denaturing gradient gel electrophoresis (DGGE) and automatic amino-acid analyser were used to investigate the microbial diversity and free amino acids (FAAs) content of 10 commercial Douchi samples. The correlations between microbial communities and FAAs were analysed by statistical analysis. Ten strains with significant positive correlation were identified. Then an experiment on Douchi fermentation by identified strains was carried out, and the nutritional composition in Douchi was analysed. Results showed that FAAs and relative content of isoflavone aglycones in verification Douchi samples were generally higher than those in commercial Douchi samples. CONCLUSIONS: Our study indicated that fungi, yeasts, Bacillus and lactic acid bacteria were the key players in Douchi fermentation, and with identified probiotic micro-organisms participating in fermentation, a higher quality Douchi product was produced. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report to analyse and confirm the key micro-organisms during Douchi fermentation by statistical analysis. This work proves fermentation micro organisms to be the key influencing factor of Douchi quality, and demonstrates the feasibility of fermenting Douchi using identified starter micro-organisms. PMID- 26251196 TI - Release of the Water Molecule Encapsulated Inside an Open-Cage Fullerene through Hydrogen Bonding Mediated by Hydrogen Fluoride. AB - A reversible wetting/dewetting procedure is reported for an open-cage fullerene with an 18-membered orifice. In a homogeneous mixture of H2O/EtOH/CHCl3, water was encapsulated into the cavity of the open-cage compound quantitatively at 80 degrees C. Addition of aqueous hydrogen fluoride into the water-encapsulated complex removed the encapsulated water completely at room temperature. H-bonding between the trapped water and fluoride is shown to play a key role for the water release process. PMID- 26251197 TI - Angiotensin1-7 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress by preventing ROS-associated mitochondrial dysfunction and activating the Akt signaling pathway. AB - Angiotensin1-7 (Ang1-7) is a biologically active member of the renin-angiotensin system, which has been reported to exhibit protective effect in myocardial ischemia reperfusion-induced injury. However, the molecular basis of this effect is not well understood. It has been proposed that oxidative stress-induced cardiomyocyte apoptosis is a major consequence of hypoxia/reoxygenation (H/R) injury. This study investigates the protective effect of Ang1-7 against H/R induced oxidative stress in rat H9C2 cells. Our results showed that Ang1-7 (80nM) treatment significantly protected cells from H/R-induced oxidative injury via improving cell viability and reducing cell apoptosis. The protective effect of Ang1-7 was associated with the inhibition of ROS-associated mitochondrial dysfunction as well as the induction of Akt phosphorylation. These findings may significantly contribute to better understanding the protective effect of Ang1-7, particularly in hypoxia/reoxygenation-induced heart diseases and form the basis in the therapeutic development in treating cardiovascular diseases. PMID- 26251198 TI - Evaluation of a collagen-coated, resorbable fiber scaffold loaded with a peptide basic fibroblast growth factor mimetic in a sheep model of rotator cuff repair. AB - BACKGROUND: A new scaffold design combined with a peptide growth factor was tested prospectively for safety and for improved tendon healing in sheep. METHODS: The infraspinatus tendon was detached and then surgically repaired to the humerus using sutures and anchors in 50 adult sheep. The repairs in 40 of these sheep were reinforced with a scaffold containing F2A, a peptide mimetic of basic fibroblast growth factor. The sheep were examined after 8 or 26 weeks with magnetic resonance imaging, full necropsy, and histopathologic analysis. A second cohort of 30 sheep underwent surgical repair--20 with scaffolds containing F2A. The 30 shoulders were tested mechanically after 8 weeks. RESULTS: The scaffold and F2A showed no toxicity. Scaffold-repaired tendons were 31% thicker than surgically repaired controls (P = .037) at 8 weeks. There was more new bone formed at the tendon footprint in sheep treated with F2A. Surgically repaired tendons delaminated from the humerus across 14% of the footprint area. The extent of delamination decreased to 1.3% with increasing doses of F2A (P = .004). More of the repair tissue at the footprint was tendon-like in the peptide-treated sheep. On mechanical testing, only 7 shoulders tore at the repair site. The repairs in the other 23 shoulders were already stronger than the midsubstance tendon at 8 weeks. CONCLUSIONS: The new scaffold and peptide safely improved tendon healing. PMID- 26251199 TI - Morphomics predicts response to ipilimumab in patients with stage IV melanoma. AB - INTRODUCTION: Factors predictive of response to immunotherapy are needed to select appropriate patients. As morphometric analysis can be an objective surrogate for underlying physiology, we explored the possibility that morphomics may predict response among stage IV melanoma patients treated with ipilimumab. METHODS: We identified stage IV melanoma patients treated with ipilimumab who had an appropriate CT scan within a 6 month window. Using semi-automated algorithms, we acquired several morphomic measurements. Toxicity and response rate compared by quartile using Fisher's exact test or chi-square, while survival after initiation of ipilimumab was compared by quartile using the log-rank test. RESULTS: While there was a significant correlation between toxicity and response (P < .003), morphomics failed to predict either severity of toxicity or specific side effects. Psoas density was significantly associated with response rate, both excluding stable disease (36.4% vs 9.1%, P = .054), and including stable disease (54.5% versus 18.2%, P = 0.045). Survival after initiation of ipilimumab was significantly associated with psoas density (P = 0.04) and visceral fat distance (P = 0.022). DISCUSSION: In an exploratory study of patients with metastatic melanoma being treated with ipilimumab, psoas density and spine-fascia distance correlated with response and survival. Pre-treatment morphomic analysis, as a correlate of underlying physiology, may help predict response to immunotherapy. PMID- 26251201 TI - Intensity of play behavior as a potential measure of welfare: A novel method for quantifying the integrated intensity of behavior in African elephants. AB - To the authors' knowledge there is currently no discrete index to measure the integrated intensity of a play bout in mammals, despite the potential for using intensity and duration of play bouts as a measure of physical activity and welfare. This study was developed to test an equation that quantified the intensity and duration of play bouts in a particularly gregarious mammal, African elephants (Loxodonta africana) housed at the San Diego Zoo Safari Park in Escondido, CA. To quantify these behaviors, we created a scale of intensity and a subsequent equation that produces an index value, giving each unique bout a score. A compilation of these scores provides a range of intensity of play behavior that is a representative value for that particular herd at that point in time, and thus a database to which later bouts can be compared. It can be argued that play behavior is an indicator of positive welfare, and if quantifiable, it is our belief that it can be used as an additional measure of positive welfare in zoo housed animals. Here we present the methods and technique used to calculate a standardized Integrated Play Index (IPI) that has potential for use in other socially living species that are known to exhibit play behavior. PMID- 26251202 TI - Allergic reactions to Hymenoptera stings in Turkish school children. AB - BACKGROUND: Reported prevalence of the insect stings and rates of allergic reactions vary among studies. The aim of the present study was to carry out the first epidemiological study on the prevalence of Hymenoptera allergy among school children in Izmir, Turkey. METHODS: We planned to reach 6100 children, assuming the frequency of allergic reactions to Hymenoptera stings as 20%. Thirty-seven and eight schools were chosen from rural and urban areas, respectively. Parents were asked to complete a questionnaire which included questions about history of insect stings and the presence of atopic disease. All cases with severe systemic reactions and a representative sample from the remaining population were surveyed by telephone afterwards. RESULTS: A total of 8565 questionnaires were distributed and the response rate was 70.8%. Of the 5602 children, 61.6% were stung at least once in their lifetime. Of these, 24.3% had a LLR, 8.1% had a MSR, 0.8% had a SSR. Overall reliability of the questionnaire was calculated as 40.7% for SSR and 91.6% for other reactions after telephone survey. On logistic regression analysis, male sex and rural residence were associated with a higher risk of being stung (OR: 1.39; CI 1.25-1.56; OR: 4.37; CI 3.36-5.69, respectively). Male subjects and asthmatic children were more likely to experience a SSR (OR: 2.44; CI 1.06-5.65; OR: 3.3; CI 1.52-7.19, respectively). CONCLUSION: Hymenoptera stings are common in our population and large local reactions are the most common type of reactions. Prevalence of severe reactions is low in our population compared to previous studies. PMID- 26251203 TI - Psychiatric disorders and symptoms severity in preschool children with atopic eczema. AB - BACKGROUND: To compare with a control group the frequency of psychiatric disorders and severity of psychiatric symptoms in preschool children with atopic eczema. METHODS: The study included children between the ages of 3-5 who were diagnosed to have atopic eczema. The parents of the children with atopic eczema were interviewed in person and were asked to fill in "The Early Childhood Inventory-4" form. This form assesses the psychiatric disorders and symptoms severity in children between the ages of 3-5. RESULTS: The atopic eczema group included 80 patients (38 male, 42 female) with a mean age of 48.4 +/- 15.7 months and the control group included 74 patients (41 male, 33 female) with a mean age of 49.9 +/- 15.19 months. It was established that 68.8% of the group with atopic eczema received at least one psychiatric diagnosis. Between the psychiatric disorders, ADHD (Odds ratio: 2.57, 95% CI: 1.049-6.298, p=0.035), enuresis and encopresis (Odds ratio: 2.39, 95% CI: 1.121-5.097, p=0.022) and attachment disorder (Odds ratio: 2.03, 95% CI: 1.046-3.953, p=0.035) were found to be significantly higher when compared with the healthy control group. When the groups were compared in terms of psychiatric symptom severity scores calculated by using ECI-4, ADHD severity (p=0.043), conduct disorder severity (p=0.001), anxiety disorders severity (p<0.001), eating disorders severity (p=0.011) and tic disorder severity (p=0.01) were found to be higher in the atopic eczema group. CONCLUSION: Psychiatric illnesses are frequent in preschool children with atopic eczema. PMID- 26251204 TI - Associations between estrogen receptor genetic polymorphisms, smoking status, and prostate cancer risk: a case-control study in Japanese men. AB - OBJECTIVE: Prostate cancer (PCa) is one of the major causes of death among men. Our study investigated the association of ESR1 and ESR2 genotypes with susceptibility to PCa in relation to smoking status in Japanese. METHOD: A case control study was performed with 750 Japanese prostate cancer patients and 870 healthy controls. After age-matching in case-controls, 352 controls and 352 cases were enrolled in this study. By using logistic regression analysis, the different genotypes from ESR1 and ESR2 were analyzed according to case/control status. RESULT: ESR2 rs4986938 AG and AG + AA genotypes were associated with significantly decreased risk of PCa (AG: OR = 0.68, 95 % CI 0.47-0.97, P < 0.05 and AG + AA: OR = 0.67, 95 % CI 0.47-0.94, P < 0.05). However, there was no significant association between ESR1 rs2234693 and PCa risk. When patients were grouped according to smoking status, the ESR2 rs1256049 AA genotype (OR = 0.48, 95 % CI 0.25-0.95, P < 0.05) and ESR2 rs4986938 AG + AA genotype (OR = 0.64, 95 % CI 0.41-1.00, P < 0.05) showed significantly decreased PCa risk in the ever smoker group. CONCLUSION: Our results suggest that the estrogen receptor ESR2 has a very important function to predict PCa and that different SNPs have different predictive values. Smoking may influence estrogenic activity and may influence PCa together with the estrogen receptor. PMID- 26251207 TI - Comment: Pulmonary Embolism After Early Change From Rivaroxaban to Aspirin Following Total Knee Replacement in an Obese Patient. PMID- 26251206 TI - Optimization of sulfide production by an indigenous consortium of sulfate reducing bacteria for the treatment of lead-contaminated wastewater. AB - Biological treatment with sulfate-reducing bacteria (SRB) is considered to be an excellent option to remove heavy metals from wastewater. In this study, the optimization of sulfide production for an enhanced removal of lead by a consortium of SRB was carried out based on central composite design and analyzed using response surface methodology (RSM). The sulfide production process was investigated as a function of three independent variables: solution pH (6.5-8.5), lactate concentration (32-96 mM), and sulfate concentration (16-32 mM). RSM analysis showed that the optimum conditions for a high sulfide concentration (14.2 mM) occurred at a pH of 7.5 and at lactate and sulfate concentrations of 53.4 mM and 22.6 mM, respectively. The lead removal efficiency of the SRB consortium using optimum conditions was determined in four parallel anaerobic continuous moving bed biofilm reactors (V = 2 L) that were fed with synthetic wastewater containing dissolved lead at concentrations of 0, 100, 150, 200 mg L( 1) and operated with a hydraulic retention time of 5 days. 99-100 % was removed from synthetic wastewater with lead concentrations of 100 and 150 mg L(-1) during 40 days of operation. For the highest lead concentration of 200 mg L(-1), a decrease in efficiency of removal (96 %) was observed at the end of the experiment. PMID- 26251205 TI - Quantitative magnetic resonance imaging in patients with cirrhosis: a cross sectional study. AB - Cerebral magnetic resonance imaging was undertaken, at 3 Tesla field strength, employing magnetization transfer (MT) and diffusion-weighted imaging (DWI) sequences, in 26 patients with well-compensated cirrhosis, free of overt hepatic encephalopathy. Results were compared to those from 18 aged-matched healthy volunteers. Cerebral magnetization transfer ratios (MTR) were reduced in the frontal white matter, caudate, putamen and globus pallidus in patients with cirrhosis, compared to healthy controls, while the apparent diffusion coefficients (ADC) on DWI were significantly increased in the genu and body of the corpus callosum. An association between previous excessive alcohol consumption and both MTR and ADCs was noted, but this association was lost when controls were exercised for the severity of liver disease and psychometric impairment on multivariate analysis. Eight (31 %) of the 26 patients had impaired psychometric performance consistent with a diagnosis of minimal hepatic encephalopathy. No statistically significant difference in regional cerebral MTRs or ADCs was found in relation to neuropsychiatric status, although there was a trend towards lower MTRs in patients with impaired psychometric performance. The alterations in MTR and ADC in the patients with functionally compensated cirrhosis are compatible with theories governing the genesis of hepatic encephalopathy, including changes in astrocyte membrane permeability, with subsequent redistribution of macromolecules. PMID- 26251208 TI - Acute Diaphragm Paralysis Caused by Intravenous Administration of Amiodarone. PMID- 26251209 TI - Learning nucleic acids solving by bioinformatics problems. AB - The article describes the development of a new approach to teach molecular biology to undergraduate biology students. The 34 students who participated in this research belonged to the first period of the Biological Sciences teaching course of the Instituto Federal Goiano at Urutai Campus, Brazil. They were registered in Cell Biology in the first semester of 2013. They received four 55 min-long expository/dialogued lectures that covered the content of "structure and functions of nucleic acids". Later the students were invited to attend four meetings (in a computer laboratory) in which some concepts of Bioinformatics were presented and some problems of the Rosalind platform were solved. The observations we report here are very useful as a broad groundwork to development new research. An interesting possibility is research into the effects of bioinformatics interventions that improve molecular biology learning. PMID- 26251210 TI - Resolving the Role of Plant NAD-Glutamate Dehydrogenase: III. Overexpressing Individually or Simultaneously the Two Enzyme Subunits Under Salt Stress Induces Changes in the Leaf Metabolic Profile and Increases Plant Biomass Production. AB - NAD-dependent glutamate dehydrogenase (NAD-GDH) of higher plants has a central position at the interface between carbon and nitrogen metabolism due to its ability to carry out the deamination of glutamate. In order to obtain a better understanding of the physiological function of NAD-GDH under salt stress conditions, transgenic tobacco (Nicotiana tabacum L.) plants that overexpress two genes from Nicotiana plumbaginifolia individually (GDHA and GDHB) or simultaneously (GDHA/B) were grown in the presence of 50 mM NaCl. In the different GDH overexpressors, the NaCl treatment induced an additional increase in GDH enzyme activity, indicating that a post-transcriptional mechanism regulates the final enzyme activity under salt stress conditions. A greater shoot and root biomass production was observed in the three types of GDH overexpressors following growth in 50 mM NaCl, when compared with the untransformed plants subjected to the same salinity stress. Changes in metabolites representative of the plant carbon and nitrogen status were also observed. They were mainly characterized by an increased amount of starch present in the leaves of the GDH overexpressors as compared with the wild type when plants were grown in 50 mM NaCl. Metabolomic analysis revealed that overexpressing the two genes GDHA and GDHB, individually or simultaneously, induced a differential accumulation of several carbon- and nitrogen-containing molecules involved in a variety of metabolic, developmental and stress-responsive processes. An accumulation of digalactosylglycerol, erythronate and porphyrin was found in the GDHA, GDHB and GDHA/B overexpressors, suggesting that these molecules could contribute to the improved performance of the transgenic plants under salinity stress conditions. PMID- 26251211 TI - Effect of taping on foot kinematics in persons with chronic ankle instability. AB - OBJECTIVES: To investigate differences in rigid-foot and multi-segmental foot kinematics between healthy (control) and chronic ankle instability (CAI) participants during running and to evaluate the effect of low-Dye (LD) and high Dye (HD) taping on foot kinematics of CAI subjects. DESIGN: Cross-sectional, comparative study. METHODS: Kinematic data of 12 controls and 15 CAI participants were collected by a 3D motion analysis system during running. CAI participants performed barefoot (CAI_BF) running trials as well as trials with taping. A rigid Plug-in gait Model and the Rizzoli 3D Multi-Segment Foot Model were used. Groups were compared using one-dimensional statistical parametric mapping. RESULTS: An increased inversion, a decreased dorsiflexion between the foot and tibia and a decreased external foot progression angle were found during terminal swing and early stance in the CAI_BF group. With respect to the taped conditions, post-hoc SPM{t} calculations highlighted a more dorsiflexed rearfoot (38-46% running cycle) in the CAI_HD compared to the CAI_LD, and a more inverted Mid-Met angle (6 24% running cycle) in the CAI_LD compared to the CAI_BF condition. CONCLUSIONS: This study revealed significant differences in rigid foot and multi-segmental foot kinematics between all groups. As high-dye taping embraces shank-rearfoot and forefoot, it seems to have better therapeutic features with respect to low dye taping as the latter created a more inverted forefoot which may not be recommended in this population. PMID- 26251212 TI - Diabetic foot disease: moving from roadmap to journey. PMID- 26251213 TI - Chemistry of N,S-Heterocyclic Carbene and Metallaboratrane Complexes: A New eta(3)-BCC-Borataallyl Complex. AB - A high-yielding synthetic route for the preparation of group 9 metallaboratrane complexes [Cp*MBH(L)2], 1 and 2 (1, M=Rh, 2, M=Ir; L=C7H4NS2) has been developed using [{Cp*MCl2}2] as precursor. This method also permitted the synthesis of an Rh-N,S-heterocyclic carbene complex, [(Cp*Rh)(L2)(1-benzothiazol-2-ylidene)] (3; L=C7H4NS2) in good yield. The reaction of compound 3 with neutral borane reagents led to the isolation of a novel borataallyl complex [Cp*Rh(L)2B{CH2C(CO2Me)}] (4; L=C7H4NS2). Compound 4 features a rare eta(3)-interaction between rhodium and the B-C-C unit of a vinylborane moiety. Furthermore, with the objective of generating metallaboratranes of other early and late transition metals through a transmetallation approach, reactions of rhoda- and irida-boratrane complexes with metal carbonyl compounds were carried out. Although the objective of isolating such complexes was not achieved, several interesting mixed-metal complexes [{Cp*Rh}{Re(CO)3}(C7H4NS2)3] (5), [Cp*Rh{Fe2(CO)6}(MU-CO)S] (6), and [Cp*RhBH(L)2W(CO)5] (7; L=C7H4NS2) have been isolated. All of the new compounds have been characterized in solution by mass spectrometry, IR spectroscopy, and (1)H, (11)B, and (13)C NMR spectroscopies, and the structural types of 4-7 have been unequivocally established by crystallographic analysis. PMID- 26251216 TI - Myeloid cell-mediated renal injury in rapidly progressive glomerulonephritis depends upon spleen tyrosine kinase. AB - Antibody-dependent activation of myeloid cells within the glomerulus plays a central role in rapidly progressive forms of glomerulonephritis. The spleen tyrosine kinase (Syk) is expressed by all leukocytes, except mature T cells, and is required for signalling via the B-cell receptor, Fc receptors, and some integrins. Syk has been proposed as a therapeutic target in glomerulonephritis. However, little is known of Syk activation in human kidney disease, while studies in experimental glomerulonephritis using non-selective Syk inhibitors require validation via conditional gene deletion. The current study addressed both of these important points. Syk activation (Tyr(525/526) phosphorylation) was examined in a cohort of 96 patients with different glomerulonephritides. Syk activation was evident in infiltrating leukocytes, mainly neutrophils and macrophages, in 36/40 cases of rapidly progressive glomerulonephritis. In contrast, non-proliferative diseases showed little or no Syk activation. Glomerular and interstitial cells exhibiting Syk activation correlated with renal function and systemic inflammation. Next, we examined mice with conditional Syk gene deletion in myeloid cells (Syk(My) ) versus Syk(f/f) littermate controls in nephrotoxic serum nephritis - a model of rapidly progressive glomerulonephritis. Control Syk(f/f) mice featured a transient neutrophil influx at 3 h and severe disease on day 9 of nephrotoxic serum nephritis, with crescent formation, macrophage infiltration, inflammation, kidney fibrosis, and renal dysfunction. In contrast, Syk(My) mice had significantly reduced neutrophil and macrophage infiltration despite equivalent glomerular deposition of humoral reactants. Syk(My) mice exhibited reduced crescent formation, inflammation, and fibrosis, with improved renal function on day 9 of nephrotoxic serum nephritis. In conclusion, Syk activation is prominent in infiltrating myeloid cells in human rapidly progressive glomerulonephritis, and functional studies demonstrate that Syk deletion in myeloid cells is protective in mouse nephrotoxic serum nephritis. PMID- 26251215 TI - Long-Term Recovery of Reduced Left Ventricular Ejection Fraction after Aortic Valve Replacement in Patients with Bicuspid Aortic Valve Disease. AB - Background Long-term prognosis of patients with bicuspid aortic valve (BAV) disease and poor left ventricular ejection fraction (LVEF) who underwent aortic valve replacement (AVR) is unknown. We aimed to analyze the recovery of LVEF and incidence of adverse events after AVR in patients with BAV and poor LVEF. Materials and Methods A total of 90 consecutive BAV patients (mean age 57 +/- 10 years, 89% male) with baseline LVEF <=40% underwent an isolated AVR between January 1, 1995, and June 30, 2008, and served as our study population. Follow-up data (800 patient-years) were obtained for all 90 hospital survivors. A subgroup of patients who underwent AVR for BAV stenosis (Group aortic stenosis [AS], n = 70) was compared with those who underwent AVR for BAV regurgitation (Group aortic regurgitation [AR], n = 20). Primary end point was the recovery of LVEF in AS Group versus AR Group. Secondary end points were survival and freedom from adverse cardiac events (i.e., cardiac-related death and need for reinterventions due to persisting heart failure). Results There was a significant increase in LVEF (mean follow-up 9.0 +/- 5 years) in AS versus AR Group (i.e., 32 +/- 7% [baseline] and 53 +/- 9% [follow-up], p < 0.001 in AS Group vs. 33 +/- 7% [baseline] and 38 +/- 13% [follow-up], p = 0.07 in AR Group). Recovery rate of LVEF was significantly higher in AS Group versus AR Group (i.e., 2.8 percentage points (pp)/year vs. 0.7 pp/year, respectively). In Group AS, 86% of patients were responders, whereas in Group AR, only 30% (p < 0.001). The subjects in Group AR did not show a difference between baseline and follow-up left ventricular end diastolic diameter (LVEDD) (baseline 61 +/- 12 vs. follow-up 58 +/- 8, p = 0.813), whereas in Group AS, there was a significant difference of LVEDD (baseline 56 +/- 7 vs. follow-up 54 +/- 6 mm, p = 0.019). Ten-year survival was 76 +/- 6.5% in AS Group versus 78 +/- 11% in AR Group (p = 0.3). Prevalence of late adverse cardiac events was 7% in AS Group versus 40% in AR Group (p = 0.03). Conclusion The recovery of reduced LVEF after AVR surgery is significantly impaired in patients with BAV regurgitation as compared with BAV stenosis. PMID- 26251214 TI - Antibodies to an interfering epitope in hepatitis C virus E2 can mask vaccine induced neutralizing activity. AB - Hepatitis C virus (HCV) neutralization occurring at the E2 region 412-426 (EP-I) could be enhanced when antibodies directed specifically to the E2 region 434-446 (EP-II) were removed from serum samples of persistently infected patients and vaccinated chimpanzees, a phenomenon of so-called antibody interference. Here, we show that this type of interference can be observed in individuals after immunization with recombinant E1E2 proteins. One hundred twelve blinded serum samples from a phase I, placebo-controlled, dose escalation trial using recombinant HCV E1E2 with MF59C.1 adjuvant in healthy HCV-negative adults were tested in enzyme-linked immunosorbent assay for binding reactivity to peptides representing the E2 regions 412-426 (EP-I) and 434-446 (EP-II). All samples were subsequently tested for neutralizing activity using cell-culture HCV 1a(H77)/2a chimera, HCV pseudotype particles (HCVpp) H77, and HCVpp HCV-1 after treatment to remove EP-II-specific antibodies or mock treatment with a control peptide. Among the 112 serum samples, we found 22 double positive (EP-I and EP-II), 6 EP-II positive only, 14 EP-I positive only, and 70 double negative. Depleting EP-II antibodies from double-positive serum samples increased 50% inhibitory dose (ID50) neutralizing antibody titers (up to 4.9-fold) in up to 72% of samples (P <= 0.0005), contrasting with ID50 neutralization titer increases in 2 of 70 double-negative samples (2.9%; P > 0.5). In addition, EP-I-specific antibody levels in serum samples showed a significant correlation with ID50 neutralization titers when EP-II antibodies were removed (P < 0.0003). CONCLUSION: These data show that antibodies to the region 434-446 are induced during immunization of individuals with recombinant E1E2 proteins, and that these antibodies can mask effective neutralizing activity from EP-I-specific antibodies. Elicitation of EP II-specific antibodies with interfering capacity should be avoided in producing an effective cross-neutralizing vaccine aimed at the HCV envelope proteins. PMID- 26251217 TI - The increasing burden of potentially preventable liver disease among adult liver transplant recipients: A comparative analysis of liver transplant indication by era in Australia and New Zealand. AB - BACKGROUND: Hepatitis C (HCV), hepatitis B (HBV), alcohol-related liver disease (ALD), and non-alcohol-related fatty liver disease (NAFLD) are leading indications for adult liver transplantation in Australia and New Zealand. However, these diseases are potentially preventable through effective primary and/or secondary prevention strategies. This study evaluates the relative contribution of potentially preventable liver diseases to liver transplant numbers in Australia and New Zealand over time. METHODS: Prospectively recorded clinical, demographic, and outcome data were collected from the Australian and New Zealand Liver Transplant Registry for all primary adult liver transplants performed in Australia and New Zealand from 1 January 1985 until 31 December 2012. Potentially preventable liver disease was defined as HBV, HCV, NAFLD, ALD, and HCC. The etiology of liver disease leading to liver transplantation and the proportion of preventable liver disease-related liver transplantation was compared between Era 1 (1985-1993), Era 2 (1994-2003), and Era 3 (2004-2012). RESULTS: Overall, 1252 of 3266 adult primary liver transplants (38.3%) were performed for potentially preventable liver disease. There was a significant increase in the proportion of liver transplants because of preventable liver disease from 21.2% (93 of 439) in Era 1, to 49.8% (623 of 1252) in Era 2 and 63.5% (1000 of 1575) in Era 3 (P < 0.0001). Over time, there was a significant increase in HCV (P < 0.0001), ALD (P = 0.002), and NAFLD (P < 0.0001) as a primary indication for adult liver transplant, whereas HBV has significantly decreased from Era 1 to Era 3 as an indication for transplant (P < 0.0001). The number of transplants performed for HCC also increased across Eras (P < 0.0001), with 84% due to underlying potentially preventable liver disease. CONCLUSION: Since 2004, the majority of primary adult liver transplants within Australia and New Zealand have been because of potentially preventable liver diseases and the prevalence of these diseases has increased over time. This finding represents an opportunity for clinicians to make a significant impact on the overall burden of advanced liver disease in Australia and New Zealand by improving primary and secondary prevention measures. PMID- 26251218 TI - Correlation between the Stereochemistry and Bioactivity in Octahedral Rhodium Prolinato Complexes. AB - Controlling the relative and absolute configuration of octahedral metal complexes constitutes a key challenge that needs to be overcome in order to fully exploit the structural properties of octahedral metal complexes for applications in the fields of catalysis, materials sciences, and life sciences. Herein, we describe the application of a proline-based chiral tridentate ligand to decisively control the coordination mode of an octahedral rhodium(III) complex. We demonstrate the mirror-like relationship of synthesized enantiomers and differences between diastereomers. Further, we demonstrate, using the established pyridocarbazole pharmacophore ligand as part of the organometallic complexes, the importance of the relative and absolute stereochemistry at the metal toward chiral environments like protein kinases. Protein kinase profiling and inhibition data confirm that the proline-based enantiopure rhodium(III) complexes, despite having all of the same constitution, differ strongly in their selectivity properties despite their unmistakably mutual origin. Moreover, two exemplary compounds have been shown to induce different toxic effects in an ex vivo rat liver model. PMID- 26251219 TI - Does active smoking induce hematogenous metastatic spread in colon cancer? AB - BACKGROUND: No consensus exists on the influence of active smoking on the baseline staging of colon cancer patients. METHODS: A cohort of colon cancer patients treated surgically at Massachusetts General Hospital (2004 to 2011) was reviewed. RESULTS: Of 1,071 patients, 563 reported ever smoking, among which 128 (12%) patients were current smokers. Ex-smokers and never smokers had similar rates of nodal (relative risk [RR] .9, P = .19) and metastatic disease (RR .96, P = .72), leading to comparable colon cancer-related mortality (RR 1.01, P = .95). Current smokers had similar rates of lymph node disease (RR 1.01, P = .88), but had significantly higher stage-adjusted odds of metastatic disease at presentation (odds ratio 2.57, 95% confidence interval 1.36 to 4.98, P = .005), in addition to higher stage-adjusted all-cause mortality (hazard ratio 1.44, P = .017). CONCLUSIONS: Active smoking was a stage-independent risk factor for baseline hematogenous metastasis and mortality. As this link was not present in former smokers, a potential healthcare benefit may be achieved in terms of baseline colon cancer presentation and outcomes through smoking cessation. PMID- 26251220 TI - Complexity of begomovirus and betasatellite populations associated with chilli leaf curl disease in India. AB - Chilli, which encompasses several species in the genus Capsicum, is widely consumed throughout the world. In the Indian subcontinent, production of chilli is constrained due to chilli leaf curl disease (ChiLCD) caused by begomoviruses. Despite the considerable economic consequences of ChiLCD on chilli cultivation in India, there have been scant studies of the genetic diversity and structure of the begomoviruses that cause this disease. Here we report on a comprehensive survey across major chilli-growing regions in India. Analysis of samples collected in the survey indicates that ChiLCD-infected plants are associated with a complex of begomoviruses (including one previously unreported species) with a diverse group of betasatellites found in crops and weeds. The associated betasatellites neither enhanced the accumulation of the begomovirus components nor reduced the incubation period in Nicotiana benthamiana. The ChiLCD-associated begomoviruses induced mild symptoms on Capsicum spp., but both the level of helper virus that accumulated and the severity of symptoms were increased in the presence of cognate betasatellites. Interestingly, most of the begomoviruses were found to be intra-species recombinants. The betasatellites possess high nucleotide variability, and recombination among them was also evident. The nucleotide substitution rates were determined for the AV1 gene of begomoviruses (2.60 * 10- 3 substitutions site- 1 year- 1) and the betaC1 gene of betasatellites [chilli leaf curl betasatellite (ChiLCB), 2.57 * 10- 4 substitution site- 1 year- 1; tomato leaf curl Bangladesh betasatellite (ToLCBDB), 5.22 * 10- 4 substitution site- 1 year- 1]. This study underscores the current understanding of Indian ChiLCD-associated begomoviruses and also demonstrates the crucial role of betasatellites in severe disease development in Capsicum spp. PMID- 26251222 TI - Revisiting the hyperhemolysis paradigm. AB - In this issue of Blood, 2 articles test fundamental hypotheses relating intravascular hemolysis to sickle cell disease (SCD) pathogenesis. Detterich et al confirm a role for hemolysis and cell-free plasma hemoglobin (Hb) in pulmonary and systemic endothelial dysfunction in humans. Almeida et al show in mice that hemolysis induces inflammation that is caused by nitric oxide (NO) scavenging and ameliorated by NO donors and the NO-donor properties of hydroxyurea (HU). PMID- 26251221 TI - Feasibility of screening for T1D and celiac disease in a pediatric clinic setting. AB - OBJECTIVE: Type 1 diabetes (T1D) or celiac disease (CD) develops in at least 2% of the general population. Early detection of disease-specific autoimmunity and subsequent monitoring would be possible if screening tests were more widely available. Currently, screening for islet autoimmunity is available only in a research setting, and CD-specific autoimmunity screening is limited to those in high-risk groups. This study assessed the feasibility of incorporating T1D and CD autoantibody screening into a pediatric practice. METHODS: Patient engagement strategies, blood collection preference, blood sample volume, rate of autoantibody detection in the general population, and parental satisfaction were assessed. Over 5 weeks, research staff recruited 200 patients, aged 2-6 yr from two pediatric practices in the Denver area to be screened for islet autoantibodies (IAs) and the transglutaminase antibody. RESULTS: Of the 765 parents approached, 200 (26%) completed the same-day screening. Of the 565 subjects who did not complete the screening, 345 expressed interest, but were unable to make a participation decision. A finger stick, compared with a venous draw, was the preferred method of sample collection. Both methods yielded sufficient blood volume for autoantibody determination. IAs or the transglutaminase antibody were detected in 11 subjects. Parents expressed satisfaction with all aspects of participation. CONCLUSIONS: The results of this study suggest that it is feasible to conduct this type of screening in a pediatric clinic. Such screening could lead to increased disease awareness and the possible benefits that can result from early detection. PMID- 26251223 TI - Interleukin-6 in CLL: accelerator or brake? AB - In this issue of Blood, Li et al provide insight into the interactions between immunoreceptor signals in a human cancer microenvironment presenting a novel mechanism by which microenvironment-produced interleukin (IL)-6 acts as a tumor suppressor in chronic lymphocytic leukemia (CLL) by inhibiting toll-like receptor (TLR) signaling. PMID- 26251224 TI - Evolution: IMiDs to PPMs, revolution in DLBCL? AB - In this issue of Blood, Hagner et al provide preclinical evidence that CC-122 might be active in both major molecular subtypes of diffuse large B-cell lymphoma (DLBCL). PMID- 26251225 TI - Physiochemical artifacts in FeCl3 thrombosis models. AB - In this issue of Blood, Ciciliano et al demonstrate that thrombus formation in ferric chloride (FeCl3) thrombosis models relies on physiochemical, rather than biological, mechanisms. PMID- 26251226 TI - Factors Influencing Quality of Life among People Living with HIV in Coastal South India. AB - BACKGROUND: Antiretroviral therapy (ART) has increased life expectancy of HIV/AIDS patients, but the quality of life (QOL) still remains the same. METHODS: In this cross-sectional study, 356 people living with HIV (PLHIV) were interviewed to assess their QOL using WHOQOL-HIV BREF questionnaire. The association between QOL with sociodemographic, clinical and cohabitation status of the participants was tested using ANOVA and Student t-test, and p value < .05 was considered statistically significant. RESULTS: Physical domain of QOL showed maximum score of 16.4, while a minimum score of 12.2 was seen in social relationship domain. Participants with higher socioeconomic status (SES) and self motivated to take ART had shown better scores across all the domains of QOL ( p < .05). CONCLUSION: In our study, quality of life was high among males, younger patients, married participants, higher socioeconomic status, longer duration of ART, self-motivation to take ART, absence of opportunistic infection, and with higher CD4 count. PMID- 26251228 TI - Predictors of trifecta outcomes in laparoscopic partial nephrectomy for clinical T1a renal masses. AB - OBJECTIVES: To assess trifecta outcomes for laparoscopic partial nephrectomy for clinical T1a renal masses. METHODS: A total of 63 patients who underwent laparoscopic partial nephrectomy for clinical T1a renal masses by a single surgeon between January 2007 and December 2012 were evaluated. Demographic and perioperative data were collected and statistically analyzed. We retrospectively evaluated trifecta outcomes. Multivariable logistic regression models were used to analyze predictors of trifecta outcomes. Trifecta outcomes were defined as the combination of total ischemia time <25 min, negative surgical margins and no surgical complications. RESULTS: Of the 63 patients, 39 (62%) achieved trifecta. A total of 21 patients had total ischemia time >=25 min, four patients had positive surgical margins and two patients had surgical complications. Tumor size (P < 0.001), distance from the urine collecting system or sinus (P < 0.001) and surgeon's learning curve (P < 0.01) were significantly different between the trifecta and no-trifecta group. Multivariate analysis showed tumor size and surgeon's learning curve to be independent predictors of trifecta outcomes. CONCLUSIONS: Tumor size and surgeon's learning curve seems to be strong predictors of trifecta outcomes after laparoscopic partial nephrectomy in T1a renal masses. PMID- 26251227 TI - The complex contribution of chemokines to neuroinflammation: switching from beneficial to detrimental effects. AB - Inflammation is an innate mechanism that defends organisms against harmful stimuli. Inflammation leads to the production and secretion of proinflammatory mediators that activate and recruit immune cells to damaged tissues, including the brain, to resolve the cause of inflammation. In the central nervous system, inflammation is referred to as neuroinflammation, which occurs in various pathological conditions of the brain. The primary role of neuroinflammation is to protect the brain. However, prolonged and/or inappropriate inflammation can be harmful for the brain, from individual cells to the whole tissue. This review focuses on a particular type of inflammatory mediator, chemokines, and describes their complex effects both under physiological and pathophysiological conditions of the brain. The clinical relevance of the multiple characters of chemokines is highlighted with respect to acute and chronic inflammation of the brain, including their actions in stroke and Alzheimer's disease, respectively. PMID- 26251229 TI - Effects of safety warnings and risk management plan for Thiazolidinediones in Taiwan. AB - PURPOSE: To evaluate changes in thiazolidinedione use and quality of prescription following safety warnings for thiazolidinediones and cardiac risk in 2007, Risk Management Plan (RMP) policy for rosiglitazone in 2010, and warning for pioglitazone and bladder cancer risk in 2010 in Taiwan. METHODS: We obtained 2003 2011 claims data from Taiwan's National Health Insurance Research Database. Using an interrupted time series design and segmented regression, we estimated changes in monthly prescribing rates for thiazolidinediones among all and prevalent diabetes patients with and without cardiovascular disease history (CV history). We also compared time to prescription of thiazolidinediones among new diabetes patients with CV history before and after each regulatory action using survival analysis. RESULTS: Among prevalent patients with and without CV history, the prescribing rates of rosiglitazone decreased 36.88% and 28.92% after safety warnings in 2007 respectively. Pioglitazone prescriptions increased 13% among patients with CV history, but no changes were detected among patients without CV history. After rosiglitazone's RMP policy in 2010, large reductions in prescriptions were observed in patients with CV history (-101.67%) and those without CV history (-88.04%). Among new diabetes patients with CV history, cardiac safety warnings in 2007 significantly delayed the prescription of rosiglitazone, but no significant change was found for pioglitazone. CONCLUSIONS: The Taiwan FDA regulatory actions for thiazolidinediones communicated possible risks of cardiac events and bladder cancer. Different safety regulatory actions had differential impacts on the use of rosiglitazone and pioglitazone and the quality use of these drugs among the high-risk patients. PMID- 26251231 TI - Effects of different strains Penicillium nalgiovense in the Nalzovy cheese during ripening. AB - BACKGROUND: The present study examined the influence of eight selected strains of Penicillium nalgiovense as secondary culture on the ripening of soft mould cheese. Ion-exchange chromatography, SDS-PAGE and sensory analysis were used for comparison of P. nalgiovense with common secondary mould culture (Penicillium camemberti). RESULTS: Proteolytic activity was more intensive in the case of the strains of P. nalgiovense in comparison with the control strains of P. camemberti. Some differences in the proportion and amount of free amino acids were observed between the strains of P. nalgiovense during ripening. Lower proteolytic activity of P. nalgiovense was more desirable for sensory properties of cheese, especially in case sample N2. CONCLUSION: This study provides information on the usability of selected strains of P. nalgiovense that could support the development of sensory properties of mould-ripened soft cheese. The cheese with the culture N2 had the best flavour after 35 days of storage. Moreover, this strain showed the lowest bitterness in comparison with the other used P. nalgiovense cultures. The intensity of bitterness of sample N2 was comparable to that of the control sample with P. camemberti. (c) 2015 Society of Chemical Industry. PMID- 26251230 TI - Association between rs2431697 T allele on 5q33.3 and systemic lupus erythematosus: case-control study and meta-analysis. AB - rs2431697 is located on 5q33.3, between pituitary tumor-transforming gene 1 and miR-146a. Several studies have estimated the association between rs2431697 and systemic lupus erythematosus risk. However, the results were inconsistent. A case control study was carried out to explore the association between rs2431697 and systemic lupus erythematosus risk in a central Chinese population. Meta-analyses combining present with previous studies were conducted to further explore the association. Our case-control study included 322 cases and 353 controls. rs2431697 T allele was associated with increased risk of systemic lupus erythematosus (odds ratios (ORs) = 1.461, 95% confidence intervals (CI) 1.091 1.957, P = 0.011). The association was stronger between T allele and the risk of anti-double-stranded DNA (dsDNA)-positive systemic lupus erythematosus (OR = 2.510, 95% CI 1.545-4.077, P < 0.001). The meta-analyses included 8648 systemic lupus erythematosus patients and 10947 controls. rs2431697 T allele had an overall OR of 1.262 (95% CI 1.205-1.323, P < 0.001) under fixed-effects model. After stratified by ethnicity, I (2) reduced from 24.3 to 0 %. T allele had an OR of 1.213 (95% CI 1.145-1.284, P < 0.001) in European descendant and 1.365 (95% CI 1.259-1.480, P < 0.001) in Asian under fixed-effects model. Data on women were also extracted, and T allele had an OR of 1.337 (95% CI 1.162-1.539, P < 0.001) under random-effects model. The pooled ORs were not influenced by each study in sensitivity analyses. There were no publication biases observed in these analyses. The results from our case-control study and the meta-analyses indicate that rs2431697 T allele significantly associates with the increased risk of systemic lupus erythematosus. PMID- 26251233 TI - The denominator variable in the quantitation of MRD in acute myeloid leukemia. PMID- 26251232 TI - Catechol-O-methyltransferase Val158met polymorphism interacts with early experience to predict executive functions in early childhood. AB - Numerous studies demonstrate that the Methionine variant of the catechol-O methyltransferase Val158Met polymorphism, which confers less efficient catabolism of catecholamines, is associated with increased focal activation of prefrontal cortex (PFC) and higher levels of executive function abilities. By and large, however, studies of COMT Val158Met have been conducted with adult samples and do not account for the context in which development is occurring. Effects of early adversity on stress response physiology and the inverted U shape relating catecholamine levels to neural activity in PFC indicate the need to take into account early experience when considering relations between genes such as COMT and executive cognitive ability. Consistent with this neurobiology, we find in a prospective longitudinal sample of children and families (N = 1292) that COMT Val158Met interacts with early experience to predict executive function abilities in early childhood. Specifically, the Valine variant of the COMT Val158Met polymorphism, which confers more rather than less efficient catabolism of catecholamines is associated with higher executive function abilities at child ages 48 and 60 months and with faster growth of executive function for children experiencing early adversity, as indexed by cumulative risk factors in the home at child ages 7, 15, 24, and 36 months. Findings indicate the importance of the early environment for the relation between catecholamine genes and developmental outcomes and demonstrate that the genetic moderation of environmental risk is detectable in early childhood. PMID- 26251234 TI - Comparison of apical and coronal extrusions using reciprocating and rotary instrumentation systems. AB - BACKGROUND: The aim of this study was to compare the apical and coronal extrusions by using two reciprocating and two rotary instrumentation systems. METHODS: Eighty extracted human single-rooted anterior teeth were randomly assigned to four groups. Four different root canal instrumentation systems were used according to the manufacturers instructions, including two reciprocating single-file systems, Reciproc and WaveOne, and two full-sequence rotary BLX and ProTaper instruments. Debris collected from the coronal by the instruments and apical extrusions were quantified respectively. After drying the collections, the mean weight of debris collected from apical and coronal extrusions was assessed using an electronic balance and analyzed using the Kruskal-Wallis H and Mann Whitney U tests. RESULTS: Statistically significant differences in the apical extrusion were observed among the four groups. Reciproc and WaveOne instruments produced significantly less debris than BLX and ProTaper instruments (P < 0.05). CONCLUSIONS: All of the systems produced apical extrusion of debris. However, reciprocating single-file systems produced less apical extrusion than full sequence rotary systems. No relationship was observed between apical and coronal extrusions. PMID- 26251235 TI - Non-Hsp genes are essential for HSF1-mediated maintenance of whole body homeostasis. AB - Mammalian tissues are always exposed to diverse threats from pathological conditions and aging. Therefore, the molecular systems that protect the cells from these threats are indispensable for cell survival. A variety of diseases, including neurodegenerative diseases, cause intracellular damage and disturb homeostasis. Heat shock transcription factor 1 (HSF1) positively regulates heat shock protein (Hsp) and maintains the precise folding of proteins. Moreover, HSF1 induces the non-Hsp genes expression, and degrades damaged/misfolded protein. Recently, my colleagues and I revealed non-Hsp genes have more protective roles than Hsps at the cellular level. However, whether these protective systems are similarly important to cellular defense in each tissue is still elusive. In this study, I compared polyglutamine (polyQ) protein aggregations/inclusion development in each tissue of WT- and HSF1KO-Huntington's disease (HD) mice, and examined the expression of the eight non-Hsp HSF1 target genes that have a strong suppressive effect on polyQ protein aggregation. Of these genes, Nfatc2, Pdzk3, Cryab, Csrp2, and Prame were detected in most tissues, but the other genes were not. Surprisingly, the obvious effect of HSF1 deficiency on the expression of these five genes was detected in only heart, spleen, and stomach. In addition, polyQ protein aggregations/inclusion was not detected in any tissues of WT-HD and HSF1KO-HD mice, but higher level of pre-aggregative polyQ protein was detected in HSF1KO-HD tissues. These results indicate non-Hsp genes are indispensable for the maintenance of intracellular homeostasis in mammalian tissues, resulting in whole body homeostasis. PMID- 26251236 TI - In vitro response pattern of monocytes after tmTNF reverse signaling predicts response to anti-TNF therapy in rheumatoid arthritis. AB - BACKGROUND: Treatment with TNF inhibitors is very efficient in the majority of the patients with rheumatoid arthritis (RA), but it does not achieve a sufficient treatment response in 40-50% of the cases. Goal of the study was to assess functional ex vivo-tests of RA monocytes as prognostic parameters of the subsequent treatment response. METHODS: 20 anti-TNF naive RA patients were enrolled in a prospective, open-label trial, and Etanercept therapy was initiated. Prior to treatment, reverse signaling was induced in peripheral blood monocytes by tmTNF crosslinking via TNFR2:Ig construct Etanercept in a standardized ex vivo-assay. Released cytokine and cytokine receptor concentrations were determined as parameters of the monocyte response. RESULTS: Crosslinking of tmTNF and consecutive reverse signaling led to production of pro- and anti-inflammatory cytokines and of soluble cytokine decoy receptors such as sTNFR1 and sIL-1R2. Several of the measured concentrations were found to correlate with the treatment response according to the EULAR criteria. The correlation was most pronounced in sTNFR1 concentrations (r = -0.657, p = 0.0031), which also predicted a good clinical response with the highest sensitivity and specificity according to EULAR criteria. CONCLUSIONS: Herein we propose that the tmTNF crosslinking-triggered shedding of soluble decoy receptors and production of anti-inflammatory cytokines could contribute to the clinical efficacy of TNF inhibitors, and that in vitro quantification of this secretion by RA monocytes prior to treatment can be used to predict the clinical response. Further development of such standardized tests could be a step towards personalized medicine by providing rheumatologists with a rational choice for first line biological therapy in patients with RA. PMID- 26251237 TI - beta-amyloid, microglia, and the inflammasome in Alzheimer's disease. AB - There is extensive evidence that accumulation of mononuclear phagocytes including microglial cells, monocytes, and macrophages at sites of beta-amyloid (Abeta) deposition in the brain is an important pathological feature of Alzheimer's disease (AD) and related animal models, and the concentration of these cells clustered around Abeta deposits is several folds higher than in neighboring areas of the brain [1-5]. Microglial cells phagocytose and clear debris, pathogens, and toxins, but they can also be activated to produce inflammatory cytokines, chemokines, and neurotoxins [6]. Over the past decade, the roles of microglial cells in AD have begun to be clarified, and we proposed that these cells play a dichotomous role in the pathogenesis of AD [4, 6-11]. Microglial cells are able to clear soluble and fibrillar Abeta, but continued interactions of these cells with Abeta can lead to an inflammatory response resulting in neurotoxicity. Inflammasomes are inducible high molecular weight protein complexes that are involved in many inflammatory pathological processes. Recently, Abeta was found to activate the NLRP3 inflammasome in microglial cells in vitro and in vivo thereby defining a novel pathway that could lead to progression of AD [12-14]. In this manuscript, we review possible steps leading to Abeta-induced inflammasome activation and discuss how this could contribute to the pathogenesis of AD. PMID- 26251239 TI - Correlation between the ABC classification and radiological findings for assessing gastric cancer risk. AB - PURPOSE: To investigate the correlation between ABC risk assessment and radiological findings of gastric mucosa and to propose an improved method for gastric cancer screening. MATERIALS AND METHODS: We evaluated 318 participants with Helicobacter pylori (Hp) antibody titers, serum pepsinogen (PG) and upper GI radiography and then classified them into three groups: A, double-negative; B, Hp positive, PG-negative; C, PG-positive. Group A was subclassified as: A-1, Hp antibody titer <3.0 U/ml; A-2, Hp antibody titer >=3.0 U/ml. Results for group A and non-A (B or C) participants and radiological findings of gastric mucosa (fold and area gastricae) were analyzed retrospectively. RESULTS: Radiological findings differed significantly between the 207 A-1 and 98 non-A group. Odds ratios were 17.72 for fold distribution, 10.63 for fold thickness, 6.10 for fold characteristics, and 10.62 for area gastricae. Presence of >=2 risk factors offered 90.3 % sensitivity, 94.7 % specificity, and 93.3 % accuracy. Nine (69.2 %) of the 13 A-2 group participants and 11 (5.3 %) A-1 group participants had a risk for gastric cancer according to radiological findings. CONCLUSION: A good correlation exists between ABC classifications and radiological findings for gastric cancer risk, but some discrepant cases exist. We recommend both methods as screening for gastric cancer. PMID- 26251238 TI - Do not judge a cell by its cover--diversity of CNS resident, adjoining and infiltrating myeloid cells in inflammation. AB - Specialized populations of tissue-resident myeloid cells inhabit every organ of the body. While many of these populations appear similar morphologically and phenotypically, they exhibit great functional diversity. The central nervous system (CNS), as an immune privileged organ, possesses a unique tissue-resident macrophage population, the microglia, as well as numerous myeloid cell subsets at its boarders and barriers in CNS-adjoining tissues, namely the meninges, the perivascular space, and the choroid plexus. Recent research has added much to our knowledge about microglia, whereas the populations of CNS-surrounding phagocytes are just starting to be appreciated. As guardians of CNS homeostasis, these myeloid cells perform immune surveillance and immune modulatory tasks in health and disease. As such, microglia and CNS-surrounding antigen-presenting cells have been shown to be crucially involved not only in the initiation and progression but also resolution of multiple sclerosis (MS). MS and its rodent model, experimental autoimmune encephalomyelitis, are autoimmune inflammatory demyelinating CNS pathologies. While some crucial aspects of the disease pathogenesis have been solved, much of the complex involvement and interplay of the innate immune compartment remains yet to be clarified. Here, we will discuss the current understanding of the scope of phenotypes and functions of myeloid cells involved in CNS neuroinflammation. PMID- 26251240 TI - CT measurement of splenic volume changes as a result of hypovolemic shock. AB - PURPOSE: To evaluate the changes in splenic volume during hypovolemic shock and after recovery by use of multidetector computed tomography (MDCT). MATERIALS AND METHODS: We investigated 22 cases who underwent MDCT during hypovolemic shock up to 3 h after presentation, compared the splenic volume with that after recovery, and evaluated the volume difference. We compared the volume ratio (recovery/shock) for two age groups: under 60 years (n = 10) and 60 years and over (n = 12). For cases (n = 10) undergoing CT examination twice after treatment, we compared the volume ratios by using the initial recovery CT and the second CT images. RESULTS: The average spleen volume in shock was 63 cm(3); under normal conditions it was 132 cm(3) (P < 0.001). The average volume ratio for groups under 60 years old was 2.34; for groups 60 years and over it was 2.05 (P = 0.051). The average volume ratio obtained by use of the initial post-recovery CT was 2.11; the ratio obtained by use of the second post-recovery CT was 2.16 (P = 0.386). CONCLUSIONS: Our results revealed that splenic volume was reduced during hypovolemic shock and rapidly increased after recovery. Splenic contraction is an important CT finding in shock. PMID- 26251242 TI - Dan Adams-Bugher Foundation Champion for Training and Collaboration. PMID- 26251241 TI - Cost-Utility Analysis of Mechanical Thrombectomy Using Stent Retrievers in Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Recently, 5 randomized controlled trials demonstrated the benefit of endovascular therapy compared with intravenous tissue-type plasminogen activator in acute stroke. Economic evidence evaluating stent retrievers is limited. We compared the cost-effectiveness of intravenous tissue-type plasminogen activator alone versus mechanical thrombectomy and intravenous tissue type plasminogen activator as a bridging therapy in eligible patients in the UK National Health Service. METHODS: A model-based cost-utility analysis was performed using a lifetime horizon. A Markov model was constructed and populated with probabilities, outcomes, and cost data from published sources, including 1 way and probabilistic sensitivity analysis. RESULTS: Mechanical thrombectomy was more expensive than intravenous tissue-type plasminogen activator, but it improved quality-adjusted life expectancy. The incremental cost per (quality adjusted life year) gained of mechanical thrombectomy over a 20 year period was $11 651 (L7061). The probabilistic sensitivity analysis demonstrated that thrombectomy had a 100% probability of being cost-effective at the minimum willingness to pay for a quality-adjusted life year commonly used in United Kingdom. CONCLUSIONS: Although the upfront costs of thrombectomy are high, the potential quality-adjusted life year gains mean this intervention is cost effective. This is an important factor for consideration in deciding whether to commission this intervention. PMID- 26251243 TI - Cavernous Sinus Thrombosis in Children: Imaging Characteristics and Clinical Outcomes. AB - BACKGROUND AND PURPOSE: Cavernous sinus thrombosis (CST) is a rare life threatening cerebrovascular disease known to cause carotid artery narrowing (CAN) and arterial ischemic stroke. The imaging features of CST and related complications have been reported in adults, but rarely in children. METHODS: We performed a retrospective review of children with imaging confirmed CST from 2003 to 2014, describing presenting symptoms, imaging findings, and treatment. RESULTS: Ten patients with CST were identified. All had CAN and 6 of 10 developed infarcts. Of 8 patients treated with anticoagulation therapy, 3 developed new infarcts. None required discontinuation of anticoagulation therapy because of bleeding. Visual impairment secondary to infectious neuritis was common. Imaging characteristics include cavernous sinus expansion, filling defects, restricted diffusion, arterial wall enhancement, empyema, superior ophthalmic vein enlargement and thrombosis, orbital cellulitis, and pituitary inflammation. CAN resolved in 60% of cases. Outcomes were mostly good, with a modified Rankin Scale score of <=1 for 7 of 10 patients at discharge and 1 death. CONCLUSIONS: CAN and infarcts were common in this modest cohort of children with CST. Despite the high incidence of CAN and infarction, outcomes were often favorable. Although this is the largest cohort of childhood CST reported to date, large multicenter cohorts are needed to confirm our findings and determine the preferred therapeutic strategies for childhood CST. PMID- 26251245 TI - Letter by Spence Regarding Article, "Diet and Stroke: Recent Evidence Supporting a Mediterranean-Style Diet and Food in the Primary Prevention of Stroke". PMID- 26251244 TI - Safety and Tolerability of Desmoteplase Within 3 to 9 Hours After Symptoms Onset in Japanese Patients With Ischemic Stroke. AB - BACKGROUND AND PURPOSE: This study investigated the safety and tolerability of desmoteplase administered within 3 to 9 hours after stroke symptoms onset in Japanese patients with acute ischemic stroke. METHODS: Patients were randomized to treatment with either desmoteplase or placebo in a 2:1 ratio in 2 consecutive cohorts (70 MUg/kg and then 90 MUg/kg). Included patients had a baseline National Institutes of Health Stroke Scale score of 4 to 24 and occlusion or high-grade stenosis in the middle cerebral artery segment M1 or M2 on magnetic resonance angiography. The incidence of symptomatic intracranial hemorrhage (<=72 hours) was defined as the primary end point. The occurrence of asymptomatic ICH, symptomatic cerebral edemas, and adverse events were other safety outcomes of special interest. RESULTS: Symptomatic intracranial hemorrhage was observed within 72 hours in 2 patients treated with placebo and in 1 patient treated with 70 MUg/kg desmoteplase. Any ICH (symptomatic or asymptomatic ICH) within 72 hours were observed in 7 (43.8%) patients treated with placebo, in 8 (50%) patients treated with 70 MUg/kg desmoteplase, and in 9 (56.3%) patients treated with 90 MUg/kg desmoteplase. Desmoteplase treatment with 70 or 90 MUg/kg was not associated with an increased risk of symptomatic cerebral edema compared with placebo. There were no other serious safety concerns associated with desmoteplase. CONCLUSIONS: Desmoteplase in both 70 and 90 MUg/kg doses had a favorable safety profile and was well tolerated in Japanese patients with acute ischemic stroke when administered 3 to 9 hours after stroke symptoms onset. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01104467. PMID- 26251246 TI - Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage. AB - BACKGROUND AND PURPOSE: Inflammatory responses and blood-brain barrier (BBB) dysfunction play important roles in brain injury after intracerebral hemorrhage (ICH). The metalloprotease ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type I motif, member 13) was shown to limit inflammatory responses through its proteolytic effects on von Willebrand factor. In the present study, we addressed the role of ADAMTS 13 after experimental ICH. METHODS: ICH was induced in mice by intracerebral infusion of autologous blood. The peri-hematomal inflammatory responses, levels of matrix metalloproteinase-9 and intercellular adhesion molecule-1, pericyte coverage on brain capillaries, and BBB permeability were quantified at 24 hours. Functional outcomes, cerebral edema, and hemorrhagic lesion volume were quantified at day 3. RESULTS: Treatment with recombinant ADAMTS 13 (rADAMTS 13) reduced the levels of chemokines and cytokines, myeloperoxidase activity, and microglia activation and neutrophil recruitment after ICH. rADAMTS 13 also decreased interleukin-6 expression in brain endothelial cells stimulated by lipopolysaccharide, whereas recombinant von Willebrand factor reversed this effect. The anti-inflammatory effect of rADAMTS 13 was accompanied by reduced expression of intercellular adhesion molecule-1 and less activation of matrix metalloproteinase, enhanced pericyte coverage of brain microvessels, and attenuated BBB disruption. Furthermore, neutrophil depletion protected against BBB damage, and rADAMTS 13 treatment had no further beneficial effect. Finally, treatment of mice with rADAMTS 13 reduced cerebral edema and hemorrhagic lesion volume and improved neurological functions. CONCLUSIONS: Our findings reveal the importance of rADAMTS 13 in regulating pathological inflammation and BBB function and suggest that rADAMTS 13 may provide a new therapeutic strategy for ICH. PMID- 26251247 TI - Remote Ischemic Conditioning Alters Methylation and Expression of Cell Cycle Genes in Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND AND PURPOSE: Remote ischemic conditioning (RIC) is a phenomenon in which short periods of nonfatal ischemia in 1 tissue confers protection to distant tissues. Here we performed a longitudinal human pilot study in patients with aneurysmal subarachnoid hemorrhage undergoing RIC by limb ischemia to compare changes in DNA methylation and transcriptome profiles before and after RIC. METHODS: Thirteen patients underwent 4 RIC sessions over 2 to 12 days after rupture of an intracranial aneurysm. We analyzed whole blood transcriptomes using RNA sequencing and genome-wide DNA methylomes using reduced representation bisulfite sequencing, both before and after RIC. We tested differential expression and differential methylation using an intraindividual paired study design and then overlapped the differential expression and differential methylation results for analyses of functional categories and protein-protein interactions. RESULTS: We observed 164 differential expression genes and 3493 differential methylation CpG sites after RIC, of which 204 CpG sites overlapped with 103 genes, enriched for pathways of cell cycle (P<3.8*10(-4)) and inflammatory responses (P<1.4*10(-4)). The cell cycle pathway genes form a significant protein-protein interaction network of tightly coexpressed genes (P<0.00001). CONCLUSIONS: Gene expression and DNA methylation changes in aneurysmal subarachnoid hemorrhage patients undergoing RIC are involved in coordinated cell cycle and inflammatory responses. PMID- 26251248 TI - Clipping and Coiling of Unruptured Intracranial Aneurysms Among Medicare Beneficiaries, 2000 to 2010. AB - BACKGROUND AND PURPOSE: Endovascular coiling therapy is increasingly popular for obliteration of unruptured intracranial aneurysms, but older patients face higher procedural risks and shorter periods during which an untreated aneurysm may rupture causing subarachnoid hemorrhage (SAH). We assessed trends in clipping and coiling of unruptured intracranial aneurysms, outcomes after clipping and coiling of unruptured intracranial aneurysms, and in SAH among Medicare beneficiaries. METHODS: Using 2000 to 2010 Medicare Provider Analysis and Review data, we identified 2 cohorts of patients admitted electively for clipping or coiling of an unruptured aneurysm: (1) utilization cohort (2000-2010): patients >=65 years enrolled >=1 month in a given year and (2) outcomes cohort (2001-2010): patients >=66 years of age enrolled in Medicare for >=1 year. We calculated rates of clipping, coiling, and SAH per 100 000 Medicare beneficiaries. We tested for trends in the risk of in-hospital mortality and complications, discharge destination, 30-day mortality, 30-day readmissions, and length of hospitalization. RESULTS: Characteristics of patients undergoing clipping (n=4357) or coiling (n=7942) did not change appreciably. Overall, 30-day mortality, in-hospital complications, and 30-day readmissions decreased, generally reaching their lowest levels in 2008 to 2010 (1.6%, 25.0%, and 14.5% for clipping and 1.5%, 13.8%, and 11.0% for coiling, respectively). Procedural treatment rates per 100 000 beneficiaries increased from 1.4 in 2000 to 6.0 in 2010, driven mainly by increased use of coiling but SAH rates did not decrease. CONCLUSIONS: Although outcomes tended to improve over time, increased preventative treatment of unruptured intracranial aneurysms among Medicare beneficiaries did not result in a population-level decrease in SAH rates. PMID- 26251249 TI - Patients With Ischemic Stroke and Incident Atrial Fibrillation: A Nationwide Cohort Study. AB - BACKGROUND AND PURPOSE: A substantial part of ischemic strokes is attributed to atrial fibrillation (AF). We hypothesized that patients with ischemic stroke without prior diagnosed AF were at higher risk of having a subsequent diagnosis of AF, and this was associated with multiple risk factors. METHODS: This French longitudinal cohort study was based on the national database covering hospital care from 2008 to 2012 for the entire population. RESULTS: Of 65 807 patients with ischemic stroke in 2009, 48 992 did not have AF at baseline. A total of 4828 of these patients were diagnosed as having AF during a follow-up of 15+/-15 months (incidence rate 7.9 per 100 person-years). By comparison, the yearly rate of new-onset AF for the 826 416 patients with a cardiac hospitalization was 5.9%. CHADS2 (congestive heart failure, hypertension, age >=75 years, diabetes mellitus, stroke/transient ischemic attack) and CHA2DS2-VASc (congestive heart failure, hypertension, age >=75 years, diabetes mellitus, stroke/transient ischemic attack [doubled], vascular disease, age 65-75 years, and sex category [female]) scores were both associated with the risk of new-onset AF during follow up (CHADS2: hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.66-1.75; CHA2DS2-VASc: HR 1.45, 95% CI 1.42-1.48). The c statistics were 0.700 (95% CI 0.696-0.706) for CHADS2 and 0.706 (95% CI 0.702-0.710) with CHA2DS2-VASc (P=0.003 for comparison of the 2 scores). Independent predictors of subsequent diagnosis of AF were age 65 to 74 years (HR 2.29, 95% CI 2.06-2.54), age >=75 years (HR 3.31, 95% CI 3.02-3.64), hypertension (HR 1.22, 95% CI 1.13-1.32), heart failure (HR 2.56, 95% CI 2.41-2.72), and vascular disease (HR 1.10, 95% CI 1.04-1.17). CONCLUSIONS: Ischemic stroke was associated with a substantially increased risk of incident AF, particularly among individuals with higher CHADS2 or CHA2DS2-VASc scores. These risk scores seem to be simple tools for identifying patients at higher risk of incident AF after ischemic stroke. PMID- 26251250 TI - Intracranial Carotid Calcification on Cranial Computed Tomography: Visual Scoring Methods, Semiautomated Scores, and Volume Measurements in Patients With Stroke. AB - BACKGROUND AND PURPOSE: Intracranial internal carotid artery calcification is associated with cerebrovascular risk factors and stroke, but few quantification methods are available. We tested the reliability of visual scoring, semiautomated Agatston score, and calcium volume measurement in patients with recent stroke. METHODS: We used scans from a prospective hospital stroke registry and included patients with anterior circulation ischemic stroke or transient ischemic stroke whose noncontrast cranial computed tomographic scans were available electronically. Two raters measured semiautomatic quantitative Agatston score, and calcium volume, and performed qualitative visual scoring using the original 4 point Woodcock score and a modified Woodcock score, where each image on which the internal carotid arteries appeared was scored and the slice scores summed. RESULTS: Intra- and interobserver coefficient of variations were 8.8% and 16.5% for Agatston, 8.8% and 15.5% for calcium volume, and 5.7% and 5.4% for the modified Woodcock visual score, respectively. The modified Woodcock visual score correlated strongly with both Agatston and calcium volume quantitative measures (both R(2)=0.84; P<0.0001); calcium volume increased by 0.47-mm/point increase in modified Woodcock visual score. Intracranial internal carotid artery calcification increased with age by all measures (eg, visual score, Spearman rho=0.4; P=0.005). CONCLUSIONS: Visual scores correlate highly with quantitative intracranial internal carotid artery calcification measures, with excellent observer agreements. Visual intracranial internal carotid artery scores could be a rapid and practical method for epidemiological studies. PMID- 26251251 TI - Do Patient Characteristics Explain the Differences in Outcome Between Medically Treated Patients in SAMMPRIS and WASID? AB - BACKGROUND AND PURPOSE: The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) medical group had a much lower primary end point rate than predicted from the preceding Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial. This result has been attributed to the aggressive medical therapy used in SAMMPRIS, but an alternative hypothesis is that SAMMPRIS patients were at lower risk. We undertook analyses to evaluate these competing hypotheses. METHODS: Using proportional hazards regression, we compared the SAMMPRIS primary end point between SAMMPRIS medical patients and WASID patients meeting the same qualifying criteria adjusted for confounding baseline characteristics. RESULTS: The unadjusted comparison of the SAMMPRIS primary end point showed a significantly higher risk for WASID patients (P=0.009, logrank test) with 12 month Kaplan-Meier estimates of 21.9% in WASID and 12.6% in SAMMPRIS and hazard ratio 1.9 (95% confidence interval =1.2-3.0). The analyses identified the following confounding factors that varied between the studies and that conferred a higher risk: lack of statin use at enrollment (hazard ratio =1.8, 95% confidence interval =1.1-2.9, P=0.027) that was more prevalent among WASID patients (39% versus 14%, P<0.0001) and prior infarcts in the territory of the symptomatic vessel (hazard ratio =1.8, 95% confidence interval =1.1-2.9, P=0.023) that was more prevalent among SAMMPRIS patients (34% versus 22%, P=0.015).The hazard ratio for WASID versus SAMMPRIS adjusted for these 2 characteristics was 1.9 (95% confidence interval =1.1-3.2). CONCLUSIONS: After adjustment for confounding baseline characteristics, WASID patients had an almost 2-fold higher risk of the SAMMPRIS primary end point, which supports the hypothesis that the lower rate of the primary end point in the medical arm of SAMMPRIS compared with WASID patients was as a result of the aggressive medical management used in SAMMPRIS. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00576693. PMID- 26251252 TI - Younger Stroke Patients With Large Pretreatment Diffusion-Weighted Imaging Lesions May Benefit From Endovascular Treatment. AB - BACKGROUND AND PURPOSE: Lesion volume on diffusion-weighted magnetic resonance imaging (DWI) before acute stroke therapy is a predictor of outcome. Therefore, patients with large volumes are often excluded from therapy. The aim of this study was to analyze the impact of endovascular treatment in patients with large DWI lesion volumes (>70 mL). METHODS: Three hundred seventy-two patients with middle cerebral or internal carotid artery occlusions examined with magnetic resonance imaging before treatment since 2004 were included. Baseline data and 3 months outcome were recorded prospectively. DWI lesion volumes were measured semiautomatically. RESULTS: One hundred five patients had lesions >70 mL. Overall, the volume of DWI lesions was an independent predictor of unfavorable outcome, survival, and symptomatic intracerebral hemorrhage (P<0.001 each). In patients with DWI lesions >70 mL, 11 of 31 (35.5%) reached favorable outcome (modified Rankin scale score, 0-2) after thrombolysis in cerebral infarction 2b-3 reperfusion in contrast to 3 of 35 (8.6%) after thrombolysis in cerebral infarction 0-2a reperfusion (P=0.014). Reperfusion success, patient age, and DWI lesion volume were independent predictors of outcome in patients with DWI lesions >70 mL. Thirteen of 66 (19.7%) patients with lesions >70 mL had symptomatic intracerebral hemorrhage with a trend for reduced risk with avoidance of thrombolytic agents. CONCLUSIONS: There was a growing risk for poor outcome and symptomatic intracerebral hemorrhage with increasing pretreatment DWI lesion volumes. Nevertheless, favorable outcome was achieved in every third patient with DWI lesions >70 mL after successful endovascular reperfusion, whereas after poor or failed reperfusion, outcome was favorable in only every 12th patient. Therefore, endovascular treatment might be considered in patients with large DWI lesions, especially in younger patients. PMID- 26251254 TI - Activation of Dopamine D2 Receptor Suppresses Neuroinflammation Through alphaB Crystalline by Inhibition of NF-kappaB Nuclear Translocation in Experimental ICH Mice Model. AB - BACKGROUND AND PURPOSE: Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)-induced secondary brain injury. Recently, dopamine D2 receptor (DRD2) is identified as an important component controlling innate immunity and inflammatory response in central nervous system, and alphaB crystallin (CRYAB) is a potent negative regulator on inflammatory pathways. Here, we sought to investigate the role of DRD2 on neuroinflammation after experimental ICH and the potential mechanism mediated by CRYAB. METHODS: Two hundred and twenty-four (224) male CD-1 mice were subjected to intrastriatal infusion of bacterial collagenase or autologous blood. Two DRD2 agonists quinpirole and ropinirole were administrated by daily intraperitoneal injection starting at 1 hour after ICH. DRD2 and CRYAB in vivo knockdown was performed 48 hours before ICH insult. Behavioral deficits and brain water content, Western blots, immunofluorescence staining, coimmunoprecipitation (Co-IP) assay, and proteome cytokine array were evaluated. RESULTS: Endogenous DRD2 and CRYAB expressions were increased after ICH. DRD2 knockdown aggravated the neurobehavioral deficits and the pronounced cytokine expressions. DRD2 activation by quinpirole and ropinirole ameliorated neurological outcome, brain edema, interleukin-1beta, and monocyte chemoattractant protein-1 expression, as well as microglia/macrophages activation, in the perihematomal region. These effects were abolished by pretreatment with CRYAB siRNAs. Quinpirole enhanced cytoplasmic binding activity between CRYAB and NF-kappaB and decreased nuclear NF-kappaB expression. Similar therapeutic benefits were observed using autologous blood injection model and intranasal delivery of quinpirole. CONCLUSIONS: DRD2 may have anti-inflammatory effects after ICH. DRD2 agonists inhibited neuroinflammation and attenuated brain injury after ICH, which is probably mediated by CRYAB and enhanced cytoplasmic binding activity with NF-kappaB. PMID- 26251255 TI - Copeptin Levels in Patients With Acute Ischemic Stroke and Stroke Mimics. AB - BACKGROUND AND PURPOSE: Copeptin levels are increased in patients diagnosed with stroke and other vascular diseases. Copeptin elevation is associated with adverse outcome, predicts re-events in patients with transient ischemic attack and is used in ruling-out acute myocardial infarction. We evaluated whether copeptin can also be used as a diagnostic marker in the prehospital stroke setting. METHODS: We prospectively examined patients with suspected stroke on the Stroke Emergency Mobile-an ambulance that is equipped with computed tomography and point-of-care laboratory. A blood sample was taken from patients immediately after arrival. We analyzed copeptin levels in patients with final hospital-based diagnosis of stroke or stroke mimics as well as in vascular or nonvascular patients. In addition, we examined the associations of symptom onset with copeptin levels and the prognostic value of copeptin in patients with stroke. RESULTS: Blood samples of 561 patients were analyzed. No significant differences were seen neither between cerebrovascular (n=383) and other neurological (stroke mimic; n=90) patients (P=0.15) nor between vascular (n=391) and nonvascular patients (n=170; P=0.57). We could not detect a relationship between copeptin levels and time from onset to blood draw. Three-month survival status was available in 159 patients with ischemic stroke. Copeptin levels in nonsurviving patients (n=8: median [interquartile range], 27.4 [20.2-54.7] pmol/L) were significantly higher than in surviving patients (n=151: median [interquartile range], 11.7 [5.2-30.9] pmol/L; P=0.024). CONCLUSIONS: In the prehospital setting, copeptin is neither appropriate to discriminate between stroke and stroke mimic patients nor between vascular and nonvascular patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01382862. The Pre-Hospital Acute Neurological Therapy and Optimization of Medical Care in Stroke Patients study (PHANTOM-S) was registered (NCT01382862). This sub-study was observational and not registered separately, therefore. PMID- 26251256 TI - Using research and education to implement practical bed bug control programs in multifamily housing. AB - Multifamily housing facilities serving low-income populations have been at the forefront of bed bug outbreaks. Research conducted in the past 8 years has consistently proven that integrated pest management (IPM) is the best approach for successful suppression of bed bug infestations. Bed bug IPM in multifamily settings is especially dependent upon a collaborative community or building-wide effort involving residents, building staff and pest control technicians. Other components of a bed bug IPM program include regular monitoring to detect early stage bed bug infestations and combined use of non-chemical and chemical interventions. Lastly, to reduce reinfestation rates and costs associated with bed bug control, it is critical to continue periodic monitoring and implement preventive control measures even after successful elimination of bed bugs has been achieved. PMID- 26251257 TI - Non-ablative fractional resurfacing in the treatment of scar contracture. AB - BACKGROUND AND OBJECTIVES: A 28-year-old female presented with extensive scarring after a traumatic injury to her right lower extremity. She had been hit by a vehicle one year prior to presentation and had several open fractures with extensive overlying cutaneous damage, which required multiple surgeries and skin grafts. She had limited range of motion of the affected limb secondary to scar contracture. STUDY DESIGN/MATERIALS AND METHODS: The patient received 6 treatments with a non-ablative fractional resurfacing (NAFR) device with two wavelengths (Fraxel DUAL, Solta Medical, Hayward, CA) spaced 4-8 weeks apart. The patient received two treatments with the 1927 nm NAFR thulium laser (10 mJ, 30% density, 8 passes) and two treatments with the 1550 nm NAFR laser (40 mJ, 17-26% density, 8 passes). Before and after treatment photographs were taken, as well as range of motion measurements with respect to her right ankle. RESULTS: The patient had 50-75% improvement in the texture and discoloration. There was both subjective and objective improvement in the range of motion of her right lower extremity. The patient experienced mild erythema and edema, both of which resolved after 7-10 days. CONCLUSION: Recent studies have shown great functional improvement in scar contractures with ablative fractional laser treatments; however, these treatments are accompanied by significant downtime along with risk of further scarring and infection. NAFR is an accessible treatment with a low side effect profile and to our knowledge has not been reported as efficacious in the treatment of scar contracture. This case report is novel in its demonstration of the utility of a dual wavelength NAFR in the treatment of scar contracture and functional impairment. PMID- 26251258 TI - Anti-Helicobacter pylori Antibody Profiles in Epstein-Barr virus (EBV)-Positive and EBV-Negative Gastric Cancer. AB - BACKGROUND: Helicobacter pylori is the primary cause of gastric cancer, but about 9% of cases harbor Epstein-Barr virus (EBV) in the tumor cells. There is limited evidence on the possible interaction or antagonism between these infectious agents in gastric carcinogenesis. METHODS: We compared H. pylori serologic profiles of EBV-positive (n = 58) and EBV-negative (n = 111) noncardia gastric cancer patients from the United States National Cancer Institute's International EBV-Gastric Cancer Consortium. EBV positivity of tumors was assessed by in situ hybridization. Serum levels of 15 antibodies to immunogenic proteins of H. pylori (Cad, CagA, Cagdelta, CagM, Catalase, GroEL, HcpC, HP0231, HP0305, HpaA, HyuA, NapA, Omp, UreA, VacA) were assessed using bead-based multiplex serology. Logistic regression models were used to adjust odds ratios (OR) for country, age, sex, and year of diagnosis. RESULTS: Seropositivity to individual proteins ranged up to 90% overall. Antibodies to Catalase were borderline associated with tumor EBV positivity (adjusted OR = 3.15, p = .0024, Bonferroni corrected p = .036). Distributions of other antibodies did not vary by tumor EBV status. CONCLUSION: Similarity of host-response indicates the essential etiological role of H. pylori in EBV-positive gastric cancer. PMID- 26251259 TI - Modelling Hospitalisation Ratios for Febrile Convulsions and Severe Varicella Under Combined Measles, Mumps, Rubella, and Varicella (MMRV-Priorix-TetraTM) Compared to Separate MMR + V Vaccination. AB - INTRODUCTION: Measles, mumps, rubella, and varicella combination vaccines (MMRV) facilitate varicella vaccination uptake compared with separate administration of measles, mumps, and rubella vaccine (MMR) with varicella vaccine (V). However, the risk of developing febrile convulsions (FC) is higher in children vaccinated with MMRV. OBJECTIVES: The aim was to demonstrate how to put the increased FC risk associated with MMRV into perspective by comparing it with the lower V coverage risk associated with MMR + V. METHODS: FC and varicella burdens were measured by total numbers or duration of hospitalisations. A model, based on several assumptions and integrating parameters from heterogeneous data sources relevant to Germany, was developed to evaluate hospitalisation ratios (HRs; ratios between yearly numbers of varicella-related hospitalisation days prevented by MMRV and yearly numbers of FC-related hospitalisation days attributed to MMRV, both compared with MMR + V). A sensitivity analysis estimated HR under different scenarios beyond the German experience. RESULTS: For parameter values compatible with the German experience, where MMRV (Priorix-TetraTM, GSK, Belgium) was introduced in 2006, the model predicted that transitioning from MMR + V to MMRV would induce 225 vaccine-related FC hospitalisation days whilst preventing 1976 varicella-related hospitalisation days per year. The HR estimated by Monte Carlo simulations was 8.5 (95 % confidence interval: 1.99-25.22). A sensitivity analysis on two key parameters suggested that transitioning from MMR + V to MMRV would be favourable in situations where MMRV use would significantly impact varicella vaccination uptake. CONCLUSIONS: MMRV use instead of MMR + V can substantially reduce the number of hospitalisation days, despite increased FC risk when MMRV is used as a first dose of measles-containing vaccine. PMID- 26251260 TI - Circulation stabilizing therapy and pulmonary high-resolution computed tomography in a porcine brain-dead model. AB - BACKGROUND: Currently 80% of donor lungs are not accepted for transplantation, often due to fluid overload. Our aim was to investigate if forced fluid infusion may be replaced by a new pharmacological therapy to stabilize circulation after brain death in an animal model, and to assess therapy effects on lung function and morphology trough blood gas parameters and state-of-the-art High-resolution CT (HRCT). METHODS: Brain death was caused by surgical decapitation. To maintain mean aortic pressure > 60 mmHg, pigs were treated with forced electrolyte solution infusion (GI; n = 6) or the pharmacological therapy (GII; n = 11). GIII (n = 11) were non-decapitated controls. Lung function was investigated with blood gases and lung morphology with HRCT. RESULTS: GI pigs became circulatory instable 4-6 h after brain death in spite of forced fluid infusion, five pigs showed moderate to severe pulmonary edema on HRCT and median final PaO2 /FiO2 was 29 kPa (Q1; Q3; range 26; 40; 17-76). GII and GIII were circulatory stable (mean aortic pressure > 80 mmHg) and median final PaO2 /FiO2 after 24 h was 72 kPa (Q1; Q3; range 64; 76; 53-91) (GII) and 66 kPa (55; 78; 43-90) (GIII). On HRCT, only two pigs in GII had mild pulmonary edema and none in GIII. More than 50% of HRCT exams revealed unexpected lung disease even in spite of PaO2 /FiO2 > 40 kPa. CONCLUSION: Pharmacological therapy but not forced fluid infusion prevented circulatory collapse and extensive HRCT verified pulmonary edema after acute brain death. HRCT was useful to evaluate lung morphology and revealed substantial occult parenchymal changes justifying efforts toward a more intense use of HRCT in the pre-transplant evaluation. PMID- 26251261 TI - Prognostic role of genetic biomarkers in clinical progression of prostate cancer. AB - The aim of this study was to analyze the use of 12 single-nucleotide polymorphisms in genes ELAC2, RNASEL and MSR1 as biomarkers for prostate cancer (PCa) detection and progression, as well as perform a genetic classification of high-risk patients. A cohort of 451 men (235 patients and 216 controls) was studied. We calculated means of regression analysis using clinical values (stage, prostate-specific antigen, Gleason score and progression) in patients and controls at the basal stage and after a follow-up of 72 months. Significantly different allele frequencies between patients and controls were observed for rs1904577 and rs918 (MSR1 gene) and for rs17552022 and rs5030739 (ELAC2). We found evidence of increased risk for PCa in rs486907 and rs2127565 in variants AA and CC, respectively. In addition, rs627928 (TT-GT), rs486907 (AG) and rs3747531 (CG-CC) were associated with low tumor aggressiveness. Some had a weak linkage, such as rs1904577 and rs2127565, rs4792311 and rs17552022, and rs1904577 and rs918. Our study provides the proof-of-principle that some of the genetic variants (such as rs486907, rs627928 and rs2127565) in genes RNASEL, MSR1 and ELAC2 can be used as predictors of aggressiveness and progression of PCa. In the future, clinical use of these biomarkers, in combination with current ones, could potentially reduce the rate of unnecessary biopsies and specific treatments. PMID- 26251263 TI - Prenatal ethanol exposure impairs spatial cognition and synaptic plasticity in female rats. AB - Chronic prenatal ethanol exposure (CPEE) can impair long-term potentiation (LTP) in the male hippocampus. Sexually specific alterations were frequently reported in female animals that had been prenatally exposed to ethanol. This study aimed to examine the effects of CPEE on spatial learning and memory, as well as on hippocampal synaptic plasticity in female adolescent rats. Female offspring were selected from dams that had been exposed to 4 g/kg/day of ethanol throughout the gestational period. Subsequently, performance in the Morris water maze (MWM) was determined, while LTP and depotentiation were measured in the hippocampal CA3-CA1 pathway. In the behavioral test, the escape latencies in both initial and reversal training stages were significantly prolonged. Interestingly, LTP was considerably enhanced while depotentiation was significantly depressed. Our results suggest a critical role of synaptic plasticity balance, which may prominently contribute to the cognitive deficits present in CPEE offspring. PMID- 26251264 TI - Determination of Human Chorionic Gonadotropin in Postmortem Samples in Ectopic Pregnancies. AB - Increased human chorionic gonadotropin levels (HCG) can be detected in femoral blood, bile, and vitreous humor collected during autopsy of pregnant women using a standard kit designed for living patients. In the study herein, the concentrations of HCG were measured in postmortem serum, vitreous, bile, cerebrospinal, and pericardial fluids in 4 cases of fatal ectopic pregnancy and 40 controls using a quantitative electrochemiluminescence immunoassay designed for living patients. No false-negative cases were identified in any of the analyzed samples in any of the ectopic pregnancy cases. No correlations were found between total HCG levels in postmortem serum and the other tested specimens. The results of this study would suggest that higher HCG in bile, vitreous, pericardial, and cerebrospinal fluids may confirm the existence of ectopic pregnancy and therefore identify other situations in which this hormone is increased, although gestational age cannot be reliably estimated using these values. PMID- 26251262 TI - Research Review: Executive function deficits in fetal alcohol spectrum disorders and attention-deficit/hyperactivity disorder - a meta-analysis. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD)-like symptoms are common in fetal alcohol spectrum disorders (FASD). FASD and ADHD groups both display executive function impairments; however, there is ongoing debate whether the pattern and magnitude of executive function deficits differs between these two types of disorders. METHODS: An electronic literature search was conducted (PubMed, PsychInfo; 1972-2013) to identify studies comparing the executive functioning of children with FASD with ADHD or control groups. FASD groups included those with and without dysmorphy (i.e., FAS, pFAS, ARND, and other FASD diagnoses). Effect sizes (Hedges' g, standardized mean difference) were calculated. Random effects meta-analytic models were performed using the metafor package for R. RESULTS: Fifty-one studies met inclusion criteria (FASD N = 2,115; ADHD N = 453; controls N = 1,990). Children with FASD showed the strongest and most consistent deficits in planning, fluency, and set-shifting compared to controls (Hedges' g = -0.94, -0.78) and children with ADHD (Hedges' g = -0.72, 0.32). FASD was associated with moderate to large impairments in working memory, compared to controls (Hedges' g = -.84, -.58) and small impairments relative to groups with ADHD (Hedges' g = -.26). Smaller and less consistent deficits were found on measures of inhibition and vigilance relative to controls (Hedges' g = 0.52, -0.31); FASD and ADHD were not differentiated on these measures. Moderator analyses indicated executive dysfunction was associated with older age, dysmorphy, and larger group differences in IQ. Sex and diagnostic system were not consistently related to effect size. CONCLUSIONS: While FASD is associated with global executive impairments, executive function weaknesses are most consistent for measures of planning, fluency, and set-shifting. Neuropsychological measures assessing these executive function domains may improve differential diagnosis and treatment of FASD. PMID- 26251265 TI - 1alpha,25-dihydroxyvitamin D3 acts via transforming growth factor-beta to up regulate expression of immunosuppressive CD73 on human CD4+ Foxp3- T cells. AB - Vitamin D deficiency is associated with increased incidence and severity of various immune-mediated diseases. Active vitamin D (1alpha,25-dihydroxyvitamin D3; 1,25(OH)2 D3) up-regulates CD4(+) T-cell expression of the purine ectonucleotidase CD39, a molecule that is associated with the generation of anti inflammatory adenosine. Here we aimed to investigate the direct impact of 1,25(OH)2 D3 on expression of the downstream ecto-5'-nucleotidase CD73 by human CD4 T cells, and components of the transforming growth factor-beta (TGF-beta) pathway, which have been implicated in the modulation of CD73 by murine T cells. At 10(-8) to 10(-7) m, 1,25(OH)2 D3 significantly increased expression of CD73 on peripheral human CD4(+) T cells. Although 1,25(OH)2 D3 did not affect the mRNA expression of latent TGF-beta1 , 1,25(OH)2 D3 did up-regulate expression of TGF beta-associated molecules [latency-associated peptide (LAP), glycophorin A repetitions predominant (GARP), GP96, neuropilin-1, thrombospondin-1 and alphav integrin] which is likely to have contributed to the observed enhancement in TGF beta bioactivity. CD73 was highly co-expressed with LAP and GARP following 1,25(OH)2 D3 treatment, but unexpectedly, each of these cell surface molecules was expressed primarily on CD4(+) Foxp3(-) T cells, rather than CD4(+) Foxp3(+) T cells. Notably, neutralization of TGF-beta significantly impaired 1,25(OH)2 D3 mediated induction of CD73. Collectively, we show that 1,25(OH)2 D3 enhances expression of CD73 on CD4(+) Foxp3(-) T cells in a process that is at least partially TGF-beta-dependent. These data reveal an additional contributing mechanism by which vitamin D may be protective in immune-mediated disease. PMID- 26251266 TI - [Cerebral venous thrombosis: Case report and clinical procedures]. AB - Cerebral venous and dural sinuses thrombosis (CVT) is a relatively rare but very serious disease, because of the risk of mortality. Cardinal symptoms are usually severe sudden-onset localized headaches, which may or not be accompanied by focal or generalized neurological deficits or seizures. It is particularly important to consider CVT in the presence of underlying prothrombotic conditions (genetically predisposed or acquired defects of the coagulation system) or well-known risk factors (hormonal contraception, pregnancy, puerperium, smoker status). Based on clinical findings, diagnosis is established using neuroimaging (MRI and MR venography, CT and CT venography) and D-dimer measurement. In the case of early diagnosis and onset of antithrombotic treatment, the prognosis is good. Otherwise there is a high risk of irreversible neurological deficits or even mortality. In daily clinical routine, where many patients present with similar or unspecific symptoms-most of which are harmless-it is thus particularly important that CVT be considered in the differential diagnosis. PMID- 26251267 TI - Microbial ecosystems are dominated by specialist taxa. AB - Abundance and specificity are two key characteristics of species distribution and biodiversity. Theories of species assembly aim to reproduce the empirical joint patterns of specificity and abundance, with the goal to explain patterns of biodiversity across habitats. The specialist-generalist paradigm predicts that specialists should have a local advantage over generalists and thus be more abundant. We developed a specificity index to analyse abundance-specificity relationships in microbial ecosystems. By analysing microbiota spanning 23 habitats from three very different data sets covering a wide range of sequencing depths and environmental conditions, we find that habitats are consistently dominated by specialist taxa, resulting in a strong, positive correlation between abundance and specificity. This finding is consistent over several levels of taxonomic aggregation and robust to errors in abundance measures. The relationship explains why shallow sequencing captures similar beta-diversity as deep sequencing, and can be sufficient to capture the habitat-specific functions of microbial communities. PMID- 26251277 TI - A retrospective review of required projects in systems-based practice in a single anesthesiology residency: a 10-year experience. AB - STUDY OBJECTIVE: The Accreditation Council for Graduate Medical Education has emphasized in its core competencies and more recently, in its Milestones Project, that residents understand the importance of systems-based practice (SBP). The objectives of the study are to evaluate the quality of residents' SBP projects and to determine the degrees that were subsequently implemented. DESIGN: A retrospective educational observational study. SETTING: A university-based anesthesiology training institution. SUBJECTS: One hundred forty-nine anesthesiology residents in their final (postgraduate year 4) year of training who completed SBP projects for the last 10 years (2004-2013). INTERVENTIONS: A structured SBP course was provided for postgraduate year 4 anesthesiology residents with deadlines set such as project identification, data collection, and proposal draft. Each resident's written SBP proposal received inputs by 2 members of the department executive steering committee. The SBP projects concluded with oral presentations by each resident to the department executive steering committee, who provided overall scores. MEASUREMENTS: All SBP projects were categorized into 7 categories: safety initiatives, economic analysis, process analysis, policy change recommendations, education initiatives, teamwork/communication, and operating room efficiency. Evaluation scores using a Likert scale (1-9, where 9 is the best) were analyzed. The rate of implementation of project ideas within the department based on the presentations to the executive committee was examined. MAIN RESULTS: Of 149 projects, policy change recommendations was the most frequently chosen category (46 projects; 30.9%), followed by process analysis (36 projects; 24.2%). The overall evaluation score was 7.6 +/- 0.6 (mean +/- SD). A total of 53 projects (35.6%) were implemented in the department. There was no statistical difference between SBPs with implementation vs SBPs without implementation in terms of evaluation scores, year of the presentation, or categories. CONCLUSIONS: This SBP project has given residents the opportunity to participate in a hospital system change aiming to improve efficiency and safety. PMID- 26251276 TI - A global analysis of the complex landscape of isoforms and regulatory networks of p63 in human cells and tissues. AB - BACKGROUND: The transcription factor p63 belongs to the p53/p63/p73 family and plays key functional roles during normal epithelial development and differentiation and in pathological states such as squamous cell carcinomas. The human TP63 gene, located on chromosome 3q28 is driven by two promoters that generate the full-length transactivating (TA) and N-terminal truncated (DeltaN) isoforms. Furthermore alternative splicing at the C-terminus gives rise to additional alpha, beta, gamma and likely several other minor variants. Teasing out the expression and biological function of each p63 variant has been both the focus of, and a cause for contention in the p63 field. RESULTS: Here we have taken advantage of a burgeoning RNA-Seq based genomic data-sets to examine the global expression profiles of p63 isoforms across commonly utilized human cell lines and major tissues and organs. Consistent with earlier studies, we find DeltaNp63 transcripts, primarily that of the DeltaNp63alpha isoforms, to be expressed in most cells of epithelial origin such as those of skin and oral tissues, mammary glands and squamous cell carcinomas. In contrast, TAp63 is not expressed in the majority of normal cell-types and tissues; rather it is selectively expressed at moderate to high levels in a subset of Burkitt's and diffuse large B-cell lymphoma cell lines. We verify this differential expression pattern of p63 isoforms by Western blot analysis, using newly developed DeltaN and TA specific antibodies. Furthermore using unsupervised clustering of human cell lines, tissues and organs, we show that DeltaNp63 and TAp63 driven transcriptional networks involve very distinct sets of molecular players, which may underlie their different biological functions. CONCLUSIONS: In this study we report comprehensive and global expression profiles of p63 isoforms and their relationship to p53/p73 and other potential transcriptional co-regulators. We curate publicly available data generated in part by consortiums such as ENCODE, FANTOM and Human Protein Atlas to delineate the vastly different transcriptomic landscapes of DeltaNp63 and TAp63. Our studies help not only in dispelling prevailing myths and controversies on p63 expression in commonly used human cell lines but also augur new isoform- and cell type-specific activities of p63. PMID- 26251278 TI - A scale for evaluating the difficulty of tracheal tube passage though the glottis is needed; good laryngoscopy does not always ensure intubation success. PMID- 26251279 TI - Iowa Satisfaction with Anesthesia Scale for regional anesthesia. PMID- 26251280 TI - Non-classical MHC I-E negatively regulates macrophage activation and Th17 cell development in NOD mice. AB - Transgenic expression of I-E molecules prevents diabetes in NOD mice. So far, the precise role of these non-classical MHC II molecules remains elusive. Here, we showed that transgenic expression of I-E(k) alpha 16 molecule in NOD mice selectively reduced Th17 cells in the thymus and pancreatic draining lymph nodes. The reduction in Th17 cells was associated with both attenuated IL-6 production and decreased activation of macrophages. Mechanistically, transgenic expression of the I-E molecule diminished expression of intracellular classical MHC II molecule and led to impaired TLR4-mediated signaling. In contrast to classical MHC II molecule, this non-classical MHC II molecule negatively regulates the inflammatory responses of macrophages. Altogether, our study reveals a novel regulatory role of I-E molecules in modulating inflammatory immune responses. PMID- 26251281 TI - Risk Factors for Long-Term Coronary Artery Calcium Progression in the Multi Ethnic Study of Atherosclerosis. AB - BACKGROUND: Coronary artery calcium (CAC) detected by noncontrast cardiac computed tomography scanning is a measure of coronary atherosclerosis burden. Increasing CAC levels have been strongly associated with increased coronary events. Prior studies of cardiovascular disease risk factors and CAC progression have been limited by short follow-up or restricted to patients with advanced disease. METHODS AND RESULTS: We examined cardiovascular disease risk factors and CAC progression in a prospective multiethnic cohort study. CAC was measured 1 to 4 times (mean 2.5 scans) over 10 years in 6810 adults without preexisting cardiovascular disease. Mean CAC progression was 23.9 Agatston units/year. An innovative application of mixed-effects models investigated associations between cardiovascular disease risk factors and CAC progression. This approach adjusted for time-varying factors, was flexible with respect to follow-up time and number of observations per participant, and allowed simultaneous control of factors associated with both baseline CAC and CAC progression. Models included age, sex, study site, scanner type, and race/ethnicity. Associations were observed between CAC progression and age (14.2 Agatston units/year per 10 years [95% CI 13.0 to 15.5]), male sex (17.8 Agatston units/year [95% CI 15.3 to 20.3]), hypertension (13.8 Agatston units/year [95% CI 11.2 to 16.5]), diabetes (31.3 Agatston units/year [95% CI 27.4 to 35.3]), and other factors. CONCLUSIONS: CAC progression analyzed over 10 years of follow-up, with a novel analytical approach, demonstrated strong relationships with risk factors for incident cardiovascular events. Longitudinal CAC progression analyzed in this framework can be used to evaluate novel cardiovascular risk factors. PMID- 26251282 TI - Sepsis After Cardiac Surgery Early in Infancy and Adverse 4.5-Year Neurocognitive Outcomes. AB - BACKGROUND: We aimed to determine whether sepsis is associated with neurocognitive outcomes 4.5 years after congenital heart disease surgery in early infancy. METHODS AND RESULTS: A secondary analysis from a prospective inception cohort included all children having congenital heart disease surgery done at <=6 weeks of age with cardiopulmonary bypass at the Western Canadian referral center from 1996 to 2009. Follow-up at the referral center determined the primary outcomes at 4.5 years with full-scale, performance, and verbal intelligence quotients on the Wechsler Preschool and Primary Scale of Intelligence. Perioperative variables were collected prospectively, and confirmation of blood culture-positive sepsis was done retrospectively. Multiple linear regression models for neurocognitive outcomes and multiple Cox proportional hazards regression for mortality were determined. Sepsis occurred in 97 of 502 patients (19%) overall and in 76 of 396 survivors (19%) with 4.5-year follow-up. By 4.5 years, there were 91 (18%) deaths, and 396 of 411 survivors (96%) had follow-up completed. Extracorporeal membrane oxygenation was associated with worse scores on all neurocognitive outcomes on multivariable regression; the association between extracorporeal membrane oxygenation and full-scale intelligence quotient had a regression coefficient of -13.6 (95% CI -21.3 to -5.9; P=0.001). Sepsis perioperatively was associated with performance and verbal intelligence quotients, with a trend for full-scale intelligence quotient (P=0.058) on multivariable regression. The regression coefficient for sepsis was strongest for performance intelligence quotient (-5.31; 95% CI -9.84 to -0.78; P=0.022). Sepsis was not but extracorporeal membrane oxygenation was associated with mortality by 4.5 years. CONCLUSIONS: Perioperative sepsis and extracorporeal membrane oxygenation were associated with adverse neurocognitive outcomes on multivariable regression. Quality improvement to prevent sepsis has the potential to improve long-term neurocognitive outcomes in infants after surgery for congenital heart disease. PMID- 26251283 TI - Association Between Comorbidities and Outcomes in Heart Failure Patients With and Without an Implantable Cardioverter-Defibrillator for Primary Prevention. AB - BACKGROUND: Implantable cardioverter-defibrillator (ICD) therapy is associated with improved outcomes in patients with heart failure (HF), but whether this association holds among older patients with multiple comorbid illnesses and worse HF burden remains unclear. METHODS AND RESULTS: Using the National Cardiovascular Data Registry's ICD Registry and the Get With The Guidelines-Heart Failure (GWTG HF) registry linked with Medicare claims, we examined outcomes associated with primary-prevention ICD versus no ICD among HF patients aged >=65 years in clinical practice. We included patients with an ejection fraction <=35% who received (ICD Registry) and who did not receive (GWTG-HF) an ICD. Compared with patients with an ICD, patients in the non-ICD group were older and more likely to be female and white. In matched cohorts, the 3-year adjusted mortality rate was lower in the ICD group versus the non-ICD group (46.7% versus 55.8%; adjusted hazard ratio [HR] 0.76; 95% CI 0.69 to 0.83). There was no associated difference in all-cause readmission (HR 0.99; 95% CI 0.92 to 1.08) but a lower risk of HF readmission (HR 0.88; 95% CI 0.80 to 0.97). When compared with no ICD, ICDs were also associated with better survival in patients with <=3 comorbidities (HR 0.77; 95% CI 0.69 to 0.87) and >3 comorbidities (HR 0.77; 95% CI 0.64 to 0.93) and in patients with no hospitalization for HF (HR 0.75; 95% CI 0.65 to 0.86) and at least 1 prior HF hospitalization (HR 0.69; 95% CI 0.58 to 0.82). In subgroup analyses, there were no interactions between ICD and mortality risk for comorbidity burden (P=0.95) and for prior HF hospitalization (P=0.46). CONCLUSION: Among older HF patients, ICDs for primary prevention were associated with lower risk of mortality even among those with high comorbid illness burden and prior HF hospitalization. PMID- 26251284 TI - Brain Arterial Diameters as a Risk Factor for Vascular Events. AB - BACKGROUND: Arterial luminal diameters are routinely used to assess for vascular disease. Although small diameters are typically considered pathological, arterial dilatation has also been associated with disease. We hypothesize that extreme arterial diameters are biomarkers of the risk of vascular events. METHODS AND RESULTS: Participants in the Northern Manhattan Study who had a time-of-flight magnetic resonance angiography were included in this analysis (N=1034). A global arterial Z-score, called the brain arterial remodeling (BAR) score, was obtained by averaging the measured diameters within each individual. Individuals with a BAR score <-2 SDs were considered to have the smallest diameters, individuals with a BAR score >-2 and <2 SDs had average diameters, and individuals with a BAR score >2 SDs had the largest diameters. All vascular events were recorded prospectively after the brain magnetic resonance imaging. Spline curves and incidence rates were used to test our hypothesis. The association of the BAR score with death (P=0.001), vascular death (P=0.02), any vascular event (P=0.05), and myocardial infarction (P=0.10) was U-shaped except for ischemic stroke (P=0.74). Consequently, incidence rates for death, vascular death, myocardial infarction, and any vascular event were higher in individuals with the largest diameters, whereas individuals with the smallest diameters had a higher incidence of death, vascular death, any vascular event, and ischemic stroke compared with individuals with average diameters. CONCLUSIONS: The risk of death, vascular death, and any vascular event increased at both extremes of brain arterial diameters. The pathophysiology linking brain arterial remodeling to systemic vascular events needs further research. PMID- 26251285 TI - Spermatogonial stem cells specific marker identification in channel catfish, Ictalurus punctatus and blue catfish, I. furcatus. AB - Testicular germ cells of channel catfish, Ictalurus punctatus, and blue catfish, I. furcatus were separated into four layers with Percoll density gradient centrifugation, containing different cell types (40% in the first layer were spermatogonial stem cells, SSCs). Expression of seventeen genes was analyzed for cells from different layers by real-time quantitative PCR. Pfkfb4, Urod, Plzf, Integrin6, IntegrinV, Thy1 and Cdh1 genes showed the same expression change pattern in both channel and blue catfish as these genes were down-regulated in the spermatocytes and even more so in spermatids. Plzf and Integrin6 had especially high expression in SSCs and can be used as SSCs specific markers. Sox2 gene was up-regulated in spermatocytes and even more highly up-regulated in spermatids, which indicated it could be a spermatid marker. In contrast to channel catfish, Id4, Smad5 and Prdm14 gene expressions were strongly down regulated in spermatocyte cells, but up-regulated in spermatid cells in blue catfish. Smad5 gene was down-regulated in spermatocytes, but up-regulated in both spermatogonia and spermatids, allowing identification as a marker for spermatocytes in blue catfish. Oct4, Id4, Gfralpha2, Pum2 and Prdm14 genes showed different expression patterns in the testicular germ cells of channel and blue catfish. This may be a partial explanation to the differing responses of channel catfish and blue catfish to induced spawning technologies. The SSCs specific markers can be used for further SSCs labeling, which can increase the SSCs sorting efficiency and be applied in various studies involving SSCs and other germ cells. PMID- 26251286 TI - Developmental profiles and expression of the DNA methyltransferase genes in the fathead minnow (Pimephales promelas) following exposure to di-2-ethylhexyl phthalate. AB - DNA methylation is an epigenetic regulator of gene expression, and this process has been shown to be disrupted by environmental contaminants. Di-2-(ethylhexyl) phthalate (DEHP) and related phthalate esters have been shown to affect development in early life stages of fish and can alter genomic methylation patterns in vertebrates. The objectives of this study were the following: (1) Describe the expression patterns of the DNA methyltransferase (dnmt) genes during early fathead minnow (FHM) development. These genes are critical for methylation and imprinting during development. (2) Determine the effects of DEHP on the development of FHM larvae [1 and 14 days post-hatch (dph)]. (3) Determine the effect of DEHP on dnmt expression and global methylation status in larval FHM. FHMs were first collected over a developmental time course [1, 3, 5, 6, and 14 days post-fertilization (dpf)] to investigate the expression patterns of five dnmt isoforms. The expression of dnmt1 and dnmt7 was relatively high in embryos at 1 dpf but was variable in expression, and these transcripts were later expressed at a lower level (>3 dpf); dnmt3 was significantly higher in embryos at 1 dpf compared to those at 3 dpf. Dnmt6 showed more of a constitutive pattern of expression during the first 2 weeks of development, and the mRNA levels of dnmt8 were higher in embryos at 5 and 6 dpf compared to those at 1 and 3 dpf, corresponding to the hatching period of the embryos. A waterborne exposure to three concentrations of DEHP (1, 10 and 100 ug/L) was conducted on 1-day FHM embryos for 24 h and on larval fish for 2 weeks, ending at 14 dpf. DEHP did not negatively affect survival, hatch rate, or the expression of dnmt isoforms in FHMs. There were no differences in global cytosine methylation following DEHP treatments in 14 dpf larvae, suggesting that environmentally relevant levels of DEHP may not affect global methylation at this stage of FHM development. However, additional targeted methylome studies are required to determine whether specific gene promoters are differently methylated following exposure to DEHP. This study offers new insight into the roles of the dnmt enzymes during FHM development. PMID- 26251287 TI - Demonstration of primary cilia and acetylated alpha-tubulin in fish endothelial, epithelial and fibroblast cell lines. AB - Primary cilia (PC) were demonstrated for the first time in fish endothelial, epithelial and fibroblast cell lines through immunofluorescence staining with the monoclonal antibody, 6-11B-1, against acetylated alpha-tubulin. The study was carried out with eight recently developed cell lines from the walleye, Sander vitreus (Mitchill). These were three fibroblast-like cell lines, WE-cfin11f, WE skin11f and WE-liver3 from, respectively, the caudal fin, skin and liver, and three epithelial-like cell lines, WE-cfin11e, WE-spleen6 and WErpe from, respectively, the caudal fin, spleen and retina. Also, endothelial-like WEBA from the bulbus arteriosus and glial-like WE-brain5 from the brain were used. Immunocytochemistry revealed strong staining for acetylated alpha-tubulin in mitotic spindles and midbodies for all cell lines, and in PC for all cell lines except WE-skin11f. Staining of cytoplasmic microtubules (fibrils) was absent in three cell lines, including WEBA, but present in the others, especially WE skin11f, which might have obscured PC detection in these cells. Tubacin, an inhibitor of histone deacetylase 6, induced cytoplasmic fibrils in WEBA and the intensity of their staining in WE-cfin11f. These results suggest that the cell lines might differ in their deacetylase activities, making them useful for studying this tubulin modification in teleosts, as well as for studying PC. PMID- 26251288 TI - Role of peptidases of the intestinal microflora and prey in temperature adaptations of the digestive system in planktivorous and benthivorous fish. AB - Many fish enzymatic systems possess limited adaptations to low temperature; however, little data are available to judge whether enzymes of fish prey and intestinal microbiota can mitigate this deficiency. In this study, the activity of serine peptidases (casein-lytic, mainly trypsin and hemoglobin-lytic, mainly chymotrypsin) of intestinal mucosa, chyme and intestinal microflora in four species of planktivorous (blue bream) and benthivorous (roach, crucian carp, perch) was investigated across a wide temperature range (0-70 degrees C) to identify adaptations to low temperature. At 0 degrees C, the relative activity of peptidases of intestinal mucosa (<13%) and usually intestinal microflora (5 12.6%) is considerably less than that of chyme peptidases (up to 40% of maximal activity). The level of peptidase relative activity in crucian carp intestinal microflora was 45% of maximal activity. The shape of t degrees -function curves of chyme peptidase also differs in fish from different biotopes. Fish from the littoral group are characterized by a higher degree of adaptation of chyme casein lytic peptidases to functioning at low temperatures as compared to fish from the pelagic group. The role of intestinal microbiota and prey peptidases in digestive system adaptations of planktivorous and benthivorous fish to low temperatures is discussed. PMID- 26251289 TI - Enhancing Endocrine Therapy for Hormone Receptor-Positive Advanced Breast Cancer: Cotargeting Signaling Pathways. AB - Overcoming primary or secondary endocrine resistance in breast cancer remains critical to further enhancing the benefit of existing therapies such as tamoxifen or an aromatase inhibitor (AI). Much progress has been made in understanding the molecular biology associated with secondary endocrine resistance. Cotargeting the estrogen receptor, together with various key intracellular proliferation and cell survival signaling pathways, has been explored as a strategy either to treat endocrine resistance once it develops in the second-line setting or to enhance first-line endocrine responsiveness by preventing secondary resistance from developing via blockade of specific pathways from the outset. While attempts to improve endocrine therapy by adding growth factor inhibitors have been disappointing, success resulting in new drug approvals has been seen in secondary endocrine resistance by treating patients with the mTOR antagonist everolimus in combination with the AI exemestane and, more recently, in the first-line setting, by the addition of the CDK 4/6 inhibitor palbociclib to the AI letrozole. Numerous other therapeutics are being evaluated in combination with endocrine therapies based on supportive preclinical evidence, including inhibitors of PI3K, Akt, HDAC, Src, IGFR-1, and FGFR. Appropriate clinical trial design and patient selection based on prior therapy exposure, together with predictive biomarkers derived through real-time molecular profiling, are needed to enrich future trials and maximize any additional benefit that cotargeting may bring to current endocrine therapies for estrogen receptor-positive breast cancer. PMID- 26251291 TI - Dr Isaac Henry Gosset (1907-1965) inventor of the 'Gosset' icterometer and founder of Northamptonshire neonatal paediatrics. PMID- 26251290 TI - A Multicenter, Open-Label Phase II Clinical Trial of Combined MEK plus EGFR Inhibition for Chemotherapy-Refractory Advanced Pancreatic Adenocarcinoma. AB - PURPOSE: On the basis of preclinical evidence of synergistic activity between MEK and EGFR inhibitors in pancreatic ductal adenocarcinoma (PDAC), we evaluated the safety and efficacy of selumetinib, a MEK1/2 inhibitor, plus erlotinib in patients with previously treated advanced PDAC. EXPERIMENTAL DESIGN: In this single-arm phase II trial, eligible patients received the combination of erlotinib 100 mg plus selumetinib 100 mg daily in 3-week cycles. Study assessments included measurement of clinical outcomes, with a primary endpoint of overall survival, and exploration of potential molecular predictors of treatment benefit. RESULTS: Forty-six patients were enrolled and received a median of two cycles (range, 1-7). Although no objective responses were observed, 19 patients (41%) showed evidence of stable disease for >=6 weeks, and 13 of 34 patients (38%) had a CA19-9 decline >=50%. Median progression-free survival was 1.9 months [95% confidence interval (CI), 1.4-3.3 months], with a median overall survival of 7.3 months (95% CI, 5.2-8.0 months). Common adverse events included rash, diarrhea, and nausea/vomiting. Patients with tumors exhibiting an epithelial phenotype (demonstrated by a high level of E-cadherin expression) were more likely to be sensitive to study treatment. Tumor-derived DNA was detectable in plasma from the majority of patients using next-generation digital DNA sequencing, and its relative abundance correlated with tumor burden. CONCLUSIONS: A therapeutic strategy of dual targeted inhibition of the MEK and EGFR pathways shows modest antitumor activity in pancreatic cancer. Specific molecular subtypes may derive greatest benefit from this combination. Further exploration, both with more potent MEK inhibitors and in molecularly enriched patient subsets, is warranted. PMID- 26251292 TI - A tool for developing an automatic insect identification system based on wing outlines. AB - For some insect groups, wing outline is an important character for species identification. We have constructed a program as the integral part of an automated system to identify insects based on wing outlines (DAIIS). This program includes two main functions: (1) outline digitization and Elliptic Fourier transformation and (2) classifier model training by pattern recognition of support vector machines and model validation. To demonstrate the utility of this program, a sample of 120 owlflies (Neuroptera: Ascalaphidae) was split into training and validation sets. After training, the sample was sorted into seven species using this tool. In five repeated experiments, the mean accuracy for identification of each species ranged from 90% to 98%. The accuracy increased to 99% when the samples were first divided into two groups based on features of their compound eyes. DAIIS can therefore be a useful tool for developing a system of automated insect identification. PMID- 26251293 TI - Sulfobutyl ether beta-cyclodextrin (Captisol((r)) ) and methyl beta-cyclodextrin enhance and stabilize fluorescence of aqueous indocyanine green. AB - As the only FDA-approved near-infrared fluorophore, indocyanine green (ICG) is commonly used to image vasculature in vivo. ICG degrades rapidly in solution, which limits its usefulness in certain applications, including time-sensitive surgical procedures. We propose formulations that address this shortcoming via complexation with beta-cyclodextrin derivatives (beta-CyD), which are known to create stabilizing inclusion complexes with hydrophobic molecules. Here, we complexed ICG with highly soluble methyl beta-CyD and FDA-approved sulfobutyl ether beta-CyD (Captisol((r)) ) in aqueous solution. We measured the fluorescence of the complexes over 24 h. We found that both CyD+ICG complexes exhibit sustained fluorescence increases of >2.0* versus ICG in water and >20.0* in PBS. Using transmission electron microscopy, we found evidence of reduced aggregation in complexes versus ICG alone. We thus conclude that this reduction in aggregation helps mitigate fluorescence autoquenching of CyD+ICG complexes compared in ICG alone. We also found that while ICG complexed with methyl beta CyD severely reduced the viability of MRC-5 fibroblasts, ICG complexed with sulfobutyl ether beta-CyD had no effect on viability. These results represent an important first step toward enhancing the utility of aqueous ICG by reducing aggregation-dependent fluorescence degradation. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1457-1464, 2016. PMID- 26251294 TI - The ambiguities of the 'partnership' between civil society and the state in Uganda's AIDS response during the 1990s and 2000s as demonstrated in the development of TASO. AB - This article critically investigates state-civil society relations in the Ugandan AIDS response by tracing the history of Uganda's 'multisectoral' and 'partnership' approaches, particularly as it pertains to The AIDS Support Organisation (TASO). It finds that the Ugandan government's reputation for good leadership on AIDS is more ambiguous than commonly supposed and that the much vaunted 'partnership' approach has not enabled strong critical civil society voices to emerge or prevented the harmful impact of a socially conservative agenda. By the 1990s, TASO had become the most important provider of medical and psychosocial support services to HIV/AIDS patients, but was less effective in influencing policy or holding the state accountable (because the political context prevented a more activist stance). The effectiveness of civil society has been constrained by an authoritarian political culture and institutions that discourage vocal criticism. Despite these limitations, however, state-civil society partnership did contribute to the emergence of a relatively effective coalition for action against HIV/AIDS. Donors were essential in encouraging the emergence of this coalition. PMID- 26251295 TI - Different switching patterns of beta-thalassaemic mutations at the proximal and distal CACCC box of the human HBB (beta-globin) gene. PMID- 26251296 TI - Gender and asthma-severity differences in sleep disordered breathing in children with asthma. PMID- 26251297 TI - Measuring Hostile Interpretation Bias: The WSAP-Hostility Scale. AB - Hostile interpretation biases are central to the development and maintenance of anger, yet have been inconsistently assessed. The Word Sentence Association Paradigm (WSAP) was used to develop a new measure of hostile interpretation biases, the WSAP-Hostility. Study 1 examined the factor structure and internal consistency of the WSAP-Hostility, as well as its relationship with trait anger. Study 2 provided convergent and divergent validity data by examining its associations with trait anger, aggression, depression, and anxiety. Study 3 examined the relationship between WSAP-Hostility and another measure of hostile interpretation biases, as well as another word sentence association measure, in a sample of community participants. Study 4 also used a sample of community participants to offer further evidence of convergent validity. Across the studies, the WSAP-Hostility demonstrated convergent and divergent validity and internal consistency, supporting its use as a measure of hostile interpretation biases. PMID- 26251298 TI - Erratum. AB - Breitenstein, S. M., Gross, D., Christophersen, R. (2014). Digital delivery methods of parenting training interventions: A systematic review. Worldviews on Evidence-Based Nursing, 11(3), 168-176. doi: 10.1111/wvn.12040. In the second paragraph of the Data Analysis Procedures section on page 170, the effect size calculation for d is incorrect. The correct calculation is below. PMID- 26251299 TI - Combination of agrin and laminin increase acetylcholine receptor clustering and enhance functional neuromuscular junction formation In vitro. AB - Clustering of acetylcholine receptors (AChR) at the postsynaptic membrane is a crucial step in the development of neuromuscular junctions (NMJ). During development and after denervation, aneural AChR clusters form on the sarcolemma. Recent studies suggest that these receptors are critical for guiding and initiating synaptogenesis. The aim of this study is to investigate the effect of agrin and laminin-1; agents with known AChR clustering activity; on NMJ formation and muscle maturation. Primary myoblasts were differentiated in vitro on collagen, laminin or collagen and laminin-coated surfaces in the presence or absence of agrin and laminin. The pretreated cells were then subject to innervation by PC12 cells. The number of neuromuscular junctions was assessed by immunocytochemical co-localization of AChR clusters and the presynaptic marker synaptophysin. Functional neuromuscular junctions were quantitated by analysis of the level of spontaneous as well as neuromuscular blocker responsive contractile activity and muscle maturation was assessed by the degree of myotube striation. Agrin alone did not prime muscle for innervation while a combination of agrin and laminin pretreatment increased the number of neuromuscular junctions formed and enhanced acetylcholine based neurotransmission and myotube striation. This study has direct clinical relevance for treatment of denervation injuries and creating functional neuromuscular constructs for muscle tissue repair. PMID- 26251300 TI - Development of a disease-specific health-related quality of life (HRQoL) questionnaire intended to be used in conjunction with the general European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) in renal cell carcinoma patients. AB - BACKGROUND: Studying health-related quality of life (HRQoL) following cancer treatment has become part of a growing number of standardized treatment protocols. The European Organization for Research and Treatment of Cancer (EORTC) has developed HRQoL questionnaires aimed at cancer patients. A disease-specific part is not available for renal cell carcinoma (RCC) patients, and the present aim was to develop an EORTC-compatible RCC-specific HRQoL questionnaire. MATERIAL AND METHODS: In total 413 RCC patients were treated with radical or partial nephrectomies in Western Norway during the period from 1997 to 2010. Three hundred and nine patients with histologically proven cancer were still alive at the inclusion time point and 185 RCC patients (71% response rate) returned the questionnaires. We determined HRQoL by the EORTC-QLQ C30 questionnaire. We also asked 13 candidates questions aimed at constituting a disease-specific part. Furthermore, we tested parts of personality by the Eysenck Personality Inventory and coping by the COPE questionnaire. Given tumor treatment, TNM stage, alcohol consumption level and smoking levels were also determined from the hospital records. RESULTS: A factor analysis showed that five factors were formed: one general symptomatic, one general functional, one with disease-specific questions (flank pain, blood in the urine, flank edema, urinary tract infection), one about sexuality and one about weight loss or gain. Ten RCC-specific HRQoL questions were derived from a factor analysis, including four questions related particularly to pain, mobility and social functioning, also representing a short version of the EORTC C30. The psychometric properties and the relation to other psychological and clinical variables were further determined to be satisfactory. CONCLUSIONS: The suggested disease-specific EORTC-QLQ-style RCC10 version adds important information about the HRQoL of RCC patients, providing additional apparent value to the general questionnaire and personality variables, as well as being psychometrically satisfactory. The questionnaire has a potential as a "stand alone" HRQoL questionnaire among RCC patients. PMID- 26251301 TI - The Final Answer to the Question of Whether We Should Use a Single Postoperative Instillation of Chemotherapy After Resection of pTa and pT1 Bladder Tumors. PMID- 26251302 TI - Keep calm and have a good night: nurses' strategies to promote inpatients' sleep in the hospital environment. AB - Patients in the hospital environment are suffering from disrupted sleep, which adversely affects their recovery process, health and well-being. The aim of this study was to explore nurses' experiences and their strategies to promote inpatients' sleep. An empirical qualitative design was applied. Eight nurses at a hospital in Sweden were purposefully selected to be included in semi-structured interviews. Burnard's method for inductively analysing interview transcripts was applied. The findings are presented in four categories: (i) prevention and planning as a sleep-promoting nursing strategy; (ii) adaptation of the environment as a sleep-promoting nursing strategy; (iii) use of drugs as a sleep promoting nursing strategy; and (iv) caring conversation as a sleep-promoting nursing strategy. Using strategies to promote sleep is important as it affects the recovery of the patients. We argue for the use of simple strategies of sensory reduction as cost-effective sleep-promoting measures that also reduce the use of sedative drugs. PMID- 26251303 TI - Review of established and innovative detection methods for carbapenemase producing Gram-negative bacteria. AB - The minimal antibiotic options for carbapenemase-producing Gram-negative bacteria necessitate their rapid detection. A literature review of a variety of phenotypic and genotypic methods is presented. Advances in culture methods and screening media are still subject to long incubation hours. Biochemical methods have shorter turnaround times and higher sensitivities and specificities, but cannot differentiate between various types and variants. Spectrophotometric methods are cheap and efficient, but are uncommon in many clinical settings, while the MALDI TOF MS is promising for species identification, typing and resistance gene determination. Although next generation sequencing (NGS) technologies provide a better platform to detect, type and characterize carbapenem-resistant bacteria, the different NGS platforms, the large computer memories and space needed to process and store genomic data and the nonuniformity in data analysis platforms are still a challenge. The sensitivities, specificities and turnaround times recorded in the various studies reviewed favours the use of the biochemical tests (Carba NP or Rapid Carb screen tests) for the detection of putative carbapenemase producing isolates. MALDI-TOF MS and/or molecular methods like microarray, loop mediated isothermal amplification and real-time multiplex PCR assays could be used for further characterization in a reference laboratory. NGS may be used for advanced epidemiological and molecular studies. PMID- 26251304 TI - Economic evaluation alongside factorial trials: a systematic review of empirical studies. AB - Although economic evaluations have been performed alongside factorial trials, there seems to be limited guidance/consensus on appropriate methods of analysis. Following Centre for Review and Dissemination guidance, a systematic review of published literature for all years was performed to explore how economic evaluation alongside factorial trials have been conducted and only full economic evaluations conducted alongside factorial trials were included. A total of 16 relevant studies were identified, and an assessment of these indicated that two methods: within-the-table and at-the-margins approaches were used for the analysis. With the exception of one study, all others did not consider interactions in costs and outcomes or give a detailed explanation of why a particular approach was adopted. The authors recommend that additional guidance is needed, and further research is required to evaluate the impact of alternative methods on policy recommendations and establish good practice methods for the economic analysis of factorial trials. PMID- 26251305 TI - First Total Synthesis of Trehalose-Containing Branched Oligosaccharide OSE-1 of Mycobacterium gordonae (Strain 990). AB - The first total synthesis of the branched oligosaccharide OSE-1 of Mycobacterium gordonae (strain 990) is reported. An intramolecular aglycon delivery approach was used for constructing the desymmetrized 1,1'-alpha,alpha-linked trehalose moiety. A [3+2] glycosylation of the trisaccharide donor and trehalose acceptor furnished the right hand side pentasaccharide. Regioselective O3 glycosylation of L-rhamnosyl 2,3-diol allowed expedient synthesis of the left hand side tetrasaccharide. The nonasaccharide was assembled in a highly convergent fashion through a [4+5] glycosylation. PMID- 26251306 TI - Genome plasticity of triple-reassortant H1N1 influenza A virus during infection of vaccinated pigs. AB - To gain insight into the evolution of influenza A viruses (IAVs) during infection of vaccinated pigs, we experimentally infected a 3-week-old naive pig with a triple-reassortant H1N1 IAV and placed the seeder pig in direct contact with a group of age-matched vaccinated pigs (n = 10). We indexed the genetic diversity and evolution of the virus at an intra-host level by deep sequencing the entire genome directly from nasal swabs collected at two separate samplings during infection. We obtained 13 IAV metagenomes from 13 samples, which included the virus inoculum and two samples from each of the six pigs that tested positive for IAV during the study. The infection produced a population of heterogeneous alleles (sequence variants) that was dynamic over time. Overall, 794 polymorphisms were identified amongst all samples, which yielded 327 alleles, 214 of which were unique sequences. A total of 43 distinct haemagglutinin proteins were translated, two of which were observed in multiple pigs, whereas the neuraminidase (NA) was conserved and only one dominant NA was found throughout the study. The genetic diversity of IAVs changed dynamically within and between pigs. However, most of the substitutions observed in the internal gene segments were synonymous. Our results demonstrated remarkable IAV diversity, and the complex, rapid and dynamic evolution of IAV during infection of vaccinated pigs that can only be appreciated with repeated sampling of individual animals and deep sequence analysis. PMID- 26251308 TI - Reliability of Canadian Emergency Department Triage and Acuity Scale (CTAS) in Saudi Arabia. AB - BACKGROUND: The Canadian Emergency Department Triage and Acuity Scale (CTAS) is an integral part of the Canadian emergency medicine triaging system. There is growing interest and implementation of CTAS worldwide. However, little is known about its reliability outside Canada. The aim of this study was to determine the reliability agreement of CTAS in a tertiary care emergency center in Saudi Arabia. METHODS: Ten triage nurses (five senior and five junior nurses) utilized CTAS guidelines to independently assign a triage level for 160 real case-based scenarios. Quadratic weighted kappa statistics were used to measure raters' agreements. RESULTS: Raters provided 1600 triage category assignments to case scenarios for analysis. Intra-rater agreement was similar for both senior and junior nurses; for senior nurses (SN1) kappa 0.871 95 % CI (0.840-0.897), and for junior nurses (SN2) kappa 0.871 95 % CI (0.839-0.898). Inter-rater agreement for the SN1 versus SN2 nurses had statistically meaningful agreement across different triage levels (weighted kappa = 0.770) 95 % CI (0.742-0.797). CONCLUSIONS: CTAS has good reliability among emergency department (ED) triage nurses in King Abdulaziz Medical City (KAMC), Saudi Arabia. The findings suggest that CTAS might be a reliable instrument when applied in countries outside Canada. PMID- 26251307 TI - Exacerbated venous thromboembolism in mice carrying a protein S K196E mutation. AB - Protein S (PS) acts as an anticoagulant cofactor for activated protein C in regulation of blood coagulation. The K196E mutation in PS is a race-specific genetic risk factor for venous thromboembolism with a prevalence of ~2% within the Japanese population. To evaluate the thrombosis risk of the PS-K196E mutation, we generated PS-K196E knockin mice and heterozygous PS-deficient mice. We analyzed their thrombotic states, comparing with mice carrying the factor V Leiden mutation (FV-R504Q), a race-specific genetic risk for venous thrombosis in whites. PS-K196E mice grew normally but had decreased activated protein C cofactor activity in plasma. Purified recombinant murine PS-K196E showed the same decreased activated protein C cofactor activity. A deep vein thrombosis model of electrolytic inferior vena cava injury and pulmonary embolism models induced by infusion of tissue factor or polyphosphates revealed that PS-K196E mice, heterozygous PS-deficient mice, and FV-R504Q mice were much more susceptible to venous thrombosis compared with wild-type mice. Transient middle cerebral artery ischemia-reperfusion injury model studies demonstrated that both PS-K196E mice and heterozygous PS-deficient mice had cerebral infarction similar to wild-type mice, consistent with human observations. Our in vitro and in vivo results support a causal relationship between the PS-K196E mutation and venous thrombosis and indicate that PS-K196E mice can provide an in vivo evaluation system to help uncovering racial differences in thrombotic diseases. PMID- 26251309 TI - Methylated Cytokinins from the Phytopathogen Rhodococcus fascians Mimic Plant Hormone Activity. AB - Cytokinins (CKs), a class of phytohormones that regulate plant growth and development, are also synthesized by some phytopathogens to disrupt the hormonal balance and to facilitate niche establishment in their hosts. Rhodococcus fascians harbors the fasciation (fas) locus, an operon encoding several genes homologous to CK biosynthesis and metabolism. This pathogen causes unique leafy gall symptoms reminiscent of CK overproduction; however, bacterial CKs have not been clearly correlated with the severe symptoms, and no virulence-associated unique CKs or analogs have been identified. Here, we report the identification of monomethylated N(6)-(?(2)-isopentenyl)adenine and dimethylated N(6)-(?(2) isopentenyl)adenine (collectively, methylated cytokinins [MeCKs]) from R. fascians. MeCKs were recognized by a CK receptor and up-regulated type-A ARABIDOPSIS THALIANA RESPONSE REGULATOR genes. Treatment with MeCKs inhibited root growth, a hallmark of CK action, whereas the receptor mutant was insensitive. MeCKs were retained longer in planta than canonical CKs and were poor substrates for a CK oxidase/dehydrogenase, suggesting enhanced biological stability. MeCKs were synthesized by S-adenosyl methionine-dependent methyltransferases (MT1 and MT2) that are present upstream of the fas genes. The best substrate for methylation was isopentenyl diphosphate. MT1 and MT2 catalyzed distinct methylation reactions; only the MT2 product was used by FAS4 to synthesize monomethylated N(6)-(?(2)-isopentenyl)adenine. The MT1 product was dimethylated by MT2 and used as a substrate by FAS4 to produce dimethylated N(6) (?(2)-isopentenyl)adenine. Chemically synthesized MeCKs were comparable in activity. Our results strongly suggest that MeCKs function as CK mimics and play a role in this plant-pathogen interaction. PMID- 26251310 TI - Tryptophan-Independent Indole-3-Acetic Acid Synthesis: Critical Evaluation of the Evidence. PMID- 26251311 TI - Asymmetric Fluorolactonization with a Bifunctional Hydroxyl Carboxylate Catalyst. AB - We report the first successful example of a highly enantioselective fluorolactonization with an electrophilic fluorinating reagent, Selectfluor((r)), in the presence of a novel bifunctional organocatalyst. The catalyst design includes a carboxylate anion functioning as a phase-transfer agent and a benzyl alcohol unit to capture the substrate through hydrogen bonding. Fluorinated isobenzofuranones were obtained in good yields with up to 94% ee (97:3 er). On the basis of mechanistic studies, we propose a unique reaction mechanism with potential for further applications. PMID- 26251313 TI - Synthesis and antidepressant activities of 4-(substituted-phenyl)tetrazolo[1,5 a]quinazolin-5(4H)-ones and their derivatives. AB - A series of novel 4-(substituted-phenyl) tetrazolo[1,5-a]quinazolin-5(4H)-ones (6a-x) and their derivatives with tetrazole and other heterocyclic substituents (7-14) were designed, synthesized, and evaluated for antidepressant activities in mice. Pharmacological tests showed that three compounds (6l, 6u, and 6v) at a dose of 50 mg/kg significantly reduced the immobility time in the forced swimming test. The most active compound was 4-(p-tolyl)tetrazolo[1,5-a]quinazolin-5(4H) one (6v), which decreased the immobility time by 82.69 % at 50 mg/kg. Moreover, 6v did not affect spontaneous activity in the open-field test, and this effect was comparable to the antidepressant effect of fluoxetine. Noradrenaline (NE) and 5-hydroxytryptamine (5-HT) levels in the brains of mice in the test sample groups significantly increased at a dose of 50 mg/kg compared with that in the control group. The monoamine oxidase (MAO) level of all test groups was reduced, but this result was not significantly different between the groups. Therefore, we can infer that their underlying mechanisms may involve the regulation of brain monoamine neurotransmitter homeostasis, based on the detected content of NE, 5 HT, and MAO in mouse brain tissue. PMID- 26251312 TI - Effects of new over-the-counter periodontal ointment-containing applicator with single-tuft brush on cytokine levels in gingival crevicular fluid during supportive periodontal therapy phase: a randomized double-blind clinical trial. AB - BACKGROUND AND OBJECTIVE: The biochemical effects of an over-the-counter (OTC) medication were studied, which consists of a single-tuft brush containing cetylpyridinium chloride as a bactericidal agent, dipotassium glycyrrhizate as an anti-inflammatory drug and allantoin as a promoter of cell proliferation and wound healing, for delivery to hardly brushed sites. MATERIAL AND METHODS: This randomized controlled double-blind study was performed in 61 subjects with chronic periodontitis in supportive periodontal therapy phase (test group: n = 27; placebo group: n = 28; dropout: n = 6). The OTC medication was self-applied twice a day for 12 wk to two molars with probing pocket depths of 4-6 mm. Biochemical indicators were evaluated at baseline and 12 wk using the suspension array system for eight cytokines and chemokines (interleukin [IL]-1beta, IL-1ra, IL-4, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1 and tumor necrosis factor [TNF]-alpha) in gingival crevicular fluid. RESULTS: The levels of IL 1beta, IL-6, IL-8 and TNF-alpha remained significantly lower in the test group compared to the placebo group. In the placebo group, when the probing pocket depth at baseline was 4 mm, IL-1beta increased, particularly in the second molar tooth, and the greatest increase was seen when PPD at baseline was 5-6 mm. In the test group, IL-1beta decreased markedly in cases with furcation involvement and low bleeding on probing at baseline. In both groups, IL-1beta, IL-6 and TNF-alpha were closely correlated with each other. CONCLUSION: This OTC medication is biochemically effective for steady chronic periodontitis in the supportive periodontal therapy phase. PMID- 26251314 TI - Percutaneous Coronary Intervention for Septic Emboli in the Left Main Trunk as a Complication of Infective Endocarditis. AB - Infective endocarditis (IE) complicated by acute myocardial infarction (AMI) is frequently fatal and may require emergent interventions. However, the optimal treatment of this rare condition remains controversial as it lacks established guidelines. We successfully treated a patient with IE complicated by AMI during the acute phase using percutaneous coronary intervention (PCI) followed by surgery. A 73-year-old man was diagnosed with IE of the mitral and aortic valves caused by Streptococcus oralis. Four weeks after the initiation of antibiotics sensitive to the causative bacteria, he suddenly developed AMI manifested by chest pain and dyspnoea with cardiovascular collapse. Emergent coronary angiography revealed that the myocardial infarction was secondary to septic emboli in the left main trunk. Emergent PCI comprising aspiration and stent deployment, was successfully performed, and his vital signs were immediately stabilised. He subsequently underwent mitral and aortic valve replacement and debridement without major post-operative complications. Although the optimal treatment strategy for haemodynamically unstable AMI secondary to IE requires further discussion, the present case indicates the importance of early diagnosis and the potential effectiveness of aggressive PCI as a bridge to the following surgery. PMID- 26251315 TI - Headache in a Patient with Complex Congenital Heart Disease: Diagnostic and Therapeutic Considerations. AB - Headache in adult patients with congenital heart disease may be a manifestation of the underlying cardiac condition or more common alternative causes of headache. In patients with pre-existing congenital heart disease, consideration of potentially uncommon aetiologies of headache is important. We report an uncommon case of headache in a patient with complex congenital heart disease characterised by Ebstein's anomaly with previous surgical repair complicated by idiopathic intracranial hypertension. This case illustrates the importance of understanding the implications of headache with reference to the underlying cardiac disease as well as specific issues related to a relatively young cohort of patients. PMID- 26251316 TI - Mixed Supra- and Intracardiac Totally Anomalous Pulmonary Venous Connection in an Adult Female: Pre- and Postoperative Evaluation with Emphasis on MDCT Angiographic Advantages. AB - All cases with total anomalous pulmonary venous connection (TAPVC) were reported in neonates and children in the previous literature. This report describes the only case in which a mixed supra- and intracardiac TAPVC was discovered in a 25 year-old adult female and multidetector-row computed tomography (MDCT) angiography was used in its pre- and postoperative evaluation. Multidetector-row computed tomography angiography is superior to echocardiography in showing the draining sites and courses of the anomalous connected pulmonary veins, as well as postoperative evaluation in a patient with mixed TAPVC. It indicates that MDCT angiography may be a more suitable diagnostic modality for use in the pre- and postoperative evaluation of the mixed TAPVC. PMID- 26251317 TI - Prevalence of chronic hepatitis B virus (HBV) infection in U.S. households: National Health and Nutrition Examination Survey (NHANES), 1988-2012. AB - The number of persons with chronic hepatitis B virus (HBV) infection in the United States is affected by diminishing numbers of young persons who are susceptible because of universal infant vaccination since 1991, offset by numbers of HBV-infected persons migrating to the United States from endemic countries. The prevalence of HBV infection was determined by serological testing and analysis among noninstitutionalized persons age 6 years and older for: antibody to hepatitis B core antigen (anti-HBc), indicative of previous HBV infection; hepatitis B surface antigen (HBsAg), indicative of chronic (current) infection; and antibody to hepatitis B surface antigen (anti-HBs), indicative of immunity from vaccination. These prevalence estimates were analyzed in three periods of the National Health and Nutrition Examination Survey (NHANES): 1988-1994 (21,260 persons); 1999-2008 (29,828); and 2007-2012 (22,358). In 2011-2012, for the first time, non-Hispanic Asians were oversampled in NHANES. For the most recent period (2007-2012), 3.9% had anti-HBc, indicating approximately 10.8 (95% confidence interval [CI]: 9.4-12.2) million noninstitutionalized U.S. residents having ever been infected with HBV. The overall prevalence of chronic HBV infection has remained constant since 1999: 0.3% (95% CI: 0.2-0.4), and since 1999, prevalence of chronic HBV infection among non-Hispanic blacks has been 2- to 3-fold greater than the general population. An estimated 3.1% (1.8%-5.2%) of non-Hispanic Asians were chronically infected with HBV during 2011-2012, which reflects a 10-fold greater prevalence than the general population. Adjusted prevalence of vaccine induced immunity increased 16% since 1999, and the number of persons (mainly young) with serological evidence of vaccine protection from HBV infection rose from 57.8 (95% CI: 55.4-60.1) million to 68.5 (95% CI: 65.4-71.2) million. CONCLUSION: Despite increasing immune protection in young persons vaccinated in infancy, an analysis of chronic hepatitis B prevalence in racial and ethnic populations indicates that during 2011-2012, there were 847,000 HBV infections (which included ~400,000 non-Hispanic Asians) in the noninstitutionalized U.S. POPULATION. PMID- 26251318 TI - Triglyceride glucose index as a surrogate measure of insulin sensitivity in obese adolescents with normoglycemia, prediabetes, and type 2 diabetes mellitus: comparison with the hyperinsulinemic-euglycemic clamp. AB - BACKGROUND: There is a need for simple surrogate estimates of insulin sensitivity in epidemiological studies of obese youth because the hyperinsulinemic-euglycemic clamp is not feasible on a large scale. OBJECTIVE: (i) To examine the triglyceride glucose (TyG) index (Ln[fasting triglycerides (mg/dL) * fasting glucose (mg/dL)/2]) and its relationship to in vivo insulin sensitivity in obese adolescents (OB) along the spectrum of glucose tolerance and (ii) to compare TyG index with triglyceride/high-density lipoprotein TG/HDL and 1/fasting insulin (1/IF ), other surrogates of insulin sensitivity. PATIENTS AND DESIGN: Cross sectional data in 225 OB with normal glucose tolerance (NGT), prediabetes (preDM), and type 2 diabetes (T2DM) who had a 3-h hyperinsulinemic-euglycemic clamp and fasting lipid measurement. RESULTS: Insulin-stimulated glucose disposal (Rd) declined significantly across the glycemic groups from OB-NGT to OB-preDM to OB-T2DM with a corresponding increase in TyG index (8.3 +/- 0.5, 8.6 +/- 0.5, 8.9 +/- 0.6, p < 0.0001). The correlation of TyG index to Rd was -0.419 (p < 0.0001). The optimal TyG index for diagnosis of insulin resistance was 8.52 [receiver operating characteristic-area under the ROC curves (ROC-AUC) 0.750, p < 0.0001]. The ROC-AUC for 1/IF was 0.836. In multiple regression analysis, 64.8% of the variance in Rd was explained by TyG index, 1/IF , body mass index (BMI) z-score, glycemic group, and sex. CONCLUSION: The TyG index affords an easily and widely available simple laboratory method as a surrogate estimate of insulin sensitivity that could be used repeatedly in large-scale observational and/or interventional cohorts of OB. Although not superior to 1/IF , TyG index offers the advantage of having a standardized method of measuring triglyceride and glucose, which is not the case for insulin assays. PMID- 26251319 TI - Bacterial response to different surface chemistries fabricated by plasma polymerization on electrospun nanofibers. AB - Control over bacterial attachment and proliferation onto nanofibrous materials constitutes a major challenge for a variety of applications, including filtration membranes, protective clothing, wound dressings, and tissue engineering scaffolds. To develop effective devices, the interactions that occur between bacteria and nanofibers with different morphological and physicochemical properties need to be investigated. This paper explores the influence of fiber surface chemistry on bacterial behavior. Different chemical functionalities were generated on the surface of electrospun polystyrene nanofibers through plasma polymerization of four monomers (acrylic acid, allylamine, 1,7-octadiene, and 1,8 cineole). The interactions of Escherichia coli with the surface modified fibers were investigated through a combination of scanning electron microscopy and confocal laser scanning microscopy. Fiber wettability, surface charge, and chemistry were found to affect the ability of bacterial cells to attach and proliferate throughout the nanofiber meshes. The highest proportion of viable cells attachment occurred on the hydrophilic amine rich coating, followed by the hydrophobic octadiene. The acrylic acid coating rich in carboxyl groups showed a significantly lower attraction of bacterial cells. The 1,8-cineole retained the antibacterial activity of the monomer, resulting with a high proportion of dead isolated cells attached onto the fibers. Results showed that the surface chemistry properties of nanofibrous membranes can be strategically tuned to control bacterial behavior. PMID- 26251320 TI - Systems toxicology identifies mechanistic impacts of 2-amino-4,6-dinitrotoluene (2A-DNT) exposure in Northern Bobwhite. AB - BACKGROUND: A systems toxicology investigation comparing and integrating transcriptomic and proteomic results was conducted to develop holistic effects characterizations for the wildlife bird model, Northern bobwhite (Colinus virginianus) dosed with the explosives degradation product 2-amino-4,6 dinitrotoluene (2A-DNT). A subchronic 60 d toxicology bioassay was leveraged where both sexes were dosed via daily gavage with 0, 3, 14, or 30 mg/kg-d 2A-DNT. Effects on global transcript expression were investigated in liver and kidney tissue using custom microarrays for C. virginianus in both sexes at all doses, while effects on proteome expression were investigated in liver for both sexes and kidney in males, at 30 mg/kg-d. RESULTS: As expected, transcript expression was not directly indicative of protein expression in response to 2A-DNT. However, a high degree of correspondence was observed among gene and protein expression when investigating higher-order functional responses including statistically enriched gene networks and canonical pathways, especially when connected to toxicological outcomes of 2A-DNT exposure. Analysis of networks statistically enriched for both transcripts and proteins demonstrated common responses including inhibition of programmed cell death and arrest of cell cycle in liver tissues at 2A-DNT doses that caused liver necrosis and death in females. Additionally, both transcript and protein expression in liver tissue was indicative of induced phase I and II xenobiotic metabolism potentially as a mechanism to detoxify and excrete 2A-DNT. Nuclear signaling assays, transcript expression and protein expression each implicated peroxisome proliferator activated receptor (PPAR) nuclear signaling as a primary molecular target in the 2A-DNT exposure with significant downstream enrichment of PPAR-regulated pathways including lipid metabolic pathways and gluconeogenesis suggesting impaired bioenergetic potential. CONCLUSION: Although the differential expression of transcripts and proteins was largely unique, the consensus of functional pathways and gene networks enriched among transcriptomic and proteomic datasets provided the identification of many critical metabolic functions underlying 2A-DNT toxicity as well as impaired PPAR signaling, a key molecular initiating event known to be affected in di- and trinitrotoluene exposures. PMID- 26251321 TI - Neuromechanical factors involved in the formation and propulsion of fecal pellets in the guinea-pig colon. AB - BACKGROUND: The neuromechanical processes involved in the formation and propulsion of fecal pellets remain incompletely understood. METHODS: We analyzed motor patterns in isolated segments of the guinea-pig proximal and distal colon, using video imaging, during oral infusion of liquid, viscous material, or solid pellets. KEY RESULTS: Colonic migrating motor complexes (CMMCs) in the proximal colon divided liquid or natural semisolid contents into elongated shallow boluses. At the colonic flexure these boluses were formed into shorter, pellet shaped boluses. In the non-distended distal colon, spontaneous CMMCs produced small dilations. Both high- and low-viscosity infusions evoked a distinct motor pattern that produced pellet-shaped boluses. These were propelled at speeds proportional to their surface area. Solid pellets were propelled at a speed that increased with diameter, to a maximum that matched the diameter of natural pellets. Pellet speed was reduced by increasing resistive load. Tetrodotoxin blocked all propulsion. Hexamethonium blocked normal motor patterns, leaving irregular propagating contractions, indicating the existence of neural pathways that did not require nicotinic transmission. CONCLUSIONS & INFERENCES: Colonic migrating motor complexes are responsible for the slow propulsion of the soft fecal content in the proximal colon, while the formation of pellets at the colonic flexure involves a content-dependent mechanism in combination with content-independent spontaneous CMMCs. Bolus size and consistency affects propulsion speed suggesting that propulsion is not a simple reflex but rather a more complex process involving an adaptable neuromechanical loop. PMID- 26251322 TI - Universal health insurance coverage for 1.3 billion people: What accounts for China's success? AB - China successfully achieved universal health insurance coverage in 2011, representing the largest expansion of insurance coverage in human history. While the achievement is widely recognized, it is still largely unexplored why China was able to attain it within a short period. This study aims to fill the gap. Through a systematic political and socio-economic analysis, it identifies seven major drivers for China's success, including (1) the SARS outbreak as a wake-up call, (2) strong public support for government intervention in health care, (3) renewed political commitment from top leaders, (4) heavy government subsidies, (5) fiscal capacity backed by China's economic power, (6) financial and political responsibilities delegated to local governments and (7) programmatic implementation strategy. Three of the factors seem to be unique to China (i.e., the SARS outbreak, the delegation, and the programmatic strategy.) while the other factors are commonly found in other countries' insurance expansion experiences. This study also discusses challenges and recommendations for China's health financing, such as reducing financial risk as an immediate task, equalizing benefit across insurance programs as a long-term goal, improving quality by tying provider payment to performance, and controlling costs through coordinated reform initiatives. Finally, it draws lessons for other developing countries. PMID- 26251323 TI - Local health care expenditure plans and their opportunity costs. AB - BACKGROUND: In the UK, approval decisions by Health Technology Assessment bodies are made using a cost per quality-adjusted life year (QALY) threshold, the value of which is based on little empirical evidence. We test the feasibility of estimating the "true" value of the threshold in NHS Scotland using information on marginal services (those planned to receive significant (dis)investment). We also explore how the NHS makes spending decisions and the role of cost per QALY evidence in this process. DATA AND METHODS: We identify marginal services using NHS Board-level responses to the 2012/13 Budget Scrutiny issued by the Scottish Government, supplemented with information on prioritisation processes derived from interviews with Finance Directors. We search the literature for cost effectiveness evidence relating to marginal services. RESULTS: The cost effectiveness estimates of marginal services vary hugely and thus it was not possible to obtain a reliable estimate of the threshold. This is unsurprising given the finding that cost-effectiveness evidence is rarely used to justify expenditure plans, which are driven by a range of other factors. DISCUSSION AND CONCLUSIONS: Our results highlight the differences in objectives between HTA bodies and local health service decision makers. We also demonstrate that, even if it were desirable, the use of cost-effectiveness evidence at local level would be highly challenging without extensive investment in health economics resources. PMID- 26251324 TI - Balancing the Duty to Treat Patients with Ebola Virus Disease with the Risks to Dialysis Personnel. AB - In 2014, the author was invited to present at the American Society for Nephrology's annual conference in Philadelphia on the ethics of treating patients with Ebola virus disease. The argument was made that the status of health care workers, including nephrologists, was the dominant ethical standard that generated both the duty to treat and the conflicts between this commitment and other ethical commitments that arise in public health emergencies. Conflicts between duty to treat and personal safety, duty to community, and duty to colleagues were illustrated, and suggestions for designing ethics into medical practice were given. This article is a summary of that presentation. PMID- 26251326 TI - The Effects of Class-Specific Histone Deacetylase Inhibitors on the Development of Limbs During Organogenesis. AB - Histone deacetylases (HDACs) play a major role in chromatin remodeling, gene regulation, and cellular signaling. While the role of each class of HDAC during normal development is unclear, several HDAC inhibitors are embryotoxic; the mechanisms leading to the teratogenicity of HDAC inhibitors are not known. Here, we investigated the effects of class-specific HDAC inhibitors on the development of organogenesis-stage murine limbs. Timed-pregnant COL2A1-ECFP, COL10A1-mCherry, and COL1A1-YFP CD1 reporter mice were euthanized on gestation day 12; embryonic forelimbs were excised and cultured in vitro for 1, 3, and 6 days in the presence or absence of MS275 (a class I HDAC inhibitor), MC1568 (a class III HDAC inhibitor), Sirtinol (a class II HDAC inhibitor), or valproic acid, our positive control. Fluorescently tagged COL2A1, COL10A1, and COL1A1 served as markers of the differentiation of proliferative chondrocytes, hypertrophic chondrocytes, and osteoblasts, respectively. MS275 and valproic acid caused a reduction in expression of all three markers, suggesting effects on both chondrogenesis and osteogenesis. MC1568 had no effect on chondrocyte markers and mildly inhibited COL1A1 expression at 6 days. Sirtinol had no effect on COL2A1 expression or chondrocyte differentiation 1 day following exposure; however, it caused a drastic regression in limb cartilage and reduced the expression of all three differentiation markers to nearly undetectable levels at 6 days. MS275 and Sirtinol caused a 2.2- and 2.7-fold increase, respectively, in cleaved-caspase 3, a marker of apoptosis, suggesting embryotoxicity. These data demonstrate that inhibition of class I or III HDACs causes severe developmental toxicity and is highly teratogenic. PMID- 26251325 TI - Incorporating High-Throughput Exposure Predictions With Dosimetry-Adjusted In Vitro Bioactivity to Inform Chemical Toxicity Testing. AB - We previously integrated dosimetry and exposure with high-throughput screening (HTS) to enhance the utility of ToxCast HTS data by translating in vitro bioactivity concentrations to oral equivalent doses (OEDs) required to achieve these levels internally. These OEDs were compared against regulatory exposure estimates, providing an activity-to-exposure ratio (AER) useful for a risk-based ranking strategy. As ToxCast efforts expand (ie, Phase II) beyond food-use pesticides toward a wider chemical domain that lacks exposure and toxicity information, prediction tools become increasingly important. In this study, in vitro hepatic clearance and plasma protein binding were measured to estimate OEDs for a subset of Phase II chemicals. OEDs were compared against high-throughput (HT) exposure predictions generated using probabilistic modeling and Bayesian approaches generated by the U.S. Environmental Protection Agency (EPA) ExpoCast program. This approach incorporated chemical-specific use and national production volume data with biomonitoring data to inform the exposure predictions. This HT exposure modeling approach provided predictions for all Phase II chemicals assessed in this study whereas estimates from regulatory sources were available for only 7% of chemicals. Of the 163 chemicals assessed in this study, 3 or 13 chemicals possessed AERs < 1 or < 100, respectively. Diverse bioactivities across a range of assays and concentrations were also noted across the wider chemical space surveyed. The availability of HT exposure estimation and bioactivity screening tools provides an opportunity to incorporate a risk-based strategy for use in testing prioritization. PMID- 26251327 TI - Ecstasy (MDMA) Alters Cardiac Gene Expression and DNA Methylation: Implications for Circadian Rhythm Dysfunction in the Heart. AB - MDMA (ecstasy) is an illicit drug that stimulates monoamine neurotransmitter release and inhibits reuptake. MDMA's acute cardiotoxicity includes tachycardia and arrhythmia which are associated with cardiomyopathy. MDMA acute cardiotoxicity has been explored, but neither long-term MDMA cardiac pathological changes nor epigenetic changes have been evaluated. Microarray analyses were employed to identify cardiac gene expression changes and epigenetic DNA methylation changes. To identify permanent MDMA-induced pathogenetic changes, mice received daily 10- or 35-day MDMA, or daily 10-day MDMA followed by 25-day saline washout (10 + 25 days). MDMA treatment caused differential gene expression (p < .05, fold change >1.5) in 752 genes following 10 days, 558 genes following 35 days, and 113 genes following 10-day MDMA + 25-day saline washout. Changes in MAPK and circadian rhythm gene expression were identified as early as 10 days. After 35 days, circadian rhythm genes (Per3, CLOCK, ARNTL, and NPAS2) persisted to be differentially expressed. MDMA caused DNA hypermethylation and hypomethylation that was independent of gene expression; hypermethylation of genes was found to be 71% at 10 days, 68% at 35 days, and 91% at 10 + 25 days washout. Differential gene expression paralleled DNA methylation in 22% of genes at 10-day treatment, 17% at 35 days, and 48% at 10 + 25 days washout. We show here that MDMA induced cardiac epigenetic changes in DNA methylation where hypermethylation predominated. Moreover, MDMA induced gene expression of key elements of circadian rhythm regulatory genes. This suggests a fundamental organism-level event to explain some of the etiologies of MDMA dysfunction in the heart. PMID- 26251328 TI - Understanding the Interplay Between Neighborhood Structural Factors, Social Processes, and Alcohol Outlets on Child Physical Abuse. AB - This article seeks to understand the relative influence of neighborhood structural characteristics (e.g., disadvantage) and social processes (e.g., interactions between residents) on child physical abuse. Using multilevel modeling in a sample of 3,023 parents in 194 zip codes, structural characteristics of factor scores representing residential stability and foreign born Latino males were negatively related to child physical abuse. High proportions of naturalized and Asian/Pacific Islander families were positively related to the frequency of physical abuse. Higher levels of neighborhood social disorder were related to more frequent physical abuse, while higher levels of collective efficacy were related to less frequent physical abuse. Programs designed to alleviate disorder and increase neighborly interactions may be effective at reducing physical abuse. By understanding the relative importance of the demographic characteristics of neighborhoods and the actions and interactions of residents within the neighborhoods, policy and practice can be tailored more effectively to prevent maltreatment. PMID- 26251329 TI - RE: nab-Paclitaxel Plus Gemcitabine for Metastatic Pancreatic Cancer: Long-Term Survival From a Phase III Trial. PMID- 26251330 TI - Response. PMID- 26251331 TI - Time-course effect of high-glucose-induced reactive oxygen species on mitochondrial biogenesis and function in human renal mesangial cells. AB - The present study investigated the time-course effect of high-glucose-induced reactive oxygen species (ROS) on mitochondrial biogenesis and function in human renal mesangial cells and the effect of direct inhibition of ROS on mitochondria. The cells were cultured for 1, 4, and 7 days in normal glucose or high glucose in the presence and absence of Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP) or catalase. Mitochondrial ROS production was assessed by confocal microscope. mtDNA copy number and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha), nuclear respiratory factors 1 (NRF-1), and mitochondrial transcription factor A (TFAM) transcripts were analyzed by real time PCR. PGC-1alpha, NRF-1, and TFAM proteins were analyzed by Western blotting. Mitochondrial function was determined by assessing mitochondrial membrane potential and adenosine triphosphate (ATP) levels. High glucose induced significant increases in mitochondrial superoxide and hydrogen peroxide (H2 O2 ) at day 1, which remained significantly elevated at days 4 and 7. The copy number of mtDNA and expression of PGC-1alpha, NRF-1, and TFAM were significantly increased at 1 day in high glucose but were significantly decreased at 4 and 7 days. A progressive decrease in mitochondrial membrane potential was observed at 1, 4, and 7 days in high glucose, and this was associated with decreased ATP levels. Treatment of cells with MnTBAP or catalase during high-glucose incubation attenuated ROS production and reversed the alterations in mitochondrial biogenesis and function. Increased mitochondrial biogenesis in human renal mesangial cells may be an early adaptive response to high-glucose-induced ROS, and prolonged ROS production induced by chronic high glucose decreased mitochondrial biogenesis and impaired mitochondrial function. Protection of mitochondria from high-glucose-induced ROS may provide a potential approach to retard the development and progression of diabetic nephropathy. PMID- 26251332 TI - Exclusion of black potential living kidney donors by CT angiogram. PMID- 26251333 TI - Assessment of efficacy and tolerability of different concentrations of trichloroacetic acid vs. carbon dioxide laser in treatment of xanthelasma palpebrarum. AB - BACKGROUND: There are numerous methods currently available for the management of xanthelasma. These include surgical excision, laser ablation using a variety of lasers and chemical cauterization. However, each method of treatment is associated with particular limitations and side effects. OBJECTIVES: To assess the clinical efficacy and tolerability of different concentrations of topical trichloroacetic acid (TCA) vs. carbon dioxide laser in the treatment of patients with xanthelasma palpebrarum. METHODS: Thirty patients with xanthelasma palpebrarum were classified into four groups, treated by TCA 35%, 50%, 70%, and CO2 laser, respectively. Lipid profile was estimated for all patients. RESULTS: Both TCA peeling 70% and carbon dioxide laser ablation showed more significant clinical efficacy and tolerability with least number of sessions in the treatment of xanthelasma palpebrarum than 50% and 35% TCA peeling. Post-therapy erythema and hypopigmentation were more with TCA 70%. Post-therapy hyperpigmentation was more with TCA (50%). There was a significant improvement in patients with normal lipid profile than those with abnormal profile. CONCLUSION: Both TCA peeling 70% and carbon dioxide laser ablation are highly effective and well tolerated with least number of sessions in the treatment of xanthelasma palpebrarum. PMID- 26251334 TI - A renaissance for botanical insecticides? AB - Botanical insecticides continue to be a subject of keen interest among the international research community, reflected in the steady growth in scientific publications devoted to the subject. Until very recently though, the translation of that theory to practice, i.e. the commercialisation and adoption of new botanical insecticides in the marketplace, has seriously lagged behind. Strict regulatory regimes, long the bane of small pesticide producers, are beginning to relax some of the data requirements for 'low-risk' pesticide products, facilitating movement of more botanicals into the commercial arena. In this paper I discuss some of the jurisdictions where botanicals are increasingly finding favour, some of the newer botanical insecticides in the plant and animal health arsenal and some of the specific sectors where botanicals are most likely to compete effectively with other types of insecticidal product. PMID- 26251335 TI - Middle East Respiratory Syndrome Coronavirus Patients in the ICU. PMID- 26251336 TI - Prevalence and Course of Atrial Fibrillation in Critically Ill Trauma Patients. AB - Atrial fibrillation (AF) is the most common cardiac dysrhythmia. Its prevalence, risk factors, course, and complications are not well described in critically ill trauma patients. This was a retrospective, single-center, cohort study at an academic, level 1 trauma center. Trauma patients >18 years, identified from the trauma registry and admitted to the intensive care unit (ICU), were sequentially screened for AF. A matched cohort was created by selecting patients consecutively admitted before and after the patients who experienced AF. Of 2591 patients screened, 191 experienced AF, resulting in a prevalence of 7.4%. There was no difference in injury severity score (ISS) between those with and without AF, but patients with AF had higher observed mortality (15.5% vs 6.7%, P < .001). Patients with a history of AF (n = 75) differed from new-onset AF (n = 106) in their mean age, 78.9 +/- 8.4 versus 69.2 +/- 17.9 years; mean time to AF onset, 1.1 +/- 2.3 versus 5.2 +/- 10.2 days; median duration of AF, 29.8 (1-745.2) versus 5.9 (0-757) hours; and rate of AF resolution, 28% versus 82.1%, respectively. Despite a higher ISS, Sequential Organ Failure Assessment and length of stay, the new-onset AF group experienced a similar rate of mortality compared to the history of AF group (14.7% vs 16.0%). Patients with AF had a higher mortality when compared to those in sinus rhythm. The course of AF in the new-onset AF group occurred later was shorter and was more likely to convert; however, these patients had a longer ICU stay when compared to those who had a history of AF. PMID- 26251337 TI - Author's Response to Letter to Editor on "Characteristics and Outcomes of Middle East Respiratory Syndrome Coronavirus Patients Admitted to an Intensive Care Unit in Jeddah, Saudi Arabia". PMID- 26251338 TI - Occupational allergic contact dermatitis following exposure to the Central American hardwood cocobolo. PMID- 26251339 TI - Rapid local adaptation mediates zooplankton community assembly in experimental mesocosms. AB - Adaptive evolution can occur over similar timescales as ecological processes such as community assembly, but its particular effects on community assembly and structure and their magnitude are poorly understood. In experimental evolution trials, Daphnia magna were exposed to varying environments (presence and absence of fish and artificial macrophytes) for 2 months. Then, in a common gardening experiment, we compared zooplankton community composition when either experimentally adapted or D. magna from the original population were present. Local adaptation of D. magna significantly altered zooplankton community composition, leading to a suppression of abundances for some zooplankton taxa and facilitation for others. The effect size of D. magna adaptation was similar to that of adding fish or macrophytes to mesocosms, two important drivers of zooplankton community structure. Our results suggest that substantial amounts of variation in community composition in natural systems may be unexplained if evolutionary dynamics are ignored. PMID- 26251340 TI - Impact of chemotherapy on survival in surgically resected retroperitoneal sarcoma. AB - BACKGROUND: The role of systemic chemotherapy (CT) in the multimodality treatment strategy for retroperitoneal sarcomas (RPS) remains controversial. We hypothesized that chemotherapy does not improve overall survival for patients with surgically resected RPS. METHODS: The National Cancer Database was used to identify all patients with RPS that underwent surgical resection from 1998 to 2011. Univariate and multivariable Cox proportional hazards modeling were used to assess overall survival (OS) and logistic regression was used for associations. Propensity score (PS) modeling was performed to create balanced cohorts for analysis. RESULTS: A total of 8653 patients with surgically resected RPS were identified; 1525 (17.6%) received CT; 10.6% of patients (n = 163) in the neoadjuvant setting. Factors associated with receipt of CT included moderate (OR 2.3) to poorly differentiated (OR 4.3) tumors, leiomyosarcoma (OR 1.8) or undifferentiated pleomorphic sarcoma (OR 2.3) histology, and R2 resection status (OR 2.2) (all p < 0.05). Unadjusted median OS for patients receiving CT compared to surgery alone was 40 vs 68.2 months respectively (p < 0.01). Following propensity score matching, worse median OS persisted among the CT cohort (40 vs 52 months, p = 0.002). Receipt of chemotherapy was not associated with improved long term survival in adjusted models for the raw and propensity matched cohorts (HR 1.17, 95% CI: 1.04-1.31; p = 0.009). CONCLUSION: Current available chemotherapy regimens for RPS do not confer a survival benefit. Routine use of chemotherapy for RPS should be discouraged until new effective systemic agents become available. PMID- 26251341 TI - Reduced preoperative serum albumin and absence of peritoneal dissemination may be predictive factors for long-term survival with advanced gastric cancer with positive cytology test. AB - BACKGROUND: Peritoneal lavage cytology cancer-positive (CY1) is a critical prognostic factor and is taken as representing stage IV in gastric cancer. There is no consensus treatment strategy for CY1-gastric cancer, and the detailed clinicopathological features remain obscure. PATIENTS AND METHODS: Among 790 gastric cancer patients between 2005 and 2009, 52 cases of CY1 were identified (6.6%). A multivariate prognostic model was applied to the univariate prognostic factors to identify independent prognostic factors and factors associated with long-term survival in CY1-gastric cancer. RESULTS: (1) Five-year overall survival (OS) was 17.6% in CY1-gastric cancer as compared with 93.9% in CYX and 77.7% in CY0 (77.7%), where tumors with pT2 or beyond were included in 11% of CYX, 73% of CY0, and 98% of CY1 cases. (2) On univariate analysis, factors associated with a negative prognosis were the presence of peritoneal dissemination (p = 0.029) and high preoperative serum albumin (p = 0.011) in CY1-gastric cancer. The multivariate Cox proportional hazards and logistic regression model using propensity score identified preoperative albumin as a critical independent prognostic indicator. (3) Long-term survivors were identified and, were often characterized by long-term postoperative adjuvant treatment. CONCLUSION: Reduced preoperative serum albumin and absence of peritoneal dissemination may be predictive factors for long-term survival in patients with advanced gastric cancer with positive cytology test. Long-term postoperative adjuvant therapy might improve survival of patients with CY1. PMID- 26251342 TI - Variation in circumferential resection margin: Reporting and involvement in the South-Netherlands. AB - BACKGROUND: Since the introduction of total mesorectal surgery the outcome of rectal cancer patients has improved significantly. Involvement of the circumferential resection margin (CRM) is an important predictor of increased local recurrence, distant metastases and decreased overall survival. Abdomino perineal excision (APE) is associated with increased risk of CRM involvement. Aim of this study was to analyze reporting of CRM and to identify predictive factors for CRM involvement. METHODS: A population-based dataset was used selecting 2153 patients diagnosed between 2008 and 2013 with primary rectal cancer undergoing surgery. Variation in CRM reporting was assessed and predictive factors for CRM involvement were calculated and used in multivariate analyses. RESULTS: Large variation in CRM reporting was found between pathology departments, with missing cases varying from 6% to 30%. CRM reporting increased from 77% in 2008 to 90% in 2012 (p < 0.001). CRM involvement significantly decreased from 12% to 6% over the years (p < 0.001). In multivariate analysis type of operation, low anterior resection or APE, did not influence the risk of CRM involvement. Clinical T4 stage [odds ratio (OR) = 3.51; 95% confidence interval (CI) = 1.85-6.65) was associated with increased risk of CRM involvement, whereas neoadjuvant treatment (5 * 5 gray radiotherapy [OR 0.39; CI 0.25-0.62] or chemoradiation therapy [OR 0.30; CI 0.17-0.53]) were associated with significant decreased risk of CRM involvement. CONCLUSION: Although significant improvements are made during the last years there still is variation in reporting of CRM involvement in the Southern Netherlands. In multivariate analysis APE was no longer associated with increased risk of CRM involvement. PMID- 26251343 TI - Adding chemotherapy to hormonal therapy prolongs survival in metastatic prostate cancer, study finds. PMID- 26251344 TI - Correction for Ng et al., Selectivity for the configural cues that identify the gender, ethnicity, and identity of faces in human cortex. PMID- 26251345 TI - Correction for Godec et al., Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8+ T-cell effector differentiation. PMID- 26251346 TI - Facilitating Vocabulary Acquisition of Children With Cochlear Implants Using Electronic Storybooks. AB - The present intervention study explored the word learning of 18 children with cochlear implants in response to E-book instruction. Capitalizing on the multimedia options available in electronic storybooks, the intervention incorporated videos and definitions to provide a vocabulary intervention that includes evidence-based teaching strategies. The extent of the children's word learning was assessed using three assessment tasks: receptive pointing, expressively labeling, and word defining. Children demonstrated greater immediate expressive labeling gains and definition generation gains for words taught in the treatment condition compared to those in the comparison condition. In addition, the children's performance on delayed posttest vocabulary assessments indicated better retention across the expressive vocabulary task for words taught within the treatment condition as compared to the comparison condition. Findings suggest that children with cochlear implants with functional speech perception can benefit from an oral-only multimedia-enhanced intensive vocabulary instruction. PMID- 26251347 TI - Musculoskeletal anatomical changes that accompany limb reduction in lizards. AB - Muscles, bones, and tendons in the adult tetrapod limb are intimately integrated, both spatially and functionally. However, muscle and bone evolution do not always occur hand in hand. We asked, how does the loss of limb bones affect limb muscle anatomy, and do these effects vary among different lineages? To answer these questions, we compared limb muscular and skeletal anatomy among gymnophthalmid lizards, which exhibit a remarkable variation in limb morphology and different grades of digit and limb reduction. We mapped the characters onto a phylogeny of the group to assess the likelihood that they were acquired independently. Our results reveal patterns of reduction of muscle and bone elements that did not always coincide and examples of both, convergent and lineage-specific non pentadactyl musculoskeletal morphologies. Among lineages in which non pentadactyly evolved independently, the degree of convergence seems to depend on the number of digits still present. Most tetradactyl and tridactyl limbs exhibited profound differences in pattern and degree of muscle loss/reduction, and recognizable morphological convergence occurred only in extremely reduced morphologies (e.g., spike-like appendix). We also found examples of muscles that persisted although the bones to which they plesiomorphically attach had been lost, and examples of muscles that had been lost although their normal bony attachments persisted. Our results demonstrate that muscle anatomy in reduced limbs cannot be predicted from bone anatomy alone, meaning that filling the gap between osteological and myological data is an important step toward understanding this recurrent phenomenon in the evolution of tetrapods. PMID- 26251348 TI - Two great medical discoveries and the wretchedness they caused their discoverers. PMID- 26251349 TI - The U.S. Health Care Crisis Five Years After Passage of the Affordable Care Act: A Data Snapshot. AB - Despite passage of the Affordable Care Act in 2010, the U.S. health care crisis continues. While coverage has been expanded, the reform will leave 27 million people uninsured in 2024, according to the Congressional Budget Office. Much of the new coverage is of low actuarial value with high cost-sharing requirements, creating barriers to access. Choice of physician is restricted to narrow networks of providers. Recent measures of uninsurance, underinsurance, access to care, and health care costs are given. Changes in Medicare, particularly privatization and the rise of specialty drug tiers that limit access to medically necessary medications, are reviewed. Data on a new wave of consolidation among hospitals, medical groups, insurers, and drug companies are presented. The rise of ultra high-price drugs, such as Solvadi, is raising pharmaceutical costs, particularly in Medicaid, the program for low-income Americans. International health comparisons continue to show the United States performing poorly in relation to other countries. Recent polling data are presented, showing support for more fundamental reform. PMID- 26251350 TI - Highlighting risk of diseases is most effective in changing attitudes to vaccines, US study finds. PMID- 26251352 TI - Kidney Function and Cerebral Blood Flow: The Rotterdam Study. AB - CKD is linked with various brain disorders. Whereas brain integrity is dependent on cerebral perfusion, the association between kidney function and cerebral blood flow has yet to be determined. This study was performed in the framework of the population-based Rotterdam Study and included 2645 participants with mean age of 56.6 years (45% men). We used eGFR and albumin-to-creatinine ratio to assess kidney function and performed phase-contrast magnetic resonance imaging of basilar and carotid arteries to measure cerebral blood flow. Participants had an average (SD) eGFR of 86.3 (13.4) ml/min per 1.73 m(2) and a median (interquartile range) albumin-to-creatinine ratio of 3.4 (2.2-6.1) mg/g. In age- and sex adjusted models, a higher albumin-to-creatinine ratio was associated with lower cerebral blood flow level (difference in cerebral blood flow [milliliters per minute per 100 ml] per doubling of the albumin-to-creatinine ratio, -0.31; 95% confidence interval, -0.58 to -0.03). The association was not present after adjustment for cardiovascular risk factors (P=0.10). Each 1 SD lower eGFR was associated with 0.42 ml/min per 100 ml lower cerebral blood flow (95% confidence interval, 0.01 to 0.83) adjusted for cardiovascular risk factors. Thus, in this population-based study, we observed that lower eGFR is independently associated with lower cerebral blood flow. PMID- 26251351 TI - Extracellular Vesicles in Renal Diseases: More than Novel Biomarkers? AB - Extracellular vesicles from the urine and circulation have gained significant interest as potential diagnostic biomarkers in renal diseases. Urinary extracellular vesicles contain proteins from all sections of the nephron, whereas most studied circulating extracellular vesicles are derived from platelets, immune cells, and the endothelium. In addition to their diagnostic role as markers of kidney and vascular damage, extracellular vesicles may have functional significance in renal health and disease by facilitating communication between cells and protecting against kidney injury and bacterial infection in the urinary tract. However, the current understanding of extracellular vesicles has derived mostly from studies with very small numbers of patients or in vitro data. Moreover, accurate assessment of these vesicles remains a challenge, in part because of a lack of consensus in the methodologies to measure extracellular vesicles and the inability of most techniques to capture the entire size range of these vesicles. However, newer techniques and standardized protocols to improve the detection of extracellular vesicles are in development. A clearer understanding of the composition and biology of extracellular vesicles will provide insights into their pathophysiologic, diagnostic, and therapeutic roles. PMID- 26251353 TI - New cases of HIV among people who inject drugs in Hungary: False alarm or early warning? AB - Between 2009 and the first quarter of 2014, only one case of HIV (contracted outside Hungary) was detected among PWIDs in Hungary. However, more recent evidence suggests increased sharing of injecting paraphernalia among PWIDs. This is linked to the emergence of new designer drugs that require frequent injection, alongside funding cuts to the Hungarian needle exchange program (NEP) which has reduced access to sterile injecting equipment. During the past five years in Hungary, drug use has become increasingly discussed in moral as opposed to public health terms, and drug consumption has been re-criminalized. The largest NEP in Hungary was closed because of political pressure and government funding for regular HCV/HIV testing/counselling and seroprevalence studies among PWIDs has been stopped. This paper describes the detection of two new cases of HIV infection in PWIDs attending two NEPs in Budapest in May 2014. These new cases may indicate an unfolding HIV outbreak among PWIDs-similar to those reported in Greece and Romania. Yet the question remains: If no further HIV cases are detected, is this because there are no new cases or because there are no testing facilities for PWID? PMID- 26251354 TI - Retrospective Studies. PMID- 26251355 TI - Modern imaging techniques: applications in the management of acute aortic pathologies. AB - Acute aortic pathologies include traumatic and non-traumatic life-threatening emergencies of the aorta. Since the clinical manifestation of these entities can be non-specific and may overlap with other conditions presenting with chest pain, non-invasive imaging plays a crucial role in their rapid and accurate evaluation. The early diagnosis and accurate radiological assessment of acute aortic diseases is essential for improved clinical outcomes. Multidetector CT is the imaging modality of choice for evaluation of acute aortic diseases with MRI playing more of a problem-solving role. The management can be medical, endovascular or surgical depending upon pathology, and imaging remains an indispensable management-guiding tool. It is important to understand the pathogenesis, natural history, and imaging principles of acute aortic diseases for appropriate use of advanced imaging modalities. This understanding helps to formulate a more appropriate management and follow-up plan for optimised care of these patients. Imaging reporting pearls for day-to-day radiology as well as treatment options based on latest multidisciplinary guidelines are discussed. With newer techniques of image acquisition and processing, we are hopeful that imaging would further help in predicting aortic disease progression and assessing the haemodynamic parameters based on which decisions on management can be made. PMID- 26251356 TI - Group of private eye surgeons fined L0.5m for breaching competition law. PMID- 26251357 TI - Human epidermal neural crest stem cells as a source of Schwann cells. AB - We show that highly pure populations of human Schwann cells can be derived rapidly and in a straightforward way, without the need for genetic manipulation, from human epidermal neural crest stem cells [hEPI-NCSC(s)] present in the bulge of hair follicles. These human Schwann cells promise to be a useful tool for cell based therapies, disease modelling and drug discovery. Schwann cells are glia that support axons of peripheral nerves and are direct descendants of the embryonic neural crest. Peripheral nerves are damaged in various conditions, including through trauma or tumour-related surgery, and Schwann cells are required for their repair and regeneration. Schwann cells also promise to be useful for treating spinal cord injuries. Ex vivo expansion of hEPI-NCSC isolated from hair bulge explants, manipulating the WNT, sonic hedgehog and TGFbeta signalling pathways, and exposure of the cells to pertinent growth factors led to the expression of the Schwann cell markers SOX10, KROX20 (EGR2), p75NTR (NGFR), MBP and S100B by day 4 in virtually all cells, and maturation was completed by 2 weeks of differentiation. Gene expression profiling demonstrated expression of transcripts for neurotrophic and angiogenic factors, as well as JUN, all of which are essential for nerve regeneration. Co-culture of hEPI-NCSC-derived human Schwann cells with rodent dorsal root ganglia showed interaction of the Schwann cells with axons, providing evidence of Schwann cell functionality. We conclude that hEPI-NCSCs are a biologically relevant source for generating large and highly pure populations of human Schwann cells. PMID- 26251358 TI - Public support for smoke-free policies in Jordan, a high tobacco burden country with weak implementation of policies: Status, opportunities, and challenges. AB - Several Eastern Mediterranean (EM) countries, including Jordan, suffer from high smoking prevalence but weak implementation of smoking bans (SB). Public support (PS) influences successful implementation of SB, but little is known about PS for SB in EM countries with weak SB implementation. We conducted a cross-sectional survey measuring knowledge and perceptions of a large purposive sample of the Jordanian public regarding tobacco harms and anti-tobacco laws. Among 1169 respondents, 46% of whom used tobacco, PS for SB varied from 98% to 39% based on venue, being highest for health facilities and lowest for coffee shops. In venues with relatively lower PS (restaurants, coffee shops), lower educational groups, older age groups, nonsmokers, and those who had more knowledge regarding tobacco and secondhand smoke harms were significantly more likely to support SB than the highest educational group, the youngest age group, smokers, and those who had less knowledge (respectively). Our results suggest that aggressive promotion of SB is needed in countries like Jordan (where smoking is increasing), tailored to venue and specific sociodemographic characteristics of the public accessing these venues, particularly restaurants and coffee shops. Multifaceted health messages that enhance public knowledge can be of benefit in improving PS for SB. PMID- 26251359 TI - Global burden of genetic disease and the role of genetic screening. AB - It is estimated that 5.3% of newborns will suffer from a genetic disorder, when followed up until the age of 25 years. In developing, as compared to western countries, hemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency have a higher incidence due to severe falciparum malaria in the distant past, and autosomal recessive disorders have a higher frequency due to greater proportion of consanguineous marriages. Chromosomal disorders have a combined frequency of 1 in 153 births, therefore screening for chromosomal disorders is essential, using biochemical markers, ultrasonography, and recently by non-invasive prenatal diagnosis based on cell-free fetal DNA in maternal plasma. Preconceptional counseling should be encouraged. For genetic disorders screening should be carried out, ideally after marriage, but before pregnancy. The disorders to be screened depend upon ethnicity. Metabolic disorders have a high incidence in developing countries due to greater rate of consanguineous marriages. Newborn screening is recommended to reduce the burden of these disorders, as many metabolic disorders can be treated. Hearing and critical congenital heart disease should both be screened in the newborn period. PMID- 26251360 TI - Differential reduction in cardiac and liver monolysocardiolipin acyltransferase-1 and reduction in cardiac and liver tetralinoleoyl-cardiolipin in the alpha subunit of trifunctional protein heterozygous knockout mice. AB - The contribution of alpha-subunit of trifunctional protein (alphaTFP) to cardiolipin (CL) (diphosphatidylglycerol) remodelling and mitochondrial supercomplex formation was examined in heart and liver mitochondria from wild type (WT) and alphaTFP heterozygous knockout [Mtpa(+/-)] mice. Mtpa(+/-) mouse heart and liver exhibited an approximate 55% and 50% reduction in alphaTFP protein expression compared with WT respectively. Monolysocardiolipin (MLCL) acyltransferase (MLCL AT)-1 protein derived from alphaTFP was reduced by 30% in Mtpa(+/-) mouse heart but not in liver compared with WT. In vitro acylation of MLCL was significantly reduced in heart but not in liver mitochondria of Mtpa(+/ ) mice compared with WT. CL mass was reduced and significant reductions in linoleate-containing CL species, in particular tetralinoleoyl-CL (L4-CL) and trilinoleoyl-CL (L3-MLCL) species, were observed in heart and liver mitochondria of Mtpa(+/-) mice compared with WT. Cardiac and liver mitochondrial supercomplex assembly and NADH dehydrogenase (complex I) activity within these supercomplexes were unaltered in both Mtpa(+/-) mouse heart and Mtpa(+/-) mouse liver compared with WT. The results indicate that alphaTFP may modulate CL molecular species composition in murine heart and liver. In addition, L4-CL might not be an essential requirement for mitochondrial supercomplex assembly. PMID- 26251362 TI - Exploring childhood cancer survivors' views about sex and sexual experiences findings from online focus group discussions. AB - PURPOSE: To explore childhood cancer survivors' views about sex and sexual experiences and, as an additional aim, their possible needs for care and support from health care professionals regarding sexual life. METHODS: Written online focus group discussions were performed with survivors of childhood cancer, identified through the Swedish Childhood Cancer Registry; 133 (36%; aged 16-25) participated. Written text was analysed using qualitative content analysis. RESULTS: The analysis resulted in one main category: Could my cancer experience have an impact on my sexual life? with four generic categories: Sex considered to be good, Feeling insecure and falling behind, Relating sex to a stable relationship and Concerns related to the physical body. In general, participants had not reflected on the possibility that their cancer experience could impact on sexual life. Sex was often considered to be something natural, important and taken for granted. However, thoughts and worries were expressed including being shy, feeling insecure and falling behind peers. Physical concerns included vaginal dryness and difficulties related to erection and reaching orgasm. Many participants stated that sexual issues had not been discussed with health care professionals, however, the need for such support differed. CONCLUSIONS: Many of the childhood cancer survivors' did not relate their sexual experiences to previous cancer treatment. However, problems were expressed, both of emotional and physical nature. Many participants stated that they had not received any information or support regarding sexual issues from health care professionals, why it is recommended to be regularly addressed in follow-up care. PMID- 26251361 TI - Chronic Noise Exposure Acts Cumulatively to Exacerbate Alzheimer's Disease-Like Amyloid-beta Pathology and Neuroinflammation in the Rat Hippocampus. AB - A putative etiological association exists between noise exposure and Alzheimer's disease (AD). Amyloid-beta (Abeta) pathology is thought to be one of the primary initiating factors in AD. It has been further suggested that subsequent dysregulation of Abeta may play a mechanistic role in the AD-like pathophysiology associated with noise exposure. Here, we used ELISA, immunoblotting, cytokine arrays, and RT-PCR, to examine both hippocampal Abeta pathology and neuroinflammation in rats at different time points after noise exposure. We found that chronic noise exposure significantly accelerated the progressive overproduction of Abeta, which persisted for 7 to 14 days after the cessation of exposure. This effect was accompanied by up-regulated expression of amyloid precursor protein (APP) and its cleavage enzymes, beta- and gamma-secretases. Cytokine analysis revealed that chronic noise exposure increased levels of tumor necrosis factor-alpha and the receptor for advanced glycation end products, while decreasing the expression of activin A and platelet-derived growth factor-AA. Furthermore, we found persistent elevations of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 expression that closely corresponded to the noise-induced increases in Abeta and neuroinflammation. These studies suggest that lifelong environmental noise exposure may have cumulative effects on the onset and development of AD. PMID- 26251363 TI - A participatory study of teenagers and young adults views on access and participation in cancer research. AB - PURPOSE: The purpose of this study was to elicit young people's views on access and participation in cancer research. METHODS: Eight young people aged 18-25 years with a previous cancer diagnosis aged 15-24 participated in a one day workshop utilising participatory methodology. The workshop consisted of four exercises: role play/scene setting; focus group examining thoughts and opinions of research access and participation; individual reflection on access to different types of research; and creative interpretation of the workshop. Further consultation with 222 young people with cancer was conducted using an electronic survey. RESULTS: Three themes emerged: * Patient choice: Young people thought it was their right to know all options about available research. Without knowledge of all available studies they would be unable to make an informed choice about participation. * Role of healthcare professionals as facilitators/barriers: Young people suggested non-clinical healthcare professionals such as social workers and youth support coordinators may be more suited to approaching young people about participation in psychosocial and health services research. * Value of the research: The what, when and how information was delivered was key in relaying the value of the study and assisting young people in their decision to participate. Further consultation showed approximately 70% wanted to find out about all available research. However, one third trusted healthcare professionals to decide which research studies to inform them of. CONCLUSION: Effective ways to support healthcare professionals approaching vulnerable populations about research are needed to ensure young people are empowered to make informed choices about research participation. PMID- 26251364 TI - Effective ovarian cancer treatment is underused, US study finds. PMID- 26251365 TI - Motion-perfusion mismatch-pattern on rest-gated SPECT suggests non-transmural necrosis on cardiac magnetic resonance. PMID- 26251366 TI - (18)F-FDG PET/CT imaging of squamous cell carcinoma induced by Vemurafenib. PMID- 26251367 TI - Ten year experience of laparoscopic repair of pediatric hydrocele and the long term follow-up results. AB - PURPOSE: This study aims to assess the efficacy and safety of laparoscopic repair for pediatric hydroceles and its long-term follow-up results. METHODS: We performed this procedure to 284 patients from 2002 to 2011 using our specially designed curved awl. The patent internal ring was enclosed and fixed under laparoscopy and fluid within the patent processus vaginalis was emptied by percutaneous needle aspiration. RESULTS: The median operation time was 16minutes. Fifty-seven contralateral open internal rings were diagnosed during laparoscopic exploration and closed at the same time. During our 10-year follow-up only four kids had recurrence of moderate amount of fluid accumulation 1-3months after the surgery and 3 of them spontaneously resolved during the outpatient follow-ups. Only one of them was treated by percutaneous needle aspiration successfully. No abdominal viscera injury happened. CONCLUSIONS: Laparoscopic hydrocele repair proved to be applicable and effective with satisfactory long-term results according to our experience. PMID- 26251368 TI - Rib overgrowth may be a contributing factor for pectus excavatum: Evaluation of prepubertal patients younger than 10years old. AB - BACKGROUND/PURPOSE: We compared the costal cartilage and rib length between prepubertal patients with symmetric pectus excavatum and age- and sex-matched controls without anterior chest wall depression to evaluate if rib overgrowth is a contributing factor for pectus excavatum METHODS: The sample included 18 prepubertal patients <10years old with symmetric pectus excavatum and 18 age-and sex-matched controls without chest wall deformity. The full lengths of the fourth to sixth ribs and costal cartilage were measured using three-dimensional volume rendered computed tomography and curved multiplanar reformatting techniques. The rib and costal cartilage lengths, total combined rib and costal cartilage length, and costal index ([length of cartilage/length of rib]*100 [%]) at the fourth to sixth levels were compared between the groups. RESULTS: The rib lengths in the patient group were significantly longer than in the control group for the 6th right rib and 4th, 5th, and 6th left ribs. The costal cartilage lengths and costal indices were not different between two groups. CONCLUSIONS: In patients with symmetric pectus excavatum aged <10years old, several of the ribs were longer than those of controls, suggesting that abnormal rib overgrowth may be a contributing factor responsible for pectus excavatum rather than cartilage overgrowth. PMID- 26251369 TI - The Role of Mobile Applications in Improving Alcohol Health Literacy in Young Adults With Type 1 Diabetes: Help or Hindrance? AB - BACKGROUND: Mobile health (mHealth) is an expanding field which includes the use of social media and mobile applications (apps). Apps are used in diabetes self management but it is unclear whether these are being used to support safe drinking of alcohol by people with type 1 diabetes (T1DM). Alcohol health literacy is poor among young adults with T1DM despite specific associated risks. METHODS: Systematic literature review followed by critical appraisal of commercially available apps. An eSurvey investigating access to mHealth technology, attitudes toward apps for diabetes management and their use to improve alcohol health literacy was completed by participants. RESULTS: Of 315 articles identified in the literature search, 7 met the inclusion criteria. Ten diabetes apps were available, most of which lacked the educational features recommended by clinical guidelines. In all, 27 women and 8 men with T1DM, aged 19 31 years were surveyed. Of them, 32 had access to a smartphone/tablet; 29 used apps; 20 used/had used diabetes apps; 3 had used apps related to alcohol and diabetes; 11 had discussed apps with their health care team; 22 felt more communication with their health care team would increase awareness of alcohol associated risks. CONCLUSIONS: Use of mobile apps is commonplace but the use of apps to support safe drinking in this population was rare. Most participants expressed a preference for direct communication with their health care teams about this subject. Further research is needed to determine the preferences of health care professionals and how they can best support young adults in safe drinking. PMID- 26251370 TI - IQWiG Reanalyzes and Raises Questions About an Article by Ly et al Which Concluded Low Glucose Suspend Is Very Beneficial. AB - In 2013, Ly et al published a study in JAMA reporting a massive reduction in the frequency of severe hypoglycemic events when the patients used sensor augmented insulin pump therapy with low glucose suspense. The data of this study were reanalyzed by the IQWiG when this German institute started its evaluation of the evidence for continuous glucose monitoring (CGM) usage. The IQWiG came to a contrary conclusion than the authors of the Ly study. Decisive for this was the statistical analysis of the Ly study that led the IQWiG to evaluate this result as a lack of evidence for the superiority of CGM (plus pump) for preventing hypoglycemia. In this commentary, a direct English translation of the IQWiG analysis is provided to enable the reader to come to his or her own conclusion about this study. PMID- 26251372 TI - Mobile Phone Usage and Willingness to Receive Health-Related Information Among Patients Attending a Chronic Disease Clinic in Rural Puducherry, India. PMID- 26251373 TI - Reversible 1,2-Alkyl Migration to Carbene and Ammonia Activation in an N Heterocyclic Carbene-Zirconium Complex. AB - Addition of trimethylphosphine to a bis(phenolate)benzylimidazolylidene(dibenzyl)zirconium complex induces migration of a benzyl ligand from the metal center to the C(carbine) atom. This process may be reversed, resulting in Csp(3)-Csp(3) activation, by abstraction of the phosphine, an example of regulated, reversible alkyl migration. Addition of ammonia to the dibenzyl complex results in migration of one benzyl group and protonolysis of the other to generate a bis(NH2)-bridged dimer via an NMR observable intermediate NH3 adduct. PMID- 26251371 TI - Influence of Inspiratory Muscle Training on Changes in Fasting Hyperglycemia in the Older Adult: The Epidoso Project. PMID- 26251374 TI - A nuclear shadow from Hiroshima and Nagasaki to Fukushima. PMID- 26251375 TI - Time to introduce organ donation to the concept of precision? PMID- 26251376 TI - Paying a high price for cancer drugs. PMID- 26251377 TI - Hiroshima, Nagasaki, and Fukushima. PMID- 26251379 TI - Hiroshima survivors remember. PMID- 26251378 TI - Health effects of nuclear weapons testing. PMID- 26251380 TI - 50 years of Medicare. PMID- 26251381 TI - Koichi Tanigawa: a passionate voice in radiation disaster medicine. PMID- 26251382 TI - An ounce of prevention. PMID- 26251383 TI - Alan Jurgen Brotherton. PMID- 26251384 TI - How many more missing women? PMID- 26251385 TI - Prevention of violence against women and girls at the community level. PMID- 26251386 TI - Cancer survival: [corrected] the CONCORD-2 study. PMID- 26251387 TI - Cancer survival: [corrected] the CONCORD-2 study - Authors' reply. PMID- 26251388 TI - Cancer survival: [corrected] the CONCORD-2 study. PMID- 26251389 TI - Stunting in earthquake-affected districts in Nepal. PMID- 26251390 TI - Prednisone for community-acquired pneumonia: not yet time. PMID- 26251391 TI - Age-specific incidence of Ebola virus disease. PMID- 26251392 TI - Long-term effects of radiation exposure on health. AB - Late-onset effects of exposure to ionising radiation on the human body have been identified by long-term, large-scale epidemiological studies. The cohort study of Japanese survivors of the atomic bombings of Hiroshima and Nagasaki (the Life Span Study) is thought to be the most reliable source of information about these health effects because of the size of the cohort, the exposure of a general population of both sexes and all ages, and the wide range of individually assessed doses. For this reason, the Life Span Study has become fundamental to risk assessment in the radiation protection system of the International Commission on Radiological Protection and other authorities. Radiation exposure increases the risk of cancer throughout life, so continued follow-up of survivors is essential. Overall, survivors have a clear radiation-related excess risk of cancer, and people exposed as children have a higher risk of radiation-induced cancer than those exposed at older ages. At high doses, and possibly at low doses, radiation might increase the risk of cardiovascular disease and some other non-cancer diseases. Hereditary effects in the children of atomic bomb survivors have not been detected. The dose-response relation for cancer at low doses is assumed, for purposes of radiological protection, to be linear without a threshold, but has not been shown definitively. This outstanding issue is not only a problem when dealing appropriately with potential health effects of nuclear accidents, such as at Fukushima and Chernobyl, but is of growing concern in occupational and medical exposure. Therefore, the appropriate dose-response relation for effects of low doses of radiation needs to be established. PMID- 26251393 TI - Health effects of radiation and other health problems in the aftermath of nuclear accidents, with an emphasis on Fukushima. AB - 437 nuclear power plants are in operation at present around the world to meet increasing energy demands. Unfortunately, five major nuclear accidents have occurred in the past--ie, at Kyshtym (Russia [then USSR], 1957), Windscale Piles (UK, 1957), Three Mile Island (USA, 1979), Chernobyl (Ukraine [then USSR], 1986), and Fukushima (Japan, 2011). The effects of these accidents on individuals and societies are diverse and enduring. Accumulated evidence about radiation health effects on atomic bomb survivors and other radiation-exposed people has formed the basis for national and international regulations about radiation protection. However, past experiences suggest that common issues were not necessarily physical health problems directly attributable to radiation exposure, but rather psychological and social effects. Additionally, evacuation and long-term displacement created severe health-care problems for the most vulnerable people, such as hospital inpatients and elderly people. PMID- 26251394 TI - Nuclear disasters and health: lessons learned, challenges, and proposals. AB - Past nuclear disasters, such as the atomic bombings in 1945 and major accidents at nuclear power plants, have highlighted similarities in potential public health effects of radiation in both circumstances, including health issues unrelated to radiation exposure. Although the rarity of nuclear disasters limits opportunities to undertake rigorous research of evidence-based interventions and strategies, identification of lessons learned and development of an effective plan to protect the public, minimise negative effects, and protect emergency workers from exposure to high-dose radiation is important. Additionally, research is needed to help decision makers to avoid premature deaths among patients already in hospitals and other vulnerable groups during evacuation. Since nuclear disasters can affect hundreds of thousands of people, a substantial number of people are at risk of physical and mental harm in each disaster. During the recovery period after a nuclear disaster, physicians might need to screen for psychological burdens and provide general physical and mental health care for many affected residents who might experience long-term displacement. Reliable communication of personalised risks has emerged as a challenge for health-care professionals beyond the need to explain radiation protection. To overcome difficulties of risk communication and provide decision aids to protect workers, vulnerable people, and residents after a nuclear disaster, physicians should receive training in nuclear disaster response. This training should include evidence-based interventions, support decisions to balance potential harms and benefits, and take account of scientific uncertainty in provision of community health care. An open and joint learning process is essential to prepare for, and minimise the effects of, future nuclear disasters. PMID- 26251395 TI - Towards long-term responses in Fukushima. PMID- 26251396 TI - Leukaemic vasculitis with myelodysplastic syndrome. PMID- 26251397 TI - Leukaemic vasculitis from myelodysplastic syndrome in context. PMID- 26251398 TI - Regional disparities in cancer mortality across the rural-urban axis: a case study from north-eastern Greece. AB - INTRODUCTION: The aim of this study was to identify differences in cancer mortality in north-eastern Greece, to describe potential drivers operating at the population level and to propose practical interventions and mitigation strategies. METHODS: Cancer mortality data were collected from local registries using the WHO 10th edition of International Classification of Disease (ICD-10). The direct standardization method was used to address demographic differences in the two regions, with the Standard European Population as reference. Rate ratios (RR) were employed for comparisons and 95% confidence intervals (95%CI) were calculated according to the Poisson approximation method. RESULTS: An increased risk of digestive system cancers (excluding liver neoplasms) was observed in rural versus urban areas (RR=1.25, 95%CI=1.02-1.54). Stomach cancer, in particular, was more prevalent in the older cohorts (>65 years), suggesting a historical epidemiological perspective. A more pronounced discrepancy was observed for prostate cancer mortality (RR=1.86, 95%CI=1.10-3.14), indicating a strong positive correlation with rurality. CONCLUSIONS: Cancer mortality disparities have been observed between rural and urban regions of north-eastern Greece. Health promotion and education, including improved access to medical facilities and early cancer screening, can help mitigate the burden and extend survival rates. Decreasing cancer staging at the time of diagnosis and reversing social and economic inequalities is key for combating these types of malignancy. PMID- 26251399 TI - In-hospital organization of primary care of patients presenting a life threatening emergency: A French national survey in 32 university hospitals. AB - INTRODUCTION: The development of specialized units dedicated to life-threatening management has demonstrated to improve the prognosis of patients requiring such treatments. However, apart those focused on trauma and stroke, networks are still lacking in France. Despite, the implementation of standardisation of practices and guidelines, particularly in prehospital care, in-hospital clinical practices at admission remain heterogenous. This survey aimed to assess the structural and human organization of teaching hospitals in France concerning the primary in hospital care for critically ill patients. MATERIAL AND METHOD: A questionnaire of 45 items was sent by e-mail to 32 teaching hospitals between January and March 2013. It included information related to the description of the emergency department, of ICUs, and both structural and human organizations for primary in hospital care of life-threatening patients. RESULTS: Seventy-five percent of teaching hospitals answered to the survey. Seven hundred to 1400 patients were admitted to emergency units per week and among them 10 to 20 were admitted for critically ill conditions. These latter were addressed in a specialized room of the emergency unit (Service d'admission des urgences vitales [SAUV]) in 40% of hospitals and in specialized room in ICU in 18% of cases. Intensivists were involved in 50% of hospitals, emergency physicians in 26% and it was mixed in 24% of hospitals. CONCLUSION: This survey is the first to assess the in-hospital organization of primary care for instable and life-threatening patients in France. Our results confirmed the extreme heterogeneity of structural and human organizations for primary in-hospital care of patients presenting at least one organ failure. Thus, a consensus is probably needed to homogenize and improve our practices. PMID- 26251400 TI - Serum level of proximal renal tubular epithelial cell-binding immunoglobulin G in patients with lupus nephritis. AB - In vitro data showed that immunoglobulin G (IgG) from lupus nephritis (LN) patients could bind to proximal renal tubular epithelial cells (PTEC), but the clinical relevance of such binding remained unclear. Binding of IgG and subclasses to PTEC was measured by cellular ELISA (expressed as OD index) in 189 serial serum samples from 23 Class III/IV +/- V LN patients who had repeated renal flares (48 during renal flares, 141 during low level disease activity (LLDA)), and compared with 64 patients with non-lupus glomerular diseases (NLGD) and 23 healthy individuals. Total IgG PTEC-binding index was 0.34 +/- 0.16, 0.29 +/- 0.16, 0.62 +/- 0.27 and 0.83 +/- 0.38 in healthy controls, NLGD, LN patients during LLDA, and LN patients during nephritic flare, respectively (p < 0.001, LLDA vs. renal flare; p < 0.001, healthy controls or NLGD vs. LN during LLDA or renal flare). PTEC-binding index for IgG1 was 0.09 +/- 0.05, 0.16 +/- 0.12, 0.44 +/- 0.34 and 0.71 +/- 0.46 for the corresponding groups (p < 0.001, LLDA vs. renal flare; p < 0.001, healthy controls or NLGD vs. LN during LLDA or renal flare). Sixteen of 48 episodes (33.3%) of nephritic flare showed persistent PTEC binding IgG seropositivity for more than 9.4 +/- 3.1 months, despite clinical response to immunosuppressive treatment. Total IgG and IgG1 PTEC-binding correlated with anti-dsDNA level (r = 0.34 and 0.52, respectively, p < 0.001 for both), and inversely with C3 level (r = -0.26 and -0.50, respectively, p = 0.002 and<0.001). Sensitivity/specificity of PTEC-binding index in detecting renal flares was 45.8%/80.1% for total IgG (ROC AUC 0.630, p = 0.007) and 87.5%/35.5% for IgG1 (ROC AUC 0.615, p = 0.018). IgG1 PTEC-binding index correlated with tubulo-interstitial inflammation score in renal biopsy from corresponding patients. Our data suggested that total IgG and IgG1 PTEC-binding index in serum of LN patients correlate with serological activity, and in combination could predict renal flares. The correlation between IgG1 PTEC-binding and tubulo interstitial inflammation suggests potential pathogenetic significance. PMID- 26251401 TI - Discoid lupus erythematosus with squamous cell carcinoma: a case report and review of the literature in Indian patients. AB - We report a case of a patient with localized discoid lupus erythematosus (DLE) who was found to have high-grade squamous dysplasia (carcinoma in situ) over the upper lip. This report also consists of a brief review of 16 other cases of DLE with squamous cell carcinoma (SCC) we came across while going through the literature in an Indian scenario.Incidence of SCC over DLE in the Indian population is found to be 0.98% to 3.4% with a male-to-female ratio of 1.6:1. The latent period between onset of DLE and development of SCC was 9.59 +/- 5.6 years.There was history of chronic sun exposure in 81.8% of patients, which indicates a possible role of prolonged ultraviolet light exposure in malignant transformation. The lips were the most commonly affected area (28.57%), with the upper lip being more commonly involved than the lower lip. We also observed that the latent period (5 +/- 2.7 years) in lip tumours was shorter than that in other sites (11.22 +/- 6.78 years), indicating a more rapid transformation in lips (p value = 0.038). Well differentiated was the most common (46.2%) type of SCC noted. Lymph node involvement was found in three of 17 cases (25%) and one case (8.3%) had recurrence of lesions after excision.We conclude that in India though SCC is rare per se, its occurrence in the context of DLE is not uncommon and is aggressive in nature. PMID- 26251402 TI - Heterogeneity of peripheral blood monocytes, endothelial dysfunction and subclinical atherosclerosis in patients with systemic lupus erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by increased cardiovascular morbidity and mortality. SLE patients have increased prevalence of subclinical atherosclerosis, although the mechanisms of this observation remain unclear. Considering the emerging role of monocytes in atherosclerosis, we aimed to investigate the relationship between subclinical atherosclerosis, endothelial dysfunction and the phenotype of peripheral blood monocytes in SLE patients. METHODS: We characterized the phenotype of monocyte subsets defined by the expression of CD14 and CD16 in 42 patients with SLE and 42 non-SLE controls. Using ultrasonography, intima-media thickness (IMT) of carotid arteries and brachial artery flow-mediated dilation (FMD) as well as nitroglycerin-induced dilation (NMD) were assessed. RESULTS: Patients with SLE had significantly, but only modestly, increased IMT when compared with non-SLE controls (median (25th/75th percentile) 0.65 (0.60/0.71) mm vs 0.60 (0.56/0.68) mm; p < 0.05). Importantly, in spite of early atherosclerotic complications in the studied SLE group, marked endothelial dysfunction was observed. CD14dimCD16+proinflammatory cell subpopulation was positively correlated with IMT in SLE patients. This phenomenon was not observed in control individuals. Interestingly, endothelial dysfunction assessed by FMD was not correlated with any of the studied monocyte subsets. CONCLUSIONS: Our observations suggest that CD14dimCD16+monocytes are associated with subclinical atherosclerosis in SLE, although the mechanism appears to be independent of endothelial dysfunction. PMID- 26251403 TI - EphA4 Receptor Forward Signaling Inhibits Glucagon Secretion From alpha-Cells. AB - The loss of inhibition of glucagon secretion exacerbates hyperglycemia in type 1 and 2 diabetes. However, the molecular mechanisms that regulate glucagon secretion in unaffected and diabetic states remain relatively unexplained. We present evidence supporting a new model of juxtacrine-mediated regulation of glucagon secretion where neighboring islet cells negatively regulate glucagon secretion through tonic stimulation of alpha-cell EphA receptors. Primarily through EphA4 receptors, this stimulation correlates with maintenance of a dense F-actin network. In islets, additional stimulation and inhibition of endogenous EphA forward signaling result in inhibition and enhancement, respectively, of glucagon secretion, accompanied by an increase and decrease, respectively, in alpha-cell F-actin density. Sorted alpha-cells lack endogenous stimulation of EphA forward signaling from neighboring cells, resulting in enhanced basal glucagon secretion as compared with islets and the elimination of glucose inhibition of glucagon secretion. Restoration of EphA forward signaling in sorted alpha-cells recapitulates both normal basal glucagon secretion and glucose inhibition of glucagon secretion. Additionally, alpha-cell-specific EphA4(-/-) mice exhibit abnormal glucagon dynamics, and EphA4(-/-) alpha-cells contain less dense F-actin networks than EphA4(+/+) alpha-cells. This juxtacrine-mediated model provides insight into the functional and dysfunctional regulation of glucagon secretion and opens up new therapeutic strategies for the clinical management of diabetes. PMID- 26251405 TI - Links between food manufacturers and Spanish health institutions are highlighted in report. PMID- 26251404 TI - Activation of FoxM1 Revitalizes the Replicative Potential of Aged beta-Cells in Male Mice and Enhances Insulin Secretion. AB - Type 2 diabetes incidence increases with age, while beta-cell replication declines. The transcription factor FoxM1 is required for beta-cell replication in various situations, and its expression declines with age. We hypothesized that increased FoxM1 activity in aged beta-cells would rejuvenate proliferation. Induction of an activated form of FoxM1 was sufficient to increase beta-cell mass and proliferation in 12-month-old male mice after just 2 weeks. Unexpectedly, at 2 months of age, induction of activated FoxM1 in male mice improved glucose homeostasis with unchanged beta-cell mass. Cells expressing activated FoxM1 demonstrated enhanced glucose-stimulated Ca2+ influx, which resulted in improved glucose tolerance through enhanced beta-cell function. Conversely, our laboratory has previously demonstrated that mice lacking FoxM1 in the pancreas display glucose intolerance or diabetes with only a 60% reduction in beta-cell mass, suggesting that the loss of FoxM1 is detrimental to beta-cell function. Ex vivo insulin secretion was therefore examined in size-matched islets from young mice lacking FoxM1 in beta-cells. Foxm1-deficient islets indeed displayed reduced insulin secretion. Our studies reveal that activated FoxM1 increases beta-cell replication while simultaneously enhancing insulin secretion and improving glucose homeostasis, making FoxM1 an attractive therapeutic target for diabetes. PMID- 26251406 TI - Sudden onset diffuse erythema and oedema of the breast. PMID- 26251407 TI - Trends of diagnosis-specific work disability after newly diagnosed diabetes: a 4 year nationwide prospective cohort study. AB - OBJECTIVE: We examined trends of diagnosis-specific work disability after newly diagnosed diabetes, comparing individuals with diabetes with those without diabetes, and identified the subgroups with the highest levels of work disability. RESEARCH DESIGN AND METHODS: The register data of diabetes medication and in- and outpatient hospital visits were used to identify all recorded new diabetes cases among the population aged 25-59 years in Sweden in 2006 (n = 14,098). Data for a 4-year follow-up of ICD-10 physician-certified sickness absence and disability pension days (2007-2010) were obtained from the Swedish Social Insurance Agency. Comparisons were made using a random sample of the population without recorded diabetes (n = 39,056). RESULTS: The most common causes of work disability were mental and musculoskeletal disorders; diabetes as a reason for disability was rare. Most of the excess work disability among people with diabetes compared with those without diabetes was owing to mental disorders (mean difference adjusted for confounding factors 18.8-19.8 compensated days/year), musculoskeletal diseases (12.1-12.8 days/year), circulatory diseases (5.9-6.5 days/year), diseases of the nervous system (1.8-2.0 days/year), and injuries (1.0-1.2 days/year). The disparity in mental disorders first widened and then narrowed, while the difference in other major diagnostic categories was stable over 4 years. The highest rate (45.3 days/year) was found among people who had diabetes, lived alone, and were disabled from work owing to mental disorders. CONCLUSIONS: The increased risk of work disability among those with diabetes is largely attributed to comorbid mental, musculoskeletal, and circulatory diseases. It is important to monitor comorbid conditions and take account of socioeconomic disadvantage. PMID- 26251409 TI - Predicting decline and survival in severe acute brain injury: the fourth trajectory. PMID- 26251410 TI - It's not just about the money, money, money. PMID- 26251408 TI - Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. AB - OBJECTIVE: Metformin is used as a first-line oral treatment for type 2 diabetes (T2D). However, the underlying mechanism is not fully understood. Here, we aimed to comprehensively investigate the pleiotropic effects of metformin. RESEARCH DESIGN AND METHODS: We analyzed both metabolomic and genomic data of the population-based KORA cohort. To evaluate the effect of metformin treatment on metabolite concentrations, we quantified 131 metabolites in fasting serum samples and used multivariable linear regression models in three independent cross sectional studies (n = 151 patients with T2D treated with metformin [mt-T2D]). Additionally, we used linear mixed-effect models to study the longitudinal KORA samples (n = 912) and performed mediation analyses to investigate the effects of metformin intake on blood lipid profiles. We combined genotyping data with the identified metformin-associated metabolites in KORA individuals (n = 1,809) and explored the underlying pathways. RESULTS: We found significantly lower (P < 5.0E 06) concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) when comparing mt-T2D with four control groups who were not using glucose lowering oral medication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of these metabolites decreased significantly in patients after they started metformin treatment during 7 years' follow-up. The reduction of these metabolites was also associated with a lowered blood level of LDL cholesterol (LDL-C). Variations of these three metabolites were significantly associated with 17 genes (including FADS1 and FADS2) and controlled by AMPK, a metformin target. CONCLUSIONS: Our results indicate that metformin intake activates AMPK and consequently suppresses FADS, which leads to reduced levels of the three acyl-alkyl PCs and LDL-C. Our findings suggest potential beneficial effects of metformin in the prevention of cardiovascular disease. PMID- 26251411 TI - Does a low FODMAP diet help IBS? AB - Irritable bowel syndrome (IBS) is a common condition that can have a significant impact on a person's quality of life. The cause of IBS is unknown but several mechanisms have been proposed including visceral hypersensitivity, central sensitisation, abnormal gut motility and altered gut microbiota. IBS is challenging to manage and many patients report insufficient symptomatic relief from treatment. Approximately 60% of patients identify food as a trigger for their symptoms, and there has been interest in exclusion diets for managing IBS. Dietary adaptation is a common self-management strategy for patients with IBS, with many self-diagnosing intolerance to specific foods. This may lead to patients adopting over-restrictive or inappropriate diets. In recent years, a diet low in poorly absorbed short-chain carbohydrates, known collectively as FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols), has been advocated for the treatment of IBS. Here, we discuss the background to the FODMAP diet and review the evidence supporting its use for people with IBS. PMID- 26251412 TI - Total skin self-examination at home for people treated for cutaneous melanoma: development and pilot of a digital intervention. AB - OBJECTIVES: To develop a digital intervention to prompt, support, and respond to the outcomes of total skin self-examinations (TSSEs) at home by people treated for cutaneous melanoma. DESIGN: A complex intervention development study. SETTING: Northeast Scotland. PARTICIPANTS: Semistructured scoping interviews; people previously treated for cutaneous melanoma (n=21). Pilot testing: people treated for melanoma stages 0-2C (n=20); general practitioners (n=6); and a nurse specialist in dermatology (n=1). INTERVENTION: A tablet-based digital intervention designed to prompt and support TSSEs comprising instructional videos and electronic reporting (including photographs) to a clinical nurse specialist in dermatology, with subsequent clinical triage. PRIMARY AND SECONDARY OUTCOME MEASURES: Qualitative assessment of intervention feasibility and acceptability, and quantitative assessment of intentions and confidence to perform TSSEs in pilot participants. RESULTS: The majority of pilot participants were strongly positive and adhered well to the intervention (n=15), with 7 of these reporting symptoms of concern at some point during the 6-month pilot. 4 patients complied intermittently, 3 reporting skin problems at least once during the pilot, and 1 withdrew. 2 patients underwent skin surgery as a result of participating in the pilot, with 1 diagnosed as having a recurrent melanoma and the other, a benign lesion. A number of practical issues to improve the usability of the intervention were identified. The proportion of participants reporting intention to check their skin at least monthly increased during the intervention as did confidence to conduct a skin check. CONCLUSIONS: People previously treated for cutaneous melanoma are prepared to use digital technology to support them in conducting TSSE. An intervention has been developed which is practical, effective and safe, and after addressing minor practical issues, could now be evaluated for clinical outcomes in a randomised clinical trial. PMID- 26251414 TI - Relationship Between 18F-FDG Uptake on PET and Recurrence Patterns After Curative Surgical Resection in Patients with Advanced Gastric Cancer. AB - This study evaluated the predictive value of 18F-FDG PET for distant metastasis free survival and peritoneal recurrence-free survival as well as recurrence-free survival and overall survival after curative surgical resection in patients with advanced gastric cancer (AGC). METHODS: Two hundred seventy-nine patients with AGC who underwent preoperative 18F-FDG PET and subsequent curative surgical resection were included. The tumor-to-normal liver uptake ratio (TLR) of cancer lesions was measured, and the prognostic significance of TLR and tumor factors for distant metastasis-free survival, peritoneal recurrence-free survival, recurrence-free survival, and overall survival was assessed. RESULTS: The 5-y recurrence-free survival, peritoneal recurrence-free survival, distant metastasis free survival, and overall survival rates were 46.9%, 68.5%, 76.0%, and 58.1%, respectively. Depth of tumor invasion, lymph node metastasis, lymphovascular invasion, and TLR were independent prognostic factors for both recurrence-free survival and overall survival (P<0.05). For distant metastasis-free survival, lymphovascular invasion and TLR were independent risk factors (P<0.05). In patients with a TLR of 2.0 or less, the 5-y distant metastasis-free survival rate was 95.5%; in patients with a TLR greater than 2.0, the 5-y distant metastasis free survival rate was 68.8%. For peritoneal recurrence-free survival, TLR showed no statistical significance (P=0.7) whereas pT stage, lymph node metastasis, Lauren classification, and Bormann type were independent prognostic factors (P<0.05). CONCLUSION: 18F-FDG uptake of AGC is an independent prognostic factor for distant metastasis-free survival, recurrence-free survival, and overall survival. The possibility of distant metastasis during follow-up should be considered in patients with high 18F-FDG uptake. PMID- 26251413 TI - Protocol for a randomised controlled trial for Reducing Arthritis Fatigue by clinical Teams (RAFT) using cognitive-behavioural approaches. AB - INTRODUCTION: Rheumatoid arthritis (RA) fatigue is distressing, leading to unmanageable physical and cognitive exhaustion impacting on health, leisure and work. Group cognitive-behavioural (CB) therapy delivered by a clinical psychologist demonstrated large improvements in fatigue impact. However, few rheumatology teams include a clinical psychologist, therefore, this study aims to examine whether conventional rheumatology teams can reproduce similar results, potentially widening intervention availability. METHODS AND ANALYSIS: This is a multicentre, randomised, controlled trial of a group CB intervention for RA fatigue self-management, delivered by local rheumatology clinical teams. 7 centres will each recruit 4 consecutive cohorts of 10-16 patients with RA (fatigue severity >= 6/10). After consenting, patients will have baseline assessments, then usual care (fatigue self-management booklet, discussed for 5-6 min), then be randomised into control (no action) or intervention arms. The intervention, Reducing Arthritis Fatigue by clinical Teams (RAFT) will be cofacilitated by two local rheumatology clinicians (eg, nurse/occupational therapist), who will have had brief training in CB approaches, a RAFT manual and materials, and delivered an observed practice course. Groups of 5-8 patients will attend 6 * 2 h sessions (weeks 1-6) and a 1 hr consolidation session (week 14) addressing different self-management topics and behaviours. The primary outcome is fatigue impact (26 weeks); secondary outcomes are fatigue severity, coping and multidimensional impact, quality of life, clinical and mood status (to week 104). Statistical and health economic analyses will follow a predetermined plan to establish whether the intervention is clinically and cost-effective. Effects of teaching CB skills to clinicians will be evaluated qualitatively. ETHICS AND DISSEMINATION: Approval was given by an NHS Research Ethics Committee, and participants will provide written informed consent. The copyrighted RAFT package will be freely available. Findings will be submitted to the National Institute for Health and Care Excellence, Clinical Commissioning Groups and all UK rheumatology departments. TRIAL REGISTRATION NUMBER: ISRCTN: 52709998; Protocol v3 09.02.2015. PMID- 26251415 TI - 18F-FDG PET Improves Diagnosis in Patients with Focal-Onset Dementias. AB - Alzheimer disease is the cause of up to one-third of cases of primary progressive aphasia or corticobasal syndrome. The primary objective of this study was to determine the accuracy of 18F-FDG PET metabolic imaging for the detection of Alzheimer disease in patients with primary progressive aphasia or corticobasal syndrome. METHODS: A cohort of patients (n=94), including those with an expert clinical diagnosis of logopenic (n=19), nonfluent (n=16), or semantic (n=13) variants of primary progressive aphasia, corticobasal syndrome (n=14), or Alzheimer disease (n=24), underwent 18F-FDG metabolic and 11C-labeled Pittsburgh compound B (11C-PiB) amyloid PET brain imaging. 18F-FDG PET scans interpreted with Neurostat and 3D-SSP displays were classified as revealing Alzheimer disease or "other" by interpreters who were unaware of the clinical assessments and 11C PiB PET results. 11C-PiB PET imaging was considered to be the diagnostic reference standard, with a threshold standardized uptake value ratio of 1.5 being indicative of Alzheimer disease pathology. To address possible bias from subgroup selection for the Alzheimer disease binary classifier, we calculated both conventional and balanced accuracies. RESULTS: Diagnoses of Alzheimer disease based on 18F-FDG PET resulted in 84% accuracy (both conventional and balanced). In comparison, diagnoses based on clinical assessments resulted in 65% conventional accuracy and 67% balanced accuracy. CONCLUSION: Brain 18F-FDG PET scans interpreted with Neurostat and 3D-SSP displays accurately detected Alzheimer disease in patients with primary progressive aphasia or corticobasal syndrome as focal-onset dementias. In such diagnostically challenging cohorts, (18)F-FDG PET imaging can provide more accurate diagnoses, enabling more appropriate therapy. PMID- 26251416 TI - Clinical Translation of an Albumin-Binding PET Radiotracer 68Ga-NEB. AB - Suitably labeled Evans blue dye has been successfully applied to evaluate cardiac function, vascular permeability, and lymphatic imaging in preclinical settings. This study documented the first-in-human application of 68Ga-1,4,7 triazacyclononane-N,N',N"-triacetic acid (NOTA)-NEB. METHODS: The NOTA-conjugated truncated form of Evans blue, NEB, was labeled with 68Ga and tested in BALB/C mice for dynamic PET and ex vivo biodistribution studies. Three healthy volunteers (2 men and 1 woman) underwent 90-min whole-body dynamic PET. The absorbed doses for major organs and whole body were calculated using OLINDA/EXM software. Eleven patients with focal hepatic lesions diagnosed by enhanced CT or MR imaging were subjected to whole-body PET/CT acquisitions at 30 min after intravenous injection of 111-148 MBq (3-4 mCi) of 68Ga-NEB. RESULTS: NEB dye was labeled with 68Ga (half-time, 68 min) with high yield and purity. After intravenous injection, 68Ga-NEB formed a complex with serum albumin, thus most of the radioactivity was retained in blood circulation. The tracer was demonstrated to be safe in both healthy volunteers and recruited patients without side effects or allergies. Among the 11 patients, hemangiomas showed much higher 68Ga-NEB signal intensity than the surrounding normal hepatic tissues, whereas no apparent difference between lesions and hepatic tissues was identified on 18F-FDG PET. All other focal hepatic lesions including hepatocellular carcinoma, hepatic cysts, and neuroendocrine tumor liver metastases showed negative 68Ga-NEB contrast to hepatic tissues. CONCLUSION: As a blood-pool imaging agent, 68Ga-NEB is safe to use in the clinic, and our preliminary studies demonstrate the value of differentiating hepatic hemangioma from other benign or malignant focal hepatic lesions. Easy labeling with different positron emitters of various half-lives, excellent pharmacokinetics, and imaging quality warrant further clinical applications of NEB-based PET tracers. PMID- 26251417 TI - Quantification of beta-Amyloidosis and rCBF with Dedicated PET, 7 T MR Imaging, and High-Resolution Microscopic MR Imaging at 16.4 T in APP23 Mice. AB - We present a combined PET/7 T MR imaging and 16.4 T microscopic MR imaging dual modality imaging approach enabling quantification of the amyloid load at high sensitivity and high resolution, and of regional cerebral blood flow (rCBF) in the brain of transgenic APP23 mice. Moreover, we demonstrate a novel, voxel-based correlative data analysis method for in-depth evaluation of amyloid PET and rCBF data. METHODS: We injected 11C-Pittsburgh compound B (PIB) intravenously in transgenic and control APP23 mice and performed dynamic PET measurements. rCBF data were recorded with a flow-sensitive alternating inversion recovery approach at 7 T. Subsequently, the animals were sacrificed and their brains harvested for ex vivo microscopic MR imaging at 16.4 T with a T2*-weighted gradient-echo sequence at 30-MUm spatial resolution. Additionally, correlative amyloid histology was performed. The 11C-PIB PET data were quantified to nondisplaceable binding potentials (BPND) using the Logan graphical analysis; flow-sensitive alternating inversion recovery data were quantified with a simplified version of the Bloch equation. RESULTS: Amyloid load assessed by both 11C-PIB PET and amyloid histology was highest in the frontal cortex of transgenic mice (11C-PIB BPND: 0.93+/-0.08; amyloid histology: 15.1%+/-1.5%), followed by the temporoparietal cortex (11C-PIB BPND: 0.75+/-0.08; amyloid histology: 13.9%+/ 0.7%) and the hippocampus (11C-PIB BPND: 0.71+/-0.09; amyloid histology: 9.2%+/ 0.9%), and was lowest in the thalamus (11C-PIB BPND: 0.40+/-0.07; amyloid histology: 6.6%+/-0.6%). However, 11C-PIB BPND and amyloid histology linearly correlated (R2=0.82, P<0.05) and were significantly higher in transgenic animals (P<0.01). Similarly, microscopic MR imaging allowed quantifying the amyloid load, in addition to the detection of substructures within single amyloid plaques correlating with amyloid deposition density and the measurement of hippocampal atrophy. Finally, we found an inverse relationship between 11C-PIB BPND and rCBF MR imaging in the voxel-based analysis that was absent in control mice (slopetg: 0.11+/-0.03; slopeco: 0.004+/-0.005; P=0.014). CONCLUSION: Our dual-modality imaging approach using 11C-PIB PET/7 T MR imaging and 16.4 T microscopic MR imaging allowed amyloid-load quantification with high sensitivity and high resolution, the identification of substructures within single amyloid plaques, and the quantification of rCBF. PMID- 26251418 TI - Development of 68Ga- and 89Zr-Labeled Exendin-4 as Potential Radiotracers for the Imaging of Insulinomas by PET. AB - Clinical studies have demonstrated the potential of radiometallated exendin-4 derivatives for the imaging of glucagonlike peptide-1 receptor-overexpressing insulinomas. Recently investigated exendin-4 derivatives were radiolabeled with the SPECT isotopes 99mTc or 111In. Despite promising results, the low spatial resolution associated with SPECT and the occasional need to perform imaging several days after injection for the demarcation of insulinomas from the kidneys represent current limitations. The aim of this work was the development of exendin-4 derivatives for the imaging of insulinomas by high-resolution PET at early or late time points after injection of the radiotracer. METHODS: An exendin 4 derivative conjugated to desferrioxamine (DFO) was used for radiolabeling with the PET isotopes 68Ga and 89Zr. Both radiotracers were evaluated in vitro with RIN-m5F cells for their cell internalization properties as well as affinities and specificities toward the glucagonlike peptide-1 receptor. Serum stabilities of the radiopeptides were assessed in blood serum, and their distribution coefficient was determined by the shake-flask method. Biodistribution experiments were performed with nude mice bearing RIN-m5F xenografts. For all experiments, clinically evaluated [Lys40-(AHX-DTPA-111In)NH2]exendin-4 was used as a reference compound. RESULTS: [Lys40-(AHX-DFO)NH2]exendin-4 was labeled with 89Zr and 68Ga in high radiochemical yield and purity. In vitro experiments showed favorable cell uptake and receptor affinity for [Lys40-(AHX-DFO-68Ga)NH2]exendin-4, and [Lys40-(AHX-DFO-89Zr)NH2]exendin-4 and [Lys40-(AHX-DTPA-111In)NH2]exendin-4 performed similarly well. In biodistribution experiments, [Lys40-(AHX-DFO 68Ga)NH2]exendin-4 exhibited a significantly enhanced tumor uptake 1 h after injection in comparison to the other 2 radiotracers. Tumor uptake of [Lys40-(AHX DFO-89Zr)NH2]exendin-4 was comparable to that of [Lys40-(AHX-DTPA 111In)NH2]exendin-4 at 1-48 h after injection. All compounds showed a fast blood clearance and low accumulation in receptor-negative organs and tissue with the exception of the kidneys, a known characteristic for exendin-4-based radiotracers. CONCLUSION: 68Ga- and 89Zr-radiolabeled [Lys40-(AHX-DFO)NH2]exendin 4 exhibit characteristics comparable or superior to the clinically tested reference compound [Lys40-(AHX-DTPA-111In)NH2]exendin-4 and, thus, represent potential new tracers for the imaging of insulinomas by PET. PMID- 26251419 TI - Clinical Relevance of Targeting the Gastrin-Releasing Peptide Receptor, Somatostatin Receptor 2, or Chemokine C-X-C Motif Receptor 4 in Breast Cancer for Imaging and Therapy. AB - Imaging and therapy using radioligands targeting receptors overexpressed on tumor cells is successfully applied in neuroendocrine tumor patients. Because expression of the gastrin-releasing peptide receptor (GRPR), somatostatin receptor 2 (SSTR2), and chemokine C-X-C motif receptor 4 (CXCR4) has been demonstrated in breast cancer, targeting these receptors using radioligands might offer new imaging and therapeutic opportunities for breast cancer patients. The aim of this study was to correlate messenger RNA (mRNA) expression of GRPR, SSTR2, and CXCR4 with clinicopathologic and biologic factors, and with prognosis and prediction to therapy response, in order to identify specific breast cancer patient groups suited for the application of radioligands targeting these receptors. METHODS: First, we studied GRPR and SSTR2 expression in 13 clinical breast cancer specimens by in vitro autoradiography and correlated this with corresponding mRNA levels to investigate whether mRNA levels reliably represent cell surface expression. Next, GRPR, SSTR2, and CXCR4 mRNA levels were measured by quantitative reverse transcriptase polymerase chain reaction in 915 primary breast cancer tissues and correlated with known clinicopathologic and biologic factors, disease-free survival, distant metastasis-free survival, and overall survival (DFS, MFS, and OS, respectively). In 224 adjuvant hormonal treatment naive estrogen receptor (ER, ESR1)-positive patients who received tamoxifen as first-line therapy for recurrent or metastatic disease, the expression levels of the receptors were correlated with progression-free survival. RESULTS: Our results showed a significant positive correlation between GRPR and SSTR2 expression analyzed by in vitro autoradiography and by quantitative reverse transcriptase polymerase chain reaction (Spearman's rank correlation coefficient [Rs]=0.94, P<0.001, and Rs=0.73, P=0.0042, respectively). Furthermore, high GRPR and SSTR2 mRNA levels were observed more frequently in ESR1-positive specimens, whereas high CXCR4 expression was associated with ESR1-negative specimens. Also, high mRNA expression of CXCR4 was associated with a prolonged DFS, MFS, and OS (multivariate hazard ratio MFS=0.76 [95% confidence interval, 0.64-0.90], P=0.001), whereas high mRNA levels of GRPR were associated with a prolonged progression-free survival after the start of first-line tamoxifen treatment (multivariate hazard ratio=0.68 [95% confidence interval, 0.48-0.97], P=0.031). CONCLUSION: Our data indicate that imaging and therapy using GRPR or SSTR2 radioligands might especially be beneficial for ESR1-positive breast cancer and CXCR4 radioligands for ESR1-negative breast cancer. PMID- 26251423 TI - Reply: Repeatability of Tumor SUV Quantification: The Role of Variable Blood SUV. PMID- 26251420 TI - Multimodal Molecular Imaging Reveals High Target Uptake and Specificity of 111In- and 68Ga-Labeled Fibrin-Binding Probes for Thrombus Detection in Rats. AB - We recently showed the high target specificity and favorable imaging properties of 64Cu and Al18F PET probes for noninvasive imaging of thrombosis. Here, our aim was to evaluate new derivatives labeled with either with 68Ga, 111In, or 99mTc as thrombus imaging agents for PET and SPECT. In this study, the feasibility and potential of these probes for thrombus imaging was assessed in detail in 2 animal models of arterial thrombosis. The specificity of the probes was further evaluated using a triple-isotope approach with multimodal SPECT/PET/CT imaging. METHODS: Radiotracers were synthesized using a known fibrin-binding peptide conjugated to 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid monoamide (DOTA-MA), or a diethylenetriamine ligand (DETA-propanoic acid [PA]), followed by labeling with 68Ga (FBP14, 68Ga-NODAGA), 111In (FBP15, 111In-DOTA-MA), or 99mTc (FBP16, 99mTc(CO)3-DETA-PA), respectively. PET or SPECT imaging, biodistribution, pharmacokinetics, and metabolic stability were evaluated in rat models of mural and occlusive carotid artery thrombosis. In vivo target specificity was evaluated by comparing the distribution of the SPECT and PET probes with preformed 125I labeled thrombi and with a nonbinding control probe using SPECT/PET/CT imaging. RESULTS: All 3 radiotracers showed affinity similar to soluble fibrin fragment DD(E) (inhibition constant=0.53-0.83 MUM). After the kidneys, the highest uptake of 68Ga-FBP14 and 111In-FBP15 was in the thrombus (1.0+/-0.2 percentage injected dose per gram), with low off-target accumulation. Both radiotracers underwent fast systemic elimination (half-life, 8-15 min) through the kidneys, which led to highly conspicuous thrombi on PET and SPECT images. 99mTc-FBP16 displayed low target uptake and distribution consistent with aggregation or degradation. Triple isotope imaging experiments showed that both 68Ga-FBP14 and 111In-FBP15, but not the nonbinding derivative 64Cu-D-Cys-FBP8, detected the location of the 125I labeled thrombus, confirming high target specificity. CONCLUSION: 68Ga-FBP14 and 111In-FBP15 have high fibrin affinity and thrombus specificity and represent useful PET and SPECT probes for thrombus detection. PMID- 26251424 TI - Identification of the Corticobulbar Tracts of the Tongue and Face Using Deterministic and Probabilistic DTI Fiber Tracking in Patients with Brain Tumor. AB - BACKGROUND AND PURPOSE: The corticobulbar tract of the face and tongue, a critical white matter tract connecting the primary motor cortex and the pons, is rarely detected by deterministic DTI fiber tractography. Detection becomes even more difficult in the presence of a tumor. The purpose of this study was to compare identification of the corticobulbar tract by using deterministic and probabilistic tractography in patients with brain tumor. MATERIALS AND METHODS: Fifty patients with brain tumor who underwent DTI were studied. Deterministic tractography was performed by using the fiber assignment by continuous tractography algorithm. Probabilistic tractography was performed by using a Monte Carlo simulation method. ROIs were drawn of the face and tongue motor homunculi and the pons in both hemispheres. RESULTS: In all subjects, fiber assignment by continuous tractography was ineffectual in visualizing the entire course of the corticobulbar tract between the face and tongue motor cortices and the pons on either side. However, probabilistic tractography successfully visualized the corticobulbar tract from the face and tongue motor cortices in all patients on both sides. No significant difference (P < .08) was found between both sides in terms of the number of voxels or degree of connectivity. The fractional anisotropy of both the face and tongue was significantly lower on the tumor side (P < .03). When stratified by tumor type, primary-versus-metastatic tumors, no differences were observed between tracts in terms of the fractional anisotropy and connectivity values (P > .5). CONCLUSIONS: Probabilistic tractography successfully reconstructs the face- and tongue-associated corticobulbar tracts from the lateral primary motor cortex to the pons in both hemispheres. PMID- 26251425 TI - Diagnostic Accuracy of 4 Commercially Available Semiautomatic Packages for Carotid Artery Stenosis Measurement on CTA. AB - BACKGROUND AND PURPOSE: Semiautomatic measurement of ICA stenosis potentially increases observer reproducibility. In this study, we assessed the diagnostic accuracy and interobserver reproducibility of a commercially available semiautomatic ICA stenosis measurement on CTA and estimated the agreement among different software packages. MATERIALS AND METHODS: We analyzed 141 arteries from 90 patients with TIA or ischemic stroke. Manual stenosis measurements were performed by 2 neuroradiologists. Semiautomatic measurements by using 4 methods (3mensio and comparable software from Philips, TeraRecon, and Siemens) were performed by 2 observers. Diagnostic accuracy was estimated by comparing semiautomatic with manual measurements. Interobserver reproducibility and agreement between different packages was assessed by calculation of the intraclass correlation coefficient and Bland-Altman 95% limits of agreement. False-negative classifications were retrospectively inspected by a neuroradiologist. RESULTS: There was no significant difference in the diagnostic performance of the 4 semiautomatic methods. The sensitivity for detecting >=50% and >=70% degree of stenosis was between 76% and 82% and 46% and 62%, respectively. Specificity and overall diagnostic accuracy were between 92% and 97% and 85% and 90%, respectively. The interobserver intraclass correlation coefficient was between 0.83 and 0.96 for semiautomatic measurements and 0.81 for manual measurement. The limits of agreement between each pair of semiautomatic packages ranged from -18%-24% to -33%-31%. False-negative classifications were caused by ulcerative plaques and observer variation in stenosis and reference measurements. CONCLUSIONS: Semiautomatic methods have a low-to-good sensitivity and a good specificity and overall diagnostic accuracy. The high interobserver reproducibility makes semiautomatic stenosis measurement valuable for clinical practice, but semiautomatic measurements should be checked by an experienced radiologist. PMID- 26251426 TI - The Preventive Effect of Endovascular Treatment for Recurrent Hemorrhage in Patients with Spinal Cord Arteriovenous Malformations. AB - BACKGROUND AND PURPOSE: Spinal cord AVMs represent rare and insufficiently studied pathologic entities. Embolization is thought to play an important role in the management of spinal cord AVMs. Factors for recurrent hemorrhage and the impact of endovascular treatment on prevention of recurrent hemorrhage remain to be confirmed. We aimed to assess recurrent hemorrhagic incidence of spinal cord AVMs and its prevention by endovascular treatment. MATERIALS AND METHODS: We reviewed 80 patients with spinal cord AVMs by spinal cord angiography who had hemorrhage before the first endovascular treatment at New York University Medical Center, Beth Israel Medical Center, or Roosevelt Hospital in New York. We compared the baseline and radiologic characteristics of patients with and without recurrent hemorrhage by the log-rank test and the Cox proportional hazards model. RESULTS: We observed recurrent hemorrhage in 35 (44%) patients (1/41 patients with endovascular treatment and 34/39 patients without endovascular treatment). The median length of total follow-up was 659 days (interquartile range, 129-2640 days), and the median length from first-to-recurrent hemorrhage was 369 days (interquartile range, 30-1596 days). The log-rank test revealed that endovascular treatment and venous thrombosis reduced recurrent hemorrhage, and associated aneurysm was related to recurrent hemorrhage. Even in multivariate analysis, the endovascular treatment reduced (hazard ratio, 0.027; P < .0001) and associated aneurysm increased (hazard ratio, 3.4; P = .044) the risk of recurrent hemorrhage. CONCLUSIONS: Endovascular embolization is the first choice of treatment for spinal cord AVMs and is effective in preventing recurrent hemorrhage. PMID- 26251427 TI - Risk Factors for Hemorrhagic Complications following Pipeline Embolization Device Treatment of Intracranial Aneurysms: Results from the International Retrospective Study of the Pipeline Embolization Device. AB - BACKGROUND AND PURPOSE: Spontaneous intraparenchymal hemorrhage is a dreaded complication of unknown etiology following flow-diversion treatment. Using the International Retrospective Study of the Pipeline Embolization Device registry, we studied demographic, aneurysm, and procedural characteristics associated with intraparenchymal hemorrhage following Pipeline Embolization Device treatment. MATERIALS AND METHODS: We identified patients in the International Retrospective Study of the Pipeline Embolization Device registry with intraparenchymal hemorrhage unrelated to index aneurysm rupture post-Pipeline Embolization Device treatment. The rate of intraparenchymal hemorrhage was determined by baseline demographics, comorbidities, aneurysm characteristics, and procedural characteristics (including anticoagulation use, platelet testing, number of devices used, sheaths, catheters, and guidewires). Categoric variables were compared with chi(2) testing, and continuous variables were compared with the Student t test. RESULTS: Of 793 patients with 906 aneurysms, 20 (2.5%) had intraparenchymal hemorrhage. Fifteen intraparenchymal hemorrhages (75.0%) occurred within 30 days of treatment (median, 5 days; range, 0-150 days). Nine patients with intraparenchymal hemorrhage (45.0%) died, 10 (50.0%) had major neurologic morbidity, and 1 had minor neurologic morbidity (5.0%). Intraparenchymal hemorrhage was ipsilateral to the Pipeline Embolization Device in 16 patients (80%) and contralateral in 3 patients (15.0%). Variables associated with higher odds of intraparenchymal hemorrhage included treatment of ruptured aneurysms (OR, 4.44; 95% CI, 1.65-11.94; P = .005) and the use of >= 3 Pipeline Embolization Devices (OR, 4.10; 95% CI, 1.34-12.58; P = .04). The Shuttle sheath was not associated with intraparenchymal hemorrhage (OR, 0.97; 95% CI, 0.38-2.45; P = .95). CONCLUSIONS: Spontaneous intraparenchymal hemorrhage following Pipeline Embolization Device treatment is a rare-but-devastating complication, with nearly all patients having morbidity or mortality. Variables associated with intraparenchymal hemorrhage included the use of multiple Pipeline Embolization Devices and treatment of ruptured aneurysms. The Shuttle, a device that was previously thought to be associated with intraparenchymal hemorrhage, was not associated with it. PMID- 26251428 TI - Evolution of Flow-Diverter Endothelialization and Thrombus Organization in Giant Fusiform Aneurysms after Flow Diversion: A Histopathologic Study. AB - BACKGROUND AND PURPOSE: Treatment of giant fusiform aneurysms with flow diverters has been associated with a relatively high rate of complications. Our goal was to study the evolution of flow-diverter endothelialization and thrombus organization at different time points after flow-diverter treatment in giant fusiform aneurysms to better understand reasons for flow-diverter thrombosis and delayed aneurysm ruptures. MATERIALS AND METHODS: Two giant anterior and 2 posterior circulation aneurysms, all of which had partially thrombosed before treatment, were studied. An unruptured, untreated posterior circulation aneurysm was used as a control. Each specimen was removed at 7 days or at 6, 9, or 13 months after flow-diverter treatment. The 3 patients who survived longer than 7 days were followed up by angiography and MR imaging. Formaldehyde-fixed paraffin-embedded sections were stained by using H&E, Van Gieson elastic, CD34, h-Caldesmon, and Picrosirius stains and studied by light microscopy. RESULTS: According to angiography, aneurysms were found to be obliterated partially at 6 and 9 months and completely at 13 months. MR imaging revealed that mass effect remained unchanged in each case. Sections of the flow diverter within the normal parent artery were covered by an endothelialized fibrous layer as early as 6 months, but there was no tissue coverage or endothelialization seen even at 13 months inside the aneurysm itself. Each treated aneurysm had a thin wall with complete lack of smooth muscle cells. No signs of thrombus organization were found at any of the time points studied. CONCLUSIONS: Endothelialization of the flow diverter in giant fusiform aneurysms may not occur and thrombus organization may not be initiated inside these aneurysms for as long as 1 year, which explains delayed flow-diverter thrombosis and the possibility of delayed ruptures. PMID- 26251429 TI - Intraplaque Hemorrhage and the Plaque Surface in Carotid Atherosclerosis: The Plaque At RISK Study (PARISK). AB - BACKGROUND AND PURPOSE: An important characteristic of vulnerable plaque, intraplaque hemorrhage, may predict plaque rupture. Plaque rupture can be visible on noninvasive imaging as a disruption of the plaque surface. We investigated the association between intraplaque hemorrhage and disruption of the plaque surface. MATERIALS AND METHODS: We selected the first 100 patients of the Plaque At RISK study, an ongoing prospective noninvasive plaque imaging study in patients with mild-to-moderate atherosclerotic lesions in the carotid artery. In carotid artery plaques, disruption of the plaque surface (defined as ulcerated plaques and/or fissured fibrous cap) and intraplaque hemorrhage were assessed by using MDCTA and 3T MR imaging, respectively. We used a chi(2) test and multivariable logistic regression to assess the association between intraplaque hemorrhage and disrupted plaque surface. RESULTS: One hundred forty-nine carotid arteries in 78 patients could be used for the current analyses. Intraplaque hemorrhage and plaque ulcerations were more prevalent in symptomatic compared with contralateral vessels (hemorrhage, 38% versus 11%; P < .001; and ulcerations, 27% versus 7%; P = .001). Fissured fibrous cap was more prevalent in symptomatic compared with contralateral vessels (13% versus 4%; P = .06). After adjustment for age, sex, diabetes mellitus, and degree of stenosis, intraplaque hemorrhage was associated with disrupted plaque surface (OR, 3.13; 95% CI, 1.25-7.84) in all vessels. CONCLUSIONS: Intraplaque hemorrhage is associated with disruption of the plaque surface in patients with a carotid artery stenosis of <70%. Serial studies are needed to investigate whether intraplaque hemorrhage indeed increases the risk of plaque rupture and subsequent ischemic stroke during follow-up. PMID- 26251430 TI - Combined Selective Cerebral Hypothermia and Mechanical Artery Recanalization in Acute Ischemic Stroke: In Vitro Study of Cooling Performance. AB - BACKGROUND AND PURPOSE: Therapeutic hypothermia represents a promising neuroprotective treatment for patients with ischemic stroke. Selective, intracarotid blood cooling may initiate rapid and early brain hypothermia, reduce systemic effects, and allow combined endovascular mechanical thrombectomy. For this approach, a balloon cooling catheter system was designed and studied in vitro to optimize its cooling performance. MATERIALS AND METHODS: Computational fluid dynamics of blood cooling was performed within the common carotid artery lumen by using 3 different catheter designs (1-, 2-, and 4-balloon array). On the basis of these results, a first catheter prototype was manufactured, and its heat exchange performance was tested in an artificial in vitro circulation simulating the common carotid artery lumen at different flow rates (inflow temperature of 37 degrees C). RESULTS: In the computational fluid dynamics model, the catheter with the 4-balloon array achieved the highest cooling rate of -1.6 degrees C, which may be attributed to disruption of the thermal boundary layers. In the in vitro study, cooling of the blood substitute at flow rates of 400 mL/min (normal common carotid artery flow) and 250 mL/min (reduced common carotid artery flow due to distal MCA occlusion) achieved a temperature drop inside the blood substitute along the cooling balloons of -1.6 degrees C and -2.2 degrees C, respectively. CONCLUSIONS: The feasibility of intracarotid blood cooling using a new catheter system was demonstrated in vitro. A serial 4-balloon array led to an optimized cooling capacity approaching optimum target temperatures of mild therapeutic hypothermia. To determine the therapeutic efficacy of combined selective therapeutic hypothermia and mechanical thrombectomy, further in vivo studies by using a model of temporary ischemia with large-vessel occlusion and recanalization are required. PMID- 26251431 TI - Bone-Subtracted Spinal CT Angiography Using Nonrigid Registration for Better Visualization of Arterial Feeders in Spinal Arteriovenous Fistulas. AB - BACKGROUND AND PURPOSE: Pretreatment diagnosis for the location of shunts and arterial feeders of spinal arteriovenous fistulas is crucial. This study aimed to evaluate the utility of subtracted CT angiography imaging by using nonrigid registration (R-CTA) in patients with spinal arteriovenous fistulas compared with conventional CTA imaging. MATERIALS AND METHODS: The records of 15 consecutive subjects (mean age, 65 years; 2 women) who had undergone CTA and digital subtraction angiography for clinically suspected spinal arteriovenous fistula were reviewed. From CTA images obtained at the arterial and late arterial phases, warped images of the late arterial phase were obtained by using nonrigid registration that was adjusted to the arterial phase images. R-CTA images were then obtained by subtracting the warped images from the arterial phase images. The accuracies of using nonrigid registration and conventional spinal CTA and the time required for detecting arterial feeders in spinal arteriovenous fistulas were analyzed for each patient with DSA results as a standard reference. The difference between R-CTA and conventional spinal CTA was assessed by the Welch test and the McNemar chi(2) test. RESULTS: R-CTA had a higher accuracy compared with conventional spinal CTA (80% versus 47%, P = .025). The time for interpretation was reduced in R-CTA compared with conventional spinal CTA (45.1 versus 97.1 seconds, P = .002). CONCLUSIONS: Our subtracted CTA imaging by using nonrigid registration detects feeders of spinal arteriovenous fistulas more accurately and quickly than conventional CTA. PMID- 26251432 TI - Meta-Analysis of CSF Diversion Procedures and Dural Venous Sinus Stenting in the Setting of Medically Refractory Idiopathic Intracranial Hypertension. AB - BACKGROUND AND PURPOSE: In medically refractory idiopathic intracranial hypertension, optic nerve sheath fenestration or CSF shunting is considered the next line of management. Venous sinus stenosis has been increasingly recognized as a treatable cause of elevated intracranial pressure in a subset of patients. In this article, we present the results of the largest meta-analysis of optic nerve sheath fenestration, CSF shunting, and dural venous sinus stenting. This is the only article that compares these procedures, to our knowledge. MATERIALS AND METHODS: We performed a PubMed search of all peer-reviewed articles from 1988 to 2014 for patients who underwent a procedure for medically refractory idiopathic intracranial hypertension. RESULTS: Optic nerve sheath fenestration analysis included 712 patients. Postprocedure, there was improvement of vision in 59%, headache in 44%, and papilledema in 80%; 14.8% of patients required a repeat procedure with major and minor complication rates of 1.5% and 16.4%, respectively. The CSF diversion procedure analysis included 435 patients. Postprocedure, there was improvement of vision in 54%, headache in 80%, and papilledema in 70%; 43% of patients required at least 1 additional surgery. The major and minor complication rates were 7.6% and 32.9%, respectively. The dural venous sinus stenting analysis included 136 patients. After intervention, there was improvement of vision in 78%, headache in 83%, and papilledema in 97% of patients. The major and minor complication rates were 2.9% and 4.4%, respectively. Fourteen additional procedures were performed with a repeat procedure rate of 10.3%. Three patients had contralateral stent placement, while 8 had ipsilateral stent placement within or adjacent to the original stent. Only 3 patients required conversion to CSF diversion or 2.2% of patients with stents. CONCLUSIONS: Patients with medically refractory idiopathic intracranial hypertension have traditionally undergone a CSF diversion procedure as the first intervention. This paradigm may need to be re-examined, given the high technical and clinical success and low complication rates with dural venous sinus stenting. PMID- 26251433 TI - CT Metal Artifact Reduction in the Spine: Can an Iterative Reconstruction Technique Improve Visualization? AB - BACKGROUND AND PURPOSE: Metal-related artifacts from spine instrumentation can obscure relevant anatomy and pathology. We evaluated the ability of CT images reconstructed with and without iterative metal artifact reduction to visualize critical anatomic structures in postoperative spines and assessed the potential for implementation into clinical practice. MATERIALS AND METHODS: We archived CT projection data in patients with instrumented spinal fusion. CT images were reconstructed by using weighted filtered back-projection and iterative metal artifact reduction. Two neuroradiologists evaluated images in the region of spinal hardware and assigned a score for the visualization of critical anatomic structures by using soft-tissue and bone windows (critical structures totally obscured, n = 0; anatomic recognition with high diagnostic confidence, n = 5). Using bone windows, we measured the length of the most pronounced linear artifacts. For each patient, neuroradiologists made recommendations regarding the optimal use of iterative metal artifact reduction and its impact on diagnostic confidence. RESULTS: Sixty-eight patients met the inclusion criteria. Visualization of critical soft-tissue anatomic structures was significantly improved by using iterative metal artifact reduction compared with weighted filtered back-projection (median, 1 +/- 1.5 versus 3 +/- 1.3, P < .001), with improvement in the worst visualized anatomic structure in 88% (60/68) of patients. There was not significant improvement in visualization of critical osseous structures. Linear metal artifacts were reduced from 29 to 11 mm (P < .001). In 87% of patients, neuroradiologists recommended reconstructing iterative metal artifact reduction images instead of weighted filtered back-projection images, with definite improvement in diagnostic confidence in 32% (22/68). CONCLUSIONS: Iterative metal artifact reduction improves visualization of critical soft-tissue structures in patients with spinal hardware. Routine generation of these images in addition to routine weighted filtered back projection is recommended. PMID- 26251434 TI - Accuracy of Parenchymal Cerebral Blood Flow Measurements Using Pseudocontinuous Arterial Spin-Labeling in Healthy Volunteers. AB - BACKGROUND AND PURPOSE: The arterial spin-labeling method for CBF assessment is widely available, but its accuracy is not fully established. We investigated the accuracy of a whole-brain arterial spin-labeling technique for assessing the mean parenchymal CBF and the effect of aging in healthy volunteers. Phase-contrast MR imaging was used as the reference method. MATERIALS AND METHODS: Ninety-two healthy volunteers were included: 49 young (age range, 20-30 years) and 43 elderly (age range, 65-80 years). Arterial spin-labeling parenchymal CBF values were averaged over the whole brain to quantify the mean pCBF(ASL) value. Total CBF was assessed with phase-contrast MR imaging as the sum of flows in the internal carotid and vertebral arteries, and subsequent division by brain volume returned the pCBF(PCMRI) value. Accuracy was considered as good as that of the reference method if the systematic difference was less than 5 mL/min/100 g of brain tissue and if the 95% confidence intervals were equal to or better than +/ 10 mL/min/100 g. RESULTS: pCBF(ASL) correlated to pCBF(PCMRI) (r = 0.73; P < .001). Significant differences were observed between the pCBF(ASL) and pCBF(PCMRI) values in the young (P = .001) and the elderly (P < .001) volunteers. The systematic differences (mean +/- 2 standard deviations) were -4 +/- 14 mL/min/100 g in the young subjects and 6 +/- 12 mL/min/100 g in the elderly subjects. Young subjects showed higher values than the elderly subjects for pCBF(PCMRI) (young, 57 +/- 8 mL/min/100 g; elderly, 54 +/- 7 mL/min/100 g; P = .05) and pCBF(ASL) (young, 61 +/- 10 mL/min/100 g; elderly, 48 +/- 10 mL/min/100 g; P < .001). CONCLUSIONS: The limits of agreement were too wide for the arterial spin-labeling method to be considered satisfactorily accurate, whereas the systematic overestimation in the young subjects and underestimation in the elderly subjects were close to acceptable. The age-related decrease in parenchymal CBF was augmented in arterial spin-labeling compared with phase contrast MR imaging. PMID- 26251435 TI - Platelet Testing is Associated with Worse Clinical Outcomes for Patients Treated with the Pipeline Embolization Device. AB - BACKGROUND AND PURPOSE: The necessity for platelet-inhibition testing before aneurysm treatment in patients premedicated with antiplatelet agents is controversial. Using the International Retrospective Study of Pipeline Embolization Device registry, we studied complication rates in groups of patients who underwent platelet testing and those who did not undergo platelet testing to determine if these test results were associated with improved outcomes. MATERIALS AND METHODS: Patients in the International Retrospective Study of Pipeline Embolization Device registry with an unruptured aneurysm were categorized as those who underwent platelet testing before Pipeline embolization device treatment or those who did not. Complication rates were compared by using the Fisher exact or Pearson chi(2) test. Multivariate analysis was performed to determine if platelet function testing was independently associated with poor outcomes after adjusting for age, number of devices and aneurysms, aneurysm location and size, and practitioner and center volume. RESULTS: Compared with the patients who received a Pipeline embolization device without platelet testing, those who underwent platelet testing and Pipeline embolization device placement experienced higher rates of intracranial hemorrhage (0 of 187 [0.0%] vs 12 of 511 [2.3%], respectively; P = .04), neurologic morbidity (4 of 187 [2.1%] vs 42 of 511 [8.2%], respectively; P < .01), and combined neurologic morbidity and mortality (6 of 187 [3.2%] vs 45 of 511 [8.8%], respectively; P = .01). More patients in the platelet testing and Pipeline embolization device group were treated with multiple devices (227 [38.0%] vs 56 [27.8] patients, respectively; P = .01). On multivariate analysis, the group of patients who underwent platelet testing and Pipeline embolization device placement had higher odds of neurologic morbidity (OR, 3.25 [95% CI, 1.10-9.61]; P = .03). CONCLUSIONS: Platelet testing in patients who undergo Pipeline embolization device placement is associated with higher rates of morbidity. Additional prospective studies are needed to determine if and when platelet testing in these patients is appropriate. PMID- 26251436 TI - Differentiation between Cystic Pituitary Adenomas and Rathke Cleft Cysts: A Diagnostic Model Using MRI. AB - BACKGROUND AND PURPOSE: Cystic pituitary adenomas may mimic Rathke cleft cysts when there is no solid enhancing component found on MR imaging, and preoperative differentiation may enable a more appropriate selection of treatment strategies. We investigated the diagnostic potential of MR imaging features to differentiate cystic pituitary adenomas from Rathke cleft cysts and to develop a diagnostic model. MATERIALS AND METHODS: This retrospective study included 54 patients with a cystic pituitary adenoma (40 women; mean age, 37.7 years) and 28 with a Rathke cleft cyst (18 women; mean age, 31.5 years) who underwent MR imaging followed by surgery. The following imaging features were assessed: the presence or absence of a fluid-fluid level, a hypointense rim on T2-weighted images, septation, an off midline location, the presence or absence of an intracystic nodule, size change, and signal change. On the basis of the results of logistic regression analysis, a diagnostic tree model was developed to differentiate between cystic pituitary adenomas and Rathke cleft cysts. External validation was performed for an additional 16 patients with a cystic pituitary adenoma and 8 patients with a Rathke cleft cyst. RESULTS: The presence of a fluid-fluid level, a hypointense rim on T2-weighted images, septation, and an off-midline location were more common with pituitary adenomas, whereas the presence of an intracystic nodule was more common with Rathke cleft cysts. Multiple logistic regression analysis showed that cystic pituitary adenomas and Rathke cleft cysts can be distinguished on the basis of the presence of a fluid-fluid level, septation, an off-midline location, and the presence of an intracystic nodule (P = .006, .032, .001, and .023, respectively). Among 24 patients in the external validation population, 22 were classified correctly on the basis of the diagnostic tree model used in this study. CONCLUSIONS: A systematic approach using this diagnostic tree model can be helpful in distinguishing cystic pituitary adenomas from Rathke cleft cysts. PMID- 26251437 TI - Reply: To PMID 25977480. PMID- 26251438 TI - Intracranial Pressure versus Phase-Contrast MR Imaging for Normal Pressure Hydrocephalus. PMID- 26251439 TI - Binding partners of the kinase domains in Drosophila obscurin and their effect on the structure of the flight muscle. AB - Drosophila obscurin (Unc-89) is a titin-like protein in the M-line of the muscle sarcomere. Obscurin has two kinase domains near the C-terminus, both of which are predicted to be inactive. We have identified proteins binding to the kinase domains. Kinase domain 1 bound Ballchen (Ball, an active kinase), and both kinase domains 1 and 2 bound MASK (a 400-kDa protein with ankyrin repeats). Ball was present in the Z-disc and M-line of the indirect flight muscle (IFM) and was diffusely distributed in the sarcomere. MASK was present in both the M-line and the Z-disc. Reducing expression of Ball or MASK by siRNA resulted in abnormalities in the IFM, including missing M-lines and multiple Z-discs. Obscurin was still present, suggesting that the kinase domains act as a scaffold binding Ball and MASK. Unlike obscurin in vertebrate skeletal muscle, Drosophila obscurin is necessary for the correct assembly of the IFM sarcomere. We show that Ball and MASK act downstream of obscurin, and both are needed for development of a well defined M-line and Z-disc. The proteins have not previously been identified in Drosophila muscle. PMID- 26251440 TI - Children's Immediate Postoperative Distress and Mothers' and Fathers' Touch Behaviors. AB - OBJECTIVE: This study examined mothers' and fathers' use of child-directed touch in the postanesthesia care unit. METHODS: In all, 142 mothers and 112 fathers of 143 children aged 2-11 years undergoing outpatient surgery participated. Parent touch (instrumental, empathic) and child distress were coded. Mothers' and fathers' rates of touch were compared, and interrelations between touch and child distress were examined (overall and sequentially). RESULTS: The proportion of mothers and fathers who used touch did not differ, but mothers' rates of touch were higher than fathers'. Parental instrumental touch and mothers embracing touch were positively correlated with children's distress. Mothers were more likely to use embracing touch in response to children's distress than at any other time. CONCLUSIONS: Results point to potential differences in mothers' and fathers' roles in the postoperative setting, and potentially different functions of touch. Results suggest that mothers may provide embracing touch to soothe or prevent children's distress. PMID- 26251441 TI - Association between diabetic retinopathy and subclinical atherosclerosis in China: Results from a community-based study. AB - PURPOSE: To evaluate the association of diabetic retinopathy with subclinical atherosclerosis in middle-aged and elderly Chinese with type 2 diabetes. METHODS: A cross-sectional community-based study was performed among 1607 patients aged 40 years or older in Shanghai. Non-mydriatic digital fundus photography examination was used in diabetic retinopathy detection. Presence of elevated carotid intima media thickness or carotid plaque was defined as subclinical atherosclerosis. RESULTS: The prevalence of diabetic retinopathy was 15.1% in total patients. Patients with diabetic retinopathy were more likely to have elevated carotid intima-media thickness, carotid plaque and subclinical atherosclerosis than those without diabetic retinopathy (37.9% vs 30.7%, 57.6% vs 49.6% and 64.6% vs 57.1%, respectively). The presence of diabetic retinopathy was significantly associated with increased odds of subclinical atherosclerosis (odds ratio = 1.93, 95% confidence interval = 1.03-3.60) after full adjustments. CONCLUSION: The presence of diabetic retinopathy was significantly associated with subclinical atherosclerosis in middle-aged and elderly patients with type 2 diabetics in China. PMID- 26251442 TI - TOR signalling in plants. AB - Although the eukaryotic TOR (target of rapamycin) kinase signalling pathway has emerged as a key player for integrating nutrient-, energy- and stress-related cues with growth and metabolic outputs, relatively little is known of how this ancient regulatory mechanism has been adapted in higher plants. Drawing comparisons with the substantial knowledge base around TOR kinase signalling in fungal and animal systems, functional aspects of this pathway in plants are reviewed. Both conserved and divergent elements are discussed in relation to unique aspects associated with an autotrophic mode of nutrition and adaptive strategies for multicellular development exhibited by plants. PMID- 26251443 TI - Carbohydrate-binding module assisting glycosynthase-catalysed polymerizations. AB - Carbohydrate-binding modules (CBMs) are found within multi-modular polysaccharide degrading enzymes [glycoside hydrolases (GHs)]. CBMs play a critical role in the recognition of plant cell-wall polysaccharides and enhance the hydrolase activity of their cognate catalytic domains by increasing enzyme substrate proximity. Mimicking their role in Nature, we, in the present study, propose that CBMs may assist in vitro glycosynthase-catalysed polymerization reactions to produce artificial polysaccharides. Glycosynthases are GHs that have been engineered to catalyse glycoside bond formation for the synthesis of oligosaccharides, glycoconjugates and glycans. The degree of polymerization (DP) of the glycans generated is limited by the solubility of the polymeric product. In the present study, we have targeted the synthesis of artificial 1,3-1,4-beta-glucans with a regular sequence using the glycosynthase E(134)S derived from a Bacillus licheniformis lichenase. We show that the addition of CBM11, which binds mixed linked beta-glucans, either as an isolated protein or fused to the glycosynthase E(134)S, has an effect on the DP of the polysaccharide products that is dependent on the rate of polymerization. The mechanism by which CBM influences the DP of the synthesized glycans is discussed. PMID- 26251444 TI - Novel actions of 2-deoxy-D-glucose: protection against Shiga toxins and changes in cellular lipids. AB - 2-Deoxy-D-glucose (2DG) is a structural analogue of glucose with well-established applications as an inhibitor of glycolysis and N-glycosylation. Importantly, 2DG has been shown to improve the efficacy of several cancer chemotherapeutic agents in vivo and thus it is in clinical studies in combination with chemotherapy and radiotherapy. However, although 2DG has been demonstrated to modulate many cellular functions, including autophagy, apoptosis and cell cycle control, little is known about the effects of 2DG on intracellular transport, which is of great importance when predicting the effects of 2DG on therapeutic agents. In addition to proteins, lipids play important roles in cellular signalling and in controlling cellular trafficking. We have, in the present study, investigated the effects of 2DG on cellular lipid composition and by use of protein toxins we have studied 2DG-mediated changes in intracellular trafficking. By quantifying more than 200 individual lipid species from 17 different lipid classes, we have found that 2DG treatment changes the levels and/or species composition of several lipids, such as phosphatidylinositol (PI), diacylglycerol (DAG), cholesteryl ester (CE), ceramide (Cer) and lysophospho-lipids. Moreover, 2DG becomes incorporated into the carbohydrate moiety of glycosphingolipids (GSLs). In addition, we have discovered that 2DG protects cells against Shiga toxins (Stxs) and inhibits release of the cytotoxic StxA1 moiety in the endoplasmic reticulum (ER). The data indicate that the 2DG-induced protection against Stx is independent of inhibition of glycolysis or N-glycosylation, but rather mediated via the depletion of Ca(2+) from cellular reservoirs by 2DG. In conclusion, our results reveal novel actions of 2DG on cellular lipids and Stx toxicity. PMID- 26251445 TI - Escherichia coli ClpB is a non-processive polypeptide translocase. AB - Escherichia coli caseinolytic protease (Clp)B is a hexameric AAA+ [expanded superfamily of AAA (ATPase associated with various cellular activities)] enzyme that has the unique ability to catalyse protein disaggregation. Such enzymes are essential for proteome maintenance. Based on structural comparisons to homologous enzymes involved in ATP-dependent proteolysis and clever protein engineering strategies, it has been reported that ClpB translocates polypeptide through its axial channel. Using single-turnover fluorescence and anisotropy experiments we show that ClpB is a non-processive polypeptide translocase that catalyses disaggregation by taking one or two translocation steps followed by rapid dissociation. Using single-turnover FRET experiments we show that ClpB containing the IGL loop from ClpA does not translocate substrate through its axial channel and into ClpP for proteolytic degradation. Rather, ClpB containing the IGL loop dysregulates ClpP leading to non-specific proteolysis reminiscent of ADEP (acyldepsipeptide) dysregulation. Our results support a molecular mechanism where ClpB catalyses protein disaggregation by tugging and releasing exposed tails or loops. PMID- 26251446 TI - Mapping the heparin-binding site of the BMP antagonist gremlin by site-directed mutagenesis based on predictive modelling. AB - Gremlin is a member of the CAN (cerberus and DAN) family of secreted BMP (bone morphogenetic protein) antagonists and also an agonist of VEGF (vascular endothelial growth factor) receptor-2. It is critical in limb skeleton and kidney development and is re-expressed during tissue fibrosis. Gremlin binds strongly to heparin and heparan sulfate and, in the present study, we sought to investigate its heparin-binding site. In order to explore a putative non-contiguous binding site predicted by computational molecular modelling, we substituted a total of 11 key arginines and lysines located in three basic residue sequence clusters with homologous sequences from cerberus and DAN (differential screening selected gene abberative in neuroblastoma), CAN proteins which lack basic residues in these positions. A panel of six Myc-tagged gremlin mutants, MGR-1-MGR-6 (MGR, mutant gremlin), each containing different combinations of targeted substitutions, all showed markedly reduced affinity for heparin as demonstrated by their NaCl elution on heparin affinity chromatography, thus verifying our predictions. Both MGR-5 and MGR-6 retained BMP-4-binding activity comparable to that of wild-type gremlin. Low-molecular-mass heparin neither promoted nor inhibited BMP-4 binding. Finally, glutaraldehyde cross-linking demonstrated that gremlin forms non covalent dimers, similar behaviour to that of DAN and also PRDC (protein related to cerberus and DAN), another CAN protein. The resulting dimer would possess two heparin-binding sites, each running along an exposed surface on the second beta strand finger loop of one of the monomers. PMID- 26251449 TI - Metalloprotease meprin beta is activated by transmembrane serine protease matriptase-2 at the cell surface thereby enhancing APP shedding. AB - Increased expression of metalloprotease meprin beta is associated with fibrotic syndromes and Alzheimer's disease (AD). Hence, regulation of meprin activity might be a suitable strategy for the treatment of these conditions. Meprin beta is a type 1 transmembrane protein, but can be released from the cell surface by ectodomain shedding. The protease is expressed as an inactive zymogen and requires proteolytic maturation by tryptic serine proteases. In the present study, we demonstrate, for the first time, the differences in the activation of soluble and membrane bound meprin beta and suggest transmembrane serine protease 6 [TMPRSS6 or matriptase-2 (MT2)] as a new potent activator, cleaving off the propeptide of meprin beta between Arg(61) and Asn(62) as determined by MS. We show that MT2, but not TMPRSS4 or pancreatic trypsin, is capable of activating full-length meprin beta at the cell surface, analysed by specific fluorogenic peptide cleavage assay, Western blotting and confocal laser scanning microscopy (CLSM). Maturation of full-length meprin beta is required for its activity as a cell surface sheddase, releasing the ectodomains of transmembrane proteins, as previously shown for the amyloid precursor protein (APP). PMID- 26251447 TI - Transition metals activate TFEB in overexpressing cells. AB - Transition metal toxicity is an important factor in the pathogenesis of numerous human disorders, including neurodegenerative diseases. Lysosomes have emerged as important factors in transition metal toxicity because they handle transition metals via endocytosis, autophagy, absorption from the cytoplasm and exocytosis. Transcription factor EB (TFEB) regulates lysosomal biogenesis and the expression of lysosomal proteins in response to lysosomal and/or metabolic stresses. Since transition metals cause lysosomal dysfunction, we proposed that TFEB may be activated to drive gene expression in response to transition metal exposure and that such activation may influence transition metal toxicity. We found that transition metals copper (Cu) and iron (Fe) activate recombinant TFEB and stimulate the expression of TFEB-dependent genes in TFEB-overexpressing cells. In cells that show robust lysosomal exocytosis, TFEB was cytoprotective at moderate levels of Cu exposure, decreasing oxidative stress as reported by the expression of heme oxygenase-1 (HMOX1) gene. However, at high levels of Cu exposure, particularly in cells with low levels of lysosomal exocytosis, activation of overexpressed TFEB was toxic, increasing oxidative stress and mitochondrial damage. Based on these data, we conclude that TFEB-driven gene network is a component of the cellular response to transition metals. These data suggest limitations and disadvantages of TFEB overexpression as a therapeutic approach. PMID- 26251448 TI - The NHERF2 sequence adjacent and upstream of the ERM-binding domain affects NHERF2-ezrin binding and dexamethasone stimulated NHE3 activity. AB - In the brush border of intestinal and kidney epithelial cells, scaffolding proteins ezrin, Na(+)-H(+) exchanger regulatory factor (NHERF)1 and NHERF2 play important roles in linking transmembrane proteins to the cytoskeleton and assembling signalling regulatory complexes. The last 30 carboxyl residues of NHERF1 and NHERF2 form the EBDs [ezrin, radixin and moesin (ERM)-binding domain]. The current study found that NHERF1/2 contain an ERM-binding regulatory sequence (EBRS), which facilitates the interaction between the EBD and ezrin. The EBRSs are located within 24 and 19 residues immediately upstream of EBDs for NHERF1 and NHERF2 respectively. In OK (opossum kidney) epithelial cells, EBRSs are necessary along with the EBD to distribute NHERF1 and NHERF2 exclusively to the apical domain. Furthermore, phosphorylation of Ser(303) located in the EBRS of NHERF2, decreases the binding affinity for ezrin, dislocates apical NHERF2 into the cytosol and increases the NHERF2 microvillar mobility rate. Moreover, increased phosphorylation of Ser(303) was functionally significant preventing acute stimulation of NHE3 (Na(+)-H(+) exchanger 3) activity by dexamethasone. PMID- 26251450 TI - Structural and biochemical studies reveal UbiG/Coq3 as a class of novel membrane binding proteins. AB - UbiG and Coq3 (orthologue in eukaryotes) are SAM-MTases (S-adenosylmethionine dependent methyltransferases) that catalyse both O-methylation steps in CoQ biosynthesis from prokaryotes to eukaryotes. However, the detailed molecular mechanism by which they function remains elusive. In the present paper, we report that UbiG/Coq3 defines a novel class of membrane-binding proteins. Escherichia coli UbiG binds specifically to liposomes containing PG (phosphatidylglycerol) or CL (cardiolipin, or diphosphatidylglycerol), two major lipid components of the E. coli plasma membrane, whereas human and yeast Coq3 display a strong preference for liposomes enriched with CL, a signature lipid of the mitochondrial membrane. The crystal structure of UbiG from E. coli was determined at 2.1 A (1 A = 0.1 nm) resolution. The structure exhibits a typical Class I SAM-MTase fold with several variations, including a unique insertion between strand beta5 and helix alpha10. This insertion is highly conserved and is required for membrane binding. Mutation of the key residues renders UbiG unable to efficiently bind liposome in vitro and the mutant fails to rescue the phenotype of DeltaubiG strain in vivo. Taken together, our results shed light on a novel biochemical function of the UbiG/Coq3 protein. PMID- 26251451 TI - Functional dissection of proliferating-cell nuclear antigens (1 and 2) in human malarial parasite Plasmodium falciparum: possible involvement in DNA replication and DNA damage response. AB - Eukaryotic PCNAs (proliferating-cell nuclear antigens) play diverse roles in nucleic acid metabolism in addition to DNA replication. Plasmodium falciparum, which causes human malaria, harbours two PCNA homologues: PfPCNA1 and PfPCNA2. The functional role of two distinct PCNAs in the parasite still eludes us. In the present study, we show that, whereas both PfPCNAs share structural and biochemical properties, only PfPCNA1 functionally complements the ScPCNA mutant and forms distinct replication foci in the parasite, which PfPCNA2 fails to do. Although PfPCNA1 appears to be the primary replicative PCNA, both PfPCNA1 and PfPCNA2 participate in an active DDR (DNA-damage-response) pathway with significant accumulation in the parasite upon DNA damage induction. Interestingly, PfPCNA genes were found to be regulated not at the transcription level, but presumably at the protein stability level upon DNA damage. Such regulation of PCNA has not been shown in eukaryotes before. Moreover, overexpression of PfPCNA1 and PfPCNA2 in the parasite confers a survival edge on the parasite in a genotoxic environment. This is the first evidence of a PfPCNA mediated DDR in the parasite and gives new insights and rationale for the presence of two PCNAs as a parasite survival strategy and its probable success. PMID- 26251452 TI - Role of plasma-membrane-bound sialidase NEU3 in clathrin-mediated endocytosis. AB - Gangliosides are sialic acid-containing glycosphingolipids mainly expressed at the outer leaflet of the plasma membrane. Sialidase NEU3 is a key enzyme in the catabolism of gangliosides with its up-regulation having been observed in human cancer cells. In the case of CME (clathrin-mediated endocytosis), although this has been widely studied, the role of NEU3 and gangliosides in this cellular process has not yet been established. In the present study, we found an increased internalization of Tf (transferrin), the archetypical cargo for CME, in cells expressing complex gangliosides with high levels of sialylation. The ectopic expression of NEU3 led to a drastic decrease in Tf endocytosis, suggesting the participation of gangliosides in this process. However, the reduction in Tf endocytosis caused by NEU3 was still observed in glycosphingolipid-depleted cells, indicating that NEU3 could operate in a way that is independent of its action on gangliosides. Additionally, internalization of alpha2-macroglobulin and low-density lipoprotein, other typical ligands in CME, was also decreased in NEU3 expressing cells. In contrast, internalization of cholera toxin beta-subunit, which is endocytosed by both clathrin-dependent and clathrin-independent mechanisms, remained unaltered. Kinetic assays revealed that NEU3 caused a reduction in the sorting of endocytosed Tf to early and recycling endosomes, with the Tf binding at the cell surface being also reduced. NEU3-expressing cells showed an altered subcellular distribution of clathrin adaptor AP-2 (adaptor protein 2), but did not reveal any changes in the membrane distribution of clathrin, PtdIns(4,5)P2 or caveolin-1. Overall, these results suggest a specific and novel role of NEU3 in CME. PMID- 26251453 TI - Loss of DNase II function in the gonad is associated with a higher expression of antimicrobial genes in Caenorhabditis elegans. AB - Three waves of apoptosis shape the development of Caenorhabditis elegans. Although the exact roles of the three DNase II genes (nuc-1, crn-6 and crn-7), which are known to mediate degradation of apoptotic DNA, in the embryonic and larval phases of apoptosis have been characterized, the DNase II acting in the third wave of germ cell apoptosis remains undetermined. In the present study, we performed in vitro and in vivo assays on various mutant nematodes to demonstrate that NUC-1 and CRN-7, but not CRN-6, function in germ cell apoptosis. In addition, in situ DNA-break detection and anti-phosphorylated ERK (extracellular signal-regulated kinase) staining illustrated the sequential and spatially regulated actions of NUC-1 and CRN-7, at the pachytene zone of the gonad and at the loop respectively. In line with the notion that UV-induced DNA fragment accumulation in the gonad activates innate immunity responses, we also found that loss of NUC-1 and CRN-7 lead to up-regulation of antimicrobial genes (abf-2, spp 1, nlp-29, cnc-2, and lys-7). Our observations suggest that an incomplete digestion of DNA fragments resulting from the absence of NUC-1 or CRN-7 in the gonad could induce the ERK signalling, consequently activating antimicrobial gene expression. Taken together, the results of the present study demonstrate for the first time that nuc-1 and crn-7 play a role in degrading apoptotic DNA in distinct sites of the gonad, and act as negative regulators of innate immunity in C. elegans. PMID- 26251454 TI - Public health coming home. PMID- 26251456 TI - Brain Network Connectivity and Topological Analysis During Voluntary Arm Movements. AB - Functional connectivity estimates the temporal synchrony among functionally homogeneous brain regions based on the assessment of the dynamics of topologically localized neurophysiological responses. The aim of this study was to investigate task-related changes in brain activity and functional connectivity by applying different methods namely event-related desynchronization (ERD), coherence, and graph-theoretical analysis to electroencephalographic (EEG) recordings, for comparing their respective descriptive power and complementarity. As it is well known, ERD provides an estimate of differences in power spectral densities between active (or task) and rest conditions, functional connectivity allows assessing the level of synchronization between the signals recorded at different scalp locations and graph analysis enables the estimation of the functional network features and topology. EEG activity was recorded on 10 subjects during left/right arm movements. The theta, alpha, and beta bands were considered. Conventional analysis showed a significant ERD in both alpha and beta bands over the sensorimotor cortex during the left arm movement and in beta band during the right arm movement, besides identifying the regions involved in the task, as it was expected. On the other hand, connectivity assessment highlighted that stronger connections are those that involved the motor regions for which graph analysis revealed reduced accessibility and an increased centrality during the movement. Jointly, the last two methods allow identifying the cortical areas that are functionally related in the active condition as well as the topological organization of the functional network. Results support the hypothesis that network analysis brings complementary knowledge with respect to established approaches for modeling motor-induced functional connectivity and could be profitably exploited in clinical contexts. PMID- 26251455 TI - The N-terminal acetyltransferase Naa10 is essential for zebrafish development. AB - N-terminal acetylation, catalysed by N-terminal acetyltransferases (NATs), is among the most common protein modifications in eukaryotes and involves the transfer of an acetyl group from acetyl-CoA to the alpha-amino group of the first amino acid. Functions of N-terminal acetylation include protein degradation and sub-cellular targeting. Recent findings in humans indicate that a dysfunctional Nalpha-acetyltransferase (Naa) 10, the catalytic subunit of NatA, the major NAT, is associated with lethality during infancy. In the present study, we identified the Danio rerio orthologue zebrafish Naa 10 (zNaa10). In vitro N-terminal acetylation assays revealed that zNaa10 has NAT activity with substrate specificity highly similar to that of human Naa10. Spatiotemporal expression pattern was determined by in situ hybridization, showing ubiquitous expression with especially strong staining in brain and eye. By morpholino-mediated knockdown, we demonstrated that naa10 morphants displayed increased lethality, growth retardation and developmental abnormalities like bent axis, abnormal eyes and bent tails. In conclusion, we identified the zebrafish Naa10 orthologue and revealed that it is essential for normal development and viability of zebrafish. PMID- 26251457 TI - Electrophysiological Correlates of Aberrant Motivated Attention and Salience Processing in Unaffected Relatives of Schizophrenia Patients. AB - Patients with schizophrenia (SCZ) exhibit debilitating deficits in attention and affective processing, which are often resistant to treatment and associated with poor functional outcomes. Impaired orientation to task-relevant target information has been indexed by diminished P3b event-related potentials in patients, as well as their unaffected first-degree relatives, suggesting that P3b may be a vulnerability marker for schizophrenia. Despite intact affective valence processing, patients are unable to employ cognitive change strategies to reduce electrophysiological responses to aversive stimuli. Less is known about the attentional processing of emotionally salient task-irrelevant information in patients and unaffected first-degree relatives. The goal of the present study was to examine the neural correlates of salience processing, as indexed by the late positive potential (LPP), during the processing of emotionally salient distractor stimuli in 31 patients with SCZ, 28 first-degree relatives, and 47 control participants using an oddball paradigm. Results indicated that despite intact novelty detection (P3a), both SCZ and first-degree relatives demonstrated deficiencies in attentional processing, reflected in attenuated target-P3b, and aberrant motivated attention, with reduced early-LPP amplitudes for aversive stimuli relative to controls. First-degree relatives revealed a unique enhancement of the late-LPP response, possibly underlying an exaggerated evaluation of salient information and a compensatory engagement of neural circuitry. Furthermore, reduced early-LPP and target-P3b amplitudes were associated with enhanced symptom severity. These findings suggest that, in addition to P3b, LPP may be useful for monitoring clinical state. Future studies will explore the value of P3 and LPP responses as vulnerability markers for early detection and prediction of psychopathology. PMID- 26251458 TI - Pericarditis and pericardial effusions in the military patient. AB - The pericardium is the thin double-walled sac encapsulating the heart which has a number of important physiological roles including fixing the heart in the mediastinum, protecting it from cross-organ infection (eg, lung) and lubricating cardiac contraction. The pericardium is associated with several disease syndromes that occasionally affect the military population. These include acute and recurrent pericarditis, pericardial effusion and tamponade, which may result from a large number of different aetiological agents. Pericardial diseases have a wide range of clinical manifestations and the diagnosis of pericardial diseases can be a challenge. This article reviews the anatomy and pathophysiology of pericarditis and pericardial effusions before outlining their clinical features, recommended investigations and management options. Particular emphasis is placed on the impact of these diseases for patients in a military occupational environment. PMID- 26251459 TI - Building extended families through embryo donation: the experiences of donors and recipients. AB - STUDY QUESTION: How do embryo donors and recipients understand and experience embryo donation (ED)? SUMMARY ANSWER: Donors and recipients regard the genetic link between donors and donor-conceived child as significant, and draw on metaphors of ED as adoption and as building extended family networks in order to manage the complex interplay of genetic, gestational and social aspects of reproduction and family-building. WHAT IS KNOWN ALREADY: The uptake of embryo donation internationally is relatively low and there has been little research into the outcomes and experiences of ED for donor and recipient families. STUDY DESIGN, SIZE, DURATION: Embryo donors and recipients in New Zealand were interviewed between March and October 2012 as to their understandings and experiences of embryo donation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were recruited from across New Zealand and interviews were conducted with 22 donors (10 couples, 2 individuals) and 15 recipients (5 couples, 5 individuals). Interview data were analysed thematically to identify factors that influenced their perspectives and affected their experiences. MAIN RESULTS AND THE ROLE OF CHANCE: The genetic link between donors and offspring is regarded as bestowing immutable social ties by both donors and recipients. This makes ED a difficult choice for both donors, who experience a sense of ongoing responsibility for offspring welfare, and for recipients, who may have concerns about the donor-offspring bond. Disclosure of genetic background is regarded as critical for the welfare of both the donor-conceived child as well as siblings in the donor family. Both donors and recipients draw parallels between ED and open adoption practices, and draw on extended family constructs in order to describe their relationship to each other. LIMITATIONS, REASONS FOR CAUTION: Donors and recipients were interviewed at various stages of the ED process, and experiences may change over time. WIDER IMPLICATIONS OF THE FINDINGS: The comparison of ED with open adoption practice and the metaphor of extended family-building both help make sense of and complicate the ED experience. These concepts help to structure expectations for the assessment for ED, the disclosure of donor conception, and the nature of relationships, information-exchange and contact. STUDY FUNDING/COMPETING INTERESTS: This study was funded by an AUT University Faculty of Health Environmental Sciences research grant. PMID- 26251460 TI - Ex vivo culture of human fetal gonads: manipulation of meiosis signalling by retinoic acid treatment disrupts testis development. AB - STUDY QUESTION: What are the effects of experimentally manipulating meiosis signalling by addition of retinoic acid (RA) in cultured human fetal gonads? SUMMARY ANSWER: RA-treatment accelerated meiotic entry in cultured fetal ovary samples, while addition of RA resulted in a dysgenetic gonadal phenotype in fetal testis cultures. WHAT IS KNOWN ALREADY: One of the first manifestations of sex differentiation is the initiation of meiosis in fetal ovaries. In contrast, meiotic entry is actively prevented in the fetal testis at this developmental time-point. It has previously been shown that RA-treatment mediates initiation of meiosis in human fetal ovary ex vivo. STUDY DESIGN, SIZE, DURATION: This was a controlled ex vivo study of human fetal gonads treated with RA in 'hanging-drop' tissue cultures. The applied experimental set-up preserves germ cell-somatic niche interactions and the investigated outcomes included tissue integrity and morphology, cell proliferation and survival and the expression of markers of meiosis and sex differentiation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Tissue from 24 first trimester human fetuses was included in this study, all from elective terminations at gestational week (GW) 7-12. Gonads were cultured for 2 weeks with and without addition of 1 uM RA. Samples were subsequently formalin fixed and investigated by immunohistochemistry and cell counting. Proteins investigated and quantified included; octamer-binding transcription factor 4 (OCT4), transcription factor AP-2 gamma (AP2gamma) (embryonic germ cell markers), SRY (sex determining region Y)-box 9 (SOX9), anti-Mullerian hormone (AMH) (immature Sertoli cell markers), COUP transcription factor 2 (COUP-TFII) (marker of interstitial cells), forkhead box L2 (FOXL2) (granulosa cell marker), H2A histone family, member X (gammaH2AX) (meiosis marker), doublesex and mab-3 related transcription factor 1 (DMRT1) (meiosis regulator), cleaved poly ADP ribose polymerase (PARP), cleaved Caspase 3 (apoptosis markers) and Ki-67 antigen (Ki-67) (proliferation marker). Also, proliferation was determined using a 5' bromo-2'-deoxyuridine (BrdU) incorporation assay. MAIN RESULTS AND THE ROLE OF CHANCE: A novel ex vivo 'hanging-drop' culture model for human fetal gonads was successfully established. Continued proliferation of cells without signs of increased apoptosis was observed after 2 weeks of culture. In cultured fetal ovaries treated with RA, an increased number of meiotic germ cells (P < 0.05) and DMRT1-positive oogonia initiating meiosis (P < 0.05) was observed, which is in agreement with a previous study. In fetal testes, RA-treatment resulted in a decreased number of gonocytes (P < 0.05), a reduced percentage of proliferating gonocytes (P < 0.05), altered expression pattern of the somatic cell markers AMH and COUP-TFII, as well as disrupted seminiferous cord structure and testis morphology. LIMITATIONS, REASONS FOR CAUTION: The number of samples included in this study was relatively small due to the limited availability of human fetal tissue. WIDER IMPLICATIONS OF THE FINDINGS: The hanging-drop culture, similarly to other organ culture approaches, allows studies of germ cell-somatic niche interactions and determination of effects after manipulating specific signalling pathways. Our novel finding of disrupted fetal testis development after treatment with RA indicates that abnormal meiosis regulation can potentially cause gonadal dysgenesis. Further studies will elucidate the exact mechanisms and timing of observed effects. STUDY FUNDING/COMPETING INTERESTS: This work was supported in part by an ESPE Research Fellowship, sponsored by Novo Nordisk A/S to A.Jo. Additional funding for this project was obtained from The Research Council of the Capital Region of Denmark (E.R.-D.M.), The Research Fund at Rigshospitalet (A.Ju. and J.E.N.), Familien Erichssens Fund (A.Jo.), Dagmar Marshalls Fund (A.Jo.) and Aase & Ejnar Danielsens Fund (A.Jo.). The authors have no conflicts of interest. PMID- 26251461 TI - Only a minority of sex chromosome abnormalities are detected by a national prenatal screening program for Down syndrome. AB - STUDY QUESTION: How does a national prenatal screening program for Down syndrome (DS) perform in detecting sex chromosome abnormalities (SCAs)-Turner syndrome (TS), Klinefelter syndrome, 47,XXX and 47,XYY syndromes. SUMMARY ANSWER: The SCA detection rate resulting from DS screening was below 50% for all four groups of SCAs. WHAT IS KNOWN ALREADY: The detection rates of SCAs are higher in countries with DS screening. TS is associated with greater nuchal translucency (NT) and lower pregnancy-associated plasma protein-A (PAPP-A). However, specific detection rates of SCAs using prenatal DS screening have not been determined. No clear trend in PAPP-A, free beta human chorionic gonadotropin (beta-hCG) and NT has been found in the remaining SCAs. Several lines of inquiry suggest that it would be advantageous for individuals with SCA to be detected early in life, leading to prevention or treatment of accompanying conditions. There is limited information about pre- and perinatal status that distinguishes SCA embryogenesis from normal fetal development. STUDY DESIGN, SIZE, DURATION: A register-based case-control study from the Danish Central Cytogenetic Register (DCCR), cross-linked with the Danish Fetal Medicine Database (DFMD), was performed from 2008 to 2012. Groups of SCAs were compared with DS and then matched with non-SCA controls to assess differences between these groups in prenatal markers and birth outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included cases with prenatal and post-natal SCA karyotypes (n = 213), DS (n = 802) and 168 056 controls. We screened 275 037 individuals examined prenatally. We retrieved information regarding maternal age, NT, beta-hCG and PAPP-A, as well as details regarding maternal and newborn characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: The DS screening procedure detected 87 per 100 000 TS (42% of expected), 19 per 100 000 Klinefelter syndrome (13% of expected), 16 per 100 000 47,XXX (16% of cases) and 5 per 100 000 47,XYY (5% of expected) SCAs, with an overall detection rate of 27%. Compared with controls, all four SCA groups showed significantly higher NT and lower PAPP-A compared with controls (all P < 0.01) and similar to DS. The legal abortion rate was high for all four syndromes (47,XXX: 24%; 47,XYY: 29%; Klinefelter syndrome: 48%, TS: 84%). For SCA fetuses carried to term, only TS fetuses had consistently lower birthweights and placenta weights than non-SCA controls (both P = 0.0001). A few SCA cases localized in DCCR could not be found in DFMD (n = 16). LIMITATIONS, REASON FOR CAUTION: Controls were matched on sex of the fetus of cases, meaning that all electively aborted fetuses (before week 12) were excluded, possibly reducing the diversity in the control group. We were not able to localize all diagnosed cases of SCA and DS in DFMD. Although these cases were present in DCCR, we were not able to account for the discrepancy. In addition, we suspect that several SCA children have not been diagnosed yet and future post-natal diagnosis of these cases would reduce the diagnostic yield reported here even further. WIDER IMPLICATIONS OF THE FINDINGS: The prenatal detection rate is below 50% for all SCAs. The approach used for detecting DS cannot be extended to also include SCAs. In addition, all SCAs have low PAPP-A and increased NT, thus probably reflecting an abnormal embryogenesis. Growth retardation of TS fetuses is if anything more pronounced than previously reported, both when evaluating fetus and placenta. STUDY FUNDING/COMPETING INTERESTS: This study received support from Aarhus University and the Novo Nordisk Foundation. The authors have no competing interests that may be relevant to the study. PMID- 26251462 TI - Rheology of sheared gels based on low acyl-gellan gum. AB - Sheared gels containing 0.2 wt% low-acyl gellan gum were prepared by different processing protocols using Na(+) or Ca(2+) as gel-promoting ions. Rheology and confocal laser scanning microscopy were used to gain information on the sample structure. Confocal laser scanning microscopy revealed the formation of a heterogeneous microstructure consisting of a dispersion of gel-like clusters. Small amplitude oscillatory shear stress results indicated that their viscoelastic properties had a predominant elastic component. Flow curves exhibited very high viscosities at low shear stress, an apparent yield stress and very shear thinning behaviour, supporting their applications as a stabilizer. PMID- 26251464 TI - Linking Insects with Crustacea: Physiology of the Pancrustacea: An Introduction to the Symposium. AB - Insects and crustaceans represent critical, dominant animal groups (by biomass and species number) in terrestrial and aquatic systems, respectively. Insects (hexapods) and crustaceans are historically grouped under separate taxonomic classes within the Phylum Arthropoda, and the research communities studying hexapods and crustaceans are quite distinct. More recently, the hexapods have been shown to be evolutionarily derived from basal crustaceans, and the clade Pancrustacea recognizes this relationship. This recent evolutionary perspective, and the fact that the Society for Integrative and Comparative Biology has strong communities in both invertebrate biology and insect physiology, provides the motivation for this symposium. Speakers in this symposium were selected because of their expertise in a particular field of insect or crustacean physiology, and paired in such a way as to provide a comparative view of the state of the current research in their respective fields. Presenters discussed what aspects of the physiological system are clearly conserved across insects and crustaceans and how cross-talk between researchers utilizing insects and crustaceans can fertilize understanding of such conserved systems. Speakers were also asked to identify strategies that would enable improved understanding of the evolution of physiological systems of the terrestrial insects from the aquatic crustaceans. The following collection of articles describes multiple recent advances in our understanding of Pancrustacean physiology. PMID- 26251463 TI - Validation of 64Cu-ATSM damaging DNA via high-LET Auger electron emission. AB - Radioactive copper (II) (diacetyl-bis N4-methylthiosemicarbazone) (Cu-ATSM) isotopes were originally developed for the imaging of hypoxia in tumors. Because the decay of a (64)Cu atom is emitting not only positrons but also Auger electrons, this radionuclide has great potential as a theranostic agent. However, the success of (64)Cu-ATSM internal radiation therapy would depend on the contribution of Auger electrons to tumor cell killing. Therefore, we designed a cell culture system to define the contributions to cell death from Auger electrons to support or refute our hypothesis that the majority of cell death from (64)Cu-ATSM is a result of high-LET Auger electrons and not positrons or other low-LET radiation. Chinese hamster ovary (CHO) wild type and DNA repair deficient xrs5 cells were exposed to (64)Cu-ATSM during hypoxic conditions. Surviving fractions were compared with those surviving gamma-radiation, low-LET hadron radiation, and high-LET heavy ion exposure. The ratio of the D(10) values (doses required to achieve 10% cell survival) between CHO wild type and xrs5 cells suggested that (64)Cu-ATSM toxicity is similar to that of high-LET Carbon ion radiation (70 keV/MUm). gammaH2AX foci assays confirmed DNA double-strand breaks and cluster damage by high-LET Auger electrons from (64)Cu decay, and complex types of chromosomal aberrations typical of high-LET radiation were observed after (64)Cu-ATSM exposure. The majority of cell death was caused by high-LET radiation. This work provides strong evidence that (64)Cu-ATSM damages DNA via high-LET Auger electrons, supporting further study and consideration of (64)Cu-ATSM as a cancer treatment modality for hypoxic tumors. PMID- 26251465 TI - Is the "Heart Age" Concept Helpful or Harmful Compared to Absolute Cardiovascular Disease Risk? An Experimental Study. AB - BACKGROUND: Cardiovascular disease (CVD) prevention guidelines are generally based on the absolute risk of a CVD event, but there is increasing interest in using 'heart age' to motivate lifestyle change when absolute risk is low. Previous studies have not compared heart age to 5-year absolute risk, or investigated the impact of younger heart age, graphical format, and numeracy. OBJECTIVE: Compare heart age versus 5-year absolute risk on psychological and behavioral outcomes. DESIGN: 2 (heart age, absolute risk) * 3 (text only, bar graph, line graph) experiment. SETTING: Online. PARTICIPANTS: 570 Australians aged 45-64 years, not taking CVD-related medication. INTERVENTION: CVD risk assessment. MEASUREMENTS: Intention to change lifestyle, recall, risk perception, emotional response, perceived credibility, and lifestyle behaviors after 2 weeks. RESULTS: Most participants had lifestyle risk factors (95%) but low 5-year absolute risk (94%). Heart age did not improve lifestyle intentions and behaviors compared to absolute risk, was more often interpreted as a higher-risk category by low-risk participants (47% vs 23%), and decreased perceived credibility and positive emotional response. Overall, correct recall dropped from 65% to 24% after 2 weeks, with heart age recalled better than absolute risk at 2 weeks (32% vs 16%). These results were found across younger and older heart age results, graphical format, and numeracy. LIMITATIONS: Communicating CVD risk in a consultation rather than online may produce different results. CONCLUSIONS: There is no evidence that heart age motivates lifestyle change more than 5-year absolute risk in individuals with low CVD risk. Five-year absolute risk may be a better way to explain CVD risk, because it is more credible, does not inflate risk perception, and is consistent with clinical guidelines that base lifestyle and medication recommendations on absolute risk. PMID- 26251466 TI - Ileo-ileal knotting as an uncommon cause of acute intestinal obstruction. AB - Small bowel obstruction (SBO) is one of the most common acute surgical conditions that require urgent evaluation and treatment. Several common causes are known in the general surgical practice, and the causes are different in the developing and developed world. In this article, we present a case of an acute SBO secondary to ileo-ileal knotting in a 50 years old Ethiopian female patient. The diagnostic difficulty and the need for urgent treatment of the condition are discussed. PMID- 26251467 TI - Deaths of teenagers in car crashes: a child death review. AB - MVCs are a leading cause of death and disability for teenagers. In Wales, a child death review process has been established to carry out thematic reviews of deaths; this approach is believed to highlight opportunities for prevention that individual case review could not. Cases were 13-year-old to 17-year-old Welsh residents who died as car drivers or passengers between 1 January 2006 and 31 December 2010. An expert panel was convened to review these cases. 28 MVCs occurred and 34 13-17 year olds died; 24 males, 10 females. 51 vehicles were involved; 23 driven by 17-year-old to 19-year-old males. 19 of the 28 MVCs occurred between 21:00 and 05:00. The risk factors identified were consistent with global research on MVC deaths and injuries to teenagers. However, there is a lack of effective interventions to tackle these in the UK. It is recommended that the implementation of Graduated Driver Licensing is considered. PMID- 26251468 TI - The anti-inflammatory effect and potential mechanism of cardamonin in DSS-induced colitis. AB - Cardamonin is a naturally occurring chalcone with strong anti-inflammatory activity. However, the direct effect of cardamonin on intestinal inflammation remains elusive. In the present study, we found that cardamonin markedly ameliorated dextran sulfate sodium-induced mouse body weight loss, diarrhea, colon shortening, spleen swelling, and histological damage, which correlated with a decline in the activity of myeloperoxidase and the production of nitric oxide, tumor necrosis factor-alpha and interleukin-6 in the colon. The upregulation of toll-like receptor 4 after dextran sulfate sodium treatment was associated with an increase in the activation of myeloid differentiation factor 88, interleukin-1 receptor-associated kinase-1, nuclear factor-kappaB (NF-kappaB) p65, inhibitor kappaBalpha, and inhibitor kappaB kinase-alpha/beta, as well as the mitogen activated protein kinase molecules of extracellular signal-regulated kinase and c Jun NH2-terminal kinase, and this upregulation was reversed by cardamonin administration. Moreover, cardamonin blocked the nuclear translocation of NF kappaB p65, inhibited NF-kappaB-luciferase activity, and downregulated NF-kappaB target genes expression. The present study clearly demonstrates a beneficial effect of cardamonin on experimental inflammatory bowel disease via a mechanism associated with suppression of toll-like receptor 4 expression and inactivation of NF-kappaB and mitogen-activated protein kinase pathways. This study may give insight into the further evaluation of the therapeutic potential of cardamonin or its derivatives for human inflammatory bowel disease. PMID- 26251469 TI - Phenotypic divergence in two lines of L-Fabp-/- mice reflects substrain differences and environmental modifiers. AB - Phenotypic divergence in diet-induced obesity (DIO) and hepatic steatosis has been reported in two independently generated lines of L-Fabp(-/-) mice [New Jersey (NJ) L-Fabp(-/-) vs. Washington University (WU) L-Fabp(-/-) mice]. We performed side-by-side studies to examine differences between the lines and investigate the role of genetic background, intestinal microbiota, sex, and diet in the divergent phenotypes. Fasting-induced steatosis was attenuated in both L Fabp(-/-) lines compared with C57BL/6J controls, with restoration of hepatic triglyceride levels following adenoviral L-Fabp rescue. Both lines were protected against DIO after high-saturated-fat diet feeding. Hepatic steatosis was attenuated in WU but not NJ L-Fabp(-/-) mice, although this difference between the lines disappeared upon antibiotic treatment and cohousing. In contrast, there was phenotypic divergence in L-Fabp(-/-) mice fed a high cocoa butter fat diet, with WU L-Fabp(-/-) mice, but not NJ L-Fabp(-/-) mice, showing protection against both DIO and hepatic steatosis, with some sex-dependent (female > male) differences. Dense mapping revealed no evidence of unintended targeting, duplications, or deletions surrounding the Fabp1 locus in either line and only minor differences in mRNA expression of genes located near the targeted allele. However, a C57BL/6 substrain screen showed that the NJ L-Fabp(-/-) line contains ~40% C57BL/6N genomic DNA, despite reports that these mice were backcrossed six generations. Overall, these findings suggest that some of the phenotypic divergence between the two L-Fabp(-/-) lines may reflect unanticipated differences in genetic background, underscoring the importance of genetic background in phenotypic characterization. PMID- 26251470 TI - Acetaldehyde accelerates HCV-induced impairment of innate immunity by suppressing methylation reactions in liver cells. AB - Alcohol exposure worsens the course and outcomes of hepatitis C virus (HCV) infection. Activation of protective antiviral genes is induced by IFN-alpha signaling, which is altered in liver cells by either HCV or ethanol exposure. However, the mechanisms of the combined effects of HCV and ethanol metabolism in IFN-alpha signaling modulation are not well elucidated. Here, we explored a possibility that ethanol metabolism potentiates HCV-mediated dysregulation of IFN alpha signaling in liver cells via impairment of methylation reactions. HCV infected Huh7.5 CYP2E1(+) cells and human hepatocytes were exposed to acetaldehyde (Ach)-generating system (AGS) and stimulated with IFN-alpha to activate IFN-sensitive genes (ISG) via the Jak-STAT-1 pathway. We observed significant suppression of signaling events by Ach. Ach exposure decreased STAT-1 methylation via activation of protein phosphatase 2A and increased the protein inhibitor of activated STAT-1 (PIAS-1)-STAT-1 complex formation in both HCV(+) and HCV(-) cells, preventing ISG activation. Treatment with a promethylating agent, betaine, attenuated all examined Ach-induced defects. Ethanol metabolism induced changes in ISGs are methylation related and confirmed by in vivo studies on HCV(+) transgenic mice. HCV- and Ach-induced impairment of IFN signaling temporarily increased HCV RNA levels followed by apoptosis of heavily infected cells. We concluded that Ach potentiates the suppressive effects of HCV on activation of ISGs attributable to methylation-dependent dysregulation of IFN alpha signaling. A temporary increase in HCV RNA sensitizes the liver cells to Ach-induced apoptosis. Betaine reverses the inhibitory effects of Ach on IFN signaling and thus can be used for treatment of HCV(+) alcohol-abusing patients. PMID- 26251472 TI - Classification of functional bowel disorders by objective physiological criteria based on endoluminal image analysis. AB - We have previously developed an original method to evaluate small bowel motor function based on computer vision analysis of endoluminal images obtained by capsule endoscopy. Our aim was to demonstrate intestinal motor abnormalities in patients with functional bowel disorders by endoluminal vision analysis. Patients with functional bowel disorders (n = 205) and healthy subjects (n = 136) ingested the endoscopic capsule (Pillcam-SB2, Given-Imaging) after overnight fast and 45 min after gastric exit of the capsule a liquid meal (300 ml, 1 kcal/ml) was administered. Endoluminal image analysis was performed by computer vision and machine learning techniques to define the normal range and to identify clusters of abnormal function. After training the algorithm, we used 196 patients and 48 healthy subjects, completely naive, as test set. In the test set, 51 patients (26%) were detected outside the normal range (P < 0.001 vs. 3 healthy subjects) and clustered into hypo- and hyperdynamic subgroups compared with healthy subjects. Patients with hypodynamic behavior (n = 38) exhibited less luminal closure sequences (41 +/- 2% of the recording time vs. 61 +/- 2%; P < 0.001) and more static sequences (38 +/- 3 vs. 20 +/- 2%; P < 0.001); in contrast, patients with hyperdynamic behavior (n = 13) had an increased proportion of luminal closure sequences (73 +/- 4 vs. 61 +/- 2%; P = 0.029) and more high-motion sequences (3 +/- 1 vs. 0.5 +/- 0.1%; P < 0.001). Applying an original methodology, we have developed a novel classification of functional gut disorders based on objective, physiological criteria of small bowel function. PMID- 26251471 TI - Obesity and intestinal epithelial deletion of the insulin receptor, but not the IGF 1 receptor, affect radiation-induced apoptosis in colon. AB - Current views suggest that apoptosis eliminates genetically damaged cells that may otherwise form tumors. Prior human studies link elevated insulin and reduced apoptosis to risk of colorectal adenomas. We hypothesized that hyperinsulinemia associated with obesity would lead to reduced colon epithelial cell (CEC) apoptosis after radiation and that this effect would be altered by deletion of the insulin-like growth factor (IGF) 1 receptor (IGF1R) or the insulin receptor (IR). Mice with villin-Cre-mediated IGF1R or IR deletion in CECs and floxed littermates were fed a high-fat diet to induce obesity and hyperinsulinemia or control low-fat chow. Mice were exposed to 5-Gy abdominal radiation to induce DNA damage and euthanized 4 h later for evaluation of apoptosis by localization of cleaved caspase-3. Obese mice exhibited decreased apoptosis of genetically damaged CECs. IGF1R deletion did not affect CEC apoptosis in lean or obese animals. In contrast, IR loss increased CEC apoptosis in both diet groups but did not prevent antiapoptotic effects of obesity. Levels of p53 protein were significantly reduced in CECs of obese mice with intact IR but increased in both lean and obese mice without IR. Levels of mRNAs encoding proapoptotic Perp and the cell cycle inhibitor Cdkn1b/p27 were reduced in CECs of obese mice and increased in lean mice lacking IR. Together, our studies provide novel evidence for antiapoptotic roles of obesity and IR, but not IGF1R, in colonic epithelium after DNA damage. However, neither IR nor IGF1R deletion prevented a reduction in radiation-induced CEC apoptosis during obesity and hyperinsulinemia. PMID- 26251475 TI - On positional asphyxia and death in custody. PMID- 26251474 TI - Oncostatin M induces IL-33 expression in liver endothelial cells in mice and expands ST2+CD4+ lymphocytes. AB - Interleukin (IL)-33 is crucially involved in liver pathology and drives hepatoprotective functions. However, the regulation of IL-33 by cytokines of the IL-6 family, including oncostatin M (OSM) and IL-6, is not well studied. The aim of the present study was to determine whether OSM mediates regulation of IL-33 expression in liver cells. Intramuscular administration in mice of an adenovirus encoding OSM (AdOSM) leads to increase in expression of OSM in muscles, liver, and serum of AdOSM-infected mice compared with control mice. The increase of circulating OSM markedly regulated mRNA of genes associated with blood vessel biology, chemotaxis, cellular death, induction of cell adhesion molecules, and the alarmin cytokine IL-33 in liver. Steady-state IL-33 mRNA was upregulated by OSM at an early phase (8 h) following AdOSM infection. At the protein level, the expression of IL-33 was significantly induced in liver endothelial cells [liver sinusoidal endothelial cells (LSEC) and vascular endothelial cells] with a peak at 8 days post-AdOSM infection in mice. In addition, we found OSM-stimulated human microvascular endothelial HMEC-1 cells and human LSEC/TRP3 cells showed a significant increase in expression of IL-33 mRNA in a dose-dependent manner in cell culture. The OSM-mediated overexpression of IL-33 was associated with the activation/enrichment of CD4(+)ST2(+) cells in liver of AdOSM-infected mice compared with adenovirus encoding green fluorescent protein-treated control mice. In summary, these data suggest that the cytokine OSM regulates the IL-33 expression in liver endothelial cells in vivo and in HMEC-1/TRP3 cells in vitro and may specifically expand the target CD4(+)ST2(+) cells in liver. PMID- 26251473 TI - Glycomacropeptide is a prebiotic that reduces Desulfovibrio bacteria, increases cecal short-chain fatty acids, and is anti-inflammatory in mice. AB - Glycomacropeptide (GMP) is a 64-amino acid (AA) glycophosphopeptide with application to the nutritional management of phenylketonuria (PKU), obesity, and inflammatory bowel disease (IBD). GMP is a putative prebiotic based on extensive glycosylation with sialic acid, galactose, and galactosamine. Our objective was to determine the prebiotic properties of GMP by characterizing cecal and fecal microbiota populations, short-chain fatty acids (SCFA), and immune responses. Weanling PKU (Pah(enu2)) and wild-type (WT) C57Bl/6 mice were fed isoenergetic AA, GMP, or casein diets for 8 wk. The cecal content and feces were collected for microbial DNA extraction to perform 16S microbiota analysis by Ion Torrent PGM sequencing. SCFA were determined by gas chromatography, plasma cytokines via a Bio-Plex Pro assay, and splenocyte T cell populations by flow cytometry. Changes in cecal and fecal microbiota are primarily diet dependent. The GMP diet resulted in a reduction from 30-35 to 7% in Proteobacteria, genera Desulfovibrio, in both WT and PKU mice with genotype-dependent changes in Bacteroidetes or Firmicutes. Cecal concentrations of the SCFA acetate, propionate, and butyrate were increased with GMP. The percentage of stimulated spleen cells producing interferon-gamma (IFN-gamma) was significantly reduced in mice fed GMP compared with casein. In summary, plasma concentrations of IFN-gamma, TNF-alpha, IL-1beta, and IL-2 were reduced in mice fed GMP. GMP is a prebiotic based on reduction in Desulfovibrio, increased SCFA, and lower indexes of inflammation compared with casein and AA diets in mice. Functional foods made with GMP may be beneficial in the management of PKU, obesity, and IBD. PMID- 26251476 TI - Task shifting of mental health care services in Ghana: ease of referral, perception and concerns of stakeholders about quality of care. AB - OBJECTIVES: To examine the perceptions of stakeholders about the ease of referral of patients from community mental health workers (CMHWs) to psychiatrists in Ghana and the level of stakeholder concerns about the quality of care provided to these community health cadres. DESIGN: A cross-sectional survey. PARTICIPANTS: Eleven psychiatrists, 26 health policy directors and 164 community mental health workers, including 71 (43.3%) community psychiatric nurses, 19 (11.6%) clinical psychiatric officers and 74 (45.1%) community mental health officers. METHODS: We administered three separate, self-administered, semi-structured questionnaires to the study participants. RESULTS: Although many respondents including almost all CMHWs perceive that it is easy for them to refer difficult cases to a psychiatrist who will usually see such patients in a timely manner, less than a quarter of these health cadres reported that they always or often refer patients to see a psychiatrist. The majority of CMHWs were of the opinion that patients, psychiatrists and other healthcare workers have concerns about the quality of care they provide, sentiments that were echoed by all psychiatrists and over half of all the health policy directors. CONCLUSION: There is also a need for policy directors to educate CMHWs about their roles and to clarify referral pathways so that cases that are difficult to manage will be appropriately referred to psychiatrists or appropriately trained and incentivized district medical doctors for further management. PMID- 26251478 TI - "Stepping Up" Activity Poststroke: Ankle-Positioned Accelerometer Can Accurately Record Steps During Slow Walking. AB - BACKGROUND: As physical activity in people poststroke is low, devices that monitor and provide feedback of walking activity provide motivation to engage in exercise and may assist rehabilitation professionals in auditing walking activity. However, most feedback devices are not accurate at slow walking speeds. OBJECTIVE: This study assessed the accuracy of one accelerometer to measure walking steps of community-dwelling individuals poststroke. DESIGN: This was a cross-sectional study. METHODS: Two accelerometers were positioned on the nonparetic waist and ankle of participants (N=43), and walking steps from these devices were recorded at 7 speeds (0.3-0.9 m/s) and compared with video recordings (gold standard). RESULTS: When positioned at the waist, the accelerometer had more than 10% error at all speeds, except 0.8 and 0.9 m/s, and numerous participants recorded zero steps at 0.3 to 0.5 m/s. The device had 10% or less error when positioned at the ankle for all speeds between 0.4 and 0.9 m/s. LIMITATIONS: Some participants were unable to complete the faster walking speeds due to their walking impairments and inability to maintain the requested walking speed. CONCLUSIONS: Although not recommended by the manufacturer, positioning the accelerometer at the ankle (compared with the waist) may fill a long-standing need for a readily available device that provides accurate feedback for the altered and slow walking patterns that occur with stroke. PMID- 26251479 TI - Promoting Community Health and Eliminating Health Disparities Through Community Based Participatory Research. AB - In physical therapy, there is increasing focus on the need at the community level to promote health, eliminate disparities in health status, and ameliorate risk factors among underserved minorities. Community-based participatory research (CBPR) is the most promising paradigm for pursuing these goals. Community-based participatory research stresses equitable partnering of the community and investigators in light of local social, structural, and cultural elements. Throughout the research process, the CBPR model emphasizes coalition and team building that joins partners with diverse skills/expertise, knowledge, and sensitivities. This article presents core concepts and principles of CBPR and the rationale for its application in the management of health issues at the community level. Community-based participatory research is now commonly used to address public health issues. A literature review identified limited reports of its use in physical therapy research and services. A published study is used to illustrate features of CBPR for physical therapy. The purpose of this article is to promote an understanding of how physical therapists could use CBPR as a promising way to advance the profession's goals of community health and elimination of health care disparities, and social responsibility. Funding opportunities for the support of CBPR are noted. PMID- 26251477 TI - Impact of Diabetic Complications on Balance and Falls: Contribution of the Vestibular System. AB - Diabetes causes many complications, including retinopathy and peripheral neuropathy, which are well understood as contributing to gait instability and falls. A less understood complication of diabetes is the effect on the vestibular system. The vestibular system contributes significantly to balance in static and dynamic conditions by providing spatially orienting information. It is noteworthy that diabetes has been reported to affect vestibular function in both animal and clinical studies. Pathophysiological changes in peripheral and central vestibular structures due to diabetes have been noted. Vestibular dysfunction is associated with impaired balance and a higher risk of falls. As the prevalence of diabetes increases, so does the potential for falls due to diabetic complications. The purpose of this perspective article is to present evidence on the pathophysiology of diabetes-related complications and their influence on balance and falls, with specific attention to emerging evidence of vestibular dysfunction due to diabetes. Understanding this relationship may be useful for screening (by physical therapists) for possible vestibular dysfunction in people with diabetes and for further developing and testing the efficacy of interventions to reduce falls in this population. PMID- 26251481 TI - Genome Sequences of Four Staphylococcus capitis NRCS-A Isolates from Geographically Distant Neonatal Intensive Care Units. AB - Staphylococcus capitis pulsotype NRCS-A was previously reported as a frequent cause of late-onset sepsis in neonatal intensive care units (NICUs) worldwide. Here, we report the whole-genome shotgun sequences of four S. capitis pulsotype NCRS-A strains, CR03, CR04, CR05, and CR09, isolated from Belgium, Australia, the United Kingdom, and France, respectively. PMID- 26251482 TI - Draft Genome Sequences of Burkholderia contaminans, a Burkholderia cepacia Complex Species That Is Increasingly Recovered from Cystic Fibrosis Patients. AB - Burkholderia contaminans belongs to the Burkholderia cepacia complex (BCC), a group of bacteria that are ubiquitous in the environment and capable of infecting the immunocompromised and people with cystic fibrosis. We report here draft genome sequences for the B. contaminans type strain LMG 23361 and an Argentinian cystic fibrosis sputum isolate. PMID- 26251480 TI - Study of Hyperkyphosis, Exercise and Function (SHEAF) Protocol of a Randomized Controlled Trial of Multimodal Spine-Strengthening Exercise in Older Adults With Hyperkyphosis. AB - BACKGROUND: Hyperkyphosis negatively affects health status, physical mobility, and quality of life, but there is no standard protocol for treating people with hyperkyphosis. Treatment options include targeted exercise. OBJECTIVES: This single-site randomized controlled trial (RCT) will determine the efficacy of a targeted multimodal spine-strengthening exercise program, compared with no exercise intervention, among community-dwelling men and women aged >=60 years. DESIGN: The RCT is a parallel-group design, with 1:1 randomization to exercise and attentional control groups. SETTING: The study will be conducted at one primary site (one academic medical center partnered with one local community medical center). PARTICIPANTS: One hundred men and women, aged >=60 years, with thoracic kyphosis >=40 degrees will be randomized. INTERVENTION: The targeted multimodal spine-strengthening exercise intervention includes exercise and postural training delivered by a physical therapist in a group of 10 participants, 3 times a week for 6 months. Controls receive monthly health education meetings in a group of 10 participants and monthly calls from the study coordinator to monitor physical activity and any adverse events. MEASUREMENTS: The primary outcome is change in Cobb angle of kyphosis measured from lateral spine radiographs at baseline and 6 months. Secondary outcomes include change in physical function (assessed with the modified Physical Performance Test, Timed "Up & Go" Test, timed loaded standing, 4-m walk, and Six-Minute Walk Test) and health-related quality of life (assessed with the modified Scoliosis Research Society instrument [SRS-30] self-image domain and Patient Reported Outcomes Measurement Information System [PROMIS] global health and physical function indexes). Additional secondary outcomes include pain, physical activity level, spinal flexion and extension muscle strength, paraspinal extensor muscle density, and adverse events. LIMITATIONS: Blinding of the participants and instructors providing the intervention is not possible. CONCLUSIONS: The efficacy of a high quality, adequately powered exercise intervention in men and women with kyphosis >=40 degrees will be evaluated to determine whether targeted multimodal spine strengthening exercise reduces hyperkyphosis in older adults and improves important secondary outcomes of physical function and health-related quality of life. PMID- 26251483 TI - Complete Genome Sequence of Nova Virus, a Hantavirus Circulating in the European Mole in Belgium. AB - The complete genome sequence of Nova virus, a divergent hantavirus, originating from the kidney tissue of a European mole (Talpa europaea) from Belgium was determined. The 3 genomic segments have a total length of 11,979 nucleotides, and nucleotide identities to other Nova viruses are between 80 and 89%. PMID- 26251484 TI - Complete Genome Sequences of Mandrillus leucophaeus and Papio ursinus Cytomegaloviruses. AB - The complete genome sequences of Mandrillus leucophaeus and Papio ursinus cytomegaloviruses were determined. An isolate from a drill monkey, OCOM6-2, and an isolate from a chacma baboon, OCOM4-52, were subjected to pyrosequencing and assembled. Comparative alignment of published primate cytomegaloviruses (CMVs) showed variable sequence conservation between species. PMID- 26251485 TI - Genome Sequence of Schizochytrium sp. CCTCC M209059, an Effective Producer of Docosahexaenoic Acid-Rich Lipids. AB - Schizochytrium is an effective species for producing omega-3 docosahexaenoic acid (DHA). Here, we report a genome sequence of Schizochytrium sp. CCTCC M209059, which has a genome size of 39.09 Mb. It will provide the genomic basis for further insights into the metabolic and regulatory mechanisms underlying the DHA formation. PMID- 26251486 TI - Draft Genome Sequence of Delftia tsuruhatensis MTQ3, a Strain of Plant Growth Promoting Rhizobacterium with Antimicrobial Activity. AB - Delftia tsuruhatensis MTQ3 is a plant growth-promoting rhizobacterium (PGPR) isolated from tobacco rhizosphere. Here, we report the draft genome sequence of D. tsuruhatensis MTQ3. Several functional genes related to antimicrobial activity and environment adaption have been found in the genome. This is the first genome sequence of D. tsuruhatensis related to PGPR. PMID- 26251487 TI - Draft Genome Sequence of the Pathogenic Filamentous Fungus Aspergillus udagawae Strain IFM 46973T. AB - The incidence of aspergillosis by Aspergillus infection has dramatically increased in recent years. Aspergillus udagawae, a species related to Aspergillus fumigatus, is known as an emerging pathogen of aspergillosis. Here, we present the draft genome sequence of A. udagawae strain IFM 46973(T). PMID- 26251488 TI - Complete Genome Sequence of Enterobacter cloacae UW5, a Rhizobacterium Capable of High Levels of Indole-3-Acetic Acid Production. AB - We report the complete genome sequence of Enterobacter cloacae UW5, an indole-3 acetic acid-producing rhizobacterium originally isolated from the rhizosphere of grass. The 4.9-Mbp genome has a G+C content of 54% and contains 4,496 protein coding sequences. PMID- 26251489 TI - Complete Genome Sequences of Chrysanthemum Stunt Viroid from a Single Chrysanthemum Cultivar. AB - The chrysanthemum stunt viroid (CSVd), a member of the genus Pospiviroid with a single circular RNA genome, infects many chrysanthemum species. Here, we report 25 complete genome sequences of CSVd in a single chrysanthemum cultivar, revealing 20 variants. PMID- 26251490 TI - Complete Genome Sequence of Bacillus megaterium Siphophage Stills. AB - Bacillus megaterium is a soil-dwelling bacterium frequently used in research as a model organism and in industry in protein production applications. Bacteriophages may be used to enhance the use of this bacterium. Here, we describe the complete genome of B. megaterium siphophage Stills and its core features. PMID- 26251491 TI - Complete Genome Sequence of Bacillus megaterium Siphophage Stahl. AB - Stahl is a siphophage active against Bacillus megaterium, a Gram-positive bacterium often used as a model system in research and as a protein production strain in industrial applications. Here, we present the complete annotated genome of phage Stahl and describe its major features. PMID- 26251492 TI - Draft Genome Sequence of Streptomyces sp. Strain Wb2n-11, a Desert Isolate with Broad-Spectrum Antagonism against Soilborne Phytopathogens. AB - Streptomyces sp. strain Wb2n-11, isolated from native desert soil, exhibited broad-spectrum antagonism against plant pathogenic fungi, bacteria, and nematodes. The 8.2-Mb draft genome reveals genes putatively responsible for its promising biocontrol activity and genes which enable the soil bacterium to directly interact beneficially with plants. PMID- 26251493 TI - Draft Genome Sequence of Paenibacillus polymyxa Strain Mc5Re-14, an Antagonistic Root Endophyte of Matricaria chamomilla. AB - Paenibacillus polymyxa strain Mc5Re-14 was isolated from the inner root tissue of Matricaria chamomilla (German chamomile). Mc5Re-14 revealed promising in vitro antagonistic activity against plant and opportunistic human pathogens. The 6.0-Mb draft genome reveals genes putatively involved in pathogen suppression and direct and indirect plant growth promotion. PMID- 26251494 TI - High-Quality Genome Sequence of Bacillus vireti DSM 15602T for Setting Up Phylogenomics for the Genomic Taxonomy of Bacillus-Like Bacteria. AB - Bacillus vireti DSM 15602(T) is a Gram-negative, spore-forming, and facultatively anaerobic bacterium. Here, we report the 5.309-Mb draft genome sequence of B. vireti DSM 15602(T), which will provide useful information for setting up phylogenomics for the genomic taxonomy of Bacillus-like bacteria, as well as for the functional gene mining and application of B. vireti. PMID- 26251496 TI - Draft Whole-Genome Sequence and Annotation of the Entomopathogenic Bacterium Xenorhabdus khoisanae Strain MCB. AB - We report here the draft genome sequence of Xenorhabdus khoisanae strain MCB, a Gram-negative bacterium and symbiont of a Steinernema entomopathogenic nematode. The genome assembly consists of 266 contigs covering 4.68 Mb. Genome annotation revealed 3,869 protein-coding sequences, with a G+C content of 43.5%. PMID- 26251495 TI - Draft Genome Sequence of Corynebacterium striatum 1961 BR-RJ/09, a Multidrug Susceptible Strain Isolated from the Urine of a Hospitalized 37-Year-Old Female Patient. AB - Corynebacterium striatum commonly colonizes the normal skin and nasopharyngeal tract of humans; however, this potentially pathogenic bacterium has been identified as the causative agent of several nosocomial infections. The current study describes the draft genome of strain 1961 BR-RJ/09, isolated from the urine of a hospitalized patient from Brazil. PMID- 26251497 TI - Draft Genome Sequences of Three Pectobacterium Strains Causing Blackleg of Potato: P. carotovorum subsp. brasiliensis ICMP 19477, P. atrosepticum ICMP 1526, and P. carotovorum subsp. carotovorum UGC32. AB - Blackleg is a disease caused by several species of Pectobacterium that results in losses to potato crops worldwide. Here, we report the draft genomes of three taxonomically and geographically distinct blackleg-causing strains of Pectobacterium: P. carotovorum subsp. brasiliensis ICMP 19477, P. atrosepticum ICMP 1526, and P. carotovorum subsp. carotovorum UGC32. Comparison of these genomes will support the identification of common traits associated with their capacity to cause blackleg. PMID- 26251498 TI - Draft Genome Sequence for ICMP 5702, the Type Strain of Pectobacterium carotovorum subsp. carotovorum That Causes Soft Rot Disease on Potato. AB - Pectobacterium species are economically important bacteria that cause soft rotting of potato tubers in the field and in storage. Here, we report the draft genome sequence of the type strain for P. carotovorum subsp. carotovorum, ICMP 5702 (ATCC 15713). The genome sequence of ICMP 5702 will provide an important reference for future phylogenomic and taxonomic studies of the phytopathogenic Enterobacteriaceae. PMID- 26251499 TI - Draft Genome Sequence of Mycobacterium bohemicum Strain DSM 44277T. AB - The Mycobacterium bohemicum strain is a nontuberculosis species mainly responsible for pediatric cervical lymphadenitis. The draft genome of M. bohemicum DSM 44277(T) comprises 5,097,190 bp exhibiting a 68.64% G+C content, 4,840 protein-coding genes, and 75 predicted RNA genes. PMID- 26251500 TI - Complete Genome Sequence of Escherichia coli NCM3722. AB - Escherichia coli NCM3722 is a prototrophic K-12 strain with robust physiologic phenotypes. We report the complete 4,678,045-bp chromosome and 67,545-bp F-like plasmid of this unique model organism. PMID- 26251501 TI - Genome Sequence of the Moderately Acidophilic Sulfate-Reducing Firmicute Desulfosporosinus acididurans (Strain M1T). AB - Microbial dissimilatory sulfate reduction is commonplace in many anaerobic environments, though few acidophilic bacteria are known to mediate this process. We report the 4.64-Mb draft genome of the type strain of the moderate acidophile Desulfosporosinus acididurans, which was isolated from acidic sediment in a river draining the Soufriere volcano, Montserrat. PMID- 26251502 TI - Complete Genome Sequence of Enteroinvasive Escherichia coli O96:H19 Associated with a Severe Foodborne Outbreak. AB - We present here the complete genome sequence of a strain of enteroinvasive Escherichia coli O96:H19 from a severe foodborne outbreak in a canteen in Italy in 2014. The complete genome may provide important information about the acquired pathogenicity of this strain and the transition between commensal and pathogenic E. coli. PMID- 26251503 TI - Genome Sequence of the Acidophilic Sulfate-Reducing Peptococcaceae Strain CEB3. AB - We report the draft genome of the Peptococcaceae strain CEB3 that originated from an acidic (pH 2.5) stream draining an abandoned copper mine. Strain CEB3 is one of the very few reported acidophilic sulfate-reducing isolates. The 5.04-Mb draft genome harbors 5,069 predicted protein-encoding and 66 RNA genes. PMID- 26251505 TI - Insights into the Hydrocarbon Tolerance of Two Devosia Isolates, D. chinhatensis Strain IPL18T and D. geojensis Strain BD-c194T, via Whole-Genome Sequence Analysis. AB - Hexachlorocyclohexane (HCH) was among the most commonly used pesticides after the Second World War. The extensive use of this hydrocarbon for almost six decades has created a contamination problem on a global scale, and bioremediation methods are being extensively explored. The reported ability of some Devosia species to grow in the presence of appreciable amounts of hydrocarbons (2,000 mg/kg of contaminated soil) is attracting closer attention. Here, we report the de novo genome assembly of two hydrocarbon-tolerating Devosia isolates, D. chinhatensis strain IPL18(T) and D. geojensis strain BD-c194(T), as a first step toward understanding the metabolic pathways involved in their environmental adaptation and tolerance toward hydrocarbons. PMID- 26251504 TI - Draft Genome Sequence of Frankia sp. Strain DC12, an Atypical, Noninfective, Ineffective Isolate from Datisca cannabina. AB - Frankia sp. strain DC12, isolated from root nodules of Datisca cannabina, is a member of the fourth lineage of Frankia, which is unable to reinfect actinorhizal plants. Here, we report its 6.88-Mbp high-quality draft genome sequence, with a G+C content of 71.92% and 5,858 candidate protein-coding genes. PMID- 26251506 TI - A quality improvement project to improve early sepsis care in the emergency department. AB - BACKGROUND: Sepsis causes substantial morbidity and mortality in hospitalised patients. Although many studies describe the use of protocols in the management of patients with severe sepsis and septic shock, few have addressed emergency department (ED) screening and management for patients initially presenting with uncomplicated sepsis (ie, patients without organ failure or hypotension). OBJECTIVE: A quality improvement task force at a large, quaternary care referral hospital sought to develop a protocol focusing on early identification of patients with uncomplicated sepsis, in addition to severe sepsis and septic shock. INTERVENTION: The three-tiered intervention consisted of (1) a nurse driven screening tool and management protocol to identify and initiate early treatment of patients with sepsis, (2) a computer-assisted screening algorithm that generated a 'Sepsis Alert' pop-up screen in the electronic medical record for treating clinical healthcare providers and (3) automated suggested sepsis specific order sets for initial workup and resuscitation, antibiotic selection and goal-directed therapy. DESIGN: A before and after retrospective cohort study was undertaken to determine the intervention's impact on compliance with recommended sepsis management, including serum lactate measured in the ED, 2 L of intravenous fluid administered within 2 h of triage, antibiotics administered within 3 h of triage and blood cultures drawn before antibiotic administration. Mortality rates for patients in the ED with a sepsis-designated ICD-9 code present on admission were also analysed. RESULTS: Overall bundle compliance increased by 154%, from 28% at baseline to 71% in the last quarter of the study (p<0.001). Bundle, antibiotic and intravenous fluid compliance all increased significantly after launch of the sepsis initiative (eg, bundle and intravenous fluid compliance increased by 74% and 54%, respectively; p<0.001). Bundle and antibiotic compliance both showed further significant increases after implementation of suggested order sets (31% and 25% increases, respectively; p<0.001). The mortality rate for patients in the ED admitted with sepsis was 13.3% before implementation and fell to 11.1% after (p=0.230); mortality in the last two quarters of the study was 9.3% (p=0.107). CONCLUSIONS: The new protocol demonstrates that early screening interventions can lead to expedited delivery of care to patients with sepsis in the ED and could serve as a model for other facilities. Mortality was not significantly improved by our intervention, which included patients with uncomplicated sepsis. PMID- 26251507 TI - Routine failures in the process for blood testing and the communication of results to patients in primary care in the UK: a qualitative exploration of patient and provider perspectives. AB - BACKGROUND: The testing and result communication process in primary care is complex. Its successful completion relies on the coordinated efforts of a range of staff in primary care and external settings working together with patients. Despite the importance of diagnostic testing in provision of care, this complexity renders the process vulnerable in the face of increasing demand, stretched resources and a lack of supporting guidance. METHODS: We conducted a series of focus groups with patients and staff across four primary care practices using process-improvement strategies to identify and understand areas where either unnecessary delay is introduced, or the process may fail entirely. We then worked with both patients and staff to arrive at practical strategies to improve the current system. RESULTS: A total of six areas across the process were identified where improvements could be introduced. These were: (1) delay in phlebotomy, (2) lack of a fail-safe to ensure blood tests are returned to practices and patients, (3) difficulties in accessing results by telephone, (4) role of non-clinical staff in communicating results, (5) routine communication of normal results and (6) lack of a protocol for result communication. CONCLUSIONS: A number of potential failures in testing and communicating results to patients were identified, and some specific ideas for improving existing systems emerged. These included same-day phlebotomy sessions, use of modern technology methods to proactively communicate routine results and targeted training for receptionists handling sensitive data. There remains an urgent need for further work to test these and other potential solutions. PMID- 26251508 TI - Antiproliferative and anti-inflammatory properties of diindolylmethane and lupeol against N-butyl-N-(4-hydroxybutyl) nitrosamine induced bladder carcinogenesis in experimental rats. AB - INTRODUCTION: Chemoprevention may involve perturbation of a variety of steps in tumor initiation, promotion, and progression. OBJECTIVE: To investigate the antiproliferative and anti-inflammatory potential effects of diindolylmethane (DIM) and lupeol on experimental bladder carcinogenesis. METHODS: Sixty healthy male Wistar rats were selected and randomly divided into six groups, with 10 rats in each group. Group I: control; group II: N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN; 150 mg/gavage/twice a week) for 8 weeks, and then they were given 100 ppm concentrations of dimethylarsenic acid (DMA) in the drinking water for 28 weeks; group III: BBN + DMA + DIM (5 mg/kg body weight (b.w.)/day) treatment was started after BBN treatment, and it was orally administered for 28 weeks); group IV: BBN + DMA + lupeol (50 mg/kg b.w./day) treatment was started after BBN treatment, and it was orally administered for 28 weeks); and groups V and VI: DIM and lupeol treatment alone for 36 weeks. Bladder tissues were collected after 36th week study protocol for further analysis. RESULTS: Our results revealed that DIM and lupeol treatment showed inhibition of tumor growth in the bladder by histopathological confirmations as well as significantly (p < 0.001) increased the expression of phosphotensin (PTEN) and significantly (p < 0.001) decreased the expression of tumor necrosis factor alpha, nuclear factor kappabeta (p65) were quantified using Western blot analysis. DIM and lupeol treatment significantly (p < 0.001) decreased the levels of Cox-2 in bladder tissue samples and NMP 22 in urine samples were quantified using enzyme-linked immunosorbent assay method. CONCLUSION: Preventive DIM and lupeol administration act as potent Cox-2 inhibitors, which activates the tumor suppressor protein PTEN against experimental bladder carcinogenesis by antiproliferative and anti-inflammatory properties. PMID- 26251509 TI - Cytochrome redox states and respiratory control in mouse and beef heart mitochondria at steady-state levels of hypoxia. AB - Mitochondrial control of cellular redox states is a fundamental component of cell signaling in the coordination of core energy metabolism and homeostasis during normoxia and hypoxia. We investigated the relationship between cytochrome redox states and mitochondrial oxygen consumption at steady-state levels of hypoxia in mitochondria isolated from beef and mouse heart (BHImt, MHImt), comparing two species with different cardiac dynamics and local oxygen demands. A low-noise, rapid spectrophotometric system using visible light for the measurement of cytochrome redox states was combined with high-resolution respirometry. Monophasic hyperbolic relationships were observed between oxygen consumption, JO2, and oxygen partial pressure, Po2, within the range <1.1 kPa (8.3 mmHg; 13 MUM). P50j (Po2 at 0.5.Jmax) was 0.015 +/- 0.0004 and 0.021 +/- 0.003 kPa (0.11 and 0.16 mmHg) for BHImt and MHImt, respectively. Maximum oxygen consumption, Jmax, was measured at saturating ADP levels (OXPHOS capacity) with Complex I linked substrate supply. Redox states of cytochromes aa3 and c were biphasic hyperbolic functions of Po2. The relationship between cytochrome oxidation state and oxygen consumption revealed a separation of distinct phases from mild to severe and deep hypoxia. When cytochrome c oxidation increased from fully reduced to 45% oxidized at 0.1 Jmax, Po2 was as low as 0.002 kPa (0.02 MUM), and trace amounts of oxygen are sufficient to partially oxidize the cytochromes. At higher Po2 under severe hypoxia, respiration increases steeply, whereas redox changes are small. Under mild hypoxia, the steep slope of oxidation of cytochrome c when flux remains more stable represents a cushioning mechanism that helps to maintain respiration high at the onset of hypoxia. PMID- 26251510 TI - Effect of carbohydrate feeding on the bone metabolic response to running. AB - Bone resorption is increased after running, with no change in bone formation. Feeding during exercise might attenuate this increase, preventing associated problems for bone. This study investigated the immediate and short-term bone metabolic responses to carbohydrate (CHO) feeding during treadmill running. Ten men completed two 7-day trials, once being fed CHO (8% glucose immediately before, every 20 min during, and immediately after exercise at a rate of 0.7 g CHO . kg body mass(-1) . h(-1)) and once being fed placebo (PBO). On day 4 of each trial, participants completed a 120-min treadmill run at 70% of maximal oxygen consumption (Vo2 max). Blood was taken at baseline (BASE), immediately after exercise (EE), after 60 (R1) and 120 (R2) min of recovery, and on three follow-up days (FU1-FU3). Markers of bone resorption [COOH-terminal telopeptide region of collagen type 1 (beta-CTX)] and formation [NH2-terminal propeptides of procollagen type 1 (P1NP)] were measured, along with osteocalcin (OC), parathyroid hormone (PTH), albumin-adjusted calcium (ACa), phosphate, glucagon like peptide-2 (GLP-2), interleukin-6 (IL-6), insulin, cortisol, leptin, and osteoprotogerin (OPG). Area under the curve was calculated in terms of the immediate (BASE, EE, R1, and R2) and short-term (BASE, FU1, FU2, and FU3) responses to exercise. beta-CTX, P1NP, and IL-6 responses to exercise were significantly lower in the immediate postexercise period with CHO feeding compared with PBO (beta-CTX: P = 0.028; P1NP: P = 0.021; IL-6: P = 0.036), although there was no difference in the short-term response (beta-CTX: P = 0.856; P1NP: P = 0.721; IL-6: P = 0.327). No other variable was significantly affected by CHO feeding during exercise. We conclude that CHO feeding during exercise attenuated the beta-CTX and P1NP responses in the hours but not days following exercise, indicating an acute effect of CHO feeding on bone turnover. PMID- 26251511 TI - Sympathoexcitation and arterial hypertension associated with obstructive sleep apnea and cyclic intermittent hypoxia. AB - Obstructive sleep apnea (OSA) is characterized by repetitive episodes of upper airway obstruction during sleep. These obstructive episodes are characterized by cyclic intermittent hypoxia (CIH), by sleep fragmentation, and by hemodynamic instability, and they result in sustained sympathoexcitation and elevated arterial pressure that persist during waking, after restoration of normoxia. Early studies established that 1) CIH, rather than sleep disruption, accounts for the increase in arterial pressure; 2) the increase in arterial pressure is a consequence of the sympathoactivation; and 3) arterial hypertension after CIH exposure requires an intact peripheral chemoreflex. More recently, however, evidence has accumulated that sympathoactivation and hypertension after CIH are also dependent on altered central sympathoregulation. Furthermore, although many molecular pathways are activated in both the carotid chemoreceptor and in the central nervous system by CIH exposure, two specific neuromodulators-endothelin-1 and angiotensin II-appear to play crucial roles in mediating the sympathetic and hemodynamic response to intermittent hypoxia. PMID- 26251512 TI - Doublet potentiation in the triceps surae is limited by series compliance and dynamic fascicle behavior. AB - Activation of skeletal muscle twice in quick succession results in nonlinear force summation (i.e., doublet potentiation). The force contributed by a second activation is typically of augmented amplitude, longer in duration, and generated at a greater rate. The purpose of this study was to examine force summation in a muscle attached to a compliant tendon, where considerable internal shortening occurs during a fixed-end contraction. The triceps surae of 21 (Experiment 1) and 9 (Experiment 2) young adults were maximally activated with doublet stimulation of different interstimulus intervals (ISIs) (5-100 ms) at several muscle lengths. Ultrasound images acquired from lateral gastrocnemius and soleus muscles allowed quantification of dynamic fascicle behavior. Force summation was muscle length dependent. Force augmentation was limited to a short muscle length. Lateral gastrocnemius and soleus fascicles underwent large amounts of active shortening and achieved high velocities in response to doublet stimulation, dynamics unfavorable for force production. Summation amplitude and the sensitivity of summation to ISI were dramatically depressed in the triceps surae after comparison to muscles with less fixed-end compliance. We propose that the internal shortening permitted by high series compliance limited force augmentation by offsetting and/or interfering with activation and cross-bridge processes driving augmentation. High series compliance may also reduce the sensitivity of the summated response to ISI, an assertion supported by predictions from a Hill-type muscle model. These muscles may exhibit greater force augmentation during more accustomed stretch-shorten tasks (i.e., hopping), where the compliance of the Achilles tendon actually enables near-isometric fascicle behavior. PMID- 26251513 TI - In vivo assessment of contractile strength distinguishes differential gene function in skeletal muscle of zebrafish larvae. AB - The accessible genetics and extensive skeletal musculature of the zebrafish make it a versatile and increasingly used model for studying muscle contraction. We here describe the development of an in vivo assay for measuring the contractile force of intact zebrafish at the larval stage. In addition, as proof of applicability, we have used this assay to quantify contractile strength of zebrafish larvae in a morphant model of deranged rbfox function. Average maximum tetanic (180 Hz) whole body forces produced by wild-type larvae at 2, 3, 4, and 5 days postfertilization amounted to 3.0, 7.2, 9.1, and 10.8 mN, respectively. To compare at potentially different stages of muscle development, we developed an immunohistological assay for empirically determining the cross-sectional area of larval trunk skeletal muscle to quantify muscle-specific force per cross sectional area. At 4-5 days postfertilization, specific force amounts to ~ 300 mN/mm(2), which is similar to fully developed adult mammalian skeletal muscle. We used these assays to measure contractile strength in zebrafish singly or doubly deficient for two rbfox paralogs, rbfox1l and rbfox2, which encode RNA-binding factors shown previously to modulate muscle function and muscle-specific splicing. We found rbfox2 morphants produce maximal tetanic forces similar to wild-type larvae, whereas rbfox1l morphants demonstrate significantly impaired function. rbfox1l/rbfox2 morphants are paralyzed, and their lack of contractile force production in our assay suggests that paralysis is a muscle-autonomous defect. These quantitative functional results allow measurement of muscle specific phenotypes independent of neural input. PMID- 26251514 TI - HIGH LIFE: High altitude fatalities led to pulse oximetry. AB - In 1875, Paul Bert linked high altitude danger to the low partial pressure of oxygen when 2 of 3 French balloonists died euphorically at about 8,600 m altitude. World War I fatal crashes of high altitude fighter pilots led to a century of efforts to use oximetry to warn pilots. The carotid body, discovered in 1932 to be the hypoxia detector, led to most current physiologic understanding of the body's respiratory responses to hypoxia and CO2. The author describes some of his UCSF group's work: In 1963, we reported both the brain's ventral medullary near-surface CO2 (and pH) chemosensors and the role of cerebrospinal fluid in acclimatization to altitude. In 1966, we reported the effect of altitude on cerebral blood flow and later the changes of carotid body sensitivity at altitude and the differences in natives of high altitude. In 1973, pulse oximetry was invented when Japanese biophysicist Takuo Aoyagi read and applied to pulses a largely forgotten 35-year-old discovery by English medical student J. R. Squire of a method of computing oxygen saturation from red and infrared light passing through both perfused and blanched tissue. PMID- 26251515 TI - Age and sex relationship with flow-mediated dilation in healthy children and adolescents. AB - Flow-mediated dilation (FMD) is a noninvasive technique used to measure conduit artery vascular function. Limited information is available on normative FMD values in healthy children and adolescents. The objective of this study was to assess relationships between age and sex with FMD across childhood and adolescence. Nine hundred and seventy-eight asymptomatic children (12 +/- 3 yr, range 6-18 yr, 530 male) underwent ultrasonic brachial artery assessment before and after 5 min of forearm ischemia. Sex differences in FMD and baseline artery diameter were assessed using mixed linear models. Baseline artery diameter was smaller in females than males [2.96 mm (95% CI: 2.92-3.00) vs. 3.24 mm (3.19 3.28), P < 0.001] and increased with age across the cohort (P < 0.001). Diameter increased between ages 6 and 17 yr in males [from 2.81 mm (2.63, 3.00) to 3.91 mm (3.68, 4.14)] but plateaued at age 12 yr in females. Males had a lower FMD [7.62% (7.33-7.91) vs. 8.31% (7.95-8.66), P = 0.024], specifically at ages 17 and 18 yr. There was a significant effect of age on FMD (P = 0.023), with a reduction in FMD apparent postpuberty in males. In conclusion, the brachial artery increases structurally with age in both sexes; however, there are sex differences in the timing and rate of growth, in line with typical sex-specific adolescent growth patterns. Males have a lower FMD than females, and FMD appears to decline with age; however, these findings are driven by reductions in FMD as males near maturity. The use of age- and sex-specific FMD data may therefore not be pertinent in childhood and adolescence. PMID- 26251516 TI - Sumoylation of the GTPase Ran by the RanBP2 SUMO E3 Ligase Complex. AB - The SUMO E3 ligase complex RanBP2/RanGAP1*SUMO1/Ubc9 localizes at cytoplasmic nuclear pore complex (NPC) filaments and is a docking site in nucleocytoplasmic transport. RanBP2 has four Ran binding domains (RBDs), two of which flank RanBP2's E3 ligase region. We thus wondered whether the small GTPase Ran is a target for RanBP2-dependent sumoylation. Indeed, Ran is sumoylated both by a reconstituted and the endogenous RanBP2 complex in semi-permeabilized cells. Generic inhibition of SUMO isopeptidases or depletion of the SUMO isopeptidase SENP1 enhances sumoylation of Ran in semi-permeabilized cells. As Ran is typically associated with transport receptors, we tested the influence of Crm1, Imp beta, Transportin, and NTF2 on Ran sumoylation. Surprisingly, all inhibited Ran sumoylation. Mapping Ran sumoylation sites revealed that transport receptors may simply block access of the E2-conjugating enzyme Ubc9, however the acceptor lysines are perfectly accessible in Ran/NTF2 complexes. Isothermal titration calorimetry revealed that NTF2 prevents sumoylation by reducing RanGDP's affinity to RanBP2's RBDs to undetectable levels. Taken together, our findings indicate that RanGDP and not RanGTP is the physiological target for the RanBP2 SUMO E3 ligase complex. Recognition requires interaction of Ran with RanBP2's RBDs, which is prevented by the transport factor NTF2. PMID- 26251517 TI - A p7 Ion Channel-derived Peptide Inhibits Hepatitis C Virus Infection in Vitro. AB - Viral infection is an early stage of its life cycle and represents a promising target for antiviral drug development. Here we designed and characterized three peptide inhibitors of hepatitis C virus (HCV) infection based on the structural features of the membrane-associated p7 polypeptide of HCV. The three peptides exhibited low toxicity and high stability while potently inhibiting initial HCV infection and suppressed established HCV infection at non-cytotoxic concentrations in vitro. The most efficient peptide (designated H2-3), which is derived from the H2 helical region of HCV p7 ion channel, inhibited HCV infection by inactivating both intracellular and extracellular viral particles. The H2-3 peptide inactivated free HCV with an EC50 (50% effective concentration) of 82.11 nm, which is >1000-fold lower than the CC50 (50% cytotoxic concentration) of Huh7.5.1 cells. H2-3 peptide also bound to cell membrane and protected host cells from viral infection. The peptide H2-3 did not alter the normal electrophysiological profile of the p7 ion channel or block viral release from Huh7.5.1 cells. Our work highlights a new anti-viral peptide design strategy based on ion channel, giving the possibility that ion channels are potential resources to generate antiviral peptides. PMID- 26251519 TI - HMGA1 overexpression is associated with a particular subset of human breast carcinomas. AB - OBJECTIVES: Breast cancer represents the second leading cause of cancer mortality among American women and accounts for more than 40 000 deaths annually. High mobility group A1 (HMGA1) expression has been implicated in the pathogenesis and progression of human malignant tumours, including breast carcinomas. The aim of this study was to evaluate HMGA1 detection as an indicator for the diagnosis and prognosis of human breast carcinoma. METHODS: HMGA1 expression has been analysed by immunohistochemistry in a large series of breast carcinoma resections (1338) combined on a tissue microarray mainly including the ductal carcinoma variant. The results were then correlated with clinicopathological parameters of patients. RESULTS: HMGA1 overexpression was found in the large majority of breast carcinoma samples and its overexpression positively correlated with HER-2/neu amplification and progesterone receptor, while a negative correlation was found with oestrogen receptor. Conversely, no HMGA1 expression was found in normal breast tissues. CONCLUSIONS: The data reported here indicate that HMGA1 is overexpressed in human breast carcinomas and its levels are associated with a particular endocrine status. PMID- 26251518 TI - The Protein Acetyltransferase PatZ from Escherichia coli Is Regulated by Autoacetylation-induced Oligomerization. AB - Lysine acetylation is an important post-translational modification in the metabolic regulation of both prokaryotes and eukaryotes. In Escherichia coli, PatZ (formerly YfiQ) is the only known acetyltransferase protein and is responsible for acetyl-CoA synthetase acetylation. In this study, we demonstrated PatZ-positive cooperativity in response to acetyl-CoA and the regulation of acetyl-CoA synthetase activity by the acetylation level. Furthermore, functional analysis of an E809A mutant showed that the conserved glutamate residue is not relevant for the PatZ catalytic mechanism. Biophysical studies demonstrated that PatZ is a stable tetramer in solution and is transformed to its octameric form by autoacetylation. Moreover, this modification is reversed by the sirtuin CobB. Finally, an in silico PatZ tetramerization model based on hydrophobic and electrostatic interactions is proposed and validated by three-dimensional hydrodynamic analysis. These data reveal, for the first time, the structural regulation of an acetyltransferase by autoacetylation in a prokaryotic organism. PMID- 26251520 TI - Connexin 43 expression predicts poor progression-free survival in patients with non-muscle invasive urothelial bladder cancer. AB - OBJECTIVES: To evaluate the protein expression of connexin 43 (Cx43) in primary urothelial bladder cancer and test its association with the histopathological characteristics and clinical outcome. METHODS: A tissue microarray containing 348 tissue samples from 174 patients with primary urothelial carcinomas of the bladder was immunohistochemically stained for Cx43. The intensity of staining was semiquantitatively evaluated (score 0, 1+, 2+), and the association with clinicopathological features was assessed. Univariable and multivariable analyses were performed to identify predictors for progression-free survival (PFS). RESULTS: Membranous Cx43 immunoreactivity was detected in 118 (67.8%) of 174 analysable urothelial carcinomas, of which 31 (17.8%) showed even a strong (score 2+) and mainly homogeneous staining. Strong expression levels of Cx43 (score 2+) were associated with higher tumour grade, multiplicity and increased proliferation (all p<0.05). In the subgroup of patients with stage pTa and pT1 bladder tumours (n=158), strong Cx43 expression (p<0.001), solid growth pattern (p<0.001) and increased Ki-67 proliferation fraction (p<0.05) were significantly associated with shorter PFS in an univariable Cox regression analysis. In multivariable Cox regression models, Cx43 immunoreactivity and histological growth pattern remained highly significant and adverse risk factors for PFS. CONCLUSIONS: The expression levels of Cx43 are frequent in non-muscle invasive bladder cancer (NMIBC), with high expression levels being associated with poor prognosis. Routine assessment of Cx43 expression may improve the identification of high-risk NMIBC. PMID- 26251521 TI - Clinicopathological characteristics of RHOA mutations in a Central European gastric cancer cohort. AB - Genomically stable gastric cancers (GCs) are enriched for the diffuse phenotype and hotspot mutations of RHOA. Here we aimed to validate the occurrence, phenotype and clinicopathological characteristics of RHOA mutant GCs in an independent Central European GC cohort consisting of 415 patients. The RHOA genotype (exon 2 and 3) was correlated with various genotypic, phenotypic and clinicopathological patient characteristics. Sixteen (3.9%) tumours had a RHOA mutation including four hitherto unreported mutations, that is, p.G17Efs*24, p.V24F, p.T37A and p.L69R. RHOA mutation was more prevalent in women (5.4% vs 2.8%), distal GCs (4.5% vs 2.4%), in poorly differentiated GCs (G3/G4; 4.8% vs 1.1%), T1/T2 tumours (6.2% vs 3.1%) and lacked distant metastases. Nine RHOA mutant GCs had a diffuse, four an intestinal, two an unclassified and one a mixed Lauren phenotype. KRAS and RHOA mutations were mutually exclusive. A single case showed both a RHOA and a PIK3CA mutation. No significant difference was found in the overall survival between RHOA mutant and wildtype GCs. Our study confirms the occurrence and clinicopathological characteristics of RHOA hotspot mutations in an independent patient cohort. However, we found no evidence for a prognostic or growth advantageous effect of RHOA mutations in GC. PMID- 26251522 TI - Fibulin-5 is a tumour suppressor inhibiting cell migration and invasion in ovarian cancer. AB - AIMS: Fibulin-5 is an extracellular matrix (ECM) glycoprotein which has a role in the organisation and stabilisation of ECM structures and regulating cell proliferation and tumourigenesis. Here, the expression of fibulin-5 and its functional effects on the migration and invasion of ovarian cancer cells were assessed. METHODS: Expression of fibulin-5 was detected in 44 ovarian tumour tissues by qRT-PCR, Western blotting and immunohistochemistry. We performed cell migration and invasion assays, and cell cycle analysis in fibulin-5 transfected SKOV3 (SKOV3-FBLN5) cells and the parental SKOV3 cells. We further examined the expression of three tissue inhibitors of metalloproteinases (TIMPs) and seven matrix metalloproteinases (MMPs) by RT-PCR. RESULTS: mRNA and protein expression of fibulin-5 were down-regulated (0.05-fold and 0.1-fold) in ovarian carcinomas compared with control tissues (p<0.01 and p=0.022). In wound-healing and invasion assays, significantly fewer SKOV3-FBLN5 cells than SKOV3 control cells migrated and invaded (39.1%, p=0.046 and 70%, p=0.03, respectively), which was reversed by siRNA-treatment. Overexpression of fibulin-5 induced G2/M arrest and increased cyclin B1, CDC2 and CDC25C. Expression of TIMP-2 (0.56-fold), MMP-3 (0.43-fold) and MMP-13 (0.18-fold) was lower and MMP-9 expression (2.20-fold) was higher in SKOV3-FBLN5 cells than in control cells. CONCLUSIONS: Fibulin-5 is significantly down-regulated in ovarian carcinoma and acts as a tumour suppressor by inhibiting the migration and invasion of ovarian cancer cells. PMID- 26251523 TI - Morphogenesis of the papillary lesions of the breast: phenotypic observation. AB - Papillary lesions of the breast are a heterogeneous group of diseases characterised by the presence epithelial proliferation supported by fibrovascular stalks. Normal breast tissue does not show papillary morphology and the mechanisms underlying papillary morphogenesis in breast tumours remain poorly understood. Current clinical evidence indicates an indolent behaviour of malignant papillary breast tumours. Herein, we present some phenotypic features that may explain the development of papillary morphology of breast lesions. Active papillary morphogenesis, which appears to reflect a unique mechanism involving interaction between epithelial and mesenchymal elements, is best appreciated in intraductal papilloma and papillary carcinoma. Morphological evidence suggests papillary morphogenesis during oncogenesis is a dynamic process with variable degrees of papillary differentiation among the same lesion and between primary and metastatic tumours. Secondary papillary-like architecture of non-papillary breast lesions exists. Further studies of the molecular mechanisms underlying papillary morphogenesis in the breast and its association with a better outcome are warranted. PMID- 26251525 TI - Adult Small Gut Intussusception Caused by Ascaris as a Lead Point. PMID- 26251524 TI - Interspecific Differential Expression Analysis of RNA-Seq Data Yields Insight into Life Cycle Variation in Hydractiniid Hydrozoans. AB - Hydrozoans are known for their complex life cycles, which can alternate between an asexually reproducing polyp stage and a sexually reproducing medusa stage. Most hydrozoan species, however, lack a free-living medusa stage and instead display a developmentally truncated form, called a medusoid or sporosac, which generally remains attached to the polyp. Although evolutionary transitions in medusa truncation and loss have been investigated phylogenetically, little is known about the genes involved in the development and loss of this life cycle stage. Here, we present a new workflow for evaluating differential expression (DE) between two species using short read Illumina RNA-seq data. Through interspecific DE analyses between two hydractiniid hydrozoans, Hydractinia symbiolongicarpus and Podocoryna carnea, we identified genes potentially involved in the developmental, functional, and morphological differences between the fully developed medusa of P. carnea and reduced sporosac of H. symbiolongicarpus. A total of 10,909 putative orthologs of H. symbiolongicarpus and P. carnea were identified from de novo assemblies of short read Illumina data. DE analysis revealed 938 of these are differentially expressed between P. carnea developing and adult medusa, when compared with H. symbiolongicarpus sporosacs, the majority of which have not been previously characterized in cnidarians. In addition, several genes with no corresponding ortholog in H. symbiolongicarpus were expressed in developing medusa of P. carnea. Results presented here show interspecific DE analyses of RNA-seq data to be a sensitive and reliable method for identifying genes and gene pathways potentially involved in morphological and life cycle differences between species. PMID- 26251526 TI - Borderline Lepromatous Leprosy with Type 1 (Reversal) Reactions in a Chinese Man. PMID- 26251527 TI - Local and sex-specific biases in crossover vs. noncrossover outcomes at meiotic recombination hot spots in mice. AB - Meiotic recombination initiated by programmed double-strand breaks (DSBs) yields two types of interhomolog recombination products, crossovers and noncrossovers, but what determines whether a DSB will yield a crossover or noncrossover is not understood. In this study, we analyzed the influence of sex and chromosomal location on mammalian recombination outcomes by constructing fine-scale recombination maps in both males and females at two mouse hot spots located in different regions of the same chromosome. These include the most comprehensive maps of recombination hot spots in oocytes to date. One hot spot, located centrally on chromosome 1, behaved similarly in male and female meiosis: Crossovers and noncrossovers formed at comparable levels and ratios in both sexes. In contrast, at a distal hot spot, crossovers were recovered only in males even though noncrossovers were obtained at similar frequencies in both sexes. These findings reveal an example of extreme sex-specific bias in recombination outcome. We further found that estimates of relative DSB levels are surprisingly poor predictors of relative crossover frequencies between hot spots in males. Our results demonstrate that the outcome of mammalian meiotic recombination can be biased, that this bias can vary depending on location and cellular context, and that DSB frequency is not the only determinant of crossover frequency. PMID- 26251530 TI - BVA survey highlights the challenges of recruitment. PMID- 26251531 TI - RCVS trial of an alternative dispute resolution system nears completion. PMID- 26251532 TI - Company contributes to its local community. PMID- 26251528 TI - ALS mutations in TLS/FUS disrupt target gene expression. AB - Amyotrophic lateral sclerosis (ALS) is caused by mutations in a number of genes, including the gene encoding the RNA/DNA-binding protein translocated in liposarcoma or fused in sarcoma (TLS/FUS or FUS). Previously, we identified a number of FUS target genes, among them MECP2. To investigate how ALS mutations in FUS might impact target gene expression, we examined the effects of several FUS derivatives harboring ALS mutations, such as R521C (FUS(C)), on MECP2 expression in transfected human U87 cells. Strikingly, FUS(C) and other mutants not only altered MECP2 alternative splicing but also markedly increased mRNA abundance, which we show resulted from sharply elevated stability. Paradoxically, however, MeCP2 protein levels were significantly reduced in cells expressing ALS mutant derivatives. Providing a parsimonious explanation for these results, biochemical fractionation and in vivo localization studies revealed that MECP2 mRNA colocalized with cytoplasmic FUS(C) in insoluble aggregates, which are characteristic of ALS mutant proteins. Together, our results establish that ALS mutations in FUS can strongly impact target gene expression, reflecting a dominant effect of FUS-containing aggregates. PMID- 26251533 TI - Raising awareness of biosecurity on farms. PMID- 26251534 TI - Prime Minister opens practice's new hospital premises. PMID- 26251535 TI - Investigations reveal rare mutation event in avian influenza outbreak. PMID- 26251536 TI - Veterinary and medical associations mark a One Health milestone. PMID- 26251537 TI - Supporting the advancement of veterinary dermatology. PMID- 26251538 TI - Northern Ireland disease surveillance report, April to June 2015. PMID- 26251539 TI - Rabies: 100 per cent fatal, 100 per cent preventable. PMID- 26251540 TI - Overwintering of the brown dog tick in residential properties in England--raising awareness. PMID- 26251547 TI - Intercalating in global health. PMID- 26251548 TI - First-year student diary. PMID- 26251549 TI - Room for Improvement in Nutrition Knowledge and Dietary Intake of Male Football (Soccer) Players in Australia. AB - Athletes require sufficient nutrition knowledge and skills to enable appropriate selection and consumption of food and fluids to meet their health, body composition, and performance needs. This article reports the nutrition knowledge and dietary habits of male football (soccer) players in Australia. Players age 18 years and older were recruited from 1 A-League club (professional) and 4 National Premier League clubs (semiprofessional). No significant difference in general nutrition knowledge (GNK; 54.1% +/- 13.4%; 56.8% +/- 11.7%; M +/- SD), t(71) = 0.91, p = .37, or sports nutrition knowledge (SNK; 56.9% +/- 15.5%; 61.3% +/- 15.9%), t(71) = -1.16, p = .25) were noted between professional (n = 29) and semiprofessional (n = 44) players. In general, players lacked knowledge in regard to food sources and types of fat. Although nutrition knowledge varied widely among players (24.6-82.8% correct responses), those who had recently studied nutrition answered significantly more items correctly than those who reported no recent formal nutrition education (62.6% +/- 11.9%; 54.0% +/- 11.4%), t(67) = 2.88, p = .005). Analysis of 3-day estimated food diaries revealed both professionals (n = 10) and semiprofessionals (n = 31) consumed on average less carbohydrate (3.5 +/- 0.8 gC/kg; 3.9 +/- 1.8 gC/kg) per day than football specific recommendations (FIFA Medical and Assessment Research Centre [F-MARC]: 5 10 gC/kg). There was a moderate, positive correlation between SNK and carbohydrate intake (n = 41, rho = 0.32, p = .04), indicating that players who exhibited greater SNK had higher carbohydrate intakes. On the basis of these findings, male football players in Australia would benefit from nutrition education targeting carbohydrate and fat in an attempt to improve nutrition knowledge and dietary practices. PMID- 26251550 TI - Caffeinated Energy Drinks Improve High-Speed Running in Elite Field Hockey Players. AB - The aim of this investigation was to determine the efficacy of a caffeine containing energy drink to improve physical performance of elite field hockey players during a game. On 2 days separated by a week, 13 elite field hockey players (age and body mass = 23.2 +/- 3.9 years and 76.1 +/- 6.1 kg) ingested 3 mg of caffeine per kg of body mass in the form of an energy drink or the same drink without caffeine (placebo drink). After 60 min for caffeine absorption, participants played a simulated field hockey game (2 * 25 min). Individual running pace and instantaneous speed during the game were assessed using GPS devices. The total number of accelerations and decelerations was determined by accelerometry. Compared with the placebo drink, the caffeinated energy drink did not modify the total distance covered during the game (6,035 +/- 451 m and 6,055 +/- 499 m, respectively; p = .87), average heart rate (155 +/- 13 beats per min and 158 +/- 18 beats per min, respectively; p = .46), or the number of accelerations and decelerations (697 +/- 285 and 618 +/- 221, respectively; p = .15). However, the caffeinated energy drink reduced the distance covered at moderate-intensity running (793 +/- 135 and 712 +/- 116, respectively; p = .03) and increased the distance covered at high-intensity running (303 +/- 67 m and 358 +/- 117 m; p = .05) and sprinting (85 +/- 41 m and 117 +/- 55 m, respectively; p = .02). Elite field hockey players can benefit from ingesting caffeinated energy drinks because they increase the running distance covered at high-intensity running and sprinting. Increased running distance at high speed might represent a meaningful advantage for field hockey performance. PMID- 26251551 TI - A Place-Oriented, Mixed-Level Regionalization Method for Constructing Geographic Areas in Health Data Dissemination and Analysis. AB - Similar geographic areas often have great variations in population size. In health data management and analysis, it is desirable to obtain regions of comparable population by decomposing areas of large population (to gain more spatial variability) and merging areas of small population (to mask privacy of data). Based on the Peano curve algorithm and modified scale-space clustering, this research proposes a mixed-level regionalization (MLR) method to construct geographic areas with comparable population. The method accounts for spatial connectivity and compactness, attributive homogeneity, and exogenous criteria such as minimum (and approximately equal) population or disease counts. A case study using Louisiana cancer data illustrates the MLR method and its strengths and limitations. A major benefit of the method is that most upper level geographic boundaries can be preserved to increase familiarity of constructed areas. Therefore, the MLR method is more human-oriented and place-based than computer-oriented and space-based. PMID- 26251552 TI - A Fully-Implantable Cochlear Implant SoC with Piezoelectric Middle-Ear Sensor and Arbitrary Waveform Neural Stimulation. AB - A system-on-chip for an invisible, fully-implantable cochlear implant is presented. Implantable acoustic sensing is achieved by interfacing the SoC to a piezoelectric sensor that detects the sound-induced motion of the middle ear. Measurements from human cadaveric ears demonstrate that the sensor can detect sounds between 40 and 90 dB SPL over the speech bandwidth. A highly reconfigurable digital sound processor enables system power scalability by reconfiguring the number of channels, and provides programmable features to enable a patient-specific fit. A mixed-signal arbitrary waveform neural stimulator enables energy-optimal stimulation pulses to be delivered to the auditory nerve. The energy-optimal waveform is validated with in-vivo measurements from four human subjects which show a 15% to 35% energy saving over the conventional rectangular waveform. Prototyped in a 0.18 MUm high-voltage CMOS technology, the SoC in 8-channel mode consumes 572 MUW of power including stimulation. The SoC integrates implantable acoustic sensing, sound processing, and neural stimulation on one chip to minimize the implant size, and proof-of concept is demonstrated with measurements from a human cadaver ear. PMID- 26251553 TI - Changing Sibship Size and Educational Progress During Childhood: Evidence From the Philippines. AB - This paper investigates the association between changes in coresident sibship size and children's educational progress in the Philippines. When conceptualized at the household level, sibship size is a dynamic aspect of the family context with potentially important implications for resources needed to support a child's education. Individual-level change models suggested that adding younger siblings in early childhood (from birth to age 9) and losing both younger and older siblings later in childhood (from age 9 to 19) were associated with less educational progress by the focal child between ages 9 and 19. These effects were additive and indicated the importance of assessing both type of change and timing in evaluating the relationship between coresident sibship size and educational progress during childhood. PMID- 26251554 TI - Efficient generation of volatile cadmium species using Ti(III) and Ti(IV) and application to determination of cadmium by cold vapor generation inductively coupled plasma mass spectrometry (CVG-ICP-MS). AB - In this study, a highly efficient chemical vapor generation (CVG) approach is reported for determination of cadmium (Cd). Titanium (III) and titanium (IV) were investigated for the first time as catalytic additives along with thiourea, L cysteine and potassium cyanide (KCN) for generation of volatile Cd species. Both Ti(III) and Ti(IV) provided the highest enhancement with KCN. The improvement with thiourea was marginal (ca. 2-fold), while L-cysteine enhanced signal slightly only with Ti(III) in H2SO4. Optimum CVG conditions were 4% (v/v) HCl + 0.03 M Ti(III) + 0.16 M KCN and 2% (v/v) HNO3 + 0.03 M Ti(IV) + 0.16 M KCN with a 3% (m/v) NaBH4 solution. The sensitivity was improved about 40-fold with Ti(III) and 35-fold with Ti(IV). A limit of detection (LOD) of 3.2 ng L-1 was achieved with Ti(III) by CVG-ICP-MS. The LOD with Ti(IV) was 6.4 ng L-1 which was limited by the blank signals in Ti(IV) solution. Experimental evidence indicated that Ti(III) and Ti(IV) enhanced Cd vapor generation catalytically; for best efficiency mixing prior to reaction with NaBH4 was critical. The method was highly robust against the effects of transition metal ions. No significant suppression was observed in the presence of Co(II), Cr(III), Cu(II), Fe(III), Mn(II), Ni(II) and Zn(II) up to 1.0 MUg mL-1. Among the hydride forming elements, no interference was observed from As(III) and Se(IV) at 0.5 MUg mL-1 level. The depressive effects from Pb(II) and Sb(III) were not significant at 0.1 MUg mL-1 while those from Bi(III) and Sn(II) were marginal. The procedures were validated with determination of Cd by CVG-ICP-MS in a number certified reference materials, including Nearshore seawater (CASS-4), Bone ash (SRM 1400), Dogfish liver (DOLT 4), Mussel tissue (SRM 2976) and Domestic Sludge (SRM 2781). PMID- 26251555 TI - Evaluations of a noise control for roof bolting machines. AB - In collaboration with Kennametal Inc. and Corry Rubber Corporation, the U.S. National Institute for Occupational Safety and Health (NIOSH) developed a drill bit isolator to address noise overexposures associated with roof bolting machines in underground coal mines. NIOSH laboratory studies confirmed that the drill bit isolator reduces noise during drilling. Field studies were needed to confirm that a noise reduction could be obtained under working conditions and that the device was sufficiently durable. This paper reports results of field tests of the device conducted at five underground coal mines. Noise reduction was assessed by comparing the operator's noise exposure during drilling with and without the drill bit isolator. Durability was assessed by recording the number of holes and total feet drilled with each bit isolator until either the test period ended or the device failed. The results from these tests showed that the device is an effective noise control in a mine environment. The field-tested drill bit isolators provided a noise reduction of 3-5 dB(A). Of nine devices tested for durability, five exceeded 610 m (2,000 ft) drilled and two exceeded 762 m (2,500 ft) drilled before failure. Durability issues found in the field tests led to final production optimizations that have resulted in a commercially available product for drilling with 35-mm- (1.3-in.-) diameter roof bits and hexagonal drill steels. PMID- 26251556 TI - Isogeometric Kirchhoff-Love shell formulations for biological membranes. AB - Computational modeling of thin biological membranes can aid the design of better medical devices. Remarkable biological membranes include skin, alveoli, blood vessels, and heart valves. Isogeometric analysis is ideally suited for biological membranes since it inherently satisfies the C1-requirement for Kirchhoff-Love kinematics. Yet, current isogeometric shell formulations are mainly focused on linear isotropic materials, while biological tissues are characterized by a nonlinear anisotropic stress-strain response. Here we present a thin shell formulation for thin biological membranes. We derive the equilibrium equations using curvilinear convective coordinates on NURBS tensor product surface patches. We linearize the weak form of the generic linear momentum balance without a particular choice of a constitutive law. We then incorporate the constitutive equations that have been designed specifically for collagenous tissues. We explore three common anisotropic material models: Mooney-Rivlin, May Newmann-Yin, and Gasser-Ogden-Holzapfel. Our work will allow scientists in biomechanics and mechanobiology to adopt the constitutive equations that have been developed for solid three-dimensional soft tissues within the framework of isogeometric thin shell analysis. PMID- 26251557 TI - Fleet Safety: Developing & Sustaining an Effective Program With ANSI/ASSE Z15.1. AB - Millions of U.S. workers are at risk for a work-related motor vehicle crash. Fatality data show that across all industries, motor vehicle crashes are consistently the leading cause of work-related fatalities. Of 43,025 work-related fatalities reported by BLS between 2003 and 2010, 10,202 were the result of single- or multiple-vehicle crashes of workers driving or riding in a vehicle on a public roadway, and 2,707 were pedestrian workers struck by a motor vehicle. During the same period, an additional 2,487 workers died in crashes that occurred off a public roadway or on industrial premises (BLS, 2013). PMID- 26251558 TI - Toward an ecologically meaningful view of resource stoichiometry in DOM-dominated aquatic systems. AB - Research on nutrient controls of planktonic productivity tends to focus on a few standard fractions of inorganic or total nitrogen (N) and phosphorus (P). However, there is a wide range in the degree to which land-derived dissolved organic nutrients can be assimilated by biota. Thus, in systems where such fractions form a majority of the macronutrient resource pool, including many boreal inland waters and estuaries, our understanding of bacterio- and phytoplankton production dynamics remains limited. To adequately predict aquatic productivity in a changing environment, improved standard methods are needed for determining the sizes of active (bioavailable) pools of N, P and organic carbon (C). A synthesis of current knowledge suggests that variation in the C:N:P stoichiometry of bioavailable resources is associated with diverse processes that differentially influence the individual elements across space and time. Due to a generally increasing organic nutrient bioavailability from C to N to P, we hypothesize that the C:N and N:P of bulk resources often vastly overestimates the corresponding ratios of bioavailable resources. It is further proposed that basal planktonic production is regulated by variation in the source, magnitude and timing of terrestrial runoff, through processes that have so far been poorly described. PMID- 26251559 TI - Multilevel built environment features and individual odds of overweight and obesity in Utah. AB - Based on the data from the Behavioral Risk Factor Surveillance System (BRFSS) in 2007, 2009 and 2011 in Utah, this research uses multilevel modeling (MLM) to examine the associations between neighborhood built environments and individual odds of overweight and obesity after controlling for individual risk factors. The BRFSS data include information on 21,961 individuals geocoded to zip code areas. Individual variables include BMI (body mass index) and socio-demographic attributes such as age, gender, race, marital status, education attainment, employment status, and whether an individual smokes. Neighborhood built environment factors measured at both zip code and county levels include street connectivity, walk score, distance to parks, and food environment. Two additional neighborhood variables, namely the poverty rate and urbanicity, are also included as control variables. MLM results show that at the zip code level, poverty rate and distance to parks are significant and negative covariates of the odds of overweight and obesity; and at the county level, food environment is the sole significant factor with stronger fast food presence linked to higher odds of overweight and obesity. These findings suggest that obesity risk factors lie in multiple neighborhood levels and built environment features need to be defined at a neighborhood size relevant to residents' activity space. PMID- 26251560 TI - Optimizing Locomotion Controllers Using Biologically-Based Actuators and Objectives. AB - We present a technique for automatically synthesizing walking and running controllers for physically-simulated 3D humanoid characters. The sagittal hip, knee, and ankle degrees-of-freedom are actuated using a set of eight Hill-type musculotendon models in each leg, with biologically-motivated control laws. The parameters of these control laws are set by an optimization procedure that satisfies a number of locomotion task terms while minimizing a biological model of metabolic energy expenditure. We show that the use of biologically-based actuators and objectives measurably increases the realism of gaits generated by locomotion controllers that operate without the use of motion capture data, and that metabolic energy expenditure provides a simple and unifying measurement of effort that can be used for both walking and running control optimization. PMID- 26251561 TI - Acceleration Techniques for Recombination of Gases in Electrolysis Microactuators with Nafion(r)-Coated Electrocatalyst. AB - Recombination of electrolysis gases (oxidation of hydrogen and reduction of oxygen) is an important factor in operation efficiency of devices employing electrolysis such as actuators and also unitized regenerative fuel cells. Several methods of improving recombination speed and repeatability were developed for application to electrolysis microactuators with Nafion(r)-coated catalytic electrodes. Decreasing the electrolysis chamber volume increased the speed, consistency, and repeatability of the gas recombination rate. To further improve recombination performance, methods to increase the catalyst surface area, hydrophobicity, and availability were developed and evaluated. Of these, including in the electrolyte pyrolyzed-Nafion(r)-coated Pt segments contained in the actuator chamber accelerated recombination by increasing the catalyst surface area and decreasing the gas transport diffusion path. This approach also reduced variability in recombination encountered under varying actuator orientation (resulting in differing catalyst/gas bubble proximity) and increased the rate of recombination by 2.3 times across all actuator orientations. Repeatability of complete recombination for different generated gas volumes was studied through cycling. PMID- 26251562 TI - In psychiatrically healthy individuals, overweight women but not men have lower tryptophan levels. AB - Gender differences in tryptophan (TRP) breakdown in obese individuals have been previously reported. This could be both contributory to, as well as a consequence of, gender differences in mood changes among obese people. To exclude the potential effect of depression on TRP breakdown and its levels in obesity, we replicated analyses in psychiatrically healthy individuals. In 1000 participants, plasma kynurenine (KYN), TRP, and the KYN/TRP ratio were compared between overweight/obese and normal-weight individuals using analysis of covariance, with adjustment for age and gender. Bivariate post hoc tests were also conducted. There were no significant relationships between KYN, TRP, or the KYN/TRP ratio and overall overweight/obese status. However, a significant gender by weight category interaction was identified for TRP only, with overweight/obese women having lower TRP than overweight/obese men (p = 0.02). No gender differences in TRP were found in non-obese participants. Our study in psychiatrically healthy individuals suggested that lower TRP levels in obese women were not secondary to depression, strengthening the possibility that TRP levels could mediate depression in vulnerable women. Thus experimental manipulations of TRP levels could be used to advance theoretical knowledge, prevention, and clinical control of depression in obese women. PMID- 26251563 TI - Assessing the Relationship Between Perceived Message Sensation Value and Perceived Message Effectiveness: Analysis of PSAs From an Effective Campaign. AB - The current study is an analysis of public service announcements (PSAs) from an effective safer sex campaign that utilized a sensation-seeking targeting (SENTAR) approach. Two random samples of heterosexually active young adults (sample one N = 1,463, sample two N = 895) viewed different sets of safer sex PSAs on a laptop computer and answered questions about their perceived sensation value and perceived effectiveness. Multiple regression analyses examined the impact of (a) demographic, (b) individual difference, (c) sexual context, and (d) message variables including perceived message sensation value (PMSV) on the perceived message effectiveness (PME) of the PSAs. Results indicated that females, African Americans, condom users, and those with less education viewed the PSAs as slightly more effective than males, Caucasians, non-condom users, and those with more education. PMSV and personal utility emerged as the strongest predictors of PME, even after controlling for all of the aforementioned variables. Implications for further research on PMSV and perceived and actual effectiveness of PSAs are offered. PMID- 26251564 TI - Aging-related viscoelasticity variation of tendon stem cells (TSCs) characterized by quartz thickness shear mode (TSM) resonators. AB - Aging not only affects the whole body performance but also alters cellular biological properties, including cell proliferation and differentiation. This study was designed to determine the effect of aging on the mechanical properties of tendon stem cells (TSCs), a newly discovered stem cell type in tendons, using quartz thickness shear mode (TSM) resonators. TSCs were isolated from both old and young rats, and allowed to grow to confluency on the surface of TSM resonators. The admittance spectrums of TSM with TSC monolayer were acquired, and a series of complex shear modulus G' + jG" as well as average thickness hTSC were calculated based on a two-layer-loading transmission line model (TLM) for TSM resonator sensor. The results showed an overall increase in G', G" and hTSC during aging process. Specifically, the storage modulus G' of aging TSCs was over ten times than that of young, revealing an important increase in stiffness of aging TSCs. Additionally, through phase-contrast and scanning electronic microscopy, it was shown that aging TSCs were large, flat and heterogeneous in morphologies while young TSCs were uniformly elongated. Increased cell size and irregular cell shape might be associated with the dense cytoskeleton organization, which could lead to an increase in both stiffness and viscosity. These results are in agreement with previously published data using different measurement methods, indicating TSM resonator sensor as a promising tool to measure the mechanical properties of cells. PMID- 26251565 TI - Examination of water spray airborne coal dust capture with three wetting agents. AB - Water spray applications are one of the principal means of controlling airborne respirable dust in coal mines. Since many coals are hydrophobic and not easily wetted by water, wetting agents can be added to the spray water in an effort to improve coal wetting and assist with dust capture. In order to study wetting agent effects on coal dust capture, laboratory experiments were conducted with three wetting agents used by the coal industry on -325 mesh sized Pocahontas No. 3 coal dust. Significant differences in coal dust sink times were observed among the three wetting agents at water mixture concentrations of 0.05%, 0.1% and 0.2%. The best wetting agent as identified by the coal dust sink test was only tested at the lowest 0.05% water mixture concentration and was found to have a negligible effect on spray airborne dust capture. Water spray airborne dust capture results for all three wetting agents tested at a 0.2% water mixture concentration showed that all three wetting agents exhibit similar but small improvements in dust capture efficiency as compared with water. These results indicate that the coal dust sink test may not be a good predictor for the capture of airborne dust. Additional research is needed to examine if the coal dust sink test is a better predictor of wetting agent dust suppression effects during cutting, loading, conveying and dumping of coal products by comparison to airborne dust capture from sprays. PMID- 26251566 TI - Examination of redirected continuous miner scrubber discharge configurations for exhaust face ventilation systems. AB - The U.S. National Institute for Occupational Safety and Health (NIOSH) Office of Mine Safety and Health Research (OMSHR) has recently studied several redirected scrubber discharge configurations in its full-scale continuous miner gallery for both dust and gas control when using an exhaust face ventilation system. Dust and gas measurements around the continuous mining machine in the laboratory showed that the conventional scrubber discharge directed outby the face with a 12.2-m (40-ft) exhaust curtain setback appeared to be one of the better configurations for controlling dust and gas. Redirecting all the air toward the face equally up both sides of the machine increased the dust and gas concentrations around the machine. When all of the air was redirected toward the face on the off-curtain side of the machine, gas accumulations tended to be reduced at the face, at the expense of increased dust levels in the return and on the curtain side of the mining machine. A 6.1-m (20-ft) exhaust curtain setback without the scrubber operating resulted in the lowest dust levels around the continuous mining machine, but this configuration resulted in some of the highest levels of dust in the return and gas on the off-curtain side of the mining face. Two field studies showed some similarities to the laboratory findings, with elevated dust levels at the rear corners of the continuous miner when all of the scrubber exhaust was redirected toward the face either up the off-tubing side or equally up both sides of the mining machine. PMID- 26251567 TI - Case study of controlled recirculation at a Wyoming trona mine. AB - Controlled recirculation has been used in the metal/nonmetal mining industry for energy savings when heating and cooling air, in undersea mining and for increasing airflow to mining areas. For safe and effective use of controlled district recirculation, adequate airflow to dilute contaminants must exist prior to implementation, ventilation circuit parameters must be accurately quantified, ventilation network modeling must be up to date, emergency planning scenarios must be performed and effective monitoring and control systems must be installed and used. Safety and health issues that must be considered and may be improved through the use of controlled district recirculation include blasting fumes, dust, diesel emissions, radon and contaminants from mine fires. Controlled recirculation methods are expected to become more widely used as mines reach greater working depths, requiring that these health and safety issues be well understood. The U.S. National Institute for Occupational Safety and Health (NIOSH) conducted two controlled recirculation tests over three days at a Wyoming trona mine, utilizing an inline booster fan to improve airflow to a remote and difficult-to-ventilate development section. Test results were used to determine the effect that recirculation had on air qualities and quantities measured in that section and in other adjacent areas. Pre-test conditions, including ventilation quantities and pressures, were modeled using VnetPC. During each test, ventilation quantities and pressures were measured, as well as levels of total dust. Sulfur hexafluoride (SF 6 ) tracer gas was used to simulate a mine contaminant to monitor recirculation wave cycles. Results showed good correlation between the model results and measured values for airflows, pressure differentials, tracer gas arrival times, mine gasses and dust levels. PMID- 26251568 TI - Effect of lactoferrin protein on red blood cells and macrophages: mechanism of parasite-host interaction. AB - BACKGROUND: Lactoferrin is a natural multifunctional protein known to have antitumor, antimicrobial, and anti-inflammatory activity. Apart from its antimicrobial effects, lactoferrin is known to boost the immune response by enhancing antioxidants. Lactoferrin exists in various forms depending on its iron saturation. The present study was done to observe the effect of lactoferrin, isolated from bovine and buffalo colostrum, on red blood cells (RBCs) and macrophages (human monocytic cell line-derived macrophages THP1 cells). METHODS: Lactoferrin obtained from both species and in different iron saturation forms were used in the present study, and treatment of host cells were given with different forms of lactoferrin at different concentrations. These treated host cells were used for various studies, including morphometric analysis, viability by MTT assay, survivin gene expression, production of reactive oxygen species, phagocytic properties, invasion assay, and Toll-like receptor-4, Toll-like receptor-9, and MDR1 expression, to investigate the interaction between lactoferrin and host cells and the possible mechanism of action with regard to parasitic infections. RESULTS: The mechanism of interaction between host cells and lactoferrin have shown various aspects of gene expression and cellular activity depending on the degree of iron saturation of lactoferrin. A significant increase (P<0.05) in production of reactive oxygen species, phagocytic activity, and Toll-like receptor expression was observed in host cells incubated with iron saturated lactoferrin when compared with an untreated control group. However, there was no significant (P>0.05) change in percentage viability in the different groups of host cells treated, and no downregulation of survivin gene expression was found at 48 hours post-incubation. Upregulation of the Toll-like receptor and downregulation of the P-gp gene confirmed the immunomodulatory potential of lactoferrin protein. CONCLUSION: The present study details the interaction between lactoferrin and parasite host cells, ie, RBCs and macrophages, using various cellular processes and expression studies. The study reveals the possible mechanism of action against various intracellular pathogens such as Toxoplasma, Plasmodium, Leishmania, Trypanosoma, and Mycobacterium. The presence of iron in lactoferrin plays an important role in enhancing the various activities taking place inside these cells. This work provides a lot of information about targeting lactoferrin against many parasitic infections which can rule out the exact pathways for inhibition of diseases caused by intracellular microbes mainly targeting RBCs and macrophages for their survival. Therefore, this initial study can serve as a baseline for further evaluation of the mechanism of action of lactoferrin against parasitic diseases, which is not fully understood to date. PMID- 26251569 TI - Zinc supplementation induces apoptosis and enhances antitumor efficacy of docetaxel in non-small-cell lung cancer. AB - BACKGROUND: Exposure to exogenous zinc results in increased apoptosis, growth inhibition, and altered oxidative stress in cancer cells. Previous studies also suggested that zinc sensitizes some cancer cells to cytotoxic agents depending on the p53 status. Therefore, zinc supplementation may show anticancer efficacy solely and may increase docetaxel-induced cytotoxicity in non-small-cell lung cancer cells. METHODS: Here, we report the effects of several concentrations of zinc combined with docetaxel on p53-wild-type (A549) and p53-null (H1299) cells. We evaluated cellular viability, apoptosis, and cell cycle progression as well as oxidative stress parameters, including superoxide dismutase, glutathione peroxidase, and malondialdehyde levels. RESULTS: Zinc reduced the viability of A549 cells and increased the apoptotic response in both cell lines in a dose dependent manner. Zinc also amplified the docetaxel effects and reduced its inhibitory concentration 50 (IC50) values. The superoxide dismutase levels increased in all treatment groups; however, glutathione peroxidase was slightly increased in the combination treatments. Zinc also caused malondialdehyde elevations at 50 MUM and 100 MUM. CONCLUSION: Zinc has anticancer efficacy against non-small-cell lung cancer cells in the presence of functionally active p53 and enhances docetaxel efficacy in both p53-wild-type and p53-deficient cancer cells. PMID- 26251570 TI - The chemopreventive potential of Curcuma purpurascens rhizome in reducing azoxymethane-induced aberrant crypt foci in rats. AB - Curcuma purpurascens BI. rhizome, a member of the Zingiberaceae family, is a popular spice in Indonesia that is traditionally used in assorted remedies. Dichloromethane extract of C. purpurascens BI. rhizome (DECPR) has previously been shown to have an apoptosis-inducing effect on colon cancer cells. In the present study, we examined the potential of DECPR to prevent colon cancer development in rats treated with azoxymethane (AOM) (15 mg/kg) by determining the percentage inhibition in incidence of aberrant crypt foci (ACF). Starting from the day immediately after AOM treatment, three groups of rats were orally administered once a day for 2 months either 10% Tween 20 (5 mL/kg, cancer control), DECPR (250 mg/kg, low dose), or DECPR (500 mg/kg, high dose). Meanwhile, the control group was intraperitoneally injected with 5-fluorouracil (35 mg/kg) for 5 consecutive days. After euthanizing the rats, the number of ACF was enumerated in colon tissues. Bax, Bcl-2, and proliferating cell nuclear antigen (PCNA) protein expressions were examined using immunohistochemical and Western blot analyses. Antioxidant enzymatic activity was measured in colon tissue homogenates and associated with malondialdehyde level. The percentage inhibition of ACF was 56.04% and 68.68% in the low- and high-dose DECPR-treated groups, respectively. The ACF inhibition in the treatment control group was 74.17%. Results revealed that DECPR exposure at both doses significantly decreased AOM-induced ACF formation, which was accompanied by reduced expression of PCNA. Upregulation of Bax and downregulation of Bcl-2 suggested the involvement of apoptosis in the chemopreventive effect of DECPR. In addition, the oxidative stress resulting from AOM treatment was significantly attenuated after administration of DECPR, which was shown by the elevated antioxidant enzymatic activity and reduced malondialdehyde level. Taken together, the present data clearly indicate that DECPR significantly inhibits ACF formation in AOM-treated rats and may offer protection against colon cancer development. PMID- 26251571 TI - Gallic acid attenuates dextran sulfate sodium-induced experimental colitis in BALB/c mice. AB - Gallic acid (GA) is a polyhydroxy phenolic compound that has been detected in various natural products, such as green tea, strawberries, grapes, bananas, and many other fruits. In inflammatory bowel disease, inflammation is promoted by oxidative stress. GA is a strong antioxidant; thus, we evaluated the cytoprotective and anti-inflammatory role of GA in a dextran sulfate sodium (DSS) induced mouse colitis model. Experimental acute colitis was induced in male BALB/c mice by administering 2.5% DSS in the drinking water for 7 days. The disease activity index; colon weight/length ratio; histopathological analysis; mRNA expressions of IL-21 and IL-23; and protein expression of nuclear erythroid 2-related factor 2 (Nrf2) were compared between the control and experimental mice. The colonic content of malondialdehyde and the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activity were examined as parameters of the redox state. We determined that GA significantly attenuated the disease activity index and colon shortening, and reduced the histopathological evidence of injury. GA also significantly (P<0.05) reduced the expressions of IL-21 and IL-23. Furthermore, GA activates/upregulates the expression of Nrf2 and its downstream targets, including UDP-GT and NQO1, in DSS-induced mice. The findings of this study demonstrate the protective effect of GA on experimental colitis, which is probably due to an antioxidant nature of GA. PMID- 26251572 TI - Combined treatment with olmesartan medoxomil and amlodipine besylate attenuates atherosclerotic lesion progression in a model of advanced atherosclerosis. AB - INTRODUCTION: Besides their blood pressure-lowering effects, olmesartan medoxomil and amlodipine besylate exhibit additional anti-inflammatory mechanisms in atherosclerosic disease. Most of the studies investigating the effects of atherosclerosis focused on early atherosclerotic lesions, whereas lesions in human disease, at the time when medical treatment is started, are already well established. Therefore, we set up a model of advanced atherosclerosis and investigated the effects of olmesartan medoxomil, amlodipine besylate, and the combination of both on atherosclerotic lesion size and lesion composition. MATERIALS AND METHODS: Olmesartan medoxomil (1 mg/kg/day), amlodipine besylate (1.5 mg/kg/day), and the combination of both was added to chow and was fed to apolipoprotein E-deficient (ApoE(-/-)) mice at 25 weeks of age. Mice were sacrificed after 25 weeks of drug administration and perfused with formalin. Innominate arteries were dissected out and paraffin embedded. Serial sections were generated, and lesion sizes and their composition - such as minimal thickness of the fibrous cap, size of the necrotic core, and presence of calcification - were analyzed. Electrophoretic mobility shift assays were used to detect DNA-binding activity of the transcription factor nuclear factor-kappa B (NF-kappaB) in aortic tissue. RESULTS: Treatment with the combination of olmesartan medoxomil and amlodipine besylate led to a significant reduction in atherosclerotic lesion size in ApoE(-/-) mice (olmesartan medoxomil/amlodipine besylate: 122,277+/-6,795 MUm(2), number [n]=14; versus control: 177,502+/-10,814 MUm(2), n=9; P<0.001). Treatment with amlodipine besylate (n=5) alone did not reach significance. However, a trend toward a decrease in lesion size in the amlodipine besylate-treated animals could be observed. In the histological analysis of atherosclerotic lesion composition, significantly thicker fibrous caps were found in treatment with amlodipine besylate (amlodipine: 5.12+/-0.26 MUm, n=6; versus control: 3.98+/-0.18 MUm, n=10; P<0.01). Furthermore, all sections revealed morphological signs of calcification, but no difference could be detected. Treatment with the combination of olmesartan medoxomil and amlodipine besylate showed no effect on lesion composition. Electrophoretic mobility shift assays of nuclear extracts demonstrated reduced activity of the transcription factor NF-kappaB when treated with olmesartan medoxomil, amlodipine besylate, or their combination, as compared to controls. CONCLUSION: Combined treatment with olmesartan medoxomil and amlodipine besylate attenuated atherosclerotic lesion progression, possibly due to anti-inflammatory mechanisms. Our data support the hypothesis that even in advanced atherosclerosis anti inflammatory treatment, using angiotensin II type 1 receptor blockers and calcium channel antagonists of the dihydropyridine type can attenuate atherosclerotic lesion progression. PMID- 26251573 TI - A novel in situ gel base of deacetylase gellan gum for sustained ophthalmic drug delivery of ketotifen: in vitro and in vivo evaluation. AB - In this study, an ion-activated ketotifen ophthalmic delivery system was developed by using a natural polysaccharide, deacetylase gellan gum. Its rheological characteristics, stability, in vitro gelation, release in vitro, and pharmacodynamic activity in vivo were investigated. The formulation had an optimum viscosity that will allow easy drop as a liquid, which then underwent a rapid sol-gel transition due to ionic interaction. There were negligible alterations in the initial values of viscosity of the formulations over a storage period of 180 days. The in vitro release profiles indicated that the release of ketotifen from in situ gels exhibited a sustained feature. Scintigraphic studies indicated that deacetylase gellan gum could increase the residence time of the formulation. At the same dose, in situ gels demonstrated a typical sustained and prolonged drug-effects behavior compared with the common drops. PMID- 26251574 TI - Edible bird's nest attenuates procoagulation effects of high-fat diet in rats. AB - Edible bird's nest (EBN) is popular in Asia, and has long been used traditionally as a supplement. There are, however, limited evidence-based studies on its efficacy. EBN has been reported to improve dyslipidemia, which is closely linked to hypercoagulation states. In the present study, the effects of EBN on high-fat diet- (HFD-) induced coagulation in rats were evaluated. Rats were fed for 12 weeks with HFD alone or in combination with simvastatin or EBN. Food intake was estimated, and weight measurements were made during the experimental period. After sacrifice, serum oxidized low-density lipoprotein (oxLDL), adiponectin, leptin, von willibrand factor, prostacyclin, thromboxane and lipid profile, and whole blood coagulation indices (bleeding time, prothrombin time, activated partial thromboplastin time, red blood count count, and platelet count) were estimated. Furthermore, hepatic expression of coagulation-related genes was evaluated using multiplex polymerase chain reaction. The results indicated that EBN could attenuate HFD-induced hypercholesterolemia and coagulation similar to simvastatin, partly through transcriptional regulation of coagulation-related genes. The results suggested that EBN has the potential for lowering the risk of cardiovascular disease-related hypercoagulation due to hypercholesterolemia. PMID- 26251575 TI - Improved oral absorption of cilostazol via sulfonate salt formation with mesylate and besylate. AB - OBJECTIVE: Cilostazol is a Biopharmaceutical Classification System class II drug with low solubility and high permeability, so its oral absorption is variable and incomplete. The aim of this study was to prepare two sulfonate salts of cilostazol to increase the dissolution and hence the oral bioavailability of cilostazol. METHODS: Cilostazol mesylate and cilostazol besylate were synthesized from cilostazol by acid addition reaction with methane sulfonic acid and benzene sulfonic acid, respectively. The salt preparations were characterized by nuclear magnetic resonance spectroscopy. The water contents, hygroscopicity, stress stability, and photostability of the two cilostazol salts were also determined. The dissolution profiles in various pH conditions and pharmacokinetic studies in rats were compared with those of cilostazol-free base. RESULTS: The two cilostazol salts exhibited good physicochemical properties, such as nonhygroscopicity, stress stability, and photostability, which make it suitable for the preparation of pharmaceutical formulations. Both cilostazol mesylate and cilostazol besylate showed significantly improved dissolution rate and extent of drug release in the pH range 1.2-6.8 compared to the cilostazol-free base. In addition, after oral administration to rats, cilostazol mesylate and cilostazol besylate showed increases in C max and AUC t of approximately 3.65- and 2.87-fold and 3.88- and 2.94-fold, respectively, compared to cilostazol-free base. CONCLUSION: This study showed that two novel salts of cilostazol, such as cilostazol mesylate and cilostazol besylate, could be used to enhance its oral absorption. The findings warrant further preclinical and clinical studies on cilostazol mesylate and cilostazol besylate at doses lower than the usually recommended dosage, so that it can be established as an alternative to the marketed cilostazol tablet. PMID- 26251576 TI - Celecoxib coupled to dextran via a glutamic acid linker yields a polymeric prodrug suitable for colonic delivery. AB - Celecoxib, a selective cyclooxygenase-2 inhibitor, is potentially useful for the treatment of colonic diseases such as colorectal cancer and colitis. However, the cardiovascular toxicity of celecoxib limits its routine use in the clinic. Generally, colon-specific delivery of a drug both increases the therapeutic availability in the large intestine and decreases the systemic absorption of the drug, most likely resulting in enhanced therapeutic effects against colonic diseases such as colitis and reduced systemic side effects. To develop a colon specific prodrug of celecoxib that could reduce its cardiovascular toxicity and improve its therapeutic activity, dextran-glutamic acid-celecoxib conjugate (glutam-1-yl celecoxib-dextran ester [G1CD]) was prepared and evaluated. While stable in pH 1.2 and 6.8 buffer solutions and small-intestinal contents, G1CD efficiently released celecoxib in cecal contents. Oral administration of G1CD to rats delivered a larger amount of celecoxib to the large intestine than free celecoxib. G1CD prevented the systemic absorption of celecoxib and did not decrease the serum level of 6-ketoprostaglandin F1alpha, an inverse indicator of cardiovascular toxicity of celecoxib. Collectively, G1CD may be a polymeric colon specific celecoxib prodrug with therapeutic and toxicological advantages. PMID- 26251577 TI - Nasalseptal hematoma/abscess: management and outcome in a tertiary hospital of a developing country. AB - BACKGROUND: Nasal hematoma/abscess is an uncommon entity, but capable of leading to serious consequences if not handled meticulously, and with urgency. OBJECTIVE: To present the management, and outcome of nasal septal hematoma/abscess in a Nigerian tertiary institution. METHOD: Consecutive patients diagnosed with nasal septal hematoma/abscess over a 10-year period, treated at the University of Nigeria Teaching Hospital, Enugu, Nigeria, were prospectively studied. The processes leading to diagnosis, treatment, and outcome were sequentially evaluated. RESULTS: Fifty-three patients (37 males and 16 females), age 5-65 years (with mean age of 23.10 years), were included. Surgical drainage of the hematoma/abscess, intranasal packing with insertion of drain was performed with total resolution of problem in all the cases. CONCLUSION: Incision and drainage, and intranasal packing with insertion of drain was effective in treating nasal septal hematoma/abscess. PMID- 26251578 TI - Approaching patient engagement in research: what do patients with cardiovascular disease think? AB - Movement toward patient-centered health care must be supported by an evidence base informed by greater patient engagement in research. Efforts to better understand patients' interest in and perspectives on involvement in the research process are fundamental to supporting movement of research programs toward greater patient engagement. We describe preliminary efforts to engage members of a community group of patients living with heart disease to better understand their interest and perspectives on involvement in research. A semi-structured focus group guide was developed to probe willingness to participate in the following three phases of research: preparation, execution, and translation. The focus group discussion, and our summary of key messages gleaned from said discussion, was organized around the phases of research that patients may be involved in, with the goal of delineating degrees of interest expressed for engagement in each phase. Consistent with what is known from the literature, a clear preference for engagement during the preparation and translation phase of the research process emerged. This preliminary conversation will guide our ongoing research efforts toward greater inclusion of patients throughout the research process. PMID- 26251580 TI - Erratum: Smoking cessation in Asians: focus on varenicline [Corrigendum]. AB - [This corrects the article on p. 579 in vol. 9, PMID: 25926724.]. PMID- 26251579 TI - The relationship between caregiver impacts and the unmet needs of survivors of stroke. AB - BACKGROUND: Caregivers play a crucial role in meeting the needs of survivors of stroke. Yet, little is known about how they are impacted by their caregiving role. OBJECTIVES: To describe the relationship between survivor long-term unmet needs (>12 months) and caregiver impacts, and identify characteristics that are associated with reported moderate to severe impacts on caregivers. METHOD: This was a cross-sectional survey using data from the Australian Stroke Survivor and Carer Needs Survey. Community dwelling adults 12+ months poststroke and their caregivers participated. Caregivers and survivors were asked about the extent to which the domains of work, leisure and family, and friend and spousal relationships had been impacted using a Likert scale of responses. The extent to which survivor needs were being met was measured over the domains of health, everyday living, work, leisure, and finances, and the total number of unmet needs was calculated. The association between survivor unmet needs and caregiver impacts was assessed using multivariable logistic regression adjusted for caregiver and survivor characteristics. RESULTS: Of the 738 completed survivor surveys, 369 contained matched caregiver data (survivors: median age, 71 years; 67% male) (caregivers: median age, 64 years; 26% male). For caregivers, the domains of work, leisure, and friendships were most impacted. The odds of a caregiver experiencing moderate to extreme impacts increased with the number of reported survivor unmet needs. This was greatest for spousal (aOR [adjusted odds ratio]: 1.14; 95% CI [confidence interval]: 1.07, 1.21; P<0.001) and friend relationships (aOR: 1.14; 95% CI: 1.07, 1.21; P<0.001). Caring for a survivor who needed daily living assistance was associated with moderate to extreme caregiver impacts across all domains. CONCLUSION: Caregivers of survivors of stroke experience large negative impacts, the extent to which is associated with survivors unmet needs. Targeted, long-term solutions are needed to support survivors and caregivers living in the community. PMID- 26251581 TI - No gynecologist in town: the gynecological care of women in rural Taiwan. AB - BACKGROUND: A shortage of gynecologists exists in many countries. Even within an affluent country, gynecological clinics might not be evenly distributed. The purpose of the study was to investigate the disparity in gynecological care between adult women living in towns with and without gynecologists in Taiwan. METHODS: Data sources were the cohort datasets of the National Health Insurance Research Database, with claims data of 1 million beneficiaries in 2010. A woman's residency was operationally inferred from the locations where she had most frequently visited physicians' clinics or local community hospitals within the year. RESULTS: In Taiwan, 145 (39.4%) of 368 towns had no practicing gynecologist. Of 382,167 women with health care use in the datasets, 21,794 (5.7%) lived in towns without a gynecologist. The overwhelming majority of these towns lay in sparsely populated, rural areas. During the year, 132,702 women (34.7%) had sought medical help for gynecological diseases and 113,698 (29.8%) had visited gynecologists for gynecological diseases. Women in towns without a gynecologist were less likely to consult for gynecological diseases (23.8% versus 35.4%; P<0.001) and visit gynecologists (18.7% versus 30.4%; P<0.001) than women in towns with a gynecologist. The disparity existed in each age group. Among 5,189 adult women living in towns without a gynecologist and having gynecological diseases, 78.5% (number [n]=4,074) visited gynecologists out of town, especially for infertility, benign disorders of the uterus and ovaries, gynecological examinations, and contraceptive problems, and by contrast 23.3% (n=1,209) visited nongynecologists in town, most commonly for menopausal disorders, endometriosis and pelvic pain, menstrual disorders and hormonal dysfunction, and genital dysplasia. CONCLUSION: Gynecological care of rural women was adversely affected by the shortage of gynecologists. The consequences of accessibility in underserved areas deserve further investigation. PMID- 26251582 TI - The care continuum in acromegaly: how patients, nurses, and physicians can collaborate for successful treatment experiences. AB - Patients with acromegaly (a condition of chronic growth hormone hypersecretion by a pituitary adenoma) often require pharmacological treatment. Somatostatin analogs (SSAs) such as pasireotide, lanreotide, and octreotide are frequently used as first-line medical therapy. As SSAs are delivered by regular subcutaneous or intramuscular injections, they can result in injection-related pain or anxiety and can be challenging to fit into patients' lifestyles. When combined with the prolonged, debilitating psychological complications associated with acromegaly, these administration challenges can negatively impact compliance, adherence, and quality of life. Proactively managing patients' expectations and providing appropriate, timely guidance are crucial for maximizing adherence, and ultimately, optimizing the treatment experience. As part of ongoing clinical research since 1997, our team at the University of Michigan has used SSAs to treat 30 patients with acromegaly. Based on our clinical experiences with multiple SSA administration regimens (long-acting intramuscular, long-acting deep subcutaneous, and twice-daily subcutaneous), we generated a dialog map that guides health care professionals through the many sensitive and complex patient communication issues surrounding this treatment process. Beginning with diagnosis, the dialog map includes discussion of treatment options, instruction on proper drug administration technique, and ensuring of appropriate follow-up care. At each step, we provide talking points that address the following: the patients' clinical situation; their geographic, economic, and psychological concerns; and their inclination to communicate with clinicians. We have found that involving patients, nurses, and physicians as equal partners in the treatment process optimizes treatment initiation, adherence, and persistence in acromegaly. By encouraging collaboration across the care continuum, this dialog map can facilitate identification of the treatment plan that is most likely to yield the best possible outcome. PMID- 26251583 TI - Prospective investigation of change in the prostate-specific antigens after various urologic procedures. AB - PURPOSE: Prostate-specific antigen (PSA) is the most important marker in the diagnosis and follow-up of patients with prostate cancer. The primary objective of this study was to evaluate the effect of various urologic procedures in prostatic area on serum free and total PSA levels. SUBJECTS AND METHODS: A series of 62 patients (8 after digital rectal examination [DRE], 12 after transrectal ultrasonography [TRUS], 11 after rigid cystoscopy, 13 after prostatic massage, 8 after TRUS-guided prostate biopsy, and 10 after transurethral resection of prostate [TURP]) were enrolled in the study. Blood samples were taken from each patient before procedure and at 10, 30, 60, and 120 minutes after procedures. RESULTS: Prostate massage, rigid cystoscopy, TURP, and TRUS-guided prostate biopsy caused statistically significant rise in total and free PSA levels in the serum. There was no significant increase in total and free PSA levels in the serum after DRE and TRUS. The mean differences were greater for free PSA level in the serum for TURP, TRUS-guided prostate biopsy, prostate massage, and rigid cystoscopy. CONCLUSION: Total and free PSA levels in the serum are altered by prostate massage, rigid cystoscopy, TRUS-guided prostate biopsy, and TURP. The PSA rises were related to the stimulation strength of the procedures. The total and free PSA levels were increased significantly from 10 minutes after procedures, except DRE and TRUS, and were increased to maximal level at 60 minutes after procedures. PMID- 26251584 TI - Clinical characteristics of the asthma-COPD overlap syndrome--a systematic review. AB - BACKGROUND AND OBJECTIVE: In recent years, the so-called asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) has received much attention, not least because elderly individuals may present characteristics suggesting a diagnosis of both asthma and COPD. At present, ACOS is described clinically as persistent airflow limitation combined with features of both asthma and COPD. The aim of this paper is, therefore, to review the currently available literature focusing on symptoms and clinical characteristics of patients regarded as having ACOS. METHODS: Based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, a systematic literature review was performed. RESULTS: A total of 11 studies met the inclusion criteria for the present review. All studies dealing with dyspnea (self-reported or assessed by the Medical Research Council dyspnea scale) reported more dyspnea among patients classified as having ACOS compared to the COPD and asthma groups. In line with this, ACOS patients have more concomitant wheezing and seem to have more cough and sputum production. Compared to COPD-only patients, the ACOS patients were found to have lower FEV1% predicted and FEV1/FVC ratio in spite of lower mean life-time tobacco exposure. Furthermore, studies have revealed that ACOS patients seem to have not only more frequent but also more severe exacerbations. Comorbidity, not least diabetes, has also been reported in a few studies, with a higher prevalence among ACOS patients. However, it should be acknowledged that only a limited number of studies have addressed the various comorbidities in patients with ACOS. CONCLUSION: The available studies indicate that ACOS patients may have more symptoms and a higher exacerbation rate than patients with asthma and COPD only, and by that, probably a higher overall respiratory-related morbidity. Similar to patients with COPD, ACOS patients seem to have a high occurrence of comorbidity, including diabetes. Further research into the ACOS, not least from well-defined prospective studies, is clearly needed. PMID- 26251585 TI - Variants in multiple genes polymorphism association analysis of COPD in the Chinese Li population. AB - BACKGROUND: It is known that the contribution of risk alleles to chronic obstructive pulmonary disease (COPD) may vary between populations. Further, previous studies involving various ethnic groups have revealed associations between COPD and genetic polymorphisms in families with sequence similarity 13, member A (FAM13A), micro-RNA 2054 (MIR2054), SET domain containing protein 7 (SETD7), ring finger protein 150 (RNF150), hedgehog interacting protein (HHIP), and vascular endothelial growth factor A (VEGFA). Our objective was to explore the association between these gene polymorphism and COPD in members of Chinese Li minority population. MATERIALS AND METHODS: The Chinese Li population case control study was conducted to assess genetic associations with COPD risk. Seven single nucleotide polymorphisms (SNPs) located on chromosome 4, including FAM13A, MIR2054, SETD7, RNF150, and HHIP, and nine SNPs in the VEGFA gene were genotyped among 234 cases and 240 controls using Sequenom Mass-ARRAY((r)) platform. Linkage disequilibrium (LD) analysis was performed using Haploview software and the associations of the SNP frequencies with COPD were analyzed using chi-square (chi(2)) tests, genetic models analysis, and haplotype analysis. RESULTS: By chi(2) we found the minor allele "G" of rs17050782 was with increased COPD risk in allele model. In genetic models, we found the minor allele of rs7671167 (P=0.028 by dominant model) and rs17050782 (P=0.008 by recessive model) was associated with the increased risk of COPD disease. Likewise, an increased risk of developing COPD was associated with the "GGCGC" haplotype of VEGFA (odds ratio =1.48, 95% confidence interval =1.02-2.12, P=0.037). CONCLUSION: Our results were the first time to reveal that SNPs from FAM13A (rs7671167), SETD7 (rs17050782), and a haplotype of VEGFA ("GGCGC") are potential susceptibility loci associated with increased COPD risk in Chinese Li minority population. PMID- 26251586 TI - Clinical characteristics of patients with chronic obstructive pulmonary disease with comorbid bronchiectasis: a systemic review and meta-analysis. AB - BACKGROUND: In the 2014 Global initiative for chronic Obstructive Lung Disease guidelines, bronchiectasis was for the first time defined as a comorbidity of chronic obstructive pulmonary disease (COPD), and this change has been retained in the 2015 update, which emphasizes the influence of bronchiectasis in the natural history of COPD. The present meta-analysis was aimed at summarizing the impact of bronchiectasis on patients with COPD. METHODS: Databases including Embase, PubMed, and the Cochrane Central Register of Controlled Trials were searched comprehensively to identify all relevant human clinical studies published until August 2014. Bronchiectasis was confirmed either by computed tomography or high-resolution computed tomography. One or more clinicopathological or demographical characteristics, including age, sex, smoking history, daily sputum production, exacerbations, inflammatory biomarkers, lung function, and colonization by potentially pathogenic microorganisms (PPMs), were compared between COPD patients with and without bronchiectasis. RESULTS: Six observational studies with 881 patients were included in the meta-analysis. The mean prevalence of bronchiectasis in patients with COPD was 54.3%, ranging from 25.6% to 69%. Coexistence of bronchiectasis and COPD occurred more often in male patients with longer smoking history. Patients with COPD and comorbid bronchiectasis had greater daily sputum production, more frequent exacerbation, poorer lung function, higher level of inflammatory biomarkers, more chronic colonization by PPMs, and higher rate of Pseudomonas aeruginosa isolation. CONCLUSION: In spite of the heterogeneity between included studies and detectable publication bias, this meta-analysis demonstrated the impact of bronchiectasis in patients with COPD in all directions, indicating that coexistence of bronchiectasis should be considered a pathological phenotype of COPD, which may have a predictive value. PMID- 26251587 TI - Application of the new GOLD COPD staging system to a US primary care cohort, with comparison to physician and patient impressions of severity. AB - BACKGROUND: In 2011, the traditional Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD spirometry-based severity classification system was revised to also include exacerbation history and COPD Assessment Test (CAT) and modified Medical Research Council Dyspnea Scale (mMRC) scores. This study examined how COPD patients treated in primary care are reclassified by the new GOLD system compared to the traditional system, and each system's level of agreement with patient's or physician's severity assessments. METHODS: In this US multicenter cross-sectional study, COPD patients were recruited by 83 primary care practitioners (PCPs) to complete spirometry testing and a survey. Patients were classified by the traditional spirometry-based system (stages 1-4) and under the new system (grades A, B, C, D) using spirometry, exacerbation history, mMRC, and/or CAT results. Concordance between physician and patient-reported severity, spirometry stage, and ABCD grade based on either mMRC or CAT scores was examined. RESULTS: Data from 445 patients with spirometry-confirmed COPD were used. As compared to the traditional system, the GOLD mMRC system reclassifies 47% of patients, and GOLD CAT system reclassifies 41%, but the distributions are very different. The GOLD mMRC system resulted in relatively equal distributions by ABCD grade (33%, 22%, 19%, 26%, respectively), but the GOLD CAT system put most into either B or D groups (9%, 45%, 4%, and 42%). The addition of exacerbation history reclassified only 19 additional patients. Agreement between PCPs' severity rating or their patients' self-assessment and the new ABCD grade was very poor (kappa=0.17 or less). CONCLUSION: As compared to the traditional system, the GOLD 2011 multidimensional system reclassified nearly half of patients, but how they were reclassified varied greatly by whether the mMRC or CAT questionnaire was chosen. Either way, the new system had little correlation with the PCPs or their patients' impressions about the COPD severity. PMID- 26251588 TI - Is asymptomatic peripheral arterial disease associated with walking endurance in patients with COPD? AB - OBJECTIVE: Symptomatic peripheral arterial disease (PAD) is associated with impaired walking endurance in patients with chronic obstructive pulmonary disease (COPD). However, it is unknown whether asymptomatic PAD is associated with impaired walking endurance in patients with COPD. METHODS: This prospective cross sectional study enrolled 200 COPD patients (mean age: 70.9 years) who volunteered to perform ankle-brachial index (ABI) and 6-minute walk test (6MWT) consecutively. Demographic data, lung function, dyspnea scales, and cardiovascular risk factors were recorded. The ABI was used to detect PAD (ABI <0.90). All patients were free of PAD symptoms at enrollment. RESULTS: Of the 200 COPD patients, 17 (8.5%) were diagnosed with asymptomatic PAD. The COPD patients without asymptomatic PAD did not walk significantly further on the 6MWT than the COPD patients with asymptomatic PAD (439+/-86 m vs 408+/-74 m, P=0.159). The strongest correlation with the distance walked on the 6MWT was Medical Research Council dyspnea scale (r (2)=-0.667, P<0.001), followed by oxygen-cost diagram (r (2)=0.582, P<0.001) and forced expiratory volume in 1 second (r (2)=0.532, P<0.001). In multivariate linear regression analysis, only age, forced expiratory volume in 1 second, and baseline pulse oximetry were independently correlated with the distance covered on the 6MWT (P<0.05). However, body mass index, baseline heart rate, and ABI were not correlated with the distance covered on the 6MWT. CONCLUSION: Asymptomatic PAD is not associated with walking endurance in patients with COPD. Therefore, it is important to detect and treat asymptomatic PAD early so that COPD patients do not progress to become exercise intolerant. Limited by the small sample size and predominantly male (99%) population in the study, further large-scale prospective studies are needed to verify the results. PMID- 26251589 TI - Prevalence, risk factors, and health-related quality of life of osteoporosis in patients with COPD at a community hospital in Taiwan. AB - BACKGROUND: Data regarding osteoporosis in COPD patients in Taiwan remain limited. The primary end point of this study was to evaluate the prevalence and risk factors of osteoporosis in COPD patients in Taiwan. The secondary end point was to examine the association between osteoporosis and health-related quality of life (HRQL) in COPD patients. MATERIALS AND METHODS: This prospective cross sectional study enrolled 125 COPD patients (mean age 73.6 years, forced expiratory volume in 1 second [FEV1] 1.19+/-0.43 L) who had bone mineral-density measurements performed consecutively. Demographic data, lung function, and HRQL including modified Medical Research Council dyspnea scale, St George's Respiratory Questionnaire, oxygen-cost diagram, Center for Epidemiologic Studies depression scale, and COPD Assessment Test scores were recorded. RESULTS: A total of 50 (40%) participants were diagnosed as having osteoporosis. In a multivariate logistic regression model including age, smoking amount (pack-year), body mass index (BMI), and FEV1, only BMI (odds ratio 0.824, 95% confidence interval 0.73-0.93; P=0.002) and FEV1 (odds ratio 0.360, 95% confidence interval 0.13-0.98; P=0.046) were negatively associated with an increased risk of osteoporosis in COPD patients. In addition, COPD patients with osteoporosis had significantly higher modified Medical Research Council dyspnea scale scores (1.7+/-0.8 vs 1.4+/-0.8, P=0.046), St George's Respiratory Questionnaire scores (36.6 vs 28.0, P=0.01), and COPD Assessment Test scores (14.7+/-8 vs 11.5+/-7, P=0.019), and lower oxygen-cost diagram score (4.8+/-1.8 vs 5.4+/-1.6, P=0.045) than patients without osteoporosis. CONCLUSION: The prevalence of osteoporosis in COPD patients was high at a community hospital in Taiwan. BMI and FEV1 were the independent risk factors for osteoporosis in COPD. In addition, COPD patients with osteoporosis had worse HRQL than those without osteoporosis. PMID- 26251591 TI - Efficacy and safety of once-daily glycopyrronium in predominantly Chinese patients with moderate-to-severe chronic obstructive pulmonary disease: the GLOW7 study [Corrigendum]. PMID- 26251590 TI - Bronchoscopic lung volume reduction by endobronchial valve in advanced emphysema: the first Asian report. AB - PURPOSE: Endobronchial valve (EBV) therapy is increasingly being seen as a therapeutic option for advanced emphysema, but its clinical utility in Asian populations, who may have different phenotypes to other ethnic populations, has not been assessed. PATIENTS AND METHODS: This prospective open-label single-arm clinical trial examined the clinical efficacy and the safety of EBV in 43 consecutive patients (mean age 68.4+/-7.5, forced expiratory volume in 1 second [FEV1] 24.5%+/-10.7% predicted, residual volume 208.7%+/-47.9% predicted) with severe emphysema with complete fissure and no collateral ventilation in a tertiary referral hospital in Korea. RESULTS: Compared to baseline, the patients exhibited significant improvements 6 months after EBV therapy in terms of FEV1 (from 0.68+/-0.26 L to 0.92+/-0.40 L; P<0.001), 6-minute walk distance (from 233.5+/-114.8 m to 299.6+/-87.5 m; P=0.012), modified Medical Research Council dyspnea scale (from 3.7+/-0.6 to 2.4+/-1.2; P<0.001), and St George's Respiratory Questionnaire (from 65.59+/-13.07 to 53.76+/-11.40; P=0.028). Nine patients (20.9%) had a tuberculosis scar, but these scars did not affect target lobe volume reduction or pneumothorax frequency. Thirteen patients had adverse events, ten (23.3%) developed pneumothorax, which included one death due to tension pneumothorax. CONCLUSION: EBV therapy was as effective and safe in Korean patients as it has been shown to be in Western countries. ( TRIAL REGISTRATION: ClinicalTrials.gov: NCT01869205). PMID- 26251592 TI - Sustained co-delivery of BIO and IGF-1 by a novel hybrid hydrogel system to stimulate endogenous cardiac repair in myocardial infarcted rat hearts. AB - Dedifferentiation and proliferation of endogenous cardiomyocytes in situ can effectively improve cardiac repair following myocardial infarction (MI). 6 Bromoindirubin-3-oxime (BIO) and insulin-like growth factor 1 (IGF-1) are two potent factors that promote cardiomyocyte survival and proliferation. However, their delivery for sustained release in MI-affected areas has proved to be challenging. In the current research, we present a study on the sustained co delivery of BIO and IGF-1 in a hybrid hydrogel system to simulate endogenous cardiac repair in an MI rat model. Both BIO and IGF-1 were efficiently encapsulated in gelatin nanoparticles, which were later cross-linked with the oxidized alginate to form a novel hybrid hydrogel system. The in vivo results indicated that the hybrid system could enhance the proliferation of cardiomyocytes in situ and could promote revascularization around the MI sites, allowing improved cardiac function. Taken together, we concluded that the hybrid hydrogel system can co-deliver BIO and IGF-1 to areas of MI and thus improve cardiac function by promoting the proliferation of cardiomyocytes and revascularization. PMID- 26251593 TI - Characterization of pulmonary protein profiles in response to zinc oxide nanoparticles in mice: a 24-hour and 28-day follow-up study. AB - Although zinc oxide nanoparticles (ZnONPs) are recognized to cause systemic disorders, little is known about the mechanisms that underlie the time-dependent differences that occur after exposure. The objective of this study was to investigate the mechanistic differences at 24 hours and 28 days after the exposure of BALB/c mice to ZnONPs via intratracheal instillation. An isobaric tag for the relative and absolute quantitation coupled with liquid chromatography/tandem mass spectrometry was used to identify the differential protein expression, biological processes, molecular functions, and pathways. A total of 18 and 14 proteins displayed significant changes in the lung tissues at 24 hours and 28 days after exposure, respectively, with the most striking changes being observed for S100-A9 protein. Metabolic processes and catalytic activity were the main biological processes and molecular functions, respectively, in the responses at the 24-hour and 28-day follow-up times. The glycolysis/gluconeogenesis pathway was continuously downregulated from 24 hours to 28 days, whereas detoxification pathways were activated at the 28-day time point after exposure. A comprehensive understanding of the potential time dependent effects of exposure to ZnONPs was provided, which highlights the metabolic mechanisms that may be important in the responses to ZnONP. PMID- 26251594 TI - Controllable drug uptake and nongenomic response through estrogen-anchored cyclodextrin drug complex. AB - Breast cancer is a leading killer of women worldwide. Cyclodextrin-based estrogen receptor-targeting drug-delivery systems represent a promising direction in cancer therapy but have rarely been investigated. To seek new targeting therapies for membrane estrogen receptor-positive breast cancer, an estrogen-anchored cyclodextrin encapsulating a doxorubicin derivative Ada-DOX (CDE1-Ada-DOX) has been synthesized and evaluated in human breast cancer MCF-7 cells. First, we synthesized estrone-conjugated cyclodextrin (CDE1), which formed the complex CDE1 Ada-DOX via molecular recognition with the derivative adamantane-doxorubicin (Ada DOX) (Kd =1,617 M(-1)). The structure of the targeting vector CDE1 was fully characterized using (1)H- and (13)C-nuclear magnetic resonance, mass spectrometry, and electron microscopy. CDE1-Ada-DOX showed two-phase drug-release kinetics with much slower release than Ada-DOX. The fluorescence polarization analysis reveals that CDE1-Ada-DOX binds to recombinant human estrogen receptor alpha fragments with a Kd of 0.027 uM. Competition assay of the drug complex with estrogen ligands demonstrated that estrone and tamoxifen competed with CDE1-Ada DOX for membrane estrogen receptor binding in MCF-7 cells. Intermolecular self assembly of CDE1 molecules were observed, showing tail-in-bucket and wire-like structures confirmed by transmission electronic microscopy. CDE1-Ada-DOX had an unexpected lower drug uptake (when the host-guest ratio was >1) than non targeting drugs in MCF-7 cells due to ensconced ligands in cyclodextrins cavities resulting from the intermolecular self-assembly. The uptake of CDE1-Ada-DOX was significantly increased when the host-guest ratio was adjusted to be less than half at the concentration of CDE1 over 5 uM due to the release of the estrone residues. CDE1 elicited rapid activation of mitogen-activated protein kinases (p44/42 MAPK, Erk1/2) in minutes through phosphorylation of Thr202/Tyr204 in MCF 7 cells. These results demonstrate a targeted therapeutics delivery of CDE1-Ada DOX to breast cancer cells in a controlled manner and that the drug vector CDE1 can potentially be employed as a molecular tool to differentiate nongenomic from genomic mechanism. PMID- 26251595 TI - Ultrasmall cationic superparamagnetic iron oxide nanoparticles as nontoxic and efficient MRI contrast agent and magnetic-targeting tool. AB - Fully dispersible, cationic ultrasmall (7 nm diameter) superparamagnetic iron oxide nanoparticles, exhibiting high relaxivity (178 mM(-1)s(-1) in 0.47 T) and no acute or subchronic toxicity in Wistar rats, were studied and their suitability as contrast agents for magnetic resonance imaging and material for development of new diagnostic and treatment tools demonstrated. After intravenous injection (10 mg/kg body weight), they circulated throughout the vascular system causing no microhemorrhage or thrombus, neither inflammatory processes at the mesentery vascular bed and hepatic sinusoids (leukocyte rolling, adhesion, or migration as evaluated by intravital microscopy), but having been spontaneously concentrated in the liver, spleen, and kidneys, they caused strong negative contrast. The nanoparticles are cleared from kidneys and bladder in few days, whereas the complete elimination from liver and spleen occurred only after 4 weeks. Ex vivo studies demonstrated that cationic ultrasmall superparamagnetic iron oxide nanoparticles caused no effects on hepatic and renal enzymes dosage as well as on leukocyte count. In addition, they were readily concentrated in rat thigh by a magnet showing its potential as magnetically targeted carriers of therapeutic and diagnostic agents. Summarizing, cationic ultrasmall superparamagnetic iron oxide nanoparticles are nontoxic and efficient magnetic resonance imaging contrast agents useful as platform for the development of new materials for application in theranostics. PMID- 26251596 TI - Gold nanorods/mesoporous silica-based nanocomposite as theranostic agents for targeting near-infrared imaging and photothermal therapy induced with laser. AB - Photothermal therapy (PTT) is widely regarded as a promising technology for cancer treatment. Gold nanorods (GNRs), as excellent PTT agent candidates, have shown high-performance photothermal conversion ability under laser irradiation, yet two major obstacles to their clinical application are the lack of selective accumulation in the target site following systemic administration and the greatly reduced photothermal conversion efficiency caused by self-aggregating in aqueous environment. Herein, we demonstrate that tLyp-1 peptide-functionalized, indocyanine green (ICG)-containing mesoporous silica-coated GNRs (I-TMSG) possessed dual-function as tumor cells-targeting near-infrared (NIR) fluorescent probe and PTT agents. The construction of the nanostructure began with synthesis of GNRs by seed-mediated growth method, followed by the coating of mesoporous silica, the chemical conjugation of PEG and tLyp-1 peptide, and the enclosure of ICG as an NIR imaging agent in the mesoporous. The as-prepared nanoparticles could shield the GNRs against their self-aggregation, improve the stability of ICG, and exhibit negligible dark cytotoxicity. More importantly, such a theranostic nanocomposite could realize the combination of GNRs-based photothermal ablation under NIR illumination, ICG-mediated fluorescent imaging, and tLyp-1-enabled more easy endocytosis into breast cancer cells. All in all, I TMSG nanoparticles, in our opinion, possessed the strong potential to realize the effective diagnosis and PTT treatment of human mammary cancer. PMID- 26251597 TI - Polycaprolactone/maltodextrin nanocarrier for intracellular drug delivery: formulation, uptake mechanism, internalization kinetics, and subcellular localization. AB - Prostate cancer (PCa) disease progression is associated with significant changes in intracellular and extracellular proteins, intracellular signaling mechanism, and cancer cell phenotype. These changes may have direct impact on the cellular interactions with nanocarriers; hence, there is the need for a much-detailed understanding, as nanocarrier cellular internalization and intracellular sorting mechanism correlate directly with bioavailability and clinical efficacy. In this study, we report the differences in the rate and mechanism of cellular internalization of a biocompatible polycaprolactone (PCL)/maltodextrin (MD) nanocarrier system for intracellular drug delivery in LNCaP, PC3, and DU145 PCa cell lines. PCL/MD nanocarriers were designed and characterized. PCL/MD nanocarriers significantly increased the intracellular concentration of coumarin 6 and fluorescein isothiocyanate-labeled bovine serum albumin, a model hydrophobic and large molecule, respectively. Fluorescence microscopy and flow cytometry analysis revealed rapid internalization of the nanocarrier. The extent of nanocarrier cellular internalization correlated directly with cell line aggressiveness. PCL/MD internalization was highest in PC3 followed by DU145 and LNCaP, respectively. Uptake in all PCa cell lines was metabolically dependent. Extraction of endogenous cholesterol by methyl-beta-cyclodextrin reduced uptake by 75%+/-4.53% in PC3, 64%+/-6.01% in LNCaP, and 50%+/-4.50% in DU145, indicating the involvement of endogenous cholesterol in cellular internalization. Internalization of the nanocarrier in LNCaP was mediated mainly by macropinocytosis and clathrin-independent pathways, while internalization in PC3 and DU145 involved clathrin-mediated endocytosis, clathrin-independent pathways, and macropinocytosis. Fluorescence microscopy showed a very diffused and non compartmentalized subcellular localization of the PCL/MD nanocarriers with possible intranuclear localization and minor colocalization in the lysosomes with time. PMID- 26251598 TI - Niosomal carriers enhance oral bioavailability of carvedilol: effects of bile salt-enriched vesicles and carrier surface charge. AB - Carvedilol (CRV) is an antihypertensive drug with both alpha and beta receptor blocking activity used to preclude angina and cardiac arrhythmias. To overcome the low, variable oral bioavailability of CRV, niosomal formulations were prepared and characterized: plain niosomes (without bile salts), bile salt enriched niosomes (bilosomes containing various percentages of sodium cholate or sodium taurocholate), and charged niosomes (negative, containing dicetyl phosphate and positive, containing hexadecyl trimethyl ammonium bromide). All formulations were characterized in terms of encapsulation efficiency, size, zeta potential, release profile, stability, and morphology. Various formulations were administered orally to ten groups of Wistar rats (n=6 per group). The plasma levels of CRV were measured by a validated high-performance liquid chromatography (HPLC) method and pharmacokinetic properties of different formulations were characterized. Contribution of lymphatic transport to the oral bioavailability of niosomes was also investigated using a chylomicron flow-blocking approach. Of the bile salt-enriched vesicles examined, bilosomes containing 20% sodium cholate (F2) and 30% sodium taurocholate (F5) appeared to give the greatest enhancement of intestinal absorption. The relative bioavailability of F2 and F5 formulations to the suspension was estimated to be 1.84 and 1.64, respectively. With regard to charged niosomes, the peak plasma concentrations (Cmax) of CRV for positively (F7) and negatively charged formulations (F10) were approximately 2.3- and 1.7 fold higher than after a suspension. Bioavailability studies also revealed a significant increase in extent of drug absorption from charged vesicles. Tissue histology revealed no signs of inflammation or damage. The study proved that the type and concentration of bile salts as well as carrier surface charge had great influences on oral bioavailability of niosomes. Blocking the lymphatic absorption pathway significantly reduced oral bioavailability of CRV niosomes. Overall twofold enhancement in bioavailability in comparison with drug suspension confers the potential of niosomes as suitable carriers for improved oral delivery of CRV. PMID- 26251599 TI - Targeted delivery of chemically modified anti-miR-221 to hepatocellular carcinoma with negatively charged liposomes. AB - Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. Gene therapy was established as a new strategy for treating HCC. To explore the potential delivery system to support the gene therapy of HCC, negatively charged liposomal delivery system was used to deliver miR-221 antisense oligonucleotide (anti-miR-221) to the transferrin (Tf) receptor over expressed HepG2 cells. The liposome exhibited a mean particle size of 122.5 nm, zeta potential of -15.74 mV, anti-miR-221 encapsulation efficiency of 70%, and excellent colloidal stability at 4 degrees C. Anti-miR-221-encapsulated Tf targeted liposome demonstrated a 15-fold higher delivery efficiency compared to nontargeted liposome in HepG2 cells in vitro. Anti-miR-221 Tf-targeted liposome effectively delivered anti-miR-221 to HepG2 cells, upregulated miR-221 target genes PTEN, P27(kip1), and TIMP3, and exhibited greater silencing efficiency over nontargeted anti-miR-221 liposome. After intravenous injection into HepG2 tumor bearing xenografted mice with Cy3-labeled anti-miR-221 Tf-targeted liposome, Cy3 anti-miR-221 was successfully delivered to the tumor site and increased the expressions of PTEN, P27(kip1), and TIMP3. Our results demonstrate that the Tf targeted negatively charged liposome could be a potential therapeutic modality in the gene therapy of human HCC. PMID- 26251600 TI - Pituitary dysfunction following traumatic brain injury: clinical perspectives. AB - Traumatic brain injury (TBI) is a well recognized public health problem worldwide. TBI has previously been considered as a rare cause of hypopituitarism, but an increased prevalence of neuroendocrine dysfunction in patients with TBI has been reported during the last 15 years in most of the retrospective and prospective studies. Based on data in the current literature, approximately 15% 20% of TBI patients develop chronic hypopituitarism, which clearly suggests that TBI-induced hypopituitarism is frequent in contrast with previous assumptions. This review summarizes the current data on TBI-induced hypopituitarism and briefly discusses some clinical perspectives on post-traumatic anterior pituitary hormone deficiency. PMID- 26251601 TI - Genetic association between G protein-coupled receptor kinase 6/beta-arrestin 2 and dopamine supersensitivity psychosis in schizophrenia. AB - BACKGROUND/AIM: Dopamine supersensitivity psychosis (DSP), clinically characterized by unstable and severe psychosis or tardive dyskinesia and often categorized as treatment-resistant schizophrenia, is promoted by long-term antipsychotic treatment. An upregulation of the dopamine D2 receptor caused by antipsychotic(s) is involved in the development of DSP. The present study explored the potential roles of G protein-coupled receptor kinase 6 (GRK6) and beta-arrestin 2 (ARRB2) that are involved in the trafficking of DRD2 in patients with DSP. METHODS: We conducted a genetic association study of GRK6/ARRB2 between the patients with DSP episodes [DSP(+) group: N=108] and the patients without DSP(-) episodes [DSP(-) group: N=169] from the total group of patients (N=333). Based on the patients' treatment history, a DSP episode was defined as withdrawal psychosis, developed tolerance to antipsychotic effect, and tardive dyskinesia (the remaining 56 patients were excluded due to insufficient information). RESULTS: The results revealed that none of the allelic or genotyping distributions of five single nucleotide polymorphisms (SNPs) of GRK6 and three SNPs of ARRB2 showed any significant difference between the DSP(+) and DSP(-) groups. CONCLUSION: The results suggest that the SNP analyses of these two molecules fail to classify patients into the potential clinical subtype of DSP(+) or DSP(-) group. However, since GRK6 and ARRB2 are surely involved in dopamine D2 receptor metabolism, further studies based on prospective observations of the onset of DSP under specific antipsychotic treatments are needed. PMID- 26251603 TI - Disturbed spontaneous brain activity pattern in patients with primary angle closure glaucoma using amplitude of low-frequency fluctuation: a fMRI study. AB - OBJECTIVE: The aim of this study is to use amplitude of low-frequency fluctuation (ALFF) as a method to explore the local features of spontaneous brain activity in patients with primary angle -closure glaucoma (PACG) and ALFFs relationship with the behavioral performances. METHODS: A total of twenty one patients with PACG (eight males and 13 females), and twenty one healthy subjects (nine males and twelve females) closely matched in age, sex, and education, each underwent a resting-state functional magnetic resonance imaging scan. The ALFF method was used to assess the local features of spontaneous brain activity. The correlation analysis was used to explore the relationships between the observed mean ALFF signal values of the different areas in PACG patients and the thickness of the retinal nerve fiber layer (RNFL). RESULTS: Compared with the healthy subjects, patients with PACG had significant lower ALFF areas in the left precentral gyrus, bilateral middle frontal gyrus, bilateral superior frontal gyrus, right precuneus, and right angular gyrus, and higher areas in the right precentral gyrus. In the PACG group, there were significant negative correlations between the mean ALFF signal value of the right middle frontal gyrus and the left mean RNFL thickness (r=-0.487, P=0.033), and between the mean ALFF signal value of the left middle frontal gyrus and the right mean RNFL thickness (r=-0.504, P=0.020). CONCLUSION: PACG mainly involved in the dysfunction in the frontal lobe, which may reflect the underlying pathologic mechanism of PACG. PMID- 26251604 TI - Paclitaxel reduces formation of hypertrophic scars in the rabbit ear model. AB - BACKGROUND AND OBJECTIVE: The onset and progression of pathological scarring involves multiple cytokines and complex mechanisms. However, hyperplasia of fibroblasts and neovascularization plays important roles, which can be inhibited by paclitaxel. The aim of this study was to investigate the efficacy of paclitaxel in the treatment of hypertrophic scars on rabbit ears. METHODS: Rabbit ear models of hypertrophic scars were established to observe the therapeutic effects of paclitaxel at different concentrations (12 mg/L, 24 mg/L, 48 mg/L, 96 mg/L, 18 mg/L, 54 mg/L, 162 mg/L, 486 mg/L, 30 mg/L, 150 mg/L, 750 mg/L, 3,750 mg/L). The outcome measures included hypertrophic index (HI), density of fibroblasts, density of collagenous fibers, and microvessel density. RESULTS: In comparison with the control group, the concentrations of 96 mg/L, 150 mg/L, and 162 mg/L significantly reduce the formation of hypertrophic scars in the rabbit ear models. However, local necrosis was found in the rabbit ear models treated with paclitaxel solution >400 mg/L. CONCLUSION: Paclitaxel has strong inhibitory effects on the hyperplasia of fibroblasts, deposition of collagen, and microangiogenesis in hypertrophic scars on rabbit ears within the concentration range from 48 mg/L to 162 mg/L, without causing local necrosis. PMID- 26251602 TI - Differential effects of dopamine-directed treatments on cognition. AB - Dopamine, a prominent neuromodulator, is implicated in many neuropsychiatric disorders. It has wide-ranging effects on both cortical and subcortical brain regions and on many types of cognitive tasks that rely on a variety of different learning and memory systems. As neuroscience and behavioral evidence for the existence of multiple memory systems and their corresponding neural networks accumulated, so did the notion that dopamine's role is markedly different depending on which memory system is engaged. As a result, dopamine-directed treatments will have different effects on different types of cognitive behaviors. To predict what these effects will be, it is critical to understand: which memory system is mediating the behavior; the neural basis of the mediating memory system; the nature of the dopamine projections into that system; and the time course of dopamine after its release into the relevant brain regions. Consideration of these questions leads to different predictions for how changes in brain dopamine levels will affect automatic behaviors and behaviors mediated by declarative, procedural, and perceptual representation memory systems. PMID- 26251605 TI - Fluid accumulation threshold measured by acute body weight change after admission in general surgical intensive care units: how much should be concerning? AB - BACKGROUND: The objective of this study (ClinicalTrials.gov: NCT01351506) was to identify the threshold level of fluid accumulation measured by acute body weight (BW) change during the first week in a general surgical intensive care unit (ICU), which is associated with ICU mortality and other adverse outcomes. METHODS: Four hundred sixty-five patients were prospectively followed for a 28 day period. The maximum BW change threshold during the first week was evaluated by the maximum percentage change in BW from the ICU admission weight (Max%DeltaBW). Daily screening of adverse events in the ICU were recorded. The cutoff point of Max%DeltaBW on ICU mortality was defined by considering the area under the receiver operating characteristic (ROC) curve, intersection of the sensitivity and specificity, and the Youden Index. Univariable and multivariable regression analyses were used to demonstrate the associations. Statistical significance was defined as P<0.05. RESULTS: The appropriate cutoff value of Max%DeltaBW threshold was 5%. Regarding the multivariable regression model, in overall patients, the occurrence of the following adverse events (expressed as adjusted odds ratio [95% confidence interval]) were significantly associated with a Max%DeltaBW of >5%: ICU mortality (2.38 [1.25-4.54]) (P=0.008), ICU mortality in patients without renal replacement therapy (RRT) (2.47 [1.21-5.06]) (P=0.013), reintubation within 72 hours (2.51 [1.04-6.00]) (P=0.039), RRT requirement (2.67 [1.13-6.33]) (P=0.026), and delirium (1.97 [1.08-3.57]) (P=0.025). Regarding the postoperative subgroup, a Max%DeltaBW value of more than 5% was significantly associated with: ICU mortality (3.87 [1.38-10.85]) (P=0.010), ICU mortality in patients without RRT (6.32 [1.85-21.64]) (P=0.003), reintubation within 72 hours (4.44 [1.30-15.16]) (P=0.017), and vasopressor requirement (2.04 [1.04-4.01]) (P=0.037). CONCLUSION: Fluid accumulation, measured as acute BW change of more than the threshold of 5% during the first week of ICU admission, is associated with adverse outcomes of higher ICU mortality, especially in the patients without RRT, with reintubation within 72 hours, with RRT requirement, with vasopressor requirement, and with delirium. Some of these effects were higher in postoperative patients. This threshold value might be an indicator for caution during fluid management in surgical ICU. PMID- 26251606 TI - Massive hemorrhage management-a best evidence topic report. AB - INTRODUCTION: Massive hemorrhage remains a major cause of potentially preventable deaths. Better control of bleeding could improve survival rates by 10%-20%. Transfusion intervention concepts have been formulated in order to minimize acute traumatic coagulopathy. These interventions still have not been standardized and vary among medical centers. MATERIALS AND METHODS: Based on a literature search using free term keywords and Medical Subject Heading (MeSH) index, we analyzed published articles addressing massive hemorrhage, component therapy, fresh whole blood, and fibrinogen from the year 2000 onward, in journals with impact factor >1.000, in Medline, PubMed, and Google Scholar. The evidence was grouped into topics including laboratory testing and transfusion interventions/viscoelastic assays vs standard laboratory tests, the effect of component therapy on patient outcome, the effect of warm fresh whole blood on patient outcome, and the effects of fibrinogen in severe bleeding. The obtained information was compared, evaluated, confronted, and was focused on to present an adequate and individual based massive hemorrhage management approach. RESULTS: Viscoelastic whole-blood assays are superior to standard coagulation blood tests for the identification of coagulopathy and for guiding decisions on appropriate therapy in patients with severe bleeding. Replacement of plasma, red blood cells, platelets, and fibrinogen in a ratio of 1:1:1:1 has appeared to be the best substitution for lost whole blood. There is no evidence that cryoprecipitate improves the outcome of patients with severe hemorrhage. Current literature promotes the transfusion of warm fresh whole blood, which seems to be superior to the component therapy in certain clinical situations. Some authors recommend that fibrinogen and other coagulation factors be administered according to the viscoelastic attributes of the blood clot. CONCLUSION: This best-evidence topic report brings comprehensive information about massive hemorrhage management. PMID- 26251607 TI - New developments in the treatment of chronic lymphocytic leukemia: role of obinutuzumab. AB - Obinutuzumab is a novel glycoengineered type II anti-CD20 monoclonal antibody with a higher affinity for CD20 epitope, enhanced antibody-dependent cellular cytotoxicity and direct cell death, leading to superior cytotoxicity compared with rituximab. The approval of obinutuzumab by US Food and Drug Administration was based on a pivotal, phase III, randomized trial of chlorambucil monotherapy (n=118), chlorambucil plus obinutuzumab (n=333), or chlorambucil plus rituximab (n=330) in previously untreated patients with CLL. Obinutuzumab was administered intravenously as 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles. Obinutuzumab plus chlorambucil was associated with an overall response rate of 78% and a median progression-free survival of 26.7 months. Overall, obinutuzumab was fairly well tolerated in this pivotal study. The incidence of grade 3 or higher adverse events was infusion-related reactions (20%), neutropenia (33%), thrombocytopenia (10%), and infections (7%). Obinutuzumab in combination with chlorambucil is a safe and effective new treatment option for previously untreated elderly patients with CLL. It should become the new standard of care for these patients with significant co-morbidities who are not candidates for fludarabine-based therapy. Obinutuzumab combination therapy with several agents that inhibit kinases involved in the B-cell receptor signaling pathway, as well as many other agents utilized in the frontline and relapsed/refractory setting, is currently under investigation. As the results from these studies become available, the role of obinutuzumab is expected to expand to other settings. PMID- 26251608 TI - Critical evaluation of ramucirumab in the treatment of advanced gastric and gastroesophageal cancers. AB - Gastric (GC) and gastroesophageal junction (GEJ) cancers are two global health problems with a relatively high mortality, particularly in the advanced stage. Inhibition of angiogenesis is now contemplated as a classic treatment preference for myriad tumor types encompassing renal cell carcinoma, non-small cell lung cancer, colorectal cancer, glioblastoma, and ovarian cancer, among others. Bevacizumab and ramucirumab have been widely investigated in GC and GEJ cancer, with some controversy about their therapeutic role. Ramucirumab is a monoclonal antibody for vascular endothelial growth factor receptor-2, with demonstrated activity both as a monotherapy and as a part of combination strategy in the management of advanced GC/GEJ cancer. In this review article, we present a critical evaluation of the preclinical and clinical data underlying the use of this drug in this indication. Moreover, we provide a spotlight on the future perspectives in systemic therapy for advanced GC/GEJ cancer. PMID- 26251609 TI - Sex differences in predictors of ischemic stroke: current perspectives. AB - Globally, stroke is a significant public health concern affecting more than 33 million individuals. Of growing importance are the differences between males and females in the predictors and overall risk of stroke. Given that women have a higher lifetime risk for stoke and account for more than half of all stroke deaths, sex-specific stroke risk factors merit investigation and may help target public health interventions. This review aims to discuss the current body of knowledge regarding sex-specific predictors of ischemic stroke including both modifiable and non-modifiable risk factors, as well as specific pathologies known to increase stroke risk. PMID- 26251612 TI - The expression and significance of Gal-3 and MUC1 in colorectal cancer and colon cancer. AB - OBJECTIVE: The objective of the present investigation was to explore the expression and significance of Gal-3 and MUC1 in colorectal cancer tissue and tissue adjacent to carcinoma. METHODS: In this study we collected colorectal cancer tissues and the tissues adjacent to carcinoma from 45 cases from the Colorectal Cancer Surgery Department of Zhengzhou People's Hospital from December of 2009 to June of 2010. At the same time, this study also collected nontumor tissues adjacent to carcinoma from 20 cases as the control group. The expression of Gal-3 and MUC1 of these tissues was detected by using immunohistochemistry streptavidin-peroxidase method, and the correlation between colorectal cancer and expression of Gal-3 and MUC1 was analyzed. RESULTS: The positive expression rates of Gal-3 in the tissues adjacent to carcinoma and colorectal cancer were 15.0% and 73.3%, respectively. The positive expression rate of Gal-3 in colorectal cancer was significantly higher than that in the tissue adjacent to carcinoma. The positive expression rate of Gal-3 of the patients without lymph node metastasis was 61.5% (16/26). The positive expression rate of Gal-3 in the patients with lymph node metastasis was 89.5% (17/19), and the difference was statistically significant (P=0.0363). The positive expression rates of MUC1 in the tissues adjacent to carcinoma and in colorectal cancer tissues were 0.0% and 54.5%, respectively. The positive expression rate of MUC1 in colorectal cancer tissues was significantly higher than that in the normal tissues adjacent to carcinoma (P<0.05); the positive expression rate of MUC1 in the patients without lymph node metastasis was 34.6% (9/26). The positive expression rate of MUC1 in the patients with lymph node metastasis was 84.2% (16/19), and the expression difference was statistically significant (P=0.0009). CONCLUSION: The expression of Gal-3 and MUC1 was significantly higher than that in the nontumor tissue adjacent to carcinoma. There was a correlation between Gal-3 and MUC1 expression and lymphatic metastasis. PMID- 26251610 TI - Multidisciplinary management of clear-cell renal cell carcinoma in Africa and the Middle East: current practice and recommendations for improvement. AB - The management of renal cell carcinoma (RCC) has evolved considerably in recent years. This report represents the consensus of 22 relevant medical specialists from Africa and the Middle East region engaged in the management of RCC. Partial or radical nephrectomy is the standard of care for most patients with localized RCC. It is essential that patients are followed up appropriately after surgery to enable local and distant relapses to be identified and treated promptly. The treatment of advanced/metastatic disease has changed dramatically with the introduction of targeted therapies. Follow-up of these patients enables therapy optimization and assessment of response to treatment. There was universal agreement on the importance of management of RCC by a multidisciplinary team supported by a multidisciplinary tumor board. Barriers hindering this approach were identified. These included lack of awareness of the benefits of multidisciplinary team role, poor communication among relevant disciplines, time constraints, and specifics of private practice. Other challenges include shortage of expert specialists as urologists and oncologists and lack of local management guidelines in some countries. Solutions were proposed and discussed. Medical educational initiatives and awareness activities were highlighted as keys to encouraging cooperation between specialties to improve patients' outcome. Establishing combined genitourinary cancer clinics and formal referral systems should encourage a culture of effective communication. Joining forces with professionals in peripheral areas and the private sector is likely to help standardize care. Sustained action will be required to ensure that all patients with RCC in the region benefit from up-to-date care. PMID- 26251611 TI - Successful management of Barth syndrome: a systematic review highlighting the importance of a flexible and multidisciplinary approach. AB - This review describes and summarizes the available evidence related to the treatment and management of Barth syndrome. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards were used to identify articles published between December 2004 and January 2015. The Cochrane Population, Intervention, Control, Outcome, Study Design (PICOS) approach was used to guide the article selection and evaluation process. Of the 128 articles screened, 28 articles matched the systematic review inclusion criteria. The results of this review indicate the need for a flexible and multidisciplinary approach to manage the symptoms most commonly associated with Barth syndrome. It is recommended that a comprehensive care team should include individuals with Barth syndrome, their family members and caregivers, as well as medical, rehabilitative, nutritional, psychological, and educational professionals. The evidence for specific treatments, therapies, and techniques for individuals with Barth syndrome is currently lacking in both quality and quantity. PMID- 26251613 TI - Peritumoral SPARC expression and patient outcome with resectable intrahepatic cholangiocarcinoma. AB - BACKGROUND AND OBJECTIVES: Cholangiocarcinoma (CCA) affects thousands worldwide with increasing incidence. SPARC (secreted protein acidic and rich in cysteine) plays an important role in cellular matrix interactions, wound repair, and cellular migration, and has been reported to prevent malignancy from growth. SPARC undergoes epigenetic silencing in pancreatic malignancy, but is frequently expressed by stromal fibroblasts adjacent to infiltrating pancreatic adenocarcinomas. CCA is also a desmoplastic tumor, similar to pancreatic adenocarcinoma. SPARC's clinical influence on clinicopathological characteristics of mass-forming (MF)-CCA still remains unclear. In this study, we evaluate the expression of SPARC in tumor and stromal tissue to clarity its relation with prognosis. METHODS: Seventy-eight MF-CCA patients who underwent hepatectomy with curative intent were enrolled for an immunohistochemical study of SPARC. The expression of immunostaining of SPARC was characterized for both tumor and stromal tissues. We conducted survival analysis with 16 clinicopathological variables. The overall survival (OS) was analyzed by Kaplan-Meier analysis and Cox proportional hazards regression modeling. RESULTS: Thirty-three men and 45 women with MF-CCA were studied. Within total 78 subjects, 12 (15.4%) were classified as tumor negative/stroma negative, 37 (47.4%) as tumor positive/stroma negative, four (5.1%) as tumor negative/stroma positive, and 25 (32.1%) as tumor positive/stroma positive. With a median follow-up of 13.6 months, the 5-year OS was 14.9%. Cox proportional hazard analysis revealed that SPARC tumor positive and stromal negative immunostaining and curative hepatectomy predicted favorable OS in patients with MF-CCA after hepatectomy. CONCLUSION: MF-CCA patients with SPARC tumor positive and stromal negative expression may have favorable OS rates after curative hepatectomy. PMID- 26251614 TI - Malignant glomus tumor of the lung with multiorgan metastases: case report and literature review. AB - Glomus tumor is an exceedingly rare neoplasm that is derived from cells of the neuromyoarterial glomus or glomus body. It rarely occurs in the visceral organs where glomus body may be sparse or even absent, such as the stomach, intestines, mediastinum, and respiratory tract. It is unusual for a glomus tumor to demonstrate atypical or malignant histopathological characteristics. It is also rare for such a tumor to express clinically aggressive behavior. However, when metastasis does occur, this disease is often fatal. We herein report an interesting case of a middle-age woman admitted due to progressive cough and hemoptysis. A polypoid mass was found to occlude the left lingular lobar bronchus. Final histopathologic examination showed the presence of malignant glomus tumor, confirmed by immunoreactivity for smooth muscle actin and vimentin. Two months later, the patient developed abdominal distension and gastrointestinal bleeding. Further evaluation lead to the discovery of widespread metastatic disease to the gastrointestinal tract, spleen, and the left adrenal gland. We further entail a review of the literature on the clinicopathologic features and diagnosis of this uncommon tumor. PMID- 26251616 TI - Hypoxia-inducible factor-1alpha induces multidrug resistance protein in colon cancer. AB - Multidrug resistance is the major cause of chemotherapy failure in many solid tumors, including colon cancer. Hypoxic environment is a feature for all solid tumors and is important for the development of tumor resistance to chemotherapy. Hypoxia-inducible factor (HIF)-1alpha is the key transcription factor that mediates cellular response to hypoxia. HIF-1alpha has been shown to play an important role in tumor resistance; however, the mechanism is still not fully understood. Here, we found that HIF-1alpha and the drug resistance-associated gene multidrug resistance associated protein 1 (MRP1) were induced by treatment of colon cancer cells with the hypoxia-mimetic agent cobalt chloride. Inhibition of HIF-1alpha by RNA interference and dominant-negative protein can significantly reduce the induction of MRP1 by hypoxia. Bioinformatics analysis showed that a hypoxia response element is located at -378 to -373 bp upstream of the transcription start site of MRP1 gene. Luciferase reporter assay combined with mutation analysis confirmed that this element is essential for hypoxia-mediated activation of MRP gene. Furthermore, RNA interference revealed that HIF-1alpha is necessary for this hypoxia-driven activation of MRP1 promoter. Importantly, chromatin immunoprecipitation analysis demonstrated that HIF-1alpha could directly bind to this HRE site in vivo. Together, these data suggest that MRP1 is a downstream target gene of HIF-1alpha, which provides a potential novel mechanism for HIF-1alpha-mediated drug resistance in colon cancer and maybe other solid tumors as well. PMID- 26251615 TI - Profile of veliparib and its potential in the treatment of solid tumors. AB - Inhibition of poly(ADP-ribose) polymerase (PARP) is an attractive therapeutic strategy because of the importance of this pathway in restoring DNA damage. Small molecule inhibitors of PARP appear most effective when used to treat tumors with underlying defects in DNA repair, or when combined with DNA-damaging agents. Veliparib is one of several recently developed oral inhibitors of PARP currently in clinical trials. This review summarizes the pharmacology, mechanisms of action, toxicity, and activity of veliparib seen in clinical trials to date. Also discussed are proposed mechanisms of resistance, potential biomarkers of activity, and issues regarding patient selection and combination therapies that may optimize use of this exciting new agent. PMID- 26251617 TI - Prognostic value of IGF-1R expression in bone and soft tissue sarcomas: a meta analysis. AB - Accumulated evidence has indicated a correlation between IGF-1R and bone and soft tissue sarcoma (BSTS) progression. However, research on the prognostic role of IGF-1R in sarcomas has revealed very different or even totally opposite results. This meta-analysis aimed to unveil the controversial role IGF-1R plays in predicting the outcome of BSTS patients. We systematically reviewed the evidence for the effect of IGF-1R expression in multiple types of BSTSs, including osteosarcoma, Ewing's sarcoma, synovial sarcoma, liposarcoma, and rhabdomyosarcoma, to elucidate this issue. The prognostic value of IGF-1R expression in BSTS patients was evaluated regarding overall survival, measured by pooled hazard ratios (HRs) with 95% confidence intervals (CIs). Seven studies including 627 patients were enrolled in this meta-analysis. Our results demonstrated that IGF-1R expression was associated with poor outcome in terms of overall survival in BSTS patients (pooled HR =2.15, 95% CI: 1.06-4.38; P=0.03). In subtypes of BSTSs, elevated IGF-1R expression was revealed to be significantly correlated with worse prognosis in osteosarcoma (pooled HR =2.20, 95% CI: 1.59 0.03; P<0.001), while no statistical significance was discovered in Ewing's sarcoma (pooled HR =1.01, 95% CI: 0.45-2.27; P=0.99). Expression of IGF-1R could be a negative prognostic biomarker for patients suffering from BSTSs. PMID- 26251618 TI - -148 C/T polymorphism of Axin2 contributes to a decreased risk of cancer: evidence from a meta-analysis. AB - Several studies have reported an association between -148 C/T polymorphism of Axis inhibition protein 2 (Axin2) and cancer risk; however, the results are inconsistent. In this study, a meta-analysis was performed to assess the association between -148 C/T polymorphism of Axin2 and susceptibility to cancer. Published case-control and cohort-based studies from PubMed, Embase, Wanfang, and CNKI were retrieved, and data were manually extracted. The odds ratios (ORs) and 95% confidence intervals (CIs) of the included studies were pooled. Begg's and Egger's tests were used to evaluate publication bias. Cumulative and recursive cumulative meta-analyses (CMA) were performed as evidence accumulated to investigate the trends and stability of the effect size. Nine articles with 1,664 cases and 1,796 controls were included. The pooled effect size showed an association between -148 C/T polymorphism and the risk of cancer (dominant model, OR: 0.72, 95% CI: 0.63-0.83; allele model, OR: 0.81, 95% CI: 0.73-0.90). CMA showed an association trend, and the recursive CMA indicated that more evidence is needed to make conclusions about significance. In a subgroup analysis, a significant association between -148 C/T polymorphism and low cancer susceptibility was detected for lung cancer (dominant model, 0.69, 95% CI: 0.56 0.85; recessive model, OR: 0.75, 95% CI: 0.56-0.99; allele model, 0.76, 95% CI: 0.66-0.86). The -148 C/T polymorphism was also associated with low cancer susceptibility among Asians (dominant model, OR: 0.68, 95% CI: 0.57-0.81; recessive model, OR: 0.75, 95% CI: 0.56-0.99; allele model, OR: 0.76, 95% CI: 0.66-0.86). The Axin2 -148 C/T polymorphism was found to be significantly associated with a decreased risk of cancer, particularly lung cancer, in Asians and population-based controls. Thus, Axin2 should be considered as a potential therapeutic target for preventing tumor growth. PMID- 26251619 TI - Is there any association between hormonal contraceptives and cervical neoplasia in a poor Nigerian setting? AB - BACKGROUND: The association between hormonal contraception and cervical cancer is controversial. These controversies may hamper the uptake of hormonal contraceptives. OBJECTIVE: To determine the association between hormonal contraceptives and cervical neoplasia. MATERIALS AND METHODS: This was a case control study in which Pap-smear results of 156 participants on hormonal contraceptives were compared with those of 156 participants on no form of modern contraception. Modern contraception is defined as the use of such contraceptives as condoms, pills, injectables, intrauterine devices, implants, and female or male sterilization. Those found to have abnormal cervical smear cytology results were subjected further to colposcopy. Biopsy specimens for histology were collected from the participants with obvious cervical lesions or those with suspicious lesions on colposcopy. The results were analyzed with descriptive and inferential statistics at a 95% level of confidence. RESULTS: A total of 71 (45.5%), 60 (38.5%), and 25 (16.0%) of the participants on hormonal contraceptives were using oral contraceptives, injectable contraceptives, and implants, respectively. Cervical neoplasia was significantly more common among participants who were >=35 years old (6% versus 1%, P<0.0001), rural dwellers (6% versus 3.5%, P<0.0001), unmarried (7.6% versus 3.5%, P<0.0001), unemployed (6.8% versus 3.5%, P<0.0001), less educated (6% versus 3.8%, P<0.0001), and had high parity (6.8% versus 3.6%, P<0.0001). There was no statistical significant difference in cervical neoplasia between the two groups of participants (7 [4.5%] versus 6 [3.8%], P=1.0). CONCLUSION: There was no association between hormonal contraceptives and cervical neoplasia in this study. PMID- 26251620 TI - Progress toward curing HIV infection with hematopoietic cell transplantation. AB - HIV-1 infection afflicts more than 35 million people worldwide, according to 2014 estimates from the World Health Organization. For those individuals who have access to antiretroviral therapy, these drugs can effectively suppress, but not cure, HIV-1 infection. Indeed, the only documented case for an HIV/AIDS cure was a patient with HIV-1 and acute myeloid leukemia who received allogeneic hematopoietic cell transplantation (HCT) from a graft that carried the HIV resistant CCR5-?32/?32 mutation. Other attempts to establish a cure for HIV/AIDS using HCT in patients with HIV-1 and malignancy have yielded mixed results, as encouraging evidence for virus eradication in a few cases has been offset by poor clinical outcomes due to the underlying cancer or other complications. Such clinical strategies have relied on HIV-resistant hematopoietic stem and progenitor cells that harbor the natural CCR5-?32/?32 mutation or that have been genetically modified for HIV-resistance. Nevertheless, HCT with HIV-resistant cord blood remains a promising option, particularly with inventories of CCR5 ?32/?32 units or with genetically modified, human leukocyte antigen-matched cord blood. PMID- 26251621 TI - Role of small colony variants in persistence of Pseudomonas aeruginosa infections in cystic fibrosis lungs. AB - Pseudomonas aeruginosa is an opportunistic pathogen that predominates during the later stages of cystic fibrosis (CF) lung infections. Over many years of chronic lung colonization, P. aeruginosa undergoes extensive adaptation to the lung environment, evolving both toward a persistent, low virulence state and simultaneously diversifying to produce a number of phenotypically distinct morphs. These lung-adapted P. aeruginosa strains include the small colony variants (SCVs), small, autoaggregative isolates that show enhanced biofilm formation, strong attachment to surfaces, and increased production of exopolysaccharides. Their appearance in the sputum of CF patients correlates with increased resistance to antibiotics, poor lung function, and prolonged persistence of infection, increasing their relevance as a subject for clinical investigation. The evolution of SCVs in the CF lung is associated with overproduction of the ubiquitous bacterial signaling molecule cyclic-di-GMP, with increased cyclic-di-GMP levels shown to be responsible for the SCV phenotype in a number of different CF lung isolates. Here, we review the current state of research in clinical P. aeruginosa SCVs. We will discuss the phenotypic characteristics underpinning the SCV morphotype, the clinical implications of lung colonization with SCVs, and the molecular basis and clinical evolution of the SCV phenotype in the CF lung environment. PMID- 26251622 TI - Impact of space flight on bacterial virulence and antibiotic susceptibility. AB - Manned space flight induces a reduction in immune competence among crew and is likely to cause deleterious changes to the composition of the gastrointestinal, nasal, and respiratory bacterial flora, leading to an increased risk of infection. The space flight environment may also affect the susceptibility of microorganisms within the spacecraft to antibiotics, key components of flown medical kits, and may modify the virulence characteristics of bacteria and other microorganisms that contaminate the fabric of the International Space Station and other flight platforms. This review will consider the impact of true and simulated microgravity and other characteristics of the space flight environment on bacterial cell behavior in relation to the potential for serious infections that may appear during missions to astronomical objects beyond low Earth orbit. PMID- 26251623 TI - Medical resource utilization for administration of trastuzumab in a New Zealand oncology outpatient setting: a time and motion study. AB - BACKGROUND: In New Zealand, trastuzumab is standard therapy for human epidermal growth factor receptor-2 (HER2)-positive early and metastatic breast cancer. Given the requirement for ongoing adjuvant or maintenance treatment and intravenous (IV) delivery, such a regimen consumes considerable health care resources. The development of a subcutaneous (SC) trastuzumab formulation with a short administration time offers the potential to reduce hospital expenditure. The aim of this study was to determine medical resource utilization associated with administration of trastuzumab SC injection via handheld syringe vs trastuzumab IV infusion in patients with HER2-positive breast cancer in New Zealand. METHODS: This noninterventional, descriptive study was conducted at the outpatient oncology centers at Auckland City and Tauranga Hospitals. Trained observers recorded times associated with health care professional (HCP) tasks and consumables use associated with preparation and administration of trastuzumab IV or SC in women with early or metastatic breast cancer. The cost for each formulation was calculated as the mean cost of HCP time (based on Pharmaceutical Management Agency hourly rates) plus the mean cost of consumables used. RESULTS: Use of trastuzumab SC vs IV reduced mean chair time by 36.95 minutes and total nurse time by 6.12 minutes; there was a 20.45-minute reduction in pharmacist time when the SC formulation was used. After adding consumable costs, the overall estimated saving with trastuzumab SC vs IV was $76.94 (New Zealand dollars) per patient per cycle. CONCLUSIONS: Compared with trastuzumab IV infusion, administration of trastuzumab via SC injection reduced time spent in the clinic and decreased HCP resources and consumables needed to administer treatment. These reductions could contribute to a decrease in health care costs and an improvement in the efficiency of HER2-positive breast cancer treatment delivery. PMID- 26251625 TI - Evaluation of a topical treatment for the relief of sensitive skin. AB - BACKGROUND: Approximately, 50% of the population claim to have sensitive skin, which has created an important challenge for dermatologists and the cosmetic industry. This study evaluates the properties of QV Face Rescue Gel (Rescue Gel) that contains a combination of moisturizing and anti-irritant ingredients, and which is used to relieve the symptoms of sensitive facial skin. METHODS: The ability of Rescue Gel to induce collagen types I and III in cultured neonatal human foreskin fibroblasts compared to transforming growth factor beta 1, a known potent inducer of collagen types I and III, was measured using immunofluorescence staining. Furthermore, healthy volunteers were recruited to measure the potential for Rescue Gel to reduce erythema induced by solar-simulated ultraviolet radiation on the skin compared to 0.5% hydrocortisone cream (positive control) as well as it's ability to decrease transepidermal water loss compared to baseline levels. In addition, the formulation was tested for its potential to be 1) nonstinging using a facial sting/discomfort assay performed on volunteers who reacted positively to lactic acid, 2) nonirritating as determined by repeat insult patch tests, and 3) noncomedogenic. RESULTS: Rescue Gel significantly induced collagen types I and III in cultured human foreskin fibroblasts similarly to transforming growth factor beta 1. In volunteers, Rescue Gel was shown to significantly reduce erythema induced by solar-simulated ultraviolet radiation similarly to 0.5% hydrocortisone, and to significantly reduce transepidermal water loss compared to baseline levels. Further, the formulation was found to be nonstinging, nonirritating, and noncomedogenic. No adverse events were observed. CONCLUSION: In this study, Rescue Gel has been shown to exhibit properties that make it effective for use on sensitive or irritated facial skin, without exacerbation of the symptoms associated with sensitive skin. PMID- 26251624 TI - Anti-atherosclerotic effects of sitagliptin in patients with type 2 diabetes mellitus. AB - BACKGROUND: Advanced glycation end products, selectins, and adiponectin play important roles in the development of atherosclerosis in individuals with diabetes. Sitagliptin has been shown to reduce the concentration of glycated hemoglobin in diabetic patients. However, its effects on soluble receptor for advanced glycation end products (sRAGEs), selectins, and adiponectin in these patients are poorly understood. This study was conducted to assess the effects of sitagliptin on the circulating levels of sRAGEs, monocyte chemoattractant protein 1 (MCP-1), selectins, and adiponectin in patients with type 2 diabetes. METHODS: Diabetic patients eligible for sitagliptin monotherapy or combination therapy (eg, sitagliptin plus a sulfonylurea) were administered sitagliptin (50 mg/day) for 6 months. Levels of soluble P-selectin (sP-selectin), soluble E-selectin (sE selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1), MCP-1, sRAGEs, and adiponectin were measured by ELISA at baseline and after 3 and 6 months of treatment. RESULTS: At baseline, the levels of MCP-1, sP-selectin, sE-selectin, and sVCAM-1 were higher and the level of adiponectin was lower in diabetic patients than in nondiabetic patients. Sitagliptin therapy for 3 and 6 months significantly reduced plasma levels of sP-selectin, sE-selectin, sVCAM-1, and MCP 1 relative to baseline, while significantly increasing adiponectin levels. sRAGEs did not exhibit a statistical significance, although there was an increasing tendency. Furthermore, the reductions in sP-selectin, sE-selectin, sVCAM-1, and MCP-1 during sitagliptin therapy were significantly greater in responders, defined as patients with a significant increase in adiponectin levels, than in nonresponders. In contrast, responders showed a significant increase in the plasma concentration of sRAGEs. CONCLUSION: Sitagliptin shows an adiponectin dependent anti-atherothrombotic effect, which may be beneficial for primary prevention of atherothrombosis, in patients with type 2 diabetes. PMID- 26251626 TI - Serum magnesium concentrations in patients receiving sodium picosulfate and magnesium citrate bowel preparation: an assessment of renal function and electrocardiographic conduction. AB - BACKGROUND: We performed a post hoc analysis of two clinical trials to assess whether sodium picosulfate and magnesium (Mg(2+)) citrate (Prepopik((r)) [P/MC]), a dual-action bowel preparation for colonoscopy, has an impact on serum Mg(2+) levels and cardiac electrophysiology. Although rare, hypermagnesemia has been reported in patients consuming Mg(2+)-containing cathartics, especially patients who are elderly and have renal impairment. METHODS: Data were analyzed from two prospective, Phase III, randomized, assessor-blinded, active-control, multicenter, pivotal studies that investigated split-dose/day-before P/MC. Serum Mg(2+) and creatinine clearance (CrCl) were measured at screening, on the day of colonoscopy, and 24-48 hours, 7 days, and 4 weeks after colonoscopy; electrocardiograms also were obtained at these time points. RESULTS: In total, 304 patients received split-dose P/MC and 294 patients received day-before P/MC. Only 10% of the patients had serum Mg(2+) above the upper limit of normal (1.05 mmol/L) on the day of colonoscopy. There was a slight inverse correlation between CrCl and Mg(2+) levels on the day of colonoscopy; however, even at the lowest CrCl, serum Mg(2+) remained below clinically significant levels of 2.0 mmol/L. Increases in serum Mg(2+) were transient, with levels returning to baseline within 24-48 hours, regardless of renal function. No patients with elevated Mg(2+) experienced a corrected QT (QTc) interval >500 milliseconds or a QTc interval increase of >=60 milliseconds from baseline. P/MC had no impact on PR or QRS interval. CONCLUSION: P/MC produces little impact on serum Mg(2+) levels with no clinically significant effect on cardiac conduction in patients, including those with mild-to-moderate renal impairment. PMID- 26251627 TI - Accelerated partial breast irradiation with brachytherapy: patient selection and technique considerations. AB - Accelerated partial breast irradiation (APBI) through breast brachytherapy is a relatively recent development in breast radiotherapy that has gained international favor because of its reduction in treatment duration and normal tissue irradiation while maintaining favorable cancer-specific and cosmetic outcomes. Despite the fact that several large national trials have not reported final results yet, many providers are currently offering APBI to select patients and APBI is listed as a treatment option for selecting patients in the National Comprehensive Cancer Network guidelines. Multiple consensus guidelines exist in selecting patients for APBI, some with conflicting recommendations. In this review, the existing patient selection guidelines are reported, compared, and critiqued, grouping them in helpful subcategories. Unique patient and technical selection factors for APBI with brachytherapy are explored. PMID- 26251628 TI - Clinical management of grade III oligodendroglioma. AB - Oligodendrogliomas represent the third most common type of glioma, comprising 4% 15% of all gliomas and can be classified by degree of malignancy into grade II and grade III, according to WHO classification. Only 30% of oligodendroglial tumors have anaplastic characteristics. Anaplastic oligodendroglioma (AO) is often localized as a single lesion in the white matter and in the cortex, rarely in brainstem or spinal cord. The management of AO is deeply changed in the recent years. Maximal safe surgical resection followed by radiotherapy (RT) was considered as the standard of care since paramount findings regarding molecular aspects, in particular co-deletion of the short arm of chromosome 1 and the long arm of chromosome 19, revealed that these subsets of AO, benefit in terms of overall survival (OS) and progression-free survival (PFS), from the addition of chemotherapy to RT. Allelic losses of chromosomes 1p and 19q occur in 50%-70% of both low-grade and anaplastic tumors, representing a strong prognostic factor and a powerful predictor of prolonged survival. Several other molecular markers have potential clinical significance as IDH1 mutations, confirming the strong prognostic role for OS. Malignant brain tumors negatively impacts on patients' quality of life. Seizures, visual impairment, headache, and cognitive disorders can be present. Moreover, chemotherapy and RT have important side effects. For these reasons, "health-related quality of life" is becoming a topic of growing interest, investigating on physical, mental, emotional, and social well-being. Understanding the impact of medical treatment on health-related quality of life will probably have a growing effect both on health care strategies and on patients. PMID- 26251630 TI - Age-specific cancer survival in Estonia: recent trends and data quality. AB - BACKGROUND: A number of population-based studies have demonstrated lower cancer survival in elderly patients than among middle-aged or younger patients. Also, data quality in cancer registries has been shown to be associated with age. The objective of this study was to examine the recent age-specific cancer survival trends and age-specific quality of cancer data in Estonia. METHODS: Using Estonian Cancer Registry data, we calculated relative survival ratios (RSRs) for eight common cancers in Estonia in 1995-1999 (cohort method) and 2005-2009 (period method) for four major age groups (15-54, 55-64, 65-74, and 75-84 years at diagnosis). The main data quality indicators were calculated, and the age specific effect of missing death certificate initiated (DCI) cases on survival was estimated comparing 5-year RSRs computed from the complete data set with those from data set without DCI cases. RESULTS: We observed overall rise in 5 year RSR for all eight cancers over the study period, with a considerable variation by age, with the lowest survival among the oldest patients. The widest age gradient in 5-year RSR was seen for bladder cancer (20% units in 2005-2009), followed by cancers of lung (16% units), kidney (15% units), breast and prostate (13% units), stomach and rectum (11% units), and colon (5% units). All data quality indicators, including proportion of cases with unknown stage showed a similar age-related pattern with the lowest quality in the oldest age group. The effect of missing DCI cases on survival estimates increased by age and was around 3% units for prostate and kidney cancers among the oldest patients. CONCLUSION: Young or middle-aged patients in Estonia experienced larger survival gain since the late 1990s than elderly patients. Decreasing quality of cancer registry data along with increasing patient age suggests less thorough clinical investigations in older age groups. PMID- 26251629 TI - New and emerging factors in tumorigenesis: an overview. AB - This article provides an overview of the genes and cellular processes that have emerged recently as new key factors in tumorigenesis. We review these in the context of three broad categories. First, genome-scale sequencing studies have revealed a set of frequently mutated genes in cancer. Genes that are mutated in >5% of all cancers across tissue types are discussed, with a highlighted focus on the two most frequently mutated genes, TP53 and PIK3CA. Second, the mechanisms of resistance to targeted therapy are reviewed. These include acquired resistance under targeted therapy selection owing to mutations and amplification of genes in the same or parallel signaling pathways. Importantly, sequencing of primary tumors has revealed that therapy-resistant clones already exist prior to targeted therapy, demonstrating that tumor heterogeneity in primary tumors confers a mechanism for inherent therapy resistance. Third, "metastasis-specific genes", or rather lack thereof, are discussed. While many genes have been shown to be capable of promoting metastasis in experimental systems, no common genetic alterations have been identified specific to metastatic lesions. Rather, the same gene mutations frequently found in primary tumors are also found prevalent in metastases, suggesting that the genes that drive tumorigenesis may also drive metastasis. In this light, an emerging view of metastatic progression is discussed. Collectively, these recent advances in cancer research have refined our knowledge on cancer etiology and progression but also present challenges that will require innovative new approaches to treat and manage cancer. PMID- 26251631 TI - A case of blowout fracture of the orbital floor in early childhood. AB - There are few reports of blowout fractures of the orbital floor in children younger than 5 years of age; in a search of the literature, we found only six reported cases which revealed the exact age, correct diagnosis, and treatment. We herein report the case of a 3-year-old boy with a blowout fracture of the orbital floor. Computed tomography showed a pure blowout fracture of the left orbital floor with a slight dislocation of the orbital contents. The patient was treated conservatively due to the absence of abnormal limitation of eye movement or enophthalmos. The patient did not develop any complications that necessitated later surgical intervention. Computed tomography at 6 months after the injury showed the regeneration of the orbital floor in the area of the fracture and no abnormalities in the left maxillary sinus. We herein present our case and the details of six other cases reported in the literature, and discuss their etiology, diagnosis, and treatment methods. PMID- 26251632 TI - Tizanidine-induced acute severe cystitis in a female taking famotidine. AB - Cystitis is a possible adverse drug reaction associated with the use of tizanidine. Such cases have been rarely reported in literature because of the difficulty in establishing the causality. However, from a pharmacovigilance point of view, it is better to report such cases of a possible association between a drug's use and potential adverse drug reactions. We report a case of a 26-year old Asian female on famotidine who presented with acute severe urinary burning after taking tizanidine. PMID- 26251633 TI - Special considerations for placement of an inflatable penile prosthesis for the patient with Peyronie's disease: techniques and patient preference. AB - Placement of an inflatable penile prosthesis (IPP) is the mainstay of surgical treatment for patients with Peyronie's disease (PD) and concomitant medication refractory erectile dysfunction. Special considerations and adjunctive surgical techniques during the IPP procedure are often required for patients with PD to improve residual penile curvature, as well as postoperative penile length. The surgical outcomes and various adjunctive techniques are not significantly different from one another, and selection of the appropriate technique must be tailored to patient-specific factors including the extent of the deformity, the degree of penile shortening, and preoperative patient expectations. The aims of this review were to assess the current literature on published outcomes and surgical techniques involving IPP placement in the treatment of PD. Patient satisfaction and preferences are reported, along with the description and patient selection for surgical techniques that include manual penile modeling, management of refractory curvature with concurrent plication, and correction of severe residual curvature and penile shortening with tunica release and plaque incision and grafting. A thorough description of the available techniques and their associated outcomes may help guide surgeons to the most appropriate choice for their patients. PMID- 26251634 TI - Baclofen for narcolepsy with cataplexy: two cases. AB - Narcolepsy is a disabling sleep disorder characterized by daytime hypersomnolence. Those with cataplexy have spells of muscle weakness precipitated by strong emotions, especially laughter or surprise. Cataplexy treatments include antidepressants or a GABA-B agonist, gamma hydroxybutyrate (GHB). GHB is the most effective treatment for cataplexy, but is expensive and can have significant side effects. A recent report of a murine model of narcolepsy-cataplexy suggests R baclofen has potential efficacy against cataplexy. We report on two narcolepsy patients with multiple daily cataplexy episodes, one of whom had been effectively treated with GHB, but had to discontinue it for unrelated medical reasons. Both subsequently tried baclofen and experienced almost complete resolution of cataplexy. This report suggests baclofen can be an effective treatment for cataplexy in humans and warrants further study. PMID- 26251635 TI - Validity and reliability of the Patient-Reported Arthralgia Inventory: validation of a newly-developed survey instrument to measure arthralgia. AB - BACKGROUND: There is a need for a survey instrument to measure arthralgia (joint pain) that has been psychometrically validated in the context of existing reference instruments. We developed the 16-item Patient-Reported Arthralgia Inventory (PRAI) to measure arthralgia severity in 16 joints, in the context of a longitudinal cohort study to assess aromatase inhibitor-associated arthralgia in breast cancer survivors and arthralgia in postmenopausal women without breast cancer. We sought to evaluate the reliability and validity of the PRAI instrument in these populations, as well as to examine the relationship of patient-reported morning stiffness and arthralgia. METHODS: We administered the PRAI on paper in 294 women (94 initiating aromatase inhibitor therapy and 200 postmenopausal women without breast cancer) at weeks 0, 2, 4, 6, 8, 12, 16, and 52, as well as once in 36 women who had taken but were no longer taking aromatase inhibitor therapy. RESULTS: Cronbach's alpha was 0.9 for internal consistency of the PRAI. Intraclass correlation coefficients of test-retest reliability were in the range of 0.87-0.96 over repeated PRAI administrations; arthralgia severity was higher in the non-cancer group at baseline than at subsequent assessments. Women with joint comorbidities tended to have higher PRAI scores than those without (estimated difference in mean scores: -0.3, 95% confidence interval [CI] -0.5, 0.2; P<0.001). The PRAI was highly correlated with the Functional Assessment of Cancer Therapy-Endocrine Subscale item "I have pain in my joints" (reference instrument; Spearman r range: 0.76-0.82). Greater arthralgia severity on the PRAI was also related to decreased physical function (r=-0.47, 95% CI -0.55, -0.37; P<0.001), higher pain interference (r=0.65, 95% CI 0.57-0.72; P<0.001), less active performance status (estimated difference in location (-0.6, 95% CI -0.9, 0.4; P<0.001), and increased morning stiffness duration (r=0.62, 95% CI 0.54 0.69; P<0.0001). CONCLUSION: We conclude that the psychometric properties of the PRAI are satisfactory for measuring arthralgia severity. PMID- 26251636 TI - Retracting Inconclusive Research: Lessons from the Seralini GM Maize Feeding Study. AB - In September 2012, Gilles-Eric Seralini and seven coauthors published an article in Food and Chemical Toxicology claiming that rats fed Roundup(c)-resistant genetically modified maize alone, genetically modified maize with Roundup(c), or Roundup(c) for 2 years had a higher percentage of tumors and kidney and liver damage than normal controls. Shortly after this study was published, numerous scientists and several scientific organizations criticized the research as methodologically and ethically flawed. In January 2014, the journal retracted the article without the authors' consent on the grounds that the research was inconclusive. In June 2014, Environmental Sciences Europe published a slightly modified version of the retracted paper. The publication, retraction and subsequent republication of the Seralini study raise important scientific and ethical issues for journal editors. Decisions to retract an article should be made on the basis of well-established policies. Articles should be retracted only for serious errors that undermine the reliability of the data or results, or for serious ethical lapses, such as research misconduct or mistreatment of animal or human subjects. Inconclusiveness, by itself, is not a sufficient reason for retracting an article, though a flawed study design might be. Retracted articles that are submitted for republication should undergo scientific review to ensure that they meet appropriate standards. Republished articles should be linked to the original, retracted publication. Journals that are reviewing studies with significant scientific and social implications should take special care to ensure that peer review is rigorous and fair. PMID- 26251637 TI - "Real-world" precision, bias, and between-laboratory variation for surface area measurement of a titanium dioxide nanomaterial in powder form. AB - Accurate characterization of nanomaterial properties is a critical component of any nanotoxicology testing strategy. Data that describes the performance of various laboratories in measuring the characteristics of the same nanomaterial are scarce. We conducted an inter-laboratory study to evaluate "real-world" precision and bias of specific surface area measurements using a powered material containing sub-30 nm primary crystallites. Each participant was provided a sample of NIST Standard Reference Material 1898 (Titanium Dioxide Nanomaterial) and a sample preparation and analysis protocol. Based on results from 19 laboratories, overall performance was good. Estimates of precision ranged from 0.10 to 3.96 % and measurement bias was generally within +/-5 % of the certified surface area value of the material. Between-laboratory variability accounted for 91 % of the total variance and is likely explained by gravimetric errors. Reliable determination of intrinsic nanomaterial properties such as surface area will permit development of protocols for toxicity testing, verification of laboratory proficiency, and consistency in interpretation of toxicity study data. PMID- 26251639 TI - Supporting the use of a coagulometric method for rivaroxaban control: a hypothesis-generating study to define the safety cut-offs. AB - AIMS: Although quantitative anti-FXa assays can be used to measure rivaroxaban plasma levels, they are not widely performed or available. We aimed to tentatively determine the cut-off for thromboembolism and bleeding prevention based on the clotting effect of non-rivaroxaban conjugate-activated FX plasma levels in patients with rivaroxaban using a coagulometric method. METHODS AND RESULTS: Rivaroxaban was added in vitro to normal plasma at a range of 0 to 241 MUg/L to cover expected peak and trough levels. Rivaroxaban chromogenic (MUg/L) and RVV-confirm as a ratio were determined. Patient plasma samples were assayed with the RVV-confirm reagent. The appropriate rivaroxaban plasma concentration to inhibit clotting mechanisms was based on the remaining FXa in plasma, which was expressed as the ratio of patients/normal, R-C. There is a high correlation between R-C in vitro and spiked normal plasma rivaroxaban concentration (R-Square 0.910, linear equation; 0.971 quadratic equation, p < 0.0001 for both) but not with plasma rivaroxaban chromogenic assays. We propose a cut-off R-C value of 1.65 and 4.5 for safety. Based on the proposed therapeutic range, in 158 assays performed in 58 patients, 6.3 % assays were above the level of bleeding tendency at the peak (R-C 5.39 +/- 1.01, median 5.13) and 42 % assays were below the prevention cut-off at the trough (R-C 1.31 +/- 0.18, median 1.35). CONCLUSIONS: RVVconfirm(r) is fast and sensitive to measure the effect of rivaroxaban. Clinical studies are needed to establish whether this cut-off is useful for identifying patients at increased risk of hemorrhage or those who exhibit a low level of anticoagulation. PMID- 26251640 TI - CellProfiler: Novel Automated Image Segmentation Procedure for Super-Resolution Microscopy. AB - BACKGROUND: Super resolution (SR) microscopy enabled cell biologists to visualize subcellular details up to 20 nm in resolution. This breakthrough in spatial resolution made image analysis a challenging procedure. Direct and automated segmentation of SR images remains largely unsolved, especially when it comes to providing meaningful biological interpretations. RESULTS: Here, we introduce a novel automated imaging analysis routine, based on Gaussian, followed by a segmentation procedure using CellProfiler software (www.cellprofiler.org). We tested this method and succeeded to segment individual nuclear pore complexes stained with gp210 and pan-FG proteins and captured by two-color STED microscopy. Test results confirmed accuracy and robustness of the method even in noisy STED images of gp210. CONCLUSIONS: Our pipeline and novel segmentation procedure may benefit end-users of SR microscopy to analyze their images and extract biologically significant quantitative data about them in user-friendly and fully automated settings. PMID- 26251638 TI - Etoposide induces cell death via mitochondrial-dependent actions of p53. AB - BACKGROUND: Etoposide has been used clinically in cancer treatment, as well as in numerous research studies, for many years. However, there is incomplete information about its exact mechanism of action in induction of cell death. METHODS: Etoposide was compared at various concentrations to characterize the mechanisms by which it induces cell death. We investigated its effects on mouse embryonic fibroblasts (MEFs) and focused on both transcriptional and non transcriptional responses of p53. RESULTS: Here we demonstrate that treatment of MEFs with higher concentrations of etoposide induce apoptosis and activate the transcription-dependent functions of p53. Interestingly, lower concentrations of etoposide also induced apoptosis, but without any evidence of p53-dependent transcription up-regulation. Treatment of MEFs with an inhibitor of p53, Pifithrin-alpha, blocked p53-dependent transcription but failed to rescue the cells from etoposide-induced apoptosis. Treatment with PES, which inhibits the mitochondrial arm of the p53 pathway inhibited etoposide-induced cell death at all concentrations tested. CONCLUSIONS: We have demonstrated that transcriptional functions of p53 are dispensable for etoposide-induced cell death. The more recently characterized effects of p53 at the mitochondria, likely involving its interactions with BCL-2 family members, are thus more important for etoposide's actions. PMID- 26251641 TI - Tubulinopathies and Their Brain Malformation Syndromes: Every TUB on Its Own Bottom. PMID- 26251642 TI - Issues in PNES Treatment. PMID- 26251644 TI - Undiplomatic immunity: epilepsy and autoimmune disease. PMID- 26251643 TI - Outcome of Newly Diagnosed Epilepsy in Children: "Drugs Don't Work in Patients Who Don't [Always] Take Them". PMID- 26251645 TI - Auras Are Frequent in Patients With Generalized Epilepsy. PMID- 26251646 TI - The Risk-Benefit Ratio for Temporal Lobe Resection in Patients with Bilateral Mesial Temporal Lobe Epilepsy. PMID- 26251647 TI - The Perimenstrual Delta Force: A Trojan Horse for Neurosteroid Effects. PMID- 26251648 TI - TALE of an SCN8A-Associated Epileptic Encephalopathy Mouse Model. PMID- 26251649 TI - DREADDnoughts Join in the Battle for Seizure Control. PMID- 26251650 TI - Blocking Astrocyte Transformation at the Dysfunctional Blood Brain Barrier. PMID- 26251651 TI - The Long and the Short of It: Seizures Induce Cardiac Remodeling and Arrhythmia. PMID- 26251652 TI - Constrained by The Matrix: Will Chloride Ions Be Set Free? PMID- 26251653 TI - Is There Equipoise Between Phenytoin and Levetiracetam for Seizure Prevention in Traumatic Brain Injury? PMID- 26251655 TI - The implications of selective attrition for estimates of intergenerational elasticity of family income. AB - Numerous studies have estimated a high intergenerational correlation in economic status. Such studies do not typically attend to potential biases that may arise due to survey attrition. Using the Panel Study of Income Dynamics - the data source most commonly used in prior studies - we demonstrate that attrition is particularly high for low-income adult children with low-income parents and particularly low for high-income adult children with high-income parents. Because of this pattern of attrition, intergenerational upward mobility has been overstated for low-income families and downward mobility has been understated for high-income families. The bias among low-income families is greater than the bias among high-income families implying that intergenerational elasticity in family income is higher than previous estimates with the Panel Study of Income Dynamics would suggest. PMID- 26251654 TI - A proteomic profile of synoviocyte lesions microdissected from formalin-fixed paraffin-embedded synovial tissues of rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the synovial joints. Early intervention followed by early diagnosis can result in disease remission; however, both early stage diagnosis and provision of effective treatment have been impeded by the heterogeneity of RA, which details of pathological mechanism are unclear. Regardless of numerous investigations of RA by means of genomic and proteomic approaches, proteins interplaying in RA synovial tissues that contain various types of synoviocytes, are not yet sufficiently understood. Hence we have conducted an HPLC/mass spectrometry-based exploratory proteomic analysis focusing on synoviocyte lesions laser-microdissected (LMD) from formalin-fixed paraffin embedded (FFPE) synovial tissues (RA, n = 15; OA, n = 5), where those of Osteoarthritis (OA) were used as the control. RESULTS: A total of 508 proteins were identified from the RA and OA groups. With the semi-quantitative comparisons, the spectral index (SpI), log2 protein ratio (R SC ) based on spectral counting, and statistical G-test, 98 proteins were found to be significant (pair-wise p < 0.05) to the RA synovial tissues. These include stromelysin-1 (MMP3), proteins S100-A8 and S100-A9, plastin-2, galectin-3, calreticulin, cathepsin Z, HLA-A, HLA-DRB1, ferritin, neutrophil defensin 1, CD14, MMP9 etc. CONCLUSIONS: Our results confirmed the involvement of known RA biomarkers such as stromelysin-1 (MMP3) and proteins S100-A8 and S100-A9, and also that of leukocyte antigens such as HLA-DRB1. Network analyses of protein protein interaction for those proteins significant to RA revealed a dominant participation of ribosome pathway (p = 5.91 * 10(-45)), and, interestingly, the associations of the p53 signaling (p = 2.34 * 10(-5)). An involvement of proteins including CD14, S100-A8/S100-A9 seems to suggest an activation of the NF-kB/MAPK signaling pathway. Our strategy of laser-microdissected FFPE-tissue proteomic analysis in Rheumatoid Arthritis thus demonstrated its technical feasibility in profiling proteins expressed in synovial tissues, which may play important roles in the RA pathogenesis. PMID- 26251656 TI - Working Memory and Response Inhibition in Patients With Bipolar I Disorder During Euthymic Period. AB - BACKGROUND: Several cognitive domains, including attention, memory, and executive functions are impaired in bipolar disorder. OBJECTIVES: This study aimed to investigate two executive functions (working memory and response inhibition) in patients with bipolar I disorder during remission of the symptoms. PATIENTS AND METHODS: In this case-control design, 30 bipolar I patients (18 to 45 years old) were matched with 30 ones in the control group in terms of age, gender, and education. The patients were selected from Roozbeh Psychiatric Hospital (a hospital affiliated to Tehran University of Medical Sciences) from May to October 2013. They were evaluated and contrasted using working memory (Spatial Span and Spatial Working Memory (SSP and SWM)) and response inhibition (Stop Signal Task (SST)) tests. RESULTS: We used independent t-tests for comparing and contrasting 2 groups on total and sub-scales scores of these 3 tests. In terms of SWM test there was a significant difference in between-group error between the two groups (P = 0.05); there was also a meaningful difference between the strategies used by two groups (P = 0.05). In SSP test, a significant difference appeared between averages of span length of the two groups. In the first and last item delays, there was also a clear difference, but the total error index was not noticeably different. In SST test, the direction error indicator in start-stop trials indicated a major difference, while in successful stops ratio, the case group had a lower ratio. In addition, reaction time to stop signs in bipolar group was meaningfully lower than the control group. CONCLUSION: In conclusion, even during remission phase, executive dysfunction is detectable at least in some areas in patients with bipolar disorder. PMID- 26251657 TI - The Help of Hypnodontics to a Patient With Scleroderma - Case Report. AB - INTRODUCTION: Scleroderma, or systemic sclerosis, is a chronic connective tissue disease generally classified as one of the autoimmune rheumatic diseases. CASE PRESENTATION: A 58-year-old woman was informed of her scleroderma, while receiving oral prosthetic rehabilitation. Mouth opening limitation had unfortunately led to treatment interruption. The psychological load of the disease itself, along with dental treatment cessation, resulted in patient's disappointment and social separation. Three hypnosis sessions were conducted for normalizing patient's psychological status primarily, and for the facilitation of dental treatment, as well. The range of mouth opening changed from 3.7 to 6.2 cm, allowing for easier entrance of dental appliances into the mouth for completion of prosthetic rehabilitation. With the tooth prostheses in place, the patient gained more social confidence and started sharing her experience with other patients with the same condition. DISCUSSION: This case illustrates that hypnosis therapy may prove beneficial for patients with limited mouth opening secondary to scleroderma, facilitating the prosthetic rehabilitation programs for both dental specialists and patients, with a secondary important impact on the patient's social perception of himself. PMID- 26251658 TI - Concurrent Validity of the Behavior Rating Inventory of Executive Function in Children With Attention Deficit Hyperactivity Disorder. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in which impairment of executive functions plays an important role. OBJECTIVES: The main objective of this study was to assess the validity of the Behavior Rating Inventory of Executive Function (BRIEF) in children with ADHD. PATIENTS AND METHODS: Thirty children, aged 7-12 years, attending the child and adolescent clinic of Roozbeh hospital and diagnosed with ADHD according to interview with a child and adolescent psychiatrist, formed our ADHD group. In contrast, thirty participants of the control group were selected from 7 to 12 year-old students according to Conners' Teacher/Parent Rating Scale and did not have ADHD. The kiddie schedule for affective disorders and schizophrenia-present and lifetime version-Persian version was also completed for all children to rule out other psychiatric disorders. After oral consent, parents of 60 children (ADHD = 30, control = 30), completed three questionnaires of ADHD Rating Scale-IV, Conners' Parent Rating Scale-Revised: Short Version and BRIEF. RESULTS: Children in ADHD group got higher scores than those in the control group in all subscales and indices of BRIEF (P < 0.001). There were also good correlations between subscales and indices of BRIEF and the two other rating scales (P < 0.001). CONCLUSION: BRIEF could be used as a valid tool to assess behavioral aspects of executive functions, especially to discriminate children with ADHD and normal ones. PMID- 26251659 TI - Comparing Mindfulness-Based Group Therapy With Treatment as Usual for Opioid Dependents: A Pilot Randomized Clinical Trial Study Protocol. AB - BACKGROUND: In response to high burden of opioid abuse in Iran, Ministry of Health has launched a large-scale opioid maintenance treatment program, delivered through a network of certified drug treatment centers. To promote opioid pharmacotherapies, there is an urgent need to develop and introduce evidence based psychosocial interventions into the network. PATIENTS AND METHODS: This is a randomized clinical trial (RCT) to investigate feasibility and effectiveness of adding mindfulness-based group therapy to opioid pharmacotherapies as compared to opioid pharmacotherapies alone. The primary outcomes were treatment retention and percentage of weekly morphine, methamphetamine, and benzodiazepine negative tests. DISCUSSION: This is the first RCT that explores the effectiveness of mindfulness-based relapse prevention group therapy among opioid dependent clients in Iran. The feasibility of group therapy and comparison of outcomes in intervention and control groups should be discussed in the outcome article. PMID- 26251660 TI - Effectiveness of Acceptance-Commitment Therapy on Anxiety and Depression among Patients on Methadone Treatment: A Pilot Study. AB - BACKGROUND: Substance dependence disorder is a psychiatric disorders with different factors that influence its nature, severity, outcome, and treatment options. OBJECTIVES: This study evaluates the effectiveness of Acceptance Commitment Therapy (ACT) to decrease anxiety and depression in patients with opioid dependencies who are undergoing methadone maintenance treatment (MMT). MATERIALS AND METHODS: The present study was done in Mashhad from 2011-2012. Twenty-eight patients (18-50 yr) with opioid dependency who were on MMT were selected using purposive sampling and were divided equally between case and control groups. The case group received 8 sessions of individual psychotherapy with ACT. The level of depression and anxiety of these patients were measured using the Beck Depression Inventory-II and Beck Anxiety Inventory before the initiation of ACT as a pretest, 2 weeks after the termination of ACT as the posttest, and 3-months after the termination as a follow-up. The collected data was analyzed with SPSS (ver. 20) using chi2, paired t-test, ANOVA, and MANOVA. RESULTS: The pretest-posttest-follow up of anxiety showed no significant differences between the two groups (P = 0.05); however, the case group had lower depression scores in the posttest and follow-up than the control group (P = 0.04). Evaluating the results of the case group revealed that depression significantly decreased in the posttest group when compared to the pretest (P = 0.01) and there were no significant decreases in the follow up compared to the pretest (P = 0.34). CONCLUSION: Short-term ACT for opioid dependent patients on MMT are not associated with a significant decrease in the level of anxiety; however, it is associated with a significant decrease in the level of depression. Nonetheless, this reduction was not maintained long term. PMID- 26251661 TI - Effect of Psycho Education on Depression and Anxiety Symptoms in Patients on Hemodialysis. AB - BACKGROUND: Hemodialysis as a solution for patients with chronic renal failure is a stressful process. Anxiety and depression after hemodialysis could have negative impacts on quality of life, treatment and prognosis of the disease. Some studies indicated that educating patients prior to hemodialysis could enhance patients' quality of life and increase the likelihood of their survival. OBJECTIVES: This study investigated psychological impacts of psycho education on anxiety and depression symptoms in patients under dialysis. PATIENTS AND METHODS: This was a prospective, experimental intervention study with pretest and post test. Eligible patients (n = 60) were selected randomly from dialysis center of Imam Khomeini Hospital in Sari in 2009. Hospital Anxiety Depression Scale (HADS) score of patients were eight or greater. They were divided into two matched groups. In one group, patients were given psycho education during three sessions of one-hour, while patients in the control group did not receive any education. HADS was completed for both groups before dialysis and one month after the end of educational sessions. The data were compared and analyzed using paired t-test and Chi-square test. RESULTS: Psycho education decreased depression score (P < 0.001) and the HADS (P = 0.008) significantly. These decreases were not significant for anxiety scores of patients (P = 0.185). CONCLUSION: This research indicated that psycho education based on the designed protocol decreased the scores of depression and total scores of HADS. PMID- 26251662 TI - Alcohol, Cannabinoids, and Opioids Abuse and Dependence Among Psychiatric Inpatients. AB - BACKGROUND: While substance abuse among psychiatric patients is a widely known problem in clinical practice, there is no local study about prevalence and co occurrence of substance abuse in north of Iran. OBJECTIVES: The present study was designed to determine the frequency of smoking, alcohol, opioid and cannabinoid substances, and prescription medicines abuse or dependence among Psychiatric Inpatients. PATIENTS AND METHODS: A cross-sectional 2-year case register study was conducted on all (n = 492) psychiatric inpatients of Zare Psychiatric Hospital in Sari located in north of Iran. The data were obtained by using a standardized and validated questionnaire that contained demographic information along with information on co-morbid psychiatric problems and alcohol, cannabinoids, opioids, and cigarette usage. RESULTS: The mean (+/- SD) age of samples was 39.9 (+/- 11.9) years and male:female ratio was 3.6. Opium with or without using other illicit substances was the most frequently abused substance (67%). Significant association were found between illicit substance abuse and demographic variables of male gender, a low level of literacy, living in the urban area, unemployment, cigarette smoking, and young age. There were statistically significant association between schizophrenia and substance abuse (P < 0.001). CONCLUSION: High prevalence of dual diagnosis warrants attention to the management of substance misuse while treating mental disorders, and should be incorporated in the holistic treatment plan of psychiatric inpatients. PMID- 26251663 TI - A Fresh Look at the Potential Mechanisms of Progressive Muscle Relaxation Therapy on Depression in Female Patients With Multiple Sclerosis. AB - BACKGROUND: According to the World Health Organization (WHO) report released in 2000, about 121 million people worldwide suffer from depression. The major depressive disorder (MDD) among multiple sclerosis (MS) patients is one of the most common mood disorders experienced during life. MS patients who simultaneously suffer from depression have reported more severe symptoms of disease and slower adaptation to new conditions, which ultimately increase the cost of treatment. OBJECTIVES: The aim of this study was to assess the effectiveness of progressive muscle relaxation therapy (PMRT) as an adjunctive therapy for reducing level of depression for MS patients. MATERIALS AND METHODS: This research had the randomized controlled trial design with pre and posttest. Thirty female patients based on criteria of MS and MDD disease, were selected from the MS Society of Shiraz, Iran. Beck Depression Inventory (BDI-II) was administered at pre and posttest. The participants were randomly allocated to two groups (experimental and control). Twelve sessions of PMRT using Bernstein and Borkovec's method were held for the experimental group. Levin's test, covariance and ANOVA with repeated measures were used for data analysis. RESULTS: Experimental and control groups were compared before and after treatment. Analysis of covariance showed that seven levels of depression decreased in the experimental group and analysis of repeated measure showed that 49% of the changes were related to PMRT. CONCLUSION: According to the results, PMRT is effective in reducing depression. This therapy enables patients to reach relaxation quickly, and thus can cope with depression reactions effectively. PMID- 26251664 TI - Psychiatrists and Their Role in an Integrative Approach to Sexual Problems. AB - Sexuality is a unit part of humans that has been evaluated as several fragmented particles for years. Although many biomedical and psychosocial approaches have been developed in the field of sex, these approaches usually have not been led to the complete satisfaction of the patients. It seems that for a comprehensive evaluation and management of the sexual problems, the unity of sex should be respected and the biopsychosocial multilayer aspects of the sex should be apprehended. Psychiatry is a unique point that both biomedical and psychosocial sciences reach each other. Therefore, psychiatrists should play a critical role as a modulator in the multidisciplinary team for management of the sexual problems. In this regard, comprehensive training of psychiatrists is highly recommended. One of the primary steps could be developing the psychosexual fellowship. PMID- 26251665 TI - Changes in blood pressure, glucose levels, insulin secretion and anthropometry after long term exposure to antiretroviral therapy in South African women. AB - BACKGROUND: A number of metabolic abnormalities, such as dysglycaemia, insulin resistance, lipodystrophy and dyslipidaemia, are associated with the use of antiretroviral drugs. We aimed to assess the effects of long-term antiretroviral exposure on blood pressure, glycaemia, insulin secretion and anthropometric measures in black South African women. METHODS: A convenience sample of HIV infected women on first-line ART for a median of 16 months at baseline, had the following evaluations twice, at baseline and after approximately 5 years: anthropometry, including skin fold thicknesses, blood pressure, oral glucose test, and insulin. Insulin sensitivity and secretion (HOMA-IR, IGI and DIo) were estimated. RESULTS: At baseline more than half the 103 women were using stavudine and efavirenz. The median interval between baseline and follow-up evaluation was 66 months. Weight, waist circumference, and waist-hip ratio increased over time, while limb skinfold thickness decreased over time. Systolic and diastolic blood pressure increased significantly and the proportion of participants with hypertension increased from 3.9 to 15.5% (p < 0.001). There were increases from baseline in plasma glucose concentrations at 30 and 120 min; insulin concentrations at 0 and 30 min; and IGI and DIo. The proportion of participants with diabetes increased from 1 to 7.5% (p = 0.070). CONCLUSION: In black South African women with long-term exposure to ART, increases in hypertension and possibly diabetes were observed. Participants experienced an increase in central fat and a decrease in peripheral fat distribution. Early identification and management of these metabolic changes are important, especially in a region with the highest HIV-infected population in the world. PMID- 26251666 TI - Cardio-metabolic and immunological impacts of extra virgin olive oil consumption in overweight and obese older adults: a randomized controlled trial. AB - BACKGROUND: Both aging and obesity are related to dysregulated immune function, which may be responsible for increased risk of infection and also chronic non infectious diseases. Dietary lipids have been shown to impact immune and inflammatory responses and cardio-metabolic risk factors. No information on the impact of olive oil on immune responses of overweight and obese older adults is available. OBJECTIVE: We aimed to determine the effect of replacing oils used in a typical American diet with extra virgin olive oil for 3 months on immune responses and cardio-metabolic risk factors in overweight and obese older adults. METHODS: This was a randomized, single-blinded and placebo-controlled trial in 41 overweight or obese participants (aged >= 65) who consumed a typical American diet. Participants in the control (CON, n = 21) group were provided with a mixture of corn, soybean oil and butter, and those in the olive oil (OO, n = 20) group, with extra virgin olive oil, to replace substitutable oils in their diet. At baseline and 3 months, we measured blood pressure, biochemical and immunological parameters using fasting blood, and delayed-type hypersensitivity (DTH) skin response. RESULTS: Compared to the CON group, the OO group showed decreased systolic blood pressure (P < 0.05), a strong trend toward increased plasma HDL-C concentrations (P = 0.06), and increased anti-CD3/anti-CD28 stimulated T cell proliferation (P < 0.05). No differences were found in T cell phenotype, cytokine production, and DTH response between the two groups. CONCLUSIONS: Our results indicate that substitution of oils used in a typical American diet with extra virgin olive oil in overweight and obese older adults may have cardio-metabolic and immunological health benefits. This trial was registered at clinicaltrials.gov as NCT01903304. PMID- 26251667 TI - Exercise training improves liver steatosis in mice. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is rapidly turning into the most common liver disorder worldwide. One of the strategies that has been shown to effectively improve NAFLD is regular exercise, which seems to lower steatosis partly independent of weight loss. However, limited data are available about the mechanisms involved. The aim of the present study was to identify the mechanisms underlying the effect of regular exercise on liver steatosis. METHODS: Non-obese male mice were rendered steatotic by feeding a sucrose-enriched choline-deficient diet. They were then subjected to daily treadmill running for three weeks, whereas the control mice remained sedentary. RESULTS: Compared to the untrained mice, trained mice showed similar adipose tissue mass but had significantly reduced size of lipid droplets in the liver coupled with a reduction in liver triglyceride content (~30 %, P < 0.05). Levels of various plasma lipid parameters and plasma glucose were similar between the trained and untrained mice, whereas levels of hepatic glycogen were significantly higher in the trained mice. Hepatic triglyceride secretion rate and de novo lipogenesis were unchanged between the two sets of mice, as were indicators of lipolysis and autophagy. Finally, whole genome expression profiling indicated a mild stimulatory effect of exercise training on PPARalpha-mediated regulation of oxidative metabolism, including fatty acid oxidation. CONCLUSIONS: Taken together, our study suggests that the lowering of hepatic steatosis by repeated exercise is likely due to activation of fuel oxidation pathways in liver. PMID- 26251668 TI - A comparison of the effects of rhythm and robotic interventions on repetitive behaviors and affective states of children with Autism Spectrum Disorder (ASD). AB - Repetitive behaviors and poor affect regulation are commonly seen in children with Autism Spectrum Disorder (ASD). We compared the effects of two novel interventions - rhythm and robotic therapies, with those of a standard-of-care intervention, on the repetitive behaviors and affective states of 36 children with ASD between 5 and 12 years using a randomized controlled trial design. We coded for frequencies of sensory, negative, and stereotyped behaviors and the duration of positive, negative, and interested affective states in children during early, mid, and late training sessions. In terms of repetitive behaviors, in the early session, the rhythm and robot groups engaged in greater negative behaviors, whereas the comparison group engaged in greater sensory behaviors. With training, the rhythm group reduced negative behaviors whereas there were no training-related changes in the other groups. In terms of affective states, the rhythm and robot groups showed greater negative affect, whereas the comparison group demonstrated greater interested affect across all sessions. With training, the rhythm group showed a reduction in negative affect and an increase in interested affect whereas the robot group showed a reduction in positive affect. Overall, it appears that rhythm-based interventions are socially engaging treatment tools to target core impairments in autism. PMID- 26251669 TI - Promising upshot of silver nanoparticles primed from Gracilaria crassa against bacterial pathogens. AB - BACKGROUND: The study on newer antimicrobial agent from metal based nano materials has augmented in recent years for the management of multidrug resistance microorganisms. In our present investigation, we synthesized silver nanoparticles (AgNP's) from red algae, Gracilaria crassa as beginning material which effectively condensed the silver ions to silver nanoparticles with less price tag and no risk. METHODS: Silver nanoparticles were prepared by simple reaction of 1 mM AgNO3 with G. crassa extracts at room temperature. The fabricated AgNP's were subjected for characterization and screened against various microorganisms for antibacterial activity. RESULTS: UV-Vis spectroscopy (200-800 nm), XRD, FESEM and EDAX, were performed for AgNP's. UV-Vis spectroscopy demonstrated the absorption edge at 443 nm and EDAX pattern is purely due to the particle size and face centered cubic (fcc) symmetry of nanoparticles. Average size lays at 122.7 nm and zeta potential was found to be -34.9 mV. The antibacterial outcome of synthesized AgNP's (at the dose of 20 and 40 ug/ml) was evaluated against Escherichia coli, Proteus mirabilis, Bacillus subtilis and Pseudomonas aeruginosa. The mechanism of synthesized AgNP's bactericidal bustle is discussed in terms of interaction with the cell membrane of bacteria. The activity was found to be sky-scraping in a dose dependent manner. CONCLUSION: Thus, environmental friendly, cost effective, non hazardous stable nanoparticles were prepared by green synthesis using red algae, G. crassa. Synthesized G. crassa AgNP's were in acceptable size and shape. Further, it elicits better bactericidal activity against microorganism. This will assure the out put of superior antibacterial formulation for near future. PMID- 26251670 TI - Are traumatic bilateral adrenal injuries associated with higher morbidity and mortality?-A prospective observational study. AB - BACKGROUND: Traumatic bilateral adrenal injuries are uncommon. Adrenal injuries are overall associated with worse outcome than non-adrenal injuries. However, direct comparative evidence between unilateral and bilateral adrenal injuries is unavailable in literature. This study aims to investigate clinical significance of bilateral adrenal hematomas in terms of injury severity, morbidity and mortality. METHODS: All blunt trauma abdomen patients with adrenal gland involvement on initial CECT scans of abdomen presenting to our Level 1 trauma centre over 21 months were prospectively included and followed-up. Patients were divided into unilateral and bilateral adrenal hematoma groups. For all patients, mechanism of injury, initial pulse, blood pressure, respiratory rate, Glasgow Coma Scale (GCS) scores, Injury Severity Score (ISS), New Injury Severity Score (NISS), length of ICU stay (LOI), length of hospital stay (LOS), total blood products (TBP) received were recorded. Final outcome was noted as complete recovery; discharge with poor prognosis and death. Quantitative parameters between both groups were compared using appropriate statistical tests and P < 0.05 was considered significant. RESULTS: Forty seven patients were detected to have adrenal hematomas, 34 with unilateral (30 right and 4 left) and 13 with bilateral involvement. An oval mass replacing the gland was the most common appearance of injury (35/60) and periadrenal fat stranding was most common associated finding (47/60). Patients with bilateral adrenal hematoma had significantly lower GCS (13 vs 15, P < 0.01), ISS (38 vs 22, P < 0.01), NISS (47 vs 21, P < 0.01), LOI as proportion of LOS (91.7 % vs 10.5 %, P = 0.01) and TBP received (10 vs 4 units, P < 0.05). Outcome in bilateral group was comparatively worse with higher proportion of deaths or discharge with poor prognosis (P = 0.000). CONCLUSIONS: Patients with bilateral adrenal injury are associated with higher injury severity, morbidity and mortality compared to unilateral adrenal injury. PMID- 26251671 TI - Connecting Students to Mental Health Care: Pilot Findings from an Engagement Program for School Nurses. AB - Schools function as the major provider of mental health services (MHS) for youth, but can struggle with engaging them in services. School nurses are well positioned to facilitate referrals for MHS. This pilot study examined the feasibility, acceptability, and preliminary efficacy of an engagement protocol (EP) designed to enhance school nurses' utilization of evidence-based engagement practices when referring youth to MHS. Participants were six school nurses and twenty-five adolescents in a large, urban school district. School nurses reported positive attitudes towards the EP, suggesting that they found it feasible and acceptable. Though there were small increases in school nurses' use of engagement practices and in adolescents' readiness for services following training, due to limited sample size, differences were not statistically significant. Still, pilot results suggest preliminary efficacy of training school nurses to strategically implement evidence-based engagement practices to increase adolescents' engagement in MHS. PMID- 26251672 TI - In vitro reversion of activated primary human hepatic stellate cells. AB - BACKGROUND: Liver fibrosis is characterized by the excessive formation and accumulation of matrix proteins as a result of wound healing in the liver. A main event during fibrogenesis is the activation of the liver resident quiescent hepatic stellate cell (qHSC). Recent studies suggest that reversion of the activated HSC (aHSC) phenotype into a quiescent-like phenotype could be a major cellular mechanism underlying fibrosis regression in the liver, thereby offering new therapeutic perspectives for the treatment of liver fibrosis. Whether human HSCs have the ability to undergo a similar reversion in phenotype is currently unknown. The aim of the present study is to identify experimental conditions that can revert the in vitro activated phenotype of primary human HSCs and consequently to map the molecular events associated with this reversion process by gene expression profiling. RESULTS: We find that epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2) synergistically downregulate the expression of ACTA2 and LOX in primary human aHSCs. Their combination with oleic acid, palmitic acid, and retinol further potentiates a more quiescent-like phenotype as demonstrated by the abundant presence of retinyl ester-positive intra-cytoplasmic lipid droplets, low expression levels of activation markers, and a reduced basal as well as cytokine-stimulated proliferation and matrix metalloproteinase activity. Gene expression profiling experiments reveal that these in vitro reverted primary human HSCs (rHSCs) display an intermediary phenotype that is distinct from qHSCs and aHSCs. Interestingly, this intermediary phenotype is characterized by the increased expression of several previously identified signature genes of in vivo inactivated mouse HSCs such as CXCL1, CXCL2, and CTSS, suggesting also a potential role for these genes in promoting a quiescent-like phenotype in human HSCs. CONCLUSIONS: We provide evidence for the ability of human primary aHSCs to revert in vitro to a transitional state through synergistic action of EGF, FGF2, dietary fatty acids and retinol, and provide a first phenotypic and genomic characterization of human in vitro rHSCs. PMID- 26251674 TI - Chemoenzymatic Synthesis of ortho-, meta-, and para-Substituted Derivatives of l threo-3-Benzyloxyaspartate, An Important Glutamate Transporter Blocker. AB - A simple, three-step chemoenzymatic synthesis of l-threo-3-benzyloxyaspartate (l TBOA), as well as l-TBOA derivatives with F, CF3, and CH3 substituents at the aromatic ring, starting from dimethyl acetylenedicarboxylate was investigated. These chiral amino acids, which are extremely difficult to prepare by chemical synthesis, form an important class of inhibitors of excitatory amino acid transporters involved in the regulation of glutamatergic neurotransmission. In addition, a new chemical procedure for the synthesis of racemic mixtures of TBOA and its derivatives was explored. These chemically prepared racemates are valuable reference compounds in chiral-phase HPLC to establish the enantiopurities of the corresponding chemoenzymatically prepared amino acids. PMID- 26251673 TI - Proteogenomic analysis of psoriasis reveals discordant and concordant changes in mRNA and protein abundance. AB - BACKGROUND: Psoriasis is a chronic disease characterized by the development of scaly red skin lesions and possible co-morbid conditions. The psoriasis lesional skin transcriptome has been extensively investigated, but mRNA levels do not necessarily reflect protein abundance. The purpose of this study was therefore to compare differential expression patterns of mRNA and protein in psoriasis lesions. METHODS: Lesional (PP) and uninvolved (PN) skin samples from 14 patients were analyzed using high-throughput complementary DNA sequencing (RNA-seq) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: We identified 4122 differentially expressed genes (DEGs) along with 748 differentially expressed proteins (DEPs). Global shifts in mRNA were modestly correlated with changes in protein abundance (r = 0.40). We identified similar numbers of increased and decreased DEGs, but 4-fold more increased than decreased DEPs. Ribosomal subunit and translation proteins were elevated within lesions, without a corresponding shift in mRNA expression (RPL3, RPS8, RPL11). We identified 209 differentially expressed genes/proteins (DEGPs) with corresponding trends at the transcriptome and proteome levels. Most DEGPs were similarly altered in at least one other skin disease. Psoriasis-specific and non-specific DEGPs had distinct cytokine-response patterns, with only the former showing disproportionate induction by IL-17A in cultured keratinocytes. CONCLUSIONS: Our findings reveal global imbalance between the number of increased and decreased proteins in psoriasis lesions, consistent with heightened translation. This effect could not have been discerned from mRNA profiling data alone. High-confidence DEGPs were identified through transcriptome-proteome integration. By distinguishing between psoriasis-specific and non-specific DEGPs, our analysis uncovered new functional insights that would otherwise have been overlooked. PMID- 26251675 TI - MicroRNA-101 is repressed by EZH2 and its restoration inhibits tumorigenic features in embryonal rhabdomyosarcoma. AB - BACKGROUND: Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma arising from myogenic precursors that have lost their capability to differentiate into skeletal muscle. The polycomb-group protein EZH2 is a Lys27 histone H3 methyltransferase that regulates the balance between cell proliferation and differentiation by epigenetically silencing muscle-specific genes. EZH2 is often over-expressed in several human cancers acting as an oncogene. We previously reported that EZH2 inhibition induces cell cycle arrest followed by myogenic differentiation of RMS cells of the embryonal subtype (eRMS). MiR-101 is a microRNA involved in a negative feedback circuit with EZH2 in different normal and tumor tissues. To that, miR-101 can behave as a tumor suppressor in several cancers by repressing EZH2 expression. We, therefore, evaluated whether miR-101 is de-regulated in eRMS and investigated its interplaying with EZH2 as well as its role in the in vitro tumorigenic potential of these tumor cells. RESULTS: Herein, we report that miR-101 is down-regulated in eRMS patients and in tumor cell lines compared to their controls showing an inverse pattern of expression with EZH2. We also show that miR-101 is up-regulated in eRMS cells following both genetic and pharmacological inhibition of EZH2. In turn, miR-101 forced expression reduces EZH2 levels as well as restrains the migratory potential of eRMS cells and impairs their clonogenic and anchorage-independent growth capabilities. Finally, EZH2 recruitment to regulatory region of miR-101-2 gene decreases in EZH2-silenced eRMS cells. This phenomenon is associated to reduced H3K27me3 levels at the same regulatory locus, indicating that EZH2 directly targets miR-101 for repression in eRMS cells. CONCLUSIONS: Altogether, our data show that, in human eRMS, miR-101 is involved in a negative feedback loop with EZH2, whose targeting has been previously shown to halt eRMS tumorigenicity. They also demonstrate that the re-induction of miR-101 hampers the tumor features of eRMS cells. In this scenario, epigenetic dysregulations confirm their crucial role in the pathogenesis of this soft tissue sarcoma. PMID- 26251676 TI - Left Aberrant Gastric Vein Causing Isolated Left Hepatic Portal Venous Gas Secondary to an Incarcerated Diaphragmatic Hernia. AB - BACKGROUND: Hepatic portal venous gas (HPVG) is an ominous radiological sign suggestive of underlying intestinal sepsis, infection or trauma. Portal pneumatosis secondary to gastric pathologies is rare. CASE REPORT: We report a rare case of a 34-year-old man who presented with acute epigastric pain and vomiting, diagnosed to have an incarcerated diaphragmatic hernia causing gastric pneumatosis and resultant portal venous gas. CONCLUSIONS: Our case highlights an unusual presentation of gastric pneumatosis secondary to an incarcerated hiatal hernia with resultant portal venous gas involving only the left lobe of the liver. An aberrant left gastric vein was responsible for this phenomenon in our case. A sound understanding of anatomical variants is thus crucial to radiological diagnosis. PMID- 26251677 TI - Neuroimaging of Cerebral Venous Thrombosis (CVT) - Old Dilemma and the New Diagnostic Methods. AB - BACKGROUND: Cerebral venous thrombosis is a relatively uncommon neurologic disorder that is potentially reversible with prompt diagnosis and appropriate medical care. The pathogenesis is multifactorial and the disease may occur at any age. CVT is often associated with nonspecific symptoms. Radiologists play a crucial role in patient care by providing early diagnosis through interpretation of imaging studies. Underdiagnosis or misdiagnosis can increase the risk of severe complications, including hemorrhagic stroke or death. The purpose of this study is to investigate radiological and clinical characteristics of cerebral venous thrombosis (CVT) based on material from 34 patients under care of our hospital. MATERIAL/METHODS: A total of 34 patients were diagnosed with CVT from August 2009 until March 2015. A clinical and radiological database of patients with final diagnosis of CVT was analyzed. RESULTS: Patient group included 22 women and 12 men at a mean age of 48.7 years (ranging from 27 to 77 years). In the study group 8 patients (23.5%) suffered from hemorrhagic infarction, whereas 16 patients (47%) were diagnosed with venous infarction without hemorrhage. Thirty patients (88%) had transverse sinus thrombosis. CONCLUSIONS: According to our study, CVT was more prevalent in women. Transverse sinus was the most common location. Among all age groups, the highest prevalence was seen in the fifth decade (n=14). Contrast-enhanced CT and MR venography were the most sensitive imaging modalities. PMID- 26251678 TI - The Epidemiological Scale of Alzheimer's Disease. AB - Alzheimer's disease (AD) has increased from a few cases in a country at the beginning of the 20th century to an incidence of recording a case every 7 seconds in the world. From a rare disease it has reached the top 8 of major health problems in the world. One of the epidemiological problems of AD is the fact that authors from different countries use different reporting units. Some report numbers to 100,000 inhabitants, others to 1,000 inhabitants and others report the total number of cases in a country. Standardization of these reports is strictly necessary. The rise in incidence and prevalence with age is known, but interesting to see is that the incidence and prevalence do not rise in a parallel manner with age as simple logic would assume. Between the ages of 60 and 90, the incidence in men increases two times and in women 41 times, prevalence increase in men is 55.25-fold and in women 77-fold. Regarding the women/men ratio, the incidence is 20.5-fold increased, and prevalence is merely 1.3936-fold increased. These numbers raise concerns about the evolution of the disease. Regarding mild cognitive impairment (MCI)/AD ratio, only about 1 in 2 people get AD (raising?) issues about the pathogenic disease relatedness. PMID- 26251679 TI - Do Biliary Salts Have Role on Acute Kidney Injury Development? AB - Acute kidney injury (AKI) is a major complication in patients with acute liver failure and chronic liver disease. Hemodynamic changes appear to be the principal alterations in these conditions, therefore there should be no known structural abnormalities responsible for AKI. On the other hand, several authors have published data on structural changes known as bile cast nephropathy or cholemic nephrosis, which basically consist of the presence of bile casts in tubular lumen analogous to those observed in myeloma. Although these findings are well documented, there is a lack of reproducibility by other authors. This paper aims to discuss, through evidence-based medical literature, the role of biliary salts on kidney injury development. PMID- 26251680 TI - Categorization of Fetal Heart Rate Decelerations in American and European Practice: Importance and Imperative of Avoiding Framing and Confirmation Biases. AB - Interpretation of electronic fetal monitoring (EFM) remains controversial and unsatisfactory. Fetal heart rate (FHR) decelerations are the commonest aberrant feature on cardiotocographs and considered "center-stage" in the interpretation of EFM. A recent American study suggested that the lack of correlation of American three-tier system to neonatal acidemia may be due to the current peculiar nomenclature of FHR decelerations leading to loss of meaning. The pioneers like Hon and Caldeyro-Barcia classified decelerations based primarily on time relationship to contractions and not on etiology per se. This critical analysis debates pros and cons of significant anchoring/framing and confirmation biases in defining different types of decelerations based primarily on the shape (slope) or time of descent. It would be important to identify benign early decelerations correctly to avoid unnecessary intervention as well as to improve the positive predictive value of the other types of decelerations. Currently the vast majority of decelerations are classed as "variable". This review shows that the most common rapid decelerations during contractions with trough corresponding to peak of contraction cannot be explained by "cord-compression" hypothesis but by direct/pure (defined here as not mediated through baro-/chemoreceptors) or non hypoxic vagal reflex. These decelerations are benign, most likely and mainly a result of head-compression and hence should be called "early" rather than "variable". Standardization is important but should be appropriate and withstand scientific scrutiny. Significant framing and confirmation biases are necessarily unscientific and the succeeding three-tier interpretation systems and structures embodying these biases would be dysfunctional and clinically unhelpful. Clinical/pathophysiological analysis and avoidance of flaws/biases suggest that a more physiological and scientific categorization of decelerations should be based on time relationship to contractions alone irrespective of shape or descent time as indeed proposed by pioneers like Hon and Caldeyro-Barcia. Such meaningful categorization, apart from being a scientific necessity, could improve the practical performance of three-tier FHR interpretation systems and possibly application of dependent complementary techniques like fetal ECG/pulse oximetry/computer-aided analysis, thus facilitating future progress in the field of intrapartum fetal monitoring. PMID- 26251681 TI - One-Step Approach to Treating Venous Insufficiency. AB - BACKGROUND: Patients with venous insufficiency can be treated with office-based, minimally invasive means like radiofrequency ablation (RFA) and ultrasound-guided foam sclerotherapy (UGFS). Traditional treatment involves ablation of the great saphenous vein (GSV) and the short saphenous vein (SSV) with RFA as a first step. The remaining refluxing tributaries are treated at a later session with UGFS or microphlebectomy. This approach is associated with an increased risk of thrombophlebitis while awaiting the second procedure. We, instead, elected to treat all the refluxing veins in one procedure which combines RFA of the truncal and perforating vein with UGFS to the accessory and tributary veins. METHODS: A controlled non-randomized clinical trial, in which a total of 72 extremities were treated for vein incompetence in 63 consecutive patients aged 26 - 78 years, was conducted. Sixty-three extremities (87.5%) received treatment for reflux in GSV, 10 extremities (13.9%) were treated for reflux in SSV, and 11 (15.3%) were treated for reflux in the perforators. Reflux duration > 1 second to increase specificity and truncal vein diameter > 5 mm were identified in the treated limbs. The treatment was performed at our office and it involved delivering radiofrequency thermal energy to the truncal and perforating vein and then using foam sclerotherapy with the guidance of ultrasound to close the tributary and accessory veins in a single procedure. The results were monitored at 1 week and 6 weeks post-operatively by venous duplex ultrasound. RESULTS: One hundred percent of the treated GSV and SSV and 91.7% of tributary veins were completely closed after the index procedure. Only 10 of 72 extremities (13.9%) needed a follow-up treatment to achieve closure of the perforator and accessory veins. By combining RFA with UGFS, our cohort did not experience thrombophlebitis or deep vein thrombosis (DVT) post-operatively. No major or minor complications were found upon follow-up evaluation. CONCLUSION: We believe that combining RFA with UGFS in a solo practice lowers the incidence of thrombophlebitis in the tributaries. Using this approach allowed us to achieve more complete resolution of venous reflux disease with lower complication rates in comparison with the popular staged strategy. This could have implications for financial savings to both the patient and the health system. PMID- 26251682 TI - Defunctioning Ileostomy Reversal Rates and Reasons for Delayed Reversal: Does Delay Impact on Complications of Ileostomy Reversal? A Study of 170 Defunctioning Ileostomies. AB - BACKGROUND: Temporary defunctioning ileostomy can reduce the consequences of anastomotic leak following low anterior resection. However, some patients never have their ileostomy reversed and in other cases the time to reversal of ileostomy can be delayed. The aim of this study was to identify the ileostomy closure rate following anterior resection, time to closure of ileostomy, reasons for delay in reversal and whether delay was associated with an increased complication rate. METHODS: Data were collected retrospectively on consecutive patients undergoing defunctioning ileostomy following anterior resection for rectal cancer, between January 2009 and August 2013. Data were collected on reversal of ileostomy rates, time to reversal, reasons for delayed reversal (defined as > 6 months) and complications following reversal. RESULTS: One hundred seventy patients were studied (median age 69 years, range 41 - 90 years), of whom 117 (69%) were male. One hundred twenty-seven (75%) patients had their ileostomies reversed. Median time to reversal was 6 months (range 1 - 42). In 63 patients who had delayed reversal, reasons were adjuvant chemotherapy (22, 35%), medical illness (14, 22%), anastomotic leak (9, 14%), and others (4, 7%). Postoperative complications occurred in 33 patients (26%). There was no postoperative mortality. Univariate analysis showed that delayed reversal was associated with an increased rate of complications and longer length of hospital stay following reversal (P < 0.05). CONCLUSIONS: One in four defunctioning ileostomies are not closed following anterior resection in our unit. Of those that are closed, approximately 50% have delayed closure beyond 6 months which is associated with increased risk of complications following their ileostomy reversal. PMID- 26251683 TI - Minimally Symptomatic Atrial Fibrillation Patients Derive Significant Symptom Relief Following Rate Control or Rhythm Control Therapy. AB - BACKGROUND: It can be challenging to convince asymptomatic to minimally symptomatic patients to pursue treatment of their atrial fibrillation (AF). We hypothesized that once in sinus rhythm, asymptomatic to minimally symptomatic patients would realize they were compensating for moderate symptoms, and that we could quantify this via the Canadian Cardiovascular Society Severity of AF (CCS SAF) score. METHODS: All patients in our study come from the Symptom Mitigation in Atrial Fibrillation (SMART) study. Upon enrollment all patients were assigned a CCS-SAF score. Patients receiving a CCS-SAF score of 0 or 1 that elected to pursue intervention were contacted by phone and asked about their symptoms post intervention as compared to pre-intervention. Paired t-test was used for analysis. RESULTS: Out of 800 patients in the SMART study to date, 48 patients have qualified for our phone survey and presented for follow-up in our clinic. In our cohort, the revised pre-intervention CCS-SAF score was 1.69 +/- 1.36 and the post-intervention CCS-SAF score was 0.52 +/- 0.80. Thirty-seven patients reported symptom improvement; those who improved were on average 72.4% improved from baseline. CONCLUSIONS: We conclude asymptomatic to minimally symptomatic AF patients benefit from therapy and should be offered intervention despite lack of symptoms. PMID- 26251684 TI - Efficacy and Clinical Characteristics of Liraglutide in Japanese Patients With Type 2 Diabetes. AB - BACKGROUND: Liraglutide was first released in Japan as a long-acting once-daily glucagon-like peptide-1 receptor agonist. The maximum dose in Japan is 0.9 mg/day, which is half of that used in the United States and the European Union (1.8 mg/day). The efficacy of this maximum allowable dose of liraglutide for Japanese patients and the profiles of those patients for whom this agent should be recommended remain unclear. METHODS: This study aimed to examine the effective use of liraglutide in Japanese type 2 diabetic patients. We administered liraglutide to 60 patients, who had been managed with oral hypoglycemic agents or diet and exercise therapy only, during a period of 6 months. RESULTS: Though HbA1c levels significantly decreased, by approximately 1.5%, after 6 months of liraglutide administration, no significant changes in body weights were observed. The 0.6 mg dose was effective in approximately 40% of patients. In contrast, the effects of a dose increase from 0.6 mg to 0.9 mg were small. The greatest efficacy, as shown by a 2.5% HbA1c decrease, was achieved in non-obese patients. Thus, efficacy decreased as the degree of obesity increased. In addition, efficacy was higher in patients who had a diabetes duration of less than 10 years and was also higher in the group that had a low sulfonylurea (SU) index, when we define the SU index as mg/glimepiride * years of treatment. CONCLUSIONS: As appetite suppressions and associated decreases in body weights were not observed in obese patients, the efficacy of liraglutide at 0.9 mg did not appear to be high. Rather, it appeared to be highly effective for patients who were non-obese and for whom amelioration of blood glucose elevations could be anticipated via the stimulation of insulin secretion. Therefore, we found that liraglutide at doses of 0.9 mg was highly effective in non-obese patients who were in the early stages of diabetes and was particularly effective in patients who had not yet been administered SU agents. PMID- 26251685 TI - Comparison of Energy Expenditure and Oxygen Consumption of Spontaneous Breathing Trial Conducted With and Without Automatic Tube Compensation. AB - BACKGROUND: Weaning from mechanical ventilation is defined as the process of release of ventilatory support and how the evaluation of this phase is conducted in the spontaneous breathing trial (SBT). One of the most used modes of SBT is the continuous positive airway pressure (CPAP), which applies a continuous positive pressure in both inspiration and expiration. However, together with the mechanical ventilation modes, the automatic tube compensation (ATC) can be used, which compensates the resistance imposed by the endotracheal tube. The objective of this study was to compare oxygen consumption (VO2) and energy expenditure (EE) during SBT conducted with and without ATC. METHODS: The study was prospective, randomized and crossover. Forty mechanically ventilated patients were admitted to an intensive care unit of a university tertiary hospital. The participants were randomly allocated in group 1, in which SBT was initiated with CPAP and ATC, followed by CPAP without ATC or in group 2, in which SBT was initiated with CPAP without ATC, followed by CPAP with ATC. Indirect calorimetry helped to measure VO2 and EE during SBT. RESULTS: The differences between VO2 and EE obtained during SBT with ATC and without ATC were -1.6 mL/kg/min (95% CI: -4.36 - 1.07) and 5.4 kcal/day (95% CI: -21.67 - 10.79), respectively. CONCLUSIONS: We concluded that VO2 and EE obtained during SBT with and without ATC were not different. PMID- 26251687 TI - Risk of Intrapartum Cervical Lacerations in Vaginal Singleton Deliveries in Women With Cerclage. AB - BACKGROUND: We examined the obstetric outcomes of singleton vaginal deliveries in women with cerclage at our institute to confirm the risk of intrapartum cervical lacerations in vaginal deliveries of women with cerclage. METHODS: Data on all Japanese singleton vaginal deliveries at >= 34 weeks' gestation managed at the Japanese Red Cross Katsushika Maternity Hospital between 2008 and 2014 were collected. RESULTS: During the study period, cervical cerclage was performed in 95 of 9,490 (1.0%) women with singleton pregnancy at 12 - 22 weeks of singleton pregnancy who delivered at >= 34 weeks' gestation. The incidence of intrapartum cervical lacerations and postpartum hemorrhage >= 1,000 mL in the women with cerclage were higher significantly than that in the women without cerclage (cervical lacerations: crude odds ratio (OR): 26.9, 95% confidence interval (CI): 14 - 51, P < 0.01; postpartum hemorrhage: crude OR: 2.86, 95% CI: 1.6 - 4.9, P < 0.01). Using a multivariate analysis, cerclage was independently associated with the increased incidence of intrapartum cervical lacerations (P < 0.01). CONCLUSIONS: Cervical cerclage is an independent risk factor of intrapartum cervical lacerations in vaginal deliveries. PMID- 26251686 TI - Procalcitonin Kinetics in the First 72 Hours Predicts 30-Day Mortality in Severely Ill Septic Patients Admitted to an Intermediate Care Unit. AB - BACKGROUND: Severe sepsis and septic shock are leading causes of morbidity and mortality among critically ill patients, thus the identification of prognostic factors is crucial to determine their outcome. In this study, we explored the value of procalcitonin (PCT) variation in predicting 30-day mortality in patients with sepsis admitted to an intermediate care unit. METHODS: This prospective observational study enrolled 789 consecutive patients with severe sepsis and septic shock admitted to a medical intermediate care unit between November 2012 and February 2014. Kinetics of PCT expressed as percentage were defined by the variation between admission and 72 hours, and 24 and 72 hours; they were defined as Delta-PCT0-72h and Delta-PCT24-72h, respectively. RESULTS: The final study group of 144 patients featured a mean age of 73 +/- 14 years, with a high prevalence of comorbidities (Charlson index greater than 6 in 39%). Overall, 30 day mortality was 28.5% (41/144 patients). A receiver-operating-characteristic (ROC) analysis identified a decrease of Delta-PCT0-72h less than 15% (area under the curve: 0.75; 95% confidence interval (CI): 0.67 - 0.82) and a decrease of Delta-PCT24-72h less than 20% (area under the curve: 0.83; 95% CI: 0.74 - 0.92) as the most accurate cut-offs in predicting mortality. Decreases of Delta-PCT0 72h less than 15% (HR: 3.9, 95% CI: 1.6 - 9.5; P < 0.0001) and Delta-PCT24-72h less than 20% (HR: 3.1, 95% CI: 1.2 - 7.9; P < 0.001) were independent predictors of 30-day mortality. CONCLUSIONS: Evaluation of PCT kinetics over the first 72 hours is a useful tool for predicting 30-day mortality in patients with severe sepsis and septic shock admitted to an intermediate care unit. PMID- 26251688 TI - Severe Hyponatremia Due to Valproic Acid Toxicity. AB - Hyponatremia is a very commonly encountered clinical entity with potentially dangerous effects and for which many precipitating factors have been identified. We present a case of valproic acid (VPA) overdose causing profound hyponatremia, with one of the lowest serum sodium levels ever documented in literature. A 54 year-old woman with hypothyroidism, hypertension and bipolar disorder presented with somnolence after intentionally ingesting 7,500 mg VPA. She was drowsy but easily arousable with no hemodynamic compromise and an unremarkable physical exam. There was no clinical suspicion for organic neurological or pulmonary disease, adrenal insufficiency or volume depletion. She was found to have a serum sodium of 99 mEq/L, low plasma osmolality (211 mOsm/kg H2O), and high urine osmolality (115 mOsm/kg H2O). Her urine sodium was 18 mEq/L. She was euthyroid (TSH: 3.06 mIU/L) and compliant with thyroxine replacement. She was admitted to the intensive care unit for close monitoring and VPA was withheld. Over 36 hours her VPA level fell from 59.3 mg/L to 22.8 mg/L, serum sodium steadily rose to 125 mEq/L and there was concomitant improvement in her mental status. At 72 hours, she was transferred for an inpatient psychiatric evaluation and her sodium level was 135 mEq/L. She luckily did not experience any seizures or decline in neurological function. The clinical presentation in this patient is consistent with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) leading to a dramatic fall in sodium to a level of 99 mEq/L. Chronic VPA use has been associated with SIADH and chronic hyponatremia. Review of records in this patient from 1 year prior revealed that her last measured sodium level was 127 mEq/L. It is therefore most likely that our case is one of acute on chronic hyponatremia provoked by VPA overdose in the setting of chronic VPA use. Whilst our patient's course was relatively benign, this case illustrates a rare consequence of VPA toxicity, which if unnoticed in another patient may be tragic. PMID- 26251689 TI - A Rare Case of Cardiac Tamponade Induced by Chronic Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease primarily involving the joint synovium. RA is a systemic disease which has many known extra articular manifestations. We present a unique case of a patient with long standing RA who presented with a primary complaint of chest and back pain. Echocardiography revealed borderline normal left ventricular function and a large pericardial effusion with the finding of elevated intrapericardial pressure suspicious for cardiac tamponade. Infectious workup was all found to be negative. The presence and elevation of anti-cyclic citrullinated peptide antibody, rheumatoid factor and C-reactive protein (CRP) confirmed the patient was having an active flare-up of RA. It was determined that this flare-up was the cause of the cardiac tamponade. A pericardiocentesis was performed and 850 mL of bloody fluid was drained. The patient remained stable following the pericardiocentesis. At his follow-up visit, repeat echocardiogram showed no signs for pericardial effusion. Although there has been extensive study of RA, there are only a few documented cases noting the occurrence of cardiac tamponade in these patients. Therefore, it is important for the clinician to be aware of and recognize this potentially serious cardiac outcome associated with a common rheumatologic condition. PMID- 26251690 TI - Coronary Artery Calcification Seen Through Chest Radiography. AB - Patients with end-stage renal disease (ESRD) on dialysis have poor overall survival, and cardiovascular (CV) is the main cause of mortality among these patients. Coronary calcification is an independent predictor of mortality and CV events in dialysis patients and can be accessed by using a computerized tomography scanning. The high cost of this procedure, however, precludes routine implementation of this method for the purposes of risk stratification. Aortic arch calcification has been associated with CV mortality in the general population. Also, vascular calcification beyond the thoracic aorta has been shown to be associated with mortality in ESRD patients. We presented here a case of a young patient with ESRD in which the coronary calcification could be cleared seen through simple chest radiography. This is a 35-year-old man with a history of ESRD secondary to pyelonephritis, who was receiving conventional hemodialysis thrice a week for the last 5 years. He was submitted to chest radiography as part of routine annual cardiac screening. His blood pressure was within the target limits, although much higher in lower limbs, generating a high ankle brachial index of 1.3. He also had secondary hyperparathyroidism. His physical examination was unremarkable, except for the presence of non-functioning arteriovenous fistulas in both arms and a central venous catheter. The last routine blood test showed calcium 9.0 mg/dL, phosphate 5.7 mg/dL, potassium 4.7 mEq/L, creatinine 7.4 mg/dL, alkaline phosphatase 175 U/L, and parathyroid hormone 1,745 pg/mL. Surprisingly, the chest radiography revealed a calcified aortic valve and a calcified coronary artery. This patient had sudden cardiac death few months after this radiography had been taken. We present here a case of coronary calcification that can be seen through simple chest radiography. Such images are not usually seen, although the risk of vascular calcification is high in this population, and is closely related to CV risk. Chest radiographs, nearly universally available provide a method for assessing coronary artery calcification. Such a finding is intriguing and should alert nephrologists and cardiologists for the high risk of CV death in these patients. PMID- 26251691 TI - Benign Mature Teratoma in Anterior Mediastinum. AB - Teratoma of mediastinum is rare germ cell tumor. Anterior mediastinum is the most common extragonadal site. Benign mediastinal teratoma accounts for 60% of all mediastinal germ cell tumors. Benign mature teratoma has excellent prognosis after surgical excision. We present a case of 20-year-old woman diagnosed as benign mature teratoma which compressed main pulmonary trunk. The patient underwent surgical excision. PMID- 26251692 TI - Hemichorea-Hemiballism Secondary to Non-Ketotic Hyperglycemia. AB - Non-ketotic hyperglycemia is an unusual and rare cause of hemichorea hemiballismus. Correction of the hyperglycemia usually results in total resolution of the signs and symptoms. We present the case and medical imaging findings of a 66-year-old female who presented with steadily worsening choreiform and ballistic movements of the right upper and lower extremities over a 2-week period. Her serum glucose was greater than 600 mg/dL, and no ketones were present. CT scan and MR demonstrated left basal ganglia abnormalities suggesting hyperglycemia-related hemichorea-hemiballismus syndrome. Restoration of euglycemia led to eventual resolution of all symptoms. Knowledge of this disorder is paramount so as to rule out other causes of intracranial pathology. PMID- 26251693 TI - The Insulin-like Growth Factor Axis, Adipokines, Physical Activity, and Obesity in Relation to Breast Cancer Incidence and Recurrence. AB - BACKGROUND: Obesity, a risk factor for the development of postmenopausal breast cancer and certain other cancer types, has also been associated with poorer response to cancer therapy and cancer recurrence. The insulin-like growth factor (IGF) axis also influences cancer risk. METHODS: In this commentary, we consider the literature on IGF and its binding proteins and the risk of breast cancer, along with effects of obesity, adipokines, and insulin resistance on breast cancer, and the potential for lifestyle interventions to address weight gain and physical inactivity among at-risk women. RESULTS: Greater body fatness is associated with a higher risk of postmenopausal breast cancer. The association may be explained, in part, by hyperinsulinemia and alterations in adipokines and estrogens. Nutrition, energy balance, and levels of physical activity are determinants of IGF bioactivity. Alterations in the IGF axis can increase cancer risk and progression. Results from epidemiologic studies indicate that higher circulating levels of IGF-I are associated with an increased risk of breast cancer. CONCLUSIONS: Intervention studies are needed to determine how to sustain the positive effects of exercise over time and to identify the optimal mode, intensity, frequency, duration, and timing of exercise for breast cancer survivors, including important subgroups of survivors such as African American and Hispanic women. Future epidemiologic studies of the relationships between the IGF axis and breast cancer should include adequate numbers of African American women, Hispanic women, and other minority women who have been underrepresented in studies completed to date. PMID- 26251694 TI - How local and state regulations affect the child care food environment: A qualitative study of child care center directors' perspectives. AB - Almost one-third of preschoolers spend regular time in child care centers where they can consume the majority of their daily dietary intake. The child care setting influences children's dietary intake. Thus, it is important to examine factors, such as local and state regulations, that influence the food environment at the center. This qualitative study explored directors' perceptions of how regulations influence the foods available at child care centers. Ten directors of centers in Travis County, Texas completed semi-structured interviews. Directors reported that changes in local health department regulations (e.g., kitchen specifications) result in less-healthful foods being served (e.g., more prepackaged foods). Directors of centers that do not participate in the federal Child and Adult Care Food Program (CACFP) said the state licensing regulations clarify the portion size and nutritional requirements for preschoolers thereby improving the nutritional quality of the food served. Directors of centers participating in CACFP said they are not affected by state mandates, because the CACFP regulations are more stringent. These findings suggest that state regulations that specify and quantify nutritional standards may beneficially impact preschoolers' diets. However, local health department regulations enacted to improve food safety may negatively influence the nutritional value of food served in centers. PMID- 26251695 TI - Sex differences in gut fermentation and immune parameters in rats fed an oligofructose-supplemented diet. AB - BACKGROUND: Mechanistic data to support health claims is often generated using rodent models, and the influence of prebiotic supplementation has largely been evaluated using male rodents. Given that sex-based differences in immune parameters are well recognized and recent evidence suggests differences in microbiota composition between sexes, validation of the effectiveness of prebiotics merits assessment in both males and females. Here, we have compared the effect of oligofructose (OF) supplementation on the fecal bacterial community, short chain fatty acid profiles, and gut mucosal and systemic immune parameters in male and female rats. METHODS: Male and female rats were fed rodent chow or chow supplemented with OF (5 % w/w). Fecal community change was examined by analyzing 16S rRNA gene content. To compare effects of OF between sexes at the gut microbial and mucosal immune level, fecal short chain fatty acid and tissue cytokine profiles were measured. Serum lipopolysaccharide levels were also evaluated by the limulus amebocyte lysate assay as an indirect means of determining gut permeability between sexes. RESULTS: In the fecal community of females, OF supplementation altered community structure by increasing abundance in the Phylum Bacteroidetes. In male rats, no changes in fecal community structure were observed, although fecal butyrate levels significantly increased. Liver Immunoglobulin A (IgA) levels were higher in males relative to females fed OF, and serum LPS concentrations were higher in males independent of diet. Females had higher basal levels of the regulatory cytokine interleukin-10 (IL-10) in the colon and liver, while males had higher basal levels of the pro inflammatory cytokines IL-6 and cytokine-induced neutrophil chemoattractant-1 (CINC-1) in the cecum and liver. CONCLUSIONS: We have shown that male and female rat gut communities metabolize an OF-supplemented diet differently. Sex-specific responses in both the fecal community and systemic immune parameters suggest that this difference may result from an increase in the availability of gut peptidyl nitrogen in the males. These findings demonstrate the importance of performing sex-comparative studies when investigating potential health effects of prebiotics using rodent models. PMID- 26251696 TI - Upregulated IL-1beta in dysferlin-deficient muscle attenuates regeneration by blunting the response to pro-inflammatory macrophages. AB - BACKGROUND: Loss-of-function mutations in the dysferlin gene (DYSF) result in a family of muscle disorders known collectively as the dysferlinopathies. Dysferlin deficient muscle is characterized by inflammatory foci and macrophage infiltration with subsequent decline in muscle function. Whereas macrophages function to remove necrotic tissue in acute injury, their prevalence in chronic myopathy is thought to inhibit resolution of muscle regeneration. Two major classes of macrophages, classical (M1) and alternative (M2a), play distinct roles during the acute injury process. However, their individual roles in chronic myopathy remain unclear and were explored in this study. METHODS: To test the roles of the two macrophage phenotypes on regeneration in dysferlin-deficient muscle, we developed an in vitro co-culture model of macrophages and muscle cells. We assayed the co-cultures using ELISA and cytokine arrays to identify secreted factors and performed transcriptome analysis of molecular networks induced in the myoblasts. RESULTS: Dysferlin-deficient muscle contained an excess of M1 macrophage markers, compared with WT, and regenerated poorly in response to toxin injury. Co-culturing macrophages with muscle cells showed that M1 macrophages inhibit muscle regeneration whereas M2a macrophages promote it, especially in dysferlin-deficient muscle cells. Examination of soluble factors released in the co-cultures and transcriptome analysis implicated two soluble factors in mediating the effects: IL-1beta and IL-4, which during acute injury are secreted from M1 and M2a macrophages, respectively. To test the roles of these two factors in dysferlin-deficient muscle, myoblasts were treated with IL 4, which improved muscle differentiation, or IL-1beta, which inhibited it. Importantly, blockade of IL-1beta signaling significantly improved differentiation of dysferlin-deficient cells. CONCLUSIONS: We propose that the inhibitory effects of M1 macrophages on myogenesis are mediated by IL-1beta signals and suppression of the M1-mediated immune response may improve muscle regeneration in dysferlin deficiency. Our studies identify a potential therapeutic approach to promote muscle regeneration in dystrophic muscle. PMID- 26251697 TI - Synthesis of Norbornane Bisether Antibiotics via Silver-mediated Alkylation. AB - A small series of norbornane bisether diguanidines have been synthesized and evaluated as antibacterial agents. The key transformation-bisalkylation of norbornane diol 6-was not successful using Williamson methodology but has been accomplished using Ag2O mediated alkylation. Further functionalization to incorporate two guanidinium groups gave rise to a series of structurally rigid cationic amphiphiles; several of which (16d, 16g and 16h) exhibited antibiotic activity. For example, compound 16d was active against a broad range of bacteria including Pseudomonas aeruginosa (MIC = 8 ug/mL), Escherichia coli (MIC = 8 ug/mL) and methicillin-resistant Staphylococcus aureus (MIC = 8 ug/mL). PMID- 26251698 TI - Comparison of variations detection between whole-genome amplification methods used in single-cell resequencing. AB - BACKGROUND: Single-cell resequencing (SCRS) provides many biomedical advances in variations detection at the single-cell level, but it currently relies on whole genome amplification (WGA). Three methods are commonly used for WGA: multiple displacement amplification (MDA), degenerate-oligonucleotide-primed PCR (DOP-PCR) and multiple annealing and looping-based amplification cycles (MALBAC). However, a comprehensive comparison of variations detection performance between these WGA methods has not yet been performed. RESULTS: We systematically compared the advantages and disadvantages of different WGA methods, focusing particularly on variations detection. Low-coverage whole-genome sequencing revealed that DOP-PCR had the highest duplication ratio, but an even read distribution and the best reproducibility and accuracy for detection of copy-number variations (CNVs). However, MDA had significantly higher genome recovery sensitivity (~84 %) than DOP-PCR (~6 %) and MALBAC (~52 %) at high sequencing depth. MALBAC and MDA had comparable single-nucleotide variations detection efficiency, false-positive ratio, and allele drop-out ratio. We further demonstrated that SCRS data amplified by either MDA or MALBAC from a gastric cancer cell line could accurately detect gastric cancer CNVs with comparable sensitivity and specificity, including amplifications of 12p11.22 (KRAS) and 9p24.1 (JAK2, CD274, and PDCD1LG2). CONCLUSIONS: Our findings provide a comprehensive comparison of variations detection performance using SCRS amplified by different WGA methods. It will guide researchers to determine which WGA method is best suited to individual experimental needs at single-cell level. PMID- 26251700 TI - Aneurysms and pseudoaneurysms in dialysis access. AB - Aneurysms are a common and often difficult complication seen with arteriovenous vascular access for haemodialysis. The purpose of this narrative review is to define and describe the scale of the problem and suggested therapeutic strategies. A narrative review of the published literature illustrated by individual cases is presented with the aim of summarising the relevant literature. The definitions of aneurysm are inconsistent throughout the literature and therefore systematic review is impossible. They vary from qualitative descriptions to quantitative definitions using absolute size, relative size and also size plus characteristics. The incidence and aetiology are also ill defined but separation into true aneurysms and false, or pseudoaneurysms may be helpful in planning treatment, which may be conservative, surgical or radiological. The lack of useful definitions and classification along with the multitude of management strategies proposed make firm evidence based conclusions difficult to draw. Further robust well designed studies are required to define best practice for this common problem. PMID- 26251699 TI - Uraemic toxins and new methods to control their accumulation: game changers for the concept of dialysis adequacy. AB - The current concept of an adequate dialysis based only on the dialysis process itself is rather limited. We now have considerable knowledge of uraemic toxicity and improved tools for limiting uraemic toxin accumulation. It is time to make use of these. A broader concept of adequacy that focusses on uraemic toxicity is required. As discussed in the present review, adequacy could be achieved by many different methods in combination with, or instead of, dialysis. These include preservation of renal function, dietary intake, reducing uraemic toxin generation rate and intestinal absorption, isolated ultrafiltration and extracorporeal adsorption of key uraemic toxins. A better measure of the quality of dialysis treatment would quantify the uraemic state in the patient using levels of a panel of key uraemic toxins. Treatment would focus on controlling uraemic toxicity while reducing harm or inconvenience to the patient. Delivering more dialysis might not be the best way to achieve this. PMID- 26251701 TI - High convection volume in online post-dilution haemodiafiltration: relevance, safety and costs. AB - Increasing evidence suggests that treatment with online post-dilution haemodiafiltration (HDF) improves clinical outcome in patients with end-stage kidney disease, if compared with haemodialysis (HD). Although the primary analyses of three large randomized controlled trials (RCTs) showed inconclusive results, post hoc analyses of these and previous observational studies comparing online post-dilution HDF with HD showed that the risk of overall and cardiovascular mortality is lowest in patients who are treated with high-volume HDF. As such, the magnitude of the convection volume seems crucial and can be considered as the 'dose' of HDF. In this narrative review, the relevance of high convection volume in online post-dilution HDF is discussed. In addition, we briefly touch upon some safety and cost issues. PMID- 26251702 TI - Lactate clearance and metabolic aspects of continuous high-volume hemofiltration. AB - Lactic acidosis is associated with high morbidity and mortality in hospitalized patients. Treatment of lactic acidosis is targeted on correcting the underlying causes and optimizing adequate oxygen delivery to the tissues. Even though evidence is lacking, continuous renal replacement therapy (CRRT) and dialysis have been advocated as treatments for lactic acidosis. We report a 28-year-old Caucasian male with a history of hemophagocytic lymphohistiocytosis who presented with septic shock, severe lactic acidosis and multiple organ failure. Metabolic acidosis was corrected after bicarbonate therapy and CRRT with a hemofiltration rate of 7 L/h (58 mL/kg/h). Lactate clearance was calculated to be 79 mL/min. Compared with reported rates of lactate overproduction in septic shock, the rate of lactate clearance is quite small. Our case suggests that CRRT with high-volume hemofiltration is not effective for severe lactic acidosis. Lactic acidosis alone should not be considered as a nonrenal indication for CRRT. PMID- 26251703 TI - Usefulness and feasibility of measuring ionized calcium in haemodialysis patients. AB - BACKGROUND: Measuring blood calcium level is recommended in haemodialysis (HD) patients. The Kidney Disease Improving Global Outcomes position states that the measurement of ionized calcium (ICa) level is preferred, but in the clinical setting, due to technical difficulties, total calcium (tCa) level is preferred to ICa. AIM: The aim of this study was to test the possibility of delayed ICa analysis using frozen serum, and so to identify the factors associated with predialysis ICa level and compare the ability of tCa and Alb-Ca to predict ICa level and finally to compare the survival rate according to the three calcium measurements. METHODS: All prevalent HD patients, dialysed by a native AV fistula in a 3 * 4 to 3 * 8 h schedule, had their predialysis ICa, tCa and Alb-Ca levels and usual mid-week biology recorded. Intergroup comparisons between ICa quartile were performed. Bland-Altman plots and linear regression were used to assess the differences between 30 fresh and frozen samples. Survival analyses were performed using ICa and tCa levels. RESULTS: Comparing fresh blood and frozen serum samples, linear regression (y = 0.98 + 0.02, r = 0.961) showed that the two methods were quite identical with the same mean ICa value (1.1 +/- 0.1 mmol/L, P = 0.45). A total of 160 HD patients were included in the study. Hypocalcaemia, using ICa values, was highly prevalent in our population (40%) whereas hypercalcaemia was observed only in three cases (1.8%). In predicting ICa hypocalcaemia (<1.12 mmol/L, n = 64), the use of tCa was accurate in 48.4% of patients, and the use of Alb-Ca was accurate in only 17.2% of patients; tCa was not a predictive factor for hypercalcaemia (ICa > 1.32 mmol/L, n = 3); Alb-Ca value predicted hypercalcaemia in 2/3 of the patients. In predicting normocalcaemia, the use of tCa values was correct in 92.4% of patients and the use of Alb-Ca values in 88.1% of patients; only younger age (P = 0.03) and female sex (P = 0.01) were associated with higher ICa quartile. None of the three calcium measures was significantly associated with survival rate using log-rank and Cox models adjusted for age, dialysis vintage, diabetes and sex. CONCLUSION: In the present study, we report that (1) delayed ICa measure is feasible in dialysis patients using a freezing technique, (2) hypocalcaemia is highly prevalent in HD patients and poorly predicted by Alb-Ca level, (3) the main factor associated with ICa level is sex of the individual and (4) calcaemia is not associated with survival rate using any of the three methods. PMID- 26251704 TI - Kinetics of serum 25-hydroxyvitamin D in haemodialysis patients treated with monthly oral cholecalciferol. AB - BACKGROUND: We previously reported that oral cholecalciferol (CCF) (100 000 IU) taken monthly by haemodialysis patients is effective in accomplishing serum 25 hydroxyvitamin D (25-D) levels >75 nmol/L in >80% of cases. We aimed to study the weekly kinetecs of serum 25-D in HD patients receiving oral CCF during the first 6 months of HD. METHODS: All new HD patients at our dialysis centre during the autumn months of 2011-2014 were offered entry into the study if their baseline serum 25-D level was <75 nmol/L. Oral CCF (100 000 IU) was administrated monthly during an HD session. The kinetic study included weekly serum sampling for 16 weeks, and every other week thereafter. Biological and treatment data were compared between baseline and 6 months after starting HD and CCF. Patients who required calcimimetics, calcitriol and analogues were excluded from the study. RESULTS: The data from 21 patients were available for analysis. These patients had a mean age of 72.2 +/- 12 years, 33% were women, 28.5% had diabetes, and 33% had a central venous catheter. Serum 25-D levels increased from 26.8 +/- 13 nmol/L at baseline to 102.3 +/- 24 nmol/L after 6 months (P < 0.001). Serum calcium and albumin levels both increased during the study period. Serum phosphate level did not change significantly, and serum parathyroid hormone (PTH) level decreased. Serum 25-D level reached a plateau after 11 weeks of oral CCF. Two patients (9.5%) with low baseline 25-D values, had a stable 25-D level <75 nmol/L after 6 months. No peak effect was observed 48 h after the first dose of CCF. CONCLUSION: The oral administration of 100 000 IU CCF once a month maintains a normal serum level in 90% of HD patients. Serum 25-D level reaches a plateau level after 12 weeks of therapy. PMID- 26251705 TI - A neglected issue in dialysis practice: haemodialysate. AB - The intended function of dialysate fluid is to correct the composition of uraemic blood to physiologic levels, both by reducing the concentration of uraemic toxins and correcting electrolyte and acid-base abnormalities. This is accomplished principally by formulating a dialysate whose constituent concentrations are set to approximate normal values in the body. Sodium balance is the cornerstone of intradialysis cardiovascular stability and good interdialytic blood pressure control; plasma potassium concentration and its intradialytic kinetics certainly play a role in the genesis of cardiac arrhythmias; calcium is related to haemodynamic stability, mineral bone disease and also cardiac arrhythmias; the role of magnesium is still controversial; lastly, acid buffering by means of base supplementation is one of the major roles of dialysis. In conclusion, learning about the art and the science of fashioning haemodialysates is one of the best ways to further the understanding of the pathophysiologic processes underlying myriad acid-base, fluid, electrolyte as well as blood pressure abnormalities of the uraemic patient on maintenance haemodialysis. PMID- 26251706 TI - Observation of microbubbles during standard dialysis treatments. AB - BACKGROUND: The infusion of microbubbles as a side effect of haemodialysis was repeatedly demonstrated in recent publications, but the knowledge on the source of microbubbles and on microbubble formation is scarce. METHODS: Microbubbles in the range of 10-500 um were measured by a non-invasive bubble counter based on a pulsed ultrasonic Doppler system in a non-interventional study of a single centre. Totally, 29 measurements were performed in standard treatments covering a broad range of patient and treatment conditions (types of blood access, treatment modes, blood flow rates and arterial pressures). RESULTS: Several possible sources of microbubbles could be identified such as an arterial luer lock connector at negative pressure and remnant bubbles from insufficient priming, but some sources of microbubbles remain unknown. Microbubbles were found in all treatments, haemodialysis (HD) and online haemodiafiltration. The lowest average microbubble rates (17 +/- 16 microbubbles per minute) were observed in patients treated by online haemodiafiltration at medium blood flow rates and moderate arterial pressures and the highest average microbubble rates (117 +/- 63 microbubbles per minute) at high blood flow rates (550 mL/min) and low arterial pressures (-210 mmHg). Generally, the microbubble rate correlated to both blood flow rate (correlation coefficient r = 0.45) and negative arterial pressure (r = 0.67). CONCLUSIONS: Microbubbles are a general side effect of HD; origin and pathophysiologic consequences of this phenomenon are not well understood, and deserve further study. PMID- 26251707 TI - From the nephrologist's point of view: diversity of causes and clinical features of acute kidney injury. AB - Acute kidney injury (AKI) is a clinical syndrome with multiple entities. Although AKI implies renal damage, functional impairment or both, diagnosis is solely based on the functional parameters of serum creatinine and urine output. The latest definition was provided by the Kidney Disease Improving Global Outcomes (KDIGO) working group in 2012. Independent of the underlying disease, and even in the case of full recovery, AKI is associated with an increased morbidity and mortality. Awareness of the patient's individual risk profile and the diversity of causes and clinical features of AKI is pivotal for optimization of prophylaxes, diagnosis and therapy of each form of AKI. A differentiated and individualized approach is required to improve patient mortality, morbidity, long term kidney function and eventually the quality of life. In this review, we provide an overview of the different clinical settings in which specific forms of AKI may occur and point out possible diagnostic as well as therapeutic approaches. Secifically AKI is discussed in the context of non-kidney organ failure, organ transplantation, sepsis, malignancy and autoimmune disease. PMID- 26251708 TI - Acute kidney injury associated with androgenic steroids and nutritional supplements in bodybuilders(?). AB - Four bodybuilders who injected anabolic steroids and ingested commercial protein (78-104 g/day) and creatine (15 g/day) products presented with serum creatinine levels between 229.84 and 335.92 umol/L (2.6-3.8 mg/dL). Renal biopsies revealed acute tubular necrosis. Four weeks after discontinuing injections and supplements, serum creatinine was in the normal range and estimated glomerular filtration rate > 1.00 mL/s (60 mL/min), including two patients with biopsies showing >30% interstitial fibrosis and tubular atrophy. The findings highlight a risk for acute and potentially chronic kidney injury among young men abusing anabolic steroids and using excessive amounts of nutritional supplements. PMID- 26251709 TI - Proximal tubular dysfunction and kidney injury associated with tenofovir in HIV patients: a case series. AB - BACKGROUND: Tenofovir disoproxil fumarate (TDF) may cause acute kidney injury and proximal tubular dysfunction. However, no detailed studies document urinary phosphate wasting as a marker of TDF-induced tubulopathy. METHODS: Records of HIV infected patients with presumed TDF toxicity were reviewed. We describe the characteristics and clinical course of 15 patients who had documented elevated (>20%) fractional excretion of phosphate (FEphos). RESULTS: Patients were predominantly Caucasian and male (73 and 80%, respectively), with a mean age of 56 years (range 38-76). Of the 15 patients, 11 had a estimated glomerular filtration rate (eGFR) of >90 mL/min/1.73(2) at time of TDF initiation. The mean duration of TDF therapy prior to diagnosis of TDF toxicity was 64 months. Mean FEphos was 34% (range 20-62). The mean eGFR at TDF initiation was 104 mL/min/1.73 m(2) [standard deviation (SD) 17.0] with a gradual decline to 69 mL/min/1.73 m(2) (SD 19.0) by the time of TDF discontinuation. Of 10 patients with repeated FEphos after TDF discontinuation, 9 had improvement of their FEphos. Of these individuals, 6 had normalization of their FEphos. Estimated GFR improved in 12 patients after discontinuation of TDF, though importantly, none returned to their baseline eGFR. CONCLUSIONS: Urinary phosphate wasting is a sensitive marker for TDF-induced proximal tubulopathy and is associated with unrecognized and permanent renal function decline. Tubular dysfunction can develop after years of TDF therapy in those with normal kidney function at the time of drug initiation. This suggests that continuing vigilance be maintained in all those on TDF. PMID- 26251710 TI - Renovascular acute renal failure precipitated by extracorporeal shock wave lithotripsy for pancreatic stones. AB - Extracorporeal shock wave lithotripsy (ESWL) for pancreatic stones is considered a safe and efficient method to facilitate fragmentation and stone removal. We describe the case of a 73-year-old woman with a solitary functioning kidney who presented an acute-onset anuria and renovascular renal failure the day after ESWL. We speculate that vascular calcifications in the area targeted by shock waves played a critical role in renal artery obstruction in the present case. PMID- 26251711 TI - A review of the re-emergence of adrenocorticotrophic hormone therapy in glomerular disease, more than a drug of last resort? AB - There has been a re-emergence of interest in adrenocorticotropic hormone (ACTH) in patients with resistant nephrotic syndrome. We describe a patient with severe nephrosis and advanced chronic kidney disease with idiopathic membranous nephropathy resistant to conventional immunosuppressive therapies that achieved lasting remission with ACTH therapy. We explore the literature showing the extra renoprotective effects which might explain the response of proteinuric renal diseases to this treatment. PMID- 26251712 TI - Glomerular IgG subclasses in idiopathic and malignancy-associated membranous nephropathy. AB - BACKGROUND: In idiopathic membranous nephropathy (MN), antibodies directed towards the glomerular phospholipase A2 receptor (PLA2R) have mainly been reported to be of IgG4 subclass. However, the role of the different IgG subclasses in the pathogenesis of MN, both in idiopathic MN and in secondary cases, is still unclear. In this retrospective study, we test the hypothesis that the absence of glomerular IgG4 and PLA2R in patients with MN indicates malignant disease. METHODS: The distribution pattern of glomerular IgG subclasses and PLA2R was studied in 69 patients with idiopathic MN and 16 patients with malignancy associated MN who were followed up for a mean of 83 months. RESULTS: A significant correlation between the absence of IgG4 and PLA2R and malignancy associated MN was found. Thus, IgG4 was positive in 45 of 69 patients (65%) with idiopathic MN but only in 5 of 16 patients (31%) with malignancy-associated MN. The other IgG subclasses did not differ statistically between the groups, IgG2 positivity being present in more than 94% of patients in both groups. Thirty-five of 63 patients (56%) with idiopathic MN and 3 of 16 (19%) patients with malignancy-associated MN had glomerular deposits of PLA2R. CONCLUSIONS: We have found that the absence of glomerular IgG4 and PLA2R is common in patients with malignancy-associated MN. In our material, IgG2 could not be used as a marker of underlying malignant disease. Finally, neither IgG1 nor IgG3 seems to be involved in the pathogenesis of MN. PMID- 26251713 TI - Membranous nephropathy in autologous hematopoietic stem cell transplant: autologous graft-versus-host disease or autoimmunity induction? AB - With the increasing utility of hematopoietic stem cell transplantation (SCT) as a treatment for cancer and noncancerous disorders, more challenges and complications associated with SCT have emerged. Renal injury immediately after transplant is common and well understood, but long-term renal injury is becoming more evident. Chronic graft-versus-host disease (GVHD) is a known long-term complication of SCT, and membranous nephropathy (MN) is emerging as the most common cause of SCT-associated glomerular pathology. In this case report, we present a patient who developed features of anti-PLA2R antibody-negative MN following autologous SCT. The renal injury responded well to steroids and further response to rituximab therapy was noted, suggesting antibody-mediated autoimmune glomerular disease. We also present a review of the literature on autologous GVHD and the role of T and B cells in induction of autoimmunity by SCT. PMID- 26251714 TI - Eculizumab-induced reversal of dialysis-dependent kidney failure from C3 glomerulonephritis. AB - C3 glomerulopathy (C3G) is characterized by C3 deposits with minimal immunoglobulin deposition caused by alternative complement pathway dysregulation. Unfortunately, no therapeutic intervention has consistently improved outcomes for patients with C3G. Eculizumab, a monoclonal antibody to C5, is currently the only approved complement-specific agent with some efficacy in the treatment of C3 glomerulonephritis (C3GN). Here, we describe a patient with acute crescentic C3GN with no identified complement mutation or family history of renal disease who required dialysis for 6 months. Five months after initiation of eculizumab, she became dialysis independent, showing improvement is possible after adequate time on eculizumab. PMID- 26251715 TI - Timing of eculizumab therapy for C3 glomerulonephritis. AB - Eculizumab is an anti-C5 antibody that inhibits C5 cleavage and prevents the generation of the terminal complement complex C5b-9. Eculizumab is licensed to treat paroxysmal nocturnal haemoglobinuria or atypical haemolytic uraemic syndrome (aHUS). Clinical trials are ongoing for C3 glomerulopathy. Given the unfamiliarity of physicians with these rare diseases and the variability of clinical presentation, a delayed initiation of eculizumab therapy is common. Thus, the question arises as to what extent improvement of kidney function may be expected when patients have been dialysis dependent for weeks or months already when eculizumab is initiated. Furthermore, given the high cost and potential adverse effects of eculizumab, the question arises of when to stop therapy because of futility when patients with kidney-only manifestations remain dialysis dependent. In literature reports, eculizumab was stopped as early as after 3 weeks because the patient remained dialysis dependent. In this issue of CKJ, Inman et al. report on eculizumab-induced reversal of dialysis-dependent kidney failure from C3 glomerulonephritis, illustrating both the potential benefit of eculizumab for this complement-mediated disease and the need for lengthy therapy dialysis independency was reached after 5 months of eculizumab. Indeed, there are reports of renal function recovery when eculizumab was initiated after 4 months on dialysis and of recovery of renal function 2.0-3.5 months after initiation of eculizumab in dialysis-dependent patients with C3 glomerulopathy or aHUS. PMID- 26251716 TI - Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole. AB - Mutations in CYP24A1, encoding the vitamin D 24-hydroxlase enzyme, are known to cause a range of clinical phenotypes and presentations including idiopathic infantile hypercalcaemia and adult-onset nephrocalcinosis and nephrolithiasis. In the context of raised or borderline high serum calcium levels, suppressed PTH and persistently elevated 1,25 dihydroxy vitamin D levels, this rare condition should be considered. We present a case where this biochemical pattern was seen and mutations in CYP24A1 were confirmed. We were able to successfully control serum calcium levels and reduce urinary calcium excretion by treatment with low-dose fluconazole, which inhibits vitamin D-synthesizing enzymes (including 25 hydroxylases and 1-alpha-hydroxylase) thereby reducing levels of 1,25-dihydroxy vitamin D. PMID- 26251717 TI - The hypercalcaemia of CYP24A1 inactivation: new ways to improve diagnosis and treatment. AB - This case report presents fluoconazole efficacy to reduce hypercalcaemia and increased urinary calcium excretion in a patient with nephrocalcinosis after a long history of recurrent renal stones caused by a loss-of-function mutation of the CYP24A1 gene. The CYP24A1 gene codes for a key enzyme in the vitamin D endocrine system that protects against vitamin D toxicity by degrading the circulating excess of both 1,25-dihydroxyvitamin D, the hormonal form of vitamin D, and its precursor, 25-hydroxyvitamin D. In order to expedite the identification of this rare disorder and improve therapies to avoid its progression to nephrocalcinosis, this editorial updates the current knowledge on the frequency of CYP24A1-inactivating mutations, the features of their early clinical presentation and progression, and the pathophysiology of vitamin D activation in health and in granulomatous disorders that may help improve current treatment. PMID- 26251718 TI - Hydrochlorothiazide reduces urinary calcium excretion in a child with Lowe syndrome. AB - There is a growing recognition that children with Lowe syndrome are at risk of nephrocalcinosis and nephrolithiasis from hypercalciuria. Increased fluid intake and correction of metabolic acidosis have remained the focus for intervention but are not always successful. Thiazide diuretics, which reduce urinary calcium excretion, have not been used in these children, due to concerns that (i) they may not work as a result of the underlying tubular abnormalities and (ii) their risk may outweigh the potential benefits they have to offer. Herein we report a child with Lowe syndrome who was successfully treated with thiazides in managing his hypercalciuria. PMID- 26251719 TI - Performance of a brief survey to assess health literacy in patients receiving hemodialysis. AB - BACKGROUND: Health literacy is associated with important outcomes among patients with kidney disease, but widely used measures of health literacy can be burdensome. In an effort to make a practical assessment available, we compared the performance of the three-item brief health literacy screen (BHLS) to other widely used measures of health literacy among patients with end-stage renal disease (ESRD). METHODS: Adult hemodialysis patients (n = 150) from four urban dialysis facilities participated in a cross-sectional study from 2009 to 2012. Three health literacy measures were administered including (i) the rapid estimate of adult literacy in medicine (REALM), (ii) the short test of functional health literacy in adults (S-TOFHLA) and (iii) the three-item BHLS. The mini-mental state exam assessed cognitive status, and the chronic hemodialysis knowledge survey (CHeKS) and perceived kidney disease knowledge survey (PiKS) assessed kidney knowledge. Spearman's rhos and area under the receiver-operating curves examined relationships between the aforementioned variables. RESULTS: Participants had received dialysis for a mean of 4.6 years. They were 49% female, 73% African American and averaged 52 years of age. Less education and less cognitive capacity were each associated (P < 0.05) with lower health literacy for all three health literacy measures. Performance on the BHLS was significantly associated with the REALM [0.35 (95% confidence interval (95% CI): 0.20-0.49); P < 0.001] and S-TOFHLA [0.49 (95% CI: 0.35-0.69); P < 0.001], the CHeKS [0.43 (95% CI: 0.28-0.55); P < 0.001] and PiKS [0.41 (95% CI: 0.27-0.54); P < 0.001]. CONCLUSIONS: The BHLS demonstrates evidence of construct validity among ESRD patients. Furthermore, health literacy was associated with kidney knowledge, supporting it as a potential intervention target to improve outcomes among patients with lower health literacy. PMID- 26251720 TI - End-stage kidney disease patient evaluation of the Australian 'My Kidneys, My Choice' decision aid. AB - BACKGROUND: A multidisciplinary team in Australia and New Zealand utilized a current decision-making theory to develop the 'My Kidneys, My Choice' decision aid (MKDA) to support end-stage kidney disease (ESKD) treatment options in decision-making. Assessment of the MKDA was deemed critical to practice integration. METHODS: A multisite pre-test, post-test study design was used. Routine ESKD education was supported by the MKDA. Knowledge levels, worries and priorities were assessed pre- and post-education with Likert-scale questions. MKDA usability and treatment option preferences were surveyed post-test. Data were analysed in SPSS. RESULTS: Ninety-seven participants completed the pre survey and 72 (70%) the post-survey. Mean pre-test knowledge scores ranged from: 0.88 (SD 1.5) for conservative care to 1.32 (SD 1.3) for centre-based dialysis. Post-decision-making knowledge levels increased significantly (P < 0.001). Worry and flexibility scores all increased significantly (P < 0.05) from pre- to post test; about future pre- 4.15 (SD 1.3), post- 4.61 (SD 0.76); change to lifestyle 4.23 (SD 1.05), 4.59 (SD 0.8); ability to work/do leisure activities 3.67 (SD 1.56) 4.27 (SD 1.17) and desire for flexibility 4.51 (SD 0.86), 4.76 (SD 0.66). MKDA usability scores were high: easy to understand 4.64, (SD 0.77), easy to follow 4.65, (SD 0.66) and supporting decision-making 4.76 (SD 0.61). MKDA section scores ranged from 4.21 (SD 0.75) for writing treatment choices to 4.90 (SD 0.41) for the use of the treatment option comparison grid. CONCLUSIONS: Preliminary MKDA assessment revealed high patient acceptance and usability. Patients had equitable knowledge of all treatment options but experienced higher post-worries levels than anticipated. PMID- 26251721 TI - A review of feed efficiency in swine: biology and application. AB - Feed efficiency represents the cumulative efficiency with which the pig utilizes dietary nutrients for maintenance, lean gain and lipid accretion. It is closely linked with energy metabolism, as the oxidation of carbon-containing components in the feed drive all metabolic processes. While much is known about nutrient utilization and tissue metabolism, blending these subjects into a discussion on feed efficiency has proven to be difficult. For example, while increasing dietary energy concentration will almost certainly increase feed efficiency, the correlation between dietary energy concentration and feed efficiency is surprisingly low. This is likely due to the plethora of non-dietary factors that impact feed efficiency, such as the environment and health as well as individual variation in maintenance requirements, body composition and body weight. Nonetheless, a deeper understanding of feed efficiency is critical at many levels. To individual farms, it impacts profitability. To the pork industry, it represents its competitive position against other protein sources. To food economists, it means less demand on global feed resources. There are environmental and other societal implications as well. Interestingly, feed efficiency is not always reported simply as a ratio of body weight gain to feed consumed. This review will explain why this arithmetic calculation, as simple as it initially seems, and as universally applied as it is in science and commerce, can often be misleading due to errors inherent in recording of both weight gain and feed intake. This review discusses the importance of feed efficiency, the manner in which it can be measured and reported, its basis in biology and approaches to its improvement. It concludes with a summary of findings and recommendations for future efforts. PMID- 26251722 TI - Does additional antimicrobial treatment have a better effect on URTI cough resolution than homeopathic symptomatic therapy alone? A real-life preliminary observational study in a pediatric population. AB - BACKGROUND: The effectiveness of a homeopathic syrup on cough has been demonstrated in an adult population in a previous double-blind randomized study. The present prospective observational study investigated children affected by wet acute cough caused by non-complicated URTIs, comparing those who received the homeopathic syrup versus those treated with the homeopathic syrup plus antibiotic. OBJECTIVES: The aims were: 1) to assess whether the addition of antibiotics to a symptomatic treatment had a role in reducing the severity and duration of acute cough in a pediatric population, as well as in improving cough resolution; 2) to verify the safety of the two treatments. METHODS: Eighty-five children were enrolled in an open study: 46 children received homeopathic syrup alone for 10 days and 39 children received homeopathic syrup for 10 days plus oral antibiotic treatment (amoxicillin/clavulanate, clarithromycin, and erythromycin) for 7 days. To assess cough severity we used a subjective verbal category-descriptive (VCD) scale. RESULTS: Cough VCD score was significantly (P < 0.001) reduced in both groups starting from the second day of treatment (-0.52 +/ 0.66 in the homeopathic syrup group and -0.56 +/- 0.55 in children receiving homeopathic syrup plus oral antibiotic treatment). No significant differences in cough severity or resolution were found between the two groups of children in any of the 28 days of the study. After the first week (day 8) cough was completely resolved in more than one-half of patients in both groups. Two children (4.3 %) reported adverse effects in the group treated with the homeopathic syrup alone, versus 9 children (23.1 %) in the group treated with the homeopathic syrup plus antibiotics (P = 0.020). CONCLUSIONS: Our data confirm that the homeopathic treatment in question has potential benefits for cough in children as well, and highlight the strong safety profile of this treatment. Additional antibiotic prescription was not associated with a greater cough reduction, and presented more adverse events than the homeopathic syrup alone. PMID- 26251724 TI - Mean amplitude deviation calculated from raw acceleration data: a novel method for classifying the intensity of adolescents' physical activity irrespective of accelerometer brand. AB - BACKGROUND: Using raw acceleration data to assess the intensity of physical activity enables direct comparisons between studies using different accelerometer brands. Mean amplitude deviation (MAD in mg) calculated from resultant tri-axial raw acceleration signal was recently shown to perform best in classifying the intensity of physical activity in adults irrespective of the accelerometer brand. This study compared MAD values and cut-points between two different accelerometers in adolescents. METHODS: Twenty voluntary participants (10 girls and 10 boys) of average age of 14 wore two accelerometers (Actigraph GTX3, Pensacola FL, USA and Hookie AM13, Espoo, Finland) and heart rate monitors (M61, Polar Electro Oy, Kempele, Finland) while completing ten 2-min patterns of typical activities ranging from sedentary behaviour to light, moderate and vigorous-intensity locomotion. Bland-Altman method examined the agreement of MAD values between the accelerometers. Correlation coefficient between individual heart rates and MAD values indicated the validity of pattern-based intensity classification. Generalized ordinal logistic regression determined the intensity specific MAD cut-points for both accelerometers. RESULTS: MAD values varied from 3 mg (lying supine) to 1609 mg (running). Hookie gave higher values than Actigraph in accelerations exceeding 700 mg. The correlation coefficient between MAD values and heart rates was 0.96 for Hookie and 0.97 for Actigraph. Respectively, the MAD cut-points were 29 and 27 (light), 338 and 330 (moderate), and 604 and 558 (vigorous). CONCLUSIONS: MAD values and cut-points of Hookie and Actigraph showed excellent agreement. Analysing raw accelerometer data with MAD values may enable the comparison of accelerometer results between different studies also in adolescents. PMID- 26251725 TI - Outcomes of partial nephrectomy in patients who meet percutaneous ablation criteria. AB - INTRODUCTION: Treatment options for small renal masses include partial nephrectomy (PN), ablation and active surveillance. We sought to compare patients who met the criteria for percutaneous ablation but underwent robotic PN to the rest of our robotic PN cohort. This was done in order to detect any safety concerns and to define any risk factors that might contraindicate the use of robotic PN, an oncologically superior procedure, in patients who qualify for ablation. MATERIAL AND METHODS: Our departmental renal mass registry was queried for patients who underwent robotic PN but also met criteria for percutaneous ablation. These were compared to the rest of the robotic PN cohort. Demographics, perioperative characteristics and recurrence data were compared. RESULTS: Overall, 321 robotic PNs were identified. Of these, 26 (8.1%) met ablation criteria. Among patient characteristics, age and BMI were similar in both groups. Among operative characteristics, estimated blood loss (EBL) and operative time were similar. Warm ischemia time was significantly less for patients who met ablation criteria (14 vs. 17 minutes, p = 0.002). Mean tumor size was smaller for patients who met ablation criteria (2.3 vs. 2.7 cm, p = 0.012). Among postoperative characteristics, complications were similar overall and when present, stratified by Clavien grade. CONCLUSIONS: Robotic PN is a safe, effective treatment option for small renal masses, even in patients who meet ablation criteria. There were no recurrences in our cohort and the majority of complications were Clavien grade 1. PMID- 26251726 TI - What matters when selecting candidates for renal ablation: tumor size or the patient's condition? PMID- 26251723 TI - Amelogenin and Enamel Biomimetics. AB - Mature tooth enamel is acellular and does not regenerate itself. Developing technologies that rebuild tooth enamel and preserve tooth structure is therefore of great interest. Considering the importance of amelogenin protein in dental enamel formation, its ability to control apatite mineralization in vitro, and its potential to be applied in fabrication of future bio-inspired dental material this review focuses on two major subjects: amelogenin and enamel biomimetics. We review the most recent findings on amelogenin secondary and tertiary structural properties with a focus on its interactions with different targets including other enamel proteins, apatite mineral, and phospholipids. Following a brief overview of enamel hierarchical structure and its mechanical properties we will present the state-of-the-art strategies in the biomimetic reconstruction of human enamel. PMID- 26251727 TI - Can robotic partial nephrectomy replace the ablative techniques in the treatment of small renal masses? PMID- 26251728 TI - AUTHOR'S REPLY. PMID- 26251729 TI - Survival up to 5-15 years in young women following genital sparing radical cystectomy and neobladder: oncological outcome and quality of life. Single surgeon and single-institution experience. AB - INTRODUCTION: This is an observational retrospective study utilising long term patient follow-up for 15 years to determine the survival and quality of life in women (age range 20-54 years) after having been treated for carcinoma of the bladder by radical cystectomy with preservation of genital organs. MATERIAL AND METHODS: The study included 13 female patients with urothelial carcinoma of the bladder treated with genital sparing radical cystectomy during the period of 1995 until 2006. They had orthotopic ileal neobladder. Follow-up included recurrence free survival, metastases-free survival, overall survival, continence, and sexual function. RESULTS: Genital sparing cystectomy was done in 13 women. Seven women were between the ages of 20-37, and 6 women were aged 38-54. Overall survival of 10-15 years was 61.53%, survival from 5 to 9 years was 38.46%. The procedure was done in 9 women with a muscle-invasive tumor of stage T2- T3a. Non-muscle invasive T1 tumor was present in four patients. Quality of life was assessed by continence, which was good in 10/13 patients. Three women needed CIC. Sexual function was tested by female sexual function index >20-30 and was scored at 84.61%. CONCLUSIONS: The study provides evidence of safety and efficacy of radical cystectomy with sparing of genital organs in women aged 20 to 54 with urothelial carcinoma of the bladder. Oncological outcome for 5-15 years was good; continence and sexual function were good. This procedure should be considered when surgical approach appears to be feasible. The limitation of our findings is the small sample size of this case series. PMID- 26251730 TI - Sparing radical cystectomy - How much is enough? PMID- 26251731 TI - AUTHOR'S REPLY. PMID- 26251732 TI - External validation of extended prostate biopsy nomogram. AB - INTRODUCTION: Historical nomograms for the prediction of cancer on prostate biopsy, developed in the sextant biopsy era are no more accurate today. The aim of this study was an independent external validation of a 10-core biopsy nomogram by Chun et al. (2007). MATERIAL AND METHODS: A total of 322 patients who presented for their initial biopsy in a tertiary care center and had all the necessary data available were included in the retrospective analysis. To validate the nomogram, receiver operator characteristic (ROC) curves and calibration plots were constructed. RESULTS: Area under the ROC curve calculated for our data using the nomogram was 0.773, similar to that reported originally. However, the nomogram systematically overestimated prostate cancer risk, which, for our data, could be resolved by subtracting 24 points from the total number of points of the nomogram. CONCLUSIONS: The nomogram yielded overall good predictive accuracy as measured by the area under the ROC curve, but it systematically overestimated PC probability in individual patients. However, we showed how the nomogram could easily be adapted to our patient sample, resolving the bias issue. PMID- 26251733 TI - Extrarenal nephroblastoma. AB - INTRODUCTION: Nephroblastoma is one of the most common solid tumours in children. The occurrence of extrarenal nephroblastoma is exceedingly rare. What can be defined as extrarenal Wilms' tumor must satisfy the following criteria: histologically confirmed nephroblastoma and extrarenal location. MATERIAL AND METHODS: Current data on extrarenal nephroblastoma based on a selective review of the literature. RESULTS: The retroperineal location is reported to be typical in males, whereas the inguinal region is believed to predominate in females. There are no characteristic manifestations of extrarenal nephroblastoma. The symptoms depend on the location and stage upon diagnosis. US, CT and MRI are used to detect tumours in the retroperiteneal space, inguinal, sacro-coccal and scrotal area. However, extrarenal nephroblastoma does not show characteristic radiological features. CONCLUSIONS: In absence of typical clinical presentation or conclusive imaging tests, the diagnosis is based on histology after the resection of the tumor. The recommended management of the extrarenal nephroblastoma is similar to the treatment of intrarenal nephroblastoma. PMID- 26251735 TI - Contemporary hormone therapy with LHRH agonists for prostate cancer: avoiding osteoporosis and fracture. AB - INTRODUCTION: Prostate cancer is a large clinical burden across Europe. It is, in fact, the most common cancer in males, accounting for more than 92,300 deaths annually throughout the continent. Prostate cancer is androgen-sensitive; thus an androgen deprivation therapy (ADT) is often used for treatment by reducing androgen to castrate levels. Several ADT agents have achieved benefits with effective palliation, but, unfortunately, severe adverse events are frequent. Contemporary ADT (Luteinising Hormone Releasing Hormone agonist - LHRHa injections) can result in side effects that include osteoporosis and fractures, compromising quality of life and survival. METHODS: In this review we analysed the associated bone toxicity consequent upon contemporary ADT and based on the literature and our own experience we present future perspectives that seek to mitigate this associated toxicity both by development of novel therapies and by better identification and prediction of fracture risk. RESULTS: Preliminary results indicate that parenteral oestrogen can mitigate associated osteoporotic risk and that CT scans could provide a more accurate indicator of overall bone quality and hence fracture risk. CONCLUSIONS: As healthcare costs increase globally, cheap and effective alternatives that achieve ADT, but mitigate or avoid such bone toxicities, will be needed. More so, innovative techniques to improve both the measurement and the extent of this toxicity, by assessing bone health and prediction of fracture risk, are also required. PMID- 26251734 TI - The role of epigenetics in kidney malignancies. AB - INTRODUCTION: Renal cell carcinomas (RCC) are collectively the third most common type of genitourinary neoplasms, surpassed only by prostate and bladder cancer. Cure rates for renal cell carcinoma are related to tumor grade and stage; therefore, diagnostic methods for early detection and new therapeutic modalities are of paramount importance. Epigenetics can be defined as inherited modifications in gene expression that are not encoded in the DNA sequence itself. Epigenetics may play an important role in the pursuit of early diagnosis, accurate prognostication and identification of new therapeutic targets. MATERIAL AND METHODS: We used PubMed to conduct a comprehensive search of the English medical literature using search terms including epigenetics, DNA methylation, histone modification, microRNA regulation (miRNA) and RCC. In this review, we discuss the potential application of epigenetics in the diagnosis, prognosis and treatment of kidney cancer. RESULTS: During the last decade, many different types of epigenetic alterations of DNA have been found to be associated with malignant renal tumors. This has led to the research of the diagnostic and prognostic implications of these changes in renal malignancies as well as to the development of novel drugs to target these changes, with the aim of achieving a survival benefit. CONCLUSIONS: Epigenetics has become a promising field in cancer research. The potential to achieve early detection and accurate prognostication in kidney cancer might be feasible through the application of epigenetics. The possibility to reverse these epigenetic changes with new therapeutic agents motivates researchers to continue pursuing better treatment options for kidney cancer and other malignancies. PMID- 26251736 TI - The effect of complete transurethral resection of the prostate on symptoms, quality of life, and voiding function improvement. AB - INTRODUCTION: Transurethral resection of the prostate (TURP) still remains the most popular surgical treatment for patients with lower urinary tract symptoms. However, in some patients, the improvement of symptoms after TURP is insufficient. The aim of our study was to evaluate the impact of the resected prostate tissue weight (RPTW) on the improvement of symptoms (IPSS), quality of life (QoL), and voiding function after TURP. MATERIAL AND METHODS: The study included 89 men who had undergone TURP in our institution. IPSS, QoL, post voiding residual urine volume (PVR) and Qmax were recorded before the operation and six months after TURP. The total prostate volume (TPV) and transition zone volume (TZV) were measured before the operation by transrectal ultrasound. The impact of RPTW, RPTW/TZV ratio, and RPTW/TPV ratio were analyzed according to the efficacy of TURP. RESULTS: The mean Qmax after TURP increased by 10.15 mL/s, IPSS decreased by 16.7 points, QoL increased by 3.57 points, and PVR decreased by 95.3 mL. According to Qmax, the treatment was effective in 74.2%, according to IPSS, in 91%, and according to QoL, in 74.2% of patients. The ROC analysis demonstrated that RPTW/TZV and RPTW/TPV ratios were the most significant predictors of obtaining favorable results. Survival analysis (life table) shows that in order to achieve 50% improvement on Qmax, QoL, and IPSS, more than 30-35% of TPV and more than 60% of the TZV should be removed. CONCLUSIONS: The efficacy of the TURP at short term follow-up depends on the completeness of the resection. PMID- 26251738 TI - Is flexible ureterorenoscopy and laser lithotripsy the new gold standard for lower pole renal stones when compared to shock wave lithotripsy: Comparative outcomes from a University hospital over similar time period. AB - INTRODUCTION: Renal lower pole stones pose difficulty in management due to anatomical variation, stone size, hardness and patient demographics. Flexible ureterorenoscopy and laser lithotripsy (FURSL) and shock wave lithotripsy (SWL) are preferred for stones 1-2 cm in size. We wanted to compare the outcomes of FURSL and SWL for lower pole stones during the same time period. MATERIAL AND METHODS: All patients who were treated for lower pole stones with FURSL and SWL during a 19-month period were included. The stone free rate (SFR) was defined as <=3 mm fragments on follow-up imaging or stone free endoscopically. Data was recorded in an excel spreadsheet with SPSS version 21 used for statistical analysis. RESULTS: A total of 161 lower pole procedures were done (93 SWL and 63 FURSL). The mean stone size for SWL (7.4 mm; range: 4-16 mm) was significantly smaller than for FURSL (13.4 mm; 4-53 mm). The mean operating time and hospital stay for FURSL was 65 minutes (range: 30-160 minutes) and 0.5 days (range: 0-7 days) respectively. The SFR was significantly better (p <0.001) for FURSL (n = 63, 93%) compared to SWL (n = 23, 25%). There were 4 (6%) complications (3 Clavien II and 1 Clavien I) in the FURSL group (2 urosepsis, 1 UTI and 1 stent pain). Three patients in the SWL group (Clavien I) were readmitted with renal colic but there were no other complications. CONCLUSIONS: FURSL for lower pole stones seems to be a much better alternative than SWL with a high SFR even for larger stones and seems to be the new gold standard for lower pole stone management. PMID- 26251737 TI - The role of lasers in modern urology. AB - INTRODUCTION: The functioning of modern urological departments and the high level of service they provide is possible through, among other things, the use of modern laser techniques. MATERIAL AND METHODS: Open operations have been replaced by minimally invasive procedures, and classical surgical tools by advanced lasers. The search for new applications with lasers began as technology developed. Among many devices available, holmium, diode and thulium lasers are currently the most popular. RESULTS: Depending on the wavelength, the absorption by water and hemoglobin and the depth of penetration, lasers can be used for coagulation, vaporization and enucleation. In many centres, after all the possibilities of pharmacological treatment have been exhausted, lasers are used as the primary treatment for patients with benign prostatic hyperplasia, with therapeutic results that are better than those obtained through open or endoscopic operations. The use of lasers in the treatment of urolithiasis, urinary strictures and bladder tumours has made treatment of older patients with multiple comorbidities safe, without further necessity to modify the anticoagulant drug treatment. Laser procedures are additionally less invasive, reduce hospitalization time and enable a shorter bladder catheterization time, sometimes even eliminating the need for bladder catherterization completely. Such procedures are also characterized by more stable outcomes and a lower number of reoperations. CONCLUSIONS: There are also indications that with the increased competition among laser manufacturers, decreased purchase and maintenance costs, and increased operational safety, laser equipment will become mandatory and indispensable asset in all urology wards. PMID- 26251739 TI - Combined ureterorenoscopy for ureteral and renal calculi is not associated with adverse outcomes. AB - INTRODUCTION: We intended to evaluate the feasibility and effectiveness of the simultaneous rigid and flexible ureteroscopic treatment of symptomatic ureteral and ipsilateral small simultaneous calyceal stones. Outcomes of combined therapy were compared with monotherapy alone. MATERIAL AND METHODS: In this retrospective study, group 1 consisted of 45 patients with middle or lower ureteral and ipsilateral small simultaneous calyceal stones treated by combined therapy. Group 2 included 45 patients with middle or lower ureteral stones only and treated by monotherapy. Stone characteristics, operative time, hospital stay, stone free rates, and complications were compared between groups 1 and 2. Stone free status was defined as no fragments and/or the presence of asymptomatic fragments smaller than 4 mm. RESULTS: Mean BMI were 29.3 +/-0.9 kg/m(2) and 27.6 +/-0.6 kg/m(2) in groups 1 and 2, respectively. Mean ureteral stone size (7.6 +/-0.4 mm vs. 8.0 +/ 0.4 mm, p = 0.261) and ureteral stone burden (56.0 +/-5.5 mm(2) vs. 54.8 +/-6.1 mm(2), p = 0.487) were similar between groups. Mean renal stone size and renal stone burden for group 1 were 7.1 +/-0.8 mm and 83.7 +/-11.3 mm(2). The mean operative time was significantly longer (for a mean of 32.5+/-1.2 minutes) for group 1 (p = 0.001). Ureteral stents were left in 38 (84.4%) and 19 (42.2%) patients in group 1 and group 2 (p = 0.001). Hospital stay and complication rates were similar between groups. SFRs were 100% for ureteral stones in both groups and 88.9% for renal stones within group 1. CONCLUSIONS: Simultaneous ureteroscopic treatment of the ureteral and ipsilateral small calyceal stones prolongs operative time and increases use of ureteral stent without leaving any residual renal stones. PMID- 26251740 TI - Feasibility and safety of bilateral same-session flexible ureteroscopy (FURS) for renal and ureteral stone disease. AB - INTRODUCTION: With rising incidence of urolithiasis, treatment of stones (both symptomatic and asymptomatic) in multiple locations including bilateral stones can be controversial and challenging. We report our experience and treatment outcomes in patients undergoing bilateral, same-session ureterorenoscopy (BS-URS) for bilateral ureteric and/or renal calculi, and discuss the advantages and disadvantages of such procedures. MATERIAL AND METHODS: Between May 2012 and October 2013, 251 patients underwent ureteroscopic surgery for stone disease at our institution. Of these, 21 patients underwent 25 bilateral same-session ureterorenoscopy (BS-URS) procedures during this period. Stone-free status was defined as endoscopically stone-free or radiological fragments <2 mm. RESULTS: The mean bilateral stone size was 21mm (range: 4-63 mm) with a mean operating time of 70 minutes (range 35-129 minutes). Fifteen procedures (60%) were done as day case procedures with a mean stay of 0.9 days (range 0-7 days). Of the 42 renal units treated, 80% (34/42) were stone-free after a single bilateral ureteroscopy session. A further 12% (5/42) were cleared after a re-look procedure making the overall stone free rate 92.8% (39/42). There were no major complications and 3 minor complications (2 early stent removals due to stent symptoms and 1 pyelonephritis requiring intravenous antibiotics). CONCLUSIONS: Bilateral same-session ureteroscopy is a safe and effective treatment option for patients with bilateral ureteric and/or renal calculi, even with stones in multiple locations and increasing stone loads. However, as with all surgery, proper patient and equipment selection is crucial in terms of reducing complication rates and improving treatment outcomes. PMID- 26251741 TI - More aggressive intrarenal endoscopic maneuvers are assuring a stone free outcome and safety. PMID- 26251742 TI - AUTHOR'S REPLY. PMID- 26251743 TI - AUTHOR'S REPLY. PMID- 26251744 TI - Pain control using pethidine in combination with diazepam compared to diclofenac in combination with hyoscine-n-butyl bromide: in patients undergoing extracorporeal shock wave lithotripsy. AB - INTRODUCTION: Extracorporeal Shock Wave Lithotripsy (ESWL) remains the preferred least invasive treatment for urinary tract stones. The main purpose of this study was to compare two treatment modalities for pain control during the ESWL procedure. MATERIAL AND METHODS: From 2013 to 2014, 220 patients received ESWL for kidney stones. Before the procedure, the weight and height were measured to determine the body mass index (BMI); in addition, oxygen saturation and the pulse of the patients, as well as pain level were determined. The pain control provided included two different methods: diclofenac sodium plus hyoscine-N-butyl bromide in the first group and pethidine plus diazepam in the second group. The pain level of the patients was determined using two different scales: the Wong-Baker and the Visual Analogue scales (VAS). At the end of three sessions, all patients were evaluated for the stone fragmentation rate by plain abdominal X-ray, and the findings were recorded and analyzed. RESULTS: A total of 220 patients were enrolled in this study. There were 91 patients in the first group (diclofenac sodium + hyoscine-N-butyl bromide) (male/female: 63/28) and 129 (male/female: 83/46) patients in the second group (pethidine HCL +diazepam). The mean age with SD according to each group was 42.03 (+/-16.43) and 42.56 (+/-14.23), respectively (p = 0.8). With regard to pain scores (using the Wong-Baker and VAS scales), the responses were significantly lower in the second group (p <0.001). CONCLUSIONS: Pethidine in combination with diazepam was superior to diclofenac and Hyoscine-N-butyl bromide for pain in patients undergoing ESWL. PMID- 26251746 TI - The 'complements' to virtual simulation. PMID- 26251745 TI - The current role of simulation in urological training. AB - INTRODUCTION: Simulation is becoming an increasingly popular educational tool in numerous surgical specialities, including urology. This article reviews the current role of urological simulators; discussing their need, availability, incorporation and current limitations. MATERIAL AND METHODS: A literature review of the electronic databases Medline, Embase and Google Scholar was performed. RESULTS: For increasingly limited urological training programs, simulation can act as a valuable adjunct to clinical training. Evidence suggests that simulation enables the trainee to bypass the early, error-prone part of the surgical learning curve. It should be incorporated into proficiency-based curricula, with junior trainees initially beginning with low fidelity simulators to grasp basic surgical skills before moving onto full-procedural simulation as they progress through their training. A wide variety of simulators of differing fidelity are currently available, teaching both technical (eg. cystoscopy) and non-technical (eg. communication) urological surgical skills. Whist numerous studies have assessed the face, content and construct validity of various urological simulators, further work needs to be undertaken to determine whether the skills learnt actually improve trainee performance in the operating room. Then, educators will be able to make informed decisions about whether these resource demanding (financially and in terms of demands on faculty) simulators are a worthwhile educational tool. CONCLUSIONS: Although further investigation is required, urological simulators appear to have a considerable role for developing both technical and non-technical urological skills in an increasingly restricted educational environment in modern urogynecology. PMID- 26251747 TI - Simulation - the need for a paradigm shift in urological training. PMID- 26251748 TI - Improvement in sexual function after robot-assisted radical prostatectomy: A rehabilitation program with involvement of a clinical sexologist. AB - INTRODUCTION: To prospectively evaluate if the inclusion of a clinical sexologist in a penile and sexual rehabilitation program improves sexual function one year after prostate cancer surgery. MATERIAL AND METHODS: Twelve months after da Vinci Radical Prostatectomy (dVRP) for prostate cancer, 28 fully potent (IIEF-5 >21) and sexually active men (ages 47-69 years, mean 61) who, in 2008, were enrolled in a prospectively monitored penile rehabilitation program (reference group) were compared with 79 fully potent (IIEF-5 >21) and sexually active men (ages 45-74 years, mean 61) enrolled in 2009 (study group); whose program differed by the inclusion of evaluation and treatment by a clinical sexologist. RESULTS: Twelve months after dVRP, seventeen patients in the reference group (61%) were sexually active with regular penetrating sexual activity compared to sixty-six (84%) in the study group (p = 0.02). These findings were independent of whether they had undergone a nerve sparing or non-nerve sparing procedure. Almost 94% (74 patients) in the study group had at some time been able to perform penetrating sexual activity; 14 patients required additional visits to the clinical sexologist beyond the routine follow-up, 9 for short-term cognitive behavior therapy. CONCLUSIONS: Inclusion of a clinical sexologist in a penile and sexual rehabilitation program appears to improve the ability to have regular sexual activity with penetrating sex one year after da Vinci Robotic Radical Prostatectomy. PMID- 26251749 TI - Sexual rehabilitation or penile rehabilitation - do we have an optimal post prostatectomy regimen? PMID- 26251750 TI - Transrectal-ultrasound prostatic biopsy preparation: rectal enema vs. mechanical bowel preparation. AB - INTRODUCTION: Transrectal prostate biopsy (TRUSbx) is the standard for the diagnosis of prostate cancer. Different bowel preparations are used for patients undergoing TRUSbx. The aim of our study was to compare two different bowel preparations for TRUSbx. MATERIAL AND METHODS: From May 2012 and onwards, a selected group of men undergoing TRUS 12-core prostate biopsy were enrolled into a prospective database. Patients were randomized 1:1 to receive a rectal enema (Group A) the night before the procedure or polyethylene glycol 34.8 grams/4 liters of water the day before the procedure (Group B). A VAS scale to evaluate the patients' discomfort according to the two preparations was collected. The same antibiotic prophylaxis was performed in both groups. All complications were prospectively recorded and graded according to the Clavien Classification System (CCS). RESULTS: A total of 198 patients were consecutively enrolled. Mean age was 67.5 +/-7.9 years, mean body mass index (BMI) was 27.1 +/-4.2 Kg/m(2), mean PSA value was 9.3 +/-12.6 ng/ml and the mean prostatic volume was 60.6 +/-29 ml. 97 patients were enrolled in Group A and 101 in Group B. Overall post-biopsy morbidity rate was 60%. No significant differences for low-grade and high-grade complications was observed between the two groups. Patients receiving the rectal enema presented with a significantly lower VAS score (3.1 +/-1.1 vs. 5.9 +/-1.7; p = 0.02). CONCLUSIONS: Our study confirmed that a rectal enema should be considered as the standard bowel preparation in patients undergoing a TRUS biopsy; it is as effective as PEG and associated with less discomfort. PMID- 26251751 TI - A single 80 mg intravenous gentamicin dose prior to prostate needle biopsy does not reduce procedural infectious complications. AB - INTRODUCTION: Rates of infectious complications continue to increase following transrectal ultrasound guided prostate needle biopsy (TRUS PNB). Administration of a parenteral antibiotic at time of procedure represents one potential prophylaxis strategy. The efficacy of this practice remains incompletely defined. MATERIAL AND METHODS: Our institutional TRUS PNB database was reviewed to identify consecutive men undergoing a biopsy over a 48-month period. The peri operative intravenous antibiotic regimen (when used) included gentamicin 80 mg administered intravenously (IV) 30 minutes prior to biopsy. The incidence of infections post-biopsy was compared between patients receiving oral alone versus IV plus oral antibiotic prophylaxis. RESULTS: 182 of 522 men (34.9%) included in this study received peri-procedural IV gentamicin at time of TRUS PNB, with a significant increase in utilization during the study time period (p <0.001). In total, 39 patients (7.5%) developed an infectious complication post-biopsy. No differences in infection rates were observed between patients receiving only oral prophylaxis (27 of 340, 7.9%) versus those receiving oral with IV gentamicin (12 of 182, 6.6%) (p = 0.73). CONCLUSIONS: In this 4-year cohort analysis, a single peri-procedural dose of 80 mg of intravenous gentamicin failed to confer a reduction in infectious complications following prostate needle biopsy. Such data underscore the need to better understand the dose, route, and type of antimicrobial therapy to limit procedural infections. PMID- 26251752 TI - Santosh PGI pouch: A new innovation in urinary diversion. AB - INTRODUCTION: To know the feasibility and outcome of the Santosh PGI pouch as a new innovative technique of continent cutaneous diversion (CCD) following cystectomy. MATERIAL AND METHODS: Twelve patients (eleven with carcinoma of the bladder and one with an exstrophy of the bladder) underwent CCD using the Santosh PGI pouch after cystectomy. A 50-cm segment of terminal ileum was isolated 15-20 cm proximal to the ileocecal junction. The ileal segment was folded into the form of an 'S' configuration. On the antimesenteric border three longitudinal incisions were performed of about 7 cm in length. The terminal 8 cm portion of the distal part of the pouch was used for creating the intussuscepted nipple valve. Demucosalization of the interior of the nipple, fixing the nipple valve with the serosa of the pouch wall and wrapping of the catheterizable channel with a pouch wall for providing continence was done. The uretero-pouch anastomosis was done using the serosal lined tunnel technique. The catheterizable channel was brought out through the right rectus muscle. RESULTS: Median follow-up of the patients was 13.5 months. No significant complications were noted in the pouch reconstruction. Duration of the pouch reconstruction was around 75-110 min. Postoperatively, one patient had a UTI and another had paralytic ileus on the follow-up. All patients were doing regular CIC with acceptable continence of up to 400 ml. No ureteroileal anastomotic stricture or difficulty in catheterizing the pouch was seen. CONCLUSIONS: The Santosh PGI pouch, which is a type of CCD, is technically feasible, easy to reconstruct with acceptable continence and offers minimal morbidity. PMID- 26251753 TI - Robot-assisted laparoscopic total extraperitoneal hernia repair during prostatectomy: technique and initial experience. AB - INTRODUCTION: To describe the technique of total extraperitoneal inguinal hernia repair performed during Robot-assisted Endoscopic Extraperitoneal Radical Prostatectomy (R-EERPE) and to present the initial outcomes. MATERIAL AND METHODS: 12 patients underwent inguinal hernia repair during 120 R-EERPEs performed between July 2011 and March 2012. All patients had a clinically palpable inguinal hernia preoperatively. The hernia was repaired using a Total Extraperitoneal Patch (TEP) at the end of the procedure. RESULTS: Sac dissection and mesh placement was simpler compared to conventional laparoscopy due to improved, magnified, 3-D vision along with 7 degrees of movement, and better control of mesh placement. The median operating time was 185 minutes, with on average, an additional 12 minutes incurred per hernia repair. The median blood loss for the procedures was 250 ml, and the mean pathological prostate weight was 55 gm. No additional blood loss was noted and there were no postoperative complications. None of the patients had a recurrence at 12 months. We await long term follow-up data. CONCLUSIONS: Robot-assisted TEP is feasible and should be considered in patients with hernia at the time of R-EERPE. PMID- 26251754 TI - An up-to-date overview of minimally invasive treatment methods in ureteropelvic junction obstruction. AB - INTRODUCTION: Over the last two decades, minimally invasive treatment options for ureteropelvic junction obstruction have been developed and are bcoming more popular. Multiple series of laparoscopic pyeloplasty have demonstrated high success rates and low perioperative morbidity in pediatric and adult populations, for both the transperitoneal and retroperitoneal approaches. In this review, we aimed to analyze the current status of minimally invasive therapy of ureteropelvic junction obstruction. MATERIAL AND METHODS: A PubMed database search was conducted to examine minimally invasive treatments of ureteropelvic junction obstruction. RESULTS: A large number of cases have been reported for adult patients, confirming that robotic pyeloplasty represents a viable option for either primary or secondary repair. Comparative studies demonstrate similar success and complication rates between minimally invasive and open pyeloplasty in both the adult and pediatric populations. A clear advantage, in terms of hospital stay, of minimally invasive over open pyeloplasty was observed only in the adult population. CONCLUSIONS: Studies have shown that minimally invasive pyeloplasty techniques are a safe, effective, and feasible in adult and pediatric populations. PMID- 26251755 TI - Is it possible to distinguish testicular torsion from other causes of acute scrotum in patients who underwent scrotal exploration? A multi-center clinical trial. AB - INTRODUCTION: To assess the clinical presentation of patients who underwent surgical exploration for acute scrotum and to investigate the potentially related factors for differential dignosis. MATERIAL AND METHODS: We retrospectively analyzed the medical records of 97 patients who underwent surgical exploration for acute scrotum between May 2007 and July 2013. The patients were divided into two groups as follows: Group1 included patients with testicular torsion (TT) and Group 2 contained patients with acute scrotal pathologies other than TT, including torsion of the testicular appendage, epididymo-orchitis, trauma and Henoch-Schonlein purpura. The physical examination findings, colour Doppler ultrasound (CDUS) and laboratory findings for the groups were compared. RESULTS: In total, 97 scrotal explorations were carried out for acute scrotum. Group 1 included 72 patients (74.2%) and Group 2 included 25 patients (25.8%). Group 2 was comprised of patients with torsion of the testicular appendage (n = 13), epididymo-orchitis (n = 8), testicular trauma (n = 2) and Henoch-Schonlein purpura (n = 2). In Group 1, 32 cases (44.4%) presented to a hospital less than 6 hours after onset of pain. More than half (64%) of Group 2's cases presented more than 24 hours after pain onset. Fever and pyuria appeared more frequently in Group 2 than in Group 1 and the results reached statistical significance (p = 0.001 and p = 0.044, respectively). Group 1 had more testicular tenderness than Group 2 (p <0.001). Our testicular salvage rate was 59.7%, and 40.3% of patients underwent orchiectomy. CONCLUSIONS: CDUS predicted the diagnosis of TT (sensitivity 98.6%). Furthermore, clinical findings may also play a substantial role in the differential diagnosis of acute scrotum. PMID- 26251756 TI - EVC gene polymorphisms and risks of isolated hypospadias - a preliminary study. AB - INTRODUCTION: Hypospadias has a complex etiology with both genetic and environmental factors contributing to the condition. Urogenital abnormalities including hypospadias, are found in 22% of cases with Ellis van Creveld syndrome (EvC). Mutations in the EVC gene can cause major and minor anomalies, which form phenotypes that partially overlap with those present in EvC. The aim of this study was to evaluate the association between nucleotide variants of the EVC gene and the risk of hypospadias. MATERIAL AND METHODS: Four single nucleotide polymorphisms (SNPs) of the EVC gene (rs3774856, rs2302075, rs1383180, rs7680768) were taken under investigation in 96 patients with isolated hypospadias and 284 matched controls. Genotyping of all polymorphisms was carried out by PCR and followed by appropriate restriction enzyme digestion (PCR-RFLP). RESULTS: Individuals homozygous for the SNP rs2302075 (p.Thr449Lys) showed an elevated risk for hypospadias. Haplotypes containing the rs2302075 variant also revealed modest associations with hypospadias, which did not survive multiple testing corrections. None of the other tested EVC polymorphisms displayed significant association with the risk of hypospadias, either in dominant or recessive inheritance models. CONCLUSIONS: The results of this study suggest that polymorphic variants of the EVC gene do not substantially contribute to the risk of hypospadias based on our study population. However, further studies should help to clarify the relationship between polymorphisms of EVC and hypospadias. PMID- 26251757 TI - Robotic adrenalectomy for a 3 cm sized left adrenal mass suggesting Cushing's syndrome. PMID- 26251758 TI - Lopinavir/Ritonavir Impairs Physical Strength in Association with Reduced Igf1 Expression in Skeletal Muscle of Older Mice. AB - BACKGROUND: Late-middle age HIV patients are prone to fatigue despite effective viral control by antiretroviral therapies. Rodent models to recapitulate this phenotype are still not available. HYPOTHESIS: Drug treatment may compromise muscle strength and physical performance more in older individuals with pre existing metabolic disorders than normal young ones. METHODS: Kaletra was given to overweight male mice at late-middle age and normal young adults; both on a rodent diet containing 30% fat calorie. Body composition and grip strength were measured at baseline and after drug treatment. Rota-rod running, insulin and glucose tolerance were measured at the end of the experiment. Drug effect on metabolic activity and spontaneous movements were assessed using the metabolic cage system. Representative muscle and fat tissue were analyzed for protein and mRNA expression. Selected findings were tested using murine C2C12 myotubes. RESULTS: Kaletra reduced grip strength in both young and older mice but impaired rotarod performance only in the old. Spontaneous movements were also reduced in Kaletra-treated old mice. Kaletra reduced IGF-1 expression in all muscle groups tested for the old and in cultured myotubes but to a less extent in the muscle of young animals. Reduced IGF-1 expression correlated with increased expression of muscle-specific atrogene MAFbx and MuRF1. Kaletra also increased abdominal fat mass markedly in the old animals and to a less extend in the young. CONCLUSION: Long-term Kaletra intake aggravated abdominal obesity and impaired muscle strength. This effect was worse in older animals than in normal young adults. PMID- 26251759 TI - Direct and Indirect Serum Markers of Liver Fibrosis Compared with Transient Elastography among Women in the Women's Interagency HIV Study. AB - OBJECTIVE: The aim of this study was to determine the test characteristics of direct and indirect biomarkers for liver fibrosis compared with transient elastography (TE) among a group of human immunodeficiency virus (HIV)-infected and uninfected women with or without Hepatitis C virus (HCV) infection. METHODS: Women enrolled in the Women's Interagency HIV Study (WIHS) from Washington DC, San Francisco, and Chicago with a body mass index (BMI)<35 underwent liver stiffness measurement using TE between October, 2010 and September, 2012. Serum samples were tested for hyaluronic acid to calculate the SHASTA and aspartate aminotransferase to platelet ratio index (APRI). Receiver operator characteristics (ROC) of significant liver fibrosis (liver stiffness >= 7.1 kPa by TE, correlating with a METAVIR fibrosis score of F2-F4) predicted by SHASTA and APRI were compared. RESULTS: Among 308 women, the median age was 48 years, BMI was 25.6, 67% were non-Hispanic black, 27% HCV+, and 78% HIV+. The overall prevalence of significant liver fibrosis was 20%, and among HIV+ women, 22%. Overall, there was no statistically significant difference in the area under ROC curve (AUROC) between SHASTA and APRI relative to significant fibrosis by TE. Among HCV+ women (with or without HIV), the AUROC ranged from 0.70-0.73 for both the SHASTA and APRI compared to TE. Both SHASTA and APRI were associated with significant misclassification with a false negative rate of 33-40% for significant fibrosis compared with TE among women with HCV infection, with or without HIV. CONCLUSION: Both the SHASTA and APRI, direct and indirect serum biomarkers of liver fibrosis respectively, are comparable at detection of significant liver fibrosis among women with HCV infection, regardless of HIV status. However, there was a high false negative rate in detection of significant liver fibrosis of up to 40% which is a significant limitation of use of these biomarkers. PMID- 26251760 TI - Bifunctional Peptide Inhibitors Suppress Interleukin-6 Proliferation and Ameliorates Murine Collagen-Induced Arthritis. AB - The objective of this study is to evaluate the efficacy and potential mechanism of action of type-II collagen bifunctional peptide inhibitor (CII-BPI) molecules in suppressing rheumatoid arthritis in the collagen-induced arthritis (CIA) mouse model. CII-BPI molecules (CII-BPI-1, CII-BPI-2, and CII-BPI-3) were formed through conjugation between an antigenic peptide derived from type-II collagen and a cell adhesion peptide LABL (CD11a237-246) from the I-domain of LFA-1 via a linker molecule. The hypothesis is that the CII-BPI molecules simultaneously bind to MHC-II and ICAM-1 on the surface of APC and block maturation of the immunological synapse. As a result, the differentiation of naive T cells is altered from inflammatory to regulatory and/or suppressor T cells. The efficacies of CII-BPI molecules were evaluated upon intravenous injections in CIA mice. Results showed that CII-BPI-1 and CIIBPI-2 suppressed the joint inflammations in CIA mice in a dose-dependent manner and were more potent than the respective antigenic peptides alone. CII-BPI-3 was not as efficacious as CII-BPI-1 and CII BPI-2. Significantly less joint damage was observed in CII-BPI-2 and CII-2 treated mice than in the control. The production of IL-6 was significantly lower at the peak of disease in mice treated with CII-BPI-2 compared to those treated with CII-2 and control. In conclusion, this is the first proof-of-concept study showing that BPI molecules can be used to suppress RA and may be a potential therapeutic strategy for the treatment of rheumatoid arthritis. PMID- 26251761 TI - Analysis of the anti-proliferative and the pro-apoptotic efficacy of Syk inhibition in multiple myeloma. AB - BACKGROUND: Multiple myeloma (MM) is a clonal B cell malignancy characterized by proliferation of malignant plasma cells in the bone marrow. Despite high-dose melphalan therapy with autologous stem cell transplantation (ASCT) and the introduction of immunomodulatory drugs like bortezomib or lenalidomide, that have been associated with improved survival, MM is still incurable and new treatment options are needed. In B cell malignancies such as chronic lymphocytic leukaemia (CLL) or diffuse large B cell lymphoma (DLBCL), Syk (spleen tyrosine kinase) inhibitors have shown promising in vitro and first clinical results. In our study, we analyzed the potential of Syk as a target in MM. METHODS: The MM cell lines AMO-1, U266 and RPMI8226 and primary MM cells were treated with the Syk inhibitors BAY61-3606, R406 or Piceatannol and proliferation, migration and apoptosis induction were analyzed. Effects on involved intracellular signaling cascades were determined by Western blotting. Furthermore, we analyzed synergistic and additive effects of Syk inhibitors in combination with established anti-myeloma drugs and experimental inhibitors (e.g. PI-3-Kinase inhibitor NVP-BEZ235). RESULTS: Incubation of MM cell lines as well as primary MM cells with Syk inhibitors resulted in a reduced proliferation and stromal cell derived factor-1 alpha (SDF-1 alpha) induced migration that was accompanied by a concentration dependent inhibition of the MAP-Kinase, characterized by reduced phosphorylation of ERK an p38 molecules, and NF-kappaB signalling pathways. Furthermore, Syk inhibition induced apoptosis in MM cells in a dose-dependent manner, characterized by reduced expression of pro-caspase 3, increased PARP-1 cleavage and enhanced release of cytochrome c. In addition combined treatment of MM cells with Syk inhibitors and NVP-BEZ235 (dual PI3-kinase/mTOR inhibitor) or MAPK inhibitors (PD98059, SP600125, U0126, SB203580) resulted in increased apoptotic activity of the drugs. CONCLUSIONS: Our results show that Syk inhibition might represent a promising new treatment option in MM with an increased efficacy when combined with MAP kinase inhibitors. Furthermore, our study strongly underlines the potency of Syk inhibitors as a potential therapeutic treatment option for MM patients. PMID- 26251762 TI - Tissue factor-dependent and -independent pathways of systemic coagulation activation in acute myeloid leukemia: a single-center cohort study. AB - BACKGROUND: In acute myeloid leukemia (AML), disseminated intravascular coagulation (DIC) contributes to morbidity and mortality, but the underlying pathomechanisms remain incompletely understood. METHODS: We conducted a prospective study on 69 patients with newly diagnosed AML to further define the correlates of systemic coagulation activation in this hematological malignancy. Tissue factor procoagulant activity (TF PCA) of isolated peripheral blood mononuclear cells (PBMCs) and TF expression by circulating microparticles (MPs) were assessed by single-stage clotting and thrombin generation assay, respectively. Soluble plasma TF antigen and secretion of vascular endothelial growth factor (VEGF) by cultured PBMCs were measured by ELISA. Cell-free plasma DNA was quantified by staining with a fluorescent dye. RESULT: TF PCA of PBMCs was significantly increased in AML patients as compared to healthy controls. Furthermore, TF PCA was significantly associated with decompensated DIC at presentation, as defined by a plasma fibrinogen level of <=1 g/L (n = 11). In addition to TF PCA and circulating blasts, serum lactate dehydrogenase, a surrogate marker for leukemic cell turnover, correlated with plasma D-Dimer in the total patient cohort and was significantly increased in DIC patients, suggesting a role for myeloblast apoptosis/necrosis in activation of the TF dependent coagulation pathway. Consistently, TF-bearing plasma MPs were more frequently detected and levels of soluble TF antigen were significantly higher in DIC vs. non-DIC patients. No association was found between TF PCA expression and VEGF secretion by isolated PBMCs, but significantly increased levels of cell-free plasma DNA pointed to a contribution of the intrinsic contact pathway to systemic coagulation activation in the total patient cohort and in patients with lower TF PCA expression. While PBMC-associated TF PCA had no effect on long-term survival, DIC occurrence at presentation increased the risk of early mortality. CONCLUSION: In newly diagnosed AML, TF expression by PBMCs and shedding of TF-bearing plasma MPs are central to the pathogenesis of DIC, but additional pathways, such as DNA liberation, may contribute to systemic coagulation activation. PMID- 26251763 TI - Pregnancy and Postpartum Related Weight Counseling Practices of U.S. Obstetrician Gynecologists: Results from the Doc Styles Survey, 2010. AB - OBJECTIVE: To describe factors and provider characteristics associated with weight-related counseling practices among U.S. obstetrician-gynecologists (OB/GYNs). METHODS: Data were from a 2010 cross-sectional survey of 250 OB/GYNs. The OB/GYNs were asked how often they used pre-pregnancy body mass index (BMI) to determine the appropriate range of gestational weight gain (GWG), counseled pregnant patients on appropriate rate of GWG, and counseled postpartum patients on weight loss or maintenance. They were also asked how often they counseled pregnant and postpartum patients on five weight-related behaviors [consumption of Fruits and Vegetables (FV), Sugar-Sweetened Beverages (SSB), or high-fat or sugary foods, breastfeeding, and Physical Activity (PA)]. RESULTS: Less than half of providers reported "always" using BMI to determine appropriate GWG (42%); however 65% reported "always" counseling about appropriate GWG rate. About one third of providers reported counseling about postpartum weight loss or maintenance (38%).Providers reported counseling pregnant and postpartum patients on all weight-related behaviors only 58% and 27% of the time, respectively. Providers with normal BMI had a greater odds of counseling pregnant patients on FV consumption (adjusted odds ratio (aOR): 3.2; 95% confidence interval (CI): 1.5 7.0) and postpartum patients on FV (aOR: 1.9; 95% CI: 1.1-3.6) compared to overweight/obese providers. Providers who exercised regularly had a greater odds of counseling pregnant and postpartum patients on SSB (aOR: 2.2; 95% CI: 1.1-4.8, and aOR: 2.6; 95% CI: 1.4-4.9, respectively) compared to those providers not exercising regularly. Providers who used podcasts for continuing medical education(CME) had a greater odds of providing counseling on several behaviors, including postpartum patients on FV consumption (aOR: 3.1; 95% CI: 1.3-7.2). CONCLUSIONS: Improvements can be made in weight-related counseling practices of OB/GYNs for both pregnant and postpartum patients. Strategies to improve counseling practices, such as podcasts for CME, could be investigated further. PMID- 26251764 TI - Impaired signaling intrinsic to sinoatrial node pacemaker cells affects heart rate variability during cardiac disease. AB - The normal heart beat intervals are neither strictly stationary nor completely random, and continuously shift from one period to another. Decoding the ECG identifies this "hidden" information that imparts inherent complexity to the heart-beating interval time series. Loss of this complexity in cardiovascular disease is manifested as a reduction in heart rate variability (HRV) and this reduction correlates with an increase in both morbidity and mortality. Because HRV measurements are noninvasive and easy to perform, they have emerged as an important tool in cardiology. However, the identities of specific mechanisms that underline the changes in HRV that occur in cardiovascular diseases remain largely unknown. Changes in HRV have mainly been interpreted on a neural basis, ie due to changes in autonomic impulses to the heart: sympathetic activity decreases both the average heart beat interval and HRV, and parasympathetic activity increases both. It has now become clear, however, that the heart rate and HRV are also determined by intrinsic properties of the pacemaker cells that comprise the sinoatrial node, and the responses of these properties to autonomic receptor stimulation. Here we review how changes in the properties of coupled-clock mechanisms intrinsic to pacemaker cells that comprise the sinoatrial node and their impaired response to autonomic receptor stimulation are implicated in the changes of HRV observed in heart diseases. PMID- 26251765 TI - Pathogenic mechanisms and the prospect of gene therapy for choroideremia. AB - INTRODUCTION: Choroideremia is a rare, X-linked disorder recognized by its specific ocular phenotype as a progressive degenerative retinopathy resulting in blindness. New therapeutic approaches, primarily based on genetic mechanisms, have emerged that aim to prevent the progressive vision loss. AREAS COVERED: This article will review the research that has progressed incrementally over the past two decades from mapping to gene discovery, uncovering the presumed mechanisms triggering the retinopathy to preclinical testing of potential therapies. EXPERT OPINION: While still in an evaluative phase, the introduction of gene replacement as a potential therapy has been greeted with great enthusiasm by patients, advocacy groups and the medical community. PMID- 26251767 TI - 'Salvage Treatment' of Aggressive Giant Cell Tumor of Bones with Denosumab. AB - Giant cell tumor of the bone (GCTB) presents as a lytic lesion of epiphyseometaphyseal regions of the long bones usually during the second to the fourth decade with female predilection. Histologically, they are formed of neoplastic mononuclear cells with a higher receptor activator of nuclear factor kappa-B ligand (RANKL) expression responsible for the aggressive osteolytic nature of the tumour. RANKL helps in the formation and functioning of osteoclasts. A newer molecule, Denosumab, is a monoclonal antibody directed against RANKL and thus prevents the formation and function of osteoclasts. Management of refractory, multicentric, recurrent, or metastatic GCTB remains challenging as achieving a tumor-free margin surgically is not always possible. Denosumab may play a crucial role, especially in the management of such difficult lesions. We present three cases of locally aggressive GCTB (involving proximal humerus, sacrum, and proximal femur) that were treated and responded very well to Denosumab therapy. PMID- 26251766 TI - Hypersexuality Addiction and Withdrawal: Phenomenology, Neurogenetics and Epigenetics. AB - Hypersexuality is now part of the DSM-V and has been defined as abnormally increased sexual activity. Epidemiological and clinical studies have shown that this non-paraphilic condition consists of "excessive" sexual behaviors and disorders accompanied by personal distress and social and medical morbidity. Hypersexual disorder is conceptualized as primarily a non-paraphilic sexual desire disorder with impulsivity. Pathophysiological perspectives include dysregulation of sexual arousal and desire, sexual impulsivity, sexual addiction, and sexual compulsivity. The nucleus accumbens, situated within the ventral striatum, mediates the reinforcing effects of drugs of abuse, such as cocaine, alcohol, nicotine, and food as well as music. Indeed, it is believed that this structure mandates behaviors elicited by incentive stimuli. These behaviors include natural rewards like feeding, drinking, sexual behavior, and exploratory locomotion. An essential rule of positive reinforcement is that motor responses will increase in magnitude and vigor if followed by a rewarding event. Here, we are hypothesizing that there is a common mechanism of action (MOA) for the powerful effects drugs, music, food, and sex have on human motivation. The human drive for the three necessary motivational behaviors "hunger, thirst, and sex" may all have common molecular genetic antecedents that, if impaired, lead to aberrant behaviors. We hypothesize that based on a plethora of scientific support hypersexual activity is indeed like drugs, food, and music that activate brain mesolimbic reward circuitry. Moreover, dopaminergic gene and possibly other candidate neurotransmitter-related gene polymorphisms affect both hedonic and anhedonic behavioral outcomes. There is little known about both the genetics and epigenetics of hypersexuality in the current literature. However, we anticipate that future studies based on assessments with clinical instruments combined with genotyping of sex addicts will provide evidence for specific clustering of sexual typologies with polymorphic associations. The authors are also encouraging both clinical and academic scientists to embark on research using neuroimaging tools to examine natural dopaminergic agonistic agents targeting specific gene polymorphisms to "normalize" hyper- or hyposexual response. PMID- 26251768 TI - Economic Performance of Oblique Lateral Lumbar Interbody Fusion (OLLIF) with a Focus on Hospital Throughput Efficiency. AB - Oblique lateral lumbar interbody fusion (OLLIF) is a minimally invasive lumbar surgery. Differences in resource consumption between open spinal surgeries, transformational lumbar interbody fusions (TLIF) and OLLIF, are not documented. We monetize quantifiable differences in resource utilization between the two procedures. A retrospective review of 124 surgeries was performed (OLLIF=69, TLIF=55). Standard conversion factors were used and values reported based on the levels (1-4) addressed at surgery. One level surgery time (OLLIF 62.9 vs. TLIF 134.9 minutes) and surgical expense (OLLIF $5,253 vs. TLIF $11,264) were reduced in the OLLIF population. Inpatient costs (OLLIF $5,712 vs. TLIF $9,271) and length of stay (LOS) were also reduced (OLLIF 2.6 vs. TLIF 4.2 days). Per case, reduced resource consumption suggests lower total hospital costs. Reduced surgical time and LOS can result in greater patient throughput per operating room and patient bed for OLLIF patients in hospitals that have resourced constrained environments. PMID- 26251770 TI - Chronic Intermittent Abdominal Bloating and Change in Bowel Habit: An Eight Year Diagnostic Problem Associated with Intra-Abdominal Adhesions. AB - Abdominal bloating is a common clinical presentation and can impact significantly on the quality of life. It can be functional or signify more serious pathology. We present a case presentation of a 38-year-old man who presented with recurrent episodes of abdominal bloating and severe debilitation for many years. He had suffered weight loss and was unable to tolerate solids. Ten years ago, he underwent an emergency laparotomy for sigmoid volvulus. In the presence of anaemia, normal imaging, and normal endoscopy, a laparoscopy was performed. At surgery, several adhesional bands were identified and resected. He had an uncomplicated recovery. Acute and chronic adhesional bowel obstruction are common presentations and carry a significant morbidity and mortality. Elective laparoscopy can be a valuable tool for diagnostic and treatment purposes. Pathology should be suspected in cases where weight loss is a feature. PMID- 26251769 TI - Predictors of Neurocognitive Syndromes in Combat Veterans. AB - Traumatic brain injury, depression and posttraumatic stress disorder (PTSD) are neurocognitive syndromes often associated with impairment of physical and mental health, as well as functional status. These syndromes are also frequent in military service members (SMs) after combat, although their presentation is often delayed until months after their return. The objective of this prospective cohort study was the identification of independent predictors of neurocognitive syndromes upon return from deployment could facilitate early intervention to prevent disability. We completed a comprehensive baseline assessment, followed by serial evaluations at three, six, and 12 months, to assess for new-onset PTSD, depression, or postconcussive syndrome (PCS) in order to identify baseline factors most strongly associated with subsequent neurocognitive syndromes. On serial follow-up, seven participants developed at least one neurocognitive syndrome: five with PTSD, one with depression and PTSD, and one with PCS. On univariate analysis, 60 items were associated with syndrome development at p < 0.15. Decision trees and ensemble tree multivariate models yielded four common independent predictors of PTSD: right superior longitudinal fasciculus tract volume on MRI; resting state connectivity between the right amygdala and left superior temporal gyrus (BA41/42) on functional MRI; and single nucleotide polymorphisms in the genes coding for myelin basic protein as well as brain derived neurotrophic factor. Our findings require follow-up studies with greater sample size and suggest that neuroimaging and molecular biomarkers may help distinguish those at high risk for post-deployment neurocognitive syndromes. PMID- 26251771 TI - Diffusion theory and knowledge dissemination, utilization and integration. AB - Part of the Community Health and Preventive Medicine Commons, Health and Medical Administration Commons, Health Policy Commons, Health Services Administration Commons, Health Services Research Commons, and the Public Health Education and Promotion Commons. Many accomplishments of public health have been distributed unevenly among populations. This article reviews the concepts of applying evidence-based practice in public health in the face of the varied cultures and circumstances of practice in these varied populations. Key components of EBPH include: making decisions based on the best available scientific evidence, using data and information systems systematically, applying program planning frameworks, engaging the community and practitioners in decision making, conducting sound evaluation, and disseminating what is learned. The usual application of these principles has overemphasized the scientific evidence as the starting point, whereas this review suggests engaging the community and practitioners as an equally important starting point to assess their needs, assets and circumstances, which can be facilitated with program planning frameworks and use of local assessment and surveillance data. PMID- 26251772 TI - Strategy to Increase Research in Latin America: Project on Education in Research by AOSpine Latin America. PMID- 26251773 TI - Posterior fossa ependymoblastoma diagnosed in the second month of life: uneventful 12 years survival after gross total resection followed by chemotherapy. AB - We report on an infant who underwent gross total resection (GTR) of a posterior fossa ependymoblastoma in the second month of life followed by chemotherapy with uneventful long-term survival for 12 years. Postoperative radiotherapy has been considered obligate to have a chance for prolonged survival, but is inadvisable in infants. To our knowledge, this is the first reported long-term survival in an infant treated for ependymoblastoma. PMID- 26251774 TI - Orthogonality, Lommel integrals and cross product zeros of linear combinations of Bessel functions. AB - The cylindrical Bessel differential equation and the spherical Bessel differential equation in the interval [Formula: see text] with Neumann boundary conditions are considered. The eigenfunctions are linear combinations of the Bessel function [Formula: see text] or linear combinations of the spherical Bessel functions [Formula: see text]. The orthogonality relations with analytical expressions for the normalization constant are given. Explicit expressions for the Lommel integrals in terms of Lommel functions are derived. The cross product zeros [Formula: see text] and [Formula: see text] are considered in the complex plane for real as well as complex values of the index [Formula: see text] and approximations for the exceptional zero [Formula: see text] are obtained. A numerical scheme based on the discretization of the two-dimensional and three dimensional Laplace operator with Neumann boundary conditions is presented. Explicit representations of the radial part of the Laplace operator in form of a tridiagonal matrix allow the simple computation of the cross product zeros. PMID- 26251775 TI - Phylogenetic analysis of methionine synthesis genes from Thalassiosira pseudonana. AB - Diatoms are unicellular algae responsible for approximately 20% of global carbon fixation. Their evolution by secondary endocytobiosis resulted in a complex cellular structure and metabolism compared to algae with primary plastids. The sulfate assimilation and methionine synthesis pathways provide S-containing amino acids for the synthesis of proteins and a range of metabolites such as dimethylsulfoniopropionate. To obtain an insight into the localization and organization of the sulfur metabolism pathways we surveyed the genome of Thalassiosira pseudonana-a model organism for diatom research. We have identified and annotated genes for enzymes involved in respective pathways. Protein localization was predicted using similarities to known signal peptide motifs. We performed detailed phylogenetic analyses of enzymes involved in sulfate uptake/reduction and methionine metabolism. Moreover, we have found in up-stream sequences of studied diatoms methionine biosynthesis genes a conserved motif, which shows similarity to the Met31, a cis-motif regulating expression of methionine biosynthesis genes in yeast. PMID- 26251776 TI - The effectiveness of varicocele embolisation for the treatment of varicocele related orchalgia. AB - PURPOSE: Orchalgia is a common problem with varicoceles however the association between varicocele embolisation for the treatment of varicocele related pain has not been widely investigated. We aim to investigate the effectiveness of varicocele embolisation for the treatment of orchalgia secondary to varicoceles; and to see if pre-embolisation pain scores can be used to predict treatment outcomes. METHODS: A prospectively collected database of patients undergoing varicocele embolisation for pain was analysed over a 10-year period. Pain scores were assessed with a 10-point visual analogue score. Analgesia requirements and satisfaction scores were assessed with questionnaires. RESULTS: Total of 96 cases. Median age was 34 years old. Median pain scores reduced significantly following embolisation (p < 0.001). 74% had reduced pain (30% of these had resolution of pain), 24% had no change in symptoms and 1% had worsening pain. Those with moderate or severe pain had a reduction of pain in 81 and 79% of cases respectively, however 64% of cases with mild pain did not experience any benefit. We also noted a reduction in analgesia requirements and a median satisfaction score of 8/10. CONCLUSION: Primary varicocele embolisation can successfully reduce varicocele related orchalgia. It works best in those with moderate or severe pain. The majority of patients with mild pain may not experience any benefit so should be counseled appropriately. The classification of patients into those with mild, moderate or severe symptoms prior to embolisation should be done, so robust consenting can be performed. PMID- 26251777 TI - Genomic analysis reveals the biotechnological and industrial potential of levan producing halophilic extremophile, Halomonas smyrnensis AAD6T. AB - Halomonas smyrnensis AAD6T is a gram negative, aerobic, and moderately halophilic bacterium, and is known to produce high levels of levan with many potential uses in foods, feeds, cosmetics, pharmaceutical and chemical industries due to its outstanding properties. Here, the whole-genome analysis was performed to gain more insight about the biological mechanisms, and the whole-genome organization of the bacterium. Industrially crucial genes, including the levansucrase, were detected and the genome-scale metabolic model of H. smyrnensis AAD6T was reconstructed. The bacterium was found to have many potential applications in biotechnology not only being a levan producer, but also because of its capacity to produce Pel exopolysaccharide, polyhydroxyalkanoates, and osmoprotectants. The genomic information presented here will not only provide additional information to enhance our understanding of the genetic and metabolic network of halophilic bacteria, but also accelerate the research on systematical design of engineering strategies for biotechnology applications. PMID- 26251778 TI - Ice swimming and changes in body core temperature: a case study. AB - INTRODUCTION: 'Ice Mile' swimming is a new discipline in open-water swimming introduced in 2009. This case study investigated changes in body core temperature during preparation for and completion of two official 'Ice Miles', defined as swimming 1.609 km in water of 5 degrees C or colder, in one swimmer. CASE DESCRIPTION: One experienced ice swimmer (56 years old, 110.2 kg body mass, 1.76 m body height, BMI of 35.6 kg/m(2), 44.8% body fat) recorded data including time, distance and body core temperature from 65 training units and two 'Ice Miles'. DISCUSSION AND EVALUATION: During training and the 'Ice Miles', body core temperature was measured using a thermoelectric probe before, during and after swimming. During trainings and the 'Ice Miles', body core temperature increased after start, dropped during swimming but was lowest during recovery. During training, body core temperature at start was the only predictor (beta = -0.233, p = 0.025) for the increase in body core temperature. Water temperature (beta = 0.07, p = 0.006) and body core temperature at start (beta = -0.90, p = 0.006) explained 61% of the variance for the non-significant decrease in body core temperature. Water temperature (beta = 0.077, p = 0.0059) and body core temperature at finish (beta = 0.444, p = 0.02) were the most important predictors for the lowest body core temperature. In 'Ice Miles', body core temperature was highest ~6-18 min after the start (38.3-38.4 degrees C), dropped during swimming by 1.7 degrees C to ~36.5 degrees C and was lowest ~40-56 min after finish. The lowest body core temperature (34.5-35.0 degrees C) was achieved ~100 min after start. CONCLUSIONS: In an experienced ice swimmer with a high BMI (>35 kg/m(2)) and a high percent body fat (~45%), body core temperature decreased by 1.7 degrees C while swimming and by 3.2-3.7 degrees C after the swim to reach the lowest temperature in an official 'Ice Mile'. The swimmer suffered no hypothermia during ice swimming, but body core temperature dropped to <36 degrees C after ice swimming. Future athletes intending to swim an 'Ice Mile' should be aware that a large body fat prevents from suffering hypothermia during ice swimming, but not after ice swimming. PMID- 26251779 TI - Genome sizes of 227 accessions of Gagea (Liliaceae) discriminate between the species from the Netherlands and reveal new ploidies in Gagea. AB - Nuclear genome size, as measured by flow cytometry with propidium iodide, was used to investigate the relationships within the genus Gagea (Liliaceae), mainly from the Netherlands. The basic chromosome number for Gagea is x = 12. The inferred ploidy in the Dutch and German accessions varies from diploid to decaploid. Consequently there is a large range of genome sizes (DNA 2C-values) from 14.9 to 75.1 pg. Genome sizes are evaluated here in combination with the results of morphological observations. Five species and the hybrid G. * megapolitana are reported. Apart from 14 diploid G. villosa, six plants of G. villosa with an inferred tetraploidy were found. For the 186 Dutch accessions investigated 85 turned out to be the largely sterile G. pratensis (inferred to be pentaploid). Inferred tetraploid and hexaploid G. pratensis were found in 30 and 20 localities, respectively. In one locality an inferred decaploid (10*) plant was found that could represent a doubled pentaploid G. pratensis. An inferred decaploid G. pratensis was never reported before. The genome size of Gagea * megapolitana from Germany fitted with its origin as a cross between the two hexaploids G. pratensis and G. lutea. Gagea spathacea from the Netherlands was inferred to be nonaploid as was recorded from plants across Europe. The aim of the study was to use flow cytometry as a tool to elucidate the taxonomic position of the Dutch Gagea. PMID- 26251781 TI - Surgical Management of a Functional Paraganglioma of the Infratemporal Fossa. AB - Background Paragangliomas are rare neural crest tumors that can manifest in the head and neck as either functional or more commonly as nonfunctional lesions. Paragangliomas of the infratemporal fossa are exceedingly rare, with no more than a handful of documented cases. Like other tumors of this space, surgical management is challenging on account of complex anatomy and nearby critical structures. Methods A 44-year-old man presented with a right infratemporal fossa functional paraganglioma. Following preemptive embolization and autonomic pharmacotherapy, his tumor was successfully resected via a transfacial maxillary swing approach. Results This case highlights the surgical management of a functional paraganglioma of the infratemporal fossa while demonstrating the effectiveness of a transfacial maxillary swing approach for both exposure and resection. Conclusion Although this report summarizes much of the literature on paragangliomas, there is still much to uncover regarding the fundamental features and genetic etiology of these lesions. PMID- 26251780 TI - The impact of chemotherapy dose intensity and supportive care on the risk of febrile neutropenia in patients with early stage breast cancer: a prospective cohort study. AB - BACKGROUND: Febrile neutropenia (FN) is a major dose-limiting toxicity of cancer chemotherapy resulting in considerable morbidity, mortality, and cost. This study evaluated the time course of neutropenic events and patterns of supportive care interventions in patients receiving chemotherapy for early-stage breast cancer treated in oncology community practices. METHODS: A prospective cohort study of adult cancer patients initiating a new chemotherapy regimen was conducted at 115 US sites. Toxicity associated with chemotherapy including neutropenic and infectious complications was recorded over four cycles. Clinical interventions were recorded including reductions in chemotherapy dose intensity and use of supportive care measures. RESULTS: A total of 1,202 patients with stage I-III breast cancer were evaluated. The majority of neutropenic (116 of 196) and infection events (179 of 325) occurred in the initial cycle. A decrease in occurrence of FN and infection was observed in the subsequent cycles, along with an increase in utilization of colony stimulating factors (CSFs), antibiotics and reductions in chemotherapy dose intensity. The overall risk of FN in all patients was 16.3%. In patients who started treatment at or near full dose intensity, the FN risk reached 21.0% without primary CSF prophylaxis and it was 9.0% with prophylaxis. There was no significant difference in FN rates by menopausal or hormone receptors status. CONCLUSIONS: The risk of neutropenic complications is greatest in the initial cycle when most patients receive full-dose chemotherapy. A decrease in neutropenic events during subsequent cycles is associated with reduced dose intensity or increased use of supportive care measures. However, the cumulative risk of FN remains high in patients with early-stage breast cancer receiving full dose chemotherapy without prophylactic measures. PMID- 26251782 TI - Surgical Treatment of Inadvertent Internal Carotid Artery Lesion by Extraintracranial High-flow Bypass. A Case Report and Review of the Literature. AB - Internal carotid artery (ICA) injury following transsphenoidal surgery is a rare but potentially fatal complication. Usually, endovascular occlusion of the ICA or stent graft placement is the treatment of these vascular complications described in literature. We present a case of ICA perforation during transsphenoidal surgery in a patient with limited collateral cerebral blood flow and with ectasia of the ICA that rule out an endovascular treatment. We report the surgical revascularization via high-flow extra-intracranial radial artery bypass and consicutive artery ligation. PMID- 26251783 TI - De Novo Aneurysm Formation Following Gamma Knife Surgery for Arteriovenous Malformation: A Case Report. AB - Background Stereotactic radiosurgery plays a critical role in the treatment of central nervous system neoplasm and cerebrovascular malformations. This procedure is purportedly less invasive, but problems occurring later including tumor formation, necrosis, and vasculopathy-related diseases have been reported. Clinical Presentation We report on a 65-year-old man who had experienced a de novo aneurysm in an irradiated field and an acute onset of right hemiparesis and aphasia. He had undergone gamma knife radiosurgery to treat an arteriovenous malformation 15 and 12 years prior, with 18 and 22 Gy marginal doses. At current admission, radiologic studies showed a de novo aneurysm in the irradiated field without recurrence of malformation. The aneurysm was resected. Histologic findings showed a disruption of the internal elastic lamina accompanied by fibrous degeneration. Conclusion Stereotactic radiosurgery is a promising treatment tool, but long-term risks have not been fully researched. The treatment procedure for benign lesions should be chosen prudently. PMID- 26251784 TI - Entrapment of the Temporal Horn as a Cause of Pure Wernicke Aphasia: Case Report. AB - Entrapment of the temporal horn is an extremely rare pathologic condition occurring as a result of surgery for tumors, intraventricular infections, hemorrhage, or traumatic events involving the peritrigonal area. We report a case of a 58-year-old man who presented with pure Wernicke aphasia (never described before in the albeit rare cases of isolated temporal horn dilatation) that regressed completely following successful ventriculoperitoneal shunting. The relevant literature is also briefly reviewed. PMID- 26251785 TI - Endoscopic Endonasal Infrapetrous Transpterygoid Approach to the Petroclival Junction for Petrous Apex Chondrosarcoma: Technical Report. AB - Chondrosarcomas of the skull base are rare tumors that present difficult management considerations due to the pathoanatomical relationships of the tumor to adjacent structures. We present the case of a 25-year-old female patient presenting with a chondrosarcoma of the right petrous apex extending inferiorly, medial to the cranial nerves. The tumor was resected via an endoscopic endonasal infrapetrous transpterygoid approach that achieved complete resection and an excellent long-term outcome with no complications. Technical nuances and potential pitfalls of the case are discussed in depth including measures to protect the carotid artery while performing the required drilling of the skull base to access the lesion. PMID- 26251786 TI - Spontaneous Cerebrospinal Fluid Otorrhea from a Persistent Tympanomeningeal Fissure Presenting as Recurrent Serous Otitis Media. AB - We describe spontaneous cerebrospinal fluid (CSF) otorrhea through a patent tympanomeningeal (Hyrtl) fissure presenting as recurrent serous otitis media. The CSF leak was observed when a drain was placed through the tympanic membrane by an otologist. The diagnosis was then confirmed by computed tomography and magnetic resonance imaging, and the patient underwent a successful surgical treatment via a retrosigmoid approach. We describe the case and review causes of spontaneous CSF rhinorrhea/otorrhea. PMID- 26251787 TI - Intractable Hiccups Due to Posterior Inferior Cerebellar Artery Aneurysm. AB - This is the third reported case of a posterior inferior cerebellar artery (PICA) aneurysm presenting as intractable hiccups (IH). A previously healthy 29-year-old woman was admitted with a 2-week history of hiccups occurring >100 times per minute. Symptoms persisted despite numerous noninvasive therapies. Magnetic resonance imaging and magnetic resonance angiogram of the brain showed a left PICA aneurysm that was confirmed by catheter angiography. Symptoms resolved following suboccipital craniotomy and resection. Although rare, PICA aneurysm is a potentially curable cause of IH. PMID- 26251788 TI - Subdural Metastasis of Prostate Cancer. AB - Dural metastasis from prostate cancer is rare and may mimic a subdural hematoma (SDH). Preoperatively diagnosis may be difficult and only reveal its presence during surgery. We present such a case and review the literature to identify common characteristics. A 65-year-old man presented with headache, confusion, and progressive right upper limb weakness. Past history included a prostate adenocarcinoma with bone metastasis 3 years earlier. Head computed tomography (CT) scan without contrast revealed a multinodular bilateral hyperdense extra axial lesion interpreted as acute SDH. At surgery planned for SDH drainage no blood was found; instead there was an en plaque subdural yellowish tumor. Histopathologic examination was consistent with metastatic adenocarcinoma of the prostate. We found 11 cases reported as dural metastasis of prostate cancer mimicking SDH. Surgery was performed on nine cases with no suspicion of dural metastasis. On preoperative nonenhanced CT scan images, three types of image patterns can be described: a nodule in SDH, multinodular metastasis surrounded by SDH, and large en plaque subdural tumor. The latter group consists of those cases where no blood but rather an en plaque subdural tumor was found at surgery. Even though rare, dural metastasis should be considered among the differential diagnoses in a patient known for prostate cancer. PMID- 26251789 TI - Primary Spinal Glioblastoma Multiforme with Secondary Manifestation as a Cerebral "Angioglioma." Literature Review and Case Report. AB - Primary intramedullary spinal glioblastoma multiforme (sGBM) with a secondary cerebral manifestation is a very rare entity with a poor outcome. Case studies show a mean average of survival of 10 months after diagnosis. These tumors tend to develop at a young age. A combination with an arteriovenous malformation in the same location has never been published before. Vascular malformations in association with cerebral glioblastomas have only been reported in five cases so far. Proangiogenic factors are assumed to be involved in the appearance of both entities. We present a case study and a review of the literature. PMID- 26251790 TI - Solitary Osteochondroma of the Skull Base: A Case Report and Literature Review. AB - We report a case of an osteochondroma in the posterior clinoid process that occurred in a 43-year-old man with trochlear nerve palsy. Although the potential preoperative diagnoses based on computed tomography and magnetic resonance imaging included other intracranial tumors such as calcified meningioma, thallium 201 single-photon emission computed tomography effectively differentiated osteochondroma from those possibilities. Via an orbitozygomatic approach, a subtotal resection was achieved with a good relief of symptoms. Twenty-two cases of solitary osteochondromas in the skull base have been reported that have demonstrated little risk of recurrence or malignant transformation. However, surgery for skull base osteochondromas does carry a significant risk with a reported mortality > 10%. Although some previous reports advocate complete resection as the only curative method for skull base osteochondromas, the risks of total resection should be weighed against the chance for recurrence; our review of the literature demonstrated a relatively high mortality and an extremely low incidence of recurrence. PMID- 26251791 TI - Intraosseous Schwannoma of the Petrous Apex. AB - Background and Importance Intraosseous schwannoma is a relatively rare clinical entity that typically arises in vertebral and mandibular bone. Intraosseous schwannoma located entirely within the petrous bone is exceedingly rare, and only two cases have been reported to date. Clinical Presentation A 47-year-old Asian man was referred to our hospital with a chief complaint of double vision. Neurologic examination revealed left abducens nerve palsy. Radiologic imaging showed a 35-mm osteolytic expansive lesion located in the left petrous apex. We made a preoperative diagnosis of chondrosarcoma and performed surgical resection. Surgery was performed via a left subtemporal epidural approach with anterior petrosectomy. The histopathologic diagnosis of the tumor was schwannoma. Schwannoma arising from cranial nerves was excluded from intraoperative findings in conjunction with the results for cranial nerves, and intraosseous schwannoma was diagnosed. Postoperative course was uneventful, and abducens nerve palsy resolved immediately after surgery. Conclusion The differential diagnosis of intraosseous schwannoma should be considered for an osteolytic mass lesion within the petrous apex. Subcapsular tumor removal was considered ideal in terms of preservation of the cranial nerves and vessels around the tumor. PMID- 26251793 TI - Multi-size, Multi-angle Microbipolar Forceps for Skull Base Surgery: Technical Note. AB - Objective Hemorrhage control in skull base surgery is critical but hindered by the lack of instruments suitable for coagulating structural curves and corners. The main impediment is that most of the instruments currently used are right angled and unsuitable because anatomical and pathologic structures are three dimensional objects having complex curves and corners. In this article, we present a solution: the use of angled bipolar microforceps having a range of small diameters and angles for dissection and coagulation. Methods Utilizing modern design software and up-to-date synthetic and metallic materials, a variety of nonstick bipolar microforceps with different angles and very fine tips (0.2 1.2 mm) were designed and constructed for use on different anatomical and pathologic curves. The tips of the forceps were made very fine to improve coagulation precision as well as to improve microdissection dexterity. The blades were made long and thin to improve visibility during coagulation and dissection procedures. As a result, these multi-size, multiangle micro instruments can be used not only for coagulation but also for microdissection or tumor removal in most anatomical areas accessed during the course of skull base surgery Results The research, design, and construction of a new bipolar microforceps with different angles and sizes represents a technical innovation that can lead to improved surgical outcomes. Conclusion The new micro-instruments enhance the quality and quantity of tumor and tissue resection and dissection in skull base surgery and open the possibility of new surgical approaches to microscopic tumor resection and hemorrhage coagulation in the anatomical areas of the skull base. PMID- 26251792 TI - A Rare Case of Isolated Cerebral Sarcoidosis Presenting as Suprasellar Mass Lesion with Salt-Wasting Hypopituitarism. AB - Background Sarcoidosis is a systemic disorder of unknown origin characterized by noncaseating granulomas. Clinical symptoms due to central nervous system (CNS) involvement occur in 5 to 7% of all cases; subclinical involvement is more frequent. Sole CNS involvement is very rare. Case Report A 25-year-old man presented with increasing polyuria and polydipsia over 8 weeks. Magnetic resonance imaging (MRI) revealed a supra- and infra-chiasmatic pre-thalamic mass lesion 1.0 * 1.4 * 1.4cm in diameter. Microsurgical biopsy verified a necrotizing noncaseating epithelioid cell tumor indicative for neurosarcoidosis. All symptoms dissolved within 3 months under stringent corticoid therapy. Conclusion Intracranial mass lesions as the primary and only manifestation of neuronal sarcoidosis are rare. Because conservative treatment is safe and effective, surgery is limited to biopsy and the alleviation of pressure-related symptoms to preserve neurologic function. PMID- 26251794 TI - Malignant Transformation of Grade II Ependymoma in a 2-Year-Old Child: Case Report. AB - Ependymomas are central nervous system neoplasms that account for a third of all posterior fossa tumors in children. The most common location for infratentorial ependymoma is within the fourth ventricle. We present a case report of malignant transformation of an infratentorial grade II ependymoma in a 2-year-old child who presented with vomiting and visual disturbance. An infratentorial brain tumor in the left cerebellar area was totally removed, and the initial pathologic diagnosis was grade II ependymoma. The tumor recurred aggressively 1 year later; subtotal removal and adjuvant chemotherapy were performed. After a second operation, a histopathologic study was performed. The second specimen was defined as a grade III anaplastic ependymoma. Transformation to grade III anaplastic ependymoma is possible for a grade II ependymoma but very rare. The diagnosis of the anaplastic variant of intracranial ependymomas is difficult. Surgical treatment remains the mainstay of the treatment for all cases. Ependymomas in young infants have a worse prognosis than older children, so we need individual clinical evaluation and close follow-up of such cases. This article highlights the requirement of a close follow-up for grade II ependymomas for anaplastic transformation. PMID- 26251795 TI - Plasmacytoma of the Clivus Presenting as Bilateral Sixth Nerve Palsy. AB - Background and Importance Plasmacytomas are monoclonal proliferations of plasma cells that may arise within soft tissue or bone. The skull base is a rare site for plasmacytomas to occur, and few cases have been reported in the literature. When present in the skull base, plasmacytomas may result in cranial neuropathies and often progress to multiple myeloma more rapidly than other intracranial or skeletal plasmacytomas. Clinical Presentation A 69-year-old man presented with a primary complaint of diplopia and an examination consistent with bilateral abducens nerve palsy. No other deficits were noted. Magnetic resonance imaging of the skull base demonstrated a large T1 isointense moderately enhancing lesion centered within the clivus. Endoscopic biopsy of the mass revealed sheets and aggregates of mature monoclonal plasma cells. The patient's initial systemic work up revealed that this was a solitary lesion, and he was treated with radiation therapy to the skull base with a durable local effect at 18-month follow-up. Unfortunately he progressed to multiple myeloma with peripheral osteolytic lesions but has been stabilized on chemotherapeutics. Conclusion The clivus is an unusual site for intracranial plasmacytomas, and enhancing lesions must be differentiated from chordoma. Characteristic findings on histopathology include an immunoglobulin light-chain restricted clonal proliferation of plasma cells. Treatment is most commonly radiotherapy with surgery reserved for biopsy and palliation. Clinicians should be aware of the increased risk of progression to multiple myeloma in skull base plasmacytomas. PMID- 26251796 TI - Glioblastoma Multiforme in a Patient with Isolated Hemimegalencephaly. AB - We present an exceptional case of a patient with hemimegalencephaly and secondary intractable epilepsy treated with vagus nerve stimulation (VNS) and subsequent glioblastoma development in the hemimegalencephalic hemisphere 6 years after surgery. VNS (at age 18 years) led to a 60% reduction of intractable seizures. However, symptoms of intracranial hypertension suddenly occurred 6 years after surgery. A computed tomography scan revealed a brain tumor in the hemimegalencephalic hemisphere. Pathologic examination confirmed glioblastoma multiforme. The genetic background of hemimegalencephaly is discussed here, with attention paid to the available data about the malignant transformation of malformations of cortical development (MCDs). The case points to the need for adequate clinical and radiologic follow-up care for patients with MCDs including hemimegalencephaly. PMID- 26251797 TI - Bilateral Chronic Subdural Nontraumatic Hematoma in a Woman Affected by AL Amyloidosis. AB - Chronic subdural hematoma (CSDH) is a condition frequently seen in neurosurgical practice, especially among the elderly. It is often preceded by head injury, even a trivial trauma. Light chain (AL) amyloidosis is a disorder involving extracellular tissue deposition of misfolded native proteins called amyloids. The several types of amyloidosis differ by source of proteins, organ involvement, treatment, and prognosis. We describe the case of a 59-year-old woman affected by AL amyloidosis, harboring surgically treated bilateral chronic nontraumatic subdural hematoma, and we suggest a possible correlation between the clinical entities of CSDH and AL amyloidosis. PMID- 26251798 TI - Histoplasmosis with Deep CNS Involvement: Case Presentation with Discussion and Literature Review. AB - Central nervous system (CNS) histoplasmosis is rare and difficult to diagnose because it is often overlooked or mistaken for other pathologies due to its nonspecific symptoms. A 32-year-old Hispanic man with advanced acquired immunodeficiency virus presented with altered mental status and reported confusion for the past 3 months. He had a Glasgow Coma Scale of 12, repetitive nonfluent speech, and a disconjugate gaze with a right gaze preference. Lung computed tomography (CT) findings indicated a pulmonary histoplasmosis infection. Magnetic resonance imaging of the brain revealed a ring-enhancing lesion in the left caudate nucleus. A CT-guided left retroperitoneal node biopsy was performed and indicated a benign inflammatory process with organisms compatible with fungal yeast. Treatment with amphotericin B followed by itraconazole was initiated in spite of negative cerebrospinal fluid (CSF) cultures and proved effective in mitigating associated CNS lesions and resolving neurologic deficits. The patient was discharged 3 weeks later in stable condition. Six weeks later, his left basal ganglia mass decreased. Early recognition of symptoms and proper steps is key in improving outcomes of CNS histoplasmosis. Aggressive medical management is possible in the treatment of intracranial deep mass lesions, and disseminated histoplasmosis with CNS involvement can be appropriately diagnosed and treated, despite negative CSF and serology studies. PMID- 26251799 TI - Intraoperative Extracorporeal Irradiation for the Treatment of the Meningioma Infiltrated Calvarium. AB - Objectives Complete removal of infiltrated bone is required to achieve a Simpson Grade 1 meningioma resection. Reconstruction of the resulting bone defect is typically achieved with a nonnative implant that can result in poor cosmesis, foreign body reaction, or infection. Extracorporeal irradiation and reimplantation of tumorous bone has been used for limb-sparing surgery with excellent results, but this treatment option is not routinely considered in meningioma surgery. We present a case of anterior fossa meningioma with tumorous overlying calvarium that was successfully managed with intraoperative extracorporeal irradiation and reimplantation. Design, Setting, and Participant A 37-year-old woman with persistent chronic headaches was found to have an anterior skull base meningioma with extension into the forehead frontal bone. Concurrently with mass resection, the bone flap was irradiated intraoperatively with 120 Gy. After resection of the tumor, the bone flap was replaced in its native position. Main Outcome Measures and Results Twenty-nine months postoperatively, the patient had an excellent cosmetic outcome with no radiographic evidence of tumor recurrence or significant bone flap resorption. Conclusion Intraoperative extracorporeal irradiation of tumorous calvaria during meningioma surgery is an effective, logistically feasible treatment option to achieve local tumor control and excellent cosmetic outcome. PMID- 26251800 TI - Aneurysmal Bone Cyst of the Temporal Bone Presenting with Headache and Partial Facial Palsy. AB - Background Aneurysmal bone cysts (ABCs) are benign bony lesions that rarely affect the skull base. Very few cases of temporal bone ABCs have been reported. We describe the first case of a temporal bone ABC that was thought to be consistent with a meningioma based on preoperative magnetic resonance imaging (MRI) findings. Clinical Presentation An otherwise healthy 23-year-old woman presented with a pulsatile noise in her left ear and a 4-week history of throbbing headache with nausea. There was no associated emesis, visual or auditory changes, or other neurologic features. Neurologic examination revealed a left lower motor neuron facial paresis. Computed tomography and MRI studies demonstrated a large lesion in the left middle cranial fossa skull base with erosion of the petrous temporal bone. Based on the presence of a "dural tail" on preoperative contrast-enhanced T1-weighted imaging, the lesion was interpreted to likely be consistent with a meningioma. An orbitozygomatic approach was utilized for surgical excision. Histopathologic evaluation was consistent with an ABC. Conclusion Postoperatively the patient had improvement in the lower motor neuron facial paresis. It is important to consider ABC in the differential diagnosis of intracranial lesions accompanied by the dural tail sign on MRI. PMID- 26251801 TI - Case Report: Intraneural Intracanalicular Ganglion Cyst of the Hypoglossal Nerve Treated by Extradural Transcondylar Approach. AB - We report a case of an intraneural ganglion cyst of the hypoglossal canal. The patient presented with unilateral hypoglossal nerve palsy, and magnetic resonance imaging showed a small lesion in the hypoglossal canal with no contrast enhancement and high signal on T2-weighted imaging. The lesion was assumed to be a cystic schwannoma of the hypoglossal nerve. Stereotactic irradiation was considered, but in accordance with the patient's wishes, surgical exploration was performed. This revealed that, rather than a schwannoma, the patient had an intraneural ganglion cyst, retrospectively contraindicating irradiation as an option. This case illustrates a very rare location of an intraneural ganglion cyst in the hypoglossal nerve. To our knowledge there are no previous reports of an intraneural ganglion cyst confined to the hypoglossal canal. PMID- 26251802 TI - Conus Medullaris Teratoma with Utilization of Fiber Tractography: Case Report. AB - Objective Conus medullaris teratomas are very rare tumors. Traditional preoperative diagnosis depended on the findings from magnetic resonance imaging (MRI). Tractography is a novel technique that has recently been utilized to diagnose spinal cord lesions. This case report shows that fiber tractography has great potential in preoperative diagnosis and postoperative follow-up of teratomas of the conus medullaris. Methods A 50-year-old man with a conus medullaris teratoma underwent tractography with the aim of visualizing the tumor in relation to the white matter tracts. The patient underwent a T12-L2 laminectomy, and the lesion was resected. The histopathology diagnosis was of a mature teratoma. Study Design Case report. Results Diffusion tensor imaging (DTI) and tractography provide more details about the white matter tracts in relation to space-occupying lesions that may be more sensitive than conventional MRI and have recently been utilized in spinal cord lesions. Fiber tracking has the ability to visualize the integrity of the white matter tracts at the level of the conus medullaris in relation to the lesion. The tracts appeared to be displaced by the lesion at the conus medullaris. Tractography also showed no white matter tracts within the lesion. Such findings are consistent with the characteristics of a benign lesion. Exploiting tractography in this case was helpful in predicting the nature of the lesion preoperatively and in planning the surgical intervention. Conclusions Conus medullaris teratomas mostly affect adults. Patients generally present with a long history of clinical symptoms prior to diagnosis. Surgery is required for diagnosis, and the goal should be complete tumor excision without sacrificing any neurologic functions. The use of DTI and tractography, in addition to conventional MRI, has the potential to be very valuable for the diagnosis, surgical planning, and follow-up of patients with conus medullaris teratomas. PMID- 26251803 TI - Brain Slump Caused by Jugular Venous Stenoses Treated by Stenting: A Hypothesis to Link Spontaneous Intracranial Hypotension with Idiopathic Intracranial Hypertension. AB - Spontaneous intracranial hypotension, of which brain slump is an extreme expression, is caused by a cerebrospinal fluid leak. The reason the leak develops in the first place, however, is unknown, and some cases can be very difficult to manage. We describe a patient with severe symptoms of spontaneous intracranial hypotension and brain slump documented by magnetic resonance imaging whose clinical syndrome and structural brain anomaly resolved completely after treatment directed exclusively at improving cranial venous outflow. Diagnostics included computed tomography (CT) venography, catheter venography, and jugular venoplasty. CT venography showed narrowing of both internal jugular veins below the skull base. Catheter venography confirmed that these were associated with pressure gradients. Jugular venoplasty performed on two separate occasions as a clinical test gave temporary respite. Lasting remission (2 years of follow-up) was achieved by stenting the dominant internal jugular vein. These findings and this outcome suggest a mechanism for the development of spontaneous intracranial hypotension that would link it to idiopathic intracranial hypertension and have cranial venous outflow obstruction as the underlying cause. PMID- 26251804 TI - Diffuse Large B-Cell Lymphoma of the Frontal Sinus Presenting as a Pott Puffy Tumor: Case Report. AB - Objective Sinonasal non-Hodgkin lymphoma (NHL) is a very rare condition. NHL located specifically in the frontal sinus is even rarer with only 14 cases in the literature reported to date. A unique case of diffuse large B-cell lymphoma of the frontal sinus that presented first and was treated as suspected Pott puffy tumor is presented along with a review of the literature. Case Report A 69-year old white man with a history of sinusitis and two recent endoscopic sinus surgeries presented with enlargement of his right forehead. Computed tomography and magnetic resonance images revealed a dense opacification of the frontal sinus bilaterally, thickening and enhancement of the dura mater behind the right frontal sinus, and local osteomyelitis-like lytic bone changes. A bifrontal craniotomy was performed. Radical exoneration of the frontal sinus, copious antibiotic-impregnated irrigation after culture swabs, and resection of presumed granulation tissue was performed. Culture swabs remained negative, but histopathology revealed diffuse large B-cell lymphoma. Subsequent chemotherapy was administered. Conclusion Sinonasal NHL is very rare but can occur in the frontal sinus and may present as a suspected Pott puffy tumor. A high clinical suspicion is necessary for early diagnosis and treatment. PMID- 26251805 TI - Concomitant Intraspinal and Retroperitoneal Hemorrhage Caused by an Aneurysm on the Celiac Artery: A Case Report. AB - Spontaneous spinal hemorrhage is a rare condition. We present a case in which the diagnosis was complicated by a concomitant intra-abdominal hemorrhage. The patient, taking coumarins, presented with acute back pain and abdominal pain and progressive paresis of the lower limbs. Computed tomography angiography of the abdomen showed an intra-abdominal hemorrhage and an aneurysm of the celiac trunk. MR (magnetic resonance) imaging of the spine revealed a combined subdural and epidural hemorrhage from C1 to L1. Both sites were treated conservatively. After 6 months the patient regained strength in both legs with some persistent loss of strength in the left leg. Follow-up MR imaging showed complete resolution of the spinal hemorrhage. The celiac artery aneurysm was treated conservatively. We suggest that the rupture of the celiac artery aneurysm caused increased intra abdominal pressure leading to spinal hemorrhage. Emergency staff should be aware of the possibility of two rare but concomitant conditions. PMID- 26251806 TI - An Intraventricular Schwannoma with Associated Hydrocephalus and Ventricular Entrapment: A Case Report. AB - Intraventricular schwannomas are rare primary brain tumors, with fewer than 25 cases reported in the literature. Here, we present the case of a 20-year-old male patient with a 2 year history of blurry vision and dysesthesia involving his right occiput and upper neck. Imaging demonstrated a homogeneously enhancing mass located within the atrium of the right lateral ventricle with associated right lateral ventricular entrapment. Pathology confirmed the tumor to be an intraventricular schwannoma. Imaging findings, presentation, complications, and treatment options for intraventricular schwannomas are described. PMID- 26251807 TI - Endoscopic Transnasal Approach for Urgent Decompression of the Craniocervical Junction in Acute Skull Base Osteomyelitis. AB - Ventral epidural abscess with osteomyelitis at the craniocervical junction is a rare occurrence that typically mandates spinal cord decompression via a transoral approach. However, given the potential for morbidity with transoral surgery, especially in the setting of immunosuppression, together with the advent of extended endonasal techniques, the transnasal approach could be attractive for selected patients. We present two cases of ventral epidural abscess and osteomyelitis at the craniocervical junction involving C1/C2 that were successfully treated via the endoscopic transnasal approach. Both were treated in staged procedures involving posterior cervical fusion followed by endoscopic transnasal resection of the ventral C1 arch and odontoid process for decompression of the ventral spinal cord and medulla. Dural repairs were successfully performed using multilayered, onlay techniques where required. Both patients tolerated surgery exceedingly well, had brief postoperative hospital stays, and recovered uneventfully to their neurologic baselines. Postoperative magnetic resonance imaging confirmed complete decompression of the foramen magnum and upper C-spine. These cases illustrate the advantages and low morbidity of the endonasal endoscopic approach to the craniocervical junction in the setting of frank skull base infection and immunosuppression, representing to our knowledge a unique application of this technique to osteomyelitis and epidural abscess at the craniocervical junction. PMID- 26251808 TI - Role of Evaluating MGMT Status and 1p36 Deletion in Radiosurgery-Induced Anaplastic Ependymoma That Rapidly and Completely Resolved by Temozolomide Alone: Case Report and Review of the Literature. AB - Stereotactic gamma knife surgery (GKS)-induced brain tumors are extremely rare, and no ependymal tumors induced by GKS have been reported. Therefore, little is known about their clinical, pathologic, and genetic features. In addition, a regimen of adjuvant chemotherapy for anaplastic ependymoma (AE) has not been established. A 77-year-old man presented with a gait disturbance and left-side cerebellar ataxia more than 19 years after GKS performed for a cerebellar arteriovenous malformation. Imaging studies demonstrated an enhancing mass in the irradiated field with signs of intraventricular dissemination. Surgical resection confirmed the diagnosis of AE. Temozolomide (TMZ) was administrated postoperatively because the methylated promoter region of O(6)-methylguanine-DNA methyltransferase (MGMT) and 1p36 deletion were observed. Surprisingly, images 16 days after TMZ initiation demonstrated a complete resolution of the residual tumor that was maintained after three cycles of TMZ. This first case report of GKS-induced AE emphasizes the importance of genetic evaluation of MGMT and chromosomal deletion of 1p36 that are not commonly performed in primary ependymal tumors. In addition, it is speculated that a GKS-induced tumor may have a different genetic background compared with the primary tumor because the pathogenesis of the tumors differed. PMID- 26251809 TI - A Rare Finding of Schwannoma of the Vidian Canal: A Case Report. AB - Background Schwannomas of the vidian canal are an extremely rare type of intracranial tumor that can have variable clinical presentations including headache, facial pain, facial muscle paralysis, decreased lacrimation, or nasal dryness. We present an atypical case of an incidentally identified asymptomatic vidian canal schwannoma. Case Description A 49-year-old woman with a history of multiple sclerosis presented for routine surveillance magnetic resonance imaging that detected an ovoid mass originating in the vidian canal. Given the unusual location of the lesion, an endoscopic endonasal biopsy was performed and confirmed the diagnosis of a vidian canal schwannoma, for which the patient chose to receive fractionated radiation therapy. Conclusion When a vidian canal tumor is identified, endoscopic endonasal biopsy can be used to confirm the diagnosis before pursuing either surgical or radiotherapy treatment. In particular, fractionated radiation therapy offers a radiobiologically safe means of delivering radiation when there is concern for late radiation-related side effects following treatment completion. PMID- 26251810 TI - Lipochoristoma of the Internal Auditory Canal. AB - Objective Lipochoristomas comprise 0.1% of all cerebellopontine angle tumors and may be misdiagnosed as vestibular schwannomas. We describe a lipochoristoma of the internal auditory canal (IAC) and present the salient features of the evaluation, diagnosis, and management. Study Design and Methods Retrospective case review. Results (Case Report) A 51-year-old woman presented with left-sided severe hearing loss, tinnitus, mild episodic vertigo, and facial paresthesias progressive over 1 year. Magnetic resonance imaging (MRI) demonstrated a small (5 * 4 mm) T1 hyperintense lobulated lesion in the distal internal auditory canal. With fat-suppressed images, there was no enhancement of the lesion. A diagnosis of IAC lipochoristoma was made. Conservative management was recommended, and on 17-month follow-up there was no interval growth. The patient remains symptomatically stable with improved equilibrium but persistent left-sided hearing loss. Conclusions Differential diagnosis of an enhancing lesion in the IAC includes acoustic neuroma, meningioma, epidermoid and arachnoid cysts, lipochoristoma, and metastatic tumors. Fat-suppressed MRI sequences aid in a definitive diagnosis of lipochoristomas. Because lipochoristomas may have a tendency for more indolent growth and intimate involvement of the auditory nerve, conservative management with interval imaging is recommended. Surgical treatment is reserved for growing lesions or those with disabling vestibular symptoms. PMID- 26251811 TI - Low-Grade Oligodendroglioma of the Pineal Region: Case Report. AB - Background Although germ cell tumors and pineal cell tumors account for most of the histologic tumor subtypes, > 17 different tumors can arise in this location. We report a rare case of a low-grade oligodendroglioma that arose in the pineal region. Clinical Presentation A young woman complaining of a headache underwent magnetic resonance imaging that showed a mass in the pineal region and mild hydrocephalus. A ventriculoperitoneal shunt was performed followed by a near total tumor removal, due to tumor invasion of the tectal plate and thalamus. The histologic examination confirmed the diagnosis of a low-grade oligodendroglioma. The patient then underwent chemotherapy and radiotherapy as adjuvant therapies. Conclusion Although the pineal region is a common place for a large number of tumoral lesions, low-grade oligodendrogliomas are extremely rare in this location. This case is only the second account of a benign oligodendroglioma of the pineal region reported in the literature. PMID- 26251812 TI - Management of Trigeminal Neuralgia Caused by an Intraneural Spiral Trigeminocerebellar Artery: A Case Report. AB - The trigeminocerebellar artery (TCA) is a branch of the basilar artery that may have an intraneural course and may cause trigeminal neuralgia. We report a case of trigeminal neuralgia with right vertebral artery aneurysm caused by an intraneural TCA that compressed the trigeminal nerve in multiple places. We performed proximal trapping for the fusiform aneurysm with extra-intracranial bypass to preserve flow of the posterior inferior cerebellar artery, followed by microvascular decompression that successfully changed the course of the TCA. This procedure provided relief from the neuralgia without direct bisection of the trigeminal nerve that may cause severe nerve injury. Reshaping of the course of the artery can achieve good pain relief. PMID- 26251813 TI - Pseudo-Cerebrospinal Fluid Rhinorrhea Resulting from Aberrant Cross-Innervation of Trigeminal and Facial Nerves following Skull Base Surgery. AB - Objectives Pseudo-cerebrospinal fluid (CSF) rhinorrhea is a rare phenomenon, presumed to result from aberrant autonomic reinnervation of the paranasal mucosa following injury to the greater superficial petrosal nerve or periarterial plexus. In this report, we discuss the case of a postoperative patient with pseudo-CSF rhinorrhea exacerbated by chewing and propose a novel mechanism of pseudo-CSF rhinorrhea. Case Report A 46-year-old man was found to have mastication-induced unilateral clear rhinorrhea following transtemporal resection of a cerebellopontine angle tumor. Computed tomography cisternogram and beta-2 transferrin analysis proved negative for any evidence of CSF leak. Conclusions Pseudo-CSF rhinorrhea exacerbated by mastication has not been previously reported in the literature. We propose aberrant cross-innervation of the trigeminal and facial nerves as the mechanism underlying the patient's condition. Pseudo-CSF rhinorrhea is an important entity to identify following skull base surgery because it may spare patients from the unnecessary invasive procedures and morbidity associated with the management of a presumed CSF leak. PMID- 26251814 TI - Rare Presentation of Giant Cell Tumor in the Internal Auditory Canal: Case Report and Review of the Literature. AB - Giant cell tumor (GCT) is a benign but locally aggressive bone tumor that usually involves the end of long bones. It is a relatively common neoplasm in patients, constituting 5 to 10% of all benign bone tumors. Approximately 2% of GCTs occur in the craniofacial skeleton with a predilection for the ethmoid, sphenoid, and temporal bones. The skull base location is unique and not commonly described. Hearing loss, headache, tinnitus, and subcutaneous masses are the most commonly reported symptoms in GCTs of the skull base. In this case report we present the first description of a GCT within the internal auditory canal causing cranial neuropathy and review the recent pertinent literature. PMID- 26251815 TI - Fibrin Glue Injection for Cavernous Sinus Hemostasis Associated with Cranial Nerve Deficit: A Case Report. AB - Fibrin glue injection has been used to control intraoperative cavernous sinus (CS) venous bleeding. There have been no reported complications related to this maneuver. We present a case where a patient developed a sensory trigeminal nerve deficit after injection of fibrin glue into the posterior CS during resection of a petrosal meningioma. We believe that this deficit was due to the compression of the trigeminal ganglion similar to balloon compression procedures. Although fibrin glue injection may achieve satisfactory cavernous sinus homeostasis, the volume and rate of injection should be kept in mind to avoid a compressive lesion on traversing cranial nerves and surrounding structures, or retrograde filling of the venous tributaries. PMID- 26251816 TI - Continuous Local Intra-Arterial Nimodipine for the Treatment of Cerebral Vasospasm. AB - Vasospasm (VSP) is one of the major causes for prolonged neurologic deficit in patients with aneurysmal subarachnoid hemorrhage. Few case series have reported about continuous local intra-arterial nimodipine administration (CLINA) in refractory VSP. We report our experience with CLINA in a patient with refractory cerebral VSP. PMID- 26251817 TI - Delayed Occurrence of Escherichia coli Subdural Empyema Following Head Injury in an Elderly Patient: A Case Report and Literature Review. AB - Subdural empyema is a rare but serious intracranial infection that warrants prompt management to reduce morbidity and avoid mortality. However, clinical and radiologic features may be subtle or ambivalent. Thus a diagnosis of subdural empyema should not be discounted, especially in a patient with a history of head trauma. Treatment consists of surgery to establish bacteriologic identification and subsequently guide antibiotic therapy. Here we present a case of delayed Escherichia coli subdural empyema following a head injury in an elderly patient without significant risk factors. Computed tomography imaging was equivocal for subdural empyema. The patient underwent surgery and was treated with intravenous antibiotic therapy. Although initial improvement in the patient's clinical condition was observed, he eventually succumbed to nosocomial pneumonia. In this article, we discuss the presentation, diagnostic tools, and treatment options for subdural empyema with an emphasis on the challenges. The management conundrum that follows prompted us subsequently to review the literature. PMID- 26251818 TI - Endoscopic Repair of Frontal Sinus Cerebrospinal Fluid Leaks after Firearm Injuries: Report of Two Cases. AB - Objectives To describe two cases of cerebrospinal fluid (CSF) leak repair after gunshot wound to the head. Design Retrospective review of two cases. Settings A large regional tertiary care facility. Participants Two patients with gunshot wounds to the skull base. Main Outcome Measures Preoperative and postoperative physical and radiologic findings. Results Patients in this series underwent endoscopic surgery, debridement, and repair of CSF leaks after gunshot wounds to the head. To date, the patients are without CSF leak. Conclusions Endoscopic closure of anterior skull base CSF leaks in patients with gunshot wounds can be safe and effective. Treatment should be decided by the severity of neurologic deterioration throughout the emergency period and the existence or absence of associated intracranial lesions. Timing for surgery should be decided with great care and with a multidisciplinary approach. PMID- 26251819 TI - Life-Threatening Intracranial Hypotension after Skull Base Surgery with Lumbar Drainage. AB - Although lumbar drainage (LD) is widely used in skull base surgery (SBS), no cases with intracranial hypotension (IH) following LD-assisted SBS have been reported, and skull base surgeons lack awareness of this potentially life threatening condition. We report two cases of IH after LD-assisted SBS, a spheno orbital meningioma and an osteosarcoma in the orbit. Despite a minimal amount of cerebrospinal fluid (CSF) drainage and early LD removal, severe postural headache and even a deteriorating consciousness level were observed in the early postoperative course. Neuroimages demonstrated epidural fluid collections, severe midline shift, and tonsillar sag compatible with IH. Epidural blood patch (EBP) immediately and completely reversed the clinical and radiologic findings in both patients. IH should be included in the differential diagnosis of postural headache after LD-assisted SBS that can be managed successfully with EBP. Persistent leakage of CSF at the LD-inserted site leads to IH. Broad dural dissection and wide removal of bony structure may be involved in the midline shift. EBP should be performed soon after conservative management fails. Further reports will determine the risk factors for IH development following LD-assisted SBS. PMID- 26251820 TI - Nondysraphic Intramedullary Cervical Cord Lipoma with Exophytic Component: Case Report. AB - Introduction Spinal intradural lipoma is a rare condition, accounting for < 1% of all spinal cord tumors. Spinal cord lipomas are frequently associated with dysraphism and occur in the thoracic spine. Another common finding is that spinal cord lipomas tend to present in the pediatric population. Isolated nondysraphic cervical lipomas are a rare entity. We discuss a case of nondysraphic cervical lipoma with an exophytic component. Case A 31 year-old woman presented with bilateral numbness in her hands and a burning and aching sensation in her arms for ~ 6 months. The patient did not have any weakness or myelopathic signs. Magnetic resonance imaging T1 showed a T1 hyperintense, T2 hypointense, non contrast-enhancing mass on the dorsal aspect of the spinal cord with significant compression. The patient underwent a dorsal cervical laminectomy with subtotal resection of an isolated cervical lipoma with an exophytic component. The pathology confirmed the diagnosis of a lipoma. Conclusions Surgical management of this rare pathology has a wide variety of options. Depending on the neurologic deficits, observation to gross total resection may be reasonable options. In our case, a subtotal resection was achieved with no further worsening of neurologic symptoms. PMID- 26251821 TI - Metastatic Diffuse Intrinsic Pontine Glioma to the Peritoneal Cavity Via Ventriculoperitoneal Shunt: Case Report and Literature Review. AB - Extraneural metastatic disease resulting from a primary central nervous system neoplasm is a rare clinical finding in the pediatric population. We report a case of peritoneal glioblastoma carcinomatosis following placement of a ventriculoperitoneal shunt and chemoradiotherapy in a 6-year-old female patient who initially presented with diffuse intrinsic pontine glioma. This case demonstrates the importance of evaluation of extraspinal structures when imaging for extension of disease. Additionally, this report highlights the cross sectional imaging characteristics of glioblastoma peritoneal carcinomatosis and presents additional information that will facilitate the timely diagnosis of extraneural metastases of primary high-grade glial neoplasms in the pediatric population. PMID- 26251822 TI - Spontaneous Intracranial Extradural Hematoma in Sickle Cell Disease. AB - Spontaneous extradural hematoma is rare in patients with sickle cell disease. We report a clinical case of a 19-year-old young man with sickle cell anemia who presented a sickle cell crisis complicated by the development of multiple acute extradural and subgaleal hematomas that had not been treated surgically. We discuss the physiopathology of this event. Although it is rare, clinicians should be aware of this phenomenon as part of a spectrum of neurologic complications in these patients. PMID- 26251823 TI - Treatment of Binge Eating Disorder. AB - Binge eating disorder is a common eating disorder that recently has received increasing attention. Goals in treating binge eating disorder typically include controlling binge eating and diminishing excess body weight. A variety of treatment approaches have been used, including diet/lifestyle modification, psychotherapy, and pharmacologic treatment. Diet and lifestyle interventions are somewhat effective in diminishing the binge eating behavior and lead to modest weight loss, but the weight effects are limited and not typically lasting. A number of psychotherapies have been shown to be beneficial, mostly for stopping binge eating, and tend to show little impact on weight loss. Numerous pharmacologic interventions have been developed, with the focus on antidepressants (used for their anti-binge eating effects) and weight loss drugs. Both have been shown to be helpful but again, for antidepressants, bringing about lasting weight loss appears to be difficult. The most effective approach to treating binge eating disorder (if available) is likely psychotherapy combined with medication management as indicated. PMID- 26251824 TI - The Vulnerable Ventral Tegmental Area in Parkinson's Disease. AB - INTRODUCTION: The involvement of dopaminergic neurons in the ventral tegmental area (VTA) in Parkinson's disease (PD) has not been universally recognized by neuroscientists and neurologists. Here, we conduct a review of previous research documenting dopaminergic neuronal loss in both the substantia nigra pars compacta (SNpc) and VTA and add three new post-mortem PD cases to the literature. METHODS: PD and control brains were sectioned, stained for tyrosine hydroxylase, and cells in the SNpc and VTA were counted. RESULTS: Based on the review, we report two main results: 1) the VTA does degenerate in PD, and 2) the VTA degenerates less than the SNpc. CONCLUSION: Inconsistent clinical information about these cases limits our ability to interpret how the VTA contributes to PD symptoms. However, our data in combination with prior PD neuropathological cases in the literature unequivocally establish that the VTA is involved in PD, and could be relevant for future investigation of non-motor symptoms in PD. PMID- 26251825 TI - Microarray analysis of the in vivo response of microglia to Abeta peptides in mice with conditional deletion of the prostaglandin EP2 receptor. AB - Amyloid-beta (Abeta) peptides accumulate in the brains of patients with Alzheimer's disease (AD), where they generate a persistent inflammatory response from microglia, the innate immune cells of the brain. The immune modulatory cyclooxygenase/prostaglandin E2 (COX/PGE2) pathway has been implicated in preclinical AD development, both in human epidemiology studies1 and in transgenic rodent models of AD2, 3. PGE2 signals through four G-protein-coupled receptors, including the EP2 receptor that has been investigated for its role in mediating the inflammatory and phagocytic responses to Abeta4. To identify transcriptional differences in microglia lacking the EP2 receptor, we examined mice with EP2 conditionally deleted in Cd11b-expressing immune cells. We injected Abeta peptides or saline vehicle into the brains of adult mice, isolated primary microglia, and analyzed RNA expression by microarray. The resulting datasets were analyzed in two studies5, 6, one describing the basal status of microglia with or without EP2 deletion, and the second study analyzing the microglial response to Abeta. Here we describe in detail the experimental design and data analyses. The raw data from these studies are deposited in GEO, accession GSE57181 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE57181). PMID- 26251826 TI - Gene expression profiling distinguishes proneural glioma stem cells from mesenchymal glioma stem cells. AB - Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Previously we identified and characterized two mutually exclusive GSC subtypes with distinct activated signaling pathways and biological phenotypes. One GSC subtype presented with a gene signature resembling Proneural (PN) HGG, whereas the other was similar to Mesenchymal (Mes) HGG. Classical HGG-derived GSCs were sub-classified as either one of these two subtypes. Differential mRNA expression analysis of PN and Mes GSCs identified 5,796 differentially expressed genes, revealing a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. Expression of ALDH1A3 - one of the most up-regulated Mes representative genes and a universal cancer stem cell marker in non-brain cancers - was associated with self-renewal and a multi-potent stem cell population in Mes but not PN samples. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs in vitro. Lastly, radiation treatment of PN GSCs up-regulated Mes associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs in vitro. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3-mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature. Here, we describe the gene expression analysis, including pre-processing methods for the data published by Mao and colleagues in PNAS [1], integration of microarray data from this study with The Cancer Genome Atlas (TCGA) glioblastoma data and also with another published study. PMID- 26251827 TI - Regulation of physiological processes by microRNAs in insects. AB - MicroRNAs (miRNAs) are small non-coding RNAs that function in gene regulatory processes in plants and animals by targeting sites within messenger RNA. In insects, miRNAs have been shown to regulate a variety of physiological processes throughout insect development, including molting, metamorphosis, oogenesis, embryogenesis, behavior and host-pathogen interactions. The roles of miRNAs in the model organism, Drosophila melanogaster, have been studied extensively due to the conserved nature of miRNA function among highly divergent species. However, seeking to understand miRNA function in non-drosophilid insect species has become a growing trend in insect science. Here, we highlight the recent discoveries regarding miRNA function in insect physiology and development. PMID- 26251828 TI - Epidemiology and the prognosis of healthcare-associated infective endocarditis in China: the significance of non-nosocomial acquisition. AB - Limited research has been conducted on healthcare-associated infective endocarditis (HAIE), although it is of increasing importance. The aim of this study is to compare the epidemiology, clinical characteristics, and prognosis of community-acquired IE (CA-IE) with HAIE and non-nosocomial healthcare-associated IE (NNHCA-IE). A retrospective, consecutive case-series analysis was organized and performed during the 20-year study period in Huashan Hospital, Shanghai, China. A total of 154 patients were enrolled, including 126 (81.8%) who had CA-IE and 28 (18.2%) who had HAIE, among whom 20 (71.4%) had non-nosocomial IE. Patients with HAIE compared to patients with CA-IE had poorer clinical conditions (Charlson comorbidity index >=2: 35.7% vs. 15.1%, P = 0.012; immunosuppressive therapy: 21.4% vs. 4.0%, P = 0.005), underwent more prosthetic valve replacement (35.7% vs. 7.1%, P <0.001), had less streptococcus infection (16.7% vs. 51.1%, P = 0.007) but more atypical bacterial infection (50.0% vs. 21.1%, P = 0.017) and poorer outcomes (17.9% vs. 4.0%, P = 0.019). It is noteworthy that the results were quite similar between the comparison of patients with NNHCA-IE and those with CA-IE. Overall, in-hospital mortality was 6.5%. The IE acquisition site and low serum albumin levels (odds ratio (OR): 0.8; P = 0.04) were significantly associated with an increased risk of mortality. Nosocomial IE patients had an 8.3 fold and NNHCA-IE patients had 6.5-fold increase in the risk of mortality compared to CA-IE patients. In conclusion, HAIE and NNHCA-IE have important epidemiological and prognostic implications. Because NNHCA-IE usually occurs in patients residing in the community, it is suggested that these patients should be identified and treated by the community primary care clinical staff as early as possible. PMID- 26251829 TI - Possible basis for the emergence of H1N1 viruses with pandemic potential from avian hosts. AB - Influenza A viruses of the H1N1 subtype have emerged from the avian influenza gene pool in aquatic birds and caused human pandemics at least twice during the past century. Despite this fact, surprisingly little is known about the H1N1 gene pool in the aquatic bird reservoir. A preliminary study showed that an H1N1 virus from a shorebird of the Charadriiformes order was transmitted between animals through the airborne route of infection, whereas an H1N1 virus from a bird of the Anseriformes order was not. Here we show that two of the three H1N1 viruses isolated from Charadriiformes species in 2009 were transmitted between animals through the airborne route of infection, and five H1N1 isolates from Anseriformes species were not. The one H1N1 virus from a Charadriiformes species that failed to transmit through the airborne route was a reassortant possessing multiple internal gene segments from Anseriformes species. The molecular differences between the airborne-transmissible and non-airborne-transmissible H1N1 viruses were multigenic, involving the selection of virus with human-like receptor binding specificity (alpha2-6 sialic acid) and multiple differences in the polymerase complex, mainly in the PB2, PB1-F2, and nonstructural genes. PMID- 26251830 TI - Novel katG mutations causing isoniazid resistance in clinical M. tuberculosis isolates. AB - We report the discovery and confirmation of 23 novel mutations with previously undocumented role in isoniazid (INH) drug resistance, in catalase-peroxidase (katG) gene of Mycobacterium tuberculosis (Mtb) isolates. With these mutations, a synonymous mutation in fabG1 (g609a), and two canonical mutations, we were able to explain 98% of the phenotypic resistance observed in 366 clinical Mtb isolates collected from four high tuberculosis (TB)-burden countries: India, Moldova, Philippines, and South Africa. We conducted overlapping targeted and whole-genome sequencing for variant discovery in all clinical isolates with a variety of INH resistant phenotypes. Our analysis showed that just two canonical mutations (katG 315AGC-ACC and inhA promoter-15C-T) identified 89.5% of resistance phenotypes in our collection. Inclusion of the 23 novel mutations reported here, and the previously documented point mutation in fabG1, increased the sensitivity of these mutations as markers of INH resistance to 98%. Only six (2%) of the 332 resistant isolates in our collection did not harbor one or more of these mutations. The third most prevalent substitution, at inhA promoter position -8, present in 39 resistant isolates, was of no diagnostic significance since it always co-occurred with katG 315. 79% of our isolates harboring novel mutations belong to genetic group 1 indicating a higher tendency for this group to go down an uncommon evolutionary path and evade molecular diagnostics. The results of this study contribute to our understanding of the mechanisms of INH resistance in Mtb isolates that lack the canonical mutations and could improve the sensitivity of next generation molecular diagnostics. PMID- 26251831 TI - Structural analysis of a novel rabbit monoclonal antibody R53 targeting an epitope in HIV-1 gp120 C4 region critical for receptor and co-receptor binding. AB - The fourth conserved region (C4) in the HIV-1 envelope glycoprotein (Env) gp120 is a structural element that is important for its function, as it binds to both the receptor CD4 and the co-receptor CCR5/CXCR4. It has long been known that this region is highly immunogenic and that it harbors B-cell as well as T-cell epitopes. It is the target of a number of antibodies in animal studies, which are called CD4-blockers. However, the mechanism by which the virus shields itself from such antibody responses is not known. Here, we determined the crystal structure of R53 in complex with its epitope peptide using a novel anti-C4 rabbit monoclonal antibody R53. Our data show that although the epitope of R53 covers a highly conserved sequence (433)AMYAPPI(439), it is not available in the gp120 trimer and in the CD4-bound conformation. Our results suggest a masking mechanism to explain how HIV-1 protects this critical region from the human immune system. PMID- 26251833 TI - Comparison of Quality of Life and Nutritional Status in Gastric Cancer Patients Undergoing Gastrectomies. AB - The aim of this study was to compare the quality of life (QoL) depending on the postoperative survival period or nutritional status in gastric cancer patients. Surviving gastric cancer patients (n = 222) after the gastrectomy were included in the study at Soonchunhyang University Bucheon Hospital from April 2010 to August 2012. The Korean versions of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and a gastric cancer-specific module, the EORTC QLQ-STO22, were used to assess the QoL. The postoperative survival period of the patients fell into two groups; the less than-1-year group or the more-than-1-year group, and the nutritional status of the patients fell into three groups by a score of patient generated-subjective global assessment (SGA)-A, B, and C. As a result, the rate of malnutrition was 34.5% in the less-than-1-year group and 19.8% in the more-than-1-year group, respectively. Score for the fatigue (p = 0.006), loss of appetite (p = 0.002), reflux (p = 0.027) and body image (p = 0.004) in which the QoL was significantly lower in the less-than-1-year group than in the more-than-1-year group. The score of QoL according to the nutritional status of all subjects, overall health status (p = 0.043), physical functioning (p = 0.016), fatigue (p = 0.006), pain (p = 0.028), loss of appetite (p = 0.017), reflux (p = 0.003), eating restriction (p = 0.002), anxiety (p = 0.010), and body image (p = 0.001) was significantly lower in the SGA-C group than in other SGA groups. These results suggest that the nutritional status of the gastrectomy patients with stomach cancer may impact on their QoL. It is necessary to to develop nutritional intervention to improve QoL in gastric cancer patients with postoperative malnutrition. PMID- 26251832 TI - Nutritional Management of Kidney Stones (Nephrolithiasis). AB - The incidence of kidney stones is common in the United States and treatments for them are very costly. This review article provides information about epidemiology, mechanism, diagnosis, and pathophysiology of kidney stone formation, and methods for the evaluation of stone risks for new and follow-up patients. Adequate evaluation and management can prevent recurrence of stones. Kidney stone prevention should be individualized in both its medical and dietary management, keeping in mind the specific risks involved for each type of stones. Recognition of these risk factors and development of long-term management strategies for dealing with them are the most effective ways to prevent recurrence of kidney stones. PMID- 26251834 TI - Effect of Spinach, a High Dietary Nitrate Source, on Arterial Stiffness and Related Hemodynamic Measures: A Randomized, Controlled Trial in Healthy Adults. AB - Diets rich in fruits and vegetables reduce risk of adverse cardiovascular events. However, the constituents responsible for this effect have not been well established. Lately, the attention has been brought to vegetables with high nitrate content with evidence that this might represent a source of vasoprotective nitric oxide. We hypothesized that short-term consumption of spinach, a vegetable having high dietary nitrate content, can affect the arterial waveform indicative of arterial stiffness, as well as central and peripheral blood pressure (BP). Using a placebo-controlled, crossover design, 27 healthy participants were randomly assigned to receive either a high-nitrate (spinach; 845 mg nitrate/day) or low-nitrate soup (asparagus; 0.6 mg nitrate/day) for 7 days with a 1-week washout period. On days 1 and 7, profiles of augmentation index, central, and brachial BP were obtained over 180 min post-consumption in 4 fasted visits. A postprandial reduction in augmentation index was observed at 180 min on high-nitrate compared to low-nitrate intervention (-6.54 +/- 9.7% vs. 0.82 +/- 8.0%, p = 0.01) on Day 1, and from baseline on Day 7 (-6.93 +/- 8.7%, p < 0.001; high vs. low: -2.28 +/- 12.5%, p = 0.35), suggesting that the nitrate intervention is not associated with the development of tolerance for at least 7 days of continued supplementation. High vs. low-nitrate intervention also reduced central systolic (-3.39 +/- 5.6 mmHg, p = 0.004) and diastolic BP (-2.60 +/- 5.8 mmHg, p = 0.028) and brachial systolic BP (-3.48 +/- 7.4 mmHg, p = 0.022) at 180 min following 7-day supplementation only. These findings suggest that dietary nitrate from spinach may contribute to beneficial hemodynamic effects of vegetable-rich diets and highlights the potential of developing a targeted dietary approach in the management of elevated BP. PMID- 26251835 TI - Fennel (Foeniculum vulgare) and Fenugreek (Trigonella foenum-graecum) Tea Drinking Suppresses Subjective Short-term Appetite in Overweight Women. AB - Appetite controlling has been an main strategy for regulating food intake and energy balance in obesity treatment. The aim of this study was to examine the effects of drinking tea of the medicinal herbs, fennel and fenugreek, on the subjective appetite in overweight Korean women. The study was conducted using a placebo-controlled, single-blinded, randomized, and 3-way crossover design. Nine healthy women were given fennel tea (FT), fenugreek tea (FGT), or placebo tea (PT). After drinking a given tea, a lunch buffet was provided and then food consumption of subjects was analyzed. Subjective appetite, hunger, fullness, desire to eat, and prospective food consumption were measured at seven independent time point using a visual analog scale (VAS). Mean age of 9 subjects were 49.7 +/- 4.5 years and their mean body mass index were 24.6 +/- 0.6 kg/m(2). There was no significant difference in food consumption in the lunch buffet after drinking each tea; however, with respect to the subjective appetite scale, FGT decreased hunger, led to less prospective food consumption, and increased feelings of fullness compared with the PT (p < 0.05). Similarly, the consumption of FT resulted in decreased hunger, less prospective food consumption, and increased feelings of fullness compared with the PT (p < 0.05). The area under the curve of VAS graph indicated that FGT resulted in a higher feeling of fullness than the PT (p < 0.05). In conclusion, drinking the FT and FGT were significantly effective aid to suppress subjective appetite among overweight women in South Korea. PMID- 26251836 TI - Comparative Study of Serum Leptin and Insulin Resistance Levels Between Korean Postmenopausal Vegetarian and Non-vegetarian Women. AB - The present study was conducted to compare serum leptin and insulin resistance levels between Korean postmenopausal long-term semi-vegetarians and non vegetarians. Subjects of this study belonged to either a group of postmenopausal vegetarian women (n = 54), who maintained a semi-vegetarian diet for over 20 years or a group of non-vegetarian controls. Anthropometric characteristics, serum leptin, serum glucose, serum insulin, insulin resistance (HOMA-IR; Homeostasis Model Assessment of Insulin Resistance), and nutrient intake were compared between the two groups. The vegetarians showed significantly lower body weight (p < 0.01), body mass index (p < 0.001), percentage (%) of body fat (p < 0.001), and serum levels of leptin (p < 0.05), glucose (p < 0.001), and insulin (p < 0.01), than the non-vegetarians. The HOMA-IR of the vegetarians was significantly lower than that of the non-vegetarians (p < 0.01) after adjustment for the % of body fat. A long-term vegetarian diet might be related to lower insulin resistance independent of the % of body fat in postmenopausal women. PMID- 26251837 TI - Dietary Very Long Chain Saturated Fatty Acids and Metabolic Factors: Findings from the Korea National Health and Nutrition Examination Survey 2013. AB - The present study was aim to evaluate the association between very long chain saturated fatty acids (VLSFAs) and metabolic syndrome (MetS) in Korean population. The study population were recruited from the Korea National Health and Nutrition Examination Survey VI (2013). Using the cross-sectional study design, socio-demographic factors, medical history, and clinical measurements were investigated according to quartiles of VLSFAs intake. The associations between each and sum of VLSFAs intake and MetS were assessed by logistic regression. The result indicated that higher intake of VLSFAs was significantly associated with favorable metabolic status, including lower levels of circulating triglyceride (TG) (p < 0.05). Additionally, subjects with higher intake of arachidic acid and total VLSFAs were negatively associated with MetS risk compared to subjects with lower intake of those fatty acids (p < 0.05). In conclusion, dietary VLSFAs intake was associated with metabolic risk factors and lower risk of MetS in Korean population. PMID- 26251838 TI - Eating Habits and Food Preferences of Elementary School Students in Urban and Suburban Areas of Daejeon. AB - This study investigated the dietary habits and food preferences of elementary school students. The survey was conducted by means of a questionnaire distributed to 4th and 5th grade elementary school students (400 boys and 400 girls) in urban and suburban areas of Daejeon. The results of this study were as follows: male students in urban areas ate breakfast, unbalanced diets, and dairy products more frequently than male students in suburban areas (p < 0.05). Female students in urban areas ate dairy products (p < 0.01) and fruits (p < 0.001) more frequently than female students in suburban areas. Students had the high preferences for boiled rice and noodles with black bean sauce, beef rib soup, steamed beef rib, steamed egg, beef boiled in soy sauce, egg roll, bulgogi, pork cutlet, deep-fried pork covered with sweet and sour starchy sauce, and honeyed juice mixed with fruit as a punch. All students preferred kimchi, although students in the suburban areas preferred kimchi-fried rice (p < 0.05), and those in the urban areas preferred bean-paste soup (p < 0.01). Students in suburban areas showed a greater preference for seasoned bean sprouts and Altari kimchi. All of the students preferred fruits, rice cake made with glutinous rice, and pizza among other foods. Overall, there were distinct differences in the eating habits and food preferences of elementary school students according to the place of residence. PMID- 26251839 TI - Six-month Outcomes of Mobile Phone Application-based Self-management in a Patient with Type 2 Diabetes. AB - We report the case in order to examine the effect of a mobile application program ("Diabetes & Nutrition") developed in 2011-2012 for self-management in patients with type 2 diabetes and to recommend important considerations when the mobile application program is developed. A 46-year-old man was newly diagnosed with type 2 diabetes in 2013 and had no complications. The height of the patient was 168 cm and the body weight was 75.6 kg. Nutrition education was conducted according to a medical prescription, and follow-up nutrition education was conducted after 3 and 6 months. After nutrition education, the patient was engaged in self-management using "Diabetes & Nutrition" program during 3 months. At 3 months, the body weight had decreased by 4.4 kg (from 75.6 to 71.2 kg), waist circumference by 5 cm (from 88 to 83 cm) and HbA1c level from 7.9% to 6.1%. Also at 3 months, the medication was reduced from from the dose of 850 mg to the dose of 500 mg metformin per twice a day. Since then, the patient did not continue to use the "Diabetes & Nutrition" because the level of blood glucose had stabilized, and the patient felt inconvenient and annoying to use the program. At 6 months, no significant change in the body weight and body composition was observed in comparison with those at 3 months. The present case demonstrates that the early use of "Diabetes & Nutrition" could be helpful for self-management of glycemic control in patients with type 2 diabetes. Developing self-management mobile application programs in the future will require strategies of how to promote continuous use of application program and self-management of type 2 diabetes. PMID- 26251840 TI - Gemcitabine-(C4-amide)-[anti-HER2/neu] Anti-Neoplastic Cytotoxicity in Dual Combination with Mebendazole against Chemotherapeutic-Resistant Mammary Adenocarcinoma. AB - INTRODUCTION: Gemcitabine is a pyrimidine nucleoside analog that becomes triphosphorylated and competitively inhibits cytidine incorporation into DNA strands. Diphosphorylated gemcitabine irreversibly inhibits ribonucleotide reductase thereby preventing deoxyribonucleotide synthesis. Functioning as a potent chemotherapeutic, gemcitabine decreases neoplastic cell proliferation and induces apoptosis which accounts for its effectiveness in the clinical treatment of several leukemia and carcinoma cell types. A brief plasma half-life due to rapid deamination, chemotherapeutic-resistance and sequelae restrict gemcitabine utility in clinical oncology. Selective "targeted" gemcitabine delivery represents a molecular strategy for prolonging its plasma half-life and minimizing innocent tissue/organ exposure. METHODS: A previously described organic chemistry scheme was applied to synthesize a UV-photoactivated gemcitabine intermediate for production of gemcitabine-(C4-amide)-[anti HER2/neu]. Immunodetection analysis (Western-blot) was applied to detect the presence of any degradative fragmentation or polymerization. Detection of retained binding-avidity of gemcitabine-(C4-amide)-[anti-HER2/neu] was determined by cell-ELISA using populations of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) that highly over-express the HER2/neu trophic membrane receptor. Cytotoxic anti-neoplastic potency of gemcitabine-(C4-amide)-[anti HER2/neu] and the benzimidazole tubulin/microtubule inhibitors, albendazole, flubendazole and mebendazole was established against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Related investigations evaluated the potential for gemcitabine-(C4-amide)-[anti-HER2/neu] in dual combination with mebendazole to evoke increased levels of cytotoxic anti-neoplatic potency compared to gemcitabine-(C4-amide)-[anti-HER2/neu]. RESULTS: Covalent gemcitabine-(C4-amide) [anti-HER2/neu] immunochemotherapeutic and each benzimidazole (n=3) exerted cytotoxic anti-neoplastic potency against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Covalent gemcitabine-(C4-amide)-[anti-HER2/neu] immunochemotherapeutic or gemcitabine in dual combination with mebendazole created increased levels of cytotoxic anti-neoplastic potency that were greater than attained with gemcitabine-(C4-amide)-[anti-HER2/neu] or gemcitabine alone. CONCLUSION: Gemcitabine-(C4-amide)-[anti-HER2/neu] in dual combination with benzimidazoles can produce enhanced levels of cytotoxic anti-neoplastic activity and potentially provide a basis for treatment regimens with a wider margin-of safety. Such benefits would be possible through the collective properties of; [i] selective "targeted" gemcitabine delivery; [ii] relatively lower toxicity of benzimidazoles compared to many if not most conventional chemotherapeutics; [iii] reduced total dosage requirements faciliated by additive or synergistic anti cancer properties; and [iv] differences in sequelae for gemcitabine-(C4-amide) [anti-HER2/neu] compared to benzimidazole tubulin/microtubule inhibitors. PMID- 26251841 TI - Gene therapy to treat inherited and complex retinal degenerative diseases. PMID- 26251842 TI - Quantitative radiomics: impact of stochastic effects on textural feature analysis implies the need for standards. AB - Image heterogeneity metrics such as textural features are an active area of research for evaluating clinical outcomes with positron emission tomography (PET) imaging and other modalities. However, the effects of stochastic image acquisition noise on these metrics are poorly understood. We performed a simulation study by generating 50 statistically independent PET images of the NEMA IQ phantom with realistic noise and resolution properties. Heterogeneity metrics based on gray-level intensity histograms, co-occurrence matrices, neighborhood difference matrices, and zone size matrices were evaluated within regions of interest surrounding the lesions. The impact of stochastic variability was evaluated with percent difference from the mean of the 50 realizations, coefficient of variation and estimated sample size for clinical trials. Additionally, sensitivity studies were performed to simulate the effects of patient size and image reconstruction method on the quantitative performance of these metrics. Complex trends in variability were revealed as a function of textural feature, lesion size, patient size, and reconstruction parameters. In conclusion, the sensitivity of PET textural features to normal stochastic image variation and imaging parameters can be large and is feature-dependent. Standards are needed to ensure that prospective studies that incorporate textural features are properly designed to measure true effects that may impact clinical outcomes. PMID- 26251843 TI - Does Electrodiagnostic Confirmation of Radiculopathy Predict Pain Reduction after Transforaminal Epidural Steroid Injection? A Multicenter Study. AB - OBJECTIVE: Minimal definitive literature identifies patients with radicular pain who would benefit most from epidural steroid injection (ESI). This study investigated if electromyographic (EMG) confirmation of radiculopathy with active or chronic denervation predicts a positive treatment outcome following ESI. DESIGN: Longitudinal cohort study of adults who underwent EMG and subsequent transforaminal ESI within 6 months. The proportion of individuals who experienced >50% pain relief and mean change in daily morphine equivalents (DME) were calculated. RESULTS: 170 individuals with respective mean (Standard Deviation) age and duration of symptoms of 55 (15) years and 36 (56) months were included. Mean time to <30 day and >30 day follow-up post-injection were 18 (6) and 99 (130) days, respectively. At >30 day follow-up, a larger proportion of EMG confirmed individuals (37.7%) reported >50% pain reduction compared to EMG negative individuals (17.8%) (p=0.03). This was significant for lumbosacral (40% vs. 15%, p=0.01) but not cervical symptoms (p>0.05). Mean decrease in DME at long term follow-up in EMG-confirmed compared to EMG-negative individuals trended toward significance (-4 vs. -1, p=0.11). There was no significant relationship between myotomal spontaneous activity and pain or opioid use. CONCLUSIONS: Needle EMG predicts long-term pain reduction from transforaminal ESI in patients with lumbosacral radiculopathy, regardless of the presence of active denervation. PMID- 26251844 TI - Needs assessment for emerging oral microbiome knowledge in dental hygiene education. AB - The curricula of dental hygiene education reflect the knowledge gained through research and clinical advances. Emerging knowledge is often complex and tentative. The purpose of this study is to assess dental hygiene students' confidence in their knowledge about the oral microbiome and to conduct a knowledge needs assessment for expanding their exposure to emerging knowledge about the oral microbiome. Sixty dental hygiene students were surveyed, using a Likert-type scale about their confidence and about current and emerging bacteriological research. The majority of students (60%) reported being confident in their knowledge. The mean score for the ten items was 35.2% (standard deviation, 20.6%). The results of this study indicate a need for emphasis on emerging oral microbiome research in dental hygiene education. This is important so that dental hygiene students can properly share information with their patients about advances in dental care. PMID- 26251846 TI - Transcriptome-based reconstructions from the murine knockout suggest involvement of the urate transporter, URAT1 (slc22a12), in novel metabolic pathways. AB - URAT1 (slc22a12) was identified as the transporter responsible for renal reabsorption of the medically important compound, uric acid. However, subsequent studies have indicated that other transporters make contributions to this process, and that URAT1 transports other organic anions besides urate (including several in common with the closely related multi-specific renal organic anion transporters, OAT1 (slc22a6) and OAT3 (slc22a8)). These findings raise the possibility that urate transport is not the sole physiological function of URAT1. We previously characterized mice null for the murine ortholog of URAT1 (mURAT1; previously cloned as RST), finding a relatively modest decrement in urate reabsorptive capacity. Nevertheless, there were shifts in the plasma and urinary concentrations of multiple small molecules, suggesting significant metabolic changes in the knockouts. Although these molecules remain unidentified, here we have computationally delineated the biochemical networks consistent with transcriptomic data from the null mice. These analyses suggest alterations in the handling of not only urate but also other putative URAT1 substrates comprising intermediates in nucleotide, carbohydrate, and steroid metabolism. Moreover, the analyses indicate changes in multiple other pathways, including those relating to the metabolism of glycosaminoglycans, methionine, and coenzyme A, possibly reflecting downstream effects of URAT1 loss. Taken together with the available substrate and metabolomic data for the other OATs, our findings suggest that the transport and biochemical functions of URAT1 overlap those of OAT1 and OAT3, and could contribute to our understanding of the relationship between uric acid and the various metabolic disorders to which it has been linked. PMID- 26251847 TI - Toward live-cell imaging of dopamine neurotransmission with fluorescent neurotransmitter analogues. AB - We report a novel 'fluorescent dopamine' that possesses essential features of natural dopamine. Our method is simple and is readily extended to monoamine neurotransmitters such as L-norepinephrine, serotonin and GABA, providing a more practical approach. Because of its compatibility with sensitive fluorescent measurements, we envisage that our approach will have a broad range of applications in neural research. PMID- 26251848 TI - A tubular perovskite solar cell: improvement of charge separation at the perovskite/HTM interface. AB - Organolead iodide perovskite showing tubular morphology was fabricated on mesoporous TiO2 film via a one-step spin-coating procedure. These perovskite tubes with the external diameter of 1 MUm were found to facilitate the charge separation at perovskite/hole-transport material (HTM) interfaces. This engenders a tubular perovskite device showing a higher fill factor over the device with planar perovskite, and improves power conversion efficiency accordingly. PMID- 26251845 TI - Individuality and variation of personal regulomes in primary human T cells. AB - Here we survey variation and dynamics of active regulatory elements genome-wide using longitudinal samples from human individuals. We applied Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) to map chromatin accessibility in primary CD4+ T cells isolated from standard blood draws of 12 healthy volunteers over time, from cancer patients, and during T cell activation. Over 4,000 predicted regulatory elements (7.2%) showed reproducible variation in accessibility between individuals. Gender was the most significant attributable source of variation. ATAC-seq revealed previously undescribed elements that escape X chromosome inactivation and predicted gender-specific gene regulatory networks across autosomes, which coordinately affect genes with immune function. Noisy regulatory elements with personal variation in accessibility are significantly enriched for autoimmune disease loci. Over one third of regulome variation lacked genetic variation in cis, suggesting contributions from environmental or epigenetic factors. These results refine concepts of human individuality and provide a foundational reference for comparing disease associated regulomes. PMID- 26251849 TI - A mild carbon-boron bond formation from diaryliodonium salts. AB - The direct metal-free borylation of diaryliodonium salts with diboron reagents is now demonstrated to be a feasible process toward formation of aryl boronic esters without any additive or catalysts, and it can be extended to a two-step C-C coupling of both aryl groups of the initial diaryliodonium reagent. PMID- 26251850 TI - Triflyloxy-substituted carboranes as useful weakly coordinating anions. AB - New carborane anions carrying one or three triflyloxy substituents are described. The mono-triflyloxy substituted carborane can be halogenated to give pentabromo and decachloro derivatives with preservation of the B-OTf linkage. The use of [HCB11Cl10OTf](-) as a weakly coordinating anion is demonstrated. PMID- 26251851 TI - Authors' reply. PMID- 26251852 TI - Authors' reply. PMID- 26251853 TI - Bitter orange, ephedra, and hydroxycitric acid: issues with the article "Dietary supplements for improving body composition and reducing body weight: where is the evidence?". PMID- 26251854 TI - Survey of Attitudes of Japanese Women Toward Genetic/Genomic Research. AB - Previous surveys have suggested that elderly Japanese women have the lowest scientific interest and literacy within the Japanese population and among populations across Western countries. Because recent tremendous advances in genome analysis are likely to be incorporated into standard biomedical assessments throughout the world, we conducted surveys to investigate the attitudes toward genetic/genomic research of Japanese women aged between 55 and 65 years. Current surveys indicate that obtaining adequate informed consent from elderly Japanese women is complicated. The limitation is especially relevant to participants' literacy in genetics and genomic studies. Results of the surveys also indicate that even after the informed consent is obtained, researchers must continue to supply updated study information to the study subjects, which enables them to obtain additional information on the use of their samples and genetic/genomic information. Failure to consider these obligations may lead to a loss of the public's trust and thus affect research progress on medical genomics. PMID- 26251855 TI - Everolimus-Eluting Stents or Bypass Surgery for Coronary Disease. PMID- 26251856 TI - The European Society of Cardiology global scientific activities in Arabia 2015. AB - European Society of Cardiology representatives, including past and present ESC presidents, discussed the latest cardiology developments at the 26th Saudi Heart Association (SHA) Congress. PMID- 26251857 TI - Can ivabradine still be used in clinical practice after the 'SIGNIFY' trial? PMID- 26251858 TI - The new postgraduate course in heart failure (PCHF): update on 1st PCHF and announcement of the 2nd PCHF. A project of the European Society of Cardiology Heart Failure Association, the ESC European Heart Academy, the Zurich Heart House and the University of Zurich. PMID- 26251859 TI - Jake MacMillan (1924-2014). PMID- 26251860 TI - Lab budgets: A numbers game. PMID- 26251861 TI - Research Resources Survey: Radiology Junior Faculty Development. AB - RATIONALE AND OBJECTIVES: To assess resources available to junior faculty in US academic radiology departments for research mentorship and funding opportunities and to determine if certain resources are more common in successful programs. MATERIALS AND METHODS: An anonymous survey covering scientific environment and research mentorship and was sent to vice-chairs of research of radiology departments. Results were evaluated to identify practices of research programs with respect to mentorship, resources, and opportunities. Academy of Radiology Research's 2012 National Institutes of Health (NIH) grants and awards list was used to determine if environment and practices correlate with funding. RESULTS: There was a 51% response rate. A greater fraction of clinical faculty gets promoted from assistant to associate professor than research faculty. Research faculty overall submits more funding applications. Most programs support start-up costs and K-awards. Over half of the departments have a vice-chair for faculty development, and most have formal mentorship programs. Faculty members are expected to teach, engage in service, publish, and apply for and get research funding within 3 years of hire. Top-tier programs as judged by NIH awards have a combination of MDs who devote >50% effort to research and PhD faculty. Key factors holding back both clinical and research junior faculty development were motivation, resources, and time, although programs reported high availability of resources and support at the department level. CONCLUSIONS: Better marketing of resources for junior faculty, effort devoted to mentoring clinical faculty in research, and explicit milestones/expectations for achievement could enhance junior faculty success, promote interest in the clinician-scientist career path for radiologists, and lead to greater research success. PMID- 26251862 TI - Lessons Learned Preparing Volunteer Midwives for Service in Haiti: After the Earthquake. AB - INTRODUCTION: Midwives for Haiti is an organization that focuses on the education and training of skilled birth attendants in Haiti, a country with a high rate of maternal and infant mortality and where only 26% of births are attended by skilled health workers. Following the 2010 earthquake, Midwives for Haiti received requests to expand services and numerous professional midwives answered the call to volunteer. This author was one of those volunteers. The purpose of the study was: 1) to develop a description of the program's strengths and its deficits in order to determine if there was a need to improve the preparation of volunteers prior to service and 2) to make recommendations aimed at strengthening the volunteers' contributions to the education of Haiti and auxiliary midwives. METHODS: Three distinct but closely related questionnaires were developed to survey Haitian students, staff midwives, and volunteers who served with Midwives for Haiti. Questions were designed to elicit information about how well the volunteers were prepared for their experience, the effectiveness of translation services, and suggestions for improving the preparation of volunteers and strengthening the education program. RESULTS: Analysis of the surveys of volunteers, staff, midwives, and the Haitian students generated several common themes. The 3 groups agreed that the volunteers made an effective contribution to the program of education and that the volunteer midwives need more preparation prior to serving in Haiti. The 3 groups also agreed on the need for better translators and recommended more structure to the education program. DISCUSSION: The results of this study are significant to international health care organizations that use volunteer health care professionals to provide services. The results support a growing body of knowledge that international health aid organizations may use to strengthen the preparation, support, and effectiveness of volunteer health providers. PMID- 26251863 TI - Reflections: Neurology And The Humanities. Silvia's blessing. PMID- 26251864 TI - Author Response. PMID- 26251865 TI - Author Response. PMID- 26251866 TI - What is aging for? That remains the question. PMID- 26251867 TI - Nanoscale Heterostructures Based on Fe2O3@WO3-x Nanoneedles and Their Direct Integration into Flexible Transducing Platforms for Toluene Sensing. AB - Nanoscale heterostructures based on WO3-x nanoneedles functionalized with Fe2O3 nanoparticles are integrated directly into flexible polymer-based transducing platforms via aerosol-assisted chemical vapor deposition. Results demonstrate that the incorporation of Fe2O3 nanoparticles at the surface of WO3-x nanoneedles enhances the electronic and sensing properties of WO3-x, providing a 6-fold increase in sensitivity to toluene and low cross-sensitivity to hydrogen and ethanol. These enhanced-sensing properties are comparable to those obtained via functionalization with precious metal (Pt) nanoparticles, which are commonly used to enhance sensor performance. PMID- 26251868 TI - Comparison of Feeding Practices in Infants in the WIC Supplemental Nutrition Program Who Were Enrolled in Child Care as Opposed to Those with Parent Care Only. AB - BACKGROUND: The environment or setting to which an infant is exposed is crucial to establishing healthy eating habits and to preventing obesity. This study aimed to compare infant feeding practices and complementary food type between parent care (PC) and childcare (CC) settings among infants receiving the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). MATERIALS AND METHODS: This study sampled 105 dyads of mothers and infants between 2 to 8 months of age from a WIC office in Central Illinois. Mothers completed a cross sectional survey to assess their infant feeding practices and demographic characteristics. CC was defined as infants receiving 10 hours or more per week of care from a nonparental caregiver. RESULTS: Almost half of the infants (44%) were enrolled in CC. Infants in CC had an average of 29 hours of care per week compared with 0.64 hours in the PC group (p<0.01). There were no differences between the two groups in age, sex, race/ethnicity, preterm birth, and birth weight. Overall, there were no significant differences in breastfeeding initiation and duration. The average age at formula introduction was earlier for PC infants (0.90 +/- 1.16 months) than for CC infants (1.66 +/- 1.64 months) (p = 0.03). PC infants stopped breastfeeding at 1.96 +/- 1.15 months compared with 2.31 +/- 1.64 months for CC infants (p = 0.080). Among complementary foods introduced to infants, the primary food type was infant cereal, followed by baby food of fruits and vegetables, 100% fruit juice, and meat-based baby food. The timing of introduction and the types of complementary foods were similar between study groups. CONCLUSIONS: CC use is not a significant influence on breastfeeding rates, introduction of complementary foods, and types of complementary foods; however, it does influence when formula is introduced. The findings support the need for infant nutrition education and breastfeeding promotion targeting WIC mothers, regardless of their pattern of CC. PMID- 26251869 TI - The benefits of being a senior mentor: Cultivating resilience through the mentorship of health professions students. AB - Senior Mentor Programs (SMPs) pair community-dwelling older adults with health professions students to facilitate knowledge, improve communication skills, and promote positive attitudes regarding the aging process. Although evidence exists that SMPs meet these goals, the programs' psychosocial impact on the senior mentors remains unexplored. The current study assessed 101 mostly female (64.4%) senior mentors (M age = 77.6) pre- and postprogram. Although mentors had no change in the amount of perceived ageism experienced or expectation of experiencing ageism, their concern/anxiety over ageism significantly decreased from pre- (M = 21.58) to posttest (M = 20.19). Qualitative thematic analysis indicated meaningfulness of program and scheduling difficulties as prevalent themes. Mentors who reported less concern about ageism following the program were more likely to have experienced ageism in the year prior to the program and to attend religious services more often, another potential intergenerational contact. These results highlight possible benefits of mentor service for older adults. PMID- 26251870 TI - Halobacteriovorax, an underestimated predator on bacteria: potential impact relative to viruses on bacterial mortality. AB - Predation on bacteria and accompanying mortality are important mechanisms in controlling bacterial populations and recycling of nutrients through the microbial loop. The agents most investigated and seen as responsible for bacterial mortality are viruses and protists. However, a body of evidence suggests that predatory bacteria such as the Halobacteriovorax (formerly Bacteriovorax), a Bdellovibrio-like organism, contribute substantially to bacterial death. Until now, conclusive evidence has been lacking. The goal of this study was to better understand the contributors to bacterial mortality by addressing the poorly understood role of Halobacteriovorax and how their role compares with that of viruses. The results revealed that when a concentrated suspension of Vibrio parahaemolyticus was added into microcosms of estuarine waters, the native Halobacteriovorax were the predators that responded first and most rapidly. Their numbers increased by four orders of magnitude, whereas V. parahaemolyticus prey numbers decreased by three orders of magnitude. In contrast, the extant virus population showed little increase and produced little change in the prey density. An independent experiment with stable isotope probing confirmed that Halobacteriovorax were the predators primarily responsible for the mortality of the V. parahaemolyticus. The results show that Halobacteriovorax have the potential to be significant contributors to bacterial mortality, and in such cases, predation by Halobacteriovorax may be an important mechanism of nutrient recycling. These conclusions add another dimension to bacterial mortality and the recycling of nutrients. PMID- 26251871 TI - Global diversity and biogeography of deep-sea pelagic prokaryotes. AB - The deep-sea is the largest biome of the biosphere, and contains more than half of the whole ocean's microbes. Uncovering their general patterns of diversity and community structure at a global scale remains a great challenge, as only fragmentary information of deep-sea microbial diversity exists based on regional scale studies. Here we report the first globally comprehensive survey of the prokaryotic communities inhabiting the bathypelagic ocean using high-throughput sequencing of the 16S rRNA gene. This work identifies the dominant prokaryotes in the pelagic deep ocean and reveals that 50% of the operational taxonomic units (OTUs) belong to previously unknown prokaryotic taxa, most of which are rare and appear in just a few samples. We show that whereas the local richness of communities is comparable to that observed in previous regional studies, the global pool of prokaryotic taxa detected is modest (~3600 OTUs), as a high proportion of OTUs are shared among samples. The water masses appear to act as clear drivers of the geographical distribution of both particle-attached and free living prokaryotes. In addition, we show that the deep-oceanic basins in which the bathypelagic realm is divided contain different particle-attached (but not free-living) microbial communities. The combination of the aging of the water masses and a lack of complete dispersal are identified as the main drivers for this biogeographical pattern. All together, we identify the potential of the deep ocean as a reservoir of still unknown biological diversity with a higher degree of spatial complexity than hitherto considered. PMID- 26251872 TI - Core-satellite populations and seasonality of water meter biofilms in a metropolitan drinking water distribution system. AB - Drinking water distribution systems (DWDSs) harbor the microorganisms in biofilms and suspended communities, yet the diversity and spatiotemporal distribution have been studied mainly in the suspended communities. This study examined the diversity of biofilms in an urban DWDS, its relationship with suspended communities and its dynamics. The studied DWDS in Urbana, Illinois received conventionally treated and disinfected water sourced from the groundwater. Over a 2-year span, biomass were sampled from household water meters (n=213) and tap water (n=20) to represent biofilm and suspended communities, respectively. A positive correlation between operational taxonomic unit (OTU) abundance and occupancy was observed. Examined under a 'core-satellite' model, the biofilm community comprised 31 core populations that encompassed 76.7% of total 16 S rRNA gene pyrosequences. The biofilm communities shared with the suspended community highly abundant and prevalent OTUs, which related to methano-/methylotrophs (i.e., Methylophilaceae and Methylococcaceae) and aerobic heterotrophs (Sphingomonadaceae and Comamonadaceae), yet differed by specific core populations and lower diversity and evenness. Multivariate tests indicated seasonality as the main contributor to community structure variation. This pattern was resilient to annual change and correlated to the cyclic fluctuations of core populations. The findings of a distinctive biofilm community assemblage and methano-/methyltrophic primary production provide critical insights for developing more targeted water quality monitoring programs and treatment strategies for groundwater-sourced drinking water systems. PMID- 26251873 TI - A modified prognostic score for critically ill patients with cirrhosis: An observational study. AB - BACKGROUND AND AIMS: It is controversial whether patients with cirrhosis benefit from the intensive care unit (ICU) management. To identify the patients in whom ICU care may offer recovery, this study aimed to determine specific risk factors and to establish a novel prognostic score for 3-month mortality in critically ill patients with cirrhosis. METHODS: An observational study was performed from August 2008 to May 2014, encompassing 349 critically ill patients with cirrhosis during their ICU stay (a 70% training and 30% validation set). RESULTS: The overall 3-month mortality rate was 68.1% in training cohort. Prothrombin time, serum bilirubin, use of vasopressors, hepatic encephalopathy, and systemic inflammatory response syndrome at admission were identified as being strongly correlated with the 3-month prognosis. Based on these five variables, a modified score for critically ill cirrhosis (MSCIC) was developed. An increasing MSCIC was significantly correlated with a reduction in the rate of survival (P < 0.001). Moreover, excellent predictive power was found when the MSCIC was used (area under the receiver operating characteristic curve: 0.856 +/- 0.047), which was significantly better than the prognostic efficiency of Acute Physiology and Chronic Health Evaluation II (P < 0.001), Model for End-stage Liver Disease (P = 0.02), Simplified Acute Physiology Score (P = 0.023), and the Child-Turcotte-Pugh score (P = 0.01); the MSCIC score was slightly better than that of Chronic Liver Failure-Sequential Organ Failure Assessment (P = 0.068). The similar result was obtained in validation set. CONCLUSIONS: The MSCIC is an easily adopted tool with a high prognostic efficacy for patients with advanced cirrhosis; MSCIC may act as a supplement to the clinical judgment of physicians when considering the prognosis. PMID- 26251874 TI - Oxidative stress biomarkers and paraoxonase 1 polymorphism frequency in farmers occupationally exposed to pesticides. AB - Previous evidence has demonstrated that chemical classes of pesticides, including organophosphates (OP), can induce oxidative stress in exposed workers. The resulting increase in free radicals causes damage to biological macromolecules, and promotes the formation of novel compounds, including advanced glycation end products (AGE) and advanced oxidation protein products (AOPP). The present study aimed to evaluate the common genetic polymorphisms of the paraoxonase 1 (PON1) gene in a group of 55 farmers exposed to pesticides, as well as the association between these polymorphisms and serum levels of AGE and AOPP. The 192Q wild-type (WT) allele was present at a significantly higher frequency, compared with the 192R mutated allele (0.74 and 0.26, respectively). The WT allele was predominantly represented by the homozygote 192QQ genotype (51%). The mutated 192QR heterozygotic allele was prevalent, at a frequency of 45.4%, whereas the mutated homozygotes were present at a frequency of 3.6%. A significant decrease in the levels of AGE and AOPP was observed in farmers exhibiting the homozygotic 192RR mutated genotype (14,7221 AU/ml and 0.64 nmol/ml, respectively), compared with the WT genotype (16,1400 AU/ml and 1.76 nmol/ml, respectively), and 192QR genotype (15,2312 AU/ml and 1.60 nmol/ml, respectively). Therefore, due to the high catalytic activity of PON1, the 192RR genotype provides an important genetic predictor of the toxic effects associated with OP pesticide exposure. It determines a minor risk of developing oxidative damage following pesticide exposure, and measuring the levels of AOPP may provide a novel biomarker for oxidative damage in subjects exposed to OP. PMID- 26251875 TI - Utility of the hypertriglyceridemic waist phenotype in the cardiometabolic risk assessment of youth stratified by body mass index. AB - BACKGROUND: It is unclear whether the hypertriglyceridemic waist phenotype (HTWP) can be used to identify those at most risk of cardiometabolic disorders. OBJECTIVES: The utility of the HTWP as a useful predictor of cardiometabolic risk in youth stratified by body mass index was assessed. METHODS: Three hundred and eighty-seven children (12-17.5 years) were used within this cross-sectional study. Participants were classified as normal weight or overweight/obese according to the International Obesity Task Force criteria. The HTWP phenotype was defined as having a waist circumference >=90th percentile for age and gender with concomitant triglyceride concentrations >=1.24 mmol L(-1) . Cardiometabolic risk profiles were compared using MANCOVA. RESULTS: Normal weight participants with the HTWP had significantly higher levels of C-reactive protein 2.6 +/- 0.4 vs. 1.6 +/- 0.3 mg L(-1) (P < 0.05) and cardiometabolic risk scores (1.3 +/- 0.3 vs. -0.7 +/- 0.2 and 2.1 +/- 0.4 vs. -0.5 +/- 0.2; both P < 0.05) compared with those of a normal weight without the HTWP. Overweight/obese participants with the HTWP had significantly higher C-reactive protein levels (3.5 +/- 0.6 vs. 2.6 +/- 0.5; P < 0.05) as well as both cardiometabolic risk scores (1.6 +/- 0.6 vs. 0.9 +/- 0.2 and 2.2 +/- 0.6 vs. 0.8 +/- 0.2; both P < 0.001) when compared with overweight/obese participants without the HTWP. CONCLUSIONS: The HTWP may serve as a simple and clinically useful approach to identify youth at increased cardiometabolic risk. PMID- 26251876 TI - PLGA-encapsulated perfluorocarbon nanoparticles for simultaneous visualization of distinct cell populations by 19F MRI. AB - AIM: In vivo imaging using (19)F MRI is advantageous, due to its ability to quantify cell numbers, but is limited for a lack of suitable labels. Here, we formulate two stable and clinically applicable labels for tracking two populations of primary human dendritic cells (DCs) simultaneously. MATERIALS & METHODS: Plasmacytoid and myeloid DCs are able to take up sufficient nanoparticles (200 nm) for imaging (10(12 19)F's per cell), despite being relatively nonphagocytic. RESULTS: Clinically relevant numbers of labeled DCs could be imaged in about 10 min, even on a clinical scanner. CONCLUSION: We demonstrate the use of perfluorocarbon nanoparticles for simultaneous (19)F MRI of distinct cell populations in a clinical setting, without spectroscopic imaging. PMID- 26251877 TI - Involvement of ROP6 and clathrin in nodulation factor signaling. AB - The symbiotic association between the legume Lotus japonicus and the nitrogen fixing bacterium Mesorhizobium loti results in the formation of root nodules. This process begins with the recognition of the rhizobial nodulation factor (NF) by the NF receptors (NFR) at the cell surface of the host roots. The downstream signaling cascades after NFR recognition have not been fully characterized. We recently identified a clathrin heavy chain 1 (CHC1) from L. japonicus as a potential target of the NF signaling cascades. CHC is a known central component in the clathrin-mediated endocytosis (CME) in eukaryotic cells. The CHC1 gene was highly expressed in Rhizobium-infected root hairs and the CHC1 protein was present in cytoplasmic punctate structures near the infection pockets and along the infection thread membrane. Furthermore, expression of a dominant-negative variant of CHC1 or treatment with a chemical inhibitor of CME resulted in impaired phenotypes in the NF signaling, rhizobial infection and nodulation. These findings open a new avenue for future work aiming at understanding the role of endocytosis in NF signaling pathway and rhizobial infection. PMID- 26251878 TI - Arabidopsis phosphatase under-producer mutants pup1 and pup3 contain mutations in the AtPAP10 and AtPAP26 genes. AB - Production and secretion of acid phosphatases (APases) is a hallmark adaptive response of plants to phosphate (Pi) deprivation. Researchers have long hypothesized that Pi starvation-induced APases are involved in internal Pi recycling and remobilization as well as in external Pi utilization. Two phosphatase under-producer (pup) mutants, pup1 and pup3, were previously isolated in Arabidopsis. Characterization of these 2 pup mutants provided the first genetic evidence for the above hypothesis. To date, however, the molecular lesions in these 2 pup mutants remain unknown. In this work, we demonstrate that pup1 and pup3 contain point mutations in the Arabidopsis purple acid phosphatase gene AtPAP10 and AtPAP26, respectively. Our results answer a long-standing question about the molecular identity of the PUP1 and PUP3 genes and corroborate the conclusions from previous studies regarding the function of AtPAP10 and AtPAP26 in plant acclimation to Pi deprivation. PMID- 26251879 TI - Translocation and accumulation of nicotine via distinct spatio-temporal regulation of nicotine transporters in Nicotiana tabacum. AB - In plants, secondary metabolites play important roles in adaptation to the environment. Nicotine, a pyridine alkaloid in Nicotiana tabacum, functions as chemical barrier against herbivores. Nicotine produced in the root undergoes long distance transport and accumulates mainly in the leaves. Since production of such defensive compounds is costly, plants must regulate the allocation of the products to their tissues; however, the molecular mechanism of nicotine translocation remains unclear. Our recent studies identified a novel multidrug and toxic compound extrusion (MATE)-type nicotine transporter, JAT2 (jasmonate inducible alkaloid transporter 2). This transporter is specifically expressed in leaves, localizes to the tonoplast, and transports nicotine as its substrate. The specific induction of JAT2 expression in leaves by methyl jasmonate (MeJA) treatment suggests that this transporter plays an important role in nicotine distribution to leaves, especially under herbivore attack, by transporting nicotine into the vacuole. Considering JAT2, together with the previously identified MATE transporters JAT1, MATE1, and MATE2, and the PUP (purine permease) transporter NUP1 (nicotine uptake permease1), we show a model of nicotine translocation and accumulation via distinct spatio-temporal regulation of nicotine transporter expression. Furthermore, we discuss the possible role of nicotine transporters in determining outcrossing rates and seed production. PMID- 26251880 TI - BiP3 supports the early stages of female gametogenesis in the absence of BiP1 and BiP2 in Arabidopsis thaliana. AB - Immunoglobulin binding protein (BiP) is an essential heat shock protein 70 (Hsp70) in the endoplasmic reticulum (ER) that functions in various processes including protein translocation, protein folding and quality control. Arabidopsis thaliana harbors ubiquitously expressed genes BIP1 and BIP2, as well as BIP3, which is induced only by ER stress. Recently, we reported that these BIP genes are expressed in male gametophytes and cooperate with each other to support male gametogenesis and pollen competitiveness. Here, we report that the BIP genes cooperate to support female gametogenesis. As reported previously, the bip1 bip2 double mutation causes defects in the fusion of polar nuclei during female gametogenesis. By contrast, the bip triple mutant female gametophytes exhibited defects during the early stages of female gametophyte development, which suggests that BIP3 supports the early stages of female gametophyte development, but not polar nuclear fusion, in the absence of BiP1 and BiP2. PMID- 26251881 TI - The state of cell wall pectin monitored by wall associated kinases: A model. AB - The Wall Associated Kinases (WAKs) bind to both cross-linked polymers of pectin in the plant cell wall, but have a higher affinity for smaller fragmented pectins that are generated upon pathogen attack or wounding. WAKs are required for cell expansion during normal seedling development and this involves pectin binding and a signal transduction pathway involving MPK3 and invertase induction. Alternatively WAKs bind pathogen generated pectin fragments to activate a distinct MPK6 dependent stress response. Evidence is provided for a model for how newly generated pectin fragments compete for longer pectins to alter the WAK dependent responses. PMID- 26251882 TI - (E)-beta-farnesene gene reduces Lipaphis erysimi colonization in transgenic Brassica juncea lines. AB - Aphids are the major concern that significantly reduces the yield of crops. (E) beta-farnesene (Ebetaf) is the principal component of the alarm pheromone of many aphids. The results of current research support the direct defense response of (E)-beta-farnesene (Ebetaf) against aphid Lipaphis erysimi (L.) Kaltenbach in Brassica juncea. Ebetaf gene was isolated from Mentha arvensis and transformed into B. juncea, showed direct repellent against aphid colonization. The seasonal mean population (SMP) recorded under field condition showed significantly higher aphid colonization in wild type in comparison to most of the transgenic lines, and shows positive correlation with the repellency of transgenic plant expressing (E)-beta-farnesene. The current research investigation provides direct evidence for aphid control in B. juncea using Ebetaf, a non-toxic mode of action. PMID- 26251883 TI - New insights into the dimerization of small GTPase Rac/ROP guanine nucleotide exchange factors in rice. AB - Molecular links between receptor-kinases and Rac/ROP family small GTPases mediated by activator guanine nucleotide exchange factors (GEFs) govern diverse biological processes. However, it is unclear how the Rac/ROP GTPases orchestrate such a wide variety of activities. Here, we show that rice OsRacGEF1 forms homodimers, and heterodimers with OsRacGEF2, at the plasma membrane (PM) and the endoplasmic reticulum (ER). OsRacGEF2 does not bind directly to the receptor-like kinase (RLK) OsCERK1, but forms a complex with OsCERK1 through OsRacGEF1 at the ER. This complex is transported from ER to the PM and there associates with OsRac1, resulting in the formation of a stable immune complex. Such RLK-GEF heterodimer complexes may explain the diversity of Rac/ROP family GTPase signalings. PMID- 26251884 TI - Strigolactone signaling in root development and phosphate starvation. AB - Strigolactones (SLs), have recently been recognized as phytohormone involve in orchestrating shoot and root architecture. In, roots SLs positively regulate root hair length and density, suppress lateral root formation and promote primary root meristem cell number. The biosynthesis and exudation of SLs increases under low phosphate level to regulate root responses. This hormonal response suggests an adaptation strategy of plant to optimize growth and development under nutrient limitations. However, little is known on signal-transduction pathways associated with SL activities. In this review, we outline the current knowledge on SL biology by describing their role in the regulation of root development. Also, we discuss the recent findings on the non-cell autonomous signaling of SLs, that involve PIN polarization, vesicle trafficking, changes in actin architecture and dynamic in response to phosphate starvation. PMID- 26251885 TI - Regulation of Cu delivery to chloroplast proteins. AB - Plastocyanin is a copper (Cu)-requiring protein that functions in photosynthetic electron transport in the thylakoid lumen of plants. To allow plastocyanin maturation, Cu must first be transported into the chloroplast stroma by means of the PAA1/HMA6 transporter and then into the thylakoid lumen by the PAA2/HMA8 transporter. Recent evidence indicated that the chloroplast regulates Cu transport into the thylakoids via Clp protease-mediated turnover of PAA2/HMA8. Here we present further genetic evidence that this regulatory mechanism for the adjustment of intra-cellular Cu distribution depends on stromal Cu levels. A key transcription factor mediating Cu homeostasis in plants is SQUAMOSA promoter binding protein-like7 (SPL7). SPL7 transcriptionally regulates Cu homeostasis when the nutrient becomes limiting by up-regulating expression of Cu importers at the cell membrane, and down-regulating expression of seemingly non-essential cuproproteins. It was proposed that this latter mechanism favors Cu delivery to the chloroplast. We propose a 2-tiered system which functions to control plant leaf Cu homeostasis: SPL7 dependent transcriptional regulation of cuproproteins, and PAA2/HMA8 turnover by the Clp system, which is independent on SPL7. PMID- 26251886 TI - Overexpression of a CYP94 family gene CYP94C2b increases internode length and plant height in rice. AB - Plant growth is controlled by intrinsic developmental programmes and environmental cues. Jasmonate (JA) has important roles in both processes, by regulating cell division and differentiation, as well as in defense responses and senescence. We report an increase in rice plant height caused by overexpression of a gene encoding a cytochrome P450 enzyme, CYP94C2b, which promoted deactivation of JA-Ile. The height increase occurred through enhanced elongation of internodes in the absence of concomitant cell elongation, unlike previous findings with coi1 knock-down plants. Thus, modulating JA metabolism can increase the number of elongated cells in an internode. Based on these and previous findings, we discuss the difference in the effects of CYP94C2b overexpression vs. coi1 knock-down. PMID- 26251887 TI - Using molecular biology to study mycorrhizal fungal community ecology: Limits and perspectives. AB - Molecular tools have progressively replaced morphological approaches to characterize microbial communities in nature. Arbuscular mycorrhizal (AM) fungi are no exception to this rule. Yet, one challenge posed by these symbionts is that they colonize simultaneously both plant roots and soil, which complicates their detection and quantification. In most studies conducted to date, AM fungal communities have been characterized from roots only, soil only or spores only. Here, we discuss the pitfalls associated to drawing ecological inferences using such datasets. We also conclude by arguing that molecular biology will contribute most to advance knowledge in AM fungal ecology if it is integrated into broader perspectives taking into account the natural history of these organisms. This calls for a better merging of molecular and morphological approaches, and the establishment of intensive, long-term research programs. PMID- 26251889 TI - An Unusual Carbohydrate Conformation is Evident in Moraxella catarrhalis Oligosaccharides. AB - Oligosaccharide structures derived from the lipooligosaccharide of M. catarrhalis show that the highly branched glucose-rich inner core of the oligosaccharide has an altered conformation compared to the most truncated tetra-glucose-Kdo lgt1/4Delta oligosaccharide structure. Addition of one residue each to the (1-4) and (1-6) chains to give the lgt2Delta oligosaccharide is the minimum requirement for this conformational change to occur. Extensive molecular modeling and NMR investigations have shown that the (1-3), (1-4), and (1-6) glycosidic linkages from the central alpha-D-Glcp have significantly altered conformational preferences between the two structures. For the lgt1/4Delta oligosaccharide the (1-3) and (1-4) linkage populates predominantly the syn minimum on the conformational free energy map and for the (1-6) linkage conformational flexibility is observed, which is supported by 1H-NMR T1 measurements. For the lgt2Delta oligosaccharide the unusual "(1-4)anti-psi(1-6)gg" conformation, which could be confirmed by long-range NOE signals, is a dominant conformation in which the oligosaccharide is very compact with the terminal alpha-D-GlcNAc residue folding back towards the center of the molecule leading to an extensive intra molecular hydrophobic interaction between the terminal residues. Comparing effective H-H distances, which were calculated for conformational sub-ensembles, with the NOE distances revealed that typically multiple conformations could be present without significantly violating the measured NOE restraints. For lgt2Delta the presence of more than one conformation is supported by the NOE data. PMID- 26251888 TI - Adequacy of published screening criteria for retinopathy of prematurity. AB - BACKGROUND: Criteria for screening preterm infants for retinopathy of prematurity vary around the world. We aimed to analyse the efficacy of alternative screening criteria. DESIGN: We collected retrospective data at a tertiary level neonatal nursery. PARTICIPANTS: Our participants were 1007 babies, born between 1997 and 2011, at <32 weeks gestational age or <1500 g birth weight (as recommended by the National Health and Medical Research Council in 1996), who had completed follow up to full retinal vascularization, with defined presence or absence of retinopathy of prematurity. METHODS: We determined whether disease would be detected using an alternative Australian screening model (gestational age <30 weeks or birth weight <1250 g) or screening criteria utilized in developed countries with similar standards of neonatal care. MAIN OUTCOME MEASURES: Detection of retinopathy of prematurity is our main outcome. RESULTS: Using several of the alternative criteria, two neonates with clinically significant retinopathy of prematurity, one of whom required laser treatment to preserve sight, would not have been screened, and their disease may have gone undetected. Use of <30 weeks gestational age or <1500 g birth weight as the criteria would still have screened these infants but would have reduced the number of infants screened by 24.9%. CONCLUSIONS: Some commonly utilized international screening criteria for retinopathy of prematurity may risk clinically significant cases being missed and others may screen babies unnecessarily. Alternative criteria should be considered and '<30 weeks gestational age and/or <1500 g birth weight' appears a viable option. PMID- 26251890 TI - Protective Effect of 2,4',5'-Trihydroxyl-5,2'-dibromo diphenylmethanone, a New Halophenol, against Hydrogen Peroxide-Induced EA.hy926 Cells Injury. AB - Vascular endothelial cells produce reactive oxygen species (ROS) during the process of energy metabolism in aerobic respiration. A growing body of evidence indicates that excessive ROS is implicated in the pathogenesis of cardiovascular diseases including atherosclerosis. The newly synthesized halophenol, 2,4',5' trihydroxyl-5,2'-dibromo diphenylmethanone (TDD), exhibits antioxidative and cytoprotective activities in vitro. In this study, the protective effect of TDD against hydrogen peroxide (H2O2)-induced oxidative injury of EA.hy926 cells was investigated. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5 dephenyltetrazolium bromide (MTT) assay, while the effect of TDD on the transcription profile of EA.hy926 cells subjected to H2O2-induced oxidative injury was evaluated by microarray analysis. Several signaling pathways, including apoptosis, were significantly associated with TDD. Flow cytometric analysis was used to evaluate anti-apoptotic effect of TDD. Subsequently, RT-PCR and Western blot were used to detect the expressions of the apoptosis-associated protein, Bcl-2 and Bax. Meanwhile the expression of cleaved caspase-3, an executioner of apoptosis, was also detected by Western blot. The results showed that pretreatment of EA.hy926 cells with TDD prevented the decrease of cell viability induced by H2O2, and attenuated H2O2-induced elevation of Bax and cleaved caspase-3 while increased Bcl-2 expressions. In summary, TDD inhibited H2O2-induced oxidative injury of EA.hy926 cells through negative regulation of apoptosis. These findings suggest that TDD is a potential candidate for therapeutic intervention in oxidative stress-associated cardiovascular diseases. PMID- 26251891 TI - Evolution of Macromolecular Docking Techniques: The Case Study of Nickel and Iron Metabolism in Pathogenic Bacteria. AB - The interaction between macromolecules is a fundamental aspect of most biological processes. The computational techniques used to study protein-protein and protein nucleic acid interactions have evolved in the last few years because of the development of new algorithms that allow the a priori incorporation, in the docking process, of experimentally derived information, together with the possibility of accounting for the flexibility of the interacting molecules. Here we review the results and the evolution of the techniques used to study the interaction between metallo-proteins and DNA operators, all involved in the nickel and iron metabolism of pathogenic bacteria, focusing in particular on Helicobacter pylori (Hp). In the first part of the article we discuss the methods used to calculate the structure of complexes of proteins involved in the activation of the nickel-dependent enzyme urease. In the second part of the article, we concentrate on two applications of protein-DNA docking conducted on the transcription factors HpFur (ferric uptake regulator) and HpNikR (nickel regulator). In both cases we discuss the technical expedients used to take into account the conformational variability of the multi-domain proteins involved in the calculations. PMID- 26251892 TI - The Stability, Sustained Release and Cellular Antioxidant Activity of Curcumin Nanoliposomes. AB - Curcumin is a multifunctional and natural agent considered to be pharmacologically safe. However, its application in the food and medical industry is greatly limited by its poor water solubility, physicochemical instability and inadequate bioavailability. Nanoliposome encapsulation could significantly enhance the solubility and stability of curcumin. Curcumin nanoliposomes exhibited good physicochemical properties (entrapment efficiency = 57.1, particle size = 68.1 nm, polydispersity index = 0.246, and zeta potential = -3.16 mV). Compared with free curcumin, curcumin nanoliposomes exhibited good stability against alkaline pH and metal ions as well as good storage stability at 4 degrees C. Curcumin nanoliposomes also showed good sustained release properties. Compared with free curcumin, curcumin nanoliposomes presented an equal cellular antioxidant activity, which is mainly attributed to its lower cellular uptake as detected by fluorescence microscopy and flow cytometry. This study provide theoretical and practical guides for the further application of curcumin nanoliposomes. PMID- 26251893 TI - Removal of 4-Ethylphenol and 4-Ethylguaiacol with Polyaniline-Based Compounds in Wine-Like Model Solutions and Red Wine. AB - Volatile phenols, such as 4-ethyphenol (4-EP) and 4-ethylguaiacol (4-EG), are responsible for the "Brett character" found in wines contaminated with Brettanomyces yeast (i.e., barnyard, animal, spicy and smoky aromas). In these trials, we explore the effectiveness of polyaniline-based compounds (polyaniline emeraldin salt (PANI-ES) and polyanaline emeraldin base (PANI-EB)), for the removal of 4-EP and 4-EG from acidic model solutions and red wine. First, a screening study, performed in an acidified 12% ethanol solution, was used to optimize parameters such as contact time and the amount of polymers required to remove 4-EP and 4-EG. Then, the trapping ability of PANI agents towards 4-EP and 4-EG was evaluated in a model solution containing other wine phenolics that could potentially be trapped by PANI (i.e., gallic acid and 4-methylcatechol). The results of this trial showed that both PANI compounds were capable of removing 4 EP, 4-EG, regardless of the presence of other phenolic compounds present at a much higher concentration. Finally, the capturing ability of PANI was evaluated in a red wine sample containing 5 mg.L-1 of 4-EP, 5 mg.L-1 of 4-EG and 2.03 +/- 0.02 g.L-1 of total phenolics. The results showed that PANI-EB removed significantly more 4-EP and 4-EG than PANI-ES. For instance, a treatment with 10 mg.mL-1 of PANI-EB produced a 67.8% reduction of 4-EP, 50% reduction of 4-EG and 41.38% decrease in total phenols. PMID- 26251895 TI - Hepatitis C in Special Patient Cohorts: New Opportunities in Decompensated Liver Cirrhosis, End-Stage Renal Disease and Transplant Medicine. AB - Worldwide, hepatitis C virus (HCV) is a common infection. Due to new antiviral approaches and the approval of direct-acting antiviral agents (DAA), HCV therapy has become more comfortable. Nevertheless, there are special patient groups, in whom treatment of HCV is still challenging. Due to only few data available, tolerability and efficacy of DAAs in special patient cohorts still remain unclear. Such special patient cohorts comprise HCV in patients with decompensated liver disease (Child-Pugh Class B or C), patients with chronic kidney disease, and patients on waiting lists to renal/liver transplantation or those with HCV recurrence after liver transplantation. HCV infection in these patient cohorts has been shown to be associated with increased morbidity and mortality and may lead to reduced graft survival after transplantation. Successful eradication of HCV results in a better outcome concerning liver-related complications and in a better clinical outcome of these patients. In this review, we analyze available data and results from recently published literature and provide an overview of current recommendations of HCV-therapy regimen in these special patient cohorts. PMID- 26251894 TI - Stromal Cell-Derived Factor-1alpha Plays a Crucial Role Based on Neuroprotective Role in Neonatal Brain Injury in Rats. AB - Owing to progress in perinatal medicine, the survival of preterm newborns has markedly increased. However, the incidence of cerebral palsy has risen in association with increased preterm birth. Cerebral palsy is largely caused by cerebral hypoxic ischemia (HI), for which there are no effective medical treatments. We evaluated the effects of stromal cell-derived factor-1alpha (SDF 1alpha) on neonatal brain damage in rats. Left common carotid (LCC) arteries of seven-day-old Wistar rat pups were ligated, and animals were exposed to hypoxic gas to cause cerebral HI. Behavioral tests revealed that the memory and spatial perception abilities were disturbed in HI animals, and that SDF-1alpha treatment improved these cognitive functions. Motor coordination was also impaired after HI but was unimproved by SDF-1alpha treatment. SDF-1alpha reduced intracranial inflammation and induced cerebral remyelination, as indicated by the immunohistochemistry results. These data suggest that SDF-1alpha specifically influences spatial perception abilities in neonatal HI encephalopathy. PMID- 26251898 TI - Assessing Transformations of Algal Organic Matter in the Long-Term: Impacts of Humification-Like Processes. AB - Algae and cyanobacteria are important contributors to the natural organic matter (NOM) of eutrophic water resources. The objective of this work is to increase knowledge on the modifications of algal organic matter (AOM) properties in the long term to anticipate blooms footprint in such aquatic environments. The production of AOM from an alga (Euglena gracilis) and a cyanobacteria (Microcystis aeruginosa) was followed up and characterized during the stationary phase and after one year and four months of cultivation, in batch experiments. Specific UV absorbance (SUVA) index, organic matter fractionation according to hydrophobicity and apparent molecular weight were combined to assess the evolution of AOM. A comparison between humic substances (HS) mainly derived from allochthonous origins and AOM characteristics was performed to hypothesize impacts of AOM transformation processes on the water quality of eutrophic water resources. Each AOM fraction underwent a specific evolution pattern, depending on its composition. Impacts of humification-like processes were predominant over release of biopolymers due to cells decay and led to an increase in the hydrophobic compounds part and molecular weights over time. However, the hydrophilic fraction remained the major fraction whatever the growth stage. Organic compounds generated by maturation of these precursors corresponded to large and aliphatic structures. PMID- 26251897 TI - miR-199a and miR-497 Are Associated with Better Overall Survival due to Increased Chemosensitivity in Diffuse Large B-Cell Lymphoma Patients. AB - Micro-RNAs (miRNAs) are short non-coding single-stranded RNA molecules regulating gene expression at the post-transcriptional level. miRNAs are involved in cell development, differentiation, apoptosis, and proliferation. miRNAs can either function as tumor suppressor genes or oncogenes in various important pathways. The expression of specific miRNAs has been identified to correlate with tumor prognosis. For miRNA expression analysis real-time PCR on 81 samples was performed, including 63 diffuse large B-cell lymphoma (DLBCL, 15 of germinal center B-cell like subtype, 17 non germinal center B-cell, 23 transformed, and eight unclassified) and 18 controls, including nine peripheral B-cells, 5 germinal-center B-cells, four lymphadenitis samples, and 4 lymphoma cell lines (RI-1, SUDHL4, Karpas, U2932). Expression levels of a panel of 11 miRNAs that have been previously involved in other types of cancer (miR-15b_2, miR-16_1*, miR 16_2, miR-16_2*, miR-27a, miR-27a*, miR-98-1, miR-103a, miR-185, miR-199a, and miR-497) were measured and correlated with clinical data. Furthermore, cell lines, lacking miR-199a and miR-497 expression, were electroporated with the two respective miRNAs and treated with standard immunochemotherapy routinely used in patients with DLBCL, followed by functional analyses including cell count and apoptosis assays. Seven miRNAs (miR-16_1*, miR-16_2*, miR-27a, miR-103, miR-185, miR-199, and miR-497) were statistically significantly up-regulated in DLBCL compared to normal germinal cells. However, high expression of miR-497 or miR 199a was associated with better overall survival (p = 0.042 and p = 0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in aggressive lymphoma patients most likely by modifying drug sensitivity to immunochemotherapy. This functional impairment may serve as a potential novel therapeutic target in future treatment of patients with DLBCL. PMID- 26251896 TI - Genes and Pathways Involved in Adult Onset Disorders Featuring Muscle Mitochondrial DNA Instability. AB - Replication and maintenance of mtDNA entirely relies on a set of proteins encoded by the nuclear genome, which include members of the core replicative machinery, proteins involved in the homeostasis of mitochondrial dNTPs pools or deputed to the control of mitochondrial dynamics and morphology. Mutations in their coding genes have been observed in familial and sporadic forms of pediatric and adult onset clinical phenotypes featuring mtDNA instability. The list of defects involved in these disorders has recently expanded, including mutations in the exo /endo-nuclease flap-processing proteins MGME1 and DNA2, supporting the notion that an enzymatic DNA repair system actively takes place in mitochondria. The results obtained in the last few years acknowledge the contribution of next generation sequencing methods in the identification of new disease loci in small groups of patients and even single probands. Although heterogeneous, these genes can be conveniently classified according to the pathway to which they belong. The definition of the molecular and biochemical features of these pathways might be helpful for fundamental knowledge of these disorders, to accelerate genetic diagnosis of patients and the development of rational therapies. In this review, we discuss the molecular findings disclosed in adult patients with muscle pathology hallmarked by mtDNA instability. PMID- 26251899 TI - UV Differentially Induces Oxidative Stress, DNA Damage and Apoptosis in BCR-ABL1 Positive Cells Sensitive and Resistant to Imatinib. AB - Chronic myeloid leukemia (CML) cells express the active BCR-ABL1 protein, which has been targeted by imatinib in CML therapy, but resistance to this drug is an emerging problem. BCR-ABL1 induces endogenous oxidative stress promoting genomic instability and imatinib resistance. In the present work, we investigated the extent of oxidative stress, DNA damage, apoptosis and expression of apoptosis related genes in BCR-ABL1 cells sensitive and resistant to imatinib. The resistance resulted either from the Y253H mutation in the BCR-ABL1 gene or incubation in increasing concentrations of imatinib (AR). UV irradiation at a dose rate of 0.12 J/(m2 . s) induced more DNA damage detected by the T4 pyrimidine dimers glycosylase and hOGG1, recognizing oxidative modifications to DNA bases in imatinib-resistant than -sensitive cells. The resistant cells displayed also higher susceptibility to UV-induced apoptosis. These cells had lower native mitochondrial membrane potential than imatinib-sensitive cells, but UV-irradiation reversed that relationship. We observed a significant lowering of the expression of the succinate dehydrogenase (SDHB) gene, encoding a component of the complex II of the mitochondrial respiratory chain, which is involved in apoptosis sensing. Although detailed mechanism of imatinib resistance in AR cells in unknown, we detected the presence of the Y253H mutation in a fraction of these cells. In conclusion, imatinib-resistant cells may display a different extent of genome instability than their imatinib-sensitive counterparts, which may follow their different reactions to both endogenous and exogenous DNA-damaging factors, including DNA repair and apoptosis. PMID- 26251900 TI - Neurological and Epigenetic Implications of Nutritional Deficiencies on Psychopathology: Conceptualization and Review of Evidence. AB - In recent years, a role for epigenetic modifications in the pathophysiology of disease has received significant attention. Many studies are now beginning to explore the gene-environment interactions, which may mediate early-life exposure to risk factors, such as nutritional deficiencies and later development of behavioral problems in children and adults. In this paper, we review the current literature on the role of epigenetics in the development of psychopathology, with a specific focus on the potential for epigenetic modifications to link nutrition and brain development. We propose a conceptual framework whereby epigenetic modifications (e.g., DNA methylation) mediate the link between micro- and macro nutrient deficiency early in life and brain dysfunction (e.g., structural aberration, neurotransmitter perturbation), which has been linked to development of behavior problems later on in life. PMID- 26251903 TI - Distributed Density Estimation Based on a Mixture of Factor Analyzers in a Sensor Network. AB - Distributed density estimation in sensor networks has received much attention due to its broad applicability. When encountering high-dimensional observations, a mixture of factor analyzers (MFA) is taken to replace mixture of Gaussians for describing the distributions of observations. In this paper, we study distributed density estimation based on a mixture of factor analyzers. Existing estimation algorithms of the MFA are for the centralized case, which are not suitable for distributed processing in sensor networks. We present distributed density estimation algorithms for the MFA and its extension, the mixture of Student's t factor analyzers (MtFA). We first define an objective function as the linear combination of local log-likelihoods. Then, we give the derivation process of the distributed estimation algorithms for the MFA and MtFA in details, respectively. In these algorithms, the local sufficient statistics (LSS) are calculated at first and diffused. Then, each node performs a linear combination of the received LSS from nodes in its neighborhood to obtain the combined sufficient statistics (CSS). Parameters of the MFA and the MtFA can be obtained by using the CSS. Finally, we evaluate the performance of these algorithms by numerical simulations and application example. Experimental results validate the promising performance of the proposed algorithms. PMID- 26251904 TI - Non-Destructive Evaluation for Corrosion Monitoring in Concrete: A Review and Capability of Acoustic Emission Technique. AB - Corrosion of reinforced concrete (RC) structures has been one of the major causes of structural failure. Early detection of the corrosion process could help limit the location and the extent of necessary repairs or replacement, as well as reduce the cost associated with rehabilitation work. Non-destructive testing (NDT) methods have been found to be useful for in-situ evaluation of steel corrosion in RC, where the effect of steel corrosion and the integrity of the concrete structure can be assessed effectively. A complementary study of NDT methods for the investigation of corrosion is presented here. In this paper, acoustic emission (AE) effectively detects the corrosion of concrete structures at an early stage. The capability of the AE technique to detect corrosion occurring in real-time makes it a strong candidate for serving as an efficient NDT method, giving it an advantage over other NDT methods. PMID- 26251901 TI - A Review of Cell Adhesion Studies for Biomedical and Biological Applications. AB - Cell adhesion is essential in cell communication and regulation, and is of fundamental importance in the development and maintenance of tissues. The mechanical interactions between a cell and its extracellular matrix (ECM) can influence and control cell behavior and function. The essential function of cell adhesion has created tremendous interests in developing methods for measuring and studying cell adhesion properties. The study of cell adhesion could be categorized into cell adhesion attachment and detachment events. The study of cell adhesion has been widely explored via both events for many important purposes in cellular biology, biomedical, and engineering fields. Cell adhesion attachment and detachment events could be further grouped into the cell population and single cell approach. Various techniques to measure cell adhesion have been applied to many fields of study in order to gain understanding of cell signaling pathways, biomaterial studies for implantable sensors, artificial bone and tooth replacement, the development of tissue-on-a-chip and organ-on-a-chip in tissue engineering, the effects of biochemical treatments and environmental stimuli to the cell adhesion, the potential of drug treatments, cancer metastasis study, and the determination of the adhesion properties of normal and cancerous cells. This review discussed the overview of the available methods to study cell adhesion through attachment and detachment events. PMID- 26251906 TI - The Thirty Gigahertz Instrument Receiver for the QUIJOTE Experiment: Preliminary Polarization Measurements and Systematic-Error Analysis. AB - This paper presents preliminary polarization measurements and systematic-error characterization of the Thirty Gigahertz Instrument receiver developed for the QUIJOTE experiment. The instrument has been designed to measure the polarization of Cosmic Microwave Background radiation from the sky, obtaining the Q, U, and I Stokes parameters of the incoming signal simultaneously. Two kinds of linearly polarized input signals have been used as excitations in the polarimeter measurement tests in the laboratory; these show consistent results in terms of the Stokes parameters obtained. A measurement-based systematic-error characterization technique has been used in order to determine the possible sources of instrumental errors and to assist in the polarimeter calibration process. PMID- 26251905 TI - Occurrence and Concentrations of Toxic VOCs in the Ambient Air of Gumi, an Electronics-Industrial City in Korea. AB - This study was carried out to characterize the occurrence and concentrations of a variety of volatile organic compounds (VOCs) including aliphatic, aromatic, halogenated, nitrogenous, and carbonyl compounds, in the ambient air of Gumi City, where a large number of electronics industries are found. Two field monitoring campaigns were conducted for a one year period in 2003/2004 and 2010/2011 at several sampling sites in the city, representing industrial, residential and commercial areas. More than 80 individual compounds were determined in this study, and important compounds were then identified according to their abundance, ubiquity and toxicity. The monitoring data revealed toluene, trichloroethylene and acetaldehyde to be the most significant air toxics in the city, and their major sources were mainly industrial activities. On the other hand, there was no clear evidence of an industrial impact on the concentrations of benzene and formaldehyde in the ambient air of the city. Overall, seasonal variations were not as distinct as locational variations in the VOCs concentrations, whereas the within-day variations showed a typical pattern of urban air pollution, i.e., increase in the morning, decrease in the afternoon, and an increase again in the evening. Considerable decreases in the concentrations of VOCs from 2003 to 2011 were observed. The reductions in the ambient concentrations were confirmed further by the Korean PRTR data in industrial emissions within the city. Significant decreases in the concentrations of benzene and acetaldehyde were also noted, whereas formaldehyde appeared to be almost constant between the both campaigns. The decreased trends in the ambient levels were attributed not only to the stricter regulations for VOCs in Korea, but also to the voluntary agreement of major companies to reduce the use of organic solvents. In addition, a site planning project for an eco-friendly industrial complex is believed to play a contributory role in improving the air quality of the city. PMID- 26251907 TI - Study of QCL Laser Sources for the Realization of Advanced Sensors. AB - We study the nonlinear dynamics of a quantum cascade laser (QCL) with a strong reinjection provided by the feedback from two external targets in a double cavity configuration. The nonlinear coupling of interferometric signals from the two targets allows us to propose a displacement sensor with nanometric resolution. The system exploits the ultra-stability of QCLs in self-mixing configuration to access the intrinsic nonlinearity of the laser, described by the Lang-Kobayashi model, and it relies on a stroboscopic-like effect in the voltage signal registered at the QCL terminals that relates the "slow" target motion to the "fast" target one. PMID- 26251908 TI - Decision Fusion with Channel Errors in Distributed Decode-Then-Fuse Sensor Networks. AB - Decision fusion for distributed detection in sensor networks under non-ideal channels is investigated in this paper. Usually, the local decisions are transmitted to the fusion center (FC) and decoded, and a fusion rule is then applied to achieve a global decision. We propose an optimal likelihood ratio test (LRT)-based fusion rule to take the uncertainty of the decoded binary data due to modulation, reception mode and communication channel into account. The average bit error rate (BER) is employed to characterize such an uncertainty. Further, the detection performance is analyzed under both non-identical and identical local detection performance indices. In addition, the performance of the proposed method is compared with the existing optimal and suboptimal LRT fusion rules. The results show that the proposed fusion rule is more robust compared to these existing ones. PMID- 26251902 TI - Exploiting the Pleiotropic Antioxidant Effects of Established Drugs in Cardiovascular Disease. AB - Cardiovascular disease is a leading cause of death and reduced quality of life worldwide. Arterial vessels are a primary target for endothelial dysfunction and atherosclerosis, which is accompanied or even driven by increased oxidative stress. Recent research in this field identified different sources of reactive oxygen and nitrogen species contributing to the pathogenesis of endothelial dysfunction. According to lessons from the past, improvement of endothelial function and prevention of cardiovascular disease by systemic, unspecific, oral antioxidant therapy are obviously too simplistic an approach. Source- and cell organelle-specific antioxidants as well as activators of intrinsic antioxidant defense systems might be more promising. Since basic research demonstrated the contribution of different inflammatory cells to vascular oxidative stress and clinical trials identified chronic inflammatory disorders as risk factors for cardiovascular events, atherosclerosis and cardiovascular disease are closely associated with inflammation. Therefore, modulation of the inflammatory response is a new and promising approach in the therapy of cardiovascular disease. Classical anti-inflammatory therapeutic compounds, but also established drugs with pleiotropic immunomodulatory abilities, demonstrated protective effects in various models of cardiovascular disease. However, results from ongoing clinical trials are needed to further evaluate the value of immunomodulation for the treatment of cardiovascular disease. PMID- 26251909 TI - Investigating Driver Fatigue versus Alertness Using the Granger Causality Network. AB - Driving fatigue has been identified as one of the main factors affecting drivers' safety. The aim of this study was to analyze drivers' different mental states, such as alertness and drowsiness, and find out a neurometric indicator able to detect drivers' fatigue level in terms of brain networks. Twelve young, healthy subjects were recruited to take part in a driver fatigue experiment under different simulated driving conditions. The Electroencephalogram (EEG) signals of the subjects were recorded during the whole experiment and analyzed by using Granger-Causality-based brain effective networks. It was that the topology of the brain networks and the brain's ability to integrate information changed when subjects shifted from the alert to the drowsy stage. In particular, there was a significant difference in terms of strength of Granger causality (GC) in the frequency domain and the properties of the brain effective network i.e., causal flow, global efficiency and characteristic path length between such conditions. Also, some changes were more significant over the frontal brain lobes for the alpha frequency band. These findings might be used to detect drivers' fatigue levels, and as reference work for future studies. PMID- 26251910 TI - Security Analysis of Image Encryption Based on Gyrator Transform by Searching the Rotation Angle with Improved PSO Algorithm. AB - Gyrator transform has been widely used for image encryption recently. For gyrator transform-based image encryption, the rotation angle used in the gyrator transform is one of the secret keys. In this paper, by analyzing the properties of the gyrator transform, an improved particle swarm optimization (PSO) algorithm was proposed to search the rotation angle in a single gyrator transform. Since the gyrator transform is continuous, it is time-consuming to exhaustedly search the rotation angle, even considering the data precision in a computer. Therefore, a computational intelligence-based search may be an alternative choice. Considering the properties of severe local convergence and obvious global fluctuations of the gyrator transform, an improved PSO algorithm was proposed to be suitable for such situations. The experimental results demonstrated that the proposed improved PSO algorithm can significantly improve the efficiency of searching the rotation angle in a single gyrator transform. Since gyrator transform is the foundation of image encryption in gyrator transform domains, the research on the method of searching the rotation angle in a single gyrator transform is useful for further study on the security of such image encryption algorithms. PMID- 26251911 TI - Electrochemical Impedance Immunosensor Based on Self-Assembled Monolayers for Rapid Detection of Escherichia coli O157:H7 with Signal Amplification Using Lectin. AB - Escherichia coli O157:H7 is a predominant foodborne pathogen with severe pathogenicity, leading to increasing attention given to rapid and sensitive detection. Herein, we propose an impedance biosensor using new kinds of screen printed interdigitated microelectrodes (SPIMs) and wheat germ agglutinin (WGA) for signal amplification to detect E. coli O157:H7 with high sensitivity and time efficiency. The SPIMs integrate the high sensitivity and short response time of the interdigitated electrodes and the low cost of the screen-printed electrodes. Self-assembling of bi-functional 3-dithiobis-(sulfosuccinimidyl-propionate) (DTSP) on the SPIMs was investigated and was proved to be able to improve adsorption quantity and stability of biomaterials. WGA was further adopted to enhance the signal taking advantage of the abundant lectin-binding sites on the bacteria surface. The immunosensor exhibited a detection limit of 102 cfu.mL(-1), with a linear detection range from 10(2) to 10(7) cfu.mL(-1) (r2 = 0.98). The total detection time was less than 1 h, showing its comparable sensitivity and rapid response. Furthermore, the low cost of one SPIM significantly reduced the detection cost of the biosensor. The biosensor may have great promise in food safety analysis and lead to a portable biosensing system for routine monitoring of foodborne pathogens. PMID- 26251913 TI - A Hygroscopic Sensor Electrode for Fast Stabilized Non-Contact ECG Signal Acquisition. AB - A capacitive electrocardiography (cECG) technique using a non-invasive ECG measuring technology that does not require direct contact between the sensor and the skin has attracted much interest. The system encounters several challenges when the sensor electrode and subject's skin are weakly coupled. Because there is no direct physical contact between the subject and any grounding point, there is no discharge path for the built-up electrostatic charge. Subsequently, the electrostatic charge build-up can temporarily contaminate the ECG signal from being clearly visible; a stabilization period (3-15 min) is required for the measurement of a clean, stable ECG signal at low humidity levels (below 55% relative humidity). Therefore, to obtain a clear ECG signal without noise and to reduce the ECG signal stabilization time to within 2 min in a dry ambient environment, we have developed a fabric electrode with embedded polymer (FEEP). The designed hygroscopic FEEP has an embedded superabsorbent polymer layer. The principle of FEEP as a conductive electrode is to provide humidity to the capacitive coupling to ensure strong coupling and to allow for the measurement of a stable, clear biomedical signal. The evaluation results show that hygroscopic FEEP is capable of rapidly measuring high-accuracy ECG signals with a higher SNR ratio. PMID- 26251914 TI - Three Three-Axis IEPE Accelerometers on the Inner Liner of a Tire for Finding the Tire-Road Friction Potential Indicators. AB - Direct tire-road contact friction estimation is essential for future autonomous cars and active safety systems. Friction estimation methods have been proposed earlier for driving conditions in the presence of a slip angle or slip ratio. However, the estimation of the friction from a freely-rolling tire is still an unsolved topic. Knowing the existing friction potential would be beneficial since vehicle control systems could be adjusted before any remarkable tire force has been produced. Since accelerometers are well-known and robust, and thus a promising sensor type for intelligent tires, this study uses three three-axis IEPE accelerometers on the inner liner of a tire to detect friction potential indicators on two equally smooth surfaces with different friction levels. The equal roughness was chosen for both surfaces in order to study the friction phenomena by neglecting the effect of surface texture on vibrations. The acceleration data before the contact is used to differentiate the two friction levels between the tire and the road. In addition, the contact lengths from the three accelerometers are used to validate the acceleration data. A method to differentiate the friction levels on the basis of the acceleration signal is also introduced. PMID- 26251912 TI - Simultaneous Detection of alpha-Fetoprotein and Carcinoembryonic Antigen Based on Si Nanowire Field-Effect Transistors. AB - Primary hepatic carcinoma (PHC) is one of the most common malignancies worldwide, resulting in death within six to 20 months. The survival rate can be improved by effective treatments when diagnosed at an early stage. The alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) have been identified as markers that are expressed at higher levels in PHC patients. In this study, we employed silicon nanowire field-effect transistors (SiNW-FETs) with polydimethylsiloxane (PDMS) microfluidic channels to simultaneously detect AFP and CEA in desalted human serum. Dual-channel PDMS was first utilized for the selective modification of AFP and CEA antibodies on SiNWs, while single-channel PDMS offers faster and more sensitive detection of AFP and CEA in serum. During the SiNW modification process, 0.1% BSA was utilized to minimize nonspecific protein binding from serum. The linear dynamic ranges for the AFP and CEA detection were measured to be 500 fg/mL to 50 ng/mL and 50 fg/mL to 10 ng/mL, respectively. Our work demonstrates the promising potential of fabricated SiNW-FETs as a direct detection kit for multiple tumor markers in serum; therefore, it provides a chance for early stage diagnose and, hence, more effective treatments for PHC patients. PMID- 26251915 TI - Melanoma in the Italian Population and Regional Environmental Influences: A National Retrospective Survey on 2001-2008 Hospitalization Records. AB - OBJECTIVE: To assess the burden of regional environmental factors influencing the incidence of Melanoma in the Italian population and overcome the problem of partial population coverage by local cancer registries and thematic archives. METHODS: We analyzed the Italian national hospitalization records from 2001 to 2008 provided by the Ministry of Health, excluding hospital re-admissions of the same patients, in order to assess the occurrence of Melanoma over a 8-year period. Data were presented by age groups (absolute number of cases from 20 to >=80 years old) and per Region (rates per 100,000 inhabitants) for each year. RESULTS: The overall number of new hospitalizations due to malignant Melanoma increased by 16.8% from 2001 (n = 4846) to 2008 (n = 5823), with the rate per 100,000 inhabitants passing from 10.5 to almost 12.0 at a national level. The majority of new diagnoses of malignant Melanoma was observed in two age groups: 61-70 years old (from 979 in 2001 up to 2109 in 2008, corresponding to 15.1 and 18.1 new cases per 100,000 inhabitants, respectively) and 71-80 years old (from 954 in 2001 up to 1141 in 2008, corresponding to 19.5 and 21.8 new cases per 100,000 inhabitants, respectively). The number of hospitalizations due to Melanoma increased in all age groups with the only exception of the youngest patients aged 20-30 years old. The highest increases over the 8-year period were observed in people aged >=81 years old (+34%), 61-70 years old (+20%) and surprisingly in the age group 31-40 years old (+17%). Southern Regions showed lower hospitalization rates compared to Northern Italy and Region Lazio. The highest increases between 2001 and 2008 were observed in Trentino/Alto Adige, Friuli Venezia Giulia, Valla d'Aosta and Veneto Region. CONCLUSIONS: Hospitalizations due to malignant Melanoma in Italy seem to be influenced by environmental or population-related factors showing a decreasing incidence rate from the Northern to Southern Regions. PMID- 26251916 TI - Relationship between Acute Phase of Chronic Periodontitis and Meteorological Factors in the Maintenance Phase of Periodontal Treatment: A Pilot Study. AB - The acute phase of chronic periodontitis may occur even in patients during supportive periodontal therapy. However, the details are not fully understood. Since the natural environment, including meteorology affects human health, we hypothesized that weather conditions may affect occurrence of acute phase of chronic periodontitis. The aim of this study was to investigate the relationship between weather conditions and acute phase of chronic periodontitis in patients under supportive periodontal therapy. Patients who were diagnosed with acute phase of chronic periodontitis under supportive periodontal therapy during 2011 2013 were selected for this study. We performed oral examinations and collected questionnaires and meteorological data. Of 369 patients who experienced acute phase of chronic periodontitis, 153 had acute phase of chronic periodontitis without direct-triggered episodes. When using the autoregressive integrated moving average model of time-series analysis, the independent covariant of maximum hourly range of barometric pressure, maximum hourly range of temperature, and maximum daily wind speed were significantly associated with occurrence of acute phase of chronic periodontitis (p < 0.05), and 3.1% of the variations in these occurrence over the study period were explained by these factors. Meteorological variables may predict occurrence of acute phase of chronic periodontitis. PMID- 26251917 TI - Parity, Age at First Birth, and Risk of Death from Non-Hodgkin's Lymphoma: A Population-Based Cohort Study in Taiwan. AB - We undertook this study to examine whether there exists an association between parity and age at first birth and risk of death from non-Hodgkin's lymphoma (NHL). Our sample included a total of 1,292,462 women who had a first and singleton childbirth between 1 January 1978 and 31 December 1987. We followed each subject from their first childbirth to 31 December 2009, and determined their vital status by merging natality data with Taiwan's national death certificate database. Hazard ratios (HR) of death from NHL associated with parity and age at first birth were estimated using Cox proportional hazard regression models. In all, 412 NHL deaths were recorded during 34,980,246 person-years of follow-up. NHL mortality rate was 1.18 cases per 100,000 person-years. Older age at first birth (>23 vs. <=23 years) was linked to an increased risk of death from NHL (adjusted HR = 1.41; 95% CI = 1.13-1.75). Controlling for age at first birth, the adjusted HR were 0.74 (95% CI = 0.55-0.98) for women with 2 births, and 0.71 (95% CI = 0.53-0.95) for women with 3 births or more, respectively, when compared with women with only 1 birth. A statistically significant downward trend in the adjusted HR for NHL death was detected with increasing parity (p for trend = 0.05). The HR of death from NHL was decreased by 7% (HR = 0.93; 95% CI = 0.87 0.99) for each additional parity. Our findings are consistent with reproductive factors (parity and early age at first birth) conferring a protective effect against the risk of NHL death. PMID- 26251918 TI - The Relationship between Dietary Patterns and Metabolic Health in a Representative Sample of Adult Australians. AB - Studies assessing dietary intake and its relationship to metabolic phenotype are emerging, but limited. The aims of the study are to identify dietary patterns in Australian adults, and to determine whether these dietary patterns are associated with metabolic phenotype and obesity. Cross-sectional data from the Australian Bureau of Statistics 2011 Australian Health Survey was analysed. Subjects included adults aged 45 years and over (n = 2415). Metabolic phenotype was determined according to criteria used to define metabolic syndrome (0-2 abnormalities vs. 3-7 abnormalities), and additionally categorized for obesity (body mass index (BMI) >=30 kg/m2 vs. BMI <30 kg/m2). Dietary patterns were derived using factor analysis. Multivariable models were used to assess the relationship between dietary patterns and metabolic phenotype, with adjustment for age, sex, smoking status, socio-economic indexes for areas, physical activity and daily energy intake. Twenty percent of the population was metabolically unhealthy and obese. In the fully adjusted model, for every one standard deviation increase in the Healthy dietary pattern, the odds of having a more metabolically healthy profile increased by 16% (odds ratio (OR) 1.16; 95% confidence interval (CI): 1.04, 1.29). Poor metabolic profile and obesity are prevalent in Australian adults and a healthier dietary pattern plays a role in a metabolic and BMI phenotypes. Nutritional strategies addressing metabolic syndrome criteria and targeting obesity are recommended in order to improve metabolic phenotype and potential disease burden. PMID- 26251919 TI - Relationship between Carotenoids, Retinol, and Estradiol Levels in Older Women. AB - BACKGROUND: In vitro evidence suggests anti-estrogenic properties for retinol and carotenoids, supporting a chemo-preventive role of these phytochemicals in estrogen-dependent cancers. During aging there are significant reductions in retinol and carotenoid concentrations, whereas estradiol levels decline during menopause and progressively increase from the age of 65. We aimed to investigate the hypothesis of a potential relationship between circulating levels of retinol, carotenoids, and estradiol (E2) in a cohort of late post-menopausal women. METHODS: We examined 512 women >= 65 years from the InCHIANTI study. Retinol, alpha-caroten, beta-caroten, beta-criptoxantin, lutein, zeaxanthin, and lycopene levels were assayed at enrollment (1998-2000) by High-Performance Liquid Chromatography. Estradiol and testosterone (T) levels were assessed by Radioimmunometry (RIA) and testosterone-to-estradiol ratio (T/E2), as a proxy of aromatase activity, was also calculated. General linear models adjusted for age (Model 1) and further adjusted for other confounders including Body Mass Index (BMI) BMI, smoking, intake of energy, lipids, and vitamin A; C-Reactive Protein, insulin, total cholesterol, liver function, and testosterone (Model 2) were used to investigate the relationship between retinol, carotenoids, and E2 levels. To address the independent relationship between carotenoids and E2 levels, factors significantly associated with E2 in Model 2 were also included in a fully adjusted Model 3. RESULTS: After adjustment for age, alpha-carotene (beta +/- SE = -0.01 +/- 0.004, p = 0.02) and beta-carotene (beta +/- SE = -0.07 +/- 0.02, p = 0.0007) were significantly and inversely associated with E2 levels. alpha Carotene was also significantly and positively associated with T/E2 ratio (beta +/- SE = 0.07 +/- 0.03, p = 0.01). After adjustment for other confounders (Model 2), the inverse relationship between alpha-carotene (beta +/- SE = -1.59 +/- 0.61, p = 0.01), beta-carotene (beta +/- SE = -0.29 +/- 0.08, p = 0.0009), and E2 persisted whereas the relationship between alpha-carotene and T/E2 ratio was attenuated (beta +/- SE = 0.22 +/- 0.12, p = 0.07). In a fully adjusted model (Model 3), only beta-carotene (beta +/- SE = -0.05 +/- 0.02, p = 0.03) was significantly and inversely associated with E2 levels independent of alpha carotene. No association was found between retinol, total non-pro-vitamin A carotenoids, lutein, zeaxanthin, and lycopene, and E2 levels. CONCLUSIONS: In older women, beta-carotene levels are independently and inversely associated with E2. PMID- 26251920 TI - Effects of a Low Dose of Fish Oil on Inflammatory Markers of Brazilian HIV Infected Adults on Antiretroviral Therapy: A Randomized, Parallel, Placebo Controlled Trial. AB - BACKGROUND: The benefits of antiretroviral therapy for HIV-infected subjects have been limited by an increased risk of metabolic and cardiovascular diseases. The objective of this study was to assess the effects of a low dose of marine omega-3 fatty acids on inflammatory marker concentrations in HIV-infected subjects under antiretroviral therapy (ART). METHODS: This was a randomized, parallel, placebo controlled trial that investigated the effects of 3 g fish oil/day (540 mg of eicosapentaenoic acid-EPA plus 360 mg of docosahexaenoic acid-DHA) or 3 g soy oil/day (placebo) for 24 weeks in 83 male and non-pregnant female HIV-infected adults on ART. RESULTS: There were no differences between groups for the measures at baseline. Multilevel analyses revealed no statistically significant relationship between the longitudinal changes in high sensitivity-C reactive protein (hs-CRP) (Wald Chi2 = 0.17, p = 0.918), fibrinogen (Wald Chi2 = 3.82, p = 0.148), and factor VIII (Wald Chi2 = 5.25, p = 0.073) with fish oil. No significant changes in interleukin-6 (IL6), interleukin-1 beta (IL1-beta) and tumor necrosis factor-alpha (TNF-alpha) serum concentrations were observed with fish oil supplements for 12 weeks. CONCLUSIONS: Compared to placebo, a low dose of 900 mg omega-3 fatty acids (EPA plus DHA) in fish oil capsules did not change hs-CRP, fibrinogen, factor VIII, IL6, IL1-beta and TNF-alpha serum concentrations in HIV-infected subjects on ART. Further investigations should consider the assessment of more sensitive inflammatory markers or higher doses to evaluate the effects of marine omega-3 fatty acids in this population. Registered at the Nederlands Trial Register, Identifier no. NTR1798. PMID- 26251922 TI - Effects of Hydrogen Peroxide on Different Toxigenic and Atoxigenic Isolates of Aspergillus flavus. AB - Drought stress in the field has been shown to exacerbate aflatoxin contamination of maize and peanut. Drought and heat stress also produce reactive oxygen species (ROS) in plant tissues. Given the potential correlation between ROS and exacerbated aflatoxin production under drought and heat stress, the objectives of this study were to examine the effects of hydrogen peroxide (H2O2)-induced oxidative stress on the growth of different toxigenic (+) and atoxigenic (-) isolates of Aspergillus flavus and to test whether aflatoxin production affects the H2O2 concentrations that the isolates could survive. Ten isolates were tested: NRRL3357 (+), A9 (+), AF13 (+), Tox4 (+), A1 (-), K49 (-), K54A (-), AF36 (-), and Aflaguard (-); and one A. parasiticus isolate, NRRL2999 (+). These isolates were cultured under a H2O2 gradient ranging from 0 to 50 mM in two different media, aflatoxin-conducive yeast extract-sucrose (YES) and non conducive yeast extract-peptone (YEP). Fungal growth was inhibited at a high H2O2 concentration, but specific isolates grew well at different H2O2 concentrations. Generally the toxigenic isolates tolerated higher concentrations than did atoxigenic isolates. Increasing H2O2 concentrations in the media resulted in elevated aflatoxin production in toxigenic isolates. In YEP media, the higher concentration of peptone (15%) partially inactivated the H2O2 in the media. In the 1% peptone media, YEP did not affect the H2O2 concentrations that the isolates could survive in comparison with YES media, without aflatoxin production. It is interesting to note that the commercial biocontrol isolates, AF36 (-), and Aflaguard (-), survived at higher levels of stress than other atoxigenic isolates, suggesting that this testing method could potentially be of use in the selection of biocontrol isolates. Further studies will be needed to investigate the mechanisms behind the variability among isolates with regard to their degree of oxidative stress tolerance and the role of aflatoxin production. PMID- 26251921 TI - G-Protein-Coupled Receptors: Next Generation Therapeutic Targets in Head and Neck Cancer? AB - Therapeutic outcome in head and neck squamous cell carcinoma (HNSCC) is poor in most advanced cases. To improve therapeutic efficiency, novel therapeutic targets and prognostic factors must be discovered. Our studies have identified several G protein-coupled receptors (GPCRs) as promising candidates. Significant epigenetic silencing of GPCR expression occurs in HNSCC compared with normal tissue, and is significantly correlated with clinical behavior. Together with the finding that GPCR activity can suppress tumor cell growth, this indicates that GPCR expression has potential utility as a prognostic factor. In this review, we discuss the roles that galanin receptor type 1 (GALR1) and type 2 (GALR2), tachykinin receptor type 1 (TACR1), and somatostatin receptor type 1 (SST1) play in HNSCC. GALR1 inhibits proliferation of HNSCC cells though ERK1/2-mediated effects on cell cycle control proteins such as p27, p57, and cyclin D1, whereas GALR2 inhibits cell proliferation and induces apoptosis in HNSCC cells. Hypermethylation of GALR1, GALR2, TACR1, and SST1 is associated with significantly reduced disease-free survival and a higher recurrence rate. Although their overall activities varies, each of these GPCRs has value as both a prognostic factor and a therapeutic target. These data indicate that further study of GPCRs is a promising strategy that will enrich pharmacogenomics and prognostic research in HNSCC. PMID- 26251923 TI - Determination of Ochratoxin A in Wheat and Maize by Solid Bar Microextraction with Liquid Chromatography and Fluorescence Detection. AB - Solid bar microextraction (SBME), followed by liquid chromatography with fluorescence detection (HPLC-FLD), for the quantification of ochratoxin A in wheat and maize was developed. Ground wheat and maize grains were extracted with acetonitrile-water-acetic acid (79:20:1, v/v/v), followed by defatting with cyclohexane, and subjected to SBME-LC-FLD analysis. SBME devices were constructed by packing 2 mg sorbent (C18) into porous polypropylene micro-tubes (2.5 cm length, 600 MUm i.d., and 0.2 MUm pore size). SBME devices were conditioned with methanol and placed into 5 mL stirred sample solutions for 70 min. After extraction, OTA was desorbed into 200 MUL of methanol for 15 min, the solution was removed in vacuum, the residue was dissolved in 50 MUL of methanol-water (1:1, v/v) and ochratoxin A content was determined by HPLC-FLD. Under optimized extraction conditions, the limit of detection of 0.9 MUg.kg(-1) and 2.5 MUg.kg( 1) and the precision of 3.4% and 5.0% over a concentration range of 1 to 100 MUg.kg(-1) in wheat and maize flour, respectively, were obtained. PMID- 26251924 TI - Compositional and in Vitro Evaluation of Nonwoven Type I Collagen/Poly-dl-lactic Acid Scaffolds for Bone Regeneration. AB - Poly-dl-lactic acid (PDLLA) was blended with type I collagen to attempt to overcome the instantaneous gelation of electrospun collagen scaffolds in biological environments. Scaffolds based on blends of type I collagen and PDLLA were investigated for material stability in cell culture conditions (37 degrees C; 5% CO2) in which post-electrospinning glutaraldehyde crosslinking was also applied. The resulting wet-stable webs were cultured with bone marrow stromal cells (HBMSC) for five weeks. Scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), Fourier transform infra-red spectroscopy (FTIR) and biochemical assays were used to characterise the scaffolds and the consequent cell-scaffold constructs. To investigate any electrospinning-induced denaturation of collagen, identical PDLLA/collagen and PDLLA/gelatine blends were electrospun and their potential to promote osteogenic differentiation investigated. PDLLA/collagen blends with w/w ratios of 40/60, 60/40 and 80/20 resulted in satisfactory wet stabilities in a humid environment, although chemical crosslinking was essential to ensure long term material cell culture. Scaffolds of PDLLA/collagen at a 60:40 weight ratio provided the greatest stability over a five-week culture period. The PDLLA/collagen scaffolds promoted greater cell proliferation and osteogenic differentiation compared to HMBSCs seeded on the corresponding PDLLA/gelatine scaffolds, suggesting that any electrospinning induced collagen denaturation did not affect material biofunctionality within 5 weeks in vitro. PMID- 26251925 TI - Temperature Shift Experiments Suggest That Metabolic Impairment and Enhanced Rates of Photorespiration Decrease Organic Acid Levels in Soybean Leaflets Exposed to Supra-Optimal Growth Temperatures. AB - Elevated growth temperatures are known to affect foliar organic acid concentrations in various plant species. In the current study, citrate, malate, malonate, fumarate and succinate decreased 40 to 80% in soybean leaflets when plants were grown continuously in controlled environment chambers at 36/28 compared to 28/20 degrees C. Temperature effects on the above mentioned organic acids were partially reversed three days after plants were transferred among optimal and supra-optimal growth temperatures. In addition, CO2 enrichment increased foliar malate, malonate and fumarate concentrations in the supra optimal temperature treatment, thereby mitigating effects of high temperature on respiratory metabolism. Glycerate, which functions in the photorespiratory pathway, decreased in response to CO2 enrichment at both growth temperatures. The above findings suggested that diminished levels of organic acids in soybean leaflets upon exposure to high growth temperatures were attributable to metabolic impairment and to changes of photorespiratory flux. Leaf development rates differed among temperature and CO2 treatments, which affected foliar organic acid levels. Additionally, we report that large decreases of foliar organic acids in response to elevated growth temperatures were observed in legume species. PMID- 26251926 TI - Case study of remission in adults with immune thrombocytopenia following cessation of treatment with the thrombopoietin mimetic romiplostim. AB - OBJECTIVES: In adults, immune thrombocytopenia (ITP), characterized by platelet counts <100 * 10(9)/l, is typically chronic, with remission reported infrequently >=3 years post-diagnosis. The thrombopoietin mimetic romiplostim increases platelet counts and reduces use of concomitant ITP medications in chronic ITP. While often perceived as a long-term treatment, dose-adjustment rules allow romiplostim to be discontinued when hemostatic platelet counts are reached, as reported in Amgen trials. METHODS: Eight romiplostim trials were examined for remission, defined as >=26 consecutive weeks of platelets >=50 * 10(9)/l without treatment. RESULTS: Remission was identified in 27 patients; median (quartile 1 [Q1], quartile 3 [Q3]) ITP duration of 2.1 (0.5, 4.2) years, 17/27 (63%) having ITP for >1 year, mean baseline platelets 20.9 * 10(9)/l, median preremission maximum dose 3.0 ug/kg, 12/27 (44%) were splenectomized at baseline, and there were 40-276 cumulative weeks of romiplostim with median time to remission 7.1 months. DISCUSSION/CONCLUSION: No clear-cut predictors of remission were apparent; however, a number of patients had ITP for <1 year and received romiplostim for <1 year. PMID- 26251929 TI - A Summer Bonanza of Upper Extremity Articles. PMID- 26251930 TI - 5 Points on Shoulder Examination of the Overhead Athlete. PMID- 26251928 TI - In situ studies on controlling an atomically-accurate formation process of gold nanoclusters. AB - Knowledge of the molecular formation mechanism of metal nanoclusters is essential for developing chemistry for accurate control over their synthesis. Herein, the "top-down" synthetic process of monodisperse Au13 nanoclusters via HCl etching of polydisperse Aun clusters (15 <= n <= 65) is traced by a combination of in situ X ray/UV-vis absorption spectroscopy and time-dependent mass spectrometry. It is revealed experimentally that the HCl-induced synthesis of Au13 is achieved by accurately controlling the etching process with two distinctive steps, in sharp contrast to the traditional thiol-etching mechanism through release of the Au(i) complex. The first step involves the direct fragmentation of the initial larger Aun clusters into metastable intermediate Au8-Au13 smaller clusters. This is a critical step, which allows for the secondary size-growth step of the intermediates toward the atomically monodisperse Au13 clusters via incorporating the reactive Au(i)-Cl species in the solution. Such a secondary-growth pathway is further confirmed by the successful growth of Au13 through reaction of isolated Au11 clusters with AuClPPh3 in the HCl environment. This work addresses the importance of reaction intermediates in guiding the way towards controllable synthesis of metal nanoclusters. PMID- 26251931 TI - The Burden of Craft in Arthroscopic Rotator Cuff Repair: Where Have We Been and Where We Are Going. AB - The rather turbulent history of arthroscopic rotator cuff repair went through stages of innovation, conflict, disruption, assimilation, and transformation that might be anticipated when a new and advanced technology (arthroscopic cuff repair) displaces an entrenched but outdated discipline (open cuff repair). The transition from open to arthroscopic rotator cuff repair has been a major paradigm shift that has greatly benefited patients. However, this technical evolution/revolution has also imposed a higher "burden of craft" on the practitioners of arthroscopic rotator cuff repair. Technological advancements in surgery demand that surgeons accept this burden of craft and master the advanced technology for the benefit of their patients. This article outlines the author's involvement in the development of arthroscopic rotator cuff repair, and it also explores the surgeon's obligation to accept the burden of craft that is imposed by this discipline. PMID- 26251932 TI - Commentary to "The Burden of Craft in Arthroscopic Rotator Cuff Repair: Where We Have Been and Where We Are Going. PMID- 26251933 TI - Simultaneous Bilateral Functional Radiography in Ulnar Collateral Ligament Lesion of the Thumb: An Original Technique. AB - In any thumb injury, particularly one caused by hyperabduction, an ulnar collateral ligament lesion (gamekeeper's or skier's thumb) must be considered. If the diagnosis is suspected, and radiographs show no fracture, comparative radiographs should be obtained in forced valgus. This examination, which uses a stress test to cause joint tilt, is crucial in making an accurate diagnosis and deciding on the most appropriate therapeutic approach. The forced valgus maneuver typically is performed by the examiner, who must stay with the patient in the radiography room and wear radiologic protection. We report on a simple, reliable, reproducible method that allows the patient's thumbs to be compared, under the same force application conditions, on a single radiograph. This technique reduces the patient's and examiner's exposure to x-rays and is well tolerated by the patient. Anesthesia for the thumb is usually not necessary. PMID- 26251934 TI - Trends in Thumb Carpometacarpal Interposition Arthroplasty in the United States, 2005-2011. AB - We conducted a study to investigate current trends in carpometacarpal (CMC) interposition arthroplasty across time, sex, age, and region of the United States; per-patient charges and reimbursements; and the association between this procedure and concomitantly performed carpal tunnel syndrome (CTS) and carpal tunnel release (CTR). Patients who underwent CMC interposition arthroplasty (N = 41,171) were identified in a national database. Between 2005 and 2011, the number of patients who had CMC interposition arthroplasty increased 46.2%. Females had the procedure more frequently than males at all time points, though the percentage of patients who were male increased throughout the study period. Of the patients who had CMC interposition arthroplasty, 40.9% also had a diagnosis of CTS. Between 15.5% and 17.3% of these patients had CTR performed concomitantly. Despite a lack of evidence that thumb CMC interposition arthroplasty is superior to other surgical treatment options, the number of patients who are having this procedure has increased significantly. The impetus for these trends requires additional investigation. PMID- 26251935 TI - Cadaveric Study of Appropriate Screw Length for Distal Radius Stabilization Using Volar Plate Fixation. AB - We conducted a study to highlight areas of risk with distal radius fixation to prevent occurrence of extensor tendon injury without compromising the security and stability of the fixation. Twelve cadaveric forearms were used. The volar locking plate was placed to best anatomical and radiologic fit on the distal radius of each arm. All 7 holes in the plate were drilled, and bicortical length was measured using a depth gauge under fluoroscopy to estimate screw lengths. Screws were secured into place, and dorsal prominence was measured. The central screw positions had the least dorsal screw prominence, mean (SD) of 0.50 (1.06) mm, and were considered low-risk. The radial and ulnar screw positions had more dorsal screw prominence, 3.38 (1.38) mm and 1.03 (1.30) mm, respectively. Although only radial prominence was statistically significant, both radial and ulnar screw positions were considered high-risk and in need of screw length adjustments. The data suggest that screw length for this plate should be decreased by about 3 mm for the radial positions and by 1 mm for the ulnar positions to decrease the risk for tendon rupture and irritation secondary to dorsal screw prominence. PMID- 26251936 TI - Closed Rupture of the Flexor Profundus Tendon of Ring Finger: Case Report and Treatment Recommendations. AB - Zone III midsubstance flexor tendon rupture without underlying pathology is rare. The most common mechanism of injury for a spontaneous rupture is forced extension of an actively flexed distal interphalangeal joint. We describe a patient who experienced closed midsubstance zone III rupture of the flexor digitorum profundus (FDP) tendon of the ring finger at the lumbrical origin in the palm while lifting a heavy object. On exploration, there was no evidence of underlying tendon pathology, and primary end-to-end repair of the FDP was possible. This case highlights the importance of correct preoperative clinical localization of the rupture level, as well as a suggested surgical plan in equivocal cases. PMID- 26251937 TI - Thoracic Outlet Syndrome: Current Concepts, Imaging Features, and Therapeutic Strategies. AB - Thoracic outlet syndrome describes a set of disorders resulting from compression of the brachial plexus and/or subclavian vessels. Early recognition is essential, as diagnostic or treatment delays are associated with significant morbidity. In this article, we describe the imaging features of thoracic outlet syndrome with an emphasis on use of computed tomography and magnetic resonance imaging angiography and venography in association with postural maneuvers to demonstrate dynamic compression of the neurovascular structures. The pathophysiology, clinical features, and management options, which depend on the affected structures and degree of severity, are also presented in this article. PMID- 26251938 TI - Using Plate Osteosynthesis to Treat Isolated Greater Tuberosity Fractures. AB - Isolated greater tuberosity fractures make up a small subset of proximal humerus fractures. We conducted a study to evaluate the radiologic and clinical outcomes of patients who underwent a novel use of plate osteosynthesis in the treatment of displaced greater tuberosity fractures. Eleven consecutive patients with a displaced greater tuberosity fracture were treated. Mean age at surgery was 60.3 years old (range, 37-71 years). Mean follow-up was 27 months (range, 16-44 months). All 11 patients experienced radiographic union. Three of the 11 had a loss of anatomical reduction. Mean Penn Shoulder Score was 79, and mean Single Assessment Numeric Evaluation score was 72. At most recent follow-up, mean forward elevation was 147 degrees , and mean external rotation was 25 degrees . Plate osteosynthesis is a novel technique for the treatment of displaced greater tuberosity fractures. This technique resulted in excellent fracture reduction, a 100% union rate, minimal fracture migration, and good return of range of motion. PMID- 26251939 TI - The Top 100 Cited Articles in Clinical Orthopedic Sports Medicine. AB - Orthopedic sports medicine continues to evolve, owing much of its clinical management and practice to rigorous academic research. In this review, we identify and describe the top 100 cited articles in clinical sports medicine and recognize the authors and institutions driving the research. We collected articles (excluding basic science, animal, and cadaveric studies) from the 25 highest-impact sports medicine journals and analyzed them by number of citations, journal, publication date, institution, country, topic, and author. Mean number of citations was 408 (range, 229-1629). The articles were published in 7 journals, most in the 1980s to 2000s, and represented 15 countries. Thirty topics were addressed, with a heavy emphasis on anterior cruciate ligament injury and reconstruction, knee rating systems, rotator cuff reconstruction, and chondrocyte transplantation. The 3 most cited articles, by Insall and colleagues, Constant and Murley, and Tegner and Lysholm, addressed a knee, a shoulder, and another knee rating system, respectively. Several authors contributed multiple articles. The Hospital for Special Surgery and the University of Bern contributed the most articles (5 each). This study provides a comprehensive list of the past century's major academic contributions to sports medicine. Residents and fellows may use this list to guide their scholarly investigations. PMID- 26251940 TI - Use of a Topical Thrombin-Based Hemostatic Agent in Shoulder Arthroplasty. AB - Shoulder arthroplasty is associated with significant blood loss, often requiring blood transfusion. Hemostatic agents are used in various surgical specialties to minimize blood loss, but to date few studies have examined their efficacy in shoulder arthroplasty. We retrospectively reviewed 211 consecutive shoulder arthroplasty cases performed by a single surgeon. Our hypothesis was that patients treated with a topical thrombin prepared with a hemostatic matrix (Surgiflo) would have decreased perioperative blood loss. Patients with humeral fractures or preexisting blood disease were excluded. Control patients were managed December 2012 through April 2013. Study patients were managed May 2013 through August 2013 using the same surgical technique with the additional application of the hemostatic agent before closure. Charts were reviewed for demographics, estimated blood loss, drain output, transfusion rates, and complications. Hidden blood loss was calculated using a validated method. There were no differences in estimated blood loss (P = .301), drain output (P = .906), or hidden blood loss (P = .601) between groups. There was no increased incidence of transfusion between study (25%) and control (20%) groups (P = .407). No increased complications resulted from use of the hemostatic agent (P = .764). On the basis of these results, we cannot conclude that this topical hemostatic agent is effective as a blood loss management tool in shoulder arthroplasty. PMID- 26251941 TI - Length of Stay and Readmission After Total Shoulder Arthroplasty: An Analysis of 1505 Cases. AB - We conducted a study to characterize the risk factors for extended length of stay (LOS) and readmission after primary total shoulder arthroplasty (TSA). Patients who were 60 years or older and underwent TSA between 2011 and 2012 were identified from the American College of Surgeons National Surgical Quality Improvement Program database. Bivariate and multivariate analyses were used to test patient characteristics for association with extended LOS and readmission within 30 days. Extended LOS was defined as LOS of more than 3 days (90th percentile LOS). Of the 1505 TSA patients identified, 49 (3.3%) were readmitted. Multivariate analysis revealed that extended LOS was independently associated with age 70 years or older and history of diabetes. Readmission was independently associated with history of heart disease and history of hypertension. The identified risk factors may be useful for preoperative discussions, surgical decision-making, and postoperative planning for THA patients. PMID- 26251942 TI - Xanthogranulomatous Osteomyelitis of Proximal Femur Masquerading as Benign Bone Tumor. AB - We describe a case of xanthogranulomatous osteomyelitis (XO) of the proximal femur in a 65-year-old woman who presented with pain of 6 months' duration in the right hip. Plain radiographs showed a lytic well-defined lesion in the right peritrochanteric region suggestive of a benign neoplastic etiology. The gross and histopathologic examination of the curettage specimen was consistent with XO. Xanthogranulomatous osteomyelitis is a rare chronic inflammatory process that is characterized by the presence of a large number of lipid-containing macrophages with an admixture of lymphocytes, plasma cells, and neutrophils. Gross and radiologic examination of this entity can mimic malignancy, and differentiation should be confirmed by histopathologic evaluation. To the best of our knowledge, XO of the femur has not been reported in the English-language literature. The rarity of this condition and its resemblance to bone tumors form the basis of this case report. PMID- 26251943 TI - Bilateral Superior Labrum Anterior to Posterior (SLAP) Tears With Abnormal Anatomy of Biceps Tendon. AB - There have been several descriptions of variant anatomy of the long head of the biceps tendon (LHBT). A recent literature review identified 8 cases of anomalous intracapsular attachment of the LHBT. In this report, we discuss a distinctive case of a young athlete who presented with symptoms consistent with bilateral superior labrum anterior to posterior (SLAP) tears that were unresponsive to conservative measures. Magnetic resonance imaging and arthroscopic findings of this patient confirmed that the patient had type II SLAP tears, a Buford complex anteriorly, and perhaps most important, confluence of the biceps tendon itself to the undersurface of the capsule within the rotator interval. Our case proposes that anomalous insertion of the LHBT, as well as other labral and biceps anchor variations, are not always a benign finding at the time of arthroscopy. In this particular case, the tethering of the biceps tendon to the capsule is thought to have increased stress on the superior labrum and contributed to the development of the bilateral symptomatic type II SLAP tears that were identified and treated in this young athlete. PMID- 26251944 TI - Iatrogenic Femoral Neck Fracture After Closed Reduction of Anterior Hip Dislocation in the Emergency Department. AB - This is a case report detailing an iatrogenic femoral neck fracture (FNF) after closed reduction of an anterior hip dislocation. While iatrogenic FNF is a known complication of closed reduction, there are few published reports of the circumstances surrounding these fractures, and there has been no discussion of possible risk factors predisposing to this injury. This case report and review of the literature identifies the current incidence of FNF with closed reduction of anterior dislocations of the hip, as well as possible antecedent risk factors for this complication. As a result of this case report, we have changed our protocol for treatment of these injuries. PMID- 26251945 TI - Congenital Absence of the Anterior Cruciate Ligament. AB - The incidence of congenital absence of the anterior cruciate ligament (ACL) is extremely low. Congenital ACL absence has most often been found in association with conditions such as knee dislocation, knee dysplasia, proximal focal femoral deficiency, and fibular hemimelia. We report on the incidental finding of ACL aplasia in a patient with a medial meniscal tear and history of leg-length discrepancy. As has been found in prior case studies, this patient had hypertrophy of the meniscofemoral ligament of Humphrey, which likely lent her stability. This case highlights the importance of differentiating between a stable and an unstable knee in congenital absence of the ACL. PMID- 26251946 TI - Giant Solitary Synovial Chondromatosis Mimicking Chondrosarcoma: Report of a Rare Histologic Presentation and Literature Review. AB - Synovial chondromatosis is a benign lesion of the synovium, and giant solitary synovial chondromatosis (GSSCM) is a rare presentation of it. In this article, we describe clinical, imaging, and pathologic features of a hip GSSCM with an unusual histologic presentation. PMID- 26251947 TI - Fracture Blisters After Primary Total Knee Arthroplasty. AB - Fracture blisters are tense vesicles that arise on markedly swollen skin overlying traumatized soft tissue. While this relatively uncommon complication has been well described in the trauma literature, this article reports for the first time a case of fracture blisters after primary total knee arthroplasty. The fracture blisters developed within 36 hours of surgery and were associated with profound swelling and erythema. There was no evidence of vascular injury, compartment syndrome, iatrogenic fracture, or deep venous thrombosis. The patient was treated with leg elevation, loosely applied nonadhesive dressings, and a short course of oral antibiotics after skin desquamation. Blood-filled blisters required longer time to reepithelialization than fluid-filled blisters. Knee stiffness developed because of pain and fear of participation with physical therapy, but the patient was able to resume intensive rehabilitation after resolution of the blisters. Patient factors, surgical factors, and review of the literature are discussed. PMID- 26251948 TI - Intrinsic Healing of the Anterior Cruciate Ligament in an Adolescent. AB - The anterior cruciate ligament (ACL) is an important ligamentous stabilizer of the knee. The natural primary healing potential of the ACL has been shown to be extremely poor. We report the case of a 12-year-old boy who was involved in a motor vehicle collision and sustained a grade IIIB open tibial fracture, distal fibula fracture, medial and lateral meniscus tears, avulsion fracture of the femoral metaphysis, and anterior and posterior cruciate ligament tears. Because of delayed union of his tibia fracture, treatment of the ligamentous injuries was postponed to 16 months after initial injury. However, magnetic resonance imaging at that time showed complete healing. At 20 months, the patient returned to competitive hockey. Based on this case, we believe there is some natural primary healing potential within the ACL. PMID- 26251949 TI - The Challenge of Surgeon Self-Improvement. PMID- 26251950 TI - Hepatitis B virus X protein modifies invasion, proliferation and the inflammatory response in an HTR-8/SVneo cell model. AB - Mother-to-infant transmission of hepatitis B virus (HBV) can occur as an intrauterine, intrapartum or postpartum infection. In the present study, we induced a multifunctional viral regulator of HBV gene products, HBx, and its different fragments to overexpress in a tropho-blast cell line, HTR-8/SVneo. We then identified the biological effects of HBx on HTR-8/SVneo cells. Our results indicated that HBx inhibited apoptosis and induced invasion as detected using Annexin V/propidium iodide (PI) double staining and Transwell assay, respectively. Furthermore, we carried out western blot analysis to analyze the possible related signaling pathway. We confirmed that HBx and its different fragments can activate the Smad signaling pathway, accompanied by downregulation of E-cadherin, and upregulation of vimentin and N-cadherin. TGF-beta1 was used as a control to activate the Smad signaling pathway in HTR-8/SVneo cells. HBx activated the Smad signaling pathway in the HTR-8/SVneo cells. After the signaling pathway was activated, reduced apoptosis, higher invasive ability and enhanced inflammatory response were observed in the HTR-8/SVneo cells. PMID- 26251951 TI - An in vitro human skin test for assessing sensitization potential. AB - Sensitization to chemicals resulting in an allergy is an important health issue. The current gold-standard method for identification and characterization of skin sensitizing chemicals was the mouse local lymph node assay (LLNA). However, for a number of reasons there has been an increasing imperative to develop alternative approaches to hazard identification that do not require the use of animals. Here we describe a human in-vitro skin explant test for identification of sensitization hazards and the assessment of relative skin sensitizing potency. This method measures histological damage in human skin as a readout of the immune response induced by the test material. Using this approach we have measured responses to 44 chemicals including skin sensitizers, pre/pro-haptens, respiratory sensitizers, non-sensitizing chemicals (including skin-irritants) and previously misclassified compounds. Based on comparisons with the LLNA, the skin explant test gave 95% specificity, 95% sensitivity, 95% concordance with a correlation coefficient of 0.9. The same specificity and sensitivity were achieved for comparison of results with published human sensitization data with a correlation coefficient of 0.91. The test also successfully identified nickel sulphate as a human skin sensitizer, which was misclassified as negative in the LLNA. In addition, sensitizers and non-sensitizers identified as positive or negative by the skin explant test have induced high/low T cell proliferation and IFNgamma production, respectively. Collectively, the data suggests the human in vitro skin explant test could provide the basis for a novel approach for characterization of the sensitizing activity as a first step in the risk assessment process. PMID- 26251952 TI - Amide and Peptide Bond Formation in Water at Room Temperature. AB - A general and environmentally responsible method for the formation of amide/peptide bonds in an aqueous micellar medium is described. Use of uronium salt (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU) as a coupling reagent, 2,6-lutidine, and TPGS-750-M represents mild conditions associated with these valuable types of couplings. The aqueous reaction medium is recyclable leading to low E Factors. PMID- 26251953 TI - Managing Mental Health Problems Among Immigrant Women Attending Primary Health Care Services. AB - Researchers in Norway explore treatment options in primary care for immigrant women with mental health problems compared with nonimmigrant women. Three national registers were linked together for 2008. Immigrant women from Sweden, Poland, the Philippines, Thailand, Pakistan, and Russia were selected for analysis and compared with Norwegian women. Using logistic regression, we investigated whether treatment type varied by country of origin. Rates of sickness leave and psychiatric referrals were similar across all groups. Conversational therapy and use of antidepressants and anxiolytics were lower among Filipina, Thai, Pakistani, and Russian women than among Norwegians. Using the broad term "immigrants" masks important differences in treatment and health service use. By closely examining mental health treatment differences by country of origin, gaps in service provision and treatment uptake may be identified and addressed with more success. PMID- 26251954 TI - Current and Projected Heat-Related Morbidity and Mortality in Rhode Island. AB - BACKGROUND: Climate change is expected to cause increases in heat-related mortality, especially among the elderly and very young. However, additional studies are needed to clarify the effects of heat on morbidity across all age groups and across a wider range of temperatures. OBJECTIVES: We aimed to estimate the impact of current and projected future temperatures on morbidity and mortality in Rhode Island. METHODS: We used Poisson regression models to estimate the association between daily maximum temperature and rates of all-cause and heat related emergency department (ED) admissions and all-cause mortality. We then used downscaled Coupled Model Intercomparison Project Phase 5 (CMIP5; a standardized set of climate change model simulations) projections to estimate the excess morbidity and mortality that would be observed if this population were exposed to the temperatures projected for 2046-2053 and 2092-2099 under two representative concentration pathways (RCP): RCP 8.5 and 4.5. RESULTS: Between 2005 and 2012, an increase in maximum daily temperature from 75 to 85 degrees F was associated with 1.3% and 23.9% higher rates of all-cause and heat-related ED visits, respectively. The corresponding effect estimate for all-cause mortality from 1999 through 2011 was 4.0%. The association with all-cause ED admissions was strongest for those < 18 or >= 65 years of age, whereas the association with heat related ED admissions was most pronounced among 18- to 64-year-olds. If this Rhode Island population were exposed to temperatures projected under RCP 8.5 for 2092-2099, we estimate that there would be 1.2% (range, 0.6-1.6%) and 24.4% (range, 6.9-41.8%) more all-cause and heat-related ED admissions, respectively, and 1.6% (range, 0.8-2.1%) more deaths annually between April and October. CONCLUSIONS: With all other factors held constant, our findings suggest that the current population of Rhode Island would experience substantially higher morbidity and mortality if maximum daily temperatures increase further as projected. CITATION: Kingsley SL, Eliot MN, Gold J, Vanderslice RR, Wellenius GA. 2016. Current and projected heat-related morbidity and mortality in Rhode Island. Environ Health Perspect 124:460-467; http://dx.doi.org/10.1289/ehp.1408826. PMID- 26251955 TI - Acetate as a Metabolic and Epigenetic Modifier of Cancer Therapy. AB - Metabolic networks are significantly altered in neoplastic cells. This altered metabolic program leads to increased glycolysis and lipogenesis and decreased dependence on oxidative phosphorylation and oxygen consumption. Despite their limited mitochondrial respiration, cancer cells, nonetheless, derive sufficient energy from alternative carbon sources and metabolic pathways to maintain cell proliferation. They do so, in part, by utilizing fatty acids, amino acids, ketone bodies, and acetate, in addition to glucose. The alternative pathways used in the metabolism of these carbon sources provide opportunities for therapeutic manipulation. Acetate, in particular, has garnered increased attention in the context of cancer as both an epigenetic regulator of posttranslational protein modification, and as a carbon source for cancer cell biomass accumulation. However, to date, the data have not provided a clear understanding of the precise roles that protein acetylation and acetate oxidation play in carcinogenesis, cancer progression or treatment. This review highlights some of the major issues, discrepancies, and opportunities associated with the manipulation of acetate metabolism and acetylation-based signaling in cancer development and treatment. PMID- 26251956 TI - Selective induction of apoptosis in human gastric cancer cells by Lactobacillus kefiri (PFT), a novel kefir product. AB - The present study was undertaken to evaluate the effect of Lactobacillus kefiri (PFT), a novel kefir product, on apoptosis of gastric cancer cells (AGS), breast cancer cells (4T1), and human peripheral blood mononuclear cells (PBMCs). Cells were cultured with PFT and apoptosis was determined by flow cytometry using 7-AAD dye and cytospin preparation. Mitochondrial dysfunction and expression of Bcl2 were monitored by flow cytometry. Results showed that PFT induced apoptosis in AGS gastric cancer cells in a dose-dependent manner. Apoptosis was detected at a concentration of 0.3 mg/ml (20.8%), increased to 25.8% at 0.6 mg/ml, 37% at 1.2 mg/ml, 53.1% at 2.5 mg/ml, and peaked at 66.3% at 5.0 mg/ml. Apoptosis is associated with the decreased polarization of mitochondrial membrane potential (MMP) and decreased Bcl2 expression. PFT-treated AGS cells manifested membrane blebbing, nuclear condensation, and fragmentation as identified in cytospin cytocentrifuge Giemsa stained preparations. On the other hand, flow cytometry analysis showed that PFT did not induce apoptosis in 4T1 breast cancer cells nor in PBMCs. These results suggest that PFT is safe for white blood cells and selectively induces apoptotic effects in gastric cancer cells. Hence, it may have potential as a therapeutic agent for the treatment of gastric cancers. PMID- 26251957 TI - Inhibition of microRNA-155 relieves sepsis-induced liver injury through inactivating the JAK/STAT pathway. AB - The present study aimed to investigate whether the microRNA (miR)-155 inhibitor has an anti-inflammatory effect on sepsis-associated liver injury and whether this effect is associated with the activity of the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. BALB/c mice were randomly divided into three groups (n=40 per group): Control, lipopolysaccharide (LPS) and miR-155 inhibitor plus LPS groups. Liver injury was induced by injection of LPS (20 mg kg-1). In the inhibitor plus LPS group, LPS was administered after injecting the miR-155 inhibitor (80 mg kg-1) for 3 days. Liver tissues were collected at 6, 12, 24 and 48 h after LPS exposure. Hematoxylin and eosin was used to identify the histological changes in the liver. The expression levels of miR-155, suppressor of cytokine signaling 1 (SOCS1) and STAT1 were determined by reverse transcription-quantitative polymerase chain reaction. The protein expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 were detected by ELISA. miR-155 inhibitor pretreatment alleviated the symptoms of LPS-exposed mice, and reduced LPS-induced mortality and liver injury. Compared with the LPS group, expression of miR-155 was significantly reduced in the miR 155 inhibitor plus LPS group at 6 h (P<0.05). SOCS1 expression was significantly increased in miR-155 inhibitor plus LPS group compared with the control and the LPS group at 12 h (P<0.05). There was a lower level of STAT1 in the miR-155 inhibitor plus LPS group compared with the LPS group (P<0.05). In addition, TNF alpha and IL-10 were significantly decreased in the miR-155 inhibitor plus LPS group compared with the LPS group (P<0.05). In conclusion, the miR-155 inhibitor relieves liver injury by enhancing the expression of SOCS1 and inactivating JAK/STAT signaling. PMID- 26251958 TI - Randomized trial of allergen-induced asthmatic response in smokers and non smokers: effects of inhaled corticosteroids. AB - BACKGROUND: It is thought that asthmatics who smoke cigarettes respond less well to inhaled corticosteroid (ICS) therapy than asthmatics who do not smoke. OBJECTIVE: To evaluate the effects of smoking on allergen-induced airway responses in asthmatics treated with ICS. METHODS: Randomized, double-blind, crossover study evaluating twice daily fluticasone propionate (FP) 100 MUg, FP 500 MUg and placebo, for 7 days, on allergen-induced asthmatic responses in 18 non-smoking and 17 smoking atopic asthmatics (NCT01400906). At 1 h post-morning dose on Day 6, forced expiratory volume in 1 sec (FEV1 ) was measured up to 10 h post-challenge. Exhaled nitric oxide (eNO), induced sputum cell counts, and responsiveness to methacholine were assessed the following day. RESULTS: The late asthmatic response (LAR) was suppressed by FP in smokers and non-smokers; with placebo, the LAR was also attenuated in smokers versus non-smokers (adjusted mean minimum change in FEV1 (L) over 4-10 h [95% CI] in non-smokers: placebo -1.01 [1.31, 0.70], FP 100 MUg -0.38 [0.54, 0.22], FP 500 MUg -0.35 [0.54-0.22]; and in smokers: placebo -0.63 [0.84, 0.43]; FP 100 MUg -0.44 [0.65, 0.23]; FP 500 MUg 0.46 [0.59-0.32]). The Early AR was suppressed by FP treatment in non-smokers, but was not impacted in smokers. The reduction in methacholine hyperresponsiveness after FP was greater in non-smokers (1.5- and twofold doubling dose difference from placebo after FP 100 MUg and FP 500 MUg) than smokers (1.0 and 1.3 difference, respectively). Allergen-induced increases in eNO and sputum eosinophils were lower in smokers than non-smokers and were suppressed in both groups by FP. CONCLUSION AND CLINICAL RELEVANCE: Allergen-induced LARs were of a similar amplitude in both smoking and non-smoking atopic asthmatics at the end of ICS treatment, but attenuation of the LAR in smokers was only partly associated with ICS treatment. The marked attenuation of the LAR observed in smokers in the absence of ICS treatment is a novel observation. PMID- 26251959 TI - Epidural Baclofen for the Management of Postoperative Pain in Children With Cerebral Palsy. AB - INTRODUCTION: Children with cerebral palsy undergoing soft tissue and bony procedures often experience pain and spasticity postoperatively. Differentiation of pain from spasticity complicates management, so controlling spasticity with a continuous infusion of baclofen, an antispasmodic, through an already present indwelling epidural catheter holds interest. METHODS: A retrospective chart review was performed of patients with cerebral palsy undergoing single event, multilevel lower extremity surgery at a single institution who received epidural analgesia with or without continuous baclofen infusion. Primary outcomes included need for supplemental narcotic analgesics and benzodiazepines postoperatively. Duration of hospitalization, pain scores, and complications were also evaluated. RESULTS: Forty-four patients were identified, ranging in age from 3 to 17 years, 19 of whom received epidural baclofen. No differences were found in use of supplemental narcotic analgesia, benzodiazepines, or duration of hospitalization. Differences in pain scores were not statistically significant (0.82+/-0.95 for baclofen vs. 1.48+/-0.99 for controls) (P=0.391). Mean arterial pressure was lower in patients receiving baclofen (P=0.004). No potential side effects attributable to baclofen were noted. CONCLUSIONS: Continuous epidural baclofen infusion seems unlikely to alter the pain-spasm cycle experienced by patients with cerebral palsy following orthopaedic surgery to a clinically significant degree. More effective, and cost-effective, measures at assessing and controlling pain and muscle spasm should be explored to benefit cerebral palsy patients postoperatively. LEVEL OF EVIDENCE: Level III-therapeutic study. PMID- 26251960 TI - Rate of Correction and Recurrence of Ankle Valgus in Children Using a Transphyseal Medial Malleolar Screw. AB - BACKGROUND: Transphyseal medial malleolar screw (TMMS) hemiepiphysiodesis is an effective treatment for ankle valgus in children. There is limited evidence on the effect of age and diagnosis on the rate of correction as well as the deformity recurrence after screw removal. The purpose of this study was to determine (1) the rate of correction of ankle valgus after hemiepiphysiodesis using a TMMS, (2) the effects of clinical diagnosis and age at surgery on the rate of correction, and (3) the rate of valgus recurrence after TMMS removal. METHODS: In this retrospective study we included 16 male and 21 female patients (63 ankles) with an average age at surgery of 11.0 years (range, 5.4 to 14.8 y) who underwent TMMS hemiepiphysiodesis for the treatment of ankle valgus. There was a mean radiographic follow-up of 1.6 years (range, 0.4 to 4.9 y) before screw removal. For subjects who received screw removal (43 ankles), the average time from insertion to removal of the screw was 1.4 years (range, 0.4 to 5.2 y). Valgus deformity was assessed on anteroposterior ankle radiographs by measurement of tibiotalar angle. Linear mixed effects models were used to determine rates of correction and valgus recurrence. RESULTS: The average rate of correction in tibiotalar angle was 0.37+/-0.04 degrees per month (P<0.001). Clinical diagnosis and age at surgery significantly affected the amount of postoperative correction in tibiotalar angle (P<0.05). Eighteen of 22 ankles (81.8%) demonstrated recurrence of ankle valgus after screw removal. The average recurrence rate in patients who underwent screw removal was 0.28+/-0.08 degrees per month (22 ankles, P=0.002). CONCLUSIONS: This study supports the effectiveness of the TMMS hemiepiphysiodesis for treating pediatric ankle valgus, but the effects of additional skeletal growth should be considered as the ankle may rebound into valgus after correction and screw removal. The results from this study can help with surgical planning to predict the amount of correction that may be achieved depending on underlying diagnosis and age at surgery. LEVEL OF EVIDENCE: Level IV retrospective study. PMID- 26251961 TI - Characterization of dense particle suspensions under flow. PMID- 26251962 TI - Mechanism of Uranium Reduction and Immobilization in Desulfovibrio vulgaris Biofilms. AB - The prevalent formation of noncrystalline U(IV) species in the subsurface and their enhanced susceptibility to reoxidation and remobilization, as compared to crystalline uraninite, raise concerns about the long-term sustainability of the bioremediation of U-contaminated sites. The main goal of this study was to resolve the remaining uncertainty concerning the formation mechanism of noncrystalline U(IV) in the environment. Controlled laboratory biofilm systems (biotic, abiotic, and mixed biotic-abiotic) were probed using a combination of U isotope fractionation and X-ray absorption spectroscopy (XAS). Regardless of the mechanism of U reduction, the presence of a biofilm resulted in the formation of noncrystalline U(IV). Our results also show that biotic U reduction is the most effective way to immobilize and reduce U. However, the mixed biotic-abiotic system resembled more closely an abiotic system: (i) the U(IV) solid phase lacked a typically biotic isotope signature and (ii) elemental sulfur was detected, which indicates the oxidation of sulfide coupled to U(VI) reduction. The predominance of abiotic U reduction in our systems is due to the lack of available aqueous U(VI) species for direct enzymatic reduction. In contrast, in cases where bicarbonate is present at a higher concentration, aqueous U(VI) species dominate, allowing biotic U reduction to outcompete the abiotic processes. PMID- 26251963 TI - Analysis of the advantage features of Beijing surveillance network for Creutzfeldt-Jakob disease. AB - Since 2006, China has conducted the surveillance program for Creutzfeldt-Jakob disease (CJD) and other subtypes of prion diseases covering 12 provinces. In this study, the characteristics and special role of Beijing CJD surveillance network in the national CJD surveillance system were analyzed. Based on the registered permanent resident places, all reporting suspected CJD cases and diagnosed CJD cases via Beijing CJD surveillance network between 2006 and 2013 were grouped as the cases from Beijing and from outside of Beijing. Both numbers of the suspected and diagnosed CJD cases via Beijing CJD surveillance network constantly increased along with the years, totally 532 reporting cases and 192 diagnosed CJD cases were obtained in the past 8 y. About 75% of suspected and diagnosed CJD cases via Beijing CJD surveillance network came from other provinces, mainly from neighboring provinces. Altogether, 46 different hospitals in the Beijing region have reported suspected CJD cases to the CJD surveillance system during the period from 2006 to 2013. Five hospitals continually reported suspected CJD cases during those 8 y and 5 other hospitals had reported cases except for 1 to 2 y. Additionally, we found that the diagnosed CJD patients from Beijing region had less numbers of hospital transfer and shorter interval from the disease onset to the final diagnosis than those outside of Beijing. It indicates that as the most important component, Beijing CJD surveillance network functions more actively, which supplies the special medical services not only for Beijing residents but also for patients from all of China. PMID- 26251964 TI - Metabolic syndrome in first-time hospitalized patients with depression: a 1-year follow-up study. AB - OBJECTIVE: Studies on metabolic syndrome (MetS) in younger patients with depression are few. We examined the prevalence and progression of MetS in first time hospitalized patients with depression during 1 year of follow-up. Furthermore, we explored putative risk factors of MetS. METHOD: We evaluated MetS and its components in first-time hospitalized patients with depression (N = 52) and healthy controls (N = 50) (18-45 years). Physical activity, aerobic fitness, sleeping disturbances, smoking and dietary habits, and psychopharmacological treatment were recorded at baseline for all participants and after 1 year for the patients. RESULTS: Patients had significantly higher waist circumference (WC) and lower high-density lipoproteins compared with healthy controls (P < 0.05). Patients had higher prevalence of MetS, but this was not significant when adjusted for age. Patients had significant increase in WC and triglycerides and a non-significant increase in the prevalence of MetS. Antipsychotic medication (OR 10.5, 95% CI 1.18-94.14) and low aerobic fitness (OR 0.79, 95% CI 0.68-0.93) were significantly correlated with MetS (P < 0.05). CONCLUSION: Metabolic syndrome is highly prevalent in younger, severely depressed patients and the incidence increases during 1 year of follow-up. Low aerobic fitness and use of atypical antipsychotics are strongly correlated with MetS. PMID- 26251965 TI - Effects of memory strategy training on performance and event-related brain potentials of children with ADHD in an episodic memory task. AB - Evidence for memory problems in children with attention deficit hyperactivity disorder (ADHD) is accumulating. Attempting to counter such problems, in the present study children with ADHD aged 8-12 years underwent a six-week metacognitive memory strategy training (MST) or one of two other active trainings, either a metacognitive attention-perceptual-motor training (APM) or placebo training consisting of playing board games (PLA). Effects of the training on episodic memory and underlying brain processes were investigated by comparing performance and event-related brain potentials (ERPs) on pre- and post-training sessions in an old/new recognition task between the three training groups. Potential far transfer effects of the memory strategy training were investigated by measuring performance on neuropsychological attention and memory-span tasks and parent-rated ADHD symptoms. The metacognitive memory strategy training led to significantly improved memory performance and enhanced amplitude of left parietal P600 activity associated with the process of memory recollection when compared to PLA, but APM training evoked similar improvements. Memory performance gains were significantly correlated with the memory-related ERP effects. Preliminary far transfer effects of MST training were found on attention and working memory performance and on parent-rated ADHD symptoms, although these results need replication with larger and better IQ-matched groups. PMID- 26251966 TI - Normative Spatiotemporal Parameters During 100-m Sprints in Amputee Sprinters Using Running-Specific Prostheses. AB - The aim of this study was to develop a normative sample of step frequency and step length during maximal sprinting in amputee sprinters. We analyzed elite level 100-m races of 255 amputees and 93 able-bodied sprinters, both men and women, from publicly-available Internet broadcasts. For each sprinter's run, the average forward velocity, step frequency, and step length over the 100-m distance were analyzed by using the official record and number of steps in each race. The average forward velocity was greatest in able-bodied sprinters (10.04 +/- 0.17 m/s), followed by bilateral transtibial (8.77 +/- 0.27 m/s), unilateral transtibial (8.65 +/- 0.30 m/s), and transfemoral amputee sprinters (7.65 +/- 0.38 m/s) in men. Differences in velocity among 4 groups were associated with step length (able-bodied vs transtibial amputees) or both step frequency and step length (able-bodied vs transfemoral amputees). Although we also found that the velocity was greatest in able-bodied sprinters (9.10 +/- 0.14 m/s), followed by unilateral transtibial (7.08 +/- 0.26 m/s), bilateral transtibial (7.06 +/- 0.48 m/s), and transfemoral amputee sprinters (5.92 +/- 0.33 m/s) in women, the differences in the velocity among the groups were associated with both step frequency and step length. Current results suggest that spatiotemporal parameters during a 100-m race of amputee sprinters is varied by amputation levels and sex. PMID- 26251967 TI - (15)N NMR spectroscopy unambiguously establishes the coordination mode of the diimine linker 2-(2'-pyridyl)pyrimidine-4-carboxylic acid (cppH) in Ru(ii) complexes. AB - We investigated the reactivity of three Ru(ii) precursors -trans,cis,cis [RuCl2(CO)2(dmso-O)2], cis,fac-[RuCl2(dmso-O)(dmso-S)3], and trans-[RuCl2(dmso S)4] - towards the diimine linker 2-(2'-pyridyl)pyrimidine-4-carboxylic acid (cppH) or its parent compound 4-methyl-2-(2'-pyridyl)pyrimidine ligand (mpp), in which a methyl group replaces the carboxylic group on the pyrimidine ring. In principle, both cppH and mpp can originate linkage isomers, depending on how the pyrimidine ring binds to ruthenium through the nitrogen atom ortho (N(o)) or para (N(p)) to the group in position 4. The principal aim of this work was to establish a spectroscopic fingerprint for distinguishing the coordination mode of cppH/mpp also in the absence of an X-ray structural characterization. By virtue of the new complexes described here, together with the others previously reported by us, we successfully recorded {(1)H,(15)N}-HMBC NMR spectra at natural abundance of the (15)N isotope on a consistent number of fully characterized Ru(ii)-cppH/mpp compounds, most of them being stereoisomers and/or linkage isomers. Thus, we found that (15)N NMR chemical shifts unambiguously establish the binding mode of cppH and mpp - either through N(o) or N(p)- and can be conveniently applied also in the absence of the X-ray structure. In fact, coordination of cppH to Ru(ii) induces a marked upfield shift for the resonance of the N atoms directly bound to the metal, with coordination induced shifts (CIS) ranging from ca.-45 to -75 ppm, depending on the complex, whereas the unbound N atom resonates at a frequency similar to that of the free ligand. Similar results were found for the complexes of mpp. This work confirmed our previous finding that cppH has no binding preference, whereas mpp binds exclusively through N(p). Interestingly, the two cppH linkage isomers trans,cis [RuCl2(CO)2(cppH-kappaN(p))] (5) and trans,cis-[RuCl2(CO)2(cppH-kappaN(o))] (6) were easily obtained in pure form by exploiting their different solubility properties. PMID- 26251968 TI - Exercise in Young Adulthood with Simultaneous and Future Changes in Fruit and Vegetable Intake. AB - OBJECTIVES: Regarding weight management, changes in exercise behavior can also influence nutrition behavior by application of self-regulatory psychological resources across behaviors (transfer effect). This study aimed to determine: (1) if changes in exercise frequency in young adulthood predict simultaneous changes in fruit/vegetable intake (transfer as co-occurrence); and (2) if exercise frequency affects future fruit/vegetable intake (transfer as carry-over). METHODS: 6244 respondents of the National Longitudinal Survey of Youth 1997 were followed at ages 18-22 (Time-1), 23-27 (Time-2), and 27-31 (Time-3). Repeated measures analysis of variance and hierarchical multiple regression determined if the change in exercise frequency between Time-1 and Time-2 was associated with simultaneous and sequential changes in fruit/vegetable intake frequency, controlling for sex, race/ethnicity, education, income, body mass index, and baseline fruit/vegetable intake. RESULTS: Only 9% continued exercising for 30 minutes more than 5 days/week, while 15% transitioned to adequate exercise and another 15% transitioned to inadequate exercise; for both fruits and vegetables, intake of once per day or more increased with age. Males were more likely to exercise adequately and females to consume fruits/vegetables adequately. Exercise frequency transition was linearly associated with concurrent fruit/vegetable intake during Time-1 and Time-2. The highest increase in mean fruit/vegetable intake occurred for participants who transitioned from inadequate to adequate exercise. A significant Time-2 exercise frequency effect on Time-3 fruit/vegetable intake emerged, after accounting for baseline intake. Increase in Time-2 exercise by one day/week resulted in increased Time-3 fruit and vegetable intakes by 0.17 and 0.13 times/week, respectively. CONCLUSION: Transfer effects, although usually discussed in interventions, may also be applicable to voluntary behavior change processes. Newly engaging in and continuing exercise behavior over time may establish exercise habits that facilitate improved fruit/vegetable consumption. Interventions that facilitate transferring resources across behaviors likely will enhance this effect. PMID- 26251969 TI - Pulse-Gradient Spin-Echo (1)H, (7)Li, and (19)F NMR Diffusion and Ionic Conductivity Measurements of 14 Organic Electrolytes Containing LiN(SO2CF3)2. AB - The self-diffusion coefficients of the lithium ion, the anion, and the solvent in lithium bis(trifluromethanesulfonyl)imide (LiTFSI, LiN(SO2CF3)2) solvent systems were measured using the pulse-gradient spin-echo (PGSE) NMR method. Fourteen different organic solvents that are commonly used as organic solution electrolytes in lithium batteries were studied. The self-diffusion coefficients of the corresponding pure solvents were also measured. Since a good correlation between the self-diffusion coefficients of the pure solvents and the inverse of the viscosity was obtained, the results are discussed in terms of the Stokes Einstein equation. Comparisons of the self-diffusion coefficients of the solvent, the lithium ion, and the anion (TFSI ion) illustrate the solvation behavior for each solvent. The relationship between the ionic conductivity and the sum of the diffusion coefficients of the lithium ion and the anion gives the degree of ion pair formation and permits the roles of the solvents in the electrolytes to be clearly explained. PMID- 26251970 TI - GESSE: Predicting Drug Side Effects from Drug-Target Relationships. AB - The in silico prediction of unwanted side effects (SEs) caused by the promiscuous behavior of drugs and their targets is highly relevant to the pharmaceutical industry. Considerable effort is now being put into computational and experimental screening of several suspected off-target proteins in the hope that SEs might be identified early, before the cost associated with developing a drug candidate rises steeply. Following this need, we present a new method called GESSE to predict potential SEs of drugs from their physicochemical properties (three-dimensional shape plus chemistry) and to target protein data extracted from predicted drug-target relationships. The GESSE approach uses a canonical correlation analysis of the full drug-target and drug-SE matrices, and it then calculates a probability that each drug in the resulting drug-target matrix will have a given SE using a Bayesian discriminant analysis (DA) technique. The performance of GESSE is quantified using retrospective (external database) analysis and literature examples by means of area under the ROC curve analysis, "top hit rates", misclassification rates, and a chi(2) independence test. Overall, the robust and very promising retrospective statistics obtained and the many SE predictions that have experimental corroboration demonstrate that GESSE can successfully predict potential drug-SE profiles of candidate drug compounds from their predicted drug-target relationships. PMID- 26251971 TI - Post-traumatic Growth in the Italian Experience of Long-term Disease-free Cancer Survivors. AB - Cancer survivors often report post-traumatic growth. Since culture influences the development of post-traumatic growth, the aims of this study were to measure the prevalence of post-traumatic growth in Italian long-term disease-free and treatment-free cancer survivors (>=5 years) and explore the relationship between post-traumatic growth and sociodemographic and clinical variables. Three hundred sixty long-term disease-free and treatment-free cancer survivors were assessed with Post-traumatic Growth Inventory (PTGI), Brief COPE and Multidimensional Scale of Perceived Social Support (MSPSS). Mean age was 58.6 years, and mean survival was 11 years (range 5-32). The PTGI average total score was higher in younger survivors, in those without comorbidities, in survivors engaged in physical activity. Positive correlation between PTGI and Brief COPE and between PTGI and MSPSS were found. The variables more associated with post-traumatic growth were age, comorbidity, physical activity and two coping subscales. The prevalence of post-traumatic growth in this sample of cancer survivors was lower than previous studies. We discussed some possible explanations, including the consideration that cultural differences may affect the development of post traumatic growth in cancer survivors. Having less comorbidities, receiving social support from friends, having the ability to adaptively cope and engaging in physical activity were found to be strongly associated with post-traumatic growth. PMID- 26251972 TI - Mercury contamination of fungi genus Xerocomus in the Yunnan province in China and the region of Europe. AB - This article presents the results of the study on accumulation, distribution, contamination and probable dietary intake of total mercury (THg) in fruiting bodies of several species of Fungi genus Xerocomus, which emerged in the circum Pacific mercuriferous belt region in southwestern China in Yunnan and beyond of the mercuriferous belts in the region of Europe. The mushrooms X. puniceus (Boletus amygdalinus), X. spadiceus (Boletus ferrugineus) and X. versicolor (X. rubellus) were from the Yunnan land, and X. badius (Boletus badius) was from the region of Europe in Belarus and X. badius, X. chrysenteron, X. ferrugineus, X. versicolor (X. rubellus) and X. subtomentosus from Poland. The THg in the fungal and soil materials was determined using validated method by cold-vapour atomic absorption spectroscopy. Estimated was also probable dietary intake and health risk from THg in Xerocomus spp. examined by consumers. The data showed that THg content of Xerocomus spp. emerged in the European localizations in Poland and Belarus is at an order of magnitude lower level than determined in samples from the Yunnan Province. A reason for an elevated content of THg in mushrooms from Yunnan can be related to abundance of Hg in the geochemical background of soils there. The assessed doses showed that a single meal composed of 300 g of fresh fruiting bodies of X. spadiceus from the Wuding localization in Yunnan in China if consumed once a week will provide THg at dose close to the provisional tolerable weekly intake (PTWI) value set for THg, while doses will be lower for all other localizations in Yunnan and Europe. In the Wuding localization in Yunnan a frequent consumption of X. spadiceus in volume exceeding 300 g of fresh fruiting bodies per week will provide THg at a dose exceeding the value of PTWI. PMID- 26251973 TI - Nutritional Considerations for the Overweight Young Athlete. AB - Nutritional considerations for the overweight young athlete have not been thoroughly discussed in the scientific literature. With the high prevalence of childhood obesity, more children participating in sports are overweight or obese. This is particularly true for select sports, such as American football, where large size provides an added advantage. While sport participation should be encouraged because of the many benefits of physical activity, appropriate nutritional practices are vital for growth, and optimizing performance and health. The overweight young athlete may face certain challenges because of variable energy costs and nutrient requirements for growth and routine training, compared with nonoverweight athletes. Special attention should be given to adopting healthy lifestyle choices to prevent adverse health effects due to increased adiposity. In this review, we aim to discuss special nutritional considerations and highlight gaps in the literature concerning nutrition for overweight young athletes compared with their nonoverweight peers. PMID- 26251974 TI - Cyclic mechanical stretch promotes energy metabolism in osteoblast-like cells through an mTOR signaling-associated mechanism. AB - Energy metabolism is essential for maintaining function and substance metabolism in osteoblasts. However, the role of cyclic stretch in regulating osteoblastic energy metabolism and the underlying mechanisms remain poorly understood. In this study, we found that cyclic stretch (10% elongation at 0.1 Hz) significantly enhanced glucose consumption, lactate levels (determined using a glucose/lactate assay kit), intracellular adenosine triphosphate (ATP) levels (quantified using rLuciferase/Luciferin reagent) and the mRNA expression of energy metabolism related enzymes [mitochondrial ATP synthase, L-lactate dehydrogenase A (LDHA) and enolase 1; measured by RT-qPCR], and increased the phosphorylation levels of Akt, mammalian target of rapamycin (mTOR) and p70s6k (measured by western blot analysis) in human osteoblast-like MG-63 cells. Furthermore, the inhibition of Akt or mTOR with an antagonist (wortmannin or rapamycin) suppressed the stretch induced increase in glucose consumption, lactate levels, intracellular ATP levels and the expression of mitochondrial ATP synthase and LDHA, indicating the significance of the Akt/mTOR/p70s6k pathway in regulating osteoblastic energy metabolism in response to mechanical stretch. Thus, we concluded that cyclic stretch regulates energy metabolism in MG-63 cells partially through the Akt/mTOR/p70s6k signaling pathway. The present findings provide novel insight into osteoblastic mechanobiology from the perspective of energy metabolism. PMID- 26251975 TI - Climate change and maize yield in southern Africa: what can farm management do? AB - There is concern that food insecurity will increase in southern Africa due to climate change. We quantified the response of maize yield to projected climate change and to three key management options - planting date, fertilizer use and cultivar choice - using the crop simulation model, agricultural production systems simulator (APSIM), at two contrasting sites in Zimbabwe. Three climate periods up to 2100 were selected to cover both near- and long-term climates. Future climate data under two radiative forcing scenarios were generated from five global circulation models. The temperature is projected to increase significantly in Zimbabwe by 2100 with no significant change in mean annual total rainfall. When planting before mid-December with a high fertilizer rate, the simulated average grain yield for all three maize cultivars declined by 13% for the periods 2010-2039 and 2040-2069 and by 20% for 2070-2099 compared with the baseline climate, under low radiative forcing. Larger declines in yield of up to 32% were predicted for 2070-2099 with high radiative forcing. Despite differences in annual rainfall, similar trends in yield changes were observed for the two sites studied, Hwedza and Makoni. The yield response to delay in planting was nonlinear. Fertilizer increased yield significantly under both baseline and future climates. The response of maize to mineral nitrogen decreased with progressing climate change, implying a decrease in the optimal fertilizer rate in the future. Our results suggest that in the near future, improved crop and soil fertility management will remain important for enhanced maize yield. Towards the end of the 21st century, however, none of the farm management options tested in the study can avoid large yield losses in southern Africa due to climate change. There is a need to transform the current cropping systems of southern Africa to offset the negative impacts of climate change. PMID- 26251976 TI - Tailor-made dimensions of diblock copolymer truncated micelles on a solid by UV irradiation. AB - We investigated the structural evolution of truncated micelles in ultrathin films of polystyrene-block-poly(2-vinylpyridine), PS-b-P2VP, of monolayer thickness on bare silicon substrates (SiOx/Si) upon UV irradiation in air- (UVIA) and nitrogen rich (UVIN) environments. The structural evolution of micelles upon UV irradiation was monitored using GISAXS measurements in situ, while the surface morphology was probed using atomic force microscopy ex situ and the chemical composition using X-ray photoelectron spectroscopy (XPS). This work provides clear evidence for the interpretation of the relationship between the structural evolution and photochemical reactions in PS-b-P2VP truncated micelles upon UVIA and UVIN. Under UVIA treatment, photolysis and cross-linking reactions coexisted within the micelles; photolysis occurred mainly at the top of the micelles, whereas cross-linking occurred preferentially at the bottom. The shape and size of UVIA-treated truncated micelles were controlled predominantly by oxidative photolysis reactions, which depended on the concentration gradient of free radicals and oxygen along the micelle height. Because of an interplay between photolysis and photo-crosslinking, the scattering length densities (SLD) of PS and P2VP remained constant. In contrast, UVIN treatments enhanced the contrast in SLD between the PS shell and the P2VP core as cross-linking dominated over photolysis in the presence of nitrogen. The enhancement of the SLD contrast was due to the various degrees of cross-linking under UVIN for the PS and P2VP blocks. PMID- 26251977 TI - The PA profession and substance use disorder. PMID- 26251978 TI - Systemic lupus erythematosus: an update on treat-to-target. AB - Systemic lupus erythematosus involves many organ systems, and its vague and multisystem manifestations make early diagnosis and treatment difficult. However, early diagnosis and treatment offer the best chance of reducing end-organ damage and achieving remission. This article describes a new strategy called treat-to target that may help patients achieve remission. PMID- 26251979 TI - Care transitions in a changing healthcare environment. AB - Readmissions are a significant element in the ongoing healthcare debate, and new evidence suggests that high readmissions can be a surrogate marker for poor quality healthcare. Additionally, although readmissions can offer a financial incentive for some hospitals, that model is being phased out; readmissions in a pay-for-performance or bundled payment model represent significant financial risk for providers and hospitals. Although no specific strategy at discharge has proven to be effective in reducing readmissions, practices that include good posthospital communication to the patient and care team, access to follow-up, and attention to mobility and self-care deficits are important factors in limiting readmissions. PAs play a key role in assessing for high readmission risk and implementing prevention strategies in real time. PMID- 26251980 TI - Adolescents and web porn: a new era of sexuality. AB - BACKGROUND: Pornography can affect the lifestyles of adolescents, especially in terms of their sexual habits and porn consumption, and may have a significant influence on their sexual attitudes and behaviors. OBJECTIVE: The aim of this study was to understand and analyze the frequency, duration, and perception of web porn utilization by young Italians attending high school. MATERIALS AND METHODS: A total of 1565 students attending the final year of high school were involved in the study, and 1492 have agreed to fill out an anonymous survey. The questions representing the content of this study were: 1) How often do you access the web? 2) How much time do you remain connected? 3) Do you connect to pornographic sites? 4) How often do you access pornographic sites? 5) How much time you spend on them? 6) How often do you masturbate? and 7) How do you rate the attendance of these sites? Statistical analysis was performed by Fischer's test. RESULTS: All young people, on an almost daily basis, have access to Internet. Among those surveyed, 1163 (77.9%) of Internet users admit to the consumption of pornographic material, and of these, 93 (8%) access pornographic websites daily, 686 (59%) boys accessing these sites perceive the consumption of pornography as always stimulating, 255 (21.9%) define it as habitual, 116 (10%) report that it reduces sexual interest towards potential real-life partners, and the remaining 106 (9.1%) report a kind of addiction. In addition, 19% of overall pornography consumers report an abnormal sexual response, while the percentage rose to 25.1% among regular consumers. CONCLUSION: It is necessary to educate web users, especially young users, to a safe and responsible use of the Internet and of its contents. Moreover, public education campaigns should be increased in number and frequency to help improve knowledge of Internet-related sexual issues both by adolescents and by parents. PMID- 26251981 TI - Prevalence and correlates of the perpetration of cyberbullying among in-school adolescents in Oyo State, Nigeria. AB - OBJECTIVE: Cyberharassment/cyberbullying is a global problem that has been inadequately investigated in developing countries. In this paper, we present findings on the prevalence and predictors of perpetration of cyberbullying among in-school adolescents in Oyo state, Nigeria. METHODS: A total of 653 students were selected via multi-stage sampling. Information on history of perpetrating harassment via an electronic medium in the 3-month period preceding the survey was obtained. RESULTS: Respondents' mean age was 14.2+/-2.2 years and 51.3% were females. All respondents had personal mobile phones and about half had Internet access. About 40% accessed the Internet every day while about 48% accessed it at least once to several times a week and <5% accessed it about once every 2 weeks. One hundred and fifty-six (23.9%) had harassed someone electronically, 260 (39.8%) had been victimized, and 137 (21.0%) were both victims and perpetrators. Common modes of harassment were via phone calls 99 (63.5%), chat rooms 70 (44.9%), and text messages 60 (38.5%). Students who had been victims of cyberbullying (OR=21.76, 95% CI=12.64-37.47) and those with daily Internet access (OR=2.32, 95% CI=1.28-4.19) had significantly higher Oods of being perpetrators. CONCLUSION: About a quarter of students were perpetrators of cyberbullying, and the correlates of perpetration were history of cyber victimization and daily Internet access. Intervention programs must be instituted for victims as well as frequent users of the Internet to curb the problem in the study area. PMID- 26251982 TI - Dietary habits and sedentary behaviors among health science university students in Bahrain. AB - OBJECTIVE: The aim of this study was to investigate the dietary patterns and sedentary behaviors among university students in Bahrain. MATERIALS AND METHODS: A cross-sectional study was carried out with students of the College of Health Sciences in Bahrain using a self-reported questionnaire. All the students enrolled in this college were included in this study (642 students; 90 males and 552 females). The mean age of the sample was 20.1+/-2.0 years. A pre-tested questionnaire was used to collect information on the students' breakfast intake, snacking, food frequency intake, and sedentary habits. RESULTS: More than 50% of the students did not consume breakfast on a daily basis. A statistically significant difference (p<0.003) was found between males (19%) and females (35%) in relation to the intake of an afternoon snack. There were no significant gender differences regarding frequency of food intake, except for carbonated beverages (p<0.001) and nuts (p<0.047) consumption. Females were more likely than males to spend time watching television, use the Internet, use a mobile phone and sleep; however, the only significant difference found was for Internet use (p<0.003). Being physically active on a daily basis was more prevalent among males (41.6%) than females (16%) (p<0.001). Females (42.9%) were more prone to sleep for less time (<7 h) than males (34.4%)(p<0.08). CONCLUSION: The findings indicated that a high percentage of health science students in Bahrain had unhealthy dietary habits and sedentary behaviors. Thus, an intervention program to promote healthy dietary patterns and lifestyle habits among university students is highly recommended. PMID- 26251983 TI - A pilot project of an online cross-age tutoring program: crescent school virtual learning (vLearning). AB - Traditional classroom teaching is the standard of education. However, there may be some students who feel uncomfortable approaching their teachers and may feel more at ease if they ask for assistance from their peers. There are two types of student-to-student tutoring methods that are supplements to classroom learning: peer tutoring between same-age students and cross-age tutoring between different age children. Cross-age tutoring programs in which the tutor is 2-3 years older than the tutee have been reported to be more effective than those between same age students in promoting student responsibility, empowerment and academic performance. A pilot online cross-age tutoring program was launched in September 2014 at Crescent School. A new website was designed, created and implemented with the permission and regular monitoring of the Student Services faculty for the online program - Crescent School Virtual Learning (vLearning). The program was well received and will undergo evaluation in the future. PMID- 26251984 TI - Prognostic value and characterization of the ovarian cancer-specific antigen CA166-9. AB - COC166-9 is an ovarian cancer-specific monoclonal antibody, and COC166-9-based immunotherapy has been shown to possess killing effects against ovarian cancer cells in vitro and in vivo. However the antigen recognized by COC166-9 (COC166-9 Ag, CA166-9) has not been identified and the clinical significance of CA166-9 expression remains unknown. We found that CA166-9 was positive in 53.1% of ovarian cancer tissues. Expression of CA166-9 was strongly correlated with the cancer recurrence (P<0.001). Patients with positive CA166-9 had substantially shorter overall survival (P=0.026) and disease-free survival (P=0.002). CA166-9 was also shown to be an independent predictive factor for overall survival (HR=2.454, P=0.016) and disease-free survival (HR=2.331, P=0.021). We identified CA166-9 as human immunoglobulin gamma-1 heavy chain constant region (IGHG1). Purified IGHG1 promoted proliferation, migration, and invasion of CA166-9 negative ovarian cancer HOC1A cells, whereas it had minimal effects on the phenotypes of CA166-9-positive ovarian cancer CAOV-3 cells. In addition, overexpression of IGHG1 enhanced migration of ovarian cancer cells. On the contrary, COC166-9 inhibited proliferation, migration, and invasion of CAOV-3 cells, but had no effects on HOC1A cells. Therefore, IGHG1 similarly to CA166-9, could play an important role in ovarian cancer development and may serve as a potential prognostic marker and a therapeutical target for ovarian cancer. PMID- 26251985 TI - The use of navigation systems in naturalistic driving. AB - OBJECTIVE: In this study, we assessed the use of portable navigation systems in everyday driving by applying in-vehicle naturalistic driving. METHOD: Experienced users of navigation systems, 7 females and 14 males, were provided with a specially equipped vehicle for approximately 1 month. Their trips were recorded using 4 cameras, Global Positioning System (GPS) data, and other sensor data. The drivers' navigation system use data were coded from the video recordings, which showed how often and for how long the system was activated and how often and for how long a driver operated the system. RESULTS: The system was activated for 23% of trips, predominantly on longer and unique trips. Analyses of the percentage of time for which the speed limit was exceeded showed no evidence of differences between trips for which the navigation system was used or not used. On trips for which the navigation system was activated, participants spent about 5% of trip time interacting with the device. About 40% of interacting behavior took place in the first 10% of the trip time, and about 35% took place while the car was standing still or moving at a very low speed; that is, 0-10 km/h. CONCLUSION: These results shed light on how and when drivers use navigation systems. They suggest that although drivers regulate their use of such systems to some extent, they often perform risky tasks while driving. PMID- 26251987 TI - Exposure to Rabies in Small Indian Mongooses (Herpestes auropunctatus) from Two Regions in Puerto Rico. AB - The small Indian mongoose (Herpestes auropunctatus) was introduced to several Caribbean Islands to control rat (Rattus spp.) damage to sugarcane plantations. Mongooses failed at suppressing rat populations and are now considered pests throughout most of their introduced range. Importantly, mongooses are rabies reservoirs on several Caribbean Islands. In Puerto Rico, mongooses have been implicated in up to 70% of reported animal rabies cases. There is no rabies vaccination program for wildlife in Puerto Rico, and data on rabies in mongooses are limited. We conducted a serosurvey of mongooses in two different ecologic environments in Puerto Rico: El Yunque National Forest and Cabo Rojo National Wildlife Refuge. We collected 119 serum samples from 112 mongooses, 44 (39.3%) of which were positive for rabies virus-neutralizing antibodies. We also collected oral swabs from 147 mongooses, including 88 from which we also collected serum. No oral swabs were positive for rabies virus RNA. Our data support previous research suggesting rabies virus is circulating within the mongoose population on Puerto Rico. PMID- 26251986 TI - AGE AND REPEATED BIOPSY INFLUENCE ANTEMORTEM PRP(CWD) TESTING IN MULE DEER (ODOCOILEUS HEMIONUS) IN COLORADO, USA. AB - Biopsy of rectal mucosa-associated lymphoid tissue provides a useful, but imperfect, live-animal test for chronic wasting disease (CWD) in mule deer (Odocoileus hemionus). It is difficult and expensive to complete these tests on free-ranging animals, and wildlife health managers will benefit from methods that can accommodate test results of varying quality. To this end, we developed a hierarchical Bayesian model to estimate the probability that an individual is infected based on test results. Our model was estimated with the use of data on 210 adult female mule deer repeatedly tested during 2010-14. The ability to identify infected individuals correctly declined with age and may have been influenced by repeated biopsy. Fewer isolated lymphoid follicles (where PrP(CWD) accumulates) were obtained in biopsies of older deer and the proportion of follicles showing PrP(CWD) was reduced. A deer's genotype in the prion gene (PRNP) also influenced detection. At least five follicles were needed in a biopsy to assure a 95% accurate test in PRNP genotype 225SS deer. PMID- 26251988 TI - Natural Infection of Wild Canids (Cerdocyon thous and Lycalopex gymnocercus) with the Intraendothelial Piroplasm Rangelia vitalii in Southern Brazil. AB - Rangelia vitalii is a piroplasm that infects canines, causing lesions typical of a hemolytic disorder. Two wild canids, a crab-eating fox (Cerdocyon thous) and a Pampas fox (Lycalopex gymnocercus), were presented for necropsy in Setor de Patologia Veterinaria at the Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. On gross examination, both animals had pale mucosae and moderate tick infestation (Amblyomma aureolatum). There was severe splenomegaly, and the liver had a diffusely orange-reddish lobular pattern. The mesenteric lymph nodes were brownish and slightly enlarged. Structures compatible with R. vitalii were observed in the cytoplasm of endothelial cells in the liver, stomach, heart, kidney, lungs, lymph nodes, and bladder. The agent was characterized by PCR and genetic sequencing of liver samples and ticks. We show that parasitism with R. vitalii follows an epidemiologic cycle in which wild canids act as reservoirs. PMID- 26251989 TI - Avian Cholera Causes Marine Bird Mortality in the Bering Sea of Alaska. AB - The first known avian cholera outbreak among wild birds in Alaska occurred during November 2013. Liver, intestinal, and splenic necrosis consistent with avian cholera was noted, and Pasteurella multocida serotype 1 was isolated from liver and lung or spleen in Crested Auklets (Aethia cristatella), Thick-billed Murres (Uria lomvia), Common Eider (Somateria mollissima), Northern Fulmars (Fulmarus glacialis), and gulls (Larus spp.). PMID- 26251990 TI - Fructosamine: An Alternative to Serum Glucose Measurement in White-tailed Deer (Odocoileus virginianus). AB - We determined the relationship between fructosamine and serum glucose in free ranging white-tailed deer (Odocoileus virginianus) harvested during two seasonally stressful periods for deer in coastal North Carolina, US: July 2008 represented the postparturition and lactation period, and March 2009 represented the late winter and pre-green-up period. Serum glucose and fructosamine concentrations were similar between time periods but were uncorrelated within each season. However, when serum glucose was separated into high and low categories based on the median blood glucose score within each time period, we detected statistically significant differences between July and March for serum glucose. Fructosamine was more stable than serum glucose for evaluating the white tailed deer physiologic condition. PMID- 26251991 TI - Lead Exposure Risk from Trash Ingestion by the Endangered California Condor (Gymnogyps californianus). AB - Lead poisoning from ingestion of spent lead ammunition is one of the greatest threats to the recovery of California Condors (Gymnogyps californianus) in the wild. Trash ingestion by condors is well documented, yet the extent that trash presents a lead exposure risk is unknown. We evaluated 1,413 trash items collected from condor nest areas and nestlings in the Transverse Range of Ventura County, California, US, from 2002 to 2008, for their potential as a lead exposure risk to condors. We visually identified 71 items suspected to contain sufficient lead to be of toxicologic concern. These items were leached with weak acid and analyzed for lead. Twenty-seven of the 71 leached items (~2% of the 1,413 items) were "lead containing" based on criteria of a leachate lead concentration >1 MUg/mL, with the majority of these items (22; 81% of the 27 lead items) being ammunition related (e.g., spent bullet casings and jacketed bullets). Only three of the 1,413 items collected were lead containing but were clearly not ammunition related; the other two lead-containing items were unidentified. Our results suggest that trash ingestion of nonammunition items does not pose a significant lead exposure risk to the California Condor population in California. PMID- 26251992 TI - RABIES SURVEILLANCE AMONG BATS IN TENNESSEE, USA, 1996-2010. AB - Rabies virus (RABV) infects multiple bat species in the Americas, and enzootic foci perpetuate in bats principally via intraspecific transmission. In recent years, bats have been implicated in over 90% of human rabies cases in the US. In Tennessee, two human cases of rabies have occurred since 1960: one case in 1994 associated with a tricolored bat (Perimyotis subflavus) RABV variant and another in 2002 associated with the tricolored/silver-haired bat (P. subflavus/Lasionycteris noctivagans) RABV variant. From 1996 to 2010, 2,039 bats were submitted for rabies testing in Tennessee. Among 1,943 bats in satisfactory condition for testing and with a reported diagnostic result, 96% (1,870 of 1,943) were identified to species and 10% (196 of 1,943) were rabid. Big brown (Eptesicus fuscus), tricolored, and eastern red (Lasiurus borealis) bats comprised 77% of testable bat submissions and 84% of rabid bats. For species with five or more submissions during 1996-2010, the highest proportion of rabid bats occurred in hoary (Lasiurus cinereus; 46%), unspecified Myotis spp. (22%), and eastern red (17%) bats. The best model to predict rabid bats included month of submission, exposure history of submission, species, and sex of bat. PMID- 26251993 TI - Ultrasound Strain Relaxation Time Ratio: A Quantitative Marker for the Assessment of Cortical Inflammation/Edema in Renal Allografts. AB - Purpose: To evaluate the ability of ultrasound strain relaxation time ratio to assess cortical inflammation/edema in renal allografts. Materials and Methods: We prospectively assessed renal allograft cortical inflammation/edema in 16 renal transplants using ultrasound elasticity imaging and correlated the findings with kidney biopsy. Strain relaxation times in the renal cortex and reference soft tissue were produced by free-hand compression with the ultrasound transducer and estimated with 2 D speckle tracking. Compression was performed in 3-second compression-relaxation cycles (push for 1 second, constant pressure for 1 second, and release for 1 second). We propose a strain relaxation time ratio (time of cortical strain to return to zero/time of the reference strain return to zero) to assess the relationship of compression-induced time-dependent strain relaxation in the cortex and reference tissue. 16 patients were divided into a group with <= 25 % (n = 8) and a group with > 26 % (n = 8) cortical inflammation/edema based on the Banff score. A t-test was used to examine the difference in the strain relaxation time ratio between the two groups. The diagnostic accuracy, inter rater reliability, and reproducibility of this technique in discriminating between the groups were tested. Results: The strain relaxation time ratio of cortex/reference tissue was significantly higher in patients with > 26 % than in patients with <= 25 % cortical inflammation/edema (1.15 +/- 0.10 vs. 0.91 +/- 0.08, P = 0.0002). The strain relaxation time ratio has high reliability (Pearson correlation coefficient, R2 = 0.93), reproducibility (intraclass correlation coefficient = 0.98, P = 0.000), and accuracy (area under curve = 1) in determining > 26 % renal cortical inflammation/edema. Conclusion: The strain relaxation time ratio of cortex/reference tissue can be used as a quantitative marker for the assessment of cortical inflammation/edema in renal allografts. PMID- 26251994 TI - Transient Elastography to Assess the Cervical Ripening during Pregnancy: A Preliminary Study. AB - Purpose To explore the feasibility of transient elastography (TE) to quantify cervical stiffness changes during normal pregnancy and its spatial variability. Materials and Methods TE was used to quantify the cervical stiffness in four anatomical regions. 42 women between 17 and 43 years of age and at 6 - 41 weeks of gestation were studied. The stiffness was related to gestational age at the time of examination, interval from ultrasound examination to delivery and cervical length to evaluate the potential of TE to assess cervical ripening. In addition, a sensitivity analysis based on Cronbach's alpha coefficient was carried out to assess the concordance between inter/intra-operator measurements. Results There were significant correlations between cervical stiffness measured in the four regions with gestational age and the remaining time for delivery. Results confirm stiffness variability within the cervix. No significant association was found between cervical length and stiffness in the four ROIs. Associations between gestational age and remaining time for delivery with cervical length present weaker correlations than with cervical stiffness. The external part of the cervix was significantly softer than the internal one, and these stiffness values vary significantly in the anterior compared to the posterior cervix. The measurements taken by the same and by two different observers for different regions in the cervix were reliable and reproducible. Conclusion It is feasible to objectively quantify the decrease of cervical stiffness correlated to gestational age. Transient elastography is a valuable promising tool to provide additional information on the process of cervical effacement to that obtained from digital examination and conventional ultrasound. Further studies are needed to assess the feasibility of the technique in obstetric clinical applications, such as prediction of preterm birth or success in labor induction. PMID- 26251995 TI - Comparison of Two High-End Ultrasound Systems for Contrast-Enhanced Ultrasound Quantification of Mural Microvascularity in Crohn's Disease. AB - PURPOSE: To verify the reproducibility of contrast-enhanced ultrasound (CEUS) quantification results of two different high-end ultrasound systems and to evaluate the clinical utility of the method in patients with Crohn's disease (CD). MATERIALS AND METHODS: 18 patients with histologically confirmed CD (36.8 % women, 63.2 % men; mean age 43.7 +/- 14.1 years) and wall segments thicker than 5 mm were recruited. CEUS quantification and conventional ultrasound investigation were performed under standardized settings using Toshiba Aplio500 and Siemens Acuson S3000 high-end ultrasound systems. CEUS was performed at a low mechanical index of 0.1 after bolus application of 4.8 ml of SonoVue((r)) contrast medium. The recorded DICOM clips were quantified using VueBox((r)) (version 4.3) calculating 11 quantitative parameters. Subsequently, CEUS quantification and conventional ultrasound results were analyzed. RESULTS: Correlation of quantitative parameters between the Aplio500 and AcusonS3000 systems for peak enhancement (PE), rise time (RT), wash-in-rate (WiR) and quality of fit (QOF) yielded significance levels of p < 0.05 and p < 0.0001 for wash-in-wash-out area under the curve (WiWoAUC). Spearman rank test showed moderate levels of correlation for PE, RT, WiR and QOF (r = 0.5, 0.49, 0.49 and 0.5 respectively), and high correlation for WiWoAUC (r = 0.89) between the two ultrasound systems. CONCLUSION: Due to multiple uncontrollable affecting factors, the method of CEUS quantification by VueBox in the intestine cannot be recommended for device independent multicenter studies. Therefore we suggest to use identical ultrasound systems and probes as well as to establish adequate reference ROIS, like a AIF ROI. PMID- 26251996 TI - Novel Non-invasive Treatment With High-intensity Focused Ultrasound (HIFU). AB - Ultrasound is not only used for diagnostic purposes but it also can be applied therapeutically so far that nowadays high-intensity focused ultrasound (HIFU) even represents a novel non-invasive treatment modality for various solid tumors. HIFU works by causing selectively deep tissue destruction of target lesions within the body without harming adjacent and overlying structures. In this article, we present an overview on both the mode of action and requirements for a HIFU treatment as well as on the safety and the current status of indications and possible applications with regard to benign and malignant gynecological diseases. Based on numerous studies and original articles, HIFU proved to be an effective and low-risk treatment option particularly for uterine fibroids and adenomyosis, but it also seems to be effective for breast fibroadenomas or even for breast cancer in special cases and other rare entities. PMID- 26251997 TI - Oncolytic adenovirus-mediated mda-7/IL-24 expression suppresses osteosarcoma growth and enhances sensitivity to doxorubicin. AB - Osteosarcoma (OS) is a malignant disease with a high mortality rate and poor response to current chemotherapy. Melanoma differentiation associated gene-7 (Mda7)/interleukin (IL)-24 has been demonstrated to suppress the growth of OS. However, the expression level of Mda7/IL-24 mediated by the current adenoviral vector is limited for effective clinical treatment of OS. In order to solve this issue, an oncolytic adenovirus was employed to express IL-24 (OA-IL-24) in OS cells. Quantitative polymerase chain reaction, immunoblot and ELISA assays verified that OA-IL-24 expressed IL-24 at a higher level than the replication deficient adenoviral vector, Ad-IL24. OA-IL-24 infection led to decreased cell viability and increased apoptosis of OS cells, compared with Ad-IL-24. Animal studies further confirmed the increased anti-tumor activity of OA-IL-24. Notably, OA-IL-24 was also found to sensitize OS cells to doxorubicin. OA-IL-24-induced multiple drug resistance reversion was associated with reduced expression of Pgp and BCRP1, as well as minimized autophagy. Furthermore, restoring Pgp and BCRP1 expression as well as autophagy, was able to rescue the effect of IL-24 on the cytotoxicity of doxorubicin to OS. In conclusion, a method for inducing a high expression of IL-24 in OS was provided. In addition, IL-24 was demonstrated to increase the sensitivity of OS to doxorubicin. PMID- 26251998 TI - PhenomeCentral: a portal for phenotypic and genotypic matchmaking of patients with rare genetic diseases. AB - The discovery of disease-causing mutations typically requires confirmation of the variant or gene in multiple unrelated individuals, and a large number of rare genetic diseases remain unsolved due to difficulty identifying second families. To enable the secure sharing of case records by clinicians and rare disease scientists, we have developed the PhenomeCentral portal (https://phenomecentral.org). Each record includes a phenotypic description and relevant genetic information (exome or candidate genes). PhenomeCentral identifies similar patients in the database based on semantic similarity between clinical features, automatically prioritized genes from whole-exome data, and candidate genes entered by the users, enabling both hypothesis-free and hypothesis-driven matchmaking. Users can then contact other submitters to follow up on promising matches. PhenomeCentral incorporates data for over 1,000 patients with rare genetic diseases, contributed by the FORGE and Care4Rare Canada projects, the US NIH Undiagnosed Diseases Program, the EU Neuromics and ANDDIrare projects, as well as numerous independent clinicians and scientists. Though the majority of these records have associated exome data, most lack a molecular diagnosis. PhenomeCentral has already been used to identify causative mutations for several patients, and its ability to find matching patients and diagnose these diseases will grow with each additional patient that is entered. PMID- 26251999 TI - How Social and Nonsocial Context Affects Stay/Leave Decision-Making: The Influence of Actual and Expected Rewards. AB - This study investigated whether deciding to either stay with or leave a social relationship partner, based on a sequence of collaborative social interactions, is impacted by (1) observed and (2) anticipated gains and losses associated with the collaboration; and, importantly, (3) whether these effects differ between social and nonsocial contexts. In the social context, participants played an iterated collaborative economic game in which they were dependent on the successes and failures of a game partner in order to increase their monetary payoff, and in which they were free to stop collaborating with this partner whenever they chose. In Study 1, we manipulated the actual success rate of partners, and demonstrated that participants decided to stay longer with 'better' partners. In Study 2, we induced prior expectations about specific partners, while keeping the objective performance of all partners equal, and found that participants decided to stay longer with partners whom they expected to be 'better' than others, irrespective of actual performance. Importantly, both Study 1 and 2 included a nonsocial control condition that was probabilistically identical to the social conditions. All findings were replicated in nonsocial context, but results demonstrated that the effect of prior beliefs on stay/leave decision-making was much less pronounced in a social than a nonsocial context. PMID- 26252000 TI - Gentle Mechanical Skin Stimulation Inhibits Micturition Contractions via the Spinal Opioidergic System and by Decreasing Both Ascending and Descending Transmissions of the Micturition Reflex in the Spinal Cord. AB - Recently, we found that gentle mechanical skin stimulation inhibits the micturition reflex in anesthetized rats. However, the central mechanisms underlying this inhibition have not been determined. This study aimed to clarify the central neural mechanisms underlying this inhibitory effect. In urethane anesthetized rats, cutaneous stimuli were applied for 1 min to the skin of the perineum using an elastic polymer roller with a smooth, soft surface. Inhibition of rhythmic micturition contractions by perineal stimulation was abolished by naloxone, an antagonist of opioidergic receptors, administered into the intrathecal space of the lumbosacral spinal cord at doses of 2-20 MUg but was not affected by the same doses of naloxone administered into the subarachnoid space of the cisterna magna. Next, we examined whether perineal rolling stimulation inhibited the descending and ascending limbs of the micturition reflex. Perineal rolling stimulation inhibited bladder contractions induced by electrical stimulation of the pontine micturition center (PMC) or the descending tract of the micturition reflex pathway. It also inhibited the bladder distension-induced increase in the blood flow of the dorsal cord at L5-S1, reflecting the neural activity of this area, as well as pelvic afferent-evoked field potentials in the dorsal commissure at the lumbosacral level; these areas contain long ascending neurons to the PMC. Neuronal activities in this center were also inhibited by the rolling stimulation. These results suggest that the perineal rolling stimulation activates the spinal opioidergic system and inhibits both ascending and descending transmissions of the micturition reflex pathway in the spinal cord. These inhibitions would lead to the shutting down of positive feedback between the bladder and the PMC, resulting in inhibition of the micturition reflex. Based on the central neural mechanisms we show here, gentle perineal stimulation may be applicable to several different types of overactive bladder. PMID- 26252001 TI - The Effects of Different Training Backgrounds on VO2 Responses to All-Out and Supramaximal Constant-Velocity Running Bouts. AB - To investigate the impact of different training backgrounds on pulmonary oxygen uptake (VO2) responses during all-out and supramaximal constant-velocity running exercises, nine sprinters (SPRs) and eight endurance runners (ENDs) performed an incremental test for maximal aerobic velocity (MAV) assessment and two supramaximal running exercises (1-min all-out test and constant-velocity exercise). The VO2 responses were continuously determined during the tests (K4b2, Cosmed, Italy). A mono-exponential function was used to describe the VO2 onset kinetics during constant-velocity test at 110%MAV, while during 1-min all-out test the peak of VO2 (VO2peak), the time to achieve the VO2peak (tVO2peak) and the VO2 decrease at last of the test was determined to characterize the VO2 response. During constant-velocity exercise, ENDs had a faster VO2 kinetics than SPRs (12.7 +/- 3.0 vs. 19.3 +/- 5.6 s; p < 0.001). During the 1-min all-out test, ENDs presented slower tVO2peak than SPRs (40.6 +/- 6.8 and 28.8 +/- 6.4 s, respectively; p = 0.002) and had a similar VO2peak relative to the VO2max (88 +/- 8 and 83 +/- 6%, respectively; p = 0.157). Finally, SPRs was the only group that presented a VO2 decrease in the last half of the test (-1.8 +/- 2.3 and 3.5 +/- 2.3 ml.kg-1.min-1, respectively; p < 0.001). In summary, SPRs have a faster VO2 response when maximum intensity is required and a high maximum intensity during all-out running exercise seems to lead to a higher decrease in VO2 in the last part of the exercise. PMID- 26252002 TI - Interstitial Telomeric Motifs in Squamate Reptiles: When the Exceptions Outnumber the Rule. AB - Telomeres are nucleoprotein complexes protecting the physical ends of linear eukaryotic chromosomes and therefore helping to ensure their stability and integrity. Additionally, telomeric sequences can be localized in non-terminal regions of chromosomes, forming so-called interstitial telomeric sequences (ITSs). ITSs are traditionally considered to be relics of chromosomal rearrangements and thus very informative in the reconstruction of the evolutionary history of karyotype formation. We examined the distribution of the telomeric motifs (TTAGGG)n using fluorescence in situ hybridization (FISH) in 30 species, representing 17 families of squamate reptiles, and compared them with the collected data from another 38 species from literature. Out of the 68 squamate species analyzed, 35 possess ITSs in pericentromeric regions, centromeric regions and/or within chromosome arms. We conclude that the occurrence of ITSs is rather common in squamates, despite their generally conserved karyotypes, suggesting frequent and independent cryptic chromosomal rearrangements in this vertebrate group. PMID- 26252003 TI - Alternative Ultrasound Gel for a Sustainable Ultrasound Program: Application of Human Centered Design. AB - This paper describes design of a low cost, ultrasound gel from local products applying aspects of Human Centered Design methodology. A multidisciplinary team worked with clinicians who use ultrasound where commercial gel is cost prohibitive and scarce. The team followed the format outlined in the Ideo Took Kit. Research began by defining the challenge "how to create locally available alternative ultrasound gel for a low-resourced environment? The "End-Users," were identified as clinicians who use ultrasound in Democratic Republic of the Congo and Ethiopia. An expert group was identified and queried for possible alternatives to commercial gel. Responses included shampoo, oils, water and cornstarch. Cornstarch, while a reasonable solution, was either not available or too expensive. We then sought deeper knowledge of locally sources materials from local experts, market vendors, to develop a similar product. Suggested solutions gleaned from these interviews were collected and used to create ultrasound gel accounting for cost, image quality, manufacturing capability. Initial prototypes used cassava root flour from Great Lakes Region (DRC, Rwanda, Uganda, Tanzania) and West Africa, and bula from Ethiopia. Prototypes were tested in the field and resulting images evaluated by our user group. A final prototype was then selected. Cassava and bula at a 32 part water, 8 part flour and 4 part salt, heated, mixed then cooled was the product design of choice. PMID- 26252004 TI - What's a Weed? Knowledge, Attitude and Behaviour of Park Visitors about Weeds. AB - Weeds are a major threat to biodiversity globally degrading natural areas of high conservation value. But what are our attitudes about weeds and their management including weeds in national parks? Do we know what a weed is? Do we consider weeds a problem? Do we support their management? Are we unintentionally spreading weeds in parks? To answer these questions, we surveyed visitors entering a large popular national park near the city of Brisbane, Australia. Park visitors were knowledgeable about weeds; with >75% correctly defining weeds as 'plants that grow where they are not wanted'. About 10% of the visitors, however, provided their own sophisticated definitions. This capacity to define weeds did not vary with people's age, sex or level of education. We constructed a scale measuring visitors' overall concern about weeds in parks using the responses to ten Likert scale statements. Over 85% of visitors were concerned about weeds with older visitors, hikers, and those who could correctly define weeds more concerned than their counterparts. The majority think visitors unintentionally introduce seeds into parks, with many (63%) having found seeds on their own clothing. However, over a third disposed of these seeds in ways that could facilitate weed spread. Therefore, although most visitors were knowledgeable and concerned about weeds, and support their control, there is a clear need for more effective communication regarding the risk of visitors unintentionally dispersing weed seeds in parks. PMID- 26252006 TI - Correction: Causality Analysis: Identifying the Leading Element in a Coupled Dynamical System. PMID- 26252005 TI - Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis. AB - Cryptococcus neoformans is the most common cause of fungal meningoencephalitis in AIDS patients. Depletion of CD4 cells, such as occurs during advanced AIDS, is known to be a critical risk factor for developing cryptococcosis. However, the role of HIV-induced innate inflammation in susceptibility to cryptococcosis has not been evaluated. Thus, we sought to determine the role of Type I IFN induction in host defense against cryptococci by treatment of C. neoformans (H99) infected mice with poly-ICLC (pICLC), a dsRNA virus mimic. Unexpectedly, pICLC treatment greatly extended survival of infected mice and reduced fungal burdens in the brain. Protection from cryptococcosis by pICLC-induced Type I IFN was mediated by MDA5 rather than TLR3. PICLC treatment induced a large, rapid and sustained influx of neutrophils and Ly6Chigh monocytes into the lung while suppressing the development of eosinophilia. The pICLC-mediated protection against H99 was CD4 T cell dependent and analysis of CD4 T cell polyfunctionality showed a reduction in IL-5 producing CD4 T cells, marginal increases in Th1 cells and dramatic increases in RORgammat+ Th17 cells in pICLC treated mice. Moreover, the protective effect of pICLC against H99 was diminished in IFNgamma KO mice and by IL-17A neutralization with blocking mAbs. Furthermore, pICLC treatment also significantly extended survival of C. gattii infected mice with reduced fungal loads in the lungs. These data demonstrate that induction of type I IFN dramatically improves host resistance against the etiologic agents of cryptococcosis by beneficial alterations in both innate and adaptive immune responses. PMID- 26252007 TI - The Prion Protein N1 and N2 Cleavage Fragments Bind to Phosphatidylserine and Phosphatidic Acid; Relevance to Stress-Protection Responses. AB - Internal cleavage of the cellular prion protein generates two well characterised N-terminal fragments, N1 and N2. These fragments have been shown to bind to anionic phospholipids at low pH. We sought to investigate binding with other lipid moieties and queried how such interactions could be relevant to the cellular functions of these fragments. Both N1 and N2 bound phosphatidylserine (PS), as previously reported, and a further interaction with phosphatidic acid (PA) was also identified. The specificity of this interaction required the N terminus, especially the proline motif within the basic amino acids at the N terminus, together with the copper-binding region (unrelated to copper saturation). Previously, the fragments have been shown to be protective against cellular stresses. In the current study, serum deprivation was used to induce changes in the cellular lipid environment, including externalisation of plasma membrane PS and increased cellular levels of PA. When copper-saturated, N2 could reverse these changes, but N1 could not, suggesting that direct binding of N2 to cellular lipids may be part of the mechanism by which this peptide signals its protective response. PMID- 26252008 TI - Efficacy and Safety of Antidepressants for the Treatment of Irritable Bowel Syndrome: A Meta-Analysis. AB - AIM: The aim of this meta-analysis was to analyze the efficacy and safety of antidepressants for the treatment of irritable bowel syndrome. METHODS: We searched MEDLINE, EMBASE, Scopus and The Cochrane Library for randomized controlled trials investigating the efficacy and safety of antidepressants in the treatment of irritable bowel syndrome. Article quality was evaluated by Jadad score. RevMan 5.0 and Stata 12.0 were used for the meta-analysis. RESULTS: Twelve randomized controlled trials were included in this study and most of these trials were of high quality (Jadad score >=4). Five articles focused on tricyclic antidepressants, six articles involved selective serotonin reuptake inhibitors, and one article investigated both types of treatment. The pooled risk ratio showed antidepressant treatment can improve global symptoms (RR = 1.38, 95% CI 1.08, 1.77). In the subgroup analysis, treatment with tricyclic antidepressants showed an improvement in global symptoms (RR = 1.36, 95% CI 1.07, 1.71), while treatment with selective serotonin reuptake inhibitors showed no statistically significant difference in global symptoms compared with the control groups (RR = 1.38, 95% CI 0.83, 2.28). The pooled risk ratio of dropout due to side effects following antidepressant treatment was 1.71 with 95% CI (0.98, 2.99). The subgroup analysis showed the pooled risk ratio of dropout in the tricyclic antidepressants group was 1.92 with 95% CI (0.89, 4.17). In the selective serotonin reuptake inhibitors group, the pooled risk ratio of dropout was 1.5 with 95% CI (0.67, 3.37). Selective serotonin reuptake inhibitors showed no benefit in alleviating abdominal pain and improving quality of life. There was no difference in the incidence of common adverse events between treatment and control groups. CONCLUSIONS: TCAs can improve global symptoms of irritable bowel syndrome, while there was no strong evidence to confirm the effectiveness of SSRIs for the treatment of IBS. PMID- 26252009 TI - Embelin-Induced Apoptosis of Human Prostate Cancer Cells Is Mediated through Modulation of Akt and beta-Catenin Signaling. AB - There is increasing evidence that embelin, an active component of Embelia ribes, induces apoptosis in human cancer cells, but the detailed mechanisms are still unclear. Here, we have investigated the effect of embelin on the growth of human prostate cancer cells. Embelin strongly inhibited cell growth especially in human prostate cancer cell lines, including PC3, DU145, LNCaP-LN3 and normal prostate epithelial cell, RWPE-1 compared to breast cancer (MDA-MB-231, MCF-7, and T47D), hepatoma (HepG2, Hep3B, and HuH-7), or choriocarcinoma (JEG-3). We observed that embelin induced apoptosis of PC3 cells in a time-dependent manner correlated with decreased expression of Bcl-2, Bcl-xL, and Mcl-1, increased translocation of Bax into mitochondria, and a reduction in the mitochondrial membrane potential. Furthermore, embelin induced voltage-dependent anion channel (VDAC) 1 expression and oligomerization, which may promote cytochrome c and AIF release. Because embelin was able to inhibit Akt activation and cyclooxygenase-2 expression, the effects on Wnt/ beta-catenin signaling were determined. Embelin activated glycogen synthase kinase (GSK)-3beta by preventing phosphorylation and suppressed beta-catenin expression. Attenuation of beta-catenin-mediated TCF transcriptional activity and gene transcription, such as cyclin D1, c-myc, and matrix metalloproteinase (MMP)-7, were shown in embelin-treated cells. The changes in beta-catenin levels in response to embelin were blocked by lithium chloride, a GSK-3 inhibitor, indicating that embelin may decrease beta-catenin expression via GSK-3beta activation. Furthermore, exposure of PC3 cells to embelin resulted in a significant decrease in cell migration and invasion. In conclusion, these findings suggest that inhibition of Akt signaling and activation of GSK-3beta partially contributes to the pro-apoptotic effect of embelin in prostate cancer cells. PMID- 26252010 TI - Antagonistic Interplay between MicroRNA-155 and IL-10 during Lyme Carditis and Arthritis. AB - MicroRNA-155 has been shown to play a role in immune activation and inflammation, and is suppressed by IL-10, an important anti-inflammatory cytokine. The established involvement of IL-10 in the murine model of Borrelia burgdorferi induced Lyme arthritis and carditis allowed us to assess the interplay between IL 10 and miR-155 in vivo. As reported previously, Mir155 was highly upregulated in joints from infected severely arthritic B6 Il10-/- mice, but not in mildly arthritic B6 mice. In infected hearts, Mir155 was upregulated in both strains, suggesting a role of miR-155 in Lyme carditis. Using B. burgdorferi-infected B6, Mir155-/-, Il10-/-, and Mir155-/- Il10-/- double-knockout (DKO) mice, we found that anti-inflammatory IL-10 and pro-inflammatory miR-155 have opposite and somewhat compensatory effects on myeloid cell activity, cytokine production, and antibody response. Both IL-10 and miR-155 were required for suppression of Lyme carditis. Infected Mir155-/- mice developed moderate/severe carditis, had higher B. burgdorferi numbers, and had reduced Th1 cytokine expression in hearts. In contrast, while Il10-/- and DKO mice also developed severe carditis, hearts had reduced bacterial numbers and elevated Th1 and innate cytokine expression. Surprisingly, miR-155 had little effect on Lyme arthritis. These results show that antagonistic interplay between IL-10 and miR-155 is required to balance host defense and immune activation in vivo, and this balance is particularly important for suppression of Lyme carditis. These results also highlight tissue-specific differences in Lyme arthritis and carditis pathogenesis, and reveal the importance of IL-10-mediated regulation of miR-155 in maintaining healthy immunity. PMID- 26252011 TI - Seroprevalence of Herpes Simplex Virus Type 1 and 2 in Taiwan and Risk Factor Analysis, 2007. AB - BACKGROUND: Herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) are common human pathogens and might cause severe illness. Following primary infection, the viruses establish lifelong latent infection and are transmitted by close contact, both sexual and nonsexual. However, the information about the seroprevalence of HSV-1 and HSV-2 across all age groups is limited. METHODS: Residual sera collected during the nationwide serosurvey in 2007 in Taiwan were selected for the study. The enzyme-linked immunosorbent assay was used to detect anti-HSV-1 and anti-HSV-2 type-specific glycoprotein IgG. Demographics and personal health data were used for risk analysis. RESULTS: A total of 1411 and 1072 serum samples were included for anti-HSV-1 and anti-HSV-2 seroprevalence analysis, respectively. The weighted overall seroprevalence was 63.2% for HSV-1, and 7.7% for HSV-2, respectively. The HSV-1 seropositive rate was 19.2% for those less than 5 years old, increased to 46.4% for those aged 5-13 years, 60.9% for those aged 14-29 years, and reached as much as 95.0% for those aged over 30 years. In contrast, the HSV-2 seropositve rate was 1.6% for those less than 30 years old, rose to 10.1% for those age 30-39 years, and was up to 31.2% for those aged over 60 years. A significantly higher HSV-2 seropositive rate was noted in females than males aged over 40 years (26.3% v.s. 16.8%), and the overall HSV-2 seropositive rate was almost twice higher in females than males. Smoking history, drinking habit, and educational level were associated with the HSV-1 seropositivity. Female gender and rural residence were independent factors for the HSV-2 seropositivity. CONCLUSIONS: An obvious increase of primary HSV-1 infection occurred in late adolescents and young adults, joined by the rise of HSV-2 infection in middle-aged adults, especially females. The acquistion and transmission of HSV warrant further studies in the susceptible population. PMID- 26252013 TI - Educational Inequalities in Exit from Paid Employment among Dutch Workers: The Influence of Health, Lifestyle and Work. AB - BACKGROUND: Individuals with lower socioeconomic status are at increased risk of involuntary exit from paid employment. To give sound advice for primary prevention in the workforce, insight is needed into the role of mediating factors between socioeconomic status and labour force participation. Therefore, it is aimed to investigate the influence of health status, lifestyle-related factors and work characteristics on educational differences in exit from paid employment. METHODS: 14,708 Dutch employees participated in a ten-year follow-up study during 1999-2008. At baseline, education, self-perceived health, lifestyle (smoking, alcohol, sports, BMI) and psychosocial (demands, control, rewards) and physical work characteristics were measured by questionnaire. Employment status was ascertained monthly based on tax records. The relation between education, health, lifestyle, work-characteristics and exit from paid employment through disability benefits, unemployment, early retirement and economic inactivity was investigated by competing risks regression analyses. The mediating effects of these factors on educational differences in exit from paid employment were tested using a stepwise approach. RESULTS: Lower educated workers were more likely to exit paid employment through disability benefits (SHR:1.84), unemployment (SHR:1.74), and economic inactivity (SHR:1.53) but not due to early retirement (SHR:0.92). Poor or moderate health, an unhealthy lifestyle, and unfavourable work characteristics were associated with disability benefits and unemployment, and an unhealthy lifestyle with economic inactivity. Educational differences in disability benefits were explained for 40% by health, 31% by lifestyle, and 12% by work characteristics. For economic inactivity and unemployment, up to 14% and 21% of the educational differences could be explained, particularly by lifestyle-related factors. CONCLUSIONS: There are educational differences in exit from paid employment, which are partly mediated by health, lifestyle and work characteristics, particularly for disability benefits. Health promotion and improving working conditions seem important measures to maintain a productive workforce, particularly among workers with a low education. PMID- 26252012 TI - Anti-Retroviral Lectins Have Modest Effects on Adherence of Trichomonas vaginalis to Epithelial Cells In Vitro and on Recovery of Tritrichomonas foetus in a Mouse Vaginal Model. AB - Trichomonas vaginalis causes vaginitis and increases the risk of HIV transmission by heterosexual sex, while Tritrichomonas foetus causes premature abortion in cattle. Our goals were to determine the effects, if any, of anti-retroviral lectins, which are designed to prevent heterosexual transmission of HIV, on adherence of Trichomonas to ectocervical cells and on Tritrichomonas infections in a mouse model. We show that Trichomonas Asn-linked glycans (N-glycans), like those of HIV, bind the mannose-binding lectin (MBL) that is part of the innate immune system. N-glycans of Trichomonas and Tritrichomonas bind anti-retroviral lectins (cyanovirin-N and griffithsin) and the 2G12 monoclonal antibody, each of which binds HIV N-glycans. Binding of cyanovirin-N appears to be independent of susceptibility to metronidazole, the major drug used to treat Trichomonas. Anti retroviral lectins, MBL, and galectin-1 cause Trichomonas to self-aggregate and precipitate. The anti-retroviral lectins also increase adherence of ricin resistant mutants, which are less adherent than parent cells, to ectocervical cell monolayers and to organotypic EpiVaginal tissue cells. Topical application of either anti-retroviral lectins or yeast N-glycans decreases by 40 to 70% the recovery of Tritrichomonas from the mouse vagina. These results, which are explained by a few simple models, suggest that the anti-retroviral lectins have a modest potential for preventing or treating human infections with Trichomonas. PMID- 26252014 TI - Alpha-Particle-Induced Complex Chromosome Exchanges Transmitted through Extra Thymic Lymphopoiesis In Vitro Show Evidence of Emerging Genomic Instability. AB - Human exposure to high-linear energy transfer alpha-particles includes environmental (e.g. radon gas and its decay progeny), medical (e.g. radiopharmaceuticals) and occupational (nuclear industry) sources. The associated health risks of alpha-particle exposure for lung cancer are well documented however the risk estimates for leukaemia remain uncertain. To further our understanding of alpha-particle effects in target cells for leukaemogenesis and also to seek general markers of individual exposure to alpha-particles, this study assessed the transmission of chromosomal damage initially-induced in human haemopoietic stem and progenitor cells after exposure to high-LET alpha particles. Cells surviving exposure were differentiated into mature T-cells by extra-thymic T-cell differentiation in vitro. Multiplex fluorescence in situ hybridisation (M-FISH) analysis of naive T-cell populations showed the occurrence of stable (clonal) complex chromosome aberrations consistent with those that are characteristically induced in spherical cells by the traversal of a single alpha particle track. Additionally, complex chromosome exchanges were observed in the progeny of irradiated mature T-cell populations. In addition to this, newly arising de novo chromosome aberrations were detected in cells which possessed clonal markers of alpha-particle exposure and also in cells which did not show any evidence of previous exposure, suggesting ongoing genomic instability in these populations. Our findings support the usefulness and reliability of employing complex chromosome exchanges as indicators of past or ongoing exposure to high-LET radiation and demonstrate the potential applicability to evaluate health risks associated with alpha-particle exposure. PMID- 26252015 TI - Three-Dimensional Evaluation of the Upper Airway Morphological Changes in Growing Patients with Skeletal Class III Malocclusion Treated by Protraction Headgear and Rapid Palatal Expansion: A Comparative Research. AB - OBJECTIVE: The aim of this study was to evaluate the morphological changes of upper airway after protraction headgear and rapid maxillary expansion (PE) treatment in growing patients with Class III malocclusion and maxillary skeletal deficiency compared with untreated Class III patients by cone-beam computed tomography (CBCT). METHODS: Thirty growing patients who have completed PE therapy were included in PE group. The control group (n = 30) was selected from the growing untreated patients with the same diagnosis. The CBCT scans of the pre treatment (T1) and post-treatment (T2) of PE group and the control group were collected. Reconstruction and registration of the 3D models of T1 and T2 were completed. By comparing the data obtained from T1, T2 and control group, the morphological changes of the upper airway during the PE treatment were evaluated. RESULTS: Comparing with the data from T1 group, the subspinale (A) of maxilla and the upper incisor (UI) of the T2 group were moved in the anterior direction. The gnathion (Gn) of mandible was moved in the posterior-inferior direction. The displacement of the hyoid bone as well as the length and width of dental arch showed significant difference. The volume and mean cross-sectional area of nasopharynx, velopharynx and glossopharynx region showed significant difference. The largest anteroposterior/the largest lateral (AP/LR) ratios of the velopharynx and glossopharynx were increased, but the AP/LR ratio of the hypopharynx was decreased. In addition, the length and width of the maxillary dental arch, the displacement of the hyoid bone, the volume of nasopharynx and velopharynx, and the AP/LR ratio of the hypopharynx and velopharynx showed significant difference between the data from control and T2 group. CONCLUSION: The PE treatment of Class III malocclusion with maxillary skeletal hypoplasia leads to a significant increase in the volume of nasopharynx and velopharynx. PMID- 26252016 TI - Centripetal Acceleration Reaction: An Effective and Robust Mechanism for Flapping Flight in Insects. AB - Despite intense study by physicists and biologists, we do not fully understand the unsteady aerodynamics that relate insect wing morphology and kinematics to lift generation. Here, we formulate a force partitioning method (FPM) and implement it within a computational fluid dynamic model to provide an unambiguous and physically insightful division of aerodynamic force into components associated with wing kinematics, vorticity, and viscosity. Application of the FPM to hawkmoth and fruit fly flight shows that the leading-edge vortex is the dominant mechanism for lift generation for both these insects and contributes between 72-85% of the net lift. However, there is another, previously unidentified mechanism, the centripetal acceleration reaction, which generates up to 17% of the net lift. The centripetal acceleration reaction is similar to the classical inviscid added-mass in that it depends only on the kinematics (i.e. accelerations) of the body, but is different in that it requires the satisfaction of the no-slip condition, and a combination of tangential motion and rotation of the wing surface. Furthermore, the classical added-mass force is identically zero for cyclic motion but this is not true of the centripetal acceleration reaction. Furthermore, unlike the lift due to vorticity, centripetal acceleration reaction lift is insensitive to Reynolds number and to environmental flow perturbations, making it an important contributor to insect flight stability and miniaturization. This force mechanism also has broad implications for flow induced deformation and vibration, underwater locomotion and flows involving bubbles and droplets. PMID- 26252017 TI - Reduced Nav1.6 Sodium Channel Activity in Mice Increases In Vivo Sensitivity to Volatile Anesthetics. AB - Nav1.6 is a major voltage-gated sodium channel in the central and peripheral nervous systems. Within neurons, the channel protein is concentrated at the axon initial segment and nodes of Ranvier, where it functions in initiation and propagation of action potentials. We examined the role of Nav1.6 in general anesthesia using two mouse mutants with reduced activity of Nav1.6, Scn8amedJ/medJ and Scn8a9J/9J. The mice were exposed to the general anesthetics isoflurane and sevoflurane in step-wise increments; the concentration required to produce loss of righting reflex, a surrogate for anesthetic-induced unconsciousness in rodents, was determined. Mice homozygous for these mutations exhibited increased sensitivity to both isoflurane and sevoflurane. The increased sensitivity was observed during induction of unconsciousness but not during the recovery phase, suggesting that the effect is not attributable to compromised systemic physiology. Electroencephalographic theta power during baseline waking was lower in mutants, suggesting decreased arousal and reduced neuronal excitability. This is the first report linking reduced activity of a specific voltage-gated sodium channel to increased sensitivity to general anesthetics in vivo. PMID- 26252018 TI - More Cercospora Species Infect Soybeans across the Americas than Meets the Eye. AB - Diseases of soybean caused by Cercospora spp. are endemic throughout the world's soybean production regions. Species diversity in the genus Cercospora has been underestimated due to overdependence on morphological characteristics, symptoms, and host associations. Currently, only two species (Cercospora kikuchii and C. sojina) are recognized to infect soybean; C. kikuchii causes Cercospora leaf blight (CLB) and purple seed stain (PSS), whereas C. sojina causes frogeye leaf spot. To assess cryptic speciation among pathogens causing CLB and PSS, phylogenetic and phylogeographic analyses were performed with isolates from the top three soybean producing countries (USA, Brazil, and Argentina; collectively accounting for ~80% of global production). Eight nuclear genes and one mitochondrial gene were partially sequenced and analyzed. Additionally, amino acid substitutions conferring fungicide resistance were surveyed, and the production of cercosporin (a polyketide toxin produced by many Cercospora spp.) was assessed. From these analyses, the long-held assumption of C. kikuchii as the single causal agent of CLB and PSS was rejected experimentally. Four cercosporin producing lineages were uncovered with origins (about 1 Mya) predicted to predate agriculture. Some of the Cercospora spp. newly associated with CLB and PSS appear to represent undescribed species; others were not previously reported to infect soybeans. Lineage 1, which contained the ex-type strain of C. kikuchii, was monophyletic and occurred in Argentina and Brazil. In contrast, lineages 2 and 3 were polyphyletic and contained wide-host range species complexes. Lineage 4 was monophyletic, thrived in Argentina and the USA, and included the generalist Cercospora cf. flagellaris. Interlineage recombination was detected, along with a high frequency of mutations linked to fungicide resistance in lineages 2 and 3. These findings point to cryptic Cercospora species as underappreciated global considerations for soybean production and phytosanitary vigilance, and urge a reassessment of host-specificity as a diagnostic tool for Cercospora. PMID- 26252019 TI - Components of Attention in Grapheme-Color Synesthesia: A Modeling Approach. AB - Grapheme-color synesthesia is a condition where the perception of graphemes consistently and automatically evokes an experience of non-physical color. Many have studied how synesthesia affects the processing of achromatic graphemes, but less is known about the synesthetic processing of physically colored graphemes. Here, we investigated how the visual processing of colored letters is affected by the congruence or incongruence of synesthetic grapheme-color associations. We briefly presented graphemes (10-150 ms) to 9 grapheme-color synesthetes and to 9 control observers. Their task was to report as many letters (targets) as possible, while ignoring digit (distractors). Graphemes were either congruently or incongruently colored with the synesthetes' reported grapheme-color association. A mathematical model, based on Bundesen's (1990) Theory of Visual Attention (TVA), was fitted to each observer's data, allowing us to estimate discrete components of visual attention. The models suggested that the synesthetes processed congruent letters faster than incongruent ones, and that they were able to retain more congruent letters in visual short-term memory, while the control group's model parameters were not significantly affected by congruence. The increase in processing speed, when synesthetes process congruent letters, suggests that synesthesia affects the processing of letters at a perceptual level. To account for the benefit in processing speed, we propose that synesthetic associations become integrated into the categories of graphemes, and that letter colors are considered as evidence for making certain perceptual categorizations in the visual system. We also propose that enhanced visual short term memory capacity for congruently colored graphemes can be explained by the synesthetes' expertise regarding their specific grapheme-color associations. PMID- 26252020 TI - Knowledge-Based Analysis for Detecting Key Signaling Events from Time-Series Phosphoproteomics Data. AB - Cell signaling underlies transcription/epigenetic control of a vast majority of cell-fate decisions. A key goal in cell signaling studies is to identify the set of kinases that underlie key signaling events. In a typical phosphoproteomics study, phosphorylation sites (substrates) of active kinases are quantified proteome-wide. By analyzing the activities of phosphorylation sites over a time course, the temporal dynamics of signaling cascades can be elucidated. Since many substrates of a given kinase have similar temporal kinetics, clustering phosphorylation sites into distinctive clusters can facilitate identification of their respective kinases. Here we present a knowledge-based CLUster Evaluation (CLUE) approach for identifying the most informative partitioning of a given temporal phosphoproteomics data. Our approach utilizes prior knowledge, annotated kinase-substrate relationships mined from literature and curated databases, to first generate biologically meaningful partitioning of the phosphorylation sites and then determine key kinases associated with each cluster. We demonstrate the utility of the proposed approach on two time-series phosphoproteomics datasets and identify key kinases associated with human embryonic stem cell differentiation and insulin signaling pathway. The proposed approach will be a valuable resource in the identification and characterizing of signaling networks from phosphoproteomics data. PMID- 26252022 TI - MiR-214 promotes osteosarcoma tumor growth and metastasis by decreasing the expression of PTEN. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs, which function as critical gene regulators by targeting mRNAs for translational repression or degradation, and they are essential in cancer development and progression. Several previous studies have indicated that abnormal expression of miRNAs occurs frequently in human osteosarcoma (OS) tissues compared with that of adjacent normal tissues. In the present study, the role of miR-214 in the progression and metastasis of OS was investigated. The expression of miR-214 was frequently increased in OS tissues and cell lines. Inhibition of miR-214 in OS cell lines markedly suppressed cell proliferation, migration and invasion. Phosphatase and tensin homolog (PTEN) was identified as a direct target of miR-214, and ectopic expression of miR-214 inhibited PTEN by directly binding to its 3'-untranslated region. The expression of miR-214 negatively correlated with PTEN in OS tissues. Together, these data indicated that miR-214 acts as an oncogenic miRNA and may contribute to the progression, and metastasis of OS, suggesting that miR-214 may be a potential novel diagnostic and therapeutic target of OS. PMID- 26252023 TI - A New Crystal Structure of Au36 with a Au14 Kernel Cocapped by Thiolate and Chloride. AB - This study presents a new crystal structure of a gold nanocluster coprotected by thiolate and chloride, with the formula of Au36(SCH2Ph-(t)Bu)8Cl20. This nanocluster is composed of a Au14 core with two Cl atoms, a pair of pentameric Au5(SCl5) staple motifs, and a pair of hexameric Au6(S3Cl4) motifs. It is noteworthy that the "Au-Cl-Au" staple motifs are observed for the first time in thiolate protected gold nanoclusters. More importantly, the formation of the Cl Au3 motifs is found to be mainly responsible for the configuration of the gold nanocluster. This work will offer a new perspective to understand how the ligands affect the crystal structure of gold nanocluster. PMID- 26252021 TI - Bortezomib Plus Continuous B Cell Depletion Results in Sustained Plasma Cell Depletion and Amelioration of Lupus Nephritis in NZB/W F1 Mice. AB - METHODS: NZB/W F1 mice were treated with: 1) anti-CD20, 2) anti-CD20 plus bortezomib, 3) anti-CD20 plus anti-LFA-1/anti-VLA-4 blocking antibodies, 4) anti CD20 plus bortezomib and anti-LFA-1/anti-VLA4 blocking antibodies. Short- and long-lived plasma cells including autoreactive cells in the bone marrow and spleen were enumerated by flow cytometry and ELISPOT seven days after treatment. Based on these data in another experiment, mice received one cycle of anti-CD20 plus bortezomib followed by four cycles of anti-CD20 therapy every 10 days and were monitored for its effect on plasma cells and disease. RESULTS: Short-lived plasma cells in bone marrow and spleen were efficiently depleted by all regimens targeting plasma cells. Conversely, LLPCs and anti-dsDNA-secreting plasma cells in bone marrow and spleen showed resistance to depletion and were strongly reduced by bortezomib plus anti-CD20. The effective depletion of plasma cells by bortezomib complemented by the continuous depletion of their precursor B cells using anti-CD20 promoted the persistent reduction of IgG anti-dsDNA antibodies, delayed nephritis and prolonged survival in NZB/W F1 mice. CONCLUSIONS: These findings suggest that the effective depletion of LLPCs using bortezomib in combination with a therapy that continuously targeting B cells as their precursors may prevent the regeneration of autoreactive LLPCs and, thus, might represent a promising treatment strategy for SLE and other (auto)antibody mediated diseases. PMID- 26252024 TI - MicroRNA-144 affects radiotherapy sensitivity by promoting proliferation, migration and invasion of breast cancer cells. AB - Radiotherapy resistance remains a major obstacle for patients with breast cancer. miRNAs are important regulators in many biological processes including proliferation, apoptosis, invasion and metastasis and response to treatment in different types of tumors. Here, we describe the role of miRNA-144 in the regulation of radiotherapy sensitivity, migration and invasion of breast cancer cells. The cell survival rate of breast cancer cells was measured by WST-1 assay after irradiation. The caspase-3/-7 activity and apoptotic proteins were analyzed by Caspase-Glo3/7 assay and western blot analysis, respectively. The migration and invasion of breast cancer cells were evaluated by BD Transwell migration and Matrigel invasion assays. The EMT markers were detected by western blot analysis. We found that overexpression of miR-144 increased the proliferation rate of MDA MB-231 cells without radiation. Both MDA-MB-231 and SKBR3 cells exhibited significantly increased radiation resistance after overexpression of miR-144. Meanwhile, the migration and invasion of both MDA-MB-231 and SKBR3 cells were changed by altered miR-144 expression. In addition, the overexpression of miR-144 inhibited E-cadherin expression and promoted Snail expression. miR-144 activated AKT by downregulation of PTEN in breast cancer cells. Our results strongly suggest that miR-144 acts as an important regulator of tumorigenesis and tumor progression of breast cancer. These results indicate that miR-144 might serve as a potential molecular target for breast cancer treatment. PMID- 26252025 TI - An Up-to-15-Year Comparison of the Survival and Complication Burden of Three-Unit Tooth-Supported Fixed Dental Prostheses and Implant-Supported Single Crowns. AB - PURPOSE: To assess and compare the outcomes and economic complication burden of three-unit tooth-supported fixed dental prostheses (TFDPs) and implant-supported single crowns (ISCs) provided to a sequential cohort in a specialist prosthodontic practice over a 15-year period. MATERIALS AND METHODS: Sequential patients requiring replacement of a single missing tooth between 1996 and 2010 with a metal-ceramic three-unit TFDP (n = 145 patients, n = 174 prostheses) or ISC (n = 174 patients, n = 220 prostheses) were included. Prostheses subjectively judged at insertion to have an unfavorable 10-year prognosis (17 TFDPs, 0 ISCs) were removed from statistical analyses. The estimated cumulative survival (ECS) was calculated with the life table actuarial method and standard errors calculated with the Greenwood formula. Differences in outcomes between all prostheses and those replacing only anterior or only posterior teeth were assessed with the log rank test. Complication incidence, severity, and economic burden, measured in time/cost accounting units (TAUs), were tallied and compared descriptively. RESULTS: The 15-year ECS did not differ for 112 TFDPs (92.75% +/- 3.28%) and 81 ISCs (95.95% +/- 2.92%) replacing posterior teeth. However, the 15 year ECS was significantly greater for 139 ISCs (93.33% +/- 6.44%) than for 45 TFDPs (82.82% +/- 6.50%) replacing anterior teeth. The economic burden of nonterminal complications for both prostheses was low (mean = 0.3 and 0.2 TAUs per prosthesis for TFDPs and ISCs, respectively). This equated to 3 TAUs/100 years in clinical service and 4 TAUs/100 years in clinical service for the TFDPs and ISCs, respectively. CONCLUSION: The survival of three-unit TFDPs and ISCs over 15 years was not statistically different when replacing posterior teeth, but ISCs survived significantly better when replacing anterior teeth. The complication rates of the TFDPs and ISCs were similar, but the economic burden for the TFDPs was greater. PMID- 26252027 TI - The Effect of a Combination of Implant Controller and Handpiece from Different Manufacturers on the Torque Value. AB - PURPOSE: To determine the accuracy of applied torque of different implant controller and handpiece combinations by using an electronic torque gauge. MATERIALS AND METHODS: Four combinations of the following devices were tested: Surgic XT controller (NSK), XIP10 controller (Saeshin), X-SG20L handpiece (NSK), CRB26LX handpiece (Saeshin). For five torque settings, 30 measurements were recorded at 30 revolutions per minute by using an electronic torque gauge fixed to jigs, and means were calculated. RESULTS: Applied torques were generally higher than the set torque of 10 and 20 Ncm and lower than the set values of 40 and 50 Ncm. The average torque deviations differed significantly among the combinations (P < .05). At 10 and 20 Ncm, the Surgic XT/X-SG20L combination yielded the closest value to the intended torque, followed by the XIP10/X-SG20L combination. At 30 Ncm, the XIP10/X-SG20L combination showed the nearest value. At 40 Ncm, the Surgic XT/X-SG20L, XIP10/CRB26LX, and XIP10/X-SG20L combinations showed deviations within 10%. At 50 Ncm, all the combinations showed lower applied torque than the set value. Large standard deviations were observed in the Surgic XT/CRB26LX (13.288) and Surgic XT/X-SG20L (7.858) combinations. CONCLUSION: Different combinations of implant controllers and handpieces do not generate significant variations in applied torque. The actual torque varies according to the torque setting. It is necessary to calibrate devices before use to reduce potentially problematic torque. PMID- 26252026 TI - Biochemical Responses of Anodized Titanium Implants with a Poly(lactide-co glycolide)/Bone Morphogenetic Protein-2 Submicron Particle Coating. Part 2: An In Vivo Study. AB - PURPOSE: A biochemical approach to implant surfaces can improve bone growth, resulting in desirable bone-implant interfaces. This study was conducted to identify the effect on osseointegration of direct coating of titanium (Ti) implants with poly(D,L-lactide-co-glycolide)(PLGA)/recombinant human bone morphogenetic 2 (rhBMP-2) submicron particles by electrospray. MATERIALS AND METHODS: Anodized Ti implants were used as a control group, and implants coated with 80 MUL of PLGA/rhBMP-2 (50 MUg/mL rhBMP-2 per implant) submicron particles by electrospray were used as the experimental group in an in vivo rabbit tibia model. After 3 or 7 weeks of healing, specimens were obtained and prepared for histologic and histomorphometric analyses. RESULTS: The implant surface coated with submicron PLGA/rhBMP-2 showed new bone growth in the apical direction earlier than control implants. In the experimental group at 3 weeks, the bone-to implant contact ratio and bone area of the three best consecutive threads were significantly higher than those in the control group. However, there was no significant difference between groups at 7 weeks. CONCLUSION: Within the limitations of this study, the PLGA/rhBMP-2-coated implants facilitated osseointegration between bone and the Ti surface during the early healing phase. PMID- 26252028 TI - Meta-Analysis of Correlations Between Marginal Bone Resorption and High Insertion Torque of Dental Implants. AB - PURPOSE: To evaluate correlations between marginal bone resorption and high insertion torque value (> 50 Ncm) of dental implants and to assess the significance of immediate and early/conventional loading of implants under a certain range torque value. MATERIALS AND METHODS: Specific inclusion and exclusion criteria were used to retrieve eligible articles from Ovid, PubMed, and EBSCO up to December 2013. Screening of eligible studies, quality assessment, and data extraction were conducted in duplicate. The results were expressed as random/fixed-effects models using weighted mean differences for continuous outcomes with 95% confidence intervals. RESULTS: Initially, 154 articles were selected (11 from Ovid, 112 from PubMed, and 31 from EBSCO). After exclusion of duplicate articles and articles that did not meet the inclusion criteria, six clinical studies were selected. Assessment of P values revealed that correlations between marginal bone resorption and high insertion torque were not statistically significant and that there was no difference between immediately versus early/conventionally loaded implants under a certain range of torque. CONCLUSION: None of the meta-analyses revealed any statistically significant differences between high insertion torque and conventional insertion torque in terms of effects on marginal bone resorption. PMID- 26252029 TI - Three-Dimensional Displacement of Nine Different Abutments for an Implant with an Internal Hexagon Platform. AB - PURPOSE: Clinicians need to know whether there are any differences among the many abutment options available for restoring a particular implant. This study aims to compare nine abutments for one implant system for positional changes between hand tightening and torqueing. MATERIALS AND METHODS: Nine Tapered Screw-Vent (TSV) implants were placed into a resin block. Five specimens of nine different abutments (n = 45) were tried in one of the nine implants. Initially, the abutments were torqued to 20 Ncm to represent hand tightening. Abutments were tightened to 30 Ncm using a torque driver as recommended by the manufacturer for final seating. Images were recorded in 12-second intervals for approximately 10 minutes after the torque was applied. The spatial relationship of the abutments to the resin block was determined using three-dimensional digital image correlation. Commercial image correlation software was used to analyze the displacements. Mean displacements for the nine different abutments were calculated in all three dimensions and for overall displacement in space. A t test with a step-down Bonferroni correction was used for a pairwise comparison of each abutment's mean displacements to the other abutments to determine statistical differences (alpha = .05). RESULTS: The Atlantis titanium, Inclusive titanium, and Legacy zirconia abutments showed mean displacements that were statistically significantly higher than other abutments in the horizontal direction. The overall three-dimensional displacement of the Atlantis titanium abutment after an applied 30-Ncm torque was significantly higher than that of six of the other eight abutments (P < .0144). CONCLUSION: Within the limitations of this in vitro study, the Zimmer PSA demonstrated less displacement between hand tightening and torqueing than the Atlantis titanium or Inclusive titanium abutments when used to restore a TSV implant. PMID- 26252030 TI - Effect of Macrogeometry on the Surface Topography of Dental Implants. AB - PURPOSE: Because the microtopography of titanium implants influences the biomaterial-tissue interaction, surface microtexturing treatments are frequently used for dental implants. However, surface treatment alone may not determine the final microtopography of a dental implant, which can also be influenced by the implant macrogeometry. This work analyzed the effects on surface roughness parameters of the same treatment applied by the same manufacturer to implants with differing macro-designs. MATERIALS AND METHODS: Three groups of titanium implants with different macro-designs were investigated using laser interferometry and scanning electron microscopy. Relevant surface roughness parameters were calculated for different regions of each implant. Two flat disks (treated and untreated) were also investigated for comparison. RESULTS: The tops of the threads and the nonthreaded regions of all implants had very similar roughness parameters, independent of the geometry of the implant, which were also very similar to those of flat disks treated with the same process. In contrast, the flanks and valleys of the threads presented larger irregularities (Sa) with higher slopes (Sdq) and larger developed surface areas (Sdr) on all implants, particularly for implants with threads with smaller heights. The flanks and valleys displayed stronger textures (Str), particularly on the implants with threads with larger internal angles. CONCLUSION: Parameters associated with the height of the irregularities (Sa), the slope of the asperities (Sdq), the presence of a surface texture (Str), and the developed surface area of the irregularities (Sdr) were significantly affected by the macrogeometry of the implants. Flat disks subjected to the same surface treatment as dental implants reproduced only the surface topography of the flat regions of the implants. PMID- 26252031 TI - Mechanical Evaluation of Two Grades of Titanium Used in Implant Dentistry. AB - PURPOSE: To investigate the effect of core dental implant materials supporting single crowns on the probability of survival and failure modes. MATERIALS AND METHODS: Thirty-six standard external-hex titanium implants (4.0 mm in diameter) were selected to restore single crowns and divided into two groups according to core material: commercially pure grade 2 titanium (G2) and grade 5 titanium aluminum-vanadium alloy (Ti-6Al-4V) (G5). Abutments were screwed to the implants, and standardized maxillary central incisor metal crowns were cemented and subjected to step-stress accelerated life testing in water. Use-level probability Weibull curves and reliability for missions of 100,000 cycles at 150 N and 200 N (with 90% two-sided confidence intervals [CIs]) were calculated. Polarized light and scanning electron microscopes were used to determine the failure modes. RESULTS: Use-level probability Weibull calculations showed beta values of 0.59 (CI, 0.31 to 1.11) and 1.22 (CI 0.81 to 1.84) for G2 and G5, respectively, and significantly higher characteristic strength and Weibull modulus for G5. The calculated reliability (90% CIs) for a mission of 100,000 cycles at 150 N showed that cumulative damage would lead to survival of 45% of implant-supported crowns of G2 and 98% of G5. At 200 N the probability of survival decreased to 0.03% for G2 and 21% for G5. Abutment screw fracture was the failure mode for all groups. CONCLUSION: Reliability, characteristic strength, and Weibull modulus were significantly higher for Ti-6Al-4V dental implants than for commercially pure (grade 2) titanium implants. Failure modes were similar for both groups. PMID- 26252032 TI - Effect of Diamondlike Carbon Coating on Reliability of Implant-Supported Crowns. AB - PURPOSE: To evaluate the effect of diamondlike carbon (DLC) coating on abutments and/or abutment screws on the reliability, characteristic strength, and Weibull modulus of implant-supported single crowns. MATERIALS AND METHODS: Seventy-two external hexagon implants (Emfills Implant 4 mm diameter, 10 mm length, Emfills) were divided into four groups (n = 18 each), according to the presence or not of a DLC coating in the abutment and/or abutment screw, as follows: abutment without coating, screw without coating (AwcSwc); abutment without coating with coated screw (AwcSC); abutment coated with noncoated screw (ACSwc), and coated abutment with coated screw (ACSC). Abutments and screws were evaluated with scanning electron microscopy. The specimens were subjected to step-stress accelerated life testing in water. Use-level probability Weibull curves and reliability for a mission of 100,000 cycles at 150 N (90% two-sided confidence intervals) were calculated. Polarized light and scanning electron microscopes were used for fractographic analysis. RESULTS: For a mission of 100,000 cycles at 150 N, reliability was 0.45 (0.20 to 0.67), 0.12 (0.00 to 0.47), 0.56 (0.17 to 0.82), and 0.44 (0.07 to 0.77) for AwcSwc, AwcSC, ACSwc, and ACSC, respectively. The probability Weibull calculation showed a Weibull modulus (m) of m = 5.50, m = 11.64, m = 16.96, and m = 15.08 and the characteristic strengths (eta, which indicates the load at which 63.2% of the specimens of each group fail) of eta = 202.67 N, n = 206.64 N, n = 192.54 N, and n = 203.59 N for AwcSwc, AwcSC, ACSwc, and ACSC, respectively. Abutment screw fracture was the chief failure outcome in all groups. CONCLUSION: Characteristic strength values were not different among groups; neither was reliability. However, an increase in Weibull modulus (indicating low variability of the results) was observed with DLC coating of abutment or screw or both. PMID- 26252033 TI - Comparison of Virtual Dental Implant Planning Using the Full Cross-Sectional and Transaxial Capabilities of Cone Beam Computed Tomography vs Reformatted Panoramic Imaging and 3D Modeling. AB - PURPOSE: To compare the choice and placement of virtual dental implants in the posterior edentulous bounded regions using the full cross-sectional and transaxial capabilities of cone beam computed tomography (CBCT) vs reformatted panoramic images and three-dimensional (3D) virtual models. MATERIALS AND METHODS: Fifty-two cases with posterior bounded edentulous regions (61 dental implant sites) were identified from a retrospective audit of 4,014 radiographic volumes. Two image sets were created from selected CBCT data: (1) a combination of reformatted panoramic imaging and a 3D model (PIref/3D), and (2) the full 3D power in CBCT image volume analyses (XS). One virtual implant was placed by consensus of three prosthodontists in each image set: PIref/3D and XS. The choice of implant length and the perceived need for ridge augmentation were recorded for implant placement in both test situations. All the virtual implant placements from both PIref/3D and XS image sets were inspected retrospectively using virtual 3D models, and the number of exposed threads on both the buccal and lingual/palatal aspects of the virtual dental implant was evaluated. The chi square and paired t tests were used with the level of significance set at alpha = .05. RESULTS: Shorter implants were chosen more often using XS than PIref/3D (P = .001). Fewer threads were exposed when placed with XS than with PIref/3D (P = .001). The use of XS reduced the perceived need for ridge augmentation compared with PIref/3D (P = .001). CONCLUSION: The use of the full 3D power of CBCT (including cross-sectional images in all three orthagonal planes and transaxially) provides supplemental information that significantly changes the choice of virtual implant length and vertical position of the implant, and reduces the frequency of perceived need for ridge augmentation before implant placement. PMID- 26252034 TI - The Evaluation of the Heat Generated by the Implant Osteotomy Preparation Using a Modified Method of the Measuring Temperature. AB - PURPOSE: To establish a method for measuring the heat generated when preparing an osteotomy site, and to assess for correlations of rotational speed, proceeding speed, loading value of the drill (contact pressure), motion pattern, and bone density with temperature increases. MATERIALS AND METHODS: A thermocouple was placed in the internal irrigation hole of a 2.0-mm-diameter twist drill used for measuring osteotomy site temperature. In the artificial blocks, two different densities were used to drill under varying conditions including drill proceeding, rotating speed, and motion pattern. The drilling procedure was repeated five times for each combination, and the data collected were statistically analyzed using multiple regression analysis. RESULTS: Strong positive correlations were found among bone density, drill motion pattern, and maximum temperature, and a positive correlation was found in proceeding speed (P < .001). Rotation speed and maximum temperature were not correlated (P < .001). Conversely, loading values of the drill increased with the lower rotation speed and higher proceeding speed, which were effective in controlling the temperature rise. CONCLUSION: When preparing a simulated bone for an osteotomy with a thermocouple inserted into a twist drill with internal irrigation, the drilling motion pattern, bone density, drill speed, and proceeding rate affected bone temperature, in descending order. It was also observed that bone temperature correlated positively with speed and negatively with proceeding speed, independent of density. This indicates that lower drill speed and higher proceeding speed without excessive loading values minimize the bone temperature heat. PMID- 26252035 TI - Bone Response to Static Compressive Stress at Bone-Implant Interface: A Pilot Study of Critical Static Compressive Stress. AB - PURPOSE: Mechanical imbalance caused by mechanical overload or poor bone quality around a dental implant can result in osseointegration failure. To avoid that, it is important to identify an appropriate safety stress margin (critical stress level). For this study, a novel device was developed to generate a quantitative amount of static compressive stress under an aseptic closed condition. The aim was to clarify the amount of critical stress produced on the cortical bone when static compression is applied to the osseointegrated bone-implant interface. MATERIALS AND METHODS: Small parts for bone sustaining, load generation, and load transmittance were developed to generate quantitative static compressive stress at the bone-implant interface and implanted inside the tibial cortical bone in adult beagle dogs. Each tibia in two dogs received bone-sustaining parts, then after 2 months, the load-transmitting parts were placed into the bone-sustaining parts. After another 2 months, various magnitudes of static compressive stress (0 180 MPa) were generated by tightening the load-generating part to the osseointegrated bone-implant interface. After 7 days, the animals were euthanized, and dissected blocks were prepared for histomorphometric analyses. RESULTS: There were no obvious signs of bone resorption or loss of osseointegration in any of the dogs. The change in shape of osteon was not influenced by the amount of static compressive stress. However, periosteal reactions were observed under the cortical bone on the opposite side. CONCLUSION: These results indicate that osseointegrated bone-implant interfaces show minimal response based on the magnitude of static compressive stress, even when such stress is greater than 120 MPa. PMID- 26252036 TI - Microbiologic and Clinical Findings of Implants in Healthy Condition and with Peri-Implantitis. AB - PURPOSE: To compare implants in healthy conditions and implants with peri implantitis with regard to their clinical parameters and the microbiologic composition at the peri-implant sulcus, inside the implant connection, and the gingival sulcus of neighboring teeth. MATERIALS AND METHODS: A cross-sectional study was performed including consecutive patients with implants in healthy conditions and with peri-implantitis. Clinical parameters for which patients were screened included bleeding on probing, pocket depth, and plaque index at six sites. Samples for microbiologic analysis were obtained from three locations: the peri-implant sulcus, inside the implant connection, and the gingival sulcus of neighboring teeth. Quantitative real-time polymerase chain reaction (PCR) was carried out for total counts of 10 microorganisms: Aggregatibacter actinomycetemcomitans, Porphyromona gingivalis, Tanerella forsythia, Tanerella denticola, Prevotela intermedia, Peptostreptococcus micros, Fusobacterium nucleatum, Campylobacter rectus, Eikenella corrodens, and Candida albicans. The response variables were the percentage of positive sites and total bacterial counts. RESULTS: One hundred twenty-two implants in 57 patients were analyzed in the healthy group and 113 implants in 53 patients in the peri-implantitis group. Differences between the groups were statistically significant for bruxism, probing pocket depth, bleeding on probing, and radiographic bone level. Orange complex species (P intermedia, P micros, F nucleatum) were the most prevalent in the three types of sites for both groups, and prevalence values were higher in the peri-implantitis group. Differences in prevalence between groups were more marked inside the connection than in the peri-implant sulcus. Absolute loads of most microbes and total bacterial counts were higher for the peri-implantitis group in the three locations. Again, differences were bigger inside the connection than at the peri-implant sulcus. Significant interactions were found for prevalence and absolute microbial loads between groups and locations, and for the interaction of group * location. CONCLUSION: Clinical and microbiologic differences were observed between healthy subjects and those with peri implantitis. Microbiologic differences between groups were more marked inside the connection than in the peri-implant sulcus. The potential role of the implant connection as a microbial reservoir for peri-implant diseases and in the outcome of their treatment should be confirmed with further studies. PMID- 26252037 TI - Resonance Frequency Analysis of Thermal Acid-Etched, Hydrophilic Implants During First 3 Months of Healing and Osseointegration in an Early-Loading Protocol. AB - PURPOSE: Safe loading of dental implants requires an optimal osseointegration. This osseointegration process during healing could be analyzed by resonance frequency analysis (RFA). The purpose of the study was to evaluate RFA changes during healing in splinted, early-loaded, thermal acid-etched, hydrophilic implants over time. MATERIALS AND METHODS: Patients received a minimum of two implants: an implant with the prosthetic abutment connection at the crestal bone level (bone level) and one with the prosthetic abutment connection at a 2.5-mm supracrestal site (tissue level). Implant stability was measured at weeks 0, 2, 3, and 12 using the Osstell device. RESULTS: Seventy-six implants were placed in 32 patients. By week 2, early-loaded tissue-level implants showed a significant drop in mean +/- standard deviation (SD) implant stability quotient (ISQ) values of 2.2 +/- 3.6 (P < .001). Changes in ISQ values were significant between weeks 3 and 12 and also between weeks 0 and 12, with mean differences of 4.2 (P < .001) and 2.8 (P < .001), respectively. Early-loaded bone-level implants show a significant change in ISQ of 2.3 +/- 3.7 at week 2 (P < .01) and -1.3 +/- 4.7 at week 12 when compared to an ISQ value of 2.9 +/- 4.9 at week 3 (P < .01). Bone level implants achieved higher ISQ values compared with tissue-level implants at weeks 0, 2, 3, and 12, with mean differences being 3.8 +/- 5.5 (P < .01), 3.8 +/- 6.1 (P < .01), 3.7 +/- 6.7 (P < .01), and 2.3 +/- 5.8 (P < .05), respectively. CONCLUSION: This study found a significant dip in ISQ values, with the lowest point seen at week 2. ISQ values remained higher in bone-level implants throughout the process of healing and osseointegration. PMID- 26252038 TI - Inferior Meatal Antrostomy as a Prophylactic Maneuver to Prevent Sinusitis After Zygomatic Implant Placement Using the Intrasinusal Technique. AB - PURPOSE: To determine whether performing an inferior meatal antrostomy as a prophylactic intraoperative maneuver in patients who underwent zygomatic implant surgery significantly reduces the incidence of postoperative sinusitis. MATERIALS AND METHODS: A double-blind randomized controlled trial was implemented. The study included 44 patients seen at the Oral and Maxillofacial Surgery Department at Universidad El Bosque in Bogota, Colombia, who required zygomatic implant surgery. Patients were randomly allocated to either group 1 (without inferior meatal antrostomy) or group 2 (with inferior meatal antrostomy). Patients were evaluated clinically and radiographically 15 days and 3 months after surgery, and classified depending on whether they did or did not develop sinusitis. Results were analyzed using descriptive and bivariate statistics. The control group event rate, experimental group event rate, relative risk, relative risk reduction, absolute risk reduction, and number needed to treat values were calculated for further analysis. RESULTS: Three patients allocated to group 1 showed clinical and radiographic signs of sinusitis after zygomatic implant surgery, for an overall rate of sinusitis of 13.6%. No patient in group 2 developed clinical or radiographic signs of sinusitis. CONCLUSION: The results of this study suggest that performing an inferior meatal antrostomy as a prophylactic intraoperative maneuver in patients who require zygomatic implant surgery is an effective method to prevent postoperative sinusitis. PMID- 26252039 TI - Effect of UV Photofunctionalization on Biologic and Anchoring Capability of Orthodontic Miniscrews. AB - PURPOSE: Treatment of titanium with UV light immediately before use, or photofunctionalization, is gaining traction as a simple method to improve the biologic capability and clinical performance of dental implants. The objective of this study was to examine the effect of photofunctionalization on the biologic capability and mechanical anchorage of orthodontic miniscrews. MATERIALS AND METHODS: Untreated and photofunctionalized Ti-6Al-4V orthodontic miniscrews were placed into rat femurs. Photofunctionalization was performed by treating miniscrews with UV light for 12 minutes using a photo device immediately before placement. After 3 weeks of healing, miniscrews were pushed laterally to measure the resistance against the tipping force. The miniscrews were also evaluated for morphology and chemistry of tissue formed around them using scanning electron microscopy and energy dispersive spectroscopy. Rat bone marrow-derived osteoblasts were cultured on Ti-6Al-4V disks with and without photofunctionalization. The number of osteoblasts attached to the disks and the behaviors, alkaline phosphatase activity, and mineralization capability of osteoblasts were evaluated. RESULTS: Photofunctionalization converted both disk and screw surfaces from hydrophobic to superhydrophilic. In vivo biomechanical testing showed that the displacement of untreated screws was 1.5 to 1.7 times greater than that of photofunctionalized screws when subjected to lateral tipping force. Robust bone formation was observed around photofunctionalized miniscrews with strong elemental peaks of calcium and phosphorus, whereas the tissue around untreated miniscrews appeared thin and showed no clear peak of calcium. The attachment, initial spreading, adhesion, and expression of functional phenotypes of osteoblasts were significantly increased on photofunctionalized Ti-6Al-4V disks. CONCLUSION: These in vivo and in vitro results comprehensively and consistently demonstrate that photofunctionalization increases the bioactivity of Ti-6Al-4V and improves the anchoring capability of orthodontic miniscrews. PMID- 26252040 TI - Calvarial Bone Grafting for Three-Dimensional Reconstruction of Severe Maxillary Defects: A Case Series. AB - PURPOSE: To evaluate the efficacy, associated morbidity, and results of a three dimensional reconstruction technique for repairing severe defects of the maxilla using a calvarial autogenous bone graft and a soft tissue double-layered surgical approach in preparation for placing dental implants. MATERIALS AND METHODS: Bone defects of the maxilla consecutively reconstructed with calvarial autologous graft in the authors' institution were retrospectively evaluated. Patients with combined maxilla alveolar ridge defects with a width less than 4 mm and a height less than 7 mm (to the level of the maxillary sinus or the nostril), with at least three teeth involved, were included in the study. Calvarial bone blocks were sagittally sectioned in fine layers and fixed three-dimensionally in a boxlike structure with particulate bone inside. The purpose was to obtain an adequate amount of vertical and horizontal alveolar bone to enable restoration with dental implants at least 3.4 mm in diameter and 11 mm in length. RESULTS: Eleven reconstructive procedures were performed in 10 patients. Bone graft integration was successful in all of them. No major complications were observed in the donor cranial site. A mean bone gain of 5.04 mm (range, 3.4 to 7.8 mm) in height was obtained (standard deviation [SD], 1.69). The implant surgery was performed between the 15th and 19th weeks. A total of 28 implants were placed, and the mean follow-up time was 45 months (range, 23 to 65 months; SD, 12). The mean graft vertical resorption was 0.78 mm (range, 0.50-1.50 mm; SD, 0.00) 41 months after implant fixation. CONCLUSION: Three-dimensional reconstruction technique using calvarial bone grafts to restore severe segmental or crestal bone defects in the maxilla is an effective and predictable procedure that can increase the horizontal and vertical bone volume in preparation for the successful placement of dental implants. PMID- 26252041 TI - Evaluation of the Ideal Implant Insertion Time in Human Bone Biopsies After Sinus Elevation Using a Combination of Autologous Bone and Graft Substitute. AB - PURPOSE: To evaluate the ideal implant insertion time in human bone biopsies after sinus elevation with a composite graft consisting of an equal amount of biomaterial and autologous bone, by comparing the bone regeneration obtained 4 to 5 months after surgery with that obtained after 6 to 8 months, and using the adjacent native bone as reference. MATERIALS AND METHODS: Twenty-six biopsy specimens of 11 patients were analyzed. Two groups were created depending on the time of implant insertion: group t1 at 4 to 5 months (n = 13) and group t2 at 6 to 8 months (n = 13). The same volume of grafted bone and native bone were analyzed for each biopsy with microcomputed tomography (microCT) and gene expression analysis. RESULTS: Statistically significant differences were found in bone mineral density (BMD), bone volume fraction, and trabecular separation (TbSp) between native and grafted bone in both groups, with higher grafted bone values, except for the variable TbSp, which was lower in the grafted bone. This decrease in TbSp in the grafted bone in both groups can be explained by the significant increase in trabecular thickness in group t2 and the trabecular number in group t1, compared with native bone. No significant differences were found between the two groups in the morphometric parameters and BMD of the grafted bone. Also, no significant changes in the messenger RNA (mRNA) levels of bone formation, bone resorption, and inflammatory markers were found between both groups, with the exception that alkaline phosphatase mRNA levels were significantly lower in group t1 relative to native bone. CONCLUSION: This composite graft showed no differences in three-dimensional microstructure, BMD, or at the molecular level between 4 to 5 months and 6 to 8 months of healing time. Thus, this time can be shortened to 4 months with the security of a grafted area of mature bone. PMID- 26252042 TI - The Effect of Interimplant Distance on Peri-implant Bone and Soft Tissue Dimensional Changes: A Nonrandomized, Prospective, 2-Year Follow-up Study. AB - PURPOSE: To prospectively evaluate peri-implant bone and soft tissue dimension changes around adjacent implants placed at different horizontal interimplant distances. MATERIALS AND METHODS: Thirty partially edentulous patients, who underwent rehabilitation with two adjacent implant-supported crowns as part of their treatment plan, were assigned to three groups based on their prosthetic needs. Patients in group A (10 patients, 20 implants) were to have two implants placed at a 2-mm interimplant distance, patients in group B (10 patients, 20 implants) were to have two implants placed at a 3-mm interimplant distance, and patients in group C (10 patients, 20 implants) were to have two implants placed at an interimplant distance of > 4 mm according to their prosthetic needs. All patients received single-crown restorations after 3 months. Clinical examinations were performed at the time of crown placement (T3), and 6 months (T6), 12 months (T12), and 24 months (T24) after implant placement. Peri-implant bone levels were assessed radiographically at the time of implant placement (T0), and at T3, T12, and T24. RESULTS: One patient from group C did not return for follow-up examinations after implant placement. The mean (+/- standard deviation) horizontal interimplant distance was 1.97 +/- 0.44 mm for implants in group A, 3.12 +/- 0.15 mm for implants in group B, and 5.3 +/- 0.64 mm for implants in group C. For group A, the mean marginal bone loss was 0.29 +/- 0.51 mm at the T0 T3 interval, 0.31 +/- 0.36 mm at the T0-T12 interval, and 0.27 +/- 0.33 mm at the T0-T24 interval. For group B, the mean marginal bone loss was 0.16 +/- 0.29 mm at the T0-T3 interval, 0.20 +/- 0.28 mm at the T0-T12 interval, and 0.23 +/- 0.28 mm at the T0-T24 interval. For group C, the mean marginal bone loss was 0.51 +/- 0.84 mm at the T0-T3 interval, 0.45 +/- 0.72 mm at the T0-T12 interval, and 0.44 +/- 0.74 mm at the T0-T24 interval. For group A, the mean midproximal bone loss was 0.33 +/- 0.50 mm at the T0-T3 interval, 0.45 +/- 0.35 mm at the T0-T12 interval, and 0.40 +/- 0.32 mm at the T0-T24 interval. For group B, the mean midproximal loss was 0.31 +/- 0.37 mm at the T0-T3 interval, 0.32 +/- 0.39 mm at the T0-T12 interval, and 0.33 +/- 0.42 mm at the T0-T24 interval. For group C, the mean midproximal bone loss was 0.40 +/- 0.44 mm at the T0-T3 interval and 0.41 +/- 0.50 mm at both the T0-T12 and T0-T24 intervals. There were no statistically significant differences in marginal and midproximal bone crest loss between the different groups at any time point. CONCLUSION: The study failed to support the hypothesis that horizontal interimplant distance has an effect on peri-implant bone and soft tissue dimension changes for implants with internal conical implant-abutment interface connection and platform-switching characteristics. PMID- 26252043 TI - Changes in Thickness of Mucosa Adjacent to Implants Using Tissue Matrix Allograft: A Clinical and Histologic Evaluation. AB - PURPOSE: To clinically and histologically evaluate the soft tissue thickening seen on acellular human dermis grafting at implant placement, taking into consideration the biotype. MATERIALS AND METHODS: Mucosal thickness was measured before and 4 months after implant placement, when the thickness of the epithelium and corium and the inflammation were histologically evaluated with a skin biopsy. Results were analyzed using the Mann-Whitney U test and linear regression analysis. RESULTS: In a total of 47 implant sites (22 uncovered and 25 covered by the allograft matrix), the grafted sites showed a significantly greater increase in thickness compared with the control sites. Histology was unable to show differences between groups. Nevertheless, using an individual variation index involving the histologic and initial clinical thickness, the increase in thickness of grafted sites was statistically significant (P = .017) compared with the decrease in control sites. Furthermore, the greatest thickness increase was recorded in sites with thin biotype, whereas a decrement was found in control sites. The inflammation index was similar in both groups. CONCLUSION: This study demonstrated the effectiveness of evaluating the increase in mucosal thickness with acellular human dermis grafting, particularly in subjects with thin biotype. PMID- 26252044 TI - Three-Year Analysis of Fixed and Removable Telescopic Attachment-Retained Implant Supported Dental Prostheses: Survival and Need for Maintenance. AB - PURPOSE: The purpose of this retrospective clinical study was to evaluate the clinical outcomes of fixed implant-supported dental prostheses (FISDPs) and removable ISDPs (RISDPs) retained by telescopic attachments, the factors influencing survival, and the type and number of maintenance treatments required during the observation period. MATERIALS AND METHODS: This retrospective clinical study is based on patients who were provided with ISDPs between 2004 and 2010. Patient sex, type of prosthesis, location, opposing dentition, and the effect of continuous follow-up on the probability of a favorable outcome, as well as the number of maintenance treatments, were analyzed. A statistical analysis was performed using the Kaplan-Meier method. RESULTS: A sample of 233 patients with 157 FISDPs and 76 RISDPs supported by a total of 567 implants was randomized and included in the analysis. The mean observation period was 15.9 +/- 15.4 months (maximum, 66.0 months). During the observation period, 3.9% of prostheses (7/157 FISDPs and 2/76 RISDPs) ceased to function and 2.3% of implants (13 implants) were lost. The mean survival time was 59.7 +/- 2.3 months, with a survival probability of 90.2% after 3 years. Prostheses in the mandible showed significantly higher survival rates than those in the maxilla. Maintenance treatments had to be performed at an earlier stage for patients with RISDPs than for patients with FISDPs. In patients with a conventional removable prosthesis in the opposing arch, the time until maintenance was needed was significantly shorter. CONCLUSION: Within the limitations of a retrospective study, it can be concluded that the FISDPs and RISDPs show equally good survival rates after 3 years in function. RISDPs showed a greater and earlier need for maintenance treatments during the first years in function. PMID- 26252045 TI - Clinical Outcomes of Reamer- vs Osteotome-Mediated Sinus Floor Elevation with Simultaneous Implant Placement: A 2-Year Retrospective Study. AB - PURPOSE: This retrospective study evaluated and compared the 2-year outcomes for sinus floor elevation performed via either an osteotome-mediated sinus floor elevation (OSFE) technique or a reamer-mediated sinus floor elevation (RSFE) technique. Implant survival, as well as surgical and postoperative complications, were used as measures of comparison. MATERIALS AND METHODS: Patients were analyzed according to defined inclusion criteria. Orthopantography was used to assess preoperative; immediate postoperative; and 6-, 12-, and 24-month postoperative bone level changes. Implant survival and the incidence of complications, including sinus membrane perforation, were evaluated using appropriate statistical tests. RESULTS: From 2008 to 2010, 126 implants were placed simultaneously with sinus floor elevation in 85 patients (n = 43 women and 42 men; mean age +/- standard deviation [SD] = 58.1 +/- 10.2 years). The OSFE procedure (control) was used to place 65 implants in 45 patients, and the RSFE procedure (experimental) was used to place 61 implants in 40 patients. The mean maxillary residual bone height was 7.1 +/- 1.6 mm. Endosinus bone gains were 5.7 +/- 1.5 mm and 5.6 +/- 2.3 mm for the experimental and control groups (P = .164), respectively, and the 2-year survival rates were 98.4% and 98.5%, respectively. Although no significant differences were observed between the two groups, three (6.7%) membrane perforations occurred in the OSFE group, and none occurred in the RSFE group. Other postoperative complications, including nasal bleeding, postoperative headache, and dizziness, were documented in 7 (15.6%) of 45 OSFE cases and 3 (7.5%) of 40 RSFE cases. CONCLUSION: The results presented herein indicate that comparable survival rates were achieved for implants placed in conjunction with a reamer- vs osteotome-mediated technique. Therefore, RSFE is a reliable and predictable procedure for implant placement in the posterior maxilla, with a low incidence of complications. PMID- 26252046 TI - The Effect of Vertical Implant Position in Relation to Adjacent Teeth on Marginal Bone Loss in Posterior Arches: A Retrospective Study. AB - PURPOSE: The aim of this retrospective study was to investigate the possible association between peri-implant marginal bone loss and the apicocoronal (vertical) positioning of dental implants placed adjacent to a tooth. MATERIALS AND METHODS: Dental records at the University of Michigan, School of Dentistry, were screened. To be included in the study, the patient had to have at least one implant in the premolar or molar region, unilaterally or bilaterally, in either arch, with an immediately mesial adjacent tooth. The implant had to have been functionally loaded for at least 3 years after crown insertion, and clear, nondistorted periapical films had to be available. Several landmarks were identified: the cementoenamel junction (CEJ) and crestal bone (CB) of the tooth adjacent to the implant, the implant platform (PL), and the first radiographic implant-bone contact (BL). The following parameters were measured: CEJ-PL, CEJ CB, CB-PL, horizontal distance between the adjacent tooth and PL (HD), and vertical distance between BL and the first implant thread at the mesial (BL-m) and distal (BL-d) implant surfaces. RESULTS: A total of 139 patients with a mean age of 62.1 +/- 9.3 years were included. The mean follow-up period was 4.42 +/- 2.5 years. When the implant was placed more than 3 mm apical to the CEJ of the adjacent tooth, significantly greater peri-implant bone loss occurred at the mesial (difference of means = 0.57 mm) and distal (difference of means = 0.83 mm) implant surfaces. CONCLUSION: In this study population, implants placed in the posterior area with a vertical distance greater than 3 mm from the CEJ of the adjacent tooth displayed more peri-implant bone loss. Further investigation is required to determine whether this increased peri-implant bone loss predisposes a site to peri-implantitis. PMID- 26252047 TI - Implant-Supported Telescopic Crown-Retained Overdentures for Oral Rehabilitation of Patients with Severe Bony Defects: A 5-Year Retrospective Study. AB - PURPOSE: To evaluate the performance of dental implant-supported telescopic crown (TC)-retained overdentures to restore the oral function of patients who have insufficient jawbone volume resulting from tumor resection or trauma. MATERIALS AND METHODS: From January 2004 to December 2008, implant-supported TC-retained overdentures were used to restore the oral function of patients with severe bony defects resulting from tumor resection or trauma. Clinical data, including implant success and survival rates, biologic and mechanical complications, prosthodontic maintenance efforts, and patient satisfaction, were analyzed annually after delivery of the final prostheses. RESULTS: Twenty-four patients were treated, and a total of 88 implants were inserted to support TC-retained overdentures. The mean modified plaque index of implants remained low (<20%), and the majority of implants (>76.3%) in the study showed the absence of bleeding on probing at follow-up visits. Peri-implant marginal bone loss (MBL) ranged from 0.8 to 1.2 mm. There was no statistically significant difference in the MBL between maxillary and mandibular implants (P = .43). The implant success rate was 100% after 5 years, and the prosthodontic maintenance and complication rate was 0.22 times per year. More than 90% of patients were satisfied with the restoration of their oral function using TCs. CONCLUSION: Based on our study of 24 patients treated with TC-retained overdentures, it appears that this treatment may be a viable option for patients with insufficient jawbone volume. PMID- 26252048 TI - Comparison of Gene Expression in Peri-implant Soft Tissue and Oral Mucosal Tissue by Microarray Analysis. AB - PURPOSE: Implant placement entails disruption of the epithelial continuity, which can lead to various complications. Therefore, the area of mucosal penetration is of particular interest clinically. The goal of the present study was to compare gene expression in peri-implant soft tissue (PIST) with that in oral mucosal tissue (OMT) using microarray analysis, and to investigate which genes were specifically expressed in PIST. MATERIALS AND METHODS: The bilateral upper first molars were extracted from 4-week-old rats and titanium alloy implants placed only in the left-side extraction sockets. Four weeks after surgery, samples were harvested from the left-side PIST and right-side OMT and total RNA samples isolated. Microarray analysis was used to compare gene expression in PIST and OMT, which was then confirmed using quantitative real-time polymerase chain reaction. Immunohistochemical staining was also performed to confirm protein level expression. RESULTS: The number of genes expressed with more than a twofold change in PIST compared with OMT was 1,102, of which 750 genes were upregulated and 352 genes were downregulated. The messenger RNA (mRNA) expression of three selected genes-Ceacam1, Ifitm1, and MUC4-were more significantly expressed in PIST than in OMT(P < .01). Immunohistochemical localization of CEACAM1, IFITM1, and MUC4 was observed in PIST, but no immunoreaction was recognized in OMT. CONCLUSION: The result of microarray analysis showed that, because of implant placement, 750 genes were upregulated in PIST compared with OMT. CEACAM1, IFITM1, and MUC4 were specifically upregulated in PIST. PMID- 26252049 TI - Bone-Conditioned Medium Changes Gene Expression in Bone-Derived Fibroblasts. AB - PURPOSE: Autologous bone is used for augmentation in the course of oral implant placement. Bone grafts release paracrine signals that can modulate mesenchymal cell differentiation in vitro. The detailed genetic response of the bone-derived fibroblasts to these paracrine signals has remained elusive. Paracrine signals accumulate in bone-conditioned medium (BCM) prepared from porcine cortical bone chips. MATERIALS AND METHODS: In this study, bone-derived fibroblasts were exposed to BCM followed by a whole genome expression profiling and downstream quantitative reverse transciptase polymerase chain reaction of the most strongly regulated genes. RESULTS: The data show that ADM, IL11, IL33, NOX4, PRG4, and PTX3 were differentially expressed in response to BCM in bone-derived fibroblasts. The transforming growth factor beta (TGF-beta) receptor 1 antagonist SB431542 blocked the effect of BCM on the expression of the gene panel, except for IL33. CONCLUSION: These in vitro results extend existing evidence that cortical bone chips release paracrine signals that provoke a robust genetic response in mesenchymal cells that is not exclusively mediated via the TGF-beta receptor. The present data provide further insights into the process of graft consolidation. PMID- 26252050 TI - Obesity and antiplatelet effects of acetylsalicylic acid and clopidogrel in patients with stable angina pectoris after percutaneous coronary intervention. AB - INTRODUCTION: Obesity is a cluster of medical conditions affecting several pathophysiological processes, including platelet (PLT) function. OBJECTIVES: We evaluated the association between obesity and PLT response to dual antiplatelet therapy over 1 month in patients with stable angina pectoris after percutaneous coronary intervention (PCI). PATIENTS AND METHODS: Patients with stable angina pectoris (n = 130) and prior therapy with acetylsalicylic acid (ASA, 75 mg/d) after PCI were enrolled into the study and divided based on a body mass index (BMI): BMI <25 kg/m2 (group A); BMI = 25-29.9 kg/m2 (group B); and BMI >=30 kg/m2 (group C). PLT function was assessed by impedance aggregometry 24 hours after PCI and a loading dose (LD) of clopidogrel (CLO, 600 mg) and after 30 days of a maintenance dose (MD) of CLO and ASA of 75 mg/d. The delta values were calculated as the difference between the tests performed 30 days and 24 hours after PCI. RESULTS: The PLT function changed significantly over a 30-day follow-up. The initial PLT reactivity to adenosine diphosphate (ADP1) was lower in group A and was the highest in group C (P <0.05). The PLT reactivity to collagen (COL1) and arachidonic acid was lower in group A (P <0.05) with no differences between groups B and C. There were no differences among the subgroups in PLT reactivity assessed after 30 days. A multivariate regression analysis showed that BMI (P = 0.03), creatinine serum concentration (P <0.01), male sex (P <0.01), and active smoking (P <0.001) are the independent predictors of DeltaADP. CONCLUSIONS Obesity is associated with a lower response to CLO LD but PLT function after 30 days of CLO MD is similar in patients with obesity and normal-weight. PMID- 26252051 TI - Carbon-Confined SnO2-Electrodeposited Porous Carbon Nanofiber Composite as High Capacity Sodium-Ion Battery Anode Material. AB - Sodium resources are inexpensive and abundant, and hence, sodium-ion batteries are promising alternative to lithium-ion batteries. However, lower energy density and poor cycling stability of current sodium-ion batteries prevent their practical implementation for future smart power grid and stationary storage applications. Tin oxides (SnO2) can be potentially used as a high-capacity anode material for future sodium-ion batteries, and they have the advantages of high sodium storage capacity, high abundance, and low toxicity. However, SnO2-based anodes still cannot be used in practical sodium-ion batteries because they experience large volume changes during repetitive charge and discharge cycles. Such large volume changes lead to severe pulverization of the active material and loss of electrical contact between the SnO2 and carbon conductor, which in turn result in rapid capacity loss during cycling. Here, we introduce a new amorphous carbon-coated SnO2-electrodeposited porous carbon nanofiber (PCNF@SnO2@C) composite that not only has high sodium storage capability, but also maintains its structural integrity while ongoing repetitive cycles. Electrochemical results revealed that this SnO2-containing nanofiber composite anode had excellent electrochemical performance including high-capacity (374 mAh g(-1)), good capacity retention (82.7%), and large Coulombic efficiency (98.9% after 100th cycle). PMID- 26252052 TI - Tetronic(r) 904-containing polymeric micelles overcome the overexpression of ABCG2 in the blood-brain barrier of rats and boost the penetration of the antiretroviral efavirenz into the CNS. AB - AIM: To assess the involvement of ABCG2 in the pharmacokinetics of efavirenz in the blood-brain barrier (BBB) and investigate a nanotechnology strategy to overcome its overexpression under a model of chronic oral administration. Materials & methods A model of chronic efavirenz (EFV) administration was established in male Sprague-Dawley rats treated with a daily oral dose over 5 days. Then, different treatments were conducted and drug concentrations in plasma and brain measured. RESULTS: Chronic treatment with oral EFV led to the overexpression of ABCG2 in the BBB that was reverted after a brief washout period. Moreover, gefitinib and the polymeric amphiphile Tetronic((r)) 904 significantly inhibited the activity of the pump and potentiated the accumulation of EFV in CNS. The same effect was observed when the drug was administered within mixed micelles containing TetronicT904 as the main component. CONCLUSION: Tetronic 904-containing polymeric micelles overcame the overexpression of ABCG2 in the BBB caused by chronic administration of EFV then boosting its penetration into the CNS. PMID- 26252053 TI - Surveying Lactation Professionals Regarding Marijuana Use and Breastfeeding. AB - BACKGROUND: Breastfeeding is associated with substantial benefits for both the child and mother. Most guidelines state that women who use illicit drugs should not breastfeed. Although this recommendation has traditionally included marijuana, this drug's changing legal status and the limited scientific research regarding marijuana's effect on breastfeeding and the nursing child may lead to varying recommendations made by lactation professionals to clients who use marijuana. Additionally, to our knowledge, there are no data estimating the prevalence of marijuana use among breastfeeding women, making it unclear how common it is. This study assessed recommendations around breastfeeding and marijuana use and estimated the prevalence of marijuana use among breastfeeding women. MATERIALS AND METHODS: A convenience sample of lactation professionals who practice throughout New England and were attending the 2014 Vermont Lactation Consultant Association conference was offered the opportunity to complete a five item survey. RESULTS: Of 120 conference attendees, 74 completed the survey. Forty four percent reported their recommendations around breastfeeding and marijuana use depended on factors like the severity of maternal use. Another 41% reported recommending continued breastfeeding because the benefits outweigh the harms. The remaining 15% reported recommending that a woman should stop breastfeeding if she cannot stop using marijuana. Survey completers estimated that 15% (1,203/7,843) of their breastfeeding clients in the past year used marijuana. CONCLUSIONS: Lactation professionals vary widely in their recommendations to breastfeeding clients who use marijuana. The estimate of prevalence also suggests this is a relatively common issue. More research is needed to assess the generalizability of these findings. PMID- 26252054 TI - Lentivirus-delivered nemo-like kinase small interfering RNA inhibits laryngeal cancer cell proliferation in vitro. AB - Laryngeal squamous cell carcinoma is the most common form of head and neck squamous cell carcinoma. Multiple approaches have been applied to treat this type of cancer; however, no significant improvement in survival rate has been achieved. In the present study, the role of nemo-like kinase (NLK) in human laryngeal carcinoma Hep-2 cells was investigated. NLK has been identified as an important regulator of cell growth, patterning and cell death in a variety of organisms. Lentivirus-mediated-shRNA was employed to silence endogenous NLK expression. Downregulation of the expression of NLK following lentivirus infection was confirmed using reverse transcription quantitative polymerase chain reaction and western blot analysis. The effects of NLK downregulation on Hep-2 cell proliferation and cell cycle progression were analyzed using an MTT assay and flow cytometry, respectively. Downregulation of NLK also inhibited tumorigenesis and regulated the expression of cell cycle protein expression levels. Therefore, it was hypothesized that NLK is necessary for cell survival and tumorigenesis in laryngeal cancer cells. Furthermore, the absence of NLK may lead to cancer cell death. Collectively, the results of the present study demonstrated that the lentivirus-mediated targeted disruption of NLK may be a promising therapeutic method for the treatment of laryngeal cancer. PMID- 26252055 TI - Detection of KRAS mutations in circulating tumor cells from patients with metastatic colorectal cancer. AB - BACKGROUND: Quantification of Circulating Tumor Cells (CTCs) as a prognostic marker in metastatic colorectal cancer (mCRC) has already been validated and approved for routine use. However, more than quantification, qualification or characterization of CTCs is gaining importance, since the genetic characterization of CTCs may reflect, in a real time fashion, genetic profile of the disease. OBJECTIVE: To characterize KRAS mutations (codon 12 and 13) in CTCs from patients with mCRC and to compare with matched primary tumor. Additionally, correlate these mutations with clinical and pathological features of patients. METHODS: Blood samples were collected from 26 patients with mCRC from the AC Camargo Cancer Center (Sao Paulo-Brazil). CTCs were isolated by ISET technology (Isolation by Size of Epithelial Tumors; Rarecells Diagnostics, France) and mutations analyzes were performed by pyrosequencing (QIAGEN). RESULTS: KRAS mutation was detected in 7 of the 21 cases (33%) of samples from CTCs. In matched primary tumors, 9 of the 24 cases (37.5%) were found KRAS mutated. We observed that 5 of the 9 samples with KRAS mutation in their primary tumor had also KRAS mutation in CTCs, meaning a concordance of 71% of matched cases (P = 0.017). KRAS mutation neither on primary tumor nor in CTCs was associated with clinical pathological parameters analyzed. CONCLUSION: Faced with a polyclonal disease like colorectal cancer, which is often treated with alternating and successive lines of chemotherapy, real time genetic characterization of CTCs, in a fast and feasible fashion, can provide important information to clinical management of metastatic patients. Although our cohort was limited, it was possible to show a high grade of concordance between primary tumor and CTCs, which suggests that CTCs can be used as surrogate of primary tumors in clinical practice, when the knowledge of mutation profile is necessary and the primary tumor is not available. PMID- 26252057 TI - Meloxicam combined with sorafenib synergistically inhibits tumor growth of human hepatocellular carcinoma cells via ER stress-related apoptosis. AB - Sorafenib (SOR) is a promising treatment for advanced hepatocellular carcinoma (HCC). However, the precise mechanisms of toxicity and drug resistance have not been fully explored and new strategies are urgently needed for HCC therapy. Meloxicam (MEL) is a selective cyclooxygenase-2 (COX-2) inhibitor which elicits antitumor effects in human HCC cells. In the present study, we investigated the interaction between MEL and SOR in human SMMC-7721 cells and the role endoplasmic reticulum (ER) stress exerts in the combination of SOR with MEL treatment-induced cytotoxicity. Our results revealed that the combination treatment synergistically inhibited cell proliferation and enhanced apoptosis. Furthermore, the combination treatment enhanced ER stress-related molecules which involved in SMMC-7721 cell apoptosis. GRP78 knockdown by siRNA or co-treatment with MG132 significantly increased this combination treatment-induced apoptosis. In addition, we found that the combination treatment suppressed tumor growth by way of activation of ER stress in in vivo models. We concluded that the combination of SOR with MEL treatment-induced ER stress, and eventually apoptosis in human SMMC-7721 cells. Knockdown of GRP78 using siRNA or proteosome inhibitor enhanced the cytotoxicity of the combination of SOR with MEL-treatment in SMMC-7721 cells. These findings provided a new potential treatment strategy against HCC. PMID- 26252056 TI - Exploring the associations between microRNA expression profiles and environmental pollutants in human placenta from the National Children's Study (NCS). AB - The placenta is the principal regulator of the in utero environment, and disruptions to this environment can result in adverse offspring health outcomes. To better characterize the impact of in utero perturbations, we assessed the influence of known environmental pollutants on the expression of microRNA (miRNA) in placental samples collected from the National Children's Study (NCS) Vanguard birth cohort. This study analyzed the expression of 654 miRNAs in 110 term placentas. Environmental pollutants measured in these placentas included dichlorodiphenyldichloroethylene (DDE), bisphenol A (BPA), polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), arsenic (As), mercury (Hg), lead (Pb), and cadmium (Cd). A moderated t-test was used to identify a panel of differentially expressed miRNAs, which were further analyzed using generalized linear models. We observed 112 miRNAs consistently expressed in >70% of the samples. Consistent with the literature, miRNAs located within the imprinted placenta-specific C19MC cluster, specifically mir-517a, mir-517c, mir 522, and mir-23a, are among the top expressed miRNA in our study. We observed a positive association between PBDE 209 and miR-188-5p and an inverse association between PBDE 99 and let-7c. Both PCBs and Cd were positively associated with miR 1537 expression level. In addition, multiple let-7 family members were downregulated with increasing levels of Hg and Pb. We did not observe DDE or BPA levels to be associated with placental miRNA expression. This is the first birth cohort study linking environmental pollutants and placental expression of miRNAs. Our results suggest that placental miRNA profiles may signal in utero exposures to environmental chemicals. PMID- 26252058 TI - GLP-1 Increases Preovulatory LH Source and the Number of Mature Follicles, As Well As Synchronizing the Onset of Puberty in Female Rats. AB - Control of estrous cycle and reproductive capacity involves a large number of central and peripheral factors, integrating numerous nutritional and metabolic signals. Here we show that glucagon-like peptide-1 (GLP-1), a peptide with anorexigenic and insulinotropic actions, and the GLP-1 receptor agonist Exendin-4 (Ex4) exert a regulatory influence on the gonadal axis, in both adult and prepubertal female rats. In adult rats, Glp-1 receptor expression varies during the estrous cycle at the hypothalamus, pituitary, and ovary. Furthermore, acute treatment with GLP-1 in the morning proestrus doubled the amplitude of the preovulatory LH surge, as well as influencing estradiol and progesterone levels along the estrous cycle. These changes provoked an important increase in the number of Graafian follicles and corpora lutea, as well as in the litter size. Conversely, Ex4 diminished the levels of LH, later producing a partial blockade at the preovulatory surge, yet not affecting either the number of mature follicles or corpora lutea. Chronic administration of low doses of GLP-1 to prepubertal rats synchronized vaginal opening and increased LH levels on the 35th day of life, yet at these doses it did not modify their body weight, food intake, or ovarian and uterine weight. By contrast, chronic exposure to Ex4 produced a significant reduction in ovarian and uterine weight, and serum LH, and the animals treated chronically with Ex4 showed no vaginal opening in the period studied. Overall, our results demonstrate that GLP-1 and Ex4 act on the gonadal axis, involving the hypothalamic kisspeptin system, to influence reproductive efficiency in female rats. PMID- 26252059 TI - Heme Oxygenase-1 Induction Prevents Autoimmune Diabetes in Association With Pancreatic Recruitment of M2-Like Macrophages, Mesenchymal Cells, and Fibrocytes. AB - Immunoregulatory and regenerative processes are activated in the pancreas during the development of type 1 diabetes (T1D) but are insufficient to prevent the disease. We hypothesized that the induction of cytoprotective heme oxygenase-1 (HO-1) by cobalt protophoryrin (CoPP) would prevent T1D by promoting anti inflammatory and pro-repair processes. Diabetes-prone BioBreeding rats received ip CoPP or saline twice per week for 3 weeks, starting at 30 days and were monitored for T1D. Immunohistochemistry, confocal microscopy, quantitative RT PCR, and microarrays were used to evaluate postinjection pancreatic changes at 51 days, when islet inflammation is first visible. T1D was prevented in CoPP-treated rats (29% vs 73%). Pancreatic Hmox1 was up-regulated along with islet-associated CD68(+)HO-1(+) cells, which were also observed in a striking peri-lobular interstitial infiltrate. Most interstitial cells expressed the mesenchymal marker vimentin and the hematopoietic marker CD34. Spindle-shaped, CD34(+)vimentin(+) cells coexpressed collagen V, characteristic of fibrocytes. M2 macrophage factors Kruppel-like factor 4, CD163, and CD206 were expressed by interstitial cells, consistent with pancreatic upregulation of several M2-associated genes. CoPP upregulated islet-regenerating REG genes and increased neogenic REG3beta(+) and insulin(+) clusters. Thus, short-term induction of HO-1 promoted a protective M2 like milieu in the pancreas and recruited mesenchymal cells, M2 macrophages, and fibrocytes that imparted immunoregulatory and pro-repair effects, preventing T1D. PMID- 26252060 TI - Anti-Mullerian Hormone Is a Marker for Chemotherapy-Induced Testicular Toxicity. AB - Due to increased numbers of young cancer patients and improved survival, the impact of anticancer treatments on fertility has become a major health concern. Despite mounting research on ovarian toxicity, there is paucity of data regarding reliable biomarkers of testicular toxicity. Our aim was to evaluate anti Mullerian hormone (AMH) as a marker for chemotherapy-induced testicular toxicity. Serum AMH and a panel of gonadal hormones were measured in male cancer patients at baseline and after chemotherapy. In the preclinical setting, mice were injected with diverse chemotherapies and were killed 1 week or 1, 3, or 6 months later. We evaluated spermatogenesis by AMH as well as qualitative and quantitative sperm parameters. Nineteen patients were enrolled, the median age was 38 years (21-44 y). Serum AMH was correlated with increased FSH and T and decreased inhibin-B in gonadotoxic protocols (cisplatin or busulfan) and remained unchanged in nongonadotoxic protocols (capecitabine). AMH expression had the same pattern in mice serum and testes; it was negatively correlated with testicular/epididymal weight and sperm motility. The increase in testicular AMH expression was also correlated with elevated apoptosis (terminal transferase mediated deoxyuridine 5-triphosphate nick-end labeling) and reduced proliferation (Ki67, proliferating cell nuclear antigen; all seminiferous tubules cells were analyzed). Severely damaged mice testes demonstrated a marked costaining of AMH and GATA-4, a Sertoli cell marker; staining that resembled the pattern of the Sertoli cell-only condition. Our study indicates that the pattern of serum AMH expression, in combination with other hormones, can delineate testicular damage, as determined in both experimental settings. Future large-scale clinical studies are warranted to further define the role of AMH as a biomarker for testicular toxicity. PMID- 26252062 TI - Vitamin D Deficiency in BALB/c Mouse Pregnancy Increases Placental Transfer of Glucocorticoids. AB - The prevalence of vitamin D deficiency in pregnancy is increasing and implicated in adverse consequences for the health of offspring in later life. The aim of this study was to determine whether vitamin D deficiency increases fetal exposure to glucocorticoids, which are known to alter fetal development and result in adverse adult health outcomes. Female BALB/c mice were placed on either a vitamin D control (2195 IU/kg) or deficient (0 IU/kg) diet for 5 weeks before and during pregnancy. Maternal serum, placentas and fetal brains were collected at embryonic day 14.5 or 17.5 for morphological and gene expression analysis. Vitamin D deficiency during pregnancy increased maternal corticosterone concentrations and reduced placental weight. Maternal vitamin D deficiency decreased placental expression of 11beta-hydroxysteroid dehydrogenase type II, which inactivates glucocorticoids thereby protecting the fetus from inappropriate glucocorticoid exposure. There was a corresponding increase in placental and fetal expression of the highly glucocorticoid-sensitive factor glucocorticoid-induced leucine zipper. Furthermore, placental expression of the angiogenic factor vascular endothelial growth factor-A was reduced in vitamin D-deficient pregnancies, with a corresponding decline in fetal capillary volume within the placenta. Overall, we show that prenatal vitamin D deficiency leads to an increase in maternal corticosterone, alterations in genes indicative of increased fetal glucocorticoid exposure and impairment in placental vascular development. Thus, the long-term adverse health consequences of vitamin D deficiency during early development may not just be due to alteration in direct vitamin D-related pathways but also altered fetal glucocorticoid exposure. PMID- 26252061 TI - The Posterodorsal Medial Amygdala Regulates the Timing of Puberty Onset in Female Rats. AB - Obesity is the major risk factor for early puberty, but emerging evidence indicates other factors including psychosocial stress. One key brain region notable for its role in controlling calorie intake, stress, and behavior is the amygdala. Early studies involving amygdala lesions that included the medial nucleus advanced puberty in rats. More recently it was shown that a critical site for lesion-induced hyperphagia and obesity is the posterodorsal subnucleus of the medial amygdala (MePD), which may explain the advancement of puberty. Glutamatergic activity also increases in the MePD during puberty without a corresponding gamma-aminobutyric acid (GABA)ergic change, suggesting an overall activation of this brain region. In the present study, we report that neurotoxic lesioning of the MePD advances puberty and increases weight gain in female rats fed a normal diet. However, MePD lesioned rats fed a 25% nonnutritive bulk diet also showed the dramatic advancement of puberty but without the increase in body weight. In both dietary groups, MePD lesions resulted in an increase in socialization and a decrease in play fighting behavior. Chronic GABAA receptor antagonism in the MePD from postnatal day 21 for 14 days also advanced puberty, increased socialization, and decreased play fighting without altering body weight, whereas glutamate receptor antagonism delayed puberty and decreased socialization without affecting play fighting. In conclusion, our results suggest the MePD regulates the timing of puberty via a novel mechanism independent of change in body weight and caloric intake. MePD glutamatergic systems advance the timing of puberty whereas local GABAergic activation results in a delay. PMID- 26252063 TI - Stereotypes and attitudes toward older people among children transitioning from middle childhood into adolescence: Time matters. AB - Ageism is fueled by stereotypes and negative attitudes about aging and older adults, which can lead to individual-level prejudice and discrimination. Through survey methodology, this study explored stereotypes and ageist beliefs of youth transitioning from middle childhood into adolescence (age 11-13 years) (N = 69) in the southwest of England. The results indicate that positive more than negative stereotypes were acknowledged, and more positive stereotyping was positively correlated with more positive attitudes toward older adults. Contact with older adults and age that one considers "old" were significant in predicting attitudes toward older people. The results suggest that time matters, in terms of contact with an older adult and time to reach "old age" in shaping youths' attitudes and stereotypes. Intergenerational and educational programs that seek to address aging myths and increase contact between youth and older adults are discussed as ways to improve attitudes amongst youth transitioning from middle childhood into adolescence. PMID- 26252065 TI - Synthesis and Electroluminescence of Novel Pyrene-Fused Chromophores. AB - Using 4,9-dibromopyrene as a key intermediate, two new fused-core compounds, TP PFF and TP-PFC-TP, were synthesized. These compounds not only exhibited excellent thermal stability but also yielded superior electroluminescence (EL) devices with a lower turn-on voltage, over 50% greater efficiency, and over 3 times longer lifetime than did a similar compound lacking a fused core. This new core-forming method can be applied in various applications with many different core groups. PMID- 26252064 TI - Use of Adeno-Associated Virus to Enrich Cardiomyocytes Derived from Human Stem Cells. AB - Cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) show great promise as autologous donor cells to treat heart disease. A major technical obstacle to this approach is that available induction methods often produce heterogeneous cell population with low percentage of cardiomyocytes. Here we describe a cardiac enrichment approach using nonintegrating adeno-associated virus (AAV). We first examined several AAV serotypes for their ability to selectively transduce iPSC-derived cardiomyocytes. Results showed that AAV1 demonstrated the highest in vitro transduction efficiency among seven widely used serotypes. Next, differentiated iPSC derivatives were transduced with drug selectable AAV1 expressing neomycin resistance gene. Selection with G418 enriched the cardiac cell fraction from 27% to 57% in 2 weeks. Compared with other enrichment strategies such as integrative genetic selection, mitochondria labeling, or surface marker cell sorting, this simple AAV method described herein bypasses antibody or dye labeling. These findings provide proof of concept for large-scale cardiomyocyte enrichment by exploiting AAV's intrinsic tissue tropism. PMID- 26252066 TI - Corynebacterium pseudodiphtheriticum: Putative probiotic, opportunistic infector, emerging pathogen. PMID- 26252067 TI - Historical Context and Recent Advances in Exposure-Response Estimation for Deriving Occupational Exposure Limits. AB - Virtually no occupational exposure standards specify the level of risk for the prescribed exposure, and most occupational exposure limits are not based on quantitative risk assessment (QRA) at all. Wider use of QRA could improve understanding of occupational risks while increasing focus on identifying exposure concentrations conferring acceptably low levels of risk to workers. Exposure-response modeling between a defined hazard and the biological response of interest is necessary to provide a quantitative foundation for risk-based occupational exposure limits; and there has been considerable work devoted to establishing reliable methods quantifying the exposure-response relationship including methods of extrapolation below the observed responses. We review several exposure-response modeling methods available for QRA, and demonstrate their utility with simulated data sets. PMID- 26252068 TI - Bioavailability and Electroreactivity of Zinc Complexed to Strong and Weak Organic Ligands. AB - Laboratory experiments have established the importance of complexation by organic ligands in determining the bioavailability of trace metals to marine phytoplankton, while electrochemical measurements with field samples have demonstrated that a large fraction of bioactive trace metals are complexed to strong organic ligands in seawater. Using the model organic ligands, EDTA and histidine, we show a quantitative correspondence between the bioavailability of Zn to the diatom Thalassiosira weissflogii, and its reduction at -1.2 V (vs Ag/AgCl) on a hanging mercury drop electrode. Equilibrium calculations and polarographic data indicate that Zn bound in inorganic complexes and the 1:1 Zn histidine complex, but not in the 1:2 Zn-histidine complex or the Zn-EDTA complexes, is taken up by the organism and reduced at the electrode surface, confirming a previous report of the bioavailability of weak Zn complexes. Electrochemical measurements of Zn speciation in seawater do not generally reveal the presence of weak (and potentially bioavailable) complexes; but such measurements (particularly by Anodic Stripping Voltammetry) should nonetheless often provide good estimates of the bioavailable Zn concentrations. These results can likely be generalized to other bioactive divalent trace metals. PMID- 26252069 TI - Finite element implementation of a new model of slight compressibility for transversely isotropic materials. AB - Modelling transversely isotropic materials in finite strain problems is a complex task in biomechanics, and is usually addressed by using finite element (FE) simulations. The standard method developed to account for the quasi incompressible nature of soft tissues is to decompose the strain energy function (SEF) into volumetric and deviatoric parts. However, this decomposition is only valid for fully incompressible materials, and its use for slightly compressible materials yields an unphysical response during the simulation of hydrostatic tension/compression of a transversely isotropic material. This paper presents the FE implementation as subroutines of a new volumetric model solving this deficiency in two FE codes: Abaqus and FEBio. This model also has the specificity of restoring the compatibility with small strain theory. The stress and elasticity tensors are first derived for a general SEF. This is followed by a successful convergence check using a particular SEF and a suite of single-element tests showing that this new model does not only correct the hydrostatic deficiency but may also affect stresses during shear tests (Poynting effect) and lateral stretches during uniaxial tests (Poisson's effect). These FE subroutines have numerous applications including the modelling of tendons, ligaments, heart tissue, etc. The biomechanics community should be aware of specificities of the standard model, and the new model should be used when accurate FE results are desired in the case of compressible materials. PMID- 26252070 TI - Combinatorial interactions between LBD10 and LBD27 are essential for male gametophyte development in Arabidopsis. AB - The LATERAL ORGAN BOUNDARIES DOMAIN/ASYMMETRIC LEAVES2-LIKE (LBD/ASL) genes encodes a unique class of transcription factors that play roles in diverse aspects of lateral organ development in plants. The Arabidopsis LBD gene family comprises 42 members and biological functions of most of the LBD genes are unknown. Our molecular genetic analysis and a variety of functional assays including expression analysis, genetic transmission and pollen viability assays, and pollen development analysis demonstrated that LBD10 co-acts with SIDECAR POLLEN(SCP)/LBD27 to control an early stage of microspore development but also plays a distinct role at later bicellular and tricellular pollen stages and that these 2 LBD genes are essential for Arabidopsis pollen development. We also showed that LBD10 and LBD27 interact with each other to be localized into the nucleus. Our subcellular localization analysis of LBD10 in comparison with LBD27 during pollen development indicated that regulated protein degradation may be involved in determining spatially and temporally distinct and overlapping expression patterns of these LBD transcription factors, contributing to distinct and combinatorial roles of LBD10 and LBD27 in Arabidopsis pollen development. PMID- 26252071 TI - Associations Between Selected Xenobiotics and Antinuclear Antibodies in the National Health and Nutrition Examination Survey, 1999-2004. AB - BACKGROUND: Potential associations between background environmental chemical exposures and autoimmunity are understudied. OBJECTIVES: Our exploratory study investigated exposure to individual environmental chemicals and selected mixtures in relation to the presence of antinuclear antibodies (ANA), a widely used biomarker of autoimmunity, in a representative sample of the U.S. METHODS: This cross-sectional analysis used data on 4,340 participants from the National Health and Nutrition Examination Survey (1999-2004), of whom 14% were ANA positive, to explore associations between ANA and concentrations of dioxins, dibenzofurans, polychlorinated biphenyls, organochlorines, organophosphates, phenols, metals, and other environmental exposures and metabolites measured in participants' serum, whole blood, or urine. For dioxin-like compounds with toxic equivalency factors, we developed and applied a new statistical approach to study selected mixtures. Lognormal models and censored-data methods produced estimates of chemical associations with ANA in males, nulliparous females, and parous females; these estimates were adjusted for confounders and accommodated concentrations below detectable levels. RESULTS: Several associations between chemical concentration and ANA positivity were observed, but only the association in males exposed to triclosan remained statistically significant after correcting for multiple comparisons (mean concentration ratio = 2.8; 95% CI: 1.8, 4.5; p < 0.00001). CONCLUSIONS: These data suggest that background levels of most xenobiotic exposures typical in the U.S. population are not strongly associated with ANA. Future studies should ideally reduce exposure misclassification by including prospective measurement of the chemicals of concern and should track changes in ANA and other autoantibodies over time. CITATION: Dinse GE, Jusko TA, Whitt IZ, Co CA, Parks CG, Satoh M, Chan EKL, Rose KM, Walker NJ, Birnbaum LS, Zeldin DC, Weinberg CR, Miller FW. 2016. Associations between selected xenobiotics and antinuclear antibodies in the National Health and Nutrition Examination Survey, 1999-2004. Environ Health Perspect 124:426-436; http://dx.doi.org/10.1289/ehp.1409345. PMID- 26252072 TI - How are bodies special? Effects of body features on spatial reasoning. AB - Embodied views of cognition argue that cognitive processes are influenced by bodily experience. This implies that when people make spatial judgments about human bodies, they bring to bear embodied knowledge that affects spatial reasoning performance. Here, we examined the specific contribution to spatial reasoning of visual features associated with the human body. We used two different tasks to elicit distinct visuospatial transformations: object-based transformations, as elicited in typical mental rotation tasks, and perspective transformations, used in tasks in which people deliberately adopt the egocentric perspective of another person. Body features facilitated performance in both tasks. This result suggests that observers are particularly sensitive to the presence of a human head and body, and that these features allow observers to quickly recognize and encode the spatial configuration of a figure. Contrary to prior reports, this facilitation was not related to the transformation component of task performance. These results suggest that body features facilitate task components other than spatial transformation, including the encoding of stimulus orientation. PMID- 26252073 TI - Seafood Allergy, Toxicity, and Intolerance: A Review. AB - Seafood allergies have been increasing their presence in the last 2 decades. Allergic reactions to seafood can range from mild urticarial and oral allergy syndrome to life-threatening anaphylactic reactions. Ingestion of seafood infested with Anisakis larvae can cause a disease known as anisakiasis with symptoms similar to true seafood allergy. Furthermore, some adverse reactions to seafood including histamine fish poisoning (HFP), and intolerance to histamine can trigger clinical symptoms, which, although nonallergic in origin, are similar to true immunoglobulin E (IgE)-mediated allergic reactions. Because seafood allergy usually remains a lifelong food allergy, this review focuses on the current knowledge on fish and shellfish allergens and emphasizes the importance of differentiating seafood allergy from other allergy-like reactions (anisakiasis, HFP, and intolerance to histamine). Key teaching points: * Fish and shellfish are potent allergens that can provoke serious IgE antibody-mediated adverse reactions in sensitive individuals. * Sensitization to seafood allergens can be achieved by ingestion, inhalation, or skin contact. * Shellfish major allergen, tropomyosin, shares significant homology to arthropods (dust mites and cockroaches). * Accidental exposures to seafood products cross-contaminated with fish or shellfish allergens (hidden allergens) during processing may present a health risk for sensitive individuals. * Allergens of fish parasite A. simplex present common hidden allergens in seafood, particularly in raw and undercooked home-made fish dishes. * Symptoms caused by HFP, histamine intolerance, and anisakiasis are similar to true seafood allergy. PMID- 26252076 TI - Erratum. PMID- 26252077 TI - Biomechanical and Electromyographic Comparisons of Isometric Trunk Flexor Endurance Test Postures: Prone Plank Versus V-Sit. AB - The objective of this study was to investigate why holding times on 2 different tests of isometric trunk flexor endurance capacity (prone plank and v-sit) are weakly correlated. Body position and ground reaction force data from 10 men and 10 women were used to conduct static biomechanical analyses of both test postures, and bilateral activations of the rectus abdominis, internal and external obliques, latissimus dorsi, and lumbar and thoracic erector spinae were measured in a second sample of 15 men and 15 women while holding the test postures. No between-posture differences in net low back flexor moments were found (P = .111), but the lumbar spine was 28 degrees more flexed in the v-sit than in the plank (P < .001). No between-posture differences were detected in the rectus abdominis (P = .397), external obliques (P = .204), internal obliques (P = .226), or lumbar erector spinae (P = .116) activation levels, but those of the thoracic erector spinae (P = .0253) and latissimus dorsi (P < .001) were greater in the plank than in the v-sit. Altogether, the findings suggest that differences between plank and v-sit holding times are most likely related to between-test differences in lumbar spine postures and shoulder demands. PMID- 26252078 TI - Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates. AB - Transition state and high energy intermediate mimetics have the potential to be very potent enzyme inhibitors. In this study, a model of peptide hydrolysis in the active site of insulin-regulated aminopeptidase (IRAP) was developed using density functional theory calculations and the cluster approach. The 3D structure models of the reaction coordinates were used for virtual screening to obtain new chemical starting points for IRAP inhibitors. This mechanism-based virtual screening process managed to identify several known peptidase inhibitors from a library of over 5 million compounds, and biological testing identified one compound not previously reported as an IRAP inhibitor. This novel methodology for virtual screening is a promising approach to identify new inhibitors mimicking key transition states or intermediates of an enzymatic reaction. PMID- 26252079 TI - Leaching of S-metolachlor, terbuthylazine, desethyl-terbuthylazine, mesotrione, flufenacet, isoxaflutole, and diketonitrile in field lysimeters as affected by the time elapsed between spraying and first leaching event. AB - The effect of elapsed time between spraying and first leaching event on the leaching behavior of five herbicides (terbuthylazine, S-metolachlor, mesotrione, flufenacet, and isoxaflutole) and two metabolites (desethyl-terbuthylazine and diketonitrile) was evaluated in a 2011-2012 study in northwest Italy. A battery of 12 lysimeters (8.4 m(2) long with a depth of 1.8 m) were used in the study, each filled with silty-loam soil and treated during pre-emergence with the selected herbicides by applying a mixture of commercial products Lumax (4 L ha( 1)) and Merlin Gold (1 L ha(-1)). During treatment periods, no gravity water was present in lysimeters. Irrigation events capable of producing leaching (40 mm) were conducted on independent groups of three lysimeters on 1 day after treatment (1 DAT), 7 DAT, 14 DAT, and 28 DAT. The series was then repeated 14 days later. Leachate samples were collected a few days after irrigation; compounds were extracted by solid phase extraction and analyzed by high-performance liquid chromatography and gas chromatography-mass spectrometry. Under study conditions, terbuthylazine and S-metolachlor showed the highest leaching potentials. Specifically, S-metolachlor concentrations were always found above 0.25 ug L(-1). Desethyl-terbuthylazine was often detected in leached waters, in most cases at concentrations above 0.1 ug L(-1). Flufenacet leached only when irrigation occurred close to the time of herbicide spraying. Isoxaflutole and mesotrione were not measured (<0.1 ug L(-1)), while diketonitrile was detected in concentrations above 0.1 ug L(-1) on 1 DAT in 2011 only. PMID- 26252080 TI - The Acute Effects of Supramaximal High-Intensity Intermittent Exercise on Vascular Function in Lean vs. Obese Prepubescent Boys. AB - PURPOSE: To determine the acute effects of high-intensity intermittent exercise (HIIE) on vascular function. METHODS: Lean (n = 18, BMI = 17.1 +/- 0.7) and obese (n = 17, BMI = 25.4 +/- 0.8) prepubescent boys aged 10.2 +/- 0.2 years were studied. HIIE consisted of 8 sets of 20 s of cycle ergometry at 100, 130, and 170% of VO2peak alternating with 10 s of rests. RESULTS: The obese group had higher (p < .05) body mass, BMI, body fat percentage, waist-hip ratio than the lean group. Carotid artery wall thickness and arterial stiffness as assessed by brachial-ankle pulse wave velocity (baPWV) were greater in the obese than in the lean group (p < .05). Brachial artery flow-mediated dilation (FMD) was not different between the groups. Total energy expenditure increased gradually as the exercise intensity increased in both groups (p < .05). The obese group had significantly greater total energy expenditure in all three HIIE intensities than the lean group. FMD tended to be higher and baPWV lower as the exercise intensity increased in both groups. Only the HIIE at 170% demonstrated greater FMD compared with the baseline in both groups. baPWV decreased significantly after HIIE at 130 and 170% VO2peak in both groups. CONCLUSION: Supramaximal HIIE can be a feasible exercise modality for improving vascular function in obese prepubescent boys. Future exercise intervention studies are warranted. PMID- 26252081 TI - The combined use of miRNAs and mRNAs as biomarkers for the diagnosis of papillary thyroid carcinoma. AB - Thyroid carcinoma (TC) is the most common malignancy of the endocrine system, and papillary thyroid carcinoma (PTC) accounts for the largest proportion of cases with TC. Although histology is considered the gold standard in the diagnosis of PTC, the sensitivity and specificity of this method is low. Therefore, developing novel diagnostic and prognostic biomarkers for PTC is essential. MicroRNAs (miRNAs or miRs) and their target RNAs play critical roles in tumorigenesis and tumor progression. Thus, the characteristic miRNA and mRNA expression profiles may function as diagnostic biomarkers for tumors, making it possible to predict the tumor stage and the prognosis of patients. In the present study, we detected miRNAs and mRNAs which can function as novel biomarkers for the diagnosis of PTC. The sensitivity of the diagnostic tests was evaluated by receiver operating characteristic curve analysis. Pearson's correlation analysis was used to determine the correlation between mRNAs and miRNAs, and cancer types. We found that the area under the curve (AUC) values of 8 miRNAs (miR-106a, miR-15a, miR 30a, miR-30b, miR-20a, miR-20b, miR-30d and miR-30e) and 8 mRNAs [axis inhibition protein 2 (AXIN2), integrin, alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) (ITGA3), tumor protein p53 inducible nuclear protein (TP53INP)1, TP53INP2, B-cell CLL/lymphoma 2 (BCL2), phosphatase and tensin homolog (PTEN), FOS and K(lysine) acetyltransferase 2B (KAT2B)] were >0.90. The combination of miR-15a and AXIN2 significantly improved the diagnostic accuracy. Therefore, our data indicate that the differential expression of miRNAs combined with that of their target mRNAs may serve as a powerful biomarker for distinguishing PTC from benign tissues. PMID- 26252082 TI - Downregulation of BCRP and anti-apoptotic proteins by proadifen (SKF-525A) is responsible for the enhanced mitoxantrone accumulation and toxicity in mitoxantrone-resistant human promyelocytic leukemia cells. AB - Multidrug resistance caused by the overexpression of ABC transporter proteins in cancer cells remains a major obstacle limiting chemotherapy efficacy. Drugs inhibiting these transporters have been shown to increase the anti-proliferative properties of chemotherapeutics. As we previously described, proadifen, a P450 monooxygenase inhibitor, might also be able to inhibit some ABC transporters, including breast cancer resistance protein (BCRP). Because mitoxantrone (MTX) is a strong BCRP substrate and is often used in the treatment of leukemia, we investigated the effect of 24 h proadifen pre-treatment on the cytotoxicity of MTX in leukemic cell lines that are sensitive to MTX (HL-60) and MTX-resistant ABCG2-overexpressing subclone (cBCRP). We show for the first time that proadifen is able to enhance the cytotoxic properties of MTX in cBCRP cells, particularly through the inhibition of BCRP expression and activity. This proadifen-MTX synergism was also mediated by the inhibition of various cellular proteins engaged in apoptosis, including Mc-1, Bcl-xL, survivin and activation of procaspase-3. Proadifen also decreased the expression of gammaH2AX, which is involved in the recruitment of reparation proteins. Moreover, the inhibition of DNA damage repair proteins Ku86 and B23 after proadifen treatment indicate a possible role of proadifen in DNA repair blockage, thus suppressing the reparation rate of MTX-induced DSBs. PMID- 26252083 TI - A new oxolane from Enterobacter cloacae. AB - Enterobacter cloacae is a highly pathogenic Gram-negative proteobacterium which is responsible for a wide array of infections. In the present study, the fermentation culture of E. cloacae has yielded one new oxolane compound, Rimboxo (1) in addition to three known compounds, i.e. Maculosine (2), phenylacetic acid (3) and methyl myristate (4). These compounds were isolated and characterised using extensive chromatographic and spectroscopic methods, and were subjected to cytotoxicity evaluations. PMID- 26252084 TI - [Analysis of parental origin of de novo SCN1A mutations in Dravet syndrome]. AB - OBJECTIVE: To analyze the parental origin of de novo SCN1A mutations in 22 patients with Dravet syndrome (DS). METHODS: Clinical data and peripheral blood DNA of the patients and their parents were collected. SCN1A gene mutation was screened by polymerase chain reaction (PCR) and Sanger sequencing. For de novo mutations, allele-specific-PCR (AS-PCR) was used to determine their parental origins. Should the mutations be of paternal origin, semen specimen for their fathers was analyzed using PCR and Sanger sequencing for SCN1A gene mutations. RESULTS: The parental origins of 22 de novo mutations were successfully determined by AS-PCR. Nineteen (86.4%) of the mutations had a paternal origin and 3 (13.6%) had a maternal origin. For those with a paternal origin, semen samples from 9 fathers were analyzed, but no mutation was found. CONCLUSION: The majority of de novo SCN1A mutations were of paternal origin. The same mutation was not found in semen samples from the fathers, for which deep sequencing may be necessary. PMID- 26252085 TI - [Effect of curcumin on oligomer formation and mitochondrial ATP-sensitive potassium channels induced by overexpression or mutation of alpha-synuclein]. AB - OBJECTIVE: To investigate the effect of curcumin on oligomer formation and mitochondrial ATP-sensitive potassium channels (mitoKATP) induced by overexpression or mutation of alpha-synuclein. METHODS: Recombinant plasmids alpha-synuclein-pEGFP-A53T and alpha-synuclein-pEGFP-WT were transfected into PC12 cells by lipofectamin method, and intervened by application of curcumin (20 MUmol/L) and 5-hydroxydecanoate (5-HD). Oligomer formation in the cultured cells was identified by Western blotting and Dot blotting. Cytotoxicity and apoptosis of the PC12 cells were measured by lactate dehydrogenase (LDH) and JC-1 assays. mitoKATP were identified by Western blotting and whole cell patch clamp. RESULTS: Curcumin has significantly reduced the oligomer formation induced by overexpression or mutation of alpha-synuclein in the cultured cells. LDH has decreased by 36.3% and 23.5%, and red/green fluorescence ratio of JC-1 was increased respectively by 48.46% and 50.33% after application of curcumin (P<0.05). Protein expression of Kir6.2 has decreased and mitoKATP channel current has significantly increased (P<0.05). CONCLUSION: Curcumin can inhibit alpha synuclein gene overexpression or mutation induced alpha-synuclein oligomers formation. It may block apoptosis induced by wild-type overexpression or mutation of alpha-synuclein. By stabilizing mitochondrial membrane potential. Opening of mitoKATP channel may have been the initiating protective mechanism of apoptosis induced by wild-type overexpression or mutation of alpha-synuclein. Curcumin may antagonize above cytotoxicity through further opening the mitoKATP channel. PMID- 26252086 TI - [Analysis of USH2A gene mutation in a Chinese family affected with Usher syndrome]. AB - OBJECTIVE: To investigate the disease-causing mutation in a Chinese family affected with Usher syndrome type II. METHODS: All of the 11 members from the family underwent comprehensive ophthalmologic examination and hearing test, and their genomic DNA were isolated from venous leukocytes. PCR and direct sequencing of USH2A gene were performed for the proband. Wild type and mutant type minigene vectors containing exon 42, intron 42 and exon 43 of the USH2A gene were constructed and transfected into Hela cells by lipofectamine reagent. Reverse transcription (RT)-PCR was carried out to verify the splicing of the minigenes. RESULTS: Pedigree analysis and clinical diagnosis indicated that the patients have suffered from autosomal recessive Usher syndrome type II. DNA sequencing has detected a homozygous c.8559-2A>G mutation of the USH2A gene in the proband, which has co-segregated with the disease in the family. The mutation has affected a conserved splice site in intron 42, which has led to inactivation of the splice site. Minigene experiment has confirmed the retaining of intron 42 in mature mRNA. CONCLUSION: The c.8559-2A>G mutation in the USH2A gene probably underlies the Usher syndrome type II in this family. The splice site mutation has resulted in abnormal splicing of USH2A pre-mRNA. PMID- 26252087 TI - [Analysis of chromosome regions 8q11.1-q13.3, 1q32-q34.3 and 14q31.1-q13.3 in a Chinese family with congenital preauricular fistula]. AB - OBJECTIVE: To identify the candidate chromosomal region for congenital preauricular fistula (CPF) through analysis of an affected Chinese family. METHODS: Conventional linkage analysis using short tandem repeats (STR) markers was performed to investigate three chromosomal regions 8q11.1-q13.3, 1q32-q34.3 and 14q31.1-q31.3. RESULTS: None of 16 STRs could attain a LOD score of more than -2.0 (theta=0). Therefore, the three regions were all excluded as the candidate region for the disease. CONCLUSION: CPF features high genetic heterogeneity. The family may have a causative gene elsewhere. Whole-genome-based study is needed to identify its genetic etiology. PMID- 26252088 TI - [Mutation analysis of the TRAPPC2 gene in a Chinese family with X-linked spondyloepiphyseal dysplasia tarda]. AB - OBJECTIVE: To identify potential mutation of TRAPPC2 gene in a Chinese family affected with X-linked spondyloepiphyseal dysplasia tarda (X-SEDL), and explore its underlying molecular mechanism. METHODS: Peripheral blood samples were collected from 32 members of the family and 50 healthy adults to extract genomic DNA. DNA sequences of exons 3 to 6 and their exon/intron boundaries were amplified with PCR amplification. Direct bi-directional sequencing analysis was performed on the PCR products. The sequences were aligned to the reference sequences from the GenBank to determine mutation site and type. RESULTS: A nucleotide substitution of the splice-donor in TRAPPC2 intron 3, c.93+5G>A, was detected in the proband, but no sequence change was detected in TRAPPC2 exons 3 to 6. All of the 6 male patients and 8 female carriers from the family were detected to have carried this mutation. The same mutation was not found in the remaining 18 family members with a normal phenotype and 50 healthy controls. CONCLUSION: We have detected a c.93+5G>A mutation in the TRAPPC2 gene in a Chinese family affected with X-SEDL. Our results have expanded the spectrum of TRAPPC2 mutations and is helpful for presymptomatic and prenatal diagnoses of this disease. PMID- 26252089 TI - [Mutation analysis of HOXD13 gene in a Chinese family affected with autosomal dominant synpolydactyly]. AB - OBJECTIVE: To detect potential mutation in a Chinese family affected with autosomal-dominant synpolydactyly and to provide the basis for prenatal diagnosis. METHODS: Inheritance pattern was determined by clinical examination and pedigree analysis. Blood samples were obtained from members of the family. Genomic DNA was extracted and sequenced following PCR amplification. Suspected mutation was confirmed by subclone sequencing and agarose gel electrophoresis. RESULTS: A 27 bp expansion mutation in exon 1 of HOXD13 was identified in all affected individuals from the family but not in unaffected members and normal controls. The mutation has caused insertion of 9 alanines in the polyalanine expansion region of HOXD13 protein. CONCLUSION: A polyalanine-expansion within the HOXD13 probably underlies the disease in this family. PMID- 26252090 TI - [A novel mutation T8821G in mitochondrial DNA may be associated with Leber's hereditary optic neuropathy]. AB - OBJECTIVE: To report on clinical, genetic and molecular characterization of two Chinese families with Leber's hereditary optic neuropathy. METHODS: Ophthalmological examinations have revealed variable severity and age at onset of visual loss among the probands and other matrilineal relatives of both families. The entire mitochondrial genome of the two probands was amplified with PCR in 24 overlapping fragments using sets of oligonucleotide primers. RESULTS: The ophthalmological examinations showed that penetrance was 12.5% and 30.0% respectively in the two families. Sequence analysis of the complete mitochondrial genomes in these pedigrees has identified unreported homoplasmic T8821G mutation in the ATPase 6 gene and distinct sets of polymorphisms belonging to haplogroups M10a. The T8821G mutation has occurred at the extremely conserved nucleotide (conventional position 99) of the ATPase6. Thus, this mutation may alter structural formation of ATPase6, thereby leading to failure in the synthesis of ATP involved in visual impairment. CONCLUSION: Above observations have suggested that the ATPase6 T8821G mutation may be involved in the pathogenesis of optic neuropathy in these families. PMID- 26252091 TI - [Genetic and prenatal diagnosis for a Chinese family with primary carnitine deficiency]. AB - OBJECTIVE: To identify potential mutation of SLC22A5 gene in a 5-month-old boy affected with primary carnitine deficiency and provide genetic counseling and prenatal diagnosis for the members of his family. METHODS: DNA was extracted from peripheral blood samples derived from the proband, his parents and elder sister, as well as amniotic fluid from his pregnant mother. All of the 10 exons of the SLC22A5 gene were amplified by PCR and subjected to Sanger sequencing. The amniotic fluid sample was also subjected to G-banded karyotyping and multiplex ligation-dependent probe amplification (MLPA). RESULTS: A homozygous mutation c.760C>T (p.R254X) of the SLC22A5 gene was detected in the proband. Heterozygous mutation c.760C>T (p.R254X) was also found in other family members including the fetus. The karyotyping and chromosomal microdeletion testing for the amniotic fluid sample were both normal. CONCLUSION: The newly identified homozygous nonsense c.760C>T (p.R254X) mutation of the SLC22A5 gene probably underlies the primary carnitine deficiency of the proband. Genetic counseling and prenatal diagnosis have been provided for this family. PMID- 26252092 TI - [Detection of a recurrent de novo mutation in a Chinese family affected with Duchenne muscular dystrophy]. AB - OBJECTIVE: To provide genetic analysis for a family affected with Duchenne muscular dystrophy (DMD) with a recurrent de novo mutation. METHODS: Multiplex ligation dependent probe amplification (MLPA) was used to detect potential deletion and duplication of the DMD gene, and the DNA products were sequenced on a Genetic Analyzer 3130 sequencer. Haplotype analysis was performed using four short tandem repeat polymorphism loci (44C/A, 45C/A, 49C/A and 63C/A) of the DMD gene for the family. RESULTS: A same deletional mutation (Del 48-50) of the DMD gene was detected in the proband and fetus, but not in their mother. The proband and fetus have inherited the same haplotype of the DMD gene from their mother. The fetus was predicted to be affected by the disease. CONCLUSION: Above findings suggested that the mother was very likely to have a germline mosaicism for the DMD gene mutation. For the de novo DMD mutation, although genetic analysis of peripheral blood DNA has indicated that the proband's mother was not a carrier, germline mosaicism could still not be ruled out, and prenatal gene diagnosis should be provided for subsequent pregnancies. PMID- 26252093 TI - [Regulation of Smad ubiquitination regulatory factor 1 expression by NF-kappaB]. AB - OBJECTIVE: To identify a nuclear factor kappaB (NF-kappaB) responsive element within the Smad ubiquitination regulatory factor 1 (SMURF1) gene promoter, and to demonstrate its role in the regulation of SMURF1 expression. METHODS: A series of truncated luciferase reporter plasmids of the SMURF1 promoter were constructed and transfected into hepatic cancer Hep G2 cells. Luciferase assays were carried out to assess the activities of such promoters. DNA binding and chromatin immunoprecipitation (ChIP) assays were used to identify an NF-kappaB responsive element within the SMURF1 promoter. Lucifease plasmid with mutated NF-kappaB site was constructed and its activity was assessed. The expression of SMURF1 in Hep G2 cells was detected after transfection of NF-kappaB specific small interfering RNA (siRNA). RESULTS: The SMURF1 promoter showed a high transcription activity, and the region of -519 to -378 was demonstrated to be a positive regulatory region. 411 to -420 of the SMURF1 promoter was an NF-kappaB responsive element, and NF kappaB may specifically bind to this site. Mutation of this element may prominently decrease the activity of the promoter. Transfection of NF-kappaB siRNA evidently down-regulated SMURF1 expression. CONCLUSION: NF-kappaB can specifically bind to the -411 to -420 region of the SMURF1 promoter and plays an essential role in the expression of SMURF1. PMID- 26252094 TI - [Analysis of clinical features and AGL gene mutations in a family with glycogen storage disease type IIIa]. AB - OBJECTIVE: To investigate the clinical features and AGL gene mutations in a family with glycogen storage disease type IIIa (GSD IIIa). METHODS: Clinical data for diagnosis, treatment and follow-up of a sick child with GSD III was collected and analyzed. Genomic DNA was extracted from the peripheral blood samples from the patient and his parents. Polymerase chain reaction and direct DNA sequencing were utilized to analyze all of the exons of the AGL gene. RESULTS: The genotype of the child was found to be c.3710_3711delTA/IVS14+1G>T. The former was a maternally-inherited mutation, which has not been reported previously. The latter was an abnormal splice-site mutation inherited from the father. CONCLUSION: Based on its clinical and molecular evidences, the patient was diagnosed as GSD IIIa in conjunction with retrobular optic neuritis. PMID- 26252095 TI - [Analysis of TSC gene mutation in a patient with tuberous sclerosis]. AB - OBJECTIVE: To identify pathogenic mutation of the TSC1 and TSC2 genes in a patient with tuberous sclerosis. METHODS: Peripheral venous blood samples and clinical data of a pregnant woman with tuberous sclerosis and 4 family members (parents, uncle and husband) were collected. Genomic DNA was extracted. All coding exons of the TSC1 and TSC2 genes and their flanking intronic sequences were amplified by polymerase chain reaction and subjected to direct sequencing. RESULTS: The patient has presented facial angiofibroma and prefrons fibrous plaque for 20 years, and lumbar connective tissue nevus for 10 years. She also had mental retardation but no epilepsy. A novel frame-shift mutation c.4258 4261delTCAG was detected in exon 34 of the TSC2 gene, which had led to a premature stop codon TAG after the 55th amino acids. The same mutation was not found in the unaffected family members and 100 unrelated healthy controls. CONCLUSION: The novel frame-shifting mutation c.4258-4261delTCAG (p.Ser1420GlyfsX55) in the TSC2 gene may be responsible for the disease in the patient. PMID- 26252096 TI - [Suspected pathogenic mutation identified in two cases with oculocutaneous albinism]. AB - OBJECTIVE: To detect potential mutations in genes related with non-syndromic oculocutaneous albinism I-IV and ocular albinism type I in two couples who had given births to children with albinism. METHODS: All exons of the non-syndromic albinism related genes TYR, OCA2, TYRP-1, MITF, SLC45A2 and GPR143 were subjected to deep sequencing. The results were verified with Sanger sequencing. RESULTS: For the two female carriers, the coding region of the TYR gene was found to harbor a frameshift mutation c.925_926insC, which was also suspected to have been pathogenic. In one of the male partners, a nonsense mutations c.832C>T was found, which was also known to be pathogenic. Another male partner was found to harbor a TYR gene mutation c.346C>T, which was also known to be a pathogenic nonsense mutation. CONCLUSION: The coding region of the TYR gene c.925_926insC (p.Thr309ThrfsX9) probably underlies the OCA1 disease phenotype. PMID- 26252097 TI - [Prenatal diagnosis of a case with combined Wolf-Hirschhorn syndrome and Jacobsen syndrome]. AB - OBJECTIVE: To detect chromosomal imbalance in a fetus with complex congenital heart disease, and to correlate the genotype with the phenotype. METHODS: Routine G-banding was carried out to analyze the karyotypes of the fetus and its parents, and single nucleotide polymorphisms array (SNP-array) was used for delineating fine genomic aberrations. The detected aberrations were confirmed with multiplex ligation-dependent probe amplification (MLPA). RESULTS: The fetus and its parents all showed a normal karyotype, while array-SNP has detected a 13.87 Mb duplication at 4p16.3-p15.33 and a 15.65 Mb deletion at 11q23.3-q25 in the fetus. The results were confirmed by the MLPA assay. CONCLUSION: The partial trisomy 4p (Wolf-Hirschhorn syndrome) and partial monosomy 11q (Jacobsen syndrome) probably underlie the complex heart defects detected in the fetus. Analysis of the karyotypes of its parents offered no help for the determination of the aberrant type and recurrent risk. Compared with routine karyotype analysis, aberrant regions can be identified with array-SNP with greater resolution and accuracy. This has provided useful information for prenatal diagnosis and genetic counseling. PMID- 26252098 TI - [Analysis of copy number variations in alpha-globin gene in the cases with combined increased levels of HbF with beta thalassemia]. AB - OBJECTIVE: To detect copy number changes of alpha-globin gene, and analyze molecular mechanism of the impacts of fetal hemoglobin (HbF) levels for alpha globin gene copy numbers loss or increase. METHODS: A total of 15 cases with combined increased levels of fetal hemoglobin with beta-thalassemia were collected. Firstly, three common alpha-thalassemia deletions were validated by Gap-PCR. Secondly, the largest deletions of the beta-globin gene cluster were detected by multiplex ligation-dependent probe amplification (MLPA). RESULTS: Among the 15 cases, there was 1 case with duplication of the alpha-globin gene cluster, 3 cases of SEA heterozygote deletion of the alpha-globin gene, 1 cases of alpha 3.7 deletion heterozygote of the alpha-globin gene, 1 case of alpha 4.2 deletion homozygote of the alpha-globin gene, 1 case of deletion homozygote in the like alpha-globin gene. A compound heterozygous for SEA and alpha 3.7 of the alpha-globin gene was also detected. However, 7 cases showed no copy numbers loss and increase of the the alpha-globin gene cluster. CONCLUSION: Additional alpha globin gene can produce excessive alpha-chain, which can aggravate imbalance for alpha and beta-chain, and cause clinical symptoms in patients with beta thalassemia. Yet, copy number loss or mutation in alpha-globin gene will cause a milder clinical phenotype. PMID- 26252099 TI - [Phenotypic and genetic analysis of a patient presented with Tietz/Waardenburg type II a syndrome]. AB - OBJECTIVE: To determine the genetic cause for a patient featuring decreased pigmentation of the skin and iris, hearing loss and multiple congenital anomalies. METHODS: Routine chromosomal banding was performed to analyze the karyotype of the patient and his parents. Single nucleotide polymorphism array (SNP array) was employed to identify cryptic chromosome aberrations, and quantitative real-time PCR was used to confirm the results. RESULTS: Karyotype analysis has revealed no obvious anomaly for the patient and his parents. SNP array analysis of the patient has demonstrated a 3.9 Mb deletion encompassing 3p13p14.1, which caused loss of entire MITF gene. The deletion was confirmed by quantitative real-time PCR. Clinical features of the patient have included severe bilateral hearing loss, decreased pigmentation of the skin and iris and multiple congenital anomalies. CONCLUSION: The patient, carrying a 3p13p14.1 deletion, has features of Tietz syndrome/Waardenburg syndrome type IIa. This case may provide additional data for the study of genotype-phenotype correlation of this disease. PMID- 26252100 TI - [Analysis of C.3925_3929 deletional mutations of APC gene in pedigrees with familial adenomatous polyposis]. AB - OBJECTIVE: To analyze the characteristics of germline mutations of adenomatous polyposis coli (APC) gene in pedigrees affected with familial adenomatous polyposis (FAP). METHODS: Genomic DNA was extracted from peripheral blood samples from members of the 13 FAP pedigrees. Multiplex ligation-dependent probe amplification (MLPA) was used to detect large fragment deletions of the APC gene. Subsequently, potential mutation was screened from all exons of the APC gene with PCR amplification and direct sequencing. RESULTS: Germline mutations have been identified in 5 FAP pedigrees, which included c.3184_3187delCAAA, c.5432C>T, c.3925_3928delAAAA and c.3925_3929del AAAAG(in two pedigrees). Small deletional mutations were found primarily in the area of AAAAG tandem repeat sequences. CONCLUSION: C.3925_3929 located in AAAAG tandem repeats is probably the hot spot for APC gene mutations, which are mostly deletional mutations, especially the 5 bp base deletion at codon 1309. PMID- 26252101 TI - [Diagnosis of a case with Williams-Beuren syndrome by single nucleotide polymorphism array]. AB - OBJECTIVE: To explore the genetic cause for a child with mental retardation, developmental delay and multi-systemic developmental disorders by analyzing the copy number variations (CNVs) and correlating the genotype with the phenotype. METHODS: Routine G-banding was performed to analyze the karyotype of the patient and her parents. In addition, single nucleotide polymorphisms array (SNP-array) was used to determine the CNVs, which was confirmed by fluorescence in situ hybridization (FISH). RESULTS: No karyotypic abnormality was detected upon chromosome analysis. However, SNP-array has identified a de novo hemizygous deletion of 1673 kb on chromosome region 7q11.23, which has been associated with Williams-Beuren syndrome. The microdeletion was confirmed by FISH testing. CONCLUSION: A child with Williams-Beuren syndrome has been diagnosed by SNP-array and FISH. The de novo 7q11.23 microdeletion probably underlies the clinical manifestation of the patient. Compared with routine karyotype analysis, SNP-array is more useful for diagnosing children with multiple congenital anomalies with unclear etiology. PMID- 26252102 TI - [Application of next-generation DNA sequencing for prenatal testing of fetal chromosomal aneuploidies]. AB - OBJECTIVE: To explore the value of next-generation sequencing for the non invasive prenatal testing of fetal chromosomal aneuploidies. METHODS: Plasma from 4004 women with singleton pregnancy at a gestational age between 12-35(+5) weeks was collected prior to amniocentesis between April 19th 2011 and December 31st 2013. The samples were divided into three groups: (1) High risk for Down syndrome by biochemical screening; (2) Advanced maternal age; (3) Abnormalities by ultrasound or other methods. Plasma DNA extracted from above samples was sequenced at low coverage. Positive results were verified against the karyotypes of the fetuses. For those with negative results, the fetuses were followed up by telephone call for at least six months after birth. RESULTS: Among 4003 samples subjected to non-invasive prenatal diagnosis, 66 (1.65%) had a positive result. In group 1, 22 cases of trisomy 21 (T21), 3 cases of trisomy 18 (T18), 1 case of 13 trisomy (T13), 8 cases of 45,X and 2 cases of other chromosomal abnormality were detected. In group 2, 13 cases of T21, 2 cases of T18, 1 case of T13, 5 cases of 45,X, 2 cases of 47,XXN and 1 case of other chromosomal abnormality were detected. In group 3, 1 case of T21, 1 case of T18, 1 case of T13, and 3 cases of 47,XXN were detected. For 55 samples underwent prenatal diagnosis, 30 cases of T21 and 4 cases of T18 were discovered, which was consistent with the results of non-invasive prenatal diagnosis. For the 13 cases indicated as 45,X, 3 were verified by karyotype analysis, 2 were verified as mosaicism (45,X/46,XN), 8 were 46,XN (false positives). For the 5 cases indicated as 47,XXN, 2 were verified by karyotype analysis, the other 3 were 46,XN (false positives). Karyotypes of 3 cases suspected for other chromosomal abnormalities were all verified as 46,XN (false positive). Until May 1st 2014, telephone follow-up for those with negative screening results only identified a boy with facial abnormalities and developmental delay, which was similar to his older sister, combined karyotyping and fluorescence in situ hybridization analysis has verified the karyotype of the boy as 46,XY,rec(14)dup(14q)inv(14)(p12q14)pat. CONCLUSION: Our results indicated that sequencing of plasma free DNA can rapidly detect fetal chromosomal aneuploidies. The method is non-invasive, and the results are highly consistent with karyotype analysis in terms of accuracy and specificity. Non-invasive testing can be used as an effective adjunct to conventional prenatal diagnostic methods, which can greatly reduce unnecessary invasive prenatal diagnosis. However, the sensitivity and accuracy for aneuploidy detection other than chromosome 13/18/21 still need to be improved. PMID- 26252103 TI - [Association of single nucleotide polymorphisms of cytochrome P450 gene with susceptibility to gout in ethnic Han males from coastal regions of Shandong province]. AB - OBJECTIVE: To assess the association of cytochrome P450 gene single nucleotide polymorphisms (SNPs) with susceptibility to gout in ethnic Han males from coastal regions of Shandong province. METHODS: Four hundred and eighty male patients with gout and 480 healthy male controls were included. Genotyping was carried out with a custom Illumina GoldenGate Genotyping assay to detect SNP rs2275620 of CYP2C8 gene, SNP rs2070676 of CYP2E1 gene, SNP rs837395 of CYP4B1 gene, and SNP rs194150 of TBXAS1 gene. The association was assessed with chi-square test. RESULTS: No significant difference has been found between the two groups in regard to the genotypic and allelic frequencies of the TT, AT, AA genotypes and A, T alleles of the SNP rs2275620 of the CYP2C8 gene (P=0.88; P=0.97), the CC, CG, GG genotypes and C,G alleles of SNP rs2070676 of the CYP2E1 gene (P=0.24; P=0.09), the TT, AT, AA genotypes and A, T alleles of SNP rs837395 of the CYP4B1 (P=0.88; P=0.97), and TT, AT, AA genotypes and the A,T alleles of SNP rs194150 of TBXAS1 gene (P=0.15; P=0.06). CONCLUSION: This study has identified no association of SNP loci rs2275620(A/T) of CYP2C8, rs2070676(C/G) of CYP2E1, rs837395(A/T) of CYP4B1 and rs194150(A/T) of TBXAS1 with gout in ethnic Han males from coastal regions in Shandong province. However, our result needs to be replicated in larger sets of patients collected from other regions and populations. PMID- 26252104 TI - [Association of prostasin gene rs12597511 polymorphism with outcomes of pregnancy with severe preeclampsia]. AB - OBJECTIVE: To assess the association of prostasin gene rs12597511 polymorphism with clinical features and pregnancy outcomes among patients with severe preeclampsia. METHODS: Clinical manifestations, pregnancy outcomes and the genotypes of 179 patients with severe preeclampsia [early-onset group (<=34 gestational weeks): 79 cases; Late-onset group (>34 gestational weeks): 100 cases] and 222 normal-term pregnant women (control group) were collected. RESULTS: In the early-onset group, the patients with TC or CC genotype at rs12597511 had higher incidences of total complications, liver dysfunction, neonatal asphyxia, neonatal intracranial hemorrhage and perinatal mortality compared with those with TT genotype (P>0.05). Multiple logistic regression analysis showed that the complication rates of severe preeclampsia patients are closely related to TC or CC genotypes, 24 h urinary protein and gestational weeks of onset (OR=1.049, 95% CI:1.007-1.093, P=0.021; OR=1.031, 95% CI: 0.350-0.883, P=0.013; OR=0.733, 95% CI: 0.566-0.950, P=0.019), and the perinatal mortality is related to gestational weeks at delivery (OR=0.542, 95% CI: 0.331-0.887, P=0.015). CONCLUSION: Polymorphism of the prostasin gene is closely associated with poor pregnancy outcomes of early-onset severe preeclampsia. PMID- 26252105 TI - [Association of plasma homocysteine level and polymorphism of methione synthase reductase gene with essential hypertension in ethnic Uyghurs and Hans from Xinjiang]. AB - OBJECTIVE: To assess the association of plasma homocysteine (Hcy) level and 66A/G and 524C/T polymorphisms of methionine synthase reductase (MSR) gene with essential hypertension (EH) in ethnic Uygurs and Hans from Xinjiang. METHODS: From September 2011 to July 2014, 199 Uyghur and 216 Han patients were collected, while 195 healthy Uyghur ethnics and 217 healthy Han ethnics were recruited as the controls. Polymerase chain reaction and restriction fragment length polymorphism (PCR-RELP) was adopted to detect the above polymorphisms. Enzyme immunological assay was applied to measure the levels of plasma Hcy. RESULTS: Compared with the control, plasma Hcy levels were significantly higher in EH group in both Uyghur and Han ethnics (P<0.05). In both ethnic groups, there were also significant differences in MSR 524C/T polymorphism between the patients and controls (Uyghur: chi-square=6.559, P=0.038; Han: chi-square=12.684, P=0.002). No significant difference was found in MSR 66A/G polymorphism between the patients and controls in both ethnic groups (P>0.05). Plasma Hcy level in those with a 66G/524C genotype was statistically higher than that with 66A/524T (P<0.05). After adjusting confounding factors such as gender and age, Logistic regression analysis indicated that age (OR=1.924, 95% CI:1.177- 3.164, P=0.009), obesity (OR=2.491, 95% CI: 1.584-3.920, P<0.01), hyperhomocysteine (OR=1.609, 95% CI: 1.016-2.548, P=0.043) were independent risk factors for EH in Uygurs, while age (OR=1.133, 95% CI: 1.010-81.272, P=0.033), hyperhomocysteine level (OR=3.894, 95% CI: 2.432-6.237, P<0.01), and obesity (OR=1.864, 95% CI: 1.141-3.046, P=0.013) were independent risk factors for EH in Han ethnics. No association was found between the polymorphisms and EH in Uygurs and Hans. CONCLUSION: Age, hyperhomocysteine and obesity were common independent risk factors for EH in both Uygur and Han ethnics from Xinjiang. The MSR 66G genotype can increase the plasma concentration of Hcy, while MSR 524T genotype may reduce it. MSR 524C/T TT genotype may be a protective factor for EH. MSR polymorphisms 66A/G and 524C/T are not independent risk factors for EH in Uygur and Han ethnics from Xinjiang. PMID- 26252106 TI - [Study of molecular mechanism and antigen expression of CisAB01 blood group]. AB - OBJECTIVE: To explore the molecular mechanism of CisAB01 subtype in the ABO blood group system, and to investigate the expression of A and B antigens in red blood cells (RBCs). METHODS: For 5 unrelated individuals with the CisAB phenotype, the molecular basis for the blood type was studied with serological assay, DNA sequencing and haplotype analysis. Bioinformatics analysis was carried out to investigate the changes in structure and function of relevant enzymes. Expression of A and B antigens in RBCs of CisAB01 was detected by flow cytometry. RESULTS: All of the 5 samples were found to have a CisAB01 subtype. The underlying mutations, 467C>T and 803G>C in exon 7, have resulted in replacement of amino acid P156L and G268A. The mean fluorescence intensity (MFI) of A antigen in CisAB01 cases was 135, while the control group was 172. The B antigens in CisAB01 cases (MFI=38) showed significant decrease in MFI compared with the control group (MFI=164). CONCLUSION: 803G>C mutation of the ABO gene probably underlies the CisAB01 subtype. Fluorescence intensity of A antigens in CisAB01 subtype cases is slightly lower than the normal type, while the B antigen was significantly lower. PMID- 26252107 TI - [Sequence analysis of O04 allele expression of A antigen]. AB - OBJECTIVE: To study the molecular basis of O04 allele expression of weak A antigen at the ABO locus. METHODS: Serological assays were performed to characterize the erythrocyte phenotype of a proband. Mutations of the ABO gene were screened with polymerase chain reaction (PCR), reverse-transcription PCR (RT PCR) and DNA sequencing. RESULTS: The proband was identified as weak AB phenotype by serological assays. A B101 allele and an O04 allele were identified by gene sequencing, gene cloning and RT-PCR. CONCLUSION: A B101 allele and an O04 allele were confirmed by the sequencing based typing in a suspicious ABO blood group. The O04 allele is characterized by expression of weak A antigen. PMID- 26252108 TI - [Transglutaminase and neurodegenerative diseases]. AB - Transglutaminase (TG) is a kind of calcium-dependent enzymes. The TGase family found in rodents and human contains 9 types, including TG1-7, blood coagulation factor XIIIa and erythrocyte membrane protein 4.2, with the former 8 types possessing catalytic activity. TG catalyzes various conversion reactions of glutamine, including transamination, deamination and esterification, and participates in post-transcriptional modification of proteins such as cross linking peptides glutamine residue and lysyl-residue, stabilizing protein structure and catalyzing formation of protein aggregates. TGase has been found to contribute to a variety of important physiological and pathological processes and play a role in the pathogenesis of multiple diseases. Notably, neurodegenerative diseases such as Huntington's disease, spinocerebellar ataxia, Alzheimer's disease and Parkinson's disease, have a close connection with TGase's role in the human body. PMID- 26252109 TI - [Diseases of offspring conceived by assisted reproductive technology and epigenetics]. AB - The number of offspring conceived by assisted reproductive technology (ART) has reached over 5 million. As the primary means for treating infertility, the health of offspring produced by ART has been a long concern. Both procedures of ART and factors underlying infertility can lead to epigenetic changes which can cause certain diseases. This paper has reviewed diseases noted among offspring conceived by ART, which include imprinting disorders, metabolic syndromes and cancers. We also tried to explore the pathogenesis of such diseases from an epigenetic perspective, which may help with evaluation the influence of ART on the offspring and its safety for application. PMID- 26252110 TI - [Essential tremor: a pedigree with six cases]. PMID- 26252112 TI - [A pedigree with olivopontocerebellar atrophy]. PMID- 26252111 TI - [Two pedigree with familial thyroid goiter]. PMID- 26252113 TI - [Essential tremor: a pedigree with eight cases]. PMID- 26252114 TI - A Bioorthogonal Ligation of Cyclopropenones Mediated by Triarylphosphines. AB - Bioorthogonal chemistries have been widely used to probe biopolymers in living systems. To date, though, only a handful of broadly useful transformations have been identified because of the stringent requirements placed on the reactants. Here we report a novel bioorthogonal ligation between cyclopropenones and functionalized phosphines. These components are stable in physiological buffers and react rapidly with one another to form covalent adducts. The cyclopropenone ligation is also distinct from other bioorthogonal chemistries in that it makes use of readily accessible, commercially available reagents and proceeds via a nucleophilic reaction pathway. On the basis of these features, the cyclopropenone ligation is poised to join the ranks of chemistries with utility in living systems. PMID- 26252116 TI - Old boy biotech. PMID- 26252117 TI - 'Financial toxicity' looms as cancer combinations proliferate. PMID- 26252115 TI - MicroRNA-205 promotes the tumorigenesis of nasopharyngeal carcinoma through targeting tumor protein p53-inducible nuclear protein 1. AB - Nasopharyngeal carcinoma (NPC) is a common type of cancer in southern China, miRNAs have been shown to be involved in the tumorigenesis of multiple cancer types. The present study aimed to explore the potential role of miR-205 in NPC. Reverse transcription quantitative polymerase chain reaction was used to determine the expression levels of miR-205 in 20 fresh NPC specimens and 20 normal nasopharyngeal tissues. The function of miR-205 in the proliferation, migration, invasion and apoptosis of NPC-derived cells was detected by MTT assay, colony formation assay, wound healing assay, Transwell assay and flow cytometry. Furthermore, a target gene of miR-205 was identified using the luciferase reporter assay. The expression of miR-205 was increased in NPC tissues compared with that in normal tissues. Overexpression of miR-205 was found to promote the proliferation, migration and invasion of NPC-derived cells, while apoptosis was suppressed. Tumor protein p53-inducible nuclear protein 1 was identified as a target gene of miR-205. Overall, the present study demonstrated that miR-205 may function as an oncogene in NPC tumorigenesis. PMID- 26252118 TI - New class PCSK9 blockers stride into cholesterol market. PMID- 26252119 TI - Microbial cocktails join fecal transplants in IBD treatment trials. PMID- 26252120 TI - Blockbuster expectations for hepatitis B therapeutic vaccine. PMID- 26252122 TI - Alnylam, Dicerna tussle over RNAi tech. PMID- 26252121 TI - NCI-MATCH pairs tumor mutations with matching drugs. PMID- 26252123 TI - Court invalidates Sequenom's prenatal test patent. PMID- 26252124 TI - Oxitec trials GM sterile moth to combat agricultural infestations. PMID- 26252125 TI - BGI goes head-to-head with Illumina. PMID- 26252126 TI - PureTech floats away. PMID- 26252127 TI - Around the world in a month. PMID- 26252128 TI - 2Q15-Running of the biotech bulls. PMID- 26252129 TI - Drug pipeline: 2Q15. PMID- 26252130 TI - To share is human. PMID- 26252132 TI - First Rounders Podcast. PMID- 26252131 TI - In house expertise. PMID- 26252133 TI - Health ROI as a measure of misalignment of biomedical needs and resources. PMID- 26252134 TI - Benchmarking the scientific output of the Innovative Medicines Initiative. PMID- 26252135 TI - What does the current biotech stock market value? PMID- 26252136 TI - The smart and gentle microscope. PMID- 26252137 TI - The emergence of agbiogenerics. PMID- 26252139 TI - Deep learning for regulatory genomics. PMID- 26252140 TI - A time and a place for sugar in your ears. PMID- 26252142 TI - New PAMs for Cas. PMID- 26252143 TI - A flexible mesh to record the brain. PMID- 26252144 TI - Erratum: Public biotech 2013-the numbers. PMID- 26252145 TI - Corrigendum: The ethics of publishing human germline research. PMID- 26252146 TI - Corrigendum: Suppression of vascular permeability and inflammation by targeting of the transcription factor c-Jun. PMID- 26252147 TI - Corrigendum: Long-term persistence and development of induced pancreatic beta cells generated by lineage conversion of acinar cells. PMID- 26252148 TI - Erratum: A mass-tolerant database search identifies a large proportion of unassigned spectra in shotgun proteomics as modified peptides. PMID- 26252149 TI - Second-quarter biotech job picture. PMID- 26252154 TI - Branched Polymer-Drug Conjugates for Multivalent Blockade of Angiotensin II Receptors. AB - The use of angiotensin receptor blockers (ARBs) for treatment of ocular diseases associated with neovascularizations, such as proliferative diabetic retinopathy, shows tremendous promise but is presently limited due to short intravitreal half life. Conjugation of ARB molecules to branched polymers could vastly augment their therapeutic efficacy. EXP3174, a potent non-peptide ARB, was conjugated to branched poly(ethylene glycol) (PEG) and poly(amido amine) (PAMAM) dendrimers: 7.8 ligand molecules were tethered to each 40 kDa PEG molecule whereas 16.7 ligand molecules were linked to each PAMAM generation 5 dendrimer. The multivalent PEG and PAMAM conjugates blocked AT1R signaling with an IC50 of 224 and 36.3 nM, respectively. The 6-fold higher affinity of the multivalent ligand conjugated PAMAM dendrimers was due to their unique microarchitecture and ability to suppress polymer-drug interactions. Remarkably, both polymer-drug conjugates exhibited no cytotoxicity, in stark contrast to plain PAMAM dendrimers. With sufficiently long vitreous half-lives, both synthesized polymer-ARB conjugates have the potential to pave a new path for the therapy of ocular diseases accompanied by retinal neovascularizations. PMID- 26252155 TI - Spatial patterns and predictors of trophic control in marine ecosystems. AB - A key question in ecology is under which conditions ecosystem structure tends to be controlled by resource availability vs. consumer pressure. Several hypotheses derived from theory, experiments and observational field studies have been advanced, yet a unified explanation remains elusive. Here, we identify common predictors of trophic control in a synthetic analysis of 52 observational field studies conducted within marine ecosystems across the Northern Hemisphere and published between 1951 and 2014. Spatial regression analysis of 45 candidate variables revealed temperature to be the dominant predictor, with unimodal effects on trophic control operating both directly (r(2) = 0.32; P < 0.0001) and indirectly through influences on turnover rate and quality of primary production, biodiversity and omnivory. These findings indicate that temperature is an overarching determinant of the trophic dynamics of marine ecosystems, and that variation in ocean temperature will affect the trophic structure of marine ecosystems through both direct and indirect mechanisms. PMID- 26252157 TI - Using admixture analysis to examine birth-cohort effects on age at onset of bipolar disorder. AB - OBJECTIVE: It is suggested that age at onset (AAO) of bipolar I disorder (BP-I) is decreasing. We tested for a birth-cohort effect on AAO using admixture analysis. METHOD: A clinical sample of 3896 BP-I cases was analysed using two approaches: (i) in a subsample with untruncated AAO * birth year distribution (n = 1865), we compared the best-fitting model for the observed AAO in patients born <=1960 and >1960, (ii) to control for potential confounders, two separate subsamples born <=1960 and >1960 were matched for age at interview (n = 250), and a further admixture analysis was undertaken. RESULTS: The two approaches indicated that the proportion of cases in the early AAO category was significantly greater in cases born >1960; manic onsets were also more frequent in the early onset BP-I cases born >1960. CONCLUSION: The decrease in AAO of BP-I in recent birth-cohorts appears to be associated with an increase in the proportion of cases in the early onset subgroup; not with a decrease in the mean AAO in each putative subgroup. This could indicate temporal changes in exposure to risk factors for mania. PMID- 26252158 TI - Mesoporous silica particle-PLA-PANI hybrid scaffolds for cell-directed intracellular drug delivery and tissue vascularization. AB - Instructive materials are expected to revolutionize stem cell based tissue engineering. As many stem cell cues have adverse effects on normal tissue homeostasis, there is a need to develop bioactive scaffolds which offer locally retained and cell-targeted drug delivery for intracellular release in targeted cell populations. Further, the scaffolds need to support vascularization to promote tissue growth and function. We have developed an electrospun PLA-PANI fiber scaffold, and incorporated mesoporous silica nanoparticles within the scaffold matrix to obtain cell-targeted and localized drug delivery. The isotropy of the scaffold can be tuned to find the optimal morphology for a given application and the scaffold is electroactive to support differentiation of contractile tissues. We demonstrate that there is no premature drug release from particles under physiological conditions over a period of one week and that the drug is released upon internalization of particles by cells within the scaffold. The scaffold is biocompatible, supports muscle stem cell differentiation and cell seeded scaffolds are vascularized in vivo upon transplantation on the chorioallantoic membrane of chicken embryos. The scaffold is a step towards instructive biomaterials for local control of stem cell differentiation, and tissue formation supported by vascularization and without adverse effects on the homeostasis of adjacent tissues due to diffusion of biological cues. PMID- 26252159 TI - Telomere shortening correlates with accelerated replicative senescence of bronchial fibroblasts in asthma. PMID- 26252151 TI - Epigenetic alterations in the suprachiasmatic nucleus and hippocampus contribute to age-related cognitive decline. AB - Circadian rhythm dysfunction and cognitive decline, specifically memory loss, frequently accompany natural aging. Circadian rhythms and memory are intertwined, as circadian rhythms influence memory formation and recall in young and old rodents. Although, the precise relationship between circadian rhythms and memory is still largely unknown, it is hypothesized that circadian rhythm disruption, which occurs during aging, contributes to age-associated cognitive decline, specifically memory loss. While there are a variety of mechanisms that could mediate this effect, changes in the epigenome that occur during aging has been proposed as a potential candidate. Interestingly, epigenetic mechanisms, such as DNA methylation and sirtuin1 (SIRT1) are necessary for both circadian rhythms and memory. During aging, similar alterations of epigenetic mechanisms occur in the suprachiasmatic nucleus (SCN) and hippocampus, which are necessary for circadian rhythm generation and memory, respectively. Recently, circadian rhythms have been linked to epigenetic function in the hippocampus, as some of these epigenetic mechanisms oscillate in the hippocampus and are disrupted by clock gene deletion. The current paper will review how circadian rhythms and memory change with age, and will suggest how epigenetic changes in these processes might contribute to age-related cognitive decline. PMID- 26252161 TI - Induction of E/Z isomerization in a pendant metal-bound azobenzene: a synthetic, spectroscopic and theoretical study. AB - Re(CO)3 conjugates 1 and 2 that incorporate azobenzenes can be readily generated via one-pot reactions using Schiff base reaction forming conditions. Excitation of the MLCT bands in 1 and 2 results in isomerization of the azobenzene moiety, and this process has been investigated via time-resolved photophysics and TDDFT calculations. PMID- 26252160 TI - Long-Term Maternal Stress and Post-traumatic Stress Symptoms Related to Developmental Outcome of Extremely Premature Infants. AB - In this study, we examined the relations between the severity of developmental outcomes of extremely low birth weight (ELBW) children and their mothers' stress and post-traumatic stress disorder (PTSD) symptoms, 4-16 years after birth. Israeli mothers (N = 78) of a cohort of extremely premature infants (24-27 weeks) born 4-16 years earlier were asked to report about the medical and developmental condition of their child and their current perceived stress and PTSD symptoms. Results show that mothers of ELBW children with normal development reported the lowest perceived stress compared with mothers of ELBW children with developmental difficulties. We also found that 25.6% of the mothers had the potential to suffer from PTSD following the birth of an ELBW child. Furthermore, the severity of prematurity developmental outcomes made a significant contribution to mothers' perceived stress. To sum, mothers of ELBW infants' perceived stress is related to their children's severity of prematurity developmental outcomes, 4-16 years after birth. Clinical implications of these findings are discussed. PMID- 26252162 TI - Participant-driven matchmaking in the genomic era. AB - Whole-genome and whole-exome sequencing are increasingly useful diagnostic tools for novel monogenic conditions. In order to confirm diagnoses made using these technologies, genomic matchmaking-the matching of cases with similar phenotypic and/or genotypic profiles, to narrow the number of candidate genes or ascertain a condition's etiology with greater certainty-is essential. Yet, due to current limitations on the size of matchmaking networks and data sets available to support them, identifying a match can be difficult. We argue that matchmaking efforts led by affected individuals and their families-participant-led efforts offer a twofold solution to this need, in that participants both have the capacity to access larger networks and to provide more detailed sets of phenotypic and genotypic data. These features of participant-led efforts have the potential to increase the value of matchmaking networks, both in terms of number of matches and in terms of the overall energy of the network. We provide two examples of participant-led matchmaking, and propose a model for scaling these efforts. PMID- 26252163 TI - Synergistic effect of a tissue kallikrein 1 and tissue inhibitor of matrix metalloproteinase 1 co-expression vector on the proliferation of rat vascular smooth muscle cells. AB - Tissue kallikrein 1 (TK1) and tissue inhibitor of matrix metalloproteinase 1 (TIMP1) are important in inhibiting vascular smooth muscle cell (VSMC) proliferation and improving vascular remodeling, respectively. It was hypothesized that a combination of TK1 and TIMP1 genes, mediated by an adenovirus vector could augment or act in synergy to enhance the inhibitory effects. The promoter, mCMV carrying hTIMP1 cDNA was subcloned into pDC316-hTK1 to construct a recombinant plasmid carrying hTK1 and hTIMP1 genes. Subsequently, the double gene plasmid and adenovirus backbone plasmid were packaged into HEK293A cells. Gene transcription and protein expression were examined, respectively using reverse transcription-quantitative polymerase chain reaction (PCR) and western blotting assays. VSMC proliferation was assessed using cell counting and methyl-thiazolyl tetrazoliuin methods. The constructed plasmid containing hTK1 and hTIMP1 genes was correctly identified by means of PCR, double digestion and sequencing analysis. The co-expression vector, Ad-hTK1-hTIMP1 was successfully constructed and packaged into HEK293A cells. When VSMCs were transfected with the co expression vector, the mRNA transcription and protein expression of hTK1 and hTIMP1 exhibited abundant expression in a concentration-dependent and time dependent manner, independently. In conclusion, the co-expression vector synergistically inhibited the cell growth and proliferation induced by platelet derived growth factor-BB compared with the single gene vector. PMID- 26252165 TI - Bone marrow-derived mesenchymal stem cells co-expressing interleukin-18 and interferon-beta exhibit potent antitumor effect against intracranial glioma in rats. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) are promising gene vehicles for cancer gene therapy. In our previous study, we reported that BMSCs expressing interleukin (IL)-18 effectively inhibit the growth of glioma in rats. In the present study, we further detected the effect of BMSCs co-expressing IL-18 and interferon (IFN)-beta, both of which are immunostimulatory cytokines. BMSCs were genetically engineered to express IL-18 and IFN-beta by transfection of recombinant lentivirus-mediated gene transfer. Results showed that BMSCs co expressing the two cytokines displayed more significant inhibition effect on glioma cell growth in vitro when compared with BMSCs solely expressing IL-18 or IFN-beta. Treatment of BMSCs co-expressing IL-18 and IFN-beta significantly prolonged the survival and inhibited tumor growth in a rat intracranial glioma model. Furthermore, these genetically engineered BMSCs remarkably promoted cell apoptosis, antitumor cytokine production and CD4+ and CD8+ T-cell infiltration in intracranial glioma tissues than BMSCs solely expressing IL-18 or IFN-beta. Results of the present study suggested that IL-18 and IFN-beta had a synergistic effect on glioma inhibition. Moreover, results provided evidence that delivery of IL-18 and IFN-beta by BMSCs may be an excellent and promising approach to develop an effective treatment protocol for glioma therapy. PMID- 26252164 TI - FOXD3 Promotes PAX3 Expression in Melanoma Cells. AB - Several key transcription factors regulate cell growth, survival, and differentiation during neural crest and melanoblast development in the embryo, and these same pathways may be reactivated in tumors arising from the progenitors of these cells. The transcription factors PAX3 and FOXD3 have essential roles in melanoblasts and melanoma. In this study, we define a regulatory pathway where FOXD3 promotes the expression of PAX3. Both factors are expressed in melanoma cells and there is a positive correlation between the transcript levels of PAX3 and FOXD3. The PAX3 gene contains two FOX binding motifs within highly conserved enhancer regulatory elements that are essential for neural crest development. FOXD3 binds to both of these motifs in vitro but only one of these sites is preferentially utilized in melanoma cells. Overexpression of FOXD3 upregulates PAX3 levels while inhibition of FOXD3 function does not alter PAX3 protein levels, supporting that FOXD3 is sufficient but not necessary to drive PAX3 expression in melanoma cells. Here, we identify a molecular pathway where FOXD3 upregulates PAX3 expression and therefore contributes to melanoma progression. PMID- 26252166 TI - The strikingly different miscibility of n-octanol in highly-confined and quasi confined water. AB - n-Octanol, normally a water-immiscible alcohol, is found to be significantly miscible with highly-confined water, but immiscible with quasi-confined water within the water pool of a reverse micelle as revealed by fluorescence modulation of an excited state proton transfer (ESPT) probe, 8-hydroxypyrene-1,3,6 trisulfonate (HPTS), internalized in the core. Dynamic light scattering (DLS) measurements show a very different pattern of size alteration of the reverse micelle upon octanol addition depending on the initial state of the encapsulating water (confined vs. quasi-confined) indicating different types of partitioning of octanol in the two cases. PMID- 26252167 TI - David and Goliath in a dog's blood. PMID- 26252169 TI - Correction to Octa-Coordination and the Aqueous Ba(2+) Ion. PMID- 26252168 TI - Silver nanoparticles anchored on nitrogen-doped graphene as a novel electrochemical biosensing platform with enhanced sensitivity for aptamer-based pesticide assay. AB - Silver nanoparticles (NPs) decorated nitrogen doped graphene (NG) nanocomposites were prepared through a one-step thermal-treatment route using arginine as the nitrogen source. By integrating the excellent electrical properties and large surface area of Ag NPs and NG, the obtained Ag/NG nanocomposites show more effective electron transfer and high loading capacity than Ag-graphene and pure NG. In the presence of a target, the stronger interaction between the aptamer and the target promotes the formation of a target-aptamer complex on the electrode surface which blocks the electron transfer. Based on this sensing mechanism, a novel and highly sensitive biosensing platform by the use of Ag/NG as enhancing materials is demonstrated for detection of the model target, acetamiprid. The presented aptasensor exhibited a wide linear response for acetamiprid in the range of 1 * 10(-13) M to 5 * 10(-9) M with a low detection limit of 3.3 * 10( 14) M (S/N = 3). Moreover, this electrochemical aptasensor avoided complicated labeling procedures and showed magnificent sensitivity, high selectivity and low cost, which made it not only convenient but also time-saving and applicable. Furthermore, the proposed design may offer a promising way to develop a new electrochemical aptasensor for sensitive and specific detection of a wide spectrum of analytes in food, medical and environmental fields. PMID- 26252170 TI - Readability, Content, and Quality Assessment of Web-Based Patient Education Materials Addressing Neuraxial Labor Analgesia. AB - BACKGROUND: Studies in a variety of disciplines have shown that the readability of Web-based patient education materials is above that of the sixth grade reading level recommended by the U.S. Department of Health and Human Services. The aim of this study was to evaluate the readability, content, and quality of English- and Spanish-language patient education materials addressing neuraxial labor analgesia. METHODS: The websites of 122 U.S. academic medical centers with obstetric anesthesia divisions were searched for English- and Spanish-language patient education materials. Readability of English-language patient education materials was assessed with 3 validated indices: Flesch-Kincaid Grade Level, Simple Measure of Gobbledygook, and Gunning Frequency of Gobbledygook. Readability of Spanish-language patient education materials was assessed using the Spanish Lexile Measure. A 1-sample t test was used to evaluate the mean readability level against the recommended sixth grade reading level. A scoring matrix was developed to evaluate the content of patient education materials. Website quality was assessed using the Patient Education Materials Assessment Tool for Print. RESULTS: We identified 72 English-language and 29 Spanish language patient education materials. The mean readability levels of all patient education materials were higher than the recommended sixth grade reading level using all indices (Flesch-Kincaid Grade Level: 9.1 +/- 1.9, Simple Measure of Gobbledygook: 8.6 +/- 1.4, Gunning Frequency of Gobbledygook: 11.8 +/- 2.1; P < 0.001 for all). All patient education materials discussed the benefits of neuraxial analgesia. However, only 14% (upper 95% confidence interval: 24%) discussed contraindications to neuraxial anesthesia. Postdural puncture headache and hypotension were the most commonly addressed complications (92%). All other complications were addressed by less than half of patient education materials. Patient Education Materials Assessment Tool for Print scores were consistent with poor website understandability (median score, 64%; interquartile range, 64-73). CONCLUSIONS: The mean readability of Web-based patient education materials addressing neuraxial labor analgesia was above the recommended sixth grade reading level. Although most patient education materials explained the benefits of neuraxial analgesia, possible contraindications and complications were not consistently presented. The content, readability, and quality of patient education materials are poor and should be improved to help patients make more informed decisions about analgesic options during labor and delivery. PMID- 26252171 TI - Transversus Abdominis Plane Block Versus Surgical Site Infiltration for Pain Management After Open Total Abdominal Hysterectomy. AB - BACKGROUND: Surgical site infiltration and transversus abdominis plane (TAP) blocks are commonly used to improve pain relief after lower abdominal surgery. This randomized, observer-blinded study was designed to compare the analgesic efficacy of TAP blocks with surgical site infiltration in patients undergoing open total abdominal hysterectomy via a Pfannenstiel incision. METHODS: Patients were randomized to receive either bilateral ultrasound-guided TAP blocks using bupivacaine 0.5% 20 mL on each side (n = 30) or surgical site infiltration with liposomal bupivacaine 266 mg diluted to 60 mL injected in the preperitoneal, subfascial, and subcutaneous planes (n = 30). The remaining aspects of the perioperative care were standardized. An investigator blinded to the group allocation documented pain scores at rest and with coughing, opioid requirements, nausea, vomiting, and rescue antiemetics in the postanesthesia care unit and at 2, 6, 12, 24, and 48 hours postoperatively. The primary outcome measure was pain scores on coughing at 6 hours postoperatively. RESULTS: One patient in each group was excluded from the analysis because of reoperation within 24 hours in the TAP block group and change of incision type in the infiltration group. The pain scores at rest and with coughing were significantly lower in the surgical site infiltration group at all postoperative time points (P < 0.0001) except at rest in the postanesthesia care unit. The opioid requirements between 24 and 48 hours were significantly lower in the infiltration group (P = 0.009). The nausea scores, occurrence of vomiting, and need for rescue antiemetics were similar. CONCLUSIONS: Surgical site infiltration provided superior pain relief at rest and on coughing, as well as reduced opioid consumption for up to 48 hours. Future studies need to compare TAP blocks with liposomal bupivacaine with surgical site infiltration with liposomal bupivacaine. PMID- 26252172 TI - Correction to Thermodynamic Characterization of a Thermostable Antibiotic Resistance Enzyme, the Aminoglycoside Nucleotidyltransferase (4'). AB - Biochemistry 2012, 51 (45), 9147-9155. DOI: 10.1021/bi301126g. Page 9148. A corrected version of the Figure 2 legend appears here: Figure 2. Backbone of the ANT D80Y variant in ribbon representation. Two monomer subunits are colored red and green. Bound kanamycin A molecules are colored blue, and Mg-AMPCPP molecules are colored yellow (Protein Data Bank entry 1KNY).14 Page 9148 (last line). The sentence should read, "A thermostable variant of ANT, T130K, was obtained from thermophilic cyanobacterium T. elongatus." PMID- 26252173 TI - TIEG1 Inhibits Angiotensin II-induced Cardiomyocyte Hypertrophy by Inhibiting Transcription Factor GATA4. AB - The transforming growth factor (TGF-beta)-inducible early gene (TIEG1), a member of the Sp1/Kruppel-like family of transcription factors, plays an important role in regulating cell growth, differentiation, and apoptosis in many human diseases, including breast cancer, osteoporosis, and atherosclerosis. However, little is known about the role of TIEG1 in the heart. In this study, we investigated the role of TIEG1 in angiotensin II (Ang II)-induced cardiomyocyte hypertrophy and its underlying mechanism. Our results showed that TIEG1 expression was downregulated in Ang II-induced hypertrophic cardiomyocytes. Gene silencing of TIEG1 by RNA interference upregulated cellular surface area and ANF and BNP messenger RNA levels, whereas TIEG1 overexpression inhibited the expression of those genes. Mechanistically, TIEG1 could inhibit the expression and transcriptional activity of transcription factor GATA4 in cardiomyocytes, which was recognized as an important factor mediating cardiac gene transcription. In summary, our data disclose a novel role of TIEG1 as an inhibitor in Ang II induced hypertrophic cardiomyocytes through GATA4 signal pathway. PMID- 26252174 TI - Recognizing Physicians with Breastfeeding Expertise. PMID- 26252175 TI - Emerging advances in cancer nanotheranostics with graphene nanocomposites: opportunities and challenges. AB - As an inorganic nanomaterial, graphene nanocomposites have gained much attention in cancer nanotechnology compared with the other inorganic nanomaterial in recent times. Although a relatively new drug carrier, it has been extensively explored as a potential chemotherapeutic carrier and theranostic because of its numerous physicochemical properties, including, capability of multiple pay load, functionalization for drug targeting and photothermal effect. Despite potential benefit, its translation from bench to bed-side in cancer therapy is challenged due to its toxicity concern. Here, we discussed the present progress and future possibilities of graphene nanocomposites as a cancer theranostic. Moreover, the paper also exemplifies the effects of graphene/graphene oxide on tissues and organ functions in order to understand the extent and mechanism of toxicity. PMID- 26252176 TI - Adipokines and beta-cell dysfunction in normoglycemic women with previous gestational diabetes mellitus. AB - INTRODUCTION: An increased risk of developing type 2 diabetes in women with a history of gestational diabetes mellitus(gestational diabetes mellitus - GDM) may be associated with increased insulin resistance and subclinical inflammation. However, approximately half of women with previous GDM (pGDM) do not develop diabetes. These women were the population of focus in the present study. OBJECTIVES: The aim of the study was to assess beta-cell function, insulin resistance, and the levels of pro- and anti inflammatory adipokines in normoglycemic women with pGDM. PATIENTS AND METHODS: A study group included 199 women with pGDM; the mean time after delivery was 7.4 years. A control group included 50 women without pGDM. All patients underwent an oral glucose tolerance test (OGTT) with the assessment of glycemia and insulinemia, beta-cell function (HOMA-%beta), and insulin resistance (HOMA-IR), as well as the levels of soluble tumor necrosis factor alpha receptor (sTNF-alpha-R2), interleukin 6 (IL-6), adiponectin, and visfatin. RESULTS: Normal glucose tolerance was found in 113 women with pGDM (56.8%; the NGT-GDM[+] group) and in 44 control subjects (88.0%). In comparison with controls, the NGT-GDM[+] group had significantly higher glycemia in the OGTT and significantly lower HOMA-%beta values, with comparable HOMA-IR and body mass index values. The NGT-GDM(+) group was shown to have significantly higher levels of sTNF-alpha-R2 and IL-6, with similar adiponectin and visfatin levels. CONCLUSIONS: Normoglycemic women with a history of GDM are characterized by concomitant disturbances in insulin secretion and subclinical inflammation, with normal body weight and insulin sensitivity. It is not known whether these disturbances were present before a GDM-complicated pregnancy or whether they were induced by pregnancy. PMID- 26252177 TI - SHSST-cyclodextrin complex inhibits TGF-beta/Smad3/CTGF to a greater extent than silymarin in a rat model of carbon tetrachloride-induced liver injury. AB - At present, cirrhosis is an incurable liver disease. Transforming growth factor beta (TGF-beta) is important in myofibroblast induction during the cirrhosis initiation process. The current approach in the development of hepatoprotective drugs depends on TGF-beta inhibition. San Huang Shel Shin Tang (SHSST) is a traditional herbal decoction able to exert a protective effect on the liver, however, similar to silymarin, it is limited by its hydrophobicity. In the present study, SHSST was modified with beta-cyclodextrin to form a hydrophilic complex, which improved its bioavailability. In the carbon tetrachloride-induced acute injury animal model, the effects of pretreatment with silymarin, baicalein, SHSST and the SHSST-beta-CD-complex (SHSSTc) at a low and high dose were assessed. The biopsy results revealed marked liver protection following treatment with silymarin, baicalein and SHSST and these effects were improved further following pretreatment with SHSSTc. Protein analysis demonstrated that the hepatoprotective effects of silymarin occurred through inhibition of the TGF beta/Smad-3/connective tissue growth factor (CTGF) signaling pathway. SHSSTc exerted the same protective mechanism, however, SHSSTc suppressed CTGF level to a greater extent compared with the groups treated with SHSST or silymarin. Only pretreatment with SHSST and SHSSTc exhibited partial enhancement in the expression of proteins involved in the regulation of liver regeneration, including extracellular-signal-regulated kinase 5, phospho-nuclear factor of activated T cells 3 and phospho-GATA4. PMID- 26252178 TI - Decrease of mitochondrial p53 during late apoptosis is linked to its dephosphorylation on serine 20. AB - Following a genotoxic stress, the tumor suppressor p53 translocates to mitochondria to take part in direct induction of apoptosis, via interaction with BCL-2 family members such as BAK and BAX. We determined the kinetics of the mitochondrial translocation of p53 in HCT-116 and PA-1 cells exposed to different genotoxic stresses (doxorubicin, camptothecin, UVB). This analysis revealed an early escalation in the amount of mitochondrial p53, followed by a peak amount and a decrease of mitochondrial p53 at later time points. We show that the serine 20 phosphorylated form of p53 is present at the mitochondria and that the decrease of p53 mitochondrial level during late apoptosis correlates with a decrease of Ser-20 phosphorylation. Moreover, the S20A p53 mutant translocates well to mitochondria after a genotoxic stress but its mitochondrial localization is very low during late apoptosis when compared to wt p53. The S20A mutant also appears to be compromised for interaction with BAK. We propose here that the level of serine 20 phosphorylation is influential on p53 mitochondrial localization during late apoptosis. Additionally, we report the presence of a new ?45 kDa caspase-cleaved fragment of p53 in the cytosolic and mitochondrial fractions of apoptotic cells. PMID- 26252180 TI - MicroRNA-374a promotes esophageal cancer cell proliferation via Axin2 suppression. AB - MicroRNA-374a (miR-374a) is involved in the progress of various types of cancer, and may indicate a poor prognosis. However, its role in esophageal cancer remains to be determined. In the present study, the role of miR-374a in esophageal cancers and cancer cell growth was examined using miR-374a overexpression and underexpression models. The results showed that miR-374a was markedly increased in esophageal cancer cell lines and tumor samples from patients with esophageal cancer. In esophageal cancer Eca109 cells, the ectopic overexpression of miR-374a promoted cell growth. Additionally, cell growth was reduced by miR-374a inhibition. The mechanisms underlying the promotive role were examined and it was found that miR-374a significantly decreased the expression and transcription activity of axis inhibition protein 2 (Axin2). Axin2, a tumor suppressor, exhibited a marked inhibitory effect on Eca109 cell growth. The results identified a new role of miR-374a in esophageal cancer involving Axin2 suppression. PMID- 26252179 TI - Offspring DNA methylation of the aryl-hydrocarbon receptor repressor gene is associated with maternal BMI, gestational age, and birth weight. AB - Prenatal smoke exposure, maternal obesity, aberrant fetal growth, and preterm birth are all risk factors for offspring metabolic syndrome. Cord blood aryl hydrocarbon receptor repressor (AHRR) DNA methylation is responsive to maternal smoking during pregnancy. AHRR serves not only to inhibit aryl-hydrocarbon receptor (AHR) transcription, which is involved in mediating xenobiotic metabolism, but it is also involved in cell growth and differentiation. Other than maternal smoking, other predictors of offspring AHRR DNA methylation status remain unknown; we sought to identify them among newborns. We enrolled pregnant women in the PROGRESS birth cohort in Mexico City. Using pyrosequencing, we analyzed DNA methylation of 3 CpG sites within the AHRR gene promoter from the umbilical cord blood of 531 infants. We used generalized estimating equations to account for the correlation of DNA methylation between CpG sites. Multivariable models were used to adjust for maternal age, BMI, education, parity, smoke exposure, infant sex, gestational age, and birth weight-for-gestational age. AHRR DNA methylation was positively associated with maternal BMI (P = 0.0009) and negatively associated with the length of gestation (P < 0.0001) and birth weight for-gestational age (P < 0.0001). AHRR DNA methylation was 2.1% higher in offspring of obese vs. normal weight mothers and 3.1% higher in preterm vs. term infants, representing a third and a half standard deviation differences in methylation, respectively. In conclusion, offspring AHRR DNA methylation was associated with maternal obesity during pregnancy as well as infant gestational age and birth weight-for-gestational age. Further work to discover the health impacts of altered AHRR DNA methylation is warranted. PMID- 26252181 TI - From discharge planner to "concierge": recommendations for hospital social work by clients with intracerebral hemorrhage. AB - The Affordable Care Act and budget cuts have changed the role of hospital social workers by placing pressure on them to conduct speedy discharges and decrease readmission rates. This qualitative study aimed to assess if hospital social work is meeting the needs of clients in the hospital and postdischarge. Semistructured interviews with 10 clients with intracerebral hemorrhage (ICH) and 11 caregivers were conducted. Participants reported that social work services were not meeting their needs. Clients with ICH and their caregivers expressed needs from social workers that surpassed their roles as discharge planners, including counseling, help with finances and insurance, and advocacy. Participants wanted social work services to begin early in acute treatment with continuity postdischarge. Social workers should conduct ethical social work by meeting clients where they are, addressing needs as prioritized by the client, and advocating individually and organizationally for clients. PMID- 26252182 TI - Recognition performance on words interrupted (10 ips, 50% duty cycle) with two interruption patterns referenced to word onset: Young listeners with normal hearing for pure tones and older listeners with sensorineural hearing loss. AB - OBJECTIVE: To determine in an interrupted word paradigm (Maryland CNCs; 10 ips, 50% duty cycle) if different locations of the interruption pattern produce different recognition performances. DESIGN: Repeated measures using two interruption patterns that were complementary halves referenced to word onset; one started with word onset (0-ms), the other started 50 ms later. The hypothesis was that recognition performance would be better on the 0-ms condition than on the 50-ms condition, but there would be some words with the reverse relation. STUDY SAMPLE: Twenty-four young adults with normal hearing for pure tones and 32 older adults (mean = 67 years) with sensorineural hearing loss participated. RESULTS: With the young listeners mean recognition performance on the 0-ms condition (63.1%) was significantly better than the mean performance on the 50-ms condition (47.8%). About twice as many words had better performance on the 0-ms condition. With the older listeners, who were given only stimuli on which performances were > 58% by the young normals, performances on the two conditions were the same. CONCLUSIONS: The hypothesis was supported with the young listeners. The equal performance by the older listeners on the two conditions was attributed to the manner in which the words were selected. PMID- 26252183 TI - Tandem Chloropalladation/Cyclization and Dearomative Cyclization toward Functionalized Tricyclic Bridged [3.2.1] Skeleton Compounds. AB - A palladium-catalyzed tandem reaction is reported that involves chloropalladation/cyclization and dearomative cyclization to construct a tricyclic bridged [3.2.1] carbocyclic-skeleton and oxa- and aza-skeletons. In this domino process, a level of ring strain and other competitive reactions, i.e., protonolysis, beta-hydride elimination, and chlorination of the C-Pd bond, were suppressed to the lowest level under mild reaction conditions. PMID- 26252184 TI - Modeling the impact of interventions against Acinetobacter baumannii transmission in intensive care units. AB - The efficacy of infection control interventions against Acinetobacter baumannii remains unclear, despite such information being critical for effective prevention of the transmission of this pathogen. Mathematical modeling offers an alternative to clinical trials, which may be prohibitively expensive, unfeasible or unethical, in predicting the impact of interventions. Furthermore, it allows the ability to ask key "what if" questions to evaluate which interventions have the most impact. We constructed a transmission dynamic model to quantify the effects of interventions on reducing A. baumannii prevalence and the basic reproduction ratio (R0) in intensive care units (ICUs). We distinguished between colonization and infection, and incorporated antibiotic exposure and transmission from free living bacteria in the environment. Under the assumptions and parameterization in our model, 25% and 18% of patients are colonized and infected with A. baumannii, respectively; and R0 is 1.4. Improved compliance with hand hygiene (>=87%), enhanced environmental cleaning, reduced length of ICU stay of colonized patients (<= 10 days), shorter durations of antibiotic treatment of A. baumannii (<=6 days), and isolation of infected patients combined with cleaning of isolation rooms are effective, reducing R0 to below unity. In contrast, expediting the recovery of the intestinal microbiota (e.g. use of probiotics) is not effective. This study represents a biologically realistic model of the transmission dynamics of A. baumannii, and the most comprehensive analysis of the effectiveness of interventions against this pathogen. Our study provides important data for designing effective infection control interventions. PMID- 26252186 TI - Transgenic Expression of miR-222 Disrupts Intestinal Epithelial Regeneration by Targeting Multiple Genes Including Frizzled-7. AB - Defects in intestinal epithelial integrity occur commonly in various pathologies. miR-222 is implicated in many aspects of cellular function and plays an important role in several diseases, but its exact biological function in the intestinal epithelium is underexplored. We generated mice with intestinal epithelial tissue specific overexpression of miR-222 to investigate the function of miR-222 in intestinal physiology and diseases in vivo. Transgenic expression of miR-222 inhibited mucosal growth and increased susceptibility to apoptosis in the small intestine, thus leading to mucosal atrophy. The miR-222-elevated intestinal epithelium was vulnerable to pathological stress, since local overexpression of miR-222 not only delayed mucosal repair after ischemia/reperfusion-induced injury, but also exacerbated gut barrier dysfunction induced by exposure to cecal ligation and puncture. miR-222 overexpression also decreased expression of the Wnt receptor Frizzled-7 (FZD7), cyclin-dependent kinase 4 and tight junctions in the mucosal tissue. Mechanistically, we identified the Fzd7 messenger ribonucleic acid (mRNA) as a novel target of miR-222 and found that [miR-222/Fzd7 mRNA] association repressed Fzd7 mRNA translation. These results implicate miR-222 as a negative regulator of normal intestinal epithelial regeneration and protection by downregulating expression of multiple genes including the Fzd7. Our findings also suggest a novel role of increased miR-222 in the pathogenesis of mucosal growth inhibition, delayed healing and barrier dysfunction. PMID- 26252188 TI - Retrospective Exposure Assessment for Occupational Disease of an Individual Worker Using an Exposure Database and Trend Analysis. AB - This article outlines a hierarchy of data required for retrospective exposure assessment for occupational disease of an individual worker. It then outlines in a step-wise manner how trend analysis using a relatively large exposure database can be used to estimate such exposure. The process of how a large database containing exposure measurements can be prepared for estimating historic occupational exposures of individual workers in relation to their illnesses is described. The asbestos subset from a large government collected air monitoring database called Medical Surveillance (MESU) was selected to illustrate the cleaning and analysis processes. After unidentifiable values were removed, the cleaned dataset was examined for possible sources of variability such as changes to sampling protocol. Limit of detection (LOD) values were substituted for all non-detectable values prior to the calculation of descriptive statistic using left censored analysis methods (i.e., maximum likelihood estimation (MLE), Kaplan Meier (KM), and simple substitution). The JoinPoint Regression Program was used to perform trend analysis and calculate an annual percentage change (APC) value for the available sampling period. An asbestos case study is presented to illustrate how the APC can then be combined with more recent job and/or process specific exposure data to estimate historic levels. The MESU asbestos dataset contained 1,610 samples from 1984-1995. An average of 17% of this data was left censored. The asbestos air sampling methods in Ontario changed around 1990. LOD values of 0.06 f/cc and 0.02 f/cc were substituted for LOD values pre- and post 1990, respectively. The annual mean fiber levels for the MLE method were an average of 44% lower than KM and substitution methods. The corresponding APC for MLE method was -6.5% and -7.7% for KM and simple substitution. The findings of this paper illustrate how the temporal trend of an exposure databases can be used to efficiently estimate historic contaminant levels in the presence of limited historical information. PMID- 26252185 TI - Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension. AB - Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The prevalence of idiopathic pulmonary arterial hypertension (IPAH) and hereditary pulmonary arterial hypertension (HPAH) is approximately two- to four-fold higher in women than in men. Paradoxically, there is an opposite male bias in typical rodent models of PH (chronic hypoxia or monocrotaline); in these models, administration of estrogenic compounds (for example, estradiol-17beta [E2]) is protective. Further complexities are observed in humans ingesting anorexigens (female bias) and in rodent models, such as after hypoxia plus SU5416/Sugen (little sex bias) or involving serotonin transporter overexpression or dexfenfluramine administration (female bias). These complexities in sex bias in PH remain incompletely understood. We recently discovered that conditional deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells abrogated the male bias in PH in hypoxic mice and that late-stage obliterative lesions in patients of both sexes with IPAH and HPAH showed reduced STAT5a/b, reduced Tyr-P-STAT5 and reduced B-cell lymphoma 6 protein (BCL6). In trying to understand the significance of these observations, we realized that there existed a well-characterized E2-sensitive central neuroendocrine mechanism of sex bias, studied over the last 40 years, that, at its peripheral end, culminated in species-specific male ("pulsatile") versus female ("more continuous") temporal patterns of circulating growth hormone (GH) levels leading to male versus female patterned activation of STAT5a/b in peripheral tissues and thus sex-biased expression of hundreds of genes. In this report, we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations. PMID- 26252187 TI - Stimulation of Brain AMP-Activated Protein Kinase Attenuates Inflammation and Acute Lung Injury in Sepsis. AB - Sepsis and septic shock are enormous public health problems with astronomical financial repercussions on health systems worldwide. The central nervous system (CNS) is closely intertwined in the septic process but the underlying mechanism is still obscure. AMP-activated protein kinase (AMPK) is a ubiquitous energy sensor enzyme and plays a key role in regulation of energy homeostasis and cell survival. In this study, we hypothesized that activation of AMPK in the brain would attenuate inflammatory responses in sepsis, particularly in the lungs. Adult C57BL/6 male mice were treated with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR, 20 ng), an AMPK activator, or vehicle (normal saline) by intracerebroventricular (ICV) injection, followed by cecal ligation and puncture (CLP) at 30 min post-ICV. The septic mice treated with AICAR exhibited elevated phosphorylation of AMPKalpha in the brain along with reduced serum levels of aspartate aminotransferase, tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta) and interleukin-6 (IL-6), compared with the vehicle. Similarly, the expressions of TNF-alpha, IL-1beta, keratinocyte-derived chemokine and macrophage inflammatory protein-2 as well as myeloperoxidase activity in the lungs of AICAR-treated mice were significantly reduced. Moreover, histological findings in the lungs showed improvement of morphologic features and reduction of apoptosis with AICAR treatment. We further found that the beneficial effects of AICAR on septic mice were diminished in AMPKalpha2 deficient mice, showing that AMPK mediates these effects. In conclusion, our findings reveal a new functional role of activating AMPK in the CNS to attenuate inflammatory responses and acute lung injury in sepsis. PMID- 26252189 TI - Profile and Fate of Bacterial Pathogens in Sewage Treatment Plants Revealed by High-Throughput Metagenomic Approach. AB - The broad-spectrum profile of bacterial pathogens and their fate in sewage treatment plants (STPs) were investigated using high-throughput sequencing based metagenomic approach. This novel approach could provide a united platform to standardize bacterial pathogen detection and realize direct comparison among different samples. Totally, 113 bacterial pathogen species were detected in eight samples including influent, effluent, activated sludge (AS), biofilm, and anaerobic digestion sludge with the abundances ranging from 0.000095% to 4.89%. Among these 113 bacterial pathogens, 79 species were reported in STPs for the first time. Specially, compared to AS in bulk mixed liquor, more pathogen species and higher total abundance were detected in upper foaming layer of AS. This suggests that the foaming layer of AS might impose more threat to onsite workers and citizens in the surrounding areas of STPs because pathogens in foaming layer are easily transferred into air and cause possible infections. The high removal efficiency (98.0%) of total bacterial pathogens suggests that AS treatment process is effective to remove most bacterial pathogens. Remarkable similarities of bacterial pathogen compositions between influent and human gut indicated that bacterial pathogen profiles in influents could well reflect the average bacterial pathogen communities of urban resident guts within the STP catchment area. PMID- 26252190 TI - Contribution of muscle hypertrophy to strength gain after training in elderly adults. PMID- 26252191 TI - Photomodulation of strigolactone biosynthesis and accumulation during sunflower seedling growth. AB - Present investigations report the presence of strigolactones (SLs) and photomodulation of their biosynthesis in sunflower seedlings (roots, cotyledons and first pair of leaves) during early phase of seedling development. Qualitative analyses and characterization by HPLC, ESI-MS and FT-IR revealed the presence of more than one type of SLs. Orobanchyl acetate was detected both in roots and leaves. Five-deoxystrigol, sorgolactone and orobanchol were exclusively detected in seedling roots. Sorgomol was detectable only in leaves. HPLC eluted fraction from seedling roots and leaves co-chromatographing with GR24 (a synthetic SL) could also bring about germination in Orobanche cernua (a weed) seeds, which are established to exhibit SL - mediated germination, thereby indicating the SL identity of the eluates using this bioassay. SLs accumulation was always more in the roots of light-grown seedlings, it being maximum at 4 d stage. Although significant activity of carotenoid cleavage dioxygenase (CCD, the enzyme critical for SL biosynthesis) was detected in 2 d old seedling roots, SLs remained undetectable in cotyledons at all stages of development and also in the roots of 2 d old light and dark-grown seedlings. Roots of light-grown seedlings showed maximum CCD activity during early (2 d) stage of development, thereby confirming photomodulation of enzyme activity. These observations indicate the migration of a probable light-sensitized signaling molecule (yet to be identified) or a SL precursor from light exposed aerial parts to the seedling roots maintained in dark. Thus, a photomodulation and migration of SL precursor/s is evident from the present work. PMID- 26252192 TI - Diffusion-weighted and PET/MR Imaging after Radiation Therapy for Malignant Head and Neck Tumors. AB - Interpreting imaging studies of the irradiated neck constitutes a challenge because of radiation therapy-induced tissue alterations, the variable appearances of recurrent tumors, and functional and metabolic phenomena that mimic disease. Therefore, morphologic magnetic resonance (MR) imaging, diffusion-weighted (DW) imaging, positron emission tomography with computed tomography (PET/CT), and software fusion of PET and MR imaging data sets are increasingly used to facilitate diagnosis in clinical practice. Because MR imaging and PET often yield complementary information, PET/MR imaging holds promise to facilitate differentiation of tumor recurrence from radiation therapy-induced changes and complications. This review focuses on clinical applications of DW and PET/MR imaging in the irradiated neck and discusses the added value of multiparametric imaging to solve diagnostic dilemmas. Radiologists should understand key features of radiation therapy-induced tissue alterations and potential complications seen at DW and PET/MR imaging, including edema, fibrosis, scar tissue, soft-tissue necrosis, bone and cartilage necrosis, cranial nerve palsy, and radiation therapy induced arteriosclerosis, brain necrosis, and thyroid disorders. DW and PET/MR imaging also play a complementary role in detection of residual and recurrent disease. Interpretation pitfalls due to technical, functional, and metabolic phenomena should be recognized and avoided. Familiarity with DW and PET/MR imaging features of expected findings, potential complications, and treatment failure after radiation therapy increases diagnostic confidence when interpreting images of the irradiated neck. Online supplemental material is available for this article. PMID- 26252193 TI - Development of municipal solid waste classification in Korea based on fossil carbon fraction. AB - Environmental problems and climate change arising from waste incineration are taken quite seriously in the world. In Korea, the waste disposal methods are largely classified into landfill, incineration, recycling, etc. and the amount of incinerated waste has risen by 24.5% from 2002. In the analysis of CO2emissions estimations of waste incinerators fossil carbon content are main factor by the IPCC. FCF differs depending on the characteristics of waste in each country, and a wide range of default values are proposed by the IPCC. This study conducted research on the existing classifications of the IPCC and Korean waste classification systems based on FCF for accurate greenhouse gas emissions estimation of waste incineration. The characteristics possible for sorting were classified according to FCF and form. The characteristics sorted according to fossil carbon fraction were paper, textiles, rubber, and leather. Paper was classified into pure paper and processed paper; textiles were classified into cotton and synthetic fibers; and rubber and leather were classified into artificial and natural. The analysis of FCF was implemented by collecting representative samples from each classification group, by applying the 14C method, and using AMS equipment. And the analysis values were compared with the default values proposed by the IPCC. In this study of garden and park waste and plastics, the differences were within the range of the IPCC default values or the differences were negligible. However, coated paper, synthetic textiles, natural rubber, synthetic rubber, artificial leather, and other wastes showed differences of over 10% in FCF content. IPCC is comprised of largely 9 types of qualitative classifications, in emissions estimation a great difference can occur from the combined characteristics according with the existing IPCC classification system by using the minutely classified waste characteristics as in this study. IMPLICATIONS: Fossil carbon fraction (FCF) differs depending on the characteristics of waste in each country; and a wide range of default values are proposed by the IPCC. This study conducted research on the existing classifications of the IPCC and Korean waste classification systems based on FCF for accurate greenhouse gas emissions estimation of waste incineration. PMID- 26252194 TI - The Central Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Septic Pathogen Lipid Transport and Clearance. AB - Microbial cell walls contain pathogenic lipids, including LPS in gram-negative bacteria, lipoteichoic acid in gram-positive bacteria, and phospholipomannan in fungi. These pathogen lipids are major ligands for innate immune receptors and figure prominently in triggering the septic inflammatory response. Alternatively, pathogen lipids can be cleared and inactivated, thus limiting the inflammatory response. Accordingly, biological mechanisms for sequestering and clearing pathogen lipids from the circulation have evolved. Pathogen lipids released into the circulation are initially bound by transfer proteins, notably LPS binding protein and phospholipid transfer protein, and incorporated into high-density lipoprotein particles. Next, LPS binding protein, phospholipid transfer protein, and other transfer proteins transfer these lipids to ApoB-containing lipoproteins, including low-density (LDL) and very-low-density lipoproteins and chylomicrons. Pathogen lipids within these lipoproteins and their remnants are then cleared from the circulation by the liver. Hepatic clearance involves the LDL receptor (LDLR) and possibly other receptors. Once absorbed by the liver, these lipids are then excreted in the bile. Recent evidence suggests pathogen lipid clearance can be modulated. Importantly, reduced proprotein convertase subtilisin/kexin type 9 activity increases recycling of the LDLR and thereby increases LDLR on the surface of hepatocytes, which increases clearance by the liver of pathogen lipids transported in LDL. Increased pathogen lipid clearance, which can be achieved by inhibiting proprotein convertase subtilisin/kexin type 9, may decrease the systemic inflammatory response to sepsis and improve clinical outcomes. PMID- 26252195 TI - Spinal Kinematics of Adolescent Male Rowers with Back Pain in Comparison with Matched Controls During Ergometer Rowing. AB - There is a high prevalence of low back pain (LBP) in adolescent male rowers. In this study, regional lumbar spinal kinematics and self-reported LBP intensity were compared between 10 adolescent rowers with moderate levels of LBP relating to rowing with 10 reporting no history of LBP during a 15-minute ergometer trial using an electromagnetic tracking system. Adolescent male rowers with LBP reported increasing pain intensity during ergometer rowing. No significant differences were detected in mean upper or lower lumbar angles between rowers with and without LBP. However, compared with rowers without pain, rowers with pain: (1) had relatively less excursion of the upper lumbar spine into extension over the drive phase, (2) had relatively less excursion of the lower lumbar spine into extension over time, (3) had greater variability in upper and lower lumbar angles over the 15-minute ergometer trial, (4) positioned their upper lumbar spine closer to end range flexion for a greater proportion of the drive phase, and (5) showed increased time in sustained flexion loading in the upper lumbar spine. Differences in regional lumbar kinematics exist between adolescent male rowers with and without LBP, which may have injury implication and intervention strategies. PMID- 26252196 TI - CSAR Benchmark of Flexible MedusaDock in Affinity Prediction and Nativelike Binding Pose Selection. AB - While molecular docking with both ligand and receptor flexibilities can help capture conformational changes upon binding, correct ranking of nativelike binding poses and accurate estimation of binding affinities remains a major challenge. In addition to the commonly used scoring approach with intermolecular interaction energies, we included the contribution of intramolecular energies changes upon binding in our flexible docking method, MedusaDock. In CSAR 2013 2014 binding prediction benchmark exercises, the new scoring function MScomplex was found to better recapitulate experimental binding affinities and correctly identify ligand-binding sequences from decoy receptors. Our further analysis with the DUD data sets indicates significant improvement of virtual screening enrichment using the new scoring function when compared to the previous intermolecular energy based scoring method. Our postanalysis also suggests a new approach to select nativelike poses in the clustering-based pose ranking approach by MedusaDock. Since the calculation of intramolecular energy changes and clustering-based pose ranking and selection are not MedusaDock specific, we expect a broad application in force-field based estimation of binding affinities and pose ranking using flexible ligand-receptor docking. PMID- 26252197 TI - Matrine and oxymatrine in corroborant plant extracts and fertilizers: HPLC/MS-MS method development and single-laboratory validation. AB - A reversed phase high-performance liquid chromatographic method (HPLC/MS-MS) has been developed and validated for detection of alkaloids matrine and oxymatrine in fertilizer with labeled enhancer plant defense activities. The analytical method was validated statistically. The results show a strong matrix effect, requiring quantification by standard addition method. The regression lines showed r(2) > 0.994. Recoveries ranging from 97 to 104% were obtained for the fortification level of 0.01% wt wt(-1) and the relative standard deviations ranged from 3 to 4% (n = 10). The limits of detection were below 0.0001% wt wt(-1), while the limits of quantification did not exceed 0.0004% wt wt(-1). The method is currently applied in ICQRF Laboratory of Catania on fertilized and corroborant plant extract collected in the Italian market in the frame of MIPAAF institutional quality control activity, with the aim to dectect these unpermitted active substances. PMID- 26252198 TI - Independent Associations of Organized Physical Activity and Weight Status with Children's Cognitive Functioning: A Matched-Pairs Design. AB - PURPOSE: This study tested whether participation in organized physical activity (active vs. inactive) or weight status (normal weight vs. overweight or obese) independently relate to children's cognition, using a matched-pairs design. DESIGN AND METHODS: Normal weight, active children (8-11 yrs, 5th-75th percentile BMI) were recruited from extracurricular physical activity programs while normal weight inactive (5th-75th percentile BMI) and overweight inactive children (BMI >=85th percentile) were recruited from local Augusta, Georgia area schools. Measures included the Cognitive Assessment System, anthropometrics, and parent- and self-report of physical activity. Paired t tests compared cognition scores between matched groups of normal weight active vs. normal weight inactive (N = 24 pairs), normal weight inactive vs. overweight inactive (N = 21 pairs), and normal weight active vs. overweight inactive children (N = 16 pairs). Children in each comparison were matched for race, gender, age, and socioeconomic status. RESULTS: Normal weight active children had higher Planning (M+/- SD = 109 +/- 11 vs. 100 +/- 11, p = .011) and Attention scores (108 +/- 11 vs. 100 +/- 11, p = .013) than overweight inactive children. Normal weight inactive children had higher Attention scores than overweight inactive children (105 +/- 13 vs. 93 +/- 12, p = .008). When compared with normal weight inactive children, normal weight active children had higher Planning (113 +/- 10 vs. 102 +/- 13, p = .008) and marginally higher Attention scores (111 +/- 11 vs. 104 +/- 12, p = .06). CONCLUSION: Findings suggest independent associations of children's weight status with selective attention, and physical activity with higher-order processes of executive function. PMID- 26252199 TI - Morin hydrate attenuates the acrylamide-induced imbalance in antioxidant enzymes in a murine model. AB - Liver diseases are among the most serious health issues nowadays. Hepatocellular carcinoma, one of the most lethal types of cancer worldwide, can be caused by chemically-induced oxidative stress. In the present study, we aimed to evaluate the protective effects of morin hydrate (MH) against acrylamide (AA)-induced hepatotoxicity in male ICR mice. The mice were randomly allocated into 4 groups [the control, the group subcutaneously injected with AA alone (50 mg/kg body weight), the group subcutaneously injected with AA (50 mg/kg body weight) and MH (5 mg/kg body weight) and the group subcutaneously injected with AA (50 mg/kg body weight) and MH (15 mg/kg body weight) for 5 consecutive days]. Histopathological evaluations were performed and the levels of serum hepatic enzymes were analyzed to determine initial liver injury, and the mice in the AA treated groups were compared with the mice receiving no treatment and with the mice administered MH in combination with AA. Furthermore, oxidative stress, hepatic inflammation and the levels of DNA damage-related markers were evaluated to determine the extent of liver damage induced by AA within a short-term period. The subcutaneous administration of AA induced severe hepatic injury, and combined treatment with AA and MH resulted in a significant improvement in all evaluated parameters. This recovery was most obvious in the group receiving AA and 15 mg/kg body weight dose of MH. The findings of our study demonstrated that MH protected mice from severe hepatic injury induced by AA. Moreover, MH is a natural polyphenolic compound, and thus it has potential for use in the treatment of severe liver diseases, in place of many synthetic drugs. PMID- 26252200 TI - MicroRNA-24 upregulation inhibits proliferation, metastasis and induces apoptosis in bladder cancer cells by targeting CARMA3. AB - Increasing evidence has confirmed that dysregulation of microRNAs (miRNAs) can contribute to the progression and metastasis of human tumors. Previous studied have shown dysregulation of miR-24 in a variety of tumors. However, the roles of miR-24 in human bladder cancer have not been well clarified. Therefore, we investigated the biological functions and molecular mechanisms of miR-24 in human bladder cancer cell lines, evaluating whether it could be a therapeutic biomarker of bladder cancer in the future. In our study, we found that miR-24 is downregulated in human bladder cancer cell lines. Moreover, the low level of miR 24 was associated with increased expression of CARMA3 in bladder cancer cells. Upregulation of miR-24 significantly inhibited proliferation, arrested cell cycle and induced apoptosis in bladder cancer cells. In addition, invasion and epithelial to mesenchymal transition (EMT) of bladder cancer cells was suppressed by overexpressing miR-24. Bioinformatics analysis predicted that the CARMA3 was a potential target gene of miR-24. Further study by luciferase reporter assay demonstrated that miR-24 could directly target CARMA3. Overexpression of CARMA3 in bladder cancer cells transfected with miR-24 mimic partially reversed the inhibitory effect of miR-24. In conclusion, miR-24 inhibited cell proliferation, invasion and EMT in bladder cancer cells by downregulation of CARMA3, and that downregulation of CARMA3 was essential for the miR-24-inhibited cell proliferation, invasion and EMT in bladder cancer cells. PMID- 26252201 TI - A new cytotoxic biflavonoid from the rhizome of Wikstroemia indica. AB - One new chalcone-flavone biflavonoid, 3'-hydroxydaphnodorin A (1), together with 12 known biflavonoids (2-13), was isolated from the rhizome of Wikstroemia indica. Their structures were established on the basis of extensive spectroscopic methods. Eight isolated compounds 1-3, 6, 7, 9, 12 and 13 were evaluated for their cytotoxic activities against cancer-derived cell lines Hep3B, HepG2 and CNE2, and 1 was found to possess moderate cytotoxicity against HepG2 and CNE2 cell lines, with IC50 values of 65.5 +/- 11.4 and 53.6 +/- 10.1 MUM, respectively. PMID- 26252202 TI - Total or near-total thyroidectomy versus subtotal thyroidectomy for multinodular non-toxic goitre in adults. AB - BACKGROUND: Total thyroidectomy (TT) and subtotal thyroidectomy (ST) are worldwide treatment options for multinodular non-toxic goitre in adults. Near TT, defined as a postoperative thyroid remnant less than 1 mL, is supposed to be a similarly effective but safer option than TT. ST has been shown to be marginally safer than TT, but it may leave an undetected thyroid cancer in place. OBJECTIVES: The objective was to assess the effects of total or near-total thyroidectomy compared to subtotal thyroidectomy for multinodular non-toxic goitre. SEARCH METHODS: We searched the Cochrane Library, MEDLINE, PubMed, EMBASE, as well as the ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was 18 June 2015 for all databases. No language restrictions were applied. SELECTION CRITERIA: Two review authors independently scanned the abstract, title or both sections of every record retrieved to identify randomised controlled trials (RCTs) on thyroidectomy for multinodular non-toxic goitre for further assessment. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed studies for risk of bias and evaluated overall study quality utilising the GRADE instrument. We calculated the odds ratio (OR) and corresponding 95% confidence interval (CI) for dichotomous outcomes. A random-effects model was used for pooling data. MAIN RESULTS: We examined 1430 records, scrutinized 14 full-text publications and included four RCTs. Altogether 1305 participants entered the four trials, 543 participants were randomised to TT and 762 participants to ST. A total of 98% and 97% of participants finished the trials in the TT and ST groups, respectively. Two trials had a duration of follow-up between 12 and 39 months and two trials a follow-up of 5 and 10 years, respectively. Risk of bias across studies was mainly unknown for selection, performance and detection bias. Attrition bias was generally low and reporting bias high for some outcomes. In the short-term postoperative period no deaths were reported for both TT and ST groups. However, longer-term data on all-cause mortality were not reported (1284 participants; 4 trials; moderate quality evidence). Goiter recurrence was lower in the TT group compared to ST. Goiters recurred in 0.2% (1/425) of the TT group compared to 8.4% (53/632) of the ST group (OR 0.05 (95% CI 0.01 to 0.21); P < 0.0001; 1057 participants; 3 trials; moderate quality evidence). Re-intervention due to goitre recurrence was lower in the TT group compared to ST. Re-intervention was necessary in 0.5% (1/191) of TT patients compared to 0.8% (3/379)of ST patients (OR 0.66 (95% CI 0.07 to 6.38); P = 0.72; 570 participants; 1 trial; low quality evidence). The incidence of permanent recurrent laryngeal nerve palsy was lower for ST compared with TT. Permanent recurrent laryngeal nerve palsy occurred in 0.8% (6/741) of ST patients compared to 0.7% (4/543) of TT patients (OR 1.28, (95% CI 0.38 to 4.36); P = 0.69; 1275 participants; 4 trials; low quality evidence). The incidence of permanent hypoparathyroidism was lower for ST compared with TT. Permanent hypoparathyroidism occurred in 0.1% (1/741) of ST patients compared to 0.6% (3/543) of TT patients (OR 3.09 (95% CI 0.45 to 21.36); P = 0.25; 1275 participants: 4 trials; low quality evidence). The incidence of thyroid cancer was lower for ST compared with TT. Thyroid cancer occurred in 6.1% (41/669) of ST patients compared to 7.3% (34/465)of TT patients (OR 1.32 (95% CI 0.81 to 2.15); P = 0.27; 1134 participants; 3 trials; low quality evidence). No data on health-related quality of life or socioeconomic effects were reported in the included studies. AUTHORS' CONCLUSIONS: The body of evidence on TT compared with ST is limited. Goiter recurrence is reduced following TT. The effects on other key outcomes such as re-interventions due to goitre recurrence, adverse events and thyroid cancer incidence are uncertain. New long-term RCTs with additional data such as surgeons level of experience, treatment volume of surgical centres and details on techniques used are needed. PMID- 26252203 TI - Patients' Experiences of Cancer Diagnosis as a Result of an Emergency Presentation: A Qualitative Study. AB - INTRODUCTION: Cancers diagnosed following visits to emergency departments (ED) or emergency admissions (emergency presentations) are associated with poor survival and may result from preventable diagnostic delay. To improve outcomes for these patients, a better understanding is needed about how emergency presentations arise. This study sought to capture patients' experiences of this diagnostic pathway in the English NHS. METHODS: Eligible patients were identified in a service evaluation of emergency presentations and invited to participate. Interviews, using an open-ended biographical structure, captured participants' experiences of healthcare services before diagnosis and were analysed thematically, informed by the Walter model of Pathways to Treatment and NICE guidance in an iterative process. RESULTS: Twenty-seven interviews were conducted. Three typologies were identified: A: Rapid investigation and diagnosis, and B: Repeated cycles of healthcare seeking and appraisal without resolution, with two variants where B1 appears consistent with guidance and B2 has evidence that management was not consistent with guidance. Most patients' (23/27) experiences fitted types B1 and B2. Potentially avoidable breakdowns in diagnostic pathways caused delays when patients were conflicted by escalating symptoms and a benign diagnosis given earlier by doctors. ED was sometimes used as a conduit to rapid testing by primary care clinicians, although this pathway was not always successful. CONCLUSIONS: This study draws on patients' experiences of their diagnosis to provide novel insights into how emergency presentations arise. Through these typologies, we show that the typical experience of patients diagnosed through an emergency presentation diverges significantly from normative pathways even when there is no evidence of serious service failures. Consultations were not a conduit to diagnosis when they inhibited patients' capacity to appraise their own symptoms appropriately and when they resulted in a reluctance to seek further healthcare. RECOMMENDATIONS: The findings also point to potentially avoidable breakdowns in the diagnostic process. In particular, to encourage patients to return to the GP if symptoms escalate, a stronger emphasis is needed on diagnostic uncertainty in discussions between patients and doctors in both primary and secondary care. To improve appropriate access to rapid investigations, systems are needed for primary care to communicate directly with secondary care at the time of referral. PMID- 26252204 TI - Identification and Risk Assessment for Worldwide Invasion and Spread of Tuta absoluta with a Focus on Sub-Saharan Africa: Implications for Phytosanitary Measures and Management. AB - To support management decisions, molecular characterization of data and geo reference of incidence records of Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) were combined with data on the biology and ecology of the pest to estimate its climatic suitability and potential spread at regional and global scale. A CLIMEX model was developed and used for the global prediction of current and future climate-induced changes in the distributional shifts of T. absoluta. Results revealed that temperature and moisture characterized T. absoluta population growth while the pest ability to survive the cold, hot, wet and dry stress conditions are the primary characteristics defining its range frontiers. Simulated irrigation also played an important role in the model optimization. Model predictions suggest that T. absoluta represents an important threat to Africa, Asia, Australia, Northern Europe, New Zealand, Russian Federation and the United States of America (USA). Under climate change context, future predictions on distribution of T. absoluta indicated that the invasive nature of this pest will result in significant crop losses in certain locations whereas some parts of Africa may witness diminution in ranges. The following scenarios may occur: 1) T. absoluta damage potential may upsurge moderately in areas of Africa where the pest currently exists; 2) a range diminution in temperate to Sahel region with moderate upsurge in damage potential; 3) a range expansion in tropical Africa with reasonable upsurge of damage potential. These possible outcomes could be explained by the fact that the continent is already warm, with the average temperature in majority of localities near the threshold temperatures for optimal development and survival of T. absoluta. Outputs from this study should be useful in helping decision-makers in their assessment of site-specific risks of invasion and spread of T. absoluta with a view to developing appropriate surveillance, phytosanitary measures and management strategies. PMID- 26252206 TI - Modification of Male Courtship Motivation by Olfactory Habituation via the GABAA Receptor in Drosophila melanogaster. AB - A male-specific component, 11-cis-vaccenyl acetate (cVA) works as an anti aphrodisiac pheromone in Drosophila melanogaster. The presence of cVA on a male suppresses the courtship motivation of other males and contributes to suppression of male-male homosexual courtship, while the absence of cVA on a female stimulates the sexual motivation of nearby males and enhances the male-female interaction. However, little is known how a male distinguishes the presence or absence of cVA on a target fly from either self-produced cVA or secondhand cVA from other males in the vicinity. In this study, we demonstrate that male flies have keen sensitivity to cVA; therefore, the presence of another male in the area reduces courtship toward a female. This reduced level of sexual motivation, however, could be overcome by pretest odor exposure via olfactory habituation to cVA. Real-time imaging of cVA-responsive sensory neurons using the neural activity sensor revealed that prolonged exposure to cVA decreased the levels of cVA responses in the primary olfactory center. Pharmacological and genetic screening revealed that signal transduction via GABAA receptors contributed to this olfactory habituation. We also found that the habituation experience increased the copulation success of wild-type males in a group. In contrast, transgenic males, in which GABA input in a small subset of local neurons was blocked by RNAi, failed to acquire the sexual advantage conferred by habituation. Thus, we illustrate a novel phenomenon in which olfactory habituation positively affects sexual capability in a competitive environment. PMID- 26252207 TI - Hypercoagulability Is a Stronger Risk Factor for Ischaemic Stroke than for Myocardial Infarction: A Systematic Review. AB - BACKGROUND AND PURPOSE: Hypercoagulability increases the risk of arterial thrombosis; however, this effect may differ between various manifestations of arterial disease. METHODS: In this study, we compared the effect of coagulation factors as measures of hypercoagulability on the risk of ischaemic stroke (IS) and myocardial infarction (MI) by performing a systematic review of the literature. The effect of a risk factor on IS (relative risk for IS, RRIS) was compared with the effect on MI (RRMI) by calculating their ratio (RRR = RRIS/RRMI). A relevant differential effect was considered when RRR was >1+ its own standard error (SE) or <1-SE. RESULTS: We identified 70 publications, describing results from 31 study populations, accounting for 351 markers of hypercoagulability. The majority (203/351, 58%) had an RRR greater than 1. A larger effect on IS risk than MI risk (RRE>1+1SE) was found in 49/343 (14%) markers. Of these, 18/49 (37%) had an RRR greater than 1+2SE. On the opposite side, a larger effect on MI risk (RRR<1-1SE) was found in only 17/343 (5%) markers. CONCLUSIONS: These results suggest that hypercoagulability has a more pronounced effect on the risk of IS than that of MI. PMID- 26252208 TI - Analysis of a Modern Hybrid and an Ancient Sugarcane Implicates a Complex Interplay of Factors in Affecting Recalcitrance to Cellulosic Ethanol Production. AB - Abundant evidence exists to support a role for lignin as an important element in biomass recalcitrance. However, several independent studies have also shown that factors apart from lignin are also relevant and overall, the relative importance of different recalcitrance traits remains in dispute. In this study we used two genetically distant sugarcane genotypes, and performed a correlational study with the variation in anatomical parameters, cell wall composition, and recalcitrance factors between these genotypes. In addition we also tracked alterations in these characteristics in internodes at different stages of development. Significant differences in the development of the culm between the genotypes were associated with clear differential distributions of lignin content and composition that were not correlated with saccharification and fermentation yield. Given the strong influence of the environment on lignin content and composition, we hypothesized that sampling within a single plant could allow us to more easily interpret recalcitrance and changes in lignin biosynthesis than analysing variations between different genotypes with extensive changes in plant morphology and culm anatomy. The syringyl/guaiacyl (S/G) ratio was higher in the oldest internode of the modern genotype, but S/G ratio was not correlated with enzymatic hydrolysis yield nor fermentation efficiency. Curiously we observed a strong positive correlation between ferulate ester level and cellulose conversion efficiency. Together, these data support the hypothesis that biomass enzymatic hydrolysis recalcitrance is governed by a quantitative heritage rather than a single trait. PMID- 26252205 TI - Plasma Concentrations of Hepcidin in Anemic Zimbabwean Infants. AB - OBJECTIVE: Anemia in infancy is a global public health problem. We evaluated the relative contributions of iron deficiency and inflammation to infant anemia. METHODS: We measured plasma hepcidin, ferritin, soluble transferrin receptor (sTfR), alpha-1-acid glycoprotein and C-reactive protein (CRP) by ELISA on archived plasma from 289 HIV-unexposed anemic or non-anemic Zimbabwean infants at ages 3 mo, 6 mo and 12 mo. Among anemic infants, we determined the proportion with iron-deficiency anemia (IDA) and anemia of inflammation (AI). We undertook regression analyses of plasma hepcidin and anemia status, adjusting for sex, age and birthweight. RESULTS: Anemic infants at 3 mo were more stunted and had higher CRP (median 0.45 vs 0.21 mg/L; P = 0.037) and hepcidin (median 14.7 vs 9.7 ng/mL; P = 0.022) than non-anemic infants, but similar levels of ferritin and sTfR; 11% infants had IDA and 15% had AI. Anemic infants at 6 mo had higher hepcidin (median 7.9 vs 4.5 ng/mL; P = 0.016) and CRP (median 2.33 vs 0.32 mg/L; P<0.001), but lower ferritin (median 13.2 vs 25.1 MUg/L; P<0.001) than non-anemic infants; 56% infants had IDA and 12% had AI. Anemic infants at 12 mo had lower ferritin (median 3.2 vs 22.2 MUg/L; P<0.001) and hepcidin (median 0.9 vs 1.9 ng/mL; P = 0.019), but similar CRP levels; 48% infants had IDA and 8% had AI. Comparing anemic with non-anemic infants, plasma hepcidin was 568% higher, 405% higher and 64% lower at 3 mo, 6 mo and 12 mo, respectively, after adjusting for sex and birthweight (all p<0.01). Plasma hepcidin declined significantly with age among anemic but not non-anemic infants. Girls had 61% higher hepcidin than boys, after adjusting for age, anemia and birthweight (p<0.001). CONCLUSION: Anemia is driven partly by inflammation early in infancy, and by iron deficiency later in infancy, with plasma hepcidin concentrations reflecting the relative contribution of each. However, there is need to better characterize the drivers of hepcidin during infancy in developing countries. PMID- 26252209 TI - The Crosstalk of Pathways Involved in Immune Response Maybe the Shared Molecular Basis of Rheumatoid Arthritis and Type 2 Diabetes. AB - Rheumatoid arthritis (RA) and Type 2 diabetes (T2D) are both systemic diseases linked with altered immune response, moderate mortality when present together. The treatment for both RA and T2D are not satisfied, partly because of the linkage between them has not yet been appreciated. A comprehensive study for the potential associations between the two disorders is needed. In this study, we used RNA sequencing to explore the differently expressed genes (DEGs) in peripheral blood mononuclear cells (PBMC) of 10 RA and 10 T2D patients comparing with 10 healthy volunteers (control). We used bioinformatics analysis and the Ingenuity Pathways Analysis (IPA) to predict the commonalities on signaling pathways and molecular networks between those two diseases. 212 DEGs in RA and 114 DEGs in T2D patients were identified compared with healthy controls, respectively. 32 DEGs were shared between the two comparisons. The top 10 shared pathways interacted in cross-talking networks, regulated by 5 shared predicted upstream regulators, leading to the activated immune response were explored, which was considered as partly of the association mechanism of this two disorders. These discoveries would be considered as new understanding on the associations between RA and T2D, and provide novel treatment or prevention strategy. PMID- 26252211 TI - Diversity of Pneumolysin and Pneumococcal Histidine Triad Protein D of Streptococcus pneumoniae Isolated from Invasive Diseases in Korean Children. AB - Pneumolysin (Ply) and pneumococcal histidine triad protein D (PhtD) are candidate proteins for a next-generation pneumococcal vaccine. We aimed to analyze the genetic diversity and antigenic heterogeneity of Ply and PhtD for 173 pneumococci isolated from invasive diseases in Korean children. Allele was designated based on the variation of amino acid sequence. Antigenicity was predicted by the amino acid hydrophobicity of the region. There were seven and 39 allele types for the ply and phtD genes, respectively. The nucleotide sequence identity was 97.2% 99.9% for ply and 91.4%-98.0% for phtD gene. Only minor variations in hydrophobicity were noted among the antigenicity plots of Ply and PhtD. Overall, the allele types of the ply and phtD genes were remarkably homogeneous, and the antigenic diversity of the corresponding proteins was very limited. The Ply and PhtD could be useful antigens for universal pneumococcal vaccines. PMID- 26252210 TI - Microstructural White Matter Properties Mediate the Association between APOE and Perceptual Speed in Very Old Persons without Dementia. AB - BACKGROUND: Reduced white matter integrity, as indicated by lower fractional anisotropy (FA) and higher mean diffusivity (MD), has been related to poorer perceptual speed (PS) performance. As the epsilon4 allele has been associated with lower white matter integrity in old age, this represents a potential mechanism through which APOE may affect PS. OBJECTIVE: To examine whether the association between APOE and PS is mediated by white matter microstructure in very old persons without dementia. METHOD: Participants were selected from the population-based SNAC-K study. After excluding persons with dementia, preclinical dementia, and other neurological disorders, 652 persons (age range 78-90) were included in the study, of which 89 had data on diffusion tensor imaging (DTI). We used structural equation modeling to form seven latent white matter factors (FA and MD) and one latent PS factor. Separate analyses were performed for FA and MD and mediational analyses were carried out for tracts where significant associations were observed to both APOE and PS. RESULTS: APOE was associated with white matter microstructure in 2 out of 14 tracts; epsilon4 carriers had significantly lower FA in forceps major and higher MD in the cortico-spinal tract. Allowing the white matter microstructure indicators in these tracts to mediate the association between APOE and PS resulted in a markedly attenuated association between these variables. Bootstrapping statistics in the subsample with DTI data (n = 89) indicated that FA in forceps major significantly mediated the association between APOE and PS (indirect effect: -0.070, 95% bias corrected CIs -0.197 to -0.004). CONCLUSION: Lower white matter integrity may represent one of several mechanisms through which APOE affects PS performance in elderly persons free of dementia and preclinical dementia. PMID- 26252212 TI - Implementation of a Cloud-Based Electronic Medical Record to Reduce Gaps in the HIV Treatment Continuum in Rural Kenya. AB - BACKGROUND: Electronic medical record (EMR) systems are increasingly being adopted to support the delivery of health care in developing countries and their implementation can help to strengthen pathways of care and close gaps in the HIV treatment cascade by improving access to and use of data to inform clinical and public health decision-making. METHODS: This study implemented a novel cloud based electronic medical record system in an HIV outpatient setting in Western Kenya and evaluated its impact on reducing gaps in the HIV treatment continuum including missing data and patient eligibility for ART. The impact of the system was assessed using a two-sample test of proportions pre- and post-implementation of EMR-based data verification and clinical decision support. RESULTS: Significant improvements in data quality and provision of clinical care were recorded through implementation of the EMR system, helping to ensure patients who are eligible for HIV treatment receive it early. A total of 2,169 and 764 patient records had missing data pre-implementation and post-implementation of EMR-based data verification and clinical decision support respectively. A total of 1,346 patients were eligible for ART, but not yet started on ART, pre-implementation compared to 270 patients pre-implementation. CONCLUSION: EMR-based data verification and clinical decision support can reduce gaps in HIV care, including missing data and eligibility for ART. A cloud-based model of EMR implementation removes the need for local clinic infrastructure and has the potential to enhance data sharing at different levels of health care to inform clinical and public health decision-making. A number of issues, including data management and patient confidentiality, must be considered but significant improvements in data quality and provision of clinical care are recorded through implementation of this EMR model. PMID- 26252213 TI - Increased Expression of TGFbetaR2 Is Associated with the Clinical Outcome of Non Small Cell Lung Cancer Patients Treated with Chemotherapy. AB - To investigate the prognostic significance of TGFbetaR2 expression and chemotherapy in Chinese non-small cell lung cancer (NSCLC) patients, TGFbetaR2 expression NSCLC was analyzed in silico using the Oncomine database, and subsequently analyzed with quantitative RT-PCR in 308 NSCLC biopsies, 42 of which were paired with adjacent non-neoplastic tissues. Our results show that TGFbetaR2 expression was also increased in NSCLC biopsies relative to normal tissue samples and correlated with poor prognosis. TGFbetaR2 expression was also significantly correlated with other clinical parameters such as tumor differentiation, invasion of lung membrane, and chemotherapy. Moreover, overall survival (OS) and disease free survival (DFS) was increased in patients with low TGFbetaR2 expressing NSCLC and who had undergone chemotherapy. Thus, high expression of TGFbetaR2 is a significant risk factor for decreased OS and DFS in NSCLC patients. Thus, TGFbetaR2 is a potential prognostic tumor biomarker for chemotherapy. PMID- 26252214 TI - Molecular Dynamics Simulation Studies of dTTP Binding and Catalysis Mediated by YhdE Dimerization. AB - YhdE is a Maf-like (multicopy associated filamentation) protein that primarily acts as dTTPase to hydrolyze dTTP into dTMP and two phosphate molecules in cell metabolism pathway. Two crystal structures of YhdE have been previously determined, representing the open and closed active site conformations, respectively. Based on the structures, we have carried out molecular dynamics simulations and free energy calculations to investigate dTTP binding to and hydrolysis by YhdE. Our results suggest that YhdE closed state is structurally more compact than its open state at room temperature. YhdE open state is a favorable conformation for dTTP binding and closed state is a structurally favorable conformation for catalytic reaction. This observation is supported by the structure of YhdE homolog in complex with a nucleotide analog. Free energy calculations reveal that YhdE dimerization occurs preferentially in dTTP binding and is favorable for successive cooperative reaction. The key residues R11, R12 and K80, are found to contribute to the substrate stabilization. Further, YhdE dimerization and binding of dTTP induce the cooperative effect through a direct allosteric communication network in YhdE from the dTTP binding sites in the catalytic center to the intermolecular beta-strand in YhdE dimer. PMID- 26252215 TI - The bHLH Transcription Factor Hand Regulates the Expression of Genes Critical to Heart and Muscle Function in Drosophila melanogaster. AB - Hand proteins belong to the highly conserved family of basic Helix-Loop-Helix transcription factors and are critical to distinct developmental processes, including cardiogenesis and neurogenesis in vertebrates. In Drosophila melanogaster a single orthologous hand gene is expressed with absence of the respective protein causing semilethality during early larval instars. Surviving adult animals suffer from shortened lifespan associated with a disorganized myofibrillar structure being apparent in the dorsal vessel, the wing hearts and in midgut tissue. Based on these data, the major biological significance of Hand seems to be related to muscle development, maintenance or function; however, up to now the physiological basis for Hand functionality remains elusive. Thus, the identification of genes whose expression is, directly or indirectly, regulated by Hand has considerable relevance with respect to understanding its biological functionality in flies and vertebrates. Beneficially, hand mutants are viable and exhibit affected tissues, which renders Drosophila an ideal model to investigate up- or downregulated target genes by a comparative microarray approach focusing on the respective tissues from mutant specimens. Our present work reveals for the first time that Drosophila Hand regulates the expression of numerous genes of diverse physiological relevancy, including distinct factors required for proper muscle development and function such as Zasp52 or Msp-300. These results relate Hand activity to muscle integrity and functionality and may thus be highly beneficial to the evaluation of corresponding hand phenotypes. PMID- 26252216 TI - Correction: Phylogeography of the Rock Shell Thais clavigera (Mollusca): Evidence for Long-Distance Dispersal in the Northwestern Pacific. PMID- 26252217 TI - PARP-1 Inhibition Is Neuroprotective in the R6/2 Mouse Model of Huntington's Disease. AB - Poly (ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that is involved in physiological processes as DNA repair, genomic stability, and apoptosis. Moreover, published studies demonstrated that PARP-1 mediates necrotic cell death in response to excessive DNA damage under certain pathological conditions. In Huntington's disease brains, PARP immunoreactivity was described in neurons and in glial cells, thereby suggesting the involvement of apoptosis in HD. In this study, we sought to determine if the PARP-1 inhibitor exerts a neuroprotective effect in R6/2 mutant mice, which recapitulates, in many aspects, human HD. Transgenic mice were treated with the PARP-1 inhibitor INO-1001 mg/Kg daily starting from 4 weeks of age. After transcardial perfusion, histological and immunohistochemical studies were performed. We found that INO 1001-treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the vehicle treated ones. Primary outcome measures such as striatal atrophy, morphology of striatal neurons, neuronal intranuclear inclusions and microglial reaction confirmed a neuroprotective effect of the compound. INO-1001 was effective in significantly increasing activated CREB and BDNF in the striatal spiny neurons, which might account for the beneficial effects observed in this model. Our findings show that PARP-1 inhibition could be considered as a valid therapeutic approach for HD. PMID- 26252218 TI - Mutation Spectrum of Common Deafness-Causing Genes in Patients with Non-Syndromic Deafness in the Xiamen Area, China. AB - In China, approximately 30,000 babies are born with hearing impairment each year. However, the molecular factors causing congenital hearing impairment in the Xiamen area of Fujian province have not been evaluated. To provide accurate genetic testing and counseling in the Xiamen area, we investigated the molecular etiology of non-syndromic deafness in a deaf population from Xiamen. Unrelated students with hearing impairment (n = 155) who attended Xiamen Special Education School in Fujian Province were recruited for this study. Three common deafness related genes, GJB2, SLC26A4, and mtDNA12SrRNA, were analyzed using all-exon sequencing. GJB2 mutations were detected in 27.1% (42/155) of the entire cohort. The non-syndromic hearing loss (NSHL) hotspot mutations c.109G>A (p.V37I) and c.235delC were found in this population, whereas the Caucasian hotspot mutation c.35delG was not. The allelic frequency of the c.109G>A mutation was 9.03% (28/310), slightly higher than that of c.235delC (8.39%, 26/310), which is the most common GJB2 mutation in most areas of China. The allelic frequency of the c.109G>A mutation was significantly higher in this Xiamen's deaf population than that in previously reported cohorts (P = 0.00). The SLC26A4 mutations were found in 16.77% (26/155) of this cohort. The most common pathogenic allele was c.IVS7 2A>G (6.13%, 19/310), and the second most common was the c.1079C>T (p.A360V) mutation (1.94%, 6/310) which has rarely been reported as a hotspot mutation in other studies. The mutation rate of mtDNA12SrRNA in this group was 3.87% (6/155), all being the m.A1555G mutation. These findings show the specificity of the common deaf gene-mutation spectrum in this area. According to this study, there were specific hotspot mutations in Xiamen deaf patients. Comprehensive sequencing analysis of the three common deaf genes can help portray the mutation spectrum and develop optimal testing strategies for deaf patients in this area. PMID- 26252220 TI - Emotional Processing, Recognition, Empathy and Evoked Facial Expression in Eating Disorders: An Experimental Study to Map Deficits in Social Cognition. AB - BACKGROUND: Difficulties in social cognition have been identified in eating disorders (EDs), but the exact profile of these abnormalities is unclear. The aim of this study is to examine distinct processes of social-cognition in this patient group, including attentional processing and recognition, empathic reaction and evoked facial expression in response to discrete vignettes of others displaying positive (i.e. happiness) or negative (i.e. sadness and anger) emotions. METHOD: One hundred and thirty-eight female participants were included in the study: 73 healthy controls (HCs) and 65 individuals with an ED (49 with Anorexia Nervosa and 16 with Bulimia Nervosa). Self-report and behavioural measures were used. RESULTS: Participants with EDs did not display specific abnormalities in emotional processing, recognition and empathic response to others' basic discrete emotions. However, they had poorer facial expressivity and a tendency to turn away from emotional displays. CONCLUSION: Treatments focusing on the development of non-verbal emotional communication skills might be of benefit for patients with EDs. PMID- 26252219 TI - Widespread Reassortment Shapes the Evolution and Epidemiology of Bluetongue Virus following European Invasion. AB - Genetic exchange by a process of genome-segment 'reassortment' represents an important mechanism for evolutionary change in all viruses with segmented genomes, yet in many cases a detailed understanding of its frequency and biological consequences is lacking. We provide a comprehensive assessment of reassortment in bluetongue virus (BTV), a globally important insect-borne pathogen of livestock, during recent outbreaks in Europe. Full-genome sequences were generated and analysed for over 150 isolates belonging to the different BTV serotypes that have emerged in the region over the last 5 decades. Based on this novel dataset we confirm that reassortment is a frequent process that plays an important and on-going role in evolution of the virus. We found evidence for reassortment in all ten segments without a significant bias towards any particular segment. However, we observed biases in the relative frequency at which particular segments were associated with each other during reassortment. This points to selective constraints possibly caused by functional relationships between individual proteins or genome segments and genome-wide epistatic interactions. Sites under positive selection were more likely to undergo amino acid changes in newly reassorted viruses, providing additional evidence for adaptive dynamics as a consequence of reassortment. We show that the live attenuated vaccines recently used in Europe have repeatedly reassorted with field strains, contributing to their genotypic, and potentially phenotypic, variability. The high degree of plasticity seen in the BTV genome in terms of segment origin suggests that current classification schemes that are based primarily on serotype, which is determined by only a single genome segment, are inadequate. Our work highlights the need for a better understanding of the mechanisms and epidemiological consequences of reassortment in BTV, as well as other segmented RNA viruses. PMID- 26252221 TI - Modularity of Protein Folds as a Tool for Template-Free Modeling of Structures. AB - Predicting the three-dimensional structure of proteins from their amino acid sequences remains a challenging problem in molecular biology. While the current structural coverage of proteins is almost exclusively provided by template-based techniques, the modeling of the rest of the protein sequences increasingly require template-free methods. However, template-free modeling methods are much less reliable and are usually applicable for smaller proteins, leaving much space for improvement. We present here a novel computational method that uses a library of supersecondary structure fragments, known as Smotifs, to model protein structures. The library of Smotifs has saturated over time, providing a theoretical foundation for efficient modeling. The method relies on weak sequence signals from remotely related protein structures to create a library of Smotif fragments specific to the target protein sequence. This Smotif library is exploited in a fragment assembly protocol to sample decoys, which are assessed by a composite scoring function. Since the Smotif fragments are larger in size compared to the ones used in other fragment-based methods, the proposed modeling algorithm, SmotifTF, can employ an exhaustive sampling during decoy assembly. SmotifTF successfully predicts the overall fold of the target proteins in about 50% of the test cases and performs competitively when compared to other state of the art prediction methods, especially when sequence signal to remote homologs is diminishing. Smotif-based modeling is complementary to current prediction methods and provides a promising direction in addressing the structure prediction problem, especially when targeting larger proteins for modeling. PMID- 26252222 TI - Self-Knowledge Dim-Out: Stress Impairs Metacognitive Accuracy. AB - Modulation of frontal lobes activity is believed to be an important pathway trough which the hypothalamic-pituitary-adrenal (HPA) axis stress response impacts cognitive and emotional functioning. Here, we investigate the effects of stress on metacognition, which is the ability to monitor and control one's own cognition. As the frontal lobes have been shown to play a critical role in metacognition, we predicted that under activation of the HPA axis, participants should be less accurate in the assessment of their own performances in a perceptual decision task, irrespective of the effect of stress on the first order perceptual decision itself. To test this prediction, we constituted three groups of high, medium and low stress responders based on cortisol concentration in saliva in response to a standardized psycho-social stress challenge (the Trier Social Stress Test). We then assessed the accuracy of participants' confidence judgments in a visual discrimination task. As predicted, we found that high biological reactivity to stress correlates with lower sensitivity in metacognition. In sum, participants under stress know less when they know and when they do not know. PMID- 26252223 TI - Genetic Variants Associated with Lipid Profiles in Chinese Patients with Type 2 Diabetes. AB - Dyslipidemia is a strong risk factor for cardiovascular disease among patients with type 2 diabetes (T2D). The aim of this study was to identify lipid-related genetic variants in T2D patients of Han Chinese ancestry. Among 4,908 Chinese T2D patients who were not taking lipid-lowering medications, single nucleotide polymorphisms (SNPs) in seven genes previously found to be associated with lipid traits in genome-wide association studies conducted in populations of European ancestry (ABCA1, GCKR, BAZ1B, TOMM40, DOCK7, HNF1A, and HNF4A) were genotyped. After adjusting for multiple covariates, SNPs in ABCA1, GCKR, BAZ1B, TOMM40, and HNF1A were identified as significantly associated with triglyceride levels in T2D patients (P < 0.05). The associations between the SNPs in ABCA1 (rs3890182), GCKR (rs780094), and BAZ1B (rs2240466) remained significant even after correction for multiple testing (P = 8.85*10(-3), 7.88*10(-7), and 2.03*10(-6), respectively). BAZ1B (rs2240466) also was associated with the total cholesterol level (P = 4.75*10(-2)). In addition, SNP rs157580 in TOMM40 was associated with the low density lipoprotein cholesterol level (P = 6.94*10(-3)). Our findings confirm that lipid-related genetic loci are associated with lipid profiles in Chinese patients with type 2 diabetes. PMID- 26252224 TI - Improved Synthesis of the Unnatural Amino Acids AHMOD and AMD, Components of the Anticancer Peptaibol Culicinin D. AB - An improved second-generation synthesis of the unnatural amino acid components of the anticancer peptaibol culicinin D has been developed. With a protected glutamic acid derivate as the starting material, the process readily delivered the Fmoc-protected free acid derivatives of AHMOD ((2S)-amino-(6R)-hydroxy-(4S) methyl-8-oxodecanoic acid) and AMD ((2S)-amino-(4S)-methyldecanoic acid) required to support solid phase peptide synthesis (SPPS) for structure-activity studies of the natural product. The same approach also provides improved access to pipecolic acid derivatives. A novel Wittig reagent for one-carbon homologation of aldehydes, developed during this work, is also reported. PMID- 26252225 TI - Association between Blood Lead Levels and Age-Related Macular Degeneration. AB - PURPOSE: To investigate the association between blood lead levels and prevalence of age-related macular degeneration (AMD). METHODS: A nationwide population-based cross-sectional study included 4,933 subjects aged over 40 years who participated in the 2008-2012 Korean National Health and Nutrition Examination Survey, and for whom fundus photographs were available. All participants underwent a standardized interview, evaluation of blood lead concentration, and a comprehensive ophthalmic examination. Digital fundus photographs (45 degrees ) were taken of both eyes under physiological mydriasis. All fundus photographs were graded using an international classification and grading system. RESULTS: Mean blood lead levels were 3.15 MUg/dL in men and 2.27 MUg/dL in women (P < 0.001). After adjusting for potential confounders including age, gender, smoking status, total cholesterol levels, triglyceride levels, heart problems and strokes, the adjusted odds ratio (OR) in women for any AMD was 1.86 (95% Confidence Interval [CI], 1.03-3.36) and for early AMD was 1.92 (95% CI, 1.06-3.48), for those in the highest quintile of lead level compared with the lowest quintile. In men, however, blood lead level was not significantly associated with AMD. CONCLUSIONS: Blood lead levels were higher in men, but were only associated with AMD in women. Increased levels of blood lead may be involved in the pathogenesis of AMD development in women. PMID- 26252226 TI - High-mobility group box 1 has a prognostic role and contributes to epithelial mesenchymal transition in human hepatocellular carcinoma. AB - High-mobility group box 1 (HMGB1), a member of the high-mobility group protein family, was originally characterized as a non-histone, nuclear DNA-binding protein. While the roles of HMGB1 in inflammation and cell differentiation have been previously reported, its role in tumor cell migration and invasion, particularly in hepatocellular carcinoma (HCC), has remained elusive. The present study reported that the expression of HMGB1 in HCC tissues was significantly higher than that in matched tumor-adjacent tissues (P<0.05). HMGB1 was expressed at significantly elevated levels in tumors of patients with large tumor size, high histological grade and advanced tumor-node-metastasis stage (P<0.05). The positive expression of HMGB1 correlated with a poor three-year overall and disease-free survival of HCC patients (P<0.05). In addition, HMGB1 was an independent factor for predicting the three-year overall and disease-free survival of HCC patients (P<0.05). An in vitro experiment revealed that knockdown of HMGB1 inhibited cell migration and invasion in the HCC cell lines Huh7 and MHCC97H (P<0.05). Furthermore, western blot analysis showed that HMGB1 knockdown markedly inhibited epithelial mesenchymal transition in Huh7 and MHCC97H cells. These results suggested that HMGB1 may be utilized as an independent prognostic marker in HCC and may promote tumor progression by promoting cell migration and invasion. PMID- 26252228 TI - A study of energy absorption rate in a quantum dot and metallic nanosphere hybrid system. AB - We have studied energy absorption rate in a quantum dot-metallic nanosphere system embedded on a dielectric substrate. We applied a control field to induce dipole moments in the quantum dot and the metal nanosphere, and monitored the energy absorption using a probe field. These external fields induce dipole moments in the metal nanosphere and the quantum dot, and these two structures interact with one another via the dipole-dipole interaction. The density matrix method was used to evaluate the absorption, indicating that it can be shifted by moving the metal nanosphere close to the quantum dot. Also, absorption efficiency can either be quenched or enhanced by the addition of a metal nanosphere. This hybrid system can be used to create ultrafast switching and sensing nanodevices. PMID- 26252227 TI - PRR11 Is a Prognostic Marker and Potential Oncogene in Patients with Gastric Cancer. AB - PRR11 is a potential candidate oncogene that has been implicated in the pathogenesis of lung cancer, however the role of PRR11 in gastric cancer is currently unclear. In the present study, we investigated the role of PRR11 in gastric cancer by evaluating its expression status in samples from a cohort of 216 patients with gastric cancer. PRR11 was found to be overexpressed in 107 (49.5%) patients by immunohistochemistry of tissue microarrays generated using the patient samples. Furthermore, PRR11 overexpression was found to correlate significantly with clinicopathologic features such as tumor invasion, tumor differentiation, and disease stage. Survival analysis of the cohort revealed that PRR11 is an independent prognostic factor for gastric cancer patients. PRR11 was stably silenced in a gastric carcinoma cell line using an shRNA-based approach, and treated cells showed decreased cellular proliferation and colony formation in vitro and cell growth in vivo, companied by decreased expression of CTHRC1 and increased expression of LXN, proteins involved in tumor progression. Evaluation of human gastric cancer samples demonstrated that PRR11 expression was also associated with increased CTHRC1 and decreased LXN expression. These data indicate that PRR11 may be widely activated in human gastric cancer and are consistent with the hypothesis that PRR11 functions as an oncogene in the development and progression of gastric cancer. PMID- 26252229 TI - Synthesis and Evaluation as Prodrugs of Hydrophilic Carbamate Ester Analogues of Resveratrol. AB - Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is an unfulfilled promise for health care: its exploitation is hindered by rapid conjugative metabolism in enterocytes and hepatocytes; low water solubility is a serious practical problem. To advantageously modify the physicochemical properties of the compound we have developed prodrugs in which all or part of the hydroxyl groups are linked via an N-monosubstituted carbamate ester bond to promoieties derived from glycerol or galactose, conferring higher water solubility. Kinetic studies of hydrolysis in aqueous solutions and in blood indicated that regeneration of resveratrol takes place in an appropriate time frame for delivery via oral administration. Despite their hydrophilicity some of the synthesized compounds were absorbed in the gastrointestinal tract of rats. In these cases the species found in blood after administration of a bolus consisted mainly of partially deprotected resveratrol derivatives and of the products of their glucuronidation, thus providing proof-of principle evidence of behavior as prodrugs. The soluble compounds largely reached the lower intestinal tract. Upon administration of resveratrol, the major species found in this region was dihydroresveratrol, produced by enzymes of the intestinal flora. In experiments with a fully protected (trisubstituted) deoxygalactose containing prodrug, the major species were the prodrug itself and partially deprotected derivatives, along with small amounts of dihydroresveratrol. We conclude that the N-monosubstituted carbamate moiety is suitable for use in prodrugs of polyphenols. PMID- 26252231 TI - Not endangered, but evolving. PMID- 26252232 TI - Creating capacity through partnership: a palliative care skills development programme. AB - This paper presents the development and implementation of a recurrently funded, rolling, 6-month palliative care secondment programme for NHS community staff nurses based in a rural health economy in Southwest England. The programme is a key tool in a wider development plan for improving access to, and the quality of, palliative and end-of-life care for a dispersed rural population. This is part of a much bigger programme of integration to meet the shared challenges of service capacity, equity, and sustainability that are presented by the geographical and demographical profile of the locality. The 'bigger picture' is defined and set in the context of the national drive and evidence base for integration in order to explain the reasons behind the secondment programme. This is followed by outlining the iterative process of design and implementation--the 'what?' and 'how?'--and key learning points to date are shared. PMID- 26252230 TI - Inverse relationship between body mass index and mortality in older nursing home residents: a meta-analysis of 19,538 elderly subjects. AB - Body mass index (BMI) and mortality in old adults from the general population have been related in a U-shaped or J-shaped curve. However, limited information is available for elderly nursing home populations, particularly about specific cause of death. A systematic PubMed/EMBASE/CINAHL/SCOPUS search until 31 May 2014 without language restrictions was conducted. As no published study reported mortality in standard BMI groups (<18.5, 18.5-24.9, 25-29.9, >=30 kg/m(2)), the most adjusted hazard ratios (HRs) according to a pre-defined list of covariates were obtained from authors and pooled by random-effect model across each BMI category. Out of 342 hits, 20 studies including 19,538 older nursing home residents with 5,223 deaths during a median of 2 years of follow-up were meta analysed. Compared with normal weight, all-cause mortality HRs were 1.41 (95% CI = 1.26-1.58) for underweight, 0.85 (95% CI = 0.73-0.99) for overweight and 0.74 (95% CI = 0.57-0.96) for obesity. Underweight was a risk factor for higher mortality caused by infections (HR = 1.65 [95% CI = 1.13-2.40]). RR results corroborated primary HR results, with additionally lower infection-related mortality in overweight and obese than in normal-weight individuals. Like in the general population, underweight is a risk factor for mortality in old nursing home residents. However, uniquely, not only overweight but also obesity is protective, which has relevant nutritional goal implications in this population/setting. PMID- 26252233 TI - Use of continence pads to manage urinary incontinence in older people. AB - Urinary incontinence is a symptom that should be investigated and whenever possible treated in order to enable the person to regain continence. Sometimes, it is not possible or appropriate to promote continence, and the focus shifts to that of managing incontinence sensitively to enable the person to maintain dignity and avoid the complications of poorly managed urinary incontinence. This article examines how nurses and health professionals can promote wellbeing by assessing a person's need for incontinence pads, enabling the person to use the appropriate type of pad and minimising risks of skin damage, odour, embarrassment, and leakage. PMID- 26252235 TI - Preventing and treating peristomal skin conditions in stoma patients. PMID- 26252236 TI - Multiple stakeholder views on changes in delivery of public health nursing services in Ireland. AB - In contrast with community nursing services in the UK and other parts of the world, the public health nursing service in the Republic of Ireland operates as a generalist service, providing both public health and wellbeing services in addition to clinical nursing services to a wide range of patient groups. While much discussion has taken place over the years about the benefits and challenges of a generalist service, little consensus has emerged about whether the current generalist approach should be maintained or whether a more specialised approach is required. This article presents key findings from an evaluation, using research methods, of a community nursing service that was restructured from a generalist, geographically based service, to a more specialist team-based model. The findings across multiple stakeholders show a number of positive effects in the areas of quality, safety, risk, governance, active caseload management, and finances. Some challenges were also identified, particularly with respect to continuity of services, loss of expertise, role of the team leader, and engagement in population-based activities. PMID- 26252237 TI - Understanding how older adults living in deprived neighbourhoods address ageing issues. AB - Older adults living in deprived areas are at risk of developing frailty and becoming care dependent. The aim of this qualitative study is to explore how community-dwelling, older adults living in deprived neighbourhoods address ageing issues. In-depth interviews were conducted with 20 participants who were community-dwelling (independently living), aged 65 years and older, not dependent on care, and living in a socioeconomically deprived urban neighbourhood in the northern part of the Netherlands. Data were analysed using the constant comparative method. Our findings emphasise the resourcefulness of these older adults when coping with apparent adversities. Simultaneously, the findings convey deficits concerning knowledge about ageing and health. Despite this, it appeared that these older adults possess an optimistic view of life, accept their situation, and are content with the capacities they still possess. Perspectives on how older adults address ageing issues are important for developing leads for nursing practice. Nurses will be challenged to recognise the coping strategies of older adults, particularly considering their deficits in health knowledge. The results of this study may serve as a basis for community nurses to manage care for older adults in deprived neighbourhoods. PMID- 26252238 TI - Assessing the skills of home care workers in helping older people take their prescribed medications. AB - The Southern Health and Social Care Trust in Northern Ireland applied a modified version of the Objective Structured Clinical Examination (OSCE) to assess the skills of home care workers in assisting older people taking prescribed medications. In Northern Ireland, home care workers are care workers employed by health and social care trusts or private agencies. The application of the model has developed the skills of this staff group, improved the relationship between the commissioner and provider, significantly reduced the time spent by community nurses in individual training and assessment, and enhanced the patient experience for those taking medication. Overall, the application of this model has provided assurances to the Trust board, the executive director of nursing, and operational directors that home care workers are competent in assisting older people in this high-risk activity. PMID- 26252239 TI - Understanding the Code: the duty of candour. AB - A key recommendation of the Mid Staffordshire Inquiry (Francis, 2013) was to establish a culture of openness in all health services through a duty of candour. A professional duty of candour is a key requirement of the Nursing and Midwifery Council's revised Code (2015). It requires all district nurses to be candid with patients about any errors in their care and treatment. District nurses working in England are also subject to a statutory duty of candour imposed on their employer by the Care Quality Commission. In this article, the author considers the organisational and professional duties of candour and their effect on a district nurse's practice. PMID- 26252240 TI - Dying at home: reconciling with patient and family wishes. PMID- 26252241 TI - Helping people living with cancer adjust to their 'new normal'. PMID- 26252242 TI - Perverse consequences of regulation. PMID- 26252243 TI - Genetic Variation and Insulin Resistance in Middle-Aged Chinese Men. AB - We investigated the effect of variants in the first three genes in the insulin signaling pathway and genes identified from genome wide association studies (GWAS) of T2D quantitative traits with IR (fasting insulin and the homeostasis model assessment of IR, HOMA-IR) and evaluated gene-environment interactions with IR traits among 1879 nondiabetic middle-aged men from a population-based study conducted in Shanghai, China. One candidate gene, IGF1, was associated with fasting insulin and HOMA-IR. We observed four BMI-gene interactions (P < 0.05) with HOMA-IR (INRS rs7254060, INRS rs7254358, GLU4 rs2113050, and GLU4 rs7713127) and seven BMI-gene interactions with fasting insulin (INRS rs7254060, INRS rs7254358, INRS rs10417205, INRS rs1799817, GLU4 rs12054720 GLU4 rs2113050, and GLU4 rs7713127). There were four WHR-gene interactions with HOMA-IR (INRS rs10417205, INRS rs12971499, INRS rs7254060, and INRS rs7254358), five WHR-gene interactions with fasting insulin (INRS rs10417205, INRS rs7254060, INRS rs7254358, GLU4 rs2113050, and GLU4 rs7713127), eight physical activity-gene interactions with HOMA-IR (INRS rs10411676, INRS rs11671297, INRS rs2229431, INRS rs12461909, INRS rs6510950, INRS rs10420382, IRS2 rs913949, and IRS2 rs2241745) and five physical activity-gene interactions with fasting insulin (INRS rs2229431, INRS rs12461909, INRS rs10420382, IRS2 rs913949, and IRS2 rs2241745). Our results suggest that BMI, WHR and physical activity may modify IR-associated variants. PMID- 26252244 TI - Sustained Pax6 Expression Generates Primate-like Basal Radial Glia in Developing Mouse Neocortex. AB - The evolutionary expansion of the neocortex in mammals has been linked to enlargement of the subventricular zone (SVZ) and increased proliferative capacity of basal progenitors (BPs), notably basal radial glia (bRG). The transcription factor Pax6 is known to be highly expressed in primate, but not mouse, BPs. Here, we demonstrate that sustaining Pax6 expression selectively in BP-genic apical radial glia (aRG) and their BP progeny of embryonic mouse neocortex suffices to induce primate-like progenitor behaviour. Specifically, we conditionally expressed Pax6 by in utero electroporation using a novel, Tis21-CreERT2 mouse line. This expression altered aRG cleavage plane orientation to promote bRG generation, increased cell-cycle re-entry of BPs, and ultimately increased upper layer neuron production. Upper-layer neuron production was also increased in double-transgenic mouse embryos with sustained Pax6 expression in the neurogenic lineage. Strikingly, increased BPs existed not only in the SVZ but also in the intermediate zone of the neocortex of these double-transgenic mouse embryos. In mutant mouse embryos lacking functional Pax6, the proportion of bRG among BPs was reduced. Our data identify specific Pax6 effects in BPs and imply that sustaining this Pax6 function in BPs could be a key aspect of SVZ enlargement and, consequently, the evolutionary expansion of the neocortex. PMID- 26252246 TI - Transcription factor WRKY46 modulates the development of Arabidopsis lateral roots in osmotic/salt stress conditions via regulation of ABA signaling and auxin homeostasis. AB - The development of lateral roots (LR) is known to be severely inhibited by salt or osmotic stress. However, the molecular mechanisms underlying LR development in osmotic/salt stress conditions are poorly understood. Here we show that the gene encoding the WRKY transcription factor WRKY46 (WRKY46) is expressed throughout lateral root primordia (LRP) during early LR development and that expression is subsequently restricted to the stele of the mature LR. In osmotic/salt stress conditions, lack of WRKY46 (in loss-of-function wrky46 mutants) significantly reduces, while overexpression of WRKY46 enhances, LR development. We also show that exogenous auxin largely restores LR development in wrky46 mutants, and that the auxin transport inhibitor 2,3,5-triiodobenzoic acid (TIBA) inhibits LR development in both wild-type (WT; Col-0) and in a line overexpressing WRKY46 (OV46). Subsequent analysis of abscisic acid (ABA)-related mutants indicated that WRKY46 expression is down-regulated by ABA signaling, and up-regulated by an ABA independent signal induced by osmotic/salt stress. Next, we show that expression of the DR5:GUS auxin response reporter is reduced in roots of wrky46 mutants, and that both wrky46 mutants and OV46 display altered root levels of free indole-3 acetic acid (IAA) and IAA conjugates. Subsequent RT-qPCR and ChIP-qPCR experiments indicated that WRKY46 directly regulates the expression of ABI4 and of genes regulating auxin conjugation. Finally, analysis of wrky46 abi4 double mutant plants confirms that ABI4 acts downstream of WRKY46. In summary, our results demonstrate that WRKY46 contributes to the feedforward inhibition of osmotic/salt stress-dependent LR inhibition via regulation of ABA signaling and auxin homeostasis. PMID- 26252247 TI - Association of Fatigue with Perceived Stress in Chinese Women with Early Stage Breast Cancer Awaiting Adjuvant Radiotherapy. AB - Cancer-related fatigue (CRF) is common in women with breast cancer, but little is known of its relationship with perceived stress. We conducted a cross-sectional study to explore the associations of CRF with perceived stress, anxiety, depression, pain and sleep quality in 133 Chinese women (aged 25-68 years) with early stage breast cancer. The majority of women had completed surgery and chemotherapy and were awaiting radiotherapy. Self-administered questionnaires consisting of the Brief Fatigue Inventory, Perceived Stress Scale-10, Hospital Anxiety and Depression Scale, Brief Pain Inventory, and Pittsburgh Sleep Quality Index were used to collect data. Forty-five per cent of the women were severely fatigued. Compared with local healthy women and US breast cancer patients, the group's mean perceived stress score was significantly higher (both p < 0.01). Higher perceived stress (beta = 0.18, p = 0.032), higher anxiety (beta = 0.30, p < 0.001) and higher pain severity (beta = 0.38, p < 0.001) were associated with increased severity of CRF. The association of CRF with perceived stress was partially mediated by anxiety, suggesting a possible pathway from cancer and cancer treatment to CRF via stress appraisals and emotional distress. The findings indicate the importance of monitoring the psychological status of patients during treatment. PMID- 26252245 TI - Spontaneous hepatic haemorrhage: a review of pathogenesis, aetiology and treatment. AB - BACKGROUND: A spontaneous hepatic haemorrhage (SHH) is a rare condition that presents acutely to both hepatobiliary and general surgeons. Management of the condition is challenging because of the emergent presentation requiring immediate intervention, the presence of underlying chronic liver disease and the multiple potential underlying aetiological conditions. METHODS: A literature search on a spontaneous hepatic haemorrhage was instituted on Medline (1966-2014), Cochrane Register of Controlled Trials, EMBASE (1947-2014), PubMed, Web of Science and Google Scholar. The specific topics of interest were causes - including rare causes, pathophysiological mechanisms and management options. A narrative review was planned from the outset. RESULTS: After 1546 abstracts were reviewed, 74 studies were chosen for inclusion. Hepatocellular carcinoma (HCC) is the commonest cause of a spontaneous haemorrhage with 10% of HCC presenting with bleeding. Other causes are benign hepatic lesions (hemangioma, adenoma, focal nodular hyperplasia, nodular regenerative hyperplasia, biliary cystadenoma and angiomyelolipoma), malignant hepatic tumours (angiosarcoma, haemangioendothelioma, hepatoblastoma and rhabdoid sarcoma), peliosis hepatis, amyloid, systemic lupus erythematosis, polyarteritis nodosa, HELLP syndrome and acute fatty liver of pregnancy. Treatment practice emphasizes arterial embolization to obtain haemostasis with a hepatectomy reserved for tumour-bearing patients after staging and assessment of liver function. CONCLUSION: A spontaneous hepatic haemorrhage is an acute presentation of a spectrum of conditions that requires early diagnosis and multidisciplinary management. PMID- 26252248 TI - Gold dithiolene complexes: easy access to 2-alkylthio-thiazoledithiolate complexes. AB - In the presence of MeI or EtI, N-tert-butyl-1,3-thiazoline-2-thione derivatives undergo a transformation to 2-alkylthio-thiazoledithiolate pro-ligands with elimination of the tert-butyl substituent. The corresponding Au(III) dithiolene complexes [Au(RS-tzdt)2](-) (R = Me, Et) oxidize readily to the neutral radical species, such as the semi-conducting [Au(EtS-tzdt)2], which organizes into dimers in the solid state. PMID- 26252249 TI - A New Homozygous IGF1R Variant Defines a Clinically Recognizable Incomplete Dominant form of SHORT Syndrome. AB - Here, we describe a child, born from consanguineous parents, with clinical features of SHORT syndrome, high IGF1 levels, developmental delay, CNS defects, and marked progeroid appearance. By exome sequencing, we identified a new homozygous c.2201G>T missense mutation in the IGF1R gene. Proband's parents and other relatives, all heterozygous carriers of the mutation, presented with milder phenotype including high IGFI levels, short stature, and type 2 diabetes. Functional studies using patient's cell lines showed a lower IGF1R expression that leads to the alteration of IGF1R-mediated PI3K/AKT/mTOR downstream pathways, including autophagy. This study defines a clinically recognizable incomplete dominant form of SHORT syndrome, and provides relevant insights into the pathophysiological and phenotypical consequences of IGF1R mutations. PMID- 26252250 TI - Resveratrol inhibits oligomeric Abeta-induced microglial activation via NADPH oxidase. AB - Microglia-mediated neuroinflammation is key in the pathogenesis of Alzheimer's disease (AD). Several studies have suggested that NADPH oxidase contributes to microglia-mediated neuroinflammation. Resveratrol, which is a natural polyphenolic compound, exerts neuroprotective effects in AD due to its anti inflammatory properties. The present study aimed to investigate the effects of resveratrol on the activation of oligomeric amyloid beta (oAbeta)-induced BV-2 microglia, and to determine the role of NADPH oxidase in these effects. Microglial proliferation was measured by high-content screening cell counting and using a bromodeoxyuridine incorporation assay. In addition, the levels of reactive oxygen species (ROS), nitric oxide (NO), tumor necrosis factor (TNF) alpha and interleukin (IL)-1beta were assessed. The results of the present study demonstrated that resveratrol inhibited the proliferation of oAbeta-induced microglia and the production of pro-inflammatory factors, including ROS, NO, TNF alpha and IL-1beta. Subsequent mechanistic investigations demonstrated that resveratrol inhibited the oAbeta-induced mRNA and protein expression levels of p47phox and gp91phox. These results suggested that NADPH oxidase may be a potential target for AD treatment, and resveratrol may be a valuable natural product possessing therapeutic potential against AD. PMID- 26252251 TI - Serum levels of IFN-beta are associated with days of evolution but not with severity of dengue. AB - The serum levels of beta interferon (IFN-beta) were evaluated in clinical samples taken in the acute phase of dengue fever for 107 patients during the 2011 dengue outbreak in Yucatan, Mexico. Dengue diagnoses were confirmed by NS1 or IgM/IgG serology in all patients. Average serum IFN-beta levels in patients with dengue fever without warning signs (n = 53) were 140 pg/ml, and 105 pg/ml for patients with warning signs (n = 54). There was no statistically significant difference between IFN-beta levels for the two groups (Mann-Whitney U Test P > 0.05) and no association with warning or mild signs (OR: 0.57; 95%CI: 0.26-1.22) was indicated. Thrombocytopenia was the most prevalent warning sign (91%) in one group of patients (49) with mean 113 pg/ml IFN-beta levels. In contrast, the patients without thrombocytopenia (50) had 126 pg/ml of IFN-beta, but this level was not statistically significant (Mann-Whitney U Test P > 0.05). The average levels of IFN-beta were also found to have statistically similar results, using the 1997 WHO classification system. The amount of IFN-beta at 1-3, 4-6, and 7-9 days after onset of illness, however, did show significant differences (ANOVA P = 0.038) between patients for the 1-3 and 4-6 days pair (Scheffe post-hoc P = 0.043). These results suggest that serum levels of IFN-beta do not correlate well with the severity of dengue illness, but there is a clear association between changes in IFN-beta levels and the days of evolution during the acute phase of the disease. PMID- 26252252 TI - A Molecular Docking and Dynamics Study to Screen Potent Anti-Staphylococcal Compounds Against Ceftaroline Resistant MRSA. AB - World Health Organization reports that methicillin-resistant Staphylococcus aureus (MRSA) is the origin of higher proportion of hospital acquired infections. In order to combat the effect of MRSA infection, an ideal drug should stimulate the allosteric exposure of active site, prompting penicillin binding proteins (PBP2a) to bind with that particular compound. Ceftaroline shows high binding affinity towards PBP2a and also confers resistance against degrading enzymes. Recently, two amino acid alterations in the allosteric site of PBP2a, asparagine (N) to lysine (K) at position 146 and glutamic acid (E) to lysine at position 150 are reported to confer resistance against ceftaroline resulting in the rise of ceftaroline-resistant MRSA strains. The present study focuses on the identification of potential ligands that can effectively bind with allosteric site of PBP2a, that leads to the access of active site and entry of a beta-lactam antibiotic for effective inhibition. The results obtained from our study will be useful for designing effective compounds with potential therapeutic effects against ceftaroline resistant MRSA strains. PMID- 26252254 TI - MicroRNA-122 affects cell aggressiveness and apoptosis by targeting PKM2 in human hepatocellular carcinoma. AB - Human hepatocellular carcinoma (HCC) is a highly invasive tumor with frequent distant metastasis, which is the main cause for the poor prognosis. However, the mechanisms for metastasis remain poorly investigated. MicroRNAs (miRNAs) have been implicated in HCC progression. MicroRNA-122 (miR-122) is considered as a tumor suppressor in human cancer. In the present study, miR-122 expression was found to be significantly lower in HCC than the level in normal tumor-adjacent tissues. miR-122 was clearly silenced or downregulated in five HCC cell lines (HepG2, Hep3B, MHCC97H, Huh7 and SMMC-7721) compared with normal hepatocytes (LO2). HCC patients with low expression of miR-122 had a poor 3-year survival. Univariate analysis and multivariate Cox regression analysis indicated that miR 122 is an independent prognostic factor in HCC. Downregulation of miR-122 promoted proliferation and inhibited apoptosis in Hep3B cells. We found that the public miRNA database (TargetScan) predicted that PKM2 may be a target for miR 122, and the 3'-untranslated region (3'-UTR) of PKM2 contains a highly conserved binding site for miR-122. To identify this, pre-miR-122/anti-miR-122 were respectively transfected into the Hep3B cell line. We found that miR-122 overexpression significantly reduced the level of PKM2. Moreover, knockdown of PKM2 significantly increased miR-122 inhibitor-mediated Hep3B cell apoptosis and reduced miR-122 inhibitor-mediated Hep3B cell migration and invasion. Moreover, re-expression of PKM2 partially abrogated miR-122-induced HCC cell growth arrest and apoptosis in vivo. In conclusion, miR-122 serves as a prognostic biomarker and induces apoptosis and growth arrest by downregulating PKM2 in HCC. PMID- 26252255 TI - Nematic ordering of polarizable colloidal rods in an external electric field: theory and experiment. AB - We employ the coupled dipole method [B. W. Kwaadgras, et al., J. Chem. Phys., 2011, 135, 134105] to calculate the orientation-dependent interaction of polarizable colloidal rods with an external electric field. We project the angular distribution function of a system of such rods on a quasi-two-dimensional slab, corresponding to the focal plane of a microscope, and show that the 3D nematic order parameter and its measurable projected analogue are very similar. We compare our results to confocal microscopy measurements on the orientation distribution function of systems of polarizable colloidal silica rods in an external electric field, demonstrating reasonably good agreement between theory and experiment without any free fit parameter. PMID- 26252253 TI - Synchronization of the mammalian circadian timing system: Light can control peripheral clocks independently of the SCN clock: alternate routes of entrainment optimize the alignment of the body's circadian clock network with external time. AB - A vast network of cellular circadian clocks regulates 24-hour rhythms of behavior and physiology in mammals. Complex environments are characterized by multiple, and often conflicting time signals demanding flexible mechanisms of adaptation of endogenous rhythms to external time. Traditionally this process of circadian entrainment has been conceptualized in a hierarchical scheme with a light-reset master pacemaker residing in the hypothalamus that subsequently aligns subordinate peripheral clocks with each other and with external time. Here we review new experiments using conditional mouse genetics suggesting that resetting of the circadian system occurs in a more "federated" and tissue-specific fashion, which allows for increased noise resistance and plasticity of circadian timekeeping under natural conditions. PMID- 26252256 TI - Treatment options in the young patient with Graves' disease. AB - The treatment options in the young patient with Graves' disease are the same as in adults, namely antithyroid drug (ATD), surgery (partial or total thyroidectomy) and radioiodine. However, the emphasis and expectation is different in the young person, reflecting a range of considerations including age, pubertal status, disease natural history, likely impact of ATD on disease course and the implications of radiation exposure. New therapeutic strategies that could increase the likelihood of long-term remission are being explored. PMID- 26252257 TI - [Troponins and chronic kidney disease]. AB - Coronary thrombosis was recognized since 19th century as clinical entity with bad outcomes; only in 1912 it was reported that acute myocardial infarction had to been distinguished from angina pectoris. First diagnostic test was electrocardiogram, while white blood cells count and erythrocytes sedimentation rate were the only available laboratory tests. Late in the 60s and 70s glutammic oxaloacetic and glutamic pyravate transaminase, lactate dehydrogenase and creatine kinase were added to biomarkers pool to provide a diagnosis of myocardial infarction related to myocardial cells injury. Only in 1987 assays for cardiac troponin were developed to assess structural damage of myocardial cells and in 2010 high sensibility troponins first dosage kits became available. It is well known that the population with chronic kidney disease (CKD) is at greater risk for cardiovascular disease and death than the general population. The use and interpretation of high sensitivity cardiac troponin (hs-cTn) assays have been particularly challenging in these patients with the majority having elevated levels at baseline. Aim of this review is to evaluate hs-cTn in patients with CKD for the diagnosis of AMI and for the prognostic significance of elevated levels in CKD patients without AMI. PMID- 26252258 TI - [Sodium Glucose Co-transporter Type 2 (SGLT2) Inhibitors in CKD]. AB - Among the new drugs used for the treatment of Diabetes Mellitus type 2, sodium glucose cotransporter 2 (SGLT2) inhibitors represent a promising therapeutic option. Since their ability to lower glucose is proportional to GFR, their effect is reduced in patients with chronic kidney disease (CKD). The antidiabetic mechanism of these drugs is insulin-independent and, therefore, complimentary to that of others antihyperglicaemic agents. Moreover, SGLT2 inhibitors are able to reduce glomerular hyperfiltration, systemic and intraglomerular pressure and uric acid levels, with consequent beneficial effects on the progression of kidney disease in non diabetic patients as well. Only few studies have been performed to evaluate the effects of SGLT2 inhibitors in patients with CKD. Therefore, safety and efficacy of SGLT2 inhibitors should be better clarified in the setting of CKD. In this paper, we will review the use of SGLT2 inhibitors in diabetic patients, including those with CKD. PMID- 26252259 TI - [Treatment of vitamin D deficiency in the general population and in patients with chronic kidney disease]. AB - Vitamin D is an essential micronutrient for humans. Vitamin D functions are not limited to the regulation of bone; it plays many pleiotropic effects due to ubiquitous distribution of VDR (Vitamin D Receptor). The vitamin D deficiency (defined as plasma levels of 25 - OH - vitamin D < 30 ng / ml) is now a public health problem worldwide. It is therefore essential to define protocols for supplementation of vitamin D in the general population and in patients with Chronic Kidney Disease and indications on the use of different Vitamins D available. PMID- 26252260 TI - [Horseshoe kidney: not a simple fusion anomaly]. AB - The horseshoe kidney is a congenital anatomical defect of the kidney that occurs in 0,25% of the population and is generally characterized by the fusion of the lower poles of the two kidneys through an isthmus and to which may be associated with urogenital and renal vascular anomalies. Asymptomatic in 1/3 of the cases and, most of time, accidentally discovered during a radiological examination, promotes nephrolithiasis, ureteropelvic junction obstruction, hydronephrosis, vesicoureteral reflux and pyelonephritis. We report two cases of patients with kidney horseshoe, characterized by the abrupt onset of a septic state with oligo anuric acute renal failure, electrolyte and acid-base abnormalities, rapid decay of the general conditions, with detection of nephrolithiasis, hydronephrosis and acute pyelonephritis and whose clinical management resulted in a significant and synergistic nefro-urology involvment. The kidney horseshoe not represent so only a simple fusion anomaly but rather an important anatomical condition that, once diagnosed, it would be worthy of a careful clinical, radiological and laboratory surveillance, in order to prevent the potential complications that may be also particularly severe. PMID- 26252261 TI - [An unusual cause of acute pyelonephritis: the retrocaval ureter]. AB - Retrocaval ureter is a rare congenital malformation in which the proximal right ureter courses toward the midline on the posterior aspect of the inferior vena cava before emerging medial and anterior to this structure and then descending into the pelvis. This anatomical anomaly may be asymptomatic or manifest clinically, usually starting from the fourth decade of life, with flank pain, pyelonephritis, gross hematuria or other rarer signs. We describe the case of a young woman being hospitalized because of acute pyelonephritis; she had previously complained of flank pain associated with episodes of high fever. Computed tomography of the abdomen identified the malformation. The patient underwent surgical correction by laparoscopy and, at one year of follow-up, did not show any further clinical problem. PMID- 26252262 TI - [IDPN: effects on the treatment of CKD-MBD]. AB - In the population in hemodialysis a protein-calorie malnutrition is a frequent finding although of difficult evaluation, since the incidence of malnourished subjects is assessed between 35% and 60%, in relation to nutritional markers considered and their variability for reason related to uremia. Even in the management of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is necessary the evaluation of the nutritional status of patients, and for a more correct assessment of clinical cases observed, both for the correct use of pharmacological treatement. The aim of this study is the evaluation of the most common parameters for the monitoring and of the nutritional status and the CKD MBD induced by the use of intradialytic parenteral nutrition ( IDPN), for a period exceeding 12 months. The study raises the hypotesis that IDPN, by stimulating protein synthesis and reducing anorexia and inadeguate dietary behaviours in hemodialysis patients selected, in medium term, leads to a stable balance of serum calcium, phosphorus, PTH and alkaline phosphatase with modification of therapy in the treatement of CKD-MBD and a reduction dose of drugs. The changes made during the follow-up period to therapeutic means for the control of CKD-MBD emphasise the importance of evaluation of the nutritional status of the patient in order to use and adjust them correctly and, furthermore, how IDPN in cases of protein-calorie malnutrition may represents a suitable protection. PMID- 26252263 TI - [The use of Cinacalcet in chronic kidney disease: a case report]. AB - Secondary Hyperparathyroidism is an important concurrent cause of cardiovascular and osteo-articular events, as well as, high morbidity and mortality for patients suffering from chronic kidney disease in conservative therapy and dialysis. The usual therapies, such as the vitamin D active metabolites and the phosphate binders did not always demonstrate effective in SHP control. New drugs, such as the calcimimetics, are available, resulting beneficial in highly reducing PTH levels. The only calcimimetic drug clinically used is cinacalcet, whose use is planned only in patients undergoing dialysis (peritoneal and extracorporeal). We describe the clinical case of a caucasian woman of 82 yrs old, with chronic kidney disease and secondary hyperparathyroidism resistant to usual therapies, in conservative treatment, which is prescribed cinacalcet (off-label). At first we found a worsening of the indices of renal function secondary to the effects of the drug on the hydrosaline balance. Increasing the hydrosaline intake we have seen the reduction and the subsequent stability of exams. Cinacalcet was effective in controlling the levels of parathyroid hormone and has contributed significantly to the achievement of optimal calcium-phosphorus balance. In view of these data, there is no doubt in taking in consideration the use of this drug also in the earliest stages of IRC. PMID- 26252264 TI - [A rare case of acute renal failure related to amanita proxima ingestion]. AB - OBJECTIVE: The first cases of acute renal tubulopathy related to Amanita proxima poisoning were described in 1994; the mushroom contains a toxin responsible for the allenic-norleucine syndrome, characterised by a kidney damage that occur earlier than in Cortinarius orellanus poisoning and generally improve with complete resolution within ten days. CASE REPORT: A 45 years old woman was admitted to the hospital because of nausea, vomiting, and heartburn started the day before. Symptoms occurred eight hours after eating a single big wild mushroom; three friends who had the same meal were all asymptomatic. Twelve hours after the admission the woman became anuric and blood tests showed an impaired renal function: creatinine 13 mg/dL urea 240 mg/dL, AST 240 U / L, ALT 350 U / l. The patient was transferred to the nephrology unit of the Hospital Di Venere of Bari and the PCC of Milan was consulted. The toxicologist supposed a nephrotoxic syndrome caused by the consumption of Amanita proxima and sent a picture of the mushroom ingested to a mycologist who identified the specie as Amanita proxima Dume, Bull (typical volva reddish-orange, ivory white hat, scaly stalk) sometimes mistaken for Amanita ovoidea. Haemodialysis was performed for five days followed by supportive care. Urine output gradually increased, serum creatinine decreased and Ast - Alt normalized. CONCLUSIONS: Amanita proxima contains an allenic norleucine toxin (different from orellanine for the absence of inhibition of alkaline phosphatase), responsible for the reversible kidney damage, characterised by tubulointerstitial nephritis with acute tubular necrosis and renal failure. Occurrence and seriousness of symptoms seem to be variable and dependent on the amount ingested. PMID- 26252265 TI - [The nephropathy in the Anderson-Fabry disease: new recommendations for the diagnosis, the follow-up and the therapy]. AB - Anderson-Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations of the GLA gene that encodes alpha-galactosidase A. It is a characterized by the involvement of several systems: renal, neurological, hearth, cochleovestibular and cutaneous systems are the most involved. Despite recent studies have provided new insights in the this disease, there are still lacks and discrepancies among all insiders regarding the diagnosis, clinical and therapeutic management. Enzyme replacement have been demonstrated to improve the course of the disease, especially when the diagnosis is early. There are still some debates on diagnosis and management of patients, in particular in the heterozygote female and the start of enzyme replacement. Thus, an Italian board, composed by nephrologists, cardiologists, genetics, pediatricians and neurologists has been established in order to approve through a consensus a diagnostic and therapeutic Italian management. Authors report the renal clinical and therapeutic management, a useful tool either for expert physicians or for those with a few experience in the diagnosis and management of this disease. PMID- 26252266 TI - [Metformin-associated lactic acidosis]. AB - INTRODUCTION: Metformin is the first choice drug in type II diabetes. This drug has a renal excretion and its use requires caution in a setting of glomerular filtration rate reduction; an accumulation can be associated with a lactic acidosis, complication burden with a high rate mortality. METHODS: In a user base of 390.000 people we reviewed all the cases of metformin-associated lactic acidosis treated at the First Aid in a 15 months period; we considered the patients characteristics, their risk factors and the outcome. RESULTS: We observed 11 cases (incidence 60/year/100.000 patients). 10 had an acute renal failure due to dehydration. None had absolute contraindications to metformin, but most of the patients had at least one risk factor for acute kidney injury. 10 patients had been treated with hemodialysis. The total mortality rate was 36%. CONCLUSIONS: In our experience we found a higher incidence compared to literature, probably because of the widespread use of this drug in more and more fragile patients. We confirm the need of a strict adherence to prescription with a specific attention, not only to renal function, but also to the concomitant presence of risk factors (age over 80, use of Ace-inhibitors, angiotensin receptor blockers and diuretics). We draw the attention to the importance of acute clinical events and we reaffirm the need of an adequate education of the patient and his relatives for a better management of the acute event. PMID- 26252267 TI - [Burnout in healthcare professionals: a study carried out in the Nephrology Unit of San Raffaele Hospital]. AB - Burnout is a work stress syndrome caused by a prolonged contact with users which present physical and emotional suffering. C. Maslach, one of the main authors, refers that this syndrome is characterized by emotional exhaustion, depersonalization and reduced personal skills. However, the researches done within the Nephrology and Dialysis Departments on this phenomenon are still few in the literature, despite the peculiar characteristics of the care relationship that develops between caregivers and patients on dialysis treatment. The present study aims to highlight the importance of assessing the levels of burnout and strategies of adaptation to stress (coping) in healthcare workers of Nephrology and Dialysis Unit, so that their psychological well-being could be preserved, preventing the possibility of a progressive deterioration of the care relationship with the patient. The implementation of psychological training courses for healthcare workers seems to be a useful tool aimed at the prevention and management of the burnout syndrome. PMID- 26252268 TI - [Article 32 of the Italian Constitution: The Republic protects health as a fundamental right of the individual and collective interest, and guarantees free medical care to patients. Is it really so?]. PMID- 26252270 TI - Genetic Association Between NFKBIA -881A>G Polymorphism and Cancer Susceptibility. AB - Several epidemiological studies have focused on the role of nuclear factor-kappa B inhibitor-alpha (NFKBIA) -881 A>G polymorphism in cancer susceptibility. However, the published data have led to contentious results. This study was designed to examine the association between -881 A>G polymorphism and cancer risk.Comprehensive search of PubMed, Web of science and Embase, identified a total of 5 case-control studies. To assess the association, comparison among all subjects plus subgroup analysis by ethnicity was performed and odds ratio (OR) along with 95% confidence interval (CI) was calculated with the fixed-effect model or the random-effects model dependent on the heterogeneity.The pooling data consisting of 1965 cancer cases and 2717 cancer-free controls demonstrated no significant association with overall cancer risk. However, the subgroup of Asian populations showed statistical evidence for an increase in risk of cancer (GG vs. AA, OR, 2.14; 95% CI, 1.03-4.46; GG + GA vs. AA, OR, 1.22; 95% CI, 1.01-1.47; GG vs. GA + AA, OR, 2.09; 95% CI, 1.01-4.34).This investigation on the association of -881 A>G polymorphism and cancer susceptibility reveals that -881 A>G polymorphism may act as a candidate for cancer development in Asian populations. PMID- 26252271 TI - Renal Angiomyolipoma With Caval Extension and Pulmonary Fat Embolism: A Case Report. AB - Renal angiomyolipoma (AML) is a rare benign tumor of the kidney. Occasionally, it may extend into the renal vein or the inferior vena cava (IVC), but so far of pulmonary embolism in patients with renal AML was rarely reported. Here, a case of symptomatic pulmonary embolism secondary to AML that was placed IVC filter before the operation and then treated with radical nephrectomy is reported.This case highlights the rare possibility of renal vein and IVC involvement with symptomatic pulmonary fat embolism in renal AML, which may potentially result in fatal complications if not appropriately and cautiously managed with surgical intervention. PMID- 26252269 TI - Movement and Other Neurodegenerative Syndromes in Patients with Systemic Rheumatic Diseases: A Case Series of 8 Patients and Review of the Literature. AB - Patients with rheumatic diseases can present with movement and other neurodegenerative disorders. It may be underappreciated that movement and other neurodegenerative disorders can encompass a wide variety of disease entities. Such disorders are strikingly heterogeneous and lead to a wider spectrum of clinical injury than seen in Parkinson's disease. Therefore, we sought to stringently phenotype movement and other neurodegenerative disorders presenting in a case series of rheumatic disease patients. We integrated our findings with a review of the literature to understand mechanisms which may account for such a ubiquitous pattern of clinical injury.Seven rheumatic disease patients (5 Sjogren's syndrome patients, 2 undifferentiated connective tissue disease patients) were referred and could be misdiagnosed as having Parkinson's disease. However, all of these patients were ultimately diagnosed as having other movement or neurodegenerative disorders. Findings inconsistent with and more expansive than Parkinson's disease included cerebellar degeneration, dystonia with an alien limb phenomenon, and nonfluent aphasias.A notable finding was that individual patients could be affected by cooccurring movement and other neurodegenerative disorders, each of which could be exceptionally rare (ie, prevalence of ~1:1000), and therefore with the collective probability that such disorders were merely coincidental and causally unrelated being as low as ~1-per-billion. Whereas our review of the literature revealed that ubiquitous patterns of clinical injury were frequently associated with magnetic resonance imaging (MRI) findings suggestive of a widespread vasculopathy, our patients did not have such neuroimaging findings. Instead, our patients could have syndromes which phenotypically resembled paraneoplastic and other inflammatory disorders which are known to be associated with antineuronal antibodies. We similarly identified immune-mediated and inflammatory markers of injury in a psoriatic arthritis patient who developed an amyotrophic lateral sclerosis (ALS)-plus syndrome after tumor necrosis factor (TNF)-inhibitor therapy.We have described a diverse spectrum of movement and other neurodegenerative disorders in our rheumatic disease patients. The widespread pattern of clinical injury, the propensity of our patients to present with co-occurring movement disorders, and the lack of MRI neuroimaging findings suggestive of a vasculopathy collectively suggest unique patterns of immune-mediated injury. PMID- 26252272 TI - Surgery for Liver Metastases From Gastric Cancer: A Meta-Analysis of Observational Studies. AB - The role of surgical therapy in patients with liver metastases from gastric cancer is still controversial. In this study, we investigated the results obtained with local treatment of hepatic metastases in patients with gastric cancer, by performing a systematic literature review and meta-analysis.We performed a systematic review and meta-analysis of observational studies published between 1990 and 2014. These works included multiple studies that evaluated the different survival rate among patients who underwent local treatment, such as hepatectomy or radiofrequency ablation, for hepatic metastases derived from primary gastric cancer. The collected studies were evaluated for heterogeneity, publication bias, and quality, and a pooled hazard ratio (HR) was calculated with a confidence interval estimated at 95% (95% CI).After conducting a thorough research among all published works, 2337 studies were found and after the review process 11 observational studies were included in the analysis. The total amount of patients considered in the survival analysis was 1010. An accurate analysis of all included studies reported a significantly higher survival rate in the group of patients who underwent the most aggressive local treatment for hepatic metastases (HR 0.54, 95% CI 0.46-0.95) as opposed to patients who underwent only palliation or systemic treatment. Furthermore, palliative local treatment of hepatic metastases had a higher survival rate if compared to surgical (without liver surgery) and systemic palliation (HR 0.50, 95% CI 0.26-0.96). Considering the only 3 studies where data from multivariate analyses was available, we found a higher survival rate in the local treatment groups, but the difference was not significant (HR 0.50, 95% CI 0.22 1.15).Curative and also palliative surgery of liver metastases from gastric cancer may improve patients' survival. However, further trials are needed in order to better understand the role of surgery in this group of patients. PMID- 26252273 TI - Early Thiopurines Versus Conventional Step-Care Therapy for Modifying the Disease Course of Early Crohn's Disease: A Tertiary Referral Center Cohort Study. AB - The impact of thiopurines (TP) on the long-term outcome of early Crohn disease (CD) is still controversial. The present study designed as a comparison of conventional step-care to alternative treatment paradigms for disease progression.This longitudinal cohort study examined the established CD patients from a university-based inflammatory bowel disease referral center. Outcomes of mucosal healing (MH), CD-related surgery or hospitalization, and clinical remission were compared based on timing of initiation of TP therapy. The cumulative incidence of events was estimated by Kaplan-Meier method.One-hundred ninety patients with early CD were included. After a median follow-up of 57 months (interquartile range, 31.3-76.2), 29 patients undergone abdominal surgeries, 48 patients hospitalized, and 68 patients experienced clinical flares. A higher cumulative proportion of patients in the top-down (TD) group achieving MH than both the accelerated step-up (AC) group and conventional management (CM) group at month 36 (78.8% vs 39.9% and 42.2%, respectively; P = 0.001). There was a trend, albeit not significant, for an increased proportion of patients free of CD-related intestinal surgery in the TD group at month 60 (P = 0.16). However, among secondary outcomes, an early TP-based AC or TD strategy was not associated with improvement in clinical remission rates compared with a CM strategy at month 60 (P = 0.79). No significant difference was observed between early TP and CM for rates of MH, CD-related intestinal surgery or hospitalization, and clinical remission.Both AC and CM strategy were minimally effective for disease modification. TD strategy has the potential of achieving higher rates MH. Our results support the TD strategy in patients with early CD at risk for a disabling course. PMID- 26252275 TI - Oral Burning With Dysphagia and Weight Loss. AB - Fibromyalgia is a disorder characterized by an abnormal pain regulation. Widespread pain, fatigue, and sleep disturbance are the prevalent symptoms. When unusual symptoms are overbearingly predominant at clinical presentation, the diagnosis becomes challenging.We report on the case of a patient with fibromyalgia, who presented with dysphagia, odynophagia, and glossodynia as prevalent symptoms. Difficulty in swallowing gradually developed over a month prior hospitalization, and worsened progressively so that nourishment and fluid intake were impeded.Because anemia with mild iron deficiency was found, esophagogastroduodenoscopy was performed, but no lesions were seen in the upper digestive tract. Levels of zinc and vitamin B12 were normal. Intense pain at pelvis and the inferior limbs, which was at a first glance referred to as osteoarthrosis, associated with oral symptoms and feeling of being in the clouds allowed us to diagnose fibromyalgia. Amitriptyline was used, with relief of symptoms.Although oropharyngeal symptoms were occasionally reported in fibromyalgia, they are often overlooked. The present case, therefore, testifies the need to consider the diagnosis of fibromyalgia when the patient presents with such symptoms that cannot be readily explained on other grounds. PMID- 26252274 TI - Preoperative Computed Tomography to Predict and Stratify the Risk of Severe Pancreatic Fistula After Pancreatoduodenectomy. AB - The aim of this article is to assess whether measures of abdominal fat distribution, visceral density, and antropometric parameters obtained from computed tomography (CT) may predict postoperative pancreatic fistula (POPF) occurrence.We analyzed 117 patients who underwent pancreatoduodenectomy (PD) and had a preoperative CT scan as staging in our center. CT images were processed to obtain measures of total fat volume (TFV), visceral fat volume (VFV), density of spleen, and pancreas, and diameter of pancreatic duct. The predictive ability of each parameter was investigated by receiver-operating characteristic (ROC) curves methodology and assessing optimal cutoff thresholds. A stepwise selection method was used to determine the best predictive model.Clinically relevant (grades B and C) POPF occurred in 24 patients (20.5%). Areas under ROC-curves showed that none of the parameters was per se significantly predictive. The multivariate analysis revealed that a VFV >2334 cm, TFV >4408 cm, pancreas/spleen density ratio <0.707, and pancreatic duct diameter <5 mm were predictive of POPF. The risk of POPF progressively increased with the number of factors involved and age.It is possible to deduce objective information on the risk of POPF from a simple and routine preoperative radiologic workup. PMID- 26252276 TI - Renal Vein Thrombosis in a Newborn With Abnormal Factor VIII Level: Clinical Case Report. AB - Renal vein thrombosis (RVT) in neonates is a rare condition of low mortality but significant morbidity due to renal impairment.We report the case of a male term newborn with left RVT and elevated serum factor VIII (FVIII).The main symptoms of the patient and the important clinical findings: prompt diagnosis of RVT was possible because the classic clinical presentation of macroscopic hematuria, thrombocytopenia, and palpable flank mass were present in this newborn infant.The main diagnoses: finally, the reason of RVT was established when the infant was 3 months of age: the increased level of FVIII was confirmed. We discuss the diagnosis, therapy, and outcome of the patient and compare with the literature.Therapeutics interventions: however, despite anticoagulant therapy the left kidney developed areas of scarring and then atrophy.Conclusions and outcomes: Prothrombotic defects should be considered in all patients with perinatal RVT. Elevated factor VIII as a reason of RVT in neonatal period is particularly rare. Given a poor renal outcome in children associated with elevated levels of factor VIII, consideration could be given to more aggressive antithrombotic therapy in such cases. PMID- 26252277 TI - Factors Associated With Outcomes in Endoscopic Submucosal Dissection of Gastric Cardia Tumors: A Retrospective Observational Study. AB - Tumors of the gastric cardia are among the most technically difficult lesions to remove by endoscopic submucosal dissection (ESD). This study aimed to evaluate the therapeutic outcomes of ESD in gastric cardia tumors according to clinicopathologic characteristics, and to assess the predictive factors for incomplete resection.We conducted a retrospective observational study of 82 patients with adenomas and early cancers of the gastric cardia who underwent ESD between January 2006 and December 2013 at the Pusan National University Hospital. Therapeutic outcomes of ESD and procedure-related complications were analyzed.En bloc resection, complete resection, and curative resection rates were 87%, 79%, and 66%, respectively. Deep submucosal invasion was the most common cause of noncurative resection in the cases in which complete resection was achieved. On multivariate analyses, hemispheric distribution (anterior hemisphere; odds ratio [OR] 4.808) and depth of tumor invasion (submucosal cancer; OR 22.056) were independent factors associated with incomplete resection. The rates of procedure related bleeding, perforation, and stenosis were 6%, 1%, and 0%, respectively; none of the complications required surgical intervention.In conclusion, ESD is a safe, effective, and feasible treatment for gastric cardia tumors. However, the complete resection rate decreases for tumors that are located in the anterior hemisphere or have deep submucosal invasion. PMID- 26252278 TI - Endoscopy Assessment at 1-Year Identifies Long-Term Responders to Thiopurines Maintenance Therapy in Patients With Crohn's Disease. AB - When treating Crohn disease (CD) with thiopurines, achievement of an objective response is essential. However, the minimal degree of mucosal improvement required to alter disease outcomes of CD is unknown.To determine the endoscopic responses of thiopurine monotherapy and to determine the minimal degree of mucosal improvement required to alter disease outcomes of CD.One hundred thirty CD patients who had evaluable ileocolonoscopy with evident of mucosal ulceration at baseline were included. The endpoints were endoscopic responses at the 2 follow-up endoscopies performed at 12 months (M12) and 36 month (M36) from the initiation of thiopurines.At M12, mucosal healing (MH) and a positive endoscopic response (PR) were documented in 38% and 46% of patients, respectively. At the second follow-up, merely a further 14% (13/93) of patients on monotherapy had a PR and a total of 46% (43/93) presented with MH. In a Cox regression model, both a PR (P < 0.02) and MH (P < 0.001) at M12 were associated with response at M36 in patients continuing thiopurine treatment. MH at M12 was associated with long-term disease outcomes of CD at M36, with an area under the Receiver Operator Characteristic curve of 0.54 for predicting clinical remission, 0.69 for hsCRP normalization, 0.69 for MH, and 0.74 for PR, respectively. A PR at M12, defined as a decrease in endoscopic activity score by >=2 points from baseline, yielded similar results.Endoscopy at M12 can help to identify responders to thiopurine monotherapy in active CD. A PR could represent the minimal clinically important improvement in endoscopic disease activity. PMID- 26252279 TI - Therapy of Severe Heatshock in Combination With Multiple Organ Dysfunction With Continuous Renal Replacement Therapy: A Clinical Study. AB - This study aimed to compare the clinical effects of continuous renal replacement therapy (CRRT) and routine therapy in heatshock (HS) patients.We retrospectively reviewed the clinical information of 33 severe exertional HS patients who were treated from February 1998 to October 2013. On the basis of whether or not CRRT therapy was used in addition to conventional therapy, patients were divided into a CRRT group (n = 15) and a control group (n = 18). Body temperature, blood gas analysis, routine blood tests, blood eletrolytes, enzymes and kidney function data, and APACHE II scores were obtained and compared between the 2 groups on admission and 3, 5, and 7 days after admission. Mortality was also compared between the 2 groups.CRRT treatment combined with conventional treatment resulted in a higher hospital-discharge rate, a faster return to normal of body temperature, greater increase in platelets, a greater decrease in WBC, neutrophils, and serum markers for liver and kidney dysfunction, greater improvement of organ dysfunction, and lower APACHE II scores than conventional treatment used alone.The addition of CRRT to conventional treatment for HS improves survival and causes a faster return to normal of serum markers and organ function. PMID- 26252280 TI - Health Behaviors of Cancer Survivors in Nationwide Cross-Sectional Survey in Korea: Higher Alcohol Drinking, Lower Smoking, and Physical Inactivity Pattern in Survivors with Higher Household Income. AB - This study investigated the prevalence of smoking, alcohol consumption, and physical activity in cancer survivors and examined the sociodemographic factors affecting these health-related behaviors.We used data from the 4th and 5th Korean National Health and Nutrition Examination Survey conducted between 2007 and 2012, which identified 1153 cancer cases and 36,451 people without a history of cancer >=20 years of age. We used a structured questionnaire to obtain information concerning cancer diagnosis, health-related behaviors, and sociodemographic characteristics.The proportion of cancer survivors who were current drinkers, heavy drinkers, current smokers, or engaged in physical activity were 49.1, 9.0, 9.2, or 50.7%, respectively. Compared with people with no history of cancer, cancer survivors were less likely to be current drinkers (odds ratio [OR] = 0.45; 95% confidence interval [CI] 0.36-0.56), heavy drinkers (OR = 0.53; 95% CI 0.36 0.78), current smokers (OR = 0.37; 95% CI 0.24-0.55), or physically inactive (OR = 0.77; 95% CI 0.63-0.95). Cancer survivors with higher household incomes had higher odds of current drinking and heavy drinking (P trend = 0.039 and 0.033, respectively) and were less likely to be current smokers or physically inactive (P trend = 0.016 and 0.046, respectively). Age, sex, sites of cancer, and the time since diagnosis affected the health behaviors in cancer survivors. Furthermore, we confirmed that these unhealthy behaviors are interrelated.We found that household income had a bidirectional effect on health behaviors and confirmed an aggregation of unhealthy lifestyles. Identification of survivors vulnerable to unhealthy lifestyles, focusing on household income level would allow intervention programs to be more effective. PMID- 26252281 TI - Comparison of Multidetector Computed Tomography and Flat-Panel Computed Tomography Regarding Visualization of Cortical Fractures, Cortical Defects, and Orthopedic Screws: A Phantom Study. AB - To compare the visualization of cortical fractures, cortical defects, and orthopedic screws in a dedicated extremity flat-panel computed tomography (FPCT) scanner and a multidetector computed tomography (MDCT) scanner.We used feet of European roe deer as phantoms for cortical fractures, cortical defects, and implanted orthopedic screws. FPCT and MDCT scans were performed with equivalent dose settings. Six observers rated the scans according to number of fragments, size of defects, size of defects opposite orthopedic screws, and the length of different screws. The image quality regarding depiction of the cortical bone was assessed. The gold standard (real number of fragments) was evaluated by autopsy.The correlation of reader assessment of fragments, cortical defects, and screws with the gold standard was similar for FPCT and MDCT. Three readers rated the subjective image quality of the MDCT to be higher, whereas the others showed no preferences.Although the image quality was rated higher in the MDCT than in the FPCT by 3 out of 6 observers, both modalities proved to be comparable regarding the visualization of cortical fractures, cortical defects, and orthopedic screws and of use to musculoskeletal radiology regarding fracture detection and postsurgical evaluation in our experimental setting. PMID- 26252283 TI - Chinese Adaptation of the Bad Sobernheim Stress Questionnaire for Patients With Adolescent Idiopathic Scoliosis Under Brace Treatment. AB - Bad Sobernheim Stress Questionnaire (BSSQ)-Deformity and BSSQ-Brace are the most widely used instruments for evaluating stress levels in adolescent idiopathic scoliosis (AIS) patients under brace treatment, and good reliability and validity have been demonstrated across different cultures. Great stress has been found among many adolescents, becoming a major concern for professionals. However, no previous research has addressed the cultural adaptations and psychometric testing of BSSQ-Deformity and BSSQ-Brace in China or the stress levels in AIS patients. The purposes of our study were to evaluate the cross-cultural adaptation and validation of the BSSQ-Deformity and BSSQ-Brace and to investigate stress levels in Chinese (AIS) patients under brace treatment.The original (German) versions of BSSQ-Deformity and BSSQ-Brace were cross-culturally translated according to international guidelines. Psychometric properties such as reliability and construct validity were tested. Eighty-six AIS patients were included in our study, and 50 patients paid a second visit 3 to 7 days later to test reproducibility. Cronbach alpha and the intraclass coefficient were determined to assess internal consistency and reproducibility. Scoliosis Research Society patient questionnaire-22 (SRS-22) was applied to evaluate construct validity.The mean BSSQ-Deformity and BSSQ-Brace scores were 15.3 and 13.4 points, respectively. Severe stress was observed in 12% of patients due to brace treatment. Item analysis demonstrated that each item was scored under a normal distribution with no redundancy. Psychometric analysis revealed excellent internal consistency (Cronbach alpha = 0.85 and 0.80, respectively) and reproducibility (intraclass correlation coefficient = 0.85 and 0.90, respectively) for BSSQ-Deformity and BSSQ-Brace. The correlation coefficients of BSSQ-Deformity, BSSQ-Brace and SRS-22 were 0.48 and 0.63, respectively.In conclusion, BSSQ-Deformity and BSSQ-Brace have been successfully adapted to a Chinese background and psychometrically validated with excellent reliability and construct validity. Brace wearing is considered the main cause of stress in AIS patients under brace treatment. PMID- 26252282 TI - The Role of Neoadjuvant Chemoradiation Therapy in Patients With Borderline Resectable Pancreatic Cancer With Isolated Venous Vascular Involvement. AB - The rationale for neoadjuvant chemoradiation therapy (Neo-CRT) and the definition of borderline resectable pancreatic cancer (BRPC) are still controversial. In particular, surgical treatment of BRPC with isolated venous vascular involvement (IVVI) is debatable.From January 2000 to December 2013, 84 patients diagnosed with BRPC according to NCCN guidelines were identified, and 70 patients were found to have BRPC with IVVI. We divided all 70 patients into 3 groups: surgery first without Neo-CRT (Group 1); pancreatectomy following Neo-CRT (Group 2); and no operation following Neo-CRT (Group 3). Patient characteristics including oncologic outcomes were analyzed for each of the 3 patients groups.Thirty-seven patients were female and 33 were male, with a mean age of 61.7 +/- 9.74 years. Among the 70 BRPC patients with IVVI, 28 patients (40%) belonged to Group 1, 30 patients (42.9%) belonged to Group 2, and 12 patients (17.1%) belonged to Group 3. Pathological tumor size (P < 0.001), pT stage (P = 0.001), pTNM stage (P=0.002), combined vascular resection (P = 0.003), completeness of adjuvant therapy (P = 0.004) were found to be statistically significantly different between Groups 1 and 2. In addition, disease-free survival (P = 0.055) and disease-specific survival (DSS) (P=0.006) were improved in Group 2. Interestingly, when comparing DSS, there was no statistically significant difference between Groups 1 and 3 (P = 0.991).The clinical practice of pancreatectomy following Neo-CRT in BRPC with IVVI provided favorable oncologic outcomes. The effect of Neo-CRT in BRPC with IVVI may be multifactorial, providing proper patient selection, complete adjuvant chemotherapy, and potential therapeutic (downstaging) effect. PMID- 26252285 TI - Surgical Management in a Patient With Complex Uveitic Glaucoma: A Case Report. AB - Uveitic glaucoma (UG) is secondary glaucoma, present as a clinical challenge in both diagnosis and management.We report a case of complex UG, which initially presented as pupillary block and rupture of the anterior lens capsule. We performed cataract extraction with preservation of posterior capsule. Then, the case turned to aphakic malignant glaucoma. We performed anterior vitrectomy with posterior capsule resection in this case. After the second operation, the patient had a satisfactory recovery. Specifically, ultrasonographic biomicroscopy was useful during the diagnosis process and follow-up period in this case.UG presenting as pupillary block, rupture of the anterior lens capsule, and aqueous misdirection seldom presents in clinical practice. Earlier and more active surgical intervention may be necessary for effective preservation of visual function in complex cases of UG. PMID- 26252284 TI - Meta-Analysis of Prognostic and Clinical Significance of CD44v6 in Esophageal Cancer. AB - CD44v6 is a cell adhesion molecule that plays an important role in the development and progression of esophageal cancer. However, the prognostic value and clinical significance of CD44v6 in esophageal cancer remains controversial. In the present study, we aimed to clarify these relationships through a meta analysis.We performed a comprehensive search of studies from PubMed, EMBASE, Ovid library database, Google scholar, and Chinese National Knowledge Infrastructure databases that were published before June 2015. The odds ratio (OR) and pooled hazard ratio (HR) with the 95% confidence intervals (CI) were used to estimate the effects.Twenty-one studies including 1504 patients with esophageal cancer were selected to assess the prognostic value and clinical significance of CD44v6 in these patients. The results showed that the expression of CD44v6 was higher in esophageal cancer tissue than in normal colorectal tissue (OR=9.19, 95% CI=6.30 13.42). Moreover, expression of CD44v6 was higher in patients with lymphoid nodal metastasis, compared to those without (OR=6.91, 95% CI=4.81-9.93). The pooled results showed that CD44v6 was associated with survival in patients with esophageal cancer (HR = 2.47, 95% CI = 1.56-3.92). No significant difference in CD44v6 expression was found in patients with different histological types and tumor stages (both P>0.05). Moreover, no publication bias was found among the studies (all P > 0.05).This meta-analysis demonstrates that CD44v6 is associated with the metastasis of esophageal cancer and a poor prognosis, but is not associated with the histological types and tumor stages. PMID- 26252286 TI - Serum Gamma-Glutamyltransferase Levels Predict Mortality in Patients With Peritoneal Dialysis. AB - Serum gamma-glutamyltransferase (GGT) level has been considered marker of oxidative stress as well as liver function. Serum GGT level has been reported to be associated with the mortality in hemodialysis patients. However, it is not well established whether serum GGT level is associated with all-cause mortality in peritoneal dialysis (PD) patients. The aim of this study was to determine the association between serum GGT levels and all-cause mortality in PD patients.PD patients were included from the Clinical Research Center registry for end-stage renal disease cohort, a multicenter prospective observational cohort study in Korea. Patients were categorized into 3 groups by tertile of serum GGT levels as follows: tertile 1, GGT < 16 IU/L; tertile 2, GGT = 16 to 27 IU/L; and tertile 3, GGT > 27 IU/L. Primary outcome was all-cause mortality.A total of 820 PD patients were included. The median follow-up period was 34 months. Kaplan-Meier analysis showed that the all-cause mortality rate was significantly different according to tertiles of GGT (P = 0.001, log-rank). The multivariate Cox regression analysis showed that higher tertiles significantly associated with higher risk for all cause mortality (tertile 2: hazard ratio [HR] 2.08, 95% confidence interval [CI], 1.17-3.72, P = 0.013; tertile 3: HR 1.83, 95% CI, 1.04-3.22, P = 0.035) in using tertile 1 as the reference group after adjusting for clinical variables.Our study demonstrated that high serum GGT levels were an independent risk factor for all cause mortality in PD patients. Our findings suggest that serum GGT levels might be a useful biomarker to predict all-cause mortality in PD patients. PMID- 26252287 TI - Cumulative Cardiovascular Polypharmacy Is Associated With the Risk of Acute Kidney Injury in Elderly Patients. AB - Polypharmacy is common in the elderly due to multimorbidity and interventions. However, the temporal association between polypharmacy and renal outcomes is rarely addressed and recognized. We investigated the association between cardiovascular (CV) polypharmacy and the risk of acute kidney injury (AKI) in elderly patients.We used the Taiwan National Health Insurance PharmaCloud system to investigate the relationship between cumulative CV medications in the 3 months before admission and risk of AKI in the elderly at their admission to general medical wards in a single center. Community-dwelling elderly patients (>60 years) were prospectively enrolled and classified according to the number of preadmission CV medications. CV polypharmacy was defined as use of 2 or more CV medications.We enrolled 152 patients, 48% with AKI (based upon Kidney Disease Improving Global Outcomes [KDIGO] classification) and 64% with CV polypharmacy. The incidence of AKI was higher in patients taking more CV medications (0 drugs: 33%; 1 drug: 50%; 2 drugs: 57%; 3 or more drugs: 60%; P = 0.05) before admission. Patients with higher KDIGO grades also took more preadmission CV medications (P = 0.04). Multiple regression analysis showed that patients who used 1 or more CV medications before admission had increased risk of AKI at admission (1 drug: odds ratio [OR] = 1.63, P = 0.2; 2 drugs: OR = 4.74, P = 0.03; 3 or more drugs: OR = 5.92, P = 0.02), and that CV polypharmacy is associated with higher risk of AKI (OR 2.58; P = 0.02). Each additional CV medication increased the risk for AKI by 30%.We found that elderly patients taking more CV medications are associated with risk of adverse renal events. Further study to evaluate whether interventions that reduce polypharmacy could reduce the incidence of geriatric AKI is urgently needed. PMID- 26252288 TI - 125I Seed Implant Brachytherapy for Painful Bone Metastases After Failure of External Beam Radiation Therapy. AB - The purpose of this study was to evaluate the safety and therapeutic efficacy of computed tomography (CT)-guided I seed implant brachytherapy in patients with painful metastatic bone lesions after failure of external beam radiation therapy (EBRT).From August 2012 to July 2014, 26 patients with painful bone metastases after failure of EBRT were treated with CT-guided I seed implant brachytherapy. Patient pain and analgesic use were measured using the Brief Pain Inventory before treatment, weekly for 4 weeks, and every 4 weeks thereafter for a total of 24 weeks. Opioid analgesic medications and complications were monitored at the same follow-up intervals.Before I seed implantation, the mean score for worst pain in a 24-hour period was 7.3 out of 10. Following treatment, at weeks 1, 4, 8, 12, and 24, worst pain decreased to 5.0 (P < 0.0001), 3.0 (P < 0.0001), 2.8 (P < 0.0001), 2.6 (P < 0.0001), and 2.0 (P = 0.0001), respectively. Opioid usage significantly decreased at weeks 4, 8, and 12. Overall response rates of osseous metastases after I seed implantation at 1, 4, 8, 12, and 24 weeks were 58%, 79%, 81%, 82%, and 80%, respectively. Adverse events were seen in 4 patients, including Grade 1 myelosuppression and Grade 1 late skin toxicity.I seed brachytherapy is a safe and effective treatment for patients with painful bone metastases after failure of EBRT. PMID- 26252289 TI - GAD Antibodies as Key Link Between Chronic Intestinal Pseudoobstruction, Autonomic Neuropathy, and Limb Stiffness in a Nondiabetic Patient: A CARE Compliant Case Report and Review of the Literature. AB - Chronic intestinal pseudoobstruction (CIP) can be a severe burden and even a life threatening disorder. Typically, several years of uncertainty are passing before diagnosis. We are reporting the case of a young woman with a decade of severe, progressive gastrointestinal dysmotility. Unusually, she had also developed an autonomic neuropathy, and a stiff limb syndrome.In addition to achalasia and CIP the young woman also developed neuropathic symptoms: orthostatic intolerance, urinary retention, a Horner syndrome, and lower limb stiffness. Careful interdisciplinary diagnostics excluded underlying infectious, rheumatoid, metabolic or tumorous diseases.The detection of GAD (glutamic acid decarboxylase) antibodies, however, seemed to link CIP, autonomic neuropathy, and limb stiffness and pointed at an autoimmune origin of our patient's complaints. This was supported by the positive effects of intravenous immunoglobulin. In response to this therapy the body weight had stabilized, orthostatic tolerance had improved, and limb stiffness was reversed.The case suggested that GAD antibodies should be considered in CIP also in nondiabetic patients. This may support earlier diagnosis and immunotherapy. PMID- 26252291 TI - Left Lateral Sectionectomy of the Native Liver and Combined Living-Related Liver Kidney Transplantation for Primary Hyperoxaluria Type 1. AB - Primary hyperoxaluria type I (PH1), the most severe form of primary hyperoxalurias, is a liver disease of the metabolic defect in glyoxylate detoxification that can be corrected by liver transplantation. A 21-year-old man presented to our center after 4 months of regular hemodialysis for kidney failure caused by nephrolithiasis. A diagnosis of PH1 was confirmed by mutations of the AGXT gene. Left lateral sectionectomy of the native liver was performed; and auxiliary partial orthotopic liver transplantation (APOLT) and kidney transplantation were carried out synchronously using a living donor. After transplantation, the patient's plasma oxalate and creatinine levels substantially decreased and the patient recovered well with good dual grafts function. APOLT and kidney transplantation can compensate the liver deficient in liver enzyme production and aid the renal elimination of oxalate, thus serving as an effective treatment option for patients with PH1. In conclusion, left lateral sectionectomy of the native liver and combined living-related liver-kidney transplantation can be a surgical option for PH1. PMID- 26252290 TI - Isoflurane and Propofol Contribute to Increasing the Antioxidant Status of Patients During Minor Elective Surgery: A Randomized Clinical Study. AB - Isoflurane is a volatile halogenated anesthetic used especially for anesthesia maintenance whereas propofol is a venous anesthetic utilized for anesthesia induction and maintenance, and reportedly an antioxidant. However, there are still controversies related to isoflurane-induced oxidative stress and it remains unanswered whether the antioxidant effects occur in patients under propofol anesthesia.Taking into account the importance of better understanding the role of anesthetics on oxidative stress in anesthetized patients, the present study was designed to evaluate general anesthesia maintained with isoflurane or propofol on antioxidant status in patients who underwent minimally invasive surgeries.We conducted a prospective randomized trial in 30 adult patients without comorbidities who underwent elective minor surgery (septoplasty) lasting at least 2 h admitted to a Brazilian tertiary hospital.The patients were randomly allocated into 2 groups, according to anesthesia maintenance (isoflurane, n = 15 or propofol, n = 15). Peripheral blood samples were drawn before anesthesia (baseline) and 2-h after anesthesia induction.The primary outcomes were to investigate the effect of either isoflurane or propofol anesthesia on aqueous plasma oxidizability and total antioxidant performance (TAP) by fluorometry as well as several individual antioxidants by high-performance liquid chromatography. As secondary outcome, oxidized genetic damage (7,8-dihydro-8 oxoguanine, known as 8-oxo-Gua) was investigated by the comet assay.Both anesthesia techniques (isoflurane or propofol) for a 2-h period resulted in a significant decrease of plasma alpha-tocopherol, but not other antioxidants including uric acid, carotenoids, and retinol (P > 0.05). Propofol, in contrast to isoflurane anesthesia, significantly increased (P < 0.001) anti inflammatory/antioxidant plasma gamma-tocopherol concentration in patients. Both anesthesia types significantly enhanced hydrophilic antioxidant capacity and TAP, with no significant difference between them, and 8-oxo-Gua remained unchanged during anesthesia in both groups. In addition, both anesthetics showed antioxidant capacity in vitro.This study shows that anesthesia maintained with either propofol or isoflurane increase both hydrophilic and total antioxidant capacity in plasma, but only propofol anesthesia increases plasma gamma tocopherol concentration. Additionally, both types of anesthetics do not lead to oxidative DNA damage in patients without comorbidities undergoing minimally invasive surgery. PMID- 26252292 TI - The Association Between Body Mass Index and the Prognosis and Postoperative Complications of Hepatocellular Carcinoma: A Meta-Analysis. AB - Previous studies have reported the association between excess body mass index (BMI) and increased risk of hepatocellular carcinoma (HCC). However, whether BMI is associated with the prognosis and postoperative complications of HCC is still not clear.We searched PubMed and Embase for relevant studies published until the date of August 30, 2014. Additional studies were manually identified by searching reference lists of retrieved articles. Pooled hazard ratios (HRs) with 95% confidence intervals (95% CIs) for overall survival (OS), disease-free survival (DFS), and risk ratios (RRs) with 95% CIs for postoperative complications were calculated using random effects or fixed effects models according to heterogeneities between studies.A total of 14 studies were included in the present meta-analysis. The pooled results showed that excess BMI was not significantly associated with improved OS (HR = 0.94; 95% CI: 0.74-1.19, P = 0.588) or DFS (HR = 0.93; 95% CI: 0.79-1.10, P = 0.382). In addition, higher BMI was not associated with increased rate of a number of complications including ascites (RR = 1.25, 95% CI: 0.94-1.65, P = 0.119), bile leaks (RR = 1.22, 95% CI: 0.81-1.83, P = 0.345), and 30-day mortality (RR = 1.05, 95% CI: 0.57-1.96, P = 0.871). However, HCC patients with higher BMI had increased incidence of wound infections (RR = 2.17, 95% CI: 1.28-3.68, P = 0.004).BMI was not an independent prognostic factor for the evaluation of the prognosis in HCC patients, and it was not associated with postoperative complications except for wound infections that as significantly associated with higher BMI scores. PMID- 26252293 TI - Primary Adrenal Lymphoma Possibly Associated With Epstein-Barr Virus Reactivation Due to Immunosuppression Under Methotrexate Therapy. AB - Primary adrenal lymphoproliferative disorder (LPD) is an extremely rare disease that is widely known to be associated with methotrexate (MTX) use in patients with rheumatoid arthritis (RA).A 70-year-old man was incidentally found to have a tumor at the dorsal part of the liver in a medical check-up. He had a history of RA treated with MTX. Abdominal ultrasonography demonstrated a low echoic mass (30 mm in diameter) at the dorsal part of the liver, located close to the inferior vena cava. Preoperative differential diagnoses included intrahepatic cholangiocarcinoma, adrenal tumor, and hepatic malignant lymphoma, but no definitive diagnosis was reached. On exploratory laparotomy, the tumor seemed to be derived from the right adrenal gland and adhered tightly to segment 7 of the liver. Therefore, right adrenectomy with partial resection of segment 7 of the liver was performed. Pathological findings revealed diffuse inflammatory cell infiltration with a population of small atypical lymphoid cells, with positive immunohistochemical evidence for Epstein-Barr virus (EBV). Final diagnosis was primary adrenal iatrogenic EBV-positive LPD, classified as "other iatrogenic immunodeficiency-associated LPDs: Hodgkin-like lesions."In this report, we described the possibility of the spontaneous healing of MTX-associated LPD (MTX LPD) before treatment and the importance of doubting MTX-LPD and doing immunostaining to necrotic tissue. To our knowledge, this is the first reported case of MTX-related EBV-positive LPD, Hodgkin-like lesion, of the unilateral adrenal gland in patient with RA. PMID- 26252294 TI - Primary Pulmonary Paraganglioma: A Case Report and Review of Literature. AB - Primary pulmonary paraganglioma is a rare disease. We report a case of a 37-year old female patient with space-occupying lesions in the right lower pulmonary lobe during a routine examination without any symptoms. The patient underwent video assisted thoracoscopic surgery (VATS) resection of the right middle lobe and dissection of hilar and mediastinal lymph nodes under general anesthesia. She recovered without recrudescence. Preoperative diagnosis is difficult. Accurate diagnosis requires pathological examination, and immunohistochemical test is particularly important. Complete resection is the first treatment option for solitary primary pulmonary paraganglioma; however, VATS is a better technique. Given the high local control rates and few complications of radiotherapy, it is considered as a standard treatment. PMID- 26252295 TI - Posttransplant Lymphoproliferative Disorder of the Thorax: CT and FDG-PET Features in a Single Tertiary Referral Center. AB - To investigate the chest computed tomography (CT) and F-18 fluoro-2-deoxy-D glucose positron emission tomographic (FDG-PET) findings of posttransplant lymphoproliferative disorder (PTLD) in the thorax.From November 2004 to February 2013, the cases of 12 adult patients (3 female and 9 male, age range 34-68, and median age 46 years) with proven PTLD were retrospectively reviewed. The transplanted organs included the kidney (5/12), liver (4/12), heart (1/12), combined kidney and pancreas (1/12), and hematopoietic stem cell (1/12). We investigated the relationship of the Epstein-Barr virus (EBV) to the patients' long-term follow-up, and evaluated the characteristics of the lesions on the chest CT and FDG-PET. The lesions were classified into 2 patterns: that of lymph node and lung involvement.The interval between the transplantation and the onset of PTLD was 2 to 128 months (median, 49). Positive EBV-encoded RNA in the pathologic specimens was found in 10 patients (83.3%). Eight patients were positive for EBV PCR in their blood, and 3 patients showed seroconversion without antiviral therapy. The responses to treatment were complete in 7 cases (58.3%), partial remission in 4 cases (33.3%), and undetermined in 1 case (8.3%). The more common chest CT patterns showed lymph node involvement (10/12) rather than lung involvement (3/12). The median maximum-standardized uptake value on the FDG-PET scans was 7.7 (range, 2.7-25.5).In patients with PTLD involving the thorax, lymphadenopathy was the more common manifestation on the chest CT rather than lung involvement. The lesions showed hypermetabolism on FDG-PET. PMID- 26252296 TI - Low Serum Bicarbonate Predicts Residual Renal Function Loss in Peritoneal Dialysis Patients. AB - Low residual renal function (RRF) and serum bicarbonate are associated with adverse outcomes in peritoneal dialysis (PD) patients. However, a relationship between the 2 has not yet been determined in these patients. Therefore, this study aimed to investigate whether low serum bicarbonate has a deteriorating effect on RRF in PD patients.This prospective observational study included a total of 405 incident patients who started PD between January 2000 and December 2005. We determined risk factors for complete loss of RRF using competing risk methods and evaluated the effects of time-averaged serum bicarbonate (TA-Bic) on the decline of RRF over the first 3 years of dialysis treatment using generalized linear mixed models.During the first 3 years of dialysis, 95 (23.5%) patients became anuric. The mean time until patients became anuric was 20.8 +/- 9.0 months. After adjusting for multiple potentially confounding covariates, an increase in TA-Bic level was associated with a significantly decreased risk of loss of RRF (hazard ratio per 1 mEq/L increase, 0.84; 0.75-0.93; P = 0.002), and in comparison to TA-Bic >= 24 mEq/L, TA-Bic < 24 mEq/L conferred a 2.62-fold higher risk of becoming anuric. Furthermore, the rate of RRF decline estimated by generalized linear mixed models was significantly greater in patients with TA-Bic < 24 mEq/L compared with those with TA-Bic >= 24 mEq/L (-0.16 vs -0.11 mL/min/mo/1.73 m, P < 0.001).In this study, a clear association was found between low serum bicarbonate and loss of RRF in PD patients. Nevertheless, whether correction of metabolic acidosis for this indication provides additional protection for preserving RRF in these patients is unknown. Future interventional studies should more appropriately address this question. PMID- 26252297 TI - Discordant Diagnosis of Lower Extremity Peripheral Artery Disease Using American Heart Association Postexercise Guidelines. AB - To determine whether postexercise criteria for peripheral artery disease (PAD) diagnosis recommended by the American Heart Association (AHA) identifies the same group of PAD patients.Diagnosis of PAD is performed using ankle-brachial index at rest (resting-ABI). When resting-ABI is not contributive, an AHA scientific statement recommend to use 1 of 2 following criteria: a postexercise ABI decrease of greater than 20% or a postexercise ankle pressure decrease of greater than 30 mm Hg.Between 1996 and 2012, 31,663 consecutive patients underwent lower extremity arterial study at Mayo Clinic. Among them, only unique patients who had exercise treadmill testing were analyzed. In this retrospective analysis, resting ABI, postexercise ABI, and postexercise decrease of ankle pressure measured at 1 minute were measured in each patient. We conducted an analysis of agreement between postexercise criteria expressing the agreement separately for the positive and the negative ratings. Twelve thousand three hundred twelve consecutive patients were studied with a mean age of 67 +/- 12 years, 61% male. According to resting-ABI, 4317 (35%) patients had PAD. In the whole population, if a clinician diagnoses "PAD" with 1 postexercise criterion, the probability that other clinicians would also diagnose "PAD" is 74.3%. If a clinician diagnoses "no PAD", the probability that other clinicians would also diagnose "no PAD" is 82.4%. In the patients to be of potential benefit from treadmill test when the resting-ABI > 0.90, if a clinician diagnoses "PAD" with 1 postexercise criterion, the probability that other clinicians would also diagnose "PAD" is 58.4% whereas if a clinician diagnoses "no PAD," the probability that other clinicians would also diagnose "no PAD" is 87.5%.Postexercise criteria do not identify the same group of PAD patients. In our opinion, postexercise criteria to define PAD deserve additional study. PMID- 26252298 TI - Efficacy of Addition of Antiangiogenic Agents to Taxanes-Containing Chemotherapy in Advanced Nonsmall-Cell Lung Cancer: A Meta-Analysis and Systemic Review. AB - Preclinical researches indicated a potential synergistic effect of taxanes containing chemotherapy (TCC) and antiangiogenic agents (AAs) on the treatment of advanced nonsmall-cell lung cancer (NSCLC). The advantage of adding AA to TCC in the real world remains confusing. We summarized the current evidences from relevant phase II/III randomized controlled trials (RCTs) by performing this meta analyses.Electronic databases were searched for eligible literatures. The primary endpoint was overall survival (OS). Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were calculated using RevMan 5.2.A total of 14 phase II/III RCTs involving 9703 participants were included. Compared to standard TCC, the addition of AA was associated with the significant better OS (HR 0.92, 95% CI 0.87-0.97, P = 0.002), prolonged progression-free survival (HR 0.79, 95% CI 0.71 0.87, P < 0.00001), superior response rate (risk ratio [RR] 1.69, 95% CI 1.47 1.95, P < 0.0001), and disease control rate (RR 1.19, 95% CI 1.08-1.32, P < 0.00001). Subgroup analyses indicated that patient treated with monoclonal antibodies (HR 0.89, 95% CI 0.82-0.96, P = 0.02) as well as application in second line (HR 0.91, 95% CI 0.85-0.96, P = 0.02) acquired significant OS improvement. Other clinical factors directing significant OS improvement by the combination strategy included nonsquamous cancer (P = 0.002), nonsmokers (P = 0.0005), and female (P = 0.02). Toxicities were greater but generally mild or moderate in the combination group, and were mostly manageable.In summary, the addition of AAs to TCC could improve prognosis of advanced NSCLC. Furthermore, proper selection of patient population and AAs is crucial for clinical trials design and clinical practice in the future. PMID- 26252299 TI - A Healthier Lifestyle Pattern for Cardiovascular Risk Reduction Is Associated With Better Bone Mass in Southern Chinese Elderly Men and Women. AB - Lifestyle factors have been linked to bone health, however little is known about their combined impact on bone. Cardiovascular disease (CVD) and osteoporosis are 2 major public health problems that share some common pathophysiology. We aimed to assess whether higher adherence to American Heart Association diet and lifestyle recommendations (AHA-DLR) was associated with better bone health in Chinese elderly.This was a cross-sectional study using data from the largest population-based study on osteoporosis in Asia (Mr and Ms Os, Hong Kong). The study recruited 4000 independent walking Chinese men and women aged >=65 year. Information on demographic, health, and lifestyle factors was obtained by standardized questionnaires. An overall lifestyle score was estimated based on a modified adherence index of AHA-DLR. Bone mineral measurements of the whole body, total hip, lumbar spine, and femoral neck were made by dual-energy X-ray absorptiometry.Most lifestyle factors alone were not significantly associated bone mass. Overall lifestyle score in the highest quartile compared with the lowest quartile had significantly better bone mass at all sites in a dose response manner. Every 10-unit of lifestyle score increase was associated with 0.005, 0.004, and 0.007 g/cm increases of bone mineral density (BMD) at whole body, femur neck, and total hip, respectively (all P < 0.05), and 13.2% (odds ratio 0.868; 95% CI 0.784, 0.961) decreased risk of osteoporosis at total hip after adjustment for potential covariates.Our study suggested that greater adherence to an overall healthy lifestyle for CVD risk reduction was associated with better bone mass among Chinese elderly. PMID- 26252300 TI - KRAS Mutation Status Is Not a Predictor for Tumor Response and Survival in Rectal Cancer Patients Who Received Preoperative Radiotherapy With 5-Fluoropyrimidine Followed by Curative Surgery. AB - We evaluated the tumor response and survival according to the KRAS oncogene status in locally advanced rectal cancer. One hundred patients with locally advanced rectal cancer (cT3-4N0-2M0) received preoperative radiation of 50.4 Gy in 28 fractions with 5-fluorouracil and total mesorectal excision. Tumor DNA from each patient was obtained from pretreatment biopsy tissues. A Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation was found in 26 (26%) of the 100 patients. Downstaging (ypT0-2N0M0) rates after preoperative chemoradiotheray were not statistically different between the wild-type and mutant-type KRAS groups (30.8% vs 27.0%, P = 0.715, respectively). After a median follow-up time of 34 months, there was no statistically significant difference in the 3-year relapse-free survival (82.2% vs 82.6%, P = 0.512) and overall survival (94.7% vs 92.3%, P = 0.249) rates between wild-type and mutant-type KRAS groups, respectively. The KRAS mutation status does not influence the tumor response to the radiotherapy and survival in locally advanced rectal cancer patients who received preoperative chemoradiotherapy and curative surgery. PMID- 26252301 TI - Bilateral Diaphragmatic Paralysis in a Patient With Critical Illness Polyneuropathy: A Case Report. AB - Bilateral diaphragmatic paralysis (BDP) manifests as respiratory muscle weakness, and its association with critical illness polyneuropathy (CIP) was rarely reported. Here, we present a patient with BDP related to CIP, who successfully avoided tracheostomy after diagnosis and management.A 71-year-old male presented with acute respiratory failure after sepsis adequately treated. Repeated intubation occurred because of carbon dioxide retention after each extubation. After eliminating possible factors, septic shock-induced respiratory muscle weakness was suspected. Physical examination, a nerve conduction study, and chest ultrasound confirmed our impression.Pulmonary rehabilitation and reconditioning exercises were arranged, and the patient was discharged with a diagnosis of BDP.The diagnosis of BDP is usually delayed, and there are only sporadic reports on its association with polyneuropathy, especially in patients with preserved limb muscle function. Therefore, when physicians encounter patients that are difficult to wean from mechanical ventilation, CIP associated with BDP should be considered in the differential diagnosis. PMID- 26252302 TI - A Functional Polymorphism in the Promoter of MiR-143/145 Is Associated With the Risk of Cervical Squamous Cell Carcinoma in Chinese Women: A Case-Control Study. AB - MiR-143/145 is down-regulated in cervical cancer, which may serve as a tumor suppressor by targeting KRAS and Ras-responsive element-binding protein (RREB1). Activated KRAS leads to down-regulation of miR-143/145 transcription in a RREB1 dependent manner, establishing a miR-143/145-KRAS-RREB1 feedback loop. A polymorphism rs4705343C/T in the promoter of miR-143/145 might influence the binding of TATA-binding protein. We hypothesized that the miR-143/145 rs4705343 and KRAS rs712 may be related to the occurrence of cervical squamous cell carcinoma (CSCC). In this study, we genotyped the 2 polymorphisms in 415 patients with CSCC and 504 controls using polymerase chain reaction-restriction fragment length polymorphism. The promoter activities were measured by the Dual-Luciferase Reporter Assay System. We found that the rs4705343TC genotype was associated with an increased risk of CSCC (adjusted odds ratio [OR] = 1.37; 95% confidence interval [CI], 1.05-1.80). The significantly increased association was also observed in a dominant genetic model (adjusted OR = 1.32; 95% CI, 1.01-1.72). Combined analysis showed that individuals carrying the genotypes of rs4705343 TC/CC and rs712GT/TT had a 1.47-fold increased risk of CSCC (adjusted OR = 1.47; 95% CI, 1.01-2.15). By using multifactor dimensionality reduction software method, we identified a significant interaction between the miR-143/145 rs4705343 and KRAS rs712. Dual-Luciferase Reporter Assay showed that the luciferase activity was significantly lower in cells transfected with the rs4705343C allele than that of the rs4705343T allele. These findings indicate that miR-143/145 rs4705343 and KRAS rs712 may contribute to the etiology of CSCC in Chinese women. PMID- 26252303 TI - Usefulness of 18F-Fluorodeoxyglucose Positron Emission Tomography for Follow-Up of 13-cis-Retinoic Acid Treatment for Residual Neuroblastoma After Myeloablative Chemotherapy. AB - 13-cis-retinoic acid (13-cis-RA) treatment is used as a second-line treatment for residual or recurrent neuroblastoma. However, determining the duration of 13-cis RA treatment for residual and recurrent neuroblastoma can be a problem because it is difficult to evaluate the effectiveness of the treatment.We performed 13-cis RA treatment to remove residual active neuroblastoma cells in an 8-year-old boy with stage 4 neuroblastoma that developed from a left sympathetic ganglion and had been treated with chemotherapy, surgery, autologous peripheral blood stem cell transplantation, and radiotherapy. F-fluorodeoxyglucose positron emission tomography (F-FDG-PET) and iodine-123 metaiodobenzylguanidine (I-MIBG) scintigraphy obtained immediately before 13-cis-RA treatment both showed positive findings in the area of the primary lesion. At 18 months after 13-cis-RA treatment, there was accumulation on I-MIBG scintigraphy but no uptake on F-FDG PET, and 13-cis-RA treatment was suspended. The patient has been in complete remission for 3 years. In comparing the effectiveness of the 2 imaging modalities for monitoring the response to 13-cis-RA treatment, we considered that F-FDG-PET was superior to I-MIBG scintigraphy because F-FDG-PET images were not affected by the cell differentiation induced by 13-cis-RA treatment in our case. Thus, F-FDG PET was useful for determining the treatment response and outcomes.We have reported a case of residual neuroblastoma treated with differentiation-inducing 13-cis-RA therapy. Different results were produced with F-FDG-PET and I-MIBG scintigraphy. The cessation of 13-cis-RA treatment was based on F-FDG-PET findings and there has been no relapse for 3 years. PMID- 26252304 TI - Prognostic Effect of Pretreatment Serum Carcinoembryonic Antigen Level: A Useful Tool for Prediction of Distant Metastasis in Locally Advanced Rectal Cancer Following Neoadjuvant Chemoradiotherapy and Total Mesorectal Excision. AB - Many studies have reported the prognostic value of pretreatment serum carcinoembryonic antigen (pre-CEA) levels on colorectal cancer outcomes. However, controversy remains concerning the significance of pre-CEA levels in patients with rectal cancer treated with neoadjuvant chemoradiotherapy (CRT). Our aim in this study was to investigate the prognostic role of the pre-CEA level in patients with locally advanced rectal cancer undergoing neoadjuvant CRT followed by total mesorectal excision (TME).A total of 419 patients with stages II and III rectal cancer treated with neoadjuvant CRT followed by TME with available pre-CEA data were included. The outcomes studied were 5-year local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and disease-free survival (DFS). Optimal pre-CEA cutoff values to predict DMFS were determined based on current smoking history.The median pre-CEA level of smokers was 3.8 ng/mL, and that of nonsmokers was 2.8 ng/mL (P < 0.01). Pre-CEA levels of 6.6 ng/mL for nonsmokers and 11.4 ng/mL for smokers were determined to best separate patients on the basis of time to distant metastasis by using log-rank statistics. The pre-CEA level was associated with DMFS (hazard ratio = 1.743, 95% confidence interval = 1.129-2.690, P = 0.01). The pre-CEA level was not associated with LRFS or DFS.The pre-CEA level appears to be a significant preoperative prognostic factor. Moreover, it is as valuable as any known pathologic factor. Future studies evaluating oncologic outcomes should take into consideration the pre-CEA level. PMID- 26252305 TI - Heparin Saline Versus Normal Saline for Flushing and Locking Peripheral Venous Catheters in Decompensated Liver Cirrhosis Patients: A Randomized Controlled Trial. AB - A prospective randomized, controlled, single-blinded trial to compare the effectiveness and safety of heparin saline (HS) to those of normal saline (NS) as flushing and locking solutions for peripheral venous catheter (PVC) in decompensated liver cirrhosis (DLC) patients.Patients with DLC at our institution between April 2012 and March 2013 were enrolled after obtaining informed consent. The patients were randomly allocated into 2 groups: the NS group received preservative-free 0.9% sodium chloride as the flushing and locking solution, while the HS group received HS (50 U/mL). PVC-related events and the duration of PVC maintenance were compared between the 2 groups. Moreover, the preinfusion and postinfusion levels of prothrombin time (PT), activated partial thromboplastin time (APTT), and platelet (PLT) were also compared.A total of 32 and 36 DLC patients in the NS (125 PVCs) and HS (65 PVCs) groups, respectively, were analyzed. Baseline characteristics, including gender, age, Child-Pugh grade, PVC type and administration of anticoagulant, and irritant agents, were comparable between the 2 groups (P > 0.05). The maintenance times of the HS and NS groups were 80.27 +/- 26.47 and 84.19 +/- 29.32 hours, respectively (P = 0.397). Removal of PVC for abnormal reasons occurred in 30.7% and 22.4% of patients in the HS and NS groups (P = 0.208). The PVC occlusion rates were 6.2% and 5.6% in the HS and NS groups, respectively (OR = 1.11, 95% CI 0.31-3.92). The PT, APTT, and PLT levels were comparable between the 2 groups both before and after infusion (P > 0.05). Incremental analyses showed that Child-Pugh grade C might be a risk factor for the suppression of PLT in the HS group.We consider NS to be as effective as and safer than conventional HS for flushing and locking PVC in decompensated liver cirrhosis patients. PMID- 26252306 TI - A Meta-Analysis of Randomized Controlled Trials on Antiplatelet Agents Versus Placebo/Control for Treating Peripheral Artery Disease. AB - Effect of aspirin (antiplatelet agents) in patients with peripheral artery disease (PAD) was still controversial. Varying studies reported varying results. Therefore, we did this meta-analysis to investigate if aspirin could reduce cardiovascular events in patients with PAD.A comprehensive literature search (PubMed, CCTR, Embase, Web of Science, CNKI, CBM-disc, and relevant websites) was conducted from 1990 to September 2014. The key search terms ("aspirin," "PAD," "peripheral arterial occlusive diseases," and "claudication") produced 9 high quality randomized controlled trials (RCTs) of aspirin versus placebo/control. Mantel-Haenszel random-effects model was used to analysis of the 9 RCTs. The primary outcome was the cardiovascular events.Nine RCTs, composed of 9526 patients (4786 aspirin-treated and 4740 placebo or control-treated patients), were meta-analyzed. The results indicated that compared to placebo/control, aspirin could not significantly reduce the cardiovascular events (OR = 0.81, 95% CI = 0.56-1.15). Moreover, aspirin could not produce better effect on prevention of nonfatal myocardial infarction (OR = 0.98, 95% CI = 0.52-1.84), nonfatal stroke (OR = 0.89, 95% CI = 0.69-1.14), cardiovascular death (OR = 0.97, 95% CI = 0.68-1.38), any death (OR = 1.05, 95% CI = 0.85-1.30), and major bleeding (OR = 1.16, 95% CI = 0.82-1.65) than placebo/control. But aspirin, as monotherapy therapy, did significantly reduce the risk of nonfatal stroke (OR = 0.42, 95% CI = 0.21-0.84).Aspirin, as monotherapy or combination therapy, did not result in a significant decrease in the cardiovascular events. But aspirin, as monotherapy therapy, did significantly reduce the risk of nonfatal stroke. Our conclusion might help clinicians in clinical treating PAD. Future studies are needed to draw firm conclusions about the clinical benefit and risks of aspirin and other antiplatelet agents. PMID- 26252307 TI - The Evolution of and Risk Factors for Neck Muscle Atrophy and Weakness in Nasopharyngeal Carcinoma Treated With Intensity-Modulated Radiotherapy: A Retrospective Study in an Endemic Area. AB - The aim of this study was to investigate the evolution of sternocleidomastoid muscle (SCM) atrophy in nasopharyngeal carcinoma (NPC) patients following intensity-modulated radiotherapy (IMRT), and the relationship between SCM atrophy and neck weakness.Data were retrospectively analyzed from 223 biopsy-proven NPC patients with no distant metastasis who underwent IMRT with or without chemotherapy. The volume of SCM was measured on pretreatment magnetic resonance imaging (MRI), and MRIs were conducted 1, 2, and 3 years after the completion of IMRT. Change in SCM volume was calculated and classified using the late effects of normal tissues-subjective, objective, management, and analytic system. The grade of neck muscle weakness, classified by the Common Terminology Criteria for Adverse Events V 3.0, was measured 3 years after the completion of IMRT.The average SCM atrophy ratio was -10.97%, -18.65%, and -22.25% at 1, 2, and 3 years postirradiation, respectively. Multivariate analysis indicated N stage and the length of time after IMRT were independent prognostic variables. There were significant associations between the degree of SCM atrophy and neck weakness.Radical IMRT can cause significant SCM atrophy in NPC patients. A more advanced N stage was associated with more severe SCM atrophy, but no difference was observed between N2 and N3. SCM atrophy progresses over time during the 3 years following IMRT. Grade of SCM atrophy is significantly associated with neck weakness. PMID- 26252308 TI - Impact of Comorbidity and Age on Determinants Therapeutic Strategies in Advanced Pancreatic Head Cancer Patients With Obstructive Jaundices. AB - The current retrospective study aimed to investigate the relationship between prognostic factors and overall survival (OS) in patients with advanced pancreatic head cancers who initially presented with obstructive jaundice. Furthermore, the impact of age and comorbidities on therapeutic strategies in such patients was evaluated.A total of 79 advanced pancreatic head cancer patients who were treated at our institution between January 2006 and November 2013 were reviewed. We analyzed OS risk factors including sex, age, laboratory characteristics, Eastern Cooperative Oncology Group performance status, Charlson Comorbidity Index Scores (CCIS), and therapeutic strategies using Cox proportional hazards regression models.There was no difference in the OS of patients according to the type biliary drainage procedure they underwent. Other related factors, such as better performance status, lower CCIS, and receiving chemotherapy significantly correlated with survival in multivariate analyses. There was a significant survival benefit in systemic chemotherapy compared to best supportive care (BSC) or local radiotherapy. However, no survival benefit was found in elderly patients (age >70 years) undergoing systemic therapy compared to younger patients, except in those elderly patients with CCIS <= 1.In advanced pancreatic head cancer patients with obstructive jaundice, systemic therapy and adequate biliary drainage were still the most effective procedures for improving OS in the general population. However, in elderly patients with relatively higher CCIS, BSC with adequate biliary drainage was palliative and no less effective than systemic/local therapies. PMID- 26252309 TI - Use of a Novel Integrase-Deficient Lentivirus for Targeted Anti-Cancer Therapy With Survivin Promoter-Driven Diphtheria Toxin A. AB - As an immunotoxin, diphtheria toxin has been widely used in gene therapy and gene function assays for its roles in protein synthesis inhibition, and the aim of our study is to set up a nonintegrating lentiviral system for specific expression of diphtheria toxin A (DTA) used in cancer gene therapy.Here, we established a lentiviral system that could coordinately express fluorescent protein and DTA driven by the cytomegalovirus (CMV) promoter, which is convenient for us to precisely trace the expression of DTA and monitor the process of lentivirus packaging. To achieve safer cancer therapy, we replaced the CMV promoter with the Survivin promoter, a specific promoter that is dramatically activated in cancer tissues and cells, but not in normal tissues and cells, and that will impose greater therapeutic potential because a significant expression difference occurred between these 2 groups. Meanwhile, we obtained integrase-deficient lentivirus (IDLV) after packaging with the integrase mutant, which expresses defective integrase RRK262263264AAH, to minimize the side effects that derived from the insertional mutagenesis of the host genome.Our results suggest that the IDLV system that we generated possesses therapeutic potential in cancers in vitro and in vivo. PMID- 26252310 TI - Association Between Expression of Cancer Stem Cell Markers and Poor Differentiation of Hepatocellular Carcinoma: A Meta-Analysis (PRISMA). AB - The role of cancer stem cell (CSC) markers in differentiation of hepatocellular carcinoma (HCC) remains uncertain. We conducted a meta-analysis to first investigate the association between expression of CSC markers (CD133, CD90, CD44, and EpCAM) and poor differentiation of HCC, and second, to determine if these CSC markers can be classified as biomarkers for patient classification and HCC differentiated therapy.The relevant literature was searched using PubMed, EMBASE, Elsevier, and Chinese Biological Medicine databases for association between CSC markers and HCC from January 1, 2000 to June 30, 2014. Data were synthesized using random-effect or fixed-effect models. The effect sizes were estimated by measuring odds ratios (OR) with 95% confidence interval (CI).The meta-analysis included 27 studies consisting of 2897 patients with HCC. The positive expression of CSC markers was associated with poor differentiation (OR = 2.37, 95% CI = 2.03 2.77, P < 0.00001). Similarly, the positive expression of CSC markers was only associated with HCC tissues compared with noncancerous liver tissues (OR = 9.26, 95% CI = 3.10-27.65, P < 0.0001). CD90 has a specificity of 91.9% for HCC and a sensitivity of 48.22% in predicting poor differentiation.The positive expression of CSC markers is associated with poor differentiation and aggressive phenotype of patients with HCC. The CD90 marker might be a promising target for patient with HCC classification and differentiation therapy. PMID- 26252311 TI - A Clinical Trial of Optimal Time Interval Between Ablation and Diagnostic Activity When a Pretherapy RAI Scanning Is Performed on Patients With Differentiated Thyroid Carcinoma. AB - This article investigates the association of the time interval between the diagnostic dose and ablation with the stunning effect, when a 74 MBq I pretherapy scanning was performed on patients with differentiated thyroid carcinoma (DTC); the patients who were diagnosed as DTC and would be performed radioiodine (RAI) ablation of thyroid remnants or metastases were recruited during January 2011 and May 2012 in our hospital.Thirty-seven patients with DTC who had the RAI ablation of thyroid remnants or metastases for the first time were recruited. All the patients received a dose of 1850 to 7400 MBq of I for ablation and a diagnostic scan was performed 24 hours after the administration of 74 MBq I before ablation. A posttherapy scan was performed 2 to 7 days after the ablation. The patients were broken down into 3 groups (G1, G2, and G3) according to the interval time between the diagnostic dose and therapy (1-3, 4-7, and >7 days). The fractional concentrations of I in remnants or functional metastases were quantified and expressed as therapeutic/diagnostic (Rx/Dx). The level of significance was set at 0.05.Sixty-seven foci were found both on pretherapy and posttherapy scans, the mean ratio of Rx/Dx was 0.43 +/- 0.29, and the ratio of 49 foci (73.13%) was <0.6. The ratios in G1, G2, and G3 were 0.46 +/- 0.29, 0.29 +/- 0.18, and 0.55 +/ 0.33, respectively. The differences between G1 and G2, and G2 and G3 were statistically significant (t = 2.40, P = 0.021 and t = 3.28, P = 0.002), whereas the difference between G1 and G3 was not significant (t = 1.01, P = 0.319).By a diagnostic scan of 74 MBq I, stunning prominently occurs with a time of 4 to 7 days between the diagnostic dose and ablation. We recommend that for less stunning effect, RAI ablation should be performed within 3 days or postponed until 1 week after the diagnostic dose administrated. PMID- 26252312 TI - Clinicopathological Characteristics and Survival Outcomes of Invasive Cribriform Carcinoma of Breast: A SEER Population-Based Study. AB - Invasive cribriform carcinoma (ICC) is a rare histologic subtype of breast cancer. We aimed to investigate the clinicopathological characteristics and survival outcomes of ICC.Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 233,337 female patients diagnosed with ICC (n = 618) or infiltrating ductal carcinoma (IDC) (n = 232,719). Univariate and multivariate survival analyses were utilized to calculate and compare disease specific survival (DSS) and overall survival (OS). A 1:1 paired match was carried out on age, tumor stage, tumor grade, estrogen receptor (ER) status, and progesterone receptor (PR) status. Baseline characteristics and survival outcomes were also analyzed in ER-positive tumors. Subgroup analyses summarized the hazard ratio (HR) of IDC versus ICC using a forest plot.ICCs presented smaller size, lower grade, higher ER and PR positive rate, less nodal metastasis, and were less likely to be treated with mastectomy compared to IDCs. Five-year DSS rates were significantly better for patients with ICC than for patients with IDC (98.8% vs. 93%, P < 0.001). Five-year OS rates were 95.3% versus 90.1% (P < 0.001). After adjustment for common clinicopathological factors in the multivariate analysis, patients with ICC showed limited DSS advantage over the IDC group (HR = 0.75, 95% CI: 0.38-1.51, P = 0.421). No significant difference in DSS nor OS was observed in matched groups between ICC and IDC. Analysis among ER-positive patients revealed similar prognostic factors as among all patients. Survival analysis in different tumor grade subgroups showed no significant difference between ICC and IDC.ICCs have unique clinicopathological characteristics, higher rates of breast conserving surgery, and more favorable prognosis compared to the overall IDC population. Difference in tumor grade between the 2 groups may partially explain the different outcome. Improved clinical and biological understanding of ICC might lead to more individualized and tailored therapy for breast cancer patients. PMID- 26252313 TI - Oral Motor Intervention Improved the Oral Feeding in Preterm Infants: Evidence Based on a Meta-Analysis With Trial Sequential Analysis. AB - Oral feeding for preterm infants has been a thorny problem worldwide. To improve the efficacy of oral feeding in preterm infants, oral motor intervention (OMI), which consists of nonnutritive sucking, oral stimulation, and oral support, was developed. Published studies demonstrated that OMI may be as an alternative treatment to solve this problem; however, these results remain controversial. We conducted a meta-analysis with trial sequential analysis (TSA) to objectively evaluate the potential of OMI for improving the current status of oral feeding in preterm infants.A search of PubMed, EMBASE, Web of Science, the Cochrane Library, and China National Knowledge Infrastructure was performed to capture relevant citations until at the end of October, 2014. Lists of references of eligible studies and reviews were also hand-checked to include any latent studies. Two independent investigators screened literature, extracted data, and assessed the methodology, and then a meta-analysis and TSA was performed by using Reviewer Manager (RevMan) 5.3 and TSA 0.9 beta, respectively.A total of 11 randomized controlled trials (RCTs), which included 855 participants, were incorporated into our meta-analysis. The meta-analyses suggested that OMI is associated with the reduced transition time (ie, the time needed from tube feeding to totally oral feeding) (mean difference [MD], -4.03; 95% confidence interval [CI], -5.22 to 2.84), shorten hospital stays (MD, -3.64; 95% CI, -5.57 to -1.71), increased feeding efficiency (MD, 0.08; 95% CI, 0.36-1.27), and intake of milk (MD, 0.14; 95% CI, 0.06-0.21) rather than weight gain. Results of TSA for each outcomes of interest confirmed these pooled results.With present evidences, OMI can be as an alternative to improve the condition of transition time, length of hospital stays, feeding efficiency, and intake of milk in preterm infants. However, the pooled results may be impaired due to low quality included, and thus, well designed and large RCTs were needed to further established effects. PMID- 26252314 TI - Role of Enteral Immunonutrition in Patients Undergoing Surgery for Gastric Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Gastric cancer (GC) is one of the most common upper gastrointestinal malignancies. Surgical resection remains the mainstay of curative treatment for GC. Enteral immunonutrition (EIN) has been increasingly used to enhance host immunity and relieve inflammatory response of patients undergoing surgery for GC; however, conclusions across studies still remain unclear. We aimed to evaluate the effects of EIN for such patients.We searched some electronic databases including PubMed, EBSCO-Medline, Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE to identify any latent studies which investigated the effects of EIN compared with standard EN on GC patients who undergoing surgery until the end of December 30, 2014. Relative risk (RR), mean difference (MD), or standard mean difference (SMD) with 95% confidence interval (CI) were calculated and we also assessed heterogeneity by using Cochrane Q and I statistic combined with corresponding P-value.We included 9 eligible studies which included 785 patients eventually. The meta-analysis results shown that EIN increased level of IgA (MD, 0.31; 95% CI, 0.12-0.51), IgG (MD, 1.5; 95% CI, 0.73-2.28), IgM (MD, 0.22; 95% CI, 0.06-0.39), CD4 (SMD, 0.81; 95% CI, 0.53-1.09), CD3 (SMD, 0.68; 95% CI, 0.21-1.15), CD4/CD8 ratio (MD, 0.56; 95% CI, 0.12-1.01), and NK cell (MD, 2.35; 95% CI, 0.66-4.05); decreased IL-6 (MD, -98.22; 95% CI, -156.16 to -40.28) and TNF-alpha (MD, -118.29; 95% CI, -162.00 to -74.58), but not improve remained outcomes of interest involving postoperative complications, length of hospitalization, serum total protein, and CD8. Descriptive analysis suggested that EIN also increased the concentration of IL-2 but not CRP. Impact on lymphocytes remains inconsistent.EIN is effective for enhancing host immunity and relieving the inflammatory response in GC patients undergoing gastrectomy, but clinical outcomes cannot be benefit from it. Heterogeneity caused by different compositions and timing of administration of EIN regimes and not enough sample size and number of eligible studies in most of sensitive analyses with subgroup analysis may impaired the power of our study, and thus some large-scale and well designed studies are warranted to further establish effects. PMID- 26252316 TI - A Double Blind Randomized Clinical Trial of Remote Ischemic Conditioning in Live Donor Renal Transplantation. AB - Ischemic conditioning involves the delivery of short cycles of reversible ischemic injury in order to induce protection against subsequent more prolonged ischemia. This randomized controlled trial was designed to determine the safety and efficacy of remote ischemic conditioning (RC) in live donor kidney transplantation.This prospective randomized clinical trial, 80 patients undergoing live donor kidney transplantation were randomly assigned in a 1:1 ratio to either RC or to a control group. RC consisted of cycles of lower limb ischemia induced by an arterial tourniquet cuff placed around the patient's thigh. In the RC treatment group, the cuff was inflated to 200 mm Hg or systolic pressure +25 mm Hg for 4 cycles of 5 min ischemia followed by 5 min reperfusion. In the control group, the blood pressure cuff was inflated to 25 mm Hg. Patients and medical staff were blinded to treatment allocation. The primary end-point was renal function measured by estimated glomerular filtration rate (eGFR) at 1 and 3 months posttransplant.Donor and recipient demographics were similar in both groups (P < 0.05). There were no significant differences in eGFR at 1 month (control 52 +/- 14 vs RC 54 +/- 17 mL/min; P = 0.686) or 3 months (control 50 +/- 14 vs RC 49 +/- 18 mL/min; P = 0.678) between the control and RC treatment groups. The RC technique did not cause any serious adverse effects.RC, using the protocol described here, did not improve renal function after live donor kidney transplantation. PMID- 26252315 TI - The Origin of Variation in Primary Care Process and Outcome Indicators: Patients, Professionals, Centers, and Health Districts. AB - Healthcare providers are often evaluated by studying variability in their indicators. However, the usefulness of this analysis may be limited if we do not distinguish the variability attributable to health professionals and organizations from that associated with their patients.Our objectives are to describe the main process and outcome indicators of primary healthcare services, analyzing the contribution to variability in these indicators from different levels: individual, health professional, health center, and health district.This is a cross-sectional study that includes all.All the individuals covered by the public Basque Health Service (children [age 0-13], n = 247,493; adults [>=14 years old], n = 1,959,682) over a 12-month period.We calculated the number of visits to primary care doctors, number of referrals, prescription costs, and potentially avoidable hospitalizations for ambulatory care sensitive conditions (ACSCs). Using multilevel analysis, we determined the percentage of variance attributable to each level.After adjusting for the characteristics of patients (demographic, socioeconomic, and morbidity), doctors (panel size), health center (size, staff satisfaction, demographic structure of the community), and health district, the variance in the indicators was mainly attributable to differences between patients, independently of the attending health professional, the center, or the healthcare organization, both in children (94.21% for visits to the doctor; 96.66% for referrals; 98.57% for prescription costs; 90.02% for potentially avoidable hospitalizations for ACSCs) and in adults (88.10%; 96.26%; 97.92%; and 93.77%, respectively).The limited contribution of health professionals and organizations to variability in indicators should be taken into account when performing evaluations and planning quality improvement strategies. PMID- 26252317 TI - Prevalence of Depression in Patients With Hypertension: A Systematic Review and Meta-Analysis. AB - Prevalence estimates of depression in hypertensive patients varied widely in existing studies. We conducted a systematic review and meta-analysis of observational studies to summarize the point prevalence of depressive symptoms in adults with hypertension.Comprehensive electronic searches of PubMed, Web of Knowledge, China National Knowledge Internet (CNKI), Wangfang, and Weipu databases were conducted to identify any study in each database published from initial state to November 31, 2014, reporting the prevalence of depression in hypertensive patients. Random-effects model was used to estimate the prevalence of depressive symptoms. We also limited the analyses to studies using clinical interview and prespecified criteria for diagnosis. All statistical calculations were made by using the Stata Version 12.0 (College Station, TX) and Statsdirect Version 2.7.9.We identified 41 studies with a total population of 30,796 in the present meta-analysis. The summarized prevalence of depression among hypertensive patients is 26.8% (95% confidence interval (CI): 21.7%-32.3%). Subgroup analysis shows the following results: for male 24.6%, 95% CI: 14.8%-35.9%, for female 24.4%, 95% CI: 14.6%-35.8%. For China: 28.5% (95% CI: 22.2%-35.3%); for other region (22.1%, 95% CI: 12.1%-34.1%); for community: 26.3% (95% CI: 17.7%-36.0%), for hospital: 27.2% (95% CI: 20.6%-34.5%). Estimated prevalence by interview was 21.3% (95% CI: 14.2%-30.0%); prevalence of depressive symptoms adjudicated by self-rating scales was 29.8% (95% CI: 23.3%-36.7%).The observed heterogeneity in depression prevalence of hypertension may be attributed to differences in method of evaluation. Self-report scales should be cautious of estimating the presence of depression. Thus, interview-defined depression affects approximately one third of hypertensive patients. Effective interventions for depression on patient centered are needed. PMID- 26252318 TI - Compression Therapy in the Prevention of Postthrombotic Syndrome: A Systematic Review and Meta-Analysis. AB - Although compression therapy has been widely used after deep vein thrombosis (DVT), its efficacy in prevention of postthrombotic syndrome (PTS) remains disputable. We aimed to update the meta-analysis to comprehensively evaluate the effect of compression therapy on the prevention of PTS in adult patients after DVT.PubMed, Embase, and Cochrane library databases were systematically searched. Randomized controlled trials (RCTs) evaluating the preventive effect of compression therapy on PTS in adult patients after DVT were included. The primary outcome was the incidence of PTS. All meta-analyses were performed using random effects models regardless of the heterogeneity. Subgroup and sensitivity analysis were also performed to examine the robustness of the pooled effects according to our predesigned plan. Potential publication bias was assessed.Eight RCTs with 1598 patients were included. Overall, compression therapy could significantly reduce the incidence of PTS (estimate 0.68, 95% confidence interval [CI] 0.52 0.90; P = 0.007). However, it was only associated with a reduction in the incidence of mild/moderate PTS (relative risk [RR] 0.66, 95% CI 0.46-0.93; P = 0.019) but not in the incidence of severe PTS (RR 0.64, 95% CI 0.27-1.50; P = 0.31). Additionally, compression therapy failed to reduce the incidence of recurrent venous thromboembolism (RR 0.91, 95% CI 0.65-1.27; P = 0.58), the incidence of ulceration (RR 0.74, 95% CI 0.36-1.53; P = 0.42), or mortality (RR 0.99, 95% CI 0.72-1.37; P = 0.96). No publication bias was observed.Current evidence still supports compression therapy to be a clinical practice for prophylaxis of PTS in adult patients after DVT. However, our findings should be cautiously interpreted because of heterogeneity and hence more large-scale and well-designed RCTs are still warranted. PMID- 26252319 TI - Glutamine Supplementation in Intensive Care Patients: A Meta-Analysis of Randomized Clinical Trials. AB - The role of glutamine (GLN) supplementation in critically ill patients is controversial. Our aim was to analyze its potential effect in patients admitted to intensive care unit (ICU).We performed a systematic literature review through Medline, Embase, Pubmed, Scopus, Ovid, ISI Web of Science, and the Cochrane Controlled Trials Register searching for randomized clinical trials (RCTs) published from 1983 to 2014 and comparing GLN supplementation to no supplementation in patients admitted to ICU. A random-effect meta-analysis for each outcome (hospital and ICU mortality and rate of infections) of interest was carried out. The effect size was estimated by the risk ratio (RR).Thirty RCTs were analyzed with a total of 3696 patients, 1825 (49.4%) receiving GLN and 1859 (50.6%) no GLN (control groups). Hospital mortality rate was 27.6% in the GLN patients and 28.6% in controls with an RR of 0.93 (95% CI = 0.81-1.07; P = 0.325, I = 10.7%). ICU mortality was 18.0 % in the patients receiving GLN and 17.6% in controls with an RR of 1.01 (95% CI = 0.86-1.19; P = 0.932, I = 0%). The incidence of infections was 39.7% in GLN group versus 41.7% in controls. The effect of GLN was not significant (RR = 0.88; 95% CI = 0.76-1.03; P = 0.108, I = 56.1%).These results do not allow to recommend GLN supplementation in a generic population of critically ills. Further RCTs are needed to explore the effect of GLN in more specific cohort of patients. PMID- 26252321 TI - Design of biomaterials for intracellular delivery of carbon monoxide. AB - Carbon monoxide (CO) is recognized as one of the most important gas signaling molecules involved in governing various therapeutic responses. Intracellular generation of CO is spatiotemporally controlled by catalytic reactions of heme oxygenases (HOs). Thus, the ability to control intracellular CO delivery with modulation of the CO-release rate in specific amounts and locations is expected to improve our fundamental understanding of the functions of CO and the development of clinical applications. For this purpose, CO-releasing molecules (CORMs) have been developed and investigated in vitro and in vivo. Most CORMs are based on transition metal carbonyl complexes. Recently, various biomaterials consisting of metal carbonyls with biomacromolecular scaffolds have been reported to improve the properties of bare metal carbonyls. In this mini-review, current progress in CO delivery, recent strategies for the development of CORMs, and future directions in this field are discussed. PMID- 26252320 TI - Role of Micro RNAs in the Pathogenesis of Rheumatoid Arthritis: Novel Perspectives Based on Review of the Literature. AB - The contributions of micro RNAs (miRNAs) to rheumatoid arthritis (RA) are beginning to be uncovered during the last decade. Many studies in efforts to use miRNAs as biomarkers in disease diagnosis, prognosis, and treatment are ongoing.We conducted a systematic literature review to reveal the role of miRNAs in the pathogenesis of RA in order to inform future research.We analyzed all the literature which is searched by keywords "microRNA" and "arthritis" in PubMed from December 2007 to June 2015, and the references cited by the articles searched were also considered.Relevant literature focusing on the field of miRNAs and RA was identified. The searching process was conducted by 5 independent investigators. The experts in the field of miRNAs and Rheumatology were involved in the process of analyzing.Relevant literature was analyzed according to the objective of this review and the availability of full text.The crucial role of miRNAs in maintaining immune and inflammatory responses is revealed. In addition, it is now clear that miRNAs are implicated in the development of RA synovial phenotype including synovial hyperplasia and joint destruction. Intriguingly, the biomedical application of several miRNAs may result in the effects of "double edged sword." Moreover, there appears to have a feedback loop for expression of some miRNAs related to disease activity in inflammatory milieu of rheumatoid joint.This review underscores the potential importance of miRNAs to diagnosis, prognosis, and treatment of RA. Further investigations are required to identify the unique miRNAs signatures in RA and characterize the mechanisms mediated by miRNAs in the pathology of RA. PMID- 26252322 TI - Imaging of Scrub Typhus by PET/CT. AB - A 19-year-old man had an unexplained fever, dizziness, headache, fatigue, and pain in the scrotum. An FDG PET/CT imaging was acquired to assess fever of unknown origin. The images showed multiple foci of increased FDG activity in the enlarged lymph nodes in the body. In addition, mildly increased activity in the enlarged spleen and lung bases was also noted. The patient was eventually diagnosed with scrub typhus based on positive results of the Weil-Felix agglutination test, eschar in the scrotum, and effective therapy. PMID- 26252323 TI - Role of FDG-PET/CT in Extramedullary Multiple Myeloma: Correlation of FDG-PET/CT Findings With Clinical Outcome. AB - PURPOSE: The aim of this study was to describe FDG-PET/CT findings in extramedullary multiple myeloma (EMM) correlating them with clinical outcome. METHODS: In this institutional review board-approved HIPAA-compliant retrospective study, we reviewed the FDG-PET/CT scans of 35 patients with EMM (16 women, 19 men; mean age, 56 years; median follow-up after the diagnosis of EMM, 14 months) out of 156 patients diagnosed with MM at our institute between 2004 and 2012. The distribution and metabolic activity of EMM on the scans were reviewed. Clinical data were extracted from electronic medical records. Statistical analysis was performed to determine differences in outcome based on time of detection and distribution of EMM. RESULTS: Extramedullary multiple myeloma was present at diagnosis in 12 of 35 patients and during disease progression in 23 of 35 patients. Indications for FDG-PET/CT were initial staging (12/35), restaging for disease progression (18/23), or assessment of response to therapy (5/23). Extramedullary multiple myeloma was FDG-avid (mean SUVmax, 8.4; range, 1.2-31), solitary in 10 patients (29%) and multifocal in 25 patients (71%). Two patterns of distribution were noted: direct extension of osseous plasmacytomas in 18 (51%) of 35 patients and hematogeneous/lymphangiogenic dissemination in 33 (94%) of 35 patients. Mean SUVmax in lesions with direct osseous extension was statistically higher than hematogeneous/lymphangiogenic EMM (Mann-Whitney U test, P = 0.03). The most common sites of hematogeneous/lymphangiogenic spread of EMM were lymph nodes (21/35 [60%]), liver (10/35 [29%]), lung (9/35 [26%]), muscles away from bones (7/35 [20%]), and peritoneum/mesentery (7/35 [20%]). There was no statistically significant difference in distribution of EMM at presentation and during disease progression (chi2 test, P > 0.05); 24 (69%) of 35 patients died (median interval after diagnosis of EMM, 7 months). There was no statistically significant difference in outcome for EMM at presentation and during disease progression (log-rank test, P = 0.068). Involvement of any of the following 3 sites: liver, lung, and muscles away from bones, was associated with statistically significant shorter survival (log-rank test, P = 0.0008). CONCLUSIONS: Extramedullary multiple myeloma is more often seen on FDG-PET/CT in the context of a hematogeneous/lymphangiogenic spread pattern and less commonly as a direct extension of osseous plasmacytomas. Extramedullary multiple myeloma has poor outcome whether detected at presentation or during follow-up. Extramedullary multiple myeloma involving the liver, lung, and muscles was associated with shorter survival in our study. PMID- 26252324 TI - 18F-FDG PET/CT of Primary Cervical Granulocytic Sarcoma. AB - Granulocytic sarcoma is an uncommon solid extramedullary tumor composed of immature leukocytes and commonly associated with acute myelogenous leukemia. Isolated granulocytic sarcoma in the cervix of uterus is exceedingly rare. Hereby we describe a case of FDG PET/CT finding of cervical granulocytic sarcoma without acute myelogenous leukemia in a 51-year-old patient. PMID- 26252325 TI - Metastatic Renal Cell Cancer Treated With Antiangiogenic Therapy Monitoring by 18F-FDG PET/CT. AB - Renal cell carcinoma (RCC) is resistant to chemotherapy and radiotherapy in most cases, and surgery is the preferred option in patients with local tough advanced disease. Even in metastatic RCC, patient survival has been reported to improve after surgery. Considering the importance of angiogenesis in RCC pathogenesis, new inhibitors of vascular endothelial growth factor pathway show promising results. Imaging monitoring with F-FDG PET/CT may allow selecting the appropriateness and right time to implement these drugs, according to disease outcome. PMID- 26252326 TI - 18F-Choline PET/CT and Prostate MRI for Staging Patients With Biochemical Relapse After Irradiation for Prostate Cancer. AB - PURPOSE: The aim of this study was to assess the value of combining MRI and F fluorocholine (FCH) PET/CT for patients with a biochemical relapse (BR) after prostate radiotherapy or brachytherapy. PATIENTS AND METHODS: All patients with a BR (BR definition: nadir prostate-specific antigen, +2 ng/mL) had a multiparametric MRI and FCH PET/CT if there was no clinical sign of relapse. Identification of the relapse was considered positive if both imaging techniques were concordant or in case of pathological relapse confirmation. RESULTS: Sixty five consecutive patients were analyzed. Initial treatment was external beam radiation therapy (EBRT; n = 40), surgery followed by EBRT (n = 11), or brachytherapy (n = 14). Gleason score was 6 in 23 patients, 7 in 35 patients, and 8 to 10 in 7 patients. Median prostate-specific antigen value at the time of relapse was 7.6 ng/mL. Determination of relapse location was identified in 46 patients (70.7%). Relapses were only local in 24 patients (37%), nodal in 16 (24.6%), and distant in 9 (14%). In 4 cases, MRI showed a local relapse not seen by FCH PET/CT. Among the 24 patients with an isolated local relapse, 13 underwent a confirmatory biopsy and 9 were positive. At the end, only 7 patients (11%) could have a salvage local treatment: cryotherapy of the prostate in 6 cases and 1 nodal EBRT. CONCLUSIONS: In case of BR after radiotherapy or brachytherapy, combining MRI and FCH PET/CT could identify the site of relapse in 70% of patients. This could facilitate the selection of the patients for local salvage treatment. PMID- 26252327 TI - 18F-FDG PET/CT of Bronchial Mucous Gland Adenoma. AB - Bronchial mucous gland adenoma is a very rare benign tumor that arises from the bronchial mucous-secreting glands. Its detection and appearance using F-FDG PET/CT has not been well characterized. We present a case of a 59-year-old man with FDG-avid mucous gland adenoma that mimicked lung cancer on F-FDG PET/CT. PMID- 26252328 TI - Diffuse 18F-FDG Muscle Uptake in Trichinella spiralis Infection. AB - Two patients were referred to our emergency department with myalgia, fever, general malaise, eosinophilia, and elevated serum levels of creatine kinase and troponin T. 18F-FDG PET/CT scan was performed showing a diffuse and homogenous moderately elevated glucose uptake in all muscle groups. Trichinella spiralis infection was confirmed by a muscle biopsy and detection of trichinella antibodies. The muscle biopsy was taken in the left quadriceps because of equal involvement of the skeletal muscles. The differential diagnosis of diffuse 18F FDG muscle uptake should include trichinella infection, in particular, in the presence of infectious symptoms, eosinophilia, and biochemical signs of muscle damage. PMID- 26252329 TI - Unusual Bone Superscan, MIBG Superscan, and 68Ga DOTATATE PET/CT in Metastatic Pheochromocytoma. AB - A 17-year-old adolescent boy with biochemically raised 2-hour urinary metanephrine and normetanephrine as well as CT findings of retroperitoneal soft tissue mass and bony metastases was referred for further assessment. Apart from Ga DOTATATE PET/CT evaluation, pretargeted systemic radionuclide therapy assessment with I-MIBG scintigraphy showed unusual phenomenon of MIBG superscan. Postsurgically, restaging Tc-MDP bone scintigraphy showed typical bone superscan features. The MIBG superscan was better delineated on post-I-MIBG therapy images. PMID- 26252330 TI - FDG PET/CT Manifestation of Rare Widespread Metastatic Chemoradiation-Refractory Thymic Squamous Cell Carcinoma. AB - A 74-year-old man underwent excisional biopsy of an anterior mediastinal mass that revealed squamous cell carcinoma of thymic origin. Immunohistochemistry revealed insulin-like growth factor-1 receptor positivity, which has been associated with worse prognosis. Restaging FDG PET/CT revealed extensive soft tissue and osseous metastases despite surgery and chemoradiation therapy. Patient was then enrolled in a clinical trial with anti-insulin-like growth factor-1 receptor therapy. A 3-month follow-up FDG PET/CT showed disease progression with an increase in size and number of hypermetabolic metastatic lesions, including interval development of multiple new metastases. PMID- 26252331 TI - Lymphatic Path of the Inguinal Lymph Node Metastases in Anorectal Cancer: The Springbok Pattern. AB - Sentinel lymph node biopsy has been established as a feasible and effective method for defining the inguinal node status in patients with anal adenocarcinoma exceeding the dentate line. We present the axial lymphoscintigraphic image that depicts thoroughly the injection site around the anus, the lymphatic path, and the inguinal sentinel lymph nodes, bilaterally. The distinct springbok pattern was named after the unique horn shape of the African gazelle. This image puts on the map the anoinguinal lymphatic path and highlights the need for complete inguinal lymph node and related lymphatic path dissection in metastatic anal cancer. PMID- 26252333 TI - Crossed Fused Renal Ectopia: Presentations on 99mTc-MAG3 Scan, 99mTc-DMSA SPECT, and Multidetector CT. AB - Crossed renal ectopia is an uncommon developmental anomaly in which both kidneys are located on the same side of the body. The present case describes a 20-year old man who underwent the military entrance physical examination. The ultrasound showed the right kidney in normal site with slightly increased size, but the left kidney was not identified. Tc-MAG3 scan showed a single kidney with 2 ureters, and the orifices of the ureters were connected at both sides of bladder. Tc-DMSA SPECT and contrast-enhanced multidetector CT were performed and revealed crossed fused renal ectopia. PMID- 26252332 TI - Three-Phase 99mTc-MDP Bone Scintigraphy and SPECT/CT in Pediatric Pseudodystrophy. AB - Pseudodystrophy is a rare condition clinically resembling reflex sympathetic dystrophy. Distinction between both disorders is based on clinical features and bone scintigraphy. We report a case of 12-year-old girl presented with pain, swelling, and functional impairment of left foot after minor trauma. Clinical assessment revealed atrophy of left calf, cyanosis and coldness of left foot. Laboratory investigations were normal. X-ray and MRI of the foot were unremarkable. Bone scintigraphy showed hypoperfusion and diffusely reduced tracer uptake in the left lower leg and left foot. Diagnosis of pseudodystrophy was made on the basis of history, clinical examination, and bone scintigraphy findings. PMID- 26252334 TI - Negative Impact of Indwelling Biliary Stent on Gallbladder Visualization on Cholescintigraphy. AB - PURPOSE: Presence of biliary stent may alter biliary dynamics, which may change the results of cholescintigraphy. We assessed the frequency of gallbladder (GB) nonvisualization and its specificity for acute cholecystitis (AC) in patients with stent. PATIENTS AND METHODS: Of 44 with stent who had cholescintigraphy, 22 were excluded because of prior cholecystectomy or little to no radiotracer excretion from the liver precluding assessment of GB filling. Cholescintigraphy performed on the remaining 22 with stent and their medical records were reviewed. We also assessed the frequency of GB nonvisualization in the comparison group of 1044 without stent who had cholescintigraphy for evaluation of AC. RESULTS: Gallbladder was not visualized in 21 (96%) of 22 with stent, 10 of whom did not have high clinical suspicion of AC. Gallbladder was visualized in only 1 patient on delayed imaging at 4 hours. Four had cholecystectomy, 3 had chronic cholecystitis and 1 AC superimposed on chronic cholecystitis. The highest possible specificity derived from our data assuming an extreme hypothetical scenario was only 25% with the true specificity likely being 7% or lower. In contrast to patients with stents, only 188 (18%) of the 1044 without stent had GB nonvisualization (P < 0.0001). CONCLUSIONS: In patients with stents, cholescintigraphy using morphine augmentation or 4-hour delayed imaging is futile to evaluate for AC because the frequency of GB nonvisualization is high and the specificity of GB visualization is low. It is unknown whether further delayed imaging at 24 hours would improve the study efficacy in this population. PMID- 26252335 TI - False-Positive 131I Uptake in a Benign Bone Lesion on Post-therapy Scan. AB - A 56-year-old woman underwent near-total thyroidectomy and papillary thyroid carcinoma without extrathyroidal extension was diagnosed. The serum thyroglobulin (Tg) level was 2.4 ug/L, and anti-Tg was negative when serum thyroid-stimulating hormone level was 85 uIU/mL. She received 100 mCi (3.7 GBq) of 131I. Besides the residual thyroid tissue, a focal uptake in the left clavicular bone was seen on posttherapy 131I images. Then, CT and MRI were performed to diagnosis. All imaging findings suggested that it was a benign bone cyst. At 6-month follow-up, the serum Tg level was undetectable with the thyroid-stimulating hormone level of more than 150 uIU/mL. PMID- 26252336 TI - Bleeding Small Intestine Pyogenic Granuloma on 18F-FDG PET/CT. AB - A 53-year-old man with metastatic melanoma, in remission, presented with an 8 week history of melena and anemia. Initial investigations including upper and lower gastrointestinal endoscopy, capsule endoscopy, and Tc-labeled red blood cell scan did not reveal a source of bleeding. Given the concern over melanoma recurrence, F-FDG PET/CT was performed that demonstrated a focus of intense uptake in the small bowel. Uncomplicated surgical resection of the segment of jejunum containing the lesion was performed, after which the patient reported no further gastrointestinal bleeding. Histopathological assessment of the lesion was consistent with pyogenic granuloma. PMID- 26252337 TI - Localized Airspace Consolidation of Pulmonary Alveolar Proteinosis Mimicking Malignant Lesions in 18F-FDG PET/CT Imaging: One Case Report. AB - Pulmonary alveolar proteinosis is a rare lung disease caused by diffuse, abnormal intra-alveolar surfactant accumulation. Here, we report a case of autoimmune pulmonary alveolar proteinosis with heterogeneous accumulation of F-FDG in both lungs shown on the combined F-FDG PET/CT. PMID- 26252338 TI - Cholesterol Granuloma: An Unusual and Benign Cause of Focal FDG Uptake in the Breast Detected on PET/CT. AB - Cholesterol granulomas are benign lesions, rarely seen in the breast, which are indistinguishable from malignancy on anatomical imaging. The FDG PET/CT of a patient referred for melanoma staging revealed a mildly FDG-avid, soft tissue nodule in the left breast. This finding was felt unlikely to represent metastatic melanoma due to the relatively low level of uptake. The lesion was not seen on follow-up mammography. Ultrasound-guided biopsy was performed, which identified this lesion as a cholesterol granuloma. This case illustrate that cholesterol granuloma can be misinterpreted as a malignant lesion on both anatomical imaging and FDG PET/CT. PMID- 26252339 TI - Identification and characterization of oxidative metabolites of 1-chloropyrene. AB - Polycyclic aromatic hydrocarbons (PAHs) and chlorinated PAHs (ClPAHs) are ubiquitous contaminants that bind to the aryl hydrocarbon receptor (AhR) and exhibit mutagenic potential. It is difficult to monitor human exposure levels to ClPAHs because the exposure routes are complicated, and environmental concentrations are not always correlated with the levels of PAHs. Urinary PAH metabolites are useful biomarkers for evaluating PAH exposure, and ClPAH metabolites may therefore contribute to the estimation of ClPAH exposure. One of the most abundant ClPAHs present in the environment is 1-chloropyrene (ClPyr), and urinary ClPyr metabolites have the potential to be good biomarkers to evaluate the level of exposure to ClPAHs. Since the metabolic pathways involving ClPAHs are still undetermined, we investigated the effect of human cytochrome P450 enzymes on ClPyr and identified three oxidative metabolites by liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance. We found that ClPyr was metabolized most efficiently by the P450 1A1 enzyme, followed by the 1B1 and 1A2 enzymes. Similar to ClPyr, these metabolites were shown to have agonist activity for the human AhR. We detected these metabolites when ClPyr reacted with a pooled human liver S9 fraction as well as in human urine samples. These results suggest that the metabolites may be used as biomarkers to evaluate the extent of exposure to ClPAHs. PMID- 26252340 TI - Utility of Equations to Estimate Peak Oxygen Uptake and Work Rate From a 6-Minute Walk Test in Patients With COPD in a Clinical Setting. AB - PURPOSE: To determine the utility of equations that use the 6-minute walk test (6MWT) results to estimate peak oxygen uptake ((Equation is included in full-text article.)o2) and peak work rate with chronic obstructive pulmonary disease (COPD) patients in a clinical setting. METHODS: This study included a systematic review to identify published equations estimating peak (Equation is included in full text article.)o2 and peak work rate in watts in COPD patients and a retrospective chart review of data from a hospital-based pulmonary rehabilitation program. The following variables were abstracted from the records of 42 consecutively enrolled COPD patients: measured peak (Equation is included in full-text article.)o2 and peak work rate achieved during a cycle ergometer cardiopulmonary exercise test, 6MWT distance, age, sex, weight, height, forced expiratory volume in 1 second, forced vital capacity, and lung diffusion capacity. Estimated peak (Equation is included in full-text article.)o2 and peak work rate were estimated from 6MWT distance using published equations. The error associated with using estimated peak (Equation is included in full-text article.)o2 or peak work to prescribe aerobic exercise intensities of 60% and 80% was calculated. RESULTS: Eleven equations from 6 studies were identified. Agreement between estimated and measured values was poor to moderate (intraclass correlation coefficients = 0.11 0.63). The error associated with using estimated peak (Equation is included in full-text article.)o2 or peak work rate to prescribe exercise intensities of 60% and 80% of measured values ranged from mean differences of 12 to 35 and 16 to 47 percentage points, respectively. CONCLUSIONS: There is poor to moderate agreement between measured peak (Equation is included in full-text article.)o2 and peak work rate and estimations from equations that use 6MWT distance, and the use of the estimated values for prescription of aerobic exercise intensity would result in large error. Equations estimating peak (Equation is included in full-text article.)o2 and peak work rate are of low utility for prescribing exercise intensity in pulmonary rehabilitation programs. PMID- 26252341 TI - Feasibility of Assessing 2 Cardiac Rehabilitation Quality Indicators. AB - PURPOSE: The Canadian Cardiovascular Society initiated a pan-Canadian process for development of quality indicators (QIs) for cardiac rehabilitation (CR). Before implementation, the QIs underwent pilot testing to ensure they were acceptable and feasible for field implementation. The objectives of this test were to assess (1) the technical feasibility of measuring the QIs; (2) the workload required to measure the QIs; and (3) acceptability of measuring the QIs and issues with their implementation. METHODS: The 2 indicators chosen for field testing were QI-1 (% of eligible inpatients referred) and 2b (median wait time from CR referral receipt to enrollment). The approach consisted of 3 steps: (1) data extraction to test technical feasibility; (2) completing a workload diary; and (3) providing input through a semistructured interview regarding acceptability and implementation issues. Three academic CR sites were selected to undertake the field test. RESULTS: QI-1 ranged from 51.0% to 68.4%, and QI-2b was reported as 27 days (median) by one site, and 22 days (mean) by another. It was not considered feasible for CR programs to assess all potentially CR-eligible inpatients for CR referral exclusions. Compilation required 4.2 hours for QI-1 and 1.8 hours for QI-2b. QI assessment was acceptable to the programs, but changes in practice would be needed at each site to implement the QIs. CONCLUSIONS: CR programs may require enhancement of information-tracking processes to enable QI measurement. It was recommended that the QIs be implemented, but should undergo minor revisions to enhance feasibility. PMID- 26252342 TI - Effects of Combined Resistance and Endurance Training Versus Resistance Training Alone on Strength, Exercise Capacity, and Quality of Life in Patients With COPD. AB - PURPOSE: To compare the effects of 12-week training periods (2 d.wk) involving resistance training only with the effects of 12-week training periods involving combined resistance (once weekly) and endurance (once weekly) training on strength, endurance performance, and quality of life. METHODS: Thirty-six patients with moderate-to-severe chronic obstructive pulmonary disease were randomized to combined training (REG), resistance training alone (RG), or control (CG) groups. Patients were tested for maximal strength of the upper and lower extremities, power output of the lower extremities, maximal (Wmax) and submaximal exercise capacity, performance on a 6-minute walk test (6MWT), and quality of life. RESULTS: REG and RG induced similar maximal strength gains. Muscle power increased 19% (P <= .01) and Wmax improved 13% (P < .05) in REG. Reductions (P < .05) in the heart rate and blood lactate at a given submaximal workload were observed in REG. Improvements in 6MWT and quality of life were similar in both training groups. CONCLUSIONS: Compared with a twice-weekly resistance training program, the combination of once-weekly resistance and once-weekly endurance training not only produced similar gains in maximal strength, 6MWT performance, and quality of life but also produced improvements in muscle power and endurance performance. These findings may have implications for the prescription of resistance and endurance exercise for patients with chronic obstructive pulmonary disease. PMID- 26252343 TI - Field Walking Tests Are Reliable and Responsive to Exercise Training in People With Non-Cystic Fibrosis Bronchiectasis. AB - PURPOSE: The 6-Minute Walk Test (6MWT) and Incremental Shuttle Walk Test (ISWT) are used to assess exercise capacity, but the reliability and responsiveness of these tests in individuals with non-cystic fibrosis (CF) bronchiectasis have not been determined. This study aimed to determine the reliability and responsiveness of both tests in adults with non-CF bronchiectasis. METHODS: Eighty-five participants completed 2 6MWTs and 2 ISWTs in random order. Testing was repeated at the conclusion of an 8-week intervention period of exercise training. Reliability was assessed using intraclass correlation coefficients (ICC) and Bland-Altman analysis. Responsiveness was measured by effect size (ES) and standardized response mean (SRM). RESULTS: At baseline, test-retest reliability was high for both tests (ICC >= 0.95). The mean (95% CI) increase in the 6MWT from test 1 to test 2 was 20 m (13-26 m): 3% (0-5%) change. The mean (95% CI) increase in the ISWT was 15 m (4-25m): 4% (2-6%) change. A significant learning effect persisted after 8 weeks for the 6MWT (P = .04), but not the ISWT (P = .61). The 6MWT ES was 0.32 and SRM was 0.68; for the ISWT, ES was 0.42 with SRM of 0.71. CONCLUSION: The 6MWT and ISWT are reliable measures of exercise capacity in non-CF bronchiectasis and responsive to exercise training. The small learning effect in both measures at baseline suggests that 2 of each test are necessary to correctly assess exercise capacity. Completion of 2 6MWTs at followup may minimize the risk of underestimating a treatment effect. PMID- 26252344 TI - Six-Minute Walk Test Distances in Fast-Track and Traditional Cardiac Rehabilitation: A 3-YEAR DATABASE REVIEW. AB - PURPOSE: Home-based and center-based cardiac rehabilitation (CR) have demonstrated similar levels of risk factor reduction. Cardiac rehabilitation models with fewer exercise sessions may be as effective as traditional models. This study reviewed a community phase II CR database from 2007 to 2010. METHODS: A fast-track CR (FTCR) group was introduced alongside an existing traditional CR (TCR) program. The 2 programs ran concurrently on different days. Both FTCR and TCR treatment groups undertook supervised low to moderate intensity exercise training for 6 weeks and were provided with home exercise advice. Fast-track CR included once-weekly exercise sessions and a 1-time 7-hour education session; TCR included twice-weekly exercise and education sessions. Similar education was provided in both programs. Six-minute walk test distance (6MWD) was assessed pre CR and post-CR for both groups. RESULTS: Six hundred and twenty patients enrolled in CR during the period, and patients elected or were assigned (not randomized) to FTCR (n = 197) or to TCR (n = 423) treatment groups. Complete 6MWD data sets were available for 115 FTCR and 254 TCR subjects. Repeated-measures analysis of variance found 6MWD outcomes to be similar for both groups over both assessments combined and at each assessment point. Improvements in 6MWD post-CR were different for men and women in the CR database (8% vs 5%, respectively, P < .001). CONCLUSIONS: Six-minute walk test distance outcomes were not different for subjects undergoing once-weekly or twice-weekly supervised CR exercise sessions. CR models with fewer supervised exercise sessions may provide similar functional outcomes to traditional CR models. PMID- 26252345 TI - Graded Exercise Testing Versus Simulated Competition Exercise in Trained Older Males. AB - PURPOSE: Exercise-based rehabilitation is a standard therapy for patients with heart disease. Despite examples of patients who have extended normal rehabilitation exercise into competitive participation, there are no clear-cut guidelines for patients whether they should participate in competitive-level exercise. This study investigated the occurrence of complications, physiologic responses, and exercise patterns during simulated competitive exercise in active, older nonathletes (most with a history of cardiovascular disease) and compared these with responses during maximal incremental exercise. METHODS: Fourteen trained older males, 7 with stable cardiovascular disease, performed an incremental exercise test and time trial of 55 kJ (equivalent to running ~1 mile) on a semirecumbent stepping ergometer. Variables of gas exchange, hemodynamics, perception, and power output were measured in both tests. RESULTS: Subjects attained a remarkably high physiologic and psychologic strain (respiratory exchange ratio >1.0; average peak rating of perceived exertion >8) in both tests, with no evidence of symptomatic, hemodynamic, or electrocardiographic abnormalities. Peak physiologic responses were not significantly different between simulated competition and incremental exercise. The fixed-work time trial was finished in 8.97 +/- 1.85 minutes, mean power output of 100 +/- 26 W. Results showed a distinct pacing pattern in the relative power output, consisting of a conservative start, an even-paced middle portion, and an end spurt. CONCLUSIONS: Results suggest that in trained individuals with normal incremental exercise test results, competitive-level efforts may be undertaken with no apparent side effects. This may provide a strategy whereby physicians can advise patients concerning their decision to perform in competitive events. PMID- 26252346 TI - Conjugated linoleic acid: A potent fatty acid linked to animal and human health. AB - Conjugated linoleic acid (CLA) is a mixture of isomers of linoleic acid (C18:2 n 6), which is mostly found in the ruminant meat and dairy products. The CLA is known to have many potential health benefits, and considered a potent powerful fatty acid, which is linked to animal and human health. The present work aims to discuss the source and production, mechanism of action, and effects of CLA on humans, poultry, and ruminants by reviewing the recent studies carried out on CLA. Despite most of the recent studies indicating beneficial effects of CLA on improving body weight control parameters, its effects on reducing risk factors of cardiovascular diseases (CVD), inflammation, blood glucose, and insulin are still controversial, and need to be further studied in different hosts. PMID- 26252347 TI - Performance evaluation of head and neck contour adaptation with cone beam CT using two commercial software systems. PMID- 26252349 TI - Development of a method for functional aspect identification in parotid using dynamic contrast-enhanced magnetic resonance imaging and concurrent stimulation. PMID- 26252350 TI - Raloxifene neutralizes the adverse effects of glutamate on cultured neurons by regulation of calcium oscillations. AB - Calcium dyshomeostasis is an important pathology of memory impairment. However, the mechanism of how calcium dyshomeostasis impairs neurons has remained elusive. The aim of the present study was to reveal the influence of calcium dyshomeostasis on the expression of calcium memory-associated proteins and the ability of raloxifene to neutralize the adverse effects of glutamate on cultured neurons by regulation of calcium oscillations. After neurons were treated with various concentrations of glutamate alone or with raloxifene, the expression of calcium memory-associated proteins and the influence on calcium dyshomeostasis was assessed. The results indicated that glutamate regulated calcium oscillation waves and expression of calcium memory-associated protein in a concentration dependent manner. Raloxifene increased the expression of these proteins as well as neuronal survival. It is therefore concluded that glutamate regulated calcium oscillations in a dose-dependent manner, while raloxifene protected neurons from destruction through glutamate exposure and at the same time neutralized the decrease in expression of the memory-associated proteins. PMID- 26252352 TI - Low expression of ITIH5 in adenocarcinoma of the lung is associated with unfavorable patients' outcome. AB - Inter-alpha-trypsin inhibitor heavy chain 5 (ITIH5) is supposed to be involved in extracellular matrix stability and thus may play a key role in the inhibition of tumor progression. The current study is the first to analyze in depth ITIH5 expression and DNA methylation, as well as its potential clinical impact in non small-cell lung carcinoma (NSCLC). We examined ITIH5 mRNA expression in tumor and adjacent normal lung tissue specimens of NSCLC patients. In addition, methylation frequency of the ITIH5 promoter was investigated using methylation-specific PCR and pyrosequencing. Significance of our data was validated by independent data sets from The Cancer Genome Atlas and the Kaplan-Meier Plotter platform. Furthermore, ITIH5 protein expression was evaluated by immunohistochemistry utilizing a tissue microarray with 385 distinct lung tissue samples. Based on our tissue collections, ITIH5 mRNA expression was significantly decreased in NSCLC compared to normal lung tissue in line with an increased methylation frequency in lung cancer tissue. Independent TCGA data confirmed significant expression loss of ITIH5 in lung cancer concordant with ITIH5 promoter hypermethylation in NSCLC. Of interest, low ITIH5 mRNA expression was particularly found in the magnoid and squamoid ADC expression subtype, concordant with an unfavorable patients' outcome in squamoid as well as tobacco smoking ADC patients. In conclusion, ITIH5 may be a novel putative tumor suppressor gene in NSCLC with a potential molecular significance in the squamoid ADC subtype and further clinical impact for risk stratification of adenocarcinoma patients. In addition, ITIH5 may serve as a novel biomarker for prognosis of tobacco smoking ADC patients. PMID- 26252351 TI - Sphingosine kinase inhibitors decrease viability and induce cell death in natural killer-large granular lymphocyte leukemia. AB - Sphingolipid metabolism has been identified as a potential therapeutic target in cancer. Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid metabolite produced by sphingosine kinases-1 and -2 (SPHK1 and SPHK2). Elevated SPHK1 has been found in numerous cancer types and been shown to contribute to survival, chemotherapeutic resistance and malignancy. However, its role in large granular Natural Killer (NK) large granular lymphocyte (LGL) leukemia has not been investigated. Here, we examine SPHK1 as a therapeutic target in LGL leukemia. We found that SPHK1 is overexpressed in peripheral blood mononuclear cells (PBMCs) from LGL leukemia patients which results in elevated S1P in the sera. The use of SPHK1 inhibitors, SKI-II or SKI-178, decreased leukemic NK cell viability and induced caspase-dependent apoptosis. SKI-II and SKI-178 restored the sphingolipid balance by increasing ceramide and decreasing S1P in leukemic NKL cells. SKI-II and SKI-178 also induced apoptosis in primary NK-LGLs from leukemia patients. Mechanistic studies in NK-LGL cell lines demonstrated that SKI 178 and SKI-II induced cell cycle arrest at G2/M. We found that SKI-178 induced phosphorylation of Bcl-2 at Ser70, and that this was dependent on CDK1. We further show that SPHK1 inhibition with SKI-178 leads to decreased JAK-STAT signaling. Our data demonstrate that SPHK1 represents a novel therapeutic target for the treatment of NK-LGL leukemia. PMID- 26252353 TI - RRM1, TUBB3, TOP2A, CYP19A1, CYP2D6: Difference between mRNA and protein expression in predicting prognosis of breast cancer patients. AB - The study investigated the clinical significance of RRM1 (ribonucleoside reductase subunit M1), TUBB3 (tubulin-beta-III), TOP2A (DNA topoisomerase II), CYP19A1 (cytochrome P450, family 19, subfamily A, polypeptide 1) and CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) for the diagnosis and possible predictive roles in breast cancer. Tissue microarray detected the expression of RRM1, tubulin-beta-III, Topo IIalpha, CYP19A1 and CYP2D6 protein in breast cancer tissue and tissue adjacent to tumors (TATs). In addition, a publically available tool, was used to assess the prognostic value of their gene expression in breast cancer (http://kmplot.com). Analysis for relapse-free survival (RFS), disease-free survival (DFS) and overall survival (OS) was performed. Cytoplasmic RRM1, tubulin-beta-III, CYP19A1 and Topo IIalpha staining were significantly higher in breast cancer tissues compared with TATs (P<0.050). Significant correlation occurred between RRM1 expression with pathological classification (P=0.018), lymph node involvement (P=0.035) and ER status (P=0.003). Tubulin-beta-III and CYP2D6 expression correlated significantly with tumor grade (P=0.021 for tubulin-beta-III and P=0.029 for CYP2D6, respectively). Cox analysis showed that the protein expression of CYP2D6, CYP19A1, RRM1, Topo IIalpha or tubulin-beta-III was not an independent prognostic factor. A significant association occurred between RFS and TUBB3, TOP2A, CYP19A1, and CYP2D6 mRNA expression. With CYP19A1 (P<0.001) and CYP2D6 (P<0.001), a high expression was associated with good clinical outcome. Conversely, a low expression of TUBB3 (P<0.001) and TOP2A (P<0.001) was associated with good clinical outcome. TUBB3 (P=0.0004) and TOP2A (P<0.001) were significant prognostic factors in predicting the patient OS. The expression of RRM1, tubulin beta-III, Topo IIalpha and CYP19A1 in tumor tissues was significantly higher than that in TATs. TUBB3, TOP2A, CYP19A1 and CYP2D6 gene expression, but not protein expression, was associated with patient survival. PMID- 26252354 TI - Prevalence of marijuana and other substance use before and after Washington State's change from legal medical marijuana to legal medical and nonmedical marijuana: Cohort comparisons in a sample of adolescents. AB - BACKGROUND: A growing number of states have new legislation extending prior legalization of medical marijuana by allowing nonmedical marijuana use for adults. The potential influence of this change in legislation on adolescent marijuana and other substance use (e.g., spillover or substitution effects) is uncertain. We capitalize on an ongoing study to explore the prevalence of marijuana and other substance use in 2 cohorts of adolescents who experienced the nonmedical marijuana law change in Washington State at different ages. METHODS: Participants were 8th graders enrolled in targeted Tacoma, Washington public schools and recruited in 2 consecutive annual cohorts. The analysis sample was 238 students who completed a baseline survey in the 8th grade and a follow-up survey after the 9th grade. Between the 2 assessments, the second cohort experienced the Washington State nonmedical marijuana law change, whereas the first cohort did not. Self-report survey data on lifetime and past-month marijuana, cigarette, and alcohol use were collected. RESULTS: Multivariate multilevel modeling showed that cohort differences in the likelihood of marijuana use were significantly different from those for cigarette and alcohol use at follow-up (adjusting for baseline substance initiation). Marijuana use was higher for the second cohort than the first cohort, but this difference was not statistically significant. Rates of cigarette and alcohol use were slightly lower in the second cohort than in the first cohort. CONCLUSIONS: This exploratory study found that marijuana use was more prevalent among teens shortly after the transition from medical marijuana legalization only to medical and nonmedical marijuana legalization, although the difference between cohorts was not statistically significant. The findings also provided some evidence of substitution effects. The analytic technique used here may be useful for examining potential long-term effects of nonmedical marijuana laws on adolescent marijuana use and substitution or spillover effects in future studies. PMID- 26252355 TI - Surgery-Induced Weight Loss Is Associated With the Downregulation of Genes Targeted by MicroRNAs in Adipose Tissue. AB - CONTEXT: Molecular mechanisms associated with physiological variations in adipose tissue (AT) are not fully recognized. The most recent reports highlight the critical relevance of microRNAs (miRNAs) found in AT. OBJECTIVE: To identify changes in messenger RNA (mRNA) and miRNA expressions and their interaction in human AT before and after surgery-induced weight loss. Research Design and Setting: Genome-wide mRNA and miRNA expressions were assessed by microarrays in abdominal subcutaneous AT of 16 morbidly obese women before and 2 years after laparoscopic Roux-en-Y gastric bypass. The association of changes in miRNAs with their respective mRNA targets was studied. The results were replicated in publicly available microarray datasets. Validation was made by real-time polymerase chain reaction in additional fat samples from 26 age-matched lean women and in isolated human adipocytes. RESULTS: A total of 5018 different mRNA probe sets and 15 miRNAs were differentially expressed after surgery-induced weight loss. The clustering of similar expression patterns for gene products with related functions revealed molecular footprints that elucidate significant changes in cell cycle, development, lipid metabolism, and the inflammatory response. The participation of inflammation was demonstrated by results assessed in isolated adipocytes. Interestingly, when transcriptomes were analyzed taking into account the presence of miRNA target sites, miRNA target mRNAs were upregulated in obese AT (P value = 2 * 10(-181)) and inflamed adipocytes (P value = 4 * 10(-61)), according to the number of target sites harbored by each transcript. CONCLUSIONS: Current findings suggest impaired miRNA target gene expression in obese AT in close association with inflammation, both improving after weight loss. PMID- 26252356 TI - A Novel Syndrome of Generalized Lipodystrophy Associated With Pilocytic Astrocytoma. AB - CONTEXT: A rare presentation of hypothalamic tumors in infants and young children is profound emaciation and generalized loss of sc adipose tissue, also known as "diencephalic syndrome." Similar loss of sc fat can be observed in children with acquired generalized lipodystrophy or congenital generalized lipodystrophy. Precise diagnosis may be challenging early in the course of the disease, especially in the absence of metabolic abnormalities. CASE DESCRIPTION: We report three males who presented with poor weight gain and generalized loss of sc fat at birth to 3 years of age consistent with generalized lipodystrophy, with subsequent development of pilocytic astrocytoma. Two of them had hypothalamic tumors, and one had a multicentric tumor with a large right parietal mass. Our patients are unique because the onset of lipodystrophy occurred 2.5 to 7.3 years before the diagnosis of brain tumor, and all of them gained body fat or weight after surgical removal and/or chemotherapy. One patient had hepatosplenomegaly and impaired glucose tolerance, and another patient had severe hyperglycemia and hypertriglyceridemia during the course of the disease. Two patients presented with central precocious puberty and advanced bone age at the chronological age of 6 years. CONCLUSIONS: It is likely that pilocytic astrocytoma may induce generalized lipodystrophy by paraneoplastic antiadipocyte antibody formation or by excessive hormones or cytokine secretion resulting in excess lipolysis from adipocytes. We conclude that young children presenting with idiopathic acquired generalized lipodystrophy or atypical congenital generalized lipodystrophy, with or without metabolic abnormalities, should prompt investigation for brain tumors. PMID- 26252357 TI - Efficient and General Aerobic Oxidative Cross-Coupling of THIQs with Organozinc Reagents Catalyzed by CuCl2: Proof of a Radical Intermediate. AB - A general new method for the highly concise synthesis of C-1-alkylated tetrahydroisoquinolines (THIQ) is reported. The CuCl2-catalyzed procedure is based on a coupling of nonfunctionalized THIQs with organozinc reagents under aerobic conditions. It proceeds in high yields and is broadly applicable to a wide range of substrates. It relies on a regioselective sp(3) C-H bond activation allowing for an sp(3)-sp(3) bond union under mild reaction conditions in a rapid and effective manner. Mechanistically it involves an iminium ion intermediate that is formed via an organic radical involving a single-electron-transfer process. For the first time for this type of reaction a radical intermediate has been proven by EPR spectroscopy. PMID- 26252359 TI - Effects of genetic polymorphisms of glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) on the risk of diabetic nephropathy: a meta-analysis. AB - INTRODUCTION: Glutathione S-transferases (GSTs) belong to a family of ubiquitous and multifunctional enzymes that protect the cells against oxidative stress. OBJECTIVES: The aim of the study was to evaluate the association between the polymorphisms of glutathione-S-transferase (GST) genes and diabetic nephropathy (DN). PATIENTS AND METHODS: PubMed, EMBASE, and Google Scholar databases were systematically searched to identify relevant studies. The odds ratio (OR) for the association was determined using a fixed or random effects model. Tests for heterogeneity of the results and sensitivity analyses were performed. RESULTS: A total of 9 publications (874 patients in the study group, 966 controls) were included. With the exception of 1 study, GSTT1 and GSTM1 genotypes were not assessed by methods that measure a gene copy number. A significantly increased risk of DN was found for the GSTM1(-) genotype (OR, 1.27; 95% CI, 1.02-1.58) and the combination of GSTT1(-)/GSTM1(-) (OR,2.02; 95% CI, 1.22-3.36). We did not observe a correlation between DN and the GSTT1(-) genotype or the presence of Val alleles. In a subgroup analysis, an association between DN and the GSTM1(-) genotype was significant in Asians but not in Caucasians. CONCLUSIONS: Our results indicate that the GSTM1(-) genotype and the combination of GSTT1( )/GSTM1(-) increase the risk of DN. The combination of the GST polymorphisms rather than individual polymorphismshould be investigated. Genotyping allowing a trimodular determination of the GST copy number variations may better describe an association between the risk of disease and a given genotype. PMID- 26252358 TI - Microaggregate-associated protein involved in invasion of epithelial cells by Mycobacterium avium subsp. hominissuis. AB - The environmental opportunistic pathogen Mycobacterium avium subsp hominissuis (MAH), a member of the nontuberculous mycobacteria (NTM) cluster, causes respiratory as well as disseminated disease in patients such as those with chronic respiratory illnesses or AIDS. Currently, there is no effective method to prevent NTM respiratory infections. The formation of mycobacterial microaggregates comprises of phenotypic changes that lead to efficient adherence and invasion of the respiratory mucosa in vitro and in vivo. Microaggregate adhesion to the respiratory epithelium is mediated in part through the mycobacterial protein, MAV_3013 (MBP-1). Through DNA microarray analysis, the small hypothetical gene MAV_0831 (Microaggregate Invasion Protein-1, MIP-1) was identified as being upregulated during microaggregate formation. When MIP-1 was overexpressed in poorly-invasive Mycobacterium smegmatis, it provided the bacterium the ability to bind and enter epithelial cells. In addition, incubating microaggregates with recombinant MIP-1 protein enhanced the ability of microaggregates to invade HEp-2 cells, and exposure to anti-MIP-1 immune serum reduced the invasion of the host epithelium. Through protein-protein interaction assays, MIP-1 was found to bind to the host protein filamin A, a cytoskeletal actin-binding protein integral to the modulation of host cell shape and migration. As visualized by immunofluorescence, filamin A was able to co-localize with microaggregates and to a lesser extent planktonic bacteria. Invasion of HEp 2 cells by microaggregates and planktonic bacteria was also inhibited by the addition of anti-filamin A antibody suggesting that filamin A plays an important role during infection. In addition, at earlier time points binding and invasion assay results suggest that MBP-1 participates significantly during the first interactions with the host cell while MIP-1 becomes important once the bacteria adhere to the host epithelium. In summary, we have unveiled one more step associated with MAH crossing the respiratory mucosa. PMID- 26252361 TI - Integrating Language, Pragmatics, and Social Intervention in a Single-Subject Case Study of a Child With a Developmental Social Communication Disorder. AB - PURPOSE: This clinical focus article presents an illustration of a complex communication intervention, the Social Communication Intervention Programme (SCIP), as delivered to a child who has a social communication disorder (SCD). The SCIP intervention combined language processing and pragmatic and social understanding therapies in a program of individualized therapy activities and in close liaison with families. METHOD: The study used an enhanced AB single-subject design in which an 8-year-old child with an SCD participated in 20 therapy sessions with a specialist speech-language pathologist. A procedure of matching assessment findings to intervention choices was followed to construct an individualized treatment program. Examples of intervention content and the embedded structure of SCIP are illustrated. Observational and formal measurements of receptive and expressive language, conversation, and parent-teacher ratings of social communication were completed before therapy, after therapy, and at a 6 month follow-up session. RESULTS: Outcomes revealed change in total and receptive language scores but not in expressive language. Conversation showed marked improvement in responsiveness, appreciation of listener knowledge, turn taking, and adaptation of discourse style. Teacher-reported outcomes included improved classroom behavior and enhanced literacy skills. Parent-reported outcomes included improved verbal interactions with family members and personal narratives. CONCLUSIONS: This clinical focus article demonstrates the complexity of needs in a child with an SCD and how these can be addressed in individualized intervention. Findings are discussed in relation to the essential nature of language support including pragmatic therapy for children with SCDs. Discussion of the role of formal and functional outcome measurement as well as the proximity of chosen outcomes to the intervention is included. PMID- 26252362 TI - Mechanical properties of porcine spinal segments after intervertebral disc fenestration: an in vitro preliminary study. PMID- 26252360 TI - Novel nanoparticle vaccines for Listeriosis. AB - In recent years, nanomedicine has transformed many areas of traditional medicine, and enabled fresh insights into the prevention of previously difficult to treat diseases. An example of the transformative power of nanomedicine is a recent nano vaccine against listeriosis, a serious bacterial infection affecting not only pregnant women and their neonates, but also immune-compromised patients with neoplastic or chronic autoimmune diseases. There is a major unmet need for an effective and safe vaccine against listeriosis, with the challenge that an effective vaccine needs to generate protective T cell immunity, a hitherto difficult to achieve objective. Now utilizing a gold nanoparticle antigen delivery approach together with a novel polysaccharide nanoparticulate adjuvant, an effective T-cell vaccine has been developed that provides robust protection in animal models of listeriosis, raising the hope that one day this nanovaccine technology may protect immune-compromised humans against this serious opportunistic infection. PMID- 26252363 TI - Ab Initio Study of the Adsorption of Small Molecules on Metal-Organic Frameworks with Oxo-centered Trimetallic Building Units: The Role of the Undercoordinated Metal Ion. AB - The interactions of H2, CO, CO2, and H2O with the undercoordinated metal centers of the trimetallic oxo-centered M3(III)(MU3-O)(X) (COO)6 moiety are studied by means of wave function and density functional theory. This trimetallic oxo centered cluster is a common building unit in several metal-organic frameworks (MOFs) such as MIL-100, MIL-101, and MIL-127 (also referred to as soc-MOF). A combinatorial computational screening is performed for a large variety of trimetallic oxo-centered units M3(III)O (M = Al(3+), Sc(3+), V(3+), Cr(3+), Fe(3+), Ga(3+), Rh(3+), In(3+), Ir(3+)) interacting with H2O, H2, CO, and CO2. The screening addresses interaction energies, adsorption enthalpies, and vibrational properties. The results show that the Rh and Ir analogues are very promising materials for gas storage and separations. PMID- 26252364 TI - The effect of indole-3-carbinol on PIN1 and PIN2 in Arabidopsis roots. AB - The phytochemical indole-3-carbinol is produced in Cruciferous plants upon tissue rapture and deters herbivores. We recently showed that indole-3-carbinol modulates auxin signaling in root tips. Here we present transcript profiling experiments which further reveal the influence of indole-3-carbinol on auxin signaling in root tips, and also show that I3C affects auxin transporters. Brief treatment with indole-3-carbinol led to a reduction in the amount of PIN1 and to mislocalization of PIN2. PMID- 26252365 TI - Image-guided Treatment in the Hepatobiliary System: Role of Imaging in Treatment Planning and Posttreatment Evaluation. AB - In the past decade, image-guided targeted treatments such as percutaneous ablation, intra-arterial embolic therapies, and targeted radiation therapy have shown substantial promise in management of hepatobiliary malignancies. Imaging is integral to patient selection, treatment delivery, and assessment of treatment effectiveness. Preprocedural imaging is crucial and allows local tumor staging, evaluation of surrounding structures, and selection of suitable therapeutic options and strategies for treatment delivery. Postprocedural imaging is required to monitor therapeutic success, detect residual or recurrent disease, and identify procedure-related complications to guide appropriate future therapy. Technical innovations in cross-sectional imaging techniques such as computed tomography (CT) and magnetic resonance (MR) imaging, combined with advances in image postprocessing and new types of contrast agents, allow precise morphologic assessment and functional evaluation of hepatobiliary tumors. Advanced postprocessing techniques such as image fusion and volumetric assessment not only facilitate procedural planning and treatment delivery but also enhance posttreatment imaging surveillance. In addition, molecular imaging techniques such as fluorodeoxyglucose positron emission tomography (PET), PET/CT, and PET/MR imaging offer opportunities to evaluate various physiologic properties of tumors. PMID- 26252366 TI - Precursor reductions and ground-level ozone in the Continental United States. AB - Numerous papers analyze ground-level ozone (O3) trends since the 1980s, but few have linked O3trends with observed changes in nitrogen oxide (NOx) and volatile organic compound (VOC) emissions and ambient concentrations. This analysis of emissions and ambient measurements examines this linkage across the United States on multiple spatial scales from continental to urban. O3concentrations follow the general decreases in both NOx and VOC emissions and ambient concentrations of precursors (nitrogen dioxide, NO2; nonmethane organic compounds, NMOCs). Annual fourth-highest daily peak 8-hr average ozone and annual average or 98th percentile daily maximum hourly NO2concentrations show a statistically significant (p < 0.05) linear fit whose slope is less than 1:1 and intercept is in the 30 to >50 ppbv range. This empirical relationship is consistent with current understanding of O3photochemistry. The linear O3-NO2relationships found from our multispatial scale analysis can be used to extrapolate the rate of change of O3with projected NOx emission reductions, which suggests that future declines in annual fourth-highest daily average 8-hr maximum O3concentrations are unlikely to reach 65 ppbv or lower everywhere in the next decade. Measurements do not indicate increased annual reduction rates in (high) O3concentrations beyond the multidecadal precursor proportionality, since aggressive measures for NOx and VOC reduction are in place and have not produced an accelerated O3reduction rate beyond that prior to the mid-2000s. Empirically estimated changes in O3with emissions suggest that O3is less sensitive to precursor reductions than is found by the CAMx (v. 6.1) photochemical model. Options for increasing the rate of O3change are limited by photochemical factors, including the increase in NOx sensitivity with time (NMOC/NOx ratio increase), increase in O3production efficiency at lower NOx concentrations (higher O3/NOy ratio), and the presence of natural NOx and NMOC precursors and background O3. IMPLICATIONS: This analysis demonstrates empirical relations between O3and precursors based on long term trends in U.S. LOCATIONS: The results indicate that ground-level O3concentrations have responded predictably to reductions in VOC and NOx since the 1980s. The analysis reveals linear relations between the highest O3and NO2concentrations. Extrapolation of the historic trends to the future with expected continued precursor reductions suggest that achieving the 2014 proposed reduction in the U.S. National Ambient Air Quality Standard to a level between 65 and 70 ppbv is unlikely within the next decade. Comparison of measurements with national results from a regulatory photochemical model, CAMx, v. 6.1, suggests that model predictions are more sensitive to emissions changes than the observations would support. PMID- 26252368 TI - Kinematic and Kinetic Indicators of Sit-to-Stand. AB - Variation in the timing indicators separating sit-to-stand (STS) into movement phases complicates both research comparisons and clinical applications. The purpose of this study was to use kinetic reference standards to identify accurate kinematic and kinetic indicators for STS movement analysis such that consistent indicators might be used for STS from varied initial postures. Healthy adults performed STS using 4 foot placements: foot-neutral, foot-back, right-staggered, and left-staggered. Kinetic and kinematic data were collected from force platforms and an 8-camera video system. Initiation, seat-off, vertical posture, and termination were detected with 5% start and 7.5% end thresholds for changes in kinetic and kinematic STS indicators. Timing differences between kinetic and kinematic indicator time points and the reference vertical seated reaction force end point (seat-off) were determined. Kinematic indicators were compared with selected kinetic indicators using timing differences, statistical similarity, and internal consistency measures. Our results suggest that a single force platform system measuring vertical GRF or a simple camera system to evaluate the shoulder marker position and velocity can accurately and consistently detect STS initiation, seat-off, and vertical posture. In addition, these suggested STS indicators for initiation, seat-off, and vertical posture were not dependent upon foot placement. PMID- 26252367 TI - Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension. AB - RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases. OBJECTIVES: To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs). METHODS: A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6 minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Single-nucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort. MEASUREMENTS AND MAIN RESULTS: Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute walk distance at 12 and 18 months and marginally significant at 24 months. CONCLUSIONS: ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed. PMID- 26252369 TI - Effect of Dursban 480 EC (chlorpyrifos) and Talstar 10 EC (bifenthrin) on the physiological and genetic diversity of microorganisms in soil. AB - This investigation was undertaken to determine the impact of the insecticides Dursban 480 EC (with organophosphate compound chlorpyrifos as the active ingredient) and Talstar 10 EC (with pyrethroid bifenthrin as the active ingredient) on the respiration activity and microbial diversity in a sandy loam luvisol soil. The insecticides were applied in two doses: the maximum recommended dose for field application (15 mg kg(-1) for Dursban 480 EC and 6 mg kg(-1) for Talstar 10 EC) and a 100-fold higher dose for extrapolation of their effect. Bacterial and fungal genetic diversity was analysed in soil samples using PCR DGGE and the functional diversity (catabolic potential) was studied using BIOLOG EcoPlates at 1, 3, 7, 14, 28, 56 and 112 days after insecticide application. Five bacterial groups (alpha, beta, gamma proteobacteria, firmibacteria and actinomycetes) and five groups of fungi or fungus-like microorganisms (Ascomycota, Basidiomycota, Chytridiomycota, Oomycota and Zygomycota) were analysed using specific primer sets. This approach provides high resolution of the analysis covering majority of microorganisms in the soil. Only the high-dose Dursban 480 EC significantly changed the community of microorganisms. We observed its negative effect on alpha- and gamma-proteobacteria, as the number of OTUs (operational taxonomic units) decreased until the end of incubation. In the beta proteobacteria group, initial increase of OTUs was followed by strong decrease. Diversity in the firmibacteria, actinomycetes and Zygomycota groups was minimally disturbed by the insecticide application. Dursban 480 EC, however, both positively and negatively affected certain species. Among negatively affected species Sphingomonas, Flavobacterium or Penicillium were detected, but Achromobacter, Luteibacter or Aspergillus were supported by applied insecticide. The analysis of BIOLOG plates using AWCD values indicated a significant increase in metabolic potential of microorganisms in the soil after the high-dose Dursban application. Analysis of respiration demonstrated high microbial activity after insecticide treatments; thus, microbial degradation was relatively fast. The half life of the active insecticide compounds were estimated within the range of 25 to 27 days for Talstar and 6 to 11 days for Dursban and higher doses stimulated degradation. The recommended dose levels of both insecticides can be considered as safe for microbial community in the soil. PMID- 26252370 TI - The Development of Activity Profiles in Adolescent Females and their Association with Adiposity. AB - OBJECTIVES: This study aims to (1) use the objective activPAL activity monitor to assess physical activity behaviors, including sitting/lying, standing, and both light (LIPA) and moderate-to-vigorous physical activity (MVPA); (2) to develop distinct activity profiles based on time spent in each behavior in a sample of adolescent females; and (3) examine whether levels of adiposity differ across these activity profiles. METHODS: Female adolescents (n = 195; 14-18 y) had body mass index (median = 21.7 [IQR = 5.2] kg/m2) and 4-site skinfold thickness (median 62.0 mm; IQR = 37.1) measured. Physical activity behaviors were measured using the activPAL. Hierarchical cluster analysis grouped participants into activity profiles based on similar physical activity characteristics. Linear mixed models explored differences in body composition across activity profiles. RESULTS: Three activity profiles were identified, a low (n = 35), moderate (n = 110), and a high activity profile (n = 50). Significant differences across activity profiles were observed for skinfold thickness (p = .046), with higher values observed in the low activity profile compared with the high activity profile. CONCLUSIONS: Profiling free-living activity using behaviors from across the activity intensity continuum may account for more of the variability in energy expenditure then examining specific activity intensities, such as MVPA alone. The use of activity profiles may enable the identification of individuals with unhealthy activity behaviors, leading to the development and implementation of more targeted interventions. PMID- 26252371 TI - Mechanism of gemcitabine-induced suppression of human cholangiocellular carcinoma cell growth. AB - Although gemcitabine (2',2'-difluorocytidine monohydrochloride) is a common anticancer agent of cholangiocellular carcinoma (CCC), its growth inhibitory effects and gemcitabine resistance in CCC cells are poorly understood. Our aims were to uncover the mechanism underlying the antitumor effect of gemcitabine and to analyze the mechanism regulating in vitro CCC cell gemcitabine resistance. In addition, we sought to identify miRNAs associated with the antitumor effects of gemcitabine in CCCs. Using a cell proliferation assay and flow cytometry, we examined the ability of gemcitabine to inhibit cell proliferation in three types of human CCC cell lines (HuCCT-1, Huh28, TKKK). We also employed western blotting to investigate the effects of gemcitabine on cell cycle-related molecules in CCC cells. In addition, we used array chips to assess gemcitabine-mediated changes in angiogenic molecules and activated tyrosine kinase receptors in CCC cells. We used miRNA array chips to comprehensively analyze gemcitabine-induced miRNAs and examined clusters of differentially expressed miRNAs in cells with and without gemcitabine treatment. Gemcitabine inhibited cell proliferation in a dose- and time-dependent manner in HuCCT-1 cells, whereas cell proliferation was unchanged in Huh28 and TKKK cells. Gemcitabine inhibited cell cycle progression in HuCCT-1 cells from G0/G1 to S phase, resulting in G1 cell cycle arrest due to the reduction of cyclin D1 expression. In addition, gemcitabine upregulated the angiogenic molecules IL-6, IL-8, ENA-78 and MCP-1. In TKKK cells, by contrast, gemcitabine did not arrest the cell cycle or modify angiogenic molecules. Furthermore, in gemcitabine-sensitive HuCCT-1 cells, gemcitabine markedly altered miRNA expression. The miRNAs and angiogenic molecules altered by gemcitabine contribute to the inhibition of tumor growth in vitro. PMID- 26252372 TI - In vitro anti-tumor activity of the tanshinone IIA against SKOV3 cells. AB - The aim of this study was to determine the anti-tumour activity of tanshinone IIA in SKOV3 cells. Results suggested that tanshinone IIA could significantly inhibit (IC50 value = 19.6 MUM) the proliferation and induce apoptosis of SKOV3 cells as demonstrated by flow cytometry analysis. In addition, tanshinone IIA treatment induced G2/M phase cell cycle arrest in SKOV3 cells. The results of Western blotting indicated that tanshinone IIA can suppress the expression of anti apoptotic protein Bcl-2, increase (0.28 vs. 0.62) the expression of pro-apoptotic protein Bax (0.83 vs. 0.24) in SKOV3 cells. It can be concluded that the tanshinone IIA may be a possible therapeutic candidate having cytotoxic and anti tumour potential. PMID- 26252373 TI - Interventions for prevention of herpes simplex labialis (cold sores on the lips). AB - BACKGROUND: Herpes simplex labialis (HSL), also known as cold sores, is a common disease of the lips caused by the herpes simplex virus, which is found throughout the world. It presents as a painful vesicular eruption, forming unsightly crusts, which cause cosmetic disfigurement and psychosocial distress. There is no cure available, and it recurs periodically. OBJECTIVES: To assess the effects of interventions for the prevention of HSL in people of all ages. SEARCH METHODS: We searched the following databases up to 19 May 2015: the Cochrane Skin Group Specialised Register, the Oral Health Group Specialised Register, CENTRAL in the Cochrane Library (Issue 4, 2015), MEDLINE (from 1946), EMBASE (from 1974), LILACS (from 1982), the China National Knowledge Infrastructure (CNKI) database, Airiti Library, and 5 trial registers. To identify further references to relevant randomised controlled trials, we scanned the bibliographies of included studies and published reviews, and we also contacted the original researchers of our included studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions for preventing HSL in immunocompetent people. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, extracted data, and assessed the risk of bias. A third author was available for resolving differences of opinion. MAIN RESULTS: This review included 32 RCTs, with a total of 2640 immunocompetent participants, covering 19 treatments. The quality of the body of evidence was low to moderate for most outcomes, but was very low for a few outcomes. Our primary outcomes were 'Incidence of HSL' and 'Adverse effects during use of the preventative intervention'.The evidence for short-term (<= 1 month) use of oral aciclovir in preventing recurrent HSL was inconsistent across the doses used in the studies: 2 RCTs showed low quality evidence for a reduced recurrence of HSL with aciclovir 400 mg twice daily (risk ratio (RR) 0.26, 95% confidence interval (CI) 0.13 to 0.51; n = 177), while 1 RCT testing aciclovir 800 mg twice daily and 2 RCTs testing 200 mg 5 times daily found no similar preventive effects (RR 1.08, 95% CI 0.62 to 1.87; n = 237; moderate quality evidence and RR 0.46, 95% CI 0.20 to 1.07; n = 66; low quality evidence, respectively). The direction of intervention effect was unrelated to the risk of bias. The evidence from 1 RCT for the effect of short-term use of valaciclovir in reducing recurrence of HSL by clinical evaluation was uncertain (RR 0.55, 95% CI 0.23 to 1.28; n = 125; moderate quality evidence), as was the evidence from 1 RCT testing short-term use of famciclovir.Long-term (> 1 month) use of oral antiviral agents reduced the recurrence of HSL. There was low quality evidence from 1 RCT that long-term use of oral aciclovir reduced clinical recurrences (1.80 versus 0.85 episodes per participant per a 4-month period, P = 0.009) and virological recurrence (1.40 versus 0.40 episodes per participant per a 4-month period, P = 0.003). One RCT found long-term use of valaciclovir effective in reducing the incidence of HSL (with a decrease of 0.09 episodes per participant per month; n = 95). One RCT found that a long-term suppressive regimen of valaciclovir had a lower incidence of HSL than an episodic regimen of valciclovir (difference in means (MD) -0.10 episodes per participant per month, 95% CI -0.16 to -0.05; n = 120).These trials found no increase in adverse events associated with the use of oral antiviral agents (moderate quality evidence).There was no evidence to show that short-term use of topical antiviral agents prevented recurrent HSL. There was moderate quality evidence from 2 RCTs that topical aciclovir 5% cream probably has little effect on preventing recurrence of HSL (pooled RR 0.91, 95% CI 0.48 to 1.72; n = 271). There was moderate quality evidence from a single RCT that topical foscarnet 3% cream has little effect in preventing HSL (RR 1.08, 95% CI 0.82 to 1.40; n = 295).The efficacy of long-term use of topical aciclovir cream was uncertain. One RCT found significantly fewer research-diagnosed recurrences of HSL when on aciclovir cream treatment than on placebo (P < 0.05), but found no significant differences in the mean number of participant-reported recurrences between the 2 groups (P >= 0.05). One RCT found no preventive effect of topical application of 1,5-pentanediol gel for 26 weeks (P > 0.05). Another RCT found that the group who used 2-hydroxypropyl-beta-cyclo dextrin 20% gel for 6 months had significantly more recurrences than the placebo group (P = 0.003).These studies found no increase in adverse events related to the use of topical antiviral agents.Two RCTs found that the application of sunscreen significantly prevented recurrent HSL induced by experimental ultraviolet light (pooled RR 0.07, 95% CI 0.01 to 0.33; n = 111), but another RCT found that sunscreen did not prevent HSL induced by sunlight (RR 1.13, 95% CI 0.25 to 5.06; n = 51). These RCTs did not report adverse events.There were very few data suggesting that thymopentin, low-level laser therapy, and hypnotherapy are effective in preventing recurrent HSL, with one to two RCTs for each intervention. We failed to find any evidence of efficacy for lysine, LongoVital(r) supplementation, gamma globulin, herpes simplex virus (HSV) type I subunit vaccine, and yellow fever vaccine in preventing HSL. There were no consistent data supporting the efficacy of levamisole and interferon, which were also associated with an increased risk of adverse effects such as fever. AUTHORS' CONCLUSIONS: The current evidence demonstrates that long-term use of oral antiviral agents can prevent HSL, but the clinical benefit is small. We did not find evidence of an increased risk of adverse events. On the other hand, the evidence on topical antiviral agents and other interventions either showed no efficacy or could not confirm their efficacy in preventing HSL. PMID- 26252374 TI - Streptomycin Induced Stress Response in Salmonella enterica Serovar Typhimurium Shows Distinct Colony Scatter Signature. AB - We investigated the streptomycin-induced stress response in Salmonella enterica serovars with a laser optical sensor, BARDOT (bacterial rapid detection using optical scattering technology). Initially, the top 20 S. enterica serovars were screened for their response to streptomycin at 100 MUg/mL. All, but four S. enterica serovars were resistant to streptomycin. The MIC of streptomycin sensitive serovars (Enteritidis, Muenchen, Mississippi, and Schwarzengrund) varied from 12.5 to 50 MUg/mL, while streptomycin-resistant serovar (Typhimurium) from 125-250 MUg/mL. Two streptomycin-sensitive serovars (Enteritidis and Mississippi) were grown on brain heart infusion (BHI) agar plates containing sub inhibitory concentration of streptomycin (1.25-5 MUg/mL) and a streptomycin resistant serovar (Typhimurium) was grown on BHI containing 25-50 MUg/mL of streptomycin and the colonies (1.2 +/- 0.1 mm diameter) were scanned using BARDOT. Data show substantial qualitative and quantitative differences in the colony scatter patterns of Salmonella grown in the presence of streptomycin than the colonies grown in absence of antibiotic. Mass-spectrometry identified overexpression of chaperonin GroEL, which possibly contributed to the observed differences in the colony scatter patterns. Quantitative RT-PCR and immunoassay confirmed streptomycin-induced GroEL expression while, aminoglycoside adenylyltransferase (aadA), aminoglycoside efflux pump (aep), multidrug resistance subunit acrA, and ribosomal protein S12 (rpsL), involved in streptomycin resistance, were unaltered. The study highlights suitability of the BARDOT as a non-invasive, label-free tool for investigating stress response in Salmonella in conjunction with the molecular and immunoassay methods. PMID- 26252375 TI - Molecular and Immunohistochemical Characterization of Historical Long-Term Preserved Fixed Tissues from Different Human Organs. AB - University and museum collections are very important sources of biological samples that can be used to asses the past and present genetic diversity of many species. Modern genetic and immunohistochemical techniques can be used on long term preserved fixed tissues from museum specimens to answer epidemiological questions. A proof of principle was established to apply modern molecular genetics and immunohistochemical methods to these old specimens and to verify the original diagnosis. We analysed 19 specimens from our university collection including human organs that had been in fixative for more than 80 years. The tissues originated from lung, colon, brain, heart, adrenal gland, uterus and skin. We isolated amplifiable DNA from these wet preparations and performed mutational analysis of BRAF, KRAS and EGFR. The tissues were also embedded in paraffin and used for modern histology and immunohistochemistry. Our data show that amplifiable DNA is extractable and ranged from 0.25 to 22.77 MUg of total DNA. In three specimens BRAFV600E or KRASG12D mutations were found. Additionally, expression of different proteins like vimentin and GFAP was detected immunohistochemical in six investigated specimens. On the basis of our results the original diagnosis was altered in three specimens. Our work showed that it is possible to extract amplifiable DNA suitable for sequence analysis from long-term fixed tissue. Furthermore, histology and immunohistochemistry is feasible in specimens fixed long time ago. We conclude that these old preparations are suitable for further epidemiological research and that our methods open up new opportunities for future studies. PMID- 26252376 TI - The Human Acid-Sensing Ion Channel ASIC1a: Evidence for a Homotetrameric Assembly State at the Cell Surface. AB - The chicken acid-sensing ion channel ASIC1 has been crystallized as a homotrimer. We address here the oligomeric state of the functional ASIC1 in situ at the cell surface. The oligomeric states of functional ASIC1a and mutants with additional cysteines introduced in the extracellular pore vestibule were resolved on SDS PAGE. The functional ASIC1 complexes were stabilized at the cell surface of Xenopus laevis oocytes or CHO cells either using the sulfhydryl crosslinker BMOE, or sodium tetrathionate (NaTT). Under these different crosslinking conditions ASIC1a migrates as four distinct oligomeric states that correspond by mass to multiples of a single ASIC1a subunit. The relative importance of each of the four ASIC1a oligomers was critically dependent on the availability of cysteines in the transmembrane domain for crosslinking, consistent with the presence of ASIC1a homo-oligomers. The expression of ASIC1a monomers, trimeric or tetrameric concatemeric cDNA constructs resulted in functional channels. The resulting ASIC1a complexes are resolved as a predominant tetramer over the other oligomeric forms, after stabilization with BMOE or NaTT and SDS-PAGE/western blot analysis. Our data identify a major ASIC1a homotetramer at the surface membrane of the cell expressing functional ASIC1a channel. PMID- 26252377 TI - Nitrogen-Use Efficiency, Nitrous Oxide Emissions, and Cereal Production in Brazil: Current Trends and Forecasts. AB - The agriculture sector has historically been a major source of greenhouse gas (GHG) emissions into the atmosphere. Although the use of synthetic fertilizers is one of the most common widespread agricultural practices, over-fertilization can lead to negative economic and environmental consequences, such as high production costs, depletion of energy resources, and increased GHG emissions. Here, we provide an analysis to understand the evolution of cereal production and consumption of nitrogen (N) fertilizers in Brazil and to correlate N use efficiency (NUE) with economic and environmental losses as N2O emissions. Our results show that the increased consumption of N fertilizers is associated with a large decrease in NUE in recent years. The CO2 eq. of N2O emissions originating from N fertilization for cereal production were approximately 12 times higher in 2011 than in 1970, indicating that the inefficient use of N fertilizers is directly related to environmental losses. The projected N fertilizer forecasts are 2.09 and 2.37 million ton for 2015 and 2023, respectively. An increase of 0.02% per year in the projected NUE was predicted for the same time period. However, decreases in the projected CO2 eq. emissions for future years were not predicted. In a hypothetical scenario, a 2.39% increase in cereal NUE would lead to $ 21 million savings in N fertilizer costs. Thus, increases in NUE rates would lead not only to agronomic and environmental benefits but also to economic improvement. PMID- 26252378 TI - Complexity of Multi-Dimensional Spontaneous EEG Decreases during Propofol Induced General Anaesthesia. AB - Emerging neural theories of consciousness suggest a correlation between a specific type of neural dynamical complexity and the level of consciousness: When awake and aware, causal interactions between brain regions are both integrated (all regions are to a certain extent connected) and differentiated (there is inhomogeneity and variety in the interactions). In support of this, recent work by Casali et al (2013) has shown that Lempel-Ziv complexity correlates strongly with conscious level, when computed on the EEG response to transcranial magnetic stimulation. Here we investigated complexity of spontaneous high-density EEG data during propofol-induced general anaesthesia. We consider three distinct measures: (i) Lempel-Ziv complexity, which is derived from how compressible the data are; (ii) amplitude coalition entropy, which measures the variability in the constitution of the set of active channels; and (iii) the novel synchrony coalition entropy (SCE), which measures the variability in the constitution of the set of synchronous channels. After some simulations on Kuramoto oscillator models which demonstrate that these measures capture distinct 'flavours' of complexity, we show that there is a robustly measurable decrease in the complexity of spontaneous EEG during general anaesthesia. PMID- 26252379 TI - Cancer Associated Fibroblasts in Stage I-IIIA NSCLC: Prognostic Impact and Their Correlations with Tumor Molecular Markers. AB - BACKGROUND: Cancer Associated Fibroblasts (CAFs) are thought to regulate tumor growth and metastasis. Fibroblast Activating Protein 1 (FAP-1) is a marker for fibroblast activation and by many recognized as the main marker of CAFs. Alpha Smooth Muscle Actin (alpha-SMA) is a general myofibroblast marker, and can be used to identify CAFs. This study investigates the prognostic impact of FAP-1 and alpha-SMA in non-small cell lung cancer (NSCLC) patients and correlates their expression to 105 proteins investigated in the same cohort. METHODS: Tumor specimens from 536 NSCLC patients were obtained and tissue micro-arrays were constructed. Immunohistochemistry was used to evaluate the expression of FAP-1 and alpha-SMA and explore their impact on survival and association with other tumor molecular markers in NSCLC patients. RESULTS: High expression of FAP-1, but not alpha-SMA, in squamous cell carcinoma (SCC, P = 0.043, HR = 0.63 95% CI 0.40 0.99) was significantly associated with increased disease-specific survival. FAP 1 and alpha-SMA were not significantly correlated to each other. Analyses of FAP 1 and alpha-SMA associated with other tumor-related proteins revealed histotype specific correlation patterns. CONCLUSION: The presence of FAP-1 expressing CAFs is an indicator of positive outcome for NSCLC-SCC patients. In addition, correlation analyses suggest FAP-1 and alpha-SMA to label different subsets of fibroblasts and their associations with other tumor-related proteins diverge according to histological subtype. PMID- 26252380 TI - Wear Fast, Die Young: More Worn Teeth and Shorter Lives in Iberian Compared to Scottish Red Deer. AB - Teeth in Cervidae are permanent structures that are not replaceable or repairable; consequently their rate of wear, due to the grinding effect of food and dental attrition, affects their duration and can determine an animal's lifespan. Tooth wear is also a useful indicator of accumulative life energy investment in intake and mastication and their interactions with diet. Little is known regarding how natural and sexual selection operate on dental structures within a species in contrasting environments and how these relate to life history traits to explain differences in population rates of tooth wear and longevity. We hypothesised that populations under harsh environmental conditions should be selected for more hypsodont teeth while sexual selection may maintain similar sex differences within different populations. We investigated the patterns of tooth wear in males and females of Iberian red deer (Cervus elaphus hispanicus) in Southern Spain and Scottish red deer (C. e. scoticus) across Scotland, that occur in very different environments, using 10343 samples from legal hunting activities. We found higher rates of both incisor and molar wear in the Spanish compared to Scottish populations. However, Scottish red deer had larger incisors at emergence than Iberian red deer, whilst molars emerged at a similar size in both populations and sexes. Iberian and Scottish males had earlier tooth depletion than females, in support of a similar sexual selection process in both populations. However, whilst average lifespan for Iberian males was 4 years shorter than that for Iberian females and Scottish males, Scottish males only showed a reduction of 1 year in average lifespan with respect to Scottish females. More worn molars were associated with larger mandibles in both populations, suggesting that higher intake and/or greater investment in food comminution may have favoured increased body growth, before later loss of tooth efficiency due to severe wear. These results illustrate how independent selection in both subspecies, that diverged 11,700 years BP, has resulted in the evolution of different longevity, although sexual selection has maintained a similar pattern of relative sex differences in tooth depletion. This study opens interesting questions on optimal allocation in life history trade-offs and the independent evolution of allopatric populations. PMID- 26252381 TI - Child Centred Approach to Climate Change and Health Adaptation through Schools in Bangladesh: A Cluster Randomised Intervention Trial. AB - BACKGROUND: Bangladesh is one of the most vulnerable countries to climate change. People are getting educated at different levels on how to deal with potential impacts. One such educational mode was the preparation of a school manual, for high school students on climate change and health protection endorsed by the National Curriculum and Textbook Board, which is based on a 2008 World Health Organization manual. The objective of this study was to test the effectiveness of the manual in increasing the knowledge level of the school children about climate change and health adaptation. METHODS: This cluster randomized intervention trial involved 60 schools throughout Bangladesh, with 3293 secondary school students participating. School upazilas (sub-districts) were randomised into intervention and control groups, and two schools from each upazila were randomly selected. All year seven students from both groups of schools sat for a pre-test of 30 short questions of binary response. A total of 1515 students from 30 intervention schools received the intervention through classroom training based on the school manual and 1778 students of the 30 control schools did not get the manual but a leaflet on climate change and health issues. Six months later, a post intervention test of the same questionnaire used in the pre-test was performed at both intervention and control schools. The pre and post test scores were analysed along with the demographic data by using random effects model. RESULTS: None of the various school level and student level variables were significantly different between the control and intervention group. However, the intervention group had a 17.42% (95% CI: 14.45 to 20.38, P = <0.001) higher score in the post-test after adjusting for pre-test score and other covariates in a multi-level linear regression model. CONCLUSIONS: These results suggest that school-based intervention for climate change and health adaptation is effective for increasing the knowledge level of school children on this topic. PMID- 26252382 TI - Neural Resolution of Formant Frequencies in the Primary Auditory Cortex of Rats. AB - Pulse-resonance sounds play an important role in animal communication and auditory object recognition, yet very little is known about the cortical representation of this class of sounds. In this study we shine light on one simple aspect: how well does the firing rate of cortical neurons resolve resonant ("formant") frequencies of vowel-like pulse-resonance sounds. We recorded neural responses in the primary auditory cortex (A1) of anesthetized rats to two-formant pulse-resonance sounds, and estimated their formant resolving power using a statistical kernel smoothing method which takes into account the natural variability of cortical responses. While formant-tuning functions were diverse in structure across different penetrations, most were sensitive to changes in formant frequency, with a frequency resolution comparable to that reported for rat cochlear filters. PMID- 26252383 TI - Use of Mobile Information Technology during Planning, Implementation and Evaluation of a Polio Campaign in South Sudan. AB - BACKGROUND: Use of mobile information technology may aid collection of real-time, standardised data to inform and improve decision-making for polio programming and response. We utilised Android-based smartphones to collect data electronically from more than 8,000 households during a national round of polio immunisation in South Sudan. The results of the household surveys are presented here, together with discussion of the application of mobile information technology for polio campaign planning, implementation and evaluation in a real-time setting. METHODS: Electronic questionnaires were programmed onto Android-based smartphones for mapping, supervision and survey activities during a national round of polio immunisation. National census data were used to determine the sampling frame for each activity and select the payam (district). Individual supervisors, in consultation with the local district health team, selected villages and households within each payam. Data visualisation tools were utilised for analysis and reporting. RESULTS: Implementation of mobile information technology and local management was feasible during a national round of polio immunisation in South Sudan. Red Cross visits during the polio campaign were equitable according to household wealth index and households who received a Red Cross visit had significantly higher odds of being aware of the polio campaign than those who did not. Nearly 95% of children under five were reported to have received polio immunisation (according to maternal recall) during the immunisation round, which varied by state, county and payam. A total of 11 payams surveyed were identified with less than 90% reported immunisation coverage and the least poor households had significantly higher odds of being vaccinated than the most poor. More than 95% of households were aware of the immunisation round and households had significantly higher odds of being vaccinated if they had prior awareness of the campaign taking place. CONCLUSION: Pre-campaign community education and household awareness of polio is important to increase campaign participation and subsequent immunisation coverage in South Sudan. More emphasis should be placed on ensuring immunisation is equitable according to geographic area and household socio economic index in future rounds. We demonstrate the utility of mobile information technology for household mapping, supervision and survey activities during a national round of polio immunisation and encourage future studies to compare the effectiveness of electronic data collection and its application in polio planning and programming. PMID- 26252384 TI - Inhibition of Aspergillus fumigatus and Its Biofilm by Pseudomonas aeruginosa Is Dependent on the Source, Phenotype and Growth Conditions of the Bacterium. AB - Aspergillus fumigatus (Af) and Pseudomonas aeruginosa (Pa) are leading fungal and bacterial pathogens, respectively, in many clinical situations. Relevant to this, their interface and co-existence has been studied. In some experiments in vitro, Pa products have been defined that are inhibitory to Af. In some clinical situations, both can be biofilm producers, and biofilm could alter their physiology and affect their interaction. That may be most relevant to airways in cystic fibrosis (CF), where both are often prominent residents. We have studied clinical Pa isolates from several sources for their effects on Af, including testing involving their biofilms. We show that the described inhibition of Af is related to the source and phenotype of the Pa isolate. Pa cells inhibited the growth and formation of Af biofilm from conidia, with CF isolates more inhibitory than non-CF isolates, and non-mucoid CF isolates most inhibitory. Inhibition did not require live Pa contact, as culture filtrates were also inhibitory, and again non-mucoid>mucoid CF>non-CF. Preformed Af biofilm was more resistant to Pa, and inhibition that occurred could be reproduced with filtrates. Inhibition of Af biofilm appears also dependent on bacterial growth conditions; filtrates from Pa grown as biofilm were more inhibitory than from Pa grown planktonically. The differences in Pa shown from these different sources are consistent with the extensive evolutionary Pa changes that have been described in association with chronic residence in CF airways, and may reflect adaptive changes to life in a polymicrobial environment. PMID- 26252386 TI - Homogentisate 1-2-Dioxygenase Downregulation in the Chronic Persistence of Pseudomonas aeruginosa Australian Epidemic Strain-1 in the CF Lung. AB - Some Pseudomonas aeruginosa strains including Australian Epidemic Strain-1 (AES-1 or AUS-01) cause persistent chronic infection in cystic fibrosis (CF) patients, with greater morbidity and mortality. Factors conferring persistence are largely unknown. Previously we analysed the transcriptomes of AES-1 grown in Luria broth, nematode growth medium for Caenorhabditis elegans assay (both aerobic) and artificial sputum medium (mainly hypoxic). Transcriptional comparisons included chronic AES-1 strains against PAO1 and acute AES-1 (AES-1R) against its chronic isogen (AES-1M), isolated 10.5 years apart from a CF patient and not eradicated in the meantime. Prominent amongst genes downregulated in AES-1M in all comparisons was homogentisate-1-2-dioxygenase (hmgA); an oxygen-dependent gene known to be mutationally deactivated in many chronic infection strains of P. aeruginosa. To investigate if hmgA downregulation and deactivation gave similar virulence persistence profiles, a hmgA mutant made in UCBPP-PA14 utilising RedS recombinase and AES-1M were assessed in the C. elegans virulence assay, and the C57BL/6 mouse for pulmonary colonisation and TNF-alpha response. In C. elegans, hmgA deactivation resulted in significantly increased PA14 virulence while hmgA downregulation reduced AES-1M virulence. AES-1M was significantly more persistent in mouse lung and showed a significant increase in TNF-alpha (p<0.0001), sustained even with no detectable bacteria. PA14DeltahmgA did not show increased TNF-alpha. This study suggests that hmgA may have a role in P. aeruginosa persistence in chronic infection and the results provide a starting point for clarifying the role of hmgA in chronic AES-1. PMID- 26252387 TI - Correction: Introgression of the SbASR-1 Gene Cloned from a Halophyte Salicornia brachiata Enhances Salinity and Drought Endurance in Transgenic Groundnut (Arachis hypogaea) and Acts as a Transcription Factor. PMID- 26252385 TI - Rhomboid Enhancer Activity Defines a Subset of Drosophila Neural Precursors Required for Proper Feeding, Growth and Viability. AB - Organismal growth regulation requires the interaction of multiple metabolic, hormonal and neuronal pathways. While the molecular basis for many of these are well characterized, less is known about the developmental origins of growth regulatory structures and the mechanisms governing control of feeding and satiety. For these reasons, new tools and approaches are needed to link the specification and maturation of discrete cell populations with their subsequent regulatory roles. In this study, we characterize a rhomboid enhancer element that selectively labels four Drosophila embryonic neural precursors. These precursors give rise to the hypopharyngeal sensory organ of the peripheral nervous system and a subset of neurons in the deutocerebral region of the embryonic central nervous system. Post embryogenesis, the rhomboid enhancer is active in a subset of cells within the larval pharyngeal epithelium. Enhancer-targeted toxin expression alters the morphology of the sense organ and results in impaired larval growth, developmental delay, defective anterior spiracle eversion and lethality. Limiting the duration of toxin expression reveals differences in the critical periods for these effects. Embryonic expression causes developmental defects and partially penetrant pre-pupal lethality. Survivors of embryonic expression, however, ultimately become viable adults. In contrast, post-embryonic toxin expression results in fully penetrant lethality. To better define the larval growth defect, we used a variety of assays to demonstrate that toxin targeted larvae are capable of locating, ingesting and clearing food and they exhibit normal food search behaviors. Strikingly, however, following food exposure these larvae show a rapid decrease in consumption suggesting a satiety like phenomenon that correlates with the period of impaired larval growth. Together, these data suggest a critical role for these enhancer-defined lineages in regulating feeding, growth and viability. PMID- 26252388 TI - Selection and Evaluation of Tissue Specific Reference Genes in Lucilia sericata during an Immune Challenge. AB - The larvae of the common green bottle fly Lucilia sericata (Diptera: Calliphoridae) have been used for centuries to promote wound healing, but the molecular basis of their antimicrobial, debridement and healing functions remains largely unknown. The analysis of differential gene expression in specific larval tissues before and after immune challenge could be used to identify key molecular factors, but the most sensitive and reproducible method qRT-PCR requires validated reference genes. We therefore selected 10 candidate reference genes encoding products from different functional classes (18S rRNA, 28S rRNA, actin, beta-tubulin, RPS3, RPLP0, EF1alpha, PKA, GAPDH and GST1). Two widely applied algorithms (GeNorm and Normfinder) were used to analyze reference gene candidates in different larval tissues associated with secretion, digestion, and antimicrobial activity (midgut, hindgut, salivary glands, crop and fat body). The Gram-negative bacterium Pseudomonas aeruginosa was then used to boost the larval immune system and the stability of reference gene expression was tested in comparison to three immune genes (lucimycin, defensin-1 and attacin-2), which target different pathogen classes. We observed no differential expression of the antifungal peptide lucimycin, whereas the representative targeting Gram-positive bacteria (defensin-1) was upregulated in salivary glands, crop, nerve ganglion and reached its maximum in fat body (up to 300-fold). The strongest upregulation in all immune challenged tissues (over 50,000-fold induction in the fat body) was monitored for attacin-2, the representative targeting Gram-negative bacteria. Here we identified and validated a set of reference genes that allows the accurate normalization of gene expression in specific tissues of L. sericata after immune challenge. PMID- 26252389 TI - Stimulation of Glia Reveals Modulation of Mammalian Spinal Motor Networks by Adenosine. AB - Despite considerable evidence that glia can release modulators to influence the excitability of neighbouring neurons, the importance of gliotransmission for the operation of neural networks and in shaping behaviour remains controversial. Here we characterise the contribution of glia to the modulation of the mammalian spinal central pattern generator for locomotion, the output of which is directly relatable to a defined behaviour. Glia were stimulated by specific activation of protease-activated receptor-1 (PAR1), an endogenous G-protein coupled receptor preferentially expressed by spinal glia during ongoing activity of the spinal central pattern generator for locomotion. Selective activation of PAR1 by the agonist TFLLR resulted in a reversible reduction in the frequency of locomotor related bursting recorded from ventral roots of spinal cord preparations isolated from neonatal mice. In the presence of the gliotoxins methionine sulfoximine or fluoroacetate, TFLLR had no effect, confirming the specificity of PAR1 activation to glia. The modulation of burst frequency upon PAR1 activation was blocked by the non-selective adenosine-receptor antagonist theophylline and by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, but not by the A2A receptor antagonist SCH5826, indicating production of extracellular adenosine upon glial stimulation, followed by A1-receptor mediated inhibition of neuronal activity. Modulation of network output following glial stimulation was also blocked by the ectonucleotidase inhibitor ARL67156, indicating glial release of ATP and its subsequent degradation to adenosine rather than direct release of adenosine. Glial stimulation had no effect on rhythmic activity recorded following blockade of inhibitory transmission, suggesting that glial cell-derived adenosine acts via inhibitory circuit components to modulate locomotor-related output. Finally, the modulation of network output by endogenous adenosine was found to scale with the frequency of network activity, implying activity dependent release of adenosine. Together, these data indicate that glia play an active role in the modulation of mammalian locomotor networks, providing negative feedback control that may stabilise network activity. PMID- 26252390 TI - A Novel Virus Causes Scale Drop Disease in Lates calcarifer. AB - From 1992 onwards, outbreaks of a previously unknown illness have been reported in Asian seabass (Lates calcarifer) kept in maricultures in Southeast Asia. The most striking symptom of this emerging disease is the loss of scales. It was referred to as scale drop syndrome, but the etiology remained enigmatic. By using a next-generation virus discovery technique, VIDISCA-454, sequences of an unknown virus were detected in serum of diseased fish. The near complete genome sequence of the virus was determined, which shows a unique genome organization, and low levels of identity to known members of the Iridoviridae. Based on homology of a series of putatively encoded proteins, the virus is a novel member of the Megalocytivirus genus of the Iridoviridae family. The virus was isolated and propagated in cell culture, where it caused a cytopathogenic effect in infected Asian seabass kidney and brain cells. Electron microscopy revealed icosahedral virions of about 140 nm, characteristic for the Iridoviridae. In vitro cultured virus induced scale drop syndrome in Asian seabass in vivo and the virus could be reisolated from these infected fish. These findings show that the virus is the causative agent for the scale drop syndrome, as each of Koch's postulates is fulfilled. We have named the virus Scale Drop Disease Virus. Vaccines prepared from BEI- and formalin inactivated virus, as well as from E. coli produced major capsid protein provide efficacious protection against scale drop disease. PMID- 26252392 TI - A Hybrid Optimization Method for Solving Bayesian Inverse Problems under Uncertainty. AB - In this paper, we investigate the application of a new method, the Finite Difference and Stochastic Gradient (Hybrid method), for history matching in reservoir models. History matching is one of the processes of solving an inverse problem by calibrating reservoir models to dynamic behaviour of the reservoir in which an objective function is formulated based on a Bayesian approach for optimization. The goal of history matching is to identify the minimum value of an objective function that expresses the misfit between the predicted and measured data of a reservoir. To address the optimization problem, we present a novel application using a combination of the stochastic gradient and finite difference methods for solving inverse problems. The optimization is constrained by a linear equation that contains the reservoir parameters. We reformulate the reservoir model's parameters and dynamic data by operating the objective function, the approximate gradient of which can guarantee convergence. At each iteration step, we obtain the relatively 'important' elements of the gradient, which are subsequently substituted by the values from the Finite Difference method through comparing the magnitude of the components of the stochastic gradient, which forms a new gradient, and we subsequently iterate with the new gradient. Through the application of the Hybrid method, we efficiently and accurately optimize the objective function. We present a number numerical simulations in this paper that show that the method is accurate and computationally efficient. PMID- 26252391 TI - Peripheral Blood Mononuclear Cells Enhance Cartilage Repair in in vivo Osteochondral Defect Model. AB - This study characterized peripheral blood mononuclear cells (PBMC) in terms of their potential in cartilage repair and investigated their ability to improve the healing in a pre-clinical large animal model. Human PBMCs were isolated with gradient centrifugation and adherent PBMC's were evaluated for their ability to differentiate into adipogenic, chondrogenic and osteogenic lineages and also for their expression of musculoskeletal genes. The phenotype of the PBMCs was evaluated using Stro-1, CD34, CD44, CD45, CD90, CD106, CD105, CD146 and CD166 cell surface markers. Osteochondral defects were created in the medial femoral condyle (MFC) of 24 Welsh mountain sheep and evaluated at a six month time point. Four cell treatment groups were evaluated in combination with collagen-GAG scaffold: (1) MSC alone; (2) MSCs and PBMCs at a ratio of 20:1; (3) MSCs and PBMC at a ratio of 2:1 and (4) PBMCs alone. Samples from the surgical site were evaluated for mechanical properties, ICRS score and histological repair. Fresh PBMC samples were 90% positive for hematopoietic cell surface markers and negative for the MSC antibody panel (<1%, p = 0.006). However, the adherent PBMC population expressed mesenchymal stem cell markers in hypoxic culture and lacked CD34/45 positive cells (<0.2%). This finding demonstrated that the adherent cells had acquired an MSC-like phenotype and transformed in hypoxia from their original hematopoietic lineage. Four key genes in muskuloskeletal biology were significantly upregulated in adherent PBMCs by hypoxia: BMP2 4.2-fold (p = 0.0007), BMP6 10.7-fold (p = 0.0004), GDF5 2.0-fold (p = 0.002) and COL1 5.0-fold (p = 0.046). The monolayer multilineage analysis confirmed the trilineage mesenchymal potential of the adherent PBMCs. PBMC cell therapy was equally good as bone marrow MSC therapy for defects in the ovine large animal model. Our results show that PBMCs support cartilage healing and oxygen tension of the environment was found to have a key effect on the derivation of a novel adherent cell population with an MSC-like phenotype. This study presents a novel and easily attainable point-of-care cell therapy with PBMCs to treat osteochondral defects in the knee avoiding any cell manipulations outside the surgical room. PMID- 26252393 TI - Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active alpha-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase. AB - Migalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of alpha-galactosidase A (alpha-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased alpha-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, alpha-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC alpha-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased alpha-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified. TRIAL REGISTRATION: ClinicalTrials.gov NCT01196871. PMID- 26252394 TI - Irradiation of Neurons with High-Energy Charged Particles: An In Silico Modeling Approach. AB - In this work, a stochastic computational model of microscopic energy deposition events is used to study for the first time damage to irradiated neuronal cells of the mouse hippocampus. An extensive library of radiation tracks for different particle types is created to score energy deposition in small voxels and volume segments describing a neuron's morphology that later are sampled for given particle fluence or dose. Methods included the construction of in silico mouse hippocampal granule cells from neuromorpho.org with spine and filopodia segments stochastically distributed along the dendritic branches. The model is tested with high-energy (56)Fe, (12)C, and (1)H particles and electrons. Results indicate that the tree-like structure of the neuronal morphology and the microscopic dose deposition of distinct particles may lead to different outcomes when cellular injury is assessed, leading to differences in structural damage for the same absorbed dose. The significance of the microscopic dose in neuron components is to introduce specific local and global modes of cellular injury that likely contribute to spine, filopodia, and dendrite pruning, impacting cognition and possibly the collapse of the neuron. Results show that the heterogeneity of heavy particle tracks at low doses, compared to the more uniform dose distribution of electrons, juxtaposed with neuron morphology make it necessary to model the spatial dose painting for specific neuronal components. Going forward, this work can directly support the development of biophysical models of the modifications of spine and dendritic morphology observed after low dose charged particle irradiation by providing accurate descriptions of the underlying physical insults to complex neuron structures at the nano-meter scale. PMID- 26252396 TI - The Conversion of 4-Anilinoquinazoline- and 3-Aryl-4-imino-3,4-dihydro quinazoline-2-carbonitriles into Benzo[4,5]imidazo[1,2-c]quinazoline-6 carbonitriles via Oxidative and Nonoxidative C-N Couplings. AB - Benzo[4,5]imidazo[1,2-c]quinazoline-6-carbonitriles are prepared in high yields via three new routes: (1) a Cu(OTf)2 (0-5 mol %) catalyzed hypervalent iodine [PhI(OTf)2] mediated oxidative coupling of 4-anilinoquinazoline-2-carbonitriles in neat trifluoroacetic acid (TFA); (2) a Pd(OAc)2 (10 mol %) or CuI (10 mol %) mediated nonoxidative coupling of 4-(2-bromoanilino)quinazoline-2-carbonitrile; and (3) a nonoxidative Pd(Ar3P)3 [Ar = 3,5-(F3C)2C6H3] [aka Superstable Pd(0) Catalyst] (10 mol %) mediated intramolecular C-N cyclization of 3-(2-bromophenyl) 4-imino-3,4-dihydroquinazoline-2-carbonitriles. All new compounds are fully characterized. PMID- 26252395 TI - Label-Free Density Measurements of Radial Peripapillary Capillaries in the Human Retina. AB - Radial peripapillary capillaries (RPCs) comprise a unique network of capillary beds within the retinal nerve fibre layer (RNFL) and play a critical role in satisfying the nutritional requirements of retinal ganglion cell (RGC) axons. Understanding the topographical and morphological characteristics of these networks through in vivo techniques may improve our understanding about the role of RPCs in RGC axonal health and disease. This study utilizes a novel, non invasive and label-free optical imaging technique, speckle variance optical coherence tomography (svOCT), for quantitatively studying RPC networks in the human retina. Six different retinal eccentricities from 16 healthy eyes were imaged using svOCT. The same eccentricities were histologically imaged in 9 healthy donor eyes with a confocal scanning laser microscope. Donor eyes were subject to perfusion-based labeling techniques prior to retinal dissection, flat mounting and visualization with the microscope. Capillary density and diameter measurements from each eccentricity in svOCT and histological images were compared. Data from svOCT images were also analysed to determine if there was a correlation between RNFL thickness and RPC density. The results are as follows: (1) The morphological characteristics of RPC networks on svOCT images are comparable to histological images; (2) With the exception of the nasal peripapillary region, there were no significant differences in RPC density measurements between svOCT and histological images; (3) Capillary diameter measurements were significantly greater in svOCT images compared to histology; (4) There is a positive correlation between RPC density and RNFL thickness. The findings in this study suggest that svOCT is a reliable modality for analyzing RPC networks in the human retina. It may therefore be a valuable tool for aiding our understanding about vasculogenic mechanisms that are involved in RGC axonopathies. Further work is required to explore the reason for some of the quantitative differences between svOCT and histology. PMID- 26252397 TI - Smoke Rings: Towards a Comprehensive Tobacco Free Policy for the Olympic Games. AB - BACKGROUND: The tobacco industry has long sought affiliation with major sporting events, including the Olympic Games, for marketing, advertising and promotion purposes. Since 1988, each Olympic Games has adopted a tobacco-free policy. Limited study of the effectiveness of the smoke-free policy has been undertaken to date, with none examining the tobacco industry's involvement with the Olympics or use of the Olympic brand. METHODS AND FINDINGS: A comparison of the contents of Olympic tobacco-free policies from 1988 to 2014 was carried out by searching the websites of the IOC and host NOCs. The specific tobacco control measures adopted for each Games were compiled and compared with measures recommended by the WHO Tobacco Free Sports Initiative and Article 13 of the Framework Convention on Tobacco Control (FCTC). This was supported by semi-structured interviews of key informants involved with the adoption of tobacco-free policies for selected games. To understand the industry's interests in the Olympics, the Legacy Tobacco Documents Library (http://legacy.library.ucsf.edu) was systematically searched between June 2013 and August 2014. Company websites, secondary sources and media reports were also searched to triangulate the above data sources. This paper finds that, while most direct associations between tobacco and the Olympics have been prohibited since 1988, a variety of indirect associations undermine the Olympic tobacco-free policy. This is due to variation in the scope of tobacco free policies, limited jurisdiction and continued efforts by the industry to be associated with Olympic ideals. CONCLUSIONS: The paper concludes that, compatible with the IOC's commitment to promoting healthy lifestyles, a comprehensive tobacco-free policy with standardized and binding measures should be adopted by the International Olympic Committee and all national Olympic committees. PMID- 26252398 TI - Molecular aspects of the pathogenesis of periodontitis. AB - The past decade of basic research in periodontology has driven radical changes in our understanding and perceptions of the pathogenic processes that drive periodontal tissue destruction. The core elements of the classical model of disease pathogenesis, developed by Page & Kornman in 1997, remain pertinent today; however, our understanding of the dynamic interactions between the various microbial and host factors has changed significantly. The molecular era has unraveled aspects of genetics, epigenetics, lifestyle and environmental factors that, in combination, influence biofilm composition and the host's inflammatory immune response, creating a heterogenic biological phenotype that we label as 'periodontitis'. In this volume of Periodontology 2000, experts in their respective fields discuss these emerging concepts, such as a health-promoting biofilm being essential for periodontal stability, involving a true symbiosis between resident microbial species and each other and also with the host response to that biofilm. Rather like the gut microbiome, changes in the local environment, which may include inflammatory response mediators or viruses, conspire to drive dysbiosis and create a biofilm that supports pathogenic species capable of propagating disease. The host response is now recognized as the major contributor to periodontal tissue damage in what becomes a dysfunctional, poorly targeted and nonresolving inflammation that only serves to nourish and sustain the dysbiosis. The role of epithelial cells in signaling to the immune system is becoming clearer, as is the role of dendritic cells as transporters of periodontal pathogens to distant sites within the body, namely metastatic infection. The involvement of nontraditional immune cells, such as natural killer cells, is being recognized, and the simple balance between T-helper 1- and T helper 2-type T-cell populations has become less clear with the emergence of T regulatory cells, T-helper 17 cells and follicular helper cells. The dominance of the neutrophil has emerged, not only as a potential destructor when poorly regulated but as an equally unpredictable effector cell for specific B-cell immunity. The latter has emerged, in part, from the realization that neutrophils live for 5.4 days in the circulation, rather than for 24 h, and are also schizophrenic in nature, being powerful synthesizers of proinflammatory cytokines but also responding to prostaglandin signals to trigger a switch to a pro resolving phenotype that appears capable of regenerating the structure and function of healthy tissue. Key to these outcomes are the molecular signaling pathways that dominate at any one time, but even these are influenced by microRNAs capable of 'silencing' certain inflammatory genes. This volume of Periodontology 2000 tries to draw these complex new learnings into a contemporary model of disease pathogenesis, in which inflammation and dysbiosis impact upon whether the outcome is driven toward acute resolution and stability, chronic resolution and repair, or failed resolution and ongoing periodontal tissue destruction. PMID- 26252400 TI - Periodontal herpesviruses: prevalence, pathogenicity, systemic risk. AB - Periodontitis is an infectious/inflammatory disease characterized by the loss of periodontal ligament and alveolar bone. Herpesviruses are frequent inhabitants of periodontitis lesions, and the periodontopathogenicity of these viruses is the topic of this review. In 26 recent studies from 15 countries, subgingival cytomegalovirus, Epstein-Barr virus and herpes simplex virus type 1, respectively, yielded median prevalences of 49%, 45% and 63% in aggressive periodontitis, 40%, 32% and 45% in chronic periodontitis, and 3%, 7% and 12% in healthy periodontium. An active herpesvirus infection of the periodontium exhibits site specificity, is a potent stimulant of cellular immunity, may cause upgrowth of periodontopathic bacteria and tends to be related to disease-active periodontitis. Pro-inflammatory cytokines induced by the herpesvirus infection may activate matrix metalloproteinases and osteoclasts, leading to breakdown of the tooth-supportive tissues. The notion that a co-infection of herpesviruses and specific bacteria causes periodontitis provides a plausible etiopathogenic explanation for the disease. Moreover, herpesvirus virions from periodontal sites may dislodge into saliva or enter the systemic circulation and cause diseases beyond the periodontium. Periodontal treatment can diminish significantly the periodontal load of herpesviruses, which may lower the incidence and magnitude of herpesvirus dissemination within and between individuals, and subsequently the risk of acquiring a variety of medical diseases. Novel and more effective approaches to the prevention and treatment of periodontitis and related diseases may depend on a better understanding of the herpesvirus-bacteria-immune response axis. PMID- 26252401 TI - Epithelial barrier and oral bacterial infection. AB - The oral epithelial barrier separates the host from the environment and provides the first line of defense against pathogens, exogenous substances and mechanical stress. It consists of underlying connective tissue and a stratified keratinized epithelium with a basement membrane, whose cells undergo terminal differentiation resulting in the formation of a mechanically resistant surface. Gingival keratinocytes are connected by various transmembrane proteins, such as tight junctions, adherens junctions and gap junctions, each of which has a specialized structure and specific functions. Periodontal pathogens are able to induce inflammatory responses that lead to attachment loss and periodontal destruction. A number of studies have demonstrated that the characteristics of pathogenic oral bacteria influence the expression and structural integrity of different cell-cell junctions. Tissue destruction can be mediated by host cells following stimulation with cytokines and bacterial products. Keratinocytes, the main cell type in gingival epithelial tissues, express a variety of proinflammatory cytokines and chemokines, including interleukin-1alpha, interleukin-1beta, interleukin-6, interleukin-8 and tumor necrosis factor-alpha. Furthermore, the inflammatory mediators that may be secreted by oral keratinocytes are vascular endothelial growth factor, prostaglandin E2 , interleukin-1 receptor antagonist and chemokine (C-C motif) ligand 2. The protein family of matrix metalloproteinases is able to degrade all types of extracellular matrix protein, and can process a number of bioactive molecules. Matrix metalloproteinase activities under inflammatory conditions are mostly deregulated and often increased, and those mainly relevant in periodontal disease are matrix metalloproteinases 1, 2, 3, 8, 9, 13 and 24. Viral infection may also influence the epithelial barrier. Studies show that the expression of HIV proteins in the mucosal epithelium is correlated with the disruption of epithelial tight junctions, suggesting a possible enhancement of human papilloma virus infection by HIV-associated disruption of tight junctions. Altered expression of matrix metalloproteinases was demonstrated in keratinocytes transformed with human papilloma virus-16 or papilloma virus-18,. To summarize, the oral epithelium is able to react to a variety of exogenous, possibly noxious influences. PMID- 26252399 TI - Microbial protection and virulence in periodontal tissue as a function of polymicrobial communities: symbiosis and dysbiosis. AB - This review discusses polymicrobial interactions with the host in both health and disease. As our ability to identify specific bacterial clonal types, with respect to their abundance and location in the oral biofilm, improves, we will learn more concerning their contribution to both oral health and disease. Recent studies examining host- bacteria interactions have revealed that commensal bacteria not only protect the host simply by niche occupation, but that bacterial interactions with host tissue can promote the development of proper tissue structure and function. These data indicate that our host-associated polymicrobial communities, such as those found in the oral cavity, co-evolved with us and have become an integral part of who we are. Understanding the microbial community factors that underpin the associations with host tissue that contribute to periodontal health may also reveal how dysbiotic periodontopathic oral communities disrupt normal periodontal tissue functions in disease. A disruption of the oral microbial community creates dysbiosis, either by overgrowth of specific or nonspecific microorganisms or by changes in the local host response where the community can now support a disease state. Dysbiosis provides the link between systemic changes (e.g. diabetes) and exogenous risk factors (e.g. smoking), and the dysbiotic community, and can drive the destruction of periodontal tissue. Many other risk factors associated with periodontal disease, such as stress, aging and genetics, are also likely to affect the microbial community, and more research is needed, utilizing sophisticated bacterial taxonomic techniques, to elucidate these effects on the microbiome and to develop strategies to target the dysbiotic mechanisms and improve periodontal health. PMID- 26252402 TI - Oral keratinocyte stem/progenitor cells: specific markers, molecular signaling pathways and potential uses. AB - Oral keratinocyte stem cells reside in the basal layers of the oral epithelium, representing a minor population of cells with a great potential to self-renew and proliferate over the course of their lifetime. As a result of the potential uses of oral keratinocyte stem cells in regenerative medicine and the key roles they play in tissue homeostasis, inflammatory conditions, wound healing and tumor initiation and progression, intense scientific efforts are currently being undertaken to identify, separate and reprogram these cells. Although currently there is no specific marker that can characterize and isolate oral keratinocyte stem cells, several suggestions have been made. Thus, different stem/progenitor cell subpopulations have been categorized based on combinations of positive and/or negative membrane-surface markers, which include integrins, clusters of differentiation and cytokeratins. Important advances have also been made in understanding the molecular pathways that govern processes such as self-renewal, differentiation, proliferation, wound healing and programmed cell death. A thorough understanding of stem-cell biology and the molecular players that govern cellular fate is paramount in the quest for using stem-cell-derived therapies in the treatment of various oral pathologies. The current review focuses on recent advances in understanding the molecular signaling pathways coordinating the behavior of these cells and in identifying suitable markers used for their isolation and characterization. Special emphasis will also be placed on the roles played by oral keratinocyte stem and progenitor cells in normal and diseased oral tissues and on their potential uses in the fields of general medicine and dentistry. PMID- 26252404 TI - Diverse functions of defensins and other antimicrobial peptides in periodontal tissues. AB - Defensins are antimicrobial peptides that exhibit direct microbicidal activity as well as mediator-like functions by, for example, activating immature dendritic cells. This review focuses on defensins and other antimicrobial peptides that are present in periodontal tissues. Their antimicrobial capacity against periodontal microorganisms, their regulation and their expression profiles during periodontal diseases is discussed. As antimicrobial peptides may possess great potential for new diagnostic, preventive and therapeutic strategies, a better understanding of how antimicrobial peptides are regulated as part of the innate host immune response is crucial. PMID- 26252405 TI - Neutrophil activation and periodontal tissue injury. AB - Neutrophilic polymorphonuclear leukocytes (PMNL) track, engage and eliminate foreign entities, including bacteria, fungi and subcellular particles. PMNL are the major host-cell line involved in the acute response during the early stages of infections, including those in the oral cavity. Rather short lived, they are among the fastest moving cells in the human body and travel great distances only to be immolated after encountering and neutralizing antigens. Although their role as the first line of host defense is well established, their role in chronic granulomatous inflammations, diseases and infections remains poorly understood, and many questions on the activation, motility, bactericidity and termination of PMNL in these conditions remain unanswered. This review aims to summarize our current understanding of the molecular mechanisms of PMNL activation and signaling events. Recent evidence indicates the presence of collateral tissue damage caused by poorly regulated PMNL pursuits of periodontal bacteria. Imbalances between the antigenic challenge and the primary host response may augment periodontal tissue breakdown. Thereafter, orchestrated regulation of the resolution of inflammation fails in the presence of a pathogenic periodontal biofilm. PMID- 26252403 TI - The inflammasome and danger molecule signaling: at the crossroads of inflammation and pathogen persistence in the oral cavity. AB - Inflammasomes are an oligomeric assembly of multiprotein complexes that activate the caspase-1-dependent maturation and the subsequent secretion of inflammatory interleukin-1beta and interleukin-18 cytokines in response to a 'danger signal' in vertebrates. The assessment of their significance continues to grow rapidly as the complex biology of various chronic inflammatory conditions is better dissected. Increasing evidence strongly links inflammasomes and host-derived small 'danger molecule ATP' signaling with the modulation of the host immune response by microbial colonizers as well as with potential altering of the microbiome structure and intermicrobial interactions in the host. All of these factors eventually lead to the destructive chronic inflammatory disease state. In the oral cavity, a highly dynamic and multifaceted interplay takes place between the signaling of endogenous danger molecules and colonizing microbes on the mucosal surfaces. This interaction may redirect the local microenvironment to favor the conversion of the resident microbiome toward pathogenicity. This review outlines the major components of the known inflammasome complexes/mechanisms and highlights their regulation, in particular, by oral microorganisms, in relation to periodontal disease pathology. Better characterization of the cellular and molecular biology of the inflammasome will probably identify important potential therapeutic targets for the treatment and prevention of periodontal disease, as well as for other debilitating chronic diseases. PMID- 26252406 TI - The role of natural killer cells in periodontitis. AB - Periodontitis is the most common chronic inflammatory disease of humans. The microbial etiology of the disease is well documented, as is the major role of the host response in disease pathogenesis. As natural killer cells are one of the most important components of innate immunity against bacteria and viruses, they can be expected to act as major players in the development of the disease. Through direct interaction with periodontal pathogens, natural killer cells produce pro-inflammatory cytokines that subsequently may lead to tissue destruction. Indeed, using a murine periodontitis model, such mechanisms have been shown to be involved in bacterial-induced alveolar bone loss. In the present review we document the available literature and evidence base regarding the origin, biology and characteristics of natural killer cells, and their interactions with periodontal pathogens. The potential role of natural killer cells in periodontal pathogenesis and the mechanisms involved are discussed. PMID- 26252409 TI - T- and B-cell subsets in periodontitis. AB - A large amount of information is available, in the medical literature, on the molecular and immunological mechanisms in which T- and B-cells are involved in the pathogenesis of inflammatory diseases. This review attempts to describe the most important features of the T-cell subsets and their cytokine networks in periodontitis, including the interaction of pathogens with different cell subsets and their gene-expression profiles. Additionally, the known interactions of T- and B-cell subsets in periodontitis are described. The purpose of this article was to provide an overview of the cell interactions and cytokine networks specifically involved in the pathogenesis of periodontitis, and models and paradigms from recent research in this area are presented. However, the review of the literature also revealed that relatively little is known about the genetic or structural factors that confer cross-reactivity of natural and/or autoreactive antibodies in the immunopathogenesis of periodontitis. Pathogens, in turn, are continuously evolving and creating mechanisms to evade immunological reactions controlled and modulated by T- and B-cells. PMID- 26252407 TI - Basic biology and role of interleukin-17 in immunity and inflammation. AB - Interleukin-17 (also known as interleukin-17A) is a key cytokine that links T cell activation to neutrophil mobilization and activation. As such, interleukin 17 can mediate protective innate immunity to pathogens or contribute to the pathogenesis of inflammatory diseases, such as psoriasis and rheumatoid arthritis. This review summarizes the basic biology of interleukin-17 and discusses its emerging role in periodontal disease. The current burden of evidence from human and animal model studies suggests that the net effect of interleukin-17 signaling promotes disease development. In addition to promoting neutrophilic inflammation, interleukin-17 has potent pro-osteoclastogenic effects that are likely to contribute to the pathogenesis of periodontitis, rheumatoid arthritis and other diseases involving bone immunopathology. Systemic treatments with anti-interleukin-17 biologics have shown promising results in clinical trials for psoriasis and rheumatoid arthritis; however, their impact on the highly prevalent periodontal disease has not been investigated or reported. Future clinical trials, preferably using locally administered interleukin-17 blockers, are required to implicate conclusivelyinterleukin-17 in periodontitis and, more importantly, to establish an effective adjunctive treatment for this oral inflammatory disease. PMID- 26252408 TI - Dendritic cells: microbial clearance via autophagy and potential immunobiological consequences for periodontal disease. AB - Dendritic cells are potent antigen-capture and antigen-presenting cells that play a key role in the initiation and regulation of the adaptive immune response. This process of immune homeostasis, as maintained by dendritic cells, is susceptible to dysregulation by certain pathogens during chronic infections. Such dysregulation may lead to disease perpetuation with potentially severe systemic consequences. Here we discuss in detail how intracellular pathogens exploit dendritic cells and escape degradation by altering or evading autophagy. This novel mechanism explains, in part, the chronic, persistent nature observed in several immuno-inflammatory diseases, including periodontal disease. We also propose a hypothetical model of the plausible role of autophagy in the context of periodontal disease. Promotion of autophagy may open new therapeutic strategies in the search of a 'cure' for periodontal disease in humans. PMID- 26252411 TI - Local inflammatory reactions in patients with diabetes and periodontitis. AB - The impact of diabetes mellitus on the prevalence, severity and progression of periodontal disease has been known for many years and intense efforts have been made to elucidate the underlying mechanisms. It is widely reported that hyperglycemia causes numerous systemic changes, including altered innate immune cell function and metabolic changes. The aim of this review was to summarize and discuss the evidence for mechanisms that probably play a role in the altered local inflammatory reactions in the periodontium of patients with diabetes, focusing on local changes in cytokine levels, matrix metalloproteinases, reactive oxygen species, advanced glycation end-products, immune-cell functions, the RANKL/osteoprotegerin axis and toll-like receptors. Apart from the systemic effects of diabetes, recent evidence suggests that local changes in the periodontal tissues are characterized by enhanced interactions between leukocytes and endothelial cells and by altered leukocyte functions [resulting in increased levels of reactive oxygen species and of proinflammatory cytokines (interleukin 1beta, interleukin-6 and tumor necrosis factor-alpha)]. These local changes are amplified by the enhanced accumulation of advanced glycation end-products and their interaction with receptors for advanced glycation end-products. Furthermore, the increased levels of proinflammatory cytokines lead to an up regulation of RANKL in periodontal tissues, stimulating further periodontal tissue breakdown. PMID- 26252410 TI - Mini but mighty: microRNAs in the pathobiology of periodontal disease. AB - MicroRNAs (miRNAs) are a family of small, noncoding RNA molecules that negatively regulate protein expression either by inhibiting initiation of the translation of mRNA or by inducing the degradation of mRNA molecules. Accumulating evidence suggests that miRNA-mediated repression of protein expression is of paramount importance in a broad range of physiologic and pathologic conditions. In particular, miRNA-induced dysregulation of molecular processes involved in inflammatory pathways has been shown to contribute to the development of chronic inflammatory diseases. In this review, first of all we provide an overview of miRNA biogenesis, the main mechanisms of action and the miRNA profiling tools currently available. Then, we summarize the available evidence supporting a specific role for miRNAs in the pathobiology of periodontitis. Based on a review of available data on the differential expression of miRNAs in gingival tissues in states of periodontal health and disease, we address specific roles for miRNAs in molecular and cellular pathways causally linked to periodontitis. Our review points to several lines of evidence suggesting the involvement of miRNAs in periodontal tissue homeostasis and pathology. Although the intricate regulatory networks affected by miRNA function are still incompletely mapped, further utilization of systems biology tools is expected to enhance our understanding of the pathobiology of periodontitis. PMID- 26252413 TI - Merkel cell carcinoma in a patient with GATA2 deficiency: a novel association with primary immunodeficiency. AB - A 55-year-old woman with GATA2 deficiency and neurofibromatosis 1 was diagnosed with Merkel cell carcinoma (MCC). This polyomavirus-associated cutaneous malignancy has previously been associated with immunosuppression and acquired immunodeficiencies such as HIV/AIDS. However, MCC has not been previously reported in the setting of underlying primary or inherited immunodeficiency. PMID- 26252412 TI - Activation and resolution of periodontal inflammation and its systemic impact. AB - Inflammation is a highly organized event impacting upon organs, tissues and biological systems. Periodontal diseases are characterized by dysregulation or dysfunction of resolution pathways of inflammation that results in failure to heal and in a dominant chronic, progressive, destructive and predominantly unresolved inflammation. The biological consequences of inflammatory processes may be independent of the etiological agents, such as trauma, microbial organisms and stress. The impact of the inflammatory pathological process depends upon the tissues or organ system affected. Whilst mediators are similar, there is tissue specificity for the inflammatory events. It is plausible that inflammatory processes in one organ could directly lead to pathologies in another organ or tissue. Communication between distant parts of the body and their inflammatory status is also mediated by common signaling mechanisms mediated via cells and soluble mediators. This review focuses on periodontal inflammation, its systemic associations and advances in therapeutic approaches based on mediators acting through orchestration of natural pathways to resolution of inflammation. We also discuss a new treatment concept in which natural pathways of resolution of periodontal inflammation can be used to limit systemic inflammation and promote healing and regeneration. PMID- 26252414 TI - Depression and anxiety after total joint replacement among older adults: a meta analysis. AB - OBJECTIVE: Patients usually experience good physical recovery after total joint replacement (TJR); however, it is unclear whether mood also improves. The current meta-analysis examined changes in depression and anxiety following TJR in older (>=50 years) patients in order to address this gap in the literature. METHODS: Data from 26 studies (4045 TJR, 55 controls) that assessed depression and/or anxiety pre- and post-surgery in TJR patients, with or without a control group, were analyzed. Prevalence rates and Cohen's d effect sizes were used to evaluate changes in the prevalence and severity of depression/anxiety, respectively. RESULTS: Approximately 23% of TJR patients had clinically significant levels of depression prior to surgery, which decreased to 13% one year later. The prevalence of anxiety could not be evaluated due to the limited available data. TJR patients did not show any clinically meaningful reductions in symptoms of depression or anxiety, following surgery. Compared to controls, there was no difference in symptom progression over time; although only one study examined this. CONCLUSIONS: TJR patients appear to have higher rates of clinically significant symptoms of depression before and after surgery, compared to the general population, however more research with adequate control groups is needed to confirm this. Only a modest improvement in the severity of depression and anxiety symptoms was noted post-surgery. However, existing research is limited; preventing definite conclusions regarding the impact of TJR on mood. PMID- 26252415 TI - K604, a specific acyl-CoA:cholesterol acyltransferase 1 inhibitor, suppresses proliferation of U251-MG glioblastoma cells. AB - Glioblastoma is the most aggressive type of brain tumor and has a poor prognosis. Increased levels of cholesteryl ester and simultaneous expression of acyl CoA:cholesterol acyltransferase 1 (ACAT1) in tumor cells indicated that cholesterol esterification is critical to tumor growth. The present study confirmed that human glioblastoma tissues as well as the glioblastoma cell line U251-MG showed significant expression of ACAT1. ACAT1 expression in U251-MG cells increased in a cell proliferation-dependent manner. K604, a selective ACAT1 inhibitor, suppressed the proliferation of U251-MG cells and downregulated the activation of Akt and extracellular signal-regulated kinase in proliferating glioblastoma cells. These results suggested that ACAT1 may be a therapeutic target for the treatment of glioblastoma, with K604 as an effective therapeutic agent. PMID- 26252416 TI - MicroRNA-29a inhibits mesenchymal stem cell viability and proliferation by targeting Roundabout 1. AB - Secreted Slit glycoproteins and their Roundabout (Robo) receptors have been identified as important axon guidance molecules. The pivotal role of Slit-Robo signaling is in regulating cell proliferation. MicroRNAs (miRNAs), a class of small non-coding RNAs, function as critical regulators of gene expression by binding to the 3'-untranslated region of mRNAs and causing mRNA degradation or translational repression. The present study demonstrated that downregulation of Robo1 using small interfering RNA inhibited mesenchymal stem cell (MSC) proliferation. Additionally, four miRNAs (miR), including miR-218, miR-29a, miR 146 and miR-148, inhibited the protein expression of Robo1 in the MSCs, with miR 29 having the most marked effect. A luciferase reporter assay identified Robo1 as a novel target of miR-29a. Overexpression of miR-29a suppressed the protein expression levels of Robo1 and Slit2 and inhibited the viability and proliferation of the MSCs. By contrast, overexpression of Robo1 partly rescued these inhibitory effects of miR-29a on the MSCs confirming that miR-29a inhibited MSC viability and proliferation, at least partially, by directly targeting Robo1. These results indicated that the miR-29a/Robo1 axis is crucial for the regulation of MSC viability and proliferation, suggesting that miR-29a may serve as a potential clinical target for MSC expansion and stem cell transplantation. PMID- 26252418 TI - In vitro fermentation of lupin seeds (Lupinus albus) and broad beans (Vicia faba): dynamic modulation of the intestinal microbiota and metabolomic output. AB - Broad beans (Vicia faba) and lupin seeds (Lupinus albus) are legumes rich in a wide range of compounds, which may represent a useful dietary approach for modulating the human gut microbiome. In this work, after in vitro digestion, legume samples were used as carbon sources in anaerobic batch cultures to evaluate their impact on the intestinal microbiota composition and on their metabolic products. The fermentations were monitored by a decrease in pH, generation of short chain fatty acids (SCFA) and lactate and the changes in the dynamic bacterial populations by fluorescence in situ hybridization (FISH). The total SCFA at the end of fermentation was 81.52 mM for lupin seeds and 78.41 mM for broad beans accompanied by a decrease of the pH for both legumes. The microbial groups that increased significantly (P < 0.05) were Bifidobacterium spp., Lactobacillus-Enterococcus, Atopobium, Bacteroides-Pretovella, Clostridium coccoides-Eubacterium rectale, Faecalibacterium prausnitzii and Roseburia intestinalis. This impact on the intestinal microbiota suggests that lupin seeds and broad beans may be used in the development of novel functional foods, which can be included in dietary strategies for human health promotion. PMID- 26252419 TI - Take Pax6 for a Cortical 6-Pack. AB - This synopsis examines the implications of a new study that imposes primate-like expression of the transcription factor Pax6 on the developing mouse cortex and finds evidence of primate-like proliferation of neuronal progenitors. PMID- 26252417 TI - Determinants of sugar-sweetened beverage consumption in young children: a systematic review. AB - Sugar-sweetened beverage (SSB) consumption is associated with adverse health outcomes. Improved understanding of the determinants will inform effective interventions to reduce SSB consumption. A total of 46,876 papers were identified through searching eight electronic databases. Evidence from intervention (n = 13), prospective (n = 6) and cross-sectional (n = 25) studies on correlates/determinants of SSB consumption was quality assessed and synthesized. Twelve correlates/determinants were associated with higher SSB consumption (child's preference for SSBs, TV viewing/screen time and snack consumption; parents' lower socioeconomic status, lower age, SSB consumption, formula milk feeding, early introduction of solids, using food as rewards, parental-perceived barriers, attending out-of-home care and living near a fast food/convenience store). Five correlates/determinants were associated with lower SSB consumption (parental positive modelling, parents' married/co-habiting, school nutrition policy, staff skills and supermarket nearby). There was equivocal evidence for child's age and knowledge, parental knowledge, skills, rules/restrictions and home SSB availability. Eight intervention studies targeted multi-level (child, parents, childcare/preschool setting) determinants; four were effective. Four intervention studies targeted parental determinants; two were effective. One (effective) intervention targeted the preschool environment. There is consistent evidence to support potentially modifiable correlates/determinants of SSB consumption in young children acting at parental (modelling), child (TV viewing) and environmental (school policy) levels. PMID- 26252420 TI - The Demand-Induced Strain Compensation Questionnaire: A Cross-national Validation Study. AB - The demand-induced strain compensation model is a theoretical job stress model that has been tested in different kinds of empirical study in several countries. To measure key concepts in the model (job demands and job resources), the demand induced strain compensation questionnaire (DISQ) was developed and has been used in many empirical studies. However, most studies neither focused on the psychometric properties of the DISQ nor tested it cross-nationally. In this study, we examined the psychometric properties of the DISQ tested on Italian (n = 422) and Dutch (n = 1629) employees. Results indicated that the six-factor model, consisting of cognitive, emotional and physical job demands as well as cognitive, emotional and physical job resources, provided a better fit to the data than an alternative two-factor model (demands and resources only). Findings were invariant across Italian and Dutch samples. Internal consistencies were satisfactory. Additionally, the six dimensions of DISQ were found to be meaningfully related to employee active learning behaviour, emotional exhaustion and musculoskeletal disorders. Results suggest the DISQ questionnaire is a valid and reliable instrument to measure the proposed dimensions of job demands and job resources in both Italian and Dutch work contexts. PMID- 26252421 TI - A fluorescent turn-on H2S-responsive probe: design, synthesis and application. AB - Hydrogen sulfide (H2S) is considered as the third signaling molecule in vivo and it plays an important role in various physiological processes and pathological processes in vivo, such as vasodilation, apoptosis, neurotransmission, ischemia/reperfusion-induced injury, insulin secretion and inflammation. Developing a highly selective and sensitive method that can detect H2S in the biological system is very important. In this work, a colorimetric and "turn-on" fluorescent probe is developed. Furthermore, this probe displays a highly selective response to H2S in aqueous solution and possesses good capability for bioimaging H2S without interference in living cells. The results suggest that a H2S-selective probe has good water-solubility, biocompatibility and cell penetrability and can serve as an efficient tool for probing H2S in the cell level. PMID- 26252422 TI - Crumpling deformation regimes of monolayer graphene on substrate: a molecular mechanics study. AB - Experiments and simulations demonstrating reversible and repeatable crumpling of graphene warrant a detailed understanding of the underlying mechanisms of graphene crumple formation, especially for design of tailored nanostructures. To systematically study the formation of crumples in graphene, we use a simple molecular dynamics model, and perform a series of simulations to characterize the finite number of deformation regimes of graphene on substrate after compression. We formulate a quantitative measure of predicting these deformations based on observed results of the simulations and distinguish graphene crumpling considered in this study from others. In our study, graphene is placed on a model substrate while controlling and varying the interfacial energy between graphene and substrate and the substrate roughness through a set of particles embedded in the substrate. We find that a critical value of interfacial adhesion energy marks a transition point that separates two deformation regimes of graphene on substrate under uniaxial compression. The interface between graphene and substrate plays a major role in the formation of crumples, and we show that the choice of substrate can help in designing desired topologies in graphene. PMID- 26252424 TI - Prevalence of hepatitis B markers in Senegalese HIV-1-infected patients. AB - The study aimed to estimate the prevalence of Hepatitis B virus (HBV) infection and to describe the HBV virological profiles among Senegalese HIV-1-infected patients. We conducted a retrospective study between 2006 and 2010 among Senegalese HIV-1-infected patients from the antiretroviral therapy cohort. Samples were screened using Determine((r)) HBsAg or MONOLISA((r)) POC test. The HBsAg positivity status was confirmed by Architect((r)) HBsAg. Detection of HBeAg, anti-HBe Ab, and HBV DNA load were done for the HBsAg-positive samples. Then, Anti-HBcAb was tested for the HBsAg-negative samples. Microsoft Excel was used for data collection and statistical analyses were performed using Epi info 3.5.1. Overall, 466 HIV-infected patients were enrolled including 271 women (58.4%), and 193 men (41.6%) with a median age of 39 years (19-74 years). The global prevalence of HIV/HBV coinfection (HBsAg positive) was 8.8% (41/466). For HBsAg positives samples, the prevalence of HBeAg and the anti-HBeAb were, respectively, 24.4 and 69.2% and the median of HBV DNA viral load, for 27 HBsAg positive samples, was 3.75 log10 copies/ml. The virological profiles were the following: 7, 15, and 5 patients infected, respectively, by a replicative virus, an inactive virus and a probably mutant virus. For HBsAg-negative samples, 83 out of 109 were positive for anti-HBcAb. This study showed a significant decrease of the prevalence of HBV/HIV coinfection between 2004 and 2014 (P = 0.003), which highlighted the performance of the Senegalese HBV vaccine program. However, implementing a systematic quantification of HBV DNA viral load could improve the monitoring of HBV-infected patient. PMID- 26252425 TI - Accelerated fracture healing in transgenic mice overexpressing an anabolic isoform of fibroblast growth factor 2. AB - The effect of targeted expression of an anabolic isoform of basic fibroblast growth factor (FGF2) in osteoblastic lineage on tibial fracture healing was assessed in mice. Closed fracture of the tibiae was performed in Col3.6-18 kDaFgf2-IRES-GFPsaph mice in which a 3.6 kb fragment of type I collagen promoter (Col3.6) drives the expression of only the 18 kD isoform of FGF2 (18 kDaFgf2/LMW) with green fluorescent protein-sapphire (GFPsaph) as well as Vector mice (Col3.6 IRES-GFPsaph, Vector) that did not harbor the FGF2 transgene. Radiographic, micro CT, DEXA, and histologic analysis of fracture healing of tibiae harvested at 3, 10 and 20 days showed a smaller fracture callus but accelerated fracture healing in LMWTg compared with Vector mice. At post fracture day 3, FGF receptor 3 and Sox 9 mRNA were significantly increased in LMWTg compared with Vector. Accelerated fracture healing was associated with higher FGF receptor 1, platelet derived growth factors B, C, and D, type X collagen, vascular endothelial cell growth factor, matrix metalloproteinase 9, tartrate resistant acid phosphatase, cathepsin K, runt-related transcription factor-2, Osterix and Osteocalcin and lower Sox9, and type II collagen expression at 10 days post fracture. We postulate that overexpression of LMW FGF2 accelerated the fracture healing process due to its effects on factors that are important in chondrocyte and osteoblast differentiation and vascular invasion. PMID- 26252423 TI - Sequencing of 15 622 gene-bearing BACs clarifies the gene-dense regions of the barley genome. AB - Barley (Hordeum vulgare L.) possesses a large and highly repetitive genome of 5.1 Gb that has hindered the development of a complete sequence. In 2012, the International Barley Sequencing Consortium released a resource integrating whole genome shotgun sequences with a physical and genetic framework. However, because only 6278 bacterial artificial chromosome (BACs) in the physical map were sequenced, fine structure was limited. To gain access to the gene-containing portion of the barley genome at high resolution, we identified and sequenced 15 622 BACs representing the minimal tiling path of 72 052 physical-mapped gene bearing BACs. This generated ~1.7 Gb of genomic sequence containing an estimated 2/3 of all Morex barley genes. Exploration of these sequenced BACs revealed that although distal ends of chromosomes contain most of the gene-enriched BACs and are characterized by high recombination rates, there are also gene-dense regions with suppressed recombination. We made use of published map-anchored sequence data from Aegilops tauschii to develop a synteny viewer between barley and the ancestor of the wheat D-genome. Except for some notable inversions, there is a high level of collinearity between the two species. The software HarvEST:Barley provides facile access to BAC sequences and their annotations, along with the barley-Ae. tauschii synteny viewer. These BAC sequences constitute a resource to improve the efficiency of marker development, map-based cloning, and comparative genomics in barley and related crops. Additional knowledge about regions of the barley genome that are gene-dense but low recombination is particularly relevant. PMID- 26252427 TI - Body Mass-Related Predictors of the Female Athlete Triad Among Adolescent Athletes. AB - Early detection of the female athlete triad is essential for the long-term health of adolescent female athletes. The purpose of this study was to assess relationships between common anthropometric markers (ideal body weight [IBW] via the Hamwi formula, youth-percentile body mass index [BMI], adult BMI categories, and body fat percentage [BF%]) and triad components, (low energy availability [EA], measured by dietary restraint [DR], menstrual dysfunction [MD], low bone mineral density [BMD]). In the sample (n = 320) of adolescent female athletes (age 15.9+/- 1.2 y), Spearman's rho correlations and multiple logistic regression analyses evaluated associations between anthropometric clinical cutoffs and triad components. All underweight categories for the anthropometric measures predicted greater likelihood of MD and low BMD. Athletes with an IBW >85% were nearly 4 times more likely to report MD (OR = 3.7, 95% CI [1.8, 7.9]) and had low BMD (OR = 4.1, 95% CI [1.2, 14.2]). Those in <5th percentile for their age-specific BMI were 9 times more likely to report MD (OR 9.1, 95% CI [1.8, 46.9]) and had low BMD than those in the 50th to 85th percentile. Athletes with a high BF% were almost 3 times more likely to report DR (OR = 2.8, 95% CI [1.4, 6.1]). Our study indicates that low age-adjusted BMI and low IBW may serve as evidence-based clinical indicators that may be practically evaluated in the field, predicting MD and low BMD in adolescents. These measures should be tested for their ability as tools to minimize the risk for the triad. PMID- 26252426 TI - Disappearing liver metastases from colorectal cancer: impact of modern imaging modalities. AB - BACKGROUND: Chemotherapy is often used before a resection for colorectal liver metastases. After chemotherapy, metastases may disappear on cross-sectional imaging but residual metastatic disease may still exist. The aim of this retrospective study was to investigate the impact of new advancements in imaging technology such as magnetic resonance imaging (MRI) with liver-specific contrast (Gd-EOB-DTPA) and contrast-enhanced intra-operative ultrasound (CE-IOUS) on disappearing liver metastases (DLM). METHODS: Twenty-nine patients with one or more DLM undergoing surgical exploration were included. Pre-operative imaging consisted of contrast-enhanced multi-detector computed tomography (MDCT) and/or MRI with liver-specific contrast. At surgery, CE-IOUS was used when tumours known from pre-chemotherapy imaging were not found by inspection or intra-operative ultrasound. RESULTS: Patients presented 66 DLM. At surgical exploration, 42 DLM were identified and treated (64%). CE-IOUS detected one additional DLM not found by intra-operative ultrasound. For metastases <=10 mm on histological analysis, imaging sensitivities for MRI and MDCT before surgery but after chemotherapy were 26/49 (53%) and 24/66 (36%), respectively. CONCLUSION: A majority of DLM are identified during surgery using intra-operative ultrasound, with only little additional value of CE-IOUS. The sensitivities of post-chemotherapy imaging modalities for small metastases are low in the setting of DLM. For surgical planning, an optimized pre-chemotherapy imaging is essential. PMID- 26252428 TI - Brain signatures of perceiving a smile: Time course and source localization. AB - Facial happiness is consistently recognized faster than other expressions of emotion. In this study, to determine when and where in the brain such a recognition advantage develops, EEG activity during an expression categorization task was subjected to temporospatial PCA analysis and LAURA source localizations. Happy, angry, and neutral faces were presented either in whole or bottom-half format (with the mouth region visible). The comparison of part- versus whole-face conditions served to examine the role of the smile. Two neural signatures underlying the happy face advantage emerged. One peaked around 140 ms (left N140) and was source-located at the left IT cortex (MTG), with greater activity for happy versus non-happy faces in both whole and bottom-half face format. This suggests an enhanced perceptual encoding mechanism for salient smiles. The other peaked around 370 ms (P3b and N3) and was located at the right IT (FG) and dorsal cingulate (CC) cortices, with greater activity specifically for bottom-half happy versus non-happy faces. This suggests an enhanced recruitment of face-specific information to categorize (or reconstruct) facial happiness from diagnostic smiling mouths. Additional differential brain responses revealed a specific "anger effect," with greater activity for angry versus non-angry expressions (right N170 and P230; right pSTS and IPL); and a coarse "emotion effect," with greater activity for happy and angry versus neutral expressions (anterior P2 and posterior N170; vmPFC and right IFG). PMID- 26252429 TI - Molecular dynamics simulations and NMR spectroscopy studies of trehalose-lipid bilayer systems. AB - The disaccharide trehalose (TRH) strongly affects the physical properties of lipid bilayers. We investigate interactions between lipid membranes formed by 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and TRH using NMR spectroscopy and molecular dynamics (MD) computer simulations. We compare dipolar couplings derived from DMPC/TRH trajectories with those determined (i) experimentally in TRH using conventional high-resolution NMR in a weakly ordered solvent (bicelles), and (ii) by solid-state NMR in multilamellar vesicles (MLV) formed by DMPC. Analysis of the experimental and MD-derived couplings in DMPC indicated that the force field used in the simulations reasonably well describes the experimental results with the exception for the glycerol fragment that exhibits significant deviations. The signs of dipolar couplings, not available from the experiments on highly ordered systems, were determined from the trajectory analysis. The crucial step in the analysis of residual dipolar couplings (RDCs) in TRH determined in a bicelle-environment was access to the conformational distributions derived from the MD trajectory. Furthermore, the conformational behavior of TRH, investigated by J-couplings, in the ordered and isotropic phases is essentially identical, indicating that the general assumptions in the analyses of RDCs are well founded. PMID- 26252431 TI - CLIPing Staufen to secondary RNA structures: size and location matter! AB - hiCLIP (RNA hybrid and individual-nucleotide resolution ultraviolet cross-linking and immunoprecipitation), is a novel technique developed by Sugimoto et al. (2015). Here, the use of different adaptors permits a controlled ligation of the two strands of a RNA duplex allowing the identification of each arm in the duplex upon sequencing. The authors chose a notoriously difficult to study double stranded RNA-binding protein (dsRBP) termed Staufen1, a mammalian homolog of Drosophila Staufen involved in mRNA localization and translational control. Using hiCLIP, they discovered a dominance of intramolecular RNA duplexes compared to the total RNA duplexes identified. Importantly, the authors discovered two different types of intramolecular duplexes in the cell: highly translated mRNAs with long-range duplexes in their 3'-UTRs and poorly translated mRNAs with duplexes in their coding region. In conclusion, the authors establish hiCLIP as an important novel technique for the identification of RNA secondary structures that serve as in vivo binding sites for dsRBPs. PMID- 26252430 TI - Protective effect of neutralizing anti-IL-18alpha monoclonal antibody on a mouse model of acute graft-versus-host disease. AB - Graft-versus-host disease (GVHD) is a devastating complication of hematopoietic stem cell transplantation (HSCT), and is characterized by systemic inflammation and tissue damage in multiple organs, such as the liver and small intestine. Interleukin-18 (IL-18), an important pro-inflammatory cytokine, is elevated during the course of acute GVHD (aGVHD), and is associated with the severe clinical manifestations of the disease. The biological activity of IL-18 is based on its interaction with the IL-18 receptor (IL-18R) expressed in a variety of cells. The aim of this study was to assess whether blocking the interaction of IL 18 with IL-18R by the anti-IL-18Ralpha antibody could attenuate the severity of aGVHD. We used a well-established mouse bone marrow transplantation (BMT) model (B6->BALB/c) to block the IL-18/IL-18R interaction by a neutralizing monoclonal antibody (mAb) against murine IL-18Ralpha. Administration of anti-IL-18Ralpha mAb had a significant protective effect on the clinical and pathologic manifestations of aGVHD, resulting in a markedly improved survival rate, modified inflammatory response and decreased tissue damage. Interfering with IL-18/IL-18R interaction affected levels of Th1, Th2 and Th17 subsets in the peripheral blood of the aGVHD animals. Additionally, it led to decreased tissue expression of IL-18 and apoptosis-associated molecules (Fas and FasL), and lower phosphorylation levels of p38MAPK in the liver and small intestine. These changes coincided with the decrease in cell apoptosis in aGVHD target organs. Thus, anti-IL-18Ralpha therapy may, therefore, represent a new therapeutic interference approach for treating aGVHD. PMID- 26252432 TI - The expression of microvesicles in the blood of patients with Graves' disease and its relationship to treatment. AB - OBJECTIVE: Graves' disease (GD) is an autoimmune disease characterized by the presence of circulating autoantibodies against thyroid-stimulating hormone (TSH) receptor. Despite extensive research, the pathogenic mechanisms remain unclear. Immune responses associated with the disease may lead to cell activation/apoptosis and the release of microvesicles (MVs) into the circulation. MVs can display biological activities which may aggravate GD further. We studied immune mechanisms in GD by investigating the numbers and phenotype of circulating MVs in patients before and after antithyroid therapy with thiamazole. PATIENTS AND MEASUREMENTS: Samples were obtained from 15 patients with GD in the acute phase of hyperthyroidism and following 17-26 months treatment and 14 healthy controls. MVs from platelets, endothelial cells and monocytes exposing inflammation/activation markers (P-selectin, CD40 ligand, E-selectin and HMGB1) and MVs containing nuclear molecules were measured with flow cytometry. RESULTS: Patients had elevated baseline values of MVs (P < 0.001 for all types of MVs), while the levels decreased during thiamazole treatment (P < 0.05 for all types of MVs). The majority of MV populations remained, however, significantly higher in patients after treatment compared to levels in controls. CONCLUSIONS: GD patients have elevated levels of MVs that carry molecules with potential biological activities. MVs are significantly reduced after antithyroid treatment with thiamazole but still higher compared to levels in healthy controls. Assessment of MV levels and pattern may therefore provide additional information on underlying immune disturbances not obtained by measurements of hormone levels alone. PMID- 26252433 TI - Influence of Acute Kidney Injury Defined by the Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease Score on the Clinical Course of PICU Patients. AB - OBJECTIVE: To evaluate the predictive value of the pediatric-modified Risk, Injury, Failure, Loss, End-stage renal disease criteria for disease course severity in patients with or without acute kidney injury admitted to a PICU. DESIGN: Retrospective cohort study. SETTING: A 12-bed PICU at a tertiary referral center in Southern Brazil. PATIENTS: All patients admitted to the study unit over a 1-year period. INTERVENTIONS: A database of all eligible patients was analyzed retrospectively. MEASUREMENTS AND MAIN RESULTS: Patients were classified by pediatric-modified Risk, Injury, Failure, Loss, End-stage renal disease score at admission and worst pediatric-modified Risk, Injury, Failure, Loss, End-stage renal disease score during PICU hospitalization. The outcomes of interest were length of PICU stay, duration of mechanical ventilation, duration of vasoactive drug therapy, and mortality. The Pediatric Index of Mortality 2 was used to assess overall disease severity at the time of PICU admission. Of 375 patients, 169 (45%) presented acute kidney injury at the time of admission and 37 developed acute kidney injury during PICU stay, for a total of 206 of 375 patients (55%) diagnosed with acute kidney injury during the study period. The median Pediatric Index of Mortality 2 score predicted a mortality rate of 9% among non-acute kidney injury patients versus a mortality rate of 16% among acute kidney injury patients (p = 0.006). The mortality of patients classified as pediatric-modified Risk, Injury, Failure, Loss, End-stage renal disease F was double that predicted by Pediatric Index of Mortality 2 (7 vs 3.2). Patients classified as having severe acute kidney injury (pediatric-modified Risk, Injury, Failure, Loss, End stage renal disease I + F) exhibited higher mortality (14.1%; p = 0.001) and prolonged PICU length of stay (median, 7 d; p = 0.001) when compared with other patients. Acute kidney injury is a very frequent occurrence among patients admitted to PICUs. CONCLUSIONS: The degree of acute kidney injury severity, as assessed by the pediatric-modified Risk, Injury, Failure, Loss, End-stage renal disease criteria, is a good predictor of morbidity and mortality in this population. Pediatric Index of Mortality 2 tends to underestimate mortality in pediatric patients with severe acute kidney injury. PMID- 26252434 TI - Surface confined self-assembly of polyampholytes generated from charge-shifting polymers. AB - Polyampholyte-based films can be efficiently self-assembled onto a surface in a one-pot manner. By using a gradient of protons, morphogens, generated at an electrode surface, a charge-shifting polyelectrolyte present in solution can be transformed into a polyampholyte, leading to the continuous buildup of a film based on polyelectrolyte complexation. PMID- 26252435 TI - Head and Neck Cancer and Sexuality: A Review of the Literature. AB - BACKGROUND: Individuals treated for head and neck cancer are at risk of sexual problems, particularly given the probability for disfigurement, body image disturbance, depressive symptoms, and functional difficulties that result from treatment. Because oncology nurses are an important source of information and support for patients, it is important that they be familiar with the current literature as well as opportunities for research. OBJECTIVE: The aim of this study was to present a review of the literature on head and neck cancer and sexuality. METHODS: PubMed, PsycINFO, CINAHL, and Ovid databases were searched using the terms "head and neck cancer" and "sexuality." Publications had to be peer-reviewed, empirical studies, written in English, and published within the last 10 years. Selected publications were compared based on study aims, leading investigator, study location, conceptual framework, study design, sample, instruments, and study findings. RESULTS: Nine publications were analyzed in this review. Incidence of individuals reporting a negative effect of head and neck cancer on sexuality varied from 24% to 100% depending on the study. CONCLUSIONS: There is a paucity of data regarding sexuality among patients with head and neck cancer. Existing studies indicate that sexuality is of considerable significance, particularly after treatment for head and neck cancer. IMPLICATIONS FOR PRACTICE: Holistic care includes information about sexuality during and after treatment for head and neck cancer. Oncology nurses should be aware that this topic is of importance to many patients, and they should familiarize themselves with available resources. It is also important that nurse scientists facilitate research in the area of sexuality. PMID- 26252437 TI - Inorganic and methylated thioarsenates pass the gastrointestinal barrier. AB - Arsenic forms different species that are toxic for humans. Toxicity to internal organs is, however, only relevant if the respective species passes the gastrointestinal barrier. Thioarsenates were known to be produced by gut microbiota and to be toxic to bladder and liver cells, but their intestinal transport was largely unknown. Using a Caco-2 cell model, we show here that dimethylmonothioarsenate has the highest cellular retention and intestinal transport of all methylated species. Mono- and trithioarsenate show little cellular retention like arsenate, but their intestinal transport is much higher than that of arsenate; for trithioarsenate, it is almost as high as that for arsenite. The transport of all thioarsenates increases in the absence of phosphate. With the present study, we link previous reports of thioarsenate formation and toxicity by proving their bioavailability and confirm the relevance of their consideration in As risk assessments. PMID- 26252436 TI - A Systematic Review of the Symptom Distress Scale in Advanced Cancer Studies. AB - BACKGROUND: The 13-item Symptom Distress Scale (SDS) is a widely used symptom measurement tool, yet a systematic review summarizing the symptom knowledge generated from its use in patients with advanced cancer is nonexistent. OBJECTIVES: This was a systematic review of the research literature in which investigators utilized the SDS as the measure of symptoms in patients with advanced cancer. METHODS: We searched PubMed, CINAHL, EMBASE, and Web of Science for primary research studies published between 1978 and 2013 that utilized the SDS as the measurement tool in patients with advanced cancer. Nine hundred eighteen documents were found. Applying inclusion/exclusion criteria, 21 articles and 2 dissertations were included. RESULTS: The majority of investigators utilized descriptive, cross-sectional research designs conducted with convenience samples. Inconsistent reporting of SDS total scores, individual item scores, age ranges and means, gender distributions, cancer types, cancer stages, and psychometric properties made comparisons difficult. Available mean SDS scores ranged from 17.6 to 38.8. Reports of internal consistency ranged from 0.67 to 0.88. Weighted means indicated fatigue to be the most prevalent and distressing symptom. Appetite ranked higher than pain intensity and pain frequency. CONCLUSIONS: The SDS captures the patient's symptom experience in a manner that informs the researcher or clinician about the severity of the respondents' reported symptom distress. IMPLICATIONS FOR PRACTICE: The SDS is widely used in a variety of cancer diagnoses. The SDS is a tool clinicians can use to assess 11 symptoms experienced by patients with advanced cancer. PMID- 26252438 TI - Asenapine in the Treatment of Acute Mania: A Real-World Observational Study With 6 Months Follow-Up. AB - Asenapine is a second-generation antipsychotic with a unique pharmacological profile that was recently approved for the treatment of moderate/severe manic episodes. Real-world data on rapidity of action in inpatient settings are lacking.The aims of the current real-world observational study were to evaluate: (i) short-term efficacy of asenapine after 7 days (T0-T1) in patients hospitalized for a manic episode in the course of bipolar I disorder or schizoaffective disorder (group A), (ii) differences in length of stay (LoS), and (iii) rehospitalization compared to a control population (group B) with a 6-month follow-up.Twenty patients were included in each group. The mean total Young Mania Rating Scale score decreased by 12.6 (SD +/-10.3; t(17) = 5.2, P < 0.005), implying a mean 37.8% improvement. A statistically significant reduction was observed for all Young Mania Rating Scale items, except for "sexual interest." The mean total BPRS score decreased by 17.2 (SD +/-14.9; t(17) = 4.9, P < 0.005). A statistically significant reduction was observed for several items, including "conceptual disorganization," "grandiosity," "unusual thought content," and "excitement". Length of stay was 17.9 (SD +/-9.0) days for group A and 14.7 (SD +/-12.7) days for group B; the result of the Kruskal-Wallis test showed no significant differences (chi = 2.199, P = 0.138). Despite a high discontinuation rate, only 17.7% of patients in group A were rehospitalized in the following 6 months compared to 41.2% of those in group B (relative risk = 0.43, 95% confidence interval, 0.13-1.39).Findings from this small, preliminary study at least partially support the results of previous trials, confirming effectiveness and tolerability in the context of comorbidity and polypsychopharmacology. PMID- 26252439 TI - Acute Laryngeal Dystonia With Novel Antipsychotics: A Case Report and Review of Literature. PMID- 26252440 TI - Schizophreniform Psychosis During Treatment With Alitretinoin. PMID- 26252441 TI - Piracetam for Sialorrhea in 2 Children With Intellectual Disability. PMID- 26252442 TI - Food-grade micro-encapsulation systems that may induce satiety via delayed lipolysis: A review. AB - The increasing prevalence of overweight and obesity requires new, effective prevention and treatment strategies. One approach to reduce energy intake is by developing novel foods with increased satiating properties, which may be accomplished by slowing down lipolysis to deliver substrates to the ileum, thereby enhancing natural gut-brain signaling pathways of satiety that are normally induced by meal intake. To develop slow release food additives, their processing in the gastrointestinal tract has to be understood; therefore, we start from a general description of the digestive system and relate that to in vitro modeling, satiety, and lipolytic mechanisms. The effects of physicochemical lipid composition, encapsulation matrix, and interfacial structure on lipolysis are emphasized. We give an overview of techniques and materials used, and discuss partitioning, which may be a key factor for encapsulation performance. Targeted release capsules that delay lipolysis form a real challenge because of the high efficiency of the digestive system; hardly any proof was found that intact orally ingested lipids can be released in the ileum and thereby induce satiety. We expect that this challenge could be tackled with structured o/w-emulsion-based systems that have some protection against lipase, e.g., by hindering bile salt adsorption and/or delaying lipase diffusion. PMID- 26252443 TI - Perylene Derivatives As Useful SERRS Reporters, Including Multiplexing Analysis. AB - Five perylene bisimide (PBI) derivatives were designed and synthesized, on the basis of quantum-chemical calculations. The influence of halogen substituents on the shape and energy of the frontier orbitals and the Raman spectra were calculated, in the prospect use in surface-enhanced resonance Raman scattering (SERRS) studies. The corresponding experiments confirmed a very strong SERRS response in the presence of pristine (i.e., uncoated) gold nanoparticles. These spectra can be used for multiplexing measurements, namely measurements in which, by using a single laser excitation, one can recognize the simultaneous presence of several analytes. PMID- 26252444 TI - Three-Dimensional Networked Nanoporous Ta2O(5-x) Memory System for Ultrahigh Density Storage. AB - Oxide-based resistive memory systems have high near-term promise for use in nonvolatile memory. Here we introduce a memory system employing a three dimensional (3D) networked nanoporous (NP) Ta2O5-x structure and graphene for ultrahigh density storage. The devices exhibit a self-embedded highly nonlinear I V switching behavior with an extremely low leakage current (on the order of pA) and good endurance. Calculations indicated that this memory architecture could be scaled up to a ~162 Gbit crossbar array without the need for selectors or diodes normally used in crossbar arrays. In addition, we demonstrate that the voltage point for a minimum current is systematically controlled by the applied set voltage, thereby offering a broad range of switching characteristics. The potential switching mechanism is suggested based upon the transformation from Schottky to Ohmic-like contacts, and vice versa, depending on the movement of oxygen vacancies at the interfaces induced by the voltage polarity, and the formation of oxygen ions in the pores by the electric field. PMID- 26252445 TI - Acceptance of the 2015 Clark P. Read Mentor Award: Mentoring--Perspectives from Both the Mentee and Mentor Sides of the Desk. PMID- 26252446 TI - Stretchable and Conductive Polymer Films Prepared by Solution Blending. AB - Stretchable and conductive materials can have important application in many areas, such as wearable electronics and healthcare devices. Conducting polymers have very limited elasticity because of their rigid conjugated backbone. In this work, highly stretchable and conductive polymer films are prepared by coating or casting aqueous solution of poly(3,4-ethylenedioxythiophene):polystyrenesulfonate ( PEDOT: PSS) and a soft polymer, including poly(ethylene glycol), poly(ethylene oxide), or poly(vinyl alcohol). The soft polymers can greatly improve the stretchability and the conductivity of PEDOT: PSS. The elongation at break can be increased from 2% up to 55%. The soft polymers can also enhance the conductivity of PEDOT: PSS from 0.2 up to 75 S cm(-1). The conductivity is further enhanced by adding dimethyl sulfoxide (DMSO) or ethylene glycol (EG) into the aqueous solutions of the polymer blends. Polymer blends with an elongation at break of close to 50% and a conductivity of 172 S cm(-1) are attained. PMID- 26252447 TI - Expression of microRNA-26b and identification of its target gene EphA2 in pituitary tissues in Yanbian cattle. AB - microRNAs (miRNAs/miRs) are a class of single-stranded non-coding RNA molecules of 19-24 nucleotides (nt) in length. They are widely expressed in animals, plants, bacteria and viruses. Via specific mRNA complementary pairing of target genes, miRNAs are able to regulate the expression of mRNA levels or inhibit protein translation following transcription. miRNA expression has a time- and space specificity, and it is involved in cell proliferation and differentiation, apoptosis, development, tumor metastasis occurrence and other biological processes. miR-26b is an miRNA of 22 nt and is important in the regulation of cellular processes. With the advancement of molecular biology techniques in recent years, there have been extensive investigations into miR-26b. Numerous studies have observed that miR-26b is involved in early embryonic development, cell proliferation regulation, pituitary hormone secretion and other physiological activities. miRNAs are associated with the function of propagation. The present study used reverse transcription quantitative polymerase chain reaction to detect the relative expression levels of miR-26b in the pituitary tissue of Yanbian cattle at different developmental stages. The 2-??Ct method was used to calculate the relative gene expression levels. The miRNA target gene database TargetScan and RNA22 were used for prediction of the miR-26b target gene and selective recognition was also performed. The results demonstrated that miR 26b is expressed in the pituitary tissues of Yanbian cattle at 6 and 24 months of age. The relative expression levels of miR-26b in the pituitary tissues of 24 month-old Yanbian cattle were 2.41 times that of those in the six-month-old Yanbian cattle, demonstrating significant differences in the relative expression (P<0.01). The relative expression of the candidate target genes, EphA2 and miR 26b, exhibited the opposite expression pattern. The relative expression levels in the pituitary tissues of six-month-old Yanbian cattle were 3.34 times that of those in 24-month-old Yanbian cattle (P<0.01). There are miR-26b binding sites in the 3'-untranslated region (3'-UTR) of EphA2 in bovine, human, murine and other mammalian mRNAs, suggesting that the EphA2 gene may be a target gene of miR-26b. The results of a Luciferase reporter system assay revealed that miR-26b is able to suppress EphA2 expression at the transcription level. Following the site directed mutagenesis of plasmid EphA2 3'-UTR pmirGLO-MUT- and miR-26b mimic transfected HeLa cells, the dual-luciferase reporter gene assay revealed that there were three consecutive nucleotide mutations in the 3'-UTR, binding with the predicted seed region. This may have caused the miR-26b inhibition of luciferase activity to decrease from 60% in the wild-type to 26%, suggesting that miR-26b achieved its function via binding with the TACTTGAA sequence of the 3'-UTR in EphA2. In conclusion, the present study successfully assessed the expression pattern of miR-26b in the pituitary tissue of Yanbian cattle, and also confirmed that EphA2 was a target gene of miR-26b in Yanbian cattle in vitro. The present study provided the theoretical basis to further investigate the role of miR-26b in early embryonic development, pituitary hormone secretion and other reproductive functions. PMID- 26252448 TI - Novel kinetochore function of Topoisomerase IIalpha. PMID- 26252450 TI - Letter to the Editor: Respecting the Plurality of Value and the Messiness of Scientific Practice. AB - Evaluations of authorship and recommendations for authorship policies best heed the plurality of valuation cultures that traverse scientific practices and respect the messiness of scientific practices, for those are reflected in authorship and authorship sequence decisions. PMID- 26252449 TI - Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression. AB - Several studies have described phenotypic changes in the offspring of mice exposed to a variety of environmental factors, including diet, toxins, and stress; however, the molecular pathways involved in these changes remain unclear. Using a high fat diet (HFD)-induced obesity mouse model, we examined liver gene expression in male offspring and analyzed chromatin of paternal spermatozoa. We found that the hepatic mRNA level of 7 genes (out of 20 evaluated) was significantly altered in HFD male offspring compared to control mice, suggesting that phenotypic changes in the offspring depend on parental diet. We examined 7 imprinted loci in spermatozoa DNA from HFD-treated and control fathers by bisulfite sequencing, but did not detect changes in DNA methylation associated with HFD. Using chromatin immunoprecipitation followed by high-throughput sequencing, we found differential histone H3-occupancy at genes involved in the regulation of embryogenesis and differential H3K4me1-enrichment at transcription regulatory genes in HFD fathers vs. control mice. These results suggest that dietary exposure can modulate histone composition at regulatory genes implicated in developmental processes. PMID- 26252452 TI - Higher dose rate Gamma Knife radiosurgery may provide earlier and longer-lasting pain relief for patients with trigeminal neuralgia. AB - OBJECT: Gamma Knife radiosurgery (GKRS) utilizes cobalt-60 as its radiation source, and thus dose rate varies as the fixed source decays over its half-life of approximately 5.26 years. This natural decay results in increasing treatment times when delivering the same cumulative dose. It is also possible, however, that the biological effective dose may change based on this dose rate even if the total dose is kept constant. Because patients are generally treated in a uniform manner, radiosurgery for trigeminal neuralgia (TN) represents a clinical model whereby biological efficacy can be tested. The authors hypothesized that higher dose rates would result in earlier and more complete pain relief but only if measured with a sensitive pain assessment tool. METHODS: One hundred thirty-three patients were treated with the Gamma Knife Model 4C unit at a single center by a single neurosurgeon during a single cobalt life cycle from January 2006 to May 2012. All patients were treated with 80 Gy with a single 4-mm isocenter without blocking. Using an output factor of 0.87, dose rates ranged from 1.28 to 2.95 Gy/min. The Brief Pain Inventory (BPI)-Facial was administered before the procedure and at the first follow-up office visit 1 month from the procedure (mean 1.3 months). Phone calls were made to evaluate patients after their procedures as part of a retrospective study. Univariate and multivariate linear regression was performed on several independent variables, including sex, age in deciles, diagnosis, follow-up duration, prior surgery, and dose rate. RESULTS: In the short-term analysis (mean 1.3 months), patients' self-reported pain intensity at its worst was significantly correlated with dose rate on multivariate analysis (p = 0.028). Similarly, patients' self-reported interference with activities of daily living was closely correlated with dose rate on multivariate analysis (p = 0.067). A 1 Gy/min decrease in dose rate resulted in a 17% decrease in pain intensity at its worst and a 22% decrease in pain interference with activities of daily living. In longer-term follow-up (mean 1.9 years), GKRS with higher dose rates (> 2.0 Gy/min; p = 0.007) and older age in deciles (p = 0.012) were associated with a lower likelihood of recurrence of pain. DISCUSSION: Prior studies investigating the role of dose rate in Gamma Knife radiosurgical ablation for TN have not used validated outcome tools to measure pain preoperatively. Consequently, differences in pain outcomes have been difficult to measure. By administering pain scales both preoperatively as well as postoperatively, the authors have identified statistically significant differences in pain intensity and pain interference with activities of daily living when comparing higher versus lower dose rates. Radiosurgery with a higher dose rate results in more pain relief at the early follow-up evaluation, and it may result in a lower recurrence rate at later follow-up. PMID- 26252451 TI - Abnormal functional global and local brain connectivity in female patients with anorexia nervosa. AB - BACKGROUND: Previous resting-state functional connectivity studies in patients with anorexia nervosa used independent component analysis or seed-based connectivity analysis to probe specific brain networks. Instead, modelling the entire brain as a complex network allows determination of graph-theoretical metrics, which describe global and local properties of how brain networks are organized and how they interact. METHODS: To determine differences in network properties between female patients with acute anorexia nervosa and pairwise matched healthy controls, we used resting-state fMRI and computed well established global and local graph metrics across a range of network densities. RESULTS: Our analyses included 35 patients and 35 controls. We found that the global functional network structure in patients with anorexia nervosa is characterized by increases in both characteristic path length (longer average routes between nodes) and assortativity (more nodes with a similar connectedness link together). Accordingly, we found locally decreased connectivity strength and increased path length in the posterior insula and thalamus. LIMITATIONS: The present results may be limited to the methods applied during preprocessing and network construction. CONCLUSION: We demonstrated anorexia nervosa-related changes in the network configuration for, to our knowledge, the first time using resting-state fMRI and graph-theoretical measures. Our findings revealed an altered global brain network architecture accompanied by local degradations indicating wide-scale disturbance in information flow across brain networks in patients with acute anorexia nervosa. Reduced local network efficiency in the thalamus and posterior insula may reflect a mechanism that helps explain the impaired integration of visuospatial and homeostatic signals in patients with this disorder, which is thought to be linked to abnormal representations of body size and hunger. PMID- 26252453 TI - Endoscopic endonasal translacerum approach to the inferior petrous apex. AB - OBJECTIVE: The surgical approach to lesions involving the inferior petrous apex (IPA) is still challenging. The purpose of this study is to demonstrate the anatomical features of the IPA and to assess the applicability of an endoscopic endonasal approach through the foramen lacerum (translacerum approach) to the IPA. METHODS: The surgical simulation of the endoscopic endonasal translacerum approach was conducted in 3 cadaver heads. The same technique was applied in 4 patients harboring tumors involving the IPA (3 chordomas and 1 chondro-sarcoma). RESULTS: By removing the fibrocartilaginous component of the foramen lacerum, a triangular space was created between the anterior genu of the petrous portion of the carotid artery and the eustachian tube, through which the IPA could be approached. The range of the surgical maneuver reached laterally up to the internal auditory canal, jugular foramen, and posterior vertical segment of the petrous portion of the carotid artery. In clinical application, the translacerum approach provided sufficient space to handle tumors at the IPA. Gross-total and partial removal was achieved in 3 and 1 cases, respectively, without permanent surgery-related morbidity and mortality. CONCLUSIONS: The endoscopic endonasal translacerum approach provides reliable access to the IPA. It is indicated alone for lesions confined to the IPA and in combination with other approaches for more extensive lesions. PMID- 26252454 TI - Improved versus worsened endocrine function after transsphenoidal surgery for nonfunctional pituitary adenomas: rate, time course, and radiological analysis. AB - OBJECTIVE: The impact of transsphenoidal surgery for nonfunctional pituitary adenomas (NFAs) on preoperative hypopituitarism relative to the incidence of new postoperative endocrine deficits remains unclear. The authors investigated rates of hypopituitarism resolution and development after transsphenoidal surgery. METHODS: Over a 5-year period, 305 transsphenoidal surgeries for NFAs performed at The California Center for Pituitary Disorders were retrospectively reviewed. RESULTS: Patients with preoperative endocrine deficits (n = 153, 50%) were significantly older (mean age 60 vs 54 years; p = 0.004), more frequently male (65% vs 44%; p = 0.0005), and had larger adenomas (2.4 cm vs 2.1 cm; p = 0.02) than patients without preoperative deficits (n = 152, 50%). Of patients with preoperative endocrine deficits, 53% exhibited symptoms. Preoperative deficit rates were 26% for the thyroid axis; 20% and 16% for the male and female reproductive axes, respectively; 13% for the adrenocorticotropic hormone (ACTH)/cortisol axis, and 19% for the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Laboratory normalization rates 6 weeks and 6 months after surgery without hormone replacement were 26% and 36% for male and 13% and 13% for female reproductive axes, respectively; 30% and 49% for the thyroid axis; 3% and 3% for the cortisol axis; and 9% and 22% for the IGF-1 axis (p < 0.05). New postoperative endocrine deficits occurred in 42 patients (13.7%). Rates of new deficits by axes were: male reproductive 3% (n = 9), female reproductive 1% (n = 4), thyroid axis 3% (n = 10), cortisol axis 6% (n = 19), and GH/IGF-1 axis 4% (n = 12). Patients who failed to exhibit any endocrine normalization had lower preoperative gland volumes than those who did not (0.24 cm(3) vs 0.43 cm(3), respectively; p < 0.05). Multivariate analyses revealed that no variables predicted new postoperative deficits or normalization of the female reproductive, cortisol, and IGF-1 axes. However, increased preoperative gland volume and younger age predicted the chances of a patient with any preoperative deficit experiencing normalization of at least 1 axis. Younger age and less severe preoperative hormonal deficit predicted normalization of the thyroid and male reproductive axes (p < 0.05). CONCLUSIONS: After NFA resection, endocrine normalization rates in this study varied with the hormonal axis and were greater than the incidence of new endocrine deficits. Low preoperative gland volume precluded recovery. Patient age and the severity of the deficiency influenced the recovery of the thyroid and male reproductive axes, the most commonly impaired axes and most likely to normalize postoperatively. This information can be of use in counseling patients with hypopituitarism who undergo NFA surgery. PMID- 26252455 TI - Dorsal anterior cingulotomy and anterior capsulotomy for severe, refractory obsessive-compulsive disorder: a systematic review of observational studies. AB - OBJECT The object of this study was to perform a systematic review, according to Preferred Reporting Items of Systematic reviews and Meta-Analyses (PRISMA) and Agency for Healthcare Research and Quality (AHRQ) guidelines, of the clinical efficacy and adverse effect profile of dorsal anterior cingulotomy compared with anterior capsulotomy for the treatment of severe, refractory obsessive-compulsive disorder (OCD). METHODS The authors included studies comparing objective clinical measures before and after cingulotomy or capsulotomy (surgical and radiosurgical) in patients with OCD. Only papers reporting the most current follow-up data for each group of investigators were included. Studies reporting results on patients undergoing one or more procedures other than cingulotomy or capsulotomy were excluded. Case reports and studies with a mean follow-up shorter than 12 months were excluded. Clinical response was defined in terms of a change in the Yale Brown Obsessive Compulsive Scale (Y-BOCS) score. The authors searched MEDLINE, PubMed, PsycINFO, Scopus, and Web of Knowledge through October 2013. English and non-English articles and abstracts were reviewed. RESULTS Ten studies involving 193 participants evaluated the length of follow-up, change in the Y-BOCS score, and postoperative adverse events (AEs) after cingulotomy (n = 2 studies, n = 81 participants) or capsulotomy (n = 8 studies, n = 112 participants). The average time to the last follow-up was 47 months for cingulotomy and 60 months for capsulotomy. The mean reduction in the Y-BOCS score at 12 months' follow-up was 37% for cingulotomy and 55% for capsulotomy. At the last follow-up, the mean reduction in Y-BOCS score was 37% for cingulotomy and 57% for capsulotomy. The average full response rate to cingulotomy at the last follow-up was 41% (range 38%-47%, n = 2 studies, n = 51 participants), and to capsulotomy was 54% (range 37%-80%, n = 5 studies, n = 50 participants). The rate of transient AEs was 14.3% across cingulotomy studies (n = 116 procedures) and 56.2% across capsulotomy studies (n = 112 procedures). The rate of serious or permanent AEs was 5.2% across cingulotomy studies and 21.4% across capsulotomy studies. CONCLUSIONS This systematic review of the literature supports the efficacy of both dorsal anterior cingulotomy and anterior capsulotomy in this highly treatment-refractory population. The observational nature of available data limits the ability to directly compare these procedures. Controlled or head-to-head studies are necessary to identify differences in efficacy or AEs and may lead to the individualization of treatment recommendations. PMID- 26252457 TI - Major nerve injury after contraceptive implant removal: case illustration. PMID- 26252456 TI - Adenoid cystic carcinoma of the skull base: results with an aggressive multidisciplinary approach. AB - OBJECT Adenoid cystic carcinoma (ACC) is a locally aggressive tumor of salivary gland origin. Little data exist to guide treatment when this tumor extends to involve the structures of the skull base. METHODS Fifty-one patients with a diagnosis of ACC affecting the skull base were identified from a prospective database at MD Anderson Cancer Center (from 1992 to 2010). RESULTS Median follow up for study patients was 6.75 years. The 5- and 10-year overall survival (OS) rates were 78% and 50%, respectively. Sixty-six percent of patients had progression of their disease. The 5- and 10-year progression-free survival (PFS) rates were 46.7% and 21.0%, respectively. Gross-total resection was achieved in 75% of patients, with 49% having microscopically negative margins at the time of first operation. On univariate analysis, resections with microscopically negative margins were associated with a significant OS advantage (20.1 +/- 3.3 years) compared with resections that left residual disease, even if microscopic (10.3 +/ 1.6 years, p = 0.035). In patients who underwent reoperation, the effect persisted, with improved OS in those with negative margins (21.4 +/- 0.0 vs 16.7 +/- 4.0 years, p = 0.06). The use of adjuvant radiotherapy was associated with an OS advantage (16.2 +/- 2.5 vs 5.5 +/- 2.2 years, p = 0.03) at initial diagnosis and improved PFS (7.8 +/- 1.0 vs 2.1 +/- 0.62 years, p = 0.005), whereas repeat irradiation provided no benefit. The use of adjuvant chemotherapy at diagnosis or at recurrence was not associated with any significant advantage. Multivariate analysis revealed margin-negative resection at initial operation and at recurrence retained OS significance, even after controlling for age, radiation therapy, and T stage. CONCLUSIONS ACC of the skull base is best treated with a multidisciplinary approach aimed at maximal, safe resection. Adjuvant radiotherapy should be offered, whereas chemotherapy does not confer benefit. PMID- 26252458 TI - Evaluating innovation. Part 1: The concept of progressive scholarly acceptance. AB - Understanding how the relevant medical community accepts new therapies is vital to patients, physicians, and society. Increasingly, focus is placed on how medical innovations are evaluated. But recognizing when a treatment has become accepted practice-essentially, acceptance by the scientific community-remains a challenge and a barrierto investigating treatment development. This report aims to demonstrate the theory, method, and limitations of a model for measuring a new metric that the authors term "progressive scholarly acceptance." A model was developed to identify when the scientific community has accepted an innovation, by observing when researchers have moved beyond the initial study of efficacy. This model could enable further investigations into the methods and influences of treatment development. PMID- 26252460 TI - Optical coherence tomography of traumatic aneurysms of the internal carotid artery: report of 2 cases. AB - The pathophysiology of extracranial traumatic aneurysm formation has not been fully elucidated. Intraarterial optical coherence tomography (OCT), an imaging modality capable of micrometer cross-sectional resolution, was used to evaluate patients presenting with saccular traumatic aneurysms of the internal carotid artery (ICA). Two consecutive trauma patients diagnosed with saccular traumatic aneurysms of the cervical ICA, per the institutional screening protocol for traumatic cerebrovascular injury, underwent digital subtraction angiography (DSA) with OCT. Optical coherence tomography demonstrated disruption of the intima with preservation and stretching of the more peripheral layers. In 1 patient the traumatic aneurysm was associated with thrombus formation and a separate, more proximal dissection not visible on CT angiography (CTA) or DSA. Imaging with OCT indicates that saccular traumatic aneurysms may develop from disruption of the intima with at least partial preservation of the media and adventitia. This provides in vivo evidence that saccular traumatic aneurysms result from a partial arterial wall tear rather than complete disruption. Interestingly, OCT was also able to detect arterial injury and thrombi not visible on CTA or DSA. PMID- 26252459 TI - Evaluating innovation. Part 2: Development in neurosurgery. AB - OBJECT Patients, practitioners, payers, and regulators are advocating for reform in how medical advances are evaluated. Because surgery does not adhere to a standardized developmental pathway, how the medical community accepts a procedure remains unclear. The authors developed a new model, using publication data and patterns, that quantifies this process. Using this technique, the authors identified common archetypes and influences on neurosurgical progress from idea inception to acceptance. METHODS Seven neurosurgical procedures developed in the past 15-25 years were used as developmental case studies (endovascular coil, deep brain stimulation, vagus nerve stimulation, 1,3-bis(2-chloroethyl)-l-nitrosourea wafer, and 3 radiosurgery procedures), and the literature on each topic was evaluated. A new metric the authors termed "progressive scholarly acceptance" (PSA) was used as an end point for community acceptance. PSA was reached when the number of investigations that refine or improve a procedure eclipsed the total number of reports assessing initial efficacy. Report characteristics, including the number of patients studied, study design, and number of authoring groups from the first report to the point of PSA, were assessed. RESULTS Publication data implicated factors that had an outsized influence on acceptance. First, procedural accessibility to investigators was found to influence the number of reports, number of patients studied, and number of authoring groups contributing. Barriers to accessibility included target disease rarity, regulatory restrictions, and cost. Second, the ease or difficulty in applying a randomized controlled trial had an impact on study design. Based on these 2 factors, 3 developmental archetypes were characterized to generally describe the development of surgery. CONCLUSIONS Common surgical development archetypes can be described based on factors that impact investigative methods, data accumulation, and ultimate acceptance by society. The approach and proposed terminologies in this report could inform future procedural development as well as any attempts to regulate surgical innovation. PMID- 26252461 TI - Gamma Knife surgical treatment for partially embolized cerebral arteriovenous malformations. AB - OBJECTIVE: A combination of embolization and radiosurgery is used as a common strategy for the treatment of large and complex cerebral arteriovenous malformations (AVMs). This study presents the experiences of partially embolized cerebral AVMs followed by Gamma Knife surgery (GKS) and assesses predictive factors for AVM obliteration and hemorrhage. METHODS: The interventional neuroradiology database that was reviewed included 404 patients who underwent AVM embolization. Using this database, the authors retrospectively analyzed all partially embolized AVM cases followed by GKS for a residual nidus. Except for cases of complete AVM obliteration, the authors excluded all patients with radiological follow-up of less than 2 years. Logistic regression analysis was used to analyze the predictive factors related to AVM obliteration and hemorrhage following GKS. Kaplan-Meier analysis was used to evaluate the obliteration with a cutoff AVM nidus volume of 3 cm(3) and 10 cm(3). RESULTS: One hundred sixty-two patients qualified for the study. The median patient age was 26 years and 48.8% were female. Hemorrhage presented as the most common symptom (48.1%). The median preembolization volume of an AVM was 14.3 cm(3). The median volume and margin dose for GKS were 10.92 cm(3) and 16.0 Gy, respectively. The median radiological and clinical follow-up intervals were 47 and 79 months, respectively. The annual hemorrhage rate was 1.71% and total obliteration rate was 56.8%. Noneloquent area (p = 0.004), superficial location (p < 0.001), decreased volume (p < 0.001), lower Spetzler-Martin grade (p < 0.001), lower Virginia Radiosurgery AVM Scale (RAS; p < 0.001), lower Pollock-Flickinger score (p < 0.001), lower modified Pollock-Flickinger score (p < 0.001), increased maximum dose (p < 0.001), and increased margin dose (p < 0.001) were found to be statistically significant in predicting the probability of AVM obliteration in the univariate analysis. In the multivariate analysis, only volume (p = 0.016) was found to be an independent prognostic factor for AVM obliteration. The log-rank (Mantel-Cox) test of the Kaplan-Meier analysis (chi-square = 54.402, p < 0.001) showed a significantly decreased obliteration rate of different cutoff AVM volume groups of less than 3 cm(3), 3-10 cm(3), and more than 10 cm(3). No independent prognostic factor was found for AVM hemorrhage in multivariate analysis. CONCLUSIONS: Partially embolized AVMs are amenable to successful treatment with GKS. The volume of the nidus significantly influences the outcome of radiosurgical treatment. The Virginia RAS and Pollock-Flickinger score were found to be reliable scoring systems for selection of patient candidates and prediction of partially embolized AVM closure and complications for GKS. PMID- 26252462 TI - Patient validation of retrospective data. PMID- 26252463 TI - Spontaneous retroclival hematoma: a case series. AB - OBJECTIVE: Retroclival hematomas are rare, appearing mostly as posttraumatic phenomena in children. Spontaneous retroclival hematoma (SRH) in the absence of trauma also has few descriptions in the literature. None of the reported clinical cases features the combination of an SRH and intraventricular hemorrhage (IVH). Nevertheless, despite extensive cases of idiopathic or angiographically negative subarachnoid hemorrhage (SAH) of the posterior fossa, only a single case report of a patient with a unique spontaneous retroclival hematoma has been identified. In this study, the authors reviewed the presentation, management, and clinical outcome of this rare entity. METHODS: The authors performed a retrospective analysis of all patients with diagnosed SRH at their institution over a 3-year period. Collected data included clinical history, laboratory results, treatment, and review of all imaging studies performed. RESULTS: Four patients had SRH. All were appropriately evaluated for coagulopathic and/or traumatic etiologies of hemorrhage, though no etiology could be found. Moreover, all of the patients demonstrated SRH that both clearly crossed the basioccipital synchondrosis and was contained within a nondependent configuration along the retroclival dura mater. CONCLUSIONS: Spontaneous retroclival hematoma, often associated with IVH, is a rare subtype of intracranial hemorrhage frequently recognized only when MRI demonstrates compartmentalization of the posterior fossa hemorrhage. When angiography fails to reveal an underlying lesion, SRH patients, like patients with traditional angiographically negative SAH, enjoy a remarkably good prognosis. PMID- 26252464 TI - Morbidity after intracranial tumor surgery: sensitivity and specificity of retrospective review of medical records compared with patient-reported outcomes at 30 days. AB - OBJECT: Published outcome reports in neurosurgical literature frequently rely on data from retrospective review of hospital records at discharge, but the sensitivity and specificity of retrospective assessments of surgical morbidity is not known. The aim of this study was to elucidate the sensitivity and specificity of retrospective assessment of morbidity after intracranial tumor surgery by comparing it to patient-reported outcomes at 30 days. METHODS: In 191 patients who underwent surgery for the treatment of intracranial tumors, we evaluated newly acquired neurological deficits within the motor, language, and cognitive domains. Traditional retrospective discharge data were collected by review of hospital records. Patient-reported data were obtained by structured phone interviews at 30 days after surgery. Data on perioperative medical and surgical complications were obtained from both hospital records and patient interviews conducted 30 days postoperatively. RESULTS: Sensitivity values for retrospective review of hospital records as compared with patient-reported outcomes were 0.52 for motor deficits, 0.4 for language deficits, and 0.07 for cognitive deficits. According to medical records, 158 patients were discharged with no new or worsened deficits, but only 117 (74%) of these patients confirmed this at 30 days after surgery. Specificity values were high (0.97-0.99), indicating that new deficits were unlikely to be found by retrospective review of hospital records at discharge when the patients did not report any at 30 days. Major perioperative complications were all identified through retrospective review of hospital records. CONCLUSIONS: Retrospective assessment of medical records at discharge from hospital may greatly underestimate the incidence of new neurological deficits after brain tumor surgery when compared with patient-reported outcomes after 30 days. PMID- 26252465 TI - Dendritic cell-based immunotherapy targeting Wilms' tumor 1 in patients with recurrent malignant glioma. AB - OBJECT: Dendritic cell (DC)-based vaccination is considered a potentially effective therapy against advanced cancer. The authors conducted a Phase I study to investigate the safety and immunomonitoring of Wilms' tumor 1 (WT1)-pulsed DC vaccination therapy for patients with relapsed malignant glioma. METHODS: WT1 pulsed and/or autologous tumor lysate-pulsed DC vaccination therapy was performed in patients with relapsed malignant gliomas. Approximately 1 * 10(7) to 2 * 10(7) pulsed DCs loaded with WT1 peptide antigen and/or tumor lysate were intradermally injected into the axillary areas with OK-432, a streptococcal preparation, at 2 week intervals for at least 5-7 sessions (1 course) during an individual chemotherapy regimen. RESULTS: Ten patients (3 men, 7 women; age range 24-64 years [median 39 years]) with the following tumors were enrolled: glioblastoma (6), anaplastic astrocytoma (2), anaplastic oligoastrocytoma (1), and anaplastic oligodendroglioma (1). Modified WT1 peptide-pulsed DC vaccine was administered to 7 patients, tumor lysate-pulsed DC vaccine to 2 patients, and both tumor lysate pulsed and WT1-pulsed DC vaccine to 1 patient. The clinical response was stable disease in 5 patients with WT1-pulsed DC vaccination. In 2 of 5 patients with stable disease, neurological findings improved, and MR images showed tumor shrinkage. No serious adverse events occurred except Grade 1-2 erythema at the injection sites. WT1 tetramer analysis detected WT1-reactive cytotoxic T cells after vaccination in patients treated with WT1-pulsed therapy. Positivity for skin reaction at the injection sites was 80% (8 of 10 patients) after the first session, and positivity remained for these 8 patients after the final session. CONCLUSIONS: This study of WT1-pulsed DC vaccination therapy demonstrated safety, immunogenicity, and feasibility in the management of relapsed malignant gliomas. PMID- 26252466 TI - Inception of a national multidisciplinary registry for stereotactic radiosurgery. AB - Stereotactic radiosurgery (SRS) represents a multidisciplinary approach to the delivery of ionizing high-dose radiation to treat a wide variety of disorders. Much of the radiosurgical literature is based upon retrospective single-center studies along with a few randomized controlled clinical trials. More timely and effective evidence is needed to enhance the consistency and quality of and clinical outcomes achieved with SRS. The authors summarize the creation and implementation of a national SRS registry. The American Association of Neurological Surgeons (AANS) through NeuroPoint Alliance, Inc., started a successful registry effort with its lumbar spine initiative. Following a similar approach, the AANS and NeuroPoint Alliance collaborated with corporate partners and the American Society for Radiation Oncology to devise a data dictionary for an SRS registry. Through administrative and financial support from professional societies and corporate partners, a framework for implementation of the registry was created. Initial plans were devised for a 3-year effort encompassing 30 high volume SRS centers across the country. Device-specific web-based data-extraction platforms were built by the corporate partners. Data uploaders were then used to port the data to a common repository managed by Quintiles, a national and international health care trials company. Audits of the data for completeness and veracity will be undertaken by Quintiles to ensure data fidelity. Data governance and analysis are overseen by an SRS board comprising equal numbers of representatives from the AANS and NeuroPoint Alliance. Over time, quality outcome assessments and post hoc research can be performed to advance the field of SRS. Stereotactic radiosurgery offers a high-technology approach to treating complex intracranial disorders. Improvements in the consistency and quality of care delivered to patients who undergo SRS should be afforded by the national registry effort that is underway. PMID- 26252468 TI - Instability of Amide Bond Comprising the 2-Aminotropone Moiety: Cleavable under Mild Acidic Conditions. AB - An unusual hydrolysis/solvolysis of the classical acyclic amide bond, derived from N-troponylaminoethylglycine (Traeg) and alpha-amino acids, is described under mild acidic conditions. The reactivity of this amide bond is possibly owed to the protonation of the troponyl carbonyl functional group. The results suggest that the Traeg amino acid is a potential candidate for protecting and caging of the amine functional group of bioactive molecules via a cleavable amide bond. PMID- 26252467 TI - The Amino Acid Specificity for Activation of Phenylalanine Hydroxylase Matches the Specificity for Stabilization of Regulatory Domain Dimers. AB - Liver phenylalanine hydroxylase is allosterically activated by phenylalanine. The structural changes that accompany activation have not been identified, but recent studies of the effects of phenylalanine on the isolated regulatory domain of the enzyme support a model in which phenylalanine binding promotes regulatory domain dimerization. Such a model predicts that compounds that stabilize the regulatory domain dimer will also activate the enzyme. Nuclear magnetic resonance spectroscopy and analytical ultracentrifugation were used to determine the ability of different amino acids and phenylalanine analogues to stabilize the regulatory domain dimer. The abilities of these compounds to activate the enzyme were analyzed by measuring their effects on the fluorescence change that accompanies activation and on the activity directly. At concentrations of 10-50 mM, d-phenylalanine, l-methionine, l-norleucine, and (S)-2-amino-3-phenyl-1 propanol were able to activate the enzyme to the same extent as 1 mM l phenylalanine. Lower levels of activation were seen with l-4-aminophenylalanine, l-leucine, l-isoleucine, and 3-phenylpropionate. The ability of these compounds to stabilize the regulatory domain dimer agreed with their ability to activate the enzyme. These results support a model in which allosteric activation of phenylalanine hydroxylase is linked to dimerization of regulatory domains. PMID- 26252469 TI - Assessment of remodeling in chronic obstructive pulmonary disease using imaging methods. AB - INTRODUCTION: While spirometry plays a key role in diagnosing chronic obstructive pulmonary disease (COPD), imaging methods including endobronchial ultrasound (EBUS) and chest computed tomography (CT) appear to be useful for investigating structural changes in the lungs. OBJECTIVES: The aim of this study was to evaluate remodeling in COPD patients using EBUS and chest CT. PATIENTS AND METHODS: The study included 33 patients with COPD, 15 patients with severe asthma, and 15 control subjects. All subjects underwent pulmonary function tests and bronchoscopy with EBUS to measure the total thickness of the bronchial wall and its layers. Additionally, in COPD patients, a chest CT was performed to measure total bronchial wall thickness. RESULTS: The total bronchial wall thickness measured by EBUS in patients with COPD (1.192 +/-0.079 mm) was significantly smaller than that in asthmatic patients (1.433 +/-0.230 mm, P = 0.001) and significantly greater than in control subjects (1.099 +/-0.095 mm, P = 0.04), and was positively correlated with residual volume (RV) / total lung capacity (r = 0.5, P = 0.02), RV (r = 0.6, P = 0.007), and RV (%) (r = 0.5, P = 0.05). The thickness of the bronchial wall layers in patients with COPD were as follows: L1 = 0.135 +/-0.018 mm, L2 = 0.151 +/-0.026 mm, and L3-5 = 0.906 +/ 0.065 mm. There was no correlation between the thickness of the bronchial wall layers and forced expiratory volume in 1 second. CONCLUSIONS: The results of this study show that EBUS is a useful method for evaluating bronchial wall layers not only in asthma but also in COPD, and suggest that the pattern of remodeling differs in each of these diseases. PMID- 26252470 TI - 4-Hydroxynonenal: A Superior Oxidative Biomarker Compared to Malondialdehyde and Carbonyl Content Induced by Carbon Tetrachloride in Rats. AB - Carbon tetrachloride (CCl4), a halogenated substance that generates free radical species during metabolism in vivo, induces hepatotoxicity, produces oxidative DNA damage, and increased levels of protein carbonyl, malondialdehyde (MDA), and 4 hydroxynonenal (4-HNE). In this study, Sprague-Dawley rats received single or repeated ip injections of carbon tetrachloride (CCl4), and formation and persistence of carbonyls, MDA, and 4-HNE in plasma were measured using gas chromatography-mass spectrometry. After a single injection of 500 mg/kg CCl4 the in vivo half-lives of MDA and carbonyl content were 1.5 d and 2 d, respectively, while that of 4-HNE was approximately 10 d. Treatment with CCl4 (50, 100, 500, or 1000 mg/kg) dose-dependently increased these oxidative biomarkers in blood. However, formation of protein carbonyls and MDA was less sensitive than 4-HNE to CCl4. Levels of serum glutamic oxaloacetic transaminase (SGOT) and glutamic pyruvic transaminase (SGPT) (hepatotoxicity markers) rose with CCl4 doses. After a single injection (500 mg/kg), the peak level of SGOT was observed after 8 h but SGPT after 24 h. Overall, 4-HNE was more dose-sensitive and showed greater formation subchronically than other biomarkers. Multiple ip treatments with 300 mg CCl4 /kg (d 1, 3, 6, 10, 14, and 21) demonstrated that 4-HNE formation was highest (18-fold, peak/control) and subchronic up to d 21 (last treatment day), unlike other biomarkers. Data suggest that 4-HNE, MDA, and carbonyl content may be useful oxidative biomarkers for exposure to free radical generating halogenated compounds. However, 4-HNE appears to be a more sensitive and sustainable biomarker for toxicological and risk assessments. PMID- 26252471 TI - Reduction of (Formazanate)boron Difluoride Provides Evidence for an N Heterocyclic B(I) Carbenoid Intermediate. AB - Despite the current interest in structure and reactivity of sub-valent main group compounds, neutral boron analogues of N-heterocyclic carbenes have been elusive due to their high reactivity. Here we provide evidence that 2-electron reduction of a (formazanate)BF2 precursor leads to NaF elimination and formation of an N heterocyclic boron carbenoid, and describe the formation of a series of unusual BN heterocycles that result from trapping of this fragment. Subsequent chemical oxidation by XeF2 demonstrates that the trapped (formazanate)B fragment retains carbenoid character and regenerates the boron difluoride starting material in good yield. These results indicate that the formazanate ligand framework provides a unique entry into sub-valent boron chemistry. PMID- 26252473 TI - In vitro comparison between mechanical properties and elastographic characterization of porcine intervertebral disc. PMID- 26252472 TI - Propensity Score Matching Analysis of Changes in Alpha-Fetoprotein Levels after Combined Radiotherapy and Transarterial Chemoembolization for Hepatocellular Carcinoma with Portal Vein Tumor Thrombus. AB - BACKGROUND AND AIM: To investigate the value of changes in alpha-fetoprotein (AFP) levels for the prediction of radiologic response and survival outcomes in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) who received combined treatment of 3-dimensional conformal radiotherapy (3D-CRT) and transarterial chemoembolization (TACE). METHODS: A database of 154 HCC patients with PVTT and elevated AFP levels (>20 ng/mL) treated with 3D-CRT and TACE as an initial treatment between August 2002 and August 2008 was retrospectively reviewed. AFP levels were determined 1 month after radiotherapy, and AFP response was defined as an AFP level reduction of >20% from the initial level. Radiologic response, overall survival (OS), and progression-free survival (PFS) rates were compared between AFP responders and non-responders. Propensity score based matching analysis was performed to minimize the effect of potential confounding bias. RESULTS: The median follow-up period was 11.1 months (range, 3.1-82.7 months). In the propensity-score matching cohort (92 pairs), a best radiologic response of CR or PR occurred in more AFP responders than AFP non responders (41.3% vs. 10.9%, p < 0.001). OS and PFS were also longer in AFP responders than in non-responders (median OS 13.2 months vs. 5.6 months, p < 0.001; median PFS 8.7 months vs. 3.5 months, p < 0.001). CONCLUSIONS: AFP response is a significant predictive factor for radiologic response. Furthermore, AFP response is significant for OS and PFS outcomes. AFP evaluation after combined radiotherapy and TACE appears to be a useful predictor of clinical outcomes in HCC patients with PVTT. PMID- 26252474 TI - Combining the Sterile Insect Technique with Wolbachia-Based Approaches: II--A Safer Approach to Aedes albopictus Population Suppression Programmes, Designed to Minimize the Consequences of Inadvertent Female Release. AB - Due to the absence of a perfect method for mosquito sex separation, the combination of the sterile insect technique and the incompatible insect technique is now being considered as a potentially effective method to control Aedes albopictus. In this present study first we examine the minimum pupal irradiation dose required to induce complete sterility in Wolbachia triple-infected (HC), double-infected (GUA) and uninfected (GT) female Ae. albopictus. The HC line is a candidate for Ae. albopictus population suppression programmes, but due to the risk of population replacement which characterizes this triple infected line, the individuals to be released need to be additionally irradiated. After determining the minimum irradiation dose required for complete female sterility, we test whether sterilization is sufficient to prevent invasion of the triple infection from the HC females into double-infected (GUA) populations. Our results indicate that irradiated Ae. albopictus HC, GUA and GT strain females have decreased fecundity and egg hatch rate when irradiated, inversely proportional to the dose, and the complete sterilization of females can be acquired by pupal irradiation with doses above 28 Gy. PCR-based analysis of F1 and F2 progeny indicate that the irradiated HC females, cannot spread the new Wolbachia wPip strain into a small cage GUA population, released at a 1:5 ratio. Considering the above results, we conclude that irradiation can be used to reduce the risk of population replacement caused by an unintentional release of Wolbachia triple-infected Ae. albopictus HC strain females during male release for population suppression. PMID- 26252475 TI - Microglial Activation Promotes Cell Survival in Organotypic Cultures of Postnatal Mouse Retinal Explants. AB - The role of microglia during neurodegeneration remains controversial. We investigated whether microglial cells have a neurotoxic or neuroprotective function in the retina. Retinal explants from 10-day-old mice were treated in vitro with minocycline to inhibit microglial activation, with LPS to increase microglial activation, or with liposomes loaded with clodronate (Lip-Clo) to deplete microglial cells. Flow cytometry was used to assess the viability of retinal cells in the explants and the TUNEL method to show the distribution of dead cells. The immunophenotypic and morphological features of microglia and their distribution were analyzed with flow cytometry and immunocytochemistry. Treatment of retinal explants with minocycline reduced microglial activation and simultaneously significantly decreased cell viability and increased the presence of TUNEL-labeled cell profiles. This treatment also prevented the migration of microglial cells towards the outer nuclear layer, where cell death was most abundant. The LPS treatment increased microglial activation but had no effect on cell viability or microglial distribution. Finally, partial microglial removal with Lip-Clo diminished the cell viability in the retinal explants, showing a similar effect to that of minocycline. Hence, cell viability is diminished in retinal explants cultured in vitro when microglial cells are removed or their activation is inhibited, indicating a neurotrophic role for microglia in this system. PMID- 26252476 TI - In Silico Generation of Peptides by Replica Exchange Monte Carlo: Docking-Based Optimization of Maltose-Binding-Protein Ligands. AB - Short peptides can be designed in silico and synthesized through automated techniques, making them advantageous and versatile protein binders. A number of docking-based algorithms allow for a computational screening of peptides as binders. Here we developed ex-novo peptides targeting the maltose site of the Maltose Binding Protein, the prototypical system for the study of protein ligand recognition. We used a Monte Carlo based protocol, to computationally evolve a set of octapeptides starting from a polialanine sequence. We screened in silico the candidate peptides and characterized their binding abilities by surface plasmon resonance, fluorescence and electrospray ionization mass spectrometry assays. These experiments showed the designed binders to recognize their target with micromolar affinity. We finally discuss the obtained results in the light of further improvement in the ex-novo optimization of peptide based binders. PMID- 26252477 TI - Association between Changes in Muscle Quality with Exercise Training and Changes in Cardiorespiratory Fitness Measures in Individuals with Type 2 Diabetes Mellitus: Results from the HART-D Study. AB - INTRODUCTION: Type 2 diabetes mellitus (T2DM) is associated with a reduction in muscle quality. However, there is inadequate empirical evidence to determine whether changes in muscle quality following exercise are associated with improvement in cardiorespiratory fitness (CRF) in individuals with T2DM. The objective of this study was to investigate the association between change in muscle quality following a 9-month intervention of aerobic training (AT), resistance training (RT) or a combination of both (ATRT) and cardiorespiratory fitness (CRF) in individuals with T2DM. MATERIAL AND METHODS: A total of 196 participants were randomly assigned to a control, AT, RT, or combined ATRT for a 9-months intervention. The exposure variable was change in muscle quality [(Post: leg muscle strength/leg muscle mass)-[(Pre: leg muscle strength/leg muscle mass)]. Dependent variables were change in CRF measures including absolute and relative VO2peak, and treadmill time to exhaustion (TTE) and estimated metabolic equivalent task (METs). RESULTS: Continuous change in muscle quality was independently associated with change in absolute (beta = 0.015; p = 0.019) and relative (beta = 0.200; p = 0.005) VO2peak, and TTE (beta = 0.170; p = 0.043), but not with estimated METs (p > 0.05). A significant trend was observed across tertiles of change in muscle quality for changes in absolute (beta = 0.050; p = 0.005) and relative (beta = 0.624; p = 0.002) VO2peak following 9 months of exercise training. No such association was observed for change in TTE and estimated METs (p > 0.05). DISCUSSION: The results from this ancillary study suggest that change in muscle quality following exercise training is associated with a greater improvement in CRF in individuals with T2DM. Given the effect RT has on increasing muscle quality, especially as part of a recommended training program (ATRT), individuals with T2DM should incorporate RT into their AT regimens to optimize CRF improvement. TRIAL REGISTRATION: Clinicaltrials.gov NCT00458133. PMID- 26252478 TI - Lack of ADAM2, CALR3 and SAGE1 Cancer/Testis Antigen Expression in Lung and Breast Cancer. AB - Immunotherapy is emerging as a supplement to conventional cancer treatment, and identifying antigen targets for specific types of cancer is critical to optimizing therapeutic efficacy. Cancer/testis antigens are highly promising targets for immunotherapy due to their cancer-specific expression and antigenic properties, but the expression patterns of most of the more than 200 identified cancer/testis antigens in various cancers remain largely uncharacterized. In this study, we investigated the expression of the cancer/testis antigens ADAM2, CALR3 and SAGE1 in lung and breast cancer, the two most frequent human cancers, with the purpose of providing novel therapeutic targets for these diseases. We used a set of previously uncharacterized antibodies against the cancer/testis antigens ADAM2, CALR3 and SAGE1 to investigate their expression in a large panel of normal tissues as well as breast and lung cancers. Staining for the well-characterized MAGE-A proteins was included for comparison. Immunohistochemical staining confirmed previous mRNA analysis demonstrating that ADAM2, CALR3 and SAGE1 proteins are confined to testis in normal individuals. Negative tissues included plancenta, which express many other CT antigens, such as MAGE-A proteins. Surprisingly, we detected no ADAM2, CALR3 and SAGE1 in the 67 lung cancers (mainly non-small lung cancer) and 189 breast cancers, while MAGE-A proteins were present in 15% and 7-16% of these tumor types, respectively. Treatment with DNA methyltransferase inhibitors has been proposed as an attractive strategy to increase the expression of cancer/testis antigens in tumors before immunotargeting; however, neither ADAM2, CALR3 nor SAGE1 could be significantly induced in lung and breast cancer cell lines using this strategy. Our results suggest that ADAM2, CALR3 and SAGE1 cancer/testis antigens are not promising targets for immunotherapy of breast and lung cancer. PMID- 26252479 TI - Individual and Co Transport Study of Titanium Dioxide NPs and Zinc Oxide NPs in Porous Media. AB - The impact of pH and ionic strength on the mobility (individual and co-transport) and deposition kinetics of TiO2 and ZnO NPs in porous media was systematically investigated in this study. Packed column experiments were performed over a series of environmentally relevant ionic strengths with both NaCl (0.1-10 mM) and CaCl2 (0.01-0.1mM) solutions and at pH 5, 7, and 9. The transport of TiO2 NPs at pH 5 was not significantly affected by ZnO NPs in solution. At pH 7, a decrease in TiO2 NP transport was noted with co-existence of ZnO NPs, while at pH 9 an increase in the transport was observed. At pH 5 and 7, the transport of ZnO NPs was decreased when TiO2 NPs was present in the solution, and at pH 9, an increase was noted. The breakthrough curves (BTC) were noted to be sensitive to the solution chemistries; the decrease in the breakthrough plateau with increasing ionic strength was observed under all examined pH (5, 7, and 9). The retention profiles were the inverse of the plateaus of BTCs, as expected from mass balance considerations. Overall, the results from this study suggest that solution chemistries (ionic strength and pH) are likely the key factors that govern the individual and co-transport behavior of TiO2 and ZnO NPs in sand. PMID- 26252480 TI - Understandings of Participation in Behavioural Research: A Qualitative Study of Gay and Bisexual Men in Scotland. AB - An array of empirical research has emerged related to public participation in health research. To date, few studies have explored the particular perspectives of gay and bisexual men taking part in behavioural surveillance research, which includes the donation of saliva swabs to investigate HIV prevalence and rates of undiagnosed HIV. Semi-structured interviews were conducted with twenty-nine gay and bisexual men in Scotland who had participated in a bar-based survey. Thematic analysis of men's accounts of their motives for participation and their perceptions of not receiving individual feedback on HIV status suggested a shared understanding of participation in research as a means of contributing to 'community' efforts to prevent the spread of HIV. Most men expressed sophisticated understandings of the purpose of behavioural research and distinguished between this and individual diagnostic testing. Despite calls for feedback on HIV results broadly, for these men feedback on HIV status was not deemed crucial. PMID- 26252482 TI - Molecular and Cytogenetic Characterization of Wild Musa Species. AB - The production of bananas is threatened by rapid spreading of various diseases and adverse environmental conditions. The preservation and characterization of banana diversity is essential for the purposes of crop improvement. The world's largest banana germplasm collection maintained at the Bioversity International Transit Centre (ITC) in Belgium is continuously expanded by new accessions of edible cultivars and wild species. Detailed morphological and molecular characterization of the accessions is necessary for efficient management of the collection and utilization of banana diversity. In this work, nuclear DNA content and genomic distribution of 45S and 5S rDNA were examined in 21 diploid accessions recently added to ITC collection, representing both sections of the genus Musa. 2C DNA content in the section Musa ranged from 1.217 to 1.315 pg. Species belonging to section Callimusa had 2C DNA contents ranging from 1.390 to 1.772 pg. While the number of 45S rDNA loci was conserved in the section Musa, it was highly variable in Callimusa species. 5S rRNA gene clusters were found on two to eight chromosomes per diploid cell. The accessions were genotyped using a set of 19 microsatellite markers to establish their relationships with the remaining accessions held at ITC. Genetic diversity done by SSR genotyping platform was extended by phylogenetic analysis of ITS region. ITS sequence data supported the clustering obtained by SSR analysis for most of the accessions. High level of nucleotide diversity and presence of more than two types of ITS sequences in eight wild diploids pointed to their origin by hybridization of different genotypes. This study significantly expands the number of wild Musa species where nuclear genome size and genomic distribution of rDNA loci is known. SSR genotyping identified Musa species that are closely related to the previously characterized accessions and provided data to aid in their classification. Sequence analysis of ITS region provided further information about evolutionary relationships between individual accessions and suggested that some of analyzed accessions were interspecific hybrids and/or backcross progeny. PMID- 26252481 TI - Antibody response to revaccination among adult non-responders to primary Hepatitis B vaccination in China. AB - About 10% adult failed to develop antibody response after primary hepatitis B vaccination, and revaccination may be an option to improve immune response, but the antibody responses to revaccination in adult non-responders have not been fully examined. Adult non-responders to primary 3-dose hepatitis B vaccination were randomly divided into 2 groups and revaccinated with 20 MUg hepatitis B vaccine (HepB) derived from Saccharomyces Cerevisiae (HepB-SC) or 20 MUg HepB derived from Chinese hamster ovary cells (HepB-CHO), respectively, at 0-, 1-, 6- month. Seroconversion rate and titer of antibody against hepatitis B surface antigen (anti-HBs) was measured one month after the 1st and 3rd revaccination dose. Anti-HBs seroconversion rates significantly increased from 54.98% [95% confidence interval (CI) 48.60%-61.24%] after the 1st revaccination dose to 89.24% (95% CI: 84.74%-92.79%) after the 3rd revaccination dose (P < 0.001), and the geometric mean titer (GMT) of anti-HBs increased from 12.18 mIU/ml (95%CI: 7.81-18.98 mIU/ml) to 208.31 mIU/ml (95% CI: 148.87-291.47 mIU/ml) (P = 0.008).Compared with those with anti-HBs titer <2 mIU/ml after primary vaccination, those with antibody titer >= 2 mIU/ml after primary vaccination had higher seroconversion rate after the 1st dose revaccination (38.36% vs. 78.10%, P < 0.001) and after the 3rd dose of revaccination (84.25% vs. 96.19%, P = 0.003), and had higher antibody titer after the 1st dose of revaccination (3.32 mIU/ml vs. 74.21 mIU/ml, P < 0.0001) and after the 3rd dose of revaccination (145.73 mIU/ml vs. 342.34 mIU/ml, P = 0.01). Anti-HBs titer was significantly higher in those revaccinated with HepB-CHO than those revaccinated with HepB-SC after the 3rd dose (131.46 mIU/ml vs. 313.38 mIU/ml, P = 0.01). Revaccination on adult HepB non-responders increased the immune response to HepB and may confer further protection against hepatitis B virus infection. If possible, revaccination might be an option to HepB non-responders to secure more protection. PMID- 26252484 TI - Total Synthesis of Hyperforin. AB - A 10-step total synthesis of the polycyclic polyprenylated acylphloroglucinol (PPAP) natural product hyperforin from 2-methylcyclopent-2-en-1-one is reported. This route was enabled by a diketene annulation reaction and an oxidative ring expansion strategy designed to complement the presumed biosynthesis of this complex meroterpene. The described work enables the preparation of a highly substituted bicyclo[3.3.1]nonane-1,3,5-trione motif in only six steps and thus serves as a platform for the construction of easily synthesized, highly diverse PPAPs modifiable at every position. PMID- 26252485 TI - First-In-Human, Phase 1, Randomized, Dose-Escalation Trial with Recombinant Anti IL-20 Monoclonal Antibody in Patients with Psoriasis. AB - BACKGROUND: The current trial was a first-in-human clinical trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the recombinant monoclonal anti-interleukin-20 (IL-20) antibody, NNC0109-0012, which targets the inflammatory cytokine IL-20. METHODS: In total, 48 patients aged 18 to 75 years with moderate to severe stable chronic plaque psoriasis with affected body surface area >=15% and physician global assessment score >=3 were enrolled in this randomized, double-blind, multicenter, placebo controlled, phase 1 dose-escalation trial. Patients were randomized within each single dose cohort (0.01, 0.05, 0.2, 0.6, 1.5, or 3.0 mg/kg) or multiple dose cohort (0.05, 0.2, 0.5, 1.0, or 2.0 mg/kg; 1 dose every other week for 7 weeks) of NNC0109-0012 or placebo in a 3:1 ratio. In the expansion phase, 7 patients were randomized to weekly doses of 2.0 mg/kg NNC0109-0012 or placebo for 7 weeks. The primary objective, safety and tolerability, was assessed by evaluating adverse events (AEs). Additional endpoints included pharmacokinetics, pharmacodynamics, and clinical response (assessed using the Psoriasis Area and Severity Index [PASI] score). RESULTS: AEs were reported in 85% of patients (n = 40) in the initial study phases (NNC0109-0012, 83%; placebo, 92%) and in 4 of 7 patients in the multiple-dose expansion phase. One serious AE was reported but was judged not to be causally related to NNC0109-0012. No dose-limiting toxicities were reported. NNC0109-0012 pharmacokinetics was similar to other monoclonal antibodies, with an average half-life of approximately 3 weeks. There was a dose-proportional increase in area under the curve and maximum concentration after single dosing. No substantial changes in pharmacodynamic parameters were observed. The expansion phase was terminated early due to apparent lack of PASI improvement. CONCLUSION: Single and multiple doses of NNC0109-0012, ranging from 0.05 to 3.0 mg/kg, were well tolerated in patients with psoriasis and exhibited pharmacokinetics similar to that of other monoclonal antibodies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01261767. PMID- 26252486 TI - Trends in Emergency Department Visit Rates for Hypoglycemia and Hyperglycemic Crisis among Adults with Diabetes, United States, 2006-2011. AB - BACKGROUND: Despite concerns about hypoglycemia events from overly aggressive glycemic reduction, population trends in hypoglycemia and hyperglycemic crisis incidence are unclear. To address this gap, we examined changes in emergency department (ED) visit rates for hypoglycemia and hyperglycemic crisis 2006-2011. METHODS: Using data from the Nationwide Emergency Department Sample, we estimated the number of ED visits for hypoglycemia and hyperglycemic crisis via ICD-9-CM among adults with diabetes. Using data from the National Health Interview Survey, we estimated the population of adults with diabetes and calculated ED visit rates. RESULTS: From 2006 to 2011, ED visit rates for hypoglycemia declined by 22% from 1.8 to 1.4 per 100 adults (p = 0.003). The rates decreased in all age groups (all P<0.05) except those aged 18 to 44 years (P = 0.31). Hypoglycemia rates displayed a J-shaped curve across age, with the highest rates among adults aged 75 years or older (P <0.001). ED visit rates for hyperglycemic crisis did not change overall but increased 17% for adults aged 65 to 74 years (P = 0.02) and 29% for women (P = 0.01). Hyperglycemic crisis rates were highest among adults aged 18 to 44 years (P <0.001). CONCLUSIONS: Hypoglycemia rates have declined for all adults but persons aged 18-44 years while rates for hyperglycemic crisis remained stable. Future preventive efforts should target on the susceptible population of adults aged 18 to 44 years and those aged 75 years or older. PMID- 26252488 TI - Correction: Laboratory Rodent Diets Contain Toxic Levels of Environmental Contaminants: Implications for Regulatory Tests. PMID- 26252487 TI - Ligands Binding to Cell Surface Ganglioside GD2 Cause Src-Dependent Activation of N-Methyl-D-Aspartate Receptor Signaling and Changes in Cellular Morphology. AB - Ganglioside GD2 is a plasma membrane glycosphinogolipid. In healthy adults it is expressed at low levels, but it is over-expressed in many cancers. For cancer therapy, GD2 is targeted with anti-GD2 monoclonal antibodies (mAbs), and one adverse side effect is severe visceral pain. Pain is not neuropathic, cannot be blocked with morphine, and stops on discontinuation of mAb therapy. Here, we provide evidence that ligand binding to cell surface GD2 induces rapid and transient activation of Src-family kinases, followed by Src-dependent phosphorylation of NMDA-receptor NR2B subunits selectively, activation of Ca++ fluxes, production of cAMP, and changes in cellular morphology. These GD2-ligand activated signals differ in kinetics and in pharmacology from activation of the same signals in the same cells by BDNF, the growth factor agonist of the TrkB receptor, suggesting biological specificity. Hence, cell surface GD2 regulates pathways that can be associated with neoplasia and with morphine-intractable pain; and this can explain why expression of GD2 correlates with these two pathologies. PMID- 26252489 TI - An Immediate Innate Immune Response Occurred In the Early Stage of E. granulosus Eggs Infection in Sheep: Evidence from Microarray Analysis. AB - BACKGROUND: Cystic Echinococcosis(CE), caused by infection with the larval stage of the cestode Echinococcus granulosus (E. granulosus), is a chronic parasitic zoonosis, with highly susceptible infection in sheep. However, the comprehensive molecular mechanisms that underlie the process of E. granulosus infection in the early stage remain largely unknown. The objective of this present study was to gain a cluster of genes expression profiles in the intestine tissue of sheep infected with CE. METHODS: Nine healthy sheep were divided into infection group and healthy controls, with six infected perorally 5000 E. granulosus eggs suspended in 1000 MUl physiological saline and three controls perorally injected 1000 MUl physiological saline. All animals were sacrificed at 4 hours post infection, respectively. The intestine tissue was removed and the RNA was extracted. In the infection group, the biology replicates were designed to make sure the accuracy of the data. The ovine microarrays were used to analyze changes of gene expression in the intestine tissue between CE infected sheep and healthy controls. Real-time PCR was used to assess reliability of the microarray data. RESULTS: By biology repeats, a total of 195 differentially expressed genes were identified between infected group and controls at 4 hours post-infection, with 105 genes related to immune responses, while 90 genes associated with functions including energy metabolism, fat soluble transport, etc. Among the 105 immunity genes, 72 genes showed up-regulated expression levels while 33 showed down regulation levels. Function analysis showed that most of up-regulated genes were related to innate immune responses, such as mast cell, NK cell, cytokines, chemokines and complement. In addition, Real-time PCR analysis of a random selection of nine genes confirmed the reliability of the microarray data. CONCLUSION: To our knowledge, this is the first report describing gene expression profiles in the intestine tissue of CE infection sheep. These results suggested that the innate immune system was activated to elicit immediate defense in the intestine tissue where E. granulosus invaded in at 4 hour-post infection. Furthermore, future interest will also focus on unraveling similar events, especially for the function of adaptive immunity, but at late stage infection. PMID- 26252490 TI - Analysing the Effect of Mutation on Protein Function and Discovering Potential Inhibitors of CDK4: Molecular Modelling and Dynamics Studies. AB - The cyclin-dependent kinase 4 (CDK4)-cyclin D1 complex plays a crucial role in the transition from the G1 phase to S phase of the cell cycle. Among the CDKs, CDK4 is one of the genes most frequently affected by somatic genetic variations that are associated with various forms of cancer. Thus, because the abnormal function of the CDK4-cyclin D1 protein complex might play a vital role in causing cancer, CDK4 can be considered a genetically validated therapeutic target. In this study, we used a systematic, integrated computational approach to identify deleterious nsSNPs and predict their effects on protein-protein (CDK4-cyclin D1) and protein-ligand (CDK4-flavopiridol) interactions. This analysis resulted in the identification of possible inhibitors of mutant CDK4 proteins that bind the conformations induced by deleterious nsSNPs. Using computational prediction methods, we identified five nsSNPs as highly deleterious: R24C, Y180H, A205T, R210P, and R246C. From molecular docking and molecular dynamic studies, we observed that these deleterious nsSNPs affected CDK4-cyclin D1 and CDK4 flavopiridol interactions. Furthermore, in a virtual screening approach, the drug 5_7_DIHYDROXY_ 2_ (3_4_5_TRI HYDROXYPHENYL) _4H_CHROMEN_ 4_ONE displayed good binding affinity for proteins with the mutations R24C or R246C, the drug diosmin displayed good binding affinity for the protein with the mutation Y180H, and the drug rutin displayed good binding affinity for proteins with the mutations A205T and R210P. Overall, this computational investigation of the CDK4 gene highlights the link between genetic variation and biological phenomena in human cancer and aids in the discovery of molecularly targeted therapies for personalized treatment. PMID- 26252491 TI - Determination of Parameters for the Supercritical Extraction of Antioxidant Compounds from Green Propolis Using Carbon Dioxide and Ethanol as Co-Solvent. AB - The aim of this study was to determine the best processing conditions to extract Brazilian green propolis using a supercritical extraction technology. For this purpose, the influence of different parameters was evaluated such as S/F (solvent mass in relation to solute mass), percentage of co-solvent (1 and 2% ethanol), temperature (40 and 50 degrees C) and pressure (250, 350 and 400 bar) using supercritical carbon dioxide. The Global Yield Isotherms (GYIs) were obtained through the evaluation of the yield, and the chemical composition of the extracts was also obtained in relation to the total phenolic compounds, flavonoids, antioxidant activity and 3,5-diprenyl-4-hydroxicinnamic acid (Artepillin C) and acid 4-hydroxycinnamic (p-coumaric acid). The best results were identified at 50 degrees C, 350 bar, 1% ethanol (co-solvent) and S/F of 110. These conditions, a content of 8.93+/-0.01 and 0.40+/-0.05 g/100 g of Artepillin C and p-coumaric acid, respectively, were identified indicating the efficiency of the extraction process. Despite of low yield of the process, the extracts obtained had high contents of relevant compounds, proving the viability of the process to obtain green propolis extracts with important biological applications due to the extracts composition. PMID- 26252492 TI - Improved Detection of Microsatellite Instability in Early Colorectal Lesions. AB - Microsatellite instability (MSI) occurs in over 90% of Lynch syndrome cancers and is considered a hallmark of the disease. MSI is an early event in colon tumor development, but screening polyps for MSI remains controversial because of reduced sensitivity compared to more advanced neoplasms. To increase sensitivity, we investigated the use of a novel type of marker consisting of long mononucleotide repeat (LMR) tracts. Adenomas from 160 patients, ranging in age from 29-55 years old, were screened for MSI using the new markers and compared with current marker panels and immunohistochemistry standards. Overall, 15 tumors were scored as MSI-High using the LMRs compared to 9 for the NCI panel and 8 for the MSI Analysis System (Promega). This difference represents at least a 1.7-fold increase in detection of MSI-High lesions over currently available markers. Moreover, the number of MSI-positive markers per sample and the size of allelic changes were significantly greater with the LMRs (p = 0.001), which increased confidence in MSI classification. The overall sensitivity and specificity of the LMR panel for detection of mismatch repair deficient lesions were 100% and 96%, respectively. In comparison, the sensitivity and specificity of the MSI Analysis System were 67% and 100%; and for the NCI panel, 75% and 97%. The difference in sensitivity between the LMR panel and the other panels was statistically significant (p<0.001). The increased sensitivity for detection of MSI-High phenotype in early colorectal lesions with the new LMR markers indicates that MSI screening for the early detection of Lynch syndrome might be feasible. PMID- 26252493 TI - Viewing Complex, Dynamic Scenes "Through the Eyes" of Another Person: The Gaze Replay Paradigm. AB - We present a novel "Gaze-Replay" paradigm that allows the experimenter to directly test how particular patterns of visual input-generated from people's actual gaze patterns-influence the interpretation of the visual scene. Although this paradigm can potentially be applied across domains, here we applied it specifically to social comprehension. Participants viewed complex, dynamic scenes through a small window displaying only the foveal gaze pattern of a gaze "donor." This was intended to simulate the donor's visual selection, such that a participant could effectively view scenes "through the eyes" of another person. Throughout the presentation of scenes presented in this manner, participants completed a social comprehension task, assessing their abilities to recognize complex emotions. The primary aim of the study was to assess the viability of this novel approach by examining whether these Gaze-Replay windowed stimuli contain sufficient and meaningful social information for the viewer to complete this social perceptual and cognitive task. The results of the study suggested this to be the case; participants performed better in the Gaze-Replay condition compared to a temporally disrupted control condition, and compared to when they were provided with no visual input. This approach has great future potential for the exploration of experimental questions aiming to unpack the relationship between visual selection, perception, and cognition. PMID- 26252494 TI - Transmission of Leishmania donovani in the Hills of Eastern Nepal, an Outbreak Investigation in Okhaldhunga and Bhojpur Districts. AB - BACKGROUND: In the Indian subcontinent, Visceral leishmaniasis is endemic in a geographical area coinciding with the Lower Gangetic Plain, at low altitude. VL occurring in residents of hill districts is therefore often considered the result of Leishmania donovani infection during travel. Early 2014 we conducted an outbreak investigation in Okhaldhunga and Bhojpur districts in the Nepal hills where increasing number of VL cases have been reported. METHODOLOGY/PRINCIPAL FINDINGS: A house-to-house survey in six villages documented retrospectively 35 cases of Visceral Leishmaniasis (VL). Anti-Leishmania antibodies were found in 22/23 past-VL cases, in 40/416 (9.6%) persons without VL and in 12/155 (7.7%) domestic animals. An age- and sex- matched case-control study showed that exposure to known VL-endemic regions was no risk factor for VL, but having a VL case in the neighbourhood was. SSU-rDNA PCR for Leishmania sp. was positive in 24 (5%) of the human, in 18 (12%) of the animal samples and in 16 (14%) bloodfed female Phlebotomus argentipes sand flies. L. donovani was confirmed in two asymptomatic individuals and in one sand fly through hsp70-based sequencing. CONCLUSIONS/SIGNIFICANCE: This is epidemiological and entomological evidence for ongoing local transmission of L. donovani in villages at an altitude above 600 meters in Nepal, in districts considered hitherto non-endemic for VL. The VL Elimination Initiative in Nepal should therefore consider extending its surveillance and control activities in order to assure VL elimination, and the risk map for VL should be redesigned. PMID- 26252495 TI - Green Plants in the Red: A Baseline Global Assessment for the IUCN Sampled Red List Index for Plants. AB - Plants provide fundamental support systems for life on Earth and are the basis for all terrestrial ecosystems; a decline in plant diversity will be detrimental to all other groups of organisms including humans. Decline in plant diversity has been hard to quantify, due to the huge numbers of known and yet to be discovered species and the lack of an adequate baseline assessment of extinction risk against which to track changes. The biodiversity of many remote parts of the world remains poorly known, and the rate of new assessments of extinction risk for individual plant species approximates the rate at which new plant species are described. Thus the question 'How threatened are plants?' is still very difficult to answer accurately. While completing assessments for each species of plant remains a distant prospect, by assessing a randomly selected sample of species the Sampled Red List Index for Plants gives, for the first time, an accurate view of how threatened plants are across the world. It represents the first key phase of ongoing efforts to monitor the status of the world's plants. More than 20% of plant species assessed are threatened with extinction, and the habitat with the most threatened species is overwhelmingly tropical rain forest, where the greatest threat to plants is anthropogenic habitat conversion, for arable and livestock agriculture, and harvesting of natural resources. Gymnosperms (e.g. conifers and cycads) are the most threatened group, while a third of plant species included in this study have yet to receive an assessment or are so poorly known that we cannot yet ascertain whether they are threatened or not. This study provides a baseline assessment from which trends in the status of plant biodiversity can be measured and periodically reassessed. PMID- 26252496 TI - High HIV Burden in Men Who Have Sex with Men across Colombia's Largest Cities: Findings from an Integrated Biological and Behavioral Surveillance Study. AB - BACKGROUND: Among Latin America's concentrated HIV epidemics, little is known about men who have sex with men (MSM) in Colombia, the region's third largest country. To date, surveillance studies have been limited to Bogota, while 80% of HIV cases and deaths originate from Colombia's other cities and departments. The extent to which interventions should prioritize MSM outside of Bogota is unknown. METHODS: We recruited 2603 MSM using respondent-driven sampling from seven of Colombia's largest cities. HIV prevalence was estimated by site from dried blood spot samples. Behavioral data were collected through face-to-face interviews and risk factors for HIV infection analyzed using weighted, multi-level logistical regression models accounting for recruitment patterns. RESULTS: Across cities, HIV prevalence averaged 15%, varied from 6% to 24% and was highest in Cali, Bogota, and Barranquilla. In the past 12 months, 65% of MSM had >= 5 casual male partners and 23% had a female partner. Across partnerships (i.e., casual, stable, and commercial), the proportion of MSM engaging in unprotected sex was >= 52% with male partners and >= 66% with female partners. Self-reported history of STI (24%) and past-year illicit drug use (38%) were also common. In multivariate analysis, age >= 35 (adjusted odds ratio [AOR], 19.2) and 25-39 (AOR, 5.6) relative to <= 18-24 years, identifying as homosexual relative to heterosexual (AOR 0.1), meeting casual partners on the Internet (adjusted odds ratio [AOR], 3.1) and age of sexual debut of <= 13 years (AOR, 3.1) predicted HIV infection. HIV testing and prevention messaging reached just 24% of MSM in the past year. CONCLUSIONS: Findings support consistently elevated HIV burden among MSM throughout Colombia's largest cities and a need for enhanced behavioral prevention and HIV testing, emphasizing men who use the Internet as well as physical venues to meet sex partners. PMID- 26252497 TI - Beyond the Whole-Genome Duplication: Phylogenetic Evidence for an Ancient Interspecies Hybridization in the Baker's Yeast Lineage. AB - Whole-genome duplications have shaped the genomes of several vertebrate, plant, and fungal lineages. Earlier studies have focused on establishing when these events occurred and on elucidating their functional and evolutionary consequences, but we still lack sufficient understanding of how genome duplications first originated. We used phylogenomics to study the ancient genome duplication occurred in the yeast Saccharomyces cerevisiae lineage and found compelling evidence for the existence of a contemporaneous interspecies hybridization. We propose that the genome doubling was a direct consequence of this hybridization and that it served to provide stability to the recently formed allopolyploid. This scenario provides a mechanism for the origin of this ancient duplication and the lineage that originated from it and brings a new perspective to the interpretation of the origin and consequences of whole-genome duplications. PMID- 26252498 TI - Toxicity of mancozeb, chlorothalonil, captan, fluopyram, boscalid, and difenoconazole to Didymella applanata isolates from Serbia. AB - Field isolates of Didymella applanata, the causal agent of spur blight of raspberry, were evaluated in vitro for their sensitivity to mancozeb, chlorothalonil, captan, fluopyram, boscalid and difenoconazole. A total of 10 isolates, collected during 2013 at five localities in the major raspberry growing region in Serbia, and characterized as copper hydroxide, dithianon, and tebuconazole (sensitive), pyraclostrobin (sensitive or highly resistant) and fluazinam (sensitive or moderately resistant), were used in this study. The EC50 values for the isolates ranged from 1.33 to 2.88 mg L(-1) for mancozeb, from 3.18 to 6.65 mg L(-1) for chlorothalonil, from 15.75 to 24.69 mg L(-1) for captan and from 1.80 to 8.20 mg L(-1) for fluopyram. The narrowest range of EC50 values was recorded for difenoconazole (0.23-0.49 mg L(-1)), whereas the widest range was obtained for boscalid (4.49-49.25 mg L(-1)). The calculated resistance factors showed that all D. applanata isolates were sensitive to mancozeb, chlorothalonil, captan, and difenoconazole. Four isolates were moderately resistant to boscalid, while three of them were also moderately resistant to fluopyram. This finding of moderately resistant isolates to these SDHI fungicides indicates a possible cross resistance which should be clarified in further investigations. PMID- 26252499 TI - The Multimedia Piers-Harris Children's Self-Concept Scale 2: Its Psychometric Properties, Equivalence with the Paper-and-Pencil Version, and Respondent Preferences. AB - A multimedia version of Piers-Harris Children's Self-Concept Scale 2 (Piers Harris 2) was created with audio and cartoon animation to facilitate the measurement of self-concept among younger children. This study aimed to assess the psychometric qualities of the computer version of Piers-Harris 2 scores, examine its score equivalence with the paper-and-pencil version, and survey the respondent preference of the two versions. Two hundred and forty eight Taiwanese students from the first to fourth grade were recruited. In regard to the psychometric properties, high internal consistency (alpha = .91) was found for the total score of multimedia Piers-Harris 2. High interscale correlations (.77 to .83) of the multimedia Piers-Harris 2 scores and the results of confirmatory factor analysis suggested the multimedia Piers-Harris 2 contained good structural characteristics. The scores of the multimedia Piers-Harris 2 also had significant correlations with the scores of the Elementary School Children's Self Concept Scale. The equality of convergence and criterion-related validities of Piers Harris 2 scores for the multimedia and paper-and-pencil versions and the results of ICCs between the scores of the multimedia and paper-and-pencil Piers-Harris 2 suggested their high level of equivalence. Participants showed more positive attitudes towards the multimedia version. PMID- 26252500 TI - THB1 regulates nitrate reductase activity and THB1 and THB2 transcription differentially respond to NO and the nitrate/ammonium balance in Chlamydomonas. AB - Nitric oxide (NO) has emerged as an important regulator of the nitrogen assimilation pathway in plants. Nevertheless, this free radical is a double-edged sword for cells due to its high reactivity and toxicity. Hemoglobins, which belong to a vast and ancestral family of proteins present in all kingdoms of life, have arisen as important NO scavengers, through their NO dioxygenase (NOD) activity. The green alga Chlamydomonas reinhardtii has 12 hemoglobins (THB1-12) belonging to the truncated hemoglobins family. THB1 and THB2 are regulated by the nitrogen source and respond differentially to NO and the nitrate/ammonium balance. THB1 expression is upregulated by NO in contrast to THB2, which is downregulated. THB1 has NOD activity and thus a role in nitrate assimilation. In fact, THB1 is upregulated by nitrate and is under the control of NIT2, the major transcription factor in nitrate assimilation. In Chlamydomonas, it has been reported that nitrate reductase (NR) has a redox regulation and is inhibited by NO through an unknown mechanism. Now, a model in which THB1 interacts with NR is proposed for its regulation. THB1 takes electrons from NR redirecting them to NO dioxygenation. Thus, when cells are assimilating nitrate and NO appears (i.e. as a consequence of nitrite accumulation), THB1 has a double role: 1) to scavenge NO avoiding its toxic effects and 2) to control the nitrate reduction activity. PMID- 26252501 TI - Antibiotics for asymptomatic bacteriuria in pregnancy. AB - BACKGROUND: Asymptomatic bacteriuria occurs in 2% to 10% of pregnancies and, if not treated, up to 30% of mothers will develop acute pyelonephritis. Asymptomatic bacteriuria has been associated with low birthweight and preterm birth. OBJECTIVES: To assess the effect of antibiotic treatment for asymptomatic bacteriuria on the development of pyelonephritis and the risk of low birthweight and preterm birth. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (19 March 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomized trials comparing antibiotic treatment with placebo or no treatment in pregnant women with asymptomatic bacteriuria found on antenatal screening. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: Fourteen studies, involving almost 2000 women, were included. Antibiotic treatment compared with placebo or no treatment reduced the incidence of pyelonephritis (average risk ratio (RR) 0.23, 95% confidence interval (CI) 0.13 to 0.41; 11 studies, 1932 women; very low quality evidence). Antibiotic treatment was also associated with a reduction in the incidence of low birthweight babies (average RR 0.64, 95% CI 0.45 to 0.93; six studies, 1437 babies; low quality evidence) and preterm birth (RR 0.27, 95% CI 0.11 to 0.62; two studies, 242 women; low quality evidence). A reduction in persistent bacteriuria at the time of delivery was seen (average RR 0.30, 95% CI 0.18 to 0.53; four studies; 596 women). There were very limited data on which to estimate the effect of antibiotics on other infant outcomes and maternal adverse effects were rarely described.Overall, all 14 studies were assessed as being at high or unclear risk of bias. While many studies lacked an adequate description of methods and the risk of bias could only be assessed as unclear, in almost all studies there was at least one domain where the risk of bias was judged as high. The three primary outcomes were assessed with GRADE software and given a quality rating. Evidence for pyelonephritis, preterm birth and birthweight less than 2500 g was assessed as of low or very low quality. AUTHORS' CONCLUSIONS: While antibiotic treatment is effective in reducing the risk of pyelonephritis in pregnancy, the estimate of the effect is very uncertain because of the very low quality of the evidence. The reduction in low birthweight and preterm birth with antibiotic treatment is consistent with theories about the role of infection in adverse pregnancy outcomes, but this association should be interpreted with caution given the very poor quality of the included studies. PMID- 26252502 TI - Inhibition of carbonic anhydrase IX (CA9) sensitizes renal cell carcinoma to ionizing radiation. AB - While normal kidneys are relatively sensitive to ionizing radiation (IR), renal cell carcinoma (RCC) is considered radioresistant. Carbonic anhydrase IX (CA9), an enzyme that maintains intracellular pH by carbon dioxide dissolution, is upregulated in the majority of RCC, but not in normal kidneys. Since regulation of intracellular pH may enhance radiation effects, we hypothesized that inhibition of CA9 may radiosensitize RCC. Clonogenic survival assay of human clear cell RCC 786-O and murine RCC RAG cells in the presence of a pharmacological CA9 inhibitor or with shRNA-mediated knockdown of CA9 was performed to investigate the response to IR in vitro (single dose or fractionated) and in vivo. Extracellular pH changes were measured in vitro. Treatment with AEBS [4-(2-aminoethyl)benzene sulfonamide], a sulfonamide, was used as a pharmacological inhibitor of the enzymatic activity of CA9. Nude mice bearing subcutaneous xenografts of 786-O cells stably expressing CA9 shRNA or scrambled control were irradiated (6 Gy). Tumor growth was followed longitudinally in the 786-O-bearing mice receiving AEBS (50-200 ug/ml drinking water) or control (vehicle only) which were irradiated (6 Gy) and compared with mice receiving either IR or AEBS alone. In vitro inhibition of CA9 activity or expression significantly sensitized RCC cells to the effects of IR (p<0.05), an effect even more significant when hypofractionated IR was applied. In vivo irradiated xenografts from RCC cells transfected with CA9 shRNA were significantly smaller compared to irradiated xenografts from the scrambled shRNA controls (p<0.05). RCC xenografts from mice treated with AEBS in combination with IR grew significantly slower than all controls (p<0.05). Inhibition of CA9 expression or activity resulted in radiation sensitization of RCC in a preclinical mouse model. PMID- 26252503 TI - The Effects of 8-Week Plyometric Training on Physical Performance in Young Tennis Players. AB - OBJECTIVES: The aim of this study was to analyze the effects of an 8-week (conducted biweekly for a total of 16 sessions) plyometric training program (PT) (e.g., upper- and lower-body exercises) combined with regular tennis training on physical qualities in young tennis players. DESIGN: Sixty tennis players between the ages of 12 and 13 years (age 12.5 +/- 0.3 years, weight 44.2 +/- 7.0 kg, height 156.6 +/- 7.1 cm) were allocated to either the control group (standard in season regimen) (CG; n = 30) or the experimental group, which received an additional PT (TG; n = 30) for 30-60 min as a substitute for some tennis training within the usual 90-min practice. METHODS: Pre- and posttests included: anthropometric measures; vertical countermovement jump (CMJ); standing long jump (SLJ); 20 m sprint time (with 5 and 10 m splits); a modified 505 agility test; overhead medicine ball throw; and serve velocity test. RESULTS: After the training intervention, the TG showed significant (p < .01) improvements in all the parameters analyzed, with percentages of change and effect sizes ranging from 3.1% to 10.1% and 0.4 (small) to 1.3 (moderate), respectively. No significant changes were observed in the CG after the training intervention. CONCLUSIONS: PT was shown as an important stimulus for enhancing explosive actions in young tennis players. PMID- 26252505 TI - Characteristics and management of domestic waste in a rural area of the Tibetan Plateau. AB - In the rural area of the Tibetan Plateau (RATP), the characteristics of domestic waste, people's environmental awareness, people's willingness to pay and their influence factors were firstly studied by questionnaires, field samplings and laboratory tests. The results showed that, in the RATP, the generation of domestic waste was 85 g*d-1 per capita and it was mainly composed of plastics, inert waste, kitchen waste, glass and paper. The waste bulk density, moisture content, ash, combustible and low calorific value were 65 kg*m-3, 19.25%, 44.90%, 35.85% and 10,520 kJ*kg-1 respectively. These characteristics are influenced by income sources and geographical position to some extent. Classified collection should be promoted widely on the household and the village basis. Compost, fermentation, landfill, bioreactor landfill and semi-aerobic landfill have been approved as effective techniques to treat domestic waste, except incineration. The distance of 50-800 m between each collection facility and the disposal fee of around $0.8 per month per household are suggested. For suburbs or large population villages, it's better to treat domestic waste by the centralized way. But for the remote rural areas, a decentralized way is proposed. Significantly, the educational and economic influence should be considered into an effective domestic waste management program. IMPLICATIONS: The current situatio n of the environment in the rural areas of the Tibetan Plateau (RATP) was surveyed. There, the generation of organics and moisture of domestic waste were low but ash, recyclables, and combustibles were high. People's knowledge of domestic waste was absent but their participation in management was strong. Based on the current situation, compost, fermentation, and landfill were effective but incineration was inappropriate. Also, a localized mini landfill for a cluster of villages and or settlements was the best method there. PMID- 26252504 TI - Prostaglandin E1 protects bone marrow-derived mesenchymal stem cells against serum deprivation-induced apoptosis. AB - Mesenchymal stem cells (MSCs) have become a recent focus of experimental and clinical research regarding myocardial regeneration. However, the therapeutic potential of these cells is limited by poor survival. Prostaglandin E1 (PGE1) is known to have anti-inflammatory and anti-apoptotic effects on the myocardium. The aim of the present study was to determine whether PGE1 could protect MSCs against serum deprivation (SD)-induced apoptosis. An SD model was used to induce apoptosis in MSCs in vitro. Apoptotic morphological changes were detected by Hoechst 33258 fluorescent nuclear staining; and Annexin V-fluorescein isothiocyanate/propidium iodide (PI) double staining and flow cytometry was used to quantify the rate of apoptosis. Western blot analysis was used to detect the expression levels of the apoptosis-associated proteins Bcl-2, Bax and caspase-3. The results of the present study demonstrated that SD induced apoptosis of MSCs, and that treatment with PGE1 attenuated the morphological changes characteristic of apoptosis. Annexin V/PI staining showed that the rate of apoptosis gradually increased with the duration of ischemia. Furthermore, treatment with PGE1 significantly reduced SD-induced apoptosis, decreased the protein expression levels of Bax and caspase-3, and increased the expression levels of Bcl-2. These data suggest that PGE1 is able to influence the survival of MSCs under certain conditions. These results may aid in improving the therapeutic efficacy of MSC transplantation used to treat chronic ischemic heart disease. PMID- 26252506 TI - Anisotropic magnetic responses of a 2D-superconducting Bi2Te3/FeTe heterostructure. AB - We have investigated the anisotropic magnetic responses of a 2D-superconducting Bi2Te3/FeTe heterostructure. Cross-sectional STEM imaging revealed that the excess Fe atoms in the FeTe layer occupy specific interstitial sites. They were found to show strong anisotropic magnetic responses under a magnetic field either perpendicular or parallel to the sample surface. Under perpendicular magnetic fields within 1000 Oe, conventional paramagnetic Meissner effect, superconducting diamagnetism, and anomalous enhancement of magnetization successively occur as the magnetic field increases. In contrast, under parallel magnetic fields, superconducting diamagnetism was not observed explicitly in the magnetization measurements and the anomalous enhancement of magnetization appears only for fields higher than 1000 Oe. The observed strong magnetic anisotropy provides further evidence that the induced superconductivity at the interface of the Bi2Te3/FeTe heterostucture has a 2D nature. PMID- 26252507 TI - Effect of short-term application of kinesio tape on the flexion-relaxation phenomenon, trunk postural control and trunk repositioning in healthy females. AB - This study was designed to investigate the potential effects of kinesio tape on the flexion-relaxation phenomenon, trunk postural control and trunk position sense when applied for a short period (30 min) to the low back of healthy female participants. Twenty-four participants were assigned to one of two groups: kinesio tape applied in either the recommended stretched or non-stretched (control) manner over the low back. Tests were performed at three time points (pre-tape, with tape, post-tape) to assess low-back muscle flexion-relaxation, position sense during active trunk repositioning and trunk postural control during seated balance. Results demonstrated that wearing kinesio tape did not affect the angle at which the erector spinae muscles became silent during trunk flexion (flexion-relaxation). Trunk repositioning error increased when wearing kinesio tape in both the stretched and non-stretched manner, and this increased error persisted after the tape was removed. Seated balance control improved when wearing kinesio tape in both the stretched and non-stretched manner, and these improvements persisted after the tape was removed. In conclusion, these findings do not support the general suggestions that short-term use of kinesio tape on the low-back region alter low-back muscle activation and enhance tasks related to proprioception, at least under these taping conditions in a group of healthy females. PMID- 26252508 TI - Real-time monitoring in vivo behaviors of theranostic nanoparticles by contrast enhanced T1 imaging. AB - The innovative applications of engineered nanoparticles (NPs) in medicine, such as diagnosis and therapy, have attracted considerable attention. It is highly important to predict the interactions between engineered NPs and the complex biological system as well as the impacts on the subsequent behaviors in living subjects. Herein, we report the use of T1 contrast-enhanced magnetic resonance imaging (MRI) to monitor the in vivo behaviors of NPs in a real-time manner. We chose ultrasmall Pd nanosheets (SPNSs) as the object of NPs because of their promise in theranostics and fitness for diverse surface chemistry. SPNSs were modified with different surface coating ligands (e.g., polyethylene glycol, zwitterionic ligands, polyethylenimine) and functionalized with Gd-chelates to render T1 contrast-enhanced capability. MRI real-time monitoring recorded the location and accumulation of SPNSs in small animals and revealed the prominent roles of surface coating ligands in pharmacokinetics. These results highlighted the significance of selecting proper surface coating for particular biomedical assignment. Moreover, we demonstrated a powerful and noninvasive means to predict and detect the behaviors of NPs in living subjects, which may be helpful for rational design and screening of engineered NPs in biomedical applications. PMID- 26252510 TI - Analysis of the differences in whole-genome expression related to asthma and obesity. AB - INTRODUCTION: Concomitant obesity significantly impairs asthma control. Obese asthmatics show more severe symptoms and an increased use of medications. OBJECTIVES: The primary aim of the study was to identify genes that are differentially expressed in the peripheral blood of asthmatic patients with obesity, asthmatic patients with normal body mass, and obese patients without asthma. Secondly, we investigated whether the analysis of gene expression in peripheral blood may be helpful in the differential diagnosis of obese patients who present with symptoms similar to asthma. PATIENTS AND METHODS: The study group included 15 patients with asthma (9 obese and 6 normal-weight patients), while the control group-13 obese patients in whom asthma was excluded. The analysis of whole-genome expression was performed on RNA samples isolated from peripheral blood. RESULTS: The comparison of gene expression profiles between asthmatic patients with obesity and those with normal body mass revealed a significant difference in 6 genes. The comparison of the expression between controls and normal-weight patients with asthma showed a significant difference in 23 genes. The analysis of genes with a different expression revealed a group of transcripts that may be related to an increased body mass (PI3, LOC100008589, RPS6KA3, LOC441763, IFIT1, and LOC100133565). Based on gene expression results, a prediction model was constructed, which allowed to correctly classify 92% of obese controls and 89% of obese asthmatic patients, resulting in the overall accuracy of the model of 90.9%. CONCLUSIONS: The results of our study showed significant differences in gene expression between obese asthmatic patients compared with asthmatic patients with normal body mass as well as in obese patients without asthma compared with asthmatic patients with normal body mass. PMID- 26252509 TI - The primary somatosensory cortex and the insula contribute differently to the processing of transient and sustained nociceptive and non-nociceptive somatosensory inputs. AB - Transient nociceptive stimuli elicit consistent brain responses in the primary and secondary somatosensory cortices (S1, S2), the insula and the anterior and mid-cingulate cortex (ACC/MCC). However, the functional significance of these responses, especially their relationship with sustained pain perception, remains largely unknown. Here, using functional magnetic resonance imaging, we characterize the differential involvement of these brain regions in the processing of sustained nociceptive and non-nociceptive somatosensory input. By comparing the spatial patterns of activity elicited by transient (0.5 ms) and long-lasting (15 and 30 s) stimuli selectively activating nociceptive or non nociceptive afferents, we found that the contralateral S1 responded more strongly to the onset of non-nociceptive stimulation as compared to the onset of nociceptive stimulation and the sustained phases of nociceptive and non nociceptive stimulation. Similarly, the anterior insula responded more strongly to the onset of nociceptive stimulation as compared to the onset of non nociceptive stimulation and the sustained phases of nociceptive and non nociceptive stimulation. This suggests that S1 is specifically sensitive to changes in incoming non-nociceptive input, whereas the anterior insula is specifically sensitive to changes in incoming nociceptive input. Second, we found that the MCC responded more strongly to the onsets as compared to the sustained phases of both nociceptive and non-nociceptive stimulation, suggesting that it could be involved in the detection of change regardless of sensory modality. Finally, the posterior insula and S2 responded maximally during the sustained phase of non-nociceptive stimulation but not nociceptive stimulation, suggesting that these regions are preferentially involved in processing non-nociceptive somatosensory input. PMID- 26252511 TI - Bioinformatics Analysis Reveals Abundant Short Alpha-Helices as a Common Structural Feature of Oomycete RxLR Effector Proteins. AB - RxLR effectors represent one of the largest and most diverse effector families in oomycete plant pathogens. These effectors have attracted enormous attention since they can be delivered inside the plant cell and manipulates host immunity. With the exceptions of a signal peptide and the following RxLR-dEER and C-terminal W/Y/L motifs identified from the sequences themselves, nearly no functional domains have been found. Recently, protein structures of several RxLRs were revealed to comprise alpha-helical bundle repeats. However, approximately half of all RxLRs lack obvious W/Y/L motifs, which are associated with helical structures. In this study, secondary structure prediction of the putative RxLR proteins was performed. We found that the C-terminus of the majority of these RxLR proteins, irrespective of the presence of W/Y/L motifs, contains abundant short alpha-helices. Since a large-scale experimental determination of protein structures has been difficult to date, results of the current study extend our understanding on the oomycete RxLR effectors in protein secondary structures from individual members to the entire family. Moreover, we identified less alpha-helix rich proteins from secretomes of several oomycete and fungal organisms in which RxLRs have not been identified, providing additional evidence that these organisms are unlikely to harbor RxLR-like proteins. Therefore, these results provide additional information that will aid further studies on the evolution and functional mechanisms of RxLR effectors. PMID- 26252512 TI - Polymyxin E Induces Rapid Paenibacillus polymyxa Death by Damaging Cell Membrane while Ca2+ Can Protect Cells from Damage. AB - Polymyxin E, produced by Paenibacillus polymyxa, is an important antibiotic normally against Gram-negative pathogens. In this study, we found that polymyxin E can kill its producer P. polymyxa, a Gram-positive bacterium, by disrupting its cell membrane. Membrane damage was clearly revealed by detecting the leakage of intracellular molecules. The observation using scanning electron microscopy also supported that polymyxin E can destroy the cell membrane and cause an extensive cell surface alteration. On the other hand, divalent cations can give protection against polymyxin E. Compared with Mg2+, Ca2+ can more effectively alleviate polymyxin E-induced damage to the cell membrane, thus remarkably increasing the P. polymyxa survival. Our findings would shed light on a not yet described bactericidal mechanism of polymyxin E against Gram-positive bacteria and more importantly the nature of limited fermentation output of polymyxin E from P. polymyxa. PMID- 26252513 TI - The RhoGAP activity of CYK-4/MgcRacGAP functions non-canonically by promoting RhoA activation during cytokinesis. AB - Cytokinesis requires activation of the GTPase RhoA. ECT-2, the exchange factor responsible for RhoA activation, is regulated to ensure spatiotemporal control of contractile ring assembly. Centralspindlin, composed of the Rho family GTPase activating protein (RhoGAP) MgcRacGAP/CYK-4 and the kinesin MKLP1/ZEN-4, is known to activate ECT-2, but the underlying mechanism is not understood. We report that ECT-2-mediated RhoA activation depends on the ability of CYK-4 to localize to the plasma membrane, bind RhoA, and promote GTP hydrolysis by RhoA. Defects resulting from loss of CYK-4 RhoGAP activity can be rescued by activating mutations in ECT 2 or depletion of RGA-3/4, which functions as a conventional RhoGAP for RhoA. Consistent with CYK-4 RhoGAP activity contributing to GEF activation, the catalytic domains of CYK-4 and ECT-2 directly interact. Thus, counterintuitively, CYK-4 RhoGAP activity promotes RhoA activation. We propose that the most active form of the cytokinetic RhoGEF involves complex formation between ECT-2, centralspindlin and RhoA. PMID- 26252514 TI - Lamprey VLRB response to influenza virus supports universal rules of immunogenicity and antigenicity. AB - Immunoglobulins (Igs) are a crown jewel of jawed vertebrate evolution. Through recombination and mutation of small numbers of genes, Igs can specifically recognize a vast variety of natural and man-made organic molecules. Jawless vertebrates evolved a parallel system of humoral immunity, which recognizes antigens not with Ig, but with a structurally unrelated receptor called the variable lymphocyte receptor B (VLRB). We exploited the convergent evolution of Ig and VLRB antibodies (Abs) to investigate if intrinsic chemical features of foreign proteins determine their antigenicity and immunogenicity. Surprisingly, we find lamprey VLRB and mouse Ig responses to influenza A virus are extremely similar. Each focuses ~80% of the response on hemagglutinin (HA), mainly through recognition of the major antigenic sites in the HA globular head domain. Our findings predict basic conservation of Ab responses to protein antigens, strongly supporting the use of animal models for understanding human Ab responses to viruses and protein immunogens. PMID- 26252515 TI - Mass enhances speed but diminishes turn capacity in terrestrial pursuit predators. AB - The dynamics of predator-prey pursuit appears complex, making the development of a framework explaining predator and prey strategies problematic. We develop a model for terrestrial, cursorial predators to examine how animal mass modulates predator and prey trajectories and affects best strategies for both parties. We incorporated the maximum speed-mass relationship with an explanation of why larger animals should have greater turn radii; the forces needed to turn scale linearly with mass whereas the maximum forces an animal can exert scale to a 2/3 power law. This clarifies why in a meta-analysis, we found a preponderance of predator/prey mass ratios that minimized the turn radii of predators compared to their prey. It also explained why acceleration data from wild cheetahs pursuing different prey showed different cornering behaviour with prey type. The outcome of predator prey pursuits thus depends critically on mass effects and the ability of animals to time turns precisely. PMID- 26252516 TI - Population Structure of and Conservation Strategies for Wild Pyrus ussuriensis Maxim. in China. AB - Pyrus ussriensis Maxim. is native to the northern part of China, but whose habitats are currently being destroyed by environmental changes and human deforestation. An investigation of population structure and genetic diversity of wild Ussurian pear is a priority in order to acquire fundamental knowledge for conservation. A total of 153 individuals of wild Ussurian pear from the main habitats, Heilongjiang, Jilin, and Inner Mongolia in China, possessed low genetic diversity as a result of habitat fragmentation. The genetic diversity of the populations in Inner Mongolia and north east of Heilongjiang was especially low and there was the possibility of inbreeding. Wild Ussurian pears were divided into 5 groups based on the Bayesian clustering method using 20 nuclear SSRs (nSSRs) and 5 groups by haplotype distributions using 16 chloroplast SSRs (cpSSRs), and the populations in Inner Mongolia and north east of Heilongjiang represented unique genotypes. AMOVA indicated there was a 20.05% variation in nSSRs and a 44.40% variation in cpSSRs among populations. These values are relatively high when compared to those of other tree species. Haplotype E, positioned in the center of the cpSSR analysis network and showed the largest number of connections with other haplotypes, represented the most important haplotype. Inner Mongolia and the north east of Heilongjiang are two areas that need urgent conservation because of their genetic vulnerability and peculiarity. We determined 4 conservation units based on the clustering by nSSRs and cpSSRs, and geographic factor. This information is helpful in deciding the conservation strategies for wild Ussurian pear in China. PMID- 26252517 TI - Psychotropic Drug Use in Sao Paulo, Brazil--An Epidemiological Survey. AB - OBJECTIVE: To estimate the prevalence of one month psychotropic drug use in Sao Paulo, Brazil, and to assess the gap treatment between the presence of mental disorders and psychotropic drug users. METHOD: A probabilistic sample of non institutionalized individuals from the general population of Sao Paulo (n = 2336; turnout: 84.5%) who were 15 years or older were interviewed by a trained research staff, applying the Composite International Diagnostic Interview 2.1 (CIDI WHO) (depression, anxiety-phobia, OCD?PTSD, alcoholism sections), and an inventory investigating psychotropic drug use during the 12-month and one-month periods immediately preceding the interview. Logistic models were fitted to investigate associations between psychotropic drug use as well as socio-demographic and clinical variables. RESULTS: The one month prevalence of psychotropic drug use in Sao Paulo was 5.89%, the most commonly used drugs were antidepressants (3.15%) and tranquilizers (2.67%). A higher consumption of psychotropic drugs (overall, antidepressants and tranquilizers) was observed among women (OR:2.42), older individuals (OR:1.04), individuals with higher levels of formal education (1.06), and individuals with a family (OR:2.29) or personal history of mental illness (OR:3.27). The main psychotropic drug prescribers were psychiatrists (41%), followed by general practitioners (30%); 60% of psychotropic drugs were obtained through a government-run dispensing program. Most individuals who obtained a positive diagnosis on the CIDI 2.1 during the previous month were not using psychotropic medication (85%). Among individuals with a diagnosis of moderate to severe depression, 67.5% were not on any pharmacological treatment. CONCLUSION: There is a change in the type of psychotropic more often used in Sao Paulo, from benzodiazepines to antidepressants, this event is observed in different cultures. The prevalence of use is similar to other developing countries. Most of the patients presenting a psychiatric illness in the month prior to testing were not receiving any sort of psychiatric medication. This may be explained by a failure to identify cases in primary care, which could be improved (and access to treatment could be facilitated) if professionals received more specialized training in managing cases with mental health problems. PMID- 26252518 TI - Endometrial Endometrioid Carcinoma Metastases Show Decreased ER-Alpha and PR-A Expression Compared to Matched Primary Tumors. AB - Patients with endometrial endometrioid carcinoma (EEC) that present with advanced primary disease and develop recurrences have a poor outcome. The phenotype of EEC metastases and recurrences is poorly studied. We evaluated the morphological features and ER-alpha/PRA/p53 immunohistochemical expression of a sample of 45 EEC metastases compared to matched primary tumors. Additionally, we studied methylation levels of ER-alpha/PRA gene promoters. The distribution of histological FIGO grade was significantly different in metastases, which disclosed higher grade than primary tumors (p = 0.005). Mitotic index was significantly lower in metastases compared to matched primary tumors (p<0.001). ER-alpha (p = 0.002) and PRA (p<0.001) median H-scores were significantly lower in metastases than in matched primary EECs, but there was no significant difference concerning p53 expression (p = 0.056). ER-alpha/PRA expression differences did not correlate with differences in metastases morphology. ER alpha/PRA gene promoter levels were globally low (range: 0% to 11.9%). One case showed higher ER-alpha gene promoter methylation in metastasis compared to matched EEC primary tumor. Regarding PRA, there was a significant higher frequency of its promotor methylation in metastases compared to primary tumors (51.6% vs. 22.7%, p = 0.022). In conclusion, EEC metastatic disease displays phenotypic changes along with ER-alpha and PRA decreased expression compared to primary tumors. ER-alpha and PRA gene promoter methylation seems to play a limited role in the etiology of these alterations. PR expression assessment for hormonal treatment decision of patients with advanced tumors, may be more adequate in metastases than in EEC primary tumors. PMID- 26252519 TI - Methods for Improving Human Gut Microbiome Data by Reducing Variability through Sample Processing and Storage of Stool. AB - Gut microbiome community analysis is used to understand many diseases like inflammatory bowel disease, obesity, and diabetes. Sampling methods are an important consideration for human microbiome research, yet are not emphasized in many studies. In this study, we demonstrate that the preparation, handling, and storage of human faeces are critical processes that alter the outcomes of downstream DNA-based bacterial community analyses via qPCR. We found that stool subsampling resulted in large variability of gut microbiome data due to different microenvironments harbouring various taxa within an individual stool. However, we reduced intra-sample variability by homogenizing the entire stool sample in liquid nitrogen and subsampling from the resulting crushed powder prior to DNA extraction. We experimentally determined that the bacterial taxa varied with room temperature storage beyond 15 minutes and beyond three days storage in a domestic frost-free freezer. While freeze thawing only had an effect on bacterial taxa abundance beyond four cycles, the use of samples stored in RNAlater should be avoided as overall DNA yields were reduced as well as the detection of bacterial taxa. Overall we provide solutions for processing and storing human stool samples that reduce variability of microbiome data. We recommend that stool is frozen within 15 minutes of being defecated, stored in a domestic frost-free freezer for less than three days, and homogenized prior to DNA extraction. Adoption of these simple protocols will have a significant and positive impact on future human microbiome research. PMID- 26252520 TI - AdHu5Ag85A Respiratory Mucosal Boost Immunization Enhances Protection against Pulmonary Tuberculosis in BCG-Primed Non-Human Primates. AB - Persisting high global tuberculosis (TB) morbidity and mortality and poor efficacy of BCG vaccine emphasizes an urgent need for developing effective novel boost vaccination strategies following parenteral BCG priming in humans. Most of the current lead TB vaccine candidates in the global pipeline were developed for parenteral route of immunization. Compelling evidence indicates respiratory mucosal delivery of vaccine to be the most effective way to induce robust local mucosal protective immunity against pulmonary TB. However, despite ample supporting evidence from various animal models, there has been a lack of evidence supporting the safety and protective efficacy of respiratory mucosal TB vaccination in non-human primates (NHP) and humans. By using a rhesus macaque TB model we have evaluated the safety and protective efficacy of a recombinant human serotype 5 adenovirus-based TB vaccine (AdHu5Ag85A) delivered via the respiratory mucosal route. We show that mucosal AdHu5Ag85A boost immunization was safe and well tolerated in parenteral BCG-primed rhesus macaques. A single AdHu5Ag85A mucosal boost immunization in BCG-primed rhesus macaques enhanced the antigen specific T cell responses. Boost immunization significantly improved the survival and bacterial control following M.tb challenge. Furthermore, TB-related lung pathology and clinical outcomes were lessened in BCG-primed, mucosally boosted animals compared to control animals. Thus, for the first time we show that a single respiratory mucosal boost immunization with a novel TB vaccine enhances protection against pulmonary TB in parenteral BCG-primed NHP. Our study provides the evidence for the protective potential of AdHu5Ag85A as a respiratory mucosal boost TB vaccine for human application. PMID- 26252521 TI - Inhibition of cell proliferation, invasion and migration by the cardenolides digitoxigenin monodigitoxoside and convallatoxin in human lung cancer cell line. AB - Cardiac glycosides consist of a large family of naturally derived compounds that are clinically used to treat congestive heart failure, and also present anticancer properties. In this study, the cytotoxic effects of two cardenolides, digitoxigenin monodigitoxoside (DGX) and convallatoxin (CON) were screened in four human tumour cell lines. Both compounds showed anti-proliferative effects in all tumour cells, at nanomolar concentrations. Since the human lung cancer cell line A549 was the most sensitive, we investigated the anti-proliferative, anti migratory and anti-invasive effects of these cardenolides. DGX and CON reduced A549 cell migration, being able to reduce more than 90% of cell invasion. Their effects on the expression of key regulators of metastatic mechanism showed decreased levels of MMP-2, MMP-9 and p-FAK. Both compounds also presented low toxicity for healthy cells. Finally, this work provides the first insights into the effects of these cardenolides on key steps of lung cancer metastasis. PMID- 26252522 TI - Effect of Paralysis at the Time of ProSeal Laryngeal Mask Airway Insertion on Pharyngolaryngeal Morbidities. A Randomized Trial. AB - Neuromuscular block results in the loss of muscular tone in the upper airway, which might contribute to the increased postoperative airway morbidity followed by ProSeal laryngeal mask airway (PLMA) insertion. We compared the pharyngolaryngeal discomfort exerted by the PLMA according to the neuromuscular block. One hundred sixty patients undergoing surgery for breast disease or inguinal hernia were anesthetized with propofol and remifentanil by target controlled infusion. Rocuronium 0.6 mg/kg (NMBA group, n = 80) or normal saline (No-NMBA group, n = 80) was administered after the loss of consciousness, and one anesthesiologist inserted the PLMA. Postoperative pharyngolaryngeal discomfort was evaluated at postoperative 1 h. Traumatic event was recorded based on the blood trace on the surface of the PLMA cuff. Insertion time, insertion attempt number, sealing pressure, and fiberoptic brochoscopic grades were evaluated. Patients' characteristics and the PLMA insertion condition (insertion time, successful insertion attempt number, fiberoptic bronchoscopic grade, and sealing pressure) were similar between the two groups. The PLMA can be successfully inserted in non-paralyzed patients with less postoperative pharyngolaryngeal discomfort than when a neuromuscular blocking agent is used (13.8% vs. 30.0%, P = 0.021). The incidence of traumatic events is also reduced when no neuromuscular blocking agent is used (16.3% vs. 32.5%, P = 0.026). Regardless of whether or not a surgical procedure requires muscular relaxation, there is no need to administer neuromuscular blocking agents solely for the purpose of PLMA insertion. PMID- 26252523 TI - Origin and evolution of Nipah virus. AB - Nipah virus, member of the Paramyxoviridae family, is classified as a Biosafety Level-4 agent and category C priority pathogen. Nipah virus disease is endemic in south Asia and outbreaks have been reported in Malaysia, Singapore, India, and Bangladesh. Bats of the genus Pteropus appear to be the natural reservoir of this virus. The aim of this study was to investigate the genetic diversity of Nipah virus, to estimate the date of origin and the spread of the infection. The mean value of Nipah virus N gene evolutionary rate, was 6.5 * 10(-4) substitution/site/year (95% HPD: 2.3 * 10(-4)-1.18 * 10(-3)). The time-scaled phylogenetic analysis showed that the root of the tree originated in 1947 (95% HPD: 1888-1988) as the virus entered in south eastern Asiatic regions. The segregation of sequences in two main clades (I and II) indicating that Nipah virus had two different introductions: one in 1995 (95% HPD: 1985-2002) which correspond to clade I, and the other in 1985 (95% HPD: 1971-1996) which correspond to clade II. The phylogeographic reconstruction indicated that the epidemic followed two different routes spreading to the other locations. The trade of infected pigs may have played a role in the spread of the virus. Bats of the Pteropus genus, that are able to travel to long distances, may have contributed to the spread of the infection. Negatively selected sites, statistically supported, could reflect the stability of the viral N protein. PMID- 26252524 TI - On Reminder Effects, Drop-Outs and Dominance: Evidence from an Online Experiment on Charitable Giving. AB - We present the results of an experiment that (a) shows the usefulness of screening out drop-outs and (b) tests whether different methods of payment and reminder intervals affect charitable giving. Following a lab session, participants could make online donations to charity for a total duration of three months. Our procedure justifying the exclusion of drop-outs consists in requiring participants to collect payments in person flexibly and as known in advance and as highlighted to them later. Our interpretation is that participants who failed to collect their positive payments under these circumstances are likely not to satisfy dominance. If we restrict the sample to subjects who did not drop out, but not otherwise, reminders significantly increase the overall amount of charitable giving. We also find that weekly reminders are no more effective than monthly reminders in increasing charitable giving, and that, in our three months duration experiment, standing orders do not increase giving relative to one-off donations. PMID- 26252525 TI - Intrinsic Functional Connectivity in Salience and Default Mode Networks and Aberrant Social Processes in Youth at Ultra-High Risk for Psychosis. AB - Social processes are key to navigating the world, and investigating their underlying mechanisms and cognitive architecture can aid in understanding disease states such as schizophrenia, where social processes are highly impacted. Evidence suggests that social processes are impaired in individuals at ultra high risk for the development of psychosis (UHR). Understanding these phenomena in UHR youth may clarify disease etiology and social processes in a period that is characterized by significantly fewer confounds than schizophrenia. Furthermore, understanding social processing deficits in this population will help explain these processes in healthy individuals. The current study examined resting state connectivity of the salience (SN) and default mode networks (DMN) in association with facial emotion recognition (FER), an integral aspect of social processes, as well as broader social functioning (SF) in UHR individuals and healthy controls. Consistent with the existing literature, UHR youth were impaired in FER and SF when compared with controls. In the UHR group, we found increased connectivity between the SN and the medial prefrontal cortex, an area of the DMN relative to controls. In UHR youth, the DMN exhibited both positive and negative correlations with the somatosensory cortex/cerebellum and precuneus, respectively, which was linked with better FER performance. For SF, results showed that sensory processing links with the SN might be important in allowing for better SF for both groups, but especially in controls where sensory processing is likely to be unimpaired. These findings clarify how social processing deficits may manifest in psychosis, and underscore the importance of SN and DMN connectivity for social processing more generally. PMID- 26252527 TI - Promoter methylation, mRNA expression of goat tumor-associated genes and mRNA expression of DNA methyltransferase in enzootic nasal tumors. AB - The aim of the present study was to investigate the promoter methylation status and mRNA expression of goat tumor-associated genes, in addition to the mRNA expression of DNA methyltransferase genes in enzootic nasal tumors (ENT). Methylation-specific polymerase chain reaction and SYBR Green reverse transcription-quantitative polymerase chain reaction were used to detect the methylation status and the mRNA expression levels of DNA methyltransferases (DNMTs), O6-methylguanine-DNA methyltransferase (MGMT), the tumor suppressor genes P73, P53, GADD45G, CHFR and THBS1, the transcription factor CEBPA, the proto-oncogenes KRAS, NRAS and C-myc and EGFR in 24 nasal tumor tissue samples and 20 normal nasal epithelia tissue samples. The associations between promoter methylation and DNMT, and promoter methylation and mRNA expression of the genes were analyzed. The results indicated that the expression levels of DNMT1 increased by 56% compared with those in normal nasal epithelial tissues, while MGMT, DNMT3a and DNMT3b had similar expression levels in the two tissue types. The expression levels of P53 decreased by 36.8% and those of THBS1 by 43%, while C-myc increased by 2.9-fold and CEBPA by 2-fold compared with that in normal nasal epithelial tissues. GADD45G, P73, CHFR and NRAS were observed to have similar expression levels in the two tissue types. However, no expression was observed for EGFR and KRAS. CHFR, GADD45G and THBS1 were identified to be methylated in tumor suppressor genes. The methylation expression rate of the CHFR gene was ~60% in the two tissue types and for THBS1 it was 100% in the nasal tumor tissues as opposed to 20% in the normal nasal epithelial tissues. The exhaustive methylation expression rate of GADD45G was 62.5% and the partial methylation expression rate was 37.5% in nasal tumor tissue, while no methylation was observed in normal nasal epithelial tissues. C-myc was the only gene identified to be methylated amongst proto-oncogenes. The methylation expression rate of C-myc was 87.5% in nasal tumor tissues and 15% in normal nasal epithelial tissues. The methylation expression rate of CEBPA was 100% in nasal tumor tissues and 40% in normal nasal epithelial tissues. The methylation expression rate of the EGFR gene was ~80% in the two tissues. In summary, the present study identified abnormal methylation of the C-myc, CEBPA, GADD45G and THBS1 genes in nasal tumor tissues. The expression levels of DNMT1, C-myc and CEBPA were upregulated and the expression of P53 and THBSI were downregulated in nasal tumor tissues, with a significant difference between the two groups (P<0.05). Therefore, it is suggested that these six genes may be used as diagnostic marker candidates for ENT. The results may serve as a foundation for screening of tumor specific markers for early diagnosis of ENT and further investigate the epigenetic mechanisms of enzootic nasal tumor virus (ENTV)-induced nasal epithelium cell carcinoma. PMID- 26252526 TI - A Phase I Double Blind, Placebo-Controlled, Randomized Study of the Safety and Immunogenicity of Electroporated HIV DNA with or without Interleukin 12 in Prime Boost Combinations with an Ad35 HIV Vaccine in Healthy HIV-Seronegative African Adults. AB - BACKGROUND: Strategies to enhance the immunogenicity of DNA vaccines in humans include i) co-administration of molecular adjuvants, ii) intramuscular administration followed by in vivo electroporation (IM/EP) and/or iii) boosting with a different vaccine. Combining these strategies provided protection of macaques challenged with SIV; this clinical trial was designed to mimic the vaccine regimen in the SIV study. METHODS: Seventy five healthy, HIV-seronegative adults were enrolled into a phase 1, randomized, double-blind, placebo-controlled trial. Multi-antigenic HIV (HIVMAG) plasmid DNA (pDNA) vaccine alone or co administered with pDNA encoding human Interleukin 12 (IL-12) (GENEVAX IL-12) given by IM/EP using the TriGrid Delivery System was tested in different prime boost regimens with recombinant Ad35 HIV vaccine given IM. RESULTS: All local reactions but one were mild or moderate. Systemic reactions and unsolicited adverse events including laboratory abnormalities did not differ between vaccine and placebo recipients. No serious adverse events (SAEs) were reported. T cell and antibody response rates after HIVMAG (x3) prime-Ad35 (x1) boost were independent of IL-12, while the magnitude of interferon gamma (IFN-gamma) ELISPOT responses was highest after HIVMAG (x3) without IL-12. The quality and phenotype of T cell responses shown by intracellular cytokine staining (ICS) were similar between groups. Inhibition of HIV replication by autologous T cells was demonstrated after HIVMAG (x3) prime and was boosted after Ad35. HIV specific antibodies were detected only after Ad35 boost, although there was a priming effect with 3 doses of HIVMAG with or without IL-12. No anti-IL-12 antibodies were detected. CONCLUSION: The vaccines were safe, well tolerated and moderately immunogenic. Repeated administration IM/EP was well accepted. An adjuvant effect of co-administered plasmid IL-12 was not detected. TRIAL REGISTRATION: ClinicalTrials.gov NCT01496989. PMID- 26252528 TI - Polar Nature of Biomimetic Fluorapatite/Gelatin Composites: A Comparison of Bipolar Objects and the Polar State of Natural Tissue. AB - The correspondence of the state of alignment of macromolecules in biomimetic materials and natural tissues is demonstrated by investigating a mechanism of electrical polarity formation: An in vitro grown biomimetic FAp/gelatin composite is investigated for its polar properties by second harmonic (SHGM) and scanning pyroelectric microscopy (SPEM). Hexagonal prismatic seed crystals formed in gelatin gels represent a monodomain polar state, due to aligned mineralized gelatin molecules. Later growth stages, showing dumbbell morphologies, develop into a bipolar state because of surface recognition by gelatin functionality: A reversal of the polar alignment of macromolecules, thus, takes place close to that basal plane of the seed. In natural hard tissues (teeth and bone investigated by SPEM) and the biomimetic FAp/gelatin composite, we find a surprising analogy in view of growth-induced states of polarity: The development of polarity in vivo and in vitro can be explained by a Markov-type mechanism of molecular recognition during the attachment of macromolecules. PMID- 26252530 TI - Screening for undiagnosed obstructive airway disease: Does it make sense? PMID- 26252531 TI - Respiratory medicine in Saskatchewan: An historical perspective. PMID- 26252532 TI - Venous air embolism from blunt chest trauma. PMID- 26252533 TI - Six minute walk distance is a predictor of survival in patients with chronic obstructive pulmonary disease undergoing pulmonary rehabilitation. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive and distressing disease with a trajectory that is often difficult to predict. OBJECTIVE: To determine whether initial 6 min walk distance (6MWD) or change in 6MWD following inpatient pulmonary rehabilitation (PR) predicted survival. METHODS: Patients referred for PR in 2010 were studied in a retrospective chart review. Measures of 6MWD before and following PR were recorded. Initial 6MWD was categorized as >=250 m, 150 m to 249 m and <=149 m. Government databases provided survival status up until December 2013 and survival analyses were performed. Initial 6MWD and a minimally important difference (MID) of >=30 m were used for survival analysis. RESULTS: The cohort consisted of 237 patients (92 men, 145 women) with severe COPD. Mean (+/- SD) forced expiratory volume in 1 s (FEV1) was 0.75+/-0.36 L, with a mean FEV1/forced vital capacity (FVC) ratio of 0.57+/-0.16. Overall three-year survival was 58%. Mean survival for the study period as per predefined categories of 6MWD of >=250 m, 150 m to 249 m and <=149 m was 42.2, 37.0 and 27.8 months (P<0.001), respectively, with a three-year survival of 81%, 66% and 34% observed, respectively. Overall mean change in 6MWD was 62+/-57 m, and a minimal improvement of >=30 m was observed in 72% of patients. In the lowest walking group, early mortality was significantly higher among those who did not achieve minimal improvement. Older age, male sex and shorter initial 6MWD were negative predictors of survival. CONCLUSION: In patients with severe COPD, initial 6MWD was predictive of survival. Overall survival at three years was only 58% and was especially poor (34%) in patients with low (<150 m) initial walk distance. PMID- 26252534 TI - Effects of ASM-024, a modulator of acetylcholine receptor function, on airway responsiveness and allergen-induced responses in patients with mild asthma. AB - OBJECTIVES: To evaluate the safety, tolerability and clinical activity of ASM 024, a new cholinergic compound with dual nicotinic and muscarinic activity, in mild allergic asthma. METHODS: The present study involved 24 stable, mild allergic asthmatic subjects. In a cross-over design, ASM-024 (50 mg or 200 mg) or placebo were administered once daily by nebulization over three periods of nine consecutive days separated by a three-week washout. The effect of each treatment on the forced expiratory volume in 1 s (FEV1), provocative concentration of methacholine causing a 20% decline in FEV1 (PC20), early and late asthmatic responses, and allergen-induced inflammation were measured. RESULTS: Seventeen subjects completed the study. During treatment with ASM-024 at 50 mg or 200 mg, the PC20 value increased respectively from a mean (+/- SD) 2.56+/-3.86 mg/mL to 4.11 mg/mL (P=0.007), and from 3.12+/-4.37 mg/mL to 5.23 mg/mL (P=0.005) (no change with placebo). On day 7 (day preceding allergen challenge), postdosing FEV1 increased by 2.0% with 50 mg (P=0.005) and 1.9% with 200 mg (P=0.008) (placebo -1.1%). ASM-24 had no inhibitory effect on early and late asthmatic responses, nor on sputum eosinophil or neutrophil levels. ASM-024 induced no serious adverse events, but caused cough in 22% and 48% of the subjects with 50 mg and 200 mg, respectively, compared with 10% who were on placebo. CONCLUSIONS: ASM-024 did not inhibit allergen-induced asthmatic response and related airway inflammation, but reduced methacholine airway responsiveness and slightly improved lung function. The mechanism by which ASM-024 improves these outcomes requires further study. PMID- 26252535 TI - Self-expandable metallic stents in nonmalignant large airway disease. AB - Airway self-expandable metallic stents (SEMS) were initially studied in malignant airway obstruction; however, their use in benign airway diseases has become progressively more frequent. This may be explained by their ease of insertion compared with silicone stents, which require rigid bronchoscopy for insertion. While initial experience with SEMS in benign disease suggested efficacy and promising short-term safety profile, long-term follow-up revealed significant complication rates. In addition to a high complication rate, the management of these complications is made more difficult by the semipermanent nature of these devices. Reported complications include infection, granulation tissue formation, stent migration, stent fracture, airway perforation and fistula formation, as well as extension of the initial injury, potentially eliminating other therapeutic options such as surgical resection. Therefore, SEMS should only be used in nonmalignant large airway disease as a last resort for patients in whom other endoscopic methods, including silicone stents and dilations, as well as surgical options have failed or are technically not feasible. PMID- 26252536 TI - Corrigendum: Re: RW Smith, K Downey, N Snow, S Dell, WG Smith. Association among fraction of exhaled nitrous oxide, bronchodilator response and inhaled corticosteroid type. PMID- 26252538 TI - Correction: Microbial Inactivation in the Liquid Phase Induced by Multigas Plasma Jet. PMID- 26252537 TI - Moving through Life-Space Areas and Objectively Measured Physical Activity of Older People. AB - OBJECTIVES: Physical activity-an important determinant of health and function in old age-may vary according to the life-space area reached. Our aim was to study how moving through greater life-space areas is associated with greater physical activity of community-dwelling older people. The association between objectively measured physical activity and life-space area reached on different days by the same individual was studied using one-week longitudinal data, to provide insight in causal relationships. METHODS: One-week surveillance of objectively assessed physical activity of community-dwelling 70-90-year-old people in central Finland from the "Life-space mobility in old age" cohort substudy (N = 174). In spring 2012, participants wore an accelerometer for 7 days and completed a daily diary including the largest life-space area reached (inside home, outside home, neighborhood, town, and beyond town). The daily step count, and the time in moderate (incl. walking) and low activity and sedentary behavior were assessed. Differences in physical activity between days on which different life-space areas were reached were tested using Generalized Estimation Equation models (within group comparison). RESULTS: Participants' mean age was 80.4+/-4.2 years and 63.5% were female. Participants had higher average step counts (p < .001) and greater moderate and low activity time (p < .001) on days when greater life-space areas were reached, from the home to the town area. Only low activity time continued to increase when moving beyond the town. CONCLUSION: Community-dwelling older people were more physically active on days when they moved through greater life-space areas. While it is unknown whether physical activity was a motivator to leave the home, intervention studies are needed to determine whether facilitation of daily outdoor mobility, regardless of the purpose, may be beneficial in terms of promoting physical activity. PMID- 26252539 TI - Practical Peptide Synthesis Mediated by a Recyclable Hypervalent Iodine Reagent and Tris(4-methoxyphenyl)phosphine. AB - 6-(3,5-Bis(trifluoromethyl)phenyl)-1H,4H-2alambda(3)-ioda-2,3 dioxacyclopenta[hi]indene-1,4-dione (p-BTFP-iodosodilactone, 1a) was synthesized and demonstrated to be an efficient hypervalent iodine(III) reagent for the synthesis of dipeptides from various standard amino acids, including sterically hindered amino acids, in good to high yields within 30 min in the presence of tris(4-methoxyphenyl)phosphine. In addition, the combined system of 1a/(4 MeOC6H4)3P was used to synthesize the pentapeptide leu-enkephalin in protected form. It is worth noting that 1a can be regenerated readily after reaction. PMID- 26252540 TI - Epstein-Barr virus encephalitis in a renal transplant recipient manifesting as hemorrhagic, ring-enhancing mass lesions. AB - Epstein-Barr virus (EBV) encephalitis has been infrequently described in immunocompromised patients. Here, we report a unique case of biopsy-proven EBV encephalitis in a renal transplant recipient presenting with altered mental status, prominent visual disturbances, and hemorrhagic, ring-enhancing mass lesions on magnetic resonance imaging. The patient was successfully treated with a prolonged course of antivirals. This case illustrates the difficulty in interpretation of cerebrospinal fluid EBV polymerase chain reaction assay, given the lack of specificity in immunocompromised patients. PMID- 26252541 TI - Alzheimer's in 3D culture: challenges and perspectives. AB - Alzheimer's disease (AD) is the most common cause of dementia, and there is currently no cure. The "beta-amyloid cascade hypothesis" of AD is the basis of current understanding of AD pathogenesis and drug discovery. However, no AD models have fully validated this hypothesis. We recently developed a human stem cell culture model of AD by cultivating genetically modified human neural stem cells in a three-dimensional (3D) cell culture system. These cells were able to recapitulate key events of AD pathology including beta-amyloid plaques and neurofibrillary tangles. In this review, we will discuss the progress and current limitations of AD mouse models and human stem cell models as well as explore the breakthroughs of 3D cell culture systems. We will also share our perspective on the potential of dish models of neurodegenerative diseases for studying pathogenic cascades and therapeutic drug discovery. PMID- 26252542 TI - Neonatal Respiratory Failure with Retarded Perinatal Lung Maturation in Mice Caused by Reticulocalbin 3 Disruption. AB - Reticulocalbin 3 (Rcn3) is an endoplasmic reticulum lumen protein localized to the secretory pathway. As a Ca2t-binding protein of 45 kDa (Cab45)/Rcn/ER Ca2t binding protein of 55 kDa (ERC45)/calumenin (CREC) family member, Rcn3 is reported to function as a chaperone protein involved in protein synthesis and secretion; however, the biological role of Rcn3 is largely unknown. The results presented here, for the first time, depict an indispensable physiological role of Rcn3 in perinatal lung maturation by using an Rcn3 gene knockout mouse model. These mutant mice die immediately at birth owing to atelectasis-induced neonatal respiratory distress, although these embryos are produced with grossly normal development. This respiratory distress results from a failure of functional maturation of alveolar epithelial type II cells during alveogenesis. This immaturity of type II cells is associated with a dramatic reduction in surfactant protein A and D, a disruption in surfactant phospholipid homeostasis, and a disorder in lamellar body. In vitro studies further show that Rcn3 deficiency blunts the secretion of surfactant proteins and phospholipids from lung epithelial cells, suggesting a decrease in availability of surfactants for their surface activity. Collectively, these observations indicate an essential role of Rcn3 in perinatal lung maturation and neonatal respiratory adaptation as well as shed additional light on the mechanism of neonatal respiratory distress syndrome development. PMID- 26252543 TI - Recurrent spontaneous coronary artery dissection: First case report in men with three episodes of spontaneous coronary dissection in separate vascular territories. AB - Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome. In the literature, more than 1,200 cases of SCAD have been reported, with a low rate of recurrent spontaneous coronary artery dissection (r-SCAD) described in only 63 cases. Among these patients with r-SCAD, just three cases had three separate episodes of dissection and all were in women. We report the first case of r-SCAD in men, with three episodes of dissection in different coronary arteries and review the published literature on predisposing factors for r-SCAD and its management. PMID- 26252544 TI - Quantifying vorticity in magnetic particle suspensions driven by symmetric and asymmetric multiaxial fields. AB - We recently reported two methods of inducing vigorous fluid vorticity in magnetic particle suspensions. The first method employs symmetry-breaking rational fields. These fields are comprised of two orthogonal ac components whose frequencies form a rational number and an orthogonal dc field that breaks the symmetry of the biaxial ac field to create the parity required to induce deterministic vorticity. The second method is based on rational triads, which are fields comprised of three orthogonal ac components whose frequency ratios are rational (e.g., 1 : 2 : 3). For each method a symmetry theory has been developed that enables the prediction of the direction and sign of vorticity as functions of the field frequencies and phases. However, this theory has its limitations. It only applies to those particular phase angles that give rise to fields whose Lissajous plots, or principal 2-d projections thereof, have a high degree of symmetry. Nor can symmetry theory provide a measure of the magnitude of the torque density induced by the field. In this paper a functional of the multiaxial magnetic field is proposed that not only is consistent with all of the predictions of the symmetry theories, but also quantifies the torque density. This functional can be applied to fields whose Lissajous plots lack symmetry and can thus be used to predict a variety of effects and trends that cannot be predicted from the symmetry theories. These trends include the dependence of the magnitude of the torque density on the various frequency ratios, the unexpected reversal of flow with increasing dc field amplitude for certain symmetry-breaking fields, and the existence of off-axis vorticity for rational triads, such as 1 : 3 : 5, that do not have the symmetry required to analyze by symmetry theory. Experimental data are given that show the degree to which this functional is successful in predicting observed trends. PMID- 26252545 TI - Myeloid sarcoma of the vulva as the initial presentation of acute myeloid leukaemia. PMID- 26252546 TI - Phosphorylation and dephosphorylation regulate APC/C(Cdh1) substrate degradation. AB - The Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin ligase activated by its G1 specific adaptor protein Cdh1 is a major regulator of the cell cycle. The APC/C(Cdh1) mediates degradation of dozens of proteins, however, the kinetics and requirements for their degradation are largely unknown. We demonstrate that overexpression of the constitutive active CDH1(m11) mutant that is not inhibited by phosphorylation results in mitotic exit in the absence of the FEAR and MEN pathways, and DNA re-replication in the absence of Cdc7 activity. This mode of mitotic exit also reveals additional requirements for APC/C(Cdh1) substrate degradation, which for some substrates such as Pds1 or Clb5 is dephosphorylation, but for others such as Cdc5 is phosphorylation. PMID- 26252547 TI - High-intensity Exercise Modifies the Effects of Stanozolol on Brain Oxidative Stress in Rats. AB - We analyzed the effects of high-intensity exercise (HIE) and anabolic androgenic steroids (AAS) on brain redox status. 40 male Wistar rats were randomly distributed in 4 experimental groups (n=10) with or without HIE and with or without weekly Stanozolol administration. Thiobarbituric acid-reactive substances (TBARs) and protein carbonyl content (PCC) were assessed. Total superoxide dismutase (tSOD), manganese superoxide dismutase (Mn-SOD), copper/zinc superoxide dismutase (CuZn-SOD) and catalase (CAT) activities were measured. Finally, protein expression levels of glutathione peroxidase (GPx), NAD(P)H dehydrogenase, Quinone 1 (NQO1), NF-E2-Related Factor 2 (Nrf2), glial fibrillary acidic protein (GFAP), nuclear factor kappa beta p65 (NF-kappabeta) and signal transducer and activator of transcription 3 were determined. Brain PCC concentrations were lower in the HIE groups compared to the untrained controls, whereas CAT activity was higher (both, p<0.01). Both HIE and AAS groups exhibited higher expression levels of GFAP and GPx, but lower NQO1 levels (all, p<0.05). There were increased expression levels of NF-kappabeta in the AAS groups (p<0.01). In addition, there was increased expression of Nrf2 in the HIE groups (p<0.001). HIE*AAS interactions were found on TBARs content and GFAP expression, with HIE downregulating and upregulating AAS-mediated increases in TBARs and GFAP, respectively (p<0.05). Overall, HIE appeared to reduce the AAS-mediated negative effect on brain redox status. PMID- 26252548 TI - Effects of Gender Difference and Caffeine Supplementation on Anaerobic Muscle Performance. AB - The primary purpose of this study was to investigate the effects of gender difference and caffeine supplementation to maximal voluntary isometric contractions (MVIC) and submaximal voluntary isometric contractions (T(lim)). 10 male (age: 20.10 +/- 2.18 years, BMI: 22.23+/-1.96 kg/m(2)) and 10 female (age: 19.90+/-0.99 years, BMI: 21.76+/-2.65 kg/m(2)) elite collegiate athletes were recruited. Subjects ingested caffeine (6 mg/kg) or a placebo in a randomized, double-blind, placebo-control, and counter-balanced fashion. MVIC and T(lim) were measured after supplementations. T(lim) result was calculated based on the time to exhaustion of isometric contraction with 50% MVIC. Fatigue index (FI%) referred to the MVIC tested 20 s after the cessation of T(lim) test, and was indexed by the percentage of MVIC decline. No significant interaction effect was found between the gender factor and the supplementation factor for all dependent variables. Compared to the placebo, caffeine supplementation significantly increased MVIC (5.9%) and T(lim) (15.5%) (p<0.05) whereas it had no significant effect on FI%. This study demonstrates that caffeine supplementation at a 6 mg/kg dosage facilitates performances in MVIC and T(lim). The ergogenic effect of caffeine on muscle power and muscle endurance does not show a gender bias. PMID- 26252549 TI - Vascular Mechanisms of Post-exercise Blood Pressure Responses in Peripheral Artery Disease. AB - This study aimed to analyze the vascular mechanisms involved in post-resistance decreases in blood pressure in patients with peripheral artery disease. 17 patients underwent 2 experimental sessions conducted in random order: resistance exercise (REx-3*10 reps in 8 exercises with intensity of ~ 60% of 1 RM) and control (C- resting on the exercise machines for 50 min). Before and after each experimental session, blood pressure, reflected wave indicators, pulse wave velocity, blood flow, blood flow post-reactive hyperemia and peripheral vascular resistance responses were obtained. Both sessions increased brachial systolic, diastolic and mean blood pressure (greatest increase REx: 11 mmHg; greatest increase C: 19 mmHg; P<0.01); however, the increases were greater after the C session (P<0.01). Reflected wave indicators increased only after the C session (P<0.06), while pulse wave velocity increased similarly after both sessions (P=0.66). Individual analyses indicated a large variability between patients in vascular variables responses. A single bout of REx decreased blood pressure in peripheral artery disease patients, and these responses were followed by changes in reflected wave indicators. The other factors presented high individual variability, and thus it was not possible to identify specific factors associated with blood pressure reduction in peripheral artery disease patients. PMID- 26252550 TI - Hemodynamic Responses and Perceived Exertion During Continuous and Discontinuous Resistance Exercise. AB - This study compared acute responses of systolic and diastolic blood pressure (SBP/DBP), cardiac output (Q), heart rate (HR), stroke volume (SV), total peripheral resistance (TPR) and rate of perceived exertion (RPE) during resistance exercise performed continuously and discontinuously. Hemodynamic responses and RPE were assessed in the last of 4 sets of 12 repetitions of the knee extension with load corresponding to 70% of 12 repetition maximum, performed continuously (C) or discontinuously, with pauses of 5 s (D5) or 10 s (D10) interspersed in the middle of sets. The increase in SBP was higher for D10 (34.0+/-8.4%) and D5 (34.1+/-13.2%) vs. C (19.8+/-10.3%; P<0.001), while no difference was detected for DBP. Q (P=0.03) and SV (P=0.02) were higher, but HR was lower (P=0.04) in discontinuous vs. continuous. TPR remained stable during continuous, but significant decreases occurred during the pauses in the discontinuous protocols (P<0.001). The BP was higher in discontinuous than in continuous protocols, but the RPE was attenuated in discontinuous compared to continuous exercise. In conclusion, hemodynamic responses were exacerbated during resistance exercise performed discontinuously, but the perceived exertion was lowered. PMID- 26252551 TI - Physical Demands of Sprinting in Professional Road Cycling. AB - The aim of this study was to quantify the demands of road competitions ending with sprints in male professional cycling. 17 races finished with top-5 results from 6 male road professional cyclists (age, 27.0+/-3.8 years; height, 1.76+/ 0.03 m; weight, 71.7+/-1.1 kg) were analysed. SRM power meters were used to monitor power output, cadence and speed. Data were averaged over the entire race, different durations prior to the sprint (60, 10, 5 and 1 min) and during the actual sprint. Variations in power during the final 10 min of the race were quantified using exposure variation analysis. This observational study was conducted in the field to maximize the ecological validity of the results. Power, cadence and speed were statistically different between various phases of the race (p<0.001), increasing from 316+/-43 W, 95+/-4 rpm and 50.5+/-3.3 km.h(-1) in the last 10 min, to 487+/-58 W, 102+/-6 rpm and 55.4+/-4.7 km.h(-1) in the last min prior to the sprint. Peak power during the sprint was 17.4+/-1.7 W.kg(-1). Exposure variation analysis revealed a significantly greater number of short duration high-intensity efforts in the final 5 min of the race, compared with the penultimate 5 min (p=0.010). These findings quantify the power output requirements associated with high-level sprinting in men's professional road cycling and highlight the need for both aerobic and anaerobic fitness. PMID- 26252552 TI - Typology of "Fatigue" by Heart Rate Variability Analysis in Elite Nordic-skiers. AB - This study investigated changes in heart rate variability (HRV) in elite Nordic skiers to characterize different types of "fatigue" in 27 men and 30 women surveyed from 2004 to 2008. R-R intervals were recorded at rest during 8 min supine (SU) followed by 7 min standing (ST). HRV parameters analysed were powers of low (LF), high (HF) frequencies, (LF+HF) (ms(2)) and heart rate (HR, bpm). In the 1 063 HRV tests performed, 172 corresponded to a "fatigue" state and the first were considered for analysis. 4 types of "fatigue" (F) were identified: 1. F(HF(-)LF(-))SU_ST for 42 tests: decrease in LFSU (- 46%), HFSU (- 70%), LFST (- 43%), HFST (- 53%) and increase in HRSU (+ 15%), HRST (+ 14%). 2. F(LF(+) SULF(-) ST) for 8 tests: increase in LFSU (+ 190%) decrease in LFST (- 84%) and increase in HRST (+ 21%). 3. F(HF(-) SUHF(+) ST) for 6 tests: decrease in HFSU (- 72%) and increase in HFST (+ 501%). 4. F(HF(+) SU) for only 1 test with an increase in HFSU (+ 2161%) and decrease in HRSU (- 15%). Supine and standing HRV patterns were independently modified by "fatigue". 4 "fatigue"-shifted HRV patterns were statistically sorted according to differently paired changes in the 2 postures. This characterization might be useful for further understanding autonomic rearrangements in different "fatigue" conditions. PMID- 26252553 TI - A 200-m All-out Front-crawl Swim Modifies Competitive Swimmers' Shoulder Joint Position Sense. AB - We tested the hypothesis that an all-out-effort 200-m front-crawl swim trial affects competitive swimmers' shoulder joint position sense. On Day 1, we measured shoulder joint position sense before and after the swim trial, and on Day 2 before and after 2 min of seated rest. On both days, shoulder joint position sense was measured in the seated position using electromagnetic movement sensors in a position-matching paradigm. An investigator abducted participants' left (reference) shoulder joint in the frontal plane to test angles of 90 degrees , 135 degrees , and 180 degrees . Participants then actively abducted the right (indicator) shoulder joint to match the position of the left, reference arm. After the 200-m all-out front-crawl swim trial, the indicator relative to the reference angle differed by 4.4 degrees toward adduction at the 180 degrees (vertical) testing position (P<0.05). Variation in absolute matching error was 3.2 degrees or 2.2 times greater after swim compared with the no-swim control trial. An all-out 200-m front-crawl swim trial can selectively increase competitive swimmers' shoulder joint position sense error and increase variation in matching error in horizontal arm position. PMID- 26252554 TI - Improving Practice in Electroconvulsive Therapy: A Nationwide Survey in Belgium. AB - OBJECTIVE: The aims of this study were to review the practice of electroconvulsive therapy (ECT) in Belgium and to compare it with the practice of ECT a decade ago. METHODS: A 30-item questionnaire on the practice of ECT was sent to all institutions providing ECT. Results were compared with the results of a survey performed in 2003. RESULTS: In 2013 to 2014, ECT was performed in 13.7% of all psychiatric services, equaling 1 ECT unit per 584,187 inhabitants. Fifteen of the 19 psychiatric services (78.94%) providing ECT replied to the questionnaire. Practice of ECT has improved significantly. LIMITATIONS: This questionnaire study relies upon answers given by psychiatrists and did not audit actual practices. CONCLUSIONS: The past decade, Belgium has witnessed significant changes in the practice of ECT. The number of facilities providing ECT almost halved adding to the growing expertise of fewer but larger ECT facilities. A possible down side to specialization is a potential diminution of the availability of ECT, requiring adequate referral policies in hospitals without ECT facilities. Although the practice significantly improved, continuous education is needed. PMID- 26252555 TI - Patient-Centered Electroconvulsive Therapy Care: A Call to Action. AB - We present our experience applying the IOM's "10 Simple Rules" to our ECT Service at a major teaching hospital in order to achieve patient-centered care. We encourage all ECT providers to partner with their patients in engaging family members and significant others in each aspect of ECT care, especially the ECT treatment itself. PMID- 26252556 TI - The Clinical and Service Outcomes of Unilateral and Bilateral ECT Electrode Placements in Australian Aged Psychiatry Services. AB - OBJECTIVE: The aim of the study was to determine whether depressed aged inpatients treated with brief pulse unilateral electroconvulsive therapy (ECT) differed from those treated with bilateral (bitemporal or bifrontal) ECT with respect to numbers of treatments, length of hospital admission, changes in scores on depression and cognitive scales, and serious adverse effects. METHODS: An audit of routinely collected data regarding 221 acute ECT courses in 7 public aged psychiatry services in Victoria, Australia. RESULTS: Patients given unilateral, bifrontal, and bitemporal treatments were similar with respect to personal, clinical, and treatment characteristics. Most treatments were administered in line with local clinical guidelines and were rated as effective. Psychiatrists preferred unilateral ECT in the first instance with stimulus dosing based on patients' seizure thresholds. Approximately a quarter of unilateral courses were switched later to bitemporal placement, most probably because of insufficient progress. Bilateral treatments were associated with a larger number of treatments, less improvement in scores on mood and cognitive scales, and more refusals to continue treatment than unilateral-only ECT. DISCUSSION: Brief pulse unilateral ECT proved more effective than bitemporal and bifrontal ECT for most aged patients, especially when coupled with stimulus dosing based on seizure threshold. PMID- 26252557 TI - Autobiographical Memory Specificity in Major Depression Treated With Electroconvulsive Therapy. AB - OBJECTIVE: Autobiographical memory in major depression is characterized by reduced specificity, which reflects the tendency to summarize categories of events rather than recall specific instances of events situated in a time and place. This widely studied cognitive marker for depression has not been extensively examined in patients treated with electroconvulsive therapy (ECT). METHODS: We conducted a retrospective chart review of a naturalistic cohort of patients receiving a course of brief-pulse predominantly bitemporal ECT for a major depressive episode. Patients completed the recent life section of the Kopelman Autobiographical Memory Interview (AMI) at pre-ECT baseline, end of treatment course, and 3-month follow-up as part of routine clinical practice. Mood was assessed using the 24-item Hamilton Rating Scale for Depression. RESULTS: We identified 48 patients (mean age, 61.6; female, 62.5%) meeting inclusion criteria. A total of 77.1% of patients responded to the ECT course, 29.7% subsequently relapsed. There were no significant changes over time on either AMI total score or semantic and episodic subscales. However, patients were markedly impaired on episodic autobiographical memory compared with the normative sample at all 3 assessment points, whereas personal semantic memory recall was normal. Specificity of episodic autobiographical memory at baseline did not predict response to ECT or likelihood of relapse. CONCLUSIONS: We found reduced specificity of episodic autobiographical memory in depressed patients before ECT, which persisted at long-term follow-up despite significant improvement in mood. The finding of no detectable retrograde amnesia likely reflects lack of sensitivity of the recent life section of the AMI to detect ECT-induced changes. PMID- 26252558 TI - Changes in Problem-Solving Capacity and Association With Spontaneous Brain Activity After a Single Electroconvulsive Treatment in Major Depressive Disorder. AB - BACKGROUND: Modified electroconvulsive therapy (MECT) has been regarded as the most effective antidepressant therapy, despite its cognitive side effects. However, how MECT influences problem-solving capacity in major depressive disorder (MDD), as well as its underlying neurobiological mechanisms, remains unclear. The present study aimed to assess alterations in problem-solving capacity after MECT and to explore spontaneous brain activity using amplitudes of low-frequency fluctuations (ALFF)/fractional ALFF. METHODS: Thirteen first episode, treatment-naive MDD patients treated by MECT were recruited. We collected resting-state functional magnetic resonance imaging, and we evaluated their Modified Card Sorting Test performance before and after single-session MECT. Another 11 MDD patients without MECT were also recruited and interviewed with Modified Card Sorting Test twice as a control group. RESULTS: After a single MECT, MDD patients showed significantly decreased ALFF in the right cerebellar posterior lobe. Compared to the control group, perseverative errors significantly decreased after MECT, controlling for practice effects. Some cognitive functional changes significantly correlated to changed ALFF in several brain regions, including Brodmann areas BA9, BA19, BA 21, and BA48, right thalamus, left cerebellum, and right postcentral gyrus. CONCLUSIONS: The MECT could improve problem-solving capacity, even after controlling for practice effects, and it could induce changes in spontaneous brain activity. These changes in cognitive functioning might result from changes in the cerebral functions of some regions, including frontal cortex, a key region for problem-solving capacity. PMID- 26252559 TI - Quantifying non-ergodic dynamics of force-free granular gases. AB - Brownian motion is ergodic in the Boltzmann-Khinchin sense that long time averages of physical observables such as the mean squared displacement provide the same information as the corresponding ensemble average, even at out-of equilibrium conditions. This property is the fundamental prerequisite for single particle tracking and its analysis in simple liquids. We study analytically and by event-driven molecular dynamics simulations the dynamics of force-free cooling granular gases and reveal a violation of ergodicity in this Boltzmann-Khinchin sense as well as distinct ageing of the system. Such granular gases comprise materials such as dilute gases of stones, sand, various types of powders, or large molecules, and their mixtures are ubiquitous in Nature and technology, in particular in Space. We treat-depending on the physical-chemical properties of the inter-particle interaction upon their pair collisions-both a constant and a velocity-dependent (viscoelastic) restitution coefficient epsilon. Moreover we compare the granular gas dynamics with an effective single particle stochastic model based on an underdamped Langevin equation with time dependent diffusivity. We find that both models share the same behaviour of the ensemble mean squared displacement (MSD) and the velocity correlations in the limit of weak dissipation. Qualitatively, the reported non-ergodic behaviour is generic for granular gases with any realistic dependence of epsilon on the impact velocity of particles. PMID- 26252560 TI - The Effects of a Lateral Wedge Insole on Knee and Ankle Joints During Slope Walking. AB - The purpose of this study was to determine whether a lateral wedge insole reduces the external knee adduction moment during slope walking. Twenty young, healthy subjects participated in this study. Subjects walked up and down a slope using 2 different insoles: a control flat insole and a 7 degrees lateral wedge insole. A three-dimensional motion analysis system and force plate were used to examine the knee adduction moment, the ankle valgus moment, and the moment arm of the ground reaction force to the knee joint center in the frontal plane. The lateral wedge insole significantly decreased the moment arm of the ground reaction force, resulting in a reduction of the knee adduction moment during slope walking, similar to level walking. The reduction ratio of knee adduction moment by the lateral wedge insole during the early stance of up-slope walking was larger than that of level walking. Conversely, the lateral wedge insole increased the ankle valgus moment during slope walking, especially during the early stance phase of up-slope walking. Clinicians should examine the utilization of a lateral wedge insole for knee osteoarthritis patients who perform inclined walking during daily activity, in consideration of the load on the ankle joint. PMID- 26252562 TI - Lighting up micromotors with quantum dots for smart chemical sensing. AB - A new "on-the-fly" chemical optical detection strategy based on the incorporation of fluorescence CdTe quantum dots (QDs) on the surface of self-propelled tubular micromotors is presented. The motion-accelerated binding of trace Hg to the QDs selectively quenches the fluorescence emission and leads to an effective discrimination between different mercury species and other co-existing ions. PMID- 26252561 TI - Di- and Trinuclear Mixed-Valence Copper Amidinate Complexes from Reduction of Iodine. AB - Molecular examples of mixed-valence copper complexes through chemical oxidation are rare but invoked in the mechanism of substrate activation, especially oxygen, in copper-containing enzymes. To examine the cooperative chemistry between two metals in close proximity to each other we began studying the reactivity of a dinuclear Cu(I) amidinate complex. The reaction of [(2,6-Me2C6H3N)2C(H)]2Cu2, 1, with I2 in tetrahydrofuran (THF), CH3CN, and toluene affords three new mixed valence copper complexes [(2,6-Me2C6H3N)2C(H)]2Cu2(MU2-I3)(THF)2, 2, [(2,6 Me2C6H3N)2C(H)]2Cu2(MU2-I) (NCMe)2, 3, and [(2,6-Me2C6H3N)2C(H)]3Cu3(MU3-I)2, 4, respectively. The first two compounds were characterized by UV-vis and electron paramagnetic resonance spectroscopies, and their molecular structure was determined by X-ray crystallography. Both di- and trinuclear mixed-valence intermediates were characterized for the reaction of compound 1 to compound 4, and the molecular structure of 4 was determined by X-ray crystallography. The electronic structure of each of these complexes was also investigated using density functional theory. PMID- 26252563 TI - Unusual strains of Microsporum audouinii causing tinea in Europe. AB - We comment on an unusual strain of Microsporum (M.) audouinii. It was isolated from tinea corporis of a boy who lived in Germany and most likely had acquired his infection during a stay on a farm with animal husbandry in Poland. The strain showed features of M. canis (plenty of markedly rough-walled macroconidia, growth on rice, positive hair perforation) as well as of M. audouinii (white thallus, long macroconidia with central constriction) and in vitro it degraded hair of various mammals. Because its ribosomal internal transcribed spacer region showed 99.9% homology to a M. audouinii reference strain it was finally identified as M. audouinii. We relate these findings with recent observations of M. audouinii causing tinea in Europe. This appraisal suggests that irrespective of an identical ribosomal ITS region distinct M. audouinii strains can display a spectrum of morphological and physiological features that is broader than currently outlined in mycological textbooks. Certain unusual characteristics like an enhanced capacity to utilise keratins may even be associated with unexpected transmission routes. Above all sporadic M. audouinii infections in Europe that bear no relation to an endemic area should be analysed from this perspective. PMID- 26252564 TI - The management of children with Down syndrome and profound hearing loss. AB - INTRODUCTION: Although, the association between Down syndrome (DS) and conductive hearing loss is well recognized, the fact that a small proportion of these children may have a severe to profound sensorineural hearing loss that could benefit from cochlear implantation (CI) is less well understood. The management of significant co-morbidities in children with DS can delay initial diagnosis of hearing impairment and assessment of suitability for CI can likewise be challenging, due to difficulties conditioning to behavioural hearing tests. METHODS: We performed a retrospective case note review of three children with DS referred to the Manchester Cochlear Implant Programme. RESULTS: Three illustrative cases are described including CI in a 4 years old. Using conventional outcome measurement instruments, the outcome could be considered to be suboptimal with a Categories of Auditory Performance score of 4 at 6 months post-op and at last follow up. In part, this is likely to reflect the delay in implantation, but the role of cognitive impairment must be considered. The cases described emphasize the importance of comprehensive radiological and audiological assessment in children with DS being considered for CI. CONCLUSION: The influence of cognitive impairment upon outcome of CI must be taken into account, but should not be considered a contra-indication to implantation in children with DS. Benefit that might be considered limited when quantified using existing general outcome measurement instruments, may have a significant impact upon psychosocial development and quality of life in children with significant cognitive impairment, or other additional needs. PMID- 26252566 TI - Estimating joint space of the knee during weight-bearing squatting activity using motion capture - preliminary results of a new method. PMID- 26252567 TI - Factorial combinations of protein interactions generate a multiplicity of florigen activation complexes in wheat and barley. AB - The FLOWERING LOCUS T (FT) protein is a central component of a mobile flowering signal (florigen) that is transported from leaves to the shoot apical meristem (SAM). Two FT monomers and two DNA-binding bZIP transcription factors interact with a dimeric 14-3-3 protein bridge to form a hexameric protein complex. This complex, designated as the 'florigen activation complex' (FAC), plays a critical role in flowering. The wheat homologue of FT, designated FT1 (= VRN3), activates expression of VRN1 in the leaves and the SAM, promoting flowering under inductive long days. In this study, we show that FT1, other FT-like proteins, and different FD-like proteins, can interact with multiple wheat and barley 14-3-3 proteins. We also identify the critical amino acid residues in FT1 and FD-like proteins required for their interactions, and demonstrate that 14-3-3 proteins are necessary bridges to mediate the FT1-TaFDL2 interaction. Using in vivo bimolecular fluorescent complementation (BiFC) assays, we demonstrate that the interaction between FT1 and 14-3-3 occurs in the cytoplasm, and that this complex is then translocated to the nucleus, where it interacts with TaFDL2 to form a FAC. We also demonstrate that a FAC including FT1, TaFDL2 and Ta14-3-3C can bind to the VRN1 promoter in vitro. Finally, we show that relative transcript levels of FD-like and 14-3-3 genes vary among tissues and developmental stages. Since FD like proteins determine the DNA specificity of the FACs, variation in FD-like gene expression can result in spatial and temporal modulation of the effects of mobile FT-like signals. PMID- 26252569 TI - Invasive Fungal Infections in Pediatric Acute Myelogenous Leukemia. AB - This study investigates invasive fungal infections (IFIs) in patients with acute myelogenous leukemia who were included in the Enfant Leucemie Aigue 02 protocol between 2005 and 2011. Among 387 patients, 15 had aspergillosis, 9 had candidiasis, and 2 had mucormycosis. The most frequent localization of IFIs was in the lungs. It was found that after a median of 34 months, 2 deaths were attributable to IFI without any difference in survival between the groups with and without IFI. PMID- 26252565 TI - Specific in vivo knockdown of protein function by intrabodies. AB - Intracellular antibodies (intrabodies) are recombinant antibody fragments that bind to target proteins expressed inside of the same living cell producing the antibodies. The molecules are commonly used to study the function of the target proteins (i.e., their antigens). The intrabody technology is an attractive alternative to the generation of gene-targeted knockout animals, and complements knockdown techniques such as RNAi, miRNA and small molecule inhibitors, by passing various limitations and disadvantages of these methods. The advantages of intrabodies include very high specificity for the target, the possibility to knock down several protein isoforms by one intrabody and targeting of specific splice variants or even post-translational modifications. Different types of intrabodies must be designed to target proteins at different locations, typically either in the cytoplasm, in the nucleus or in the endoplasmic reticulum (ER). Most straightforward is the use of intrabodies retained in the ER (ER intrabodies) to knock down the function of proteins passing the ER, which disturbs the function of members of the membrane or plasma proteomes. More effort is needed to functionally knock down cytoplasmic or nuclear proteins because in this case antibodies need to provide an inhibitory effect and must be able to fold in the reducing milieu of the cytoplasm. In this review, we present a broad overview of intrabody technology, as well as applications both of ER and cytoplasmic intrabodies, which have yielded valuable insights in the biology of many targets relevant for drug development, including alpha-synuclein, TAU, BCR ABL, ErbB-2, EGFR, HIV gp120, CCR5, IL-2, IL-6, beta-amyloid protein and p75NTR. Strategies for the generation of intrabodies and various designs of their applications are also reviewed. PMID- 26252568 TI - Risk of Disease After Isoniazid Preventive Therapy for Mycobacterium tuberculosis Exposure in Young HIV-uninfected Children. AB - BACKGROUND: The risk of developing tuberculosis (TB) disease in HIV-uninfected children after isoniazid preventive therapy (IPT) for a positive QuantiFERON-TB Gold In-Tube test (QFT-GIT) is unknown. The aim of this study was to evaluate risk of TB disease after IPT in young HIV-uninfected children with a positive QFT GIT result, or household TB contact. METHODS: HIV-uninfected South African infants aged 4-6 months were screened for enrolment in a TB vaccine trial. Baseline household TB contact and positive QFT-GIT result were exclusion criteria, and these infants were referred for IPT. Outcome data are reported for 36 months after IPT referral. RESULTS: Four thousand seven hundred forty-nine infants were screened. Household TB contact was reported in 131 (2.8%) infants; 279 (6.0%) were QFT-GIT positive, and 138 of these 410 infants (34.0%) started IPT. Forty-four cases of TB disease (11.0%) were recorded within 991 child years of observation. TB disease incidence was 4.8 versus 3.6 per 100 child years in household exposed versus QFT-GIT-positive children [incidence rate ratio: 1.35; 95% confidence interval (CI): 0.67-2.88] and 2.4 versus 5.5 per 100 child years in children who received versus did not receive IPT, respectively (incidence rate ratio: 0.44; 95% CI: 0.17-0.96). Adjusted hazard ratio (Cox regression) for TB disease was 0.48 (95% CI: 0.21-1.05) for those who received IPT. CONCLUSION: In young HIV-uninfected children, the effect of IPT on risk of TB disease is similar, whether TB exposure was defined by household contact history or by positive QFT-GIT result. International IPT guidelines for HIV-uninfected children with a positive QFT-GIT result should be updated. PMID- 26252570 TI - Coxiella burnetii Infection Is Lower in Children than in Adults After Community Exposure: Overlooked Cause of Infrequent Q Fever Reporting in the Young. AB - BACKGROUND: Q fever is rarely reported in children/adolescents. Although lower reporting rates are commonly attributed to milder disease and subsequent underdiagnosis in infected children/adolescents, pertinent evidence is scarce. We present data from a large, well-defined single-point source outbreak of Q fever to fill this gap. METHODS: We compared (A) Q fever testing and notification rates in children/adolescents who were 0-19 years of age with those in adults 20+ years of age in October 2009; (B) serological attack rates of acute Q fever in children/adolescents with the rates in adults after on-source exposure on the outbreak farm's premises; (C) incidence of Q fever infection in children/adolescents with that in adults after off-source exposure in the municipality located closest to the farm. RESULTS: (A) Children/adolescents represented 19.3% (59,404 of 307,348) of the study area population, 12.1% (149 of 1217) of all subjects tested in October 2009 and 4.3% (11 of 253) of notified laboratory-confirmed community cases. (B) Serological attack rate of acute Q fever in children with on-source exposure was 71% (12 of 17), similar to adults [68% (40 of 59)]. (C) Incidence of infection in children/adolescents after community (off-source) exposure was 4.5% (13 of 287) versus 11.0% (12 of 109) in adults (adjusted odds ratio: 0.36; 95% confidence interval: 0.16-0.84; P = 0.02). No children/adolescents reported clinical symptoms. Proportion of notified infections was significantly lower in children/adolescents (2.5%) than in adults (10.4%; risk ratio: 0.26; 95% confidence interval: 0.08-0.80, P = 0.02). CONCLUSION: Notified Q fever was less frequent in children/adolescents than in adults. Although underrecognition contributed to this phenomenon, lower rates of infection in children after community exposure played an unexpected major role. On-source (presumed high-dose) exposure, by contrast, was associated with high serological and clinical attack rates not only in adults but also in children/adolescents. Our findings allow for improved age-specific clinical and public health risk assessment in Q fever outbreaks. PMID- 26252571 TI - Socio-Economic and Clinical Factors as Predictors of Disease Evolution and Acute Events in COPD Patients. AB - BACKGROUND: Socio-economic, cultural and environmental factors are becoming increasingly important determinants of chronic obstructive pulmonary disease (COPD). We conducted a study to investigate socio-demographic, lifestyle and clinical factors, and to assess their role as predictors of acute events (mortality or hospitalization for respiratory causes) in a group of COPD patients. METHODS: Subjects were recruited among outpatients who were undertaking respiratory function tests at the Pneumology Unit of the Sant'Orsola-Malpighi Hospital, Bologna. Patients were classified according to the GOLD Guidelines. RESULTS: 229 patients with COPD were included in the study, 44 with Mild, 68 Moderate, 52 Severe and 65 Very Severe COPD (GOLD stage). Significant differences among COPD stage, in terms of smoking status and fragility index, were detected. COPD stage significantly affected the values of all clinical tests (spirometry and ABG analysis). Kaplan-Meier estimates showed a significant difference between survival curves by COPD stage with lower event-free probability in very severe COPD stage. Significant risk factors for acute events were: underweight (HR = 4.08; 95% CI 1.01-16.54), having two or more comorbidities (HR = 4.71; 95% CI 2.52-8.83), belonging to moderate (HR = 3.50; 95% CI 1.01-12.18) or very severe COPD stage (HR = 8.23; 95% CI 2.35-28.85). CONCLUSIONS: Our findings indicate that fragility is associated with COPD stage and that comorbidities and the low body mass index are predictors of mortality or hospitalization. Besides spirometric analyses, FeNO measure and comorbidities, body mass index could also be considered in the management and monitoring of COPD patients. PMID- 26252573 TI - Mutation analysis of CACNA1S and SCN4A in patients with hypokalemic periodic paralysis. AB - Mutations in CACNA1S (calcium channel, voltage-dependent, L type, alpha 1S subunit) and SCN4A (sodium channel, voltage-gated, type IV, alpha subunit) are associated with hypokalemic periodic paralysis (HPP). The aim of the current study was to investigate CACNA1S and SCN4A mutations in patients with HPP. Mutations in CACNA1S and SCN4A were detected in three familial hypokalemic periodic paralysis (FHPP) pedigrees and in two thyrotoxic hypokalemic periodic paralysis (THPP) pedigrees using polymerase chain reaction, DNA sequencing and sequence alignment with GenBank data. A single base mutation from cytosine to guanine at site 1582 was identified in exon 11 of CACNA1S in one FHPP pedigree, resulting in an arginine to glycine (R528G) substitution. A single base mutation from thymine to cytosine at site 2012 was identified in exon 12 of SCN4A in one THPP pedigree, resulting in a phenylalanine to serine (F671S) substitution. No mutations in CACNA1S or SCN4A were identified in the remaining three pedigrees. The present study indicated that CACNA1S and SCN4A mutations are relatively rare in patients with HPP, and further studies are required to determine whether these mutation-associated substitutions are representative of patients with HPP. PMID- 26252572 TI - Biomechanical analysis of engineered bone with anti-BMP2 antibody immobilized on different scaffolds. AB - Recently we have demonstrated the ability of monoclonal antibodies (mAb) specific for bone morphogenetic protein (BMP)-2 immobilized on different scaffolds to mediate bone formation, a process referred to as Antibody Mediated Osseous Regeneration (AMOR). One of the key properties of regenerated bone is its biomechanical strength, in particular in load-bearing areas. This study sought to test the hypothesis that the biomechanical strength of regenerated bone depends of the mode of regeneration, as well as the scaffold used. Four different scaffolds, namely titanium granules (Ti), alginate hydrogel, anorganic bovine bone mineral (ABBM), and absorbable collagen sponge (ACS) were functionalized with anti-BMP-2 or isotype control mAb and implanted into rat critical-size calvarial defects. The morphology, density and strength of the regenerated bone were evaluated after 8 weeks. Results demonstrated that scaffolds functionalized with anti-BMP-2 mAb exhibited varying degrees of bone volume and density. Ti and ABBM achieved the highest bone volume, density, and strength of bone. When anti BMP-2 mAb was immobilized on Ti or ABBM, the strength of the regenerated bone were 80% and 77% of native bone respectively, compared with 60% of native bone in sites implanted with rh-BMP-2. Control interventions with isotype mAb did not promote considerable bone regeneration and exhibited significantly lower mechanical properties. SEM analysis showed specimens immobilized with anti-BMP-2 mAb formed new bone with organized structure bridging the crack areas. Altogether, the present data demonstrated that the morphological and mechanical properties of bone bioengineered through AMOR could approximate that of native bone, when appropriate scaffolds are used. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1465-1473, 2016. PMID- 26252574 TI - Amino Acid Mixture Enriched With Arginine, Alanine, and Phenylalanine Stimulates Fat Metabolism During Exercise. AB - Although there have been many investigations of the beneficial effects of both exercise and amino acids (AAs), little is known about their combined effects on the single-dose ingestion of AAs for lipid metabolism during exercise. We hypothesize that taking a specific combination of AAs implicated in glucagon secretion during exercise may increase fat metabolism. We recently developed a new mixture, d-AA mixture (D-mix), that contains arginine, alanine, and phenylalanine to investigate fat oxidation. In a double-blind, placebo-controlled crossover study, 10 healthy male volunteers were randomized to ingest either D mix (3 g/dose) or placebo. Subjects in each condition subsequently performed a physical task that included workload trials on a cycle ergometer at 50% of maximal oxygen consumption for 1 hr. After oral intake of D-mix, maximum serum concentrations of glycerol (9.32 +/- 6.29 mg/L and 5.22 +/- 2.22 mg/L, respectively; p = .028), free fatty acid level (0.77 +/- 0.26 mEq/L and 0.63 +/- 0.28 mEq/L, respectively; p = .022), and acetoacetic acid levels (37.9 +/- 17.7 MUmol/L and 30.3 +/- 13.9 MUmol/L, respectively; p = .040) were significantly higher than in the placebo groups. The area under the curve for glucagon during recovery was numerically higher than placebo (6.61 +/- 1.33 MUg/L . min and 6.06 +/- 1.23 MUg/L . min, respectively; p = .099). These results suggest that preexercise ingestion of D-mix may stimulate fat metabolism. Combined with exercise, the administration of AA mixtures could prove to be a useful nutritional strategy to maximize fat metabolism. PMID- 26252576 TI - Phenotypic side effects prediction by optimizing correlation with chemical and target profiles of drugs. AB - Despite technological progresses and improved understanding of biological systems, discovery of novel drugs is an inefficient, arduous and expensive process. Research and development cost of drugs is unreasonably high, largely attributed to the high attrition rate of candidate drugs due to adverse drug reactions. Computational methods for accurate prediction of drug side effects, rooted in empirical data of drugs, have the potential to enhance the efficacy of the drug discovery process. Identification of features critical for specifying side effects would facilitate efficient computational procedures for their prediction. We devised a generalized ordinary canonical correlation model for prediction of drug side effects based on their chemical properties as well as their target profiles. While the former is based on 2D and 3D chemical features, the latter enumerates a systems-level property of drugs. We find that the model incorporating chemical features outperforms that incorporating target profiles. Furthermore we identified the 2D and 3D chemical properties that yield best results, thereby implying their relevance in specifying adverse drug reactions. PMID- 26252575 TI - Nutlin-3 sensitizes nasopharyngeal carcinoma cells to cisplatin-induced cytotoxicity. AB - The small-molecule inhibitor of p53-Mdm2 interaction, Nutlin-3, is known to be effective against cancers expressing wild-type (wt) p53. p53 mutations are rare in nasopharyngeal carcinoma (NPC), hence targeting disruption of p53-Mdm2 interaction to reactivate p53 may offer a promising therapeutic strategy for NPC. In the present study, the effects of Nutlin-3 alone or in combination with cisplatin, a standard chemotherapeutic agent, were tested on C666-1 cells, an Epstein-Barr virus (EBV)-positive NPC cell line bearing wt p53. Treatment with Nutlin-3 activated the p53 pathway and sensitized NPC cells to the cytotoxic effects of cisplatin. The combined treatment also markedly suppressed soft agar colony growth formation and increased apoptosis of NPC cells. The effect of Nutlin-3 on NPC cells was inhibited by knockdown of p53, suggesting that its effect was p53-dependent. Extended treatment with increasing concentrations of Nutlin-3 did not result in emergence of p53 mutations in the C666-1 cells. Collectively, the present study revealed supportive evidence of the effectiveness of combining cisplatin and Nutlin-3 as a potential therapy against NPC. PMID- 26252578 TI - Aggravated Cardiac Remodeling post Aortocaval Fistula in Unilateral Nephrectomized Rats. AB - BACKGROUND: Aortocaval fistula (AV) in rat is a unique model of volume-overload congestive heart failure and cardiac hypertrophy. Living donor kidney transplantation is regarded as beneficial to allograft recipients and not particularly detrimental to the donors. Impact of AV on animals with mild renal dysfunction is not fully understood. In this study, we explored the effects of AV in unilateral nephrectomized (UNX) rats. METHODS: Adult male Sprague-Dawley (SD) rats were divided into Sham (n = 10), UNX (right kidney remove, n = 10), AV (AV established between the levels of renal arteries and iliac bifurcation, n = 18) and UNX+AV (AV at one week after UNX, n = 22), respectively. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, fractional excretion of sodium, albuminuria, plasma creatinine, and cystatin C. Focal glomerulosclerosis (FGS) incidence was evaluated by renal histology. Cardiac function was measured by echocardiography and hemodynamic measurements. RESULTS: UNX alone induced compensatory left kidney enlargement, increased plasma creatinine and cystatin C levels, and slightly reduced glomerular filtration rate and increased FGS. AV induced significant cardiac enlargement and hypertrophy and reduced cardiac function and increased FGS, these changes were aggravated in UNX+AV rats. CONCLUSIONS: Although UNX only induces minor renal dysfunction, additional chronic volume overload placement during the adaptation phase of the remaining kidney is associated with aggravated cardiac dysfunction and remodeling in UNX rats, suggesting special medical care is required for UNX or congenital monokidney subjects in case of chronic volume overload as in the case of pregnancy and hyperthyroidism to prevent further adverse cardiorenal events in these individuals. PMID- 26252583 TI - Scintillating Discussions. PMID- 26252577 TI - Environmental Pressure May Change the Composition Protein Disorder in Prokaryotes. AB - Many prokaryotic organisms have adapted to incredibly extreme habitats. The genomes of such extremophiles differ from their non-extremophile relatives. For example, some proteins in thermophiles sustain high temperatures by being more compact than homologs in non-extremophiles. Conversely, some proteins have increased volumes to compensate for freezing effects in psychrophiles that survive in the cold. Here, we revealed that some differences in organisms surviving in extreme habitats correlate with a simple single feature, namely the fraction of proteins predicted to have long disordered regions. We predicted disorder with different methods for 46 completely sequenced organisms from diverse habitats and found a correlation between protein disorder and the extremity of the environment. More specifically, the overall percentage of proteins with long disordered regions tended to be more similar between organisms of similar habitats than between organisms of similar taxonomy. For example, predictions tended to detect substantially more proteins with long disordered regions in prokaryotic halophiles (survive high salt) than in their taxonomic neighbors. Another peculiar environment is that of high radiation survived, e.g. by Deinococcus radiodurans. The relatively high fraction of disorder predicted in this extremophile might provide a shield against mutations. Although our analysis fails to establish causation, the observed correlation between such a simplistic, coarse-grained, microscopic molecular feature (disorder content) and a macroscopic variable (habitat) remains stunning. PMID- 26252579 TI - Strategically Modified Rhodamine-Quinoline Conjugate as a CHEF-Assisted FRET Probe for Au(3+): DFT and Living Cell Imaging Studies. AB - A systematic journey from O-donor through S-donor to N-donor chelator led to the development of a highly selective Au(3+) chemosensor that operates via a CHEF induced FRET mechanism. This sensing protocol avoids unwanted possible side reactions observed in alkyne-based gold sensors. DFT studies strongly support the experimental facts. The probe RT-2 detects Au(3+) in the presence of the masking agent KI to minimize Hg(2+) interference; however, RQ-2 selectively detects Au(3+) without any interference and shows reversibility in the sensing in the presence of tetrabutylammonium cyanide. The probe efficiently images Au(3+) in living HeLa cells under a fluorescence microscope. PMID- 26252584 TI - Acute Migraine Treatment. AB - PURPOSE OF REVIEW: This article provides a systematic, evidence-based approach to acute medication choices for the patient with migraine. RECENT FINDINGS: Recent clinical trials, meta-analyses, and practice guidelines have confirmed that four nonsteroidal anti-inflammatory drugs (NSAIDs) with randomized controlled trial evidence for efficacy in migraine (ibuprofen, naproxen sodium, diclofenac potassium, and acetylsalicylic acid) and seven triptans (sumatriptan, rizatriptan, eletriptan, zolmitriptan, almotriptan, frovatriptan, and naratriptan) are appropriate medications for acute migraine treatment. Dihydroergotamine (DHE) is also suitable for selected patients. SUMMARY: NSAIDs and triptans are the mainstays of acute migraine therapy, and antiemetic drugs can be added as necessary. Opioids and combination analgesics containing opioids should not be used routinely. Patient-specific clinical features should help guide the selection of an acute medication for an individual patient. Acute medications can be organized into four treatment strategies for use in various clinical settings. The acetaminophen-NSAID strategy is suitable for patients with attacks of mild to moderate severity. The triptan strategy is suitable for patients with severe attacks and for those with attacks of moderate severity who do not respond well to NSAIDs. The refractory migraine strategies may be useful for patients who do not respond well to the NSAIDs or triptans alone and include using triptans and NSAIDs simultaneously in combination, DHE, and rescue medications (eg, dopamine antagonists, combination analgesics, and corticosteroids) when the patient's usual medications fail. Strategies for patients with contraindications to vasoconstricting drugs include use of NSAIDs, combination analgesics, and dopamine antagonists.Acetaminophen is the safest acute migraine drug during pregnancy, and acetaminophen with codeine is also an option. Sumatriptan may be an option during pregnancy for selected patients and is compatible with breast-feeding. PMID- 26252585 TI - Preventive Migraine Treatment. AB - PURPOSE OF REVIEW: This article reviews the evidence base for the preventive treatment of migraine. RECENT FINDINGS: Evidence-based guidelines for the preventive treatment of migraine have recently been published by the American Academy of Neurology (AAN) and the Canadian Headache Society (CHS), providing valuable guidance for clinicians. Strong evidence exists to support the use of metoprolol, timolol, propranolol, divalproex sodium, sodium valproate, and topiramate for migraine prevention, according to the AAN. Based on best available evidence, adverse event profile, and expert consensus, topiramate, propranolol, nadolol, metoprolol, amitriptyline, gabapentin, candesartan, Petasites (butterbur), riboflavin, coenzyme Q10, and magnesium citrate received a strong recommendation for use from the CHS. SUMMARY: Migraine preventive drug treatments are underutilized in clinical practice. Principles of preventive treatment are important to improve compliance, minimize side effects, and improve patient outcomes. Choice of preventive treatment of migraine should be based on the presence of comorbid and coexistent illness, patient preference, reproductive potential and planning, and best available evidence. PMID- 26252586 TI - Migraine Management During Menstruation and Menopause. AB - PURPOSE OF REVIEW: Migraine is most prevalent in women during their reproductive years. An understanding of the effects of menstruation and menopause on migraine can enable neurologists to provide targeted and appropriate medical and hormonal strategies, enabling their patients to achieve better control of migraine and reduced disability. This article reviews the effects of hormonal events on migraine and summarizes the evidence-based options available for management. RECENT FINDINGS: Estrogen "withdrawal" during the late luteal phase of the natural menstrual cycle and the hormone-free interval of combined hormonal contraceptives has long been implicated in the pathophysiology of menstrual migraine. However, more recent research suggests that other independent mechanisms may be relevant. Prostaglandin inhibitors used for management of dysmenorrhea are effective for associated menstrual migraine, suggesting a common pathophysiology. The interplay between serotonin and estrogen also deserves further research. SUMMARY: Menstrual and perimenopausal migraine can be managed effectively using a variety of strategies, the choice of which depends on the efficacy of acute treatment, predictability and regularity of menstruation, use of contraception, and presence of menstrual disorders or perimenopausal vasomotor symptoms. PMID- 26252587 TI - Emergency Department and Inpatient Management of Status Migrainosus and Intractable Headache. AB - PURPOSE OF REVIEW: This article discusses the treatment of status migrainosus in the emergency department and the treatment of intractable migraine in an inpatient setting. RECENT FINDINGS: Multiple agents of various drug classes have been tried for the treatment of acute migraine in the emergency department, but few have adequate medical evidence to support their use. Opioids, which are less effective than other medications used for the acute treatment of migraine and also carry the risk of adverse CNS side effects, habituation, and addiction, have been prescribed for migraine in the emergency department at an increasing rate over the last decade, which is a worrisome trend. Very few patients with migraine derive sustained relief from pain after emergency department treatment, and most have a high frequency of headache recurrence. SUMMARY: Treatment of status migrainosus and intractable migraine should focus on adequate fluid hydration and combination IV therapy with multiple nonopioid medications from multiple drug classes. Dopamine receptor antagonists appear to have some of the highest medical evidence for efficacy. PMID- 26252588 TI - Nutraceutical and Other Modalities for the Treatment of Headache. AB - PURPOSE OF REVIEW: Nutraceutical, biobehavioral, and physical treatments, including complementary and alternative medicines, may benefit patients with migraine and other headache disorders. This article summarizes the evidence for the use of these therapies with discussion on evidence quality and product controversies. RECENT FINDINGS: The evidence for the use of nutraceuticals is low or conflicting. For migraine prevention in adults, Level B evidence, at best, exists for the use of feverfew, magnesium, and riboflavin (vitamin B2). Level C evidence exists for coenzyme Q10 (CoQ10) and Level U evidence for melatonin. While Level A evidence exists for the use of Petasites, caution should be exercised given the potential for hepatic toxicity. The evidence level for IV magnesium for acute migraine treatment is B or U, depending on the interpretation of the existing literature. The evidence level for adding biobehavioral adjunctive treatment for headache management is A. The evidence level for exercise in reducing migraine is B-C. SUMMARY: Strong evidence supports behavioral therapy as adjunctive treatment for migraine prevention. Modest evidence exists for exercise and a variety of nutraceuticals for migraine prevention in adults and IV magnesium for acute migraine therapy. In children and adolescents, the evidence is low for all nutraceuticals. Petasites has been associated with hepatic toxicity, and caution should be exercised regarding its use. PMID- 26252589 TI - Unique Migraine Subtypes, Rare Headache Disorders, and Other Disturbances. AB - PURPOSE OF REVIEW: The medical aphorism that common things happen commonly makes unique (and less common) migraine subtypes especially appropriate to review for the general neurologist. This article also identifies some rare headache disorders and other disturbances, and offers strategies to manage them. RECENT FINDINGS: This article discusses migraine with brainstem aura, which is troublesome clinically and has had a change in terminology in the International Classification of Headache Disorders, Third Edition, beta version (ICHD-3 beta), and hemiplegic migraine, which is also troublesome in practice. The rare headache disorder hypnic headache and the exploding head syndrome are also discussed. When hypnic headache is recognized, it is eminently treatable, while exploding head syndrome is a benign condition with no reported consequences. SUMMARY: Unique migraine subtypes, rare headache disorders, and other disturbances present to neurologists. When recognized, they can often be managed very well, which offers significant benefits to patients and practice satisfaction to neurologists. PMID- 26252590 TI - Trigeminal Autonomic Cephalalgias. AB - PURPOSE OF REVIEW: This article reviews the clinical features of and treatment options for the trigeminal autonomic cephalalgias (TACs). RECENT FINDINGS: The TACs are a group of primary headache disorders characterized by short-lasting episodes of severe unilateral headaches that are associated with ipsilateral cranial autonomic symptoms. The best known and most commonly seen TAC in clinical practice is cluster headache. The other syndromes within this group include paroxysmal hemicrania, hemicrania continua, and short-lasting unilateral neuralgiform headache attacks. Although these disorders share a similar phenotype, they are distinguished by differences in attack frequency and duration. Recognition of these clinical differences is paramount because treatment options vary; paroxysmal hemicrania and hemicrania continua demonstrate an absolute response to treatment with indomethacin, while the other syndromes respond to other agents. SUMMARY: Although much less common than other headache disorders seen in clinical practice, recognition of the TACs is especially important as they are among the most severe and disabling syndromes in headache medicine. PMID- 26252591 TI - Thunderclap Headache. AB - PURPOSE OF REVIEW: A thunderclap headache is a very severe headache that reaches its maximum intensity within 1 minute. Patients with thunderclap headache must be evaluated emergently and comprehensively to rule out underlying disorders that can be associated with high mortality and morbidity, determine the cause for the thunderclap headache, and initiate targeted therapy. This review presents an up to-date summary on the clinical presentation, diagnostic evaluation, and causes of thunderclap headache. RECENT FINDINGS: Numerous etiologies for thunderclap headaches have been identified, with the most common causes being subarachnoid hemorrhage and reversible cerebral vasoconstriction syndrome. Other relatively common causes include cervical artery dissection, cerebral venous sinus thrombosis, and spontaneous intracranial hypotension. Although "primary" thunderclap headache is typically accepted to exist, it may be that such cases represent missed diagnoses of underlying causes. The urgent evaluation of the patient with thunderclap headache includes brain CT, followed by lumbar puncture if the brain CT is nondiagnostic. If a diagnosis is not reached following brain CT and lumbar puncture, brain MRI and imaging of the brain and cervical vasculature are indicated. SUMMARY: Patients with thunderclap headache require an emergent and comprehensive evaluation to identify the underlying cause and to initiate appropriate therapy. PMID- 26252592 TI - Cranial Neuralgias. AB - PURPOSE OF REVIEW: Pain arising from cranial neuralgias represents a significant health burden. Successful treatment depends on accurate diagnosis, which requires knowledge of neuroanatomy and pathophysiology as well as familiarity with the varied clinical presentations encountered in neurologic practice. This article delineates the relevant anatomy, clinical features, and management of the most common primary and secondary cranial neuralgias. RECENT FINDINGS: Trigeminal neuralgia, which can result from neurovascular compression or demyelination, is a particularly severe form of facial pain. Herpes zoster virus is a common cause of neuralgia that causes herpes zoster ophthalmicus acutely and postherpetic neuralgia chronically. Rarer facial pain syndromes arising from a single nerve include glossopharyngeal neuralgia, nervus intermedius neuralgia, and paratrigeminal oculosympathetic syndrome. SUMMARY: In patients presenting with a cranial neuralgia, unless the etiology is apparent (eg, herpes zoster), cranial imaging studies should be undertaken to look for structural abnormalities such as neoplasm, granulomatous disease, demyelinating disease, or vascular malformations. Management of both common and rare cranial neuralgias is often challenging and is best guided by the most recent available evidence. PMID- 26252593 TI - Spontaneous Intracranial Hypotension. AB - PURPOSE OF REVIEW: Spontaneous intracranial hypotension results from CSF volume depletion, nearly always from spontaneous CSF leaks. Spontaneous intracranial hypotension is increasingly diagnosed in practice; the number of atypical, unconfirmed, and doubtful cases is also increasing, as are treatment failures. These confront neurologists and create many challenges. This review provides neurologists with a guide to diagnosis, evaluation, and treatment of spontaneous intracranial hypotension. RECENT FINDINGS: The clinical spectrum of spontaneous intracranial hypotension is expanding. Spontaneous CSF leak is considered a disorder with a variety of clinical manifestations and imaging features, sometimes quite different from what may be seen after dural puncture. The anatomy of the spontaneous CSF leak is frequently complex, with contributions from disorders of the connective tissue matrix and associated preexisting areas of dural weakness and meningeal diverticula. To locate the site of the leak, CT myelography is still the study of choice. For rapid-flow leaks, dynamic CT myelography has been very helpful, while slow-flow leaks can remain a lingering challenge. The fundamental question of whether a CSF leak is present in uncertain cases can be best answered by radioisotope cisternography. In most cases, epidural blood patch is the main treatment; however, bilevel or multilevel epidural injections are gaining some momentum as treatment for selected cases. SUMMARY: This article outlines various clinical aspects of spontaneous intracranial hypotension, including headache characteristics, CSF changes, and imaging findings and their underlying mechanisms, as well as treatments and disease complications. PMID- 26252594 TI - The Eye and Headache. AB - PURPOSE OF REVIEW: This article highlights painful conditions involving the eyes that are encountered in practice, emphasizing those that do not have obvious findings on the neurologic examination. RECENT FINDINGS: Peripheral and central sensitization are associated with chronic neuropathic ocular pain, and hyperalgesia is associated with dry eyes. The aorta and its branches are involved in 25% of patients with giant cell arteritis. SUMMARY: Eye pain is a common concern and one of the most difficult symptoms for the clinician to evaluate. Eye pain may be a manifestation of a primary headache disorder, as is common in migraine, the trigeminal autonomic cephalalgias, and primary stabbing headache. Secondary headache disorders, such as posterior communicating artery aneurysm, Tolosa-Hunt syndrome, and microvascular ocular motor neuropathies, frequently produce eye pain. Ophthalmic conditions producing eye pain include orbital masses, angle-closure glaucoma, intraocular inflammation, and ocular surface (corneal) disease. Of these, corneal problems are the most commonly encountered. PMID- 26252595 TI - Risk Factors for and Management of Medication-Overuse Headache. AB - PURPOSE OF THE REVIEW: This review focuses on patients with migraine who frequently use acute medications. RECENT FINDINGS: Chronic migraine and medication-overuse headache are common in the general population and often coexist. According to new diagnostic criteria, both diagnoses can be made for an individual patient. Evidence is slowly emerging on the most appropriate management approach for both disorders. SUMMARY: Although the relationship of the primary headache disorder and the pattern of overuse varies, medication-overuse headache is a secondary disorder attributable to the overuse of acute medications. While distinguishing chronic migraine and medication-overuse headache may not always be possible, treatment approaches are similar for the two disorders. PMID- 26252596 TI - Pediatric Headache. AB - PURPOSE OF REVIEW: Headache is one of the most common health concerns in children and adolescents, yet remains underrecognized as a disease. A variety of factors, including the unique aspects of childhood headaches, contribute to this underrecognition. RECENT FINDINGS: Improving recognition of childhood and adolescent headaches and using a standardized approach for their evaluation is expected to lead to the appropriate diagnosis and subsequent additional evaluation and management to improve the overall outcome in children and adolescents with headaches. Building on limited studies in children and adolescents and translating adult studies to children can assist in designing a multidisciplinary treatment plan. SUMMARY: This review focuses on some of the unique aspects of evaluating children and adolescents with headaches; the impact of these headaches on school, home, and family function; determination of disability and influence of comorbid conditions; and development of a treatment plan that incorporates acute, preventive, and biobehavioral management tools. PMID- 26252597 TI - The Ethics of Disclosing Another Physician's Medical Error. AB - The disclosure of medical errors has been shown to improve quality of care and decrease litigation and cost. However, much less attention has been given to how to manage situations in which a patient has been treated less than optimally at another institution or by another physician. The same ethical principles that support disclosing one's own errors apply to disclosure of other people's errors. Disclosing errors and encouraging quality improvement at other institutions or by other providers must be performed in a sensitive and judicious manner. PMID- 26252598 TI - Screening Patients With Headaches for Abuse. AB - Nearly 6 in 10 patients with migraine have experienced childhood maltreatment. Asking about childhood or ongoing abuse is essential in developing optimal treatment plans. By using the Adverse Childhood Experiences Study questionnaire, neurologists can capture information about childhood adversity. Childhood adversity is associated with chronic migraine, but can also lead to psychiatric comorbidity. Knowing how to address previous adversity can improve health outcomes. PMID- 26252599 TI - Coding for Headaches. PMID- 26252600 TI - Appendix A: Summary of Evidence-based Guideline for Clinicians, Update: Pharmacologic Treatment for Episodic Migraine Prevention in Adults. PMID- 26252601 TI - Appendix B: Summary of Evidence-based Guideline for Clinicians, Update: NSAIDs and Other Complementary Treatments for Episodic Migraine Prevention in Adults. PMID- 26252602 TI - Appendix C: AAN Classification of Evidence for the Rating of a Therapeutic Study. PMID- 26252603 TI - Appendix D: Classification of Recommendations. PMID- 26252604 TI - Appendix E: Summary of Evidence-based Guideline for Clinicians: Pharmacological Treatment of Migraine Headache in Children and Adolescents. PMID- 26252608 TI - Patient Management Problem. PMID- 26252609 TI - Patient Management Problem-Preferred Responses. PMID- 26252611 TI - Effect of semolina-jaggery diet on survival and development of Drosophila melanogaster. AB - Drosophila melanogaster is an ideal model organism for developmental studies. This study tests the potential of semolina-jaggery (SJ) diet as a new formulation for bulk rearing of flies. Semolina and jaggery are organic products obtained from wheat endosperm and cane sugar, respectively. Semolina is a rich source of carbohydrates and protein. Jaggery has a high content of dietary sugars. Moreover, preparation of semolina jaggery diet is cost-effective and easy. Thus, the current study aimed to compare survival and developmental parameters of flies fed the SJ diet to flies fed the standard cornmeal-sugar-yeast (CSY) diet. SJ diet enhanced survival of flies without affecting fecundity; male flies showed increased resistance to starvation. A higher number of flies emerged at F2 and F3 generation when fed the SJ diet than when fed the control CSY diet. SJ diet did not increase fly body weight and lipid percentage. Therefore, SJ diet can be used for bulk rearing of healthy flies at par with the standard cornmeal-sugar-yeast diet. PMID- 26252612 TI - Orbital Magnetization of Quantum Spin Hall Insulator Nanoparticles. AB - Both spin and orbital degrees of freedom contribute to the magnetic moment of isolated atoms. However, when inserted in crystals, atomic orbital moments are quenched because of the lack of rotational symmetry that protects them when isolated. Thus, the dominant contribution to the magnetization of magnetic materials comes from electronic spin. Here we show that nanoislands of quantum spin Hall insulators can host robust orbital edge magnetism whenever their highest occupied Kramers doublet is singly occupied, upgrading the spin edge current into a charge current. The resulting orbital magnetization scales linearly with size, outweighing the spin contribution for islands of a few nm in size. This linear scaling is specific of the Dirac edge states and very different from Schrodinger electrons in quantum rings. By modeling Bi(111) flakes, whose edge states have been recently observed, we show that orbital magnetization is robust with respect to disorder, thermal agitation, shape of the island, and crystallographic direction of the edges, reflecting its topological protection. PMID- 26252613 TI - Multi-3,3'-Bicarbazole-Substituted Arylsilane Host Materials with Balanced Charge Transport for Highly Efficient Solution-Processed Blue Phosphorescent Organic Light-Emitting Diodes. AB - A series of 3,3'-bicarbazole (mCP)-functionalized tetraphenylsilane derivatives (SimCPx), including bis(3,5-di(9H-carbazol-9-yl)phenyl)diphenylsilane (SimCP2), tris(3,5-di(9H-carbazol-9-yl)phenyl)methylsilane (SimCP3-CH3), tris(3,5-di(9H carbazol-9-yl)phenyl)phenylsilane (SimCP3-Ph), and tetrakis(3,5-di(9H-carbazol-9 yl)phenyl)silane (SimCP4), serving as bipolar blue hosts for bis[2-(4,6 difluorophenyl)pyridyl-N,C2']iridium(III) (FIrpic), have been synthesized by incorporating different ratios of mCP subunits into a central silicon atom. All of the SimCPx derivatives have wide bandgaps and high triplet energies because of the indirect linkage by silicon between each mCP subunit. The good solubility and high thermal and morphological stability of SimCPx are beneficial for forming amorphous and homogeneous films through solution processing. Density functional theory simulations manifest the better bipolar characteristics for SimCPx using three and four mCP units rather than the represented bipolar host SimCP2. As a result, SimCP4 presents the best electron-transporting ability for charge balance. Consequently, the lowest driving voltage of 4.8 eV, and the favorable maximum efficiencies of 14.2% for external quantum efficiency (28.4 cd A(-1), 13.5 lm W(-1)), are achieved by solution-processed, SimCP4-based blue phosphorescent organic light-emitting diodes as the highest performance among SimCPx, in which 32% improved device efficiencies compared to that of SimCP2 are obtained. It is inspiring to develop efficient bipolar hosts for blue phosphors by just incorporating monopolar carbazole into arylsilanes in two steps. PMID- 26252614 TI - Letter to the Editor: Regulations and Innovation Lead to Clean Diesels. PMID- 26252615 TI - Prevalence of Schistosoma haematobium Infection among School-Age Children in Afar Area, Northeastern Ethiopia. AB - In this study, the prevalence and intensity of Schistosoma haematobium infection was determined among school-age children living in the Middle and Lower Awash Valley, Afar Regional State of Ethiopia. Between February and May 2014, urine samples were collected from 885 school-age children (5-16 years of age) from the Middle (n = 632; 4 villages) and Lower (n = 253; 3 villages) Awash Valley. All samples were processed using urine filtration to detect and quantify S. haematobium eggs. In addition, a subset of the urine samples was tested for hematuria using a urine dipstick (n = 556). The overall prevalence was 20.8% (95% Confidence Interval (CI) = 18.1%, 23.5%), based on urine filtration but the prevalence considerably varied across villages both in the Middle (from 12.5% to 37.0%) and Lower Awash Valley (from 0 to 5.3%). The overall mean urine egg count (UEC) among the infected children was 4.0 eggs/10 ml of urine (95% CI = 2.43, 5.52). The infection intensity varied from 0.4 eggs/10 ml of urine to 7.7 eggs/10 ml of urine in the Middle Awash Valley, and from 0 to 1.1 eggs/10 ml of urine in Lower Awash Valley. Age and sex were not associated with S. haematobium infection based on the multivariable logistic regression model. The prevalence of hematuria was 56.3% (95% CI = 52.2%, 60.4%) among a subset of the study participants (556) examined using the urine dipstick. The prevalence of hematuria also varies with villages from 8.3% to 93.2%. In conclusion, the prevalence of S. haematobium infection in the Middle Awash Valley was high and it varies across villages. Hence, children living in the present study villages of the Middle Awash Valley need to be treated with praziquantel to reduce morbidity and disrupt transmission. PMID- 26252616 TI - Comparative Cytotoxicity and Sperm Motility Using a Computer-Aided Sperm Analysis System (CASA) for Isomers of Phthalic Acid, a Common Final Metabolite of Phthalates. AB - The general population is exposed to phthalates through consumer products, diet, and medical devices. Phthalic acid (PA) is a common final metabolite of phthalates, and its isomers include isophthalic acid (IPA), terephthalic acid (TPA), and phthalaldehyde (o-phthalic acid, OPA). The purpose of this study was to investigate whether PA and PA isomers exert reproductive toxicity, including altered sperm movement. In vitro cell viability assays were comparatively performed using Sertoli and liver cell lines. In animal experiments, PA or PA isomers (10, 100, or 1000 mg/kg) were administered orally to Sprague-Dawley (SD) rats, and semen samples were analyzed by computer-aided sperm analysis (CASA). PA treatment produced a significant effect on curvilinear velocity (VCL), straight line velocity (VSL), mean velocity or average path velocity (VAP), amplitude of lateral head displacement (ALH), and frequency of head displacement or beat cross frequency (BCF), whereas IPA, TPA, and OPA induced no marked effects. In vitro cell viability assays showed that mouse normal testis cells (TM4) and human testis cancer cells (NTERA 2 cl. D1) were more sensitive to PA and OPA than mouse liver normal cells (NCTC clone 1469) and human fetal liver cells (FL 62891). Our study suggests that PA and PA isomers specifically produced significant in vitro and in vivo reproductive toxicity, particularly sperm toxicity and testis cell cytotoxicity. Of the isomers examined, PA appeared to be the most toxic and may serve as a surrogate biomarker for reproductive toxicity following mixed exposure to phthalates. PMID- 26252617 TI - Effects of rotigaptide (ZP123) on connexin43 remodeling in canine ventricular fibrillation. AB - The present study investigated the effects of rotigaptide (ZP123) on the expression, distribution and phosphorylation of connexin43 (Cx43) in myocardial cell membranes in cardioversion of ventricular fibrillation (VF). A model of prolonged VF (8, 12 and 30 min) was established in mongrel dogs (n=8/group), following treatment with ZP123 or normal saline (NS control). A sham control was included. Cardiopulmonary resuscitation was begun at the start of VF followed by defibrillation. Animals received a maximum of three defibrillations of increasing energy (70, 100 and 150 J biphasic shock) as required. The average defibrillation energy, defibrillation success rate, return of spontaneous circulation and survival rate were recorded. Cx43 and phosphorylated (p-)Cx43 expression in cardiomyocyte membranes was detected by western blot and immunofluorescence analyses. Compared with the NS-treated control groups, the success defibrillation rate in the 8-min and 12-min ZP123 groups was significantly higher (P<0.05), while the average defibrillation energy was significantly lower (P<0.05). Cx43 expression in the VF groups was significantly lower than that in the sham control group (P<0.05). Cx43 expression was higher in the 12-min and 30-min ZP123 groups than that in the NS control group (P<0.05), while p-Cx43 expression decreased, although the levels were significantly higher than those in the control groups (P<0.05). Cx43 expression was positively correlated with the defibrillation success rate (r=0.91; P<0.01) and negatively with the mean defibrillation energy (r=-0.854; P<0.01), while p-Cx43 expression was positively correlated with the success rate of the previous three defibrillations (r=0.926; P<0.01).In conclusion, ZP123 reduced Cx43 remodeling through regulating the expression, distribution and phosphorylation of Cx43, thereby reducing the defibrillation energy required for successful cardioversion. PMID- 26252620 TI - Effect of Disease Improvement with Self-Measurement Compliance (Measurement Frequency Level) in SmartCare Hypertension Management Service. AB - BACKGROUND: This study's purpose was to analyze the effect of the SmartCare pilot project, which was conducted in 2011 in South Korea. Recent studies of telehealth mostly compare the intervention group and the control group. Therefore, it is necessary to analyze the disease improvement effect depending on the self measurement compliance (measurement frequency level) of patients who are receiving the hypertension management services. MATERIALS AND METHODS: In the SmartCare center, health managers (nurses, nutritionists, and exercise prescribers) monitored the measurement data transmitted by participants through the SmartCare system. The health managers provided the prevention, consultation, and education services remotely to patients. Of the 231 participants who were enrolled in the study, the final analysis involved 213 individuals who completed their blood pressure measurements and SmartCare services until the end of a 6 month service period. The evaluated measurement group was classified into three groups (Low, Middle, and High) by evenly dividing the monthly average frequency of measurement for 6 months. The evaluation indices were systolic blood pressure (SBP), diastolic blood pressure (DBP), weight, and body mass index (BMI); this information was transmitted through the SmartCare system. RESULTS: For changes in the evaluation indices after 6 months compared with the initial baseline, in the Low Group, SBP and DBP slightly decreased, and weight and BMI slightly increased (difference not statistically significant). In the Middle Group, SBP and DBP decreased slightly (difference not statistically significant); however, both weight and BMI decreased (difference statistically significant). In the High Group, SBP, DBP, weight, and BMI decreased (difference statistically significant). CONCLUSIONS: Patients who received the SmartCare services with higher measurement frequency levels at home showed greater effectiveness regarding the provided services compared with those patients with lower levels of BP, weight, and BMI control. PMID- 26252619 TI - Reduction of Tetrathionate by Mammalian Thioredoxin Reductase. AB - Tetrathionate, a polythionate oxidation product of microbial hydrogen sulfide and reactive oxygen species from immune cells in the gut, serves as a terminal electron acceptor to confer a growth advantage for Salmonella and other enterobacteria. Here we show that the rat liver selenoenzyme thioredoxin reductase (Txnrd1, TR1) efficiently reduces tetrathionate in vitro. Furthermore, lysates of selenium-supplemented murine macrophages also displayed activity toward tetrathionate, while cells lacking TR1 were unable to reduce tetrathionate. These studies suggest that upregulation of TR1 expression, via selenium supplementation, may modulate the gut microbiome, particularly during inflammation, by regulating the levels of tetrathionate. PMID- 26252618 TI - Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype. AB - Aldosterone-producing adenomas (APAs) and bilateral adrenal hyperplasia are important causes of secondary hypertension. Somatic mutations in KCNJ5, CACNA1D, ATP1A1, ATP2B3 and CTNNB1 have been described in APAs. OBJECTIVE: To characterize clinical-pathological features in APAs and unilateral adrenal hyperplasia, and correlate them with genotypes. DESIGN: Retrospective study. SUBJECTS AND MEASUREMENTS: Clinical and pathological characteristics of 90 APAs and seven diffusely or focally hyperplastic adrenal glands were reviewed, and samples were examined for mutations in known disease genes by Sanger or exome sequencing. RESULTS: Mutation frequencies were as follows: KCNJ5, 37.1%; CACNA1D, 10.3%; ATP1A1, 8.2%; ATP2B3, 3.1%; and CTNNB1, 2.1%. Previously unidentified mutations included I157K, F154C and two insertions (I150_G151insM and I144_E145insAI) in KCNJ5, all close to the selectivity filter, V426G_V427Q_A428_L433del in ATP2B3 and A39Efs*3 in CTNNB1. Mutations in KCNJ5 were associated with female and other mutations with male gender (P = 0.007). On computed tomography, KCNJ5-mutant tumours displayed significantly greater diameter (P = 0.023), calculated area (P = 0.002) and lower precontrast Hounsfield units (P = 0.0002) vs tumours with mutations in other genes. Accordingly, KCNJ5-mutant tumours were predominantly comprised of lipid-rich fasciculata-like clear cells, whereas other tumours were heterogeneous (P = 5 * 10(-6) vs non-KCNJ5 mutant and P = 0.0003 vs wild-type tumours, respectively). CACNA1D mutations were present in two samples with hyperplasia without adenoma. CONCLUSIONS: KCNJ5-mutant tumours appear to be associated with fasciculata-like clear cell predominant histology and tend to be larger with a characteristic imaging phenotype. Novel somatic KCNJ5 variants likely cause adenomas by loss of potassium selectivity, similar to previously described mutations. PMID- 26252621 TI - Alzheimer's Disease: A Heme-Abeta Perspective. AB - Redox active iron is utilized in biology for various electron transfer and catalytic reactions essential for life, yet this same chemistry mediates the formation of partially reduced oxygen species (PROS). Oxidative stress derived from the iron accumulated in the amyloid plaques originating from amyloid beta (Abeta) peptides and neurofibrillary tangles derived from hyperphosphorylated tau proteins has been implicated in the pathogenesis of Alzheimer's disease (AD). Altered heme homeostasis leading to dysregulation of expression of heme proteins and heme deposits in the amyloid plaques are characteristic of the AD brain. However, the pathogenic significance of heme in neurodegeneration in AD has been unappreciated due to the lack of detailed understanding of the chemistry of the interaction of heme and Abeta peptides. As a result, the biochemistry and biophysics of heme complexes of Abeta peptides (heme-Abeta) remained largely unexplored. In this Account, we discuss the active site environment of heme bound Abeta complexes, which involves three amino acid residues unique in mammalian Abeta (Arg5, Tyr10, and His13) and missing in Abeta from rodents, which do not get affected by AD. The histidine residue binds heme, while the arginine and the tyrosine act as key second sphere residues of the heme-Abeta active site that play a crucial role in its reactivity. Generation of PROS, enhanced peroxidase activity, and oxidation of neurotransmitters such as serotonin (5-HT) are all found to be catalyzed by heme-Abeta in in vitro assays, and these reactivities can potentially be linked to the observed neuropathologies in AD brain. Association of Cu with heme-Abeta leads to the formation of heme-Cu-Abeta. The heme-Cu-Abeta complex produces a greater amount of PROS than reduced heme-Abeta or Cu-Abeta alone. Nitric oxide (NO), a signaling molecule, is found to ameliorate the detrimental effects of heme-Abeta and Cu bound heme-Abeta complexes by detaching heme from the heme-Abeta complex and releasing it into the environment solution. Heme-Abeta complexes show fast electron transfer with oxidized cytochrome c and rapid heme transfer with apomyoglobin and aponeuroglobin. NO, cytochrome c, and apoglobins can all lead to reduction in PROS generated by reduced heme-Abeta. Synthetic analogues of heme, offering a hydrophobic distal environment, have been used to trap oxygen bound intermediates, which provides insight into the mechanism of PROS generation by reduced heme-Abeta. Artificial constructs of Abeta on nonbiological platforms are used not only to stabilize metastable and physiologically relevant large and small amyloid aggregates but also to monitor the interaction of various drug candidates with heme and Cu bound Abeta aggregates, representing a tractable avenue for testing therapeutic agents targeting metals and cofactors in AD. PMID- 26252622 TI - Embryonal tumor with multilayered rosettes of the fourth ventricle: case report. AB - Embryonal tumor with multilayered rosettes (ETMR) is a recently described pathological entity. These primitive central nervous system tumors harbor amplification of the 19q13.42 locus and resultant overexpression of the LIN28A protein. Although the WHO currently recognizes 3 distinct histopathological entities-embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma-recent studies indicate that these tumors have a common molecular profile and clinical course and that they are now classified as a single entity. Here the authors present a case of ETMR located in the fourth ventricle in a 12-month-old boy. The histopathology featured areas of neuropil-like stroma and highly cellular foci with characteristic multilayered rosettes. The authors discuss the clinical, radiological, and histopathological findings in this case and compare them with data in previously published cases in the literature. A review of studies assessing the molecular mechanisms underlying these tumors is also presented. PMID- 26252623 TI - Polar bear mother-offspring interactions in maternity dens in captivity. AB - Two female polar bears at Dierenrijk Zoo in the Netherlands were monitored at their maternity den one day before the birth of their cubs and three days postpartum. Each bear was monitored for 96 hr to document behaviour and vocalisations. The goal was to obtain insight into the differences between the mother that lost her litter and the other that successfully reared her cubs. Six groups of cub vocalisations were identified: Comfort, Discomfort, Distress, Nursing Attempts, Nursing, and No Vocalisation. Maternal vocalisations were split into three groups: Calm, Grooming, and Stress. Maternal behaviours were also split into three groups: Active, Rest, and Stress. The unsuccessful mother produced more stress vocalisations before and during the birth of her cub, whereas the successful mother appeared less stressed. Vocalisations indicate that the cub that died tried to nurse but was unsuccessful. The unsuccessful mother showed less stress as her cub got weaker and vocalised less. From this I suggest that maternal stress was a factor in cub mortality. PMID- 26252624 TI - Avoiding ambiguity with the Type I error rate in noninferiority trials. AB - This review article sets out to examine the Type I error rates used in noninferiority trials. Most papers regarding noninferiority trials only state Type I error rate without mentioning clearly which Type I error rate is evaluated. Therefore, the Type I error rate in one paper is often different from the Type I error rate in another paper, which can confuse readers and makes it difficult to understand papers. Which Type I error rate should be evaluated is related directly to which paradigm is employed in the analysis of noninferiority trial, and to how the historical data are treated. This article reviews the characteristics of the within-trial Type I error rate and the unconditional across-trial Type I error rate which have frequently been examined in noninferiority trials. The conditional across-trial Type I error rate is also briefly discussed. In noninferiority trials comparing a new treatment with an active control without a placebo arm, it is argued that the within-trial Type I error rate should be controlled in order to obtain approval of the new treatment from the regulatory agencies. I hope that this article can help readers understand the difference between two paradigms employed in noninferiority trials. PMID- 26252625 TI - Ultrasensitive Electrochemical Biosensor for HIV Gene Detection Based on Graphene Stabilized Gold Nanoclusters with Exonuclease Amplification. AB - Because human immunodeficiency virus (HIV) has been one of the most terrible viruses in recent decades, early diagnosis of the HIV gene is of great importance for all scientists around the world. In our work, we developed a novel electrochemical biosensor based on one-step ultrasonic synthesized graphene stabilized gold nanocluster (GR/AuNC) modified glassy carbon electrode (GCE) with an exonuclease III (Exo III)-assisted target recycling amplification strategy for the detection of HIV DNA. It is the first time that GR/AuNCs have been used as biosensor platform and aptamer with cytosine-rich base set as capture probe to construct the biosensor. With the combination of cytosine-rich capture probe, good conductivity and high surfaces of GR/AuNCs, and Exo III-assisted target recycling amplification, we realized high sensitivity and good selectivity detection of target HIV DNA with a detection limit of 30 aM (S/N = 3). Furthermore, the proposed biosensor has a promising potential application for target detection in human serum analysis. PMID- 26252626 TI - Post-assembly Modification of Tetrazine-Edged Fe(II)4L6 Tetrahedra. AB - Post-assembly modification (PAM) is a powerful tool for the modular functionalization of self-assembled structures. We report a new family of tetrazine-edged Fe(II)4L6 tetrahedral cages, prepared using different aniline subcomponents, which undergo rapid and efficient PAM by inverse electron-demand Diels-Alder (IEDDA) reactions. Remarkably, the electron-donating or -withdrawing ability of the para-substituent on the aniline moiety influences the IEDDA reactivity of the tetrazine ring 11 bonds away. This effect manifests as a linear free energy relationship, quantified using the Hammett equation, between sigma(para) and the rate of the IEDDA reaction. The rate of PAM can thus be adjusted by varying the aniline subcomponent. PMID- 26252627 TI - Monte Carlo analysis of the enhanced transcranial penetration using distributed near-infrared emitter array. AB - Transcranial near-infrared (NIR) treatment of neurological diseases has gained recent momentum. However, the low NIR dose available to the brain, which shows severe scattering and absorption of the photons by human tissues, largely limits its effectiveness in clinical use. Hereby, we propose to take advantage of the strong scattering effect of the cranial tissues by applying an evenly distributed multiunit emitter array on the scalp to enhance the cerebral photon density while maintaining each single emitter operating under the safe thermal limit. By employing the Monte Carlo method, we simulated the transcranial propagation of the array emitted light and demonstrated markedly enhanced intracranial photon flux as well as improved uniformity of the photon distribution. These enhancements are correlated with the source location, density, and wavelength of light. To the best of our knowledge, we present the first systematic analysis of the intracranial light field established by the scalp-applied multisource array and reveal a strategy for the optimization of the therapeutic effects of the NIR radiation. PMID- 26252628 TI - Scapairrins A-Q, Labdane-Type Diterpenoids from the Chinese Liverwort Scapania irrigua and Their Cytotoxic Activity. AB - Seventeen new labdane-type diterpenoids, scapairrins A-Q (1-17), including six pairs of diastereoisomers, and three known analogues (18-20) were isolated from the Chinese liverwort Scapania irrigua. The structures of 1-17 were determined based on a combination of the analysis of their MS and NMR spectroscopic data, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Cytotoxicity testing showed that compounds 7-10 exhibited inhibitory activities against a small panel of human cancer cell lines. PMID- 26252629 TI - Synthesis of 1-(beta-D-Galactopyranosyl)Thymine-6'-O-Triphosphate - A Potential Probe to Generate Reactive Dialdehyde for DNA-Enzyme Cross-Linking. AB - Concise, facile, and efficient synthesis of 1-(beta-D-galactopyranosyl)thymine-6' O-triphosphate, a potential probe that can generate reactive dialdehyde for DNA enzyme cross-linking applications, was described starting from O,O' bis(trimethylsilyl)thymine. Stannic chloride promoted glycosylation of 1,2,3,4,6 penta-O-acetyl-alpha-D-galactopyranose with O,O'-bis(trimethylsilyl)thymine, resulting in the formation of 1-(2,3,4,6-O-tetraacetyl-beta-D galactopyranosyl)thymine in 91% yield. Acetyl deprotection using methanolic ammonia afforded 1-(beta-D-galactopyranosyl)thymine in 98% yield. The modified one-pot methodology was used to convert 1-(beta-D-galactopyranosyl)thymine into 1 (beta-D-galactopyranosyl)thymine-6'-O-triphosphate in 72% yield, which involves the formation of 1-(beta-D-galactopyranosyl)thymine dichlorophosphoridate using POCl3 as the reagent at the monophosphorylation step followed by reaction with tributylammonium pyrophosphate and hydrolysis of resulting cyclic intermediate. PMID- 26252630 TI - Design and Facile Synthesis of New Dinucleotide Cap Analog Containing Both 2' and 3'-OH Modification on M7Guanosine Moiety. AB - The first example of the synthesis of new dinucleotide cap analog containing 2('),3(')-diacetyl group on m(7)guanosine moiety is described. The desired modified cap analog, m(7,2)(')(,3)(')(-diacetyl)G[5(')]ppp[5(')]G has been obtained by the coupling reaction of triethylamine salt of m(7,2)(')(,3)(')( diacetyl)GDP with ImGMP in presence of ZnCl2 as a catalyst in 62% yield with high purity. The structure of new cap analog has been confirmed by (1)H and (31)P NMR and mass data. PMID- 26252631 TI - Synthesis and Anti-HIV Activity of Novel 4'-Trifluoromethylated 5' Deoxycarbocyclic Nucleoside Phosphonic Acids. AB - Efficient synthetic route to novel 4'-trifluoromethylated 5'-deoxycarbocyclic nucleoside phosphonic acids was described from alpha-trifluoromethyl-alpha,beta unsaturated ester. Coupling of purine nucleosidic bases with cyclopentanol using a Mitsunobu reaction gave the nucleoside intermediates which were further phosphonated and hydrolyzed to reach desired nucleoside analogs. Synthesized nucleoside analogs were tested for anti-HIV activity as well as cytotoxicity. Adenine analog 22 shows significant anti-HIV activity (EC50 = 8.3 MUM) up to 100 MUM. PMID- 26252632 TI - Nucleoside Analog Activity in Malignant Melanoma Cell Lines. AB - Mitochondrial deoxyguanosine kinase (dGK), is an enzyme responsible for activation of nucleoside analogs (NAs) to phosphorylated compounds which exert profound cytotoxicity, especially in hematological malignancies. Screening malignant melanoma cell lines against NAs revealed high sensitivity to several of them. This was believed to be due to the high levels of dGK expression in these cells. Downregulation of dGK in the melanoma cell line RaH5 using siRNA did not cause resistance to NAs as expected, but instead cells became more sensitive. This was probably partly due to the increased activity of another mitochondrial enzyme, thymidine kinase 2, seen in transfected cells. PMID- 26252633 TI - Phylogenetic Analysis of Selected Menthol-Producing Species Belonging to the Lamiaceae Family. AB - Menthol is an organic compound with diverse medicinal and commercial applications, and is made either synthetically or through extraction from mint oils. The aim of the present study was to investigate menthol levels in selected menthol-producing species belonging to the Lamiaceae family, and to determine phylogenetic relationships of menthol dehydrogenase gene sequence among these species. Three genus of Lamiaceae, namely Mentha, Salvia, and Micromeria, were selected for phytochemical and phylogenetic analyses. After identification of each species based on menthol dehydrogenase gene in NCBI, BLAST software was used for the sequence alignment. MEGA4 software was used to draw phylogenetic tree for various species. Phytochemical analysis revealed that the highest and lowest amounts of both essential oil and menthol belonged to Mentha spicata and Micromeria hyssopifolia, respectively. The species Mentha spicata and Mentha piperita, which were assigned to one cluster in the dendrogram, contained the highest amounts of essential oil and menthol while Micromeria species, which was in the distinct cluster and placed in the farther evolutionary distance, contained the lowest amount of essential oil and menthol. Phylogenetic and phytochemistry analyses showed that essential oil and menthol contents of menthol producing species are associated with menthol dehydrogenase gene sequence. PMID- 26252636 TI - Correction: Correction: Signatures of Adaptation in Human Invasive Salmonella Typhimurium ST313 Populations from Sub-Saharan Africa. PMID- 26252635 TI - IL-6 Inhibits the Targeted Modulation of PDCD4 by miR-21 in Prostate Cancer. AB - Prostate cancer is the most common cancer among men in the Unites States. The cytokine IL-6 activates several prostate cancer pathways, but its upstream trans signaling pathway remains poorly understood. In this study, we evaluated the role of IL-6 in PDCD4 gene expression and how the microRNA miR-21 regulates this process in prostate cancer cell lines PC-3 and LNCaP. The expression pattern of PDCD4 from samples from human prostate cancer, precancerous lesions, and benign prostatic hyperplasia was investigated by immunohistochemistry. PDCD4 transcription and translation were detected by quantitative real-time PCR (qRT PCR) and Western blot analysis, respectively. The targeted modulation of PDCD4 by miR-21 was analyzed in PC-3 and LNCaP cells, and the effect of IL-6 on the expression of PDCD4 was studied in vitro. PDCD4 expression in samples from the 3 tissue types progressively increased, and the expression levels of PDCD4 and prostate-specific antigen were negatively correlated. The levels of PDCD4 mRNA and protein in PC-3 and LNCaP cells transfected with anti-miR-21 constructs were lower than those in control cells. The expression of PDCD4 was inhibited by IL-6, but this effect was weakened in cell lines with low expression of miR-21. Our study demonstrates that the regulation of PDCD4 by miR-21 is targeted and IL-6 inhibits expression of the PDCD4 gene in PC-3 and LNCaP cells through the targeted function of miR-21 on PDCD4. These findings support the feasibility of future efforts for diagnosis and gene therapy for prostate cancer that are based on IL-6, miR-21, and PDCD4. PMID- 26252637 TI - Analysis of Feedback Mechanisms with Unknown Delay Using Sparse Multivariate Autoregressive Method. AB - This paper discusses the study of two interacting processes in which a feedback mechanism exists between the processes. The study was motivated by problems such as the circadian oscillation of gene expression where two interacting protein transcriptions form both negative and positive feedback loops with long delays to equilibrium. Traditionally, data of this type could be examined using autoregressive analysis. However, in circadian oscillation the order of an autoregressive model cannot be determined a priori. We propose a sparse multivariate autoregressive method that incorporates mixed linear effects into regression analysis, and uses a forward-backward greedy search algorithm to select non-zero entries in the regression coefficients, the number of which is constrained not to exceed a pre-specified number. A small simulation study provides preliminary evidence of the validity of the method. Besides the circadian oscillation example, an additional example of blood pressure variations using data from an intervention study is used to illustrate the method and the interpretation of the results obtained from the sparse matrix method. These applications demonstrate how sparse representation can be used for handling high dimensional variables that feature dynamic, reciprocal relationships. PMID- 26252638 TI - Dual effects of human adipose tissue-derived mesenchymal stem cells in human lung adenocarcinoma A549 xenografts and colorectal adenocarcinoma HT-29 xenografts in mice. AB - Human adipose tissue-derived mesenchymal stem cells (hATMSCs) have great potential as a therapy for various diseases. However, emerging evidence shows that there are conflicting results concerning effects of hATMSCs on tumor progression. Our objective was to determine whether and how hATMSCs modulate tumor growth. After cancer cell lines were subcutaneously inoculated into BALB/c nude and hairless severe combined immunodeficient mice, hATMSCs were intratumorally injected into the mice. The growth of the A549 tumors was inhibited by hATMSCs, yet that of the HT-29 tumors was significantly promoted by hATMSCs in the in vivo xenograft models. In vitro study using a co-culture system of cancer cells and hATMSCs was consistent with the in vivo experiments. To reveal the molecular events induced by hATMSCs in the xenograft models, global gene expression profiles of the A549 and HT-29 tumors in the absence or presence of hATMSCs were determined. Significant numbers of genes involved in biological processes were altered in the hATMSC-treated A549 tumors, whereas no biological process was regulated by treatment with hATMSCs in the HT-29 tumors, reflecting the different effects of hATMSCs in the different types of cancer. Notably, histone cluster 1, H2aj and neuropeptide Y receptor Y4 were found to be expressed in direct or inverse proportion to tumor size in both xenograft models. In addition, nuclear factor kappaB (NF-kappaB) p65 was differentially phosphorylated by the hATMSCs dependent on the source of the cancer cells. In conclusion, the identified gene profiling and NF-kappaB signaling provide molecular evidence to explain the conflicting findings in tumor-MSC studies, although further study is needed to confirm these findings using various types of cancer. PMID- 26252640 TI - Voxel-based morphometry for separation of schizophrenia from other types of psychosis in first episode psychosis. AB - BACKGROUND: Schizophrenia is a psychiatric disorder which involves distortions in thought and perception, blunted affect, and behavioural disturbances. The longer psychosis goes unnoticed and untreated, the more severe the repercussions for relapse and recovery. There is some evidence that early intervention services can help, and diagnostic techniques that could contribute to early intervention may offer clinical utility in these situations. The index test being evaluated in this review is the structural magnetic resonance imaging (MRI) analysis technique known as voxel-based morphometry (VBM) that estimates the distribution of grey matter tissue volume across several brain regions. This review is an exploratory examination of the diagnostic 'potential' of VBM for use as an additional tool in the clinical examination of patients with first episode psychosis to establish whether an individual will progress on to developing schizophrenia as opposed to other types of psychosis. OBJECTIVES: To determine whether VBM applied to the brain can be used to differentiate schizophrenia from other types of psychosis in participants who have received a clinical diagnosis of first episode psychosis. SEARCH METHODS: In December 2013, we updated a previous search (May 2012) of MEDLINE, EMBASE, and PsycInfo using OvidSP. SELECTION CRITERIA: We included retrospective and prospective studies that consecutively or randomly selected adolescent and adult participants (< 45 years) with a first episode of psychosis; and that evaluated the diagnostic accuracy of VBM for differentiating schizophrenia from other psychoses compared with a clinical diagnosis made by a qualified mental health professional, with or without the use of standard operational criteria or symptom checklists. We excluded studies in children, and in adult participants with organic brain disorders or who were at high risk for schizophrenia, such as people with a genetic predisposition. DATA COLLECTION AND ANALYSIS: Two review authors screened all references for inclusion. We assessed the quality of studies using the QUADAS-2 instrument. Due to a lack of data, we were not able to extract 2 x 2 data tables for each study nor undertake any meta analysis. MAIN RESULTS: We included four studies with a total of 275 participants with first episode psychosis. VBM was not used to diagnose schizophrenia in any of the studies, instead VBM was used to quantify the magnitude of differences in grey matter volume. Therefore, none of the included studies reported data that could be used in the analysis, and we summarised the findings narratively for each study. AUTHORS' CONCLUSIONS: There is no evidence to currently support diagnosing schizophrenia (as opposed to other psychotic disorders) using the pattern of brain changes seen in VBM studies in patients with first episode psychosis. VBM has the potential to discriminate between diagnostic categories but the methods to do this reliably are currently in evolution. In addition, the lack of applicability of the use of VBM to clinical practice in the studies to date limits the usefulness of VBM as a diagnostic aid to differentiate schizophrenia from other types of psychotic presentations in people with first episode of psychosis. PMID- 26252639 TI - Norepinephrine and Epinephrine Enhanced the Infectivity of Enterovirus 71. AB - BACKGROUND: Enterovirus 71 (EV71) infections may be associated with neurological complications, including brainstem encephalitis (BE). Severe EV71 BE may be complicated with autonomic nervous system (ANS) dysregulation and/or pulmonary edema (PE). ANS dysregulation is related to the overactivation of the sympathetic nervous system, which results from catecholamine release. OBJECTIVE: The aims of this study were to explore the effects of catecholamines on severe EV71 infection and to investigate the changes in the percentages of EV71-infected cells, virus titer, and cytokine production on the involvement of catecholamines. STUDY DESIGN: Plasma levels of norepinephrine (NE) and epinephrine (EP) in EV71 infected patients were measured using an enzyme-linked immunoassay. The expression of adrenergic receptors (ADRs) on RD, A549, SK-N-SH, THP-1, Jurkat and human peripheral blood mononuclear cells (hPBMCs) were detected using flow cytometry. The percentages of EV71-infected cells, virus titer, and cytokine production were investigated after treatment with NE and EP. RESULTS: The plasma levels of NE and EP were significantly higher in EV71-infected patients with ANS dysregulation and PE than in controls. Both alpha1A- and beta2-ADRs were expressed on A549, RD, SK-N-SH, HL-60, THP-1, Jurkat cells and hPBMCs. NE treatment elevated the percentages of EV71-infected cells to 62.9% and 22.7% in THP-1 and Jurkat cells, respectively. Via treatment with EP, the percentages of EV71-infected cells were increased to 64.6% and 26.9% in THP-1 and Jurkat cells. The percentage of EV71-infected cells increased upon NE or EP treatment while the alpha- and beta-blockers reduced the percentages of EV71-infected cells with NE or EP treatment. At least two-fold increase in virus titer was observed in EV71 infected A549, SK-N-SH and hPBMCs after treatment with NE or EP. IL-6 production was enhanced in EV71-infected hPBMCs at a concentration of 102 pg/mL NE. CONCLUSION: The plasma levels of NE and EP elevated in EV71-infected patients with ANS dysregulation and PE. Both NE and EP enhanced the percentages of infected cells and virus titers in EV71 infection in vitro. NE and EP may play a role in the pathogenesis of EV71 BE complicated with ANS dysregulation and PE. PMID- 26252641 TI - Tectonic 1 accelerates gastric cancer cell proliferation and cell cycle progression in vitro. AB - Hedgehog (Hh) pathway is important in development and cancer. Hh signaling is constitutively active in gastric cancer. Recently, tectonic 1 (TCTN1) was identified as one regulator of the Hh pathway. In the present study, the biological role of TCTN1 was examined in gastric cancer via an RNA interference lentivirus system. The constructed lentivirus efficiently suppressed TCTN1 expression in three gastric cancer cell lines. The proliferation of gastric cancer cells was significantly inhibited in TCTN1 knockdown cells, as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. Furthermore, in order to determine the underlying mechanism, the cell cycle progression of MGC80-3 cells was analyzed by flow cytometry. Knockdown of TCTN1 led to cell cycle arrest at the G2/M phase, which contributed to inhibition of growth. In conclusion, the results demonstrated that TCTN1 was essential in the growth of gastric cancer cells in vitro, suggesting TCTN1 as a potential target candidate for the treatment of gastric cancer. PMID- 26252642 TI - Effects of Short-Term Exercise Training With and Without Milk Intake on Cardiometabolic and Inflammatory Adaptations in Obese Adolescents. AB - There is some evidence that a combination of factors can reduce inflammation and associated metabolic risk factors. We studied the early cardiometabolic and inflammatory adaptations to a short-term exercise intervention with and without milk in obese adolescents. Fifty-four adolescents were randomized to consume milk post exercise (MILK) or a carbohydrate beverage (CONT) during one-week of daily exercise. Insulin levels were not different between the groups post training. Glucose was reduced over time in both groups (-9 +/- 13 mg/ dl MILK and -6 +/- 14 mg/dl CONT, p < .05) but not different between groups. There was a greater decrease in mean arterial pressure (MAP) in the MILK group (-3 +/- 6 mmHg MILK vs. 2 +/- 7 mmHg CONT, p < .04). Milk provided postexercise did not affect C reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha) or interleukin-6 (IL-6). The exercise intervention led to an increase in TNF-alpha in both groups (0.27 +/- 0.7 pg/ml MILK and 0.48 +/- 0.6 pg/ml CONT, p < .001). The early adaptations to a short-term exercise intervention in obese adolescents include a reduction in MAP and an increase in some inflammatory markers. PMID- 26252643 TI - Origin of the Yeast Whole-Genome Duplication. AB - Whole-genome duplications (WGDs) are rare evolutionary events with profound consequences. They double an organism's genetic content, immediately creating a reproductive barrier between it and its ancestors and providing raw material for the divergence of gene functions between paralogs. Almost all eukaryotic genome sequences bear evidence of ancient WGDs, but the causes of these events and the timing of intermediate steps have been difficult to discern. One of the best characterized WGDs occurred in the lineage leading to the baker's yeast Saccharomyces cerevisiae. Marcet-Houben and Gabaldon now show that, rather than simply doubling the DNA of a single ancestor, the yeast WGD likely involved mating between two different ancestral species followed by a doubling of the genome to restore fertility. PMID- 26252644 TI - Victor and Erika Webnovela: An Innovative Generation @ Audience Engagement Strategy for Prevention. AB - Entertainment-education (E-E) approaches for young audiences continue to evolve in order to keep stride with younger generations' affinity for technology. E-E and novelas have been used with a wide variety of audiences in the United States, in particular hard-to-reach Latino populations, and have demonstrated effectiveness in disseminating culturally relevant prevention information for a wide variety of health-related risk factors and behaviors. This study discusses the formative research and active engagement of Latino youth living in Langley Park, Maryland, for the development and filming of an innovative 6-episode webnovela titled Victor and Erika (V&E). V&E is part of a larger branding strategy of the Adelante Positive Youth Development intervention that seeks to prevent substance abuse, sexual risk, and interpersonal violence among Latino youth; V&E is also an intervention component. The V&E webnovela is a dramatic portrayal of the lives of 2 immigrant Latino teenagers that also disseminates risk prevention messages. The storyline represents the turning the corner (to a better life) theme that underlies the Adelante intervention brand. Formative research was conducted for character development (n = 20) and creative development of the episodes (n = 14). Results of the formative research showed that youth recommended inclusion of the following topics in V&E episodes: sex, unintended pregnancy, fidelity, trust, family dynamics, immigration status, violence, school dropout, respect, home life, and poverty. Detailed character and episode descriptions are provided, and the implications of using the V&E series as a tool for in-person and online engagement of youth and the dissemination of prevention messages are also discussed. PMID- 26252646 TI - Analysis of the spectroscopy of a hybrid system composed of a superconducting flux qubit and diamond NV(-) centers. AB - A hybrid system that combines the advantages of a superconductor flux qubit and an electron spin ensemble in diamond is one of the promising devices to realize quantum information processing. Exploring the properties of the superconductor diamond system is essential for the efficient use of this device. When we perform spectroscopy of this system, significant power broadening is observed. However, previous models to describe this system are known to be applicable only when the power broadening is negligible. Here, we construct a new approach to analyze this system with strong driving, and succeed in reproducing the spectrum with the power broadening. Our results provide an efficient way to analyze this hybrid system. PMID- 26252645 TI - Molecular Cloning, Heterologous Expression, and Functional Characterization of an NADPH-Cytochrome P450 Reductase Gene from Camptotheca acuminata, a Camptothecin Producing Plant. AB - Camptothecin (CAM), a complex pentacyclic pyrroloqinoline alkaloid, is the starting material for CAM-type drugs that are well-known antitumor plant drugs. Although many chemical and biological research efforts have been performed to produce CAM, a few attempts have been made to uncover the enzymatic mechanism involved in the biosynthesis of CAM. Enzyme-catalyzed oxidoreduction reactions are ubiquitously presented in living organisms, especially in the biosynthetic pathway of most secondary metabolites such as CAM. Due to a lack of its reduction partner, most catalytic oxidation steps involved in the biosynthesis of CAM have not been established. In the present study, an NADPH-cytochrome P450 reductase (CPR) encoding gene CamCPR was cloned from Camptotheca acuminata, a CAM-producing plant. The full length of CamCPR cDNA contained an open reading frame of 2127-bp nucleotides, corresponding to 708-amino acid residues. CamCPR showed 70 ~ 85% identities to other characterized plant CPRs and it was categorized to the group II of CPRs on the basis of the results of multiple sequence alignment of the N terminal hydrophobic regions. The intact and truncate CamCPRs with N- or C terminal His6-tag were heterologously overexpressed in Escherichia coli. The recombinant enzymes showed NADPH-dependent reductase activity toward a chemical substrate ferricyanide and a protein substrate cytochrome c. The N-terminal His6 tagged CamCPR showed 18- ~ 30-fold reduction activity higher than the C-terminal His6-tagged CamCPR, which supported a reported conclusion, i.e., the last C terminal tryptophan of CPRs plays an important role in the discrimination between NADPH and NADH. Co-expression of CamCPR and a P450 monooxygenase, CYP73A25, a cinnamate 4-hydroxylase from cotton, and the following catalytic formation of p coumaric acid suggested that CamCPR transforms electrons from NADPH to the heme center of P450 to support its oxidation reaction. Quantitative real-time PCR analysis showed that CamCPR was expressed in the roots, stems, and leaves of C. acuminata seedlings. The relative transcript level of CamCPR in leaves was 2.2 fold higher than that of roots and the stems showed 1.5-fold transcript level higher than the roots. The functional characterization of CamCPR will be helpful to disclose the mysterious mechanisms of the biosynthesis of CAM. The present study established a platform to characterize the P450 enzymes involved in the growth, development, and metabolism of eukaryotic organisms. PMID- 26252647 TI - Are the new starting block facilities beneficial for backstroke start performance? AB - We aimed to analyse the handgrip positioning and the wedge effects on the backstroke start performance and technique. Ten swimmers completed randomly eight 15 m backstroke starts (four with hands on highest horizontal and four on vertical handgrip) performed with and without wedge. One surface and one underwater camera recorded kinematic data. Standardised mean difference (SMD) and 95% confidence intervals (CI) were used. Handgrip positioning did not affect kinematics with and without wedge use. Handgrips horizontally positioned and feet over wedge displayed greater knee angular velocity than without it (SMD = -0.82; 95% CI: -1.56, -0.08). Hands vertically positioned and feet over wedge presented greater take-off angle (SMD = -0.81; 95% CI: -1.55, -0.07), centre of mass (CM) vertical positioning at first water contact (SMD = -0.97; 95% CI: -1.87, -0.07) and CM vertical velocity at CM immersion (SMD = 1.03; 95% CI: 0.08, 1.98) when comparing without wedge use. Swimmers extended the hip previous to the knee and ankle joints, except for the variant with hands vertically positioned without wedge (SMD = 0.75; 95% CI: -0.03, 1.53). Swimmers should preserve biomechanical advantages achieved during flight with variant with hands vertically positioned and wedge throughout entry and underwater phase. PMID- 26252648 TI - Intracavity OptoGalvanic Spectroscopy not suitable for ambient level radiocarbon detection. AB - IntraCavity OptoGalvanic Spectroscopy as a radiocarbon detection technique was first reported by the Murnick group at Rutgers University, Newark, NJ, in 2008. This technique for radiocarbon detection was presented with tremendous potentials for applications in various fields of research. Significantly cheaper, this technique was portrayed as a possible complementary technique to the more expensive and complex accelerator mass spectrometry. Several groups around the world started developing this technique for various radiocarbon related applications. The IntraCavity OptoGalvanic Spectroscopy setup at the University of Groningen was constructed in 2012 in close collaboration with the Murnick group for exploring possible applications in the fields of radiocarbon dating and atmospheric monitoring. In this paper we describe a systematic evaluation of the IntraCavity OptoGalvanic Spectroscopy setup at Groningen for radiocarbon detection. Since the IntraCavity OptoGalvanic Spectroscopy setup was strictly planned for dating and atmospheric monitoring purposes, all the initial experiments were performed with CO2 samples containing contemporary levels and highly depleted levels of radiocarbon. Because of recurring failures in differentiating the two CO2 samples, with the radiocarbon concentration 3 orders of magnitude apart, CO2 samples containing elevated levels of radiocarbon were prepared in-house and experimented with. All results obtained thus far at Groningen are in sharp contrast to the results published by the Murnick group and rather support the results put forward by the Salehpour group at Uppsala University. From our extensive test work, we must conclude that the method is unsuited for ambient level radiocarbon measurements, and even highly enriched CO2 samples yield insignificant signal. PMID- 26252649 TI - Combination of Azathioprine and Aminosalicylate Treatment Prevent Risk of Cardiovascular Disease in Women with Ulcerative Colitis by Reducing Inflammation. AB - BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with involvement of the immune system. Chronic inflammatory diseases have been associated with increased risk of cardiovascular disease (CVD) but few studies have assessed this risk in patients with UC and the influence of drug treatment. Thus, we evaluated the risk of development of CVD in women with UC in clinical remission, considering the drug treatment. MATERIAL AND METHODS: Twenty-one women with UC participated in this study: 12 used aminosalicylates (ASA group) and 9 used azathioprine added to aminosalicylates (AZA+ASA group). The healthy control group was matched for age. We evaluated blood pressure, body composition, and biochemical and immunological parameters. RESULTS: Compared to the respective control group, the UC groups showed expansion of body fat and less lean body mass. Blood pressure, pro-inflammatory cytokines, nitric oxide, C reactive protein, erythrocyte sedimentation rate (ESR), and anti-oxidized LDL antibodies were higher in UC groups. Only AZA+ASA group showed increased anti-inflammatory cytokines (IL-10 and TGF-beta). Framingham scores showed higher risk of CVD in UC groups. UC groups were compared and women treated with azathioprine showed reduction of total protein, globulin, ESR, and lymphocytes, with increased IL-6, TNF, IL-10, and TGF-beta. CONCLUSIONS: Our data suggest that women with UC in clinical remission have a higher risk for development of atherosclerosis and CVD when compared to the control group, while women treated with azathioprine seem more protected than those treated only with aminosalicylates, due to better regulation of the inflammatory process. PMID- 26252650 TI - Asking about Sex in General Health Surveys: Comparing the Methods and Findings of the 2010 Health Survey for England with Those of the Third National Survey of Sexual Attitudes and Lifestyles. AB - OBJECTIVES: Including questions about sexual health in the annual Health Survey for England (HSE) provides opportunities for regular measurement of key public health indicators, augmenting Britain's decennial National Survey of Sexual Attitudes and Lifestyles (Natsal). However, contextual and methodological differences may limit comparability of the findings. We examine the extent of these differences between HSE 2010 and Natsal-3 and investigate their impact on parameter estimates. METHODS: Complex survey analyses of data from men and women in the 2010 HSE (n = 2,782 men and 3,588 women) and Natsal-3 undertaken 2010-2012 (n = 4,882 men and 6,869 women) aged 16-69y and resident in England, both using probability sampling, compared their characteristics, the amount of non-response to, and estimates from, sexual health questions. Both surveys used self completion for the sexual behaviour questions but this was via computer-assisted self-interview (CASI) in Natsal-3 and a pen-and-paper questionnaire in HSE 2010. RESULTS: The surveys achieved similar response rates, both around 60%, and demographic profiles largely consistent with the census, although HSE participants tended to be less educated, and reported worse general health, than Natsal-3 participants. Item non-response to the sexual health questions was typically higher in HSE 2010 (range: 9-18%) relative to Natsal-3 (all <5%). Prevalence estimates for sexual risk behaviours and STI-related indicators were generally slightly lower in HSE 2010 than Natsal-3. CONCLUSIONS: While a relatively high response to sexual health questions in HSE 2010 demonstrates the feasibility of asking such questions in a general health survey, differences with Natsal-3 do exist. These are likely due to the HSE's context as a general health survey and methodological limitations such as its current use of pen-and-paper questionnaires. Methodological developments to the HSE should be considered so that its data can be interpreted in combination with those from dedicated sexual health surveys, thus improving our ability to monitor trends in sexual health. PMID- 26252651 TI - The Use of Three Long Non-Coding RNAs as Potential Prognostic Indicators of Astrocytoma. AB - Long noncoding RNAs (lncRNAs) are pervasively transcribed and play a key role in tumorigenesis. The aim of the study was to determine the lncRNA expression profile in astrocytomas and to assess its potential clinical value. We performed a three-step analysis to establish the lncRNA profile for astrocytoma: a) the lncRNA expression was examined on 3 astrocytomas as well as 3 NATs (normal adjacent tissues) using the lncRNA microarray; b) the top-hits were validated in 40 astrocytomas (WHO grade II-IV) by quantitative real time-PCR (qRT-PCR); c) the hits with significant differences were re-evaluated using qRT-PCR in 90 astrocytomas. Finally, 7 lncRNAs were found to have a significantly different expression profile in astrocytoma samples compared to the NAT samples. Unsupervised clustering analysis further revealed the potential of the 7-lncRNA profile to differentiate between tumors and NAT samples. The upregulation of ENST00000545440 and NR_002809 was associated with advanced clinical stages of astrocytoma. Using Kaplan-Meier survival analysis, we showed that the low expression of BC002811 or XLOC_010967, or the high expression of NR_002809 was significantly associated with poor patient survival. Moreover, Cox proportional hazard regression analysis revealed that this prognostic impact was independent of other clinicopathological factors. Our results indicate that the lncRNA profile may be a potential prognostic biomarker for the prediction of post surgical outcomes. PMID- 26252652 TI - Chemical composition, protoscolicidal effects and acute toxicity of Pistacia atlantica Desf. fruit extract. AB - The present study was designed to evaluate the chemical composition and scolicidal effects of Pistacia atlantica Desf. extract against protoscoleces of hydatid cysts and its acute toxicity in mice model. Various concentrations of the methanolic extract (5-50 mg/mL) were used for 10-60 min. Viability of protoscoleces was confirmed using eosin exclusion test (0.1%). Acute toxicity was also determined in mice model. The main components were beta-myrcene (41.4%), alpha-pinene (32.48%) and limonene (4.66%). Findings demonstrated that P. atlantica extract at the concentrations of 25 and 50 mg/mL after 20 and 10 min of exposure killed 100% protoscoleces. The LD50 of the intraperitoneal injection of the P. atlantica methanolic extract was 2.43 g/kg and the maximum non-fatal dose was 1.66 g/kg. Obtained results showed the potential of P. atlantica extract as a natural source with no significant toxicity for the production of new scolicidal agent to use in hydatid cyst surgery. PMID- 26252653 TI - Soccer Offside Judgments in Laypersons with Different Types of Static Displays. AB - Four experiments investigated offside decisions in laypersons with different types of static displays. Previous research neglected this group although the majority of assistant referees in soccer games at the amateur level are laypersons. The aims of our research were (a) to investigate the spatial resolution in laypersons' perception of offside situations, (b) to search for biases in laypersons' offside judgments, and (c) to develop useful displays for future research. The displays showed the moment when a midfielder passes the ball to a forward moving in the vicinity of a defender. We varied the spatial location of the forward around the defender in eleven steps and participants made their offside decision by pressing a key. Across experiments, displays varied in abstractness (simple shapes, clipart figures, photographs). There were two major findings. Firstly, both accuracy and speed of offside judgments deteriorated when the spatial distance between forward and defender decreased, approaching guessing rate at the smallest distances. Secondly, participants showed a consistent bias in favor of the non-offside response, in contrast to most studies on professional assistant referees. In sum, the results highlight the limited spatial resolution of the visual system and underscore the role of response bias in offside-judgment tasks. PMID- 26252655 TI - Detection of human bocavirus type 1 infection in Panamanian children with respiratory illness. AB - The human bocavirus (HBoV) was added as a new member of the Parvoviridae family in 2005 upon its discovery in nasopharyngeal aspirates from children with respiratory infection. Recently, there has been increasing evidence of worldwide circulation of HBoV; however, in Latin America few studies have been conducted. In order to detect the circulation of HBoV in Panama, based on the National Flu Surveillance System, we developed this retrospective, cross-sectional study, from January 2011 to January 2012. Children younger than 6 years old who presented with respiratory disease were enrolled in this study. Nasopharyngeal swabs were taken in sentinel surveillance sites. Samples were tested to detect mRNA from HBoV, as well as viral RNA and DNA from others respiratory viruses. A total of 1078 patients were enrolled in this study. Overall, 44 (4.1%) of the patients presented HBoV. The most common symptoms were cough (84.6%), fever (82.1%), rhinorrhea (74.4%), and sore throat (38.5%). Less than half (45.5%) of HBoV infected patients presented with monoinfection while 54.5% of cases presented with coinfection with others respiratory viruses. Both, outpatients and inpatients were included in this study. Outpatients corresponded to 52.3% of the cases and 47.7% were inpatients. Coinfection was observed in the 50% of the inpatient cases. Phylogenetic analyses indicated that the circulating strains belonged to different clades of HBoV genotype 1. Taken together, our results support the pathogenic nature of this viral agent, especially in younger children. PMID- 26252654 TI - TGF-beta Negatively Regulates CXCL1 Chemokine Expression in Mammary Fibroblasts through Enhancement of Smad2/3 and Suppression of HGF/c-Met Signaling Mechanisms. AB - Fibroblasts are major cellular components of the breast cancer stroma, and influence the growth, survival and invasion of epithelial cells. Compared to normal tissue fibroblasts, carcinoma associated fibroblasts (CAFs) show increased expression of numerous soluble factors including growth factors and cytokines. However, the mechanisms regulating expression of these factors remain poorly understood. Recent studies have shown that breast CAFs overexpress the chemokine CXCL1, a key regulator of tumor invasion and chemo-resistance. Increased expression of CXCL1 in CAFs correlated with poor patient prognosis, and was associated with decreased expression of TGF-beta signaling components. The goal of these studies was to understand the role of TGF-beta in regulating CXCL1 expression in CAFs, using cell culture and biochemical approaches. We found that TGF-beta treatment decreased CXCL1 expression in CAFs, through Smad2/3 dependent mechanisms. Chromatin immunoprecipitation and site-directed mutagenesis assays revealed two new binding sites in the CXCL1 promoter important for Smad2/3 modulation of CXCL1 expression. Smad2/3 proteins also negatively regulated expression of Hepatocyte Growth Factor (HGF), which was found to positively regulate CXCL1 expression in CAFs through c-Met receptor dependent mechanisms. HGF/c-Met signaling in CAFs was required for activity of NF-kappaB, a transcriptional activator of CXCL1 expression. These studies indicate that TGF beta negatively regulates CXCL1 expression in CAFs through Smad2/3 binding to the promoter, and through suppression of HGF/c-Met autocrine signaling. These studies reveal novel insight into how TGF-beta and HGF, key tumor promoting factors modulate CXCL1 chemokine expression in CAFs. PMID- 26252656 TI - Wireless Monitoring of Changes in Crew Relations during Long-Duration Mission Simulation. AB - Group structure and cohesion along with their changes over time play an important role in the success of missions where crew members spend prolonged periods of time under conditions of isolation and confinement. Therefore, an objective system for unobtrusive monitoring of crew cohesion and possible individual stress reactions is of high interest. For this purpose, an experimental wireless group structure (WLGS) monitoring system integrated into a mobile psychophysiological system was developed. In the presented study the WLGS module was evaluated separately in six male subjects (27-38 years old) participating in a 520-day simulated mission to Mars. Two days per week, each crew member wore a small sensor that registered the presence and distance of the sensors either worn by the other subjects or strategically placed throughout the isolation facility. The registration between two sensors was on average 91.0% in accordance. A correspondence of 95.7% with the survey video on day 475 confirmed external reliability. An integrated score of the "crew relation time index" was calculated and analyzed over time. Correlation analyses of a sociometric questionnaire (r = .35-.55, p< .05) and an ethological group approach (r = .45-.66, p < 05) provided initial evidence of the method's validity as a measure of cohesion when taking behavioral and activity patterns into account (e.g. only including activity phases in the afternoon). This confirms our assumption that the registered amount of time spent together during free time is associated with the intensity of personal relationships. PMID- 26252657 TI - A Quasi-Steady Lifting Line Theory for Insect-Like Hovering Flight. AB - A novel lifting line formulation is presented for the quasi-steady aerodynamic evaluation of insect-like wings in hovering flight. The approach allows accurate estimation of aerodynamic forces from geometry and kinematic information alone and provides for the first time quantitative information on the relative contribution of induced and profile drag associated with lift production for insect-like wings in hover. The main adaptation to the existing lifting line theory is the use of an equivalent angle of attack, which enables capture of the steady non-linear aerodynamics at high angles of attack. A simple methodology to include non-ideal induced effects due to wake periodicity and effective actuator disc area within the lifting line theory is included in the model. Low Reynolds number effects as well as the edge velocity correction required to account for different wing planform shapes are incorporated through appropriate modification of the wing section lift curve slope. The model has been successfully validated against measurements from revolving wing experiments and high order computational fluid dynamics simulations. Model predicted mean lift to weight ratio results have an average error of 4% compared to values from computational fluid dynamics for eight different insect cases. Application of an unmodified linear lifting line approach leads on average to a 60% overestimation in the mean lift force required for weight support, with most of the discrepancy due to use of linear aerodynamics. It is shown that on average for the eight insects considered, the induced drag contributes 22% of the total drag based on the mean cycle values and 29% of the total drag based on the mid half-stroke values. PMID- 26252658 TI - Localization of Motor Neurons and Central Pattern Generators for Motor Patterns Underlying Feeding Behavior in Drosophila Larvae. AB - Motor systems can be functionally organized into effector organs (muscles and glands), the motor neurons, central pattern generators (CPG) and higher control centers of the brain. Using genetic and electrophysiological methods, we have begun to deconstruct the motor system driving Drosophila larval feeding behavior into its component parts. In this paper, we identify distinct clusters of motor neurons that execute head tilting, mouth hook movements, and pharyngeal pumping during larval feeding. This basic anatomical scaffold enabled the use of calcium imaging to monitor the neural activity of motor neurons within the central nervous system (CNS) that drive food intake. Simultaneous nerve- and muscle recordings demonstrate that the motor neurons innervate the cibarial dilator musculature (CDM) ipsi- and contra-laterally. By classical lesion experiments we localize a set of CPGs generating the neuronal pattern underlying feeding movements to the subesophageal zone (SEZ). Lesioning of higher brain centers decelerated all feeding-related motor patterns, whereas lesioning of ventral nerve cord (VNC) only affected the motor rhythm underlying pharyngeal pumping. These findings provide a basis for progressing upstream of the motor neurons to identify higher regulatory components of the feeding motor system. PMID- 26252660 TI - Agmatine-Containing Bioreducible Polymer for Gene Delivery Systems and Its Dual Degradation Behavior. AB - Agmatine-containing bioreducible polymer, poly(cystaminebis(acrylamide)-agmatine) (poly(CBA-AG)) was synthesized for gene delivery systems. It could form 200-300 nm sized and positively charged polyplexes with pDNA, which could release pDNA in reducing the environment due to the internal disulfide bonds cleavage. Poly(CBA AG) also showed a spontaneous degradation behavior in aqueous condition in contrast to the backbone polymer, poly(cystaminebis(acrylamide)-diaminobutane) (poly(CBA-DAB)) lacking guanidine moieties, probably due to the self-catalyzed hydrolysis of internal amide bonds by guanidine moieties. The cytotoxicity of poly(CBA-AG) was cell-dependent but minimal. Poly(CBA-AG) exhibited highly enhanced transfection efficiency in comparison with poly(CBA-DAB) and even higher transfection efficiency than PEI25k. However, cellular uptake efficiency of the polyplexes did not show positive correlation with the transfection efficiency. Confocal microscopy observation revealed that pDNA delivered by poly(CBA-AG) was strongly accumulated in cell nuclei. These results suggested that high transfection efficiency of poly(CBA-AG) may be derived from the efficient pDNA localization in cell nuclei by guanidine moieties and that the polyplexes dissociation via self-catalyzed hydrolysis as well as disulfide bonds cleavage in cytosol also may facilitate the transfection process. Finally, poly(CBA-AG)/pJDK apoptin polyplex showed a high anticancer activity induced by apoptosis, demonstrating a potential of poly(CBA-AG) as a gene carrier for cancer gene therapy. PMID- 26252659 TI - Identification of Region-Specific Myocardial Gene Expression Patterns in a Chronic Swine Model of Repaired Tetralogy of Fallot. AB - Surgical repair of Tetralogy of Fallot (TOF) is highly successful but may be complicated in adulthood by arrhythmias, sudden death, and right ventricular or biventricular dysfunction. To better understand the molecular and cellular mechanisms of these delayed cardiac events, a chronic animal model of postoperative TOF was studied using microarrays to perform cardiac transcriptomic studies. The experimental study included 12 piglets (7 rTOF and 5 controls) that underwent surgery at age 2 months and were further studied after 23 (+/- 1) weeks of postoperative recovery. Two distinct regions (endocardium and epicardium) from both ventricles were analyzed. Expression levels from each localization were compared in order to decipher mechanisms and signaling pathways leading to ventricular dysfunction and arrhythmias in surgically repaired TOF. Several genes were confirmed to participate in ventricular remodeling and cardiac failure and some new candidate genes were described. In particular, these data pointed out FRZB as a heart failure marker. Moreover, calcium handling and contractile function genes (SLN, ACTC1, PLCD4, PLCZ), potential arrhythmia-related genes (MYO5B, KCNA5), and cytoskeleton and cellular organization-related genes (XIRP2, COL8A1, KCNA6) were among the most deregulated genes in rTOF ventricles. To our knowledge, this is the first comprehensive report on global gene expression profiling in the heart of a long-term swine model of repaired TOF. PMID- 26252661 TI - MicroRNA-34a induces apoptosis in PC12 cells by reducing B-cell lymphoma 2 and sirtuin-1 expression. AB - MicroRNA-34a (miR-34a) is a direct target of p53 and was reported to induce cell cycle arrest, apoptosis and senescence. Inhibition of the NAD-dependent deacetylase sirtuin-1 (SIRT1) by miR-34a leads to an increase in acetylated p53, which promotes cell apoptosis. B-cell lymphoma 2 (Bcl-2) is also involved in apoptosis, and was originally characterized with respect to its role in controlling outer mitochondrial membrane integrity. The effect of miR-34a in PC12 cells has not yet been reported. In the present study, it was hypothesized that Bcl-2 and SIRT1 may be critical downstream targets of miR-34a that participate in apoptosis induction. miR-34a mimics and inhibitors were transfected into PC12 cells, and the apoptosis and proliferation rates were compared between groups. It was demonstrated that induction of miR-34a promotes apoptosis and senescence, inhibits proliferation, and leads to marked alterations in SIRT1, Bcl-12 and acetyl (ac)-p53 expression. These data indicate that miR-34a may be important in neuropathy. PMID- 26252664 TI - Can social support work virtually? Evaluation of rheumatoid arthritis patients' experiences with an interactive online tool. AB - BACKGROUND: There is strong empirical evidence that the support that chronic patients receive from their environment is fundamental for the way they cope with physical and psychological suffering. Nevertheless, in the case of rheumatoid arthritis (RA), providing the appropriate social support is still a challenge, and such support has often proven to be elusive and unreliable in helping patients to manage the disease. OBJECTIVES: To explore whether and how social support for RA patients can be provided online, and to assess the conditions under which such support is effective. An online support tool was designed to provide patients with both tailored information and opportunities to interact online with health professionals and fellow sufferers. The general purpose was to identify where the support provided did - or did not - help patients, and to judge whether the determinants of success lay more within patients - their engagement and willingness to participate - or within the design of the website itself. METHODS: The present study reports qualitative interviews with 19 users of the tool. A more specific purpose was to elaborate qualitatively on results from a quantitative survey of users, which indicated that any positive impact was confined to practical matters of pain management rather than extending to more fundamental psychological outcomes such as acceptance. RESULTS AND CONCLUSIONS: Overall, online learning and interaction can do much to help patients with the everyday stresses of their disease; however, its potential for more durable positive impact depends on various individual characteristics such as personality traits, existing social networks, and the severity and longevity of the disease. PMID- 26252665 TI - Development of the Adolescent Cancer Suffering Scale. AB - BACKGROUND: While mortality due to pediatric cancer has decreased, suffering has increased due to complex and lengthy treatments. Cancer in adolescence has repercussions on personal and physical development. Although suffering can impede recovery, there is no validated scale in French or English to measure suffering in adolescents with cancer. OBJECTIVE: To develop an objective scale to measure suffering in adolescents with cancer. METHODS: A methodological design for instrument development was used. Following a MEDLINE search, semistructured interviews were conducted with adolescents 12 to 19 years of age who had undergone four to six weeks of cancer treatment, and with a multidisciplinary cohort of health care professionals. Adolescents with advanced terminal cancer or cognitive impairment were excluded. Enrollment proceeded from the hematology oncology department/clinic in Montreal, Quebec, from December 2011 to March 2012. Content validity was assessed by five health care professionals and four adolescents with cancer. RESULTS: Interviews with 19 adolescents and 16 health care professionals identified six realms of suffering: physical, psychological, spiritual, social, cognitive and global. Through iterative feedback, the Adolescent Cancer Suffering Scale (ACSS) was developed, comprising 41 questions on a four-point Likert scale and one open-ended question. Content validity was 0.98, and inter-rater agreement among professionals was 88% for relevance and 86% for clarity. Adolescents considered the scale to be representative of their suffering. CONCLUSIONS: The ACSS is the first questionnaire to measure suffering in adolescents with cancer. In future research, the questionnaire should be validated extensively and interventions developed. Once validated, the ACSS will contribute to promote a holistic approach to health with appropriate intervention or referral. PMID- 26252666 TI - Adjudicating fibromyalgia. Confusion, concerns and possible solutions. PMID- 26252668 TI - Functional Connectivity Alterations in Epilepsy from Resting-State Functional MRI. AB - The study of functional brain connectivity alterations induced by neurological disorders and their analysis from resting state functional Magnetic Resonance Imaging (rfMRI) is generally considered to be a challenging task. The main challenge lies in determining and interpreting the large-scale connectivity of brain regions when studying neurological disorders such as epilepsy. We tackle this challenging task by studying the cortical region connectivity using a novel approach for clustering the rfMRI time series signals and by identifying discriminant functional connections using a novel difference statistic measure. The proposed approach is then used in conjunction with the difference statistic to conduct automatic classification experiments for epileptic and healthy subjects using the rfMRI data. Our results show that the proposed difference statistic measure has the potential to extract promising discriminant neuroimaging markers. The extracted neuroimaging markers yield 93.08% classification accuracy on unseen data as compared to 80.20% accuracy on the same dataset by a recent state-of-the-art algorithm. The results demonstrate that for epilepsy the proposed approach confirms known functional connectivity alterations between cortical regions, reveals some new connectivity alterations, suggests potential neuroimaging markers, and predicts epilepsy with high accuracy from rfMRI scans. PMID- 26252669 TI - Phase-Imprinting of Bose-Einstein Condensates with Rydberg Impurities. AB - We show how the phase profile of Bose-Einstein condensates can be engineered through its interaction with localized Rydberg excitations. The interaction is made controllable and long range by off-resonantly coupling the condensate to another Rydberg state with laser light. Our technique allows the mapping of entanglement generated in systems of few strongly interacting Rydberg atoms onto much larger atom clouds in hybrid setups. As an example we discuss the creation of a spatial mesoscopic superposition state from a bright soliton. Additionally, the phase imprinted onto the condensate using the Rydberg excitations is a diagnostic tool for the latter. For example, a condensate time-of-flight image would permit reconstructing the pattern of an embedded Rydberg crystal. PMID- 26252667 TI - Draft De Novo Transcriptome of the Rat Kangaroo Potorous tridactylus as a Tool for Cell Biology. AB - The rat kangaroo (long-nosed potoroo, Potorous tridactylus) is a marsupial native to Australia. Cultured rat kangaroo kidney epithelial cells (PtK) are commonly used to study cell biological processes. These mammalian cells are large, adherent, and flat, and contain large and few chromosomes-and are thus ideal for imaging intra-cellular dynamics such as those of mitosis. Despite this, neither the rat kangaroo genome nor transcriptome have been sequenced, creating a challenge for probing the molecular basis of these cellular dynamics. Here, we present the sequencing, assembly and annotation of the draft rat kangaroo de novo transcriptome. We sequenced 679 million reads that mapped to 347,323 Trinity transcripts and 20,079 Unigenes. We present statistics emerging from transcriptome-wide analyses, and analyses suggesting that the transcriptome covers full-length sequences of most genes, many with multiple isoforms. We also validate our findings with a proof-of-concept gene knockdown experiment. We expect that this high quality transcriptome will make rat kangaroo cells a more tractable system for linking molecular-scale function and cellular-scale dynamics. PMID- 26252670 TI - Observation of a Topological Transition in the Bulk of a Non-Hermitian System. AB - We present the first experimental observation of a topological transition in a non-Hermitian system. In contrast to standard methods for examining topological properties, which involve probing edge (or surface) states, we monitor the topological transition by employing bulk dynamics only. The system is composed of a lattice of evanescently coupled optical waveguides, and non-Hermitian behavior is engineered by inducing bending loss by spatially "wiggling" every second waveguide. PMID- 26252671 TI - Superadditivity of Private Information for Any Number of Uses of the Channel. AB - The quantum capacity of a quantum channel is always smaller than the capacity of the channel for private communication. Both quantities are given by the infinite regularization of the coherent and the private information, respectively, which makes their evaluation very difficult. Here, we construct a family of channels for which the private and coherent information can remain strictly superadditive for unbounded number of uses, thus demonstrating that the regularization is necessary. We prove this by showing that the coherent information is strictly larger than the private information of a smaller number of uses of the channel. This implies that even though the quantum capacity is upper bounded by the private capacity, the nonregularized quantities can be interleaved. PMID- 26252672 TI - Experimental Satellite Quantum Communications. AB - Quantum communication (QC), namely, the faithful transmission of generic quantum states, is a key ingredient of quantum information science. Here we demonstrate QC with polarization encoding from space to ground by exploiting satellite corner cube retroreflectors as quantum transmitters in orbit and the Matera Laser Ranging Observatory of the Italian Space Agency in Matera, Italy, as a quantum receiver. The quantum bit error ratio (QBER) has been kept steadily low to a level suitable for several quantum information protocols, as the violation of Bell inequalities or quantum key distribution (QKD). Indeed, by taking data from different satellites, we demonstrate an average value of QBER=4.6% for a total link duration of 85 s. The mean photon number per pulse MU_{sat} leaving the satellites was estimated to be of the order of one. In addition, we propose a fully operational satellite QKD system by exploiting our communication scheme with orbiting retroreflectors equipped with a modulator, a very compact payload. Our scheme paves the way toward the implementation of a QC worldwide network leveraging existing receivers. PMID- 26252673 TI - Efficiency Statistics and Bounds for Systems with Broken Time-Reversal Symmetry. AB - Universal properties of the statistics of stochastic efficiency for mesoscopic time-reversal symmetry broken energy transducers are revealed in the Gaussian approximation. We also discuss how the second law of thermodynamics restricts the statistics of stochastic efficiency. The tight-coupling limit becomes unfavorable, characterized by an infinitely broad distribution of efficiency at all times, when time-reversal symmetry breaking leads to an asymmetric Onsager response matrix. The underlying physics is demonstrated through the quantum Hall effect and further elaborated in a triple-quantum-dot three-terminal thermoelectric engine. PMID- 26252675 TI - Hidden Topological Angles in Path Integrals. AB - We demonstrate the existence of hidden topological angles (HTAs) in a large class of quantum field theories and quantum mechanical systems. HTAs are distinct from theta parameters in the Lagrangian. They arise as invariant angles associated with saddle points of the complexified path integral and their descent manifolds (Lefschetz thimbles). Physical effects of HTAs become most transparent upon analytic continuation in n_{f} to a noninteger number of flavors, reducing in the integer n_{f} limit to a Z_{2} valued phase difference between dominant saddles. In N=1 super Yang-Mills theory we demonstrate the microscopic mechanism for the vanishing of the gluon condensate. The same effect leads to an anomalously small condensate in a QCD-like SU(N) gauge theory with fermions in the two-index representation. The basic phenomenon is that, contrary to folklore, the gluon condensate can receive both positive and negative contributions in a semiclassical expansion. In quantum mechanics, a HTA leads to a difference in semiclassical expansion of integer and half-integer spin particles. PMID- 26252674 TI - Limits on Anisotropy in the Nanohertz Stochastic Gravitational Wave Background. AB - The paucity of observed supermassive black hole binaries (SMBHBs) may imply that the gravitational wave background (GWB) from this population is anisotropic, rendering existing analyses suboptimal. We present the first constraints on the angular distribution of a nanohertz stochastic GWB from circular, inspiral-driven SMBHBs using the 2015 European Pulsar Timing Array data. Our analysis of the GWB in the ~2-90 nHz band shows consistency with isotropy, with the strain amplitude in l>0 spherical harmonic multipoles ?40% of the monopole value. We expect that these more general techniques will become standard tools to probe the angular distribution of source populations. PMID- 26252677 TI - Hyperfine Anomalies in Fr: Boundaries of the Spherical Single Particle Model. AB - We have measured the hyperfine splitting of the 7P_{1/2} state at the 100 ppm level in Fr isotopes (^{206g,206m,207,209,213,221}Fr) near the closed neutron shell (N=126 in ^{213}Fr). The measurements in five isotopes and a nuclear isomeric state of francium, combined with previous determinations of the 7S_{1/2} splittings, reveal the spatial distribution of the nuclear magnetization, i.e., the Bohr-Weisskopf effect. We compare our results with a simple shell model consisting of unpaired single valence nucleons orbiting a spherical nucleus, and find good agreement over a range of neutron-deficient isotopes (^{207-213}Fr). Also, we find near-constant proton anomalies for several even-N isotopes. This identifies a set of Fr isotopes whose nuclear structure can be understood well enough for the extraction of weak interaction parameters from parity nonconservation studies. PMID- 26252678 TI - Two-Color Strong-Field Photoelectron Spectroscopy and the Phase of the Phase. AB - The presence of a weak second-harmonic field in an intense-laser ionization experiment affects the momentum-resolved electron yield, depending on the relative phase between the omega and the 2omega component. The proposed two-color "phase-of-the-phase spectroscopy" quantifies for each final electron momentum a relative-phase contrast (RPC) and a phase of the phase (PP) describing how much and with which phase lag, respectively, the yield changes as a function of the relative phase. Experimental results for RPC and PP spectra for rare gas atoms and CO_{2} are presented. The spectra demonstrate a rather universal structure that is analyzed with the help of a simple model based on electron trajectories, wave-packet spreading, and (multiple) rescattering. Details in the PP and RPC spectra are target sensitive and, thus, may be used to extract structural (or even dynamical) information with high accuracy. PMID- 26252679 TI - Sub-Poissonian Statistics of Jamming Limits in Ultracold Rydberg Gases. AB - Several recent experiments have established by measuring the Mandel Q parameter that the number of Rydberg excitations in ultracold gases exhibits sub-Poissonian statistics. This effect is attributed to the Rydberg blockade that occurs due to the strong interatomic interactions between highly excited atoms. Because of this blockade effect, the system can end up in a state in which all particles are either excited or blocked: a jamming limit. We analyze appropriately constructed random-graph models that capture the blockade effect, and derive formulae for the mean and variance of the number of Rydberg excitations in jamming limits. This yields an explicit relationship between the Mandel Q parameter and the blockade effect, and comparison to measurement data shows strong agreement between theory and experiment. PMID- 26252680 TI - Coherent Addressing of Individual Neutral Atoms in a 3D Optical Lattice. AB - We demonstrate arbitrary coherent addressing of individual neutral atoms in a 5*5*5 array formed by an optical lattice. Addressing is accomplished using rapidly reconfigurable crossed laser beams to selectively ac Stark shift target atoms, so that only target atoms are resonant with state-changing microwaves. The effect of these targeted single qubit gates on the quantum information stored in nontargeted atoms is smaller than 3*10^{-3} in state fidelity. This is an important step along the path of converting the scalability promise of neutral atoms into reality. PMID- 26252681 TI - Precision Measurement for Metastable Helium Atoms of the 413 nm Tune-Out Wavelength at Which the Atomic Polarizability Vanishes. AB - We present the first measurement for helium atoms of the tune-out wavelength at which the atomic polarizability vanishes. We utilize a novel, highly sensitive technique for precisely measuring the effect of variations in the trapping potential of confined metastable (2^{3}S_{1}) helium atoms illuminated by a perturbing laser light field. The measured tune-out wavelength of 413.0938(9_{stat})(20_{syst}) nm compares well with the value predicted by a theoretical calculation [413.02(9) nm] which is sensitive to finite nuclear mass, relativistic, and quantum electrodynamic effects. This provides motivation for more detailed theoretical investigations to test quantum electrodynamics. PMID- 26252682 TI - Efimov Resonance and Three-Body Parameter in a Lithium-Rubidium Mixture. AB - We study collisional heating in a cold ^{7}Li-^{87}Rb mixture near a broad Feshbach resonance at 661 G. At the high field slope of the resonance, we find an enhanced three-body recombination rate that we interpret as a heteronuclear Efimov resonance. With improved Feshbach spectroscopy of two further resonances, a model for the molecular potentials has been developed that now consistently explains all known Feshbach resonances of the various Li-Rb isotope mixtures. The model is used to determine the scattering length of the observed Efimov state. Its value of -1870a_{0} Bohr radii supports the currently discussed assumption of universality of the three-body parameter also in heteronuclear mixtures. PMID- 26252683 TI - Nonequilibrium Quantum Criticality and Non-Markovian Environment: Critical Exponent of a Quantum Phase Transition. AB - We show that the critical exponent of a quantum phase transition in a damped driven open system is determined by the spectral density function of the reservoir. We consider the open-system variant of the Dicke model, where the driven boson mode and also the large N spin couple to independent reservoirs at zero temperature. The critical exponent, which is 1 if there is no spin-bath coupling, decreases below 1 when the spin couples to a sub-Ohmic reservoir. PMID- 26252684 TI - Atom-Light Hybrid Interferometer. AB - A new type of hybrid atom-light interferometer is demonstrated with atomic Raman amplification processes replacing the beam splitting elements in a traditional interferometer. This nonconventional interferometer involves correlated optical and atomic waves in the two arms. The correlation between atoms and light developed with the Raman process makes this interferometer different from conventional interferometers with linear beam splitters. It is observed that the high-contrast interference fringes are sensitive to the optical phase via a path change as well as the atomic phase via a magnetic field change. This new atom light correlated hybrid interferometer is a sensitive probe of the atomic internal state and should find wide applications in precision measurement and quantum control with atoms and photons. PMID- 26252685 TI - Generation of Bright, Spatially Coherent Soft X-Ray High Harmonics in a Hollow Waveguide Using Two-Color Synthesized Laser Pulses. AB - We investigate the efficient generation of low-divergence high-order harmonics driven by waveform-optimized laser pulses in a gas-filled hollow waveguide. The drive waveform is obtained by synthesizing two-color laser pulses, optimized such that highest harmonic yields are emitted from each atom. Optimization of the gas pressure and waveguide configuration has enabled us to produce bright and spatially coherent harmonics extending from the extreme ultraviolet to soft x rays. Our study on the interplay among waveguide mode, atomic dispersion, and plasma effect uncovers how dynamic phase matching is accomplished and how an optimized waveform is maintained when optimal waveguide parameters (radius and length) and gas pressure are identified. Our analysis should help laboratory development in the generation of high-flux bright coherent soft x rays as tabletop light sources for applications. PMID- 26252686 TI - Dissipative Phase Solitons in Semiconductor Lasers. AB - We experimentally demonstrate the existence of nondispersive solitary waves associated with a 2pi phase rotation in a strongly multimode ring semiconductor laser with coherent forcing. Similarly to Bloch domain walls, such structures host a chiral charge. The numerical simulations based on a set of effective Maxwell-Bloch equations support the experimental evidence that only one sign of chiral charge is stable, which strongly affects the motion of the phase solitons. Furthermore, the reduction of the model to a modified Ginzburg-Landau equation with forcing demonstrates the generality of these phenomena and exposes the impact of the lack of parity symmetry in propagative optical systems. PMID- 26252687 TI - Discontinuous Buckling of Wide Beams and Metabeams. AB - We uncover how nonlinearities dramatically alter the buckling of elastic beams. First, we show experimentally that sufficiently wide ordinary elastic beams and specifically designed metabeams-beams made from a mechanical metamaterial-exhibit discontinuous buckling, an unstable form of buckling where the postbuckling stiffness is negative. Then we use simulations to uncover the crucial role of nonlinearities, and show that beams made from increasingly nonlinear materials exhibit an increasingly negative postbuckling slope. Finally, we demonstrate that for sufficiently strong nonlinearity, we can observe discontinuous buckling for metabeams as slender as 1% numerically and 5% experimentally. PMID- 26252688 TI - Boundary-Layer Effects on Acoustic Transmission Through Narrow Slit Cavities. AB - We explore the slit-width dependence of the resonant transmission of sound in air through both a slit array formed of aluminum slats and a single open-ended slit cavity in an aluminum plate. Our experimental results accord well with Lord Rayleigh's theory concerning how thin viscous and thermal boundary layers at a slit's walls affect the acoustic wave across the whole slit cavity. By measuring accurately the frequencies of the Fabry-Perot-like cavity resonances, we find a significant 5% reduction in the effective speed of sound through the slits when an individual viscous boundary layer occupies only 5% of the total slit width. Importantly, this effect is true for any airborne slit cavity, with the reduction being achieved despite the slit width being on a far larger scale than an individual boundary layer's thickness. This work demonstrates that the recent prevalent loss-free treatment of narrow slit cavities within acoustic metamaterials is unrealistic. PMID- 26252689 TI - Drag Moderation by the Melting of an Ice Surface in Contact with Water. AB - We report measurements of the effects of a melting ice surface on the hydrodynamic drag of ice-shell-metal-core spheres free falling in water at a Reynolds of number Re~2*10^{4}-3*10^{5} and demonstrate that the melting surface induces the early onset of the drag crisis, thus reducing the hydrodynamic drag by more than 50%. Direct visualization of the flow pattern demonstrates the key role of surface melting. Our observations support the hypothesis that the drag reduction is due to the disturbance of the viscous boundary layer by the mass transfer from the melting ice surface. PMID- 26252690 TI - Molecular-Atomic Transition along the Deuterium Hugoniot Curve with Coupled Electron-Ion Monte Carlo Simulations. AB - We have performed simulations of the principal deuterium Hugoniot curve using coupled electron-ion Monte Carlo calculations. Using highly accurate quantum Monte Carlo methods for the electrons, we study the region of maximum compression along the Hugoniot, where the system undergoes a continuous transition from a molecular fluid to a monatomic fluid. We include all relevant physical corrections so that a direct comparison to experiment can be made. Around 50 GPa we find a maximum compression of 4.85. This compression is approximately 5.5% higher than previous theoretical predictions and 15% higher than the most accurate experimental data. Thus first-principles simulations encompassing the most advanced techniques are in disagreement with the results of the best experiments. PMID- 26252691 TI - Observation of a Fragmented, Strongly Interacting Fermi Gas. AB - We study the emergence of a fragmented state in a strongly interacting Fermi gas subject to a tunable disorder. We investigate its properties using a combination of high-resolution in situ imaging and conductance measurements. The fragmented state exhibits saturated density modulations, a strongly reduced density percolation threshold, lower than the average density, and a resistance equal to that of a noninteracting Fermi gas in the same potential landscape. The transport measurements further indicate that this state is connected to the superfluid state as disorder is reduced. We propose that the fragmented state consists of unpercolated islands of bound pairs, whose binding energy is enhanced by the disorder. PMID- 26252692 TI - Topological Superradiant States in a Degenerate Fermi Gas. AB - We predict the existence of a topological superradiant state in a two-component degenerate Fermi gas in a cavity. The superradiant light generation in the transversely driven cavity mode induces a cavity-assisted spin-orbit coupling and opens a bulk gap at half filling. This mechanism can simultaneously drive a topological phase transition in the system, yielding a topological superradiant state. We map out the steady-state phase diagram in the presence of an effective Zeeman field, and identify a critical tetracritical point beyond which the topological and the conventional superraidiant phase boundaries separate. The topological phase transition can be detected from its signatures in either the momentum distribution of the atoms or the variation of the cavity photon occupation due to the nontrivial feedback of the atoms on the cavity field. PMID- 26252693 TI - Interaction-Driven Topological Insulator in Fermionic Cold Atoms on an Optical Lattice: A Design with a Density Functional Formalism. AB - We design an interaction-driven topological insulator for fermionic cold atoms in an optical lattice; that is, we pose the question of whether we can realize in a continuous space a spontaneous symmetry breaking induced by the interatom interaction into a topological Chern insulator. Such a state, sometimes called a "topological Mott insulator," has yet to be realized in solid-state systems, since this requires, in the tight-binding model, large off-site interactions on top of a small on-site interaction. Here, we overcome the difficulty by introducing a spin-dependent potential, where a spin-selective occupation of fermions in A and B sublattices makes the on-site interaction Pauli forbidden, while a sizeable intersite interaction is achieved by a shallow optical potential with a large overlap between neighboring Wannier orbitals. This puts the system away from the tight-binding model, so that we adopt density functional theory for cold atoms, here extended to accommodate noncollinear spin structures emerging in the topological regime, to quantitatively demonstrate the phase transition to the topological Mott insulator. PMID- 26252694 TI - Crossover from Localized to Cascade Relaxations in Metallic Glasses. AB - Thermally activated deformation is investigated in two metallic glass systems with different cooling histories. By probing the atomic displacements and stress changes on the potential energy landscape, two deformation modes, a localized process and cascade process, have observed. The localized deformation involves fewer than 30 atoms and appears in both systems, and its size is invariant with cooling history. However, the cascade deformation is more frequently observed in the fast quenched system than in the slowly quenched system. The origin of the cascade process in the fast quenched system is attributed to the higher density of local minima on the underlying potential energy landscape. PMID- 26252676 TI - Measurement of the Effective Weak Mixing Angle in pp[over -]->Z/gamma^{*} >e^{+}e^{-} Events. AB - We present a measurement of the fundamental parameter of the standard model, the weak mixing angle sin^{2}theta_{eff}^{l} which determines the relative strength of weak and electromagnetic interactions, in pp[over -]->Z/gamma^{*}->e^{+}e^{-} events at a center of mass energy of 1.96 TeV, using data corresponding to 9.7 fb^{-1} of integrated luminosity collected by the D0 detector at the Fermilab Tevatron. The effective weak mixing angle is extracted from the forward-backward charge asymmetry as a function of the invariant mass around the Z boson pole. The measured value of sin^{2}theta_{eff}^{l}=0.23147+/-0.00047 is the most precise measurement from light quark interactions to date, with a precision close to the best LEP and SLD results. PMID- 26252695 TI - Noncontact Atomic Force Microscope Dissipation Reveals a Central Peak of SrTiO_{3} Structural Phase Transition. AB - The critical fluctuations at second order structural transitions in a bulk crystal may affect the dissipation of mechanical probes even if completely external to the crystal surface. Here, we show that noncontact force microscope dissipation bears clear evidence of the antiferrodistortive phase transition of SrTiO_{3}, known for a long time to exhibit a unique, extremely narrow neutron scattering "central peak." The noncontact geometry suggests a central peak linear response coupling connected with strain. The detailed temperature dependence reveals for the first time the intrinsic central peak width of order 80 kHz, 2 orders of magnitude below the established neutron upper bound. PMID- 26252696 TI - Electronic Friction-Based Vibrational Lifetimes of Molecular Adsorbates: Beyond the Independent-Atom Approximation. AB - We assess the accuracy of vibrational damping rates of diatomic adsorbates on metal surfaces as calculated within the local-density friction approximation (LDFA). An atoms-in-molecules (AIM) type charge partitioning scheme accounts for intramolecular contributions and overcomes the systematic underestimation of the nonadiabatic losses obtained within the prevalent independent-atom approximation. The quantitative agreement obtained with theoretical and experimental benchmark data suggests the LDFA-AIM scheme as an efficient and reliable approach to account for electronic dissipation in ab initio molecular dynamics simulations of surface chemical reactions. PMID- 26252697 TI - Onset of Area-Dependent Dissipation in Droplet Spreading. AB - We probe the viscous relaxation of structured liquid droplets in the partial wetting regime using a diblock copolymer system. The relaxation time of the droplets is measured after a step change in temperature as a function of three tunable parameters: droplet size, equilibrium contact angle, and the viscosity of the fluid. Contrary to what is typically observed, the late-stage relaxation time does not scale with the radius of the droplet-rather, relaxation scales with the radius squared. Thus, the energy dissipation depends on the contact area of the droplet, rather than the contact line. PMID- 26252698 TI - Correlation-Driven Charge and Spin Fluctuations in LaCoO_{3}. AB - The spin transition in LaCoO_{3} has been investigated using density-functional theory in combination with dynamical mean-field theory employing continuous time quantum Monte Carlo and exact diagonalization impurity solvers. Calculations on the experimental rhombohedral atomic structure with two Co sites per unit cell show that an independent treatment of the Co atoms results in a ground state with strong charge fluctuations induced by electronic correlations. Each atom shows a contribution from either a d^{5} or a d^{7} state in addition to the main d^{6} state. These states play a relevant role in the spin transition which can be understood as a low spin-high spin (LS-HS) transition with significant contributions (~10%) to the LS and HS states of d^{5} and d^{7} states, respectively. We report spectra as well as optical conductivity data for all cases. A thermodynamic analysis reveals a significant kinetic energy gain through introduction of charge fluctuations, which in addition to the potential energy reduction lowers the total energy of the system. PMID- 26252699 TI - Thermal Conductivity through the Quantum Critical Point in YbRh_{2}Si_{2} at Very Low Temperature. AB - The thermal conductivity of YbRh_{2}Si_{2} has been measured down to very low temperatures under field in the basal plane. An additional channel for heat transport appears below 30 mK, both in the antiferromagnetic and paramagnetic states, respectively, below and above the critical field suppressing the magnetic order. This excludes antiferromagnetic magnons as the origin of this additional contribution to thermal conductivity. Moreover, this low temperature contribution prevails a definite conclusion on the validity or violation of the Wiedemann Franz law at the field-induced quantum critical point. PMID- 26252700 TI - Infrared-Induced Sluggish Dynamics in the GeSbTe Electron Glass. AB - The electron-glass dynamics of Anderson-localized GeSbTe films is dramatically slowed down following a brief infrared illumination that increases the system carrier concentration (and thus its conductance). These results demonstrate that the dynamics exhibited by electron glasses is more sensitive to carrier concentration than to disorder. In turn, this seems to imply that many-body effects such as the orthogonality catastrophe must play a role in the sluggish dynamics observed in the intrinsic electron glasses. PMID- 26252701 TI - Temperature-Dependent Three-Dimensional Anisotropy of the Magnetoresistance in WTe_{2}. AB - Extremely large magnetoresistance (XMR) was recently discovered in WTe_{2}, triggering extensive research on this material regarding the XMR origin. Since WTe_{2} is a layered compound with metal layers sandwiched between adjacent insulating chalcogenide layers, this material has been considered to be electronically two-dimensional (2D). Here we report two new findings on WTe_{2}: (1) WTe_{2} is electronically 3D with a mass anisotropy as low as 2, as revealed by the 3D scaling behavior of the resistance R(H,theta)=R(epsilon_{theta}H) with epsilon_{theta}=(cos^{2}theta+gamma^{-2}sin^{2}theta)^{1/2}, theta being the magnetic field angle with respect to the c axis of the crystal and gamma being the mass anisotropy and (2) the mass anisotropy gamma varies with temperature and follows the magnetoresistance behavior of the Fermi liquid state. Our results not only provide a general scaling approach for the anisotropic magnetoresistance but also are crucial for correctly understanding the electronic properties of WTe_{2}, including the origin of the remarkable "turn-on" behavior in the resistance versus temperature curve, which has been widely observed in many materials and assumed to be a metal-insulator transition. PMID- 26252702 TI - Many-Body Localization Characterized from a One-Particle Perspective. AB - We show that the one-particle density matrix rho can be used to characterize the interaction-driven many-body localization transition in closed fermionic systems. The natural orbitals (the eigenstates of rho) are localized in the many-body localized phase and spread out when one enters the delocalized phase, while the occupation spectrum (the set of eigenvalues of rho) reveals the distinctive Fock space structure of the many-body eigenstates, exhibiting a steplike discontinuity in the localized phase. The associated one-particle occupation entropy is small in the localized phase and large in the delocalized phase, with diverging fluctuations at the transition. We analyze the inverse participation ratio of the natural orbitals and find that it is independent of system size in the localized phase. PMID- 26252703 TI - Rashba Spin-Orbit Coupling in Image Potential States. AB - The search in two-dimensional condensed matter systems of Rashba-type spin polarized electronic states is aimed by the possibility to control and manipulate the spin orientation. In this Letter, for the first time, we report on the experimental evidence of a Rashba-type spin splitting in the n=1 image potential state. The image potential state Rashba splitting here measured at the graphene/Ir(111) interface, as confirmed by theoretical considerations, can be detectable to any metal surface with a significant spin-orbit coupling. PMID- 26252704 TI - Microwave Emission from Hybridized States in a Semiconductor Charge Qubit. AB - We explore the microwave radiation emitted from a biased double quantum dot due to the inelastic tunneling of single charges. Radiation is detected over a broad range of detuning configurations between the dot energy levels, with pronounced maxima occurring in resonance with a capacitively coupled transmission line resonator. The power emitted for forward and reverse resonant detuning is found to be in good agreement with a rate equation model, which considers the hybridization of the individual dot charge states. PMID- 26252705 TI - Radio Frequency Magnetic Field Limits of Nb and Nb_{3}Sn. AB - Superconducting radio frequency (srf) cavities, essential components of many large particle accelerators, rely on the metastable flux-free state of superconducting materials. In this Letter, we present results of experiments measuring the magnetic field limits of two srf materials, Nb and Nb_{3}Sn. Resonators made using these materials were probed using both high power rf pulses and dc magnetic fields. Nb, which is the current standard material for srf cavities in applications, was found to be limited by the superheating field H_{sh} when prepared using methods to avoid excessive rf dissipation at high fields. Nb_{3}Sn, which is a promising alternative material that is still in the early stages of development for srf purposes, was found to be limited between the onset field of metastability H_{c1} and H_{sh}. Analysis of the results shows that the limitation is consistent with nucleation of flux penetration at defects in the rf layer. PMID- 26252706 TI - Frozen State and Spin Liquid Physics in Na_{4}Ir_{3}O_{8}: An NMR Study. AB - Na_{4}Ir_{3}O_{8} is a unique case of a hyperkagome 3D corner sharing triangular lattice that can be decorated with quantum spins. It has spurred a lot of theoretical interest as a spin liquid candidate. We present a comprehensive set of NMR data taken on both the ^{23}Na and ^{17}O sites. We show that disordered magnetic freezing of all Ir sites sets in below T_{f}~7 K, well below J=300 K, with a drastic slowing down of fluctuations to a static state revealed by our T_{1} measurements. Above typically 2T_{f}, physical properties are relevant to the spin liquid state induced by this exotic geometry. While the shift data show that the susceptibility levels off below 80 K, 1/T_{1} has little variation from 300 K to 2T_{f}. We discuss the implication of our results in the context of published experimental and theoretical work. PMID- 26252707 TI - Block Magnetic Excitations in the Orbitally Selective Mott Insulator BaFe_{2}Se_{3}. AB - Iron pnictides and selenides display a variety of unusual magnetic phases originating from the interplay between electronic, orbital, and lattice degrees of freedom. Using powder inelastic neutron scattering on the two-leg ladder BaFe_{2}Se_{3}, we fully characterize the static and dynamic spin correlations associated with the Fe_{4} block state, an exotic magnetic ground state observed in this low-dimensional magnet and in Rb_{0.89}Fe_{1.58}Se_{2}. All the magnetic excitations of the Fe_{4} block state predicted by an effective Heisenberg model with localized spins are observed below 300 meV and quantitatively reproduced. However, the data only account for 16(3)MU_{B}^{2} per Fe^{2+}, approximatively 2/3 of the total spectral weight expected for localized S=2 moments. Our results highlight how orbital degrees of freedom in iron-based magnets can conspire to stabilize an exotic magnetic state. PMID- 26252708 TI - Electric Field Control of Interfacial Ferromagnetism in CaMnO_{3}/CaRuO_{3} Heterostructures. AB - New mechanisms for achieving direct electric field control of ferromagnetism are highly desirable in the development of functional magnetic interfaces. To that end, we have probed the electric field dependence of the emergent ferromagnetic layer at CaRuO_{3}/CaMnO_{3} interfaces in bilayers fabricated on SrTiO_{3}. Using polarized neutron reflectometry, we are able to detect the ferromagnetic signal arising from a single atomic monolayer of CaMnO_{3}, manifested as a spin asymmetry in the reflectivity. We find that the application of an electric field of 600 kV/m across the bilayer induces a significant increase in this spin asymmetry. Modeling of the reflectivity suggests that this increase corresponds to a transition from canted antiferromagnetism to full ferromagnetic alignment of the Mn^{4+} ions at the interface. This increase from 1 MU_{B} to 2.5-3.0 MU_{B} per Mn is indicative of a strong magnetoelectric coupling effect, and such direct electric field control of the magnetization at an interface has significant potential for spintronic applications. PMID- 26252709 TI - First Passage Times, Lifetimes, and Relaxation Times of Unfolded Proteins. AB - The dynamics of proteins in the unfolded state can be quantified in computer simulations by calculating a spectrum of relaxation times which describes the time scales over which the population fluctuations decay to equilibrium. If the unfolded state space is discretized, we can evaluate the relaxation time of each state. We derive a simple relation that shows the mean first passage time to any state is equal to the relaxation time of that state divided by the equilibrium population. This explains why mean first passage times from state to state within the unfolded ensemble can be very long but the energy landscape can still be smooth (minimally frustrated). In fact, when the folding kinetics is two-state, all of the unfolded state relaxation times within the unfolded free energy basin are faster than the folding time. This result supports the well-established funnel energy landscape picture and resolves an apparent contradiction between this model and the recently proposed kinetic hub model of protein folding. We validate these concepts by analyzing a Markov state model of the kinetics in the unfolded state and folding of the miniprotein NTL9 (where NTL9 is the N-terminal domain of the ribosomal protein L9), constructed from a 2.9 ms simulation provided by D. E. Shaw Research. PMID- 26252710 TI - Stabilization of Helical Macromolecular Phases by Confined Bending. AB - By means of extensive replica-exchange simulations of generic coarse-grained models for helical polymers, we systematically investigate the structural transitions into all possible helical phases for flexible and semiflexible elastic polymers with self-interaction under the influence of torsion barriers. The competing interactions lead to a variety of conformational phases including disordered helical arrangements, single helices, and ordered, tertiary helix bundles. Most remarkably, we find that a bending restraint entails a clear separation and stabilization of the helical phases. This aids in understanding why semiflexible polymers such as double-stranded DNA tend to form pronounced helical structures and proteins often exhibit an abundance of helical structures, such as helix bundles, within their tertiary structure. PMID- 26252711 TI - Comment on "Holographic Thermalization, Stability of Anti-de Sitter Space, and the Fermi-Pasta-Ulam Paradox". PMID- 26252712 TI - Balasubramanian et al. Reply. PMID- 26252713 TI - Validation of AshTest as a Non-Invasive Alternative to Transjugular Liver Biopsy in Patients with Suspected Severe Acute Alcoholic Hepatitis. AB - BACKGROUND/AIMS: According to guidelines, the histological diagnosis of severe alcoholic steatohepatitis (ASH) can require liver biopsy if a specific treatment is needed. The blood test AshTest (BioPredictive, Paris, France) has been initially validated for the non-invasive diagnosis of ASH in a large population of heavy drinkers. The aim was to validate the AshTest accuracy in the specific context of use of patients with suspected severe ASH, in order to reduce the need for transjugular biopsy before deciding treatment. METHODS: The reference was liver biopsy, performed using the transjugular route, classified according to its histological severity as none, minimal, moderate or severe. Biopsies were assessed by the same experienced pathologist, blinded to simultaneous AshTest results. RESULTS: A total of 123 patients with severe clinical ASH (recent jaundice and Maddrey function greater or equal to 32) were included, all had cirrhosis and 80% had EASL histological definition of ASH. 95% of patients received prednisolone; and the 2-year mortality was 63%. The high AshTest performance was confirmed both for the binary outcome [AUROC = 0.803 (95%CI 0.684 0.881)] significantly higher than the AST/ALT AUROC [0.603 (0.462-0.714); P<0.001], and for the severity of ASH-score system by the Obuchowski measures for [mean (SE) 0.902 (0.017) vs. AST/ALT 0.833 (0.023); P = 0.01], as well as for the diagnosis and severity of ballooning, PMN and Mallory bodies. According to attributability of discordances, AshTest had a 2-7% risk of 2 grades misclassification. CONCLUSION: These results confirmed the diagnostic performance of AshTest in cirrhotic patients with severe clinical ASH, in the specific context of use of corticosteroid treatment. AshTest is an appropriate non invasive alternative to transjugular liver biopsy. PMID- 26252715 TI - Correction: A Lead-In with Silibinin Prior to Triple-Therapy Translates into Favorable Treatment Outcomes in Difficult-To-Treat HIV/Hepatitis C Coinfected Patients. PMID- 26252714 TI - Cerebral White Matter Lesions and Affective Episodes Correlate in Male Individuals with Bipolar Disorder. AB - BACKGROUND: Cerebral white matter lesions (WML) have been found in normal aging, vascular disease and several neuropsychiatric conditions. Correlations of WML with clinical parameters in BD have been described, but not with the number of affective episodes, illness duration, age of onset and Body Mass Index in a well characterized group of euthymic bipolar adults. Herein, we aimed to evaluate the associations between bipolar course of illness parameters and WML measured with volumetric analysis. METHODS: In a cross-sectional study 100 euthymic individuals with BD as well as 54 healthy controls (HC) were enrolled to undergo brain magnetic resonance imaging using 3T including a FLAIR sequence for volumetric assessment of WML-load using FSL-software. Additionally, clinical characteristics and psychometric measures including Structured Clinical Interview according to DSM-IV, Hamilton-Depression, Young Mania Rating Scale and Beck's Depression Inventory were evaluated. RESULTS: Individuals with BD had significantly more (F = 3.968, p < .05) WML (Mdn = 3710 mm3; IQR = 2961 mm3) than HC (Mdn = 2185 mm3; IQR = 1665 mm3). BD men (Mdn = 4095 mm3; IQR = 3295 mm3) and BD women (Mdn = 3032 mm3; IQR = 2816 mm3) did not significantly differ as to the WML-load or the number and type of risk factors for WML. However, in men only, the number of manic/hypomanic episodes (r = 0.72; p < .001) as well as depressive episodes (r = 0.51; p < .001) correlated positively with WML-load. CONCLUSIONS: WML-load strongly correlated with the number of manic episodes in male BD patients, suggesting that men might be more vulnerable to mania in the context of cerebral white matter changes. PMID- 26252716 TI - Fluorophore-Conjugated Holliday Junctions for Generating Super-Bright Antibodies and Antibody Fragments. AB - The site-specific modification of proteins with fluorophores can render a protein fluorescent without compromising its function. To avoid self-quenching from multiple fluorophores installed in close proximity, we used Holliday junctions to label proteins site-specifically. Holliday junctions enable modification with multiple fluorophores at reasonably precise spacing. We designed a Holliday junction with three of its four arms modified with a fluorophore of choice and the remaining arm equipped with a dibenzocyclooctyne substituent to render it reactive with an azide-modified fluorescent single-domain antibody fragment or an intact immunoglobulin produced in a sortase-catalyzed reaction. These fluorescent Holliday junctions improve fluorescence yields for both single-domain and full sized antibodies without deleterious effects on antigen binding. PMID- 26252717 TI - Microhydration of Protonated Nalpha-Acetylhistidine: A Theoretical Approach. AB - Extensive exploration of the potential energy surfaces of protonated Nalpha acetylhistidine hydrated by 0-3 molecules of water was performed. The methodology combined hierarchical and genealogical (Darwin family tree) approaches using polarizable AMOEBA force field and M06 functional. It is demonstrated that this mixed approach allows recovering a larger number of conformers than the number recovered by using any one of the two methods alone. Hydration enthalpies of protonated Nalpha-acetylhistidine and of model compounds have been computed using higher theoretical methods, up to the G4MP2 procedure. Excellent agreement with experiment is observed for successive hydration of methylamonium and imidazolium cations using MP2/6-311++G(2d,2p)//M06/6-311++G(d,p) and G4MP2 methods, thereby validating the theory levels used for hydrated protonated Nalpha-acetylhistidine. It is found that the first hydration enthalpy of protonated Nalpha acetylhistidine is ca. 10 kJ mol(-1) lower than that of imidazolium, a result explained by the local environment of the positively charged imidazolium moiety. PMID- 26252719 TI - Systematic and simulation-free coarse graining of homopolymer melts: a relative entropy-based study. AB - We applied the systematic and simulation-free strategy proposed in our previous work (D. Yang and Q. Wang, J. Chem. Phys., 2015, 142, 054905) to the relative entropy-based (RE-based) coarse graining of homopolymer melts. RE-based coarse graining provides a quantitative measure of the coarse-graining performance and can be used to select the appropriate analytic functional forms of the pair potentials between coarse-grained (CG) segments, which are more convenient to use than the tabulated (numerical) CG potentials obtained from structure-based coarse graining. In our general coarse-graining strategy for homopolymer melts using the RE framework proposed here, the bonding and non-bonded CG potentials are coupled and need to be solved simultaneously. Taking the hard-core Gaussian thread model (K. S. Schweizer and J. G. Curro, Chem. Phys., 1990, 149, 105) as the original system, we performed RE-based coarse graining using the polymer reference interaction site model theory under the assumption that the intrachain segment pair correlation functions of CG systems are the same as those in the original system, which de-couples the bonding and non-bonded CG potentials and simplifies our calculations (that is, we only calculated the latter). We compared the performance of various analytic functional forms of non-bonded CG pair potential and closures for CG systems in RE-based coarse graining, as well as the structural and thermodynamic properties of original and CG systems at various coarse-graining levels. Our results obtained from RE-based coarse graining are also compared with those from structure-based coarse graining. PMID- 26252718 TI - Association of Serum Uric Acid Level With Blood Pressure Variability in Newly Diagnosed Essential Hypertension. AB - Serum uric acid (UA) is independently associated with hypertension and blood pressure (BP) variability (BPV) is associated with cardiovascular events and mortality in hypertensive patients. The aim of the present study was to assess the association of serum UA with BPV in 300 untreated essential hypertension patients (mean age 57.3+/-13.6 years). BPV was quantified as the standard deviation (SD) of the 24-hour, daytime, and nighttime mean values obtained by using ambulatory BP monitoring. In correlation analysis, log UA values were found to be positively correlated with 24-hour systolic BPV and nighttime systolic and diastolic BPV (Pearson coefficients of 0.246, 0.280, and 0.353, respectively; P<.001 for all). In multivariate analysis, log UA had an independent association with 24-hour systolic BPV and nighttime systolic and diastolic BPV. This study show for the first time that increased serum UA is independently associated with BPV in untreated essential hypertension patients. PMID- 26252721 TI - Treating depression with botulinum toxin: a pooled analysis of randomized controlled trials. AB - INTRODUCTION: Botulinum toxin A (BTA) injection into the glabellar region is currently being studied as a treatment for major depressive disorder (MDD). Here we explore efficacy data of this novel approach in a pooled analysis. METHODS: A literature search revealed 3 RCTs on this topic. Individual patient data and clinical end points shared by these 3 trials were pooled and analyzed as one study (n=134) using multiple regression models with random effects. RESULTS: In the pooled sample, the BTA (n=59) and the placebo group (n=75) did not differ in the baseline variables. Efficacy outcomes revealed BTA superiority over placebo: Improvement in the Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale 6 weeks after baseline was 45.7% for BTA vs. 14.6% for placebo (p<0.0001), corresponding to a BTA response rate of 54.2% (vs. 10.7%) and a BTA remission rate of 30.5% (vs. 6.7%). DISCUSSION: Equalling the status of a meta-analysis, this study increases evidence that a single treatment of BTA into the glabellar region can reduce symptoms of MDD. Further studies are needed to better understand how BTA exerts its mood-lifting effect. PMID- 26252722 TI - Retrospective analysis of therapeutic drug monitoring data for treatment of bipolar disorder with lamotrigine. AB - INTRODUCTION: Lamotrigine is licensed for treatment of epilepsy and prevention or at least delay of depressive episodes in bipolar disorder. The accepted therapeutic reference range (TRR) of lamotrigine for anticonvulsant treatment is 3 000-14 000 ng/ml. This TRR is often used for the therapy of bipolar disorders as well. This work presents serious doubts about this approach. METHODS: KONBEST, a large TDM database containing patients' characteristics including diagnoses, doses, comedication and serum concentrations, was analyzed. Out of a total of 3 459 lamotrigine samples, 360 patients suffered from bipolar disorder. 82 of them benefitted from therapy with lamotrigine as judged by the clinical global impression of improvement (CGI-I) scale. Patients with a score of minimally (3), much (2) or very much improved (1) were considered as responders. RESULTS: The recommended lamotrigine maintenance dose for bipolar disorder is 200 mg/day; the doses prescribed in our samples ranged from 25 to 450 mg/day. Only 32 concentrations (39.0%) fitted into the TRR recommended for therapy of epilepsy; 50 (61.0%) did not reach it, none exceeded it. The lowest concentration was 177 ng/ml, the highest 11 871 ng/ml. A mean lamotrigine serum concentration of 3 341+/-2 563 ng/ml (x+/-SD) was detected in the patients who benefitted. DISCUSSION: The authors conclude that in bipolar disorder lower lamotrigine serum concentrations lead to therapeutic benefit. PMID- 26252723 TI - The Case of Pharmacological Neuroenhancement: Medical, Judicial and Ethical Aspects from a German Perspective. AB - Pharmacological neuroenhancement (PN) describes the use of psychoactive drugs for the purpose of enhancing cognition (e. g., fatigue, concentration, memory etc.) by healthy subjects without medical need. Drugs used for this purpose can be divided into freely available, over-the-counter drugs (e. g., methylxanthines such as caffeine), prescription drugs (e. g., antidementia drugs, methylphenidate) and illicit drugs (e. g., illicit amphetamines). Clinical studies have shown that the aforementioned substances only have limited pro cognitive effects and have considerable safety risks and side effects.The German judicial perspective shows legal differences between substances (drugs, food, food supplements, fortified food) that can be bought in a supermarket, drugs that can be bought in a pharmacy as over-the-counter- (OTC-) drugs, drugs with or without the need for a prescription and illicit drugs. Supermarket drugs and fortified food can be sold freely and follow the general rules of civil and penal law; regarding acquisition, parents are responsible for their children. OTC drugs require special information about therapy. Regarding prescription drugs, there are legal problems caused by an off-label use and the non-medical purposes of PN drugs. Furthermore, prescription stimulants for PN are governed by the specialized law for narcotics, and their use might be punished. Beyond the general lack of rules for regulation for PN drug use there are specific needs for prevention (e. g., control of the black market, etc.).Possible future policy will depend, among others, on the probability with which effective PN drugs with an acceptable risk-benefit ratio will be available, on individual and societal implications, and on public opinion towards PN. While 4 different general policy scenarios can be identified, it is important to advance a broad societal debate on PN to collect relevant empirical data and to address enhancement-related conceptual issues. PMID- 26252724 TI - The Benefits of a Nurse-Driven, Patient- and Family-Centered Pediatric Palliative Care Program. AB - This article describes the program and outcomes of a nurse driven, patient- and family-centered pediatric advanced comprehensive care team (PACCT) palliative program. This care delivery model improved patient outcomes by providing care across the healthcare continuum for pediatric patients. Since the inception of PACCT, no child has died on a ventilator in the pediatric ICU associated with end of-life-related issues. PMID- 26252725 TI - Lean Manufacturing Improves Emergency Department Throughput and Patient Satisfaction. AB - A multidisciplinary team led by nursing leadership and physicians developed a plan to meet increasing demand and improve the patient experience in the ED without expanding the department's current resources. The approach included Lean tools and engaged frontline staff and physicians. Applying Lean management principles resulted in quicker service, improved patient satisfaction, increased capacity, and reduced resource utilization. Incorporating continuous daily management is necessary for sustainment of continuous improvement activities. PMID- 26252726 TI - pi-Hole aerogen bonding interactions. AB - In this manuscript we combine high level ab initio calculations (RI-MP2/aug-cc pVTZ) and the analysis of several crystal structures to demonstrate the existence of pi-hole aerogen bonding interactions in Xe(iv) compounds. The ability of XeF4 and Xe(OMe)4 to interact with electron rich molecules is rationalized using several computational tools, including molecular electrostatic potential surfaces, energetic and geometric features of the complexes and "atoms in molecules" (AIM) and Natural Bond Orbital (NBO) analyses. We have found support for the pi-hole interaction involving the xenon atom from the solid state architecture of several X-ray structures retrieved from the crystal structural depot. Particularly, pi-hole aerogen bonding interactions are quite common in the solid state of Xe(IV) compounds. PMID- 26252727 TI - Effect of Electrode Location on Task-Dependent Electromyography Responses Within the Human Biceps Femoris Muscle. AB - In some muscles, nonuniform surface electromyography (EMG) responses have been demonstrated within a muscle, meaning that the electrode location could be critical in the results of surface EMG. The current study investigated possible region-specific EMG responses within the human biceps femoris (BF) muscle. Surface EMG was recorded from various regions along the longitudinal axis of the BF muscle with 20 electrodes. Ten healthy men performed maximal isometric contractions of hip extension and knee flexion, which involve the BF muscle. The ratio of the EMG amplitude between hip extension and knee flexion tasks (HE/KF) was calculated and compared among the regions. There were no significant differences in HE/KF among the regions along the BF muscle (P > .05). This suggests that the entire superficial region of the BF muscle is equally regulated in the 2 different tasks. We suggest that the electrode location is not critical in estimating the activation properties and/or functional role of the superficial region, which corresponds with approximately 50% of the muscle length of the BF muscle, using surface EMG during maximal contraction. PMID- 26252728 TI - Li2Ni(0.5)Mn(0.5)SnO4/C: A Novel Hybrid Composite Electrode for High Rate Applications. AB - A novel Li2Ni(0.5)Mn(0.5)SnO4/C composite electrode, existing as a hybrid consisting of monoclinic Li2SnO3 and layered LiNi(0.5)Mn(0.5)O2, has been identified and validated for high capacity and high rate lithium battery applications. Of the components, LiNi(0.5)Mn(0.5)O2 upon discharge forms the corresponding dilithium oxide, viz., Li2Ni(0.5)Mn(0.5)O2, and facilitates the progressive electrochemical performance of the composite electrode. Similarly, Li2SnO3 upon discharge forms Li2O and SnO2, wherein the unacceptable volume expansion related issues of SnO2 are addressed by the buffering activity of Li2O phase. A combination of alloying/dealloying, conversion, and redox mechanism is responsible for the excellent electrochemical behavior of Li2Ni(0.5)Mn(0.5)SnO4/C electrode. With this newer formulation of dilithium stannate composite, a superior capacity of >3000 mAh g(-1) at 100 mA g(-1) current density has been demonstrated. The study opens up a newer gateway for the entry of Li2SnO3.LiM1M2O2 hybrid formulations for exploitation up to 1 A g(-1) rate, thus ensuring the sustainable development of potential electrode materials for high rate applications. PMID- 26252729 TI - Adsorption of fluorinated anesthetics within the pores of a molecular crystal. AB - Commonly used inhalation anesthetics-enflurane, isoflurane, sevoflurane, halothane, and methoxyflurane-are adsorbed within the pores of a porous fluorinated molecular crystal to the tune of up to 73.4(+/-0.2)% by weight. Uptake of all studied anesthetics is quite fast, typically reaching saturation in less than three minutes. PMID- 26252730 TI - Laser tympanic neurectomy for post-cochlear implant pain: A new technique. AB - OBJECTIVES: To present the case histories and management by LASER tympanic neurectomy of two patients who presented with pain as their only symptom after cochlear implantation, avoiding the need for device removal. CLINICAL PRESENTATION: Two of our patients presented with otalgia, which appeared 6 months after cochlear implantation and resulted in their refusing to use the device. The pain was not controlled by repeated remapping or medical management. Neither patient showed evidence of infection or inflammation around their device. X-rays showed that there were no extracochlear electrodes or evidence of extrusion. One patient had current leakage from two electrodes, which were switched off, but the pain persisted. INTERVENTION: Both patients received an intratympanic injection of 1 ml of 0.5% Bupivacaine to anaesthetize the tympanic plexus in the middle ear and were then observed for a day, found to have relief of their pain and were able to use the implant with audiological benefit for this short time, until the effect of the anaesthetic had worn off. Therefore we planned and performed a tympanic neurectomy on both patients using CO2 laser. CONCLUSION: Tympanic neurectomy removed the pain in two cochlear implant patients who presented with pain which was present only when the implant was switched on. PMID- 26252732 TI - Anteroposterior compression of the spinal cord leading to cervical myelopathy: a finite element analysis. PMID- 26252731 TI - Antibody humanization by structure-based computational protein design. AB - Antibodies derived from non-human sources must be modified for therapeutic use so as to mitigate undesirable immune responses. While complementarity-determining region (CDR) grafting-based humanization techniques have been successfully applied in many cases, it remains challenging to maintain the desired stability and antigen binding affinity upon grafting. We developed an alternative humanization approach called CoDAH ("Computationally-Driven Antibody Humanization") in which computational protein design methods directly select sets of amino acids to incorporate from human germline sequences to increase humanness while maintaining structural stability. Retrospective studies show that CoDAH is able to identify variants deemed beneficial according to both humanness and structural stability criteria, even for targets lacking crystal structures. Prospective application to TZ47, a murine anti-human B7H6 antibody, demonstrates the approach. Four diverse humanized variants were designed, and all possible unique VH/VL combinations were produced as full-length IgG1 antibodies. Soluble and cell surface expressed antigen binding assays showed that 75% (6 of 8) of the computationally designed VH/VL variants were successfully expressed and competed with the murine TZ47 for binding to B7H6 antigen. Furthermore, 4 of the 6 bound with an estimated KD within an order of magnitude of the original TZ47 antibody. In contrast, a traditional CDR-grafted variant could not be expressed. These results suggest that the computational protein design approach described here can be used to efficiently generate functional humanized antibodies and provide humanized templates for further affinity maturation. PMID- 26252733 TI - In vivo Rac/Rop localization as well as interaction with RhoGAP and RhoGDI in tobacco pollen tubes: analysis by low-level expression of fluorescent fusion proteins and bimolecular fluorescence complementation. AB - Polarized Rac/Rop GTPase signaling plays a key role in polar cell growth, which is essential for plant morphogenesis. The molecular and cellular mechanisms responsible for the polarization of Rac/Rop signaling during polar cell growth are only partially understood. Mutant variants of Rac/Rop GTPases lacking specific functions are important tools to investigate these mechanisms, and have been employed to develop a model suggesting that RhoGAP (GTPase activating protein) and RhoGDI (Guanine Nucleotide Dissociation Inhibitor) mediated recycling of Rac/Rop GTPases maintains apical polarization of Rac/Rop activity in pollen tubes, which elongate by 'tip growth' (an extreme form of polar cell growth). Despite the importance of these mutant variants for Rac/Rop functional characterization, their distinct intracellular distributions have not been thoroughly comparatively and quantitatively analyzed. Furthermore, support for the proposed RhoGAP and RhoGDI functions in apical polarization of Rac/Rop activity based on the analysis of in vivo interactions between these proteins and Rac/Rop GTPases has been missing. Here, extensive fluorescent protein tagging and bimolecular fluorescence complementation (BiFC) analyses are described of the intracellular distributions of wild type and mutant variants of the tobacco pollen tube Rac/Rop GTPase Nt-Rac5, as well as of interactions of these Nt-Rac5 variants with RhoGAP and RhoGDI proteins, in normally growing transiently transformed pollen tubes. Presented results substantially enhance our understanding of apical dynamics of pollen tube Rac/Rop signaling proteins, confirm previously proposed RhoGAP and RhoGDI functions in Rac/Rop polarization and provide important technical insights facilitating future in vivo protein localization and BiFC experiments in pollen tubes. PMID- 26252734 TI - ISCHEMIC RETINOPATHY IN NEUROFIBROMATOSIS TYPE 1. AB - PURPOSE: To describe a patient with severe ischemic retinopathy and maculopathy in the context of neurofibromatosis Type 1. METHODS: Case report illustrated with multimodal clinical imaging. A 16-year-old female with neurofibromatosis Type 1 presented with visual deterioration over several weeks. Her right eye was amblyopic because of an optic nerve glioma treated in childhood with chemotherapy. RESULTS: Corrected visual acuities were counting fingers in the right eye and 20/150 in the left eye. Examination revealed bilateral optic disk pallor. In the left eye, severe and extensive ischemic retinopathy and maculopathy were noted with collateral formation and neovascularization. Proximal arterial occlusion at the level of the internal carotid and ophthalmic arteries was excluded on neuroimaging, including computed tomography angiography. CONCLUSION: Neurofibromatosis Type 1 may present in the ocular fundus with a variety of lesion types, including vasoproliferative tumors, hamartoma, uveal melanoma, and hemangioma. Vascular occlusions are relatively uncommon. Ocular ischemic syndrome secondary to moyamoya syndrome is well described in neurofibromatosis Type 1 but was excluded in our patient. A spectrum of retinal microvascular abnormalities has also been described, but disease-specific evidence to guide treatment is lacking. PMID- 26252735 TI - Quadrupedal Locomotion-Respiration Entrainment and Metabolic Economy in Cross Country Skiers. AB - A 1:1 locomotion-respiration entrainment is observed in galloping quadrupeds, and is thought to improve running economy. However, this has not been tested directly in animals, as animals cannot voluntarily disrupt this entrainment. The purpose of this study was to evaluate metabolic economy in a human gait involving all four limbs, cross-country skiing, in natural entrainment and forced nonentrainment. Nine elite cross-country skiers roller skied at constant speed using the 2-skate technique. In the first and last conditions, athletes used the natural entrained breathing pattern: inhaling with arm recovery and exhaling with arm propulsion, and in the second condition, the athletes disentrained their breathing pattern. The rate of oxygen uptake (VO2) and metabolic rate (MR) were measured via expired gas analysis. Propulsive forces were measured with instrumented skis and poles. VO2 and MR increased by 4% and 5% respectively when skiers used the disentrained compared with the entrained breathing pattern. There were no differences in ski or pole forces or in timing of the gait cycle between conditions. We conclude that breathing entrainment reduces metabolic cost of cross-country skiing by approximately 4%. Further, this reduction is likely a result of the entrainment rather than alterations in gait mechanics. PMID- 26252736 TI - Alteration of O-GlcNAcylation affects serine phosphorylation and regulates gene expression and activity of pyruvate kinase M2 in colorectal cancer cells. AB - O-GlcNAcylation is a dynamic post-translational modification that has extensive crosstalk with phosphorylation either at the same or adjacent sites of various proteins. We have previously reported that O-GlcNAcylation level was increased in primary breast and colorectal cancer, but the interplay of the two modifications remains unclear. Therefore, we explored crosstalk of the modifications by RNA interference against O-GlcNAc transferase (OGT) in colorectal cancer cells. Two dimensional immunoblotting and mass spectrometric analysis showed that the levels of O-GlcNAc and serine phosphorylation of many proteins including serine hydroxymethyltransferase, cytokeratin-8, pyruvate kinase M2 (PKM2), heterogeneous nuclear ribonucleoprotein L, and lamin-B1, were reduced in siOGT cells compared to siScramble cells. In HT29 cells, immunoprecipitated PKM2 revealed decreased O GlcNAc and serine phosphorylation levels after siOGT knockdown, but increased levels after treatment with Thiamet-G, an inhibitor of O-GlcNAcase (OGA). In addition, when global O-GlcNAcylation was enhanced by treating cells with Thiamet G, PKM2 expression level was upregulated, but PKM2-specific activity was decreased. On the other hand, in OGT knockdown cells, PKM2 expression level was downregulated, but PKM2-specific activity was increased. Moreover, the metastatic colorectal cancer cells, SW620, had more O-GlcNAc-PKM2 and showed lower PKM2 specific activity compared to the non-metastatic colorectal cancer SW480 cells. These results suggested roles of O-GlcNAcylation in modulating serine phosphorylation, as well as in regulating PKM2 activity and expression. Interfering levels of O-GlcNAcylation of PKM2 may be a novel target in controlling cancer metabolism and tumorigenesis of colorectal cancer. PMID- 26252737 TI - Computational predictions of corroles as a class of Hsp90 inhibitors. AB - Corroles have been shown experimentally to cause cell cycle arrest, and there is some evidence that this might be attributed to an inhibitory effect of corroles on Heat shock protein 90 (Hsp90), which is known to play a vital role in cancer cell proliferation. In this study, we used molecular dynamics to examine the interaction of gallium corroles with Hsp90, and found that they can bind preferentially to the ATP-binding N-terminal site. We also found that structural variations of the corrole ring can influence the binding energies and affinities of the corrole to Hsp90. We predict that both the bis-carboxylated corrole (4-Ga) and a proposed 3,17-bis-sulfonated corrole (7-Ga) are promising alternatives to Ga(III) 5,10,15-tris(pentafluorophenyl)-2,17-bis(sulfonic acid)-corrole (1-Ga) as anti-cancer agents. PMID- 26252738 TI - MiR-132 inhibits cell proliferation, invasion and migration of hepatocellular carcinoma by targeting PIK3R3. AB - MicroRNA-132 (miR-132) has been reported to play a tumor suppressive role in different human malignancies. However, its role and underling mechanism in hepatocellular carcinoma (HCC) remains poorly defined due to lack of target gene information. In the present study, we demonstrated that the mean level of miR-132 in hepatocellular carcinoma (HCC) tissues was significantly lower than that in matched tumor-adjacent tissues, and its expression negatively correlated with tumor differentiation (P<0.01), TNM stage (P<0.01) and lymph node metastasis (P<0.01). Similarly, the expression of miR-132 was obviously reduced in HCC cell lines as compared with a normal hepatic cell line. Ectopic expression of miR-132 inhibited cell proliferation, colony formation, migration and invasion, and induced apoptosis in HepG2 cells. In vivo studies showed that miR-132 inhibited tumor growth of HCC and decreased tumor volume and weight. In addition, phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) was identified as a direct target of miR-132 by a luciferase reporter assay. Western blot and qRT-PCR analysis indicated that PIK3R3 was significantly downregulated by miR-132 in HCC cells. miR-132 expression inversely correlated with PIK3R3 mRNA expression in clinical HCC tissues. Investigations into possible mechanisms revealed that miR 132 inactivated the AKT/mTOR signaling pathway, which may contribute to inhibition of proliferation, migration, and invasion of HCC. These findings suggested that miR-132 may serve as a potential target in the treatment of human HCC. PMID- 26252740 TI - Cooperative Multicatalytic System for the One-Pot Synthesis of Octahydrospiro beta-carbolines. AB - A domino cyclization of 3-((3-(2-aminophenyl)prop-2-ynylamino)methyl)but-3-en-1 ol with aldehydes has been accomplished employing 5 mol % of the Ph3PAuCl/AgSbF6/In(OTf)3 system to afford the corresponding octahydrospiro[pyran 4,4'-pyrido[3,4-b]indole] derivatives in good yields with high selectivity. This is the first report on the synthesis of spiro-beta-carbolines through a multicatalytic cascade process. PMID- 26252739 TI - The Psychometric Properties of the Center for Epidemiologic Studies Depression Scale in Chinese Primary Care Patients: Factor Structure, Construct Validity, Reliability, Sensitivity and Responsiveness. AB - BACKGROUND: The Center for Epidemiologic Studies Depression Scale (CES-D) is a commonly used instrument to measure depressive symptomatology. Despite this, the evidence for its psychometric properties remains poorly established in Chinese populations. The aim of this study was to validate the use of the CES-D in Chinese primary care patients by examining factor structure, construct validity, reliability, sensitivity and responsiveness. METHODS AND RESULTS: The psychometric properties were assessed amongst a sample of 3686 Chinese adult primary care patients in Hong Kong. Three competing factor structure models were examined using confirmatory factor analysis. The original CES-D four-structure model had adequate fit, however the data was better fit into a bi-factor model. For the internal construct validity, corrected item-total correlations were 0.4 for most items. The convergent validity was assessed by examining the correlations between the CES-D, the Patient Health Questionnaire 9 (PHQ-9) and the Short Form-12 Health Survey (version 2) Mental Component Summary (SF-12 v2 MCS). The CES-D had a strong correlation with the PHQ-9 (coefficient: 0.78) and SF-12 v2 MCS (coefficient: -0.75). Internal consistency was assessed by McDonald's omega hierarchical (omegaH). The omegaH value for the general depression factor was 0.855. The omegaH values for "somatic", "depressed affect", "positive affect" and "interpersonal problems" were 0.434, 0.038, 0.738 and 0.730, respectively. For the two-week test-retest reliability, the intraclass correlation coefficient was 0.91. The CES-D was sensitive in detecting differences between known groups, with the AUC >0.7. Internal responsiveness of the CES-D to detect positive and negative changes was satisfactory (with p value <0.01 and all effect size statistics >0.2). The CES-D was externally responsive, with the AUC>0.7. CONCLUSIONS: The CES-D appears to be a valid, reliable, sensitive and responsive instrument for screening and monitoring depressive symptoms in adult Chinese primary care patients. In its original four-factor and bi-factor structure, the CES-D is supported for cross-cultural comparisons of depression in multi-center studies. PMID- 26252741 TI - Femtosecond Intrastromal Lenticular Implantation Combined With Accelerated Collagen Cross-Linking for the Treatment of Keratoconus--Initial Clinical Result in 6 Eyes. AB - PURPOSE: To evaluate the initial outcomes of femtosecond intrastromal lenticular implantation (FILI) combined with accelerated collagen cross-linking in patients with progressive keratoconus. METHODS: In this interventional, prospective, exploratory case series, patients with progressive keratoconus and contact lens intolerance were included. All eyes underwent femtosecond laser-enabled placement of stromal donor tissue and simultaneous accelerated collagen cross-linking. Follow-up of patients was conducted for a mean period of 190 +/- 13 days (range, 177-193 days). RESULTS: Six eyes from 6 patients were included in the study. Based on values before and 6 months after the procedure, clinical improvement was noted in uncorrected distance visual acuity (1.06 +/- 0.48 logMAR vs. 0.38 +/- 0.27 logMAR), corrected distance visual acuity (0.51 +/- 0.20 logMAR vs. 0.20 +/- 0.24 logMAR), and manifest spherical equivalent (-3.47 +/- 1.15 D vs. -1.77 +/- 1.7 D). There was flattening of mean keratometry in 3-mm and 5-mm zones by 3.42 +/- 2.09 D and 1.70 +/- 1.31 D, respectively. Mean pachymetry in the central and midperipheral zones increased by 18.3 +/- 7.3 MUm and 33.0 +/- 8.8 MUm, respectively. All eyes had reduction in higher-order aberrations, specifically coma. No eye lost lines of corrected distance visual acuity. No adverse events such as haze, infection, or allogeneic graft rejection were observed. CONCLUSIONS: Initial experience with this small number of eyes suggests that the combination of tissue addition and accelerated collagen cross-linking may be a feasible option for low to moderate keratoconus. A larger cohort and longer follow-up are required to validate our results and establish long-term safety and efficacy of the procedure. PMID- 26252742 TI - Efficacy of Primary Collagen Cross-Linking with Photoactivated Chromophore (PACK CXL) for the Treatment of Staphylococcus aureus-Induced Corneal Ulcers. AB - PURPOSE: To evaluate the efficacy of corneal collagen cross-linking (CXL) with photoactivated riboflavin (PACK-CXL) as primary therapy for Staphylococcus aureus induced corneal ulcers in a rabbit model. METHODS: The right eye of 40 rabbits was inoculated with S. aureus to induce formation of central corneal ulcers (day 1). The ulcer was examined on day 5, and rabbits were randomly assigned to 4 groups-group A: no treatment (control); group B: topical antibiotic treatment (cefazolin 50 mg/mL, garamycin 14 mg/mL drops, chloramphenicol 5% ointment every 2 hours); group C: PACK-CXL; group D: PACK-CXL + topical antibiotics. Follow-up by biomicroscopy was performed on day 5 and then every week for 1 month. The main outcome measures included infiltrates or the scar diameter, time to healing, time to full epithelialization, and a change in corneal thickness. RESULTS: After 1 month of treatment, group C ulcers had the smallest mean scar diameter (8.8 mm), followed by groups D (11.2 mm), B (13.0 mm), and A (24.5 mm) (P = 0.011). Group C had the shortest mean healing time (15.5 days), followed by groups D (17.2 days), B (19.7 days), and A (21.8 days). Analysis of relative reduction in the infiltrate size from day 5 yielded better results for groups C (P = 0.039) and D (P = 0.034) than those of group B. CONCLUSIONS: We demonstrate a beneficial effect of PACK-CXL as primary treatment, either as stand-alone or as an adjuvant to antimicrobial therapy. PMID- 26252743 TI - Predicting Corneal Graft Rejection by Confocal Microscopy. AB - PURPOSE: This study aims at estimating corneal healing by activated keratocyte (AK) counting with in vivo confocal microscopy after perforating keratoplasty (PK). It assesses the value of AK counting in predicting corneal graft rejection. METHODS: This prospective single-center observational study included 45 patients who benefited from PK in 2013 and were followed up over 2 years. All were monitored by confocal microscopy at day 1, day 7, and monthly thereafter. The AKs were counted in 5 optical sections in each of the anterior, middle, and posterior stroma. The ability of AKs in predicting the occurrence of corneal rejection was assessed by comparison of AK counts between patients with and without clinical signs of rejection. RESULTS: In patients with graft rejection, the AK counts increased significantly 2 months before the clinical diagnosis of rejection, whereas it remained stable after 4 months in patients without rejection. In patient with graft rejection, the AK count reached a maximum at the rejection diagnosis and antirejection treatment initiation but decreased significantly 1 month after treatment initiation. CONCLUSIONS: This study confirmed the predictive value of AK counting in corneal graft rejection. The increase in the AK count allowed predicting graft rejection 2 months before the clinical diagnosis of rejection; it may then be the first sign of subclinical rejection. PMID- 26252745 TI - Nanoscale Mapping of the Magnetic Properties of (111)-Oriented La(0.67)Sr(0.33)MnO3. AB - Spatially resolved analysis of magnetic properties on the nanoscale remains challenging, yet strain and defects on this length-scale can profoundly affect a material's bulk performance. We present a detailed investigation of the magnetic properties of La0.67Sr0.33MnO3 thin films in both free-standing and nanowire form and assess the role of strain and local defects in modifying the films' magnetic properties. Lorentz transmission electron microscopy is used to measure the magnetocrystalline anisotropy and to map the Curie temperature and saturation magnetization with nanometric spatial resolution. Atomic-scale defects are identified as pinning sites for magnetic domain wall propagation. Measurement of domain wall widths and crystalline strain are used to identify a strong magnetoelastic contribution to the magnetic anisotropy. Together, these results provide unique insight into the relationship between the nanostructure and magnetic functionality of a ferromagnetic complex oxide film. PMID- 26252744 TI - The mysterious multi-modal repellency of DEET. AB - DEET is the most effective insect repellent available and has been widely used for more than half a century. Here, I review what is known about the olfactory and contact mechanisms of DEET repellency. For mosquitoes, DEET has at least two molecular targets: Odorant Receptors (ORs) mediate the effect of DEET at a distance, while unknown chemoreceptors mediate repellency upon contact. Additionally, the ionotropic receptor Ir40a has recently been identified as a putative DEET chemosensor in Drosophila. The mechanism of how DEET manipulates these molecular targets to induce insect avoidance in the vapor phase is also contested. Two hypotheses are the most likely: DEET activates an innate olfactory neural circuit leading to avoidance of hosts (smell and avoid hypothesis) or DEET has no behavioral effect on its own, but instead acts cooperatively with host odors to drive repellency (confusant hypothesis). Resolving this mystery will inform the search for a new generation of insect repellents. PMID- 26252746 TI - Conserving Biogeography: Habitat Loss and Vicariant Patterns in Endemic Squamates of the Cerrado Hotspot. AB - Little is known about the threat levels and impacts of habitat loss over the Cerrado Squamate fauna. The region is under severe habitat loss due to mechanized agriculture, accelerated by changes in the Brazilian National Forest Code. The Squamate fauna of the Cerrado is rich in endemics and is intrinsically associated with its surrounding microhabitats, which make up a mosaic of phitophysiognomies throughout the region. Herein we evaluate current conservation status of Squamate biogeographic patterns in the Brazilian Cerrado, the single savanna among global biodiversity hotspots. To do so, we first updated point locality data on 49 endemic Squamates pertaining to seven non-random clusters of species ranges in the Cerrado. Each cluster was assumed to be representative of different biogeographic regions, holding its own set of species, herein mapped according to their extent of occurrence (EOO). We then contrasted these data in four different scenarios, according to the presence or absence of habitat loss and the presence or absence of the current protected area (PA) cover. We searched for non-random patterns of habitat loss and PA coverage among these biogeographic regions throughout the Cerrado. Finally, with the species EOO as biodiversity layers, we used Zonation to discuss contemporary PA distribution, as well as to highlight current priority areas for conservation within the Cerrado. We ran Zonation under all four conservation scenarios mentioned above. We observed that habitat loss and PA coverage significantly differed between biogeographic regions. The southernmost biogeographic region is the least protected and the most impacted, with priority areas highly scattered in small, disjunct fragments. The northernmost biogeographic region (Tocantins-Serra Geral) is the most protected and least impacted, showing extensive priority areas in all Zonation scenarios. Therefore, current and past deforestation trends are severely threatening biogeographic patterns in the Cerrado. Moreover, PA distribution is spatially biased, and does not represent biogeographic divisions of the Cerrado. Consequently, we show that biogeographic patterns and processes are being erased at an accelerated pace, reinforcing the urgent need to create new reserves and to avoid the loss of the last remaining fragments of once continuous biogeographic regions. These actions are fundamental and urgent for conserving biogeographic and evolutionary information in this highly imperiled savanna hotspot. PMID- 26252747 TI - Wound Area Measurement with Digital Planimetry: Improved Accuracy and Precision with Calibration Based on 2 Rulers. AB - INTRODUCTION: In the treatment of chronic wounds the wound surface area change over time is useful parameter in assessment of the applied therapy plan. The more precise the method of wound area measurement the earlier may be identified and changed inappropriate treatment plan. Digital planimetry may be used in wound area measurement and therapy assessment when it is properly used, but the common problem is the camera lens orientation during the taking of a picture. The camera lens axis should be perpendicular to the wound plane, and if it is not, the measured area differ from the true area. RESULTS: Current study shows that the use of 2 rulers placed in parallel below and above the wound for the calibration increases on average 3.8 times the precision of area measurement in comparison to the measurement with one ruler used for calibration. The proposed procedure of calibration increases also 4 times accuracy of area measurement. It was also showed that wound area range and camera type do not influence the precision of area measurement with digital planimetry based on two ruler calibration, however the measurements based on smartphone camera were significantly less accurate than these based on D-SLR or compact cameras. Area measurement on flat surface was more precise with the digital planimetry with 2 rulers than performed with the Visitrak device, the Silhouette Mobile device or the AreaMe software-based method. CONCLUSION: The calibration in digital planimetry with using 2 rulers remarkably increases precision and accuracy of measurement and therefore should be recommended instead of calibration based on single ruler. PMID- 26252748 TI - Proline-Rich Peptide Mimics Effects of Enamel Matrix Derivative on Rat Oral Mucosa Incisional Wound Healing. AB - BACKGROUND: Proline-rich peptides have been shown to promote periodontal regeneration. However, their effect on soft tissue wound healing has not yet been investigated. The aim of this study is to evaluate the effect of enamel matrix derivative (EMD), tyrosine-rich amelogenin peptide (TRAP), and a synthetic proline-rich peptide (P2) on acute wound healing after a full-thickness flap procedure in an incisional rat model. METHODS: This experimental study has a split-mouth, randomized, placebo-controlled design. Test and control wounds were created on the palatal mucosa of 54 Sprague-Dawley rats. Wounds were histologically processed, and reepithelialization, leukocyte infiltration, and angiogenesis were assessed at days 1, 3, and 7 post-surgery. RESULTS: EMD and P2 significantly promoted early wound closure at day 1 (P <0.001 and P = 0.004, respectively). EMD maintained a significant acceleration of reepithelialization at day 3 (P = 0.004). Wounds treated by EMD and P2 showed increased angiogenesis during the first 3 days of healing (P = 0.03 and 0.001, respectively). Leukocyte infiltration was decreased in EMD-treated wounds at day 1 (P = 0.03), and P2 and TRAP induced a similar effect at days 3 (P = 0.002 and P <0.0001, respectively) and 7 (P = 0.005 and P <0.001). CONCLUSION: EMD and P2 promoted reepithelialization and neovascularization in full-thickness surgical wounds on rat oral mucosa. PMID- 26252750 TI - The Influence of Glycated Hemoglobin on the Cross Susceptibility Between Type 1 Diabetes Mellitus and Periodontal Disease. AB - BACKGROUND: Periodontal disease is a major complication of type 1 diabetes mellitus (T1DM). The aim of the present study is to investigate the relationship between glycated hemoglobin and circulating levels of interleukin (IL)-6, IL-8, and C-X-C motif chemokine ligand 5 (CXCL5) in non-smoking patients suffering from T1DM, with and without periodontitis. In addition, to determine the effect of advanced glycation end products (AGE) in the presence and absence of Porphyromonas gingivalis lipopolysaccharide (LPS) on IL-6, IL-8, and CXCL5 expression by THP-1 monocytes and OKF6/TERT-2 cells. METHODS: There were 104 participants in the study: 19 healthy volunteers, 23 patients with periodontitis, 28 patients with T1DM, and 34 patients with T1DM and periodontitis. Levels of blood glucose/glycated hemoglobin (International Federation of Clinical Chemistry [IFCC]) were determined by high-performance liquid chromatography. Levels of IL 6, IL-8, and CXCL5 in plasma were determined by enzyme-linked immunosorbent assay (ELISA). In vitro stimulation of OKF6/TERT-2 cells and THP-1 monocytes was performed with combinations of AGE and P. gingivalis LPS. Changes in expression of IL-6, IL-8, and CXCL5 were monitored by ELISA and real-time polymerase chain reaction. RESULTS: Patients with diabetes and periodontitis had higher plasma levels of IL-8 than patients with periodontitis alone. Plasma levels of IL-8 correlated significantly with IFCC units, clinical probing depth, and attachment loss. AGE and LPS, alone or in combination, stimulated IL-6, IL-8, and CXCL5 expression in both OKF6/TERT-2 cells and THP-1 monocytes. CONCLUSIONS: Elevated plasma levels of IL-8 potentially contribute to the cross-susceptibility between periodontitis and T1DM. P. gingivalis LPS and AGE in combination caused significantly greater expression of IL-6, IL-8, and CXCL5 from THP-1 monocytes and OKF6/TERT-2 cells than LPS alone. PMID- 26252751 TI - Clinical and Microbiologic Evaluation of Scaling and Root Planing per Quadrant and One-Stage Full-Mouth Disinfection Associated With Azithromycin or Chlorhexidine: A Clinical Randomized Controlled Trial. AB - BACKGROUND: Conflicting data about the protocol of choice for non-surgical periodontal therapy with adjuvant use are still reported. This study aims to evaluate, through clinical and microbiologic parameters, the systemic use of azithromycin (AZ) and chlorhexidine (CHX) as adjuvants to non-surgical periodontal treatment performed by one-stage full-mouth disinfection (FMD) within 24 hours or conventional quadrant scaling (QS) in four weekly sections. METHODS: In this randomized controlled trial, 85 patients diagnosed with chronic periodontitis underwent different treatment protocols, in six groups: three FMD groups and three QS groups, each with no adjuvants, with CHX, and with AZ. Clinical periodontal parameters were recorded, and total and quantitative bacterial counts of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, and Streptococcus oralis were measured with real-time polymerase chain reaction at baseline and 90 and 180 days after treatment. RESULTS: In all groups, a significant reduction was observed in the percentage of periodontal diseased sites, gingival index, plaque index, and clinical attachment level gain at 90 days, demonstrating effectiveness of the treatment, independently of the adjuvant. The FMD with CHX group showed higher reduction in probing depth and percentage of periodontal diseases sites, as well as lower total bacterial count, than all the other groups at 180 days. CONCLUSIONS: The adjuvant use of AZ did not provide any significant benefit, independently of the treatment protocol. The adjuvant use of CHX showed a more expressive and significant improvement in clinical and microbiologic parameters, especially in the FMD protocol, followed by QS. PMID- 26252749 TI - Comparison of Azithromycin and Amoxicillin Before Dental Implant Placement: An Exploratory Study of Bioavailability and Resolution of Postoperative Inflammation. AB - BACKGROUND: Studies suggest that a single prophylactic dose of amoxicillin reduces early implant complications, but it is unclear whether other antibiotics are also effective. This study compared the local antimicrobial and anti inflammatory effects resulting from a single dose of azithromycin or amoxicillin before surgical placement of one-stage dental implants. METHODS: Healthy adult patients requiring one-stage dental implant placement were allocated randomly to receive either 2 g amoxicillin (n = 7) or 500 mg azithromycin (n = 6) before surgery. Peri-implant crevicular fluid (PICF) samples from the new implant and gingival crevicular fluid (GCF) from adjacent teeth were sampled on postoperative days 6, 13, and 20. Inflammatory mediators in the samples were analyzed by immunoassay, and antibiotic levels were measured by bioassay. RESULTS: On day 6, azithromycin concentrations in GCF and PICF were 3.39 +/- 0.73 and 2.77 +/- 0.90 MUg/mL, respectively, whereas amoxicillin was below the limit of detection. During early healing, patents in the azithromycin group exhibited a significantly greater decrease in GCF volume (P = 0.03, analysis of variance). At specific times during healing, the azithromycin group exhibited significantly lower levels of interleukin (IL)-6 and IL-8 in GCF than the amoxicillin group and exhibited significantly lower levels of granulocyte colony stimulating factor, IL-8, macrophage inflammatory protein-1beta, and interferon-gamma-inducible protein-10 in PICF. CONCLUSIONS: Azithromycin was available at the surgical site for a longer period of time than amoxicillin, and patients taking azithromycin exhibited lower levels of specific proinflammatory cytokines and chemokines in GCF and PICF. Thus, preoperative azithromycin may enhance resolution of postoperative inflammation to a greater extent than amoxicillin. PMID- 26252752 TI - Noncompliance with Human Subjects' Protection Requirements as a Reason for Retracting Papers: Survey of Retraction Notices on Medical Papers Published from 1981 to 2011. AB - Though protection of human research subjects is universally recognized as a critical requirement for the ethical conduct of research, few studies have examined retractions of medical articles through apparent noncompliance with that requirement. From our survey of 99 retracted papers published from 1981 to 2011, we found that the basis for those decisions was poorly explained in retraction notices and that most of the articles continued to be cited. In retraction notices, the current manner of explaining failure to protect human subjects is misleading and confusing. PMID- 26252753 TI - Fatsioside A-induced apoptotic death of HepG2 cells requires activation of AMP activated protein kinase. AB - Hepatocellular carcinoma (HCC) is one of the most malignant types of human primary tumor and has a poor prognosis, therefore, the development of novel therapeutic modalities is necessary. Fatsioside A is a novel baccharane-type triterpenoid glycoside, which is extracted from the fruits of Fatsia japonica. Previous data has revealed that fatsioside A can exert growth inhibition, cell cycle arrest and induce apoptosis in human glioma cells. However, no detailed investigations have been performed to determine its action on human hepatocellular cells, and the exact mechanisms underlying the induction of apoptosis remain to be elucidated. The aim of the present study was to investigate the anticancer effect of fatsioside A in the HepG2 human HCC cell line, and to investigate the underlying mechanisms by focusing on the AMP activated protein kinase (AMPK) signaling cascade. The results of the present study demonstrated that fatsioside A induced apoptotic death of the human HepG2 HCC cells, which was associated with a marked activation of AMPK and increased expression of the downstream acetyl-CoA carboxylase carboxylase. Inhibition of AMPK by RNA interference or by its inhibitor, compound C, suppressed fatsioside A induced caspase-3 cleavage and apoptosis in the HepG2 cells, while AICAR, the AMPK activator, elicited marked cytotoxic effects. Together, these results suggested that fatsioside A-induced apoptotic death requires AMPK activation in HepG2 cells. PMID- 26252754 TI - Enzymatic Alterations and Genotoxic Effects Produced by Sublethal Concentrations of Organophosphorous Temephos in Poecilia reticulata. AB - The responses of biochemical and genetic parameters were evaluated in tissues of Poecilia reticulata exposed to sublethal and environmentally relevant concentrations of 0.005, 0.01, or 0.02 mg/L of the organophosphorous (OP) pesticide temephos (TE) for 168 h. Activities of enzymes brain acetylcholinesterase (AChE) and liver carboxylesterase (CbE) were determined. Nuclear abnormalities (NA) and micronucleus (MN) frequency in gill erythrocytes were also measured. No mortality was observed over the experimental period; however, brain AChE activities were decreased significantly in guppies in all TE treatment groups after 72 h of exposure. Hepatic CbE activities of fish were increased in all TE treatment groups at 96, 120, and 144 h of exposure. The frequencies of MN and NA in fish gill erythrocytes displayed a marked rise after 168 h of exposure to concentrations of 0.01 or 0.02 mg/L TE. Thus, determination of these parameters may be employed as potential indices of exposure to TE using this sentinel organism for monitorining. PMID- 26252756 TI - Development of a Plate-Based Screening Assay to Investigate the Substrate Specificity of the PRMT Family of Enzymes. AB - There are nine protein arginine methyltransferases (PRMTs 1-9) expressed in humans that vary in both subcellular localization and substrate specificity. The variation in substrate specificity between isozymes leads to competing effects that result in either activation or repression of tumor suppressor genes. Current methods used to study substrate specificity for these enzymes utilize radioisotopic labeling of substrates, mass spectrometry analysis of complex samples, or coupled assays that monitor cofactor degradation. Herein, we report the development of a rapid, nonradioactive, and sensitive method for screening multiple peptides in parallel to gain insight into the substrate specificity of PRMT enzymes. Our assay provides a major advantage over other high-throughput screening assays (e.g., ELISA, AlphaScreen chemiluminescence) by eliminating the need for purification of individual peptides and provides a timesaving, cost effective alternative to the traditional PRMT assays. A one-bead one-compound (OBOC) peptide library was synthesized and subsequently screened against PRMT1 in a 96-well plate. This screen resulted in identification of a novel PRMT1 substrate with kinetic parameters similar to histone H4-21 (e.g., the best-known PRMT1 peptide substrate). PMID- 26252755 TI - Evaluation of the Microcirculation in Chronic Thromboembolic Pulmonary Hypertension Patients: The Impact of Pulmonary Arterial Remodeling on Postoperative and Follow-Up Pulmonary Arterial Pressure and Vascular Resistance. AB - BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is generally recognized to be caused by persistent organized thrombi that occlude the pulmonary arteries. The aim of this study was to investigate the characteristics of small vessel remodeling and its impact on the hemodynamics in CTEPH patients. METHODS AND RESULTS: Hemodynamic data were obtained from right heart catheterization in 17 CTEPH patients before pulmonary endarterectomy (PEA). Lung tissue specimens were obtained at the time of PEA. Pathological observations and evaluation of quantitative changes in pulmonary muscular arteries and veins were performed using light microscopy on 423 slides in 17 patients. The relationship between the results and the hemodynamics of CTEPH was investigated. Pulmonary arteriopathy and venopathy were recognized in most cases, although no plexiform lesions and no capillary-hemangiomatosis-like lesions were detected in any of the specimens. The severity of pulmonary arteriopathy was correlated with pulmonary vascular resistance (PVR) in the postoperative and follow-up periods. The PVR and mean pulmonary arterial pressure were significantly higher in the high obstruction group than in the low-obstruction group. The findings in pulmonary venopathy were similar to the findings seen in pulmonary veno-occlusive disease in some cases, although severe venopathy was only observed in a portion of the pulmonary veins. There was a significant correlation between the extent of pulmonary arteriopathy and venopathy, although an effect of pulmonary venopathy to hemodynamics, including pulmonary arterial wedged pressure (PAWP), could not be identified. CONCLUSION: The vascular remodeling of the pulmonary muscular arteries was closely associated with the hemodynamics of CTEPH. Severe pulmonary arteriopathy might be related to residual pulmonary hypertension after PEA. Those altered pulmonary arteries might be a new target for the persistent PH after the operation. PMID- 26252757 TI - Symptoms of gonadal dysfunction are more predictive of hypopituitarism than nonspecific symptoms in screening for pituitary dysfunction following moderate or severe traumatic brain injury. AB - OBJECTIVE: The economic and logistic burden of screening for hypopituitarism following moderate/severe traumatic brain injury (TBI) is considerable. A key recommendation in published guidelines is to prioritize for screening those patients with symptoms suggestive of pituitary dysfunction. The purpose of this study was to evaluate the utility of targeted screening for hypopituitarism in long-term survivors after moderate/severe TBI using referrals on the basis of symptoms. DESIGN: In group 1 (G1), consecutive, unselected patients were screened from the Irish National Neurosurgery Centre, whereas in group 2 (G2) patients were targeted based on the presence of symptoms suggestive of pituitary dysfunction. PATIENTS: A total of 137 patients (113 male) were systematically screened (G1) and compared to 112 patients (77 male) referred for pituitary evaluation on the basis of suggestive symptoms (G2). MAIN OUTCOME MEASURES: The rate of GH, ACTH, gonadotrophin (GT), TSH and ADH deficiency was compared among groups. RESULTS: Patients referred with menstrual dysfunction had more GH (50% vs 11%, P = 0.001), ACTH (60% vs 14%, P < 0.0001), GT (90% vs 16%, P < 0.0001) deficiency and any pituitary hormone deficit (80% vs 33%, P = 0.003) than G1. Men with symptoms of hypogonadism had more GH (33% vs 11%, P = 0.003), GT (58% vs 16%, P < 0.0001) and TSH (16% vs 1%, P = 0.03) deficiency than G1. Patients with nonspecific symptoms were no more likely to have hypopituitarism than those consecutively screened. CONCLUSIONS: Symptoms of hypogonadism are sufficiently predictive of hypopituitarism to justify screening for hypopituitarism after moderate/severe TBI. Nonspecific symptoms of hypopituitarism are no more predictive than unselected screening. PMID- 26252758 TI - Impacts of a Large Decentralized Telepathology Network in Canada. AB - BACKGROUND: Telepathology is a fast growing segment of the telemedicine field. As of yet, no prior research has investigated the impacts of large decentralized telepathology projects on patients, clinicians, and healthcare systems. This study aims to fill this gap. We report a benefits evaluation study of a large decentralized telepathology project deployed in Eastern Quebec, Canada whose main objective is to provide continuous coverage of intraoperative consultations in remote hospitals without pathologists on-site. The project involves 18 hospitals, making it one of the largest telepathology networks in the world. MATERIALS AND METHODS: We conducted 43 semistructured interviews with several telepathology users and hospital managers. Archival data on the impacts of the telepathology project (e.g., number of service disruptions, average time between initial diagnosis and surgery) were also extracted and analyzed. RESULTS: Our findings show that no service disruptions were recorded in hospitals without pathologists following the deployment of telepathology. Surgeons noted that the use of intraoperative consultations enabled by telepathology helped avoid second surgeries and improved accessibility to care services. Telepathology was also perceived by our respondents as having positive impacts on the remote hospitals' ability to retain and recruit surgeons. CONCLUSIONS: The observed benefits should not leave the impression that implementing telepathology is a trivial matter. Indeed, many technical, human, and organizational challenges may be encountered. Telepathology can be highly useful in regional hospitals that do not have a pathologist on-site. More research is needed to investigate the challenges and benefits associated with large decentralized telepathology networks. PMID- 26252759 TI - Comparison of CH...O, SH...O, Chalcogen, and Tetrel Bonds Formed by Neutral and Cationic Sulfur-Containing Compounds. AB - The ability of neutral and charged S-compounds to form different sorts of noncovalent bonds is examined by ab initio calculations. Neutrals are represented by CH3SH and fluoro-substituted FSCH3; cations are (CH3)3S(+), CH3SH2(+), and FHSCH3(+). Each is paired with N-methylacetamide (NMA) whose O atom serves as a common electron donor. Charged species engage in much stronger noncovalent bonds than do the neutral molecules, by as much as an order of magnitude. The strongest noncovalent bond for any system is a O...SF chalcogen bond wherein the O lies directly opposite a S-F covalent bond, amounting to as much as 39 kcal/mol. Second in binding energy is the SH...O H-bond, which can be as large as 34 kcal/mol. Somewhat weaker is the O...SC chalcogen bond, followed by the CH...O H bond and finally the O...C tetrel bond, which has the appearance of a trifurcated H-bond. Any CH group that participates in a CH...O H-bond shifts its NMR signal downfield by an amount roughly proportional to the strength of the H-bond. This situation is clearly distinguishable from that in a O...S chalcogen or SH...O H bond wherein the methyl protons are shifted upfield. PMID- 26252760 TI - Spatial part-set cuing facilitation. AB - Cole, Reysen, and Kelley [2013. Part-set cuing facilitation for spatial information. Journal of Experimental Psychology: Learning, Memory, & Cognition, 39, 1615-1620] reported robust part-set cuing facilitation for spatial information using snap circuits (a colour-coded electronics kit designed for children to create rudimentary circuit boards). In contrast, Drinkwater, Dagnall, and Parker [2006. Effects of part-set cuing on experienced and novice chess players' reconstruction of a typical chess midgame position. Perceptual and Motor Skills, 102(3), 645-653] and Watkins, Schwartz, and Lane [1984. Does part-set cuing test for memory organization? Evidence from reconstructions of chess positions. Canadian Journal of Psychology/Revue Canadienne de Psychologie, 38(3), 498-503] showed no influence of part-set cuing for spatial information when using chess boards. One key difference between the two procedures was that the snap circuit stimuli were explicitly connected to one another, whereas chess pieces were not. Two experiments examined the effects of connection type (connected vs. unconnected) and cue type (cued vs. uncued) on memory for spatial information. Using chess boards (Experiment 1) and snap circuits (Experiment 2), part-set cuing facilitation only occurred when the stimuli were explicitly connected; there was no influence of cuing with unconnected stimuli. These results are potentially consistent with the retrieval strategy disruption hypothesis, as well as the two- and three-mechanism accounts of part-set cuing. PMID- 26252761 TI - Engineered Coalescence by Annealing 3D Ge Microstructures into High-Quality Suspended Layers on Si. AB - The move from dimensional to functional scaling in microelectronics has led to renewed interest toward integration of Ge on Si. In this work, simulation-driven experiments leading to high-quality suspended Ge films on Si pillars are reported. Starting from an array of micrometric Ge crystals, the film is obtained by exploiting their temperature-driven coalescence across nanometric gaps. The merging process is simulated by means of a suitable surface-diffusion model within a phase-field approach. The successful comparison between experimental and simulated data demonstrates that the morphological evolution is driven purely by the lowering of surface-curvature gradients. This allows for fine control over the final morphology to be attained. At fixed annealing time and temperature, perfectly merged films are obtained from Ge crystals grown at low temperature (450 degrees C), whereas some void regions still persist for crystals grown at higher temperature (500 degrees C) due to their different initial morphology. The latter condition, however, looks very promising for possible applications. Indeed, scanning tunneling electron microscopy and high-resolution transmission electron microscopy analyses show that, at least during the first stages of merging, the developing film is free from threading dislocations. The present findings, thus, introduce a promising path to integrate Ge layers on Si with a low dislocation density. PMID- 26252762 TI - Kappa Delta Awards. PMID- 26252764 TI - Effect of variations in the nitrogen loading rate and seasonality on the operation of a free water surface constructed wetland for treatment of swine wastewater. AB - The aim of this study was to evaluate the effects of variations in the nitrogen loading rate (NLR) and seasonality on the operational efficiency of a free-water surface constructed wetland (FWS) and on the processes involved in total nitrogen (TN) removal in treating swine wastewater. The system, which operated for 550 days, consisted of a FWS mesocosm inoculated with Typha angustifolia L., using swine wastewater from a storage lagoon as an influent. After operating with nitrogen loading rates (NLRs) of 2.0 to 30.2 kg TN ha(-1).d(-1), the FWS reduced total nitrogen (TN) concentration by between 21.6 and 51.0%, achieving maximum removal (48.2 +/- 3.0%) when the system operated at a NLR below 15.0 kg TN ha( 1).d(-1). Moreover, operations over 25.0 kg TN ha(-1).d(-1) resulted in a 50.6% decrease in the maximum FWS efficiency, which may have been related to increased anoxic conditions (< 0.5 mg O2 L(-1); -169.8 +/- 70.3 mV) resulting from the high concentration of organic matter in the system (12.3 +/- 10.5 g TCOD L(-1)), which hindered nitrification. Ammonia volatilization is considered the main method to remove TN, with an average value of 14.4 +/- 6.5% (3.1-26.2%). Maximum volatilization occurred during the summer (21.5 +/- 2.4 degrees C) at an NLR higher than 25 kg TN ha(-1).d(-1) (26.6%), favored by higher temperatures (17.3 19.7 degrees C), and high NH4(+)-N (>600.0 9 mg NH4(+)-N L(-1)) and pH levels (7.1-7.9). Uptake by plants accounted for 14.9% of the TN removed, with the vegetative peak in summer (height: 105.3 cm; diameter: 2.1 cm) at an NLR of 25.3 +/- 0.3 kg TN ha(-1).d(-1). However, growth decreased to 94.4% at an NLR of over 25.3 +/- 0.3 kg TN ha(-1).d(-1) (>379.9 mg NH4(+)-N L(-1)) in autumn (17.4 +/- 2.4 degrees C). This was associated with the period of plant senescence and the effects of ammonium phytotoxicity (379.9-624.2 mg NH4(+)-N L(-1)) and continued to the end of the study with the complete loss of macrophyte species. Finally, 1.5% of the TN removed was incorporated into the sediments where NH4(+)-N is the main form of nitrogen, with an accumulative value of 2.6 g m(-2). PMID- 26252765 TI - Sub-Nanogram Detection of RDX Explosive by Monoclonal Antibodies. AB - Polyclonal and monoclonal antibodies were raised to protein carrier molecules haptenized with RDX, a major component of many plastic explosives including Semtex. Sera from immunized mice detected RDX protein conjugates in standard ELISA. Clonally purified monoclonal antibodies had detection limits in the sub ng/mL range for underivatized RDX in competition ELISA. The monoclonal antibodies are not dependent on the presence of taggants added during the manufacturing process, and are likely to have utility in the detection of any explosive containing RDX, or RDX contamination of environmental sites. PMID- 26252766 TI - Drosophila Longevity Assurance Conferred by Reduced Insulin Receptor Substrate Chico Partially Requires d4eBP. AB - Mutations of the insulin/IGF signaling (IIS) pathway extend Drosophila lifespan. Based on genetic epistasis analyses, this longevity assurance is attributed to downstream effects of the FOXO transcription factor. However, as reported FOXO accounts for only a portion of the observed longevity benefit, suggesting there are additional outputs of IIS to mediate aging. One candidate is target of rapamycin complex 1 (TORC1). Reduced TORC1 activity is reported to slow aging, whereas reduced IIS is reported to repress TORC1 activity. The eukaryotic translation initiation factor 4E binding protein (4E-BP) is repressed by TORC1, and activated 4E-BP is reported to increase Drosophila lifespan. Here we use genetic epistasis analyses to test whether longevity assurance mutants of chico, the Drosophila insulin receptor substrate homolog, require Drosophila d4eBP to slow aging. In chico heterozygotes, which are robustly long-lived, d4eBP is required but not sufficient to slow aging. Remarkably, d4eBP is not required or sufficient for chico homozygotes to extend longevity. Likewise, chico heterozygote females partially require d4eBP to preserve age-dependent locomotion, and both chico genotypes require d4eBP to improve stress-resistance. Reproduction and most measures of growth affected by either chico genotype are always independent of d4eBP. In females, chico heterozygotes paradoxically produce more rather than less phosphorylated 4E-BP (p4E-BP). Altered IRS function within the IIS pathway of Drosophila appears to have partial, conditional capacity to regulate aging through an unconventional interaction with 4E-BP. PMID- 26252767 TI - Determinants of Health Service Responsiveness in Community-Based Vector Surveillance for Chagas Disease in Guatemala, El Salvador, and Honduras. AB - BACKGROUND: Central American countries face a major challenge in the control of Triatoma dimidiata, a widespread vector of Chagas disease that cannot be eliminated. The key to maintaining the risk of transmission of Trypanosoma cruzi at lowest levels is to sustain surveillance throughout endemic areas. Guatemala, El Salvador, and Honduras integrated community-based vector surveillance into local health systems. Community participation was effective in detection of the vector, but some health services had difficulty sustaining their response to reports of vectors from the population. To date, no research has investigated how best to maintain and reinforce health service responsiveness, especially in resource-limited settings. METHODOLOGY/PRINCIPAL FINDINGS: We reviewed surveillance and response records of 12 health centers in Guatemala, El Salvador, and Honduras from 2008 to 2012 and analyzed the data in relation to the volume of reports of vector infestation, local geography, demography, human resources, managerial approach, and results of interviews with health workers. Health service responsiveness was defined as the percentage of households that reported vector infestation for which the local health service provided indoor residual spraying of insecticide or educational advice. Eight potential determinants of responsiveness were evaluated by linear and mixed-effects multi-linear regression. Health service responsiveness (overall 77.4%) was significantly associated with quarterly monitoring by departmental health offices. Other potential determinants of responsiveness were not found to be significant, partly because of short- and long-term strategies, such as temporary adjustments in manpower and redistribution of tasks among local participants in the effort. CONCLUSIONS/SIGNIFICANCE: Consistent monitoring within the local health system contributes to sustainability of health service responsiveness in community-based vector surveillance of Chagas disease. Even with limited resources, countries can improve health service responsiveness with thoughtful strategies and management practices in the local health systems. PMID- 26252768 TI - "Direct DICOM Slice Landmarking" A Novel Research Technique to Quantify Skeletal Changes in Orthognathic Surgery. AB - The limitations of the current methods of quantifying the surgical movements of facial bones inspired this study. The aim of this study was the assessment of the accuracy and reproducibility of directly landmarking of 3D DICOM images (Digital Imaging and Communications in Medicine) to quantify the changes in the jaw bones following surgery. The study was carried out on plastic skull to simulate the surgical movements of the jaw bones. Cone beam CT scans were taken at 3mm, 6mm, and 9mm maxillary advancement; together with a 2mm, 4mm, 6mm and 8mm "down graft" which in total generated 12 different positions of the maxilla for the analysis. The movements of the maxilla were calculated using two methods, the standard approach where distances between surface landmarks on the jaw bones were measured and the novel approach where measurements were taken directly from the internal structures of the corresponding 3D DICOME slices. A one sample t-test showed that there was no statistically significant difference between the two methods of measurements for the y and z directions, however, the x direction showed a significant difference. The mean difference between the two absolute measurements were 0.34+/-0.20mm, 0.22+/-0.16mm, 0.18+/-0.13mm in the y, z and x directions respectively. In conclusion, the direct landmarking of 3D DICOM image slices is a reliable, reproducible and informative method for assessment of the 3D skeletal changes. The method has a clear clinical application which includes the analysis of the jaw movements "orthognathic surgery" for the correction of facial deformities. PMID- 26252769 TI - Kinetics of Local and Systemic Leucocyte and Cytokine Reaction of Calves to Intrabronchial Infection with Chlamydia psittaci. AB - Infection of cattle with chlamydiae is ubiquitous and, even in the absence of clinical sequeleae, has a quantifiable negative impact on livestock productivity. Despite recent progress, our knowledge about immune response mechanisms capable of counteracting the infection and preventing its detrimental effects is still limited. A well-established model of bovine acute respiratory Chlamydia (C.) psittaci infection was used here to characterize the kinetics of the local and systemic immune reactions in calves. In the course of two weeks following inoculation, leukocyte surface marker expression was monitored by flow cytometry in blood and bronchoalveolar lavage fluid (BALF). Immune-related protein and receptor transcription were determined by quantitative real-time reverse transcription PCR in blood, BALF and lung tissue. An early increase of IL2RA, IL10 and HSPA1A mRNA expressions was followed by a rise of lymphocytes, monocytes, and granulocytes exhibiting activated phenotypes in blood. Monocytes showed elevated expression rates of CD11b, CD14 and MHC class II. The rates of CD62L expression on CD8hi T cells in blood and on CD4+ T cells in BALF were also augmented and peaked between 2 and 4 dpi. Notably, CD25 antigen expression was significantly elevated, not only on CD8dim/CD62L+ and CD8-/CD62L+ cells in blood, but also on granulocytes in blood and BALF between 2-3 dpi. From 4 dpi onwards, changes declined and the calves recovered from the infection until 10 dpi. The findings highlight the effectiveness of rapid local and systemic immune reaction and indicate activated T cells, monocytes and granulocytes being essential for rapid eradication of the C. psittaci infection. PMID- 26252770 TI - Addressing Parental Vaccine Concerns: Engagement, Balance, and Timing. AB - The recent United States measles epidemic has sparked another contentious national discussion about childhood vaccination. A growing number of parents are expressing concerns about the safety of vaccines, often fueled by misinformation from the internet, books, and other nonmedical sources. Many of these concerned parents are choosing to refuse or delay childhood vaccines, placing their children and surrounding communities at risk for serious diseases that are nearly 100% preventable with vaccination. Between 10% and 15% of parents are asking physicians to space out the timing of vaccines, which often poses an ethical dilemma for physicians. This trend reflects a tension between personal liberty and public health, as parents fight to control the decisions that affect the health of their children and public health officials strive to maintain high immunization rates to prevent outbreaks of vaccine-preventable diseases. Interventions to address this emerging public health issue are needed. We describe a framework by which web-based interventions can be used to help parents make evidence-based decisions about childhood vaccinations. PMID- 26252771 TI - Melatonin Cytotoxicity Is Associated to Warburg Effect Inhibition in Ewing Sarcoma Cells. AB - Melatonin kills or inhibits the proliferation of different cancer cell types, and this is associated with an increase or a decrease in reactive oxygen species, respectively. Intracellular oxidants originate mainly from oxidative metabolism, and cancer cells frequently show alterations in this metabolic pathway, such as the Warburg effect (aerobic glycolysis). Thus, we hypothesized that melatonin could also regulate differentially oxidative metabolism in cells where it is cytotoxic (Ewing sarcoma cells) and in cells where it inhibits proliferation (chondrosarcoma cells). Ewing sarcoma cells but not chondrosarcoma cells showed a metabolic profile consistent with aerobic glycolysis, i.e. increased glucose uptake, LDH activity, lactate production and HIF-1alpha activation. Melatonin reversed Ewing sarcoma metabolic profile and this effect was associated with its cytotoxicity. The differential regulation of metabolism by melatonin could explain why the hormone is harmless for a wide spectrum of normal and only a few tumoral cells, while it kills specific tumor cell types. PMID- 26252772 TI - Promotion of Erythropoietic Differentiation in Hematopoietic Stem Cells by SOCS3 Knock-Down. AB - Suppressor of cytokine signaling 3 (SOCS3) plays an important role in mice fetal liver erythropoiesis, but the roles of SOCS3 in human hematopoietic stem cells (HSCs) have not been well investigated. In the present study, lentiviral small interference RNA expression vectors (shRNA) of SOCS3 were constructed and stably transferred into HSCs. We found that SOCS3 knockdown induced erythroid expansion in HSCs. Conversely, Ectopic expression of SOCS3 in progenitor cells blocked erythroid expansion and erythroid colony formation of HSCs. To further explore the involved mechanism, we compared gene expression profiles of SOCS3-shRNA tranduced HSCs with that of control HSCs by whole genome microarrays. The results indicated that cell developmental process related genes, especially hematopoietic lineage-specific genes, associated with the responses to SOCS3 in HSCs.Downexpression of SOCS3 in HSCs or differentiated erythroid progenitor cells induced a transcriptional program enriched for erythroid development relative genes. Our results proved that SOCS3 down-expression induced lineage commitment towards erythroid progenitor cell fate by activation of erythroid-specific gene in HSCs and provided new insight into the mechanism of erythropoietic development. PMID- 26252773 TI - The Overexpression of IQGAP1 and beta-Catenin Is Associated with Tumor Progression in Hepatocellular Carcinoma In Vitro and In Vivo. AB - The IQ-domain GTPase-activating protein 1 (IQGAP1) is a multifunctional scaffold protein, which interacts with diverse proteins to regulate cell adhesion and cell migration. The abnormal expression of IQGAP1 widely exists in many cancers, but biological roles of IQGAP1 cooperation with its interacting proteins to involve in tumorigenesis remain to clarify. In this study, we have found that IQGAP1 interacts with beta-catenin and regulates beta-catenin expression in hepatocellular carcinoma (HCC) cells. The expression levels of IQGAP1 and beta catenin and their associations have a positive correlation with cell metastasis ability in several HCC cell lines. The up-regulation of IQGAP1 and beta-catenin improves cell proliferation and migration ability of HCC cells, whereas the knockdown of IQGAP1 by small interfering RNA can decrease beta-catenin expression, which results in the reduction of cell proliferation and migration ability in vitro. In addition, a significantly higher expression of IQGAP1 and beta-catenin also usually exists in human HCC tissues, especially their overexpression is clinicopathologically associated with tumor malignancy. Generally the overexpression and interactions of IQGAP1 and beta-catenin contribute to HCC progression by promoting cell proliferation and migration. PMID- 26252774 TI - The Canary in the Coal Mine Tweets: Social Media Reveals Public Perceptions of Non-Medical Use of Opioids. AB - OBJECTIVE: Non-medical prescription opioid use is a growing public health concern. Social media is an emerging tool to understand health attitudes, beliefs, and behaviors. METHODS: We retrieved a sample of publicly available Twitter messages in early 2014, using common opioid medication names and slang search terms. We used content analysis to code messages by user, context of message (personal vs general experiences), and key content themes. RESULTS: We reviewed 540 messages, of which 375 (69%) messages were related to opioid behaviors. Of these, 316 (84%) originated from individual user accounts; 125 messages expressed personal experience with opioids. The majority of personal messages referenced using opioids to obtain a "high", use for sleep, or other non intended use (87,70%). General attitudes regarding opioid use included positive sentiment (52, 27%), comments on others peoples opioid use (57, 30%), and messages containing public health information or links (48, 25%). CONCLUSIONS: In a sample of social media messages mentioning opioid medications, the most common theme amongst English users related to various forms of opioid misuse. Social media can provide insights into the types of misuse of opioids that might aid public health efforts to reduce non-medical opioid use. PMID- 26252775 TI - A Human Cell Line Model for Interferon-alpha Driven Dendritic Cell Differentiation. AB - The CD34+ MUTZ-3 acute myeloid leukemia cell line has been used as a dendritic cell (DC) differentiation model. This cell line can be cultured into Langerhans cell (LC) or interstitial DC-like cells using the same cytokine cocktails used for the differentiation of their primary counterparts. Currently, there is an increasing interest in the study and clinical application of DC generated in the presence of IFNalpha, as these IFNalpha-DC produce high levels of inflammatory cytokines and have been suggested to be more potent in their ability to cross present protein antigens, as compared to the more commonly used IL-4-DC. Here, we report on the generation of IFNalpha-induced MUTZ-DC. We show that IFNalpha MUTZ DC morphologically and phenotypically display characteristic DC features and are functionally equivalent to "classic" IL-4 MUTZ-DC. IFNalpha MUTZ-DC ingest exogenous antigens and can subsequently cross-present HLA class-I restricted epitopes to specific CD8+ T cells. Importantly, mature IFNalpha MUTZ-DC express CCR7, migrate in response to CCL21, and are capable of priming naive antigen specific CD8+ T cells. In conclusion, we show that the MUTZ-3 cell line offers a viable and sustainable model system to study IFNalpha driven DC development and functionality. PMID- 26252776 TI - Wnt Signalling Promotes Actin Dynamics during Axon Remodelling through the Actin Binding Protein Eps8. AB - Upon arrival at their synaptic targets, axons slow down their growth and extensively remodel before the assembly of presynaptic boutons. Wnt proteins are target-derived secreted factors that promote axonal remodelling and synaptic assembly. In the developing spinal cord, Wnts secreted by motor neurons promote axonal remodelling of NT-3 responsive dorsal root ganglia neurons. Axon remodelling induced by Wnts is characterised by growth cone pausing and enlargement, processes that depend on the re-organisation of microtubules. However, the contribution of the actin cytoskeleton has remained unexplored. Here, we demonstrate that Wnt3a regulates the actin cytoskeleton by rapidly inducing F-actin accumulation in growth cones from rodent DRG neurons through the scaffold protein Dishevelled-1 (Dvl1) and the serine-threonine kinase Gsk3beta. Importantly, these changes in actin cytoskeleton occurs before enlargement of the growth cones is evident. Time-lapse imaging shows that Wnt3a increases lamellar protrusion and filopodia velocity. In addition, pharmacological inhibition of actin assembly demonstrates that Wnt3a increases actin dynamics. Through a yeast two hybrid screen, we identified the actin-binding protein Eps8 as a direct interactor of Dvl1, a scaffold protein crucial for the Wnt signalling pathway. Gain of function of Eps8 mimics Wnt-mediated axon remodelling, whereas Eps8 silencing blocks the axon remodelling activity of Wnt3a. Importantly, blockade of the Dvl1-Eps8 interaction completely abolishes Wnt3a-mediated axonal remodelling. These findings demonstrate a novel role for Wnt-Dvl1 signalling through Eps8 in the regulation of axonal remodeling. PMID- 26252777 TI - Efficacy of Berberine in Patients with Non-Alcoholic Fatty Liver Disease. AB - OBJECTIVES: A randomized, parallel controlled, open-label clinical trial was conducted to evaluate the effect of a botanic compound berberine (BBR) on NAFLD. METHODS: A randomized, parallel controlled, open-label clinical trial was conducted in three medical centers (NIH Registration number: NCT00633282). A total of 184 eligible patients with NAFLD were enrolled and randomly received (i) lifestyle intervention (LSI), (ii) LSI plus pioglitazone (PGZ) 15mg qd, and (iii) LSI plus BBR 0.5g tid, respectively, for 16 weeks. Hepatic fat content (HFC), serum glucose and lipid profiles, liver enzymes and serum and urine BBR concentrations were assessed before and after treatment. We also analyzed hepatic BBR content and expression of genes related to glucose and lipid metabolism in an animal model of NAFLD treated with BBR. RESULTS: As compared with LSI, BBR treatment plus LSI resulted in a significant reduction of HFC (52.7% vs 36.4%, p = 0.008), paralleled with better improvement in body weight, HOMA-IR, and serum lipid profiles (all p<0.05). BBR was more effective than PGZ 15mg qd in reducing body weight and improving lipid profile. BBR-related adverse events were mild and mainly occurred in digestive system. Serum and urine BBR concentrations were 6.99ng/ml and 79.2ng/ml, respectively, in the BBR-treated subjects. Animal experiments showed that BBR located favorably in the liver and altered hepatic metabolism-related gene expression. CONCLUSION: BBR ameliorates NAFLD and related metabolic disorders. The therapeutic effect of BBR on NAFLD may involve a direct regulation of hepatic lipid metabolism. TRIAL REGISTRATION: ClinicalTrials.gov NCT00633282. PMID- 26252778 TI - 1H-MRS Measured Ectopic Fat in Liver and Muscle in Danish Lean and Obese Children and Adolescents. AB - OBJECTIVES: This cross sectional study aims to investigate the associations between ectopic lipid accumulation in liver and skeletal muscle and biochemical measures, estimates of insulin resistance, anthropometry, and blood pressure in lean and overweight/obese children. METHODS: Fasting plasma glucose, serum lipids, serum insulin, and expressions of insulin resistance, anthropometry, blood pressure, and magnetic resonance spectroscopy of liver and muscle fat were obtained in 327 Danish children and adolescents aged 8-18 years. RESULTS: In 287 overweight/obese children, the prevalences of hepatic and muscular steatosis were 31% and 68%, respectively, whereas the prevalences in 40 lean children were 3% and 10%, respectively. A multiple regression analysis adjusted for age, sex, body mass index z-score (BMI SDS), and pubertal development showed that the OR of exhibiting dyslipidemia was 4.2 (95%CI: [1.8; 10.2], p = 0.0009) when hepatic steatosis was present. Comparing the simultaneous presence of hepatic and muscular steatosis with no presence of steatosis, the OR of exhibiting dyslipidemia was 5.8 (95%CI: [2.0; 18.6], p = 0.002). No significant associations between muscle fat and dyslipidemia, impaired fasting glucose, or blood pressure were observed. Liver and muscle fat, adjusted for age, sex, BMI SDS, and pubertal development, associated to BMI SDS and glycosylated hemoglobin, while only liver fat associated to visceral and subcutaneous adipose tissue and intramyocellular lipid associated inversely to high density lipoprotein cholesterol. CONCLUSION: Hepatic steatosis is associated with dyslipidemia and liver and muscle fat depositions are linked to obesity-related metabolic dysfunctions, especially glycosylated hemoglobin, in children and adolescents, which suggest an increased cardiovascular disease risk. PMID- 26252779 TI - An RNA chaperone, AtCSP2, negatively regulates salt stress tolerance. AB - Cold shock domain (CSD) proteins are RNA chaperones that destabilize RNA secondary structures. Arabidopsis Cold Shock Domain Protein 2 (AtCSP2), one of the 4 CSD proteins (AtCSP1-AtCSP4) in Arabidopsis, is induced during cold acclimation but negatively regulates freezing tolerance. Here, we analyzed the function of AtCSP2 in salt stress tolerance. A double mutant, with reduced AtCSP2 and no AtCSP4 expression (atcsp2-3 atcsp4-1), displayed higher survival rates after salt stress. In addition, overexpression of AtCSP2 resulted in reduced salt stress tolerance. These data demonstrate that AtCSP2 acts as a negative regulator of salt stress tolerance in Arabidopsis. PMID- 26252782 TI - The Association Between Waist Circumference and FITNESSGRAM(r) Aerobic Capacity Classification in Sixth-Grade Children. AB - Cardiorespiratory fitness is often assessed through measures of maximal oxygen uptake, sometimes referred to as aerobic capacity (26). The importance of adequate aerobic capacity for optimal health has been observed in numerous studies examining both adults (1,2,20) and children (17,24). An increased risk of overweight and metabolic syndrome in adults can result from a reduction in aerobic capacity from childhood to adolescence (4,11). PMID- 26252780 TI - Metabolic syndrome and drug discontinuation in schizophrenia: a randomized trial comparing aripiprazole olanzapine and haloperidol. AB - OBJECTIVE: To determine whether the prescription of aripiprazole, compared with olanzapine and haloperidol, was associated with a lower frequency of metabolic syndrome (MS) and treatment discontinuation at 1 year. METHOD: Patients were randomly assigned to be treated open-label and according to usual clinical practice with either aripiprazole, olanzapine, or haloperidol and followed up for 1 year. RESULTS: Three hundred out-patients with persistent schizophrenia were recruited in 35 mental health services. The intention-to-treat (ITT) analysis found no significant differences in the rate of MS between aripiprazole (37%), olanzapine (47%), and haloperidol (42%). Treatment discontinuation for any cause was higher for aripiprazole (52%) than for olanzapine (33%; OR, 0.41; P = 0.004), or haloperidol (37%; OR, 0.51; P = 0.030). No significant difference was found between olanzapine and haloperidol. Time to discontinuation for any cause was longer for olanzapine than for aripiprazole (HR, 0.55; P < 0.001). No significant differences were found between haloperidol and aripiprazole, or between olanzapine and haloperidol. CONCLUSION: The prescription of aripiprazole did not significantly reduce the rates of MS, but its treatment retention was worse. Aripiprazole cannot be considered the safest and most effective drug for maintenance treatment of schizophrenia in routine care, although it may have a place in antipsychotic therapy. PMID- 26252781 TI - Potential Signals of Natural Selection in the Top Risk Loci for Coronary Artery Disease: 9p21 and 10q11. AB - BACKGROUND: Coronary artery disease (CAD) is a complex disease and the leading cause of death in the world. Populations of different ancestry do not always share the same risk markers. Natural selective processes may be the cause of some of the population differences detected for specific risk mutations. OBJECTIVE: In this study, 384 single nucleotide polymorphisms (SNPs) located in four genomic regions associated with CAD (1p13, 1q41, 9p21 and 10q11) are analysed in a set of 19 populations from Europe, Middle East and North Africa and also in Asian and African samples from the 1000 Genomes Project. The aim of this survey is to explore for the first time whether the genetic variability in these genomic regions is better explained by demography or by natural selection. RESULTS: The results indicate significant differences in the structure of genetic variation and in the LD patterns among populations that probably explain the population disparities found in markers of susceptibility to CAD. CONCLUSIONS: The results are consistent with potential signature of positive selection in the 9p21 region and of balancing selection in the 9p21 and 10q11. Specifically, in Europe three CAD risk markers in the 9p21 region (rs9632884, rs1537371 and rs1333042) show consistent signals of positive selection. The results of this study are consistent with a potential selective role of CAD in the configuration of genetic diversity in current human populations. PMID- 26252783 TI - Preoperative epidural spinal injections increase the risk of surgical wound complications but do not affect overall complication risk or patient-perceived outcomes. AB - OBJECT A lack of information exists on the relationship between preoperative epidural spinal injections and outcomes after spine surgery. There is concern that injections might cause local changes, increasing the infection risk and surgical difficulty. Therefore, the authors explored the relationship between preoperative spinal injections and postoperative outcome. METHODS The cohort was comprised of patients who underwent thoracic and/or lumbar arthrodesis during the years 2007-2010 and had complete (preoperatively and 3 months postoperatively) outcome scores. Patients' clinical courses were reviewed to determine the occurrence of major complications within a 30-day postoperative period. Patient perceived outcomes were evaluated using the Oswestry Disability Index (ODI) and the SF-12 (12-Item Short Form Health Survey): mental component summary (MCS) and physical component summary (PCS) scores. Analyses were based on exposure to injections and were performed using chi-square exact tests and paired and unpaired t-tests. RESULTS Two hundred eighty patients met the inclusion criteria: 117 patients (41.8%) received and 163 patients (58.2%) did not receive preoperative epidural spinal injections. Overall, the likelihood of complication did not differ with respect to exposure (13.7% injection vs 11.7% noninjection); however, injected patients observed a 7.4-fold risk of developing surgical wound complications over noninjected patients (5.1% vs 0.6%, p = 0.02). Patient perceived outcomes measures demonstrated no differences between groups. Three months postoperatively, the MCS and ODI scores were similar (MCS: 49.6 +/- 11.6 injection vs 47.4 +/- 12.8 noninjection; ODI: 35.8 +/- 18.0 vs 34.4 +/- 19.1). MCS or ODI score improvement (preoperatively compared with 3 months postoperatively) did not vary between groups. Injected patients maintained a 2 point lower PCS score at entry and 3 months postoperatively as compared with noninjected peers (entry: 27.6 +/- 8.2 injection vs 29.5 +/- 9.3 noninjection, p = 0.09; 3 months: 33.3 +/- 8.6 vs 35.7 +/- 9.0, p = 0.03); the PCS score improvements between injected and noninjected groups were similar (5.7 +/- 9.9 vs 6.2 +/- 9.7). CONCLUSIONS Patients exposed to preoperative epidural injections had similar complication rates to those who never received a spinal injection. However, they had a greater risk of developing wound complications. These complications had no effect on short-term improvements in outcome measures. PMID- 26252784 TI - A case of pituitary apoplexy following posterior lumbar fusion surgery. AB - Pituitary adenoma is a common primary brain neoplasm. Pituitary apoplexy (PA) is a rare complication of pituitary adenoma and occurs as the result of sudden tumor growth and following different comorbidities. The authors describe the first case of PA following posterior lumbar fusion surgery performed while the patient was prone. In patients with a preexisting pituitary adenoma, thorough clinical and laboratory investigations should be conducted using an interdisciplinary approach before any planned surgery. In unknown cases of pituitary adenoma, PA should be kept in mind for the differential diagnosis in a case with headache, nausea, vomiting, ophthalmoplegia, visual loss, and electrolyte imbalance concurrent with an ongoing disease state. PMID- 26252785 TI - Long-term cure of high-grade spinal cord glioma in a pediatric patient who underwent cordectomy. AB - High-grade spinal cord gliomas are rare and carry a poor prognosis. A number of treatment modalities exist for spinal cord gliomas, but no consensus exists regarding their management. Cordectomy represents a possible option for treating these lesions; however, few cases have been reported in adults, and none have been reported in the pediatric population. The authors describe the use of cordectomy for the treatment of a high-grade spinal glioma in a 9-year-old boy who remains cancer free 14 years following his initial presentation. PMID- 26252786 TI - An insight into antimicrobial activity of the freshwater bryozoan Pectinatella magnifica. AB - The antimicrobial activity of five crude extracts of the freshwater bryozoan Pectinatella magnifica (Leidy, 1851) was evaluated in vitro for the first time. P. magnifica acetone extract exhibited the highest antibacterial activity (minimum inhibitory concentrations (MIC) 0.004-0.350 mg/mL and MBC 0.007-0.500 mg/mL), while its methanol extract showed the most promising antifungal activity (MIC 0.03-0.12 mg/mL and MFC 0.06-0.25 mg/mL). Furthermore, at a concentration of 0.25 MIC, the methanol extract reduced biofilm formation of the bacterial strain Pseudomonas aeruginosa PAO1 in a considerable extent (59.14%). FTIR spectra of the most active extracts indicate the presence of carbonyl compounds, long-chain alcohols and/or sterols. According to the experimental data obtained, P. magnifica methanol extract may be considered as a good resource of novel natural products with potent antibiofilm activity against the bacterium well known for its resistance. PMID- 26252787 TI - Phase I safety data of lenalidomide, bortezomib, dexamethasone, and elotuzumab as induction therapy for newly diagnosed symptomatic multiple myeloma: SWOG S1211. PMID- 26252789 TI - Correction: Modeling the Origin and Possible Control of the Wealth Inequality Surge. PMID- 26252788 TI - A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. AB - In this phase 2 open-label randomized study, 31 patients with intermediate-2 or high-risk myelofibrosis received fedratinib 300, 400 or 500 mg once daily in consecutive 4-week cycles. Mean spleen volume reductions at 12 weeks (primary end point) were 30.3% (300 mg), 33.1% (400 mg) and 43.3% (500 mg). Spleen response rates (patients achieving ?35% spleen reduction) at 12/24 weeks were 30%/30% (300 mg), 50%/60% (400 mg) and 64%/55% (500 mg), respectively. By 4 weeks, improvements in myelofibrosis (MF)-associated symptoms were observed. At 48 weeks, 68% of patients remained on fedratinib and 16% had discontinued because of adverse events (AEs). Common grade 3/4 AEs were anemia (58%), fatigue (13%), diarrhea (13%), vomiting (10%) and nausea (6%). Serious AEs included one case of reversible hepatic failure and one case of Wernicke's encephalopathy (after analysis cutoff). Fedratinib treatment led to reduced STAT3 phosphorylation but no meaningful change in JAK2V617F allele burden. Significant modulation (P<0.05, adjusted for multiple comparisons) of 28 cytokines was observed, many of which correlated with spleen reduction. These data confirm the clinical activity of fedratinib in MF. After the analysis cutoff date, additional reports of Wernicke's encephalopathy in other fedratinib trials led to discontinuation of the sponsored clinical development program. PMID- 26252790 TI - Phenotypic and Genotypic Characteristics of Members of the Genus Streptobacillus. AB - The genus Streptobacillus (S.) remained monotypic for almost 90 years until two new species were recently described. The type species, S. moniliformis, is one of the two etiological agents of rat bite fever, an under-diagnosed, worldwide occurring zoonosis. In a polyphasic approach field isolates and reference strains of S. moniliformis, S. hongkongensis, S. felis as well as divergent isolates were characterized by comparison of molecular data (n = 29) and from the majority also by their physiological as well as proteomic properties (n = 22). Based on growth independent physiological profiling using VITEK2-compact, API ZYM and the Micronaut system fastidious growth-related difficulties could be overcome and streptobacilli could definitively be typed despite generally few differences. While differing in their isolation sites and dates, S. moniliformis isolates were found to possess almost identical spectra in matrix-assisted laser desorption ionization-time of flight mass spectrometry and Fourier transform infrared spectroscopy. Spectroscopic methods facilitated differentiation of S. moniliformis, S. hongkongensis and S. felis as well as one divergent isolate. Sequencing of 16S rRNA gene as well as functional genes groEL, recA and gyrB revealed only little intraspecific variability, but generally proved suitable for interspecies discrimination between all three taxa and two groups of divergent isolates. PMID- 26252791 TI - Establishment and Validation of a Non-Radioactive Method for In Vitro Transcription Assay Using Primer Extension and Quantitative Real Time PCR. AB - Primer extension-dependent in vitro transcription assay is one of the most important approaches in the research field of gene transcription. However, conventional in vitro transcription assays incorporates radioactive isotopes that cause environmental and health concerns and restricts its scope of application. Here we report a novel non-radioactive method for in vitro transcription analysis by combining primer extension with quantitative real time PCR (qPCR). We show that the DNA template within the transcription system can be effectively eliminated to a very low level by our specially designed approach, and that the primers uniquely designed for primer extension and qPCR can specifically recognize the RNA transcripts. Quantitative PCR data demonstrate that the novel method has successfully been applied to in vitro transcription analyses using the adenovirus E4 and major late promoters. Furthermore, we show that the TFIIB recognition element inhibits transcription of TATA-less promoters using both conventional and nonradioactive in vitro transcription assays. Our method will benefit the laboratories that need to perform in vitro transcription but either lack of or choose to avoid radioactive facilities. PMID- 26252792 TI - Diversity of Vibrio spp in Karstic Coastal Marshes in the Yucatan Peninsula. AB - Coastal bodies of water formed by the combination of seawater, underground rivers and rainwater comprise the systems with the greatest solar energy flow and biomass production on the planet. These characteristics make them reservoirs for a large number species, mainly microorganisms. Bacteria of the genus Vibrio are natural inhabitants of these environments and their presence is determined by variations in the nutrient, temperature and salinity cycles generated by the seasonal hydrologic behavior of these lagoon systems. This study determined the diversity of the genus Vibrio in 4 coastal bodies of water on the Yucatan Peninsula (Celestun Lagoon, Chelem Lagoon, Rosada Lagoon and Sabancuy Estuary). Using the molecular technique of 454 pyrosequencing, DNA extracted from water samples was analyzed and 32,807 reads were obtained belonging to over 20 culturable species of the genus Vibrio and related genera. OTU (operational taxonomic unit) richness and Chao2 and Shannon Weaver diversity indices were obtained with the database from this technique. Physicochemical and environmental parameters were determined and correlated with Vibrio diversity measured in OTUs. PMID- 26252794 TI - Emerging Role of Endoscopic Ultrasound in the Diagnostic Evaluation of Idiopathic Pancreatitis. AB - BACKGROUND: "Idiopathic pancreatitis" is diagnosed when clinical, laboratory and conventional radiologic methods do not provide a clear etiology for the episode. Given its associated morbidity and mortality, it is important to determine the cause of pancreatitis to provide early treatment and prevent recurrence. METHODS: The aim of this systematic review was to evaluate the utility of endoscopic ultrasound (EUS) in determining an etiology in patients classified as having idiopathic pancreatitis and to assess how EUS performed compared with other modalities. A PubMed search for relevant articles (January 2000-November 2014) was performed using the search terms "(pancreatitis or idiopathic pancreatitis or unexplained pancreatitis) and (EUS or endoscopic ultrasound)." RESULTS: The search yielded a total of 963 articles, and 13 studies were included in the final review. In some studies, the yield of EUS was higher than magnetic resonance cholangiopancreatography in idiopathic pancreatitis. EUS more accurately detected biliary stones, whereas magnetic resonance cholangiopancreatography more often identified pancreatic duct abnormalities. The yield of EUS was lower in patients postcholecystectomy but was not influenced by gender, severity of pancreatitis, or recurrent disease. The most frequent diagnoses by EUS for those with idiopathic pancreatitis were biliary tract disease (41%). Overall, EUS identified additional diagnostic information in 61% of patients with idiopathic pancreatitis. CONCLUSIONS: Given the high incidence of microlithiasis and/or biliary sludge as a cause of idiopathic pancreatitis as well as the safety and high accuracy, EUS should be considered 1st for evaluation of idiopathic pancreatitis if conventional cross-sectional radiography fails to reveal a cause. PMID- 26252793 TI - Influential Factors on the Relative Age Effect in Alpine Ski Racing. AB - The relative age effect (RAE), which refers to an over-representation of selected athletes born early in the selection year, was proven to be present in alpine ski racing in all age categories at both national and international levels. However, the influential factors on, or the causal mechanisms of, the RAE are still unknown. Therefore, the aim of the present study was to examine three possible influential factors on the relative age effect in alpine skiing: physical performance, anthropometric characteristics and biological maturational status. The study included the investigation of 282 elite Austrian youth ski racers and 413 non-athletes (comparison group) of the same age (10-13 years) and region. Six physical performance tests were performed, body mass and height were assessed, and the age at peak height velocity (APHV) was calculated. A significant RAE was present in the ski racers. No differences were shown in the physical performance characteristics or in the calculated APHV between the relative age quarters. These results suggest that ski racers born in the last quarter can counteract the relative age disadvantages if they already present the same level of physical performance and maturational status as those born at the beginning of the year. The height and weight of ski racers born at the beginning of the year were significantly higher compared to the non-athletes, and ski racers born in relative age quarter 1 were taller and heavier compared to the ski racers of the other quarters. This indicates that the anthropometric characteristics influence the selection process in alpine ski racing, and that relatively older athletes are more likely to be selected if they exhibit advanced anthropometric characteristics. PMID- 26252795 TI - A Genetic Predisposition for Lethal Arrhythmias: No Need for Preventive Treatment? PMID- 26252796 TI - The Role of Leisure Engagement for Health Benefits Among Korean Older Women. AB - This qualitative study was designed to examine the benefits of leisure to older Korean women. Using a constructive grounded theory methodology, in this study we identified three categories of benefits from leisure activities: (a) developing social connections, (b) enhancing psychological well-being, and (c) improving physical health. The findings of this study demonstrate that involvement in leisure activities offers substantial physical, psychological, and social benefits for older Korean women. The results also suggest that these benefits can provide an opportunity for older Korean adults to improve their health and well being, which, in turn, may help promote successful aging. PMID- 26252797 TI - Effect of transplanted adipose-derived stem cells in mice exhibiting idiopathic pulmonary fibrosis. AB - Stem cell-based cell therapy has provided a promising method for the treatment of pulmonary diseases, including idiopathic pulmonary fibrosis (IPF). Furthermore, adipose-derived stem cells (ADSCs) have been reported to be effective in lung repair and regeneration. In the current study, IPF was induced in mice by intratracheal instillation of bleomycin (BLM), and ADSCs were delivered systemically into the mice via the tail vein to evaluate the effects of ADSC transplantation. The ADSC engraftment rate and morphometric changes in lung tissue samples in vivo were investigated by histochemistry and immunohistochemistry, as well as by western blotting. The results indicated that ADSCs may relieve IPF and provide a significant contribution to lung repair when administered at an early stage. PMID- 26252798 TI - Momordica cochinchinensis Spreng. seed extract suppresses breast cancer growth by inducing cell cycle arrest and apoptosis. AB - The herb Momordica cochinchinensis has been used for a variety of purposes, and been shown to have anti-cancer properties. The present study assessed the potency and the underlying mechanisms of action of the ethyl acetate extract of seeds of Momordica cochinchinensis (ESMC2) on breast cancer cells. Therefore, the effects of ESMC2 on the cell viability, cell cycle and apoptosis of MDA-MB-231 cells were investigated. The results showed that ESMC2 exerted a marked growth inhibitory effect on the cells. Cell cycle arrest in G2 phase following treatment with ESMC2 was associated with a marked increase in the protein levels of cyclin B1, cyclin E and cyclin-dependent kinase 1 and a decrease in cyclin D1 expression. In addition, ESMC2 dose-dependently induced cell apoptosis, which was mediated via upregulation of the apoptosis-associated proteins p53, B-cell lymphoma 2 (Bcl-2) associated X protein, Bcl-2 homologous antagonist killer and Bcl-2-associated death promoter expression, as well as downregulation of nuclear factor kappa B, Bcl-2 and myeloid cell leukemia-1. Furthermore, the activation of extracellular signal-regulated kinase 1/2, p38, c-Jun N-terminal kinase (JNK) and Akt phosphorylation were decreased by ESMC2 in a dose-dependent manner, indicating that ESMC2 exerted its effects via the mitogen-activated protein kinase/JNK pathway. Furthermore, nude mouse xenotransplant models were used to evaluate the tumor growth inhibitory effects of ESMC2. The possible chemical components of ESMC2 were analyzed by gas chromatography-mass spectrometry, and 12 compounds were detected from the major peaks based on the similarity index with entries of a compound database. The results of the present study may aid in the development of novel therapies for breast cancer. PMID- 26252800 TI - Genotoxic Impurities in Pharmaceutical Manufacturing: Sources, Regulations, and Mitigation. PMID- 26252799 TI - Short Communication: Exploring Antibody Potential as Prophylactic/Therapeutic Strategies for Prevention of Early Mucosal HIV-1 Infection. AB - Mucosal tissues are the predominant sites for genital HIV-1 transmission. We investigated the mechanisms by which broadly neutralizing antibodies (bNAbs) inhibit HIV-1 replication in a coculture model including primary mucosal dendritic cells (DCs), such as Langerhans cells, interstitial dendritic cells, and CD4(+) T lymphocytes. We show that bNAbs efficiently prevent HIV-1 infection by inhibiting HIV-1 transmission to CD4(+) T lymphocytes. This inhibition of cell to-cell transmission was observed with equal potency as the inhibition of cell free infection of primary CD4(+) T lymphocytes. In addition, a decrease in HIV-1 replication in DCs and the induction of DC maturation were detected. This additional inhibition was Fc mediated as it was blocked by the use of specific anti-FcgammaR monoclonal Abs. The DC maturation by bNAbs during HIV transmission may contribute to mucosal protection. Therefore, multiple antibody-mediated inhibitory functions should be combined for the improvement of future preventive/therapeutic strategies to cure HIV. PMID- 26252801 TI - (1)H NMR Relaxation Study of a Magnetic Ionic Liquid as a Potential Contrast Agent. AB - A proton nuclear magnetic relaxation dispersion (1)H NMRD study of the molecular dynamics in mixtures of magnetic ionic liquid [P66614][FeCl4] with [P66614][Cl] ionic liquid and mixtures of [P66614][FeCl4] with dimethyl sulfoxide (DMSO) is presented. The proton spin-lattice relaxation rate, R1, was measured in the frequency range of 8 kHz-300 MHz. The viscosity of the binary mixtures was measured as a function of an applied magnetic field, B, in the range of 0-2 T. In the case of DMSO/[P66614][FeCl4] the viscosity was found to be independent from the magnetic field, while in the case of the [P66614][Cl]/[P66614][FeCl4] system viscosity decreased with the increase of the magnetic field strength. The spin lattice relaxation results were analyzed for all systems taking into account the relaxation mechanisms associated with the molecular motions with correlation times in a range between 10(-11) and 10(-7)s, usually observed by NMRD, and the paramagnetic relaxation contributions associated with the presence of the magnetic ions in the systems. In the case of the DMSO/[P66614][FeCl4] system the R1 dispersion shows the relaxation enhancement due to the presence of the magnetic ions, similar to that reported for contrast agents. For the [P66614][Cl]/[P66614][FeCl4] system, the R1 dispersion presents a much larger paramagnetic relaxation contribution, in comparison with that observed for the DMSO/[P66614][FeCl4] mixtures but different from that reported for other magnetic ionic liquid system. In the [P66614][Cl]/[P66614][FeCl4] system the relaxation enhancement associated with the paramagnetic ions is clearly not proportional to the concentration of magnetic ions, in contrast with what is observed for the DMSO/[P66614][FeCl4] system. PMID- 26252802 TI - Aqueous Sulfate Separation by Crystallization of Sulfate-Water Clusters. AB - An effective approach to sulfate separation from aqueous solutions is based on the crystallization of extended [SO4(H2O)5(2-)]n sulfate-water clusters with a bis(guanidinium) ligand. The ligand was generated in situ by hydrazone condensation in water, thereby bypassing the need for elaborate syntheses, tedious purifications, and organic solvents. Crystallization of sulfate-water clusters represents an alternative approach to the now established sulfate separation strategies that involve encapsulation of the "naked" anion. PMID- 26252803 TI - Faceted fatty acid vesicles formed from single-tailed perfluorinated surfactants. AB - The aggregation behavior and rheological properties of two mixtures of perfluorononanoic acid (PFNA)/NaOH and perfluorodecanoic acid (PFDA)/NaOH were investigated in aqueous solutions. Interestingly, pH-sensitive polyhedral fatty acid vesicles were spontaneously formed in both systems, which were determined by freeze-fracture transmission electron microscopy (FF-TEM) measurements. Especially, a phase transition from faceted vesicles to the L3 phase with the increase of pH was observed in the PFNA/NaOH system while it was not observed in the PFDA/NaOH system. Differential scanning calorimetry (DSC) and wide angle X ray scattering (WAXS) measurements confirmed that the bilayers of the faceted vesicles were in the crystalline station indicating that the crystallization of fluorocarbon chains was the main driving force for their formation. Besides, the two systems of faceted perfluorofatty acid vesicles exhibit interesting rheological properties, for instance, they showed high viscoelasticity and shear thinning behaviour, and the elastic modulus (G') and viscous modulus (G'') of PFDA/NaOH vesicles were much higher than those of PFNA/NaOH vesicles. Conversely, the solution of the L3 phase with fluid bilayers did not present viscoelastic properties. Therefore, the viscoelastic properties of vesicles resulted from the crystalline fluorinated alkyl chains with high rigidity at room temperature and the dense packing of vesicles. As far as we know, such faceted fatty acid vesicles formed from single-tailed perfluorinated surfactants have been rarely reported. Our work successfully constructs polyhedral fatty acid vesicles and proposes their formation mechanism, which should be a great advance in the fundamental research of fatty acid vesicles. PMID- 26252804 TI - ERRATUM. PMID- 26252806 TI - Mediation and moderation effect of the big five personality traits on the relationship between self-perceived malocclusion and psychosocial impact of dental esthetics. AB - OBJECTIVE: To explore the mediation and moderation effects of personality traits on the relationship between self-perceived malocclusion and the psychosocial impact of dental esthetics. MATERIALS AND METHODS: The sample included 252 subjects (62% female) aged 12-39 years. Self-perceived malocclusion was estimated using the 10-point scale Aesthetic Component of the Index of Orthodontic Treatment Need. The Psychosocial Impact of Dental Aesthetics Questionnaire was used to assess the psychological impact and the Big Five Inventory for personality traits. Moderation and mediation effects were evaluated with Pearson correlations and stepwise regression analysis, respectively. RESULTS: Self perceived malocclusion ranged from 1 to 8 and was the most significant predictor of psychosocial impact of dental esthetics, whose unique contribution accounted for 11%-36.4% of variability, while age and sex accounted for 1.2%-2.5%. Personality traits had no mediating effect on this relationship. The moderating effect of agreeableness was present in the relationship between self-perceived degree of malocclusion and Social Impact (SI), Psychological Impact (PI), and Aesthetic Concern (AC) (DeltaR2 = 0.035, 0.020, and 0.013, respectively; P < .001), while conscientiousness affected the relationship between perception of malocclusion and SI and PI (DeltaR2 = 0.018 and 0.016, respectively; P < .05). In people with lower agreeableness and conscientiousness, increasing the severity of self-perceived malocclusion leads to less increase in SI and PI. In people with lower agreeableness, the increase influences AC in a similar manner. Extraversion, neuroticism, and openness do not have a moderating effect. CONCLUSIONS: The relationship between self-perceived malocclusion and the psychosocial impact of dental esthetics appears to be moderated and not mediated by personality traits. Adolescents and young adults with lower agreeableness and conscientiousness seem to be less affected by the increased severity of self perceived malocclusion, as demonstrated in reporting some psychosocial impacts. PMID- 26252808 TI - Characterization of Phosphate and Arsenate Adsorption onto Keggin-Type Al30 Cations by Experimental and Theoretical Methods. AB - Keggin-type aluminum oxyhydroxide species such as the Al30 (Al30O8(OH)56(H2O)26(18+)) polycation can readily sequester inorganic and organic forms of P(V) and As(V), but there is a limited chemical understanding of the adsorption process. Herein, we present experimental and theoretical structural and chemical characterization of [(TBP)2Al2(MU4-O8)(Al28(MU2-OH)56(H2O)22)](14+) (TBP = t-butylphosphonate), denoted as (TBP)2Al30-S. We go on to consider the structure as a model for studying the reactivity of oxyanions to aluminum hydroxide surfaces. Density functional theory (DFT) calculations comparing the experimental structure to model configurations with P(V) adsorption at varying sites support preferential binding of phosphate in the Al30 beltway region. Furthermore, DFT calculations of R-substituted phosphates and their arsenate analogues consistently predict the beltway region of Al30 to be most reactive. The experimental structure and calculations suggest a shape-reactivity relationship in Al30, which counters predictions based on oxygen functional group identity. PMID- 26252807 TI - Effects of different instrumentation techniques on calcium hydroxide removal from simulated immature teeth. AB - The aim of this study was to evaluate the effectiveness of endodontic instrument systems in the removal of calcium hydroxide [Ca(OH)(2)] from simulated immature teeth. The root canals of 106 human single-rooted teeth were shaped with ProTaper rotary files up to an F5 file size. Simulation of roots with immature apices was carried out using size 4 green 1.5-mm diameter Unicore drills. A non-setting Ca(OH)(2) was injected into each root canal and inserted into the working length using lentulo spiral, after which cotton pellets were placed over canal orifices. The apical and coronal side of the roots were then sealed with glass ionomer cement and light cured. Specimens were stored in distilled water for 3 months at 37 degrees C. After 3 months, the temporary coronal seal was removed and the samples were randomly divided into five experimental groups according to the method used for Ca(OH)(2) removal (ProTaper, Reciproc, OneShape, WaveOne, and Manual) (n = 20), one positive control group (n = 3) and one negative control group (n = 3). The amount of remaining Ca(OH)(2) in the canal walls was measured under a stereomicroscope at 30* magnification. The data were analyzed using Kruskal-Wallis test and Mann-Whitney U test at a significance level of 0.05. Positive and negative control groups were found to be statistically different from all other groups (p < 0.05). There were no significant differences among the ProTaper, Reciproc, OneShape, WaveOne, and Manual groups (p > 0.05). As a conclusion, none of the techniques completely removed Ca(OH)(2) from simulated immature teeth. PMID- 26252809 TI - Leukodepleted blood components do not remove the potential for long-term transfusion-associated microchimerism in Australian major trauma patients. AB - Despite the introduction of leukodepleted blood components, it has been shown that donor leukocyte engraftment (microchimerism) remains a long-term consequence of red blood cell (RBC) transfusion. The incidence of microchimerism may be affected by international disparities in blood processing methods or variations in transfusion practices. This study was conducted to determine the prevalence of microchimerism in Australian trauma patients. A secondary aim was to examine whether any patient complications correlated to the incidence of microchimerism. Australian trauma patients (n = 86) who had been transfused with red blood cell (RBC) units between 2000 and 2012 with an injury severity score (ISS) of greater than 15 were recruited. The prevalence of microchimerism was determined using genetic screening with a panel of insertion/deletion biallelic polymorphisms. The mean storage age of the transfused RBC units was 20 +/- 8 days and the mean length of stay (LOS) in hospital was 40 +/- 39 days. There were no significant associations in this study sample to bias for patient age, gender, number of transfused RBC units or ISS. Nine of the 55 (16.3%) patients transfused with non leukodepleted blood components displayed an incidence of microchimerism. Of the 31 patients transfused with leukodepleted RBC units, 3 (9.6%) displayed an incidence of microchimerism. Therefore, despite the universal introduction of leukodepleted blood components in Australia, the prevalence of transfusion associated microchimerism was found to be unchanged. Furthermore, half of the patients exhibiting microchimerism were recorded to have had splenic injury or required splenectomy at the time of transfusion. PMID- 26252810 TI - Association Between Hypertension, Menopause, and Cognition in Women. AB - The aim of this study was to investigate the cognitive state in women and its relation to menopause and hypertension (HTN). The authors included 1034 women aged 47.13+/-15.71 years. The prevalence of HTN was 47.1%, with 67.8% of patients treated and 48.6% controlled. Cognitive impairment was higher among hypertensive menopausal (mini-Boston Naming Test: 7.4+/-3.1 vs 8.5+/-2.4, P<.001; Clock Drawing Test: 5.2+/-2 vs 5.6+/-1.6, P<.01). Using logistic regression adjusted by age and education level, statistical differences were found in the results from the mini-Boston Naming Test between menopausal hypertensive vs menopausal normotensive women (odds ratio, 1.48; 95% confidence interval, 1.06-2.07; P=.021), and no difference between nonmenopausal hypertensive vs menopausal normotensive women (odds ratio, 0.89; 95% confidence interval, 0.51-1.57; P=.697). The P interaction between both groups was significant (P=.038). The possibility of alteration in cortical functions in menopausal hypertensive woman showed a relative increment of 48% (P=.021). The association between HTN and menopause increases the possibility of compromising the semantic memory by 50%. PMID- 26252811 TI - Reversible DNA i-motif to hairpin switching induced by copper(II) cations. AB - i-Motif DNA structures have previously been utilised for many different nanotechnological applications, but all have used changes in pH to fold the DNA. Herein we describe how copper(II) cations can alter the conformation of i-motif DNA into an alternative hairpin structure which is reversible by chelation with EDTA. PMID- 26252812 TI - Retraction. AB - This article has been retracted at the request of: Editor-in-Chief and Authors 'Cross-talk of alpha tocopherol-associated protein and JNK controls the oxidative stress-induced apoptosis in prostate cancer cells' by Baoyi Zhu, Xiaojuan Li, Yuying Zhang, Chunwei Ye, Yu Wang, Songwang Cai, Huaiqiu Huang, Yi Cai, Shuyuan Yeh, Zhenhua Huang, Ruihan Chen, Yiran Tao and Xingqiao Wen The above article, published online on 28 November 2012 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, Prof. Peter Lichter, and Wiley Periodicals, Inc. The Retraction has been agreed due to errors that were detected in Fig. 6b. Some images were duplicated and erroneously presented as unique. Although the authors firmly stand by the major conclusion of this paper, they believe the most responsible course of action is to retract it. Reference Zhu, B., Li, X., Zhang, Y., Ye, C., Wang, Y., Cai, S., Huang, H., Cai, Y., Yeh, S., Huang, Z., Chen, R., Tao, Y. and Wen, X. (2013), Cross-talk of alpha tocopherol-associated protein and JNK controls the oxidative stress-induced apoptosis in prostate cancer cells. Int. J. Cancer, 132: 2270-2282. doi: 10.1002/ijc.27927. PMID- 26252813 TI - Retraction. AB - This article has been retracted at the request of: Editor-in-Chief and Co-author 'COX-2 inhibitors suppress integrin alpha5 gene expression in human lung carcinoma cells through activation of Erk: involvement of Sp1 and AP-1 sites' by ShouWei Han and Jesse Roman The above article, published online on 11 April 2005 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the co-author, the journal Editor-in-Chief, Prof. Peter Lichter, and Wiley Periodicals, Inc. The Retraction has been agreed because serious errors related to image duplication were identified in some of the figures presented. An investigation found that the errors were performed by the first and corresponding author, ShouWei Han, without the knowledge of the co-author. ShouWei Han has not responded to requests by the journal or the co-author. Therefore, the co-author has requested the Retraction of this article and apologizes to the readers of the journal. Reference Han, S. and Roman, J. (2005), COX-2 inhibitors suppress integrin alpha5 expression in human lung carcinoma cells through activation of Erk: Involvement of Sp1 and AP-1 sites. Int. J. Cancer, 116: 536-546. doi: 10.1002/ijc.21125. PMID- 26252814 TI - Erratum. PMID- 26252815 TI - Erratum. PMID- 26252816 TI - Erratum. PMID- 26252818 TI - Erratum. PMID- 26252817 TI - Erratum. PMID- 26252819 TI - Drink driving and risky behavior among university students in southwestern Nigeria-Implications for policy development. AB - BACKGROUND: Drink driving contributes significantly to road traffic injuries. Little is known about the relationship between drink driving and other high-risk behaviors in non-Western countries. The study aimed to assess the relationship between drink driving and other risky behaviors including making phone calls, sending text messages, nonuse of protective gear, and driving against traffic. METHODS: A cross-sectional survey of risky behavior among undergraduates was conducted. A stratified random sampling method was used to identify young undergraduates who had driven a motorized vehicle in the past year. The Alcohol Use Disorder Identification Test (AUDIT) and other tools developed by researchers were used to identify the risky behaviors. RESULTS: Of 431 respondents, 10.7% had engaged in drink driving in the past 12 months. The most common risky behavior was making phone calls (63.7%), followed by nonuse of helmets (54.7%), driving against traffic (49.2%), nonuse of seat belts (46.8%), and sending text messages (26.1%). Alcohol use was significantly associated with making phone calls (U = 1.148; P < .0001), sending text messages (U = 1.598; P = .021), nonuse of helmets (U = 1.147; P < .0001), driving against traffic (U = 1.234; P < .0001), and nonuse of seat belts (U = 3.233; P = .001). Drink driving was associated with all risky behaviors except nonuse of seat belts (U = 1.842; P = .065). CONCLUSION: Alcohol use and drink driving were associated with multiple risky driving behaviors. This provides useful insight for policy development and presents additional challenges for traffic injury prevention. PMID- 26252821 TI - Erratum. PMID- 26252820 TI - Repurposed biological scaffolds: kidney to pancreas. AB - Advances in organ regeneration have been facilitated by gentle decellularization protocols that maintain distinct tissue compartments, and thereby allow seeding of blood vessels with endothelial lineages separate from populations of the parenchyma with tissue-specific cells. We hypothesized that a reconstituted vasculature could serve as a novel platform for perfusing cells derived from a different organ: thus discordance of origin between the vascular and functional cells, leading to a hybrid repurposed organ. The need for a highly vascular bed is highlighted by tissue engineering approaches that involve transplantation of just cells, as attempted for insulin production to treat human diabetes. Those pancreatic islet cells present unique challenges since large numbers are needed to allow the cell-to-cell signaling required for viability and proper function; however, increasing their number is limited by inadequate perfusion and hypoxia. As proof of principle of the repurposed organ methodology we harnessed the vasculature of a kidney scaffold while seeding the collecting system with insulin producing cells. Pig kidneys were decellularized by sequential detergent, enzymatic and rinsing steps. Maintenance of distinct vascular and collecting system compartments was demonstrated by both fluorescent 10 micron polystyrene microspheres and cell distributions in tissue sections. Sterilized acellular scaffolds underwent seeding separately via the artery (fibroblasts or endothelioma cells) and retrograde (murine betaTC-tet cells) up the ureter. After three-day bioreactor incubation, histology confirmed separation of cells in the vasculature from those in the collecting system. betaTC-tet clusters survived in tubules, glomerular Bowman's space, demonstrated insulin immunolabeling, and thereby supported the feasibility of kidney-to-pancreas repurposing. PMID- 26252822 TI - Impairments in Negative Facial Emotion Recognition in Chinese Schizophrenia Patients Detected With a Newly Designed Task. AB - Facial emotion recognition has been found to be impaired in schizophrenia, although overall results have been inconclusive. A new set of facial emotion stimuli with Chinese faces was developed, using static and dynamic avatars, the identification of which were subsequently validated in 562 healthy control subjects. This test was then used to identify facial emotion recognition accuracy in 44 patients with schizophrenia and 41 healthy controls. Overall, patients identified facial emotions significantly worse than healthy controls (p = 0.018) with a significant main effect for type of emotion (p = 0.016). Patients performed significantly worse in fear (p = 0.029) and sadness (p = 0.037), and marginally worse in anger (p = 0.052). No significant differences were evident in contempt (p = 0.254) or happiness (p = 0.943). Regarding error rates of misattribution, patients overidentified contempt (p = 0.035) and sadness (p = 0.01), but not anger, fear, or happiness. Conclusion, patients of Chinese ethnicity with schizophrenia may have significantly greater difficulties identifying negative, but not positive emotions. PMID- 26252823 TI - Lexical Characteristics of Emotional Narratives in Schizophrenia: Relationships With Symptoms, Functioning, and Social Cognition. AB - Previous research has suggested that complexity of speech, speech rate, use of emotion words, and use of pronouns are all potential indicators of important clinical components of schizophrenia, but little research has examined the relationships of these disturbances to cognitive variables impaired in schizophrenia, including social cognition. The current study examined these lexical differences to better characterize the cognitive substrates of speech disturbances in schizophrenia. Brief narratives of individuals with schizophrenia (n = 42) and non-clinical controls (n = 48) were compared according to their lexical characteristics, and these were examined for relationships to social cognition and real-world functioning. Significant differences between the groups were found in words per sentence (related to functioning, but not negative symptoms) as well as pronoun use (related to attributional style and theory of mind). Additionally, lexical characteristics effectively distinguished individuals with schizophrenia from non-clinical controls. Language disturbances in schizophrenia seem related to social cognition impairments and real-world functioning, and are a robust indicator of clinical status. PMID- 26252824 TI - Prospective Study of Posttraumatic Stress in Adolescents 6 and 24 Months After the 2010 Yushu Earthquake in China. AB - Adolescents who have suffered through earthquakes often experience symptoms of posttraumatic stress disorder (PTSD). This particular population has received increasing attention from researchers. The goals of the present study are to describe longitudinally the prevalence and the severity of PTSD in adolescent survivors of the Yushu earthquake in China and to explore the risk factors which lead to psychiatric disorders. The PTSD Check List (Civilian Version) was used to assess the PTSD symptoms in participants. The rates of PTSD were found to be 10.9% after 6 months and 5.8% after 24 months. Bereavement, being buried in the ruins, and personal injury were found to be significant risk factors for the development of PTSD. We suggest that intervention strategies should be addressed and more attention should be paid to adolescents. PMID- 26252825 TI - Asthma, Depression, and Suicidality: Results from the 2007, 2009, and 2011 Youth Risk Behavior Surveys. AB - We assessed the association between asthma and suicidality in a nationally representative sample of US high school students. Data came from the 2007, 2009, and 2011 Youth Risk Behavioral Surveys. Weighted prevalence estimates and adjusted odds ratios were calculated. Subjects with asthma are more likely to report 2-week sadness (35.2%) compared to those without asthma (26.7%). Teens with asthma are also more likely to report suicide ideation (20.1% vs. 15%), planning (15.7% vs. 12.1%), attempt (10.1% vs. 6.9%), and treatment for attempt (3.5% vs. 2%). Although the unadjusted association between lifetime asthma and suicide attempts is statistically significant (crude odds ratio 1.5 (95% CI 1.3 1.8)), after controlling for confounders, that association is no longer statistically significant (AOR 1.2 (1-1.6)). Thus, this increase in suicidality seems to be due to the increased prevalence of sadness among teens with asthma. Similar patterns were seen in the 2007 and 2009 surveys. PMID- 26252826 TI - Evidence of Contrasting Patterns for Suppression and Reappraisal Emotion Regulation Strategies in Alexithymia. AB - Alexithymia generally refers to difficulties in identifying and describing emotions. In this paper, two studies explored whether the emotion deficits observed in alexithymia may be related to the use of emotion regulation strategies. Relations with various sociodemographic variables were also explored. In the first study, 255 students completed the Emotion Regulation Questionnaire (ERQ) and the Toronto Alexithymia Scale-20. For the second study, 1107 participants from the general population completed the ERQ and the Bermond-Vorst Alexithymia Questionnaire. Results demonstrated that alexithymia was related to the use of a suppression strategy and in particular to difficulties verbalizing emotions, suggesting that the capacity to communicate and name one's emotion is a central aspect in alexithymia. Concerning sociodemographic variables, alexithymia and the use of a suppression strategy were found to be related to age and to be higher in males. The results of these studies and their clinical implications for treatment are discussed. PMID- 26252827 TI - Four New Amaryllidaceae Alkaloids from Lycoris radiata and Their Cytotoxicity. AB - Four new Amaryllidaceae alkaloids, named lycoranines C-F (1-4), together with seven known ones (5-11) were isolated from the bulbs of Lycoris radiata. Their structures with absolute configurations were elucidated by nuclear magnetic resonance, high-resolution electrospray ionization mass spectrometry, circular dichroism spectra, modified Mosher's method, and molecular modeling calculation. Compounds 6, 7, 10, and 11 exhibited a potent inhibitory effect on A549 and LoVo cells with IC50 values ranging from 3.97 +/- 0.36 to 17.37 +/- 1.57 uM. PMID- 26252828 TI - Seco-ursane-type Triterpenoids from Salvia urmiensis with Apoptosis-inducing Activity. AB - Fractionation of an acetone extract of the aerial parts of Salvia urmiensis led to the isolation of a new (1) and a known (2) E-seco-ursane-type triterpenoid, together with four other known compounds. Their structures were established by 1D and 2D nuclear magnetic resonance as well as high-resolution electrospray ionization mass spectrometry. The effect of compounds 1 and 2 on cell viability of HeLa and HepG2 cells was investigated with the MTT assay. We also report the mechanism of action of compound 2 as a potential anticancer agent in HeLa cells. Bcl-2, Bax, and caspases signaling pathway expression in HeLa cells was analyzed. HeLa cells treated with compound 2 were assayed for the cleavage of poly-(ADP ribose)-polymerase and DNA fragmentation resulting in nuclear shrinkage. Taken together, these results suggest that treatment of HeLa cells with compound 2 can induce apoptosis by regulating Bcl-2 family members and by suppressing caspase cascade activation. PMID- 26252829 TI - Salviaolate Protects Rat Brain from Ischemia-Reperfusion Injury through Inhibition of NADPH Oxidase. AB - Salviaolate is a group of depside salts isolated from Danshen (a traditional Chinese herbal medicine), with >= 85 % of magnesium lithospermate B. This study aims to investigate whether salviaolate is able to protect the rat brain from ischemia/reperfusion injury and the underlying mechanisms. Rats were subjected to 2 h of cerebral ischemia and 24 h of reperfusion to establish an ischemia/reperfusion injury model. The neuroprotective effects of salviaolate at different dosages were evaluated. A dosage (25 mg/kg) was chosen to explore the neuroprotective mechanisms of salviaolate. Neurological function, infarct volume, cellular apoptosis, nicotinamide adenine dinucleotide phosphate-oxidase activity, and H2O2 content were measured. In a nerve cell model of hypoxia/reoxygenation injury, magnesium lithospermate B was applied. Cellular apoptosis, lactate dehydrogenase, nicotinamide adenine dinucleotide phosphate-oxidase activity, and H2O2 content were examined. Ischemia/reperfusion treatment significantly increased the neurological deficit score, infarct volume, and cellular apoptosis accompanied by the elevated nicotinamide adenine dinucleotide phosphate-oxidase activity and H2O2 content in the rat brains. Administration of salviaolate reduced ischemia/reperfusion-induced cerebral injury in a dose-dependent manner concomitant with a decrease in nicotinamide adenine dinucleotide phosphate oxidase activity and H2O2 production. Magnesium lithospermate B (20 mg/kg) and edaravone (6 mg/kg, the positive control) achieved the same beneficial effects as salviaolate did. In the cell experiments, the injury (indicated by apoptosis ratio and lactate dehydrogenase release), nicotinamide adenine dinucleotide phosphate-oxidase activity and H2O2 content were dramatically increased following hypoxia/reoxygenation, which were attenuated in the presence of magnesium lithospermate B (10(-5) M), VAS2870 (nicotinamide adenine dinucleotide phosphate oxidase inhibitor), or edaravone (10(-5) M). The results suggest that salviaolate is able to protect the brain from ischemia/reperfusion oxidative injury, which is related to the inhibition of nicotinamide adenine dinucleotide phosphate-oxidase and a reduction of reactive oxygen species production. PMID- 26252830 TI - Dihydrogoniothalamin, an Endothelium and NO-Dependent Vasodilator Drug Isolated from Aniba panurensis. AB - Dihydrogoniothalamin is a styrylpyrone isolated from the leaves of Aniba panurensis. The present work aimed at investigating the vasorelaxant activity of dihydrogoniothalamin and its underlying mechanism of action in the rat aorta. Dihydrogoniothalamin (0.01-100 uM) induced a concentration-dependent vasodilatation of aortas precontracted with phenylephrine. Endothelium removal or pretreatment of the preparation with NG nitro-L-arginine-methyl-ester abolished the vasodilator response for dihydrogoniothalamin. Pretreatment with calmidazolium did not affect the vasodilator response of dihydrogoniothalamin. On the other hand, wortmannin, a nonselective inhibitor of phosphatidylinositol 3 kinases, and protein kinase B inhibitor IV significantly shifted the concentration-response curve of dihydrogoniothalamin to the right and reduced its maximal effect. A nonselective antagonist of estrogen receptors, ICI 182,780, and a selective antagonist of estrogen receptor alpha, methyl-piperidino-pyrazole, were able to reduce the relaxation induced by dihydrogoniothalamin, but no effect was observed in the presence of the selective antagonists of estrogen receptor beta and G protein-coupled receptor 30, 4-[2-phenyl-5,7 bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP), and G-15, respectively. Dihydrogoniothalamin also increased the phosphorylation of the activation sites of endothelial nitric oxide synthase and protein kinase B. The present results led us to conclude that dihydrogoniothalamin is a vasodilator drug acting in an endothelium- and nitric oxide-dependent manner through a mechanism involving the activation of nitric oxide synthase via the phosphatidylinositol 3-kinase/protein kinase B pathway, partially by stimulation of estrogen receptor alpha. PMID- 26252831 TI - Efficacy and Mechanism of Action of Yiru Tiaojing Granule Against Hyperprolactinemia In Vitro and In Vivo. AB - Yiru Tiaojing Granule, a traditional Chinese medicine formula, is used to treat hyperprolactinemia. This study was conducted to evaluate the mechanism of action and pharmacological activity of Yiru Tiaojing Granule on prolactin secretion. The animal model of hyperprolactinemia was induced by metoclopramide. The dopamine D2 receptor in hyperprolactinemia rat models was analyzed by immunohistochemistry. The biochemical parameters, including a follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, testosterone, and prolactin, were measured by an enzyme-linked immunosorbent assay. Furthermore, the expression of prolactin and the dopamine D2 receptor was analyzed by Western blotting. The components in the Yiru Tiaojing Granule-medicated serum were assayed by liquid chromatography tandem mass spectrometry. The Yiru Tiaojing Granule significantly decreased the prolactin level in the hyperprolactinemia rat model, and increased the estradiol, luteinizing hormone, and progesterone levels. The high and medium doses of Yiru Tiaojing Granule reduced dopamine D2 receptor expression in the brain (p < 0.001) and produced a similar effect on bromocriptine (p < 0.001). Yiru Tiaojing Granule medicated serum reduced (p < 0.001) prolactin expression in MMQ cells in a concentration-dependent manner, but had no effects on GH3 cells. The level of the dopamine D2 receptor in MMQ cells was also increased dose-dependently (p < 0.05). In addition, the protein kinase A and cyclic adenosine monophosphate in MMQ cells were significantly attenuated dose-dependently by treatment with a high and medium dose of Yiru Tiaojing Granule-medicated serum (p < 0.05) and bromocriptine medicated serum (p < 0.01). The results suggested that Yiru Tiaojing Granule was effective against hyperprolactinemia, and the activation of the dopamine D2 receptor, which was related to the second messenger cyclic adenosine monophosphate and protein kinase A, might be the potential mechanism. PMID- 26252832 TI - The association between plasma thiol levels and left ventricular diastolic dysfunction in patient with hypertension. AB - The balance of oxidant and antioxidant status plays an important role in the left ventricular diastolic dysfunction (LVDD) in patients with hypertension (HT). Thiol is an important part of antioxidant system in the body. The aim of this study was to investigate the relationship between plasma thiol levels and LVDD in patients with HT. A total of 138 patients with newly diagnosed essential hypertensive and 20 age-gender matched subjects as control group enrolled in the study. After echocardiographic assessment, the hypertensive patients were divided into three groups: Group 1: without LVDD (n = 41); group 2: with LVDD grade 1 (n = 57); and group 3: with LVDD grade 2 (n = 40). Plasma thiol, lipid and glucose levels were measured in all subjects. Plasma thiol levels were significantly different between the groups (all of p < 0.05). While the lowest thiol level was in the group 3, the highest level was in the control group. The presence of LVDD was correlated with age, systolic and diastolic blood pressure, thiol levels, and history of coronary artery disease and hyperlipidemia (all of p < 0.05). Age and thiol were however independent predictors of LVDD in multivariate analyses (beta = 0.318, p < 0.001, and beta = - 0.314, p < 0.001, respectively). ROC-curve analysis revealed that thiol levels over 163 MUmol/L predict LVDD in hypertensive patients with 75% sensitivity and 70% specificity (AUC = 0.783; 95% CI: 0.714 0.852). Plasma thiol is an independent predictor for the presence of LVDD. This suggests that thiol plays a role in the pathogenesis of diastolic function. Increased thiol levels may provide protection against the development of diastolic dysfunction. PMID- 26252833 TI - Anatase-driven charge transfer involving a spin transition in cobalt iron cyanide nanostructures. AB - A charge transfer between Fe and Co in cobalt hexacyanoferrate has been observed for the first time by anatase doping. The charge transfer, which involves a spin transition at the Co site, is supported by high-resolution XANES spectra. EXAFS evidenced a consistent change (10%) of the Co-N first shell. PMID- 26252834 TI - Molecular characterization and follow-up of five CML patients with new BCR-ABL1 fusion transcripts. AB - We report five chronic myeloid leukaemia (CML) patients in whom we identified and characterized undescribed BCR-ABL1 fusion transcripts. We investigated the precise features of the molecular rearrangements and the minimal residual disease follow-up for these five patients. Three resulted from new rearrangements between the BCR and ABL1 sequences (the breakpoints being located within BCR exon 13 in two cases and within BCR exon 18 in one case). The other two cases revealed a complex e8-[ins]-a2 fusion transcript involving a third partner gene, PRDM12 and SPECC1L, respectively. Moreover, single nucleotide polymorphism-array analysis performed in the latter two cases showed copy number alterations shared by the two patients, thus identifying genes that were deleted during rearrangement and suggesting their potential role in CML pathogenesis. Interestingly, we highlight that the prognosis of alterations, such as the presence of an e8a2 transcript or the deletion of various genes, which have been controversial, may be definitively erased by the introduction of tyrosine kinase inhibitors (TKIs). PMID- 26252835 TI - The Relationship Between Postural Control and Self-Reported Engagement in Physical Activity in Young and Older Age. AB - Physical activity is known to have beneficial effects on a host of factors related to physical and mental health, and positively affects postural control. However, there is no agreement on which measures of postural control and to what extent they are dependent on the past and present physical activity in older adults. To answer this question we compared the postural performance in a 20-s quiet stance with eyes open on a Kistler force plate in 38 subjects, aged 60-92, who were formerly and are currently physically active (AA) with those who were always inactive (II) and those who were either formerly (AI) or are currently (IA) active. Results indicated that only current activity promoted better postural control while former activity was ineffective. Postural control in AA and IA was very similar and much better than in II and AI who, in contrast, displayed similarly deteriorated postural control. PMID- 26252836 TI - A [2+2+2]-Cyclotrimerization Approach to Selectively Substituted Fluorenes and Fluorenols, and Their Conversion to 9,9'-Spirobifluorenes. AB - Synthesis of selectively substituted fluorenes and fluorenols was achieved by using catalytic [2+2+2]cyclotrimerization. Various starting diynes were reacted with different alkynes in the presence of a catalytic amount of Wilkinson's catalyst (RhCl(PPh3)3) providing the compounds possessing the fluorene scaffold in good isolated yields. A set of four regioselectively substituted fluorenols was converted to the corresponding 9,9'-spirobifluorenes and their spectral characteristics were measured. PMID- 26252837 TI - A Comparison of Gluteus Maximus, Biceps Femoris, and Vastus Lateralis Electromyography Amplitude in the Parallel, Full, and Front Squat Variations in Resistance-Trained Females. AB - Front, full, and parallel squats are some of the most popular squat variations. The purpose of this investigation was to compare mean and peak electromyography (EMG) amplitude of the upper gluteus maximus, lower gluteus maximus, biceps femoris, and vastus lateralis of front, full, and parallel squats. Thirteen healthy women (age = 28.9 +/- 5.1 y; height = 164 +/- 6.3 cm; body mass = 58.2 +/ 6.4 kg) performed 10 repetitions of their estimated 10-repetition maximum of each respective variation. There were no statistical (P <= .05) differences between full, front, and parallel squats in any of the tested muscles. Given these findings, it can be concluded that the front, full, or parallel squat can be performed for similar EMG amplitudes. However, given the results of previous research, it is recommended that individuals use a full range of motion when squatting, assuming full range can be safely achieved, to promote more favorable training adaptations. Furthermore, despite requiring lighter loads, the front squat may provide a similar training stimulus to the back squat. PMID- 26252838 TI - NOTCH2 signaling confers immature morphology and aggressiveness in human hepatocellular carcinoma cells. AB - The NOTCH family of membranous receptors plays key roles during development and carcinogenesis. Since NOTCH2, yet not NOTCH1 has been shown essential for murine hepatogenesis, NOTCH2 rather than NOTCH1 may be more relevant to human hepatocarcinogenesis; however, no previous studies have supported this hypothesis. We therefore assessed the role of NOTCH2 in human hepatocellular carcinoma (HCC) by immunohistochemistry and cell culture. Immunohistochemically, 19% of primary HCCs showed nuclear staining for NOTCH2, indicating activated NOTCH2 signaling. NOTCH2-positive HCCs were on average in more advanced clinical stages, and exhibited more immature cellular morphology, i.e. higher nuclear cytoplasmic ratios and nuclear densities. Such features were not evident in NOTCH1-positive HCCs. In human HCC cell lines, abundant NOTCH2 expression was associated with anaplasia, represented by loss of E-cadherin. When NOTCH2 signaling was stably downregulated in HLF cells, an anaplastic HCC cell line, the cells were attenuated in potential for in vitro invasiveness and migration, as well as in vivo tumorigenicity accompanied by histological maturation. Generally, inverse results were obtained for a differentiated HCC cell line, Huh7, manipulated to overexpress activated NOTCH2. These findings suggested that the NOTCH2 signaling may confer aggressive behavior and immature morphology in human HCC cells. PMID- 26252839 TI - A genetic polymorphism (rs17251221) in the calcium-sensing receptor is associated with ovarian cancer susceptibility. AB - Calcium-sensing receptor (CaSR) is a G-protein- coupled receptor that senses blood calcium. In vivo, CaSR is required for normal epidermal differentiation by mediating calcium signaling. CaSR was confirmed to be a tumor suppressor in colon and breast cancer. The single-nucleotide polymorphism (SNP) rs17251221, located on the intron, is a genetic variation of the CaSR gene. We analyzed rs17251221 in ovarian cancer using an allelic discrimination assay. Cycling probes were used for genotyping 290 ovarian cancer patients and 312 age-matched cancer-free females. rs17251221 and clinicopathological characteristics of ovarian cancer were analyzed statistically. The AG and GG genotypes were confirmed to appear in fewer cancer cases than in controls and the genotype distribution between cases and controls was statistically significant. The AG+GG genotype was correlated with low ovarian cancer risk, while rs17251221 was not associated with clinicopathological variables including age at diagnosis, tumor size, histologic type, pathological subtype, lymph node metastasis, CA-125 expression, clinical stage, or degree of differentiation. The rs17251221 polymorphism genotype was not correlated with survival in ovarian cancer. These results suggest that the G allele of the CaSR rs17251221 polymorphism is protective against ovarian cancer and the homozygous GG genotype may be a protective genotype as well. The rs17251221 may play an important role in the development of ovarian cancer and could be used as a biomarker for predicting ovarian cancer. PMID- 26252840 TI - Remarkably enhanced red-NIR broad spectral absorption via gold nanoparticles: applications for organic photosensitive diodes. AB - For organic films, remarkably enhanced red-NIR broad spectral absorption was achieved via the incorporation of gold nanoparticles (AuNPs) using a simple and facile preparation. The relevant thermal evaporation method has produced size controllable AuNPs in the range of 0-20 nm diameter. The potential use of localized surface plasmon resonance (LSPR) enhanced organic photosensitive diodes (OPDs) as sensitive broadband sensors was discussed in this context. Here we showed that, by combining organic heterojunctions with size-controllable plasmonic AuNPs, the efficiency of organic photodetectors could be increased by up to one order of magnitude, because of LSPR and scattering effects of the AuNPs. Fabricated OPD devices showed a large photoresponse under radiation from wavelengths between 650 and 830 nm, accompanied by a low power consumption profile. A schematic energy level model combined with theoretical simulation analysis was proposed to explain the experimental data. More importantly, to the best of our knowledge, this work demonstrated the broadest photosensitivity with high responsivity from AuNP-based photodetectors, proving the potential of AuNPs as a promising material for efficient optoelectronic devices. PMID- 26252841 TI - Enantioselective Synthesis of 3,3-Disubstituted Oxindoles Bearing Two Different Heteroatoms at the C3 Position by Organocatalyzed Sulfenylation and Selenenylation of 3-Pyrrolyl-oxindoles. AB - Catalytic asymmetric sulfenylation and selenenylation of 3-pyrrolyl-oxindoles for the synthesis of 3,3-disubstituted oxindoles bearing two different heteroatoms at the C3 position have been achieved with commercially available cinchonidine as catalyst. A wide range of optically active 3-thio-3-pyrrolyl-oxindoles and 3 seleno-3-pyrrolyl-oxindoles could be smoothly obtained under mild conditions with satisfactory results. The promising applicability of the protocol was also demonstrated by large-scale production. PMID- 26252843 TI - Increased Lymph Node Yield Is Associated With Improved Survival in Rectal Cancer Irrespective of Neoadjuvant Treatment: Results From a National Cohort Study. AB - BACKGROUND: It has been proposed that the lymph node yield achieved during rectal cancer resection is associated with survival. It is debated whether a high lymph node yield improves survival, per se, or whether it does so by diminishing the International Union Against Cancer stage drifting effect. OBJECTIVE: The purpose of this study was to evaluate the prognostic implications of the lymph node yield in curative resected rectal cancer. DESIGN: This study was based on data from a prospectively maintained colorectal cancer database. SETTINGS: This was a national cohort study. PATIENTS: All 6793 patients in Denmark who were diagnosed with International Union Against Cancer stage I to III adenocarcinoma of the rectum and so treated in the period from 2003 to 2011 were included in the analysis. MAIN OUTCOME MEASURES: The primary outcome measure was overall survival. RESULTS: The observed percentages of patients with International Union Against Cancer stage III disease with a lymph node yield less than 12 or 12 or more were 28.1 % and 40.7% (p < 0.0001) in the non-neoadjuvant treatment group and 26.9% and 38.3% (p < 0.0001) in the neoadjuvant treatment group. The 5-year overall survival rates for patients with a lymph node yield <12 or 12 or more were 73.1% and 80.6% in International Union Against Cancer stages I to II (p < 0.0001) and 57.4% and 53.3% in stage III (p < 0.142) in the neoadjuvant treatment group and 70.4% and 79.2% in stages I to II (p < 0.0001) and 46.6% and 59.1% in International Union Against Cancer stage III (p < 0.0001) in the non-neoadjuvant treatment group. In multivariate analysis, the lymph node yield turned out to be an independent prognostic factor, irrespective of neoadjuvant treatment. LIMITATIONS: It is not possible in an observational study to tell whether the findings are associations rather than causal relationships. CONCLUSIONS: Increased lymph node yield was associated with better overall survival in rectal cancer, irrespective of neoadjuvant treatment. Stage migration was observed. PMID- 26252842 TI - Novel therapy for locally advanced triple-negative breast cancer. AB - To evaluate a novel therapy for triple-negative breast cancer (TNBC), the biological responses to vitamin K3 (VK3) should be considered with the understanding of the features of breast cancer. In human breast cancer cell lines, the effects of VK3 on cell growth inhibition and the cellular signaling pathway were determined by MTT assay and western blotting. In the in vivo study, a subcutaneous tumor model of breast cancer was created, VK3 was injected into the subcutaneous tumors, and tumor size was measured. The IC50 of VK3 for breast cancer cells was calculated to be 11.3-25.1 uM. VK3 induced phosphorylation of whole tyrosine and epidermal growth factor receptor. VK3 mediated phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) for 30 min. ERK but not JNK phosphorylation was maintained for at least 6 h. In contrast, another antioxidant agent, catalase, showed no effect on either ERK phosphorylation or growth inhibition. On built-up tumors under the skin of mice, local treatment with VK3 was effective in a time- and dose-dependent manner, and the experiments for total tumor volume also showed a dose-dependent effect of VK3. The expression of phosphorylated ERK was clearly detected at 10.9 times the control in tumor tissue, whereas ethanol itself showed no effect. In conclusion, ERK plays a critical role in VK3-induced growth inhibition, and it will be the focus of next steps in the development of molecular therapy for TNBC. PMID- 26252844 TI - Difference in Time to Locoregional Recurrence Between Patients With Right-Sided and Left-Sided Colon Cancers. AB - BACKGROUND: Locoregional recurrence rates after curative resection for colon cancer vary widely. Identification of factors associated with locoregional recurrence may help in patient management. OBJECTIVE: The purpose of this study was to compare time to locoregional recurrence and distribution of locoregional recurrence after curative resection of colon cancer according to primary tumor location and to investigate risk factors for locoregional recurrence of colon cancer. DESIGN: This was a retrospective observational study. SETTINGS: This study was conducted at a single institution. PATIENTS: This study analyzed 1632 patients with colonic adenocarcinoma without distant metastasis who underwent curative resection at the National Cancer Center in Korea between January 2001 and December 2009. The primary end point of the study was time from surgery to locoregional recurrence. The Kaplan-Meier method was used to estimate the cumulative incidence of locoregional recurrence, and the log-rank test was used to test the difference in time to locoregional recurrence between patient subgroups. Cox proportional hazards models were used to investigate the risk factors for locoregional recurrence. MAIN OUTCOME MEASURES: The time from surgery to locoregional recurrence was compared between patients with right-sided and left-sided colon cancers. RESULTS: The time to locoregional recurrence was significantly different between patients with right-sided and left-sided colon cancers (HR = 2.35 for right-sided; p < 0.001). The overall 5-year locoregional recurrence rate was 5.7%, and that in patients with right-sided and left-sided colon cancers was 8.5% and 4.1%. Multivariable analysis demonstrated that right sided location, female sex, T4 disease, lymph node metastasis, and perineural invasion were independent risk factors for locoregional recurrence of colon cancer. LIMITATIONS: This was a retrospective design and single-institution study. CONCLUSIONS: Patients with right-sided colon cancers presented with significantly increased risk of locoregional recurrence. Right-sided location, female sex, T4 disease, lymph node metastasis, and perineural invasion are independent risk factors for locoregional recurrence of colon cancer. PMID- 26252845 TI - Improving Quality of Life for People with Incurable Large-Bowel Obstruction: Randomized Control Trial of Colonic Stent Insertion. AB - BACKGROUND: Surgery remains the dominant treatment for large-bowel obstruction, with emerging data on self-expanding metallic stents. OBJECTIVE: The aim of this study was to assess whether stent insertion improves quality of life and survival in comparison with surgical decompression. DESIGN: This study reports on a randomized control trial (registry number ACTRN012606000199516). SETTING: This study was conducted at Royal Prince Alfred Hospital, Sydney, and Western Hospital, Melbourne. PATIENTS AND INTERVENTION: Patients with malignant incurable large-bowel obstruction were randomly assigned to surgical decompression or stent insertion. MAIN OUTCOME MEASURES: The primary end point was differences in EuroQOL EQ-5D quality of life. Secondary end points included overall survival, 30 day mortality, stoma rates, postoperative recovery, complications, and readmissions. RESULTS: Fifty-two patients of 58 needed to reach the calculated sample size were evaluated. Stent insertion was successful in 19 of 26 (73%) patients. The remaining 7 patients required a stoma compared with 24 of 26 (92%) surgery group patients (p < 0.001). There were no stent-related perforations or deaths. The surgery group had significantly reduced quality of life compared with the stent group from baseline to 1 and 2 weeks (p = 0.001 and p = 0.012), and from baseline to 12 months (p = 0.01) in favor of the stent group, whereas both reported reduced quality of life. The stent group had an 8% 30-day mortality compared with 15% for the surgery group (p = 0.668). Median survival was 5.2 and 5.5 months for the groups (p = 0.613). The stent group had significantly reduced procedure time (p = 0.014), postprocedure stay (p = 0.027), days nothing by mouth (p = 0.002), and days before free access to solids (p = 0.022). LIMITATIONS: This study was limited by the lack of an EQ-5D Australian-based population set. CONCLUSIONS: Stent use in patients with incurable large-bowel obstruction has a number of advantages with faster return to diet, decreased stoma rates, reduced postprocedure stay, and some quality-of-life benefits. PMID- 26252847 TI - Assessment of the Quality of Patient-Orientated Information on Surgery for Crohn's Disease on the Internet. AB - BACKGROUND: The Internet is a vast resource for patients to search for health information on the treatment of Crohn's disease. OBJECTIVE: This study examines the quality of Web sites that provide information to adults regarding Crohn's disease, including treatment options and surgery. DESIGN: Two search engines (Google and Yahoo) and the search terms "surgery for Crohn's disease" were used. The first 50 sites of each search were assessed. Sites that fulfilled the inclusion criteria were evaluated for content and scored by using the DISCERN instrument, which evaluates the quality of health information on treatment choices. RESULTS: One hundred sites were examined, of which 13 were duplicates. Sixty-two sites provided patient-orientated information. The other sites included 7 scientific articles, 3 blogs, 2 links, 6 forums, 3 video links, and 4 dead links. Of the 62 Web sites that provided patient information for adults, only 15 (24.2%) had been updated within the past 2 years. Only 9 (14.5%) were affiliated with hospitals and clinics. The majority of sites (33, 53.2%) were associated with private companies with commercial interests. Only half of the Web sites provided details on treatment options, and most Web sites did not provide any information on symptoms and procedure details. Just 5 Web sites (8.1%) described the risks of surgery, and only 7 (11.3%) provided any information on the timescale for recovery. Overall, only 1 Web site (1.6%) was identified as being "good" or "excellent" with the use of the DISCERN criteria. LIMITATIONS: Although the internet is constantly evolving, this study captures data at a specific time point. Search results may vary depending on geographical location. This study only assessed English language websites. CONCLUSIONS: The quality of patient information on surgery for Crohn's disease is highly variable and generally poor. There is potential for the Internet to provide valuable information, and clinicians should identify high-quality Web sites to guide their patients. PMID- 26252846 TI - Outcomes After En Bloc Iliac Vessel Excision and Reconstruction During Pelvic Exenteration. AB - BACKGROUND: Advanced pelvic cancers involving the lateral pelvic compartment, and particularly the iliac vasculature, are difficult to manage. Common or external iliac vessel involvement has traditionally been considered a contraindication for curative surgery. OBJECTIVE: The purpose of this study was to investigate pathological and surgical outcomes, particularly postoperative morbidity of pelvic exenteration with en bloc major iliac vascular excision and reconstruction. DESIGN: This study was a case series. SETTINGS: The study was conducted at a quaternary referral center for pelvic exenteration in Sydney. PATIENTS: Patients included those undergoing en bloc iliac vessel excision as part of their pelvic exenteration for a locally advanced pelvic malignancy. MAIN OUTCOME MEASURES: Over the study period, 336 patients underwent pelvic exenteration. Twenty-one patients (6.3%) underwent en bloc vascular excision of 29 vessels for tumor involvement. Twenty-four vessels required reconstruction. The primary outcomes were postoperative complications and pathologic outcomes. Survival rates were estimated using the Kaplan-Meier technique. RESULTS: Operating time for patients who underwent vascular excision and reconstruction was longer, but this did not reach significance (631 vs 531 minutes; p = 0.052). Mean blood loss was significantly higher in the vascular excision and reconstruction group (6.8 vs 3.4 L; p < 0.001). Patients who required en bloc vascular excision were less likely to have R0 margins compared with patients who did not (38% vs 78%; p < 0.001). There was no intraoperative or 30-day mortality. Overall graft patency and limb loss at 1 year were 96% and 0%. A total of 52% of patients had at least 1 vascular related complication. Median overall and disease free survival times were 34 and 26 months. LIMITATIONS: This study is limited by a relatively small number of heterogeneous patients. CONCLUSIONS: En bloc vascular resection and reconstruction for contiguous tumor involvement is feasible and safe in selected patients. Advanced pelvic tumors involving iliac vessels should not be precluded from curative surgery in specialized institutions. PMID- 26252848 TI - Single-Site Laparoscopic Colorectal Surgery Provides Similar Clinical Outcomes Compared With Standard Laparoscopic Surgery: An Analysis of 626 Patients. AB - BACKGROUND: Compared with standard laparoscopy, single-site laparoscopic colorectal surgery may potentially offer advantages by creating fewer surgical incisions and providing a multifunctional trocar. Previous comparisons, however, have been limited by small sample sizes and selection bias. OBJECTIVE: The purpose of this study was to compare 60-day outcomes between standard laparoscopic and single-site laparoscopic colorectal surgery patients undergoing elective and urgent surgeries. DESIGN: This was an unselected, retrospective cohort study comparing patients who underwent elective and unplanned standard laparoscopic or single-site laparoscopic colorectal resections for benign and malignant disease between 2008 and 2014. Outcomes were compared using univariate analyses. SETTINGS: This study was conducted at a single institution. PATIENTS: A total of 626 consecutive patients undergoing laparoscopic colorectal surgery were included. MAIN OUTCOME MEASURES: Morbidity and mortality rates within 60 postoperative days were measured. RESULTS: A total of 318 (51%) and 308 patients (49%) underwent standard laparoscopic and single-site laparoscopic procedures. No significant differences were noted in mean operative time (standard laparoscopy, 182.1 +/- 81.3 vs single-site laparoscopy, 177.0 +/- 86.5; p = 0.30) or postoperative length of stay (standard laparoscopy, 4.8 +/- 3.4 vs single-site laparoscopy, 5.5 +/- 6.9; p = 0.14). Conversions to laparotomy and 60-day readmissions were also similar for both cohorts across all of the procedures performed. A significant difference was identified in the number of patients who developed postoperative complications (standard laparoscopy, 19.2% vs single-site laparoscopy, 10.7%; p = 0.004), especially with respect to surgical-site infections (standard laparoscopy, 11.3% vs single-site laparoscopy, 5.8%; p = 0.02). LIMITATIONS: This was a retrospective, single institution study. CONCLUSIONS: Single-site laparoscopic colorectal surgery demonstrates similar results to standard laparoscopic colorectal surgery with regard to operative time, length of stay, and readmissions. Single-site laparoscopic colorectal surgery may provide advantages in limiting the development of certain complications, such as superficial surgical-site infections. PMID- 26252849 TI - Nonsteroidal Anti-inflammatory Drugs: Do They Increase the Risk of Anastomotic Leaks Following Colorectal Operations? AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs have become an important component of narcotic-sparing postoperative pain management protocols. However, conflicting evidence exists regarding the adverse association of nonsteroidal anti-inflammatory drug use with intestinal anastomotic healing in colorectal surgery. OBJECTIVE: This study compares patients receiving nonsteroidal anti inflammatory drugs on postoperative day 1 with patients who did not receive nonsteroidal anti-inflammatory drugs with regard to the occurrence of anastomotic leaks. DESIGN: This is a retrospective study from a protocol-driven prospectively collected statewide database. A propensity score model was used to adjust for differences between the groups in patient demographics, characteristics, comorbidities, and laboratory values. SETTINGS: The multicenter data set used in this analysis represents a variety of academic and community hospitals within the state of Michigan from July 2012 through February 2014. PATIENTS: Nonpregnant patients over the age of 18 who underwent colon and rectal surgery with bowel anastomosis were selected. MAIN OUTCOME MEASURES: Occurrence of anastomotic leak, composite surgical site infection, sepsis, and death within 30 days of surgery were the primary outcomes measured. RESULTS: A total of 4360 patients met inclusion criteria, of which 1297 (29.7%) received nonsteroidal anti-inflammatory drugs and 3063 (70.3%) did not receive nonsteroidal anti-inflammatory drugs. There was no statistically significant difference between the 2 groups in the proportion of cases with anastomotic leak (OR, 1.33; CI, 0.86-2.05; p = 0.20), composite surgical site infection (OR, 1.26; CI, 0.96-1.66; p = 0.09), or death within 30 days (OR, 0.58; CI, 0.28-1.19; p = 0.14). There was a significantly greater risk of sepsis for patients given nonsteroidal anti-inflammatory drugs than for those patients not given nonsteroidal anti-inflammatory drugs (OR, 1.47; CI, 1.05-2.06; p = 0.03). LIMITATIONS: This is a nonrandomized study performed retrospectively, and it is based on data collected only within a subset of hospitals in the state of Michigan. CONCLUSIONS: No statistically significant increase in the proportion of patients with anastomotic leak was observed when prescribing nonsteroidal anti-inflammatory drugs for analgesia in the early postoperative period for patients undergoing elective colorectal surgery. Unexpectedly, there was an increased risk of sepsis that warrants further investigation (see video, Supplemental Digital Content 1, http://links.lww.com/DCR/A192, for a synopsis of this study). PMID- 26252850 TI - Spin Is Common in Studies Assessing Robotic Colorectal Surgery: An Assessment of Reporting and Interpretation of Study Results. AB - BACKGROUND: Spin has been defined previously as "specific reporting that could distort the interpretation of results and mislead readers." OBJECTIVE: The purpose of this study was to determine the frequency and extent of misrepresentation of results in robotic colorectal surgery. DATA SOURCES: Publications referenced in MEDLINE or EMBASE between 1992 and 2014 were included in this study. STUDY SELECTION: Studies comparing robotic colorectal surgery with other techniques with a nonsignificant difference in the primary outcome(s) were included. INTERVENTIONS: Interventions included robotic versus alternative techniques. MAIN OUTCOME MEASURES: Frequency, strategy, and extent of spin, as previously defined, were the main outcome measures RESULTS: : A total of 38 studies (including 24,303 patients) were identified for inclusion in this study. Evidence of spin was found in 82% of studies. The most common form of spin was concluding equivalence between surgical techniques based on nonsignificant differences (76% of abstracts and 71% of conclusions). Claiming improved benefits, despite nonsignificance, was also commonly observed (26% of abstracts and 45% of conclusions). Because of the small sample size, we did not find evidence of an association between spin and study design, type of funding, publication year, or study size. Acknowledging the equivocal nature of the study happened rarely (47% of abstracts and 34% of conclusions). The absence of spin predicted whether authors acknowledged equivocal results (p = 0.02). A total of 50% of studies did not disclose whether they received funding, whereas 39% of studies failed to state whether a conflict of interest existed. LIMITATIONS: A limited number of randomized controlled trials were available. CONCLUSIONS: Spin occurred in >80% of included studies. Many studies concluded that robotic surgery was as safe as more traditional techniques, despite small sample sizes and limited follow-up. Authors often failed to recognize the difference between nonsignificance and equivalence. Failure to disclose financial relationships, which could represent potential conflict(s) of interest, is concerning. Readers of these articles need to be critical of author conclusions, and publishers should ensure that conclusions correspond with the study methods and results. PMID- 26252851 TI - Dynamic Article: Tandem Robotic Technique of Extralevator Abdominoperineal Excision and Rectus Abdominis Muscle Harvest for Immediate Closure of the Pelvic Floor Defect. AB - BACKGROUND: Extralevator abdominoperineal excision for distal rectal cancers involves cylindrical excision of the mesorectum with wide division of the levator ani muscles. Although this technique has been shown to decrease local cancer recurrence and improve survival, it leaves the patient with a considerable pelvic floor defect that may require reconstruction. OBJECTIVE: We developed an innovative technique of robotic extralevator abdominoperineal excision combined with robotic harvest of the rectus abdominis muscle flap for immediate reconstruction of the pelvic floor defect. DESIGN: This was a retrospective review pilot study. SETTING: This study was conducted at a tertiary care cancer center. PATIENTS: Three patients who underwent robotic extralevator abdominoperineal excision with robotic rectus abdominis flap harvest for distal rectal adenocarcinoma were included. MAIN OUTCOMES MEASURES: Intraoperative and postoperative outcomes included operative time, intraoperative complications, length of hospital stay, wound complications, incidence of perineal hernia, persistent pain, and functional limitations. RESULTS: Three patients underwent this procedure. The median operative time was 522 minutes with median hospital stay of 6 days. One patient experienced perineal wound complication requiring limited incision and drainage followed by complete healing of the wound by secondary intention. The other 2 patients did not experience any wound complications. Longest follow-up was 16 months. None of the patients developed perineal hernias during this time period. LIMITATIONS: The small sample size and retrospective nature were limitations. CONCLUSIONS: This technique confers multiple advantages including improved visualization and dexterity within the pelvis and accurate wide margins at the pelvic floor. An incisionless robotic flap harvest with preservation of the anterior rectus sheath obviates the risk of ventral hernia while providing robust tissue closure of the radiated abdominoperineal excision wound. This technique may result in faster postoperative recovery, decreased morbidity, improved functional outcomes and cosmesis. Further studies are needed to prospectively analyze this approach (Supplemental Digital Content 1, video abstract, http://links.lww.com/DCR/A188). PMID- 26252852 TI - Evaluation of an Anal Insert Device for the Conservative Management of Fecal Incontinence. AB - BACKGROUND: Management of fecal incontinence remains challenging owing to the limited availability of consistently safe, effective, and/or tolerable treatment options. OBJECTIVE: The aim of this study was to evaluate the efficacy, safety, and tolerability of an anal insert device for the conservative management of fecal incontinence. DESIGN: This is a multicenter, prospective, open-label study of a single-arm cohort. SETTING: Patients were recruited between November 2009 and June 2011 from 3 US clinical sites. PATIENTS: Subjects who were >=18 years old with incontinence severity scores >=12 of 20, and at least weekly leakage of solid and/or liquid stool, were selected. INTERVENTIONS: Patients underwent 12 weeks of continuous anal insert device use. MAIN OUTCOME MEASURES: The primary outcomes measured were bowel diaries, incontinence severity, satisfaction, and adverse events. The percentage of reduction in leakage frequency and severity was assessed weekly. Sample size calculations predicted that 47 subjects would demonstrate that 70% of subjects would have >=50% reduction of incontinence frequency. The paired t test and Wilcoxon tests were used as appropriate. RESULTS: Seventy-seven percent of the 73 completers and 62% of the 91 intent-to treat subjects achieved a >=50% reduction in incontinence frequency. Median fecal incontinence frequency was reduced by 82% from 0.9 (mean 1.1 +/- 0.9) at baseline to 0.2 (mean 0.3 +/- 0.4) episodes of leakage per day at 12 weeks (p < 0.001). Mean fecal incontinence severity scores improved by 32.4% (16.2, +/-2.1 vs 10.9, +/-4.4 of 20, p < 0.001) and 78% of completers were very or extremely satisfied with the device with no serious adverse events related to device use. LIMITATIONS: This study was limited by the nonvalidated modification of the severity score and the lack of randomization, control comparison group, blinded assessments, and quality-of-life measures. CONCLUSIONS: The anal insert device provides a conservative, safe, and effective management strategy for individuals with fecal incontinence, with high patient satisfaction and low adverse event rates. PMID- 26252853 TI - Quality of Life After Total Proctocolectomy With Ileostomy or IPAA: A Systematic Review. AB - BACKGROUND: The standard surgical treatment for ulcerative colitis involves either a total proctocolectomy and end ileostomy or an IPAA. Both treatments result in similar control of disease but differ in terms of patient experience and daily functioning. OBJECTIVE: The aim of this systematic review was to determine whether one surgical approach was superior with regard to health related quality of life. DATA SOURCES: An electronic literature search of PubMed, MEDLINE, EMBASE, and the Cochrane Database of Collected Reviews was performed for dates from 1978 to 2014. The search included the following terms: "inflammatory bowel disease," "colitis," "colectomy," and "ileal pouch-anal anastomosis." STUDY SELECTION: Studies were included if they reported on a comparison of total proctocolectomy and end ileostomy with an IPAA and evaluated some aspect of quality of life. INTERVENTION(S): All of the studies were systematically reviewed. No meta-analysis was performed secondary to significant heterogeneity across studies in different health-related quality-of-life measures. MAIN OUTCOME MEASURES: End points were a mixture of global, generic, and disease-specific measures of quality of life. RESULTS: Thirteen studies reporting a total of 1604 patients who underwent total proctocolectomy with ileostomy (N = 820) or IPAA (N = 783) were included for review. Neither procedure was found to be clearly superior with regard to health-related quality of life. LIMITATIONS: The conclusions of this review were limited by small study sample size, significant between-study heterogeneity, observational designs, and limited follow-up. CONCLUSIONS: Despite being limited by poor study quality, both total proctocolectomy with ileostomy and IPAA appear equivalent in terms of overall health-related quality of life. Most patients are satisfied with their choice regardless of procedure. Most of the improvement in quality of life after surgery is related to the control of disease-related symptoms. These findings indicate that both IPAA and permanent ileostomy should be discussed in detail with patients preoperatively to help them make an informed decision. PMID- 26252854 TI - The Drive Toward Transanal Total Mesorectal Excision - Science or Rhetoric? PMID- 26252855 TI - The Rationale for Transanal Total Mesorectal Excision. PMID- 26252856 TI - Comment on Kennelly et al: Time to Rethink ELAPE? PMID- 26252861 TI - A real-time computational model for estimating kinematics of ankle ligaments. AB - BACKGROUND: An accurate assessment of ankle ligament kinematics is crucial in understanding the injury mechanisms and can help to improve the treatment of an injured ankle, especially when used in conjunction with robot-assisted therapy. A number of computational models have been developed and validated for assessing the kinematics of ankle ligaments. However, few of them can do real-time assessment to allow for an input into robotic rehabilitation programs. METHOD: An ankle computational model was proposed and validated to quantify the kinematics of ankle ligaments as the foot moves in real-time. This model consists of three bone segments with three rotational degrees of freedom (DOFs) and 12 ankle ligaments. This model uses inputs for three position variables that can be measured from sensors in many ankle robotic devices that detect postures within the foot-ankle environment and outputs the kinematics of ankle ligaments. Validation of this model in terms of ligament length and strain was conducted by comparing it with published data on cadaver anatomy and magnetic resonance imaging. RESULTS: The model based on ligament lengths and strains is in concurrence with those from the published studies but is sensitive to ligament attachment positions. CONCLUSIONS: This ankle computational model has the potential to be used in robot-assisted therapy for real-time assessment of ligament kinematics. The results provide information regarding the quantification of kinematics associated with ankle ligaments related to the disability level and can be used for optimizing the robotic training trajectory. PMID- 26252859 TI - One-Pot Catalytic Asymmetric Synthesis of Tetrahydrocarbazoles. AB - A one-pot asymmetric synthesis of 1,2,3,4-tetrahydrocarbazoles has been developed via an enantioselective [3 + 3] annulation of 2-alkynylindoles and donor-acceptor cyclopropanes. In the presence of chiral Lewis acids as catalysts, a series of optically active tetrahydrocarbazoles were furnished in high yields (63-87%) with good to excellent levels of enantioselectivity (up to 94% ee). PMID- 26252862 TI - Hepatoma-derived growth factor-2 is highly expressed during development and in spinal cord injury. AB - Hepatoma-derived growth factor-2 (HDGF-2) is expressed in neurons, astrocytes and oligodendrocytes of the adult mouse brain. However, it has remained elusive whether HDGF-2 is expressed in the spinal cord and is involved in the its development and repair. In the present study, the expression of HDGF-2 was investigated in rat spinal cords at different developmental stages and following spinal cord injury (SCI). Protein levels of HDGF-2 were examined using western blot analysis, while the distribution pattern and cell populations of HDGF-2 protein expression were characterized using immunohistochemistry. Western blot analysis demonstrated that the levels of HDGF-2 protein expression were the greatest in the spinal cord on embryonic day 19, and were also highly expressed in rat spinal cords on post-natal day 7 (P7); however, they were low at P14 and not detectable at two months. HDGF-2 expression was significantly upregulated in the embryonic spinal cord and injured spinal cord. By contrast, the expression of HDGF-2 was low in uninjured adult spinal cords. HDGF-2 expression in the fetal rat spinal cord and injured spinal cord was significantly higher than that in uninjured adult spinal cord tissues (P<0.05). The number of cells positive for HDGF-2 was 141+/-62, 107+/-33 and 92+/-18 at days 1, 21 and 45 following SCI, respectively, as opposed to 50+/-9 in uninjured rats, and a significant difference was identified between the different time-points following SCI (P<0.01). In conclusion, the overexpression of HDGF-2 in the embryonic spinal cord and injured spinal cord may be involved in fetal spinal cord development and repair of SCI, respectively. PMID- 26252863 TI - Correction to Characterization of Particulate Matter Emissions from a Current Technology Natural Gas Engine. PMID- 26252864 TI - The influence of ageism, experience, and relationships with older adults on physical therapy students' perception of geriatrics. AB - INTRODUCTION: Increased exposure to geriatrics throughout a student's professional education has been reported to improve the desire to work in this area; however, factors that influence the perception of geriatric physical therapy may prohibit students from actively seeking those experiences. PURPOSE: The purpose of this study was to examine the perceptions of geriatric physical therapy by first-year graduate physical therapy students. DESIGN: A qualitative case study research approach was performed. METHOD: Three focus groups were completed using students enrolled in their second semester of a graduate-level physical therapy program. Dialogue was reviewed and coded by three raters. Twenty five subcategories of open-coding terms were triangulated and grouped into 4 themes via axial coding. RESULTS: Four themes emerged: (1) ageism exists in health care, (2) personal and professional experiences serve as a framework for students' perception of geriatrics, (3) interpersonal relationships formed within geriatric practice are highly valued, and (4) additional contextual barriers exist in geriatrics. CONCLUSIONS: To meet the needs of a highly skilled geriatric workforce, students should participate in enhanced geriatric experiences in didactic coursework as well as within interprofessional geriatric clinics throughout their education. PMID- 26252866 TI - High-Intensity Telemedicine Decreases Emergency Department Use by Senior Living Community Residents. AB - BACKGROUND: The failure to provide timely acute illness care can lead to adverse consequences or emergency department (ED) use. We evaluated the effect on ED use of a high-intensity telemedicine program that provides acute illness care for senior living community (SLC) residents. MATERIALS AND METHODS: We performed a prospective cohort study over 3.5 years. Six SLCs cared for by a primary care geriatrics practice were intervention facilities, with the remaining 16 being controls. Consenting patients at intervention facilities could access telemedicine for acute illness care. Patients were provided patient-to-provider, real-time, or store-and-forward high-intensity telemedicine (i.e., technician assisted with resources beyond simple videoconferencing) to diagnose and treat acute illnesses. The primary outcome was the rate of ED use. RESULTS: We enrolled 494 of 705 (70.1%) subjects/proxies in the intervention group; 1,058 subjects served as controls. Control and intervention subjects visited the ED 2,238 and 725 times, respectively, with 47.3% of control and 43.4% of intervention group visits resulting in discharge home. Among intervention subjects, ED use decreased at an annualized rate of 18% (rate ratio [RR]=0.82; 95% confidence interval [CI], 0.70-0.95), whereas in the control group there was no statistically significant change in ED use (RR=1.01; 95% CI, 0.95-1.07; p=0.009 for group-by-time interaction). Primary care use and mortality were not significantly different. CONCLUSIONS: High-intensity telemedicine significantly reduced ED use among SLC residents without increasing other utilization or mortality. This alternative to traditional acute illness care can enhance access to acute illness care and should be integrated into population health programs. PMID- 26252865 TI - Antileukemic Efficacy of Continuous vs Discontinuous Dexamethasone in Murine Models of Acute Lymphoblastic Leukemia. AB - Osteonecrosis is one of the most common, serious, toxicities resulting from the treatment of acute lymphoblastic leukemia. In recent years, pediatric acute lymphoblastic leukemia clinical trials have used discontinuous rather than continuous dosing of dexamethasone in an effort to reduce the incidence of osteonecrosis. However, it is not known whether discontinuous dosing would compromise antileukemic efficacy of glucocorticoids. Therefore, we tested the efficacy of discontinuous dexamethasone against continuous dexamethasone in murine models bearing human acute lymphoblastic leukemia xenografts (n = 8 patient samples) or murine BCR-ABL+ acute lymphoblastic leukemia. Plasma dexamethasone concentrations (7.9 to 212 nM) were similar to those achieved in children with acute lymphoblastic leukemia using conventional dosages. The median leukemia-free survival ranged from 16 to 59 days; dexamethasone prolonged survival from a median of 4 to 129 days in all seven dexamethasone-sensitive acute lymphoblastic leukemias. In the majority of cases (7 of 8 xenografts and the murine BCR-ABL model) we demonstrated equal efficacy of the two dexamethasone dosing regimens; whereas for one acute lymphoblastic leukemia sample, the discontinuous regimen yielded inferior antileukemic efficacy (log-rank p = 0.002). Our results support the clinical practice of using discontinuous rather than continuous dexamethasone dosing in patients with acute lymphoblastic leukemia. PMID- 26252867 TI - Two-Dimensional Superlattices of Bi Nanoclusters Formed on a Au(111) Surface Using Porous Supramolecular Templates. AB - We used porous supramolecular structures as templates to make two-dimensional (2D) superlattices of Bi nanoclusters on a Au(111) surface. First, we applied on surface self-assembly to prepare 2D porous supramolecular structures containing well-ordered nanopores. Then, we deposited Bi atoms on the surface. The Bi atoms were confined in the supramolecular pores and formed nanoclusters of a critical size that is defined by the pore size. These nanoclusters were arranged as a 2D superlattice dictated by the structure of the supramolecular templates. The nanocluster size and superlattice periodicity can be adjusted by appropriately designing the supramolecular structures. We further studied the formation mechanism of the nanoclusters. We found that Bi atoms could diffuse across the pore boundaries at room temperature and nucleated as clusters inside the pores. The clusters grew until they reached the critical size and became stable. We used kinetic Monte Carlo simulations to reproduce the experimental results and quantified the interpore diffusion barrier to be 0.65 eV. PMID- 26252868 TI - A Controlled Trial Using Natural Language Processing to Examine the Language of Suicidal Adolescents in the Emergency Department. AB - What adolescents say when they think about or attempt suicide influences the medical care they receive. Mental health professionals use teenagers' words, actions, and gestures to gain insight into their emotional state and to prescribe what they believe to be optimal care. This prescription is often inconsistent among caregivers, however, and leads to varying outcomes. This variation could be reduced by applying machine learning as an aid in clinical decision support. We designed a prospective clinical trial to test the hypothesis that machine learning methods can discriminate between the conversation of suicidal and nonsuicidal individuals. Using semisupervised machine learning methods, the conversations of 30 suicidal adolescents and 30 matched controls were recorded and analyzed. The results show that the machines accurately distinguished between suicidal and nonsuicidal teenagers. PMID- 26252869 TI - Quantum Chemical Molecular Dynamics Simulations of 1,3-Dichloropropene Combustion. AB - Oxidative decomposition of 1,3-dichloropropene was investigated using quantum chemical molecular dynamics (QM/MD) at 1500 and 3000 K. Thermal oxidation of 1,3 dichloropropene was initiated by (1) abstraction of allylic H/Cl by O2 and (2) intra-annular C-Cl bond scission and elimination of allylic Cl. A kinetic analysis shows that (2) is the more dominant initiation pathway, in agreement with QM/MD results. These QM/MD simulations reveal new routes to the formation of major products (H2O, CO, HCl, CO2), which are propagated primarily by the chloroperoxy (ClO2), OH, and 1,3-dichloropropene derived radicals. In particular, intra-annular C-C/C-H bond dissociation reactions of intermediate aldehydes/ketones are shown to play a dominant role in the formation of CO and CO2. Our simulations demonstrate that both combustion temperature and radical concentration can influence the product yield, however not the combustion mechanism. PMID- 26252870 TI - Ageing and the group-reference effect in memory. AB - The present study examines age differences in the memory benefits from group referncing. While prior work establishes that the memory performance of younger and older adults similarly benefits from relating information to the self, this study assessed whether those benefits extend to referencing a meaningful group membership. Young and older adult participants encoded trait words by judging whether each word describes themselves, describes their group membership (selected for each age group), or is familiar. After a retention interval, participants completed a surprise recognition memory test. The results indicate that group-referencing increased recognition memory performance compared to the familiarity judgements for both young and older groups. However, the group reference benefit is limited, emerging as smaller than the benefit from self referencing. These results challenge previous findings of equivalent benefits for group-referencing and self-referencing, suggesting that such effects may not prevail under all conditions, including for older adults. The findings also highlight the need to examine the mechanisms of group-referencing that can lead to variability in the group-reference effect. PMID- 26252871 TI - The Importance of Lateral Connections in the Parietal Cortex for Generating Motor Plans. AB - Substantial evidence has highlighted the significant role of associative brain areas, such as the posterior parietal cortex (PPC) in transforming multimodal sensory information into motor plans. However, little is known about how different sensory information, which can have different delays or be absent, combines to produce a motor plan, such as executing a reaching movement. To address these issues, we constructed four biologically plausible network architectures to simulate PPC: 1) feedforward from sensory input to the PPC to a motor output area, 2) feedforward with the addition of an efference copy from the motor area, 3) feedforward with the addition of lateral or recurrent connectivity across PPC neurons, and 4) feedforward plus efference copy, and lateral connections. Using an evolutionary strategy, the connectivity of these network architectures was evolved to execute visually guided movements, where the target stimulus provided visual input for the entirety of each trial. The models were then tested on a memory guided motor task, where the visual target disappeared after a short duration. Sensory input to the neural networks had sensory delays consistent with results from monkey studies. We found that lateral connections within the PPC resulted in smoother movements and were necessary for accurate movements in the absence of visual input. The addition of lateral connections resulted in velocity profiles consistent with those observed in human and non human primate visually guided studies of reaching, and allowed for smooth, rapid, and accurate movements under all conditions. In contrast, Feedforward or Feedback architectures were insufficient to overcome these challenges. Our results suggest that intrinsic lateral connections are critical for executing accurate, smooth motor plans. PMID- 26252873 TI - Zinc Oxide-Containing Porous Boron-Carbon-Nitrogen Sheets from Glycine-Nitrate Combustion: Synthesis, Self-Cleaning, and Sunlight-Driven Photocatalytic Activity. AB - We developed a single-step thermal method that enables successful inclusion of ZnO components in the porous boron-carbon-nitrogen (BCN) framework to form a new class of functional hybrid. ZnO-containing BCN hybrids were prepared by treating a mixture of B2O3, glycine, and zinc nitrate at 500 degrees C. Glycine-nitrate decomposition along with B2O3 acts as a source for ZnO-BCN formation. The incorporation of ZnO onto BCN has extended the photoresponse of ZnO in the visible region, which makes ZnO-BCN a preferable photocatalyst relative to ZnO upon sunlight exposure. It is interesting to note that as-prepared 2D ZnO-BCN sheets dispersed in PDMS form a stable coating over aluminum alloys. The surface exhibited a water contact angle (CA) of 157.6 degrees with 66.6 wt % ZnO-BCN in polydimethylsiloxane (PDMS) and a water droplet (7 MUL) roll-off angle of <6 degrees and also demonstrates oil fouling resistant superhydrophobicity. In brief, the present study focuses on the gram scale synthesis of a new class of sunlight-driven photocatalyst and also its application toward the development of superhydrophobic and oleophobic coating. PMID- 26252872 TI - Variations in the FRA10AC1 Fragile Site and 15q21 Are Associated with Cerebrospinal Fluid Abeta1-42 Level. AB - Proteolytic fragments of amyloid and post-translational modification of tau species in Cerebrospinal fluid (CSF) as well as cerebral amyloid deposition are important biomarkers for Alzheimer's Disease. We conducted genome-wide association study to identify genetic factors influencing CSF biomarker level, cerebral amyloid deposition, and disease progression. The genome-wide association study was performed via a meta-analysis of two non-overlapping discovery sample sets to identify genetic variants other than APOE epsilon4 predictive of the CSF biomarker level (Abeta1-42, t-Tau, p-Tau181P, t-Tau:Abeta1-42 ratio, and p Tau181P:Abeta1-42 ratio) in patients enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Loci passing a genome-wide significance threshold of P < 5 x 10-8 were followed-up for replication in an independent sample set. We also performed joint meta-analysis of both discovery sample sets together with the replication sample set. In the discovery phase, we identified variants in FRA10AC1 associated with CSF Abeta1-42 level passing the genome-wide significance threshold (directly genotyped SNV rs10509663 PFE = 1.1 x 10-9, imputed SNV rs116953792 PFE = 3.5 x 10-10), rs116953792 (Pone-sided = 0.04) achieved replication. This association became stronger in the joint meta-analysis (directly genotyped SNV rs10509663 PFE = 1.7 x 10-9, imputed SNV rs116953792 PFE = 7.6 x 10-11). Additionally, we identified locus 15q21 (imputed SNV rs1503351 PFE = 4.0 x 10-8) associated with CSF Abeta1-42 level. No other variants passed the genome-wide significance threshold for other CSF biomarkers in either the discovery sample sets or joint analysis. Gene set enrichment analyses suggested that targeted genes mediated by miR-33, miR-146, and miR-193 were enriched in various GWAS analyses. This finding is particularly important because CSF biomarkers confer disease susceptibility and may be predictive of the likelihood of disease progression in Alzheimer's Disease. PMID- 26252874 TI - Hyperphosphatemia Is an Independent Risk Factor for Mortality in Critically Ill Patients: Results from a Cross-Sectional Study. AB - BACKGROUND: Phosphate imbalances or disorders have a high risk of morbidity and mortality in patients with chronic kidney disease. It is unknown if this finding extends to mortality in patients presenting at an emergency room with or without normal kidney function. METHODS AND PATIENTS: This cross sectional analysis included all emergency room patients between 2010 and 2011 at the Inselspital Bern, Switzerland. A multivariable cox regression model was applied to assess the association between phosphate levels and in-hospital mortality up to 28 days. RESULTS: 22,239 subjects were screened for the study. Plasma phosphate concentrations were measured in 2,390 patients on hospital admission and were included in the analysis. 3.5% of the 480 patients with hypophosphatemia and 10.7% of the 215 patients with hyperphosphatemia died. In univariate analysis, phosphate levels were associated with mortality, age, diuretic therapy and kidney function (all p<0.001). In a multivariate Cox regression model, hyperphosphatemia (OR 3.29, p<0.001) was a strong independent risk factor for mortality. Hypophosphatemia was not associated with mortality (p>0.05). CONCLUSION: Hyperphosphatemia is associated with 28-day in-hospital mortality in an unselected cohort of patients presenting in an emergency room. PMID- 26252875 TI - Randomized comparison of daclatasvir + asunaprevir versus telaprevir + peginterferon/ribavirin in Japanese hepatitis C virus patients. AB - BACKGROUND AND AIM: Daclatasvir combined with asunaprevir is the first all-oral, ribavirin-free treatment of hepatitis C virus genotype 1b infection in Japan. This study compared the efficacy and safety of daclatasvir plus asunaprevir versus telaprevir plus peginterferon/ribavirin in Japanese treatment-naive patients infected with hepatitis C virus genotype 1b. METHODS: Treatment-naive patients (20-70 years; baseline viral load, >= 100,000 IU/mL) were randomly assigned (stratified by IL28B rs8099917 TT/non-TT status) to receive either daclatasvir 60 mg tablets once daily and asunaprevir 100 mg softgel capsules twice daily for 24 weeks or telaprevir 750 mg (3 * 250 mg tablets) three times daily for 12 weeks and peginterferon/ribavirin per Japanese prescribing information for 24 weeks. A cohort of prior relapsers to peginterferon/ribavirin (20-75 years; baseline viral load, >= 100,000 IU/mL) received daclatasvir plus asunaprevir. RESULTS: In treatment-naive patients, sustained virologic response at post-treatment week 12 in daclatasvir plus asunaprevir recipients was non inferior (treatment difference, +25.8% in favor of daclatasvir plus asunaprevir) and higher (89.1%, 106/119) than telaprevir plus peginterferon/ribavirin recipients (62.2%, 69/111); sustained viral response was achieved in 95.5% (n = 21/22) of relapsers. Numerically, fewer patients receiving daclatasvir plus asunaprevir compared with telaprevir plus peginterferon/ribavirin experienced serious adverse events (4.2% vs. 5.4%), adverse events leading to discontinuation of any drug (5.0% vs. 62.2%), grade 3/4 treatment-related adverse events (14.3% vs. 72.1%), rash-related events (0% vs. 13.5%), or anemia (0% vs. 47.7%). CONCLUSION: Marked differences were observed in the efficacy and safety profile of daclatasvir in combination with asunaprevir, compared with telaprevir plus peginterferon/ribavirin. PMID- 26252876 TI - Assessment of PM10 pollution level and required source emission reduction in Belgrade area. AB - The aim of this study was to assess PM10 pollution level and estimate required source emission reduction in Belgrade area, the second largest urban center in the Balkans. Daily mass concentrations and trace metal content (As, Cd, Cr, Mn, Ni, Pb) of PM10 were evaluated for three air quality monitoring sites of different types: urban-traffic (Slavija), suburban (Lazarevac) and rural (Grabovac) under the industrial influence, during the period of 2012-13. Noncompliance with current Air Quality Standards (AQS) was noticeable: annual means were higher than AQS at Slavija and Lazarevac, and daily frequency threshold was exceeded at all three locations. Annual means of As at Lazarevac were about four times higher than the target concentration, which could be attributed to the proximity of coal-fired power plants, and dust resuspension from coal basin and nearby ash landfills. Additionally, levels of Ni and Cr were significantly higher than in other European cities. Carcinogenic health risk of inhabitants' exposure to trace metals was assessed as well. Cumulative cancer risk exceeded the upper limit of acceptable US EPA range at two sites, with Cr and As as the major contributors. To estimate source emission reduction, required to meet AQS, lognormal, Weibull and Pearson 5 probability distribution, functions (PDF) were used to fit daily PM10 concentrations. Based on the rollback equation and best fitting PDF, estimated reduction was within the range of 28-98%. Finally, the required reduction obtained using two-parameter exponential distribution suggested that risks associated to accidental releases of pollutants should be of greater concern. PMID- 26252877 TI - Face Recognition and Visual Search Strategies in Autism Spectrum Disorders: Amending and Extending a Recent Review by Weigelt et al. AB - The purpose of this review was to build upon a recent review by Weigelt et al. which examined visual search strategies and face identification between individuals with autism spectrum disorders (ASD) and typically developing peers. Seven databases, CINAHL Plus, EMBASE, ERIC, Medline, Proquest, PsychInfo and PubMed were used to locate published scientific studies matching our inclusion criteria. A total of 28 articles not included in Weigelt et al. met criteria for inclusion into this systematic review. Of these 28 studies, 16 were available and met criteria at the time of the previous review, but were mistakenly excluded; and twelve were recently published. Weigelt et al. found quantitative, but not qualitative, differences in face identification in individuals with ASD. In contrast, the current systematic review found both qualitative and quantitative differences in face identification between individuals with and without ASD. There is a large inconsistency in findings across the eye tracking and neurobiological studies reviewed. Recommendations for future research in face recognition in ASD were discussed. PMID- 26252878 TI - Taenia solium: Development of an Experimental Model of Porcine Neurocysticercosis. AB - Human neurocysticercosis (NC) is caused by the establishment of Taenia solium larvae in the central nervous system. NC is a severe disease still affecting the population in developing countries of Latin America, Asia, and Africa. While great improvements have been made on NC diagnosis, treatment, and prevention, the management of patients affected by extraparenchymal parasites remains a challenge. The development of a T. solium NC experimental model in pigs that will allow the evaluation of new therapeutic alternatives is herein presented. Activated oncospheres (either 500 or 1000) were surgically implanted in the cerebral subarachnoid space of piglets. The clinical status and the level of serum antibodies in the animals were evaluated for a 4-month period after implantation. The animals were sacrificed, cysticerci were counted during necropsy, and both the macroscopic and microscopic characteristics of cysts were described. Based on the number of established cysticerci, infection efficiency ranged from 3.6% (1000 oncospheres) to 5.4% (500 oncospheres). Most parasites were caseous or calcified (38/63, 60.3%) and were surrounded by an exacerbated inflammatory response with lymphocyte infiltration and increased inflammatory markers. The infection elicited specific antibodies but no neurological signs. This novel experimental model of NC provides a useful tool to evaluate new cysticidal and anti-inflammatory approaches and it should improve the management of severe NC patients, refractory to the current treatments. PMID- 26252879 TI - Injuries, Death, and Disability Associated with 11 Years of Conflict in Baghdad, Iraq: A Randomized Household Cluster Survey. AB - BACKGROUND: The objective of this study was to characterize injuries, deaths, and disabilities arising during 11 years of conflict in Baghdad. METHODS: Using satellite imagery and administrative population estimated size for Baghdad, 30 clusters were selected, proportionate to population size estimates. Interviews were conducted during April and May 2014 in 900 households containing 5148 persons. Details about injuries and disabilities occurring from 2003 through May 2014 and resultant disabilities were recorded. FINDINGS: There were 553 injuries reported by Baghdad residents, 225 of which were intentional, and 328 unintentional. For intentional injuries, the fatality rate was 39.1% and the disability rate 56.0%. Gunshots where the major cause of injury through 2006 when blasts/explosions became the most common cause and remained so through 2014. Among unintentional injuries, the fatality rate was 7.3% and the disability rate 77.1%. The major cause of unintentional injuries was falls (131) which have increased dramatically since 2008, followed by traffic related injuries (81), which have steadily increased. The proportion of injuries ending in disabilities remained fairly constant through the survey period. INTERPRETATION: Intentional injuries added substantially to the burden of unintentional injuries for the population. For Baghdad, the phases of the Iraqi conflict are reflected in the patterns of injuries and consequent deaths reported. The scale of injuries during conflict is most certainly under-reported. Difficulties recalling injuries in a survey covering 11 years is a limitation, but it is likely that minor injuries were under-reported more than severe injuries. The in- and out-migration of Baghdad populations likely had effects on the events reported which we could not measure or estimate. Damage to the health infrastructure and the flight of health workers may have contributed to mortality and morbidity. Civilian injuries as well as mortality should be measured during conflicts, though not currently done. PMID- 26252880 TI - Serum miR-210 Contributes to Tumor Detection, Stage Prediction and Dynamic Surveillance in Patients with Bladder Cancer. AB - MiR-210 is the master hypoxamir that generally exhibits oncogenic properties in most human solid tumors including bladder cancer (BC). However, it remains unknown about the clinical significance of circulating miR-210 levels in BC. In this study, we found that serum miR-210 was up-regulated in patients with BC, and serum levels of miR-210 increased with advancing stage and grade. Moreover, serum miR-210 expression was found to be significantly reduced in paired post-operative samples and elevated in most patients with relapsed BC. Taken together, our data suggest that serum miR-210 could be a potential noninvasive biomarker for screening, predicting and monitoring BC. PMID- 26252882 TI - Correction: Invasive Breast Cancer Incidence in 2,305,427 Screened Asymptomatic Women: Estimated Long Term Outcomes during Menopause Using a Systematic Review. PMID- 26252881 TI - Exhaustive Analysis of a Genotype Space Comprising 10(15 )Central Carbon Metabolisms Reveals an Organization Conducive to Metabolic Innovation. AB - All biological evolution takes place in a space of possible genotypes and their phenotypes. The structure of this space defines the evolutionary potential and limitations of an evolving system. Metabolism is one of the most ancient and fundamental evolving systems, sustaining life by extracting energy from extracellular nutrients. Here we study metabolism's potential for innovation by analyzing an exhaustive genotype-phenotype map for a space of 10(15) metabolisms that encodes all possible subsets of 51 reactions in central carbon metabolism. Using flux balance analysis, we predict the viability of these metabolisms on 10 different carbon sources which give rise to 1024 potential metabolic phenotypes. Although viable metabolisms with any one phenotype comprise a tiny fraction of genotype space, their absolute numbers exceed 10(9) for some phenotypes. Metabolisms with any one phenotype typically form a single network of genotypes that extends far or all the way through metabolic genotype space, where any two genotypes can be reached from each other through a series of single reaction changes. The minimal distance of genotype networks associated with different phenotypes is small, such that one can reach metabolisms with novel phenotypes- viable on new carbon sources--through one or few genotypic changes. Exceptions to these principles exist for those metabolisms whose complexity (number of reactions) is close to the minimum needed for viability. Increasing metabolic complexity enhances the potential for both evolutionary conservation and evolutionary innovation. PMID- 26252883 TI - Effects of a Cognitively Demanding Aerobic Intervention During Recess on Children's Physical Fitness and Executive Functioning. AB - The objective of this study was to analyze the effects of a physical activity program including both aerobic exercise and cognitively engaging physical activities on children's physical fitness and executive functions. Children from 3 primary schools (aged 8-12 years) were recruited. A quasi-experimental design was used. Children in the intervention group (n = 53; 19 boys, 34 girls) participated in a 22-week physical activity program for 30 min during lunch recess, twice a week. Children in the control group (n = 52; 32 boys, 20 girls) followed their normal lunch routine. Aerobic fitness, speed and agility, and muscle strength were assessed using the Eurofit test battery. Executive functions were assessed using tasks measuring inhibition (Stroop test), working memory (Visual Memory Span test, Digit Span test), cognitive flexibility (Trailmaking test), and planning (Tower of London). Children in the intervention group showed significantly greater improvement than children in the control group on the Stroop test and Digit Span test, reflecting enhanced inhibition and verbal working memory skills, respectively. No differences were found on any of the physical fitness variables. A physical activity program including aerobic exercise and cognitively engaging physical activities can enhance aspects of executive functioning in primary school children. PMID- 26252884 TI - Modifications of membrane lipids in response to wounding of Arabidopsis thaliana leaves. AB - Mechanical wounding of Arabidopsis thaliana leaves results in modifications of most membrane lipids within 6 hours. Here, we discuss the lipid changes, their underlying biochemistry, and possible relationships among activated pathways. New evidence is presented supporting the role of the processive galactosylating enzyme SENSITIVE TO FREEZING2 in the wounding response. PMID- 26252885 TI - Symptom characteristics of depressive episodes prior to the onset of mania or hypomania. AB - OBJECTIVE: Depressive episodes are typically the initial presentation of bipolar disorder. The evidence as to whether depressive episodes occurring in persons who later convert to bipolar disorder are symptomatically distinct from episodes of unipolar depression remains controversial. As there are crucial differences in the therapeutic management, symptom profiles indicating subsequent bipolar conversion may aid in appropriate treatment. METHOD: A representative community sample of originally N = 3021 adolescents and young adults aged 14-24 years at baseline was assessed up to four times over 10 years. Assessment of symptoms was conducted by clinically trained interviewers using the standardized M-CIDI. Symptom profiles of depressive episodes were compared via logistic regression between subjects that subsequently developed (hypo-)manic episodes (n = 35) or remained unipolar depressive (n = 659). RESULTS: Initial depression amongst prospective converters was characterized by significantly increased suicidality (odds ratio, OR = 2.31), higher rates of feelings of worthlessness and excessive guilt (OR = 2.52), complete loss of pleasure (OR = 2.53) and diurnal variation (OR = 4.30). No differences were found for hyperphagia, hypersomnia and psychomotor alterations. CONCLUSION: Findings suggest that the symptom profile of initial depressive episodes may be useful in the identification of subjects with an elevated risk for the subsequent conversion to bipolar disorder. PMID- 26252886 TI - Long time-course monitoring of ZFP809-mediated gene silencing in transgene expression driven by promoters containing MLV-derived PBS. AB - Expression of Moloney murine leukemia virus (MoMLV)-typed retroviral vectors is strictly suppressed in immature cells such as embryonic stem cells. The phenomenon known as gene silencing is primed by the sequence-specific binding of the zinc finger protein 809 (ZFP809) to the primer-binding site of the vectors. However, it has yet to be determined whether the ZFP809-mediated gene silencing is maintained over a long period. In this study, we established an experimental system that can monitor gene silencing during a long-term cell culture using flow cytometry technology combined with fluorescent reporters for the expression of ZFP809 and the transgene expression driven by the promoters of interest. Time course analysis using our system revealed that ZFP809 maintains gene silencing effect even at a longtime period. Furthermore, our system was useful for the monitoring of ZFP809-mediated gene silencing regardless of the types of vectors and cell lines. PMID- 26252887 TI - Muscle damage produced during a simulated badminton match in competitive male players. AB - The purpose of the study was to assess the occurrence of muscle damage after a simulated badminton match and its influence on physical and haematological parameters. Sixteen competitive male badminton players participated in the study. Before and just after a 45-min simulated badminton match, maximal isometric force and badminton-specific running/movement velocity were measured to assess muscle fatigue. Blood samples were also obtained before and after the match. The badminton match did not affect maximal isometric force or badminton-specific velocity. Blood volume and plasma volume were significantly reduced during the match and consequently haematite, leucocyte, and platelet counts significantly increased. Blood myoglobin and creatine kinase concentrations increased from 26.5 +/- 11.6 to 197.3 +/- 70.2 ug.L(-1) and from 258.6 +/- 192.2 to 466.0 +/- 296.5 U.L(-1), respectively. In conclusion, a simulated badminton match modified haematological parameters of whole blood and serum blood that indicate the occurrence of muscle fibre damage. However, the level of muscle damage did not produce decreased muscle performance. PMID- 26252888 TI - Antimicrobial Susceptibility and Molecular Mechanisms of Fosfomycin Resistance in Clinical Escherichia coli Isolates in Mainland China. AB - Escherichia coli is one of the most common pathogens in nosocomial and community acquired infections in humans. Fosfomycin is a broad-spectrum antibiotic which inhibits peptidoglycan synthesis responsible for bacterial cell wall formation. Although low, the exact E. coli susceptibility to fosfomycin as well as the mechanisms of resistance in the population from Mainland China are mostly unknown. 1109 non-duplicate clinical E. coli strains isolated from urine, sputum, blood and pus samples in 20 widely dispersed tertiary hospitals from Mainland China were collected from July 2009 to June 2010, followed by determination of minimum inhibitory concentrations of fosfomycin. Detection of the murA, glpT, uhpT, fosA, fosA3 and fosC genes was performed in fosfomycin non-susceptible E. coli strains and conjugation experiments were employed to determine the mobility of fosA3 gene. In this study, 7.8% (86/1109) E. coli strains were fosfomycin non susceptible. Amino acid substitutions in GlpT and MurA were found in six and four E.coli strains, respectively, while the uhpT gene was absent in eighteen E.coli strains. Twenty-nine isolates carried the transferable plasmid with the fosA3 gene at high frequencies of around 10(-6) to 10(-7) per donor cell in broth mating. The majority of isolates were susceptible to fosfomycin, showing that the drug is still viable in clinical applications. Also, the main mechanism of E. coli resistance in Mainland China was found to be due to the presence of the fosA3 gene. PMID- 26252889 TI - A Systematic Review Exploring the Social Cognitive Theory of Self-Regulation as a Framework for Chronic Health Condition Interventions. AB - BACKGROUND: Theory is often recommended as a framework for guiding hypothesized mechanisms of treatment effect. However, there is limited guidance about how to use theory in intervention development. METHODS: We conducted a systematic review to provide an exemplar review evaluating the extent to which use of theory is identified and incorporated within existing interventions. We searched electronic databases PubMed, PsycINFO, CENTRAL, and EMBASE from inception to May 2014. We searched clinicaltrials.gov for registered protocols, reference lists of relevant systematic reviews and included studies, and conducted a citation search in Web of Science. We included peer-reviewed publications of interventions that referenced the social cognitive theory of self-regulation as a framework for interventions to manage chronic health conditions. Two reviewers independently assessed articles for eligibility. We contacted all authors of included studies for information detailing intervention content. We describe how often theory mechanisms were addressed by interventions, and report intervention characteristics used to address theory. RESULTS: Of 202 articles that reported using the social cognitive theory of self-regulation, 52% failed to incorporate self-monitoring, a main theory component, and were therefore excluded. We included 35 interventions that adequately used the theory framework. Intervention characteristics were often poorly reported in peer-reviewed publications, 21 of 35 interventions incorporated characteristics that addressed each of the main theory components. Each intervention addressed, on average, six of eight self monitoring mechanisms, two of five self-judgement mechanisms, and one of three self-evaluation mechanisms. The self-monitoring mechanisms 'Feedback' and 'Consistency' were addressed by all interventions, whereas the self-evaluation mechanisms 'Self-incentives' and 'External rewards' were addressed by six and four interventions, respectively. The present review establishes that systematic review is a feasible method of identifying use of theory as a conceptual framework for existing interventions. We identified the social cognitive theory of self-regulation as a feasible framework to guide intervention development for chronic health conditions. PMID- 26252890 TI - Evaluation of the BDCA2-DTR Transgenic Mouse Model in Chronic and Acute Inflammation. AB - BACKGROUND AND AIMS: Plasmacytoid dendritic cells (pDCs) are a small subset of dendritic cells and the main producers of type I interferons. Besides their contribution to tolerance, they are known to be involved in autoimmune diseases and have recently been implicated in atherosclerosis. However, their precise involvement, particularly in advanced lesion development, remains elusive. Hence, we investigated the role of pDCs in atherogenesis vs atheroprogression by specifically depleting this cell population using the BDCA2-DTR mouse model bred to Apolipoprotein E (Apoe-/-) deficient mice. METHODS AND RESULTS: Our results revealed that continuous diphtheria toxin-induced pDC depletion in Apoe-/- BDCA2 DTR mice receiving a high-fat diet (HFD) for 4 weeks did not alter lesion size or composition. Instead, these mice displayed increased B cell numbers and altered levels of inflammatory cytokines. Analysis of depletion efficiency showed that complete pDC depletion could only be sustained for one week and reoccurring pDCs sorted after 4 weeks did not express DTR anymore. Consequently, we analyzed lesion development in a model of partial carotid ligation, inducing established lesions after 5 weeks of HFD feeding, and only depleted pDCs during the last week of 5 weeks HFD feeding. Despite short-term, but efficient pDC depletion, we observed no differences in atherosclerotic lesion development, but changes in inflammatory cytokine titers. To assure the functionality of the BDCA2-DTR model in acute settings, we additionally examined the effect of pDC depletion in an indirect acute lung injury (iALI) model. This time, efficient pDC depletion resulted in a significantly reduced macrophage and neutrophil accumulation in the lung 12 hours after LPS challenge, underlining a pro-inflammatory role of pDCs in the innate immune response in iALI. CONCLUSION: Taken together, the BDCA2-DTR mouse model only allows efficient pDC depletion for one week, which subsequently restricts its usability to more acute but not chronic inflammatory disease models. PMID- 26252891 TI - Multimodal Imaging of Orthotopic Mouse Model of Endometrial Carcinoma. AB - BACKGROUND: Orthotopic endometrial cancer models provide a unique tool for studies of tumour growth and metastatic spread. Novel preclinical imaging methods also have the potential to quantify functional tumour characteristics in vivo, with potential relevance for monitoring response to therapy. METHODS: After orthotopic injection with luc-expressing endometrial cancer cells, eleven mice developed disease detected by weekly bioluminescence imaging (BLI). In parallel the same mice underwent positron emission tomography-computed tomography (PET-CT) and magnetic resonance imaging (MRI) employing 18F-fluorodeoxyglocose (18F-FDG) or 18F- fluorothymidine (18F-FLT) and contrast reagent, respectively. The mice were sacrificed when moribund, and post-mortem examination included macroscopic and microscopic examination for validation of growth of primary uterine tumours and metastases. PET-CT was also performed on a patient derived model (PDX) generated from a patient with grade 3 endometrioid endometrial cancer. RESULTS: Increased BLI signal during tumour growth was accompanied by increasing metabolic tumour volume (MTV) and increasing MTV x mean standard uptake value of the tumour (SUVmean) in 18F-FDG and 18F-FLT PET-CT, and MRI conspicuously depicted the uterine tumour. At necropsy 82% (9/11) of the mice developed metastases detected by the applied imaging methods. 18F-FDG PET proved to be a good imaging method for detection of patient derived tumour tissue. CONCLUSIONS: We demonstrate that all imaging modalities enable monitoring of tumour growth and metastatic spread in an orthotopic mouse model of endometrial carcinoma. Both PET tracers, 18F-FDG and 18F-FLT, appear to be equally feasible for detecting tumour development and represent, together with MRI, promising imaging tools for monitoring of patient derived xenograft (PDX) cancer models. PMID- 26252892 TI - Effect of Postnatal Myostatin Inhibition on Bite Mechanics in Mice. AB - As a negative regulator of muscle size, myostatin (Mstn) impacts the force production capabilities of skeletal muscles. In the masticatory system, measures of temporalis-stimulated bite forces in constitutive myostatin KOs suggest an absolute, but not relative, increase in jaw-muscle force. Here, we assess the phenotypic and physiologic impact of postnatal myostatin inhibition on bite mechanics using an inducible conditional KO mouse in which myostatin is inhibited with doxycycline (DOX). Given the increased control over the timing of gene inactivation in this model, it may be more clinically-relevant for developing interventions for age-associated changes in the musculoskeletal system. DOX was administered for 12 weeks starting at age 4 months, during which time food intake was monitored. Sex, age and strain-matched controls were given the same food without DOX. Bite forces were recorded just prior to euthanasia after which muscle and skeletal data were collected. Food intake did not differ between control or DOX animals within each sex. DOX males were significantly larger and had significantly larger masseters than controls, but DOX and control females did not differ. Although there was a tendency towards higher absolute bite forces in DOX animals, this was not significant, and bite forces normalized to masseter mass did not differ. Mechanical advantage for incisor biting increased in the DOX group due to longer masseter moment arms, likely due to a more anteriorly-placed masseter insertion. Despite only a moderate increase in bite force in DOX males and none in DOX females, the increase in masseter mass in males indicates a potentially positive impact on jaw muscles. Our data suggest a sexual dimorphism in the role of mstn, and as such investigations into the sex-specific outcomes is warranted. PMID- 26252894 TI - Perceptions of Competence, Strength, and Age Influence Voters to Select Leaders with Lower-Pitched Voices. AB - Voters prefer leaders with lower-pitched voices because they are perceived as stronger, having greater physical prowess, more competent, and having greater integrity. An alternative hypothesis that has yet to be tested is that lower pitched voices are perceived as older and thus wiser and more experienced. Here the relationships between candidate voice pitch, candidate age, and electoral success are examined with two experiments. Study 1 tests whether voters discriminate on candidate age. The results show that male and female candidates in their 40s and 50s, the time in the lifecycle when voice pitch is at its lowest, are preferred over candidates in their 30s, 60s, and 70s. Study 2 shows that the preference for leaders with lower-pitched voices correlates with the perception that speakers with lower voices are stronger, more competent, and older, but the influence of perception of age on vote choice is the weakest of the three. PMID- 26252893 TI - Voxel Based Morphometry Alterations in Mal de Debarquement Syndrome. AB - BACKGROUND: Mal de debarquement syndrome (MdDS) is a disorder of chronic self motion perception that occurs though entrainment to rhythmic background motion, such as from sea voyage, and involves the perception of low-frequency rocking that can last for months or years. The neural basis of this persistent sensory perception abnormality is not well understood. METHODS: We investigated grey matter volume differences underlying persistent MdDS by performing voxel-based morphometry on whole brain and pre-specified ROIs in 28 individuals with MdDS and comparing them to 18 age, sex, and handedness matched controls. RESULTS: MdDS participants exhibited greater grey matter volume in the left inferior parietal lobule, right inferior occipital gyrus (area V3v), right temporal pole, bilateral cerebellar hemispheric lobules VIII/IX and left lobule VIIa/VIIb. Grey matter volumes were lower in bilateral inferior frontal, orbitofrontal, pregenual anterior cingulate cortex (pgACC) and left superior medial gyri (t = 3.0, p<0.005uncorr). In ROI analyses, there were no volume differences in the middle occipital gyrus (region of V5/MT) or parietal operculum 2 (region of the parietoinsular vestibular cortex). Illness duration was positively related to grey matter volume in bilateral inferior frontal gyrus/anterior insula (IFG/AI), right posterior insula, superior parietal lobule, left middle occipital gyrus (V5/MT), bilateral postcentral gyrus, anterior cerebellum, and left cerebellar hemisphere and vermian lobule IX. In contrast, illness duration was negatively related to volume in pgACC, posterior middle cingulate gyrus (MCC), left middle frontal gyrus (dorsolateral prefrontal cortex-DLPFC), and right cerebellar hemispheric lobule VIIIb (t = 3.0, p<0.005uncorr). The most significant differences were decreased volume in the pgACC and increased volume in the left IFG/AI with longer illness duration (qFDRcorr <0.05). Concurrent medication use did not correlate with these findings or have a relationship with duration of illness. MdDS participants showed positive correlations between grey matter volume in pgACC and bilateral cerebellar lobules VIII/IX, which was not seen in controls. CONCLUSIONS: Individuals with MdDS show brain volume differences from healthy controls as well as duration of illness dependent volume changes in (a) visual-vestibular processing areas (IPL, SPL, V3, V5/MT), (b) default mode network structures (cerebellar IX, IPL, ACC), (c) salience network structures (ACC and IFG/AI) (d) somatosensory network structures (postcentral gyrus, MCC, anterior cerebellum, cerebellar lobule VIII), and (e) a structure within the central executive network (DLPFC). The identification of these associations may enhance future investigations into how exposure to oscillating environments can modulate brain function and affect motion perception as well cognitive and affective control. PMID- 26252896 TI - Correction: Data Gathering Bias: Trait Vulnerability to Psychotic Symptoms? PMID- 26252895 TI - Comparison of Porcine Small Intestinal Submucosa versus Polypropylene in Open Inguinal Hernia Repair: A Systematic Review and Meta-Analysis. AB - BACKGROUND: A systematic review and meta-analysis was performed in randomized controlled trials (RCTs) to compare porcine small intestinal submucosa (SIS) with polypropylene in open inguinal hernia repair. METHOD: Electronic databases MEDLINE, Embase, and the Cochrane Library were used to compare patient outcomes for the two groups via meta-analysis. RESULT: A total of 3 randomized controlled trials encompassing 200 patients were included in the meta-analysis. There was no significant difference in recurrence (P = 0.16), hematomas (P = 0.06), postoperative pain within 30 days (P = 0.45), or postoperative pain after 1 year (P = 0.12) between the 2 groups. The incidence of discomfort was significantly lower (P = 0.0006) in the SIS group. However, the SIS group experienced a significantly higher incidence of seroma (P = 0.03). CONCLUSIONS: Compared to polypropylene, using SIS in open inguinal hernia repair is associated with a lower incidence of discomfort and a higher incidence of seroma. However, well designed larger RCT studies with a longer follow-up period are needed to confirm these findings. PMID- 26252897 TI - Satisfaction of Basic Psychological Needs, Self-Determined Exercise Motivation, and Psychological Well-Being in Mothers Exercising in Group-Based Versus Individual-Based Contexts. AB - We compared mothers who exercised predominantly in group settings, those who exercised predominantly in individual settings, and those who exercised equally in group and individual contexts among the following: (a) satisfaction of basic psychological needs (autonomy, competence, and relatedness); (b) self-determined exercise motivation; and (c) psychological well-being. With clear implications for mothers' exercise interventions we found that exercising either predominantly in group contexts or in mixed group and individual settings was associated with mothers having significantly higher satisfaction of basic psychological needs and self-determined exercise motivation than those exercising predominantly alone. PMID- 26252899 TI - Nonalcoholic Fatty Liver Disease Is Independently Associated with Early Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes. AB - Accumulating evidence suggests that nonalcoholic fatty liver disease (NAFLD) is associated with left ventricular diastolic dysfunction (LVDD) in nondiabetic individuals. To date, there are very limited data on this topic in patients with type 2 diabetes and it remains uncertain whether NAFLD is independently associated with the presence of LVDD in this patient population. We performed a liver ultrasonography and trans-thoracic echocardiography (with speckle-tracking strain analysis) in 222 (156 men and 66 women) consecutive type 2 diabetic outpatients with no previous history of ischemic heart disease, chronic heart failure, valvular diseases and known hepatic diseases. Binary logistic regression analysis was used to examine the association between NAFLD and the presence/severity of LVDD graded according to the current criteria of the American Society of Echocardiography, and to identify the variables that were independently associated with LVDD, which was included as the dependent variable. Patients with ultrasound-diagnosed NAFLD (n = 158; 71.2% of total) were more likely to be female, overweight/obese, and had longer diabetes duration, higher hemoglobin A1c and lower estimated glomerular filtration rate (eGFR) than those without NAFLD. Notably, they also had a remarkably greater prevalence of mild and/or moderate LVDD compared with those without NAFLD (71% vs. 33%; P<0.001). Age, hypertension, smoking, medication use, E/A ratio, LV volumes and mass were comparable between the two groups of patients. NAFLD was associated with a three fold increased odds of mild and/or moderate LVDD after adjusting for age, sex, body mass index, hypertension, diabetes duration, hemoglobin A1c, eGFR, LV mass index and ejection fraction (adjusted-odds ratio 3.08, 95%CI 1.5-6.4, P = 0.003). In conclusion, NAFLD is independently associated with early LVDD in type 2 diabetic patients with preserved systolic function. PMID- 26252898 TI - Comprehensive Evolutionary and Expression Analysis of FCS-Like Zinc finger Gene Family Yields Insights into Their Origin, Expansion and Divergence. AB - Plant evolution is characterized by frequent genome duplication events. Expansion of habitat resulted in the origin of many novel genes and genome duplication events which in turn resulted in the expansion of many regulatory gene families. The plant-specific FCS-Like Zinc finger (FLZ) gene family is characterized by the presence of a FCS-Like Zinc finger (FLZ) domain which mediates the protein protein interaction. In this study, we identified that the expansion of FLZ gene family size in different species is correlated with ancestral and lineage specific whole genome duplication events. The subsequent gene loss found to have a greater role in determining the size of this gene family in many species. However, genomic block duplications played the significant role in the expansion of FLZ gene family in some species. Comparison of Arabidopsis thaliana and Oryza sativa FLZ gene family revealed monocot and dicot specific evolutionary trends. The FLZ genes were found to be under high purifying selection. The spatiotemporal expression analyses of Arabidopsis thaliana FLZ gene family revealed that majority of the members are highly expressed in reproductive organs. FLZ genes were also found to be highly expressed during vegetative-to-reproductive phase transition which is correlated with the proposed role of this gene family in sugar signaling. The comparison of sequence, structural and expression features of duplicated genes identified lineage-specific redundancy and divergence. This extensive evolutionary analysis and expression analysis of Arabidopsis thaliana FLZ genes will pave the way for further functional analysis of FLZ genes. PMID- 26252900 TI - Selective Targeting to Glioma with Nucleic Acid Aptamers. AB - Malignant glioma is characterised by a rapid growth rate and high capacity for invasive infiltration to surrounding brain tissue; hence, diagnosis and treatment is difficult and patient survival is poor. Aptamers contribute a promising and unique technology for the in vitro imaging of live cells and tissues, with a potentially bright future in clinical diagnostics and therapeutics for malignant glioma. The binding selectivity, uptake capacity and binding target of two DNA aptamers, SA43 and SA44, were investigated in glioma cells and patient tissues. The binding assay showed that SA43 and SA44 bound with strong affinity (Kd, 21.56 +/- 4.60 nM and Kd, 21.11 +/- 3.30 nM respectively) to the target U87MG cells. Quantitative analysis by flow cytometry showed that the aptamers were able to actively internalise in U87MG and 1321N1 glioma cells compared to the non cancerous and non-glioma cell types. Confocal microscopy confirmed staining in the cytoplasm, and co-localisation studies with endoplasmic reticulum, Golgi apparatus and lysosomal markers suggested internalisation and compartmentalisation within the endomembrane system. Both aptamers selectively bound to Ku 70 and Ku 80 DNA repair proteins as determined by aptoprecipitation (AP) followed by mass spectrometry analysis and confirmation by Western blot. In addition, aptohistochemical (AHC) staining on paraffin embedded, formalin fixed patient tissues revealed that the binding selectivity was significantly higher for SA43 aptamer in glioma tissues (grade I, II, III and IV) compared to the non cancerous tissues, whereas SA44 did not show selectivity towards glioma tissues. The results indicate that SA43 aptamer can differentiate between glioma and non cancerous cells and tissues and therefore, shows promise for histological diagnosis of glioma. PMID- 26252901 TI - Activation of protease-activated receptor-2 is associated with increased expression of inflammatory factors in the adipose tissues of obese mice. AB - Previous studies have indicated that mast cells are critical for the pathogenesis of inflammatory diseases. Proteases released from mast cells have been reported to stimulate protease-activated receptors (PAR), which induces microleakage and widespread inflammation. In order to investigate the pro-inflammatory effect of PAR-2 activation on adipose inflammation in obese mice, the varying distributions of macrophages and PAR-2 in adipose tissue samples were compared between C57BL/6J (C57) and obese mice [B6(D)-Leprdb/J, BKS(D)-Leprdb/J and B6.V-Lepob/J (ob/ob)] using immunohistochemical staining. Murine primary adipocytes and bone marrow derived macrophages (BMDMs) were used and the alterations in expression levels of inflammatory factors, induced by PAR-2 activation, were detected by reverse transcription-quantitative polymerase chain reaction and ELISA. In addition, the migratory capacity of primary BMDMs and the macrophage cell line, RAW264.7 were evaluated by co-culture with primary adipocytes. The current study demonstrated a larger number of macrophages in the adipose tissues of obese mice compared with C57 mice. Furthermore, PAR-2 expression was detected in various adipose tissues of mice and the protein expression levels of PAR-2 were observed to be significantly higher in the total adipose tissues of ob/ob mice when compared with the C57 mice. The expression levels of inflammatory factors were increased in adipocytes and macrophages, and enhanced migratory ability was observed in macrophages pretreated with PAR-2 agonists. The data of the current study suggests that PAR-2 is involved in the process of obesity-associated chronic low grade systemic inflammation, which indicates that the PAR-2 signaling pathway may be a potential target for the treatment of obesity and its associated diseases. PMID- 26252903 TI - Recent Advances in Bulk Heterojunction Polymer Solar Cells. PMID- 26252904 TI - Apparent hydrodynamic slip induced by density inhomogeneities at fluid-solid interfaces. AB - This study demonstrates that even when the no-slip condition is satisfied on the surface of a solid wall, apparent hydrodynamic slip can be clearly seen owing to a continuous variation of viscosity associated with density inhomogeneity near the wall. The relationship between the apparent slip length and the local fluid properties, such as viscosity and/or density, has been established theoretically. The apparent slip length depends on the flow type and three cases are considered: shear-driven flow, body force-driven flow, and flow driven by external force acting on adsorbed solutes. Particle-based simulations have been performed and the consistency between our theory and the simulation has been verified. PMID- 26252902 TI - Optical Coherence Tomography in Alzheimer's Disease: A Meta-Analysis. AB - BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder, which is likely to start as mild cognitive impairment (MCI) several years before the its full-blown clinical manifestation. Optical coherence tomography (OCT) has been used to detect a loss in peripapillary retina nerve fiber layer (RNFL) and a reduction in macular thickness and volume of people affected by MCI or AD. Here, we performed an aggregate meta-analysis combining results from different studies. METHODS AND FINDINGS: Data sources were case-control studies published between January 2001 and August 2014 (identified through PubMed and Google Scholar databases) that examined the RNFL thickness by means of OCT in AD and MCI patients compared with cognitively healthy controls. RESULTS: 11 studies were identified, including 380 patients with AD, 68 with MCI and 293 healthy controls (HC). The studies suggest that the mean RNFL thickness is reduced in MCI (weighted mean differences in MUm, WMD = -13.39, 95% CI: -17.34 to -9.45, p = 0.031) and, even more so, in AD (WMD = -15.95, 95% CI: -21.65 to -10.21, p<0.0001) patients compared to HC. RNFL in the 4 quadrants were all significantly thinner in AD superior (superior WMD = -24.0, 95% CI: -34.9 to -13.1, p<0.0001; inferior WMD = -20.8, 95% CI: -32.0 to -9.7, p<0.0001; nasal WMD = -14.7, 95% CI: -23.9 to -5.5, p<0.0001; and temporal WMD = -10.7, 95% CI: -19.9 to -1.4, p<0.0001); the same significant reduction in quadrant RNFL was observed in MCI patients compared with HC (Inferior WMD = -20.22, 95% CI: -30.41 to -10.03, p = 0.0001; nasal WMD = -7.4, 95% CI: -10.08 to -4.7, p = 0.0000; and temporal WMD = 6.88, 95% CI: -12.62 to -1.13, p = 0.01), with the exception of superior quadrant (WMD = -19.45, 95% CI: -40.23 to 1.32, p = 0.06). CONCLUSION: Results from the meta-analysis support the important role of OCT for RNFL analysis in monitoring the progression of AD and in assessing the effectiveness of purported AD treatments. PMID- 26252905 TI - Potential of D-Octaarginine-Linked Polymers as an in Vitro Transfection Tool for Biomolecules. AB - We have been investigating the potential use of cell-penetrating peptide-linked polymers as a novel penetration enhancer. Since previous in vivo studies demonstrated that poly(N-vinylacetamide-co-acrylic acid) bearing D-octaarginine, a typical cell-penetrating peptide, enhanced membrane permeation of biomolecules, its potential as an in vitro transfection tool was evaluated in this study. A plasmid DNA encoding green fluorescent protein (pGFP-C1), beta-galactosidase, and bovine serum albumin (BSA) were used as model biomolecules. Anionic pGFP-C1 interacted electrostatically with cationic d-octaarginine-linked polymers. When the ratio of mass concentration of polymers to that of pGFP-C1 reached 2.5, complexes whose size and zeta potential were approximately 200 nm and 15 mV, respectively, were obtained. GFP expression was observed in cells incubated with complexes prepared under conditions in which the polymer/pDNA concentration ratio exceeded 2.5. The expression level elevated with an increase in the concentration ratio, but physicochemical properties of the complexes remained unchanged. Results suggested that free polymers contributed to pGFP-C1 internalization. Another cell study demonstrated that beta-galactosidase premixed with polymers was taken up into cells in its active tetrameric form. Similar electrostatic interaction-driven complex formation was observed for BSA charged negatively in neutral solution. However, it appeared that the internalization processes of BSA differed from those of pGFP-C1. A mass concentration-dependent increase in internalized BSA was observed, irrespective of the polymer/protein concentration ratio. Due to frail interactions, polymers that were released from the complexes and subsequently immobilized on cell membranes might also contribute to membrane permeation of BSA. PMID- 26252906 TI - Phenethyl isothiocyanate enhances adriamycin-induced apoptosis in osteosarcoma cells. AB - Adriamycin (ADM) is a first-line agent administered during the therapeutic regimes against osteosarcoma. Clinical administration of ADM produces systemic toxicity and resistance in patients, which restricts its applicability. In the present study the effects of phenethyl isothiocyanate (PEITC) on ADM-induced apoptosis in osteosarcoma cells was evaluated. Using U2-OS osteosarcoma cell line cells, treatment with PEITC or ADM for 24 h was observed to dose-dependently inhibit proliferation of U2-OS cells with half maximal inhibitory concentration (IC50) values of 5.33 uM and 10.32 ug/ml, respectively. When U2-OS cells were treated with a combination of the two agents, the inhibition was apparently enhanced, as the IC50 values decreased to 2 uM for PEITC and 1 ug/ml for ADM. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling revealed that treatment with PEITC or ADM alone reduced the viability of the U2 OS cells. Furthermore, the viability of the U2-OS cells was additionally reduced when treatment was with PEITC and ADM together. Supporting this finding, the activity and expression of caspase-3 were observed to be enhanced in the U2-OS cells following treatment with either PEITC or ADM, or a combination of the two. These results clearly indicate that PEITC enhances ADM-induced apoptosis in osteosarcoma cells. PMID- 26252907 TI - Synthesis of highly nanoporous YBO3 architecture via a co-precipitation approach and tunable luminescent properties. AB - We present a simple co-precipitation method to prepare highly nanoporous YBO(3) architecture using NaBO(3) . 4H(2)O as a boric source and 600 degrees C as the annealing temperature. The reaction was carried out under an aqueous condition without any organic solvent, surfactant, or catalysts. The prepared samples were characterized by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The photoluminescence of doped nanoporous YBO(3):Eu(3+) was further investigated. It is expected that highly nanoporous YBO(3) architecture can be an ideal candidate for applications in catalysis, adsorption, and optoelectronic devices. PMID- 26252908 TI - Corrigendum. PMID- 26252909 TI - Comparison of Breastmilk Odor and Vanilla Odor on Mitigating Premature Infants' Response to Pain During and After Venipuncture. AB - OBJECTIVE: The main purpose of this study was to investigate the calming effects of breastmilk odor and vanilla odor on preterm infants during and after venipuncture. SUBJECTS AND METHODS: One hundred thirty-five preterm infants were randomly selected and divided into three groups: control, vanilla odor, and breastmilk odor. Infants in the breastmilk group were exposed to breastmilk odor, and infants in the vanilla group were exposed to vanilla odor from 5 minutes before the start of sampling until 30 seconds after sampling. The Premature Infant Pain Profile was used for calculating quality of pain in infants during and after sampling. RESULTS: Statistical analyses showed that both vanilla and breastmilk odors had calming effects on premature infants during sampling, but just breastmilk odor had calming effects on infants after the end of sampling. Compared with vanilla odor, breastmilk odor has more calming effects on premature infants. CONCLUSIONS: Breastmilk odor can be used for calming premature infants during and after venipuncture. PMID- 26252910 TI - Efficacy of pediatric acute pancreatitis scores at a Japanese tertiary center. AB - BACKGROUND: Pediatric acute pancreatitis (AP) is a rare but important clinical entity associated with significant morbidity. Predicting the severity and outcome of AP in pediatric patients can be challenging because there are few validated severity scoring systems. Moreover, the etiology of pediatric AP in the Japanese population is different from that of Western populations. The performance of severity scores in pediatric AP with a high prevalence of severe cases is still unknown. The aim of this study was to assess the performance of existing severity scoring systems when used for Japanese children at a tertiary care center. METHODS: We reviewed the electronic medical records of all children (<=18 years) treated for AP at between 2002 and 2012 at National Center for Child Health and Development, Tokyo. The modified Glasgow acute pancreatitis severity score (modified Glasgow), Ranson criteria (Ranson), Balthazar computed tomography severity index (CTSI), and pediatric acute pancreatitis severity (PAPS) score were assessed for their ability to distinguish severe pancreatitis from the milder forms. RESULTS: Thirty-three Japanese children with AP were identified. Among them, 37 episodes were analyzed for the performance of the scoring systems and 33 for the etiology. The most common etiology of AP was structural abnormality (n = 8). Sensitivity for the modified Glasgow, Ranson, PAPS, and CTSI was 42.9%, 52.4%, 81.0%, and 50.0%, respectively, while specificity was 81.3%, 81.3%, 37.5%, and 76.9%, respectively. CONCLUSION: We found PAPS to be the most reliable when used for discriminating the severe form of AP from the milder forms at a Japanese tertiary pediatric care center. PMID- 26252912 TI - New data on photochemistry of the interstellar molecule: HNCS. Identification of the S...HCN complex. AB - Phototransformations of isothiocyanic acid (HNCS) induced by tunable UV laser were studied in low-temperature matrices. Two isomers of the precursor HNCS molecule are formed during UV irradiation of HNCS/Ar and HNCS/N2 samples: thiocyanic acid (HSCN) and isothiofulminic acid (HSNC). In addition, a complex between hydrogen cyanide and a ground state ((3)P) sulfur atom appears at irradiation with wavelength lambda < 290 nm. The vibrational bands of the SHCN complex are observed at 3217.0 and 746.5 cm(-1) in Ar and 3223.5 and 764.5/752.0 cm(-1) in N2. At the beginning of irradiation SHCN is produced from the HNCS precursor. At longer times the main sources of the complex are HSCN and HSNC species. In solid nitrogen, HCN monomers are observed besides SHCN, indicating efficient escape of atomic sulfur out of the matrix cage occupied by the precursor. Differences in the extent of the observed processes are discussed in relation to the wavelength of the UV radiation applied and the type of matrices. Results of the computational studies on the SHCN geometry and infrared spectra are presented and compared with experimental data. PMID- 26252911 TI - Age, Body Mass Index, and Daytime and Nocturnal Hypoxia as Predictors of Hypertension in Patients With Obstructive Sleep Apnea. AB - A growing body of evidence links obstructive sleep apnea (OSA) with hypertension. The authors performed a retrospective cohort study using the University Hospital of Larissa Sleep Apnea Database (1501 patients) to determine predictors of in laboratory diagnosed OSA for development of hypertension. Differences in continuous variables were assessed via independent samples t test, whereas discrete variables were compared by Pearson's chi-square test. Multivariate analysis was performed via discriminant function analysis. There were several significant differences between hypertensive and normotensive patients. Age, body mass index, comorbidity, daytime oxygen saturation, and indices of hypoxia during sleep were deemed the most accurate predictors of hypertension, whereas apnea hypopnea index and desaturation index were not. The single derived discriminant function was statistically significant (Wilk's lambda=0.771, chi(2) =289.070, P<.0001). Daytime and nocturnal hypoxia as consequences of chronic intermittent hypoxia play a central role in OSA-related hypertension and should be further evaluated as possible severity markers in OSA. PMID- 26252913 TI - Dedifferentiated Liposarcoma of the Anterior Mediastinum: A Rare Case. PMID- 26252914 TI - Clinical Features of Lysosomal Acid Lipase Deficiency. AB - OBJECTIVE: The aim of this study was to characterize key clinical manifestations of lysosomal acid lipase deficiency (LAL D) in children and adults. METHODS: Investigators reviewed medical records of LAL D patients ages >=5 years, extracted historical data, and obtained prospective laboratory and imaging data on living patients to develop a longitudinal dataset. RESULTS: A total of 49 patients were enrolled; 48 had confirmed LAL D. Mean age at first disease-related abnormality was 9.0 years (range 0-42); mean age at diagnosis was 15.2 years (range 1-46). Twenty-nine (60%) were male patients, and 27 (56%) were <20 years of age at the time of consent/assent. Serum transaminases were elevated in most patients with 458 of 499 (92%) of alanine aminotransferase values and 265 of 448 (59%) of aspartate aminotransferase values above the upper limit of normal. Most patients had elevated low-density lipoprotein (64% patients) and total cholesterol (63%) at baseline despite most being on lipid-lowering therapies, and 44% had high-density lipoprotein levels below the lower limit of normal. More than half of the patients with liver biopsies (n = 31, mean age 13 years) had documented evidence of steatosis (87%) and/or fibrosis (52%). Imaging assessments revealed that the median liver volume was ~1.15 multiples of normal (MN) and median spleen volume was ~2.2 MN. Six (13%) patients had undergone a liver transplant (ages 9-43.5 years). CONCLUSION: This study provides the largest longitudinal case review of patients with LAL D and confirms that LAL D is predominantly a pediatric disease causing early and progressive hepatic dysfunction associated with dyslipidemia that often leads to liver failure and transplantation. PMID- 26252916 TI - Author's Response. PMID- 26252917 TI - Endoscopic Treatment of Gastric Outlet Obstruction Secondary to Accidental Acid Ingestion in a Child. AB - Accidental corrosive ingestion is not rare in pediatric patients in developing countries. We report a case of gastric outlet obstruction after the accidental ingestion of an acidic substance by a child who was successfully treated with endoscopic balloon dilatation. PMID- 26252915 TI - Prevalence and Clinical, Endoscopic, and Pathological Features of Duodenitis in Children. AB - OBJECTIVES: Although gastritis and esophagitis are well studied in children, there is very limited literature on duodenitis in children. We aimed to assess the prevalence, etiology, clinical, endoscopic, and pathological features in a large cohort of unselected children with duodenitis. METHODS: We reviewed the pathology reports of all the upper endoscopies performed at our institution during 5 years to identify children with duodenitis. Biopsy sections were reviewed to confirm the diagnosis of duodenitis. Demographic, clinical, endoscopic data, and the presence of associated gastritis and esophagitis were noted in all of the children with duodenitis. The etiology of duodenitis was correlated with the patients' clinical diagnosis. RESULTS: Out of 2772 children who had endoscopy, 352 had duodenitis with the prevalence rate of 12.7%. Gastritis was seen in 64% of children with duodenitis compared with 46% of children without duodenitis (P < 0.001). Common indications for endoscopy in children with duodenitis were abdominal pain, positive celiac serology, and diarrhea. The most common etiology was celiac disease (32%), followed by Crohn disease (13%), ulcerative colitis (3%), and Helicobacter pylori infection (6%). In 63% of cases, the endoscopic appearance of duodenum was normal. Cryptitis, villous changes, and cellular infiltration were noted on histology. CONCLUSIONS: Prevalence of duodenitis is 12.7% in children undergoing endoscopy. Celiac disease and inflammatory bowel disease are common causes of duodenitis. Associated gastritis is common in children with duodenitis, and the correlation of endoscopic appearance with histology is poor. PMID- 26252918 TI - Manifestations of Cow's-Milk Protein Intolerance in Preterm Infants. AB - OBJECTIVES: Cow's-milk protein intolerance (CMPI) is poorly recognized in preterm infants. This study examined the clinical events that preceded the diagnosis of CMPI in preterm infants. METHODS: This was a retrospective study of infants in a level-III neonatal intensive care unit of those who received parenteral nutrition (PN) support during a 12-month period. Parameters assessed included birth weight (g), diagnosis, duration and frequency on PN, type of enteral feeds at initiation, and achievement of enteral autonomy. CMPI was diagnosed based on persistent feeding intolerance that resolved after change of feeds from intact protein to a protein hydrolysate or crystalline amino acid formula. RESULTS: Three hundred forty-eight infants with birth weight (median/range) 1618 g (425 5110) received PN. Fifty-one (14%) infants required multiple courses of PN, and 19 of 348 (5%) were diagnosed with CMPI. The requirement for multiple courses on PN versus single course was associated with a high likelihood of CMPI: 14 of 51 versus 5 of 297, P < 0.001. Nine of the 14 infants identified with CMPI were initially diagnosed with necrotizing enterocolitis (NEC) after a median duration of 22 days (19-57) on intact protein feeds. After recovery from NEC, they had persistent feeding intolerance including recurrence of "NEC-like illness" (N = 3) that resolved after change of feeds to a protein hydrolysate or crystalline amino acid formula. CONCLUSIONS: The requirement for multiple courses of PN because of persistent feeding intolerance after recovery from NEC and recurrence of "NEC like illness" may be a manifestation of CMPI in preterm infants. PMID- 26252919 TI - Electromagnetic Guided Postpyloric Tube Placement in Children: A Feasible and Promising Technique. AB - OBJECTIVES: Postpyloric feeding tube (PPFT) placement can be cumbersome. Fluoroscopic and endoscopic placements are required when unguided placement fails. We aimed to evaluate the feasibility and safety of PPFT placement in children, using an electromagnetic (EM) guided system as a rescue strategy in case unguided tube insertion fails. METHODS: In a single-center prospective study, we included all the children (weight >2.5 kg) in whom unguided PPFT placement failed between 2009 and 2012. EM guided PPFT placement was attempted before regular fluoroscopic and endoscopic placement was attempted, respectively. RESULTS: Forty-nine children were included (mean age 3.5 years). EM guided PPFT placement was successful in 82% of the children. No adverse events occurred. Age or indication for the PPFT did not influence the success rate of the procedure. A trend of a learning curve of 25 patients was noticed. Costs of EM placement were slightly higher than those of fluoroscopic placement in our hospital setting. CONCLUSION: With enough expertise, EM guided PPFT placement seems safe and can prevent fluoroscopic or endoscopic tube placement in 82% of children. PMID- 26252920 TI - Factors Determining Optimal Fatty Acid Absorption in Preterm Infants. AB - OBJECTIVES: The aim of the present study was to quantify absorption coefficients of specific fatty acids in preterm infants as a function of diet, formula or breast milk (BM), and postnatal age; to identify the fatty acid structural characteristics that determine optimal fatty acid absorption. METHODS: Fatty acids from dietary and fecal samples were extracted and quantified by gas chromatography-mass spectroscopy. Fatty acid absorption coefficients (FA-CFAs) were calculated by comparing the total amount of fatty acids supplied by the diet to the amount quantified in the total fecal output during a 3-day period. RESULTS: A total of 18 infants (BM 8, formula 10) were studied at 2 weeks of age, and 20 infants (BM 10, formula 10) were studied at 6 weeks of age. FA-CFAs decreased with increasing carbon length in formula-fed infants at 2 and 6 weeks. Results were similar but less in magnitude in BM-fed infants at 2 weeks with no difference at 6 weeks. CONCLUSIONS: Preterm infants fed formula demonstrated lower FA-CFAs as a function of increasing carbon length. This is consistent with limited pancreatic lipase production and with lipase being present in BM but not in formula. The fact that this pattern was seen in BM-fed infants at 2 weeks but not 6 weeks of age suggests that intestinal immaturity may also play a role in impaired fatty acid absorption. These data highlight principles that need to be considered to optimize delivery and absorption of dietary long-chain polyunsaturated fatty acids in preterm infants. PMID- 26252921 TI - Physical Activity Is Prospectively Associated With Adolescent Nonalcoholic Fatty Liver Disease. AB - OBJECTIVES: The aim of the present study was to assess whether objectively measured physical activity at mean ages 12 and 14 years are prospectively associated with ultrasound scan liver fat and stiffness (alanine aminotransferase, aspartate aminotransferase [AST], and gamma-glutamyl transferase [GGT]) assessed at mean age 17.8 years. METHODS: Participants were from the Avon Longitudinal Study of Parents and Children. Total physical activity (counts per minute) and minutes of moderate to vigorous physical activity (MVPA) were measured using ActiGraph accelerometers at mean ages 12 and 14 years. RESULTS: Greater total physical activity and MVPA at ages 12 and 14 years were associated with lower odds of liver fat and lower GGT levels at mean age 17.8 years, such as per 15-minute increase in daily MVPA at age 12 years, the confounder adjusted odds ratio of liver fat was 0.47 (95% confidence interval [CI] 0.27-0.84). Associations attenuated after additional adjustment for fat mass as a potential confounder (eg, per 15-minute increase in daily MVPA at age 12 years, the odds ratio of liver fat attenuated to 0.65 [95% CI 0.35-1.21]) or a potential mediator (eg, per 15-minute increase in daily MVPA at age 12 years the odds ratio of liver fat attenuated to 0.59 [95% CI 0.32-1.09]). Results did not further attenuate after additional adjustment for insulin resistance. There was some evidence that greater total physical activity and MVPA at age 12 years were associated with the higher AST levels. CONCLUSIONS: Adolescents who were more active in childhood have lower odds of fatty liver and lower GGT levels. These findings are likely to be, at least in part, explained by adiposity. PMID- 26252922 TI - Avoid Endoscopy in Children With Suspected Inflammatory Bowel Disease Who Have Normal Calprotectin Levels. AB - In children with suspected inflammatory bowel disease, adding calprotectin stool testing to the screening strategy has been recommended to distinguish organic from nonorganic disease. In this cohort study with historical controls, we could not confirm that screening with stool calprotectin improves the diagnostic yield (ratio inflammatory bowel disease-positive endoscopies and total number of endoscopies); however, in patients with normal fecal calprotectin levels (<50 MUg/g) endoscopic and histological abnormalities were not seen. We propose to refrain from endoscopy when stool calprotectin levels are normal. PMID- 26252923 TI - Severe Liver Disease in Children With alpha-1 Antitrypsin Deficiency in France (DEFI-ALPHA Cohort). PMID- 26252924 TI - Congenital Oesophageal Web Treated Successfully With Endoscopy and Balloon Dilatation. PMID- 26252925 TI - Comment on the Safety of Enterococcus faecium SF68. PMID- 26252926 TI - mHealth Apps Empower Individuals. PMID- 26252927 TI - They Came, They Liked, They Commented: Social Influence on Facebook News Channels. AB - Due to the increasing importance of social networking sites as sources of information, news media organizations have set up Facebook channels in which they publish news stories or links to articles. This research investigated how journalistic texts are perceived in this new context and how reactions of other users change the influence of the main articles. In an online experiment (N=197), a Facebook posting of a reputable news site and the corresponding article were shown. The type of user comments and the number of likes were systematically varied. Negative comments diminished the persuasive influence of the article, while there were no strengthening effects of positive comments. When readers perceived the topic as personally relevant, comments including relevant arguments were more influential than comments with subjective opinions, which can be explained by higher levels of elaboration. However, against expectations of bandwagon perceptions, a high number of likes did not lead to conformity effects, which suggests that exemplifying comments are more influential than statistical user representations. Results are discussed with regard to effects of news media content and the mechanisms of social influence in Web 2.0. PMID- 26252928 TI - When Sharing Is a Bad Idea: The Effects of Online Social Network Engagement and Sharing Passwords with Friends on Cyberbullying Involvement. AB - Every day, children and adolescents communicate online via social networking sites (SNSs). They also report sharing passwords with peers and friends, a potentially risky behavior in regard to cyber safety. This longitudinal study tested the hypotheses that social network engagement in multiple settings would predict more cyberbullying involvement over time, and that youth who reported sharing passwords would also experience an increase in cyberbullying involvement. Data were collected at two time points one year apart from 1,272 third through eighth grade students. In line with the first study hypothesis, participating in more online SNSs was associated with increased cyberbullying involvement over time, as well as sharing passwords over time. Cyberbullying involvement at T1 predicted decreases in sharing passwords over time, suggesting that youth become aware of the dangers of sharing passwords as a result of their experience. Sharing passwords at T1 was unrelated to cyberbullying involvement at T2. Although it seems that youth may be learning from their previous mistakes, due to the widespread use of social media and normality of sharing passwords among young people, it is important to continue to educate youth about cyber safety and risky online behavior. PMID- 26252929 TI - My Friends Right Next to Me: A Laboratory Investigation on Predictors and Consequences of Experiencing Social Closeness on Social Networking Sites. AB - In the last decade, research has provided a series of insights into how and why the use of social networking sites (SNSs) can be socially and psychologically beneficial for individuals. The present research extends this evidence by focusing on the concept of social closeness as a feeling experienced when using SNSs. In a laboratory setting, participants (N=60) spent 10 minutes on Facebook, and then reported their experiences during this session. Analyses of participants' usage behavior and their experiences revealed that the more time users spent interacting with other users (e.g., commenting on updates), the closer they felt to other people. Interacting with others also predicted users' positive emotional states after Facebook use; this effect may be explained by the perception of social closeness. This study is one of the first to employ momentary measures, offering a further theoretical link between active SNS use and well-being. PMID- 26252930 TI - How Much Is Too Much to Pay for Internet Access? A Behavioral Economic Analysis of Internet Use. AB - The popularity of online recreational activities, such as social networking, has dramatically increased the amount of time spent on the Internet. Excessive or inappropriate use of the Internet can result in serious adverse consequences. The current study used a behavioral economic task to determine if the amount of time spent online by problematic and nonproblematic users can be modified by price. The Internet Purchase Task was used to determine how much time undergraduate students (N=233) would spend online at 13 different prices. Despite high demand for Internet access when access was free, time spent online by both problematic and nonproblematic users decreased dramatically, even at low prices. These results suggest that the amount of time spent online may be modified by having a tangible cost associated with use, whereas having free access to the Internet may encourage excessive, problematic use. PMID- 26252931 TI - Social Support and Social Anxiety in Use and Perceptions of Online Mental Health Resources: Exploring Social Compensation and Enhancement. AB - This study used the frameworks of social compensation and social enhancement to examine how social anxiety and social support were related to college students' (N=443) use and perceptions of online mental health resources (Web sites and online support groups). Potential interactions between social support and social anxiety were also examined. Consistent with the social compensation hypothesis, perceived usefulness of Web sites was positively associated with social support. Perceived usefulness of online support groups was positively associated with social support when participants reported average or high, but not low, social anxiety. In contrast, previous use of Web sites was consistent with the social compensation hypothesis. Participants who reported less social support were more likely to have used a Web site for a mental or emotional problem. These findings suggest that college students' use and perceptions of online mental health resources vary as a function of social support and social anxiety, and that patterns suggestive of social compensation and social enhancement depend on whether perceptions or actual use of resources are examined. Combined with the significant interaction between social support and social anxiety on perceived usefulness of online support groups, these findings highlight the potential complexity of social compensation and enhancement phenomena. PMID- 26252932 TI - Interdependent Self-Construal, Self-Efficacy, and Community Involvement as Predictors of Perceived Knowledge Gain Among MMORPG Players. AB - This study explored the relationship between interdependent self-construal, video game self-efficacy, massively multiplayer online role-playing game (MMORPG) community involvement, and self-reported learning outcomes. The results suggested that self-efficacy and interdependent self-construal were positive and significant predictors of MMORPG community involvement. For its part, MMORPG community involvement was a positive predictor of self-reported learning in both focused and incidental forms. Supplementary analyses suggested that self-efficacy was a comparatively more robust predictor of MMORPG community involvement when compared to self-construal. Moreover, the present data suggest that community involvement significantly facilitated indirect relationships between self construal, game-relevant self-efficacy, and both focused and incidental learning. PMID- 26252933 TI - Altered Brain Reactivity to Game Cues After Gaming Experience. AB - Individuals who play Internet games excessively show elevated brain reactivity to game-related cues. This study attempted to test whether this elevated cue reactivity observed in game players is a result of repeated exposure to Internet games. Healthy young adults without a history of excessively playing Internet games were recruited, and they were instructed to play an online Internet game for 2 hours/day for five consecutive weekdays. Two control groups were used: the drama group, which viewed a fantasy TV drama, and the no-exposure group, which received no systematic exposure. All participants performed a cue reactivity task with game, drama, and neutral cues in the brain scanner, both before and after the exposure sessions. The game group showed an increased reactivity to game cues in the right ventrolateral prefrontal cortex (VLPFC). The degree of VLPFC activation increase was positively correlated with the self-reported increase in desire for the game. The drama group showed an increased cue reactivity in response to the presentation of drama cues in the caudate, posterior cingulate, and precuneus. The results indicate that exposure to either Internet games or TV dramas elevates the reactivity to visual cues associated with the particular exposure. The exact elevation patterns, however, appear to differ depending on the type of media experienced. How changes in each of the regions contribute to the progression to pathological craving warrants a future longitudinal study. PMID- 26252934 TI - Role-Playing and Real-Time Strategy Games Associated with Greater Probability of Internet Gaming Disorder. AB - Research indicates that a small subset of those who routinely play video games show signs of pathological habits, with side effects ranging from mild (e.g., being late) to quite severe (e.g., losing a job). However, it is still not clear whether individual types, or genres, of games are most strongly associated with Internet gaming disorder (IGD). A sample of 4,744 University of Wisconsin-Madison undergraduates (Mage=18.9 years; SD=1.9 years; 60.5% female) completed questionnaires on general video game playing habits and on symptoms of IGD. Consistent with previous reports: 5.9-10.8% (depending on classification criteria) of individuals who played video games show signs of pathological play. Furthermore, real-time strategy and role-playing video games were more strongly associated with pathological play, compared with action and other games (e.g., phone games). The current investigation adds support to the idea that not all video games are equal. Instead, certain genres of video games, specifically real time strategy and role-playing/fantasy games, are disproportionately associated with IGD symptoms. PMID- 26252937 TI - Australia and Other Nations Are Failing to Meet Sedentary Behaviour Guidelines for Children: Implications and a Way Forward. AB - BACKGROUND: Australia has joined a growing number of nations that have evaluated the physical activity and sedentary behavior status of their children. Australia received a "D minus" in the first Active Healthy Kids Australia Physical Activity Report Card. METHODS: An expert subgroup of the Australian Report Card Research Working Group iteratively reviewed available evidence to answer 3 questions: (a) What are the main sedentary behaviors of children? (b) What are the potential mechanisms for sedentary behavior to impact child health and development? and (c) What are the effects of different types of sedentary behaviors on child health and development? RESULTS: Neither sedentary time nor screen time is a homogeneous activity likely to result in homogenous effects. There are several mechanisms by which various sedentary behaviors may positively or negatively affect cardiometabolic, neuromusculoskeletal, and psychosocial health, though the strength of evidence varies. National surveillance systems and mechanistic, longitudinal, and experimental studies are needed for Australia and other nations to improve their grade. CONCLUSIONS: Despite limitations, available evidence is sufficiently convincing that the total exposure and pattern of exposure to sedentary behaviors are critical to the healthy growth, development, and wellbeing of children. Nations therefore need strategies to address these common behaviors. PMID- 26252938 TI - Fine Time Scaling of Purifying Selection on Human Nonsynonymous mtDNA Mutations Based on the Worldwide Population Tree and Mother-Child Pairs. AB - A high-resolution mtDNA phylogenetic tree allowed us to look backward in time to investigate purifying selection. Purifying selection was very strong in the last 2,500 years, continuously eliminating pathogenic mutations back until the end of the Younger Dryas (~11,000 years ago), when a large population expansion likely relaxed selection pressure. This was preceded by a phase of stable selection until another relaxation occurred in the out-of-Africa migration. Demography and selection are closely related: expansions led to relaxation of selection and higher pathogenicity mutations significantly decreased the growth of descendants. The only detectible positive selection was the recurrence of highly pathogenic nonsynonymous mutations (m.3394T>C-m.3397A>G-m.3398T>C) at interior branches of the tree, preventing the formation of a dinucleotide STR (TATATA) in the MT-ND1 gene. At the most recent time scale in 124 mother-children transmissions, purifying selection was detectable through the loss of mtDNA variants with high predicted pathogenicity. A few haplogroup-defining sites were also heteroplasmic, agreeing with a significant propensity in 349 positions in the phylogenetic tree to revert back to the ancestral variant. This nonrandom mutation property explains the observation of heteroplasmic mutations at some haplogroup-defining sites in sequencing datasets, which may not indicate poor quality as has been claimed. PMID- 26252939 TI - Executive Summary: 30th Report on Physician Assistant Educational Programs in the United States. AB - PURPOSE: The purpose of this executive summary was to provide an overview of key findings from By the Numbers: 30th Report on Physician Assistant Educational Programs in the United States. METHODS: The 2014 Program Survey is a Web-based survey and is administered annually to all member physician assistant (PA) program directors. This executive summary will focus on 4 of the 7 sections of the survey instrument: general, financial, program personnel, and students. RESULTS: The typical PA program's sponsoring institution is private and in a nonacademic health center. Most PA programs (93.0%) offer a master's degree as the primary or highest credential. The average total program budget was $2,221,751 (SD=$2,426,852). The average total resident tuition was $64,961, and the average total nonresident tuition was $75,964. Overall, 181 programs reported 1843 program faculty. Of those, 1467 were identified as core faculty and 376 were identified as adjunct faculty. A typical first-year PA student is 26 years old (SD=2.51), female (70.3%, n=5898), non-Hispanic (89.3%, n=3631), White (79.9%, n=3712), and has an overall undergraduate and science grade point average (GPA) of 3.52 (SD=0.14) and 3.47 (SD=0.16), respectively. In 2014, there were approximately 7556 graduates from 164 responding programs. CONCLUSION: By gaining a better understanding of the characteristics of PA programs and their faculty and students, policy makers can be better informed. Physician assistant educators and stakeholders are encouraged to use this information to advance and advocate for the profession. PMID- 26252940 TI - Academic Integrity Across Physician Assistant Programs in the United States. AB - PURPOSE: The purpose of this study was to describe how academic integrity is addressed in physician assistant (PA) programs across the United States. METHODS: A descriptive survey was developed dividing questions into 2 groups: demographic information and academic integrity questions. The survey tool was distributed to program directors at all PA programs in the United States that were both fully accredited and provisionally accredited. RESULTS: A total of 171 surveys were distributed with a response of 110 surveys. Most institutions have honor codes in place (86.14%), with most having had an honor code for more than 10 years (62.38%). A notable percentage (25.45%) of program directors believes that academic integrity is a problem at their institution. Overall, 45.45% responded that academic integrity is voiced as an issue by faculty in all disciplines at their institution. Yet, when participants were asked to rate their concern about academic integrity at their program, 49.50% had little or no concern, 30.69% were neutral, and 19.80% reported great or extreme concern about academic integrity within their program. CONCLUSIONS: This study provided baseline data on how academic integrity is currently addressed in PA programs. Drawing from this baseline data and the review of the literature, the next step is to develop academic integrity recommendations that PA programs can adopt. PMID- 26252941 TI - Diagnostic utility of phosphorylated signal transducer and activator of transcription 5 immunostaining in the diagnosis of mammary analogue secretory carcinoma of the salivary gland: A comparative study of salivary gland cancers. AB - BACKGROUND: Mammary analogue secretory carcinoma (MASC) with an ETS variant gene 6 (ETV6)-neurotrophic tyrosine kinase receptor type 3 (NTRK3) translocation is a newly described type of salivary gland cancer. It is known that overexpression of signal transducer and activator of transcription 5a (STAT5a) occurs in secretory carcinoma of the breast and MASC, and STAT5a expression may be related to the ETV6-NTRK3 translocation. It was hypothesized that phosphorylated signal transducer and activator of transcription 5 (p-STAT5) might be specifically expressed in MASC of the salivary gland. METHODS: The expression of p-STAT5 and mammaglobin (MMG) was examined with immunohistochemistry (IHC)/immunocytochemistry (ICC) in tissue sections from 58 salivary gland cancers (8 MASCs and 50 other salivary gland cancers) and in cytological smears from 17 salivary gland cancers (7 MASCs with paired histologic samples and 10 other salivary gland cancers). RESULTS: p-STAT5 IHC was clearly increased in MASC versus normal salivary gland tissue and other salivary gland cancers. p-STAT5 expression was found in 7 of 8 MASCs (87.5%) and in none of the 50 other salivary gland cancers (0%) by IHC. On cytology, p-STAT5 expression was found in all cases of MASC (7 of 7 or 100%) but in none of the 10 other salivary gland cancers (0%) by ICC. The expression rate of MMG by histology and cytology was higher than that of p-STAT5 in the other salivary gland cancers. CONCLUSIONS: p-STAT5 might be useful as a detection marker of MASC in the differential diagnosis of salivary gland cancers, and initial screening with p-STAT5 IHC/ICC, combined with auxiliary fluorescence in situ hybridization confirmation, is a reliable, economical approach to identifying MASC of the salivary gland. PMID- 26252942 TI - Theoretical study on the structures and optical absorption of Si172 nanoclusters. AB - The structures and optical properties of silicon nanoclusters (Si NCs) have attracted continuous interest in the last few decades. However, it is a great challenge to determine the structures of Si NCs for accurate property calculation due to the complication and competition of various structural motifs. In this work, a Si172 NC with a size of about 1.8 nm was investigated using a genetic algorithm combined with tight-binding and DFT calculations. We found that a diamond crystalline core with 50 atoms (1.2 nm) was formed in the Si172 NC. It can be expected that at a size of about 172 atoms, a diamond crystalline structure can nucleate from the center of the Si NCs. The optical properties of the pure and hydrogenated Si172 NC structures also have been studied using the TDDFT method. Compared with the pure Si172 NC, the absorption peaks of the hydrogenated Si172 NC are obviously blue-shifted. PMID- 26252943 TI - Airway responsiveness to mannitol in asthma is associated with chymase-positive mast cells and eosinophilic airway inflammation. AB - BACKGROUND: Airway hyperresponsiveness (AHR) to inhaled mannitol is associated with indirect markers of mast cell activation and eosinophilic airway inflammation. It is unknown how AHR to mannitol relates to mast cell phenotype, mast cell function and measures of eosinophilic inflammation in airway tissue. We compared the number and phenotype of mast cells, mRNA expression of mast cell associated genes and number of eosinophils in airway tissue of subjects with asthma and healthy controls in relation to AHR to mannitol. METHODS: Airway hyperresponsiveness to inhaled mannitol was measured in 23 non-smoking, corticosteroid-free asthmatic individuals and 10 healthy controls. Mast cells and eosinophils were identified in mucosal biopsies from all participants. Mast cells were divided into phenotypes based on the presence of chymase. mRNA expression of mast cell-associated genes was measured by real-time PCR. RESULTS: The proportion of submucosal MCTC was higher in asthmatic individuals with AHR to mannitol compared with asthmatic individuals without AHR (median: 40.3% vs. 18.7%, P = 0.03). Increased submucosal MCTC numbers were associated with increased levels of mRNA for thymic stromal lymphopoietin (TSLP) and CPA3 in asthmatics. Reactivity to mannitol correlated significantly with eosinophils in submucosa (r(s): 0.56, P = 0.01). CONCLUSION: Airway hyperresponsiveness to inhaled mannitol is associated with an altered submucosal mast cell profile in asthmatic individuals. This mast cell profile is associated with increased levels of TSLP and CPA3. The degree of AHR to mannitol is correlated with the degree of eosinophilic inflammation in the airway submucosa. PMID- 26252944 TI - MicroRNA-338-3p functions as tumor suppressor in breast cancer by targeting SOX4. AB - MicroRNA-338-3p (miR-338-3p), a recently discovered miRNA, has been reported to be downregulated and play tumor suppressor roles in gastric cancer, ovarian cancer, colorectal carcinoma and lung cancer by targeting several genes. However, the role and potential mechanism of miR-338-3p in breast cancer (BC) is still unclear. In the present study, we investigated the roles and mechanisms of miR 338-3p in human breast cancer. miR-338-3p expression was determined by qRT-PCR in human BC cell lines, and clinical significantly of miR-338-3p expression was further evaluated. Furthermore, the function of miR-338-3p in breast cancer also was investigated by several in vitro approaches and in nude mouse models. Luciferase assay and western blot analysis were performed to validate the potential targets of miR-338-3p after the preliminary screening by employing open access software. It was found that miR-338-3p was significantly downregulated in both BC tissues and cell lines and the low expression of miR-338-3p was inversely correlated with lymph node metastatic and TNM stage status (P<0.01). Function assay showed that the overexpression of miR-338-3p in BC cells significantly inhibited cell proliferation, colony formation, migration and invasion, and induced cell apoptosis and cell cycle arrest at G1/G0 stage, as well as suppressed tumor growth in the nude mouse model. Luciferase assay and western blot analysis identified sex-determining region Y-box 4 (SOX4) as a direct and functional target of miR-338-3p. These findings revealed that miR-338-3p may act as a tumor suppressor in breast cancer by targeting SOX4, suggesting miR-338-3p as a novel strategy for breast cancer treatment. PMID- 26252945 TI - Effects of Aftermarket Control Technologies on Gas and Particle Phase Oxidative Potential from Diesel Engine Emissions. AB - Particulate matter (PM) originating from diesel combustion is a public health concern due to its association with adverse effects on respiratory and cardiovascular diseases and lung cancer. This study investigated emissions from three stationary diesel engines (gensets) and varying power output (230 kW, 400 kW, and 600 kW) at 50% and 90% load to determine concentrations of gaseous (GROS) and PM reactive oxygen species (PMROS). In addition, the influence of three modern emission control technologies on ROS emissions was evaluated: active and passive diesel particulate filters (A-DPF and P-DPF) and a diesel oxidation catalyst (DOC). PMROS made up 30-50% of the total ROS measured without aftermarket controls. All applied controls removed PMROS by more than 75% on average. However, the oxidative potential of PM downstream of these devices was not diminished at the same rate and particles surviving the A-PDF had an even higher oxidative potential on a per PM mass basis compared to the particles emitted by uncontrolled gensets. Further, the GROS as compared to PMROS emissions were not reduced with the same efficiency (<36%). GROS concentrations were highest with the DOC in use, indicating continued formation of GROS with this control. Correlation analyses showed that PMROS and to a lesser extent GROS have a good correlation with semivolatile organic carbon (OC1) subfraction. In addition, results suggest that chemical composition, rather than PM size, is responsible for differences in the PM oxidative potential. PMID- 26252946 TI - PRKX, a Novel cAMP-Dependent Protein Kinase Member, Plays an Important Role in Development. AB - The human protein kinase X gene (PRKX) and cAMP-dependent protein kinase (PKA) are both c-AMP-dependent serine/threonine protein kinases within the protein kinase AGC subgroup. Of all the protein kinases in this group, PRKX is the least studied. PRKX has been isolated from patients with chondrodysplasia punctate and is involved in numerous processes, including sexual differentiation and fertilization, normal kidney development and autosomal dominant polycystic kidney disease (ADPKD), blood maturation, neural development, and angiogenesis in vitro. Although the role of PRKX in development and disease has been reported recently, the underlying mechanism of PRKX activity is largely unknown. In addition, based on the expression pattern of PRKX and the extensive role of PKA in disease and development, PRKX might have additional crucial functions that have not been addressed in the literature. In this review, we summarize the characteristics and developmental functions of PRKX that have been reported by recent studies. In particular, we elucidate the structural and functional differences between PRKX and PKA, as well as the possible roles of PRKX in development and related diseases. Finally, we propose future studies that could lead to important discoveries of more PRKX functions and the underlying mechanisms involved. PMID- 26252947 TI - Statistical Learning, Syllable Processing, and Speech Production in Healthy Hearing and Hearing-Impaired Preschool Children: A Mismatch Negativity Study. AB - OBJECTIVES: The objectives of the present study were to investigate temporal/spectral sound-feature processing in preschool children (4 to 7 years old) with peripheral hearing loss compared with age-matched controls. The results verified the presence of statistical learning, which was diminished in children with hearing impairments (HIs), and elucidated possible perceptual mediators of speech production. DESIGN: Perception and production of the syllables /ba/, /da/, /ta/, and /na/ were recorded in 13 children with normal hearing and 13 children with HI. Perception was assessed physiologically through event-related potentials (ERPs) recorded by EEG in a multifeature mismatch negativity paradigm and behaviorally through a discrimination task. Temporal and spectral features of the ERPs during speech perception were analyzed, and speech production was quantitatively evaluated using speech motor maximum performance tasks. RESULTS: Proximal to stimulus onset, children with HI displayed a difference in map topography, indicating diminished statistical learning. In later ERP components, children with HI exhibited reduced amplitudes in the N2 and early parts of the late disciminative negativity components specifically, which are associated with temporal and spectral control mechanisms. Abnormalities of speech perception were only subtly reflected in speech production, as the lone difference found in speech production studies was a mild delay in regulating speech intensity. CONCLUSIONS: In addition to previously reported deficits of sound-feature discriminations, the present study results reflect diminished statistical learning in children with HI, which plays an early and important, but so far neglected, role in phonological processing. Furthermore, the lack of corresponding behavioral abnormalities in speech production implies that impaired perceptual capacities do not necessarily translate into productive deficits. PMID- 26252948 TI - Analysis of Response Elements Involved in the Regulation of the Human Neonatal Fc Receptor Gene (FCGRT). AB - Human epithelial, endothelial and PMA-differentiated THP-1 cell lines were used as model systems to study the transcriptional regulation of the human FCGRT gene encoding the alpha chain of hFcRn. The data obtained from site-directed mutagenesis in transient transfection experiments indicate that the Sp1 sites at positions -641, -635, and -313, CF1/YY1 elements at positions -586 and -357, and the AP-1 motif at -276 within the-660/-233 fragment of the human FCGRT promoter (hFCGRT) participate in the regulation of human FCGRT in all selected cell lines. However, their individual contribution to promoter activity is not equivalent. The Sp1 binding site at -313 and the AP-1 site at -276 are critical for the activity of the hFCGRT promoter in epithelial and endothelial cells. Moreover, the CF1/YY1 site at -586 in differentiated THP-1 cells, plays an essential role in the transcriptional activity of the promoter. In addition, the C/EBPbeta binding site at -497 of the hFCGRT promoter in epithelial and endothelial cells, and the C/EBPbeta motif located at -497 and -233 within the hFCGRT promoter in differentiated THP-1 cells may function as positive regulatory sequences in response to LPS or PMA stimulation. EMSA and supershift analyses showed that the functionally identified binding motifs in the hFCGRT promoter were able to specifically interact with their corresponding (Sp1, Sp2, Sp3, c-Fos, c-Jun, YY1, and C/EBPbeta or C/EBPdelta) transcription factors (TFs), suggesting their possible involvement in the regulation of the human FCGRT gene expression. PMID- 26252949 TI - Adult Human Biliary Tree Stem Cells Differentiate to beta-Pancreatic Islet Cells by Treatment with a Recombinant Human Pdx1 Peptide. AB - Generation of beta-pancreatic cells represents a major goal in research. The aim of this study was to explore a protein-based strategy to induce differentiation of human biliary tree stem cells (hBTSCs) towards beta-pancreatic cells. A plasmid containing the sequence of the human pancreatic and duodenal homeobox 1 (PDX1) has been expressed in E. coli. Epithelial-Cell-Adhesion-Molecule positive hBTSCs or mature human hepatocyte cell line, HepG2, were grown in medium to which Pdx1 peptide was added. Differentiation toward pancreatic islet cells were evaluated by the expression of the beta-cell transcription factors, Pdx1 and musculoapo-neurotic fibrosarcoma oncogene homolog A, and of the pancreatic hormones, insulin, glucagon, and somatostatin, investigated by real time polymerase chain reaction, western blot, light microscopy and immunofluorescence. C-peptide secretion in response to high glucose was also measured. Results indicated how purified Pdx1 protein corresponding to the primary structure of the human Pdx1 by mass spectroscopy was efficiently produced in bacteria, and transduced into hBTSCs. Pdx1 exposure triggered the expression of both intermediate and mature stage beta-cell differentiation markers only in hBTSCs but not in HepG2 cell line. Furthermore, hBTSCs exposed to Pdx1 showed up regulation of insulin, glucagon and somatostatin genes and formation of 3 dimensional islet-like structures intensely positive for insulin and glucagon. Finally, Pdx1-induced islet-like structures exhibited glucose-regulated C-peptide secretion. In conclusion, the human Pdx1 is highly effective in triggering hBTSC differentiation toward functional beta-pancreatic cells. PMID- 26252950 TI - Association of baseline plasma des-acyl ghrelin level with the response to rikkunshito in patients with functional dyspepsia. AB - BACKGROUND AND AIM: We recently conducted a randomized placebo-controlled trial on the efficacy and safety of rikkunshito, a standardized Japanese herbal medicine, for the treatment of functional dyspepsia (FD). The present post-hoc study aimed to evaluate the differences in clinical characteristics between responders and non-responders among FD patients who received rikkunshito for 8 weeks. METHODS: Rikkunshito responders were defined by using a global patient assessment. Candidate predictors included age, gender, smoking, alcohol consumption, body mass index, comorbidity, Helicobacter pylori infection, plasma levels of acyl ghrelin and des-acyl ghrelin, severity of dyspeptic symptoms, FD subgroup, previous medication, and the type of recruiting institution (clinic or hospital). We calculated hazard ratios (HRs) by using Cox regression analysis with the factors that were indicated to be associated with responders. RESULTS: We assigned 83 and 42 patients to responder and non-responder categories, respectively. Lack of alcohol consumption (HR, 2.04; 95% confidence interval, 1.08-3.88) and low plasma des-acyl ghrelin levels (< 177 fmol/mL; HR, 2.42; 95% confidence interval, 1.24-4.73) were significantly associated with the efficacy of rikkunshito. Lack of alcohol consumption was associated with the efficacy of rikkunshito especially among H. pylori-infected participants. On the other hand, the low plasma des-acyl ghrelin was associated with the efficacy of rikkunshito especially among H. pylori-negative participants. CONCLUSIONS: A low baseline level of plasma des-acyl ghrelin was associated with an increased treatment efficacy of rikkunshito against FD. Lack of alcohol consumption was also clinically useful for predicting the response to rikkunshito. PMID- 26252952 TI - Sample-Based Vegetation Distribution Information Synthesis. AB - In constructing and visualizing a virtual three-dimensional forest scene, we must first obtain the vegetation distribution, namely, the location of each plant in the forest. Because the forest contains a large number of plants, the distribution of each plant is difficult to obtain from actual measurement methods. Random approaches are used as common solutions to simulate a forest distribution but fail to reflect the specific biological arrangements among types of plants. Observations show that plants in the forest tend to generate particular distribution patterns due to growth competition and specific habitats. This pattern, which represents a local feature in the distribution and occurs repeatedly in the forest, is in line with the "locality" and "static" characteristics in the "texture data", making it possible to use a sample-based texture synthesis strategy to build the distribution. We propose a vegetation distribution data generation method that uses sample-based vector pattern synthesis. A sample forest stand is obtained first and recorded as a two dimensional vector-element distribution pattern. Next, the large-scale vegetation distribution pattern is synthesized automatically using the proposed vector pattern synthesis algorithm. The synthesized distribution pattern resembles the sample pattern in the distribution features. The vector pattern synthesis algorithm proposed in this paper adopts a neighborhood comparison technique based on histogram matching, which makes it efficient and easy to implement. Experiments show that the distribution pattern synthesized with this method can sufficiently preserve the features of the sample distribution pattern, making our method meaningful for constructing realistic forest scenes. PMID- 26252951 TI - Pregnancy-Associated Heart Failure: A Comparison of Clinical Presentation and Outcome between Hypertensive Heart Failure of Pregnancy and Idiopathic Peripartum Cardiomyopathy. AB - AIMS: There is controversy regarding the inclusion of patients with hypertension among cases of peripartum cardiomyopathy (PPCM), as the practice has contributed significantly to the discrepancy in reported characteristics of PPCM. We sought to determine whether hypertensive heart failure of pregnancy (HHFP) (i.e., peripartum cardiac failure associated with any form of hypertension) and PPCM have similar or different clinical features and outcome. METHODS AND RESULTS: We compared the time of onset of symptoms, clinical profile (including electrocardiographic [ECG] and echocardiographic features) and outcome of patients with HHFP (n = 53; age 29.6 +/- 6.6 years) and PPCM (n = 30; age 31.5 +/ 7.5 years). The onset of symptoms was postpartum in all PPCM patients, whereas it was antepartum in 85% of HHFP cases (p<0.001). PPCM was more significantly associated with the following features than HHFP (p<0.05): twin pregnancy, smoking, cardiomegaly with lower left ventricular ejection fraction on echocardiography, and longer QRS duration, QRS abnormalities, left atrial hypertrophy, left bundle branch block, T wave inversion and atrial fibrillation on ECG. By contrast, HHFP patients were significantly more likely (p<0.05) to have a family history of hypertension, hypertension and pre-eclampsia in a previous pregnancy, tachycardia at presentation on ECG, and left ventricular hypertrophy on echocardiography. Chronic heart failure, intra-cardiac thrombus and pulmonary hypertension were found significantly more commonly in PPCM than in HHFP (p<0.05). There were 5 deaths in the PPCM group compared to none among HHFP cases (p = 0.005) during follow-up. CONCLUSION: There are significant differences in the time of onset of heart failure, clinical, ECG and echocardiographic features, and outcome of HHFP compared to PPCM, indicating that the presence of hypertension in pregnancy-associated heart failure may not fit the case definition of idiopathic PPCM. PMID- 26252953 TI - Lack of Physiological Depth Patterns in Conspecifics of Endemic Antarctic Brown Algae: A Trade-Off between UV Stress Tolerance and Shade Adaptation? AB - A striking characteristic of endemic Antarctic brown algae is their broad vertical distribution. This feature is largely determined by the shade adaptation in order to cope with the seasonal variation in light availability. However, during spring-summer months, when light penetrates deep in the water column these organisms have to withstand high levels of solar radiation, including UV. In the present study we examine the light use characteristics in parallel to a potential for UV tolerance (measured as content of phenolic compounds, antioxidant activity and maximum quantum yield of fluorescence) in conspecific populations of four Antarctic brown algae (Ascoseira mirabilis, Desmarestia menziesii, D. anceps and Himantothallus grandifolius) distributed over a depth gradient between 5 and 30 m. The main results indicated that a) photosynthetic efficiency was uniform along the depth gradient in all the studied species, and b) short-term (6 h) exposure to UV radiation revealed a high tolerance measured as chlorophyll fluorescence, phlorotannin content and antioxidant capacity. Multivariate analysis of similarity indicated that light requirements for photosynthesis, soluble phlorotannins and antioxidant capacity are the variables determining the responses along the depth gradient in all the studied species. The suite of physiological responses of algae with a shallower distribution (A. mirabilis and D. menziesii) differed from those with deeper vertical range (D. anceps and H. grandifolius). These patterns are consistent with the underwater light penetration that defines two zones: 0-15 m, with influence of UV radiation (1% of UV-B and UV-A at 9 m and 15 m respectively) and a zone below 15 m marked by PAR incidence (1% up to 30 m). These results support the prediction that algae show a UV stress tolerance capacity along a broad depth range according to their marked shade adaptation. The high contents of phlorotannins and antioxidant potential appear to be strongly responsible for the lack of clear depth patterns in light demand characteristics and UV tolerance. PMID- 26252954 TI - High-Throughput Assay Development for Cystine-Glutamate Antiporter (xc-) Highlights Faster Cystine Uptake than Glutamate Release in Glioma Cells. AB - The cystine-glutamate antiporter (system xc-) is a Na+-independent amino acid transporter that exchanges extracellular cystine for intracellular glutamate. It is thought to play a critical role in cellular redox processes through regulation of intracellular glutathione synthesis via cystine uptake. In gliomas, system xc- expression is universally up-regulated while that of glutamate transporters down regulated, leading to a progressive accumulation of extracellular glutamate and excitotoxic cell death of the surrounding non-tumorous tissue. Additionally, up regulation of system xc- in activated microglia has been implicated in the pathogenesis of several neurodegenerative disorders mediated by excess glutamate. Consequently, system xc- is a new drug target for brain cancer and neuroinflammatory diseases associated with excess extracellular glutamate. Unfortunately no potent and selective small molecule system xc- inhibitors exist and to our knowledge, no high throughput screening (HTS) assay has been developed to identify new scaffolds for inhibitor design. To develop such an assay, various neuronal and non-neuronal human cells were evaluated as sources of system xc-. Human glioma cells were chosen based on their high system xc- activity. Using these cells, [14C]-cystine uptake and cystine-induced glutamate release assays were characterized and optimized with respect to cystine and protein concentrations and time of incubation. A pilot screen of the LOPAC/NINDS libraries using glutamate release demonstrated that the logistics of the assay were in place but unfortunately, did not yield meaningful pharmacophores. A larger, HTS campaign using the 384-well cystine-induced glutamate release as primary assay and the 96-well 14C-cystine uptake as confirmatory assay is currently underway. Unexpectedly, we observed that the rate of cystine uptake was significantly faster than the rate of glutamate release in human glioma cells. This was in contrast to the same rates of cystine uptake and glutamate release previously reported in normal human fibroblast cells. PMID- 26252955 TI - Latent Autoimmune Diabetes in Adults in the United Arab Emirates: Clinical Features and Factors Related to Insulin-Requirement. AB - AIMS: To describe and to characterize clinical features of latent autoimmune diabetes in adults (LADA) compared to type 1 and type 2 diabetes in the UAE. METHODS: In this cross-sectional study a dataset including 18,101 subjects with adult-onset (>30 years) diabetes was accessed. 17,072 subjects fulfilled the inclusion/exclusion criteria. Data about anthropometrics, demographics, autoantibodies to Glutamic Acid Decarboxylase (GADA) and to Islet Antigen 2 (anti IA2), HbA1c, cholesterol and blood pressure were extracted. LADA was diagnosed according to GADA and/or anti-IA2 positivity and time to insulin therapy. RESULTS: 437 (2.6%) patients were identified as LADA and 34 (0.2%) as classical type 1 diabetes in adults. Mean age at diagnosis, BMI, waist circumference, systolic blood pressure and HbA1c significantly differed between, LADA, type 2 and type 1 diabetes, LADA showing halfway features between type 2 and type 1 diabetes. A decreasing trend for age at diagnosis and waist circumference was found among LADA subjects when subdivided by positivity for anti-IA2, GADA or for both antibodies (p=0.013 and p=0.011 for trend, respectively). There was a gradual downward trend in autoantibody titre in LADA subjects requiring insulin within the first year from diagnosis to subjects not requiring insulin after 10 years of follow-up (p<0.001). CONCLUSIONS: This is the first study describing the clinical features of LADA in the UAE, which appear to be different from both type 1 and type 2 diabetes. Furthermore, we showed that the clinical phenotype of LADA is dependent on different patterns of antibody positivity, influencing the time to insulin requirement. PMID- 26252957 TI - Correction: Carbon Ion Radiation Inhibits Glioma and Endothelial Cell Migration Induced by Secreted VEGF. PMID- 26252956 TI - Impact of Soil Heavy Metal Pollution on Food Safety in China. AB - Food safety is a major concern for the Chinese public. This study collected 465 published papers on heavy metal pollution rates (the ratio of the samples exceeding the Grade II limits for Chinese soils, the Soil Environmental Quality Standard-1995) in farmland soil throughout China. The results showed that Cd had the highest pollution rate of 7.75%, followed by Hg, Cu, Ni and Zn, Pb and Cr had the lowest pollution rates at lower than 1%. The total pollution rate in Chinese farmland soil was 10.18%, mainly from Cd, Hg, Cu, and Ni. The human activities of mining and smelting, industry, irrigation by sewage, urban development, and fertilizer application released certain amounts of heavy metals into soil, which resulted in the farmland soil being polluted. Considering the spatial variations of grain production, about 13.86% of grain production was affected due to the heavy metal pollution in farmland soil. These results many provide valuable information for agricultural soil management and protection in China. PMID- 26252958 TI - Identification of a novel mutation associated with familial adenomatous polyposis and colorectal cancer. AB - Colorectal cancer (CRC) is among the most fatal forms of solid tumor in men and women. While the majority of diagnosed CRC cases are sporadic, 15-25% of patients have a family history of adenomatous polyposis and CRC; however, the associated gene mutations remain largely unidentified. The aim of the present study was to investigate the genomes of a four-generational Chinese Han family with familial adenomatous polyposis and CRC to identify the potential genetic anomalies associated with the disease. Diagnoses were made by physical and enteroscopic examinations of all the family members. Mutational analyses of the potential CRC associated genes were carried out by direct gene sequencing, and the statistically significant differences in polymorphisms between normal and diseased populations were determined. Multiple sequence alignment and protein modeling were conducted using the Vector NTI and DNAMAN software tools. Clinical and pathological features of all the examined patients were consistent with typical familial adenomatous polyposis (FAP) syndrome. From the genomes of these family members, a 131564T>C (p.1125Val>Ala) mutation was identified in exon 15 of the APC gene, and a 1126G>C (p.324Gln>His) mutation was identified in exon 12 of the MUTYH gene. The 131564T>C mutation co-segregated with the affected individuals in the family and was specifically associated with the incidence of CRC (P=0.018<0.05). The 1125Val residue was highly conserved in the APC protein, and the p.1125Val>Ala mutation led to changes in the secondary structure and hydrophilicity of the APC protein. In conclusion, the APC gene mutation 131564T>C is associated with FAP and the pathogenesis of CRC. PMID- 26252959 TI - An analysis of perceived access to health care in Europe: How universal is universal coverage? AB - The objective of this paper is to examine variations in perceptions of access to health care across and within 29 European countries. Using data from the 2008 round of the European Social Survey, we investigate the likelihood of an individual perceiving that they will experience difficulties accessing health care in the next 12 months, should they need it (N=51,835). We find that despite most European countries having mandates for universal health coverage, individuals who are low income, in poor health, lack citizenship in the country where they reside, 20-30 years old, unemployed and/or female have systematically greater odds of feeling unable to access care. Focusing on the role of income, we find that while there is a strong association between low income and perceived access barriers across countries, within many countries, perceptions of difficulties accessing care are not concentrated uniquely among low-income groups. This implies that factors that affect all income groups, such as poor quality care and long waiting times may serve as important barriers to access in these countries. Despite commitments to move towards universal health coverage in Europe, our results suggest that there is still significant heterogeneity among individuals' perceptions of access and important barriers to accessing health care. PMID- 26252960 TI - Lung cancer risk of airborne particles for Italian population. AB - Airborne particles, including both ultrafine and supermicrometric particles, contain various carcinogens. Exposure and risk-assessment studies regularly use particle mass concentration as dosimetry parameter, therefore neglecting the potential impact of ultrafine particles due to their negligible mass compared to supermicrometric particles. The main purpose of this study was the characterization of lung cancer risk due to exposure to polycyclic aromatic hydrocarbons and some heavy metals associated with particle inhalation by Italian non-smoking people. A risk-assessment scheme, modified from an existing risk model, was applied to estimate the cancer risk contribution from both ultrafine and supermicrometric particles. Exposure assessment was carried out on the basis of particle number distributions measured in 25 smoke-free microenvironments in Italy. The predicted lung cancer risk was then compared to the cancer incidence rate in Italy to assess the number of lung cancer cases attributed to airborne particle inhalation, which represents one of the main causes of lung cancer, apart from smoking. Ultrafine particles are associated with a much higher risk than supermicrometric particles, and the modified risk-assessment scheme provided a more accurate estimate than the conventional scheme. Great attention has to be paid to indoor microenvironments and, in particular, to cooking and eating times, which represent the major contributors to lung cancer incidence in the Italian population. The modified risk assessment scheme can serve as a tool for assessing environmental quality, as well as setting up exposure standards for particulate matter. PMID- 26252961 TI - Analytical method for the determination and a survey of parabens and their derivatives in pharmaceuticals. AB - Exposure of humans to parabens is a concern due to the estrogenic activity of these compounds. Parabens are widely used as preservatives in some personal care products, foodstuffs and pharmaceuticals owing to their low cost, high water solubility and broad spectrum antimicrobial properties. Despite this, little is known on the occurrence of parabens in pharmaceutical products. In this study, a method based on solid-liquid or liquid-liquid extraction (SLE or LLE), and high performance liquid chromatography (HPLC) coupled with triple quadrupole tandem mass spectrometry (QqQ or MS/MS) was developed for the determination of six most frequently used parabens and four paraben derivatives (methyl- and ethyl protocatechuates, and mono- and di-hydroxybenzoic acids) in pharmaceuticals. A sample-purification step involving solid phase extraction (SPE) was optimized for the analysis of solid and lipid-rich pharmaceuticals. To our knowledge, this is the first comprehensive report on the occurrence of parabens in pharmaceuticals. The developed method was applied for the analysis of 128 liquid/syrup, cream, solid, prescription or over-the counter (OTC) drugs collected from the USA and a few other countries in Europe and Asia. Although majority of the drugs analyzed in the study did not contain parabens, concentrations as high as 2 mg/g were found in some drugs. Methyl- and propyl- parabens were the frequently detected compounds. 4-Hydroxybenzoic acid was the major metabolite found in pharmaceutical products. PMID- 26252962 TI - Structural and computational study on inhibitory compounds for endonuclease activity of influenza virus polymerase. AB - Seasonal epidemics and occasional pandemics caused by influenza viruses are global threats to humans. Since the efficacy of currently approved drugs is limited by the emerging resistance of the viruses, the development of new antiviral drugs is still demanded. Endonuclease activity, which lies in the influenza polymerase acidic protein N-terminal domain (PA(N)), is a potent target for novel antiviral agents. Here, we report the identification of some novel inhibitors for PA(N) endonuclease activity. The binding mode of one of the inhibitory compounds to PA(N) was investigated in detail by means of X-ray crystal structure analysis and molecular dynamics (MD) simulation. It was observed in the crystal structure that three molecules of the same kind of inhibitor were bound to one PA(N). One of the three molecules is located at the active site and makes a chelation to metal ions. Another molecule is positioned at the space adjacent to the metal-chelated site. The other molecule is located at a site slightly apart from the metal-chelated site, causing a conformational change of Arg124. The last binding site was not observed in previous crystallographic studies. Hence, the stability of inhibitor binding was examined by performing 100-ns MD simulation. During the MD simulation, the three inhibitor molecules fluctuated at the respective binding sites at different amplitudes, while all of the molecules maintained interactions with the protein. Molecular mechanics/generalized Born surface area (MM/GBSA) analysis suggested that the molecule in the last binding site has a higher affinity than the others. Structural information obtained in this study will provide a hint for designing and developing novel potent agents against influenza viruses. PMID- 26252963 TI - Novel diazabicycloalkane delta opioid agonists. AB - Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (delta) opioid agonists, as conformationally constrained homologues of the reference delta agonist (+)-4-[(alphaR) alpha((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of delta opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10 diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed delta agonism behaviour and remarkable affinity to delta receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved delta affinity and selectivity relative to SNC80. PMID- 26252964 TI - Prevalence and factors associated with prelacteal feeding in Western Nepal. AB - BACKGROUND: Newborn infants are often given prelacteal feeds in Nepal despite government policies encouraging exclusive breastfeeding for the first six months of life. AIM: This study investigated the prevalence, reasons, types and factors associated with prelacteal feeding in the south-western region of Nepal. METHODS: Information on prelacteal feeding was obtained from 735 recently delivered women who were recruited for a prospective community-based cohort study conducted during 2014 in the Rupandehi district of Nepal. Factors associated with prelacteal feeding were assessed using logistic regression analysis. FINDINGS: A total of 225 (30.6%) mothers reported giving prelacteal feeds to their infants. The most popular prelacteal food was formula milk (41.7%), followed by cow or buffalo milk (26.6%), and sugar/glucose water (12.4%). Caesarean delivery (17.3%), cultural preference (16.4%) and being tired after childbirth (10.6%) were the most commonly cited reasons. Almost half (48%) of the mothers were advised by their mother/mother-in-law on prelacteal feeding method. Higher parity (adjusted odds ratio (OR) 2.05; 95% confidence interval (CI) 1.18-3.54), low birthweight (OR 1.97; 95% CI 1.23-3.16), caesarean delivery (OR 3.70; 95% CI 2.37 5.80) and wealthy status (OR 2.49; 95% CI 1.52-4.06) were associated with prelacteal feeding. CONCLUSION: Nearly one-third of the infants in this study were given prelacteal feeds. Future breastfeeding promotion programmes should focus on the mothers with low birthweight infants, of high parity, from a wealthy family and those who had caesarean delivery. PMID- 26252965 TI - [Not Available]. PMID- 26252966 TI - [Not Available]. PMID- 26252967 TI - beta-(1->3),(1->6)-Glucans: medicinal activities, characterization, biosynthesis and new horizons. AB - Biological activities of medicinal mushrooms have been attributed to beta-(1 >3),(1->6)-glucans that are present in the cell wall of fungi and some plants. Antitumor, immunomodulatory, antimicrobial, antinociception, antiinflammatory, prebiotic, antioxidant, and antidiabetic are some of different properties already described for beta-(1->3),(1->6)-glucans. Immune activation systems, including specific beta-glucan receptors like Dectin-1, complement (CR3), and Toll (TLR), have been identified to clarify these biological effects. The beta-(1->3)-glucans are synthesized by beta-(1->3)-glucan synthase (GLS), an enzyme belonging to the glucosyltransferase group, which has a catalytic unit (FKS) and another regulatory (RHO). The mechanisms for adding beta-(1->6) branches to the non reducing ends of the beta-(1->3)-glucan chains are unclear until now. Due to the biological importance of beta-(1->3),(1->6)-glucan, it is necessary to understand the biochemical and molecular mechanisms of its synthesis, both to optimize the production of bioactive compounds and to develop antifungal drugs that interrupt this process. Therefore, the aim of this review is to gather information about the potential of beta-(1->3),(1->6)-glucans, their methods of isolation, purification, and chemical characterization, as well as how these biomolecules are synthesized by fungi and what studies involving biotechnology or molecular biology have contributed to this subject. PMID- 26252968 TI - Fine-tuning recA expression in Staphylococcus aureus for antimicrobial photoinactivation: importance of photo-induced DNA damage in the photoinactivation mechanism. AB - Bacterial cell envelope is generally accepted as the primary target for a photo induced oxidative stress. It is plausible that DNA damage occurs during the antimicrobial photoinactivation. Here we investigate the correlation between DNA damage and photoinactivation by evaluating the level of RecA-based DNA repair system in Staphylococcus aureus. By using exogenous photosensitizers (new methylene blue (NMB), toluidine blue O (TBO), 5,10,15,20-tetrakis(1-methyl-4 pyridinio)porphyrin tetra(p-toluenesulfonate) (TMPyP), zinc phthalocyanine (ZnPc), Rose Bengal (RB)) and ALA-induced endogenous porphyrin-dependent blue light (405 nm), several outcomes were observed: (i) an increase of DNA damage (from gel electrophoresis in DNA damage assay), (ii) an increase of recA expression (luminescence assay in recA-lux strain), and (iii) an increase of RecA protein level (Western blotting). When recA expression was repressed by novobiocin, or abolished by deleting the gene, S. aureus susceptibility towards photoinactivation was increased at approximately a hundred-fold. The absence of RecA increases DNA damage to yield bactericidal effect. In novobiocin-resistant mutant (gyrB), as opposed to wild type, neither RecA protein level nor cell's susceptibility was affected by photoinactivation (when novobiocin is present). This is to suggest that GyrB-dependent inhibition mediated recA repression. Therefore, we have established the role of RecA in DNA damage during photoinactivation. With the use of rifampicin mutation frequency and Ames tests, we demonstrated that photoinactivation did not increase S. aureus mutagenesis and potentially is not mutagenic toward eukaryotic cells. The results suggest that the treatment is considered safe. In conclusion, we provide an evidence that recA inhibitor may serve as therapeutic adjuvant for antimicrobial photoinactivation. Clinical relevance of our findings warrants further investigations. PMID- 26252969 TI - Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells. AB - Combination chemotherapy is standard treatment for pancreatic cancer. However, current drugs lack efficacy for most patients, and selection and evaluation of new combination regimens is empirical and time-consuming. The efficacy of gemcitabine, a standard-of-care agent, combined with birinapant, a pro-apoptotic antagonist of Inhibitor of Apoptosis Proteins (IAPs), was investigated in pancreatic cancer cells. PANC-1 cells were treated with vehicle, gemcitabine (6, 10, 20 nM), birinapant (50, 200, 500 nM), and combinations of the two drugs. Temporal changes in cell numbers, cell cycle distribution, and apoptosis were measured. A basic pharmacodynamic (PD) model based on cell numbers, and a mechanism-based PD model integrating all measurements, were developed. The basic PD model indicated that synergistic effects occurred in both cell proliferation and death processes. The mechanism-based model captured key features of drug action: temporary cell cycle arrest in S phase induced by gemcitabine alone, apoptosis induced by birinapant alone, and prolonged cell cycle arrest and enhanced apoptosis induced by the combination. A drug interaction term Psi was employed in the models to signify interactions of the combination when data were limited. When more experimental information was utilized, Psi values approaching 1 indicated that specific mechanisms of interactions were captured better. PD modeling identified the potential benefit of combining gemcitabine and birinapant, and characterized the key interaction pathways. An optimal treatment schedule of pretreatment with gemcitabine for 24-48 h was suggested based on model predictions and was verified experimentally. This approach provides a generalizable modeling platform for exploring combinations of cytostatic and cytotoxic agents in cancer cell culture studies. PMID- 26252970 TI - Touchless Technologies for Decontamination in the Hospital: a Review of Hydrogen Peroxide and UV Devices. AB - Reduction of microbial contamination of the hospital environment is a challenge, yet has potential impacts on infection prevention efforts. Fumigation and UV light devices for environmental cleaning have expanded into the health care setting with the goal of decontamination of difficult to clean or overlooked surfaces. In an era of increased scrutiny of hospital-acquired infections, increasingly, health care centers are adopting these "touchless" cleaning techniques as adjuncts to traditional manual cleaning. The evidence for improved clinical outcomes is lacking; yet, the experience with these devices continues to accumulate in the literature. We review the recently published data related to the use of hydrogen peroxide and UV light-based decontamination systems for cleaning of hospital rooms. Touchless cleaning technologies may provide an incremental benefit to standard practices by limiting cross-transmission of pathogens via environmental surfaces, though evidence of prevention of infections remains limited. PMID- 26252971 TI - Theoretical and experimental studies of phenol oxidation by ruthenium complex with N,N,N-tris(benzimidazol-2yl-methyl)amine. AB - The ruthenium complex with (N,N,N-tris(benzimidazol-2yl-methyl)amine, L(1)) was prepared, and characterized. Fukui data were used to localize the reactive sites on the ligand. The structural and electronic properties of the complex were analyzed by DFT in different oxidation states in order to evaluate its oxidant properties for phenol oxidation. The results show that the hard Ru(IV) cation bonds preferentially with a hard base (Namine = amine nitrogen, or axial chloride ion), and soft Ru(II) with a soft base (Nbzim = benzimidazole nitrogen or axial triphenyl phosphine). Furthermore, the Jahn-Teller effect causes an elongation of the axial bond in the octahedral structure. The bonding nature and the orbital contribution to the electronic transitions of the complex were studied. The experimental UV-visible bands were interpreted by using TD-DFT studies. The complex oxidizes phenol to benzoquinone in the presence of H2O2 and the intermediate was detected by HPLC and (13)C NMR. A possible mechanism and rate law are proposed for the oxidation. The adduct formation of phenol with [Ru(O)L(1)](2+) or [Ru(OH)L(1)](+) is theoretically analyzed to show that [Ru(OH)L(1)-OPh](+) could produce the phenol radical. PMID- 26252972 TI - Effect of mismatch on binding of ADAR2/GluR-2 pre-mRNA complex. AB - RNA editing plays an important role in realizing the full potential of a given genome. Different from RNA splicing, RNA editing fine-tunes the sequence of RNA by changing only one or two nucleotides. A-I editing [deamination of adenosine (A) to create inosine (I)] is best characterized in mammals and occurs in the regions of double-stranded RNA (dsRNA). Adenosine deaminases acting on RNA (ADARs) are members of a family of enzymes involved in A-I deamination editing in numerous mRNA and pre-mRNA transcripts. Experimental study shows that ADAR2 selectively edits the R/G site, while ADAR1 edits more promiscuously at several other adenosines. How ADAR2 selects specific sites for deamination is poorly understood. Mismatches have been suggested to be important factors that allow the ADAR2 to achieve specific deamination. Using molecular dynamic simulation, we studied the effect of mismatch on binding stability of the dsRNA/ADAR2 complex. By comparison of two binding domains of ADAR2, we found that ADAR2 dsRBM2 (second binding domain of ADAR2) does not bind well with mismatch reversed GluR-2 RNA. When mismatch is reversed, dsRBM2 of ADAR2 slides along the RNA duplex in the simulation. Detailed structural analysis indicates that the minor groove width of dsRNA and global shape of RNA may play an important role in the specific reading mechanism of ADAR2. PMID- 26252973 TI - The stability and decomposition mechanism of the catenated nitrogen compounds. AB - Through theoretical calculation and experimental data, the decomposition mechanism of the N,N'-azo azole poly-nitrogen compounds were obtained. The compounds with the decomposition caused by the rupture of the -N-N=N-N- bridge are more stable than the ones with the ring-opening decomposition mechanisms. The catenated -N-N=N-N- bridge can strengthen the stability of the nitrogen chain. Preventing the hybridization change of the N atom where the ring-opening reaction occurs is essential for the nitrogen chain elongation on the ring system. Moreover, the introduction of energetic substituents like nitro group can further improve the performances of poly-nitrogen compounds; and such a modification should be based on a stable poly-nitrogen backbone. PMID- 26252974 TI - Predicting Daily Satisfaction with Spouse Responses Among People with Rheumatoid Arthritis. AB - BACKGROUND: Social support has been strongly linked to health outcomes. However, the factors associated with satisfaction with social support remain poorly understood. PURPOSE: We examined the impact of different types of support, affect, marital satisfaction, personality, and disease-related variables on day to-day and overall satisfaction with spouse responses. METHODS: Sixty-nine married people with rheumatoid arthritis completed an initial structured interview, followed by twice-daily phone interviews for 1 week. RESULTS: Higher levels of esteem support were associated with increased satisfaction, whereas negative spouse responses were related to decreased satisfaction across the day. Greater positive affect and lower pain were associated with higher concurrent satisfaction, but the effects did not last over the day. At the between-person level, older age and lower fatigue were related to higher satisfaction. CONCLUSIONS: Several key factors related to support satisfaction were identified. Esteem support appeared to play a particularly important role and warrants attention in future research. PMID- 26252975 TI - Bone status in glucocorticoid-treated men and women. AB - We recorded the results of areal bone mineral density (aBMD) and microarchitecture of the bone measured by trabecular bone score (TBS) in 416 glucocorticoid-treated men and women aged 40 years and older with or without fracture to 1104 controls. TBS better discriminated those with fracture compared to aBMD. These differences were the greatest in men. INTRODUCTION: The aim of this study is to evaluate glucocorticoid (GC)-induced effects on areal bone mineral density (aBMD) and bone microarchitectural texture measured by trabecular bone score (TBS). METHODS: TBS and aBMD were evaluated at L1-L4 postero-anterior (PA) spine by dual X-ray absorptiometry (DXA) in 1520 men and women aged 40 years and over. Four hundred sixteen subjects who received GCs (>=5 mg/day, for >=3 months) were matched with 1104 sex-, age-, and BMI-matched control subjects. Clinical data, osteoporotic fractures (OPF), and dietary habits were documented in the medical report. RESULTS: GC-treated patients were characterized by a significant decrease of TBS (1.267 vs. 1.298, p < 0.001) compared with control matched subjects while no change in BMD was observed at any sites. These decreases were even more pronounced when fracture status was taken into account (1.222 vs. 1.298, p < 0.001). The odds ratio (OR) for TBS was 1.44 (1.095-1.89) for OPF, whereas no association was found for BMD at any sites (all p > 0.3). A similar effect on microarchitecture measured by TBS was seen by the presence of fracture as by the use of glucocorticoids. An influence on TBS by sex was also noted with a decrease in TBS of greater magnitude in men. CONCLUSIONS: GC-treated individuals have a significant deterioration of bone microarchitectural texture as assessed by TBS which is more marked in those with OPF and in men. TBS seems to be more sensitive than aBMD for GC-related fracture detection and should be a good surrogate indicator of bone health in such secondary osteoporosis. PMID- 26252976 TI - Role of endocortical contouring methods on precision of HR-pQCT-derived cortical micro-architecture in postmenopausal women and young adults. AB - Precision errors of cortical bone micro-architecture from high-resolution peripheral quantitative computed tomography (pQCT) ranged from 1 to 16 % and did not differ between automatic or manually modified endocortical contour methods in postmenopausal women or young adults. In postmenopausal women, manually modified contours led to generally higher cortical bone properties when compared to the automated method. INTRODUCTION: First, the objective of the study was to define in vivo precision errors (coefficient of variation root mean square (CV%RMS)) and least significant change (LSC) for cortical bone micro-architecture using two endocortical contouring methods: automatic (AUTO) and manually modified (MOD) in two groups (postmenopausal women and young adults) from high-resolution pQCT (HR pQCT) scans. Second, it was to compare precision errors and bone outcomes obtained with both methods within and between groups. METHODS: Using HR-pQCT, we scanned twice the distal radius and tibia of 34 postmenopausal women (mean age +/ SD 74 +/- 7 years) and 30 young adults (27 +/- 9 years). Cortical micro architecture was determined using AUTO and MOD contour methods. CV%RMS and LSC were calculated. Repeated measures and multivariate ANOVA were used to compare mean CV% and bone outcomes between the methods within and between the groups. Significance was accepted at P < 0.05. RESULTS: CV%RMS ranged from 0.9 to 16.3 %. Within-group precision did not differ between evaluation methods. Compared to young adults, postmenopausal women had better precision for radial cortical porosity (precision difference 9.3 %) and pore volume (7.5 %) with MOD. Young adults had better precision for cortical thickness (0.8 %, MOD) and tibial cortical density (0.2 %, AUTO). In postmenopausal women, MOD resulted in 0.2-54 % higher values for most cortical outcomes, as well as 6-8 % lower radial and tibial cortical BMD and 2 % lower tibial cortical thickness. CONCLUSIONS: Results suggest that AUTO and MOD endocortical contour methods provide comparable repeatability. In postmenopausal women, manual modification of endocortical contours led to generally higher cortical bone properties when compared to the automated method, while no between-method differences were observed in young adults. PMID- 26252977 TI - Risk factors for hip impact during real-life falls captured on video in long-term care. AB - Hip fracture risk is increased by landing on the hip. We examined factors that contribute to hip impact during real-life falls in long-term care facilities. Our results indicate that hip impact is equally likely in falls initially directed forward as sideways and more common among individuals with dependent Activities of Daily Living (ADL) performance. INTRODUCTION: The risk for hip fracture in older adults increases 30-fold by impacting the hip during a fall. This study examined biomechanical and health status factors that contribute to hip impact through the analysis of real-life falls captured on video in long-term care (LTC) facilities. METHODS: Over a 7-year period, we captured 520 falls experienced by 160 residents who provided consent for releasing their health records. Each video was analyzed by a three-member team using a validated questionnaire to determine whether impact occurred to the hip or hand, the initial fall direction and landing configuration, attempts of stepping responses, and use of mobility aids. We also collected information related to resident physical and cognitive function, disease diagnoses, and use of medications from the Minimum Data Set. RESULTS: Hip impact occurred in 40 % of falls. Falling forward or sideways was significantly associated with higher odds of hip impact, compared to falling backward (OR 4.2, 95 % CI 2.4-7.1) and straight down (7.9, 4.1-15.6). In 32 % of sideways falls, individuals rotated to land backward. This substantially reduced the odds for hip impact (0.1, 0.03-0.4). Tendency for body rotation was decreased for individuals with dependent ADL performance (0.43, 0.2-1.0). CONCLUSIONS: Hip impact was equally likely in falls initially directed forward as sideways, due to the tendency for axial body rotation during descent. A rotation from sideways to backward decreased the odds of hip impact 10-fold. Our results may contribute to improvements in risk assessment and strategies to reduce risk for hip fracture in older adults. PMID- 26252978 TI - High-normal free thyroxine levels are associated with low trabecular bone scores in euthyroid postmenopausal women. AB - Trabecular bone scores (TBS) have recently been developed as a diagnostic tool to assess bone texture. We studied thyroid status and TBS in a population-based cohort and demonstrated that high-normal thyroxine levels are associated with low TBS in healthy euthyroid postmenopausal women. INTRODUCTION: Increased thyroid hormone levels affect bone mineral density (BMD) and, if untreated, increase the risk of fracture. However, the relationship between thyroid function and bone microarchitecture has not yet been established. Trabecular bone scores (TBS) are gray-level textural measurements of dual energy X-ray absorptiometry (DXA) images. The TBS has been proposed as an indirect index of bone microarchitecture. The goal of this study was to characterize the relationship between thyroid function and TBS in euthyroid men and postmenopausal euthyroid women. METHODS: A total of 1376 euthyroid subjects (648 postmenopausal women and 728 men) were recruited from a community-based cohort in Korea. Free thyroxine (fT4) levels, thyroid stimulating hormone (TSH) levels, BMD, and TBS were measured and compared. RESULTS: There was no significant relationship between either fT4 or TSH levels and BMD in men and women. Multiple linear regression analysis showed that high-normal fT4 levels were negatively correlated with TBS (beta = -0.111; P = 0.002, after adjusting for both age and body mass index [BMI]) in postmenopausal women. In men, however, there was no significant correlation between fT4 levels and TBS. TSH levels were not significantly associated with TBS in either men or women. CONCLUSION: Higher fT4 levels within the normal reference range are associated with deterioration of trabecular microarchitecture in healthy euthyroid postmenopausal women. PMID- 26252979 TI - One size does not fit all: the risk of using amplicon size of chloroplast SSR marker for genetic relationship studies. AB - KEY MESSAGE: Even within closely related taxa, total length variation of PCR amplicons from chloroplast SSR must be confirmed by sequencing to avoid misinterpreting genetic relationships. PMID- 26252980 TI - Effect of legal status of pharmacy syringe sales on syringe purchases by persons who inject drugs in San Francisco and San Diego, CA. AB - BACKGROUND: Sharing blood-contaminated syringes is the main risk factor for acquiring and transmitting blood-borne infections among persons who inject drugs (PWID). To reduce this risk, in 2005, California enacted legislation allowing local health jurisdictions to legalize non-prescription syringe sales after approving a disease prevention demonstration project (DPDP). With San Francisco approving a DPDP immediately and San Diego never approving one, we compared PWID across cities for their use of pharmacies PWID to obtain syringes. METHODS: PWID age 18-30 years old were recruited into separate studies in San Francisco (n=243) and San Diego (n=338) between 2008 and 2011. We used multivariable logistic regression to compare the proportions of PWID who obtained syringes from pharmacies by city while controlling for sociodemographics, injection practices and other risk behaviors. RESULTS: Overall, most PWID were White (71%), male (63%), and between the ages of 18-25 years (55%). Compared to San Francisco, a smaller proportion of PWID in San Diego had bought syringes from pharmacies in the prior three months (16.9% vs. 49.8%; p<0.001), which remained statistically significant after adjusting for sociodemographic and behavioral factors (adjusted odds ratio=4.45, 95% confidence interval: 2.98, 6.65). CONCLUSIONS: Use of pharmacies to obtain syringes was greater where it was legal to do so. Public health policy can influence HIV and hepatitis C associated risk among PWID; however, implementation of these policies is crucial for the benefits to be realized. PMID- 26252982 TI - Experience with a Low Single Cervical Incision for Implantation of a Vagus Nerve Stimulator: Technique and Advantages. AB - OBJECTIVE: This report describes the technique for implanting a vagus nerve stimulator via a single low anterior cervical incision and discusses the advantages of this technique over that of the more commonly used 2-incision technique. METHODS: The authors performed a retrospective review of all patients who underwent implantation of a vagus nerve stimulator by the senior author over a 10-year period. RESULTS: One hundred thirty-one patients underwent implantation of vagus nerve stimulators via the single-incision technique. There were no instances of vagus nerve injury, postoperative hematoma, or wound infection, and cosmesis was excellent. CONCLUSION: The single-incision technique described here for implantation of vagus nerve stimulators is technically straightforward and safe, and has significant advantages over the 2-incision technique. PMID- 26252981 TI - Propagation Curve and Velocity of Swallowing Pressure in Healthy Young Adults. AB - The objective of this study is to construct a propagation curve and determine propagation velocities in young healthy adults examined using a 2.64-mm-diameter high-resolution manometry catheter with 36 circumferential sensors; to explore data reproducibility; and to determine whether the swallowing pressure (SP) propagation velocity correlated with bolus volume. Repeated measures with subjects serving as their own controls. Thirty healthy subjects (average age 25.3 years) swallowed saliva and 2, 5, and 10 mL of cold water to determine the maximum SP from the soft palate to the cervical esophagus. The SP propagation curve was obtained by plotting the duration to reach each SP peak. The SP propagation velocity was calculated for each region. These parameters were examined according to bolus size and gender. The intra-class correlation coefficient for estimating the SP propagation curves was >0.61 (i.e., highly consistent). The propagation velocity was maximal at the meso-hypopharynx and minimal at the UES and cervical esophagus. The SP propagation curve was very reproducible within any subject. Neither the water volume (with the exception of 2 and 5 mL) nor gender exerted any apparent effect on velocity in any region. However, the velocity was quite variable at the cervical esophagus. PMID- 26252983 TI - CLIPPERS Syndrome: An Entity to be Faced in Neurosurgery. AB - BACKGROUND: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disorder of the central nervous system; it has only recently been defined and to date has received only limited attention. Its cause is as yet unknown. The pathologic characteristics are infiltration of T lymphocytes into the perivascular spaces of the pons, responsiveness to immunotherapy, and gadolinium-enhancing punctiform lesions in the brainstem seen on magnetic resonance imaging (MRI). CASE DESCRIPTION: We report here on the clinical, MRI, and brain biopsy findings in a 68-year-old man who presented with dysphagia, numbness and paresthesia on the right side of his face, as well as progressive gait ataxia. Brain and spinal MRI showed lesions in the pons and in the cervical spinal cord. The pontine lesion became progressively larger extending to the middle cerebellar peduncle and a tumor was suspected. After repeated biopsy, the histopathologic diagnosis confirmed CLIPPERS. CONCLUSIONS: CLIPPERS syndrome may become manifest with a progressive tumor-like pontine lesion. This report adds clinical and radiologic aspects to the limited number of CLIPPERS cases reported to date, and underlines the importance of considering CLIPPERS in the differential diagnosis of tumor like pontine processes. PMID- 26252985 TI - Music and Medicine: The Tragic Case of Gershwin's Brain Tumor and the Challenges of Neurosurgery in the First Half of the 20th Century. AB - OBJECTIVE: Although neurosurgery has gone through moments of great renewal in recent decades, at the beginning of the 20th century it was still dealing with the unfathomable mysteries of the nervous system and its disorders. Historical insight improves understanding of the great personalities of the past and allows us to look at the efforts of pioneering surgeons with greater awareness. METHODS: The literature was reviewed using online databases, textbooks, and retrieved articles. RESULTS: An overview of the case of Gershwin's brain tumor and its surgical resection is presented. CONCLUSIONS: This article presents the tragic case of Gershwin's brain tumor. Through his story, it is possible to get an idea of the difficulties with which the great neuroscientists and surgeons of the past approached the human nervous system and its pathologic manifestations. The first part of this article deals with the evolution of Gershwin's disease over the years and the subsequent brain surgery. In the second part, general considerations on the most striking symptoms experienced by the composer are reported, as well as a description of the different hypotheses on the nature of Gershwin's tumor. PMID- 26252984 TI - Endoscopic Endonasal Approach for Adrenocorticotropic Hormone-Secreting Pituitary Adenomas: Outcomes and Analysis of Remission Rates and Tumor Biochemical Activity with Respect to Tumor Invasiveness. AB - OBJECTIVE: The purpose of this study was to analyze the outcomes and complications of the endoscopic endonasal approach (EEA) performed on patients with Cushing disease at our Pituitary Center during the past 11 years. METHODS: Clinical information and imaging in electronic medical records were reviewed for patients who underwent EEA. Statistical analysis was performed with chi2 testing and Student's t-test. RESULTS: Remission was achieved in 39 patients (79.6%) at initial evaluation within 2 weeks of surgery. At last follow-up, remission persisted in 70% of 50 patients with EEA alone (mean follow-up time, 37.5 +/- 4.6 months; median, 26.2 months; range, 2.5-155.0 months). At last follow-up, remission rates were 80% among magnetic resonance imaging-negative adenomas, 70.6% among noninvasive or minimally invasive adenomas (Knosp 0, 1, 2), and 50% among invasive adenomas (Knosp 3, 4). There were no statistical differences in the remission rates among these categories (P = 0.444). Women had higher proportions of initial remission than men (P = 0.033) and patients who had no initial remission were older (P = 0.046). Higher preoperative normalized adrenocroticotropic hormone level was associated with a greater degree of invasiveness (P = 0.021). However, there was no association between preoperative normalized urine-free cortisol levels and degree of invasiveness (P = 0.582). Complications included panhypopituitarism (n = 3), hypothyroidism (n = 3), growth hormone deficiency (n = 1), hypogonadism (n = 1), postoperative cerebrospinal fluid leak (n = 2), and transient diabetes insipidus (n = 4). CONCLUSIONS: The EEA for Cushing disease resulted in remission and complication rates comparable with previous analyses of EEA, as well as microsurgical series. Preoperative adrenocorticotropic hormone levels were associated with invasiveness. PMID- 26252986 TI - Mapping the Mirror Neuron System in Neurosurgery. AB - BACKGROUND: Brain mapping is considered an important approach in neurosurgery to achieve better functional outcomes. The mirror neuron system (MNS) is a brain network implicated in understanding of action and imitation. No previous study has focused on identifying and monitoring the function of the MNS during the perioperative period in brain lesions. The aim of this study was to describe the application of a functional magnetic resonance imaging (fMRI) protocol to identify the MNS in a patient with a lesion in the premotor region. CASE DESCRIPTION: A specific fMRI protocol to identify regions belonging to the MNS was performed on a 19-year-old female patient who presented a cavernous angioma in the premotor region. The patient showed signs of impairment when imitating simple and complex hand movements. The fMRI protocol was performed before and 3 months after the surgical procedure. The protocol consisted of observation and execution conditions of a simple intransitive finger movement (precision grasping). MNS regions were identified during the pre- and postsurgical fMRI trials. Such mirror areas were respected during the procedure. The activation of these regions improved notably after the procedure, with a correlation between recovery of the ability to imitate simple and complex hand movements and higher and better-defined MNS activity. CONCLUSION: The use of an fMRI protocol with observation and execution conditions based on simple intransitive finger actions allows the easy identification and preservation of the MNS. Increased activity on postoperative fMRI may be associated with improvement in motor functions. PMID- 26252987 TI - Retractorless Surgery for Anterior Circulation Aneurysms via a Pterional Keyhole Approach. AB - Brain retraction is required during many intracranial procedures to provide more working space. However, it is difficult to avoid brain retraction injury. Here, we report on retractorless surgery for anterior circulation aneurysms via a pterional keyhole approach. All patients undergoing a minimally invasive pterional keyhole approach within 3 days after hemorrhage by the same surgeon were included in the study. Patients were randomly assigned into group I (with the retractorless technique) and group II (with fixed retractors). Data on adequate clipping level, intraoperative ischemia induced by retraction, operation time, brain retraction injury, intraoperative blood loss, intraoperative aneurysm rupture, and modified Rankin Scale were collected for the 2 groups. A consecutive series of 47 patients (21 patients in group I, 26 patients in group II) successfully underwent a minimally invasive pterional keyhole approach. Statistical analysis revealed no significant between-group differences with regard to sex, age, Hunt-Hess grade, adequate clipping level, operation time, intraoperative blood loss, and aneurysm rupture (P > 0.05). However, no intraoperative ischemia was detected in group I, whereas 23.1% (6 of 26) of patients in group II had reversible ischemia. Furthermore, the proportion of brain retraction injuries in group I (5.3%) was lower than that in group II (34.6%). In addition, a better prognosis was obtained in patients who underwent retractorless surgery. With the careful and accurate use of a handheld suction device and operating instruments, the retractorless technique can replace fixed retraction, reduce brain retraction injury, and is applicable to surgeries on anterior circulation aneurysms via pterional keyhole approaches. PMID- 26252988 TI - Selective reduction of cerebral cortex GABA neurons in a late gestation model of fetal alcohol spectrum disorder. AB - Fetal alcohol spectrum disorders (FASD) are associated with cognitive and behavioral deficits, and decreased volume of the whole brain and cerebral cortex. Rodent models have shown that early postnatal treatments, which mimic ethanol toxicity in the third trimester of human pregnancy, acutely induce widespread apoptotic neuronal degeneration and permanent behavioral deficits. However, the lasting cellular and anatomical effects of early ethanol treatments are still incompletely understood. This study examined changes in neocortex volume, thickness, and cellular organization that persist in adult mice after postnatal day 7 (P7) ethanol treatment. Post mortem brain volumes, measured by both MRI within the skull and by fluid displacement of isolated brains, were reduced 10 13% by ethanol treatment. The cerebral cortex showed a similar reduction (12%) caused mainly by lower surface area (9%). In spite of these large changes, several features of cortical organization showed little evidence of change, including cortical thickness, overall neuron size, and laminar organization. Estimates of total neuron number showed a trend level reduction of about 8%, due mainly to reduced cortical volume but unchanged neuron density. However, counts of calretinin (CR) and parvalbumin (PV) subtypes of GABAergic neurons showed a striking >30% reduction of neuron number. Similar ethanol effects were found in male and female mice, and in C57BL/6By and BALB/cJ mouse strains. Our findings indicate that the cortex has substantial capacity to develop normal cytoarchitectonic organization after early postnatal ethanol toxicity, but there is a selective and persistent reduction of GABA cells that may contribute to the lasting cognitive and behavioral deficits in FASD. PMID- 26252989 TI - Adjunctive surgical atrial fibrillation ablation during cardiac surgery: real life experiences. AB - AIM: Several tools have been invented for surgical atrial fibrillation (AF) ablation. In this study, we investigated the real world efficacy of intraoperative AF ablation (AFA) with radiofrequency-energy or cryo-ablation and performed an electro-anatomical remap in some patients with recurrences. METHODS: Seventy-three consecutive patients (53 male, median age of 69 +/- 7 years) with history of AF underwent cardiac surgery for valve repair (74 % mitral defects, 60 % aortic defects) and/or coronary artery bypass graft procedures (56 %). During a follow-up of 23 +/- 11 months after AFA we performed intensified holter monitoring (4-7 days). Patients with symptomatic relapse of atrial arrhythmias (AA) were offered the opportunity for additional electrophysiological examination (EPE). RESULTS: During 23 +/- 11 months after AFA, 45 patients (62 %) had recurrent AA. In eight patients we performed EPE. In all 8 cases, septal circumferential lesions could be demonstrated during mapping with discrete gaps. All lateral veins were isolated however, posteriorly deep inside the vein leaving the antral region completely untreated. Neither roof lines nor mitral isthmus lines were complete. Performing catheter ablation, all veins could be isolated and seven patients were free of any arrhythmias during follow up (9 +/- 5 months) without taking antiarrhythmic drugs. CONCLUSION: Surgical AF ablation may often be incomplete rendering sobering results in unselected patients. Completion of the ablation is feasible with catheter ablation with good clinical outcome. PMID- 26252991 TI - A case of episcleral tattooing--an emerging body modification trend. AB - BACKGROUND: In 2007 an article was published describing the first forays into the practice of episcleral tattooing. Currently only a handful of people worldwide have undergone this procedure, whereby a needle is used to inject dye under the bulbar conjunctiva. To date there have been no previous reports of the risks and complications of this emerging practice in the medical literature. We present a case involving a complication that arose in one of the few people in Britain to have undergone episcleral tattooing for cosmetic purposes. CASE PRESENTATION: A 43-year-old Caucasian man presented to the eye casualty clinic with red, lumpy conjunctivae bilaterally, having undergone episcleral tattooing 7 weeks previously. On examination there were 3 distinct areas of conjunctival swelling in each eye, representing a total of 6 injection sites. No other gross abnormalities were identified. The clinical picture remained unchanged 6 months on, apart from a degree of fading of the conjunctival dye. He will remain under our care to ensure that any further complications such as granulomatous inflammation are managed and documented. CONCLUSION: Episcleral tattooing is carried out by individuals with no medical training. The short-term complications reported so far include: headaches, severe photophobia, persistent foreign body sensation, and migration of ink staining. More serious short-term risks such as infection, globe penetration, and peri-ocular haemorrhage could occur. For now we can only speculate as to the long-term consequences, but these may include carcinogenic change or granulomatous inflammation. We feel that the potential risks of the procedure should be communicated more widely to those body modification practitioners undertaking it. This practice could result in more serious presentations to acute eye services in the future. PMID- 26252990 TI - Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach. AB - Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation. PMID- 26252993 TI - Biomarker discovery and gene expression responses in Lycopersicon esculentum root exposed to lead. AB - Gene expression analysis has shown particular promise for the identification of molecular biomarkers that can be used for further evaluation of potential toxicity of chemicals present in agricultural soil. In the study, we focused on the development of molecular markers to detect Pb toxicity in agricultural soil. Using the results obtained from microarray analysis, twelve Pb-responsive genes were selected and tested in different Pb concentrations to examine their concentration-response characteristics using real-time quantitative polymerase chain reaction (RT-qPCR). All the Pb treatments set in our study could generally induce the differential expression of the 12 genes, while the lowest observable adverse effect concentration (LOAEC) of Pb for seed germination, root elongation, biomass and structural modification derived from 1,297, 177, 177, and 1,297 mg Pb/kg soil, respectively, suggesting that the transcriptional approach was more sensitive than the traditional end points of death, growth, and morphology for the evaluation of Pb toxicity. The relative expression of glycoalkaloid metabolism 1 (P=-0.790), ethylene-responsive transcription factor ERF017 (P= 0.686) and CASP-like protein 4C2 (P=-0.652) demonstrates a dose-dependent response with Pb content in roots, implying that the three genes can be used as sensitive bioindicators of Pb stress in Lycopersicon esculentum. PMID- 26252992 TI - Atomic-scale investigation of the interactions between tetrabromobisphenol A, tetrabromobisphenol S and bovine trypsin by spectroscopies and molecular dynamics simulations. AB - Tetrabromobisphenol A (TBBPA) and its replacement alternative tetrabromobisphenol S (TBBPS) are used widely as brominated flame retardants (BFRs). However, the potential risk of their effects on bovine trypsin remains largely unknown. We investigated the effects of TBBPA and TBBPS to bovine trypsin by the fluorescence spectroscopy, circular dichroism and molecular dynamics (MD) simulations. They statically quenched the intrinsic fluorescence of bovine trypsin in a concentration-dependent mode and caused slight red-shifted fluorescence. The short and long fluorescence lifetime decay components of bovine trypsin were both affected, partly due to the disturbed microenvironmental changes of Trp215. The beta-sheet content of bovine trypsin was significantly reduced from 82.4% to 75.7% and 76.6% by TBBPA and TBBPS, respectively, possibly impairing the physiological function of bovine trypsin. TBBPA and TBBPS bind at the 8 anilinonaphthalene-1-sulfonate (ANS) binding site with an association constant of 1.09*10(4) M(-1) and 2.41*10(4) M(-1) at 298 K, respectively. MD simulations revealed that van der Waals interactions and hydrogen bond interactions are dominant for TBBPA, whereas electrostatic interactions are critical for TBBPS. Our in vitro and in silico studies are beneficial to the understanding of risk assessment and future design of environmental benign BFRs. PMID- 26252994 TI - Supported liquid membrane based removal of lead(II) and cadmium(II) from mixed feed: Conversion to solid waste by precipitation. AB - Simultaneous removal of two heavy metals, lead(II) and cadmium(II), from mixed feed using supported liquid membrane (SLM) based technique is investigated in this work. The carrier-solvent combination of "sodium salt of Di-2 ethylhexylphosphoric acid (D2EHPA) (4% w/w) in environmentally benign coconut oil" was immobilized into the pores of solid polymeric polyvinylidene fluoride (PVDF) support. Sodium carbonate (Na2CO3) was used as the stripping agent. Carbonate salts of lead(II) and cadmium(II) were formed in the stripping side interface and they were insoluble in water leading to precipitation inside the stripping solution. The transportation of solute is positively affected due to the precipitation. Lead(II) removal was found to be preferential due to its favorable electronic configuration. The conversion of the liquid waste to the solid one was added advantage for the final removal of hazardous heavy metals. PMID- 26252995 TI - Visualization and analysis of nanoparticle transport and ageing in reactive porous media. AB - We present quasi-3D visualization and analysis of engineered nanoparticle (ENP) transport behavior in an experimental setup that uses a transmitted light imaging technique. A flow cell was packed with specially adapted, water-transparent, spherical polyacrylamide beads, which carry a negative surface charge representative of many natural environments. Ubiquitous, oppositely-charged ENPs Au and Ag NPs - were synthesized and introduced into a flow cell subjected to a macroscopically uniform flow field via point source pulse injection, at three different flow rates. The negatively-charged ENPs behaved like a conservative tracer, in terms of spatio-temporal plume evolution. The positive AgNPs, however, displayed a decrease in their initially strong tendency to attach to the oppositely-charged porous medium. As a result, immobilization of the positive AgNPs was spatially and temporally limited to the vicinity of the point of injection; beyond this region, the AgNPs were mobile and effluent contained AgNPs with hydrodynamic diameters significantly larger than those of the injected AgNPs. This behavior is understood by dynamic light scattering and zeta potential measurements, which showed aggregation processes and inversion in particle surface charge to occur during transport of the positive ENPs. These findings have broad implications for ENP mobility and reactivity in the environment. PMID- 26252996 TI - Copper-promoted cementation of antimony in hydrochloric acid system: A green protocol. AB - A new method of recovering antimony in hydrochloric acid system by cementation with copper powder was proposed and carried out at laboratory scale. Thermodynamic analysis and cyclic voltammetry test were conducted to study the cementation process. This is a novel antimony removal technology and quite meets the requirements of green chemistry. The main cement product Cu2Sb is a promising anodic material for lithium and sodium ion battery. And nearly all consumed copper powder are transformed into CuCl which is an important industrial material. The effect of reaction temperature, stoichiometric ratio of Cu to Sb(III), stirring rate and concentration of HCl on the cementation efficiency of antimony were investigated in detail. Optimized cementation condition is obtained at 60 degrees C for 120 min and stirring rate of 600 rpm with Cu/Sb(III) stoichiometric ratio of 6 in 3 mol L(-1) HCl. At this time, nearly all antimony can be removed by copper powder and the cementation efficiency is over 99%. The structure and morphologies of the cement products were characterized by X-ray diffraction and scanning electron microscopy, respectively. Results show that the reaction temperature has little influence on the morphology of the cement products which consist of particles with various sizes. The activation energy of the cementation antimony on copper is 37.75 kJ mol(-1), indicating a chemically controlled step. Inductively coupled plasma mass spectrometry results show that no stibine generates during the cementation process. PMID- 26252997 TI - Using mixture design of experiments to assess the environmental impact of clay based structural ceramics containing foundry wastes. AB - This work describes the leaching behavior of potentially hazardous metals from three different clay-based industrial ceramic products (wall bricks, roof tiles, and face bricks) containing foundry sand dust and Waelz slag as alternative raw materials. For each product, ten mixtures were defined by mixture design of experiments and the leaching of As, Ba, Cd, Cr, Cu, Mo, Ni, Pb, and Zn was evaluated in pressed specimens fired simulating the three industrial ceramic processes. The results showed that, despite the chemical, mineralogical and processing differences, only chrome and molybdenum were not fully immobilized during ceramic processing. Their leaching was modeled as polynomial equations, functions of the raw materials contents, and plotted as response surfaces. This brought to evidence that Cr and Mo leaching from the fired products is not only dependent on the corresponding contents and the basicity of the initial mixtures, but is also clearly related with the mineralogical composition of the fired products, namely the amount of the glassy phase, which depends on both the major oxides contents and the firing temperature. PMID- 26252998 TI - Preoperative airway colonization prior to transthoracic esophagectomy predicts postoperative pulmonary complications. AB - PURPOSE: Respiratory complications are responsible to a high degree for postoperative morbidity and mortality after Ivor-Lewis esophagectomy. The etiology of respiratory failure is known to be multifactorial with preoperative impaired lung function being the most important one. The aim of this study was to investigate the correlation between preoperative airway colonization (PAC) and postoperative respiratory complications. METHODS: In this observational study, 64 patients with esophageal cancer were included. All patients underwent Ivor-Lewis esophagectomy with laparoscopic or open gastric mobilization. After induction of anesthesia and intubation with a double-lumen tube, bronchial exudate was collected by random endoluminal suction for further microbiological work-up. Length of postoperative mechanical ventilation (<24 h, 24-72 h, >72 h), re intubation, and tracheostomy were recorded as primary and secondary study endpoints. RESULTS: In 13 of 64 study patients (20.3 %), pathological colonization of the bronchial airways could be proved prior to esophagectomy. Haemophilus species was the most frequently identified pathogen. PAC was associated with a longer history of smoking (p = 0.025), a lower preoperative forced expiratory volume (FEV1, p = 0.009) or vital capacity (VC, p = 0.038), a prolonged postoperative mechanical ventilation (p < 0.001), and a higher frequency of re-intubation (p < 0.001) and tracheostomy (p = 0.017). In the multivariate analysis, PAC was identified as an independent predictor of respiratory failure (hazard ratio 11.4, 95 % confidence interval 2.6-54, p = 0.002). Mortality in the PAC group was 30.8 % compared to 0 % in patients without PAC (p < 0.0001). CONCLUSION: PAC is a significant risk factor for postoperative respiratory failure. A routine bronchoscopy and bronchoalveolar lavage as part of preoperative management prior to esophagectomy need to be discussed. PMID- 26252999 TI - Clinical significance of mediastinoscope-assisted transhiatal esophagectomy in patients with esophageal cancer. AB - PURPOSE: Mediastinoscope-assisted transhiatal esophagectomy (MATHE) is a useful surgical procedure in esophageal cancer patients who have limited indications for transthoracic operations due to preoperative complications. METHODS: In the last 10 years, 63 patients underwent MATHE at our department. We examined the clinical data of these patients and assessed the indications, postoperative outcomes, and prognostic factors of MATHE. RESULTS: The 5-year overall survival (OS) rate was 53.4 %, and disease-free survival (DFS) rate was 66.0 %. Postoperative complications were observed in 22 cases (34.9 %), and recurrent disease occurred in 17 cases (27.0 %). On univariate analyses of OS, location of the tumor, tumor depth, lymph node metastasis, clinical stage, simultaneous resection of other organs, postoperative pneumonia, and blood loss were significant prognostic factors. On multivariate analyses, location of the tumor and lymph node metastasis were independent prognostic factors of OS. On univariate analyses, location of the tumor, tumor depth, lymph node metastasis, clinical stage, and blood loss were significant prognostic factors of DFS, while on multivariate analyses of DFS, lymph node metastasis and blood loss were independent prognostic factors. CONCLUSION: MATHE is a useful procedure for the middle to lower thoracic esophageal cancer patients without clinical lymph node metastasis with serious complications who were unable to undergo thoracotomy. PMID- 26253000 TI - Effects of subsampling on characteristics of RNA-seq data from triple-negative breast cancer patients. AB - BACKGROUND: Data from RNA-seq experiments provide a wealth of information about the transcriptome of an organism. However, the analysis of such data is very demanding. In this study, we aimed to establish robust analysis procedures that can be used in clinical practice. METHODS: We studied RNA-seq data from triple negative breast cancer patients. Specifically, we investigated the subsampling of RNA-seq data. RESULTS: The main results of our investigations are as follows: (1) the subsampling of RNA-seq data gave biologically realistic simulations of sequencing experiments with smaller sequencing depth but not direct scaling of count matrices; (2) the saturation of results required an average sequencing depth larger than 32 million reads and an individual sequencing depth larger than 46 million reads; and (3) for an abrogated feature selection, higher moments of the distribution of all expressed genes had a higher sensitivity for signal detection than the corresponding mean values. CONCLUSIONS: Our results reveal important characteristics of RNA-seq data that must be understood before one can apply such an approach to translational medicine. PMID- 26253001 TI - Regulatory risk assessment approaches for synthetic mineral fibres. AB - Exposure to synthetic mineral fibres (SMF) may occur in a number of workplace scenarios. To protect worker health, a number of different organisations worldwide have assessed the health risk of these materials and established workplace exposure limits. This paper outlines the basic principles of risk assessment and the scientific methods used to derive valid (justifiable) occupational exposure limits (OELs) and goes on to show how, for SMF, and particularly for refractory ceramic fibre (otherwise known as aluminosilicate wool, RCF/ASW), the methods used and the associated outcomes differ widely. It is argued that the resulting differences in established OELs prevent consistent and appropriate risk management of SMF worldwide, and that development of a transparent and harmonised approach to fibre risk assessment and limit-setting is required. PMID- 26253002 TI - Efficacy of topical tenofovir against transmission of a tenofovir-resistant SHIV in macaques. AB - BACKGROUND: Topically delivered tenofovir (TFV) from intravaginal rings, tablets, or gels is being evaluated for HIV prevention. We previously demonstrated that TFV delivered vaginally by gel protected macaques from vaginal infection with SHIV. Here we investigated efficacy of the TFV gel against vaginal transmission of a TFV-resistant SHIV containing the K65R mutation (SHIV162P3K65R) and its relationship to drug levels in vaginal tissues. RESULTS: SHIV162P3K65R shows approximately a 5-fold reduction in susceptibility to TFV compared to wild-type SHIV. Efficacy was evaluated in pig-tailed macaques exposed vaginally twice weekly (up to 10 weeks) to SHIV162P3K65R 30 min after receiving placebo (n = 6) or 1% TFV (n = 6) gel. Four of the six controls were infected after a median of 5 exposures. In contrast, five of six macaques that received TFV gel remained uninfected after 20 vaginal SHIV162P3K65R exposures, resulting in an estimated efficacy of 75%. The mean intracellular TFV-diphosphate (TFV-DP) concentrations in vaginal lymphocytes 4 h after a single gel dose were found to be high (1,631 fmol/10(6) cells, range 492-3,847) and within the in vitro IC75 range (1,206 fmol/10(6) cells) for SHIV162P3K65R. CONCLUSION: Both the modest resistance conferred by K65R and the high TFV-DP exposure in vaginal lymphocytes, likely explain the observed protection. The findings in this model do not predict complete loss of protection by topical TFV against vaginal exposure to HIV-1K65R viruses and provide a tissue drug target for high efficacy. These data will facilitate the development of TFV delivery platforms that have high activity on both wild-type and TFV-resistant viruses. PMID- 26253004 TI - When Can You Discard Stem Cells? PMID- 26253003 TI - Adaptive mutations in sugar metabolism restore growth on glucose in a pyruvate decarboxylase negative yeast strain. AB - BACKGROUND: A Saccharomyces cerevisiae strain carrying deletions in all three pyruvate decarboxylase (PDC) genes (also called Pdc negative yeast) represents a non-ethanol producing platform strain for the production of pyruvate derived biochemicals. However, it cannot grow on glucose as the sole carbon source, and requires supplementation of C2 compounds to the medium in order to meet the requirement for cytosolic acetyl-CoA for biosynthesis of fatty acids and ergosterol. RESULTS: In this study, a Pdc negative strain was adaptively evolved for improved growth in glucose medium via serial transfer, resulting in three independently evolved strains, which were able to grow in minimal medium containing glucose as the sole carbon source at the maximum specific rates of 0.138, 0.148, 0.141 h(-1), respectively. Several genetic changes were identified in the evolved Pdc negative strains by genomic DNA sequencing. Among these genetic changes, 4 genes were found to carry point mutations in at least two of the evolved strains: MTH1 encoding a negative regulator of the glucose-sensing signal transduction pathway, HXT2 encoding a hexose transporter, CIT1 encoding a mitochondrial citrate synthase, and RPD3 encoding a histone deacetylase. Reverse engineering of the non-evolved Pdc negative strain through introduction of the MTH1 (81D) allele restored its growth on glucose at a maximum specific rate of 0.053 h(-1) in minimal medium with 2% glucose, and the CIT1 deletion in the reverse engineered strain further increased the maximum specific growth rate to 0.069 h(-1). CONCLUSIONS: In this study, possible evolving mechanisms of Pdc negative strains on glucose were investigated by genome sequencing and reverse engineering. The non-synonymous mutations in MTH1 alleviated the glucose repression by repressing expression of several hexose transporter genes. The non synonymous mutations in HXT2 and CIT1 may function in the presence of mutated MTH1 alleles and could be related to an altered central carbon metabolism in order to ensure production of cytosolic acetyl-CoA in the Pdc negative strain. PMID- 26253005 TI - Epstein-Barr Virus-Related Post-Transplantation Lymphoproliferative Disorder after Unmanipulated Human Leukocyte Antigen Haploidentical Hematopoietic Stem Cell Transplantation: Incidence, Risk Factors, Treatment, and Clinical Outcomes. AB - We examined the incidence, risk factors, treatments, and clinical outcomes of post-transplantation lymphoproliferative disorder (PTLD) after unmanipulated haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) in 1184 patients between 2006 and 2012. Age-, transplantation time-, and transplantation duration-matched controls were randomly selected from the same cohort. Forty-five patients experienced PTLD. The median time from HSCT to PTLD occurrence was 61 (range, 33 to 360) days and the 1-year cumulative incidence of total PTLD after haplo-HSCT was 3.0%. In multivariate analysis, a lower absolute count of CD8(+) T lymphocytes at day 30, a lower absolute count of immunoglobulin M at day 30, and cytomegalovirus DNAemia after HSCT were significantly associated with higher risk of PTLD. The 2-year probability of overall survival (OS) after HSCT was 42.8%, which was comparable between the probable PTLD and the proven PTLD patients. Patients who received rituximab-based therapy had significantly better 2-year OS (48.2% versus 13.2%, P = .02). Thus, we were able to identify individuals at a high risk of developing PTLD after unmanipulated haplo-HSCT. Rituximab-based therapy can help to improve the outcomes of PTLD patients. PMID- 26253006 TI - Higher Stem Cell Dose Infusion after Intensive Chemotherapy Does Not Improve Symptom Burden in Older Patients with Multiple Myeloma and Amyloidosis. AB - Autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma (MM) is associated with high symptom burden, particularly for older patients and those with amyloid light-chain (AL) amyloidosis. Symptom burden peaks during leukopenia. We hypothesized that higher doses of CD34(+) stem cells would be associated with an improved symptom outcome. Patients undergoing ASCT for MM who were >=60 years old or had AL amyloidosis were randomized to receive either a standard (4 to 6 * 10(6) cells/kg) or high dose (10 to 15 * 10(6) cells/kg) of CD34(+) cells after melphalan 200 mg/m(2). Symptom burden was assessed via the MD Anderson Symptom Inventory MM module. Eighty patients were enrolled. Median CD34(+) cell doses were 5.1 * 10(6) cells/kg (standard dose) and 10.5 * 10(6) cells/kg (high dose). The most severe symptoms during the first week were fatigue, lack of appetite, drowsiness, disturbed sleep, and pain. The area under the curve for the mean composite severity score of these symptoms was similar between treatment arms (P = .819). Median times to neutrophil, lymphocyte, and platelet engraftment were also similar between groups. IL-6 increased similarly for both groups throughout the ASCT course. Infusion of higher autologous stem cell dose after high-dose chemotherapy does not yield a difference in symptom burden or engraftment time in the first few weeks after ASCT. PMID- 26253008 TI - [Uraemic and non-uraemic calcific arteriopathy: The need for rapid diagnosis and therapy]. AB - Calcific arteriopathy (CA), also commonly known as calciphylaxis, is a disease carrying a poor prognosis. It is seen primarily in patients with chronic renal insufficiency (CRI), particularly those on haemodialysis (HD), where it is referred to as uraemic calcific arteriopathy (UCA), but it also occurs outside this setting, in which case it is known as non-uraemic calcific arteriopathy (NUCA). It is caused by thrombotic cutaneous arteriolar microangiopathy associated with fine calcium deposits in the media associated with hyperplasia of the intima of the dermal and hypodermal arterioles. Its course comprises two phases: a silent phase in which the arteriolar abnormalities begin, followed by a symptomatic phase, frequently triggered by specific factors, with sudden appearance of necrotic ischaemic plaques on the skin. Several clinical forms exist, proximal, distal and mixed, depending on the main site of the lesions. The prognosis is poor due to septic complications and the involvement of other organs. Diagnosis is based on the patient's history, clinical examination, laboratory examinations and skin biopsy with Von Kossa staining. The physiopathology, which is complex and is becoming increasingly well understood, involves high phosphorous and calcium levels and hyperparathyroidism, as well as other factors (inflammation, factors promoting or inhibiting calcification, coagulation disorders and traumatisms). Treatment involves a multidisciplinary and medical-surgical approach. PMID- 26253009 TI - Do human brain areas involved in visuomotor actions show a preference for real tools over visually similar non-tools? AB - Neuroimaging has revealed a left-lateralized network of brain areas implicated in understanding the conceptual and sensorimotor aspects of tool perception and tool use. Often this network of areas is identified by contrasting brain activity when participants view pictures of tools vs. pictures of non-tools (e.g., animals or buildings). It is unclear, however, what aspect of tools drive activity in the tool network as both tools and non-tools tend to differ in their low-level features. For instance, areas in the tool network may simply activate to elongated objects or to handheld objects over round or ungraspable objects irrespective of object category. To test whether tools indeed drive activity in tool-selective areas over non-tools, participants passively viewed real tools and non-tools matched on low-level features during functional magnetic resonance imaging (fMRI). To maximize the potential for action, participants saw real-tools as opposed to pictures of tools. The non-tools were created by chopping the business ends of tools into pieces and attaching the pieces to both ends of the original tool handles. In doing so, the tools and non-tools were matched for elongation and real-world size. Importantly, tools and non-tools were viewed directly without the use of mirrors and placed within the participants' reach. Stimuli were presented at two opposite horizontal orientations to investigate whether areas that are selective for tools also show greater activation when the tool's handle is directed towards the hand as opposed to away from it. Our results showed that, even after the low-level differences between tools and non tools were controlled, tools evoked more activation in the tool network as well as in sensorimotor areas. The orientation of the tool handles did not mediate effects within these sensorimotor areas. In sum, when we passively view tools, even without an intent to act, functional associations are automatically evoked and these associations are not specific to a particular hand. PMID- 26253007 TI - Reduced-Intensity Allografting as First Transplantation Approach in Relapsed/Refractory Grades One and Two Follicular Lymphoma Provides Improved Outcomes in Long-Term Survivors. AB - This study was conducted to compare long-term outcomes in patients with refractory/relapsed grades 1 and 2 follicular lymphoma (FL) after allogeneic (allo) versus autologous (auto) hematopoietic cell transplantation (HCT) in the rituximab era. Adult patients with relapsed/refractory grades 1 and 2 FL undergoing first reduced-intensity allo-HCT or first autograft during 2000 to 2012 were evaluated. A total of 518 rituximab-treated patients were included. Allo-HCT patients were younger and more heavily pretreated, and more patients had advanced stage and chemoresistant disease. The 5-year adjusted probabilities, comparing auto-HCT versus allo-HCT groups for nonrelapse mortality (NRM) were 5% versus 26% (P < .0001); relapse/progression: 54% versus 20% (P < .0001); progression-free survival (PFS): 41% versus 58% (P < .001), and overall survival (OS): 74% versus 66% (P = .05). Auto-HCT was associated with a higher risk of relapse/progression beyond 5 months after HCT (relative risk [RR], 4.4; P < .0001) and worse PFS (RR, 2.9; P < .0001) beyond 11 months after HCT. In the first 24 months after HCT, auto-HCT was associated with improved OS (RR, .41; P < .0001), but beyond 24 months, it was associated with inferior OS (RR, 2.2; P = .006). A landmark analysis of patients alive and progression-free at 2 years after HCT confirmed these observations, showing no difference in further NRM between both groups, but there was significantly higher risk of relapse/progression (RR, 7.3; P < .0001) and inferior PFS (RR, 3.2; P < .0001) and OS (RR, 2.1; P = .04) after auto-HCT. The 10-year cumulative incidences of second hematological malignancies after allo-HCT and auto-HCT were 0% and 7%, respectively. Auto-HCT and reduced-intensity-conditioned allo-HCT as first transplantation approach can provide durable disease control in grades 1 and 2 FL patients. Continued disease relapse risk after auto-HCT translates into improved PFS and OS after allo-HCT in long-term survivors. PMID- 26253010 TI - Is there a positive bias in false recognition? Evidence from confabulating amnesia patients. AB - Although there is some evidence for a positive emotional bias in the content of confabulations in brain damaged patients, findings have been inconsistent. The present study used the semantic-associates procedure to induce false recall and false recognition in order to examine whether a positive bias would be found in confabulating amnesic patients, relative to non-confabulating amnesic patients and healthy controls. Lists of positive, negative and neutral words were presented in order to induce false recall or false recognition of non-presented (but semantically associated) words. The latter were termed 'critical intrusions'. Thirteen confabulating amnesic patients, 13 non-confabulating amnesic patients and 13 healthy controls were investigated. Confabulating patients falsely recognised a higher proportion of positive (but unrelated) words, compared with non-confabulating patients and healthy controls. No differences were found for recall memory. Signal detection analysis, however, indicated that the positive bias for false recognition memory might reflect weaker memory in the confabulating amnesic group. This suggested that amnesia patients with weaker memory are more likely to confabulate and the content of these confabulations are more likely to be positive. PMID- 26253011 TI - Introduction to EER Special Issue on ocular fibrosis. PMID- 26253012 TI - Preliminary Results of a Prospective Study on Methods of Cranial Reconstruction. AB - PURPOSE: Given its biological and anatomic features, autologous bone is the first choice for cranioplasty after bone decompression. When autologous bone is not available or must be replaced, surgeons can choose among various materials to create an alloplastic cranioplasty. The Italian Society for Neurosurgery promoted a prospective study conducted at 4 Italian neurosurgical units to compare different methods of cranioplasty and to assess the clinical results and incidence of complications. MATERIALS AND METHODS: Patients older than 14 years who underwent repositioning of autologous bone or 3-dimensional image-guided reconstruction with prostheses made of an alloplastic material (polyetheretherketone, polymethylmethacrylate, or hydroxyapatite) after cranial decompression were enrolled prospectively from January 2008 through December 2013. The collected data included the material used to produce the prosthesis, the type of cranioplasty (primary or secondary), and complications that required surgical removal of the prosthesis (eg, infection, bone resorption, and fracture of the cranioplasty). RESULTS: Ninety-six patients met the study criteria. Fifty cases were reconstructed with hydroxyapatite, 31 with bone, 13 with polymethylmethacrylate, and 2 with polyetheretherketone. Seven patients (7.3%) developed complications related to the cranioplastic implant that required reoperation. These complications included infection (4 cases), bone resorption (2 cases), and fracture of the cranioplastic prosthesis (1 case). Statistical analysis showed a higher rate of complications with the use of autologous bone versus alloplastic materials (P = .03). Owing to the limited number of cases, no statistically meaningful complication was seen among the different alloplastic materials or when the cranioplastic implant was placed as secondary treatment. CONCLUSIONS: These data and those of other reports suggest that cranioplasty conducted using alloplastic 3-dimensional reconstruction materials have a lower rate of complications than those conducted using autologous bone. PMID- 26253013 TI - Histopathologic and Histomorphometric Analysis of Irradiation Injury in Bone and the Surrounding Soft Tissues of the Jaws. AB - PURPOSE: Surgery of irradiated tissue has an increased complication rate because of the development of hypovascular, hypocellular, and hypoxic tissue. This study was undertaken to perform histopathologic and histomorphometric analyses of irradiation tissue injury in bone and the surrounding soft tissues. MATERIAL AND METHODS: The histopathologic findings of 40 human mandibular bones and the surrounding soft tissue specimens obtained from different patients who underwent surgical procedures for treatment of osteoradionecrosis of the jaws were reviewed. RESULTS: Histopathologic examination showed 7 processes in the following order of appearance: hyperemia, endarteritis, thrombosis, cell loss, hypovascularity, increase of fat in the bone marrow cavity, and fibrosis. Histomorphometric analysis showed significant hypocellularity (P = .007), hypovascularity (P < .001), and fibrosis (P < .001) in irradiated specimens compared with control specimens. CONCLUSION: These results showed that radiation injuries affect the bone and surrounding soft tissues. However, the irradiation induced injuries, such as cellular loss (hypocellularity) and fibrosis, were more expressive in bone tissue than in the surrounding soft tissues. PMID- 26253014 TI - Quality indicators for pediatric colonoscopy: results from a multicenter consortium. AB - BACKGROUND AND AIMS: Currently, there are no quality measures specific to children undergoing GI endoscopy. We aimed to determine the baseline quality of pediatric colonoscopy by using the Pediatric Endoscopy Database System-Clinical Outcomes Research Initiative (PEDS-CORI), a central registry. METHODS: We conducted prospective data collection by using a standard computerized report generator and central registry (PEDS-CORI) to examine key quality indicators from 14 pediatric centers between January 2000 and December 2011. Specific quality indicators, including bowel preparation, ileal intubation rate, documentation of American Society of Anesthesiologists Physical Status Classification System (ASA) class, and procedure time, were compared during the study period. RESULTS: We analyzed 21,807 colonoscopy procedures performed in patients with a mean age of 11.5 +/- 4.8 years. Of the 21,807 reports received during the study period, 56% did not include bowel preparation quality, and 12.7% did not include ASA classification. When bowel preparation was reported, the quality was described as excellent, good, or fair in 90.3%. The overall ileal intubation rate was 69.4%, and 15.6% reported cecal intubation only, calculated to be 85% cecum or ileum intubation. Thus, 15% of colonoscopy procedures did not report reaching the cecum or ileum. When excluding the proportion of procedures not intended to reach the ileum (31.5%), the overall ileal intubation rate increased to 84.0%. The rate of ileum examination varied from 85% to 95%, depending on procedure indication. CONCLUSIONS: Colonoscopy reports from our central registry revealed significant variations and inconsistent documentation in pediatric colonoscopy. Our study identifies areas for quality improvement and highlights the need for developing accepted quality measures specific to pediatric endoscopy. PMID- 26253015 TI - The role of deep enteroscopy in the management of small-bowel disorders. PMID- 26253016 TI - Impact of next-generation sequencing on the clinical diagnosis of pancreatic cysts. AB - BACKGROUND AND AIMS: The value of next-generation sequencing (NGS) of pancreatic cyst fluid relative to the clinical and imaging impression has not been well studied. The aim of this study was to assess the impact of NGS on the clinical diagnosis from imaging and carcinoembryonic antigen (CEA) and thus the management of pancreatic cysts. METHODS: Ninety-two pancreatic cyst fluids from 86 patients were analyzed by cytology, CEA, and targeted NGS. Cysts were classified by imaging as nonmucinous, mucinous, or not specified. NGS results were compared with the imaging impression stratified by CEA and cytology. RESULTS: NGS impacted the clinical diagnosis by defining a cyst as mucinous in 48% of cysts without elevated CEA levels. The VHL gene in 2 intraductal papillary mucinous neoplasms (IPMNs) supported a serous cystadenoma. Twenty percent of cysts that were nonmucinous by imaging were mucinous by NGS. Of the 14 not-specific cysts, CEA levels were not elevated in 12 (86%), and NGS established a mucinous etiology in 3 (25%). A KRAS or GNAS mutation supported an IPMN with nonmucinous CEA in 71%. A KRAS mutation reclassified 19% of nonneoplastic cysts with nonmucinous CEA as mucinous. Seven cyst fluids (8%) had either a TP53 mutation or loss of CDKN2A or SMAD4 in addition to KRAS and/or GNAS mutations; 5 of 7 (71%) were clinically malignant, and high-grade cytology was detected in all 5. Overall, CEA was more specific for a mucinous etiology (100%), but NGS was more sensitive (86% vs 57%). CONCLUSIONS: NGS of pancreatic cyst fluid impacts clinical diagnosis and patient management by defining, supporting, or changing the clinical diagnosis based on imaging and CEA. NGS was most valuable in identifying mucinous cysts with nonmucinous CEA. An added benefit is the potential to detect mutations late in the progression to malignancy that may increase the risk classification of the cyst based on imaging and cytology. PMID- 26253017 TI - Refractory gastroparesis can be successfully managed with endoscopic transpyloric stent placement and fixation (with video). AB - BACKGROUND AND AIMS: Medical treatment options for gastroparesis are limited. Data from studies of botulinum toxin and surgical pyloroplasty suggest that disruption of the pylorus can result in symptomatic improvement in some patients with refractory gastroparetic symptoms. The aim of this study was to determine the clinical response to transpyloric stent (TPS) placement in patients with gastroparetic symptoms refractory to standard therapy. METHODS: Patients with gastroparesis refractory to medical treatment were referred for TPS placement for salvage therapy. Self-reported symptom improvement, stent migration rate, and pre and post-stent gastric-emptying study results were collected. RESULTS: A total of 30 patients with refractory gastroparesis underwent 48 TPS procedures. Of these, 25 of 48 (52.1%) were performed in patients admitted to the hospital with intractable gastroparetic symptoms. Successful stent placement in the desired location across the pylorus (technical success) was achieved during 47 procedures (98%). Most (n = 24) stents were anchored to the gastric wall by using endoscopic suturing with a mean number of sutures of 2 (range 1-3) per procedure. Clinical response was observed in 75% of patients, and all inpatients were successfully discharged. Clinical success in patients with the predominant symptoms of nausea and vomiting was higher than in those patients with a predominant symptom of pain (79% vs 21%, P = .12). A repeat gastric-emptying study was performed in 16 patients, and the mean 4-hour gastric emptying normalized in 6 patients and significantly improved in 5 patients. Stent migration was least common (48%) when stents were sutured. CONCLUSION: TPS placement is a feasible novel endoscopic treatment modality for gastroparesis and improves both symptoms and gastric emptying in patients who are refractory to medical treatment, especially those with nausea and vomiting. TPS placement may be considered as salvage therapy for inpatients with intractable symptoms or potentially as a method to select patients who may respond to more permanent therapies directed at the pylorus. PMID- 26253018 TI - Quantitative analysis of high-resolution microendoscopic images for diagnosis of neoplasia in patients with Barrett's esophagus. AB - BACKGROUND AND AIMS: Previous studies show that microendoscopic images can be interpreted visually to identify the presence of neoplasia in patients with Barrett's esophagus (BE), but this approach is subjective and requires clinical expertise. This study describes an approach for quantitative image analysis of microendoscopic images to identify neoplastic lesions in patients with BE. METHODS: Images were acquired from 230 sites from 58 patients by using a fiberoptic high-resolution microendoscope during standard endoscopic procedures. Images were analyzed by a fully automated image processing algorithm, which automatically selected a region of interest and calculated quantitative image features. Image features were used to develop an algorithm to identify the presence of neoplasia; results were compared with a histopathology diagnosis. RESULTS: A sequential classification algorithm that used image features related to glandular and cellular morphology resulted in a sensitivity of 84% and a specificity of 85%. Applying the algorithm to an independent validation set resulted in a sensitivity of 88% and a specificity of 85%. CONCLUSIONS: This pilot study demonstrates that automated analysis of microendoscopic images can provide an objective, quantitative framework to assist clinicians in evaluating esophageal lesions from patients with BE. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01384227 and NCT02018367.). PMID- 26253019 TI - Association of distal hyperplastic polyps and proximal neoplastic lesions: a prospective study of 5613 subjects. AB - BACKGROUND AND AIMS: Current evidence of whether distal hyperplastic polyps (HPs) are markers of proximal neoplasia (PN) is mixed. We evaluated the association between distal neoplasia and synchronous PN in asymptomatic subjects. METHODS: We recruited 5819 Chinese asymptomatic screening participants 50 to 70 years of age who underwent colonoscopy in Hong Kong from 2008 to 2014, of whom 206 subjects with distal advanced neoplasia or cancer were excluded. The association between distal pathology (tubular adenomas [TAs], HPs, no polyps) and proximal pathology (PN, proximal advanced neoplasia [PAN]) was assessed by multivariate regression models, overall and stratified by the Asia Pacific Colorectal Screening scoring system (scores of 4-7, high risk; scores of 0-3, lower risk). RESULTS: The prevalence of PN in the no distal polyps group, distal HPs group, and distal TAs group was 14.8%, 19.3%, and 29.4%, respectively. The corresponding prevalence of PAN was 1.8%, 3.2%, and 3.5%. Participants with distal HPs did not have significantly higher odds of PN (adjusted odds ratio [AOR] 1.24; 95% confidence interval [CI], 0.97-1.59; P = .089), and their association with PAN was marginally significant (AOR 1.77; 95% CI, 1.00-3.13; P = .052), except in lower risk subjects for whom the odds of PAN were marginally higher in the distal HPs group than the no distal polyps group (AOR 1.97; 95% CI, 1.01-3.85; P = .048). Overall, the distal polyps group had significantly lower odds of PN than the distal TAs group (AOR 0.55; 95% CI, 0.40-0.76; P < .001). The increased risk of PN and PAN among those with distal HPs was modest. CONCLUSIONS: A direct association between distal HPs and PN is lacking, and this implies a need for a multivariate assessment of the risk of PAN. Recommending colonoscopy for every patient with distal HPs detected by screening sigmoidoscopy is not supported by this study. PMID- 26253020 TI - Lethal hemorrhage from duodenal ulcer due to small pancreatic cancer. AB - Gastrointestinal massive arterial hemorrhage is difficult to stop endoscopically, especially from a duodenal ulcer (DU), because of the anatomically narrow lumen. Here we report a rare case of small pancreatic cancer-induced lethal hemorrhagic DU. The 69-year-old patient was transferred due to massive hematemesis, hypotension and loss of consciousness. Emergency upper endoscopy revealed a DU with active bleeding from an unclear hemorrhagic spot, which stopped transiently by itself. Subsequently he began to vomit blood again and angiography showed extravasation from the gastroduodenal artery (GDA). Hemostasis by transcatheter arterial embolization (TAE) was achieved but the patient unfortunately died soon after because of hemorrhagic shock (10 h after his first hematemesis). The autopsy revealed a small pancreatic cancer (poorly differentiated adenocarcinoma, 10 * 25 mm in size) infiltrating into one-half of the penetrating DU with a nearby ruptured GDA wall, suggesting that the DU was caused by the pancreatic cancer. Our 7-year analysis of emergency endoscopies in our department for upper gastrointestinal bleeding revealed that TAE was performed in more cases of duodenal hemorrhage (5.7 %) than stomach hemorrhage (1.8 %), showing the difficulty in stopping hemorrhage from DU endoscopically. This case raises the possibility that intractable lethal hemorrhagic DU could be caused by a very small pancreatic tumor. PMID- 26253021 TI - Assessment of CD27 expression as a tool for active and latent tuberculosis diagnosis. AB - There are still no reliable tests to distinguish active tuberculosis (TB) from latent TB infection (LTBI). Assessment of CD27 modulation on CD4+ T-cells has been suggested as a tool to diagnose different TB stages. OBJECTIVES: To use several cytometric approaches to evaluate CD27 expression on Mycobacterium tuberculosis (Mtb)-specific CD4+ T-cells to differentiate TB stages. METHODS: 55 HIV-uninfected subjects were enrolled: 13 active TB; 12 cured TB; 30 LTBI. Whole blood was stimulated with RD1-proteins or Cytomegalovirus-lysate (CMV). Interferon (IFN)-gamma response was evaluated by cytometry. The proportion of CD27(+/-) within the IFN-gamma+ CD4+ T-cells or RATIO of the CD27-median fluorescence intensity (MFI) of CD4+ T-cells over the CD27 MFI of IFN-gamma+ CD4+ T-cells was evaluated. RESULTS: The greatest diagnostic accuracy in discriminating active TB vs. LTBI or cured TB was reached by evaluating the CD27(+) CD45RA(-) cells within the IFN-gamma+ CD4+ T-cell subset (76.92 sensitivity for both, and 90% and 91.67% specificity, respectively), although the use of the CD27 MFI RATIO allows for stricter data analysis, independent of the operator. CONCLUSIONS: the study of CD27 expression using different approaches, whether it involves evaluation of CD45RA expression or not, is a robust biomarker for discriminating TB stages. PMID- 26253022 TI - Parry-Romberg syndrome associated with complete agenesis of the corpus callosum: An uncommon case report. PMID- 26253023 TI - Difference in microchip electrophoretic mobility between partially and fully PEGylated poly(amidoamine) dendrimers. AB - The objective of this study was to investigate the difference in electrophoretic mobility between partially and fully poly(ethylene glycol)-conjugated poly(amidoamine) dendrimers (part-PEG-PAMAM and full-PEG-PAMAM, respectively) using a microchip capillary gel electrophoresis (MCGE). While MCGE allowed size based separation of PEG-PAMAMs prepared with monomethoxy PEG-nitrophenyl carbonate, full-PEG-PAMAMs migrated slower than part-PEG-PAMAMs that were similar in size or larger. When the measured molecular weights obtained from MCGE analysis and the calculated molecular weights were plotted, each part-PEG-PAMAM and full-PEG-PAMAM showed correlation coefficients greater than 0.98. This study indicates that MCGE would be useful for characterizing PEG-PAMAMs with different PEGylation degrees. PMID- 26253024 TI - Developing the HIV Workforce: The MATEC Clinician Scholars Program. AB - Engaging new clinical providers in the HIV workforce is a critical need due to rapidly evolving treatment paradigms, aging out of existing providers, and special population needs. The 1-year competency-based Clinician Scholar Program for minority-serving providers with limited HIV care experience was individually tailored for each provider (n = 74), mostly nurse practitioners, physicians, and clinical pharmacists. Baseline and endpoint self-assessments of clinical knowledge and skills showed significant improvements in all 11 targeted competencies, particularly in managing antiretroviral medications, screening and testing methods, incorporating prevention into HIV care, understanding risk reduction methods, and describing current care standards. Faculty mentor assessments also showed significant improvement in most competencies. Additional benefits included ongoing access to mentorship and training, plus sustained engagement in local and statewide HIV care networks. Our intensive mentoring program model is replicable in other AIDS Education and Training Centers and in other structured training programs. PMID- 26253025 TI - Addicted to AA (Acetoacetate): A Point of Convergence between Metabolism and BRAF Signaling. AB - In this issue Kang et al. (2015) show that oncogenic BRAF(V600E) stimulates expression of ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA lyase and promotes the formation of the ketone body acetoacetate, which subsequently enhances BRAF(V600E)/MEK/ERK signaling. PMID- 26253026 TI - Pathogenic Hijacking of ER-Associated Degradation: Is ERAD Flexible? AB - ER-associated degradation (ERAD) is a protein clearance mechanism by which misfolded, misassembled, or metabolically regulated proteins are specifically dislocated from the ER into the cytosol and degraded by the ubiquitin proteasome system. ERAD very likely evolved to maintain proteostasis and sterol homeostasis in the ER. However, the ironic truth is that membrane-penetrating transportation and protein degradation machineries in ERAD are preferably hijacked by exogenous pathogens such as viruses and toxins for their invasion and evasion from immunological surveillance. In this Review, we provide an overview of our current understanding of the pathogenic hijacking of the host cell ERAD, in which pathogens exploit the complex ERAD machinery in a variety of manners for their own use, suggesting flexibility and plasticity of the molecular machinery of ERAD. PMID- 26253027 TI - Target Discrimination in Nonsense-Mediated mRNA Decay Requires Upf1 ATPase Activity. AB - RNA quality-control pathways get rid of faulty RNAs and therefore must be able to discriminate these RNAs from those that are normal. Here we present evidence that the adenosine triphosphatase (ATPase) cycle of the SF1 helicase Upf1 is required for mRNA discrimination during nonsense-mediated decay (NMD). Mutations affecting the Upf1 ATPase cycle disrupt the mRNA selectivity of Upf1, leading to indiscriminate accumulation of NMD complexes on both NMD target and non-target mRNAs. In addition, two modulators of NMD-translation and termination codon proximal poly(A) binding protein-depend on the ATPase activity of Upf1 to limit Upf1-non-target association. Preferential ATPase-dependent dissociation of Upf1 from non-target mRNAs in vitro suggests that selective release of Upf1 contributes to the ATPase dependence of Upf1 target discrimination. Given the prevalence of helicases in RNA regulation, ATP hydrolysis may be a widely used activity in target RNA discrimination. PMID- 26253029 TI - Monitoring Mitochondrial Pyruvate Carrier Activity in Real Time Using a BRET Based Biosensor: Investigation of the Warburg Effect. AB - The transport of pyruvate into mitochondria requires a specific carrier, the mitochondrial pyruvate carrier (MPC). The MPC represents a central node of carbon metabolism, and its activity is likely to play a key role in bioenergetics. Until now, investigation of the MPC activity has been limited. However, the recent molecular identification of the components of the carrier has allowed us to engineer a genetically encoded biosensor and to monitor the activity of the MPC in real time in a cell population or in a single cell. We report that the MPC activity is low in cancer cells, which mainly rely on glycolysis to generate ATP, a characteristic known as the Warburg effect. We show that this low activity can be reversed by increasing the concentration of cytosolic pyruvate, thus increasing oxidative phosphorylation. This biosensor represents a unique tool to investigate carbon metabolism and bioenergetics in various cell types. PMID- 26253028 TI - A Dominant Mutation in Human RAD51 Reveals Its Function in DNA Interstrand Crosslink Repair Independent of Homologous Recombination. AB - Repair of DNA interstrand crosslinks requires action of multiple DNA repair pathways, including homologous recombination. Here, we report a de novo heterozygous T131P mutation in RAD51/FANCR, the key recombinase essential for homologous recombination, in a patient with Fanconi anemia-like phenotype. In vitro, RAD51-T131P displays DNA-independent ATPase activity, no DNA pairing capacity, and a co-dominant-negative effect on RAD51 recombinase function. However, the patient cells are homologous recombination proficient due to the low ratio of mutant to wild-type RAD51 in cells. Instead, patient cells are sensitive to crosslinking agents and display hyperphosphorylation of Replication Protein A due to increased activity of DNA2 and WRN at the DNA interstrand crosslinks. Thus, proper RAD51 function is important during DNA interstrand crosslink repair outside of homologous recombination. Our study provides a molecular basis for how RAD51 and its associated factors may operate in a homologous recombination independent manner to maintain genomic integrity. PMID- 26253030 TI - In silico identification of novel IL-1beta inhibitors to target protein-protein interfaces. AB - Interleukin-1beta is a drug target in rheumatoid arthritis and several auto immune disorders. In this study, a set of 48 compounds with the determined IC50 values were used for QSAR analysis by MOE. The QSAR model was developed by using training set of 41 compounds, based on 12 unique descriptors. Model was validated by predicting the IC50 values for a test set of 7 compounds. A correlation analysis was carried out comparing the statistics of the measured IC50 values with predicted ones. Subsequently, model was used for the screening of a large data set of 7,397,957 compounds obtained from "Drugs Now" category of ZINC database. The activities of those compounds were predicted by developed model. 708,960 compounds that showed best predicted activities were chosen for further studies. Additionally this set of 708,960 compounds was screened by pharmacophore modeling that led to the retrieval of 1809 molecules. Finally docking of 1809 molecules was conducted at the IL-1beta receptor binding site using MOE and FRED docking program. Several new compounds were predicted as IL-1beta inhibitors in silico. This study provides valuable insight for designing more potent and selective inhibitors for the treatment of inflammatory diseases. PMID- 26253031 TI - Prognostic value of the second ictal intracranial pattern for the outcome of epilepsy surgery. AB - OBJECTIVE: To investigate the prognostic value of the second ictal pattern (SIP) that follows the first ictal pattern (FIP) seen at seizure onset in order to predict seizure control after epilepsy surgery. METHODS: SIPs were analysed in 344 electro-clinical and subclinical seizures recorded with intracranial electrodes in 63 patients. SIPs were classified as (a) electrodecremental event (EDE); (b) fast activity (FA); (c) runs of spikes; (d) spike-wave activity; (e) sharp waves; (f) alpha activity; (g) delta activity and (h) theta activity. Engel surgical outcome scale was used. RESULTS: The mean follow-up period was 42.1 months (SD=30.1). EDE was the most common SIP seen (41%), followed by FA (19%), spike-wave activity (18%), alpha activity (8%), sharp-wave activity (8%), delta activity (3%), runs of spikes (2%) and theta activity (2%). EDE as SIP was associated with favourable outcome when compared with FA (p=0.0044) whereas FA was associated with poor outcome when compared with any other pattern (p=0.0389). FA as SIP tends to occur after EDE (75%) whereas EDE tends to evolve from a FIP containing FA (77%). SIP extent was focal in 46% of patients, lobar in 24%, multilobar in 14% and bilateral in 16%. There is a gradual decrease in the proportion of Engel grade I with the extent of SIP. Focal and delayed (in temporal lobe epilepsy) SIPs appear to be associated with better outcome. CONCLUSIONS: As SIP, EDE was associated with favourable surgical outcome whereas FA was associated with poor outcome, probably because outcome is dominated by FIP. SIGNIFICANCE: EDE as SIP should not discourage surgery. However, FA as SIP should be contemplated with caution. SIP focality and latency can have prognostic value in epilepsy surgery. PMID- 26253033 TI - Seeing the forest before the trees-spatial orientation in freshwater stingrays (Potamotrygon motoro) in a hole-board task. AB - Freshwater stingrays (Potamotrygon motoro) have been shown to use a variety of spatial learning strategies including directional, landmark and place learning. In the present study, the significance of landmarks and geometric cues was investigated in a hole-board task. The aim was to determine cue preferences and collect additional information on the orientation mechanisms used in elasmobranchs. In four experiments, five juvenile stingrays had to memorize a fixed goal location within either a rectangular or a circular arena in the presence of goal-associated, signaling landmarks, proximal and distal cues. Transfer tests elucidated which cues the rays used or favored to reach the goal position. All rays successfully solved three of four tasks; as expected, different strategies were used in the process. Small alterations in the positioning of signaling landmarks (causing a spatial conflict between the previous feeding location and the new position of the signaling landmark) caused individuals to visit both locations equally often, whereas large alterations caused animals to ignore signaling cues and return to the previous feeding location. In the last and most complex experiment, three of five rays found the feeding location by remembering the positions of both proximate and distal landmarks in addition to memorizing particular swimming paths. Results showed that rays generally placed more importance on the overall environmental or geometric arrangement of the arena than on (individual) landmarks. This seems ecologically feasible, as distinct landmarks (e.g. rocks, pieces of wood, water plants) in the rays' natural environment may be more easily altered, removed or obscured from view than global ones (e.g. a river bend), which tend to be more stable. Overall, these results confirm those of previous studies, in that freshwater stingrays orient visually, learn quickly and can apply various orientation strategies, which are not mutually exclusive. PMID- 26253032 TI - Probing the interaction of the ipsilateral posterior parietal cortex with the premotor cortex using a novel transcranial magnetic stimulation technique. AB - OBJECTIVE: Functional imaging studies have shown that control of planned movement involves a distributed network that involves the premotor (PMv) and posterior parietal cortices (PPC). Similarly, anatomical studies show that these regions are densely interconnected via white matter tracts. We therefore hypothesized that the PPC influence over the motor cortex is partly via a connection with the PMv. METHODS: Using a novel three-pulse ipsilateral transcranial magnetic stimulation technique, we preconditioned the PPC (80% RMT) at ISIs from 4-15 ms prior to stimulating the PMv and M1 at ISIs of 4 and 6 ms. RESULTS: As previously shown, PMv-M1 paired-pulse stimulation resulted in inhibition of the MEP (90% RMT, 4-6 ms) and PPC-M1 paired-pulse stimulation resulted in facilitation of the MEP (90% RMT, 4-8 ms). PPC-M1 paired-pulse stimulation at 80% RMT preconditioning had no effect on M1. PPC-PMv-M1 stimulation resulted in reversal of inhibition observed with PMv-M1 stimulation at ISIs ranging from 6 to 15 ms. CONCLUSIONS: The reversal of inhibition observed with PPC-PMv-M1 stimulation suggests that the parietal connection to the PMv plays a role in the modulation of M1. SIGNIFICANCE: This is the first study to stimulate three intrahemispheric regions in order to test a disynaptic connection with M1. The described network may be important in a variety of movement disorders. PMID- 26253034 TI - [Late onset dementia: Specific clinical and pathophysiological features]. PMID- 26253035 TI - [Pneumonia and empyema due to Actinomyces meyeri: case report of an 80 year-old patient and a literature review]. PMID- 26253036 TI - Cardiac implantable electronic device infection in patients with end-stage renal disease. AB - INTRODUCTION: Cardiac implantable electronic devices (CIED) are increasingly being used in end-stage renal disease (ESRD) patients. These patients have a high risk of device infection. OBJECTIVES: To study the optimal management of device infections in patients with ESRD. METHOD: We used the United States Renal Data System (USRDS) to assess the presence of a CIED and associated comorbidities, risk factors for infection, and mortality following device extraction or medical management in ESRD patients with CIED infection. Univariable, multivariable, and survival analyses were performed using USRDS data from 2005 to 2009. RESULTS: Of 546,769 patients, 6.4% had CIED and 8.0% of those developed CIED infection. The major risk factors for device infection were black race, temporary dialysis catheter, and body mass index >25. Patients with artificial valves were excluded from the analysis. Only 28.4% of infected CIED were removed. CIED removal was more common in those with congestive heart failure. The median time to death following diagnosis of a CIED infection was 15.7 months versus 9.2 months for those treated via device extraction versus medical-only therapy (hazard ratio: 0.75; 95% confidence interval: 0.68-0.82). CONCLUSION: Patients with ESRD and infected CIEDs have a poor prognosis. Rates of device extraction are low, but this strategy appears to be associated with modest improvement in survival. PMID- 26253037 TI - Cardiac imaging to define infarct transmurality and guide ventricular tachycardia ablation strategy in patients with ischemic cardiomyopathy. PMID- 26253039 TI - Testosterone supplementation. PMID- 26253040 TI - Quick call 911 or maybe not... More than little old women.... PMID- 26253038 TI - Mathematical Model of Oxygen Transport in Tuberculosis Granulomas. AB - Pulmonary granulomas--the hallmark of Mycobacterium tuberculosis (MTB) infection- are dense cellular lesions that often feature regions of hypoxia and necrosis, partially due to limited transport of oxygen. Low oxygen in granulomas can impair the host immune response, while MTB are able to adapt and persist in hypoxic environments. Here, we used a physiologically based mathematical model of oxygen diffusion and consumption to calculate oxygen profiles within the granuloma, assuming Michaelis-Menten kinetics. An approximate analytical solution--using a priori and newly estimated parameters from experimental data in a rabbit model of tuberculosis--was able to predict the size of hypoxic and necrotic regions in agreement with experimental results from the animal model. Such quantitative understanding of transport limitations can inform future tuberculosis therapeutic strategies that may include adjunct host-directed therapies that facilitate oxygen and drug delivery for more effective treatment. PMID- 26253041 TI - What Burden of Prostate Cancer Can Radiologists Rule Out on Multiparametric Magnetic Resonance Imaging? A Sensitivity Analysis Based on Varying the Target Condition in Template Prostate Mapping Biopsies. AB - OBJECTIVE: To evaluate the minimum disease burden of prostate cancer at which multiparametric magnetic resonance imaging (MRI) optimally performs. METHODS: Between 2006 and 2008, 64 men underwent multiparametric MRI imaging (index test) followed by template prostate mapping biopsy (reference test). Three radiologists independently reported each quadrant of every prostate on a scale of 1 to 5: highly likely benign, likely benign, equivocal, likely malignant, highly likely malignant (>=3 or >=4 was considered positive). There were 256 prostate sectors; bootstrapping adjustment was used to account for nonindependence. The target condition indicating cancer on biopsies was varied by changing the maximum cancer core length (MCCL) and total cancer core length (TCCL) within each sector from 1 mm to 10 mm. The sensitivity, specificity, and positive (PPVs) and negative predictive values (PPVs) were calculated for each MCCL and TCCL. Gleason <=3+3 and Gleason >=3+4 cancers were analyzed separately. RESULTS: Mean age was 62 years (range, 40-76 years), and mean prostate-specific antigen level was 8.2 MUg/L (range, 2.1-43 MUg/L). Fifty percent of quadrants (127 of 256) had prostate cancer, of which 65% (83 of 127) were Gleason <=3+3. For Gleason <=3+3, multiparametric MRI had an NPV of >=95% at an MCCL of >=5 mm and at a TCCL of >=7 mm (MRI score >=3). For Gleason >=3+4, an NPV of >=95% was seen at an MCCL of >=5 mm (MRI score >=3) and TCCL >=6 mm. CONCLUSION: Multiparametric MRI may allow areas of the prostate which test negative to avoid biopsy. Whether multiparametric MRI can be used as a "triage" test before the first biopsy requires results from ongoing prospective validating cohort studies. PMID- 26253042 TI - Trends in Endovascular Aortic Aneurysm Repair Length of Stay over a Decade at a Tertiary Academic Institution. AB - BACKGROUND: Length of stay (LOS) is used as a quality metric to reduce cost and improve value of delivery of care. We sought to analyze trends in endovascular aortic aneurysm repair (EVAR) LOS at a tertiary academic institution over the last decade. METHODS: A retrospective review of prospectively collected data was performed. Infrarenal EVARs from 2001 to 2013 were divided into 3 groups: group I (2001-2004), EVARs were performed as part of clinical trials; group II (2005 2008), EVARs were referred to a tertiary referral center with the most experience with EVAR; group III (2009-2013), EVARs were referred to academic institutions in the presence of severe patient comorbidities. Trends in LOS and correlation with severity of illness (SOI) as based on All Patient Refined Diagnosis Related Groups and admission and/or disposition status were analyzed. LOS index (LOSI) at our institution was then compared with University HealthSystem Consortium (UHC) Hospitals over the past 3 years. RESULTS: A total of 1,265 EVARs were performed during this time period: 325 in group I, 547 in group II, and 393 in group III. The median LOS was 4 days (inter quartile range [IQR], 2-6) vs. 3 days (IQR, 2-5) +/- 0.28 vs. 4 days (IQR, 3-7), respectively (P < 0.01). Although moderate SOI was fairly constant over time (P = 0.66), major and/or extreme SOI constituted a greater proportion of patients in group I, was reduced in group II, and was again increased in group III, P < 0.01. The complication rate paralleled this pattern (group I, 15.2%; group II, 8.6%; group III, 10.4%; P = 0.02). The percentage of patients discharged to nursing home and/or rehab was 5.7% in group I, 8.2% in group II, 11.5% in group III (P = 0.03). Cases that were performed urgently and/or emergently increased over time: 11.6% in group I, 14.9% in group II, 21.6% in group III (P = 0.01). The risk-adjusted LOSI at our institution was significantly greater (1.25) when compared with UHC hospitals (0.75). CONCLUSIONS: Our study suggests a relationship between time period of EVAR, SOI, complications, admission status, and LOS. Attention to these trends could be used to decrease LOS in an increasingly complex patient population. PMID- 26253043 TI - Crossover Thrombectomy of Hypogastric Arteries. AB - To describe a case of intraoperative thrombotic occlusion of the left hypogastric artery (HA) during endovascular treatment for acute Leriche syndrome and a feasible technique for HA embolectomy and prevention of pelvic ischemia. After bilateral transfemoral vascular access Fogarty thrombectomy of the infrarenal aorta and bilateral common and external iliac arteries was performed. Then, an intraoperative angiography revealed new thrombotic occlusion of the left HA. Ipsilateral transfemoral approach was impeded by a strong angulation between HA and iliac artery. Therefore, a right-transfemoral approach was used for crossover Fogarty thrombectomy. The thrombus was mobilized into the left common iliac artery and could easily be removed by left-transfemoral embolectomy. No complications occurred. Crossover thrombectomy is a feasible technique for endovascular treatment of acute thrombotic occlusion of HAs. Occlusion of HA should be treated whenever possible. PMID- 26253044 TI - A Rising Generation of Diversity in the Vascular Surgery Workforce. PMID- 26253045 TI - Observation May Be Safe in Selected Cases of Blunt Traumatic Abdominal Aortic Injury. AB - BACKGROUND: Blunt traumatic abdominal aortic injury (BTAAI) is a rare lesion, often associated with extensive intraperitoneal injuries. Optimal management remains unclear, including the role of prosthetic aortic graft replacement with concomitant bowel injury and the management of small pseudoaneurysms. METHODS: We reviewed BTAAI cases occurring between 2000 and 2014. Thoracic and isolated iliac artery injuries were excluded. We included patient demographics, mechanism of injury, admission physiology, and reviewed available imaging to characterize aortic injury type and severity. RESULTS: BTAAI was noted in 16 of 8,751 (0.2%) blunt abdominal trauma patients admitted during the study period. Of these, 56% were males and the median age was 47 years (range, 5-80). Aortic repair was attempted in 7 patients, including 3 open prosthetic aortobi-iliac bypass grafts, 1 endovascular repair, and 2 primary repairs. One patient died before repair. The remaining patients were medically managed for their aortic injury, including 3 with pseudoaneurysm and 3 with large intimal flaps. There were 5 in-hospital deaths (31%) but only 1 attributed to aortic injury. Among patients surviving to discharge, there were no readmissions or delayed deaths. All nonoperative and surgically repaired patients seen in follow-up had stable aortic lesions. No patient with graft or endograft repair had evidence of graft infection on follow up (median, 52 months; range, 21-121). CONCLUSIONS: BTAAI is a rare entity and is associated with high in-hospital mortality, primarily due to associated injuries. Observation of selected small pseudoaneurysms and intimal flaps appear safe. Survival after hospital discharge is excellent, and aortic-related complications are rare. The indications for repair and the role of revascularization with in situ prosthetic graft in the setting of concomitant bowel injuries are not well defined. PMID- 26253046 TI - Homage to Professor Soubbotich and His Relavance in the Treatment of War Wounds. PMID- 26253047 TI - Evaluation of Vaccination Policies Among Utah Pediatric Clinic Employees. AB - INTRODUCTION: Pediatric health care settings are high-risk environments for spreading communicable and vaccine-preventable diseases from health care workers to susceptible patients. METHOD: All managers of pediatric clinics operating in the state of Utah were included. Participants were invited to complete a two-page questionnaire regarding their clinic vaccination policies. RESULTS: Half (n = 23) of Utah pediatric outpatient clinic managers recommend employee vaccinations, although employee refusal was allowed without consequence. Of all adult vaccines, influenza was most often included by managers as part of the employee vaccination policy. Some managers required unvaccinated employees to wear masks in the event of illness, but many had no additional requirements for unvaccinated and ill employees. DISCUSSION: Vaccination of health care workers is an effective approach to reduce disease transmission. Mandatory vaccination policies can significantly improve vaccination rates among health care workers. PMID- 26253048 TI - China's emerging and re-emerging infections: A Pandora's box for Western physicians. PMID- 26253049 TI - Vascular protection with fibroblast growth factor 21 in diabetes: its potential beyond glucose and lipid control. PMID- 26253050 TI - High-density mapping of atrial fibrillation in a chronic substrate: evidence for distinct modes of repetitive wavefront propagation. AB - BACKGROUND: Temporal dynamics of electrical wave propagation during AF is unknown. There are reports of transient linking of atrial activation. We aim to characterize temporal dynamics of wave propagation patterns during AF in an established chronically remodeled substrate. METHODS: Bi-atrial epicardial mapping of AF (mean duration 62+/-61s) was performed in 13 sheep with induced hypertension using custom-designed plaques. Wave propagation patterns were classified into periods of repetitive activity termed modes. RESULTS: In total, we identified 9241 distinct depolarization events which were classified as: passing wave (69% occurrence, 68.6% of total time), point source (20.4%, 13.1%), wave collision (4%, 2.8%), re-entrant wave (0.7%, 6.3%), half-rotation (2.9%, 4.4%), wave splitting (2.7%, 4.3%), conduction block (0.05%, 0.03%) and figure of eight reentry (0.05%, 0.05%). Episodes of re-entrant activity had mean length 701+/-1012ms. A total of 435 modes of distinct periods of repetitive activity were detected (121 in LA and 314 in RA). Looking at temporal changes between modes, we found a preferential transition: change between train of waves propagating from direction of coronary sinus and reentrant activity. High density mapping of the hypertensive fibrillating atria observed 20% point sources and 0.7% of reentrant activation which may have served as drivers of AF. Remaining activations were peripheral waves. Majority of the activation was organized into events of transient linking with existence of preferential types of transitions. CONCLUSIONS: These findings support the importance of substrate based regions of anatomically or functionally determined preferential conduction in the maintenance of AF. PMID- 26253051 TI - Synthesis and Postpolymerization Modification of Thermoresponsive Coatings Based on Pentaerythritol Monomethacrylate: Surface Analysis, Wettability, and Protein Adsorption. AB - Properties of novel temperature-responsive hydroxyl-containing poly(pentaerythritol monomethacrylate) (PPM) coatings, polymerized from oligoperoxide grafted to glass surface premodified with (3 aminopropyl)triethoxysilane, are presented. Molecular composition, chemical state, thickness, and wettability are examined with time of flight-secondary ion mass spectrometry (ToF-SIMS), X-ray photoelectron spectroscopy (XPS), ellipsometry, and contact angle measurements, respectively. Temperature-induced changes in hydrophobicity of grafted PPM brushes are revealed by water contact angle and ellipsometric measurements. Partial postpolymerization modification of hydroxyl groups (maximum a few percent), performed with acetyl chloride or pyromellitic acid chloride, is demonstrated to preserve thermal response of coatings. Adsorption of bovine serum albumin to PPM brushes, observed with fluorescence microscopy, is higher than on glass in contrast to similar hydroxyl containing layers reported as nonfouling. Enhanced and temperature-controlled protein adsorption is obtained after postpolymerization modification with pyromellitic acid chloride. PMID- 26253052 TI - Clinician trialist rounds: 28. When RCT participants are lost to follow-up. Part 1: Why even a few can matter. PMID- 26253054 TI - Championing values-based frameworks for primary care: a call for action. PMID- 26253053 TI - Developmental ecdysteroid titers and DNA puffs in larvae of two sciarid species, Rhynchosciara americana and Rhynchosciara milleri (Diptera: Sciaridae). AB - Ecdysteroid titers, developmental landmarks and the presence of prominent amplifying regions (DNA puffs) have been compared during late larval to pupal development in four groups of Rhynchosciara americana larvae and in R. americana and Rhynchosciara milleri. Three prominent DNA puffs (B2, C3 and C8) expand and regress sequentially on the rising phase of the 20-hydroxyecdysone (20E) titer in R. americana as a firm, cellular cocoon is being constructed. A sharp rise in 20E coincides with the regression of these puffs. The shape of the 20E curve is similar in R. milleri, a species that does not construct a massive cocoon, but the behavior of certain DNA puffs and their temporal relationship to the curve differs. Regions corresponding to B2 and C3 can be identified in R. milleri by banding pattern similarity with R. americana chromosomes and, in the case of B2, by hybridization to an R. americana probe. A B2 puff appears in R. milleri as the 20E titer rises but remains small in all gland regions. A puff similar to the R. americana C3 puff occurs in posterior gland cells of R. milleri (C3(Rm)) after the B2 puff, but this site did not hybridize to R. americana C3 probes. C3(Rm) incorporated (3)H-thymidine above background, but showed less post-puff DNA accumulation than C3 of R. americana. R. americana C8 probes hybridized to a more distal region of the R. milleri C chromosome that did not appear to amplify or form a large puff. These differences can be related to developmental differences, in particular differences in cocoon construction between the two species. PMID- 26253055 TI - Funding the teaching of medical students in general practice: a formula for the future? PMID- 26253056 TI - Supporting early-career GP educators in the United Kingdom. PMID- 26253057 TI - Quality assurance of the Applied Knowledge Test (AKT) of the MRCGP examination - an immediate post-test questionnaire evaluation of the candidates' views. AB - The Applied Knowledge Test (AKT) of the Membership of the Royal College of General Practitioners (MRCGP) examination is a computer-based assessment delivered three times a year. A computerised questionnaire, administered immediately after the test, sought candidates' views as part of the test evaluation. Of 1681 candidates taking the test 1418 (84%) responded. Most candidates believed that the test assessed their knowledge of problems relevant to general practice. Their feedback highlighted areas where improvements could be made. Candidates' views of postgraduate specialty medical examinations in the UK are rarely sought or published. We are not aware of other published evidence. The use of computer-based testing enables immediate candidate feedback and can be used routinely to evaluate the test validity and formats. The views of candidates are an important component of quality assurance in reviewing the content, format and educational experience of a high-stakes examination. PMID- 26253058 TI - Collaborative engagement with colleagues may provide better care for 'heart-sink' patients. AB - INTRODUCTION: In this article we show how a group of general practitioners' (GPs') professionalism was enhanced through collaborative engagement. Complexity, uncertainty and so-called 'heart-sink' patients are naturally embedded in clinical practice. GPs need to deal with, and even embrace, uncertainty, enabling them to provide patient-centred care. METHODS: A relatively fixed group of Danish GPs have met regularly for more than 14 years, discussing difficult and complex cases. Their experiences were researched through two focus group interviews using semi-structured interviews comprising open and closed questions, which were audiotaped and transcribed. The qualitative findings were analysed employing grounded theory principles. RESULTS: Participation in the GP group was perceived to have had a positive impact on participants' personal and professional lives by reducing the number of 'heart-sink' patients, by strengthening their ability to reflect and deal with uncertainty, by boosting self-confidence by improved professional selfawareness, by providing them with a safe environment and by enhancing their working enjoyment and professional motivation. A number of features of the group's structure and ways of working, which appear to have secured the long-lasting sustainability of the group, have been identified. DISCUSSION AND CONCLUSION: This group of Danish GPs experienced personal and professional growth through collaborative engagement. They have apparently learned to embrace and even value the fundamental uncertain and complex nature of primary care, which seems to benefit their 'heart-sink' patients. The features, which have ensured the long-lasting sustainability of this group, could perhaps inspire other younger GPs to work in such reflective groups. PMID- 26253059 TI - Embracing uncertainty. PMID- 26253060 TI - The use of child actors to simulate paediatric patients in the MRCGP Clinical Skills Assessment (CSA): developing an effective model. AB - Role-player consistency between candidates is a crucial component of the reliability of the Objective Structured Clinical Examination (OSCE) format used for clinical skills assessment (CSA). It is particularly important in a high stakes licensing assessment such as the Membership of the Royal College of General Practitioners' (MRCGP's) CSA. The current organisation of the CSA examination poses particular challenges for child actors. The stringent licensing process for child actors limits the working hours of children aged under 13 years considerably, making it impossible for them to perform in both the morning and afternoon circuits on examination days. Children aged nine years or younger are not able to complete even a single morning or afternoon circuit. Younger children also appear disproportionately to become fatigued and less consistent with time. All children require significant support from their adult role-player parent. Careful piloting has allowed us to develop a solution which requires the use of natural pairs of adult and child role players in two teams for the morning and afternoon circuits. A new process for training and calibrating the children the day before their performance in addition to calibration on the day appears to improve the consistency of their performance. The aim of this paper is to describe the action research-based cycle through which we developed our training procedures for child actors for the MRCGP CSA. We believe, given the challenges we have outlined, our experience will be of interest to all educators involved in the CSA process. PMID- 26253061 TI - Teaching and learning clinical reasoning: tutors' perceptions of change in their own clinical practice. AB - BACKGROUND: Clinical reasoning is an important skill for all clinicians and historically has rarely been formally taught either at undergraduate or postgraduate level. Clinical reasoning is taught as a formal course in the fourth year of the undergraduate programme at Keele School of Medicine by tutors who are all practicing general practitioners. AIM: We aimed to explore the tutors' perceptions about how teaching on the course has impacted on their own consultation skills. DESIGN AND SETTING: All 11 course tutors who had taught on the course for at least one full academic year were invited to take part in recorded individual semi-structured interviews with an experienced, non-clinical, qualitative researcher. The data were analysed using qualitative methods. RESULTS: Eleven tutors participated, with a range of 7 to 32 years of clinical experience. They reported better decision-making, greater use of metacognition, more self-awareness, more reflective practice, more confidence and greater job satisfaction. They also reported positive impacts on their own knowledge and learning, and assumed concomitant benefits for their patients. CONCLUSION: All clinicians in this group perceived benefits on their consultation skills as a result of teaching clinical reasoning. There is a need to provide education, training and continuing professional development in cognitive consultation skills to students, trainees and established practitioners. PMID- 26253063 TI - Lesson planning in primary care. PMID- 26253064 TI - How to develop a large-scale mock AKT style examination. PMID- 26253065 TI - The value of mentoring as a learning experience during GP specialist training. PMID- 26253066 TI - A new GP innovative training post in healthcare policy: a narrative of our experiences. PMID- 26253067 TI - Being and becoming a clinician: ethnographic insights. PMID- 26253068 TI - Overcoming challenges in primary care education in South Africa. PMID- 26253069 TI - Use the PDSA model for effective change management. PMID- 26253070 TI - International Exchanges in Family Medicine: the Hippokrates Exchange Programme. PMID- 26253071 TI - Spaced Learning for Continuous Professional Development in Primary Care. PMID- 26253072 TI - UK alcohol guidance has little relevance to people's lives, study finds. PMID- 26253074 TI - Correction to "The Minimal Pharmacophore for Silent Agonism of the alpha7 Nicotinic Acetylcholine Receptor". PMID- 26253073 TI - Chronic active disease pattern predicts early damage in juvenile systemic lupus erythematosus. AB - OBJECTIVE: The objective of this article is to assess disease activity patterns and their relationship to damage, death and growth failure in a cohort of juvenile lupus. METHODS: Chronic active, relapsing-remitting and long quiescent activity patterns were retrospectively classified according to longitudinal scores of both the Modified SLEDAI-2K and ECLAM. The Pediatric SLICC/ACR Damage Index (Ped-SDI) was scored at the last visit in patients followed more than six months. Survival analysis was performed considering death, damage and growth failure, and stratified according to disease activity patterns. Cox model analysis identified predictors for damage and growth failure among onset clinical variables. RESULTS: Thirty-seven patients with 11 years mean age at diagnosis and 3.2 years mean follow-up were studied. According to the Modified SLEDAI-2K, activity pattern was 67.5% relapsing-remitting, 29.8% chronic active and 2.7% long quiescent and by ECLAM, 45.9%, 48.7% and 5.4%, respectively. The five-year survival was 90%. Damage accrued in 62.5% and growth failure in 31.3%. Chronic active cases progressed to damage earlier than relapsing-remitting (log-rank test, p < 0.05). Damage was associated with disease duration (p < 0.0001), thrombocytopenia (p < 0.05) and alopecia (p < 0.004). Growth failure was associated with disease duration (p < 0.007) and renal failure (p < 0.007). CONCLUSION: Damage was observed in nearly two-thirds of patients, and occurred earlier in the chronic active pattern. Disease duration, thrombocytopenia and alopecia at onset predicted damage. PMID- 26253075 TI - Doxepin and imipramine but not fluoxetine reduce the activity of the rat glutamate transporter EAAT3 expressed in Xenopus oocytes. AB - BACKGROUND: Many researchers have suggested that the glutamatergic system may be involved in the effects of antidepressant therapies. We investigated the effects of doxepin, imipramine, and fluoxetine on the excitatory amino acid transporter type 3 (EAAT3). METHODS: EAAT3 was expressed in Xenopus oocytes by injection of EAAT3 mRNA. Membrane currents were recorded after application of L-glutamate (30 MUM) in the presence or absence of various concentrations of doxepin, imipramine, and fluoxetine. To study the effects of protein kinase C (PKC) activation on EAAT3 activity, oocytes were pre-incubated with phorbol 12-myristate-13-acetate (PMA) before application of imipramine and doxepin. RESULTS: Doxepin at 0.063 1.58 MUM significantly decreased EAAT3 activity. Imipramine reduced EAAT3 activity in a concentration-dependent manner at 0.16-0.95 MUM. However, fluoxetine did not affect EAAT3 activity, and PMA increased EAAT3 activity. At 0.32 MUM, imipramine caused an equivalent decrease in EAAT3 activity in the presence or absence of PMA. However, 0.79 MUM doxepin did not abolish the enhancement of EAAT3 activity by PMA. CONCLUSIONS: We showed that doxepin and imipramine, but not fluoxetine, inhibited EAAT3 activity at clinically relevant concentrations. This reveals a novel mechanism of action for doxepin and imipramine; that they increase glutamatergic neurotransmission. PKC may be involved in the effects of doxepin on EAAT3, but is not involved in the effects of imipramine at the concentrations studied. PMID- 26253076 TI - The Q705K and F359L Single-Nucleotide Polymorphisms of NOD-Like Receptor Signaling Pathway: Association with Chronic Pancreatitis, Pancreatic Cancer, and Periodontitis. AB - The aim of this study was to establish the correlation between the occurrence of Q705K and F359L polymorphisms in patients diagnosed with pancreatic diseases and periodontal conditions of various degrees of severity. The above-mentioned genetic markers were assessed in patients with pancreatic cancer (n = 18) and chronic pancreatitis (n = 39) as well as in a healthy control group (n = 115). The established inclusion criteria were the following: Caucasian descent, non smoking, and age range 20-80, with different levels of periodontitis activity according to S. Offenbacher's scale. The genotyping reactions were performed by means of an RT-PCR with the use of TaqMan((r)) genotyping assay. Results of the study revealed that the state of periodontium was significantly worse in patients with chronic pancreatitis. The Q705K and F359L polymorphisms were associated with more advanced cases of periodontitis measured by clinical attachment level, whereas the Q705K was associated with intensified bleeding index. Furthermore, the F359L single-nucleotide polymorphism was significantly higher in the group with chronic pancreatitis (p < 0.0001; OR = 6.8571). Whereas, the prevalence of Q705K polymorphism was higher in the group of pancreatic cancer (p = 0.107; OR = 3.3939). This study suggests that the exaggerated inflammatory response provoked by Q705K and F359L might be the common denominator for periodontitis, pancreatic cancer, and chronic pancreatitis. These findings might constitute the basis for a new diagnostic and therapeutic approach. PMID- 26253077 TI - Suburbanisation of oral cavity cancers: evidence from a geographically-explicit observational study of incidence trends in British Columbia, Canada, 1981-2010. AB - BACKGROUND: Recent studies have demonstrated an elevated risk of oral cavity cancers (OCC) among socioeconomically deprived populations, whose increasing presence in suburban neighbourhoods poses unique challenges for equitable health service delivery. The majority of studies to date have utilised aspatial methods to identify OCC. In this study, we use high-resolution geographical analyses to identify spatio-temporal trends in OCC incidence, emphasising the value of geospatial methods for public health research. METHODS: Using province-wide population incidence data from the British Columbia Cancer Registry (1981-2009, N = 5473), we classify OCC cases by census-derived neighbourhood types to differentiate between urban, suburban, and rural residents at the time of diagnosis. We map geographical concentrations by decade and contrast trends in age-adjusted incidence rates, comparing the results to an index of socioeconomic deprivation. RESULTS: Suburban cases were found to comprise a growing proportion of OCC incidence. In effect, OCC concentrations have dispersed from dense urban cores to suburban neighbourhoods in recent decades. Significantly higher age adjusted oral cancer incidence rates are observed in suburban neighbourhoods from 2006 to 2009, accompanied by rising socioeconomic deprivation in those areas. New suburban concentrations of incidence were found in neighbourhoods with a high proportion of persons aged 65+ and/or born in India, China, or Taiwan. CONCLUSIONS: While the aging of suburban populations provides some explanation of these trends, we highlight the role of the suburbanisation of socioeconomically deprived and Asia-born populations, known to have higher rates of risk behaviours such as tobacco, alcohol, and betel/areca consumption. Specifically, betel/areca consumption among Asia-born populations is suspected to be a primary driver of the observed geographical shift in incidence from urban cores to suburban neighbourhoods. We suggest that such geographically-informed findings are complementary to potential and existing place-specific cancer control policy and targeting prevention efforts for high-risk sub-populations, and call for the supplementation of epidemiological studies with high-resolution mapping and geospatial analysis. PMID- 26253078 TI - Francisella tularensis type B DeltadsbA mutant protects against type A strain and induces strong inflammatory cytokine and Th1-like antibody response in vivo. AB - Francisella tularensis subspecies tularensis is a highly virulent intracellular bacterial pathogen, causing the disease tularemia. However, a safe and effective vaccine for routine application against F. tularensis has not yet been developed. We have recently constructed the deletion mutants for the DsbA homolog protein (DeltadsbA/FSC200) and a hypothetical protein IglH (DeltaiglH/FSC200) in the type B F. tularensis subsp. holarctica FSC200 strain, which exerted different protection capacity against parental virulent strain. In this study, we further investigated the immunological correlates for these different levels of protection provided by DeltadsbA/FSC200 and DeltaiglH/FSC200 mutants. Our results show that DeltadsbA/FSC200 mutant, but not DeltaiglH/FSC200 mutant, induces an early innate inflammatory response leading to strong Th1-like antibody response. Furthermore, vaccination with DeltadsbA/FSC200 mutant, but not with DeltaiglH/FSC200, elicited protection against the subsequent challenge with type A SCHU S4 strain in mice. An immunoproteomic approach was used to map a spectrum of antigens targeted by Th1-like specific antibodies, and more than 80 bacterial antigens, including novel ones, were identified. Comparison of tularemic antigens recognized by the DeltadsbA/FSC200 post-vaccination and the SCHU S4 post challenge sera then revealed the existence of 22 novel SCHU S4 specific antibody clones. PMID- 26253079 TI - What to do about pertussis vaccines? Linking what we know about pertussis vaccine effectiveness, immunology and disease transmission to create a better vaccine. AB - Pertussis (whooping cough) is a respiratory disease caused by the bacterium Bordetella pertussis. Despite the implementation of immunization programs and high vaccine coverage in most jurisdictions, pertussis is still one of the most common vaccine-preventable diseases, suggesting that the current vaccines and immunization schedules have not been sufficiently effective. Several factors are thought to contribute to this. The acellular pertussis vaccine that has been used in many jurisdictions since the 1990s is less effective than the previously used whole-cell vaccine, with immunity waning over time. Both whole-cell and acellular pertussis vaccines are effective at reducing disease severity but not transmission, resulting in outbreaks in vaccinated cohorts. In this review, we discuss various limitations of the current approaches to protection from pertussis and outline various options for reducing the burden of pertussis on a population level. PMID- 26253080 TI - Non-invasive prognostic protein biomarker signatures associated with colorectal cancer. AB - The current management of colorectal cancer (CRC) would greatly benefit from non invasive prognostic biomarkers indicative of clinicopathological tumor characteristics. Here, we employed targeted proteomic profiling of 80 glycoprotein biomarker candidates across plasma samples of a well-annotated patient cohort with comprehensive CRC characteristics. Clinical data included 8 year overall survival, tumor staging, histological grading, regional localization, and molecular tumor characteristics. The acquired quantitative proteomic dataset was subjected to the development of biomarker signatures predicting prognostic clinical endpoints. Protein candidates were selected into the signatures based on significance testing and a stepwise protein selection, each within 10-fold cross-validation. A six-protein biomarker signature of patient outcome could predict survival beyond clinical stage and was able to stratify patients into groups of better and worse prognosis. We further evaluated the performance of the signature on the mRNA level and assessed its prognostic value in the context of previously published transcriptional signatures. Additional signatures predicting regional tumor localization and disease dissemination were also identified. The integration of rich clinical data, quantitative proteomic technologies, and tailored computational modeling facilitated the characterization of these signatures in patient circulation. These findings highlight the value of a simultaneous assessment of important prognostic disease characteristics within a single measurement. PMID- 26253082 TI - University Researcher and Law Enforcement Collaboration. AB - In 2012, heads of local law enforcement agencies in Benton County, Oregon, contacted researchers at Oregon State University to discuss a problem: a sharp rise in the number of contacts between police and suspects displaying symptoms of mental illness. This initial inquiry led to an ongoing collaborative examination of the nature, causes, and consequences of the rise in police contacts. In this article, the authors describe this collaboration between researchers and law enforcement officials from the perspective of both parties, situating it within the context of mental illness in the U.S. criminal justice system. The collaborators draw on firsthand experiences and prior collaborations to discuss the benefits of, challenges in, and recommendations for university-police research collaborations. Although such collaborations may pose challenges (related to relationship definition, data collection and analysis, outputs, and relationship maintenance), the potential benefits-for researchers and law enforcement agencies-are substantial. PMID- 26253081 TI - Prediction of colorectal cancer diagnosis based on circulating plasma proteins. AB - Non-invasive detection of colorectal cancer with blood-based markers is a critical clinical need. Here we describe a phased mass spectrometry-based approach for the discovery, screening, and validation of circulating protein biomarkers with diagnostic value. Initially, we profiled human primary tumor tissue epithelia and characterized about 300 secreted and cell surface candidate glycoproteins. These candidates were then screened in patient systemic circulation to identify detectable candidates in blood plasma. An 88-plex targeting method was established to systematically monitor these proteins in two large and independent cohorts of plasma samples, which generated quantitative clinical datasets at an unprecedented scale. The data were deployed to develop and evaluate a five-protein biomarker signature for colorectal cancer detection. PMID- 26253083 TI - Race Differences in Patterns of Risky Behavior and Associated Risk Factors in Adolescence. AB - Using data from the National Longitudinal Study of Adolescent Health (Add Health), this study expands on previous research by (a) examining differences across race in patterns or "subgroups" of adolescents based on nine self-reported behaviors (e.g., delinquency, substance use, risky sexual practices) and (b) comparing the risk factors (e.g., peer association, parenting, neighborhood cohesion), both within and across the race-specific subgroups, related to membership into the identified latent classes. The data used in this study include respondents aged 13 to 17 who participated in Waves 1 and 2 of the Add Health in-home interview. Latent class analysis (LCA) identified key differences in the number and characteristics of the latent classes across the racial subgroups. In addition, both similarities and differences in the risk factors for membership into the latent classes were identified across and within the race specific subgroups. Implications for understanding risky behavior in adolescence, as well as directions for future research, are discussed. PMID- 26253084 TI - Successful treatment of phlegmasia cerulea dolens in a nonagenarian patient with chronic iliac vein occlusion using a Cleaner thrombectomy device. AB - A 91-year-old man was admitted to the emergency room with a 3-day history of severe pain, swelling and cyanosis in his left leg. Duplex ultrasound findings were suggestive of acute left popliteal and iliofemoral venous thrombosis. Heparin was initiated and pharmacomechanical thrombolysis (PMT) was performed with the use of a Cleaner thrombectomy device. At the completion of PMT, repeat venography revealed chronic proximal iliac vein occlusion. After the procedure, alteplase was infused via the intra-arterial catheter at a rate of 0.5 mg/h over 24 h to clear the thrombus distal to the popliteal vein and residual thrombus. The patient's signs and symptoms improved markedly after the intervention. There were no minor or systemic bleeding problems. He was discharged home 10 days after the procedure without any complications. PMID- 26253085 TI - Occupationally acquired asbestosis in a healthcare worker. PMID- 26253086 TI - CX3CR1-expressing inflammatory dendritic cells contribute to the progression of steatohepatitis. AB - Liver monocytes play a major role in the development of NASH (non-alcoholic steatohepatitis). In inflamed tissues, monocytes can differentiate in both macrophages and dendritic cells. In the present study, we investigated the role of moDCs (monocyte-derived inflammatory dendritic cells) in experimental steatohepatitis induced in C57BL/6 mice by feeding on a MCD (methionine/choline deficient) diet. The evolution of steatohepatitis was characterized by an increase in hepatic CD45+ / CD11b+ myeloid cells displaying the monocyte/macrophage marker F4-80(+). In the early phases (4 weeks of treatment), Ly6C(high)/CD11b(+)/F4-80(+) inflammatory macrophages predominated. However, their frequency did not grow further with the disease progression (8 weeks of treatment), when a 4-fold expansion of CD11b(+)/F4-80(+) cells featuring the fractalkine receptor (CX3CR1) was evident. These CX3CR1+ cells were also characterized by the combined expression of inflammatory monocyte (Ly6C, CD11b) and dendritic cell (CD11c, MHCII) markers as well as by a sustained TNFalpha (tumour necrosis factor alpha) production, suggesting monocyte differentiation into inflammatory moDCs. The expansion of TNFalpha-producing CX3CR1+ moDCs was associated with an elevation in hepatic and circulating TNFalpha level and with the worsening of parenchymal injury. Hydrogen sulfide (H2S) has been shown to interfere with CX3CR1 up-regulation in monocyte-derived cells exposed to pro inflammatory stimuli. Treating 4-week-MCD-fed mice with the H2S donor NaHS while continuing on the same diet prevented the accumulation of TNFalpha-producing CX3CR1+ moDCs without interfering with hepatic macrophage functions. Furthermore, NaHS reduced hepatic and circulating TNFalpha levels and ameliorated transaminase release and parenchymal injury. Altogether, these results show that inflammatory CX3CR1+ moDCs contributed in sustaining inflammation and liver injury during steatohepatitis progression. PMID- 26253088 TI - Pharmacokinetics of high dosage of linezolid in two morbidly obese patients. PMID- 26253087 TI - Carnitine palmitoyltransferase-1 up-regulation by PPAR-beta/delta prevents lipid induced endothelial dysfunction. AB - Fatty acids cause endothelial dysfunction involving increased ROS (reactive oxygen species) and reduced NO (nitric oxide) bioavailability. We show that in MAECs (mouse aortic endothelial cells), the PPARbeta/delta (peroxisome- proliferator-activated receptor beta/delta) agonist GW0742 prevented the decreased A23187-stimulated NO production, phosphorylation of eNOS (endothelial nitric oxide synthase) at Ser1177 and increased intracellular ROS levels caused by exposure to palmitate in vitro. The impaired endothelium-dependent relaxation to acetylcholine in mouse aorta induced by palmitate was restored by GW0742. In vivo, GW0742 treatment prevented the reduced aortic relaxation, phosphorylation of eNOS at Ser1177, and increased ROS production and NADPH oxidase in mice fed on a high-fat diet. The PPARbeta/delta antagonist GSK0660 abolished all of these protective effects induced by GW0742. This agonist enhanced the expression of CPT (carnitine palmitoyltransferase)-1. The effects of GW0742 on acetylcholine- induced relaxation in aorta and on NO and ROS production in MAECs exposed to palmitate were abolished by the CPT-1 inhibitor etomoxir or by siRNA targeting CPT-1. GW0742 also inhibited the increase in DAG (diacylglycerol), PKCalpha/betaII (protein kinase Calpha/betaII) activation, and phosphorylation of eNOS at Thr495 induced by palmitate in MAECs, which were abolished by etomoxir. In conclusion, PPARbeta/delta activation restored the lipid-induced endothelial dysfunction by up-regulation of CPT-1, thus reducing DAG accumulation and the subsequent PKC-mediated ROS production and eNOS inhibition. PMID- 26253089 TI - Lack of correlation between the promastigote back-transformation assay and miltefosine treatment outcome. AB - OBJECTIVES: Widespread antimony resistance in the Indian subcontinent has enforced a therapy shift in visceral leishmaniasis treatment primarily towards miltefosine and secondarily also towards paromomycin. In vitro selection of miltefosine resistance in Leishmania donovani turned out to be quite challenging. Although no increase in IC50 was detected in the standard intracellular amastigote susceptibility assay, promastigote back-transformation remained positive at high miltefosine concentrations, suggesting a more 'resistant' phenotype. This observation was explored in a large set of Nepalese clinical isolates from miltefosine cure and relapse patients to assess its predictive value for patient treatment outcome. METHODS: The predictive value of the promastigote back-transformation for treatment outcome of a set of Nepalese L. donovani field isolates (n = 17) derived from miltefosine cure and relapse patients was compared with the standard susceptibility assays on promastigotes and intracellular amastigotes. RESULTS: In-depth phenotypic analysis of the clinical isolates revealed no correlation between the different susceptibility assays, nor any clear link to the actual treatment outcome. In addition, the clinical isolates proved to be phenotypically heterogeneous, as reflected by the large variation in drug susceptibility among the established clones. CONCLUSIONS: This in vitro laboratory study shows that miltefosine treatment outcome is not necessarily exclusively linked with the susceptibility profile of pre-treatment isolates, as determined in standard susceptibility assays. The true nature of miltefosine treatment failures still remains ill defined. PMID- 26253090 TI - Comment on: Persistence and adherence to single-tablet regimens in HIV treatment: a cohort study from the French National Healthcare Insurance Database. PMID- 26253091 TI - Inventorship and Authorship. AB - Ownership of a U.S. patent is based on inventorship. In the United States, an inventor is the owner of the claimed invention unless it is assigned to another entity. The correct naming of inventors is important, and the improper naming of inventors in a patent can be grounds for rendering the patent unenforceable. Each inventor must make an intellectual contribution, solely or jointly, to at least one element of a claim in the patent. This is in contrast to authorship of a research article, where authors may be named to acknowledge contribution to the reported research rather than an intellectual contribution. Thus, identifying inventors for a patent is not the same as identifying authors for a publication. PMID- 26253092 TI - Advances in Diagnostic Assays for Tuberculosis. AB - Approximately one-third of the global burden of tuberculosis (TB) remains undiagnosed each year and the vast majority of cases of multidrug-resistant TB remain undetected. Many countries still place heavy reliance on outdated technologies that are blunt and ineffective tools for controlling this epidemic. However, during the past 10 years, there has been substantial progress within the TB diagnostics developmental pipeline. Old technologies have been reviewed and improved and new technologies have been developed and evaluated and are now being implemented. This review summarizes these developments and describes the currently available diagnostic tools. Consideration is given to the requirements of future diagnostic tests and how these should be evaluated not only with regard to their diagnostic accuracy and operational feasibility, but ultimately in terms of whether they impact clinical outcomes cost effectively, especially for those most in need. PMID- 26253093 TI - Therapy of Delta Hepatitis. AB - Delta hepatitis is the less frequently encountered but most severe form of viral hepatitis. Acute delta hepatitis, as a result of coinfection with hepatitis B and hepatitis delta, is rare, but may lead to fulminant hepatitis, and no therapy exists for this form. Chronic delta hepatitis (CDH) mostly develops as a result of superinfection of a hepatitis B surface antigen (HBsAg) carrier with hepatitis delta virus (HDV). In general, HDV is the dominant virus. However, a dynamic shift of the dominant virus may occur with time in rare instances, and hepatitis B virus (HBV) may become the dominant virus, at which time nucleos(t)ide analog therapy may be indicated. Otherwise, the only established management of CDH consists of conventional or pegylated interferon therapy, which has to be administered at doses used for hepatitis B for a duration of at least 1 year. Posttreatment week-24 virologic response is the most widely used surrogate marker of treatment efficacy, but it does not represent a sustained virologic response, and late relapse can occur. As an easy-to-use simple serological test, anti-HDV immunoglobulin M (IgM) correlates with histological inflammatory activity and clinical long-term outcome; however, it is not as sensitive as HDV RNA in assessing treatment response. No evidence-based rules for treating CDH exist, and treatment duration needs to be individualized based on virologic response at end of treatment or end of follow-up. Effective treatment may decrease liver-related complications, such as decompensation or liver-related mortality. In patients with decompensated cirrhosis, interferons are contraindicated and liver transplantation has to be considered. Alternative treatment options are an urgent need in CDH. New treatment strategies targeting different steps of the HDV life cycle, such as hepatocyte entry inhibitors or prenylation inhibitors, are emerging and provide hope for the future. PMID- 26253094 TI - Genome-Wide Sequencing for Prenatal Detection of Fetal Single-Gene Disorders. AB - New sequencing methods capable of rapidly analyzing the genome at increasing resolution have transformed diagnosis of single-gene or oligogenic genetic disorders in pediatric and adult medicine. Targeted tests, consisting of disease focused multigene panels and diagnostic exome sequencing to interrogate the sequence of the coding regions of nearly all genes, are now clinically offered when there is suspicion for an undiagnosed genetic disorder or cancer in children and adults. Implementation of diagnostic exome and genome sequencing tests on invasively and noninvasively obtained fetal DNA samples for prenatal genetic diagnosis is also being explored. We predict that they will become more widely integrated into prenatal care in the near future. Providers must prepare for the practical, ethical, and societal dilemmas that accompany the capacity to generate and analyze large amounts of genetic information about the fetus during pregnancy. PMID- 26253095 TI - PUF60: a prominent new target of the autoimmune response in dermatomyositis and Sjogren's syndrome. AB - OBJECTIVES: Autoantibodies are used clinically to phenotype and subset patients with autoimmune rheumatic diseases. We detected a novel 60 kDa autoantibody specificity by immunoblotting using a dermatomyositis (DM) patient's serum. Our objective was to identify the targeted autoantigen and to evaluate disease specificity and clinical significance of this new autoantibody. METHODS: A new 60 kDa specificity was detected by immunoblotting HeLa cell lysates. The targeted autoantigen was identified as poly(U)-binding-splicing factor 60 kDa (PUF60) using (i) a human protein array and (ii) two-dimensional gel electrophoresis and liquid chromatography tandem mass spectrometry peptide sequencing. Anti-PUF60 antibodies were assayed by ELISA using sera from patients with primary Sjogren's syndrome (SS; n=84), systemic lupus erythematosus (SLE; n=71), DM (n=267), polymyositis (n=45), inclusion body myositis (n=45) and healthy controls (n=38). RESULTS: PUF60 was identified as a new autoantigen. Anti-PUF60 antibodies were present in 25/84 (30%) patients with SS, 6/71 (8.5%) patients with SLE and 2/38 (5.0%) control subjects (SS vs controls, p=0.002; SLE vs controls, p=0.711). Anti PUF60 antibodies were present in 48/267 (18.0%) patients with DM versus 4/45 (8.9%) and 5/45 (11.1%) patients with inclusion body myositis and polymyositis, respectively. The antibody was significantly associated with anti-Ro52 antibodies, rheumatoid factor and hyperglobulinemia in the patients with primary SS. In patients with DM, the antibody was associated with anti-transcription intermediary factor 1 gamma seropositivity and Caucasian race. CONCLUSIONS: PUF60 represents a novel autoantigen in patients with SS and DM. PUF60 antibodies are associated with distinct clinical features and different immune responses in different diseases. PMID- 26253096 TI - Interleukin-6 and chondrocyte mineralisation act in tandem to promote experimental osteoarthritis. AB - OBJECTIVES: Basic calcium phosphate (BCP) crystal and interleukin 6 (IL-6) have been implicated in osteoarthritis (OA). We hypothesise that these two factors may be linked in a reciprocal amplification loop which leads to OA. METHODS: Primary murine chondrocytes and human cartilage explants were incubated with hydroxyapatite (HA) crystals, a form of BCP, and the modulation of cytokines and matrix-degrading enzymes assayed. The ability of IL-6 to stimulate chondrocyte calcification was assessed in vitro. The mechanisms underlying the effects of HA on chondrocytes were investigated using chemical inhibitors, and the pathways mediating IL-6-induced calcification characterised by quantifying the expression of genes involved in chondrocyte mineralisation. The role of calcification in vivo was studied in the meniscectomy model of murine OA (MNX), and the link between IL-6 and cartilage degradation investigated by histology. RESULTS: In chondrocytes, BCP crystals stimulated IL-6 secretion, further amplified in an autocrine loop, through signalling pathways involving Syk and PI3 kinases, Jak2 and Stat3 molecules. Exogenous IL-6 promoted calcium-containing crystal formation and upregulation of genes involved in calcification: the pyrophosphate channel Ank, the calcium channel Annexin5 and the sodium/phosphate cotransporter Pit-1. Treatment of chondrocytes with IL-6 inhibitors significantly inhibited IL-6 induced crystal formation. In meniscectomised mice, increasing deposits of BCP crystals were observed around the joint and correlated with cartilage degradation and IL-6 expression. Finally, BCP crystals induced proteoglycan loss and IL-6 expression in human cartilage explants, which were reduced by an IL-6 inhibitor. CONCLUSIONS: BCP crystals and IL-6 form a positive feedback loop leading to OA. Targeting calcium-containing crystal formation and/or IL-6 are promising therapeutic strategies in OA. PMID- 26253097 TI - Response to: 'The significance of the squeeze test to identify arthritis was underestimated or not?' by Luo et al. PMID- 26253098 TI - Response to: 'Synovitis in knee osteoarthritis: a precursor or concomitant feature?' by Zeng et al. PMID- 26253099 TI - Descemet stripping automated endothelial keratoplasty in Fuchs' corneal endothelial dystrophy: anterior segment optical coherence tomography and in vivo confocal microscopy analysis. AB - BACKGROUND: To evaluate the in vivo corneal changes using in vivo confocal microscopy (IVCM) and anterior segment optical coherence tomography (AS-OCT) in patients with Fuchs' dystrophy who underwent Descemet stripping automated endothelial keratoplasty (DSAEK) and the relationship between these changes and the postoperative visual recovery up to 1-year follow-up. METHODS: Before DSAEK and 1 day, 3, 6 and 12 months after surgery 31 patients (39 pseudophakic eyes) underwent a complete ophthalmological evaluation including best corrected visual acuity (BCVA), IVCM (subepithelial haze, interface haze, graft thickness) and AS OCT (graft thickness). RESULTS: Graft thickness measurements by AS-OCT were strongly correlated to those obtained using IVCM at every follow-up stage (intraclass correlation coefficient = 0.95 to 0.97 between 3 and 12 months, P < 0.001 for all coefficients). No correlation between BCVA and graft thickness measured by AS-OCT at any follow-up stage was found, while at 3 and 6 postoperative months the correlations between BCVA and preoperative subepithelial haze (r = 0.61, P < 0.001 and r = 0.46, P = 0.002), interface haze (r = 0.51, P < 0.001 and r = 0.46, P = 0.003), postoperative subepithelial haze (r = 0.43, P = 0.004 and r = 0.39, P = 0.001) were significant. CONCLUSIONS: The study confirmed corneal subepithelial haze and interface haze as important factors limiting visual acuity after DSAEK, while graft thickness was not related to BCVA. PMID- 26253100 TI - Spatial video geonarratives and health: case studies in post-disaster recovery, crime, mosquito control and tuberculosis in the homeless. AB - BACKGROUND: A call has recently been made by the public health and medical communities to understand the neighborhood context of a patient's life in order to improve education and treatment. To do this, methods are required that can collect "contextual" characteristics while complementing the spatial analysis of more traditional data. This also needs to happen within a standardized, transferable, easy-to-implement framework. METHODS: The Spatial Video Geonarrative (SVG) is an environmentally-cued narrative where place is used to stimulate discussion about fine-scale geographic characteristics of an area and the context of their occurrence. It is a simple yet powerful approach to enable collection and spatial analysis of expert and resident health-related perceptions and experiences of places. Participants comment about where they live or work while guiding a driver through the area. Four GPS-enabled cameras are attached to the vehicle to capture the places that are observed and discussed by the participant. Audio recording of this narrative is linked to the video via time stamp. A program (G-Code) is then used to geotag each word as a point in a geographic information system (GIS). Querying and density analysis can then be performed on the narrative text to identify spatial patterns within one narrative or across multiple narratives. This approach is illustrated using case studies on post-disaster psychopathology, crime, mosquito control, and TB in homeless populations. RESULTS: SVG can be used to map individual, group, or contested group context for an environment. The method can also gather data for cohorts where traditional spatial data are absent. In addition, SVG provides a means to spatially capture, map and archive institutional knowledge. CONCLUSIONS: SVG GIS output can be used to advance theory by being used as input into qualitative and/or spatial analyses. SVG can also be used to gain near-real time insight therefore supporting applied interventions. Advances over existing geonarrative approaches include the simultaneous collection of video data to visually support any commentary, and the ease-of-application making it a transferable method across different environments and skillsets. PMID- 26253101 TI - Developing a computerised search to help UK General Practices identify more patients for palliative care planning: a feasibility study. AB - BACKGROUND: Approximately 600,000 people die in the UK annually, usually after months or years of increasing debility. Many patients with advanced conditions are not identified for appropriate support before they die because they are not seen as having "palliative" care needs. General practice information technology systems can improve care by identifying patients with deteriorating health so that their healthcare needs can be reviewed more systematically and effectively. The aim was to develop and test a computerised search of primary care records in routine clinical practice as a tool to improve patient identification for a palliative care approach. METHODS: An iterative process of search design and testing followed by implementation and extended testing of the search output in clinical practice. A three-phase feasibility study: developing a computerised search, determining its ability to identify patients with deteriorating health from any advanced condition, and assessing how primary care clinicians use the results to improve patient care. The setting was twelve primary care teams in two Health Boards in Scotland. RESULTS: The search identified 0.6-1.7 % of patients in each practice who were not already on the palliative care register. Primary care clinicians judged that 30-60 % of these patients were at risk of dying or deterioration over the next 6-12 months. The most common action taken by GPs was to start an electronic anticipatory care plan. CONCLUSIONS: It is possible to significantly improve the identification of patients for palliative care needs assessment using a computerised search however barriers remain to GPs' finding it acceptable. Time-efficient systems were important as was a generic tool for anticipatory care planning not linked to 'palliative' care. PMID- 26253102 TI - The variable phenotype and low-risk nature of RAS-positive thyroid nodules. AB - BACKGROUND: Oncogenic mutations are common in thyroid cancers. While the frequently detected RAS-oncogene mutations have been studied for diagnostic use in cytologically indeterminate thyroid nodules, no investigation has studied such mutations in an unselected population of thyroid nodules. No long-term study of RAS-positive thyroid nodules has been performed. METHODS: We performed a prospective, blinded cohort study in 362 consecutive patients presenting with clinically relevant (>1 cm) thyroid nodules. Fine needle aspiration cytology and mutational testing were obtained for all nodules. Post-operative histopathology was obtained for malignant or indeterminate nodules, and benign nodules were sonographically followed. Histopathological features were compared between RAS- and BRAF-positive malignancies. RAS-positive benign nodules were analyzed for growth or cellular change from prior aspirations. RESULTS: Overall, 17 of 362 nodules were RAS-positive. Nine separate nodules were BRAF-positive, of which eight underwent surgery and all proved malignant (100%). Out of the 17 RAS positive nodules, ten underwent surgery, of which eight proved malignant (47%). All RAS-positive malignancies were low risk - all follicular variants of papillary carcinoma, without extrathyroidal extension, metastases, or lymphovascular invasion. RAS-positivity was associated with malignancy in younger patients (P = 0.028). Of the nine RAS-positive benign nodules, five had long-term prospective sonographic follow-up (mean 8.3 years) showing no growth or signs of malignancy. Four of these nodules also had previous aspirations (mean 5.8 years prior), all with similar benign results. CONCLUSIONS: While RAS-oncogene mutations increase malignancy risk, these data demonstrate a low-risk phenotype for most RAS-positive cancers. Furthermore, cytologically benign, yet RAS positive nodules behave in an indolent fashion over years. RAS-positivity alone should therefore not dictate clinical decisions. PMID- 26253103 TI - Acute angle-closure glaucoma in retinopathy of prematurity following pupil dilation. AB - BACKGROUND: Pupil dilation is a known risk factor for acute angle-closure glaucoma. Regular retinal evaluation is necessary for retinopathy of prematurity (ROP) cases. An acute attack of angle-closure glaucoma following pupil dilation in regressed ROP has never been reported. CASE PRESENTATION: A five-year-old girl presented to the hospital for a routine retina check-up. The patient was born prematurely with a gestation age of 27 weeks and a body weight of 980 grams. She had a history of stage 4A ROP in the right eye and received scleral buckling. After pupil dilation with 1 % tropicamide and 10 % phenylephrine for retinal examination, acute elevation of intraocular pressure (IOP) was observed in the right eye. Her IOP remained over 50 mmHg in the right eye even under treatment with oral acetazolamide and maximal tolerated doses of topical anti-glaucoma medications. Ultrasound biomicroscopy (UBM) showed that the angle in the right eye was closed 360 degrees circumferentially. In order to lower IOP, trabeculectomy with mitomycin C (0.2 mg/cc) was performed under general anesthesia. Postoperatively, the cornea became clear, the filtering bleb functioned well, and IOP returned to normal values. In the two-year follow-up, IOP was kept around 15 mmHg without anti-glaucoma medications. Although mild lens opacity was noted, her postoperative VA remained 20/200 in the right eye. CONCLUSION: Regular retinal evaluation will be necessary for the increasing number of ROP cases to be seen in the future. Ophthalmologists should bear in mind that pupil dilation for a retina check-up could result in acute angle closure glaucoma in ROP patients. PMID- 26253104 TI - Localization of P2X receptor subtypes 2, 3 and 7 in human urinary bladder. AB - BACKGROUND: Voiding dysfunctions are a common problem that has a severe negative impact on the quality of life. Today there is a need for new drug targets for these conditions. The role of ATP receptors in bladder physiology has been studied for some time, primarily in animal models. The aim of this work is to investigate the localization of the ATP receptors P2X2, P2X3 and P2X7 and their colocalization with vimentin and actin in the human urinary bladder. METHODS: Immunohistochemical analysis was conducted on full-thickness bladder tissues from fundus and trigonum collected from 15 patients undergoing open radical cystectomy due to chronic cystitis, bladder cancer or locally advanced prostate cancer. Colocalization analyses were performed between the three different P2X subtypes and the structural proteins vimentin and actin. Specimens were examined using epifluorescence microscopy and correlation coefficients were calculated for each costaining as well as the mean distance from the laminin positive basal side of the urothelium to the vimentin positive cells located in the suburothelium. RESULTS: P2X2 was expressed in vimentin positive cells located in the suburothelium. Less distinct labelling of P2X2 was also observed in actin positive smooth muscle cells and in the urothelium. P2X3 was expressed in vimentin positive cells surrounding the smooth muscle, and in vimentin positive cells located in the suburothelium. Weaker P2X3 labelling was seen in the urothelium. P2X7 was expressed in the smooth muscle cells and the urothelium. In the suburothelium, cells double positive for P2X2 and vimentin where located closer to the urothelium while cells double positive for P2X3 and vimentin where located further from the urothelium. CONCLUSION: The results from this study demonstrate that there is a significant difference in the expression of the purinergic P2X2, P2X3 and P2X7 receptors in the different histological layers of the human urinary bladder. PMID- 26253105 TI - Knowledge-based analysis of genetic associations of rheumatoid arthritis to inform studies searching for pleiotropic genes: a literature review and network analysis. AB - INTRODUCTION: Pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. Gene variants directly affect the normal processes of a series of physiological and biochemical reactions, and therefore cause a variety of diseases traits to be changed accordingly. Moreover, a shared genetic susceptibility mechanism may exist between different diseases. Therefore, shared genes, with pleiotropic effects, are important to understand the sharing pathogenesis and hence the mechanisms underlying comorbidity. METHODS: In this study, we proposed combining genome-wide association studies (GWAS) and public knowledge databases to search for potential pleiotropic genes associated with rheumatoid arthritis (RA) and eight other related diseases. Here, a GWAS-based network analysis is used to recognize risk genes significantly associated with RA. These RA risk genes are re-extracted as potential pleiotropic genes if they have been proved to be susceptible genes for at least one of eight other diseases in the OMIM or PubMed databases. RESULTS: In total, we extracted 116 potential functional pleiotropic genes for RA and eight other diseases, including five hub pleiotropic genes, BTNL2, HLA-DRA, NOTCH4, TNXB, and C6orf10, where BTNL2, NOTCH4, and C6orf10 are novel pleiotropic genes identified by our analysis. CONCLUSIONS: This study demonstrates that pleiotropy is a common property of genes associated with disease traits. Our results ascertained the shared genetic risk profiles that predisposed individuals to RA and other diseases, which could have implications for identification of molecular targets for drug development, and classification of diseases. PMID- 26253107 TI - 3D chemical characterization of frozen hydrated hydrogels using ToF-SIMS with argon cluster sputter depth profiling. AB - Hydrogels have been used extensively in bioengineering as artificial cell culture supports. Investigation of the interrelationship between cellular response to the hydrogel and its chemistry ideally requires methods that allow characterization without labels and can map species in three-dimensional to follow biomolecules adsorbed to, and absorbed into, the open structure before and during culture. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) has the potential to be utilized for through thickness characterization of hydrogels. The authors have established a simple sample preparation procedure to successfully achieve analysis of frozen hydrated hydrogels using ToF-SIMS without the need for dry glove box entry equipment. They demonstrate this on a poly(2-hydroxyethyl methacrylate) (pHEMA) film where a model protein (lysozyme) is incorporated using two methods to demonstrate how protein distribution can be determined. A comparison of lysozyme incorporation is made between the situation where the protein is present in a polymer dip coating solution and where lysozyme is in an aqueous medium in which the film is incubated. It is shown that protonated water clusters H(H2O)n (+) where n = 5-11 that are indicative of ice are detected through the entire thickness of the pHEMA. The lysozyme distribution through the pHEMA hydrogel films can be determined using the intensity of a characteristic amino acid secondary ion fragment. PMID- 26253106 TI - Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate gastric cancer progression. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) have recently emerged as important regulators in governing fundamental biological processes, and many of which are likely to have functional roles in tumorigenesis. Maternally expressed gene 3 (MEG3) gene encodes a lncRNA whose expression is lost in an expanding list of primary human tumors and tumor cell lines, however its biological role and regulatory mechanism in gastric cancer (GC) development and progression are poorly defined. METHODS: Quantitative RT-PCR analysis was used to determine whether aberrant MEG3 expression was associated with GC patients pTNM stage and pM state. Furthermore, the effect of ectopic expression of MEG3 on cell proliferation, migration, invasion and cell apoptosis was assessed by using CCK 8, wound healing, transwell invasion assays and flow cytometric analysis, respectively, in GC cell lines HGC-27 and MGC-803. Moreover, the competing endogenous RNA (ceRNA) activity of MEG3 on miR-181a was investigated via luciferase reporter assay and immunoblot analysis. RESULTS: MEG3 is decreased in GC patients and cell lines, and its expression was associated with metastatic GC. Furthermore, ectopic expression of MEG3 in HGC-27 and MGC-803 cells inhibited cell proliferation, migration, invasion, and promoted cell apoptosis, which might be due to MEG3 sequestering oncogenic miR-181 s in GC cells. Furthermore, MEG3 could up-regulated Bcl-2 via its competing endogenous RNA (ceRNA) activity on miR 181a. CONCLUSIONS: These findings suggest that lncRNA MEG3, a ceRNA of miR-181 s, could regulate gastric carcinogenesis and may serve as a potential target for antineoplastic therapies. PMID- 26253108 TI - Time of flight secondary ion mass spectrometry of bone-Impact of sample preparation and measurement conditions. AB - Time of flight secondary ion mass spectrometry (ToF-SIMS) enables the simultaneous detection of organic and inorganic ions and fragments with high mass and spatial resolution. Due to recent technical developments, ToF-SIMS has been increasingly applied in the life sciences where sample preparation plays an eminent role for the quality of the analytical results. This paper focusses on sample preparation of bone tissue and its impact on ToF-SIMS analysis. The analysis of bone is important for the understanding of bone diseases and the development of replacement materials and new drugs for the cure of diseased bone. The main purpose of this paper is to find out which preparation process is best suited for ToF-SIMS analysis of bone tissue in order to obtain reliable and reproducible analytical results. The influence of the embedding process on the different components of bone is evaluated using principal component analysis. It is shown that epoxy resin as well as methacrylate based plastics (Epon and Technovit) as embedding materials do not infiltrate the mineralized tissue and that cut sections are better suited for the ToF-SIMS analysis than ground sections. In case of ground samples, a resin layer is smeared over the sample surface due to the polishing step and overlap of peaks is found. Beside some signals of fatty acids in the negative ion mode, the analysis of native, not embedded samples does not provide any advantage. The influence of bismuth bombardment and O2 flooding on the signal intensity of organic and inorganic fragments due to the variation of the ionization probability is additionally discussed. As C60 sputtering has to be applied to remove the smeared resin layer, its effect especially on the organic fragments of the bone is analyzed and described herein. PMID- 26253109 TI - Magnetic separation-based blood purification: a promising new approach for the removal of disease-causing compounds? AB - Recent studies report promising results regarding extracorporeal magnetic separation-based blood purification for the rapid and selective removal of disease-causing compounds from whole blood. High molecular weight compounds, bacteria and cells can be eliminated from blood within minutes, hence offering novel treatment strategies for the management of intoxications and blood stream infections. However, risks associated with incomplete particle separation and the biological consequences of particles entering circulation remain largely unclear. This article discusses the promising future of magnetic separation-based purification while keeping important safety considerations in mind. PMID- 26253110 TI - Clinical, morphological, and hemodynamic independent characteristic factors for rupture of posterior communicating artery aneurysms. AB - OBJECTIVE: To identify clinical, morphological, and hemodynamic independent characteristic factors that discriminate posterior communicating artery (PCoA) aneurysm rupture status. METHODS: 173 patients with single PCoA aneurysms (108 ruptured, 65 unruptured) between January 2012 and June 2014 were retrospectively collected. Patient-specific models based on their three-dimensional digital subtraction angiography images were constructed and analyzed by a computational fluid dynamic method. All variables were analyzed by univariate analysis and multivariate logistic regression analysis. RESULTS: Two clinical factors (younger age and atherosclerosis), three morphological factors (higher aspect ratio, bifurcation type, and irregular shape), and six hemodynamic factors (lower mean and minimum wall shear stress, higher oscillatory shear index, a greater portion of area under low wall shear stress, unstable and complex flow pattern) were significantly associated with PCoA aneurysm rupture. Independent factors characterizing the rupture status were identified as age (OR 0.956, p=0.015), irregular shape (OR 6.709, p<0.001), and minimum wall shear stress (OR 0.001, p=0.038). CONCLUSIONS: We combined clinical, morphological, and hemodynamic characteristics analysis and found the three strongest independent factors for PCoA aneurysm rupture were younger age, irregular shape, and low minimum wall shear stress. This may be useful for guiding risk assessments and subsequent treatment decisions for PCoA aneurysms. PMID- 26253111 TI - Computational fluid dynamics evaluation of flow reversal treatment of giant basilar tip aneurysm. AB - Therapeutic parent artery flow reversal is a treatment option for giant, partially thrombosed basilar tip aneurysms. The effectiveness of this treatment has been variable and not yet studied by applying computational fluid dynamics. Computed tomography images and blood flow velocities acquired with transcranial Doppler ultrasonography were obtained prior to and after bilateral endovascular vertebral artery occlusion for a giant basilar tip aneurysm. Patient-specific geometries and velocity waveforms were used in computational fluid dynamics simulations in order to determine the velocity and wall shear stress changes induced by treatment. Therapeutic parent artery flow reversal lead to a dramatic increase in aneurysm inflow and wall shear stress (30 to 170 Pa) resulting in an increase in intra-aneurysmal circulation. The enlargement of the circulated area within the aneurysm led to a re-normalization of the wall shear stress and the aneurysm remained stable for more than 8 years thereafter. Therapeutic parent artery flow reversal can lead to unintended, potentially harmful changes in aneurysm inflow which can be quantified and possibly predicted by applying computational fluid dynamics. PMID- 26253112 TI - A comparative study on the availability of modern contraceptives in public and private health facilities in a peri-urban community in Ghana. AB - BACKGROUND: Sub-Saharan Africa reports low use of family planning methods and high unmet need. Availability of these methods is one of the major barriers to contraceptive use in the region. This study determined the availability of modern contraceptives and perceived factors affecting this in health facilities in the Ga East municipality of Ghana. METHODS: This was a cross-sectional study involving quantitative and qualitative techniques. Data was obtained from 51 randomly selected health facilities using a checklist. Relationships between certain attributes of the facilities and availability of each category of contraceptive identified was tested using univariate and and multiple logistic regression techniques. The qualitative data was obtained by conducting in-depth interviews with the managers of the facilities and then analysed according to emerging themes. RESULTS: The study gave an indication that there was a low availability of long acting reversible contraceptives (LARC) such as implants (14%) and IUDs (14%) in the health facilities. Male condoms (78%) and combined oral contraceptives (82%) were the most available At the bivariate level, emergency contraceptives were less likely to be found in public health facilities (OR = 0.11, p = 0.05). Facility managers cited 'profit' and 'preference' as some of the reasons for availability of their contraceptives. CONCLUSION: Availability of modern contraceptives differ according to the type and brand of contraceptive. There is however a low availability of LARC methods in all the health facilities. Factors such as 'profit' accounted for the low availability of this method. PMID- 26253113 TI - Can radical parametrectomy be omitted in occult cervical cancer after extrafascial hysterectomy? AB - BACKGROUND: Occult invasive cervical cancer discovered after simple hysterectomy is not common, radical parametrectomy (RP) is a preferred option for young women. However, the morbidity of RP was high. The aim of our study is to assess the incidence of parametrial involvement in patients who underwent radical parametrectomy for occult cervical cancer or radical hysterectomy for early-stage cervical cancer and to suggest an algorithm for the triage of patients with occult cervical cancer to avoid RP. METHODS: A total of 13 patients with occult cervical cancer who had undergone RP with an upper vaginectomy and pelvic lymphadenectomy were included in this retrospective study. Data on the clinicopathologic characteristics of the cases were collected. The published literature was also reviewed, and low risk factors for parametrial involvement in early-stage cervical cancer were analyzed. RESULTS: Of the 13 patients, 9 had a stage IB1 lesion, and 4 had a stage IA2 lesion. There were four patients with grade 1 disease, seven with grade 2 disease, and two with grade 3 disease. The median age of the entire patients was 41 years. The most common indication for extrafascial hysterectomy was cervical intraepithelial neoplasia 3. Three patients had visible lesions measuring 10-30 mm, in diameter and ten patients had cervical stromal invasions with depths ranging from 4 to 9 mm; only one patient had more than 50% stromal invasion, and four patients had lymph-vascular space invasion (LVSI). Perioperative complications included intraoperative bowel injury, blood transfusion, vesico-vaginal fistula, and ileus (1 case for each). Postoperative pathologic examination results did not show residual disease or parametrial involvement. One patient with positive lymph nodes received concurrent radiation therapy. Only one patient experienced recurrence. CONCLUSIONS: Perioperative complications following RP were common, whereas the incidence of parametrial involvement was very low among selected early-stage cervical cancer patients. Based on these results, we thought that patients with very low-risk parametrial involvement(tumor size <= 2 cm, no LVSI, less than 50% stromal invasion, negative lymph nodes) may benefit from omitting RP. Further prospective data are warranted. PMID- 26253114 TI - [Diagnostic workup of fragrance allergy]. AB - The diagnostic workup of contact allergy to fragrances must not be limited to patch testing with the two well-established fragrance mixes. False-positive reactions to these mixes occur in up to 50 % of the patch tested patients. For the diagnostic work-up of positive reactions, and in cases of suspected fragrance allergy, patch testing with the single mix components and additional fragrances is mandatory. Frequently sensitizing fragrance materials are the 14 components of the two fragrance mixes and tree moss (Evernia furfuracea), ylang ylang oil (I + II; Cananga odorata), lemongrass oil (Cymbopogon schoenanthus), sandalwood oil (Santalum album), jasmine absolute (Jasminum spp.), and, less frequently, clove oil (Eugenia caryophyllus), cedarwood oil (Cedrus atlantica/deodara, Juniperus virginiana), Neroli oil (Citrus aurantium amara flower oil), salicylaldehyde, narcissus absolute (Narcissus spp.), and patchouli oil (Pogostemon cablin). PMID- 26253115 TI - [Nonablative fractional lasers: Acne scars and other indications]. AB - Nonablative photothermolysis has become an established technique in laser dermatology. It is mainly used for restructuring dermal connective tissue in order to treat, for example, acne scars or solar elastosis. It is also applied to the treatment of melasma and other benign cutaneous pigment disorders. This article discusses various indications in light of published observations and with regard to practical considerations. PMID- 26253116 TI - A zeta potential value determines the aggregate's size of penta-substituted [60]fullerene derivatives in aqueous suspension whereas positive charge is required for toxicity against bacterial cells. AB - BACKGROUND: The cause-effect relationships between physicochemical properties of amphiphilic [60]fullerene derivatives and their toxicity against bacterial cells have not yet been clarified. In this study, we report how the differences in the chemical structure of organic addends in 10 originally synthesized penta substituted [60]fullerene derivatives modulate their zeta potential and aggregate's size in salt-free and salt-added aqueous suspensions as well as how these physicochemical characteristics affect the bioenergetics of freshwater Escherichia coli and marine Photobacterium phosphoreum bacteria. Dynamic light scattering, laser Doppler micro-electrophoresis, agarose gel electrophoresis, atomic force microscopy, and bioluminescence inhibition assay were used to characterize the fullerene aggregation behavior in aqueous solution and their interaction with the bacterial cell surface, following zeta potential changes and toxic effects. RESULTS: Dynamic light scattering results indicated the formation of self-assembled [60]fullerene aggregates in aqueous suspensions. The measurement of the zeta potential of the particles revealed that they have different surface charges. The relationship between these physicochemical characteristics was presented as an exponential regression that correctly described the dependence of the aggregate's size of penta-substituted [60]fullerene derivatives in salt-free aqueous suspension from zeta potential value. The prevalence of DLVO-related effects was shown in salt-added aqueous suspension that decreased zeta potential values and affected the aggregation of [60]fullerene derivatives expressed differently for individual compounds. A bioluminescence inhibition assay demonstrated that the toxic effect of [60]fullerene derivatives against E. coli cells was strictly determined by their positive zeta potential charge value being weakened against P. phosphoreum cells in an aquatic system of high salinity. Atomic force microscopy data suggested that the activity of positively charged [60]fullerene derivatives against bacterial cells required their direct interaction. The following zeta potential inversion on the bacterial cells surface was observed as an early stage of toxicity mechanism that violates the membrane-associated energetic functions. CONCLUSIONS: The novel data about interrelations between physicochemical parameters and toxic properties of amphiphilic [60]fullerene derivatives make possible predicting their behavior in aquatic environment and their activity against bacterial cells. PMID- 26253118 TI - Better tools, new problems: New technologies help to advance research in the life sciences, but the quantities of data generated are proving hard to manage and interpret. PMID- 26253119 TI - Syphilis in the economic center of South China: results from a real-time, web based surveillance program. AB - BACKGROUND: Guangzhou is the economic center of South China, which is currently suffering an insidious re-emergence of syphilis. Syphilis epidemic in this area is a matter of serious concern, because of the special economic position of Guangzhou and its large migrant population. Therefore, a comprehensive analysis of surveillance data is needed to provide further information for developing targeted control programs. METHOD: Case-based surveillance data obtained from a real-time, web-based system were analyzed. A hierarchical clustering method was applied to classify the 12 districts of Guangzhou into several epidemiological regions. The district-level annual incidence and clustering results were displayed on the same map to show the spatial patterns of syphilis in Guangzhou. RESULTS: A total of 60,178 syphilis cases were reported during the period from 2005 to 2013, among which primary/secondary syphilis accounted for 15,864 cases (26.36 %), latent syphilis for 41,078 cases (68.26 %) and congenital syphilis for 2,090 cases (3.47 %). Moreover, primary/secondary syphilis burden slightly decreased from 17.5-18.0 cases per 100,000 people in the first years to 10.6 cases per 100,000 in 2013, with latent syphilis largely increasing from 18.5 cases per 100,000 to 43.4 cases per 100,000. Districts of Guangzhou could be classified into 3 epidemiological regions according to the syphilis burden over the last 3 years of the study period. CONCLUSIONS: The burden of primary/secondary syphilis appears to be decreasing in recent years, whereas that of latent syphilis is increasing. Given the epidemiological features and the annual changes found in this study, it is suggested that future control programs should be more population-specific and spatially targeted. PMID- 26253117 TI - Harnessing the apoptotic programs in cancer stem-like cells. AB - Elimination of malignant cells is an unmet challenge for most human cancer types even with therapies targeting specific driver mutations. Therefore, a multi pronged strategy to alter cancer cell biology on multiple levels is increasingly recognized as essential for cancer cure. One such aspect of cancer cell biology is the relative apoptosis resistance of tumor-initiating cells. Here, we provide an overview of the mechanisms affecting the apoptotic process in tumor cells emphasizing the differences in the tumor-initiating or stem-like cells of cancer. Further, we summarize efforts to exploit these differences to design therapies targeting that important cancer cell population. PMID- 26253120 TI - Youth, suicide attempts and low level of education: A Danish historical register based cohort study of the outcome of suicide attempt. AB - BACKGROUND: In Denmark, it is a political goal that 95% of all young people should complete an upper secondary education. For some young people, this goal can be difficult to achieve. An association has been established between suicidal behaviour and school performance. AIM: We hypothesise that young people who have attempted suicide have a lower chance of finishing secondary education. METHODS: We used Danish historical population registers to perform a longitudinal cohort design and extended Cox regression modelling to estimate crude and adjusted estimates of the effect of suicide attempt on secondary education. We used the birth cohorts 1983-1989, and all subjects were followed from birth until the end of 2011 (n = 355,725). RESULTS: For suicide attempters, the likelihood of completing secondary education was one-third of non-attempters (crude hazard ratio = 0.38). A part of the impact can be explained by confounding factors. Individuals with a suicide attempt at age 16-20 years or with multiple suicide attempts were most likely not to complete secondary education. Compared to mentally ill non-attempters, suicide attempters with mental illness were more likely not to finish secondary education. CONCLUSION: A suicide attempt is not necessarily causal for not finishing secondary education, but it is a marker, and it predicts an increased likelihood of not finishing secondary education. We need to identify individuals at risk for suicide attempts and subsequently provide the necessary support. Completing secondary education is important, as it provides better chances of employment, higher wages and more opportunities for individuals in the future. PMID- 26253121 TI - Detection, identification and genotyping of Borrellia spp. in rodents in Slovenia by PCR and culture. AB - BACKGROUND: Borrelia burgdorferi sensu lato, the agent of Lyme borreliosis, is mainly maintained in natural foci through the transmission cycles of competent tick vectors (Ixodes sp.) and a vertebrate reservoir. Specific rodents have been identified as the principal reservoir of Borrelia burgdorferi sensu lato in Europe. Borrelia miyamotoi is the only relapsing fever spirochete transmitted by the same tick. The aim of the present study was to perform an epidemiological survey to determine the presence of B. burgdorferi sensu lato in rodents occurring in Slovenia and to explore the presence of Borrelia miyamotoi. The study was performed in two parts, retrospective and prospective; a total of 297 rodents was analyzed. Detection and identification of borrelia was performed by molecular methods and additionally in the prospective study by isolation and genotyping (MluI-LRFP and MLST). RESULTS: During the prospective part of the study, borrelia was isolated from 2/46 (4.3 %) lung specimens and from 10/46 (21.7 %) heart specimens of rodents. All isolated strains were identified as B. afzelii subtype Mla1, and MLST analysis revealed 5 distinct sequence types. Borrelia DNA was successfully detected by one or other of the PCR methods in 18/46 (39.1 %) and 75/251 (29.9 %) samples in the prospective and retrospective studies, respectively. LightMix(r) was found to be more sensitive than the ''in house" nested PCR (91/297 (30.6 %) vs 48/297 (16.1 %)). Borrelia miyamotoi DNA was detected in 1/251 (0.4 %) and in 1/46 (2.2 %) heart specimens, in the retrospective and prospective parts of the study, respectively. CONCLUSION: We determined the prevalence of B. afzelii in rodents and report for the first time the presence of B. miyamotoi in Slovenia. PMID- 26253122 TI - Physician and other healthcare personnel responses to hospital stroke quality of care performance feedback: a qualitative study. AB - BACKGROUND: Understanding how physicians and other healthcare personnel respond to hospital performance feedback initiatives may have important implications for quality improvement efforts. Our objective was to explore responses to the inaugural feedback of hospital performance on stroke quality of care measures among relevant physicians and personnel at the US Department of Veterans Health Administration (VHA) hospitals. METHODS: Qualitative interviews with hospital administrators, physicians, nurses and quality managers at 12 VHA hospitals in the USA after the inaugural national release of the report on quality of acute stroke care processes. Interview transcripts were analysed using an immersion/crystallisation approach to identify recurrent themes. RESULTS: Interviews were completed with 41 individuals at 12 VHA hospitals from diverse regions of the USA; the majority were clinicians, either physicians or nurses, and nearly all had 20 years of experience or more. Interviewees described general perceptions of internal performance feedback that were both positive and negative, such as the notion that performance feedback could provide value to clinicians and hospitals, but at the same time voiced concerns about being inundated with such data. Interviewees also expressed scepticism about public reporting of performance data, citing numerous concerns and limitations. However, when interviewees described specific experiences with performance feedback, nearly all reactions were positive, including excitement, interest and feeling validated about a job well done. DISCUSSION: Physicians and other healthcare personnel described hospital performance feedback on stroke quality of care measures to be broadly valuable but identified areas of concern related to the measurement process and public reporting. PMID- 26253123 TI - David Oliver: Who is to blame for older people's readmission? PMID- 26253124 TI - Malnutrition Matters in Canadian Hospitalized Patients: Malnutrition Risk in Hospitalized Patients in a Tertiary Care Center Using the Malnutrition Universal Screening Tool. AB - BACKGROUND: Malnutrition is common in Canadian hospitalized patients, yet system wide malnutrition screening is not mandatory in Canada. AIMS: Our goal was to define the point prevalence of malnutrition risk at a major tertiary care center in Hamilton, Ontario, using the Malnutrition Universal Screening Tool (MUST) to determine feasibility of hospital-wide screening in the Canadian context. METHODS: After research ethics approval was obtained, we arranged for a clinical nutrition support team to conduct the MUST screening on all inpatients at Hamilton Health Sciences, Juravinski site, a large academic acute care hospital. RESULTS: A total of 315 patients were included (female, n = 160 [51%]; male, n = 155 [49%]; average age, 71 years). We identified 31% at high risk for malnutrition and 14% at medium risk, keeping with reported rates of malnutrition in the literature. Survey of dietitians and interns indicated that the MUST was easy to use and perform and that they had support of their unit supervisors. All respondents thought that the screen was useful and they wanted to repeat it. CONCLUSION: The MUST is an easy and efficient way to define point prevalence of malnutrition risk in Canadian hospitalized patients. Moving to system-wide nutritional screening will bring about the best practices in nutrition care with the involvement of key stakeholders and decision makers. Nutritional screening will allow us to utilize nutrition resources more efficiently, engage administrators in addressing shortfalls in nutrition care, and form a baseline for which to measure the efficacy of future nutritional interventions. PMID- 26253125 TI - Hypertension in the military patient. AB - Hypertension and hypertension-related diseases are a leading cause of morbidity and mortality worldwide. A diagnosis of hypertension can have serious occupational implications for military personnel. This article examines the diagnosis and management of hypertension in military personnel, in the context of current international standards. We consider the consequences of hypertension in the military environment and potential military-specific issues relating to hypertension. PMID- 26253126 TI - Porcine reproductive and respiratory syndrome virus 3C protease cleaves the mitochondrial antiviral signalling complex to antagonize IFN-beta expression. AB - Porcine reproductive and respiratory syndrome, a highly infectious disease caused by porcine reproductive and respiratory syndrome virus (PRRSV), has developed various strategies to evade the host innate immune response, including the suppression of type I IFN activation. The mitochondrial antiviral signalling protein (MAVS) is an important bridging adaptor of retinoic acid-inducible gene I/melanoma differentiation-associated protein 5 signalling pathways. Here, we demonstrated that the 3C-like protease (3CLSP) of PRRSV prevented the induction of IFN-beta by cleaving MAVS in a proteasome- and caspase-independent manner. Moreover, this cleavage ability was dependent on the protease activity of 3CLSP. Mutations specifically disrupting the cysteine protease activity of 3CLSP eliminated MAVS cleavage and the inhibition of IFN induction. Subsequently, we determined that 3CLSP cleaved MAVS at Glu268. Remarkably, a MAVS point mutation at Glu268 rendered MAVS resistant to 3CLSP cleavage. These results reveal a novel PRRSV mechanism to escape host immunity by directly cleaving MAVS. PMID- 26253127 TI - Ectopic ACTH secretion (EAS) associated to a well-differentiated peritoneal mesothelioma: case report. AB - BACKGROUND: The association between mesotheliomas and ectopic ACTH secretion has been rarely reported; we present the first case of ectopic ACTH secretion (EAS) associated with a well-differentiated peritoneal mesothelioma in whom the high dose dexamethasone suppression test (HDDST) results and plasmatic ACTH levels were similar to those found in Cushing's disease (CD). CASE PRESENTATION: A 43 year-old hispanic woman with a 20 year history of treatment resistant diabetes mellitus and arterial hypertension. She had a full moon face, a buffalo hump, increased volume in both supraclavicular regions, purple striae in her arms and abdomen, truncal obesity, polymenorrhea and umbilical hernia. A cortisol suppression test with low dose dexamethasone (LDDST) with a result of 16.6 MUg/dL and ACTH plasma levels were measured at 32.6 pg/mL. The high dose dexamethasone test suppression percentage was 84.8% and magnetic resonance imaging (MRI) showed no evidence of pituitary alterations, computed tomography (CT) showed images suggestive of uterine fibroid and an intra-abdominal tumor that correlated with an umbilical hernia, which reinforcement after contrast. Surgery was performed, finding uterine fibroids and paracolic tumor implants as well as on the omentum, bladder, bowel, ovaries and appendix. Pathology reported a well-differentiated peritoneal mesothelioma with positive immunohistochemistry for ACTH. CONCLUSIONS: Although most cases of ectopic secretion of ACTH derive from rapidly-developing lung tumors, with very high plasma ACTH levels and cortisol suppression percentages with high doses of dexamethasone under 60%, there is a small percentage of slow-developing, chronic tumors that are biochemically undistinguishable from Cushing's disease. Following the expert recommendations regarding imaging techniques it is possible to identify the associated tumor in most cases. PMID- 26253129 TI - Worsening renal function in patients with baseline renal impairment treated with intravenous voriconazole: A systematic review. AB - The objective of this paper was to review the risk of worsening renal function in patients with pre-existing renal impairment receiving intravenous voriconazole (IVV). Controversy exists regarding the cause and risk of renal dysfunction in patients treated with IVV. Whilst some studies implicate renally excreted cyclodextrin, a pharmaceutical formulation stabiliser, as the cause of renal dysfunction following voriconazole administration, others provide contradicting evidence. Here we analyse the available literature to gain an insight into the significance of renal toxicity in patients treated with IVV. PubMed was searched for relevant studies to December 2014. To account for publication bias, abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy, the Infectious Diseases Society of America/ID Week, and the European Congress of Clinical Microbiology and Infectious Diseases from 2008-2014 were reviewed. Bibliographies of all identified articles were reviewed and cross-referenced for additional sources. Seven retrospective studies were identified for inclusion in the review; no prospective studies were identified. Based on the available evidence, we conclude that there is no strong evidence suggesting an increased incidence of worsening renal function with IVV use. No study thus far has provided direct conclusive evidence for cellular and physiological renal toxicity due to IVV at clinically prevalent doses. PMID- 26253130 TI - Oral health in prehistoric San Pedro de Atacama oases, Northern Chile. AB - After almost 2000 years of local development, including limited trading with neighboring ethnic groups, the societies that occupied the oases of San Pedro de Atacama, Northern Chile, became part of the trade web of the Tiwanaku empire, between 500 and 1000 CE. Archaeological evidence tends to support the idea that the period under the influence of the altiplano (high plane) empire was very affluent. Here we investigate the possibility that this affluence had a positive impact on the health status of the Atacameneans, using the oral health as an indirect indicator of quality of life. Dental decay, dental abscess, dental wear, linear enamel hypoplasia, periodontal disease and dental calculus were analyzed on 371 skeletons from 12 sites from San Pedro de Atacama oases. We believe that if, indeed, there were better biological conditions during the altiplano influence, this could have been caused by the access to a more diversified food intake promoted by the intensification of the trading network established by Tiwanaku in the central-south Andes, of which San Pedro de Atacama became an important node. PMID- 26253128 TI - Carcinogenic effects of circadian disruption: an epigenetic viewpoint. AB - Circadian rhythms refer to the endogenous rhythms that are generated to synchronize physiology and behavior with 24-h environmental cues. These rhythms are regulated by both external cues and molecular clock mechanisms in almost all cells. Disruption of circadian rhythms, which is called circadian disruption, affects many biological processes within the body and results in different long term diseases, including cancer. Circadian regulatory pathways result in rhythmic epigenetic modifications and the formation of circadian epigenomes. Aberrant epigenetic modifications, such as hypermethylation, due to circadian disruption may be involved in the transformation of normal cells into cancer cells. Several studies have indicated an epigenetic basis for the carcinogenic effects of circadian disruption. In this review, I first discuss some of the circadian genes and regulatory proteins. Then, I summarize the current evidence related to the epigenetic modifications that result in circadian disruption. In addition, I explain the carcinogenic effects of circadian disruption and highlight its potential role in different human cancers using an epigenetic viewpoint. Finally, the importance of chronotherapy in cancer treatment is highlighted. PMID- 26253131 TI - Real-time prediction of inpatient length of stay for discharge prioritization. AB - OBJECTIVE: Hospitals are challenged to provide timely patient care while maintaining high resource utilization. This has prompted hospital initiatives to increase patient flow and minimize nonvalue added care time. Real-time demand capacity management (RTDC) is one such initiative whereby clinicians convene each morning to predict patients able to leave the same day and prioritize their remaining tasks for early discharge. Our objective is to automate and improve these discharge predictions by applying supervised machine learning methods to readily available health information. MATERIALS AND METHODS: The authors use supervised machine learning methods to predict patients' likelihood of discharge by 2 p.m. and by midnight each day for an inpatient medical unit. Using data collected over 8000 patient stays and 20 000 patient days, the predictive performance of the model is compared to clinicians using sensitivity, specificity, Youden's Index (i.e., sensitivity + specificity - 1), and aggregate accuracy measures. RESULTS: The model compared to clinician predictions demonstrated significantly higher sensitivity (P < .01), lower specificity (P < .01), and a comparable Youden Index (P > .10). Early discharges were less predictable than midnight discharges. The model was more accurate than clinicians in predicting the total number of daily discharges and capable of ranking patients closest to future discharge. CONCLUSIONS: There is potential to use readily available health information to predict daily patient discharges with accuracies comparable to clinician predictions. This approach may be used to automate and support daily RTDC predictions aimed at improving patient flow. PMID- 26253132 TI - Active learning: a step towards automating medical concept extraction. AB - OBJECTIVE: This paper presents an automatic, active learning-based system for the extraction of medical concepts from clinical free-text reports. Specifically, (1) the contribution of active learning in reducing the annotation effort and (2) the robustness of incremental active learning framework across different selection criteria and data sets are determined. MATERIALS AND METHODS: The comparative performance of an active learning framework and a fully supervised approach were investigated to study how active learning reduces the annotation effort while achieving the same effectiveness as a supervised approach. Conditional random fields as the supervised method, and least confidence and information density as 2 selection criteria for active learning framework were used. The effect of incremental learning vs standard learning on the robustness of the models within the active learning framework with different selection criteria was also investigated. The following 2 clinical data sets were used for evaluation: the Informatics for Integrating Biology and the Bedside/Veteran Affairs (i2b2/VA) 2010 natural language processing challenge and the Shared Annotated Resources/Conference and Labs of the Evaluation Forum (ShARe/CLEF) 2013 eHealth Evaluation Lab. RESULTS: The annotation effort saved by active learning to achieve the same effectiveness as supervised learning is up to 77%, 57%, and 46% of the total number of sequences, tokens, and concepts, respectively. Compared with the random sampling baseline, the saving is at least doubled. CONCLUSION: Incremental active learning is a promising approach for building effective and robust medical concept extraction models while significantly reducing the burden of manual annotation. PMID- 26253133 TI - Nonamyloid tumoral light-chain-deposition disease (aggregoma) of the paraspinal region. AB - Aggregomas are rare localized masses of monoclonal nonamyloid immunoglobulin light-chain deposits. To date, there have been only a few reports of isolated aggregomas, with the majority detailing renal, lymph node and brain deposition. We present a rare case of paraspinal aggregoma in a 67-year-old female who presented with a complaint of cough and chest pain. Imaging demonstrated a left sided paravertebral mass extending from T7-T10. Pathological analysis showed lamellar deposition of extracellular eosinophilic material with an associated lymphoplasmacytic nonamyloid infiltrate. To our knowledge, this is the first report of a paraspinal aggregoma. While exceedingly rare, this tumor can be included in the radiologic differential diagnosis of paravertebral soft tissue tumors in adults. The observation of our case adds to the limited understanding of the etiology, pathogenesis, natural history, and treatment of nonamyloid light chain depositions. PMID- 26253134 TI - A new duck circovirus sequence, detected in velvet scoter (Melanitta fusca) supports great diversity among this species of virus. AB - BACKGROUND: The aim of this study was to investigate the presence of circoviruses in wild bird populations, in Poland. Circoviruses possess immuno-suppressive properties and might interfere with the health of wild birds. METHOD: 83 birds, which belonged to 23 species, were tested with broad-range, nested PCR. The obtained PCR products were sequenced and new primers designed, to analyse the full-length, viral genome. A phylogenetic analysis was conducted, to find any relationship to known circoviruses. RESULTS: The circovirus DNA sequence was found in 4 birds. All samples originated from the velvet scoter (Melanitta fusca) a marine duck from the Merginae sub-family. Birds which tested positive for the circovirus were found dead in fishing nets, off the Baltic coast. During post mortem examination, carcasses of two of the scoters showed only light emaciation, while the two other birds appeared healthy. The obtained, full-length, circovirus sequence revealed 1,988 nucleotides and the presence of typical features (i.e. Cap, Rep and ORF3). Nucleotide similarity to other duck circoviruses was 84 to 86 %. Phylogenetic analysis of the complete genome and cap gene, indicated that the new circovirus is related to known duck circoviruses, especially to sub-types sometimes referred to as duck circovirus genotype 1, but not genotype 2. CONCLUSIONS: In this study, we have reported a new duck circovirus sequence detected in the velvet scoter, a species of marine duck. Sequence comparison and phylogenetic analysis of the new virus sequence support previous reports that duck circovirus (DuCV) is a species with a high degree of diversity. The viral sequence obtained from the velvet scoter suggests that DuCV may infect birds from the Anatinae sub-family. More studies are needed to prove if the velvet scoter and other marine ducks act as a reservoir for DuCV. PMID- 26253135 TI - Local sparsity enhanced compressed sensing magnetic resonance imaging in uniform discrete curvelet domain. AB - BACKGROUND: Compressed sensing(CS) has been well applied to speed up imaging by exploring image sparsity over predefined basis functions or learnt dictionary. Firstly, the sparse representation is generally obtained in a single transform domain by using wavelet-like methods, which cannot produce optimal sparsity considering sparsity, data adaptivity and computational complexity. Secondly, most state-of-the-art reconstruction models seldom consider composite regularization upon the various structural features of images and transform coefficients sub-bands. Therefore, these two points lead to high sampling rates for reconstructing high-quality images. METHODS: In this paper, an efficient composite sparsity structure is proposed. It learns adaptive dictionary from lowpass uniform discrete curvelet transform sub-band coefficients patches. Consistent with the sparsity structure, a novel composite regularization reconstruction model is developed to improve reconstruction results from highly undersampled k-space data. It is established via minimizing spatial image and lowpass sub-band coefficients total variation regularization, transform sub-bands coefficients l 1 sparse regularization and constraining k-space measurements fidelity. A new augmented Lagrangian method is then introduced to optimize the reconstruction model. It updates representation coefficients of lowpass sub-band coefficients over dictionary, transform sub-bands coefficients and k-space measurements upon the ideas of constrained split augmented Lagrangian shrinkage algorithm. RESULTS: Experimental results on in vivo data show that the proposed method obtains high-quality reconstructed images. The reconstructed images exhibit the least aliasing artifacts and reconstruction error among current CS MRI methods. CONCLUSIONS: The proposed sparsity structure can fit and provide hierarchical sparsity for magnetic resonance images simultaneously, bridging the gap between predefined sparse representation methods and explicit dictionary. The new augmented Lagrangian method provides solutions fully complying to the composite regularization reconstruction model with fast convergence speed. PMID- 26253136 TI - Myanmar ministers and opposition leaders agree plan to eliminate malaria by 2030. PMID- 26253137 TI - CoMEt: a statistical approach to identify combinations of mutually exclusive alterations in cancer. AB - Cancer is a heterogeneous disease with different combinations of genetic alterations driving its development in different individuals. We introduce CoMEt, an algorithm to identify combinations of alterations that exhibit a pattern of mutual exclusivity across individuals, often observed for alterations in the same pathway. CoMEt includes an exact statistical test for mutual exclusivity and techniques to perform simultaneous analysis of multiple sets of mutually exclusive and subtype-specific alterations. We demonstrate that CoMEt outperforms existing approaches on simulated and real data. We apply CoMEt to five different cancer types, identifying both known cancer genes and pathways, and novel putative cancer genes. PMID- 26253139 TI - Fungal dimorphism: the switch from hyphae to yeast is a specialized morphogenetic adaptation allowing colonization of a host. AB - The ability of pathogenic fungi to switch between a multicellular hyphal and unicellular yeast growth form is a tightly regulated process known as dimorphic switching. Dimorphic switching requires the fungus to sense and respond to the host environment and is essential for pathogenicity. This review will focus on the role of dimorphism in fungi commonly called thermally dimorphic fungi, which switch to a yeast growth form during infection. This group of phylogenetically diverse ascomycetes includes Talaromyces marneffei (recently renamed from Penicillium marneffei), Blastomyces dermatitidis (teleomorph Ajellomyces dermatitidis), Coccidioides species (C. immitis and C. posadasii), Histoplasma capsulatum (teleomorph Ajellomyces capsulatum), Paracoccidioides species (P. brasiliensis and P. lutzii) and Sporothrix schenckii (teleomorph Ophiostoma schenckii). This review will explore both the signalling pathways regulating the morphological transition and the transcriptional responses necessary for intracellular growth. The physiological requirements of yeast cells during infection will also be discussed, highlighting recent advances in the understanding of the role of iron and calcium acquisition during infection. PMID- 26253138 TI - Proton irradiation impacts age-driven modulations of cancer progression influenced by immune system transcriptome modifications from splenic tissue. AB - Age plays a crucial role in the interplay between tumor and host, with additional impact due to irradiation. Proton irradiation of tumors induces biological modulations including inhibition of angiogenic and immune factors critical to 'hallmark' processes impacting tumor development. Proton irradiation has also provided promising results for proton therapy in cancer due to targeting advantages. Additionally, protons may contribute to the carcinogenesis risk from space travel (due to the high proportion of high-energy protons in space radiation). Through a systems biology approach, we investigated how host tissue (i.e. splenic tissue) of tumor-bearing mice was altered with age, with or without whole-body proton exposure. Transcriptome analysis was performed on splenic tissue from adolescent (68-day) versus old (736-day) C57BL/6 male mice injected with Lewis lung carcinoma cells with or without three fractionations of 0.5 Gy (1 GeV) proton irradiation. Global transcriptome analysis indicated that proton irradiation of adolescent hosts caused significant signaling changes within splenic tissues that support carcinogenesis within the mice, as compared with older subjects. Increases in cell cycling and immunosuppression in irradiated adolescent hosts with CDK2, MCM7, CD74 and RUVBL2 indicated these were the key genes involved in the regulatory changes in the host environment response (i.e. the spleen). Collectively, these results suggest that a significant biological component of proton irradiation is modulated by host age through promotion of carcinogenesis in adolescence and resistance to immunosuppression, carcinogenesis and genetic perturbation associated with advancing age. PMID- 26253140 TI - The effect of subjective and objective social class on health-related quality of life: new paradigm using longitudinal analysis. AB - BACKGROUND: To investigate the impact of the gap between subjective and objective social status on health-related quality of life. METHODS: We analyzed data from 12,350 participants aged >= 18 years in the Korean Health Panel Survey. Health related quality of life was measured by EuroQol-Visual analogue scale. Objective (income and education) and subjective social class (measured by MacArthur scale) was classified into three groups (High, Middle, Low). In terms of a gap between objective and subjective social class, social class was grouped into nine categories ranging from High-High to Low-Low. A linear mixed model was used to investigate the association between the combined social class and health-related quality of life. RESULTS: The impact of the gap between objective and subjective status on Health-related quality of life varied according to the type of gap. Namely, at any given subjective social class, an individual's quality of life declined with a decrease in the objective social class. At any given objective social class (e.g., HH, HM, HL; in terms of both education and income), an individual's quality of life declined with a one-level decrease in subjective social class. CONCLUSION: Our results suggest that studies of the relationship between social class and health outcomes may consider the multidimensional nature of social status. PMID- 26253142 TI - A Multicenter Performance Evaluation of a Blood Glucose Monitoring System in 21 Leading Hospitals in Spain. AB - BACKGROUND: Self-monitoring of blood glucose is crucial for the effective self management of diabetes. The present study evaluated the accuracy of the Contour(r) XT blood glucose monitoring system (BGMS) compared to the reference method in a large multicenter study under routine lab conditions at each hospital site. METHODS: This study was conducted at 21 leading hospitals in Spain using leftover whole blood samples (n = 2100). Samples were tested with the BGMS using 1 commercial strip lot and the local laboratory hexokinase method. BGMS accuracy was assessed and results were compared to ISO 15197:2013 accuracy limit criteria and by using mean absolute relative difference analysis (MARD), consensus (Parkes) error grid (CEG), and surveillance error grid analyses (SEG). RESULTS: Pooled analysis of 2100 measurements from all sites showed that 99.43% of the BGMS results were within the ranges accepted by the accuracy limit criteria. The overall MARD was 3.85%. MARD was 4.47% for glucose concentrations < 70 mg/dL and 3.81% for concentrations of 70-300 mg/dL. In CEG, most results (99.8%) were within zone A ("no effect on clinical action"); the remaining ones (0.2%) were in zone B ("little to no effect on clinical action"). The SEG analysis showed that most of the results (98.4%) were in the "no risk" zone, with the remaining results in the "slight, lower" risk zone. CONCLUSIONS: This is the largest multicenter study of Contour XT BGMS to date, and shows that this BGMS meets the ISO 15197:2013 accuracy limit criteria under local routine conditions in 21 leading Spanish hospitals. PMID- 26253141 TI - Exposure to 3G mobile phone signals does not affect the biological features of brain tumor cells. AB - BACKGROUND: The increase in mobile phone use has generated concerns about possible risks to human health, especially the development of brain tumors. Whether tumor patients should continue to use mobile telephones has remained unclear because of a paucity of information. Herein, we investigated whether electromagnetic fields from mobile phones could alter the biological features of human tumor cells and act as a tumor-promoting agent. METHODS: Human glioblastoma cell lines, U251-MG and U87-MG, were exposed to 1950-MHz time division synchronous code division multiple access (TD-SCDMA) at a specific absorption rate (maximum SAR = 5.0 W/kg) for 12, 24, and 48 h. Cell morphologies and ultra structures were observed by microscopy and the rates of apoptosis and cell cycle progression were monitored by flow cytometry. Additionally, cell growth was determined using the CKK-8 assay, and the expression levels of tumor and apoptosis-related genes and proteins were analyzed by real-time PCR and western blotting, respectively. Tumor formation and invasiveness were measured using a tumorigenicity assay in vivo and migration assays in vitro. RESULTS: No significant differences in either biological features or tumor formation ability were observed between unexposed and exposed glioblastoma cells. Our data showed that exposure to 1950-MHz TD-SCDMA electromagnetic fields for up to 48 h did not act as a cytotoxic or tumor-promoting agent to affect the proliferation or gene expression profile of glioblastoma cells. CONCLUSIONS: Our findings implied that exposing brain tumor cells in vitro for up to 48 h to 1950-MHz continuous TD SCDMA electromagnetic fields did not elicit a general cell stress response. PMID- 26253143 TI - A C-Peptide-Based Model of Pancreatic Insulin Secretion in Extremely Preterm Neonates in Intensive Care. AB - BACKGROUND: Model-based glycemic control relies on sufficiency of underlying models to describe underlying patient physiology. In particular, very preterm infant glucose-insulin metabolism can differ significantly from adults, and is relatively unstudied. In this study, C-peptide concentrations are used to develop insulin-secretion models for the purposes of glycemic control in neonatal intensive care. METHODS: Plasma C-peptide, insulin, and blood glucose concentrations (BGC) were retrospectively analyzed from a cohort of 41 hyperglycemic very preterm (median age 27.2 [26.2-28.7] weeks) and very low birth weight infants (median birth weight 839 [735-1000] g). A 2-compartment model of C peptide kinetics was used to estimate insulin secretion. Insulin secretion was examined with respect to nutritional intake, exogenous and plasma insulin concentration, and BGC. RESULTS: Insulin secretion was found to be highly variable between patients and over time, and could not be modeled with respect to age, weight, or protein or dextrose intake. In 13 of 54 samples exogenous insulin was being administered, and insulin secretion was lower. However, low data numbers make this result inconclusive. Insulin secretion was found to increase with BG, with a stronger association in female infants than males (R(2) = .51 vs R(2) = .13, and R(2) = .26 for the combined cohort). CONCLUSIONS: A sex-based insulin secretion model was created and incorporated into a model-based glycemic control framework. Nutritional intake did not predict insulin secretion, indicating that insulin secretion is a complex function of a number of metabolic factors. PMID- 26253144 TI - An Automatic Assessment System of Diabetic Foot Ulcers Based on Wound Area Determination, Color Segmentation, and Healing Score Evaluation. AB - BACKGROUND: For individuals with type 2 diabetes, foot ulcers represent a significant health issue. The aim of this study is to design and evaluate a wound assessment system to help wound clinics assess patients with foot ulcers in a way that complements their current visual examination and manual measurements of their foot ulcers. METHODS: The physical components of the system consist of an image capture box, a smartphone for wound image capture and a laptop for analyzing the wound image. The wound image assessment algorithms calculate the overall wound area, color segmented wound areas, and a healing score, to provide a quantitative assessment of the wound healing status both for a single wound image and comparisons of subsequent images to an initial wound image. RESULTS: The system was evaluated by assessing foot ulcers for 12 patients in the Wound Clinic at University of Massachusetts Medical School. As performance measures, the Matthews correlation coefficient (MCC) value for the wound area determination algorithm tested on 32 foot ulcer images was .68. The clinical validity of our healing score algorithm relative to the experienced clinicians was measured by Krippendorff's alpha coefficient (KAC) and ranged from .42 to .81. CONCLUSION: Our system provides a promising real-time method for wound assessment based on image analysis. Clinical comparisons indicate that the optimized mean-shift-based algorithm is well suited for wound area determination. Clinical evaluation of our healing score algorithm shows its potential to provide clinicians with a quantitative method for evaluating wound healing status. PMID- 26253146 TI - Proteomic analysis of 3-MCPD and 3-MCPD dipalmitate-induced toxicity in rat kidney. AB - 3-Chloropropane-1,2-diol (3-MCPD) and its fatty acid esters are formed during thermal treatment of fat-containing foodstuff in the presence of salt. Toxicological studies indicate a carcinogenic potential of 3-MCPD, pointing to the kidney as the main target organ. It is assumed that the toxicological property of 3-MCPD esters is constituted by the release of 3-MCPD during digestion. In a repeated-dose 28-day oral toxicity study using Wistar rats, animals were treated with equimolar doses of either 3-MCPD (10 mg/kg body weight) or 3-MCPD dipalmitate (53 mg/kg body weight). A lower dose of 3-MCPD dipalmitate (13.3 mg/kg body weight) was also applied. No histopathologically visible toxicity was observed in the study. To address molecular mechanisms leading to toxicity of 3-MCPD and its esters, kidney samples were analyzed by a comparative, two-dimensional gel electrophoresis/mass spectrometry proteomic approach. After either 3-MCPD or 3-MCPD dipalmitate treatment, alterations in proteins related to various metabolic pathways, including carbohydrate, amino acid, and fatty acid metabolism, were detected. These findings confirm and complement previous data on the inhibition of glucose metabolism by 3-MCPD. Altogether, broad overlap of 3 MCPD- and 3-MCPD dipalmitate-induced proteomic changes was observed. Further analyses revealed that the observed induction of glutathione S-transferase pi 1 (Gstp1) occurred at the transcriptional level and was not related to nuclear factor (erythroid-derived 2)-like 2 activation. Overall, the results indicate common mechanisms of toxicity for 3-MCPD and its dipalmitate ester. Furthermore, data suggest Gstp1 as a sensitive marker for early 3-MCPD-induced effects in rat kidney. PMID- 26253147 TI - Initial experience in setting up a medical student first responder scheme in South Central England. AB - Prehospital emergency medicine (PHEM) is a recently recognised subspecialty of emergency medicine, and anaesthetics, intensive care and acute medicine, in the UK, and yet it receives little to no mention in many undergraduate medical curricula. However, there is growing interest in PHEM among medical students and junior doctors. Several programmes are in existence across the UK that serve to provide teaching and exposure of prehospital care to medical students and junior doctors. However, relatively few students are able to gain significant first-hand experience of treating patients in the prehospital phase. In this short report, we discuss our experience of launching the student first responder (SFR) scheme across three counties in the Thames Valley. Medical students are trained by the regional ambulance service and respond to life-threatening medical emergencies in an ambulance response vehicle. The scheme is likely to benefit the ambulance service by providing a wider pool of trained volunteer first responders able to attend to emergency calls, to benefit patients by providing a quick response at their time of need, and to benefit medical students by providing first-hand experience of medical emergencies in the community. In its first 15 months of operation, SFRs were dispatched to 343 incidents. This scheme can serve as a training model for other ambulance services and medical schools across the UK. PMID- 26253148 TI - Top 10 ways to reconcile social media and 'traditional' education in emergency care. AB - Social media has been viewed by some as a threat to traditional medical education. In emergency care, the underpinning educational principles of social media, while sometimes innovative in their delivery, are often no different than long-standing techniques and methods. This article aims to encourage discussion and debate that reduces the divide between these two communities of practice. PMID- 26253145 TI - Reciprocal relationship of T regulatory cells and monocytic myeloid-derived suppressor cells in LP-BM5 murine retrovirus-induced immunodeficiency. AB - Immunomodulatory cellular subsets, including myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs), contribute to the immunosuppressive tumour microenvironment and are targets of immunotherapy, but their role in retroviral-associated immunosuppression is less well understood. Due to known crosstalk between Tregs and MDSCs in the tumour microenvironment, and also their hypothesized involvement during human immunodeficiency virus/simian immunodeficiency virus infection, studying the interplay between these immune cells during LP-BM5 retrovirus-induced murine AIDS is of interest. IL-10 producing FoxP3+ Tregs expanded after LP-BM5 infection. Following in vivo adoptive transfer of natural Treg (nTreg)-depleted CD4+T-cells, and subsequent LP BM5 retroviral infection, enriched monocytic MDSCs (M-MDSCs) from these nTreg depleted mice displayed altered phenotypic subsets. In addition, M-MDSCs from LP BM5-infected nTreg-depleted mice exhibited increased suppression of T-cell, but not B-cell, responses, compared with M-MDSCs derived from non-depleted LP-BM5 infected controls. Additionally, LP-BM5-induced M-MDSCs modulated the production of IL-10 by FoxP3+ Tregs in vitro. These collective data highlight in vitro and for the first time, to the best of our knowledge, in vivo reciprocal modulation between retroviral-induced M-MDSCs and Tregs, and may provide insight into the immunotherapeutic targeting of such regulatory cells during retroviral infection. PMID- 26253149 TI - Efficacy of an Organizational Skills Intervention for College Students With ADHD Symptomatology and Academic Difficulties. AB - OBJECTIVE: We sought to elucidate the effects of an organization, time management, and planning (OTMP) skills training intervention for college students reporting elevated levels of ADHD symptomatology and academic impairment. METHOD: Undergraduate participants enrolled in either the intervention ( n = 22) or comparison ( n = 15) condition in exchange for psychology course credit. Those in the intervention condition attended three weekly group meetings designed to improve organizational skills. Treatment effectiveness was evaluated by comparing pre- and postmeasurements of academic impairment, inattention, hyperactivity/impulsivity, and OTMP skills utilization. RESULTS: Intervention group participants improved significantly on ratings of inattention, hyperactivity/impulsivity, and academic impairment, relative to the comparison group. Intervention group participants also improved in their use of OTMP skills, relative to their baseline ratings. CONCLUSION: This study suggests an organizational skills intervention has the potential to ameliorating ADHD symptomatology and academic impairment among college students. PMID- 26253150 TI - Expression of chicken interleukin-2 by a highly virulent strain of Newcastle disease virus leads to decreased systemic viral load but does not significantly affect mortality in chickens. AB - BACKGROUND: In mammals, interleukin 2 (IL-2) has been shown to decrease replication or attenuate pathogenicity of numerous viral pathogens (herpes simplex virus, vaccinia virus, human respiratory syncytial virus, human immunodeficiency virus) by activating natural killer cells (NK), cytotoxic T lymphocytes and expanding subsets of memory cells. In chickens, IL-2 has been shown to activate T cells, and as such it might have the potential to affect replication and pathogenesis of Newcastle disease virus (NDV). METHODS: To assess the effect of IL-2 during NDV infection in chickens, we produced a recombinant virulent NDV strain expressing chicken IL-2 (rZJ1-IL2). The effects of IL-2 expression were investigated in vivo using the intracerebral pathogenicity index (ICPI) in day-old chicks and pathogenesis experiments in 4-week-old chickens. In these studies, rZJ1-IL2 was compared to a control virus expressing the green fluorescent protein (rZJ1-GFP). Assessed parameters included survival curves, detailed histological and immunohistochemical grading of lesions in multiple organs, and virus isolation in blood, spleen and mucosal secretions of infected birds. RESULTS: At the site of infection (eyelid), expression of IL-2 was demonstrated in areas of rZJ-IL2 replication, confirming IL-2 production in vivo. Compared to rZJ1-GFP strain, rZJ1-IL2 caused milder lesions and displayed decreased viral load in blood, spleen and mucosal secretions of infected birds. In the rZJ1-IL2-infected group, virus level in the blood peaked at day 4 post infection (pi) (10(3.46) EID50 /0.1 ml) and drastically decreased at day 5 pi (10(0.9) EID50/0.1 ml), while in the rZJ1-GFP-infected group virus levels in the blood reached 10(5.35) EID50/0.1 ml at day 5. However, rZJ1-IL2-infected groups presented survival curves similar to control birds infected with rZJ1-GFP, with comparable clinical signs and 100 % mortality. Further, expression of IL-2 did not significantly affect the ICPI scores, compared to rZJ1-GFP strain. CONCLUSIONS: Increased expression of chicken IL-2 during virulent NDV replication in naive chickens decreased viral titers in blood, spleens, oral and cloacal secretions on day 4-5 post infection. This is consistent with the previously described role of IL-2 in enhancing the clearance of viruses in mammals, such as human respiratory syncytial virus. PMID- 26253151 TI - Epidemiology of Brucella infection in the human, livestock and wildlife interface in the Katavi-Rukwa ecosystem, Tanzania. AB - BACKGROUND: Brucellosis is a zoonosis of public health importance worldwide. In Tanzania, the disease is underreported due to insufficient awareness, inadequate diagnostic protocols, including lack of appropriate reagents for diagnosis. Livestock and wildlife are considered potential sources of infection to humans; however, the role played by these carriers in the epidemiology of the disease in the ecosystems in Tanzania is not fully understood. The objective of this study was to establish the prevalence of anti-Brucella antibodies in humans, wildlife and livestock; and molecular prevalence of Brucella spp in cattle and goats in the Katavi- Rukwa ecosystem. RESULTS: Anti-Brucella antibodies were detected in humans at 0.6 % (95 % CI: 0.1, 2.1 %); cattle at 6.8 % (95 % CI: 5.4, 8.5 %), goats at 1.6 % (95 % CI: 0.4, 4.1 %) and buffaloes at 7.9 % (95 % CI: 1.7, 21.4 %). One of the two sampled lions tested positive. Cattle had a significantly higher prevalence of anti-Brucella antibodies as compared to goats (P < 0.05). A significantly higher seroprevalence was found in female than in male cattle and in adult than in young cattle (P < 0.05). There was an agreement of 95 and 89 % in cattle and goats, respectively, for the Rose Bengal plate Test (RBPT) and Competitive Enzyme Linked Immunosorbent Assay (c-ELISA) in detecting Brucella infection. Eight (3.5 %) out of 231 milk samples tested were positive for Brucella spp on Polymerase Chain Reaction (PCR), and Brucella abortus biovar 1 was detected in cattle milk. However, no Brucella spp were detected in goat milk. CONCLUSION: This study has shown the presence of anti- Brucella antibodies in humans, livestock, and wildlife in the Katavi- Rukwa ecosystem. Transmission of the infection between wildlife, livestock and humans is likely to continue due to increasing human activities in the human wildlife interface. This information is an important contribution to public health policy development in the human wildlife interface of the Katavi- Rukwa ecosystem. PMID- 26253152 TI - The MAM'Out project: a randomized controlled trial to assess multiannual and seasonal cash transfers for the prevention of acute malnutrition in children under 36 months in Burkina Faso. AB - BACKGROUND: Wasting is a public health issue but evidence gaps remain concerning preventive strategies not primarily based on food products. Cash transfers, as part of safety net approach, have potential to prevent under-nutrition. However, most of the cash transfer programs implemented and scientifically evaluated do not have a clear nutritional objective, which leads to a lack of evidence regarding their nutritional benefits. METHODS/DESIGN: The MAM'Out research project aims at evaluating a seasonal and multiannual cash transfer program to prevent acute malnutrition in children under 36 months, in terms of effectiveness and cost-effectiveness in the Tapoa province (Eastern region of Burkina Faso, Africa). The program is targeted to economically vulnerable households with children less than 1 year old at the time of inclusion. Cash is distributed to mothers and the transfers are unconditional, leading to beneficiaries' self determination on the use of cash. The study is designed as a two-arm cluster randomized intervention trial, based on the randomization of rural villages. One group receives cash transfers via mobile phones and one is a control group. The main outcomes are the cumulative incidence of acute malnutrition and the cost effectiveness. Child anthropometry (height, weight and MUAC) is followed, as well as indicators related to dietary diversity, food security, health center utilization, families' expenses, women empowerment and morbidities. 24 h-food recalls are also carried out. Individual interviews and focus group discussions allow collecting qualitative data. Finally, based on a theory framework built a priori, the pathways used by the cash to have an effect on the prevention of under-nutrition will be assessed. DISCUSSION: The design chosen will lead to a robust assessment of the effectiveness of the proposed intervention. Several challenges appeared while implementing the study and discrepancies with the research protocol, mainly due to unforeseen events, can be highlighted, such as delay in project implementation, switch to e-data collection and implementation of a supervision process. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT01866124, registered May 7, 2013. PMID- 26253154 TI - Endometriosis causing acute appendicitis complicated with hemoperitoneum. AB - Endometriosis is a painful disorder characterized by endometrial tissue outside the uterine cavity. It usually affects the pelvis, but in rare cases it might extend to other parts of the body. The report is based on a case of a 39-year-old woman, who presented symptoms of acute appendicitis and diagnosis confirmed with ultrasonography and a computed tomography scan procedures. Laparoscopic appendicectomy was performed. After entering the abdominal cavity, hemoperitoneum was discovered with no associated pelvic or abdominal lesions. Biopsy confirmed acute appendicitis with endometrial glands and stroma infiltrating its muscular tissue. Patient recovered without complications and was discharged 48 h after surgery. The appendix is rarely affected by endometrial infiltration. The literature describes an incidence of 0.8%, just a few cases have been associated with acute appendicitis; however, none of them are described to present hemoperitoneum, being our patient the first one reported with such complication. PMID- 26253153 TI - Autophagy capacity and sub-mitochondrial heterogeneity shape Bnip3-induced mitophagy regulation of apoptosis. AB - BACKGROUND: Mitochondria are key regulators of apoptosis. In response to stress, BH3-only proteins activate pro-apoptotic Bcl2 family proteins Bax and Bak, which induce mitochondrial outer membrane permeabilization (MOMP). While the large scale mitochondrial release of pro-apoptotic proteins activates caspase-dependent cell death, a limited release results in sub-lethal caspase activation which promotes tumorigenesis. Mitochondrial autophagy (mitophagy) targets dysfunctional mitochondria for degradation by lysosomes, and undergoes extensive crosstalk with apoptosis signaling, but its influence on apoptosis remains undetermined. The BH3 only protein Bnip3 integrates apoptosis and mitophagy signaling at different signaling domains. Bnip3 inhibits pro-survival Bcl2 members via its BH3 domain and activates mitophagy through its LC3 Interacting Region (LIR), which is responsible for binding to autophagosomes. Previously, we have shown that Bnip3 activated mitophagy prior to apoptosis induction can reduce mitochondrial activation of caspases, suggesting that a reduction to mitochondrial levels may be pro-survival. An outstanding question is whether organelle dynamics and/or recently discovered subcellular variations of protein levels responsible for both MOMP sensitivity and crosstalk between apoptosis and mitophagy can influence the cellular apoptosis decision event. To that end, here we undertook a systems biology analysis of mitophagy-apoptosis crosstalk at the level of cellular mitochondrial populations. RESULTS: Based on experimental findings, we developed a multi-scale, hybrid model with an individually adaptive mitochondrial population, whose actions are determined by protein levels, embedded in an agent based model (ABM) for simulating subcellular dynamics and local feedback via reactive oxygen species signaling. Our model, supported by experimental evidence, identified an emergent regulatory structure within canonical apoptosis signaling. We show that the extent of mitophagy is determined by levels and spatial localization of autophagy capacity, and subcellular mitochondrial protein heterogeneities. Our model identifies mechanisms and conditions that alter the mitophagy decision within mitochondrial subpopulations to an extent sufficient to shape cellular outcome to apoptotic stimuli. CONCLUSION: Overall, our modeling approach provides means to suggest new experiments and implement findings at multiple scales in order to understand how network topologies and subcellular heterogeneities can influence signaling events at individual organelle level, and hence, determine the emergence of heterogeneity in cellular decisions due the actions of the collective intra-cellular population. PMID- 26253155 TI - Guide to Suturing. PMID- 26253156 TI - Microbial Metabolism of Atovaquone and Cytotoxicity of the Produced Phase I Metabolite. AB - BACKGROUND AND OBJECTIVES: Atovaquone is a hydroxynaphthoquinone with selective action in the mitochondrial respiratory chain of malaria parasite. It is employed for both the treatment and prevention of malaria, in a combination with proguanil. The aim of this study was to elucidate the in vitro metabolites from atovaquone and to evaluate their cytotoxic activities. METHODS: The biotransformation of atovaquone was performed using Mucor rouxii NRRL 1894, Cunninghamella echinulata var. elegans ATCC 8688a and C. elegans ATCC 10028b, which have been reported as microbial models of mammalian drug metabolism. Experiments were also carried out with two probiotic strains from the human intestinal tract: Bifidobacterium sp. and Lactobacillus acidophilus. The phase I metabolite was isolated, its chemical structure was elucidated and its toxicity was evaluated using the neoplastic cell line SKBR-3 derived from human breast cancer and normal human fibroblast cell line GM07492-A. Cell cytotoxicity assays were also carried out with atovaquone. RESULT: Only the fungi were able to convert atovaquone to metabolite trans-3-[4'-(4"-chlorophenyl)cyclohexyl)-1,2 dioxo-dihydro-1H-indene-3-carboxylic acid. The metabolite displayed 50 % inhibitory concentration (IC50) values of 110.20 +/- 2.2 and 108.80 +/- 1.5 umol/L against breast cancer cell line SKBR-3 and fibroblasts cell line GM07492 A, respectively. The IC50 values of atovaquone were 282.30 +/- 1.8 and 340.50 +/- 1.4 umol/L against breast cancer and normal fibroblasts cell lines, respectively. CONCLUSIONS: The produced metabolite was more toxic than atovaquone and was not selective to normal or cancer cell lines. The present study is the first to report the production of atovaquone metabolite. PMID- 26253158 TI - Reliable emotion recognition system based on dynamic adaptive fusion of forehead biopotentials and physiological signals. AB - In this study, we proposed a new adaptive method for fusing multiple emotional modalities to improve the performance of the emotion recognition system. Three channel forehead biosignals along with peripheral physiological measurements (blood volume pressure, skin conductance, and interbeat intervals) were utilized as emotional modalities. Six basic emotions, i.e., anger, sadness, fear, disgust, happiness, and surprise were elicited by displaying preselected video clips for each of the 25 participants in the experiment; the physiological signals were collected simultaneously. In our multimodal emotion recognition system, recorded signals with the formation of several classification units identified the emotions independently. Then the results were fused using the adaptive weighted linear model to produce the final result. Each classification unit is assigned a weight that is determined dynamically by considering the performance of the units during the testing phase and the training phase results. This dynamic weighting scheme enables the emotion recognition system to adapt itself to each new user. The results showed that the suggested method outperformed conventional fusion of the features and classification units using the majority voting method. In addition, a considerable improvement, compared to the systems that used the static weighting schemes for fusing classification units, was also shown. Using support vector machine (SVM) and k-nearest neighbors (KNN) classifiers, the overall classification accuracies of 84.7% and 80% were obtained in identifying the emotions, respectively. In addition, applying the forehead or physiological signals in the proposed scheme indicates that designing a reliable emotion recognition system is feasible without the need for additional emotional modalities. PMID- 26253157 TI - Eisosome Ultrastructure and Evolution in Fungi, Microalgae, and Lichens. AB - Eisosomes are among the few remaining eukaryotic cellular differentations that lack a defined function(s). These trough-shaped invaginations of the plasma membrane have largely been studied in Saccharomyces cerevisiae, in which their associated proteins, including two BAR domain proteins, have been identified, and homologues have been found throughout the fungal radiation. Using quick-freeze deep-etch electron microscopy to generate high-resolution replicas of membrane fracture faces without the use of chemical fixation, we report that eisosomes are also present in a subset of red and green microalgae as well as in the cysts of the ciliate Euplotes. Eisosome assembly is closely correlated with both the presence and the nature of cell walls. Microalgal eisosomes vary extensively in topology and internal organization. Unlike fungi, their convex fracture faces can carry lineage-specific arrays of intramembranous particles, and their concave fracture faces usually display fine striations, also seen in fungi, that are pitched at lineage-specific angles and, in some cases, adopt a broad-banded patterning. The conserved genes that encode fungal eisosome-associated proteins are not found in sequenced algal genomes, but we identified genes encoding two algal lineage-specific families of predicted BAR domain proteins, called Green BAR and Red-BAR, that are candidate eisosome organizers. We propose a model for eisosome formation wherein (i) positively charged recognition patches first establish contact with target membrane regions and (ii) a (partial) unwinding of the coiled-coil conformation of the BAR domains then allows interactions between the hydrophobic faces of their amphipathic helices and the lipid phase of the inner membrane leaflet, generating the striated patterns. PMID- 26253159 TI - Functional conservation analysis and expression modes of grape anthocyanin synthesis genes responsive to low temperature stress. AB - In grape cultivation, low temperature generally increases the expression of genes involved in synthesis of anthocyanin. In this study, multi-type structural analysis of the proteins encoded by five anthocyanin biosynthesis genes VvF3H, VvPAL, VvCHS3, VvCHS2 and VvLDOX, in addition to nine of their homologous genes revealed that proteins in grapevine shared a high similarity with that in kiwi, red orange and some other species in which the biosynthesis of anthocyanin significantly influenced by low temperature as proved by previous studies. Low temperature regulatory elements were also found in the promoter region of the grapevine genes VvCHS2, VvPAL and VvF3H. These findings indicate that the functions of anthocyanin biosynthesis genes in grapevine are conservative and might be sensitive to low temperature. In order to identify the specific expression patterns of the five anthocyanin biosynthesis genes and the changes of polyphenols, anthocyanins and flavonoids under low temperature stress. The transcription analysis of the five genes and the content of polyphenols, anthocyanins and flavonoids in grape skins were examined, by using Vitis vinifera L. cv. 'Yongyou 1' and 'Juxing' berries as experimental material and treated at 4 degrees C and 25 degrees C for 24h, 48 h, 72 h and 96 h. The results showed that low temperature greatly enhanced the expression of the five anthocyanin biosynthesis genes. Low temperature greatly slowed down the decomposition of polyphenol, anthocyanin, and flavonoid in grape skins. Our study also found that cv. 'Juxing' responded more sensitively to low temperature than cv. 'Yongyou 1'. All the findings would provide a basis for further study on the mechanism of anthocyanin biosynthesis under environmental stress. PMID- 26253160 TI - Prognostic and biological significance of microRNA-221 in breast cancer. AB - INTRODUCTION: Breast cancer (BC) is the most notorious cancer between females with high rates of morbidity and mortality. The aim of this study was to determine the differential expression of breast tissues microRNA-221 (miR-221) and assess its prognostic and biological significance in breast cancer (BC). METHODS: A quantitative reverse transcription PCR (qPCR) assay was performed to detect the expression of breast tissue miR-221 in different subtypes of BC (n=76) and controls (n=36) and its correlations with clinicopathological factors of patients. Univariate and multivariate analyses using the Cox proportional hazards model were performed to analyze the prognostic significance of miR-221 expression. RESULT: Our data indicated that the relative level of miR-221 expression in BC tissues was significantly higher than that in noncancerous breast tissues (p<0.01). Of 76 BC patients, 62 (81.6%) were positive cases. By statistical analyses, high miR-221 expression was observed to be closely correlated with advanced clinical stage (p<0.01). Moreover, patients with high miR-221 expression had worse 5-year relapse free survival (p=0.0124). Univariate and multivariate analyses indicated that high miR-221 expression was an independent poor prognostic factor for BC patients. CONCLUSION: miR-221 is a potential biomarker for predicting the survival of BC patients and may be a molecular therapeutic target for BC. PMID- 26253161 TI - Unique synteny and alternate splicing of the chitin synthases in closely related heliothine moths. AB - Chitin is an extracellular biopolymer that contributes to the cuticular structural matrix in arthropods. As a consequence of its rigid structure, the chitinous cuticle must be shed and replaced to accommodate growth. Two chitin synthase genes that encode for chitin synthase A (ChSA), which produces cuticular exoskeleton, and chitin synthase B (ChSB), which produces peritrophic membrane, were characterized in the genomes of two heliothine moths: the corn earworm/cotton bollworm, Helicoverpa zea (Boddie) (Lepidoptera: Noctuidae) and the cotton bollworm, Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae). In both moths, the two genes were arranged in tandem with the same orientation on the same strand with ChSB located 5' of ChSA. Sequence comparisons showed that the coding sequences were highly conserved with homologues from other species but that the tandem juxtaposed genomic arrangement of the two genes was unique in these insects. The mechanism that has led to this arrangement is unclear but is most likely a recent recombinational event. Transcript mapping of HzChSB and HzChSA in H. zea demonstrated that both transcripts were differentially spliced in various tissues and larval stages. The identification of the HzChSB-E12b alternate spliced transcript is the first report of alternate splicing for the ChSB group. The importance of this splice form is not clear because the protein produced would lack any enzymatic activity but retain the membrane insertion motifs. As for other insects, these genes provide an important target for potential control through RNAi but also provide a subject for broad scale genomic recombinational events. PMID- 26253162 TI - STR-based genetic structure of the Berber population of Bejaia (Northern Algeria) and its relationships to various ethnic groups. AB - Patterns of genetic variation in human populations have been described for decades. However, North Africa has received little attention and Algeria, in particular, is poorly studied, Here we genotyped a Berber-speaking population from Algeria using 15 short tandem repeat (STR) loci D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818 and FGA from the commercially available AmpF/STR Identifiler kit. Altogether 150 unrelated North Algerian individuals were sampled across 10 administrative regions or towns from the Bejaia Wilaya (administrative district). We found that all of the STR loci met Hardy-Weinberg equilibrium expectations, after Bonferroni correction and that the Berber-speaking population of Bejaia presented a high level of observed heterozygosity for the 15 STR system (>0.7). Genetic parameters of forensic interest such as combined power of discrimination (PD) and combined probability of exclusion (PE) showed values higher than 0.999, suggesting that this set of STRs can be used for forensic studies. Our results were also compared to those published for 42 other human populations analyzed with the same set. We found that the Bejaia sample clustered with several North African populations but that some geographically close populations, including the Berber-speaking Mozabite from Algeria were closer to Near-Eastern populations. While we were able to detect some genetic structure among samples, we found that it was not correlated to language (Berber-speaking versus Arab-speaking) or to geography (east versus west). In other words, no significant genetic differences were found between the Berber-speaking and the Arab-speaking populations of North Africa. The genetic closeness of European, North African and Near-Eastern populations suggest that North Africa should be integrated in models aiming at reconstructing the demographic history of Europe. Similarly, the genetic proximity with sub-Saharan Africa is a reminder of the links that connect all African regions. PMID- 26253163 TI - Non-apoptotic role for caspase-7 in hair follicles and the surrounding tissue. AB - Hair follicles are unique organs undergoing regular cycles of proliferation, differentiation, and apoptosis. The final step of apoptosis is, in general, mediated by executioner caspases comprising caspase-3, -6 and -7. Despite their commonly accepted apoptotic function, executioner caspases also participate in non-apoptotic processes. In the present study, we investigated activation (cleavage) of caspase-7 in mouse hair follicles and surrounding tissue during embryonic development into adulthood. Casp7 (-/-) mice were examined to understand the effect of caspase-7 deficiency in the skin. The activated form of caspase-7 was observed during embryonic hair follicle development, as well as in the first hair cycle. In general, activation of caspase-7 did not correlate with apoptosis and activation of caspase-3, except during physiological hair follicle regression. Notably, cleaved caspase-7 was observed in mast cells and its deficiency in the adult skin resulted in increased mast cell number. Our study shows for the first time activated caspase-7 in hair follicles and mast cells and indicates its non-apoptotic roles in the skin. PMID- 26253164 TI - Symptoms of Concussion and Comorbid Disorders. AB - Symptoms of concussion are divided into three major domains: physical, cognitive, and emotional. These symptoms including headache, neck pain, vision changes, cognitive deficits, and emotional changes can be seen immediately after the injury and usually resolve within the first 3 months. However, some of these symptoms may persist for several months afterward. Risk factors have been identified for prolonged symptoms. Certain early interventions may decrease persistent symptoms. In this chapter, we discuss common acute and persistent symptoms after concussion and provide an overview of assessment tools and management options. PMID- 26253165 TI - Preventing bioenergetic failure in the preterm infant. PMID- 26253166 TI - Neonatal deaths: prospective exploration of the causes and process of end-of-life decisions. AB - OBJECTIVE: To determine the causes and process of death in neonates in Canada. DESIGN: Prospective observational study. SETTING: Nineteen tertiary level neonatal units in Canada. PARTICIPANTS: 942 neonatal deaths (215 full-term and 727 preterm). EXPOSURE AND OUTCOME: Explored the causes and process of death using data on: (1) the rates of withdrawal of life-sustaining treatment (WLST); (2) the reasons for raising the issue of WLST; (3) the extent of consensus with parents; (4) the consensual decision-making process both with parents and the multidisciplinary team; (5) the elements of WLST; and (6) the age at death and time between WLST and actual death. RESULTS: The main reasons for deaths in preterm infants were extreme immaturity, intraventricular haemorrhage and pulmonary causes; in full-term infants asphyxia, chromosomal anomalies and syndromic malformations. In 84% of deaths there was discussion regarding WLST. WLST was agreed to by parents with relative ease in the majority of cases. Physicians mainly offered WLST for the purpose of avoiding pain and suffering in imminent death or survival with a predicted poor quality of life. Consensus with multidisciplinary team members was relatively easily obtained. There was marked variation between centres in offering WLST for severe neurological injury in preterm (10%-86%) and severe hypoxic-ischaemic encephalopathy in full-term infants (5%-100%). CONCLUSIONS AND RELEVANCE: In Canada, the majority of physicians offered WLST to avoid pain and suffering or survival with a poor quality of life. Variation between units in offering WLST for similar diagnoses requires further exploration. PMID- 26253167 TI - M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide. AB - BACKGROUND: Tumor associated macrophages (TAMs) are present in high density in solid tumors. TAMs share many characteristics with alternatively activated macrophages, also called M2. They have been shown to favor tumor development and a role in chemoresistance has also been suggested. Here, we investigated the effects of M2 in comparison to M1 macrophages on cancer cell sensitivity to etoposide. METHODS: We set up a model of macrophage polarization, starting from THP-1 monocytes differentiated into macrophages using PMA (Phorbol 12-myristate 13-acetate). Once differentiated (M0 macrophages), they were incubated with IL-4 and IL-13 in order to obtain M2 polarized macrophages or with IFN-gamma and LPS for classical macrophage activation (M1). To mimic the communication between cancer cells and TAMs, M0, M1 or M2 macrophages and HepG2 or A549 cancer cells were co-cultured during respectively 16 (HepG2) or 24 (A549) hours, before etoposide exposure for 24 (HepG2) or 16 (A549) hours. After the incubation, the impact of etoposide on macrophage polarization was studied and cancer cell apoptosis was assessed by western-blot for cleaved caspase-3 and cleaved PARP-1 protein, caspase activity assay and FACS analysis of Annexin V and PI staining. RESULTS: mRNA and protein expression of M1 and M2 markers confirmed the polarization of THP-1-derived macrophages, which provide a new, easy and well characterized model of polarized human macrophages. Etoposide-induced cancer cell apoptosis was markedly reduced in the presence of THP-1 M2 macrophages, while apoptosis was increased in cells co-cultured with M1 macrophages. On the other hand, etoposide did not influence M1 or M2 polarization. CONCLUSIONS: These results evidence for the first time a clear protective effect of M2 on the contrary to M1 macrophages on etoposide-induced cancer cell apoptosis. PMID- 26253168 TI - Acupuncture at homotopic acupoints exerts dual effects on bladder motility in anesthetized rats. AB - BACKGROUND: In Chinese medicine, dual effects on target organs are considered a primary characteristic of acupoint. Acupoints may be classified as heterotopic or homotopic in terms of spinal segmental innervation: homotopic acupoints contain afferent innervation in the same segment from which efferent fibers innervate target visceral organs, and heterotopic acupoints utilize different spinal segments to innervate target visceral organs than the segment receiving the afferent signal. It is well-known that dual effects of acupuncture on the bladder can be generated based on different states of the bladder, however, the dual effects of single acupoint stimulation and acupoint site-specificity (homotopic acupoints and heterotopic acupoints) on the bladder have yet to be investigated. METHODS: Twenty Sprague-Dawley rats were anesthetized and the intravesical pressure was measured via a manometric balloon inserted into the bladder. The acupuncture needle was separately inserted to a depth of 4 mm at the acupoints RN1 (Huiyin), RN3 (Zhongji), BL28 (Pangguangshu), BL32 (Ciliao), RN2 (Qugu) or BL23 (Shenshu), and manually rotated right then left with a frequency of 2 Hz for 1 min. Following acupuncture stimulation, bladder pressure was recorded and compared against the pre-stimulation measurements. RESULTS: During the bladder's active state, manual acupuncture (MA) at RN1, RN3, BL28, BL32 or RN2 inhibited bladder motility (P < 0.01). In the static bladder, MA at RN1, RN3, BL28, BL32, RN2 or BL23 increased bladder motility (P < 0.01). CONCLUSIONS: MA at homotopic acupoints may produce dual effects on bladder motility: inhibiting bladder motility when in an active state and enhancing bladder motility when in a static state. PMID- 26253169 TI - Effect of glucocorticoids on expression of cutaneous antimicrobial peptides in northern leopard frogs (Lithobates pipiens). AB - BACKGROUND: Many species of frogs secrete cutaneous antimicrobial peptides that are capable of killing Batrachochytrium dendrobatidis. Some of these species are nonetheless susceptible to chytridiomycosis, suggesting that host factors causing dysregulation of this innate immune response may be important in pathogenesis. Since stresses, such as from environmental perturbations, are a potential cause of such dysregulation, this study investigated the effect of glucocorticoid on cutaneous gene expression of these antimicrobial peptides. RESULTS: Northern leopard frogs (Lithobates pipiens) were injected with either the corticosteroid methylprednisolone or saline every 48 h. Norepinephrine-elicited cutaneous secretions were collected every 8 days for 40 days. Gene expression of antimicrobial peptides (brevinin-1P and ranatuerin-2P) in the cutaneous secretions was measured relative to the reference genes EF1-alpha and RPL8 using quantitative RT-PCR. Corticosteroid treatment was associated with a significant increase in brevinin-1P gene expression, which was most notable at 24-40 days of corticosteroid administration. Ranatuerin-2P expression followed a similar but non-significant trend. CONCLUSION: This treatment protocol, including corticosteroid-administration and frequent norepinephrine-induced secretion, increased AMP gene expression in the skin of L. pipiens under these experimental conditions. The findings do not support the hypothesis that environmental stress predisposes frogs to chytridiomycosis by causing glucocorticoid-induced suppression of antimicrobial peptide defences. PMID- 26253170 TI - A New Fungal Diterpene Induces VDAC1-dependent Apoptosis in Bax/Bak-deficient Cells. AB - The pro-apoptotic Bax and Bak proteins are considered central to apoptosis, yet apoptosis occurs in their absence. Here, we asked whether the mitochondrial protein VDAC1 mediates apoptosis independently of Bax/Bak. Upon screening a fungal secondary metabolite library for compounds inducing apoptosis in Bax/Bak deficient mouse embryonic fibroblasts, we identified cyathin-R, a new cyathane diterpenoid compound able to activate apoptosis in the absence of Bax/Bak via promotion of the VDAC1 oligomerization that mediates cytochrome c release. Diphenylamine-2-carboxilic acid, an inhibitor of VDAC1 conductance and oligomerization, inhibited cyathin-R-induced VDAC1 oligomerization and apoptosis. Similarly, Bcl-2 overexpression conferred resistance to cyathin-R-induced apoptosis and VDAC1 oligomerization. Silencing of VDAC1 expression prevented cyathin-R-induced apoptosis. Finally, cyathin-R effectively attenuated tumor growth and induced apoptosis in Bax/Bak-deficient cells implanted into a xenograft mouse model. Hence, this study identified a new compound promoting VDAC1-dependent apoptosis as a potential therapeutic option for cancerous cells lacking or presenting inactivated Bax/Bak. PMID- 26253171 TI - Interactions of Yeast Dynein with Dynein Light Chain and Dynactin: GENERAL IMPLICATIONS FOR INTRINSICALLY DISORDERED DUPLEX SCAFFOLDS IN MULTIPROTEIN ASSEMBLIES. AB - Intrinsically disordered protein (IDP) duplexes composed of two IDP chains cross linked by bivalent partner proteins form scaffolds for assembly of multiprotein complexes. The N-terminal domain of dynein intermediate chain (N-IC) is one such IDP that forms a bivalent scaffold with multiple dynein light chains including LC8, a hub protein that promotes duplex formation of diverse IDP partners. N-IC also binds a subunit of the dynein regulator, dynactin. Here we characterize interactions of a yeast ortholog of N-IC (N-Pac11) with yeast LC8 (Dyn2) or with the intermediate chain-binding subunit of yeast dynactin (Nip100). Residue level changes in Pac11 structure are monitored by NMR spectroscopy, and binding energetics are monitored by isothermal titration calorimetry (ITC). N-Pac11 is monomeric and primarily disordered except for a single alpha-helix (SAH) at the N terminus and a short nascent helix, LH, flanked by the two Dyn2 recognition motifs. Upon binding Dyn2, the only Pac11 residues making direct protein-protein interactions are in and immediately flanking the recognition motifs. Dyn2 binding also orders LH residues of Pac11. Upon binding Nip100, only Pac11 SAH residues make direct protein-protein interactions, but LH residues at a distant sequence position and L1 residues in an adjacent linker are also ordered. The long distance, ligand-dependent ordering of residues reveals new elements of dynamic structure within IDP linker regions. PMID- 26253172 TI - The homeodomain transcription factors antennapedia and POU-M2 regulate the transcription of the steroidogenic enzyme gene Phantom in the silkworm. AB - The steroid hormone ecdysone, which controls insect molting and metamorphosis, is synthesized in the prothoracic gland (PG), and several steroidogenic enzymes that are expressed specifically in the PG are involved in ecdysteroidogenesis. In this study, we identified new regulators that are involved in the transcriptional control of the silkworm steroidogenic enzyme genes. In silico analysis predicted several potential cis-regulatory elements (CREs) for the homeodomain transcription factors Antennapedia (Antp) and POU-M2 in the proximal promoters of steroidogenic enzyme genes. Antp and POU-M2 are expressed dynamically in the PG during larval development, and their overexpression in silkworm embryo-derived (BmE) cells induced the expression of steroidogenic enzyme genes. Importantly, luciferase reporter analyses, electrophoretic mobility shift assays, and chromatin immunoprecipitation assays revealed that Antp and POU-M2 promote the transcription of the silkworm steroidogenic enzyme gene Phantom (Phm) by binding directly to specific motifs within overlapping CREs in the Phm promoter. Mutations of these CREs in the Phm promoter suppressed the transcriptional activities of both Antp and POU-M2 in BmE cells and decreased the activities of mutated Phm promoters in the silkworm PG. In addition, pulldown and co immunoprecipitation assays demonstrated that Antp can interact with POU-M2. Moreover, RNA interference-mediated down-regulation of either Antp or POU-M2 during silkworm wandering not only decreased the ecdysone titer but also led to the failure of metamorphosis. In summary, our results suggest that Antp and POU M2 coordinate the transcription of the silkworm Phm gene directly, indicating new roles for homeodomain proteins in regulating insect ecdysteroidogenesis. PMID- 26253173 TI - Isoprenaline induces epithelial-mesenchymal transition in gastric cancer cells. AB - The emerging role of stress-related signaling in regulating cancer development and progression has been recognized. However, whether stress serves as a mechanism to promote gastric cancer metastasis is not clear. Here, we show that the beta2-AR agonist, isoprenaline, upregulates expression levels of CD44 and CD44v8-10 in gastric cancer cells. CD44, a cancer stem cell-related marker, is expressed at high levels in gastric cancer tissues, which strongly correlates with the occurrence of epithelial-mesenchymal transition (EMT)-associated phenotypes both in vivo and in vitro. Combined with experimental observations in two human gastric cancer cell lines, we found that beta2-AR signaling can initiate EMT. It led to an increased expression of mesenchymal markers, such as alpha-SMA, vimentin, and snail at mRNA and protein levels, and conversely a decrease in epithelial markers, E-cadherin and beta-catenin. Isoprenaline stimulation of beta2-AR receptors activates the downstream target STAT3, which functions as a positive regulator and mediated the phenotypic switch toward a mesenchymal cell type in gastric cancer cells. Our data provide a mechanistic understanding of the complex signaling cascades involving stress-related hormones and their effects on EMT. In light of our observations, pharmacological interventions targeting beta2-AR-STAT3 signaling can potentially be used to ameliorate stress-associated influences on gastric cancer development and progression. PMID- 26253175 TI - No Reduction of Severe Fatigue in Patients With Postpolio Syndrome by Exercise Therapy or Cognitive Behavioral Therapy: Results of an RCT. AB - BACKGROUND: People with postpolio syndrome (PPS) commonly experience severe fatigue that persists over time and negatively affects functioning and health related quality of life (HRQoL). OBJECTIVES: To study the efficacy of exercise therapy (ET) and cognitive behavioral therapy (CBT) on reducing fatigue and improving activities and HRQoL in patients with PPS. METHODS: We conducted a multicenter, single-blinded, randomized controlled trial. Over 4 months, severely fatigued patients with PPS received ET, CBT, or usual care (UC). The primary end point (fatigue) was assessed using the subscale fatigue severity of the Checklist Individual Strength (CIS20-F). Secondary end points included activities and HRQoL, which were assessed with the Sickness Impact Profile and the 36-Item Short Form, respectively. End points were measured at baseline and at 4, 7, and 10 months. RESULTS: A total of 68 patients were randomized. No differences were observed between the intervention groups and UC group for fatigue (mean differences in CIS20-F score = 1.47, 95%CI = -2.84 to 5.79, for ET versus UC; and 1.87, 95%CI = -2.24 to 5.98, for CBT versus UC), activities, or HRQoL. CONCLUSIONS: Our results demonstrate that neither ET nor CBT were superior to UC in reducing fatigue in severely fatigued PPS patients. Further research should investigate explanations for the lack of efficacy of these 2 currently advised approaches in clinical practice, which may provide clues to improving treatment aimed at reducing fatigue in PPS. PMID- 26253174 TI - The role of PPARgamma in TBBPA-mediated endocrine disrupting effects in human choriocarcinoma JEG-3 cells. AB - The goal of the present study was to investigate the action of TBBPA on PPARgamma protein expression in vitro in human choriocarcinoma-derived placental JEG-3 cells. We also analyzed TBBPA for its action on placental secretion of progesterone and beta-hCG, cell viability, and apoptosis. Our results showed that after TBBPA treatment at 10 nM and 10 uM, PPARgamma protein expression increased in a time-dependent manner until 48 h and then slightly decreased at 72 h but was still above the control level. This alteration in PPARgamma protein expression was accompanied by a decreased beta-hCG level. Interestingly, co-treatment with the PPARgamma antagonist GW9662 reversed the TBBPA-mediated changes in PPARgamma protein expression but, according to beta-hCG secretion, potentiated an inhibitory effect of TBBPA. Additionally, in our study, we assessed the ability of TBBPA to increase progesterone levels in JEG-3 cells compared with those of controls. Finally, in the present study, we demonstrated that TBBPA at all of the tested doses significantly increased caspase-3 activity compared with that of the vehicle control. The apoptotic action of TBBPA was also confirmed by Hoechst 33342 staining. These results showed the up-regulation of PPARgamma protein expression after TBBPA exposure in human placental cells. Although co-treatment with antagonist of PPARgamma reversed the TBBPA-mediated increase in this protein expression and restored it to the control level, it did not reverse the effect on beta-hCG secretion. This indicated that the mechanism of TBBPA-induced changes in beta-hCG secretion is PPARgamma-independent. PMID- 26253176 TI - Prediction of Balance Compensation After Vestibular Schwannoma Surgery. AB - Background Balance compensation after vestibular schwannoma (VS) surgery is under the influence of specific preoperative patient and tumor characteristics. Objective To prospectively identify potential prognostic factors for balance recovery, we compared the respective influence of these preoperative characteristics on balance compensation after VS surgery. Methods In 50 patients scheduled for VS surgical ablation, we measured postural control before surgery (BS), 8 (AS8) days after, and 90 (AS90) days after surgery. Based on factors found previously in the literature, we evaluated age, body mass index and preoperative physical activity (PA), tumor grade, vestibular status, and preference for visual cues to control balance as potential prognostic factors using stepwise multiple regression models. Results An asymmetric vestibular function was the sole significant explanatory factor for impaired balance performance BS, whereas the preoperative PA alone significantly contributed to higher performance at AS8. An evaluation of patients' balance recovery over time showed that PA and vestibular status were the 2 significant predictive factors for short-term postural compensation (BS to AS8), whereas none of these preoperative factors was significantly predictive for medium-term postoperative postural recovery (AS8 to AS90). Conclusions We identified specific preoperative patient and vestibular function characteristics that may predict postoperative balance recovery after VS surgery. Better preoperative characterization of these factors in each patient could inform more personalized presurgical and postsurgical management, leading to a better, more rapid balance recovery, earlier return to normal daily activities and work, improved quality of life, and reduced medical and societal costs. PMID- 26253177 TI - Intensive Rehabilitation Enhances Lymphocyte BDNF-TrkB Signaling in Patients With Parkinson's Disease. AB - Background In a combined animal and human study, we have previously found that a 5-day treatment that enhances cortical plasticity also facilitates brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling and increases activated TrkB and N-methyl-d-aspartate receptor (NMDAR) association in both the cortex and the peripheral lymphocytes. Patients with Parkinson's disease (PD), in general, show decreased cortical plasticity, as demonstrated by electrophysiological and behavioral studies. Here, we test the hypothesis that an exercise program that improves motor function and seems to slow down symptom progression can enhance BDNF-TrkB signaling in lymphocytes. Methods A total of 16 patients with PD underwent a 4-week multidisciplinary intensive rehabilitation treatment (MIRT), which included aerobic training and physical and occupational therapy. Blood was collected before and after 2 and 4 weeks of MIRT. Lymphocytes were isolated to examine BDNF-TrkB signaling induced by incubation with recombinant human BDNF. TrkB signaling complexes, extracellular-signal-regulated kinase-2 and protein-kinase-B were immunoprecipitated; the content of immunocomplexes was determined by Western blotting. Results After MIRT, all patients showed improvement in motor function. TrkB interaction with NMDAR and BDNF-TrkB signaling increased in peripheral lymphocytes at receptor, intracellular mediator, and downstream levels. The decrements in Unified Parkinson's Disease Rating Scale II (UPDRSII) and total scores were significantly correlated with the increases in TrkB signaling at receptor, intracellular mediator, and NMDAR interaction levels. Conclusions The significant correlation between reduced UPDRS scores and the changes in lymphocyte activity suggest that enhanced BDNF-TrkB signaling in lymphocyte and reduced severity of PD symptoms may be related. PMID- 26253178 TI - Physiological characterization of maize tolerance to low dose of aluminum, highlighted by promoted leaf growth. AB - MAIN CONCLUSION: Effects of a low aluminum (Al) dose were characterized. The Al supplement inhibited root growth but enhanced leaf growth in maize lines with different Al sensitivities. High levels of Al are phytotoxic especially in acidic soils. The beneficial effects of low Al levels have been reported in some plant species, but not in maize. Maize is relatively more sensitive to Al toxicity than other cereals. Seedlings, at the three leaf stage, of four Chinese maize foundation parent inbred lines with different Al tolerances, were exposed to complete Hoagland's nutrient solution at pH 4.5 supplemented with 48 MUM Al(3+) under controlled growth conditions, and then the Al stress (AS) was removed. The leaf and root growth, root cell viability, superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), ions (K(+), Ca(++) and Mg(++)), photosynthetic rate and chlorophyll, protein and malondialdehyde contents in tissues were assayed. In conclusion, a low Al dose inhibits root growth but enhances leaf growth in maize. The Al-promoted leaf growth is likely a result of increased protein synthesis, a lowered Ca(++) level, and the discharge of the growth-inhibitory factors. The Al promoted leaf growth may be a 'memory' effect caused by the earlier AS in maize. Al causes cell wall rupture, and a loss of K(+), Ca(++) and Mg(++) from root cells. CAT is an auxiliary antioxidant enzyme that works selectively with either SOD or POD against AS-related peroxidation, depending on the maize tissue. CAT is a major antioxidant enzyme responsible for root growth, but SOD is important for leaf growth during AS and after its removal. Our results contribute to understanding how low levels of Al affect maize and Al-resistant mechanisms in maize. PMID- 26253179 TI - Impact of cuticle on calculations of the CO2 concentration inside leaves. AB - MAIN CONCLUSION: Water vapor over-estimates the CO 2 entering leaves during photosynthesis because the cuticle and epidermis transmit more water vapor than CO 2 . Direct measurements of internal CO 2 concentrations may be preferred. The CO2 concentration inside leaves (c i) is typically calculated from the relationship between water vapor diffusing out while CO2 diffuses in. Diffusion through the cuticle/epidermis is usually not considered. This study was undertaken to determine how much the calculations would be affected by including cuticle properties. Previous studies indicate that measurable amounts of CO2 and water vapor move through the cuticle, although much less CO2 than water vapor. The present experiments were conducted with sunflower (Helianthus annuus L) leaves in a gas exchange apparatus designed to directly measure c i, while simultaneously calculating c i. Results showed that, in normal air, calculated c i were always higher than directly measured ones, especially when abscisic acid was fed to the leaves to close the stomata and cause gas exchange to be dominated by the cuticle. The effect was attributed mostly to the reliance on the gas phase for the calculations without taking cuticle properties into account. Because cuticle properties are usually unknown and vary with the turgor of the leaf, which can stretch the waxes, it is difficult to include cuticle properties in the calculation. It was concluded that direct measurement of c i may be preferable to the calculations. PMID- 26253181 TI - A non-inferiority trial of an evidence-based secondary HIV prevention behavioral intervention compared to an adapted, abbreviated version: Rationale and intervention description. AB - BACKGROUND: Real-world clinical settings like addiction treatment programs are ill-equipped to deploy and sustain the existing resource-demanding evidence-based interventions (EBIs) that target HIV-infected people who use drugs (PWUDs), and this has left a critical void in current HIV prevention efforts. In response to this unmet need, we have conducted formative research in addiction treatment settings that has resulted in Holistic Health for HIV (3H+) - an empirically adapted, substantially abbreviated version of Holistic Health Recovery Program (HHRP+), a CDC-recommended EBI targeting HIV-infected PWUDs. METHODS: Using a non inferiority randomized controlled trial design, we will determine whether the abbreviated 3H+ intervention is comparable (i.e., within a 10% margin) and cost effective relative to the original HHRP+ intervention in terms of reducing HIV risk behaviors and improving antiretroviral therapy (ART) adherence among HIV infected PWUDs in addiction treatment who report drug- or sex-related HIV risk behaviors. CONCLUSIONS: This article provides a description of the development and adaptation of the 3H+ intervention, the innovative non-inferiority comparative experimental design for testing the 3H+ to the HHRP+. Furthermore, it provides empirical evidence from a formal cost-effectiveness analysis justifying the cost-effectiveness of the 3H+ intervention when compared to the HHRP+ intervention. If confirmed to be comparable and more cost-effective, as hypothesized, the 3H+ intervention has the potential to be readily and immediately integrated within common clinical settings where large numbers of HIV infected PWUDs receive clinical services. PMID- 26253182 TI - A randomized controlled trial of outpatient CAncer REhabilitation for older adults: The CARE Program. AB - BACKGROUND: Large numbers of older adults (aged 65years or older) are surviving cancer; however, many survivors report decreased quality of life (QOL) and limitations in activities of daily living (ADL) and instrumental activities of daily living (IADL) both during and after treatment [1-3]. Occupational and physical therapy (OT/PT) are services focused on improving functional status and QOL that are largely unexplored and underutilized in cancer survivorship care [4,5]. METHODS/DESIGN: This is a randomized, single-blind, two-arm, single institution pilot study. Eighty-two patients will be recruited from a university affiliated outpatient oncology clinic. Inclusion criteria include the following: aged 65years or older, diagnosis of cancer within 5years, English speaking, has at least one functional deficit, and able to safely participate in an outpatient rehabilitation program. Exclusion criteria are: currently receiving rehabilitation or eligible for hospice. Consented patients will be randomized into two groups: (1) the CARE (CAncer REhabilitation) Program consisting of outpatient OT/PT and (2) standard of care. PRIMARY OUTCOME: change in Nottingham Extended Activities of Daily Living (NEADL) scores from baseline to 3months between CARE and control. DISCUSSION: This study is one of the first RCTs aimed at examining the effect of OT/PT in older adults with cancer. If positive, findings from this study will suggest the potential for outpatient OT/PT to improve the functional ability and QOL of older adults with cancer. PMID- 26253183 TI - Rapid NOS-1-derived nitric oxide and peroxynitrite formation act as signaling agents for inducible NOS-2 expression in vascular smooth muscle cells. AB - Septic vascular dysfunction is characterized by hypotension and hyporeactivity to vasoconstrictors and nitric oxide (NO), reactive oxygen species and peroxynitrite have a prominent role in this condition. However, the mechanism whereby the vascular dysfunction is initiated is poorly understood. Based on previous studies of our group and the literature,we hypothesize that constitutive nitric oxide synthases (c-NOS) and peroxynitrite may play a role in the development of septic vascular dysfunction. Bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN) were used to stimulate rat aorta smooth muscle cells (A7r5) and rat aorta slices. This stimulation led to a rapid (within minutes) production of NO and superoxide anion, which led to peroxynitrite formation. When this rapid initial burst was reduced, through the inhibition of c-NOS and NADPH oxidases (NOX) or the scavenging of NO and superoxide the NF-kappaB activation, NOS-2 expression and nitrite production were significantly attenuated. Although vascular smooth muscle cells express both c-NOS isoforms, gene knockdown revealed that only NOS-1 dependent NO and peroxynitrite formation are important for the later NOS-2 expression. Similar findings were obtained by knockdown NOX-1 gene, one source of superoxide for peroxynitrite formation. Taking together, we show that smooth muscle cell activation by LPS/IFN leads to a rapid formation of NOS-1-derived NO and NOX-1-derived superoxide, forming peroxynitrite; and that this species act as a trigger for NOS-2 expression through NF-kappaB activation. Therefore, our findings suggest a critical role for NOS-1 and NOX-1 in the initiation of the vascular dysfunction associated with sepsis and septic shock. PMID- 26253184 TI - Representations of pesticides and social practices: the case of French farmers. AB - Pesticides and their use in agriculture are important social issues. We conducted research to study the construction of this sensitive social object through the lens of social representations (study of the structural organisation of the social representations of pesticides) and their anchoring in three contexts that differ in terms of farming practices (Martinique, Brittany and Southern France). Our research was composed of two phases: hierarchical associations (n = 213) and a context independence test questionnaire (n = 124), conducted among farmers from the three study sites. The results indicate three representational fields that reflect salient issues in each agricultural territory. These illustrate the heuristic nature of social representations in the analysis of agricultural practices and pesticide use among French farmers. PMID- 26253185 TI - Transfer of metal(loid)s in a small vineyard catchment: contribution of dissolved and particulate fractions in river for contrasted hydrological conditions. AB - The use of inorganic pesticides in viticulture leads to the accumulation of metal(loid)s in soils which can be transferred to the hydro-systems (groundwater and surface water) via several processes. This study reports on the occurrence and behavior of metal(loid)s (Li, Al, Cr, Ni, Cu, Zn, As, Sr, and Ba), with a particular focus on Cu, Zn, and As, in a small stream draining a vineyard catchment. Base flow and flood events were monitored in order to assess the spatiotemporal variability of metal(loid) concentrations and to evaluate the contribution of the particulate fraction to the transfer of metal(loid)s according to the hydrological conditions. Results show that very different patterns of metal(loid)s were observed in the Morcille River according to the hydrological conditions. In base flow conditions, Cu and As were mainly transported in dissolved phase, which contributed to more than 70 and 80%, respectively, of the total load during this period. On the contrary, during base flow, Zn was mainly transported as associated to particles (90%). During the two storm events monitored, the particulate fraction was dominant, as its represented around 74-80%, 97%, and 50-70% of the total Cu, Zn, and As load in the river, respectively. Thus, despite a weaker affinity for particles during floods (decrease of particulate content during floods), metal(loid)s were mainly brought as particles, given that high amounts of suspended particulate matter (up to 2031 mg/L) were mobilized. Finally, comprehensive fluxes estimations confirmed that floods were responsible for more than 90% of the total Cu, Zn and 75% for As load transiting in the Morcille River in August within a very short period of time (less than 17%). PMID- 26253186 TI - A comparison study of toluene removal by two-stage DBD-catalyst systems loading with MnO(x), CeMnO(x), and CoMnO(x). AB - This paper studies the toluene removal by a two-stage dielectric barrier discharge (DBD)-catalyst system with three catalysts: MnO(x)/ZSM-5, CoMnO(x)/ZSM 5, and CeMnO(x)/ZSM-5. V-Q Lissajous method, Brunauer-Emmett-Teller (BET) surface area, X-ray diffraction (XRD), and X-ray photoelectron (XPS) are used to characterize the DBD and catalysts. The DBD processing partially oxidizes the toluene, and the removal efficiency has a linear relationship with ozone generation. Three DBD-catalyst systems are compared in terms of their toluene removal efficiency, Fourier transform infrared (FTIR) spectra, carbon balance, CO selectivity, CO2 selectivity, and ozone residual. The results show that the DBD catalyst system with CoMnO(x)/ZSM-5 performs better than the other two systems. It has the highest removal efficiency of about 93.7%, and the corresponding energy yield is 4.22 g/kWh. The carbon balance and CO2 selectivity of CoMnO(x)/ZSM-5 is also better than the other two catalysts. The measurements of two important byproducts including aerosols and ozone are also presented. PMID- 26253188 TI - Experimental assessment of effects of antiproliferative drugs of drug-eluting stents on endothelial cells. AB - BACKGROUND: Late and very late stent thrombosis after drug-eluting stent implantation is a major concern. The present study evaluated difference in the effects of sirolimus, paclitaxel and zotarolimus on endothelial cells. METHODS: Mouse endothelial cells were seeded in a 6-well plate. Cells were cultured with an antiproliferative drug at the expected concentrations for each well for 24 hours before making 3 scratch lines with a pipette tip. After a 4.5 hour incubation period, 3 reference scratch lines, vertically across the original scratch lines, were made in the same way. The experiment was repeated at least 6 times (6 plates). Measurements were performed at 9 crossings of each well. Wound healing ratio was calculated as 1-(distance of the first scratch/distance of the second scratch). % cell migration was calculated as (wound healing ratio at an expected drug concentration/wound healing ratio with no drug) * 100. Average % cell migration at 54 crossings of 6 plates was calculated. RESULTS: Paclitaxel inhibited cell migration in a concentration-dependent manner. On the other hand, concentration-dependent inhibition was not observed for sirolimus or zotarolimus. Sirolimus showed a stronger inhibitory effect on migration of endothelial cells compared to zotarolimus. CONCLUSIONS: The difference in the effect of antiproliferative drugs of drug-eluting stents on endothelial cells may be associated with relatively faster re-endothelialization of zotarolimus-eluting stent compared to the 1st generation DES. PMID- 26253187 TI - Changes in Standing and Walking Performance Under Dual-Task Conditions Across the Lifespan. AB - Simultaneous performance of a postural and a concurrent task is rather unproblematic as long as the postural task is executed in an automatic way. However, in situations where postural control requires more central processing, cognitive resources may be exceeded by the addition of an attentionally demanding task. This may lead to interference between the two tasks, manifested in a decreased performance in one or both tasks (dual-task costs). Owing to changes in attentional demands of postural tasks as well as processing capacities across the lifespan, it might be assumed that dual-task costs are particularly pronounced in children and older adults probably leading to a U-shaped pattern for dual-task costs as a function of age. However, these changes in the ability of dual-tasking posture from childhood to old age have not yet been systematically reviewed. Therefore, Web of Science and PubMed databases were searched for studies comparing dual-task performance with one task being standing or walking in healthy groups of young adults and either children or older adults. Seventy-nine studies met inclusion criteria. For older adults, the expected increase in dual task costs could be confirmed. In contrast, in children there was only feeble evidence for a trend towards enlarged dual-task costs. More good-quality studies comparing dual-task ability in children, young, and, ideally, also older adults within the same paradigm are needed to draw unambiguous conclusions about lifespan development of dual-task performance in postural tasks. There is evidence that, in older adults, dual-task performance can be improved by training. For the other age groups, these effects have yet to be investigated. PMID- 26253189 TI - Head and Neck Cancer Stem Cells: From Identification to Tumor Immune Network. AB - Head and neck squamous cell carcinoma (HNSCC) is the most common form of head and neck cancer. Annually, more than half a million individuals are diagnosed with this devastating disease, with increasing incidence in Europe and Southeast Asia. The diagnosis of HNSCC often occurs in late stages of the disease and is characterized by manifestation of a high-grade primary tumor and/or lymph node metastasis, precluding timely management of this deadly cancer. Recently, HNSCC cancer stem cells have emerged as an important factor for cancer initiation and maintenance of tumor bulk. Like normal stem cells, cancer stem cells can undergo self-renewal and differentiation. This unique trait allows for maintenance of the cancer stem cell pool and facilitates differentiation into heterogeneous neoplastic progeny when necessary. Recent studies have suggested coexistence of different cancer stem cell populations within a tumor mass, where the tumor initiation and metastasis properties of these cancer stem cells can be uncoupled. Cancer stem cells also possess resistant phenotypes that evade standard chemotherapy and radiotherapy, resulting in tumor relapse. Therefore, understanding distinctive pathways relating to cancer stem cells will provide insight into early diagnosis and treatment of HNSCC. In this review, we highlight current advances in identifying cancer stem cells, detail the interactions of these cells with the immune system within the tumor niche, and discuss the potential use of immunotherapy in managing HNSCC. PMID- 26253190 TI - Composition of Mineral Produced by Dental Mesenchymal Stem Cells. AB - Mesenchymal stem cells isolated from different dental tissues have been described to have osteogenic/odontogenic-like differentiation capacity, but little attention has been paid to the biochemical composition of the material that each produces. Here, we used Raman spectroscopy to analyze the mineralized materials produced in vitro by different dental cell populations, and we compared them with the biochemical composition of native dental tissues. We show that different dental stem cell populations produce materials that differ in their mineral and matrix composition and that these differ from those of native dental tissues. In vitro, BCMP (bone chip mass population), SCAP (stem cells from apical papilla), and SHED (stem cells from human-exfoliated deciduous teeth) cells produce a more highly mineralized matrix when compared with that produced by PDL (periodontal ligament), DPA (dental pulp adult), and GF (gingival fibroblast) cells. Principal component analyses of Raman spectra further demonstrated that the crystallinity and carbonate substitution environments in the material produced by each cell type varied, with DPA cells, for example, producing a more carbonate-substituted mineral and with SCAP, SHED, and GF cells creating a less crystalline material when compared with other dental stem cells and native tissues. These variations in mineral composition reveal intrinsic differences in the various cell populations, which may in turn affect their specific clinical applications. PMID- 26253192 TI - In vivo effects of human adipose-derived stem cells reseeding on acellular bovine pericardium in nude mice. AB - Tissue-engineered biologic products may be a viable option in the reconstruction of pelvic organ prolapse (POP). This study was based on the hypothesis that human adipose-derived stem cells (hASCs) are viable in acellular bovine pericardium (ABP), when reseeded by two different techniques, and thus, aid in the reconstruction. To investigate the reseeding of hASCs on ABP grafts by using non invasive bioluminescence imaging (BLI), and to identify the effective hASCs scaffold combinations that enabled regeneration. Thirty female athymic nude mice were randomly divided into three groups: In the VIVO group, ABPs were implanted in the subcutaneous pockets and enhanced green fluorescent protein luciferase (eGFP.Luc)-hASCs (1 * 10(6) cells/50 uL) were injected on the ABP at the same time. In the VITRO group, the mice were implanted with grafts that ABP were co cultured with eGFP.Luc-hASCs in vitro. The BLANK group mice were implanted with ABP only. The eGFP.Luc-hASCs reseeded on ABP were analyzed by BLI, histology, and immunohistochemistry. The eGFP.Luc-hASCs reseeded on ABP could be visualized at 12 weeks in vivo. Histology revealed that the VIVO group displayed the highest cell ingrowths, small vessels, and percent of collagen content per unit area. Desmin and alpha-smooth muscle actin were positive at the same site in the VIVO group cells. However, few smooth muscles were observed in the VITRO and BLANK groups. These results suggest that hASCs reseeded on ABP in vivo during surgery may further enhance the properties of ABP and may promote regeneration at the recipient site, resulting in a promising treatment option for POP. PMID- 26253193 TI - Women treated with breast conserving surgery do better than those with mastectomy independent of detection mode, prognostic and predictive tumor characteristics. AB - BACKGROUND: Primary breast conserving treatment (BCT) is well known to have similar long-term survival as mastectomy in breast cancer patients. However, recent studies are suggesting better survival among women treated with BCT compared with mastectomy. More knowledge is needed to understand how disease specific survival is influenced by detection mode, prognostic and predictive tumor characteristics. We aimed to investigate this issue among women targeted by the Norwegian Breast Cancer Screening Program. METHOD: Information about 9547 women aged 50-69 years diagnosed with primary invasive breast cancer without distant metastasis, who underwent either BCT or mastectomy, 2005-2011, were included in the study. Kaplan-Meier plots were used to estimate six years survival, while Cox proportional hazards models were used to estimate the hazard ratio (HR) of breast cancer death associated with surgical treatment. Information about molecular subtype, detection mode, age at diagnosis, tumor size, lymph node involvement, and histologic grade, in addition to radiation treatment, chemotherapy and endocrine therapy were included in adjusted analyses. RESULTS: BCT was performed among 61.9% of the women included in the study. Women treated with BCT had prognostic and predictive favorable tumor characteristics compared to women treated with mastectomy. Adjusted analyses revealed a 1.7 (95% CI: 1.3 2.4) higher risk of breast cancer death among women who underwent mastectomy compared with BCT. CONCLUSION: Women treated with BCT have significantly better breast cancer-specific survival and a lower risk of dying from breast cancer compared to women treated with mastectomy, independent of detection mode, prognostic and predictive tumor characteristic. PMID- 26253191 TI - Human respiratory syncytial virus non-structural protein NS1 modifies miR-24 expression via transforming growth factor-beta. AB - Human respiratory syncytial virus (RSV) is a major health challenge in the young and elderly owing to the lack of a safe and effective vaccine and proven antiviral drugs. Understanding the mechanisms by which viral genes and proteins modulate the host response to infection is critical for identifying novel disease intervention strategies. In this study, the RSV non-structural protein NS1 was shown to suppress miR-24 expression during infection. Lack of NS1 was linked to increased expression of miR-24, whilst NS1 overexpression suppressed miR-24 expression. NS1 was found to induce Kruppel-like factor 6 (KLF6), a transcription factor that positively regulates the transforming growth factor (TGF)-b pathway to induce cell cycle arrest. Silencing of KLF6 led to increased miR-24 expression via downregulation of TGF-beta. Treatment with exogenous TGF-beta suppressed miR 24 expression and induced KLF6. Confocal microscopy showed co-localization of KLF6 and RSV NS1. These findings indicated that RSV NS1 interacts with KLF6 and modulates miR-24 expression and TGF-beta, which facilitates RSV replication. PMID- 26253194 TI - Perioperative platin-based chemotherapy for locally advanced esophagogastric adenocarcinoma: Postoperative chemotherapy has a substantial impact on outcome. AB - BACKGROUND: A combination of platin-based perioperative chemotherapy (PBPC) plus surgical resection has become the standard of care in Europe for locally advanced esophagogastric adenocarcinoma (EGAC). In contrast to preoperative chemotherapy, the postoperative administration of chemotherapy is omitted in a high percentage of patients. We conducted this database study to analyse the impact of postoperative completion of perioperative chemotherapy on patient outcome. METHODS: Patients with EGAC (cT3-4 and/or cN+) were treated with preoperative PBPC plus curative surgical resection. Patient demographics, postoperative tumour stages, histopathological regression (HPR) and administration of postoperative chemotherapy were correlated with overall survival. RESULTS: Of one-hundred thirty-four patients, 76 received preoperative docetaxel, folinic acid, fluorouracil, oxaliplatin (FLOT), 53 patients epirubicin, cisplatin, folinic acid (ECF) and 5 epirubicin, oxaliplatin, capecitabine (EOX) chemotherapy. The 5-year survival for the whole collective was 58%. Designated postoperative chemotherapy was omitted in 36% of the patients. 5-year-survival was 75.8% in patients who received pre- and post-operative chemotherapy and 40.3% in patients with only preoperative chemotherapy (p < 0.001). Histopathological regression, postoperative nodal status and administration of postoperative chemotherapy were identified as independent prognostic factors. Analysis of subgroups revealed a pronounced survival benefit after administration of postoperative chemotherapy in patients with ypN+ stages (5-year-survival 64.5% vs 9.7%, p = 0.002) and poor HPR (5-year-survival 55.5% vs 19.3%, p = 0.015). CONCLUSION: Our study provides further evidence that administration of postoperative chemotherapy may contribute to the achieved survival benefit of PBPC in patients with EGAC and implies a beneficial effect especially in presence of lymphonodular tumour involvement and limited HPR. PMID- 26253195 TI - Small Molecules Take a Big Step by Converting Fibroblasts into Neurons. AB - Direct lineage conversion could provide a rich source of somatic cell types for translational medicine, but concerns over the use of transgenic reprogramming factors have limited its potential. In this issue of Cell Stem Cell, Li et al. (2015) and Hu et al. (2015) identify small-molecule cocktails that can convert fibroblasts into functional neurons without exogenous genetic factors. PMID- 26253197 TI - Cell Cycle Rules Pluripotency. AB - Stem cell self-renewal is intrinsically associated with cell cycle control. However, the precise mechanisms coordinating cell fate choices and cell cycle remain to be fully uncovered. Now in Cell, Gonzales et al. (2015) and colleagues demonstrate that factors controlling the G2/M phase are necessary to block pluripotency upon induction of differentiation. PMID- 26253196 TI - Resistance in the Ribosome: RUNX1, pre-LSCs, and HSPCs. AB - Therapeutic targeting of pre-leukemic stem cells (pre-LSCs) may be a viable strategy to eradicate residual disease and prevent leukemia relapse. Now in Cell Stem Cell, Cai et al. (2015) show that loss-of-function mutations in RUNX1 reduce ribosome biogenesis and provide pre-LSCs a selective advantage over normal hematopoietic cells through increased stress resistance. PMID- 26253198 TI - MT-Nanotubes: Lifelines for Stem Cells. AB - Niche cells produce secreted factors that promote the self-renewal of stem cells in their immediate proximity, but how signaling is restricted to stem cells is not well understood. Inaba et al. (2015) report that microtubule (MT) structures called MT-nanotubes control activation of the primary self-renewal pathway in Drosophila testes. PMID- 26253199 TI - Patient-Funded Trials: Opportunity or Liability? AB - Patient-funded trials (PFTs) are gaining traction as a means of accelerating clinical translation. However, such trials sidestep mechanisms that promote rigor, relevance, efficiency, and fairness. We recommend that funding bodies or research institutions establish mechanisms for merit review of patient-funded trials, and we offer some basic criteria for evaluating PFT protocols. PMID- 26253200 TI - dsRNA Released by Tissue Damage Activates TLR3 to Drive Skin Regeneration. AB - Regeneration of skin and hair follicles after wounding--a process known as wound induced hair neogenesis (WIHN)--is a rare example of adult organogenesis in mammals. As such, WIHN provides a unique model system for deciphering mechanisms underlying mammalian regeneration. Here, we show that dsRNA, which is released from damaged skin, activates Toll-Like Receptor 3 (TLR3) and its downstream effectors IL-6 and STAT3 to promote hair follicle regeneration. Conversely, TLR3 deficient animals fail to initiate WIHN. TLR3 activation promotes expression of hair follicle stem cell markers and induces elements of the core hair morphogenetic program, including ectodysplasin A receptor (EDAR) and the Wnt and Shh pathways. Our results therefore show that dsRNA and TLR3 link the earliest events of mammalian skin wounding to regeneration and suggest potential therapeutic approaches for promoting hair neogenesis. PMID- 26253201 TI - Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons. AB - Recently, direct reprogramming between divergent lineages has been achieved by the introduction of regulatory transcription factors. This approach may provide alternative cell resources for drug discovery and regenerative medicine, but applications could be limited by the genetic manipulation involved. Here, we show that mouse fibroblasts can be directly converted into neuronal cells using only a cocktail of small molecules, with a yield of up to >90% being TUJ1-positive after 16 days of induction. After a further maturation stage, these chemically induced neurons (CiNs) possessed neuron-specific expression patterns, generated action potentials, and formed functional synapses. Mechanistically, we found that a BET family bromodomain inhibitor, I-BET151, disrupted the fibroblast-specific program, while the neurogenesis inducer ISX9 was necessary to activate neuron specific genes. Overall, our findings provide a "proof of principle" for chemically induced direct reprogramming of somatic cell fates across germ layers without genetic manipulation, through disruption of cell-specific programs and induction of an alternative fate. PMID- 26253202 TI - Direct Conversion of Normal and Alzheimer's Disease Human Fibroblasts into Neuronal Cells by Small Molecules. AB - Neuronal conversion from human fibroblasts can be induced by lineage-specific transcription factors; however, the introduction of ectopic genes limits the therapeutic applications of such induced neurons (iNs). Here, we report that human fibroblasts can be directly converted into neuronal cells by a chemical cocktail of seven small molecules, bypassing a neural progenitor stage. These human chemical-induced neuronal cells (hciNs) resembled hiPSC-derived neurons and human iNs (hiNs) with respect to morphology, gene expression profiles, and electrophysiological properties. This approach was further applied to generate hciNs from familial Alzheimer's disease patients. Taken together, our transgene free and chemical-only approach for direct reprogramming of human fibroblasts into neurons provides an alternative strategy for modeling neurological diseases and for regenerative medicine. PMID- 26253204 TI - Rapid ethanol production at elevated temperatures by engineered thermotolerant Kluyveromyces marxianus via the NADP(H)-preferring xylose reductase-xylitol dehydrogenase pathway. AB - Conversion of xylose to ethanol by yeasts is a challenge because of the redox imbalances under oxygen-limited conditions. The thermotolerant yeast Kluyveromyces marxianus grows well with xylose as a carbon source at elevated temperatures, but its xylose fermentation ability is weak. In this study, a combination of the NADPH-preferring xylose reductase (XR) from Neurospora crassa and the NADP(+)-preferring xylitol dehydrogenase (XDH) mutant from Scheffersomyces stipitis (Pichia stipitis) was constructed. The xylose fermentation ability and redox balance of the recombinant strains were improved significantly by over-expression of several downstream genes. The intracellular concentrations of coenzymes and the reduced coenzyme/oxidized coenzyme ratio increased significantly in these metabolic strains. The byproducts, such as glycerol and acetic acid, were significantly reduced by the disruption of glycerol-3-phosphate dehydrogenase (GPD1). The resulting engineered K. marxianus YZJ088 strain produced 44.95 g/L ethanol from 118.39 g/L xylose with a productivity of 2.49 g/L/h at 42 degrees C. Additionally, YZJ088 realized glucose and xylose co-fermentation and produced 51.43 g/L ethanol from a mixture of 103.97 g/L xylose and 40.96 g/L glucose with a productivity of 2.14 g/L/h at 42 degrees C. These promising results validate the YZJ088 strain as an excellent producer of ethanol from xylose through the synthetic xylose assimilation pathway. PMID- 26253205 TI - Tensile properties and interfacial bonding of multi-layered, high-purity titanium strips fabricated by ARB process. AB - Severe plastic deformation (SPD) processing has shown very effective in promotion of mechanical properties of metals and alloys. In this study, the results of investigating mechanical properties and also inter-layer bond performance of accumulative roll bonded high purity titanium (HP-Ti) strips are presented. High purity titanium plates were severely deformed by use of a combination of cold rolling (CR) to a thickness reduction of approximately 87% and then accumulative roll bonding (ARB) for three cycles (N=3) at ambient temperature. Optical and scanning electron microscopy, tensile testing, and hardness measurements were conducted. The ARB strips exhibited lower tensile strength and ductility in comparison to cold rolled one which can basically be attributed to the poor function of the latest bonds established in the centerlines of the strips. Fractographic examinations revealed the interfacial de-bonding along the centerline between the layers having undergone roll bonding for just one cycle. It was while the interfaces having experienced roll bonding for more cycles showed much higher resistance against delaminating. PMID- 26253203 TI - Variation in guideline adherence in non-Hodgkin's lymphoma care: impact of patient and hospital characteristics. AB - BACKGROUND: The objective of this observational study was to assess the influence of patient, tumor, professional and hospital related characteristics on hospital variation concerning guideline adherence in non-Hodgkin's lymphoma (NHL) care. METHODS: Validated, guideline-based quality indicators (QIs) were used as a tool to assess guideline adherence for NHL care. Multilevel logistic regression analyses were used to calculate variation between hospitals and to identify characteristics explaining this variation. Data for the QIs regarding diagnostics, therapy, follow-up and organization of care, together with patient, tumor and professional related characteristics were retrospectively collected from medical records; hospital characteristics were derived from questionnaires and publically available data. RESULTS: Data of 423 patients diagnosed with NHL between October 2010 and December 2011 were analyzed. Guideline adherence, as measured with the QIs, varied considerably between the 19 hospitals: >20 % variation was identified in all 20 QIs and high variation between the hospitals (>50 %) was seen in 12 QIs, most frequently in the treatment and follow-up domain. Hospital variation in NHL care was associated more than once with the characteristics age, extranodal involvement, multidisciplinary consultation, tumor type, tumor aggressiveness, LDH level, therapy used, hospital region and availability of a PET-scanner. CONCLUSION: Fifteen characteristics identified at the patient level and at the hospital level could partly explain hospital variation in guideline adherence for NHL care. Particularly age was an important determinant: elderly were less likely to receive care as measured in the QIs. The identification of determinants can be used to improve the quality of NHL care, for example, for standardizing multidisciplinary consultations in daily practice. PMID- 26253206 TI - A novel ex vivo model of compressive immature rib fractures at pathophysiological rates of loading. AB - INTRODUCTION: Compressive rib fractures are considered to be indicative of non accidental injury (NAI) in infants, which is a significant and growing issue worldwide. The diagnosis of NAI is often disputed in a legal setting, and as a consequence there is a need to model such injuries ex vivo in order to characterise the forces required to produce non-accidental rib fractures. However, current models are limited by type of sample, loading method and rate of loading. Here, we aimed to: i) develop a loading system for inducing compressive fractures in whole immature ribs that is more representative of the physiological conditions and mechanism of injury employed in NAI and ii) assess the influence of loading rate and rib geometry on the mechanical performance of the tissue. METHODS: Porcine ribs (5-6 weeks of age) from 12 animals (n=8 ribs/animal) were subjected to axial compressive load directed through the anterior-posterior rib axis at loading rates of 1, 30, 60 or 90 mm/s. Key mechanical parameters (including peak load, load and percentage deformation to failure and effective stiffness) were quantified from the load-displacement curves. Measurements of the rib length, thickness at midpoint, distance between anterior and posterior extremities, rib curvature and fracture location were determined from radiographs. RESULTS: This loading method typically produced incomplete fractures around the midpoint of the ribs, with 87% failing in this manner; higher loads and less deformation were required for ribs to completely fracture through both cortices. Loading rate, within the range of 1-90 mm/s, did not significantly affect any key mechanical parameters of the ribs. Load-displacement curves displaying characteristic and quantifiable features were produced for 90% of the ribs tested, and multiple regression analyses indicate that, in addition to the geometrical variables, there are other factors such as the micro- and nano structure that influence the measured mechanical data. CONCLUSIONS: A reproducible method of inducing fractures in a consistent location in immature porcine ribs has been successfully developed. Fracture appearance may be indicative of the amount of load and deformation that produced the fracture, which is an important finding for NAI, where knowledge of the aetiology of fractures is vital. Characteristic rib behaviour independent of loading rate and, to an extent, rib geometry has been demonstrated, allowing further investigation into how the complex micro- and nano-structure of immature ribs influences the mechanical performance under compressive load. This research will ultimately enable improved characterisation of the loading pattern involved in non accidental rib fractures. PMID- 26253207 TI - Photo-crosslinked fabrication of novel biocompatible and elastomeric star-shaped inositol-based polymer with highly tunable mechanical behavior and degradation. AB - Biodegradable and star-shaped polymers with highly tunable structure and properties have attracted much attention in recent years for potential biomedical applications, due to their special structure. Here, inositol-based star-shaped poly-L-lactide-poly(ethylene glycol) (INO-PLLA-PEG) biomedical polymer implants were for the first time synthesized by a facile photo-crosslinking method. This biomaterials show controlled elastomeric mechanical properties (~18 MPa in tensile strength, ~200 MPa in modulus, ~200% in elongation), biodegradability and osteoblasts biocompatibility. These results make INO-PLLA-PEG implants highly promising for bone tissue regeneration and drug delivery applications. PMID- 26253208 TI - Early resin luting material damage around a circular fiber post in a root canal treated premolar by using micro-computerized tomographic and finite element sub modeling analyses. AB - This study utilizes micro-computerized tomographic (micro-CT) and finite element (FE) sub-modeling analyses to investigate the micro-mechanical behavior associated with voids/bubbles stress behavior at the luting material layer to understand the early damage in a root canal treated premolar. 3-dimensional finite element (FE) models of a macro-root canal treated premolar and two sub models at the luting material layer to provide the void/bubble distribution and dimensions were constructed from micro-CT images and simulated to receive axial and lateral forces. The boundary conditions for the sub-models were determined from the macro-premolar model results and applied in sub-modeling analysis. The first principal stresses for the dentin, luting material layer and post in macro premolar model and for luting material void/bubble in sub-models were recorded. The simulated results revealed that the macro-premolar model dramatically underestimated the luting material stress because the voids/bubbles at the adhesive layer cannot be captured due to coarse mesh and high stress gradient and the variations between sub- and macro-models ranging from 2.65 to 4.5 folds under lateral load at the mapping location. Stress concentrations were found at the edge of the voids/bubbles and values over 20 MPa in sub-modeling analysis immediately caused the luting material failure/micro-crack. This study establishes that micro-CT and FE sub-modeling techniques can be used to simulate the stress pattern at the micro-scale luting material layer in a root canal treated premolar, suggesting that attention must be paid to resin luting material initial failure/debonding when large voids/bubbles are generated during luting procedures. PMID- 26253209 TI - Diverse origins of hepatitis C virus in HIV co-infected men who have sex with men in Hong Kong. AB - BACKGROUND: Worldwide, Hepatitis C (HCV) infection has been increasingly recognized in HIV-positive men who have sex with men (MSM). The objective of this study was to characterize the transmission dynamics of acute HCV infection in HIV positive MSM in Hong Kong using a molecular approach. FINDINGS: We retrospectively examined 24 HIV-positive MSM with acute HCV infection diagnosed between 2009 and 2014 in Hong Kong. Detection and molecular characterization of HCV was successfully performed in 22 (91.7 %) patients. Genotype 3a was the most prevalent as identified in 14 (63.6 %) MSM, followed by 1a in 4 (18.2 %), 6a in 2 (9.1 %), and 1each (4.5 %) for 1b and 2a. The high prevalence of genotype 3a in MSM was in stark contrast to its rarity among HCV infected injection drug users (IDU) in Hong Kong. Phylogenetic analyses revealed a monophyletic HCV-3a cluster composing of MSM without injection history, and a homologous pair with HCV-6a genotype. There was otherwise no temporal or genetic clustering of the corresponding HIV sequences. CONCLUSIONS: The origin of sexually acquired acute HCV infections in HIV-positive MSM was diverse and not directly linked with local IDU. The transmission dynamics of HIV and HCV infections in MSM in Hong Kong were evidently unrelated. PMID- 26253211 TI - The COMT val(158)met polymorphism in ultra-endurance athletes. AB - Chronic levels of physical activity have been associated with increased dopamine (D2) receptors resulting in increased sensitivity to dopamine release. The catechol-O-methyltransferase enzyme, responsible for dopamine degradation, contains a functional polymorphism, which plays an important role in dopamine regulation within the prefrontal cortex. This polymorphism has previously been shown to affect human cognition and personality. However, the effect of this polymorphism has not been shown in ultra-endurance athletes. AIM: To examine the association of the COMT val(158)met variant with personality traits (harm avoidance, novelty seeking, reward dependence, resilience) and psychological distress (K10) of habitual physically active Ironman athletes compared to recreationally active controls. METHODS: 51 ultra-endurance Ironman athletes and 56 recreationally active controls were genotyped for the catechol-O methyltransferase val(158)met polymorphism. Of the 107 participants, 55 ultra endurance athletes and 32 recreationally active controls completed online personality questionnaires (harm avoidance, novelty seeking, reward dependence, resilience) and a psychological distress questionnaire (K10). RESULTS: The personality trait, harm avoidance (p=0.001) and psychological distress (p=0.003) were significantly lower in Ironman athlete participants. Novelty seeking was significantly higher (p=0.02) in Ironman athlete participants with a significantly higher (p=0.04) score in Met(158) homozygous allele carriers. CONCLUSION: Chronic levels of physical activity, as seen in ultra-endurance athletes, show increased novelty seeking scores in Met(158) homozygous allele carriers. PMID- 26253210 TI - Arsenic and Rice: Translating Research to Address Health Care Providers' Needs. PMID- 26253212 TI - Evidence for the contribution of multiple mechanisms in the feeding pattern of rats exposed to p-chloro-diphenyl diselenide-supplemented diets. AB - Preliminary findings suggest that food intake reduction induced by p-chloro diphenyl diselenide [(p-ClPhSe)2] in rats is mediated by a satiating action; however, additional experiments are necessary to clarify its actions. The purpose of this study was to investigate the effects of diets supplemented with (p ClPhSe)2 on feeding behavior of rats as well as the (p-ClPhSe)2 effectiveness in producing aversive reactions or specific flavor. The results demonstrated that behavioral satiety sequence (BSS) was preserved in animals exposed to (p-ClPhSe)2 supplemented diets (0.01 and 0.1%) and associated with a shift of the onset of resting to the left indicating a satiating action at the first contact. In addition, the frequency, the mean duration and the mean size of meals were decreased in rats exposed to a 0.1% (p-ClPhSe)2 diet. Alternatively, a second contact with a 0.01% (p-ClPhSe)2 diet caused disruption of BSS and pronounced changes in the meal pattern, suggesting that it produces aversiveness. In fact, rats developed a significant taste aversion to the saccharin solution after receiving the administration of (p-ClPhSe)2 (1 and 10mg/kg; i.p.). Lastly, a diet containing 0.1% of (p-ClPhSe)2 seems to alter the palatability of food given that rats had a preference for the control diet. The findings of the present study suggest that (p-ClPhSe)2 reduced the food intake of rats by inducing a satiating action at the first contact, but it also produced aversive reactions when rats were re-exposed to it. A specific flavor seems also to contribute to (p-ClPhSe)2 suppressant effects on feeding. PMID- 26253214 TI - Voluntary exercise enhances activity rhythms and ameliorates anxiety- and depression-like behaviors in the sand rat model of circadian rhythm-related mood changes. AB - Physical exercise is a non-pharmacological treatment for affective disorders. The mechanisms of its effects are unknown although some suggest a relationship to synchronization of circadian rhythms. One way to explore mechanisms is to utilize animal models. We previously demonstrated that the diurnal fat sand rat is an advantageous model for studying the interactions between photoperiods and mood. The current study was designed to evaluate the effects of voluntary exercise on activity rhythms and anxiety and depression-like behaviors in sand rats as a step towards better understanding of the underlying mechanisms. Male sand rats were housed in short photoperiod (SP; 5h light/19 h dark) or neutral light (NP; 12h light/12h dark) regimens for 3 weeks and divided into subgroups with or without running wheels. Activity was monitored for 3 additional weeks and then animals were tested in the elevated plus-maze, the forced swim test and the social interaction test. Activity rhythms were enhanced by the running wheels. As hypothesized, voluntary exercise had significant effects on SP animals' anxiety- and depression-like behaviors but not on NP animals. Results are discussed in the context of interactions between physical exercise, circadian rhythms and mood. We suggest that the sand rat model can be used to explore the underlying mechanism of the effects of physical exercise for mood disorders. PMID- 26253213 TI - Autonomic function responses to training: Correlation with body composition changes. AB - AIM: The causal relation between autonomic function and adiposity is an unresolved issue. Thus, we studied whether resting heart rate variability (HRV) changes could be used to predict changes in body composition after 16 weeks of individualized exercise training. METHODS: A total of 117 sedentary overweight/obese adults volunteered to join an intervention group (IN, n=82) or a control group (CON, n=35). The intervention group trained for 30-40 min three times a week with an intensity of 85-100% of individual ventilatory threshold (Thvent). At baseline and after a 16-week training period, resting HRV variables, body composition and peak oxygen uptake (VO2peak) were assessed. RESULTS: Compared with CON, exercise training significantly improved HRV and body composition and increased VO2peak (P<0.05). Significant correlations were observed between changes of HRV variables and body composition indices and VO2peak (P<0.05). Greater individual changes in HRV in response to exercise training were observed for those with greater total and central fat loss. CONCLUSION: Individual aerobic-based exercise training was for improving autonomic function and resting HRV responses to aerobic training is a potential indicator for adaptations to exercise training. PMID- 26253215 TI - Apoptotic markers and DNA damage are related to late phase of stroke: Involvement of dyslipidemia and inflammation. AB - Oxidative stress and brain inflammation are thought to contribute to the pathophysiology of cerebral injury in acute stroke, leading to apoptosis and cell death. Lipid accumulation may lead to progression of carotid plaques and inflammation, contributing to increased acute stroke risk. However, little is known about these events and markers in the late stroke (>6 months) and if dyslipidemia could contribute to disease's pathophysiology in a later phase. In this case-control study, we recruited patients in the late stroke phase (n=40) and health subjects (control group; n = 40). Dichlorodihydrofluorescein (DCFH), nitrite/nitrate (NOx), Tumor necrosis factor-alpha (TNF-alpha), Acetylcholinesterase (AChE), Caspase 8 (CASP 8), Caspase 3 (CASP 3) and Picogreen (PG) were measured in periphery blood samples. Furthermore, a correlation among all measured markers (DCFH, NOx, TNF-alpha, AChE, CASP 8, CASP 3 and PG) was realized. The marker levels were also compared to triglycerides (TG), total (CHO), LDL and HDL cholesterol levels and medications used. Statistical analyses showed that stroke patients presented an increase of DCFH, NOx, TNF-alpha and AChE levels when compared to control subjects. In addition, we observed that stroke patients had significantly higher CASP 8, CASP 3 and PG levels than control group. A significant correlation between TNF-alpha with CASP 8 (r = 0.4) and CASP 3 (r = 0.4) levels was observed, but not with oxidative/nitrosative markers. Moreover, we observed that stroke patients with dyslipidemia had significantly higher TNF-alpha, CASP 8 and CASP 3 levels than stroke without dyslipidemia and control groups. Our findings suggest that oxidative and inflammatory markers may be still increased and lead to caspase activation and DNA damage even after 6 months to cerebral injury. Furthermore, it is plausible to propose that dyslipidemia may contribute to worsen proinflammatory state in a later phase of stroke and an increased risk to new neurovascular events. PMID- 26253216 TI - The relationship between masticatory and swallowing behaviors and body weight. AB - The present study aimed to compare the main objective parameters of mastication among individuals with different body mass indexes. One hundred and sixty participants matched for gender and age were divided in the following groups according to their body mass index (BMI): Obese group (30 <= BMI < 35), Overweight group (25 <= BMI < 30), normal range group (18.5 <= BMI < 25) and underweight group (17 <= BMI < 18.5). Each group was composed by forty subjects. The maximum bite force, the masticatory performance, chewing rate and three variables related to swallowing (number of chewing cycles, chewing time, and median particle size) were assessed in all groups. The oral conditions, including the number of teeth, number of occlusal units and salivary flow (unstimulated and stimulated) were also evaluated. Regardless of the BMI, males had a larger bite force and better masticatory and swallowing performances than females. They also chewed faster than females. Individuals of the obese group had the largest median particles sizes (both after 20 chewing cycles and at the moment of swallowing), which indicates a less good masticatory performance. The median particle sizes were negatively correlated with the number of teeth and number of occlusal units in the obese group. We did not observe large differences in masticatory performance and swallowing variables among the four weight groups, although there was a tendency that individuals of the obese group swallowed larger particles. The results of this study do not support the existence of an "obese chewing style". PMID- 26253217 TI - Peripheral and central control of swallowing initiation in healthy humans. AB - We investigated (1) how peripheral inputs might assist central inputs in the control of voluntary evoked swallowing, (2) inter-individual variation in involuntary and voluntary swallowing initiation, and (3) whether natural chewing behavior affects the initiation of involuntary swallowing in healthy humans. Eleven participants completed a repetitive saliva swallowing test (RSST), chewing test (CHEW), and rest period (REST). In RSST, participants repetitively swallowed as quickly as possible. In CHEW, subjects chewed gum freely. We delivered pharyngeal electrical stimulation (PEStim) to the laryngopharynx and compared the number of swallows that occurred with and without PEStim. PEStim significantly increased the number of voluntary evoked swallows in RSST, as well as the number of swallows in CHEW and REST trials, although this facilitatory effect was larger in REST trials. We found a positive correlation between the number of swallows at RSST without PEStim and that at REST with PEStim within individuals. Additionally, we found a significant positive correlation between the number of swallows at RSST with PEStim and the sum of that at RSST without PEStim and at REST with PES. Based on the current results, we suggest that (1) peripheral inputs within a certain range appear to facilitate the central inputs that control voluntary swallowing, (2) inter-individual variations in swallowing initiation may arise from differences in the excitability of the common neural network in the lower brainstem, and (3) during chewing, food reduction in the oral cavity is prioritized, such that the neural network associated with chewing may regulate swallowing initiation. PMID- 26253218 TI - Renewal of conditioned responding to food cues in rats: Sex differences and relevance of estradiol. AB - Cues associated with food can stimulate food anticipation, procurement, and consumption, independently of hunger. These and other behaviors driven by learned cues are persistent and can reappear after extinction, because the original learned associations continue to exist. Renewal, or reinstatement, of extinguished conditioned behavior may explain the inability to change maladaptive eating habits driven by food cues, similar to the mechanisms of drug use relapse. Here, we investigated sex differences in context-induced renewal of responding to food cues, and the role of estradiol in females in a Pavlovian conditioning preparation. We compared adult male and female rats because there is evidence for sex differences in learning and memory and in the control of feeding. Context induced renewal involves conditioning and extinction in different contexts and the renewal of conditioned behavior is induced by return to the conditioning context ("ABA renewal"; experimental groups). Control groups remain in the same context during conditioning, extinction, and test. In Experiment 1, male and female rats were trained to associate a tone with food pellets during acquisition, and after extinction with tone only presentations, were tested for renewal of responding to the tone. Learning was assessed through the expression of the conditioned response, which included approach and activity directed at food receptacle (food cup behavior). Males and females learned the acquisition and extinction of tone-food associations similarly, but there were sex differences during renewal of the conditioned responses to the food cue. Males showed robust renewal of responding, while renewal in intact females was inconsistent. Males in the experimental group had significantly higher food cup behavior compared to males in the control group, while females in both groups showed similar levels of food cup behavior during the tone. In Experiment 2, we examined a potential role of estradiol in renewal, by comparing intact females with ovariectomized females with, and without, estradiol replacement. Rats in all groups acquired and extinguished tone-food associations similarly. During the test for renewal, the ovariectomized rats with estradiol replacement in the experimental group showed renewal of responding, evidenced by significantly higher food cup behavior compared to the control group. Intact and ovariectomized rats in the experimental groups had similar rates of food cup behavior as their corresponding control groups. These results provide novel evidence for sex differences and relevance of estradiol in renewal of responding to food cues and more broadly in contextual processing and appetitive associative learning, potentially relevant to maladaptive eating habits and eating disorders. PMID- 26253219 TI - Effectiveness of psychoeducation in reducing sickness absence and improving mental health in individuals at risk of having a mental disorder: a randomised controlled trial. AB - BACKGROUND: The aim of this study was to evaluate the effect of psychoeducation on return to work as an adjunct to standard case management in individuals on sick leave at risk of having a mental disorder. The participants could have different diagnoses but were all at risk of having a mental disorder. METHODS: Between 2012 and 2014, 430 participants on sick leave were randomly allocated to either an intervention or control group. The psychoeducation consisted of 2-h sessions once a week for 6 weeks. The sessions focused on stress and work life and was based on problem-solving techniques and coping strategies. The main outcome, the relative risk (RR) of a full return to work based on register data from the job centres, was determined during the first 3 and 6 months after participation in the psychoeducation programme. At baseline and at 3 and 6 months after the intervention, the participants received a questionnaire on psychological symptoms, mental health-related quality of life, and locus of control. RESULTS: During the first 6 months after inclusion, the two groups had almost the same RR of a full return to work (RR:0.97, 95% CI: 0.78;1.21), but during the first 3 months, the individuals in the intervention group had a significantly higher risk of not having fully returned to work (RR:0.68, 95% CI:0.47;0.98). The individuals in the intervention group who had participated in at least four of the six psychoeducational sessions returned to work considerably slower at both time points than did the control group. The intervention did not decrease the level of psychological symptoms or improve mental health-related quality of life; however, individuals in the intervention group improved their scores on internal locus of control at both 3 and 6 months. CONCLUSION: Offering psychoeducation to individuals on sick leave at risk of having a mental disorder had no influence on the chance of a full return to work during the first 6 months; however, it did result in a higher relative risk of not returning to work after 3 months. Therefore, we do not recommend offering psychoeducation in this form to facilitate return to work. TRIAL REGISTRATION: Clinical Trial.gov NCT01637363. Registered 6 July 2012. PMID- 26253221 TI - Technical Assistance Needs for Successful Implementation of Couples HIV Testing and Counseling (CHTC) Intervention for Male Couples at US HIV Testing Sites. AB - The African couples HIV testing and counseling (CHTC) model, which focuses on heterosexual couples, was adapted for same-sex male couples in the US. This paper presents the results of a follow-up survey conducted with representatives of the agencies that received CHTC training. The paper aims to understand the post training implementation and identify critical technical assistance gaps. There are clear needs for continual learning opportunities, focused on the key skills required for CHTC, and for resources aimed at tackling agency-level concerns about service provision and integration. Central to this is the need for implementation science research that can identify the messages that are effective in encouraging couples to utilize CHTC and test models of service integration. PMID- 26253220 TI - Fast assessment of long axis strain with standard cardiovascular magnetic resonance: a validation study of a novel parameter with reference values. AB - BACKGROUND: Assessment of longitudinal function with cardiovascular magnetic resonance (CMR) is limited to measurement of systolic excursion of the mitral annulus (MAPSE) or elaborate strain imaging modalities. The aim of this study was to develop a fast assessable parameter for the measurement of long axis strain (LAS) with CMR. METHODS: 40 healthy volunteers and 125 patients with different forms of cardiomyopathy were retrospectively analyzed. Four different approaches for the assessment of LAS with CMR measuring the distance between the LV apex and a line connecting the origins of the mitral valve leaflets in enddiastole and endsystole were evaluated. Values for LAS were calculated according to the strain formula. RESULTS: LAS derived from the distance of the epicardial apical border to the midpoint of the line connecting the mitral valve insertion points (LAS epi/mid) proved to be the most reliable parameter for the assessment of LAS among the different approaches. LAS-epi/mid displayed the highest sensitivity (81.6 %) and specificity (97.5 %), furthermore showing the best correlation with feature tracking (FTI) derived transmural longitudinal strain (r = 0.85). Moreover, LAS epi/mid was non-inferior to FTI in discriminating controls from patients (Area under the curve (AUC) = 0.95 vs. 0.94, p = NS). The time required for analysis of LAS-epi/mid was significantly shorter than for FTI (67 +/- 8 s vs. 180 +/- 14 s, p < 0.0001). Additionally, LAS-epi/mid performed significantly better than MAPSE (Delta AUC = 0.09; p < 0.005) and the ejection fraction (Delta AUC = 0.11; p = 0.0002). Reference values were derived from 234 selected healthy volunteers. Mean value for LAS-epi/mid was -17.1 +/- 2.3 %. Mean values for men were significantly lower compared to women (-16.5 +/- 2.2 vs. -17.9 +/- 2.1 %; p < 0.0001), while LAS decreased with age. CONCLUSIONS: LAS-epi/mid is a novel and fast assessable parameter for the analysis of global longitudinal function with non-inferiority compared to transmural longitudinal strain. PMID- 26253223 TI - Measurement of functional task difficulty during motor learning: What level of difficulty corresponds to the optimal challenge point? AB - The relationship between task difficulty and learning benefit was examined, as was the measurability of task difficulty. Participants were required to learn a postural control task on an unstable surface at one of four different task difficulty levels. Results from the retention test showed an inverted-U relationship between task difficulty during acquisition and motor learning. The second-highest level of task difficulty was the most effective for motor learning, while learning was delayed at the most and least difficult levels. Additionally, the results indicate that salivary alpha-amylase and the performance dimension of the National Aeronautics and Space Administration-Task Load Index (NASA-TLX) are useful indices of task difficulty. Our findings suggested that instructors may be able to adjust task difficulty based on salivary alpha-amylase and the performance dimension of the NASA-TLX to enhance learning. PMID- 26253222 TI - Mean effective sensitivity for Mycobacterium avium subsp. paratuberculosis infection in cattle herds. AB - BACKGROUND: Mycobacterium avium subsp. paratuberculosis (MAP) infections in cattle are generally challenging to detect and cost-effective test strategies are consequently difficult to identify. MAP-specific antibody ELISAs for milk and serum are relatively inexpensive, but their utility is influenced by a number of factors such as herd size, herd composition and diagnostic sensitivity. The sensitivity of the test increases with the age of the tested animal, and therefore the general, or "mean effective sensitivity" (defined as the mean of the sensitivities for all animals within a population, MES), for detecting MAP within a herd is dependent upon the age distribution of the herd. For this study we used a dataset of cattle from 4,259 dairy herds and 4,078 non-dairy herds. The aim was to investigate the MES for groups of cattle considered to be reasonable entities for MAP surveillance and control, in order to assist the decision-makers in planning and optimizing these programs economically. We compared six different groups of cattle (three dairy and three non-dairy) in Denmark by calculating the MES for each herd in each group. RESULTS: The distribution of MES showed a large variation within and between groups, and in some groups we found a bimodal distribution of MES. Dairy herds generally showed higher MES than non-dairy herds. Dairy herds in a control programme for paratuberculosis showed a MES similar to all other dairy herds from which animals > 2.0 years were tested (both groups had a median MES = 0.60). For the non-dairy groups, the sensitivity became much higher when animals < 2.0 years and herds with less than 25 cattle were excluded, resulting in a median MES of 0.65. CONCLUSION: The results showed that MES could indicate the effectivity of testing different cattle groups for MAP, given that the data used are unbiased. PMID- 26253224 TI - Post-stroke transplantation of adult subventricular zone derived neural progenitor cells--A comprehensive analysis of cell delivery routes and their underlying mechanisms. AB - With neuroprotective approaches having failed until recently, current focus on experimental stroke research has switched towards manipulation of post-ischemic neuroregeneration. Transplantation of subventricular zone (SVZ) derived neural progenitor cells (NPCs) is a promising strategy for promotion of neurological recovery. Yet, fundamental questions including the optimal cell delivery route still have to be addressed. Consequently, male C57BL6 mice were exposed to transient focal cerebral ischemia and allowed to survive for as long as 84 days post-stroke. At 6h post-stroke, NPCs were grafted using six different cell delivery routes, i.e., intravenous, intraarterial, ipsilateral intrastriatal, contralateral intrastriatal, ipsilateral intraventricular and ipsilateral intracortical injection. Control mice received PBS only using the aforementioned delivery routes. Intralesional numbers of GFP(+) NPCs were high only after ipsilateral intrastriatal transplantation, whereas other injection paradigms only yielded comparatively small numbers of grafted cells. However, acute neuroprotection and improved functional outcome were observed after both systemic (i.e., intraarterial and intravenous) and ipsilateral intrastriatal transplantation only. Whereas systemic cell delivery induced acute and long-term neuroprotection, reduction of brain injury after ipsilateral intrastriatal cell grafting was only temporary, in line with the loss of transplanted NPCs in the brain. Both systemic and ipsilateral intrastriatal NPC delivery reduced microglial activation and leukocyte invasion, thus reducing free radical formation within the ischemic brain. On the contrary, only systemic NPC administration stabilized the blood-brain-barrier and reduced leukocytosis in the blood. Although intraarterial NPC transplantation was as effective as intravenous cell grafting, mortality of stroke mice was high using the intraarterial delivery route. Consequently, intravenous delivery of native NPCs in our experimental model is an attractive and effective strategy for stroke therapy that deserves further proof-of-concept studies. PMID- 26253225 TI - Implementation of microchip electrophoresis instrumentation for future spaceflight missions. AB - We present a comprehensive discussion of the role that microchip electrophoresis (ME) instrumentation could play in future NASA missions of exploration, as well as the current barriers that must be overcome to make this type of chemical investigation possible. We describe how ME would be able to fill fundamental gaps in our knowledge of the potential for past, present, or future life beyond Earth. Despite the great promise of ME for ultrasensitive portable chemical analysis, to date, it has never been used on a robotic mission of exploration to another world. We provide a current snapshot of the technology readiness level (TRL) of ME instrumentation, where the TRL is the NASA systems engineering metric used to evaluate the maturity of technology, and its fitness for implementation on missions. We explain how the NASA flight implementation process would apply specifically to ME instrumentation, and outline the scientific and technology development issues that must be addressed for ME analyses to be performed successfully on another world. We also outline research demonstrations that could be accomplished by independent researchers to help advance the TRL of ME instrumentation for future exploration missions. The overall approach described here for system development could be readily applied to a wide range of other instrumentation development efforts having broad societal and commercial impact. PMID- 26253226 TI - Three-in-one enzyme assay based on single molecule detection in femtoliter arrays. AB - Large arrays of femtoliter-sized chambers are important tools for single molecule research as well as bioanalytical applications. We have optimized the design and fabrication of two array types consisting of 250 * 250 (62 500) femtoliter chambers either by surface etching of fused silica slides or by polydimethylsiloxane (PDMS) molding. Highly diluted solutions of beta galactosidase were enclosed in such arrays to monitor the fluorogenic reactions of hundreds of individual enzyme molecules in parallel by wide-field fluorescence microscopy. An efficient mechanical sealing procedure was developed to prevent diffusion of the fluorescent reaction product out of the chambers. Different approaches for minimizing non-specific surface adsorption were explored. The signal acquisition was optimized to grant both a large field of view and an efficient signal acquisition from each femtoliter chamber. The optimized femtoliter array has enabled a three-in-one enzyme assay system: First, the concentration of active enzyme can be determined in a digital way by counting fluorescent chambers in the array. Second, the activity of the enzyme bulk solution is given by averaging many individual substrate turnover rates without the need for knowing the exact enzyme concentration. Third-unlike conventional enzyme assays-the distribution of individual substrate turnover rates yields insight into the conformational heterogeneity in an enzyme population. The substrate turnover rates of single beta-galactosidase molecules were found to be broadly distributed and independent of the type of femtoliter array. In general, both types of femtoliter arrays are highly sensitive platforms for enzyme analysis at the single molecule level and yield consistent results. Graphical Abstract Isolation and analysis of individual enzyme molecules in large arrays of femtoliter-sized chambers. PMID- 26253227 TI - X-ray absorption near-edge structure micro-spectroscopy study of vanadium speciation in Phycomyces blakesleeanus mycelium. AB - Vanadium speciation in the fungus Phycomyces blakesleeanus was examined by X-ray absorption near-edge structure (XANES) spectroscopy, enabling assessment of oxidation states and related molecular symmetries of this transition element in the fungus. The exposure of P. blakesleeanus to two physiologically important vanadium species (V(5+) and V(4+)) resulted in the accumulation of this metal in central compartments of 24 h old mycelia, most probably in vacuoles. Tetrahedral V(5+), octahedral V(4+), and proposed intracellular complexes of V(5+) were detected simultaneously after addition of a physiologically relevant concentration of V(5+) to the mycelium. A substantial fraction of the externally added V(4+) remained mostly in its original form. However, observable variations in the pre-edge-peak intensities in the XANES spectra indicated intracellular complexation and corresponding changes in the molecular coordination symmetry. Vanadate complexation was confirmed by (51)V NMR and Raman spectroscopy, and potential binding compounds including cell-wall constituents (chitosan and/or chitin), (poly)phosphates, DNA, and proteins are proposed. The evidenced vanadate complexation and reduction could also explain the resistance of P. blakesleeanus to high extracellular concentrations of vanadium. PMID- 26253228 TI - Ti as an electrode material. How to make the future better than the present. PMID- 26253229 TI - Human excretory products of selenium are natural constituents of marine fish muscle. AB - A selenosugar (selenosugar 1, methyl-2-acetamido-2-deoxy-1-seleno-beta-D galactopyranoside) was identified in aqueous extracts of muscle tissue of three marine fish species, mackerel (Scomber scombrus), sardine (Sardina pilchardus), and tuna (Thunnus albacares), by high-performance liquid chromatography coupled to elemental and high-resolution molecular mass spectrometry. Selenoneine (2 selenyl-Nalpha, Nalpha, Nalpha-trimethyl-L-histidine), a known selenium compound in fish, was the major form of selenium in the aqueous extracts, and the methylated derivative of selenoneine, namely Se-methylselenoneine, was also identified as a minor natural constituent in the fish. Selenosugar 1, a major urinary excretion product of selenium often found in organs and body fluids related to selenium excretion, has so far not been reported in muscle tissue. Se methylselenoneine has been proposed as the main urinary metabolite from selenoneine. This first report of selenosugar 1 and Se-methylselenoneine as natural constituents of fish muscle tissue opens up a new perspective on the role of these compounds in selenium metabolism and is relevant to selenium supplementation studies. PMID- 26253230 TI - Monoterpene separation by coupling proton transfer reaction time-of-flight mass spectrometry with fastGC. AB - Proton transfer reaction mass spectrometry (PTR-MS) is a well-established technique for real-time analysis of volatile organic compounds (VOCs). Although it is extremely sensitive (with sensitivities of up to 4500 cps/ppbv, limits of detection <1 pptv and the response times of approximately 100 ms), the selectivity of PTR-MS is still somewhat limited, as isomers cannot be separated. Recently, selectivity-enhancing measures, such as manipulation of drift tube parameters (reduced electric field strength) and using primary ions other than H3O(+), such as NO(+) and O2 (+), have been introduced. However, monoterpenes, which belong to the most important plant VOCs, still cannot be distinguished so more traditional technologies, such as gas chromatography mass spectrometry (GC MS), have to be utilised. GC-MS is very time consuming (up to 1 h) and cannot be used for real-time analysis. Here, we introduce a sensitive, near-to-real-time method for plant monoterpene research-PTR-MS coupled with fastGC. We successfully separated and identified six of the most abundant monoterpenes in plant studies (alpha- and beta-pinenes, limonene, 3-carene, camphene and myrcene) in less than 80 s, using both standards and conifer branch enclosures (Norway spruce, Scots pine and black pine). Five monoterpenes usually present in Norway spruce samples with a high abundance were separated even when the compound concentrations were diluted to 20 ppbv. Thus, fastGC-PTR-ToF-MS was shown to be an adequate one instrument solution for plant monoterpene research. PMID- 26253231 TI - Dihydrithieno[2,3-b]naphto-4,9-dione analogues as anticancer agents: Synthesis and in cell pharmacological studies. AB - The synthesis of a series of highly functionalized DNTQ-based derivatives is described. In vitro, most of the compounds exerted a cytotoxic effect against several tumour cell lines comparable to or greater than that of doxorubicin. Here we demonstrate that compound 14, the less cardiotoxic compound of this series, induced cell differentiation and was distributed mainly in the cytoplasm in the human glioblastoma LN229 cell line. Moreover, compound 14 reduced both cellular glucose uptake and serine/threonine kinase AKT expression, and triggered cell apoptosis. These findings suggest that highly functionalized DTNQ-based derivatives are promising pharmacological tools for the study of human solid tumours. PMID- 26253233 TI - Combining microscopy with spectroscopic and chemical methods for tracing the origin of atmospheric fallouts from mining sites. AB - Populations living close to mining sites are often exposed to important heavy metal concentrations, especially through atmospheric fallouts. Identifying the main sources of metal-rich particles remains a challenge because of the similarity of the particle signatures from the polluted sites. This work provides an original combination of physical and chemical methods to determine the main sources of airborne particles impacting inhabited zones. Raman microspectrometry (RMS), X-ray diffraction (DRX), morphology analyses by microscopy and chemical composition were assessed. Geochemical analysis allowed the identification of target and source areas; XRD and RMS analysis identified the main mineral phases in association with their metal content and speciation. The characterization of the dominant minerals was combined with particle morphology analysis to identify fallout sources. The complete description of dust morphologies permitted the successful determination of a fingerprint of each source site. The analysis of these chemical and morphological fingerprints allowed identification of the mine area as the main contributor of metal-rich particles impacting the inhabited zone. In addition to the identification of the main sources of airborne particles, this study will also permit to better define the extent of polluted zones requiring remediation or protection from eolian erosion inducing metal-rich atmospheric fallouts. PMID- 26253234 TI - Citric acid facilitated thermal treatment: An innovative method for the remediation of mercury contaminated soil. AB - Thermal treatment is a promising technology for the remediation of mercury contaminated soils, but it often requires high energy input at heating temperatures above 600 degrees C, and the treated soil is not suitable for agricultural reuse. The present study developed a novel method for the thermal treatment of mercury contaminated soils with the facilitation of citric acid (CA). A CA/Hg molar ratio of 15 was adopted as the optimum dosage. The mercury concentration in soils was successfully reduced from 134 mg/kg to 1.1mg/kg when treated at 400 degrees C for 60 min and the treated soil retained most of its original soil physiochemical properties. During the treatment process, CA was found to provide an acidic environment which enhanced the volatilization of mercury. This method is expected to reduce energy input by 35% comparing to the traditional thermal treatment method, and lead to agricultural soil reuse, thus providing a greener and more sustainable remediation method for treating mercury contaminated soil in future engineering applications. PMID- 26253232 TI - Post-Transcriptional Coordination of the Arabidopsis Iron Deficiency Response is Partially Dependent on the E3 Ligases RING DOMAIN LIGASE1 (RGLG1) and RING DOMAIN LIGASE2 (RGLG2). AB - Acclimation to changing environmental conditions is mediated by proteins, the abundance of which is carefully tuned by an elaborate interplay of DNA-templated and post-transcriptional processes. To dissect the mechanisms that control and mediate cellular iron homeostasis, we conducted quantitative high-resolution iTRAQ proteomics and microarray-based transcriptomic profiling of iron-deficient Arabidopsis thaliana plants. A total of 13,706 and 12,124 proteins was identified with a quadrupole-Orbitrap hybrid mass spectrometer in roots and leaves, respectively. This deep proteomic coverage allowed accurate estimates of post transcriptional regulation in response to iron deficiency. Similarly regulated transcripts were detected in only 13% (roots) and 11% (leaves) of the 886 proteins that differentially accumulated between iron-sufficient and iron deficient plants, indicating that the majority of the iron-responsive proteins was post-transcriptionally regulated. Mutants harboring defects in the RING DOMAIN LIGASE1 (RGLG1)(1) and RING DOMAIN LIGASE2 (RGLG2) showed a pleiotropic phenotype that resembled iron-deficient plants with reduced trichome density and the formation of branched root hairs. Proteomic and transcriptomic profiling of rglg1 rglg2 double mutants revealed that the functional RGLG protein is required for the regulation of a large set of iron-responsive proteins including the coordinated expression of ribosomal proteins. This integrative analysis provides a detailed catalog of post-transcriptionally regulated proteins and allows the concept of a chiefly transcriptionally regulated iron deficiency response to be revisited. Protein data are available via ProteomeXchange with identifier PXD002126. PMID- 26253235 TI - Effect of anthropogenic organic complexants on the solubility of Ni, Th, U(IV) and U(VI). AB - The influence of anthropogenic organic complexants (citrate, EDTA and DTPA from 0.005 to 0.1M) on the solubility of nickel(II), thorium(IV) and uranium (U(IV) and U(VI)) has been studied. Experiments were carried out in 95%-saturated Ca(OH)2 solutions, representing the high pH conditions anticipated in the near field of a cementitious intermediate level radioactive waste repository. Results showed that Ni(II) solubility increased by 2-4 orders of magnitude in the presence of EDTA and DTPA and from 3 to 4 orders of magnitude in the case of citrate. Citrate had the greatest effect on the solubility of Th(IV) and U(IV)/(VI). XRD and SEM analyses indicate that the precipitates are largely amorphous; only in the case of Ni(II), is there some evidence of incipient crystallinity, in the form of Ni(OH)2 (theophrastite). A study of the effect of calcium suggests that U(VI) and Ni(II) may form metal-citrate-OH complexes stabilised by Ca(2+). Thermodynamic modelling underestimates the concentrations in solution in the presence of the ligands for all the elements considered here. Further investigation of the behaviour of organic ligands under hyperalkaline conditions is important because of the use of the thermodynamic constants in preparing the safety case for the geological disposal of radioactive wastes. PMID- 26253236 TI - Comprehensive waste characterization and organic pollution co-occurrence in a Hg and As mining and metallurgy brownfield. AB - The abandonment of Hg-As mining and metallurgy sites, together with long-term weathering, can dramatically degrade the environment. In this work it is exemplified the complex legacy of contamination that afflicts Hg-As brownfields through the detailed study of a paradigmatic site. Firstly, an in-depth study of the former industrial process was performed to identify sources of different types of waste. Subsequently, the composition and reactivity of As- and Hg-rich wastes (calcines, As-rich soot, stupp, and flue dust) was analyzed by means of multielemental analysis, mineralogical characterization (X-ray diffraction, electronic, and optical microscopy, microbrobe), chemical speciation, and sequential extractions. As-rich soot in the form of arsenolite, a relatively mobile by-product of the pyrometallurgical process, and stupp, a residue originated in the former condensing system, were determined to be the main risk at the site. In addition, the screening of organic pollution was also aimed, as shown by the outcome of benzo(a) pyrene and other PAHs, and by the identification of unexpected Hg organo-compounds (phenylmercury propionate). The approach followed unravels evidence from waste from the mining and metallurgy industry that may be present in other similar sites, and identifies unexpected contaminants overlooked by conventional analyses. PMID- 26253237 TI - Supported self-management for adults with type 2 diabetes and a learning disability (OK-Diabetes): study protocol for a randomised controlled feasibility trial. AB - BACKGROUND: Individuals with a learning disability (LD) are at higher risk of developing type 2 diabetes, but LD is not straightforward to define or identify, especially at the milder end of the spectrum, which makes case finding difficult. While supported self-management of health problems is now established, current material is largely educational and didactic with little that facilitates behavioural change. The interaction between the person with diabetes and others supporting their care is also largely unknown. For these reasons, there is considerable work needed to prepare for a definitive trial. The aim of this paper is to publish the abridged protocol of this preparatory work. METHODS/DESIGN: Phase I is a prospective case-finding study (target n = 120 to 350) to identify and characterise potential participants, while developing a standardised supported self-management intervention. Phase II is a randomised feasibility trial (target n = 80) with blinded outcome assessment. Patients identified in Phase I will be interviewed and consented prior to being randomised to (1) standard treatment, or (2) supported self-management. Both arms will also be provided with an 'easy read' accessible information resource on managing type 2 diabetes. The intervention will be standardised but delivered flexibly depending on patient need, including components for the participant, a supporter, and shared activities. Outcomes will be (i) robust estimates of eligibility, consent and recruitment rates with refined recruitment procedures; (ii) characterisation of the eligible population; (iii) a standardised intervention with associated written materials, (iv) adherence and negative outcomes measures; (v) preliminary estimates of adherence, acceptability, follow-up and missing data rates, along with refined procedures; and (vi) description of standard treatment. DISCUSSION: Our study will provide important information on the nature of type 2 diabetes in adults with LD living in the community, on the challenges of identifying those with milder LD, and on the possibilities of evaluating a standardised intervention to improve self-management in this population. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41897033 (registered 21 January 2013). PMID- 26253238 TI - Foetal scalp blood sampling during labour for pH and lactate measurements. AB - Second-line methods of foetal monitoring have been developed in an attempt to reduce unnecessary interventions due to continuous cardiotocography (CTG), and to better identify foetuses that are at risk of intrapartum asphyxia. Very few studies directly compared CTG with foetal scalp blood (FBS) and CTG only. Only one randomised controlled trial (RCT) was published in the 1970s and had limited power to assess neonatal outcome. Direct and indirect comparisons conclude that FBS could reduce the number of caesarean deliveries associated with the use of continuous CTG. The main drawbacks of FBS are its invasive and discontinuous nature and the need for a sufficient volume of foetal blood for analysis, especially for pH measurement, resulting in failure rates reaching 10%. FBS for lactate measurement became popular with the design of test-strip devices, requiring <0.5 mL of foetal blood. RCTs showed similar outcomes with the use of FBS for lactates compared with pH in terms of obstetrical interventions and neonatal outcomes. In conclusion, there is some evidence that FBS reduces the need for operative deliveries. However, the evidence is limited with regard to actual standards, and large RCTs, directly comparing CTG only with CTG with FBS, are still needed. PMID- 26253239 TI - Multimodal imaging of refractory Candida chorioretinitis progressing to endogenous endophthalmitis. AB - BACKGROUND: Endogenous fungal endophthalmitis is a serious vision-threatening condition that occurs in immunosuppressed patients with candidemia. FINDINGS: We report a complicated case of Candida albicans chorioretinitis that progressed to endophthalmitis. The patient required intravitreal and systemic anti-fungal medications with pars plana vitrectomy for successful treatment. Multimodal imaging using fundus photography, fluorescein angiography, spectral domain optical coherence tomography, and fundus autofluorescence was obtained throughout treatment. These modalities localized the Candida infection in the choroid, penetrating Bruch's membrane, the retinal pigment epithelium, and the retina to enter the vitreous cavity. This infectious route resulted in loss of the retinal pigment epithelium, photoreceptors, and outer retinal layers, with scar formation that resulted in vision loss and increased future risk of choroidal neovascular membranes. CONCLUSIONS: Multimodal imaging of C. albicans chorioretinitis allows for accurate diagnosis, assessment of response to therapy, and prognosis for visual recovery and future complications. PMID- 26253240 TI - 1H and 31P magnetic resonance spectroscopy in a rat model of chronic hepatic encephalopathy: in vivo longitudinal measurements of brain energy metabolism. AB - Chronic liver disease (CLD) leads to a spectrum of neuropsychiatric disorders named hepatic encephalopathy (HE). Even though brain energy metabolism is believed to be altered in chronic HE, few studies have explored energy metabolism in CLD-induced HE, and their findings were inconsistent. The aim of this study was to characterize for the first time in vivo and longitudinally brain metabolic changes in a rat model of CLD-induced HE with a focus on energy metabolism, using the methodological advantages of high field proton and phosphorus Magnetic Resonance Spectroscopy (1H- and 31P-MRS). Wistar rats were bile duct ligated (BDL) and studied before BDL and at post-operative weeks 4 and 8. Glutamine increased linearly over time (+146 %) together with plasma ammonium (+159 %). As a compensatory effect, other brain osmolytes decreased: myo-inositol (-36 %), followed by total choline and creatine. A decrease in the neurotransmitters glutamate (-17 %) and aspartate (-28 %) was measured only at week 8, while no significant changes were observed for lactate and phosphocreatine. Among the other energy metabolites measured by 31P-MRS, we observed a non-significant decrease in ATP together with a significant decrease in ADP (-28 %), but only at week 8 after ligation. Finally, brain glutamine showed the strongest correlations with changes in other brain metabolites, indicating its importance in type C HE. In conclusion, mild alterations in some metabolites involved in energy metabolism were observed but only at the end stage of the disease when edema and neurological changes are already present. Therefore, our data indicate that impaired energy metabolism is not one of the major causes of early HE symptoms in the established model of type C HE. PMID- 26253242 TI - Public debate begins in Scotland on future of NHS. PMID- 26253241 TI - Bufei Yishen granule combined with acupoint sticking improves pulmonary function and morphormetry in chronic obstructive pulmonary disease rats. AB - BACKGROUND: The integrated therapy of Bufei Yishen granule and acupoint sticking has been used in the treatment of stable chronic obstructive pulmonary disease (COPD) clinically, with remarkable benefits. This study was initiated to observe the effects of the combination of Bufei Yishen granule and acupoint sticking on pulmonary function and morphormetry in a COPD rat model. METHODS: Rats were randomized into Control, Model, Bufei Yishen (BY), Acupoint sticking (AS), Bufei Yishen + Acupoint sticking (BY + AS) and aminophyline (APL) groups. COPD rats were duplicated by repeated cigarette smoke and bacterial exposures. The rats were treated with normal saline, Bufei Yishen granule, acupoint sticking, Bufei Yishen + Acupoint sticking and aminophylline, respectively, from week 9 through 20. Pulmonary function was measured by using a whole body plethysmograph every 4 weeks. The rats were sacrificed at the end of week 20, and lung tissue histology and ultrastructure was observed under light and electron microscopes. RESULTS: The pulmonary function, including tidal volume (VT), peak expiratory flow (PEF) and expiratory flow at 50 % tidal volume (EF50), was markedly decreased from week 8 in COPD rats (P < 0.05). At week 20, VT, PEF and EF50 were significantly lower in Model group (P < 0.05). Compared with Model group, VT, PEF and EF50 were higher in BY and BY + AS groups (P < 0.05), and EF50 was higher in AS group, while VT was higher in APL group (P < 0.05). Markedly histological and ultrastructural changes, including respiratory membrane thickening, volume density of lamellar corpuscle decreasing, mitochondria reducing in type II alveolar cell, were found in COPD rats and were alleviated in the treated groups, especially in BY and BY + AS groups. CONCLUSION: Bufei Yishen granule and acupoint sticking can improve pulmonary function and lung pathological impairment in COPD rats, the curative effect of the combination is better than acupoint sticking or aminophylline only. PMID- 26253243 TI - Extracorporeal machine perfusion of the pancreas: technical aspects and its clinical implications--a systematic review of experimental models. AB - Pancreas or pancreatic islet transplantation is an important treatment option for insulin-dependent diabetes and its complications. However, as the pancreas is particularly susceptible to ischaemic-reperfusion injury, the criteria for pancreas and islet donation are especially strict. With a chronic shortage of donors, one critical challenge is to maximise organ availability and expand the donor pool. To achieve that, continuous improvement in organ preservation is required, with the aims of reducing ischaemia-reperfusion injury, prolong preservation time and improve graft function. Static cold storage, the only method used in clinical pancreas and islet cell transplant currently, has likely reached its plateau. Machine perfusion, hypothermic or normothermic, could hold the key to improving donor pancreas quality as well as quantity available for transplant. This article reviews the literature on experimental models of pancreas machine perfusion, examines the benefits of machine perfusion, the technical aspects and their clinical implications. PMID- 26253244 TI - Pancreatic neck cancer has specific and oncologic characteristics regarding portal vein invasion and lymph node metastasis. AB - BACKGROUND: Pancreatic cancer originating in the neck of the gland occurs in the small region surrounded by the common hepatic artery (CHA), gastroduodenal artery (GDA), and portal vein (PV). The specific clinicopathologic characteristics of pancreatic neck cancer remain unclear. Our aim was to identify specific biologic behaviors of pancreatic neck cancer for the improvement of treatment outcomes. METHODS: This study was a retrospective cohort study with a comparative outcomes design. In 63 of 325 consecutive patients (19.4%) with pancreatic cancer who underwent operation, the tumor was located in the pancreatic neck. Clinicopathologic characteristics and prognostic factors specific to pancreatic neck cancer were analyzed by comparison with those of pancreatic head or body/tail cancers. RESULTS: The rates of radiographic and pathologic PV and/or superior mesenteric vein (PV/SMV) invasion were greater in patients with pancreatic neck cancer (radiographic, 84%; pathologic, 37%) than those with pancreatic head and body/tail cancers (radiographic: 67% head, 25% body/tail; pathologic: 26% head, 6% body/tail). The most frequent lymph node (LN) metastases were found in the region along the CHA in pancreatic neck cancer, and the areas most likely to show a positive surgical margin were the dissected surface of the PV and the root of the GDA and/or CHA. For pancreatic neck cancer patients, 5 independent poor prognostic factors were found: pathologic PV/SMV invasion (P = .005), moderately or poorly differentiated tumors (P = .001), positive LN ratio of >=0.1 (P < .001), distance from surgical margin of <=1 mm (P = .018), and inability to complete the planned postoperative adjuvant therapy (P < .001). CONCLUSION: Pancreatic neck cancer showed specific clinicopathologic characteristics and prognostic factors after resection. PMID- 26253245 TI - The effect of cirrhosis on the risk for failure of nonoperative management of blunt liver injuries. AB - BACKGROUND: The purpose of this study was to delineate the association between cirrhosis and failure of nonoperative management (F-NOM) after blunt liver trauma. METHODS: We carried out a review of the National Trauma Databank from 2007 to 2011 including patients >= 16 years old admitted after a blunt injury. Propensity score was used to match each cirrhotic to 3 noncirrhotic patients. Primary outcome was F-NOM (liver procedure >2 hours after admission and/or operative intervention directed at the liver after angiography). RESULTS: A total of 57 cirrhotic patients who met inclusion criteria were matched with 171 noncirrhotic patients. Splenic injury was present in 41% (35% vs 43%; P = .31) and 28% had a high-grade liver injury III/VI/V (26% vs 29%; P = .73). The majority of patients in both groups were selected for a trial of NOM (77% vs 85%; P = .15). There was no difference in the rate of F-NOM between the 2 groups (14% vs 14%; P = 1.00), even for high-grade injuries (13% vs 20%; P = .72). Cirrhotic patients had a greater overall mortality (28% vs 7%; P < .01), especially if they required a laparotomy (58% vs 17%; P < .01) or if they failed NOM (50% vs 4%; P < .01). CONCLUSION: Cirrhosis has no effect on the selection of patients with blunt liver injuries for a trial of nonoperative management and does not seem to be associated with a greater risk for failure of nonoperative management within the constraints of our study. Nonoperative management in this population is highly successful and failure is rarely related directly to the liver injury itself. Failure of non-operative management increases the already high mortality risk in this population. PMID- 26253246 TI - Comprendre l'influence des facteurs contextuels sur la participation communautaire a la sante : une etude de cas dans le district sanitaire de Tenkodogo, au Burkina Faso. AB - Le Burkina Faso met en oeuvre depuis plusieurs annees la strategie de la participation communautaire. Des comites de gestion (CoGes) ont ete mis en place dans les centres de sante de la premiere ligne et doivent participer aux prises de decisions. L'objectif principal de cette strategie est de favoriser l'utilisation des services de sante et une adhesion massive des communautes aux activites de promotion de la sante. Seulement, on constate que les resultats escomptes par les autorites sanitaires tardent a se realiser. Le present article convoque les facteurs lies au contexte socioculturel du district sanitaire, pour analyser le phenomene de la participation communautaire. L'etude s'est deroulee dans le district sanitaire de Tenkodogo, situe dans la region administrative du Centre-est, a environ 190 km de la capitale. Cette etude exclusivement qualitative, a utilise deux methodes de collecte : les entretiens individuels et les focus groups. Les participants a l'etude sont les chefs de menage ( n = 48), les membres des CoGes ( n = 10), les agents de sante ( n = 8) et les agents de sante communautaire ( n = 24). La methode de l'analyse de contenu a ete utilisee pour l'analyse des donnees. Les resultats de l'etude montrent que plusieurs facteurs socioculturels influencent la dynamique de la participation communautaire dans le district. Ce sont les conditions economiques, la perception negative des services de sante, les inegalites sociales de sexe et d'age, le faible ancrage social des organisations communautaires, les rivalites inter villages et les conflits coutumiers. L'etude releve egalement que les communautes ne percoivent pas leur implication dans le processus decisionnel des services de sante comme une priorite. Leurs principales attentes s'orientent vers la disponibilite de soins de qualite et a cout reduit. PMID- 26253247 TI - A Novel Use of Regional Anesthesia for Spastic Hemiplegia Evaluation and Treatment: A Case Report. AB - Spastic hemiplegia is a common sequela of stroke. Spasticity that is not optimally reduced with systemic therapy is often treated with intramuscular botulinum toxin injections. Spastic tone can increase the difficulty of appropriately positioning the patient for botulinum toxin injections, lengthen procedure duration, and increase periprocedural pain. Our patient, a 53-year-old woman, was unable to be adequately positioned to receive botulinum toxin injections to her left upper extremity because of challenging flexion synergy posturing and related positional pain. A left interscalene brachial plexus local anesthetic block administered under ultrasound guidance was used to produce both temporary dense muscle relaxation and profound anesthesia, facilitating successful and comfortable botulinum toxin injections in this patient. PMID- 26253248 TI - Interleukin-37 expression is decreased in Behcet's disease and is associated with inflammation. AB - Interleukin-37 (IL-37) exerts broad inhibitory properties on the innate inflammatory and acquired immune responses. This study was set up to investigate the expression of IL-37 in Behcet disease (BD) and to explore its possible regulatory role during inflammation. IL-37 protein levels and mRNA expression in lipopolysaccharides (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) from 50 BD (30 patients in active stage) patients and 20 healthy controls were assayed by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Cytokines in the serum and the supernatants of stimulated PBMCs and CD4(+) T cells were assayed by ELISA. Active BD patients showed a decreased IL-37 expression and increased IL-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) levels in serum and in PBMC culture supernatants. Active BD patients treated with corticosteroids showed an enhanced IL-37 production. Recombinant IL-37 (rIL-37) induced a significant decrease of inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha). It also markedly decreased IL-17 expression in PBMCs and CD4(+) T cells from active BD patients. The present study suggests that a decreased IL-37 expression in BD patients is associated with an increased inflammatory response. Corticosteroid treatment of active BD patients is associated with an increased expression of IL-37 mRNA, which suggests that treatment may partly exert its immunosuppressive effect by regulating IL-37 production and reducing inflammatory cytokines. PMID- 26253249 TI - Impact of Parkinson's disease on the acute care treatment and medium-term functional outcome in geriatric hip fracture patients. AB - INTRODUCTION: Patients with Parkinson's disease (PD) have a heightened risk of sustaining hip fractures due to disturbed balance and gait insecurity. This study aims to determine the impact of PD on the perioperative course and medium-term functional outcome of patients with hip fractures. MATERIALS AND METHODS: A total of 402 hip fracture patients, aged >=60 years, were prospectively enrolled. On admission, the American Society of Anesthesiologists score, Mini-Mental Status Examination, and Barthel Index (BI), among other scales, were documented. The Hoehn and Yahr scale was used to assess the severity of PD. The functional outcome was assessed by performance on the BI, Tinetti test (TT), and Timed Up and Go test (TUG) at discharge and at the 6-month follow-up. Additionally, the length of hospitalization, perioperative complications, and discharge management were documented. A multivariate regression analysis was performed to control for influencing factors. RESULTS: A total of 19 patients (4.7%) had a concomitant diagnosis of PD. The functional outcome (BI, TT, and TUG) was comparable between groups (all p > 0.05). Grade II (52.6 vs. 26.1%; OR = 4.304, p = 0.008) and IV complications (15.8 vs. 4.4%; OR = 7.785, p = 0.012) occurred significantly more often among PD patients. While the diagnosis of PD was associated with a significantly longer mean length of hospital stay (beta = 0.119, p = 0.024), the transfer from acute hospital care showed no significant difference (p = 0.246). Patients with an additional diagnosis of PD had inferior results in BI at the 6 month follow-up (p = 0.038). CONCLUSION: PD on hospital admission is not an independent risk factor for in-hospital mortality or an inferior functional outcome at hospital discharge. However, patients with PD are at risk for specific complications and longer hospitalization at the time of transfer from acute care so as for reduced abilities in activities of daily living in the medium term. PMID- 26253250 TI - Abdominal pain and asthenia in a 7 years old boy. PMID- 26253251 TI - An artificial pancreas provided a novel model of blood glucose level variability in beagles. AB - Although the effects on prognosis of blood glucose level variability have gained increasing attention, it is unclear whether blood glucose level variability itself or the manifestation of pathological conditions that worsen prognosis. Then, previous reports have not been published on variability models of perioperative blood glucose levels. The aim of this study is to establish a novel variability model of blood glucose concentration using an artificial pancreas. We maintained six healthy, male beagles. After anesthesia induction, a 20-G venous catheter was inserted in the right femoral vein and an artificial pancreas (STG 22, Nikkiso Co. Ltd., Tokyo, Japan) was connected for continuous blood glucose monitoring and glucose management. After achieving muscle relaxation, total pancreatectomy was performed. After 1 h of stabilization, automatic blood glucose control was initiated using the artificial pancreas. Blood glucose level varied for 8 h, alternating between the target blood glucose values of 170 and 70 mg/dL. Eight hours later, the experiment was concluded. Total pancreatectomy was performed for 62 +/- 13 min. Blood glucose swings were achieved 9.8 +/- 2.3 times. The average blood glucose level was 128.1 +/- 5.1 mg/dL with an SD of 44.6 +/- 3.9 mg/dL. The potassium levels after stabilization and at the end of the experiment were 3.5 +/- 0.3 and 3.1 +/- 0.5 mmol/L, respectively. In conclusion, the results of the present study demonstrated that an artificial pancreas contributed to the establishment of a novel variability model of blood glucose levels in beagles. PMID- 26253252 TI - Cardiac supporting device using artificial rubber muscle: preliminary study to active dynamic cardiomyoplasty. AB - Dynamic cardiomyoplasty is a surgical treatment that utilizes the patient's skeletal muscle to support circulation. To overcome the limitations of autologous skeletal muscles in dynamic cardiomyoplasty, we studied the use of a wrapped-type cardiac supporting device using pneumatic muscles. Four straight rubber muscles (Fluidic Muscle, FESTO, Esslingen, Germany) were used and connected to pressure sensors, solenoid valves, a controller and an air compressor. The driving force was compressed air. A proportional-integral-derivative system was employed to control the device movement. An overflow-type mock circulation system was used to analyze the power and the controllability of this new device. The device worked powerfully with pumped flow against afterload of 88 mmHg, and the beating rate and contraction/dilatation time were properly controlled using simple software. Maximum pressure inside the ventricle and maximum output were 187 mmHg and 546.5 ml/min, respectively, in the setting of 50 beats per minute, a contraction/dilatation ratio of 1:2, a preload of 18 mmHg, and an afterload of 88 mmHg. By changing proportional gain, contraction speed could be modulated. This study showed the efficacy and feasibility of a pneumatic muscle for use in a cardiac supporting device. PMID- 26253253 TI - [Step-by-step toward the perfect hepatitis C treatment for all genotypes]. PMID- 26253254 TI - Simultaneous production of acetic and gluconic acids by a thermotolerant Acetobacter strain during acetous fermentation in a bioreactor. AB - The activity of bacterial strains significantly influences the quality and the taste of vinegar. Previous studies of acetic acid bacteria have primarily focused on the ability of bacterial strains to produce high amounts of acetic acid. However, few studies have examined the production of gluconic acid during acetous fermentation at high temperatures. The production of vinegar at high temperatures by two strains of acetic acid bacteria isolated from apple and cactus fruits, namely AF01 and CV01, respectively, was evaluated in this study. The simultaneous production of gluconic and acetic acids was also examined in this study. Biochemical and molecular identification based on a 16s rDNA sequence analysis confirmed that these strains can be classified as Acetobacter pasteurianus. To assess the ability of the isolated strains to grow and produce acetic acid and gluconic acid at high temperatures, a semi-continuous fermentation was performed in a 20-L bioreactor. The two strains abundantly grew at a high temperature (41 degrees C). At the end of the fermentation, the AF01 and CV01 strains yielded acetic acid concentrations of 7.64% (w/v) and 10.08% (w/v), respectively. Interestingly, CV01 was able to simultaneously produce acetic and gluconic acids during acetic fermentation, whereas AF01 mainly produced acetic acid. In addition, CV01 was less sensitive to ethanol depletion during semi-continuous fermentation. Finally, the enzymatic study showed that the two strains exhibited high ADH and ALDH enzyme activity at 38 degrees C compared with the mesophilic reference strain LMG 1632, which was significantly susceptible to thermal inactivation. PMID- 26253255 TI - Diffusion-weighted MR imaging of metastatic abdominal and pelvic tumours is sensitive to early changes induced by a VEGF inhibitor using alternative diffusion attenuation models. AB - OBJECTIVES: To assess the utility of diffusion weighted imaging for monitoring early treatment effects associated with a VEGF inhibitor. MATERIALS AND METHODS: Twenty-nine patients with metastatic abdominal and pelvic tumours were recruited and imaged with DW-MRI: twice at baseline, and after 7 and 28 days of treatment with cediranib. Tumour measures were derived using mono-exponential, bi exponential and stretched-exponential models, and parameter repeatability and treatment effects seen after 7 and 28 days were assessed. Correlations with volume changes and DCE-MRI metrics were also assessed. RESULTS: Diffusion coefficient repeatabilities from all models were < 6%; f and D* (bi-exponential) were 22% and 44%; alpha (stretched-exponential) was 4.2%. Significant increases in the diffusion coefficients from all models were observed at day 28 but not day 7. Significant decreases in D* and f.D* were observed at day 7 and in f at day 28; significant increases in alpha were observed at both time-points. Weak correlations between DW-MRI changes and volume changes and DCE-MRI changes were observed. CONCLUSION: DW-MRI is sensitive to early and late treatment changes caused by a VEGF inhibitor using non-mono-exponential models. Evidence of over fitting using the bi-exponential model suggests that the stretched-exponential model is best suited to monitor such changes. KEY POINTS: * Non-mono-exponential diffusion models widen sensitivity to a broader class of tissue properties. * A stretched-exponential model robustly detects changes after 7 days of VEGF inhibitor treatment. * There are very weak correlations between DWI-IVIM perfusion and similar DCE-MRI measures. * Diffusion-weighted MRI is a highly informative technique for assessing novel tumour therapies. PMID- 26253256 TI - Technical feasibility and validation of a coronary artery calcium scoring system using CT coronary angiography images. AB - OBJECTIVES: We validate a novel CT coronary angiography (CCTA) coronary calcium scoring system. METHODS: Calcium was quantified on CCTA images using a new patient-specific attenuation threshold: mean + 2SD of intra-coronary contrast density (HU). Using 335 patient data sets a conversion factor (CF) for predicting CACS from CCTA scores (CCTAS) was derived and validated in a separate cohort (n = 168). Bland-Altman analysis and weighted kappa for MESA centiles and Agatston risk groupings were calculated. RESULTS: Multivariable linear regression yielded a CF: CACS = (1.185 * CCTAS) + (0.002 * CCTAS * attenuation threshold). When applied to CCTA data sets there was excellent correlation (r = 0.95; p < 0.0001) and agreement (mean difference -10.4 [95% limits of agreement -258.9 to 238.1]) with traditional calcium scores. Agreement was better for calcium scores below 500; however, MESA percentile agreement was better for high risk patients. Risk stratification was excellent (Agatston groups k = 0.88 and MESA centiles k = 0.91). Eliminating the dedicated CACS scan decreased patient radiation exposure by approximately one-third. CONCLUSION: CCTA calcium scores can accurately predict CACS using a simple, individualized, semiautomated approach reducing acquisition time and radiation exposure when evaluating patients for CAD. This method is not affected by the ROI location, imaging protocol, or tube voltage strengthening its clinical applicability. KEY POINTS: * Coronary calcium scores can be reliably determined on contrast-enhanced cardiac CT * This score can accurately risk stratify patients * Elimination of a dedicated calcium scan reduces patient radiation by a third. PMID- 26253257 TI - Pancreatic neuroendocrine tumour (PNET): Staging accuracy of MDCT and its diagnostic performance for the differentiation of PNET with uncommon CT findings from pancreatic adenocarcinoma. AB - PURPOSE: To investigate staging accuracy of multidetector CT (MDCT) for pancreatic neuroendocrine tumour (PNET) and diagnostic performance for differentiation of PNET from pancreatic adenocarcinoma. MATERIAL AND METHODS: We included 109 patients with surgically proven PNET (NETG1 = 66, NETG2 = 31, NEC = 12) who underwent MDCT. Two reviewers assessed stage and presence of predefined CT findings. We analysed the relationship between CT findings and tumour grade. Using PNETs with uncommon findings, we also estimated the possibility of PNET or adenocarcinoma. RESULTS: Accuracy for T stage was 85-88% and N-metastasis was 83 89%. Common findings included well circumscribed, homogeneously enhanced, hypervascular mass, common in lower grade tumours (p < 0.05). Uncommon findings included ill-defined, heterogeneously enhanced, hypovascular mass and duct dilation, common in higher grade tumours (p < 0.05). Using 31 PNETs with uncommon findings, diagnostic performance for differentiation from adenocarcinoma was 0.760-0.806. Duct dilatation was an independent predictor for adenocarcinoma (Exp(B) = 4.569). PNETs with uncommon findings were associated with significantly worse survival versus PNET with common findings (62.7 vs. 95.7 months, p < 0.001). CONCLUSION: MDCT is useful for preoperative evaluation of PNET; it not only accurately depicts the tumour stage but also prediction of tumour grade, because uncommon findings were more common in higher grade tumours. KEY POINTS: * CT accurately depicts the T stage and node metastasis of PNET. * Uncommon findings were more common in higher grade tumours. * CT information may be beneficial for optimal therapeutic planning. PMID- 26253258 TI - Prostate diffusion-weighted imaging at 3T: effect of intravenous gadobutrol administration. AB - OBJECTIVE: To investigate whether gadolinium-based contrast agent (GBCA) administration significantly affects diffusion-weighted imaging (DWI) at 3 T in the evaluation of prostate cancer and benign tissue. METHOD: Thirty-four consecutive patients with surgically proven prostate cancer underwent preoperative DWI at 3 T before and after GBCA administration. Exponential apparent diffusion coefficient (EADC) and ADC maps were developed from DWI data. The ADC and EADC values pre- and post-contrast were measured in the cancer and benign tissue, respectively. The signal-to-noise ratio (SNR) and contrast-to noise ratio (CNR) were evaluated on pre- and post-contrast DWI. RESULTS: The ADC and EADC values of the cancer and benign transition zone were not significantly different between pre- and post-contrast, respectively (P > 0.05), while those in the benign peripheral zone were significantly different (P = 0.030 and 0.037, respectively). In all tissues, the SNRs and CNRs of the DWI, ADC map and EADC map were not significantly different between pre- and post-contrast (P > 0.05). Between pre- and post-contrast, ADC and EADC values showed excellent agreement (intraclass correlation coefficient >= 0.894) and variability of <=3.2 %. CONCLUSION: Prostate 3 T-DWI after GBCA administration may be used without a significant difference in SNR or CNR, with minimal variability of the cancer ADC and EADC values. KEY POINTS: * ADCs and EADCs have excellent agreement before and after gadobutrol administration. * SNRs of prostate DWI are similar before and after gadobutrol administration. * CNRs of cancers are similar between pre- and post-contrast DWI. PMID- 26253259 TI - Prognostic value of CT findings to predict survival outcomes in patients with pancreatic neuroendocrine neoplasms: a single institutional study of 161 patients. AB - OBJECTIVES: To evaluate the prognostic value of CT to predict recurrence-free and overall survival in patients with pancreatic neuroendocrine neoplasms (PanNENs). METHODS: Between January 2004 and December 2012, 161 consecutive patients who underwent preoperative triphasic CT and surgical resection with curative intent for PanNENs were identified. The tumour consistency, margin, presence of calcification, pancreatic duct dilatation, bile duct dilatation, vascular invasion, and hepatic metastases were evaluated. The tumour size, arterial enhancement ratio, and portal enhancement ratio were measured. The Cox proportional hazard model was used to determine the association between CT features and recurrence-free survival and overall survival. RESULTS: By multivariate analysis, tumour size (>3 cm) (hazard ratio, 3.314; p = 0.006), portal enhancement ratio (<=1.1) (hazard ratio, 2.718; p = 0.006), and hepatic metastases (hazard ratio, 4.374; p = 0.003) were independent significant variables for worse recurrence-free survival. Portal enhancement ratio (<=1.1) (hazard ratio, 5.951; p = 0.001) and hepatic metastases (hazard ratio, 4.122; p = 0.021) were independent significant variables for worse overall survival. CONCLUSIONS: Portal enhancement ratio (<=1.1) and hepatic metastases assessed on CT were common independent prognostic factors for worse recurrence-free survival and overall survival in patients with PanNENs. KEY POINTS: * CT is useful to predict survival outcomes in patients with PanNENs. * Survival outcomes are associated with portal enhancement ratio and hepatic metastases. * Portal enhancement ratio is prognostic CT biomarker in patients with PanNENs. PMID- 26253260 TI - Ultrasound guidance to perform intra-articular injection of gadolinium-based contrast material for magnetic resonance arthrography as an alternative to fluoroscopy: the time is now. AB - Magnetic resonance (MR) imaging has been definitively established as the reference standard in the evaluation of joints in the body. Similarly, magnetic resonance arthrography has emerged as a technique that has been proven to increase significantly the diagnostic performance if compared with conventional MR imaging, especially when dealing with fibrocartilage and articular cartilage abnormalities. Diluted gadolinium can be injected in the joint space using different approaches: under palpation using anatomic landmarks or using an imaging guidance, such as fluoroscopy, computed tomography, or ultrasound. Fluoroscopy has been traditionally used, but the involvement of ionizing radiation should represent a remarkable limitation of this modality. Conversely, ultrasound has emerged as a feasible, cheap, quick, and radiation-free modality that can be used to inject joints, with comparable accuracy of fluoroscopy. In the present paper, we discuss the advantages and disadvantages of using fluoroscopy or ultrasound in injecting gadolinium-based contrast agents in joints to perform magnetic resonance arthrography, also in view of the new EuroSAFE Imaging initiative promoted by the European Society of Radiology and the recent updates to the European Atomic Energy Community 2013/59 directive on the medical use of ionizing radiation. KEY POINTS: * Intra-articular contrast agent injection can be performed using different imaging modalities * Fluoroscopy is widely used, but uses ionizing radiation * Ultrasound is an accurate, quick, and radiation free modality for joint injection * X-rays should be avoided when other radiation free modalities can be used. PMID- 26253261 TI - Perfusion- and pattern-based quantitative CT indexes using contrast-enhanced dual energy computed tomography in diffuse interstitial lung disease: relationships with physiologic impairment and prediction of prognosis. AB - OBJECTIVES: To evaluate automated texture-based segmentation of dual-energy CT (DECT) images in diffuse interstitial lung disease (DILD) patients and prognostic stratification by overlapping morphologic and perfusion information of total lung. METHODS: Suspected DILD patients scheduled for surgical biopsy were prospectively included. Texture patterns included ground-glass opacity (GGO), reticulation and consolidation. Pattern- and perfusion-based CT measurements were assessed to extract quantitative parameters. Accuracy of texture-based segmentation was analysed. Correlations between CT measurements and pulmonary function test or 6-minute walk test (6MWT) were calculated. Parameters of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP) and non IPF/UIP were compared. Survival analysis was performed. RESULTS: Overall accuracy was 90.47% for whole lung segmentation. Correlations between mean iodine values of total lung, 50-97.5th (%) attenuation and forced vital capacity or 6MWT were significant. Volume of GGO, reticulation and consolidation had significant correlation with DLco or SpO2 on 6MWT. Significant differences were noted between IPF/UIP and non-IPF/UIP in 6MWT distance, mean iodine value of total lung, 25 75th (%) attenuation and entropy. IPF/UIP diagnosis, GGO ratio, DILD extent, 25 75th (%) attenuation and SpO2 on 6MWT showed significant correlations with survival. CONCLUSION: DECT combined with pattern analysis is useful for analysing DILD and predicting survival by provision of morphology and enhancement. KEY POINTS: * Dual-energy CT (DECT) produces morphologic and parenchymal enhancement information. * Automated lung segmentation enables analysis of disease extent and severity. * This prospective study showed value of DECT in DILD patients. * Parameters on DECT enable characterization and survival prediction of DILD. PMID- 26253262 TI - Chronic cadmium exposure in rats produces pancreatic impairment and insulin resistance in multiple peripheral tissues. AB - Previous studies have linked cadmium exposure to disturbances in carbohydrate and lipid metabolism. In this study we investigate the effects in Wistar rats of an oral cadmium exposure in drinking water on carbohydrates, lipids and insulin release. Also, using mathematical models we studied the effect of cadmium on insulin resistance and sensitivity in liver, muscle, adipose and cardiovascular tissue. Cadmium exposure induced hyperglycemia, increased insulin release after a glucose load, and caused increases in serum triglycerides, cholesterol, LDL-C and VLDL-C, and a decrease of HDL-C. In addition, there was an accumulation of cadmium in pancreas and an increase of insulin. After exposure, HOMA-IR was increased, while the HOMA-S%, QUICKI and Matsuda-DeFronzo indexes showed decreases. A decrease of insulin sensitivity was shown in muscle and liver. Additionally, cadmium increases insulin resistance in the liver, adipose tissue and cardiovascular system. Finally, beta-cell functioning was evaluated by HOMA B% index and insulin disposition index, which were decreased, while insulin generation index increased. In conclusion, cadmium increases insulin release, induces hyperglycemia and alters lipid metabolism. These changes likely occur as a consequence of reduced sensitivity and increased insulin resistance in multiple insulin-dependent and non-dependent tissues, producing a biochemical phenotype similar to metabolic syndrome and diabetes. PMID- 26253263 TI - Role of miR-148a in cutaneous squamous cell carcinoma by repression of MAPK pathway. AB - Dysregulation of miRNAs is a common feature in human cancers, but there are lack of studies on roles of miRNAs in cutaneous squamous cell carcinoma (CSCC). miR 148a, a member of the miR-148/152 family, has been found to be downregulated in different types of cancer and its role in CSCC remains unknown. The study was aimed to investigate the expression and cellular function of miR-148a in CSCC. We found that miR-148a was underexpressed in CSCC tissues and cell lines. MAP3K2, MAP3K4 and MAP3K9 were predicted as the target genes of miR-148a and the latter two genes were verified as the target genes of miR-148a in CSCC cells. Importantly, we demonstrated that the overexpression of miR-148a significantly inhibited CSCC cell proliferation and metastasis via down-regulation of MAP3K9 and MAP3K4 expression. MAP3K4 and MAP3K9 were negatively associated with the expression of miR-148a in CSCC tissues. Our results suggested indicated that miR 148a acts as a tumor suppressor of CSCC via inhibiting MAPK pathway. These results may provide a promising alterative strategy for CSCC therapy. PMID- 26253264 TI - Metabolomic biomarkers in diabetic kidney diseases--A systematic review. AB - Diabetic kidney disease (DKD) is generally characterized by increasing albuminuria in diabetic patients; however, few biomarkers are available to facilitate early diagnosis of this disease. The application of metabolomics has shown promises addressing this need. In this review, we conducted a search about metabolomic biomarkers in DKD patients through MEDLINE, EMBASE, and Cochrane Database up to the end of March, 2015. 12 eligible studies were selected and evaluated subsequently through the use of QUADOMICS, a quality assessment tool. 7 of the 12 included studies were classified as 'high quality'. We also recorded specific study characteristics including participants' characteristics, metabolomic techniques, sample types, and significantly altered metabolites between DKD and control groups. Products of lipid metabolisms including esterified and non-esterified fatty acids, carnitines, phospholipids and metabolites involved in branch-chained amino acids and aromatic amino acids metabolisms were frequently affected biomarkers of DKD. Other differential metabolites were also found, while some of their associations with DKD were unclear. Further more studies are required to test these findings in larger, diverse ethnic populations with elaborate study designs, and finally we could translate them into the benefits of DKD patients. PMID- 26253265 TI - Treatment of Calves with Bovine Respiratory Disease: Duration of Therapy and Posttreatment Intervals. AB - When treating bovine respiratory disease, it is important to consider the decision to initiate treatment, the treatment regimen used, and whether to continue treatment. It is necessary to define the duration of drug exposure and when a success/failure decision will be made. No data are available to define the optimal duration of antimicrobial exposure. A pattern seen in human pneumonia studies is that shorter durations of therapy were equivalent with longer durations. Some studies suggest defining success or failure based on pharmacokinetics and pharmacodynamics may lead to earlier than optimal intervention. Optimal intervals are best defined by randomized clinical trials. PMID- 26253266 TI - Feedlot Acute Interstitial Pneumonia. AB - Acute interstitial pneumonia (AIP) of feedlot cattle is a sporadically occurring respiratory condition that is often fatal. Affected cattle have a sudden onset of labored breathing. There is no confirmed effective treatment of feedlot AIP; however, administration of antibiotics effective against common bacterial respiratory pathogens and nonsteroidal anti-inflammatory drugs, especially aspirin, has been recommended. Protective strategies are not well defined, but efforts to limit dust exposure and heat stress; to ensure consistent formulation, mixing, and delivery of feed; and to identify and treat infectious respiratory disease in a timely manner may decrease rates of feedlot AIP. PMID- 26253267 TI - The functional diversity of Drosophila Ino80 in development. AB - Ino80 is well known as a chromatin remodeling protein with the catalytic function of DNA dependent ATPase and is highly conserved across phyla. Ino80 in human and Drosophila is known to form the Ino80 complex in association with the DNA binding protein Ying-Yang 1 (YY1)/Pleiohomeotic (Pho) the Drosophila homologue. We have earlier reported that Ino80 sub-family of proteins has two functional domains, namely, the DNA dependent ATPase and the DNA binding domain. In the background of the essential role of dIno80 in development, we provide evidence of Pho independent function of dIno80 in development and analyze the dual role of dIno80 in activation as well as repression in the context of the homeotic gene Scr (sex combs reduced) in imaginal discs. This differential effect of dIno80 in different imaginal discs suggests the contextual function of dIno80 as an Enhancer of Trithorax and Polycomb (ETP). We speculate on the role of dIno80 as a chromatin remodeler on one hand and a potential recruiter of epigenetic regulatory complexes on the other. PMID- 26253268 TI - Substance use among Dutch homeless people, a follow-up study: prevalence, pattern and housing status. AB - BACKGROUND: Previous studies have shown that substance use among homeless people is a prevalent problem that is associated with longer durations of homelessness. Most studies of substance use among the homeless were carried out outside Europe and have limited generalizability to European countries. This study therefore aimed to address the prevalence of substance use among homeless people in the Netherlands, the pattern of their use and the relationship with housing status at follow-up. METHODS: This study included 344 participants (67.1% of the initial cohort) who were followed from baseline to 18 months after the baseline interview. Multinomial logistic regression analyses examined the relationship between substance use and housing status. RESULTS: The most reported substances which were used among these homeless people were cannabis (43.9%) and alcohol (>=5 units on one occasion) (30.7%). Other substances were used by around 5% or less of the participants. Twenty-seven percent were classified as substance misuser and 20.9% as substance dependent. The odds to be marginally housed (4.14) or institutionalized (2.12) at follow-up compared to being housed of participants who were substance users were significantly higher than those of participants who did not use substances. The odds to be homeless were more than twice as high (2.80) for participants who were substance dependent compared with those who were not. CONCLUSION: Homeless people who use substances have a more disadvantageous housing situation at follow-up than homeless people who do not use substances. Attention is needed to prevent and reduce long-term homelessness among substance using homeless people. PMID- 26253270 TI - New Approaches to Marine Conservation Through the Scaling Up of Ecological Data. AB - In an era of rapid global change, conservation managers urgently need improved tools to track and counter declining ecosystem conditions. This need is particularly acute in the marine realm, where threats are out of sight, inadequately mapped, cumulative, and often poorly understood, thereby generating impacts that are inefficiently managed. Recent advances in macroecology, statistical analysis, and the compilation of global data will play a central role in improving conservation outcomes, provided that global, regional, and local data streams can be integrated to produce locally relevant and interpretable outputs. Progress will be assisted by (a) expanded rollout of systematic surveys that quantify species patterns, including some carried out with help from citizen scientists; (b) coordinated experimental research networks that utilize large scale manipulations to identify mechanisms underlying these patterns; PMID- 26253269 TI - Does Preoperative Antimicrobial Prophylaxis Influence the Diagnostic Potential of Periprosthetic Tissues in Hip or Knee Infections? AB - BACKGROUND: Undiagnosed low-grade prosthetic joint infections (PJI) are recognized as an important reason for early failure of presumably aseptic revisions. Preoperatively administered antimicrobial prophylaxis reduces the incidence of PJI but it may reduce the sensitivity of microbiologic periprosthetic tissue cultures and consequently increase the incidence of undiagnosed septic prosthetic joint failures, which can lead to catastrophic serial revisions. QUESTIONS/PURPOSES: We wished to determine whether administration of preoperative antibiotics decreases the likelihood of diagnosing PJI in patients undergoing revision hip or knee arthroplasty in whom infection is suspected. METHODS: We prospectively enrolled and evaluated 40 patients (29 with THAs and 11 with TKAs) who met the following inclusion criteria: older than 18 years, with suspected PJI of unknown cause, undergoing surgical revision. After arthrotomy, three tissue samples were obtained for microbiologic analysis and diagnosis, and antimicrobial prophylaxis (cefazolin 2 g intravenously) then was administered. Later during the procedure, but before debridement and irrigation, the second set of three tissue samples was obtained from the same surgical area and was cultured. Tissue concentration of prophylactic antibiotic was verified with the second set of samples. A positive culture result was defined as one or more positive cultures (growth on agar at or before 14 days). We then compared the yield on the microbiologic cultures obtained before administration of antibiotics with the yield on the cultures obtained after antibiotics were administered. An a priori analysis was performed; with the numbers available, we had 98% power to detect a difference in diagnostic sensitivity of 33%. RESULTS: With the numbers available, we found no difference in the likelihood that an infection would be diagnosed between the samples obtained before and after administration of antimicrobial prophylaxis (odds ratio [OR] for positive microbial culture = 0.99; 95% CI, 0.40-2.48; p = 0.99). All measured tissue concentrations of cefazolin were greater than the minimum inhibitory concentration, therefore we found that antibiotic prophylaxis was adequate at the time of second-set tissue specimen recovery. CONCLUSIONS: Results from this small, prospective series suggest that preoperative antimicrobial prophylaxis may be administered safely even in patients undergoing revision hip or knee arthroplasty in which microbiologic sampling is planned without compromising the diagnostic sensitivity of tissue sample cultures. However, before applying our results more generally, our findings need to be confirmed in larger, multicenter studies that would allow evaluation by sex, procedure, bacteriology, and other potentially important factors. LEVEL OF EVIDENCE: Level I, diagnostic study. PMID- 26253271 TI - Visualizing and Quantifying Oceanic Motion. AB - Here I review the use of two highly complementary acoustical technologies for measuring currents in the ocean: acoustically tracked neutrally buoyant floats and vessel-mounted acoustic Doppler current profilers (ADCPs). The beauty of floats lies in their ability to efficiently and accurately visualize fluid motion in fronts and vortices and the dispersion caused by mesoscale eddy processes. Floats complement classical hydrography by articulating mechanisms and pathways by which waters spread out from their source region. Vessel-mounted ADCPs can profile the water column at O(1 km) horizontal resolution to depths greater than 1,000 m. These vessel-based scans capture in detail the cross-stream structure of fronts and eddies as well as the impact of bathymetry on currents. Sustained sampling along selected routes builds up valuable databases both for statistical studies of the submesoscale velocity field and for accurate estimates of fluid transport, as well as how these vary over time. PMID- 26253272 TI - 18Fluorocholine PET/CT in parathyroid carcinoma: a new tool for disease staging? PMID- 26253273 TI - The efficacy of (177)Lu-labelled peptide receptor radionuclide therapy in patients with neuroendocrine tumours: a meta-analysis. AB - PURPOSE: This study was performed to evaluate the efficacy of (177)Lu-labelled peptide receptor radionuclide therapy (PRRT) in patients with inoperable or metastatic neuroendocrine tumours (NETs). METHODS: Systematic searches of MEDLINE and EMBASE databases were performed using the keywords of "neuroendocrine", "(177)Lu" and "prognosis". All published studies of neuroendocrine tumours treated with (177)Lu-labelled radiopharmaceuticals and evaluated with either Response Evaluation Criteria in Solid Tumours (RECIST) 1.0 or Southwest Oncology Group (SWOG) criteria or both were included. If there was more than one published study from the same institution, only one report with the information most relevant to this study was included. Each response criteria group was analysed for disease response rates and disease control rates, defined as the percentages of patients with complete response (CR) + partial response (PR), and CR + PR + stable disease (SD), respectively, to a therapeutic intervention in clinical trials of anticancer agents. The pooled proportions are presented with both a fixed-effects model and random-effects model. RESULTS: Six studies with 473 patients (4 in RECIST criteria group with 356 patients, 3 in SWOG criteria group with 375 patients and 1 in both groups) were included. The RECIST criteria group demonstrated disease response rates ranging between 17.6 and 43.8% with a pooled effect of 29% [95% confidence interval (CI) 24-34%]. Disease control rates ranged from 71.8 to 100%. The random-effects model showed an average disease control rate of 81% (95% CI 71-91%). The SWOG criteria group demonstrated disease response rates ranging between 7.0 and 36.5% with a pooled effect of 23% (95% CI 11-38%). Disease control rates ranged from 73.9 to 89.1%. The random-effects model showed an average disease control rate of 82% (95% CI 71-91%). CONCLUSION: (177)Lu-labelled PRRT is an effective treatment option for patients with inoperable or metastatic NETs. PMID- 26253274 TI - Liquid Li based neutron source for BNCT and science application. AB - Liquid lithium (Li) is a candidate material for a target of intense neutron source, heat transfer medium in space engines and charges stripper. For a medical application of BNCT, epithermal neutrons with least energetic neutrons and gamma ray are required so as to avoid unnecessary doses to a patient. This is enabled by lithium target irradiated by protons at 2.5 MeV range, with utilizing the threshold reaction of (7)Li(p,n)(7)Be at 1.88 MeV. In the system, protons at 2.5 MeV penetrate into Li layer by 0.25 mm with dissipating heat load near the surface. To handle it, thin film flow of high velocity is important for stable operation. For the proton accelerator, electrostatic type of the Schnkel or the tandem is planned to be employed. Neutrons generated at 0.6 MeV are gently moderated to epithermal energy while suppressing accompanying gamma-ray minimum by the dedicated moderator assembly. PMID- 26253276 TI - Analysis of the immunomodulatory properties of two heat-killed mycobacterial preparations in a human whole blood model. AB - The significant role played by mycobacteria in modulating immune responses through enhancing the crosstalk between innate and adaptive immunity has been highlighted in several studies. Owing to their unique antigenic profile, heat killed (HK) preparations of rapid-growing mycobacteria, currently undergoing clinical development, have been assessed as adjuvant therapy in various diseases. The purpose of this study is to investigate the regulation of leukocyte surface receptors, in whole blood from healthy donors, following in vitro stimulation with HK Mycobacterium vaccae (M. vaccae) or M. obuense. We have demonstrated the ability of both mycobacterial preparations to target monocytes and neutrophils and to regulate the surface expression of selected adhesion receptors, antigen presenting and costimulatory receptors, pattern recognition receptors, complement and Fc receptors, as well as cytokine/chemokine receptors. Toll-like receptors (TLRs) 1 and 2 were also shown to be involved in mediating the M. obuense-induced upregulation of selected surface receptors on monocytes. Whole blood stimulation with M. vaccae or M. obuense resulted in a significant increase in the secretion of a specific set of cytokines and chemokines. Both mycobacterial preparations induced strong antigen-specific proliferative responses in peripheral blood mononuclear cells. Collectively, our data shows that M. vaccae and M. obuense have the potential to act as potent immunomodulators. Future research based on these findings may reveal novel immune pathways induced by these preparations with potential implication for their use in diverse immunotherapeutic approaches. PMID- 26253275 TI - Functional and therapeutic significance of protein kinase D enzymes in invasive breast cancer. AB - The protein kinase D (PKD) family members, PKD1, PKD2 and PKD3 constitute a family of serine/threonine kinases that are essential regulators of cell migration, proliferation and protein transport. Multiple types of cancers are characterized by aberrant expression of PKD isoforms. In breast cancer PKD isoforms exhibit distinct expression patterns and regulate various oncogenic processes. In highly invasive breast cancer, the leading cause of cancer associated deaths in females, the loss of PKD1 is thought to promote invasion and metastasis, while PKD2 and upregulated PKD3 have been shown to be positive regulators of proliferation, chemoresistance and metastasis. In this review, we examine the differential expression pattern, mechanisms of regulation and contributions made by each PKD isoform to the development and maintenance of invasive breast cancer. In addition, we discuss the potential therapeutic approaches for targeting PKD in this disease. PMID- 26253277 TI - Intraosseous anaesthesia in children with 4 % articaine and epinephrine 1:400,000 using computer-assisted systems. AB - AIM: To assess retrospectively the efficacy of computer-assisted intraosseous anaesthesia (CAIO) in children using an anaesthetic solution with a lower concentration of epinephrine (1:400,000). METHODS: In a retrospective study, CAIO was evaluated in healthy children and adolescents for restorative and endodontic treatments, uncomplicated tooth extractions or scalings using articaine 4 % plus epinephrine 1:400,000. Anaesthesia was performed in children who showed enough compliance (score of 0-3 according to modified behaviour Venham scale). Efficacy, amount of anaesthetic solution as well as need of a complementary injection was assessed. RESULTS: A total of 421 consecutive sessions were performed on 278 patients aged 7.1 +/- 2.9 years with 518 teeth involved in the anaesthetic process and analysed process. When teeth to be anaesthetised were considered, the overall success rate was 97.2 %. In most of the cases, only 0.9 mL was needed to achieve anaesthesia. Permanent teeth needed significantly more anaesthetics than primary teeth. Sensitivity of the teeth anaesthetized reappeared in 5.7 % of cases after 30-60 min of treatment. CONCLUSIONS: These results suggest that CAIO with 4 % articaine and epinephrine diluted 1:400,000 can be an alternative to usual infiltration techniques or IO with epinephrine at a higher concentration for most of treatments in primary and permanent teeth. Further studies are needed to evaluate its efficacy in permanent teeth in case of endodontic treatment or extraction. PMID- 26253279 TI - Action of methyl-, propyl- and butylparaben on GPR30 gene and protein expression, cAMP levels and activation of ERK1/2 and PI3K/Akt signaling pathways in MCF-7 breast cancer cells and MCF-10A non-transformed breast epithelial cells. AB - In the present study, we examined cAMP levels and activation of the MAPK/ERK1/2 and PI3K/Akt signaling pathways in response to the actions of parabens on GPR30 in MCF-7 and MCF-10A cells. Cells were exposed to methyl-, propyl- or butylparaben at a concentration of 20nM; 17-beta-estradiol (10nM) was used as a positive control. 17beta-estradiol and all tested parabens increased GPR30 gene and protein expression in MCF-7 and MCF-10A cells. No parabens affected cAMP levels in either cell line, with the exception of propylparaben in MCF-10A cells. 17beta-estradiol, propylparaben, and butylparaben increased phosphorylation of ERK1/2 in MCF-7 cells, whereas 17beta-estradiol, methyl- and butylparaben, but not propylparaben, increased phosphorylation of ERK1/2 in MCF-10A cells. Akt activation was noted only in MCF-7 cells and only with propylparaben treatment. Collectively, the data presented here point to a nongenomic mechanism of action of parabens in activation GPR30 in both cancer and non-cancer breast cell lines through betagamma dimer-mediated activation of the ERK1/2 pathway, but not the cAMP/PKA pathway. Moreover, among investigated parabens, propylparaben appears to inhibit apoptosis in cancer cells through activation of Akt kinases, confirming conclusions suggested by our previously published data. Nevertheless, continuing research on the carcinogenic action of parabens is warranted. PMID- 26253280 TI - Size and site dependent biological hazard potential of particulate matters collected from different heights at the vicinity of a building construction. AB - Although building constructions are a recurring part of urbanization, the health risk of particulate matters (PM) originating from such activities have seldom been subjected to detailed studies. We sought to characterize the relative risk of air borne PM collected from different heights (ground and top floor) of a building adjacent to a building under early phase of construction. We determined the physico-chemical properties such as size and shape, elemental composition and surface charge of the PM. The oxidative stress dependent cytotoxic and pro inflammatory responses were assessed in BEAS-2B and RAW 264.7 cell lines using high-content-screening platforms. In comparison to top floor, the total mass of PM collected from ground floor was two-three folds higher and the mass fraction was dominated by PM20-35. Elemental analysis showed abundance of Si, Al, K, Ca and Fe in bigger PM while for PM0.25-0.5 it was mostly constituted by C and crystals rich in S and K. PM caused NFkappaB activation, secretion of pro inflammatory cytokines and cytotoxicity wherein PM0.25-0.5 was the most potent among the tested PM. Estimated exposure level and lung burden together with the data on hazard potential were used for developing a MATLAB based risk-assessment model which suggested that the potential for health risk is relatively higher at the ground floor. Our studies demonstrated differences in, relative abundance of PM, their physicochemical and biological properties collected from different heights adjacent to a construction site and showed that relative health risk is higher at the ground floor. PMID- 26253281 TI - Risk Factors for Occult Uterine Sarcoma Among Women Undergoing Minimally Invasive Gynecologic Surgery. AB - STUDY OBJECTIVE: To determine factors that can identify a population at increased risk for uterine leiomyosarcoma. DESIGN: Retrospective case-control study (Canadian Task Force classification II-2). SETTING: University teaching hospitals. PATIENTS: Seventy-two women who underwent minimally invasive gynecologic surgery for presumed leiomyoma. Patients diagnosed with leiomyosarcoma (cases) were matched with up to 4 controls on age, year of surgery, and surgeon specialty. INTERVENTION: Cases were identified through the pathology database, and the diagnosis of leiomyosarcoma or leiomyoma was confirmed by gynecologic pathologists. The cumulative risk of leiomyosarcoma was calculated, and factors predictive of elevated risk for leiomyosarcoma were investigated using conditional logistic regression. MEASUREMENTS AND MAIN RESULTS: Fifteen patients with the diagnosis of inadvertently morcellated leiomyosarcoma were identified and matched with 57 controls. The cumulative risk of diagnosing uterine leiomyosarcoma on pathology after performing minimally invasive gynecologic surgery with morcellation was 0.19% (95% confidence interval [CI], 0.06%-0.56%). The presence of a hematocrit value < 30% (adjusted odds ratio [aOR], 20; 95% CI, 1.08-100; p = .05) was independently associated with the diagnosis of uterine leiomyosarcoma on multivariate analysis. Increased myoma size (aOR, 9.73; 95% CI, 0.75-1.26; p = .08) and presence of a solitary myoma (aOR, 3.85; 95% CI, 0.65-25; p = .14) were associated with a greater risk of uterine leiomyosarcoma; however, the difference was not statistically significant. CONCLUSION: Anemia and myoma size >7 cm may be associated with occult leiomyosarcoma; however, these criteria are not sufficiently discriminatory to allow for preoperative identification of patients with uterine sarcoma. Future large multicenter studies are needed to further investigate these findings and the discovery of innovative ways to detect uterine leiomyosarcoma are urgently needed. PMID- 26253278 TI - mTOR and its tight regulation for iNKT cell development and effector function. AB - Invariant NKT (iNKT) cells, which express the invariant Valpha14Jalpha18 TCR that recognizes lipid antigens, have the ability to rapidly respond to agonist stimulation, producing a variety of cytokines that can shape both innate and adaptive immunity. iNKT cells have been implicated in host defense against microbial infection, in anti-tumor immunity, and a multitude of diseases such as allergies, asthma, graft versus host disease, and obesity. Emerging evidence has demonstrated crucial role for mammalian target of rapamycin (mTOR) in immune cells, including iNKT. In this review we will discuss current understanding of how mTOR and its tight regulation control iNKT cell development, effector lineage differentiation, and function. PMID- 26253282 TI - Analysis of A-phase transitions during the cyclic alternating pattern under normal sleep. AB - An analysis of the EEG signal during the B-phase and A-phases transitions of the cyclic alternating pattern (CAP) during sleep is presented. CAP is a sleep phenomenon composed by consecutive sequences of A-phases (each A-phase could belong to a possible group A1, A2 or A3) observed during the non-REM sleep. Each A-phase is separated by a B-phase which has the basal frequency of the EEG during a specific sleep stage. The patterns formed by these sequences reflect the sleep instability and consequently help to understand the sleep process. Ten recordings from healthy good sleepers were included in this study. The current study investigates complexity, statistical and frequency signal properties of electroencephalography (EEG) recordings at the transitions: B-phase--A-phase. In addition, classification between the onset-offset of the A-phases and B-phase was carried out with a kNN classifier. The results showed that EEG signal presents significant differences (p < 0.05) between A-phases and B-phase for the standard deviation, energy, sample entropy, Tsallis entropy and frequency band indices. The A-phase onset showed values of energy three times higher than B-phase at all the sleep stages. The statistical analysis of variance shows that more than 80% of the A-phase onset and offset is significantly different from the B-phase. The classification performance between onset or offset of A-phases and background showed classification values over 80% for specificity and accuracy and 70% for sensitivity. Only during the A3-phase, the classification was lower. The results suggest that neural assembles that generate the basal EEG oscillations during sleep present an over-imposed coordination for a few seconds due to the A-phases. The main characteristics for automatic separation between the onset-offset A phase and the B-phase are the energy at the different frequency bands. PMID- 26253283 TI - A signal invariant wavelet function selection algorithm. AB - This paper addresses the problem of mother wavelet selection for wavelet signal processing in feature extraction and pattern recognition. The problem is formulated as an optimization criterion, where a wavelet library is defined using a set of parameters to find the best mother wavelet function. For estimating the fitness function, adopted to evaluate the performance of the wavelet function, analysis of variance is used. Genetic algorithm is exploited to optimize the determination of the best mother wavelet function. For experimental evaluation, solutions for best mother wavelet selection are evaluated on various biomedical signal classification problems, where the solutions of the proposed algorithm are assessed and compared with manual hit-and-trial methods. The results show that the solutions of automated mother wavelet selection algorithm are consistent with the manual selection of wavelet functions. The algorithm is found to be invariant to the type of signals used for classification. PMID- 26253284 TI - An alternative approach to approximate entropy threshold value (r) selection: application to heart rate variability and systolic blood pressure variability under postural challenge. AB - This study presents an alternative approach to approximate entropy (ApEn) threshold value (r) selection. There are two limitations of traditional ApEn algorithm: (1) the occurrence of undefined conditional probability (CPu) where no template match is found and (2) use of a crisp tolerance (radius) threshold 'r'. To overcome these limitations, CPu is substituted with optimum bias setting E opt which is found by varying E from (1/N - m) to 1 in the increments of 0.05, where N is the length of the series and m is the embedding dimension. Furthermore, an alternative approach for selection of r based on binning the distance values obtained by template matching to calculate ApEnbin is presented. It is observed that ApEnmax, ApEnchon and ApEnbin converge for E opt = 0.6 in 50 realizations (n = 50) of random number series of N = 300. Similar analysis suggests E opt = 0.65 and E opt = 0.45 for 50 realizations each of fractional Brownian motion and MIX(P) series (Lu et al. in J Clin Monit Comput 22(1):23-29, 2008). E opt = 0.5 is suggested for heart rate variability (HRV) and systolic blood pressure variability (SBPV) signals obtained from 50 young healthy subjects under supine and upright position. It is observed that (1) ApEnbin of HRV is lower than SBPV, (2) ApEnbin of HRV increases from supine to upright due to vagal inhibition and (3) ApEnbin of BPV decreases from supine to upright due to sympathetic activation. Moreover, merit of ApEnbin is that it provides an alternative to the cumbersome ApEnmax procedure. PMID- 26253286 TI - Fast spatially resolved exhaust gas recirculation (EGR) distribution measurements in an internal combustion engine using absorption spectroscopy. AB - Exhaust gas recirculation (EGR) in internal combustion engines is an effective method of reducing NOx emissions while improving efficiency. However, insufficient mixing between fresh air and exhaust gas can lead to cycle-to-cycle and cylinder-to-cylinder non-uniform charge gas mixtures of a multi-cylinder engine, which can in turn reduce engine performance and efficiency. A sensor packaged into a compact probe was designed, built and applied to measure spatiotemporal EGR distributions in the intake manifold of an operating engine. The probe promotes the development of more efficient and higher-performance engines by resolving high-speed in situ CO2 concentration at various locations in the intake manifold. The study employed mid-infrared light sources tuned to an absorption band of CO2 near 4.3 MUm, an industry standard species for determining EGR fraction. The calibrated probe was used to map spatial EGR distributions in an intake manifold with high accuracy and monitor cycle-resolved cylinder specific EGR fluctuations at a rate of up to 1 kHz. PMID- 26253285 TI - Ovine HSP90AA1 gene promoter: functional study and epigenetic modifications. AB - When environmental temperatures exceed a certain threshold, the upregulation of the ovine HSP90AA1 gene is produced to cope with cellular injuries caused by heat stress. It has been previously pointed out that several polymorphisms located at the promoter region of this gene seem to be the main responsible for the differences in the heat stress response observed among alternative genotypes in terms of gene expression rate. The present study, focused on the functional study of those candidate polymorphisms by electrophoretic mobility shift assay (EMSA) and in vitro luciferase expression assays, has revealed that the observed differences in the transcriptional activity of the HSP90AA1 gene as response to heat stress are caused by the presence of a cytosine insertion (rs397514115) and a C to G transversion (rs397514116) at the promoter region. Next, we discovered the presence of epigenetic marks at the promoter and along the gene body founding an allele-specific methylation of the rs397514116 mutation in DNA extracted from blood samples. This regulatory mechanism interacts synergistically to modulate gene expression depending on environmental circumstances. Taking into account the results obtained, it is suggested that the transcription of the HSP90AA1 ovine gene is regulated by a cooperative action of transcription factors (TFs) whose binding sites are polymorphic and where the influence of epigenetic events should be also taken into account. PMID- 26253288 TI - Weighing the Facts: A Systematic Review of Expected Patterns of Weight Loss in Full-Term, Breastfed Infants. AB - All breastfeeding infants lose some weight in the early days of life. Conventionally, 5% to 7% loss of birth weight has been accepted as the normal and expected amount of weight loss before infants begin to gain weight steadily. When infants lose more than 7% of their birth weight, breastfeeding adequacy is sometimes questioned and formula supplementation is often given. Despite the fact that 5% to 7% is well known and commonly cited, little reliable evidence exists that supports use of this figure as a guide to practice. A systematic review of studies that focused on infant weight loss was conducted. The main objective was to determine the mean amount of weight loss for healthy, full-term exclusively breastfed infants after birth. One previous review and 9 primary studies published since 2008 were examined. The reported mean infant weight loss ranged widely among studies from 3.79% to 8.6%. The point at which most infants have lost the most amount of weight occurs 2 to 4 days after birth. Close examination of the studies, however, revealed significant methodological flaws in the research. Study limitations commonly included gaps in data collection, lack of documented feeding type, sample groups that lacked adequate numbers of exclusively breastfed infants, and the exclusion of breastfed infants who lost the most weight. Well-designed clinical studies that address these limitations are needed. PMID- 26253287 TI - Reduced turnaround time and improved diagnosis of invasive serogroup B Neisseria meningitidis and Streptococcus pneumoniae infections using a lyophilized quadruplex quantitative PCR. AB - Since 1996 the Meningococcal Reference Unit (MRU) in Manchester has provided a national service for PCR confirmation of meningococcal and pneumococcal disease. Neisseria meningitidis serogroup B is predominant in the UK, accounting for >60% of cases. In response to this, the MRU has developed a quadruplex quantitative PCR that detects N. meningitidis capsule transporter (ctrA), serogroup B sialyltransferase (siaDB), Streptococcus pneumoniae pneumolysin (ply) and an internal control. The assay was prepared in a ready-to-use lyophilized format by Applied Biosystems. Laboratory validation showed excellent performance in a specificity panel of 52 isolates and improved detection in comparison with the routine assay. Testing of 244 patient samples showed sensitivity of 93% [95% confidence interval (CI): 88-98%] for the ctrA assay, 95% (95% CI: 91-100%) for the siaDB assay and 100% (95% CI: 95-100%) for the ply assay. Specificity was 100% (95% CI: 98-100%) for both meningococcal targets and 95% (95% CI: 92-98%) for ply. The quadruplex also retained high performance in mixed samples and had acceptable reproducibility. After introduction of the quadruplex into routine use the turnaround time for N. meningitidis group B PCR confirmation reduced from 37 to 29 h and the internal control has proved useful for detecting inhibitory samples. The quadruplex assay provides rapid group B confirmation of meningococcal positive samples, enabling timely public health interventions for the most common disease-causing meningococcal serogroup in the UK. PMID- 26253289 TI - Factors influencing mortality in solid organ transplant recipients with bloodstream infection. AB - Although bloodstream infection (BSI) is a major cause of mortality after solid organ transplantation, information regarding its prognostic factors is scarce. To identify risk factors for 30-day mortality in solid organ transplant (SOT) recipients with BSI, we prospectively recorded all episodes of BSI occurring in adult SOT recipients from January 2007 to October 2014 at a university hospital. We identified 361 consecutive episodes of BSI involving 246 patients. The 30-day case-fatality rate from the onset of BSI was 11.4%. Factors independently associated with 30-day mortality in a logistic regression analysis were shock at presentation (OR 13.658; 95% CI 5.985-31.168), acute graft rejection in the previous 6 months (OR 3.681; 95% CI 1.059-12.795), and a platelet count of <50,000 * 10(9)/L (OR 3.070; 95% CI 1.173-8.038). Kidney recipients were the patients with the best prognosis (OR 0.375; 95% CI 0.156-0.900). Our findings may help to identify SOT recipients with BSI who are at the highest risk of death. PMID- 26253290 TI - Ten-year follow-up of hepatitis B relapse after cessation of lamivudine or telbivudine treatment in chronic hepatitis B patients. AB - The high rate of relapse after cessation of nucleos(t)ide analogues (NUCs) treatment in chronic hepatitis B (CHB) patients leads us to reassess the feasibility for off-therapy, but long-term follow-up data are scarce. We assessed the feasibility for off-therapy by a long-term observation of relapse in response to lamivudine (LAM) and telbivudine (LdT). Eighty-six NUC-naive CHB patients, treated with LAM (n = 46) or LdT (n = 40) who reached the guidelines recommended for off-therapy, were followed for up to 10 years. Hepatitis B virus (HBV), viral serology and biochemistries were periodically determined. COX model was used to predict the risk of relapse. A total of 52.3% of patients experienced relapse within a median of 115 months (range, 61-122 months). A total of 93.3% of relapses occurred within 48 months. Relapse rates in hepatitis B e antigen (HBeAg)-positive (n = 56) and HBeAg-negative (n = 30) patients were 39.3% and 76.7%, respectively (p < 0.01). HBeAg-positive patients who achieved an early viral response (EVR), defined as undetectable HBV DNA within 6 months, had a lower relapse rate compared to non-EVR patients (21.4% vs. 59.2%, p < 0.01). EVR patients who had both lower HBV DNA (<10(6) copies/mL) at baseline and lower hepatitis B surface antigen (HBsAg) at end of treatment had a relapse rate of 10.7%. The high relapse rates in CHB patients over this 10-year follow-up make LAM or LdT off therapy infeasible in most of the cases, except in the case of HBsAg loss and/or seroconversion. HBeAg-positive patients with EVR, lower HBV DNA and HBsAg had lower relapse rates and could be good candidates for off-therapy. Long-term monitoring, especially during the first 4 years, is critical for patients off-therapy. PMID- 26253291 TI - Infection-associated non-Hodgkin lymphomas. AB - Non-Hodgkin lymphomas (NHLs) are malignant proliferations of lymphoid cells. Lymphoid cells proliferate in a physiological manner in response to antigen dependent and antigen-independent signals. Some lymphotropic viruses, such as Epstein-Barr virus and human T-lymphotropic virus 1, as well as pathogens leading to chronic antigenic stimulation (such as Helicobacter pylori and hepatitis C virus), are associated with NHL. We review here some of the pathophysiological features of infection-associated NHL. PMID- 26253292 TI - MR Imaging Evaluation of the Lisfranc Ligament in Cadaveric Feet and Patients With Acute to Chronic Lisfranc Injury. AB - BACKGROUND: Magnetic resonance (MR) imaging is known to be useful to demonstrate Lisfranc ligament injury. There are few studies that report differences in MR imaging findings of acute or chronic Lisfranc ligament injuries. We applied oblique MR imaging planes parallel to the Lisfranc ligament for better visualization of the entire course of the ligament and assessed the detailed MR imaging appearances of the Lisfranc ligament in cadavers and patients with presumed Lisfranc injuries. METHODS: Twelve preserved cadaveric feet were examined using a small-diameter surface coil. Long axis, oblique sagittal, and oblique short axis cross sections parallel to the Lisfranc ligament, dorsal ligament, and plantar ligament were obtained. Twenty-six MR examinations from 23 patients with suspected Lisfranc joint injuries were evaluated. RESULTS: In the cadaveric study, the Lisfranc ligament was satisfactorily visible along its entire course in a single slice on long axis and oblique sagittal MR images. The dorsal ligament and the plantar ligament were visible separately from the Lisfranc ligament in oblique sagittal and oblique short axis planes. In the patient study, 11 MR examinations led to diagnoses of complete tears of the Lisfranc ligament that were acute injuries (3-21 days after trauma) mostly associated with disruption of the dorsal and plantar ligaments. Nine studies led to diagnoses of incomplete tears of the Lisfranc ligament that were chronic injuries (2-14 months after trauma). Recovery of the continuity of the disrupted ligament was observed in 3 patients. CONCLUSION: MR imaging demonstrated the integrity of the ligaments and was useful for diagnosing an acute Lisfranc injury. Fibrous healing of the torn ligament was observed in a chronic injury. PMID- 26253293 TI - Somatisation as a risk factor for incident depression and anxiety. AB - OBJECTIVE: In this study, we aimed to examine somatisation as a risk factor for the onset of depressive and anxiety disorders. METHODS: 4-year follow-up data from the Netherlands Study of Depression and Anxiety (NESDA), a multisite cohort study of the course of depression and anxiety, was analysed. Participants (18-65 years) without a lifetime depressive or anxiety disorder at baseline were included (n=611). Somatisation was measured at baseline with the somatisation subscale of the 4 Dimensional Symptoms Questionnaire. Onset of depression and anxiety was assessed with the CIDI interview at 2-year and 4-year follow-up. RESULTS: Somatisation was a risk factor for the incidence of depression [Hazard Ratio per unit increase (HR); 95% Confidence Interval (CI): 1.13; 1.09-1.17] and anxiety [HR; 95% CI: 1.14; 1.09-1.18]. Associations attenuated but remained statistically significant after adjusting for socio-demographic characteristics, chronic somatic disorders, and baseline levels of (subclinical) depressive or anxiety symptoms [adjusted HR for depression; 95% CI: 1.06; 1.00-1.12, adjusted HR for anxiety; 95% CI: 1.13; 1.07-1.20]. CONCLUSION: Persons who somatise have an increased risk of becoming depressed or anxious in subsequent years, over and above baseline levels of depressive or anxiety symptoms. They may represent a target group for prevention of depressive and anxiety disorders. PMID- 26253294 TI - Inflammation and Edema in the Lung and Kidney of Hemorrhagic Shock Rats Are Alleviated by Biliary Tract External Drainage via the Heme Oxygenase-1 Pathway. AB - The lung and kidney are two organs that are easily affected by hemorrhagic shock (HS). We investigated roles of biliary tract external drainage (BTED) in inflammation and edema of the lung and kidney in HS and its relationship with the heme oxygenase-1 (HO-1) pathway. Rat models of HS were induced by drawing blood from the femoral artery until a mean arterial pressure (MAP) of 40 +/- 5 mmHg was achieved. A MAP of 40 +/- 5 mmHg was maintained for 60 min. Thirty-six Sprague Dawley rats were randomized to the following groups: sham group; HS group; HS + zinc protoporphyrin IX (ZnPP), a specific HO-1 inhibitor, group; HS + BTED group; HS + BTED + ZnPP group; and HS + BTED + bile infusion (BI) group. HO-1 levels, aquaporin-1 levels, and ratios of dry/wet in the lung and kidney increased markedly after BTED, but tumor necrosis factor-alpha and myeloperoxidase levels in the lung and kidney decreased significantly after BTED under HS conditions. Under the condition that HO-1 was inhibited by ZnPP, all these effects induced by BTED disappeared in the lung and kidney. These results demonstrated that inflammation and edema of the lung and kidney of HS rats are alleviated by BTED via the HO-1 pathway. PMID- 26253295 TI - Protective Effect of Infliximab, a Tumor Necrosis Factor-Alfa Inhibitor, on Bleomycin-Induced Lung Fibrosis in Rats. AB - We aimed to investigate the preventive effect of Infliximab (IFX), a tumor necrosis factor (TNF)-alpha inhibitor, on bleomycin (BLC)-induced lung fibrosis in rats. Rats were assigned into four groups as follows: I-BLC group, a single intra-tracheal BLC (2.5 mg/kg) was installed; II-control group, a single intra tracheal saline was installed; III-IFX + BLC group, a single-dose IFX (7 mg/kg) was administered intraperitoneally (i.p.), 72 h before the intra-tracheal BLC installation; IV-IFX group, IFX (7 mg/kg) was administered alone i.p. on the same day with IFX + BLC group. All animals were sacrificed on the 14th day of BLC installation. Levels of tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, interleukin (IL)-6, periostin, YKL-40, nitric oxide (NO) in rat serum were measured, as well as, myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity, and reduced glutathione (GSH), hydroxyproline, malondialdehyde (MDA) content in lung homogenates. Lung tissues were stained with hematoxylin and eosin (H&E) for quantitative histological evaluation. The inducible nitric oxide synthase (iNOS) expression and cell apoptosis in the lung tissues were determined quantitatively by immunohistochemical staining (INOS) and by TUNNEL staining, respectively. BLC installation worsened antioxidant status (such as SOD, CAT, GPx, GSH, MPO), while it increased the serum TNF-alpha, TGF-beta, IL-6, periostin, YKL-40, and lipid peroxidation, and collagen deposition, measured by MDA and hydroxyproline, respectively. IFX pretreatment improved antioxidant status as well as BLC-induced lung pathological changes, while it decreased the TNF-alpha, TGF-beta, IL-6, periostin, YKL-40, lipid peroxidation and collagen deposition. Finally, histological, immunohistochemical, and TUNNEL evidence also supported the ability of IFX to prevent BLC-induced lung fibrosis. The results of the present study indicate that IFX pretreatment can attenuate BLC-induced pulmonary fibrosis. PMID- 26253296 TI - Citrate Attenuates Adenine-Induced Chronic Renal Failure in Rats by Modulating the Th17/Treg Cell Balance. AB - Citrate is commonly used as an anticoagulant in hemodialysis for chronic renal failure (CRF) and for the regulation of the immune dysfunction in CRF patients. The objective of this study was to investigate the effect of citrate on the balance of T helper 17 (Th17) and regulatory T (Treg) cells in CRF. The levels of blood urea nitrogen (BUN) and serum creatinine (Scr) were significantly increased in the CRF model group compared to the control group, and were decreased in the citrate-treated groups. Citrate treatment inhibited the viability of Th17 cells while elevating the viability of Treg cells in CRF rats. Moreover, Th17-related cytokines significantly decreased while the Treg-related cytokines significantly increased with citrate treatment. Moreover, citrate had a negative influence on the deviation of Th17/Treg cells in CRF rats. Therefore, our study suggests that citrate had an anti-inflammatory effect on CRF through the modulation of the Th17/Treg balance. PMID- 26253297 TI - Secondary corneal amyloidosis after perforating corneal trauma: A series of 5 cases and review of the literature. AB - We retrospectively reviewed the clinical and surgical histories of 5 patients with traumatic secondary corneal amyloidosis, a relatively rare sequela of nonsurgical and surgical perforating corneal trauma. Four had history of nonsurgical trauma, and 1 had surgical trauma to the cornea. Three specimens were obtained by penetrating keratoplasties and 2 by excision of the cornea during evisceration of the ocular contents. All the corneal specimens showed full thickness scars of a prior perforating wound with congophilic amyloid deposits that exhibited apple-green birefringence under polarized light and dichroism. All cases had variable degrees of predominantly chronic nongranulomatous inflammation. Ultrastructural examination in 1 patient disclosed 8-nm diameter fibrils in disarray, consistent with amyloid. Amyloid P immunostaining was positive in all 3 patients tested for this protein. PMID- 26253298 TI - Reversible cerebral vasoconstriction syndrome might account for the headaches simulating subarachnoid haemorrhage. PMID- 26253299 TI - Molecular imaging-its current role in cancer. AB - Medical imaging has undergone extensive growth over the last few decades and now plays a central role in clinical oncology. The future of imaging in the management of oncology patients is molecularly targeted imaging agents. Molecular imaging differs from conventional anatomical imaging in that imaging probes are utilized to visualize target molecules-of-interest. It is envisioned that molecular imaging will have a major impact on oncology and personalized medicine by allowing earlier diagnosis, assessing early response to treatment and by predicting treatment response. It will, hopefully, also have an impact on drug development by streamlining preclinical and clinical tests for new drug candidates. PMID- 26253300 TI - Erratum to: Functional expression of the human coagulation factor IX using heterologous signal peptide and propeptide sequences in mammalian cell line. PMID- 26253301 TI - Putative carotenoid genes expressed under the regulation of Shine-Dalgarno regions in Escherichia coli for efficient lycopene production. AB - OBJECTIVES: Putative genes crtE, crtB, and crtI from Deinococcus wulumiqiensis R12, a novel species, were identified by genome mining and were co-expressed using the optimized Shine-Dalgarno (SD) regions to improve lycopene yield. RESULTS: A lycopene biosynthesis pathway was constructed by co-expressing these three genes in Escherichia coli. After optimizing the upstream SD regions and the culture medium, the recombinant strain EDW11 produced 88 mg lycopene g(-1) dry cell wt (780 mg lycopene l(-1)) after 40 h fermentation without IPTG induction, while the strain EDW without optimized SD regions only produced 49 mg lycopene g( 1) dry cell wt (417 mg lycopene l(-1)). CONCLUSION: Based on the optimization of the upstream SD regions and culture medium, the yield of the strain EDW11 reached a high level during microbial lycopene production until now. PMID- 26253302 TI - Magnolin inhibits cell migration and invasion by targeting the ERKs/RSK2 signaling pathway. AB - BACKGROUND: Magnolin is a natural compound abundantly found in Magnolia flos, which has been traditionally used in oriental medicine to treat headaches, nasal congestion and anti-inflammatory reactions. Our recent results have demonstrated that magnolin targets the active pockets of ERK1 and ERK2, which are important signaling molecules in cancer cell metastasis. The aim of this study is to evaluate the effects of magnolin on cell migration and to further explore the molecular mechanisms involved. METHODS: Magnolin-mediated signaling inhibition was confirmed by Western blotting using RSK2(+/+) and RSK2(-/-) MEFs, A549 and NCI-H1975 lung cancer cells, and by NF-kappaB and Cox-2 promoter luciferase reporter assays. Inhibition of cell migration by magnolin was examined by wound healing and/or Boyden Chamber assays using JB6 Cl41 and A549 human lung cancer cells. The molecular mechanisms involved in cell migration and epithelial-to mesenchymal transition were determined by zymography, Western blotting, real-time PCR and immunocytofluorescence. RESULTS: Magnolin inhibited NF-kappaB transactivation activity by suppressing the ERKs/RSK2 signaling pathway. Moreover, magnolin abrogated the increase in EGF-induced COX-2 protein levels and wound healing. In human lung cancer cells such as A549 and NCI-H1975, which harbor constitutive active Ras and EGFR mutants, respectively, magnolin suppressed wound healing and cell invasion as seen by a Boyden chamber assay. In addition, it was observed that magnolin inhibited MMP-2 and -9 gene expression and activity. The knockdown or knockout of RSK2 in A549 lung cancer cells or MEFs revealed that magnolin targeting ERKs/RSK2 signaling suppressed epithelial-to mesenchymal transition by modulating EMT marker proteins such as N-cadherin, E cadherin, Snail, Vimentin and MMPs. CONCLUSIONS: These results demonstrate that magnolin inhibits cell migration and invasion by targeting the ERKs/RSK2 signaling pathway. PMID- 26253303 TI - Extreme bradycardia after first doses of sofosbuvir and daclatasvir in patients receiving amiodarone: 2 cases including a rechallenge. AB - Sofosbuvir and daclatasvir are direct-acting antiviral drugs used to treat chronic hepatitis C virus infection. In 2015, the Food and Drug Administration and European Medical Agency warned that bradycardia could occur when amiodarone was administered in combination with sofosbuvir, but no case reports had been published. We report extreme bradycardia within 2 hrs after intake of sofosbuvir and daclatasvir by 2 patients receiving amiodarone. The first patient had a cardiac asystole 30 min after receiving sofosbuvir and daclatasvir. Amiodarone, sofosbuvir, and daclatasvir treatment were stopped; after 10 days, the cardiac evaluation was normal and patient was discharged. The second patient was taking amiodarone and propranolol; 2 hrs after receiving sofosbuvir and daclatasvir, he had an extreme sinus node dysfunction (heart rate of 27beats/min). Amiodarone and propranolol were stopped, but the patient continued receiving sofosbuvir and daclatasvir for 3 days and sinus bradycardia was recorded each day, 2 hrs after intake of these drugs. When he stopped taking the drugs, no bradycardia was observed. Administration of sofosbuvir and daclatasvir on day 13 induced bradycardia 2 hrs after intake. However, no bradycardia occurred following a rechallenge 8 weeks after the patient stopped taking amiodarone. These observations indicate that patients treated with amiodarone should be continuously monitored within the first 48 hrs following the initiation of sofosbuvir and daclatasvir. PMID- 26253304 TI - Personalizing colonoscopy screening for elderly individuals based on screening history, cancer risk, and comorbidity status could increase cost effectiveness. AB - BACKGROUND & AIMS: Colorectal cancer (CRC) screening decisions for elderly individuals are often made primarily on the basis of age, whereas other factors that influence the effectiveness and cost effectiveness of screening are often not considered. We investigated the relative importance of factors that could be used to identify elderly individuals most likely to benefit from CRC screening and determined the maximum ages at which screening remains cost effective based on these factors. METHODS: We used a microsimulation model (Microsimulation Screening Analysis-Colon) calibrated to the incidence of CRC in the United States and the prevalence of adenomas reported in autopsy studies to determine the appropriate age at which to stop colonoscopy screening in 19,200 cohorts (of 10 million individuals), defined by sex, race, screening history, background risk for CRC, and comorbidity status. We applied a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY) gained. RESULTS: Less intensive screening history, higher background risk for CRC, and fewer comorbidities were associated with cost-effective screening at older ages. Sex and race had only a small effect on the appropriate age to stop screening. For some individuals likely to be screened in current practice (for example, 74-year-old white women with moderate comorbidities, half the average background risk for CRC, and negative findings from a screening colonoscopy 10 years previously), screening resulted in a loss of QALYs, rather than a gain. For some individuals unlikely to be screened in current practice (for example, 81-year-old black men with no comorbidities, an average background risk for CRC, and no previous screening), screening was highly cost effective. Although screening some previously screened, low-risk individuals was not cost effective even when they were 66 years old, screening some healthy, high-risk individuals remained cost effective until they reached the age of 88 years old. CONCLUSIONS: The current approach to CRC screening in elderly individuals, in which decisions are often based primarily on age, is inefficient, resulting in underuse of screening for some and overuse of screening for others. CRC screening could be more effective and cost effective if individual factors for each patient are considered. PMID- 26253307 TI - Detection of Yersinia enterocolitica in milk powders by cross-priming amplification combined with immunoblotting analysis. AB - Yersinia enterocolitica (Y. enterocolitica) is frequently isolated from a wide variety of foods and can cause human yersiniosis. Biochemical and culture-based assays are common detection methods, but require a long incubation time and easily misidentify Y. enterocolitica as other non-pathogenic Yersinia species. Alternatively, cross-priming amplification (CPA) under isothermal conditions combined with immunoblotting analysis enables a more sensitive detection in a relatively short time period. A set of specific displacement primers, cross primers and testing primers was designed on the basis of six specific sequences in Y. enterocolitica 16S-23S rDNA internal transcribed spacer. Under isothermal condition, amplification and hybridization were conducted simultaneously at 63 degrees C for 60 min. The specificity of CPA was tested for 96 different bacterial strains and 165 commercial milk powder samples. Two red lines were developed on BioHelix Express strip for all of the Y. enterocolitica strains, and one red line was shown for non-Y. enterocolitica strains. The limit of detection of CPA was 10(0)fg for genomic DNA (1000 times more sensitive than PCR assay), 10(1) CFU/ml for pure bacterial culture, and 10(0) CFU per 100 g milk powder with pre-enrichment at 37 degrees C for 24 h. CPA combined with immunoblotting analysis can achieve highly specific and sensitive detection of Y. enterocolitica in milk powder in 90 min after pre-enrichment. PMID- 26253306 TI - Characterising an implementation intervention in terms of behaviour change techniques and theory: the 'Sepsis Six' clinical care bundle. AB - BACKGROUND: Sepsis is a major cause of death from infection, with a mortality rate of 36 %. This can be halved by implementing the 'Sepsis Six' evidence-based care bundle within 1 h of presentation. A UK audit has shown that median implementation rates are 27-47 % and interventions to improve this have demonstrated minimal effects. In order to develop more effective implementation interventions, it is helpful to obtain detailed characterisations of current interventions and to draw on behavioural theory to identify mechanisms of change. The aim of this study was to illustrate this process by using the Behaviour Change Wheel; Behaviour Change Technique (BCT) Taxonomy; Capability, Opportunity, Motivation model of behaviour; and Theoretical Domains Framework to characterise the content and theoretical mechanisms of action of an existing intervention to implement Sepsis Six. METHODS: Data came from documentary, interview and observational analyses of intervention delivery in several wards of a UK hospital. A broad description of the intervention was created using the Template for Intervention Description and Replication framework. Content was specified in terms of (i) component BCTs using the BCT Taxonomy and (ii) intervention functions using the Behaviour Change Wheel. Mechanisms of action were specified using the Capability, Opportunity, Motivation model and the Theoretical Domains Framework. RESULTS: The intervention consisted of 19 BCTs, with eight identified using all three data sources. The BCTs were delivered via seven functions of the Behaviour Change Wheel, with four ('education', 'enablement', 'training' and 'environmental restructuring') supported by the three data sources. The most frequent mechanisms of action were reflective motivation (especially 'beliefs about consequences' and 'beliefs about capabilities') and psychological capability (especially 'knowledge'). CONCLUSIONS: The intervention consisted of a wide range of BCTs targeting a wide range of mechanisms of action. This study demonstrates the utility of the Behaviour Change Wheel, the BCT Taxonomy and the Theoretical Domains Framework, tools recognised for providing guidance for intervention design, for characterising an existing intervention to implement evidence-based care. PMID- 26253308 TI - Word-stem priming and recognition in type 2 diabetes mellitus, Alzheimer's disease patients and healthy older adults. AB - The present study investigated (a) whether the pattern of performance on implicit and explicit memory of patients with type 2 diabetes mellitus (DM2) is more similar to those of patients with Alzheimer's disease (AD) or to cognitively normal older adults and (b) whether glycosylated hemoglobin levels (a measure of glucose regulation) are related to performance on the two memory tasks, implicit word-stem completion and "old-new" recognition. The procedures of both memory tasks included encoding and memory test phases separated by a short delay. Three groups of participants (healthy older adults, DM2 patients and AD patients) completed medical and psychological assessments and performed both memory tasks on a computer. The results of the word-stem completion task showed similar implicit memory in the three groups. By contrast, explicit recognition of the three groups differed. Implicit memory was not affected by either normal or pathological aging, but explicit memory deteriorated in the two groups of patients, especially in AD patients, showing a severe impairment compared to the cognitively healthy older adults. Importantly, glycosylated hemoglobin levels were not related to performance on either implicit or explicit memory tasks. These findings revealed a clear dissociation between explicit and implicit memory tasks in normal and pathological aging. Neuropsychologists and clinicians working with TM2 patients should be aware that the decline of voluntary, long-term explicit memory could have a negative impact on their treatment management. By contrast, the intact implicit memory of the two clinical groups could be used in rehabilitation. PMID- 26253305 TI - A combination of molecular markers and clinical features improve the classification of pancreatic cysts. AB - BACKGROUND & AIMS: The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. METHODS: We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers. RESULTS: We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%. CONCLUSIONS: We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery. PMID- 26253309 TI - Neural mechanisms underlying the exploration of small city maps using magnetoencephalography. AB - The neural mechanisms underlying spatial cognition in the context of exploring realistic city maps are unknown. We conducted a novel brain imaging study to address the question of whether and how features of special importance for map exploration are encoded in the brain to make a spatial decision. Subjects explored by eyes small city maps exemplifying five different street network types in order to locate a hypothetical City Hall, while neural activity was recorded continuously by 248 magnetoencephalography (MEG) sensors at high temporal resolution. Monitoring subjects' eye positions, we locally characterized the maps by computing three spatial parameters of the areas that were explored. We computed the number of street intersections, the total street length, and the regularity index in the circular areas of 6 degrees of visual angle radius centered on instantaneous eye positions. We tested the hypothesis that neural activity during exploration is associated with the spatial parameters and modulated by street network type. All time series were rendered stationary and nonautocorrelated by applying an autoregressive integrated moving average model and taking the residuals. We then assessed the associations between the prewhitened time-varying MEG time series from 248 sensors and the prewhitened spatial parameters time series, for each street network type, using multiple linear regression analyses. In accord with our hypothesis, ongoing neural activity was strongly associated with the spatial parameters through localized and distributed networks, and neural processing of these parameters depended on the type of street network. Overall, processing of the spatial parameters seems to predominantly involve right frontal and prefrontal areas, but not for all street network layouts. These results are in line with findings from a series of previous studies showing that frontal and prefrontal areas are involved in the processing of spatial information and decision making. Modulation of neural processing of the spatial parameters by street network type suggests that some street network layouts may contain other types of spatial information that subjects use to explore maps and make spatial decisions. PMID- 26253310 TI - Comparative analyses of developmental transcription factor repertoires in sponges reveal unexpected complexity of the earliest animals. AB - Developmental transcription factors (DTFs) control development of animals by affecting expression of target genes, some of which are transcription factors themselves. In bilaterians and cnidarians, conserved DTFs are involved in homologous processes such as gastrulation or specification of neurons. The genome of Amphimedon queenslandica, the first sponge to be sequenced, revealed that only a fraction of these conserved DTF families are present in demosponges. This finding was in line with the view that morphological complexity in the animal lineage correlates with developmental toolkit complexity. However, as the phylum Porifera is very diverse, Amphimedon's genome may not be representative of all sponges. The recently sequenced genomes of calcareous sponges Sycon ciliatum and Leucosolenia complicata allowed investigations of DTFs in a sponge lineage evolutionarily distant from demosponges. Surprisingly, the phylogenetic analyses of identified DTFs revealed striking differences between the calcareous sponges and Amphimedon. As these differences appear to be a result of independent gene loss events in the two sponge lineages, the last common ancestor of sponges had to possess a much more diverse repertoire of DTFs than extant sponges. Developmental expression of sponge homologs of genes involved in specification of the Bilaterian endomesoderm and the neurosensory cells suggests that roles of many DTFs date back to the last common ancestor of all animals. Strikingly, even DTFs displaying apparent pan-metazoan conservation of sequence and function are not immune to being lost from individual species genomes. The quest for a comprehensive picture of the developmental toolkit in the last common metazoan ancestor is thus greatly benefitting from the increasing accessibility of sequencing, allowing comparisons of multiple genomes within each phylum. PMID- 26253311 TI - Is prostaglandin E2 (PGE2) involved in the thermogenic response to environmental cooling in healthy humans? AB - Prostaglandin E2 (PGE2) is an eicosanoid derived from cyclooxygenase, an enzyme responsible for the cyclisation and oxygenation of arachidonic acid. In response to bacterial infection, PGE2 binds to EP3 receptors on a population of GABAergic neurons in the pre-optic area. Activation of the EP3 receptor decreases the intracellular cyclic adenosine monophosphate (cAMP) concentrations of these neurons, and the resulting dis-inhibition activates spinal motor outputs responsible for shivering thermogenesis, tachycardia, and brown adipose tissue activation. These involuntary responses increase core body temperature to varying degrees depending on the magnitude of infection; an immune response which is crucial for the survival of the host. However, evidence in animal and human models, primarily through the use of cyclooxygenase inhibitors (which block the production of PGE2), suggests that PGE2 may also be an important molecule for the defence of core temperature against body cooling and cold stress (in the absence of fever). In this paper, evidence within human and animal models is discussed which supports the hypothesis that the eicosanoid PGE2 has a role in maintaining human core temperature during environmental cooling. Given that over-the-counter PGE2 inhibiting drugs [i.e. Non-Steroidal Anti Inflammatory Drugs (NSAIDS)] are frequently used worldwide, it is possible that the use of such medication during environmental cooling could impair one's ability to thermoregulate. Support for such findings could have major implications in the pathology of hypothermia, thus, we suggest that future researchers investigate this specific hypothesis in vivo, using healthy human models. Suggestions for the implementation of such experiments are provided in the present work. PMID- 26253312 TI - The effects of short- and long-term air pollutants on plant phenology and leaf characteristics. AB - Pollution adversely affects vegetation; however, its impact on phenology and leaf morphology is not satisfactorily understood yet. We analyzed associations between pollutants and phenological data of birch, hazel and horse chestnut in Munich (2010) along with the suitability of leaf morphological parameters of birch for monitoring air pollution using two datasets: cumulated atmospheric concentrations of nitrogen dioxide and ozone derived from passive sampling (short-term exposure) and pollutant information derived from Land Use Regression models (long-term exposure). Partial correlations and stepwise regressions revealed that increased ozone (birch, horse chestnut), NO2, NOx and PM levels (hazel) were significantly related to delays in phenology. Correlations were especially high when rural sites were excluded suggesting a better estimation of long-term within-city pollution. In situ measurements of foliar characteristics of birch were not suitable for bio-monitoring pollution. Inconsistencies between long- and short term exposure effects suggest some caution when interpreting short-term data collected within field studies. PMID- 26253313 TI - Modelling of oil spills in confined maritime basins: The case for early response in the Eastern Mediterranean Sea. AB - Oil spill models are combined with bathymetric, meteorological, oceanographic, and geomorphological data to model a series of oil spill accidents in the Eastern Mediterranean Sea. A total of 104 oil spill simulations, computed for 11 different locations in the Levantine Basin, show that oil slicks will reach the coast of Cyprus in four (4) to seven (7) days in summer conditions. Oil slick trajectories are controlled by prevailing winds and current eddies. Based on these results, we support the use of chemical dispersants in the very few hours after large accidental oil spills. As a corollary, we show shoreline susceptibility to vary depending on: a) differences in coastline morphology and exposure to wave action, b) the existence of uplifted wave-cut platforms, coastal lagoons and pools, and c) the presence of tourist and protected environmental areas. Mitigation work should take into account the relatively high susceptibility of parts of the Eastern Mediterranean. PMID- 26253314 TI - Assessing comparative terrestrial ecotoxicity of Cd, Co, Cu, Ni, Pb, and Zn: The influence of aging and emission source. AB - Metal exposure to terrestrial organisms is influenced by the reactivity of the solid-phase metal pool. This reactivity is thought to depend on the type of emission source, on aging mechanisms that are active in the soil, and on ambient conditions. Our work shows, that when controlling for soil pH or soil organic carbon, emission source occasionally has an effect on reactivity of Cd, Co, Cu, Ni, Pb and Zn emitted from various anthropogenic sources followed by aging in the soil from a few years to two centuries. The uncertainties in estimating the age prevent definitive conclusions about the influence of aging time on the reactivity of metals from anthropogenic sources in soils. Thus, for calculating comparative toxicity potentials of man-made metal contaminations in soils, we recommend using time-horizon independent accessibility factors derived from source-specific reactive fractions. PMID- 26253315 TI - Ozone exposure and flux-based response functions for photosynthetic traits in wheat, maize and poplar. AB - Ozone exposure- and dose-response relationships based on photosynthetic leaf traits (CO2 assimilation, chlorophyll content, Rubisco and PEPc activities) were established for wheat, maize and poplar plants grown in identical controlled conditions, providing a comparison between crop and tree species, as well as between C3 and C4 plants. Intra-specific variability was addressed by comparing two wheat cultivars with contrasting ozone tolerance. Depending on plant models and ozone levels, first-order, second-order and segmented linear regression models were used to derive ozone response functions. Overall, flux-based functions appeared superior to exposure-based functions in describing the data, but the improvement remained modest. The best fit was obtained using the POD0.5 for maize and POD3 for poplar. The POD6 appeared relevant for wheat, although intervarietal differences were found. Our results suggest that taking into account the dynamics of leaf antioxidant capacity could improve current methods for ozone risk assessment for plants. PMID- 26253316 TI - The Evolution of Bony Vertebrate Enhancers at Odds with Their Coding Sequence Landscape. AB - Enhancers lie at the heart of transcriptional and developmental gene regulation. Therefore, changes in enhancer sequences usually disrupt the target gene expression and result in disease phenotypes. Despite the well-established role of enhancers in development and disease, evolutionary sequence studies are lacking. The current study attempts to unravel the puzzle of bony vertebrates' conserved noncoding elements (CNE) enhancer evolution. Bayesian phylogenetics of enhancer sequences spotlights promising interordinal relationships among placental mammals, proposing a closer relationship between humans and laurasiatherians while placing rodents at the basal position. Clock-based estimates of enhancer evolution provided a dynamic picture of interspecific rate changes across the bony vertebrate lineage. Moreover, coelacanth in the study augmented our appreciation of the vertebrate cis-regulatory evolution during water-land transition. Intriguingly, we observed a pronounced upsurge in enhancer evolution in land-dwelling vertebrates. These novel findings triggered us to further investigate the evolutionary trend of coding as well as CNE nonenhancer repertoires, to highlight the relative evolutionary dynamics of diverse genomic landscapes. Surprisingly, the evolutionary rates of enhancer sequences were clearly at odds with those of the coding and the CNE nonenhancer sequences during vertebrate adaptation to land, with land vertebrates exhibiting significantly reduced rates of coding sequence evolution in comparison to their fast evolving regulatory landscape. The observed variation in tetrapod cis-regulatory elements caused the fine-tuning of associated gene regulatory networks. Therefore, the increased evolutionary rate of tetrapods' enhancer sequences might be responsible for the variation in developmental regulatory circuits during the process of vertebrate adaptation to land. PMID- 26253317 TI - SNP Formation Bias in the Murine Genome Provides Evidence for Parallel Evolution. AB - In this study, we show novel DNA motifs that promote single nucleotide polymorphism (SNP) formation and are conserved among exons, introns, and intergenic DNA from mice (Sanger Mouse Genomes Project), human genes (1000 Genomes), and tumor-specific somatic mutations (data from TCGA). We further characterize SNPs likely to be very recent in origin (i.e., formed in otherwise congenic mice) and show enrichment for both synonymous and parallel DNA variants occurring under circumstances not attributable to purifying selection. The findings provide insight regarding SNP contextual bias and eukaryotic codon usage as strategies that favor long-term exonic stability. The study also furnishes new information concerning rates of murine genomic evolution and features of DNA mutagenesis (at the time of SNP formation) that should be viewed as "adaptive." PMID- 26253318 TI - Multilevel Selection Theory and the Evolutionary Functions of Transposable Elements. AB - One of several issues at play in the renewed debate over "junk DNA" is the organizational level at which genomic features might be seen as selected, and thus to exhibit function, as etiologically defined. The intuition frequently expressed by molecular geneticists that junk DNA is functional because it serves to "speed evolution" or as an "evolutionary repository" could be recast as a claim about selection between species (or clades) rather than within them, but this is not often done. Here, we review general arguments for the importance of selection at levels above that of organisms in evolution, and develop them further for a common genomic feature: the carriage of transposable elements (TEs). In many species, not least our own, TEs comprise a large fraction of all nuclear DNA, and whether they individually or collectively contribute to fitness- or are instead junk--is a subject of ongoing contestation. Even if TEs generally owe their origin to selfish selection at the lowest level (that of genomes), their prevalence in extant organisms and the prevalence of extant organisms bearing them must also respond to selection within species (on organismal fitness) and between species (on rates of speciation and extinction). At an even higher level, the persistence of clades may be affected (positively or negatively) by TE carriage. If indeed TEs speed evolution, it is at these higher levels of selection that such a function might best be attributed to them as a class. PMID- 26253319 TI - Tedium vitae, death wishes, suicidal ideation and attempts in Kenya-prevalence and risk factors. AB - BACKGROUND: There has been no previous household population study of suicidal ideation and attempts in Kenya. Therefore this study aimed to establish the prevalence of suicidal ideation and attempts in a rural population in Kenya, and to assess risk factors. METHODS: An epidemiological survey of a household population, using standardised structured interviews. We examined the prevalence of suicidal ideation and suicide attempts and the predictors of suicidal thoughts and attempts, using STATA to calculate unadjusted and adjusted odds ratios. RESULTS: A quarter of the sample (24.1 %) had thought that life was not worth living (tedium vitae) at some point in their lives, while a fifth had experienced death wishes at some stage. About 7.9 % reported suicidal thoughts and 1.9 % had made actual suicide attempts at some point in their lives. It can be seen that the prevalence of suicidal thoughts was 0.7 %, 4.2 %, 3.7 % and 7.9 % for last week, last year, at some other time, and lifetime respectively, while the prevalence of suicidal attempts was 0.5 %, 1.2 %, 0.7 and 1.9 % respectively. In the adjusted analysis of factors associated with suicidal thoughts, being female (OR 1.8, p = 0.017), having CMD (OR 2.7, p = 0.001), having a number of recent life events (OR 2.3, p = 0.001 for 2-3 life events and OR 2.6, p = 0.004 for 4 or more life events), and having a large social group size (OR 7.7, p = 0.006 for social group size of 4-8 and OR 9.1, p = 0.003 for social group size of 9 or more) were all associated with increased rates of life time suicidal thoughts, but psychotic symptoms were no longer significant after adjustment for the other variables. In the adjusted analysis of suicide attempts, having any psychotic symptoms (OR 5.1, p = 0.001) was the only factor associated with suicide attempts after adjustment for other factors significant at the bivariate level. CONCLUSION: Suicidal ideation and attempts pose a significant public health burden in this poor rural area of Kenya. The findings are relevant for mental health promotion and prevention programmes, public education and professional training programmes in relevant sectors, especially in front line health workers and social workers. PMID- 26253320 TI - Two repetition time saturation transfer (TwiST) with spill-over correction to measure creatine kinase reaction rates in human hearts. AB - BACKGROUND: Phosphorus saturation transfer (ST) magnetic resonance spectroscopy can measure the rate of ATP generated from phosphocreatine (PCr) via creatine kinase (CK) in the human heart. Recently, the triple-repetition time ST (TRiST) method was introduced to measure the CK pseudo-first-order rate constant kf in three acquisitions. In TRiST, the longitudinal relaxation time of PCr while gamma ATP is saturated, T1', is measured for each subject, but suffers from low SNR because the PCr signal is reduced due to exchange with saturated gamma-ATP, and the short repetition time of one of the acquisitions. Here, a two-repetition time ST (TwiST) method is presented. In TwiST, the acquisition with gamma-ATP saturation and short repetition time is dropped. Instead of measuring T1', an intrinsic relaxation time T1 for PCr, T1 (intrinsic), is assumed. The objective was to validate TwiST measurements of CK kinetics in healthy subjects and patients with heart failure (HF). METHODS: Bloch equation simulations that included the effect of spillover irradiation on PCr were used to derive formulae for T1 (intrinsic) and kf measured by both TRiST and TwiST methods. Spillover was quantified from an unsaturated PCr measurement used in the current protocol for determining PCr and ATP concentrations. Cardiac TRiST and TwiST data were acquired at 3 T from 12 healthy and 17 HF patients. RESULTS: Simulations showed that both kf measured by TwiST and T1 (intrinsic) require spill-over corrections. In human heart at 3 T, the spill-over corrected T1 (intrinsic) = 8.4 +/- 1.4 s (mean +/- SD) independent of study group. TwiST and TRiST kf measurements were the same, but TwiST was 9 min faster. Spill-over corrected TwiST kf was 0.33 +/- 0.08 s(-1) vs. 0.20 +/- 0.06 s(-1) in healthy vs HF hearts, respectively (p < 0.0001). CONCLUSION: TwiST was validated against TRiST in the human heart at 3 T, generating the same results 9 min faster. TwiST detected significant reductions in CK kf in HF compared to healthy subjects, consistent with prior 1.5 T studies using different methodology. PMID- 26253322 TI - Is Nintendo Wii an Effective Intervention for Individuals With Stroke? A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To investigate the effectiveness of Nintendo Wii compared with no intervention or other exercise interventions in the rehabilitation of adults with stroke. DATA SOURCES: Seven electronic databases were systematically searched to source for full-text studies published in peer-reviewed journals up to July 2014. Hand searches of reference lists were performed. STUDY SELECTION: Randomized controlled trials (RCTs) comparing Wii with no intervention or other exercise interventions, in patients with stroke, were selected. DATA EXTRACTION: Methodological quality was assessed by 2 independent reviewers. Data pertaining to participants, interventions, outcomes, and clinical effectiveness were independently extracted by 2 reviewers using a standardized form and compared for accuracy. We calculated mean or standardized mean differences for analysis of continuous variables. Risk ratios were derived and 95% confidence intervals (CIs) calculated. DATA SYNTHESIS: Six studies were included. Three trials (64 participants) compared Wii and conventional rehabilitation versus conventional rehabilitation alone. Three trials (102 participants) compared Wii with other exercise interventions. The addition of Wii to conventional rehabilitation resulted in significant mean differences in favor of additional Wii compared with standard care for Timed Up and Go test (TUG) (0.81 points, CI 0.29-1.33, P = .002), but not for other mobility and functional outcomes: Functional Independence Measure (FIM) score (0.45, CI -0.21-1.11, P = .18), Berg Balance Score (-0.64, CI -3.66-2.39, P = .68), anteroposterior postural sway (0.23, CI 0.38-0.84, P = .46). No serious adverse events were reported, and when Wii was compared with exercise alone, we demonstrated a decreased risk of participants dropping out of follow-up (RR 0.40, CI 0.20-0.78, P = .007). CONCLUSIONS: The addition of Wii gaming to conventional rehabilitation in patients with chronic stroke significantly improved performance in TUG and not in the other physical measures. The pooled effect was small and not beyond the minimal detectable change. However, Wii can be used safely in patients with stroke and participants were less likely to drop out in the Wii group. This review highlights the need for further high-quality studies to demonstrate the efficacy of Wii in stroke rehabilitation. PMID- 26253321 TI - Potential role of cervicovaginal extracellular particles in diagnosis of endometriosis. AB - BACKGROUND: Macaques are an excellent model for many human diseases, including reproductive diseases such as endometriosis. A long-recognized need for early biomarkers of endometriosis has not yet resulted in consensus. While biomarker studies have examined many bodily fluids and targets, cervicovaginal secretions have been relatively under-investigated. Extracellular vesicles (EVs, including exosomes and microvesicles) are found in every biofluid examined, carry cargo including proteins and RNA, and may participate in intercellular signaling. Little is known about EVs in the cervicovaginal compartment, including the effects of reproductive tract disease on quantity and quality of EVs. CASE PRESENTATION: In September 2014, a 9-year-old rhesus macaque was diagnosed with endometriosis at The Johns Hopkins University School of Medicine. Ultrasound guided fine needle aspiration of a cyst and subsequent laparotomy confirmed diagnosis. The animal was sent to necropsy following euthanasia for humane reasons. Perimortem vaginal swabs and cervicovaginal lavages were obtained. Using a combination of methods, including ultracentrifugation and NanoSight visualization technology, approximate numbers of EVs from each sample were calculated and compared to populations of EVs from other, reproductively normal macaques. Fewer EVs were recovered from the endometriosis samples as compared with those from reproductively healthy individuals. CONCLUSION: To our knowledge, this is the first examination of EVs in primate cervicovaginal secretions, including those of a macaque with endometriosis. This case study suggests that additional research is justified to determine whether quantification of EVs-or their molecular cargo-in cervicovaginal lavage and vaginal swabs may provide a novel, relatively non-invasive diagnostic for primate endometrial disease or other reproductive tract diseases. PMID- 26253324 TI - Processing of face identity in the affective flanker task: a diffusion model analysis. AB - Affective flanker tasks often present affective facial expressions as stimuli. However, it is not clear whether the identity of the person on the target picture needs to be the same for the flanker stimuli or whether it is better to use pictures of different persons as flankers. While Grose-Fifer, Rodrigues, Hoover & Zottoli (Advances in Cognitive Psychology 9(2):81-91, 2013) state that attentional focus might be captured by processing the differences between faces, i.e. the identity, and therefore use pictures of the same individual as target and flanker stimuli, Munro, Dywan, Harris, McKee, Unsal & Segalowitz (Biological Psychology, 76:31-42, 2007) propose an advantage in presenting pictures of a different individual as flankers. They state that participants might focus only on small visual changes when targets and flankers are from the same individual instead of processing the affective content of the stimuli. The present study manipulated face identity in a between-subject design. Through investigation of behavioral measures as well as diffusion model parameters, we conclude that both types of flankers work equally efficient. This result seems best supported by recent accounts that propose an advantage of emotional processing over identity processing in face recognition. In the present study, there is no evidence that the processing of the face identity attracts sufficient attention to interfere with the affective evaluation of the target and flanker faces. PMID- 26253323 TI - The processing of visual and auditory information for reaching movements. AB - Presenting target and non-target information in different modalities influences target localization if the non-target is within the spatiotemporal limits of perceptual integration. When using auditory and visual stimuli, the influence of a visual non-target on auditory target localization is greater than the reverse. It is not known, however, whether or how such perceptual effects extend to goal directed behaviours. To gain insight into how audio-visual stimuli are integrated for motor tasks, the kinematics of reaching movements towards visual or auditory targets with or without a non-target in the other modality were examined. When present, the simultaneously presented non-target could be spatially coincident, to the left, or to the right of the target. Results revealed that auditory non targets did not influence reaching trajectories towards a visual target, whereas visual non-targets influenced trajectories towards an auditory target. Interestingly, the biases induced by visual non-targets were present early in the trajectory and persisted until movement end. Subsequent experimentation indicated that the magnitude of the biases was equivalent whether participants performed a perceptual or motor task, whereas variability was greater for the motor versus the perceptual tasks. We propose that visually induced trajectory biases were driven by the perceived mislocation of the auditory target, which in turn affected both the movement plan and subsequent control of the movement. Such findings provide further evidence of the dominant role visual information processing plays in encoding spatial locations as well as planning and executing reaching action, even when reaching towards auditory targets. PMID- 26253325 TI - Brachytherapy in the treatment of recurrent aggressive falcine meningiomas. AB - Recurrent aggressive falcine meningiomas are uncommon tumors that recur despite receiving extensive surgery and radiation therapy (RT). We have utilized brachytherapy as a salvage treatment in two such patients with a unique implantation technique. Both patients had recurrence of WHO Grade II falcine meningiomas despite multiple prior surgical and RT treatments. Radioactive I-125 seeds were made into strands and sutured into a mesh implant, with 1 cm spacing, in a size appropriate to cover the cavity and region of susceptible falcine dura. Following resection the vicryl mesh was implanted and fixed to the margins of the falx. Implantation in this interhemispheric space provides good dose conformality with targeting of at-risk tissue and minimal radiation exposure to normal neural tissues. The patients are recurrence free 31 and 10 months after brachytherapy treatment. Brachytherapy was an effective salvage treatment for the recurrent aggressive falcine meningiomas in our two patients. PMID- 26253326 TI - The characterization and prognostic significance of right ventricular glucose metabolism in non-ischemic dilated cardiomyopathy. AB - AIMS: In dilated cardiomyopathy (DCM), there are limited data on right ventricular (RV) glucose metabolism assessed by [(18)F]fludeoxyglucose positron emission tomography ((18)F-FDG PET) imaging. We aimed to characterize RV glucose metabolism and investigate the prognostic significance of RV FDG uptake in DCM. METHODS AND RESULTS: (18)F-FDG PET imaging and cardiac magnetic resonance imaging (MRI) were performed in 63 consecutive DCM patients within an interval of 3-7 days. There was a significant correlation between RVEF and RV FDG uptake whether corrected RV standard uptake value (cRVSUV) (r = -0.571, P < .001) or the relative RV FDG uptake determined as the ratio of RV to left ventricular (LV) corrected SUV (cR/L) (r = -0.405, P < .001) was used. During a median follow-up period of 804 days, 15 patients (23.8%) reached the primary endpoint of all-cause mortality or heart transplantation. On univariate Cox analysis, cRVSUV > 7.01 and cR/L > 0.795 were significantly associated with the overall survival (hazard ratio [HR] 5.415, 95% confidence interval [CI] 1.945-15.078, P < .001; HR 6.422, 95% CI 2.250-18.332, P < .001). Patients with increased RV FDG uptake had a worse outcome (cRVSUV > 7.01 vs cRVSUV <= 7.01, log-rank 13.085, P < .001; cR/L > 0.795 vs cR/L <= 0.795, log-rank 15.695, P < .001). On multivariate analysis, cR/L > 0.795 remained a significant independent predictor of the endpoint (HR 5.001, 95% CI 1.641-15.239, P = .004), while cRVSUV > 7.01 showed no significance (HR 2.611; 95% CI 0.797-8.558; P = .113). CONCLUSIONS: Increased RV FDG uptake was associated with RV dysfunction and may be a prognostic predictor of all-cause mortality or heart transplantation in patients with DCM. PMID- 26253328 TI - The time for radionuclide ventriculography resurrection is coming. PMID- 26253327 TI - Outcomes after inappropriate nuclear myocardial perfusion imaging: A meta analysis. AB - BACKGROUND: The relationship between inappropriate MPI and cardiovascular outcomes is poorly understood. We sought to systematically review the literature on appropriate use criteria (AUC) for MPI, including temporal trend of inappropriate testing and resulting cardiovascular outcomes. METHODS: We searched the MEDLINE database for studies related to AUC and MPI. The co-primary outcomes were abnormal test results and the presence of cardiac ischemia. Random effects odds ratios (OR) were constructed using DerSimonian-Laird method. RESULTS: A total of 22 studies with 23,443 patients were included. The prevalence of inappropriate testing was 14.8% [95% confidence interval (CI) 11.6%-18.7%]. Inappropriate MPI studies were less likely to be abnormal (OR 0.41 95% CI 0.35 0.49, P < .0001) and to demonstrate ischemia (OR 0.40, 95% CI 0.24-0.67, P < .0001) compared to appropriate testing. No difference in the rate of inappropriate tests was detected based on the midpoint of the enrollment year (P = .54). The pattern of ordering inappropriate studies was not different between cardiology and non-cardiology providers (OR 0.74, 95% CI 0.51-1.06, P = .10). CONCLUSION: Inappropriate MPI studies are less likely to yield abnormal results or demonstrate myocardial ischemia. The rate of inappropriate MPI has not decreased over time. PMID- 26253329 TI - Second generation bioethanol potential from selected Malaysia's biodiversity biomasses: A review. AB - Rising global temperature, worsening air quality and drastic declining of fossil fuel reserve are the inevitable phenomena from the disorganized energy management. Bioethanol is believed to clear out the effects as being an energy derivable product sourced from renewable organic sources. Second generation bioethanol interests many researches from its unique source of inedible biomass, and this paper presents the potential of several selected biomasses from Malaysia case. As one of countries with rich biodiversity, Malaysia holds enormous potential in second generation bioethanol production from its various agricultural and forestry biomasses, which are the source of lignocellulosic and starch compounds. This paper reviews potentials of biomasses and potential ethanol yield from oil palm, paddy (rice), pineapple, banana and durian, as the common agricultural waste in the country but uncommon to be served as bioethanol feedstock, by calculating the theoretical conversion of cellulose, hemicellulose and starch components of the biomasses into bioethanol. Moreover, the potential of the biomasses as feedstock are discussed based on several reported works. PMID- 26253330 TI - Flotation separation of polyvinyl chloride and polyethylene terephthalate plastics combined with surface modification for recycling. AB - Surface modification with potassium permanganate (KMnO4) solution was developed for separation of polyvinyl chloride (PVC) and polyethylene terephthalate (PET) waste plastics. The floatability of PVC decreases with increasing of KMnO4 concentration, treatment time, temperature and stirring rate, while that of PET is unaffected. Fourier transform infrared (FT-IR) analysis confirms that mechanism of surface modification may be due to oxidization reactions occurred on PVC surface. The optimum conditions are KMnO4 concentration 1.25 mM/L, treatment time 50 min, temperature 60 degrees C, stirring rate 300 r/min, frother concentration 17.5 g/L and flotation time 1 min. PVC and PET with different particle sizes were separated efficiently through two-stage flotation. Additionally, after ultrasonic assisted surface modification, separation of PVC and PET with different mass ratios was obtained efficiently through one-stage flotation. The purity and the recovery of the obtained products after flotation separation are up to 99.30% and 99.73%, respectively. A flotation process was designed for flotation separation of PVC and PET plastics combined with surface modification. This study provides technical insights into physical separation of plastic wastes for recycling industry. PMID- 26253331 TI - Pain as metaphor: metaphor and medicine. AB - Like many other disciplines, medicine often resorts to metaphor in order to explain complicated concepts that are imperfectly understood. But what happens when medicine's metaphors close off thinking, restricting interpretations and opinions to those of the negative kind? This paper considers the deleterious effects of destructive metaphors that cluster around pain. First, the metaphoric basis of all knowledge is introduced. Next, a particular subset of medical metaphors in the domain of neurology (doors/keys/wires) are shown to encourage mechanistic thinking. Because schematics are often used in medical textbooks to simplify the complex, this paper traces the visual metaphors implied in such schematics. Mechanistic-metaphorical thinking results in the accumulation of vast amounts of data through experimentation, but this paper asks what the real value of the information is since patients can generally only expect modest benefits- or none at all--for relief from chronic pain conditions. Elucidation of mechanism through careful experimentation creates an illusion of vast medical knowledge that, to a significant degree, is metaphor-based. This paper argues that for pain outcomes to change, our metaphors must change first. PMID- 26253332 TI - Prevention of delirium (POD) for older people in hospital: study protocol for a randomised controlled feasibility trial. AB - BACKGROUND: Delirium is the most frequent complication among older people following hospitalisation. Delirium may be prevented in about one-third of patients using a multicomponent intervention. However, in the United Kingdom, the National Health Service has no routine delirium prevention care systems. We have developed the Prevention of Delirium Programme, a multicomponent delirium prevention intervention and implementation process. We have successfully carried out a pilot study to test the feasibility and acceptability of implementation of the programme. We are now undertaking preliminary testing of the programme. METHODS/DESIGN: The Prevention of Delirium Study is a multicentre, cluster randomised feasibility study designed to explore the potential effectiveness and cost-effectiveness of the Prevention of Delirium Programme. Sixteen elderly care medicine and orthopaedic/trauma wards in eight National Health Service acute hospitals will be randomised to receive the Prevention of Delirium Programme or usual care. Patients will be eligible for the trial if they have been admitted to a participating ward and are aged 65 years or over. The primary objectives of the study are to provide a preliminary estimate of the effectiveness of the Prevention of Delirium Programme as measured by the incidence of new onset delirium, assess the variability of the incidence of new-onset delirium, estimate the intracluster correlation coefficient and likely cluster size, assess barriers to the delivery of the Prevention of Delirium Programme system of care, assess compliance with the Prevention of Delirium Programme system of care, estimate recruitment and follow-up rates, assess the degree of contamination due to between-ward staff movements, and investigate differences in financial costs and benefits between the Prevention of Delirium Programme system of care and standard practice. Secondary objectives are to investigate differences in the number, severity and length of delirium episodes (including persistent delirium); length of stay in hospital; in-hospital mortality; destination at discharge; health related quality of life and health resource use; physical and social independence; anxiety and depression; and patient experience. DISCUSSION: This feasibility study will be used to gather data to inform the design of a future definitive randomised controlled trial. TRIAL REGISTRATION: ISRCTN01187372 . Registered 13 March 2014. PMID- 26253333 TI - Alendronate treatment alters bone tissues at multiple structural levels in healthy canine cortical bone. AB - Bisphosphonates are widely used to treat osteoporosis, but have been associated with atypical femoral fractures (AFFs) in the long term, which raises a critical health problem for the aging population. Several clinical studies have suggested that the occurrence of AFFs may be related to the bisphosphonate-induced changes of bone turnover, but large discrepancies in the results of these studies indicate that the salient mechanisms responsible for any loss in fracture resistance are still unclear. Here the role of bisphosphonates is examined in terms of the potential deterioration in fracture resistance resulting from both intrinsic (plasticity) and extrinsic (shielding) toughening mechanisms, which operate over a wide range of length-scales. Specifically, we compare the mechanical properties of two groups of humeri from healthy beagles, one control group comprising eight females (oral doses of saline vehicle, 1 mL/kg/day, 3 years) and one treated group comprising nine females (oral doses of alendronate used to treat osteoporosis, 0.2mg/kg/day, 3 years). Our data demonstrate treatment-specific reorganization of bone tissue identified at multiple length scales mainly through advanced synchrotron x-ray experiments. We confirm that bisphosphonate treatments can increase non-enzymatic collagen cross-linking at molecular scales, which critically restricts plasticity associated with fibrillar sliding, and hence intrinsic toughening, at nanoscales. We also observe changes in the intracortical architecture of treated bone at microscales, with partial filling of the Haversian canals and reduction of osteon number. We hypothesize that the reduced plasticity associated with BP treatments may induce an increase in microcrack accumulation and growth under cyclic daily loadings, and potentially increase the susceptibility of cortical bone to atypical (fatigue like) fractures. PMID- 26253334 TI - Two unusual hepatitis C virus subtypes, 2j and 2q, in Spain: Identification by nested-PCR and sequencing of a NS5B region. AB - Many studies have reported the use of the NS5B gene to subtype hepatitis C virus (HCV). Other HCV genes, such as HCV-5' UTR, Core (C) and E1, have also been used. In some studies, NS5B have been used together with 5'-UTR or C genes to improve genotyping results obtained using commercial procedures. Only two studies in Spain have compared molecular techniques versus commercial procedures regarding the efficacy of HCV subtyping. The aim of this study was to determine whether nested PCR and sequencing of a NS5B region was more reliable than commercial procedures to subtype HCV. We analyzed the results of HCV genotyping in [726] serum specimens collected from 2001 to 2013. From 2001 to 2011, we used PCR and INNO-LiPA hybridization or its new version Versant HCV Genotype 2.0 assay (471 samples). From 2012 to 2013, we used nested PCR and sequencing of a NS5B region (255 cases). This method used two pairs of primers to amplify the RNA of the sample converted to DNA by retrotranscription. The amplification product of 270 base pairs was further sequenced. To identify the subtype, the sequences obtained were compared to those in the international database: http://hcv.lanl.gov./content/sequence/, HCV/ToolsOutline.html and Geno2pheno[hcv] http://hcv.bioinf.mpi-inf.mpg.de/index.php. Nested PCR of a NS5B region and sequencing identified all but one subtype (0.4%, 1/255), differentiated all 1a subtypes from 1b subtypes, and characterized all HCV 2-4 subtypes. This approach also distinguished two subtypes, 2j and 2q, that had rarely been detected previously in Spain. However, commercial procedures failed to subtype 12.7% (60/471) of samples and to genotype 0.6% of specimens (3/471). Nested PCR and sequencing of a NS5B region improved the subtyping of HCV in comparison with classical procedures and identified two rare subtypes in Spain: 2j and 2q. However, full length genome sequencing is recommended to confirm HCV 2j and 2q subtypes. PMID- 26253335 TI - Development of an enzyme-linked immunosorbent assay for the monitoring and surveillance of antibodies to porcine epidemic diarrhea virus based on a recombinant membrane protein. AB - The recent dramatic increase in reported cases of porcine epidemic diarrhea (PED) in pig farms is a potential threat to the global swine industry. Therefore, the accurate diagnosis, serological monitoring, and surveillance of specific antibodies in pigs resulting from porcine epidemic diarrhea virus (PEDV) infection or vaccination would be essential in helping to control the spread of PED. We developed and validated an indirect enzyme-linked immunosorbent assay (ELISA) based on the recombinant membrane (M) protein of PEDV. To detect PEDV antibodies in eight herds, 382 serum samples were collected from sows that had been immunized with a PED vaccine, and screened using the developed ELISA in parallel with a serum neutralization (SN) assay. Of the tested samples, 276 were positive for the presence of PEDV antibodies according to both assays, while 98 were negative. An excellent agreement between the ELISA and the SN assay was observed (kappa=0.947; 95% confidence interval=0.910-0.984; McNemar's test, P=0.727). No cross-reaction was detected for the developed ELISA with other coronaviruses or other common pig pathogens. The developed ELISA could be used for serological evaluation and indirect diagnosis of PED infection. PMID- 26253336 TI - What proportion of women refers moderate to severe pain during office hysteroscopy with a mini-hysteroscope? A systematic review and meta-analysis. AB - BACKGROUND: Mini-hysteroscopy is believed to be pain-free or in the least bearable. Office procedures are therefore usually performed without analgesia or anesthesia. Is it indeed as tolerable as papers and authors suggest? OBJECTIVES: To estimate what proportion of women reports moderate to severe discomfort during examination using the smaller diameter scopes. SEARCH STRATEGY: Online sources were search with key words "hysteroscopy" and "pain" from 2000 to December 2014. Thirty-five articles were retrieved for detailed analysis. SELECTION CRITERIA: Randomized controlled trials (RCT) and well-designed prospective trials (PT) studying pain as main outcome, in office mini-hysteroscopy in at least one arm. Studies or arms within a study where conscientious sedation, anesthesia, or non steroidal drugs were used were excluded. Chosen data collected was the number of women referring moderate to severe pain compared to total women with intervention in the arm or study. Authors were contacted to try to retrieve unpublished data for analysis. DATA COLLECTION AND ANALYSIS: We performed a meta-analysis from eight studies (six RCT and two PT) comparing pain reported as moderate or severe to total women in mini-hysteroscopy. MAIN RESULTS: A meta-analysis estimated the pooled prevalence of pain (>3-10 on 10 cm visual analog scale) for all studies and by two subgroups: (1) RCT and (2) PT. Due to significant heterogeneity between studies, we used the random effects model. Results revealed a high prevalence of pain in outpatient mini-hysteroscopy. CONCLUSIONS: Office mini hysteroscopy is painful. PMID- 26253337 TI - Measuring precarious employment in times of crisis: the revised Employment Precariousness Scale (EPRES) in Spain. AB - OBJECTIVE: This study examines the psychometric properties of the revised Employment Precariousness Scale (EPRES-2010) in a context of economic crisis and growing unemployment. METHODS: Data correspond to salaried workers with a contract (n=4,750) from the second Psychosocial Work Environment Survey (Spain, 2010). Analyses included acceptability, scale score distributions, Cronbach's alpha coefficient and exploratory factor analysis. RESULTS: Response rates were 80% or above, scores were widely distributed with reductions in floor effects for temporariness among permanent workers and for vulnerability. Cronbach's alpha coefficients were 0.70 or above; exploratory factor analysis confirmed the theoretical allocation of 21 out of 22 items. CONCLUSION: The revised version of the EPRES demonstrated good metric properties and improved sensitivity to worker vulnerability and employment instability among permanent workers. Furthermore, it was sensitive to increased levels of precariousness in some dimensions despite decreases in others, demonstrating responsiveness to the context of the economic crisis affecting the Spanish labour market. PMID- 26253338 TI - [Nurse prescribing, a step away from being legal]. PMID- 26253339 TI - The elimination of healthcare user fees for children under five substantially alleviates the burden on household expenses in Burkina Faso. AB - BACKGROUND: Since September 2008, an intervention has made it possible to provide free care to children under five in public health facilities in two districts of Burkina Faso. This study evaluated the intervention's impact on household expenses incurred for services (consultations and medications) to the children targeted. METHODS: The study is based on a survey of a representative panel of 1,260 households encountered in two waves, one month before and 12 months after the introduction of the intervention. The questions explored the illness episodes of all children under five in the 30 days before each wave. The analysis of health expenses incurred during an illness episode distinguished between total expenses and those incurred in public health facilities (charges for services and medications). Analyses based on multilevel simultaneous equation models were used to estimate the probability of spending and the amount spent, in a context where a large number of observations returned a count of zero. RESULTS: The burden on household expenses was greatly alleviated under the intervention. Average expenditure dropped from US$11 per episode of care to less than US$2 after the intervention was implemented. The risk of incurring an expense at a public health facility was reduced by two-thirds. The facility users' savings were primarily related to medication purchases. In rural areas, where barriers to access health services are more acute, both poor and non-poor families benefited from the intervention. The probability of spending on medications dropped dramatically for both the poor and the non-poor under the exemption (-75% vs.-77%), and the reduction in expenses for medications generated by the intervention was comparable for both groups in relative values (-86% vs.-89%). CONCLUSION: User fees abolition at the point of service substantially alleviated the burden on household expenses. The intervention benefited both poor and non-poor families and provided financial protection. PMID- 26253340 TI - Alteration of brainstem raphe measured by transcranial sonography in depression patients with or without Parkinson's disease. AB - The purpose of our study was to assess the alteration of the brainstem raphe (BR) on transcranial sonography (TCS) in depression patients with or without Parkinson's disease (PD) and to explore whether the different changes of BR could reflect an increasing impairment of raphe structures. TCS was performed in patients with PD, depression with PD, depression only, and controls. Using the red nucleus as an internal standard, the BR was rated semi-quantitatively from grades 1-4 with grades 1-3 determined as abnormal. The rate of abnormal BR (<=grade 3) was found to be only 10 % in patients with PD (4/40) and 5 % in control patients (2/40). The rate of abnormal raphe was significantly higher (p < 0.05) in patients with both depression and PD (85 %, 34/40) or patients with depression only (87.5 %, 35/40). TCS of the raphe in most patients with mild depression scored grade 3, while those with moderate depression scored grade 2-3, and those with severe depression scored grade 1. The different BR echogenicity score reflected an increasing impairment of raphe structures in depression patients with or without PD (p < 0.05). TCS provides a good tool for assessing depression, more severe depressive symptoms were associated with different aspects in TCS studies. PMID- 26253341 TI - Host, disease, and antiretroviral factors are associated with normalization of the CD4:CD8 ratio after initiating antiretroviral therapy. PMID- 26253342 TI - Look before you LEAP: Risk of anaphylaxis in high-risk infants with early introduction of peanut. PMID- 26253343 TI - Reply: To PMID 25705822. PMID- 26253344 TI - Atopic dermatitis is associated with an increased risk for rheumatoid arthritis and inflammatory bowel disease, and a decreased risk for type 1 diabetes. AB - BACKGROUND: Atopic dermatitis (AD) is characterized by epidermal barrier failure and immune-mediated inflammation. Evidence on AD as a potential risk factor for inflammatory comorbidities is scarce. OBJECTIVES: We sought to test the hypothesis that prevalent AD is a risk factor for incident rheumatoid arthritis (RA) and inflammatory bowel disease (IBD; Crohn disease [CD], ulcerative colitis [UC]) and is inversely related to type 1 diabetes (T1D) and to investigate established RA, IBD, and T1D susceptibility loci in AD. METHODS: This cohort study used data from German National Health Insurance beneficiaries aged 40 years or younger (n = 655,815) from 2005 through 2011. Prevalent AD in the period 2005 to 2006 was defined as primary exposure, and incident RA, IBD, and T1D in the period 2007 to 2011 were defined as primary outcomes. Risk ratios were calculated with generalized linear models. Established RA, IBD, and T1D loci were explored in high-density genotyping data from 2,425 cases with AD and 5,449 controls. RESULTS: Patients with AD (n = 49,847) were at increased risk for incident RA (risk ratio [RR], 1.72; 95% CI, 1.25-2.37) and/or IBD (CD: RR, 1.34; 95% CI, 1.11 1.61; UC: RR, 1.25; 95% CI, 1.03-1.53). After adjusting for health care utilization, there was a nominally significant inverse effect on T1D risk (RR, 0.72; 95% CI, 0.53-0.998). There was no disproportionate occurrence of known RA, CD, UC, or T1D risk alleles in AD. CONCLUSIONS: AD is a risk factor for the development of RA and IBD. This excess comorbidity cannot be attributed to major known IBD and RA genetic risk factors. PMID- 26253345 TI - Watchdog questions usefulness of UK's L600m health and care regulators. PMID- 26253346 TI - Multiply labeling proteins for studies of folding and stability. AB - Fluorescence spectroscopy is a powerful method for monitoring protein folding in real-time with high resolution and sensitivity, but requires the site-specific introduction of labels into the protein. The ability to genetically incorporate unnatural amino acids (Uaas) allows for the efficient synthesis of fluorescently labeled proteins with minimally perturbing fluorophores. Here, we describe recent uses of labeled proteins in dynamic structure determination experiments and advances in unnatural amino acid incorporation for dual site-specific fluorescent labeling. The advent of increasingly sophisticated bioorthogonal chemistry reactions and the diversity of Uaas available for incorporation will greatly enable protein folding and stability studies. PMID- 26253347 TI - Spatially distinct responses within willow to bark stripping by deer: effects on insect herbivory. AB - Within individual plants, cervid herbivory may cause positive or negative plant mediated effects on insect herbivores, depending on where it occurs. Using a combination of field observations and artificial bark-stripping experiments in Hokkaido, Japan, we examined the plant-mediated effects of bark stripping by sika deer (Cervus nippon yesoensis) on insect herbivory in two spatially distinct parts of willow (Salix udensis) trees: resprouting leaves below bark-stripping wounds and canopy leaves above. Natural and artificial bark stripping stimulated resprouting from trunks below wounds. Resprouting leaves on bark-stripped trees had lower total phenolics, condensed tannin, and C/N ratios than did canopy leaves on control trees. Herbivory rates were higher in resprouting leaves on bark-stripped trees than in canopy leaves on controls. Conversely, above-wound canopy leaves on bark-stripped trees had higher total phenolics than did those on controls, while herbivory rates were lower in the canopy leaves of bark-stripped trees than in those on controls. These results demonstrate that plant-mediated effects of bark stripping diverge between plant tissues below and above wounds in individual willow trees. We submit that focusing on multiple plant parts can elucidate plant-mediated effects at the whole-plant scale. PMID- 26253348 TI - [Sudden cardiac death. Risk stratification, prevention and treatment]. PMID- 26253349 TI - Long-term mortality after lower-limb amputation. AB - BACKGROUND: Mortality after amputation is known to be extremely high and is associated with a number of patient features. We wished to calculate this mortality after first-time lower-limb amputation and investigate whether any population or treatment factors are associated with worse mortality. OBJECTIVE: To follow up individuals after lower limb amputation and ascertain the mortality rate as well as population or treatment features associated with mortality. STUDY DESIGN: A prospective cohort study. METHODS: Prospective lower-limb amputations over 1 year (N = 105) at a Regional Rehabilitation Centre were followed up for 3 years. RESULTS: After 3 years, 35 individuals in the cohort had died, representing a mortality of 33%. On initial univariate analysis, those who died were more likely to have diabetes mellitus (chi(2) = 7.16, df = 1, p = 0.007) and less likely to have been fitted with a prosthesis (chi(2) = 5.84, df = 1, p = 0.016). There was no association with age, gender, level of amputation, social isolation, significant medical co-morbidity other than diabetes or presence of mood disorders. A multi-variable logistic regression (backward step) confirmed that diabetes (odds ratio = 3.04, confidence intervals = 1.25-7.40, p = 0.014) and absence of prosthesis-fitting (odds ratio = 2.60, confidence interval = 1.16 6.25, p = 0.028) were independent predictors of mortality. CONCLUSION: Mortality after amputation is extremely high and is increased in individuals with diabetes or in those who are not fitted with a prosthesis after amputation. CLINICAL RELEVANCE: The link between diabetes and mortality after amputation has been noted by others, but this is the first study to find an effect from prosthetic limb-wearing. This requires further investigation to ascertain why the wearing of a prosthetic limb, confers an independent survival benefit that is not related to the presence of medical co-morbidity. PMID- 26253350 TI - Omission of Physical Therapy Recommendations for High-Risk Patients Transitioning From the Hospital to Subacute Care Facilities. AB - OBJECTIVES: To assess the quality and explore the potential impact of the communication of physical therapy (PT) recommendations in hospital discharge summaries/orders for high-risk subacute care populations, specifically targeting recommendations for (1) maintenance of patient safety, (2) assistance required for mobility, and (3) use of assistive devices. DESIGN: Medical record abstraction of retrospective cohort comparing discharge recommendations made by inpatient PT to orders included in written hospital discharge summaries/orders, the primary form of hospital-to-subacute care communication. Data were linked to Medicare outcomes from corresponding years for all Medicare beneficiaries in the cohort. SETTING: Academic hospital. PARTICIPANTS: All hospitalized patients (N=613 overall) 18 years and older with primary diagnoses of stroke or hip fracture, with an inpatient PT consultation and discharged to subacute care during the years 2006 to 2008; 366 of these were Medicare beneficiaries. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Combined rehospitalization, emergency department visit, and/or death within 30 days of discharge. RESULTS: Omission of recommendations for maintaining patient safety occurred in 54% (316/584) of patients; for assistance required for mobility, in approximately 100% (535/537); and for use of assistive devices, in 77% (409/532). As compared with those without patient safety restriction/precaution omissions, Medicare beneficiaries with such omissions demonstrated a trend toward more negative 30 day outcomes (26% vs 18%, P=.10). Similar, albeit nonsignificant, outcome trends were observed in the other omission categories. CONCLUSIONS: PT recommendations made during a hospital stay in high-risk patients are routinely omitted from hospital discharge communications to subacute care facilities. Interventions to reliably improve this communication are needed. PMID- 26253351 TI - Arthroscopic Latarjet procedure: is optimal positioning of the bone block and screws possible? A prospective computed tomography scan analysis. AB - HYPOTHESIS: We hypothesized that the arthroscopic Latarjet procedure could be performed with accurate bone block positioning and screw fixation with a similar rate of complications to the open Latarjet procedure. METHODS: In this prospective study, 105 shoulders (104 patients) underwent the arthroscopic Latarjet procedure performed by the same senior surgeon. The day after surgery, an independent surgeon examiner performed a multiplanar bidimensional computed tomography scan analysis. We also evaluated our learning curve by comparing 2 chronologic periods (30 procedures performed in each period), separated by an interval during which 45 procedures were performed. RESULTS: Of the 105 shoulders included in the study, 95 (90.5%) (94 patients) were evaluated. The coracoid graft was accurately positioned relative to the equator of the glenoid surface in 87 of 95 shoulders (91.5%). Accurate bone-block positioning on the axial view with "circle" evaluation was obtained for 77 of 95 shoulders (81%). This procedure was performed in a lateralized position in 7 of 95 shoulders (7.3%) and in a medialized position in 11 shoulders (11.6%). The mean screw angulation with the glenoid surface was 21 degrees . One patient had transient axillary nerve palsy. Of the initial 104 patients, 3 (2.8%) underwent revision. The analysis of our results indicated that the screw-glenoid surface angle significantly predicted the accuracy of the bone-block positioning (P = .001). Our learning curve estimates showed that, compared with our initial period, the average surgical time decreased, and the risk of lateralization showed a statistically significant decrease during the last period (P = .006). CONCLUSIONS: This study showed that accurate positioning of the bone block onto the anterior aspect of the glenoid is possible, safe, and reproducible with the arthroscopic Latarjet procedure without additional complications compared with open surgery. PMID- 26253353 TI - Transition From Child to Adult Services: Current Research, Theory and Practice. PMID- 26253352 TI - Outcomes of anatomic shoulder arthroplasty in primary osteoarthritis in type B glenoids. AB - BACKGROUND: Primary glenohumeral osteoarthritis with posterior wear of the glenoid and posterior subluxation of the humerus (Walch type B) presents a challenge to the treating surgeon. Our hypothesis was that glenoids with biconcavity (B2) would be associated with worse outcomes (functional scores and complications) than B1 glenoids. MATERIALS AND METHODS: We retrospectively analyzed prospectively collected data on 112 anatomic total shoulder arthroplasties (104 patients) with B glenoids. Preoperative computed tomography identified 64 B1 glenoids and 48 B2 glenoids (50 and 37 available for follow-up). RESULTS: A significant difference between B1 and B2 glenoids was noted in average retroversion (11 degrees vs. 16 degrees ; P < .001) and average posterior humeral subluxation (65% vs. 75%; P < .001). No significant difference was seen in mean age (69.5 vs. 69.2 years) or body mass index (28.5 vs. 27.4) at time of surgery. At average follow-up of 60 months (range, 23-120 months), glenoid component radiolucencies (51.6%, B1; 47.9%, B2), range of motion, preoperative and postoperative scores of the shortened Disabilities of the Arm, Shoulder, and Hand questionnaire, and patient satisfaction were not significantly different between the 2 groups. Four revisions (4.6%) were documented for acute postoperative infection (2.3%), subscapularis failure (1.1%), and glenoid loosening (1.1%). CONCLUSIONS: Although biconcave glenoids commonly have more severe retroversion and posterior subluxation of the humerus, we were unable to find a clinical or radiographic difference in outcome of patients with B1 or B2 glenoids treated with anatomic total shoulder arthroplasty at intermediate-term follow-up. Continued clinical and radiographic follow-up of these cohorts will be necessary to assess any future divergence in outcome. PMID- 26253354 TI - Inhalation of titanium dioxide induces endoplasmic reticulum stress-mediated autophagy and inflammation in mice. AB - Titanium dioxide (TiO2) nanoparticles are widely used in cosmetics, sunscreen, electronics, drug delivery systems, and diverse bio-application fields. In the workplace, the primary exposure route for TiO2 nanoparticles is inhalation through the respiratory system. Because TiO2 nanoparticles have different physiological properties, in terms of size and bioactivity, their toxic effects in the respiratory system must be determined. In this study, to determine the toxic effect of inhaled TiO2 nanoparticles in the lung and the underlying mechanism, we used a whole-body chamber inhalation system to expose A/J mice to TiO2 nanoparticles for 28 days. During the experiments, the inhaled TiO2 nanoparticles were characterized using a cascade impactor and transmission electron microscopy. After inhalation of the TiO2 nanoparticles, hyperplasia and inflammation were observed in a TiO2 dose-dependent manner. To determine the biological mechanism of the toxic response in the lung, we examined endoplasmic reticulum (ER) and mitochondria in lung. The ER and mitochondria were disrupted and dysfunctional in the TiO2-exposed lung leading to abnormal autophagy. In summary, we assessed the potential risk of TiO2 nanoparticles in the respiratory system, which contributed to our understanding of the mechanism underlining TiO2 nanoparticle toxicity in the lung. PMID- 26253355 TI - Simultaneous improvement of solubility and permeability by fabricating binary glassy materials of Talinolol with Naringin: Solid state characterization, in vivo in-situ evaluation. AB - The aim of the current study was to prepare binary amorphous forms of Talinolol (TLN) by using Naringin (NRG) as a stabilizing agent. The secondary objective of this study was to study the effect of P-gp inhibitor NRG on the P-gp probe drug TLN. The binary amorphous samples were prepared by quench cooling technique in the molar ratios TLN:NRG (1:1), TLN:NRG (1:2), TLN:NRG (2:1). The prepared samples were characterized by DSC, FTIR and XRD. Amorphicity of the prepared binary amorphous samples was confirmed by spotting diffuse halo in the diffractograms and further corroborated by detecting glass transition event (Tg) in the thermograms of the respective samples. The Tgs for all prepared systems were found above room temperature, the highest being 45.43 degrees C. The systems were found physically stable at 25 degrees C and 40 degrees C at dry conditions for 60 days. The temperature stability of prepared amorphous forms may be attributed to strong intermolecular hydrogen bond interaction between TLN and NRG, which was confirmed by Gordon-Taylor calculations and FTIR data. The solubility of TLN in amorphous form was increased by approximately 9-fold as compared to its crystalline counterpart. The in-vivo bioavailability study conducted on wistar rats demonstrated 5.4-fold increase in the AUC0-t value for TLN as compared to its crystalline counterpart. Further to learn the contribution of P-gp inhibition by NRG on the permeability of TLN, In-vitro single pass perfusion studies were conducted on the ileum of wistar rats. The permeability of TLN in rat ileum in the presence of NRG was significantly increased to 3.16*10( 5) cm/s as compare to control value 2.48*10(-5) cm/s. The current study demonstrated the ability of binary amorphous technology to simultaneously overcome both the BCS barriers i.e. solubility and permeability. PMID- 26253357 TI - Alloantigen-specific T-cell hyporesponsiveness induced by dnIKK2 gene-transfected recipient immature dendritic cells. AB - Immature dendritic cells (iDCs) have been shown to be able to induce peripheral T cell tolerance through distinct pathways. Here, we investigated the tolerogenic property of recipient iDCs whose maturation was arrested by a dominant negative mutant of inhibitor of nuclear factor kappa-B kinase 2 (dnIKK2) gene. We found that dnIKK2-iDCs presented a typical semi-mature morphology and expressed lower levels of CD80 and CD86, slightly higher MHC-II than untransfected iDCs. The expression of these molecules had no significant change even dnIKK2-iDCs were pulsed by donor antigen. In primary mixed leukocyte reaction (MLR), dnIKK2-iDCs exhibited impaired ability to stimulate allogeneic T-cells, but induced CD4(+)CD25(-) T-cell formation. In co-culture MLR, these CD4(+)CD25(-) T-cells suppressed T-cell alloreaction in an antigen-specific manner. Besides, CD4(+)CD25(-) T-cells inhibited IL-2 and IFN-gamma release, whereas promoted IL 10 and TGF-beta secretion. These data suggested recipient dnIKK2-iDCs could maintain peripheral tolerance through down-regulating costimulatory molecule expressions and inducing CD4(+)CD25(-) T-cell formation. PMID- 26253358 TI - Minimally invasive surgery with locking plate for periprosthetic femoral fractures: technical note. AB - PURPOSE: Periprosthetic fractures of the femur are increasing due to the increase of arthroplasties and the aging population. They concern a population that is often elderly and with important comorbidities that complicate managing this already complex pathology. Usual complications of classic osteosynthesis are numerous, including infections and nonunions and the need for delayed weight bearing after surgery. METHODS-RESULTS: The development of locking plates has allowed complication avoidance. When used in minimally invasive surgery, they combine the biological advantages of closed-wound surgery to the mechanical advantages of locking plates, which have better stability in fragile bones. We propose a technical update on handling such fractures by using locking plates under minimally invasive surgery. DISCUSSION-CONCLUSION: In our experience, under certain guidelines, this allows for immediate post-operative full weight bearing, which is beneficial to these often elderly patients. PMID- 26253359 TI - Subtalar arthrodesis stabilisation with screws in an angulated configuration is superior to the parallel disposition: a biomechanical study. AB - PURPOSE: The purpose of this study was to compare the stability of two established screw configurations (SC) for subtalar arthrodesis using a cyclic loading model. METHODS: Eight paired human cadaver hindfoot specimens underwent subtalar arthrodesis with either parallel or angulated SC. The instrumented specimens were subjected to a cyclic loading protocol (1000 cycles: +/-5 Nm rotation moment, 50 N axial force). The joint range of motion (ROM) was quantified before and after cyclic loading, in the three principal motion planes of the subtalar joint using pure bending moments of +/-3 Nm. RESULTS: After instrumentation, the angulated SC showed significantly less mean ROM compared to the parallel SC in internal/external rotation (1.4 degrees +/- 2.2 degrees vs. 3.3 degrees +/- 2.8 degrees , P = 0.006) and in inversion/eversion (0.9 degrees +/- 1.4 degrees vs. 1.5 degrees +/- 1.1 degrees , P = 0.049). After cyclic loading, the angulated SC resulted in significantly less mean ROM compared to the parallel SC in internal/external rotation (3.3 degrees +/- 4.6 degrees vs. 8.8 degrees +/- 8.0 degrees , P = 0.006) and in inversion/eversion (1.9 degrees +/- 2.3 degrees vs. 3.9 degrees +/- 3.9 degrees , P = 0.017). No significant differences in the mean ROM were found between the angulated and parallel SC in dorsal extension/plantar flexion. CONCLUSION: The angulated SC resulted in decreased ROM in the subtalar arthrodesis construct after instrumentation and after cyclic loading compared to the parallel SC. The data from our study suggest that the clinical use of the angulated SC for subtalar arthrodesis might be superior to the parallel SC. PMID- 26253360 TI - Targeting PI3K/Akt/mTOR signaling pathway in the treatment of prostate cancer radioresistance. AB - The phosphatidylinositol-3-kinase/Akt and the mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is one of the most frequently activated signaling pathways in prostate cancer (CaP) and other cancers, and responsible for the survival, metastasis and therapeutic resistance. Recent advances in radiation therapy indicate that activation of this pathway is closely associated with cancer radioresistance, which is a major challenge for the current CaP radiation treatment. Therefore, targeting this pathway by inhibitors to enhance radiosensitivity has great potential for clinical benefits of CaP patients. In this review, we summarize the recent findings in the PI3K/Akt/mTOR pathway in CaP radiotherapy research and discuss the potential use of the PI3K/Akt/mTOR pathway inhibitors as radiosensitizers in the treatment of CaP radioresistance in preclinical studies to explore novel approaches for future clinical trials. PMID- 26253361 TI - [Fritz Kahn's The Life of Man: Production and Transcription of a Bestseller]. AB - This paper investigates the production and circulation of the illustrations in Fritz Kahn's five-volume series The Life of Man, one of the most popular medical publications in the German interwar period. In 1912 Kahn (1888-1968), together with a staff of illustrators, began producing what would later become his best selling series. Illustrations of this series (in particular, the poster The human factory/Der Mensch als Industriepalast) were widespread throughout Germany during the Weimar Republic. With the rise of National Socialism, Kahn was forced to emigrate in 1933. While his books were forbidden by the Nazi regime, their illustrations continued to play an important role in popular scientific discourse: they reappeared in the Nazi health-education programme and were adapted for Kahn's publications in exile at the same time. This paper discusses how their production process and collective authorship made this complex and heterogeneous reception possible. PMID- 26253362 TI - Pathophysiology of pyoderma gangrenosum (PG): an updated review. AB - Pyoderma gangrenosum is a challenging skin condition to identify and treat because of its multifactorial pathogenesis. It is a rare cutaneous manifestation diagnosed clinically by exclusion of infection, neoplasia, thrombophilia, and other inflammatory conditions. Pathogenetic and treatment studies are scarce. Abnormalities in the function of inflammatory cytokines, the immune system, and neutrophils combined with specific genetic mutations predispose patients to develop this complex disease process. Early recognition of patients at risk for pyoderma gangrenosum, the necessity to improve its early diagnosis, and the future outlook of targeted and personalized therapies relies on the improved comprehension of the complex pathogenesis of pyoderma gangrenosum. PMID- 26253363 TI - H1-antihistamines for chronic spontaneous urticaria: an abridged Cochrane Systematic Review. AB - BACKGROUND: Chronic spontaneous urticaria is characterized by recurrent itchy wheals. First-line management is with H1-antihistamines. OBJECTIVE: We sought to conduct a Cochrane Review of H1-antihistamines in the treatment of chronic spontaneous urticaria. METHODS: A systematic search of major databases for randomized controlled trials was conducted. RESULTS: We included 73 studies with 9759 participants; 34 studies provided outcome data for 23 comparisons. Compared with placebo, cetirizine 10 mg daily in the short and intermediate term (RR 2.72; 95% confidence interval [CI] 1.51-4.91) led to complete suppression of urticaria. Levocetirizine 20 mg daily was effective for short-term use (RR 20.87; 95% CI 1.37-317.60) as was 5 mg for intermediate-term use (RR 52.88; 95% CI 3.31 843.81). Desloratadine 20 mg was effective for the short term (RR 15.97; 95% CI 1.04-245.04) as was 5 mg in the intermediate term (RR 37.00; 95% CI 2.31-593.70). There was no evidence to suggest difference in adverse event rates between treatments. LIMITATIONS: Some methodological limitations were observed. Few studies for each comparison reported outcome data that could be incorporated in meta-analyses. CONCLUSIONS: At standard doses, several antihistamines are effective and safe in complete suppression of chronic spontaneous urticaria. Research on long-term treatment using standardized outcome measures and quality of life scores is needed. PMID- 26253364 TI - Health care resource use, productivity, and costs among patients with moderate to severe plaque psoriasis in the United States. AB - BACKGROUND: Comprehensive studies on costs of moderate to severe plaque psoriasis (MSPP) have not been conducted in the United States. OBJECTIVE: We sought to evaluate current health care resource use, productivity, and costs among patients with MSPP in routine practice. METHODS: A total of 200 adults seeking MSPP treatment enrolled in 9 US sites. Consented patients reported symptoms, treatment, lost productivity, and costs; 6-month retrospective chart review captured health care resource use and clinical characteristics. Costs were assigned to health care resource use and lost productivity using standard algorithms. Differences by Psoriasis Area and Severity Index (PASI) group, based on PASI score (<=10, >10-<=20, >20) at enrollment, were evaluated. Analyses included descriptive statistics and analysis of variance or Kruskal-Wallis tests. RESULTS: Most patients (79.5%) were prescribed 1 or more MSPP medications (mean: 1.5); 36.0% and 9.0% received self-administered biologics and systemic therapies, respectively. Mean number of nonprescription treatments was 12.3. Differences by PASI group were observed for overall work and activity impairment (P < .02). Six month total MSPP direct costs per patient were $11,291; indirect costs were $2101 and differed across PASI groups (P = .0008). LIMITATIONS: This study enrolled patients with MSPP actively seeking care. CONCLUSION: Despite treatment, a number of patients with MSPP continue to experience moderate to severe PASI scores, impaired functioning, and high costs suggesting a need for new treatment options. PMID- 26253365 TI - Prognostic factors and outcome in anorexia nervosa: a follow-up study. AB - BACKGROUND AND AIMS: Anorexia nervosa is an eating disorder characterized by food restriction, irrational fear of gaining weight and consequent weight loss. High mortality rates have been reported, mostly due to suicide and malnutrition. Good outcomes largely vary between 18 and 42%. We aimed to assess outcome and prognostic factors of a large group of patients with anorexia nervosa. Moreover we aimed to identify clusters of prognostic factors related to specific outcomes. METHODS: We retrospectively reviewed data of 100 patients diagnosed with anorexia nervosa previously hospitalized in a tertiary level structure. Then we performed follow-up structured telephone interviews. RESULTS: We identified four dead patients, while 34% were clinically recovered. In univariate analysis, short duration of inpatient treatment (p = 0.003), short duration of disorder (p = 0.001), early age at first inpatient treatment (p = 0.025) and preserved insight (p = 0.029) were significantly associated with clinical recovery at follow-up. In multiple logistic regression analysis, duration of first inpatient treatment, duration of disorder and preserved insight maintained their association with outcome. Moreover multiple correspondence analysis and cluster analysis allowed to identify different typologies of patients with specific features. Notably, group 1 was characterized by two or more inpatient treatments, BMI <= 14, absence of insight, history of long-term inpatient treatments, first inpatient treatment >=30 days. While group 4 was characterized by preserved insight, BMI >= 16, first inpatient treatment <=14 days, no more than one inpatient treatment, no psychotropic drugs intake, duration of illness <=4 years. CONCLUSIONS: We confirmed the association between short duration of inpatient treatment, short duration of disorder, early age at first inpatient treatment, preserved insight and clinical recovery. We also differentiated patients with anorexia nervosa in well-defined outcome groups according to specific clusters of prognostic factors. Our study might help clinicians to evaluate prognosis of patients with anorexia nervosa. PMID- 26253366 TI - Mitochondria-targeted antioxidants. AB - Redox homeostasis is maintained by the antioxidant defense system, which is responsible for eliminating a wide range of oxidants, including reactive oxygen species (ROS), lipid peroxides, and metals. Mitochondria-localized antioxidants are widely studied because the mitochondria, the major producers of intracellular ROS, have been linked to the cause of aging and other chronic diseases. Mitochondria-targeted antioxidants have shown great potential because they cross the mitochondrial phospholipid bilayer and eliminate ROS at the heart of the source. Growing evidence has identified mitochondria-targeted antioxidants, such as MitoQ and tiron, as potentially effective antioxidant therapies against the damage caused by enhanced ROS generation. This literature review summarizes the current knowledge on mitochondria-targeted antioxidants and their contribution to the body's antioxidant defense system. In addition to addressing the concerns surrounding current antioxidant strategies, including difficulties in targeting antioxidant treatment to sites of pathologic oxidative damage, we discuss promising therapeutic agents and new strategic approaches. PMID- 26253367 TI - Society for Vascular Medicine Annual Meeting - June 2015 Baltimore, Maryland, USA. PMID- 26253368 TI - Vascular disease patient information page. Inferior vena cava (IVC) filters. AB - IVC filters are medical devices that are placed in the large vein of the abdomen to prevent blood clots from traveling from the veins of the legs to the lungs. They are most commonly used when a patient cannot receive blood thinners to treat leg blood clots (DVT). IVC filter insertion can be done as an outpatient under local anesthesia, with only a puncture to a vein in the leg or neck. Most IVC filters are designed to be removed when no longer necessary. IVC filter complications are uncommon. PMID- 26253369 TI - COCATS 4 Task Force 9: Training in Vascular Medicine: Endorsed by the Society for Vascular Medicine. PMID- 26253371 TI - Evidence in Ophthalmology: Are We Doing Better? PMID- 26253373 TI - Polypyrrole/magnetic nanoparticles composite as an efficient sorbent for dispersive micro-solid-phase extraction of antidepressant drugs from biological fluids. AB - In this study, polypyrrole/magnetic nanoparticles composites in the presence of two different dopants were synthesized with the aid of chemical oxidative polymerization process for dispersive-MU-solid phase extraction (D-MU-SPE). The synthesized magnetic sorbents were characterized by various techniques. The results exhibited that the nanocomposite modified by polypyrrole with sodium perchlorate as a dopant demonstrated higher extraction efficiency for citalopram (CIT) and sertraline (STR) as the model compounds. This nanosorbent in combination with high performance liquid chromatography-UV detection was applied for extraction, preconcentration and determination of CIT and STR in urine and plasma samples. The effect of various parameters on the extraction efficiency including: sample pH, amount of sorbent, sorption time, eluent and its volume, salt content, and elution time were investigated and optimized. The opted conditions were: sample pH, 9.0; sorbent dosage, 10mg; sorption time, 7 min; elution solvent and its volume, 0.06 mol L(-1) HCl in methanol, 120 MUL; elution time, 2 min and without addition of salt to the sample. The calibration curves were linear in the concentration range of 1-800 MUg L(-1). The limits of detection (LODs) were obtained in the range of 0.2-1.0 MUg L(-1) for CIT and 0.3 0.7 MUg L(-1) for STR, respectively. The percent of extraction recoveries and relative standard deviations (n=5) were in the range of 93.4-99, 4.8-8.4 for CIT and 94-98.4, 4.3-9.2 for STR, respectively. Finally, the applicability of the method was successfully confirmed by the extraction and determination of CIT and STR in human urine and plasma samples. PMID- 26253372 TI - Impairments in Dark Adaptation Are Associated with Age-Related Macular Degeneration Severity and Reticular Pseudodrusen. AB - PURPOSE: We investigate whether ocular and person-based characteristics were associated with dark adaptation (DA). DESIGN: Cross-sectional, single-center, observational study. PARTICIPANTS: One hundred sixteen participants older than 50 years of age with a range of age-related macular degeneration (AMD) severity. METHODS: Participants underwent best-corrected visual acuity (BCVA) testing, ophthalmoscopic examination, and multimodal imaging. Presence of reticular pseudodrusen (RPD) was assessed by masked grading of fundus images and was confirmed with optical coherence tomography. Eyes also were graded for AMD features (drusen, pigmentary changes, late AMD) to generate person-based AMD severity groups. One eye was designated the study eye for DA testing. Nonparametric statistical testing was performed on all comparisons. MAIN OUTCOME MEASURES: The primary outcome of this study was the rod intercept time (RIT), which is defined as the time for a participant's visual sensitivity to recover to a stimulus intensity of 5*10(-3) cd/m(2) (a decrease of 3 log units), or until a maximum test duration of 40 minutes was reached. RESULTS: A total of 116 study eyes from 116 participants (mean age, 75.4+/-9.4 years; 58% female) were analyzed. Increased RIT was associated significantly with increasing AMD severity, increasing age (r = 0.34; P = 0.0002), decreasing BCVA (r = -0.54; P < 0.0001), pseudophakia (P = 0.03), and decreasing subfoveal choroidal thickness (r = -0.27; P = 0.003). Study eyes with RPD (15/116 [13%]) had a significantly greater mean RIT compared with eyes without RPD in any AMD severity group (P < 0.02 for all comparisons), with 80% reaching the DA test ceiling. CONCLUSIONS: Impairments in DA increased with age, worse visual acuity, presence of RPD, AMD severity, and decreased subfoveal choroidal thickness. Analysis of covariance found the multivariate model that best fit the data included age, AMD group, and presence of RPD (R(2) = 0.56), with the presence of RPD conferring the largest parameter estimate. PMID- 26253374 TI - The effect of drug and EUDRAGIT(r) S 100 miscibility in solid dispersions on the drug and polymer dissolution rate. AB - Amorphous solid dispersions of phenytoin (diphenylhydantoin: DPH) and glibenclamide (GBM) with Eudragit((r)) S 100 (S100) were prepared by a spray drying. At low drug loading ratios, DPH dissolved simultaneously with S100. However, at high drug loading ratios the DPH dissolution rates were significantly reduced in comparison with those of S100 because of the rapid crystallization of DPH during the dissolution test. All of the DPH molecules in the low drug loading spray-dried sample (SPD) intimately interacted with the S100 matrix. In the SPDs with high drug loadings, only some of the DPH molecules interacted with the S100 matrix, while the excess DPH formed DPH-rich domains. When these domains contacted the water during the dissolution test, the amorphous DPH were more easily transformed into a crystalline form. In contrast to the solid dispersion of DPH/S100, that of GBM/S100 showed the simultaneous dissolution independent of the drug loading ratio. GBM was retained in an amorphous state during the dissolution test even at high drug loadings, although GBM-rich domains were formed. The miscibility at the molecular level as well as the stability of the amorphous state of drug are crucial factors to enhance the drug dissolution rate by the simultaneous dissolution with the polymer. PMID- 26253375 TI - Triboelectrification of active pharmaceutical ingredients: week acids and their salts. AB - The effect of salt formulation on the electrostatic property of active pharmaceutical ingredients was investigated. The electrostatic property of weak acids (carboxylic acids and amide-enole type acid) and their sodium salts was evaluated by a suction-type Faraday cage meter. Free carboxylic acids showed negative chargeability, whereas their sodium salts showed more positive chargeability than the free acids. However, no such trend was observed for amide enole type acids. PMID- 26253376 TI - Towards a rational basis for selection of excipients: Excipient Efficiency for controlled release. AB - There are many factors influencing the drug release behaviour from a pharmaceutical formulation as the particle size of the drug and excipient, porosity of the system or geometrical phase transitions of the components. Therefore, the choice of the adequate excipient to achieve a specific drug release profile is mainly based on the experience and the trial and error method. Taking into account the directives towards the application of the "Quality by Design" approach, in this study the Excipient Efficiency (EE), a parameter able to quantify the capability of an excipient to control the drug release, has been developed. EE was initially calculated dividing the total porosity of the system by its diffusional release rate constant. The influence of several factors on this parameter has been evaluated. As a result, the final parameter has been corrected based on the drug solubility and the excipient particle size. EE provides a rational basis for identifying the most adequate excipients for a concrete formulation. PMID- 26253377 TI - Cremophor-free intravenous self-microemulsions for teniposide: Safety, antitumor activity in vitro and in vivo. AB - The study was designed to identify the safety and antitumor activity of teniposide self-microemulsified drug delivery system (TEN-SMEDDS) previously developed, and to provide evidence for the feasibility and effectiveness of TEN SMEDDS for application in clinic. The TEN-SMEDDS could form fine emulsion with mean diameter of 279 +/- 19 nm, Zeta potential of -6.9 +/- 1.4 mV, drug loading of 0.04 +/- 0.001% and entrapment efficiency of 98.7 +/- 1.6% after dilution with 5% glucose, respectively. The safety, including hemolysis, hypersensitivity, vein irritation and toxicity in vivo, and antitumor activity were assessed, VUNON as a reference. Sulforhodamine B assays demonstrated that the IC50 of TEN-SMEDDS against C6 and U87MG cells were higher than that of VUMON. But the effect of TEN SMEDDS on the cell cycle distribution and cell apoptotic rate was similar to that of VUMON as observed by flow cytometry. Likewise, the antitumor activity of TEN SMEDDS was considerable to that of VUMON. Finally, the TEN-SMEDDS exhibited less body weight loss, lower hemolysis and lower myelosuppression as compared with VUMON. In conclusion, promising TEN-SMEDDS retained the antitumor activity of teniposide and was less likely to cause some side effects compared to VUMON. It may be favorable for the application in clinic. PMID- 26253378 TI - VB12-coated Gel-Core-SLN containing insulin: Another way to improve oral absorption. AB - To improve the oral absorption of insulin, a novel carrier of Vitamin B12 (VB12) gel core solid lipid nanopaticles (Gel-Core-SLN, GCSLN) was designed with a gel core, lipid matrix and VB12-coated surface. VB12-stearate was synthesized and characterized by infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). Sol-gel conversion following ultrasonic heating and double emulsion technology were combined to implant the insulin-containing gel into solid lipid nanoparticles (SLN). The influence of the mode of administration, food, the amount of VB12-stearate and the particle size on the oral absorption of insulin incorporated in the VB12-GCSLN was investigated. The determined partition coefficient (LogP) of VB12-stearate in a dichloromethane (DCM)-water system was 3.4. This new structure of VB12-GCSLN had higher insulin encapsulation efficiency (EE) of 55.9%, a lower burst release of less than 10% in the first 2h. In vivo studies demonstrated that stronger absorption of insulin with a relative pharmacological availability (PA) of 9.31% compared with the normal insulin-loaded SLN and GCSLN and fairly stable blood glucose levels up to 12h were maintained without any sharp fluctuations. This study suggests that VB12-GCSLN containing insulin appears to be a promising nano carrier for oral delivery of biomacromolecules with relatively high pharmacological availability. PMID- 26253379 TI - The intracellular pharmacodynamics of siRNA is responsible for the low gene silencing activity of siRNA-loaded nanoparticles in dendritic cells. AB - The delivery of small interfering RNA (siRNA) to dendritic cells (DCs) is a challenging issue for siRNA-loaded lipid nanoparticles. The cause of this difficulty is unknown. The findings reported herein indicate that the rate limiting step in gene silencing using siRNA-loaded lipid nanoparticles in DCs, as evidenced by a quantitative analysis of each process in siRNA delivery between mouse bone marrow derived DC (BMDC) and other cell lines, was not associated with the actual delivery of siRNA. A gene silencing of only 50% was observed in BMDC, even when a high dose was used. Contrary to our expectation, the interval between cellular uptake and the delivery of siRNA to the cytosol was not responsible for the low gene silencing. Meanwhile, a drastic difference was found in the relationship between the efficiency of gene silencing and the amount of intracellular intact siRNA. This fact indicates that the processes after cytosolic delivery of siRNA, namely the intracellular pharmacodynamics (PD) of siRNA, appear to be the rate-limiting step in gene silencing in BMDC. The findings reported here demonstrate the importance of the intracellular PD of siRNA delivered to cytosol in the development of siRNA delivery systems for gene silencing in DCs. PMID- 26253380 TI - Long-circulating lipoprotein-mimic nanoparticles for smart intravenous delivery of a practically-insoluble antineoplastic drug: Development, preliminary safety evaluations and preclinical pharmacokinetic studies. AB - Chlorambucil (CHL) is a water-insoluble antineoplastic drug having a short elimination half-life. It suffers from remarkable differences in pharmacokinetics following oral administration. The current work aimed to assess safety and pharmacokinetics of CHL-loaded, lipoprotein-mimic, nanoparticles (NPs) following intravenous administration. The design of NPs was based on complexation between egg yolk lecithin (EYL) and bovine serum albumin (BSA). The NPs were preliminary evaluated via FT-IR, DSC and P-XRD. The NPs were characterized for particle size, zeta potential, morphology and drug entrapment efficiency (EE%). The best achieved NP dispersion (LP6) and CHL solution were challenged for in vitro hemolytic potential, in vivo vascular irritation studies in rabbits and in vivo pharmacokinetics following intravenous administration in rats. The results confirmed that NPs were stabilized by hydrophobic-attractions and hydrogen bondings between CHL, BSA and EYL. The amorphous dispersion of CHL within NPs was revealed. LP6 dispersion displayed monodispersed nano-spherical particles (144.33 +/- 2.17 nm). It possessed the highest negative zeta potential (-30.55 +/- 0.24 mV) and the largest EE% (86.35 +/- 2.33%). The significantly (P < 0.05) prolonged MRT(0-infinity), longer elimination t50% and reduced plasma clearance highlighted the long-circulating characteristics of LP6. The preliminary safety evaluations and the seven-fold increase in bioavailability elucidated potentiality for smart intravenous delivery of CHL. PMID- 26253382 TI - X-ray physics- and bone composition-based estimation of thickness characteristics from clinical mandibular radiographs. AB - In dentistry, clinical radiographs (also called X-ray images) reflect the intensity loss of an X-ray when being transmitted through the mandibular objects, and this loss is quantified in terms of grey values. While such images are standardly used for pathology detection by the experienced dentist, we here present a new method for getting more quantitative information out of such 2D radiographs, "extending" them into the third dimension. This "extension" requires consistent combination of X-ray physics (namely, X-ray intensity loss quantification along paths orthogonal to the panoramic clinical image and X-ray attenuation averaging for composite materials) with anatomically known upper and lower limits of vascular porosities in cortical and trabecular bone compartments. Correspondingly computed ranges of overall organ thicknesses are extremely narrow, suggesting adequate estimation of thickness characteristics from 2D radiographic panoramas used clinically, while predicted cortical and trabecular thickness ranges vary by +/-8.47% and +/-16.13%, respectively. The proposed method also identifies variations between thicknesses at similar anatomical locations left and right of the face's symmetry axis, and molar regions turn out to be thicker than those close to incisors. This paves the way to more detailed diagnostic activities, e.g. in combination with Finite Element simulations. PMID- 26253381 TI - IL-27-induced modulation of autoimmunity and its therapeutic potential. AB - Interleukin-27 (IL-27) is a new member of the IL-12 family. It is produced by activated antigen-presenting cells and plays an important role in the regulation of CD4+ T cell differentiation and immune response. IL-27 activates multiple signaling cascades, including the JAK-STAT and p38 MAPK pathways. Several studies have revealed that IL-27 promotes the differentiation of Th1 and Tr1, but inhibits Th2, Th17, and Treg cells. However, a few studies have shown an opposite effect on certain T cell subsets, such as Treg. IL-27 displays both pro- and anti inflammatory activities in different autoimmune diseases. Here, we have discussed the role of IL-27 in rheumatoid arthritis, multiple sclerosis, colitis, lupus, psoriasis, type 1 diabetes, and uveitis. Most of this information is derived from experimental models of these autoimmune diseases. The mechanistic basis of the dual role of IL-27 in inflammation and autoimmunity is still not fully defined. In general, the pro-/anti-inflammatory activity of IL-27 is influenced by the underlying immune effector pathways, the phase of the disease, the presence or absence of counter-regulatory cytokines/T cell subsets, and the tissue/cell type under study. Despite a spectrum of outcomes in various autoimmune diseases, mostly anti-inflammatory and immunomodulatory effects of IL 27 have been observed in this category of diseases. Accordingly, IL-27 represents a novel, promising target/agent for the treatment of autoimmune diseases. PMID- 26253383 TI - Usefulness of IDEAL T2 imaging for homogeneous fat suppression and reducing susceptibility artefacts in brachial plexus MRI at 3.0 T. AB - PURPOSE: To quantitatively and qualitatively compare fat-suppressed MR imaging quality using iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) with that using frequency-selective fat suppressed (FSFS) T2 images of the brachial plexus at 3.0 T. MATERIALS AND METHODS: Prospective MR image analysis was performed in 40 volunteers and 40 patients at a single centre. Oblique-sagittal and coronal IDEAL fat-suppressed T2 images and FSFS T2 images were compared. Visual assessment was performed by two independent musculoskeletal radiologists with respect to: (1) susceptibility artefacts around the neck, (2) homogeneity of fat suppression, (3) image sharpness and (4) tissue resolution contrast of pathologies. The signal-to-noise ratios (SNR) for each image sequence were assessed. RESULTS: Compared to FSFS sequences, IDEAL fat-suppressed T2 images significantly reduced artefacts around the brachial plexus and significantly improved homogeneous fat suppression (p < 0.05). IDEAL significantly improved sharpness and lesion-to-tissue contrast (p < 0.05). The mean SNRs were significantly improved on T2-weighted IDEAL images (p < 0.05). CONCLUSION: IDEAL technique improved image quality by reducing artefacts around the brachial plexus while maintaining a high SNR and provided superior homogeneous fat suppression than FSFS sequences. PMID- 26253384 TI - Comparison between MRI and CEUS in the follow-up of patients with blunt abdominal trauma managed conservatively. AB - INTRODUCTION: Over the past two decades, there has been a shift toward non operative treatment of patients undergoing a solid organ injury, thus requiring an increasing number of imaging studies to monitor the healing of lesions, which were performed by computed tomography (CT). In consideration of the use of ionizing radiation and contrast media, nowadays there is a trend toward the use contrast-enhanced ultrasound (CEUS) in the follow-up of blunt abdominal trauma. However CEUS has some limits, especially in the assessments of small lesions and in the evaluation of urinary tract lesions and vascular complications. Magnetic resonance imaging (MRI) is a useful alternative, since its lack of use of ionizing radiation, its panoramicity, the possibility to avoid contrast media and the ability to properly evaluate even small lesions. The aim of this study is to evaluate the usefulness and the feasibility of MRI in the follow-up of patients with low-grade blunt abdominal trauma. MATERIALS AND METHODS: We performed a retrospective review of a cohort including 270 consecutive patients with a history of blunt abdominal trauma; among them, 118 underwent a high-energy trauma, and 152 a low-energy trauma. 124 patients had findings of abdominal injuries at the contrast-enhanced multidetector CT (CE-MDCT), including 68 from the group of major trauma and 56 from the group of minor trauma. 39 patients were operated for incoming lesions. The remaining 85 patients were treated conservatively. Eight patients underwent surgery later for delayed bleeding. The remaining 77 underwent the full follow-up protocol. Follow-up protocol included CEUS at 24 and 72 h and CEUS and MRI at 1 month after trauma; only MRI was performed until the complete resolution. RESULTS: CEUS at 24-h and at 72-h from trauma showed a very good correlation with onset CE-MDCT in lesions staging. With respect to onset CE-MDCT, CEUS did not identified 2 adrenal injuries and 2 lesions of urinary tract, an intrinsic limit of this technique. CEUS performed at 1 month did not show traumatic lesions in 49/77 of patients. In the remaining 28/77 cases, CEUS demonstrated reduction of the size of the lesions ranging from 25 to 50%. MRI performed at 1 month from trauma did not show traumatic injuries in 37/77 patients; it demonstrated persistence of organ lesion in 40/77 patients. Therefore, in 12/77 patients MRI performed at 1-month demonstrated the persistence of minimal or moderate organ injury, while CEUS was completely negative. In addition, MRI allowed to enhance the persistence of adrenal lesions in 2 cases and the integrity of urinary tract in 2. In the remaining 28 patients, in which both CEUS and MRI showed disease persistence, MRI, however, allowed a better definition of injury extension with respect to CEUS, in terms of dimensions, edges, and morphological evolution. DISCUSSION AND CONCLUSIONS: MRI allowed to make a better assessment of injuries than CEUS, allowing also a temporal stage of lesions. Infact, there are different evolution stages corresponding to accurate imaging findings. To our knowledge, this is the first study that describes the evolution of blood collection in parenchymal abdominal organs. Therefore, in patients who underwent abdominal traumatic injuries conservatively treated, the follow-up at 1 month can be made by MRI, due to its panoramicity and its high contrast resolution, which allow a better morphological and temporal trauma staging respect to the CEUS. PMID- 26253386 TI - Unusual complication with an intramedullary lengthening device 15 months after implantation. AB - The treatment of leg length discrepancy and deformities has become more important over the last decades due to newly developed implants. Several different devices have been presented with various complications reported in literature. The purpose of this case report was to present an unusual complication 15 months after implantation of an intramedullary lengthening device (PRECICE((r))). An intramedullary lengthening device (PRECICE((r)) P1 nail) was implanted in a 74 years old male patient with a congenital leg length discrepancy in January 2014. After bone lengthening of 6cm and obvious radiological callus formation a nail breakage with severe deformity occurred 15 months after implantation. Physicians have to be aware of the risk of such late complications regarding this device with serious implications for the patient. PMID- 26253387 TI - Reamer Irrigator Aspirator bone graft harvesting: complications and outcomes in an Asian population. AB - INTRODUCTION: Autologous bone grafting has been accepted as the gold standard in the treatment of non-unions and in definitive filling of segmental bone defects. However, there have been well-recognised complications associated with their harvest. The Reamer Irrigator Aspirator (RIA) system is an alternative technique of autologous bone graft harvesting. Studies have been published in the Western population showing the efficacy and outcome of this technique. No prior studies were done in the Asian population, who has smaller average canals, different femoral geometry as compared to Caucasians and weaker bone density in both genders. We aim to present the findings and discuss its suitability in the Asian population when dealing with segmental bone loss and non-unions requiring reconstruction. METHODS: We conducted a retrospective analysis of all trauma patients with segmental bone loss and non-unions treated with RIA bone grafting over a 4.5 year period. A total of 57 cases of RIA bone grafting were conducted on 53 patients. The amount of bone graft harvested, blood loss and post-operative pain were measured. Patients were followed up for union rate as well as complications of the procedure. RESULTS: Union was achieved in 86.8% of patients. The mean time to union was 17.64 weeks. Seven patients did not achieve union after the first RIA surgery, in which six of seven were open fractures initially and six were smokers. One major intra-operative complication was recorded, that being a fractured femoral shaft due to thinning of the cortex by the RIA harvester. There were two patients who developed donor site superficial soft tissue infection that resolved after a course of antibiotics. There were no long term complications seen in all patients. CONCLUSIONS: The safety and efficacy of RIA bone graft harvesting for the management of non-union in the Asian population is promising, with adequate graft quantities, high success and low complication rates that are comparable to the Caucasian population. The diameter of the medullary canal in our population is suitable for this procedure. We believe that RIA bone graft harvesting provides a reliable and safe alternative source of autologous bone grafts for bone grafting of non-union sites. PMID- 26253385 TI - Guesstimation of posterior malleolar fractures on lateral plain radiographs. AB - BACKGROUND: Accurate assessment of articular involvement of the posterior malleolar fracture fragments in ankle fractures is essential, as this is the leading argument for internal fixation. The purpose of this study is to assess diagnostic accuracy of measurements on plain lateral radiographs. METHODS: Quantification of three-dimensional computed tomography (Q-3D-CT) was used as a reference standard for true articular involvement (mm(2)) of posterior malleolar fractures. One-hundred Orthopaedic Trauma surgeons were willing to review 31 trimalleolar ankle fractures to estimate size of posterior malleolus and answer: (1) what is the involved articular surface of the posterior malleolar fracture as a percentage of the tibial plafond? and (2) would you fix the posterior malleolus? RESULTS: The average posterior malleolar fragment involved 13.5% (SD 10.8) of the tibial plafond articular surface, as quantified using Q-3D-CT. The average involvement of articular surface of the posterior malleolar fragment, as estimated by 100 observers on plain radiographs was 24.4% (SD 10.0). The factor 1.8 overestimation of articular involvement was statistically significant (p<0.001). Diagnostic accuracy of measurements on plain lateral radiographs was 22%. Interobserver agreement (ICC) was 0.61. Agreement on operative fixation, showed an ICC of 0.54 (Haraguchi type I=0.76, Haraguchi type II=0.40, Haraguchi type III=0.25). CONCLUSIONS: Diagnostic accuracy of measurements on plain lateral radiographs to assess articular involvement of posterior malleolar fractures is poor. There is a tendency to misjudge posteromedial involvement (Haraguchi type II). PMID- 26253388 TI - A combined model for large scale batch culture MFC-digester with various wastewaters through different populations. AB - In this study, a new model of microbial fuel cell (MFC) was obtained for the first time. The modeled MFC was made using a combination of two approaches; the conduction-based method and two-step anaerobic digestion. Performance of the MFC was based on calculations for current evolution and polarization curves with different subsequent variables of the biofilm and anolyte. The model was able to make predictions for performance of the MFC for a simple substrate to more complex ones. The model was successfully validated with a variety of substrates (acetate, glucose and dairy wastewater) and the results were compared with previously published measurements. The model polarization results showed that is able to predict overshoot as a dynamic phenomenon. The ratio of acetoclastic methanogens to electrogens in the biofilm increased from an average value of 0.63*10(-2) to 1.17*10(-2) by increasing external resistance from 50 Omega to 100Omega . The attached to planktonic cells ratio was computed 0.45 for the glucose-fed MFC and for the dairy wastewater-fed MFC at 50 Omega was 8.86 and at 100 Omega was 5.46. PMID- 26253389 TI - Are conventional statistical techniques exhaustive for defining metal background concentrations in harbour sediments? A case study: The Coastal Area of Bari (Southeast Italy). AB - Sediment contamination by metals poses significant risks to coastal ecosystems and is considered to be problematic for dredging operations. The determination of the background values of metal and metalloid distribution based on site-specific variability is fundamental in assessing pollution levels in harbour sediments. The novelty of the present work consists of addressing the scope and limitation of analysing port sediments through the use of conventional statistical techniques (such as: linear regression analysis, construction of cumulative frequency curves and the iterative 2sigma technique), that are commonly employed for assessing Regional Geochemical Background (RGB) values in coastal sediments. This study ascertained that although the tout court use of such techniques in determining the RGB values in harbour sediments seems appropriate (the chemical physical parameters of port sediments fit well with statistical equations), it should nevertheless be avoided because it may be misleading and can mask key aspects of the study area that can only be revealed by further investigations, such as mineralogical and multivariate statistical analyses. PMID- 26253390 TI - A lipophilic fluorescent LipidGreen1-based quantification method for high throughput screening analysis of intracellular poly-3-hydroxybutyrate. AB - Poly-3-hydroxybutyrate (PHB), the most abundant type of polyhydroxyalkanoates (PHA) is synthesized inside a variety of microorganisms as a primary candidate for industrial PHB production. Lipophilic dyes such as Nile red and BODIPY have been used to quantify intracellular PHB, but their uses have often been limited in terms of sensitivity and accuracy. In this study, a newly developed lipophilic fluorescent dye LipidGreen1 was used to quantify intracellular PHB. LipidGreen1 stained viable colonies by adding the dye into the medium which enabled the effective selection of PHB-positive cells. Furthermore, the fluorescence intensity of LipidGreen1 maintained its fluorescence intensity much longer than that of Nile red. The fluorescence intensities of intracellular PHB stained by LipidGreen1 accurately agreed with PHB contents measured by gas chromatography. In addition, internalization of LipidGreen1 in Escherichia coli cell was not necessary to obtain quantitative measurements. PHB-synthase mutants were differentiated by fluorescence intensities with a good correlation to increased levels of PHB production. These results show that LipidGreen1 is sensitive and accurate in high-throughput screening of newly isolated and genetically modified bacteria with enhanced PHB production. PMID- 26253391 TI - Prevalence of virulence genes of biofilm producing strains of Staphylococcus epidermidis isolated from clinical samples in Iran. AB - Coagulase negative staphylococci are recognized as opportunistic pathogens and are widespread in the environment. It is possible to prevent and control infections due to these bacteria if their virulence factors are recognized. Eighty isolates of Staphylococcus epidermidis (S. epidermidis) including 42 from urine (52.5%), 23 from blood (28.75%), 15 from dialysis bags (18.75%) were studied for biofilm production on Congo red agar (CRA). The virulence genes in S. aureus were investigated using polymerase chain reaction (PCR) with primers. Out of 80 isolates studied, 40 isolated (50%) formed black colonies (biofilm-forming strains) on CRA. In 22 of these isolates (25%) reaction was strongly positive; in 12 isolates (15%) reaction was moderately positive, and in the remaining 6 isolates, reaction was weakly positive. In the 22 isolates that had strong positive reaction and produced black colonies on biofilm, all virulent genes (icaC, icaD, icaA icaB, icaR) were expressed. In the 12 isolates that had moderate positive reaction, 8 expressed all genes (icaC, icaD, icaA icaB, icaR) expressed while the remaining 4 expressed only ica A, and ica D genes. Of the 6 isolated which had weak positive reaction, only 1 isolate (2.5%) expressed all the genes, in the other 5 isolates no gene was observed. Urinary isolates more frequently form biofilms than the isolates from other clinical samples. Statistical analysis using Chi square test showed that there was a significant correlation between the type of sample and the biofilm production (P < 0.05). The results of biofilm production on CRA were largely in agreement with microtiter plate assay and PCR assay. The capacity of bacteria to produce biofilm is an important factor in infectivity and happens via expression of ica genes. Recognition of bacteria that produce biofilm is thus important to control infection due to these bacteria. PMID- 26253393 TI - Monte Carlo simulations of subsurface analysis of painted layers in micro-scale spatially offset Raman spectroscopy. AB - A recently developed micrometer-scale spatially offset Raman spectroscopy (micro SORS) method provides a new analytical capability for investigating nondestructively the chemical composition of subsurface, micrometer-scale-thick, diffusely scattering layers at depths beyond the reach of conventional confocal Raman microscopy. Here we provide, for the first time, the theoretical foundations for the micro-SORS defocusing concept based on Monte Carlo simulations. Specifically, we investigate a defocusing variant of micro-SORS that we used in our recent proof-of-concept study in conditions involving thin, diffusely scattering layers on top of an extended, diffusely scattering substrate. This configuration is pertinent, for example, for the subsurface analysis of painted layers in cultural heritage studies. The depth of the origin of Raman signal and the relative micro-SORS enhancement of the sublayer signals reached are studied as a function of layer thickness, sample photon transport length, and absorption. The model predicts that sublayer enhancement initially rapidly increases with increasing defocusing, ultimately reaching a plateau. The magnitude of the enhancement was found to be larger for thicker layers. The simulations also indicate that the penetration depths of micro-SORS can be between one and two orders of magnitude larger than those reached using conventional confocal Raman microscopy. The model provides a deeper insight into the underlying Raman photon migration mechanisms permitting the more effective optimization of experimental conditions for specific sample parameters. PMID- 26253392 TI - Reference values for hand grip strength in Japanese community-dwelling elderly: a meta-analysis. AB - OBJECTIVES: Reference values for hand grip strength in Japanese community dwelling elderly independent in activities of daily living (ADLs) were calculated by meta-analysis. METHODS: Papers reporting data on hand grip strength in elderly Japanese adults >=60 years of age and independent in ADLs were retrieved from electronic databases. Data were extracted from the selected papers and the weighted mean for hand grip strength by sex was calculated by random effect model. The association of hand grip strength with age and body weight was also analyzed using meta-regression analysis. RESULTS: Data for 15,784 individuals (5216 men and 10,568 women; mean age 67.0-79.8 years) were extracted from 97 sets of data from 33 papers. The weighted mean for hand grip strength was calculated as 33.11 kg [95 % CI 32.27-33.96] in men and 20.92 kg [95 % CI 20.45-21.39] in women. A significant negative correlation was also seen between hand grip strength and age. CONCLUSIONS: The mean hand grip strength of elderly people calculated in this study can be used as a reference value for the hand grip strength of Japanese community-dwelling elderly who are independent in ADLs. However, age needs to be considered in reference values for hand grip strength. PMID- 26253394 TI - Regulatory T Cells Promote beta-Catenin--Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis. AB - PURPOSE: Radiation-induced pulmonary fibrosis results from thoracic radiation therapy and severely limits radiation therapy approaches. CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) as well as epithelium-to-mesenchyme transition (EMT) cells are involved in pulmonary fibrosis induced by multiple factors. However, the mechanisms of Tregs and EMT cells in irradiation-induced pulmonary fibrosis remain unclear. In the present study, we investigated the influence of Tregs on EMT in radiation-induced pulmonary fibrosis. METHODS AND MATERIALS: Mice thoraxes were irradiated (20 Gy), and Tregs were depleted by intraperitoneal injection of a monoclonal anti-CD25 antibody 2 hours after irradiation and every 7 days thereafter. Mice were treated on days 3, 7, and 14 and 1, 3, and 6 months post irradiation. The effectiveness of Treg depletion was assayed via flow cytometry. EMT and beta-catenin in lung tissues were detected by immunohistochemistry. Tregs isolated from murine spleens were cultured with mouse lung epithelial (MLE) 12 cells, and short interfering RNA (siRNA) knockdown of beta-catenin in MLE 12 cells was used to explore the effects of Tregs on EMT and beta-catenin via flow cytometry and Western blotting. RESULTS: Anti-CD25 antibody treatment depleted Tregs efficiently, attenuated the process of radiation-induced pulmonary fibrosis, hindered EMT, and reduced beta-catenin accumulation in lung epithelial cells in vivo. The coculture of Tregs with irradiated MLE 12 cells showed that Tregs could promote EMT in MLE 12 cells and that the effect of Tregs on EMT was partially abrogated by beta-catenin knockdown in vitro. CONCLUSIONS: Tregs can promote EMT in accelerating radiation-induced pulmonary fibrosis. This process is partially mediated through beta-catenin. Our study suggests a new mechanism for EMT, promoted by Tregs, that accelerates radiation-induced pulmonary fibrosis. PMID- 26253395 TI - Thymineless Death Lives On: New Insights into a Classic Phenomenon. AB - The primary mechanisms by which bacteria lose viability when deprived of thymine have been elusive for over half a century. Early research focused on stalled replication forks and the deleterious effects of uracil incorporation into DNA from thymidine-deficient nucleotide pools. The initiation of the replication cycle and origin-proximal DNA degradation during thymine starvation have now been quantified via whole-genome microarrays and other approaches. These advances have fostered innovative models and informative experiments in bacteria since this topic was last reviewed. Given that thymineless death is similar in mammalian cells and that certain antibacterial and chemotherapeutic drugs elicit thymine deficiency, a mechanistic understanding of this phenomenon might have valuable biomedical applications. PMID- 26253396 TI - A Case of Hypercalcemia and Overexpression of CYP27B1 in Skeletal Muscle Lesions in a Patient with HIV Infection After Cosmetic Injections with Polymethylmethacrylate (PMMA) for Wasting. AB - Foreign body-induced granuloma is an uncommon yet clinically significant cause of hypercalcemia. The molecular mechanisms are uncertain, although extrarenal calcitriol production has been proposed. We describe severe hypercalcemia associated with increased levels of plasma calcitriol in a patient with HIV and local granulomatous reaction 5 years after injection of polymethylmethacrylate (PMMA) as dermal filler for cosmetic body sculpting. Extensive evaluation revealed no identifiable cause of increased calcitriol levels. Nuclear imaging was remarkable for diffuse uptake in the subcutaneous tissues of the buttocks. Subsequent muscle biopsy and immunohistochemical staining showed strong local expression of CYP27B1 within histiocytes surrounding globules of PMMA. This case highlights an unfortunate complication of dermal fillers and shows that inflammatory cells can express high levels of CYP27B1 even without frank granulomas. The growing trend of body contour enhancement using injectable fillers should raise suspicion for this cause of hypercalcemia in clinical practice. Patients with HIV who receive this treatment for lipodystrophy or other cosmetic purposes may have increased susceptibility to hypercalcemia in the setting of underlying chronic inflammation. This may be a concern when changing anti-retroviral therapy, since alterations in levels of HIV viremia may initiate or contribute to worsening hypercalcemia. PMID- 26253398 TI - Endogenous TGFbeta1 Plays a Crucial Role in Functional Recovery After Traumatic Brain Injury Associated with Smad3 Signal in Rats. AB - Transforming growth factor-beta 1 (TGFbeta1) has a diverse role in astrogliosis and neuronal survival, but the underlying mechanism remains to be elucidated, especially in traumatic brain injury (TBI). Here, we show that the expression of TGFbeta1 was increased in the pericontusional region, accompanied with astrogliosis and neuronal loss in TBI rats. Moreover, TGFbeta1 knockdown not only reduced the number of neurons and inhibited astrogliosis but also resulted in a significant neurological dysfunction in rats with TBI. Subsequently, Smad3, a key downstream signal of TGFbeta1, was involved in pericontusional region after TBI. These findings therefore indicate that TGFbeta1 is involved in neuroprotection and astrogliosis, via activation of down stream Smad3 signal in the brain after injury. PMID- 26253399 TI - Magnetic Control of the Glottic Opening in an Ex Vivo Sheep Larynx Model: A Preliminary Study. AB - OBJECTIVE/HYPOTHESIS: So far, a number of techniques have been described for the treatment of bilateral vocal fold paralysis. These techniques were reported to be successful in maintaining an adequate airway but also found to be associated with an increased risk of aspiration, dysphonia, and granulation tissue formation at the operation site. We aimed to investigate the effectiveness of a novel mucosa sparing technique based on the generation of a magnetic field within the larynx for the tailored lateralization of the ipsilateral vocal fold. STUDY DESIGN: This is an ex vivo experimental study. METHODS: Twenty sheep larynges that were procured from the local slaughterhouse were used as a model. For each specimen, two neodymium (Nd) disc magnets with marked poles were used to create a unilateral attractive magnetic force at the glottic level. Following insertion of the magnets, the level of vocal fold lateralization was assessed under an operating microscope. The results were analyzed for their statistical significance. RESULTS: Before the procedure, the mean value of the glottic openings of all the specimens was 4.985 mm. The postprocedure mean value was 5.640 mm. The mean amount of increase in the glottic openings after the procedure was 0.655 mm. This change was found to be statistically significant (P < 0.05). CONCLUSIONS: A statistically significant increase in the cross-sectional area of the glottic region could be achieved. The mucosal integrity of the laryngeal airway was also preserved. The idea of "magnetic control of the glottic airway" is a novel concept but seems to be a promising option. PMID- 26253400 TI - Hippo signaling is required for Notch-dependent smooth muscle differentiation of neural crest. AB - Notch signaling has well-defined roles in the assembly of arterial walls and in the development of the endothelium and smooth muscle of the vasculature. Hippo signaling regulates cellular growth in many tissues, and contributes to regulation of organ size, in addition to other functions. Here, we show that the Notch and Hippo pathways converge to regulate smooth muscle differentiation of the neural crest, which is crucial for normal development of the aortic arch arteries and cranial vasculature during embryonic development. Neural crest specific deletion of the Hippo effectors Yap and Taz produces neural crest precursors that migrate normally, but fail to produce vascular smooth muscle, and Notch target genes such as Jagged1 fail to activate normally. We show that Yap is normally recruited to a tissue-specific Jagged1 enhancer by directly interacting with the Notch intracellular domain (NICD). The Yap-NICD complex is recruited to chromatin by the DNA-binding protein Rbp-J in a Tead-independent fashion. Thus, Hippo signaling can modulate Notch signaling outputs, and components of the Hippo and Notch pathways physically interact. Convergence of Hippo and Notch pathways by the mechanisms described here might be relevant for the function of these signaling cascades in many tissues and in diseases such as cancer. PMID- 26253401 TI - Single-cell analysis of endothelial morphogenesis in vivo. AB - Vessel formation has been extensively studied at the tissue level, but the difficulty in imaging the endothelium with cellular resolution has hampered study of the morphogenesis and behavior of endothelial cells (ECs) in vivo. We are using endothelial-specific transgenes and high-resolution imaging to examine single ECs in zebrafish. By generating mosaics with transgenes that simultaneously mark endothelial nuclei and membranes we are able to definitively identify and study the morphology and behavior of individual ECs during vessel sprouting and lumen formation. Using these methods, we show that developing trunk vessels are composed of ECs of varying morphology, and that single-cell analysis can be used to quantitate alterations in morphology and dynamics in ECs that are defective in proper guidance and patterning. Finally, we use single-cell analysis of intersegmental vessels undergoing lumen formation to demonstrate the coexistence of seamless transcellular lumens and single or multicellular enclosed lumens with autocellular or intercellular junctions, suggesting that heterogeneous mechanisms contribute to vascular lumen formation in vivo. The tools that we have developed for single EC analysis should facilitate further rigorous qualitative and quantitative analysis of EC morphology and behavior in vivo. PMID- 26253402 TI - Retinoic acid signaling spatially restricts osteoblasts and controls ray-interray organization during zebrafish fin regeneration. AB - The zebrafish caudal fin consists of repeated units of bony rays separated by soft interray tissue, an organization that must be faithfully re-established during fin regeneration. How and why regenerating rays respect ray-interray boundaries, thus extending only the existing bone, has remained unresolved. Here, we demonstrate that a retinoic acid (RA)-degrading niche is established by Cyp26a1 in the proximal basal epidermal layer that orchestrates ray-interray organization by spatially restricting osteoblasts. Disruption of this niche causes preosteoblasts to ignore ray-interray boundaries and to invade neighboring interrays where they form ectopic bone. Concomitantly, non-osteoblastic blastema cells and regenerating blood vessels spread into the interrays, resulting in overall disruption of ray-interray organization and irreversible inhibition of fin regeneration. The cyp26a1-expressing niche plays another important role during subsequent regenerative outgrowth, where it facilitates the Shha-promoted proliferation of osteoblasts. Finally, we show that the previously observed distal shift of ray bifurcations in regenerating fins upon RA treatment or amputation close to the bifurcation can be explained by inappropriate preosteoblast alignment and does not necessarily require putative changes in proximodistal information. Our findings uncover a mechanism regulating preosteoblast alignment and maintenance of ray-interray boundaries during fin regeneration. PMID- 26253403 TI - Cdc42 is required for cytoskeletal support of endothelial cell adhesion during blood vessel formation in mice. AB - The Rho family of small GTPases has been shown to be required in endothelial cells (ECs) during blood vessel formation. However, the underlying cellular events controlled by different GTPases remain unclear. Here, we assess the cellular mechanisms by which Cdc42 regulates mammalian vascular morphogenesis and maintenance. In vivo deletion of Cdc42 in embryonic ECs (Cdc42(Tie2KO)) results in blocked lumen formation and endothelial tearing, leading to lethality of mutant embryos by E9-10 due to failed blood circulation. Similarly, inducible deletion of Cdc42 (Cdc42(Cad5KO)) at mid-gestation blocks angiogenic tubulogenesis. By contrast, deletion of Cdc42 in postnatal retinal vessels leads to aberrant vascular remodeling and sprouting, as well as markedly reduced filopodia formation. We find that Cdc42 is essential for organization of EC adhesion, as its loss results in disorganized cell-cell junctions and reduced focal adhesions. Endothelial polarity is also rapidly lost upon Cdc42 deletion, as seen by failed localization of apical podocalyxin (PODXL) and basal actin. We link observed failures to a defect in F-actin organization, both in vitro and in vivo, which secondarily impairs EC adhesion and polarity. We also identify Cdc42 effectors Pak2/4 and N-WASP, as well as the actomyosin machinery, to be crucial for EC actin organization. This work supports the notion of Cdc42 as a central regulator of the cellular machinery in ECs that drives blood vessel formation. PMID- 26253404 TI - Meis1 coordinates a network of genes implicated in eye development and microphthalmia. AB - Microphthalmos is a rare congenital anomaly characterized by reduced eye size and visual deficits of variable degree. Sporadic and hereditary microphthalmos have been associated with heterozygous mutations in genes fundamental for eye development. Yet, many cases are idiopathic or await the identification of molecular causes. Here we show that haploinsufficiency of Meis1, which encodes a transcription factor with evolutionarily conserved expression in the embryonic trunk, brain and sensory organs, including the eye, causes microphthalmic traits and visual impairment in adult mice. By combining analysis of Meis1 loss-of function and conditional Meis1 functional rescue with ChIP-seq and RNA-seq approaches we show that, in contrast to its preferential association with Hox-Pbx BSs in the trunk, Meis1 binds to Hox/Pbx-independent sites during optic cup development. In the eye primordium, Meis1 coordinates, in a dose-dependent manner, retinal proliferation and differentiation by regulating genes responsible for human microphthalmia and components of the Notch signaling pathway. In addition, Meis1 is required for eye patterning by controlling a set of eye territory-specific transcription factors, so that in Meis1(-/-) embryos boundaries among the different eye territories are shifted or blurred. We propose that Meis1 is at the core of a genetic network implicated in eye patterning/microphthalmia, and represents an additional candidate for syndromic cases of these ocular malformations. PMID- 26253405 TI - Leg regeneration is epigenetically regulated by histone H3K27 methylation in the cricket Gryllus bimaculatus. AB - Hemimetabolous insects such as the cricket Gryllus bimaculatus regenerate lost tissue parts using blastemal cells, a population of dedifferentiated proliferating cells. The expression of several factors that control epigenetic modification is upregulated in the blastema compared with differentiated tissue, suggesting that epigenetic changes in gene expression might control the differentiation status of blastema cells during regeneration. To clarify the molecular basis of epigenetic regulation during regeneration, we focused on the function of the Gryllus Enhancer of zeste [Gb'E(z)] and Ubiquitously transcribed tetratricopeptide repeat gene on the X chromosome (Gb'Utx) homologues, which regulate methylation and demethylation of histone H3 lysine 27 (H3K27), respectively. Methylated histone H3K27 in the regenerating leg was diminished by Gb'E(z)(RNAi) and was increased by Gb'Utx(RNAi). Regenerated Gb'E(z)(RNAi) cricket legs exhibited extra leg segment formation between the tibia and tarsus, and regenerated Gb'Utx(RNAi) cricket legs showed leg joint formation defects in the tarsus. In the Gb'E(z)(RNAi) regenerating leg, the Gb'dac expression domain expanded in the tarsus. By contrast, in the Gb'Utx(RNAi) regenerating leg, Gb'Egfr expression in the middle of the tarsus was diminished. These results suggest that regulation of the histone H3K27 methylation state is involved in the repatterning process during leg regeneration among cricket species via the epigenetic regulation of leg patterning gene expression. PMID- 26253406 TI - Protein phosphatase 2A promotes the transition to G0 during terminal differentiation in Drosophila. AB - Protein phosphatase type 2A complex (PP2A) has been known as a tumor suppressor for over two decades, but it remains unclear exactly how it suppresses tumor growth. Here, we provide data indicating a novel role for PP2A in promoting the transition to quiescence upon terminal differentiation in vivo. Using Drosophila eyes and wings as a model, we find that compromising PP2A activity during the final cell cycle prior to a developmentally controlled cell cycle exit leads to extra cell divisions and delays entry into quiescence. By systematically testing the regulatory subunits of Drosophila PP2A, we find that the B56 family member widerborst (wdb) is required for the role of PP2A in promoting the transition to quiescence. Cells in differentiating tissues with compromised PP2A retain high Cdk2 activity when they should be quiescent, and genetic epistasis tests demonstrate that ectopic Cyclin E/Cdk2 activity is responsible for the extra cell cycles caused by PP2A inhibition. The loss of wdb/PP2A function cooperates with aberrantly high Cyclin E protein levels, allowing cells to bypass a robust G0 late in development. This provides an example of how loss of PP2A can cooperate with oncogenic mutations in cancer. We propose that the PP2A complex plays a novel role in differentiating tissues to promote developmentally controlled quiescence through the regulation of Cyclin E/Cdk2 activity. PMID- 26253408 TI - Root developmental programs shape the Medicago truncatula nodule meristem. AB - Nodules on the roots of legume plants host nitrogen-fixing Rhizobium bacteria. Several lines of evidence indicate that nodules are evolutionarily related to roots. We determined whether developmental control of the Medicago truncatula nodule meristem bears resemblance to that in root meristems through analyses of root meristem-expressed PLETHORA genes. In nodules, MtPLETHORA 1 and 2 are preferentially expressed in cells positioned at the periphery of the meristem abutting nodule vascular bundles. Their expression overlaps with an auxin response maximum and MtWOX5, which is a marker for the root quiescent center. Strikingly, the cells in the central part of the nodule meristem have a high level of cytokinin and display MtPLETHORA 3 and 4 gene expression. Nodule specific knockdown of MtPLETHORA genes results in a reduced number of nodules and/or in nodules in which meristem activity has ceased. Our nodule gene expression map indicates that the nodule meristem is composed of two distinct domains in which different MtPLETHORA gene subsets are expressed. Our mutant studies show that MtPLETHORA genes function redundantly in nodule meristem maintenance. This indicates that Rhizobium has recruited root developmental programs for nodule formation. PMID- 26253407 TI - Kinesin-1 interacts with Bucky ball to form germ cells and is required to pattern the zebrafish body axis. AB - In animals, specification of the primordial germ cells (PGCs), the stem cells of the germ line, is required to transmit genetic information from one generation to the next. Bucky ball (Buc) is essential for germ plasm (GP) assembly in oocytes, and its overexpression results in excess PGCs in zebrafish embryos. However, the mechanistic basis for the excess PGCs in response to Buc overexpression, and whether endogenous Buc functions during embryogenesis, are unknown. Here, we show that endogenous Buc, like GP and overexpressed Buc-GFP, accumulates at embryonic cleavage furrows. Furthermore, we show that the maternally expressed zebrafish Kinesin-1 Kif5Ba is a binding partner of Buc and that maternal kif5Ba (Mkif5Ba) plays an essential role in germline specification in vivo. Specifically, Mkif5Ba is required to recruit GP to cleavage furrows and thereby specifies PGCs. Moreover, Mkif5Ba is required to enrich Buc at cleavage furrows and for the ability of Buc to promote excess PGCs, providing mechanistic insight into how Buc functions to assemble embryonic GP. In addition, we show that Mkif5Ba is also essential for dorsoventral (DV) patterning. Specifically, Mkif5Ba promotes formation of the parallel vegetal microtubule array required to asymmetrically position dorsal determinants (DDs) towards the prospective dorsal side. Interestingly, whereas Syntabulin and wnt8a translocation depend on kif5Ba, grip2a translocation does not, providing evidence for two distinct mechanisms by which DDs might be asymmetrically distributed. These studies identify essential roles for maternal Kif5Ba in PGC specification and DV patterning, and provide mechanistic insight into Buc functions during early embryogenesis. PMID- 26253409 TI - Osteoblast de- and redifferentiation are controlled by a dynamic response to retinoic acid during zebrafish fin regeneration. AB - Zebrafish restore amputated fins by forming tissue-specific blastema cells that coordinately regenerate the lost structures. Fin amputation triggers the synthesis of several diffusible signaling factors that are required for regeneration, raising the question of how cell lineage-specific programs are protected from regenerative crosstalk between neighboring fin tissues. During fin regeneration, osteoblasts revert from a non-cycling, mature state to a cycling, preosteoblastic state to establish a pool of progenitors within the blastema. After several rounds of proliferation, preosteoblasts redifferentiate to produce new bone. Blastema formation and proliferation are driven by the continued synthesis of retinoic acid (RA). Here, we find that osteoblast dedifferentiation and redifferentiation are inhibited by RA signaling, and we uncover how the bone regenerative program is achieved against a background of massive RA synthesis. Stump osteoblasts manage to contribute to the blastema by upregulating expression of the RA-degrading enzyme cyp26b1. Redifferentiation is controlled by a presumptive gradient of RA, in which high RA levels towards the distal tip of the blastema suppress redifferentiation. We show that this might be achieved through a mechanism involving repression of Bmp signaling and promotion of Wnt/beta catenin signaling. In turn, cyp26b1(+) fibroblast-derived blastema cells in the more proximal regenerate serve as a sink to reduce RA levels, thereby allowing differentiation of neighboring preosteoblasts. Our findings reveal a mechanism explaining how the osteoblast regenerative program is protected from adverse crosstalk with neighboring fibroblasts that advances our understanding of the regulation of bone repair by RA. PMID- 26253410 TI - Health implications of engineered nanoparticles in infants and children. AB - BACKGROUND: The nanotechnology boom and the ability to manufacture novel nanomaterials have led to increased production and use of engineered nanoparticles (ENPs). However, the increased use of various ENPs inevitably results in their release in or the contamination of the environment, which poses significant threats to human health. In recent years, extraordinary economic and societal benefits of nanoproducts as well as their potential risks have been observed and widely debated. To estimate whether ENPs are safe from the onset of their manufacturing to their disposal, evaluation of the toxicological effects of ENPs on human exposure, especially on more sensitive and vulnerable sectors of the population (infants and children) is essential. DATA SOURCES: Papers were obtained from PubMed, Web of Science, and Google Scholar. Literature search words included: "nanoparticles", "infants", "children", "exposure", "toxicity", and all relevant cross-references. RESULTS: A brief overview was conducted to 1) characterize potential exposure routes of ENPs for infants and children; 2) describe the vulnerability and particular needs of infants and children about ENPs exposure; 3) investigate the current knowledge about the potential health hazards of ENPs; and 4) provide suggestions for future research and regulations in ENP applications. CONCLUSIONS: As the manufacturing and use of ENPs become more widespread, directed and focused studies are necessary to measure actual exposure levels and to determine adverse health consequences in infants and children. PMID- 26253411 TI - Pancreatic involvement in pediatric inflammatory bowel diseases. AB - BACKGROUND: Inflammatory bowel diseases (IBDs) are a group of chronic diseases affecting the gastrointestinal tract, with a disabling course. The incidence of IBDs is increasing in different geographical areas, indicating its emergence as a global disease, especially in children. Many patients with IBDs develop extraintestinal manifestations (EIMs) during follow-up, as IBDs have a potential risk of systemic involvement.. DATA SOURCES: A systematic review of the literature was made to analyze latest studies on pancreatic involvement in children with IBD including our experience in assessing possible implications and its future application. RESULTS: The involvement of the hepatobiliary system is considered a rare EIM of children with IBD, with an incidence much higher than that in the general population. Isolated pancreatic hyperenzymemia, which occurs in the absence of typical symptoms and/or characteristic imaging findings, may be found in many patients with IBD. The frequent causes of pancreatitis are drugs, bilio-pancreatic disorders, immunologic disturbances and pancreatic auto antibodies, although in some cases idiopathic forms have been described. CONCLUSIONS: It is important to establish a correct diagnostic approach based on etiology and to assess the most appropriate therapeutic strategy, thus avoiding complications and improving the quality of life of children with IBD. PMID- 26253412 TI - Food allergy and related risk factors in 2540 preschool children: an epidemiological survey in Guangdong Province, southern China. AB - BACKGROUND: Although the number of studies on allergic diseases in the general population of southern China is increasing, only a few have addressed food allergy (FA) in children in this region. The present study aimed to investigate the prevalence, clinical manifestations, spectrum of allergens, and related risk factors of FA in preschool children in Guangdong Province, southern China. METHODS: A random cluster-sampling method was used to select 24 kindergartens from 12 cities in Guangdong Province. The parents or guardians of the children were requested to complete a questionnaire on general information and data regarding FA diagnosis and symptoms in the children and their first-degree relatives. Thereafter, the Chi-square test, multivariate regression analysis, and Spearman's rank-order correlation coefficient analysis were performed to identify statistically significant differences. RESULTS: Analysis of 2540 valid questionnaires revealed an FA prevalence rate of 4%. Adverse food reactions were due to the consumption of shrimp (4.4%), crab (3.2%), mango (2.3%), cow's milk and dairy products (1.9%), and eggs (1.4%). Logistic regression analysis indicated that a history of FA and a history of allergic rhinitis in the first degree relatives were the major factors leading to FA in children. CONCLUSIONS: The incidence of FA in children in Guangdong Province is higher than that commonly believed. An individual's genetic background is an important risk factor for FA. Hence, mitigation of the impact of lifestyle and environmental factors should be carefully considered to reduce the incidence of childhood FA. PMID- 26253413 TI - Novel mutations of the ATP7B gene in Han Chinese families with pre-symptomatic Wilson's disease. AB - BACKGROUND: Wilson's disease (WD) is an autosomal recessive genetic disorder of copper metabolism, caused by mutations in the ATP7B gene, resulting in copper accumulation in the liver, brain, kidney, and cornea and leading to significant disability or death if untreated. Early diagnosis and proper therapy usually predict a good prognosis, especially in pre-symptomatic WD. Genetic testing is the most accurate and effective diagnostic method for early diagnosis. METHODS: The clinical and biochemical features of three unrelated Han Chinese families with pre-symptomatic WD were reported. The molecular defects in these families were investigated by polymerase chain reaction and DNA sequencing. Hundred healthy children with the same ethnic background served as controls. Bioinformatic tools (polymorphism phenotyping-2, sorting intolerant from tolerant, protein analysis through evolutionary relationships, and predictor of human deleterious single nucleotide polymorphisms) were combined and used to predict the functional effects of mutations. RESULTS: We identified 2 novel ATP7B mutations (p.Leu692Pro and p.Asn728Ser) and 3 known mutations (p.Met769fs, p.Arg778Leu and p.Val1216Met) in these Chinese WD families. These mutations were not observed in the 100 normal controls. The bioinformatic method showed that p.Leu692Pro and p.Asn728Ser mutations are pathogenic. CONCLUSIONS: Our research enriches the mutation spectrum of the ATP7B gene worldwide and provides valuable information for studying the mutation types and mode of inheritance of ATP7B in the Chinese population. Liver function analysis and genetic testing in young children with WD are necessary to shorten the time to the initiation of therapy, reduce damage to the liver and brain, and improve prognosis. PMID- 26253415 TI - Resection of a dysembryoplastic neuroepithelial tumor in the precentral gyrus. AB - BACKGROUND: Dysembryoplastic neuroepithelial tumors (DNTs) are common causes of intractable epilepsy in pediatric epilepsy patients. The effect of surgical intervention is often limited when the tumor is located in the precentral gyrus. Furthermore, complete surgical resection is often not performed in order to avoid permanent neurological deficits. METHODS: Here, we present a pediatric patient with intractable epilepsy caused by a simple DNT located in the precentral gyrus. Intracranial electrodes were implanted and used in combination with magnetic resonance imaging, video-electroencephalography and electrical cortical stimulation to assess neurological function, and where the epileptogenic zone was located. RESULTS: The results of intracranial electrode monitoring suggested that the epileptogenic zone was located in the tumor area and that cortical function had been reorganized. We completely resected the tumor based on these findings. The patient has been seizure free after the surgery and has not had any neurological deficits. CONCLUSIONS: Simple form DNTs in the precentral gyrus can be completely resected with careful preoperative assessment of cortical function. Cortical reorganization could partly explain the functional preservation after surgery. PMID- 26253414 TI - Clinical characteristics of hemolytic uremic syndrome secondary to cobalamin C disorder in Chinese children. AB - BACKGROUND: The present study was undertaken to investigate the clinical characteristics of hemolytic uremic syndrome (HUS) secondary to cobalamin C disorder (cbl-C disorder). METHODS: We reviewed retrospectively the medical records of 3 children with HUS secondary to cbl-C disorder who had been treated between April 1, 2009 and October 31, 2013. RESULTS: The 3 patients with HUS secondary to cbl-C disorder presented with progressive hemolytic anemia, acute renal failure, thrombocytopenia, poor feeding, and failure to thrive. Two of the 3 patients once had high blood pressure. The mutations of c.609G>A (p.W203X), c.217C>T (p.R73X) and c.365A>T (p.H122L) in the methylmalonic aciduria (cobalamin deficiency) cbl-C type, with homocystinuria gene were detected in the 3 patients. In these patients the levels of lactate dehydrogenase and homocysteine in serum were elevated and the level of methylmalonic acid (MMA) in urine was also elevated. After treatment with hydroxocobalamin, 2 patients were discharged with no obvious abnormal growth and neurological development and 1 patient died of multiple organ failure. CONCLUSIONS: The results of this study demonstrated that cbl-C disorder should be investigated in any child presenting with HUS. The high concentrations of homocysteine and MMA could be used for timely recognization of the disease. Once the high levels of plasma homocystein and/or plasma or urine MMA are detected, the treatment with parenteral hydroxocobalamin should be prescribed immediately. The early diagnosis and treatment would contribute to the good prognosis of the disease. PMID- 26253416 TI - A simple method for differentiation of H9 cells into neuroectoderm. AB - Human embryonic stem cells (ESCs) can form neuroectoderm (NE), providing a platform for in vitro dissection of NE formation. However, human ESCs can differentiate into all three germ layers. It thus is crucial to develop efficient methods for differentiation of human ESCs into NE cells. Both plating cell density and localized cell density (LCD) affect NE differentiation. Here, we developed a cell cluster-based NE differentiation method, in which both plating cell density and LCD are under control. Using our new method, high plating cell densities promote expression of PAX6, a NE marker protein. Two SMAD signaling blockers, SB431542 and NOGGIN, downregulate OCT4 and upregulate PAX6, while does not affect mRNA expression of GATA2 after 5 d of differentiation. Moreover, IB analysis showed a time-dependent upregulation of PAX6 and beta-III-tubulin together with a downregulation of OCT4 during the neural differentiation. Coexpression of both TH and beta-III-tubulin in the H9-derived cells was also detected, proving the NE cells have an ability to differentiate into one of the specific neurons. Together, we established a simple method for generating NE cells from H9 cells, which might contribute to develop high efficient method for neural differentiation. PMID- 26253418 TI - Two stage hydrolysis of corn stover at high solids content for mixing power saving and scale-up applications. AB - A two stage hydrolysis of corn stover was designed to solve the difficulties between sufficient mixing at high solids content and high power input encountered in large scale bioreactors. The process starts with the quick liquefaction to convert solid cellulose to liquid slurry with strong mixing in small reactors, then followed the comprehensive hydrolysis to complete saccharification into fermentable sugars in large reactors without agitation apparatus. 60% of the mixing energy consumption was saved by removing the mixing apparatus in large scale vessels. Scale-up ratio was small for the first step hydrolysis reactors because of the reduced reactor volume. For large saccharification reactors in the second step, the scale-up was easy because of no mixing mechanism was involved. This two stage hydrolysis is applicable for either simple hydrolysis or combined fermentation processes. The method provided a practical process option for industrial scale biorefinery processing of lignocellulose biomass. PMID- 26253417 TI - Temporo-spatial analysis of Osterix, HNK1 and Sox10 during odontogenesis and maxillaries osteogenesis. AB - Cell differentiation is essential for maxillaries and tooth development. Facial mesenchymal tissue is formed by neural crest cells (NC). These cells are highly migratory, giving rise to various cell types, considered with a high level of plasticity, indicating that they contain progenitor cells with a great power of differentiation. In this study, it was analyzed the presence of NC cell progenitors and mesenchymal stem cells (MSC) during maxillaries osteogenesis and odontogenesis in rats. Histological slides were collected in two phases: embryonic age of 15 and 17 days; 2, 4 and 7 days after birth. Immunohistochemistry for MSC markers (Osterix) and NC cells (Sox10, HNK1) was performed. The results showed positive expression for Osterix and HNK1 in undifferentiated ectomesenchymal cells in early and late stages; Sox10 was present only in early stages in undifferentiated cells. All markers were present in differentiated cells. Although the experiments performed do not allow us to explain a possible role for Osx, HNK1 and Sox10 in both differentiated and undifferentiated cells during osteogenesis and odontogenesis, it had shown important results not yet described: the presence of HNK1 and Sox10 in osteoblasts and odontoblasts in late development stages and in the tooth germ epithelial cells and ameloblasts. PMID- 26253419 TI - Characterization of natural low transition temperature mixtures (LTTMs): Green solvents for biomass delignification. AB - The aim of this work was to characterize the natural low transition temperature mixtures (LTTMs) as promising green solvents for biomass pretreatment with the critical characteristics of cheap, biodegradable and renewable, which overcome the limitations of ionic liquids (ILs). The LTTMs were derived from inexpensive commercially available hydrogen bond acceptor (HBA) and l-malic acid as the hydrogen bond donor (HBD) in distinct molar ratios of starting materials and water. The peaks involved in the H-bonding shifted and became broader for the OH groups. The thermal properties of the LTTMs were not affected by water while the biopolymers solubility capacity of LTTMs was improved with the increased molar ratio of water and treatment temperature. The pretreatment of oil palm biomass was consistence with the screening on solubility of biopolymers. This work provides a cost-effective alternative to utilize microwave hydrothermal extracted green solvents such as malic acid from natural fruits and plants. PMID- 26253420 TI - "Tired of watching customers walk out the door because of the smoke": a content analysis of media coverage of voluntarily smokefree restaurants and bars. AB - BACKGROUND: News media are key sources of information regarding tobacco issues, and help set the tobacco control policy agenda. We examined US news coverage of voluntarily smokefree restaurants and bars in locales without mandatory policies to understand how such initiatives are perceived. METHODS: We searched three online media databases (Access World News, Lexis Nexis, and Proquest) for all news items, including opinion pieces, published from 1995 to 2011. We coded retrieved items quantitatively, analyzing the volume, type, provenance, prominence, and content of news coverage. RESULTS: We found 986 news items, most published in local newspapers. News items conveyed unambiguous support for voluntarily smokefree establishments, regardless of venue. Mandatory policies were also frequently mentioned, and portrayed positively or neutrally. Restaurant items were more likely to mention health-related benefits of going smokefree, with bar items more likely to mention business-related benefits. CONCLUSION: Voluntary smokefree rules in bars and restaurants are regarded by news media as reasonable responses to health and business-based concerns about worker and customer exposure to secondhand smoke. As efforts continue to enact comprehensive smokefree policies to protect all in such venues, the media are likely to be supportive partners in the advocacy process, helping to generate public and policymaker support. PMID- 26253421 TI - The effect of individual isometric muscle loading on the alignment of the base of the thumb metacarpal: a cadaveric study. AB - Stability of the thumb carpometacarpal joint relies upon equilibrium between its ligaments, muscular support and joint congruity. We wanted to identify the muscles important in preventing or increasing dorsoradial subluxation of this joint. In ten cadaveric hands, a Fastrak(r) motion tracking device was used to assess the effects of individual isometric muscle loading on the base of the thumb metacarpal relative to the radius and to the base of the middle finger metacarpal. We found that the first dorsal interosseous muscle caused the least dorsoradial translation and highest distal migration of the base of the first metacarpal, whereas abductor pollicis longus was the primary destabilizer, increasing dorsoradial misalignment. The findings show different impacts of these muscles on joint alignment and stability, which suggests that treatment should be targeted to enhance the action of the primary stabilizing muscle, the first dorsal interosseous muscle. PMID- 26253423 TI - Effects of safety measures on driver's speed behavior at pedestrian crossings. AB - This paper reports the results of a multi-factorial experiment that was aimed at the following: (a) analyzing driver's speed behavior while approaching zebra crossings under different conditions of vehicle-pedestrian interaction and with respect to several safety measures and (b) comparing safety measures and identifying the most effective treatment for zebra crossings. Three safety countermeasures at pedestrian crossings (curb extensions, parking restrictions and advanced yield markings) and the condition of no treatment (baseline condition) were designed on a two-lane urban road and implemented in an advanced driving simulator. Several conditions of vehicle-pedestrian interaction (in terms of the time left for the vehicle to get to the zebra crossing at the moment the pedestrian starts the crossing) were also simulated. Forty-two drivers completed the driving in the simulator. Based on the recorded speed data, two analyses were performed. The first analysis, which focused on the mean speed profiles, revealed that the driver's speed behavior was affected by conditions of vehicle-pedestrian interaction and was fully consistent with previous findings in the literature and with the Threat Avoidance Model developed by Fuller. Further analysis was based on variables that were obtained from the speed profiles of drivers (the speed at the beginning of the deceleration phase, the distance from the zebra crossing where the deceleration began, the minimum speed value reached during the deceleration, the distance from the pedestrian crossing where the braking phase ended and the average deceleration rate). Multivariate variance analysis (MANOVA) revealed that there was a significant main effect for safety measures and for pedestrian conditions (the presence and absence of a pedestrian). The results identified that the curb extension was the countermeasure that induces the most appropriate driver's speed behavior while approaching the zebra crossing. This conclusion was also confirmed by outcomes of the questionnaire on the countermeasure's effectiveness. More than 80% of the drivers perceived that the curb extensions were effective, which indicates that when this countermeasure was present, the drivers were more willing to yield and that the visibility of the pedestrian crossing was better. For this countermeasure, the lowest number of interactions in which the drivers did not yield to a pedestrian was also recorded. PMID- 26253422 TI - Nlrp6 promotes recovery after peripheral nerve injury independently of inflammasomes. AB - BACKGROUND: NOD-like receptors (Nlrs) are key regulators of immune responses during infection and autoimmunity. A subset of Nlrs assembles inflammasomes, molecular platforms that are activated in response to endogenous danger and microbial ligands and that control release of interleukin (IL)-1beta and IL-18. However, their role in response to injury in the nervous system is less understood. METHODS: In this study, we investigated the expression profile of major inflammasome components in the peripheral nervous system (PNS) and explored the physiological role of different Nlrs upon acute nerve injury in mice. RESULTS: While in basal conditions, predominantly members of NOD-like receptor B (Nlrb) subfamily (NLR family, apoptosis inhibitory proteins (NAIPs)) and Nlrc subfamily (ICE-protease activating factor (IPAF)/NOD) are detected in the sciatic nerve, injury causes a shift towards expression of the Nlrp family. Sterile nerve injury also leads to an increase in expression of the Nlrb subfamily, while bacteria trigger expression of the Nlrc subfamily. Interestingly, loss of Nlrp6 led to strongly impaired nerve function upon nerve crush. Loss of the inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and effector caspase-1 and caspase-11 did not affect sciatic nerve function, suggesting that Nlrp6 contributed to recovery after peripheral nerve injury independently of inflammasomes. In line with this, we did not detect release of mature IL-1beta upon acute nerve injury despite potent induction of pro-IL-1beta and inflammasome components Nlrp3 and Nlrp1. However, Nlrp6 deficiency was associated with increased pro-inflammatory extracellular regulated MAP kinase (ERK) signaling, suggesting that hyperinflammation in the absence of Nlrp6 exacerbated peripheral nerve injury. CONCLUSIONS: Together, our observations suggest that Nlrp6 contributes to recovery from peripheral nerve injury by dampening inflammatory responses independently of IL-1beta and inflammasomes. PMID- 26253424 TI - Profiling drunk driving recidivists in Denmark. AB - Drunk drivers are a menace to themselves and to other road users, as drunk driving significantly increases the risk of involvement in road accidents and the probability of severe or fatal injuries. Although injuries and fatalities related to road accidents have decreased in recent decades, the prevalence of drunk driving among drivers killed in road accidents has remained stable, at around 25% or more during the past 10 years. Understanding drunk driving, and in particular, recidivism, is essential for designing effective countermeasures, and accordingly, the present study aims at identifying the differences between non drunk drivers, drunk driving non-recidivists and drunk driving recidivists with respect to their demographic and socio-economic characteristics, road accident involvement and other traffic and non-traffic-related law violations. This study is based on register-data from Statistics Denmark and includes information from 2008 to 2012 for the entire population, aged 18 or older, of Denmark. The results from univariate and multivariate statistical analyses reveal a five year prevalence of 17% for drunk driving recidivism, and a significant relation between recidivism and the drunk drivers' gender, age, income, education, receipt of an early retirement pension, household type, and residential area. Moreover, recidivists are found to have a higher involvement in alcohol-related road accidents, as well as other traffic and, in particular, non-traffic-related offences. These findings indicate that drunk driving recidivism is more likely to occur among persons who are in situations of socio-economic disadvantage and marginalisation. Thus, to increase their effectiveness, preventive measures aiming to reduce drunk driving should also address issues related to the general life situations of the drunk driving recidivists that contribute to an increased risk of drunk driving recidivism. PMID- 26253425 TI - Mapping cyclist activity and injury risk in a network combining smartphone GPS data and bicycle counts. AB - In recent years, the modal share of cycling has been growing in North American cities. With the increase of cycling, the need of bicycle infrastructure and road safety concerns have also raised. Bicycle flows are an essential component in safety analysis. The main objective of this work is to propose a methodology to estimate and map bicycle volumes and cyclist injury risk throughout the entire network of road segments and intersections on the island of Montreal, achieved by combining smartphone GPS traces and count data. In recent years, methods have been proposed to estimate average annual daily bicycle (AADB) volume and injury risk estimates at both the intersection and segment levels using bicycle counts. However, these works have been limited to small samples of locations for which count data is available. In this work, a methodology is proposed to combine short and long-term bicycle counts with GPS data to estimate AADB volumes along segments and intersections in the entire network. As part of the validation process, correlation is observed between AADB values obtained from GPS data and AADB values from count data, with R-squared values of 0.7 for signalized intersections, 0.58 for non-signalized intersections and between 0.48 and 0.76 for segments with and without bicycle infrastructure. The methodology is also validated through the calibration of safety performance functions using both sources of AADB estimates, from counts and from GPS data. Using the validated AADB estimates, the factors associated with injury risk were identified using data from the entire population of intersections and segments throughout Montreal. Bayesian injury risk maps are then generated and the concentrations of expected injuries and risk at signalized intersections are identified. Signalized intersections, which are often located at the intersection of major arterials, witness 4 times more injuries and 2.5 times greater risk than non-signalized intersections. A similar observation can be made for arterials which not only have a higher concentration of injuries but also injury rates (risk). On average, streets with cycle tracks have a greater concentration of injuries due to greater bicycle volumes, however, and in accordance with recent works, the individual risk per cyclist is lower, justifying the benefits of cycle tracks. PMID- 26253426 TI - Macrocyclic lactones and their relationship to the SNPs related to benzimidazole resistance. AB - Haemonchus contortus is an abomasal nematode of ruminants that is widely present across the world. Its ability to cause death of infected animals and rapidly develop anthelmintic resistance makes it a dangerous pathogen. Ivermectin (IVM) and moxidectin (MOX) are macrocyclic lactones (MLs). They have been successfully used to treat parasitic nematodes over the last three decades. A genetic association between IVM selection and single nucleotide polymorphisms (SNPs) on the beta-tubulin isotype 1 gene was reported in H. contortus. These SNPs result in replacing phenylalanine (F, TTC) with tyrosine (Y, TAC) at position 167 or 200 on the beta-tubulin protein. Recently we reported a direct interaction of IVM with alpha- and beta-tubulin. It had been hypothesized that the SNPs (F167Y and F200Y) may change tubulin dynamics and directly affect IVM binding. The goal of the current study was to observe the effects of SNPs (F167Y and F200Y) on tubulin polymerization and IVM binding. It was also of interest to evaluate the differences between IVM and MOX on tubulin polymerization. We conclude that the SNPs cause no difference in the polymerization of wild and mutant tubulins. Furthermore, neither of the SNPs reduced IVM binding. Varying results were obtained in the degree of polymerization of parasitic and mammalian tubulin for IVM and MOX, i.e., the extent of polymerization was greater for IVM compared with MOX, for H. contortus tubulin, and vice versa for mammalian tubulin. Molecular modeling showed that IVM and MOX docked into the taxane binding pocket of both mammalian and parasitic wild type and mutant tubulins. However the binding was stronger for mammalian tubulin as compared to parasitic tubulin. PMID- 26253427 TI - Stapes malformations: the contribute of the endoscopy for diagnosis and surgery. AB - The aim of this study is to investigate the contribute of the endoscopic exclusive transcanalar approach for the management of stapes malformations. A retrospective chart review was made at our tertiary referral centers. 17 patients with stapes malformations underwent surgery with endoscopic exclusive transcanal approach. A complete audiological and radiological assessment before and after surgery was performed. 12/17 (70 %) underwent a surgical endoscopic correction, In case of fixed platina underwent five endoscopic stapedotomy and one endoscopic stapedectomy were performed. In case of mobile platina five endoscopic ossiculoplasties with partial ossiculoplasty replacement prosthesis were performed, 3 with autologous remodeling incus and 2 with malleus head remodeling. In 1 case, only an endoscopic stapes mobilization was made. In 5/17 (30 %), due to difficult anatomical findings an endoscopic explorative tympanotomy was finally performed. The mean preoperative air conduction (AC), bone conduction (BC) and air-bone gap (ABG) were, respectively, 60.7, 26.3 and 34.4 dB. The mean postoperative AC, BC and ABG were, respectively, 33.8, 26.5 and 7.3 dB, with a mean improvement of the ABG of 27.1 dB. Discharge from hospital was on the first post-surgery day. No relevant postoperative complications were noted. The median follow-up was 3.6 years (range 1-6). The endoscopic approach results very adequate for the diagnosis and treatment of stapes malformations, checking variations of the ossicles conformation and functioning and performing safe surgery, under direct control of middle ear structures. PMID- 26253428 TI - Treatment strategies in early-stage oropharyngeal squamous cell carcinoma: a French national survey. AB - The objective of the study is to perform a national survey of practices in early stage squamous cell carcinoma (SCC) of the oropharynx (base of tongue and tonsils) targeting surgical and non-surgical procedures in France. A questionnaire concerning practices in surgery, radiotherapy, HPV screening, and two clinical cases were sent to all centers participating in the French Head and Neck Oncology Society, and to public hospitals listed as authorized to treat head and neck cancer according to the French National Cancer Institute (INCa). Sixty four teams comprising almost all the University Hospitals and most of the Comprehensive Cancer Centers completed the survey questionnaire and responded to the clinical cases. Surgical and radiotherapy strategies were used in similar measure for early-stage SCC of the base of the tongue while tonsil lesions were mainly treated with surgery. The main arguments were disease control for the teams offering patients surgery, and functional results for those offering radiotherapy. However, concomitant chemoradiotherapy was chosen more frequently than radiotherapy alone in early-stage SCC of the base of tongue. Age and tobacco alcohol addiction were decisive criteria in decision making for the majority of the teams. French oncology teams offered surgical and radiotherapy strategies in similar measure to treat early-stage SCC of the oropharynx (base of tongue and tonsils) as well as a high rate of multimodality therapy. Decision making was guided by the desire to achieve oncologic results adapted to the patient and his age, as well as functional preservation taking into account life expectancy. PMID- 26253429 TI - Age, atherosclerosis and type 2 diabetes reduce human mesenchymal stromal cell mediated T-cell suppression. AB - To this end human MSCs were isolated from adipose tissue and the MSC:CD4(+) T cell suppression was assessed in a co-culture system. In summary, this study demonstrates that advanced age, atherosclerosis and type 2 diabetes mellitus reduce the functional potency of MSCs. Optimizing the criteria for the selection of MSC donors could enhance the results of cell-based therapies. PMID- 26253430 TI - Relevance of retrovirus quantification in cerebrospinal fluid for neurologic diagnosis. AB - Different human retroviruses, such as Human Immunodeficiency Virus (HIV) and Human T-cell Lymphotropic Virus (HTLV), can cause neurologic infection. However, a definitive diagnosis may be hampered by several factors. Quantification of the viral or proviral load in cerebrospinal fluid (CSF) may be helpful in the diagnosis of nervous system disorders due to retroviral infection and may influence the treatment approach. The present work discusses retrovirus infection and neurologic impairment, as well as the usefulness of the determination of the HIV and HTLV proviral or viral load in cerebrospinal fluid in cases of neurologic disorder, in light of recent advances in this field. This study also discusses the different molecular techniques for quantifying the proviral load (real-time quantitative PCR, droplet digital PCR, and semi-nested real-time reverse transcription PCR) that are currently available. PMID- 26253431 TI - Techniques aren't everything: Why conscientious well-trained surgeons make mistakes? PMID- 26253432 TI - Rectal duplication responsible for compressive symptoms is a very rare entity in adults. PMID- 26253433 TI - Drainoscopy: a doorway to the abdomen in the post-surgical patient. PMID- 26253434 TI - Artificial insemination in pigs today. AB - Use of artificial insemination (AI) for breeding pigs has been instrumental for facilitating global improvements in fertility, genetics, labor, and herd health. The establishment of AI centers for management of boars and production of semen has allowed for selection of boars for fertility and sperm production using in vitro and in vivo measures. Today, boars can be managed for production of 20 to 40 traditional AI doses containing 2.5 to 3.0 billion motile sperm in 75 to 100 mL of extender or 40 to 60 doses with 1.5 to 2.0 billion sperm in similar or reduced volumes for use in cervical or intrauterine AI. Regardless of the sperm dose, in liquid form, extenders are designed to sustain sperm fertility for 3 to 7 days. On farm, AI is the predominant form for commercial sow breeding and relies on manual detection of estrus with sows receiving two cervical or two intrauterine inseminations of the traditional or low sperm doses on each day detected in standing estrus. New approaches for increasing rates of genetic improvement through use of AI are aimed at methods to continue to lower the number of sperm in an AI dose and reducing the number of inseminations through use of a single, fixed-time AI after ovulation induction. Both approaches allow greater selection pressure for economically important swine traits in the sires and help extend the genetic advantages through AI on to more production farms. PMID- 26253435 TI - Antioxidant effect of crocin on bovine sperm quality and in vitro fertilization. AB - Reactive oxygen species (ROS) production above critical levels affects the genetic and functional integrity of spermatozoa by causing oxidative stress. Spermatozoa are susceptible to oxidative stress in terms of motility and fertilization capacity. Crocin (crocetin di-gentiobiose ester), a main constituent of Crocus Sativus L. (saffron), is known for its antioxidant activity by scavenging ROS, especially superoxide anion. The aim of the present study is to evaluate the effect of crocin on the quality characteristics of spermatozoa and fertilization rate. Frozen-thawed and washed spermatozoa from four different bulls were incubated with three different concentrations of crocin (0.5, 1, and 2 mM), for 120 and 240 minutes, in the presence of a negative control, and were evaluated in terms of motility, viability, acrosomal status, DNA fragmentation index, intracellular ROS, and lipid peroxidation. The most potent concentration of crocin (1 mM) was also added in the fertilization medium to test its impact on fertilization outcome. The results indicate that the incubation of spermatozoa with 1 mM of crocin resulted in a statistically significant lower production of ROS, lower lipid peroxidation and in better maintenance of motility, viability, and acrosomal integrity, with a very small number of fragmented cells, compared to the control and the other treated groups (P < 0.05). Crocin concentration of 1 mM resulted in a significant increase of blastocyst rate, compared to the control group (P < 0.01). These data indicate that crocin (1 mM) improves bovine sperm quality and its fertilization capability, directly and/or indirectly, by modulating ROS concentration. PMID- 26253437 TI - Nanocap array of Au:Ag composite for surface-enhanced Raman scattering. AB - We fabricated Au:Ag nanocap arrays by co-sputtering Au and Ag onto two dimensional polystyrene (PS) colloidal sphere templates in a magnetron sputtering system for the surface-enhanced Raman scattering (SERS) substrate. In contrast to the bilayer Au/Ag, the co-sputtering Au:Ag bimetal array formed the protrusion network of Ag and Au nanoparticles, which contributed to Raman enhancement in the waxberry-like structure. The metal protrusions formed waxberry-like shell in which the PS beads were encapsulated. At the same time, the Au:Ag bimetal arrays exhibit 4-fold more enhancement in the SERS signal intensity of Rhodamine 6G at the 1649cm(-1) than Au/Ag bilayer array, which is ascribed to the plasmon coupling between the nanoparticles of Au and Ag on the sample. When the PS colloidal particle templates were etched by O2-plasma before sputtering process, the nanogaps affected the surface plasmon resonance (SPR), and the optimal gaps between adjacent Au:Ag nanocaps generated even stronger SERS enhancements. This SERS substrate of Au:Ag showed high sensitivity and reproducibility. The EF of Au:Ag nanocap array substrate onto which Rhodamine 6G (R6G) were adsorbed was evaluated as 6.72*10(10). PMID- 26253436 TI - Relationship between the catechol-O-methyl transferase Val108/158Met genotype and brain volume in treatment-naive major depressive disorder: Voxel-based morphometry analysis. AB - Catechol-O-methyltransferase (COMT) is a methylation enzyme engaged in the degradation of dopamine and noradrenaline by catalyzing the transfer of a methyl group from S-adenosylmethionine. An association was found between the Valine (Val) 108/158Methionine (Met) COMT polymorphism (rs4680) and major depressive disorder (MDD). The authors prospectively investigated the relationship between the Val108/158Met COMT genotype and voxel-based morphometry (VBM) findings for patients with first-episode and treatment-naive MDD and healthy subjects (HS). Participants comprised 30 MDD patients and 48 age- and sex-matched HS who were divided according to the COMT genotype. Effects of diagnosis, COMT genotype, and the genotype-diagnosis interaction in relation to brain morphology in the Val/Met and Val/Val individuals were evaluated using a VBM analysis of high-resolution magnetic resonance imaging findings. Among the Val/Met individuals, the volume of the bilateral caudate was significantly smaller for MDD patients than for HS. In the Val/Val individuals, the caudate volume was comparable between MDD patients and HS. Significant genotype-diagnosis interaction effects on brain morphology were noted in the right caudate. PMID- 26253438 TI - A mercuric ensemble based on a cycloruthenated complex as a visual probe for iodide in aqueous solution. AB - A new water-soluble cycloruthenated complex Ru(bthiq)(dcbpy)2(+) (1, Hbthiq=1-(2 benzo[b]thiophenyl)isoquinoline, dcbpy=4,4'-dicarboxylate-2,2'-bipyridine) was designed and synthesized to form its mercuric ensemble (1-Hg(2+)) to achieve visual detection of iodide anions. The binding constant of 1-Hg(2+) is calculated to be 2.40*10(4)M(-1), which is lower than that of HgI2. Therefore, the addition of I(-) to the aqueous solution of 1-Hg(2+)lead to significant color changes from yellow to deep-red by the release of 1. The results showed that iodide anions could be easily detected by the naked eyes. The detection limit of iodide anion is calculated as 0.77MUM. In addition, an easily-prepared test strip of 1-Hg(2+) was obtained successfully to detect iodide anions. PMID- 26253439 TI - Near-infrared dispersion and spin-orbit interaction of Co doped (80-x)Sb2O3 20Na2O-xWO3 glasses. AB - The present paper discusses the fact that the absorption spectra of doped with 0.1% Co3O4 glasses with the composition (80-x)Sb2O3-20Na2O-xWO3 are measured in the spectral region 1200-1400nm. The optical structure of Co(2+) is analyzed and the energies of the electron transitions in the metal ion are determined. The spin-orbit interaction is thoroughly analyzed. The refractive index n is calculated for the examined sample with x=20mol% WO3. PMID- 26253440 TI - Novel ratio difference at coabsorptive point spectrophotometric method for determination of components with wide variation in their absorptivities. AB - Different methods have been introduced to enhance selectivity of UV spectrophotometry thus enabling accurate determination of co-formulated components, however mixtures whose components exhibit wide variation in absorptivities has been an obstacle against application of UV-spectrophotometry. The developed ratio difference at coabsorptive point method (RDC) represents a simple effective solution for the mentioned problem, where the additive property of light absorbance enabled the consideration of the two components as multiples of the lower absorptivity component at certain wavelength (coabsorptive point), at which their total concentration multiples could be determined, whereas the other component was selectively determined by applying the ratio difference method in a single step. Mixture of perindopril arginine (PA) and amlodipine besylate (AM) figures that problem, where the low absorptivity of PA relative to AM hinders selective spectrophotometric determination of PA. The developed method successfully determined both components in the overlapped region of their spectra with accuracy 99.39+/-1.60 and 100.51+/-1.21, for PA and AM, respectively. The method was validated as per the USP guidelines and showed no significant difference upon statistical comparison with reported chromatographic method. PMID- 26253441 TI - [Imaging-based indications for interventional treatment of stroke]. AB - The indications for mechanical thrombectomy are based on a proximal vessel occlusion in the absence of extensive ischemic damage in the corresponding dependent vascular territory. The maximum extent of early ischemic edema for which endovascular treatment is still useful is not clear from the studies. A benefit of mechanical thrombectomy can be safely assumed with an ASPECT score of 6-10, possibly also with lower scores. A more complex imaging with assessment of the status of collateral vessels or perfusion abnormality is scientifically interesting but usually not necessary for clinical decision-making for endovascular stroke treatment within the first 6 h after symptom onset. PMID- 26253442 TI - Erratum to: KCTU randomisation and IMP management system. PMID- 26253443 TI - Occurrence of FFZ genes in yeasts and correlation with fructophilic behaviour. AB - Fructophily has been described in yeasts as the ability to utilize fructose preferentially when fructose and glucose are available in the environment. In Zygosaccharomyces bailii and Zygosaccharomyces rouxii, fructophilic behaviour has been associated with the presence of a particular type of high-capacity and low affinity fructose transporters designated Ffz. In this study, a PCR screening was performed in several yeasts using degenerate primers suitable to detect FFZ-like genes. In parallel, fructophilic character was evaluated in the same strains by comparing the relative consumption rate of fructose and glucose. For all the strains in which FFZ-like genes were detected, fructophilic behaviour was observed (25 strains). Results show that FFZ genes are ubiquitous in the Zygosaccharomyces and Starmerella clades. Strains of Lachancea fermentati, Torulaspora microellipsoides and Zygotorulaspora florentina were not fructophilic and did not harbour FFZ genes. It is of note that these new species were recently removed by taxonomists from the Zygosaccharomyces clade, supporting the view that the presence of FFZ-like genes is a main characteristic of Zygosaccharomyces. Among the strains tested, only Hanseniaspora guilliermondii NCYC2380 was an exception, having a preference for fructose in medium with high sugar concentrations, despite no FFZ-like genes being detected in the screening. Furthermore, this study supports the previous idea of the emergence of a new family of hexose transporters (Ffz facilitators) distinct from the Sugar Porter family. PMID- 26253444 TI - Putaminal serotonergic innervation: monitoring dyskinesia risk in Parkinson disease. AB - OBJECTIVE: To explore serotonergic innervation in the basal ganglia in relation to levodopa-induced dyskinesia in patients with Parkinson disease (PD). METHODS: A total of 30 patients with PD without dementia or depression were divided into 3 matched groups (dyskinetic, nondyskinetic, and drug-naive) for this study. We acquired 2 PET scans and 3T MRI for each patient using [(11)C]-3-amino-4-(2 dimethylaminomethylphenylsulfanyl)-benzonitrile ((11)C-DASB) and N-(3 [(18)F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane ((18)F-FP-CIT). Then we analyzed binding potentials of the 2 radiotracers at basal ganglia structures and correlations with clinical variables. RESULTS: We observed no difference in (18)F-FP-CIT binding between dyskinetic and nondyskinetic patients, whereas there were differences in (11)C-DASB binding for the caudate and putamen. Binding potential ratios ((11)C-DASB/(18)F-FP-CIT) at the putamen, which indicate serotoninergic fiber innervation relative to dopaminergic fiber availability, were highest in the dyskinetic group, followed by the nondyskinetic and drug naive PD groups. (11)C-DASB/(18)F-FP-CIT ratios at the putamen and pallidum correlated positively with Unified Parkinson's Disease Rating Scale (UPDRS) total scores and duration of PD, and pallidal binding ratio also correlated with the UPDRS motor scores. Ratios were not dependent on dopaminergic medication dosages for any of the regions studied. CONCLUSIONS: Relative serotonergic innervation of the putamen and pallidum increased with clinical PD progression and was highest in patients with established dyskinesia. The serotonin/dopamine transporter ratio might be a potential marker of disease progression and an indicator of risk for levodopa-induced dyskinesia in PD. A prospective evaluation is warranted in the future. PMID- 26253445 TI - Fruit flies, bile acids, and Parkinson disease: a mitochondrial connection? PMID- 26253446 TI - Serotonin/dopamine transporter ratio as a predictor of L-dopa-induced dyskinesia. PMID- 26253447 TI - Blowing the whistle on sports concussions: Will the risk of dementia change the game? PMID- 26253448 TI - Chronic traumatic encephalopathy and athletes. AB - Recent case reports have described athletes previously exposed to repetitive head trauma while participating in contact sports who later in life developed mood disorders, headaches, cognitive difficulties, suicidal ideation, difficulties with speech, and aggressive behavior. Postmortem discoveries show that some of these athletes have pathologic findings that are collectively termed chronic traumatic encephalopathy (CTE). Current hypotheses suggest that concussions or perhaps blows to the head that do not cause the signs and symptoms necessary for making the diagnosis of concussion, so-called subconcussive blows, cause both the clinical and pathologic findings. There are, however, some athletes who participate in contact sports who do not develop the findings ascribed to CTE. Furthermore, there are people who have headaches, mood disorders, cognitive difficulties, suicidal ideation, and other clinical problems who have neither been exposed to repeated head trauma nor possessed the pathologic postmortem findings of those currently diagnosed with CTE. The current lack of prospective data and properly designed case-control studies limits the current understanding of CTE, leading to debate about the causes of the neuropathologic findings and the clinical observations. Given the potential for referral and recall bias in available studies, it remains unclear whether or not the pathologic findings made postmortem cause the presumed neurobehavioral sequela and whether the presumed risk factors, such as sports activity, cerebral concussions, and subconcussive blows, are solely causative of the clinical signs and symptoms. This article discusses the current evidence and the associated limitations. PMID- 26253449 TI - UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2(G2019S) carriers and in vivo. AB - OBJECTIVE: To further characterize mitochondrial dysfunction in LRRK2(G2019S) mutant Parkinson disease (PD) patient tissue (M-LRRK2(G2019S)), determine whether ursodeoxycholic acid (UDCA) also exerts a beneficial effect on mitochondrial dysfunction in nonmanifesting LRRK2(G2019S) mutation carriers (NM-LRRK2(G2019S)), and assess UDCA for its beneficial effect on neuronal dysfunction in vivo. METHODS: Intracellular adenosine 5'-triphosphate (ATP) levels, oxygen consumption, and activity of the individual complexes of the mitochondrial respiratory chain as well as mitochondrial morphology were measured in M LRRK2(G2019S), NM-LRRK2(G2019S), and controls. UDCA was assessed for its rescue effect on intracellular ATP levels in NM-LRRK2(G2019S) and in a LRRK2 transgenic fly model with dopaminergic expression of LRRK2(G2019S). RESULTS: Crucial parameters of mitochondrial function were similarly reduced in both M LRRK2(G2019S) and NM-LRRK2(G2019S) with a specific decrease in respiratory chain complex IV activity. Mitochondrial dysfunction precedes changes in mitochondrial morphology but is normalized after siRNA-mediated knockdown of LRRK2. UDCA improved mitochondrial function in NM-LRRK2(G2019) and rescued the loss of visual function in LRRK2(G2019S) flies. CONCLUSION: There is clear preclinical impairment of mitochondrial function in NM-LRRK2(G2019S) that is distinct from the mitochondrial impairment observed in parkin-related PD. The beneficial effect of UDCA on mitochondrial function in both NM-LRRK2(G2019S) and M-LRRK2(G2019S) as well as on the function of dopaminergic neurons expressing LRRK2(G2019S) suggests that UDCA is a promising drug for future neuroprotective trials. PMID- 26253450 TI - Signaling lymphocyte-activation molecule SLAMF1 augments mycobacteria BCG-induced inflammatory response and facilitates bacterial clearance. AB - Tuberculosis, which is caused by intracellular mycobacterium Mycobacterium tuberculosis (Mtb), remains one of the most serious global public health concerns. The mechanisms by which innate immunity regulates the inflammatory responses and affects mycobacterial infection remain unclear. In this study, signaling lymphocyte-activation molecule family 1 (SLAMF1) was significantly upregulated in Mycobacterium bovis Bacille Calmette-Guerin (BCG)-infected RAW264.7 cells. Overexpression of SLAMF1 significantly increased the production of inflammatory factors TNF-alpha and IL-1beta, as well as chemokine MCP-1, both in vitro and in vivo upon mycobacteria BCG infection. By contrast, knockdown of SLAMF1 significantly decreased the production of TNF-alpha, IL-1beta, and MCP-1. Western blot analysis indicated that the NF-kappaB signaling pathway may contribute to the elevated inflammatory response promoted by SLAMF1, as evidenced by higher levels of phosphorylated p65 and IkappaBalpha detected with SLAMF1 overexpression. Furthermore, SLAMF1 upregulation facilitated bacterial clearance in infected RAW264.7 cells and in the lungs of infected mice. In conclusion, we demonstrated that BCG infection significantly upregulated SLAMF1, which enhanced inflammatory response by activating the NF-kappaB signaling pathway and facilitated bacterial clearance in BCG-infected RAW264.7 cells and mice. PMID- 26253451 TI - The transferability of blaOXA-23 gene in multidrug-resistant Acinetobacter baumannii isolates from Saudi Arabia and Egypt. AB - Carbapenem-resistant Acinetobacter spp. have been increasingly reported worldwide including Saudi Arabia and Egypt. We examined 64, non-repetitive, Acinetobacter baumannii isolates collected in 2013 and 2014 from four different medical centres (two from Saudi Arabia and two from Egypt). All the isolates were resistant to ceftazidime and ciprofloxacin. The intI1 harbouring blaGES-11 and aac-6'-1b was detected in 19% (n=12) of the isolates. ISAba1 over-expression of blaADC gene was observed in 65% (n=42) of isolates. Of all the isolates 19% (n=12) had ISAba1 upstream of the blaOXA-51-like gene, 69% (n=44) carried the blaOXA-23 gene within the Tn2006 structure, 8% (n=5) had blaOXA-24-like gene and 9% (n=6) harboured either blaVIM-2 or blaNDM-1 gene. Eighty nine percent (n=57) of isolates were resistant to imipenem and had an MIC of >=8mg/L. Pulsed-field gel electrophoresis (PFGE) typing revealed the presence of 23 different PFGE. Three PFGE types were very widespread, ST236 (CC104) (PFGE type 1, n=15), ST208 (CC92) (PFGE type 2, n=10), ST884 (CC unassigned) (PFGE type 3, n=7) in and across all four medical centres. The blaOXA-23 gene was found to be present on a 60kb transferable plasmid in both PFGE type 1 and 2 but was absent in PFGE type 3. This is the first study to report on the emergence of ST236 in Saudi Arabia and Egypt, and spread of distinct carbapenem resistant A. baumannii clones belonging to ST884, ST945 and ST1096 in Saudi Arabia. PMID- 26253452 TI - Accuracy and completeness of patient pathways--the benefits of national data linkage in Australia. AB - BACKGROUND: The technical challenges associated with national data linkage, and the extent of cross-border population movements, are explored as part of a pioneering research project. The project involved linking state-based hospital admission records and death registrations across Australia for a national study of hospital related deaths. METHODS: The project linked over 44 million morbidity and mortality records from four Australian states between 1st July 1999 and 31st December 2009 using probabilistic methods. The accuracy of the linkage was measured through a comparison with jurisdictional keys sourced from individual states. The extent of cross-border population movement between these states was also assessed. RESULTS: Data matching identified almost twelve million individuals across the four Australian states. The percentage of individuals from one state with records found in another ranged from 3-5%. Using jurisdictional keys to measure linkage quality, results indicate a high matching efficiency (F measure 97 to 99%), with linkage processing taking only a matter of days. CONCLUSIONS: The results demonstrate the feasibility and accuracy of undertaking cross jurisdictional linkage for national research. The benefits are substantial, particularly in relation to capturing the full complement of records in patient pathways as a result of cross-border population movements. The project identified a sizeable 'mobile' population with hospital records in more than one state. Research studies that focus on a single jurisdiction will under-enumerate the extent of hospital usage by individuals in the population. It is important that researchers understand and are aware of the impact of this missing hospital activity on their studies. The project highlights the need for an efficient and accurate data linkage system to support national research across Australia. PMID- 26253453 TI - Ischemic postconditioning altered microRNAs in human valve replacement. AB - BACKGROUND: Although the involvement of microRNAs (miRNAs) has been intensively studied in myocardial infarction, there is no report on the regulation of miRNAs by ischemic postconditioning in patients undergoing cardiac surgery. We aim to explore the regulation of miRNAs by ischemic postconditioning in double valve replacement. MATERIALS AND METHODS: In this prospective, controlled clinical study, consecutive 30 patients undergoing double valve replacement were enrolled. The patients were randomized into two groups, namely an ischemic postconditioning (IPO) group (n = 15) and a control (CON) group (n = 15). For ethical considerations, samples of right atrial muscle were harvested, respectively, 10 min before cardiopulmonary bypass (pre-CPB) and 5 min after aortic declamping (post-CPB) for analysis of miRNAs, genes and apoptosis. RESULTS: Compared with the CON group, miR-1 was downregulated, whereas miR-21 was upregulated, and BCL2 messenger RNA (mRNA) was upregulated, whereas BAX mRNA and programmed cell death 4 mRNA remained unchanged in the IPO group. Likewise, a significant increase in BCL2 protein and a striking decrease in BAX protein were observed in the IPO group when compared with those in the CON group. The IPO group showed a significantly smaller increase of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive myocytes after CPB than CON group. CONCLUSIONS: Ischemic postconditioning could regulate miR-1, miR-21, and downstream effectors and resulted in actual attenuation of apoptosis in patients undergoing valvular heart surgery. PMID- 26253454 TI - Blood transfusion does not affect survival of gastric cancer patients. AB - BACKGROUND: To initially assess the impact of perioperative blood transfusions (PBTs) on overall survival of patients underwent curative resection of I-III TNM stage gastric cancer (GC) using the propensity scoring method. METHODS: The medical records of 1150 GC patients who underwent curative resection in the Tianjin Cancer Hospital between 2003 and 2008 were retrospectively analyzed. Both transfusion and nontransfusion patients were assessed the prognostic differences after surgery using the propensity score analysis. RESULTS: A total of 299 GC patients (26.0%) were administrated the PBT. With the unadjusted analysis, patients with PBT presented older age, more operative blood loss, lower hemoglobin, lower albumin level, and higher risk of the advanced disease. The 5-y survival rate for patients with PBT was 31.0%, which was significantly lower than that (47.9%) of patients without PBT (P < 0.05). However, we demonstrated that there was not any statistical 5-y survival rate difference of between patients with PBT and patients without PBT with the propensity score analysis (31.0% versus 31.3%, P > 0.05). In addition, we also found that PBT was not significantly associated with the increasing risk of mortality (hazard ratio, 1.054; P = 0.628). CONCLUSIONS: PBT could not give rise to the worse prognoses of GC patients. PMID- 26253455 TI - Effects of terlipressin on patients with sepsis via improving tissue blood flow. AB - Terlipressin (TP), an analog of arginine vasopressin, was reported beneficial in sepsis patients when combined use with norepinephrine (NE), but the undetermined action, mechanism, and safety limited it to become the first-line vasopressor for sepsis patients. With 32 septic shock patients, we investigated the effects of a small dose of TP (1.3 MUg/kg/h) on hemodynamic, tissue blood flow, vital organ function, acid-base balance, and coagulation function to systemically know the beneficial effect and side effects of TP on septic shock. The results showed that as compared with the single use of NE group (17 patients), a small dose of TP (1.3 MUg/kg/h) in combination with NE continuous infusion, except for decreasing the mortality and NE requirement, could better improve and stabilize the hemodynamics, improve the tissue blood flow, increase the blood oxygen saturation and urine volume, and decrease the lactate level and complication rate (47% versus 82.3% in NE group). Meanwhile, TP + NE did not induce blood bilirubin increase and platelet count decrease and hyponatremia that vasopressin has. The results show that low dose of TP continuous infusion can help NE achieve the good resuscitation effect by improving tissue blood flow, stabilizing hemodynamics, and protecting organ function in septic shock patients while did not induce the side effects that high dose or bonus of TP or vasopressin induced. Low dose of TP may be recommended as the first-line vasopressor for refractory hypotension after severe sepsis or septic shock. PMID- 26253456 TI - The sheep as a model for healing studies after partial nephrectomy. AB - BACKGROUND: The pig has been considered the best model for renal surgery. However, recent research has demonstrated that the kidney of pigs heals differently from that of humans. The objective of this study was to evaluate sheep as an alternative animal model for studying collecting system healing after laparoscopic partial nephrectomy. MATERIALS AND METHODS: The caudal pole of the left kidney was removed from eight female adult domestic sheep using laparoscopic partial nephrectomy. Monopolar energy was used for hemostasis only in the parenchyma, avoiding coagulation near the collecting system, which was left opened. After 14 d, all animals were euthanized, and their left kidney was removed. Serum levels of urea and creatinine were assessed preoperatively and postoperatively (on days 2, 6, 10, and 14), and peritoneal fluid samples were collected during necropsy for urea and creatinine evaluation. An ex vivo retrograde pyelogram was performed, and a retrograde injection of methylene blue ink was administered to evaluate urinary leakage. Samples from the operated pole were analyzed using histologic methods. RESULTS: During necropsy, an urinoma surrounding the operated kidney was observed in one animal. Peritoneal fluid levels of urea and creatinine were elevated. Retrograde pyelograms exhibited contrast-medium extravasation through the operated pole in all kidneys. The opened collecting system was also confirmed by methylene blue ink injection. The operated pole was covered by collagenous tissue and adhered to adjacent organs. CONCLUSIONS: Sheep should be considered as an adequate experimental model for research on collecting system healing after partial nephrectomy. PMID- 26253457 TI - Pathologic sequelae of allosensitization in liver transplantation. AB - The long-term impact of allosensitization between ABO compatible donor/recipient pairs in liver transplantation is unclear. Accumulating clinical evidence suggests that donor-specific antibody formation may lead to antibody-mediated rejection and is causally linked to pathologic injury, graft loss, and death. Although this immune-mediated graft dysfunction is increasingly being associated with poor outcomes, the specific pathologic sequelae are not defined. Herein, we examine the relationship between allosensitization, antibody-mediated rejection, and subsequent graft pathology. PMID- 26253458 TI - Corneal collagen cross-linking followed by phacoemulsification with IOL implantation for progressive keratoconus associated with high myopia and cataract. AB - PURPOSE: To evaluate the visual and topographic outcomes of a two-stage approach treatment for progressive keratoconus (KC) associated with high myopia and cataract. METHODS: Two patients, a 50-year-old man and a 54-year-old woman with high myopia (spherical equivalent greater than -10D), cataract, and progressive KC with poor spectacle-corrected vision and contact lens intolerance underwent a 2-stage approach treatment: first corneal collagen cross-linking (CXL) followed after at least 6 months by phacoemulsification with intraocular lens (IOL) implantation in both eyes. RESULTS: In both patients after a mean follow-up of 3.5 years (from 2 to 4) uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), and corneal topography pattern improved in both eyes, and the patients were satisfied with the visual improvement and happy with tolerable glasses. CONCLUSION: This 2-stage approach reported no complications and was effective in improving visual acuity and corneal patterns in patients with high myopia, cataract, and progressive KC. PMID- 26253459 TI - The 90-degree rule in posterior ptosis surgery. AB - To propose a guideline for ptosis clamp positioning to minimize the risk of globe injury during posterior ptosis surgery. Measurements of 20 consecutive patients, 40 eyelids, undergoing bilateral posterior ptosis repair surgery were taken; as a surrogate for needle tip position, measurement of the distance from the clamp base to the ocular surface was taken using a caliper with the clamp held at 90 degrees to the ocular surface and again at 45-degrees to the ocular surface. These measurements were compared to geometric predictions of the distance from the clamp base to the ocular surface. The average distance from the clamp base to the ocular surface when the clamp is held 90-degrees to the ocular surface was 7 mm, this distance decreases to 5 mm when the clamp is held 45 degrees to the ocular surface. This coincides well with geometric predictions. Posterior ptosis surgery overall has an excellent safety profile; however, complications are possible, perhaps the most severe of which is inadvertent globe and/or corneal injury. The more acute the angle the ptosis clamp is held, the closer the clamp base, and subsequently the needle tip, is to the ocular surface as would be predicted geometrically. This coincides with closer proximity of the needle to the ocular surface during surgery. The theoretical risk of globe injury should decrease as the distance of the needle from the globe increases, and this distance is greatest when the clamp is held at a 90-degree angle to the ocular surface. This distinction becomes particularly important to consider in large eye morphology patients where the distance from the needle to the globe can approach 2 mm when the clamp is held at 45-degrees. PMID- 26253460 TI - Epipolis-laser in situ keratomileusis versus photorefractive keratectomy for the correction of myopia: a meta-analysis. AB - It is unclear whether epipolis-laser in situ keratomileusis (Epi-LASIK) has any significant advantage over photorefractive keratectomy (PRK) for correcting myopia. We undertook this meta-analysis of randomized controlled trials and cohort studies to examine possible differences in efficacy, predictability, and side effects between Epi-LASIK and PRK for correcting myopia. A system literature review was conducted in the PubMed, Cochrane Library EMBASE. The statistical analysis was performed by RevMan 5.0 software. The results included efficacy outcomes (percentage of eyes with 20/20 uncorrected visual acuity post treatment), predictability (proportion of eyes within +/-0.5 D of the target refraction), epithelial healing time, and the incidence of significant haze and pain scores after surgery. There are seven articles with total 987 eyes suitable for the meta-analysis. There is no statistical significance in the predictability between Epi-LASIK and PRK, the risk ratio (RR) is 1.03, 95% confidence interval (CI) [0.92, 1.16], p = 0.18; with respect to efficacy, the odds ratio is 1.43, 95% CI = [0.85, 2.40], p = 0.56 between Epi-LASIK and PRK, there is no statistical significance either. The epithelial cell layer healing time and the pain scores and the incidence of significant haze showed no significance between these two techniques although more pains can be found in Epi-LASIK than PRK at the early-stage post-operation. According to the above analysis, Epi-LASIK has good efficacy and predictability as PRK. In addition, both techniques have low pain scores and low incidence of significant haze. PMID- 26253461 TI - Planning for the Next Global Pandemic. AB - In order to mitigate human and financial losses as a result of future global pandemics, we must plan now. As the Ebola virus pandemic declines, we must reflect on how we have mismanaged this recent international crisis and how we can better prepare for the next global pandemic. Of great concern is the increasing frequency of pandemics occurring over the last few decades. Clearly, the window of opportunity to act is closing. This editorial discusses many issues including priority emerging and re-emerging infectious diseases; the challenges of meeting international health regulations; the strengthening of global health systems; global pandemic funding; and the One Health approach to future pandemic planning. We recommend that the global health community unites to urgently address these issues in order to avoid the next humanitarian crisis. PMID- 26253463 TI - [Physical activity: Is intensity important?]. PMID- 26253462 TI - Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy. AB - Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti lymphoma therapy. PMID- 26253465 TI - Bias in randomised controlled trials: comparison of crossover group and parallel group designs. PMID- 26253467 TI - The Incidence and the Risk Factors of Silent Embolic Cerebral Infarction After Coronary Angiography and Percutaneous Coronary Interventions. AB - Silent embolic cerebral infarction (SECI) is a major complication of coronary angiography (CAG) and percutaneous coronary intervention (PCI). Patients with stable coronary artery disease (CAD) who underwent CAG with or without PCI were recruited. Cerebral diffusion-weighted magnetic resonance imaging was performed for SECI within 24 hours. Clinical and angiographic characteristics were compared between patients with and without SECI. Silent embolic cerebral infarction occurred in 12 (12%) of the 101 patients. Age, total cholesterol, SYNTAX score (SS), and coronary artery bypass history were greater in the SECI(+) group (65 +/ 10 vs 58 +/- 11 years,P= .037; 223 +/- 85 vs 173 +/- 80 mg/dL,P= .048; 30.1 +/- 2 vs 15 +/- 3,P< .001; 4 [33.3%] vs 3 [3.3%],P= .005). The SECI was more common in the PCI group (8/24 vs 4/77,P= .01). On subanalysis, the SS was significantly higher in the SECI(+) patients in both the CAG and the PCI groups (29.3 +/- 1.9 vs 15 +/- 3,P< .01; 30.5 +/- 1.9 vs 15.1 +/- 3.2,P< .001, respectively). The risk of SECI after CAG and PCI increases with the complexity of CAD (represented by the SS). The SS is a predictor of the risk of SECI, a complication that should be considered more often after CAG. PMID- 26253466 TI - Paradigm shifts in genomics through the FANTOM projects. AB - Big leaps in science happen when scientists from different backgrounds interact. In the past 15 years, the FANTOM Consortium has brought together scientists from different fields to analyze and interpret genomic data produced with novel technologies, including mouse full-length cDNAs and, more recently, expression profiling at single-nucleotide resolution by cap-analysis gene expression. The FANTOM Consortium has provided the most comprehensive mouse cDNA collection for functional studies and extensive maps of the human and mouse transcriptome comprising promoters, enhancers, as well as the network of their regulatory interactions. More importantly, serendipitous observations of the FANTOM dataset led us to realize that the mammalian genome is pervasively transcribed, even from retrotransposon elements, which were previously considered junk DNA. The majority of products from the mammalian genome are long non-coding RNAs (lncRNAs), including sense-antisense, intergenic, and enhancer RNAs. While the biological function has been elucidated for some lncRNAs, more than 98 % of them remain without a known function. We argue that large-scale studies are urgently needed to address the functional role of lncRNAs. PMID- 26253468 TI - Synergistic antitumor efficacy of combined DNA vaccines targeting tumor cells and angiogenesis. AB - To further enhance the antitumor efficacy of DNA vaccine, we proposed a synergistic strategy that targeted tumor cells and angiogenesis simultaneously. In this study, a Semliki Forest Virus (SFV) replicon DNA vaccine expressing 1-4 domains of murine VEGFR2 and IL12 was constructed, and was named pSVK-VEGFR2-GFc IL12 (CAVE). The expression of VEGFR2 antigen and IL12 adjuvant molecule in 293T cells in vitro were verified by western blot and enzyme-linked immune sorbent assay (ELISA). Then CAVE was co-immunized with CAVA, a SFV replicon DNA vaccine targeting survivin and beta-hCG antigens constructed previously. The antitumor efficacy of our combined replicon vaccines was evaluated in mice model and the possible mechanism was further investigated. The combined vaccines could elicit efficient humoral and cellular immune responses against survivin, beta-hCG and VEGFR2 simultaneously. Compared with CAVE or CAVA vaccine alone, the combined vaccines inhibited the tumor growth and improved the survival rate in B16 melanoma mice model more effectively. Furthermore, the intratumoral microvessel density was lowest in combined vaccines group than CAVE or CAVA alone group. Therefore, this synergistic strategy of DNA vaccines for tumor treatment results in an increased antitumor efficacy, and may be more suitable for translation to future research and clinic. PMID- 26253469 TI - ROS-mediated bidirectional regulation of miRNA results in distinct pathologic heart conditions. AB - Under distinct pathological heart conditions, the expression of a single miRNA can display completely opposite patterns. However, the mechanism underlying the bidirectional regulation of a single miRNA and the clinical implications of this regulation remain largely unknown. To address this issue, we examined the regulation of miR-1, one of the most abundant miRNAs in the heart, during cardiac hypertrophy and ischemia/reperfusion (I/R). Our data indicated that different magnitudes and chronicities of ROS levels in cardiomyocytes resulted in differential expression of miR-1, subsequently altering the expression of myocardin. In animal models, the administration of a miR-1 mimic attenuated cardiac hypertrophy by suppressing the transverse aortic constriction-induced increase in myocardin expression, whereas the administration of anti-miR-1 ameliorated I/R-induced cardiac apoptosis and deterioration of heart function. Our findings indicated that a pathologic stimulus such as ROS can bidirectionally alter the expression of miRNA to contribute to the development of pathological conditions exhibiting distinct phenotypes and that the meticulous adjustment of the pathological miRNA levels is required to improve clinical outcomes. PMID- 26253470 TI - Genistein inhibits activities of methylenetetrahydrofolate reductase and lactate dehydrogenase, enzymes which use NADH as a substrate. AB - Genistein (5, 7-dihydroxy-3- (4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a natural isoflavone revealing many biological activities. Thus, it is considered as a therapeutic compound in as various disorders as cancer, infections and genetic diseases. Here, we demonstrate for the first time that genistein inhibits activities of bacterial methylenetetrahydrofolate reductase (MetF) and lactate dehydrogenase (LDH). Both enzymes use NADH as a substrate, and results of biochemical as well as molecular modeling studies with MetF suggest that genistein may interfere with binding of this dinucleotide to the enzyme. These results have implications for our understanding of biological functions of genistein and its effects on cellular metabolism. PMID- 26253471 TI - Detection of nitric oxide production in cell cultures by luciferin-luciferase chemiluminescence. AB - A chemiluminescent method is proposed for quantitation of NO generation in cell cultures. The method is based on activation of soluble guanylyl cyclase by NO. The product of the guanylyl cyclase reaction, pyrophosphate, is converted to ATP by ATP sulfurylase and ATP is detected in a luciferin-luciferase system. The method has been applied to the measurement of NO generated by activated murine macrophages (RAW 264.7) and bovine aortic endothelial cells. For macrophages activated by lipopolysaccharide and gamma-interferon, the rate of NO production is about 100 amol/(cell.min). The rate was confirmed by the measurements of nitrite, the product of NO oxidation. For endothelial cells, the basal rate of NO generation is 5 amol/(cell.min); the rate approximately doubles upon activation by bradykinin, Ca(2+) ionophore A23187 or mechanical stress. For both types of cells the measured rate of NO generation is strongly affected by inhibitors of NO synthase. The sensitivity of the method is about 50 pM/min, allowing the registration of NO generated by 10(2)-10(4) cells. The enzyme-linked chemiluminescent method is two orders of magnitude more sensitive than fluorescent detection using 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF FM). PMID- 26253472 TI - Prevention of cardiac hypertrophy by the use of a glycosphingolipid synthesis inhibitor in ApoE-/- mice. AB - ApoE-/- mice fed a high fat and high cholesterol (HFHC) diet (20% fat and 1.25% cholesterol) from 12 weeks of age to 36 weeks revealed an age-dependent increase in the left ventricular mass (LV mass) and decline in fractional shortening (FS%), which worsened with HFHC diet. These traits are indicative of maladaptive pathological cardiac hypertrophy and dysfunction. This was accompanied by loading of glycosphingolipids and increased gene expression of ANP, BNP in myocardial tissue. Masson's trichrome staining revealed a significant increase in cardiomyocyte size and fibrosis. In contrast, treatment with 5 and 10 MUM D-threo 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of glucosylceramide synthase and lactosylceramide synthase, dose-dependently decreased the load of glycosphingolipids and preserved fractional shortening and maintained left ventricular mass to normal 12-week-old control levels over a 6 month treatment period. Our mechanistic studies showed that D-PDMP inhibited cardiac hypertrophy by inhibiting the phosphorylation of mitogen-activated protein kinase (MAPK). We propose that associating increased glycosphingolipid synthesis with cardiac hypertrophy could serve as a novel approach to prevent this phenotype in experimental animal models of diet -induced atherosclerotic heart disease. PMID- 26253473 TI - Progress in the application of molecular biomarkers in gliomas. AB - Gliomas are a common adult central nervous system tumor, and glioblastoma (GBM), which has a poor prognosis, is the most lethal of all gliomas. The overall survival of GBM patients is only 12-14 months after diagnosis. With progress in the precision of personal medication, therapeutic options for various tumors have become gradually dependent on the molecular profiles of patients. GBM is one of the tumors in which treatment response relies largely on the molecular characteristics of the tumor. Therefore, awareness of the genetic background of each patient will help decision-making regarding the best treatment strategy to use. In this review, a novel molecular classification of gliomas based on recent findings of their genetic characteristics is introduced. Representative molecular markers, such as IDH1 mutation, 1p19q co-deletion, MGMT promoter methylation and EGFRvIII amplification, are described. Furthermore, the development of non-coding RNAs and omics studies of GBM are briefly discussed. Finally, a novel concept for non-invasive detection that could facilitate both diagnosis and treatment monitoring is presented. There is no doubt that the use of molecular profiling by biomarkers will indeed improve the overall survival and quality of life of GBM patients. PMID- 26253474 TI - Use of a Locked Fibular Plate for Fixation of a Vertical Shear Medial Malleolus Fracture: A Case Report. AB - Vertical shear fractures of the medial malleolus are less common than transverse fractures. These fractures are often treated with lag screws, posteromedial buttress plating, antiglide plates, and neutralization plates with screws. We report on a 37-year-old male who had fractured his ankle after tripping and falling into a ditch. Initially, the patient was treated with closed reduction and a splint for a trimalleolar fracture with a laterally subluxed talus. However, on review of his preoperative radiographs and computed tomography studies, we confirmed a medial malleolus fracture with a vertical shear pattern and communition. Recently, a contoured fibular locking plate has been developed. We considered this plate to be effective for containing the bone in part because of its broader plate design. We present a case in which a fibular locking plate was used successfully as a neutralization plate as an alternative fixation method for a vertical shear medial malleolar fracture. PMID- 26253475 TI - Outcome of a Specific Compartment Fasciotomy Versus a Complete Compartment Fasciotomy of the Leg in One Patient With Bilateral Anterior Chronic Exertional Compartment Syndrome: A Case Report. AB - Chronic exertional compartment syndrome of the leg is a debilitating lower extremity condition in which increased intracompartmental pressure impedes blood flow to the involved compartments of the distal lower extremity, resulting in ischemia and pain. Owing to the lack of success with conservative management, most surgeons perform complete release fasciotomy as the preferred method of fasciotomy to avoid an unsuccessful release or outcome. Studies have been performed regarding the outcomes of complete compartmental release versus specific compartmental release, but no study has been performed comparing complete fasciotomy and compartment-specific fasciotomy in a single patient. The purpose of the present case report was to compare the efficacy of a complete fasciotomy versus a specific fasciotomy in 1 patient with properly diagnosed bilateral anterior compartment chronic exertional compartment syndrome with an 18 month follow-up period. The Lower Extremity Functional Scale and both subscales of the Foot and Ankle Ability Measure were administered to assess the functional outcomes. Circumferential measurements and range of motion photographs were taken to compare the objective data throughout the recovery process. In general, the range of motion, circumferential measurements, and functional outcome measure scores were better for the specific compartmental fasciotomy leg than for the complete fasciotomy leg during the recovery period. The overall functional outcomes were the same for both surgical approaches, with the specific fasciotomy leg returning to baseline function 13 to 23 days before the complete fasciotomy leg. The outcomes remained unchanged 18 months after surgery. PMID- 26253476 TI - Anatomic Reconstruction Technique for a Plantar Calcaneonavicular (Spring) Ligament Tear. AB - Acquired flatfoot deformity in adults is usually due to partial or complete tearing of the posterior tibial tendon, with secondary failure of other structures such as the plantar calcaneonavicular (spring) ligament (SL), which maintain the medial longitudinal arch. In flexible cases, the tibialis posterior can be replaced with the flexor digitorum longus. It is common practice to suture the SL directly in the case of a tear; however, if the tear is complete, suturing directly to the ligament alone will not be possible. Reconstruction of the ligament is needed; however, no validated methods are available to reconstruct this ligament. The operative technique of SL reconstruction described in this report as a part of acquired flatfoot deformity reconstruction consists of augmenting remnants of the spring from the navicularis to the sustentaculum tali and suspending it to the medial malleolus using 2-mm-wide, long-chain polyethylene suture tape. This technique results in the firm anatomic reconstruction of the SL, in addition to "classic" medial arch reconstruction. We recommend SL reconstruction for medial arch reconstruction when the SL is torn. PMID- 26253477 TI - Comment on: "Diagnosis of Periprosthetic Joint Infection: The Role of Nuclear Medicine May Be Overestimated" by Claudio Diaz-Ledezma, Courtney Lamberton, Paul Lichtstein and Javad Parvizi. PMID- 26253478 TI - Comparison of Tibial Insert Polyethylene Damage in Rotating Hinge and Highly Constrained Total Knee Arthroplasty: A Retrieval Analysis. AB - This study compared the damage scores and damage patterns in 19 tibial inserts from rotating hinge (RH) implants with 19 inserts from highly constrained (HC) implants. Each insert was divided into 16 damage zones and each zone was subjectively graded from a scale of 0-3 for seven different damage modes. The overall damage scores were comparable for the two groups (RH: 64.1 +/- 15.4; HC: 66.1 +/- 29.0; P = 0.59). The HC group, however, had greater post damage (compared to the post-hole of RH) while the RH group had greater backside damage. The pattern of damage was also different, with burnishing and cold flow being more common in HC group while pitting, scratching and embedded debris were more common in the RH group. PMID- 26253479 TI - In Reply. PMID- 26253480 TI - Does Robotic-Assisted Computer Navigation Affect Acetabular Cup Positioning in Total Hip Arthroplasty in the Obese Patient? A Comparison Study. AB - Obese populations present challenges for acetabular cup placement during total hip arthroplasty (THA). This study examines the accuracy of acetabular cup inclination and version in the obese patient with robotic-assisted computer navigation. A total of 105 patients underwent robotic-assisted computer navigation THA with a posterior approach. Groups were divided on body mass index (BMI, kg/m(2)) of <30, 30-35, and >35. There was no statistical difference between the BMI <30 (n=59), BMI 30-35 (n=34) and BMI >35 (n=12) groups for acetabular inclination (P=0.43) or version (P=0.95). Robotic-assisted computer navigation provided accurate and reproducible placement of the acetabular cup within safe zones for inclination and version in the obese patient. PMID- 26253481 TI - Comparison of Head Center Position and Screw Fixation Options Between a Jumbo Cup and an Offset Center of Rotation Cup in Revision Total Hip Arthroplasty: A Computer Simulation Study. AB - Jumbo acetabular cups are commonly used in revision total hip arthroplasty (THA). A straightforward reaming technique is used which is similar to primary THA. However, jumbo cups may also be associated with hip center elevation, limited screw fixation options, and anterior soft tissue impingement. A partially truncated hemispherical shell was designed with an offset center of rotation, thick superior rim, and beveled anterior and superior rims as an alternative to a conventional jumbo cup. A three dimensional computer simulation was used to assess head center position and safe screw trajectories. Results of this in vitro study indicate that a modified hemispherical implant geometry can reduce head center elevation while permitting favorable screw fixation trajectories into the pelvis in comparison to a conventional jumbo cup. PMID- 26253482 TI - In Reply. PMID- 26253483 TI - In Reply. PMID- 26253484 TI - Prevalence of Pseudotumor in Patients After Metal-On-Metal Hip Arthroplasty Evaluated with Metal Ion Analysis and MARS-MRI. AB - The purpose of this study is to quantify the prevalence of pseudotumors in patients with well-functioning and painful metal-on-metal total hip arthroplasty, to characterize the pseudotumor with the use of MARS-MRI, and to assess the relationship between pseudotumors and metal ions. We retrospectively reviewed 102 single surgeon patients. The results showed that 68.6% developed pseudotumor with 60.9% of the asymptomatic group developing pseudotumor. The symptomatic group had a higher proportion of patients with elevated serum cobalt levels (P=0.035). There was no difference found with elevated metal ions and prevalence of pseudotumor, but elevated cobalt levels were associated with larger pseudotumor size (P=0.001). The available evidence indicated that most patients that develop pseudotumors are asymptomatic, and that elevated serum cobalt levels may be associated with symptoms and pseudotumor size. PMID- 26253485 TI - Re: "Some Points to Make About an Original Article". PMID- 26253486 TI - Immorality East and West: Are Immoral Behaviors Especially Harmful, or Especially Uncivilized? AB - What makes some acts immoral? Although Western theories of morality often define harmful behaviors as centrally immoral, whether this is applicable to other cultures is still under debate. In particular, Confucianism emphasizes civility as fundamental to moral excellence. We describe three studies examining how the word immoral is used by Chinese and Westerners. Layperson-generated examples were used to examine cultural differences in which behaviors are called "immoral" (Study 1, n = 609; Study 2, n = 480), and whether "immoral" behaviors were best characterized as particularly harmful versus uncivilized (Study 3, N = 443). Results suggest that Chinese were more likely to use the word immoral for behaviors that were uncivilized, rather than exceptionally harmful, whereas Westerners were more likely to link immorality tightly to harm. More research into lay concepts of morality is needed to inform theories of moral cognition and improve understanding of human conceptualizations of social norms. PMID- 26253488 TI - A randomized phase II/III study of adverse events between sequential (SEQ) versus simultaneous integrated boost (SIB) intensity modulated radiation therapy (IMRT) in nasopharyngeal carcinoma; preliminary result on acute adverse events. AB - BACKGROUND: To investigate acute and late toxicities comparing sequential (SEQ IMRT) versus simultaneous integrated boost intensity modulated radiotherapy (SIB IMRT) in nasopharyngeal carcinoma (NPC) patients. METHODS: Newly diagnosed stage I-IVB NPC patients were randomized to receive SEQ-IMRT or SIB-IMRT, with or without chemotherapy. SEQ-IMRT consisted of two sequential radiation treatment plans: 2 Gy x 25 fractions to low-risk planning target volume (PTV-LR) followed by 2 Gy x 10 fractions to high-risk planning target volume (PTV-HR). In contrast, SIB-IMRT consisted of only one treatment plan: 2.12 Gy and 1.7 Gy x 33 fractions to PTV-HR and PTV-LR, respectively. Toxicities were evaluated according to CTCAE version 4.0. RESULTS: Between October 2010 and November 2013, 122 eligible patients were randomized between SEQ-IMRT (54 patients) and SIB-IMRT (68 patients). With median follow-up time of 16.8 months, there was no significant difference in toxicities between the two IMRT techniques. During chemoradiation, the most common grade 3-5 acute toxicities were mucositis (15.4% vs 13.6%, SEQ vs SIB, p = 0.788) followed by dysphagia (9.6% vs 9.1%, p = 1.000) and xerostomia (9.6% vs 7.6%, p = 0.748). During the adjuvant chemotherapy period, 25.6% and 32.7% experienced grade 3 weight loss in SEQ-IMRT and SIB-IMRT (p = 0.459). One year overall survival (OS) and progression-free survival (PFS) were 95.8% and 95.5% in SEQ-IMRT and 98% and 90.2% in SIB-IMRT, respectively (p = 0.472 for OS and 0.069 for PFS). CONCLUSION: This randomized, phase II/III trial comparing SIB IMRT versus SEQ-IMRT in NPC showed no statistically significant difference between both IMRT techniques in terms of acute adverse events. Short-term tumor control and survival outcome were promising. PMID- 26253487 TI - In vitro engineering of human 3D chondrosarcoma: a preclinical model relevant for investigations of radiation quality impact. AB - BACKGROUND: The benefit of better ballistic and higher efficiency of carbon ions for cancer treatment (hadron-therapy) is asserted since decades, especially for unresectable or resistant tumors like sarcomas. However, hadron-therapy with carbon ions stays underused and raises some concerns about potential side effects for patients. Chondrosarcoma is a cartilaginous tumor, chemo- and radiation resistant, that lacks reference models for basic and pre-clinical studies in radiation-biology. Most studies about cellular effects of ionizing radiation, including hadrons, were performed under growth conditions dramatically different from human homeostasis. Tridimensional in vitro models are a fair alternative to animal models to approach tissue and tumors microenvironment. METHODS: By using a collagen matrix, standardized culture conditions, physiological oxygen tension and a well defined chondrosarcoma cell line, we developed a pertinent in vitro 3D model for hadron-biology studies. Low- and high-Linear Energy Transfer (LET) ionizing radiations from GANIL facilities of ~1 keV/MUm and 103 +/- 4 keV/MUm were used respectively, at 2 Gy single dose. The impact of radiation quality on chondrosarcoma cells cultivated in 3D was analyzed on cell death, cell proliferation and DNA repair. RESULTS: A fair distribution of chondrosarcoma cells was observed in the whole 3D scaffold. Moreover, LET distribution in depth, for ions, was calculated and found acceptable for radiation-biology studies using this kind of scaffold. No difference in cell toxicity was observed between low- and high-LET radiations but a higher rate of proliferation was displayed following high-LET irradiation. Furthermore, 3D models presented a higher and longer induction of H2AX phosphorylation after 2 Gy of high-LET compared to low LET radiations. CONCLUSIONS: The presented results show the feasibility and usefulness of our 3D chondrosarcoma model in the study of the impact of radiation quality on cell fate. The observed changes in our tissue-like model after ionizing radiation exposure may explain some discrepancies between radiation biology studies and clinical data. PMID- 26253490 TI - Advances in the pharmacological activities and mechanisms of diosgenin. AB - Diosgenin, a well-known steroid sapogenin derived from plants, has been used as a starting material for production of steroidal hormones. The present review will summarize published literature concerning pharmacological potential of diosgenin, and the underlying mechanisms of actions. Diosgenin has shown a vast range of pharmacological activities in preclinical studies. It exhibits anticancer, cardiovascular protective, anti-diabetes, neuroprotective, immunomodulatory, estrogenic, and skin protective effects, mainly by inducing apoptosis, suppressing malignant transformation, decreasing oxidative stress, preventing inflammatory events, promoting cellular differentiation/proliferation, and regulating T-cell immune response, etc. It interferes with cell death pathways and their regulators to induce apoptosis. Diosgenin antagonizes tumor metastasis by modulating epithelial-mesenchymal transition and actin cytoskeleton to change cellular motility, suppressing degradation of matrix barrier, and inhibiting angiogenesis. Additionally, diosgenin improves antioxidant status and inhibits lipid peroxidation. Its anti-inflammatory activity is through inhibiting production of pro-inflammatory cytokines, enzymes and adhesion molecules. Furthermore, diosgenin drives cellular growth/differentiation through the estrogen receptor (ER) cascade and transcriptional factor PPARgamma. In summary, these mechanistic studies provide a basis for further development of this compound for pharmacotherapy of various diseases. PMID- 26253489 TI - Recent advances in isolation, synthesis, and evaluation of bioactivities of bispyrroloquinone alkaloids of marine origin. AB - The ocean continues to provide a plethora of unique scaffolds capable of remarkable biological applications. A large number of pyrroloiminoquinone alkaloids, including discorhabdins, epinardins, batzellines, makaluvamines, and veiutamine, have been isolated from various marine organisms. A class of pyrroloiminoquinone-related alkaloids, known as bispyrroloquinones, is the focus of this review article. This family of marine alkaloids, which contain an aryl substituted bispyrroloquinone ring system, includes three subclasses of alkaloids namely, wakayin, tsitsikammamines A-B, and zyzzyanones A-D. Both wakayin and the tsitsikammamines contain a tetracyclic fused bispyrroloiminoquinone ring system, while zyzzyanones contain a fused tricyclic bispyrroloquinone ring system. The unique chemical structures of these marine natural products and their diverse biological properties, including antifungal and antimicrobial activity, as well as the potent, albeit generally nonspecific and universal cytotoxicities, have attracted great interest of synthetic chemists over the past three decades. Tsitsikammamines, wakayin, and several of their analogs show inhibition of topoisomerases. One additional possible mechanism of anticancer activity of tsitsikammamines analogs that has been discovered recently is through the inhibition of indoleamine 2, 3-dioxygenase, an enzyme involved in tumoral immune resistance. This review discusses the isolation, synthesis, and evaluation of bioactivities of bispyrroloquinone alkaloids and their analogs. PMID- 26253491 TI - Effects of Ziziphus jujuba fruit extracts on cytochrome P450 (CYP1A2) activity in rats. AB - Drug-drug interactions have become a serious problem in the clinic, since plant based medicines are extensively used. The present study investigated the effects of Ziziphus jujuba fruit (ZJ) extract on the pharmacokinetics of phenacetin, a typical substrate of a cytochrome P450 enzyme CYP 1A2, in rats. The rats were pretreated with the water extract (1.0 g . kg(-1)) or the ethanolic extract (3.6 g . kg(-1)) of ZJ for 10 days, and the pharmacokinetics of phenacetin was investigated after intravenous administration. In an in vitro assay, acetaminophen formation in the hepatic microsomes of ZJ-treated rats was investigated to assess CYP1A2 activity. Our results demonstrated that the treatment with the water and ethanolic extracts of ZJ decreased the plasma concentration of phenacetin and increased the plasma concentration of acetaminophen, resulting in a 43.2% and 15.5% reduction in the AUC0-120 of phenacetin, respectively, and a 53.2% and 64.9% increase in the AUC0-120 of acetaminophen, respectively after intravenous administration. The water or ethanolic extract of ZJ significantly increased the clearance of phenacetin and acetaminophen formation in hepatic microsomes. In conclusion, ZJ extracts displayed effects on the pharmacokinetics of phenacetin and increased the CYP1A2 activity in rats. Therefore, precaution on drug-drug interactions should be taken when ZJ is co-administered with drugs metabolized by CYP1A2, which may result in decreased concentrations of these drugs. PMID- 26253492 TI - Caffeine is responsible for the bloodglucose-lowering effects of green tea and Puer tea extractsin BALB/c mice. AB - The present study was designed to determine the effects of Puer tea and green tea on blood glucose level. Male BALB/c mice were administered green tea extract (GTE) or Puer tea extract (PTE), either intragastrically or in their drinking water. The major components of these teas are epigallocatechin gallate (EGCG) and caffeine, respectively. Blood glucose measurement results showed that mice fed intragastrically or mice that drank GTE, PTE or caffeine showed significantly lower blood glucose levels compared to the control group. However, EGCG exhibited no influence on the blood glucose levels. When caffeine was eliminated from the GTE and PTE, the effect on the blood glucose levels was abolished, but the effect was recovered when caffeine was re-introduced into the extracts. Evaluation of hematological and biochemical indices at the time of the greatest caffeine induced decrease in blood glucose levels showed that the effect of caffeine was specific. Microarray analyses were performed in 3T3-L1 preadipocytes and mature adipocytes treated with 0.1 mg . mL(-1) caffeine to identify factors that might be involved in the mechanisms underlying these effects. The results showed that few genes were changed after caffeine treatment in adipocytes, and of them only phospholipid transfer protein (PLTP) may be ralated to blood glucose. In conclusion, this study indicates that caffeine may be the key constituent of tea that decreases blood glucose levels, and it may be used to treat type 2 diabetes. PMID- 26253493 TI - Screening of natural compounds with neuronal differentiation promoting effects in a cell-based model. AB - The purpose of this study was to establish a drug screening method for small molecules extracted from traditional Chinese medicines (TCM) that have neuronal differentiation promoting effects, using P19 embryonic carcinoma cell as a cell based model. First, the constructed plasmid (pTalpha1-Luc) was transfected into P19 cells to establish a screening model. Second, several TCMs were screened using the established model and all-trans-retinoic acid as a positive control. Finally, the underlying molecular mechanism was explored using immunofluorescence staining, qT-PCR, and Western blot analysis. Our results indicated that the drug screen model was established successfully and that both honokiol and hyperoside induced P19 differentiation into neurons, with the possible molecular mechanism being modulating the Wnt signaling pathway. In conclusion, the drug screening model developed in the present study provides a rapid, cell-based screening platform for identifying natural compounds with neuronal differentiation effects. PMID- 26253494 TI - Antioxidant activities of cold-nature Tibetan herbs are signifcantly greater than hot-nature ones and are associated with their levels of total phenolic components. AB - Tibetan medicinal plants have been used for more than 2 000 years. In order to find their differences in antioxidant activity, total phenolics and total flavonoids between "hot-nature" and "cold-nature" herbs, we investigated the antioxidant activities of 40 Tibetan herbs from Qinghai plateau, with 20 herbs in cold-nature and 20 herbs in hot-nature. Antioxidant capacities were evaluated by the following methods: scavenging ABTS*(+) (2, 2'azinobis-(3-ethylbenz-thiazoline 6-sulfonic acid), scavenging O2*(-), and Ferric-reducing antioxidant power (FRAP). The effects on inhibition of mitochondrion lipid peroxidation were determined by measuring the formation of TBARS (Thiobarbituric acid reactive substrates). Total phenolics and flavonoids were estimated by Folin-Ciocalteu and NaNO2-Al(NO3)3-NaOH colorimetric methods. Interestingly, the cold-nature herbs displayed higher antioxidant activities than the hot-nature ones, corresponding to nearly three-fold higher total phenolic contents in the cold-nature herbs. Moreover, the antioxidant activities correlated linearly with the levels of total phenolics for both cold-nature and hot-nature herbs, but only with the levels of total flavonoids for the hot-nature herbs. The results suggested that the phenolic compounds, but not the flavonoids, play the major role in antioxidant capacities of the cold-nature herbs. These findings could shed new lights on the study the theory of Tibetan medicine. PMID- 26253495 TI - Synthesis of 13-beta-elemene ester derivatives and evaluation of their antioxidant activity in human umbilical vein endothelial cells. AB - In the present study, a series of 13-beta-elemene ester derivatives were designed and prepared, and their antioxidant activity was investigated in the H2O2-treated human umbilical vein endothelial cells (HUVECs). Among the test compounds, the dimer compounds 5v and 5w exhibited the most potent antioxidant activity with significant ROS suppression being observed. Both compounds markedly inhibited the H2O2-induced changes in various biochemical substances, such as superoxide dismutase (SOD), malonyldialdehyde (MDA), nitric oxide (NO), and lactic dehydrogenase (LDH), which were superior to that of the positive control vitamin E. Further more, they did not produce any obvious cytotoxicity, but increased the viability of HUVECs injured by H2O2 in a dose-dependent manner. Additionally, compound 5w, designed as a prodrug-like compound, showed improved stability relative to compound 4 in vitro. PMID- 26253496 TI - Identification and characterization of three new flavonoids from Rhododendron dauricum. AB - The present study was designed to determine the major chemical constituents of the leaves of Rhododendron dauricum L. Compounds were isolated and purified by various chromatographic methods, and their structures were elucidated by physicochemical properties and spectral data. The present study identified two new C-methyl flavanones, 5, 7, 3', 5'-tetrahydroxy-6, 8-di-C-methyl flavanone (1) and 5, 4'-dihydroxy-8-C-methylflavanone-7-O-beta-D-glucopyranoside (2), and one new flavonoid glycoside, quercetin-3-O-beta-D-(6"-O-cinnamoyl)-galactoside (3), along with seven known compounds, including syzalterin (4), poriolin (5), farrerol-7-O-beta-D-glucopyranoside (6), myrciacetin (7), quercetin-3-O-beta-D-(6 p-hydroxy-benzoyl)-galactoside (8), quercetin-3-O-beta-D-(6-p-coumaroyl) galactoside (9), and 5, 7, 3', 5'-tetrahydroxyl flavanone (10). Compounds 1-3 were determined to be new flavonoids; compounds 4-6 were isolated from this species for the first time; and compounds 7-10 were reported for the first time from this genus. PMID- 26253497 TI - Pharmacokinetics of acteoside following single dose intragastric and intravenous administrations in dogs. AB - Acteoside (verbascoside), a phenylethanoid glycoside widely distributed in various plants, has been shown to have potential activity against Alzheimer's disease, attracting great attentions recently. The present study was designed to develop a selective and sensitive LC-MS/MS method for the determination of acteoside in biological samples and carry our a pharmacokinetic (PK) study in beagle dogs. The PK parameters were calculated using non-compartmental models. Following a single-dose oral administration, acteoside was rapidly absorbed and eliminated, with Tmax being between 30 to 45 min and terminal half-life being about 90 min. The areas under the time-concentration curve (AUC) were 47.28 +/- 8.74, 87.86 +/- 13.33, and 183.14 +/- 28.69 mg . min . L(-1) for oral administration of 10, 20, and 40 mg . kg(-1), respectively, demonstrating that the exposure of acteoside proportionally increased with the dose level. The absolute bioavailability of acteoside was around 4%. For all the PK parameters, there were large variations between individual dogs. In conclusion, the pharmacokinetic characteristics observed in the present study can be of great value to help better understand the pharmacological properties of acteoside and to improve the outcome of its clinical use. PMID- 26253498 TI - Evaluation of municipal solid waste management performance by material flow analysis: Theoretical approach and case study. AB - The main role of a waste management plan is to define which is the combination of waste management strategies and method needed to collect and manage the waste in such a way to ensure a given set of targets is reached. Objectives have to be sustainable and realistic, consistent with the environmental policies and regulations and monitored to verify the progressive achievement of the given targets. To get the aim, the setting up and quantification of indicators can allow the measurement of efficiency of a waste management system. The quantification of efficiency indicators requires the developing of a material flow analysis over the system boundary, from waste collection to secondary materials selling, processing and disposal. The material flow analysis has been carried out with reference to a case study for which a reliable, time- and site specific database was available. The material flow analysis allowed the evaluation of the amount of materials sent to recycling, to landfilling and to waste-to-energy, by highlighting that the sorting of residual waste can further increase the secondary materials amount. The utilisation of energy recovery to treat the low-grade waste allows the maximisation of waste diversion from landfill with a low production of hazardous ash. A preliminary economic balance has been carried out to define the gate fee of the waste management system that was in the range of 84-145 ? t(-1) without including the separate collection cost. The cost of door-by-door separate collection, designed to ensure the collection of five separate streams, resulted in 250 ? t(-1) +/-30%. PMID- 26253499 TI - Congenital heart disease in adults: Quantitative and qualitative evaluation of IR FLASH and IR SSFP MRA techniques using a blood pool contrast agent in the steady state and comparison to first pass MRA. AB - OBJECTIVES: To evaluate magnetic resonance angiography sequences during the contrast steady-state (SS-MRA) using inversion recovery (IR) with fast low-angle shot (IR-FLASH) or steady-state free precession (IR-SSFP) read-outs, following the injection of a blood-pool contrast agent, and compare them to first-pass MR angiography (FP-MRA) in adults with congenital heart disease (CHD). MATERIALS AND METHODS: Twenty-three adult patients with CHD who underwent both SS-MRA and FP MRA using a 1.5-T scanner were retrospectively identified. Signal-to-noise and contrast-to-noise ratios were obtained at eight locations within the aorta and pulmonary vessels.. Image quality and the presence of artifacts were subjectively assessed by two radiologists. The presence of pathology was noted and given a confidence score. RESULTS: There was no difference in vessel dimensions among the sequences. IR-SSFP showed better image quality and fewer artifacts than IR-FLASH and FP-MRA. Confidence scores were significantly higher for SS-MRA compared to FP MRA. Seven cases (30.4%) had findings detected at SS-MRA that were not detected at FP-MRA, and 2 cases (8.7%) had findings detected by IR-SSFP only. CONCLUSION: SS-MRA of the thoracic vasculature using a blood pool contrast agent offers superior image quality and reveals more abnormalities compared to standard FP-MRA in adults with CHD, and it is best achieved with an IR-SSFP sequence. These sequences could lead to increased detection rates of abnormalities and provide a simpler protocol image acquisition. PMID- 26253500 TI - Effects of early-developmental stress on growth rates, body composition and developmental plasticity of the HPG-axis. AB - In altricial songbirds, food restriction in early development has adverse effects on various physiological systems. When conditions improve birds can accelerate growth, but this compensatory strategy is associated with long-term adverse consequences. One system affected by altered growth rates is the hypothalamic pituitary-gonadal (HPG) axis. Here, we subjected European starlings, Sturnus vulgaris, to an unpredictable food manipulation from 35 to 115days of age. We assessed the effects of the treatment by measuring overall body mass and body composition during and following the treatment period (i.e., accelerated growth). In adulthood, we measured the long-term effects of the treatment on overall body mass, testis volume, and HPG axis function in both sexes by quantifying androgen levels before and after a gonadotropin-releasing hormone (GnRH) challenge. During the treatment period, treatment birds had less body fat than controls. Following the treatment period, treatment birds weighed more than controls, but these gains were attributed to changes in lean mass. In adulthood, treatment males had lower baseline androgen levels, but there was no difference in peak androgen levels compared to controls. Treatment females did not differ from controls on any of the androgen measures. However, females that accelerated growth faster following the termination of the treatment had lower integrated androgen levels. When faced with limited developmental resources, birds may alter the developmental trajectory of physiological systems as a compensatory strategy. Such a strategy may have long-term consequences on endocrine regulation that could affect courtship and reproductive behaviors. PMID- 26253501 TI - The Greening Role of Tour Operators. AB - This paper shows that the tour operators (TOs) can play a coordinating role in the adoption of environmental management upstream the tourism supply chain. This is done using a dynamic model to analyze the environmental management adoption by hotels in a tourism destination induced by a TO. The TO can create incentives to greening hotels' management through the sharing of an environmental price premium. We show that the extent of green management adoption depends on interest rate, the willingness to pay for environmental quality, and hotels' organizational inertia. We also show how the financial yields from green management are shared between TOs and hotels. Finally, we consider a destination manager that subsidizes hotels' green management. If the destination manager does not take the greening role of TOs into account, she could mistake the true trade off that she faces between the destination's economic and environmental outcomes for the win-win setting that characterizes the general problem. PMID- 26253502 TI - Cardiovascular responses to dry resting apnoeas in elite divers while breathing pure oxygen. AB - PURPOSE: We hypothesized that the third dynamic phase (phi3) of the cardiovascular response to apnoea requires attainment of the physiological breaking point, so that the duration of the second steady phase (phi2) of the classical cardiovascular response to apnoea, though appearing in both air and oxygen, is longer in oxygen. METHODS: Nineteen divers performed maximal apnoeas in air and oxygen. We measured beat-by-beat arterial pressure, heart rate (fH), stroke volume (SV), cardiac output (Q). RESULTS: The fH, SV and Q changes during apnoea followed the same patterns in oxygen as in air. Duration of steady phi2 was 105 +/- 37 and 185 +/- 36 s, in air and oxygen (p<0.05), respectively. At end of apnoea, arterial oxygen saturation was 1.00 +/- 0.00 in oxygen and 0.75 +/- 0.10 in air. CONCLUSIONS: The results support the tested hypothesis. Lack of hypoxaemia during oxygen apnoeas suggests that, if chemoreflexes determine phi3, the increase in CO2 stores might play a central role in eliciting their activation. PMID- 26253503 TI - Insights into the influence of the cooling profile on the reconstitution times of amorphous lyophilized protein formulations. AB - Lyophilized protein formulations must be reconstituted back into solution prior to patient administration and in this regard long reconstitution times are not ideal. The factors that govern reconstitution time remain poorly understood. The aim of this research was to understand the influence of the lyophilization cooling profile (including annealing) on the resulting cake structure and reconstitution time. Three protein formulations (BSA 50mg/ml, BSA 200mg/ml and IgG1 40mg/ml, all in 7% w/v sucrose) were investigated after cooling at either 0.5 degrees C/min, or quench cooling with liquid nitrogen with/without annealing. Significantly longer reconstitution times were observed for the lower protein concentration formulations following quench cool. Porosity measurements found concomitant increases in the surface area of the porous cake structure but a reduction in total pore volume. We propose that slow reconstitution results from either closed pores or small pores impeding the penetration of water into the lyophilized cake. PMID- 26253504 TI - Diels-Alder hydrogels with enhanced stability: First step toward controlled release of bevacizumab. AB - Eight-armed PEG was functionalized with furyl and maleimide groups (8armPEG20k Fur and 8armPEG20k-Mal); degradable hydrogels were obtained by cross-linking via Diels-Alder chemistry. To increase the stability to degradation, the macromonomers were modified by introducing a hydrophobic 6-aminohexanoic acid spacer between PEG and the reactive end-groups (8armPEG20k-Ahx-Fur and 8armPEG20k Ahx-Mal). In an alternative approach, the number of reactive groups per macromonomer was increased by branching the terminal ends of eight-armed PEG with lysine (Lys) and Ahx residues (8armPEG20k-Lys-Ahx-Fur2 and 8armPEG20k-Lys-Ahx Mal2). The hydrolytic resistance of the synthesized macromonomers was determined by UV spectroscopy; the obtained hydrogels were characterized by rheology and degradation studies. The degradation time of 5% (w/v) 8armPEG20k-Ahx hydrogels (28days) was twice as long as the degradation time of 5% (w/v) 8armPEG20k hydrogels (14days); this is explained by increased hydrolytic resistance of the maleimide group. Using dendritic 8armPEG20k-Lys-Ahx macromonomers substantially increased the stability of the resulting hydrogels; degradation of 5% (w/v) 8armPEG20k-Lys-Ahx hydrogels occurred after 34 weeks. 8armPEG20k hydrogels had the largest mesh size of all tested hydrogels, while hydrogels made from dendritic 8armPEG20k-Lys-Ahx macromonomers showed the smallest value. To evaluate their potential for the controlled release of therapeutic antibodies, the hydrogels were loaded with bevacizumab. The incorporated bevacizumab was released over 10 days (8armPEG20k) and 42days (8armPEG20k-Ahx), respectively; release from 8armPEG20k-Lys-Ahx hydrogels was not completed after 105 days. In summary, we believe that 8armPEG20k-Ahx or 8armPEG20k-Lys-Ahx hydrogels could serve as controlled release system for therapeutic antibodies such as bevacizumab. PMID- 26253505 TI - Ventricular Tachycardia and Early Fibrillation in Patients With Brugada Syndrome and Ischemic Cardiomyopathy Show Predictable Frequency-Phase Properties on the Precordial ECG Consistent With the Respective Arrhythmogenic Substrate. AB - BACKGROUND: Ventricular fibrillation (VF) has been proposed to be maintained by localized high-frequency sources. We tested whether spectral-phase analysis of the precordial ECG enabled identification of periodic activation patterns generated by such sources. METHODS AND RESULTS: Precordial ECGs were recorded from 15 ischemic cardiomyopathy and 15 Brugada syndrome (type 1 ECG) patients during induced VF and analyzed in the frequency-phase domain. Despite temporal variability, induced VF episodes lasting 19.6+/-7.9 s displayed distinctly high power at a common frequency (shared frequency, 5.7+/-1.1 Hz) in all leads about half of the time. In patients with Brugada syndrome, phase analysis of shared frequency showed a V1-V6 sequence as would be expected from patients displaying a type 1 ECG pattern (P<0.001). Hilbert-based phases confirmed that the most stable sequence over the whole VF duration was V1-V6. Analysis of shared frequency in ischemic cardiomyopathy patients with anteroseptal (n=4), apical (n=3), and inferolateral (n=4) myocardial infarction displayed a sequence starting at V1-V2, V3-V4, and V5-V6, respectively, consistent with an activation origin at the scar location (P=0.005). Sequences correlated with the Hilbert-based phase analysis (P<0.001). Posterior infarction (n=4) displayed no specific sequence. On paired comparison, phase sequences during monomorphic ventricular tachycardia correlated moderately with VF (P<0.001). Moreover, there was a dominant frequency gradient from precordial leads facing the scar region to the contralateral leads (5.8+/ 0.8 versus 5.4+/-1.1 Hz; P=0.004). CONCLUSIONS: Noninvasive analysis of ventricular tachycardia and early VF in patients with Brugada syndrome and ischemic cardiomyopathy shows a predictable sequence in the frequency-phase domain, consistent with anatomic location of the arrhythmogenic substrate. PMID- 26253507 TI - Microhabitat heterogeneity across leaves and flower organs promotes bacterial diversity. AB - Eukaryote-associated microbiomes interact with their hosts in multiple manners, thereby affecting the hosts' phenotype, physical condition and behaviour. In plants, bacteria have numerous functions, with variable net effects, both in natural and agricultural systems. However, information about the composition and diversity of the bacterial communities associated with different aboveground plant organs, particularly flowers, is lacking. In addition, the relative effects of microhabitat and environmental conditions on community establishment require further attention. Here, using culture-independent methods, we determine that leaves and three floral microhabitats (nectar, stamina and styles) of Metrosideros polymorpha (Myrtaceae), a tree endemic to Hawai'i, host unique indicator communities composed of relatively abundant bacterial taxa. These indicator communities are accompanied by a large number of ubiquitous or rare bacteria with lower abundances. In our study system, the strong effect of microhabitat filtering on plant-associated community composition and bacterial richness and diversity strongly exceeds the influence of environmental effects such as precipitation, altitude, substrate age and geographic distance. Thus, the bacterial richness of aboveground plant organs is strongly underestimated when only one microhabitat, e.g. leaves, is considered. Our study represents a first step towards a comprehensive characterization of the distribution, composition and underlying factors, of plant bacterial communities, with implications for future basic and applied research on plant health, pollination and reproduction. PMID- 26253506 TI - Identification and Functional Characterization of a Novel CACNA1C-Mediated Cardiac Disorder Characterized by Prolonged QT Intervals With Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death. AB - BACKGROUND: A portion of sudden cardiac deaths can be attributed to structural heart diseases, such as hypertrophic cardiomyopathy (HCM) or cardiac channelopathies such as long-QT syndrome (LQTS); however, the underlying molecular mechanisms are distinct. Here, we identify a novel CACNA1C missense mutation with mixed loss-of-function/gain-of-function responsible for a complex phenotype of LQTS, HCM, sudden cardiac death, and congenital heart defects. METHODS AND RESULTS: Whole exome sequencing in combination with Ingenuity variant analysis was completed on 3 affected individuals and 1 unaffected individual from a large pedigree with concomitant LQTS, HCM, and congenital heart defects and identified a novel CACNA1C mutation, p.Arg518Cys, as the most likely candidate mutation. Mutational analysis of exon 12 of CACNA1C was completed on 5 additional patients with a similar phenotype of LQTS plus a personal or family history of HCM-like phenotypes and identified 2 additional pedigrees with mutations at the same position, p.Arg518Cys/His. Whole cell patch clamp technique was used to assess the electrophysiological effects of the identified mutations in CaV1.2 and revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current. CONCLUSIONS: Through whole exome sequencing and expanded cohort screening, we identified a novel genetic substrate p.Arg518Cys/His-CACNA1C, in patients with a complex phenotype including LQTS, HCM, and congenital heart defects annotated as cardiac-only Timothy syndrome. Our electrophysiological studies, identification of mutations at the same amino acid position in multiple pedigrees, and cosegregation with disease in these pedigrees provide evidence that p.Arg518Cys/His is the pathogenic substrate for the observed phenotype. PMID- 26253508 TI - Seasonal effect and anthropogenic impact on the composition of the active bacterial community in Mediterranean orchard soil. AB - Several anthropogenic interventions, common in agriculture, may influence active bacterial communities in soil without affecting their total composition. Therefore, the composition of an active bacterial community in soil may reflect its relation to biogeochemical processes. This issue was addressed during two consecutive years in olive-orchard soil, irrigated with treated wastewater (TWW) in a Mediterranean climate, by following the active (rRNA) and total (rRNA gene) bacterial community in the soil. Although TWW irrigation did not affect the composition of the total soil bacterial community, it had an effect on the active fraction of the community. These results, based on 16S rRNA data, indicate that the organic matter and minerals in TWW were not directly utilized for the rapid proliferation of specific taxonomic groups. Activity levels, manifested by variance in the relative abundance of the active and total communities of selected operational taxonomic units, revealed annual and seasonal fluctuations and fluctuations dependent on the type of irrigation. The potential activity (nitrification rates) and community composition of ammonia-oxidizing bacteria were affected by TWW irrigation, and this group of bacteria was therefore further explored. It was concluded that irrigation with TWW had little effect on "who is there", i.e. which bacteria were present, but influenced "who is active", with a distinct effect on bacteria associated with the biochemical cycling of nitrogen. PMID- 26253509 TI - Long-term warming alters richness and composition of taxonomic and functional groups of arctic fungi. AB - Fungi, including symbionts, pathogens and decomposers, play crucial roles in community dynamics and nutrient cycling in terrestrial ecosystems. Despite their ecological importance, the response of most arctic fungi to climate warming is unknown, so are their potential roles in driving the observed and predicted changes in tundra communities. We carried out deep DNA sequencing of soil samples to study the long-term effects of experimental warming on fungal communities in dry heath and moist tussock tundra in Arctic Alaska. The data presented here indicate that fungal community composition responds strongly to warming in the moist tundra, but not in the dry tundra. While total fungal richness was not significantly affected by warming, there were clear correlations among operational taxonomic unit richness of various ecological and taxonomic groups and long-term warming. Richness of ectomycorrhizal, ericoid mycorrhizal and lichenized fungi generally decreased with warming, while richness of saprotrophic, plant and animal pathogenic, and root endophytic fungi tended to increase in the warmed plots. More importantly, various taxa within these functional guilds followed opposing trends that highlight the importance of species-specific responses to warming. We recommend that species-level ecological differences be taken into account in climate change and nutrient cycling studies that involve arctic fungi. PMID- 26253510 TI - Characterization of chitosan composites with synthetic polymers and inorganic additives. AB - In the present study, the results from thermogravimetric analysis (TGA), contact angle measurements, tensile tests, scanning electron microscopy (SEM) and atomic force microscopy (AFM) of polymer composites containing chitosan (Ch) and montmorillonite (MMT) with and without poly(vinyl alcohol) (PVA) are presented. Measurements of the contact angles for diiodomethane (D) and glycerol (G) on the surfaces of chitosan films, Ch/MMT and Ch/PVA/MMT, were made and surface free energies were calculated. It was found that the wettability of the chitosan/MMT or Ch/PVA/MMT composite films decreased relative to the wettability of chitosan. The microstructure of unmodified polymers and their composites, as observed by SEM and AFM, showed particles that are relatively well dispersed in the polymer matrix. The TGA thermograms and mass loss percentages at different decomposition temperatures showed that the thermal stability of the binary composite slightly decreases upon the addition of PVA. The film mechanical properties such as tensile strength, Young's modulus and tensile strain at break depend on the composition and varied non-uniformly. Both composites possessed a tensile strength and Young's modulus of 27.6-94.3MPa and 1.5-3.5GPa, respectively. The addition of PVA to the composite led to a reduction in tensile strength by approximately 40%. PMID- 26253511 TI - Combined spectroscopy and molecular modeling studies on the binding of galbanic acid and MMP9. AB - The molecular mechanism of galbanic acid (GBA) binding to matrix metalloproteinase 9 (MMP9) was investigated by fluorescence quenching, absorption spectroscopy, FT-IR, molecular docking and molecular dynamics (MD) simulation procedures. The fluorescence emission of MMP9 was quenched by GBA. The titration of MMP9 by various amount of GBA was also followed by UV-Vis absorption spectroscopy. The results revealed that GBA, as a biologically active sesquiterpene coumarin derivative, has an ability to bind strongly to MMP9. Molecular docking results indicated that the main active binding site for GBA has been located in a hydrophobic cavity in the vicinity of Zn atom. Moreover, MD simulation results suggested that GBA as a coumarin derivative can interact with MMP9, without affecting the secondary structure of MMP9. MD simulations, molecular docking as computational methods from one hand and experimental data from other hand reciprocally supported each other. PMID- 26253512 TI - Human and murine APOBEC3s restrict replication of koala retrovirus by different mechanisms. AB - BACKGROUND: Koala retrovirus (KoRV) is an endogenous and exogenous retrovirus of koalas that may cause lymphoma. As for many other gammaretroviruses, the KoRV genome can potentially encode an alternate form of Gag protein, glyco-gag. RESULTS: In this study, a convenient assay for assessing KoRV infectivity in vitro was employed: the use of DERSE cells (initially developed to search for infectious xenotropic murine leukemia-like viruses). Using infection of DERSE and other human cell lines (HEK293T), no evidence for expression of glyco-gag by KoRV was found, either in expression of glyco-gag protein or changes in infectivity when the putative glyco-gag reading frame was mutated. Since glyco-gag mediates resistance of Moloney murine leukemia virus to the restriction factor APOBEC3, the sensitivity of KoRV (wt or putatively mutant for glyco-gag) to restriction by murine (mA3) or human APOBEC3s was investigated. Both mA3 and hA3G potently inhibited KoRV infectivity. Interestingly, hA3G restriction was accompanied by extensive G -> A hypermutation during reverse transcription while mA3 restriction was not. Glyco-gag status did not affect the results. CONCLUSIONS: These results indicate that the mechanisms of APOBEC3 restriction of KoRV by hA3G and mA3 differ (deamination dependent vs. independent) and glyco-gag does not play a role in the restriction. PMID- 26253513 TI - Uptake and Outcomes Associated with Implementation of a Community-Based Voluntary HIV Counseling and Testing Program in Antigua and Barbuda. AB - OBJECTIVE: To evaluate the implementation of community-based voluntary HIV counseling and testing (CBVCT) in the Eastern Caribbean. METHODS: A total of 9782 unique HIV testing events performed through a national program of CBVCT in Antigua and Barbuda (2009-2012) were analyzed. The authors describe testers' demographic characteristics and assess demographic (education, housing, marital status, nationality, and age) and sexual exposure (partner gender, transactional sex, and multiple partners) factors associated with testing HIV-positivity and with condom use. RESULTS: Older men and men having sex with women and women with higher education, of Antiguan nationality, and having sex with men were less likely to test positive for HIV. Younger, educated, and unmarried men and women with multiple partners were more likely to report using condoms. CONCLUSION: The CBVCT model can be successfully implemented in Eastern Caribbean. Demographic differences persist in HIV testing, risk behavior, and infection among vulnerable populations and should be considered in HIV prevention intervention design. PMID- 26253514 TI - Stem cell therapy: a novel treatment option for cerebral malaria? AB - Cerebral malaria, a severe form of the disease, is one of the most severe complications of infection with Plasmodium parasites and a leading cause of malaria mortality. Currently available antimalarial therapy has proven insufficient to prevent neurological complications and death in all cases of cerebral malaria. Souza and colleagues observed that transplantation of bone marrow-derived mesenchymal stromal cells (BM-MSCs) increased survival, reduced parasitemia, decreased malaria pigment accumulation in the spleen, liver and kidney, elevated Kupffer cell count in liver, alleviated renal injury and lung inflammation, and improved lung mechanics in an experimental mouse model of cerebral malaria. Although plenty of challenges lie ahead, their findings show the promise of BM-MSC therapy for the treatment of cerebral malaria. PMID- 26253515 TI - A quantitative content analysis of UK newsprint coverage of proposed legislation to prohibit smoking in private vehicles carrying children. AB - BACKGROUND: Mass media representations of health issues influence public perceptions of those issues. Despite legislation prohibiting smoking in public spaces, second-hand smoke (SHS) remains a health risk in the United Kingdom (UK). Further legislation might further limit children's exposure to SHS by prohibiting smoking in private vehicles carrying children. This research was designed to determine how UK national newspapers represented the debate around proposed legislation to prohibit smoking in private vehicles carrying children. METHODS: Quantitative analysis of the manifest content of 422 articles about children and SHS published in UK and Scottish newspapers between 1st January 2003 and 16th February 2014. Researchers developed a coding frame incorporating emergent themes from the data. Each article was double-coded. RESULTS: The frequency of relevant articles rose and fell in line with policy debate events. Children were frequently characterised as victims of SHS, and SHS was associated with various health risks. Articles discussing legislation targeting SHS in private vehicles carrying children presented supportive arguments significantly more frequently than unsupportive arguments. CONCLUSIONS: The relatively positive representation of legislation prohibiting smoking in vehicles carrying children is favourable to policy advocates, and potentially indicative of likely public acceptance of legislation. Our findings support two lessons that public health advocates may consider: the utility of presenting children as a vulnerable target population, and the possibility of late surges in critical arguments preceding policy events. PMID- 26253517 TI - Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression. AB - The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription elongation. In hematologic cancers, BET proteins have been shown to regulate expression of MYC and other genes that are important to disease pathology. Pharmacologic inhibition of BET protein binding has been shown to inhibit tumor growth in MYC-dependent cancers, such as multiple myeloma. In this study, we demonstrate that small cell lung cancer (SCLC) cells are exquisitely sensitive to growth inhibition by the BET inhibitor JQ1. JQ1 treatment has no impact on MYC protein expression, but results in downregulation of the lineage-specific transcription factor ASCL1. SCLC cells that are sensitive to JQ1 are also sensitive to ASCL1 depletion by RNAi. Chromatin immunoprecipitation studies confirmed the binding of the BET protein BRD4 to the ASCL1 enhancer, and the ability of JQ1 to disrupt the interaction. The importance of ASCL1 as a potential driver oncogene in SCLC is further underscored by the observation that ASCL1 is overexpressed in >50% of SCLC specimens, an extent greater than that observed for other putative oncogenes (MYC, MYCN, and SOX2) previously implicated in SCLC. Our studies have provided a mechanistic basis for the sensitivity of SCLC to BET inhibition and a rationale for the clinical development of BET inhibitors in this disease with high unmet medical need. PMID- 26253516 TI - [Nursing workload indices TISS-10, TISS-28, and NEMS : Higher workload with agitation and delirium is not reflected]. AB - BACKGROUND: Financial resources for the treatment of ICU patients requiring high nursing workload are allocated within the German diagnostic-related groups (DRG) system in part through the Therapeutic Intervention Scoring System-10 (TISS-10). TISS-10, however, has never been validated. This study evaluated whether delirium and agitation in ICU were reflected by TISS-10, and also by the established workload indices TISS-28 and Nine Equivalents of Nursing Manpower (NEMS). Secondary aims were if indices correlated, and what effects delirium and agitation had on financial balances. MATERIALS AND METHODS: Analyses were performed retrospectively in 521 datasets from 152 patients. Nursing workload was assessed with TISS-28, TISS-10, and NEMS, delirium with the Confusion Assessment Method for Intensive Care Units (CAM-ICU), and vigilance with the Richmond Agitation-Sedation Scale (RASS). Revenues were retrieved from the institution's patient data management system, and costs calculated with the Budget Calculation Tool 2007 provided by the German Society of Anaesthesiologists. RESULTS: Delirium was found in 36.2 % of patients (n = 55). TISS-28, TISS-10, and NEMS were not higher in patients with delirium, if corrected for mechanical ventilation. TISS 28, TISS-10, and NEMS were significantly higher in deeply sedated and comatose patients (RASS <= - 3, p < 0.001), but not in agitated (RASS >= 1) and lightly sedated patients (RASS - 1/- 2). TISS-10 and TISS-28 had a linear correlation (r (2) = 0.864). Median financial balances were negative, but much more pronounced in patients with delirium that without (- 3174 ? with delirium vs. - 1721 ? without delirium, p = 0.0147). CONCLUSION: The standard workload-scores (TISS-10, TISS-28, NEMS) do not reflect higher daily workload associated with patients with delirium and agitation. PMID- 26253518 TI - Hospital cost of Clostridium difficile infection including the contribution of recurrences in French acute-care hospitals. AB - BACKGROUND: The impact of Clostridium difficile infection (CDI) on healthcare costs is significant due to the extra costs of associated inpatient care. However, the specific contribution of recurrences has rarely been studied. AIM: The aim of this study was to estimate the hospital costs of CDI and the fraction attributable to recurrences in French acute-care hospitals. METHODS: A retrospective study was performed for 2011 on a sample of 12 large acute-care hospitals. CDI costs were estimated from both hospital and public insurance perspectives. For each stay, CDI additional costs were estimated by comparison to controls without CDI extracted from the national DRG (diagnosis-related group) database and matched on DRG, age and sex. When CDI was the primary diagnosis, the full cost of stay was used. FINDINGS: A total of 1067 bacteriological cases of CDI were identified corresponding to 979 stays involving 906 different patients. Recurrence(s) were identified in 118 (12%) of these stays with 51.7% of them having occurred within the same stay as the index episode. Their mean length of stay was 63.8 days compared to 25.1 days for stays with an index case only. The mean extra cost per stay with CDI was estimated at ?9,575 (median: ?7,514). The extra cost of CDI in public acute-care hospitals was extrapolated to ?163.1 million at the national level, of which 12.5% was attributable to recurrences. CONCLUSION: The economic burden of CDI is substantial and directly impacts healthcare systems in France. PMID- 26253519 TI - Comparison of five commercially available immunochromatographic tests for the detection of norovirus in faecal specimens. AB - Five CE-marked immunochromatography assay kits for the rapid detection of norovirus were compared with the reference method of real-time polymerase chain reaction (PCR) for the detection of acute norovirus infection. The sensitivity of the assays ranged between 23% and 59% with specificity being 75-100% when compared with real-time PCR. The data suggest that a reactive immunochromatographic assay indicates norovirus infection. However, the sensitivity of the assay would need to be significantly improved to be suitable for routine diagnostic purposes or as an alternative to laboratory analysis for near-patient testing. PMID- 26253521 TI - The importance of older patients' experiences with care delivery for their quality of life after hospitalization. AB - BACKGROUND: Older patients' experiences with care delivery may be important for their quality of life over time. Evidence is however lacking. Therefore, this study aims to identify the longitudinal relationship between older patients' experiences with hospital care, perceived quality of integrated care and quality of life after hospitalization. METHODS: Our longitudinal research was based on a pilot study of older people who had recently been admitted to a hospital. In the pilot study, all patients (>= 65 years of age) who were admitted to the Vlietland hospital between June and October 2010 were asked to participate, which led to the inclusion of 500 older patients at baseline. A total of 291 patients (58% response rate) were interviewed 3 months after admission. Measures included quality of life, patients' perceptions of quality of integrated care delivery and patients' experiences with hospital care. We used descriptive statistics, correlations, and multilevel analyses. RESULTS: Being married (p <= 0.05), patients' experiences with hospital care, perceived quality of integrated care delivery (both p <= 0.01), and quality of life within 48 h of hospital admission (p <= 0.001) significantly correlated with quality of life 3 months after hospital admission. After controlling for background characteristics, multilevel analysis indicated a longitudinal relationship between patients' experiences with hospital care (p <= 0.05), perceived quality of integrated care delivery (p <= 0.01) and patients' quality of life 3 months after hospitalization. CONCLUSIONS: This study found a longitudinal relationship between patients' perceived quality of integrated care delivery, experiences with hospital care and quality of life of older patients after hospitalization. These results underscore the importance of enhancing older patients' experiences with care delivery. PMID- 26253520 TI - The effects of a protein enriched diet with lean red meat combined with a multi modal exercise program on muscle and cognitive health and function in older adults: study protocol for a randomised controlled trial. AB - BACKGROUND: Age-related muscle wasting has been strongly implicated with falls and fractures in the elderly, but it has also been associated with cognitive decline and dementia. Progressive resistance training (PRT) and adequate dietary protein are recognised as important contributors to the maintenance of muscle health and function in older adults. However, both factors also have the potential to improve brain function and prevent cognitive decline via several pathways, including the regulation of various growth and neurotrophic factors [insulin-like growth factor-1 (IGF-1)]; brain-derived growth factor (BDNF)] and/or the modulation of systemic inflammation. The primary aim of this study is to investigate whether a modest increase in dietary protein achieved through the consumption of lean red meat three days per week, when combined with PRT, can enhance muscle mass, size and strength and cognitive function in community dwelling older people. METHODS/DESIGN: The study design is a 48-week randomised controlled trial consisting of a 24-week intervention with a 24-week follow-up. Men and women (n=152) aged 65 years and over residing in the community will be randomly allocated to: 1) PRT and provided with 220 g (raw weight) of lean red meat to be cooked and divided into two 80 g servings on each of the three days that they complete their exercise session, or 2) control PRT in which participants will be provided with and advised to consume >=1 serving (~1/2 cup) of rice and/or pasta or 1 medium potato on each of the three training days. The primary outcome measures will be muscle mass, size and strength and cognitive function. Secondary outcomes will include changes in: muscle function, neural health (corticospinal excitability and inhibition and voluntary activation), serum IGF-1 and BDNF, adipokines and inflammatory markers, fat mass and inter /intra-muscular fat, blood pressure, lipids and health-related quality of life. All outcome measures will be assessed at baseline and 24 weeks, with the exception of cognitive function and the various neurobiological and inflammatory markers which will also be assessed at week 12. DISCUSSION: The findings from this study will provide important new information on whether a modest increase in dietary protein achieved through the ingestion of lean red meat can enhance the effects of PRT on muscle mass, size and strength as well as cognitive function in community-dwelling older adults. If successful, the findings will form the basis for more precise exercise and nutrition guidelines for the management and prevention of age-related changes in muscle and neural health and cognitive function in the elderly. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12613001153707 . Date registered 16(th) October, 2013. PMID- 26253523 TI - India's Supreme Court allows girl who was raped to have termination outside legal limits. PMID- 26253522 TI - Phenotypic characterization of an international Pseudomonas aeruginosa reference panel: strains of cystic fibrosis (CF) origin show less in vivo virulence than non-CF strains. AB - Pseudomonas aeruginosa causes chronic lung infections in people with cystic fibrosis (CF) and acute opportunistic infections in people without CF. Forty-two P. aeruginosa strains from a range of clinical and environmental sources were collated into a single reference strain panel to harmonise research on this diverse opportunistic pathogen. To facilitate further harmonized and comparable research on P. aeruginosa, we characterized the panel strains for growth rates, motility, virulence in the Galleria mellonella infection model, pyocyanin and alginate production, mucoid phenotype, LPS pattern, biofilm formation, urease activity, and antimicrobial and phage susceptibilities. Phenotypic diversity across the P. aeruginosa panel was apparent for all phenotypes examined, agreeing with the marked variability seen in this species. However, except for growth rate, the phenotypic diversity among strains from CF versus non-CF sources was comparable. CF strains were less virulent in the G. mellonella model than non-CF strains (P = 0.037). Transmissible CF strains generally lacked O-antigen, produced less pyocyanin and had low virulence in G. mellonella. Furthermore, in the three sets of sequential CF strains, virulence, O-antigen expression and pyocyanin production were higher in the earlier isolate compared to the isolate obtained later in infection. Overall, this full phenotypic characterization of the defined panel of P. aeruginosa strains increases our understanding of the virulence and pathogenesis of P. aeruginosa and may provide a valuable resource for the testing of novel therapies against this problematic pathogen. PMID- 26253524 TI - Balint groups - helping trainee psychiatrists make even better use of themselves. AB - OBJECTIVE: The paper presents a pilot study of Balint group work to establish it as a potential training tool in psychiatry. The aim was to test whether, in the training setting, it was possible for a cohesive group to form, such that trainees could make use of a Balint group experience. METHOD: Nine psychiatry trainees were offered three 90-minute Balint sessions and provided written feedback. RESULTS: The trainees reported unanimously that group participation was a positive and worthwhile experience. They began to feel supported by their colleagues and experienced the method as an effective way to manage stress and anxiety. They reported that they experienced doctor-patient interactions in a different way, which appeared to correspond with a greater understanding of the patient's experience. CONCLUSIONS: The pilot suggested that, within the public health training setting, a cohesive group could form such that trainees were able to make use of a Balint group experience. It suggested that this practice could be beneficial in managing the stresses, isolation and intense feelings of working with patients in this setting. The feedback indicated that the group helped trainees 'think differently' by fostering self-awareness and so furthered their development of psychodynamic skills. PMID- 26253526 TI - Retrospective Analysis of the Effectiveness of Platelet-Rich Plasma in the Treatment of Achilles Tendinopathy: Pretreatment and Posttreatment Correlation of Magnetic Resonance Imaging and Clinical Assessment. AB - Platelet-rich plasma (PRP) has been presented as a means of treating Achilles tendinopathy. Over the past dozen years, a plethora of medical articles have advocated this treatment, yet little evidentiary-based research exists in support of this approach. Treatment protocols with PRP have been performed in 2 ways during this time: administered adjunctively during tendon surgery and as a stand alone injection. The senior author has utilized PRP by both methods to treat Achilles tendinopathy over the past 7 years; 26 patients so treated were able to be recalled, half having undergone Achilles tendon surgery in combination with PRP administration and the other half PRP alone. In this retrospective study, qualified patients had pretreatment and posttreatment magnetic imaging studies and completed a Victorian Institute of Sports Assessment-Achilles questionnaire. In this limited study, PRP showed promise in the treatment of Achilles tendinopathy. Both the stand-alone injection group and surgical/injection groups had statistically significant degrees of improvement in pre-MRI and post-MRI imaging studies. There was no statistically significant difference between the 2 treatment groups. Of interest, it appears that the difference between the MRI scoring correlates with the survey score. LEVEL OF EVIDENCE: Therapeutic, Level, IV: Case series. PMID- 26253525 TI - Anger in brain and body: the neural and physiological perturbation of decision making by emotion. AB - Emotion and cognition are dynamically coupled to bodily arousal: the induction of anger, even unconsciously, can reprioritise neural and physiological resources toward action states that bias cognitive processes. Here we examine behavioural, neural and bodily effects of covert anger processing and its influence on cognition, indexed by lexical decision-making. While recording beat-to-beat blood pressure, the words ANGER or RELAX were presented subliminally just prior to rapid word/non-word reaction-time judgements of letter-strings. Subliminal ANGER primes delayed the time taken to reach rapid lexical decisions, relative to RELAX primes. However, individuals with high trait anger were speeded up by subliminal anger primes. ANGER primes increased systolic blood pressure and the magnitude of this increase predicted reaction time prolongation. Within the brain, ANGER trials evoked an enhancement of activity within dorsal pons and an attenuation of activity within visual occipitotemporal and attentional parietal cortices. Activity within periaqueductal grey matter, occipital and parietal regions increased linearly with evoked blood pressure changes, indicating neural substrates through which covert anger impairs semantic decisions, putatively through its expression as visceral arousal. The behavioural and physiological impact of anger states compromises the efficiency of cognitive processing through action-ready changes in autonomic response that skew regional neural activity. PMID- 26253527 TI - Retrocalcaneal Pain After Open Reduction and Internal Fixation of Avulsion Fracture of the Achilles Tendon Treated by Endoscopic Adhesiolysis and Endoscopic Calcaneoplasty: A Case Report. AB - Avulsion fracture of the Achilles tendon is uncommon. Open reduction and internal fixation is indicated for displaced fracture in order to restore the normal function of the Achilles tendon. We present a patient with avulsion fracture of Achilles tendon that was complicated by the development of secondary Haglund's deformity and fibrous adhesion between the Achilles tendon and the calcaneus. He was successful treated by endoscopic calcaneoplasty and endoscopic adhesiolysis. LEVELS OF EVIDENCE: Therapeutic, Level IV: Case report. PMID- 26253528 TI - Preliminary Treatment of Achilles Tendinopathy Using Low-Intensity Pulsed Ultrasound. AB - BACKGROUND: Achilles tendinopathy is a degenerative process of the tendon associated with diminished vascularity, microtrauma, and aging. Nonoperative treatments such as activity modification, immobilization, night splints, and physical therapy have good outcomes for the majority of patients. However, there are cohorts of patients that remain symptomatic despite use of all nonoperative measures that eventually require surgical intervention. The present study reports the preliminary short-term clinical outcomes of low-intensity pulsed ultrasound (LIPUS) for treatment for Achilles tendinopathy. MATERIALS AND METHODS: Fourteen patients with clinically diagnosed Achilles tendinopathy who failed previous nonoperative treatments underwent LIPUS stimulation directly over the area of maximum tendon tenderness for 20 min/d for 8 weeks total. No other treatment modalities were used during the period of LIPUS stimulation. All patients had serial clinical exams and evaluations with an average follow-up of 12 months (range, 6-50 months). RESULTS: Excellent clinical outcomes with complete resolution of pain and other symptoms were obtained in 7 patients (50%). Two patients (14%) had good outcomes with mild tendon irritation and stiffness not requiring further intervention. Five patients (36%) had minimal benefit with continued pain, swelling, and tenderness over the Achilles and functional deficits. No patients had worsening pain or progression of disability requiring surgery. CONCLUSIONS: LIPUS is an additional noninvasive treatment modality for chronic Achilles tendinopathy that may potentially help improve clinical symptoms and delay and/or prevent the need for surgical intervention. While LIPUS is easy to use, well-tolerated, and has promising early clinical results, further research is needed to determine the long-term benefits, disadvantages, and cost effectiveness of this alternative treatment for tendinopathy. LEVELS OF EVIDENCE: Therapeutic, Level IV: Case series. PMID- 26253529 TI - Excision of Morton's Neuroma Using a Longitudinal Plantar Approach: A Midterm Follow-up Study. AB - BACKGROUND: Operative procedures are indicated in the treatment of Morton's neuroma (MN) when conservative therapies have been unsuccessful. A dorsal approach for neurolysis or neurectomy was strongly recommended. The aim of this case series study was to prospectively analyze the midterm clinical outcome and complications following the excision of a MN using a plantar longitudinal approach. METHODS: Between September 2000 and January 2009, we included 44 patients (51 feet, 56 neuromas) in a prospective study treated by excision of a primary MN using a plantar longitudinal approach. The MN diagnosis was based on clinical symptoms, magnetic resonance imaging findings, and pain relief after infiltration of local anesthetics. Histological examinations were performed in all resected specimens. The patients returned for final follow-up at a mean of 54 (range = 12 to 99) months, comparing preoperative and postoperative perception of pain on a Visual Analogue Scale (VAS) and assessing clinical findings. RESULTS: The average amount of pain, according to VAS, was 8 (range = 6-9) points preoperatively and 0.4 (range = 0-5) points at final follow-up. Complications occurred in 7.1% of interventions and scar problems in 5.2%, including delayed wound healing, hypertrophic scar formation, and inclusion cyst. CONCLUSION: The present study shows a strong relief of pain after MN resection using a plantar longitudinal incision, coupled with a low rate of local complications. This surgical procedure seems to be a reliable choice for the excision of MN, even in cases with MN in adjacent webspaces, because it is technically simple and the plantar scar is not bothersome if properly located. LEVELS OF EVIDENCE: Therapeutic, Level IV: Prospective, Case series. PMID- 26253530 TI - Role of Foot Abduction and Heel Angle in Equinus Correction in Idiopathic Clubfoot: A Pilot Study. AB - Introduction The purpose of this study was to determine whether foot abduction and heel angles have any influence on resultant equinus correction and whether hindfoot dorsiflexion can be predicted based on these parameters.Material and Methods Twenty-four children with 39 unintervened idiopathic clubfeet who completed Ponseti's casting and percutaneous Achilles tenotomy with satisfactory equinus correction (>=15 degrees ) were included. Measurements included foot abduction and heel angle at the beginning of cast treatment, pre-tenotomy, and post-tenotomy along with post-tenotomy hindfoot dorsiflexion. Statistical relationships were calculated using Pearson's coefficients.Results The changes in heel angle correlated better with post-tenotomy dorsiflexion achieved than changes in foot abduction. Pre-tenotomy foot abduction or heel angle did not have any statistically significant correlation with post-tenotomy dorsiflexion. Furthermore, there was a significant relationship between post-tenotomy foot abduction and post-tenotomy dorsiflexion.Conclusions Changes in foot abduction and heel angle (from initial casting to pre-tenotomy measurement) statistically correlated to post-tenotomy hindfoot dorsiflexion achieved. Absolute degree measurements of pre-tenotomy abduction or heel valgus did not correlate with the post-tenotomy hindfoot dorsiflexion achieved. There was also significant correlation between post-tenotomy abduction and post-tenotomy hindfoot dorsiflexion. Correlation between post-tenotomy heel valgus and post-tenotomy hindfoot dorsiflexion was weak. LEVELS OF EVIDENCE: Prognostic, Level II: Prospective study. PMID- 26253531 TI - Antibodies enhance CXCL10 production during RSV infection of infant and adult immune cells. AB - Respiratory syncytial virus (RSV) bronchiolitis is a major burden in infants below three months of age, when the primary immune response is mainly dependent on innate immunity and maternal antibodies. We investigated the influence of antibodies on innate immunity during RSV infection. PBMCs from infants and adults were stimulated with live RSV and inactivated RSV in combination with antibody containing and antibody-depleted serum. The immune response was determined by transcriptome analysis and chemokine levels were measured using ELISA and flow cytometry. Microarray data showed that CXCL10 gene transcription was RSV dependent, whereas CXCL11 and IFNalpha were upregulated in an antibody-dependent manner. Although the presence of antibodies reduces RSV infection rate, it enhances the innate immune response. In adult immune cells, antibodies enhance CXCL10, CXCL11, IFNalpha and IFNgamma production in response to RSV infection. Contrary, in infant immune cells only CXCL10 was enhanced in an antibody dependent manner. Monocytes are the main source of CXCL10 and they produce CXCL10 in both an antibody- and virus-dependent manner. This study shows that antibodies enhance CXCL10 production in infant immune cells. CXCL10 has been implicated in exuberating the inflammatory response during viral infections and antibodies could therefore play a role in the pathogenesis of RSV infections. PMID- 26253532 TI - Percutaneous versus surgical strategy for tracheostomy: protocol for a systematic review and meta-analysis of perioperative and postoperative complications. AB - BACKGROUND: Tracheostomy is one of the most frequently performed procedures in intensive care medicine. The two main approaches to form a tracheostoma are the open surgical tracheotomy (ST) and the interventional strategy of percutaneous dilatational tracheotomy (PDT). It is particularly important to the critically ill patients that both procedures are performed with high success rates and low complication frequencies. Therefore, the aim of this systematic review is to summarize and analyze existing and relevant evidence for peri- and postoperative parameters of safety. METHODS/DESIGN: A systematic literature search will be conducted in The Cochrane Library, MEDLINE, LILACS, and Embase to identify all randomized controlled trials (RCTs) comparing peri- and postoperative complications between the two strategies and to define the strategy with the lower risk of potentially life-threatening events. A priori defined data will be extracted from included studies, and methodological quality will be assessed according to the recommendations of the Cochrane Collaboration. DISCUSSION: The findings of this systematic review with proportional meta-analysis will help to identify the strategy with the lowest frequency of potentially life-threatening events. This may influence daily practice, and the data may be implemented in treatment guidelines or serve as the basis for planning further randomized controlled trials. Considering the critical health of these patients, they will particularly benefit from evidence-based treatment. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015021967. PMID- 26253533 TI - 'One-component' ultrathin multilayer films based on poly(vinyl alcohol) as stabilizing coating for phenytoin-loaded liposomes. AB - Ultrathin "one-component" multilayer polymeric films for potential biomedical applications were designed based on polyvinyl alcohol,-a non-toxic, fully degradable synthetic polymer. Good uniformity of the obtained film and adequate adsorption properties of the polymeric layers were achieved by functional modification of the polymer, which involved synthesis of cationic and anionic derivatives. Synthesized polymers were characterized by FTIR, NMR spectroscopy, dynamic light scattering measurements and elemental analysis. The layer by layer assembly technique was used to build up a multilayer film and this process was followed using UV-Vis spectroscopy and ellipsometry. The morphology and thickness of the obtained multilayered film material was evaluated by atomic force microscopy (AFM). Preliminary studies on the application of the obtained multilayer film for coating of liposomal nanocarriers containing phenytoin, an antiarrhythmic drug, were performed. The coating effectively stabilizes liposomes and the effect increases with an increasing number of deposited layers until the polymeric film reaches the optimal thickness. The obtained release profiles suggest that bilayer-coated liposomes release phenytoin less rapidly than uncoated ones. The cytotoxicity studies performed for all obtained nanocarriers confirmed that none of them has negative effect on cell viability. All of the performed experiments suggest that liposomes coated with ultrathin film obtained from PVA derivatives can be attractive drug nanocarriers. PMID- 26253534 TI - DNA break-induced sumoylation is enabled by collaboration between a SUMO ligase and the ssDNA-binding complex RPA. AB - Upon genome damage, large-scale protein sumoylation occurs from yeast to humans to promote DNA repair. Currently, the underlying mechanism is largely unknown. Here we show that, upon DNA break induction, the budding yeast SUMO ligase Siz2 collaborates with the ssDNA-binding complex RPA (replication protein A) to induce the sumoylation of recombination factors and confer damage resistance. Both RPA and nuclease-generated ssDNA promote Siz2-mediated sumoylation. Mechanistically, the conserved Siz2 interaction with RPA enables Siz2 localization to damage sites. These findings provide a molecular basis for recruiting SUMO ligases to the vicinity of their substrates to induce sumoylation upon DNA damage. PMID- 26253535 TI - AUF1 promotes let-7b loading on Argonaute 2. AB - Eukaryotic gene expression is tightly regulated post-transcriptionally by RNA binding proteins (RBPs) and microRNAs. The RBP AU-rich-binding factor 1 (AUF1) isoform p37 was found to have high affinity for the microRNA let-7b in vitro (Kd = ~ 6 nM) in cells. Ribonucleoprotein immunoprecipitation, in vitro association, and single-molecule-binding analyses revealed that AUF1 promoted let-7b loading onto Argonaute 2 (AGO2), the catalytic component of the RNA-induced silencing complex (RISC). In turn, AGO2-let-7 triggered target mRNA decay. Our findings uncover a novel mechanism by which AUF1 binding and transfer of microRNA let-7 to AGO2 facilitates let-7-elicited gene silencing. PMID- 26253537 TI - Condensin promotes the juxtaposition of DNA flanking its loading site in Bacillus subtilis. AB - SMC condensin complexes play a central role in compacting and resolving replicated chromosomes in virtually all organisms, yet how they accomplish this remains elusive. In Bacillus subtilis, condensin is loaded at centromeric parS sites, where it encircles DNA and individualizes newly replicated origins. Using chromosome conformation capture and cytological assays, we show that condensin recruitment to origin-proximal parS sites is required for the juxtaposition of the two chromosome arms. Recruitment to ectopic parS sites promotes alignment of large tracks of DNA flanking these sites. Importantly, insertion of parS sites on opposing arms indicates that these "zip-up" interactions only occur between adjacent DNA segments. Collectively, our data suggest that condensin resolves replicated origins by promoting the juxtaposition of DNA flanking parS sites, drawing sister origins in on themselves and away from each other. These results are consistent with a model in which condensin encircles the DNA flanking its loading site and then slides down, tethering the two arms together. Lengthwise condensation via loop extrusion could provide a generalizable mechanism by which condensin complexes act dynamically to individualize origins in B. subtilis and, when loaded along eukaryotic chromosomes, resolve them during mitosis. PMID- 26253536 TI - mafba is a downstream transcriptional effector of Vegfc signaling essential for embryonic lymphangiogenesis in zebrafish. AB - The lymphatic vasculature plays roles in tissue fluid balance, immune cell trafficking, fatty acid absorption, cancer metastasis, and cardiovascular disease. Lymphatic vessels form by lymphangiogenesis, the sprouting of new lymphatics from pre-existing vessels, in both development and disease contexts. The apical signaling pathway in lymphangiogenesis is the VEGFC/VEGFR3 pathway, yet how signaling controls cellular transcriptional output remains unknown. We used a forward genetic screen in zebrafish to identify the transcription factor mafba as essential for lymphatic vessel development. We found that mafba is required for the migration of lymphatic precursors after their initial sprouting from the posterior cardinal vein. mafba expression is enriched in sprouts emerging from veins, and we show that mafba functions cell-autonomously during lymphatic vessel development. Mechanistically, Vegfc signaling increases mafba expression to control downstream transcription, and this regulatory relationship is dependent on the activity of SoxF transcription factors, which are essential for mafba expression in venous endothelium. Here we identify an indispensable Vegfc-SoxF-Mafba pathway in lymphatic development. PMID- 26253539 TI - An electron transfer flavoprotein is essential for viability and its depletion causes a rod-to-sphere change in Burkholderia cenocepacia. AB - Essential gene studies often reveal novel essential functions for genes with dispensable homologues in other species. This is the case with the widespread family of electron transfer flavoproteins (ETFs), which are required for the metabolism of specific substrates or for symbiotic nitrogen fixation in some bacteria. Despite these non-essential functions high-throughput screens have identified ETFs as putatively essential in several species. In this study, we constructed a conditional expression mutant of one of the ETFs in Burkholderia cenocepacia, and demonstrated that its expression is essential for growth on both complex media and a variety of single-carbon sources. We further demonstrated that the two subunits EtfA and EtfB interact with each other, and that cells depleted of ETF are non-viable and lack redox potential. These cells also transition from the short rods characteristic of Burkholderia cenocepacia to small spheres independently of MreB. The putative membrane partner ETF dehydrogenase also induced the same rod-to-sphere change. We propose that the ETF of Burkholderia cenocepacia is a novel antibacterial target. PMID- 26253538 TI - Glucagon-like peptide-1 protects against ischemic left ventricular dysfunction during hyperglycemia in patients with coronary artery disease and type 2 diabetes mellitus. AB - BACKGROUND: Enhancement of myocardial glucose uptake may reduce fatty acid oxidation and improve tolerance to ischemia. Hyperglycemia, in association with hyperinsulinemia, stimulates this metabolic change but may have deleterious effects on left ventricular (LV) function. The incretin hormone, glucagon-like peptide-1 (GLP-1), also has favorable cardiovascular effects, and has emerged as an alternative method of altering myocardial substrate utilization. In patients with coronary artery disease (CAD), we investigated: (1) the effect of a hyperinsulinemic hyperglycemic clamp (HHC) on myocardial performance during dobutamine stress echocardiography (DSE), and (2) whether an infusion of GLP-1(7 36) at the time of HHC protects against ischemic LV dysfunction during DSE in patients with type 2 diabetes mellitus (T2DM). METHODS: In study 1, twelve patients underwent two DSEs with tissue Doppler imaging (TDI)-one during the steady-state phase of a HHC. In study 2, ten patients with T2DM underwent two DSEs with TDI during the steady-state phase of a HHC. GLP-1(7-36) was infused intravenously at 1.2 pmol/kg/min during one of the scans. In both studies, global LV function was assessed by ejection fraction and mitral annular systolic velocity, and regional wall LV function was assessed using peak systolic velocity, strain and strain rate from 12 paired non-apical segments. RESULTS: In study 1, the HHC (compared with control) increased glucose (13.0 +/- 1.9 versus 4.8 +/- 0.5 mmol/l, p < 0.0001) and insulin (1,212 +/- 514 versus 114 +/- 47 pmol/l, p = 0.01) concentrations, and reduced FFA levels (249 +/- 175 versus 1,001 +/- 333 MUmol/l, p < 0.0001), but had no net effect on either global or regional LV function. In study 2, GLP-1 enhanced both global (ejection fraction, 77.5 +/- 5.0 versus 71.3 +/- 4.3%, p = 0.004) and regional (peak systolic strain 18.1 +/- 6.6 versus -15.5 +/- 5.4%, p < 0.0001) myocardial performance at peak stress and at 30 min recovery. These effects were predominantly driven by a reduction in contractile dysfunction in regions subject to demand ischemia. CONCLUSIONS: In patients with CAD, hyperinsulinemic hyperglycemia has a neutral effect on LV function during DSE. However, GLP-1 at the time of hyperglycemia improves myocardial tolerance to demand ischemia in patients with T2DM. TRIAL REGISTRATION: http://www.isrctn.org . Unique identifier ISRCTN69686930. PMID- 26253540 TI - Complications secondary to cosmetic artificial iris anterior chamber implants: a case report. AB - BACKGROUND: Artificial iris anterior chamber implants were originally developed for therapeutic purposes but have been used recently for the cosmetic alteration of eye colour. There is a growing body of evidence surrounding their associated risks. We report a case presenting with complications secondary to bilateral NewColorIris(r) implants, including the first report of pressure-induced stromal keratopathy in this context. CASE PRESENTATION: A thirty-eight year old South American man presented as an emergency in the UK with best corrected visual acuities of 1/60 OD and 6/18 OS, bilateral corneal decompensation, lens opacities and raised intraocular pressures 4 years following bilateral NewColorIris(r) implantation in Panama. Anterior segment optical coherence tomography demonstrated the direct apposition of the implant with the iris and iridocorneal angle, together with pressure-induced stromal keratopathy with a fluid interface between the corneal stroma and previous laser-assisted in situ keratomileusis flaps. We describe the successful combined medical and surgical management in this case to yield a final visual acuity 6/12 in both eyes. CONCLUSION: Artificial iris anterior chamber implants are associated with sight-threatening complications that can present years after their implantation. We caution against their use for the cosmetic alteration of eye colour. PMID- 26253542 TI - Changing Norms to Change Behavior. AB - Providing people with information about the behavior and attitudes of their peers is a strategy commonly employed by those seeking to reduce behavior deemed harmful either to individuals (e.g., high alcohol consumption) or the collective (e.g., high energy consumption). We review norm-based interventions, detailing the logic behind them and the various forms they can take. We give special attention to interventions designed to decrease college students' drinking and increase environment-friendly behaviors. We identify the conditions under which norm information has the highest likelihood of changing the targeted behavior and discuss why this is the case. PMID- 26253541 TI - Clinicopathologic characteristics and therapeutic responses of Chinese patients with non-small cell lung cancer who harbor an anaplastic lymphoma kinase rearrangement. AB - INTRODUCTION: The rearrangement of the anaplastic lymphoma kinase (ALK) gene accounts for approximately 1%-6% of lung adenocarcinoma cases and defines a molecular subgroup of tumors characterized by clinical sensitivity to ALK inhibitors such as crizotinib. This study aimed to identify the relationship between ALK rearrangement and the clinicopathologic characteristics of non-small cell lung cancer (NSCLC) and to analyze the therapeutic responses of crizotinib and conventional chemotherapy to ALK rearrangement in NSCLC patients. METHODS: A total of 487 lung cancer patients who underwent testing for ALK rearrangement in our department were included in this study. ALK rearrangement was examined by using fluorescence in situ hybridization (FISH) assay. RESULTS: Among the 487 patients, 44 (9.0%) were diagnosed with ALK rearrangement by using FISH assay. In 123 patients with adenocarcinoma who were non-smokers and of a young age (<= 58 years old), the frequency of ALK rearrangement was 20.3% (25/123). Short overall survival (OS) was associated with non-adenocarcinoma tumor type (P = 0.006), poorly differentiated tumors (P = 0.001), advanced-stage tumors (P < 0.001), smoking history (P = 0.008), and wild-type epidermal growth factor receptor (EGFR) (P = 0.008). Moreover, patients with poorly differentiated and advanced stage tumors had a shorter time to cancer progression compared with those with well differentiated (P = 0.023) and early-stage tumors (P = 0.001), respectively. CONCLUSIONS: ALK-rearranged NSCLC tends to occur in younger individuals who are either non-smokers or light smokers with adenocarcinoma. Patients with ALK rearrangement might benefit from ALK inhibitor therapy. PMID- 26253543 TI - Drug Addiction: Updating Actions to Habits to Compulsions Ten Years On. AB - A decade ago, we hypothesized that drug addiction can be viewed as a transition from voluntary, recreational drug use to compulsive drug-seeking habits, neurally underpinned by a transition from prefrontal cortical to striatal control over drug seeking and taking as well as a progression from the ventral to the dorsal striatum. Here, in the light of burgeoning, supportive evidence, we reconsider and elaborate this hypothesis, in particular the refinements in our understanding of ventral and dorsal striatal mechanisms underlying goal-directed and habitual drug seeking, the influence of drug-associated Pavlovian-conditioned stimuli on drug seeking and relapse, and evidence for impairments in top-down prefrontal cortical inhibitory control over this behavior. We further review animal and human studies that have begun to define etiological factors and individual differences in the propensity to become addicted to drugs, leading to the description of addiction endophenotypes, especially for cocaine addiction. We consider the prospect of novel treatments for addiction that promote abstinence from and relapse to drug use. PMID- 26253544 TI - Prognostic role of lactate on mortality in younger and older patients with cardio respiratory failure admitted to an acute intensive care unit. AB - BACKGROUND AND AIM: Acidosis is able to induce negative changes of different organs that increase progressively with aging. At present it is not known whether the levels of lactate may differently influence the prognosis of younger and older patients. Thus, the aim of this study is to evaluate the prognostic value of lactate levels after admission of younger and older patients to an acute intensive care unit. METHODS: Younger (<65 years, n = 118) and older (>=65 years, n = 165) patients admitted to an acute intensive care unit were prospectively enrolled and classified according to diagnosis of acute heart or/and respiratory failure. For each patient, APACHE II score, time of hospitalization and mortality, blood levels of lactate were collected. RESULTS: Both in-hospital mortality and lactate >2.5 mmol/L at the admission was higher in the older than in the younger patients (42.4 vs. 20.3 %, p < 0.01 and 57.8 vs. 31.9 %, p < 0.01, respectively). Lactate level was higher in older than in the younger patients both at admission and after 24 h (3.9 +/- 3.4 vs. 2.4 +/- 2.2 mmol/L and 2.4 +/- 2.0 vs. 1.4 +/- 1.3 mmol, p < 0.01, respectively). Accordingly, multivariate analysis shows that lactate was predictive of mortality in younger (OR = 2.65, 95 % CI 1.62-5.24, p = 0.03) and even more in the older (OR = 4.74, 95 % CI 2.10 6.70, p < 0.01) patients. CONCLUSIONS: Lactate concentration increase is associated with increased mortality in younger patients but, even more so, in older patients admitted to an acute intensive care unit. These results confirm the experimental evidence showing acidosis has a greater effect of leading to organ failure and higher mortality with increasing age. PMID- 26253545 TI - No Correlation of Morpho-Agronomic Traits of Phaseolus vulgaris (Fabaceae) Genotypes and Resistance to Acanthoscelides obtectus (Say) and Zabrotes subfasciatus (Boheman) (Coleoptera: Chrysomelidae). AB - Resistance of common bean (Phaseolus vulgaris) varieties is an important tool to control Acanthoscelides obtectus (Say) and Zabrotes subfasciatus (Boheman) (Coleoptera: Chrysomelidae: Bruchinae) worldwide. However, bioassays to characterize the resistance of a genotype can be difficult to perform. Therefore, the current study sought to correlate the morpho-agronomic traits of P. vulgaris genotypes with their resistance to A. obtectus and Z. subfasciatus to facilitate genotype characterization. Bean samples of each genotype were infested with newly emerged insect couples, and the number of adults obtained in each genotype was quantified (value used as a resistance parameter). The resistance index was calculated by dividing the number of adults obtained in each genotype by the one obtained in the cultivar Bolinha, used as the standard for susceptibility. Fifty genotypes were evaluated for A. obtectus and 202 for Z. subfasciatus. All genotypes were characterized according to their resistance to each insect and 18 other morpho-agronomic traits, for a total of 19 descriptors. Principal component analyses did not show any correlation between insect resistance and the morpho agronomic traits of the genotypes. Further, the thousand seeds weight (TSW), which is indicative of the genotype center of origin was tested considering genotypes from Mesoamerican with low TSW, while those from Andean with high TSW. Thus, the lack of correlation between genotype resistance and TSW indicates that resistance to A. obtectus and Z. subfasciatus in P. vulgaris is not related to the host center of origin. PMID- 26253546 TI - Prediction of Plant Height in Arabidopsis thaliana Using DNA Methylation Data. AB - Prediction of complex traits using molecular genetic information is an active area in quantitative genetics research. In the postgenomic era, many types of omic (e.g., transcriptomic, epigenomic, methylomic, and proteomic) data are becoming increasingly available. Therefore, evaluating the utility of this massive amount of information in prediction of complex traits is of interest. DNA methylation, the covalent change of a DNA molecule without affecting its underlying sequence, is one quantifiable form of epigenetic modification. We used methylation information for predicting plant height (PH) in Arabidopsis thaliana nonparametrically, using reproducing kernel Hilbert spaces (RKHS) regression. Also, we used different criteria for selecting smaller sets of probes, to assess how representative probes could be used in prediction instead of using all probes, which may lessen computational burden and lower experimental costs. Methylation information was used for describing epigenetic similarities between individuals through a kernel matrix, and the performance of predicting PH using this similarity matrix was reasonably good. The predictive correlation reached 0.53 and the same value was attained when only preselected probes were used for prediction. We created a kernel that mimics the genomic relationship matrix in genomic best linear unbiased prediction (G-BLUP) and estimated that, in this particular data set, epigenetic variation accounted for 65% of the phenotypic variance. Our results suggest that methylation information can be useful in whole genome prediction of complex traits and that it may help to enhance understanding of complex traits when epigenetics is under examination. PMID- 26253547 TI - Anxiety and acceptability related to participation in stillbirth research. AB - BACKGROUND: stillbirth research is often hampered by the need to 'protect' both bereaved families as well as healthy pregnant women from distress resulting from recruitment by research staff. No studies have investigated anxiety levels of recently bereaved or healthy pregnant women participating in stillbirth research. The aim of this study was to assess anxiety levels and acceptability of women participating in a stillbirth case-control study. METHOD: a follow-up questionnaire was posted to all participants of the Sydney Stillbirth Study in 2012. The questionnaire assessed the anxiety level experienced by women as a result of their participation in the study. Questions related to the initial approach of the research staff; level of anxiety at time of consent and after the interview; and reasons for and satisfaction with participation. The Spielberger (STAI-6) anxiety scale and open-field responses were included. RESULTS: 35/103 case participants and 65/192 control participants returned the completed questionnaire. The majority participated for altruistic reasons. 20/35 (cases) and 58/65 (controls) stated they disagreed/strongly disagreed that participation in the study increased their anxiety. 1 in 5 cases reported that participation in the study increased their anxiety; however this did not affect their satisfaction. Timing of interview did not affect anxiety scale responses. (F=1.2; p=0.37) 30/35 (cases) and 63/65 (controls) stated they agreed/strongly agreed that they were satisfied participating in the study. CONCLUSIONS: these findings suggest high levels of satisfaction amongst both case and control participants and no statistically significant increase in anxiety related to involvement in stillbirth research. 'Protecting' families may require further justification. PMID- 26253548 TI - Reporting quality of abstracts in phase III clinical trials of systemic therapy in metastatic solid malignancies. AB - BACKGROUND: Manuscript abstracts represent a critical source of information for oncology practitioners. Practitioners may utilize the information contained in abstracts as a basis for treatment decisions particularly when full-text articles are not accessible. In 2007, the Consolidated Standards of Reporting Trials (CONSORT) extension statement for abstracts provided a minimum list of elements that should be included in abstracts. In this study we evaluate the degree of adherence to these recommendations and accessibility of full text publications in oncology publications. METHODS: A systematic review of abstracts of randomized, controlled, phase III trials in metastatic solid malignancies published between January 2009 and December 2011 in PubMed, Medline, and Embase was completed. Abstracts were assigned a completeness score of 0-18 based on the number of CONSORT-recommended elements. Accessibility through open access was recorded. RESULTS: 174 abstracts with data for 95,956 patients were reviewed. The median completeness score was 9 (range, 3-17). Open access to full text articles was available for 80 % of abstracts. The remaining 20 % (35 out of 174) had a median cost of 38 USD (range: $22-49.95). The least frequently reported elements were: trial design description (20 %), participant allocation method (13 %), blinding (24 %), trial enrollment status (22 %), registration and name of trial (26 %) and funding source (18 %). The most frequently reported elements were eligibility criteria (98 %), study interventions (100 %), and primary endpoint (87 %). CONCLUSION: There is poor adherence to the CONSORT recommendations for abstract reporting in publications of randomized cancer clinical trials which could negatively impact clinical decision-making. Full-text articles are frequently available through open access. PMID- 26253549 TI - Variation in Women's Preferences Regarding Male Facial Masculinity Is Better Explained by Genetic Differences Than by Previously Identified Context-Dependent Effects. AB - Women's preferences for masculine versus feminine male faces are highly variable. According to a dominant theory in evolutionary psychology, this variability results from adaptations that optimize preferences by calibrating them to certain contextual factors, including women's self-perceived attractiveness, short- versus long-term relationship orientation, pathogen disgust sensitivity, and stage of the menstrual cycle. The theory does not account for the possible contribution of genetic variation on women's facial masculinity preference. Using a large sample (N = 2,160) of identical and nonidentical female Finnish twins and their siblings, we showed that the proportion of variation in women's preferences regarding male facial masculinity that was attributable to genetic variation (38%) dwarfed the variation due to the combined effect of contextual factors (< 1%). These findings cast doubt on the importance of these context-dependent effects and may suggest a need for refocusing in the field toward understanding the wide genetic variation in these preferences and how this variation relates to the evolution of sexual dimorphism in faces. PMID- 26253550 TI - A Second Look at Automatic Theory of Mind: Reconsidering Kovacs, Teglas, and Endress (2010). AB - In recent work, Kovacs, Teglas, and Endress (2010) argued that human adults automatically represented other agents' beliefs even when those beliefs were completely irrelevant to the task being performed. In a series of 13 experiments, we replicated these previous findings but demonstrated that the effects found arose from artifacts in the experimental paradigm. In particular, the critical findings demonstrating automatic belief computation were driven by inconsistencies in the timing of an attention check, and thus do not provide evidence for automatic theory of mind in adults. PMID- 26253551 TI - Sustained Attention Across the Life Span in a Sample of 10,000: Dissociating Ability and Strategy. AB - Normal and abnormal differences in sustained visual attention have long been of interest to scientists, educators, and clinicians. Still lacking, however, is a clear understanding of how sustained visual attention varies across the broad sweep of the human life span. In the present study, we filled this gap in two ways. First, using an unprecedentedly large 10,430-person sample, we modeled age related differences with substantially greater precision than have prior efforts. Second, using the recently developed gradual-onset continuous performance test (gradCPT), we parsed sustained-attention performance over the life span into its ability and strategy components. We found that after the age of 15 years, the strategy and ability trajectories saliently diverge. Strategy becomes monotonically more conservative with age, whereas ability peaks in the early 40s and is followed by a gradual decline in older adults. These observed life-span trajectories for sustained attention are distinct from results of other life-span studies focusing on fluid and crystallized intelligence. PMID- 26253552 TI - Intergenerational Effects of Parents' Math Anxiety on Children's Math Achievement and Anxiety. AB - A large field study of children in first and second grade explored how parents' anxiety about math relates to their children's math achievement. The goal of the study was to better understand why some students perform worse in math than others. We tested whether parents' math anxiety predicts their children's math achievement across the school year. We found that when parents are more math anxious, their children learn significantly less math over the school year and have more math anxiety by the school year's end-but only if math-anxious parents report providing frequent help with math homework. Notably, when parents reported helping with math homework less often, children's math achievement and attitudes were not related to parents' math anxiety. Parents' math anxiety did not predict children's reading achievement, which suggests that the effects of parents' math anxiety are specific to children's math achievement. These findings provide evidence of a mechanism for intergenerational transmission of low math achievement and high math anxiety. PMID- 26253553 TI - Pursuing the impossible: an interview with Tim Hunt. AB - Tim Hunt took an undergraduate degree in Natural Sciences at Cambridge in 1964, and his PhD and subsequent work focussed on the control of protein synthesis until 1982, when his adventitious discovery of the central cell cycle regulator cyclin, while he was teaching at the Marine Biological Laboratory in Woods Hole, redirected him to the study of cell cycle regulation. From 1990 to his retirement Tim worked in the Clare Hall Laboratories of Cancer Research UK. He shared the Nobel Prize in Physiology and Medicine with Lee Hartwell and Paul Nurse in 2001, and talked to us about the series of coincidences that led him to the prizewinning discovery. PMID- 26253554 TI - Yes, India has done it: Decriminalization of suicide in India. PMID- 26253555 TI - Guidelines for the management of Helicobacter pylori infection in Italy: The III Working Group Consensus Report 2015. AB - Knowledge on the role of Helicobacter pylori (HP) infection is continually evolving, and treatment is becoming more challenging due to increasing bacterial resistance. Since the management of HP infection is changing, an update of the national Italian guidelines delivered in 2007 was needed. In the III Working Group Consensus Report 2015, a panel of 17 experts from several Italian regions reviewed current evidence on different topics relating to HP infection. Four working groups examined the following topics: (1) "open questions" on HP diagnosis and treatment (focusing on dyspepsia, gastro-oesophageal reflux disease, non-steroidal anti-inflammatory drugs or aspirin use and extra-gastric diseases); (2) non-invasive and invasive diagnostic tests; (3) treatment of HP infection; (4) role of HP in the prevention of gastric cancer. Statements and recommendations were discussed and a consensus reached in a final plenary session held in February 2015 in Bologna. Recommendations are based on the best current evidence to help physicians manage HP infection in Italy. The guidelines have been endorsed by the Italian Society of Gastroenterology and the Italian Society of Digestive Endoscopy. PMID- 26253556 TI - Integration of Oncology and Palliative Care, a Forgotten Indicator: Shared Decision-Making. PMID- 26253557 TI - In Reply. PMID- 26253558 TI - Changing Beliefs and Practices in Women With Breast Cancer in China. PMID- 26253560 TI - Parabens in 24 h urine samples of the German Environmental Specimen Bank from 1995 to 2012. AB - Parabens are widely used as antimicrobial preservatives in personal care and consumer products, food and pharmaceuticals. Due to their ubiquity, humans are constantly exposed to these chemicals. We assessed exposure to nine parabens (methyl-, ethyl-, n- and iso-propyl-, n- and iso-butyl-, benzyl-, pentyl- and heptyl paraben) in the German population from 1995 to 2012 based on 660 24h urine samples from the German Environmental Specimen Bank (ESB) using on-line HPLC coupled to isotope dilution tandem mass spectrometry. The limit of quantification (LOQ) was 0.5 MUg/L for all parabens. We detected methyl-, ethyl- and n-propyl paraben in 79-99% of samples, followed by n-butyl paraben in 40% of samples. We infrequently detected iso-butyl-, iso-propyl- and benzyl paraben in 24%, 4% and 1.4% of samples, respectively. Urinary concentrations were highest for methyl paraben (median 39.8 MUg/L; 95th percentile 319 MUg/L) followed by n-propyl paraben (4.8 MUg/L; 95th percentile 74.0 MUg/L) and ethyl paraben (2.1 MUg/L; 95th percentile 39.1 MUg/L). Women had significantly higher urinary levels for all parabens than men, except for benzyl paraben. Samples from the ESB revealed that over the investigation period of nearly 20 years urinary paraben levels remained surprisingly constant; only methyl paraben had a significant increase, for both men and women. We found strong correlations between methyl- and n-propyl paraben and between n- and iso-butyl paraben. These results indicate that parabens are used in combination and arise from common sources of exposure. Urinary excretion factors are needed to extrapolate from individual urinary concentrations to actual doses. PMID- 26253559 TI - Trends in Radical Surgical Treatment Methods for Breast Malignancies in China: A Multicenter 10-Year Retrospective Study. AB - BACKGROUND: Incidence rates of breast cancer continue to rise in the People's Republic of China. The purpose of this study was to describe Chinese trends in radical surgical modalities and influential imaging and demographic factors for breast malignancies. MATERIALS AND METHODS: This study was a hospital-based, multicenter, 10-year (1999-2008), retrospective study. Descriptive statistical tests were used to illustrate information regarding radical surgical trends for the treatment of breast malignancies. Chi-square tests were used to assess effect of demographic factors in addition to imaging and pathological data on the specific surgical method. RESULTS: A total of 4,211 patients were enrolled in the survey. Among them, 3,335 patients with stage 0 to stage III disease undergoing mastectomy or breast-conserving surgery (BCS) were included in the final analysis. The rate of BCS increased from 1.53% in 1999 to 11.88% in 2008. The rate of mastectomy declined over this time period, from 98.47% in 1999 to 88.12% in 2008, with increasing use of diagnostic imaging methods and pathological biopsies. A significantly greater percentage of patients with office work, high education levels, unmarried status, younger age, and early pathological stages preferred BCS compared with mastectomy. CONCLUSION: Rates of mastectomy in China remain elevated due to diagnosis at higher stages; however, because of increased use of diagnostic imaging, improvement of biopsy methods, and patient education, rates of less invasive lumpectomy are increasing and rates of mastectomy have decreased in China. IMPLICATIONS FOR PRACTICE: In this study, 4,211 cases were collected from 1999 to 2008 through a multicenter retrospective study of varying geographic and socioeconomic areas to illustrate trends of surgeries in the People's Republic of China. The correlations between demographic and tumor characteristics and among methods of surgical treatment were explored. This study shows that the rate of breast-conserving surgery (BCS) increased and the rate of mastectomy declined over this time period with increasing use of diagnostic imaging methods and pathological biopsies. Patients with office work, high education levels, unmarried status, younger age, and early pathological stages preferred BCS compared with mastectomy in China. PMID- 26253561 TI - Impact of Unaccounted Risk Factors on the Interpretation of Surgical Outcomes. AB - BACKGROUND: Systems that report hospital-based risk-adjusted surgical outcomes are potentially sensitive to the underlying methods used for risk adjustment. If a body of operations has a true level of risk that is higher than the estimated risk, then these operations might generate bias in the output of these reports. The objective of this study was to quantify the impact of unaccounted risk on the results of a surgical outcomes report. STUDY DESIGN: We constructed a model simulating a universe of 500 hospitals, each providing care to 1,500 patients in a given year. The likelihood of morbidity and mortality for each of these patients was drawn from a random sampling of patients in the American College of Surgeons NSQIP. A single additional hospital was also simulated, within which a certain proportion (proportion varied from 2% to 10%) of patients had a significantly higher (odds ratio varied from 1 to 5) actual likelihood of mortality. RESULTS: The presence of even a small proportion (2%) of patients with unaccounted risk had the potential to greatly increase the likelihood of a hospital being considered a statistical outlier (poor performer). This impact was greater in the assessment of complications than mortality. CONCLUSIONS: This study shows that even a small proportion of patients with substantial levels of unaccounted risk can have a dramatic impact on the assessment of hospital-level risk-adjusted surgical outcomes. To avoid the unintended consequences associated with risk-averse behavior from providers, policy should be constructed to address this potential source of bias. PMID- 26253562 TI - Epicardial adipose tissue in long-term hemodialysis patients: its association with vascular calcification and long-term development. AB - BACKGROUND: Epicardial adipose tissue (EAT) is associated with coronary artery disease (CAD) in the general population. EAT is suggested to promote CAD by paracrine mechanisms and local inflammation. We evaluated whether in chronic hemodialysis (HD) patients EAT associates with CAD, how the amount of EAT develops over time, and if EAT independently predicts the mortality risk. METHODS: Post-hoc analysis of a prospective study in 59 chronic HD patients who underwent non-enhanced multi-slice computed tomography (MSCT) at baseline. Thirty seven patients underwent another MSCT after 24 +/- 5 months. We measured EAT volume (cm3) and Agatston calcification scores of coronary arteries (CAC) and aortic valves (AVC). All-cause mortality was assessed after a follow-up of 88 months (IQR 52-105). RESULTS: Baseline EAT was 128.2 +/- 60.8 cm3 and significantly higher than in a control group of non-renal patients (94 +/- 46 cm3; p < 0.05). Median Agatston score for CAC was 329 (IQR 23-1181) and for AVC was 0 (IQR 0-25.3) in HD patients. We observed significant positive correlations between baseline EAT and age (r = 0.386; p = 0.003), BMI (r = 0.314; p = 0.016), CAC (r = 0.278; p = 0.03), and AVC (r = 0.282; p = 0.03). In multivariate analysis, age, BMI and AVC remained as significant predictors of EAT (p < 0.01). Calcification scores significantly increased over 2 years; in contrast EAT change was not significant (+11 %, IQR -10 to 24 %; p = 0.066). The limited patient number in the present study precludes analysis of the EAT impact upon survival. CONCLUSION: EAT correlated significantly with cardiovascular calcification in long-term HD patients. Mean EAT did not significantly change over 2 years. PMID- 26253563 TI - Outcome measure for the treatment of cone photoreceptor diseases: orientation to a scene with cone-only contrast. AB - BACKGROUND: Inherited retinal degenerations (IRDs) preferentially affecting cone photoreceptor function are being considered for treatment trials aiming to improve day vision. The purpose of the current work was to develop cone-specific visual orientation outcomes that can differentiate day vision improvement in the presence of retained night vision. METHODS: A lighted wall (1.4 m wide, 2 m high) resembling a beaded curtain was formed with 900 individually addressable red, blue and green LED triplets placed in 15 vertical strips hanging 0.1 m apart. Under computer control, different combination of colors and intensities were used to produce the appearance of a door on the wall. Scotopically-matched trials were designed to be perceptible to the cone-, but not rod-, photoreceptor based visual systems. Unmatched control trials were interleaved at each luminance level to determine the existence of any vision available for orientation. Testing started with dark-adapted eyes and a scene luminance attenuated 8 log units from the maximum attainable, and continued with progressively increasing levels of luminance. Testing was performed with a three-alternative forced choice method in healthy subjects and patients with Leber congenital amaurosis (LCA) caused by mutations in GUCY2D, the gene that encodes retinal guanylate cyclase-1. RESULTS: Normal subjects could perform the orientation task using cone vision at 5 log attenuation and brighter luminance levels. Most GUCY2D-LCA patients failed to perform the orientation task with scotopically-matched test trials at any luminance level even though they were able to perform correctly with unmatched control trials. These results were consistent with a lack of cone system vision and use of the rod system under ambient conditions normally associated with cone system activity. Two GUCY2D-LCA patients demonstrated remnant cone vision but at a luminance level 2 log brighter than normal. CONCLUSIONS: The newly developed device can probe the existence or emergence of cone-based vision in patients for an orientation task involving the identification of a door on the wall under free viewing conditions. This key advance represents progress toward developing an appropriate outcome measure for a clinical trial to treat currently incurable eye diseases severely affecting cone vision despite retained rod vision. PMID- 26253564 TI - Automated interpretation of 3D laserscanned point clouds for plant organ segmentation. AB - BACKGROUND: Plant organ segmentation from 3D point clouds is a relevant task for plant phenotyping and plant growth observation. Automated solutions are required to increase the efficiency of recent high-throughput plant phenotyping pipelines. However, plant geometrical properties vary with time, among observation scales and different plant types. The main objective of the present research is to develop a fully automated, fast and reliable data driven approach for plant organ segmentation. RESULTS: The automated segmentation of plant organs using unsupervised, clustering methods is crucial in cases where the goal is to get fast insights into the data or no labeled data is available or costly to achieve. For this we propose and compare data driven approaches that are easy-to-realize and make the use of standard algorithms possible. Since normalized histograms, acquired from 3D point clouds, can be seen as samples from a probability simplex, we propose to map the data from the simplex space into Euclidean space using Aitchisons log ratio transformation, or into the positive quadrant of the unit sphere using square root transformation. This, in turn, paves the way to a wide range of commonly used analysis techniques that are based on measuring the similarities between data points using Euclidean distance. We investigate the performance of the resulting approaches in the practical context of grouping 3D point clouds and demonstrate empirically that they lead to clustering results with high accuracy for monocotyledonous and dicotyledonous plant species with diverse shoot architecture. CONCLUSION: An automated segmentation of 3D point clouds is demonstrated in the present work. Within seconds first insights into plant data can be deviated - even from non-labelled data. This approach is applicable to different plant species with high accuracy. The analysis cascade can be implemented in future high-throughput phenotyping scenarios and will support the evaluation of the performance of different plant genotypes exposed to stress or in different environmental scenarios. PMID- 26253565 TI - One-year patency control and risk analysis of eSVS(r)-mesh-supported coronary saphenous vein grafts. AB - BACKGROUND: The eSVS(r) external venous nitinol mesh (Kips Bay Medical, Minneapolis, USA) was designed to improve long-term patency of coronary saphenous vein grafts (SVG) by preventing pressure-induced wall stress and reactive neo intimal hyperplasia. We present one-year-patency rates of meshed SVGs assessed by coronary computed tomographic angiography (cCTA). PATIENTS AND METHODS: Data from consecutive patients receiving an eSVS(r) meshed coronary bypass SVG from 06/2010 to 06/2011 were prospectively collected and analysed post-hoc. Patient characteristics, coronary artery disease, SVG quality, surgery (including number of anastomoses and transit time flow-measurement: TTFM), postoperative course and graft patency by cCTA were recorded. Potential risk factors for meshed graft occlusion were evaluated. RESULTS: 22 patients received an eSVS(r) mesh (18 isolated CABG, 4 combined with aortic valve replacement). Three patients died prior to the one-year follow-up and were excluded. All 19 surviving patients (mean age 70.4 +/- 9.5 years, 3 female) completed a cCTA of all grafts at 12 +/- 0.1 months after surgery including 21 meshed SVGs (33 distal anastomoses), 7 unmeshed SVGs (13 distal anastomoses) and 22 arterial grafts (30 distal anastomoses). Mesh application was safe with patent grafts (by intraoperative TTFM) and perioperative course uneventful in all patients. The average graft/anastomosis number per patient was 2.6 +/- 0.5/3.7 +/- 0.8. Patency was unrestricted in all arterial and unmeshed SVGs (cCTA). Meshed SVG patency was 85 % (n = 28/33) for distal anastomoses and 76 % (n = 16/21) among meshed SVGs. Four SVGs with single distal anastomosis to the right coronary were completely occluded. One sequential graft to the left coronary was occluded between proximal and first distal anastomosis (see Fig. 1). Patency was independent of target site, coronary run-off, SVG quality and sequential distal grafting. All patients were asymptomatic. CONCLUSIONS: The overall one-year patency rate of eSVS(r) meshed SVGs/anastomoses was 76 %/85 %. Surgical implantation is safe independently of target site, run-off, vein quality and sequential distal anastomoses. However, graft patency of meshed veins (76 %) was inferior to non meshed (100 %) or arterial grafts (100 %). Thus our mid-term data do not sustain the concept of improving vein graft patency by external reinforcing with the eSVS(r) mesh. Further long-term follow-up is warranted. PMID- 26253566 TI - Monotherapy versus dual therapy for the initial treatment of hypertension (PATHWAY-1): a randomised double-blind controlled trial. AB - INTRODUCTION: Previous studies have suggested that more intensive initial therapy for hypertension results in better long-term blood pressure (BP) control. We test this hypothesis comparing initial monotherapy with dual therapy in the management of essential hypertension. METHODS AND ANALYSIS: The study is a prospective, multicentre, double-blind, active-controlled trial in patients with essential hypertension. Around 50% of patients studied will be newly diagnosed and the others will be known hypertensives who previously received only monotherapy. The trial is divided into three phases as follows: Phase 1 (Week 0-Week 16): Randomised, parallel-group, masked assignation to either combination or monotherapy. Phase 2 (Week 17-Week 32): Open-label combination therapy. Phase 3 (Week 33-Week 52): Open-label combination therapy plus open-label add-on (if BP is above 140/90 mm Hg). Hierarchical primary end points are: a comparison of home BP (home systolic blood pressure (HSBP)) averaged over the duration of phase 1 and 2 in the combination versus monotherapy arms. If combination is superior in this analysis, then the averaged mean HSBP between initial monotherapy and initial combination therapy at the end of phase 2 will be compared. Secondary end points include: BP control at 1 year; the role of age, baseline renin, sodium status, plasma volume, haemodynamic compensation and peripheral resistance on BP control; validation of the National Institute for Clinical Excellence/British Hypertension Society joint guideline algorithm; safety and tolerability of combination therapy; and the impact of combination versus monotherapy on left ventricular mass and aortic pulse wave velocity. A sample size of 536 (268 in each group) will have 90% power to detect a difference in means of 4 mm Hg. ETHICS AND DISSEMINATION: PATHWAY 1 was approved by UK ethics (REC Reference 09/H0308/132). Trial results will be published and all participating subjects will be informed of the results. TRIAL REGISTRATION NUMBER: UKCRN 4499 and EudraCT number 2008-007749-29 registered 27/08/2009. PMID- 26253567 TI - Comparison of single and combination diuretics on glucose tolerance (PATHWAY-3): protocol for a randomised double-blind trial in patients with essential hypertension. AB - INTRODUCTION: Thiazide diuretics are associated with increased risk of diabetes mellitus. This risk may arise from K(+)-depletion. We hypothesised that a K(+) sparing diuretic will improve glucose tolerance, and that combination of low-dose thiazide with K(+)-sparing diuretic will improve both blood pressure reduction and glucose tolerance, compared to a high-dose thiazide. METHODS AND ANALYSIS: This is a parallel-group, randomised, double-blind, multicentre trial, comparing hydrochlorothiazide 25-50 mg, amiloride 10-20 mg and combination of both diuretics at half these doses. A single-blind placebo run-in of 1 month is followed by 24 weeks of blinded active treatment. There is forced dose-doubling after 3 months. The Primary end point is the blood glucose 2 h after oral ingestion of a 75 g glucose drink (OGTT), following overnight fasting. The primary outcome is the difference between 2 h glucose at weeks 0, 12 and 24. Secondary outcomes include the changes in home systolic blood pressure (BP) and glycated haemoglobin and prediction of response by baseline plasma renin. Eligibility criteria are: age 18-79, systolic BP on permitted background treatment >= 140 mm Hg and home BP >= 130 mm Hg and one component of the metabolic syndrome additional to hypertension. Principal exclusions are diabetes, estimated-glomerular filtration rate <45 mL/min, abnormal plasma K(+), clinic SBP >200 mm Hg or DBP >120 mm Hg (box 2). The sample size calculation indicates that 486 patients will give 80% power at alpha=0.01 to detect a difference in means of 1 mmol/L (SD=2.2) between 2 h glucose on hydrochlorothiazide and comparators. ETHICS AND DISSEMINATION: PATHWAY-3 was approved by Cambridge South Ethics Committee, number 09/H035/19. The trial results will be published in a peer reviewed scientific journal. TRIAL REGISTRATION NUMBERS: Eudract number 2009 010068-41 and clinical trials registration number: NCT02351973. PMID- 26253568 TI - Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2: protocol for a randomised crossover trial to determine optimal treatment for drug-resistant hypertension. AB - INTRODUCTION: Resistant hypertension is inadequately controlled blood pressure (BP) despite treatment with at least three BP-lowering drugs. A popular hypothesis is that resistant hypertension is due to excessive Na(+)-retention, and that 'further diuretic therapy' will be superior to alternative add-on drugs. METHODS AND ANALYSIS: Placebo-controlled, random crossover study of fourth-line treatment when added to standard (A+C+D) triple drug therapy: ACE inhibitor or Angiotensin receptor blocker (A) +Calcium channel blocker (C)+Diuretic (D). Patients (aged 18-79 years) with clinical systolic BP >= 140 mm Hg (135 mm Hg in diabetics) and Home BP Monitoring (HBPM) systolic BP average >= 130 mm Hg on treatment for at least 3 months with maximum tolerated doses of A+C+D are randomised to four consecutive randomly allocated 12-week treatment cycles with an alpha-blocker, beta-blocker, spironolactone and placebo. The hierarchical coprimary end point is the difference in HBPM average systolic BP between (in order) spironolactone and placebo, spironolactone and the average of the other two active drugs, spironolactone and each of the other two drugs. A key secondary outcome is to determine whether plasma renin predicts the BP response to the different drugs. A sample size of 346 (allowing 15% dropouts) will confer 90% power to detect a 3 mm Hg HBPM average systolic BP difference between any two drugs. The study can also detect a 6 mm Hg difference in HBPM average systolic BP between each patient's best and second-best drug predicted by tertile of plasma renin. ETHICS AND DISSEMINATION: The study was initiated in May 2009 and results are expected in 2015. These will provide RCT evidence to support future guideline recommendations for optimal drug treatment of resistant hypertension. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT02369081, EUDract number: 2008-007149 30. PMID- 26253569 TI - Extensive allele-specific translational regulation in hybrid mice. AB - Translational regulation is mediated through the interaction between diffusible trans-factors and cis-elements residing within mRNA transcripts. In contrast to extensively studied transcriptional regulation, cis-regulation on translation remains underexplored. Using deep sequencing-based transcriptome and polysome profiling, we globally profiled allele-specific translational efficiency for the first time in an F1 hybrid mouse. Out of 7,156 genes with reliable quantification of both alleles, we found 1,008 (14.1%) exhibiting significant allelic divergence in translational efficiency. Systematic analysis of sequence features of the genes with biased allelic translation revealed that local RNA secondary structure surrounding the start codon and proximal out-of-frame upstream AUGs could affect translational efficiency. Finally, we observed that the cis-effect was quantitatively comparable between transcriptional and translational regulation. Such effects in the two regulatory processes were more frequently compensatory, suggesting that the regulation at the two levels could be coordinated in maintaining robustness of protein expression. PMID- 26253570 TI - Comprehensive assembly of novel transcripts from unmapped human RNA-Seq data and their association with cancer. AB - Crucial parts of the genome including genes encoding microRNAs and noncoding RNAs went unnoticed for years, and even now, despite extensive annotation and assembly of the human genome, RNA-sequencing continues to yield millions of unmappable and thus uncharacterized reads. Here, we examined > 300 billion reads from 536 normal donors and 1,873 patients encompassing 21 cancer types, identified ~300 million such uncharacterized reads, and using a distinctive approach de novo assembled 2,550 novel human transcripts, which mainly represent long noncoding RNAs. Of these, 230 exhibited relatively specific expression or non-expression in certain cancer types, making them potential markers for those cancers, whereas 183 exhibited tissue specificity. Moreover, we used lentiviral-mediated expression of three selected transcripts that had higher expression in normal than in cancer patients and found that each inhibited the growth of HepG2 cells. Our analysis provides a comprehensive and unbiased resource of unmapped human transcripts and reveals their associations with specific cancers, providing potentially important new genes for therapeutic targeting. PMID- 26253571 TI - On the Measure and Mismeasure of Narcissism: A Response to "Measures of Narcissism and Their Relations to DSM-5 Pathological Traits: A Critical Reappraisal". AB - Narcissism continues to suffer from a lack of consensual definition. Variability in the definition is reflected in the growing multitude of measures with oftentimes diverging nomological nets. Although the themes of narcissistic grandiosity and vulnerability appear to have achieved reasonable agreement on their central importance, the lower order structure of each is not well understood and debates remain about how (and whether) they can be integrated into a coherent whole. However, it is clear that a narrow focus on higher order grandiosity without consideration of concomitant vulnerability neglects clinically important features of narcissism. Occasioned by the potential for a new personality disorder model in the Diagnostic and Statistical Manual of Mental Disorders-Fifth edition, several colleagues and I demonstrated that pathological narcissism, as measured by the Pathological Narcissism Inventory, could not be adequately summarized by the lower order traits of Grandiosity and Attention Seeking, and argued that this should be reflected in the diagnostic manual in some form. Miller, Lynam, and Campbell then subjected these same data to critical reanalysis and interpretation. I respond here to several points raised by Miller and colleagues. In so doing, I highlight areas of agreement, disagreement, and suggest directions for future research. PMID- 26253572 TI - The Relationship Between Psychiatric and Cognitive Symptom Feigning Among Forensic Inpatients Adjudicated Incompetent to Stand Trial. AB - The accurate assessment of feigning is an important component of forensic assessment. Two potential strategies of feigning include the fabrication/exaggeration of psychiatric impairments and the fabrication/exaggeration of cognitive deficits. The current study examined the relationship between psychiatric and cognitive feigning strategies using the Structured Interview of Reported Symptoms and Test of Memory Malingering among 150 forensic psychiatric inpatients adjudicated incompetent to stand trial. A greater number of participants scored within the feigning range on the Structured Interview of Reported Symptoms than on the Test of Memory Malingering. Relative risk ratios indicated that individuals shown to be feigning cognitive deficits were 1.68 times more likely to feign psychiatric symptoms than those not shown to be feigning cognitive deficits. Likewise, individuals shown to be feigning psychiatric deficits were 1.86 times more likely to feign cognitive deficits than those not shown to be feigning psychiatric symptoms. Overall, findings suggest that psychiatric feigning and cognitive feigning are related, but can be employed separately as feigning strategies. Therefore, clinicians should consider evaluating for both feigning strategies in forensic assessments where cognitive and psychiatric symptoms are being assessed. PMID- 26253573 TI - Assessing Cognitive and Affective Empathy Through the Interpersonal Reactivity Index: An Argument Against a Two-Factor Model. AB - One aspect of higher order social cognition is empathy, a psychological construct comprising a cognitive (recognizing emotions) and an affective (responding to emotions) component. The complex nature of empathy complicates the accurate measurement of these components. The most widely used measure of empathy is the Interpersonal Reactivity Index (IRI). However, the factor structure of the IRI as it is predominantly used in the psychological literature differs from Davis's original four-factor model in that it arbitrarily combines the subscales to form two factors: cognitive and affective empathy. This two-factor model of the IRI, although popular, has yet to be examined for psychometric support. In the current study, we examine, for the first time, the validity of this alternative model. A confirmatory factor analysis showed poor model fit for this two-factor structure. Additional analyses offered support for the original four-factor model, as well as a hierarchical model for the scale. In line with previous findings, females scored higher on the IRI than males. Our findings indicate that the IRI, as it is currently used in the literature, does not accurately measure cognitive and affective empathy and highlight the advantages of using the original four-factor structure of the scale for empathy assessments. PMID- 26253574 TI - Professional perspectives on service user and carer involvement in mental health care planning: a qualitative study. AB - BACKGROUND: Involving users/carers in mental health care-planning is central to international policy initiatives yet users frequently report feeling excluded from the care planning process. Rigorous explorations of mental health professionals' experiences of care planning are lacking, limiting our understanding of this important translational gap. OBJECTIVES: To explore professional perceptions of delivering collaborative mental health care-planning and involving service users and carers in their care. DESIGN: Qualitative interviews and focus groups with data combined and subjected to framework analysis. SETTING: UK secondary care mental health services. PARTICIPANTS: 51 multi-disciplinary professionals involved in care planning and recruited via study advertisements. RESULTS: Emergent themes identified care-planning as a meaningful platform for user/carer involvement but revealed philosophical tensions between user involvement and professional accountability. Professionals emphasised their individual, relational skills as a core facilitator of involvement, highlighting some important deficiencies in conventional staff training programmes. CONCLUSIONS: Although internationally accepted on philosophical grounds, user-involved care-planning is poorly defined and lacks effective implementation support. Its full realisation demands greater recognition of both the historical and contemporary contexts in which statutory mental healthcare occurs. PMID- 26253575 TI - Diversity of Rhodopirellula and related planctomycetes in a North Sea coastal sediment employing carB as molecular marker. AB - Rhodopirellula is an abundant marine member of the bacterial phylum Planctomycetes. Cultivation studies revealed the presence of several closely related Rhodopirellula species in European coastal sediments. Because the 16S rRNA gene does not provide the desired taxonomic resolution to differentiate Rhodopirellula species, we performed a comparison of the genomes of nine Rhodopirellula strains and six related planctomycetes and identified carB, coding for the large subunit of carbamoylphosphate synthetase, as a suitable molecular marker. In this study, we investigated the diversity of Rhodopirellula in coastal intertidal surface sediments of Sylt island, North Sea, using the 16S rRNA and carB genes as molecular markers. The carB clone and pyrosequencing libraries revealed the presence of 12 species of Rhodopirellula and of 66 species in closely related undescribed genera, a diversity that was not detected with a 16S rRNA gene library. This study demonstrates that the carB gene is a powerful molecular marker for detecting Rhodopirellula species in the environment and may be used for the taxonomic evaluation of new strains. PMID- 26253576 TI - Profiling antibiotic resistance and electrotransformation potential of Ensifer adhaerens OV14; a non-Agrobacterium species capable of efficient rates of plant transformation. AB - Ensifer adhaerens OV14 underpins the successful crop transformation protocol termed Ensifer-mediated transformation but issues exist in regard to addressing the pleomorphic tendency of the bacterium in suboptimal conditions, identifying the optimal parameters for electrotransformation and defining the strain's antibiotic profile. Here, modifications made to growth medium composition addressed the pleomorphic trait of E. adhaerens OV14, delivering uniform E. adhaerens OV14 growth to ensure efficient rates of electroporation with plasmids up to 42.2 kb in size. Separately, 63 putative antibiotic resistance coding sequences were identified across the E. adhaerens OV14 genome, with testing confirming the strain's susceptibility to gentamicin (>=10 mg L(-1)), tetracycline (>=10 mg L(-1)), chloramphenicol (>=100 mg L(-1)) and cefotaxime (>=500 mg L(-1)) and resistance to ampicillin, paramomycin, streptomycin, spectinomycin, ticarcillin-clavulanate and kanamycin. Partial resistance against carbenicillin, rifampicin, hygromycin-B and neomycin was also recorded. Resistance to kanamycin was supported by seven independent nptII-like homologs located within the E. adhaerens OV14 genome. Transcriptional analysis of these targets highlighted two homologs (AHK42288 and AHK42618) whose transcription was significantly elevated within 2 h exposure to kanamycin and which in the case of AHK42288 was maintained out to 6 h post-exposure. In conclusion, our results have identified optimal conditions for the handling of E. adhaerens and have identified a future genome editing target (AHK42288) to negate the kanamycin resistant phenotype of E. adhaerens. PMID- 26253577 TI - Validation of ethnomedicinal potential of Tinospora cordifolia for anticancer and immunomodulatory activities and quantification of bioactive molecules by HPTLC. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tinospora cordifolia (Willd.) Miers ex Hook. f. & Thomas. (Menispermaceae) is one of the most widely used plants in various traditional medicinal systems including "Ayurveda". The plant is used for the treatment of jaundice, rheumatism, urinary disorder, skin diseases, diabetes and anemia. The phytoconstituents present in the plant belongs to different class of compounds such as alkaloids, diterpenoids lactones, glycosides, steroids, phenol, aliphatic compounds and polysaccharides. AIM OF THE STUDY: The aim of present study was the isolation, structure elucidation, quantification and pharmacological evaluation of secondary metabolites from T. cordifolia for anticancer and immunomodulatory activities. MATERIALS AND METHODS: Different extracts and fractions were prepared from the stem of T. cordifolia. Pure molecules were isolated using normal phase chromatography and characterized on the basis of NMR and mass spectroscopic techniques. The anti-cancer and immunomodulatory activities of different extracts, fractions and isolated compounds were evaluated against four different human cancer cell lines, KB (human oral squamous carcinoma), CHOK-1 (hamster ovary), HT-29 (human colon cancer) and SiHa (human cervical cancer) and murine primary cells respectively. A simple, normal phase HPTLC method was also developed for the quantification of three bioactive compounds i.e N-formylannonain (1), 11-hydroxymustakone (5) and yangambin (8) in the stem of T. cordifolia hosted on fifteen different plants. RESULTS: Chromatographic purification of different fractions led to the isolation of eight pure molecules i.e N-formylannonain (1), magnoflorine (2), jatrorrhizine (3) palmatine (4), 11-hydroxymustakone (5), cordifolioside A (6), tinocordiside (7) and yangambin (8). All extracts and fractions were active against KB and CHOK 1 cells whereas among the pure molecules palmatine (4) was found to be active against KB and HT-29; tinocordiside (7) against KB and CHOK-1; yangambin (8) against KB cells however N-formylannonain (1) and 11-hydroxymustakone (5), was found active for immunomodulatory activity. HPTLC quantification of three active molecules i.e N-formylannonain (1), 11-hydroxymustakone (5), and yangambin (8) were found in highest quantity in the stem of T. cordifolia hosted on Mangifera indica, however, other two active molecules were not quantified due to their insufficient quantity. CONCLUSION: Eight compounds have been isolated and characterized belonging to different classes. The pharmacological evaluation of extract, fractions and pure molecules revealed the ethnomedicinal value of T. cordifolia for anticancer and immunomodulatory activities. PMID- 26253578 TI - Anti-allergic effect of alpha-cubebenoate isolated from Schisandra chinensis using in vivo and in vitro experiments. AB - AIM OF THE STUDY: In Oriental countries, the dried fruits of Schisandra chinensis are extensively used in traditional medicine to treat asthma, gonorrhea, and other diseases. Recently, alpha-cubebenoate was isolated as an anti-inflammatory component from Schisandra chinensis. In the present study, the authors examined the anti-allergic effect of alpha-cubebenoate using in vivo and in vitro experiments. MATERIALS AND METHODS: alpha-Cubebenoate was isolated from an extract of Schisandra chinensis fruits. Antigen-induced degranulation and Ca(2+) mobilization were measured in RBL-2H3 mast cells. In addition, BALB/c mice were sensitized with ovalbumin and aluminum hydroxide, and then challenged with ovalbumin for three consecutive days. alpha-Cubebenoate (1mg/kg) was administered intraperitoneally 30min before each ovalbumin challenge. RESULTS: In RBL-2H3 mast cells, alpha-cubebenoate inhibited antigen-induced degranulation and increase of intracellular Ca(2+) concentrations. In the ovalbumin-induced asthma model, alpha cubebenoate suppressed bronchiolar structural changes induced by ovalbumin challenge. Furthermore, alpha-cubebenoate strongly inhibited accumulations of eosinophils, macrophages, and lymphocytes in bronchoalveolar lavage fluid. alpha Cubebenoate also suppressed Th2 cytokines (IL-4 and IL-13) and TGF-beta1 in lung tissues and in immune cells at the mRNA and protein levels. CONCLUSION: alpha Cubebenoate has an inhibitory effect on allergic inflammation and could be utilized as an agent for the treatment of asthma. PMID- 26253579 TI - Ethnobotanical study of antilithic plants of Bhopal district. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Since urolithiasis is the third most common disease, found throughout the world, with a prevalence of 1-5% in Asia and two stone belts have been identified in India, one of which includes the study area, so an ethnobotanical study was conducted in and around the Bhopal district of Madhya Pradesh, India to investigate the range of plant species used in the treatment of urolithiasis. MATERIALS AND METHODS: Survey was undertaken in 75 villages of four directions of the Bhopal district and in the 3 herbal fairs that were organized in this area during the study period. Interviews were conducted with 304 people in whom 270 people were of villages in the four directions while 18 were traditional medicine dealers or Ayurveda consultants and 16 were knowable people. RESULTS: Total 67 plant species belonging to 40 families were encountered during the study. The most predominant families in terms of number of species were Asteraceae and Papilionaceae with 5 species each. In the four directions, the people of eastern direction were found to have maximum knowledge of antilithic plants, but the Ayurveda consultants and knowable people were found to have much more knowledge than all the general people of the villages. Nine plant species, namely, Citrullus lanatus Thunb.(Cucurbitaceae), Malva sylvestris L. (Malvaceae), Urginea indica (Roxb.) Kunth (Liliaceae), Bauhinia variegata L. (Caesalpiniaceae), Dolichos uniflorus L.(Papilionaceae), Psidium guajava L. (Myrtaceae), Calotropis procera (Ait.) R.Br. (Asclepiadaceae), Picrorhiza kurroa Royle ex Benth. (Plantaginaceae) and Piper longum L. (Piperaceae) was not found to be previously mentioned for the treatment of lithiasis. Boerhaavia diffusa L. was found to have the highest use value. On the basis of habit of these plants, herbs constituted 41.79% of the total plant species used. CONCLUSIONS: From this study, it can be concluded that complete ethnobotanical knowledge can be gained only when thorough literature survey along with field survey with respect to common man, traditional medicine dealers or Ayurveda consultants and knowable people has been extensively undertaken. This study will help in making the people aware about the selected plants or other suggested plants for use in lithiasis. PMID- 26253580 TI - Jodina rhombifolia leaves lyophilized aqueous extract decreases ethanol intake and preference in adolescent male Wistar rats. AB - The leaves of Jodina rhombifolia (Hook. & Arn.) Reissek (Santalaceae) are utilized as anti-alcoholic in Argentine folk medicine. This study was designed to investigate the anti-alcohol properties in adolescent male Wistar rats (postnatal day 29; 83-105 g of weight). We utilized the "self-administration model", which ethanol was offered in the standard home-cage through two-bottle free-choice regimen between an ethanolic solution (20% in tap water, v/v) and tap water with unlimited access for 24h per day for 10 consecutive days. The results obtained show that repeated administration of J. rhombifolia lyophilized extract, markedly reduced ethanol voluntary intake on dose dependent bases. The magnitude in reduction of daily ethanol intake was approximately 29%, 44% and 68%, for the rat groups treated with 62.5, 125 and 250 mg/kg of extract, respectively. Ethanol preference (proportion of ethanol intake versus total fluid intake) was significantly reduced: 21.37% +/- 0.79 (0 mg/kg); 15.83% +/- 0.93 (62.5 mg/kg); 15.22% +/- 1.30 (125 mg/kg) and 9.38% +/- 0.57 (250 mg/kg). Daily food intake was significantly higher (p<0.05) in the group treated with 250 mg/kg of JRLE in comparison with vehicle-dose group; the reduction in ethanol intake was associated with a compensatory increase in food intake, probably because in the control group animals a part of the total caloric intake was supplied by ethanol. Treatment was very well tolerated by all animals and without apparent side effects. These results contribute to the scientific validation of the antialcoholic indication of this botanic species in Argentine folk medicine. PMID- 26253581 TI - Underweight as a risk factor for respiratory death in the Whitehall cohort study: exploring reverse causality using a 45-year follow-up. AB - Underweight adults have higher rates of respiratory death than the normal weight but it is unclear whether this association is causal or reflects illness-induced weight loss (reverse causality). Evidence from a 45-year follow-up of underweight participants for respiratory mortality in the Whitehall study (N=18 823; 2139 respiratory deaths) suggests that excess risk among the underweight is attributable to reverse causality. The age-adjusted and smoking-adjusted risk was 1.55-fold (95% CI 1.32 to 1.83) higher among underweight compared with normal weight participants, but attenuated in a stepwise manner to 1.14 (95% CI 0.76 to 1.71) after serial exclusions of deaths during the first 5-35 years of follow-up (P(trend)<0.001). PMID- 26253582 TI - Procedural surgical skill assessment in laparoscopic training environments. AB - PURPOSE: This study aimed to identify detailed differences in laparoscopic surgical processes between expert and novice surgeons in a training environment and demonstrate that surgical process modeling can be used for such detailed analysis. METHODS: Eleven expert surgeons each of whom had performed [Formula: see text] laparoscopic procedures were compared with 10 young surgeons each of whom had performed [Formula: see text] laparoscopic procedures, and five medical students. Each examinee performed a specific skill assessment task. During tasks, instrument motion was monitored using a video capture system. From the video, the corresponding workflow was recorded by labeling the surgeons' activities according to a predefined terminology. Activities represented manual work steps performed during the task, described by a combination of a verb (representing the action), a tool, and the involved structure. The results were described as the number of occurrences (times), average duration (seconds), total duration (seconds), minimal duration (seconds), maximal duration (seconds), and occupancy percentage (%). RESULTS: The terminology for describing the processes of this task included 10 actions, six tools, four structures, and three events for each hand. There were 63 combinations of different possible activities; significant differences in 12 activities were observed between the expert and novice groups (young surgeons and medical students). The expert group performed the task with fewer occurrences and shorter duration than did the novice group in the left hand. CONCLUSIONS: We identified differences in surgical process between experts and novices in laparoscopic surgical simulation. Our proposed method would be useful for education and training in laparoscopic surgery. PMID- 26253583 TI - Molecular basis of resistance to macrolides, lincosamides and streptogramins in Staphylococcus hominis strains isolated from clinical specimens. AB - Coagulase-negative staphylococci (CoNS) are the most frequently isolated bacteria from the blood and the predominant cause of nosocomial infections. Macrolides, lincosamides and streptogramin B (MLSB) antibiotics, especially erythromycin and clindamycin, are important therapeutic agents in the treatment of methicillin resistant staphylococci infections. Among CoNS, Staphylococcus hominis represents the third most common organism. In spite of its clinical significance, very little is known about its mechanisms of resistance to antibiotics, especially MLSB. Fifty-five S. hominis isolates from the blood and the surgical wounds of hospitalized patients were studied. The erm(C) gene was predominant in erythromycin-resistant S. hominis isolates. The methylase genes, erm(A) and erm(B), were present in 15 and 25% of clinical isolates, respectively. A combination of various erythromycin resistance methylase (erm) genes was detected in 15% S. hominis isolates. The efflux gene msr(A) was detected in 18% of isolates, alone in four isolates, and in different combinations in a further six. The lnu(A) gene, responsible for enzymatic inactivation of lincosamides was carried by 31% of the isolates. No erythromycin resistance that could not be attributed to the genes erm(A), erm(B), erm(C) and msr(A) was detected. In S. hominis, 75 and 84%, respectively, were erythromycin resistant and clindamycin susceptible. Among erythromycin-resistant S. hominis isolates, 68% of these strains showed the inducible MLSB phenotype. Four isolates harbouring the msr(A) genes alone displayed the MSB phenotype. These studies indicated that resistance to MLSB in S. hominis is mostly based on the ribosomal target modification mechanism mediated by erm genes, mainly the erm(C), and enzymatic drug inactivation mediated by lnu(A). PMID- 26253584 TI - Health resource utilization associated with skeletal-related events: results from a retrospective European study. AB - BACKGROUND: Bone complications, also known as skeletal-related events (SREs), are common in patients with bone metastases secondary to advanced cancers. OBJECTIVE: To provide a detailed estimate of the health resource utilization (HRU) burden associated with SREs across eight European countries. METHODS: Eligible patients from centers in Austria, the Czech Republic, Finland, Greece, Poland, Portugal, Sweden, and Switzerland with bone metastases or lesions secondary to breast cancer, prostate, or lung cancer or multiple myeloma who had experienced at least one SRE (defined as radiation to bone, long-bone pathologic fracture, other bone pathologic fracture, surgery to bone or spinal cord compression) were entered into this study. HRU data were extracted retrospectively from the patients' charts from 3.5 months before the index SRE until 3 months after the index SRE (defined as an SRE preceded by an SRE-free period of at least 6.5 months). RESULTS: Overall, the mean number of inpatient stays per SRE increased from baseline by approximately 0.5-1.5 stays, with increases in the total duration of inpatient stays of approximately 6-37 days per event. All SREs were associated with substantial increases from baseline in the frequency of procedures and the number of outpatient and day-care visits. CONCLUSIONS: SREs are associated with substantial HRU owing to considerable increases in the number and duration of inpatient stays, and in the number of procedures, outpatient visits, and day-care visits. These data collectively provide a valuable summary of the real-world SRE burden on European healthcare systems. PMID- 26253585 TI - Circulatory support exceeding five years with a continuous-flow left ventricular assist device for advanced heart failure patients. AB - Continuous-flow left ventricular assist devices (CF-LVAD) are now providing years of safe circulatory support with enhanced quality of life. We present four cases of patients with advanced heart failure who received support for greater than 5 years with the HeartMate II CF-LVAD. One patient continues with support at 7.5 years and has decided to not undergo cardiac transplantation. Another patient has also had LVAD support for 7.7 years, initially with a pulsatile flow LVAD, and then was switched to the HeartMate II, which has continued to support him for the last 6.6 years. Two other patients have undergone heart transplant after support times of 5.46 years and 5.75 years. Few complications occurred and the patients had very active lifestyles during support. Explant analysis revealed very low bearing wear and minimal pannus. PMID- 26253586 TI - Management of anemia and iron deficiency in a cancer center in France. AB - PURPOSE: Anemia affects most patients treated for cancer by chemotherapy. It is a known major contributor to fatigue and loss of quality of life and is likely to have a negative effect on prognosis and mortality from cancer. The main purpose of this study was to characterize the management of anemia and iron deficiency in a French oncology day-care center. METHODS: A retrospective study was conducted between May and November 2012 in the oncology day unit of the Jean Godinot Cancer Center (France). The 133 patients included were all over the age of 18 and being treated by chemotherapy and had mild, moderate, or severe anemia. RESULTS: Over half (58%) the patients were shown to be receiving no specific treatment for anemia. Iron balance was assessed in 71 patients and iron deficiency diagnosed in 37. Stepwise logistic regression showed that patients with severe to moderate anemia were nearly four times more likely to have an iron balance assessment than those with mild anemia (OR, 3.78; 95% CI, 1.84-7.76; P = 0.0003). Classical logistic regression shows that older patients (>=70) are three times less likely to have an iron balance assessment than patients <70 years (OR, 0.32; 95% CI, 0.12-0.86; P = 0.06). CONCLUSION: An ideal medical setting for the management of anemia and iron deficiency, and the associated quality-of-life concerns, has yet to be defined for patients with cancer. Screening and treatment of mild to moderate anemia are inadequate, despite the advent of erythropoiesis-stimulating agents. Large scale, multicenter studies are required to define a clear medical framework for the management of anemia and iron deficiency. PMID- 26253587 TI - Factors associated with aggressive end of life cancer care. AB - BACKGROUND: Many patients with cancer experience aggressive care towards the end of life (EOL) despite evidence of an association with poor outcomes such as prolonged pain and overall dissatisfaction with care. PURPOSE: To investigate socio-demographic, clinical and community health care service factors associated with aggressive EOL cancer care. METHODS: An analysis of pooled data from two mortality follow-back surveys was performed. Aggressive EOL care was defined as greater than or equal to one of the following indicators occurring during the last 3 months of life: greater than or equal to two emergency department visits, >=30 days in hospital and death in hospital. RESULTS: Of the 681 included patients, 50.1% were men and mean age at death was 75 years. The majority of patients (59.3%, 95% confidence interval (CI) 55.6-63.0%) experienced at least one indicator of aggressive EOL care: 29.7% experienced greater than or equal to two ED visits, 17.1% spent >=30 days in hospital and 37.9% died in hospital. Patients with prostate or haematological cancer were more likely to experience aggressive EOL care (adjusted odds ratio (AOR) 4.36, 95% CI 1.39-13.70, and 4.16, 95% CI 1.38-12.47, respectively, reference group lung cancer). Patients who received greater than five general practitioner (GP) home visits (AOR 0.37, 95% CI 0.17-0.82, reference group no GP visits) or had contact with district nursing (AOR 0.48, 95% CI 0.28-0.83, reference group no contact) or contact with community palliative care services (AOR 0.27, 95% CI 0.15-0.49, reference group no contact) were less likely to experience aggressive EOL care. No association was found between aggressive EOL care and patients' age, gender, marital, financial or health status. CONCLUSIONS: Community health care services, in particular contact with community palliative care, are associated with a significant reduction in the odds of cancer patients receiving aggressive EOL care. Expansion of such services may help address the current capacity crises faced by many acute health care systems. PMID- 26253588 TI - Mapping CSF biomarker profiles onto NIA-AA guidelines for Alzheimer's disease. AB - The National Institute on Aging-Alzheimer's Association (NIA-AA) guidelines for Alzheimer's disease (AD) propose the categorization of individuals according to their biomarker constellation. Though the NIA-AA criteria for preclinical AD and AD dementia have already been applied in conjunction with imaging AD biomarkers, the application of the criteria using comprehensive cerebrospinal fluid (CSF) biomarker information has not been thoroughly studied yet. The study included a monocentric cohort with healthy (N = 41) and disease (N = 22) controls and patients with AD dementia (N = 119), and a multicentric sample with healthy controls (N = 116) and patients with AD dementia (N = 102). The CSF biomarkers beta-amyloid 1-42, total tau, and phosphorylated tau at threonine 181 were measured with commercially available assays. Biomarker values were trichotomized into positive for AD, negative, or borderline. In controls the presence of normal CSF profiles varied between 13.6 and 25.4 % across the studied groups, while up to 8.6 % of them had abnormal CSF biomarkers. In 40.3-52.9 % of patients with AD dementia, a typical CSF profile for AD was detected. Approximately 40 % of the potential biomarker constellations are not considered in the NIA-AA guidelines, and more than 40 % of participants could not be classified into the NIA-AA categories with distinct biomarker constellations. Here, a refined scheme covering all potential biomarker constellations is proposed. These results enrich the discussion on the NIA-AA guidelines and point to a discordance between clinical symptomatology and CSF biomarkers even in patients with full-blown AD dementia, who are supposed to have a clearly positive for AD neurochemical profile. PMID- 26253589 TI - [Current immunotherapy of multiple sclerosis]. AB - Following the introduction of interferon beta 1b as the first immunomodulatory therapy for multiple sclerosis (MS) in 1993, there are currently nine substances or substance classes approved for the treatment of MS (i.e. alemtuzumab, azathioprine, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta, mitoxantrone, natalizumab and teriflunomide). Major developments during the last 5 years include the approval of orally administered medications (i.e. fingolimod, teriflunomide and dimethyl fumarate), a monoclonal antibody (alemtuzumab), as well as glatiramer acetate with an administration frequency three times a week and a pegylated formulation of interferon beta 1a. The broadened therapeutic options enable a more differentiated and individualized therapy of MS; however, evidence-based data for therapeutic decision-making relevant in clinical practice are not always available. Rare but potentially severe and even life-threatening side effects of immunotherapies for MS require continuous pharmacovigilance and adherence to risk management plans. PMID- 26253590 TI - Assessment of physiological and biochemical responses, metal tolerance and accumulation in two eucalypt hybrid clones for phytoremediation of cadmium contaminated waters. AB - Eucalyptus is a promising species for ecological restoration but plant performances under environmental constraints need to be better investigated. In particular, the toxic effects of metals on this plant species are poorly described in the literature. In this work, morpho-physiological and biochemical responses to cadmium were analysed in two eucalypt genotypes (hybrid clones of Eucalyptus camaldulensis * Eucalyptus globulus ssp. bicostata J.B. Kirkp named Velino ex 7 and Viglio ex 358) exposed for 3 weeks to 50 MUM CdSO4 under hydroponics. The two eucalypt clones showed a different sensitivity to the metal. The growth reduction caused by cadmium was less than 30% in clone Velino and about 50% in clone Viglio. Cadmium mostly accumulated in plant roots and, to a lesser extent, in stem, as highlighted by the low translocation factor (Tf) measured in both clones. Net photosynthesis measurement, chlorophyll fluorescence images, transpiration values and chlorophyll content revealed a cadmium-induced impairment of physiological processes at the leaf level, which was more evident in clone Viglio. Metal binding and antioxidative compound content was differentially affected by cadmium exposure in the two eucalypt clones. Particularly, the content of thiols like cysteine and glutathione, organic acids like oxalate and citrate, and polyamines were markedly modulated in plant organs by metal treatment and highlighted different defence responses between the clones. Cadmium tolerance and accumulation ability of the eucalypt clones were evaluated and the potential of E. camaldulensis for the reclamation of metal polluted-waters is discussed. PMID- 26253591 TI - Platelet participation in the pathogenesis of dermonecrosis induced by Loxosceles gaucho venom. AB - Loxosceles gaucho spider venom induces in vitro platelet activation and marked thrombocytopenia in rabbits. Herein, we investigated the involvement of platelets in the development of the dermonecrosis induced by L. gaucho venom, using thrombocytopenic rabbits as a model. L. gaucho venom evoked a drop in platelet and neutrophil counts 4 h after venom injection. Ecchymotic areas at the site of venom inoculation were noticed as soon as 4 h in thrombocytopenic animals but not in animals with initial normal platelet counts. After 5 days, areas of scars in thrombocytopenic animals were also larger, evidencing the marked development of lesions in the condition of thrombocytopenia. Histologically, local hemorrhage, collagen fiber disorganization, and edema were more severe in thrombocytopenic animals. Leukocyte infiltration, predominantly due to polymorphonuclears, was observed in the presence or not of thrombocytopenia. Thrombus formation was demonstrated by immunohistochemistry at the microvasculature, and it occurred even under marked thrombocytopenia. Taken together, platelets have an important role in minimizing not only the hemorrhagic phenomena but also the inflammatory and wound-healing processes, suggesting that cutaneous loxoscelism may be aggravated under thrombocytopenic conditions. PMID- 26253593 TI - Semantic priming increases word frequency judgments: Evidence for the role of memory strength in frequency estimation. AB - Previous research has demonstrated a systematic, nonlinear relationship between word frequency judgments and values from word frequency norms. This relationship could reflect a perceptual process similar to that found in the psychophysics literature for a variety of sensory phenomena. Alternatively, it could reflect memory strength differences that are expected for words of varying levels of prior exposure. Two experiments tested the memory strength explanation by semantically priming words prior to frequency judgments. Exposure to related word meanings produced a small but measurable increase in target word frequency ratings. Repetition but not semantic priming had a greater impact on low compared to high frequency words. These findings are consistent with a memory strength view of frequency judgments that assumes a distributed network with lexical and semantic levels of representation. PMID- 26253592 TI - Identification and functional characterization of the BBX24 promoter and gene from chrysanthemum in Arabidopsis. AB - The B-box (BBX) family is a subgroup of zinc finger transcription factors that regulate flowering time, light-regulated morphogenesis, and abiotic stress in Arabidopsis. Overexpression of CmBBX24, a zinc finger transcription factor gene in chrysanthemum, results in abiotic stress tolerance. We have investigated and characterized the promoter of CmBBX24, isolating a 2.7-kb CmBBX24 promoter sequence and annotating a number of abiotic stress-related cis-regulatory elements, such as DRE, MYB, MYC, as well as cis-elements which respond to plant hormones, such as GARE, ABRE, and CARE. We also observed a number of cis-elements related to light, such as TBOX and GBOX, and some tissue-specific cis-elements, such as those for guard cells (TAAAG). Expression of the CmBBX24 promoter produced a clear response in leaves and a lower response in roots, based on beta glucuronidase histochemical staining and fluorometric analysis. The CmBBX24 promoter was induced by abiotic stresses (mannitol, cold temperature), hormones (gibberellic acid, abscisic acid), and different light treatments (white, blue, red); activation was measured by fluorometric analysis in the leaves and roots. The deletion of fragments from the 5'-end of the promoter led to different responses under various stress conditions. Some CmBBX24 promoter segments were found to be more important than others for regulating all stresses, while other segments were relatively more specific to stress type. D0-, D1-, D2-, D3-, and D4 proCmBBX24::CmBBX24 transgenic Arabidopsis lines developed for further study were found to be more tolerant to the low temperature and drought stresses than the controls. We therefore speculate that CmBBX24 is of prime importance in the regulation of abiotic stress in Arabidopsis and that the CmBBX24 promoter is inductive in abiotic stress conditions. Consequently, we suggest that CmBBX24 is a potential candidate for the use in breeding programs of important ornamental plants. PMID- 26253594 TI - A new look on S-R associations: How S and R link. AB - Humans can learn associations between stimuli and responses which allow for faster, more efficient behavior when the same response is required to the same stimulus in the future. This is called stimulus-response (S-R) priming. Perceptual representations are known to be modular and hierarchical, i.e. different brain areas represent different perceptual features and higher brain areas represent increasingly abstract properties of the stimulus. In this study we investigated how perceptually specific the stimulus in S-R priming is. In particular we wanted to test whether basic visual features play a role in the S-R associations. We used a novel stimulus: images of objects built from basic visual features. Participants performed a classification task on the objects. We found no significant effect on reaction times of switching vs. repeating perceptual features between presentations of the same object. This suggests that S-R associations involve a perceptually non-specific stimulus representation. PMID- 26253595 TI - Eyes keep watch over you! Competition enhances joint attention in females. AB - The present study investigated if the gaze-cuing effect (i.e., the tendency for observers to respond faster to targets in locations that were cued by others' gaze direction than to not-cued targets) is modulated by the type of relationship (i.e., cooperative or competitive) established during a previous interaction with a cuing face. In two experiments, participants played a series of single-shot games of a modified version of the two-choice Prisoner's Dilemma against eight simulated contenders. They were shown a fictive feedback indicating if the opponents chose to cooperate or compete with them. Opponents' faces were then used as stimuli in a standard gaze-cuing task. In Experiment 1 females classified as average in competitiveness were tested, while in Experiment 2 females classified as high and low in competitiveness were tested. We found that only in females classified as low and average in competitiveness the gaze-cuing effect for competitive contenders was greater than for cooperative contenders. These findings suggest that competitive opponents represent a relevant source of information within the social environment and female observers with low and average levels of competition cannot prevent from keeping their eyes over them. PMID- 26253597 TI - Epileptogenesis after traumatic brain injury in Plau-deficient mice. AB - Several components of the urokinase-type plasminogen activator receptor (uPAR) interactome, including uPAR and its ligand sushi-repeat protein 2, X-linked (SRPX2), are linked to susceptibility to epileptogenesis in animal models and/or humans. Recent evidence indicates that urokinase-type plasminogen activator (uPA), a uPAR ligand with focal proteinase activity in the extracellular matrix, contributes to recovery-enhancing brain plasticity after various epileptogenic insults such as traumatic brain injury (TBI) and status epilepticus. Here, we examined whether deficiency of the uPA-encoding gene Plau augments epileptogenesis after TBI. Traumatic brain injury was induced by controlled cortical impact in the somatosensory cortex of adult male wild-type and Plau deficient mice. Development of epilepsy and seizure susceptibility were assessed with a 3-week continuous video-electroencephalography monitoring and a pentylenetetrazol test, respectively. Traumatic brain injury-induced cortical or hippocampal pathology did not differ between genotypes. The pentylenetetrazol test revealed increased seizure susceptibility after TBI (p<0.05) in injured mice. Epileptogenesis was not exacerbated, however, in Plau-deficient mice. Taken together, Plau deficiency did not worsen controlled cortical impact-induced brain pathology or epileptogenesis caused by TBI when assessed at chronic timepoints. These data expand previous observations on Plau deficiency in models of status epilepticus and suggest that inhibition of focal extracellular proteinase activity resulting from uPA-uPAR interactions does not modify epileptogenesis after TBI. PMID- 26253598 TI - Perceptions of epilepsy among first-year medical students at Mulago Hospital in Kampala, Uganda. AB - Epilepsy is associated with stigma throughout the world, which leads to poor treatment of people with epilepsy (PWE). In Uganda, there are more than 75,000 PWE and a large treatment gap. This study evaluated the knowledge, attitudes, and practices regarding epilepsy among first-year medical students at Mulago Hospital. A 22-question survey was developed based on the previous studies of Birbeck et al.'s regarding the stigma of epilepsy in Zambia. This was administered to first-year medical students (96 respondents) at Mulago Hospital in Uganda. More than 80% said that they would not allow their children to marry PWE. Most respondents believed that epilepsy was a mental illness, and many believed that PWE cannot have normal intelligence. Students reported that there was a negative perception and negative treatment of PWE in the community. Some students believed that epilepsy was caused by supernatural causes and was contagious. These misperceptions must be identified and corrected among medical students and other healthcare providers to allow for fair treatment of PWE; this should be incorporated into medical school curriculums in Uganda. PMID- 26253596 TI - Explicit Time Deficit in Schizophrenia: Systematic Review and Meta-Analysis Indicate It Is Primary and Not Domain Specific. AB - Although timing deficits are a robust finding in schizophrenia (SZ), the notion of a genuine time perception disorder in SZ is still being debated because distortions in timing might depend on neuropsychological deficits that are characteristics of the illness. Here we used meta-analytic methods to summarize the evidence of timing deficits in SZ and moderator analyses to determine whether defective timing in SZ arises from nontemporal sources or from defective time perception. PubMed Services, PsycNET, and Scopus were searched through March 2015, and all references in articles were investigated to find other relevant studies. Studies were selected if they included subjects with a primary diagnosis of SZ compared to a healthy control (HC) group and if they reported behavioral measures of duration estimation (perceptual and motor explicit timing). Data from 24 studies published from 1956 to 2015, which comprised 747 SZ individuals and 808 HC, were included. Results indicate that SZ individuals are less accurate than HC in estimating time duration across a wide range of tasks. Subgroup analyses showed that the fundamental timing deficit in SZ is independent from the length of the to-be-timed duration (automatic and cognitively controlled timing) and from methods of stimuli estimation (perceptual and motor timing). Thus, time perception per se is disturbed in SZ (not just task-specific timing processes) and this perturbation is independent from more generalized cognitive impairments. Behavioral evidence of disturbed automatic timing should be more thoroughly investigated with the aim of defining it as a cognitive phenotype for more homogeneous diagnostic subgrouping. PMID- 26253599 TI - Complex syntax in the isolated right hemisphere: Receptive grammatical abilities after cerebral hemispherectomy. AB - OBJECTIVES: In this study, we explored the syntactic competence of the right hemisphere (RH) after left cerebral hemispherectomy, on the premise that it (syntactic competence) is known to be one of the most strongly left-lateralized language functions. As basic syntactic development for individuals in this subject pool has already been extensively explored, we focused instead on the investigation of complex syntactic constructions that are normally acquired later in childhood, i.e., between 7 and 9years of age. METHODS: Grammatical competence in 10 participants who had undergone left cerebral hemispherectomy was compared to that of a group of normally developing children, with the two groups matched by the size of their vocabulary. The two tests we used for this research were created by the 1st language acquisition linguists and were designed to test sets of constructions categorized and differentiated by the order in which they are normally acquired and by the type of grammatical competence that they involve. RESULTS: We found that both groups followed the same developmental sequence of syntactic development with five (50%) postsurgical participants (all with prenatal etiologies) reaching nearly mature command of sentence grammar. Seizures negatively impacted performance on all tests. CONCLUSIONS: The isolated RH has the potential to support the complex grammatical categories that emerge relatively late in the normal acquisition of English by native speakers. Successful performance may be related to the timing of the initial insult and seizure control following hemispherectomy. PMID- 26253600 TI - Timeframe of speciation inferred from secondary contact zones in the European tree frog radiation (Hyla arborea group). AB - BACKGROUND: Hybridization between incipient species is expected to become progressively limited as their genetic divergence increases and reproductive isolation proceeds. Amphibian radiations and their secondary contact zones are useful models to infer the timeframes of speciation, but empirical data from natural systems remains extremely scarce. Here we follow this approach in the European radiation of tree frogs (Hyla arborea group). We investigated a natural hybrid zone between two lineages (Hyla arborea and Hyla orientalis) of Mio Pliocene divergence (~5 My) for comparison with other hybrid systems from this group. RESULTS: We found concordant geographic distributions of nuclear and mitochondrial gene pools, and replicated narrow transitions (~30 km) across two independent transects, indicating an advanced state of reproductive isolation and potential local barriers to dispersal. This result parallels the situation between H. arborea and H. intermedia, which share the same amount of divergence with H. orientalis. In contrast, younger lineages show much stronger admixture at secondary contacts. CONCLUSIONS: Our findings corroborate the negative relationship between hybridizability and divergence time in European tree frogs, where 5 My are necessary to achieve almost complete reproductive isolation. Speciation seems to progress homogeneously in this radiation, and might thus be driven by gradual genome-wide changes rather than single speciation genes. However, the timescale differs greatly from that of other well-studied amphibians. General assumptions on the time necessary for speciation based on evidence from unrelated taxa may thus be unreliable. In contrast, comparative hybrid zone analyses within single radiations such as our case study are useful to appreciate the advance of speciation in space and time. PMID- 26253601 TI - Biomechanical Comparison of Volar Fixed-Angle Locking Plates for AO C3 Distal Radius Fractures: Titanium Versus Stainless Steel With Compression. AB - PURPOSE: To determine biomechanical differences between a fixed-angle locking volar titanium plate (VariAx; Stryker, Kalamazoo, MI) and a fixed-angle compression locking volar stainless steel plate (CoverLoc Volar Plate; Tornier, Amsterdam, Netherlands) in the fixation of simulated AO C3 distal radius fractures. METHODS: Eighteen cadaveric upper extremities (9 matched pairs) with an average age of 54 years were tested. A 4-part AO C3 fracture pattern was created in each specimen. The fractures were reduced under direct vision and fixed with either the fixed-angle locking volar titanium plate or the fixed-angle compression locking volar stainless steel plate. Motion tracking analysis was then performed while the specimens underwent cyclic loading. Changes in displacement, rotation, load to failure, and mode of failure were recorded. RESULTS: The fragments, when secured with the fixed-angle compression locking stainless steel construct, demonstrated less displacement and rotation than the fragments secured with the fixed-angle locking titanium plate under physiological loading conditions. In the fixed-angle compression locking stainless steel group, aggregate displacement and rotation of fracture fragments were 5 mm and 3 degrees less, respectively, than those for the fixed-angle locking titanium group. The differences between axial loads at mechanical failure and stiffness were not statistically significant. The compression locking stainless steel group showed no trend in mode of failure, and the locking titanium plate group failed most often by articular fixation failure (5 of 9 specimens). CONCLUSIONS: The fixed angle compression locking stainless steel volar plate may result in less displacement and rotation of fracture fragments in the fixation of AO C3 distal radius fractures than fixation by the fixed-angle locking volar titanium plate. However, there were no differences between the plates in mechanical load to failure and stiffness. CLINICAL RELEVANCE: Fixation of distal radius AO C3 fracture patterns with the fixed-angle compression locking stainless steel plate may provide improved stability of fracture fragments. PMID- 26253602 TI - Reconstruction of First Web Space Contractures. PMID- 26253603 TI - Aneurysmal Bone Cysts of the Hand, Wrist, and Forearm. AB - PURPOSE: To determine the outcomes of surgical management of aneurysmal bone cysts (ABCs) in the hand, wrist, and forearm. METHODS: The medical records of 11 patients undergoing surgical treatment of ABCs distal to the elbow from 1994 to 2011 with at least 12 months follow-up were reviewed retrospectively. Mean follow up was 29 months (range, 13-56 months). There were 7 males and 4 females. Four lesions presented in the radius, 3 in the ulna, 2 in the metacarpals, and 2 in the phalanges. RESULTS: Ten patients underwent wide unroofing and intralesional curettage with 9 undergoing associated high-speed burring. Multiple chemical and thermal adjuvants were used. One patient underwent en bloc resection with reconstruction. There was 1 recurrence in a periphyseal lesion in a 2-year-old boy treated with curettage, burring, and adjuvant chemotherapy. Ten patients incorporated the bone graft and healed without further surgery. One patient required revision bone grafting. CONCLUSIONS: The diagnosis of ABC should remain in the differential diagnosis for cystic lesions in the upper extremity in pediatric and adult patients. Low recurrence has been obtained predominantly with intralesional curettage and high-speed burring with and without chemical and thermal adjuvant therapy. Appropriate healing has been obtained with both allograft and autograft reconstructions. Periarticular and periphyseal lesions remain challenging and provide the highest chance for incomplete resection and recurrence. Follow-up with plain radiographs did not lead to any delay in diagnosis of recurrence in any case. PMID- 26253604 TI - Hand Sensibility, Strength, and Laxity of High-Level Musicians Compared to Nonmusicians. AB - PURPOSE: To determine whether musicians have more sensitive, stronger, and flexible hands than nonmusicians. METHODS: A total of 100 musicians and 100 control subjects were assessed for 2-point discrimination, Semmes-Weinstein monofilament light touch, grip and pinch strength, and laxity. Musicians were included if enrolled as instrumental performance majors at a 4-year accredited conservatory of music. Nonmusician controls were university students who never or rarely engaged in playing an instrument. All subjects were between the ages of 18 and 28. The exclusion criterion was history of any hand condition, trauma, surgery, or diabetes. Statistical analyses were carried out using the t test, analysis of variance, and correlation coefficients as appropriate. RESULTS: High level musicians in our cohort showed the same handedness (dominance) as the general population. The musicians were weaker than the nonmusicians. Male musicians were significantly weaker in pinch and grip bilaterally than nonmusicians, whereas female musicians were significantly weaker only in grip on the right/dominant side. Two-point discrimination was significantly less in musicians for the left/nondominant index, ring, and small fingers, and the right/dominant small and dominant index finger. Semmes-Weinstein testing was significantly better for the right/dominant digits, including the thumb, but not the left digits with the exception of the ring and nondominant middle and ring. There was no difference in laxity between the 2 groups. CONCLUSIONS: High-level musicians have, in general, more sensitive but weaker hands than nonmusicians, but the differences seem small and may not be clinically important. PMID- 26253605 TI - Stepwise acquirement of hallmark neuropathology in FUS-ALS iPSC models depends on mutation type and neuronal aging. AB - Autosomal-dominant mutations within the gene FUS (fused in sarcoma) are responsible for 5% of familial cases of amyotrophic lateral sclerosis (ALS). The FUS protein is physiologically mainly located in the nucleus, while cytoplasmic FUS aggregates are pathological hallmarks of FUS-ALS. Data from non-neuronal cell models and/or models using heterologous expression of FUS mutants suggest cytoplasmic FUS translocation as a pivotal initial event which leads to neurodegeneration depending on a second hit. Here we present the first human model of FUS-ALS using patient-derived neurons carrying endogenous FUS mutations leading to a benign (R521C) or a more severe clinical phenotype (frameshift mutation R495QfsX527). We thereby showed that the severity of the underlying FUS mutation determines the amount of cytoplasmic FUS accumulation and cellular vulnerability to exogenous stress. Cytoplasmic FUS inclusions formed spontaneously depending on both, severity of FUS mutation and neuronal aging. These aggregates showed typical characteristics of FUS-ALS including methylated FUS. Finally, neurodegeneration was not specific to layer V cortical neurons perfectly in line with the current model of disease spreading in ALS. Our study highlights the value and usefulness of patient-derived cell models in FUS-ALS. PMID- 26253606 TI - Cortical neuroprosthetics from a clinical perspective. AB - Recent pilot clinical studies have demonstrated that subjects with severe disorders of movement and communication can exert direct neural control over assistive devices using invasive Brain-Machine Interface (BMI) technology, also referred to as 'cortical neuroprosthetics'. These important proof-of-principle studies have generated great interest among those with disability and clinicians who provide general medical, neurological and/or rehabilitative care. Taking into account the perspective of providers who may be unfamiliar with the field, we first review the clinical goals and fundamentals of invasive BMI technology, and then briefly summarize the vast body of basic science research demonstrating its feasibility. We emphasize recent translational progress in the target clinical populations and discuss translational challenges and future directions. PMID- 26253607 TI - Accumulation of amyloid-beta in the cerebellar cortex of essential tremor patients. AB - The accumulation of insoluble amyloid-beta (Abeta) peptides is associated with neurodegenerative disorders, such as Alzheimer's disease (AD). As essential tremor (ET) could involve neurodegenerative processes in the cerebellum, we quantified soluble and insoluble Abeta in cerebellar cortices from patients diagnosed with ET (n=9), compared to Controls (n=16) or individuals with Parkinson's disease (n=10). Although ante-mortem cognitive performance was not documented, all individuals included had the diagnosis of AD ruled out by a neuropathologist. ELISA-determined concentrations of insoluble Abeta42 in ET patients displayed a bimodal distribution, with a median 246-fold higher than in Controls (P<0.01, Kruskal-Wallis). Higher Abeta42 concentrations were measured in the parietal cortex of the same ET patients, compared to Controls (107-fold median increase, P<0.01, Kruskal-Wallis), but similar phosphorylated tau levels were detected. The rise in cerebellar insoluble Abeta42 concentrations is not associated to APP expression and processing or the ApoE4 status. However, Abeta42 levels in ET individuals were correlated with cerebellar insoluble phosphorylated tau (r(2)=0.71, P=0.005), unphosphorylated neurofilament heavy chain (NF-H; r(2)=0.50, P=0.030) and Lingo-1 (r(2)=0.73, P=0.007), indicative of a generalized neurodegenerative process involving the cerebellum. Our results suggest prevalent accumulations of insoluble Abeta42 in the cerebellum of ET, but not in age matched PD. Whether this anomaly plays a role in ET symptoms warrants further investigations. PMID- 26253608 TI - Optimizing oxygenation and intubation conditions during awake fibre-optic intubation using a high-flow nasal oxygen-delivery system. AB - BACKGROUND: Awake fibre-optic intubation is a widely practised technique for anticipated difficult airway management. Despite the administration of supplemental oxygen during the procedure, patients are still at risk of hypoxia because of the effects of sedation, local anaesthesia, procedural complications, and the presence of co-morbidities. Traditionally used oxygen-delivery devices are low flow, and most do not have a sufficient reservoir or allow adequate fresh gas flow to meet the patient's peak inspiratory flow rate, nor provide an adequate fractional inspired oxygen concentration to prevent desaturation should complications arise. METHODS: A prospective observational study was conducted using a high-flow humidified transnasal oxygen-delivery system during awake fibre optic intubation in 50 patients with anticipated difficult airways. RESULTS: There were no episodes of desaturation or hypercapnia using the high-flow system, and in all patients the oxygen saturation improved above baseline values, despite one instance of apnoea resulting from over-sedation. All patients reported a comfortable experience using the device. CONCLUSIONS: The high-flow nasal oxygen delivery system improves oxygenation saturation, decreases the risk of desaturation during the procedure, and potentially, optimizes conditions for awake fibre-optic intubation. The soft nasal cannulae uniquely allow continuous oxygenation and simultaneous passage of the fibrescope and tracheal tube. The safety of the procedure may be increased, because any obstruction, hypoventilation, or periods of apnoea that may arise may be tolerated for longer, allowing more time to achieve ventilation in an optimally oxygenated patient. PMID- 26253609 TI - c-Kit Receptor Signaling Regulates Islet Vasculature, beta-Cell Survival, and Function In Vivo. AB - The receptor tyrosine kinase c-Kit plays an integral role in maintaining beta cell mass and function. Although c-Kit receptor signaling promotes angiogenesis in multiple cell types, its role in islet vasculature is unknown. This study examines the effects of c-Kit-mediated vascular endothelial growth factor isoform A (VEGF-A) and islet vascularization on beta-cell function and survival using in vitro cell culture and in vivo mouse models. In cultured INS-1 cells and primary islets, c-Kit regulates VEGF-A expression via the Akt/mammalian target of rapamycin (mTOR) signaling pathway. Juvenile mice with mutated c-Kit (c Kit(Wv/+)) showed impaired islet vasculature and beta-cell dysfunction, while restoring c-Kit expression in beta-cells of c-Kit(Wv/+) mice rescued islet vascular defects through modulation of the Akt/mTOR/VEGF-A pathway, indicating that c-Kit signaling in beta-cells is a required regulator for maintaining normal islet vasculature. Furthermore, beta-cell-specific c-Kit overexpression (c KitbetaTg) in aged mice showed significantly increased islet vasculature and beta cell function, but, when exposed to a long-term high-fat diet, c-Kit signaling in c-KitbetaTg mice induced substantial vascular remodeling, which resulted in increased islet inflammatory responses and beta-cell apoptosis. These results suggest that c-Kit-mediated VEGF-A action in beta-cells plays a pivotal role in maintaining islet vascularization and function. PMID- 26253610 TI - Sex Differences in the Association Between Birth Weight and Adult Type 2 Diabetes. AB - Low birth weight is a well-established risk factor for type 2 diabetes, but the risk at high birth weight levels remains uncertain. Potential sex differences in the associations are unexplored. We investigated whether sex influences the association of birth weight and adult type 2 diabetes, using a cohort of 113,801 men and 109,298 women, born 1936-1983, from the Copenhagen School Health Records Register, Denmark. During 5.6 million person-years of follow-up, 7,750 men and 4,736 women had a diagnosis of adult type 2 diabetes (30 years of age or older) obtained from national registers. When birth weights between 3.251 and 3.750 kg were used as the reference group for each sex separately, women with birth weights in the categories of 2.000 to 2.750 kg and 4.751 to 5.500 kg had hazard ratios [HRs] of type 2 diabetes of 1.46 (95% CI, 1.34-1.59) and 1.56 (1.20-2.04), respectively, whereas men had HRs of 1.20 (1.12-1.30) and 0.93 (0.76-1.15). Thus, sex modified the association, with stronger risk estimates of type 2 diabetes in women at both low and high birth weights compared with men (P = 0.001). In conclusion, birth weight is more strongly associated with type 2 diabetes in women than in men. Future search for sex-specific causal mechanisms may provide new insights into the early origins of type 2 diabetes. PMID- 26253611 TI - Ceramide-Initiated Protein Phosphatase 2A Activation Contributes to Arterial Dysfunction In Vivo. AB - Prior studies have implicated accumulation of ceramide in blood vessels as a basis for vascular dysfunction in diet-induced obesity via a mechanism involving type 2 protein phosphatase (PP2A) dephosphorylation of endothelial nitric oxide synthase (eNOS). The current study sought to elucidate the mechanisms linking ceramide accumulation with PP2A activation and determine whether pharmacological inhibition of PP2A in vivo normalizes obesity-associated vascular dysfunction and limits the severity of hypertension. We show in endothelial cells that ceramide associates with the inhibitor 2 of PP2A (I2PP2A) in the cytosol, which disrupts the association of I2PP2A with PP2A leading to its translocation to the plasma membrane. The increased association between PP2A and eNOS at the plasma membrane promotes dissociation of an Akt-Hsp90-eNOS complex that is required for eNOS phosphorylation and activation. A novel small-molecule inhibitor of PP2A attenuated PP2A activation, prevented disruption of the Akt-Hsp90-eNOS complex in the vasculature, preserved arterial function, and maintained normal blood pressure in obese mice. These findings reveal a novel mechanism whereby ceramide initiates PP2A colocalization with eNOS and demonstrate that PP2A activation precipitates vascular dysfunction in diet-induced obesity. Therapeutic strategies targeted to reducing PP2A activation might be beneficial in attenuating vascular complications that exist in the context of type 2 diabetes, obesity, and conditions associated with insulin resistance. PMID- 26253612 TI - Genetic Predisposition to Weight Loss and Regain With Lifestyle Intervention: Analyses From the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials. AB - Clinically relevant weight loss is achievable through lifestyle modification, but unintentional weight regain is common. We investigated whether recently discovered genetic variants affect weight loss and/or weight regain during behavioral intervention. Participants at high-risk of type 2 diabetes (Diabetes Prevention Program [DPP]; N = 917/907 intervention/comparison) or with type 2 diabetes (Look AHEAD [Action for Health in Diabetes]; N = 2,014/1,892 intervention/comparison) were from two parallel arm (lifestyle vs. comparison) randomized controlled trials. The associations of 91 established obesity predisposing loci with weight loss across 4 years and with weight regain across years 2-4 after a minimum of 3% weight loss were tested. Each copy of the minor G allele of MTIF3 rs1885988 was consistently associated with greater weight loss following lifestyle intervention over 4 years across the DPP and Look AHEAD. No such effect was observed across comparison arms, leading to a nominally significant single nucleotide polymorphism*treatment interaction (P = 4.3 * 10( 3)). However, this effect was not significant at a study-wise significance level (Bonferroni threshold P < 5.8 * 10(-4)). Most obesity-predisposing gene variants were not associated with weight loss or regain within the DPP and Look AHEAD trials, directly or via interactions with lifestyle. PMID- 26253614 TI - Defective Natriuretic Peptide Receptor Signaling in Skeletal Muscle Links Obesity to Type 2 Diabetes. AB - Circulating natriuretic peptide (NP) levels are reduced in obesity and predict the risk of type 2 diabetes (T2D). Since skeletal muscle was recently shown as a key target tissue of NP, we aimed to investigate muscle NP receptor (NPR) expression in the context of obesity and T2D. Muscle NPRA correlated positively with whole-body insulin sensitivity in humans and was strikingly downregulated in obese subjects and recovered in response to diet-induced weight loss. In addition, muscle NP clearance receptor (NPRC) increased in individuals with impaired glucose tolerance and T2D. Similar results were found in obese diabetic mice. Although no acute effect of brain NP (BNP) on insulin sensitivity was observed in lean mice, chronic BNP infusion improved blood glucose control and insulin sensitivity in skeletal muscle of obese and diabetic mice. This occurred in parallel with a reduced lipotoxic pressure in skeletal muscle due to an upregulation of lipid oxidative capacity. In addition, chronic NP treatment in human primary myotubes increased lipid oxidation in a PGC1alpha-dependent manner and reduced palmitate-induced lipotoxicity. Collectively, our data show that activation of NPRA signaling in skeletal muscle is important for the maintenance of long-term insulin sensitivity and has the potential to treat obesity-related metabolic disorders. PMID- 26253613 TI - RAGE Suppresses ABCG1-Mediated Macrophage Cholesterol Efflux in Diabetes. AB - Diabetes exacerbates cardiovascular disease, at least in part through suppression of macrophage cholesterol efflux and levels of the cholesterol transporters ATP binding cassette transporter A1 (ABCA1) and ABCG1. The receptor for advanced glycation end products (RAGE) is highly expressed in human and murine diabetic atherosclerotic plaques, particularly in macrophages. We tested the hypothesis that RAGE suppresses macrophage cholesterol efflux and probed the mechanisms by which RAGE downregulates ABCA1 and ABCG1. Macrophage cholesterol efflux to apolipoprotein A1 and HDL and reverse cholesterol transport to plasma, liver, and feces were reduced in diabetic macrophages through RAGE. In vitro, RAGE ligands suppressed ABCG1 and ABCA1 promoter luciferase activity and transcription of ABCG1 and ABCA1 through peroxisome proliferator-activated receptor-gamma (PPARG) responsive promoter elements but not through liver X receptor elements. Plasma levels of HDL were reduced in diabetic mice in a RAGE-dependent manner. Laser capture microdissected CD68(+) macrophages from atherosclerotic plaques of Ldlr( /-) mice devoid of Ager (RAGE) displayed higher levels of Abca1, Abcg1, and Pparg mRNA transcripts versus Ager-expressing Ldlr(-/-) mice independently of glycemia or plasma levels of total cholesterol and triglycerides. Antagonism of RAGE may fill an important therapeutic gap in the treatment of diabetic macrovascular complications. PMID- 26253615 TI - Nicotine Dependence in Adolescence and Physical Health Symptoms in Early Adulthood. AB - INTRODUCTION: To examine the prospective associations of Diagnostic and Statistical Manual of Mental Disorders nicotine dependence (ND) and other individual and parental factors in adolescence on self-reported health symptoms in early adulthood. METHODS: Multiethnic prospective longitudinal cohort of adolescents from grades 6-10 and a parent (N = 908) from the Chicago Public Schools. Adolescents were interviewed five times at 6-month intervals (Waves 1-5) and once 4.5 years later (Wave 6). Parents were interviewed annually three times (W1, W3, W5). Multivariate regressions estimated prospective associations of Diagnostic and Statistical Manual of Mental Disorders ND, other individual and familial risk factors in adolescence (mean age 16.6) on physical health symptoms in early adulthood (mean age 21.3), controlling for health symptoms in adolescence. RESULTS: Levels of health symptoms declined from adolescence to early adulthood, except among dependent smokers. Nicotine dependent adolescents reported more health symptoms as young adults than nonsmokers and nondependent smokers, especially if depressed. ND and health symptoms in adolescence were the strongest predictors of health in early adulthood. These two adolescent factors, depression, and the familial factors of parental ND, depression and health conditions, each independently predicted health symptoms in young adulthood. Females reported more symptoms than males. CONCLUSIONS: There is continuity of health status over time. ND, depression, and parental factors in adolescence contribute to poor health in early adulthood. The findings highlight not only the role of adolescent behavior, but the importance of the family in the development of young adult health. Reducing smoking, particularly ND, and depression among adolescents and parents will decrease physical health burden. PMID- 26253616 TI - Associations of Proposed Relative-Risk Warning Labels for Snus With Perceptions and Behavioral Intentions Among Tobacco Users and Nonusers. AB - INTRODUCTION: The US Food and Drug Administration can require changes in warning statements for modified risk tobacco products. We report an independent analysis of a consumer perception survey sponsored by Swedish Match as part of a Modified Risk Tobacco Product application to change warning labels for Swedish snus products. METHODS: The survey exposed each of 4324 daily exclusive cigarette smokers, 1033 daily smokeless tobacco users, 1205 daily other tobacco users, 726 former users, and 5915 triers/never users to one of four current warnings and two proposed relative-risk labels (No tobacco product is safe, but this product presents lower risks to health than cigarettes, or No tobacco product is safe, but this product presents substantially lower risks to health than cigarettes) for snus. Descriptive and logistic regression analyses examined four outcomes: believability, harmfulness, motivation to use, and intention to buy snus. RESULTS: Compared with the current not-safe-alternative warning, adult tobacco users who viewed the proposed labels perceived them as less believable, perceived snus as less harmful and were more likely to use and buy snus. The proposed labels had no impact on former smokers' likelihood to use and buy snus; triers/never users viewing the substantially lower risk label were more likely to buy snus. CONCLUSIONS: Tobacco users viewing the proposed labels perceived snus as less harmful than cigarettes and may be more likely to use and buy snus. If labeling changes lead to increased snus use and cigarette reduction or abstinence, public health may benefit. If the opposite occurs, public health could suffer. PMID- 26253617 TI - Enlisting "Aunties" to Support Indigenous Pregnant Women to Stop Smoking: Feasibility Study Results. AB - INTRODUCTION: Smoking during pregnancy increases the risk of many pregnancy and birth complications. New Zealand's smoking cessation programmes rely on the smoker to take action and are embedded within New Zealand's health care. This article describes the smoking behavior outcomes of a feasibility project testing a proactive approach, utilizing Maori voluntary community health workers to identify and reach Maori pregnant women who smoke and provide cessation support. METHODS: Women, who smoked while pregnant, were identified and recruited by "Aunties" and cessation support was provided. Baseline and follow-up interviews were conducted. Outcome measures included smoking status, cigarettes smoked per day, time until first cigarette, cessation attempts during pregnancy, household smoking, and smoking inside the home or car. Simple descriptive statistics were produced and simple proportions reported. RESULTS: The majority of women were Maori, 20-30 years old, had their first cigarette within 30 minutes of waking and 58% had not tried to quit during the current pregnancy. Of the participants who completed a follow-up interview 33% had stopped smoking while they were pregnant and 57% had cut down. There was an increase at follow-up of people who had used cessation support or products. CONCLUSIONS: Aunties are well-placed to find pregnant women and provide cessation support and referral in a way consistent with traditional Maori knowledge and practices. This study suggests such an intervention could increase quit attempts and increase use of effective cessation methods. A more robust study is warranted to develop an enhanced Aunties intervention. PMID- 26253618 TI - An essay of reflection: Why does preeclampsia exist in humans, and why are there such huge geographical differences in epidemiology? AB - This workshop had four main objectives: (A) Trying to look at the preeclampsia (PE) problem "from the Space Shuttle": why preeclampsia has emerged in humans (a specific human reproductive feature among 4300 mammal species)? (B) Epidemiology: there are major geographical differences concerning early onset PE and late onset PE throughout the world. (C) Vascular: The very promising use of pravastatin in the treatment of the vascular maternal syndrome (based on the metabolism of carbon monoxide (CO), the role of inositol phosphate glycans P-type (IPG-P), a major role in comprehending the insulin resistance phenotype in preeclampsia. (D) Immunology: the specialty of these workshops since their start in 1998; our understanding of the role of the immune system and the regulation of the deep implantation of the human trophoblast (and the obligatory compromises between the fetal/placental unit and the mother) have reached a kind of "maturity," following the pivotal studies exploring the biology of repetitive sperm exposure in the female genital tract. The meeting of people who never meet each other in the course of their normal professional lives (obstetricians, evolutionists, geneticists, immunologists, fundamentalist vascular biologists, epidemiologists, anthropologists, neonatologists, etc.) permitted some fruitful reflections to be made again this year. PMID- 26253619 TI - Anti-atherogenic properties of high-density lipoproteins in psychiatric patients before and after two months of atypical anti-psychotic therapy. AB - Some of the medications used for the management of schizophrenia are associated with clinically significant increases in weight and adverse alterations in serum lipid levels. The aim of the study was to investigate the effect of short-term (two months) treatment with atypical anti-psychotics on coronary heart disease risk factors, including the functional properties of high-density lipoprotein (HDL), in psychiatric patients. Nineteen patients diagnosed with schizophrenia, schizoaffective, and bipolar disorder and ten healthy volunteers were enrolled in the study. In the present study blood was drawn at baseline and after two months of atypical anti-psychotic treatment. Wilcoxon non-parametric-test was used to examine differences in the psychotic group before and two months after treatment.Waist circumference and oxidative stress in psychiatric patients were higher compared with the control group. Serum-mediated cholesterol efflux capacity was lower in psychotic patients compared to controls. Two months of anti psychotic therapy was associated with increased abdominal obesity, decreased paraoxonase lactonase activity, but with no further change in serum-mediated cholesterol efflux from macrophages. Psychotic patients have low serum-mediated cholesterol efflux from macrophages as a parameter of HDL functionality. Atypical anti-psychotic treatment for two months increased metabolic derangements in these patients but without further decrement in serum-mediated cholesterol efflux. PMID- 26253620 TI - Acoustic startle and prepulse inhibition predict smoking lapse in posttraumatic stress disorder. AB - Most smokers who attempt to quit lapse within the first week and are ultimately unsuccessful in their quit attempt. Nicotine withdrawal exacerbates cognitive and attentional problems and may be one factor in smoking relapse. The startle reflex response and prepulse inhibition (PPI) of the response are sensitive to arousal and early attentional dysregulation. The current study examined whether startle response and PPI are related to early smoking lapse, and if this differs in people with and without posttraumatic stress disorder (PTSD). Participants with (N = 34) and without (N = 57) PTSD completed a startle reflex and PPI assessment during (1) ad lib smoking (2) on the first day of abstinence during a quit attempt. Most (88%) participants lapsed within the first week of the quit attempt. PTSD status predicted shorter time to lapse. Larger startle magnitude and greater PPI predicted a longer duration before smoking lapse. When diagnostic groups were examined separately, greater PPI predicted a longer successful quit attempt only in participants with a PTSD diagnosis. The startle reflex response and PPI may provide an objective, neurophysiological evaluation of regulation of arousal and early attentional processes by nicotine, which are important factors in smoking cessation success. PMID- 26253621 TI - Concentrations of MDPV in rat striatum correlate with the psychostimulant effect. AB - 3,4-methylenedioxypyrovalerone or MDPV is a synthetic cathinone with psychostimulant properties more potent than cocaine. We quantified this drug in the striatum after subcutaneous administration to rats. MDPV reached the brain around 5 min after its administration and peaked at 20-25 min later. The elimination half-life in the striatum (61 min) correlates with the decrease in the psychostimulant effect after 60 min. Around 11% of the administered dose reached the striatum and, considering a homogeneous brain distribution, we determined that around 86% of the plasma MDPV is distributed to the brain. MDPV induced a dose-dependent increase in locomotor activity, rearing behaviour and stereotypies, all prevented by haloperidol. A plot of locomotor activity or stereotypies versus MDPV striatal concentrations over time showed a direct relationship between factors. No free MDPV metabolites were detected in plasma, at any time, but hydrolysis with glucuronidase allowed us to identify mainly three metabolites, one of them for the first time in rat plasma. The present results contribute to evidence that MDPV induces hyperlocomotion mainly through a dopamine-dependent mechanism. Good correlation between behavioural effects and striatal levels of MDPV leads us to conclude that its psychostimulant effect is mainly due to a striatal distribution of the substance. The present research provides useful information on the pharmacokinetics of MDPV, and can help design new experiments with kinetics data as well as provide a better understanding of the effects of MDPV in humans and its potential interactions. PMID- 26253622 TI - Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 1, a pharmacokinetic/pharmacodynamic comparison with paroxetine in healthy men. AB - We compared the effect of vortioxetine, paroxetine and placebo after three days of dosing on sleep architecture. This was a randomised, double-blind, four-way crossover, placebo-controlled, multiple-dose study in 24 healthy young men. Subjects received 20mg vortioxetine, 40 mg vortioxetine, 20mg paroxetine or placebo for three consecutive days in four different periods with at least three weeks between them. Polysomnography and blood sampling for pharmacokinetic analysis were performed on the pre-dose night and nights 1 and 3 of dosing in each period. Plasma concentrations of vortioxetine and paroxetine during the polysomnography measurement were used to estimate SERT occupancies using published relationships in healthy subjects.All three active treatments significantly increased REM onset latency and decreased time spent in REM sleep. In the pharmacokinetic/pharmacodynamics analysis significant relationships were found between REM onset latency and time spent in REM sleep and vortioxetine/paroxetine exposure. The relation between REM suppression parameters and SERT occupancy was significantly different between vortioxetine and paroxetine, despite the same SERT occupancy. This indicates that vortioxetine has a different clinical pharmacological profile from paroxetine, which may explain the differences in adverse effect profile of the two drugs, for instance the lower incidence of nausea, weight gain and sexual dysfunction with vortioxetine. PMID- 26253624 TI - Kynurenine pathway (KP) inhibitors: Novel agents for the management of depression. AB - Depression is a highly prevalent and severely disabling condition globally. Despite being a major cause of disability worldwide, little progress has been made in the last three decades in developing rational and novel pharmacological treatment options for the management of depression. Recently there has been growing interest in the role of kynurenine pathway in pathophysiology of depression. In this paper, the potential role of kynurenine pathway inhibitors in the management of depression particularly in secondary and reactive depression and the development of novel antidepressant drugs targeting kynurenine pathway are discussed. PMID- 26253623 TI - Altered CB1 receptor coupling to G-proteins in the post-mortem caudate nucleus and cerebellum of alcoholic subjects. AB - Biochemical, pharmacological and genetic evidence suggests the involvement of the endocannabinoid system in alcohol dependence. The aim of the present study was to evaluate the state of CB1 receptors in post-mortem caudate nucleus, hippocampus and cerebellum of alcoholic subjects.CB1 protein levels were measured by Western blot, CB1 receptor density and affinity by [(3)H]WIN55,212-2 saturation assays and CB1 functionality by [(35)S]GTPgammaS binding assays. Experiments were performed in samples from 24 subjects classified as non-suicidal alcoholics (n = 6), suicidal alcoholics (n = 6), non-alcoholic suicide victims (n = 6) and control subjects (n = 6).Alcoholic subjects presented hyperfunctional CB1 receptors in the caudate nucleus resulting in a higher maximal effect in both alcoholic groups compared to the non-alcoholic groups (p < 0.001). Conversely, in the cerebellum the non-suicidal alcoholic subjects showed hypofunctional receptors with lower maximal effect and potency (p < 0.001). No changes were found in the CB1 protein expression in either region. In the hippocampus of alcoholic subjects, no changes were observed either in the functionality, density or protein levels.Our data support an association between endocannabinoid system activity and alcoholism. The modifications reported here could be either a consequence of high lifetime ethanol consumption or a vulnerability factor to develop alcohol addiction. PMID- 26253625 TI - Multiparametric Cardiac Magnetic Resonance Survey in Children With Thalassemia Major: A Multicenter Study. AB - BACKGROUND: Cardiovascular magnetic resonance (CMR) plays a key role in the management of thalassemia major patients, but few data are available in pediatric population. This study aims at a retrospective multiparametric CMR assessment of myocardial iron overload, function, and fibrosis in a cohort of pediatric thalassemia major patients. METHODS AND RESULTS: We studied 107 pediatric thalassemia major patients (61 boys, median age 14.4 years). Myocardial and liver iron overload were measured by T2* multiecho technique. Atrial dimensions and biventricular function were quantified by cine images. Late gadolinium enhancement images were acquired to detect myocardial fibrosis. All scans were performed without sedation. The 21.4% of the patients showed a significant myocardial iron overload correlated with lower compliance to chelation therapy (P<0.013). Serum ferritin >=2000 ng/mL and liver iron concentration >=14 mg/g/dw were detected as the best threshold for predicting cardiac iron overload (P=0.001 and P<0.0001, respectively). A homogeneous pattern of myocardial iron overload was associated with a negative cardiac remodeling and significant higher liver iron concentration (P<0.0001). Myocardial fibrosis by late gadolinium enhancement was detected in 15.8% of the patients (youngest children 13 years old). It was correlated with significant lower heart T2* values (P=0.022) and negative cardiac remodeling indexes. A pathological magnetic resonance imaging liver iron concentration was found in the 77.6% of the patients. CONCLUSIONS: Cardiac damage detectable by a multiparametric CMR approach can occur early in thalassemia major patients. So, the first T2* CMR assessment should be performed as early as feasible without sedation to tailor the chelation treatment. Conversely, late gadolinium enhancement CMR should be postponed in the teenager age. PMID- 26253627 TI - Refining the Risk for Atrial Fibrillation. PMID- 26253626 TI - Left Ventricular Systolic Dysfunction by Longitudinal Strain Is an Independent Predictor of Incident Atrial Fibrillation: A Community-Based Cohort Study. AB - BACKGROUND: The increasing prevalence of atrial fibrillation (AF) represents a public health issue. Identifying new predictors of AF is therefore necessary to plan preventive strategies. We investigated whether left ventricular (LV) systolic dysfunction by global longitudinal strain (GLS), a predictor of cardiovascular events, may predict new-onset AF in a population setting. METHODS AND RESULTS: Participants (n=675; mean age, 71+/-9 years; 60% women) in sinus rhythm from the population-based Northern Manhattan Study (NOMAS) underwent 2- and 3-dimensional echocardiography as part of the Cardiac Abnormalities and Brain Lesions (CABL) study. LV systolic function was assessed by LV ejection fraction and speckle-tracking GLS. During a mean follow-up of 63.6+/-18.7 months, 32 (4.7%) new confirmed cases of AF occurred. Lower GLS (adjusted hazard ratio/unit decrease, 1.22; 95% confidence interval, 1.04-1.43; P=0.015) and increased left atrial volume index (LAVi; adjusted hazard ratio/unit increase, 1.12; 95% confidence interval, 1.07-1.17; P<0.001) were significantly associated with incident AF, whereas LV ejection fraction was not (P=0.176). Abnormal GLS (> 14.7%) was associated with risk of new-onset AF with an adjusted hazard ratio of 3.2 (95% confidence interval, 1.4-7.5; P=0.007). The coexistence of abnormal GLS/abnormal LAVi was associated with a 28.6% incidence of AF (adjusted hazard ratio, 12.1; 95% confidence interval, 3.3-44.8; P<0.001) compared with participants with normal GLS/normal LAVi (AF incidence, 2.0%). AF incidence was intermediate in those with either abnormal GLS or abnormal LAVi (9.3% and 11.1%, respectively). GLS prognostic value for incident AF was incremental over risk factors and LAVi. CONCLUSIONS: LV systolic dysfunction by GLS was a powerful and independent predictor of incident AF. GLS assessment may improve AF risk stratification in addition to established parameters. PMID- 26253628 TI - Correction. PMID- 26253629 TI - Adjuvant endocrine therapy in pre- versus postmenopausal patients with steroid hormone receptor-positive breast cancer: results from a large population-based cohort of a cancer registry. AB - PURPOSE: Adjuvant endocrine therapy (ET) is indicated in patients with steroid hormone receptor (HR)-positive breast cancer. The aim of this study was to evaluate the quality of HR determination and adjuvant endocrine treatment of breast cancer patients in a large cohort of more than 7000 women by analyzing data from a population-based regional cancer registry. METHODS: Data from the Clinical Cancer Registry Regensburg (Bavaria, Germany) were analyzed. Female patients with primary, nonmetastatic invasive breast cancer who were diagnosed between 2000 and 2012 (n = 7421) were included. HR-status was available in 97.4 % (n = 7229) of the patients. This data set (n = 7229) was used for subsequent statistical analyses. RESULTS: Since 2009, almost a complete rate of 99.6 % of analyzed HR-status was achieved. In sum, 85.8 % of the patients (n = 6199) were HR-positive, whereas 14.2 % (n = 1030) were HR-negative. Overall, 85.3 % (n = 5285) of HR-positive patients received ET either alone or in combination with chemotherapy (CHT) and/or trastuzumab. The majority of premenopausal patients received CHT plus ET (716 patients, 52.3 %). In postmenopausal patients, the most frequent systemic therapy was ET alone (2670 patients, 55.3 %). Best overall survival (OS) was found in HER2-/HR-positive patients receiving CHT plus ET plus trastuzumab (7-year OS rate of 97.2 % in premenopausal patients versus 86.9 % in postmenopausal patients). Premenopausal patients had a reduced benefit from additional CHT than postmenopausal patients. Premenopausal patients receiving only ET had a 7-year OS rate of 95.3 % compared to 92.7 % of patients receiving CHT plus ET. In contrast, postmenopausal patients treated with CHT plus ET had a 7-year OS rate of 84.0 % in comparison with those patients receiving only ET with a 7-year OS rate of 81.7 %. CONCLUSIONS: Analysis of HR in patients with early breast cancer achieved a very high quality in recent years. The vast majority of HR-positive patients received ET, and this guideline-adherent use improved OS. Inverse effects of the CHT plus ET combination in premenopausal versus postmenopausal patients and a still existing minority of patients not receiving guideline-adherent treatment should be further investigated in future studies. PMID- 26253630 TI - Novel antibacterial active quinolone-fluoroquinolone conjugates and 2D-QSAR studies. AB - Novel, quinolone-fluoroquinolone conjugates 10a-f, 11a-f, 13a-f and 14a-f with amino acid linkers were synthesized in good yields utilizing benzotriazole chemistry. Antibacterial bioassay showed the synthesized bis-conjugates exhibit anti-bacterial properties comparable with the parent drugs. PMID- 26253631 TI - Strongylophorines, new protein tyrosine phosphatase 1B inhibitors, from the marine sponge Strongylophora strongilata collected at Iriomote Island. AB - A new meroditerpene, 26-O-ethylstrongylophorine-14 (1), was isolated from the Okinawan marine sponge Strongylophora strongilata together with six known strongylophorines: 26-O-methylstrongylophorine-16 (2) and strongylophorines-2 (3), -3 (4), -8 (5), -15 (6), and -17 (7). The structure of 1 was assigned on the basis of its spectroscopic data. Compound 1 inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 8.7 MUM, while known compounds 2-8 gave IC50 values of 8.5, >24.4, 9.0, 21.2, 11.9, and 14.8 MUM, respectively. Oleanolic acid, a positive control, inhibited PTP1B activity at 0.7 MUM (IC50). The inhibitory activities of strongylophorines possessing the acetal moiety at C-26 (1, 2, and 6) were stronger than those of the lactone derivatives (3 and 5). This is the first study to demonstrate that meroditerpenes inhibit PTP1B activity. PMID- 26253632 TI - Biarylmethoxy 2-nitroimidazooxazine antituberculosis agents: Effects of proximal ring substitution and linker reversal on metabolism and efficacy. AB - Certain biaryl analogues of antitubercular drug PA-824 displayed enhanced in vivo efficacies yet retained some susceptibility towards oxidative metabolism; therefore, two new strategies were explored to address this. Ortho-substitution of the proximal aryl ring with larger electron-withdrawing substituents maintained or improved compound stability but reduced aerobic potency; however, fluoro and cyano were well tolerated. In vivo, only 2'- or 3'-fluoro mono substitution preserved high efficacy against acute infection, although one example was twofold more effective than delamanid against chronic infection. Reversal of the 6-oxymethylene linkage also permitted high potency and improved stability towards human liver microsomes, albeit, in vivo results were inferior. These novel findings provide further insight into the preferred structural features for lead candidates in this important drug class. PMID- 26253633 TI - Identification of dialkyl diacetylene diols with potent cancer chemopreventive activity. AB - An increasing importance of chemoprevention for controlling cancer risks prompted the discovery of new active cancer chemopreventive agents. In this study, we designed and synthesized substituted hexa-2,4-diyne-1,6-diols, more structurally simplified, tunable, and easily preparable than natural gymnasterkoreaynes, and evaluated their cancer chemopreventive activities by measuring concentration of doubling quinone reductase activity (CD), cell viability, and chemopreventive index (CI). Most of the diols exhibited good CD activity and low cytotoxicity. In particular, tetradeca-5,7-diyne-4,9-diol and 2-methyltetradeca-5,7-diyne-4,9-diol showed the best cancer chemopreventive activity, approximately equipotent to that of sulforaphane. And, by synthesizing optically active stereoisomers of selected active compounds, the effect of stereochemistry was also studied. Eventually, we produced a chemopreventive compound for in vivo study. PMID- 26253634 TI - Synthesis and in vitro evaluation of [18F]FECIMBI-36: A potential agonist PET ligand for 5-HT2A/2C receptors. AB - Radiosynthesis and in vitro evaluation of [(18)F]-2-(4-bromo-2,5-dimethoxyphenyl) N-(2-(2-fluoroethoxy)benzyl)ethanamine, ([(18)F]FECIMBI-36) or ([(18)F]1), a potential agonist PET imaging agent for 5-HT2A/2C receptors is described. Syntheses of reference standard 1 and the corresponding des-fluoroethyl radiolabeling precursor (2) were achieved with 75% and 65% yields, respectively. In vitro pharmacology assay of FECIMBI-36 by [(3)H]-ketanserin competition binding assay obtained from NIMH-PDSP showed high affinities to 5-HT2AR (Ki = 1nM) and 5-HT2CR (Ki=1.7 nM). Radiolabeling of FECIMBI-36 was achieved from the boc-protected precursor 2 using [(18)F]-fluoroethyltosylate in presence of Cs2CO3 in DMSO followed by removal of the protective group. [(18)F]1 was isolated using RP-HPLC in 25 +/- 5% yield, purity > 95% and specific activity 1-2Ci/MUmol (N = 6). In vitro autoradiography studies demonstrate that [(18)F]1 selectively label 5-HT2A and 5-HT2C receptors in slide-mounted sections of postmortem human brain using phosphor imaging. Our results indicate the potential of [(18)F]1 for imaging 5-HT2A/2C receptors in the high affinity state in vivo using PET imaging. PMID- 26253635 TI - Synthesis and biological evaluation of phaitanthrin congeners as anti mycobacterial agents. AB - Natural alkaloid, tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione) and its analogues are found to exhibit potent anti-tubercular activity against MDR-TB. A novel class of indolo[2,1-b]quinazolinones have been synthesized to evaluate their anti-mycobacterial activity. Enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis is one of the key enzymes and has been validated as an effective anti-microbial target. In silico molecular docking study demonstrates that the synthesized compounds exhibit high affinity for the M. tuberculosis drug target InhA. Phaitanthrin is a natural product, which belongs to a family of tryptanthrin and exhibits structural similarity except at position 6. Phaitanthrin derivatives are prepared by modifying the keto functionality of tryptanthrin. These phaitanthrin congeners are found to display promising anti tubercular activity. PMID- 26253636 TI - Mechanism studies on anti-HepG2 cell proliferation of phenanthroline derivatives as G-quadruplex DNA stabilizers. AB - In our previous study, two similar phenanthroline derivatives (1 and 2) were confirmed to be potent and selective stabilizers of the G-quadruplex DNAs of c myc promoter and human telomere in vitro. In this study, we investigated the anti proliferative mechanism of both ligands to HepG2 cells. MTT assay indicated that IC50 values are 1.26 and 0.5 MUM for 1 and 2, respectively. Flow cytometric assays showed that both ligands could induce cell apoptosis, and 1 could arrest cell cycle in S and G2/M phases whereas the cell cycle was arrested in G0/G1 phase for 2, which are attributed to the expression decreases of the key regulating proteins cyclin B1/Cdk1 and cyclin D1/Cdk4 in the G2/M and G0/G1 phases, respectively. Both ligands could inhibit the transcription of c-myc gene and down-regulate the expression of c-myc, Sp1, and hTERT protein but up-regulate the p53 protein expression. 2 performed higher inhibitory activity than 1. Furthermore, both 1 and 2 had no effect on the elongation of telomeric DNA. The current results suggested that the decreases of c-myc, Sp1, and hTERT expressions and the increase of p53 expression, together with the reduction of cyclins/Cdks proteins in the regulation of the cell cycle, and/or the telomeric chromatin alteration led to cell cycle arrest, apoptosis, and growth inhibition induced by both ligands. PMID- 26253637 TI - Ebola: Practicing the Unknown in Sierra Leone. PMID- 26253638 TI - Improved treatment of systemic blood infections using antibiotics with extracorporeal opsonin hemoadsorption. AB - Here we describe development of an extracorporeal hemoadsorption device for sepsis therapy that employs commercially available polysulfone or polyethersulfone hollow fiber filters similar to those used clinically for hemodialysis, covalently coated with a genetically engineered form of the human opsonin Mannose Binding Lectin linked to an Fc domain (FcMBL) that can cleanse a broad range of pathogens and endotoxin from flowing blood without having to first determine their identity. When tested with human whole blood in vitro, the FcMBL hemoadsorption filter (FcMBL-HF) produced efficient (90-99%) removal of Gram negative (Escherichia coli) and positive (Staphylococcus aureus) bacteria, fungi (Candida albicans) and lipopolysaccharide (LPS)-endotoxin. When tested in rats, extracorporeal therapy with the FcMBL-HF device reduced circulating pathogen and endotoxin levels by more than 99%, and prevented pathogen engraftment and inflammatory cell recruitment in the spleen, lung, liver and kidney when compared to controls. Studies in rats revealed that treatment with bacteriocidal antibiotics resulted in a major increase in the release of microbial fragments or 'pathogen-associated molecular patterns' (PAMPs) in vivo, and that these PAMPs were efficiently removed from blood within 2 h using the FcMBL-HF; in contrast, they remained at high levels in animals treated with antibiotics alone. Importantly, cleansing of PAMPs from the blood of antibiotic-treated animals with the FcMBL-hemoadsorbent device resulted in reduced organ pathogen and endotoxin loads, suppressed inflammatory responses, and resulted in more stable vital signs compared to treatment with antibiotics alone. As PAMPs trigger the cytokine cascades that lead to development of systemic inflammatory response syndrome and contribute to septic shock and death, co-administration of FcMBL-hemoadsorption with antibiotics could offer a more effective approach to sepsis therapy. PMID- 26253639 TI - Probiotics in Colorectal Surgery. PMID- 26253641 TI - A Paradigm Shift in Axillary Breast Cancer Treatment; From "Treat All-Except," Toward "Treat None-Unless". AB - The various pitfalls that exist in using predictive systems for sentinel node positive breast cancer are described, to give insight into the background and building stones of these systems. The aim of this article was to make clinicians aware of these pitfalls before using them in the clinical decision-making process in individual patients with positive sentinel nodes. Besides these pitfalls, the implications concerning the results of the Z0011 trial as presented by Giuliano et al (Giuliano AE, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: The American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg 2010; 252:426-32, discussion 432-3) are addressed, and we point out some important issues for debate, before implementation of the conclusions of that practice-changing trial into daily clinical breast cancer practice. PMID- 26253640 TI - Functional Advantages of Proximal Gastrectomy with Jejunal Interposition Over Total Gastrectomy with Roux-en-Y Esophagojejunostomy for Early Gastric Cancer. AB - BACKGROUND: The postoperative functional advantages of a proximal gastrectomy over a total gastrectomy remain debatable. The aim of this study was to evaluate the functional outcomes of a proximal gastrectomy with jejunal interposition (PG JI), compared with those for a total gastrectomy with Roux-en-Y esophagojejunostomy (TG-RY), in patients with early gastric cancer. METHODS: Between 2007 and 2012, 65 patients underwent PG-JI and 117 underwent TG-RY for cT1 gastric cancer. Various parameters, including body weight, serum hemoglobin level, and interview-based symptoms, were prospectively evaluated in these patients. In patients who underwent PG-JI, the postoperative endoscopic findings were also assessed. RESULTS: All the surgeries were performed via a laparotomy alone. During a median postoperative follow-up of 42 months (range, 12-78 months), PG-JI offered significant reductions in body weight loss (12.5 +/- 5.8 vs. 17.4 +/- 6.4 %, P < 0.001), serum hemoglobin decline (7.0 +/- 5.7 vs. 9.7 +/- 5.4 %, P = 0.002), and dumping symptoms (11 % [7/65] vs. 30 % [35/117], P = 0.003), while being associated with similar incidences of anastomotic stricture (9 % [6/65] vs. 8 % [9/117], P = 0.781), small bowel obstruction (0 % [0/65] vs. 2 % [2/117], P = 0.538), stasis symptoms (51 % [33/65] vs. 44 % [51/117], P = 0.358), and reflux symptoms (34 % [22/65] vs. 23 % [27/117], P = 0.121), compared with TG-RY. Four cases of gastric remnant cancer and no cases of endoscopic reflux esophagitis were found after PG-JI. CONCLUSIONS: PG-JI has clear functional advantages over TG-RY, although it requires active surveillance for remnant gastric cancer. PMID- 26253642 TI - Environment, but not genetic divergence, influences geographic variation in colour morph frequencies in a lizard. AB - BACKGROUND: Identifying the causes of intraspecific phenotypic variation is essential for understanding evolutionary processes that maintain diversity and promote speciation. In polymorphic species, the relative frequencies of discrete morphs often vary geographically; yet the drivers of spatial variation in morph frequencies are seldom known. Here, we test the relative importance of gene flow and natural selection to identify the causes of geographic variation in colour morph frequencies in the Australian tawny dragon lizard, Ctenophorus decresii. RESULTS: Populations of C. decresii are polymorphic for male throat coloration and all populations surveyed shared the same four morphs but differed in the relative frequencies of morphs. Despite genetic structure among populations, there was no relationship between genetic similarity or geographic proximity and similarity in morph frequencies. However, we detected remarkably strong associations between morph frequencies and two environmental variables (mean annual aridity index and vegetation cover), which together explained approximately 45 % of the total variance in morph frequencies. CONCLUSIONS: Spatial variation in selection appears to play an important role in shaping morph frequency patterns in C. decresii. Selection associated with differences in local environmental conditions, combined with relatively low levels of gene flow, is expected to favour population divergence in morph composition, but may be counteracted by negative frequency-dependent selection favouring rare morphs. PMID- 26253643 TI - The association between HIV/AIDS-related knowledge and perception of risk for infection: a systematic review. AB - This systematic review tries to elucidate the association between what people know about HIV/AIDS and how they perceive their risk of infection. The initial search for articles yielded 1,595 abstracts, 16 of which met the inclusion criteria. Five studies found a positive correlation, four reported a negative correlation and seven found no association between knowledge and risk perception. It was found that the existing psychometrically sound measure of HIV/AIDS risk perception had not been used in any of the studies. The context in which the risk is assessed is pivotal to whether an association between knowledge and the perceived risk is found. Biases in judgement such as optimistic bias, psychological distancing, anchoring bias and overconfidence also explain how knowledge may fail to predict risk perception. It was concluded that the association between HIV/AIDS knowledge and risk perception might follow a continuum from positive to no association and finally to negative. The hypothesis, however, still needs to be studied further. PMID- 26253644 TI - Web-based acceptance and commitment therapy for depressive symptoms with minimal support: a randomized controlled trial. AB - Low-intensity interventions for people suffering from depressive symptoms are highly desirable. The aim of the present study was to investigate the outcomes of a web-based acceptance and commitment therapy (ACT)-based intervention without face-to-face contact for people suffering from depressive symptoms. Participants (N = 39) with depressive symptoms were randomly assigned to an Internet-delivered acceptance and commitment therapy (iACT) intervention or a waiting list control condition (WLC). Participants were evaluated with standardized self-reporting measures (Beck Depression Inventory [BDI-II], Symptom Checklist-90 [SCL-90], Acceptance and Action Questionnaire [AAQ-2], Five Facet Mindfulness Questionnaire [FFMQ], Automatic Thoughts Questionnaire [ATQ], and White Bear Suppression Inventory [WBSI]) at pre- and post-measurement. Long-term effects in the iACT group were examined using a 12-month follow-up. The iACT program comprised home assignments, online feedback given by master's-level students of psychology over a 7-week intervention period, and automated email-based reminders. Significant effects were observed in favor of the iACT group on depression symptomatology (between effect sizes [ESs] at post-treatment, iACT/WLC, g = .83), psychological and physiological symptoms (g = .60), psychological flexibility (g = .67), mindfulness skills (g = .53), and frequency of automatic thoughts (g = .57) as well as thought suppression (g = .53). The treatment effects in the iACT group were maintained over the 12-month follow-up period (within-iACT ES: BDI-II, g = 1.33; SCL-90, g = 1.04; ATQF/B [Frequency/Believability], FFMQ, WBSI, AAQ-II, g = .74-1.08). The iACT participants stated that they would be happy to recommend the same intervention to others with depressive symptoms. We conclude that an ACT based guided Internet-delivered treatment with minimal contact can be effective for people with depressive symptoms. PMID- 26253645 TI - Linezolid underexposure in a patient co-treated with venlafaxine. PMID- 26253646 TI - Incidence and risk factors for central venous access port-related infection in Chinese cancer patients. AB - BACKGROUND/PURPOSE: Cytotoxic chemotherapy via central venous access ports is an important part of the standard treatment for most cancers, but it is accompanied with the risk of infections. This study aimed to analyze the incidence and risk factors for central venous access port-related infection (CPI) among Chinese patients receiving cytotoxic chemotherapy. METHODS: Between January 1, 2002 and December 31, 2005 a total of 1391 cancer patients with 1449 totally implantable central venous access ports were evaluated. The log-rank test and Cox proportional hazards model were used for the analyses of risk factors. RESULTS: The overall CPI incidence rate was 0.21 per 1000 catheter-days. Hematological malignancies and head and neck cancer were associated with an increased risk of CPI (hazard ratio 4.00 and 4.11, respectively, both p < 0.001) and less infection free catheter longevity (p < 0.001) compared with other cancer types. Chemotherapy in an adjuvant setting was associated with a lower risk of infection than for patients in a nonadjuvant setting (p < 0.001). The most common pathogens isolated from CPI were Pseudomonas aeruginosa and Candida. CONCLUSION: Infection remains to be a challenging issue for totally implantable central venous ports. Implementation of an insertion bundle for the prevention of central line associated bloodstream infections is warranted, especially for those patients with hematological and head and neck cancers, as well as for patients receiving chemotherapy in the metastatic settings. PMID- 26253647 TI - Gender association with postoperative hemorrhage patient safety indicator in the United States from 2000 to 2012. AB - INTRODUCTION: Postoperative hemorrhage and hematoma (PHH) is a patient safety indicator (PSI) representing a universal complication for all surgical procedures. This study examined the association between gender and the rates of PHH from 2000 to 2012. METHODS: We performed a retrospective cohort study on PHH incidence from 2000 to 2012 using the Healthcare Cost and Utilization Project. Pairwise t tests were performed. Odds ratios and P values were calculated, using a Bonferroni-adjusted alpha threshold, to examine PHH differences by gender. RESULTS: Our study revealed that males had significantly greater PHH incidence rates compared to females in every year of the study period (P < .001). CONCLUSIONS: Contrary to our results, the current literature on PHH largely identifies females as the gender with the greater risk of PHH. Specific to our study, our definition of PHH excludes pregnancy, childbirth, and puerperium patients. This finding suggests that pregnancy-related bleeding complications have influenced the current literature and males are the higher risk gender for PHH in nonobstetric procedures. PMID- 26253648 TI - Heterogeneity in the genus Allovahlkampfia and the description of the new genus Parafumarolamoeba (Vahlkampfiidae; Heterolobosea). AB - Heterolobosean amoebae are common and diverse members of soil protist communities. In this study, we isolated seven strains of amoebae from soil samples taken in Tibet (at high altitude), Sardinia and the Netherlands, all resembling to belong to a similar heterolobosean morphospecies. However, sequences of the small subunit (SSU) rDNA and internal transcribed spacers, including the 5.8S rDNA, revealed a high heterogeneity in the genus Allovahlkampfia to which six of the isolates belong. Some unnamed strains, of which the sequences had been published before, are also included within the genus Allovahlkampfia. One Allovahlkampfia isolated in the Netherlands harbors a twin ribozyme, containing a His-Cys box, similar to the one found in strain BA of Allovahlkampfia. The other SSU rDNA sequence grouped in phylogenetic analyses with sequences obtained in environmental sequencing studies as sister to the genus Fumarolamoeba. This phylogenetic placement was supported by analyses of the 5.8S rDNA leading us to describe it as a new genus Parafumarolamoeba. PMID- 26253650 TI - How adolescents with anorexia nervosa and their parents perceive family functioning? AB - This study aims at examining whether adolescent girls diagnosed with anorexia nervosa and their parents differ in perceiving the different aspects of family functioning. Moreover, the discrepancy between adolescent girls and healthy controls on Family Adaptability and Cohesion Evaluation Scales dimensions, family communication, and family satisfaction is investigated. The study includes 36 female anorexia patients and their parents and 36 healthy controls. The results showed a different view between mothers and their daughters with regard to the dimension of rigidity. In addition, girls with anorexia nervosa were less satisfied about family environment and rated their families as less communicative, flexible, cohesive, and more disengaged, compared to controls. PMID- 26253649 TI - [Calcaneal Z osteotomy for correction of subtalar hindfoot varus deformity]. AB - OBJECTIVE: Joint-preserving correction of mild and moderate hindfoot varus deformities by Z-shaped calcaneal osteotomy. INDICATIONS: Mild and moderate subtalar varus deformities in conditions like cavovarus or equinovarus foot deformity, peroneal tendon rupture, malpositioned tarsal fusion, after ankle arthroplasty. CONTRAINDICATIONS: Supramalleolar varus deformities, ankle instability with talar tilting, varus arthritis of the ankle joint, severe subtalar arthritis, and complete loss of peroneal muscle function that should be treated by fusions. SURGICAL TECHNIQUE: Lateral curved incision at the tuber calcanei with exposure of the lateral calcaneal wall. Z-shaped osteotomy of the calcaneal bone with lateral displacement and rotation in the transversal plane of the tuber fragment combined with lateral wedge resection for frontal plane correction. Fixation of the osteotomy with K-wires or screws. In case of extended correction, prophylactic tarsal tunnel release is advisable. POSTOPERATIVE MANAGEMENT: Cast without weight-bearing for 4 weeks. After removal of K-wires, 4 weeks with partial weight-bearing in a walker. In case of screw fixation, time of immobilization and nonweight-bearing can be shortened. RESULTS: Since 2009, 20 cases have been performed in the described technique by the author. In addition, all patients had simultaneous bony and soft tissue surgery. Residual deformity or overcorrection, delayed bony healing or tibial nerve damage were not observed. No patient has undergone revision surgery. PMID- 26253651 TI - Intensive care physicians' and nurses' perception that hand hygiene prevents pathogen transmission: Belief strength and associations with other cognitive factors. AB - Besides habituation, conscious decision-making remains important for healthcare workers' hand hygiene compliance. This study compared 307 physicians and 348 nurses in intensive care at a German university medical centre regarding their belief that hand disinfection prevents pathogen transmission. Physicians perceived less risk reduction ( p < 0.001; variance explained: 4%), a comparison outscored only by lower self-rated guideline knowledge (8%). In both groups, the transmission-preventive belief was associated with high response efficacy, behavioural intention and self-efficacy, but not with self-rated knowledge. Consistent with the Health Action Process Approach, hand hygiene interventions targeting risk reduction beliefs may promote high motivation, but not action control. PMID- 26253652 TI - Alkaloid variation in New Zealand kowhai, Sophora species. AB - Alkaloid contents of leaf and seed samples of eight species of Sophora native to New Zealand, plus Sophora cassioides from Chile are reported. Fifty-six leaf and forty-two seed samples were analysed for alkaloid content by proton nuclear magnetic resonance spectroscopy, which showed major alkaloids as cytisine, N methyl cytisine and matrine. GC analyses quantified these and identified further alkaloid components. The alkaloids identified were cytisine, sparteine, and matrine-types common to Sophora from other regions of the world. Cytisine, N methyl cytisine, and matrine were generally the most abundant alkaloids across all species with seeds containing the highest concentrations of alkaloids. However, there was no clear taxonomic grouping based on alkaloid composition. A quantitative analysis of various parts of two Sophora microphylla trees showed that the seeds were the richest source of alkaloids (total 0.4-0.5% DM), followed by leaf and twig (0.1-0.3%) and then bark (0.04-0.06%), with only low amounts (<0.02%) found in the roots. This study represents the most comprehensive phytochemical investigation of New Zealand Sophora species to date and presents data for three species of Sophora for which no prior chemistry has been reported. PMID- 26253653 TI - Investigation of the strategies for targeting of the afterglow nanoparticles to tumor cells. AB - Afterglow nanoparticles have been widely investigated as new agents for cancer imaging and as a light source for photodynamic activation for cancer treatment. For both applications, the targeting of the afterglow nanoparticles to tumor cells is an important and challenging issue. Here we report the strategies for targeting Sr3MgSi2O8:Eu(2+),Dy(3+) afterglow nanoparticles to tumor cells by conjugating with variety of targeting molecules such as folic acid, RGD peptide, and R-11 peptide. For folic acid targeting, experimental observations were conducted on PC-3 cells (folate receptor negative), MCF-7 (folate receptor positive), and KB cells (folate receptor positive) to compare the cellular uptake and confirm targeted delivery. For the cyclic RGDfK peptide, experiments were carried out on the integrin alphavbeta3 positive MDA-MB-231 breast cancer cell line and the integrin alphavbeta3 negative MCF-7 breast cancer cell lines in order to compare the cellular uptakes. As for R11-SH peptide, cellular uptake of the afterglow nanoparticles was observed on LNCaP and PC3 prostate cancer cell lines. All the observations showed that the cellular uptakes of the nanoparticles were enhanced by conjugation to variety of targeting molecules which are specific for breast and prostate cancer cells. PMID- 26253654 TI - Tim-3 expression represents dysfunctional tumor infiltrating T cells in renal cell carcinoma. AB - PURPOSE: Renal cell carcinoma (RCC) is the most common cancer of kidney. Evidences have shown that RCC is sensitive to various immunotherapies. Tim-3 plays a role in suppressing Th1-mediated immune responses. However, no study has yet examined the effect of Tim-3 on tumor infiltrating lymphocytes (TILs) in RCC. METHODS: We investigated the expression and function of Tim-3 on TIL CD4+ T cells and TIL CD8+ T cells from 30 RCC patients. RESULTS: Levels of Tim-3 were significantly increased on both TIL CD4+ T cells and TIL CD8+ T cells and were associated with higher stages of the cancer. Also, GATA-3 and interferon gamma (IFN-gamma) were down-regulated, whereas T-bet was up-regulated in TIL Tim-3+ T cells, indicating that Tim-3 expression defined a population of dysfunctional TIL Th1/Tc1 cells. Mechanism analyses showed that TIL Tim-3-expressing CD8+ T cells exhibited impaired Stat5 and p38 signaling pathway. Blocking the Tim-3 pathway restored cell proliferation and increased IFN-gamma production in TIL CD4+ and CD8+ T cells of RCC. CONCLUSIONS: These results suggest that Tim-3 may be used as a novel target for increasing immune responses in RCC tumor microenvironment. PMID- 26253655 TI - Risk factors for artificial urinary sphincter failure. AB - PURPOSE: To analyze revision rates and risk factors for artificial urinary sphincter failure. METHODS: Eighty-four patients underwent implantation of an artificial urinary sphincter in one reference center. Continence rates were defined by daily pad usage. Influence of predefined risk factors for device explantation, revision, differences in preoperative pad usage, and device survival was analyzed using Chi-squared test, Wilcoxon signed-rank test, and Kaplan-Meier analysis. A multivariate analysis was performed using a logistic regression model. A p value below 0.05 was considered statistically significant. RESULTS: After a mean follow-up of 39.7 months, the device was still in situ in 64 patients. In univariate analysis, perioperative need of anticoagulation led to a significant increase in urethral erosion (6 vs. 30 %; p = 0.002) and explantation rate (15 vs. 34 %; p = 0.047). Pelvic irradiation increased postoperative infection rates significantly (0 vs. 10 %; p = 0.018). Penoscrotal approach led to significant increase in urethral erosion rate (0 vs. 21 %; p = 0.015). Implantation of a double cuff led to a significant increase in explantation rate (58 vs. 24 %; p = 0.014), revision rate (75 vs. 38 %; p = 0.017), and infection rate (17 vs. 1 %; p = 0.008). When using cuff size of 3.5 cm, revision rate (20 vs. 50 %; p = 0.026) as well as incontinence rates (40 vs. 82 %; p = 0.014) was significantly lower. In multivariate analysis, only perioperative anticoagulation and double-cuff placement were independent predictors of artificial urinary sphincter failure. CONCLUSIONS: Our findings highlight the influence of perioperative anticoagulative therapy. In addition, the current study provides further evidence that double-cuff implantation should be performed only with caution during primary implantation. PMID- 26253656 TI - Molecular hydrogen protects mice against polymicrobial sepsis by ameliorating endothelial dysfunction via an Nrf2/HO-1 signaling pathway. AB - Endothelial injury is a primary cause of sepsis and sepsis-induced organ damage. Heme oxygenase-1 (HO-1) plays an essential role in endothelial cellular defenses against inflammation by activating nuclear factor E2-related factor-2 (Nrf2). We found that molecular hydrogen (H2) exerts an anti-inflammatory effect. Here, we hypothesized that H2 attenuates endothelial injury and inflammation via an Nrf2 mediated HO-1 pathway during sepsis. First, we detected the effects of H2 on cell viability and cell apoptosis in human umbilical vein endothelial cells (HUVECs) stimulated by LPS. Then, we measured cell adhesion molecules and inflammatory factors in HUVECs stimulated by LPS and in a cecal ligation and puncture (CLP) induced sepsis mouse model. Next, the role of Nrf2/HO-1 was investigated in activated HUVECs, as well as in wild-type and Nrf(-/-) mice with sepsis. We found that both 0.3 mmol/L and 0.6 mmol/L (i.e., saturated) H2-rich media improved cell viability and cell apoptosis in LPS-activated HUVECs and that 0.6mmol/L (i.e., saturated) H2-rich medium exerted an optimal effect. H2 could suppress the release of cell adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1), and pro inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and high-mobility group box 1 protein (HMGB1). Furthermore, H2 could elevate anti-inflammatory cytokine IL-10 levels in LPS-stimulated HUVECs and in lung tissue from CLP mice. H2 enhanced HO-1 expression and activity in vitro and in vivo. HO-1 inhibition reversed the regulatory effects of H2 on cell adhesion molecules and inflammatory factors. H2 regulated endothelial injury and the inflammatory response via Nrf2-mediated HO-1 levels. These results suggest that H2 could suppress excessive inflammatory responses and endothelial injury via an Nrf2/HO-1 pathway. PMID- 26253657 TI - Inflammation in venous thromboembolism: Cause or consequence? AB - Venous thromboembolism (VTE) which includes deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE) is a moderately common disease especially in elderly population with high rate of recurrence and complications. Evidence is accumulating that VTE is not restricted to coagulation system and immune system appears to be involved in formation and resolution of thrombus. The present study was aimed at reviewing current evidences on immune system abnormalities such as alterations in cytokines, chemokines and immune cells. Also, current evidences suggest that; a, inflammation in general functions as a double-edged sword, b, inflammation can be both a cause and a consequence of VTE, and c, current anti coagulation therapies are not well-equipped with the capacity to selectively inhibit inflammatory cells and pathways. Applying such inferences for selective pharmacological targeting of immune mediators in VTE and thereby for adoption of higher effective anti-thromboinflammatory strategies, either therapeutic or prophylactic, is henceforth to be considered as the line of research for future. PMID- 26253658 TI - M2 polarized macrophages induced by CSE promote proliferation, migration, and invasion of alveolar basal epithelial cells. AB - Cigarette smoking plays an important role in the genesis of lung cancer, and tumor-associated macrophages (TAMs) are believed to accelerate the process. We therefore sought to clarify the relationship between cigarette smoking, TAMs and tumorigenesis. We treated macrophages (THP-1) with cigarette smoke extract (CSE) and found that the mRNA levels of IL-6, IL-10, IL-12 and TNF-alpha decreased, while TGF-beta mRNA levels increased. CSE significantly inhibited the phagocytic ability of macrophages, as assessed by flow cytometric analysis of FITC-dextran internalization. JAK2/STAT3 was significantly activated by CSE, as determined by Western blot analysis. When the scavenger receptor CD163, a specific marker of M2 macrophages, was analyzed by flow cytometry, its expression was significantly increased. After inducing M2 polarization of THP-1 cells, we co-cultured macrophages and alveolar basal epithelial cells (A549). The proliferation of A549 cells was detected by the MTT assay and cell cycle analysis, while their migration and invasion were detected by scratch wound assay and transwell assay. The results showed that the proliferation, migration and invasion of A549 cells were significantly promoted by M2 macrophages but were slightly inhibited by CSE. In conclusion, we demonstrated that macrophage M2 polarization induced by CSE promotes proliferation, migration, and invasion of alveolar basal epithelial cells. PMID- 26253659 TI - An introduction to stratified medicine. PMID- 26253660 TI - Distribution and Genetic Diversity of Bacteriocin Gene Clusters in Rumen Microbial Genomes. AB - Some species of ruminal bacteria are known to produce antimicrobial peptides, but the screening procedures have mostly been based on in vitro assays using standardized methods. Recent sequencing efforts have made available the genome sequences of hundreds of ruminal microorganisms. In this work, we performed genome mining of the complete and partial genome sequences of 224 ruminal bacteria and 5 ruminal archaea to determine the distribution and diversity of bacteriocin gene clusters. A total of 46 bacteriocin gene clusters were identified in 33 strains of ruminal bacteria. Twenty gene clusters were related to lanthipeptide biosynthesis, while 11 gene clusters were associated with sactipeptide production, 7 gene clusters were associated with class II bacteriocin production, and 8 gene clusters were associated with class III bacteriocin production. The frequency of strains whose genomes encode putative antimicrobial peptide precursors was 14.4%. Clusters related to the production of sactipeptides were identified for the first time among ruminal bacteria. BLAST analysis indicated that the majority of the gene clusters (88%) encoding putative lanthipeptides contained all the essential genes required for lanthipeptide biosynthesis. Most strains of Streptococcus (66.6%) harbored complete lanthipeptide gene clusters, in addition to an open reading frame encoding a putative class II bacteriocin. Albusin B-like proteins were found in 100% of the Ruminococcus albus strains screened in this study. The in silico analysis provided evidence of novel biosynthetic gene clusters in bacterial species not previously related to bacteriocin production, suggesting that the rumen microbiota represents an underexplored source of antimicrobial peptides. PMID- 26253661 TI - Efficient production of lumichrome by Microbacterium sp. strain TPU 3598. AB - Lumichrome is a photodegradation product of riboflavin and is available as a photosensitizer and fluorescent dye. To develop new efficient methods of lumichrome production, we isolated bacterial strains with high lumichrome productivity from soil. The strain with highest productivity was identified as Microbacterium sp. strain TPU 3598. Since this strain inductively produced lumichrome when cultivated with riboflavin, we developed two different methods, a cultivation method and a resting cell method, for the production of large amounts of lumichrome using the strain. In the cultivation method, 2.4 g (9.9 mmol) of lumichrome was produced from 3.8 g (10.1 mmol) of riboflavin at the 500-ml scale (98% yield). The strain also produced 4.7 g (19.4 mmol) of lumichrome from 7.6 g (20.2 mmol) of riboflavin (96% yield) by addition of riboflavin during cultivation at the 500-ml scale. In the resting cell method, 20 g of cells (wet weight) in 100 ml of potassium phosphate buffer, pH 7.0, produced 2.4 g of lumichrome from 3.8 g of riboflavin (98% yield). Since the lumichrome production by these methods was carried out in suspension, the resulting lumichrome was easily purified from the cultivation medium or reaction mixture by centrifugation and crystallization. Thus, the biochemical methods we describe here are a significant improvement in terms of simplicity and yield over the existing chemical, photolytic, and other biochemical methods of lumichrome production. PMID- 26253662 TI - Effects of Formulation on Microbicide Potency and Mitigation of the Development of Bacterial Insusceptibility. AB - Risk assessments of the potential for microbicides to select for reduced bacterial susceptibility have been based largely on data generated through the exposure of bacteria to microbicides in aqueous solution. Since microbicides are normally formulated with multiple excipients, we have investigated the effect of formulation on antimicrobial activity and the induction of bacterial insusceptibility. We tested 8 species of bacteria (7 genera) before and after repeated exposure (14 passages), using a previously validated gradient plating system, for their susceptibilities to the microbicides benzalkonium chloride, benzisothiozolinone, chlorhexidine, didecyldimethyl ammonium chloride, DMDM hydantoin, polyhexamethylene biguanide, thymol, and triclosan in aqueous solution (nonformulated) and in formulation with excipients often deployed in consumer products. Susceptibilities were also assessed following an additional 14 passages without microbicide to determine the stability of any susceptibility changes. MICs and minimum bactericidal concentrations (MBC) were on average 11-fold lower for formulated microbicides than for nonformulated microbicides. After exposure to the antimicrobial compounds, of 72 combinations of microbicide and bacterium there were 19>=4-fold (mean, 8-fold) increases in MIC for nonformulated and 8>=4 fold (mean, 2-fold) increases in MIC for formulated microbicides. Furthermore, there were 20>=4-fold increases in MBC (mean, 8-fold) for nonformulated and 10>=4 fold (mean, 2-fold) increases in MBC for formulated microbicides. Susceptibility decreases fully or partially reverted back to preexposure values for 49% of MICs and 72% of MBCs after further passage. In summary, formulated microbicides exhibited greater antibacterial potency than unformulated actives and susceptibility decreases after repeated exposure were lower in frequency and extent. PMID- 26253663 TI - Differences in Bacterial Community Structure in Two Color Morphs of the Hawaiian Reef Coral Montipora capitata. AB - Corals harbor diverse bacterial associations that contribute to the health of the host. Using 16S rRNA pyrosequencing, we compared the bacterial communities of red and orange morphs of the Hawaiian coral Montipora capitata. Although both color morphs shared dominant bacterial genera, weighted and unweighted UniFrac analyses showed distinct bacterial communities. A single operational taxonomic unit (OTU), classified as Vibrio, represented the largest driver of differences between the color morphs. This OTU comprised 35.4% (+/-5.5%) of the orange morph bacterial community yet comprised 1.1% (+/-0.6%) of the red morph bacterial community. Cultivable bacteria from the two color morphs were also compared and tested for antibacterial activity. Cultured isolates represented 14 genera (7% of the total genera identified from sequencing data), and all but two cultured isolates had a matching OTU from the sequencing data. Half of the isolates tested (8 out of 16) displayed antibacterial activity against other cultured isolates but not against two known bacterial pathogens of M. capitata. The results from this study demonstrate that the specificity of coral-bacterial associations extends beyond the level of coral species. In addition, culture-dependent methods captured bacterial diversity that was representative of both rare and abundant members of the associated bacterial community, as characterized by culture-independent methods. PMID- 26253664 TI - Semirational Directed Evolution of Loop Regions in Aspergillus japonicus beta Fructofuranosidase for Improved Fructooligosaccharide Production. AB - The Aspergillus japonicus beta-fructofuranosidase catalyzes the industrially important biotransformation of sucrose to fructooligosaccharides. Operating at high substrate loading and temperatures between 50 and 60 degrees C, the enzyme activity is negatively influenced by glucose product inhibition and thermal instability. To address these limitations, the solvent-exposed loop regions of the beta-fructofuranosidase were engineered using a combined crystal structure- and evolutionary-guided approach. This semirational approach yielded a functionally enriched first-round library of 36 single-amino-acid-substitution variants with 58% retaining activity, and of these, 71% displayed improved activities compared to the parent. The substitutions yielding the five most improved variants subsequently were exhaustively combined and evaluated. A four substitution combination variant was identified as the most improved and reduced the time to completion of an efficient industrial-like reaction by 22%. Characterization of the top five combination variants by isothermal denaturation assays indicated that these variants displayed improved thermostability, with the most thermostable variant displaying a 5.7 degrees C increased melting temperature. The variants displayed uniquely altered, concentration-dependent substrate and product binding as determined by differential scanning fluorimetry. The altered catalytic activity was evidenced by increased specific activities of all five variants, with the most improved variant doubling that of the parent. Variant homology modeling and computational analyses were used to rationalize the effects of amino acid changes lacking direct interaction with substrates. Data indicated that targeting substitutions to loop regions resulted in improved enzyme thermostability, specific activity, and relief from product inhibition. PMID- 26253665 TI - Dynamic Mechanisms of the Bactericidal Action of an Al2O3-TiO2-Ag Granular Material on an Escherichia coli Strain. AB - The bactericidal activity of an Al2O3-TiO2-Ag granular material against an Escherichia coli strain was confirmed by a culture-based method. In particular, 100% of microorganisms were permanently inactivated in 30 to 45 min. The present work aimed to investigate the mechanisms of the bactericidal action of this material and their dynamics on Escherichia coli using different techniques. Observations by transmission electron microscopy (TEM) at different times of disinfection revealed morphological changes in the bacteria as soon as they were put in contact with the material. Notably highlighted were cell membrane damage; cytoplasm detachment; formation of vacuoles, possibly due to DNA condensation, in association with regions exhibiting different levels of electron density; and membrane lysis. PCR and flow cytometry analyses were used to confirm and quantify the observations of cell integrity. The direct exposure of cells to silver, combined with the oxidative stress induced by the reactive oxygen species (ROS) generated, was identified to be responsible for these morphological alterations. From the first 5 min of treatment with the Al2O3-TiO2-Ag material, 98% of E. coli isolates were lysed. From 30 min, cell viability decreased to reach total inactivation, although approximately 1% of permeable E. coli cells and 1% of intact cells (10(5) genomic units.ml(-1)) were evidenced. This study demonstrates that the bactericidal effect of the material results from a synergic action of desorbed and supported silver. Supported silver was shown to generate the ROS evidenced. PMID- 26253666 TI - Identification of benzo[a]pyrene-metabolizing bacteria in forest soils by using DNA-based stable-isotope probing. AB - DNA-based stable-isotope probing (DNA-SIP) was used in this study to investigate the uncultivated bacteria with benzo[a]pyrene (BaP) metabolism capacities in two Chinese forest soils (Mt. Maoer in Heilongjiang Province and Mt. Baicaowa in Hubei Province). We characterized three different phylotypes with responsibility for BaP degradation, none of which were previously reported as BaP-degrading microorganisms by SIP. In Mt. Maoer soil microcosms, the putative BaP degraders were classified as belonging to the genus Terrimonas (family Chitinophagaceae, order Sphingobacteriales), whereas Burkholderia spp. were the key BaP degraders in Mt. Baicaowa soils. The addition of metabolic salicylate significantly increased BaP degradation efficiency in Mt. Maoer soils, and the BaP-metabolizing bacteria shifted to the microorganisms in the family Oxalobacteraceae (genus unclassified). Meanwhile, salicylate addition did not change either BaP degradation or putative BaP degraders in Mt. Baicaowa. Polycyclic aromatic hydrocarbon ring-hydroxylating dioxygenase (PAH-RHD) genes were amplified, sequenced, and quantified in the DNA-SIP (13)C heavy fraction to further confirm the BaP metabolism. By illuminating the microbial diversity and salicylate additive effects on BaP degradation across different soils, the results increased our understanding of BaP natural attenuation and provided a possible approach to enhance the bioremediation of BaP-contaminated soils. PMID- 26253667 TI - Gene deletion strategy to examine the involvement of the two chondroitin lyases in Flavobacterium columnare virulence. AB - Flavobacterium columnare is an important bacterial pathogen of freshwater fish that causes high mortality of infected fish and heavy economic losses in aquaculture. The pathogenesis of this bacterium is poorly understood, in part due to the lack of efficient methods for genetic manipulation. In this study, a gene deletion strategy was developed and used to determine the relationship between the production of chondroitin lyases and virulence. The F. johnsoniae ompA promoter (PompA) was fused to sacB to construct a counterselectable marker for F. columnare. F. columnare carrying PompA-sacB failed to grow on media containing 10% sucrose. A suicide vector carrying PompA-sacB was constructed, and a gene deletion strategy was developed. Using this approach, the chondroitin lyase encoding genes, cslA and cslB, were deleted. The DeltacslA and DeltacslB mutants were both partially deficient in digestion of chondroitin sulfate A, whereas a double mutant (DeltacslA DeltacslB) was completely deficient in chondroitin lyase activity. Cells of F. columnare wild-type strain G4 and of the chondroitin lyase deficient DeltacslA DeltacslB mutant exhibited similar levels of virulence toward grass carp in single-strain infections. Coinfections, however, revealed a competitive advantage for the wild type over the chondroitin lyase mutant. The results indicate that chondroitin lyases are not essential virulence factors of F. columnare but may contribute to the ability of the pathogen to compete and cause disease in natural infections. The gene deletion method developed in this study may be employed to investigate the virulence factors of this bacterium and may have wide application in many other members of the phylum Bacteroidetes. PMID- 26253668 TI - A model of extracellular enzymes in free-living microbes: which strategy pays off? AB - An initial modeling approach was applied to analyze how a single, nonmotile, free living, heterotrophic bacterial cell may optimize the deployment of its extracellular enzymes. Free-living cells live in a dilute and complex substrate field, and to gain enough substrate, their extracellular enzymes must be utilized efficiently. The model revealed that surface-attached and free enzymes generate unique enzyme and substrate fields, and each deployment strategy has distinctive advantages. For a solitary cell, surface-attached enzymes are suggested to be the most cost-efficient strategy. This strategy entails potential substrates being reduced to very low concentrations. Free enzymes, on the other hand, generate a radically different substrate field, which suggests significant benefits for the strategy if free cells engage in social foraging or experience high substrate concentrations. Swimming has a slight positive effect for the attached-enzyme strategy, while the effect is negative for the free-enzyme strategy. The results of this study suggest that specific dissolved organic compounds in the ocean likely persist below a threshold concentration impervious to biological utilization. This could help explain the persistence and apparent refractory state of oceanic dissolved organic matter (DOM). Microbial extracellular enzyme strategies, therefore, have important implications for larger-scale processes, such as shaping the role of DOM in ocean carbon sequestration. PMID- 26253669 TI - Prophage lysin Ply30 protects mice from Streptococcus suis and Streptococcus equi subsp. zooepidemicus infections. AB - Streptococcus suis and Streptococcus equi subsp. zooepidemicus are capable of infecting humans and various animals, causing significant problems for the worldwide swine industry. As antibiotic resistance has increased, lysosomal enzymes encoded by phages have shown potential for use against pathogenic bacteria. In this study, a novel bacteriophage lysin, Ply30, encoded by the S. suis prophage phi30c, was recombinantly expressed and purified. Ply30 showed high bacteriolysis activity on S. suis and S. equi subsp. zooepidemicus in vitro. The ratio of the optical density at 600 nm (OD600) with treatment versus the OD600 with no treatment for most tested S. suis and S. equi subsp. zooepidemicus strains decreased from 1 to <0.3 and <0.5, respectively, within 1 h. The results of plate viability assays showed that treated bacteria suffered a 1- to 2-log decrease in CFU within 1 h. The optimal concentration of Ply30 was 50 MUg/ml, and the optimal pH was 7. Moreover, Ply30 maintained high activity over a wide pH range (pH 6 to 10). The MICs of Ply30 against Streptococcus strains ranged from 16 to 512 MUg/ml. In vivo, a 2-mg dose of Ply30 protected 90% (9/10 mice) of mice from infection with S. equi subsp. zooepidemicus and 80% (8/10 mice) of mice from infection with S. suis. Seven days after lysin Ply30 treatment, bacterial loads were significantly decreased in all tested organs and blood compared with those at 1 h postinfection without Ply30 treatment. Ply30 showed in vitro and in vivo antimicrobial efficiency and protected mice against two kinds of bacterial infections, indicating that Ply30 may be an effective therapeutic against streptococci. PMID- 26253670 TI - Comparative Analysis of Extremely Thermophilic Caldicellulosiruptor Species Reveals Common and Unique Cellular Strategies for Plant Biomass Utilization. AB - Microbiological, genomic and transcriptomic analyses were used to examine three species from the bacterial genus Caldicellulosiruptor with respect to their capacity to convert the carbohydrate content of lignocellulosic biomass at 70 degrees C to simple sugars, acetate, lactate, CO2, and H2. Caldicellulosiruptor bescii, C. kronotskyensis, and C. saccharolyticus solubilized 38%, 36%, and 29% (by weight) of unpretreated switchgrass (Panicum virgatum) (5 g/liter), respectively, which was about half of the amount of crystalline cellulose (Avicel; 5 g/liter) that was solubilized under the same conditions. The lower yields with C. saccharolyticus, not appreciably greater than the thermal control for switchgrass, were unexpected, given that its genome encodes the same glycoside hydrolase 9 (GH9)-GH48 multidomain cellulase (CelA) found in the other two species. However, the genome of C. saccharolyticus lacks two other cellulases with GH48 domains, which could be responsible for its lower levels of solubilization. Transcriptomes for growth of each species comparing cellulose to switchgrass showed that many carbohydrate ABC transporters and multidomain extracellular glycoside hydrolases were differentially regulated, reflecting the heterogeneity of lignocellulose. However, significant differences in transcription levels for conserved genes among the three species were noted, indicating unexpectedly diverse regulatory strategies for deconstruction for these closely related bacteria. Genes encoding the Che-type chemotaxis system and flagellum biosynthesis were upregulated in C. kronotskyensis and C. bescii during growth on cellulose, implicating motility in substrate utilization. The results here show that capacity for plant biomass deconstruction varies across Caldicellulosiruptor species and depends in a complex way on GH genome inventory, substrate composition, and gene regulation. PMID- 26253671 TI - A Genomic View of Lactobacilli and Pediococci Demonstrates that Phylogeny Matches Ecology and Physiology. AB - Lactobacilli are used widely in food, feed, and health applications. The taxonomy of the genus Lactobacillus, however, is confounded by the apparent lack of physiological markers for phylogenetic groups of lactobacilli and the unclear relationships between the diverse phylogenetic groups. This study used the core and pan-genomes of 174 type strains of Lactobacillus and Pediococcus to establish phylogenetic relationships and to identify metabolic properties differentiating phylogenetic groups. The core genome phylogenetic tree separated homofermentative lactobacilli and pediococci from heterofermentative lactobacilli. Aldolase and phosphofructokinase were generally present in homofermentative but not in heterofermentative lactobacilli; a two-domain alcohol dehydrogenase and mannitol dehydrogenase were present in most heterofermentative lactobacilli but absent in most homofermentative organisms. Other genes were predominantly present in homofermentative lactobacilli (pyruvate formate lyase) or heterofermentative lactobacilli (lactaldehyde dehydrogenase and glycerol dehydratase). Cluster analysis of the phylogenomic tree and the average nucleotide identity grouped the genus Lactobacillus sensu lato into 24 phylogenetic groups, including pediococci, with stable intra- and intergroup relationships. Individual groups may be differentiated by characteristic metabolic properties. The link between phylogeny and physiology that is proposed in this study facilitates future studies on the ecology, physiology, and industrial applications of lactobacilli. PMID- 26253672 TI - Impacts of Long-Term Irrigation of Domestic Treated Wastewater on Soil Biogeochemistry and Bacterial Community Structure. AB - Freshwater scarcity and regulations on wastewater disposal have necessitated the reuse of treated wastewater (TWW) for soil irrigation, which has several environmental and economic benefits. However, TWW irrigation can cause nutrient loading to the receiving environments. We assessed bacterial community structure and associated biogeochemical changes in soil plots irrigated with nitrate-rich TWW (referred to as pivots) for periods ranging from 13 to 30 years. Soil cores (0 to 40 cm) were collected in summer and winter from five irrigated pivots and three adjacently located nonirrigated plots. Total bacterial and denitrifier gene abundances were estimated by quantitative PCR (qPCR), and community structure was assessed by 454 massively parallel tag sequencing (MPTS) of small-subunit (SSU) rRNA genes along with terminal restriction fragment length polymorphism (T-RFLP) analysis of nirK, nirS, and nosZ functional genes responsible for denitrification of the TWW-associated nitrate. Soil physicochemical analyses showed that, regardless of the seasons, pH and moisture contents (MC) were higher in the irrigated (IR) pivots than in the nonirrigated (NIR) plots; organic matter (OM) and microbial biomass carbon (MBC) were higher as a function of season but not of irrigation treatment. MPTS analysis showed that TWW loading resulted in the following: (i) an increase in the relative abundance of Proteobacteria, especially Betaproteobacteria and Gammaproteobacteria; (ii) a decrease in the relative abundance of Actinobacteria; (iii) shifts in the communities of acidobacterial groups, along with a shift in the nirK and nirS denitrifier guilds as shown by T-RFLP analysis. Additionally, bacterial biomass estimated by genus/group-specific real-time qPCR analyses revealed that higher numbers of total bacteria, Acidobacteria, Actinobacteria, Alphaproteobacteria, and the nirS denitrifier guilds were present in the IR pivots than in the NIR plots. Identification of the nirK-containing microbiota as a proxy for the denitrifier community indicated that bacteria belonged to alphaproteobacteria from the Rhizobiaceae family within the agroecosystem studied. Multivariate statistical analyses further confirmed some of the above soil physicochemical and bacterial community structure changes as a function of long-term TWW application within this agroecosystem. PMID- 26253674 TI - Identification of the Gene Cluster for the Anaerobic Degradation of 3,5 Dihydroxybenzoate (alpha-Resorcylate) in Thauera aromatica Strain AR-1. AB - Thauera aromatica strain AR-1 degrades 3,5-dihydroxybenzoate (3,5-DHB) with nitrate as an electron acceptor. Previous biochemical studies have shown that this strain converts 3,5-DHB to hydroxyhydroquinone (1,2,4-trihydroxybenzene) through water-dependent hydroxylation of the aromatic ring and subsequent decarboxylation, and they suggest a pathway homologous to that described for the anaerobic degradation of 1,3-dihydroxybenzene (resorcinol) by Azoarcus anaerobius. Southern hybridization of a T. aromatica strain AR-1 gene library identified a 25-kb chromosome region based on its homology with A. anaerobius main pathway genes. Sequence analysis defined 20 open reading frames. Knockout mutations of the most relevant genes in the pathway were generated by reverse genetics. Physiological and biochemical analyses identified the genes for the three main steps in the pathway which were homologous to those described in A. anaerobius and suggested the function of several auxiliary genes possibly involved in enzyme maturation and intermediate stabilization. However, T. aromatica strain AR-1 had an additional enzyme to metabolize hydroxyhydroquinone, a putative cytoplasmic quinone oxidoreductase. In addition, a specific tripartite ATP-independent periplasmic (TRAP) transport system was required for efficient growth on 3,5-DHB. Reverse transcription-PCR (RT-PCR) analysis showed that the pathway genes were organized in five 3,5-DHB-inducible operons, three of which have been shown to be under the control of a single LysR-type transcriptional regulator, DbdR. Despite sequence homology, the genetic organizations of the clusters in T. aromatica strain AR-1 and A. anaerobius differed substantially. PMID- 26253673 TI - Deciphering the Diversities of Astroviruses and Noroviruses in Wastewater Treatment Plant Effluents by a High-Throughput Sequencing Method. AB - Although clinical epidemiology lists human enteric viruses to be among the primary causes of acute gastroenteritis in the human population, their circulation in the environment remains poorly investigated. These viruses are excreted by the human population into sewers and may be released into rivers through the effluents of wastewater treatment plants (WWTPs). In order to evaluate the viral diversity and loads in WWTP effluents of the Paris, France, urban area, which includes about 9 million inhabitants (approximately 15% of the French population), the seasonal occurrence of astroviruses and noroviruses in 100 WWTP effluent samples was investigated over 1 year. The coupling of these measurements with a high-throughput sequencing approach allowed the specific estimation of the diversity of human astroviruses (human astrovirus genotype 1 [HAstV-1], HAstV-2, HAstV-5, and HAstV-6), 7 genotypes of noroviruses (NoVs) of genogroup I (NoV GI.1 to NoV GI.6 and NoV GI.8), and 16 genotypes of NoVs of genogroup II (NoV GII.1 to NoV GII.7, NoV GII.9, NoV GII.12 to NoV GII.17, NoV GII.20, and NoV GII.21) in effluent samples. Comparison of the viral diversity in WWTP effluents to the viral diversity found by analysis of clinical data obtained throughout France underlined the consistency between the identified genotypes. However, some genotypes were locally present in effluents and were not found in the analysis of the clinical data. These findings could highlight an underestimation of the diversity of enteric viruses circulating in the human population. Consequently, analysis of WWTP effluents could allow the exploration of viral diversity not only in environmental waters but also in a human population linked to a sewerage network in order to better comprehend viral epidemiology and to forecast seasonal outbreaks. PMID- 26253675 TI - Scarless Genome Editing and Stable Inducible Expression Vectors for Geobacter sulfurreducens. AB - Metal reduction by members of the Geobacteraceae is encoded by multiple gene clusters, and the study of extracellular electron transfer often requires biofilm development on surfaces. Genetic tools that utilize polar antibiotic cassette insertions limit mutant construction and complementation. In addition, unstable plasmids create metabolic burdens that slow growth, and the presence of antibiotics such as kanamycin can interfere with the rate and extent of Geobacter biofilm growth. We report here genetic system improvements for the model anaerobic metal-reducing bacterium Geobacter sulfurreducens. A motile strain of G. sulfurreducens was constructed by precise removal of a transposon interrupting the fgrM flagellar regulator gene using SacB/sucrose counterselection, and Fe(III) citrate reduction was eliminated by deletion of the gene encoding the inner membrane cytochrome imcH. We also show that RK2-based plasmids were maintained in G. sulfurreducens for over 15 generations in the absence of antibiotic selection in contrast to unstable pBBR1 plasmids. Therefore, we engineered a series of new RK2 vectors containing native constitutive Geobacter promoters, and modified one of these promoters for VanR-dependent induction by the small aromatic carboxylic acid vanillate. Inducible plasmids fully complemented DeltaimcH mutants for Fe(III) reduction, Mn(IV) oxide reduction, and growth on poised electrodes. A real-time, high-throughput Fe(III) citrate reduction assay is described that can screen numerous G. sulfurreducens strain constructs simultaneously and shows the sensitivity of imcH expression by the vanillate system. These tools will enable more sophisticated genetic studies in G. sulfurreducens without polar insertion effects or need for multiple antibiotics. PMID- 26253676 TI - Viral Agents Causing Brown Cap Mushroom Disease of Agaricus bisporus. AB - The symptoms of viral infections of fungi range from cryptic to severe, but there is little knowledge of the factors involved in this transition of fungal/viral interactions. Brown cap mushroom disease of the cultivated Agaricus bisporus is economically important and represents a model system to describe this transition. Differentially expressed transcript fragments between mushrooms showing the symptoms of brown cap mushroom disease and control white noninfected mushrooms have been identified and sequenced. Ten of these RNA fragments have been found to be upregulated over 1,000-fold between diseased and nondiseased tissue but are absent from the Agaricus bisporus genome sequence and hybridize to double stranded RNAs extracted from diseased tissue. We hypothesize that these transcript fragments are viral and represent components of the disease-causing agent, a bipartite virus with similarities to the family Partitiviridae. The virus fragments were found at two distinct levels within infected mushrooms, at raised levels in infected, nonsymptomatic, white mushrooms and at much greater levels (3,500 to 87,000 times greater) in infected mushrooms exhibiting brown coloration. In addition, differential screening revealed 9 upregulated and 32 downregulated host Agaricus bisporus transcripts. Chromametric analysis was able to distinguish color differences between noninfected white mushrooms and white infected mushrooms at an early stage of mushroom growth. This method may be the basis for an "on-farm" disease detection assay. PMID- 26253677 TI - Alcohol Selectivity in a Synthetic Thermophilic n-Butanol Pathway Is Driven by Biocatalytic and Thermostability Characteristics of Constituent Enzymes. AB - n-Butanol is generated as a natural product of metabolism by several microorganisms, but almost all grow at mesophilic temperatures. A synthetic pathway for n-butanol production from acetyl coenzyme A (acetyl-CoA) that functioned at 70 degrees C was assembled in vitro from enzymes recruited from thermophilic bacteria to inform efforts for engineering butanol production into thermophilic hosts. Recombinant versions of eight thermophilic enzymes (beta ketothiolase [Thl], 3-hydroxybutyryl-CoA dehydrogenase [Hbd], and 3 hydroxybutyryl-CoA dehydratase [Crt] from Caldanaerobacter subterraneus subsp. tengcongensis; trans-2-enoyl-CoA reductase [Ter] from Spirochaeta thermophila; bifunctional acetaldehyde dehydrogenase/alcohol dehydrogenase [AdhE] from Clostridium thermocellum; and AdhE, aldehyde dehydrogenase [Bad], and butanol dehydrogenase [Bdh] from Thermoanaerobacter sp. strain X514) were utilized to examine three possible pathways for n-butanol. These pathways differed in the two steps required to convert butyryl-CoA to n-butanol: Thl-Hbd-Crt-Ter-AdhE (C. thermocellum), Thl-Hbd-Crt-Ter-AdhE (Thermoanaerobacter X514), and Thl-Hbd-Crt Ter-Bad-Bdh. n-Butanol was produced at 70 degrees C, but with different amounts of ethanol as a coproduct, because of the broad substrate specificities of AdhE, Bad, and Bdh. A reaction kinetics model, validated via comparison to in vitro experiments, was used to determine relative enzyme ratios needed to maximize n butanol production. By using large relative amounts of Thl and Hbd and small amounts of Bad and Bdh, >70% conversion to n-butanol was observed in vitro, but with a 60% decrease in the predicted pathway flux. With more-selective hypothetical versions of Bad and Bdh, >70% conversion to n-butanol is predicted, with a 19% increase in pathway flux. Thus, more-selective thermophilic versions of Bad, Bdh, and AdhE are needed to fully exploit biocatalytic n-butanol production at elevated temperatures. PMID- 26253678 TI - Biochemical Characterization of the Lactobacillus reuteri Glycoside Hydrolase Family 70 GTFB Type of 4,6-alpha-Glucanotransferase Enzymes That Synthesize Soluble Dietary Starch Fibers. AB - 4,6-alpha-Glucanotransferase (4,6-alpha-GTase) enzymes, such as GTFB and GTFW of Lactobacillus reuteri strains, constitute a new reaction specificity in glycoside hydrolase family 70 (GH70) and are novel enzymes that convert starch or starch hydrolysates into isomalto/maltopolysaccharides (IMMPs). These IMMPs still have linear chains with some alpha1->4 linkages but mostly (relatively long) linear chains with alpha1->6 linkages and are soluble dietary starch fibers. 4,6-alpha GTase enzymes and their products have significant potential for industrial applications. Here we report that an N-terminal truncation (amino acids 1 to 733) strongly enhances the soluble expression level of fully active GTFB-DeltaN (approximately 75-fold compared to full-length wild type GTFB) in Escherichia coli. In addition, quantitative assays based on amylose V as the substrate are described; these assays allow accurate determination of both hydrolysis (minor) activity (glucose release, reducing power) and total activity (iodine staining) and calculation of the transferase (major) activity of these 4,6-alpha-GTase enzymes. The data show that GTFB-DeltaN is clearly less hydrolytic than GTFW, which is also supported by nuclear magnetic resonance (NMR) analysis of their final products. From these assays, the biochemical properties of GTFB-DeltaN were characterized in detail, including determination of kinetic parameters and acceptor substrate specificity. The GTFB enzyme displayed high conversion yields at relatively high substrate concentrations, a promising feature for industrial application. PMID- 26253679 TI - Circulation of Coxiella burnetii in a Naturally Infected Flock of Dairy Sheep: Shedding Dynamics, Environmental Contamination, and Genotype Diversity. AB - Q fever is a worldwide zoonosis caused by Coxiella burnetii. Domestic ruminants are considered to be the main reservoir. Sheep, in particular, may frequently cause outbreaks in humans. Because within-flock circulation data are essential to implementing optimal management strategies, we performed a follow-up study of a naturally infected flock of dairy sheep. We aimed to (i) describe C. burnetii shedding dynamics by sampling vaginal mucus, feces, and milk, (ii) assess circulating strain diversity, and (iii) quantify barn environmental contamination. For 8 months, we sampled vaginal mucus and feces every 3 weeks from aborting and nonaborting ewes (n=11 and n=26, respectively); for lactating females, milk was obtained as well. We also sampled vaginal mucus from nine ewe lambs. Dust and air samples were collected every 3 and 6 weeks, respectively. All samples were screened using real-time PCR, and strongly positive samples were further analyzed using quantitative PCR. Vaginal and fecal samples with sufficient bacterial burdens were then genotyped by multiple-locus variable number tandem-repeat analysis (MLVA) using 17 markers. C. burnetii burdens were higher in vaginal mucus and feces than in milk, and they peaked in the first 3 weeks postabortion or postpartum. Primiparous females and aborting females tended to shed C. burnetii longer and have higher bacterial burdens than nonaborting and multiparous females. Six genotype clusters were identified; they were independent of abortion status, and within-individual genotype diversity was observed. C. burnetii was also detected in air and dust samples. Further studies should determine whether the within-flock circulation dynamics observed here are generalizable. PMID- 26253680 TI - The Hybrid Pre-CTXPhi-RS1 Prophage Genome and Its Regulatory Function in Environmental Vibrio cholerae O1 Strains. AB - The cholera toxin genes of Vibrio cholerae are encoded by CTXPhi, a lysogenic bacteriophage. Infection with this phage plays a determinant role in toxigenicity conversion and the emergence of new clones of pathogenic V. cholerae. Multiple phage alleles, defined by sequence types of the repressor gene rstR, have been found, showing the divergence of phage genomes. Pre-CTXPhi, which is characterized by the absence of toxin genes, is predicted to be the precursor of CTXPhi. We have found a new pre-CTXPhi prophage genome (named pre-CTXZJPhi for its novel rstR allele) in nontoxigenic V. cholerae O1 isolates that were obtained during surveillance of the estuary water of the Zhujiang River. A novel hybrid genome of the helper phage RS1 was identified in an environmental strain carrying pre-CTXZJPhi in this study. The chromosomal integration and genomic arrangement of pre-CTXZJPhi and RS1 were determined. The RS2 of pre-CTXZJPhi was shown to have a function in replication, but it seemed to have lost its ability to integrate. The RstR of pre-CTXZJPhi exerted the highest repression of its own rstA promoter compared to other RstRs, suggesting rstR-specific phage superinfection immunity and potential coinfection with other pre-CTXPhi/CTXPhi alleles. The environmental strain carrying pre-CTXZJPhi could still be infected by CTXETPhi, the most common phage allele in the strains of the seventh cholera pandemic, suggesting that this nontoxigenic clone could potentially undergo toxigenicity conversion by CTXPhi infection and become a new toxigenic clone despite already containing the pre-CTXPhi prophage. PMID- 26253681 TI - Changes in Microbial Biofilm Communities during Colonization of Sewer Systems. AB - The coexistence of sulfate-reducing bacteria (SRB) and methanogenic archaea (MA) in anaerobic biofilms developed in sewer inner pipe surfaces favors the accumulation of sulfide (H2S) and methane (CH4) as metabolic end products, causing severe impacts on sewerage systems. In this study, we investigated the time course of H2S and CH4 production and emission rates during different stages of biofilm development in relation to changes in the composition of microbial biofilm communities. The study was carried out in a laboratory sewer pilot plant that mimics a full-scale anaerobic rising sewer using a combination of process data and molecular techniques (e.g., quantitative PCR [qPCR], denaturing gradient gel electrophoresis [DGGE], and 16S rRNA gene pyrotag sequencing). After 2 weeks of biofilm growth, H2S emission was notably high (290.7+/-72.3 mg S-H2S liter(-1) day(-1)), whereas emissions of CH4 remained low (17.9+/-15.9 mg COD-CH4 liter(-1) day(-1)). This contrasting trend coincided with a stable SRB community and an archaeal community composed solely of methanogens derived from the human gut (i.e., Methanobrevibacter and Methanosphaera). In turn, CH4 emissions increased after 1 year of biofilm growth (327.6+/-16.6 mg COD-CH4 liter(-1) day(-1)), coinciding with the replacement of methanogenic colonizers by species more adapted to sewer conditions (i.e., Methanosaeta spp.). Our study provides data that confirm the capacity of our laboratory experimental system to mimic the functioning of full-scale sewers both microbiologically and operationally in terms of sulfide and methane production, gaining insight into the complex dynamics of key microbial groups during biofilm development. PMID- 26253683 TI - Resistance of Aerosolized Bacterial Viruses to Relative Humidity and Temperature. AB - The use of aerosolized bacteriophages as surrogates for hazardous viruses might simplify and accelerate the discovery of links between viral components and their persistence in the airborne state under diverse environmental conditions. In this study, four structurally distinct lytic phages, MS2 (single-stranded RNA [ssRNA]), phi6 (double-stranded RNA [dsRNA]), phiX174 (single-stranded DNA [ssDNA]), and PR772 (double-stranded DNA [dsDNA]), were nebulized into a rotating chamber and exposed to various levels of relative humidity (RH) and temperature as well as to germicidal UV radiation. The aerosolized viral particles were allowed to remain airborne for up to 14 h before being sampled for analysis by plaque assays and quantitative PCRs. Phages phi6 and MS2 were the most resistant at low levels of relative humidity, while phiX174 was more resistant at 80% RH. Phage phi6 lost its infectivity immediately after exposure to 30 degrees C and 80% RH. The infectivity of all tested phages rapidly declined as a function of the exposure time to UVC radiation, phage MS2 being the most resistant. Taken altogether, our data indicate that these aerosolized phages behave differently under various environmental conditions and highlight the necessity of carefully selecting viral simulants in bioaerosol studies. PMID- 26253682 TI - phoD Alkaline Phosphatase Gene Diversity in Soil. AB - Phosphatase enzymes are responsible for much of the recycling of organic phosphorus in soils. The PhoD alkaline phosphatase takes part in this process by hydrolyzing a range of organic phosphoesters. We analyzed the taxonomic and environmental distribution of phoD genes using whole-genome and metagenome databases. phoD alkaline phosphatase was found to be spread across 20 bacterial phyla and was ubiquitous in the environment, with the greatest abundance in soil. To study the great diversity of phoD, we developed a new set of primers which targets phoD genes in soil. The primer set was validated by 454 sequencing of six soils collected from two continents with different climates and soil properties and was compared to previously published primers. Up to 685 different phoD operational taxonomic units were found in each soil, which was 7 times higher than with previously published primers. The new primers amplified sequences belonging to 13 phyla, including 71 families. The most prevalent phoD genes identified in these soils were affiliated with the orders Actinomycetales (13 to 35%), Bacillales (1 to 29%), Gloeobacterales (1 to 18%), Rhizobiales (18 to 27%), and Pseudomonadales (0 to 22%). The primers also amplified phoD genes from additional orders, including Burkholderiales, Caulobacterales, Deinococcales, Planctomycetales, and Xanthomonadales, which represented the major differences in phoD composition between samples, highlighting the singularity of each community. Additionally, the phoD bacterial community structure was strongly related to soil pH, which varied between 4.2 and 6.8. These primers reveal the diversity of phoD in soil and represent a valuable tool for the study of phoD alkaline phosphatase in environmental samples. PMID- 26253684 TI - Red Fluorescent Proteins for Gene Expression and Protein Localization Studies in Streptococcus pneumoniae and Efficient Transformation with DNA Assembled via the Gibson Assembly Method. AB - During the last decades, a wide range of fluorescent proteins (FPs) have been developed and improved. This has had a great impact on the possibilities in biological imaging and the investigation of cellular processes at the single-cell level. Recently, we have benchmarked a set of green fluorescent proteins (GFPs) and generated a codon-optimized superfolder GFP for efficient use in the important human pathogen Streptococcus pneumoniae and other low-GC Gram-positive bacteria. In the present work, we constructed and compared four red fluorescent proteins (RFPs) in S. pneumoniae. Two orange-red variants, mOrange2 and TagRFP, and two far-red FPs, mKate2 and mCherry, were codon optimized and examined by fluorescence microscopy and plate reader assays. Notably, protein fusions of the RFPs to FtsZ were constructed by direct transformation of linear Gibson assembly (isothermal assembly) products, a method that speeds up the strain construction process significantly. Our data show that mCherry is the fastest-maturing RFP in S. pneumoniae and is best suited for studying gene expression, while mKate2 and TagRFP are more stable and are the preferred choices for protein localization studies. The RFPs described here will be useful for cell biology studies that require multicolor labeling in S. pneumoniae and related organisms. PMID- 26253685 TI - Interactions between Cooccurring Lactic Acid Bacteria in Honey Bee Hives. AB - In contrast to the honey bee gut, which is colonized by a few characteristic bacterial clades, the hive of the honey bee is home to a diverse array of microbes, including many lactic acid bacteria (LAB). In this study, we used culture, combined with sequencing, to sample the LAB communities found across hive environments. Specifically, we sought to use network analysis to identify microbial hubs sharing nearly identical operational taxonomic units, evidence which may indicate cooccurrence of bacteria between environments. In the process, we identified interactions between noncore bacterial members (Fructobacillus and Lactobacillaceae) and honey bee-specific "core" members. Both Fructobacillus and Lactobacillaceae colonize brood cells, bee bread, and nectar and may serve the role of pioneering species, establishing an environment conducive to the inoculation by honey bee core bacteria. Coculture assays showed that these noncore bacterial members promote the growth of honey bee-specific bacterial species. Specifically, Fructobacillus by-products in spent medium supported the growth of the Firm-5 honey bee-specific clade in vitro. Metabolic characterization of Fructobacillus using carbohydrate utilization assays revealed that this strain is capable of utilizing the simple sugars fructose and glucose, as well as the complex plant carbohydrate lignin. We tested Fructobacillus for antibiotic sensitivity and found that this bacterium, which may be important for establishment of the microbiome, is sensitive to the commonly used antibiotic tetracycline. Our results point to the possible significance of "noncore" and environmental microbial community members in the modulation of honey bee microbiome dynamics and suggest that tetracycline use by beekeepers should be limited. PMID- 26253686 TI - Dipotassium glycyrrhizate via HMGB1 or AMPK signaling suppresses oxidative stress during intestinal inflammation. AB - AIMS: Oxidative stress and inflammation are always associated. Appropriate management of oxidative mediators may represent a therapeutic strategy to reduce inflammation, and use of antioxidant can be protective against inflammatory diseases. Glycyrrhizin (GL) plays an anti-inflammatory and antioxidant effect by inhibiting high mobility group box 1 (HMGB1) or 11-beta-hydroxysteroid dehydrogenase type II (11betaHSD2) enzyme. In this study, the potential role of dipotassium glycyrrhizate (DPG), a salt of GL, to reduce oxidative stress in intestinal inflammatory condition was investigated in vivo and the mechanism of action of DPG was studied in vitro. RESULTS: In a colitis mouse model DPG affected oxidative stress reducing iNOS and COX-2 expression, as well as NO and PGE2 levels. By means of LPS-stimulated macrophages we found that DPG inhibited the expression of pro-inflammatory cytokines and reduced iNOS and COX-2 expression in a time dependent manner, through two different ways of signal. DPG reduced, at a later time, both iNOS and COX-2, through a mechanism HMGB1 dependent, and at an earlier time only COX-2, through a mechanism AMP-activated kinase (AMPK)-phosphorylation-mediated. CONCLUSION: DPG has a protective effect on colitis and inflammation through the inhibition of oxidative stress. This study clarifies the two-ways mechanism by which DPG inhibits iNOS and COX-2 during inflammation and demonstrates for the first time that AMPK is a target of DPG. Uncovering this mechanism is significant to clarify the relationship between energy homeostasis and anti-oxidative responses and suggests that DPG could play a relevant role in the development of new therapy against inflammatory diseases associated to oxidative stress. PMID- 26253687 TI - Combinatorial approach to increase efficacy of Cetuximab, Panitumumab and Trastuzumab by dianthin conjugation and co-application of SO1861. AB - The therapeutic relevance of immunotoxins is based on the conjugation of monoclonal antibodies to toxins. In cancer therapies, the conjugated antibodies not only direct the binding of immunotoxins to cancer-specific receptors and mediate the elimination of tumor cells through the innate immune system, but also increase target cytotoxicity by the intrinsic toxin activity. In the present study, the therapeutic antibodies Cetuximab (anti-EGFR, Erbitux((r))), Panitumumab (anti-EGFR, Vectibix((r))) and Trastuzumab (anti-HER2, Herceptin((r))) were chemically conjugated to the toxin dianthin. In the first instance, recombinant dianthin was characterized by mass spectrometry and its stability was analyzed by circular dichroism. Dianthin showed increased cytotoxicity on MCF-7 cells when tested in combination with a glycosylated triterpenoid (SO1861) in a real-time impedance-based cytotoxicity assay. In data obtained by live cell imaging, SO1861 specifically mediated the endo/lysosomal escape of dianthin without disrupting the plasma membrane. The purity of immunotoxins was confirmed by SDS-PAGE and Western blot. Their cytotoxicity was evaluated in the presence of SO1861 and dianthin-Cetuximab presented a GI50 (50% growth inhibition) of 5.3pM, dianthin-Panitumumab of 1.5pM, and dianthin Trastuzumab of 23pM. Finally, the specificity of these immunotoxins was validated in a fluorescence-based real-time assay, where their binding to target cells was prevented by preincubation with an excess of label-free unconjugated antibody. Based on these data, we propose the use of dianthin and SO1861 as a new platform technology to enhance the efficacy of therapeutic antibodies. PMID- 26253688 TI - From covalent bonds to eco-physiological pharmacology of secondary plant metabolites. AB - Despite the availability of numerous drugs and other therapeutic modalities, the prevention and cure of over- and under-nutrition triggered metabolic and other disease states continues as a major challenge for modern medicine. Such silently progressing and eventually life-threatening diseases often accompany diverse spectrum of comorbid psychiatric disorders. Majority of the global population suffering from metabolic diseases live in economically developing or underdeveloped countries, where due to socioeconomic, cultural, and other reasons, therapies may be unavailable. Evidence from preclinical, clinical, and epidemiological studies of numerous structurally and functionally diverse secondary metabolites of plants suggest that many of these could be promising therapeutic leads for the treatment and prevention of malnutrition-associated diseases and mental health problems. The review discusses the potential therapeutic uses of secondary plant metabolites and their bacterial and mammalian catabolites based on their bioactivity profiles, with special emphasis on their modulating effects on gut microbial ecology and physiological stress responses. Based on concepts in medicinal chemistry and pharmacology considerations that evolved during the author's interactions with David Triggle, secondary plant metabolites may represent an alternative and economically feasible approach to new drugs. PMID- 26253690 TI - Trunk postural control in unstable sitting: Effect of sex and low back pain status. AB - BACKGROUND: Adequate neuromuscular control of the lumbar spine is required to prevent lumbar injuries. A trunk postural control test protocol, controlling for the influence of body size on performance, was implemented to carry out between subject comparisons. The aim of this study was to assess the effect of sex and low back pain status with the use of two measures of trunk postural control, the first based on chair motion, and the second based on trunk motion. METHODS: Thirty-six subjects (with and without low back pain) performed three 60-s trunk postural control trials with their eyes closed while seated on an instrumented wobble chair, following a calibration procedure. Chair and trunk angular kinematics were measured with an optoelectronic system. A chair-based stabilogram and a trunk-based (lumbar spine) stabilogram were created using the angular motions produced in the sagittal and frontal planes. Twenty body-sway measures were computed for each stabilogram. FINDINGS: The calibration task efficiently controlled for the influence of body size. Several sex effects were detected, with most of them originating from the trunk-based measures. Subjects with low back pain and healthy controls showed comparable trunk postural control. INTERPRETATION: Sex differences were substantiated for the first time, but almost only with the trunk-based stabilogram, showing that the kinematic information captured on the trunk segments is quite different from what is captured on the wobble chair. Contrary to previous studies, pain status was not related to lowered trunk postural control, which can be attributed to the patients recruited or measurement reliability issues. PMID- 26253689 TI - Cigarettes and alcohol: The influence of nicotine on operant alcohol self administration and the mesolimbic dopamine system. AB - Studies in human populations consistently demonstrate an interaction between nicotine and ethanol use, each drug influencing the use of the other. Here we present data and review evidence from animal studies that nicotine influences operant self-administration of ethanol. The operant reinforcement paradigm has proven to be a behaviorally relevant and quantitative model for studying ethanol seeking behavior. Exposure to nicotine can modify the reinforcing properties of ethanol during different phases of ethanol self-administration, including acquisition, maintenance, and reinstatement. Our data suggest that non-daily intermittent nicotine exposure can trigger a long-lasting increase in ethanol self-administration. The biological basis for interactions between nicotine and ethanol is not well understood but may involve the stress hormone systems and adaptations in the mesolimbic dopamine system. Future studies that combine operant self-administration with techniques for monitoring or manipulating in vivo neurophysiology may provide new insights into the neuronal mechanisms that link nicotine and alcohol use. PMID- 26253691 TI - In vitro maturation (IVM) of oocytes recovered from ovariectomy specimens in the laboratory: a promising "ex vivo" method of oocyte cryopreservation resulting in the first report of an ongoing pregnancy in Europe. AB - PURPOSE: We present our center's experience with 34 consecutive cases who underwent in vitro maturation (IVM) of oocytes obtained from ovariectomy specimens and compare our data with updated literature data. METHODS: Feasibility and efficiency of oocyte collection during ovarian tissue processing was assessed by the recovery rate, maturation rate, and embryological development after IVM. RESULTS: On average, 14 immature oocytes were retrieved per patient during ovarian tissue processing in 33/34 patients. The overall maturation rate after IVM was 36%. The maturation rate correlated with the age of the patient and the duration of IVM. Predominately, oocyte vitrification was performed. Eight couples preferred embryo cryopreservation. Here, a 65% fertilization rate was obtained and at least one good-quality day 3 embryo was cryopreserved in 7/8 couples. The retrieval of oocytes ex vivo resulted in mature oocytes or embryos available for vitrification in 79% of patients. One patient with ovarian insufficiency following therapeutic embolization of the left uterine and the right ovarian artery because of an arteriovenous malformation had an embryo transfer of one good-quality warmed embryo generated after IVM ex vivo, which resulted in an ongoing clinical pregnancy. CONCLUSIONS: IVM of oocytes obtained ex vivo during the processing of ovarian cortex prior to cryopreservation is a procedure with emerging promise for patients at risk for fertility loss, as illustrated by the reported pregnancy. However, more data are needed in order to estimate the overall success rate and safety of this novel approach. PMID- 26253693 TI - Cullin 5-RING E3 ubiquitin ligases, new therapeutic targets? AB - Ubiquitylation is a reversible post-translational modification of proteins that controls a myriad of functions and cellular processes. It occurs through the sequential action of three distinct enzymes. E3 ubiquitin ligases (E3s) play the role of conductors of the ubiquitylation pathway making them attractive therapeutic targets. This review is dedicated to the largest family of multimeric E3s, the Cullin-RING E3 (CRL) family and more specifically to cullin 5 based CRLs that remains poorly characterized. PMID- 26253692 TI - The history of the CATH structural classification of protein domains. AB - This article presents a historical review of the protein structure classification database CATH. Together with the SCOP database, CATH remains comprehensive and reasonably up-to-date with the now more than 100,000 protein structures in the PDB. We review the expansion of the CATH and SCOP resources to capture predicted domain structures in the genome sequence data and to provide information on the likely functions of proteins mediated by their constituent domains. The establishment of comprehensive function annotation resources has also meant that domain families can be functionally annotated allowing insights into functional divergence and evolution within protein families. PMID- 26253694 TI - Strategies for detection and quantification of cysteine cathepsins-evolution from bench to bedside. AB - The cysteine cathepsins are a family of closely related thiol proteases, normally found in the endosomal and lysosomal compartments of cells. A growing body of evidence has clearly linked the dysregulated activity of these proteases with many diseases and pathological conditions, offering therapeutic, prognostic and diagnostic potential. However, these proteases are synthesised as inactive precursors and once activated, are controlled by factors such as pH and presence of endogenous inhibitors, meaning that overall protein and activity levels do not necessarily correlate. In order to fully appreciate the role and potential of these proteases, tools are required that can detect and quantify overall cathepsin activity. Two main strategies have evolved; synthetic substrates and protease-labelling with affinity-binding probes (or activity-based probes). This review examines recent innovations in these approaches as the field moves towards developing tools that could ultimately be used in patients for diagnostic or prognostic applications. PMID- 26253695 TI - Revisiting the metabolism and physiological functions of caprylic acid (C8:0) with special focus on ghrelin octanoylation. AB - Caprylic acid (octanoic acid, C8:0) belongs to the class of medium-chain saturated fatty acids (MCFAs). Dairy products and specific oils like coconut oil are natural sources of dietary C8:0 but higher intakes of this fatty acid can be provided with MCT (Medium-Chain Triglycerides) oil that consists in 75% of C8:0. MCFAs have physical and metabolic properties that are distinct from those of long chain saturated fatty acids (LCFAs >= 12 carbons). Beneficial physiological effects of dietary C8:0 have been studied for a long time and MCT oil has been used as a special energy source for patients suffering from pancreatic insufficiency, impaired lymphatic chylomicron transport and fat malabsorption. More recently, caprylic acid was also shown to acylate ghrelin, the only known peptide hormone with an orexigenic effect. Through its covalent binding to the ghrelin peptide, caprylic acid exhibits an emerging and specific role in modulating physiological functions themselves regulated by octanoylated ghrelin. Dietary caprylic acid is therefore now suspected to provide the ghrelin O acyltransferase (GOAT) enzyme with octanoyl-CoA co-substrates necessary for the acyl modification of ghrelin. This review tries to highlight the discrepancy between the formerly described beneficial effects of dietary MCFAs on body weight loss and the C8:0 newly reported effect on appetite stimulation via ghrelin octanoylation. The subsequent aim of this review is to demonstrate the relevance of carrying out further studies to better understand the physiological functions of this particular fatty acid. PMID- 26253696 TI - Modulatory role of the anti-apoptotic protein kinase CK2 in the sub-cellular localization of Fas associated death domain protein (FADD). AB - The Fas associated death domain protein (FADD) is the key adaptor molecule of the apoptotic signal triggered by death receptors of the TNF-R1 superfamily. Besides its crucial role in the apoptotic machinery, FADD has proved to be important in many biological processes like tumorigenesis, embryonic development or cell cycle progression. In a process to decipher the regulatory mechanisms underlying FADD regulation, we identified the anti-apoptotic kinase, CK2, as a new partner and regulator of FADD sub-cellular localization. The blockade of CK2 activity induced FADD re-localization within the cell. Moreover, cytoplasmic FADD was increased when CK2beta was knocked down. In vitro kinase and pull down assays confirmed that FADD could be phosphorylated by the CK2 holoenzyme. We found that phosphorylation is weak with CK2alpha alone and optimal in the presence of stoichiometric amounts of CK2alpha catalytic and CK2beta regulatory subunit, showing that FADD phosphorylation is undertaken by the CK2 holoenzyme in a CK2beta-driven fashion. We found that CK2 can phosphorylate FADD on the serine 200 and that this phosphorylation is important for nuclear localization of FADD. Altogether, our results show for the first time that multifaceted kinase, CK2, phosphorylates FADD and is involved in its sub-cellular localization. This work uncovered an important role of CK2 in stable FADD nuclear localization. PMID- 26253697 TI - Cognitive decline and the neighborhood environment. AB - PURPOSE: Little research has looked beyond individual factors to consider the influence of the neighborhood environment on cognitive function. A greater density of physical resources (e.g., recreational centers and parks) and institutional resources (e.g., community centers) may buffer cognitive decline by offering opportunities for physical activity and social interaction. METHODS: Using data from the Chicago Health and Aging Project (1993-2011), a prospective cohort study of 6518 adults of age 65 years or older, we fit a three-level growth curve model to examine the role of individual and neighborhood factors (objectively observed at the block group level) on trajectories of cognitive function (composite of East Boston Memory Test, symbol digit test, and Mini Mental State Examination) in later life. RESULTS: Net of individual factors, residence in a neighborhood with community resources, proximity to public transit, and public spaces in good condition were associated with slower rates of cognitive decline, possibly by increasing opportunities for social and physical activities or access to destinations that facilitate engagement in activities. CONCLUSIONS: These results highlight the role of neighborhood environments in buffering cognitive decline among older adults aging in place. PMID- 26253698 TI - From global agenda-setting to domestic implementation: successes and challenges of the global health network on tobacco control. AB - Global policy attention to tobacco control has increased significantly since the 1990 s and culminated in the first international treaty negotiated under the auspices of the World Health Organization--the Framework Convention on Tobacco Control (FCTC). Although the political process that led to the creation of the FCTC has been extensively researched, the FCTC's progression from an aspirational treaty towards a global health governance framework with tangible policy effects within FCTC member countries has not been well-understood to date. This article analyses the role of the global health network of tobacco control advocates and scientists, which formed during the FCTC negotiations during the late 1990 s, in translating countries' commitment to the FCTC into domestic policy change. By comparing the network's influence around two central tobacco control interventions (smoke-free environments and taxation), the study identifies several scope conditions, which have shaped the network's effectiveness around the FCTC's implementation: the complexity of the policy issue and the relative importance of non-health expertise, the required scope of domestic political buy in, the role of the general public as network allies, and the strength of policy opposition. These political factors had a greater influence on the network's success than the evidence base for the effectiveness of tobacco control interventions. The network's variable success points to a trade-off faced by global health networks between their need to maintain internal cohesion and their ability to form alliances with actors in their social environment. PMID- 26253699 TI - Sciences of the brain: The long road to scientific maturity and to present-day reductionism. AB - When examined in a long-term perspective, brain sciences demonstrate certain conceptual consistencies as well as theoretical oppositions that have lasted for centuries, ever since Ancient Greece. The neurosciences have progressed more on the basis of technological than conceptual advances, and the constant recuperation of new techniques from other sciences have led to a continually reductionist view of the brain and its functions. In a different perspective, if not opposite to the reductionism, are the psychological constructs and those that constitute the functional unity of individuals, which are still mysterious. In fact, the gap between these two approaches has never been larger than it is now. This chapter discusses the enduring nature of some of these problems and their recent consequences. PMID- 26253700 TI - The use of exome capture RNA-seq for highly degraded RNA with application to clinical cancer sequencing. AB - RNA-seq by poly(A) selection is currently the most common protocol for whole transcriptome sequencing as it provides a broad, detailed, and accurate view of the RNA landscape. Unfortunately, the utility of poly(A) libraries is greatly limited when the input RNA is degraded, which is the norm for research tissues and clinical samples, especially when specimens are formalin-fixed. To facilitate the use of RNA sequencing beyond cell lines and in the clinical setting, we developed an exome-capture transcriptome protocol with greatly improved performance on degraded RNA. Capture transcriptome libraries enable measuring absolute and differential gene expression, calling genetic variants, and detecting gene fusions. Through validation against gold-standard poly(A) and Ribo Zero libraries from intact RNA, we show that capture RNA-seq provides accurate and unbiased estimates of RNA abundance, uniform transcript coverage, and broad dynamic range. Unlike poly(A) selection and Ribo-Zero depletion, capture libraries retain these qualities regardless of RNA quality and provide excellent data from clinical specimens including formalin-fixed paraffin-embedded (FFPE) blocks. Systematic improvements across key applications of RNA-seq are shown on a cohort of prostate cancer patients and a set of clinical FFPE samples. Further, we demonstrate the utility of capture RNA-seq libraries in a patient with a highly malignant solitary fibrous tumor (SFT) enrolled in our clinical sequencing program called MI-ONCOSEQ. Capture transcriptome profiling from FFPE revealed two oncogenic fusions: the pathognomonic NAB2-STAT6 inversion and a therapeutically actionable BRAF fusion, which may drive this specific cancer's aggressive phenotype. PMID- 26253701 TI - CD3+ICOS+ T cells show differences in the synthesis of nitric oxide, IFN-gamma, and IL-10 in patients with pulmonary tuberculosis or in healthy household contacts. AB - Evidence indicates that more than 90 % of infected individuals never develop active tuberculosis. This fact highlights the relevance of the immune response in tuberculosis control. The inducible co-stimulator (ICOS) is a regulator of the function, differentiation, proliferation, and activation of T cells. Moreover, T cells synthesise nitric oxide (NO), interferon gamma (IFN-gamma), and interleukin (IL)-10, which help regulate the immune response to tuberculosis. Therefore, we assessed the synthesis of NO, IFN-gamma, and IL-10 in CD3+ICOS+ T cells from healthy individuals, household contacts (HHC), and patients with active pulmonary tuberculosis (PTB), previously stimulated with the antigen H37Rv. Our results indicated a significant increase in both the percentage of ICOS+ cells and CD3+ICOS+ T cells producing NO, IFN-gamma, and IL-10 in cells obtained from patients with PTB (p < 0.01). In addition, a high mitochondrial membrane potential (DeltaPsi m) in CD3+ICOS+ T cells was observed in the cells from HHC and from PTB patients, and is associated with the activation of T cells. In conclusion, results show that the CD3+ICOS+ T cells obtained from PTB patients are the main producers of NO, IFN-gamma, and IL-10. In addition, our results imply that NO is a modulator of ICOS expression of T cells from PTB patients. PMID- 26253702 TI - Overexpression Bax interacting factor-1 protects cortical neurons against cerebral ischemia-reperfusion injury through regulation of ERK1/2 pathway. AB - Bax interacting factor-1 (Bif-1), a multifunctional protein, can regulate cell apoptosis and autophagy. Up-regulation of Bif-1 expression has been associated with neuronal survival. Moreover, several studies have reported that Bif-1 is involved in ischemic stroke. However, the specific function of Bif-1 in cerebral ischemia-reperfusion (I/R) injury is not well understood. The aim of this study is to expose the potential protective effect of Bif-1 against cerebral I/R injury and its related mechanism. In the current study, we showed that adenovirus mediated Bif-1-overexpression promoted oxygen and glucose deprivation followed by reperfusion (OGD/R)-treated cortical neurons' survival and reduced the cell apoptotic rate. We found that caspase-3 activity was inhibited by Bif-1 overexpression. In addition, we observed that Bif-1 overexpression induces cell autophagy, and the autophagy-specific inhibitor 3-Methyladenine (3-MA) attenuates cell survival. Interestingly, knockdown of Bif-1 resulted in attenuation of neuron survival, promotion of cell apoptosis and suppression of cell autophagy in neurons. In addition, knockdown of Bif-1 inhibited ERK1/2 activation. Our observations implicated Bif-1 as a novel target of cerebral I/R injury and played a neuroprotective effect via promoting cell survival and reducing apoptosis. PMID- 26253703 TI - Rapid recovery of bilateral abducens nerve palsies after venous sinus stenting for idiopathic intracranial hypertension. PMID- 26253704 TI - Transcriptional transitions in Nicotiana benthamiana leaves upon induction of oil synthesis by WRINKLED1 homologs from diverse species and tissues. AB - BACKGROUND: Carbon accumulation and remobilization are essential mechanisms in plants to ensure energy transfer between plant tissues with different functions or metabolic needs and to support new generations. Knowledge about the regulation of carbon allocation into oil (triacylglycerol) in plant storage tissue can be of great economic and environmental importance for developing new high-yielding oil crops. Here, the effect on global gene expression as well as on physiological changes in leaves transiently expressing five homologs of the transcription factor WRINKLED1 (WRI1) originating from diverse species and tissues; Arabidopsis thaliana and potato (Solanum tuberosum) seed embryo, poplar (Populus trichocarpa) stem cambium, oat (Avena sativa) grain endosperm, and nutsedge (Cyperus esculentus) tuber parenchyma, were studied by agroinfiltration in Nicotiana benthamiana. RESULTS: All WRI1 homologs induced oil accumulation when expressed in leaf tissue. Transcriptome sequencing revealed that all homologs induced the same general patterns with a drastic shift in gene expression profiles of leaves from that of a typical source tissue to a source-limited sink-like tissue: Transcripts encoding enzymes for plastid uptake and metabolism of phosphoenolpyruvate, fatty acid and oil biosynthesis were up-regulated, as were also transcripts encoding starch degradation. Transcripts encoding enzymes in photosynthesis and starch synthesis were instead down-regulated. Moreover, transcripts representing fatty acid degradation were up-regulated indicating that fatty acids might be degraded to feed the increased need to channel carbons into fatty acid synthesis creating a futile cycle. RT-qPCR analysis of leaves expressing Arabidopsis WRI1 showed the temporal trends of transcripts selected as 'markers' for key metabolic pathways one to five days after agroinfiltration. Chlorophyll fluorescence measurements of leaves expressing Arabidopsis WRI1 showed a significant decrease in photosynthesis, even though effect on starch content could not be observed. CONCLUSIONS: This data gives for the first time a general view on the transcriptional transitions in leaf tissue upon induction of oil synthesis by WRI1. This yields important information about what effects WRI1 may exert on global gene expression during seed and embryo development. The results suggest why high oil content in leaf tissue cannot be achieved by solely transcriptional activation by WRI1, which can be essential knowledge in the development of new high-yielding oil crops. PMID- 26253706 TI - Phytochemicals as potential therapeutics for thrombocytopenia. AB - Medical knowledge has always relied on plants as the main sources of important beneficial compounds. Many species have been recognized to have medicinal properties and beneficial impact on health, e.g. antioxidant activity, digestive stimulation action, anti-inflammatory, antimicrobial, hypolipidemic, antimutagenic and anticarcinogenic potential. This review focuses on the promising role of plants and their products in attenuating thrombocytopenia, a common and complex bleeding disorder. When the platelet count decreases below 150,000/ul, it causes thrombocytopenia. This bleeding disorder is observed in 2.5 % of the normal population. The risk of spontaneous muco-cutaneous bleeding and life threatening intracranial haemorrhage or gastrointestinal bleeding increases rapidly when the platelet count decreases below 10,000/ul. The inability to provide supportive treatment to increase the platelet counts often proves fatal to patients. Currently, treatment for thrombocytopenia includes use of drugs or splenectomy or platelet transfusions, in severe cases. Recently, studies have shown platelet augmenting activity of various plant extracts. The effectiveness, toxicity and side effects of the phytochemicals have to be critically evaluated in clinical trials. An in depth understanding of the role and mechanism of these phytochemicals would lead to their successful implementation in treatment and management of thrombocytopenia and other related bleeding disorders. PMID- 26253705 TI - Flavonoids and Auxin Transport Inhibitors Rescue Symbiotic Nodulation in the Medicago truncatula Cytokinin Perception Mutant cre1. AB - Initiation of symbiotic nodules in legumes requires cytokinin signaling, but its mechanism of action is largely unknown. Here, we tested whether the failure to initiate nodules in the Medicago truncatula cytokinin perception mutant cre1 (cytokinin response1) is due to its altered ability to regulate auxin transport, auxin accumulation, and induction of flavonoids. We found that in the cre1 mutant, symbiotic rhizobia cannot locally alter acro- and basipetal auxin transport during nodule initiation and that these mutants show reduced auxin (indole-3-acetic acid) accumulation and auxin responses compared with the wild type. Quantification of flavonoids, which can act as endogenous auxin transport inhibitors, showed a deficiency in the induction of free naringenin, isoliquiritigenin, quercetin, and hesperetin in cre1 roots compared with wild type roots 24 h after inoculation with rhizobia. Coinoculation of roots with rhizobia and the flavonoids naringenin, isoliquiritigenin, and kaempferol, or with the synthetic auxin transport inhibitor 2,3,5,-triiodobenzoic acid, rescued nodulation efficiency in cre1 mutants and allowed auxin transport control in response to rhizobia. Our results suggest that CRE1-dependent cytokinin signaling leads to nodule initiation through the regulation of flavonoid accumulation required for local alteration of polar auxin transport and subsequent auxin accumulation in cortical cells during the early stages of nodulation. PMID- 26253707 TI - Adequacy of preadmission oral anticoagulation with vitamin K antagonists and ischemic stroke severity and outcome in patients with atrial fibrillation. AB - It is unclear whether vitamin K antagonists affect stroke severity and outcome in patients with atrial fibrillation (AF). We aimed to evaluate this association. We prospectively studied 539 consecutive patients admitted with acute ischemic stroke (41.2 % males, age 78.9 +/- 6.6 years). The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). The outcome was assessed with dependency rates at discharge (modified Rankin scale 2-5) and with in-hospital mortality. 177 patients had a history of AF. The median NIHSS at admission did not differ between patients on acenocoumarol with INR 2.0-3.0, on acenocoumarol with INR < 2.0, on single antiplatelet treatment, on dual antiplatelet treatment, or on no treatment [4 (range 0-26), 13 (0-39), 8 (0-33), 3 (2-23) and 7 (0-33), respectively; p = 0.433]. Dependency rates were lower in patients on acenocoumarol with INR 2.0-3.0 or on dual antiplatelet treatment than in those on acenocoumarol with INR < 2.0, single antiplatelet treatment, or no treatment (20.0, 22.2, 61.5, 58.7 and 68.0 %, respectively; p = 0.024). Independent predictors of dependency were age, NIHSS at admission and history of ischemic stroke. In-hospital mortality did not differ between patients on acenocoumarol with INR 2.0-3.0, on acenocoumarol with INR < 2.0, on single antiplatelet treatment, on dual antiplatelet treatment, or on no treatment (7.7, 18.2, 16.1, 16.7 and 22.2 %, respectively; p = 0.822). In conclusion, optimally anticoagulated patients with AF have more favorable functional outcome after stroke and a trend for less severe stroke whereas patients with subtherapeutic anticoagulation have similar stroke severity and outcome with those on no treatment. PMID- 26253708 TI - Bioimpedance Analysis as a Method to Evaluate the Proportion of Fatty and Muscle Tissues in Progressive Myopathy in Pompe Disease. AB - During progressive myopathy, the space of atrophic muscle tissue is gradually filled by fatty tissue. The proportion of these two tissue types relative to body mass provides an indication of the extent of muscle tissue destruction, i.e., the progression and severity of the disease.In this study we use Pompe disease as an example to report the new possibility of using bioimpedance analysis (BIA) to assess the relative proportion of fatty and muscle tissue in diseases associated with muscle atrophy, thus enabling the assessment of disease progression and the effectiveness of treatment. Results from BIA analysis were compared with magnetic resonance images.The results of muscle magnetic resonance images and BIA analysis were similar, which suggests that BIA may provide valuable diagnostic guidance for the assessment of the progression of the disorder. PMID- 26253709 TI - Identification of Promising Urinary MicroRNA Biomarkers in Two Rat Models of Glomerular Injury. AB - MicroRNAs (miRNAs) are small, noncoding RNAs that regulate protein levels posttranscriptionally. miRNAs play important regulatory roles in many cellular processes and have been implicated in several diseases. Recent studies have reported significant levels of miRNAs in a variety of body fluids, raising the possibility that miRNAs could serve as useful biomarkers. Here, changes in miRNA expression patterns are described in 2 different rodent models of glomerular injury (acute puromycin aminonucleoside nephropathy and passive Heymann nephritis). By employing 2 different modes of glomerular insult, oxidative stress and immune-mediated toxicity, miRNA changes in both isolated glomeruli as well as urine specimens allow for identification of urinary miRNA biomarkers that are suggestive of drug-induced injury specifically to the glomerulus. Subsets of glomerular urinary miRNAs associated with these different modes of glomerular toxicity seem to be dependent on the mechanism of the induced injury, while 9 miRNAs that changed early in both glomerular and urine specimens were common to both studies. We further show that the miRNAs identified as mechanism-specific early glomerular injury biomarkers target key pathways and transcripts relevant to the type of insult, while the insult-independent changes might serve as ideal glomerular injury biomarkers. PMID- 26253710 TI - Seasonal variations in vitamin D in relation to growth in short prepubertal children before and during first year growth hormone treatment. AB - PURPOSE: This study investigated the relationship between seasonal variations in 25-hydroxyvitamin D (25(OH)D) levels and growth in prepubertal children during both the pretreatment year and the first year of GH treatment. METHODS: The study included 249 short prepubertal children with a broad range of GH secretion, GH(max) during a 24 h profile median 23; range 1-127 mU/L, 191 boys (mean age +/- SD, 8.6 +/- 2.6 years), 58 girls (7.5 +/- 1.9 years) receiving GH treatment (mean 43 ug/kg/day; range 17-99 ug/kg/day). Serum 25(OH)D was measured using an automated IDS-iSYS immunoassay. RESULTS: 25(OH)D levels showed seasonal variation, and decreased significantly during GH treatment. 25(OH)D levels at start and first year reduction in 25(OH)D, correlated (-) with the first year growth response during treatment. The degree of GH secretion capacity within our study population of mainly non-GH deficient children and 25(OH)D sufficient (67 +/- 29 nmol/L) had no influence on 25(OH)D levels. Growth during GH treatment were independent of seasonal variations in 25(OH)D. Multiple regression analysis showed that 25(OH)D levels at treatment start, together with auxological data and IGF-binding protein-(3)SDS, explained 61 % of the variation in first year gain in heightSDS. CONCLUSION: 25(OH)D levels were associated with first year growth response to GH and may be a useful contribution to future growth prediction models. PMID- 26253711 TI - The sodium iodide symporter is unlikely to be a thyroid/breast shared antigen. AB - PURPOSE: Anti-thyroid peroxidase (TPO) autoantibodies (TPOAb) seem to be protective for patients with breast cancer (BC). Thyroid and breast tissues both express the sodium iodide symporter (NIS), similarly both have a peroxidase activity, TPO and lactoperoxidase (LPO) respectively. We hypothesize a common immune response to a thyroid/breast shared antigen suggesting three putative mechanisms: (1) TPOAb react to both TPO and LPO, (2) TPO could be expressed in BC and (3) patients with TPOAb could have autoantibodies to NIS (NISAb). Previous studies excluded NISAb that block NIS activity in sera of patients with thyroid autoimmunity (TA) and/or BC. This study investigates neutral NISAb (binding without affecting function). METHODS: Clones of CHO cells stably expressing human NIS (hNIS; CHO-NIS) were isolated following transfection of hNIS in pcDNA3 vector. Expression of hNIS mRNA and surface protein was confirmed by PCR and flow cytometry respectively using a hNIS-mouse-monoclonal-antibody. CHO-NIS and controls transfected with the empty pcDNA3 vector (CHO-Empty) were incubated with 42 heat-inactivated human sera followed by an anti-human-IgG-AlexaFluor488 conjugate: 12 with BC, 11 with TA, 10 with both BC and TA and 9 with non autoimmune thyroid diseases. The Kolmogorov-Smirnov Test was used to compare the fluorescence intensity obtained with CHO-NIS and CHO-Empty, using sera from six young males as a negative control population. RESULTS: None of the 42 sera were positive for NISAb. CONCLUSIONS: NISAb are rare and NIS is unlikely to be a common thyroid/BC shared antigen. We have recently demonstrated TPO expression in BC tissue and are currently investigating TPOAb cross-reactivity with TPO/LPO. PMID- 26253712 TI - Results of a Rapid Hepatitis C Virus Screening and Diagnostic Testing Program in an Urban Emergency Department. AB - STUDY OBJECTIVE: We describe the results of an emergency department (ED) hepatitis C virus testing program that integrated birth cohort screening and screening of patients with a history of injection drug use, as well as physician diagnostic testing, according to national guidelines. METHODS: We conducted a retrospective cohort study using data collected as part of clinical care. The primary outcome was the hepatitis C virus prevalence among tested patients. We evaluated factors associated with testing positive with logistic regression. RESULTS: Of the 26,639 unique adults aged 18 years or older and presenting to the ED during the 6-month study, 2,581 (9.7%) completed hepatitis C virus screening (2,028) or diagnostic testing (553), of whom 267 were antibody positive (10.3% prevalence). Factors associated with testing positive for hepatitis C virus included injection drug use (38.4% prevalence; odds ratio [OR] 10.8; 95% confidence interval [CI] 7.5 to 15.5), homeless (25.5% prevalence; OR 3.1; 95% CI 1.5 to 6.8), diagnostic testing (14.8% prevalence; OR 2.6; 95% CI 1.7 to 3.9), birth cohort (13.7% prevalence; OR 3.6; 95% CI 2.4 to 5.3), and male sex (12.4% prevalence; OR 1.4; 95% CI 1.0 to 2.0). Of the 267 patients testing positive for hepatitis C virus antibody, 137 (51%) had documentation of result disclosure and 180 (67%) had confirmatory ribonucleic acid testing performed, of whom 126 (70%) had a positive result. Follow-up appointments at the hepatitis C virus clinic were arranged for 57 of the 126 (45%) patients with confirmed positive results, of which 30 attended. CONCLUSION: This ED screening and diagnostic testing program found a high prevalence of hepatitis C virus antibody positivity across all groups. Challenges encountered with hepatitis C virus screening included result disclosure, confirmatory testing, and linkage to care. Our results warrant continued efforts to develop and evaluate policies for ED-based hepatitis C virus screening. PMID- 26253714 TI - CXCL12 Gene Therapy Ameliorates Ischemia-Induced White Matter Injury in Mouse Brain. AB - Remyelination is an important repair process after ischemic stroke-induced white matter injury. It often fails because of the insufficient recruitment of oligodendrocyte progenitor cells (OPCs) to the demyelinated site or the inefficient differentiation of OPCs to oligodendrocytes. We investigated whether CXCL12 gene therapy promoted remyelination after middle cerebral artery occlusion in adult mice. The results showed that CXCL12 gene therapy at 1 week after ischemia could protect myelin sheath integrity in the perifocal region, increase the number of platelet-derived growth factor receptor-alpha (PDGFRalpha)-positive and PDGFRalpha/bromodeoxyuridine-double positive OPCs in the subventricular zone, and further enhance their migration to the ischemic lesion area. Coadministration of AMD3100, the antagonist for CXCL12 receptor CXCR4, eliminated the beneficial effect of CXCL12 on myelin sheath integrity and negatively influenced OPC proliferation and migration. At 5 weeks after ischemia, CXCR4 was found on the PDGFRalpha- and/or neuron/glia type 2 (NG2)-positive OPCs but not on the myelin basic protein-positive mature myelin sheaths, and CXCR7 was only expressed on the mature myelin sheath in the ischemic mouse brain. Our data indicated that CXCL12 gene therapy effectively protected white matter and promoted its repair after ischemic injury. The treatment at 1 week after ischemia is effective, suggesting that this strategy has a longer therapeutic time window than the treatments currently available. SIGNIFICANCE: This study has demonstrated for the first time that CXCL12 gene therapy significantly ameliorates brain ischemia-induced white matter injury and promotes oligodendrocyte progenitor cell proliferation in the subventricular zone and migration to the perifocal area in the ischemic mouse brain. Additional data showed that CXCR4 receptor plays an important role during the proliferation and migration of oligodendrocyte progenitor cells, and CXCR7 might play a role during maturation. In contrast to many experimental studies that provide treatment before ischemic insult, CXCL12 gene therapy was performed 1 week after brain ischemia, which significantly prolonged the therapeutic time window of brain ischemia. PMID- 26253713 TI - Concise Review: Human Dermis as an Autologous Source of Stem Cells for Tissue Engineering and Regenerative Medicine. AB - The exciting potential for regenerating organs from autologous stem cells is on the near horizon, and adult dermis stem cells (DSCs) are particularly appealing because of the ease and relative minimal invasiveness of skin collection. A substantial number of reports have described DSCs and their potential for regenerating tissues from mesenchymal, ectodermal, and endodermal lineages; however, the exact niches of these stem cells in various skin types and their antigenic surface makeup are not yet clearly defined. The multilineage potential of DSCs appears to be similar, despite great variability in isolation and in vitro propagation methods. Despite this great potential, only limited amounts of tissues and clinical applications for organ regeneration have been developed from DSCs. This review summarizes the literature on DSCs regarding their niches and the specific markers they express. The concept of the niches and the differentiation capacity of cells residing in them along particular lineages is discussed. Furthermore, the advantages and disadvantages of widely used methods to demonstrate lineage differentiation are considered. In addition, safety considerations and the most recent advancements in the field of tissue engineering and regeneration using DSCs are discussed. This review concludes with thoughts on how to prospectively approach engineering of tissues and organ regeneration using DSCs. Our expectation is that implementation of the major points highlighted in this review will lead to major advancements in the fields of regenerative medicine and tissue engineering. SIGNIFICANCE: Autologous dermis derived stem cells are generating great excitement and efforts in the field of regenerative medicine and tissue engineering. The substantial impact of this review lies in its critical coverage of the available literature and in providing insight regarding niches, characteristics, and isolation methods of stem cells derived from the human dermis. Furthermore, it provides analysis of the current state-of-the-art regenerative approaches using human-derived dermal stem cells, with consideration of current guidelines, to assist translation toward therapeutic use. PMID- 26253715 TI - Excessive Cellular Proliferation Negatively Impacts Reprogramming Efficiency of Human Fibroblasts. AB - The impact of somatic cell proliferation rate on induction of pluripotent stem cells remains controversial. Herein, we report that rapid proliferation of human somatic fibroblasts is detrimental to reprogramming efficiency when reprogrammed using a lentiviral vector expressing OCT4, SOX2, KLF4, and cMYC in insulin-rich defined medium. Human fibroblasts grown in this medium showed higher proliferation, enhanced expression of insulin signaling and cell cycle genes, and a switch from glycolytic to oxidative phosphorylation metabolism, but they displayed poor reprogramming efficiency compared with cells grown in normal medium. Thus, in contrast to previous studies, our work reveals an inverse correlation between the proliferation rate of somatic cells and reprogramming efficiency, and also suggests that upregulation of proteins in the growth factor signaling pathway limits the ability to induce pluripotency in human somatic fibroblasts. SIGNIFICANCE: The efficiency with which human cells can be reprogrammed is of interest to stem cell biology. In this study, human fibroblasts cultured in media containing different concentrations of growth factors such as insulin and insulin-like growth factor-1 exhibited variable abilities to proliferate, with consequences on pluripotency. This occurred in part because of changes in the expression of proteins involved in the growth factor signaling pathway, glycolysis, and oxidative phosphorylation. These findings have implications for efficient reprogramming of human cells. PMID- 26253716 TI - Copper complexes as a source of redox active MRI contrast agents. AB - The study reports an advance in designing copper-based redox sensing MRI contrast agents. Although the data demonstrate that copper(II) complexes are not able to compete with lanthanoids species in terms of contrast, the redox-dependent switch between diamagnetic copper(I) and paramagnetic copper(II) yields a novel redox sensitive contrast moiety with potential for reversibility. PMID- 26253717 TI - Theoretical Determination of the pK a Values of Betalamic Acid Related to the Free Radical Scavenger Capacity: Comparison Between Empirical and Quantum Chemical Methods. AB - Health benefits of dietary phytochemicals have been suggested in recent years. Among 1000s of different compounds, Betalains, which occur in vegetables of the Cariophyllalae order (cactus pear fruits and red beet), have been considered because of reducing power and potential to affect redox-modulated cellular processes. The antioxidant power of Betalains is strictly due to the dissociation rate of the acid moieties present in all the molecules of this family of phytochemicals. Experimentally, only the pK a values of betanin were determined. Recently, it was evidenced it was evidenced as the acid dissociation, at different environmental pHs, affects on its electron-donating capacity, and further on its free radical scavenging power. The identical correlation was studied on another Betalains family compound, Betalamic Acid. Experimental evidences showed that the free radical scavenging capacity of this compound drastically decreases at pH > 5, but pK a values were experimentally not measured. With the aim to justify the Betalamic Acid behavior as free radical scavenger, in this paper we tried to predict in silico the pK a values by means different approaches. Starting from the known experimental pK as of acid compounds, both phytochemicals and small organic, two empirical approaches and quantum-mechanical calculation were compared to give reliable prediction of the pK as of Betalamic Acid. Results by means these computational approaches are consistent with the experimental evidences. As shown herein, in silico, the totally dissociated species, at the experimental pH > 5 in solution, is predominant, exploiting the higher electron-donating capability (HOMO energy). Therefore, the computational estimated pK a values of Betalamic Acid resulted very reliable. PMID- 26253718 TI - In silico Identification of Ergosterol as a Novel Fungal Metabolite Enhancing RuBisCO Activity in Lycopersicum esculentum. AB - RuBisCO (EC 4.1.1.39), a key enzyme found in stroma of chloroplast, is important for fixing atmospheric CO2 in plants. Alterations in the activity of RuBisCO could influence photosynthetic yield. Therefore, to understand the activity of the protein, knowledge about its structure is pertinent. Though the structure of Nicotiana RuBisCO has been modeled, the structure of tomato RuBisCO is still unknown. RuBisCO extracted from chloroplasts of tomato leaves was subjected to MALDI-TOF-TOF followed by Mascot Search. The protein sequence based on gene identification numbers was subjected to in silico model construction, characterization and docking studies. The primary structure analysis revealed that protein was stable, neutral, hydrophilic and has an acidic pI. The result though indicates a 90 % homology with other members of Solanaceae but differs from the structure of Arabidopsis RuBisCO. Different ligands were docked to assess the activity of RuBisCO against these metabolite components. Out of the number of modulators tested, ergosterol had the maximum affinity (E = -248.08) with RuBisCO. Ergosterol is a major cell wall component of fungi and has not been reported to be naturally found in plants. It is a known immune elicitor in plants. The current study throws light on its role in affecting RuBisCO activity in plants, thereby bringing changes in the photosynthetic rate. PMID- 26253719 TI - In Silico Analysis of Conformational Changes Induced by Normal and Mutation of Macrophage Infectivity Potentiator Catalytic Residues and its Interactions with Rapamycin. AB - The Legionella pneumophila (Lp), human pathogen, causes severe and often fatal Legionnaires' disease, produces a major virulence factor, termed 'macrophage infectivity potentiator protein' (Mip), that is necessary for optimal multiplication of the bacteria within human alveolar macrophages. Mip exhibits peptidyl prolyl cis-trans isomerase (PPIase) activity, which can be inhibited by rapamycin and FK506. It was previously shown that substitutions at the catalytic residues, aspartate-142 position replaced to leucine-142 and tyrosine-185 position replaced to alanine-185 strongly reduces the PPIase activity of Mip proteins. Therefore, we aim to develop an in silico mutagenesis model for both important catalytic residues, validated the stability of the mutated model. Further, we have docked the known inhibitor rapamycin with Lp Mip (native) and mutants (D142L and Y185A) to analyze the conformational and binding mode. Electrostatic contributions and van der Waals interactions are the major driving forces for rapamycin binding and largely responsible for the binding differences between the Lp Mip (native and mutated) proteins. PMID- 26253720 TI - MSuPDA: A Memory Efficient Algorithm for Sequence Alignment. AB - Space complexity is a million dollar question in DNA sequence alignments. In this regard, memory saving under pushdown automata can help to reduce the occupied spaces in computer memory. Our proposed process is that anchor seed (AS) will be selected from given data set of nucleotide base pairs for local sequence alignment. Quick splitting techniques will separate the AS from all the DNA genome segments. Selected AS will be placed to pushdown automata's (PDA) input unit. Whole DNA genome segments will be placed into PDA's stack. AS from input unit will be matched with the DNA genome segments from stack of PDA. Match, mismatch and indel of nucleotides will be popped from the stack under the control unit of pushdown automata. During the POP operation on stack, it will free the memory cell occupied by the nucleotide base pair. PMID- 26253721 TI - In Silico Study of Variable Surface Proteins in Plasmodium Species: Perspectives in Drug Design. AB - The variable surface proteins expressed by P. falciparum and P. vivax are transported to the surface of infected erythrocyte and are exposed to the host immune system. The possibility of using variable surface proteins as a common drug target has been analyzed in both the Plasmodium species. Sequence analysis of variable surface proteins showed a low-level conservation within as well as between the species. Amino acid composition analysis revealed higher frequency of hydrophilic amino acids as compared with that of hydrophobic residues. In order to gain more insight into their diverse functional role, the three-dimensional structure was predicted using comparative modeling approach. These models were evaluated and validated by checking stereochemistry of underlying amino acids. Structural alignment of variable surface proteins by superimposing them shows less conservation. Due to differences at sequence as well as structural level, the variable surface proteins are expected to show difference in their degree of invasiveness. These differences were also cross-examined by evolutionary study, and the results obtained were in accordance with the aforesaid study. The existence of structural differences noticed in the present study showed that the variable surface proteins could not be used as a common drug target in both the malarial species. Therefore, species-specific strategy may be followed for drug targeting against variable surface proteins of P. falciparum and P. vivax. PMID- 26253723 TI - Reduced Serum Level of Interleukin-10 is Associated with Cerebral Infarction: A Case-Control and Meta-Analysis Study. AB - IL-10 expression limits inflammation and restricts the size of CNS damage from stroke. In this study, we examined the correlation between cerebral infarction (CI) and serum levels of interleukin-10 (IL-10) using a combination of case control study and meta-analysis of published data, with an aim of understanding the relevance of serum IL-10 levels to CI development. This study enrolled a total of 169 CI patients admitted to the Second Hospital of Hebei Medical University between May 2011 and November 2014. During the same period, a group of 145 individuals were recruited at the same hospital as healthy controls after thorough physical examination. Serum IL-10 levels were measured by enzyme-linked immunosorbent assay (ELISA). SPSS 19.0 (IBM, 2010, Chicago, IL, USA) and Comprehensive Meta-Analysis 2.0 (CMA 2.0) software were used for data analysis. Serum levels of IL-10 (pg/mL) were significantly lower in CI patients when compared to healthy controls (15.36 +/- 3.21 vs. 21.64 +/- 5.17, t = 13.12, P < 0.001). In addition, patients with large artery atherosclerosis (LAAS), cardioembolic infarct (CEI), and lacunar infarct (LAC) displayed drastically reduced serum levels of IL-10 (pg/mL) compared to healthy controls (LAAS 14.77 +/ 5.21, CEI 15.25 +/- 5.10, LAC 16.58 +/- 4.92, all P < 0.001). Interestingly, no significant differences were observed in the serum IL-10 levels when pair-wise comparisons were made between these three clinical subtypes of CI (all P > 0.05). Logistic regression analysis indicated that, with the exception of triglyceride (TG) and uric acid (UA) levels (both P > 0.05), the other seven parameters, including fasting blood glucose (FPG), total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), creatinine (Cr), systolic blood pressure (SBP), and diastolic blood pressure (DBP), strongly correlated with CI development (all P < 0.05). Meta-analysis of pooled data from nine case-control studies revealed an inverse correlation between the serum IL-10 levels and CI (SMD = 1.797, 95% CI 0.785~2.810, P = 0.001). Subgroup analysis based on country showed that low serum levels of IL-10 may be the major risk factor for CI in Croatia (SMD = 2.961, 95% CI 2.480~3.443, P < 0.001) and India (SMD = 1.440, 95% CI 1.129-1.750, P < 0.001). Further, subgroup analysis based on ethnicity showed that IL-10 serum levels and CI displayed negative relationship in Asians (SMD = 2.522, 95% CI 0.468~4.576, P = 0.016) but not in Caucasians (P > 0.05). Our study provided convincing evidence that the patients with CI exhibit consistently reduced serum levels of IL-10, and IL-10 may be a major player in the development and progression of CI. PMID- 26253722 TI - Small Molecule Agonists of Cell Adhesion Molecule L1 Mimic L1 Functions In Vivo. AB - Lack of permissive mechanisms and abundance of inhibitory molecules in the lesioned central nervous system of adult mammals contribute to the failure of functional recovery after injury, leading to severe disabilities in motor functions and pain. Peripheral nerve injury impairs motor, sensory, and autonomic functions, particularly in cases where nerve gaps are large and chronic nerve injury ensues. Previous studies have indicated that the neural cell adhesion molecule L1 constitutes a viable target to promote regeneration after acute injury. We screened libraries of known drugs for small molecule agonists of L1 and evaluated the effect of hit compounds in cell-based assays in vitro and in mice after femoral nerve and spinal cord injuries in vivo. We identified eight small molecule L1 agonists and showed in cell-based assays that they stimulate neuronal survival, neuronal migration, and neurite outgrowth and enhance Schwann cell proliferation and migration and myelination of neurons in an L1-dependent manner. In a femoral nerve injury mouse model, enhanced functional regeneration and remyelination after application of the L1 agonists were observed. In a spinal cord injury mouse model, L1 agonists improved recovery of motor functions, being paralleled by enhanced remyelination, neuronal survival, and monoaminergic innervation, reduced astrogliosis, and activation of microglia. Together, these findings suggest that application of small organic compounds that bind to L1 and stimulate the beneficial homophilic L1 functions may prove to be a valuable addition to treatments of nervous system injuries. PMID- 26253724 TI - Fluoride-Induced Neuron Apoptosis and Expressions of Inflammatory Factors by Activating Microglia in Rat Brain. AB - Excessive exposure to fluoride results in structural and functional damages to the central nervous system (CNS), and neurotoxicity of fluoride may be associated with neurodegenerative changes. Chronic microglial activation appears to cause neuronal damage through producing proinflammatory cytokines and is involved in many neurodegenerative disorders. It is not known about effects on microglia of fluoride. In the present study, healthy adult Wistar rats were exposed to 60 and 120 ppm fluoride in drinking water for 10 weeks, and control rats received deionized water. After 10 weeks, rats were sacrificed under anesthesia then apoptosis in neuron and inflammatory factors secreted by microglia were determined. We found that apoptosis of neurons in fluoride-treated rat brain increased and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive immunofluorescence increased with increasing fluoride concentrations. Bax protein expression increased and Bcl-2 protein expression decreased in fluoride-treated rat brain compared with that of the control rat brain. The microglia in the hippocampus and cortex of fluoride-treated rats were activated by immunostaining with OX-42, a marker of activated microglia, and OX 42-positive microglia cells were more abundant in the hippocampus than in the cortex. The levels of IL-1beta and IL-6 protein expression in OX-42-labeled microglial cells were significantly increased in the cortex and hippocampus of rats exposed to fluoride, and TNF-alpha immunoreactivity in microglial cells of the hippocampus was significantly higher in the 120 ppm fluoride-treated group than that in the control group. Our results indicate that fluoride induced neuron apoptosis and expressions of inflammatory factors by activating microglia in rat brain. PMID- 26253725 TI - Bee venom phospholipase A2 as a membrane-binding vector for cell surface display or internalization of soluble proteins. AB - We showed that bee venom phospholipase A2 can be used as a membrane-binding vector to anchor to the surface of cells a soluble protein fused to its C terminus. ZZ, a two-domain derivative of staphylococcal protein A capable of binding constant regions of antibodies was fused to the C-terminus of the phospholipase or to a mutant devoid of enzymatic activity. The fusion proteins bound to the surface of cells and could themselves bind IgGs. Their fate depended on the cell type to which they bound. On the A431 carcinoma cell line the proteins remained exposed on the cell surface. In contrast, on human dendritic cells the proteins were internalized into early endosomes. PMID- 26253727 TI - Outcome of open reduction for the neglected posterior dislocation of the elbow in a low-to-middle income country. AB - BACKGROUND: Neglected posterior dislocation of the elbow is common in developing countries. We evaluated the clinical results of open reduction focusing on range of motion (ROM), stability and pain. MATERIALS AND METHODS: Sixteen patients were treated for neglected dislocation of the elbow between January 2008 and December 2012 at St. Luke's Catholic Hospital and College of Nursing, Wolisso, Ethiopia. Mean time from injury was 2.8 months (range, 2-48 months). All patients underwent open reduction using Speed's technique. Mean follow-up was 12 months (range, 12 36 months). Range of motion (ROM) was measured, stability was checked with the lateral pivot shift apprehension test. RESULTS: All patients improved their range of motion (ROM). Pain decreased. One patient developed instability during the rehabilitation programme; in the remaining patients pivot shift test was negative. CONCLUSION: Open reduction is an effective method to restore joint stability, improve function of neglected posterior dislocation of the elbow. PMID- 26253728 TI - Relationship between levels of advanced glycation end products and their soluble receptor and adverse outcomes in adults with type 2 diabetes. AB - OBJECTIVE: This study explored whether activation of the receptor for advanced glycation end products (RAGE) is implicated in the development of diabetes complications. RESEARCH DESIGN AND METHODS: A case-cohort study was performed in 3,763 participants with prevalent diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. The hazard ratios (HRs) for death, major cardiovascular events, and new or worsening nephropathy were derived using Cox regression models, and the ability of sRAGE and AGE levels to reclassify the risk of nephropathy was assessed. RESULTS: After adjustment for a range of possible confounders and other risk factors, sRAGE levels were associated with all-cause mortality (HR 1.11 for a 1 SD increase of log sRAGE [95% CI 1.00-1.22]; P = 0.045) and new or worsening nephropathy (HR 1.20 for a 1-SD increase of log sRAGE [95% CI 1.02-1.41]; P = 0.032). Circulating AGE levels were also independently associated with new or worsening nephropathy (HR 1.21 for a 1-SD increase [95% CI 1.08-1.36]; P = 0.001). Both markers also significantly improved the accuracy with which the 5 year risk of new or worsening nephropathy could be predicted (net reclassification index in continuous model, 0.25 for sRAGE and 0.24 for AGE levels). CONCLUSIONS: In adults with type 2 diabetes, increased levels of sRAGE are independently associated with new or worsening kidney disease and mortality over the next 5 years. Higher levels of AGE are also associated with an increased risk of adverse renal outcomes. The AGE/RAGE axis may be of importance in the prevention and management of diabetes complications. PMID- 26253726 TI - Primate paternal care: Interactions between biology and social experience. AB - This article is part of a Special Issue "Parental Care".We review recent research on the roles of hormones and social experiences on the development of paternal care in humans and non-human primates. Generally, lower concentrations of testosterone and higher concentrations of oxytocin are associated with greater paternal responsiveness. Hormonal changes prior to the birth appear to be important in preparation for fatherhood and changes after the birth are related to how much time fathers spend with offspring and whether they provide effective care. Prolactin may facilitate approach and the initiation of infant care, and in some biparental non-human primates, it affects body mass regulation. Glucocorticoids may be involved in coordinating reproductive and parental behavior between mates. New research involving intranasal oxytocin and neuropeptide receptor polymorphisms may help us understand individual variation in paternal responsiveness. This area of research, integrating both biological factors and the role of early and adult experience, has the potential to suggest individually designed interventions that can strengthen relationships between fathers and their partners and offspring. PMID- 26253729 TI - Carotid plaque calcification predicts future cardiovascular events in type 2 diabetes. AB - OBJECTIVE: The presence of carotid plaques is associated with future cardiovascular events, with local plaque composition being an independent outcome predictor. We examined the association between ultrasonographically determined carotid plaque calcification and incident major adverse cardiovascular events (MACE) and death in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We enrolled 581 patients with T2D who underwent routine carotid ultrasonography. Plaques were classified as echolucent (lipid rich), heterogenous, and echogenic (calcific). We collected demographic, anthropometric, and clinical data at baseline and followed the patients for up to 9 years. RESULTS: Plaques were detected in 81.8% of the patients (echolucent in 16.4%, heterogenous in 43.2%, and echogenic in 22.2%). During follow-up (4.3 +/- 0.1 years), 58 deaths (27 cardiovascular) and 236 fatal and nonfatal MACE occurred. In univariate analyses, presence versus absence of any carotid plaque was associated with incident MACE, and the hazard ratio (95% CI) progressively increased from echolucent (1.97 [0.93 3.44]), to heterogeneous (3.10 [2.09-4.23]), to echogenic (3.71 [2.09-5.59]) plaques. Compared with echolucent plaques, echogenic plaques were associated with incident MACE independently from confounders. This association was attenuated after adjusting for the degree of stenosis, but in patients with stenosis <=30%, echogenic plaque type still predicted total and atherosclerotic MACE, even after further adjusting for mean intima-media thickness. CONCLUSIONS: In T2D, carotid plaque calcification predicts MACE, especially in patients with a low degree of stenosis. The biology of atherosclerotic calcification in diabetes needs to be further elucidated to understand the basis of this association. PMID- 26253730 TI - Inhaled Technosphere Insulin Versus Inhaled Technosphere Placebo in Insulin-Naive Subjects With Type 2 Diabetes Inadequately Controlled on Oral Antidiabetes Agents. AB - OBJECTIVE: To investigate the efficacy and safety of prandial Technosphere inhaled insulin (TI), an inhaled insulin with a distinct time action profile, in insulin-naive type 2 diabetes (T2D) inadequately controlled on oral antidiabetes agents (OADs). RESEARCH DESIGN AND METHODS: Subjects with T2D with HbA1c levels >=7.5% (58.5 mmol/mol) and <=10.0% (86.0 mmol/mol) on metformin alone or two or more OADs were randomized to add-on prandial TI (n = 177) or prandial Technosphere inhaled placebo (TP) (n = 176) to their OAD regimen in this double blind, placebo-controlled trial. Primary end point was change in HbA1c at 24 weeks. RESULTS: TI significantly reduced HbA1c by -0.8% (-9.0 mmol/mol) from a baseline of 8.3% (66.8 mmol/mol) compared with TP -0.4% (-4.6 mmol/mol) (treatment difference -0.4% [95% CI -0.57, -0.23]; P < 0.0001). More TI-treated subjects achieved an HbA1c <=7.0% (53.0 mmol/mol) (38% vs. 19%; P = 0.0005). Mean fasting plasma glucose was similarly reduced in both groups. Postprandial hyperglycemia, based on 7-point glucose profiles, was effectively controlled by TI. Mean weight change was 0.5 kg for TI and -1.1 kg for the TP group (P < 0.0001). Mild, transient dry cough was the most common adverse event, occurring similarly in both groups (TI, 23.7%; TP, 19.9%) and led to discontinuation in only 1.1% of TI-treated and 3.4% of TP-treated subjects. There was a small decline in forced expiratory volume in 1 s in both groups, with a slightly larger decline in the group receiving TI (TI, -0.13 L; TP, -0.04 L). The difference resolved after treatment discontinuation. CONCLUSIONS: Prandial TI added to one or more OADs in inadequately controlled T2D is an effective treatment option. Mild, transient dry cough was the most common adverse event. PMID- 26253731 TI - Progression of Lung Cancer Is Associated with Increased Dysfunction of T Cells Defined by Coexpression of Multiple Inhibitory Receptors. AB - Dysfunctional T cells present in malignant lesions are characterized by a sustained and highly diverse expression of inhibitory receptors, also referred to as immune checkpoints. Yet, their relative functional significance in different cancer types remains incompletely understood. In this study, we provide a comprehensive characterization of the diversity and expression patterns of inhibitory receptors on tumor-infiltrating T cells from patients with non-small cell lung cancer. In spite of the large heterogeneity observed in the amount of PD-1, Tim-3, CTLA-4, LAG-3, and BTLA expressed on intratumoral CD8(+) T cells from 32 patients, a clear correlation was established between increased expression of these inhibitory coreceptors and progression of the disease. Notably, the latter was accompanied by a progressively impaired capacity of T cells to respond to polyclonal activation. Coexpression of several inhibitory receptors was gradually acquired, with early PD-1 and late LAG-3/BTLA expression. PD-1 blockade was able to restore T-cell function only in a subset of patients. A high percentage of PD-1(hi) T cells was correlated with poor restoration of T cell function upon PD-1 blockade. Of note, PD-1(hi) expression marked a particularly dysfunctional T-cell subset characterized by coexpression of multiple inhibitory receptors and thus may assist in identifying patients likely to respond to inhibitory receptor-specific antibodies. Overall, these data may provide a framework for future personalized T-cell-based therapies aiming at restoration of tumor-infiltrating lymphocyte effector functions. PMID- 26253732 TI - Anti-Abeta single-chain variable fragment antibodies exert synergistic neuroprotective activities in Drosophila models of Alzheimer's disease. AB - Both active and passive immunotherapy protocols decrease insoluble amyloid-beta42 (Abeta42) peptide in animal models, suggesting potential therapeutic applications against the main pathological trigger in Alzheimer's disease (AD). However, recent clinical trials have reported no significant benefits from humanized anti Abeta42 antibodies. Engineered single-chain variable fragment antibodies (scFv) are much smaller and can easily penetrate the brain, but identifying the most effective scFvs in murine AD models is slow and costly. We show here that scFvs against the N- and C-terminus of Abeta42 (scFv9 and scFV42.2, respectively) that decrease insoluble Abeta42 in CRND mice are neuroprotective in Drosophila models of Abeta42 and amyloid precursor protein neurotoxicity. Both scFv9 and scFv42.2 suppress eye toxicity, reduce cell death in brain neurons, protect the structural integrity of dendritic terminals in brain neurons and delay locomotor dysfunction. Additionally, we show for the first time that co-expression of both anti-Abeta scFvs display synergistic neuroprotective activities, suggesting that combined therapies targeting distinct Abeta42 epitopes can be more effective than targeting a single epitope. Overall, we demonstrate the feasibility of using Drosophila as a first step for characterizing neuroprotective anti-Abeta scFvs in vivo and identifying scFv combinations with synergistic neuroprotective activities. PMID- 26253733 TI - Assessment of Fractional Flow Reserve in Patients With Recent Non-ST-Segment Elevation Myocardial Infarction: Comparative Study With 3-T Stress Perfusion Cardiac Magnetic Resonance Imaging. AB - BACKGROUND: The use of fractional flow reserve (FFR) in acute coronary syndromes is controversial. The British Heart Foundation Fractional Flow Reserve Versus Angiography in Guiding Management to Optimize Outcomes in Non-ST-Elevation Myocardial Infarction (FAMOUS-NSTEMI) study (NCT01764334) has recently demonstrated the safety and feasibility of FFR measurement in patients with non ST-segment-elevation myocardial infarction. We report the findings of the cardiac magnetic resonance (CMR) substudy to assess the diagnostic accuracy of FFR compared with 3.0-T stress CMR perfusion. METHODS AND RESULTS: One hundred six patients with non-ST-segment-elevation myocardial infarction who had been referred for early invasive management were included from 2 centers. FFR was measured in all major patent epicardial coronary arteries with a visual stenosis estimated at >=30%, and if percutaneous coronary intervention was performed, an FFR assessment was repeated. Myocardial perfusion was assessed with stress perfusion CMR at 3 T. The mean age was 56.7+/-9.8 years; 82.6% were men. Mean time from FFR evaluation to CMR was 6.1+/-3.1 days. The mean+/-SD left ventricular ejection fraction was 58.2+/-9.1%. Mean infarct size was 5.4+/-7.1%, and mean troponin concentration was 5.2+/-9.2 MUg/L. There were 34 fixed and 160 inducible perfusion defects. There was a negative correlation between the number of segments with a perfusion abnormality and FFR (r=-0.77; P<0.0001). The overall sensitivity, specificity, positive predictive value, and negative predictive value for an FFR of <=0.8 were 91.4%, 92.2%, 76%, and 97%, respectively. Diagnostic accuracy was 92%. The positive and negative predictive values of FFR for flow-limiting coronary artery disease (FFR<=0.8) in patients with non-ST segment-elevation myocardial infarction (n=21) who underwent perfusion CMR before invasive angiography were 92% and 93%, respectively. Receiver operating characteristic analysis indicated that the optimal cutoff value of FFR for demonstrating reversible ischemia on CMR was <=0.805 (area under the receiver operating characteristic curve, 0.94 [0.9-0.99]; P<0.0001). CONCLUSIONS: FFR in patients with recent non-ST-segment-elevation myocardial infarction showed high concordance with myocardial perfusion in matched territories as revealed by 3.0-T stress perfusion CMR. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02073422. PMID- 26253734 TI - Randomized Controlled Trial of Radiation Protection With a Patient Lead Shield and a Novel, Nonlead Surgical Cap for Operators Performing Coronary Angiography or Intervention. AB - BACKGROUND: Interventional cardiologists receive one of the highest levels of annual occupational radiation exposure. Further measures to protect healthcare workers are needed. METHODS AND RESULTS: We evaluated the efficacy of a pelvic lead shield and a novel surgical cap in reducing operators' radiation exposure. Patients undergoing coronary angiography or percutaneous coronary intervention (n=230) were randomized to have their procedure with or without a lead shield (Ultraray Medical, Oakville, Canada) placed over the patient. During all procedures, operators wore the No Brainer surgical cap (Worldwide Innovations and Technology, Kansas City, KS) designed to protect the head from radiation exposure. The coprimary outcomes for the lead shield comparison were (1) operator dose (uSv) and (2) operator dose indexed for air kerma (uSv/mGy). For the cap comparison, the primary outcome was the difference between total radiation dose (uSv; internal and external to cap). The lead shield use resulted in a 76% reduction in operator dose (mean dose, 3.07; 95% confidence interval [CI], 2.00 4.71 uSv lead shield group versus 12.57; 95% CI, 8.14-19.40 uSv control group; P<0.001). The mean dose indexed for air kerma was reduced by 72% (0.004; 95% CI, 0.003-0.005 uSv/mGy lead shield group versus 0.015; 95% CI, 0.012-0.019 uSv/mGy control group; P<0.001). The cap use resulted in a significant reduction in operator head radiation exposure (mean left temporal difference [external internal] radiation dose was 4.79 [95% CI, 3.30-6.68] uSv; P<0.001). CONCLUSIONS: The use of a pelvic lead shield and the cap reduced significantly the operator radiation exposure and can be easily incorporated into clinical practice. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02128035. PMID- 26253735 TI - Optical Coherence Tomography Guided Percutaneous Coronary Intervention With Nobori Stent Implantation in Patients With Non-ST-Segment-Elevation Myocardial Infarction (OCTACS) Trial: Difference in Strut Coverage and Dynamic Malapposition Patterns at 6 Months. AB - BACKGROUND: Incomplete strut coverage has been documented an important histopathologic morphometric predictor for later thrombotic events. This study sought to investigate whether optical coherence tomography (OCT)-guided percutaneous coronary intervention with Nobori biolimus-eluting stent implantation in patients with non-ST-segment-elevation myocardial infarction would provide improved strut coverage at 6 months in comparison with angiographic guidance only. METHODS AND RESULTS: One hundred patients were randomized 1:1 to either OCT-guided or angio-guided Nobori biolimus-eluting stent implantation. Postprocedure OCT was performed in all patients. In the OCT-guided group, prespecified criteria indicating additional intervention were related to (1) stent underexpansion, (2) strut malapposition, (3) edge dissection(s), and (4) residual stenosis at the distal or proximal reference segment(s). A final OCT was performed in case of reintervention. Six-month OCT follow-up was available in 85 patients. Twenty-three (46%) OCT-guided patients had additional postdilation or stenting. The percentage of acutely malapposed struts was substantially lower in the OCT-guided group (3.4% [interquartile range, 0.3-7.6] versus 7.8% [interquartile range, 2.3-19.4]; P<0.01). At 6-month follow-up, the OCT-guided group had a significantly lower proportion of uncovered struts; 4.3% [interquartile range, 1.2-9.8] versus 9.0% [interquartile range, 5.5-14.5], P<0.01. Furthermore, OCT-guided patients had significantly more completely covered stents: 17.5% versus 2.2%, P=0.02. The percentages of malapposed struts and struts being both uncovered and malapposed at follow-up were comparable between groups. CONCLUSIONS: OCT-guided optimization of Nobori biolimus-eluting stent implantation improves strut coverage at 6-month follow-up in comparison with angiographic guidance alone. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02272283. PMID- 26253736 TI - Measuring the Effectiveness of Percutaneous Coronary Intervention. PMID- 26253738 TI - DynaMIT: the dynamic motif integration toolkit. AB - De-novo motif search is a frequently applied bioinformatics procedure to identify and prioritize recurrent elements in sequences sets for biological investigation, such as the ones derived from high-throughput differential expression experiments. Several algorithms have been developed to perform motif search, employing widely different approaches and often giving divergent results. In order to maximize the power of these investigations and ultimately be able to draft solid biological hypotheses, there is the need for applying multiple tools on the same sequences and merge the obtained results. However, motif reporting formats and statistical evaluation methods currently make such an integration task difficult to perform and mostly restricted to specific scenarios. We thus introduce here the Dynamic Motif Integration Toolkit (DynaMIT), an extremely flexible platform allowing to identify motifs employing multiple algorithms, integrate them by means of a user-selected strategy and visualize results in several ways; furthermore, the platform is user-extendible in all its aspects. DynaMIT is freely available at http://cibioltg.bitbucket.org. PMID- 26253737 TI - Ethylene Contributes to maize insect resistance1-Mediated Maize Defense against the Phloem Sap-Sucking Corn Leaf Aphid. AB - Signaling networks among multiple phytohormones fine-tune plant defense responses to insect herbivore attack. Previously, it was reported that the synergistic combination of ethylene (ET) and jasmonic acid (JA) was required for accumulation of the maize insect resistance1 (mir1) gene product, a cysteine (Cys) proteinase that is a key defensive protein against chewing insect pests in maize (Zea mays). However, this study suggests that mir1-mediated resistance to corn leaf aphid (CLA; Rhopalosiphum maidis), a phloem sap-sucking insect pest, is independent of JA but regulated by the ET-signaling pathway. Feeding by CLA triggers the rapid accumulation of mir1 transcripts in the resistant maize genotype, Mp708. Furthermore, Mp708 provided elevated levels of antibiosis (limits aphid population)- and antixenosis (deters aphid settling)-mediated resistance to CLA compared with B73 and Tx601 maize susceptible inbred lines. Synthetic diet aphid feeding trial bioassays with recombinant Mir1-Cys Protease demonstrates that Mir1 Cys Protease provides direct toxicity to CLA. Furthermore, foliar feeding by CLA rapidly sends defensive signal(s) to the roots that trigger belowground accumulation of the mir1, signifying a potential role of long-distance signaling in maize defense against the phloem-feeding insects. Collectively, our data indicate that ET-regulated mir1 transcript accumulation, uncoupled from JA, contributed to heightened resistance to CLA in maize. In addition, our results underscore the significance of ET acting as a central node in regulating mir1 expression to different feeding guilds of insect herbivores. PMID- 26253739 TI - CRISPR-STAT: an easy and reliable PCR-based method to evaluate target-specific sgRNA activity. AB - CRISPR/Cas9 has emerged as a versatile genome-engineering tool that relies on a single guide RNA (sgRNA) and the Cas9 enzyme for genome editing. Simple, fast and economical methods to generate sgRNAs have made targeted mutagenesis routine in cultured cells, mice, zebrafish and other model systems. Pre-screening of sgRNAs for target efficacy is desirable both for successful mutagenesis and minimizing wasted animal husbandry on targets with poor activity. Here, we describe an easy, quick and cost-effective fluorescent polymerase chain reaction (PCR)-based method, CRISPR Somatic Tissue Activity Test (CRISPR-STAT), to determine target specific efficiency of sgRNA. As a proof of principle, we validated our method using 28 sgRNAs with known and varied levels of germline transmission efficiency in zebrafish by analysis of their somatic activity in injected embryos. Our data revealed a strong positive correlation between the fluorescent PCR profiles of the injected embryos and the germline transmission efficiency. Furthermore, the assay was sensitive enough to evaluate multiplex gene targeting. This method is easy to implement by laboratories with access to a capillary sequencer. Although we validated the method using CRISPR/Cas9 and zebrafish, it can be applied to other model systems and other genome targeting nucleases. PMID- 26253740 TI - Linkage of catalysis and 5' end recognition in ribonuclease RNase J. AB - In diverse bacterial species, the turnover and processing of many RNAs is mediated by the ribonuclease RNase J, a member of the widely occurring metallo beta-lactamase enzyme family. We present crystal structures of Streptomyces coelicolor RNase J with bound RNA in pre- and post-cleavage states, at 2.27 A and 2.80 A resolution, respectively. These structures reveal snapshots of the enzyme cleaving substrate directionally and sequentially from the 5' terminus. In the pre-cleavage state, a water molecule is coordinated to a zinc ion pair in the active site but is imperfectly oriented to launch a nucleophilic attack on the phosphate backbone. A conformational switch is envisaged that enables the in-line positioning of the attacking water and may be facilitated by magnesium ions. Adjacent to the scissile bond, four bases are stacked in a tightly sandwiching pocket, and mutagenesis results indicate that this organization helps to drive processive exo-ribonucleolytic cleavage. Like its numerous homologues, S. coelicolor RNase J can also cleave some RNA internally, and the structural data suggest how the preference for exo- versus endo-cleavage mode is linked with recognition of the chemical status of the substrate's 5' end. PMID- 26253741 TI - Solution structure of a DNA quadruplex containing ALS and FTD related GGGGCC repeat stabilized by 8-bromodeoxyguanosine substitution. AB - A prolonged expansion of GGGGCC repeat within non-coding region of C9orf72 gene has been identified as the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which are devastating neurodegenerative disorders. Formation of unusual secondary structures within expanded GGGGCC repeat, including DNA and RNA G-quadruplexes and R-loops was proposed to drive ALS and FTD pathogenesis. Initial NMR investigation on DNA oligonucleotides with four repeat units as the shortest model with the ability to form an unimolecular G-quadruplex indicated their folding into multiple G quadruplex structures in the presence of K(+) ions. Single dG to 8Br-dG substitution at position 21 in oligonucleotide d[(G4C2)3G4] and careful optimization of folding conditions enabled formation of mostly a single G quadruplex species, which enabled determination of a high-resolution structure with NMR. G-quadruplex structure adopted by d[(G4C2)3GG(Br)GG] is composed of four G-quartets, which are connected by three edgewise C-C loops. All four strands adopt antiparallel orientation to one another and have alternating syn anti progression of glycosidic conformation of guanine residues. One of the cytosines in every loop is stacked upon the G-quartet contributing to a very compact and stable structure. PMID- 26253742 TI - Regulation of DNA replication at the end of the mitochondrial D-loop involves the helicase TWINKLE and a conserved sequence element. AB - The majority of mitochondrial DNA replication events are terminated prematurely. The nascent DNA remains stably associated with the template, forming a triple stranded displacement loop (D-loop) structure. However, the function of the D loop region of the mitochondrial genome remains poorly understood. Using a comparative genomics approach we here identify two closely related 15 nt sequence motifs of the D-loop, strongly conserved among vertebrates. One motif is at the D loop 5'-end and is part of the conserved sequence block 1 (CSB1). The other motif, here denoted coreTAS, is at the D-loop 3'-end. Both these sequences may prevent transcription across the D-loop region, since light and heavy strand transcription is terminated at CSB1 and coreTAS, respectively. Interestingly, the replication of the nascent D-loop strand, occurring in a direction opposite to that of heavy strand transcription, is also terminated at coreTAS, suggesting that coreTAS is involved in termination of both transcription and replication. Finally, we demonstrate that the loading of the helicase TWINKLE at coreTAS is reversible, implying that this site is a crucial component of a switch between D loop formation and full-length mitochondrial DNA replication. PMID- 26253743 TI - GC skew is a conserved property of unmethylated CpG island promoters across vertebrates. AB - GC skew is a measure of the strand asymmetry in the distribution of guanines and cytosines. GC skew favors R-loops, a type of three stranded nucleic acid structures that form upon annealing of an RNA strand to one strand of DNA, creating a persistent RNA:DNA hybrid. Previous studies show that GC skew is prevalent at thousands of human CpG island (CGI) promoters and transcription termination regions, which correspond to hotspots of R-loop formation. Here, we investigated the conservation of GC skew patterns in 60 sequenced chordates genomes. We report that GC skew is a conserved sequence characteristic of the CGI promoter class in vertebrates. Furthermore, we reveal that promoter GC skew peaks at the exon 1/ intron1 junction and that it is highly correlated with gene age and CGI promoter strength. Our data also show that GC skew is predictive of unmethylated CGI promoters in a range of vertebrate species and that it imparts significant DNA hypomethylation for promoters with intermediate CpG densities. Finally, we observed that terminal GC skew is conserved for a subset of vertebrate genes that tend to be located significantly closer to their downstream neighbors, consistent with a role for R-loop formation in transcription termination. PMID- 26253744 TI - Bacterial vaginosis among women at high risk for HIV in Uganda: high rate of recurrent diagnosis despite treatment. AB - OBJECTIVES: Bacterial vaginosis (BV) is associated with increased risk for sexually transmitted infections (STIs) and HIV acquisition. This study describes the epidemiology of BV in a cohort of women at high risk for STI/HIV in Uganda over 2 years of follow-up between 2008-2011. METHODS: 1027 sex workers or bar workers were enrolled and asked to attend 3-monthly follow-up visits. Factors associated with prevalent BV were analysed using multivariate random-effects logistic regression. The effect of treatment on subsequent episodes of BV was evaluated with survival analysis. RESULTS: Prevalences of BV and HIV at enrolment were 56% (573/1027) and 37% (382/1027), respectively. Overall, 905 (88%) women tested positive for BV at least once in the study, over a median of four visits. Younger age, a higher number of previous sexual partners and current alcohol use were independently associated with prevalent BV. BV was associated with STIs, including HIV. Hormonal contraception and condom use were protective against BV. Among 853 treated BV cases, 72% tested positive again within 3 months. There was no difference in time to subsequent BV diagnosis between treated and untreated women. CONCLUSIONS: BV was highly prevalent and persistent in this cohort despite treatment. More effective treatment strategies are urgently needed. PMID- 26253745 TI - Improved glycemic control in veterans with poorly controlled diabetes mellitus using a Specialty Care Access Network-Extension for Community Healthcare Outcomes model at primary care clinics. AB - INTRODUCTION: An increasing number of patients with diabetes mellitus has created a need for innovative delivery of specialized care not only by diabetes specialists but also by primary care providers (PCPs) as well. A potential avenue to address this need is training of PCPs by specialists via telehealth. The Veteran Affairs (VA) Specialty Care Access Network-Extension for Community Healthcare Outcomes (SCAN-ECHO) program includes education and case-based learning for PCPs by a multidisciplinary specialty team utilizing videoconferencing technology. METHODS: Two PCPs completed a year of SCAN-ECHO diabetes training. These two PCPs set up "diabetes mini-clinics" to treat difficult-to-control high-risk patients with diabetes mellitus from their own panel and from their colleagues in the same community-based outpatient clinic (CBOC). We utilized a retrospective program evaluation by t-test using pre/post glycated hemoglobin (HbA1c) lab values after being seen by the two PCPs. RESULTS: A total of 39 patients, all with HbA1c > 9.0%, were seen in the two PCP mini clinics over 15 months. The mean HbA1c improved from 10.2 +/- 1.4% to 8.4 +/- 1.8% (p < 0.001) over the average follow-up period of five months. This was not explained by system-wide changes or improvements. DISCUSSION: Care of veteran patients with poorly controlled diabetes by PCPs who participated in SCAN-ECHO program leads to improvement in glycemic control. This model of health care delivery can be effective in remote or rural areas with limited availability of specialists. PMID- 26253746 TI - E-virtual reality exposure therapy in acrophobia: A pilot study. AB - Virtual reality therapy is already used for anxiety disorders as an alternative to in vivo and in imagino exposure. To our knowledge, however, no one has yet proposed using remote virtual reality (e-virtual reality). The aim of the present study was to assess e-virtual reality in an acrophobic population. Six individuals with acrophobia each underwent six sessions (two sessions per week) of virtual reality exposure therapy. The first three were remote sessions, while the last three were traditional sessions in the physical presence of the therapist. Anxiety (STAI form Y-A, visual analog scale, heart rate), presence, technical difficulties and therapeutic alliance (Working Alliance Inventory) were measured. In order to control the conditions in which these measures were made, all the sessions were conducted in hospital. None of the participants dropped out. The remote sessions were well accepted. None of the participants verbalized reluctance. No major technical problems were reported. None of the sessions were cancelled or interrupted because of software incidents. Measures (anxiety, presence, therapeutic alliance) were comparable across the two conditions. e Virtual reality can therefore be used to treat acrophobic disorders. However, control studies are needed to assess online feasibility, therapeutic effects and the mechanisms behind online presence. PMID- 26253747 TI - Effect of telemetric monitoring in the first 30 days of continuous positive airway pressure adaptation for obstructive sleep apnoea syndrome - a controlled pilot study. AB - Obstructive sleep apnoea syndrome (OSAS) is characterised by repetitive collapse of the upper airway during sleep. Continuous positive airway pressure (CPAP) applied via a mask is the standard treatment for OSAS. CPAP adherence is crucial in therapy to prevent the deleterious consequences of OSAS. We hypothesised that a combination of supervision by telemetry together with targeted telephone support in the first month of CPAP would increase CPAP adherence and treatment success. A total of 113 OSAS patients followed by telemetry-triggered interventions used the device for 5.3 h/night on 28/30 nights, significantly more than the 110 OSAS patients in the control group with 4.6 h/night and 27/30 nights. Telemetry-triggered interventions have a significant impact on adherence rate in early CPAP treatment. These results can be reached with an acceptable additional effort. PMID- 26253748 TI - Monitoring medication adherence in multiple sclerosis using a novel web-based tool: A pilot study. AB - Monitoring medication adherence in multiple sclerosis (MS) can be time consuming and expensive; however, non-adherence is common and is very costly in terms of lost therapeutic benefit and unused medications. To address this problem, we employed a web-based system to monitor and potentially modify medication adherence. Participants (n = 30) were randomized either to routine care or to the MS Home Automated Telehealth (MS HAT) system. Weekly interferon beta-1a intramuscular (INFbeta-1a IM) injections and daily vitamin D adherence were tracked over a six-month period using multiple modalities: self-reported adherence, calendar diaries, pharmacy refill rates, blood serum levels, and MS HAT alerts. Weekly INFbeta-1a IM adherence was highly correlated across measures; however, vitamin D adherence was not as consistent. Healthcare providers were able to efficiently monitor adherence in a patient-centered way by using the MS HAT system to monitor adherence rather than employing chart reviews and phone calls. In addition, patients with more preserved cognitive function appeared to benefit more from use of the MS HAT system than those with cognitive impairment. While further research is needed to understand the differential effects of MS HAT on specific medications and for different individuals, it is a promising tool for monitoring medication adherence in patients with MS. PMID- 26253750 TI - Journal of Insect Physiology. Special Issue for proceedings of The Tenth International Conference on Juvenile Hormones. Preface. PMID- 26253749 TI - Dietary intakes of expeditioners during prolonged sunlight deprivation in polar enviroments do not support bone health. AB - BACKGROUND: Early Antarctic expeditions were plagued by nutrient deficiencies, due to lack of fresh food and reliance on preserved foods. Modern Antarctic expeditioners also require provisions to be shipped in, but improved knowledge and storage options ensure foods are nutritionally sound. Despite this, nutritional imbalances are observed. OBJECTIVES: To determine the adequacy of dietary intake of Antarctic expeditioners, with reference to bone health. DESIGN: Dietary intake was determined on 225 adults (mean age 42+/-11 years, 16% female) during 12-month deployments at Australian Antarctic stations from 2004 to 2010, using weighed 3-day food records. Nutrient intake was analysed using FoodWorks. Foods were divided into the 5 food groups according to the Australian Guide to Healthy Eating. RESULTS: Men consumed below the recommended levels [recommended daily intake (RDI)/adequate intakes (AI)] of calcium (79+/-42% of RDI, p<0.001), magnesium (83+/-34% of RDI, p<0.001), potassium (86+/-29% of AI, p<0.001) and fibre (75+/-30% of AI, p<0.001), and above the upper limit (UL) for sodium (125+/ 48% of UL p<0.001), whereas women consumed below the recommended levels of calcium (68+/-21% of RDI, p<0.001) and iron (73+/-37% of RDI, p<0.001). Vitamin D intake is not substantial (<150 IU/d). Men consumed more alcohol than women (18+/ 24 g/d vs. 10+/-13 g/d, p<0.05), nearer the guideline of <=20 g/d. Men and women consumed approximately 1 serving of dairy food per day, and 3 of 5 recommended vegetable servings. Discretionary foods were consumed in excess of recommended. CONCLUSIONS: Improving consumption of calcium-rich (dairy) foods better supports bone health during sunlight deprivation. Increasing vegetable intake to recommended levels will increase fibre, potassium and magnesium intakes. The challenge is the logistics of providing these foods throughout the year. PMID- 26253751 TI - [Care against infections in rheumatic autoimmune diseases]. PMID- 26253752 TI - [Peripheral corneal melting syndrome in psoriatic arthritis treated with adalimumab]. AB - Peripheral corneal melting syndrome is a rare immune condition characterized by marginal corneal thinning and sometimes perforation. It is associated with rheumatic and non-rheumatic diseases. Few cases of peripheral corneal melting have been reported in patients with psoriasis. The pathogenesis is not fully understood but metalloproteinases may play a pathogenic role. Anti-TNF therapy has shown to decrease skin and serum metalloproteinases levels in psoriasis. We report a 61-year-old man with peripheral corneal melting syndrome associated with psoriatic arthritis who received Adalimumab to control skin and ocular inflammation. To our knowledge, this is the first case report of peripheral corneal melting syndrome in psoriatic arthritis treated with Adalimumab showing resolution of skin lesions and complete healing of corneal perforation in three months. PMID- 26253753 TI - Removing confounding factors via constraint-based clustering: An application to finding homogeneous groups of multiple sclerosis patients. AB - OBJECTIVES: Confounding factors in unsupervised data can lead to undesirable clustering results. For example in medical datasets, age is often a confounding factor in tests designed to judge the severity of a patient's disease through measures of mobility, eyesight and hearing. In such cases, removing age from each instance will not remove its effect from the data as other features will be correlated with age. Motivated by the need to find homogeneous groups of multiple sclerosis (MS) patients, we apply our approach to remove physician subjectivity from patient data. METHODS: We present a method based on constraint-based clustering to remove the impact of such confounding factors. Given knowledge about which feature (or set of features) is a confounding factor, call it F. Our method first partitions the data into b bins: if F is categorical, instances from the same category construct one bin; if F is numeric, then we split bins such that each bin contains instances of similar F value. Thus each instance is assigned to a single bin for factor F. We then remove feature F from each instance for the remaining steps. Next, we cluster the data separately in each bin. Using these clustering results, we generate pair-wise constraints and then run a constraint-based clustering algorithm to produce a final grouping. RESULTS: In a series of experiments with synthetic datasets, we compare our proposed methods to detrending when one has numeric confounding factors. We apply our method to the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Womens Hospital dataset, and find a novel grouping of patients that can help uncover the factors that impact disease progression in MS. CONCLUSIONS: Our method groups data removing the effect of confounding factors without making any assumptions about the form of the influence of these factors on the other features. We identified clusters of MS patients that have clinically recognizable differences. Because patients more likely to progress are found using this approach, our results have the potential to aid physicians in tailoring treatment decisions for MS patients. PMID- 26253754 TI - Impact imaging of aircraft composite structure based on a model-independent spatial-wavenumber filter. AB - The spatial-wavenumber filtering technique is an effective approach to distinguish the propagating direction and wave mode of Lamb wave in spatial wavenumber domain. Therefore, it has been gradually studied for damage evaluation in recent years. But for on-line impact monitoring in practical application, the main problem is how to realize the spatial-wavenumber filtering of impact signal when the wavenumber of high spatial resolution cannot be measured or the accurate wavenumber curve cannot be modeled. In this paper, a new model-independent spatial-wavenumber filter based impact imaging method is proposed. In this method, a 2D cross-shaped array constructed by two linear piezoelectric (PZT) sensor arrays is used to acquire impact signal on-line. The continuous complex Shannon wavelet transform is adopted to extract the frequency narrowband signals from the frequency wideband impact response signals of the PZT sensors. A model independent spatial-wavenumber filter is designed based on the spatial-wavenumber filtering technique. Based on the designed filter, a wavenumber searching and best match mechanism is proposed to implement the spatial-wavenumber filtering of the frequency narrowband signals without modeling, which can be used to obtain a wavenumber-time image of the impact relative to a linear PZT sensor array. By using the two wavenumber-time images of the 2D cross-shaped array, the impact direction can be estimated without blind angle. The impact distance relative to the 2D cross-shaped array can be calculated by using the difference of time-of flight between the frequency narrowband signals of two different central frequencies and the corresponding group velocities. The validations performed on a carbon fiber composite laminate plate and an aircraft composite oil tank show a good impact localization accuracy of the model-independent spatial-wavenumber filter based impact imaging method. PMID- 26253755 TI - Emergency department characteristics and capabilities in Bogota, Colombia. AB - BACKGROUND: Emergency departments (EDs) are a critical, yet heterogeneous, part of international emergency care. The National ED Inventories (NEDI) survey has been used in multiple countries as a standardized method to benchmark ED characteristics. We sought to describe the characteristics, resources, capabilities, and capacity of EDs in the densely populated capital city of Bogota, Colombia. METHODS: Bogota EDs accessible to the general public 24/7 were surveyed using the 23-item NEDI survey used in several other countries ( www.emnet-nedi.org ). ED staff were asked about ED characteristics with reference to calendar year 2011. RESULTS: Seventy EDs participated (82 % response). Most EDs (87 %) were located in hospitals, and 83 % were independent hospital departments. The median annual ED visit volume was approximately 50,000 visits. Approximately 90 % (95 % confidence interval (CI) 80-96 %) had a contiguous layout, with medical and surgical care provided in one area. Almost all EDs saw both adults and children (91 %), while 6 % saw only adults and 3 % saw only children. Availability of technological and consultant resources in EDs was variable. Nearly every ED had cardiac monitoring (99 %, 95 % CI 92-100 %), but less than half had a dedicated CT scanner (39 %, 95 % CI 28-52 %). While most EDs were able to treat trauma 24/7 (81 %, 95 % CI 69-89 %), few could manage oncological (22 %, 95 % CI 13-34 %) or dental (3 %, 95 % CI 0-11 %) emergencies 24/7. The typical ED length-of-stay was between 1 and 6 h in 59 % of EDs (95 % CI, 46-70 %), while most others reported that patients remained for >6 h (39 %). Almost half of respondents (46 %, 95 % CI 34-59 %) reported their ED was over capacity. CONCLUSIONS: Bogota EDs have high annual visit volumes and long length of-stay, and half are over capacity. To meet the emergency care needs of people in Bogota and other large cities, Colombia should consider improving urban ED capacity and training more emergency medicine specialists capable of efficiently staffing its large and crowded EDs. PMID- 26253756 TI - Science of Cardiopulmonary Resuscitation: Just Scratching the Surface. PMID- 26253757 TI - Association Between Chest Compression Interruptions and Clinical Outcomes of Ventricular Fibrillation Out-of-Hospital Cardiac Arrest. AB - BACKGROUND: Minimizing pauses in chest compressions during cardiopulmonary resuscitation is a focus of current guidelines. Prior analyses found that prolonged pauses for defibrillation (perishock pauses) are associated with worse survival. We analyzed resuscitations to characterize the association between pauses for all reasons and both ventricular fibrillation termination and patient survival. METHODS AND RESULTS: In 319 patients with ventricular tachycardia/fibrillation out-of-hospital cardiac arrest, we analyzed recordings from all defibrillators used during resuscitation and measured durations of all cardiopulmonary resuscitation pauses. Median durations were 32 seconds (25th and 75th percentile, 22 and 52 seconds) for the longest pause for any reason, 23 seconds (25th and 75th percentile, 14 and 34 seconds) for the longest perishock pause, and 24 seconds (25th and 75th percentile, 11 and 38 seconds) for the longest nonshock pause. Multivariable regression models showed lower odds for survival per 5-second increase in the longest overall pause (odds ratio, 0.89; 95% confidence interval, 0.83-0.95), longest perishock pause (odds ratio, 0.85; 95% confidence interval, 0.77-0.93), and longest nonshock pause (odds ratio, 0.83; 95% confidence interval, 0.75-0.91). In 36% of cases, the longest pause was a nonshock pause; this subgroup had lower survival than the group in whom the longest pause was a perishock pause (27% versus 44%, respectively; P<0.01) despite a higher chest compression fraction. Preshock pauses were 8 seconds (25th and 75th percentile, 4 and 17 seconds) for shocks that terminated ventricular fibrillation and 7 seconds (25th and 75th percentile, 4 and 13 seconds) for shocks that did not (P=0.18). CONCLUSIONS: Prolonged pauses have a negative association with survival not explained by chest compression fraction or decreased ventricular fibrillation termination rate. Ventricular fibrillation termination was not the mechanism linking pause duration and survival. Strategies shortening the longest pauses may improve outcome. PMID- 26253758 TI - Finite element modelling predicts changes in joint shape and cell behaviour due to loss of muscle strain in jaw development. AB - Abnormal joint morphogenesis is linked to clinical conditions such as Developmental Dysplasia of the Hip (DDH) and to osteoarthritis (OA). Muscle activity is known to be important during the developmental process of joint morphogenesis. However, less is known about how this mechanical stimulus affects the behaviour of joint cells to generate altered morphology. Using zebrafish, in which we can image all joint musculoskeletal tissues at high resolution, we show that removal of muscle activity through anaesthetisation or genetic manipulation causes a change to the shape of the joint between the Meckel's cartilage and Palatoquadrate (the jaw joint), such that the joint develops asymmetrically leading to an overlap of the cartilage elements on the medial side which inhibits normal joint function. We identify the time during which muscle activity is critical to produce a normal joint. Using Finite Element Analysis (FEA), to model the strains exerted by muscle on the skeletal elements, we identify that minimum principal strains are located at the medial region of the joint and interzone during mouth opening. Then, by studying the cells immediately proximal to the joint, we demonstrate that biomechanical strain regulates cell orientation within the developing joint, such that when muscle-induced strain is removed, cells on the medial side of the joint notably change their orientation. Together, these data show that biomechanical forces are required to establish symmetry in the joint during development. PMID- 26253759 TI - Bladder tissue biomechanical behavior: Experimental tests and constitutive formulation. AB - A procedure for the constitutive analysis of bladder tissues mechanical behavior is provided, by using a coupled experimental and computational approach. The first step pertains to the design and development of mechanical tests on specimens from porcine bladders. The bladders have been harvested, and the specimens have been subjected to uniaxial cyclic tests at different strain rates along preferential directions, considering the distribution of tissue fibrous components. Experimental results showed the anisotropic, non-linear and time dependent stress-strain behavior, due to tissue conformation with fibers distributed along preferential directions and their interaction phenomena with ground substance. In detail, experimental data showed a greater tissue stiffness along transversal direction. Viscous behavior was assessed by strain rate dependence of stress-strain curves and hysteretic phenomena. The second step pertains the development of a specific fiber-reinforced visco-hyperelastic constitutive model, in the light of bladder tissues structural conformation and experimental results. Constitutive parameters have been identified by minimizing the discrepancy between model and experimental data. The agreement between experimental and model results represent a term for evaluating the reliability of the constitutive models by means of the proposed operational procedure. PMID- 26253760 TI - A systematic review of probable posttraumatic stress disorder in first responders following man-made mass violence. AB - The current study was a systematic review examining probable posttraumatic stress disorder (PTSD) in first responders following man-made mass violence. A systematic literature search yielded 20 studies that fit the inclusion criteria. The prevalence rates of probable PTSD across all 20 studies ranged from 1.3% to 22.0%. Fifteen of the 20 articles focused on first responders following the September 11th terrorist attacks and many of the studies used the same participant recruitment pools. Overall, the results of the systematic review described here suggest that our understanding of PTSD in first responders following man-made mass violence is based on a very small set of articles that have focused on a few particular events. This paper is meant to serve as a call for additional research and to encourage more breadth in the specific incidents that are examined. PMID- 26253761 TI - Where are the South American freshwater turtle blood flukes (Trematoda: Spirorchiidae)? The first morphological and molecular analysis of spirorchiid cercariae from freshwater snails in Brazil. AB - Trematodes belonging to the family Spirorchiidae are blood parasites mainly of turtles with a worldwide distribution. These flukes were recently reported in some marine turtles from South America, where the occurrence of spirorchiids in freshwater definitive and intermediate hosts is so far unknown. In the present study, three morphotypes of brevifurcate apharyngeate distome cercariae found in freshwater molluscs from an urban reservoir in Brazil were used for morphological and molecular (nuclear 28S rDNA) evaluation. Two morphotypes of cercariae, probably congeneric species, were found in 12/17,465 specimens of Biomphalaria spp. and differ from each other by body size and sequences (0.1%). They present morphology similar to North American freshwater spirorchiids (Spirorchis spp.), however surprisingly molecular data reveals that these lineages are more closely related to marine spirorchiids. A third species found in 2/777 Pomacea sp. differs morphologically from all previously described spirorchiid cercariae and genetically from spirorchiids with available sequences (16-19%), grouping in the phylogenetic tree with freshwater North American species. This is the first report of freshwater spirorchiids in South America and the first molecular confirmation of the involvement of a caenogastropod in the life cycle of spirorchiids. PMID- 26253762 TI - Method for identification of spectral targets in discrete frequency infrared spectroscopy for clinical diagnostics. AB - Spectroscopic imaging with discrete frequency infrared (DF-IR) has the potential to have a major impact on the clinical utility of IR imaging techniques for biochemical detection of disease. This can be achieved in real time using imaging at selected wavenumbers tuned to molecular absorptions of interest enabling tissue and disease-specific contrast to be obtained from the sample. However, selecting the appropriate wavenumbers to measure for DF-IR is critical, since vital diagnostic information could be missed. Here we demonstrate the application of partial least squares discriminant analysis (PLS-DA) and variable importance for projection (VIP) to identify key diagnostic wavenumber targets for the detection of dysplasia in human colon polyp sections. A small dataset, including 41 regions of interest (25 benign, 16 dysplastic; 5175 spectra in total), was selected from Fourier transform infrared (FT-IR) images of human colon polyp sections. PLS-DA was used to differentiate between benign and cancerous human colon polyp sections (sensitivity 95%, specificity 93% cross-validated), and VIP scores were calculated for all wavenumbers. A second PLS-DA model was then calculated using only variables that VIP identified as significant, reducing the number of wavenumbers to ~25% of the full dataset. The resulting cross-validated sensitivity and specificity (93 and 90%, respectively) indicate that the VIP method selects the key diagnostic wavenumbers for this dataset. Finally, a robust subset of variables was identified by selecting wavenumbers that exceeded the minimum VIP score in >95% of our validation iterations. A cross-validated PLS-DA model using only the robustly selected wavenumber targets (~20% of the original wavenumbers) resulted in sensitivity and specificity of 91 and 82%, respectively, indicating that PLS-DA and VIP are suitable approaches for the selection of wavenumber targets in DF-IR. PMID- 26253763 TI - Shape control and compartmentalization in active colloidal cells. AB - Small autonomous machines like biological cells or soft robots can convert energy input into control of function and form. It is desired that this behavior emerges spontaneously and can be easily switched over time. For this purpose we introduce an active matter system that is loosely inspired by biology and which we term an active colloidal cell. The active colloidal cell consists of a boundary and a fluid interior, both of which are built from identical rotating spinners whose activity creates convective flows. Similarly to biological cell motility, which is driven by cytoskeletal components spread throughout the entire volume of the cell, active colloidal cells are characterized by highly distributed energy conversion. We demonstrate that we can control the shape of the active colloidal cell and drive compartmentalization by varying the details of the boundary (hard vs. flexible) and the character of the spinners (passive vs. active). We report buckling of the boundary controlled by the pattern of boundary activity, as well as formation of core-shell and inverted Janus phase-separated configurations within the active cell interior. As the cell size is increased, the inverted Janus configuration spontaneously breaks its mirror symmetry. The result is a bubble-crescent configuration, which alternates between two degenerate states over time and exhibits collective migration of the fluid along the boundary. Our results are obtained using microscopic, non-momentum-conserving Langevin dynamics simulations and verified via a phase-field continuum model coupled to a Navier Stokes equation. PMID- 26253764 TI - A common glycan structure on immunoglobulin G for enhancement of effector functions. AB - Antibodies have been developed as therapeutic agents for the treatment of cancer, infection, and inflammation. In addition to binding activity toward the target, antibodies also exhibit effector-mediated activities through the interaction of the Fc glycan and the Fc receptors on immune cells. To identify the optimal glycan structures for individual antibodies with desired activity, we have developed an effective method to modify the Fc-glycan structures to a homogeneous glycoform. In this study, it was found that the biantennary N-glycan structure with two terminal alpha-2,6-linked sialic acids is a common and optimized structure for the enhancement of antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and antiinflammatory activities. PMID- 26253766 TI - Excessive gestational weight gain and gestational diabetes: importance of the first weeks of pregnancy. AB - Gestational diabetes mellitus (GDM) is associated with many adverse neonatal and maternal outcomes and prevention of this condition is considered a key strategy for breaking the intergenerational cycle of obesity and diabetes. Whether prevention of excessive gestational weight gain in the first weeks of pregnancy is associated with a reduced risk for GDM is currently unclear. In this issue of Diabetologia, Brunner et al (DOI: 10.1007/s00125-015-3686-5) address this possible association by conducting a systematic review and a meta-analysis. The results of their study provide evidence that excessive gestational weight gain prior to a GDM screening test is associated with an increased risk of GDM compared with non-excessive gestational weight gain. These results emphasise the need for appropriate preconception care and for better prevention of early excessive gestational weight gain and GDM. PMID- 26253765 TI - Influenza A virus antibodies show no association with pancreatic islet autoantibodies in children genetically predisposed to type 1 diabetes. AB - AIMS/HYPOTHESIS: Viral infections have long been considered potential triggers of beta cell autoimmunity and type 1 diabetes. Recent studies have suggested that influenza A virus might increase the risk of type 1 diabetes. The present study evaluates this risk association in prospectively observed children at the time when islet autoimmunity starts and autoantibodies are first detected. METHODS: IgG class antibodies to influenza A virus were analysed in 95 case children whose antibody screening test turned permanently positive for two or more islet autoantibodies and from 186 autoantibody-negative and non-diabetic control children who were matched for time of birth, sex, date of sampling and HLA conferred risk of diabetes in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. Virus antibodies were measured from the first autoantibody-positive sample using an enzyme immunoassay. None of the children had been vaccinated against influenza A. RESULTS: The prevalence of influenza A virus antibodies did not differ between the case and control children (42% vs 38%; p = 0.392) and the median antibody levels were also comparable in the two groups (3.0 vs 3.8 enzyme immunoassay units). A similar result was obtained when case and control children were compared separately in subgroups according to different sex, age and HLA-DQ genotype. However, girls had higher antibody levels than boys among both case and control children (median antibody levels 9.0 vs 2.3 enzyme immunoassay units; p = 0.01). CONCLUSIONS/INTERPRETATION: Our results suggest that influenza A infections are not associated with the development of islet autoimmunity in young children with increased genetic susceptibility to type 1 diabetes. PMID- 26253767 TI - Sex of the baby and risk of gestational diabetes mellitus in the mother: a systematic review and meta-analysis. AB - AIMS/HYPOTHESIS: It has recently emerged that carrying a male fetus may be associated with poorer maternal beta cell function and an increased risk of gestational diabetes mellitus (GDM). Recognising that the overall impact of fetal sex on maternal glucose metabolism is likely to be subtle, we sought to perform a systematic review and meta-analysis of observational studies to obtain a robust estimate of the incremental maternal risk of GDM associated with the sex of the baby. METHODS: We searched PubMed and EMBASE to identify observational studies published between 1 January 1950 and 4 April 2015 that reported data on fetal sex and the prevalence of GDM. Two independent reviewers extracted the data and pooled estimates of the RR were calculated by a random-effects model. We considered male fetus as the exposure and prevalence of GDM as the outcome of interest. RESULTS: We identified 320 studies through electronic searches and nine studies through manual searches. Twenty studies met the inclusion criteria, yielding data on 2,402,643 women. Pooled analysis of these studies demonstrated an increased risk of GDM in women carrying a male fetus compared with women carrying a female fetus (RR 1.04; 95% CI 1.02, 1.06). This result was confirmed in a sensitivity analysis including only studies that applied a stringent definition of GDM (RR 1.03; 95% CI 1.01, 1.06) (I(2) = 0%, p = 0.66). CONCLUSIONS/INTERPRETATION: Pregnant women carrying a boy have a 4% higher relative risk of GDM than those carrying a girl. The fetus thus may have previously unsuspected effects on maternal glucose metabolism in pregnancy. PMID- 26253768 TI - Likelihood of 'falling through the net' relates to contemporary prevalence of gestational diabetes. PMID- 26253769 TI - [Not Available]. PMID- 26253770 TI - [Ophthalmoscopy in the era of optical coherence tomography]. AB - For more than one and a half centuries ophthalmoscopy has been the main diagnostic procedure in ophthalmology for diagnosing retinal diseases. The techniques have improved over the years and ophthalmoscopy is still the gold standard for all retinal diseases, especially for peripheral retinal diseases. The introduction of optical coherence tomography (OCT) has revolutionized ocular diagnostics of macular diseases as OCT is able to detect retinal changes that cannot be diagnosed as well with ophthalmoscopy alone. Nevertheless, diagnosis of a retinal disease should not be made on the basis of OCT findings alone but always in combination with ophthalmoscopy. If necessary further diagnostic procedures should be added to improve the accuracy of diagnosis, to follow the course of the disease and to control the success of treatment. PMID- 26253771 TI - 3D MDCT angiography for the preoperative assessment of truncus arteriosus. AB - Truncus arteriosus is an uncommon conotruncal anomaly, which is amenable to surgical correction. The systemic, pulmonary, and coronary circulations originate from a single arterial vessel that arises from the ventricular part of the heart and overrides the ventricular septum. The value of multidetector computed tomography with three-dimensional postprocessing lies in the detailed assessment of the presence or absence of the pulmonary arteries, including the number, origin, and branching patterns of major aortopulmonary collateral arteries, and extracardiac abnormalities such as aortic arch interruption. This article reviews the various imaging spectra of truncus arteriosus, which are especially important in the surgical planning. PMID- 26253772 TI - Influence of rectal gel volume on defecation during dynamic pelvic floor magnetic resonance imaging. AB - PURPOSE: To evaluate effects of altering rectal contrast volume on defecatory effort during magnetic resonance defecography (MRD). METHODS: We assessed defecation qualitatively and quantitatively as a function of rectal distention (group A: 180 cc, n=31; group B: 120 cc, n=31). Quantitative evaluation comprised measuring rectal area on midline sagittal images pre- and post-defecation. RESULTS: Resting rectal area was significantly higher for group A than for group B (35.2 vs. 28.3 cm(2), P<.0001). Post-defecation rectal area and change in area (pre- to post-defecation) were not significantly different. Subjective evaluation showed no significant difference. CONCLUSION: Decreasing rectal gel volume from 180 to 120 cc did not compromise defecation performance during MRD. PMID- 26253773 TI - Crossed legs: an unexpected occurrence during an ALN filter placement. AB - Inferior vena cava (IVC) filter placement is indicated for patients with pulmonary embolism and/or deep venous thrombosis when anticoagulation therapy is contraindicated. IVC filter placement, however, is not without complications. In this case, we noted crossing of the filter struts immediately after deployment of the ALN IVC filter (ALN Implants Chirurgicaux Ghisonaccia, France). The filter was then successfully removed. PMID- 26253774 TI - Comparison of diffusion-weighted imaging findings in brain metastases of different origin. AB - Our purpose was to estimate apparent diffusion coefficient (ADC) values from brain metastases (BMs). Our patient sample included 159 patients with 948 BMs. Magnetic resonance imaging was obtained with a 1.5-T device. For diffusion weighted imaging, a multislice single-shot echo-planar imaging sequence was used (b values of 0, 500, and 1000 s/mm(2)). The mean ADC value of BMs was 0.98 +/- 0.32 * 10(-3) mm(2) s(-1). A total of 72.8% of BM lesions showed ADC values under 0.90 * 10(-3) mm(2) s(-1). Small-cell lung cancer had the lowest ADC values (0.86 +/- 0.27) in comparison to BMs from non-small-cell lung cancer (1.17 +/- 0.49), breast carcinoma (0.97 +/- 0.21), and malignant melanoma (0.99 +/- 0.36). PMID- 26253775 TI - Crystal Structures of Arabidopsis thaliana Nudix Hydrolase NUDT7 Reveal a Previously Unobserved Conformation. PMID- 26253776 TI - Lung and Chest-Wall Metastasis of Liposarcoma. PMID- 26253777 TI - Treatment of Hypertensive Patients with a Fixed-Dose Combination of Bisoprolol and Amlodipine: Results of a Cohort study with More Than 10,000 Patients. AB - INTRODUCTION: Many patients need more than one antihypertensive agent for effective blood pressure (BP) control. Prescription of a fixed-dose combination (FDC) of bisoprolol and amlodipine in one tablet has been shown to significantly improve patient adherence. This non-interventional study investigated the effects on adherence and BP control of switching from a free-dose combination of the two antihypertensive substances to a FDC in a larger patient population. METHODS: Patients aged >=18 years with essential hypertension were switched at least 4 weeks prior to study initiation from a free-dose combination of bisoprolol and amlodipine to the FDC. Dosage adjustment was implemented only if medically indicated. Adherence was assessed on the basis of the ratio of pills used to pills dispensed (%) at each visit (pill count). BP and key laboratory values were determined at baseline, 3 and 6 months. RESULTS: 10,532 patients (average age 59 years; 48% female) were recruited between 2013 and 2014; 22% of patients had type 2 diabetes and 38% had cardiovascular disease. The mean doses of the freely combined drugs prior to switching were 5.5 mg bisoprolol and 6.1 mg amlodipine once daily. The mean daily doses prescribed in the FDC were 5.8 and 6.4 mg, respectively. Pill counts at 6 months revealed a good to excellent adherence in >95% of the patients. Comparison of BP at baseline and at 6 months showed substantial changes (mean systolic BP: 147.3 vs. 130.9 mmHg; mean diastolic BP: 87.9 vs. 79.1 mmHg). Clinically relevant improvement in systolic BP was established for 82% of patients. In patients with comorbidities, switching to FDC produced a substantial improvement in BP. A total of 89 (0.7%) adverse events (AEs) were reported, including edema, headache, dizziness, bradycardia, nausea, and skin reactions. Only three AEs were classified as serious. CONCLUSION: These data from a non-interventional study in a large patient population demonstrate the benefits of prescribing a FDC of bisoprolol-amlodipine in terms of an excellent adherence and an associated improvement in control of previously elevated BP, which may be relevant in real-life practice. FUNDING: Merck KGaA. PMID- 26253778 TI - Permutation and parametric tests for effect sizes in voxel-based morphometry of gray matter volume in brain structural MRI. AB - Permutation testing has been widely implemented in voxel-based morphometry (VBM) tools. However, this type of non-parametric inference has yet to be thoroughly compared with traditional parametric inference in VBM studies of brain structure. Here we compare both types of inference and investigate what influence the number of permutations in permutation testing has on results in an exemplar study of how gray matter proportion changes with age in a group of working age adults. High resolution T1-weighted volume scans were acquired from 80 healthy adults aged 25 64years. Using a validated VBM procedure and voxel-based permutation testing for Pearson product-moment coefficient, the effect sizes of changes in gray matter proportion with age were assessed using traditional parametric and permutation testing inference with 100, 500, 1000, 5000, 10000 and 20000 permutations. The statistical significance was set at P<0.05 and false discovery rate (FDR) was used to correct for multiple comparisons. Clusters of voxels with statistically significant (PFDR<0.05) declines in gray matter proportion with age identified with permutation testing inference (N~6000) were approximately twice the size of those identified with parametric inference (N=3221voxels). Permutation testing with 10000 (N=6251voxels) and 20000 (N=6233voxels) permutations produced clusters that were generally consistent with each other. However, with 1000 permutations there were approximately 20% more statistically significant voxels (N=7117voxels) than with >=10000 permutations. Permutation testing inference may provide a more sensitive method than traditional parametric inference for identifying age related differences in gray matter proportion. Based on the results reported here, at least 10000 permutations should be used in future univariate VBM studies investigating age related changes in gray matter to avoid potential false findings. Additional studies using permutation testing in large imaging databanks are required to address the impact of model complexity, multivariate analysis, number of observations, sampling bias and data quality on the accuracy with which subtle differences in brain structure associated with normal aging can be identified. PMID- 26253779 TI - Double Coaxial Microcatheter Technique for Glue Embolization of Renal Arteriovenous Malformations. AB - PURPOSE: To demonstrate the technical benefit of the double coaxial microcatheter technique for embolization of renal arteriovenous malformations (AVMs) with n butyl cyanoacrylate and iodized oil (glue). MATERIALS AND METHODS: Six consecutive patients (1 man and 5 women; mean age 61 years; range 44-77 years) with renal AVMs were included. Five patients had hematuria, and one had a risk of heart failure due to a large intrarenal arteriovenous shunt. All patients underwent transarterial embolization using glue and the double coaxial microcatheter technique with outer 2.6F and inner 1.9F microcatheters. After glue injection, the inner microcatheter was retracted, while the outer microcatheter was retained. We assessed the complications and clinical outcomes of this technique. RESULTS: Technical success was achieved in all patients. In 9 sessions, 34 feeding arteries were embolized with glue using the double coaxial microcatheter technique, 1 was embolized with glue using a single microcatheter, and 2 were embolized with coils. The double coaxial microcatheter technique was useful for selecting small tortuous feeding arteries, preventing glue reflux to the proximal arteries, and approaching multiple feeding arteries without complete retraction of the microcatheters. As a minor complication, glue migrated into the venous system in four patients without any sequelae. In all patients, favorable clinical outcomes, including hematuria cessation in five patients and improvement of the large intrarenal arteriovenous shunt in one patient, were obtained without deterioration of renal function. CONCLUSION: Glue embolization with the double coaxial microcatheter technique was useful for treating renal AVMs with multiple tortuous feeding arteries. PMID- 26253780 TI - Mid-Term Vascular Safety of Renal Denervation Assessed by Follow-up MR Imaging. AB - BACKGROUND/AIMS: Renal denervation (RDN) emerged as a treatment option for reducing blood pressure (BP) in patients with treatment-resistant hypertension (TRH). However, concerns have been raised regarding the incidence of late renal artery stenosis or thromboembolism after RDN. The goal of the current study was, therefore, to conduct a prospective clinical trial on the mid-term vascular integrity of the renal arteries and the perfusion of the renal parenchyma assessed by magnetic resonance imaging (MRI) in the follow-up after catheter based RDN. METHODS: In our single-centre investigator initiated study, 51 patients with true TRH underwent catheter-based RDN using the Symplicity Flex(TM) catheter (Medtronic Inc., Palo Alto, CA). Follow-up MRI was performed at a median of 11 months (interquartile range 6-18 months) after RDN on a 1.5T MR unit. High resolution MR angiography (MRA) and MRI results were compared to the baseline digital angiography of renal arteries obtained at time of RDN. In case of uncertainties (N = 2) catheter angiography was repeated. RESULTS: Both office and 24-h ambulatory BP were significantly reduced 6 and 12 months after RDN. Renal function remained unchanged 6 and 12 months after RDN. In all patients, MRA excluded new or progression of pre-existing low grade renal artery stenosis as well as focal aneurysms at the sites of radiofrequency ablation. In none of the patients new segmental perfusion deficits in either kidney were detected on MRI. CONCLUSIONS: No vascular or parenchymal complications after radiofrequency-based RDN were detected in 51 patients followed up by MRI. PMID- 26253781 TI - Anomalous Posterior Intercostal Arterial Trunk Arising From the Abdominal Aorta. AB - A common trunk of the ipsilateral posterior intercostal artery (PIA) arising from the thoracic aorta is usually an anatomical variation. However, a common trunk of bilateral posterior intercostal arterial trunk (PIAT) arising from the abdominal aorta is rare. It is important to recognize this anatomical variation of PIA when performing interventional radiological procedures. We present a rare case of an anomalous PIAT that originated from the abdominal aorta in a patient with hemoptysis caused by tuberculosis sequelae. Bilateral 4th to 11th PIAs arose from a common trunk and the trunk arising from the posterior aspect of the abdominal aorta at the level of T12/L1 intervertebral space. The pathological right 4th and 5th PIAs and bronchial arteries were embolized. Hemoptysis has been controlled for 3 months. PMID- 26253782 TI - Transmission of Babesia ovis by different Rhipicephalus bursa developmental stages and infected blood injection. AB - In this report, the transmission efficacy of Babesia ovis, the principal causative agent of ovine babesiosis, was studied by infestation of lambs with different Rhipicephalus bursa stages or by injection of infected blood. Infected blood injection induced acute babesiosis in splenectomized lambs, while only mild clinical signs were observed in intact animals. Both splenectomized and intact lambs developed high antibody titer, detectable for at least 180 days post infection. Infestation of splenectomized and intact lambs with infected tick larvae did not induce clinical babesiosis or specific serum response in any of the examined animals. Similarly, infestation of one splenectomized lamb with partially-fed infected R. bursa males did not induce any clinical response or seroconversion. Nymph infestation caused a mild clinical response followed by specific seroconversion, in one out of five lambs. All animals infested with infected unfed adults (males and females) showed mild-to-severe clinical signs 8 to 12 days post infestation. The acute phase was followed by a marked seroconversion. Our results indicate that the principal transmission of B. ovis is performed by adult R. bursa ticks, and that the host reaction can last as long as 6 months following the acute infection. PMID- 26253783 TI - Amyotrophic lateral sclerosis: Current perspectives from basic research to the clinic. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motoneurons, leading to muscle weakness and paralysis, and finally death. Considerable recent advances have been made in basic research and preclinical therapeutic attempts using experimental models, leading to increasing clinical and translational research in the context of this disease. In this review we aim to summarize the most relevant findings from a variety of aspects about ALS, including evaluation methods, animal models, pathophysiology, and clinical findings, with particular emphasis in understanding the role of every contributing mechanism to the disease for elucidating the causes underlying degeneration of motoneurons and the development of new therapeutic strategies. PMID- 26253784 TI - Patient-ventilator synchrony in Neurally Adjusted Ventilatory Assist (NAVA) and Pressure Support Ventilation (PSV): a prospective observational study. AB - BACKGROUND: Weaning from mechanical ventilation is associated with the presence of asynchronies between the patient and the ventilator. The main objective of the present study was to demonstrate a decrease in the total number of patient ventilator asynchronies in invasively ventilated patients for whom difficulty in weaning is expected by comparing neurally adjusted ventilatory assist (NAVA) and pressure support ventilation (PSV) ventilatory modes. METHODS: We performed a prospective, non-randomized, non-interventional, single-center study. Thirty patients were included in the study. Each patient included in the study benefited in an unpredictable way from both modes of ventilation, NAVA or PSV. Patients were successively ventilated for 23 h in NAVA or in PSV, and then they were ventilated for another 23 h in the other mode. Demographic, biological and ventilatory data were collected during this period. The two modes of ventilatory support were compared using the non-parametric Wilcoxon test after checking for normal distribution by the Kolmogorov-Smirnov test. The groups were compared using the chi-square test. RESULTS: The median level of support was 12.5 cmH2O (4 20 cmH2O) in PSV and 0.8 cmH2O/MUvolts (0.2-3 cmH2O/MUvolts) in NAVA. The total number of asynchronies per minute in NAVA was lower than that in PSV (0.46 vs 1, p < 0.001). The asynchrony index was also reduced in NAVA compared with PSV (1.73 vs 3.36, p < 0.001). In NAVA, the percentage of ineffective efforts (0.77 vs 0.94, p = 0.036) and the percentage of auto-triggering were lower compared with PSV (0.19 vs 0.71, p = 0.038). However, there was a higher percentage of double triggering in NAVA compared with PSV (0.76 vs 0.71, p = 0.046). CONCLUSION: The total number of asynchronies in NAVA is lower than that in PSV. This finding reflects improved patient-ventilator interaction in NAVA compared with the PSV mode, which is consistent with previous studies. Our study is the first to analyze patient-ventilator asynchronies in NAVA and PSV on such an important duration. The decrease in the number of asynchronies in NAVA is due to reduced ineffective efforts and auto-triggering. PMID- 26253785 TI - BNIP3- and BNIP3L-Mediated Mitophagy Promotes the Generation of Natural Killer Cell Memory. AB - Natural killer (NK) cells are innate lymphocytes that possess traits of adaptive immunity, such as clonal expansion, contraction, and generation of long-lived "memory" cells, processes poorly understood at the molecular level. Here, we found that as proliferating NK cells accumulated dysfunctional mitochondria during viral infection, a protective mitophagy pathway was induced during the contraction phase to promote their survival in a reactive oxygen species (ROS) dependent manner. Inhibition of mechanistic target of rapamycin (mTOR) or activation of AMP-activated protein kinase (AMPK) during the contraction-to memory phase transition of the antiviral response increased autophagic activity and enhanced memory NK cell numbers through an Atg3-dependent mechanism. Furthermore, we demonstrated a temporally regulated role for mitophagy-inducing proteins BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L) in the generation of robust NK cell memory. Thus, our study reveals the functional importance of mitophagy during the dynamic response of these cytolytic innate lymphocytes. PMID- 26253786 TI - Pancreatic beta-Cells Limit Autoimmune Diabetes via an Immunoregulatory Antimicrobial Peptide Expressed under the Influence of the Gut Microbiota. AB - Antimicrobial peptides (AMPs) expressed by epithelial and immune cells are largely described for the defense against invading microorganisms. Recently, their immunomodulatory functions have been highlighted in various contexts. However how AMPs expressed by non-immune cells might influence autoimmune responses in peripheral tissues, such as the pancreas, is unknown. Here, we found that insulin-secreting beta-cells produced the cathelicidin related antimicrobial peptide (CRAMP) and that this production was defective in non-obese diabetic (NOD) mice. CRAMP administrated to prediabetic NOD mice induced regulatory immune cells in the pancreatic islets, dampening the incidence of autoimmune diabetes. Additional investigation revealed that the production of CRAMP by beta-cells was controlled by short-chain fatty acids produced by the gut microbiota. Accordingly, gut microbiota manipulations in NOD mice modulated CRAMP production and inflammation in the pancreatic islets, revealing that the gut microbiota directly shape the pancreatic immune environment and autoimmune diabetes development. PMID- 26253787 TI - Dosimetrics of intracranial stereotactic radiosurgery: Only "an exercise of style"? PMID- 26253789 TI - Authors' reply to "Dosimetric of intracranial stereotactic radiosurgery: only 'an exercise of style'". PMID- 26253788 TI - Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and safety after a follow-up of over 12 years. AB - PURPOSE: The efficacy and safety of stereotactic radiosurgery (SRS) for treatment of intracranial meningiomas has been demonstrated in numerous studies with short- and intermediate-term follow-up. In this retrospective single-center study, we present long-term outcomes of SRS performed with a linear accelerator (LINAC) for typical intracranial meningiomas. PATIENTS AND METHODS: Between August 1990 and December 2007, 148 patients with 168 typical intracranial meningiomas were treated with stereotactic LINAC-SRS, either as primary treatment or after microsurgical resection. A median tumor surface dose of 12 Gy (range 7-20 Gy) and a median maximum dose of 24.1 Gy (range 11.3-58.6 Gy) was applied. The median target volume was 4.7 ml (range 0.2-32.8 ml, SD +/- 4.8 ml). RESULTS: Overall mean radiological follow-up was 12.6 years. Tumor shrinkage was seen in 75 (44.6 %) and stable disease in 85 (50.6 %) cases. Eight of 168 meningiomas (4.8 %) showed local tumor progression. The tumor control rate (TCR) after 5, 10, and 15 years was 93.6 % at each time point, and the progression-free survival (PSF) rates were 92, 89, and 89 %, respectively. The neurological symptoms existing prior to LINAC-SRS improved in 77 patients (59.7 %), remained unchanged in 42 (32.6 %), and deteriorated in 10 (7.8 %) patients. CONCLUSION: Our study emphasizes the efficacy of LINAC-SRS for de novo, residual and recurrent typical intracranial meningiomas. A high long-term local TCR with a low morbidity rate could be achieved. LINAC-SRS should thus be considered as a primary treatment option, as one arm of a combined treatment approach for incompletely resected meningiomas, or as a salvage therapy for recurrences. PMID- 26253790 TI - Ecotoxicological investigation of the effect of accumulation of PAH and possible impact of dispersant in resting high arctic copepod Calanus hyperboreus. AB - Due to high lipid content and a slow metabolism, there is a higher risk of bioaccumulation of oil compounds in Arctic than in temperate copepods. There is also a concern that the bioavailability of oil compounds is higher when oil is dispersed with dispersants. The purpose of this project was to increase the knowledge on how the use of dispersants on an oil spill may affect the passive uptake of PAHs in resting high arctic copepods using Calanus hyperboreus as a model organism. To evaluate this, resting high arctic C. hyperboreus were caught in Disko Bay at>250 meters depth, November 2013, and subsequent experimental work was initiated immediately after, at nearby Arctic Station at Disko Island Western Greenland. C. hyperboreus females were incubated in phenanthrene (111, 50 and 10 nM), pyrene (57, 28 and 6 nM) and benzo(a) pyrene (10, 5 and 1 nM) for three days in treatments with and without oil (corn oil) and dispersant (AGMA DR372). After exposure, the highest measured concentrations of respectively phenanthrene, pyrene and benzo(a) pyrene in the copepods were 129, 30 and 6 nmol PAH g female( 1). Results showed that with addition of oil and dispersant to the water, the accumulation of PAH was significantly reduced, due to the deposition of the PAHs in the oil phase, decreasing the available PAHs for copepod uptake. While PAH metabolites and a depuration of the PAHs were observed, the copepods still contained PAHs after 77 days of incubation in clean seawater. Differences of treatments with and without oil and dispersant on the egg production were not statistically conclusive, although it is the most likely an effect of the highly variable day-to-day egg production between individual copepods. Equally, although there was an indication that the addition of dispersant and oil increased the mortality rate, there was no statistical difference. PMID- 26253791 TI - Infrequent TRIB3 coding variants and coronary artery disease in type 2 diabetes. AB - OBJECTIVE: Genes that modulate insulin sensitivity may also be involved in shaping the risk of coronary artery disease (CAD). The relatively common TRIB3 Q84R polymorphism (rs2295490) has been associated with abnormal insulin signaling, endothelial dysfunction, insulin resistance, and pro-atherogenic phenotypes. The aim of our study was to investigate the association between low frequency TRIB3 coding variants and CAD in patients with type 2 diabetes (T2D). METHODS: Three case-control studies for CAD from Italy and US were analyzed, for a total of 1565 individuals, all with type 2 diabetes. Infrequent variants were identified by re-sequencing TRIB3 exons in 140 "extreme cases" and 140 "super controls" and then genotyped in all study subjects. RESULTS: TRIB3 infrequent variants (n = 8), considered according to a collapsing rare variants framework, were significantly associated with CAD in diabetic patients from Italy (n = 700, OR = 0.43, 95% CI 0.20-0.91; p = 0.027), but not from the US (n = 865, OR = 1.22, 95% CI 0.69-2.18; p = 0.49). In the Italian sets, the association was especially strong among individuals who also carried the common R84 variant. CONCLUSION: Although preliminary, our finding suggests a role of TRIB3 low-frequency variants on CAD among Italian patients with T2D. Further studies are needed to address the role of TRIB3 infrequent variants in other populations of both European and non European ancestries. PMID- 26253793 TI - Statin-associated muscle symptoms EAS Consensus Panel paper focuses on this neglected patient group. PMID- 26253792 TI - Common single nucleotide polymorphisms at the NPC1L1 gene locus significantly predict cardiovascular risk in coronary patients. AB - BACKGROUND: Niemann-Pick C1-like 1 (NPC1L1) is involved in dietary cholesterol absorption and is the direct molecular target of the LDL-lowering drug ezetimibe. Recently, genetic variants in NPC1L1 have been associated with the incidence of cardiovascular events, but it remains unclear if the impact of NPC1L1 on cardiovascular risk is dependent on its role in cholesterol absorption. Furthermore, no direct association of genetic variants in NPC1L1 with coronary atherosclerosis has been established. METHODS: To further address these issues, we determined the impact of 34 single nucleotide polymorphisms (SNPs) at the NPC1L1 gene locus on the presence of coronary atherosclerosis and prospectively on future cardiovascular events in a cohort of 984 angiographied Caucasian patients. RESULTS: Out of investigated SNPs, 24 variants were significantly associated with future cardiovascular events. The highest impact was observed for rs55837134 (sex-and age adjusted additive HR = 1.67 [1.28-2.18]; p = 1.3 e-4). Regression analysis conditioned on rs55837134 showed that significant associations between remaining SNPs at the NPC1L1 locus and vascular events did not persist suggesting their dependence on rs55837134. Its significant association remained almost unchanged after further adjustment for total cholesterol, LDL cholesterol, and other cardiovascular risk factors (additive HR = 1.67 [1.28-2.18]; p = 1.7 e-4). In addition, no significant association of investigated NPC1L1 variants with coronary atherosclerosis could be observed, at least after false discovery rate correction. CONCLUSIONS: Genetic variants of NPC1L1, particularly rs55837134, show a predictive impact on cardiovascular events. Further studies to determine the molecular consequences of common genetic variants in NPC1L1 are needed. PMID- 26253794 TI - Common variants associated with blood lipid levels do not affect carotid plaque composition. AB - INTRODUCTION: Although plasma lipid levels are known to influence the risk of cardiovascular disease (CVD), little is known about their effect on atherosclerotic plaque composition. To date, large-scale genome-wide association studies have identified 157 common single-nucleotide polymorphisms (SNPs) that influence plasma lipid levels, providing a powerful tool to investigate the effect of plasma lipid levels on atherosclerotic plaque composition. METHODS: In this study, we included 1443 carotid endarterectomy patients from the Athero Express Biobank Study with genotype data. Plasma concentrations of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and triglycerides (TG) were determined at the time of endarterectomy. Atherosclerotic plaques, obtained during surgery, were histologically examined. For all patients, we calculated weighted genetic burden scores (GBS) for all lipid traits on the basis of the available genotype data. Plasma lipid levels and GBS were tested for association with 7 histological features using linear and logistic regression models. RESULTS: All GBS were associated with their respective plasma lipid concentrations (pHDL-C = 2.4 * 10( 14), pLDL-C = 0.003, pTC = 2.1 * 10(-6), pTG = 3.4 * 10(-8)). Neither the measured plasma lipids, nor the GBS, were associated with histological features of atherosclerotic plaque composition. In addition, neither the plasma lipids nor the GBS were associated with clinical endpoints within 3 years of follow-up, with the notable exception of a negative association between HDL-C and composite cardiovascular endpoints. CONCLUSION: This study found no evidence that plasma lipid levels or their genetic determinants influence carotid plaque composition. PMID- 26253795 TI - Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. AB - Residual cardiovascular (CV) risk remains in dyslipidemic patients despite intensive statin therapy, underscoring the need for additional intervention. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, is incorporated into membrane phospholipids and atherosclerotic plaques and exerts beneficial effects on the pathophysiologic cascade from onset of plaque formation through rupture. Specific salutary actions have been reported relating to endothelial function, oxidative stress, foam cell formation, inflammation, plaque formation/progression, platelet aggregation, thrombus formation, and plaque rupture. EPA also improves atherogenic dyslipidemia characterized by reduction of triglycerides without raising low-density lipoprotein cholesterol. Other beneficial effects of EPA include vasodilation, resulting in blood pressure reductions, as well as improved membrane fluidity. EPA's effects are at least additive to those of statins when given as adjunctive therapy. In this review, we present data supporting the biologic plausibility of EPA as an anti atherosclerotic agent with potential clinical benefit for prevention of CV events, as well as its cellular effects and molecular mechanisms of action. REDUCE-IT is an ongoing, randomized, controlled study evaluating whether the high purity ethyl ester of EPA (icosapent ethyl) at 4 g/day combined with statin therapy is superior to statin therapy alone for reducing CV events in high-risk patients with mixed dyslipidemia. The results from this study are expected to clarify the role of EPA as adjunctive therapy to a statin for reduction of residual CV risk. PMID- 26253796 TI - Electrochemical determination of inorganic mercury and arsenic--A review. AB - Inorganic mercury and arsenic encompasses a term which includes As(III), As(V) and Hg(II) species. These metal ions have been extensively studied due to their toxicity related issues. Different analytical methods are used to monitor inorganic mercury and arsenic in a variety of samples at trace level. The present study reviews various analytical techniques available for detection of inorganic mercury and arsenic with particular emphasis on electrochemical methods especially stripping voltammetry. A detailed critical evaluation of methods, advantages of electrochemical methods over other analytical methods, and various electrode materials available for mercury and arsenic analysis is presented in this review study. Modified carbon paste electrode provides better determination due to better deposition with linear and improved response under studied set of conditions. Biological materials may be the potent and economical alternative as compared to macro-electrodes and chemically modified carbon paste electrodes in stripping analysis of inorganic mercury and arsenic. PMID- 26253797 TI - Mechanisms underlying parasite infection: influence of host body mass and age on chewing louse distribution among brown-headed cowbirds. AB - Animal populations exhibit various patterns in ectoparasite distribution across different sexes and age classes, and numerous factors can potentially contribute to ectoparasite abundance and distribution. We examined the influence of host body size and age on the distribution of a chewing louse among brown-headed cowbirds. Differences in louse prevalence (males 62.9 +/- 2.8%, females 47.5 +/- 4.9%) and intensity (males 15.42 +/- 1.51, females 9.04 +/- 1.69) were primarily driven by differences in host body mass and not host sex. Larger birds had larger louse infra-populations, which likely translated into a lower risk of local extinction, a possible explanation for higher louse prevalence observed among larger birds. Among males, younger individuals showed higher louse prevalence (70.21 +/- 4.72%) compared to older males (59.36 +/- 3.59). We speculate that this pattern is likely driven by behavioural difference and not body size, with young males spending relatively more time foraging in large groups, increasing their risk of louse transmission. By examining the mechanisms that underlie the sex- and age-biased infections observed in natural populations, we can better identify the hosts most responsible for parasite transmission. PMID- 26253798 TI - Additional information about tick parasitism in Passeriformes birds in an Atlantic Forest in southeastern Brazil. AB - The habits of birds make them more or less susceptible to parasitism by certain tick species. Therefore, while some bird species are typically found to be intensely infested, others are relatively unaffected. This study investigated the occurrence of ticks in Passeriformes inhabiting an Atlantic Forest fragment in southeastern Brazil, during the dry and rainy seasons, by means of parasitological indexes and multiple correspondence analysis, to determine the factors that influence tick parasitism in these birds. Data were collected on 2391 ticks, all classified in the Amblyomma genus, from 589 birds. The ticks identified to the species level were A. longirostre, A. nodosum, A. calcaratum, A. parkeri, and A. ovale. Thamnophilidae, Conopophagidae, Thraupidae, Dendrocolaptidae, and Platyrinchidae were the families with the highest prevalence. In terms of parasite intensity, the families Conopophagidae, Thamnophilidae, Thraupidae, Furnariidae, and Pipridae stood out with the highest values. Bird species that are generalists regarding eating habits and habitat occupation tended to have higher parasite loads, as did larger species and those inhabiting the understory. The tick prevalence was higher in the dry season than in the rainy season. The majority of the ticks were collected from the head region, mainly around the eyes and in the nape. Also, this work reports 22 new bird-parasite relations. PMID- 26253799 TI - Rapid detection and identification of four major Schistosoma species by high resolution melt (HRM) analysis. AB - Schistosomiasis, caused by blood flukes belonging to several species of the genus Schistosoma, is a serious and widespread parasitic disease. Accurate and rapid differentiation of these etiological agents of animal and human schistosomiasis to species level can be difficult. We report a real-time PCR assay coupled with a high-resolution melt (HRM) assay targeting a portion of the nuclear 18S rDNA to detect, identify, and distinguish between four major blood fluke species (Schistosoma japonicum, Schistosoma mansoni, Schistosoma haematobium, and Schistosoma mekongi). Using this system, the Schistosoma spp. was accurately identified and could also be distinguished from all other trematode species with which they were compared. As little as 10(-5) ng genomic DNA from a Schistosoma sp. could be detected. This process is inexpensive, easy, and can be completed within 3 h. Examination of 21 representative Schistosoma samples from 15 geographical localities in seven endemic countries validated the value of the HRM detection assay and proved its reliability. The melting curves were characterized by peaks of 83.65 degrees C for S. japonicum and S. mekongi, 85.65 degrees C for S. mansoni, and 85.85 degrees C for S. haematobium. The present study developed a real-time PCR coupled with HRM analysis assay for detection and differential identification of S. mansoni, S. haematobium, S. japonicum, and S. mekongi. This method is rapid, sensitive, and inexpensive. It has important implications for epidemiological studies of Schistosoma. PMID- 26253800 TI - Efficacy of a Buffered 4% Lidocaine Formulation for Incision and Drainage: A Prospective, Randomized, Double-blind Study. AB - INTRODUCTION: Incision and drainage of symptomatic emergency patients with facial swelling is painful even after local anesthetics are administered. The purpose of this prospective, randomized, double-blind study was to compare the pain of infiltration and the pain of an incision and drainage procedure of a buffered versus a nonbuffered 4% lidocaine formulation in symptomatic emergency patients presenting with a diagnosis of pulpal necrosis, associated periapical area, and an acute clinical swelling. METHODS: Eighty-eight emergency patients were randomly divided into 2 groups to receive 2 intraoral infiltration injections (mesial and distal to the swelling) of either 4% lidocaine with 1:100,000 epinephrine buffered with 0.18 mL 8.4% sodium bicarbonate using the Onpharma (Los Gatos, CA) buffering system or 4% lidocaine with 1:100,000 epinephrine. Subjects rated the pain of needle insertion, needle placement, and solution deposition for each injection using a 170-mm visual analog scale. An incision and drainage procedure was performed, and subjects rated the pain of incision, drainage, and dissection on a 170-mm visual analog scale. RESULTS: No significant differences between the buffered and nonbuffered 4% lidocaine formulations were found for needle insertion, placement, and solution deposition of the infiltration injections or for the treatment phases of incision, drainage, and dissection. CONCLUSIONS: Buffering a 4% lidocaine formulation did not significantly decrease the pain of infiltrations or significantly decrease the pain of the incision and drainage procedure when compared with a nonbuffered 4% lidocaine formulation in symptomatic patients with a diagnosis of pulpal necrosis and associated acute swelling. PMID- 26253801 TI - Disease-specific structural changes in thalamus and dentatorubrothalamic tract in progressive supranuclear palsy. AB - INTRODUCTION: The aim of this study is to identify disease-specific changes of the thalamus, basal ganglia, pons, and midbrain in patients with progressive supranuclear palsy (PSP), Parkinson's disease (PD), and multiple system atrophy with predominant parkinsonism (MSA-P) using diffusion tensor imaging and volumetric analysis. METHODS: MRI diffusion and volumetric data were acquired in a derivation of 30 controls and 8 patients with PSP and a validation cohort comprised of controls (n = 21) and patients with PSP (n = 27), PD (n = 10), and MSA-P (n = 11). Analysis was performed using regions of interest (ROI), tract based spatial statistic (TBSS), and tractography and results compared between diagnostic groups. RESULTS: In the derivation cohort, we observed increased mean diffusivity (MD) in the thalamus, superior cerebellar peduncle, and the midbrain in PSP compared to controls. Furthermore, volumetric analysis showed reduced thalamic volumes in PSP. In the validation cohort, the observations of increased MD were replicated by ROI-based analysis and in the thalamus by TBSS-based analysis. Such differences were not found for patients with PD in any of the cohorts. Tractography of the dentatorubrothalamic tract (DRTT) showed increased MD in PSP patients from both cohorts compared to controls and in the validation cohort in PSP compared to PD and MSA patients. Increased MD in the thalamus and along the DRTT correlated with disease stage and motor function in PSP. CONCLUSION: Patients with PSP, but not PD or MSA-P, exhibit signs of structural abnormalities in the thalamus and in the DRTT. These changes are associated with disease stage and impaired motor function. PMID- 26253802 TI - Analysis of methicillin-resistant Staphylococcus aureus major clonal lineages by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS). AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen associated with nosocomial infections in many countries. Multilocus sequence typing (MLST) is one of the genetic typing methods used to type MRSA with a high discriminatory power, however, it is labor-intensive, timely, and costly. Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) coupled with ClinProTools is a potential tool to discover biomarker peaks and to generate a classification model based on highly sophisticated mathematical algorithms to discriminate clonal lineages. We investigated the performance of MALDI-TOF MS for discriminating 154 MRSA-ST239, 72 MRSA-ST5, 30 MRSA-ST59, 14 MRSA-ST45, and 20 MRSA-OST (other clonal lineages). Our results indicate that the model construction and validation have good potency to discriminate ST45 from other lineages with a sensitivity and a specificity of both 100%, and a sensitivity of 95.80% and a specificity of 94.62% to identify ST239. For Biotyper classification, the sensitivity and specificity were more than of 90% for ST239, ST59 and ST45, whereas only 81.94% sensitivity for ST5. By single-peak analysis, the peaks m/z 4808 and 9614 can correctly discriminate ST45 a sensitivity and a specificity of both 100%; the peak m/z 6554 can also discriminate ST239 with a sensitivity of 91.9% and a specificity of 85.4%. In conclusion, MALDI-TOF MS coupled with ClinProTools has a high detection performance for MRSA typing with obvious advantages of being rapid, highly accurate, and being a low cost in comparison with MLST. PMID- 26253803 TI - A dual component heme biosensor that integrates heme transport and synthesis in bacteria. AB - Bacterial pathogens acquire host iron to power cellular processes and replication. Heme, an iron-containing cofactor bound to hemoglobin, is scavenged by bacterial proteins to attain iron. Methods to measure intracellular heme are laborious, involve complex chemistry, or require radioactivity. Such drawbacks limit the study of the mechanistic steps of heme transport and breakdown. Hypothesizing heme homeostasis could be measured with fluorescent methods, we coupled the conversion of heme to biliverdin IXalpha (a product of heme catabolism) by heme oxygenase 1 (HO1) with the production of near-infrared light upon binding this verdin by infrared fluorescent protein (IFP1.4). The resultant heme sensor, IFP-HO1, was fluorescent in pathogenic E. coli exposed to heme but not in the absence of the heme transporter ChuA and membrane coupling protein TonB, thereby validating their long-standing proposed role in heme uptake. Fluorescence was abolished in a strain lacking hemE, the central gene in the heme biosynthetic pathway, but stimulated by iron, signifying the sensor reports on intracellular heme production. Finally, an invasive strain of E. coli harboring the sensor was fluorescent during an active infection. This work will allow researchers to expand the molecular toolbox used to study heme and iron acquisition in culture and during infection. PMID- 26253805 TI - Microbiologic characteristics and predictors of mortality in bloodstream infections in intensive care unit patients: A 1-year, large, prospective surveillance study in 5 Italian hospitals. AB - BACKGROUND: Bloodstream infections (BSIs) from multidrug-resistant (MDR) bacteria cause morbidity and mortality in intensive care unit (ICU) patients worldwide. This study investigated the incidence of BSIs in 5 adult general ICUs in Rome, Italy, and evaluated the mortality rate and risk factors associated with these infections. METHODS: Over a 12-month period, 1,318 patients were enrolled. Demographic characteristics, Simplified Acute Physiology Score II (SAPS II), comorbidities, and BSI isolate data were collected. After stratification for the outcome, statistical analysis was performed to assess the impact of patient risk factors on in-hospital mortality. RESULTS: There were 324 BSIs in 175 patients recorded, with an in-hospital mortality rate of 46%. Univariate analysis revealed that SAPS II, cardiac comorbidity, and Klebsiella pneumoniae BSI were significantly associated with a higher risk of death. Having a K pneumoniae BSI and cardiac illness at admission were both confirmed to be associated with death by multivariate analysis (P = .0162 and P = .0158, respectively). Most of the K pneumoniae isolates showed high resistance rates to carbapenems. CONCLUSION: BSIs caused by K pneumoniae and cardiovascular comorbidity in ICU patients are associated with a higher risk of death. Thorough surveillance for MDR pathogens and stratification of the patients' risk on admission into the ICU are key to improving the outcomes of these infections. PMID- 26253804 TI - Multistage pH-responsive mucoadhesive nanocarriers prepared by aerosol flow reactor technology: A controlled dual protein-drug delivery system. AB - Nanotechnology based drug delivery systems are anticipated to overcome the persistent challenges in oral protein and peptide administration, and lead to the development of long awaited non-invasive therapies. Herein, an advanced single step aerosol flow reactor based technology was used to develop a multifunctional site specific dual protein-drug delivery nanosystem. For this purpose, mucoadhesive porous silicon (PSi) nanoparticles encapsulated into a pH-responsive polymeric nanomatrix was developed for advanced oral type 2 diabetes mellitus therapy with an antidiabetic peptide, glucagon like peptide-1 (GLP-1), and the enzyme inhibitor, dipeptidyl peptidase-4 (DPP4). Chitosan surface modification inherited the mucoadhesiveness to the nanosystem which led to enhanced cellular interactions and increased cellular compatibility. An advanced aerosol flow reactor technology was used to encapsulate the chitosan modified nanoparticles into an enteric polymeric nanomatrix. The pH-sensitive polymeric matrix simultaneously prevented the gastric degradation of the encapsulated peptide and also preserved the mucoadhesive functionality of the chitosan-modified PSi nanoparticles in the harsh stomach environment. The multidrug loaded nanosystem showed augmented intestinal permeability of GLP-1, evaluated in an in vitro cell based intestinal epithelium model, attributed to the permeation enhancer effect of chitosan and inhibition of GLP-1 degradation by the DPP4 inhibitor. The applied technology resulted in the development of a dual-drug delivery nanosystem that synergizes the antidiabetic effect of the loaded peptide and the enzyme inhibitor, thereby indicating high clinical potential of the system and preparation technique. PMID- 26253806 TI - Simultaneous determination of scopolamine, hyoscyamine and anisodamine in in vitro growth media of selected Solanaceae hairy roots by CE method. AB - An electrophoretic method for fast separation of three tropane alkaloids (hyoscyamine, anisodamine and scopolamine) was presented. The substances were complete resolved in less than one minute due to utilization of relatively short capillary (20.2cm effective length) and high voltage (25kV). Detector probing frequency was found among the parameters that significantly affected the detection sensitivity. The performed experiments showed insufficient available probing frequency of used commercial spectrophotometric detector according to capillary electrophoresis (CE) separation potential. Under the optimized conditions the background electrolyte (BGE) was composed of 20mM Tris, 6mM HCl and 20mM NaCl (pH 8.50). All analyses were carried out in fused silica capillaries of 50MUm (inner diameter) and 31.2cm (total capillary length). Samples were injected hydrodynamically (5s; 3.45kPa) without any sample preparation step and separation was performed at 25kV. The elaborated method was applied in plant cultures growth media analysis after incubation with hairy roots of selected Solanaceae species. The performed experiments proved the usefulness of CE in quality control of biotechnological processes. PMID- 26253807 TI - Simultaneous determination of subutinib and its active metabolite in human plasma by LC-MS/MS: Application to pharmacokinetic study. AB - A selective liquid chromatographic-mass spectrometric method (LC-MS/MS) has been established and validated for simultaneous determination of subutinib and its active metabolite in human plasma. Plasma samples were extracted by liquid-liquid extraction with ethyl acetate and separated on a Wondasil C18 (150mm*2.1mm, 3.5MUm), with methanol-0.2% formic acid solution (73:27, v/v) as mobile phase at flow rate of 0.2ml/min. The linear range was 0.25-100ng/mL for subutinib and 0.125-50.0ng/mL for its active metabolite, with lower limit of quantitation of 0.25ng/mL and 0.125ng/mL, respectively. Intra- and inter-run precision were within 7.0 and 13.1%, and the accuracies (relative errors) were<7.0 and 8.0%, with the extraction recoveries 97.0-101.2% and 93.0-98.1% for the two analytes, respectively. The validated method was successfully applied to a pharmacokinetic study of subutinib and its active metabolite in human after oral administration of subutinib maleate capsules. PMID- 26253808 TI - Quantification of 15 bile acids in lake charr feces by ultra-high performance liquid chromatography-tandem mass spectrometry. AB - Many fishes are hypothesized to use bile acids (BAs) as chemical cues, yet quantification of BAs in biological samples and the required methods remain limited. Here, we present an UHPLC-MS/MS method for simultaneous, sensitive, and rapid quantification of 15 BAs, including free, taurine, and glycine conjugated BAs, and application of the method to fecal samples from lake charr (Salvelinus namaycush). The analytes were separated on a C18 column with acetonitrile-water (containing 7.5mM ammonium acetate and 0.1% formic acid) as mobile phase at a flow rate of 0.25mL/min for 12min. BAs were monitored with a negative electrospray triple quadrupole mass spectrometer (Xevo TQ-STM). Calibration curves of 15 BAs were linear over the concentration range of 1.00-5,000ng/mL. Validation revealed that the method was specific, accurate, and precise. The method was applied to quantitative analysis of feces extract of fry lake charr and the food they were eating. The concentrations of analytes CA, TCDCA, TCA, and CDCA were 242.3, 81.2, 60.7, and 36.2ng/mg, respectively. However, other taurine conjugated BAs, TUDCA, TDCA, and THDCA, were not detected in feces of lake charr. Interestingly, TCA and TCDCA were detected at high concentrations in food pellets, at 71.9 and 38.2ng/mg, respectively. Application of the method to feces samples from lake charr supported a role of BAs as chemical cues, and will enhance further investigation of BAs as chemical cues in other fish species. PMID- 26253810 TI - NMR relaxometry and diffusometry in characterizing structural, interfacial and colloidal properties of heavy oils and oil sands. AB - We present a discussion of the use of NMR in the characterization of heavy oils and oil sands and their interactions with water and solid surfaces. The phenomena probed by the NMR techniques take place over different length scales, ranging from molecular, through colloidal to macroscopic. During the course of the last 15 years, NMR applications have grown from their initial use in studying conventional oils in rocks to the characterization of more viscous oils in unconsolidated porous media. In particular, (1)H NMR relaxometry and diffusometry are considered with a view to the identification of oil and water in oilfield fluids and their environment. After some theoretical considerations, various topics of current significance to petroleum recovery and production are discussed, including oil viscosity (with new experimental viscosity correlations added), oil sands characterization, heavy oil emulsions, and the identification of solvent effects on oil components and asphaltene solution behaviour and interactions. We show that, increasingly, NMR is becoming an invaluable and versatile characterization tool in petroleum science, in both laboratory and field. PMID- 26253809 TI - Development and validation of an ultra performance liquid chromatography tandem mass method for sildenafil and N-desmethyl sildenafil plasma determination and quantification. AB - Sildenafil is a selective inhibitor of cGMP-specific type 5 phosphodiesterase (PDE5) used for the treatment of masculine erectile dysfunction and Pulmonary Arterial Hypertension (PAH). Sildenafil causes vasodilatation; relax of the smooth muscle and reduction of pulmonary arterial pressure. In the liver cytocrome P450 metabolizes sildenafil into its active metabolite, N-desmethyl sildenafil. The determination of plasma levels of sildenafil and N-desmethyl sildenafil could be useful for therapy optimization and pharmacokinetic studies. We have developed and validated a new method for the quantification of sildenafil and its metabolite in human plasma by rapid protein precipitation extraction, using an UPLC system, coupled with a tandem mass spectrometric detector (UPLC MS/MS). The calibration range was fitted at least square model (r(2)>=0.999), with an accuracy and an intra- and inter-day RSD% (Relative Standard Deviation), both for sildenafil and N-desmethyl sildenafil, lower than 15%, as required by the FDA guidelines; LLOQ, LLOD, ULOQ were 3.9ng/mL, 1.95ng/mL and 1000ng/mL, respectively, for both analytes. Matrix effect, expressed as mean percent deviation of peak areas, was in the range between 2.6% and 5.8%, lower than 15% as required by guidelines. The mean recovery was 83.2 % for sildenafil and 84.5% for N-desmethyl sildenafil. This method has successfully been applied to a clinical pharmacokinetic study of sildenafil and N-desmethyl sildenafil in patients with PAH undergoing cardiac surgery. PMID- 26253811 TI - Population balance modelling of particle flocculation with attention to aggregate restructuring and permeability. AB - A population balance model based on a detailed literature review is used to describe coagulation and flocculation kinetics as well as the time evolution of aggregate size distribution in a turbulent shear flow simultaneously with the breakage and restructuring of aggregates. The fractal nature and permeability of the aggregates and their evolution with time are also part of the model. Restructuring is absent in coagulation with soluble salts, but is present in flocculation caused by large polyelectrolyte molecules; in the latter, aggregates never reach a steady-state size, but a size that decreases gradually through particle and polymer rearrangement. The model is tested against available experimental data for monodisperse polystyrene particles coagulated with hydrated aluminium sulphate at different shear rates, and precipitated calcium carbonate flocculated with a cationic polyelectrolyte of very high molecular weight at different flocculant dosages. The numerical solution of the model requires adjusting three parameters, i.e, maximum collision efficiency (alphamax), critical force needed for the breakage of the aggregates (B) and rate of aggregate restructuring (gamma), which are obtained from minimising the difference between experimental data and model predictions. The model studied for the two very different systems shows excellent agreement with experimental flocculation kinetics and a reasonably good fit for aggregate size distributions. The model is most sensitive to the fragmentation rate through parameter B, somewhat less to the collision efficiency through parameter alphamax and little to gamma. When the aggregates undergo restructuring, properties such as permeability, breakage rate and collision rate change considerably over time. When the aggregates are permeable, the collision frequency is significantly smaller than when they are impervious. PMID- 26253812 TI - 2015 Awards in the Journal of Plant Research. PMID- 26253814 TI - Clinical implications of the intrinsic molecular subtypes of breast cancer. AB - Gene-expression profiling has had a considerable impact on our understanding of breast cancer biology. During the last 15 years, 5 intrinsic molecular subtypes of breast cancer (Luminal A, Luminal B, HER2-enriched, Basal-like and Claudin low) have been identified and intensively studied. In this review, we will focus on the current and future clinical implications of the intrinsic molecular subtypes beyond the current pathological-based classification endorsed by the 2013 St. Gallen Consensus Recommendations. Within hormone receptor-positive and HER2-negative early breast cancer, the Luminal A and B subtypes predict 10-year outcome regardless of systemic treatment administered as well as residual risk of distant recurrence after 5 years of endocrine therapy. Within clinically HER2 positive disease, the 4 main intrinsic subtypes can be identified and dominate the biological and clinical phenotype. From a clinical perspective, patients with HER2+/HER2-enriched disease seem to benefit the most from neoadjuvant trastuzumab, or dual HER2 blockade with trastuzumab/lapatinib, in combination with chemotherapy, and patients with HER2+/Luminal A disease seem to have a relative better outcome compared to the other subtypes. Finally, within triple negative breast cancer (TNBC), the Basal-like disease predominates (70-80%) and, from a biological perspective, should be considered a cancer-type by itself. Importantly, the distinction between Basal-like versus non-Basal-like within TNBC might predict survival following (neo)adjvuvant multi-agent chemotherapy, bevacizumab benefit in the neoadjuvant setting (CALGB40603), and docetaxel vs. carboplatin benefit in first-line metastatic disease (TNT study). Overall, this data suggests that intrinsic molecular profiling provides clinically relevant information beyond current pathology-based classifications. PMID- 26253813 TI - Clinical implications of molecular heterogeneity in triple negative breast cancer. AB - Triple negative breast cancer (TNBC) is a molecularly heterogeneous disease lacking recurrent targetable alterations and thus therapeutic advances have been challenging. The absence of ER, PR and HER2 amplifications, leaves combination chemotherapy as the standard of care treatment option in the adjuvant, neoadjuvant and metastatic settings. Recently, multiple studies have shed some light on the heterogeneity of TNBC and identified distinct transcriptional subtypes with unique biologies. Herein we review the molecular heterogeneity and the impact on previous and future clinical trials. PMID- 26253815 TI - Longevity of implantable cardioverter-defibrillators in a single-center population. AB - BACKGROUND OR PURPOSE: Real-life comparative data of implantable cardioverter defibrillator (ICD) longevity are needed to identify the best possible device longevity for optimal patient comfort and to minimize risk for multiple replacements. METHODS: We retrospectively studied ICD longevity in a large single center population. At our institution, 1272 consecutive patients were implanted with 1665 ICD or cardiac resynchronization therapy with defibrillator (CRT-D) devices between 1998 and 2010. Device data and follow-up were retrieved from the continuous ICD clinic documentation, and generator replacements were verified from the hospital charts. Kaplan-Meier event probabilities for the time to generator replacement were calculated according to device type, pacing percentage (sum of atrial, right and left ventricular pacing, if applicable) and right ventricular pacing threshold, incidence of ICD shocks, and manufacturer. Multivariate Cox proportional hazards regression was performed in addition. RESULTS: A total of 470 devices were replaced for elective replacement indicator. These occurred after 5.4 years (95% confidence interval, 5.1 to 5.6 years) in 175 of 625 implanted Boston Scientific or Guidant devices, after 5.7 years (5.5 to 5.9 years) in 266 of 883 Medtronic devices, and 5.2 years (5.0 to 5.4 years) in 29 of 157 Biotronik devices, respectively. Differences between manufacturers remained significant upon multivariate analysis (Medtronic vs. Boston Scientific: P = 0.01; both vs. Biotronik: P < 0.01) as did differences of device type (single and dual-chamber ICD vs. CRT-D, P < 0.01) and pacing percentage (P < 0.01). Pacing output and ICD shocks did not influence battery longevity. CONCLUSION: ICD longevity differed significantly between manufacturers, independent of device type or pacing parameters. PMID- 26253816 TI - Oat consumption reduced intestinal fat deposition and improved health span in Caenorhabditis elegans model. AB - In addition to their fermentable dietary fiber and the soluble beta-glucan fiber, oats have unique avenanthramides that have anti-inflammatory and antioxidant properties that reduce coronary heart disease in human clinical trials. We hypothesized that oat consumption will increase insulin sensitivity, reduce body fat, and improve health span in Caenorhabditis elegans through a mechanism involving the daf-2 gene, which codes for the insulin/insulin-like growth factor 1-like receptor, and that hyperglycemia will attenuate these changes. Caenorhabditis elegans wild type (N2) and the null strains sir-2.1, daf-16, and daf-16/daf-2 were fed Escherichia coli (OP50) and oat flakes (0.5%, 1.0%, or 3%) with and without 2% glucose. Oat feeding decreased intestinal fat deposition in N2, daf-16, or daf-16/daf-2 strains (P < .05); and glucose did not affect intestinal fat deposition response. The N2, daf-16, or sir-2.1 mutant increased the pharyngeal pumping rate (P < .05), a surrogate marker of life span, following oat consumption. Oat consumption increased ckr-1, gcy-8, cpt-1, and cpt-2 mRNA expression in both the N2 and the sir-2.1 mutant, with significantly higher expression in sir-2.1 than in N2 (P < .01). Additional glucose further increased expression 1.5-fold of the 4 genes in N2 (P < .01), decreased the expression of all except cpt-1 in the daf-16 mutant, and reduced mRNA expression of the 4 genes in the daf-16/daf-2 mutant (P < .01). These data suggest that oat consumption reduced fat storage and increased ckr-1, gcy-8, cpt-1, or cpt-2 through the sir 2.1 genetic pathway. Oat consumption may be a beneficial dietary intervention for reducing fat accumulation, augmenting health span, and improving hyperglycemia impaired lipid metabolism. PMID- 26253818 TI - Gonadotropin-releasing hormone agonist trigger in clinical in vitro fertilization: can the suboptimal candidate be defined? PMID- 26253817 TI - Urinary concentrations of benzophenone-type ultraviolet light filters and semen quality. AB - OBJECTIVE: To assess benzophenone-type ultraviolet (UV) filter concentrations, chemicals used in sunscreen and personal care products, and semen endpoints. DESIGN: Cohort. SETTING: Not applicable. PATIENT(S): A total of 413 men provided semen and urine samples, 2005-2009. Five UV filters were quantified (ng/mL) in urine using liquid chromatography-triple quadrupole mass spectrometry: BP-1 (2,4 dihydroxybenzophenone), BP-2 (2,2',4,4'-tetrahydroxybenzophenone), BP-3 (2 hydroxy-4-methoxybenzophenone), BP-8 (2,2'-dihydroxy-4-methoxybenzophenone), and 4-OH-BP (4-hydroxybenzophenone). Using linear regression, beta-coefficients (beta) and 95% confidence intervals (CIs) for each chemical dichotomized at the 75th percentile and Box-Cox transformed semen endpoint were estimated, after adjusting for age, body mass index, cotinine, season, and site. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Thirty-five semen endpoints. RESULT(S): BP-2 was associated with diminished sperm concentration (beta = -0.74; 95% CI -1.41, 0.08), straight (beta = -4.57; 95% CI -8.95, -0.18) and linear movement (beta = 3.15; 95% CI -6.01, -0.30), more immature sperm (beta = 0.38; 95% CI 0.15, 0.62), and a decreased percentage of other tail abnormalities (beta = -0.16; 95% CI 0.31, -0.01). BP-8 was associated with decreased hypo-osmotic swelling (beta = 2.57; 95% CI -4.86, -0.29) and higher acrosome area (beta = 1.14; 95% CI 0.01, 2.26). No associations were observed for BP-1, BP-3, or 4OH-BP. CONCLUSION(S): The findings suggest that specific UV filters may be associated with some aspects of semen endpoints, but await future corroboration. PMID- 26253819 TI - Risk of preterm birth after blastocyst embryo transfer: a large population study using contemporary registry data from Australia and New Zealand. AB - OBJECTIVE: To investigate whether there is an increased risk of preterm birth with blastocyst transfer compared with cleavage-stage embryo transfer (ET) after assisted reproductive technology (ART). DESIGN: A retrospective, population-based study. SETTING: Not applicable. PATIENT(S): A total of 50,788 infants conceived after ART treatment performed from 2009 to 2012. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The rates of preterm birth, low birth weight (LBW), and small for gestational age (SGA) for 43,952 singleton and 3,418 twin deliveries after transfers of blastocyst or cleavage-stage embryos. RESULT(S): Among singletons, there was no significant difference in the odds of preterm birth between blastocyst and cleavage-stage ET (9.1% compared with 9.3%, respectively, adjusted odds ratio 1.00, 95% confidence interval 0.94-1.08). Among twins, the crude rates of preterm birth were similar after blastocyst and cleavage-stage ETs (61.5% and 64.4%, respectively). However, after adjusting for potential confounders, blastocyst transfer was associated with a lower odds of preterm birth among twins (adjusted odds ratio 0.80, 95% confidence interval 0.70-0.93). There was no difference in risks of LBW and SGA between blastocyst and cleavage-stage ETs for both singletons and twins after adjusting for potential confounders. CONCLUSION(S): In contrast with the findings from a number of other studies, blastocyst culture in Australian and New Zealand is not associated with an increased risk of preterm, LBW, and SGA for singletons. Further studies are needed to assess longer-term outcomes of children born after ART treatment and possible biological or treatment factors related to adverse outcomes. PMID- 26253820 TI - G protein-membrane interactions I: Galphai1 myristoyl and palmitoyl modifications in protein-lipid interactions and its implications in membrane microdomain localization. AB - G proteins are fundamental elements in signal transduction involved in key cell responses, and their interactions with cell membrane lipids are critical events whose nature is not fully understood. Here, we have studied how the presence of myristic and palmitic acid moieties affects the interaction of the Galphai1 protein with model and biological membranes. For this purpose, we quantified the binding of purified Galphai1 protein and Galphai1 protein acylation mutants to model membranes, with lipid compositions that resemble different membrane microdomains. We observed that myristic and palmitic acids not only act as membrane anchors but also regulate Galphai1 subunit interaction with lipids characteristics of certain membrane microdomains. Thus, when the Galphai1 subunit contains both fatty acids it prefers raft-like lamellar membranes, with a high sphingomyelin and cholesterol content and little phosphatidylserine and phosphatidylethanolamine. By contrast, the myristoylated and non-palmitoylated Galphai1 subunit prefers other types of ordered lipid microdomains with higher phosphatidylserine content. These results in part explain the mobility of Galphai1 protein upon reversible palmitoylation to meet one or another type of signaling protein partner. These results also serve as an example of how membrane lipid alterations can change membrane signaling or how membrane lipid therapy can regulate the cell's physiology. PMID- 26253821 TI - Regulation of ceramide generation during macrophage apoptosis by ASMase and de novo synthesis. AB - The survival of macrophages depends on the presence of specific cytokines that activate survival signaling events, as well as suppressing formation of apoptosis inducing pathways. We have previously shown that macrophages deprived of macrophage colony stimulating factor (M-CSF) produce ceramide that contributes to apoptosis of these cells, a pathway that is suppressed by exposure to oxidized LDL. In this study we have examined macrophages derived from mice lacking acid sphingomyelinase (ASMase) to ask whether these events are altered due to the impaired ability of these cells to break down sphingomyelin and produce ceramide. We found that these cells do survive better than cells from wild type mice, but they still undergo cell death and some ceramide is formed. We show that the ceramide is being produced by a de novo synthetic pathway. Therefore, ceramide production in M-CSF-deprived macrophages arises from a combination of ASMase activity and de novo synthesis. PMID- 26253822 TI - Stability of resting state networks in the female brain during hormonal changes and their relation to premenstrual symptoms. AB - Resting-state fMRI is a promising imaging technique to evaluate functions in the human brain in health and disease. Different hormonal stages of the female menstrual cycle and hormonal contraceptives use affect results in task-based fMRI; it is however not yet clarified whether resting state networks are also altered. A population of 18 women with a natural cycle, and 19 women using hormonal contraceptives was examined in a longitudinal study-design. The natural cycle group was scanned at 3 time-points (follicular phase, ovulation, luteal phase), and the contraceptives group was scanned twice (inactive pill-phase, active pill-phase). Blood samples were acquired to evaluate hormonal concentrations, and premenstrual symptoms were assessed through daily record of severity of problems questionnaires. Results show no major alterations in the default mode network and the executive control network between different hormonal phases, across or within groups. A positive correlation of functional connectivity in the posterior part of the default mode network (DMN) was found with premenstrual-like symptoms in the hormonal contraceptives group. Using the current methodology, the studied resting state networks seem to show a decent stability throughout menstrual cycle phases. Also, no effect of hormonal contraceptive use is found. Interestingly, we show for the first time an association of DMN alterations with premenstrual-like symptoms, experienced during the inactive pill-phase by a sub-population of women. PMID- 26253823 TI - Corticostriatal microRNAs in addiction. AB - Addiction is a chronically relapsing disorder characterized by compulsive drug use in spite of adverse consequences. Currently, there are very few effective treatments for addiction; in order to develop novel therapies, a clearer understanding of mechanisms underlying addiction is needed. Drugs of abuse induce lasting adaptations in corticostriatal and mesolimbic brain reward circuitry due to long-term alterations in gene expression. microRNAs, a class of non-coding RNAs, are powerful regulators of gene expression that bind to target mRNAs, thereby inhibiting their translation and/or causing degradation. miRNAs are increasingly implicated in gene expression changes underlying normal neuronal function as well as dysfunctions such as addiction and psychiatric disorders. This review summarizes plasticity- and drug-related miRNA expression patterns and functions in the context of corticostriatal circuitry, while proposing future directions that may reveal miRNA-mediated mechanisms regulating addiction-related behaviors in vivo. PMID- 26253824 TI - Sexual Victimization and Somatic Complaints in Pregnancy: Examination of Depression as a Mediator. AB - PURPOSE: Research suggests that women with histories of sexual victimization are more likely to experience somatic complaints in pregnancy. However, prior studies have been limited by homogenous samples, have primarily only examined the relationship of childhood sexual abuse (CSA) to somatic complaints, and have not examined potential mechanisms explaining this association. Thus, the current study examined the relationship between lifetime sexual victimization history and somatic complaints in pregnancy in an ethnically diverse sample of pregnant women. Additionally, depressive symptoms were examined as a mediator of the sexual victimization-somatic complaints relationship. PROCEDURES: Women were recruited from the waiting room of a university-affiliated obstetrics-gynecology clinic to complete a study of psychological health and negative sexual experiences. The 407 currently pregnant participants who completed measures of their sexual victimization history, depressive symptoms, and somatic complaints were primarily African American (53.6%), low to middle income (75.4%), and reported an unplanned pregnancy (72%). FINDINGS: A total of 27.7% of women had a history of CSA and/or adolescent/adult sexual assault. Mediation analyses using bootstrapping supported depression as a significant mediator of the relationship between sexual victimization and somatic complaints, with a medium-sized effect (kappa(2) = .09). CONCLUSIONS: Having a history of sexual victimization is associated with risk for poor mental and physical health during pregnancy. There are likely multiple mechanisms explaining the association between sexual victimization and somatic complaints in pregnancy, which should be investigated in future research. PMID- 26253825 TI - Beliefs About Anal Cancer among HIV-Infected Women: Barriers and Motivators to Participation in Research. AB - BACKGROUND: Infection with the human immunodeficiency virus (HIV) remains associated with a greater risk of anal cancer, despite widespread use of combination antiretroviral therapy. Evidence concerning the acceptability of anal cancer screening gives little attention to women. Because HIV-infected women have a high prevalence of depression and history of sexual trauma, understanding acceptability among this group is critical. PURPOSE: We sought to assess barriers and motivators to participation in anal cancer screening research among a racial/ethnically diverse HIV-infected female population. METHODS: We conducted a survey based on the Health Belief Model to identify characteristics of women willing to participate in anal cancer screening research (n = 200). Bivariate analyses examined associations between willingness to participate and sociodemographics, clinical characteristics, and health beliefs. Logistic regression modeled willingness to participate in research. MAIN FINDINGS: Of the women who participated, 37% screened positive for depression, 43% reported a high trauma history, and 36% screened positive for posttraumatic stress disorder. Overall, 65% reported willingness to participate in research. Those likely to participate were older, reported intravenous drug use as their HIV risk factor, and had a history of prior high-resolution anoscopy (HRA) compared with those unwilling to participate. The most commonly reported barrier to anal Pap testing was fear of pain. In adjusted analyses, a lack of fear of pain and prior experience with HRA significantly predicted willingness to participate. CONCLUSIONS: Findings suggest that, to increase participation in anal Pap and HRA related research for HIV-infected women, a single approach may not be adequate. Rather, we must harness patients' previous experiences and address psychosocial and financial concerns to overcome barriers to participation. PMID- 26253826 TI - Postpartum Contraception Use by Urban/Rural Status: An Analysis of the Michigan Pregnancy Risk Assessment Monitoring System Data. AB - OBJECTIVE: We sought to examine rural/urban differences in postpartum contraceptive use, which are underexplored in the literature. METHODS: We analyzed phase 5 (2004-2008) of the Michigan Pregnancy Risk Assessment Monitoring System (PRAMS) survey. Using Rural-Urban Commuting Area codes and weighted multinomial logistic regression, we examined the association between self reported postpartum contraceptive method and rural/urban residence among postpartum women not desiring pregnancy (n = 6,468). RESULTS: Postpartum (mean, 16.5 weeks after delivery), 14.4% of respondents were using sterilization, 6.7% long-acting reversible contraception (LARC), 37.3% moderately effective hormonal methods, 38.4% less effective methods or no method, and 3.2% abstinence. Multivariable analysis yielded sporadic geographic patterns. Odds of method use varied significantly by age, parity, body mass index, and breastfeeding status. Not discussing contraception with a prenatal healthcare provider decreased odds of postpartum LARC use (odds ratio, 0.52; 95% CI, 0.36-0.75). Number of prenatal visits and weeks since delivery were not associated with postpartum contraception method. CONCLUSIONS: We did not observe strong variation in postpartum contraceptive use based on geography. Low uptake of highly effective contraception across rural and urban areas suggests a need for education and outreach regarding these methods. PMID- 26253827 TI - Inter-rater reliability of postnatal ultrasound interpretation in infants with congenital hydronephrosis. AB - PURPOSE: The most common measurements of hydronephrosis are the anterior posterior (AP) diameter and the Society for Fetal Urology (SFU) grading systems. To date, the inter-rater reliability (IRR) of these measures has not been compared in the postnatal period. The objectives of this study were to compare the IRR of the AP diameter and the SFU grading system in infants and to determine whether ultrasound findings other than pelvicalyceal dilation are associated with higher SFU grades. METHODS: Initial postnatal ultrasounds of infants seen from February 1, 2011, to January 31, 2012, with a primary diagnosis of congenital hydronephrosis were included for review. Ultrasound images were de-identified and reviewed by four pediatric urologists. IRR was calculated using the intraclass correlation (ICC) measure. A paired t test was used to compare ICCs. Associations between SFU grade and other ultrasound findings were tested using Chi-square or Fisher's exact tests. RESULTS: A total of 112 kidneys in 56 patients were reviewed. IRR of the SFU grading system was high (right kidney ICC = 0.83, left kidney ICC = 0.85); however, IRR of AP diameter measurement was higher (right kidney ICC = 00.97, left kidney ICC = 0.98; p < 0.001). Renal asymmetry (p < 0.001), echogenicity (p < 0.001), and parenchymal thinning (p < 0.001) were significantly associated with SFU grade 4 hydronephrosis on bivariable and multivariable analysis. CONCLUSIONS: The SFU grading system is associated with excellent IRR, although the AP diameter appears to have higher IRR. Physicians may consider ultrasound findings that are not explicitly included in the SFU system when assigning hydronephrosis grade, which may lead to variability in use of this classification system. PMID- 26253829 TI - Editorial comment on: Intralesional hyaluronic acid: an innovative treatment for Peyronie's disease. PMID- 26253828 TI - Efficacy of neuromuscular electrostimulation intervention to improve physical function in haemodialysis patients. AB - BACKGROUND: Haemodialysis (HD) patients are characterised by muscle wasting, decreased physical function and poor quality of life. The objective was to analyse the effect of an intradialysis NMES training programme in muscular strength, functional capacity and quality of life in our HD patients. MATERIAL: HD patients were assigned to NMES (ESG) or control group (CG) in a 12-week single centre prospective study. Transversal quadriceps muscular area, maximum length quadriceps strength (MLQS), handgrip, sit-to-stand-to-sit 10 test (STS10), "6-min walking test" (6MWT); EuroQol-5D health-related quality of life (EQ-5D) questionnaire, subjective global assessment (SGA) and NMES symptoms questionnaires (SQ) were completed. RESULTS: Thirty-eight patients (54 % men). Mean age 69.7 years. 32.1 months on HD, 23 ESG and 15 in CG. In contrast with CG, ESG significantly (*p < 0.05) improved MLQS* (10.2 6.7 vs. 13.1 8.1 kg), STS10* (41 18.7 vs. 37.2 23.9 s), 6MWT* (12 %, 280.5 vs. 312.4 m) and EQ-5D score* (52.7 vs. 65.5) at the end of the study. However, lower SQ score* (8.5 vs. 5.8 sympt./patient) in ESG was observed, mainly due to muscular pain* (2.2 vs. 1.2), cramps* (1.6 vs. 1.2), numbness* (1.7 vs. 1.1) or stinging* (1.5 vs. 1.1). In ESG, 44 and 72 % referred better wellness sensation and physical condition in SGA, respectively. CONCLUSIONS: Intradialytic NMES of both quadriceps improved muscular strength, functional capacity and quality of life in our HD patients. With the obtained results, NMES constitutes a novel therapeutic alternative to improve the deteriorated physical condition and quality of life of these patients. PMID- 26253831 TI - Erratum to: Differential contribution of aortic and carotid sinus baroreflexes to control of heart rate and renal sympathetic nerve activity. PMID- 26253830 TI - A rare case of primary non-function of renal allograft due to adenine phosphoribosyltransferase deficiency. PMID- 26253832 TI - Comprehensive evaluation of the photo-transformation routes of trans-resveratrol. AB - Liquid chromatography (LC) combined with accurate mass spectrometry (MS), based on the use of a hybrid quadrupole time-of-flight (TOF) MS system, is employed to systematically investigate the photo-transformation routes of trans-resveratrol. Experiments were performed in quartz tubes, containing ethanolic solutions (12% v/v) of the precursor compound, exposed to different ultraviolet (UV) sources and to solar light. Time-courses of trans-resveratrol and transformation products (TPs) were investigated by direct injection of different reaction times aliquots in the LC-QTOF-MS system. Structural elucidation of detected TPs was derived from interpretation of their accurate product ion scan spectra. Trans-resveratrol labelled with (13)C6 in the mono-hydroxylated ring was also employed to further confirm the exact positions of some substituents in the generated TPs. In addition to the well-known trans-/cis-isomerization process, three different main reactions pathways were noticed under all the investigated conditions: (1) water addition to the exocycle double bond followed by oxidation to a ketone and cleavage of the molecule, (2) intramolecular cyclization to render a trihydroxylated phenanthrene, and (3) oxidation of the phenanthrene-like derivative to generate an orto-diquinone. Both, the trihydroxylated phenanthrene and the orto-diquinone underwent further aromatic hydroxylation reactions. The above transformation routes were also noticed for cis-resveratrol and the two analogue phytoalexins piceid and piceatannol. In addition to above transformation pathways, under solar light exposure, resveratrol underwent a molecular re arrangement rendering the so-called resveratrone, whose structure consists of two fused aromatic rings bonded to a linear chain containing a carbonyl group conjugated with a double bond. PMID- 26253833 TI - Dual dispersive liquid-liquid microextraction for determination of phenylpropenes in oils by gas chromatography-mass spectrometry. AB - A novel, simple and quick sample preparation method was developed and used for pre-concentration and extraction of six phenylpropenes, including anethole, estragole, eugenol, methyl eugenol, safrole and myristicin, from oil samples by dual dispersive liquid-liquid microextraction. Gas chromatography-mass spectrometry was used for determination and separation of compounds. Several experimental parameters affecting extraction efficiency were evaluated and optimized, including forward-extractant type and volume, surfactant type and concentration, water volume, and back-extractant type and volume. For all analytes (10-1000ng/mL), the limits of detection (S/N?3) ranged from 1.0 to 3.0ng/mL; the limits of quantification (S/N?10) ranged from 2.5 to 10.0ng/mL; and enrichment factors ranged from 3.2 to 37.1 times. Within-run and between-run relative standard deviations (n=6) were less than 2.61% and less than 4.33%, respectively. Linearity was excellent with determination coefficients (r(2)) above 0.9977. The experiments showed that the proposed method is a simple, effective, and environmentally friendly method of analyzing phenylpropenes in oil samples. PMID- 26253834 TI - Analysis of cytochrome P450 metabolites of arachidonic acid by stable isotope probe labeling coupled with ultra high-performance liquid chromatography/mass spectrometry. AB - Cytochrome P450 metabolites of arachidonic acid (AA) belong to eicosanoids and are potent lipid mediators of inflammation. It is well-known that eicosanoids play an important role in numerous pathophysiological processes. Therefore, quantitative analysis of cytochrome P450 metabolites of AA, including hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatreinoic acids (EETs), and dihydroxyeicosatrienoic acids (DHETs) can provide crucial information to uncover underlying mechanisms of cytochrome P450 metabolites of AA related diseases. Herein, we developed a highly sensitive method to identify and quantify HETEs, EETs, and DHETs in lipid extracts of biological samples based on stable isotope probe labeling coupled with ultra high-performance liquid chromatography/mass spectrometry. To this end, a pair of stable isotope probes, 2 dimethylaminoethylamine (DMED) and d4-2-dimethylaminoethylamine (d4-DMED), were utilized to facilely label eicosanoids. The heavy labeled eicosanoid standards were prepared and used as internal standards for quantification to minimize the matrix and ion suppression effects in mass spectrometry analysis. In addition, the detection sensitivities of DMED labeled eicosanoids improved by 3-104 folds in standard solution and 5-138 folds in serum matrix compared with unlabeled analytes. Moreover, a good separation of eicosanoids isomers was achieved upon DMED labeling. The established method provided substantial sensitivity (limit of quantification at sub-picogram), high specificity, and broad linear dynamics range (3 orders of magnitude). We further quantified cytochrome P450 metabolites of AA in rat liver, heart, brain tissues and human serum using the developed method. The results showed that 19 eicosanoids could be distinctly detected and the contents of 11-, 15-, 16-, 20-HETE, 5,6-EET, and 14,15-EET in type 2 diabetes mellitus patients and 5-, 11-, 12-, 15-, 16-, 20-HETE, 8,9-EET, and 5,6-DHET in myeloid leukemia patients had significant changes, demonstrating that these eicosanoids may have important roles on the pathogenesis of type 2 diabetes mellitus and myeloid leukemia. PMID- 26253835 TI - Polyethylenimine modified poly(ethylene terephthalate) capillary channeled polymer fibers for anion exchange chromatography of proteins. AB - Native poly(ethylene terephthalate) (PET) capillary-channeled polymer (C-CP) fibers have been previously studied as stationary phases for reversed phase and affinity protein separations. In this study, surface modified PET C-CP fibers were evaluated for the anion exchange separation of proteins. The native PET C-CP fibers were aminated using polyethylenimine (PEI) followed by a 1,4-butanediol diglycidyl ether (BUDGE) cross-linking step. Subsequent PEI/BUDGE treatments can be employed to further develop the polyamine layer on the fiber surfaces. The PEI densities of the modified fibers were quantified through the ninhydrin reaction, yielding values of 0.43-0.89MUmolg(-1). The surface modification impact on column permeability was found to be 0.66*10(-11) to 1.33*10(-11)m(2), depending on the modification time and conditions. The dynamic binding capacities of the modified fiber media were determined to be 1.99-8.54mgmL(-1) bed volume, at linear velocities of 88-438cmmin(-1) using bovine serum albumin as the model protein. It was found that increasing the mobile phase linear velocity (up to 438cmmin(-1)) had no effect on the separation quality for a synthetic protein mixture, reflecting the lack of van Deemter C-term effects for the C-CP fiber phase. The low-cost, easy modification method and the capability of fast protein separation illustrate great potential in the use of PEI/BUDGE-modified PET C-CP fibers for high-throughput protein separation and downstream processing. PMID- 26253836 TI - The influence of maternal energy status during mid-gestation on beef offspring tenderness, muscle characteristics, and gene expression. AB - The objective of this study was to determine if maternal energy status during mid gestation influences the expression of genes regulating muscle and fat development, and muscle characteristics that may impact meat tenderness. Cows grazed dormant, native range (Positive Energy Status [PES]) or were fed at 80% of maintenance energy requirements (Negative Energy Status [NES]) during mid gestation. Steer offspring were harvested after 21 d in the feedlot (weaning subsample) or after 208 d in the feedlot (final subsample). Greater 21-d tenderness was observed in NES steers, resulting from reduced collagen content in longissimus lumborum steaks. In the semitendinosus, NES steers had greater soluble collagen, and down-regulated expression of MHC-IIA and TIMP-3 at weaning, while MHC-IIA expression was up-regulated in NES steers in the final harvest. Data show mid-gestational maternal energy status may impact offspring tenderness and collagen, but differences were not detected in expression of genes important in myogenesis and adipogenesis in muscle samples obtained from steers at weaning or slaughter. PMID- 26253837 TI - Determinants of the intention to purchase an autochthonous local lamb breed: Spanish case study. AB - The aim of the paper is to study consumers' acceptability for a lamb meat from a local autochthonous breed. An intention to purchase model was developed based on the Theory of Planned Behavior (TPB) and estimated using data from a survey conducted in Spain. Results indicated that consumers were willing to buy this lamb meat because 86% of respondents said that they probably/definitely would buy it, although only 23% would if the meat is not available in their usual meat store. Then, the lack of availability in the market is an aspect limiting its consumption. The most important factors explaining the intention to purchase for consumers who would purchase this meat if it were not available in their usual store are the importance attached to the animal breed and their social embeddedness with the local area. An appropriate food policy would be to inform consumers about the importance of the animal breed in the quality of the meat and the local origin. PMID- 26253838 TI - Nuclear Protein Phosphatase 1 alpha (PP1A) Expression is Associated with Poor Prognosis in p53 Expressing Glioblastomas. AB - BACKGROUND: Protein phosphatase 1 alpha (PP1A) is an enzyme intimately associated with cell cycle, the over expression of which has been demonstrated in glioblastoma (GBM). Further, the nuclear expression of PP1A has been shown to be highly specific to GBM. In addition, PP1A has been shown to be a connecting molecule in the p53 containing GBM sub network. In view of these, we evaluated the prognostic relevance of PP1A. METHODS: GBM tissues were examined for protein expression of PP1A by immunohistochemistry (IHC). Nuclear expression of PP1A was scored in all tumor tissue samples. Survival analyses were performed by Cox Regression and Kaplan-Meier survival analysis with Log Rank tests. IDH1, ATRX and p53 IHC and stratification of all GBM cases were performed and subgroup specific evaluation of nuclear PP1A correlation with overall and progression free survival was performed. RESULTS: PP1A protein expression showed no correlation with prognosis in all cases of GBM or on stratification based on IDH1 or ATRX expression. However on p53 stratification nuclear PP1A expression emerged as strong independent predictor of poor overall survival only in p53 positive GBMs both in univariate and multivariate analysis. CONCLUSIONS: While PP1A expression uniquely associates with poor prognosis only in p53 expressing GBMs, there is a notable absence of such correlation in p53 negative GBMs; thus skewing the overall relation of this molecule with prognosis in GBM. PP1A emerging as a strong prognostic marker in p53 expressing GBMs, enables us to foresee this molecule as a potential therapeutic target. PMID- 26253839 TI - Diurnal and seasonal variation in light and dark respiration in field-grown Eucalyptus pauciflora. AB - Respiration from vegetation is a substantial part of the global carbon cycle and the responses of plant respiration to daily and seasonal fluctuations in temperature and light must be incorporated in models of terrestrial respiration to accurately predict these CO2 fluxes. We investigated how leaf respiration (R) responded to changes in leaf temperature (T(leaf)) and irradiance in field-grown saplings of an evergreen tree (Eucalyptus pauciflora Sieb. ex Spreng). Seasonal shifts in the thermal sensitivity of leaf R in the dark (R(dark)) and in the light (R(light)) were assessed by allowing T(leaf) to vary over the day in field grown leaves over a year. The Q10 of R (i.e., the relative increase in R for a 10 degrees C increase in T(leaf)) was similar for R(light) and R(dark) and had a value of ~ 2.5; there was little seasonal change in the Q10 of either R(light) or R(dark), indicating that we may be able to use similar functions to model short term temperature responses of R in the dark and in the light. Overall, rates of R(light) were lower than those of R(dark), and the ratio of R(light)/R(dark) tended to increase with rising T(leaf), such that light suppression of R was reduced at high T(leaf) values, in contrast to earlier work with this species. Our results suggest we cannot assume that R(light)/R(dark) decreases with increasing T(leaf) on daily timescales, and highlights the need for a better mechanistic understanding of what regulates light suppression of R in leaves. PMID- 26253840 TI - Male gender explains increased birthweight in children born after transfer of blastocysts. AB - STUDY QUESTION: Does extended embryo culture have a different effect on the birthweight of girls and boys? SUMMARY ANSWER: The mean birthweight of boys born after fresh and frozen-thawed blastocyst transfer was increased compared with those born after cleavage stage embryo transfer. This effect was not detected among girls. WHAT IS KNOWN ALREADY: Previous studies indicate that newborns from frozen-thawed cleavage stage embryos may present with a higher weight than newborns from fresh embryo transfers. With regard to fresh embryos, newborns after a blastocyst transfer have been reported as having higher birthweights than newborns from cleavage stage embryos. STUDY DESIGN, SIZE, DURATION: Retrospective multicentre case-control cohort study. All IVF/ICSI treatments were performed in the time-period from January 2008 to March 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Birthweight of singletons born at full-term (>=37 weeks), after fresh or frozen blastocyst embryo transfers (n = 277), were compared with weights of children born after fresh or frozen cleavage stage embryo transfers (Day 2-3) (n = 277). The cases and controls were matched by delivery week, and by gender. Data of IVF/ICSI treatments, and the treatments' outcomes were collected and analysed. MAIN RESULTS AND THE ROLE OF CHANCE: The birthweight after a fresh blastocyst transfer was significantly higher (mean 3530.6 g) than that after a transfer of cleavage stage embryos (mean 3418.8 g; weight difference 111.8 g, P = 0.047). The weights of newborns after frozen-thawed blastocyst transfers (mean 3647.5 g) and the frozen-thawed cleavage stage embryo transfers (mean 3650.9 g), were similar (weight difference 3.4 g, P = 0.95). The boys born after transfer of frozen thawed blastocysts had a significantly higher birthweight (mean 3767.9 g) than girls (3525.2 g; weight difference 242.7 g, P = 0.002), whereas the difference of birthweights between genders was only 13.5 g in cleavage stage (P = 0.863). The same effect was seen after fresh blastocyst transfers (weight difference 211.5 g, P = 0.011), but not after fresh Day 2-3 embryo transfers (weight difference 53.6 g, P = 0.478). LIMITATIONS, REASONS FOR CAUTION: The study material was large enough to detect differences between birthweights as a whole, but a larger study group would confirm these new findings. To avoid selection bias, the next possible control candidate, fulfilling the selection criteria, was included for matching cases and controls. We have matched the cases and controls by gender and gestational week at birth, with an aim to reduce their impact as confounding factors. WIDER IMPLICATIONS OF THE FINDINGS: Our findings of a similar weight at birth of newborns after frozen-thawed blastocysts and frozen-thawed cleavage stage embryos, when matching for age and duration of pregnancy, are novel. The gender of the newborn has an impact on the birthweight, and the extended embryo culture increases the weight difference between the genders, which is a new finding as well. STUDY FUNDING/COMPETING INTERESTS: The study was funded by the Fertility Society of Finland. PMID- 26253841 TI - Baseline Blood Pb Concentrations in Black-Necked Stilts on the Upper Texas Coast. AB - There are no known biological requirements for lead (Pb), and elevated Pb levels in birds can cause a variety of sub-lethal effects and mortality. Historic and current levels of Pb in mottled ducks (Anas fulvigula) suggest that environmental sources of Pb remain available on the upper Texas coast. Because of potential risks of Pb exposure among coexisting marsh birds, black-necked stilt (Himantopus mexicanus) blood Pb concentrations were measured during the breeding season. Almost 80 % (n = 120) of 152 sampled stilts exceeded the background threshold (>20 MUg/dL) for Pb exposure. However, blood Pb concentrations did not vary by age or gender, and toxic or potentially lethal concentrations were rare (<5 %). Consistent, low-level blood Pb concentrations of black-necked stilts in this study suggest the presence of readily bioavailable sources of Pb, although potential impacts on local stilt populations remain unclear. PMID- 26253842 TI - Comparative Study of Lead Concentration in Feathers of Urban and Rural Passerines in Merida, Mexico. AB - Lead is a commonly monitored heavy metal because of potential health effects on exposed organisms. We quantified lead in secondary feathers of two passerine bird species, clay-colored thrushes (Turdus grayi) and great-tailed grackles (Quiscalus mexicanus), from an urban and a rural site in the municipality of Merida, Yucatan. Urban lead concentration was significantly higher than its rural counterpart for both species (p < 0.05). In the urban site, lead concentration was similar in both species (p = 0.14). However, data from the rural site showed that lead concentration was significantly higher in thrush feathers (p < 0.05). Lead levels herein presented are among the lowest ever reported suggesting that either lead accumulation or absorption is limited. Finally, our data seem to support the hypothesis that species feeding ecology plays a major role in lead accumulation. PMID- 26253843 TI - Use of a modified Furlow Z-plasty as a secondary cleft palate repair procedure to reduce velopharyngeal insufficiency. AB - Cleft palate repair is done to allow for normal speech by separating the oral and nasal cavities and creating a functioning velopharyngeal valve. However, despite cleft palate repair, some patients demonstrate velopharyngeal insufficiency (VPI). An attempt was made to determine the effectiveness of a modified secondary Furlow Z-plasty in improving VPI. Fifty-five children aged between 12 and 15 years, with postoperative VPI following primary palatoplasty, were included in the study. These children underwent a modified Furlow Z-plasty. Nasometry was done to determine the change in velopharyngeal function due to the secondary Furlow Z-plasty by comparing the preoperative with the 1-year postoperative nasalance scores. A test-retest study was performed to determine the reliability of the nasometric measures. Reliability measurements of the nasometer passages revealed good reliability for 18 out of the 25 speech passages. There was a statistically significant reduction in VPI at 1 year postoperative in patients who were treated with the modified Furlow Z-plasty, with a P-value of <0.001 in all passages, except velar plosives, which had a P-value of 0.002. Patients with VPI after primary palatoplasty and treated using a modified Furlow Z-plasty had significantly lower nasalance scores at 1 year postoperative, indicating significantly improved velopharyngeal function. PMID- 26253844 TI - Seasonal acclimatization of the cardiac potassium currents (IK1 and IKr) in an arctic marine teleost, the navaga cod (Eleginus navaga). AB - Several freshwater fishes of north-temperate latitudes exhibit marked seasonal changes in cardiac action potential (AP) waveform as an outcome of temperature dependent changes in the density of delayed rectifiers (IKr, IKs) and inward rectifier (IK1) potassium currents. Thus far, ionic mechanisms of cardiac excitability in arctic marine fishes have not been examined. To this end we examined ventricular AP and the role of two major potassium currents (IK1, IKr) in repolarization of cardiac AP in winter-acclimatized (WA, caught in March) and summer-acclimatized (SA, caught in September) navaga cod (Eleginus navaga) of the White Sea. The duration of ventricular AP of WA navaga at 3 degrees C (APD50 = 659.5 +/- 32.8 ms) was similar to the AP duration of SA navaga at 12 degrees C (APD50 = 543.9 +/- 14.6 ms) (p > 0.05) indicating complete thermal compensation of AP duration. This acclimation effect was associated with strong up-regulation of the cardiac potassium currents in winter. Densities of ventricular IK1 (at 120 mV) and IKr (at +50 mV) of the WA navaga at 3 degrees C were 2.9 times and 2.8 times, respectively, higher than those of the SA navaga at 12 degrees C, thus indicating marked thermal overcompensation. Qualitatively similar results were obtained from atrial myocytes. Seasonal changes in IK1 and IKr are more than sufficient to explain the complete thermal compensation of ventricular AP duration. The excellent acclimation capacity of cardiac excitability of the navaga cod is probably needed to maintain high cardiac performance at subzero temperatures in winter and to increase thermal resilience of cardiac function under seasonally variable arctic temperature conditions. PMID- 26253845 TI - Revisiting time-resolved protein phosphorescence. AB - Analysis of time-resolved phosphorescence data from proteins presents certain problems. Care must be taken in establishing that the analysis is not confounded in the early part of the decay by other emitting species. These species may include tyrosine, impurities found in the solvent, or impurities bound to the protein. In this paper, analysis of the phosphorescence of simple mixtures of tryptophan, tyrosine, and tryptophan + tyrosine in glycerol-water solvent has demonstrated the necessity of accounting for tyrosine emission in the analysis of protein phosphorescence. The tyrosine emission is especially strong at cold temperatures and becomes negligible above approximately 185 K in this solvent. Two fitting procedures have been developed to describe the bimodal emission that results from a single-tryptophan protein that contains a significant number of tyrosine residues. The methods utilize either a maximum entropy method-derived lifetime distribution or the stretched exponential function. In both cases some prior information regarding the expected decay characteristics of the tryptophan residue is applied to guide the separation of the tryptophan component from the tyrosine component. This prior information is obtained by comparing the tail of the protein decay to decays of free-tryptophan in solvent at a variety of temperatures until a match is found having close overlap on a log-intensity decay plot. PMID- 26253846 TI - Current status of islet xenotransplantation. AB - Cell therapy for Type 1 diabetes (T1D) utilizing islet cell transplantation can successfully restore endogenous insulin production in affected patients. Islet cell engraftment and survival are conditional on the use of efficacious anti rejection therapies and on the availability of healthy donor cells. The scarcity of healthy human donor pancreata is a limiting factor in providing sufficient tissue to meet the demand for islet transplantation worldwide. A potential alternative to the use of cadaveric human donor pancreases is the use of animal sourced islets. Pancreatic islets obtained from pigs have emerged as an alternative to human tissues due to their great availability, physiological similarities to human islets, including the time-tested use of porcine insulin in diabetic patients and the ability to genetically modify the donor source. The evolution of refined, efficacious immunosuppressive therapies with reduced toxicity, improvements in donor management and genetic manipulation of the donor have all contributed to facilitate long-term function in pre-clinical models of pig islet grafts in non-human primates. As clinical consideration for this option is growing, and trials involving the use of porcine islets have begun, more compelling experimental data suggest that the use of pig islets may soon become a viable, safe, effective and readily available treatment for insulin deficiency in T1D patients. PMID- 26253847 TI - Risk factors for the development of metachronous bone metastasis in colorectal cancer patients after curative resection. AB - OBJECTIVE: Metachronous bone metastasis (MBM) occurs in 6-10% of colorectal cancer (CRC) patients following surgical treatment. The aim of this study is to determine the risk factors affecting the development of MBM in CRC patients following curative resection. METHOD: Clinical and pathological records of 516 CRC patients who underwent curative resection were retrospectively studied. The association between clinicopathological variables and development of MBM was investigated using univariate and multivariate analyses. RESULT: The incidence of MBM was 6.0% and the median time of developing MBM was 15 (range, 1-89) months. Univariate analysis identified that lymph node involvement (p = 0.001), tumor stage (p = 0.020) and tumor location (p = 0.015) were significantly correlated with development of MBM. Multivariate analyses showed tumor location (p = 0.039) and lymph node involvement (p = 0.003) were independent risk factors contributing to the occurrence of MBM. CONCLUSION: This study indicated that tumor location and lymph node involvement were independent risk factors for development of MBM in CRC patients after curative resection. PMID- 26253848 TI - A prospective comparative study of clinical and functional outcomes between anatomic double bundle and single bundle hamstring grafts for arthroscopic anterior cruciate ligament reconstruction. AB - BACKGROUND: Despite a number of studies comparing postoperative stability and function after anatomic single bundle and double bundle anterior cruciate ligament reconstruction, it remains unclear whether double bundle reconstruction has better functional outcome than single bundle anterior cruciate ligament reconstruction. PURPOSE: To compare the subjective functional outcome as well as clinical stability in patients treated with either anatomic single bundle or anatomic double bundle anterior cruciate ligament (ACL) reconstruction. We hypothesized that there would be no difference in the postoperative functional outcome and clinical stability between anatomical double bundle anterior cruciate ligament reconstructions when compared to single bundle anterior cruciate ligament reconstructions. METHODS: We prospectively followed 40 patients out of which, 20 patients were operated for anatomic single bundle ACL reconstruction and other 20 patients underwent anatomic double bundle ACL reconstruction. Patient evaluation using the laxity tests and outcome scales was done preoperatively and at 12, 24 and 48 months after the surgery. Clinical stability was assessed by Lachman test, Pivot shift test and Delhi active test. Functional outcome was assessed by International Knee Documentation Committee (IKDC), Lysholm and Modified Cincinnati scores. Patients in both groups were evaluated at regular intervals for a minimum period of 48 months (mean 51 months, range 48-56 months). RESULTS: For all subjective scores, double bundle group patients reported statistically significant higher scores compared to single bundle group patients. Graded stability results of the Lachman, and Pivot shift tests were significantly higher in the anatomically reconstructed double bundle patient group. CONCLUSION: We suggest that functional outcome and clinical stability may be better with anatomical double bundle anterior cruciate ligament reconstruction as compared to anatomical single bundle anterior cruciate ligament reconstruction. PMID- 26253849 TI - Breast cancer subtypes can be determinant in the decision making process to avoid surgical axillary staging: A retrospective cohort study. AB - INTRODUCTION: The need for performing axillary lymph-node dissection in early breast cancer when the sentinel lymph node (SLN) is positive has been questioned in recent years. The purpose of this study was to identify a low-risk subgroup of early breast cancer patients in whom surgical axillary staging could be avoided, and to assess the probability of having a positive lymph-node (LN). METHODS: We evaluated the cohort of 612 consecutive women affected by early breast cancer. We considered age, tumor size, histological grade, vascular invasion, lymphatic invasion and cancer subtype (Luminal A, Luminal B HER-2+, Luminal B HER-2-, HER 2+, and Triple Negative) as variables for univariate and multivariate analyses to assess probability of there being a positive SLN o nonsentinel lymph node (NSLN). Chi-square, Fisher's Exact test and Student's t tests were used to investigate the relationship between variables; whereas logit models were used to estimate and quantify the strength of the relationship among some covariates and SLN or the number of metastases. RESULTS: A significant positive effect of vascular invasion and lymphatic invasion (odds ratios are 4 and 6), and a negative effect of TN (odds ratios is 10) were noted. With respect to positive NSLN, size alone has a significant (positive) effect on tumor presence, but focusing on the number of metastases, also age has a (negative) significant effect. CONCLUSION: This work shows correlation between subtypes and the probability of having positive SLN. Patients not expressing vascular invasion, lymphatic invasion and, moreover, a triple-negative tumor subtype may be good candidates for breast conservative surgery without axillary surgical staging. PMID- 26253850 TI - Imageless navigation versus traditional method in total hip arthroplasty: A meta analysis. AB - PURPOSE: Accuracy of acetabular component orientation is improved with computer navigation in THA. In recent years, imageless navigation has become more commonplace, whereas there still exist different arguments about this technique. METHODS: We conducted a meta-analysis to assess the accuracy of imageless navigation for acetabular implantation in total hip arthroplasty. The computer based online search strategy covered the major medical databases (Cochrane Library, Medline, Pubmed, and EmbaseI) from January 2004 to December 2014. Data of selected clinical trials were analysed using Revman 5.1 software. RESULTS: 7 clinical trials enrolling 485 patients were included. Mean cup inclination and anteversion were not statistically significantly different between the conventional groups and the imageless computer navigated groups (P = 0.83 and P = 0.89 respectively). Deviation from the desired position of inclination shows no significant differences (P = 0.06), whereas deviation from the desired position of anteversion was smaller in computer navigated group (P<0.0001). Only one study gave useful information about operation time which is significantly increased (MD = 23.00, P = 0.001). CONCLUSIONS: Current literature generally hold the opinion that navigation is a reliable tool to optimize cup placement, but still there are some different voices about imageless navigation system. This meta-analysis emphasizing more on the accuracy of cup-positioning with imageless navigation reveals that imageless navigation is preferable compared with traditional method. PMID- 26253851 TI - Surgical morbidity of cervical lymphadenectomy for thyroid cancer: A retrospective cohort study over 25 years. AB - INTRODUCTION: Prognosis of thyroid cancer is strictly related to loco-regional metastases. Cervical lymphadenectomy has a specific oncologic role but may lead to significant increase of morbidity. Aim of the study is the analysis of surgical morbidity in cervical lymphadenectomy for thyroid cancer. METHODS: We retrospectively analyzed 1.765 thyroid cancers operated over a period of 25 years at S. Maria University Hospital, Terni, University of Perugia, Italy. Type of lymphadenectomy, histology and complications were analysed. RESULTS: A prevalence of differentiated and medullary cancers was observed (respectively 88% and 7.2%). Central lymphadenectomy was carried out in 425 patients, lateral modified and radical lymphadenectomy respectively in 651 and 17 cases. Following central neck dissection we observed: bilateral and unilateral temporary recurrent nerves palsy respectively of 0.7% and 3.5%, unilateral permanent palsy in 1.6% of cases, temporary and permanent hypoparathyroidism respectively in 17.6% and 4.4%. After lateral neck dissection we observed: intra and post-operative haemorrhage respectively in 2% and 0.29%, respiratory distress in 0.29%, lesions of facial nerve in 0.44%, of vagus in 0.14%, of phrenic nerve in 0.14%, of hypoglossal nerve in 0.29%, of the accessory nerve, transient in 1.34% and permanent in 0.29%, permanent lesion of cervical plexus in 0.29%, salivary fistula in 0.14% and chylous fistula in 1.04% of patients. Student's t test was used to compare groups when appliable. CONCLUSION: Central and lateral cervical lymph node dissection are associated to severe morbidity. Correct indication, surgical expertise, high volume of patients and early multidisciplinary management of complications is the key of an acceptable balance between oncologic benefits and surgical morbidity. PMID- 26253852 TI - Is postoperative cell salvage necessary in total hip or knee replacement? A meta analysis of randomized controlled trials. AB - OBJECTIVE: The purpose of this study was to determine whether there are hematological or clinical differences with the use of postoperative cell salvage after total knee (TKR) and hip replacement (THR). METHODS: A systematic literature review based on PubMed, EMBASE, the Cochrane Library Database in any language regarding postoperative cell salvage following TKR or THR was performed. High quality of randomized controlled trials were identified. The data was analyzed using Rev Man 5.2. RESULTS: 19 randomized controlled trials (12 in TKR, 4 in THR and 3 in both) about 3482 patients were identified and included in this meta-analysis. Postoperative cell salvage significantly reduced the allogeneic blood transfusion requirement after TKR (RR = 0.46, 95% CI = 0.30 to 0.72) and THR (RR = 0.46, 95%CI = 0.32 to 0.68). It also demonstrated a higher level of postoperative Hemoglobin (MD = 0.26 g/dL, 95%CI = 0.15 to 0.37) with the use of postoperative cell salvage. No significant differences were detected regarding length of hospital stay, the incidence of febrile reaction, wound infection and deep vein thrombosis. CONCLUSION: The results strengthen the fact that postoperative cell salvage is effective and safe to reduce the rate of transfusion after TKR and THR. As the relatively poor methodological quality and heterogeneity, further research is needed to confirm its safety and cost effectiveness. PMID- 26253853 TI - The lateral clavicular epiphysis: fusion timing and age estimation. AB - This study utilizes a forensic autopsy sample of twentieth century American Whites (the McCormick Clavicle Collection) to describe the morphology, variation, and fusion timing of the lateral clavicle epiphysis. Clavicles from individuals between 11 and 25 years at the time of death were used to document fusion of the lateral epiphysis (n= 133, 38 females and 95 males). The lateral epiphysis was scored as unfused, fusing, or fused. A linear weighted kappa indicates that this scoring method is highly replicable with almost perfect inter-rater agreement (kappa = 0.849), according to a widely used standard for assessing kappa values. Transition analysis, or probit regression, was employed to quantify fusion timing of the lateral epiphysis. The transition from "unfused" to "fusing" is most likely to occur at 16.5 years in females and 17.5 years in males. The transition from "fusing" to "fused" occurs at age 21 in females and age 20 in males. The earliest age at which fusion began was 15 years (n = 1), but the majority began fusing between 17 and 20 years. Most individuals (98.5 % of the sample) aged >24 years had fused lateral epiphyses. The epiphysis assumes one of two forms: (1) a separate bony flake fusing to the diaphysis or (2) a mound of bone glazing/smoothing over the diaphyseal surface. As socioeconomic status has been cited as the most influential variable on skeletal maturation rates, the fusion ages offered here should not be applied to populations with a socioeconomic status different from the greater US population. PMID- 26253854 TI - Hypotony Maculopathy: Clinical Presentation and Therapeutic Methods. AB - INTRODUCTION: Hypotony maculopathy is ocular hypotony complicated by papilledema and/or folding of the retina and choroid in the posterior pole. Our objective was to examine the current literature regarding hypotony maculopathy and treatment methods. METHODS: A systematic review of the English-language literature was conducted by performing a broad search of PubMed from 1972 through 2015 using the keywords hypotony maculopathy and hypotony. Additional articles were identified from bibliographies of relevant articles. RESULTS: Hypotony maculopathy was infrequent before the introduction of antimetabolite agents in glaucoma-filtering surgery, and the incidence of this entity is now up to 20%. Risk factors for developing hypotony maculopathy include male gender, young age, myopia, and primary filtering surgery. Correctly identifying the etiology of hypotony is essential for successful treatment. Treatment of hypotony maculopathy includes procedures to elevate the intraocular pressure, thus reversing the collapse of the scleral wall and chorioretinal wrinkling. CONCLUSION: This review discusses the definition, clinical presentation, pathophysiology, incidence and risk factors, prevention and treatment of hypotony maculopathy. PMID- 26253855 TI - Relationship of polychlorinated biphenyls (PCBs) with parasitism, iron homeostasis, and other health outcomes: Results from a cross-sectional study on recently arrived African immigrants. AB - Polychlorinated biphenyls (PCBs) are toxic and persistent chemicals produced between 1930s and 1980s, which accumulate in humans and wildlife. Although a decreasing trend of PCB levels in humans has been described in developed countries, mainly as a consequence of strict regulations and remediation plans, an inverse trend has been recently reported in people from developing countries. We had the opportunity of sampling a series of African immigrants recently arrived to the Spanish archipelago of the Canary Islands, in which high levels of PCBs have been described, and we studied the relationships between their level of contamination and health status. A total of 570 subjects who underwent a complete medical examination and a face-to-face interview were recruited for this study. Hematological and biochemical parameters (blood and urine) were determined in all participants. Serology for the diagnostic of infectious diseases was also performed, and direct identification of parasites was performed in feces, urine or blood samples when appropriate. It is remarkable that up to 26.0% of the population had intestinal parasites, and we found an inverse relationship between PCB levels and parasitism and parasitic diseases: median values of PCBs were lower in parasitized subjects than in subjects without parasites in stool (237.6ng/g fat vs. 154.4ng/g fat for marker PCBs, p=0.015) and median values of dioxin-like PCBs were lower in subjects carrying pathogen parasites than among subjects showing non-pathogen parasites in stool (0.0 ng/g fat vs. 13.1ng/g fat, respectively; p=0.001). Although this inverse association had been described in some vertebrates this is the first study reporting such an association in humans. Furthermore, it has been also recently described that PCBs may disrupt iron metabolism, and we found a direct relationship between serum iron and total PCBs burden (r=0.231, p=0.025), suggesting that PCBs, although at subclinical level, could play a role on iron homeostasis. Although the role of PCBs in parasitism and in the iron metabolism needs future research, our findings may help to understand the adverse health outcomes associated to environmental exposure to PCBs and they might be used in exposed populations as indicators of subtle effects due to environmental insult. PMID- 26253856 TI - Guest Editorial. Harmonized human biomonitoring on a European scale: experiences in seventeen countries. PMID- 26253857 TI - Bacterial cellulose as a material for wound treatment: Properties and modifications. A review. AB - Advanced approaches to wound healing have attracted much attention in the last decades due to the use of novel types of dressings that provide a moist environment and take an active part in wound protection and tissue regeneration processes. The materials for novel wound dressings should have a set of features that will contribute to efficient skin recovery. The use of bacterial cellulose (BC) is attractive for advanced wound management because of the favorable characteristics of BC, such as its biocompatibility, non-toxicity, mechanical stability, and high moisture content. Numerous approaches can be taken to modify BC to address the shortcomings of the native material and to optimize its biocompatibility, water uptake and release, and antimicrobial activity. This review highlights possible pathways for functionalization of BC, affecting all levels of its structural organization. The focus is on post-production treatment of BC, although selected studies concerning in situ modifications during the biosynthesis process are also emphasized. PMID- 26253858 TI - Anthropometric difference of the knee on MRI according to gender and age groups. AB - The purpose of this study was to analyze the anthropometric data from MRI images that were obtained from the non-arthritic knees in Asian adults, and to identify the existence of morphologic differences between age groups. This cross-sectional study included knee MR images of 535 patients (273 males, 262 females) taken for the evaluation of soft-tissue injuries, excluding cases with cartilage defect and malalignment. The age, gender, height, and BMI were also assessed. The patients were grouped into three different 20-year age groups (20-39, 40-59, and 60-79). The MRI analysis was performed on the anthropometric parameters of distal femur and posterior tibial slope. Age-related differences were found in femoral width, distance from the distal and posterior cartilage surface to the medial/lateral epicondyle, medial posterior condylar offset (PCO), and posterior condylar angle (PCA) (all P < 0.001), but not in lateral PCO, and medial/lateral tibial slopes. In the analysis of covariance analyses, significant interaction between gender and age groups was found in most parameters, but not in PCA, distance from the posterior cartilage surface to the medial epicondyle, or medial tibial slope. We found anthropometric differences among age groups exist in most of distal femoral parameters, but not in posterior tibial slope. The results of this study can be used by manufacturers to modify prostheses to be suitable for the future Asian elderly population. PMID- 26253859 TI - Variant course of extensor pollicis longus tendon in the second wrist extensor compartment. AB - Among the muscles involved in thumb movement, the extensor pollicis longus (EPL) tendon of the hand is considered the most consistent structure with the least variation among individuals. There have been a few reports regarding different types of supernumerary tendons; however, an abnormal course of the EPL tendon is extremely rare. We describe a case of a variant course of a single EPL tendon appearing in the second extensor compartment of the wrist. This case was observed incidentally during wrist surgery, and demonstrates a unique variation of tendon course, which has not been reported previously. The knowledge of this anatomic variation is helpful in surgical planning and for making accurate diagnoses. PMID- 26253860 TI - Intracoronary Infusion of Thioflavin-S to Study Microvascular Obstruction in a Model of Myocardial Infarction. AB - INTRODUCTION AND OBJECTIVES: Microvascular obstruction exerts deleterious effects after myocardial infarction. To elucidate the role of ischemia-reperfusion injury on the occurrence and dynamics of microvascular obstruction, we performed a preliminary methodological study to accurately define this process in an in vivo model. METHODS: Myocardial infarction was induced in swine by means of 90-min of occlusion of the mid left anterior descending coronary artery using angioplasty balloons. Intracoronary infusion of thioflavin-S was applied and compared with traditional intra-aortic or intraventricular instillation. The left anterior descending coronary artery perfused area and microvascular obstruction were quantified in groups with no reperfusion (thioflavin-S administered through the lumen of an inflated over-the-wire balloon) and with 1-min, 1-week, and 1-month reperfusion (thioflavin-S administered from the intracoronary catheter after balloon deflation). RESULTS: In comparison with intra-aortic and intraventricular administration, intracoronary infusion of thioflavin-S permitted a much clearer assessment of the left anterior descending coronary artery perfused area and of microvascular obstruction. Ischemia-reperfusion injury exerted a decisive role on the occurrence and dynamics of microvascular obstruction. The no-reperfusion group displayed completely preserved perfusion. With the same duration of coronary occlusion, microvascular obstruction was already detected in the 1-min reperfusion group (14%+/-7%), peaked in the 1-week reperfusion group (21%+/-7%), and significantly decreased in the 1-month reperfusion group (4%+/-3%; P<.001). CONCLUSIONS: We present proof-of-concept evidence on the crucial role of ischemia reperfusion injury on the occurrence and dynamics of microvascular obstruction. The described porcine model using intracoronary injection of thioflavin-S permits accurate characterization of microvascular obstruction after myocardial infarction. PMID- 26253862 TI - Prion infection in cells is abolished by a mutated manganese transporter but shows no relation to zinc. AB - The cellular prion protein has been identified as a metalloprotein that binds copper. There have been some suggestions that prion protein also influences zinc and manganese homeostasis. In this study we used a series of cell lines to study the levels of zinc and manganese under different conditions. We overexpressed either the prion protein or known transporters for zinc and manganese to determine relations between the prion protein and both manganese and zinc homeostasis. Our observations supported neither a link between the prion protein and zinc metabolism nor any effect of altered zinc levels on prion protein expression or cellular infection with prions. In contrast we found that a gain of function mutant of a manganese transporter caused reduction of manganese levels in prion infected cells, loss of observable PrP(Sc) in cells and resistance to prion infection. These studies strengthen the link between manganese and prion disease. PMID- 26253863 TI - Treatment Compliance in Lung Cancer Patients. PMID- 26253861 TI - Interhospital Variability in Drug Prescription After Acute Coronary Syndrome: Insights From the ACDC Study. AB - INTRODUCTION AND OBJECTIVES: To analyze the rate of patients admitted for acute coronary syndrome who concomitantly received acetylsalicylic acid, statins, and angiotensin-converting enzyme inhibitors at discharge, and to analyze interhospital variability in the prescription of these drugs and its potential prognostic impact. METHODS: Interhospital variability in drug prescription was estimated using the intraclass correlation coefficient and median odds ratio (hierarchical analysis). Cox regression analysis was used to estimate the risk of death or myocardial infarction associated with prescription of all 3 agents at 2 years of follow-up. RESULTS: In total, 489 (53.3%) of 917 patients were prescribed all 3 agents. The rate was similar in patients with hypertension and diabetes (56.8%). There was significant variability among centers in the prescription of the 3 drugs at discharge (from 23% to 77% of patients). Hypertension (odds ratio=1.93; 95% confidence interval, 1.42-2.61), ejection fraction < 45% (odds ratio=2.2; 95% confidence interval, 1.44-3.37), being in a clinical trial (odds ratio=1.89; 95% confidence interval, 1.24-2.88), and renal failure (odds ratio=0.53; 95% confidence interval, 0.29-0.94) were associated with prescription of the 3 drugs. After adjustment for these factors, residual variability persisted (intraclass correlation coefficient 0.046 [95% credibility interval, 0.007 to 0.192]; median odds ratio=1.46 [95% credibility interval, 1.16 2.32]). There was no clear association between the prescription of all 3 drugs and the risk of events during follow-up (hazard ratio=0.81, 95% confidence interval, 0.55-1.18; P=.27). CONCLUSIONS: The prescription rate for acetylsalicylic acid, angiotensin-converting enzyme inhibitors, and statins after acute coronary syndrome is suboptimal, varies among centers, and is possibly related to different health care approaches. PMID- 26253864 TI - Multi-purpose rainwater harvesting for water resource recovery and the cooling effect. AB - The potential use of rainwater harvesting in conjunction with miscellaneous water supplies and a rooftop garden with rainwater harvesting facility for temperature reduction have been evaluated in this study for Hong Kong. Various water applications such as toilet flushing and areal climate controls have been systematically considered depending on the availability of seawater toilet flushing using the Geographic Information System (GIS). For water supplies, the district Area Precipitation per Demand Ratio (APDR) has been calculated to quantify the rainwater utilization potential of each administrative district in Hong Kong. Districts with freshwater toilet flushing prove to have higher potential for rainwater harvest and utilization compared to the areas with seawater toilet flushing. Furthermore, the effectiveness of using rainwater harvesting for miscellaneous water supplies in Hong Kong and Tokyo has been analyzed and compared; this revives serious consideration of diurnal and seasonal patterns of rainfall in applying such technology. In terms of the cooling effect, the implementation of a rooftop rainwater harvesting garden has been evaluated using the ENVI-met model. Our results show that a temperature drop of 1.3 degrees C has been observed due to the rainwater layer in the rain garden. This study provides valuable insight into the applicability of the rainwater harvesting for sustainable water management practice in a highly urbanized city. PMID- 26253865 TI - Effect of static magnetic field on the oxygen production of Scenedesmus obliquus cultivated in municipal wastewater. AB - Algal-bacterial symbiotic system, with biological synergism of physiological functions of both algae and bacteria, has been proposed for cultivation of microalgae in municipal wastewater for biomass production and wastewater treatment. The algal-bacterial symbiotic system can enhance dissolved oxygen production which enhances bacterial growth and catabolism of pollutants in wastewater. Therefore, the oxygen production efficiency of microalgae in algal bacterial systems is considered as the key factor influencing the wastewater treatment efficiency. In the present study, we have proposed a novel approach which uses static magnetic field to enhance algal growth and oxygen production rate with low operational cost and non-toxic secondary pollution. The performance of oxygen production with the magnetic field was evaluated using Scenedesmus obliquus grown in municipal wastewater and was calculated based on the change in dissolved oxygen concentration. Results indicated that magnetic treatment stimulates both algal growth and oxygen production. Application of 1000 GS of magnetic field once at logarithmic growth phase for 0.5 h increased the chlorophyll-a content by 11.5% over the control after 6 days of growth. In addition, magnetization enhanced the oxygen production rate by 24.6% over the control. Results of the study confirmed that application of a proper magnetic field could reduce the energy consumption required for aeration during the degradation of organic matter in municipal wastewater in algal-bacterial symbiotic systems. PMID- 26253866 TI - The CO2 Storage Capacity of the Intercalated Diaminoalkane Graphene Oxides: A Combination of Experimental and Simulation Studies. AB - To study the effect of interlayer spacing of pillared graphene oxides (GOs) on CO2 uptake, we have obtained CO2 isotherms with respect to the interlayer distance of pillared graphene oxide by both experimental and simulation methods. Interlayer distances of GO were modulated by intercalation of three kinds of diaminoalkanes with a different number of carbon atoms (NH2(CH2) n NH2, n = 4, 8, and 12) as pillars. The intercalated GOs (IGOs) and their reduced products (RIGOs) are characterized using a variety of approaches such as X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), and N2 adsorption. Gas adsorption performance shows that the CO2 uptake of IGOs and RIGOs decrease with the increase of the interlayer distance at low pressure, while at high pressure, the adsorption capacity of IGO-12 has a larger growth than those of both IGO-4 and IGO-8 and surpasses them at 30 bar. The contribution of the electrostatics to CO2 adsorption is larger than that of van der Waals force at low pressures, whereas for the high pressures, the adsorption is dominated by van der Waals force. PMID- 26253867 TI - ERP and behavioral evidence of increased sensory attenuation for fear-related action outcomes. AB - Voluntary action selection entails the representation of the expected consequences of the action. Previous evidence suggests that accurate action effect prediction modulates both ERP and behavioral markers of sensory processing a phenomenon know as sensory attenuation. This may play an important role in monitoring the success or failure of our actions, or attributing agency. Nonetheless, the vast majority of studies in this domain focus on simplistic visual and auditory stimuli. Given that we rarely perform voluntary actions with the aim of generating such stimuli in social contexts, this provides little indication of the extent to which sensory attenuation operates in everyday behavior. The present study investigated ERP and behavioral measures of sensory attenuation for fearful and neutral facial expressions. Participants were trained to associate one voluntary action with the presentation of a fearful face, and another action with a neutral face. We measured both ERP responses and behavioral ratings following presentation of faces whose emotional content was either consistent or inconsistent with the action prediction. We observed significant modulation for fearful outcomes only, suggesting that sensory attenuation is heightened to stimuli of high social relevance. The N170 response was significantly attenuated for congruent fearful faces, but not for congruent neutral faces (in comparison to incongruent faces). Similarly, behavioral ratings were modulated only for fearful faces but not neutral faces. This provides new insight into how social and affective outcomes modulate sensory attenuation and may have implications for implicit sense of agency for socially relevant stimuli. PMID- 26253868 TI - Altered cardiorespiratory coupling in young male adults with excessive online gaming. AB - INTRODUCTION: This study aimed to investigate changes in heart rate variability and cardiorespiratory coupling in male college students with problematic Internet use (PIU) excessive gaming type during action video game play to assess the relationship between PIU tendency and central autonomic regulation. METHOD: Electrocardiograms and respiration were simultaneously recorded from 22 male participants with excessive online gaming and 22 controls during action video game play. Sample entropy (SampEn) was computed to assess autonomic regularity, and cross-SampEn was calculated to quantify autonomic coordination. RESULTS: During video game play, reduced cardiorespiratory coupling (CRC) was observed in individuals with PIU excessive gaming type compared with controls, implicating central autonomic dysregulation. The PIU tendency was associated with the severity of autonomic dysregulation. CONCLUSION: These findings indicate impaired CRC in PIU excessive gaming type, which may reflect alterations of central inhibitory control over autonomic responses to pleasurable online stimuli. PMID- 26253869 TI - Randomized Phase II Study of Adjuvant Chemotherapy with Long-term S-1 versus Cisplatin+S-1 in Completely Resected Stage II-IIIA Non-Small Cell Lung Cancer. AB - PURPOSE: The aims of this study were to evaluate the efficacy and safety of S-1 versus cisplatin (CDDP)+S-1 in patients with completely resected stage II and IIIA non-small cell lung cancer, and to identify predictive biomarkers whose expression in the tumors was significantly associated with patient outcome. EXPERIMENTAL DESIGN: A total of 200 patients were randomly assigned to receive either S-1 (40 mg/m(2) twice per day) for 2 consecutive weeks repeated every 3 weeks for 1 year (S group) or CDDP (60 mg/m(2)) on day 1 plus oral S-1 (40 mg/m(2) twice per day) for 2 consecutive weeks repeated every 3 weeks for four cycles (CS group) within 8 weeks after surgery. The primary endpoints were relapse-free survival (RFS) at 2 years and identification of predictive biomarkers whose expressions have been reported to be associated with CDDP or fluoropyrimidine sensitivity. RESULTS: The RFS rate at 2 years was 65.6% (95% confidence intervals; CI, 55.3-74.0%) in the S group and 58.1% (95% CI, 47.7 67.2%) in the CS group. The only gene with interaction of P < 0.05 was uridine monophosphate synthase (UMPS; P = 0.0348). The benefit that members of the S group had over members of the CS group was higher expression of UMPS. In vitro and in vivo experiments confirmed that overexpression of UMPS enhanced the antitumor effect of fluoropyrimidine. CONCLUSIONS: Adjuvant S-1 monotherapy might be preferable to CDDP+S-1 for patients with completely resected NSCLC. UMPS expression may define a patient subset that would benefit from long-term postoperative S-1 monotherapy. PMID- 26253871 TI - Glucose metabolism after pediatric cardiac surgery: Too many sweets will ruin your appetite. PMID- 26253870 TI - CD73 Expression Is an Independent Prognostic Factor in Prostate Cancer. AB - PURPOSE: CD73 is an adenosine-generating ecto-enzyme that suppresses antitumor immunity in mouse models of cancer, including prostate cancer. Although high levels of CD73 are associated with poor prognosis in various types of cancer, the clinical impact of CD73 in prostate cancer remains unclear. EXPERIMENTAL DESIGN: We evaluated the prognostic value of CD73 protein expression and CD8(+) cell density in 285 cases of prostate cancer on tissue microarray (TMA). Normal adjacent and tumor tissues were evaluated in duplicates. RESULTS: Univariate and multivariate analyses revealed that high levels of CD73 in normal adjacent prostate epithelium were significantly associated with shorter biochemical recurrence (BCR)-free survival. Notably, CD73 expression in normal epithelium conferred a negative prognostic value to prostate-infiltrating CD8(+) cells. Surprisingly, high levels of CD73 in the tumor stroma were associated with longer BCR-free survival in univariate analysis. In vitro studies revealed that adenosine signaling inhibited NF-kappaB activity in human prostate cancer cells via A2B adenosine receptors. Consistent with these results, CD73 expression in the prostate tumor stroma negatively correlated with p65 expression in the nuclei of prostate tumor cells. CONCLUSIONS: Our study revealed that CD73 is an independent prognostic factor in prostate cancer. Our data support a model in which CD73 expression in the prostate epithelium suppresses immunosurveillance by CD8(+) T cells, whereas CD73 expression in the tumor stroma reduces NF-kappaB signaling in tumor cells via A2B adenosine receptor signaling. CD73 expression, including in normal adjacent prostate epithelium, can thus effectively discriminate between aggressive and indolent forms of prostate cancer. PMID- 26253872 TI - A stitch (or scan) in time saves nine. PMID- 26253873 TI - Use (and misuse) of instrumental variables. PMID- 26253874 TI - Amiodarone after surgical ablation for atrial fibrillation: Is it really necessary? A prospective randomized controlled trial. AB - OBJECTIVE: Prophylactic antiarrhythmic drug (AAD) treatment is a well-established practice after catheter ablation for atrial fibrillation (AF), but it is controversial after surgical ablation. This prospective randomized controlled trial examined whether amiodarone after surgical ablation reduced atrial arrhythmia recurrence within the first 3 months after surgery. METHODS: Ninety patients were randomized to receive (n = 45) or not receive (n = 45) amiodarone after surgical ablation. Rhythm status was ascertained via clinical follow-up and 72-hour continuous monitoring at 6 and 12 weeks, using Heart Rhythm Society guidelines. Primary outcome was defined as atrial arrhythmia recurrence, cardioversion, ablation, or crossover from no-amiodarone to amiodarone as a result of atrial arrhythmia during follow-up. An intention-to-treat approach was used. RESULTS: The 2 study groups were similar in traditional predictors for failure, including left atrium size (5.0 vs 5.1 cm, P = .734), median AF duration (23 vs 20 months, P = .513), and long-standing persistent AF (44% vs 33%, P = .280). The primary outcome occurred in 52% of the no-amiodarone group (23 of 44) and 19% of the amiodarone group (8 of 43; P = .001). Cumulative freedom from primary outcome was greater in the amiodarone group (81.4% vs 47.7%, P < .001). Amiodarone was discontinued in 18 patients randomized to amiodarone for side effects, bradycardia, or noncompliance. CONCLUSIONS: Prophylactic amiodarone reduced early atrial arrhythmia recurrence. These results are consistent with catheter AF ablation findings and should inform recommendations for prophylactic class I/III AAD after surgical AF ablation, regardless of discharge rhythm status. As previously recommended, monitoring for side effects and amiodarone discontinuation by 3 months, for patients in sinus rhythm, is warranted. CLINICAL TRIAL REGISTRATION: NCT01416935. PMID- 26253876 TI - Repair of type III common arterial trunk with modified Barbero-Marcial technique. PMID- 26253875 TI - Effect of pulmonary vascular resistance before left ventricular assist device implantation on short- and long-term post-transplant survival. AB - OBJECTIVES: Pulmonary hypertension is often considered a contraindication to orthotopic heart transplantation. Left ventricular assist device support may improve pulmonary hypertension by unloading the left ventricle, making patients eligible for transplantation. We sought to investigate the effect of continuous flow left ventricular assist device support on pulmonary hypertension and compare post-transplantation outcomes in patients with preexisting pulmonary hypertension. METHODS: Between March 2004 and December 2013, 256 potential orthotopic heart transplantation candidates underwent continuous-flow left ventricular assist device implantation at Columbia University. Preimplantation right heart catheterization data were available for 227 patients. Patients were divided into 2 groups on the basis of preimplantation pulmonary vascular resistance: low (<5 Wood units) (n = 182) and high (>=5 Wood units) (n = 45). Postimplantation and post-transplantation outcomes were compared between the groups. RESULTS: Pulmonary vascular resistance in the high resistance group decreased significantly during left ventricular assist device support (P < .001). Post-transplantation in-hospital mortality was significantly higher in patients with high vascular resistance (P < .05). However, 3-year survival after transplantation was similar between groups (85.0% and 79.0% for low and high vascular resistance, respectively; P = .45). CONCLUSIONS: Continuous-flow left ventricular assist device therapy reduced pulmonary vascular resistance. Subsequent orthotopic heart transplantation in patients with significantly elevated pulmonary vascular resistance resulted in higher in-hospital mortality but similar 3-year survival. PMID- 26253877 TI - Incremental extension of a paradigm shift. PMID- 26253878 TI - Discussion. PMID- 26253879 TI - Hybrid versus Norwood: "Fifty shades of grey". PMID- 26253880 TI - Evidence of the Primary Afferent Tracts Undergoing Neurodegeneration in Horses With Equine Degenerative Myeloencephalopathy Based on Calretinin Immunohistochemical Localization. AB - Equine degenerative myeloencephalopathy (EDM) is characterized by a symmetric general proprioceptive ataxia in young horses, and is likely underdiagnosed for 2 reasons: first, clinical signs overlap those of cervical vertebral compressive myelopathy; second, histologic lesions--including axonal spheroids in specific tracts of the somatosensory and motor systems--may be subtle. The purpose of this study was (1) to utilize immunohistochemical (IHC) markers to trace axons in the spinocuneocerebellar, dorsal column-medial lemniscal, and dorsospinocerebellar tracts in healthy horses and (2) to determine the IHC staining characteristics of the neurons and degenerated axons along the somatosensory tracts in EDM-affected horses. Examination of brain, spinal cord, and nerves was performed on 2 age matched control horses, 3 EDM-affected horses, and 2 age-matched disease-control horses via IHC for calbindin, vesicular glutamate transporter 2, parvalbumin, calretinin, glutamic acid decarboxylase, and glial fibrillary acidic protein. Primary afferent axons of the spinocuneocerebellar, dorsal column-medial lemniscal, and dorsospinocerebellar tracts were successfully traced with calretinin. Calretinin-positive cell bodies were identified in a subset of neurons in the dorsal root ganglia, suggesting that calretinin IHC could be used to trace axonal projections from these cell bodies. Calretinin-immunoreactive spheroids were present in EDM-affected horses within the nuclei cuneatus medialis, cuneatus lateralis, and thoracicus. Neurons within those nuclei were calretinin negative. Cell bodies of degenerated axons in EDM-affected horses are likely located in the dorsal root ganglia. These findings support the role of sensory axonal degeneration in the pathogenesis of EDM and provide a method to highlight tracts with axonal spheroids to aid in the diagnosis of this neurodegenerative disease. PMID- 26253881 TI - Nasal Cavity Masses Resembling Chondro-osseous Respiratory Epithelial Adenomatoid Hamartomas in 3 Dogs. AB - Chondro-osseous respiratory epithelial adenomatoid hamartomas (COREAHs) are rare tumors in the nasal cavity of people, which have not been described in other species. COREAHs in people are minimally invasive and rarely recur following excision. Histologically, these tumors are composed of disorganized, mature, nasal turbinate tissue that is organized into polypoid growths. These growths are lined by respiratory epithelium, contain glandular elements, and are organized around central cores of chondro-osseous matrix. This report describes 3 cases of dogs with nasal tumors that have histomorphology similar to that of COREAH in people. The tumors were all identified within the nasal cavity and were associated with regional bony lysis of the turbinates and surrounding skull bones, a feature that has not been reported in COREAH in people. There was no evidence of metastasis or extension beyond the nasal cavity in any of the 3 cases. PMID- 26253882 TI - MicroRNA regulation of allergic inflammation and asthma. AB - Allergic diseases are prevalent and clinically heterogeneous, and are the pathologic consequence of inappropriate or exaggerated type 2 immune responses. In this review, we explore the role of microRNAs (miRNAs) in regulating allergic inflammation. We discuss how miRNAs, acting through target genes to modulate gene expression networks, impact multiple facets of immune cell function critical for type 2 immune responses including cell survival, proliferation, differentiation, and effector functions. Human and mouse studies indicate that miRNAs are significant regulators of allergic immune responses. Finally, investigations of extracellular miRNAs offer promise for noninvasive biomarkers and therapeutic strategies for allergy and asthma. PMID- 26253883 TI - Impact of age on the clinical outcomes of major trauma. AB - PURPOSE: In view of demographic changes over the past few decades, the average age of trauma patients is progressively increasing. We therefore aimed to summarize the specific characteristics of geriatric trauma and to identify potential fields for further research to improve the care of elderly trauma patients. METHODS: Review of the literature. RESULTS: Due to the diverse risk factors (e.g., pre-existing conditions, limited physiological reserve), geriatric patients are prone to developing severe complications, even after less severe trauma. Yet, age is not considered as the only predictor of worse outcomes, and it should not be considered the only criterion for limiting care in those patients. It is crucial that age-specific treatment guidelines are developed to optimize the outcomes for senior trauma patients. Based on the current literature, these guidelines should emphasize the importance of field triage directly to a trauma center, along with the activation of the trauma team. Furthermore, early intensive monitoring, aggressive resuscitation, and time of surgical intervention are of upmost importance to reduce mortality. CONCLUSION: The impact of several factors [age, premedical conditions (PMC), decreased physiological reserves, and impaired immune function] on the post-traumatic course of elderly trauma patients needs to be clarified in future experimental and clinical studies for the early identification of geriatric high-risk patients and for the development of age-adapted therapeutic strategies. PMID- 26253884 TI - Posterior malleolar fractures of the ankle. AB - Despite an increasing awareness of injuries to PM in ankle fracture-dislocations, there are still many open questions. The mere presence of a posterior fragment leads to significantly poorer outcomes. Adequate diagnosis, classification and treatment require preoperative CT examination, preferably with 3D reconstructions. The indication for surgical treatment is made individually on the basis of comprehensive assessment of the three-dimensional outline of the PM fracture and all associated injuries to the ankle including syndesmotic instability. Anatomic fixation of the avulsed posterior tibiofibular ligament will contribute to syndesmotic stability and restore the integrity of the incisura tibiae thus facilitating anatomic reduction of the distal fibula. A necessary prerequisite is mastering of posterolateral and posteromedial approaches and the technique of direct reduction and internal fixation. Further clinical studies with higher numbers of patients treated by similar methods and evaluation of pre- and postoperative CT scans will be necessary to determine reliable prognostic factors associated with certain types of PM fractures and associated injuries to the ankle. PMID- 26253885 TI - Insulin-dependent diabetes and serious trauma. AB - PURPOSE: Trauma patients with diabetes mellitus (DM) represent a unique population as the acute injury and the underlying disease may both cause hyperglycemia that leads to poor outcomes. We investigated how insulin-dependent DM (IDDM) and noninsulin-dependent DM (NIDDM) impact mortality after serious trauma without brain injury. METHODS: The National Trauma Data Bank (NTDB) version 7.0 was queried for all patients with moderate to severe traumatic injury [injury severity score (ISS) >9]. Patients were excluded if missing data, age <10 years, severe brain injury [head abbreviated injury scale (AIS) >3], dead on arrival or any AIS = 6. Logistic regression modeled the association between DM and mortality as well as IDDM, NIDDM and mortality. RESULTS: Overall 166,103 trauma patients without brain injury were analyzed. Mortality was 7.6 and 4.4 % in patients with and without DM, respectively (p < 0.01). Mortality was 9.9 % for patients with IDDM and 6.7 % for NIDDM (p < 0.01). The increased mortality associated with DM was only significantly higher for DM patients in their forties (5.6 vs. 3.3 %, p < 0.01). Regression analyses demonstrated that DM (AOR 1.14, p = 0.04) and IDDM (AOR 1.46, p < 0.01) were predictors of mortality compared to no DM, but NIDDM was not (AOR 1.02, p = 0.83). CONCLUSIONS: While DM was a predictor for higher mortality after serious trauma, this increase was only observed in IDDM and not NIDDM. Our findings suggest IDDM patients who present after serious trauma are unique and attention to their hyperglycemia and related insulin therapy may play a critical role in recovery. PMID- 26253886 TI - Hyperbilirubinemia as a predictive factor in acute appendicitis. AB - PURPOSE: Our aim was to establish the role of hyperbilirubinemia as a predictive parameter for the prediction of either acute, or gangrenous/perforated appendicitis as well as to compare other parameters in a similar role. METHODS: Medical files of the patients who underwent appendectomies between September 2013 and September 2014 were evaluated. Age, gender, preoperative white blood cell count (WBC), neutrophil count (NEU), neutrophil percentage (NEU%), C-reactive protein (CRP), total/direct/indirect bilirubin levels, and the postoperative histopathological findings were recorded. The Fisher's exact, Pearson's chi (2), ANOVA, and Kruskal-Wallis tests while logistic regression for multivariate analysis was performed. p < 0.05 was accepted as statistically significant. RESULTS: The study group of 162 patients consisted of 97 (60 %) men and 65 (40 %) women with a median age of 36 (18-90). Histopathological examinations revealed normal appendix in 21 (13 %) patients, non-complicated acute appendicitis in 100 (62 %), and appendiceal gangrene/perforation in 41 (25 %) patients. WBC, NEU, NEU%, and CRP levels were significantly higher in cases of acute and gangrenous/perforated appendicitis (p < 0.01). Total and direct bilirubin levels were also significantly elevated in patients with acute and gangrenous/perforated appendicitis (p < 0.01). According to multivariate analysis, elevated CRP levels were associated with 14 times, elevated total bilirubin levels were associated with five times, and elevated direct bilirubin levels were associated with 36 times greater risk for appendiceal gangrene/perforation (p < 0.01, p < 0.05, p < 0.01, respectively). CONCLUSIONS: Hyperbilirubinemia, especially with elevated direct bilirubin levels, may be considered as an important marker for the prediction of appendiceal gangrene/perforation. PMID- 26253887 TI - The role of pharmacological steroid therapy in preservation of renal function in severely injured patients requiring massive transfusion. AB - PURPOSE: Glucocorticoids (GC) attenuate the post-insult inflammatory response and have been observed to confer end-organ protection following a variety of ischemic insults. We aim to assess this benefit on renal perfusion and function in injured patients requiring massive transfusion. METHODS: The effect of pharmacologic methylprednisolone (MP) therapy was studied in 118 patients (pts), of whom 60, by random, received 1 g MP intraoperatively and 15 mg/kg for an additional 3 days. Postoperative measurements were made of effective renal plasma flow (ERPF), glomerular filtration by inulin (CIn), creatinine clearance (CCr) and clearances of osmoles (CCosm), sodium (CNa), and free water ([Formula: see text]). Continuous variables were compared between the two groups using the student's t test. RESULTS: Enrolled pts on average received 13.5 units of PRBCs with no differences in the resuscitation regimen. There were no statistically significant differences in the postoperative renal function as measured by ERPF (p = 0.57), CIn (p = 0.84), CCr (p = 0.99), CNa (p = 0.07), COsm (p = 0.95), and [Formula: see text] (p = 0.33). The incidence of renal compromise, as determined by an inulin clearance of <25 mL/min or serum creatinine greater than 3.0 mg/dL, was also similar. Three patients in the MP treatment group had renal compromise compared to one in the control group. CONCLUSIONS: In the absence of larger studies, this study demonstrates that GC likely have no role in preserving renal function in severely injured patients. PMID- 26253888 TI - Factors related to advanced colorectal neoplasm at the Policlinico Peruano Japones. AB - BACKGROUND: Identifying persons at high risk for advanced colorectal neoplasia can aid in the prevention of colon cancer. Previous studies have shown that some patients can present with proximal advanced neoplasia with no distal findings. AIMS: To determine the factors related to advanced neoplasia and advanced proximal colorectal neoplasia in a Latin American population. MATERIAL AND METHODS: A prospective, cross-sectional, observational, analytic study was conducted. It included patients that underwent colonoscopy at the Policlinico Peruano Japones within the time frame of January and July 2012. Advanced neoplasia was defined as the presence of lesions >= 10mm with a villous component, high-grade dysplasia, or carcinoma. The splenic flexure was the limit between the proximal and distal colon. RESULTS: A total of 846 patients were included in the study. Advanced neoplasia was detected in 108 patients (12.8%) and advanced proximal neoplasia in 55 patients (6.7%), 42 (76.4%) of whom had no neoplasia in the distal colon. Factors related to advanced neoplasia found in the multivariate analysis were age, at the intervals of 50-59 (p=0.019), 60-69 (p=0.016), and >= 70 years (0.002) and male sex (p=0.003). In the evaluation of advanced proximal neoplasia, the multivariate analysis identified the 60-69 year age interval (p=0.039) and advanced distal neoplasia (p=0.028) as factors related to advanced proximal disease. The ROC curve established the age cut-off point at 60 years for initially performing colonoscopy, rather than sigmoidoscopy. CONCLUSIONS: Age and sex are related to advanced neoplasia, whereas age and advanced distal neoplasia are related to advanced proximal neoplasia. PMID- 26253889 TI - Human fasciolosis diagnosed in the acute phase: A first clinical report in Mexico. PMID- 26253890 TI - Preparing Families With Children for International Travel. PMID- 26253891 TI - A "Syndromic" Approach for Diagnosing and Managing Travel-Related Infectious Diseases in Children. PMID- 26253892 TI - WITHDRAWN: Abstract. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.cppeds.2015.06.007. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26253893 TI - Discrepancy between explicit judgement of agency and implicit feeling of agency: Implications for sense of agency and its disorders. AB - The sense of agency refers to the feeling of authorship that "I am the one who is controlling external events through my own action". A distinction between explicit judgement of agency and implicit feeling of agency has been proposed theoretically. However, there has not been sufficient experimental evidence to support this distinction. We have assessed separate explicit and implicit agency measures in the same population and investigated their relationships. Intentional binding task was employed as an implicit measure and self-other attribution task as an explicit measure, which are known to reflect clinical symptoms of disorders in the sense of agency. The results of the implicit measure and explicit measure were not correlated, suggesting dissociation of the explicit judgement of agency and the implicit feeling of agency. PMID- 26253894 TI - Operational, design and microbial aspects related to power production with microbial fuel cells implemented in constructed wetlands. AB - This work aimed at determining the amount of energy that can be harvested by implementing microbial fuel cells (MFC) in horizontal subsurface constructed wetlands (HSSF CWs) during the treatment of real domestic wastewater. To this aim, MFC were implemented in a pilot plant based on two HSSF CW, one fed with primary settled wastewater (Settler line) and the other fed with the effluent of a hydrolytic up-flow sludge blanket reactor (HUSB line). The eubacterial and archaeal community was profiled on wetland gravel, MFC electrodes and primary treated wastewater by means of 16S rRNA gene-based 454-pyrosequencing and qPCR of 16S rRNA and mcrA genes. Maximum current (219 mA/m(2)) and power (36 mW/m(2)) densities were obtained for the HUSB line. Power production pattern correlated well with water level fluctuations within the wetlands, whereas the type of primary treatment implemented had a significant impact on the diversity and relative abundance of eubacteria communities colonizing MFC. It is worth noticing the high predominance (13-16% of relative abundance) of one OTU belonging to Geobacter on active MFC of the HUSB line that was absent for the settler line MFC. Hence, MFC show promise for power production in constructed wetlands receiving the effluent of a HUSB reactor. PMID- 26253895 TI - Dewaterability of five sewage sludges in Guangzhou conditioned with Fenton's reagent/lime and pilot-scale experiments using ultrahigh pressure filtration system. AB - Sludge conditioning with Fenton's reagent and lime is a valid method for sludge dewatering. This study investigated the influence of different organic matter content sludge on sludge dewatering and discussed the main mechanism of sludge conditioning by combined Fenton's reagent and lime. The results indicated that the specific resistance to filterability (SRF) of sludge was reduced efficiently by approximately 90%, when conditioned with Fenton's reagent and lime. Through single factor experiments, the optimal conditioning combinations were found. In addition, the relationship between VSS% and consumption of the reagents was detected. Furthermore, it was also demonstrated that the SRF and filtrate TOC values had a significant correlation with VSS% of sludge (including raw and conditioned). The main mechanism of sludge dewatering was also investigated. Firstly, it revealed that the dewaterability of sludge was closely correlated to extracellular polymeric substances (EPS) and bound water contents. Secondly, the results of scanning electron microscopy (SEM) stated that sludge particles were to be smaller and thinner after conditioning. And this structure could easily form outflow channels for releasing free water. Additionally, with the ultrahigh pressure filtration system, the water content of sludge cake conditioned with Fenton's reagent and lime could be reduced to below 50%. Moreover, the economic assessment shows that Fenton's reagent and lime combined with ultrahigh pressure filtration system can be an economical and viable technology for sewage sludge dewatering. Finally, three types of sludge were classified: (1) Fast to dewater; (2) Moderately fast to dewater; (3) Slow to dewater sludge. PMID- 26253896 TI - Development and validation of a novel modeling framework integrating ion exchange and resin regeneration for water treatment. AB - Models have been developed to simulate the process of ion exchange for water treatment. However the modeling of resin regeneration process, which can predict regeneration efficiency and residual stream for determining technology sustainability, was not incorporated into previous models. Therefore a model integrating both ion exchange and resin regeneration considering regeneration efficiency is needed for evaluating and improving ion exchange technology. This study developed an integrated model aiming to simulate ion exchange and resin regeneration in different configurations (fixed bed, fluidized bed) for the first time. The integrated model has been validated via comparing model predictions with experimental data. The impacts of dimensionless groups (i.e. the Peclet number, the diffusion modulus, and the Biot number) on ion exchange breakthrough curve have been analyzed using this model. In addition, this integrated model has been used to optimize the regeneration frequency to improve the overall performance of ion exchange. It demonstrated this integrated model could be a useful tool for further studies in ion exchange technology. PMID- 26253897 TI - Enhanced anaerobic digestion of food waste by trace metal elements supplementation and reduced metals dosage by green chelating agent [S, S]-EDDS via improving metals bioavailability. AB - This study aimed at investigating the effects of trace metals on methane production from food waste and examining the feasibility of reducing metals dosage by ethylenediamine-N,N'-disuccinic acid (EDDS) via improving metals bioavailability. The results indicated that the effects of metal elements highly depended on the supplemental concentrations. Trace metals supplemented under moderate concentrations greatly enhanced the methane yield. However, the excessive supplementation of Fe (1000 mg/L) and Ni (50 mg/L) exhibited the obvious toxicity to methanogens. The combinations of trace metals exhibited remarkable synergistic effects. The supplementation of Fe (100 mg/L) + Co (1 mg/L) + Mo (5 mg/L) + Ni (5 mg/L) obtained the greatest methane yield of 504 mL/g VSadded and the highest increment of 35.5% compared to the reactor without metals supplementation (372 mL/g VSadded). The changes of metals speciation showed the reduction of metals bioavailability during anaerobic digestion, which might weaken the stimulative effects of trace metals. However, the addition of EDDS improved metals bioavailability for microbial uptake and stimulated the activity of methanogens, and therefore, strengthened the stimulative effects of metals on anaerobic digestion of food waste. The batch and semi-continuous experiments confirmed that the addition of EDDS (20 mg/L) bonded to trace metals prior to their supplementation could obtain a 50% reduction of optimal metals dosage. This study provided a feasible method to reduce trace metals dosage without the degeneration of process performance of anaerobic digestion. PMID- 26253898 TI - Anti-oxidative and anti-apoptotic roles of spermatogonial stem cells in reversing cisplatin-induced testicular toxicity. AB - BACKGROUND AIMS: Because of reproductive toxic effects of chemotherapy, researchers have taken some techniques to preserve fertility potential. The present study was designed to point out the potential role of spermatogonial stem cell (SSC) therapy in reversing cisplatin (CP)-induced testicular toxicity and restore the spermatogenesis. METHODS: Sixty rats were randomly divided into three groups: group 1, control group; group 2, rats received CP in a dose of 7 mg/kg/day for 5 consecutive days; group 3, CP was injected at 7 mg/kg per day for 5 consecutive days, and, on the 6th day of the experiment, rats were treated with SSC. Forty days after receiving the last dose of CP, rats were euthanized under anesthesia; testes were collected, and gene expression using real-time polymerase chain reaction for P53, Bax, caspase 9 and cytochrome c, testicular histological findings and oxidative status were determined. RESULTS: Administration of cisplatin caused significant increases in malondialdehyde levels, Bax and caspase 9 genes expression levels concomitant with significant decreases in anti-oxidant enzyme activities, p53 and cytochrome c gene expression levels, along with some histopathological lesions in testicular tissue. SCC attenuated the disturbance in oxidant/anti-oxidant status and testicular apoptosis; this is associated with improvements in the histopathological view of the testicular tissue. CONCLUSIONS: The current study highlights evidence that the SCC has anti-oxidative and anti apoptotic properties that could reverse CP-induced testicular toxicity, in addition to their role in spermatogenesis. PMID- 26253899 TI - Genetic markers of cholesterol transport and gray matter diffusion: a preliminary study of the CETP I405V polymorphism. AB - Variations of the cholesteryl ester transfer protein polymorphism (CETP I405V/rs5882) have been associated with an increased risk for neurodegeneration, particularly when examined in conjunction with the epsilon 4 isoform of apolipoprotein E (ApoE4). Despite these identified relationships, the impact of I405V on gray matter microstructure remains unknown. The present study examined the impact of the CETP I405V polymorphism on gray matter integrity among 52 healthy adults between ages 51 and 85. Gray matter was measured bilaterally using diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Participants were grouped according to a dominant statistical model (II genotype vs. IV/VV genotypes) and secondary analyses were completed to examine the interactive effects of CETP and ApoE4 on DTI metrics. Compared to individuals with the IV/VV genotypes, II homozygotes demonstrated significantly higher MD in bilateral temporal, parietal, and occipital gray matter. Secondary analyses revealed higher FA and AD in the left temporal lobe of IV/VV genotypes with an ApoE4 allele. Our results provide preliminary evidence that CETP II homozygosity is a predisposing risk factor for gray matter abnormalities in posterior brain regions in healthy older adults, independent of an ApoE4 allele. PMID- 26253900 TI - G2019S LRRK2 and aging confer susceptibility to proteasome inhibitor-induced neurotoxicity in nigrostriatal dopaminergic system. AB - The leucine-rich repeat kinase 2 (LRRK2) mutation G2019S is one of the most common genetic causes in Parkinson's disease (PD). The penetrance of G2019S LRRK2 is incomplete and is age-dependent, therefore, it has been speculated that environmental toxins and aging could contribute to G2019S LRRK2-related PD pathogenesis. To prove this speculation, we performed a longitudinal investigation in mice bearing G2019S LRRK2 mutation. BAC G2019S LRRK2 transgenic (Tg) mice and their wildtype (Wt) littermates were treated with lactacystin, a specific proteasome inhibitor. The susceptibilities of mice to lactacystin induced nigrostriatal dopaminergic (DAergic) degeneration were evaluated, at 5 and 12 months of age. We found that lactacystin treatment caused a greater decline of striatal DA content in the Tg mice at either 5 or 12 months of age than their age-matched Wt littermates. Moreover, the lactacystin-treated Tg or Wt mice at 12 months of age lose much more nigral tyrosine hydroxylase (TH)-positive neurons than the mice at 5 months of age, indicating an age-associated DAergic neurotoxicity. Additionally, stereotactic injection of lactacystin induced a dramatic increase of activated microglia in substantia nigra of mice at 12 months of age, compared with mice at 5 months of age. In summary, our study suggests that expression of the G2019S mutation in the mouse LRRK2 gene confers an age associated high susceptibility to proteasome inhibition-induced nigrostriatal DAergic degeneration. PMID- 26253902 TI - Contagion from peer suicidal behavior in a representative sample of American adolescents. AB - BACKGROUND: Assortative relating is a proposed explanation for the increased occurrence of suicidal behavior among those exposed to suicidal peers. This explanation proposes that high-risk individuals associate with each other, and shared risk factors explain the effect. METHODS: Data were obtained from the ADDhealth longitudinal survey waves I and II (n=4834 school attending adolescents). People who reported peer suicidal behavior in the first wave were identified and classified as the exposure group. Potentially confounding variables were identified, and propensity scores were calculated for the exposure variable using logistic regression. Inverse-probability-of-treatment weighted regression estimated the effect of exposure on the risk for a suicide attempt during the first two waves. RESULTS: Weighted analysis showed that the group exposed to a friend's suicide attempt had a higher occurrence of suicide attempts in both waves. Exposure to peer suicide attempts was associated with increased suicide attempts at baseline (RR=1.93; 95%CI= 1.23-3.04) and 1-year follow-up (RR=1.70; 95%CI= 1.12-2.60). LIMITATION: Only two consecutive years of data are provided. Misclassification and recall bias are possible due to the use of self report. The outcome may be misclassified due to respondent misunderstanding of what constitutes a suicide attempts, versus non-suicidal self-injury. Non response and trimming reduced the sample size significantly. CONCLUSIONS: Assortative relating did not account for all the variance and is currently not sufficient to explain the increased risk after exposure to peer suicidal behavior. Clinicians should assess for exposure to suicidal behaviors in their patients. PMID- 26253901 TI - Wearable sensor-based objective assessment of motor symptoms in Parkinson's disease. AB - Effective management and development of new treatment strategies of motor symptoms in Parkinson's disease (PD) largely depend on clinical rating instruments like the Unified PD rating scale (UPDRS) and the modified abnormal involuntary movement scale (mAIMS). Regarding inter-rater variability and continuous monitoring, clinical rating scales have various limitations. Patient administered questionnaires such as the PD home diary to assess motor stages and fluctuations in late-stage PD are frequently used in clinical routine and as clinical trial endpoints, but diary/questionnaire are tiring, and recall bias impacts on data quality, particularly in patients with cognitive dysfunction or depression. Consequently, there is a strong need for continuous and objective monitoring of motor symptoms in PD for improving therapeutic regimen and for usage in clinical trials. Recent advances in battery technology, movement sensors such as gyroscopes, accelerometers and information technology boosted the field of objective measurement of movement in everyday life and medicine using wearable sensors allowing continuous (long-term) monitoring. This systematic review summarizes the current wearable sensor-based devices to objectively assess the various motor symptoms of PD. PMID- 26253903 TI - Affective temperaments and concomitant alcohol use disorders in bipolar disorder. AB - BACKGROUND: Alcohol misuse (AM) is more common in bipolar disorder (BD) than within the general population but the mechanisms of this association are unclear. We hypothesized that certain affective temperaments (including hyperthymic, cyclothymic, anxious, depressive and/or irritability) might represent 'fundamental states' contributing to risk of both AM and BD and we aimed to assess whether extremes of these five affective temperaments were associated with BD and concomitant AM status. METHODS: Our sample comprised 1420 individuals with BD who were recruited into a clinical-genetic study conducted by the Bipolar Disorder Research Network. Phenotypic assessments, including evaluation for AM and the 32-item TEMPS-A questionnaire, were conducted. Binary logistic regression was used to determine the effect of TEMPS-A scores on the likelihood of concomitant AM, with adjustment for confounders. RESULTS: Mean scores for four affective temperaments (hyperthymic, cyclothymic, depressive and irritable) were higher in cases (BD+AMs) than controls (BD only) (p<0.001). Hyperthymic and irritable temperaments in particular significantly increased the odds of concomitant AM within the BD sample after adjustment for potential confounders. LIMITATIONS: The definition of AM was not directly based on formal diagnostic classification systems. A retrospective, cross-sectional design was used. Our findings may not generalize to other countries and cultures. CONCLUSIONS: Higher scores on measures of hyperthymic and irritable temperament may contribute to the association between AM and BD. Assessing affective temperaments early in the course of BD may help to predict the development of an AM problem in vulnerable individuals. PMID- 26253904 TI - Risk factors for suicide attempt among Israeli Defense Forces soldiers: A retrospective case-control study. AB - BACKGROUND: A major risk factor for suicide is suicide attempts. The aim of the present study was to assess risk factors for nonfatal suicide attempts. Methods The study's cohort consisted of 246,814 soldiers who were divided into two groups: soldiers who made a suicide attempt (n=2310; 0.9%) and a control group of soldiers who did not (n=244,504; 99.1%). Socio-demographic and personal characteristics as well as psychiatric diagnoses were compared. Results The strongest risk factors for suicide attempt were serving less than 12 months (RR=7.09) and a history of unauthorized absence from service (RR=5.68). Moderate risk factors were low socioeconomic status (RR=2.17), psychiatric diagnoses at induction (RR=1.94), non-Jewish religion (RR=1.92), low intellectual rating score (RR=1.84), serving in non-combat unit (RR=1.72) and being born in the former Soviet Union (RR=1.61). A weak association was found between male gender and suicide attempt (RR=1.36). Soldiers who met more frequently with a primary care physician (PCP) had a higher risk for suicide attempt, as opposed to a mental health professional (MHCP), where frequent meetings were found to be a protective factor (P<0.0001). The psychiatric diagnoses associated with a suicide attempt were a cluster B personality disorder (RR=3.00), eating disorders (RR=2.78), mood disorders (RR=2.71) and adjustment disorders (RR=2.26). LIMITATIONS: Mild suicidal behavior constitutes a much larger proportion than among civilians and may have secondary gain thus distorting the suicidal behavior data. CONCLUSIONS: Training primary care physicians as gatekeepers and improved monitoring, may reduce the rate of suicide attempts. PMID- 26253905 TI - Is bipolar disorder associated with accelerating aging? A meta-analysis of telomere length studies. AB - BACKGROUND: Bipolar disorder (BD) is associated with a reduced life expectancy compared to the general population mainly due to a high prevalence of comorbid somatic illnesses. A model of accelerated aging has been proposed as a potential explanation to these epidemiological findings. Nevertheless, studies measuring telomere length (TL) in patients with BD compared to healthy controls have provided mixed results. OBJECTIVE: To compare TL between BD patients and healthy controls, and to search for potential modeP .05, all). CONCLUSIONS: The rate of olfactory decline increases with age and is greater among men than women despite adjusting for differences in psychosocial and health conditions, indicating physiologic factors as drivers. African Americans are more likely to experience initial olfactory decline, consistent with an earlier onset of aging among this subgroup. PMID- 26253910 TI - Activation of glycerol metabolic pathway by evolutionary engineering of Rhizopus oryzae to strengthen the fumaric acid biosynthesis from crude glycerol. AB - Rhizopus oryzae is strictly inhibited by biodiesel-based by-product crude glycerol, which results in low fumaric acid production. In this study, evolutionary engineering was employed to activate the glycerol utilization pathway for fumaric acid production. An evolved strain G80 was selected, which could tolerate and utilize high concentrations of crude glycerol to produce 14.9g/L fumaric acid with a yield of 0.248g/g glycerol. Key enzymes activity analysis revealed that the evolved strain displayed a significant upregulation in glycerol dissimilation, pyruvate consumption and reductive tricarboxylic acid pathways, compared with the parent strain. Subsequently, intracellular metabolic profiling analysis showed that amino acid biosynthesis, tricarboxylic acid cycle, fatty acid and stress response metabolites accounted for metabolic difference between two strains. Moreover, a glycerol fed-batch strategy was optimized to obtain the highest fumaric acid production of 25.5g/L, significantly increased by 20.9-fold than that of the parent strain of 1.2g/L. PMID- 26253911 TI - A sustainable method for effective regulation of anaerobic granular sludge: artificially increasing the concentration of signal molecules by cultivating a secreting strain. AB - This study introduces sustainable quorum sensing (QS) granulation for anaerobic granular sludge (AnGS) and investigates the efficiency of three types of signal molecules on regulating AnGS granulation. The signal molecules of a secreting strain cultured in a QS regulating reactor increased their concentrations in an expanded granular sludge bed reactor throughout the granulating process. Increasing content of autoinducer-2 (AI-2) strengthened interspecific QS communication and gave a best performance with larger granular diameters, higher extracellular polymeric substance (EPS) production and relative hydrophobicity (RH). N-butyryl-homoserine lactone (C4-HSL) QS regulation was also favorable for granular growth, but its regulation was less than that of AI-2-QS. The AnGS granulated under these two types of QS regulations guided more filamentous bacteria to take part in granulation. Under diffusible signal factor (DSF)-QS regulation, the sludge had a lower granular level with a smaller granule diameter, lower EPS production (RH) when compared that of control medium. PMID- 26253912 TI - Improved ADM1 model for anaerobic digestion process considering physico-chemical reactions. AB - The "Anaerobic Digestion Model No. 1" (ADM1) was modified in the study by improving the bio-chemical framework and integrating a more detailed physico chemical framework. Inorganic carbon and nitrogen balance terms were introduced to resolve the discrepancies in the original bio-chemical framework between the carbon and nitrogen contents in the degraders and substrates. More inorganic components and solids precipitation processes were included in the physico chemical framework of ADM1. The modified ADM1 was validated with the experimental data and used to investigate the effects of calcium ions, magnesium ions, inorganic phosphorus and inorganic nitrogen on anaerobic digestion in batch reactor. It was found that the entire anaerobic digestion process might exist an optimal initial concentration of inorganic nitrogen for methane gas production in the presence of calcium ions, magnesium ions and inorganic phosphorus. PMID- 26253913 TI - Development of a submerged anaerobic membrane bioreactor for concurrent extraction of volatile fatty acids and biohydrogen production. AB - The aim of this work was to study an externally-submerged membrane bioreactor for the cyclic extraction of volatile fatty acids (VFAs) during anaerobic fermentation, combining the advantages of submerged and external technologies for enhancing biohydrogen (BioH2) production from agrowaste. Mixing and transmembrane pressure (TMP) across a hollow fiber membrane placed in a recirculation loop coupled to a stirred tank were investigated, so that the loop did not significantly modify the hydrodynamic properties in the tank. The fouling mechanism, due to cake layer formation, was reversible. A cleaning procedure based on gas scouring and backwashing with the substrate was defined. Low TMP, 10(4)Pa, was required to achieve a 3Lh(-1)m(-2) critical flux. During fermentation, BioH2 production was shown to restart after removing VFAs with the permeate, so as to enhance simultaneously BioH2 production and the recovery of VFAs as platform molecules. PMID- 26253914 TI - Ensiling of seaweed for a seaweed biofuel industry. AB - Effective biogas production from seaweed necessitates harvest at times of peak quality of biomass and low-loss preservation for year-around supply. Ensiling of five seaweed species and storage up to 90days was investigated as a method to preserve the methane yield potential. Adequate acidification by natural lactic acid fermentation was difficult due to low rapidly fermentable carbohydrate contents, high buffering capacities and low initial numbers of lactic acid bacteria. Nevertheless, products of silage fermentation increased methane yields by up to 28% and compensated for volatile solid losses during ensiling. Preservation of the original methane yield potential was achieved for four of five seaweed species, provided that silage effluent is collected and utilised. 10 28% of the ensiled biomass was released as effluent with methane yields of 218 423LNkg(-1) VS. If further optimised, ensiling represents an effective method of preservation crucial for an efficient seaweed biofuel industry. PMID- 26253915 TI - Simultaneous production of lactobionic and gluconic acid in cheese whey/glucose co-fermentation by Pseudomonas taetrolens. AB - Substrate versatility of Pseudomonas taetrolens was evaluated for the first time in a co-fermentation system combining cheese whey and glucose, glycerol or lactose as co-substrates. Results showed that P. taetrolens displayed different production patterns depending on the co-substrate supplied. Whereas the presence of glucose led to a simultaneous co-production of lactobionic (78g/L) and gluconic acid (8.8g/L), lactose feeding stimulated the overproduction of lactobionic acid from whey with a high specific productivity (1.4g/gh) and yield (100%). Co-substrate supply of glycerol conversely led to reduced lactobionic acid yield (82%) but higher cell densities (1.8g/L), channelling the carbon source towards cell growth and maintenance. Higher carbon availability impaired the metabolic activity as well as membrane integrity, whereas lactose feeding improved the cellular functionality of P. taetrolens. Insights into these mixed carbon source strategies open up the possibility of co-producing lactobionic and gluconic acid into an integrated single-cell biorefinery. PMID- 26253916 TI - Anaerobic-ion exchange (AN-IX) process for local-scale nitrogen recovery from wastewater. AB - An anaerobic-ion exchange (AN-IX) process was developed for point-of-origin recovery of nitrogen from household wastewater. The process features upflow solids-blanket anaerobic treatment (ammonification) followed by ammonium ion exchange onto natural zeolite. The AN-IX system is configured as a series of linked upflow chambers that operate passively without energy input, and is amenable to intermittent and seasonal operation. A 57L prototype was operated for over 1.8 years treating actual wastewater under field conditions. Total nitrogen removal exceeded 96% through the first 160 days of operation and effluent ammonium nitrogen remained below detection for 300 days. Ion exchange chambers exhibited sequential NH4(+)-N breakthrough over extended operation and complete media exhaustion was approached at Day 355. The ammonium capacity of zeolite was estimated as 13.5mg NH4(+)-N per gram dry weight. AN-IX is a resilient and cost effective process for local-scale nitrogen recovery and reuse, suitable for small scale and larger systems. PMID- 26253917 TI - Accelerated hydrolysis of substituted cellulose for potential biofuel production: kinetic study and modeling. AB - In this work, kinetics of substitution accelerated cellulose hydrolysis with multiple reaction stages was investigated to lay foundation for mechanism study and molecular design of substituting compounds. High-efficiency hydrolysis of cellulose is critical for cellulose-based bioethanol production. It is known that, substitution could substantially decrease activation energy and increase reaction rate of acidic hydrolysis of glycosidic bonds in cellulose. However, reaction kinetics and mechanism of the accelerated hydrolysis were not fully revealed. In this research, it was proved that substitution therefore accelerated hydrolysis only occurred in amorphous regions of cellulose fibers, and was a process with multiple reaction stages. With molar ratio of substitution less than 1%, the overall hydrolysis rate could be increased for around 10 times. We also quantified the relationship between the hydrolysis rate of individual reaction stage and its major influences, including molar ratio of substitution, activation energy of acidic hydrolysis, pH and temperature. PMID- 26253918 TI - Optimization of bead milling parameters for the cell disruption of microalgae: process modeling and application to Porphyridium cruentum and Nannochloropsis oculata. AB - A study of cell disruption by bead milling for two microalgae, Nannochloropsis oculata and Porphyridium cruentum, was performed. Strains robustness was quantified by high-pressure disruption assays. The hydrodynamics in the bead mill grinding chamber was studied by Residence Time Distribution modeling. Operating parameters effects were analyzed and modeled in terms of stress intensities and stress number. RTD corresponded to a 2 CSTR in series model. First order kinetics cell disruption was modeled in consequence. Continuous bead milling was efficient for both strains disruption. SI-SN modeling was successfully adapted to microalgae. As predicted by high pressure assays, N. oculata was more resistant than P. cruentum. The critical stress intensity was twice more important for N. oculata than for P. cruentum. SI-SN modeling allows the determination of operating parameters minimizing energy consumption and gives a scalable approach to develop and optimize microalgal disruption by bead milling. PMID- 26253920 TI - Exocrine pancreatic insufficiency, MRI of the pancreas and serum nutritional markers in patients with coeliac disease. AB - OBJECTIVES: To determine whether exocrine pancreatic function is impaired in patients with coeliac disease (CD) in our population and to evaluate its clinical importance. METHODS: Pancreatic exocrine function was determined by measuring faecal elastase-1 (FE) concentration. CD was diagnosed by serological testing using IgA anti-tissue transglutaminase antibody (IgAtTg) and small bowel biopsy using the Marsh classification. MRI of the pancreas was performed to evaluate any morphological changes. The study took place from January 2012 to December 2013. RESULTS: 90 patients (73 women and 17 men) of mean age 43.8+/-17.7 years (range 20-80) were included in the study. Mean time from CD confirmation was 5.8+/-0.7 years (range 1-25). Exocrine pancreatic insufficiency (EPI) was diagnosed in four (4.4%) patients (one with mild EPI and three with severe EPI). MRI showed no morphological changes in any of the four patients. In all patients with EPI at least one serological nutritional marker was below the lower limit of normal. CONCLUSIONS: EPI is present in a small number of patients with CD. EPI should be excluded in all patients with CD in the presence of overt malnutrition or in cases of persistent gastrointestinal symptoms despite a gluten-free diet. Measurement of a serum nutritional panel, regardless of the presence of clinical symptoms of EPI, can be of clinical importance. MRI should be performed to exclude any morphological change in the pancreas. PMID- 26253919 TI - A network map of Interleukin-10 signaling pathway. AB - Interleukin-10 (IL-10) is an anti-inflammatory cytokine with important immunoregulatory functions. It is primarily secreted by antigen-presenting cells such as activated T-cells, monocytes, B-cells and macrophages. In biologically functional form, it exists as a homodimer that binds to tetrameric heterodimer IL 10 receptor and induces downstream signaling. IL-10 is associated with survival, proliferation and anti-apoptotic activities of various cancers such as Burkitt lymphoma, non-Hodgkins lymphoma and non-small scell lung cancer. In addition, it plays a central role in survival and persistence of intracellular pathogens such as Leishmania donovani, Mycobacterium tuberculosis and Trypanosoma cruzi inside the host. The signaling mechanisms of IL-10 cytokine are not well explored and a well annotated pathway map has been lacking. To this end, we developed a pathway resource by manually annotating the IL-10 induced signaling molecules derived from literature. The reactions were categorized under molecular associations, activation/inhibition, catalysis, transport and gene regulation. In all, 37 molecules and 76 reactions were annotated. The IL-10 signaling pathway can be freely accessed through NetPath, a resource of signal transduction pathways previously developed by our group. PMID- 26253921 TI - Development of the Biostatistics and Clinical Epidemiology Skills (BACES) assessment for medical residents. AB - BACKGROUND: Although biostatistics and clinical epidemiology are essential for comprehending medical evidence, research has shown consistently low and variable knowledge among postgraduate medical trainees. Simultaneously, there has been an increase in the complexity of statistical methods among top-tier medical journals. AIMS: To develop the Biostatics and Clinical Epidemiology Skills (BACES) assessment by (1) establishing content validity evidence of the BACES; (2) examining the model fit of the BACES items to an Item Response Theory (IRT) model; and (3) comparing IRT item estimates with those of traditional Classical Test Theory (CTT) indices. METHODS: Thirty multiple choice questions were written to focus on interpreting clinical epidemiological and statistical methods. Content validity was assessed through a four-person expert review. The instrument was administered to 150 residents across three academic medical centres in southern USA during the autumn of 2013. Data were fit to a two-parameter logistic IRT model and the item difficulty, discrimination and examinee ability values were compared with traditional CTT item statistics. RESULTS: 147 assessments were used for analysis (mean (SD) score 14.38 (3.38)). Twenty-six items, 13 devoted to statistics and 13 to clinical epidemiology, successfully fit a two-parameter logistic IRT model. These estimates also significantly correlated with their comparable CTT values. CONCLUSIONS: The strength of the BACES instrument was supported by (1) establishing content validity evidence; (2) fitting a sample of 147 residents' responses to an IRT model; and (3) correlating the IRT estimates with their CTT values, which makes it a flexible yet rigorous instrument for measuring biostatistical and clinical epidemiological knowledge. PMID- 26253922 TI - Residents' knowledge of quality improvement: the impact of using a group project curriculum. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education requires residents to learn and demonstrate proficiency in practice improvement. Quality improvement (QI) projects are a way to improve patient care as well as facilitate education on this core competency. There are inherent barriers to completing these goals in the structure of residency training including rigorous resident schedules and a limited number of projects and resources. OBJECTIVES: We developed a QI programme using an experiential class project and incorporated it into our Internal Medicine Resident Core Curriculum to improve the residents' knowledge of QI methods. We assessed the residents' experience, knowledge and interest in practice and QI subject matter with a survey preimplementation and postimplementation. METHODS: In 2009, 24 residents in the Internal Medicine resident programme completed a survey measuring their experience, knowledge and interest in QI initiatives. They then completed a QI 1-year programme, with monthly, 1-hour sessions combining didactics and a resident-designed project. At the conclusion of the year, the residents completed the same survey, and the results were compared and analysed. RESULTS: Postcurriculum questionnaires revealed residents were more knowledgeable about QI methods, showing improvement in knowledge about institutional-wide QI projects, better preparation for implementing a QI project, and more likely to participate in QI in the future. The project completed was one which improved patients' knowledge of their anticipated date of discharge from the hospital. CONCLUSIONS: A class quality project can teach QI to residents incorporating both didactic and practical methods to maximise the experience and minimise the barriers. We found that this method improved residents experience, knowledge and interest in quality initiatives. PMID- 26253923 TI - Barriers to healthcare seeking among medical students: a cross sectional study from South India. AB - OBJECTIVE: To determine the barriers to seeking help from healthcare services reported by medical students at an Indian medical school, and to compare the barriers for using physical health services with those for using mental health services. METHODS: In 2014, we invited all medical students across the nine semesters of training at a government medical college in Puducherry, India, to complete a 28 item questionnaire about perceived barriers to seeking healthcare services. The questionnaire enquired about barriers to using physical and mental healthcare services separately. RESULTS: Completed responses were available from 461 of 509 students (response rate 90.6%). Stigma, confidentiality issues, lack of awareness about where to seek help and fear of unwanted intervention were more commonly reported for mental healthcare seeking (OR 4.21, 4.01, 3.19 and 2.43, respectively), while issues relating to cost, lack of time and fear of side effects were observed less frequently (OR 0.45, 0.46 and 0.57, respectively) compared with physical healthcare seeking. In comparison with physical health, students were more indifferent to their mental health issues and preferred self diagnosis and informal consultations over formal documented care. CONCLUSIONS: Barriers to seeking healthcare services differ for mental and physical health issues. Many system based barriers such as stigma, confidentiality issues and poor awareness of service location were reported by students. Institutional programmes should use this information for improving the usage, satisfaction and effectiveness of healthcare delivery systems for medical students. PMID- 26253924 TI - Examination of the musculoskeletal system: junior doctors' perceptions of the usefulness of the Gait, Arms, Legs and Spine (GALS) technique. AB - BACKGROUND: Musculoskeletal (MSK) conditions affect millions of people around the world. Gait, Arms, Legs and Spine (GALS) is a simple and useful screening tool for routine MSK examination in hospitals and general practice and has been integrated into the undergraduate medical curriculum. Despite this, there is evidence that doctors lack competency in MSK examination and that GALS are underperformed routinely. OBJECTIVES: The study explored the views of junior doctors (JDs) on how they were taught MSK examination as undergraduates; the usefulness of GALS as a technique for excluding significant MSK problems; why MSK examination was often poorly carried out and how this could be improved. METHODS: A qualitative study was performed with data gathered through focus group interviews from 32 JDs working in two acute NHS hospitals. Six interviews were conducted over a 6-week period from mid-June to the end of July in consecutive years 2013 and 2014. RESULTS: Ninety JDs were invited to participate in the focus group interviews; 32 (36%) agreed to participate, 28 (88%) of whom had graduated in the UK. The perception of JDs was that undergraduate training for GALS and regional MSK examination was adequate, but reasons for lack of MSK competency in the workplace are multifactorial and complex. CONCLUSIONS: Proposing more practical and interactive sessions to reinforce MSK skills during postgraduate training may not resolve issues of MSK competency among JDs. Recognition of the complexity of workplace learning and the influence of tacit learning is required if MSK competency is to be enhanced. PMID- 26253925 TI - The quality and scope of information provided by medical laboratories to patients before laboratory testing: Survey of the Working Group for Patient Preparation of the Croatian Society of Medical Biochemistry and Laboratory Medicine. AB - INTRODUCTION: The aim of this work was to evaluate to what extent the scope and content of information provided to patients is standardized across medical biochemistry laboratories in Croatia. MATERIALS AND METHODS: Two on-line self report surveys were sent out: Survey A regarding attitudes on importance of patient preparation and Survey B on the contents of patient preparation instructions. RESULTS: 13/118 laboratories (11%) do not provide written instructions to patients on how to prepare for laboratory testing, and 36 (40%) do not include information about water intake in their instructions. Only half of laboratories provide instructions for prostate-specific antigen (53.8%), female sex hormones (53.7%) and therapeutic drug monitoring (TDM) (52.5%). Inadequate information about fasting status (55.0%) and 24 hour urine collection (77.9%) were frequent errors with high severity and were associated with the greatest potential to cause patient harm. CONCLUSIONS: Laboratory professionals in Croatia have a positive attitude towards the importance of patient preparation for laboratory testing. However, the information for laboratory testing is not standardized and frequently lacks guidance for tests related to TDM, coagulation and endocrinology. This study highlights the need for standardized, updated and evidence-based recommendations for patient preparation in order to minimize the risk for patients. PMID- 26253926 TI - Endovascular treatment of acute and chronic portal vein thrombosis in patients with cirrhotic and non-cirrhotic liver. AB - BACKGROUND: Treatment of patients with portal vein thrombosis (PVT) differs due to different etiology and wide range of symptoms but certain patients seems to benefit from endovascular intervention. PURPOSE: To assess the safety and efficiency of endovascular treatment of acute and chronic PVT in patients with cirrhotic and non-cirrhotic liver. MATERIAL AND METHODS: Twenty-one patients with PVT treated with an endovascular procedure in 2002-2013 were studied retrospectively. Data on etiology, onset and extension of thrombus, presenting symptoms, methods of intervention, portal pressure gradients, complications, recurrence of symptoms, re-interventions, clinical status at latest follow-up, and survival were collected. RESULTS: Four non-cirrhotic patients with acute extensive PVT and bowel ischemia were treated with local thrombolysis, in three combined with placement of a transjugular intrahepatic portosystemic shunt (TIPS) placement. Three recovered and have survived more than 6 years. In six non cirrhotic patients with chronic PVT and acute or threatening variceal bleeding recanalization and TIPS were successful in three and failed in three. Eleven cirrhotic patients with PVT and variceal bleeding or refractory ascites were successfully treated with recanalization and TIPS. Re-intervention was performed in five of these patients and five patients died, three within 12 months of intervention. Four cirrhotic patients had episodes of shunt-related encephalopathy and three had variceal re-bleeding. CONCLUSION: TIPS was found to be effective in reducing portal hypertension in patients with PVT. In patients with extensive PVT and bowel ischemia treatment with TIPS combined with thrombolysis should be considered. PMID- 26253927 TI - MR imaging findings of pilomatricomas: a radiological-pathological correlation. AB - BACKGROUND: Magnetic resonance imaging (MRI) findings of pilomatricomas have yet to be determined. PURPOSE: To assess the correlation between MRI and pathological findings of pilomatricomas. MATERIAL AND METHODS: MR images were obtained on patients with histologically proven pilomatricomas using a 1.5-T MR scanner. The images were retrospectively reviewed for size, signal intensity compared with skeletal muscles, and enhancement patterns. Furthermore, we assessed the presence of a reticular appearance, a ring-like appearance, and peritumoral fat stranding. RESULTS: We included 11 consecutive patients with 12 histologically proven pilomatricomas (3 boys/men, 8 girls/women; age range, 4-76 years; mean age, 20 years; median age, 14 years). The tumors were located in the head and neck (n = 6), upper extremities (n = 5), and lower extremities (n = 1). The maximum tumor diameter was in the range of 7-32 mm (mean, 16.5 mm). On T2-weighted (T2W) images, five tumors showed homogeneous hypointensity, whereas six showed reticular hyperintensity and one showed cystic hyperintensity. On fat-suppressed T2W images, nine tumors showed reticular hyperintensity, eight showed ring-like hyperintensity, and five showed peritumoral fat stranding. On fat-suppressed gadolinium-enhanced T1-weighted (T1W) images, one tumor showed no enhancement, whereas three showed reticular enhancement and five showed ring-like enhancement. Histologically, edematous and fibrous stroma was observed in 10 tumors, tumor capsules in 11, and inflammatory cell infiltration of the peritumoral fat tissue in nine. CONCLUSION: MRI features of pilomatricomas included reticular and ring like hyperintensities on fat-suppressed T2W images and reticular and ring-like enhancement on fat-suppressed gadolinium-enhanced T1W images. PMID- 26253928 TI - Ultrasound-guided aspiration of wrist ganglions: a follow-up survey of patient satisfaction and outcomes. AB - BACKGROUND: Ganglion cysts are one of the most frequently occurring masses of the wrist, often causing pain and interfering with daily activity. Ultrasound (US) guided aspiration is a treatment for ganglion cysts of the wrist. PURPOSE: To examine the results and patient satisfaction of US-guided aspiration of wrist ganglion cysts. MATERIAL AND METHODS: Medical records from August 2009 through December 2013 were reviewed to identify all adult patients referred to a single musculoskeletal radiologist for US-guided aspiration of a painful wrist ganglion cyst. Records were reviewed for patient demographics, cyst size, location, and morphology. Outcomes and patient satisfaction were evaluated using a telephone questionnaire at a minimum of 9 months after the procedure. RESULTS: Of 56 consecutive patients identified, follow-up data were available for 39 patients (69%) at a minimum of 9 months. There were 21 volar and 18 dorsal ganglion cysts. The overall recurrence rate was 20% (8 of 39 patients) and only five patients reported a pain score of greater than 2 out of 10. The mean age of patients with recurrence of the cyst was greater than that of patients without recurrence (52 vs. 35 years, P = 0.03). Satisfaction with the outcome was high and varied by recurrence. There were no acute complications including infection, hemorrhage, or allergic reaction. CONCLUSION: US-guided aspiration is a safe and potentially effective treatment for ganglion cysts of the wrist, with high patient satisfaction. US-guided aspiration may be particularly advantageous for volar ganglion cysts, and in patients who are poor surgical candidates. PMID- 26253929 TI - Peroneal tendon pathology evaluation using the oblique sagittal plane in ankle MR imaging. AB - BACKGROUND: Because peroneal tendons course from the lateral side of the proximal fibula through the posterior side of the distal fibula, correct diagnosis of the tendon pathology on an orthogonal sagittal plane can be difficult. PURPOSE: To evaluate the diagnostic usefulness of oblique sagittal imaging (peroneal view) for evaluation of peroneal tendon pathology. MATERIAL AND METHODS: This retrospective study included 69 patients at our institution who underwent routine ankle magnetic resonance imaging (MRI) using the peroneal view. Twenty-three patients underwent arthroscopy. Anatomic identification of the peroneal tendons on orthogonal sagittal MRI sequences and peroneal views were evaluated. Two radiologists evaluated the peroneal tendons based on an entire length view, an entire width view, and margin sharpness using a 4-point scale. Diagnostic accuracy using orthogonal sagittal and peroneal views was evaluated by calculating sensitivity, specificity, and accuracy. Arthroscopic or clinical findings were used as the reference standard. RESULTS: Total anatomical scores on the peroneal view were higher than those of the orthogonal sagittal views (P < 0.001). Both readers were able to identify anatomy of the tendon using the full length, full width and sharp margin, and determined that the peroneal view was better when compared with the orthogonal sagittal views (P < 0.001). Although the sensitivity and accuracy of the peroneal view in the diagnosis of peroneal tendon injury were slightly higher than orthogonal view, the values were not statistically significant. CONCLUSION: Peroneal views provide better anatomic evaluation of the peroneal tendons itself, although cannot show significant superiority in the diagnostic performances. PMID- 26253930 TI - Significance of combined use of MRI and perfusion SPECT for evaluation of multiple system atrophy, cerebellar type. AB - BACKGROUND: Multiple system atrophy, cerebellar type (MSA-C) sometimes shows asymmetrical findings on magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT). PURPOSE: To assess the frequency and clinical significance of asymmetrical MRI and (99m)Tc-ethyl cysteinate dimer perfusion (ECD) SPECT findings of the cerebellum, middle cerebellar peduncle (MCP), and pons in MSA-C patients. MATERIAL AND METHODS: We retrospectively reviewed 28 patients with MSA-C who underwent MRI and (99m)Tc-ECD SPECT and evaluated laterality of atrophy and signal changes on MRI, and laterality of perfusion on (99m)Tc-ECD SPECT transversely and longitudinally. RESULTS: Laterality was identified for 64%, 61%, and 21% of atrophy in the cerebellum, MCP, and pons, respectively, on MRI and for 71% of atrophy in the cerebellum on perfusion SPECT. Concerning comparisons between the latest MRI and SPECT findings, laterality of cerebellar/MCP atrophy on MRI and decreased cerebellar perfusion on SPECT was matched in 57%, mismatched in 11%, and absent in 25% of patients. On past images, MRI and SPECT showed matched laterality in 33%, mismatched laterality in 27%, no laterality in 13%, and SPECT precedent laterality in 27% of patients. Including the latest and past images, asymmetrical changes were observed in 75% of patients. We could not identify any correlation between laterality of image findings and cerebellar symptoms in most patients. CONCLUSION: Asymmetrical changes on MRI and perfusion SPECT are common in MSA-C patients. Perfusion SPECT is useful for diagnosing MSA-C in the early stages from a functional perspective. PMID- 26253931 TI - Glycosaminoglycan chemical exchange saturation transfer at 3T MRI in asymptomatic knee joints. AB - BACKGROUND: Biochemical alterations such as glycosaminoglycan (GAG) depletion occur early in the course of osteoarthritis, but cannot be detected with standard magnetic resonance techniques. With glycosaminoglycan chemical exchange saturation transfer (gagCEST), a biochemical imaging technique, it is feasible to detect biochemical components in knee joint cartilage. PURPOSE: To establish baseline values for gagCEST magnetic resonance imaging (MRI) in knee joint cartilage at 3 Tesla (T). MATERIAL AND METHODS: Twenty volunteers (8 women, 12 men; mean age, 24.55 +/- 2.35 years;age range, 21-29 years) with no history or clinical findings indicative of knee joint pathologies underwent MRI at 3T. The imaging protocol included three-dimensional (3D) double-echo steady-state sequence for morphological cartilage assessment and a prototype 3D CEST pulse sequence to evaluate the CEST effects in six cartilage regions of the knee joint: (i) lateral femoral condyle; (ii) medial femoral condyle; (iii) lateral tibial plateau; (iv) medial tibial plateau; (v) patella; and (vi) trochlea. We used the asymmetry of the magnetization transfer ratio (MTRasym) parameter to quantify the gagCEST effects in these regions. RESULTS: Regional differences revealed high MTRasym values in the patellar (1.62% +/- 1.19%) and the trochlear (1.17% +/- 1.29%) cartilages, and low MTRasym values in the medial femoral condyle (0.41% +/ 0.58%) and the lateral tibial plateau (0.52% +/- 0.53%) cartilages. CONCLUSION: Regional differences in the gagCEST values must be considered when conducting gagCEST imaging of knee joint cartilage. In the future gagCEST imaging may be an additional feature in the evaluation of the biochemical composition of knee joint cartilage. PMID- 26253933 TI - Whole-body vibration improves the anti-inflammatory status in elderly subjects through toll-like receptor 2 and 4 signaling pathways. AB - Regular physical exercise has anti-inflammatory effects in elderly subjects. Yet, the inflammatory responses after whole body vibration (WBV) training, a popular exercise paradigm for the elderly, remain to be elucidated. This study assessed the effects of WBV training on the inflammatory response associated with toll like receptors (TLRs) signaling pathways. Twenty-eight subjects were randomized to a training group (TG) or a control group (CG). TG followed an 8-week WBV training program. Blood samples were obtained before and after the training period in both groups. Peripheral blood mononuclear cells were isolated, and mRNA and protein levels of makers involved in the TLR2/TLR4 myeloid differentiation primary response gen 88 (MyD88) and TIR domain-containing adaptor inducing interferon (TRIF)-dependent pathways were analyzed. Plasma TNFalpha and C reactive protein levels were also assessed. The WBV program reduced protein expression of TLR2, TLR4, MyD88, p65, TRIF and heat shock protein (HSP) 60, while HSP70 content increased. IL-10 mRNA level and protein concentration were upregulated, and TNFalpha protein content decreased, after WBV training. Plasma concentration of C-reactive protein and TNFalpha decreased in the TG. The current data suggest WBV may improve the anti-inflammatory status of elderly subjects through an attenuation of MyD88- and TRIF-dependent TLRs signaling pathways. PMID- 26253934 TI - Elevated galanin may predict the risk of type 2 diabetes mellitus for development of Alzheimer's disease. AB - Alzheimer's disease is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. Epidemiological and clinical studies demonstrated that type 2 diabetes mellitus is an important risk factor for the development of Alzheimer's disease, i.e., the patients with type 2 diabetes mellitus are frequently companied with Alzheimer's disease symptoms. Despite many studies recently probed into the comorbid state of both diseases, so far the precise mechanism for this association is poorly understood. Emerging evidences suggest that defects in galanin play a central role on type 2 diabetes mellitus and is considered to be a risk factor for Alzheimer's disease development. This review provides a new insight into the multivariate relationship among galanin, type 2 diabetes mellitus and Alzheimer's disease, highlighting the effect of galanin system on the cross-talk between both diseases in human and rodent models. The current data support that activating central GalR2 attenuates insulin resistance and Alzheimer's disease feature in animal models. These may help us better understanding the pathogenesis of both diseases and provide useful hints for the development of novel therapeutic approaches to treat type 2 diabetes mellitus and Alzheimer's disease. PMID- 26253932 TI - Menstrual physiology: implications for endometrial pathology and beyond. AB - BACKGROUND: Each month the endometrium becomes inflamed, and the luminal portion is shed during menstruation. The subsequent repair is remarkable, allowing implantation to occur if fertilization takes place. Aberrations in menstrual physiology can lead to common gynaecological conditions, such as heavy or prolonged bleeding. Increased knowledge of the processes involved in menstrual physiology may also have translational benefits at other tissue sites. METHODS: Pubmed and Cochrane databases were searched for all original and review articles published in English until April 2015. Search terms included 'endometrium', 'menstruation', 'endometrial repair', 'endometrial regeneration' 'angiogenesis', 'inflammation' and 'heavy menstrual bleeding' or 'menorrhagia'. RESULTS: Menstruation occurs naturally in very few species. Human menstruation is thought to occur as a consequence of preimplantation decidualization, conferring embryo selectivity and the ability to adapt to optimize function. We highlight how current and future study of endometrial inflammation, vascular changes and repair/regeneration will allow us to identify new therapeutic targets for common gynaecological disorders. In addition, we describe how increased knowledge of this endometrial physiology will have many translational applications at other tissue sites. We highlight the clinical applications of what we know, the key questions that remain and the scientific and medical possibilities for the future. CONCLUSIONS: The study of menstruation, in both normal and abnormal scenarios, is essential for the production of novel, acceptable medical treatments for common gynaecological complaints. Furthermore, collaboration and communication with specialists in other fields could significantly advance the therapeutic potential of this dynamic tissue. PMID- 26253935 TI - Altered autonomic control in preterm newborns with impaired neurological outcomes. AB - PURPOSE: Very preterm newborns are at high risk of neurological injury. The objective of this work was to study the impact of neurological aggression on the autonomic nervous system. METHODS: We studied polysomnography recordings, at term corrected gestational age, for 38 preterm infants born at less than 28 weeks or weighing less than 1 kg. These infants were seen by a neuropediatrician, average age at follow up was 54.4 months. We created two groups: one with children who did not have any neurological disorder, including cerebral palsy (CP), language or mental retardation, visual or hearing disability, and attention disorder; the second group contained children with at least one of these impairments. From the polysomnography recordings, using coarse-graining spectral analysis, we compared heart rate variability indices between preterm infants with normal and abnormal neurological outcomes. RESULTS: Twenty infants had an impaired neurological outcome. Regarding the clinical characteristics, there were more babies born from smoking mothers (p = 0.025), with early-onset neonatal sepsis (p = 0.04), and abnormal results on cerebral magnetic resonance imaging (p = 0.014) in the group with impaired neurological outcomes. Spectral parameters were significantly different between active and quiet sleep. Total powers, harmonic and non-harmonic powers, high frequency and low frequency powers were higher in active sleep compared with those in quiet sleep. Preterm babies with impaired neurological development, in particular those with CP, had lower total power and non-harmonic power especially in active sleep than those with normal neurological outcome. CONCLUSION: These findings suggest that, in very preterm infants, perinatal neurological injuries could be associated with abnormal maturation of the autonomic nervous system. PMID- 26253936 TI - Posterior reversible encephalopathy syndrome as an initial neurological manifestation of primary Sjogren's syndrome. AB - It is well known that patients with peripheral neuropathy along with autonomic involvement can also exhibit autonomic hyperactivity. There are rare cases in which these patients developed posterior reversible encephalopathy syndrome (PRES). Patients with primary Sjogren's syndrome (pSS) may be more likely to exhibit autonomic hypofunction rather than autonomic hyperfunction, which is a rare event. In the present work, we report the first known case of PRES as an initial neurological manifestation of pSS. PMID- 26253937 TI - A Latent Profile Analysis of drinking motives among heavy drinking college students. AB - INTRODUCTION: Positively (Enhancement and Social) and negatively (Coping) reinforcing drinking motives have been shown to be associated with alcohol use, alcohol-related problems, and depression among college students. Although prior studies of drinking motives have mostly consisted of variable-centered analyses, the current study used a person-centered approach where individuals were grouped into categories based on shared characteristics using Latent Profile Analysis (LPA). We investigated the utility of drinking motive profiles to determine how different profiles were associated with alcohol outcomes and depressive symptoms. METHOD: Participants were 648 undergraduate students who had violated a university alcohol policy and who endorsed consuming alcohol in the past month. Social, Coping, and Enhancement subscales from the Drinking Motives Questionnaire were used as indicators. RESULTS: After examining one-through-eight class LPA solutions, the six-class solution provided the best empirical and clinically meaningful fit to the data. Classes with high coping and high positive reinforcing drinking motives consumed more alcohol than profiles of students with high coping and low positive reinforcing motives. Classes high on both coping and positively reinforcing motives reported the most alcohol related problems. Classes with higher levels of coping motives and either high or low positive reinforcing motives reported the highest depression symptoms. CONCLUSIONS: Drinking motive profiles differ in terms of alcohol outcomes and depressive symptoms. We encourage researchers to explore motives for drinking with individuals, especially assessing the relationship between coping motives and depression in the presence or absence of positively reinforcing motives. PMID- 26253938 TI - Comparing characteristics of prescription painkiller misusers and heroin users in the United States. AB - INTRODUCTION: Prescription painkiller misuse (PPM) is a major U.S. public health concern. However, as prescribing practices have tightened and prescription painkillers have become less accessible, many users have turned to heroin as a substitute. This trend suggests the face of heroin users has likely changed over the past several years. Understanding the demographic, socioeconomic, psychosocial, and substance use characteristics of different groups of opiate users is important for properly tailoring interventions. METHODS: This study used data from the 2010-2013 National Survey on Drug Use and Health to examine differences in characteristics of U.S. adults in three mutually exclusive categories of past-year opiate use: heroin-only (H-O, N=179), prescription painkiller-only (PP-O, N=9,516), and heroin and prescription painkiller (H-PP, N=506). RESULTS: Socioeconomic disadvantage, older age, disconnection from social institutions, criminal justice involvement, and easy access to heroin were associated with greater odds of being in the H-O group. HH-P users were more likely to be young white males with poor physical and mental health who also misuse other prescription medications and began such misuse as adolescents. PP-O users were the most economically stable, most connected to social institutions, least likely to have criminal justice involvement, and had the least access to heroin. CONCLUSIONS: Results suggest the socio-demographic characteristics of heroin users versus PP misusers vary widely, and the conditions leading to heroin use versus PPM versus both may be different. Ultimately, a one-size-fits-all approach to opiate prevention and treatment is likely to fail. Interventions must account for the unique needs of different user groups. PMID- 26253939 TI - Cigarette smoking cessation attempts among current US smokers who also use smokeless tobacco. AB - INTRODUCTION: Concurrent use of cigarettes and smokeless tobacco is common, but little is known regarding the association of smokeless tobacco use with cigarette smoking cessation. Dual users may have lower cigarette consumption levels, which may also play a role in smoking cessation. METHODS: The 2010-2011 Tobacco Use Supplement to the Current Population Survey included 26,760 current cigarette smokers, of which 675 concurrently used smokeless tobacco. We compared characteristics of the most recent cigarette smoking quit attempt of the past year between dual users and exclusive smokers, using multivariate regression. RESULTS: Dual users (45%) were more likely than exclusive smokers (37%) to have made a cigarette smoking quit attempt during the previous year (p<0.01), even after adjusting for demographic differences and cigarette dependence levels (ORadj 1.33, 95% CI 1.15-1.53). Half (48%) of dual users who made a quit attempt tried to quit "by switching to smokeless tobacco". However, once in a quit attempt, dual users relapsed more quickly than exclusive smokers (Cox regression HRadj 1.13, 95% CI 1.02-1.26). There was no difference in 30-day abstinence rates on the most recent quit attempt (ORadj 1.09, 95% CI 0.88-1.37). For both groups, the best predictor of past 30-day abstinence was cigarette consumption level. CONCLUSIONS: Current cigarette smokers who also use smokeless tobacco are more likely to have tried to quit, but relapse more quickly than exclusive smokers, and are not more likely to have attained 30day smoking cessation. Prospective studies at the population level are needed. PMID- 26253940 TI - Impact of Detachment Methods on M2 Macrophage Phenotype and Function. AB - The methods of cell detachment influence phenotype and function of human macrophages cultured in vitro. However, comparative studies defining the influence of cell detachment techniques on secondary characterization of M1 or M2 polarized macrophages are largely absent from the literature. In this study we evaluated the impact of trypsin, accutase, EDTA, PBS, and cell scraping on: A. cell recovery, B. phenotype and C. function of in vitro polarized macrophages. Our data demonstrate that while exposure to trypsin or accutase yields highly efficient recovery of viable cells, such chemical cleavage results in loss of select M2 cell surface markers with correlative changes in cell function. In contrast, phenotype and function are maintained following detachment by EDTA on ice. Our data suggest that seemingly "trivial" changes in methodologies for macrophage detachment induce both variable and profound changes on cell phenotype and function which can dramatically impact the results of polarization experiments. PMID- 26253942 TI - Essential and Toxic Elements in Blood Samples of Harbor Seals (Phoca vitulina) from the Islands Helgoland (North Sea) and Anholt (Baltic Sea): A Comparison Study with Urbanized Areas. AB - The harbor seals (Phoca vitulina) from Helgoland (North Sea) and Anholt (Kattegat, Baltic Sea) are top predators within the marine food web and an indicator species of the environmental contamination. Furthermore, they are a main tourist attraction. Despite these important roles, little is known about the health and pollutant contamination of these seals. The objective of this study was therefore to investigate 18 essential and nonessential/toxic elements (Al, As, Be, Ca, Cr, Cu, Fe, K, Mn, Mo, Ni, P, Pb, Rb, S, Se, Sr, and Zn) in blood samples using inductively coupled plasma mass spectrometry and total X-ray fluorescence spectrometry. Blood concentrations of mineral nutrients, such as Ca, K, P, and S, were within the reference ranges described for harbor seals. Likewise, for the trace elements, As, Be, Rb, Se, and Sr, no significant differences were observed compared with previous studies. Interestingly, blood concentrations of nine nonessential as well as essential trace metals (Al, Cr, Cu, Fe, Mn, Mo, Ni, Pb, Zn) measured significantly lower in the offshore living seals from Helgoland and Anholt compared with results obtained from animals living close to urbanized areas, such as the Wadden Sea and Elbe estuary. This suggests that industrial emissions, sewage deposition, shipping traffic and dredging tasks might be the cause of increased metal concentrations of inshore harbor seals. PMID- 26253941 TI - Prognostic significance of beta-blocker up-titration in conjunction with cardiac resynchronization therapy in heart failure management. AB - Clinical practice guidelines emphasize that optimal pharmacotherapy, including beta-blockers (BB), is a prerequisite before receiving cardiac resynchronization therapy (CRT) in eligible patients with heart failure (HF). However, the optimal dose of BB before CRT implantation cannot be tolerated in a number of patients. Sixty-three consecutive patients who underwent CRT in 2006-2013 were retrospectively investigated. Before receiving CRT, BB could not be introduced in 20 patients (32 %); the daily carvedilol-equivalent dose in other 43 patients was 5.6 +/- 7.0 mg because of significant HF and bradycardia. After receiving CRT, BB could be introduced in almost all patients (n = 61, 97 %), and the daily BB dose increased from 5.6 +/- 7.0 to 13.2 +/- 7.8 mg (P < 0.001). Multivariate analysis indicated that the change of BB dose after CRT was independently associated with improved left ventricular end-systolic volume (LVESV) [beta = -0.36; 95 % confidence interval (CI) -2.13 to -0.45; P < 0.01] after 6-months follow-up. Furthermore, Cox proportional hazard analysis also showed that the change in the BB dose (hazard ratio, 0.92; 95 % CI, 0.87-0.98; P < 0.01) as well as the New York Heart Association functional classification was an independent predictor of cardiac events. After initiating CRT, BB therapy can be introduced and up titrated in intolerant HF patients. The up-titrated dose of BB after CRT was an independent predictor for the improvement of LVESV and HF prognosis. PMID- 26253943 TI - Managing monoarthritis in children. AB - Monoarthritis, defined as inflammation of a single joint, requires a thorough physical examination in children, as pain may be lacking in 10% to 30% of cases and joint stiffness may be the only symptom. Joint aspiration is a crucial diagnostic tool that remains markedly underused. Joint aspiration may be unnecessary, however, when the family history or other investigations provide the diagnosis. Radiographs of the involved joint may supply information on the severity of the lesions. In doubtful cases and in patients with arthralgia, B mode and Doppler ultrasound or magnetic resonance imaging (MRI) may confirm the presence of synovitis. Although suspected septic arthritis is an emergency and occurs frequently, particularly before 2 years of age, acute monoarthritis is often a post-infectious manifestation and therefore associated with a good outcome. Lyme disease should be sought, particularly when a lower limb joint is involved, as tick bites often go unnoticed. Chronic monoarthritis is very often a manifestation of juvenile idiopathic arthritis (JIA), which exists as several variants. Oligoarthritis is a specifically pediatric joint disease, whereas the other patterns of JIA have corresponding forms in adults, despite a number of specific features due to their onset during childhood. Tests for antinuclear antibodies should be performed routinely in children with monoarthritis persisting longer than 3 weeks. A decline in general health or a fever should suggest arthritis revealing a malignancy, which is a hematological disease in most cases. Finally, suggestive symptoms are often present in patients with less common causes such as auto-inflammatory diseases and connective tissue diseases. PMID- 26253944 TI - A novel humanized anti-HER2 antibody conjugated with MMAE exerts potent anti tumor activity. AB - Human epidermal growth factor receptor-2 (HER2) is a validated therapeutic target for breast cancer and trastuzumab (Herceptin), a humanized anti-HER2 antibody, has significant anti-cancer effects in the clinic. However, breast cancer patients often experience disease progression after prolonged Herceptin treatment. To develop a more effective therapy, we generated humanized monoclonal antibody hertuzumab and hertuzumab-drug conjugates as novel breast cancer therapies. The hertuzumab was conjugated with small molecule cytotoxic agents monomethylauristatin E (MMAE) or monomethylauristatin F (MMAF) with various linkers to generate antibody-drug conjugates (ADCs), which were evaluated for their in vitro and in vivo anti-cancer activities. Among these ADCs, hertuzumab vc-MMAE can be effectively internalized and potently kill HER2 over-expressing tumor cells. In xenograft tumor models, hertuzumab-vc-MMAE showed a more potent anti-tumor activity than T-DM1, a FDA-approved ADC drug. More importantly, this novel ADC drug also showed superior anti-tumor activity than T-DM1 in trastuzumab and lapatinib-resistant xenograft tumor models, suggesting its potential as an improved therapy for HER2-positive breast cancers. The novel ADC, hertuzumab-vc MMAE, is an effective and selective agent for the treatment of HER2-positive breast tumors. PMID- 26253945 TI - Reduction of global 5-hydroxymethylcytosine is a poor prognostic factor in breast cancer patients, especially for an ER/PR-negative subtype. AB - DNA methylation at the 5 position of cytosine (5 mC) is an epigenetic hallmark in cancer. The 5 mC can be converted to 5-hydroxymethylcytosine (5 hmC) through a ten-eleven-translocation (TET). We investigated the impact of 5 mC, 5 hmC, TET1, and TET2 on tumorigenesis and prognosis of breast cancer. Immunohistochemistry was used to assess the levels of 5 mC, 5 hmC, TET1, and TET2 in the corresponding tumor adjacent normal (n = 309), ductal carcinoma in situ (DCIS, n = 120), and invasive ductal carcinoma (IDC, n = 309) tissues for 309 breast ductal carcinoma patients. 5 mC, 5 hmC, TET1-n, and TET2-n were significantly decreased during DCIS and IDC progression. In IDC, the decrease of 5 hmC was correlated with the cytoplasmic mislocalization of TET1 (p < 0.001) as well as poor disease-specific survival (DSS) (adjusted hazard ratio [AHR] 1.95, p = 0.003) and disease-free survival (DFS) (AHR 1.91, p = 0.006). The combined decrease of 5 mC and 5 hmC was correlated with worse DSS (AHR 2.19, p = 0.008) and DFS (AHR 1.99, p = 0.036). Stratification analysis revealed that the low level of 5 mC was associated with poor DSS (AHR 1.89, p = 0.044) and DFS (AHR 2.02, p = 0.035) for the ER/PR positive subtype. Conversely, the low level of 5 hmC was associated with worse DSS (AHR 2.77, p = 0.002) and DFS (AHR 2.69, p = 0.006) for the ER/PR-negative subtype. The decreases of 5 mC, 5 hmC, TET1-n, and TET2-n were biomarkers of tumor development. The global reduction of 5 hmC was a poor prognostic factor for IDC, especially for ER/PR-negative subtype. PMID- 26253946 TI - RNAi-mediated silencing of Anxa2 inhibits breast cancer cell proliferation by downregulating cyclin D1 in STAT3-dependent pathway. AB - Although the upregulated expression of Anxa2 has been implicated in carcinogenesis, cancer progression, and poor prognosis of cancer patients, the detailed molecular mechanisms involved in these processes remain unclear. In this study, we investigated the effect of Anxa2 downregulation with small interference RNA on breast cancer proliferation. To explore molecular mechanisms underlying Anxa2-mediated cancer cell proliferation. We analyzed cell cycle distribution and signaling pathways using semi-quantitative real-time PCR and Western blotting. Anxa2 depletion in breast cancer cells significantly inhibited cell proliferation by decelerating cell cycle progression. The retarded G1-to-S phase transition in Anxa2-silenced cells was attributed to the decreased levels of cyclin D1, which is a crucial promoting factor for cell proliferation because it regulates G1-to-S phase transition during cell cycle progression. We provided evidence that Anxa2 regulates epidermal growth factor-induced phosphorylation of STAT3. The reduced expression of phosphorylated STAT3 is the main factor responsible for decreased cyclin D1 levels in Anxa2-silenced breast cancer cells. Our results revealed the direct relationship between Anxa2 and activation of STAT3, a key transcription factor that plays a pivotal role in regulating breast cancer proliferation and survival. This study provides novel insights into the functions of Anxa2 as a critical molecule in cellular signal transduction and significantly improves our understanding of the mechanism through which Anxa2 regulates cell cycle and cancer cell proliferation. PMID- 26253947 TI - CONNJUR R: an annotation strategy for fostering reproducibility in bio-NMR protein spectral assignment. AB - Reproducibility is a cornerstone of the scientific method, essential for validation of results by independent laboratories and the sine qua non of scientific progress. A key step toward reproducibility of biomolecular NMR studies was the establishment of public data repositories (PDB and BMRB). Nevertheless, bio-NMR studies routinely fall short of the requirement for reproducibility that all the data needed to reproduce the results are published. A key limitation is that considerable metadata goes unpublished, notably manual interventions that are typically applied during the assignment of multidimensional NMR spectra. A general solution to this problem has been elusive, in part because of the wide range of approaches and software packages employed in the analysis of protein NMR spectra. Here we describe an approach for capturing missing metadata during the assignment of protein NMR spectra that can be generalized to arbitrary workflows, different software packages, other biomolecules, or other stages of data analysis in bio-NMR. We also present extensions to the NMR-STAR data dictionary that enable machine archival and retrieval of the "missing" metadata. PMID- 26253948 TI - Increasing the sensitivity of NMR diffusion measurements by paramagnetic longitudinal relaxation enhancement, with application to ribosome-nascent chain complexes. AB - The translational diffusion of macromolecules can be examined non-invasively by stimulated echo (STE) NMR experiments to accurately determine their molecular sizes. These measurements can be important probes of intermolecular interactions and protein folding and unfolding, and are crucial in monitoring the integrity of large macromolecular assemblies such as ribosome-nascent chain complexes (RNCs). However, NMR studies of these complexes can be severely constrained by their slow tumbling, low solubility (with maximum concentrations of up to 10 MUM), and short lifetimes resulting in weak signal, and therefore continuing improvements in experimental sensitivity are essential. Here we explore the use of the paramagnetic longitudinal relaxation enhancement (PLRE) agent NiDO2A on the sensitivity of (15)N XSTE and SORDID heteronuclear STE experiments, which can be used to monitor the integrity of these unstable complexes. We exploit the dependence of the PLRE effect on the gyromagnetic ratio and electronic relaxation time to accelerate recovery of (1)H magnetization without adversely affecting storage on N z during diffusion delays or introducing significant transverse relaxation line broadening. By applying the longitudinal relaxation-optimized SORDID pulse sequence together with NiDO2A to 70S Escherichia coli ribosomes and RNCs, NMR diffusion sensitivity enhancements of up to 4.5-fold relative to XSTE are achieved, alongside ~1.9-fold improvements in two-dimensional NMR sensitivity, without compromising the sample integrity. We anticipate these results will significantly advance the use of NMR to probe dynamic regions of ribosomes and other large, unstable macromolecular assemblies. PMID- 26253949 TI - A phase I-II study on the combination of rapamycin and short course radiotherapy in rectal cancer. AB - PURPOSE: This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of the combination of rapamycin, an mTOR inhibitor, with short-course radiotherapy in rectal cancer patients. Antitumor activity, changes in metabolic activity and perfusion on imaging, and changes in phosphorylation status of the mTOR pathway were also assessed. MATERIALS AND METHODS: Patients with primary resectable rectal cancer were treated with short-course hypofractionated radiotherapy (5*5 Gy) combined with oral rapamycin 1 week before and during radiotherapy, followed by surgical resection. RESULTS: Thirteen patients were entered in phase I. One patient developed a dose-limiting toxicity, consisting of a grade 4 leak and grade 4 bleeding. Because of an unexpected high rate of grade 3 postoperative toxicity, it was decided to treat patients with delayed surgery in phase II. Primary endpoint for phase II was tumor blood flow (K(trans)) assessed by perfusion CT. Thirty-one patients were treated with the MTD of 6 mg rapamycin daily. One patient (3%) developed a pathological complete response (pCR) and 3 patients (10%) had a ypT1N0 tumor at the time of resection. No change in tumor perfusion was observed on perfusion CT, but a significant decrease of metabolic activity was found on PET-scan. CONCLUSIONS: The combination of short-course radiotherapy and rapamycin turned out to be feasible, provided that the interval between neo-adjuvant treatment and surgical resection is at least 6 weeks. Although from this cohort no clear increase in pCR could be observed, a clear metabolic response after rapamycin run-in was observed, indicating a biological activity of this drug in rectal cancer. PMID- 26253950 TI - A new CT-based method to quantify radiation-induced lung damage in patients. AB - A new method to assess radiation-induced lung toxicity (RILT) using CT-scans was developed. It is more sensitive in detecting damage and corresponds better to physician-rated radiation pneumonitis than routinely-used methods. Use of this method may improve lung toxicity assessment and thereby facilitate development of more accurate predictive models for RILT. PMID- 26253951 TI - Use a survival model to correlate single-nucleotide polymorphisms of DNA repair genes with radiation dose-response in patients with non-small cell lung cancer. AB - PURPOSE: This study utilizes a survival model and clinical data with various radiation doses from prospective trials to determine radiation dose-response parameters, such as radiosensitivity, and identify single-nucleotide-polymorphism (SNP) biomarkers that can potentially predict the dose response and guide personalized radiotherapy. METHODS: The study included 92 consecutive stage-III NSCLC patients with doses varying from 60 to 91Gy. Logistic regression analysis of survival varying with SNP genotype and radiation dose was used to screen candidates for dose-response analysis. The dose-response parameter, represented by D50, was derived by fitting survival data into a model that takes into account both tumor control and treatment mortality. A candidate would be considered as a predictor if the 90% confident intervals (90% CIs) of D50 for the 2 groups stratified by the SNP genotype were separated. RESULTS: One SNP-signature (combining ERCC2:rs238406 and ERCC1:rs11615) was found to predict dose-response. D50 values are 63.7 (90% CI: 53.5-66.3) Gy and 76.1 (90% CI: 71.3, 84.6) Gy for the 2 groups stratified by the genotypes. Using this biomarker-based model, a personalized dose prescription may be generated to improve 2-year survival from ~50% to 85% and ~3% to 73% for hypothetical sensitive and resistant patients, respectively. CONCLUSIONS: We have developed a survival model that may be used to identify genomic markers, such as ERCC1/2 SNPs, to predict radiation dose response and potentially guide personalized radiotherapy. PMID- 26253952 TI - Flashes of light-radiation therapy to the brain. AB - We present a series of three patients who received therapeutic external beam radiation to the brain and experienced a phenomenon of the sensation of flashes of bright or blue light, simultaneous with radiation delivery. We relate this benign phenomenon to low-dose exposure to the eye fields and postulate that the occurrence is underreported in this treated population. PMID- 26253953 TI - Radiation-induced dose-dependent changes of the spleen following postoperative chemoradiotherapy for gastric cancer. AB - BACKGROUND AND PURPOSE: Abdominal (chemo-)radiotherapy is associated with dose limiting toxicity of various normal structures. The purpose of this retrospective study was to investigate radiation-induced changes of the spleen and their clinical consequences. PATIENTS AND METHODS: In gastric cancer patients treated with postoperative chemoradiotherapy, the spleen size and its functions were assessed at follow-up by spleen volume on CT-scan, serum leucocytes/thrombocytes, and the occurrence of infectious events consisting of pneumonia and fatal sepsis. To evaluate the effect of radiation dose, mixed effects and Cox regression models were used. RESULTS: Forty-six out of 90 consecutive patients treated from 2006 to 2011 were evaluable. All patients received 45 Gy in 25 fractions with concurrent capecitabine (n=8), and capecitabine/cisplatin (n=38). Median Dmean to the spleen was 40 Gy (range 32-46). Mean relative spleen volume reduced to 37% (95% CI 32 42%) at 4-year follow-up, which was most strongly associated to the V44 (p<0.001). Median follow-up time was 67 (95% CI 57-78) months. Eleven patients had 13 pneumonias and 3 fatal sepsis. No association with dosimetric parameters was observed. CONCLUSIONS: In postoperative chemoradiotherapy for gastric cancer, the spleen received a high radiation dose. This resulted in a progressive, radiation dose-dependent reduction of spleen volume. Pneumonia and fatal sepsis occurred frequently, possibly as a result of functional hyposplenia. PMID- 26253954 TI - Optimal codons in Tremella fuciformis end in C/G, a strong difference with known Tremella species. AB - Tremella fuciformis is a popular edible fungus with fruiting bodies that can be produced in large quantities at low costs, while it is easy to transform and cultivate as yeast. This makes it an attractive potential bioreactor. Enhanced heterologous gene expression through codon optimization would be useful, but until now codon usage preferences in T. fuciformis remain unknown. To precisely determine the preferred codon usage of T. fuciformis we sequenced the genome of strain Tr26 resulting in a 24.2 Mb draft genome with 10,040 predicted genes. 3288 of the derived predicted proteins matched the UniProtKB/Swiss-Prot databases with 40% or more similarity. Corresponding gene models of this subset were subsequently optimized through repetitive comparison of alternative start codons and selection of best length matching gene models. For experimental confirmation of gene models, 96 random clones from an existing T. fuciformis cDNA library were sequenced, generating 80 complete CDSs. Calculated optimal codons for the 3288 predicted and the 80 cloned CDSs were highly similar, indicating sufficient accuracy of predicted gene models for codon usage analysis. T. fuciformis showed a strong preference for C and then G at the third base pair position of used codons, while average GC content of predicted genes was slightly higher than the total genome sequence average. Most optimal codons ended in C or G except for one, and an increased frequency of C ending codons was observed in genes with higher expression levels. Surprisingly, the preferred codon usage in T. fuciformis strongly differed from T. mesenterica and C. neoformans. Instead, optimal codon usage was similar to more distant related species such as Ustilago maydis and Neurospora crassa. Despite much higher overall sequence homology between T. fuciformis and T. mesenterica, only 7 out of 21 optimal codons were equal, whereas T. fuciformis shared up to 20 out of 21 optimal codons with other species. Clearly, codon usage in Tremella can differ largely and should be estimated for individual species. The precise identification of optimal and high expression related codons is therefore an important step in the development of T. fuciformis as a bioreactor system. PMID- 26253955 TI - Carry-over of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) in dairy cows fed smoke contaminated maize silage or sugar beet pulp. AB - Fires and improper drying may result in contamination of feed with PCDD/Fs and PCBs. To predict the impact of elevated feed levels, it is important to understand the carry-over to edible products from food producing animals. Therefore, a carry-over study was performed with maize silage contaminated by a fire with PVC materials, and with sugar beet pulp contaminated by drying with coal, containing particles from a plastic roof. Levels of PCDD/Fs and dl-PCBs in the maize silage were 0.93 and 0.25 ng TEQ kg(-1), those in beet pulp 1.90 and 0.15 ng TEQ kg(-1) (both on 88% dry matter (DM)). Dairy cows (3 per treatment) received either 16.8 kg DM per day of maize silage or 5.6 kg DM per day of sugar beet pellets for a 33-d period, followed by clean feed for 33 days. This resulted in a rapid increase of PCDD/F levels in milk within the first 10 days with levels at day 33 of respectively 2.6 and 1.7 pg TEQ g(-1) fat for maize silage and beet pulp. Levels of dl-PCBs at day 33 were lower, 1.0 and 0.5 pg TEQ g(-1) fat. In the case of the maize silage, the carry-over rates (CORs) at the end of the exposure were calculated to be 25% and 32% for the PCDD/F- and dl-PCB-TEQ, respectively. For the dried beet pulp the CORs were 18% and 35%. This study shows that the carry-over of PCDD/Fs and dl-PCBs formed during drying processes or fires can be substantial. PMID- 26253956 TI - Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination. AB - Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia. But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia. To investigate this hypothesis, we used clemastine, an FDA approved drug with high potency in promoting oligodendroglial differentiation and myelination, on a cuprizone-induced mouse model of demyelination. The mice exposed to cuprizone (0.2% in chow) for 6 weeks displayed schizophrenia-like behavioral changes, including decreased exploration of the center in the open field test and increased entries into the arms of the Y-maze, as well as evident demyelination in the cortex and corpus callosum. Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for 3 weeks. As expected, myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes (APC-positive) and myelin basic protein. More importantly, the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle, suggesting a beneficial effect via promoting myelin repair. Our findings indicate that enhancing remyelination may be a potential therapy for schizophrenia. PMID- 26253957 TI - Comparative study of the prevalence of temporomandibular joint (TMJ) osteoarthritic changes in cone beam computed tomograms of temporomandibular disorder (TMD) and non-TMD patients: Authors' reply. PMID- 26253958 TI - The effectiveness of antibiotic prophylaxis to prevent infectious endocarditis is not easily dismissed. PMID- 26253959 TI - Clinicopathologic conference: bluish gingival nodule. PMID- 26253961 TI - Complete genome sequence of Methylophilus sp. TWE2 isolated from methane oxidation enrichment culture of tap-water. AB - The non-methane-utilizing methylotroph, Methylophilus sp. TWE2, was isolated from tap-water during the enrichment of methanotrophs with methane. The complete genome sequence of strain TWE2 showed that this bacterium may convert methanol to formaldehyde via catalysis of methanol dehydrogenase (MDH), after which formaldehyde would be assimilated to biomass through the ribulose monophosphate (RuMP) pathway or dissimilated via the tetrahydromethanopterin (H4MPT) pathway. The deficiency of glycolysis and the TCA cycle indicate that strain TWE2 may be an obligate methylotroph. This is the first complete genome sequence of the genus Methylophilus. PMID- 26253960 TI - Draft genome sequence of Herbinix hemicellulosilytica T3/55 T, a new thermophilic cellulose degrading bacterium isolated from a thermophilic biogas reactor. AB - A novel bacterial species was isolated from an industrial-scale biogas plant. The isolate Herbinix hemicellulosilytica T3/55(T) is able to degrade crystalline cellulose. Comparative 16S rRNA gene sequencing demonstrated that the isolate is closely related to environmental samples forming a hitherto unknown sub-cluster within the family Lachnospiraceae. The draft genome sequence of strain T3/55(T) was established and now provides the genetic basis for application of this microorganism in thermophilic degradation of lignocellulosic biomass. PMID- 26253962 TI - Genome sequence of Cellvibrio pealriver PR1, a xylanolytic and agarolytic bacterium isolated from freshwater. AB - Cellvibrio pealriver PR1 (CGMCC 1.14955=NBRC 110968) was isolated from a freshwater sample from the Pearl River in China. It is able to degrade various carbohydrates such as starch, xylan, agar, cellulose or chitin. The genomic feature and polysaccharide hydrolases of this strain were described in this paper. The total genome size of C. pealriver PR1 is 4,427,922 bp with 3986 coding sequences (CDS), 53 tRNAs, 16 rRNAs and 1 sRNA. The annotated full genome sequence of this strain provides the genetic basis for revealing its role as a xylanolytic and agarolytic bacterium. PMID- 26253963 TI - Methodology for the High-Throughput Identification and Characterization of tRNA Variants That Are Substrates for a tRNA Decay Pathway. AB - The rapid tRNA decay (RTD) pathway is a tRNA quality control pathway known to degrade several specific hypomodified or destabilized tRNAs in the yeast Saccharomyces cerevisiae. In this chapter, we describe seven methods for identifying RTD substrates, with a focus on two new approaches: a high-throughput approach that utilizes a suppressor tRNA library, fluorescence-activated cell sorting, and deep sequencing, and has greatly expanded the known range of RTD substrates; and a poison primer extension assay that allows for the measurement of levels of suppressor tRNA variants, even in the presence of highly similar endogenous tRNAs. We also discuss different applications of the use of the high throughput and poison primer extension methodologies for different problems in tRNA biology. PMID- 26253964 TI - Nucleoside Analysis by Hydrophilic Interaction Liquid Chromatography Coupled with Mass Spectrometry. AB - RNA molecules contain a wide variety of chemical modifications that cannot be deduced from the genomic sequence. RNA modifications confer a chemical diversity to simple RNA molecules, enabling a greater variety of biological functions. To detect RNA modifications, highly sensitive analytical tools are required. Liquid chromatography/mass spectrometry (LC/MS) has been playing a vital role in analyzing minor modified nucleosides in RNA specimens from various sources. Reverse-phase chromatography (RPC) has been used for LC/MS for a long time because RPC is compatible with electrospray ionization (ESI) MS. However, RPC is not always suitable for detecting hydrophilic or polar nucleosides. We here describe a different mode of LC/MS for detecting RNA modifications using hydrophilic interaction liquid chromatography (HILIC). HILIC/ESI-MS is a valuable alternative for profiling modified nucleosides. PMID- 26253966 TI - Recognition of Specified RNA Modifications by the Innate Immune System. AB - Microbial nucleic acids have been described as important activators of human innate immune responses by triggering so-called pattern recognition receptors (PRRs) that are expressed on innate immune cells, including plasmacytoid dendritic cells and monocytes. Although host and microbial nucleic acids share pronounced chemical and structural similarities, they significantly differ in their posttranscriptional modification profile, allowing the host to discriminate between self and nonself. In this regard, ribose 2'-O-methylation has been discovered as suppressor of RNA-induced PRR activation. Although 2'-O-methylation occurs with higher frequencies in eukaryotic than in prokaryotic RNA, the immunosuppressive properties of 2'-O-methylated nucleotides may be misused by certain bacteria as immune evasion mechanism. In the course of identifying inhibitory RNA modifications, our groups have synthesized and comparatively analyzed a series of differentially modified RNAs, so-called modivariants, for their immune stimulatory capacities. In this chapter, we will detail the protocols for the design and synthesis of RNA modivariants by molecular cut-and paste techniques (referred to as molecular surgery) and describe testing of their immune stimulatory properties upon transfection into peripheral blood mononuclear cells. PMID- 26253967 TI - Kinetic Analysis of tRNA Methyltransferases. AB - Transfer RNA (tRNA) molecules contain many chemical modifications that are introduced after transcription. A major form of these modifications is methyl transfer to bases and backbone groups, using S-adenosyl methionine (AdoMet) as the methyl donor. Each methylation confers a specific advantage to tRNA in structure or in function. A remarkable methylation is to the G37 base on the 3' side of the anticodon to generate m(1)G37-tRNA, which suppresses frameshift errors during protein synthesis and is therefore essential for cell growth in all three domains of life. This methylation is catalyzed by TrmD in bacteria and by Trm5 in eukaryotes and archaea. Although TrmD and Trm5 catalyze the same methylation reaction, kinetic analysis reveals that these two enzymes are unrelated to each other and are distinct in their reaction mechanism. This chapter summarizes the kinetic assays that are used to reveal the distinction between TrmD and Trm5. Three types of assays are described, the steady-state, the pre-steady-state, and the single-turnover assays, which collectively provide the basis for mechanistic investigation of AdoMet-dependent methyl transfer reactions. PMID- 26253965 TI - A Platform for Discovery and Quantification of Modified Ribonucleosides in RNA: Application to Stress-Induced Reprogramming of tRNA Modifications. AB - Here we describe an analytical platform for systems-level quantitative analysis of modified ribonucleosides in any RNA species, with a focus on stress-induced reprogramming of tRNA as part of a system of translational control of cell stress response. This chapter emphasizes strategies and caveats for each of the seven steps of the platform workflow: (1) RNA isolation, (2) RNA purification, (3) RNA hydrolysis to individual ribonucleosides, (4) chromatographic resolution of ribonucleosides, (5) identification of the full set of modified ribonucleosides, (6) mass spectrometric quantification of ribonucleosides, (6) interrogation of ribonucleoside datasets, and (7) mapping the location of stress-sensitive modifications in individual tRNA molecules. We have focused on the critical determinants of analytical sensitivity, specificity, precision, and accuracy in an effort to ensure the most biologically meaningful data on mechanisms of translational control of cell stress response. The methods described here should find wide use in virtually any analysis involving RNA modifications. PMID- 26253969 TI - Transcriptome-Wide Mapping of N6-Methyladenosine by m6A-Seq. AB - A detailed protocol for isolation and sequencing of an enriched population of m(6)A-methylated RNA fragments to create m(6)A methylome maps is outlined. Our approach was developed to fill a void that existed because of a lack of methods for the detection of m(6)A in RNA in an unbiased, high-throughput, and high resolution manner. This method integrates immunoprecipitation of methylated, randomly fragmented RNA using a highly specific anti-m(6)A antibody to obtain an enriched population of modified fragments and massively parallel sequencing, resulting in mapping of this modification throughout the transcriptome. PMID- 26253968 TI - Preparation of Human Nuclear RNA m6A Methyltransferases and Demethylases and Biochemical Characterization of Their Catalytic Activity. AB - N(6)-Methyladenosine (m(6)A) represents the most prevalent internal modification in messenger and long noncoding RNAs. There has been a surge of interest toward understanding the biological significance of m(6)A modification. In this chapter, we describe the methods for biochemically studying the recently uncovered m(6)A methyltransferases (METTL3 and METTL14) and demethylases (FTO and ALKBH5). How to express these proteins, perform their biochemistry reactions against various RNA probes, and characterize the methylation and demethylation activity will be discussed. PMID- 26253970 TI - Probing RNA Modification Status at Single-Nucleotide Resolution in Total RNA. AB - RNA modifications, with over one hundred known so far, are commonly proposed to fine-tune the structure and function of RNA. While modifications in rRNA and tRNA are used to modulate RNA folding and decoding properties, little is known about the function of internal modifications in mRNA/lncRNA, which includes N(6)-methyl adenosine (m(6)A), 5-methyl cytosine (m(5)C), 2'-O-methylated nucleotides (Nm), pseudouridine (Psi), and possible others. Functional studies of mRNA/lncRNA modifications have been hindered by the lack of methods for their identification at single-nucleotide resolution. Challenges for the determination of mRNA/lncRNA modifications at single-nucleotide resolution are mainly due to the low abundance of mRNA/lncRNA. Traditional deep sequencing methods cannot identify mRNA/lncRNA modifications, such as m(6)A, m(5)C, Nm, and Psi, because reverse transcriptase is insensitive to their presence in cDNA synthesis. Antibody-based approach enables the identification of m(6)A regions in mRNA/lncRNA, but currently at ~100 nucleotide resolution. Here, we describe a method that accurately identifies m(6)A position and modification fraction in human mRNA and lncRNAs at single nucleotide resolution, termed "Site-specific Cleavage And Radioactive-labeling followed by Ligation-assisted Extraction and Thin-layer chromatography (SCARLET)." This method combines two previously established techniques, site specific cleavage and splint ligation, to probe the RNA modification status at any mRNA/lncRNA site in the total RNA pool. SCARLET can potentially analyze any nucleotide that maintains Watson-Crick base pairing in the transcriptome and determine whether it contains m(6)A, m(5)C, Nm, Psi, or other modifications yet to be discovered. Precise determination of the position and modification fraction of RNA modifications reveals crucial parameters for functional investigation of RNA modifications. PMID- 26253971 TI - High-Resolution Mapping of N6-Methyladenosine in Transcriptome and Genome Using a Photo-Crosslinking-Assisted Strategy. AB - A photo-crosslinking-assisted strategy has been developed and applied to the high resolution mapping of N(6)-methylation of adenosine (N(6)-methyladenosine or m(6)A/6mA, we chose to use m(6)A to represent the RNA methylation, and 6mA to represent the DNA methylation in order to be consistent with DNA 5mC methylation nomenclature) in transcriptome and genome. The new approach introduces a covalent interaction between the anti-m(6)A antibody and the RNA/DNA molecule, followed by multiple washing steps which reduce nonspecific binding in immunoprecipitation and nuclease digestion in order to significantly increase the resolution by removing unprotected polynucleotides. By using this protocol, a high-resolution transcriptome-wide human m(6)A map and genome-wide Chlamydomonas 6mA map were obtained, providing new insights into the distribution and biological functions of the m(6)A/6mA. This well-established strategy is reproducible and widely applicable to other biological systems for high-throughput sequencing investigations of other RNA/DNA modifications. PMID- 26253972 TI - Pseudouridine in mRNA: Incorporation, Detection, and Recoding. AB - It has long been known that pseudouridine (Psi) is the most abundant modified nucleotide in stable RNAs, including tRNA, rRNA, and snRNA. Recent studies using massive parallel sequencing have uncovered the presence of hundreds of Psis in mRNAs as well. In eukaryotes and archaea, RNA pseudouridylation is introduced predominantly by box H/ACA RNPs, RNA-protein complexes each consisting of a single RNA moiety and four core proteins. It has been well established that Psi plays an essential role in regulating the structure and function of stable RNAs in several model organisms, including yeast, Xenopus laevis, and humans. However, the functional role of Psi in mRNA remains to be elucidated. One possibility (and true for stop/termination codons) is that Psi influences decoding during translation. It is imperative, therefore, to establish a system, in which one can site-specifically introduce pseudouridylation into target mRNA and biochemically test the impact of mRNA pseudouridylation on protein translation. Here, we present a method for (1) site-specific conversion of uridine into Psi in mRNA by designer box H/ACA RNP, (2) detection of Psi in target mRNA using site-specific labeling followed by nuclease digestion and thin layer chromatography, and (3) analysis of recoding of pseudouridylated premature termination codon in mRNA during translation. PMID- 26253973 TI - Pseudo-Seq: Genome-Wide Detection of Pseudouridine Modifications in RNA. AB - RNA molecules contain a variety of chemically diverse, posttranscriptionally modified bases. The most abundant modified base found in cellular RNAs, pseudouridine (Psi), has recently been mapped to hundreds of sites in mRNAs, many of which are dynamically regulated. Though the pseudouridine landscape has been determined in only a few cell types and growth conditions, the enzymes responsible for mRNA pseudouridylation are universally conserved, suggesting many novel pseudouridylated sites remain to be discovered. Here, we present Pseudo seq, a technique that allows the identification of sites of pseudouridylation genome-wide with single-nucleotide resolution. In this chapter, we provide a detailed description of Pseudo-seq. We include protocols for RNA isolation from Saccharomyces cerevisiae, Pseudo-seq library preparation, and data analysis, including descriptions of processing and mapping of sequencing reads, computational identification of sites of pseudouridylation, and assignment of sites to specific pseudouridine synthases. The approach presented here is readily adaptable to any cell or tissue type from which high-quality mRNA can be isolated. Identification of novel pseudouridylation sites is an important first step in elucidating the regulation and functions of these modifications. PMID- 26253974 TI - Pseudouridine Chemical Labeling and Profiling. AB - Pseudouridine (Psi) is the most abundant posttranscriptional RNA modification; yet little is known about its prevalence and function in messenger RNA, mostly due to the challenges in the transcriptome-wide detection of Psi. Here, we report CeU-Seq-a selective chemical labeling and pull-down method for the comprehensive analysis of transcriptome-wide pseudouridylation; this sequencing method will hopefully pave the way for functional studies of Psi-mediated biological regulation in the future. PMID- 26253975 TI - Experimental Approaches for Target Profiling of RNA Cytosine Methyltransferases. AB - RNA cytosine methyltransferases (m(5)C-RMTs) constitute an important class of RNA modifying enzymes, methylating specific cytosines within particular RNA targets in both coding and noncoding RNAs. Almost all organisms express at least one m(5)C-RMT, and vertebrates often express different types or variants of m(5)C RMTs in different cell types. Deletion or mutation of particular m(5)C-RMTs is connected to severe pathological manifestations ranging from developmental defects to infertility and mental retardation. Some m(5)C-RMTs show spatiotemporal patterns of expression and activity requiring careful experimental design for their analysis in order to capture their context-dependent targets. An essential step for understanding the functions of both the enzymes and the modified cytosines is defining the one-to-one connection between particular m(5)C RMTs and their target cytosines. Recent technological and methodological advances have provided researchers with new tools to comprehensively explore RNA cytosine methylation and methyltransferases. Here, we describe three complementary approaches applicable for both discovery and validation of candidate target sites of specific m(5)C-RMTs. PMID- 26253976 TI - RNA 5-Methylcytosine Analysis by Bisulfite Sequencing. AB - Cells have developed molecular machineries, which can chemically modify DNA and RNA nucleosides. One particular and chemically simple modification, (cytosine-5) methylation (m(5)C), has been detected both in RNA and DNA suggesting universal use of m(5)C for the function of these nucleotide polymers. m(5)C can be reproducibly mapped to abundant noncoding RNAs (transfer RNA, tRNA and ribosomal RNA, rRNA), and recently, also nonabundant RNAs (including mRNAs) have been reported to carry this modification. Quantification of m(5)C content in total RNA preparations indicates that a limited number of RNAs carry this modification and suggests specific functions for (cytosine-5) RNA methylation. What exactly is the biological function of m(5)C in RNA? Before attempting to address this question, m(5)C needs to be mapped specifically and reproducibly, preferably on a transcriptome-wide scale. To facilitate the detection of m(5)C in its sequence context, RNA bisulfite sequencing (RNA-BisSeq) has been developed. This method relies on the efficient chemical deamination of nonmethylated cytosine, which can be read out as single nucleotide polymorphism (nonmethylated cytosine as thymine vs. methylated cytosine as cytosine), when differentially comparing cDNA libraries to reference sequences after DNA sequencing. Here, the basic protocol of RNA-BisSeq, its current applications and limitations are described. PMID- 26253977 TI - Biochemical and Transcriptome-Wide Identification of A-to-I RNA Editing Sites by ICE-Seq. AB - Inosine (I) is a modified adenosine (A) in RNA. In Metazoa, I is generated by hydrolytic deamination of A, catalyzed by adenosine deaminase acting RNA (ADAR) in a process called A-to-I RNA editing. A-to-I RNA editing affects various biological processes by modulating gene expression. In addition, dysregulation of A-to-I RNA editing results in pathological consequences. I on RNA strands is converted to guanosine (G) during cDNA synthesis by reverse transcription. Thus, the conventional method used to identify A-to-I RNA editing sites compares cDNA sequences with their corresponding genomic sequences. Combined with deep sequencing, this method has been applied to transcriptome-wide screening of A-to I RNA editing sites. This approach, however, produces a large number of false positives mainly owing to mapping errors. To address this issue, we developed a biochemical method called inosine chemical erasing (ICE) to reliably identify genuine A-to-I RNA editing sites. In addition, we applied the ICE method combined with RNA-seq, referred to as ICE-seq, to identify transcriptome-wide A-to-I RNA editing sites. In this chapter, we describe the detailed protocol for ICE-seq, which can be applied to various sources and taxa. PMID- 26253979 TI - Methods in Enzymology. RNA Modification. Preface. PMID- 26253978 TI - Radical SAM-Mediated Methylation of Ribosomal RNA. AB - While RNA methylation occurs in all kingdoms of life, the type and the distribution of different methylated species varies substantially among archaea, bacteria, and eukaryotes. The most prevalent type of RNA methylation is methylation of nucleobases. However, despite recent advances in our knowledge of these marks, the biological roles of such modifications are still incompletely understood (Machnicka et al., 2013; Motorin & Helm, 2011; Sergeeva et al., 2014; Sergiev et al., 2011). A number of mechanisms have evolved to enable RNA methylation, which are tuned to the electronic demands of the substrate. Herein, we provide an overview of methods for expression, purification, and activity analysis of a specific type of RNA methylating enzymes, radical SAM methylsynthases. These enzymes modify the amidine carbon atoms of an adenosine, A2503, in bacterial 23S rRNA. The activities of these enzymes have only been recently reconstituted (Yan et al., 2010), which can be attributed to the complex anaerobic catalysis that they perform. As the substrate A2503 is located at the nascent peptide exit tunnel of the bacterial ribosome, methylations catalyzed by these enzymes have profound impact on the biology of the host strain. RlmN, an endogenous protein found in all bacteria, methylates the C2 amidine carbon and contributes to the translational fidelity (Benitez-Paez et al., 2012; Ramu et al., 2011; Vazquez-Laslop, Ramu, Klepacki, Kannan, & Mankin, 2010). Cfr, found in pathogenic species, methylates the C8 amidine carbon, a modification that confers resistance to various classes of antibiotics (Giessing et al., 2009; Long et al., 2006; Smith & Mankin, 2008). Interestingly, C2 methylated adenosine was recently detected in a subset of tRNAs, raising the question of the physiological role of this modification (Benitez-Paez et al., 2012). With an increase in available whole genome sequences, the development of methods to identify target substrates of RNA methylating enzymes (Khoddami & Cairns, 2013; Meyer et al., 2012; Tim, Katharina, & Matthias, 2010), as well as advances in the characterization of their activities, we anticipate the coming years will unravel novel aspects of mechanisms of the RNA methylation and deepen insight into the function of the resulting modification. PMID- 26253980 TI - ElipseTM, a Procedureless Gastric Balloon for Weight Loss: a Proof-of-Concept Pilot Study. AB - BACKGROUND: Endoscopic gastric balloons have been used effectively as weight loss devices for decades, but the requirement for endoscopy and sedation poses several limitations. The goal of this pilot study was to evaluate the safety and performance of a prototype version of ElipseTM, a procedureless gastric balloon. METHODS: Eight patients (mean BMI = 31.0 kg/m(2)) participated in this study. Each patient swallowed one ElipseTM balloon intended to remain in the stomach for 6 weeks, self-empty, and then pass. Each balloon was filled with 450 mL of filling fluid. Patients returned every 2 weeks for abdominal ultrasound. No specific diet or exercise plan was prescribed. RESULTS: All eight patients successfully swallowed the device. The most common adverse events were nausea and vomiting. There were no serious adverse events, and all balloons were excreted safely. Despite not being prescribed a diet or exercise plan, all eight patients lost weight. In 6/8 patients, the balloon remained full through 6 weeks, self emptied, and passed. In one patient, the balloon appeared partially collapsed on ultrasound after 11 days and was endoscopically punctured. One asymptomatic patient elected to have the balloon endoscopically punctured after 19 days. Both balloons passed in the stool after 4 days. In both cases, endoscopic examination of the upper GI tract showed no abnormalities. CONCLUSIONS: This pilot study demonstrates the safety and performance of ElipseTM, a procedureless gastric balloon for weight loss. Future studies will test a commercial design filled to 550 mL intended to last in the stomach for at least 12 weeks. PMID- 26253981 TI - The optimal atmospheric CO2 concentration for the growth of winter wheat (Triticum aestivum). AB - This study examined the optimal atmospheric CO2 concentration of the CO2 fertilization effect on the growth of winter wheat with growth chambers where the CO2 concentration was controlled at 400, 600, 800, 1000, and 1200 ppm respectively. I found that initial increase in atmospheric CO2 concentration dramatically enhanced winter wheat growth through the CO2 fertilization effect. However, this CO2 fertilization effect was substantially compromised with further increase in CO2 concentration, demonstrating an optimal CO2 concentration of 889.6, 909.4, and 894.2 ppm for aboveground, belowground, and total biomass, respectively, and 967.8 ppm for leaf photosynthesis. Also, high CO2 concentrations exceeding the optima not only reduced leaf stomatal density, length and conductance, but also changed the spatial distribution pattern of stomata on leaves. In addition, high CO2 concentration also decreased the maximum carboxylation rate (Vc(max)) and the maximum electron transport rate (J(max)) of leaf photosynthesis. However, the high CO2 concentration had little effect on leaf length and plant height. The optimal CO2 fertilization effect found in this study can be used as an indicator in selecting and breeding new wheat strains in adapting to future high atmospheric CO2 concentrations and climate change. PMID- 26253982 TI - Revisiting the risks of MRI with Gadolinium based contrast agents-review of literature and guidelines. AB - Gadolinium based contrast agents (GBCA) have been linked to the occurrence of nephrogenic systemic fibrosis (NSF) in renal impaired patients. The exact interaction between the various different available formulations and occurrence of NSF is not completely understood, but has been postulated. This association has triggered public health advisory bodies to issue guidelines and best practice recommendations on its use. As a result, the reported incidence of NSF, as well as the published use of GBCA-enhanced magnetic resonance imaging in renal impairment, has seen a decline. Understanding of the events that led to these recommendations can increase clinical awareness and the implications of their usage. We present a review of published literature and a brief overview of practice recommendations, guidelines and manuals on contrast safety to aide everyday imaging practice. TEACHING POINTS: * Low risk gadolinium based contrast agents should be the choice in renal insufficiency. * Higher doses have been linked to NSF development. Doses should be as low as possible. * Clear documentation of date, dose and type of formulation used should be noted. * Post scan dialysis should be arranged as soon as possible and feasible. * Pre- existing inflammatory state is a risk factor; liver insufficiency is not a contraindication. PMID- 26253983 TI - Imaging findings of the orbital and intracranial complications of acute bacterial rhinosinusitis. AB - In patients with acute bacterial rhinosinusitis severe orbital and intracranial complications can occur. This review will illustrate the anatomic relationship between the paranasal sinuses and the orbital and intracranial compartments. Subsequently, the spectrum of orbital and intracranial complications of rhinosinusitis and related imaging findings will be discussed and illustrated by case material from daily practice. TEACHING POINTS: * Acute bacterial rhinosinusitis can cause severe orbital and intracranial complications. * If orbital or intracranial complications are suspected, cross-sectional imaging is mandatory. * Infection can spread from the ethmoid sinus to the orbit through the lamina papyracea. * Frontal sinusitis can spread intracranially through dehiscences or osteomyelitis. * Radiologists must recognize imaging findings of complications of acute bacterial rhinosinusitis. PMID- 26253984 TI - Resynchronization therapy in heart failure with right bundle branch block: new perspectives. PMID- 26253985 TI - Engineering experience and clinical electrocardiography. PMID- 26253986 TI - Exploration of sensory impairments associated with C6 and C7 radiculopathies. AB - BACKGROUND CONTEXT: Cervical radiculopathy is a common disorder caused by compression of the cervical nerve roots and is characterized by arm pain and altered sensory-motor function. Incongruity in the locations of C6 and C7 dermatomes in competing versions of historical dermatome maps has plagued interpretation of impaired sensation associated with C6 and C7 radiculopathies. Magnetic resonance imaging (MRI) allows accurate identification of the C6 or C7 nerve root compression and therefore makes it possible to explore sensory findings that are associated with compression of specific nerve root. PURPOSE: This study compared the locations of impaired sensation in subjects with cervical radiculopathy from MRI-confirmed C6 and C7 nerve root compression. STUDY DESIGN: Case series was used for this study. PATIENT SAMPLE: A total of 122 subjects with symptoms suggestive of cervical radiculopathy were recruited by 11 spine specialist from 5 practice locations. Of these, 30 subjects had MRI-confirmed C6 and 40 subjects C7 radiculopathy. OUTCOME MEASURES: Standardized pinprick sensory examination of the forearm and hand of every subject was performed, and the locations of sensory impairments were recorded. METHODS: Sensory examination was performed before reviewing MRI results or performing motor or reflex examination. Areas of impaired sensation were recorded on drawings of the palmar and dorsal forearm and hand, and translated using a grid into 36 specific areas for analysis. Chi-square was used to compare frequencies of findings for each grid area for C6 and C7 radiculopathies. Power analysis suggested that a minimum of 27 subjects in each group were needed to detect a 30 percentage point difference in frequency of sensory impairments. Significance was set at <=.05. RESULTS: Approximately 80% of subjects had impaired sensation in at least 1 grid area, most often in the distal forearm and hand, and many had findings in multiple areas. There was nearly complete overlap for locations of impaired sensation for C6 and C7 radiculopathy, and the frequencies of impaired sensation differed only in the dorsal aspect of the distal radial forearm where it was twice as common in C6 radiculopathy (p=.02). CONCLUSIONS: The location of sensory impairments associated with symptomatic C6 and C7 nerve root compression overlap to the extent that caution should be exercised when predicting compression of either the C6 or C7 nerve roots based on locations of impaired sensation. Impaired sensation in the radial aspect of the distal forearm is more common in C6 radiculopathies. PMID- 26253987 TI - Multiple isolated spinous processes fractures. PMID- 26253989 TI - Disseminated adult spinal extramedullary myxopapillary ependymoma. PMID- 26253988 TI - A scoring system to predict postoperative medical complications in high-risk patients undergoing elective thoracic and lumbar arthrodesis. AB - BACKGROUND CONTEXT: Various surgical factors affect the incidence of postoperative medical complications following elective spinal arthrodesis. Because of the inter-relatedness of these factors, it is difficult for clinicians to accurately risk-stratify individual patients. PURPOSE: Our goal was to develop a scoring system that predicts the rate of major medical complications in patients with significant preoperative medical comorbidities, as a function of the four perioperative parameters that are most closely associated with the invasiveness of the surgical intervention. STUDY DESIGN/SETTING: This study used level 2, Prognostic Retrospective Study. PATIENT SAMPLE: The patient sample consisted of 281 patients with American Society of Anesthesiologists (ASA) scores of 3-4 who underwent elective thoracic, lumbar, or thoracolumbar fusion surgeries from 2007 to 2011. OUTCOME MEASURES: Physiologic risk factors, number of levels fused, complications, operative time, intraoperative fluids, and estimate blood loss were the outcome measures of this study. METHODS: Risk factors were recorded, and patients who suffered major medical complications within the 30-day postoperative period were identified. We used chi-square tests to identify factors that affect the medical complication rate. These factors were ranked and scored by quartiles. The quartile scores were combined to form a single composite score. We determined the major medical complication rate for each composite score, and divided the cohort into quartiles again based on score. A Pearson linear regression analysis was used to compare the incidence of complications to the score. RESULTS: The number of fused levels, operative time, volume of intraoperative fluids, and estimated blood loss influenced the complication rate of patients with ASA scores of 3-4. The quartile ranking of each of the four predictive factors was added, and the sum became the composite score. This score predicted the complication rate in a linear fashion ranging from 7.6% for the lowest risk group to 34.7% for the highest group (r=0.998, p<.001). CONCLUSIONS: Taken together, the four factors, though not independent of one another, proved to be strongly predictive of the major medical complication rate. This score can be used to guide medical management of thoracic and lumbar spinal arthrodesis patients with preexisting medical comorbidities. PMID- 26253990 TI - Treatment of sacral aneurysmal bone cyst with percutaneous sacroplasty. PMID- 26253991 TI - Evaluation of regression-based 3-D shoulder rhythms. AB - The movements of the humerus, the clavicle, and the scapula are not completely independent. The coupled pattern of movement of these bones is called the shoulder rhythm. To date, multiple studies have focused on providing regression based 3-D shoulder rhythms, in which the orientations of the clavicle and the scapula are estimated by the orientation of the humerus. In this study, six existing regression-based shoulder rhythms were evaluated by an independent dataset in terms of their predictability. The datasets include the measured orientations of the humerus, the clavicle, and the scapula of 14 participants over 118 different upper arm postures. The predicted orientations of the clavicle and the scapula were derived from applying those regression-based shoulder rhythms to the humerus orientation. The results indicated that none of those regression-based shoulder rhythms provides consistently more accurate results than the others. For all the joint angles and all the shoulder rhythms, the RMSE are all greater than 5 degrees . Among those shoulder rhythms, the scapula lateral/medial rotation has the strongest correlation between the predicted and the measured angles, while the other thoracoclavicular and thoracoscapular bone orientation angles only showed a weak to moderate correlation. Since the regression-based shoulder rhythm has been adopted for shoulder biomechanical models to estimate shoulder muscle activities and structure loads, there needs to be further investigation on how the predicted error from the shoulder rhythm affects the output of the biomechanical model. PMID- 26253993 TI - Urinary, Plasma, and Serum Biomarkers' Utility for Predicting Acute Kidney Injury Associated With Cardiac Surgery in Adults: A Meta-analysis. AB - BACKGROUND: Early accurate detection of acute kidney injury (AKI) occurring after cardiac surgery may improve morbidity and mortality. Although several novel biomarkers have been developed for the early detection of AKI, their clinical utility in the critical intraoperative and immediate postoperative period remains unclear. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Adult patients having cardiac surgery. SELECTION CRITERIA FOR STUDIES: EMBASE, CINAHL, Cochrane Library, Scopus, and PubMed from January 1990 until January 2015 were systematically searched for cohort studies reporting the utility of novel biomarkers for the early diagnosis of AKI after adult cardiac surgery. Reviewers extracted data for study design, population, timing of biomarker measurement and AKI occurrence, biomarker performance (area under the receiver operating characteristic curve [AUROC]), and risk of bias. INDEX TESTS: Novel urine, plasma, and serum AKI biomarkers, measured intraoperatively and in the early postoperative period (<24 hours). REFERENCE TESTS: AKI was defined according to the RIFLE, AKIN, or 2012 KDIGO criteria. RESULTS: We found 28 studies reporting intraoperative and/or early postoperative measurement of urine (n=23 studies) or plasma or serum (n=12 studies) biomarkers. Only 4 of these studies measured biomarkers intraoperatively. Overall, intraoperative discrimination by the urine biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury marker 1 (KIM-1) demonstrated AUROCs<0.70, whereas N-acetyl-beta-d glucosaminidase (NAG) and cystatin C had AUROCs<0.75. In the immediate 24-hour postoperative period, the urine biomarkers NGAL (16 studies), KIM-1 (6 studies), and liver-type fatty acid binding protein (6 studies) exhibited composite AUROCs of 0.69 to 0.72. The composite AUROCs for postoperative urine cystatin C, NAG, and interleukin 18 were <=0.70. Similarly, the composite AUROCs for postoperative plasma NGAL (6 studies) and cystatin-C (5 studies) were <0.70. LIMITATIONS: Heterogeneous AKI definitions. CONCLUSIONS: In adults, known urinary, plasma, and serum biomarkers of AKI possess modest discrimination at best when measured within 24 hours of cardiac surgery. PMID- 26253992 TI - Estimated GFR and Subsequent Higher Left Ventricular Mass in Young and Middle Aged Adults With Normal Kidney Function: The Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - BACKGROUND: Left ventricular hypertrophy is common and is associated with cardiovascular events and death among patients with known chronic kidney disease. However, the link between reduced glomerular filtration rate (GFR) and left ventricular mass index (LVMI) remains poorly explored among young and middle-aged adults with preserved kidney function. In this study, we examined the association of cystatin C-based estimated GFR (eGFRcys) and rapid decline in eGFR with subsequent LVMI. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: We included 2,410 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort with eGFRcys > 60mL/min/1.73m(2) at year 15 and who had an echocardiogram obtained at year 25. PREDICTOR: eGFRcys at year 15 and rapid decline in eGFRcys (defined as >3% per year over 5 years from years 15 to 20). OUTCOME: LVMI measured at year 25. MEASUREMENTS: We adjusted for age, sex, race, diabetes, body mass index, low- and high-density lipoprotein cholesterol levels, cumulative systolic blood pressure, and albuminuria. RESULTS: Mean age was 40+/-4 (SD) years, 58% were women, and 43% were black. After 10 years of follow-up, mean LVMI was 39.6+/-13.4g/m(2.7). Compared with eGFRcys > 90mL/min/1.73m(2) (n = 2,228), eGFRcys of 60 to 75mL/min/1.73m(2) (n = 29) was associated with 5.63 (95% CI, 0.90-10.36) g/m(2.7) greater LVMI (P = 0.02), but there was no association of eGFRcys of 76 to 90mL/min/1.73m(2) (n = 153) with LVMI after adjustment for confounders. Rapid decline in eGFRcys was associated with higher LVMI compared with participants without a rapid eGFRcys decline (beta coefficient, 1.48; 95% CI, 0.11-2.83; P = 0.03) after adjustment for confounders. LIMITATIONS: There were a limited number of participants with eGFRcys of 60 to 90mL/min/1.73m(2). CONCLUSIONS: Among young and middle-aged adults with preserved kidney function, eGFRcys of 60 to 75mL/min/1.73m(2) and rapid decline in eGFRcys were significantly associated with subsequently higher LVMI. Further studies are needed to understand the mechanisms that contribute to elevated LVMI in this range of eGFRcys. PMID- 26253994 TI - De novo assembly and analysis of tissue-specific transcriptomes revealed the tissue-specific genes and profile of immunity from Strongylocentrotus intermedius. AB - Strongylocentrotus intermedius is an important marine species in north China and Japan. Recent years, diseases are threating the sea urchin aquaculture industry seriously. To provide a genetic resource for S. intermedius as well as overview the immune-related genes of S. intermedius, we performed transcriptome sequencing of three cDNA libraries representing three tissues, coelomocytes, gut and peristomial membrane respectively. In total 138,421 contigs were assembled from all sequencing data. 96,764 contigs were annotated according to bioinformatics databases, including NT, nr, Swiss-Prot, KEGG, COG. 49,336 Contigs were annotated as CDS. In this study, we obtained 24,778 gene families from S. intermedius transcriptome. The gene expression analysis revealed that more genes were expressed in gut, more high expression level genes in coelomocytes when compared with other tissues. Specific expressed contigs in coelomocytes, gut, and peristomial membrane were 546, 1136, and 1012 respectively. Pathway analysis suggested 25, 17 and 36 potential specifically pathways may specific progressed in peristomial membrane, gut and coelomocytes respectively. Similarities and differences between S. intermedius and other echinoderms were analyzed. S. intermedius was more homology to Strongylocentrotus purpuratus than others sea urchin. Of 24,778 genes, 1074 genes are immune-related, immune genes were expressed with a higher level in coelomocytes than other tissues. Complement system may be the most important immune system in sea urchin. We also identified 2438 SSRs and 16,236 SNPs for S. intermedius. These results provide a transcriptome resource and foundation to study molecular mechanisms of sea urchin immune system. PMID- 26253995 TI - Transcriptomic profiling of male European eel (Anguilla anguilla) livers at sexual maturity. AB - The European eel Anguilla anguilla has a complex life cycle that includes freshwater, seawater and morphologically distinct stages as well as two extreme long distance migrations. Eels do not feed as they migrate across the Atlantic to the Sargasso Sea but nevertheless reach sexual maturity before spawning. It is not yet clear how existing energy stores are used to reach the appropriate developmental state for reproduction. Since the liver is involved in energy metabolism, protein biosynthesis and endocrine regulation it is expected to play a key role in the regulation of reproductive development. We therefore used microarrays to identify genes that may be involved in this process. Using this approach, we identified 231 genes that were expressed at higher and 111 genes that were expressed at lower levels in sexually mature compared with immature males. The up-regulated set includes genes involved in lipid metabolism, fatty acid synthesis and transport, mitochondrial function, steroid transport and bile acid metabolism. Several genes with putative enzyme functions were also expressed at higher levels at sexual maturity while genes involved in immune system processes and protein biosynthesis tended to be down-regulated at this stage. By using a high-throughput approach, we have identified a subset of genes that may be linked with the mobilization of energy stores for sexual maturation and migration. These results contribute to an improved understanding of eel reproductive biology and provide insight into the role of the liver in other teleosts with a long distance spawning migrations. PMID- 26253996 TI - Individual metatarsal and forefoot kinematics during walking in people with diabetes mellitus and peripheral neuropathy. AB - The purpose of this study was to compare in-vivo kinematic angular excursions of individual metatarsal segments and a unified forefoot segment in people with Diabetes Mellitus and peripheral neuropathy (DMPN) without deformity or ulceration to a healthy matched control group. Thirty subjects were recruited. A five- segment foot model (1st, 3rd, and 5th metatarsals, calcaneus, tibia) was used to examine relative 3D angular excursions during the terminal stance phase of walking. Student t-tests were used to assess group differences in kinematics. Pearson correlations and cross-correlations were used to assess relationships between the motion of the individual metatarsals and the unified forefoot. Significant reductions of DMPN group sagittal plane angular excursions were detected in all individual metatarsals and the unified forefoot (p < 0.01). Frontal plane 3rd metatarsal excursion was reduced (p = 0.04) in the DMPN group. The 3rd and 5th metatarsal and the unified forefoot excursions were reduced (p <= 0.02) in the DMPN group in the transverse plane. In both groups, coupling of individual metatarsal and unified forefoot motion was strongest in the sagittal plane. This study illustrates that multiple individual metatarsals have reduced motion in people with DMPN. Differences in the magnitude and coupling between individual metatarsal motion and unified forefoot motion supports the use of a two segment forefoot modeling approach in future kinematic analyses. Further study is recommended to determine if the observed kinematic profile is related to the development and location of deformity and tissue breakdown in people with DMPN. PMID- 26253997 TI - A Systematic Assessment of Absolute Treatment Effect. PMID- 26253998 TI - Relation of New Permanent Right or Left Bundle Branch Block on Short- and Long Term Mortality in Acute Myocardial Infarction Bundle Branch Block and Myocardial Infarction. AB - The aim of this study was to investigate the prognosis associated with bundle branch block (BBB) depending on location, time of appearance, and duration in patients with myocardial infarction (MI). From January 1998 to January 2008, we recruited 5,570 patients with acute MI. Thirty-day and 7-year all-cause mortality, according to BBB location, time of appearance, and duration were analyzed by multivariable analyses. BBB was present in 964 patients (17.3%); right BBB (RBBB) 10.6% and left BBB (LBBB) 6.7%. Overall mortality rate at 30 days was 13.2% (n = 738) and 7 years was 6.34 deaths per 100 patient-year. Both RBBB and LBBB were more frequently previous, 42.9% and 58.8%. Compared with non BBB, all BBB groups showed higher prevalence of co-morbidities, especially rates of diabetes (49.0% vs 34.3%, p <0.001) and more often heart failure during hospitalization (54.5% vs 26.6%, p <0.001). Compared with RBBB, patients with LBBB had a higher prevalence of co-morbidities and a higher mortality, especially the new BBB, 30 days: 52.5% versus 31.6% and 7 years (incident rate): 27.2 versus 13.3 per 100 patient-year. New transient BBB had lower heart failure on admission (42.6% vs 58.3%, p = 0.008) and 30-day mortality (20.3% vs 69.6%, p <0.001) compared with permanent in both locations. New permanent RBBB was independently associated with 30-day (hazard ratio [HR] 2.01, 95% confidence interval [CI] 1.45 to 2.79) and 7-year mortality (HR 3.12, 95% CI 2.38 to 4.09). New-permanent LBBB was independently associated with 30-day (HR 2.15, 95% CI 1.47 to 3.15) and 7 year mortality (HR 2.91, 95% CI 2.08 to 4.08). In conclusion, in patients with acute MI, the appearance of a new BBB was independently associated with a higher 30-day and 7-year all-cause mortality. PMID- 26253999 TI - Usefulness of Combining Electrocardiographic and Echocardiographic Findings and Brain Natriuretic Peptide in Early Detection of Cardiac Amyloidosis in Subjects With Transthyretin Gene Mutation. AB - Early noninvasive identification of cardiac amyloidosis (CA) is of growing clinical importance. Low voltage on electrocardiogram (ECG), increased left ventricular (LV) septal thickness (ST), and global longitudinal strain (GLS) on echocardiography, and elevated brain natriuretic peptides (BNP) are used as surrogates of CA. Thirty-five patients (50 +/- 14 years, 22 women) underwent electrocardiography to analyze low-voltage QRS (<15 mV) pathologic Q waves, poor R-wave progression, ST-T abnormalities, and left bundle branch block. An ECG was considered abnormal if at least one ECG alteration was present. Echocardiography was used to analyze LVST, E/E', and GLS. All participants also had BNP blood testing. (99m)Tc-3,3-diphosphono-1,2 propanodicarboxylic acid scintigraphy assumed as a reference method showed CA in 18 patients (51%, CA group) and no accumulation in 17 patients (no CA group). In descending order of accuracy, LVST >14 mm, E/E' >6.6, GLS <14.1, BNP >129 pg/ml, and an overall abnormal ECG showed good capability to distinguish patients with and without CA. All these parameters were predictors of CA in univariate analysis, whereas low-voltage QRS showed the worst performance. LVST >14 mm (p = 0.002) was the best independent predictor of CA, achieving sensitivity of 78% and accuracy of 89%. However, an LVST >14 mm (p = 0.005) plus an abnormal ECG (p = 0.03) show together a greater sensitivity, equal to 89%, in identifying CA. An integrated evaluation of ECG and echocardiography is a sensitive and low-cost technical approach to identify CA in patients with transthyretin gene mutation. PMID- 26254000 TI - Association Between Atopic Dermatitis and Autism Spectrum Disorders: A Systematic Review. AB - BACKGROUND: Atopic dermatitis (AD) is an allergic disorder caused by both immunological dysregulation and epidermal barrier defect. Several studies have investigated the association between AD and mental health disorders. Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions characterized by impairments in social communication and restricted, stereotyped interests and behaviors. The concurrent increased prevalence of AD and ASD in the last decades has led many scientists to investigate the relationship between the two diseases. OBJECTIVE: The aim of this systematic review was to examine the association between AD and ASD. METHODS: A systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. PubMed and ScienceDirect were searched up to March 2015 for all reports examining the association between ASD and AD. Descriptive statistics of the studies are reported. RESULTS: The review included 18 studies assessing the association between ASD and AD. Of these studies, two focused on ASD in relation to AD alone, 14 discussed ASD in relation to both AD and other atopic disorders, and two evaluated AD in parents of children with ASD. Most of these studies found a positive association between the two disorders, although there were some studies going in the opposite direction. The entity of the association is somewhat inconsistent among the different studies given that the frequencies of AD in ASD compared with a control group ranged from 7 to 64.2%. In addition, odds ratios (ORs) or hazard ratios (HRs) gave different results as three studies found a weak association with an OR below 2 and a nonsignificant p value, and three other studies found a moderate or strong association with an OR ranging from 1.52 to 7.17 and a significant p value. When all atopic disorders were considered when evaluating the risk of ASD, the association was strong with an HR of 3.4 or an OR of 1.24 and p < 0.001. CONCLUSIONS: Overall, the results of this systematic review seem to reveal an association between ASD and AD, suggesting that subjects with ASD have an increased risk of presenting with AD compared with typically developing controls, and vice versa. This association is supported by clinical/epidemiological aspects, shared genetic background and common immunological and autoimmune processes. However, the variability in study population and design, and the presence of other risk factors acting as confounding factors, sometimes contribute to inconsistent results. Further studies are needed to clarify the underlying pathophysiologic mechanism explaining the association between ASD and AD and to explore the causal association between the two conditions. PMID- 26254001 TI - Ivermectin: A Review in Rosacea. AB - Ivermectin 1% cream (Soolantra((r)); RosiverTM; Izefla((r))) is a novel topical agent indicated for the once-daily treatment of inflammatory lesions of rosacea. Ivermectin is a derivative of the avermectin family of macrocyclic lactone parasiticides. It displays anti-inflammatory properties as well as broad-spectrum anti-parasitic activity, both of which may contribute to its efficacy in treating rosacea. In phase III trials of 12 or 16 weeks' duration in adults with moderate to severe papulopustular rosacea, once-daily ivermectin 1% cream improved the symptoms of rosacea (as per Investigator Global Assessment and inflammatory lesion count) and health-related quality of life versus vehicle, and was more effective than twice-daily metronidazole 0.75% cream in terms of these measures. Ivermectin 1% cream continues to provide benefit for up to 52 weeks of treatment, according to extension studies, and is well tolerated, with the most common treatment-related adverse events (skin burning sensation, pruritus, dry skin and skin irritation) each occurring with low incidence (<2%). Thus, ivermectin 1% cream is an effective and well tolerated option for the topical treatment of inflammatory lesions of rosacea, with the convenience of once-daily application. PMID- 26254002 TI - Ecological diversity of Trypanosoma cruzi transmission in the Amazon basin. The main scenaries in the Brazilian Amazon. AB - The ecological diversity of Trypanosoma cruzi transmission in the Brazilian Amazon region is directly interlinked with the parasite's extensive reservoir, composed of 33 species of wild mammals within the following orders: Marsupialia, Chiroptera, Rodentia, Xenarthra, Carnivora and Primates; and of 16 species of wild triatomines, of which ten may be infected with T. cruzi. Four scenarios for the diversity of T. cruzi transmission in the Brazilian Amazon region are evident: (i) T. cruzi transmission between vectors and wild mammals, which is characterized as a wild enzooty encompassing the entire Amazon basin; (ii) accidental T. cruzi transmission from vectors and wild mammals to humans, when they invade the wild ecotope or when these vectors and wild mammals invade human homes; (iii) occupational Chagas disease among piassava (Leopoldinia piassaba) palm fiber gatherers, transmitted by the vector Rhodnius brethesi, for which these palm trees are the specific ecotope; (IV) oral T. cruzi transmission to humans through food contamination, particularly in juices from plants such as assai, which today is considered to be endemic in the Brazilian Amazon region, with more than 1500 cases notified. PMID- 26254003 TI - The impact of landscape transformation on the reinfestation rates of Rhodnius prolixus in the Orinoco Region, Colombia. AB - Trypanosoma cruzi, the agent responsible for Chagas disease, is widely distributed in the Americas in association to insect vectors and animal reservoirs. Triatomines are common vectors of Chagas disease and they vary in their distribution and affinity to human or sylvatic environments. Thus, control programs that include house spraying have been successful in regions were insects have a tendency to domiciliation. In the Orinoco region of Colombia, Rhodnius prolixus is the main vector presenting a stable sylvatic cycle, but is also found colonizing human dwellings. In 1997, health authorities developed a control program in the Department of Casanare spreading with insecticide houses in 667 localities. Infestation Indexes (I.I.) were calculated at the locality level before and after spraying. Times for re-infestation assessment varied between 1 and 67 months. Localities were classified into 3 groups according to their I.I. after spraying. Group 1 dropped their I.I. down to zero, Group 2 had a drop but remained positive and Group 3 increased its I.I. after spraying. We classified each group in terms of their land use characteristics before and after spraying based on satellite images obtained for the years 1997 (beginning of the study) and 2002 (end of program). We found that spraying significantly reduce the I.I. on average. However, we found that time after spraying does not produce significant differences in the I.I. Interestingly, land use changes and variations on I.I. after spraying for all groups were significantly dependent. PMID- 26254004 TI - Analysis and meta-analysis of five polymorphisms of the LINGO1 and LINGO2 genes in Parkinson's disease and multiple system atrophy in a Chinese population. AB - Whether polymorphisms rs11856808 and rs9652490 of the Leucine-rich repeat and Ig domain containing, Nogo receptor-interacting protein-1 (LINGO1) gene, as well as rs10968280, rs13362909 and rs7033345 of the LINGO2 gene, increase the risk for Parkinson's disease (PD) is controversial. Considering the overlap of the clinical and pathological characteristics among PD and multiple system atrophy (MSA), we explored the associations between these five polymorphisms and PD and MSA in a Chinese population. A total of 1055 PD patients, 320 MSA patients, and 810 healthy controls (HCs) were genotyped for these five polymorphisms in LINGO1 and LINGO 2 using Sequenom iPLEX Assay technology. Moreover, after combining our results with available published data, a meta-analysis was conducted to investigate the associations between LINGO 1 rs11856808 and rs9652490 and the risk of PD. The frequency of the minor alleles "T" of LINGO1 rs11856808 was significantly lower in PD than that in HCs (p = 0.011, OR 0.89, 95 % CI 0.81 0.97), but not in MSA. Moreover, there were no significant differences in the minor allele frequency distributions of the other four polymorphisms between PD and HCs, and between MSA and HCs. The meta-analysis showed a lack of association of rs9652490 and PD, regardless of the genetic model or ethnic origin. However, the rs11856808 allele decreased the risk of PD in patients of Asian origin in a dominant genetic model. Our findings suggest that rs11856808 plays a protective role by decreasing the risk for PD, but not for MSA, in Asian population, the other four polymorphisms do not contribute to the risk for PD and MSA. PMID- 26254005 TI - Douglas Moray Cooper Lamb Argyll Robertson (1837-1909). PMID- 26254006 TI - Comparative proteomic analyses reveal that Gnt2-mediated N-glycosylation affects cell wall glycans and protein content in Fusarium oxysporum. AB - Protein N-glycosylation is a ubiquitous post-translational modification that contributes to appropriate protein folding, stability, functionality and localization. N-glycosylation has been identified as an important process for morphogenesis and virulence in several fungal pathogens including Fusarium oxysporum. Here we conducted comparative chemical and proteome-based analyses to better understand the physiological changes associated with protein hypo-N glycosylation in F. oxysporum N-glycosyltransferase Gnt2-deficient mutant. The results suggest that lack of functional Gnt2 alters the size of galactofuranose chains in cell wall glycans, resulting in polysaccharides with a broad range of polymerization degrees and differential protein glycosylation patterns. Functional Gnt2 is necessary for normal conidium size and morphology and wild type hyphal fusion rates. Hypo-N-glycosylation in ?gnt2 mutant results in enhanced oxidative stress resistance and reduced levels of proteins involved in cell wall organization, biogenesis and remodelling. Deletion of gnt2 gene led to accumulation of trafficking vesicles at hyphal tips, reduced secretion of extracellular proteins related to detoxification of antifungal compounds and degradation of plant cell walls, and lowered extracellular polygalacturonase activity. Altogether, the results confirm that Gnt2-mediated N-glycosylation plays a crucial role in morphogenesis and virulence, and demonstrate that Gnt2 is essential for protein function, transport and relative abundance in F. oxysporum. PMID- 26254007 TI - Proteomic analysis of post translational modifications in cyanobacteria. AB - Cyanobacteria are a diverse group of Gram-negative bacteria and the only prokaryotes capable of oxygenic photosynthesis. Recently, cyanobacteria have attracted great interest due to their crucial roles in global carbon and nitrogen cycles and their ability to produce clean and renewable biofuels. To survive in various environmental conditions, cyanobacteria have developed a complex signal transduction network to sense environmental signals and implement adaptive changes. The post-translational modifications (PTMs) systems play important regulatory roles in the signaling networks of cyanobacteria. The systematic investigation of PTMs could contribute to the comprehensive description of protein species and to elucidate potential biological roles of each protein species in cyanobacteria. Although the proteomic studies of PTMs carried out in cyanobacteria were limited, these data have provided clues to elucidate their sophisticated sensing mechanisms that contribute to their evolutionary and ecological success. This review aims to summarize the current status of PTM studies and recent publications regarding PTM proteomics in cyanobacteria, and discuss the novel developments and applications for the analysis of PTMs in cyanobacteria. Challenges, opportunities and future perspectives in the proteomics studies of PTMs in cyanobacteria are also discussed. PMID- 26254008 TI - QPROT: Statistical method for testing differential expression using protein-level intensity data in label-free quantitative proteomics. AB - We introduce QPROT, a statistical framework and computational tool for differential protein expression analysis using protein intensity data. QPROT is an extension of the QSPEC suite, originally developed for spectral count data, adapted for the analysis using continuously measured protein-level intensity data. QPROT offers a new intensity normalization procedure and model-based differential expression analysis, both of which account for missing data. Determination of differential expression of each protein is based on the standardized Z-statistic based on the posterior distribution of the log fold change parameter, guided by the false discovery rate estimated by a well-known Empirical Bayes method. We evaluated the classification performance of QPROT using the quantification calibration data from the clinical proteomic technology assessment for cancer (CPTAC) study and a recently published Escherichia coli benchmark dataset, with evaluation of FDR accuracy in the latter. BIOLOGICAL SIGNIFICANCE: QPROT is a statistical framework with computational software tool for comparative quantitative proteomics analysis. It features various extensions of QSPEC method originally built for spectral count data analysis, including probabilistic treatment of missing values in protein intensity data. With the increasing popularity of label-free quantitative proteomics data, the proposed method and accompanying software suite will be immediately useful for many proteomics laboratories. This article is part of a Special Issue entitled: Computational Proteomics. PMID- 26254009 TI - Unique diversity of the venom peptides from the scorpion Androctonus bicolor revealed by transcriptomic and proteomic analysis. AB - Androctonus bicolor is one of the most poisonous scorpion species in the world. However, little has been known about the venom composition of the scorpion. To better understand the molecular diversity and medical significance of the venom from the scorpion, we systematically analyzed the venom components by combining transcriptomic and proteomic surveys. Random sequencing of 1000 clones from a cDNA library prepared from the venom glands of the scorpion revealed that 70% of the total transcripts code for venom peptide precursors. Our efforts led to a discovery of 103 novel putative venom peptides. These peptides include NaTx-like, KTx-like and CaTx-like peptides, putative antimicrobial peptides, defensin-like peptides, BPP-like peptides, BmKa2-like peptides, Kunitz-type toxins and some new type venom peptides without disulfide bridges, as well as many new-type venom peptides that are cross-linked with one, two, three, five or six disulfide bridges, respectively. We also identified three peptides that are identical to known toxins from scorpions. The venom was also analyzed using a proteomic technique. The presence of a total of 16 different venom peptides was confirmed by LC-MS/MS analysis. The discovery of a wide range of new and new-type venom peptides highlights the unique diversity of the venom peptides from A. bicolor. These data also provide a series of novel templates for the development of therapeutic drugs for treating ion channel-associated diseases and infections caused by antibiotic-resistant pathogens, and offer molecular probes for the exploration of structures and functions of various ion channels. PMID- 26254010 TI - Proteomic investigation of whole saliva in Wilson's disease. AB - Wilson's disease is a rare inherited disorder of copper metabolism, manifesting hepatic, neurological and psychiatric symptoms. Early diagnosis is often unfeasible and a unique diagnostic test is currently inapplicable. We performed the qualitative/quantitative characterization of the salivary proteome/peptidome of 32 Wilson's disease patients by an integrated top-down/bottom-up approach. Patients exhibited significant higher levels of S100A9 and S100A8 proteoforms, and their oxidized forms with respect to controls. Oxidation occurred on methionine and tryptophan residues, and on the unique cysteine residue, in position 42 in S100A8, and 3 in S100A9, that generated glutathionylated, cysteinylated, sulfinic, sulfonic, and disulfide dimeric forms. Wilson's disease patient saliva showed high levels of two new fragments of the polymeric immunoglobulin receptor, and of alpha-defensins 2 and 4. Overall, the salivary proteome of Wilson's disease patients reflected oxidative stress and inflammatory conditions characteristic of the pathology, highlighting differences that could be useful clues of disease exacerbation. PMID- 26254011 TI - Proteomic changes to the sarcoplasmic fraction of predominantly red or white muscle following acute heat stress. AB - Acute heat stress negatively impacts both human health and livestock production. In order to characterize the skeletal muscle cellular response to acute heat stress, the muscle sarcoplasmic proteome was analyzed via 2-D DIGE. Pigs (n=8 per treatment) were exposed to one of the three treatments for 12 h: heat stress (HS; 37 degrees C), thermal neutral (TN; 21 degrees C), or TN while pair-fed (PFTN; 21 degrees C, feed limited based on HS group consumption). After euthanasia, the semitendinosus muscle was excised, separated into predominately red (RST) and white (WST) fiber type portions, and sarcoplasmic proteins were extracted. Spots determined in 2D-DIGE to be different due to HS were identified using ESI-MS or LC-MS/MS. Several proteins involved in glycolysis, glycogenesis, and glycogenolysis were increased or modified, indicating enhanced glycolytic capacity in response to HS. In the WST, HS decreased abundance of tubulins and soluble actin and increased phosphorylated cofilin 2 abundance, indicating a loss of microtubule structure and a likely increase in stable actin microfilaments. HS increased manganese superoxide dismutase abundance, but decreased peroxiredoxin 2 abundance, indicating an antioxidant response to HS. The proteomic response to HS suggests marked cellular changes in carbohydrate metabolism, structure, and antioxidant machinery in skeletal muscle. SIGNIFICANCE: This paper examines the proteome response of skeletal muscle to acute (short duration, high intensity) heat stress (HS). Defining changes in the sarcoplasm proteome increases our understanding of the mechanisms of how muscle responds to HS. Moreover, demonstration of a fiber type differential response to HS illustrates the dynamic nature of muscle. The experimental design of the experiment allows for the differentiation between the true effects of HS and HS-induced hypophagia. Data such as these will provide the foundation for developing future mitigating solutions and preventative therapies to reduce the detrimental effects of acute heat stress on muscle function and metabolism. PMID- 26254012 TI - Introduction for seminar series on urothelial carcinoma with squamous differentiation. PMID- 26254013 TI - Hemodynamic assessment of ventilated ICU patients with cardiorespiratory failure using a miniaturized multiplane transesophageal echocardiography probe. AB - PURPOSE: To assess the feasibility, image quality, diagnostic accuracy, therapeutic impact and tolerance of diagnostic and hemodynamic assessment using a novel miniaturized multiplane transesophageal echocardiography (TEE) probe in ventilated ICU patients with cardiopulmonary compromise. STUDY DESIGN: Prospective, descriptive, single-center study. METHODS: Fifty-seven ventilated patients with acute circulatory or respiratory failure were assessed, using a miniaturized multiplane TEE probe and a standard TEE probe used as reference, randomly by two independent experienced operators. Measurements of hemodynamic parameters were independently performed off-line by a third expert. Diagnostic groups of acute circulatory failure (n = 5) and of acute respiratory failure (n = 3) were distinguished. Hemodynamic monitoring was performed in 9 patients using the miniaturized TEE probe. TEE tolerance and therapeutic impact were reported. RESULTS: The miniaturized TEE probe was easier to insert than the standard TEE probe. Despite lower imaging quality of the miniaturized TEE probe, the two probes had excellent diagnostic agreement in patients with acute circulatory failure (Kappa: 0.95; 95% CI: 0.85-1) and with acute respiratory failure (Kappa: 1; 95% CI: 1.0-1.0). Accordingly, therapeutic strategies derived from both TEE examinations were concordant (Kappa: 0.82; 95% CI: 0.66-0.97). The concordance between quantitative hemodynamic parameters obtained with both TEE probes was also excellent. No relevant complication secondary to TEE probes insertion occurred. CONCLUSIONS: Hemodynamic assessment of ventilated ICU patients with cardiopulmonary compromise using a miniaturized multiplane TEE probe appears feasible, well-tolerated, and relevant in terms of diagnostic information and potential therapeutic impact. Further larger-scale studies are needed to confirm these preliminary results. PMID- 26254014 TI - Impact of leadership on ICU clinicians' burnout. PMID- 26254015 TI - AMP-activated protein kinase suppresses the expression of LXR/SREBP-1 signaling induced ANGPTL8 in HepG2 cells. AB - ANGPTL8 is a liver-derived secretory protein that leads to elevated serum triglyceride and the level of circulating ANGPTL8 is strongly associated with obesity and diabetes. Here we investigated the mechanisms of activation and inhibition of ANGPTL8 expression in hepatocytes. The expression of ANGPTL8 was significantly increased in HepG2 cells exposed to palmitic acid, tunicamycin, or T0901317, and was reversed in cells treated with AICAR. Palmitic acid, tunicamycin, and T0901317 increased LXRalpha and SREBP-1c mRNA expression. The inhibitory effect of AICAR on the expression of T0901317-induced ANGPTL8 was most strongly evident in cells that were transfected with SREBP-1 siRNA. AICAR increased phosphorylation of PPARalpha and the effect of AICAR was not observed in cells treated with PPARalpha inhibitor. Metformin had a similar effect on ANGPTL8 expression to that of AICAR. These data suggest that AMPK can suppress the expression of LXR/SREBP-1 signal-induced ANGPTL8 in HepG2 cells. PMID- 26254016 TI - Improving Hospice Care Through a Proactive Telephone-Based Quality Improvement Intervention: Commentary on Davis et al. PMID- 26254017 TI - The Role of Methylphenidate in Cancer-Related Fatigue. Commentary on Mitchell et al. PMID- 26254018 TI - National multi-cohort time trends in adolescent risk preference and the relation with substance use and problem behavior from 1976 to 2011. AB - AIMS: Preference for risky activities is an important developmentally graded predictor of substance use. Population-level trends in adolescent risk preference, as well as the way in which risk preference may be a conduit to risk behavior, have never been documented. The present study examines population-level trends in risk preference among U.S. high school seniors for the 36 years from 1976 to 2011, as well as trends in the association between risk preference and substance use and other problem behaviors. METHODS: Data were drawn from yearly nationally representative cross-sectional surveys of US high school seniors (N=91,860). Risk preference was measured consistently with two items. Marijuana and cocaine use, binge drinking, and conduct problems were assessed. Trends were tested using JoinPoint software. RESULTS: The mean level of reported risk preference among US 12th graders has increased over time, especially in the 1980s. For example, the proportion of high school females who reported enjoying activities that were "a little dangerous" more than doubled, from 4.9% in 1976 to 10.8% in 1988. While risk preference reports among adolescent males leveled off in 1992, risk preference reports among females show a continued positive overall slope through 2011. The magnitude of the association between risk preference and marijuana use has increased over time. CONCLUSIONS: Reported preference for risky activities has increased among adolescents in the US, especially among young women. Reported risk preference is increasingly associated with a higher use of marijuana. Our findings argue for the importance of placing risk preference within a multi-level framework that attends to historical variation. PMID- 26254020 TI - Erythrocyte creatine as a marker of intravascular hemolysis due to left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. AB - BACKGROUND: Erythrocyte creatine, a marker of erythrocyte age that increases with shortening of erythrocyte survival, has been reported to be a quantitative and reliable marker for intravascular hemolysis. We hypothesized that hemolysis could also occur due to intraventricular obstruction in patients with hypertrophic cardiomyopathy (HCM). The purpose of this study was to examine the presence of subclinical hemolysis and the relation between intravascular hemolysis and intraventricular pressure gradient (IVPG). METHODS AND RESULTS: We measured erythrocyte creatine in 92 HCM patients. Twelve patients had left ventricular outflow tract obstruction (LVOTO), 4 had midventricular obstruction (MVO), and the remaining 76 were non-obstructive. Erythrocyte creatine levels ranged from 0.92 to 4.36MUmol/g hemoglobin. Higher levels of erythrocyte creatine were associated with higher IVPG (r=0.437, p<0.001). If erythrocyte creatine levels are high (>=1.8MUmol/g hemoglobin), subclinical hemolysis is considered to be present. Half of LVOTO patients and no MVO patients showed high erythrocyte creatine levels. Although non-obstructive patients did not show significant intraventricular obstruction at rest, some showed high erythrocyte creatine levels. When LVOT-PG was measured during the strain phase of the Valsalva maneuver in 20 non-obstructive patients, 7 of those 20 patients showed LVOTO. In the 20 patients, there was no relation between erythrocyte creatine levels and LVOT-PG before the Valsalva maneuver (r=0.125, p=0.600), whereas there was a significant correlation between erythrocyte creatine and LVOT-PG provoked by the Valsalva maneuver (r=0.695, p=0.001). CONCLUSIONS: There is biochemical evidence of subclinical hemolysis in patients with HCM, and this hemolysis seems to be associated with LVOTO provoked by daily physical activities. PMID- 26254019 TI - Impact of candesartan on cardiovascular events after drug-eluting stent implantation in patients with coronary artery disease: The 4C trial. AB - OBJECTIVE: The purpose of this study was to examine the cardiovascular protective effects of candesartan in patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DESs). BACKGROUND: Candesartan has been reported to reduce cardiovascular events when therapy was started 6 months after PCI with bare-metal stents in patients who survived restenosis. Candesartan started immediately after PCI with DESs was also effective in preventing cardiovascular events. METHODS: The 4C trial was a multicenter, prospective, randomized, open label study. A total of 1145 patients at 39 centers in Japan were randomly assigned to receive candesartan plus standard medical treatment or standard medical treatment alone. The primary endpoints were all-cause death, and a composite of non-fatal myocardial infarction (MI), unstable angina pectoris (uAP), congestive heart failure (CHF), and non-fatal cerebrovascular events. The follow-up period was up to 3 years after the index PCI (ClinicalTrials.gov NCT00139386). RESULTS: The incidence of total death, one of the primary endpoints, was comparable between the two treatment groups (3.8% each, p=0.9702). Another primary endpoint, non-fatal major cardiovascular events, tended to occur more often in the control group than in the candesartan group (9.2% vs. 12.5%, p=0.0985). In contrast, candesartan significantly reduced one of the pre specified secondary endpoints: cardiovascular events that included non-fatal MI, uAP, and CHF (4.4% vs. 6.7%, p=0.0136). Furthermore, candesartan significantly reduced another secondary endpoint that included cardiovascular events and cardiovascular death (5.0% vs. 7.7%, p=0.0493). CONCLUSIONS: The 4C trial showed that candesartan administered immediately after PCI with DESs did not improve the prognosis after the index procedure, but did reduce some cardiac-related events for 3 years. PMID- 26254021 TI - Remote sensing for mapping soil moisture and drainage potential in semi-arid regions: Applications to the Campidano plain of Sardinia, Italy. AB - The aim of this study is to investigate the potential of radar (ENVISAT ASAR and RADARSAT-2) and LANDSAT data to generate reliable soil moisture maps to support water management and agricultural practice in Mediterranean regions, particularly during dry seasons. The study is based on extensive field surveys conducted from 2005 to 2009 in the Campidano plain of Sardinia, Italy. A total of 12 small bare soil fields were sampled for moisture, surface roughness, and texture values. From field scale analysis with ENVISAT ASAR (C-band, VV polarized, descending mode, incidence angle from 15.0 degrees to 31.4 degrees ), an empirical model for estimating bare soil moisture was established, with a coefficient of determination (R(2)) of 0.85. LANDSAT TM5 images were also used for soil moisture estimation using the TVX slope (temperature/vegetation index), and in this case the best linear relationship had an R(2) of 0.81. A cross-validation on the two empirical models demonstrated the potential of C-band SAR data for estimation of surface moisture, with and R(2) of 0.76 (bias +0.3% and RMSE 7%) for ENVISAT ASAR and 0.54 (bias +1.3% and RMSE 5%) for LANDSAT TM5. The two models developed at plot level were then applied over the Campidano plain and assessed via multitemporal and spatial analyses, in the latter case against soil permeability data from a pedological map of Sardinia. Encouraging estimated soil moisture (ESM) maps were obtained for the SAR-based model, whereas the LANDSAT-based model would require a better field data set for validation, including ground data collected on vegetated fields. ESM maps showed sensitivity to soil drainage qualities or drainage potential, which could be useful in irrigation management and other agricultural applications. PMID- 26254022 TI - Systematic planning of disconnection to enhance conservation success in a modified world. AB - Maintaining spatial-temporal connectivity for conservation is necessary to allow the persistence of ecological processes and the biodiversity they sustain. However, conservation practice in human-modified environments can also benefit from prescribed disconnection through the implementation of barriers. Barriers, such as fences or dams, and buffer zones can be a cost-effective way of addressing threats caused by a globally connected world, such as the propagation of invasive species and diseases, creating refuge areas for native biodiversity and helping reduce economic losses caused by native wildlife or invasive species. Despite the global attention that disconnection has received, no clear framework exists to guide the allocation of barriers for conservation management. Here we propose that the implementation of barriers for conservation should be systematically planned, considering ecological trade-offs for multiple species (easing threats vs. interruption of ecosystem processes) and socio-economic cost benefits (implementation cost vs. reduced human-wildlife conflicts), rather than using ad-hoc opportunistic criteria or accommodating conservation needs for individual species. Such a systematic approach is necessary to ensure both socially acceptable and ecologically effective use of disconnections as a conservation tool and ideally planned across different realms so co-benefits or trade-offs can be accounted for. However, any implementation of disconnection for conservation should be cautiously considered if uncertainty in effectiveness of the barrier and ecological impacts to other species are high. We also suggest the need for improved approaches to monitoring to learn from previous successes and failures. Our recommendations should guide the systematic evaluation and allocation of barriers to help enhance the value of this conservation tool in the face of increasing propagation of threats worldwide. However, new tools and collaborative frameworks across different realms are needed to help stakeholders make better informed decision. PMID- 26254023 TI - Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors, including breast cancer. AB - PURPOSE: This phase I trial assessed afatinib, an irreversible ErbB family blocker, plus vinorelbine in Japanese patients with advanced solid tumors not amenable to standard treatment. METHODS: Primary objectives were evaluation of safety and the maximum tolerated dose (MTD) of once-daily (QD) afatinib plus weekly intravenous vinorelbine. Secondary objectives included pharmacokinetic assessments and preliminary efficacy. Dose finding utilized a 3 + 3 design, with a starting dose of afatinib 20 mg QD plus vinorelbine 25 mg/m(2) weekly. RESULTS: Seventeen patients were enrolled. Dose level 2 (afatinib 40 mg and vinorelbine 25 mg/m(2)) exceeded the MTD; dose-limiting toxicities (DLTs) were considered vinorelbine-related. Dose finding continued with modified dose levels; dose level 2a: afatinib 40 mg and a reduced dose of vinorelbine 20 mg/m(2) and dose level 3: afatinib 40 mg and vinorelbine 25 mg/m(2) allowing omission of vinorelbine for grade >=2 neutropenia/thrombocytopenia and afatinib dose modification for adverse events (AEs). At dose level 3, 1/6 patients had a DLT (upper abdominal pain requiring afatinib dose reduction). Overall, the most frequent treatment-related AEs (any/grade 3 and 4) were: neutropenia (100/71 %), leukopenia (100/59 %), diarrhea (94/0 %), anemia (71/12 %) and stomatitis (65/0 %). Two patients with breast cancer achieved a partial response; eight patients (various cancer indications) had stable disease. Pharmacokinetic analyses suggested no relevant drug-drug interactions. CONCLUSIONS: Afatinib 40 mg QD plus vinorelbine 25 mg/m(2) weekly was tolerated in Japanese patients when dose modifications for known AEs for either compound were allowed. Tumor shrinkage was also observed. This dose schedule was recommended for phase II/III trials in Japanese patients. PMID- 26254024 TI - First-line gefitinib treatment in elderly patients (aged >=75 years) with non small cell lung cancer harboring EGFR mutations. AB - PURPOSE: The efficacy of gefitinib [an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor] in elderly patients with non-small cell lung cancer (NSCLC) and EGFR mutation has not been elucidated. Therefore, the objective of this study was to investigate the efficacy and feasibility of gefitinib in elderly chemotherapy-naive patients with NSCLC harboring sensitive EGFR mutations. METHODS: We retrospectively evaluated the clinical effects of gefitinib as a first-line treatment for elderly (>=75 years) NSCLC patients with EGFR mutations (exon 19 deletion or exon 21 L858R mutation). All patients were initially treated with gefitinib (250 mg/day) at seven institutions. RESULTS: Between January 2006 and December 2012, 62 patients (17 men, 45 women) with a median age of 80 years (range, 75-89 years) were included in our analysis. The overall response and disease control rates were 61.2 and 83.8 %, respectively, and the median progression-free survival and overall survival were 13.2 and 19.0 months, respectively. Common adverse events included rash, diarrhea, and liver dysfunction. Major grade 3 or 4 toxicities included skin rash (3.2 %) and increased levels of aspartate aminotransferase or alanine aminotransferase (21.0 %). Gefitinib treatment was discontinued owing to adverse events of liver dysfunction in 3 patients, drug-induced pneumonitis in 2, and diarrhea in 1. CONCLUSION: First-line gefitinib could be a preferable standard treatment in elderly patients with advanced NSCLC harboring sensitive EGFR mutations. PMID- 26254025 TI - Absorption, distribution, metabolism, and excretion of [(14)C]BYL719 (alpelisib) in healthy male volunteers. AB - PURPOSE: To determine the pharmacokinetics of the p110alpha-selective inhibitor alpelisib (BYL719) in humans, to identify metabolites in plasma and excreta, and to characterize pathways of biotransformation. METHODS: Four healthy male volunteers received a single oral dose of [(14)C]-labeled alpelisib (400 mg, 2.78 MBq). Blood, urine, and feces samples were collected throughout the study. Total radioactivity was measured by liquid scintillation counting, and metabolites were quantified and identified by radiometry and mass spectrometry. Complementary in vitro experiments characterized the hydrolytic, oxidative, and conjugative enzymes involved in metabolite formation. RESULTS: Over 50 % of [(14)C] alpelisib was absorbed, with a T(max) of 2 h and an elimination half-life from plasma of 13.7 h. Over the first 12 h, exposure to alpelisib and the primary metabolite M4 was 67.9 and 26.7 % of total drug-related material in circulation, respectively. Mass balance was achieved, with 94.5 % of administered radioactivity recovered in excreta. In total, 38.2 % of alpelisib was excreted unchanged, while 39.5 % was excreted as M4. Based on the excreta pools analyzed, excretion occurred mainly via feces (79.8 % of administered dose); 13.1 % was excreted via urine. In vitro experiments showed that spontaneous and enzymatic hydrolysis contributed to M4 formation, while CYP3A4-mediated oxidation and UGT1A9-mediated glucuronidation formed minor metabolites. Alpelisib was well tolerated, and no new safety concerns were raised during this study. CONCLUSIONS: Alpelisib was rapidly absorbed and cleared by multiple metabolic pathways; the primary metabolite M4 is pharmacologically inactive. Alpelisib has limited potential for drug-drug interactions and is therefore a promising candidate for combination therapy. PMID- 26254026 TI - Genotyping of turkey coronavirus field isolates from various geographic locations in the Unites States based on the spike gene. AB - Turkey flocks have experienced turkey coronaviral enteritis sporadically in the United States since the 1990s. Twenty-four field isolates of turkey coronavirus (TCoV) from multiple states in the United States were recovered from 1994 to 2010 to determine the genetic relationships among them. The entire spike (S) gene of each TCoV isolate was amplified and sequenced. Pairwise comparisons were performed using the Clustal W program, revealing 90.0% to 98.4% sequence identity in the full-length S protein, 77.6% to 96.6% in the amino terminus of the S1 subunit (containing one hypervariable region in S1a), and 92.1% to 99.3% in the S2 subunit at the deduced amino acid sequence level. The conserved motifs, including two cleavage recognition sequences of the S protein, two heptad repeats, the transmembrane domain, and the Golgi retention signal were identified in all TCoV isolates. Phylogenetic analysis based on the full-length S gene was used to distinguish North American TCoV isolates from French TCoV isolates. Among the North American TCoV isolates, three distinct genetic groups with 100% bootstrap support were observed. North Carolina isolates formed group I, Texas isolates formed group II, and Minnesota isolates formed Group III. The S genes of 24 TCoV isolates from the United States remained conserved because they contained predominantly synonymous substitutions. The findings of the present study suggest endemic circulation of distinct TCoV genotypes in different geographic locations. PMID- 26254027 TI - Distribution and pollution assessment of trace elements in marine sediments in the Quintero Bay (Chile). AB - The aim of this study was to assess the levels of heavy metal pollution in the clay/silt fraction (<63 MUm fraction) of marine sediments from Quintero Bay, Chile. For this, sediment samples were collected from 14 sites from the bay and analyzed for major and minor element determination. The metal concentrations found suggest an anthropogenic origin related with Cu, Se, Mo, As, Sb and Pb. The mineralogical characteristics of the samples were determined by XRD and selected samples were examined by SEM to determine morphological differences. The results showed heavy metal-bearing particles such as Cu, Zn, As and Pb, which are most likely associated with by the copper smelter. PMID- 26254028 TI - Spectroscopic characteristics of carbon dots (C-dots) derived from carbon fibers and conversion to sulfur-bridged C-dots nanosheets. AB - We synthesized sub-10 nm carbon nanoparticles (CNPs) consistent with photoluminescent carbon dots (C-dots) from carbon fiber starting material. The production of different C-dots fractions was monitored over seven days. During the course of the reaction, one fraction of C-dots species with relatively high photoluminescence was short-lived, emerging during the first hour of reaction but disappearing after one day of reaction. Isolation of this species during the first hour of the reaction was crucial to obtaining higher-luminescent C-dots species. When the reaction proceeded for one week, the appearance of larger nanostructures was observed over time, with lateral dimensions approaching 200 nm. The experimental evidence suggests that these larger species are formed from small C-dot nanoparticles bridged together by sulfur-based moieties between the C dot edge groups, as if the C-dots polymerized by cross-linking the edge groups through sulfur bridges. Their size can be tailored by controlling the reaction time. Our results highlight the variety of CNP products, from sub-10 nm C-dots to ~200 nm sulfur-containing carbon nanostructures, that can be produced over time during the oxidation reaction of the graphenic starting material. Our work provides a clear understanding of when to stop the oxidation reaction during the top-down production of C-dots to obtain highly photoluminescent species or a target average particle size. PMID- 26254029 TI - The Pill's gestation: from birth control to cancer prevention. PMID- 26254030 TI - Endometrial cancer and oral contraceptives: an individual participant meta analysis of 27 276 women with endometrial cancer from 36 epidemiological studies. AB - BACKGROUND: Oral contraceptives are known to reduce the incidence rate of endometrial cancer, but it is uncertain how long this effect lasts after use ceases, or whether it is modified by other factors. METHODS: Individual participant datasets were sought from principal investigators and provided centrally for 27 276 women with endometrial cancer (cases) and 115 743 without endometrial cancer (controls) from 36 epidemiological studies. The relative risks (RRs) of endometrial cancer associated with oral contraceptive use were estimated using logistic regression, stratified by study, age, parity, body-mass index, smoking, and use of menopausal hormone therapy. FINDINGS: The median age of cases was 63 years (IQR 57-68) and the median year of cancer diagnosis was 2001 (IQR 1994-2005). 9459 (35%) of 27 276 cases and 45 625 (39%) of 115 743 controls had ever used oral contraceptives, for median durations of 3.0 years (IQR 1-7) and 4.4 years (IQR 2-9), respectively. The longer that women had used oral contraceptives, the greater the reduction in risk of endometrial cancer; every 5 years of use was associated with a risk ratio of 0.76 (95% CI 0.73-0.78; p<0.0001). This reduction in risk persisted for more than 30 years after oral contraceptive use had ceased, with no apparent decrease between the RRs for use during the 1960s, 1970s, and 1980s, despite higher oestrogen doses in pills used in the early years. However, the reduction in risk associated with ever having used oral contraceptives differed by tumour type, being stronger for carcinomas (RR 0.69, 95% CI 0.66-0.71) than sarcomas (0.83, 0.67-1.04; case-case comparison: p=0.02). In high-income countries, 10 years use of oral contraceptives was estimated to reduce the absolute risk of endometrial cancer arising before age 75 years from 2.3 to 1.3 per 100 women. INTERPRETATION: Use of oral contraceptives confers long-term protection against endometrial cancer. These results suggest that, in developed countries, about 400 000 cases of endometrial cancer before the age of 75 years have been prevented over the past 50 years (1965-2014) by oral contraceptives, including 200 000 in the past decade (2005-14). FUNDING: Medical Research Council, Cancer Research UK. PMID- 26254031 TI - Analysis of Circadian Rhythms in the Basal Filamentous Ascomycete Pyronema confluens. AB - Many organisms use circadian clocks to adapt to daily changes in the environment. Major insights into the molecular mechanisms of circadian oscillators have been gained through studies of the model organism Neurospora crassa; however, little is known about molecular components of circadian clocks in other fungi. An important part of the N. crassa circadian clock is the frequency (frq) gene, homologs of which can be found in Sordariomycetes, Dothideomycetes, and Leotiomycetes, but not Eurotiomycetes. Recently, we identified a frq homolog in Pyronema confluens, a member of the early-diverging Pezizomycete lineage of filamentous ascomycetes. The P. confluens FRQ shares many conserved domains with the N. crassa FRQ. However, there is no known morphological phenotype showing overt circadian rhythmicity in P. confluens. To investigate whether a molecular clock is present, we analyzed frq transcription in constant darkness, and found circadian oscillation of frq with a peak in the subjective morning. This rhythm was temperature compensated. To identify additional clock-controlled genes, we performed RNA sequencing of two time points (subjective morning and evening). Circadian expression of two morning-specific genes was verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR) over a full time course, whereas expression of two putative morning-specific and five putative evening-specific genes could not be verified as circadian. frq expression was synchronized, but not entrained by light. In summary, we have found evidence for two of the three main properties of circadian rhythms (free-running rhythm, temperature compensation) in P. confluens, suggesting that a circadian clock with rhythmically expressed frq is present in this basal filamentous ascomycete. PMID- 26254032 TI - Using food as reinforcer to shape children's non-food behavior: The adverse nutritional effect doubly moderated by reward sensitivity and gender. AB - PURPOSE: Control rules are parental practices that use food, especially those high in fat or sugar, as an instrumental reinforcer to encourage children to behave in a normative manner in non-food domains. Past laboratory experiments show that repeatedly presenting snacks as a reward or associated with adults' attention, increases children's preference for the presented food. This field study aims to examine whether control rules are associated with children's increased everyday intake of food high in sugar/fat, and whether this effect is moderated by individual differences in neurobehavioral sensitivity to reward and in gender. DESIGN: 207 six- to twelve-year-old children's parents reported the children's everyday dietary intake through a food frequency questionnaire and provided information regarding the children's sensitivity to rewards as well as the frequency of enforcing control rules. RESULTS: Children who lived in families with a high frequency of using control rules exhibited more daily fat, carbohydrate, and total energy intake than did children whose parents use control rules less often. Furthermore, the effect of control rules on dietary pattern was particularly strong for children with high reward sensitivity, especially boys. CONCLUSIONS: Control rules have adverse consequences on children's nutrition. The moderating effects of sensitivity to reward and gender are consistent to a reinforcement learning process--associating the high-fat/sugar food consumption with social-affective pleasure resulting from performing behavior desired by parents--through which parental control rules contribute to children's maladaptive dietary patterns. PMID- 26254033 TI - Monitoring the chemical and physical stability for tromethamine excipient in a lipid based formulation by HPLC coupled with ELSD. AB - Tromethamine, a UV-transparent amine base excipient, was used in the liquid phase of a self-emulsifying drug delivery system-soft gelatin capsule (SEDDS-SGC) formulation as an emulsification agent and to improve solubilization of the active drug. The level of this excipient was found to be decreasing in aged and stressed drug product capsules. The decrease could potentially affect oral bioavailability of the drug; should the amount of solubilizer decrease enough to lead to precipitation of the active drug from the formulation. Therefore, further investigation was warranted. HPLC coupled with evaporative light scattering detection (ELSD) was used to monitor the physical and chemical stability of tromethamine in the SEDDS-SGC formulation. Confirmation of the tromethamine interaction products was done by LC-MS. PMID- 26254034 TI - Unilateral video-assisted thoracoscopic extended thymectomy offers long-term outcomes equivalent to that of the bilateral approach in the treatment of non thymomatous myasthenia gravis. AB - OBJECTIVES: Video-assisted thoracoscopic extended thymectomy (VATET) is commonly performed bilaterally to remove all the thymic tissue in the mediastinum for the surgical treatment of myasthenia gravis. We hypothesize that the therapeutic efficacy of unilateral thoracoscopic thymectomy (right-sided) is comparable to that of bilateral VATET. METHODS: We retrospectively reviewed 103 consecutive patients who received VATET for non-thymomatous myasthenia gravis (NTMG), with a minimum follow-up period of 36 months. RESULTS: Bilateral VATET was performed in the first 31 patients and right-sided VATET in the following 72. No patients died perioperatively. The operating time in the right-sided VATET group was significantly shorter than that in the bilateral VATET group (169.3 +/- 19.3 vs 152.6 +/- 20.7 min, P<0.001). There were no significant differences between groups, in terms of blood loss, pain severity, drainage time, ICU stay, hospital stay and postoperative morbidity. The median follow-up was 5.2 years. Forty-eight patients achieved complete stable remission (CSR). The 5-year CSR rate, calculated by Life-table analysis, was 52% in the bilateral VATET group and 47% in the right-sided VATET group. These two operative methods did not differ significantly with respect to CSR by Kaplan-Meier analysis. Multivariate analysis identified shorter disease duration (<12 months) (P = 0.021, HR = 0.50) and thymic hyperplasia (P = 0.038, HR = 0.48) as independent predictors of higher CSR rates in patients who underwent thymectomy. CONCLUSIONS: The long-term outcome of right-sided VATET in the surgical treatment of NTMG, in terms of CSR, is comparable to that of bilateral VATET. PMID- 26254035 TI - Dose estimation, kinetics and dating of fossil marine mollusc shells from northwestern part of Turkey. AB - Electron spin resonance (ESR) spectroscopy was used to determine the geological formation age of fossil mollusc shells taken from marine terrace deposits (Ikizlercesme-Canakkale) in northwestern part of Turkey. This work reports the first results obtained by the ESR technique on shells collected from this region. In the ESR spectra of the natural and gamma-irradiated shell samples, two different signals attributed to orthorombic (gxx=2.0030, gzz=2.0015, gyy=1.9980) and isotropic (g=2.0006) CO2(-) ion radicals were overlaped (Signal C). Annealing and kinetic experiments suggest the possibility of using the ESR signal at g=2.0015 (C signal) for the estimation of accumulated geological doses. The ESR signal growth curve on additional gamma irradiation has been best fitted by a combination of two single exponential saturation functions. This may support the existence of at least two components of the g=2.0015 ESR dating signal. Based on this model, the accumulated dose of the samples was determined as 110+/-11Gy. Also the isothermal decay curves of the ESR dating signal could be best described by the combination of two first order decay functions. Activation energy and meanlifetime values at 15 degrees C of the two components were calculated as E1=1.4+/-0.1eV, E2=1.1+/-0.1eV, tau1=7.2*10(6) years and tau2=3.3*10(3) years, respectively. Uranium content of the studied shells was found to be high according to their chemical analysis. This may point out that the marine shell has received uranium from outside particularly in carbonate sediment. Therefore, the ESR age of the samples was also calculated using Early Uptake (EU), Linear Uptake (LU) and Combined Uptake (CU) models and results were discussed. PMID- 26254036 TI - Investigating membrane and mitochondrial cryobiological responses of HUVEC using interrupted cooling protocols. AB - The success of cryopreservation protocols is largely based on membrane integrity assessments after thawing, since membrane integrity can be considered to give an upper limit in assessment of cell viability and the plasma membrane is considered to be a primary site of cryoinjury. However, the exposure of cells to conditions associated with low temperatures can induce injury to cellular structure and function that may not be readily identified by membrane integrity alone. Interrupted cooling protocols (including interrupted slow cooling without a hold time (graded freezing), and interrupted rapid cooling with a hold time (two-step freezing)), can yield important information about cryoinjury by separating the damage that occurs upon cooling to (and possibly holding at) a critical intermediate temperature range from the damage that occurs upon plunging to the storage temperature (liquid nitrogen). In this study, we used interrupted cooling protocols in the absence of cryoprotectant to investigate the progression of damage to human umbilical vein endothelial cells (HUVEC), comparing an assessment of membrane integrity with a mitochondrial polarization assay. Additionally, the membrane integrity response of HUVEC to interrupted cooling was investigated as a function of cooling rate (for interrupted slow cooling) and hold time (for interrupted rapid cooling). A key finding of this work was that under slow cooling conditions which resulted in a large number of membrane intact cells immediately post thaw, mitochondria are predominantly in a non-functional depolarized state. This study, the first to look directly at mitochondrial polarization throughout interrupted cooling profiles and a detailed study of HUVEC response, highlights the complexity of the progression of cell damage, as the pattern and extent of cell injury throughout the preservation process differs by injury site. PMID- 26254037 TI - Porcine embryo production following in vitro fertilization and intracytoplasmic sperm injection from vitrified immature oocytes matured with a granulosa cell co culture system. AB - This study was designed to evaluate the capacity of vitrified-warmed porcine immature oocytes to mature and to be fertilized using in vitro fertilization or intracytoplasmic sperm injection, and to determine the subsequent embryo development. Immature oocytes were vitrified using ethylene glycol and dimethylsulphoxide as cryoprotectants and the Cryolock method. After warming oocytes were cultured 44 h for maturation. Oocytes were randomly distributed in three treatment groups and subjected to in vitro fertilization (Experiment 1) or intracytoplasmic sperm injection (Experiment 2) procedures. The results indicate that the embryo development was higher in denuded oocytes co-cultured with granulosa cells (NkO-CC group) fertilized by in vitro fertilization or intracytoplasmic sperm injection compared to cumulus-cell oocyte complexes (COCs group), showing no significant differences with control. Vitrified denuded oocytes matured with a co-culture system NkO-CC group, displayed higher cleavage rate and blastocyst production than vitrified COCs group. Blastocysts were successfully obtained after IVF and ICSI procedures; however, the development to the blastocyst stage was better after IVF. These results show that the vitrification-warming media, the employment of a granulosa cell co-culture system and the Cryolock method during vitrification, increased the nuclear and cytoplasmic maturation of vitrified porcine immature oocytes. Further experiments are required to enhance porcine embryo production after vitrification. PMID- 26254038 TI - Yeast Kluyveromyces lactis as host for expression of the bacterial lipase: cloning and adaptation of the new lipase gene from Serratia sp. AB - Many microbial lipases have been successfully expressed in yeasts, but not in industrially attractive Kluyveromyces lactis, which among other benefits can be cultivated on a medium supplemented with whey--cheap and easily available industrial waste. A new bacterial lipase from Serratia sp. was isolated and for the first time expressed into the yeast Kluyveromyces lactis by heterologous protein expression system based on a strong promoter of Kluyveromyces marxianus triosephosphate isomerase gene and signal peptide of Kluyveromyces marxianus endopolygalacturonase gene. In addition, the bacterial lipase gene was synthesized de novo by taking into account a codon usage bias optimal for K. lactis and was expressed into the yeast K. lactis also. Both resulting strains were characterized by high output level of the target protein secreted extracellularly. Secreted lipases were characterized for activity and stability. PMID- 26254039 TI - Synthesis of poly(3-hydroxybutyrate) by the autotrophic CO-oxidizing bacterium Seliberia carboxydohydrogena Z-1062. AB - The present study addresses growth parameters and physiological and biochemical characteristics of the aerobic CO-oxidizing carboxydobacterium Seliberia carboxydohydrogena Z-1062. Poly(3-hydroxybutyrate) yields were investigated in experiments with limiting concentrations of mineral nutrients (nitrogen or sulfur or nitrogen and sulfur) in batch culture of S. carboxydohydrogena Z-1062 grown on gas mixtures consisting of CO(2), O(2), H(2), and CO. CO concentrations of 10, 20, and 30 % v/v did not affect polymer synthesis, whose content after 56-h cultivation under limiting concentrations of nitrogen and sulfur was 52.6-62.8 % of biomass weight at a productivity of 0.13-0.22 g/L h. The inhibitory effect of CO on cell concentration was revealed at CO concentration of 30 % v/v. That also caused a decrease in substrate (H(2) and O(2)) use efficiency. Thus, this carboxydobacterium can be regarded as a potential producer of polyhydroxyalkanoates from industrial hydrogenous sources. PMID- 26254040 TI - Chemical improvement of chitosan-modified beads for the immobilization of Enterococcus faecium DBFIQ E36 L-arabinose isomerase through multipoint covalent attachment approach. AB - D-tagatose is produced from D-galactose by the enzyme L-arabinose isomerase (L AI) in a commercially viable bioprocess. An active and stable biocatalyst was obtained by modifying chitosan gel structure through reaction with TNBS, D fructose or DMF, among others. This led to a significant improvement in L-AI immobilization via multipoint covalent attachment approach. Synthetized derivatives were compared with commercial supports such as Eupergit((r)) C250L and glyoxal-agarose. The best chitosan derivative for L-AI immobilization was achieved by reacting 4 % (w/v) D-fructose with 3 % (w/v) chitosan at 50 degrees C for 4 h. When compared to the free enzyme, the glutaraldehyde-activated chitosan biocatalyst showed an apparent activity of 88.4 U g (gel) (-1) with a 211-fold stabilization factor while the glyoxal-agarose biocatalyst gave an apparent activity of 161.8 U g (gel) (-1) with an 85-fold stabilization factor. Hence, chitosan derivatives were comparable to commercial resins, thus becoming a viable low-cost strategy to obtain high active L-AI insolubilized derivatives. PMID- 26254041 TI - In silico model-driven cofactor engineering strategies for improving the overall NADP(H) turnover in microbial cell factories. AB - Optimizing the overall NADPH turnover is one of the key challenges in various value-added biochemical syntheses. In this work, we first analyzed the NADPH regeneration potentials of common cell factories, including Escherichia coli, Saccharomyces cerevisiae, Bacillus subtilis, and Pichia pastoris across multiple environmental conditions and determined E. coli and glycerol as the best microbial chassis and most suitable carbon source, respectively. In addition, we identified optimal cofactor specificity engineering (CSE) enzyme targets, whose cofactors when switched from NAD(H) to NADP(H) improve the overall NADP(H) turnover. Among several enzyme targets, glyceraldehyde-3-phosphate dehydrogenase was recognized as a global candidate since its CSE improved the NADP(H) regeneration under most of the conditions examined. Finally, by analyzing the protein structures of all CSE enzyme targets via homology modeling, we established that the replacement of conserved glutamate or aspartate with serine in the loop region could change the cofactor dependence from NAD(H) to NADP(H). PMID- 26254042 TI - Efficient aspartic acid production by a psychrophile-based simple biocatalyst. AB - We previously constructed a Psychrophile-based Simple bioCatalyst (PSCat) reaction system, in which psychrophilic metabolic enzymes are inactivated by heat treatment, and used it here to study the conversion of aspartic acid from fumaric acid mediated by the activity of aspartate ammonia-lyase (aspartase). In Escherichia coli, the biosynthesis of aspartic acid competes with that of L-malic acid produced from fumaric acid by fumarase. In this study, E. coli aspartase was expressed in psychrophilic Shewanella livingstonensis Ac10 heat treated at 50 degrees C for 15 min. The resultant PSCat could convert fumaric acid to aspartic acid without the formation of L-malic acid because of heat inactivation of psychrophilic fumarase activity. Furthermore, alginate-immobilized PSCat produced high yields of aspartic acid and could be re-used nine times. The results of our study suggest that PSCat can be applied in biotechnological production as a new approach to increase the yield of target compounds. PMID- 26254043 TI - Complete genome sequence and structural characterization of a novel iflavirus isolated from Opsiphanes invirae (Lepidoptera: Nymphalidae). AB - Opsiphanes invirae (Lepidopera: Nymphalidae) is a common pest of the African oil palm tree (Elaeis guineensis) in Brazil. Dead larvae were collected in canopy of oil palm trees cultivated in the amazon region (Para State) and analyzed for viral infection. Electron microscopy of caterpillar extracts showed an icosahedral picorna-like virus particle with 30nm in diameter. Total RNA extracted from partially purified virus particles was sequenced. A contig of 10,083 nucleotides (nt) was identified and showed to encode one single predicted polyprotein with 3185 amino acid residues. Phylogenetic analysis showed that the new virus was closely related to another lepidopteran infective virus Spodoptera exigua iflavirus 1(SeIV-1), with 35% amino acid pairwise identity. The novel virus fulfils all ICTV requirements for a new iflavirus species and was named Opsiphanes invirae Iflavirus 1 (OilV-1). PMID- 26254044 TI - A complexity basis for phenomenology: How information states at criticality offer a new approach to understanding experience of self, being and time. AB - In the late 19th century Husserl studied our internal sense of time passing, maintaining that its deep connections into experience represent prima facie evidence for it as the basis for all investigations in the sciences: Phenomenology was born. Merleau-Ponty focused on perception pointing out that any theory of experience must accord with established aspects of biology i.e. be embodied. Recent analyses suggest that theories of experience require non reductive, integrative information, together with a specific property connecting them to experience. Here we elucidate a new class of information states with just such properties found at the loci of control of complex biological systems, including nervous systems. Complexity biology concerns states satisfying self organized criticality. Such states are located at critical instabilities, commonly observed in biological systems, and thought to maximize information diversity and processing, and hence to optimize regulation. Major results for biology follow: why organisms have unusually low entropies; and why they are not merely mechanical. Criticality states form singular self-observing systems, which reduce wave packets by processes of perfect self-observation associated with feedback gain g = 1. Analysis of their information properties leads to identification of a new kind of information state with high levels of internal coherence, and feedback loops integrated into their structure. The major idea presented here is that the integrated feedback loops are responsible for our 'sense of self', and also the feeling of continuity in our sense of time passing. Long-range internal correlations guarantee a unique kind of non-reductive, integrative information structure enabling such states to naturally support phenomenal experience. Being founded in complexity biology, they are 'embodied'; they also fulfill the statement that 'The self is a process', a singular process. High internal correlations and Rene Thom-style catastrophes support non-digital forms of information, gestalt cognition, and information transfer via quantum teleportation. Criticality in complexity biology can 'embody' cognitive states supporting gestalts, and phenomenology's senses of 'self,' time passing, existence and being. PMID- 26254045 TI - Some assembly required: evolutionary and systems perspectives on the mammalian reproductive system. AB - In this review, we discuss the way that insights from evolutionary theory and systems biology shed light on form and function in mammalian reproductive systems. In the first part of the review, we contrast the rapid evolution seen in some reproductive genes with the generally conservative nature of development. We discuss directional selection and coevolution as potential drivers of rapid evolution in sperm and egg proteins. Such rapid change is very different from the highly conservative nature of later embryo development. However, it is not unique, as some regions of the sex chromosomes also show elevated rates of evolutionary change. To explain these contradictory trends, we argue that it is not reproductive functions per se that induce rapid evolution. Rather, it is the fact that biotic interactions, such as speciation events and sexual conflict, have no evolutionary endpoint and hence can drive continuous evolutionary changes. Returning to the question of sex chromosome evolution, we discuss the way that recent advances in evolutionary genomics and systems biology and, in particular, the development of a theory of gene balance provide a better understanding of the evolutionary patterns seen on these chromosomes. We end the review with a discussion of a surprising and incompletely understood phenomenon observed in early embryos: namely the Warburg effect, whereby glucose is fermented to lactate and alanine rather than respired to carbon dioxide. We argue that evolutionary insights, from both yeasts and tumor cells, help to explain the Warburg effect, and that new metabolic modeling approaches are useful in assessing the potential sources of the effect. PMID- 26254046 TI - The effects of tibial fracture and Ilizarov osteosynthesis on the structural reorganization of sciatic and tibial nerves during the bone consolidation phase and after fixator removal. AB - Reactive and adaptive changes in mechanically uninjured nerves during fracture healing have not been studied previously although the status of innervation is important for bone union and functional recovery. This study explores whether subclinical nerve fibre degeneration occurs in mechanically uninjured nerves in an animal fracture model and to quantify its extent and functional significance. Twenty-four dogs were deeply anaesthetized and subjected to experimental tibial shaft fracture and Ilizarov osteosynthesis. Before fracture and during the experiment, electromyography was performed. In 7, 14, 20, 35-37 and 50 days of fixation and 30, 60-90 and 120 days after fixator removal, the dogs were euthanized. Samples from sciatic, peroneal and tibial nerves were processed for semithin section histology and morphometry. On the 37th postoperative day, M response amplitudes in leg muscles were 70 % lower than preoperative ones. After fixator removal, these increased but were not restored to normal values. There were no signs of nerve injuries from bone fragments or wires from the fixator. The incidence of degenerated myelin fibres (MFs) was less than 12 %. Reorganization of Remak bundles (Group C nerve fibres-principally sensory) led to a temporal increase in numerical nerve fibre densities. Besides axonal atrophy, the peroneal nerve was characterized with demyelination-remyelination, while tibial nerve with hypermyelination. There were changes in endoneural vessel densities. In spite of minor acute MF degeneration, sustained axonal atrophy, dismyelination and retrograde changes did not resolve until 120 days after fracture healing. Correlations of morphometric parameters of degenerated MF with M-response amplitudes from electromyography underlie the subclinical neurologic changes in functional outcomes after tibial fractures even when nerves are mechanically uninjured. PMID- 26254047 TI - TRPP2 modulates ryanodine- and inositol-1,4,5-trisphosphate receptors-dependent Ca2+ signals in opposite ways in cerebral arteries. AB - TRPP2 is a cationic channel expressed in plasma membrane and in sarcoplasmic reticulum. In several cell lines, TRPP2 is described as a reticulum Ca(2+) leak channel but it also interacts with ryanodine and inositol 1,4,5-trisphosphate (InsP3) receptors to inhibit and increase the release of Ca(2+) stores, respectively. TRPP2 is known to be expressed in vascular smooth muscle cells, however its function in Ca(2+) signals remains poorly described in native cells, principally because the pharmacology is not developed. TRPP2 was expressed in cerebral arteries. Triptolide evoked Ca(2+) responses in a Ca(2+)-free solution as well as permeabilized arteries. This Ca(2+) signal was inhibited in presence of antisense oligonucleotide and siRNA directed against TRPP2 and antibody directed against the first loop of TRPP2. The partial inhibition of TRPP2 expression increased both the caffeine-evoked Ca(2+) responses and in vivo contraction. It also decreased the InsP3-evoked Ca(2+) responses. Finally, aging affected the regulations in which TRPP2 is engaged, whereas the triptolide-evoked Ca(2+) response was not modified. Taken together, our results have shown that TRPP2 is implicated in triptolide-induced Ca(2+) release from intracellular Ca(2+) stores. TRPP2 functionally interacts with both ryanodine and InsP3 receptors. These interactions were not similar in adult and old mice. PMID- 26254048 TI - Yes-associated protein (YAP) expression is involved in epithelial-mesenchymal transition in hepatocellular carcinoma. AB - PURPOSE: To investigate biological impact of the downregulation of yes-associated protein (YAP) through RNA interference in the process of epithelial-mesenchymal transition in MHCC97H and MHCC97L. METHODS: MHCC97H and MHCC97L cells were transiently transfected by YAP-siRNA. Furthermore, protein expressions and mRNA levels of characteristic markers of epithelial-mesenchymal transition (E cadherin, N-cadherin) were examined by Western blotting and real-time polymerase chain reaction, and transwell invasion assay was used to detect changes of invasiveness of MHCC97H and MHCC97L cells. RESULTS: The transfected group with YAP-siRNA in MHCC97H after 72 h by Western blotting showed obviously higher expression of E-cadherin compared with the control group (P < 0.05), and lower expression of N-cadherin (P < 0.05). In MHCC97L cells, the expression of E cadherin was also significantly increased (P < 0.05); however, N-cadherin expression did not significantly change (P > 0.05). Moreover, compared with the control group, Transwell invasion assay showed that the number of the transfected groups was significantly decreased in MHCC97H and MHCC97L cell lines (both P < 0.05). The result of real-time polymerase chain reaction indicated that mRNA levels of E-cadherin increased (P < 0.05), but the mRNA levels of N-cadherin did not significantly change (P > 0.05) in these two cell lines, indicating some effects of post-transcriptional regulation mechanism after silencing YAP. CONCLUSIONS: YAP expression in human hepatocellular carcinoma cell lines MHCC97H and MHCC97L is closely related with the characteristic markers of epithelial mesenchymal transition, N-cadherin and E-cadherin expression. PMID- 26254051 TI - Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug-related urticaria and angioedema. AB - Nonsteroidal anti-inflammatory drug (NSAID)-induced urticarial and angioedema reactions are among the most commonly encountered drug hypersensitivity reactions in clinical practice. Three major clinical phenotypes of NSAID-induced acute skin reactions manifesting with angioedema, urticaria, or both have been distinguished: NSAID-exacerbated cutaneous disease, nonsteroidal anti inflammatory drug-induced urticaria/angioedema (NIUA), and single NSAID-induced urticaria and angioedema. In some patients clinical history alone might be sufficient to establish the diagnosis of a specific type of NSAID hypersensitivity, whereas in other cases oral provocation challenges are necessary to confirm the diagnosis. Moreover, classification of the type of cutaneous reaction is critical for proper management. For example, in patients with single NSAID-induced reactions, chemically nonrelated COX-1 inhibitors can be safely used. However, there is cross-reactivity between the NSAIDs in patients with NSAID-exacerbated cutaneous disease and NIUA, and thus only use of selective COX-2 inhibitors can replace the culprit drug if the chronic treatment is necessary, although aspirin desensitization will allow for chronic treatment with NSAIDs in some patients with NIUA. In this review we present a practical clinical approach to the patient with NSAID-induced urticaria and angioedema. PMID- 26254050 TI - New genetic findings lead the way to a better understanding of fundamental mechanisms of drug hypersensitivity. AB - Drug hypersensitivity reactions are an important clinical problem for both health care and industry. Recent advances in genetics have identified a number of HLA alleles associated with a range of these adverse reactions predominantly affecting the skin but also other organs, such as the liver. The associations between abacavir hypersensitivity and HLA-B*57:01 and carbamazepine-induced Stevens-Johnson syndrome and HLA-B*15:02 have been implemented in clinical practice. There are many different mechanisms proposed in the pathogenesis of drug hypersensitivity reactions, including the hapten hypothesis, direct binding to T-cell receptors (the pharmacologic interaction hypothesis), and peptide binding displacement. A problem with all the hypotheses is that they are largely based on in vitro findings, with little direct in vivo evidence. Although most studies have focused on individual mechanisms, it is perhaps more important to consider them all as being complementary, potentially occurring at the same time with the same drug in the same patient. This might at least partly account for the heterogeneity of the immune response seen in different patients. There is a need to develop novel methodologies to evaluate how the in vitro mechanisms relate to the in vivo situation and how the highly consistent genetic findings with different HLA alleles can be more consistently used for both prediction and prevention of these serious adverse reactions. PMID- 26254049 TI - Evolving models of the immunopathogenesis of T cell-mediated drug allergy: The role of host, pathogens, and drug response. AB - Immune-mediated (IM) adverse drug reactions (ADRs) are an underrecognized source of preventable morbidity, mortality, and cost. Increasingly, genetic variation in the HLA loci is associated with risk of severe reactions, highlighting the importance of T-cell immune responses in the mechanisms of both B cell-mediated and primary T cell-mediated IM-ADRs. In this review we summarize the role of host genetics, microbes, and drugs in IM-ADR development; expand on the existing models of IM-ADR pathogenesis to address multiple unexplained observations; discuss the implications of this work in clinical practice today; and describe future applications for preclinical drug toxicity screening, drug design, and development. PMID- 26254052 TI - New approaches for predicting T cell-mediated drug reactions: A role for inducible and potentially preventable autoimmunity. AB - Adverse drug reactions (ADRs) are commonplace and occur when a drug binds to its intended pharmacologic target (type A ADR) or an unintended target (type B ADR). Immunologically mediated type B ADRs, such as drug hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms syndrome, and Stevens Johnson syndrome/toxic epidermal necrolysis, can be severe and result in a diverse set of clinical manifestations that include fever and rash, as well as multiple organ failure (liver, kidney, lungs, and/or heart) in the case of drug hypersensitivity syndrome. There is increasing evidence that specific HLA alleles influence the risk of drug reactions. Several features of T cell-mediated ADRs are strikingly similar to those displayed by patients with autoimmune diseases like type I diabetes, such as strong HLA association, organ-specific adaptive immune responses, viral involvement, and activation of innate immunity. There is a need to better predict patient populations at risk for immunologically mediated type B ADRs. Because methods to predict type 1 diabetes by using genetic and immunologic biomarkers have been developed to a high level of accuracy (predicting 100% of subjects likely to progress), new research strategies based on these methods might also improve the ability to predict drug hypersensitivity. PMID- 26254055 TI - Sibling assessment based on likelihood ratio and total number of shared alleles using 21 short tandem repeat loci included in the GlobalFilerTM kit. AB - Sibling assessment using the 15 autosomal short tandem repeat (STR) loci included in the Identifiler(r) kit can be difficult when comparing an unidentified party to an alleged sibling. Therefore, we investigated the likelihood ratio (LR) and the total number of shared alleles (TNSA) for sibship determination using the 21 autosomal STR loci included in the GlobalFilerTM kit. We computationally generated the genotypes of 10,000 sibling pairs and 10,000 unrelated pairs based on previously reported allele frequencies of the 15 Identifiler loci and the remaining 6 GlobalFiler loci. The LR and the TNSA were then calculated in each pair using the 15 and 21 loci. Next, these calculations were applied to 22 actual sibling pairs. LR values ? 10,000 were observed in 48% of the sibling pairs using the 15 loci and in 80% of the sibling pairs using the 21 loci. The TNSA distribution between siblings and unrelated pairs was more divergent in GlobalFiler than in Identifiler. TNSA values ? 20 were found only in true siblings in Identifiler, while TNSA values ?24 in GlobalFiler. In Identifiler, all pairs with TNSA ? 24 had LR values ? 10,000 and the same was true in GlobalFiler for TNSA ?29. Therefore, increasing the number of loci is very efficient for sibship determination. The LR is most reliable for determining sibship. However, TNSA values may be useful for the preliminary method of LR values because LR value demonstrated a significantly positive correlation with TNSA value in both Identifiler and GlobalFiler. PMID- 26254053 TI - Report from the National Institute of Allergy and Infectious Diseases workshop on drug allergy. AB - Allergic reactions to drugs are a serious public health concern. In 2013, the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases sponsored a workshop on drug allergy. International experts in the field of drug allergy with backgrounds in allergy, immunology, infectious diseases, dermatology, clinical pharmacology, and pharmacogenomics discussed the current state of drug allergy research. These experts were joined by representatives from several National Institutes of Health institutes and the US Food and Drug Administration. The participants identified important advances that make new research directions feasible and made suggestions for research priorities and for development of infrastructure to advance our knowledge of the mechanisms, diagnosis, management, and prevention of drug allergy. The workshop summary and recommendations are presented herein. PMID- 26254056 TI - Comparison of Costs and Quality of Life in Ulcerative Colitis Patients with an Ileal Pouch-Anal Anastomosis, Ileostomy and Anti-TNFalpha Therapy. AB - BACKGROUND AND AIMS: More data are warranted on the economic impact of different treatment strategies in ulcerative colitis (UC) patients. We compared the costs and quality of life of UC patients with a pouch reconstruction, an ileostomy or anti-tumour necrosis factor alpha (TNFalpha) therapy. METHODS: UC patients filled out 3-monthly questionnaires for 2 years. Differences in 3-monthly healthcare costs, productivity costs and patient costs were tested using mixed model analysis. Quality of life was assessed employing the ) and the inflammatory bowel disease questionnaire (IBDQ). RESULTS: Out of 915 UC patients, 81 (9%) had a pouch and 48 (5%) an ileostomy, and 34 (4%) were on anti-TNFalpha therapy. Anti TNFalpha-treated patients reported high UC related-healthcare costs per 3 months (?5350). Medication use accounted for 92% of healthcare costs. UC-attributable healthcare costs were 3-fold higher in ileostomy patients compared with pouch patients (?1581 versus ?407; p < 0.01). Main cost drivers in ileostomy patients were healthcare costs and ileostomy supplies (2 and 23% of healthcare costs, respectively). In pouch patients, the main cost driver was hospitalization, accounting for 50% of healthcare costs. Productivity loss did not differ between pouch and ileostomy patients (?483 versus ?377; p < 0.23), but was significantly higher in anti-TNFalpha-treated patients (?1085). No difference was found in IBDQ scores, but pouch patients were found to have higher quality-adjusted life years than ileostomy patients and anti-TNFalpha-treated patients (0.90 [interquartile range 0.78-1.00] versus 0.84 [0.78-1.00] and 0.84 [0.69-1.00], respectively; p < 0.01). CONCLUSION: Patients receiving anti-TNFalpha therapy reported the highest healthcare cost, in which medication use was the major cost driver. Ileostomy patients were three times more expensive than pouch patients due to frequent hospitalization and ileostomy supplies. PMID- 26254057 TI - Selective role of autophagy in neuronal function and neurodegenerative diseases. PMID- 26254058 TI - Molecular network of neuronal autophagy in the pathophysiology and treatment of depression. AB - Major depressive disorder (MDD) is a complicated multifactorial induced disease, characterized by depressed mood, anhedonia, fatigue, and altered cognitive function. Recently, many studies have shown that antidepressants regulate autophagy. In fact, autophagy, a conserved lysosomal degradation pathway, is essential for the central nervous system. Dysregulation of autophagic pathways, such as the mammalian target of rapamycin (mTOR) signaling pathway and the beclin pathway, has been studied in neurodegenerative diseases. However, autophagy in MDD has not been fully studied. Here, we discuss whether the dysregulation of autophagy contributes to the pathophysiology and treatment of MDD and summarize the current evidence that shows the involvement of autophagy in MDD. PMID- 26254059 TI - Role of autophagy in the pathogenesis of multiple sclerosis. AB - Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis (MS), a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system (CNS). Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis (EAE, a mouse model of MS). Dysfunction of mitochondria that intensively influences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene (ATG) 5 and immune-related GTPase M (IRGM) 1 are increased, while ATG16L2 is decreased, in T cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin ( mTOR), ameliorates relapsing-remitting EAE. Inflammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-II/LC3-I ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro inflammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinflammation associated with the pathogenesis of MS. PMID- 26254060 TI - Identification of autophagy signaling network that contributes to stroke in the ischemic rodent brain via gene expression. AB - Autophagy plays a vital role in cerebral ischemia and may be a potential target for developing novel therapy for stroke. In this study, we constructed an autophagy-related pathway network by analyzing the genes related to autophagy and ischemic stroke, and the risk genes were screened. Two autophagy-related modules were significantly up-regulated and clustered to influence cerebral ischemia. Besides, three key modular genes (NFKB1, RELA, and STAT3) were revealed. With 5 fold cross validation, the ROC curves of NFKB1, RELA, and STAT3 were 0.8256, 0.8462, and 0.8923. They formed a complex module and competitively mediated the activation of autophagy in cerebral ischemia. In conclusion, a module containing NFKB1, RELA, and STAT3 mediates autophagy, serving as a potential biomarker for the diagnosis and therapy of ischemic stroke. PMID- 26254061 TI - Autophagy is involved in oral rAAV/Abeta vaccine-induced Abeta clearance in APP/PS1 transgenic mice. AB - The imbalance between beta-amyloid (Abeta) generation and clearance plays a fundamental role in the pathogenesis of Alzheimer's disease (AD). The sporadic form of AD is characterized by an overall impairment in Abeta clearance. Immunotherapy targeting Abeta clearance is believed to be a promising approach and is under active clinical investigation. Autophagy is a conserved pathway for degrading abnormal protein aggregates and is crucial for Abeta clearance. We previously reported that oral vaccination with a recombinant AAV/Abeta vaccine increased the clearance of Abeta from the brain and improved cognitive ability in AD animal models, while the underlying mechanisms were not well understood. In this study, we first demonstrated that oral vaccination with rAAV/Abeta decreased the p62 level and up-regulated the LC3B-II/LC3B-I ratio in APP/PS1 mouse brain, suggesting enhanced autophagy. Further, inhibition of the Akt/mTOR pathway may account for autophagy enhancement. We also found increased anti-Abeta antibodies in the sera of APP/PS1 mice with oral vaccination, accompanied by elevation of complement factors C1q and C3 levels in the brain. Our results indicate that autophagy is closely involved in oral vaccination-induced Abeta clearance, and modulating the autophagy pathway may be an important strategy for AD prevention and intervention. PMID- 26254062 TI - Duration-dependent regulation of autophagy by isoflurane exposure in aged rats. AB - Current evidence suggests a central role for autophagy in many inflammatory brain disorders, including Alzheimer's disease (AD). Furthermore, it is also well accepted that some inhalation anesthetics, such as isoflurane, may cause AD-like neuropathogenesis and resultant postoperative cognitive dysfunction, especially in the elderly population. However, the impact of inhalation anesthetics on autophagic components in the brain remains to be documented. Hence, our objective was to investigate the effects of different durations of isoflurane exposure on hippocampus-dependent learning and hippocampal autophagy in aged rats. Aged Sprague-Dawley rats (20 months old) were randomly exposed to 1.5% isoflurane or 100% oxygen for 1 or 4 h. Animals were then trained in the Morris water maze (4 trials/day for 5 consecutive days). Hippocampal phagophore formation markers, beclin 1 and protein microtubule-associated protein 1 light chain-3B (LC3B), as well as p62, an indicator of autophagic flux, were quantified by western blotting. There was no significant difference in the escape latencies and time spent in the target quadrant, as well as hippocampal expression of beclin 1, LC3B II, and p62 at 24 h post-anesthesia between the 1-h isoflurane-exposed rats and their controls (P >0.05). Four-hour exposure to isoflurane resulted in spatial learning and memory deficits, as evidenced by prolonged escape latencies on days 4 and 5 post-anesthesia and less time spent in the target quadrant than sham exposed animals (P <0.05). These events were accompanied by a decline in hippocampal expression of LC3B-I, LC3B-II, and beclin 1 24 h after isoflurane (P <0.01 and P <0.05). Nevertheless, no significant change in p62 expression was found. Further kinetics study of autophagic changes induced by 4 h of isoflurane showed a transient upregulation of LC3B-I, LC3B-II, and beclin 1 at the end of exposure and a subsequent striking decrease within 12-24 h post-anesthesia (P <0.05). Hippocampal p62 peaked at 6 h but subsequently resolved. These results from our pilot in vivo study support a duration-dependent relationship between 1.5% isoflurane exposure, and spatial cognitive function as well as hippocampal phagophore formation. PMID- 26254063 TI - Fatty Amines from Little Black Ants, Monomorium minimum, and Their Biological Activities Against Red Imported Fire Ants, Solenopsis invicta. AB - Red imported fire ants, Solenopsis invicta, are significant invasive pests. Certain native ant species can compete with S. invicta, such as the little black ant, Monomorium minimum. Defensive secretions may contribute to the competition capacity of native ants. The chemistry of ant defensive secretions in the genus Monomorium has been subjected to extensive research. The insecticidal alkaloids, 2,5-dialkyl-pyrrolidines and 2,5-dialkyl-pyrrolines have been reported to dominate the venom of M. minimum. In this study, analysis of defensive secretions of workers and queens of M. minimum revealed two primary amines, decylamine and dodecylamine. Neither amine has been reported previously from natural sources. Toxicity and digging suppression by these two amines against S. invicta were examined. Decylamine had higher toxicity to S. invicta workers than dodecylamine, a quicker knockdown effect, and suppressed the digging behavior of S. invicta workers at lower concentration. However, the amount of fatty amines in an individual ant was not enough to knockdown a fire ant or suppress its digging behavior. These amines most likely work in concert with other components in the chemical defense of M. minimum. PMID- 26254064 TI - Consequences of long-term severe industrial pollution for aboveground carbon and nitrogen pools in northern taiga forests at local and regional scales. AB - Boreal coniferous forests act as an important sink for atmospheric carbon dioxide. The overall tree carbon (C) sink in the forests of Europe has increased during the past decades, especially due to management and elevated nitrogen (N) deposition; however, industrial atmospheric pollution, primarily sulphur dioxide and heavy metals, still negatively affect forest biomass production at different spatial scales. We report local and regional changes in forest aboveground biomass, C and N concentrations in plant tissues, and C and N pools caused by long-term atmospheric emissions from a large point source, the nickel-copper smelter in Monchegorsk, in north-western Russia. An increase in pollution load (assessed as Cu concentration in forest litter) caused C to increase in foliage but C remained unchanged in wood, while N decreased in foliage and increased in wood, demonstrating strong effects of pollution on resource translocation between green and woody tissues. The aboveground C and N pools were primarily governed by plant biomass, which strongly decreased with an increase in pollution load. In our study sites (located 1.6-39.7 km from the smelter) living aboveground plant biomass was 76 to 4888 gm(-2), and C and N pools ranged 35-2333 g C m(-2) and 0.5 35.1 g N m(-2), respectively. We estimate that the aboveground plant biomass is reduced due to chronic exposure to industrial air pollution over an area of about 107,200 km2, and the total (aboveground and belowground) loss of phytomass C stock amounts to 4.24*10(13) g C. Our results emphasize the need to account for the overall impact of industrial polluters on ecosystem C and N pools when assessing the C and N dynamics in northern boreal forests because of the marked long-term negative effects of their emissions on structure and productivity of plant communities. PMID- 26254065 TI - A laboratory-scale column study comparing organic micropollutant removal and microbial diversity for two soil types. AB - This study investigated sorption and biodegradation behaviour of 20 organic micropollutants (OMPs) in lab-scale columns filled with two types of soil (fed with the same water quality) simulating river bank filtration (RBF) under oxic conditions. Retardation factors and OMP biodegradation rates were similar for the two soils that were characterised by a different cationic exchange capacity, organic matter and sand/silt/clay content. This result was supported by the microbial community composition (richness, evenness) of the two soils that became more similar as a result of feeding both columns with the same water quality. This indicates that microbial community composition and thereby OMP removal in soils is primarily determined by the composition of the aqueous phase (organic matter quantity and quality, nutrients) rather than the soil phase. These results indicate that different RBF sites located along the same river may show similar OMP removal (in case of similar water quality and residence time). CAPSULE: This study shows that the microbial community composition and thus OMP removal is primarily determined by the aqueous phase (water quality) rather than the soil phase. PMID- 26254066 TI - Aged riverine particulate organic carbon in four UK catchments. AB - The riverine transport of particulate organic matter (POM) is a significant flux in the carbon cycle, and affects macronutrients and contaminants. We used radiocarbon to characterise POM at 9 riverine sites of four UK catchments (Avon, Conwy, Dee, Ribble) over a one-year period. High-discharge samples were collected on three or four occasions at each site. Suspended particulate matter (SPM) was obtained by centrifugation, and the samples were analysed for carbon isotopes. Concentrations of SPM and SPM organic carbon (OC) contents were also determined, and were found to have a significant negative correlation. For the 7 rivers draining predominantly rural catchments, PO14C values, expressed as percent modern carbon absolute (pMC), varied little among samplings at each site, and there was no significant difference in the average values among the sites. The overall average PO14C value for the 7 sites of 91.2 pMC corresponded to an average age of 680 14C years, but this value arises from the mixing of differently-aged components, and therefore significant amounts of organic matter older than the average value are present in the samples. Although topsoil erosion is probably the major source of the riverine POM, the average PO14C value is appreciably lower than topsoil values (which are typically 100 pMC). This is most likely explained by inputs of older subsoil OC from bank erosion, or the preferential loss of high-14C topsoil organic matter by mineralisation during riverine transport. The significantly lower average PO14C of samples from the River Calder (76.6 pMC), can be ascribed to components containing little or no radiocarbon, derived either from industrial sources or historical coal mining, and this effect is also seen in the River Ribble, downstream of its confluence with the Calder. At the global scale, the results significantly expand available information for PO14C in rivers draining catchments with low erosion rates. PMID- 26254067 TI - Plant uptake of pharmaceutical and personal care products from recycled water and biosolids: a review. AB - Reuse of treated wastewater for agricultural irrigation is growing in arid and semi-arid regions, while increasing amounts of biosolids are being applied to fields to improve agricultural outputs. These historically under-utilized resources contain "emerging contaminants", such as pharmaceutical and personal care products (PPCPs), which may enter agricultural soils and potentially contaminate food crops. In this review, we summarize recent research and provide a detailed overview of PPCPs in the soil-plant systems, including analytical methods for determination of PPCPs in plant tissues, fate of PPCPs in agricultural soils receiving treated wastewater irrigation or biosolids amendment, and plant uptake of PPCPs under laboratory and field conditions. Mechanisms of uptake and translocation of PPCPs and their metabolisms in plants are also reviewed. Field studies showed that the concentration levels of PPCPs in crops that were irrigated with treated wastewater or applied with biosolids were very low. Potential human exposure to PPCPs through dietary intake was discussed. Information gaps and questions for future research have been identified in this review. PMID- 26254068 TI - Biodegradation and reversible inhibitory impact of sulfamethoxazole on the utilization of volatile fatty acids during anaerobic treatment of pharmaceutical industry wastewater. AB - This study evaluated the chronic impact and biodegradability of sulfamethoxazole under anaerobic conditions. For this purpose, a lab-scale anaerobic sequencing batch reactor was operated in a sequence of different phases with gradually increasing sulfamethoxazole doses of 1 to 45 mg/L. Conventional parameters, such as COD, VFA, and methane generation, were monitored with corresponding antimicrobial concentrations in the reactor and the methanogenic activity of the sludge. The results revealed that anaerobic treatment was suitable for pharmaceutical industry wastewater with concentrations of up to 40 mg/L of sulfamethoxazole. Higher levels exerted toxic effects on the microbial community under anaerobic conditions, causing the inhibition of substrate/COD utilization and biogas generation and leading to a total collapse of the reactor. The adverse long-term impact was quite variable for fermentative bacteria and methanogenic achaea fractions of the microbial community based on changes inflicted on the composition of the residual organic substrate and mRNA expression of the key enzymes. PMID- 26254069 TI - Occurrence of glyphosate and AMPA in an agricultural watershed from the southeastern region of Argentina. AB - Glyphosate (GLY) and AMPA concentrations were determined in sandy soil profiles, during pre- and post-application events in two agricultural soybean fields (S1 and S2). Streamwater and sediment samples were also analyzed. Post-application sampling was carried out one month later from the event. Concentrations of GLY+AMPA in surface soils (0-5 cm depth) during pre-application period showed values 20-fold higher (0.093-0.163 MUg/g d.w.) than control area (0.005 MUg/g d.w.). After application event soils showed markedly higher pesticide concentrations. A predominance of AMPA (80%) was observed in S1 (early application), while 34% in S2 for surface soils. GLY+AMPA concentrations decreased with depth and correlated strongly with organic carbon (r between 0.74 and 0.88, p<0.05) and pH (r between -0.81 and -0.76, p<0.001). The slight enrichment of pesticides observed from 25 cm depth to deeper layer, in addition to the alkaline pH along the profile, is of high concern about groundwater contamination. Sediments from pre-application period showed relatively lower pesticide levels (0.0053-0.0263 MUg/g d.w.) than surface soil with a predominance of glyphosate, indicating a limited degradation. Levels of contaminants (mainly AMPA) in streamwater (ND-0.5 ng/mL) denote the low persistence of these compounds. However, a direct relationship in AMPA concentration was observed between sediment and streamwater. Despite the known relatively short half-life of glyphosate in soils, GLY+AMPA occurrence is registered in almost all matrices at different sampling times (pre- and post-application events). The physicochemical characteristics (organic carbon, texture, pH) and structure of soils and sediment in addition to the time elapsed from application determined the behavior of these contaminants in the environment. As a whole, the results warn us about vertical transport trough soil profile with the possibility of reaching groundwater. PMID- 26254070 TI - Comparison of ionic and carbonaceous compositions of PM2.5 in 2009 and 2012 in Shanghai, China. AB - Daily PM2.5 samples were obtained at the site of East China University of Science and Technology (ECUST) in urban Shanghai during 2009-2010 and 2011-2012. The temporal variations of PM2.5 and its chemical compositions including secondary inorganic aerosol (SIA) and carbonaceous components were studied. The concentrations of PM2.5 were (94.04+/-52.17) MUg/m3 and (68.44+/-41.57) MUg/m3 in 2009 and 2012, respectively. The concentrations and contributions of SIA to PM2.5 were significantly higher in 2012 than those in 2009. Sulfate took up above 50% of SIA in 2009 and the corresponding value decreased to 41% in 2012. The increasing trend of NO3-/SO4(2-) mass ratio implied that the contributions of mobile sources were more and more important. The molar ratios of [NH4+]/(2[SO4(2 )]+[NO3-]) were 0.57 and 0.70, lower than 1, which demonstrated that most aerosol samples were ammonium-poor. But the neutralization process of ammonium might affect the formation of sulfate and nitrate, which was indicated by the strong correlation between [NH4+]-[SO4(2-)] and [NH4+]-[NO3-]. The average molar ratio of ammonium to sulfate was 1.74 in 2009, so there was not enough ammonium to neutralize sulfate sufficiently. The higher value of 2.30 in 2012 indicated that sulfate was sufficiently neutralized by ammonium and the predominant production was (NH4)2SO4. Aerosol samples had higher char-EC/soot-EC ratios and lower OC/EC ratios in 2009 than those of samples in 2012. The higher K+/OC values demonstrated that biomass burning made important contributions to carbonaceous components in both 2009 and 2012. All backward trajectories were grouped into four clusters, mainly from the Northwest, the Circum-Bohai-Sea Region (CBSR), the Southwest and the Southeast. The cluster from the Northwest was the most polluted pathway in 2009, while the cluster from the CBSR had more effects in 2012. PSCF model for PM2.5 and carbonaceous components except soot-EC suggested that the Yangtze River Delta Region (YRDR) made significant contributions by short-range transportation in 2009 and 2012. The Northwest, the CBSR and the Pearl River Delta Region (PRDR) were also the potential source areas. However, the source pattern of soot-EC was significantly different from those of other carbonaceous components. PMID- 26254071 TI - Risk assessment of bearded vulture (Gypaetus barbatus) exposure to topical antiparasitics used in livestock within an ecotoxicovigilance framework. AB - Between 2004 and 2013, 486 suspected scavenger poisoning cases, including 24 bearded vultures (Gypaetus barbatus), were investigated in the Pyrenees and surrounding areas in Spain as part of a monitoring programme regarding accidental and intentional poisoning of wildlife. Poisoning was confirmed in 36% of all analysed cases where scavenger species were found dead within the distribution range of bearded vultures. Organophosphates and carbamates were the most frequently detected poisons. Four of the bearded vulture cases were positive for the presence of topical antiparasitics (3 with diazinon and 1 with permethrin). These likely represented accidental exposure due to the legal use of these veterinary pharmaceuticals. In order to confirm the risk of exposure to topical antiparasitics in bearded vultures, pig feet (n=24) and lamb feet (n=24) were analysed as these are one of the main food resources provided to bearded vultures at supplementary feeding stations. Pig feet had no detectable residues of topical antiparasitics. In contrast, 71.4% of lamb feet showed residues of antiparasitics including diazinon (64.3%), pirimiphos-methyl (25.4%), chlorpyrifos (7.1%), fenthion (1.6%), permethrin (0.8%) and cypermethrin (27.8%). Washing the feet with water significantly reduced levels of these topical antiparasitics, as such, this should be a recommended practice for lamb feet supplied at feeding stations for bearded vultures. Although the detected levels of antiparasitics were relatively low (<=1 MUg/g), a risk assessment suggests that observed diazinon levels may affect brain acetylcholinesterase and thermoregulation in bearded vultures subject to chronic exposure. PMID- 26254072 TI - Arsenic mineralogy and mobility in the arsenic-rich historical mine waste dump. AB - A more than 250 year-old mine dump was studied to document the products of long term arsenopyrite oxidation under natural conditions in a coarse-grained mine waste dump and to evaluate the environmental hazards associated with this material. Using complementary mineralogical and chemical approaches (SEM/EDS/WDS, XRD, micro-Raman spectroscopy, pore water analysis, chemical extraction techniques and thermodynamic PHREEQC-2 modeling), we documented the mineralogical/geochemical characteristics of the dumped arsenopyrite-rich material and environmental stability of the newly formed secondary minerals. A distinct mineralogical zonation was found (listed based on the distance from the decomposed arsenopyrite): scorodite (locally associated with native sulfur pseudomorphs) plus amorphous ferric arsenate (AFA/pitticite), kankite, As-bearing ferric (hydr)oxides and jarosite. Ferric arsenates and ferric (hydr)oxides were found to dissolve and again precipitate from downward migrating As-rich solutions cementing rock fragments. Acidic pore water (pH3.8) has elevated concentrations of As with an average value of about 2.9 mg L(-1). Aqueous As is highly correlated with pH (R2=0.97, p<0.001) indicating that incongruent dissolution of ferric arsenates controls dissolved As well as the pH of the percolating waste solution. Arsenic released from the dissolution of ferric arsenates into the pore water is, however, trapped by latter and lower-down precipitating jarosite and especially ferric (hydr)oxides. The efficiency of As sequestration by ferric (hydr)oxides in the waste dump and underlying soil has been found to be very effective, suggesting limited environmental impact of the mine waste dump on the surrounding soil ecosystems. PMID- 26254073 TI - Investigation of potential endocrine disrupting effects of mosquito larvicidal Bacillus thuringiensis israelensis (Bti) formulations. AB - Bti is successfully used as a biological control agent for mosquito control. It has proven to be ecological friendly, and thus, is used in ecologically sensitive habitats. Recent investigations of groundwater in Germany have detected estrogenic activity in five consecutive groundwater wells in a region where Bti is applied. Therefore, it was suspected that this compound can act as an environmental xenoestrogen. In the present study, five Bti formulations as well as the active ingredient, VectoBac(r) TP (TP), were investigated regarding their estrogenic activity using the LYES and ER CALUX(r) assays. Furthermore, their steroidogenesis disruption properties were studied using the H295R Steroidogenesis Assay. Additionally, field samples from a Bti application area as well as samples from an artificial pond were examined. Three of the Bti formulations and the active ingredient TP showed significant estrogenic activity in the LYES (up to 52 ng.l(-1) estradiol equivalents (EEQ) in the 18-fold concentration) and/or the ER CALUX(r) (up to 1 ng.EEQ.l(-1) in the 18-fold concentration). In the H295R significant but weak effects with no dose-response relationship on the production of estradiol, and 21-hydroxyprogesterone (WDG) as well as testosterone (TP) by H295R cells could be observed. The field samples as well as the samples from the artificial pond showed no significant increase of estrogenic activity after application of TP or WDG in the ER CALUX(r). With the exception of the controlled laboratory experiments with direct application of Bti to the utilized in vitro test systems the present study did not reveal any significant effects of Bti on endocrine functions that would indicate that the application of Bti could cause adverse endocrine effects to organisms in aquatic ecosystems. Instead, our results support previous studies that the use of Bti products against mosquitos would be safe even for sensitive habitats such as conservation areas. PMID- 26254074 TI - Variation analysis of streamflow and ecological flow for the twin rivers of the Miyun Reservoir Basin in northern China from 1963 to 2011. AB - In this paper, the Mann-Kendall test and F-test were combined to analyze the annual and seasonal streamflow variations and aberrance points for the twin rivers from 1963 to 2011. The Tennant method was subsequently used to evaluate the ecological flow assurance and deficit. Finally, the Double Mass Curve method was applied to identifying the human activities affecting the streamflow variations. The results were as follows: (1) Three similar stages of the streamflow variations were found for the twin rivers: fluctuations before 1980, the tiny downward trends from the 1980s to the 1990s, and the notably downward trends in the 2000s. (2) The seasonal streamflow also decreased continuously and dramatically, especially in summer, by 80.9% for the Chaohe River and 86.0% for the Baihe River. (3) During the spawning season, 83.3% and 73.1% of streamflow was not at the appropriate level for the Chaohe and Baihe Rivers, respectively, which indicated that the ecological environment was not optimal for the reproduction and breeding of aquatic organisms. While in other periods, the ecological flow assurance was better than that in spawning seasons for the Chaohe and Baihe Rivers, respectively. This indicated that the streamflow regimes of the twin rivers were not always optimal and conducive to the development of the aquatic ecosystem. (4) The streamflow variations of the twin rivers were influenced by increasingly intensive human activities such as changes of land use and land cover, and excessive exploitation and utilization of water resources. These influences were cumulative and showed a gradually increasing tendency. This research is helpful for understanding the streamflow regime and for forecasting of the regional extreme climate, such as drought and floods, and can provide a basis for decision making and formulating adaptive ecological security countermeasures in response to climate changes and human activities. PMID- 26254075 TI - Spatial and temporal distribution of aliphatic hydrocarbons and linear alkylbenzenes in the particulate phase from a subtropical estuary (Guaratuba Bay, SW Atlantic) under seasonal population fluctuation. AB - Guaratuba Bay, a subtropical estuary located in the SW Atlantic, is under variable anthropogenic pressure throughout the year. Samples of surficial suspended particulate matter (SPM) were collected at 22 sites during three different periods to evaluate the temporal and spatial variability of aliphatic hydrocarbons (AHs) and linear alkylbenzenes (LABs). These compounds were determined by gas chromatography with flame ionization detection (GC-FID) and mass spectrometry (GC/MS). The spatial distributions of both compound classes were similar and varied among the sampling campaigns. Generally, the highest concentrations were observed during the austral summer, highlighting the importance of the increased human influence during this season. The compound distributions were also affected by the natural geochemical processes of organic matter accumulation. AHs were associated with petroleum, derived from boat and vehicle traffic, and biogenic sources, related to mangrove forests and autochthonous production. The LAB composition evidenced preferential degradation processes during the austral summer. PMID- 26254076 TI - Measurement of ground and nearby building vibration and noise induced by trains in a metro depot. AB - Metro depots are where subway trains are parked and where maintenance is carried out. They usually occupy the largest ground areas in metro projects. Due to land utilization problems, Chinese cities have begun to develop over-track buildings above metro depots for people's life and work. The frequently moving trains, when going into and out of metro depots, can cause excessive vibration and noise to over-track buildings and adversely affect the living quality of the building occupants. Considering the current need of reliable experimental data for the construction of metro depots, field measurements of vibration and noise on the ground and inside a nearby 3-story building subjected to moving subway trains were conducted in a metro depot at Guangzhou, China. The amplitudes and frequency contents of velocity levels were quantified and compared. The composite A weighted equivalent sound levels and maximum sound levels were captured. The predicted models for vibration and noise of metro depot were proposed based on existing models and verified. It was found that the vertical vibrations were significantly greater than the horizontal vibrations on the ground and inside the building near the testing line. While at the throat area, the horizontal vibrations near the curved track were remarkably greater than the vertical vibrations. The attenuation of the vibrations with frequencies above 50 Hz was larger than the ones below 50 Hz, and the frequencies of vibration transmitting to adjacent buildings were mainly within 10-50 Hz. The largest equivalent sound level generated in the throat area was smaller than the testing line one, but the instantaneous maximum sound level induced by wheels squeal, contact between wheels and rail joints as well as turnout was close to or even greater than the testing line one. The predicted models gave a first estimation for design and assessment of newly built metro depots. PMID- 26254077 TI - Chemical speciation, mobility and phyto-accessibility of heavy metals in fly ash and slag from combustion of pelletized municipal sewage sludge. AB - Combustion of pelletized municipal sewage sludge (MSS) can generate pestilent byproducts: fly ash and slag. Comparisons of heavy metal sequential extraction results among MSS, fly ash and slag showed that after combustion, the bioavailable heavy metal fractions (acid soluble/exchangeable, reducible and oxidizable fractions) were mostly transformed into the very stable heavy metal fractions (residual fractions). On the other hand, the results of toxicity characteristic leaching procedure (TCLP), diethylenetriamine pentaacetic acid and HCl extraction (phyto-accessibility assessment) demonstrated that the mobility and toxicity of heavy metals were greatly reduced. The direct and long-term bioavailability and eco-toxicity of heavy metals in fly ash and slag were relieved, which implied that combustion of pelletized MSS could be a promising and completely safe disposal technology for MSS treatment. PMID- 26254078 TI - The pollution removal and stormwater reduction performance of street-side bioretention basins after ten years in operation. AB - This study evaluated the pollution removal and hydrologic performance of five, 10 year old street-side bioretention systems. The bioretention basins were subjected to a series of simulated rainfall events using synthetic stormwater. Four different pollution concentrations were tested on three of the bioretention basins. The four concentrations tested were: A) no pollution; B) typical Australian urban pollutant loads; C) double the typical pollution loads, and; D) five times the typical pollution loads. Tests were also undertaken to determine the levels of contaminant and heavy metals build-up that occurred in the filter media over the 10 year operational life of the bioretention systems. Although highly variable, the overall hydrological performance of the basins was found to be positive, with all basins attenuating flows, reducing both peak flow rates and total outflow volumes. Total suspended solids removal performance was variable for all tests and no correlation was found between performance and dosage. Total nitrogen (TN) removal was positive for Tests B, C and D. However, the TN removal results for Test A were found to be negative. Total phosphorus (TP) was the only pollutant to be effectively removed from all basins for all four synthetic stormwater tests. The study bioretention basins were found to export pollutants during tests where no pollutants were added to the simulated inflow water (Test A). Heavy metal and hydrocarbon testing undertaken on the bioretention systems found that the pollution levels of the filter media were still within acceptable limits after 10 years in operation. This field study has shown bioretention basin pollution removal performance to be highly variable and dependant on a range of factors including inflow pollution concentrations, filter media, construction methods and environmental factors. Further research is required in order to fully understand the potential stormwater management benefits of these systems. PMID- 26254079 TI - Pesticides in the surface waters of Lake Vistonis Basin, Greece: Occurrence and environmental risk assessment. AB - A study was undertaken for the evaluation of the pesticide pollution caused by the agricultural activities in the basin of Lake Vistonis, Greece during the years 2010-2012. Water samples were collected from Lake Vistonis, four major rivers and various small streams and agriculture drainage canals. The concentration of 302 compounds was determined after solid-phase extraction of the water samples and subsequent LC-MS/MS and GC-MS/MS analysis of the extracts. Overall, herbicides were the most frequently detected pesticides (57%), followed by insecticides (28%) and fungicides (14%). In Lake Vistonis 11 pesticides were detected. Specifically, fluometuron was detected in the 75% of the samples (maximum concentration 0.088 MUg/L) whereas lambda-cyhalothrin was detected in all the samples of spring 2011 and alphamethrin in all the samples of spring 2012 (maximum concentration 0.041 and 0.168 MUg/L, respectively). In the rivers and drainage canals 68 pesticides were detected. Specifically, fluometuron was detected in the 53% of the samples (maximum concentration 317.6 MUg/L) followed by chlorpyrifos and prometryn (16 and 13% of the samples respectively). An environmental risk assessment was performed by employing the Risk Quotient (RQ) method. The risk assessment revealed that at least one pesticide concentration led to a RQ>1 in 20% of the samples. In Lake Vistonis, alphamethrin and lambda cyhalothrin concentrations resulted in RQ>1, whereas in the other water bodies this was mainly the result of chlorpyrifos-methyl and alphamethrin exposure. In contrast, herbicide and fungicide concentrations contributed substantially less to environmental risks. PMID- 26254080 TI - Quantifying the anthropogenic and climatic contributions to changes in water discharge and sediment load into the sea: A case study of the Yangtze River, China. AB - Based on data from the Datong hydrological station and 147 meteorological stations, the influences of climate change and human activities on temporal changes in water discharge and sediment load were examined in the Yangtze River basin from 1953 to 2010. The Mann-Kendall test, abrupt change test (Mann-Kendall and cumulative anomaly test), and Morlet wavelet method were employed to analyze the water discharge and sediment load data measured at the Datong hydrological station. The results indicated that the annual mean precipitation and water discharge exhibited decreasing trends of -0.0064 mm/10 yr and -1.41*10(8) m3/yr, respectively, and that the water sediment load showed a significant decreasing trend of -46.5*10(6) t/yr. Meanwhile, an abrupt change in the water discharge occurred in 2003. The sediment load also exhibited an abrupt change in 1985. From 1970 to 2010, the climate change and human activities contributed 72% and 28%, respectively, to the water discharge reduction. The human-induced decrease in the sediment load was 914.03*10(6) t/yr during the 1970s and 3301.79*10(6) t/yr during the 2000s. The contribution from human activities also increased from 71% to 92%, especially in the 1990s, when the value increased to 92%. Climate change and human activities contributed 14% and 86%, respectively, to the sediment load reduction. Inter-annual variations in water discharge and sediment load were affected by climate oscillations and human activities. The effect of human activities on the sediment load was considerably greater than those on water discharge in the Yangtze River basin. PMID- 26254081 TI - A review and evaluation of forest canopy epiphyte roles in the partitioning and chemical alteration of precipitation. AB - Interactions between precipitation and forest canopy elements (bark, leaves, and epiphytes) control the quantity, spatiotemporal patterning, and the chemical concentration, character and constituency of precipitation to soils. Canopy epiphytes exert a range of hydrological and biogeochemical effects due to their diversity of morphological traits and nutrient acquisition mechanisms. We reviewed and evaluated the state of knowledge regarding epiphyte interactions with precipitation partitioning (into interception loss, throughfall, and stemflow) and the chemical alteration of net precipitation fluxes (throughfall and stemflow). As epiphyte species are quite diverse, this review categorized findings by common paraphyletic groups: lichens, bryophytes, and vascular epiphytes. Of these groups, vascular epiphytes have received the least attention and lichens the most. In general, epiphytes decrease throughfall and stemflow and increase interception loss. Epiphytes alter the spatiotemporal pattern of throughfall and increase overall latent heat fluxes from the canopy. Epiphytes alter biogeochemical processes by impacting the transfer of solutes through the canopy; however, the change in solute concentration varies with epiphyte type and chemical species. We discuss several important knowledge gaps across all epiphyte groups. We also explore innovative methods that currently exist to confront these knowledge gaps and past techniques applied to gain our current understanding. Future research addressing the listed deficiencies will improve our knowledge of epiphyte roles in water and biogeochemical processes coupled within forest canopies-processes crucial to supporting microbe, plant, vertebrate and invertebrate communities within individual epiphytes, epiphyte assemblages, host trees, and even the forest ecosystem as a whole. PMID- 26254082 TI - Sensitivity of the invasive bivalve Corbicula fluminea to candidate control chemicals: The role of dissolved oxygen conditions. AB - The freshwater Corbicula fluminea is a major aquatic nuisance worldwide. Current pest control methods raise cost-effectiveness and environmental concerns, which motivate research into improved mitigation approaches. In this context, the susceptibility of the clams to chemicals under reduced oxygen conditions was examined. Biocides with different mechanisms of toxicity (niclosamide, polyDADMAC, ammonium nitrate, potassium chloride and dimethoate) were tested under normoxic (>7 mg L(-1) dissolved O2) and hypoxic (<2 mg L(-1) dissolved O2) conditions. Hypoxia was observed to potentiate chemical treatment, particularly when combined with non-overwhelming doses that would produce only intermediate responses by themselves. For niclosamide, ammonium nitrate and dimethoate, clam mortality enhancements up to 400% were observed under hypoxia as compared to dosing upon normal dissolved oxygen conditions. For polyDADMAC and potassium chloride, substantially lower mortality enhancements were found. The differences in the clams' sensitivity to the chemicals under hypoxia could be linked to the expected mechanisms of action. This suggests that judicious selection of the biocide is essential if optimized combined control treatments are to be designed and provides an insight into the interference of frequent hypoxia events in the response of natural clam populations to contaminant loads. PMID- 26254083 TI - An Increased Serum N-Terminal Telopeptide of Type I Collagen, a Biochemical Marker of Increased Bone Resorption, Is Associated with Infliximab Therapy in Patients with Crohn's Disease. AB - BACKGROUND: Osteopenia and osteoporosis are considered to be extra-intestinal manifestations of inflammatory bowel disease (IBD). Anti-tumor necrosis factor (TNF)-alpha biologics have been introduced as novel medications for an active IBD. However, it is still not well documented whether anti-TNF-alpha affects the frequency of bone loss or abnormality of bone mineral markers among patients with IBD. AIMS: This study was to investigate the biochemical basis of low bone mineral density (BMD) and increased turnover in IBD during infliximab (IFX) therapy. METHODS: Forty patients with Crohn's disease (CD), 80 patients with ulcerative colitis (UC), and 65 age- and gender-matched controls were included. BMD was measured with dual-energy X-ray absorptiometry, and vitamins K and D were measured as serum undercarboxylated osteocalcin (ucOC) and 1,25-(OH)2D, respectively. Bone formation and resorption were based on measuring bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx), respectively. RESULTS: Significantly lower BMD was found in patients with UC and CD as compared to controls (P < 0.05). BAP, 1,25-(OH)2D, ucOC, and NTx were significantly higher in CD patients, but not in UC patients as compared to controls (P < 0.05). Further, serum NTx level was significantly higher in CD patients who were receiving IFX as compared to CD patients who were not receiving IFX (P < 0.01). CONCLUSIONS: A lower BMD and higher bone metabolism markers were found in CD patients as compared to controls or UC patients. A significant increased serum level of NTx, a biochemical marker of increased bone resorption, was observed in CD patients during IFX therapy. PMID- 26254084 TI - Genotyping of Cucumber mosaic virus isolates in western New York State during epidemic years: Characterization of an emergent plant virus population. AB - In the early 2000s an epidemic of cucumber mosaic virus (CMV) spread within the Midwestern and Eastern US affecting snap and dry bean (Phaseolus vulgaris L.) cultivation. Fifty one CMV isolates from this period were partially characterized from varied hosts by sequencing a section from each of the three genomic RNAs. Aside from one subgroup II strain from pepper, all isolates, including those from snap bean, fell within the IA subgroup. The nucleotide sequence diversity of virus populations sampled at multiple sites and at different years was significantly higher than that of a population from single site in a single year, although in general the number of polymorphisms was low (<11%). Complementary DNA (cDNA) clones of Bn57, a representative isolate from snap bean, were engineered for the production of infectious in vitro RNA transcripts initiated from a T7 promoter. Infections from these cDNAs resulted in symptoms consistent with those of the original field isolate, indicating that a satellite RNA is not involved in symptom expression in snap bean. These infectious clones were used to assess symptom determinants and the effects of virus infection on plant growth. Inoculations with pseudorecombinants derived from Bn57 and the non-bean infecting strain Fny confirmed RNA2 as a specific determinant for snap bean infection. Bn57, along with almost all isolates identified in this study contained the Y631 locus in the 2a protein, a determinant for systemic infection in bean. The presence of this locus extended to all non-bean hosts except two pepper infecting isolates. Infection by Bn57 in snap bean had a significant effect on pod number and mass with a 55 and 41 percent reduction in greenhouse assays, respectively. To our knowledge Bn57 is the first CMV strain isolated from P. vulgaris to be fully sequenced and cloned, providing a useful tool for analyses of CMV-host interactions. PMID- 26254085 TI - The odontoid process: a comprehensive review of its anatomy, embryology, and variations. AB - BACKGROUND: The odontoid process is a critical component of the cranio-cervical junction. Therefore, clinicians who diagnose, treat, or operate this region need a strong background in regard to the embryology, anatomy, and anatomical variations that may be seen for the odontoid process. METHODS: A literature review was performed, using standard search engines, to explore the morphology, embryology, and anatomical variants of the odontoid process. CONCLUSIONS: A sound understanding of the development of the odontoid process, both in normal and in variant forms, as well as its phenotypical morphology is a prerequisite for the diagnosis and treatment of patients presenting with disorders affecting the cranio-cervical spine. PMID- 26254086 TI - Commentary on "Syndemics of psychosocial problems and HIV risk: A systematic review of empirical tests of the disease interaction concept" by A. Tsai and B. Burns. PMID- 26254087 TI - Genome-wide identification of mononuclear cell DNA methylation sites potentially affected by fish oil supplementation in young infants: A pilot study. AB - Recent evidence suggests that the effects of n-3LCPUFA might be mediated through epigenetic mechanisms, especially DNA-methylation, during pregnancy and early life. A randomized trial was conducted in 133 9-mo-old, infants who received 3.8g/day of fish oil (FO) or sunflower oil (SO) for 9 mo. In a subset of 12 children, buffy-coat DNA was extracted before and after intervention and analyzed on Illumina-Human-Methylation 450-arrays to explore genome-wide differences between the FO and SO groups. Genome-wide-methylation analysis did not reveal significant differences between groups after adjustment for multiple testing. However, analysis of the top-ranked CpG-sites revealed 43 CpG's that appear modified with an absolute difference in methylation of >=10%. Methylation levels at these sites were associated with phenotypic changes mainly in blood pressure. In conclusion, our analyses suggest potential epigenome effects that might be associated with functional outcomes, yet the effect sizes were small and should be verified by additional investigation. PMID- 26254088 TI - Open-wedge high tibial osteotomy: incidence of lateral cortex fractures and influence of fixation device on osteotomy healing. AB - PURPOSE: Open-wedge high tibial osteotomy (HTO) is an established treatment for young and middle-aged patients with medial compartment knee osteoarthritis and varus malalignment. Although not intended, a lateral cortex fracture might occur during this procedure. Different fixation devices are available to repair such fractures. This study was performed to evaluate osteotomy healing after fixation with two different locking plates. METHODS: Sixty-nine medial open-wedge HTO without bone grafting were followed until osteotomy healing. RESULTS: In patients with an intact lateral hinge, no problems were noted with either locking plate. A fracture of the lateral cortex occurred in 21 patients (30.4 %). In ten patients, the fracture was not recognized during surgery but was visible on the radiographs at the 6-week follow-up. Lateral cortex fracture resulted in non-union with the need for surgical treatment in three out of eight (37.5 %) patients using the newly introduced locking plate (Position HTO Maxi Plate), while this did not occur with a well-established locking plate (TomoFix) (0 out of 13, p = 0.023). CONCLUSION: With regard to other adverse events, no differences between both implants were observed. In cases of lateral cortex fracture, fixation with a smaller locking plate resulted in a relevant number of non-unions. Therefore, it is recommended that bone grafting, another fixation system, or an additional lateral fixation should be used in cases with lateral cortex fracture. LEVEL OF EVIDENCE: III. PMID- 26254089 TI - Arthroscopic management of massive rotator cuff tears: an evaluation of debridement, complete, and partial repair with and without force couple restoration. AB - PURPOSE: To evaluate the effectiveness of arthroscopic debridement (DB), partial (PR), and complete repair (CR) for massive rotator cuff tears (mRCT) in terms of functional and subjective parameters, and repair integrity. METHODS: For this single-centre study, 68 consecutive shoulders with mRCT involving at least three tendons and treated with arthroscopic DB (n = 23), PR (n = 22), and CR (n = 23) were included. All patients (52-81 years) were prospectively assessed before and at a mean of 45 months after surgery using functional and subjective parameters. Preoperative tendon rupture pattern and post-operative repair integrity were assessed by MRI. A coding system describing accurately rotator cuff rupture, treatment, and integrity was established. RESULTS: All treatment groups improved significantly from pre- to post-operative (P < 0.01), while preoperative parameters, except fatty degeneration, were not significantly different. However, post-operative comparisons revealed similar scores with DB (constant score, CS 65.8 +/- 14.7, qDASH 24.1 +/- 20.6) and PR (CS 67.5 +/- 9.9, P = n.s.; qDASH 20.5 +/- 14.4, P = n.s.), while CR were significantly better (CS 80.3 +/- 8.9; qDASH 7.0 +/- 8.7; P <= 0.001). Force couple restoration of PR did not significantly influence outcome. Re-tear rates with CR (29 %) were lower compared to PR (53 %). Intact CR compared to intact PR showed better CS (83.4 +/- 7.3 vs. 68.5 +/- 10.6, P = 0.009) and qDASH (5.4 +/- 8.3 vs. 21.2 +/- 9.5, P = 0.006). The vast majority of patients were satisfied with their arthroscopic procedure (DB 87 %; PR 86 %; CR 91 %). CONCLUSION: Arthroscopic DB, PR, and CR were effective in treating mRCT involving at least three tendons. Reparability of mRCT was influenced by fatty degeneration of the muscles. However, CR showed the most favourable short-term improvements. LEVEL OF EVIDENCE: IV. PMID- 26254091 TI - A probable case of poliomyelitis imported to Malaysia. AB - We report a previously well 10-month-old Somalian girl who acquired asymmetric lower limb weakness in July 2013 in Mogadishu, Banadir, before arriving in Malaysia at 12 months of age. In May 2013, there was a wild poliomyelitis outbreak in that area, as reported by the World Health Organization. Laboratory investigation, including cerebrospinal fluid, was unremarkable, and electrophysiological studies showed active axonal denervation in the left lower limb. The whole spine T2-weighted MRI revealed non-enhancing hyperintensities of the bilateral anterior horn cells, predominantly on the left side at T11-12. The viral isolations from two stool specimens at her presentation to our centre, 2 months after the onset of illness and 2 weeks apart, were negative. Despite lacking the acute virological evidence of poliomyelitis, in view of the girl's clinical, electrophysiological and classical spinal neuroradiological features, together with her temporal relationship with a World Health Organization reported wild poliomyelitis outbreak, we believe these findings are consistent with a diagnosis of imported poliomyelitis. A review at 30 months of age showed persistent left lower limb monoplegia with little recovery. Our patient reiterates the importance of maintaining awareness of wild polio importation, and keeping abreast of the latest news of global poliomyelitis outbreaks when treating patients with flaccid paralysis, even if they arrive from non-endemic poliomyelitis areas. PMID- 26254090 TI - Dynamic balance deficits in individuals with chronic ankle instability compared to ankle sprain copers 1 year after a first-time lateral ankle sprain injury. AB - PURPOSE: To quantify the dynamic balance deficits that characterise a group with chronic ankle instability compared to lateral ankle sprain copers and non-injured controls using kinematic and kinetic outcomes. METHODS: Forty-two participants with chronic ankle instability and twenty-eight lateral ankle sprain copers were initially recruited within 2 weeks of sustaining a first-time, acute lateral ankle sprain and required to attend our laboratory 1 year later to complete the current study protocol. An additional group of non-injured individuals were also recruited to act as a control group. All participants completed the anterior, posterior-lateral and posterior-medial reach directions of the star excursion balance test. Sagittal plane kinematics of the lower extremity and associated fractal dimension of the centre of pressure path were also acquired. RESULTS: Participants with chronic ankle instability displayed poorer performance in the anterior, posterior-medial and posterior-lateral reach directions compared with controls bilaterally, and in the posterior-lateral direction compared with lateral ankle sprain copers on their 'involved' limb only. These performance deficits in the posterior-lateral and posterior-medial directions were associated with reduced flexion and dorsiflexion displacements at the hip, knee and ankle at the point of maximum reach, and coincided with reduced complexity of the centre of pressure path. CONCLUSION: In comparison with lateral ankle sprain copers and controls, participants with chronic ankle instability were characterised by dynamic balance deficits as measured using the SEBT. This was attested to reduced sagittal plane motions at the hip, knee and ankle joints, and reduced capacity of the stance limb to avail of its supporting base. LEVEL OF EVIDENCE: III. PMID- 26254092 TI - Magnetic resonance imaging of atherothrombotic plaques. AB - Atherosclerosis remains the leading cause of long term morbidity and mortality worldwide, despite significant advances in its management. Vulnerable atherothrombotic plaques are predominantly responsible for thromboembolic ischaemic events in arterial beds, such as the carotid, coronary and lower limb arteries. MRI has emerged as a non-invasive, non-irradiating and highly reproducible imaging technique which allows detailed morphological and functional assessment of such plaques. It also has the potential to monitor the efficacy of established and evolving anti-atherosclerosis drugs. It is envisaged that by careful identification and understanding of the underlying cellular and molecular mechanisms that govern atherosclerosis, novel treatment strategies can be formulated which may reduce the persistent high mortality and morbidity rates associated with this disease. MRI shows promise in achieving this goal. PMID- 26254093 TI - Fourier Transform Infrared spectroscopy discloses different types of cell death in flow cytometrically sorted cells. AB - Fourier Transform Infrared (FTIR) spectroscopy is a label free methodology showing promise in characterizing different types of cell death. Cervical adenocarcinoma (HeLa) and African monkey kidney (Vero) cells were treated with a necrosis inducer (methanol), novel apoptotic inducers (diphenylphosphino gold (I) complexes) and positive control, auranofin. Following treatment, cells stained with annexin-V and propidium iodide were sorted using a Fluorescence Activated Cell Sorter (FACS Aria) to obtain populations consisting of either viable, necrotic or apoptotic cells. Transmission Electron Microscopy confirmed successful sorting of all three populations. Four bands were identified which could discriminate between viable and necrotic cells namely 989 cm(-1), 2852 cm( 1), 2875 cm(-1) and 2923 cm(-1). In HeLa cells viable and induced apoptosis could be distinguished by 1294 cm(-1), while four bands were different in Vero cells namely; 1626 cm(-1), 1741 cm(-1), 2852 cm(-1) 2923 cm(-1). Principal Component Analysis showed separation between the different types of cell death and the loadings plots indicated an increase in an additional band at 1623 cm(-1) in dead cells. FTIR spectroscopy can be developed into an invaluable tool for the assessment of specific types of chemically induced cell death with notably different molecular signatures depending on whether the cells are cancerous and mechanism of cell death. PMID- 26254094 TI - Changing gears in Nrf1 research, from mechanisms of regulation to its role in disease and prevention. AB - The "cap'n'collar" bZIP transcription factor Nrf1 heterodimerizes with small Maf proteins to bind to the Antioxidant Response Element/Electrophile Response Element to transactivate antioxidant enzyme, phase 2 detoxification enzyme and proteasome subunit gene expression. Nrf1 specifically regulates pathways in lipid metabolism, amino acid metabolism, proteasomal degradation, the citric acid cycle, and the mitochondrial respiratory chain. Nrf1 is maintained in the endoplasmic reticulum (ER) in an inactive glycosylated state. Activation involves retrotranslocation from the ER lumen to the cytoplasm, deglycosylation and partial proteolytic processing to generate the active forms of Nrf1. Recent evidence has revealed how this factor is regulated and its involvement in various metabolic diseases. This review outlines Nrf1 structure, function, regulation and its links to insulin resistance, diabetes and inflammation. The glycosylation/deglycosylation of Nrf1 is controlled by glucose levels. Nrf1 glycosylation affects its control of glucose transport, glycolysis, gluconeogenesis and lipid metabolism. PMID- 26254095 TI - miR-302b suppresses cell invasion and metastasis by directly targeting AKT2 in human hepatocellular carcinoma cells. AB - MicroRNAs (miRNAs) have been shown to play essential roles in regulating the activity of human hepatocellular carcinoma (HCC) cells, thereby contributing to the suppression of invasion and metastasis. In this study, using gain and loss of function assays, we demonstrated that miR-302b was frequently down-regulated in clinical HCC specimens, as compared with 15 corresponding adjacent normal tissues. Overexpression of miR-302b suppressed HCC cell invasion and metastasis. Regulation of NF-kappaB and matrix metalloproteinase (MMP)-2 expression by miR 302b was mediated via AKT2 in SMMC-7721 cells. Silencing AKT2 produced effects similar to those of miR-302b overexpression, which included inhibiting SMMC-7721 cell invasion and metastasis and dereasing NF-kappaB and MMP-2 expression. Furthermore, overexpression of AKT2 attenuated the effects of miR-302b overexpression. Taken together, our findings indicate that miR-302b inhibits SMMC 7721 cell invasion and metastasis by targeting AKT2, suggesting that miR-302b might represent a potential therapeutic target for HCC intervention. PMID- 26254096 TI - Prognostic significance of serum ERBB3 and ERBB4 mRNA in lung adenocarcinoma patients. AB - Serum messenger RNA (mRNA) is an emerging prognostic tool for noninvasive malignant disease prognosis, and to study serum mRNA may have importance in the prognosis and detection of disease. This study aimed to evaluate the possible prognostic role of serum ERBB3 and ERBB4 mRNA expressions in lung adenocarcinoma patients. One hundred newly diagnosed lung adenocarcinoma patients and 100 age- and sex-matched healthy controls were included. Expression was analysed by quantitative real-time PCR and overall survival was analysed by Kaplan-Meier analysis. Serum ERBB3 and ERBB4 mRNA expressions was found to be significantly associated with distant metastases and TNM stages. It was observed that patients with distant metastases had 4.8- and 3.4-fold high ERBB3 and ERBB4 expression in contrast to patients without distant metastases, respectively. It was also found that ERBB3 and ERBB4 mRNA expression was 7.7-fold and 6.7-fold high in TNM stage IV compared to TNM stage I, respectively. Significantly, 2.6-fold increased serum ERBB4 mRNA expression was found in patients with pleural effusion compared to patients without pleural effusion (p = 0.005). Lung adenocarcinoma patients with <=8- and >8-fold increased serum ERBB3 mRNA expression had 10.0 and 5.5 months of overall median survival while serum ERBB4 mRNA with <=10- and >10-fold increased expression showed 11.4 and 5.0 months overall median survival, respectively. ERBB3 and ERBB4 together also found to be significantly associated with poor overall median survival. Patients with <=8 + <=10- and >8 + >10-fold expression showed 11.3 vs 4.8 months of overall median survival, respectively. In conclusion, serum ERBB3 and ERBB4 mRNA expressions may be a prognostic marker and monitoring of serum ERBB3 and ERBB4 mRNA can be one of the predictive factors for metastases and poor overall survival of lung adenocarcinoma patients. PMID- 26254097 TI - Regulation of activating protein-4-associated metastases of non-small cell lung cancer cells by miR-144. AB - Activating protein-4 (AP4) has been recently shown to regulate the cancer metastases in some cancers including non-small cell lung cancer (NSCLC). Specifically, AP4 regulates mTor/p21 and transforming growth factor beta (TGFbeta) receptor signaling pathway to increase an epithelial-mesenchymal transition process to augment cell invasiveness. Nevertheless, how AP4 is regulated in NSCLC has not been studied. Here, we showed that in the specimens from the NSCLC patients, the levels of miR-144 were significantly decreased and the levels of AP4 were significantly increased, compared to the paired non-tumor lung tissue. The levels of miR-144 and AP4 inversely correlated in patients' specimens. Bioinformatics analyses revealed that miR-144 targeted the 3'-UTR of AP4 mRNA to inhibit its translation, confirmed by luciferase-reporter assay. Moreover, miR-144 overexpression inhibited AP4-mediated cell invasiveness, while miR-144 depletion increased AP4-mediated cell invasiveness in NSCLC cells. Together, our data suggest that miR-144 suppression may be the cause of the increased levels of AP4, as well as the augmented cancer metastases, in NSCLC. PMID- 26254098 TI - Adaptive B cell responses in rituximab-treated diffuse large B cell lymphoma patients during complete remission. AB - Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen. Treatment using rituximab in combination with chemotherapy has dramatically improved overall survival rate of diffuse large B cell lymphoma (DLBCL). Since rituximab can deplete both lymphoma B cells and normal B cells, how rituximab treatment affects normal B cell function in DLBCL patients under remission is unclear. Here, we examined peripheral blood B cell composition and antigen specific B cell responses in DLBCL patients in remission and observed reductions in the frequencies of total B cell as well as several major B cell subsets, including CD19(+)IgD(+) naive B cells, CD19(+)IgD(-)CD27(+) memory B cells, and CD19(lo)CD27(hi) plasmablasts. Moreover, tetanus toxin (TT)-specific B cell proliferation was reduced in DLBCL patients in remission. On the other hand, HA specific IgG-secreting B cell responses could be stimulated by influenza vaccination in DLBCL patients in remission, demonstrating that the machinery for generating de novo adaptive B cell responses was functional in DLBCL patients in remission. Our results provided insights in normal B cell function in DLBCL patients in remission. PMID- 26254099 TI - Downregulation of DHRS9 expression in colorectal cancer tissues and its prognostic significance. AB - Dehydrogenase/reductase (SDR family) member 9 (DHRS9) is aberrantly expressed in colorectal cancer (CRC), but its prognostic value is unknown. The aim of the work was to investigate the prognostic significance of DHRS9 expression in CRC. We found that DHRS9 was frequently downregulated in CRC clinical samples at both the messenger RNA (mRNA) and protein levels. Decreased expression of DHRS9 was significantly correlated with increased lymph node metastasis (p = 0.032), advanced tumor-node-metastasis (TNM) stage (p = 0.021), increased disease recurrence (p = 0.001), and death (p = 0.014). Kaplan-Meier analysis indicated that low DHRS9 expression predicted poor disease-free survival (p = 0.003) and disease-specific survival (p = 0.021). Cox multivariate analysis revealed that reduced expression of DHRS9 was an independent unfavorable prognostic indicator for CRC. Furthermore, combination of DHRS9 with TNM stage was a more powerful predictor of poor prognosis than either of the two parameters alone. Our results suggest that decreased expression of DHRS9 correlates with tumor progression and may serve as a potential prognostic biomarker in CRC. PMID- 26254101 TI - Powerlessness: Dissatisfied patients' and relatives' experience of their emergency department visit. AB - AIM: The aim of this study was to disclose the meaning of patients and relatives lived experience of dissatisfaction when visiting an emergency department. INTRODUCTION: Even though most patients are pleased with the emergency department care, there are areas that dissatisfy them, for example lack of communication and unoccupied wait time. However, there are few studies that describe both patients and relatives experience of dissatisfaction. METHODS: This explorative study uses a phenomenological hermeneutic approach where patients and relatives were interviewed. RESULTS: Patients and relatives meaning of dissatisfaction mainly contain powerlessness, struggling for control over the situation, lacking knowledge and information, receiving and providing support. CONCLUSIONS: The results showed that the experiences of dissatisfaction were similar among patients and relatives. They suffer in the same way when being treated like objects during their visits. Nursing rounds are one way to decrease dissatisfaction by making patients and relatives participating in the care continually updated with information. PMID- 26254100 TI - MicroRNA-224: as a potential target for miR-based therapy of cancer. AB - MicroRNAs (miRNAs) are small noncoding RNA molecules which regulate the target gene expression posttranscriptionally. Increasing studies have shown that microRNAs play important roles in multiple biological pathways. For instance, aberrant expression of microRNA-224 (miR-224) plays a vital role in tumor biology in various types of human cancer. Here, we aim to summarize the molecular mechanisms that lead to the overexpression of miR-224 in cancers, analyze the effect of miR-224 on tumor biology, and reveal the clinical significance of miR 224. MiR-224 regulates its targets by modulating messenger RNA (mRNA) stability and/or protein translation, and it would provide new insight into molecular targeting cancer treatment. PMID- 26254102 TI - Application of Virtual Three-Dimensional Models for Simultaneous Visualization of Intracardiac Anatomic Relationships in Double Outlet Right Ventricle. AB - Our goal was to construct three-dimensional (3D) virtual models to allow simultaneous visualization of the ventricles, ventricular septal defect (VSD) and great arteries in patients with complex intracardiac anatomy to aid in surgical planning. We also sought to correlate measurements from the source cardiac magnetic resonance (CMR) image dataset and the 3D model. Complicated ventriculo arterial relationships in patients with complex conotruncal malformations make preoperative assessment of possible repair pathways difficult. Patients were chosen with double outlet right ventricle for the complexity of intracardiac anatomy and potential for better delineation of anatomic spatial relationships. Virtual 3D models were generated from CMR 3D datasets. Measurements were made on the source CMR as well as the 3D model for the following structures: aortic diameter in orthogonal planes, VSD diameter in orthogonal planes and long axis of right ventricle. A total of six patients were identified for inclusion. The path from the ventricles to each respective outflow tract and the location of the VSD with respect to each great vessel was visualized clearly in all patients. Measurements on the virtual model showed excellent correlation with the source CMR when all measurements were included by Pearson coefficient, r = 0.99 as well as for each individual structure. Construction of virtual 3D models in patients with complex conotruncal defects from 3D CMR datasets allows for simultaneous visualization of anatomic relationships relevant for surgical repair. The availability of these models may allow for a more informed preoperative evaluation in these patients. PMID- 26254103 TI - Beta2-adrenergic activity modulates vascular tone regulation in lecithin:cholesterol acyltransferase knockout mice. AB - Lecithin:cholesterol acyltransferase (LCAT) deficiency is associated with hypoalphalipoproteinemia, generally a predisposing factor for premature coronary heart disease. The evidence of accelerated atherosclerosis in LCAT-deficient subjects is however controversial. In this study, the effect of LCAT deficiency on vascular tone and endothelial function was investigated in LCAT knockout mice, which reproduce the human lipoprotein phenotype. Aortas from wild-type (Lcat(wt)) and LCAT knockout (Lcat(KO)) mice exposed to noradrenaline showed reduced contractility in Lcat(KO) mice (P<0.005), whereas acetylcholine exposure showed a lower NO-dependent relaxation in Lcat(KO) mice (P<0.05). Quantitative PCR and Western blotting analyses suggested an adequate eNOS expression in Lcat(KO) mouse aortas. Real-time PCR analysis indicated increased expression of beta2-adrenergic receptors vs wild-type mice. Aorta stimulation with noradrenaline in the presence of propranolol, to abolish the beta-mediated relaxation, showed the same contractile response in the two mouse lines. Furthermore, propranolol pretreatment of mouse aortas exposed to L-NAME prevented the difference in responses between Lcat(wt) and Lcat(KO) mice. The results indicate that LCAT deficiency leads to increased beta2-adrenergic relaxation and to a consequently decreased NO-mediated vasodilation that can be reversed to guarantee a correct vascular tone. The present study suggests that LCAT deficiency is not associated with an impaired vascular reactivity. PMID- 26254104 TI - Palmitic acid increases pro-oxidant adaptor protein p66Shc expression and affects vascularization factors in angiogenic mononuclear cells: Action of resveratrol. AB - A defect in neo-vascularization process involving circulating angiogenic mononuclear cells (CACs) dysfunction is associated with diabetes. We showed that oxidative stress was elevated in CACs cultured from blood of individuals with metabolic syndrome (MetS) and diabetes. We then assessed the action of palmitic acid (PA), a deregulated and increased NEFA in metabolic disorders, focusing on its oxidant potential. We observed that the phyto-polyphenol resveratrol normalized oxidative stress both in CACs isolated from MetS patients or treated with PA. Resveratrol further decreased the deleterious action of PA on gene expression of vascularization factors (TNFalpha, VEGF-A, SDF1alpha, PECAM-1, VEGFR2, Tie2 and CXCR4) and improved CAC motility. Particularly, resveratrol abolished the PA-induced over-expression of the pro-oxidant protein p66Shc. Neither KLF2 nor SIRT1, previously shown in resveratrol and p66Shc action, was directly involved. Silencing p66Shc normalized PA action on VEGF-A and TNFalpha specifically, without abolishing the PA-induced oxidative stress, which suggests a deleterious role of p66Shc independently of any major modulation of the cellular oxidative status in a high NEFA levels context. Besides showing that resveratrol reverses PA-induced harmful effects on human CAC function, certainly through profound cellular modifications, we establish p66Shc as a major therapeutic target in metabolic disorders, independent from glycemic control. PMID- 26254105 TI - Apelinergic system in endothelial cells and its role in angiogenesis in myocardial ischemia. AB - Apelin is a peptide known to have a vital role in cardiovascular diseases. It has been proven to induce proliferation and tube formation in endothelial cells, stabilise contacts between endothelial cells, and mediate pericyte recruitment. Since apelin level is reduced early after myocardial infarction, a supportive therapy with apelin is being investigated for its beneficial effect on blood vessel formation. It is becoming apparent, however, that the final effect of apelin often depends on stimuli the cell receives and the cross-talk with other molecules inside the cell. Hence, understanding the apelin pathway potentially can help us to improve angiogenic therapy. This review summarises recent knowledge regarding molecules involved in apelin signalling while focusing on their roles in angiogenesis within the ischemic environment after myocardial infarction. PMID- 26254106 TI - Epigenetic regulation of insulin-like growth factor signaling: A novel insight into the pathophysiology of neonatal pulmonary hypertension. AB - Burdened by high morbidity and mortality, neonatal pulmonary hypertension (PH) is a life-threatening pathophysiological condition that progressively elevates the mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). Pulmonary vascular remodeling and vasoconstriction are recognized pathophysiological features of the disease. Neonatal PH is a serious pathological condition in which persistent PH of the newborn causes hypoxemia and right-to left extrapulmonary shunting of blood flow, leading to right heart failure and serious life-threatening complications. Recently, the role of growth factors in the pathogenesis of neonatal PH has attracted much attention. Here we provide an update on the ongoing research regarding the epigenetic regulation of the insulin growth factor (IGF)-1/IGF-1 receptor pathway, with insight into the potential regulatory role such regulation in the pathogenesis of neonatal PH. PMID- 26254107 TI - Intracoronary vs intravenous abciximab in interventional cardiology: A reopened question? PMID- 26254108 TI - Direct effects of DPP-4 inhibition on the vasculature. Reconciling basic evidence with lack of clinical evidence. AB - Diabetes is burdened by macrovascular and microvascular complications that collectively reduce life expectancy. As the ultimate goal of diabetes treatment is to prevent excess morbidity and mortality associated with its complications, the interest on cardiovascular effects of glucose lowering medications is high. Dipeptidyl peptidase-4 inhibitors (DPP-4i) lower blood glucose by protecting the incretin hormone glucagon-like peptide-1 (GLP-1) from enzymatic degradation, thereby restoring meal-stimulated insulin release. DPP-4 has several non-incretin substrates, including cytokines, chemokines, and neurohormones, which can exert favourable, but also unpredictable, vascular effects, once they are stabilized by DPP-4i. Choi et al. now provide additional evidence that DPP-4i counteracts vascular smooth muscle cell proliferation and migration, resulting in an attenuation of neointimal hyperplasia. Though several other in vitro, preclinical, and preliminary clinical studies on surrogate end-points suggest that DPP-4i can exert similar direct vasculoprotective actions, results of placebo-controlled phase IV trials have so far shown no reduction cardiovascular endpoints by DPP-4i. In this commentary, we put DPP-4 pleiotropy and complexity into context, trying to reconcile why results from basic science have not yet translated into clinical evidence of cardiovascular protection. PMID- 26254109 TI - The mismatch negativity as a measure of auditory stream segregation in a simulated "cocktail-party" scenario: effect of age. AB - With age the ability to understand speech in multitalker environments usually deteriorates. The central auditory system has to perceptually segregate and group the acoustic input into sequences of distinct auditory objects. The present study used electrophysiological measures to study effects of age on auditory stream segregation in a multitalker scenario. Younger and older adults were presented with streams of short speech stimuli. When a single target stream was presented, the occurrence of a rare (deviant) syllable among a frequent (standard) syllable elicited the mismatch negativity (MMN), an electrophysiological correlate of automatic deviance detection. The presence of a second, concurrent stream consisting of the deviant syllable of the target stream reduced the MMN amplitude, especially when located nearby the target stream. The decrease in MMN amplitude indicates that the rare syllable of the target stream was less perceived as deviant, suggesting reduced stream segregation with decreasing stream distance. Moreover, the presence of a concurrent stream increased the MMN peak latency of the older group but not that of the younger group. The results provide neurophysiological evidence for the effects of concurrent speech on auditory processing in older adults, suggesting that older adults need more time for stream segregation in the presence of concurrent speech. PMID- 26254110 TI - Detecting the effect of under-correcting myopia. PMID- 26254111 TI - A new method to predict anatomical outcome after idiopathic macular hole surgery. AB - PURPOSE: To investigate whether a new macular hole closure index (MHCI) could predict anatomic outcome of macular hole surgery. METHODS: A vitrectomy with internal limiting membrane peeling, air-fluid exchange, and gas tamponade were performed on all patients. The postoperative anatomic status of the macular hole was defined by spectral-domain OCT. MHCI was calculated as (M+N)/BASE based on the preoperative OCT status. M and N were the curve lengths of the detached photoreceptor arms, and BASE was the length of the retinal pigment epithelial layer (RPE layer) detaching from the photoreceptors. Postoperative anatomical outcomes were divided into three grades: A (bridge-like closure), B (good closure), and C (poor closure or no closure). Correlation analysis was performed between anatomical outcomes and MHCI. Receiver operating characteristic (ROC) curves were derived for MHCI, indicating good model discrimination. ROC curves were also assessed by the area under the curve, and cut-offs were calculated. Other predictive parameters reported previously, which included the MH minimum, the MH height, the macular hole index (MHI), the diameter hole index (DHI), and the tractional hole index (THI) had been compared as well. RESULTS: MHCI correlated significantly with postoperative anatomical outcomes (r = 0.543, p = 0.000), but other predictive parameters did not. The areas under the curves indicated that MHCI could be used as an effective predictor of anatomical outcome. Cut-off values of 0.7 and 1.0 were obtained for MHCI from ROC curve analysis. MHCI demonstrated a better predictive effect than other parameters, both in the correlation analysis and ROC analysis. CONCLUSIONS: MHCI could be an easily measured and accurate predictive index for postoperative anatomical outcomes. PMID- 26254113 TI - Physiologically informed dynamic causal modeling of fMRI data. AB - The functional MRI (fMRI) signal is an indirect measure of neuronal activity. In order to deconvolve the neuronal activity from the experimental fMRI data, biophysical generative models have been proposed describing the link between neuronal activity and the cerebral blood flow (the neurovascular coupling), and further the hemodynamic response and the BOLD signal equation. These generative models have been employed both for single brain area deconvolution and to infer effective connectivity in networks of multiple brain areas. In the current paper, we introduce a new fMRI model inspired by experimental observations about the physiological underpinnings of the BOLD signal and compare it with the generative models currently used in dynamic causal modeling (DCM), a widely used framework to study effective connectivity in the brain. We consider three fundamental aspects of such generative models for fMRI: (i) an adaptive two-state neuronal model that accounts for a wide repertoire of neuronal responses during and after stimulation; (ii) feedforward neurovascular coupling that links neuronal activity to blood flow; and (iii) a balloon model that can account for vascular uncoupling between the blood flow and the blood volume. Finally, we adjust the parameterization of the BOLD signal equation for different magnetic field strengths. This paper focuses on the form, motivation and phenomenology of DCMs for fMRI and the characteristics of the various models are demonstrated using simulations. These simulations emphasize a more accurate modeling of the transient BOLD responses - such as adaptive decreases to sustained inputs during stimulation and the post-stimulus undershoot. In addition, we demonstrate using experimental data that it is necessary to take into account both neuronal and vascular transients to accurately model the signal dynamics of fMRI data. By refining the models of the transient responses, we provide a more informed perspective on the underlying neuronal process and offer new ways of inferring changes in local neuronal activity and effective connectivity from fMRI. PMID- 26254112 TI - Co-activation based parcellation of the human frontal pole. AB - Historically, the human frontal pole (FP) has been considered as a single architectonic area. Brodmann's area 10 is located in the frontal lobe with known contributions in the execution of various higher order cognitive processes. However, recent cytoarchitectural studies of the FP in humans have shown that this portion of cortex contains two distinct cytoarchitectonic regions. Since architectonic differences are accompanied by differential connectivity and functions, the frontal pole qualifies as a candidate region for exploratory parcellation into functionally discrete sub-regions. We investigated whether this functional heterogeneity is reflected in distinct segregations within cytoarchitectonically defined FP-areas using meta-analytic co-activation based parcellation (CBP). The CBP method examined the co-activation patterns of all voxels within the FP as reported in functional neuroimaging studies archived in the BrainMap database. Voxels within the FP were subsequently clustered into sub regions based on the similarity of their respective meta-analytically derived co activation maps. Performing this CBP analysis on the FP via k-means clustering produced a distinct 3-cluster parcellation for each hemisphere corresponding to previously identified cytoarchitectural differences. Post-hoc functional characterization of clusters via BrainMap metadata revealed that lateral regions of the FP mapped to memory and emotion domains, while the dorso- and ventromedial clusters were associated broadly with emotion and social cognition processes. Furthermore, the dorsomedial regions contain an emphasis on theory of mind and affective related paradigms whereas ventromedial regions couple with reward tasks. Results from this study support previous segregations of the FP and provide meta-analytic contributions to the ongoing discussion of elucidating functional architecture within human FP. PMID- 26254114 TI - Sources of systematic error in calibrated BOLD based mapping of baseline oxygen extraction fraction. AB - Recently a new class of calibrated blood oxygen level dependent (BOLD) functional magnetic resonance imaging (MRI) methods were introduced to quantitatively measure the baseline oxygen extraction fraction (OEF). These methods rely on two respiratory challenges and a mathematical model of the resultant changes in the BOLD functional MRI signal to estimate the OEF. However, this mathematical model does not include all of the effects that contribute to the BOLD signal, it relies on several physiological assumptions and it may be affected by intersubject physiological variability. The aim of this study was to investigate these sources of systematic error and their effect on estimating the OEF. This was achieved through simulation using a detailed model of the BOLD signal. Large ranges for intersubject variability in baseline physiological parameters such as haematocrit and cerebral blood volume were considered. Despite this the uncertainty in the relationship between the measured BOLD signals and the OEF was relatively low. Investigations of the physiological assumptions that underlie the mathematical model revealed that OEF measurements are likely to be overestimated if oxygen metabolism changes during hypercapnia or cerebral blood flow changes under hyperoxia. Hypoxic hypoxia was predicted to result in an underestimation of the OEF, whilst anaemic hypoxia was found to have only a minimal effect. PMID- 26254115 TI - Spatial memory training induces morphological changes detected by manganese enhanced MRI in the hippocampal CA3 mossy fiber terminal zone. AB - Hippocampal mossy fibers (MFs) can show plasticity of their axon terminal arbor consequent to learning a spatial memory task. Such plasticity is seen as translaminar sprouting from the stratum lucidum (SL) of CA3 into the stratum pyramidale (SP) and the stratum oriens (SO). However, the functional role of this presynaptic remodeling is still obscure. In vivo imaging that allows longitudinal observation of such remodeling could provide a deeper understanding of this presynaptic growth phenomenon as it occurs over time. Here we used manganese enhanced magnetic resonance imaging (MEMRI), which shows a high-contrast area that co-localizes with the MFs. This technique was applied in the detection of learning-induced MF plasticity in two strains of rats. Quantitative analysis of a series of sections in the rostral dorsal hippocampus showed increases in the CA3a' area in MEMRI of trained Wistar rats consistent with the increased SO+SP area seen in the Timm's staining. MF plasticity was not seen in the trained Lister-Hooded rats in either MEMRI or in Timm's staining. This indicates the potential of MEMRI for revealing neuro-architectures and plasticity of the hippocampal MF system in vivo in longitudinal studies. PMID- 26254116 TI - The revised NICE draft guideline for type 2 diabetes: still a long way to go. PMID- 26254117 TI - Effect of Transcatheter Intra-Arterial Therapies on Tumor Interstitial Fluid Pressure and Its Relation to Drug Penetration in a Rabbit Liver Tumor Model. AB - PURPOSE: To determine the change in tumor interstitial fluid pressure (IFP) after transcatheter intra-arterial (IA) therapies and its relation to drug penetration in liver cancer. MATERIALS AND METHODS: VX2 tumors were grown in the livers of 16 rabbits. The rabbits were treated with intravenous injection of doxorubicin (group 1; n = 4), hepatic IA injection of doxorubicin (group 2; n = 4), hepatic IA injection of doxorubicin followed by embolization with polyvinyl alcohol particles (group 3; n = 4), or hepatic IA injection of doxorubicin mixed with Lipiodol followed by polyvinyl alcohol embolization (group 4; n = 4). Tumor IFP was measured with a Mikro-Tip pressure catheter before and 1 hour after treatment. Doxorubicin penetration was evaluated by immunofluorescence. RESULTS: Tumor IFP after treatment decreased by 5.0% +/- 2.8, 3.9% +/- 9.0, 27.1% +/- 5.2, and 31.8% +/- 7.4 in groups 1-4, respectively. The difference in IFP reduction between embolization-treated groups (groups 3 and 4) and nonembolized groups (groups 1 and 2) was significant (P < .001). Doxorubicin penetration distances were 20.3 MUm +/- 3.7, 45.7 MUm +/- 10.5, 69.5 MUm +/- 9.3, and 47.9 MUm +/- 6.4 in groups 1-4, respectively. IFP reduction was significantly correlated with doxorubicin penetration distance (r = .671, P = .004). CONCLUSIONS: A greater reduction of tumor IFP was associated with embolization in a preclinical liver tumor model, and embolization may indirectly contribute to increased drug penetration. PMID- 26254118 TI - Effects of Pulsatile Fatigue on In Situ Antegrade Fenestrated Polyester Stent Grafts Deployed in a Patient-Specific Phantom Model of Juxtarenal Aortic Aneurysm. AB - PURPOSE: To evaluate the effects of in situ fenestration on the fabric of stent grafts deployed in a patient-specific phantom of a juxtarenal abdominal aortic aneurysm. MATERIALS AND METHODS: Four patient-specific juxtarenal abdominal aortic aneurysm polyurethane models were created, and bifurcated Zenith (Cook, Inc, Bloomington, Indiana) and Endurant (Medtronic, Minneapolis, Minneapolis) endografts were deployed into the models, covering the renal arteries. Antegrade in situ fenestration was carried out with radiofrequency puncture followed by balloon dilation with either conventional or cutting balloons. Renal covered stents were deployed and flared. Specimens were mounted onto an accelerated fatigue tester for 40M cycles (1 patient life-year), and evaluated with microscopy, caliper measurements, and fabric counts. RESULTS: Cutting balloons resulted in more fabric fraying. None of the fenestrations grew beyond the targeted 6-mm diameter despite accelerated fatigue. Fluoroscopic images demonstrated a very prominent waist of the renal fenestration in the Cook device when a conventional balloon was used compared with a cutting balloon. The average fenestration diameter for the Cook device was only 3.1 mm with the conventional balloon compared with 4.8 mm with the cutting balloon. The average fenestration diameter for the Medtronic device was 3.8 mm with the conventional balloon compared with 5.1 mm with the cutting balloon. The fabric counts suggested crowding of yarns around the fenestrations with conventional balloons but less with cutting balloons. CONCLUSIONS: This experimental work suggests that the size of in situ renal fenestrations does not expand beyond the target diameter despite cyclic fatigue. Although the small number of devices tested and selected aortorenal anatomy in this study may limit conclusions, textile analysis suggests that cutting balloons should be used for the Cook Zenith device, whereas conventional balloons should be used for the Medtronic Endurant device when performing in situ fenestration. PMID- 26254119 TI - Large prepatellar glomangioma: A case report. AB - INTRODUCTION: Glomangiomas are rare, benign tumors derived from the glomus body, typically presenting with the classic triad of pain, tenderness to palpation, and hypersensitivity to cold. Most commonly they present as a solitary lesion in the extremities, especially subungual, but they may present elsewhere. PRESENTATION OF CASE: We describe the case of a large (64mm*59mm*41mm) glomangioma on the anteroinferior aspect of a healthy 49 year old male's knee. Symptoms included constant throbbing pain with intermittent stabbing sensations localized to the mass. The mass was evaluated first by magnetic resonance (MR) imaging and then by histopathology following excision. DISCUSSION: Although rare, clinical diagnosis of glomangiomas may be sufficient in typical cases, however in atypical cases, like the one discussed here, further evaluation is often necessary. Here MR findings were suggestive of a glomangioma with low to intermediate signal strength on T1 and mixed signal strength on T2. Intravenous gadolinium infusion demonstrated marked heterogeneous enhancement of the lesion, as well as serpiginous vascular malformations surrounding the lesion. Histopathology following excision confirmed a benign glomangioma depicting monomorphic small, round eosinophilic cells with minimal atypia which stained positive for smooth muscle actin, and negative for cytokeratin, S-100 and CK-34 via immunohistochemistry. CONCLUSION: The following case report details an atypical presentation of a benign glomangioma anterior to the knee in a patient experiencing chronic minor trauma to the area. Diagnosis was suggested by clinical presentation and MR imaging, and was confirmed histologically. PMID- 26254120 TI - Pheochromocytoma as a rare cause of arterial hypertension in a patient with autosomal dominant polycystic kidney disease: A diagnostic and therapeutic dilemma. AB - INTRODUCTION: Individuals with autosomal dominant polycystic kidney disease (ADPKD) frequently suffer arterial hypertension even prior to significant loss of renal function, a clinical situation that obscures detection of modifiable secondary causes of hypertension. PRESENTATION OF CASE: A 50-year-old man with ADPKD and polycystic liver and resistant hypertension is diagnosed with a 4-cm right adrenal mass. Cross-sectional MRI is indicative of pheochromocytoma versus adrenocortical carcinoma or metastasis, though there are no typical PCC symptoms and plasma and urine metanephrines are within normal ranges. Since malignancy cannot be excluded, right adrenalectomy is performed. Considering that the enlarged liver poses an obstacle for transperitoneal open and laparoscopic approaches, a retroperitoneoscopic approach is used. Surgical pathology reveals a 4.5-cm pheochromocytoma; the patient no longer requires antihypertensive therapy. DISCUSSION & CONCLUSION: Pheochromocytoma is a rare but treatable cause of hypertension in ADPKD; given the anatomical complexities these patients present, careful preoperative planning and surgical technique are essential to a favorable outcome. PMID- 26254122 TI - Understanding and Reducing Ceruloplasmin Overuse with a Decision Support Intervention for Liver Disease Evaluation. AB - BACKGROUND: Over-testing is a source of significant health care costs, both in terms of dollars spent and the false positives generated. Clinicians frequently test patients with elevated liver enzymes (a common problem) for Wilson disease (a rare disease) using a ceruloplasmin level. METHODS: We performed a prospective pre-post study between October 2013 and November 2014. We deployed a pop-up screen in our provider order entry system to present clinicians with the guidelines for and test characteristics of ceruloplasmin use. Outcomes included rate ratios for test utilization. Indications for inpatient orders were provided by ordering clinicians and reviewed. RESULTS: Ceruloplasmin was ordered 448 and 219 times in the pre- and postintervention periods, respectively. Rate ratios for orders from gastroenterologists and general internists were 0.49; 95% confidence interval (CI), 0.40-0.59, and 0.31; 95% CI, 0.20-0.50, respectively (P <.0001, for both). Following the intervention, there was an 82% and 40% decrease in orders by internists in the outpatient and inpatient settings, respectively. Tests of confirmation (necessary for positive ceruloplasmins) were more common in the group tested following the intervention, risk ratio 1.80; 95% CI, 1.04-3.08; P = .02. Of the residual ceruloplasmin orders by inpatient internists after the intervention, 75% (18/24) were recommended by hepatology consultants. CONCLUSION: The optimal intervention for the reduction of over-testing should include automated changes to the ordering system combined with efforts to change testing culture through education. PMID- 26254121 TI - Peripheral blood cytokine and chemokine profiles in juvenile localized scleroderma: T-helper cell-associated cytokine profiles. AB - OBJECTIVE: To evaluate peripheral blood T-helper (TH) cell-associated cytokine and chemokine profiles in localized scleroderma (LS), and correlate them with clinical disease features, including disease activity parameters. METHODS: A 29 plex Luminex platform was used to analyze the humoral profile of plasma samples from 69 pediatric LS patients and 71 healthy pediatric controls. Cytokine/chemokine levels were compared between these two groups and within LS patients, focusing on validated clinical outcome measures of disease activity and damage in LS. RESULTS: Plasma levels of IP-10, MCP-1, IL-17a, IL-12p70, GM-CSF, PDGF-bb, IFN-alpha2, and IFN-gamma were significantly higher in LS subjects compared to healthy controls. Analysis within the LS group demonstrated IP-10, TNF-alpha, and GM-CSF correlated with clinical measures of disease activity. Several cytokines/chemokines correlated with anti-histone antibody, while only a few correlated with positive ANA and single-stranded DNA antibody. CONCLUSION: This is the first time that multiple cytokines and chemokines have been examined simultaneously in LS. In general, a TH1 (IFN-gamma) and TH17 (IL-17a) predominance was demonstrated in LS compared to healthy controls. There is also an IFN-gamma signature with elevated IP-10, MCP-1, and IFN-gamma, which has been previously demonstrated in systemic sclerosis, suggesting a shared pathophysiology. Within the LS patients, those with active disease demonstrated IP-10, TNF-alpha, and GM-CSF, which may potentially serve as biomarkers of disease activity in the clinical setting. PMID- 26254124 TI - [Young French neurosurgeons: Working conditions and outlook]. AB - INTRODUCTION: Due to the increase in the number of French neurosurgeon residents the neurosurgical workforce is changing. The main objective of this survey was to assess working conditions and perspectives for young French neurosurgeons. METHOD: An on-line survey was sent to young French neurosurgeons based on a mailing-list (219 mail addresses of Residents and Fellows obtained during previous meetings). The form contained questions about career, amount of work, salary, quality of life, teaching and university work. RESULTS: We received 78 replies from January to March 2014. A total of 56% from fellows saying they had undergone difficulties in obtaining a fellowship, although 78% were satisfied. Fellows considered a private career more often than residents. Overall, young neurosurgeons were worried about future employment. Some 33% admitted contemplating a different career from one they originally wanted. The average weekly working time of 76.8 hours was deemed to be excessive. Security rests after overnight shifts were lacking or incomplete in 91% of cases. The work atmosphere was good overall (3.7/5), and so was the quality of life (3.2/5). Theoretical teaching was unsatisfactory (2.43/5) as well as the time allowed for academic work (approximately 1.58 half-days per month). However, practical teaching was considered rewarding (3.63/5). CONCLUSION: This study provides some guidance for upcoming reforms, and should be considered again at a later date to evaluate progress. PMID- 26254123 TI - Two Binges of Ethanol a Day Keep the Memory Away in Adolescent Rats: Key Role for GLUN2B Subunit. AB - BACKGROUND: Binge drinking is common in adolescents, but the impact of only a few binges on learning and memory appears underestimated. Many studies have tested the effects of long and intermittent ethanol exposure on long-term synaptic potentiation, and whether long-term synaptic depression is affected remains unknown. METHODS: We studied the effects of one (3 g/kg, i.p.; blood ethanol content of 197.5+/-19 mg/dL) or 2 alcohol intoxications (given 9 hours apart) on adolescent rat's memory and synaptic plasticity in hippocampus slice after different delay. RESULTS: Animals treated with 2 ethanol intoxications 48 hours before training phase in the novel object recognition task failed during test phase. As learning is related to NMDA-dependent mechanisms, we tested ketamine and found the same effect as ethanol, whereas D-serine prevented learning deficit. In hippocampus slice, NMDA-dependent long-term synaptic depression was abolished 48 hours after ethanol or ketamine but prevented after D-serine or in a low-Mg(2+) recording medium. Long-term synaptic depression abolition was not observed 8 days after treatment. An i.p. treatment with MK-801, tetrahydroisoxazolopyridine, or muscimol was ineffective, and long-term synaptic potentiation, intrinsic excitability, and glutamate release remained unaffected. The input/ouput curve for NMDA-fEPSPs was shifted to the left 48 hours after the binges with a stronger contribution of GluN2B subunit, leading to a leftward shift of the Bienenstock-Cooper-Munro relationship. Interestingly, there were no cellular effects after only one ethanol injection. CONCLUSION: Two ethanol "binges" in adolescent rats are sufficient to reversibly abolish long-term synaptic depression and to evoke cognitive deficits via a short-lasting, repeated blockade of NMDA receptors only, inducing a change in the receptor subunit composition. Furthermore, ethanol effects developed over a 48-hour period of abstinence, indicating an important role of intermittence during a repeated long duration binge behavior. PMID- 26254126 TI - The epistemological significance of possession entering the DSM. AB - The discourse of the American Psychiatric Association's DSM reflects the inherently dialogic or contradictory nature of its stated mandate to demonstrate both 'nosological completeness' and cultural 'inclusiveness'. Psychiatry employs the dialogic discourse of the DSM in a one-sided, positivistic manner by identifying what it considers universal mental disease entities stripped of their cultural context. In 1992 the editors of the Diagnostic and Statistical Manual of Mental Disorders proposed to introduce possession into their revisions. A survey of the discussions about introducing 'possession' as a dissociative disorder to be listed in the DSM-IV indicates a missed epistemological break. Subsequently the editors of the DSM-5 politically 'recuperated' possession into its official discourse, without acknowledging the anarchic challenges that possession presents to psychiatry as a cultural practice. PMID- 26254127 TI - 'A vehicle of symbols and nothing more'. George Romanes, theory of mind, information, and Samuel Butler. AB - Today's 'theory of mind' (ToM) concept is rooted in the distinction of nineteenth century philosopher William Clifford between 'objects' that can be directly perceived and 'ejects', such as the mind of another person, which are inferred from one's subjective knowledge of one's own mind. George Romanes, a founder with Charles Darwin of the discipline of comparative psychology, considered the minds of animals as ejects, an idea that could be generalized to 'society as eject' and, ultimately, 'the world as an eject' - mind in the universe. Yet, Romanes and Clifford only vaguely connected mind with the abstraction we call 'information', which needs 'a vehicle of symbols' - a material transporting medium. However, Samuel Butler was able to address, in informational terms depleted of theological trappings, both organic evolution and mind in the universe. This view harmonizes with insights arising from modern DNA research, the relative immortality of 'selfish' genes, and some startling recent developments in brain research. PMID- 26254125 TI - Circadian and Sex Differences After Acute High-Altitude Exposure: Are Early Acclimation Responses Improved by Blue Light? AB - OBJECTIVE: The possible effects of blue light during acute hypoxia and the circadian rhythm on several physiological and cognitive parameters were studied. METHODS: Fifty-seven volunteers were randomly assigned to 2 groups: nocturnal (2200-0230 hours) or diurnal (0900-1330 hours) and exposed to acute hypoxia (4000 m simulated altitude) in a hypobaric chamber. The participants were illuminated by blue LEDs or common artificial light on 2 different days. During each session, arterial oxygen saturation (Spo2), blood pressure, heart rate variability, and cognitive parameters were measured at sea level, after reaching the simulated altitude of 4000 m, and after 3 hours at this altitude. RESULTS: The circadian rhythm caused significant differences in blood pressure and heart rate variability. A 4% to 9% decrease in waking nocturnal Spo2 under acute hypoxia was observed. Acute hypoxia also induced a significant reduction (4%-8%) in systolic pressure, slightly more marked (up to 13%) under blue lighting. Women had significantly increased systolic (4%) and diastolic (12%) pressures under acute hypoxia at night compared with daytime pressure; this was not observed in men. Some tendencies toward better cognitive performance (d2 attention test) were seen under blue illumination, although when considered together with physiological parameters and reaction time, there was no conclusive favorable effect of blue light on cognitive fatigue suppression after 3 hours of acute hypobaric hypoxia. CONCLUSIONS: It remains to be seen whether longer exposure to blue light under hypobaric hypoxic conditions would induce favorable effects against fatigue. PMID- 26254128 TI - 'S.W.' and C.G. Jung: mediumship, psychiatry and serial exemplarity. AB - On the basis of unpublished materials, this essay reconstructs Jung's seances with his cousin, Helene Preiswerk, which formed the basis of his 1902 medical dissertation, The Psychology and Pathology of so-called Occult Phenomena. It separates out Jung's contemporaneous approach to the mediumistic phenomena she exhibited from his subsequent sceptical psychological reworking of the case. It traces the reception of the work and its significance for his own self experimentation from 1913 onwards. Finally, it reconstructs the manner in which Jung continually returned to his first model and reframed it as an exemplar of his developing theories. PMID- 26254129 TI - Winifred Rushforth and the Davidson Clinic for Medical Psychotherapy: a case study in the overlap of psychotherapy, Christianity and New Age spirituality. AB - The activities of both Winifred Rushforth (1885-1983), and the Edinburgh-based Davidson Clinic for Medical Psychotherapy (1941-73) which she directed, exemplify and elaborate the overlap in Scotland of religious discourses and practices with psychoanalytic psychotherapy. Even as post-war secularization began to affect Scottish culture and society, Rushforth and the Davidson Clinic attempted to renew the biographical discourses of Christianity using the idioms and practices of psychoanalytic psychotherapy. Furthermore, alongside these Christian-inflected activities, Rushforth promoted a psychoanalytically-informed New Age spirituality. This parallel mode of belief and practice drew on Christian life narrative patterns, preserving them within psychoanalytic forms grafted onto a vitalist worldview informed by the work of Pierre Teilhard de Chardin. PMID- 26254130 TI - Kynanthropy: canine madness in Byzantine late antiquity. AB - Those afflicted bark like dogs, scramble on all fours and loiter around graveyards - canine madness, referred to as kynanthropy, was an illness concept in its own right in the medicine of late antiquity. At roughly the same time as the medical description produced by Aetius of Amida, the Syrian chronicler John of Ephesus, also from Amida, reported an epidemic of dog-like madness sweeping his home town in ad 560. The symptoms are identical and both authors are from Amida - what is the connection between the two depictions? In addition to the history of the medical concept, the example of the canine madness of Amida and its cultural embedding allows us to contextualize and interpret the significance of dog-like behaviour for the people of the sixth century AD. PMID- 26254131 TI - 'Without decontextualisation': the Stanley Royd Museum and the progressive history of mental health care. AB - This paper builds on recent scholarship exploring museum exhibitions and the heritage of mental health care. Using the development of the Stanley Royd Museum in the mid-1970s as a case study, the paper will examine the rationale for the opening of the museum and its link to changing perceptions of mental hospitals in both historical study and what was then 'current' practice. It will then provide an overview of the proposed audience for the new museum and briefly analyse its success in communicating its history to its visitors. Ultimately, it will question how successful mental health professionals were in presenting the progressive nature of institutional care at a time when the system was being radically overhauled and reoriented. PMID- 26254132 TI - German wine in an American bottle: the spread of modern psychiatry in China, 1898 1949. AB - Modern psychiatry was first introduced to mainland China around 1900 by Western missionaries. By 1949 the field had developed gradually as a result of contact with Western psychiatry and especially its American practitioners. This paper analyses the role played by key individuals and events in this process in the years prior to 1949. It argues that modern psychiatry was introduced to China through a process of cultural adaptation in which the USA served as a bridge for German thought. PMID- 26254133 TI - 'Robert Schumann's mental illnesses. (Genius and madness)', by Mlle Dr Pascal (1908a): Introduction and translation by Felicia Gordon. AB - Dr Constance Pascal's study of Robert Schumann's mental illnesses, dating from the early years of the twentieth century, reflects contemporary theories on the relations between gifted individuals and mental illness: the genius vs. madness debate. Pascal's reading of Schumann's musical career, in conjunction with his mental profile, offers a sympathetic and nuanced overview of the composer and a critical perspective on extant theories of his illness. PMID- 26254140 TI - rpoB gene high-resolution melt curve analysis: a rapid approach for diagnosis and screening of drug resistance in tuberculous meningitis. AB - Timely and rapid diagnosis of multidrug resistance in tuberculous meningitis (TBM) is a challenge both for a microbiologist and neurologist. The present study was conducted to evaluate role of real-time polymerase chain reaction (PCR) using rpoB, IS6110, and MPB64 as targets in diagnosis of TBM in 110 patients and subsequent high-resolution melt (HRM) curve analysis of rpoB gene amplicons for screening of drug resistance. The sensitivity of smear, culture, and real-time PCR was 1.8%, 10.9%, and 83.63%, respectively. All 120 control patients showed negative results. With HRM rpoB analysis, rifampicin resistance was detected in 3 out of 110 cases of TBM (3.33%). Subsequently, results of HRM analysis were confirmed by rpoB gene sequencing, and mutations were observed at 516 (2 patients) and 531 (1 patient) codons, respectively. rpoB HRM analysis can be a promising tool for rapid diagnosis and screening of drug resistance in TBM patients in 90minutes. PMID- 26254141 TI - Identification of mutations conferring streptomycin resistance in multidrug resistant tuberculosis of China. AB - We investigated the spectrum and frequency of mutations in rpsL, rrs, and gidB among 140 multidrug-resistant tuberculosis (MDR-TB) clinical isolates from China. The association between mutations and different genotypes was also analyzed. Our data revealed that 65.7% of MDR-TB were resistant to streptomycin (STR), and 90.2% of STR-resistant isolates were Beijing strains. STR resistance was correlated with Beijing family (P=0.00). Compared with phenotypic data, detection of mutations for the combination of these 3 genes exhibited 94.6% sensitivity, 91.7% specificity, and 93.6% accuracy. The most common mutations in STR-resistant isolates were rpsL128, 262, and rrs514, of which rpsL128 showed association with Beijing lineage (P=0.00). A combination of these 3 mutations can serve as the reliable predictors for STR resistance, showing the sensitivity, specificity, and accuracy of 85.9%, 97.9%, and 90.0%, respectively. Furthermore, gidBA276C, not A615G, was Beijing lineage specific. These findings are useful to develop rapid molecular diagnostic methods for STR resistance in China. PMID- 26254142 TI - In vitro activity of taurolidine gel on bacteria associated with periodontitis. AB - OBJECTIVES: The purpose of this in vitro study was to determine the antimicrobial activity of two different taurolidine gel formulations in comparison with minocycline microspheres. METHODS: Three percent taurolidine gel (TLG3) and 2 % taurolidine gel (TLG2) were compared to minocycline microspheres (MINO) against single bacterial species and a 12-species-mixture. The antimicrobial activity was proven by determination of minimal inhibitory concentrations (MICs), killing assays, after exposure of the antimicrobials as well as within a biofilm. RESULTS: The MICs against the single species were between 0.5 and 2 mg/ml of taurolidine. MICs of the used mixed microbiota were 1.5 mg/ml (TLG3) and 4 mg/ml (TLG2). Fusobacterium nucleatum and Porphyromonas gingivalis were completely killed by 10 % TLG3 and TLG2 (equivalent to 3 and 2 mg/ml taurolidine) after 6 h. The mixture of 12 species was not completely killed by any of the test substances. Taurolidine gels showed a post-antimicrobial activity, however being less than that of MINO. On biofilms, taurolidine gels reduced concentration dependently the colony forming unit (CFU) counts (multi-species biofilms by 3.63 log10 after 100 % (30 mg/ml) of TLG3), reductions were 2.12 log10 after MINO (1000 MUg/ml minocycline). CONCLUSIONS: Taurolidine gel formulations exert antimicrobial activity against bacteria associated with periodontal disease. Nevertheless, a complete elimination of biofilms seems to be impossible and underlines the importance of mechanical removal of biofilms prior to application of the antimicrobial. CLINICAL RELEVANCE: Taurolidine gels may represent a potential alternative for adjunctive topical antimicrobial treatment in periodontitis and infectious peri-implant diseases. PMID- 26254144 TI - Can inhibition of microglial activation cure schizophrenia? PMID- 26254143 TI - Salivary and serum interleukin-6 levels in proliferative verrucous leukoplakia. AB - BACKGROUND: Cytokines and chemokines have been analysed in patients with oral squamous cell carcinoma and potentially malignant disorders. We selected interleukin-6 (IL-6) because it is a multifunctional interleukin reported to be altered in potentially malignant oral disorders and in malignant lesions. To date, this has not been evaluated or tested in proliferative verrucous leukoplakia (PVL), however. OBJECTIVES: This study aimed to analyse the differences in serum and saliva IL-6 levels among patients with PVL, oral squamous cell carcinoma (OSCC) and healthy controls and to examine the relationship between salivary IL-6 levels and the extent of the verrucous area. METHODS: Using an enzyme-linked immunosorbent assay, we determined the serum and saliva IL-6 levels in three groups: 20 patients with PVL, 20 with OSCC and 20 healthy controls. RESULTS: There were significant (p < 0.01) differences in the serum and saliva IL-6 levels among the three groups and among the three grades of extent of the verrucous areas (p = 0.01). In the OSCC group, there was a significant difference in the saliva IL-6 levels between patients with and without lymph node metastasis at diagnosis (p = 0.02). CONCLUSIONS: We found that patients with OSCC had the highest salivary and serum IL-6 levels, while PVL had lower values than OSCC, but higher than the controls, and these altered levels were associated with the extent of the verrucous areas. CLINICAL RELEVANCE: Salivary and plasma IL-6 are altered in patients with PVL, with more extensive verrucous areas being associated to the highest IL-6 levels. This could be a significant tool for monitoring patients with PVL, their progression to more advances stages and their recurrences. PMID- 26254145 TI - Hope-inspiring therapeutic relationships, professional expectations and social inclusion for young people with psychosis. AB - OBJECTIVE: Personal recovery accounts suggest that a positive therapeutic relationship with an optimistic mental health professional may facilitate social inclusion. However, little empirical research has investigated the role of the therapeutic relationship in social outcomes or explored potential mechanisms of change within community psychosis care. This study investigated the direct predictive associations of the therapeutic relationship and professional expectancies for social inclusion and vocational activity for young people with psychosis, and indirect associations through hopefulness. METHOD: Young people with psychosis and their main mental health professional (n=51 dyads) participated across two time points. Measures of therapeutic relationships, professional expectancies, and vocational activity were obtained at baseline. Measures of hopefulness, social inclusion and vocational activity were obtained at follow-up. Direct and indirect associations between variables were analysed using path modelling. RESULTS: Directed path models were consistent with a positive therapeutic relationship and positive professional expectancies predicting social inclusion and vocational activity through mediation by increased patient domain-specific hopefulness. The professional-rated therapeutic relationship more directly predicts change in vocational activity status. Change in vocational activity status predicts increased patient hopefulness. CONCLUSION: The therapeutic relationship between professionals and young people with psychosis appears hope-inspiring and important to patients' social inclusion and vocational outcomes. Vocational activity may produce reciprocal gains in hopefulness. PMID- 26254146 TI - Do not scratch that mole! AB - Nevi harbor some of the same oncogene mutations that also drive malign melanoma. Further tumor promoting events are required to unleash their carcinogenic potential. Using zebrafish whose melanocytes overexpress an HRAS-oncogene, a new study reports that injury induces melanoma, possibly through recruitment of neutrophils that trigger proliferation of preneoplastic melanocytes. PMID- 26254148 TI - Neonatal Lung Sonography: Interobserver Agreement Between Physician Interpreters With Varying Levels of Experience. AB - OBJECTIVES: To assess the reliability of lung sonography in neonates between physician interpreters with different degrees of experience. METHODS: We retrospectively reviewed lung sonograms from neonates admitted to a neonatal intensive care unit with respiratory distress in the first 24 hours of life. The first scans were selected; only patients with available video clips documenting both hemithoraxes were included. The clips were independently examined by 4 different experienced observers blinded to clinical data. The interpreting physicians made a codified sonographic diagnosis, and the Cohen kappa coefficient was used to measure the reliability between a proven experienced main interpreter and expert (kappa1), intermediate (kappa2), and beginner (kappa3) control interpreters. We also calculated the specific agreement on respiratory distress syndrome and transient tachypnea of the neonate. RESULTS: Four hundred sixty-five clips were taken from 114 neonates examined over a 16-month period. The patients' median gestational age (range) was 34 weeks (25-41 weeks), and the median birth weight (range) was 2085 g (608-4134 g). Eighty-eight percent of examinations were performed within 24 hours after birth. The overall kappa coefficients (95% confidence intervals) were kappa1 = 0.94 (0.88-1.00); kappa2 = 0.72 (0.61-0.83); and kappa3 = 0.81 (0.71-0.90). For respiratory distress syndrome, kappa1 = 0.94 (0.87-1.00); kappa2 = 0.90 (0.81-0.99); and kappa3 = 0.87 (0.78-0.97). For transient tachypnea of the neonate, kappa1 = 0.95 (0.89-1.00); kappa2 = 0.76 (0.64-0.88); and kappa3 = 0.81 (0.70-0.91). CONCLUSIONS: In neonates with early respiratory distress, lung sonography has high interobserver agreement even between interpreters with varying levels of experience. PMID- 26254149 TI - Comparison Between Various Color Spectra and Conventional Grayscale Imaging for Detection of Parenchymal Liver Lesions With B-Mode Sonography. AB - OBJECTIVES: The electronic colorization of grayscale B-mode sonograms using various color schemes aims to enhance the adaptability and practicability of B mode sonography in daylight conditions. The purpose of this study was to determine the diagnostic effectiveness and importance of colorized B-mode sonography. METHODS: Fifty-three video sequences of sonographic examinations of the liver were digitized and subsequently colorized in 2 different color combinations (yellow-brown and blue-white). The set of 53 images consisted of 33 with isoechoic masses, 8 with obvious lesions of the liver (hypoechoic or hyperechoic), and 12 with inconspicuous reference images of the liver. The video sequences were combined in a random order and edited into half-hour video clips. RESULTS: Isoechoic liver lesions were successfully detected in 58% of the yellow brown video sequences and in 57% of the grayscale video sequences (P = .74, not significant). Fifty percent of the isoechoic liver lesions were successfully detected in the blue-white video sequences, as opposed to a 55% detection rate in the corresponding grayscale video sequences (P= .11, not significant). In 2 subgroups, significantly more liver lesions were detected with grayscale sonography compared to blue-white sonography. CONCLUSIONS: Yellow-brown-colorized B-mode sonography appears to be similarly effective for detection of isoechoic parenchymal liver lesions as traditional grayscale sonography. Blue-white colorization in B-mode sonography is probably not as effective as grayscale sonography, although a statistically significant disadvantage was shown only in the subgroup of hyperechoic liver lesions. PMID- 26254147 TI - AID targeting: old mysteries and new challenges. AB - Activation-induced cytidine deaminase (AID) mediates cytosine deamination and underlies two central processes in antibody diversification: somatic hypermutation and class-switch recombination. AID deamination is not exclusive to immunoglobulin loci; it can instigate DNA lesions in non-immunoglobulin genes and thus stringent checks are in place to constrain and restrict its activity. Recent findings have provided new insights into the mechanisms that target AID activity to specific genomic regions, revealing an involvement for noncoding RNAs associated with polymerase pausing and with enhancer transcription as well as genomic architecture. We review these findings and integrate them into a model for multilevel regulation of AID expression and targeting in immunoglobulin and non-immunoglobulin loci. Within this framework we discuss gaps in understanding, and outline important areas of further research. PMID- 26254150 TI - Maximum Peak Systolic Velocity and Management of Highly Vascularized Retained Products of Conception. AB - OBJECTIVES: The purpose of this study was to evaluate blood loss and procedure related complications during and after surgical removal of retained products of conception with high-velocity enhanced myometrial vascularity. METHODS: We conducted a prospective study of 18 consecutive women with a diagnosis of retained products of conception and enhanced myometrial vascularity, with a peak systolic velocity (PSV) higher than 60 cm/s. All underwent ultrasound-guided surgical removal of the retained products under general anesthesia. Blood loss during the procedure was collected and recorded. The removed tissue was sent for histologic examination. An ultrasound examination was repeated within 24 hours. RESULTS: Five patients had retained products of conception after a term delivery, 1 after a second-trimester termination of pregnancy, 7 after a spontaneous first trimester miscarriage, and 5 after a first-trimester termination elsewhere. The PSV in the area of enhanced myometrial vascularity at diagnosis ranged from 61.0 to 152.6 cm/s (mean, 104.9 cm/s). The estimated blood loss at surgery ranged from 20 to 1000 mL (mean, 200 mL). After surgery, the PSV in the myometrium dropped dramatically (<=30 cm/s in all but 1 case). In all cases, trophoblastic tissue was confirmed at histologic examination. CONCLUSIONS: Although surgical removal of retained products of conception was uneventful in most cases, heavy bleeding has to be anticipated in cases of high-velocity flow in the myometrium underlying residual trophoblastic tissue. Accordingly, in cases of high-velocity enhanced myometrial vascularity, we advocate surgical removal of the residual tissue under ultrasound guidance by an experienced surgeon and in the presence of a fully informed anesthetist. PMID- 26254151 TI - Coronal Axis Measurement of the Optic Nerve Sheath Diameter Using a Linear Transducer. AB - OBJECTIVES: The true optic nerve sheath diameter cutoff value for detecting elevated intracranial pressure is variable. The variability may stem from the technique used to acquire sonographic measurements of the optic nerve sheath diameter as well as sonographic artifacts inherent to the technique. The purpose of this study was to compare the traditional visual axis technique to an infraorbital coronal axis technique for assessing the optic nerve sheath diameter using a high-frequency linear array transducer. METHODS: We conducted a cross sectional study at an academic medical center. Timed optic nerve sheath diameter measurements were obtained on both eyes of healthy adult volunteers with a 10-5 MHz broadband linear array transducer using both traditional visual axis and coronal axis techniques. Optic nerve sheath diameter measurements were obtained by 2 sonologists who graded the difficulty of each technique and were blinded to each other's measurements for each participant. RESULTS: A total of 42 volunteers were enrolled, yielding 84 optic nerve sheath diameter measurements. There were no significant differences in the measurements between the techniques on either eye (P = .23 [right]; P = .99 [left]). Additionally, there was no difference in the degree of difficulty obtaining the measurements between the techniques (P = .16). There was a statistically significant difference in the time required to obtain the measurements between the traditional and coronal techniques (P < .05). CONCLUSIONS: Infraorbital coronal axis measurements are similar to measurements obtained in the traditional visual axis. The infraorbital coronal axis technique is slightly faster to perform and is not technically challenging. PMID- 26254152 TI - Contrast-Enhanced Sonography for Diagnosing Collateral Transformation of the Hepatic Artery After Liver Transplantation. AB - OBJECTIVES: To determine the contrast-enhanced sonographic features of hepatic artery collateral transformation in patients with hepatic artery complications after liver transplantation. METHODS: Ninety-nine liver transplant recipients who underwent contrast-enhanced sonography were recruited from April 2004 to May 2014. The reference standards were conventional angiography and computed tomographic angiography. The contrast-enhanced sonographic features of the hepatic artery in patients with and without collateral arteries were retrospectively analyzed. RESULTS: All 15 patients with hepatic artery collateral transformation had hepatic artery thrombosis (10 of 15) or hepatic artery stenosis (5 of 15). The collateral artery detection rate on contrast-enhanced sonography was 100%. The peripheral hepatic artery could not be visualized by contrast-enhanced sonography in most of the patients with hepatic artery collateral transformation (14 of 15). Additionally, many small tortuous collateral arteries in the porta hepatis region were visualized during the arterial and early portal phases, showing reticulated/patchy (15 of 15) and striped (3 of 15) enhancement patterns on contrast-enhanced sonography. CONCLUSIONS: Collateral transformation of the hepatic artery in patients with hepatic artery complications after liver transplantation appears to have characteristic features on contrast-enhanced sonography, especially a reticulated or patchy enhancement pattern in the porta hepatis region during the arterial and early portal phases combined with the absence of the peripheral hepatic artery. Contrast-enhanced sonography may be a novel method for diagnosing hepatic artery collateral transformation, which may be a highly specific sign of hepatic artery thrombosis or stenosis. PMID- 26254153 TI - In Search of the Optimal Heart Perfusion Ultrasound Imaging Platform. AB - OBJECTIVES: Quantification of myocardial perfusion by contrast echocardiography remains a challenge. Existing imaging phantoms used to evaluate the performance of ultrasound scanners do not comply with perfusion basics in the myocardium, where perfusion and motion are inherently coupled. To contribute toward an improvement, we developed a contrast echocardiographic perfusion imaging platform based on an isolated rat heart coupled to an ultrasound scanner. METHODS: Perfusion was assessed by using 3 different types of contrast agents: dextran based Promiten (Meda AB, Solna, Sweden), phospholipid-shelled SonoVue (Bracco Diagnostics, Inc, Princeton, NJ), and polymer-shelled MB-pH5-RT, developed in house. The myocardial video intensity was monitored over time from contrast agent administration to peak, and 2 characteristic constants were calculated by using an exponential fit: A, representing capillary volume; and beta, representing inflow velocity. RESULTS: Acquired experimental evidence demonstrates that the application of all 3 contrast agents allows sonographic estimation of myocardial perfusion in the isolated rat heart. Video intensity maps show that an increase in contrast concentration increases the late-plateau values, A, mimicking increased capillary volume. Estimated values of the flow, proportional to A * beta, increase when the pressure of the perfusate column increases from 80 to 110 cm of water. This finding is in agreement with the true values of the coronary flow increase measured by a flowmeter attached to the aortic cannula. CONCLUSIONS: The contrast echocardiographic perfusion imaging platform described holds promise for standardized evaluation and optimization of contrast perfusion ultrasound imaging in which real-time inflow curves at low acoustic power semiquantitatively reflect coronary flow. PMID- 26254154 TI - Evaluation of Tongue Cancer Using High-Resolution Sonography: Comparison With Magnetic Resonance Imaging. AB - OBJECTIVES: To evaluate the role of sonography in assessing tongue cancer compared with magnetic resonance imaging (MRI). METHODS: A randomized prospective study was performed on 40 cases of tongue cancer. Magnetic resonance imaging and sonography of the tongue were performed, tumor spreading to particular sites was recorded in all cases. Sonographic and MRI findings were correlated with histopathologic findings in 18 operable cases. In 22 inoperable cases, sonography was compared only with MRI. RESULTS: In operable patients, sonography achieved sensitivity of 61.1%, whereas MRI achieved sensitivity of 94.4%. The difference was statistically significant (P < .05). The results for detection of individual site involvement on sonography and MRI were as follows: intrinsic muscles only, 0 and 6, respectively; tongue base, 5 and 5; genioglossus muscle, 34 and 34; mylohyoid muscle, 9 and 8; sublingual space, 12 and 14; sublingual neurovascular bundle, 12 and 12; submandibular gland, 3 and 3; spread across the lingual septum, 17 and 17; and alveolar involvement, 0 and 1. There was no significant difference (P> .05) between sonography and MRI in detecting involvement of the above-mentioned sites except for cases with only intrinsic muscles and alveolar involvement. Tumors involving intrinsic tongue muscles only were not visualized on sonography. They all underwent surgery, resulting in reduced sensitivity of sonography in operable cases. CONCLUSIONS: Even though small tumors were difficult to visualize, sonography can play an important role in assessment of tumor extension in large growths, especially when MRI is unavailable, contraindicated, or unaffordable, and for posttreatment follow-up. PMID- 26254155 TI - Evaluation of an Obstetric Ultrasound Curriculum for Midwives in Liberia. AB - OBJECTIVES: Point-of-care ultrasound is an effective tool for clinical decision making in low- and middle-income countries, but lack of trained providers is a barrier to its utility in these settings. In Liberia, given that midwives provide most prenatal care, it is hypothesized that training them in prenatal ultrasound through an intensive condensed training course is both feasible and practical. METHODS: This quantitative prospective study of preobservational and postobservational assessment evaluated a 1-week ultrasound curriculum consisting of 4 modules, each comprising a didactic component, a practical session, and supervised patient encounters. A knowledge-based pretest and presurvey addressing prior use and comfort were administered. At the intervention conclusion, identical posttests and postsurveys were administered with an objective structured clinical examination (OSCE). The test, survey, and OSCE were repeated after 1 year. All scores and responses were tabulated, and qualitative analysis with paired t tests was performed. RESULTS: Thirty-one midwives underwent intervention and written evaluation, with 14 followed up at 1 year. Seventeen underwent the OSCE, with 8 retained at 1 year. There was a significant increase between pretest and immediate and 1-year posttest scores (36.6% versus 90% and 66%; P < .001) but no difference between immediate and 1-year posttest scores (90% versus 66%; P > .05). Average overall comfort using ultrasound increased from presurvey to immediate postsurvey scores (from 1.8 to 3.8; P< .001) and remained higher at the 1-year postsurvey (1.8 to 3.4; P< .05). Overall OSCE scores remained high from immediately after the OSCE to 1 year after the OSCE (78% to 55%; P > .05). CONCLUSIONS: Midwives in Liberia had very low baseline knowledge and comfort using ultrasound. A 1-week curriculum increased both short- and long-term knowledge and comfort and led to adequate overall OSCE scores that were retained at 1 year. PMID- 26254156 TI - Diagnosis of Placenta Accreta by Uterine Artery Doppler Velocimetry in Patients With Placenta Previa. AB - OBJECTIVES: To evaluate the potential value of uterine artery Doppler velocimetry in diagnosing placenta accreta. METHODS: Clinical records of all deliveries between April 1991 and March 2013 were retrospectively analyzed. Cases of intrauterine growth restriction, pregnancy-induced hypertension, multiple pregnancies, fetal anomalies, chromosomal abnormalities, and maternal medical illnesses such as cardiovascular disease, renal disease, and diabetes mellitus were excluded. A total of 11,210 cases were evaluated, including 403 cases of placenta previa without accreta (placenta previa) and 39 cases of placenta previa with accreta (placenta accreta). All patients underwent uterine artery Doppler velocimetry to measure the mean resistive index and pulsatility index (PI) in the third trimester. The analysis included participant characteristics such as age, parity, abortion history, previous cesarean delivery, gestational age at delivery, neonatal sex, and birth weight. RESULTS: The mean uterine artery PI was significantly lower in the placenta accreta group compared to previa alone (0.51 versus 0.57; P = .002). The odds ratios for placenta accreta were 2.4 for 2 or more previous abortions (P = .011) and 5.3 and 7.0 for 1 and 2 or more previous cesarean deliveries (P = .001 and .005). With an increase in the mean PI by 0.01, the odds ratio for placenta accreta decreased by 0.94 (P < .001). The area under the receive operating characteristic curve was 0.72 for previous cesarean delivery alone, increasing to 0.77 with the combination of the mean PI and previous cesarean delivery (P = .047). CONCLUSIONS: This study suggests that the mean PI measured by uterine artery Doppler velocimetry is reduced in patients with placenta accreta compared to those without accreta. The diagnostic accuracy of placenta accreta can be potentially improved if uterine artery Doppler values and the history of cesarean delivery are combined. PMID- 26254157 TI - Obstetric and Gynecologic Resident Ultrasound Education Project: Is the Current Level of Gynecologic Ultrasound Training in Canada Meeting the Needs of Residents and Faculty? AB - OBJECTIVES: Ultrasound is a critical diagnostic imaging tool in obstetrics and gynecology (Ob/Gyn). Obstetric ultrasound is taught during residency, but we suspected a gap in Gyn ultrasound education. Proficiency in Gyn ultrasound allows real-time interpretation and management of pelvic disease and facilitates technical skill development for trainees learning blinded procedures. This study sought to evaluate ultrasound education in Canada's Ob/Gyn residency programs and assess whether residents and physicians perceived a need for a formalized Gyn ultrasound curriculum. METHODS: We distributed a needs assessment survey to residents enrolled in Canadian Ob/Gyn residency programs and to all obstetrician/gynecologists registered as members of the Society of Obstetricians and Gynaecologists of Canada. Residents were asked to specify their current training in ultrasound and to rate the adequacy of their curriculum. All respondents rated the importance of proficiency in pelvic ultrasound for practicing obstetrician/gynecologists as well as the perceived need for formalized ultrasound training in Ob/Gyn residency programs. RESULTS: Eighty-two residents and 233 physicians completed the survey. Extents and types of ultrasound training varied across residency programs. Most residents reported inadequate exposure to Gyn ultrasound, and most residents and physicians agreed that it is important for obstetrician/gynecologists to be proficient in Gyn ultrasound and that the development of a standardized Gyn ultrasound curriculum for residency programs is important. CONCLUSIONS: Current ultrasound education in Ob/Gyn varies across Canadian residency programs. Training in Gyn ultrasound is lacking, and both trainees and physicians confirmed the need for a standardized Gyn ultrasound curriculum for residency programs in Canada. PMID- 26254158 TI - ACR Presidential Address ACR: Imagine the World Without Her. AB - Imagine the world without the ACR. Imagine that Wilhelm Conrad Roentgen had died before November 8, 1895. Imagine that Albert Soiland, MD, had not founded the ACR in 1923. What would medicine look like now? The ACR is important in many ways: advocacy and economics, education, quality and safety, clinical research, publication, leadership, and diversity. The ACR is vital to patients, radiologists, and other physicians. The ACR is unique: No other organization or group of societies could fill the void. So instead of imagining a world without the ACR, imagine a better world-one in which patients always come first, and all imaging professionals are active members of the ACR. We are the lucky ones-we can change the world. PMID- 26254159 TI - ACR Appropriateness Criteria Vomiting in Infants up to 3 Months of Age. AB - Vomiting is a commonly reported symptom in infants less than three months of age. There are a multitude of pathologies to consider, both within and outside the gastrointestinal tract. In addition to conducting a thorough history and physical examination, a clinician formulates a reasonable differential diagnosis by consideration of two main factors: the infant's age and the characterization of the vomit as bilious or nonbilious. In this endeavor, the clinician is able to determine if an imaging study is needed and, if so, the urgency of the request. A review of the appropriate imaging evaluation of vomiting infants in the newborn to three-month-old age group is provided by organizing the discussion around the following three clinical scenarios: bilious vomiting, intermittent nonbilious vomiting since birth, and new-onset bilious vomiting. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 26254160 TI - Ecological Momentary Assessments and Automated Time Series Analysis to Promote Tailored Health Care: A Proof-of-Principle Study. AB - BACKGROUND: Health promotion can be tailored by combining ecological momentary assessments (EMA) with time series analysis. This combined method allows for studying the temporal order of dynamic relationships among variables, which may provide concrete indications for intervention. However, application of this method in health care practice is hampered because analyses are conducted manually and advanced statistical expertise is required. OBJECTIVE: This study aims to show how this limitation can be overcome by introducing automated vector autoregressive modeling (VAR) of EMA data and to evaluate its feasibility through comparisons with results of previously published manual analyses. METHODS: We developed a Web-based open source application, called AutoVAR, which automates time series analyses of EMA data and provides output that is intended to be interpretable by nonexperts. The statistical technique we used was VAR. AutoVAR tests and evaluates all possible VAR models within a given combinatorial search space and summarizes their results, thereby replacing the researcher's tasks of conducting the analysis, making an informed selection of models, and choosing the best model. We compared the output of AutoVAR to the output of a previously published manual analysis (n=4). RESULTS: An illustrative example consisting of 4 analyses was provided. Compared to the manual output, the AutoVAR output presents similar model characteristics and statistical results in terms of the Akaike information criterion, the Bayesian information criterion, and the test statistic of the Granger causality test. CONCLUSIONS: Results suggest that automated analysis and interpretation of times series is feasible. Compared to a manual procedure, the automated procedure is more robust and can save days of time. These findings may pave the way for using time series analysis for health promotion on a larger scale. AutoVAR was evaluated using the results of a previously conducted manual analysis. Analysis of additional datasets is needed in order to validate and refine the application for general use. PMID- 26254161 TI - Evidence suggesting phosphodiesterase-3B regulation of NPY/AgRP gene expression in mHypoE-46 hypothalamic neurons. AB - Hypothalamic neurons expressing neuropeptide Y (NPY) and agouti related-protein (AgRP) are critical regulators of feeding behavior and body weight, and transduce the action of many peripheral signals including leptin and insulin. However, intracellular signaling molecules involved in regulating NPY/AgRP neuronal activity are incompletely understood. Since phosphodiesterase-3B (PDE3B) mediates the hypothalamic action of leptin and insulin on feeding, and is expressed in NPY/AgRP neurons, PDE3B could play a significant role in regulating NPY/AgRP neuronal activity. To investigate the direct regulation of NPY/AgRP neuronal activity by PDE3B, we examined the effects of gain-of-function or reduced function of PDE3B on NPY/AgRP gene expression in a clonal hypothalamic neuronal cell line, mHypoE-46, which endogenously express NPY, AgRP and PDE3B. Overexpression of PDE3B in mHypoE-46 cells with transfection of pcDNA-3.1-PDE3B expression plasmid significantly decreased NPY and AgRP mRNA levels and p-CREB levels as compared to the control plasmid. For the PDE3B knockdown study, mHypoE 46 cells transfected with lentiviral PDE3BshRNAmir plasmid or non-silencing lentiviral shRNAmir control plasmid were selected with puromycin, and stably transfected cells were grown in culture for 48h. Results showed that PDE3BshRNAmir mediated knockdown of PDE3B mRNA and protein levels (~60-70%) caused an increase in both NPY and AgRP gene expression and in p-CREB levels. Together, these results demonstrate a reciprocal change in NPY and AgRP gene expression following overexpression and knockdown of PDE3B, and suggest a significant role for PDE3B in the regulation of NPY/AgRP gene expression in mHypoE-46 hypothalamic neurons. PMID- 26254162 TI - Changes of the expressions of multiple metabolism genes in rat pancreatic islets after ventromedial hypothalamic lesioning. AB - It was recently reported that ventromedial hypothalamic lesions change the expression of cell proliferation-related genes and morphology-related genes in rat pancreatic islets. This study has examined how gene families involved in metabolism are regulated in rat pancreatic islets after VMH lesions formation. Total pancreatic islets RNA was extracted, and differences in the gene expression profiles between rats at day 3 after VMH lesioning and sham-VMH-lesioned rats were investigated using DNA microarray and real-time polymerase chain reaction. The VMH lesions regulated the genes that are involved in functions related to metabolism in the pancreas islets. Real-time polymerase chain reaction also confirmed that gene expressions of arachidonate 15-lipoxygenase (Alox15) was up regulated and pancreatic lipase (Pnlip) was downregulated at day 3 after the VMH lesions. Ventromedial hypothalamic lesions may change the expression of multiple metabolism genes in rat pancreatic islets. PMID- 26254163 TI - Association study of GRM7 polymorphisms and schizophrenia in the Chinese Han population. AB - Schizophrenia is a severe and complex mental disorder with high heritability. There is an evidence that metabotropic glutamate receptors (GRM) are associated with schizophrenia. GRM7 has been identified as a candidate gene for many psychiatric disorders especially schizophrenia. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in GRM7 were associated with schizophrenia. Four SNPs (rs9814881, rs13353402, rs9870680 and rs1531939) were genotyped in 1034 schizophrenic patients and 1034 healthy controls of Chinese Han origin. The results showed that the two SNPs rs13353402 and rs1531939 demonstrated significant difference between schizophrenic patients and control subjects in allele frequencies (rs13353402: P value=0.0307, rs1531939: P value=0.0328, respectively). Nevertheless, there was no significant discrepancies in genotype distribution. In summary, our results indicate that the GRM7 SNPs rs13353402 and rs1531939 might be associated with schizophrenia in Chinese Han population. PMID- 26254164 TI - Orexin-A modulates excitatory synaptic transmission and neuronal excitability in the spinal cord substantia gelatinosa. AB - Although intrathecal orexin-A has been known to be antinociceptive in various pain models, the role of orexin-A in antinociception is not well characterized. In the present study, we examined whether orexin-A modulates primary afferent fiber-mediated or spontaneous excitatory synaptic transmission using transverse spinal cord slices with attached dorsal root. Bath-application of orexin-A (100nM) reduced the amplitude of excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation of Adelta- or C-primary afferent fibers. The magnitude of reduction was much larger for EPSCs evoked by polysynaptic C-fibers than polysynaptic Adelta-fibers, whereas it was similar in EPSCs evoked by monosynaptic Adelta- or C-fibers. SB674042, an orexin-1 receptor antagonist, but not EMPA, an orexin-2 receptor antagonist, significantly inhibited the orexin-A induced reduction in EPSC amplitude from mono- or polysynaptic Adelta-fibers, as well as from mono- or polysynaptic C-fibers. Furthermore, orexin-A significantly increased the frequency of spontaneous EPSCs but not the amplitude. This increase was almost completely blocked by both SB674042 and EMPA. On the other hand, orexin-A produced membrane oscillations and inward currents in the SG neurons that were partially or completely inhibited by SB674042 or EMPA, respectively. Thus, this study suggests that the spinal actions of orexin-A underlie orexin-A induced antinociceptive effects via different subtypes of orexin receptors. PMID- 26254165 TI - Relationship between cerebral sodium-glucose transporter and hyperglycemia in cerebral ischemia. AB - Post-ischemic hyperglycemia exacerbates the development of cerebral ischemia. To elucidate this exacerbation mechanism, we focused on sodium-glucose transporter (SGLT) as a mediator that lead hyperglycemia to cerebral ischemia. SGLT transport glucose into the cell, together with sodium ion, using the sodium concentration gradient. We have previously reported that suppression of cerebral SGLT ameliorates cerebral ischemic neuronal damage. However, detail relationship cerebral between SGLT and post-ischemic hyperglycemia remain incompletely defined. Therefore, we examined the involvement of cerebral SGLT on cerebral ischemic neuronal damage with or without hyperglycemic condition. Cell survival rate of primary cultured neurons was assessed by biochemical assay. A mouse model of focal ischemia was generated using a middle cerebral artery occlusion (MCAO). Neuronal damage was assessed with histological and behavioral analyses. Concomitant hydrogen peroxide/glucose treatment exacerbated hydrogen peroxide alone-induced cell death. Although a SGLT family-specific inhibitor, phlorizin had no effect on developed hydrogen peroxide alone-induced cell death, it suppressed cell death induced by concomitant hydrogen peroxide/glucose treatment. alpha-MG induced a concentration-dependent and significant decrease in neuronal survival. PHZ administered on immediately after reperfusion had no effect, but PHZ given at 6h after reperfusion had an effect. Our in vitro study indicates that SGLT is not involved in neuronal cell death in non-hyperglycemic condition. We have already reported that post-ischemic hyperglycemia begins to develop at 6h after MCAO. Therefore, current our in vivo study show post-ischemic hyperglycemic condition may be necessary for the SGLT-mediated exacerbation of cerebral ischemic neuronal damage. PMID- 26254167 TI - Audit of Endotracheal Tube Suction in a Pediatric Intensive Care Unit. AB - We report outcomes of a clinical audit examining criteria used in clinical practice to rationalize endotracheal tube (ETT) suction, and the extent these matched criteria in the Endotracheal Suction Assessment Tool(ESAT)(c). A retrospective audit of patient notes ( N = 292) and analyses of criteria documented by pediatric intensive care nurses to rationalize ETT suction were undertaken. The median number of documented respiratory and ventilation status criteria per ETT suction event that matched the ESAT(c) criteria was 2 [Interquartile Range (IQR) 1-6]. All criteria listed within the ESAT(c) were documented within the reviewed notes. A direct link was established between criteria used for current clinical practice of ETT suction and the ESAT(c). The ESAT(c), therefore, reflects documented clinical decision making and could be used as both a clinical and educational guide for inexperienced pediatric critical care nurses. Modification to the ESAT PMID- 26254166 TI - Ecological aspects of pain in sensory modulation disorder. AB - BACKGROUND: Sensory Modulation Disorder (SMD) interferes with the daily life participation of otherwise healthy individuals and is characterized by over-, under- or seeking responsiveness to naturally occurring sensory stimuli. Previous laboratory findings indicate pain hyper-sensitivity in SMD individuals suggesting CNS alteration in pain processing and modulation. However, laboratory studies lack ecological validity, and warrant clinical completion in order to elicit a sound understanding of the phenomenon studied. Thus, this study explored the association between sensory modulation and pain in a daily life context in a general population sample. METHODS: Daily life context of pain and sensations were measured in 250 adults (aged 23-40 years; 49.6% males) using 4 self-report questionnaires: Pain Sensitivity Questionnaire (PSQ) and Pain Catastrophizing Scale (PCS) to evaluate the sensory and cognitive aspects of pain; the Sensory Responsiveness Questionnaire (SRQ) to appraise SMD; and the Short Form - 36 Health Survey, version 2 (SF36) to assess health related Quality of Life (QoL). RESULTS: Thirty two individuals (12.8%) were found with over-responsiveness type of SMD, forming the SOR-SMD group. While no group differences (SOR-SMD vs. Non SMD) were found, low-to-moderate total sample correlations were demonstrated between the SRQ-Aversive sub-scale and i) PSQ total (r=0.31, p<0.01) and sub scales scores (r=0.27-0.28, p<0.01), as well as ii) PCS total and the sub-scales of Rumination and Helplessness scores (r=0.15, p<0.05). PSQ total and sub-scale scores were more highly correlated with SRQ-Aversive in the SOR-SMD group (r=0.57 0.68, p=0.03-<0.01) compared to Non-SMD group. The Physical Health - Total score (but not the Mental Health - Total) of the SF36 was lower for the SOR-SMD group (p=0.03), mainly due to the difference in the Body pain sub-scale (p=0.04). CONCLUSIONS: Results suggest that SOR-SMD is strongly associated with the sensory aspect of pain but weakly associated with the cognitive aspect. This indicates that SMD co-occurs with daily pain sensitivity, thus reducing QoL, but less with the cognitive-catastrophizing manifestation of pain perception. PMID- 26254168 TI - Starting a Radioactive Seed Localization Program. AB - Because of disadvantages, such as the need to perform the localization and operation the same day and difficulty maintaining orientation of the center of the localization in relation to the margins of excision, alternatives to wire localization for surgery of nonpalpable breast lesions have been widely pursued. Radioactive seed localization (RSL) is one technique that has gained acceptance in many practices throughout the world and has been shown to be a safe, effective alternative to wire localization. RSL allows the localization procedure to be scheduled on a different day from the operative procedure, the operative incision to be planned with no regard for the entry point used for localization, and ongoing feedback as to the location of and distance from the lesion throughout the operation. Although RSL is an attractive technique that is intuitive to learn, beginning a new RSL program entails a multidisciplinary effort that includes several challenges. We describe recommendations for how to start a RSL program. PMID- 26254169 TI - Excising Additional Margins at Initial Breast-Conserving Surgery (BCS) Reduces the Need for Re-excision in a Predominantly African American Population: A Report of a Randomized Prospective Study in a Public Hospital. AB - BACKGROUND: Margin status is an important prognostic factor for local recurrence after breast conserving surgery (BCS) for breast cancer. We designed a prospective randomized trial to evaluate the effect of shave margins on positive margins and locoregional recurrence (LRR). METHODS: Patients were randomized to BCS or BCS with resection of 5 additional margins (BCS + M). Tumor margins were classified as negative [>2 mm for ductal carcinoma in situ (DCIS); >1 mm for invasive carcinoma] based on guidelines at the time of accrual. RESULTS: A total of 75 patients with stage 0-III breast cancer (76 samples) were randomized, mean age 59.6 years with median follow-up 39.5 months. Overall, 21 patients (27.6 %) had positive margins: 14 had undergone BCS and 7 BCS + M (p = 0.005). Of the 21 patients with positive margins, 19 had DCIS on final pathology (OR 7.56; 95 % CI 1.52-37.51).All patients with positive margins were offered re-excision; 11 had negative final margins after re-excision surgery. Overall, 6 patients (8.3 %) developed LRR with recurrence being more common in the BCS group when compared with the BCS + M group (17.2 vs 2.3 %; p = 0.025). CONCLUSIONS: Taking additional cavity shave margins at the time of initial excision resulted in a reduction in positive margin rate, a decrease in return to operating room for re-excision, and lower LRR. PMID- 26254170 TI - Uroflow Stop Test and Potency Recovery: A Surrogate for Pelvic Floor Integrity Post Robotic-Assisted Radical Prostatectomy? AB - OBJECTIVE: To study the relation between uroflow Stop Test and early recovery of potency following robot-assisted radical prostatectomy (RARP). We recently showed that the ability to completely stop urine flow during voiding, measured objectively by uroflowmetry at the time of catheter removal (uroflow Stop Test) can predict early urinary continence recovery following RARP. MATERIALS AND METHODS: In this prospective observational cohort, data were collected on 108 patients operated by a single surgeon (AEH). Eighty patients had a positive uroflow Stop Test (group one) and 28 had a negative Stop Test (group two). Patients were followed for a minimum of 2 years. Covariates included age, body mass index, international prostate symptom score and sexual health inventory for men scores, prostate-specific antigen, tumor stage, prostate volume, nerve sparing status, and estimated blood loss. RESULTS: Preoperative characteristics were comparable between both groups except nerve sparing and prostate-specific antigen which were statistically higher in group one (P <.05). Early 3- and 6 months recovery of erectile function was significantly higher in group one. Potency rates in group one and two at 1, 3, 6, 9, 12, 18, and 24 months were 25% vs 14.3% (P = .241), 54.5% vs 18.5% (P = .001), 55.4% vs 18.5% (P = .001), 56.4% vs 36% (P = .084), 66.6% vs 50% (P = .141), 65.5% vs 56% (P = .404) and 73.2% vs 57.7% (P = .160) respectively. Uroflow Stop Test was independent predictor of early potency recovery on multivariate regression analysis at 6 months [odds ratio 6.042 (confidence interval 95% 1.496-24.413) P = .012]. CONCLUSION: Uroflow Stop Test is simple and can help predict early potency recovery following RARP. PMID- 26254171 TI - Evaluation of the Learning Curve for Holmium Laser Enucleation of the Prostate Using Multiple Outcome Measures. AB - OBJECTIVE: To assess and quantify the surgical learning curve of holmium laser enucleation of the prostate (HoLEP) of a single surgeon. METHODS: A retrospective analysis of 253 consecutive cases performed by the same surgeon from 2006 to 2013 was conducted. Primary outcomes included enucleation ratio and morcellation efficiencies and complication rates. Three-month postoperative prostate-specific antigen values were used as secondary measures. Cases were divided into cohorts of 20 cases to assess changes in means analyzed through Analysis of Variance (ANOVA) tests. Scatter plots of cases with a best-fit line were drawn to analyze the learning curve. RESULTS: The mean age of patients across the cases was 69.21 years with an average transrectal ultrasound prostate volume of 95.84 cc. Enucleation ratio efficiency was significantly different between cohorts (P = .02) plateau after 50-60 cases conducted. Similarly, a significant difference is shown for morcellation efficiency (P = .01) with stabilization in performance after 60 cases. Complication rates decreased through the caseload but did not show a statistical difference (P = .62) or plateauing on the graph. Finally, no difference between 3-month postoperative prostate-specific antigen values was seen (P = .083); however, a learning curve of 50 cases was observed graphically. CONCLUSION: Within our single-surgeon cohort, we experienced a learning curve of 40-60 cases for the HoLEP procedure. Large variability in performance late into the caseload demonstrates the technical difficulty of HoLEP. Owing to this, adjuncts to training such as simulation-based training may be of use for the new surgeon to shorten the initial phase of learning. PMID- 26254172 TI - Robotic-assisted Radical Nephrectomy With Retrohepatic Vena Caval Tumor Thrombectomy (Level III) Combined With Extended Retroperitoneal Lymph Node Dissection. AB - OBJECTIVE: To describe a case of robotic-assisted radical nephrectomy (RARN) with level III retrohepatic vena caval tumor thrombectomy (11 cm) and extended retroperitoneal lymph node dissection (RPLND) for renal cell carcinoma (RCC). MATERIALS AND METHODS: A 52-year-old woman with a large right renal mass, 11-cm (level III) inferior vena cava (IVC) thrombus, with a negative metastatic workup presented to our clinic and was consented to undergo RARN. Intraoperative ultrasound confirmed the presence of tumor thrombus. After the division of the renal artery, control of the vena cava above and below the tumor thrombus as well as contralateral renal vein was obtained. A cavotomy was performed, the thrombus was removed, and the cavotomy was repaired. Additionally, an extended RPLND was performed with robotic assistance. RESULTS: Total operative time was 6 hours and 6 minutes. Estimated blood loss was 1200 cc. The final pathology demonstrated an 8.5-cm, Fuhrman grade 3, clear cell RCC with sarcomatoid features and negative surgical margins. All 44 lymph nodes removed (hilar, paracaval, precaval, retrocaval, interaortocaval, and preaortic) were negative. Final staging was pT3b, N0, M0. The patient was discharged to home 36 hours postoperatively and experienced no perioperative or postoperative complications. CONCLUSION: RARN with retrohepatic (level III) vena caval tumor thrombectomy and extended RPLND is technically feasible and has potential benefits. Robotic assistance may allow for improved intracorporal repair of the IVC and shortened recovery time, while maintaining oncologic principles. PMID- 26254173 TI - En Bloc Retroperitoneoscopic Removal of Horseshoe Kidney for End-stage Renal Disease. AB - Horseshoe kidney (HSK) is the most common renal fusion anomaly. There have been reports of an association of HSKs with medical renal disease. We report a case of a child with nephrotic-range proteinuria and a HSK. As the patient was on peritoneal dialysis, the entire HSK was removed en bloc via a retroperitoneoscopic approach with early postoperative reinitiation of peritoneal dialysis. PMID- 26254174 TI - Testicular Sperm Sampling by Subcapsular Orchiectomy in Klinefelter Patients: A New Simplified Treatment Approach. AB - OBJECTIVE: To evaluate subcapsular orchiectomy as a method to retrieve spermatozoa from minute testicular foci in men with Klinefelter syndrome (KS). METHODS: Fourteen men with KS were consecutively recruited to unilateral subcapsular orchiectomy. Testicular tissue was dissected mechanically and enzymatically to identify possible sperm. Previous testosterone replacement therapy was interrupted for 10 months (range: 9-12 months) to minimize a possible effect on the spermatogenesis. Two men with high estrogen/testosterone ratios were treated with aromatase inhibitor (letrozol, 2.5 mg/d for 3 months) before operation. RESULTS: Testicular sperm were detected in 5 of 14 KS men giving an overall success rate of 36%. The success rate was 50% (5 of 10 men) after exclusion of the 4 men previous treated with androgen substitution. So far, 3 (21%) clinical pregnancies and 2 live births or ongoing pregnancies (14%) have been obtained. Testicular sperm could not be detected in the 2 men treated with aromatase inhibitor before operation. The maximum operative time was 20 minutes, and none had surgical complications such as pain, fever, or hematomas. The mean testosterone level, measured 1-4 months after orchiectomy, decreased to 72% (7.9 +/- 2.4 nmol/L) of the preoperative level. CONCLUSION: Subcapsular orchiectomy appears to be easy and quick compared with conventional microtesticular sperm extraction. However, in this pilot study, it has not been possible to demonstrate pregnancy and live birth rates as high as that reported with microtesticular sperm extraction, and further studies are needed before the procedure should be used routinely for sperm retrieval in patients with KS. PMID- 26254175 TI - Intraosseous verrucous carcinoma arising from an infected dentigerous cyst-A case report. AB - Intraosseous verrucous carcinoma (IOVC) arising from an odontogenic cyst is extremely rare. We report a case of intraosseous verrucous carcinoma in a 74-year old male who presented with a left mandibular swelling with recurrent pus discharge from gingiva of tooth #35. Panoramic radiography revealed an impacted tooth #34 and a large well-defined, radiolucent lesion surrounding the crown of tooth #34. The clinical diagnosis was an infected dentigerous cyst. Surgical excision of the cyst together with extraction of tooth #34 was performed. Histopathological examination showed proliferation of hyperparakeratotic stratified squamous cyst lining epithelium and down-growth of broad and bulbous epithelial ridges with pushing border invasion into the fibrous cystic wall. A verrucous carcinoma arising from an infected dentigerous cyst was diagnosed. There was no recurrence of the tumor 5 months after surgery. PMID- 26254176 TI - Noncardiac DiGeorge syndrome diagnosed with multiplex ligation-dependent probe amplification: A case report. AB - DiGeorge syndrome is not really a rare disease. A microdeletion of chromosome 22q11.2 is found in most patients. Sharing the same genetic cause, a wide spectrum of clinical manifestations such as conotruncal anomaly face syndrome, Cayler cardiofacial syndrome, and velocardiofacial syndrome have been reported. Classic characteristics are cardiac defects, abnormal facial features, thymic hypoplasia, cleft palate, and hypocalcemia. We report a 6-year-old female child presenting with generalized seizure resulting from hypocalcemia. She had no cardiac defects and no hypocalcemia episode in neonatal stage, and had been said to be normal before by her parents until the diagnosis was made. This highlights the importance of extracardiac manifestations in the diagnosis of DiGeorge syndrome, and many affected patients may be underestimated with minor facial dysmorphism. As health practitioners, it is our duty to identify the victims undermined in the population, and start thorough investigations and the following rehabilitation as soon as possible. Multiplex ligation-dependent probe amplification is a rapid, reliable, and economical alternative for the diagnosis of 22q11.2 deletion. PMID- 26254177 TI - Primary Xanthoma of the Mandible: Report of a Rare Case. AB - Xanthoma is a lesion most commonly seen in soft tissues such as the skin, subcutis, or tendon sheaths. Xanthoma formation is often associated with primary or secondary hyperlipidemia. Primary bone xanthomas are extremely rare benign bone lesions not associated with hyperlipidemia, histopathologically characterized by histiocytes, abundant lipid containing macrophages (foam cells), and multinucleated giant cells. Cholesterol clefts can be found in the medullary bone. Less than ten cases of xanthoma in the mandible have been reported. We present a rare primary intrabony xanthoma in a normolipidemic patient. PMID- 26254178 TI - How does coronary stent implantation impact on the status of the microcirculation during primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction? AB - AIMS: Primary percutaneous coronary intervention (PPCI) is the optimal treatment for patients presenting with ST-elevation myocardial infarction (STEMI). An elevated index of microcirculatory resistance (IMR) reflects microvascular function and when measured after PPCI, it can predict an adverse clinical outcome. We measured coronary microvascular function in STEMI patients and compared sequential changes before and after stent implantation. METHODS AND RESULTS: In 85 STEMI patients, fractional flow reserve, coronary flow reserve, and IMR were measured using a pressure wire (Certus, St Jude Medical, St Paul, MN, USA) immediately before and after stent implantation. Stenting significantly improved all of the measured parameters of coronary physiology including IMR from 67.7 [interquartile range (IQR): 56.2-95.8] to 36.7 (IQR: 22.7-59.5), P < 0.001. However, after stenting, IMR remained elevated (>40) in 28 (32.9%) patients. In 15 of these patients (17.6% of the cohort), only a partial reduction in IMR occurred and these patients were more likely to be late presenters (pain to wire time >6 h). The extent of jeopardized myocardium [standardized beta: -0.26 (IMR unit/Bypass Angioplasty Revascularization Investigation score unit), P: 0.009] and pre-stenting IMR [standardized beta: -0.34 (IMR unit), P: 0.001] predicted a reduction in IMR after stenting (DeltaIMR = post-stenting IMR - pre-stenting IMR), whereas thrombotic burden [standardized beta: 0.24 (IMR unit/thrombus score unit), P: 0.01] and deployed stent volume [standardized beta: 0.26 (IMR unit/mm(3) of stent), P: 0.01] were associated with a potentially deleterious increase in IMR. CONCLUSION: Improved perfusion of the myocardium by stent deployment during PPCI is not universal. The causes of impaired microvascular function at the completion of PPCI treatment are heterogeneous, but can reflect a later clinical presentation and/or the location and extent of the thrombotic burden. PMID- 26254179 TI - Appropriateness of percutaneous revascularization of coronary chronic total occlusions: an overview. AB - Coronary chronic total occlusions (CTOs) are commonly encountered in patients undergoing coronary angiography. Several observational studies have demonstrated that successful CTO revascularization is associated with better cardiovascular outcomes and enhanced quality of life (QOL). However, in the absence of randomized trials, its prognostic benefit for patients remains debated. Over the past decade, the interest of the interventional community in CTO percutaneous coronary intervention (PCI) has exponentially grown due to important developments in dedicated equipment and techniques, resulting in high success and low complication rates. Both European and American guidelines have assigned a class IIa (level of evidence B) recommendation for CTO PCI. In the current review, we focus on the impact of CTO revascularization on clinical outcomes and QOL and on appropriate patient selection, and we provide a critical assessment of the current guidelines and recommendations on CTO PCI. PMID- 26254180 TI - De-novo collateral formation following acute myocardial infarction: Dependence on CCR2+ bone marrow cells. AB - Wide variation exists in the extent (number and diameter) of native pre-existing collaterals in tissues of different strains of mice, with supportive indirect evidence recently appearing for humans. This variation is a major determinant of the wide variation in severity of tissue injury in occlusive vascular disease. Whether such genetic-dependent variation also exists in the heart is unknown because no model exists for study of mouse coronary collaterals. Also owing to methodological limitations, it is not known if ischemia can induce new coronary collaterals to form ("neo-collaterals") versus remodeling of pre-existing ones. The present study sought to develop a model to study coronary collaterals in mice, determine whether neo-collateral formation occurs, and investigate the responsible mechanisms. Four strains with known rank-ordered differences in collateral extent in brain and skeletal muscle were studied: C57BLKS>C57BL/6>A/J>BALB/c. Unexpectedly, these and 5 additional strains lacked native coronary collaterals. However after ligation, neo-collaterals formed rapidly within 1-to-2 days, reaching their maximum extent in <=7 days. Rank-order for neo-collateral formation differed from the above: C57BL/6>BALB/c>C57BLKS>A/J. Collateral network conductance, infarct volume(-1), and contractile function followed this same rank-order. Neo-collateral formation and collateral conductance were reduced and infarct volume increased in MCP1(-/-) and CCR2(-/-) mice. Bone-marrow transplant rescued collateral formation in CCR2(-/-) mice. Involvement of fractalkine?CX3CR1 signaling and endothelial cell proliferation were also identified. This study introduces a model for investigating the coronary collateral circulation in mice, demonstrates that neo-collaterals form rapidly after coronary occlusion, and finds that MCP?CCR2-mediated recruitment of myeloid cells is required for this process. PMID- 26254181 TI - GYY4137 attenuates remodeling, preserves cardiac function and modulates the natriuretic peptide response to ischemia. AB - AIMS: Myocardial infarction followed by adverse left ventricular (LV) remodeling is the most frequent proximate cause of heart failure. Hydrogen sulfide (H2S) is an important endogenous modulator of diverse physiological and pathophysiological processes. Its role in post-ischemic ventricular remodeling and the associated neurohormonal responses has not been defined. Here, we aimed at evaluating whether the slow-releasing water-soluble H2S donor GYY4137 (GYY) exerts cardioprotective effects and modulates the neurohormonal response to cardiac ischemic injury. METHODS AND RESULTS: Treatment for 2 or 7 days with GYY (100 mg/Kg/48 h, IP) after acute myocardial infarction (MI) in rats preserved LV dimensions and function in vivo, compared to untreated infarcted (MI), placebo- and dl-propargylglycine- (PAG, an inhibitor of endogenous H2S synthesis) treated animals (n=9/group/time-point). LV dimensions and function in GYY-treated animals were comparable to healthy sham-operated rats. GYY-treated hearts had significantly less LV fibrosis than MI, placebo and PAG hearts. A higher density of blood vessels was found in the LV scar area of GYY-treated animals compared to all other infarcted groups. Despite preserved LV structure and function, treatment with GYY increased the levels of the natriuretic peptides ANP and BNP in association with enhanced cyclic GMP levels, paralleled by higher cGMP dependent protein kinase type I (cGKI) protein levels. CONCLUSIONS: Our data suggest that the slow-releasing H2S donor, GYY4137, preserves cardiac function, attenuates adverse remodeling and may exert post-ischemic cardioprotective (pro angiogenic, anti-apoptotic, anti-hypertrophic and anti-fibrotic) effects in part through enhanced early post-ischemic endogenous natriuretic peptide activation. PMID- 26254183 TI - Expression profiles of genes related to carbohydrate metabolism provide new insights into carbohydrate accumulation in seeds and seedlings of Ricinus communis in response to temperature. AB - Ricinus communis possesses a specific metabolic signature to adjust growth and developmental processes in response to temperature: carbohydrates are accumulated at low temperatures, whereas amino acids are accumulated at elevated temperatures. Our objective was to assess tissue-specific changes in transcript levels of genes related with carbohydrate biosynthesis and catabolism in response to temperature. For that, we measured transcript levels of genes encoding enzymes involved in starch biosynthesis, starch catabolism, and gluconeogenesis in R. communis leaves, roots, and seeds grown at 20 degrees C and 35 degrees C. Transcript levels of genes involved in starch catabolism were higher in leaves grown at 20 degrees C than at 35 degrees C, but up-regulation of genes involved in starch biosynthesis seems to compensate for this and, therefore, are the likely explanation for higher levels of starch in leaves grown at 20 degrees C. Higher levels of soluble carbohydrates in leaves grown at 20 degrees C may be caused by a coordinated increase in transcript level of genes associated with starch catabolism and gluconeogenesis pathways. In roots, transcript levels of genes associated with starch catabolism and gluconeogenesis seem to be enhanced at elevated temperatures. Higher levels of starch in seeds germinated at low temperatures is associated with higher transcript levels of genes involved in starch biosynthesis. Similarly, higher transcript levels of RcPEPCK and RcFBPase are most likely causal for fructose and glucose accumulation in seeds germinated at 20 degrees C. This study provides important insights in the understanding of the plasticity of R. communis in response to temperature that may apply to other species as well. PMID- 26254182 TI - Nifedipine attenuation of abdominal aortic aneurysm in hypertensive and non hypertensive mice: Mechanisms and implications. AB - Rupture of abdominal aortic aneurysm (AAA) is a lethal event. No oral medicine has been available to prevent or treat AAA. We have recently identified a novel mechanism of eNOS uncoupling by which AAA develops, in angiotensin II (Ang II) infused hyperphenylalaninemia 1 (hph-1) mice. Using this unique model we investigated effects on AAA formation of the L-type calcium channel blocker nifedipine, in view of the unclear relationship between hypertension and AAA, and unclear mechanisms of aneurysm protective effects of some blood pressure lowering drugs. Six-month old hph-1 mice were infused with Ang II (0.7 mg/kg/day) for 2 weeks, and fed nifedipine chow at two different doses (5 and 20 mg/kg/day). While the high dose of nifedipine reduced blood pressure, the lower dose had no effect. Interestingly, the incidence rate of AAA dropped from 71% to 7 and 12.5% for low and high dose nifedipine, respectively. Expansion of abdominal aorta, determined by ultrasound imaging, was abolished by both doses of nifedipine, which recoupled eNOS completely to improve NO bioavailability. Both also abrogated aortic superoxide production. Of note, Ang II activation of NADPH oxidase in vascular smooth muscle cells and endothelial cells, known to uncouple eNOS, was also attenuated by nifedipine. Although low dose was a sub-pressor while the high dose reduced blood pressure via inhibition of calcium channels, both doses were highly effective in preventing AAA by preserving eNOS coupling activity to eliminate sustained oxidative stress from uncoupled eNOS. These data demonstrate that oral treatment of nifedipine is highly effective in preserving eNOS function to attenuate AAA formation. Nifedipine may be used for AAA prevention either at low dose in AAA risk group, or at high dose in patients with co-existing hypertension. PMID- 26254184 TI - Metabolic cross-talk between pathways of terpenoid backbone biosynthesis in spike lavender. AB - The metabolic cross-talk between the mevalonate (MVA) and the methylerythritol phosphate (MEP) pathways in developing spike lavender (Lavandula latifolia Med) was analyzed using specific inhibitors and on the basis of (13)C-labeling experiments. The presence of mevinolin (MEV), an inhibitor of the MVA pathway, at concentrations higher than 0.5 MUM significantly reduced plant development, but not the synthesis of chlorophylls and carotenoids. On the other hand, fosmidomycin (FSM), an inhibitor of the MEP pathway, at concentrations higher than 20 MUM blocked the synthesis of chlorophyll, carotenoids and essential oils, and significantly reduced stem development. Notably, 1.2 mM MVA could recover the phenotype of MEV-treated plants, including the normal growth and development of roots, and could partially restore the biosynthesis of photosynthetic pigments and, to a lesser extent, of the essential oils in plantlets treated with FSM. Spike lavender shoot apices were also used in (13)C-labeling experiments, where the plantlets were grown in the presence of [U-(13)C6]glucose. GC-MS-analysis of 1,8-cineole and camphor indicated that the C5-precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) of both monoterpenes are predominantly biosynthesized via the methylerythritol phosphate (MEP) pathway. However, on the basis of the isotopologue profiles, a minor contribution of the MVA pathway was evident that was increased in transgenic spike lavender plants overexpressing the 3-hydroxy-3-methylglutaryl CoA reductase (HMGR), the first enzyme of the MVA pathway. Together, these findings provide evidence for a transport of MVA-derived precursors from the cytosol to the plastids in leaves of spike lavender. PMID- 26254186 TI - Is drug choice by general practitioners influenced by exposure to specialists? Record-linkage study in Italy. AB - OBJECTIVE: To investigate whether previous drug prescriptions by, or exposure to, specialists influence general practitioners' prescribing (using the example of inhibitors of the renin-angiotensin system). METHODS: Drug prescriptions in GP and specialist care, hospital records and outpatient visits in the Emilia-Romagna region (northern Italy) were linked to assess, among patients who in 2013 had been prescribed Angiotensin Converting Enzyme (ACE)-inhibitors or Angiotensin Receptor Blocker (ARBs) in general practice for the first time, whether those who had been previously prescribed these drugs by specialists (or have been recently exposed to cardiovascular, diabetes or nephrology specialists) were more likely to be prescribed an ARB or a patented ACE-inhibitor/ARB. RESULTS: A cohort of 88,926 patients was identified of whom 52,666 had not been exposed to specialists. Of these patients, 77.6% were initially prescribed ACE-inhibitors and 87.2% a non-patented drug. Higher prescription of ACE-inhibitors (82.0%) and of non-patented drugs (95.8%) in general practice were observed in the 10,243 the patients who had already been prescribed these drugs by a specialist compared to unexposed patients (p < 0.001 in both cases) and in the 14,648 patients exposed to specialists in the 90 days preceding the first prescription in general practice (79.0% and 89.6%, respectively, p < 0.001 in both cases). CONCLUSIONS: Exposure to specialists was not associated with higher prescription of ARBs and of patented drugs in this Region of Italy. The hypothesis of prescribing induction by specialists is not supported by these data. This kind of analysis can provide help inform local prescribing agreements. PMID- 26254185 TI - Regulatory B10 cell development and function. AB - B cells are known to instigate and promulgate immune responses by producing antibodies and presenting antigens to T cells. However, a rare but potent B-cell subset in both humans and mice is capable of inhibiting immune responses through the production of the anti-inflammatory cytokine IL-10. Regulatory B cells do not express any unique combination of surface markers but instead represent a small population of B cells that have acquired the unique ability to produce IL-10. This numerically rare B-cell subset is therefore functionally referred to as 'B10 cells' to reflect both their molecular program and the fact that their anti inflammatory effects in models of autoimmunity, infection and cancer are solely attributable to IL-10 production. As with most B cells, B10 cell development and function appear to be predominantly, if not exclusively, driven by antigen receptor signals. Once generated, B10 cells respond to both innate and adaptive immune signals, with a requirement for antigen-specific local interactions with T cells to induce IL-10 production and to provide optimal immune suppression in mouse models of autoimmune disease. B10 cells therefore provide an antigen specific mechanism for delivering IL-10 locally to sites of immune activation and inflammation. The ability of B10 cells to regulate innate and adaptive immune responses makes them an ideal therapeutic target for the treatment of many immune related disorders. PMID- 26254187 TI - An evaluation tool for assessing performance in priority setting and resource allocation: multi-site application to identify strengths and weaknesses. AB - INTRODUCTION: An evaluation tool should help improve formal priority setting and resource allocation (PSRA) processes in Canada and elsewhere. These are crucial to maximizing value from limited resources. METHODS: On the basis of case studies, balanced scorecard development protocols and use-focused evaluation principles, an evaluation tool was developed based on an existing framework for high PSRA performance and implemented in two health care organizations in British Columbia, Canada. RESULTS: Implementation of the tool identified areas of strength, improvement and weakness in the pilot organizations' processes for PSRA including: communication, staff engagement and culture. Refinements were identified and incorporated into the tool for future application. CONCLUSION: This is the first documented multi-site application of such an evaluation tool. Broader dissemination should have use both in further refining the basis of the tool and in catalysing improved performance of PSRA practice. PMID- 26254188 TI - Risk of atrial fibrillation in diabetes mellitus: A nationwide cohort study. AB - AIM: Diabetes has been associated with atrial fibrillation but the current evidence is conflicting. In particular knowledge regarding young diabetes patients and the risk of developing atrial fibrillation is sparse. The aim of our study was to investigate the risk of atrial fibrillation in patients with diabetes compared to the background population in Denmark. METHODS AND RESULTS: Through Danish nationwide registries we included persons above 18 years of age and without prior atrial fibrillation and/or diabetes from 1996 to 2012. The study cohort was divided into a background population without diabetes and a diabetes group. The absolute risk of developing atrial fibrillation was calculated and Poisson regression models adjusted for sex, age and comorbidities were used to calculate incidence rate ratios of atrial fibrillation. The total study cohort included 5,081,087 persons, 4,827,713 (95%) in the background population and 253,374 (5%) in the diabetes group. Incidence rates of atrial fibrillation per 1000 person years were stratified in four age groups from 18 to 39, 40 to 64, 65 to 74 and 75 to 100 years giving incidence rates (95% confidence intervals) of 0.02 (0.02-0.02), 0.99 (0.98-1.01), 8.89 (8.81-8.98) and 20.0 (19.9 20.2) in the background population and 0.13 (0.09-0.20), 2.10 (2.00-2.20), 8.41 (8.10-8.74) and 20.1 (19.4-20.8) in the diabetes group, respectively. The adjusted incidence rate ratios in the diabetes group with the background population as reference were 2.34 (1.52-3.60), 1.52 (1.47-1.56), 1.20 (1.18-1.23) and 0.99 (0.97-1.01) in the four age groups, respectively. CONCLUSION: Diabetes is an independent risk factor for developing atrial fibrillation/flutter, most pronounced in young diabetes patients. Routine screening for atrial fibrillation/flutter in diabetes patients might be beneficial and have therapeutic implications, especially in younger diabetes patients. TRANSLATIONAL PERSPECTIVE: Diabetes increases the risk of developing atrial fibrillation and especially young diabetes patients have a high relative risk. Increased focus on detecting atrial fibrillation in young diabetes patients might prove beneficial, and both anticoagulation treatment and anti-arrhythmic treatment strategies should be considered as soon as possible. PMID- 26254189 TI - The V-ATPase accessory protein Atp6ap1b mediates dorsal forerunner cell proliferation and left-right asymmetry in zebrafish. AB - Asymmetric fluid flows generated by motile cilia in a transient 'organ of asymmetry' are involved in establishing the left-right (LR) body axis during embryonic development. The vacuolar-type H(+)-ATPase (V-ATPase) proton pump has been identified as an early factor in the LR pathway that functions prior to cilia, but the role(s) for V-ATPase activity are not fully understood. In the zebrafish embryo, the V-ATPase accessory protein Atp6ap1b is maternally supplied and expressed in dorsal forerunner cells (DFCs) that give rise to the ciliated organ of asymmetry called Kupffer's vesicle (KV). V-ATPase accessory proteins modulate V-ATPase activity, but little is known about their functions in development. We investigated Atp6ap1b and V-ATPase in KV development using morpholinos, mutants and pharmacological inhibitors. Depletion of both maternal and zygotic atp6ap1b expression reduced KV organ size, altered cilia length and disrupted LR patterning of the embryo. Defects in other ciliated structures neuromasts and olfactory placodes-suggested a broad role for Atp6ap1b during development of ciliated organs. V-ATPase inhibitor treatments reduced KV size and identified a window of development in which V-ATPase activity is required for proper LR asymmetry. Interfering with Atp6ap1b or V-ATPase function reduced the rate of DFC proliferation, which resulted in fewer ciliated cells incorporating into the KV organ. Analyses of pH and subcellular V-ATPase localizations suggested Atp6ap1b functions to localize the V-ATPase to the plasma membrane where it regulates proton flux and cytoplasmic pH. These results uncover a new role for the V-ATPase accessory protein Atp6ap1b in early development to maintain the proliferation rate of precursor cells needed to construct a ciliated KV organ capable of generating LR asymmetry. PMID- 26254190 TI - Meta-Analysis of Oxaliplatin-Based Chemotherapy Combined With Traditional Medicines for Colorectal Cancer: Contributions of Specific Plants to Tumor Response. AB - This meta-analysis evaluates the clinical evidence for the addition of traditional medicines (TMs) to oxaliplatin-based regimens for colorectal cancer (CRC) in terms of tumor response rate (TRR). Eight electronic databases were searched for randomized controlled trials of oxaliplatin-based chemotherapy combined with TMs compared to the same oxaliplatin-based regimen. Data on TRR from 42 randomized controlled trials were analyzed using Review Manager 5.1. Studies were conducted in China or Japan. Publication bias was not evident. The meta-analyses suggest that the combination of the TMs with oxaliplatin-based regimens increased TRR in the palliative treatment of CRC (risk ratio [RR] 1.31 [1.20-1.42], I(2) = 0%). Benefits were evident for both injection products (RR 1.36 [1.18-1.57], I(2) = 0%) and orally administered TMs (RR 1.27 [1.15-1.41], I(2) = 0%). Further sensitivity analysis of specific plant-based TMs found that Paeonia, Curcuma, and Sophora produced consistently higher contributions to the RR results. Compounds in each of these TMs have shown growth-inhibitory effects in CRC cell-line studies. Specific combinations of TMs appeared to produce higher contributions to TRR than the TMs individually. Notable among these was the combination of Hedyotis, Astragalus, and Scutellaria. PMID- 26254192 TI - Results of closed subtalar dislocations. AB - BACKGROUND: The subtalar dislocation (SD) of the foot is an uncommon injury characterized by a simultaneous dislocation of talocalcaneal and talonavicular joints without involvement of the tibiotalar and calcaneocuboid joints. PURPOSES: The purpose of this study was to evaluate the clinical and radiological outcome in a consecutive series of close SD. METHODS: We retrospectively evaluated a case series of patients who presented a close SD. Thirteen patients were selected for this study. There were 9 patients with a medial SD, 3 patients with a lateral dislocation and 1 patient with a posterior subtalar dislocation. RESULTS: The most frequent symptoms observed in our study included transient mild pain, swelling and decreased ankle ROM, which did not restrict patients' daily activities. However, lower AOFAS scores were observed on patients with associate peritalar osseous injuries. CONCLUSION: The results of the present study suggest that detecting and treating any associate peritalar fractures are the keys to a successful long-term outcome. PMID- 26254191 TI - Impact of progesterone on stem/progenitor cells in the human breast. AB - The epithelium of the human breast is made up of a branching ductal-lobular system, which is lined by a single layer of luminal cells surrounded by a contractile basal cell layer. The co-ordinated development of stem/progenitor cells into these luminal and basal cells is fundamentally important for breast morphogenesis. The ovarian steroid hormone, progesterone, is critical in driving proliferation and normal breast development, yet progesterone analogues have also been shown to be a major driver of breast cancer risk. Studies in recent years have revealed an important role for progesterone in stimulating the mammary stem cell compartment in the mouse mammary gland, and growing evidence supports the notion that progesterone also stimulates progenitor cells in both the normal human breast and in breast cancer cells. As changes in cell type composition are one of the hallmark features of breast cancer progression, these observations have critical implications in discerning the mechanisms of how progesterone increases breast cancer risk. This review summarises recent work regarding the impact of progesterone action on the stem/progenitor cell compartment of the human breast. PMID- 26254193 TI - Non-invasive assessment of dairy products using spatially resolved diffuse reflectance spectroscopy. AB - The quality of a dairy product is largely determined by its microstructure which also affects its optical properties. Consequently, an assessment of the optical properties during production may be part of a feedback system for ensuring the quality of the production process. This paper presents a novel camera-based measurement technique that enables robust quantification of a wide range of reduced scattering coefficients and absorption coefficients. Measurements are based on hyperspectral images of diffuse reflectance in the wavelength range of 470 to 1020 nm. The optical properties of commercially available milk and yogurt products with three different levels of fat content are measured. These constitute a relevant range of products at a dairy plant. The measured reduced scattering properties of the samples are presented and show a clear discrimination between levels of fat contents as well as fermentation. The presented measurement technique and method of analysis is thus suitable for a rapid, non-contact, and non-invasive inspection that can deduce physically interpretable properties. PMID- 26254194 TI - Reliability of diagnosing incidental pulmonary embolism in cancer patients. AB - BACKGROUND: With the routine use of advanced multi-slice CT scanners, pulmonary embolism (PE) is increasingly detected as an incidental finding among cancer patients. Although this generally leads to therapeutic interventions, the accuracy of diagnosing PE on routinely performed contrast enhanced CT scans is unknown. METHODS: Consecutive cancer patients diagnosed with incidental PE were eligible for inclusion. Their CT images were reassessed in a blinded fashion by two thoracic radiologists. To ensure blindness, a total of 19 cancer staging CT images without PE were included. The inter-observer reliability for the presence of PE was calculated with use of Kappa statistics. RESULTS: A total of 62 incidental PE patients (mean age 64years, 60% male) were included. All patients received anticoagulant treatment upon diagnosis. Level of agreement between the two expert readers was high: they disagreed on the presence of PE in only two patients (3.2%), resulting in a Kappa statistic of 0.93. After final consensus reading, it was concluded that the CT images of all 62 patients initially diagnosed with incidental PE were indeed positive for PE. CONCLUSIONS: This study indicates that an incidental PE diagnosis is reliable and highly reproducible, despite the suboptimal reading conditions of a non-dedicated scan protocol. PMID- 26254195 TI - Warfarin persistence among stroke patients with atrial fibrillation. AB - INTRODUCTION: Warfarin treatment discontinuation is significant among patients with atrial fibrillation (AF). For AF patients with stroke a warfarin persistence rate of 0.45 after 2years has previously been reported. No consistent predictors for discontinuation have been established. AIMS: Evaluation of warfarin persistence and variables associated with discontinuation, in a large Swedish cohort with unselected stroke/TIA patients with AF treated with warfarin. MATERIALS AND METHODS: 4 583 patients with stroke/TIA and AF in the Swedish National Patient Register (NPR), from 1. Jan 2006 to 31. Dec 2011, were matched with the Swedish national quality register AuriculA. They were followed until treatment cessation, death or end of study. Baseline characteristics and CHA2DS2VASc score were retrieved from NPR. Treatment-time was retrieved from AuriculA. RESULTS: Overall proportion of warfarin persistence was 0.78 (95% confidence interval (CI) 0.76 to 0.80) after one year, 0.69 (95% CI 0.67 to 0.71) after 2years and 0.47 (95% CI 0.43 to 0.51) after 5years. Variables clearly associated with higher discontinuation were dementia (hazard ratio (HR) 2.22, CI 1.51-3.27) and alcohol abuse (HR 1.66, CI 1.19-2.33). Chronic obstructive pulmonary disease (COPD), cancer and chronic heart failure (CHF) were each associated with over 20% increased risk of treatment discontinuation. Higher CHA2DS2VASc score and start-age lead to lower persistence (p<0.001). CONCLUSIONS: Persistence to warfarin in unselected stroke/TIA patients with AF is in Sweden greater than previously reported. Lower persistence is found among patients with high treatment start-age, incidence of dementia, alcohol abuse, cancer, CHF, COPD and/or high CHA2DS2VASc score. PMID- 26254197 TI - Silk as a potential candidate for bone tissue engineering. AB - Regeneration of large bone defects is challenging in the next few years because the age of the population is growing. Bone grafting as a gold standard of bone repairing is limited as a result of many disadvantages. In recent years, many novel materials and processing methods have been introduced to construct the native bone extracellular matrix (ECM) and restore the functions of degenerated bone. Silk fibroin (SF) as a natural polymer, has established a good reputation for bone tissue engineering applications due to its many unique properties, including exceptional biocompatibility, biodegradability, mechanical behavior, and ease of processability. In this review, recent advances in the design and application of SF-based scaffolds for bone regeneration are discussed. PMID- 26254198 TI - Single-injection vaccines: Progress, challenges, and opportunities. AB - Currently, vaccination is the most efficient and cost-effective medical treatment for infectious diseases; however, each year 10 million infants remain underimmunized due to current vaccination schedules that require multiple doses to be administered across months or years. These dosing regimens are especially challenging in the developing world where limited healthcare access poses a major logistical barrier to immunization. Over the past four decades, researchers have attempted to overcome this issue by developing single-administration vaccines based on controlled-release antigen delivery systems. These systems can be administered once, but release antigen over an extended period of time to elicit both primary and secondary immune responses resulting in antigen-specific immunological memory. Unfortunately, unlike controlled release systems for drugs, single-administration vaccines have yet to be commercialized due to poor antigen stability and difficulty in obtaining unconventional release kinetics. This review discusses the current state of single-administration vaccination, challenges delaying the development of these vaccines, and potential strategies for overcoming these challenges. PMID- 26254199 TI - Relationship between penalties for road traffic infringements and crash risk in Queensland, Australia: a case-crossover study. AB - BACKGROUND: Most countries have detailed lists of traffic rules and elaborate legal regimes for penalizing drivers who break them. Previous research has suggested that drivers tend to drive more safely after receiving penalties for traffic infringements. METHODS: We linked driver-level data on infringements and crashes in Queensland, Australia (1995-2010) with information on the licence histories of all drivers in the state. We used a case-crossover design to examine drivers' risk of crashing in the month following an infringement penalty. We also examined whether changes in crash risk following infringement penalties varied according to driver age and gender, type of infringement and whether the offender was at fault in a subsequent crash. RESULTS: Drivers had higher risks of crashes following infringement penalties [odds ratio (OR) 1.32; 95% confidence interval (CI) 1.29-1.36], especially crashes in which the offender was at fault (1.41; 1.36-1.46). Crash risk relative to a comparable period was particularly high for teenage drivers (1.55; 1.34-1.78) and among drivers penalized for dangerous driving (3.19; 2.52-4.03) or driving under the influence of alcohol (1.99; 1.67 2.37). The risk remained relatively high for more than 6 months after the penalty, but declined steadily over this period. CONCLUSIONS: Crash risk among drivers in Queensland was higher, not lower, following receipt of penalties for traffic infringements. Penalties themselves are unlikely to increase crash risk. A more likely explanation is that penalties (or the corresponding infringements) mark episodes of risky driving. Our findings suggest that such episodes trounce any deterrent effect penalties may produce. PMID- 26254196 TI - The effect of consuming Palmaria palmata-enriched bread on inflammatory markers, antioxidant status, lipid profile and thyroid function in a randomised placebo controlled intervention trial in healthy adults. AB - PURPOSE: Palmaria palmata (P. Palmata) is reported to contain anti-inflammatory and antioxidant compounds albeit no study has investigated these effects in humans. METHODS: A randomised parallel placebo-controlled human intervention study was carried out to investigate the effect of consuming P. Palmata (5 g/day) incorporated into a bread on serum markers of inflammation [C-reactive protein (CRP); cytokine analysis] with secondary analysis investigating changes in lipids (cholesterol, triglycerides), thyroid function [thyroid-stimulating hormone (TSH)] and antioxidant status ferric reducing antioxidant power. ANCOVA with baseline values as covariates, controlling for age, BMI, sex and smoking status, was used to compare differences between treatment groups over time . In vitro studies investigated the inflammatory activity of P. Palmata extracts (hot water, cold water and ethanol extract), protein extracts and associated protein hydrolysates using a Caco-2 inflammation cell model. RESULTS: Consumption of P. Palmata-enriched bread significantly increased serum CRP (+16.1 %, P = 0.011), triglycerides (+31.9 %, P = 0.001) and TSH (+17.2 %, P = 0.017) when compared to the control group. In vitro evaluation of P. palmata extracts and protein hydrolysates identified a significant induction of IL-8 secretion by Caco-2 cells, and the hot water P. palmata extract was shown to increase adipocyte glycerol release (P < 0.05). CONCLUSION: Evidence from this human study suggests that P. palmata stimulates inflammation, increases serum triglycerides and alters thyroid function; however, these changes are not likely to impact health as changes remained within the normal clinical range. The data from the in vitro study provided indications that IL-8 may contribute to the apparent immunostimulation noted in the human study. PMID- 26254200 TI - A novel mutation in SLURP1 in patients with mal de Meleda from the Indian subcontinent. PMID- 26254201 TI - Can We Predict Sustained Virologic Response to Interferon alpha Therapy in Patients With Chronic Hepatitis Delta Virus Infection? PMID- 26254202 TI - A Rock and a Hard Place: Successful Combined Endoscopic and Surgical Treatment of Bouveret's Syndrome. PMID- 26254203 TI - Aspergillus in endodontic infection near the maxillary sinus. AB - INTRODUCTION: Diseases of the maxillary sinus have been associated with dental roots near the maxillary sinus that have undergone endodontic treatment. OBJECTIVE: To investigate the presence of filamentous fungi in patients with dental roots near the maxillary sinus who had apical periodontitis treated endodontically, and to alert practitioners that this could be a possible avenue of contamination of the sinus in patients who develop maxillary sinus infection. METHODS: Cross-sectional study in 60 palatal roots of the first maxillary molars near the maxillary sinus, that underwent endodontic treatment for apical periodontitis. After removal of the filling material, dentin shavings were collected and placed in test tubes containing Sabouraud dextrose agar and chloramphenicol. The phenotype was determined by macroscopic and microscopic examination of the colonies. For polymerase chain reaction, the primers ITS-5 and ITS-4 were used. The sequences obtained were compared with those deposited at GenBank using the Basic Local Alignment Search Tool program. RESULTS: Filamentous fungi were isolated from 6 of 60 canals (10%): Aspergillus niger (6.7%), Aspergillus versicolor (1.6%), and Aspergillus fumigatus (1.6%). CONCLUSION: Root canals near the maxillary sinus with endodontic treatment and apical periodontitis may exhibit positive cultures for filamentous fungi. Interested professionals should be alert, because these microorganisms have pathogenic characteristics that can cause disease of odontogenic origin in the maxillary sinus. PMID- 26254204 TI - Synthesis of biodiesel from pongamia oil using heterogeneous ion-exchange resin catalyst. AB - Biodiesel is a clean-burning renewable substitute fuel for petroleum. Biodiesel could be effectively produced by transesterification reaction of triglycerides of vegetable oils with short-chain alcohols in the presence of homogeneous or heterogeneous catalysts. Conventionally, biodiesel manufacturing processes employ strong acids or bases as catalysts. But, separation of the catalyst and the by product glycerol from the product ester is too expensive to justify the product use as an automobile fuel. Hence heterogeneous catalysts are preferred. In this study, transesterification of pongamia oil with ethanol was performed using a solid ion-exchange resin catalyst. It is a macro porous strongly basic anion exchange resin. The process parameters affecting the ethyl ester yield were investigated. The reaction conditions were optimized for the maximum yield of fatty acid ethyl ester (FAEE) of pongamia oil. The properties of FAEE were compared with accepted standards of biodiesel. Engine performance was also studied with pongamia oil diesel blend and engine emission characteristics were observed. PMID- 26254205 TI - Ecotoxicological risk assessment of trace metals in humid subtropical soil. AB - In this work, several physicochemical properties of sub-tropical soil (up to 20 cm depth) like water holding capacity, organic carbon content, cation exchange capacity, texture, pH, and electrical conductivity were determined along with the trace metals, Co, Cr, Cu, Mn, Ni, Pb and Zn, in order to evaluate inter-relations among the trace metals and the soil properties. The contribution of the trace metals to ecotoxicological risk was assessed using various tools. Cr, Cu, Mn and Zn contents were found to be lower than the world average, but Co, Ni, and Pb had higher contents. The trace metal concentrations were utilized to obtain the pollution index and the potential ecotoxicological aspects. The trace metals were shown to have come from similar origin and their retention in the soil was contributed by properties like organic carbon, cation exchange capacity, clay content and water holding capacity of the soil. The pollution index showed that the trace metals had the sequence of Pb (considerably polluted) > Co, Ni (moderately polluted) > Cr, Cu, Mn and Zn (unpolluted). The composite ecological risk index was the highest in agricultural land with irrigation and fertilizer use, and was the lowest in the forest land. PMID- 26254206 TI - [Rectal malignant neoplasm in a teenager patient]. PMID- 26254207 TI - Prostaglandin vaginal gel induction of labor comparing amniotomy with repeat prostaglandin gel. AB - OBJECTIVE: The purpose of this study was to compare 2 inductions of labor protocols. STUDY DESIGN: Women with live singleton pregnancies at >=37 + 0 weeks gestation who were booked for prostaglandins 2 (PGE2) vaginal gel induction with a modified Bishop's score of <7 were eligible for inclusion. After an evening dose of PGE2 vaginal gel, women were assigned randomly the next morning into the amniotomy or repeat-PGE2 group. The amniotomy group underwent artificial rupture of membranes (ARM), regardless of modified Bishop's score, and received further PGE2 doses only if ARM was not technically possible. The repeat-PGE2 group received further PGE2 (to a maximum of 3 doses) until a modified Bishop's score >=7 occurred, when an ARM was performed. In both groups, Syntocinon was commenced once membranes were ruptured. The primary outcome measure was time from commencement of induction until birth. RESULTS: Two hundred forty-five women were assigned randomly into either the amniotomy (n = 121) or repeat-PGE2 group (n = 124). The time for induction of labor-to-birth was >5 hours shorter in the amniotomy group (24.8 vs 30.0 hours; mean difference, 5.2 h; 95% confidence interval, -2.5 to -7.8). Fewer women in the amniotomy group remained undelivered after 24 hours (47.1% vs 67.7%; P < .01). However, the likelihood of an in-hours birth and the length of hospital stay were no different between the groups. There was no difference in the mode of birth or any of the secondary outcomes. CONCLUSION: After an initial dose of PGE2 vaginal gel, an amniotomy (once technically possible) is associated with a shorter induction of labor-to-birth time compared with the use of repeat doses of PGE2. Administering more PGE2 with the aim of starting contractions or making the cervix "more favorable," appears to have no clinical advantage. PMID- 26254208 TI - Quantifying radionuclide signatures from a gamma-gamma coincidence system. AB - A method for quantifying gamma coincidence signatures has been developed, and tested in conjunction with a high-efficiency multi-detector system to quickly identify trace amounts of radioactive material. The gamma-gamma system utilises fully digital electronics and list-mode acquisition to time-stamp each event, allowing coincidence matrices to be easily produced alongside typical 'singles' spectra. To quantify the coincidence signatures a software package has been developed to calculate efficiency and cascade summing corrected branching ratios. This utilises ENSDF records as an input, and can be fully automated, allowing the user to quickly and easily create/update a coincidence library that contains all possible gamma and conversion electron cascades, associated cascade emission probabilities, and true-coincidence summing corrected gamma cascade detection probabilities. It is also fully searchable by energy, nuclide, coincidence pair, gamma multiplicity, cascade probability and half-life of the cascade. The probabilities calculated were tested using measurements performed on the gamma gamma system, and found to provide accurate results for the nuclides investigated. Given the flexibility of the method, (it only relies on evaluated nuclear data, and accurate efficiency characterisations), the software can now be utilised for a variety of systems, quickly and easily calculating coincidence signature probabilities. PMID- 26254209 TI - Global deposition and transport efficiencies of radioactive species with respect to modelling credibility after Fukushima (Japan, 2011). AB - In this study we conduct a detailed comparison of the modelling response of the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident with global and local observations. We use five different model versions characterized by different horizontal and vertical resolutions of the same General Circulation Model (GCM). Transport efficiencies of (137)Cs across the world are presented as an indication of the expected radioactive impact. Activity concentrations were well represented showing lower Normalized Mean Biases (NMBs) when the better resolved versions of the GCM were used. About 95% of the results using the zoom configuration over Europe (zEur) remained within a factor of 10 from the observations. Close to Japan, the model reproduced well (137)Cs concentrations using the zoom version over Asia (zAsia) showing high correlations, while more than 64% of the modelling results were found within a factor of two from the observations and more than 92% within a factor of 10. Labile and refractory rare radionuclides calculated indirectly showed larger deviations, with about 60% of the simulated concentrations within a factor of 10 from the observations. We estimate that around 23% of the released (137)Cs remained into Japan, while 76% deposited in the oceans. Around 163 TBq deposited over North America, among which 95 TBq over USA, 40 TBq over Canada and 5 TBq over Greenland). About 14 TBq deposited over Europe (mostly in the European part of Russia, Sweden and Norway) and 47 TBq over Asia (mostly in the Asian part of Russia, Philippines and South Korea), while traces were observed over Africa, Oceania and Antarctica. Since the radioactive plume followed a northward direction before its arrival to USA and then to Europe, a significant amount of about 69 TBq deposited in the Arctic, as well. These patterns of deposition are fully consistent with the most recent reports for the accident. PMID- 26254210 TI - Imeglimin: A Potential New Multi-Target Drug for Type 2 Diabetes. AB - Imeglimin is a novel agent currently in development to treat type 2 diabetes. Laboratory studies have demonstrated that it has the potential to impact the three main pathophysiologic components of type 2 diabetes: impaired glucose uptake by muscle tissue, excess hepatic gluconeogenesis, and increased beta-cell apoptosis. Preliminary human studies that have been published within the last 2 years demonstrate that imeglimin improves hemoglobin A1c and fasting plasma glucose similarly when compared with metformin and with sitagliptin. There has also been a low incidence of adverse effects, especially hypoglycemia, reported in these early human studies. Currently, imeglimin is lacking long-term evidence to demonstrate any effects on its cardiovascular safety, and data on morbidity and mortality, though some studies are currently in progress. There is great potential for imeglimin, if FDA approved, to play a significant role in the type 2 diabetes management algorithm. PMID- 26254212 TI - More signs of neurotoxicity of surfactants and flame retardants - Neonatal PFOS and PBDE 99 cause transcriptional alterations in cholinergic genes in the mouse CNS. AB - Maternally and lactionally transferred persistent organic pollutants may interfere with CNS development. Here, 10-day-old male mice were exposed to single oral doses of PFOS (perflourooctanosulphonate) or PBDE 99 (2,2',4,4',5-penta bromodiphenyl ether), and examined for changes in cholinergic gene transcription in the CNS 24h and 7 weeks later. 24h after exposure qPCR analyses revealed decreased transcription of nAChR-beta2 and AChE in cortex, and increased mAChR-5 in hippocampus of PFOS treated mice. Neonatal PFOS treatment altered spontaneous behaviour at 2 months of age but did not affect gene transcription in adults. At 2 months of age neonatally PBDE 99 treated mice had altered spontaneous behaviour, and cortical transcription of AChE, nAChR-alpha4, nAChR-beta2 and mAChR-5 were elevated. Our results indicate that PFOS and PBDE 99 affects the developing central cholinergic system by altering gene transcription in cortex and hippocampus, which may in part account for mechanisms causing changes in spontaneous behaviour. PMID- 26254211 TI - Comparison of body mass index with waist circumference and skinfold-based percent body fat in firefighters: adiposity classification and associations with cardiovascular disease risk factors. AB - PURPOSE: This study aims to examine whether body mass index (BMI) overestimates the prevalence of overweight or obese firefighters when compared to waist circumference (WC) and skinfold-based percent body fat (PBF) and to investigate differential relationships of the three adiposity measures with other biological cardiovascular disease (CVD) risk factors. METHODS: The adiposity of 355 (347 males and eight females) California firefighters was assessed using three different measures. Other CVD risk factors (high blood pressure, high lipid profiles, high glucose, and low VO2 max) of the firefighters were also clinically assessed. RESULTS: The prevalence of total overweight and obesity was significantly (p < 0.01) higher by BMI (80.4 %) than by WC (48.7 %) and by PBF (55.6 %) in male firefighters. In particular, the prevalence of overweight firefighters was much higher (p < 0.01) by BMI (57.3 %) than by WC (24.5 %) and PBF (38.3 %). 60-64 % of male firefighters who were assessed as normal weight by WC and PBF were misclassified as overweight by BMI. When overweight by BMI was defined as 27.5-29.9 kg/m(2) (vs. the standard definition of 25.0-29.9 kg/m(2)), the agreement of the adiposity classification increased between BMI and other two adiposity measures. Obese firefighters had the highest CVD risk profiles across all three adiposity measures. Only when overweight by BMI was defined narrowly, overweight firefighters had substantially higher CVD risk profiles. Obesity and overweight were less prevalent in female and Asian male firefighters. CONCLUSIONS: BMI overestimated the prevalence of total overweight and obesity among male firefighters, compared to WC and skinfold-based PBF. Overweight by BMI needs to be more narrowly defined, or the prevalence of BMI-based overweight (27.5-29.9 kg/m(2)) should be reported additionally for prevention of CVD among male firefighters. PMID- 26254213 TI - Molecular dynamics study of the effect of active site protonation on Helicobacter pylori 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase. AB - The protein 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is involved in the quorum sensing of several bacterial species, including Helicobacter pylori. In particular, these bacteria depend on MTAN for synthesis of vitamin K2 homologs. The residue D198 in the active site of MTAN seems to be of crucial importance, by acting as a hydrogen-bond acceptor for the ligand. In this study, we investigated the conformation and dynamics of apo and holo H. pylori MTAN (HpMTAN), and assessed the effect of protonation of D198 by use of molecular dynamics simulations. Our results show that protonation of the active site of HpMTAN can cause a conformational transition from a closed state to an open state even in the absence of substrate, via inter-chain mechanical coupling. PMID- 26254214 TI - iLM-2L: A two-level predictor for identifying protein lysine methylation sites and their methylation degrees by incorporating K-gap amino acid pairs into Chou's general PseAAC. AB - As one of the most critical post-translational modifications, lysine methylation plays a key role in regulating various protein functions. In order to understand the molecular mechanism of lysine methylation, it is important to identify lysine methylation sites and their methylation degrees accurately. As the traditional experimental methods are time-consuming and labor-intensive, several computational methods have been developed for the identification of methylation sites. However, the prediction accuracy of existing computational methods is still unsatisfactory. Moreover, they are only focused on predicting whether a query lysine residue is a methylation site, without considering its methylation degrees. In this paper, a novel two-level predictor named iLM-2L is proposed to predict lysine methylation sites and their methylation degrees using composition of k-spaced amino acid pairs feature coding scheme and support vector machine algorithm. The 1st level is to identify whether a query lysine residue is a methylation site, and the 2nd level is to identify which methylation degree(s) the query lysine residue belongs to if it has been predicted as a methyllysine site in the 1st level identification. The iLM-2L achieves a promising performance with a Sensitivity of 76.46%, a Specificity of 91.90%, an Accuracy of 85.31% and a Matthew's correlation coefficient of 69.94% for the 1st level as well as a Precision of 84.81%, an accuracy of 79.35%, a recall of 80.83%, an Absolute_Ture of 73.89% and a Hamming_loss of 15.63% for the 2nd level in jackknife test. As illustrated by independent test, the performance of iLM-2L outperforms other existing lysine methylation site predictors significantly. A matlab software package for iLM-2L can be freely downloaded from https://github.com/juzhe1120/Matlab_Software/blob/master/iLM 2L_Matlab_Software.rar. PMID- 26254215 TI - Maximum sustainable yields from a spatially-explicit harvest model. AB - Spatial heterogeneity plays an important role in complex ecosystem dynamics, and therefore is also an important consideration in sustainable resource management. However, little is known about how spatial effects can influence management targets derived from a non-spatial harvest model. Here, we extended the Schaefer model, a conventional non-spatial harvest model that is widely used in resource management, to a spatially-explicit harvest model by integrating environmental heterogeneities, as well as species exchange between patches. By comparing the maximum sustainable yields (MSY), one of the central management targets in resource management, obtained from the spatially extended model with that of the conventional model, we examined the effect of spatial heterogeneity. When spatial heterogeneity exists, we found that the Schaefer model tends to overestimate the MSY, implying potential for causing overharvesting. In addition, by assuming a well-mixed population in the heterogeneous environment, we showed analytically that the Schaefer model always overestimate the MSY, regardless of the number of patches existing. The degree of overestimation becomes significant when spatial heterogeneity is marked. Collectively, these results highlight the importance of integrating the spatial structure to conduct sustainable resource management. PMID- 26254216 TI - New parameters for a better evaluation of vegetative bioremediation, leaching, and phytodesalination. AB - Vegetative bioremediation of calcareous sodic and saline-sodic soils is a biological approach for soil desalination by plants. It is based on three main processes: (i) sodium release from cation exchange sites, (ii) its leaching, and/or (iii) phytodesalination (Na(+) uptake by plant roots and its accumulation in shoots). Leaching needs sufficient rainfall and/or adequate irrigation. Thus, under non-leaching conditions, phytodesalination is the only existing process in terms of sodium removal. Several works tried to evaluate these processes; used plants were grown in field, in lysimeters, or in non-perforated pots. The evaluation of vegetative bioremediation, leaching, and phytodesalination was mainly based on plant analyses (including biomass production, sodium accumulation, test culture, and co-culture) and soil analyses (porosity, salinity, sodicity...). Nevertheless, used parameters are not enough to ensure comparisons between results found in different investigations. The present study introduces new parameters like phytodesalination efficiency, yield, and rate as well as vegetative bioremediation and leaching yields and rates. Our study is also illustrated by an estimation of all parameters for several previously published data from our own works and those of other authors. Obtained results showed usefulness of these parameters and some of them can be extended to heavy metal phytoexraction. PMID- 26254217 TI - A mathematical model for lymphangiogenesis in normal and diabetic wounds. AB - Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis) very few have been proposed for the regeneration of the lymphatic network. Moreover, lymphangiogenesis is markedly distinct from angiogenesis, occurring at different times and in a different manner. Here a model of five ordinary differential equations is presented to describe the formation of lymphatic capillaries following a skin wound. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from experimental and clinical data. The system is then solved numerically and the results are compared with the available biological literature. Finally, a parameter sensitivity analysis of the model is taken as a starting point for suggesting new therapeutic approaches targeting the enhancement of lymphangiogenesis in diabetic wounds. The work provides a deeper understanding of the phenomenon in question, clarifying the main factors involved. In particular, the balance between TGF-beta and VEGF levels, rather than their absolute values, is identified as crucial to effective lymphangiogenesis. In addition, the results indicate lowering the macrophage-mediated activation of TGF-beta and increasing the basal lymphatic endothelial cell growth rate, inter alia, as potential treatments. It is hoped the findings of this paper may be considered in the development of future experiments investigating novel lymphangiogenic therapies. PMID- 26254218 TI - How do children weigh competence and benevolence when deciding whom to trust? AB - In three experiments, we investigate how 187 3- to 5-year-olds weigh competence and benevolence when deciding whom to trust. Children were presented with two informants who provided conflicting labels for novel objects--one informant was competent, but mean, the other incompetent, but nice. Across experiments, we manipulated the order in which competence and benevolence were presented and the way in which they were described (via trait labels or descriptions of prior behavior). When competence was described via prior behavior (Experiments 1-2), children endorsed the informants' labels equally. In contrast, when competence was described via trait labels (Experiment 3), children endorsed labels provided by the competent, mean informant. When considering children's endorsement at the individual level, we found their ability to evaluate competence, not benevolence, related to their endorsements. These findings emphasize the importance of considering how children process information about informants and use this information to determine whom to trust. PMID- 26254220 TI - A Reverse-Paradigm Creed for the 21st Century: Why Many Scientists Still Have the Cart Before the Horse. PMID- 26254219 TI - Longitudinal associations between social anxiety symptoms and cannabis use throughout adolescence: the role of peer involvement. AB - There appear to be contradicting theories and empirical findings on the association between adolescent Social Anxiety Disorder (SAD) symptoms and cannabis use, suggesting potential risk as well as protective pathways. The aim of this six-year longitudinal study was to further examine associations between SAD symptoms and cannabis use over time in adolescents from the general population, specifically focusing on the potential role that adolescents' involvement with their peers may have in these associations. Participants were 497 Dutch adolescents (57 % boys; M age = 13.03 at T1), who completed annual self report questionnaires for 6 successive years. Cross-lagged panel analysis suggested that adolescent SAD symptoms were associated with less peer involvement 1 year later. Less adolescent peer involvement was in turn associated with lower probabilities of cannabis use as well as lower frequency of cannabis use 1 year later. Most importantly, results suggested significant longitudinal indirect paths from adolescent SAD symptoms to cannabis use via adolescents' peer involvement. Overall, these results provide support for a protective function of SAD symptoms in association with cannabis use in adolescents from the general population. This association is partially explained by less peer involvement (suggesting increased social isolation) for those adolescents with higher levels of SAD symptoms. Future research should aim to gain more insight into the exact nature of the relationship between anxiety and cannabis use in adolescents from the general population, especially regarding potential risk and protective processes that may explain this relationship. PMID- 26254221 TI - Acupuncture to Treat the Symptoms of Patients in a Palliative Care Setting. AB - INTRODUCTION: Patients enrolled in hospice and palliative care programs experience a vast array of symptoms requiring the expertise of a multidisciplinary team to address. Acupuncture can be an effective addition to a hospice team whose goal is maximum comfort and quality of life (QOL). The objective of this project was to examine the effectiveness of acupuncture to relieve symptoms commonly observed in patients in a hospice program. METHODS: All over 26 patients participated in the acupuncture trial, receiving a course of weekly treatments that ranged from 1 to 14 weeks. The average number of treatments was five. The Edmonton Symptom Assessment Scale (ESAS) was used to assess the severity of pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and dyspnea. A two-tailed, paired t test was applied to the data to compare symptom scores pre- versus post-acupuncture treatment. SETTINGS/PARTICIPANTS: Patients enrolled in All Care Hospice's home care program were given the option to receive acupuncture to supplement usual care offered by the hospice team. Treatment was provided by licensed acupuncturists in the patient's place of residence. RESULTS: Seven out of nine symptoms were significantly (P < .001) improved with acupuncture, the exceptions being drowsiness and appetite. Although the ESAS scale demonstrated a reduction in symptom severity post-treatment for both drowsiness and appetite, this reduction was not found to be significant. CONCLUSION: Acupuncture was found to be effective for the reduction and relief of symptoms that commonly affect patient QOL. Acupuncture effectively reduced symptoms of pain, tiredness, nausea, depression, anxiety, and shortness of breath, and enhanced feelings of well being. More research is required to assess the long-term benefits and symptom reduction of acupuncture in a palliative care setting. PMID- 26254222 TI - The Impact of a Mandatory Immersion Curriculum in Integrative Medicine for Graduating Medical Students. AB - BACKGROUND: Although many Americans utilize complementary and alternative medicine (CAM) services and products, few medical school curricula consistently provide instruction in counseling patients on the use of CAM or strategies for identifying credible evidence on the safety and effectiveness of CAM therapies. METHODS: This is a mixed methods study. A sustainable, mandatory, half-day CAM immersion curriculum for graduating medical students is described. Student comfort talking with patients about CAM, their willingness to refer patients to a CAM provider, and adequacy of the CAM curriculum was assessed. RESULTS: Students who participated in this mandatory curriculum, rated the medical school curriculum in CAM as more adequate than students at other medical schools without a mandatory curriculum. Students' narrative comments indicate the curriculum impacts students knowledge about CAM, patient use of CAM, and personal practice with CAM in the future. CONCLUSIONS: The timing of the CAM curriculum near to graduation, students' personal exploration of several CAM modalities through immersion, and student interaction with community CAM providers are aspects of the curriculum that make the curriculum successful and memorable. PMID- 26254223 TI - Curcumin inhibits angiogenesis and improves defective hematopoiesis induced by tumor-derived VEGF in tumor model through modulating VEGF-VEGFR2 signaling pathway. AB - Curcumin, a natural polyphenol compound from the perennial herb Curcuma longa, has been proved to be beneficial for tumor-bearing animals through inhibiting tumor neovasculature formation, but the underlying mechanisms are unclear. Here, we aim to test whether curcumin affects VEGF-VEGFR2 signaling pathway and attenuates defective hematopoiesis induced by VEGF in tumor model. We demonstrated that curcumin inhibited proliferation, migration of HUVEC under VEGF stimulation and caused HUVEC apoptosis, and blocked VEGFR2 activation and its downstream signaling pathways in vitro. Furthermore, in VEGF over-expressing tumor model, curcumin significantly inhibited the tumor growth accelerated by VEGF in a dose-dependent manner and improved anemia and extramedullary hematopoiesis in livers and spleens of tumor-bearing mice induced by tumor derived VEGF. Immunohistochemical analysis showed that curcumin normalized vasculature structures of livers and reduced tumor microvessel density. ELISA revealed that curcumin suppressed VEGF secretion from tumor cells both in vitro and in vivo. Survival analysis showed that curcumin significantly improved survival ability of VEGF tumor-bearing mice. Taken together, these findings establish curcumin as a modulator of VEGF and VEGF-VEGFR2 signaling pathway, with potential implication for improving the quality of life of cancer patients. PMID- 26254224 TI - COP1 enhances ubiquitin-mediated degradation of p27Kip1 to promote cancer cell growth. AB - p27 is a critical CDK inhibitor involved in cell cycle regulation, and its stability is critical for cell proliferation. Constitutive photomorphogenic 1 (COP1) is a RING-containing E3 ubiquitin ligase involved in regulating important target proteins for cell growth, but its biological activity in cell cycle progression is not well characterized. Here, we report that p27Kip1 levels are accumulated in G1 phase, with concurrent reduction of COP1 levels. Mechanistic studies show that COP1 directly interacts with p27 through a VP motif on p27 and functions as an E3 ligase of p27 to accelerate the ubiquitin-mediated degradation of p27. Also, COP1-p27 axis deregulation is involved in tumorigenesis. These findings define a new mechanism for posttranslational regulation of p27 and provide insight into the characteristics of COP1-overexpressing cancers. PMID- 26254225 TI - The HGF inhibitory peptide HGP-1 displays promising in vitro and in vivo efficacy for targeted cancer therapy. AB - HGF/MET pathway mediates cancer initiation and development. Thus, inhibition on HGF-initiated MET signaling pathway would provide a new approach to cancer targeted therapeutics. In our study, we identified a targeting peptide candidate binding to HGF which was named HGF binding peptide-1 (HGP-1) via bacterial surface display methods coupled with fluorescence-activated cell sorting (FACS). HGP-1 showed the moderate affinity when determined with surface plasmon resonance (SPR) technique and high specificity in binding to HGF while assessed by fluorescence-based ELISA assay. The results from MTT and in vitro migration assay indicated that HGF-dependent cell proliferation and migration could be inhibited by HGP-1. In vivo administration of HGP-1 led to an effective inhibitory effect on tumor growth in A549 tumor xenograft models. Moreover, findings from Western Blots revealed that HGP-1 could down-regulated the phosphorylation levels of MET and ERK1/2 initiated by HGF, which suggested that HGP-1 could disrupt the activation of HGF/MET signaling to influence the cell activity. All the data highlighted the potential of HGP-1 to be a potent inhibitor for HGF/MET signaling. PMID- 26254227 TI - 18F-FPRGD2 PET/CT imaging of musculoskeletal disorders. AB - OBJECTIVE: This work reports on musculoskeletal uptake of 18F-FPRGD2, targeting the integrin alphavbeta3, in patients who had undergone 18F-FPRGD2 positron emission tomography combined with computed tomography (PET/CT) for oncologic purposes. METHODS: Whole-body 18F-FPRGD2 PET/CT images of 62 cancer patients were retrospectively reviewed to detect foci of musculoskeletal 18F-FPRGD2 uptake. For 37 patients, a FDG PET/CT performed in clinical settings was available. In each joint with an abnormal uptake, the maximum standardized uptake value (SUVmax) was estimated. RESULTS: A total of 260 musculoskeletal foci of 18F-FPRGD2 uptake were detected. Most common sites of uptake were joints and discs (n = 160; 61.5%), entheses (osteotendinous and osteoligamentous junctions; n = 55; 21.2%) and recent fractures (n = 18; 6.9%). In addition, 27 (10.4%) miscellaneous foci were detected. Out of the 146 lesions for which a FDG PET was available, 63% showed both 18F-FPRGD2 and FDG uptake, 33.6% did not show FDG avidity and 3.4% showed only FDG uptake. The uptake intensity of the 92 lesions positive with 18F-FPRGD2 and FDG was similar with both radiopharmaceuticals, but the target-to-background (blood pool or muscle) ratios were significantly higher with 18F-FPRGD2 than with FDG (p < 0.0001). CONCLUSION: The 18F-FPRGD2 uptake in joints, spine degenerative diseases and tendons was highly prevalent in our population. Up to one-third of 18F-FPRGD2 foci showed no FDG uptake suggesting that 18F-FPRGD2 signal may not be related to inflammatory angiogenesis only. PMID- 26254226 TI - Oxidized low-density lipoprotein is a common risk factor for cardiovascular diseases and gastroenterological cancers via epigenomical regulation of microRNA 210. AB - Hyperlipidemia, including the oxidized low-density lipoprotein (oxLDL) accumulation, is a risk and highly associated with the development of cancers and cardiovascular diseases. microRNA-210 (miR-210), a hypoxia-responsive microRNA regulated by HIF-1alpha, has been implicated in cancer and cardiovascular disease formation. Furthermore, Bioinformatics analysis revealed that the promoter of the miR-210 gene contains CpG-rich regions. It is unclear whether miR-210 expression could be epigenetically regulated in these disease progresses. The study aimed to explore the relationships between lipid and miR-210 in the context of cardiovascular disease and gastrointestinal cancer. We demonstrated oxLDL can decrease methylation in the miR-210 promoter to up-regulate miR-210. HIF-1alpha can bind to miR-210 promoter, but this HIF-1alpha binding site can be blocked by methylation. We showed that subjects of carotid atherosclerosis, stroke patients and cancer patients had hypomethylation in the miR-210 promoter, especially the HIF-1alpha binding site. Furthermore, miR-210 can directly inhibit sprouty related EVH1 domain 2 (SPRED2) expressions, and SPRED2 reduces cell migration via ERK/c-Fos/MMPs pathways. Increased miR-210 and reduced SPRED2 levels were found in aorta of mice under high-fat diet and tumor tissues, which implied that miR 210 can be an underlying mechanism to explain oxLDL as a common risk factor for cardiovascular disease and gastrointestinal cancer. PMID- 26254228 TI - Clinical significance of dual-time-point 18F-FDG PET imaging in resectable non small cell lung cancer. AB - OBJECTIVE: The maximal standardized uptake value (SUVmax) of pulmonary lesions on dual-time-point (DTP) fluorodeoxyglucose positron emission tomography (FDG-PET) has been shown to be useful for differentiation between malignant and non malignant pulmonary lesions, and also to be of value for intrathoracic nodal staging of non-small cell lung cancer (NSCLC). However, a few NSCLC lesions have been found to show decreased FDG uptake on delayed images, and the significance of this finding remains unknown. PATIENTS AND METHODS: We conducted a retrospective review of the data of 284 patients with NSCLC who underwent DTP FDG PET before surgery. Cases of adenocarcinoma in situ and minimally invasive adenocarcinoma were excluded, because these lesions show little FDG uptake. Each patient was scanned at 60 min (early acquisition; SUV-E) and 115 min (delayed acquisition; SUV-D) after the radiopharmaceutical injection. The intratumoral retention index (RI) of 18F-FDG was measured for each examination by the DTP method. Recurrence-free survival (RFS) was determined by the Kaplan-Meier method and compared in relation to the SUV-E, SUV-D, and RI by univariate and multivariate analysis using models including the clinico-pathological prognostic factors. RESULTS: Of the 284 cases, the RI <= 0 was in 49 cases (17.3%). This group of patients showed lower values of SUV-E and SUV-D, a smaller tumor size, and a lower rate of lymphatic invasion or vascular invasion. It was particularly noteworthy that lymph node metastasis was not histopathologically confirmed in any of these patients. Univariate analysis identified the RI, SUV-E and SUV-D, besides age, tumor size, lymph node metastasis, and tumor differentiation grade as predictors of the RFS. On the other hand, multivariate analysis identified the RI and lymph node metastasis, but not the SUV-E and SUV-D, as independent predictors of the RFS. CONCLUSIONS: This study demonstrated that DTP FDG-PET of the primary tumor in NSCLC can be useful to predict the RFS of the patients. In addition, this method may also be useful to predict the presence/absence of intrathoracic lymph node metastasis in these patients. PMID- 26254230 TI - TMEM16, LRRC8A, bestrophin: chloride channels controlled by Ca(2+) and cell volume. AB - For many years Cl(-) transport by ion channels that are controlled by intracellular Ca(2+) or by cell volume remained enigmatic because their molecular identity was unknown. Recent years, however, have shown remarkable progress, and these channels have been identified as TMEM16A (anoctamin 1), LRRC8A (swell 1), and bestrophin 1 (BEST1), and structural information is already available for the Ca(2+)-activated channels bestrophin and TMEM16. While the structure of bestrophin revealed it is an anion-permeable pore, only indirect evidence exists that TMEM16 and LRRC8 form anion channels. This review summarizes the most recent information on the structure, function, and physiological relevance of these anion channel proteins, and highlights their overlapping functions and physiological roles. PMID- 26254229 TI - Ready, pause, go: regulation of RNA polymerase II pausing and release by cellular signaling pathways. AB - Promoter-proximal pausing by RNA polymerase II (Pol II) is a well-established mechanism to control the timing, rate, and possibly the magnitude of transcriptional responses. Recent studies have shown that cellular signaling pathways can regulate gene transcription and signaling outcomes by controlling Pol II pausing in a wide array of biological systems. Identification of the proteins and small molecules that affect the establishment and release of paused Pol II is shedding new light on the mechanisms and biology of Pol II pausing. This review focuses on the interplay between cellular signaling pathways and Pol II pausing during normal development and under disease conditions. PMID- 26254232 TI - Microglia in Alzheimer's disease: A multifaceted relationship. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting elderly people worldwide, which is mainly characterized by cerebral amyloid-beta (Abeta) plaque deposition and neurofibrillary tangle formation. The interest in microglia arose from the overwhelming experimental evidence that outlined a key role of neuroinflammation in AD pathology. Microglia constitute the powerhouse of the innate immune system in the brain. It is now widely accepted that microglia are myeloid-derived cells that infiltrate the developing brain at the early embryonic stages, and acquire a highly ramified phenotype postnatally. Microglia use these dynamic ramifications as sentinels to sense and detect any occurring alteration in brain homeostasis. Once a danger signal is detected, microglia get activated by acquiring a less ramified phenotype, and mount adequate responses that range from phagocyting cell debris to secreting inflammatory and trophic factors. Earlier reports have demonstrated, unequivocally, that microglia surround Abeta plaques and internalize Abeta microaggregates. However, the implication of these observations in AD pathology, and consequently treatment, is still a matter of debate. Nonetheless, targeting the activity of these cells constituted a convergent point in this debate. Unfortunately, the conflicting experimental findings obtained following the modulation of microglial activity in AD, further fueled the debate. This review aims at providing an overview regarding what we know about the implication of microglia in AD pathology, and treatment. The emerging role of monocytes is also discussed. PMID- 26254231 TI - Disruptions of sensorimotor gating, cytokines, glycemia, monoamines, and genes in both sexes of rats reared in social isolation can be ameliorated by oral chronic quetiapine administration. AB - The pathogenesis of schizophrenia in patients with metabolic abnormalities remains unclear. Our previous study demonstrated that isolation rearing (IR) induced longitudinal concomitant changes of pro-inflammatory cytokine (pro-CK) levels and metabolic abnormalities with a developmental origin. However, the general consensus, believes that these abnormalities are caused by antipsychotic treatment in schizophrenic patients. The IR paradigm presents with face, construct, and predictive validity for schizophrenia. Therefore, we employed IR rats of both sexes to examine whether chronic quetiapine (QTP, a second generation antipsychotic medication) treatment induces disruptions of metabolism (body weight, blood pressure, and the glycemic and lipid profiles) or cytokines [interleukin (IL)-1 beta, IL-6, IL-10, interferon-gamma, and tumor necrosis factor (TNF)-alpha], and further, whether it reverses deficits of behaviors [locomotor activity and prepulse inhibition (PPI)] and the expression of monoamines (dopamine and serotonin) and related genes (Htr1a, Htr2a, Htr3a, Drd1a, and Gabbr2). IR induced higher levels of pro-CK, dysglycemia, blood pressure, locomotor activity, and impaired PPI, simultaneously destabilizing cortico-striatal monoamines and relevant genes in both sexes, while QTP demonstrated dose-dependent reversal of these changes, suggesting that QTP might reduce the pro-CKs to regulate these abnormalities. Our data implied that antipsychotics may not be the solitary factor causing metabolic problems in schizophrenia and suggested that inflammatory changes may play a vital role in the developmental pathophysiology of schizophrenia and related metabolic abnormalities. PMID- 26254233 TI - The impact of mitochondrial aldehyde dehydrogenase (ALDH2) activation by Alda-1 on the behavioral and biochemical disturbances in animal model of depression. AB - The etiology of depression remains still unclear. Recently, it has been proposed, that mitochondrial dysfunction may be associated with development of mood disorders, such as depression, bipolar disorder and anxiety disorders. Mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme responsible for the detoxification of reactive aldehydes, is considered to exert protective function in mitochondria. We investigated the influence of Alda-1, a small-molecule activator of ALDH2, on depressive- and anxiety-like behaviors in an animal model of depression - the prenatally stressed rats - using behavioral, molecular and proteomic methods. Prolonged Alda-1 administration significantly increased the climbing time, tended to reduce the immobility time and increased the swimming time of the prenatally stressed rats in the forced swim test. Moreover, treatment of prenatally stressed rats with Alda-1 significantly increased number of entries into the open arms of the maze and the time spent therein, as assessed by elevated plus-maze test. Such actions were associated with reduction of plasma 4 HNE-protein content, decrease of TNF-alpha mRNA and increase of PGC-1alpha (regulator of mitochondrial biogenesis) mRNA level in the frontal cortex and hippocampus of the prenatally stressed rats as well as with normalization of peripheral immune parameters and significant changes in expression of 6 and 4 proteins related to mitochondrial functions in the frontal cortex and hippocampus, respectively. Collectively, ALDH2 activation by Alda-1 led to a significant attenuation of depressive- and anxiety-like behaviors in the prenatally stressed rats. The pattern of changes suggested mitoprotective effect of Alda-1, however the exact functional consequences of the revealed alterations require further investigation. PMID- 26254234 TI - NADPH oxidase 2-derived reactive oxygen species in the hippocampus might contribute to microglial activation in postoperative cognitive dysfunction in aged mice. AB - Microglial activation plays a key role in the development of postoperative cognitive dysfunction (POCD). Nox2, one of the main isoforms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the central nervous system, is a predominant source of reactive oxygen species (ROS) overproduction in phagocytes including microglia. We therefore hypothesized that Nox2-induced microglial activation is involved in the development of POCD. Sixteen-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to mimic the clinical human abdominal surgery. Behavioral tests were performed at 6 and 7 d post-surgery with open field and fear conditioning tests, respectively. The levels of Nox2, 8-hydroxy-2'-deoxyguanosine (8-OH-dG, a marker of DNA oxidation), CD11b (a marker of microglial activation), interleukin-1beta (IL 1beta), and brain-derived neurotrophic factor (BDNF) were determined in the hippocampus and prefrontal cortex at 1 d and 7 d post-surgery, respectively. For the interventional study, mice were treated with a NADPH oxidase inhibitor apocynin (APO). Our results showed that exploratory laparotomy with isoflurane anesthesia impaired the contextual fear memory, increased expression of Nox2, 8 OH-dG, CD11b, and IL-1beta, and down-regulated BDNF expression in the hippocampus at 7 d post-surgery. The surgery-induced microglial activation and neuroinflammation persisted to 7 d after surgery in the hippocampus, but only at 1 d in the prefrontal cortex. Notably, administration with APO could rescue these surgery-induced cognitive impairments and associated brain pathology. Together, our data suggested that Nox2-derived ROS in hippocampal microglia, at least in part, contributes to subsequent neuroinflammation and cognitive impairments induced by surgery in aged mice. PMID- 26254236 TI - Aerobic exercise training and low-level laser therapy modulate inflammatory response and degenerative process in an experimental model of knee osteoarthritis in rats. AB - OBJECTIVE: The aim of this study was to evaluate the effects of an aerobic exercise training and low-level laser therapy (LLLT) (associated or not) on degenerative modifications and inflammatory mediators on the articular cartilage using an experimental model of knee OA. MATERIAL AND METHODS: Fifty male Wistar rats were randomly divided into five groups: control group (CG); knee OA control group (OAC); OA plus exercise training group (OAT); OA plus LLLT group (OAL); OA plus exercise training associated with LLLT group (OATL). The exercise training (treadmill; 16 m/min; 50 min/day) and the laser irradiation (two points-medial and lateral side of the left joint; 24 sessions) started 4 weeks after the surgery, 3 days/week for 8 weeks. RESULTS: The results showed that all treated groups showed (irradiated or not) a better pattern of tissue organization, with less fibrillation and irregularities along the articular surface and chondrocytes organization, a lower degenerative process measured by OARSI score and higher thickness values. Additionally, all treated group showed a reduced expression in IL-1beta, caspase-3 and MMP-13 compared to OAC. Moreover, a lower caspase-3 expression was observed in OATL compared to OAL and OAT. CONCLUSION: These results suggest that exercise training and LLLT were effective in preventing cartilage degeneration and modulating inflammatory process induced by knee OA. PMID- 26254235 TI - The danger-associated molecular pattern HMGB1 mediates the neuroinflammatory effects of methamphetamine. AB - Methamphetamine (METH) induces neuroinflammatory effects, which may contribute to the neurotoxicity of METH. However, the mechanism by which METH induces neuroinflammation has yet to be clarified. A considerable body of evidence suggests that METH induces cellular damage and distress, particularly in dopaminergic neurons. Damaged neurons release danger-associated molecular patterns (DAMPs) such as high mobility group box-1 (HMGB1), which induces pro inflammatory effects. Therefore, we explored the notion here that METH induces neuroinflammation indirectly through the release of HMGB1 from damaged neurons. Adult male Sprague-Dawley rats were injected IP with METH (10mg/kg) or vehicle (0.9% saline). Neuroinflammatory effects of METH were measured in nucleus accumbens (NAcc), ventral tegmental area (VTA) and prefrontal cortex (PFC) at 2h, 4h and 6h after injection. To assess whether METH directly induces pro inflammatory effects in microglia, whole brain or striatal microglia were isolated using a Percoll density gradient and exposed to METH (0, 0.1, 1, 10, 100, or 1000MUM) for 24h and pro-inflammatory cytokines measured. The effect of METH on HMGB1 and IL-1beta in striatal tissue was then measured. To determine the role of HMGB1 in the neuroinflammatory effects of METH, animals were injected intra-cisterna magna with the HMGB1 antagonist box A (10MUg) or vehicle (sterile water). 24h post-injection, animals were injected IP with METH (10mg/kg) or vehicle (0.9% saline) and 4h later neuroinflammatory effects measured in NAcc, VTA, and PFC. METH induced robust pro-inflammatory effects in NAcc, VTA, and PFC as a function of time and pro-inflammatory analyte measured. In particular, METH induced profound effects on IL-1beta in NAcc (2h) and PFC (2h and 4h). Exposure of microglia to METH in vitro failed to induce a pro-inflammatory response, but rather induced significant cell death as well as a decrease in IL-1beta. METH treatment increased HMGB1 in parallel with IL-1beta in striatum. Pre-treatment with the HMGB1 antagonist box A blocked the neuroinflammatory effects (IL-1beta) of METH in NAcc, VTA and PFC. The present results suggest that HMGB1 mediates, in part, the neuroinflammatory effects of METH and thus may alert CNS innate immune cells to the toxic effects of METH. PMID- 26254237 TI - Effectiveness of exercise therapy added to general practitioner care in patients with hip osteoarthritis: a pragmatic randomized controlled trial. AB - OBJECTIVE: To assess the effectiveness of exercise therapy added to general practitioner (GP) care compared with GP care alone, in patients with hip osteoarthritis (OA) during 12 months follow-up. METHODS: We performed a multi center parallel pragmatic randomized controlled trial in 120 general practices in the Netherlands. 203 patients, aged >=45 years, with a new episode of hip complaints, complying with the ACR criteria for hip OA were randomized to the intervention group (n = 101; GP care with additional exercise therapy) or the control group (n = 102; GP care only). GP care was given by patient's own GP. The intervention group received, in addition, a maximum of 12 exercise therapy sessions in the first 3 months and hereafter three booster sessions. Blinding was not possible. Primary outcomes were hip pain and hip-related function measured with the HOOS questionnaire (score 0-100). RESULTS: The overall estimates on hip pain and function during the 12-month follow-up showed no between-group difference (intention-to-treat). At 3-months follow-up there was a statistically significant between-group difference for HOOS pain -3.7 (95% CI: -7.3; -0.2), effect size -0.23 and HOOS function -5.3 (95% CI: -8.9; -1.6), effect size -0.31. No adverse events were reported. CONCLUSIONS: No differences were found during 12 months follow-up on pain and function. At 3-months follow-up, pain and function scores differed in favor of patients allocated to the additional exercise therapy compared with GP care alone. TRIAL REGISTRATION: The Netherlands Trial Registry NTR1462. PMID- 26254238 TI - Impact of patient decision aids on appropriate and timely access to hip or knee arthroplasty for osteoarthritis: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of patient decision aids (PtDA) compared to usual education on appropriate and timely access to total joint arthroplasty in patients with osteoarthritis. METHOD: A randomized controlled trial (RCT) with patients undergoing orthopedic screening. Control and intervention arms received usual education; intervention arm also received a PtDA and a surgeon preference report. Wait times (primary outcome) were described using stratified Kaplan-Meier survival curves with patients censored at the time of death or loss to follow-up, and multivariable Cox proportional hazards regression. Secondary outcomes were compared using stratified Cochran-Mantel-Haenszel chi-squared tests. RESULTS: 343 patients were randomized to intervention (n = 174) or control (n = 169). The typical patient was 66 years old, retired, living with someone, and 51% had high school education or less. The intervention was associated with a trend towards reduction in wait time (hazard ratio (HR) 1.25, 95% confidence interval (CI) 0.99 1.60, P = 0.0653). Median wait times were 3 weeks shorter in intervention than in control at the community site with no difference at the academic site. Good decision quality was reached by 56.1% intervention and 44.5% control (Relative risk (RR) 1.25; 95% CI 1.00-1.56, P = 0.050). Surgery rates were 73.2% intervention and 80.5% controls (RR 0.91: 95% CI 0.81-1.03) with 12 intervention (7.3%) and eight control participants (4.9%) returning to have surgery within 2 years (P = 0.791). CONCLUSION: Compared to controls, decision aid recipients had shorter wait times at one site, fewer surgeries, and were more likely to reach good decision quality, but overall effect was not statistically significant. TRIALS REGISTRATION: The full trial protocol is available at ClinicalTrials.Gov (NCT00911638). PMID- 26254239 TI - The modulatory effect of CA1 GABAb receptors on ketamine-induced spatial and non spatial novelty detection deficits with respect to Ca(2+). AB - Glutamate and gamma-aminobutyric acid (GABA) are among the most abundant neurotransmitters in the central nervous system. Ketamine and other noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists are known to induce deficits in learning and the performance of cognitive tasks. The present study was designed to assess the effects of dorsal hippocampal (CA1) GABAb receptors on ketamine-induced spatial and non-spatial memory deficits with regard to the role of Ca(2+) as a defining factor. Spatial and non-spatial novelty detection of male NMRI mice were investigated in a circular open-field apparatus. According to our results, the intraperitoneal injection of ketamine at its higher dose (0.1 mg/kg) impaired both spatial and non-spatial novelty detection. Moreover, the intra-CA1 injection of baclofen (a GABAb receptor agonist) at higher doses (0.02 and 0.2 MUg/mouse) impaired the spatial but not non-spatial novelty detection. In addition, phaclofen (a GABAb receptor antagonist at 0.2 MUg/mouse) impaired both spatial and non-spatial novelty detection. Baclofen restored and induced a modulatory effect on ketamine-induced responses in the spatial and non-spatial novelty detection task, respectively. On the contrary, phaclofen restored and induced a modulatory effect on ketamine-induced responses in the non-spatial and spatial novelty detection task, respectively. Finally, the subthreshold dose of SKF96365 (a Ca(2+) channel blocker) impaired only the spatial but not non-spatial restoration effects of baclofen or phaclofen following a higher dose of ketamine. Such findings suggest that the ketamine induced impairment of memory consolidation may occur through GABAb receptors of the CA1 neurons. Moreover, baclofen and phaclofen were shown to possibly exert their effects on the ketamine-induced spatial novelty detection deficits through Ca(2+) channels. PMID- 26254241 TI - Protective effects of low molecular weight chondroitin sulfate on amyloid beta (Abeta)-induced damage in vitro and in vivo. AB - In the present study, we investigated the effects of low molecular weight chondroitin sulfate (LMWCS) on amyloid beta (Abeta)-induced neurotoxicity in vitro and in vivo. The in vitro results showed that LMWCS blocked Abeta25-35 induced cell viability loss and apoptosis, decreased intracellular calcium concentration, reactive oxygen species (ROS) levels, the mitochondrial membrane potential (MMP) depolarization, and the protein expression of Caspase-3. During in vivo experiments, LMWCS improved the cognitive impairment induced by Abeta1 40, increased the level of choline acetyltransferase (ChAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and decreased the level of malondialdehyde (MDA) and acetylcholinesterase (AChE) in the mouse brain. Moreover, LMWCS decreased the density of pyramidal cells of CA1 regions, and suppressed the protein expression of Bax/Bcl-2 and Caspase-3, -9 in the hippocampus of mice. In conclusion, LMWCS possessed neuroprotective properties against toxic effects induced by Abeta peptides both in vitro and in vivo, which might be related to anti-apoptotic activity. LMWCS might be a useful preventive and therapeutic compound for Alzheimer's disease. PMID- 26254242 TI - Developmental alterations in noxious-evoked EEG activity recorded from rat primary somatosensory cortex. AB - Primary somatosensory cortex (S1) contains a nociceptive map that localizes potential tissue damage on the body and encodes stimulus intensity. An objective and specific biomarker of pain however is currently lacking and is urgently required for use in non-verbal clinical populations as well as in the validation of pre-clinical pain models. Here we describe studies to see if the responses of the S1 in juvenile rats are different to those in the adult. We recorded electroencephalogram (EEG) responses from S1 of lightly-anesthetized Sprague Dawley rats at either postnatal day 21 or postnatal day 40 during the presentation of noxious (55 degrees C) or innocuous (30 degrees C) thermal stimuli applied to the plantar surface of the left hindpaw. The total EEG power across the recording period was the same in both ages after stimulation but the frequency distribution was significantly affected by age. Noxious heat evoked a significant increase in theta band (4-8 Hz) activity in adults only (P<0.0001 compared to baseline; P<0.0001 compared to juveniles). There were no significant differences in EEG responses to innocuous thermal stimuli. These data show that there are significant alterations in the processing of nociceptive inputs within the maturing cortex and that cortical theta activity is involved only in the adult cortical response to noxious stimulation. PMID- 26254240 TI - Organotypic brain slice cultures: A review. AB - In vitro cell cultures are an important tool for obtaining insights into cellular processes in an isolated system and a supplement to in vivo animal experiments. While primary dissociated cultures permit a single homogeneous cell population to be studied, there is a clear need to explore the function of brain cells in a three-dimensional system where the main architecture of the cells is preserved. Thus, organotypic brain slice cultures have proven to be very useful in investigating cellular and molecular processes of the brain in vitro. This review summarizes (1) the historical development of organotypic brain slices focusing on the membrane technology, (2) methodological aspects regarding culturing procedures, age of donors or media, (3) whether the cholinergic neurons serve as a model of neurodegeneration in Alzheimer's disease, (4) or the nigrostriatal dopaminergic neurons as a model of Parkinson's disease and (5) how the vascular network can be studied, especially with regard to a synthetic blood-brain barrier. This review will also highlight some limits of the model and give an outlook on future applications. PMID- 26254243 TI - Alterations in CA1 pyramidal neuronal intrinsic excitability mediated by Ih channel currents in a rat model of amyloid beta pathology. AB - Amyloid beta (Abeta) accumulation plays an important role in the pathogenesis of Alzheimer's disease (AD) by changing the neuronal excitability. However, the cellular mechanisms by which accumulation of Abeta affects intrinsic neuronal properties are not well understood. The effect of bilateral intra-frontal cortex Abeta (1-42) peptide injection on the intrinsic excitability of hippocampal CA1 pyramidal neurons with particular focus on the contribution of hyperpolarization activated (Ih) channel currents was examined using whole-cell patch-clamp recording. Passive avoidance memory impairment and morphological changes in rats receiving intra-frontal Abeta treatment were observed, which was associated with significant changes both in passive and active intrinsic electrical membrane properties of CA1 pyramidal neurons. Electrophysiological recording showed a significant decrease in neuronal excitability associated with an augmentation in the first spike after-hyperpolarization (AHP) amplitude. In addition, the depolarizing sag voltage was altered in neurons recorded from Abeta-treated group. In voltage-clamp condition, a hyperpolarizing activated inward current sensitive to ZD7288 and capsaicin was significantly increased in neurons from Abeta-treated rats. The Ih current density was increased and the activation curve was shifted toward less negative potential in the Abeta-treated group as compared to control group. The enhancing effect of Abeta treatment on Ih current was confirmed by showing upregulation of the mRNA of HCN1 channel in the CA1 pyramidal layer of hippocampi. These findings suggest the contribution of Ih and possibly TRPV1 channel currents to the changes induced by Abeta treatment in the intrinsic membrane properties, which, in turn, may provide therapeutic targets for treatment of AD. PMID- 26254244 TI - Preoperative Aspirin Therapy Reduces Early Mortality in Patients Undergoing Cardiac Surgery. PMID- 26254245 TI - Using Social Media While Waiting in Pain: A Clinical 12-Week Longitudinal Pilot Study. AB - BACKGROUND: Chronic pain places an enormous burden on health care systems. Multidisciplinary pain management services are well documented as an effective means to improve patient outcomes. However, waiting lists to access these services are long and outcomes deteriorate. Innovative solutions such as social media are gaining attention as a way to decrease this burden and improve outcomes. It is a challenge to design research that demonstrates whether social media are acceptable to patients and clinically effective. OBJECTIVE: The aim was to conduct a longitudinal pilot study to understand what aspects of research design are key to the success of running a larger-scale study of social media use in the clinical management of chronic pain. METHODS: A 12-week study examined social media use by patients on the waiting list for the Royal Melbourne Hospital Pain Management Service. Selected social media resources were suggested for use by patients waiting for an appointment at the clinic. Patients filled out measures for pain interference and pain self-efficacy before and after the study. Follow-up was conducted at monthly intervals via telephone semistructured interviews to discuss engagement and garner individual perceptions towards social media use. A social media-use instrument was also administered as part of the after-study questionnaire. RESULTS: Targeted recruitment refined 235 patient referrals to 138 (58.7%) suitable potential participants. Contact was made with 84 out of 138 (60.9%) patients. After a further exclusion of 54 out of 84 (64%) patients for various reasons, this left 30 out of 84 (36%) patients fitting the inclusion criteria and interested in study participation. A final study cohort of 17 out of 30 (57%) was obtained. Demographics of the 17 patients were mixed. Low back pain was the primary condition reported as leading to chronic pain. Semistructured interviews collected data from 16 out of 17 (94%) patients who started the trial, and at final follow-up 9 out of 17 (53%) patients completed questionnaires. Low specificity of the resources to one's condition and time poorness may have been barriers to engagement. CONCLUSIONS: Results suggest that with refinements, this study design can be implemented successfully when conducting a larger social media study. At present, comment cannot be made on what effect using social media can have on patients on hospital waiting lists, nor whether those who use social media while waiting in pain achieve better outcomes from eventual participation in a chronic pain program. Long-term follow up should be included in future studies to answer this. Future research should focus on multicenter randomized controlled trials, involving patients in the intervention design for improved participation and outcomes and for evidence to be sound. PMID- 26254246 TI - Inhibitory effect of brazilein on tyrosinase and melanin synthesis: Kinetics and in silico approach. AB - In our present study, the inhibitory effect of brazilein from Caesalpinia sappan on tyrosinase activity was investigated through multi-spectroscopic and molecular docking techniques. The result has shown that brazilein reversibly inhibited tyrosinase in a mixed type manner. The interaction of brazilein with the amino acid residues of tyrosinase has been validated through fluorescence quenching studies. Copper interaction studies suggested that brazilein could bind with copper ions of the enzyme. Circular dichroism analysis confirmed that brazilein induced secondary structural changes in tyrosinase. Docking studies further authenticate that brazilein forms hydrophobic and hydrogen bonding with the active site residues of tyrosinase. Moreover, in vitro studies confirmed that the inhibitory mechanism of cellular tyrosinase and melanin synthesis by brazilein in B16F0 melanoma cells. These results suggested that brazilein act as a potential tyrosinase inhibitor and it would contribute as a of novel tyrosinase inhibitor in food, cosmetic and pharmaceutical industry. PMID- 26254247 TI - Northern pike (Esox lucius) collagen: Extraction, characterization and potential application. AB - Acid soluble collagen (ASC) and pepsin soluble collagen (PSC) from the scales of northern pike (Esox lucius) were extracted and characterized. It was the first time that this species was used as sources of collagen. FT-IR and amino acid analysis results revealed the presence of collagen. Glycine accounts for one third of its amino acid residues and specific for collagen amino acid - hydroxyproline - is present in isolated protein. The content of imino acid: proline and hydroxyproline in ASC and PSC was similar (12.5% Pro and 6.5% Hyp). Both ASC and PSC were type I collagen. The denaturation temperature of ASC and PSC were 28.5 and 27 degrees C, respectively. Thin collagen films were obtained by casting of collagen solution onto glass plates. The surface properties of ASC and PSC films were different - the surface of ASC collagen film was more polar and less rough than PSC and we can observe the formation of collagen fibrils after solvent evaporation. ASC films showed much higher tensile properties than PSC. The obtained results suggest that northern pike scales have potential as an alternative source of collagen for use in various fields. PMID- 26254248 TI - Urinary liver-type fatty acid-binding protein change in gestational diabetes mellitus. AB - We compared urinary liver-type fatty acid-binding protein (L-FABP) among non pregnant and pregnant women with and without gestational diabetes mellitus (GDM). Higher urinary L-FABP was found in pregnant with and without GDM, and considerably higher urinary L-FABP was found in the GDM group compared with the non-GDM group. Hyperglycemia and anemia were related with high urinary L-FABP expression. PMID- 26254249 TI - Application of dopaminergic antagonist: Metoclopramide, in reproduction of crucian carp Carassius carassius (L.) under controlled conditions. AB - The effectiveness of Ovopel (two pellets/kg body weight), a complex of [D-Ala(6) Pro(9)NEt-mGnRH] and dopamine antagonist (DA e.g. Metoclopramide, MET), was compared with the application MET alone at the dose of 20mg/kg body weight in spawning crucian carp Carassius carassius (L.) in the present study. Ovulation and spermation rates were greater after MET application (90% and 100%, respectively) in comparison to the Ovopel (80% and 87.5%, respectively) when used as a broodstock reproductive stimulation agent. Sperm quality (CASA parameters) after MET treatment was very acceptable without a significant decrease in comparison to the samples from Ovopel-treated crucian carp when spermation stimulation treatments were employed. Though there were no differences in egg and sperm production between Ovopel and MET treatments, hatching rates were significantly greater after MET (84.4%) compared with Ovopel (76.2%) treatment. The usefulness of MET application without GnRHa addition for stimulation of reproduction was ascertained in the present study for the first time in crucian carp. PMID- 26254250 TI - A Study on the Optimal Positions of ECG Electrodes in a Garment for the Design of ECG-Monitoring Clothing for Male. AB - Smart clothing is a sort of wearable device used for ubiquitous health monitoring. It provides comfort and efficiency in vital sign measurements and has been studied and developed in various types of monitoring platforms such as T shirt and sports bra. However, despite these previous approaches, smart clothing for electrocardiography (ECG) monitoring has encountered a serious shortcoming relevant to motion artifacts caused by wearer movement. In effect, motion artifacts are one of the major problems in practical implementation of most wearable health-monitoring devices. In the ECG measurements collected by a garment, motion artifacts are usually caused by improper location of the electrode, leading to lack of contact between the electrode and skin with body motion. The aim of this study was to suggest a design for ECG-monitoring clothing contributing to reduction of motion artifacts. Based on the clothing science theory, it was assumed in this study that the stability of the electrode in a dynamic state differed depending on the electrode location in an ECG-monitoring garment. Founded on this assumption, effects of 56 electrode positions were determined by sectioning the surface of the garment into grids with 6 cm intervals in the front and back of the bodice. In order to determine the optimal locations of the ECG electrodes from the 56 positions, ECG measurements were collected from 10 participants at every electrode position in the garment while the wearer was in motion. The electrode locations indicating both an ECG measurement rate higher than 80.0 % and a large amplitude during motion were selected as the optimal electrode locations. The results of this analysis show four electrode locations with consistently higher ECG measurement rates and larger amplitudes amongst the 56 locations. These four locations were abstracted to be least affected by wearer movement in this research. Based on this result, a design of the garment-formed ECG monitoring platform reflecting the optimal positions of the electrode was suggested. PMID- 26254251 TI - Computer Applications in Health Science Education. AB - In recent years, computer application development has experienced exponential growth, not only in the number of publications but also in the scope or contexts that have benefited from its use. In health science training, and medicine specifically, the gradual incorporation of technological developments has transformed the teaching and learning process, resulting in true "educational technology". The goal of this paper is to review the main features involved in these applications and highlight the main lines of research for the future. The results of peer reviewed literature published recently indicate the following features shared by the key technological developments in the field of health science education: first, development of simulation and visualization systems for a more complete and realistic representation of learning material over traditional paper format; second, portability and versatility of the applications, adapted for an increasing number of devices and operative systems; third, increasing focus on open source applications such as Massive Open Online Course (MOOC). PMID- 26254252 TI - Automatic Metadata Generation Through Analysis of Narration Within Instructional Videos. AB - Current activity recognition based assistive living solutions have adopted relatively rigid models of inhabitant activities. These solutions have some deficiencies associated with the use of these models. To address this, a goal oriented solution has been proposed. In a goal-oriented solution, goal models offer a method of flexibly modelling inhabitant activity. The flexibility of these goal models can dynamically produce a large number of varying action plans that may be used to guide inhabitants. In order to provide illustrative, video based, instruction for these numerous actions plans, a number of video clips would need to be associated with each variation. To address this, rich metadata may be used to automatically match appropriate video clips from a video repository to each specific, dynamically generated, activity plan. This study introduces a mechanism of automatically generating suitable rich metadata representing actions depicted within video clips to facilitate such video matching. This performance of this mechanism was evaluated using eighteen video files; during this evaluation metadata was automatically generated with a high level of accuracy. PMID- 26254253 TI - NFC as a Childhood Obesity Treatment Tool. AB - Childhood Obesity is associated with a wide range of serious health complications and constitutes an increased risk of premature syndromes, including diabetes or heart diseases. Its treatment seems to be complicated. So, in order to help parents we have developed a system that will try to make easier the process of choosing foodstuff for overweight and obese children at the supermarket. To interact with the system, Near Field Communication mobile phones and tags are used. Those tags would have nutritional information such as energy or fat contain of each product. When the interaction takes place, the system will generate an alert determining if the product is adequate for the user diet or not. Decision will be influenced by specific prescript diets, which would have been previously generated by the system based on user profile parameters. At the same time the diet is established, the shopping list would be generated automatically. Therefore, the user could download and print both things at home easily by the PC application. The system also takes into account physical activity of the user. Children mobile phone includes an accelerometer that will detect and collect user activities in order to modify calorical requirements and, if necessary, to change physical activity too. In the future, it would be possible to extend this project system for adults, managing diets not just for obese and overweight, but also to diabetic or celiac people. PMID- 26254254 TI - Analytic Hierarchy Process to Define the Most Important Factors and Related Technologies for Empowering Elderly People in Taking an Active Role in their Health. AB - Successful management of health conditions in older population is determined by strategic involvement of a professional team of careers and by empowering patients and their caregivers to take over a central role and responsibility in the daily management of condition. Identifying, structuring and ranking the most important needs related to these aspects could pave the way for improved strategies in designing systems and technological solutions supporting user empowerment. This paper presents the preliminary results of a study aiming to elicit these needs. Healthcare professionals, working together in the European and Innovation Partnership on Active and Healthy Ageing (EIP-AHA) initiative, have defined a set of needs and factors that have been organized in two hierarchies around the concepts of patient activation and proactive and prepared care team, defined in the Chronic Care Model. The two hierarchies have been mapped, by a team of experts in computer science, with technologies and solutions that could facilitate the achievement of the identified needs. PMID- 26254255 TI - Effects of repetitive transcranial magnetic stimulation on arm function and decreasing unilateral spatial neglect in subacute stroke: a randomized controlled trial. AB - OBJECTIVE: The objective of this study is to investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on the functional recovery of stroke patients with unilateral neglect. DESIGN: Randomized controlled experimental study. SETTING: Outpatient rehabilitation hospital. SUBJECTS: Thirty patients with stroke were randomly assigned to two groups: an rTMS group (experimental) and a control group. INTERVENTIONS: Stroke patients in the experimental group underwent comprehensive rehabilitation therapy and rTMS. Stroke patients in the control group underwent sham therapy and comprehensive rehabilitation therapy. Participants in both groups received therapy 5 days per week for 4 weeks. MAIN MEASURES: Line bisection, Albert, Box and block and Grip strength tests were assessed before and after the four-week therapy period. RESULTS: A significant difference in the post-training gains in Line bisection (16.53 SD 9.78 vs. 3.60 SD 5.02), Albert (14.13 SD 4.92 vs. 3.26 SD 2.01), Box and block (15.06 SD 9.68 vs. 6.93 SD 7.52), and Grip strength tests (3.60 SD 2.66 vs 0.80 SD 1.26) was observed between the experimental group and the control group (P<0.05). In addition, the effect size for gains in the experimental and control groups was very strong in AT, BBT (effect size=2.15, 0.77 respectively). CONCLUSION: We conclude that rTMS might be effective in improvement in reduction of the unilateral neglect and motor function. PMID- 26254256 TI - Assessment of blood donation intention among medical students in Pakistan--An application of theory of planned behavior. AB - OBJECTIVE: Theory of Planned Behavior proposes a model which can measure how human actions are guided. It has been successfully utilized in the context of blood donation. We employed a decision-making framework to determine the intention of blood donation among medical students who have never donated blood before the study. METHODS: Survey responses were collected from 391 medical students from four various universities on a defined questionnaire. The tool composed of 20 questions that were formulated to explain donation intention based on theory of planned behavior. The construct included questions related to attitude, subjective norm and perceived behavior control, descriptive norm, moral norm, anticipated regret, donation anxiety and religious norm. Pearson's correlational relationships were measured between independent and dependent variables of intention to donate blood. ANOVA was applied to observe the model fit; a value of 0.000 was considered statistically significant. A multiple regression analysis was conducted to explore the relative importance of the main independent variables in the prediction of intention. Multi-collinearity was also evaluated to determine that various independent variables determine the intention. The reliability of measures composed of two items was assessed using inter-item correlations. RESULTS: Three hundred and ninety-one medical students (M:F; 1:2.2) with mean age of 21.96 years +/- 1.95 participated in this study. Mean item score was 3.8 +/- 0.83. Multiple regression analysis suggested that perceived behavioral control, anticipated regret and attitude were the most influential factors in determining intention of blood donation. Donation anxiety was least correlated and in fact bore a negative correlation with intention. ANOVA computed an F value of 199.082 with a p-value of 0.000 indicating fitness of model. The value of R square and adjusted R square was 0.811 and 0.807 respectively indicating strong correlation between various independent and dependent variables. CONCLUSIONS: Medical students as novice blood donors showed a positive attitude toward blood donation. Theory of planned behavior can be successfully utilized in determining the antecedents toward blood donation behavior. PMID- 26254257 TI - Development of a label-free immunosensor system for detecting plasma cortisol levels in fish. AB - Fishes display a wide variation in their physiological responses to stress, which is clearly evident in the plasma corticosteroid changes, chiefly cortisol levels in fish. In the present study, we describe a novel label-free immunosensor for detecting plasma cortisol levels. The method is based on immunologic reactions and amperometric measurement using cyclic voltammetry. For the immobilization of the antibody on the surface of sensing electrode, we used a self-assembled monolayer of thiol-containing compounds. Using this electrode, we detect the CV signal change caused by the generation of antigen-antibody complex. The immunosensor showed a response to cortisol levels, and the anodic peak value linearly decreased with a correlation coefficient of 0.990 in diluted plasma. The specificity of the label-free immunosensor system was investigated using other steroid hormones, such as 17alpha, 20beta-dihydroxy-4-pregnen-3-one, progesterone, estriol, estradiol, and testosterone. The specific detection of cortisol was suggested by a minimal change from -0.32 to 0.51 MUA in the anodic peak value of the other steroid hormones. The sensor system was used to determine the plasma cortisol levels in Nile tilapia (Oreochromis niloticus), and the results were compared with those of the same samples determined using the conventional method (ELISA). A good correlation was obtained between values determined using both methods (correlation coefficient 0.993). These findings suggest that the proposed label-free immunosensor could be useful for rapid and convenient analysis of cortisol levels in fish plasma samples. PMID- 26254258 TI - Root and leaf traits reflect distinct resource acquisition strategies in tropical lianas and trees. AB - In Neotropical forests, lianas are increasing in abundance relative to trees. This increased species richness may reflect a positive response to global change factors including increased temperature, atmospheric CO2, habitat fragmentation, and drought severity; however, questions remain as to the specific mechanisms facilitating the response. Previous work suggests that lianas may gain an ecological advantage over trees through leaf functional traits that offer a quick return on investment of resources, although it is unknown whether this pattern extends to root traits and relationships with fungal or bacterial symbionts belowground. We sampled confamilial pairs of liana and tree species and quantified morphological and chemical traits of leaves and fine roots, as well as root symbiont abundance, to determine whether functional traits associated with resource acquisition differed between the two. Compared to trees, lianas possessed higher specific leaf area, specific root length, root branching intensity, and root nitrogen (N) and phosphorus (P) concentrations, and lower leaf and root tissue density, leaf and root carbon (C), root diameter, root C:P and N:P, and mycorrhizal colonization. Our study provides new evidence that liana leaf and root traits are characterized by a rapid resource acquisition strategy relative to trees. These liana functional traits may facilitate their response to global change, raising questions about how increased liana dominance might affect ecosystem processes of Neotropical forests. PMID- 26254259 TI - Pulse-drought atop press-drought: unexpected plant responses and implications for dryland ecosystems. AB - In drylands, climate change is predicted to cause chronic reductions in water availability (press-droughts) through reduced precipitation and increased temperatures as well as increase the frequency and intensity of short-term extreme droughts (pulse-droughts). These changes in precipitation patterns may have profound ecosystem effects, depending on the sensitivities of the dominant plant functional types (PFTs). Here we present the responses of four Colorado Plateau PFTs to an experimentally imposed, 4-year, press-drought during which a natural pulse-drought occurred. Our objectives were to (1) identify the drought sensitivities of the PFTs, (2) assess the additive effects of the press- and pulse-drought, and (3) examine the interactive effects of soils and drought. Our results revealed that the C3 grasses were the most sensitive PFT to drought, the C3 shrubs were the most resistant, and the C4 grasses and shrubs had intermediate drought sensitivities. Although we expected the C3 grasses would have the greatest response to drought, the higher resistance of C3 shrubs relative to the C4 shrubs was contrary to our predictions based on the higher water use efficiency of C4 photosynthesis. Also, the additive effects of press- and pulse droughts caused high morality in C3 grasses, which has large ecological and economic ramifications for this region. Furthermore, despite predictions based on the inverse texture hypothesis, we observed no interactive effects of soils with the drought treatment on cover or mortality. These results suggest that plant responses to droughts in drylands may differ from expectations and have large ecological effects if press- and pulse-droughts push species beyond physiological and mortality thresholds. PMID- 26254262 TI - Somatization is associated with worse outcome in a chiropractic patient population with neck pain and low back pain. AB - AIM: To determine if psychosocial factors are associated with outcome in patients with neck pain or low back pain. METHODS: In a prospective, multi-center chiropractic practice-based cohort study in Belgium and The Netherlands, 917 patients, of which 326 with neck pain and 591 with low back pain, completed self administered questionnaires at baseline, following the second visit, and at 1, 3, 6 and 12 months. Psychosocial factors assessed at baseline were: distress, depression, anxiety and somatization via the Four Dimensional Symptom Questionnaire, patient's beliefs regarding the effect of physical activity and work on their complaint via the Fear Avoidance Beliefs Questionnaire, and social support via the Feij social support scale. Primary outcome measures were perceived recovery, pain intensity, and functional status which was measured with the Neck Disability Index and Oswestry Disability Index. A univariable regression analysis to estimate the relation between each psychological variable and outcome was followed by a multivariable multilevel regression analysis. RESULTS: There were no differences in baseline patient characteristics between the patient population from Belgium and the Netherlands. Somatization scores are consistently associated with perceived recovery, functional status and pain for both neck pain and low-back pain. Depression was associated with poorer functioning in patients with LBP. There was a small association between fear and function and pain for patients with neck pain or low-back pain. CONCLUSION: Somatization was the only variable consistently found to be associated with diminished perceived recovery, higher degree of neck or low back disability, and increased neck or low back pain. PMID- 26254261 TI - T24 HRAS transformed NIH/3T3 mouse cells (GhrasT-NIH/3T3) in serial tumorigenic in vitro/in vivo passages give rise to increasingly aggressive tumorigenic cell lines T1-A and T2-A and metastatic cell lines T3-HA and T4-PA. AB - Cancer cells often arise progressively from "normal" to "pre-cancer" to "transformed" to "local metastasis" to "metastatic disease" to "aggressive metastatic disease". Recent whole genome sequencing (WGS) and spectral karyotyping (SKY) of cancer cells and tumorigenic models have shown this progression involves three major types of genome rearrangements: ordered small step-wise changes, more dramatic "punctuated evolution" (chromoplexy), and large catastrophic steps (chromothripsis) which all occur in random combinations to generate near infinite numbers of stochastically rearranged metastatic cancer cell genomes. This paper describes a series of mouse cell lines developed sequentially to mimic this type of progression. This starts with the new GhrasT NIH/Swiss cell line that was produced from the NIH/3T3 cell line that had been transformed by transfection with HRAS oncogene DNA from the T24 human bladder carcinoma. These GhrasT-NIH/Swiss cells were injected s.c. into NIH/Swiss mice to produce primary tumors from which one was used to establish the T1-A cell line. T1-A cells injected i.v. into the tail vein of a NIH/Swiss mouse produced a local metastatic tumor near the base of the tail from which the T2-A cell line was established. T2-A cells injected i.v. into the tail vein of a nude NIH/Swiss mouse produced metastases in the liver and one lung from which the T3-HA (H=hepatic) and T3-PA (P=pulmonary) cell lines were developed, respectively. T3 HA cells injected i.v. into a nude mouse produced a metastasis in the lung from which the T4-PA cell line was established. PCR analysis indicated the human T24 HRAS oncogene was carried along with each in vitro/in vivo transfer step and found in the T2-A and T4-PA cell lines. Light photomicrographs indicate that all transformed cells are morphologically similar. GhrasT-NIH/Swiss cells injected s.c. produced tumors in 4% of NIH/Swiss mice in 6-10 weeks; T1-A cells injected s.c. produced tumors in 100% of NIH/Swiss mice in 7-10 days. T1-A, T-2A, T3-HA and T4-PA cells when injected i.v. into the tail produced local metastasis in non nude or nude NIH/Swiss mice. T4-PA cells were more widely metastatic than T3-HA cells when injected i.v. into nude mice. Evaluation of the injected mice indicated a general increase in metastatic potential of each cell line in the progression as compared to the GhrasT-NIH/3T3 transformed cells. A new photomicrographic technique to follow growth rates within six preselected 2*2mm(2) grids per plate is described. Average doubling times of the transformed cells GhrasT-NIH/3T3 (17h), T1A (17.5h), T2A (15.5h), T3-HA (17.5h) and T4-PA (18.5h) (average 17.2h) were significantly faster (P=0.006) than NIH Swiss primary embryonic cells and NIH/3T3 cells (22 h each). This cell series is currently used in this lab for studies of cancer cell inhibitors, mitochondrial biogenesis and gene expression and is available for further study by other investigators for intra- and inter-laboratory comparisons of WGS, transcriptome sequencing, SKY and other analyses. The genome rearrangements in these cells together with their phenotypic properties may help provide more insights into how one tumorigenic progression occurred to produce the various cell lines that led to the highly metastatic T4-PA cell line. PMID- 26254263 TI - Increased duration of co-contraction of medial knee muscles is associated with greater progression of knee osteoarthritis. AB - BACKGROUND: As knee osteoarthritis (OA) cannot be cured, treatments that slow structural disease progression are a priority. Knee muscle activation has a potential role in OA pathogenesis. Although enhanced knee muscle co-contraction augments joint stability; this may speed structural disease progression by increased joint load. OBJECTIVE: This study investigated the relationship between cartilage loss and duration of co-contraction of medial/lateral knee muscles in medial knee OA. DESIGN: Prospective cohort study. METHODS: Medial (vastus medialis; semimembranosus) and lateral (vastus lateralis; biceps femoris) knee muscle myoelectric activity was recorded in 50 people with medial knee OA during natural speed walking at baseline. Medial tibial cartilage volume was measured from MRI at baseline and 12 months. Relationships between percent volume loss and duration of co-contraction of medial/lateral muscles around stance phase and ratio of duration of medial to lateral muscle co-contraction were evaluated with multiple linear regression. RESULTS: Greater duration of medial muscle co contraction and greater duration of medial relative to lateral co-contraction correlated positively with annual percent loss of medial tibial cartilage volume (P = 0.003). Estimated cartilage loss was 0.14 (95% confidence interval -0.23 to 0.05) greater for each increase in medial muscle co-contraction duration of 1% of the gait cycle. Lateral muscle co-contraction inversely correlated with cartilage loss. CONCLUSION: Data support the hypothesis that augmented medial knee muscle co-contraction underpins faster progression of medial knee OA. Increased duration of lateral muscle co-contraction protected against medial cartilage loss. Exercise and biomechanical interventions to change knee muscle activation patterns provide possible candidates to slow progression of knee OA. PMID- 26254260 TI - A comparison between nailfold capillaroscopy patterns in adulthood in juvenile and adult-onset systemic sclerosis: A EUSTAR exploratory study. AB - OBJECTIVE: Qualitative capillaroscopy patterns in juvenile- and adult-onset systemic sclerosis (SSc) were studied in adulthood using data from the EULAR Scleroderma Trials and Research (EUSTAR) database. METHODS: Data collected between June 2004 and April 2013 were examined with focus on capillaroscopy. In this retrospective exploratory study, series of patients with juvenile-onset SSc were matched with series of adult-onset SSc having the same gender and autoantibody profile. RESULTS: 30 of 123 patients with juvenile-onset and 2108 of 7133 with adult-onset SSc had data on capillaroscopy. Juvenile-onset SSc showed scleroderma pattern more frequently than adult-onset SSc (93.3% and 88%). The OR was 2.44 and 95% CI 0.57-10.41. An active scleroderma pattern was present in 58% of juvenile- and 61% of adult-onset SSc. The OR was 0.91 and 95% CI 0.28-2.93. The late scleroderma pattern was present in 61% of juvenile- and 55.5% of adult onset SSc. The OR was 1.06 and 95% CI 0.34-3.56. CONCLUSION: This is the first exploratory study on the comparison of capillaroscopy between juvenile- and adult onset SSc in adulthood. Juvenile-onset SSc had an increase prevalence of scleroderma pattern, but a similar distribution of the three patterns was suggested. Further studies are needed to define this issue. PMID- 26254264 TI - Excluding people who use drugs or alcohol from access to hepatitis C treatments - Is this fair, given the available data? PMID- 26254265 TI - Comment on "Aminoacyl tRNA Synthetase-Interacting Multifunctional Protein 1 Acts as a Novel B Cell-Activating Factor In Vitro and In Vivo". PMID- 26254268 TI - Correction: miR-182 Is Largely Dispensable for Adaptive Immunity: Lack of Correlation between Expression and Function. PMID- 26254267 TI - T Cell Adolescence: Maturation Events Beyond Positive Selection. AB - Single-positive thymocytes that successfully complete positive and negative selection must still undergo one final step, generally termed T cell maturation, before they gain functional competency and enter the long-lived T cell pool. Maturation initiates after positive selection in single-positive thymocytes and continues in the periphery in recent thymic emigrants, before these newly produced T cells gain functional competency and are ready to participate in the immune response as peripheral naive T cells. Recent work using genetically altered mice demonstrates that T cell maturation is not a single process, but a series of steps that occur independently and sequentially after positive selection. This review focuses on the changes that occur during T cell maturation, as well as the molecules and pathways that are critical at each step. PMID- 26254266 TI - G-CSF and GM-CSF in Neutropenia. AB - G-CSF and GM-CSF are used widely to promote the production of granulocytes or APCs. The U.S. Food and Drug Administration approved G-CSF (filgrastim) for the treatment of congenital and acquired neutropenias and for mobilization of peripheral hematopoietic progenitor cells for stem cell transplantation. A polyethylene glycol-modified form of G-CSF is approved for the treatment of neutropenias. Clinically significant neutropenia, rendering an individual immunocompromised, occurs when their number is <1500/MUl. Current guidelines recommend their use when the risk for febrile neutropenia is >20%. GM-CSF (sargramostim) is approved for neutropenia associated with stem cell transplantation. Because of its promotion of APC function, GM-CSF is being evaluated as an immunostimulatory adjuvant in a number of clinical trials. More than 20 million persons have benefited worldwide, and >$5 billion in sales occur annually in the United States. PMID- 26254269 TI - Thioredoxin selectivity for thiol-based redox regulation of target proteins in chloroplasts. PMID- 26254270 TI - Silencing of human methionine adenosyltransferase 1A expression by methylation of the coding region. AB - This article was withdrawn by the authors before final publication on December 10, 2004. PMID- 26254271 TI - RhoB-dependent modulation of early endocytic traffic in Madin-Darby canine kidney cells. AB - This article was withdrawn by the authors before final publication on September 16, 2004. PMID- 26254272 TI - Hypoxic induction of vascular endothelial growth factor (VEGF) and angiogenesis in muscle by N terminus peroxisome proliferator-associated receptor gamma coactivator (NT-PGC)-1alpha. AB - This article was withdrawn by the authors before final publication on January 15, 2014. PMID- 26254273 TI - BASK survey of The Knee readership 2015. AB - A convenience sample of the attendees of the 2015 annual meeting of the British Association of Knee showed that the majority of the attendees who responded read The Knee, would like a section on surgical tips, more themed supplements and guest editorials. There is still not enough support for purely electronic publication. For those that have submitted papers, the experience with the publication process was positive. PMID- 26254274 TI - The potentiation of geometry by features in human children: Evidence against modularity in the domain of navigation. AB - Accumulating evidence demonstrates that humans and other animals use geometric information, such as the shape of a surrounding space, to recover from disorientation. Less clear is to what extent human children integrate geometry with featural cues, such as the color of walls within an enclosed space, for this purpose. One view holds that reorientation relies on a cognitive module that processes geometric information independently of features. Here we provide evidence against this position by demonstrating that prior exposure to features within a kite-shaped space facilitated the use of geometry in 3- and 4-year-old children, as has been shown with nonhuman animals. Children were tasked with localizing a hidden object within a kite space following disorientation. Their performance was compared across two blocks of trials. We found that children first exposed to features (two black walls and two white walls) within the kite space (first block) were subsequently better at relying on the space's geometry to localize the target object (second block) than children not previously exposed to features. Follow-up experiments ruled out nonspecific effects of practice and attention. Not only did featural cues interact with the processing of geometry, but also features specifically enhanced children's representations of the space's geometry, which they used for reorientation. We suggest that this potentiation of geometry was possible because the placement of wall colors highlighted the major axis of the kite space, which may be critical for aiding the encoding of global shape or for maintaining the representation of a complex geometry in memory. PMID- 26254275 TI - New ursane triterpenoids from Salvia urmiensis Bunge: Absolute configuration and anti-proliferative activity. AB - Two new triterpenoids, urmiensolide B (1) and urmiensic acid (2), with rare carbon skeletons together with three known compounds were isolated from the aerial parts of Salvia urmiensis Bunge, an endemic species of Iran. The structures were established by a combination of 1D and 2D NMR, and HRESIMS, and in the case of 2 and 3, their structures were confirmed by single-crystal X-ray analysis. The absolute configuration of 2 was established by electronic circular dichroism (ECD) spectra. The new compounds were evaluated for their anti proliferative activities against A549 and MCF-7 human cancer cell lines. Compounds 1 and 2 showed IC50 values of 2.8 and 1.6 MUM against MCF-7 cells, respectively. PMID- 26254276 TI - Spironolactone Add-on for Preventing or Slowing the Progression of Diabetic Nephropathy: A Meta-analysis. AB - PURPOSE: The aim of this meta-analysis was to evaluate the benefits and potential adverse effects of adding spironolactone to standard antidiabetic/renoprotective/antihypertensive (AD/RP/AHT) treatment in patients with diabetic nephropathy (DN). METHODS: PubMed/MEDLINE and Web of Knowledge were searched for relevant randomized, controlled studies (RCTs) or quasi-RCTs of the effects of adding spironolactone to standard AD/RP/AHT treatment in patients with DN. Results were summarized with a random-effects model or a fixed-effects model. FINDINGS: According to the outcomes measured (benefits and risks of adding spironolactone to standard AD/RP/AHT treatment), compared with controls, the addition of spironolactone significantly decreased end-of-treatment (EOT) 24-hour urinary albumin/protein excretion and significantly increased percentage reduction from baseline in urinary albumin/creatinine ratio (UACR), although it did not significantly affect EOT UACR. The addition of spironolactone further led to a significantly greater reduction from baseline in glomerular filtration rate (GFR)/estimated (e) GFR, although it did not significantly affect EOT GFR/eGFR. Further, the addition of spironolactone significantly reduced EOT in-office, 24 hour, and daytime systolic and diastolic blood pressure (SBP and DBP, respectively) and led to significantly greater reductions from baseline in in office SBP and DBP, although it did not significantly affect nighttime SBP or DBP. Finally, the addition of spironolactone significantly increased mean serum/plasma potassium levels and the risk for hyperkalemia. IMPLICATIONS: Spironolactone could be added to preexisting AD/RP/AHT therapy in patients with DN to prevent or slow DN progression by reducing proteinuria. The addition of spironolactone would likely provide even more beneficial effect in patients with DN and hypertension due to the BP reduction associated with spironolactone use. However, the beneficial effects of spironolactone add-on should be weighed against its potential risks, especially hyperkalemia. The long-term effects of spironolactone add-on on renal outcomes and mortality need to be studied. PMID- 26254277 TI - A qualitative study of a food intervention in a primary school: Pupils as agents of change. AB - This study explored the impact of a school-based kitchen project at a large inner London school. Timetabled kitchen classroom sessions (90 min every fortnight) were held with all 7-9 year old pupils. Semi-structured focus group discussions (with 76 pupils, 16 parents) and interviews (with headteachers, catering managers and specialist staff) were conducted at the intervention school and a matched control school. Categories and concepts were derived using a grounded theory approach. Data analysis provided three main categories each with their related concepts: Pupil factors (enthusiasm and enjoyment of cooking, trying new foods, food knowledge and awareness, producing something tangible); School factors (learning and curriculum links, resource implications and external pressures) and Home factors (take home effects, confidence in cooking and self-esteem, parents' difficulties cooking at home with children). Children's engagement and the opportunity to cook supported increased food awareness, skills and food confidence. In the grounded theory that emerged, take home effects beyond the school gate dominate, as children act as agents of change and influence cooking and food choice at home. These short term outcomes have the potential to lead to longer term outcomes including changing eating behaviour and diet. PMID- 26254278 TI - Impact of VEGF, VEGFR, PDGFR, HIF and ERCC1 gene polymorphisms on thymic malignancies outcome after thymectomy. AB - We aimed to analyze genotypes of VEGF-A, VEGFR2, Flt4, PDGFRalpha, HIF-1alpha and ERCC1 and their correlation with thymic tumor risk and patient outcome. DNA of 57 consecutive patients (43 thymomas and 14 thymic carcinomas) who underwent total thymectomy at our Institution was extracted from paraffin-embedded tissue. We selected polymorphisms in the following genes:HIF1-alpha (rs2057482T > C, rs1951795A > C, rs2301113C > A, rs10873142C > T, rs11158358G > C, rs12434438G > A, rs11549465C > T, rs11549467G > A), VEGF-A (rs2010963G > C, rs699947A > C), VEGFR-2 (rs2305948C > T, rs1870377T > A), VEGFR-3 (rs307826T > C, rs307821C > A), PDGFR-alpha (rs35597368C > T) and ERCC1 (rs11615A > G). Gene polymorphisms were determined by Real-Time PCR using TaqMan assays. As compared to the general population, the allele frequency of PDGFR-alpha rs35597368T was significantly higher (95% vs. 87%, p = 0.036), while the frequency of alleles HIF1-alpha rs2057482C (78% vs. 90%), rs1951795C (69% vs. 87%), rs2301113A (70% vs. 83%), rs10873142T (70% vs. 87%), rs11158358C (75% vs. 88%), rs12434438A (67% vs. 84%) were significantly lower. VEGFR-3 rs307821C frequency was significantly higher in thymomas vs. thymic carcinomas (79% vs. 72%, p = 0.0371). The following factors were significantly correlated with a longer overall survival: VEGFR-3 rs307826C, VEGFR-2 rs1870377A, PDGFR-alpha rs35597368T/C, HIF1-alpha rs2301113C, rs2057482C/T, rs1951795C, rs11158358G/C and rs10873142T/C, ERCC1 rs11615A (p < 0.05). Our results suggest, for the first time, that PDGFR-alpha, HIF-1alpha and VEGFR-3 SNPs are associated with thymic cancer risk and survival. PMID- 26254279 TI - Small molecule inhibitor screen identifies synergistic activity of the bromodomain inhibitor CPI203 and bortezomib in drug resistant myeloma. AB - PURPOSE: Despite significant therapeutic progress in multiple myeloma, drug resistance is uniformly inevitable and new treatments are needed. Our aim was to identify novel, efficacious small-molecule combinations for use in drug resistant multiple myeloma. EXPERIMENTAL DESIGN: A panel of 116 small molecule inhibitors was used to screen resistant myeloma cell lines for potential therapeutic targets. Agents found to have enhanced activity in the bortezomib or melphalan resistant myeloma cell lines were investigated further in combination. Synergistic combinations of interest were evaluated in primary patient cells. RESULTS: The overall single-agent drug sensitivity profiles were dramatically different between melphalan and bortezomib resistant cells, however, the bromodomain inhibitor, CPI203, was observed to have enhanced activity in both the bortezomib and melphalan resistant lines compared to their wild-type counterparts. The combination of bortezomib and CPI203 was found to be synergistic in both the bortezomib and melphalan resistant cell lines as well as in a primary multiple myeloma sample from a patient refractory to recent proteasome inhibitor treatment. The CPI203-bortezomib combination led to enhanced apoptosis and anti-proliferative effects. Finally, in contrast to prior reports of synergy between bortezomib and other epigenetic modifying agents, which implicated MYC downregulation or NOXA induction, our analyses suggest that CPI203 bortezomib synergy is independent of these events. CONCLUSION: Our preclinical data supports a role for the clinical investigation of the bromodomain inhibitor CPI203 combined with bortezomib or alkylating agents in resistant multiple myeloma. PMID- 26254280 TI - Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1alpha/XBP1 pathway. AB - Altered regulation of ER stress response has been implicated in a variety of human diseases, such as cancer and metabolic diseases. Excessive ER function contributes to malignant phenotypes, such as chemoresistance and metastasis. Here we report that the tumor suppressor p53 regulates ER function in response to stress. We found that loss of p53 function activates the IRE1alpha/XBP1 pathway to enhance protein folding and secretion through upregulation of IRE1alpha and subsequent activation of its target XBP1. We also show that wild-type p53 interacts with synoviolin (SYVN1)/HRD1/DER3, a transmembrane E3 ubiquitin ligase localized to ER during ER stress and removes unfolded proteins by reversing transport to the cytosol from the ER, and its interaction stimulates IRE1alpha degradation. Moreover, IRE1alpha inhibitor suppressed protein secretion, induced cell death in p53-deficient cells, and strongly suppressed the formation of tumors by p53-deficient human tumor cells in vivo compared with those that expressed wild-type p53. Therefore, our data imply that the IRE1alpha/XBP1 pathway serves as a target for therapy of chemoresistant tumors that express mutant p53. PMID- 26254282 TI - [Perioperative approach of patient with takotsubo syndrome]. AB - INTRODUCTION: Takotsubo cardiomyopathy (TCM) is a stress-induced cardiomyopathy. It is characterized by an acute onset of symptoms and electrocardiographic abnormalities mimicking an acute coronary syndrome in the absence of obstructive coronary artery disease. Any anesthetic-surgical event corresponds to a stressful situation, so the anesthetic management of patients with TCM requires special care throughout the perioperative period. We describe the anesthetic management of a patient with a confirmed diagnosis of TCM undergoing segmental colectomy. CASE REPORT: Female patient, 55 years old, ASA III, with history of takotsubo syndrome diagnosed 2 years ago, scheduled for segmental colectomy. The patient, without other changes in preoperative evaluation, underwent general anesthesia associated with lumbar epidural and remained hemodynamically stable during the 2hours of surgery. After a brief stay in the Post-Anesthesia Care Unit, she was transferred to the Intermediate Care Unit (IMCU), with epidural analgesia for postoperative period. CONCLUSION: TCM is a rare disease which true pathophysiology remains unclear, as well as the most appropriate anesthetic surgical strategy. In this case, through a preventive approach, with close monitoring and the lowest possible stimulus, all the perioperative period was uneventful. Because it is a rare disease, this report could help to raise awareness about TCM. PMID- 26254281 TI - Prognostic significance of TRAIL signalling molecules in cervical squamous cell carcinoma. AB - AIM: Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that preferentially induces apoptosis in cancer cells while exhibiting little or no toxicity in normal cells. In this study, we evaluated the clinicopathological significance of TRAIL signalling members' expression profiles in cervical squamous cell carcinoma (CSCC). METHODS: TRAIL, DR5, caspase-8 and cellular FLICE-inhibitory protein (c-FLIP) protein expression was investigated in 72 stage IA2-IIIA CSCC patients using immunohistochemistry. Correlation between protein expression and clinicopathological features, radiotherapy response and survival was statistically analysed. RESULTS: Positive c-FLIP expression was an independent negative indicator for disease-free survival (DFS) (p=0.015) in multivariate Cox regression analysis. The DR5 nuclear positive group (p=0.069 by log rank test) showed some advantage of radiotherapy for overall survival (OS) compared with the DR5 nuclear negative cohort (p=0.568 by log rank test). In addition, loss of TRAIL expression was associated with worse differentiation (p=0.004), while absence of caspase-8 staining was more frequently observed in cases with lymphovascular invasion (p=0.035). CONCLUSIONS: High c-FLIP expression is shown to be an independent prognostic variable, DR5 nuclear expression may serve as a predictive biomarker for radiotherapy, and TRAIL as well as caspase-8 loss may be associated with malignant progression. PMID- 26254283 TI - Prenatal acetaminophen affects maternal immune and endocrine adaptation to pregnancy, induces placental damage, and impairs fetal development in mice. AB - Acetaminophen (APAP; ie, Paracetamol or Tylenol) is generally self-medicated to treat fever or pain and recommended to pregnant women by their physicians. Recent epidemiological studies reveal an association between prenatal APAP use and an increased risk for asthma. Our aim was to identify the effects of APAP in pregnancy using a mouse model. Allogeneically mated C57Bl/6J females were injected i.p. with 50 or 250 mg/kg APAP or phosphate-buffered saline on gestation day 12.5; nonpregnant females served as controls. Tissue samples were obtained 1 or 4 days after injection. APAP-induced liver toxicity was mirrored by significantly increased plasma alanine aminotransferase levels. In uterus draining lymph nodes of pregnant dams, the frequencies of mature dendritic cells and regulatory T cells significantly increased on 250 mg/kg APAP. Plasma progesterone levels significantly decreased in dams injected with APAP, accompanied by a morphologically altered placenta. Although overall litter sizes and number of fetal loss remained unaltered, a reduced fetal weight and a lower frequency of hematopoietic stem cells in the fetal liver were observed on APAP treatment. Our data provide strong evidence that prenatal APAP interferes with maternal immune and endocrine adaptation to pregnancy, affects placental function, and impairs fetal maturation and immune development. The latter may have long-lasting consequences on children's immunity and account for the increased risk for asthma observed in humans. PMID- 26254284 TI - Safety of Epinephrine in Digital Nerve Blocks: A Literature Review. AB - BACKGROUND: Digital nerve blocks are commonly performed in emergency departments. Health care practitioners are often taught to avoid performing blocks with epinephrine due to a risk of digital necrosis. OBJECTIVE: To review the literature on the safety of epinephrine 1:100,000-200,000 (5-10 MUg/mL) with local anesthetics in digital nerve blocks in healthy patients and in patients with risk for poor peripheral circulation. METHODS: PubMed, Web of Science, and the Cochrane Library were searched in June 2014 using the query "digital block AND epinephrine OR digital block AND adrenaline". The searches were performed without any limits. RESULTS: Sixty-three articles were identified, and 39 of these were found to be relevant. These include nine reviews, 12 randomized control trials, and 18 other articles. Most studies excluded patients with risk for poor peripheral circulation. Two studies described using epinephrine on patients with vascular comorbidities. No study reported digital necrosis or gangrene attributable to epinephrine, either in healthy patients or in patients with risk for poor peripheral circulation. In total, at least 2797 digital nerve blocks with epinephrine have been performed without any complications. CONCLUSIONS: Epinephrine 1:100,000-200,000 (5-10 MUg/mL) is safe to use in digital nerve blocks in healthy patients. Physiological studies show epinephrine induced vasoconstriction to be transient. There are no reported cases of epinephrine-induced harm to patients with risk for poor peripheral circulation despite a theoretical risk of harmful epinephrine-induced vasoconstriction. A lack of reported complications suggests that the risk of epinephrine-induced vasoconstriction to digits may be overstated. PMID- 26254285 TI - Novel aspects of heart failure: from combined neurohormal blockade to embryonic stem cells. PMID- 26254286 TI - Deepak L. Bhatt MD, MPH: an inquisitive mind for solutions useful to the practicing physician. PMID- 26254287 TI - The Effect of Chemical Composition and Bioactivity of Several Essential Oils on Tenebrio molitor (Coleoptera: Tenebrionidae). AB - The major chemical components of four essential oils (EOs) extracted from dry leaves of Citrus limonum, Cymbopogon citratus, Litsea cubeba, and Muristica fragrans were analyzed with gas chromatograph-mass spectrometer and their fumigant, contact, and repellent activities against 10th instar and adults of Tenebrio molitor were also assayed. The results indicated that the major constituents of C. limonum and Cy. citrates were D-limonene (38.22%) and 3,7 dimethyl-6-octenal (26.21%), while which of L. cubeba and M. fragrans were (E)-3, 7-dimethyl-2, 6-octadienal (49.78%) and (E)-cinnamaldehyde (79.31%), respectively. Contact activities of L. cubeba and C. limonum with LC50 values of 21.2 and 13.9 ug/cm(2) at 48 h and repellence activities (>89.0% repellence indexes) (P < 0.05) at 12 h on 10th instar were better than those of the other two EOs. Nevertheless, the fumigation activities of L. cubeba on 10th instar and adults (LC50 = 2.7, 3.7 MUl/liter) were stronger than those of C. limonum (LC50 = 10.9, 12.0 MUl/liter) at 96 h and significant (not overlapping confidence intervals). The EOs of L. cubeba and C. limonum have clearly elongated the growth and development of larvae, egg, and slightly shorten pupae and adults of T. molitor compared with the control. The mainly active ingredients of L. cubeba and C. limonum, including D-limonene and beta-pinene, were demonstrated to coinhibit the actives of AChE and enhance the toxicities on 10th instar of T. molitor. These results indicate that the EOs of L. cubeba and C. limonum could have great potential as botanical insecticides against T. molitor. PMID- 26254288 TI - Retraction. PMID- 26254289 TI - Laboratory Evaluation of Acute Toxicity of the Essential Oil of Allium tuberosum Leaves and Its Selected Major Constituents Against Apolygus lucorum (Hemiptera: Miridae). AB - The aim of this research was to evaluate acute toxicity of the essential oil of leaves of Chinese chives, Allium tuberosum Rottler ex Spreng (Asparagales: Alliaceae) and its major constituents against Apolygus lucorum Meyer-Dur (Hemiptera: Miridae). The essential oil of A. tuberosum leaves was obtained by hydrodistillation and analyzed by gas chromatography and gas chromatography-mass spectrometry. The major constituents of the oil were sulfur-containing compounds, including allyl methyl trisulfide (36.24%), diallyl disulfide (27.26%), diallyl trisulfide (18.68%), and dimethyl trisulfide (9.23%). The essential oil of A. tuberosum leaves exhibited acute toxicity against Ap. lucorum with an LD50 value of 20.03 MUg per adult. Among the main compounds, diallyl trisulfide (LD50 = 10.13 MUg per adult) showed stronger acute toxicity than allyl methyl trisulfide (LD50 = 21.10 MUg per adult) and dimethyl trisulfide (LD50 = 21.65 MUg per adult). The LD50 value of diallyl disulfide against Ap. lucorum was 28.10 MUg per adult. The results indicated that the essential oil of A. tuberosum and its major constituents may have a potential to be developed as botanical insecticides against Ap. lucorum. PMID- 26254290 TI - A longitudinal population-based analysis of relationship status and mortality in KwaZulu-Natal, South Africa 2001-2011. AB - BACKGROUND: Mortality risk is lower in married than in unmarried men and women. However, little is known about the association between mortality and relationship status in South Africa where marriage rates are low, migration is common, many couples are not co-resident and HIV prevalence is high. METHOD: Using demographic surveillance data collected from 2001 to 2011, relationship status was categorised as conjugal (partners belong to the same household), non-conjugal (partners do not belong to the same household) or not partnered. Rates of relationship formation and dissolution were calculated by age and sex. Controlling for antiretroviral treatment (ART) introduction in 2005 as well as education, sex-specific and age-specific Cox proportional hazards models were used to investigate the association between relationship status and (1) all-cause mortality and (2) non-AIDS mortality. RESULTS: Before 2005, individuals in conjugal relationships had a lower hazard of all-cause mortality in all age groups than not partnered men and women. Non-conjugal relationships lowered the risk of dying compared with not partnered men and women in fewer age groups. After ART introduction, the protective association of conjugal relationships was weaker but remained generally significant for men and women but not in non conjugal relationships. In the later period, the association is reversed in young men (20-29 years) with mortality higher in conjugal and non-conjugal relationships compared with men not partnered. The analysis of non-AIDS deaths provided similar results. CONCLUSIONS: The higher degree of social connections within a shared household environment that characterises conjugal relationships affords men and women greater protection against mortality. PMID- 26254291 TI - Environmental and health impacts of 'fracking': why epidemiological studies are necessary. PMID- 26254292 TI - Student loans and racial disparities in self-reported sleep duration: evidence from a nationally representative sample of US young adults. AB - BACKGROUND: Student loans are the second largest source of personal debt in the USA and may represent an important source of financial strain for many young adults. Little attention has been paid to whether debt is associated with sleep duration, an important health-promoting behaviour. We determine if student loans are associated with sleep duration. Since black young adults are more likely to have student debt and sleep less, we also consider whether this association varies by race. METHODS: Data come from the US National Longitudinal Survey of Youth 1997. The main analytic sample includes 4714 respondents who were ever enrolled in college and who reported on sleep duration in 2010. Most respondents had completed their college education by 2010, when respondents were 25 to 31 years old. Multivariable linear regression models assessed the cross-sectional association between student loans accumulated over the course of college and sleep duration in 2010, as well as between student debt at age 25 and sleep duration in 2010. RESULTS: Black young adults with greater amounts of student loans or more student debt reported shorter sleep duration, controlling for occupation, hours worked, household income, parental net worth, marital status, number of children in the household and other sociodemographic and health indicators. There was no association between student loans or debt with sleep for white or latino adults and other racial/ethnic groups. CONCLUSIONS: Student loans may contribute to racial inequities in sleep duration. Our findings also suggest that the student debt crisis may have important implications for individuals' sleep, specifically and public health, more broadly. PMID- 26254293 TI - Health challenges in Kazakhstan and Central Asia. AB - The Central Asian region, which encompasses Kazakhstan, Uzbekistan, Tajikistan, Turkmenistan and Kyrgyzstan, is an interesting geographic region with a rich history dating back to the Silk Road, Mongol conquests and expansion of the Russian Empire. However, from a public health viewpoint, the Central Asian region is under-investigated, and many public health challenges exist, as countries of Central Asia inherited the centralised medical systems practiced in the Soviet Union, and are currently undergoing rapid transitions. A large number of low and middle-income countries around the world, including countries of Central Asia, face a double burden of chronic and infectious disease. This essay focuses on the exploration of the most important public health challenges in the Central Asian region, including limited scientific productivity, the double burden of chronic and infectious disease, the need for healthcare reform and the reduction in care variation. Central Asia has a large number of medical schools, medical centres, and emerging research institutes that can be used to foster a change in medical and public health practice in the region. PMID- 26254294 TI - The biological embedding of social differences in ageing trajectories. PMID- 26254297 TI - Correction for Grossi et al., Mono- and Dialkyl Glycerol Ether Lipids in Anaerobic Bacteria: Biosynthetic Insights from the Mesophilic Sulfate Reducer Desulfatibacillum alkenivorans PF2803T. PMID- 26254295 TI - Nanovehicles as a novel target strategy for hyperthermic intraperitoneal chemotherapy: a multidisciplinary study of peritoneal carcinomatosis. AB - In general, detection of peritoneal carcinomatosis (PC) occurs at the late stage when there is no treatment option. In the present study, we designed novel drug delivery systems that are functionalized with anti-CD133 antibodies. The C1, C2 and C3 complexes with cisplatin were introduced into nanotubes, either physically or chemically. The complexes were reacted with anti-CD133 antibody to form the labeled product of A0-o-CX-chem-CD133. Cytotoxicity screening of all the complexes was performed on CHO cells. Data showed that both C2 and C3 Pt complexes are more cytotoxic than C1. Flow-cytometry analysis showed that nanotubes conjugated to CD133 antibody have the ability to target cells expressing the CD133 antigen which is responsible for the emergence of resistance to chemotherapy and disease recurrence. The shortest survival rate was observed in the control mice group (K3) where no hyperthermic intraperitoneal chemotherapy procedures were used. On the other hand, the longest median survival rate was observed in the group treated with A0-o-C1-chem-CD133. In summary, we designed a novel drug delivery system based on carbon nanotubes loaded with Pt-prodrugs and functionalized with anti-CD133 antibodies. Our data demonstrates the effectiveness of the new drug delivery system and provides a novel therapeutic modality in the treatment of melanoma. PMID- 26254299 TI - Impact of screening colonoscopy on outcomes in colorectal cancer. AB - Colorectal cancer is one of the most common cancers in both men and women worldwide and a good candidate for screening programs. There are two modalities of colorectal cancer screening: (i) population-based screening and (ii) opportunistic screening. The first one is based on organized, well-coordinated, monitored and established programs with a systematic invitation covering the entire target population. In contrast, opportunistic screening tests are offered to people who are being examined for other reasons. Recently, a variety of colorectal cancer screening tests have become available; each country should make a choice, based on national demographics and resources, on the screening method to be used. Fecal occult blood test, especially the fecal immunochemical test, would be the best modality for decreasing colorectal cancer mortality through population-based screening. In contrast, if the aim includes the early detection of colorectal cancer and adenomas, endoscopic methods are more appropriate. PMID- 26254300 TI - Chronic total occlusion of abdominal aorta due to Takayasu's arteritis: a noteworthy finding. PMID- 26254301 TI - Early Failure of Dialysis Access among the Elderly in the Era of Fistula First. AB - BACKGROUND AND OBJECTIVES: Recent evidence indicates that fistula maturation and patency may be compromised in the elderly dialysis population compared with younger patients. The objective of this study was to characterize the short-term outcomes of arteriovenous fistulas and arteriovenous grafts for hemodialysis access in the Medicare population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective cohort study performed using Medicare Part A and B claims data from 2006 through 2011. The study population included 16,464 dialysis dependent patients age >=66 years undergoing arteriovenous fistula and arteriovenous graft creation. The primary outcome measure was incidence of repeat fistula/graft creation and tunneled catheter placements in the 12 months after arteriovenous fistula and graft creation. RESULTS: In the 12 months postindex fistula/graft, the mortality in the fistula group was 28.2% versus 29.9% in the graft group (P=0.03). A repeat fistula/graft creation was required in 26.9% of patients in the fistula group and 16.7% in the graft group (P<0.001). There was no significant difference in the proportion of patients who required a tunneled hemodialysis catheter in the 12 months after an index fistula creation (fistula 28.4% versus graft 27.3%, P=0.19). In the index fistula group, 44.4% of patients required a repeat fistula/graft creation and/or a tunneled catheter, compared with 33.7% in the graft group (P<0.001). At 365 days after the index fistula/graft, the repeat fistula/graft/catheter-free survival was 39.7% in the fistula group versus 46.0% in the graft group (P<0.001). Index fistula was associated with a higher risk of loss of repeat fistula/graft/catheter-free survival with an odds ratio of 1.19 (95% confidence interval, 1.13 to 1.24). CONCLUSIONS: Fistulas were associated with a somewhat lower mortality than grafts in the first 12 months after creation. However, the incidence of repeat fistula/graft creation and tunneled catheter placement is substantially higher in the first 12 months after fistula creation compared with grafts. One-year repeat fistula/graft/catheter-free survival is lower after fistula creation than grafts. PMID- 26254302 TI - Higher spherical equivalent refractive errors is associated with slower axial elongation wearing orthokeratology. AB - PURPOSE: To investigate the relationship between axial length (AL) increase and baseline spherical equivalent refractive errors (SER) in myopic children wearing orthokeratology contact lenses (OK). METHODS: One hundred fifteen Chinese (115 right eyes) children wearing OK were enrolled in this cohort study. Gender, age, baseline SER, corneal power, corneal astigmatism, and AL at baseline and 2 years after wearing OK were collected. Univariate analysis and trend test were used to estimate the relationship between change in AL and baseline SER. RESULTS: After univariate analysis, a statistically significant relationship was found between change in AL and baseline SER (beta=0.061, 95% CI: 0.015-0.111, P=0.015). In the trend test, after adjusting for potential confounders, higher SER was associated with smaller increases in AL (P trend=0.041). CONCLUSIONS: The SER at baseline was associated with AL growth in myopic children wearing OK. The higher SER was associated with slower AL growth and control the development of myopia. PMID- 26254303 TI - Distribution of Short-Term and Lifetime Predicted Risks of Cardiovascular Diseases in Peruvian Adults. AB - BACKGROUND: Short-term risk assessment tools for prediction of cardiovascular disease events are widely recommended in clinical practice and are used largely for single time-point estimations; however, persons with low predicted short-term risk may have higher risks across longer time horizons. METHODS AND RESULTS: We estimated short-term and lifetime cardiovascular disease risk in a pooled population from 2 studies of Peruvian populations. Short-term risk was estimated using the atherosclerotic cardiovascular disease Pooled Cohort Risk Equations. Lifetime risk was evaluated using the algorithm derived from the Framingham Heart Study cohort. Using previously published thresholds, participants were classified into 3 categories: low short-term and low lifetime risk, low short-term and high lifetime risk, and high short-term predicted risk. We also compared the distribution of these risk profiles across educational level, wealth index, and place of residence. We included 2844 participants (50% men, mean age 55.9 years [SD 10.2 years]) in the analysis. Approximately 1 of every 3 participants (34% [95% CI 33 to 36]) had a high short-term estimated cardiovascular disease risk. Among those with a low short-term predicted risk, more than half (54% [95% CI 52 to 56]) had a high lifetime predicted risk. Short-term and lifetime predicted risks were higher for participants with lower versus higher wealth indexes and educational levels and for those living in urban versus rural areas (P<0.01). These results were consistent by sex. CONCLUSIONS: These findings highlight potential shortcomings of using short-term risk tools for primary prevention strategies because a substantial proportion of Peruvian adults were classified as low short-term risk but high lifetime risk. Vulnerable adults, such as those from low socioeconomic status and those living in urban areas, may need greater attention regarding cardiovascular preventive strategies. PMID- 26254304 TI - Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis. AB - The PARK2 gene is mutated in 50% of autosomal recessive juvenile parkinsonism (ARJP) cases. It encodes parkin, an E3 ubiquitin ligase of the RBR family. Parkin exists in an autoinhibited state that is activated by phosphorylation of its N terminal ubiquitin-like (Ubl) domain and binding of phosphoubiquitin. We describe the 1.8 A crystal structure of human parkin in its fully inhibited state and identify the key interfaces to maintain parkin inhibition. We identify the phosphoubiquitin-binding interface, provide a model for the phosphoubiquitin parkin complex and show how phosphorylation of the Ubl domain primes parkin for optimal phosphoubiquitin binding. Furthermore, we demonstrate that the addition of phosphoubiquitin leads to displacement of the Ubl domain through loss of structure, unveiling a ubiquitin-binding site used by the E2~Ub conjugate, thus leading to active parkin. We find the role of the Ubl domain is to prevent parkin activity in the absence of the phosphorylation signals, and propose a model for parkin inhibition, optimization for phosphoubiquitin recruitment, release of inhibition by the Ubl domain and engagement with an E2~Ub conjugate. Taken together, this model provides a mechanistic framework for activating parkin. PMID- 26254305 TI - A Ubl/ubiquitin switch in the activation of Parkin. AB - Mutations in Parkin and PINK1 cause an inherited early-onset form of Parkinson's disease. The two proteins function together in a mitochondrial quality control pathway whereby PINK1 accumulates on damaged mitochondria and activates Parkin to induce mitophagy. How PINK1 kinase activity releases the auto-inhibited ubiquitin ligase activity of Parkin remains unclear. Here, we identify a binding switch between phospho-ubiquitin (pUb) and the ubiquitin-like domain (Ubl) of Parkin as a key element. By mutagenesis and SAXS, we show that pUb binds to RING1 of Parkin at a site formed by His302 and Arg305. pUb binding promotes disengagement of the Ubl from RING1 and subsequent Parkin phosphorylation. A crystal structure of Parkin Delta86-130 at 2.54 A resolution allowed the design of mutations that specifically release the Ubl domain from RING1. These mutations mimic pUb binding and promote Parkin phosphorylation. Measurements of the E2 ubiquitin-conjugating enzyme UbcH7 binding to Parkin and Parkin E3 ligase activity suggest that Parkin phosphorylation regulates E3 ligase activity downstream of pUb binding. PMID- 26254306 TI - Toll-like receptor 4-interacting SPA4 peptide suppresses the NLRP3 inflammasome in response to LPS and ATP stimuli. AB - Inflammation is induced because of interplay among multiple signaling pathways and molecules during infectious and noninfectious tissue injuries. Crosstalk between Toll-like receptor-4 signaling and the neuronal apoptosis inhibitor protein, major histocompatibility class 2 transcription activator, incompatibility locus protein from Podospora anserina, and telomerase-associated protein (NACHT), leucine-rich repeat (LRR), and pyrin domain-containing protein 3 (NLRP3) inflammasome against pathogen- or damage-associated molecular patterns can cause exaggerated inflammation. We previously established that the Toll-like receptor-4-interacting SPA4 peptide suppresses gram-negative bacterial lipopolysaccharide (Toll-like receptor-4 ligand)-induced nuclear factor-kappaB and inflammatory response. In the present study, we hypothesized that the SPA4 peptide exerts its anti-inflammatory effects by suppressing the crosstalk between Toll-like receptor-4 signaling and the NLRP3 inflammasome. We evaluated binding of the lipopolysaccharide-ligand to cell-surface Toll-like receptor-4 in the presence or absence of adenosine triphosphate (an NLRP3 inflammasome inducer) by flow cytometry. The expression and activity of NLRP3 inflammasome-related parameters were studied in cells challenged with lipopolysaccharide and adenosine triphosphate using molecular and immunologic methods. The cells were challenged with lipopolysaccharide and treated with SPA4 peptide before (pre-adenosine triphosphate) or after (post-adenosine triphosphate) secondary challenge with adenosine triphosphate. Our data demonstrate that the Toll-like receptor-4 interacting SPA4 peptide does not affect the binding of lipopolysaccharide to Toll-like receptor-4 in the presence or absence of adenosine triphosphate. We also found that the SPA4 peptide inhibits mRNA and cellular protein levels of pro interleukin-1beta and NLRP3, formation of the NLRP3 inflammasome, caspase activity, and release of interleukin-1beta. Furthermore, the SPA4 peptide treatment reduced the secreted levels of interleukin-1beta from cells overexpressing Toll-like receptor-4 compared with cells expressing the dominant negative form of Toll-like receptor-4. Together our results suggest that the SPA4 peptide exerts its anti-inflammatory activity by suppressing Toll-like receptor-4 priming of the NLRP3 inflammasome. PMID- 26254307 TI - Impaired innate immune response of leukocytes from ascitic fluid of patients with spontaneous bacterial peritonitis. AB - An ascitic microenvironment can condition the immune response of cells from cirrhotic patients with spontaneous bacterial peritonitis. To characterize this response, we determined the cytokine concentrations in ascitic fluid and analyzed the phenotype and function of ascitic leukocytes at diagnosis and after antibiotic-induced resolution in sterile ascites and ascitic fluid of 2 spontaneous bacterial peritonitis variants: positive and negative bacteriological culture. At diagnosis, a high concentration was found of IL-6 and IL-10 in the ascitic fluid from negative and positive bacteriological culture. The IL-6 concentration correlated with the percentage of neutrophils (R = 0.686, P < 0.001). In this context, positive and negative culture neutrophils had an impaired oxidative burst, and, after the antibiotic, the negative culture spontaneous bacterial peritonitis burst was fully recovered. Higher concentrations of IL-6 and IL-10 correlated with the presence of low granular CD 14(low) macrophages (R = -0.436, P = 0.005 and R = 0.414, P = 0.007, respectively). Positive culture spontaneous bacterial peritonitis macrophages expressed the lowest levels of CD16, CD86, CD11b and CD206, and HLA-DR, suggesting an impaired global function. Treatment increased all markers on the positive culture macrophages and CD11b and CD86 on negative culture macrophages. In negative culture spontaneous bacterial peritonitis, this increase was accompanied by phagocytic function recovery. The antibiotics then reverted the marker levels on positive and negative culture macrophages to the levels on sterile ascitis macrophages and restored ascitic negative culture cell function. PMID- 26254308 TI - HDL-apolipoprotein A-I exchange is independently associated with cholesterol efflux capacity. AB - HDL is the primary mediator of cholesterol mobilization from the periphery to the liver via reverse cholesterol transport (RCT). A critical first step in this process is the uptake of cholesterol from lipid-loaded macrophages by HDL, a function of HDL inversely associated with prevalent and incident cardiovascular disease. We hypothesized that the dynamic ability of HDL to undergo remodeling and exchange of apoA-I is an important and potentially rate-limiting aspect of RCT. In this study, we investigated the relationship between HDL-apoA-I exchange (HAE) and serum HDL cholesterol (HDL-C) efflux capacity. We compared HAE to the total and ABCA1-specific cholesterol efflux capacity of 77 subjects. We found that HAE was highly correlated with both total (r = 0.69, P < 0.0001) and ABCA1 specific (r = 0.47, P < 0.0001) efflux, and this relationship remained significant after adjustment for HDL-C or apoA-I. Multivariate models of sterol efflux capacity indicated that HAE accounted for approximately 25% of the model variance for both total and ABCA1-specific efflux. We conclude that the ability of HDL to exchange apoA-I and remodel, as measured by HAE, is a significant contributor to serum HDL efflux capacity, independent of HDL-C and apoA-I, indicating that HDL dynamics are an important factor in cholesterol efflux capacity and likely RCT. PMID- 26254309 TI - Oral rice-based vaccine induces passive and active immunity against enterotoxigenic E. coli-mediated diarrhea in pigs. AB - Enterotoxigenic Escherichia coli (ETEC) causes severe diarrhea in both neonatal and weaned pigs. Because the cholera toxin B subunit (CTB) has a high level of amino acid identity to the ETEC heat-labile toxin (LT) B-subunit (LTB), we selected MucoRice-CTB as a vaccine candidate against ETEC-induced pig diarrhea. When pregnant sows were orally immunized with MucoRice-CTB, increased amounts of antigen-specific IgG and IgA were produced in their sera. CTB-specific IgG was secreted in the colostrum and transferred passively to the sera of suckling piglets. IgA antibodies in the colostrum and milk remained high with a booster dose after farrowing. Additionally, when weaned minipigs were orally immunized with MucoRice-CTB, production of CTB-specific intestinal SIgA, as well as systemic IgG and IgA, was induced. To evaluate the cross-protective effect of MucoRice-CTB against ETEC diarrhea, intestinal loop assay with ETEC was conducted. The fluid volume accumulated in the loops of minipigs immunized with MucoRice-CTB was significantly lower than that in control minipigs, indicating that MucoRice-CTB-induced cross-reactive immunity could protect weaned pigs from diarrhea caused by ETEC. MucoRice-CTB could be a candidate oral vaccine for inducing both passive and active immunity to protect both suckling and weaned piglets from ETEC diarrhea. PMID- 26254310 TI - Intracellular Scaling Mechanisms. AB - Organelle function is often directly related to organelle size. However, it is not necessarily absolute size but the organelle-to-cell-size ratio that is critical. Larger cells generally have increased metabolic demands, must segregate DNA over larger distances, and require larger cytokinetic rings to divide. Thus, organelles often must scale to the size of the cell. The need for scaling is particularly acute during early development during which cell size can change rapidly. Here, we highlight scaling mechanisms for cellular structures as diverse as centrosomes, nuclei, and the mitotic spindle, and distinguish them from more general mechanisms of size control. In some cases, scaling is a consequence of the underlying mechanism of organelle size control. In others, size-control mechanisms are not obviously related to cell size, implying that scaling results indirectly from cell-size-dependent regulation of size-control mechanisms. PMID- 26254311 TI - Growing an Embryo from a Single Cell: A Hurdle in Animal Life. AB - A requirement that an animal be able to feed to grow constrains how a cell can grow into an animal, and it forces an alternation between growth (increase in mass) and proliferation (increase in cell number). A growth-only phase that transforms a stem cell of ordinary proportions into a huge cell, the oocyte, requires dramatic adaptations to help a nucleus direct a 10(5)-fold expansion of cytoplasmic volume. Proliferation without growth transforms the huge egg into an embryo while still accommodating an impotent nucleus overwhelmed by the voluminous cytoplasm. This growth program characterizes animals that deposit their eggs externally, but it is changed in mammals and in endoparasites. In these organisms, development in a nutritive environment releases the growth constraint, but growth of cells before gastrulation requires a new program to sustain pluripotency during this growth. PMID- 26254312 TI - Genome Biology and the Evolution of Cell-Size Diversity. AB - Cell size is highly variable among different species across the Tree of Life. For decades, biologists have generated hypotheses to explain this variation, in many cases, drawing on the correlations that exist among cell size, genome size, nucleus size, and various physiological and developmental parameters. In recent years, our understanding of the molecular processes that generate variation in genome size over evolutionary time, as well as the processes that maintain homeostasis in cell size over ontogenetic time, has increased dramatically. The goal of this article is to highlight how information from these fields can be integrated to generate new hypotheses to explain cell-size diversity. PMID- 26254314 TI - Changes in general practitioners' sensitivity to patients' distress in low back pain consultations. AB - OBJECTIVE: We aim to study GPs' sensitivity to patients' distress and communication on psychosocial factors prior to and after the introduction of the clinical guideline for low back pain. METHODS: Consultations from previous studies on doctor-patient communication in the Netherlands were available for secondary analyses. We selected consultations in which patients presented low back pain complaints (N=168; 25 from 1989, 6 from 1995, 116 from 2001, 21 from 2008) and analyzed these consultations using the Roter Interaction Analysis System (RIAS) and the Verona Coding Definitions of Emotional Sequences (VR CoDES). RESULTS: GPs more often acknowledged psychosocial factors during consultations after implementation of the guideline for non-specific low back pain. Moreover, patients more often voiced their worries, while GPs put more emphasis on providing biomedical information and counseling during these consultations. CONCLUSIONS: GPs tend to emphasize biomedical factors rather than supporting their patients emotionally. Patients are likely to voice their worries implicitly, indicating they have a need for emotional support from their GPs. PRACTICE IMPLICATIONS: GPs now face the challenge of not only recognizing psychosocial aspects during consultations with low back pain, but also actively eliciting concerns regarding these psychosocial aspects. PMID- 26254315 TI - Race/ethnicity and Americans' experiences with treatment decision making. AB - OBJECTIVE: Despite widespread documentation of racial/ethnic disparities in medical care, population-wide variation in Americans' experiences with care are not well understood. We examined whether race/ethnicity is associated with information received from physicians regarding treatment recommendations. METHODS: We conducted a secondary analysis of cross-sectional survey data from a nationally representative sample (N=1238). We assessed patients' personal experiences of receiving information about the rationale for treatment recommendations from their physicians. RESULTS: Overall, respondents of minority race/ethnicity received less information from their doctors about the rationale for treatment recommendations. After adjustment for possible confounders, doctors talked less often with patients of 'other' race/ethnicity about reasons for treatment recommendations. Both Blacks' and Hispanics' doctors less often cited their own experiences, or scientific research as a reason for treatment recommendations. CONCLUSION: Americans' experiences with information communicated by physicians regarding treatment rationale varies significantly on some dimensions by race/ethnicity, suggesting that differences in key elements of shared decision making are evident in the care of racial/ethnic minorities. PRACTICE IMPLICATIONS: Physicians should evaluate the extent to which their communication with patients varies by patient race/ethnicity, and make efforts to ensure that they share equally with all patients regarding the rationale for treatment recommendations. PMID- 26254313 TI - Cell-Size Control. AB - Cells of a given type maintain a characteristic cell size to function efficiently in their ecological or organismal context. They achieve this through the regulation of growth rates or by actively sensing size and coupling this signal to cell division. We focus this review on potential size-sensing mechanisms, including geometric, external cue, and titration mechanisms. Mechanisms that titrate proteins against DNA are of particular interest because they are consistent with the robust correlation of DNA content and cell size. We review the literature, which suggests that titration mechanisms may underlie cell-size sensing in Xenopus embryos, budding yeast, and Escherichia coli, whereas alternative mechanisms may function in fission yeast. PMID- 26254316 TI - Exploring healthcare communication models in private physiotherapy practice. AB - OBJECTIVE: This project explored whether models of healthcare communication are evident within patient-physiotherapist communication in the private practice setting. METHODS: Using qualitative ethnographic methods, fifty-two patient physiotherapist treatment sessions were observed and interviews with nine physiotherapists were undertaken. Data were analyzed using thematic analysis. RESULTS: In these clinical encounters physiotherapists led the communication. The communication was structured and focussed on physical aspects of the patient's presentation. These features were mediated via casual conversation and the use of touch to respond to the individual patient. Physiotherapists did not explicitly link their therapeutic communication style to established communication models. However, they described a purposeful approach to how they communicated within the treatment encounter. CONCLUSION: The communication occurring in the private practice physiotherapy treatment encounter is predominantly representative of a 'practitioner-centred' model. However, the subtle use of touch and casual conversation implicitly communicate competence and care, representative of a patient-centred model. Physiotherapists do not explicitly draw from theories of communication to inform their practice. PRACTICE IMPLICATIONS: Physiotherapists may benefit from further education to achieve patient-centred communication. Equally, the incorporation of casual conversation and the use of touch into theory of physiotherapy patient-centred communication would highlight these specific skills that physiotherapists already utilize in practice. PMID- 26254318 TI - Physiological responses of ectotherms to daily temperature variation. AB - Daily thermal fluctuations (DTFs) impact the capacity of ectotherms to maintain performance and energetic demands because of thermodynamic effects on physiological processes. Mechanisms that reduce the thermal sensitivity of physiological traits may buffer ectotherms from the consequences of DTFs. Species that experience varying degrees of DTFs in their environments may differ in their responses to thermally variable conditions, if thermal performance curves reflect environmental conditions. We tested the hypothesis that in response to DTFs, tadpoles from habitats characterised by small DTFs would show greater plasticity in the thermal sensitivity of physiological processes than tadpoles from environments characterised by large DTFs. We tested the thermal sensitivity of physiological traits in tadpoles of three species that differ naturally in their exposure to DTFs, raised in control (24 degrees C) and DTF treatments (20-30 degrees C and 18-38 degrees C). DTFs reduced growth in all species. Development of tadpoles experiencing DTFs was increased for tadpoles from highly thermally variable habitats (~15%), and slower in tadpoles from less thermally variable habitats (~30%). In general, tadpoles were unable to alter the thermal sensitivity of physiological processes, although DTFs induced plasticity in metabolic enzyme activity in all species, although to a greater extent in species from less thermally variable environments. DTFs increased upper thermal limits in all species (between 0.89 and 1.6 degrees C). Our results suggest that the impact of increased thermal variability may favour some species while others are negatively impacted. Species that cannot compensate for increased variability by buffering growth and development will probably be most affected. PMID- 26254317 TI - Preferences for Aftercare Among Persons Seeking Short-Term Opioid Detoxification. AB - Without aftercare treatment, the period following discharge from short-term inpatient detoxification for opioid dependence presents a high risk of relapse. Yet the role of patient preference in treatment selection is rarely discussed in the substance-abuse literature. We surveyed 485 persons initiating inpatient opioid detoxification who were predominantly male (71.3%) and had detoxed in the past (73.2%). When asked to choose the one treatment that would work best for them after discharge, 43% of participants selected medication-assisted treatment (MAT), 29% preferred residential, 12% selected drug-free counseling, 12% NA/AA meetings only, and 4% preferred no additional treatment. Residential treatment preference was significantly associated with homelessness, having been in a detox program within the past year, and having pending legal problems, indicating that there is a distinct profile of detox patients who prefer residential treatment despite its limited availability. Detox program staff should work with patients to understand reasons for treatment preferences to optimize aftercare services. PMID- 26254319 TI - Grizzly bear (Ursus arctos horribilis) locomotion: gaits and ground reaction forces. AB - Locomotion of plantigrade generalists has been relatively little studied compared with more specialised postures even though plantigrady is ancestral among quadrupeds. Bears (Ursidae) are a representative family for plantigrade carnivorans, they have the majority of the morphological characteristics identified for plantigrade species, and they have the full range of generalist behaviours. This study compared the locomotion of adult grizzly bears (Ursus arctos horribilis Linnaeus 1758), including stride parameters, gaits and analysis of three-dimensional ground reaction forces, with that of previously studied quadrupeds. At slow to moderate speeds, grizzly bears use walks, running walks and canters. Vertical ground reaction forces demonstrated the typical M-shaped curve for walks; however, this was significantly more pronounced in the hindlimb. The rate of force development was also significantly higher for the hindlimbs than for the forelimbs at all speeds. Mediolateral forces were significantly higher than would be expected for a large erect mammal, almost to the extent of a sprawling crocodilian. There may be morphological or energetic explanations for the use of the running walk rather than the trot. The high medial forces (produced from a lateral push by the animal) could be caused by frontal plane movement of the carpus and elbow by bears. Overall, while grizzly bears share some similarities with large cursorial species, their locomotor kinetics have unique characteristics. Additional studies are needed to determine whether these characters are a feature of all bears or plantigrade species. PMID- 26254320 TI - Effects of insulin and its related signaling pathways on lipid metabolism in the yellow catfish Pelteobagrus fulvidraco. AB - The influence of insulin on hepatic metabolism in fish is not well understood. The present study was therefore conducted to investigate the effects of insulin on lipid metabolism, and the related signaling pathways, in the yellow catfish Pelteobagrus fulvidraco. Hepatic lipid and intracellular triglyceride (TG) content, the activity and expression levels of several enzymes and the mRNA expression of transcription factors (PPARalpha and PPARgamma) involved in lipid metabolism were determined. Troglitazone, GW6471, fenofibrate and wortmannin were used to explore the signaling pathways by which insulin influences lipid metabolism. Insulin tended to increase hepatic lipid accumulation, the activity of lipogenic enzymes (6PGD, G6PD, ME, ICDH and FAS) and mRNA levels of FAS, G6PD, 6PGD, CPT IA and PPARgamma, but down-regulated PPARalpha mRNA level. The insulin induced effect could be stimulated by the specific PPARgamma activator troglitazone or reversed by the PI3 kinase/Akt inhibitor wortmannin, demonstrating that signaling pathways of PPARgamma and PI3 kinase/Akt were involved in the insulin-induced alteration of lipid metabolism. The specific PPARalpha pathway activator fenofibrate reduced insulin-induced TG accumulation, down-regulated the mRNA levels of FAS, G6PD and 6PGD, and up-regulated mRNA levels of CPT IA, PPARalpha and PPARgamma. The specific PPARalpha pathway inhibitor GW6471 reduced insulin-induced changes in the expression of all the tested genes, indicating that PPARalpha mediated the insulin-induced changes of lipid metabolism. The present results contribute new knowledge on the regulatory role of insulin in hepatic metabolism in fish. PMID- 26254321 TI - Hypercapnia and low pH induce neuroepithelial cell proliferation and emersion behaviour in the amphibious fish Kryptolebias marmoratus. AB - Aquatic hypercapnia may have helped to drive ancestral vertebrate invasion of land. We tested the hypothesis that amphibious fishes sense and respond to elevated aquatic PCO2 by behavioural avoidance mechanisms, and by morphological changes at the chemoreceptor level. Mangrove rivulus (Kryptolebias marmoratus) were exposed to 1 week of normocapnic control water (pH 8), air, hypercapnia (5% CO2, pH 6.8) or isocapnic acidosis (pH 6.8). We found that the density of CO2/H(+) chemoreceptive neuroepithelial cells (NECs) was increased in hypercapnia or isocapnic acidosis-exposed fish. Projection area (a measure of cell size) was unchanged. Acute exposure to progressive hypercapnia induced the fish to emerse (leave water) at water pH values ~6.1, whereas addition of HCl to water caused a more variable response with a lower pH threshold (~pH 5.5). These results support our hypothesis and suggest that aquatic hypercapnia provides an adequate stimulus for extant amphibious fishes to temporarily transition from aquatic to terrestrial habitats. PMID- 26254322 TI - A novel acoustic-vibratory multimodal duet. AB - The communication strategy of most crickets and bushcrickets typically consists of males broadcasting loud acoustic calling songs, while females perform phonotaxis, moving towards the source of the call. Males of the pseudophylline bushcricket species Onomarchus uninotatus produce an unusually low-pitched call, and we found that the immediate and most robust response of females to the male acoustic call was a bodily vibration, or tremulation, following each syllable of the call. We hypothesized that these bodily oscillations might send out a vibrational signal along the substrate on which the female stands, which males could use to localize her position. We quantified these vibrational signals using a laser vibrometer and found a clear phase relationship of alternation between the chirps of the male acoustic call and the female vibrational response. This system therefore constitutes a novel multimodal duet with a reliable temporal structure. We also found that males could localize the source of vibration but only if both the acoustic and vibratory components of the duet were played back. This unique multimodal duetting system may have evolved in response to higher levels of bat predation on searching bushcricket females than calling males, shifting part of the risk associated with partner localization onto the male. This is the first known example of bushcricket female tremulation in response to a long-range male acoustic signal and the first known example of a multimodal duet among animals. PMID- 26254323 TI - Physiological, pharmacological and behavioral evidence for a TRPA1 channel that can elicit defensive responses in the medicinal leech. AB - Transient receptor potential ankyrin subtype 1 (TRPA1) channels are chemosensitive to compounds such as allyl isothiocyanate (AITC, the active component of mustard oil) and other reactive electrophiles and may also be thermodetectors in many animal phyla. In this study, we provide the first pharmacological evidence of a putative TRPA1-like channel in the medicinal leech. The leech's polymodal nociceptive neuron was activated by both peripheral and central application of the TRPA1 agonist AITC in a concentration-dependent manner. Responses to AITC were inhibited by the selective TRPA1 antagonist HC030031, but also by the TRPV1 antagonist SB366791. Other TRPA1 activators - N methylmaleimide (NMM) and cinnamaldehyde (CIN) - also activated this nociceptive neuron, although HC030031 only inhibited the effects of NMM. The polymodal nociceptive neurons responded to moderately cold thermal stimuli (<17 degrees C) and these responses were blocked by HC030031. AITC sensitivity was also found in the pressure-sensitive sensory neurons and was blocked by HC030031, but not by SB366791. AITC elicited a nocifensive withdrawal of the posterior sucker in a concentration-dependent manner that could be attenuated with HC030031. Peripheral application of AITC in vivo also produced swimming-like behavior that was attenuated by HC030031. These results suggest the presence of a TRPA1-like channel in the medicinal leech nervous system that responds to cold temperatures and may interact with the leech TRPV-like channel. PMID- 26254324 TI - How do treadmill speed and terrain visibility influence neuromuscular control of guinea fowl locomotion? AB - Locomotor control mechanisms must flexibly adapt to both anticipated and unexpected terrain changes to maintain movement and avoid a fall. Recent studies revealed that ground birds alter movement in advance of overground obstacles, but not treadmill obstacles, suggesting context-dependent shifts in the use of anticipatory control. We hypothesized that differences between overground and treadmill obstacle negotiation relate to differences in visual sensory information, which influence the ability to execute anticipatory manoeuvres. We explored two possible explanations: (1) previous treadmill obstacles may have been visually imperceptible, as they were low contrast to the tread, and (2) treadmill obstacles are visible for a shorter time compared with runway obstacles, limiting time available for visuomotor adjustments. To investigate these factors, we measured electromyographic activity in eight hindlimb muscles of the guinea fowl (Numida meleagris, N=6) during treadmill locomotion at two speeds (0.7 and 1.3 m s(-1)) and three terrain conditions at each speed: (i) level, (ii) repeated 5 cm low-contrast obstacles (<10% contrast, black/black), and (iii) repeated 5 cm high-contrast obstacles (>90% contrast, black/white). We hypothesized that anticipatory changes in muscle activity would be higher for (1) high-contrast obstacles and (2) the slower treadmill speed, when obstacle viewing time is longer. We found that treadmill speed significantly influenced obstacle negotiation strategy, but obstacle contrast did not. At the slower speed, we observed earlier and larger anticipatory increases in muscle activity and shifts in kinematic timing. We discuss possible visuomotor explanations for the observed context-dependent use of anticipatory strategies. PMID- 26254325 TI - Forelimb kinematics during hopping and landing in toads. AB - Coordinated landing in a variety of animals involves the re-positioning of limbs prior to impact to safely decelerate the body. However, limb kinematics strategies for landing vary considerably among species. For example, human legs are increasingly flexed before impact as drop height increases, while turkeys increasingly extend their legs before impact with increasing drop height. In anurans, landing typically involves the use of the forelimbs to decelerate the body after impact. Few detailed, quantitative descriptions of anuran forelimb kinematics during jumping exist and it is not known whether they prepare for larger landing forces by changing forelimb kinematics. In this study, we used high-speed video of 51 hops from five cane toads (Bufo marinus) to test the hypothesis that forelimb kinematics change predictably with distance. We measured excursions of the elbow (flexion/extension) and humerus (protraction/retraction and elevation/depression) throughout every hop. The results indicate that elbow and humeral excursions leading up to impact increase significantly with hop length, but do so without any change in the rate of movement. Instead, because the animal is in the air longer during longer hops, near-constant velocity movements lead to the larger excursions. These larger excursions in elbow extension result in animals hitting the ground with more extended forelimbs in longer hops, which in turn allows animals to decelerate over a greater distance. PMID- 26254326 TI - Building a dishonest signal: the functional basis of unreliable signals of strength in males of the two-toned fiddler crab, Uca vomeris. AB - Males of many species use signals during aggressive contests to communicate their fighting capacity. These signals are usually reliable indicators of an individual's underlying quality; however, in several crustacean species, displays of weapons do not always accurately reflect the attribute being advertised. Male fiddler crabs possess one enlarged claw that is used to attract females and to intimidate opponents during territorial contests. After the loss of their major claw, males can regenerate a replacement claw that is similar in size but considerably weaker. As this inferior weapon can still be used to successfully intimidate rivals, it represents one of the clearest cases of unreliable signalling of strength during territorial contests. We investigated the functional mechanisms that govern signal reliability in the two-toned fiddler crab, Uca vomeris. Male U. vomeris exhibit both reliable and unreliable signals of strength via the expression of original and regenerated claw morphs. We examined the morphological, biomechanical and biochemical characteristics of original and regenerated claws to establish the best predictors of variation in claw strength. For a given claw size, regenerated claws have less muscle mass than original claws, and for a given muscle mass, regenerated claws were significantly weaker than original claws. The mechanical advantage was also lower in regenerated claws compared with original claws. However, the activity of three catabolic enzymes did not differ between claw types. We conclude that the structural and physiological predictors of force production influence the frequencies of reliable and unreliable signals of strength in U. vomeris. This study furthers our understanding of the proliferation of unreliable signals in natural populations. PMID- 26254327 TI - Overexpressing OsPIN2 enhances aluminium internalization by elevating vesicular trafficking in rice root apex. AB - Aluminium (Al) sequestration is required for internal detoxification of Al in plant cells. In this study, it was found that the rice OsPIN2 overexpression line (OX1) had significantly reduced Al content in its cell wall and increased Al concentration in cell sap only in rice root tips relative to the wild-type (WT). In comparison with WT, OX1 reduced morin staining of cytosolic Al, enhanced FM 4 64 staining of membrane vesicular trafficking in root tip sections (0-1mm), and showed morin-FM 4-64 fluorescence overlap. Recovery treatment showed that cell wall-bound Al was internalized into vacuoles via endocytic vesicular trafficking after removal of external Al. In this process, OX1 showed a higher rate of Al internalization than WT. Brefeldin A (BFA) interfered with vesicular trafficking and resulted in inhibition of Al internalization. This inhibitory effect could be alleviated when BFA was washed out, and the process of alleviation was slower in the cells of WT than in those of OX1. Microscopic observations revealed that, upon Al exposure, numerous multilamellar endosomes were detected between the cell wall and plasma membrane in the cells of OX1. Moreover, more vesicles enriched with Al complexes accumulated in the cells of OX1 than in those of WT, and these vesicles transformed into larger structures in the cells of OX1. Taken together, the data indicate that endocytic vesicular trafficking might contribute to Al internalization, and that overexpressing OsPIN2 enhances rice Al tolerance via elevated endocytic vesicular trafficking and Al internalization. PMID- 26254328 TI - Presence of state transitions in the cryptophyte alga Guillardia theta. AB - Plants and algae have developed various regulatory mechanisms for optimal delivery of excitation energy to the photosystems even during fluctuating light conditions; these include state transitions as well as non-photochemical quenching. The former process maintains the balance by redistributing antennae excitation between the photosystems, meanwhile the latter by dissipating excessive excitation inside the antennae. In the present study, these mechanisms have been analysed in the cryptophyte alga Guillardia theta. Photoprotective non photochemical quenching was observed in cultures only after they had entered the stationary growth phase. These cells displayed a diminished overall photosynthetic efficiency, measured as CO2 assimilation rate and electron transport rate. However, in the logarithmic growth phase G. theta cells redistributed excitation energy via a mechanism similar to state transitions. These state transitions were triggered by blue light absorbed by the membrane integrated chlorophyll a/c antennae, and green light absorbed by the lumenal biliproteins was ineffective. It is proposed that state transitions in G. theta are induced by small re-arrangements of the intrinsic antennae proteins, resulting in their coupling/uncoupling to the photosystems in state 1 or state 2, respectively. G. theta therefore represents a chromalveolate algae able to perform state transitions. PMID- 26254329 TI - Alagebrium inhibits neointimal hyperplasia and restores distributions of wall shear stress by reducing downstream vascular resistance in obese and diabetic rats. AB - Mechanisms of restenosis in type 2 diabetes mellitus (T2DM) are incompletely elucidated, but advanced glycation end-product (AGE)-induced vascular remodeling likely contributes. We tested the hypothesis that AGE-related collagen cross linking (ARCC) leads to increased downstream vascular resistance and altered in stent hemodynamics, thereby promoting neointimal hyperplasia (NH) in T2DM. We proposed that decreasing ARCC with ALT-711 (Alagebrium) would mitigate this response. Abdominal aortic stents were implanted in Zucker lean (ZL), obese (ZO), and diabetic (ZD) rats. Blood flow, vessel diameter, and wall shear stress (WSS) were calculated after 21 days, and NH was quantified. Arterial segments (aorta, carotid, iliac, femoral, and arterioles) were harvested to detect ARCC and protein expression, including transforming growth factor-beta (TGF-beta) and receptor for AGEs (RAGE). Downstream resistance was elevated (60%), whereas flow and WSS were significantly decreased (44% and 56%) in ZD vs. ZL rats. NH was increased in ZO but not ZD rats. ALT-711 reduced ARCC and resistance (46%) in ZD rats while decreasing NH and producing similar in-stent WSS across groups. No consistent differences in RAGE or TGF-beta expression were observed in arterial segments. ALT-711 modified lectin-type oxidized LDL receptor 1 but not RAGE expression by cells on decellularized matrices. In conclusion, ALT-711 decreased ARCC, increased in-stent flow rate, and reduced NH in ZO and ZD rats through RAGE independent pathways. The study supports an important role for AGE-induced remodeling within and downstream of stent implantation to promote enhanced NH in T2DM. PMID- 26254331 TI - Vorticity is a marker of right ventricular diastolic dysfunction. AB - Right ventricular diastolic dysfunction (RVDD) is an important prognostic indicator in pulmonary arterial hypertension (PAH). RV vortex rings have been observed in healthy subjects, but their significance in RVDD is unknown. Vorticity, the local spinning motion of an element of fluid, may be a sensitive measure of RV vortex dynamics. Using four-dimensional (4D) flow cardiac magnetic resonance imaging (CMR), we investigated the relationship between right heart vorticity with echocardiographic indexes of RVDD. Thirteen (13) PAH subjects and 10 controls underwent same-day 4D flow CMR and echocardiography. RV diastolic function was assessed using trans-tricuspid valve (TV) early (E) and late (A) velocities, E/A ratio, and e' and a' tissue Doppler velocities. RV and right atrial (RA) integrated mean vorticity was calculated for E and A-wave filling periods using 4D datasets. Compared with controls, A-wave vorticity was significantly increased in RVDD subjects in both the RV [2343 (1,559-3,295) vs. 492 (267-2,649) 1/s, P = 0.028] and RA [30 (27-44) vs. 9 (5-27) 1/s, P = 0.005]. RA E vorticity was significantly decreased [13 (7-22) vs. 28 (15-31) 1/s, P = 0.038] in RVDD. E-wave vorticity correlated TV e', E-,and TV E/A (P < 0.05), and A-wave vorticity associated with both TV A and E/A (P < 0.02). RVDD is associated with alterations in E- and A-wave vorticity, and vorticity correlates with multiple echocardiographic markers of RVDD. Vorticity may be a robust noninvasive research tool for the investigation of RV fluid and tissue mechanical interactions in PAH. PMID- 26254330 TI - alpha-Lipoic acid reduces neurogenic hypertension by blunting oxidative stress mediated increase in ADAM17. AB - We previously reported that type 2 angiotensin-converting enzyme (ACE2) compensatory activity is impaired by the disintegrin and metalloprotease 17 (ADAM17), and lack of ACE2 is associated with oxidative stress in neurogenic hypertension. To investigate the relationship between ADAM17 and oxidative stress, Neuro2A cells were treated with ANG II (100 nM) 24 h after vehicle or alpha-lipoic acid (LA, 500 MUM). ADAM17 expression was increased by ANG II (120.5 +/- 9.1 vs. 100.2 +/- 0.8%, P < 0.05) and decreased after LA (69.0 +/- 0.3 vs. 120.5 +/- 9.1%, P < 0.05). In another set of experiments, LA reduced ADAM17 (92.9 +/- 5.3 vs. 100.0 +/- 11.2%, P < 0.05) following its overexpression. Moreover, ADAM17 activity was reduced by LA in ADAM17-overexpressing cells [109.5 +/- 19.8 vs. 158.0 +/- 20.0 fluorescence units (FU).min(-1).MUg protein(-1), P < 0.05], in which ADAM17 overexpression increased oxidative stress (114.1 +/- 2.5 vs. 101.0 +/- 1.0%, P < 0.05). Conversely, LA-treated cells attenuated ADAM17 overexpression-induced oxidative stress (76.0 +/- 9.1 vs. 114.1 +/- 2.5%, P < 0.05). In deoxycorticosterone acetate (DOCA)-salt hypertensive mice, a model in which ADAM17 expression and activity are increased, hypertension was blunted by pretreatment with LA (119.0 +/- 2.4 vs. 131.4 +/- 2.2 mmHg, P < 0.05). In addition, LA improved dysautonomia and baroreflex sensitivity. Furthermore, LA blunted the increase in NADPH oxidase subunit expression, as well as the increase in ADAM17 and decrease in ACE2 activity in the hypothalamus of DOCA-salt hypertensive mice. Taken together, these data suggest that LA might preserve ACE2 compensatory activity by breaking the feedforward cycle between ADAM17 and oxidative stress, resulting in a reduction of neurogenic hypertension. PMID- 26254332 TI - Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR. AB - Exercise training (ExT) is recommended to treat hypertension along with pharmaceutical antihypertensive therapies. Effects of ExT in hypothalamic content of high mobility box 1 (HMGB1) and microglial activation remain unknown. We examined whether ExT would decrease autonomic and cardiovascular abnormalities in spontaneously hypertensive rats (SHR), and whether these effects were associated with decreased HMGB1 content, microglial activation, and inflammation in the hypothalamic paraventricular nucleus (PVN). Normotensive Wistar-Kyoto (WKY) rats and SHR underwent moderate-intensity ExT for 2 wk. After ExT, cardiovascular (heart rate and arterial pressure) and autonomic parameters (arterial pressure and heart rate variability, peripheral sympathetic activity, cardiac vagal activity, and baroreflex function) were measured in conscious and freely-moving rats through chronic arterial and venous catheterization. Cerebrospinal fluid, plasma, and brain were collected for molecular and immunohistochemistry analyses of the PVN. In addition to reduced heart rate variability, decreased vagal cardiac activity and increased mean arterial pressure, heart rate, arterial pressure variability, cardiac, and vasomotor sympathetic activity, SHR had higher HMGB1 protein expression, IkappaB-alpha phosphorylation, TNF-alpha and IL-6 protein expression, and microglia activation in the PVN. These changes were accompanied by higher plasma and cerebrospinal fluid levels of HMGB1. The ExT + SHR group had decreased expression of HMGB1, CXCR4, SDF-1, and phosphorylation of p42/44 and IkappaB-alpha. ExT reduced microglial activation and proinflammatory cytokines content in the PVN, and improved autonomic control as well. Data suggest that training-induced downregulation of activated HMGB1/CXCR4/microglia/proinflammatory cytokines axis in the PVN of SHR is a prompt neural adaptation to counterbalance the deleterious effects of inflammation on autonomic control. PMID- 26254333 TI - Two weeks of high-intensity interval training improves novel but not traditional cardiovascular disease risk factors in adolescents. AB - High-intensity interval training (HIIT) improves traditional cardiovascular disease (CVD) risk factors in adolescents, but no study has identified the influence of HIIT on endothelial and autonomic function in this group. Thirteen 13- to 14-yr-old adolescents (6 girls) completed six HIIT sessions over 2 wk. Each training session consisted of eight to ten 1-min repetitions of cycling at 90% peak power interspersed with 75 s of unloaded cycling. Traditional (triglycerides, cholesterol, glucose, insulin, and blood pressure) and novel [flow-mediated dilation (FMD), heart rate variability (HRV)] CVD risk factors were assessed in a fasted and postprandial state before (PRE), 1 day after (POST 1D), and 3 days after (POST-3D) training. Aerobic fitness was determined PRE and POST-3D. Two weeks of HIIT had no effect on aerobic fitness or traditional CVD risk factors determined in the fasted or postprandial state (P > 0.15). Compared with PRE, fasted FMD was improved POST-1D [P = 0.003, effect size (ES) = 0.70] but not POST-3D (P = 0.32, ES = 0.22). Fasted FMD was greater POST-1D compared with POST-3D (P = 0.04, ES = 0.48). Compared with PRE, postprandial FMD was greater POST-1D (P < 0.001, ES = 1.01) and POST-3D (P = 0.01, ES = 0.60). Fasted HRV was greater POST-1D (P = 0.001, ES = 0.71) and POST-3D (P = 0.02, ES = 0.44). The test meal lowered HRV in all laboratory visits (P < 0.001, ES = 0.59), but there were no differences in postprandial HRV between visits (P > 0.32 for all). Two weeks of HIIT enhanced endothelial function and HRV without improvements in traditional CVD risk factors. However, most of this favorable adaptation was lost POST-3D, suggesting that regularly performing high-intensity exercise is needed to maintain these benefits. PMID- 26254334 TI - Blockade of Ets-1 attenuates epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells. AB - Although degradation of extracellular matrix by matrix metalloproteinases (MMPs) is thought to be involved in symptomatic (S) carotid plaques in atherosclerosis, the mechanisms of MMP expression are poorly understood. Here, we demonstrate that collagen loss in vascular smooth vessel cells (VSMCs) isolated from S plaques was induced by epidermal growth factor (EGF) through the activation of p38-MAPK and JNK-MAPK pathways. Inhibitors of p38-MAPK and JNK-MAPK signaling pathways downregulated the expression of MMP-1 and MMP-9. In addition, we examined whether v-ets erythroblastosis virus E26 oncogene homologue 1 (Ets-1), an important regulator of different genes, is involved in destabilizing S plaques in patients with carotid stenosis. We demonstrate that EGF induces Ets-1 expression and decreases interstitial and basement membrane collagen in vascular smooth muscle cells (VSMCs) from patients with carotid stenosis. Increased expression of MMP-1 and -9 and decreased collagen mRNA transcripts were also found in Ets-1 overexpressed VSMCs. Transfection with both dominant-negative form of Ets-1 and small interfering RNA blocked EGF-induced MMP-1 and -9 expressions and increased the mRNA transcripts for collagen I (alpha1) and collagen III (alpha1) in S compared with asymptomatic (AS) carotid plaques. Inhibitors of p38-MAPK (SB202190) and JNK-MAPK (SP600125) signaling pathways decreased the expression of Ets-1, MMP-1, and MMP-9 and increased collagen type I and III expression in EGF treated VSMCs. This study provides a mechanistic insight into the role of Ets-1 in the plaque destabilization in patients with carotid stenosis involving p38 MAPK and JNK signaling pathways. PMID- 26254335 TI - Long-term physiological T3 supplementation in hypertensive heart disease in rats. AB - Animal studies suggest that hypertension leads to cardiac tissue hypothyroidism, a condition that can by itself lead to heart failure. We have previously shown that short-term thyroid hormone treatment in Spontaneously Hypertensive Heart Failure (SHHF) rats near heart failure is beneficial. This study tested the hypothesis that therapeutic, long-term T3 treatment in SHHF rats can prevent or attenuate cardiac dysfunction. Female SHHF rats were treated orally with a physiological T3 dose (0.04 MUg/ml) from 12 to 24 mo of age. Age-matched female SHHF and Wistar-Kyoto rats served as hypertensive and normotensive controls, respectively. SHHF rats had reduced serum free thyroid hormone levels and cardiac tissue T3 levels, LV dysfunction, and elevated LV collagen content compared with normotensive controls. Restoration of serum and cardiac tissue thyroid hormone levels in T3-treated rats was associated with no change in heart rate, but strong trends for improvement in LV systolic function and collagen levels. For instance, end-systolic diameter, fractional shortening, systolic wall stress, and LV collagen levels were no longer significantly different from controls. In conclusion, longstanding hypertension in rats led to chronic low serum and cardiac tissue thyroid hormone levels. Long-term treatment with low-dose T3 was safe. While cardiac dysfunction could not be completely prevented in the absence of antihypertensive treatment, T3 may offer additional benefits as an adjunct therapy with possible improvement in diastolic function. PMID- 26254337 TI - Chemerin promotes the proliferation and migration of vascular smooth muscle and increases mouse blood pressure. AB - Blood chemerin concentration shows positive correlation not only with body mass index and serum triglyceride level but also with systolic blood pressure. While it seems likely that chemerin influences vascular smooth muscle cell (SMC) proliferation and migration, which are crucial to the development of hypertension, this remains to be clarified. In the present study, we investigated whether chemerin controls SMC proliferation and migration in vitro and also affects blood pressure in vivo. In vitro, chemerin significantly stimulated rat mesenteric arterial SMC proliferation and migration, as determined by a cell counting assay and Boyden chamber assay, respectively. The migratory effect of chemerin was confirmed in human aortic SMCs. Chemerin significantly increased ROS production in SMCs and phosphorylation of Akt (Ser(473)) and ERK, as measured by fluorescent staining and Western blot analysis, respectively. Various inhibitors (ROS inhibitor: N-acetyl-l-cysteine, phosphatidylinositol 3-kinase inhibitor: LY 294002, MAPKK inhibitor: PD-98059, NADPH oxidase inhibitor: gp91 ds-tat, and xanthine oxidase inhibitor: allopurinol) as well as chemokine-like receptor 1 small interfering RNA significantly inhibited chemerin-induced SMC proliferation and migration. Furthermore, chemerin-neutralizing antibody prevented carotid neointimal hyperplasia in the mouse ligation model. In vivo, chronic chemerin treatment (6 MUg/kg, 6 wk) increased systolic blood pressure as well as phosphorylation of Akt and ERK in the mouse isolated aorta. In summary, we, for the first time, demonstrate that chemerin/chemokine-like receptor 1 stimulates SMC proliferation and migration via ROS-dependent phosphorylation of Akt/ERK, which may lead to vascular structural remodeling and an increase in systolic blood pressure. PMID- 26254336 TI - ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity. AB - Levels of the HER2/ErbB2 protein in the heart are upregulated in some women during breast cancer therapy, and these women are at high risk for developing heart dysfunction after sequential treatment with anti-ErbB2/trastuzumab or doxorubicin. Doxorubicin is known to increase oxidative stress in the heart, and thus we considered the possibility that ErbB2 protein influences the status of cardiac antioxidant defenses in cardiomyocytes. In this study, we measured reactive oxygen species (ROS) in cardiac mitochondria and whole hearts from mice with cardiac-specific overexpression of ErbB2 (ErbB2(tg)) and found that, compared with control mice, high levels of ErbB2 in myocardium result in lower levels of ROS in mitochondria (P = 0.0075) and whole hearts (P = 0.0381). Neonatal cardiomyocytes isolated from ErbB2(tg) hearts have lower ROS levels and less cellular death (P < 0.0001) following doxorubicin treatment. Analyzing antioxidant enzyme levels and activities, we found that ErbB2(tg) hearts have increased levels of glutathione peroxidase 1 (GPx1) protein (P < 0.0001) and GPx activity (P = 0.0031) in addition to increased levels of two known GPx activators, c-Abl (P = 0.0284) and Arg (P < 0.0001). Interestingly, although mitochondrial ROS emission is reduced in the ErbB2(tg) hearts, oxygen consumption rates and complex I activity are similar to control littermates. Compared with these in vivo studies, H9c2 cells transfected with ErbB2 showed less cellular toxicity and produced less ROS (P < 0.0001) after doxorubicin treatment but upregulated GR activity (P = 0.0237) instead of GPx. Our study shows that ErbB2 dependent signaling contributes to antioxidant defenses and suggests a novel mechanism by which anticancer therapies involving ErbB2 antagonists can harm myocardial structure and function. PMID- 26254338 TI - Colocalization of a CD1d-Binding Glycolipid with a Radiation-Attenuated Sporozoite Vaccine in Lymph Node-Resident Dendritic Cells for a Robust Adjuvant Effect. AB - A CD1d-binding glycolipid, alpha-Galactosylceramide (alphaGalCer), activates invariant NK T cells and acts as an adjuvant. We previously identified a fluorinated phenyl ring-modified alphaGalCer analog, 7DW8-5, displaying nearly 100-fold stronger CD1d binding affinity. In the current study, 7DW8-5 was found to exert a more potent adjuvant effect than alphaGalCer for a vaccine based on radiation-attenuated sporozoites of a rodent malaria parasite, Plasmodium yoelii, also referred to as irradiated P. yoelii sporozoites (IrPySpz). 7DW8-5 had a superb adjuvant effect only when the glycolipid and IrPySpz were conjointly administered i.m. Therefore, we evaluated the effect of distinctly different biodistribution patterns of alphaGalCer and 7DW8-5 on their respective adjuvant activities. Although both glycolipids induce a similar cytokine response in sera of mice injected i.v., after i.m. injection, alphaGalCer induces a systemic cytokine response, whereas 7DW8-5 is locally trapped by CD1d expressed by dendritic cells (DCs) in draining lymph nodes (dLNs). Moreover, the i.m. coadministration of 7DW8-5 with IrPySpz results in the recruitment of DCs to dLNs and the activation and maturation of DCs. These events cause the potent adjuvant effect of 7DW8-5, resulting in the enhancement of the CD8(+) T cell response induced by IrPySpz and, ultimately, improved protection against malaria. Our study is the first to show that the colocalization of a CD1d-binding invariant NK T cell-stimulatory glycolipid and a vaccine, like radiation-attenuated sporozoites, in dLN-resident DCs upon i.m. conjoint administration governs the potency of the adjuvant effect of the glycolipid. PMID- 26254339 TI - Osteoprotegerin-Mediated Homeostasis of Rank+ Thymic Epithelial Cells Does Not Limit Foxp3+ Regulatory T Cell Development. AB - In the thymus, medullary thymic epithelial cells (mTEC) regulate T cell tolerance via negative selection and Foxp3(+) regulatory T cell (Treg) development, and alterations in the mTEC compartment can lead to tolerance breakdown and autoimmunity. Both the receptor activator for NF-kappaB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) axis and expression of the transcriptional regulator Aire are involved in the regulation of thymus medullary microenvironments. However, their impact on the mechanisms controlling mTEC homeostasis is poorly understood, as are the processes that enable the thymus medulla to support the balanced production of mTEC-dependent Foxp3(+) Treg. In this study, we have investigated the control of mTEC homeostasis and examined how this process impacts the efficacy of Foxp3(+) Treg development. Using newly generated RANK Venus reporter mice, we identify distinct RANK(+) subsets that reside within both the mTEC(hi) and mTEC(lo) compartments and that represent direct targets of OPG-mediated control. Moreover, by mapping OPG expression to a subset of Aire(+) mTEC, our data show how cis- and trans-acting mechanisms are able to control the thymus medulla by operating on multiple mTEC targets. Finally, we show that whereas the increase in mTEC availability in OPG-deficient (Tnfrsf11b(-/-)) mice impacts the intrathymic Foxp3(+) Treg pool by enhancing peripheral Treg recirculation back to the thymus, it does not alter the number of de novo Rag2pGFP(+)Foxp3(+) Treg that are generated. Collectively, our study defines patterns of RANK expression within the thymus medulla, and it shows that mTEC homeostasis is not a rate-limiting step in intrathymic Foxp3(+) Treg production. PMID- 26254341 TI - MAZR and Runx Factors Synergistically Repress ThPOK during CD8+ T Cell Lineage Development. AB - Th-inducing Pox virus and zinc finger/Kruppel-like factor (ThPOK) is a key commitment factor for CD4(+) lineage T cells and is essential for the maintenance of CD4 lineage integrity; thus, the expression of ThPOK has to be tightly controlled. In this article, we demonstrate that Myc-associated zinc finger related factor (MAZR) and Runt-related transcription factor 1 (Runx1) together repressed ThPOK in preselection double-positive thymocytes, whereas MAZR acted in synergy with Runx3 in the repression of ThPOK in CD8(+) T cells. Furthermore, MAZR-Runx1 and MAZR-Runx3 double-mutant mice showed enhanced derepression of Cd4 in double-negative thymocytes and in CD8(+) T cells in comparison with Runx1 or Runx3 single-deficient mice, respectively, indicating that MAZR modulates Cd4 silencing. Thus, our data demonstrate developmental stage-specific synergistic activities between MAZR and Runx/core-binding factor beta (CBFbeta) complexes. Finally, retroviral Cre-mediated conditional deletion of MAZR in peripheral CD8(+) T cells led to the derepression of ThPOK, thus showing that MAZR is also part of the molecular machinery that maintains a repressed state of ThPOK in CD8(+) T cells. PMID- 26254340 TI - Identification of a Potent Microbial Lipid Antigen for Diverse NKT Cells. AB - Semi-invariant/type I NKT cells are a well-characterized CD1d-restricted T cell subset. The availability of potent Ags and tetramers for semi-invariant/type I NKT cells allowed this population to be extensively studied and revealed their central roles in infection, autoimmunity, and tumor immunity. In contrast, diverse/type II NKT (dNKT) cells are poorly understood because the lipid Ags that they recognize are largely unknown. We sought to identify dNKT cell lipid Ag(s) by interrogating a panel of dNKT mouse cell hybridomas with lipid extracts from the pathogen Listeria monocytogenes. We identified Listeria phosphatidylglycerol as a microbial Ag that was significantly more potent than a previously characterized dNKT cell Ag, mammalian phosphatidylglycerol. Further, although mammalian phosphatidylglycerol-loaded CD1d tetramers did not stain dNKT cells, the Listeria-derived phosphatidylglycerol-loaded tetramers did. The structure of Listeria phosphatidylglycerol was distinct from mammalian phosphatidylglycerol because it contained shorter, fully-saturated anteiso fatty acid lipid tails. CD1d-binding lipid-displacement studies revealed that the microbial phosphatidylglycerol Ag binds significantly better to CD1d than do counterparts with the same headgroup. These data reveal a highly potent microbial lipid Ag for a subset of dNKT cells and provide an explanation for its increased Ag potency compared with the mammalian counterpart. PMID- 26254342 TI - CX3CL1-CX3CR1 Interaction Increases the Population of Ly6C(-)CX3CR1(hi) Macrophages Contributing to Unilateral Ureteral Obstruction-Induced Fibrosis. AB - Chemokines modulate inflammatory responses that are prerequisites for kidney injury. The specific role of monocyte-associated CX3CR1 and its cognate ligand CX3CL1 in unilateral ureteral obstruction (UUO)-induced kidney injury remains unclear. In this study, we found that UUO caused a CCR2-dependent increase in numbers of Ly6C(hi) monocytes both in the blood and kidneys and of Ly6C( )CX3CR1(+) macrophages in the obstructed kidneys of mice. Using CX3CR1(gfp/+) knockin mice, we observed a rapid conversion of infiltrating proinflammatory Ly6C(+)CX3CR1(1o) monocytes/macrophages to anti-inflammatory Ly6C(-)CX3CR1(hi) macrophages. CX3CR1 deficiency affected neither monocyte trafficking nor macrophage differentiation in vivo upon renal obstruction, but CX3CR1 expression in monocytes and macrophages was required for increases in fibrosis in the obstructed kidneys. Mechanistically, CX3CL1-CX3CR1 interaction increases Ly6C( )CX3CR1(hi) macrophage survival within the obstructed kidneys. Therefore, CX3CL1 and CX3CR1 may represent attractive therapeutic targets in obstructive nephropathy. PMID- 26254343 TI - Novel Molecular Targets for the Therapy of Urothelial Cancer. AB - First-line platinum-based chemotherapy combinations are considered standard-of care in locally advanced and metastatic urothelial cancer. However, long-term outcomes, including disease-specific and overall survival, remain poor. In addition, a number of patients with advanced urothelial carcinoma have co existing medical issues that preclude the use of conventional chemotherapy. Improvements in our understanding over the molecular mechanisms of urothelial cancer have led to first-generation clinical trials evaluating novel agents targeting molecular pathways that may be relevant, at least in sub-populations. Emerging information regarding outcome with agents targeting novel molecular targets in advanced urothelial cancer is discussed in this review. PMID- 26254344 TI - The Role of Methylation in Breast Cancer Susceptibility and Treatment. AB - DNA methylation is a critical mechanism of epigenetic modification involved in gene expression programming, that can promote the development of several cancers, including breast cancer. The methylation of CpG islands by DNA methyltransferases is reversible and has been shown to modify the transcriptional activity of key proliferation genes or transcription factors involved in suppression or promotion of cell growth. Indeed, aberrant methylation found in gene promoters is a hallmark of cancer that could be used as non-intrusive biomarker in body fluids such as blood and plasma for early detection of breast cancer. Many biomarker genes have been evaluated for breast cancer detection. However, in the absence of a unique biomarker having the sufficient specificity and sensitivity, a panel of multiple genes should be used. Treatments targeting aberrant methylation by DNA methyltransferase inhibitors, which trigger re-expression of silenced genes, are now available and allow for better treatment efficiency. PMID- 26254345 TI - Second-line Treatment of Advanced Gastric Cancer: Current Options and Future Perspectives. AB - Due to its high incidence and poor prognosis, gastric cancer is an important health problem worldwide. The only possible curative treatment is to remove the primary tumor at an early stage of the disease. However, at diagnosis, most patients have unresectable or metastatic disease. Relapse in patients after primary surgery is frequent. In these patients, the aim of treatment is to extend the duration of survival and to improve quality of life and this accomplished by systemic therapies. Regimens containing fluoropyrimidine and platinum agents, in combination with trastuzumab in patients with overexpression of human epidermal growth factor receptor 2 (HER2), are recommended as the first-line treatment. Unfortunately, all patients develop progressive disease, but at least half of them are eligible for further treatment. This article presents current possibilities and near-future developments of chemotherapy and molecular targeted therapy in patients with advanced gastric cancer after failure of prior regimens containing fluoropyrimidine and platinum. PMID- 26254346 TI - Nitric Oxide and Aggressive Behavior of Lung Cancer Cells. AB - Nitric oxide (NO) is an important cell signaling molecule whose level is frequently elevated in many tumors including that of lung. Cellular phenotypes and behaviors are influenced by NO found in proximity to the tumor, namely the tumor microenvironment. In lung cancer, a high level of NO is linked to advanced stage and poor survival of patients. This review describes the promotory role of NO in aggressive behavior of lung cancer cells with a focus on apoptosis and anoikis resistance, cell migration and invasion and cancer stem cells, all of which are key determinants of cancer relapse and metastasis. We specifically address the effects of NO on the modulations of structure, stability, function and activity of key proteins, and discuss how these changes could affect aggressive behavior. Such knowledge will encourage additional experimental and clinical investigations that contribute to the understanding of the molecular basis of cancer pathophysiology which could lead to targeted cancer therapy. PMID- 26254347 TI - Memory Antitumor T-Cells Resist Inhibition by Immune Suppressor Cells. AB - Cancer immune therapy is difficult partly because several classes of suppressor cells, including regulatory T-cells and macrophage-derived suppressor cells, inhibit the antitumor T-cell response. We used treatment studies of implanted tumors in mice to demonstrate that the same inhibitory cells that abrogated an acute therapeutic T-cell response to established tumor did not inhibit the therapeutic response produced by memory T-cells. Generating antitumor memory T cells may be a highly potent strategy against cancer with late developing metastases. PMID- 26254348 TI - Triciribine Phosphate Monohydrate, an AKT Inhibitor, Enhances Gemcitabine Activity in Pancreatic Cancer Cells. AB - BACKGROUND: Pancreatic cancer is a highly lethal cancer due to early metastasis and resistance to current chemotherapeutic agents. Abnormal protein kinase B (AKT) activation is an important mechanism of chemoresistance to gemcitabine, the most widely used agent in pancreatic cancer. MATERIAL AND METHODS: In the study, we tested the hypothesis that combining an AKT inhibitor with gemcitabine would augment anti-tumor activity. We treated human pancreatic cancer MiaPaCa-2 cells with gemcitabine and the AKT inhibitor triciribine, alone and in combination, and evaluated treatment effects using trypan blue assay, 3-[4,5-dimethylthiazol-2-yl] 2,5 diphenyl tetrazolium (MTT) assay, and cell death enzyme-linked immunosorbant assay. Colorimetric data of MTT assay were computationally analyzed for synergism of the combination therapy by CalcuSyn2 (Biosoft, Great Shelford, Cambridge, UK). RESULTS: Both gemcitabine and triciribine inhibited cell growth in a dose dependent manner. Triciribine synergistically enhanced the cytotoxic activity of gemcitabine. The combination index (CI) provides the synergistic, additive, or antagonistic effects of the two-drug combination. CI at the 50% effective dose at 1:500 ratio of gemcitabine to triciribine was 0.74, indicating the synergistic effect of the drugs. The combination treatment with the non-apoptotic dose of each agent distinctly induced apoptosis, with gemcitabine in combination with triciribine, synergistically inhibiting pancreatic cancer cell growth and inducing apoptosis. CONCLUSION: These findings support the use of triciribine to overcome activated AKT-mediated resistance of pancreatic cancer to gemcitabine. PMID- 26254349 TI - Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, TAS-102, with Oxaliplatin on Human Colorectal and Gastric Cancer Xenografts. AB - TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluridine (FTD) and the thymidine phosphorylase inhibitor tipiracil hydrochloride (at a molar ratio of 1:0.5) that was approved in Japan in 2014 for the treatment of unresectable advanced or recurrent colorectal cancer. In the present study, the enhancement of therapeutic efficacy using a combination of TAS-102 and oxaliplatin was evaluated in a xenograft-bearing nude mouse model of colorectal and gastric cancer. TAS-102 was orally administered twice-a-day from day 1 to 14, and oxaliplatin was administered intravenously on days 1 and 8. The in vivo growth-inhibitory activity was evaluated based on the tumor volume and the growth delay period, was estimated based on the period required to reach a tumor volume five-times greater than the initial volume (RTV5). The tumor growth-inhibitory activity and RTV5 in mice administered TAS-102 with oxaliplatin were significantly superior to those associated with either monotherapy in mice with colorectal (HCT 116, SW-48; p<0.001) and gastric cancer (SC-2, MKN74; p<0.001). MKN74/5FU, a 5-fluorouracil-resistant MKN74 sub-line, was sensitive to both FTD and oxaliplatin in vitro. In vivo, TAS-102 alone was effective in MKN74/5FU, and its anti-tumor activity was significantly enhanced in combination with oxaliplatin (p<0.001). No significant decrease in body weight or toxicity was observed compared to either monotherapy. The present pre-clinical findings indicate that combination of TAS-102 and oxaliplatin is a promising treatment option for colorectal or gastric cancer, and can be utilized in both chemo-naive tumors and recurrent tumors after 5-fluorouracil treatment. PMID- 26254350 TI - Suppressor microRNA-145 Is Epigenetically Regulated by Promoter Hypermethylation in Esophageal Squamous Cell Carcinoma. AB - BACKGROUND/AIM: DNA methylation is a common epigenetic change in cancer. However, microRNA (miRNA) regulation by epigenetic alteration, especially CpG island hypermethylation, remains poorly understood in esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: miRNAs which were up-regulated after de methylation with 5-aza-2'-deoxycytidine (5-AZA) were analyzed using the Human miFinder 384HC miScript miRNA PCR Array. The DNA methylation level was evaluated by bisulfite-pyrosequencing assay. RESULTS: In two of the cell lines, 20 miRNAs, including miR-145-5p, were found to be up-regulated by more than three-fold after 5-AZA treatment. The miRNA-145 promoter was significantly more hypermethylated in the cancer tissues than in matched normal adjacent esophageal epithelial mucosa (p=0.0042; paired t-test). Moreover, the miRNA-145-5p expression levels were significantly lower in cancerous tissues (p=0.0024). CONCLUSION: miRNA-145 expression in ESCC seems to be regulated by hypermethylation of the miRNA-145 promoter region. PMID- 26254351 TI - WNT16-expressing Acute Lymphoblastic Leukemia Cells are Sensitive to Autophagy Inhibitors after ER Stress Induction. AB - BACKGROUND: Previous work from our group showed hypoxia can induce endoplasmic reticulum (ER) stress and block the processing of the WNT3 protein in cells engineered to express WNT3a. Acute lymphoblastic leukemia (ALL) cells with the t(1:19) translocation express the WNT16 gene, which is thought to contribute to transformation. RESULTS: ER-stress blocks processing of endogenous WNT16 protein in RCH-ACV and 697 ALL cells. Biochemical analysis showed an aggregation of WNT16 proteins in the ER of stressed cells. These large protein masses cannot be completely cleared by ER-associated protein degradation, and require for additional autophagic responses. Pharmacological block of autophagy significantly increased cell death in ER-stressed ALL. Furthermore, murine cells engineered to express WNT16 are similarly sensitized. CONCLUSION: ALL cells expressing WNT16 are sensitive to ER stress, and show enhanced killing after addition of chloroquine. These findings suggest a potential clinical application of inducers of ER stress with inhibitors of autophagy in patients with high-risk ALL. PMID- 26254352 TI - Angiopoietin-like Protein 2 as a Predictor of Early Recurrence in Patients After Curative Surgery for Gastric Cancer. AB - BACKGROUND: Angiopoietin-like protein-2 (ANGPTL2) mediates chronic inflammation. Tumor cell-derived ANGPTL2 promotes tumor invasion and angiogenesis. ANGPTL2 expression has not been fully investigated in gastric cancer (GC). MATERIALS AND METHODS: ANGPTL2 expression in 354 patients with GC was assessed by immunohistochemistry (IHC). IHC scores were calculated, and the association of ANGPTL2 with clinicopathological factors and patient outcomes was evaluated. RESULTS: Immunoreactive ANGPTL2 protein was expressed mainly in GC cell cytoplasm. Kaplan-Meier analysis showed that high expression of ANGPTL2 indicated significantly poorer overall disease-free survival (DFS). Among patients with curatively resected GC, multivariate analysis for DFS revealed that high ANGPTL2 expression (p<0.01), advanced T-stage (p=0.015), lymph node metastasis (p<0.01), and advanced Unio Internationalis Contra Cancrum (UICC) stage (p<0.01) were independent risk factors for poor DFS. CONCLUSION: High cytoplasmic ANGPTL2 expression in GC tissue was associated with tumor progression, invasion, metastasis, and poor prognosis. ANGPTL2 may be a useful marker for detecting early postoperative recurrence in patients with GC. PMID- 26254353 TI - Surgically-Induced Multi-organ Metastasis in an Orthotopic Syngeneic Imageable Model of 4T1 Murine Breast Cancer. AB - BACKGROUND/AIM: Murine models of breast cancer with a metastatic pattern similar to clinical breast cancer in humans would be useful for drug discovery and mechanistic studies. The 4T1 mouse breast cancer cell line was developed by Miller et al. in the early 1980s to study tumor metastatic heterogeneity. The aim of the present study was to develop a multi-organ-metastasis imageable model of 4T1. MATERIALS AND METHODS: A stable 4T1 clone highly-expressing red fluorescent protein (RFP) was injected orthotopically into the right second mammary fat pad of BALB/c mice. The primary tumor was resected on day 18 after tumor implantation, when the average tumor volume reached approximately 500-600 mm(3). RESULTS: When the post-surgical mice were sacrificed 6-8 weeks after cell implantation, metastases were found in the lung in 91%; in the lymph nodes in 100%, including axillary nodes; in the brain in 25%; and in bone in 42% of the mice. The metastases were readily visualized by fluorescence imaging. Detailed fluorescence analysis visualized extensive metastasis in the thoracic cavity and the lymphatic system. Large metastatic nodules in the lung involved most of the pulmonary parenchyma in all lobes. In the liver, fluorescent macroscopic metastatic nodules were found under the capsule. Bone metastases were found mainly in the spine and thigh bone. CONCLUSION: Metastasis appeared to be enhanced by resection of the primary tumor. The metastatic pattern in the model thus reflected the clinical metastatic pattern of breast cancer and should be of use for discovery and evaluation of novel therapeutics. PMID- 26254354 TI - A Color-coded Imageable Syngeneic Mouse Model of Stromal-cell Recruitment by Metastatic Lymphoma. AB - AIM: A syngeneic color-coded imageable lymphoma model has been developed to visualize recruitment of host stromal cells by malignant lymphoma during metastasis. The EL4 cell line was previously derived from a lymphoma induced in a C57/BL6 mouse by 9,10-dimethyl-1,2-benzanthracene. MATERIALS AND METHODS: EL4 lymphoma cells expressing red fluorescent protein (EL4-RFP) were initially established. EL4-RFP cells were subsequently injected into the tail vein of C57/BL6-GFP transgenic mice. RESULTS: EL4-RFP metastasis was observed in the lymph nodes of the upper mediastinum and in the liver 28 days after cell injection. Large EL4-RFP liver metastases in C57/BL6-GFP mice contained GFP expressing stromal cells derived from the host. In addition, EL4-RFP lymphoma metastasis was formed in peri-gastric lymph nodes, which were also enriched in host GFP-expressing cells. Furthermore, EL4-RFP lymphoma cells were also observed in the peripheral blood and bone marrow of C57/BL6-GFP transgenic mice, where they were associated with GFP-expressing host cells. CONCLUSION: Lymph node, liver and bone marrow metastases were found approximately 4 weeks after transplantation and all RFP-expressing metastases were highly enriched in GFP expressing host stromal cells. This model of malignant lymphoma can be used to study early tumor development, metastasis, and the role of the stroma, as well as for discovery and evaluation of novel therapeutics for this treatment-resistant disease. PMID- 26254355 TI - Comparison of GFP-Expressing Imageable Mouse Models of Human Esophageal Squamous Cell Carcinoma Established in Various Anatomical Sites. AB - BACKGROUND/AIMS: Esophageal squamous cell carcinoma (ESCC) is a recalcitrant cancer. Mouse models of this disease could be used for discovery of more effective therapy for ESCC. MATERIALS AND METHODS: The green fluorescent protein (GFP)-expressing human esophageal cancer EC1 cell line was established with a lentiviral expression system. Subsequently, nude mice were injected subcutaneously, intracardiac or intravenously, or orthotopically implanted with EC1-GFP cells. Tumor growth and metastasis were examined by fluorescence in vivo imaging or by open fluorescence imaging after autopsy. RESULTS: Four different mouse xenograft models of ESCC expressing GFP were established. In the subcutaneous model, primary tumor growth was monitored in real-time by whole-body fluorescence imaging. No metastasis was observed in the subcutaneous or surgical orthotopic implantation model. By 55 days after implantation, all mice had developed orthotopic esophageal cancer, but without detectable metastasis. In contrast, experimental metastasis occurred in the intracardiac and intravenous models. In the intravenous injection model, the lung was the sole organ of experimental metastasis. In the intracardiac model, extensive experimental metastases occurred in the bone, brain and lung. CONCLUSION: The mouse xenograft models of ESCC developed in the present study can provide a means of discovering more effective therapy of this recalcitrant type of cancer. PMID- 26254356 TI - Uterine Leiomyosarcoma Tumorigenesis in Lmp2-deficient Mice: Involvement of Impaired Anti-oncogenic Factor IRF1. AB - BACKGROUND/AIM: Uterine leiomyosarcoma (Ut-LMS) is a highly metastatic smooth muscle neoplasm. We have previously reported that low molecular mass protein2 Lmp2-deficient mice spontaneously developed Ut-LMS, which implicated this protein as an anti-oncogenic candidate. We also suggested that LMP2 may negatively regulate Ut-LMS independently of its role in the proteasome. Initially described as a transcription factor able to activate the expression of interferon-gamma (IFN-gamma)-responsive genes, interferon regulatory factor-1 (IRF1) has been shown to play roles in the immune response, and tumor suppression. The aim of this study was to elucidate the molecular mechanism of sarcomagenesis of Ut-LMS using human and mouse uterine tissues. MATERIALS AND METHODS: The expression of the IFN-gamma signal molecules, IRF1 and -2, STAT1, and LMP2, -3, -7 and -10 were examined by western blot analysis, electrophoretic mobility shift assay and immunohistochemistry in human and mouse uterine tissues. Physiological significance of IRF1 in sarcomagenesis of Ut-LMS was demonstrated by xenograft studies. RESULTS: In the present study, several lines of evidence indicated that although treatment with IFN-gamma strongly induced the activation of STAT1 as a transcriptional activator, its target molecule, IRF1, was not clearly produced in Lmp2-deficient uterine smooth muscle cells (Ut-SMCs). CONCLUSION: Defective expression of IRF1 in the IFN-gamma-induced signaling molecules may result in the malignant transformation of Ut-SMCs. The modulation of LMP2 may lead to new therapeutic approaches in human Ut-LMS. PMID- 26254357 TI - Lack of Contribution of Multidrug Resistance-associated Protein and Organic Anion transporting Polypeptide to Pharmacokinetics of Regorafenib, a Novel Multi-Kinase Inhibitor, in Rats. AB - We investigated whether hepatic multidrug resistance-associated protein 2 (ABCC2) is involved in the hepatobiliary excretion of regorafenib, a novel multi-kinase inhibitor, using Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBR) lacking the efflux transporter ABCC2. The involvement of organic anion transporting polypeptide 1 (OATP1; OATP in humans) and OATP2 in the hepatic uptake of regorafenib and their protein levels in the liver were also investigated in the two rat groups. When regorafenib (5 mg/kg) was administered intravenously, the plasma concentrations of regorafenib were higher in EHBR than those in SD rats. However, the slope of the plasma concentration-time curves was the same for the two groups. Although the apparent biliary clearance of regorafenib in EHBR was lower than that of SD rats, no significant difference in the biliary excretion rate was observed between them, suggesting that regorafenib is not a substrate for ABCC2 and is not excreted into bile by ABCC2. It was also found that the contribution of biliary excretion to the systemic elimination of regorafenib is small. The protein-binding profiles of regorafenib were found to be linear in both rat groups. The binding potency, which was very high in both rat groups (>99.5%), was significantly higher in EHBR than that in SD rats. No significant differences in the plasma concentrations of unbound regorafenib were observed between the two rat groups, suggesting that the differences observed in the pharmacokinetic behaviors of regorafenib between the two rat groups were due to differences in protein-binding. When the protein levels of hepatic OATP1 and OATP2 were measured by immunoblot analysis, the expression of both transporters in EHBR was less than 40% of that in SD rats. The present results suggest that regorafenib is not a substrate for OATP1 and OATP2. These findings suggest the possibility that ABCC2-mediated hepatobiliary excretion and OATP1/OATP2-mediated hepatic uptake do not play important roles in the disposition of regorafenib. PMID- 26254358 TI - Contribution of X-Ray Repair Complementing Defective Repair in Chinese Hamster Cells 3 (XRCC3) Genotype to Leiomyoma Risk. AB - AIM: The present study aimed at investigating whether X-ray repair cross complementing protein 3 (XRCC3) genotype may serve as a useful marker for detecting leiomyoma and predicting risk. MATERIALS AND METHODS: A total of 640 women (166 patients with leiomyoma and 474 healthy controls) were examined for their XRCC3 rs1799794, rs45603942, rs861530, rs3212057, rs1799796, rs861539, rs28903081 genotype. The distributions of genotypic and allelic frequencies between the two groups were compared. RESULTS: The results showed that the CT and TT genotypes of XRCC3 rs861539 were associated with increased leiomyoma risk (odds ratio=2.19, 95% confidence interval=1.23-3.90; odds ratio=3.72, 95% confidence interval=1.23-11.26, respectively). On allelic frequency analysis, we found a significant difference in the distribution of the T allelic frequency of the XRCC3 rs861539 (p=5.88 * 10(-5)). None of the other six single nucleotide polymorphisms were associated with altered leiomyoma susceptibility. CONCLUSION: The T allele (CT and TT genotypes) of XRCC3 rs861539 contributes to increased risk of leiomyoma among Taiwanese women and may serve as a early detection and predictive marker. PMID- 26254359 TI - 3-Deazaneplanocin A May Directly Target Putative Cancer Stem Cells in Biliary Tract Cancer. AB - BACKGROUND/AIM: Polycomb repressive complex 2 (PRC2), an epigenetic master regulator, contributes to progression and development of biliary tract cancer (BTC). The present study investigated the effects of the PRC2 inhibitor 3 deazaneplanocin A (DZNep) on BTC cell lines. MATERIALS AND METHODS: In vitro effects of DZNep treatment were analyzed for cell viability, gene expression and functional characteristics of cancer stem cell (CSC). RESULTS: DZNep treatment caused a cell line- and dose-dependent decrease in viability. In the EGI-1 cell line, a direct cytotoxic effect was accompanied by mRNA down-regulation of the PRC2 core components, cyclins as well as of CSC-related genes. Furthermore, DZNep affected putative CSCs by reduction of sphere formation and aldehyde dehydrogenase-1-positive cells. The stem cell characteristics of these subpopulations were verified by real-time polymerase chain reaction analysis. CONCLUSION: Taken together, our results show that DZNep might be a promising pharmacological agent for future therapies regarding BTC. PMID- 26254360 TI - The Use of Styrene Maleic Acid Nanomicelles Encapsulating the Synthetic Cannabinoid Analog WIN55,212-2 for the Treatment of Cancer. AB - Synthetic cannabinoid WIN55,212-2 (WIN) has shown a promise as an anticancer agent but causes psychoactive side-effects. In the present study, nano-micelles of styrene maleic acid (SMA)-conjugated WIN were synthesized to reduce side effects and increase drug efficacy. SMA-WIN micelles were characterised and their in vitro cytotoxic effect was compared to that of free WIN against triple negative breast cancer (MDA-MB-231), hormone receptor-positive breast cancer (MCF 7) and castration-resistant prostate cancer (PC3) cell lines. SMA-WIN micelles were synthesised with a ~15% loading, 132.7 nm average diameter, -0.0388 mV charge, and pH-dependent release rate. A dose-dependent inhibition of cell growth was observed in all three cell lines treated with both free and micellar WIN, with both formulations demonstrating equal cytotoxicity. CONCLUSION: SMA-WIN demonstrated characteristics theorized to improve in vivo drug biodistribution. Potent cytotoxicity was found against breast and prostate cancer cells in vitro, showing promise as a novel treatment against breast and prostate cancer. PMID- 26254361 TI - Vessel and Mast Cell Densities in Sporadic and Syndrome-associated Peripheral Nerve Sheath Tumors. AB - BACKGROUND/AIM: Peripheral nerve sheath (PNS) tumors constitute a heterogeneous group of solid tumors. Neurofibroma and schwannoma are the most frequently diagnosed entities. Both tumor types occur sporadically and are associated with syndromes. Current strategies to fight PNS progression by means of pharmaceuticals aim to specifically interfere with vascular growth factors identified in PNS. Furthermore, malignant transformation of PNS tumors is known to be associated with a change in vascularization. The aim of the study was to investigate vascularization of different PNS tumors with respect to sporadic or syndromal state of the entities. MATERIALS AND METHODS: One hundred and thirty two formalin-fixed and paraffin-embedded PNS tissue samples were retrieved from the archives of the Institute of Neuropathology, Eppendorf University Hospital. Lymphatic and blood vessels were immunohistochemically identified and morphometrically analyzed in PNS and controls. RESULTS: Blood vessel density in malignant tumors was significantly higher than in benign lesions (30.8/mm(2) vs. 13.46/mm(2)). In the latter, the vessel density resembled that of control tissue. Lymphatic vessel supply was significantly higher in cutaneous neurofibroma and diffuse plexiform neurofibroma (PNF) than in intra-neural localized tumors (schwannoma, nodular PNF). Lymphatic vessels showed no marked differences with respect to tumor entity. Prevalence of mast cells differed markedly between tumor types. CONCLUSION: Different vascularization of PNS may contribute to diverging tumor response following application of anti-neoplastic drugs. Mast cells may have an impact during formation and growth of neurofibroma but are unlikely to be involved in the process of de-differentiation. PMID- 26254362 TI - Apoptotic Effects of Novel Dithiocarbamate Analogs of Emetine in Prostate Cancer Cell Lines. AB - BACKGROUND/AIM: Prostate cancer is one of the leading causes of death in American males. Emetine, a naturally-derived alkaloid from the Ipecacuanha plant, has been shown to have potential for anti-tumorigenic effects for cancer treatments. The objective of this study was to characterize novel emetine dithiocarbamate (EMTDTC) analogs for potent anti-tumorigenic activity with minimal toxicity to normal prostate cells and identify targeted apoptotic regulatory genes. The leading key compounds, EMTDTC-55 and EMTDTC-56 were studied. MATERIALS AND METHODS: Established methods of cell flow cytometry were used to analyze apoptotic potential in prostate cancer cell lines (DU145, PC3 and LNCaP) and real time-polymerase chain reaction (PCR) for identifying key genes mediating apoptosis. RESULTS: The effect of EMTDTC-55 on DU145, LNCaP and PC3 revealed significant anti-tumorigenic activities. Both compounds showed highly significant apoptotic potential on days 3 and 5 in the prostate cancer cells. Key apoptotic genes were differentially regulated suggestive of cell-cycle arrest and apoptotic induction in androgen-independent cell lines, DU145 and PC3, by both compounds. However, in the androgen-dependent cell line LNCaP, cells were marginally affected by EMTDTC-55, but significant apoptosis was observed by EMTDTC-56 leading to cell-cycle arrest. CONCLUSION: Both dithiocarbamate compounds EMTDTC 55 and EMTDTC-56 have significant chemotherapeutic potential in moderately metastatic DU145 and highly metastatic PC3 cells. PMID- 26254363 TI - HPV-related Oropharyngeal Squamous Cell Carcinoma: p16INK4A Immunohistochemistry or HPV Genotyping? AB - BACKGROUND: Infection with high-risk human papillomavirus (HPV) is linked to a sub-group of squamous cell oropharyngeal tumors (OPSCC). Our aim was to compare an HPV Polymerase Chain Reaction (PCR) assay and p16(INK4A) expression status by immunohistochemistry (IHC) as a surrogate marker. MATERIALS AND METHODS: This was a retrospective study considering patients affected by squamous cell oropharyngeal tumors. All included samples were processed for IHC for p16(INK4A) and tested by PCR for detection of HPV DNA and HPV genotyping. RESULTS: A total of 84 patients affected by squamous cell oropharyngeal tumors were included and tested. A significant positive correlation was found between HPV PCR and p16(INK4A) IHC but the agreement was poor (k coefficient of 0.25). In fact, the sensitivity of p16(INK4A) IHC positivity in detecting HPV PCR positivity was low (28.21%, 95% confidence interval=16.54% - 43.78%). CONCLUSION: Positivity of p16(INK4A) by IHC had a low sensitivity in detecting HPV DNA and our results suggest the need at least to test p16(INK4A) IHC- negative samples using HPV PCR to increase detection accuracy and provide valuable information for the clinical management of these patients. PMID- 26254364 TI - Co-treatment of Salinomycin Sensitizes AZD5363-treated Cancer Cells Through Increased Apoptosis. AB - AZD5363, an inhibitor of protein kinase B (AKT), is currently in clinical trials assessing the potential of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. The purpose of the present study was to identify conditions that increase the sensitivity of cancer cells to AZD5363. Microscopic examination revealed that treatment of cancer cells with a low concentration of salinomycin reduced cellular growth of AZD5363-treated breast cancer cells. Furthermore, fluorescence-activated cell sorting (FACS) analysis, Hoechst staining, and annexin V staining revealed that co-treatment with salinomycin sensitizes AZD5363-treated cancer cells via increased apoptosis with S-phase arrest. These results suggest that salinomycin can be applied to increase treatment efficacy for AZD5363-treated cancer cells. Our findings may contribute to improving the efficacy of the development of AZD5363-based sensitization therapies for patients with cancer. PMID- 26254365 TI - Pro-apoptotic and Growth-inhibitory Effect of IFN-beta-Overexpressing Canine Adipose Tissue-derived Mesenchymal Stem Cells Against Melanoma Cells. AB - BACKGROUND: Canine melanoma is the most common type of tumor in dogs. We investigated the effects of canine interferon-beta (cIFN-beta)-overexpressing adipose tissue-derived mesenchymal stem cells (cATMSCs) on apoptosis and proliferation of canine melanoma cells. MATERIALS AND METHODS: Expression of IFN beta in cATMSCs was confirmed using reverse transcription-polymerase chain reaction and enzyme linked immunosorbent assays. Flow cytometry was performed for cell-cycle analysis and apoptotic cell quantification of LMeC (melanoma) cells. Protein expression of cyclin D1, procaspase-3, activated caspase-3, and Bcl-2 homologous antagonist killer (Bak) was evaluated by western blot analysis. RESULTS: Decreased proportions of cells in S- and G0/G1 phases were observed in parallel with decreased cyclin D1 expression in LMeC cells treated with cIFN-beta cATMSC-conditioned media. Protein expression of active forms of caspase 3 and Bak increased in response to treatment with cIFN-beta-cATMSC-conditioned media. CONCLUSION: IFN-beta overexpression by cATMSCs was associated with pro-apoptotic and growth-inhibitory effects on canine melanoma cells. The antitumor effects of these cells have therapeutic potential for the treatment of canine melanoma. PMID- 26254366 TI - Advanced Chemoembolization by Anti-angiogenic Calcium-Phosphate Ceramic Microspheres Targeting the Vascular Heterogeneity of Cancer Xenografts. AB - The purpose of the present study was to develop an advanced method of anti angiogenic chemoembolization to target morphological vascular heterogeneity in tumors and further the therapeutic efficacy of cancer treatment. This new chemoembolization approach was designed using resorbable calcium-phosphate ceramic microspheres (CPMs), in a mixture of three different sizes, which were loaded with an anti-angiogenic agent to target the tumor vasculature in highly angiogenic solid tumors in humans in vivo. The human uterine carcinosarcoma cell line, FU-MMT-3, was used in this study because the tumor is highly aggressive and exhibits a poor response to radiotherapy and chemotherapeutic agents that are in current use. CPMs loaded with TNP-470, an anti-angiogenic agent, were injected into FU-MMT-3 xenografts in nude mice three times per week for 8 weeks. The treatment with TNP-470-loaded CPMs of three different diameters achieved a greater suppression of tumor growth in comparison to treatment with single-size TNP-470-loaded CPMs alone, and the control. Severe loss of body weight was not observed in any mice treated with any size of TNP-470-loaded CPMs. These results suggest that treatment with a mixture of differently-sized anti-angiogenic CPMs might be more effective than treatment with CPMs of a single size. This advanced chemoembolization method, which incorporated an anti-angiogenic agent to target the morphological vascular heterogeneity of tumors may contribute to effective treatment of locally advanced or recurrent solid tumors. PMID- 26254367 TI - Chemoprevention of Azoxymethane-induced Colonic Carcinogenesis in Balb/c mice Using a Modified Pectin Alginate Probiotic. AB - BACKGROUND: Increased intake of probiotic dietary fibre reduces colonic cancer risk. Modified citrus pectin (MCP) requires optimal bioactivity to inhibit galectin-3 (GAL-3) and vascular endothelial growth factor (VEGF). This study evaluated the preventative effect of modified pectin alginate (MCPA) probiotic microbeads on azoxymethane (AOM)-induced colonic carcinogenesis in Balb/c mice. MATERIALS AND METHODS: Optimization of AOM dose duration: 10-15 mg/kg was administered for 2-4 weeks. The optimal AOM dose was initiated prior to intake of MCPA, alginate probiotic (AP) microbeads and MCP in Balb/c mice for 16 weeks; samples were analyzed for colonic histopathology and immunohistochemistry. RESULTS: AOM at 15 mg/kg for 4 weeks induced optimal GAL-3 and VEGF immunostaining. Furthermore, MCPA treatment reduced GAL-3 expression in the colon of AOM-treated mice compared to MCP. CONCLUSION: MCPA probiotic microbeads increase bioactivity and chemopreventative effect against pre-cancerous colonic lesions and adenocarcinoma through inhibition of GAL-3 and VEGF in the Balb/c mouse model of colonic carcinogenesis. PMID- 26254368 TI - Cytotoxic Effects of PEGylated Anti-EGFR Immunoliposomes Combined with Doxorubicin and Rhenium-188 Against Cancer Cells. AB - BACKGROUND/AIM: We aimed to construct epidermal growth factor receptor (EGFR) targeting cetuximab-immunoliposomes (IL-C225) for targeted delivery of doxorubicin and rhenium-188 (Re-188) to EGFR(+) cancer cells. MATERIALS AND METHODS: Synthesized IL-C225 was analyzed by dynamic light scattering, transmission electron microscopy, and matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy. Cell binding and internalization were examined using doxorubicin-loaded IL-C225 (DXR-IL-C225) with confocal microscopy. IL-C225 combined with doxorubicin and Re-188 ((188)Re-DXR-IL-C225) was synthesized, and the cytotoxic effects of (188)Re-DXR-IL-C225 were analyzed in EGFR(+) cancer cells using cell viability assays. RESULTS: IL-C225 bound to EGFR on A431 cancer cells and was rapidly internalized. Furthermore, IL-C225 localized within the tumor cells efficiently. (188)Re-DXR-IL-C225 exhibited outstanding cytotoxic effects against EGFR(+) cancer cells in vitro and showed superior cytotoxic effects compared to DXR-IL-C225 or (188)Re-IL-C225 alone. CONCLUSION: The new formulation of (188)Re-DXR-IL-C225 may be a potential theranostic vehicle for delivery of drugs in the treatment of EGFR-overexpressing human cancer. PMID- 26254369 TI - Angiotensin II Increases Cancer Stem Cell-like Phenotype in Lung Cancer Cells. AB - BACKGROUND: Cancer stem cells (CSCs) have been proposed as important players in cancer progression, metastasis, and chemotherapeutic resistance in many cancers, including lung cancer. However, effects of the endogenous substance angiotensin II (ANG II) on cancer stem cell-like phenotype in lung cancer are largely unknown. MATERIALS AND METHODS: Human lung cancer cells were treated with non cytotoxic concentrations of ANG II. The CSC phenotype was evaluated by spheroid formation, 3D culture, and anchorage-independent growth assays. The expression levels of CSC makers were determined by western blot analysis. RESULTS: ANG II significantly increased the ability of lung cancer cells to form spheroids. ANG II also increased the growth of cancer cells in a 3D culture Matrigel-based assay and facilitated cancer cell survival in an anchorage-independent condition. Western blot analysis revealed that cell treatment with ANG II significantly up regulated CD133 levels. CONCLUSION: The present study revealed that the endogenous substance ANG II enhances CSC-like phenotype in lung cancer cells. PMID- 26254370 TI - Role of Hyaluronan and Glucose on 4-Methylumbelliferone-inhibited Cell Proliferation in Breast Carcinoma Cells. AB - BACKGROUND/AIM: 4-methylumbelliferone (4-MU) has received considerable attention due to its potential for cancer treatment since it inhibits cell proliferation, migration and invasion. An increasing body of evidence suggests that extracellular matrix (e.g. hyaluronan) and nutrients (e.g. glucose) in the tumor microenvironment may affect cellular responses to extracellular signals. This study investigates the role of hyaluronan and glucose on 4-MU-inhibited cell proliferation in breast carcinoma cells. MATERIALS AND METHODS: 4-MU-inhibited cell proliferation was determined using the soluble formazan dye, whose absorbance is directly proportional to the number of living cells, under conditions of competent vs. deficient in producing hyaluronan, or low vs. high glucose in culture media of breast carcinoma cells. RESULTS: Cellular sensitivity to 4-MU-inhibited cell proliferation was altered by changes in the amount of hyaluronan or glucose in the tumor microenvironment. CONCLUSION: Increased amounts of hyaluronan or glucose in the tumor microenvironment reduced cellular sensitivity of breast carcinoma cells to 4-MU-inhibited cell proliferation. PMID- 26254371 TI - Q192R and L55M Polymorphisms of Paraoxonase 1 Gene in Chronic Myelogenous Leukemia and Chronic Lymphocytic Leukemia. AB - AIM: The aim of the present study was to investigate the association between Paraoxonase 1 (PON1) gene polymorphisms Q192R, and L55M in patients with Chronic Myelogenous Leukemia (CML) and Chronic Lymphocytic Leukemia (CLL) patients. MATERIALS AND METHODS: We analyzed samples from 60 patients with CML, 60 with CLL and 84 healthy controls. Polymerase Chain Reaction (PCR)--Restriction Fragment Length Polymorphism (RLFP) was performed and samples were run in agarose gel. RESULTS: We found statistically significant results showing an increase in both the RR genotype (p=0.044) and the R allele (p=0.011) for PON1 Q192R, and an increase in the MM genotype (p=0.007) and a decrease in the LL genotype (p=0.004) and R allele (p=0.001) in PON1 L55M in patients with CLL. CONCLUSION: We concluded that both the Q192R gene polymorphism with an increase in the genotype R allele, and the M/L55 with an increase in the MM genotype play a role in CLL susceptibility, and a decrease in the LL genotype can act against disease in the Turkish population. PMID- 26254372 TI - Predicting Outcome in Colonoscopic High-risk Surveillance. AB - AIM: Surveillance with colonoscopy in risk groups for colorectal cancer needs to be based on an adequate selection of individuals to examine and a well-devised timing. To stratify the risk of finding neoplasia at colonoscopy, a cohort with increased familial risk of colorectal cancer was studied. PATIENTS AND METHODS: Based on family history, 1,203 individuals with at least two-fold increased risk of colorectal cancer were offered regular colonoscopies. The impact of different variables in the family history was assessed by logistic regression for the prevalence of adenoma and advanced adenoma. Findings at first colonoscopy were assessed regarding the association with risk of future lesions. RESULTS: The prevalence of advanced lesions, when controlling for age, was associated with the number of first-degree relatives with colorectal cancer, with an age below 50 years for the youngest family member with colorectal cancer, but not with gender. Family history had a low impact on the prevalence of simple adenoma. The risk of future advanced lesions was only associated with the prevalence of advanced lesions at the screening colonoscopy, whereas a finding of subsequent adenoma was associated with advanced lesions, adenomas and hyperplastic polyps. CONCLUSION: Adenomas and advanced lesions were not associated with the same risk factors. In the present study, the most important risk factors for advanced lesions, including cancer, were the number of first-degree relatives and a young family member with colorectal cancer. Findings of simple adenomas and hyperplastic polyps did not seem to be associated with subsequent advanced lesions. PMID- 26254373 TI - A Case of Focal Small-cell Neuroendocrine Carcinoma in the Vicinity of the Extrahepatic Bile Duct, Adjacent to an Extensive Biliary Intraepithelial Neoplasm: A Diagnostic Challenge with Major Clinical Implications. AB - Gastroenteropancreatic neuroendocrine tumors are known for their aggressiveness. Diagnosis of various bile duct pathologies, like biliar intraepithelial neoplasm, mixed adenoneuroendocrine carcinomas or small cell carcinomas, is challenging. This case report focuses on a rare case of a focal primary minute small cell carcinoma in the vicinity of the extrahepatic bile duct, presenting itself next to an extensive biliar intraepithelial neoplasm. This finding led to adjuvant chemotherapy, followed by major surgery. Therapeutic approach was based on CT and MRI scans but most importantly on immunohistochemistry and histological evaluation. Initially CR seemed achievable, but metastases were to be found rapidly. The authors want to underline the fact that major clinical decisions are based on sometimes tiny specimens; as literature shows it is absolutely advisable to use markers to differentiate the dignity of investigated areas. The authors call for keeping collision of tumors in mind and adding KOC staining and using it in a routine manner examining biliary duct lesions. PMID- 26254374 TI - Prognostic Impact of ALDH1 Expression in Transitional Cell Carcinoma of the Renal Pelvis. AB - AIM: To investigate the clinical significance of aldehyde dehydrogenase 1 (ALDH1) expression in the assessment of the pathological outcomes and prognosis of carcinoma of the renal pelvis through examination of ALDH1 expression in pathological specimens. MATERIALS AND METHODS: A total of 114 patients with carcinoma of the renal pelvis who underwent radical nephroureterectomy at the First Hospital of Peking University between September 2004 and August 2007 with continuity in data were included in this study. The expression of ALDH1 was examined in pathological specimens via immunohistochemistry, and was statistically analyzed in combination with corresponding clinical and pathological information. RESULTS: The pathological specimens from 37 patients (32.5%) exhibited positive ALDH1 expression, showing correlation with T stage (p=0.001) and G grade (p=0.010), as well as lymphatic and vascular infiltration (p=0.003), but these specimens did not correlate with tumor multi-focality (p=0.398). The univariate analysis showed that tumor grade (p=0.001) and ALDH1 positive expression (p<0.001), as well as lymphatic and vascular infiltration (p=0.017) correlated with prognosis, and this analysis also showed that tumour, node and metastasis (TNM) stage (p=0.085), as well as occurrence of multiple tumors (p=0.166) had no significant correlation with prognosis. Multivariate analysis indicated advanced G grade (p=0.006) and ALDH1 expression as independent predictive factors for poor prognosis. A significant correlation was observed between positive ALDH1 expression and tumor relapse following radical resection (p<0.001). CONCLUSION: The cancer stem-like cell marker ALDH1 can be used as a predictive factor for adverse pathological outcomes and prognosis in transitional cell carcinoma. of the renal pelvis. Cancer stem cell theory plays an important role in the clinical study of transitional cell carcinoma of the upper urinary tract. PMID- 26254375 TI - Sporadic Burkitt Lymphoma Mimicking Osteomyelitis of the Mandible Revealing Clinically Unsuspected HIV Infection. AB - Adult sporadic Burkitt lymphoma is a rare and highly aggressive malignancy, accounting for approximately 1-2% of adult lymphomas in Western countries, and exclusively intra-oral localization is very uncommon. We describe a rare case of a moderately painful sporadic Burkitt lymphoma localized in the posterior third of the left mandibular bone, initially misdiagnosed as osteomyelitis-like lesion, in a patient Epstein-Barr virus infection-negative with unknown human immunodeficiency virus (HIV) positivity and acquired immunodeficiency syndrome. A 52-year-old man was referred to our Department complaining of persistent moderate pain localized in the left mandibular arch. According to clinical and radiological features, a diagnosis of post-extraction osteomyelitis was made and a surgical revision, including soft and hard tissue biopsy, was performed. Histopathology revealed the presence of a diffuse proliferation of lymphoid cells, exhibiting the typical 'starry-sky' appearance that was consistent with the diagnosis of B-type non-Hodgkin lymphoma. Unexpectedly, HIV seropositivity was also found, but the patient was unaware of this, and the history did not reveal any particular risk factor for HIV infection. Positron-emission tomography showed a highly (18)F-fluorodeoxyglucose-avid mass in the left maxillofacial region and extensive disease in bone marrow and mediastinum. Thus, the patient was referred to our onco-hematological team for final assessment and care. In conclusion, sporadic Burkitt lymphoma is an aggressive malignancy, which rarely affects adults with initial intra-oral manifestations. In the presence of abnormal gingival or alveolar lesions, a non-odontogenic disease should be suspected and the appropriate diagnostic test should be performed. PMID- 26254376 TI - Chemotherapy for Uterine Carcinosarcoma with Carboplatin, Ifosfamide and Mesna. AB - BACKGROUND/AIM: Uterine carcinosarcomas (UCSs) are highly aggressive, rare, biphasic tumors composed of epithelial and mesenchymal elements. Surgery remains the mainstay of treatment in early-stage disease. Adjuvant pelvic radiotherapy improves locoregional control without proven overall survival (OS) benefit. Although adjuvant ifosfamide-based combination chemotherapy with cisplatin or paclitaxel has shown superiority to radiotherapy or single-agent chemotherapy in randomized controlled trials, there is no consensus on a standard regimen due to toxicities. The aim of this retrospective study was to assess the efficacy and toxicity of a novel combination chemotherapy using carboplatin, ifosfamide and mesna (CIM) and compare with other regimens for patients with UCSs in both the adjuvant and palliative setting. PATIENTS AND METHODS: Between 1997 and 2010, 60 patients with UCS, 70% of whom with international federation of gynecology and obstetrics (FIGO) stage III/IV disease, were treated with adjuvant or palliative chemotherapy. Two groups were identified: Group1 (n=22) included patients receiving CIM chemotherapy; and group 2 (n=38) receiving other regimens (carboplatin/paclitaxel/cisplatin/doxorubicin/epirubicin). RESULTS: After a median follow-up of 60 months, disease in seven patients in group 1 (CIM) and 20 patients in group 2 had progressed/relapsed. Out of these, six patients in group 1 and 13 patients in group 2 had died. The progression-free survival (PFS) and OS for patients treated with adjuvant or palliative CIM was 35 months [95% confidence interval (CI) =0.26-0.43] and 47 months (95% CI=0.38-0.56; log-rank, p=0.001) respectively, whereas for group 2 patients treated with other regimens, PFS was 27.48 months (95% CI=0.20-0.33) and OS was 30 months (95% CI=0.21-0.38; log-rank, p=0.001). While none of the patients in group 1 experienced neurotoxicity or other grade 3 or 4 toxicities, 3/38 patients in group 2 experienced grade 3 neutropenia, 4/38 had peripheral sensory neuropathy, 6/38 patients had treatment deferred due to toxicities or allergic reaction to paclitaxel. CONCLUSION: In the phase III randomized controlled trial combination of ifosfamide and taxanes has shown PFS and OS benefit when compared to single agent ifosfamide at the expense of significant toxicities. Results from our study show that the combination of CIM is an effective and safe alternative regimen for patients with advanced UCSs. In addition to improved OS and PFS, the main advantage of this regimen over taxane-based regimens includes minimal neuropathy, less use of steroids, and low risk of allergic reaction. CIM should be considered in future prospective studies looking at the treatment of UCS. PMID- 26254377 TI - Radiation Therapy for Para-Aortic Lymph Node Metastasis from Uterine Cervical Cancer. AB - AIM: To evaluate the efficacy of radiation therapy for para-aortic lymph node metastases from uterine cervical cancer and to identify an optimal radiation regimen. PATIENTS AND METHODS: A total of 80 metastatic para-aortic lymph nodes, ranging from 11-50 mm (median=20 mm) on computed tomography, in 22 patients with squamous cell carcinoma of the uterine cervix were initially treated with radiation therapy. Total radiation doses for para-aortic lymph node metastases were 40-61.2 Gy (median=50.4 Gy) in 1.8-2 Gy fractions. RESULTS: Eight out of the 22 patients remained alive at a median follow-up of 32 months. Seven irradiated lymph nodes, 20-50 mm in diameter, in four patients progressed after irradiation at total doses of 44-50.4 Gy. No metastatic lymph nodes administered >50.4 Gy (median=55.8 Gy) exhibited progression after irradiation. All metastatic lymph nodes <= 25 mm in diameter irradiated with 50 or 50.4 Gy were controlled. The 3 year lymph node progression-free rates were 78% in the cohort of 22 patients and 89% considering all 80 metastatic lymph nodes. Apart from transient hematological reactions, two patients developed grade 3 or more therapy-related toxicities, including radiation proctitis in one and hemorrhagic cystitis and colitis in another. CONCLUSION: Radiation therapy can effectively control para-aortic lymph node metastases in patients with uterine cervical cancer. A total dose of 50.4 Gy in 1.8 Gy fractions is sufficient to control metastatic lymph nodes <= 25 mm in diameter, whereas a higher dose (approximately 55.8 Gy) may be required for larger nodes. PMID- 26254378 TI - PHI in the Early Detection of Prostate Cancer. AB - AIM: To evaluate changes in the serum levels of prostate specific antigen (PSA), %free PSA and -2proPSA biomarkers, and prostate health index (PHI) in the diagnostic algorithm of early prostate cancer. PATIENTS AND METHODS: The Immunoanalytical Laboratory of the University Hospital in Pilsen examined sera from 263 patients being treated at the Hospital's Urology Department with suspected prostate cancer who had undergone biopsies and were divided into a benign and malignant group. The monitored biomarkers were measured using chemiluminescence. All statistical analyses were calculated using the SAS software. RESULTS: We found statistically significantly increased levels of 2proPSA, PHI and PSA and decreased levels of %freePSA in patients diagnosed with prostate cancer by prostate biopsy vs. patients with benign prostatic hypertrophy (median values: -2proPSA: 16 vs. 21 ng/l, PHI: 35 vs. 62, total PSA: 7.2 vs. 7.7 MUg/l and %free PSA: 16.7 vs. 11.7%). Receiver operating characteristic curves showed the best performance for PHI compared to other markers. CONCLUSION: The assessment of -2proPSA and the calculation of PHI appear to be of great benefit for a more accurate differential diagnosis of benign hyperplasia and prostate cancer. PMID- 26254379 TI - Comparison of Neoadjuvant Chemotherapy to Surgery Followed by Adjuvant Chemotherapy in Japanese Patients with Peritoneal Lavage Cytology Positive for Gastric Carcinoma. AB - BACKGROUND: Therapeutic strategies for positive peritoneal lavage cytology [CY(+)] findings have not yet been established. The aim of the present study was to compare the effects of neoadjuvant systemic chemotherapy and surgery followed by S-1 adjuvant chemotherapy for treating gastric carcinoma in patients with CY(+) status without peritoneal metastasis. PATIENTS AND METHODS: Twenty-three patients with CY(+) status without peritoneal metastasis who underwent curative surgery for gastric carcinoma between October 1999 and December 2014 were included in the study. Ten patients received neoadjuvant systemic chemotherapy followed by surgery, whereas 13 patients underwent surgery, in nine cases followed by S-1 adjuvant chemotherapy. RESULTS: The 5-year survival in both groups was 15%, and no significant difference was observed. However, the prognosis for patients with CY(-) status after neoadjuvant systemic chemotherapy was significantly better than that of patients who were still CY(+) after neoadjuvant systemic chemotherapy (p<0.01). Among all patients, the prognosis of those with less than clinical N2 disease was significantly better than that of patients with clinical N3 (p<0.01). In multivariate analysis, clinical lymph node metastasis was the only independent prognostic factor for CY(+) patients without peritoneal metastasis (p<0.05). CONCLUSION: The prognosis of gastric carcinoma with CY(+) without peritoneal metastasis is still stage IV disease and is dependent on the degree of clinical lymph node metastasis, in spite of therapeutic treatment. PMID- 26254380 TI - Glasgow Prognostic Score Predicts Clinical Outcomes in Patients with Pancreatic Cancer Undergoing Adjuvant Gemcitabine Monotherapy After Curative Surgery. AB - BACKGROUND/AIM: The Glasgow Prognostic Score (GPS), an inflammation-based prognostic score, has been shown to predict the clinical outcomes of a variety of cancer types. The aim of this study was to determine whether the GPS predicts clinical outcomes of patients with pancreatic cancer treated with adjuvant chemotherapy after surgery. PATIENTS AND METHODS: Forty patients resected for pancreatic cancer who underwent adjuvant gemcitabine monotherapy after curative surgery were included. The GPS was measured prior to adjuvant therapy and correlated with clinical outcomes. RESULTS: The disease-free survival (DFS) and overall survival (OS) in patients with an elevated GPS (GPS1 or GPS2) were significantly poorer (p=0.001 and p=0.035, respectively, by log-rank test) than patients with a GPS of 0. An elevated GPS was found to be independently associated with poor DFS (p=0.002, by Cox regression model). CONCLUSION: The pre adjuvant GPS may predict clinical outcome in patients with pancreatic cancer undergoing adjuvant chemotherapy after surgery. PMID- 26254381 TI - Neoadjuvant Chemoradiotherapy Treatment for a Classic Biphasic Pulmonary Blastoma with High PD-L1 Expression. AB - Pulmonary blastomas are rare malignant tumors, comprising only 0.25-0.5% of all malignant lung neoplasms. The prognosis of pulmonary blastoma is very poor, with an overall five-year survival of 16%. No standard treatment has been defined for unresectable disease. We present the case of a 25-year-old woman with unresectable locally advanced classic biphasic pulmonary blastoma (CBPB) successfully treated with neodjuvant chemoradiotherapy based on two chemotherapy induction cycles of cisplatin plus etoposide, followed by concurrent weekly cisplatin to 50.4 Gy radiotherapy treatment. The patient had a significant reduction in tumor size, allowing for complete resection by pneumonectomy. Molecular study for epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK), proto-oncogene receptor tyrosine kinase (ROS1) and rearranged during transfection (RET) rearrangements, and programmed death ligand 1 (PD-L1) expression was performed in the pre-treatment tumor sample. Our patient presented a high expression (>90% of tumor cells) of PD-L1. To our knowledge, this is the first report of PD-L1 expression in CBPB. This could lead to new treatment options based on new immunotherapy agents blocking the PD-1/PD-L1 pathway for this rare disease with poor prognosis. PMID- 26254382 TI - Palliative Pelvic Exenteration for Pelvic Recurrence Invading the Sciatic Foramen with Chronic Cutaneous Perineal Fistula after Radical Surgery for Cervical Cancer: A Case Report. AB - Pelvic exenteration remains one of the most aggressive gynecological surgical procedures performed for patients with locally-invasive cervical cancer, usually performed with curative intent. However, there exist patients who present in a very advanced stage of the disease, in which only a palliative surgical procedure can be performed. Although in these cases the survival benefit is minimal, performing a pelvic exenteration significantly improves the quality of life. We present the case of a 63-year-old female who was submitted to palliative pelvic exenteration for a locally invasive recurrence in the left sciatic foramen after surgically-treated cervical cancer. PMID- 26254383 TI - 5-Fluorouracil Chemotherapy for Dihydropyrimidine Dehydrogenase-deficient Patients: Potential of the Dose-escalation Method. AB - BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) degrades approximately 85% of administered 5-fluorouracil (5-FU). With a reported high mortality rate, chemotherapy is generally contraindicated for patients with DPD deficiency. PATIENTS AND METHODS: Chemotherapy was initiated for a 73-year-old man with DPD deficiency. Capecitabine was administered in incrementally increasing doses, beginning with a single pill while monitoring plasma 5-FU concentration, and neutrophil and platelet counts. RESULTS: DPD protein level was 2.35 U/mg. After increasing the capecitabine dose to 1,800 mg, oxaliplatin and bevacizumab were added. Subsequent DPD protein measurement showed that the level had increased to approximately 12-fold the one before chemotherapy. Sequencing of all 23 exons of DPYD gene revealed a mutation of guanine to thymine in exon 11 (1156 G>T). CONCLUSION: This is the first report to indicate that DPD activity can be induced. These findings may provide early indications of a new method for chemotherapy for DPD-deficient patients. PMID- 26254384 TI - Impact of Chemoradiation-induced Myelosuppression on Prognosis of Patients with Locally Advanced Esophageal Cancer After Chemoradiotherapy Followed by Esophagectomy. AB - BACKGROUND: The prognosis of patients with locally advanced esophageal squamous cell carcinoma (LAESC) is extremely poor. The impact of adverse effects of chemoradiotherapy (CRT), particularly myelosuppression, on postoperative long term results has remained unclear. PATIENTS AND METHODS: A total of 44 patients with LAESC who underwent CRT followed by esophagectomy were enrolled. We compared long-term survival by various clinical variables, including myelosuppression (Grade 3 and 4 leukopenia) due to CRT, response to CRT, performance status, postoperative complications, and pathological nodal status. Finally, multivariate analysis of prognostic factors was assessed by the Cox proportional hazards model. RESULTS: The mean age of patients was 62.8 years and the male/female ratio was 32/9. The response rate to CRT was 75% (33/44), which included five cases with complete response and 28 cases with partial response. Grade 3 and 4 leukopenia was 43% (19/44). Mortality and postoperative pneumonia occurred in 3 (7.3%) and 14 cases (31.8%), respectively. Multivariate analysis demonstrated that myelosuppression was a significant negative prognostic factor in overall survival (OS) [hazard ratio (HR)=4.758, p=0.005]. The 5-year OS rate was significantly poorer in the group with myelosuppression than in the group without (15.4% vs. 69.0%, p=0.003). Discontinuation of the preoperative CRT schedule and dose reduction of chemotherapeutic agents was significantly more frequent in the group with myelosuppression than in the group without (p=0.003), and peripheral lymphocyte counts after surgery was significantly lower, which may explain poor prognosis in the group with myelosuppression. CONCLUSION: Pre-operative CRT induced myelosuppression has a negative impact on the prognosis of patients with LAESC. Our findings indicate that a careful postoperative follow-up is required for patients who develop myelosuppression after neoadjuvant CRT followed by curative resection for locally advanced esophageal cancer. PMID- 26254385 TI - Glasgow Prognostic Score as a Prognostic Clinical Marker in T4 Esophageal Squamous Cell Carcinoma. AB - Patients with clinical T4 esophageal squamous cell carcinoma (ESCC) have an unfavorable prognosis, mainly indicated by the response to chemoradiotherapy (CRT), crucial to estimating long-term survival. Other prognostic measures include systemic inflammatory or immunonutritional indices such as the Glasgow Prognostic Score (GPS) and Prognostic Nutritional Index (PNI) that have not been sufficiently documented. PATIENTS AND METHODS: This study retrospectively evaluated 91 patients with T4 ESCC treated at our Hospital between 2000 and 2013. All patients initially received CRT, including 5-fluorouracil (5FU) and cisplatin or nedaplatin with concurrent 2-Gy/fraction radiation (total dose, 40-60 Gy). Curative tumor resection was undertaken in suitable patients on completing CRT. Patients were classified as GPS0, GPS1, or GPS2 based on C-reactive protein (CRP) <= 10 mg/l and albumin >= 35 g/l, CRP >10 mg/l or albumin <35 g/l, or CRP >10 mg/l and albumin <35 g/l, respectively. PNI was calculated as 10-times the serum albumin (g/dl)+0.005 * total lymphocyte count (/mm(3)). The impact of the pre treatment GPS and PNI on the prognosis of patients with T4 ESCC was investigated in univariate and multivariate analyses. RESULTS: Sixty (67%) patients responded to CRT (9 complete responses and 51 partial responses). Forty-one (45%) patients also underwent surgical resection of the residual tumor. The overall 5-year survival rate and median survival time were 27.0% and 11.8 months, respectively. In the cohort of CRT-plus-surgical resection, the 5-year survival rate was significantly higher than in the groups treated with CRT-alone (51.1% vs. 6.5%; p < 0.01). On multivariate analysis, good response to CRT [hazard ratio (HR) =0.449, p<0.01], GPS1/2 (HR=2.151, p=0.015), and surgical resection (HR=0.282, p<0.01) were significant prognostic factors, whereas PNI was not. CONCLUSION: The GPS is a useful, simple survival marker for patients with T4 ESCC undergoing multimodal therapy. PMID- 26254386 TI - Stereotactic Body Radiotherapy Results for Pulmonary Oligometastases: A Two Institution Collaborative Investigation. AB - AIM: The current study investigated outcomes and prognostic factors of pulmonary oligometastases at two Institutions. PATIENTS AND METHODS: SBRT (stereotactic body radiotherapy) as performed for pulmonary oligometastases from January 2004 to April 2014, and patients with a biologically effective dose (BED10) >= 75 Gy were registered in the study. Control of the primary tumor was not a criterion: we included both oligo-recurrence and sync-oligometastases. RESULTS: A total of 34 patients were enrolled in the study. The median overall survival was 20 months (range=1-119 months) and the 2-year overall survival rate was 65.7% [95% confidence interval (CI)=48.3-83.1%]. The two-year local control rate was 79.1% (95% CI=62.4-95.8%). Stratified by oligo status, the 2-year overall survival rate of the oligo-recurrence group was 68.5% (95% CI=50.3-86.7%), while that of the group with sync-oligometastases was 50.0% (95% CI=1.0-99.0%). These rates were significantly different (p=0.037). No grade 5 early- or late-adverse events were recognized in the current study. CONCLUSION: SBRT for pulmonary oligometastases achieved good results and there was no serious adverse event. The oligo recurrence group, in particular, achieved fairly good results. PMID- 26254387 TI - Impact of Interstitial Changes on Radiation Pneumonitis After Stereotactic Body Radiation Therapy for Lung Cancer. AB - AIM: The aim of the present study was to evaluate the impact of interstitial changes (IC) on radiation pneumonitis (RP) after stereotactic body radiation therapy (SBRT) for lung cancer. PATIENTS AND METHODS: We analyzed 260 consecutive patients with primary lung cancer treated with SBRT. According to the presence or absence of IC on the pre-treatment computed tomography, patients were divided into two groups: an IC group (n=18) and a non-IC group (n=242). RESULTS: RP of grade 2 or more was observed in 9 (50.0%) and 14 (6.7%) patients in the IC and non-IC group, respectively. All three patients with grade 5 RP were in the IC group. As indicated by multivariate analysis, the presence of IC was the only significant predictive factor of RP of grade 2 or more. CONCLUSION: The presence of IC was a significant indicator of grade 2 or more RP after SBRT for patients with lung cancer. PMID- 26254388 TI - TP53 and FGFR3 Gene Mutation Assessment in Urine: Pilot Study for Bladder Cancer Diagnosis. AB - AIM: To assess, in a prospective clinical research study, a new non-invasive and reliable test to accurately detect tumor protein 53 (TP53) and fibroblast growth factor receptor-3 (FGFR3) mutations in cells in urine. MATERIALS AND METHODS: TP53 mutations were analyzed using the functional analysis of separated allele in yeast (FASAY) method, which allows functional analysis of the P53 protein, and FGFR3 mutations were assessed with the SNaPshot system, detecting the eight most frequent point-mutations of this gene. Chi-square test or Fisher's exact test were used to compare TP53 and FGFR3 mutations in the tumors according to tumor stage and grade. RESULTS: TP53 and FGFR3 mutations in bladder tumors increased and decreased respectively with increasing tumor stage and cellular grade (p<0.05 and p<0.001, respectively). A total of 103 tumor/urinary sediment couples were analyzed. TP53 or FGFR3 mutations were observed in 76 tumors. The sensitivity for the detection of this type of mutation in urine was 46%, the specificity was 81%, the positive predictive value was 94% and the negative predictive value was 37%. CONCLUSION: Our original data confirmed the feasibility of TP53 and FGFR3 mutation detection in urine sediment. These measurements, together with urine cytology, may increase tumor detection. The sensitivity of the TP53/FGFR3 phenotype test in the urine was less than 50% and was not able to replace standard cystoscopy in the diagnosis of bladder tumors. PMID- 26254389 TI - Impact of Itraconazole After First-line Chemotherapy on Survival of Patients with Metastatic Biliary Tract Cancer. AB - AIM: We evaluated the efficacy and safety of itraconazole after first-line chemotherapy in patients with metastatic biliary tract cancer (BTC). PATIENTS AND METHODS: We retrospectively reviewed data from patients with histologically diagnosed BTC with distant metastases who had received one or more lines of chemotherapy and subsequent itraconazole chemotherapy. RESULTS: Among 28 enrolled patients, 26 (93%) received docetaxel (35 mg/m(2)), gemcitabine (1,000 mg/m(2)), and carboplatin (AUC4) on day 1 and oral itraconazole solution (400 mg) on days 2 to 2, repeated every 2 weeks. Two patients received docetaxel plus itraconazole with irinotecan. Two complete responses and 14 partial responses were observed, with a response rate of 57%. The median overall survival was 12.0 months. During 160 cycles, 21 (75%) and 17 (61%) patients had grade 3/4 neutropenia and thrombocytopenia, respectively. Two patients (7%) experienced febrile neutropenia. CONCLUSION: Combination chemotherapy with itraconazole after first line chemotherapy is promising for patients with metastatic BTC. PMID- 26254390 TI - Two Phenotypes of Traditional Serrated Adenomas Nationwide Survey in Iceland. AB - Iceland has a total population of 300,000 inhabitants. All patients consulting for symptoms of the lower digestive tract during a four-year period (2003-2006) were subjected to a colonoscopic examination; all polyps were endoscopically removed. Out of the total 3,037 colorectal adenomas (CRAs), 308 (10.2%) were traditional serrated adenomas (TSAs). TSAs were divided according the predominant histological phenotype (>50%) into those with ectopic crypt formations (ECF), and those with unlocked serrations (US). ECF-TSA accounted for 5.9% (178/3037) and US TSA for 4.3% (130/3037). The majority of patients with ECF-TSA and US-TSA were >= 60 years of age (74.1% and 76.2%, respectively). Notwithstanding, when patients having advanced adenomas (with high-grade dysplasia, with or without intramucosal carcinoma) were listed by age, those with ECF-TSA were significantly younger than those with US-TSA (p<0.05). ECF-TSA were more frequently left-sided (71.8%), whereas US-TSA were more frequently right-sided (60.0%). Invasive carcinoma evolved more frequently in ECF-TSA (7.8%) and in US-TSA (7.7%) than in tubular adenomas and in villous/tubulovillous adenomas (0.1% and 4.4%, respectively). Comparative studies indicated that the incidence rates/year of ECF-TSA and US-TSA were significantly higher in Iceland than in Sweden or in Italy (p<0.05). Genetic and putative epigenetic (environmental) factor(s) might account for the high incidence rate/year of ECF-TSA and US-TSA in this country. PMID- 26254391 TI - Plasma TIMP-1 and CEA as Markers for Detection of Primary Colorectal Cancer: A Prospective Validation Study Including Symptomatic and Non-symptomatic Individuals. AB - BACKGROUND/AIM: The combination of plasma tissue inhibitor of metalloproteinases 1 (1) and CEA has been shown to have utility in early detection of colorectal cancer (2). A prospective study was performed to validate previous findings. PATIENTS AND METHODS: Individuals undergoing large bowel endoscopy were prospectively included (N=1965). Baseline data and co-morbidity were recorded. The primary end-point was the detection of CRC. Plasma was obtained before endoscopy and TIMP-1 and CEA levels were determined using an automated analysis platform when all samples were collected. RESULTS: CRC was detected in 32 individuals, 24 with colonic cancer (CC) and 8 with rectal cancer (RC). Other findings were 265 with adenomas and 889 with non-neoplastic pathology. The biomarker levels were elevated in plasma from patients with CRC, but also from patients with various co-morbidities compared to individuals without any findings at endoscopy. Univariate analysis demonstrated that both markers were significant predictors of CRC. The odds ratios (OR) for an elevated TIMP-1 level for the detection of CRC was 6.2 [95% confidence interval (CI)=3.1-13.0, p<0.0001] and for an elevated CEA level was 2.4 (95% CI=1.9-2.9, p<0.0001). A subset analysis with CC as the end-point showed an OR for TIMP-1 of 7.0 (95% CI=3.2-15.3, p<0.0001). Multivariable analysis including TIMP-1, CEA and age resulted in an OR for TIMP-1 of 2.0 (95% CI=0.7-5.2, p=0.078) and for CEA the OR was 2.2 (95% CI=1.8-2.8, p<0.0001). CONCLUSION: This prospective study validates a previous study testing the detection of CRC based on TIMP-1 and CEA levels (3). PMID- 26254392 TI - Strategies for Preventing Pseudomyxoma Peritonei After Resection of a Mucinous Neoplasm of the Appendix. AB - BACKGROUND/AIM: Considering the suspected link between mucinous neoplasm (MN) and pseudomyxoma peritonei (PMP), one option could be to propose prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) to selected patients in order to prevent the occurrence of PMP. The aim of this study was to identify risk factors for developing PMP after curative surgery for a MN of the appendix. PATIENTS AND METHODS: All consecutive patients referred to our single tertiary care cancer center between September 1992 and March 2014 for MN of the appendix, initially without PMP, were retrospectively studied. Patients who had received prophylactic intraperitoneal treatment were excluded from the analysis. RESULTS: Twenty-five patients with a median age of 51 (range=25-74) years were identified. At the initial appendectomy, 19 (76%) patients had a perforated MN. Nine of these patients (40%) exhibited disseminated-free acellular intraperitoneal mucin without PMP. Six (24%) patients had an unperforated MN without free intraperitoneal mucin. After a median follow-up of 50 months, 12 (52%) patients had developed PMP after a median time of 61 (range=13-121) months. Complete cytoreductive surgery plus HIPEC was possible in only seven (64%) out of these 12 patients. No factor reached statistical significance in predicting the occurrence of PMP but a trend was found in the case of perforated MN (p=0.068), associated with a 65% recurrence rate, compared to 17% without perforation. CONCLUSION: An appendicular MN cannot be considered a benign occurrence because PMP is common after resection and can occur up to 10 years after the initial appendectomy. Patients should be systematically followed up to detect PMP as early as possible. Patients with a perforated MN could be at higher risk of developing PMP. PMID- 26254393 TI - Facial Basal Cell Carcinomas in Elderly Frail Patients Treated with Low Total dose Radiotherapy. AB - AIM: A retrospective analysis was performed in our two Institutions in order to evaluate the feasibility and reliability of a hypofractionated-radiotherapy regimen in the treatment of frail elderly patients with facial basal cell carcinomas (BCCs). PATIENTS AND METHODS: The records of elderly patients (age >75 years) with histologically-confirmed BCC, T1-2, treated to a total radiation dose of 25-30 Gy over 5-6 weeks, were retrospectively analyzed. RESULTS: From February 2007-December 2010, 134 ambulatory patients with 159 BCCs were treated. Their median age was 82.5 years (range=75-103). Grade 1-2 skin acute toxicities were observed in 30.6% of patients (41/134). Complete responses were observed in 157 tumors in 132 patients. At the last follow-up, June 2014, no late toxicities had been noted; three patients had local recurrent disease. CONCLUSION: Our results seem to demonstrate both the feasibility and efficacy of curative hypofractionated radiation therapy in elderly patients with BCCs unfit for daily irradiation. PMID- 26254394 TI - Dual Anti-angiogenic Chemotherapy with Temozolomide and Celecoxib in Selected Patients with Malignant Glioma Not Eligible for Standard Treatment. AB - AIM: Due to their high rate of neo-angiogenesis, malignant gliomas may qualify for treatment with anti-angiogenic substances. We report on a series of patients with malignant glioma not eligible for standard postoperative combined radiochemotherapy due to decreased health status. PATIENTS AND METHODS: A total of nine patients with malignant glioma, postoperatively presenting with a Karnofsky performance score (KPS) below 70, were treated with standalone metronomic low-dose chemotherapy with temozolomide and celecoxib (cyclo-oxygenase 2 inhibitor). Overall survival was defined as the primary end-point and the functional status (KPS) and time to progression as secondary end-points of our analysis. RESULTS: The median KPS after surgery was 60. Treatment achieved a decrease in tumor and edema volume and, more importantly, preserved the functional status defined as the ability to care for self (KPS 70%) until disease progression. No notable side-effects were recorded. CONCLUSION: In patients with decreased general condition (KPS <70), not eligible for standard treatment, anti angiogenic therapy offers a reasonable alternative approach. Our results indicate prolonged survival and preserved quality of life in comparison to best supportive care. PMID- 26254395 TI - Preoperative Change in Peripheral Blood Monocyte Count May Predict Long-term Outcomes After Pancreaticoduodenectomy for Bile Duct Cancer. AB - BACKGROUND/AIM: The perioperative immunological response predicts long-term outcomes after resection for malignant tumors. The aim of the study was to evaluate the significance of perioperative change in the peripheral blood monocyte count regarding therapeutic outcome after pancreaticoduodenectomy for bile duct cancer. PATIENTS AND METHODS: The study comprised of 51 patients who had undergone pancreaticoduodenectomy for bile duct cancer between January 2000 and December 2012. We retrospectively investigated the relation between perioperative change in peripheral blood monocyte count and disease-free as well as overall survival. RESULTS: In multivariate analysis, advanced TNM stage, and decrease in monocyte count on postoperative day 1 in comparison with those before surgery were independent and significant predictors of poor disease-free survival and overall survival (p=0.014 and 0.004, and 0.010 and 0.006, respectively). CONCLUSION: Perioperative change in peripheral blood monocyte count is an independent and significant indicator of therapeutic outcome after pancreaticoduodenectomy in patients with bile duct cancer. PMID- 26254397 TI - Contribution of DNA Repair Xeroderma Pigmentosum Group D Genotype to Gastric Cancer Risk in Taiwan. AB - AIM: It has been proposed that genetic variations of DNA repair genes confer susceptibility to cancer, and the DNA repair gene xeroderma pigmentosum group D (XPD), the caretaker of genome stability, is thought to play a major role in the nucleotide excision repair system. We investigated three genotypes of XPD, at promoter -114 (rs3810366), and codon 312 (rs1799793), 751 (rs13181), and their associated with gastric cancer susceptibility in a Taiwanese population. MATERIALS AND METHODS: In the present study, 121 patients with gastric cancer and 363 gender- and age-matched healthy controls were recruited and genotyped for XPD by polymerase chain reaction-based restriction fragment length polymorphism (PCR RFLP) methodology, and the association of XPD genotype with gastric cancer risk was investigated. RESULTS: We found a significant difference in the distribution of A allele-bearing XPD codon 312 genotypes [odds ratio (OR)=1.64, 95% confidence interval (CI)=1.20-2.25, p=0.0019], but not in XPD codon 751 or promoter -114 sites, between the gastric cancer and control groups. Those who had G/A or A/A at XPD codon 312 had a 1.83-fold (95% CI=1.14-2.95, p=0.0159) and 1.87-fold (95% CI=1.04-3.34, p=0.0378) increased risk of gastric cancer compared to those with G/G. The risk for G/A and A/A genotypes had synergistic effects with alcohol drinking (OR=11.27, 95% CI=3.72-34.17, p=0.0001), cigarette smoking (OR=23.20, 95% CI=6.24-86.23, p=0.0001) and Helicobacter pylori infection (OR=5.38, 95% CI=2.76-10.52, p=0.0001) on gastric cancer susceptibility. CONCLUSION: Our findings suggest that the A allele of XPD codon 312 may contribute to gastric carcinogenesis and may be useful for early detection and prevention of gastric cancer. PMID- 26254396 TI - Cardiac Surveillance Findings During Adjuvant and Palliative Trastuzumab Therapy in Patients with Breast Cancer. AB - BACKGROUND/AIM: Trastuzumab therapy, the standard treatment for human epidermal growth factor receptor type-2 (HER2)-positive breast cancer, is associated with possible cardiotoxicity. We set out to retrospectively analyze the cardiac follow up data of patients with breast cancer receiving trastuzumab treatment. PATIENTS AND METHODS: The study involved 47 and 31 patients receiving adjuvant or palliative chemotherapy plus trastuzumab, respectively. Cardiovascular system assessments including echocardiography were regularly performed. RESULTS: A significant heart abnormality was detected in 44.7% of the operable and 41.9% of metastatic cases. In the adjuvant setting, left ventricular ejection fraction changes occurred mostly during treatment and less frequently after its completion (40.4% vs. 19.4%), while in the palliative setting, 35.5% and 40% in the first and the second year of therapy. An asymptomatic atrial septum aneurysm was detected in 8.5% and 13% of the patients in the two groups. CONCLUSION: Trastuzumab-related cardiotoxicity is mostly manifested in an asymptomatic decrease in left ventricular ejection fraction; hypertension, a high body mass index and left-sided irradiation are its predictors. PMID- 26254398 TI - Relation of Vitamin E and Selenium Exposure to Prostate Cancer Risk by Smoking Status: A Review and Meta-Analysis. AB - BACKGROUND: Epidemiological studies of selenium and vitamin E, two antioxidants hypothesized to reduce prostate cancer risk, have shown no discernible benefit. It has been proposed, however, that tobacco smoking may modify the effect of these nutrients. MATERIALS AND METHODS: We performed a meta-analysis of studies evaluating the relation of vitamin E and selenium exposure to prostate cancer risk in never smokers vs. ever smokers and, when feasible, former and current smokers. Overall and stratum-specific meta-risk ratios (meta-RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. RESULTS: A total of 21 studies have met the inclusion criteria. Meta-RR (95% CI) estimates of prostate cancer associated with vitamin E use were 1.03 (0.95-1.11) in never smokers and 0.98 (0.90-1.07) in ever-smokers. For selenium, meta-RRs were 1.09 (0.78-1.52 and 0.76 (0.60-0.96) for never and ever-smokers, respectively; however, results for current smokers were weaker than those for former smokers. Sub-analyses according to different exposure assessment methods and outcome definitions produced similar results across strata. CONCLUSION: The association between vitamin E and prostate cancer is not modified by smoking. Selenium exposure is associated with lower prostate cancer risk among ever-smokers; however, the lack of an association for current smokers indicates that this finding needs to be interpreted with caution. PMID- 26254399 TI - Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for First Relapse of Ovarian Cancer. AB - BACKGROUND: To assess impact of surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients treated for a first relapse of ovarian cancer (FROC). PATIENTS AND METHODS: Patients with a FROC treated with second-line chemotherapy, surgery and HIPEC were retrospectively included from 13 Institutions. Studied parameters were interval free between the end of initial treatment and the first relapse, second-line chemotherapy, peritoneal cancer index and completeness of surgery, HIPEC, mortality and morbidity, pathological results and survival. RESULTS: From 2001 to 2010, 314 patients were included. The main strategy was secondary chemotherapy followed by surgery and HIPEC (269/314 85.6%). Mortality and morbidity rates were respectively 1% and 30.9%. Median follow-up was 50 months, 5-year overall survival was 38.0%, with no difference between platinum-sensitive or -resistant patients and 5-year disease-free survival was 14%. CONCLUSION: HIPEC allows encouraging survival in the treatment of FROC, better in case of complete surgery, with acceptable mortality and morbidity rates. PMID- 26254400 TI - Pentafecta Outcomes of 230 Cases of Robotic-assisted Radical Prostatectomy with Bilateral Neurovascular Bundle Preservation. AB - AIM: We analyzed pentafecta outcomes [complication-free, continence, potency, negative surgical margins (NSM)], biochemical recurrence (BCR)-free] of 230 patients undergoing robotic-assisted radical prostatectomy (RARP) with bilateral neurovascular (NVB) preservation. PATIENTS AND METHODS: Patient outcomes (group I, cases 1-115; group II, cases 116-230) were assessed prospectively. Definitions were: continence, using no pads; potency, ability to achieve/maintain erections firm enough for sexual intercourse; positive surgical margin, presence of tumor tissue on inked specimen surface; and BCR, two consecutive PSA levels >0.2 ng/ml after RALP. RESULTS: The mean patient age was 62.5 years, mean PSA=8.62 ng/ml. The complication-free rate was 93.9% (216/230), continence rate 98.3% (226/230), potency 86.1% (198/230), NSM 77.0% (177/230) and BCR-free 92.6% (213/230). The trifecta rate (continence, potency, BCR-free) was 81.7% (188/230). The pentafecta rate was 60.4% (139/230). CONCLUSION: Pentafecta is the new standard of outcomes for RARP with bilateral NVB, with patient selection and reduced positive surgical margins attaining best outcomes. PMID- 26254401 TI - Comparative Study Between Total Laparoscopic and Total Robotic Radical Hysterectomy for Cervical Carcinoma: Clinical Study. AB - AIM: to compare surgical outcomes and health-related quality of life (HRQOL) between total laparoscopic (TLRH) and total robotic radical hysterectomy (TRRH) for cervical cancer. PATIENTS AND METHODS: Surgical outcomes and HRQOL were compared between the two groups. Pre- and postoperative HRQOL data from 36-item Short Form (SF-36) and European Organization Research and Treatment of Cancer Quality of Life-C30(EORTC QOL-C30) questionnaires were recorded. RESULTS: In the TRRH group, there were more cases of para-aortic lymphadenectomy (p<0.01), longer operative time (p<0.01), less estimated blood loss (p<0.01), and more harvested pelvic lymph nodes (p=0.04). There were no significant differences in the SF-36 and the EORTC QOL-C30 between the two groups. CONCLUSION: TRRH surgical outcomes were associated with less blood loss and more harvested pelvic lymph nodes but longer operative times with statistical significance. The short-term postoperative HRQOL outcomes did not show any significant inter-group differences. PMID- 26254402 TI - Laparoscopic Total Gastrectomy for RGC: Four Case Reports. AB - Surgery for RGC can generally be difficult because of the severity of intra abdominal adhesion due to past gastrectomy. Laparoscopic gastrectomy for RGC has been reported in some cases, but the adequacy of this procedure is still unclear. Herein we report four cases of RGC that underwent laparoscopic gastrectomy at our Hospital and discuss the benefit of the laparoscopic approach for RGC. PMID- 26254403 TI - Combination of Juvenile Papillomatosis, Juvenile Fibroadenoma and Intraductal Carcinoma of the Breast in a 15-Year-old Girl. AB - The association of juvenile papillomatosis with carcinoma is proven, but very rare, as there exist several reported cases. CASE REPORT: A 15-year-old girl with no family history of breast cancer presented with two masses in the left breast. The excisional biopsy on both lumps revealed juvenile fibroadenoma and juvenile papillomatosis epithelial proliferation multiple cystic expanded channels. In some of these channels, cytological features of intraductal carcinoma were observed. We performed a full immunohistochemical examination of the juvenile papillomatosis. The patient refused any further surgical or adjuvant treatment. There are no signs of recurrence in the 15 year follow-up. DISCUSSION: This case is a diagnostic and therapeutic challenge, taking into account the patient's age and the controversial treatment recommendations. Good collaboration between surgeons and pathologists is essential for an accurate diagnostic process and aims to avoid under- or overtreatment. PMID- 26254404 TI - Simple Risk Stratification to Detect Prostate Cancer with High Gleason Score in Repeat Biopsies in a Population Screening Follow-up Study. AB - BACKGROUND: To investigate the clinical usefulness of percentage free prostate specific antigen (%fPSA) and PSA velocity (PSAV) for detecting prostate cancer in repeat biopsies in a population-based screening cohort. PATIENTS AND METHODS: In total, 178 men with serum PSA levels within 2.1-10 ng/ml who underwent repeat biopsies after initial negative biopsy results, were enrolled. Prostate cancer detection rates with a Gleason score of 7 or more according to age, serum PSA, %fPSA, and PSAV were investigated. The cumulative probability of detecting cancer according to risk factors was also investigated. RESULTS: Out of 178 men who underwent repeat biopsy, 48 (27.0%) were diagnosed with prostate cancer during the observation period, and pathological examination revealed prostate cancer with a Gleason score of 7 or more in 17 patients (35.4%). In the multivariate logistic regression analysis, %fPSA <= 12 at repeat biopsy and PSAV >0.40 ng/ml/year were determined to be independent risk factors for prostate cancer, and %fPSA <= 12 at initial biopsy and PSAV >0.40 for cancer of Gleason score 7 or greater. The cumulative probabilities of developing high-grade cancer after 5 years were 55.8% and 4.0% in men with %fPSA <= 12 at initial biopsy and PSAV >0.40, and in men without both, respectively. There was a statistically significant difference in probabilities between groups by the log-rank test. CONCLUSION: The present results demonstrated that %fPSA and PSAV were predictors of prostate cancer with a Gleason score of 7 or more in repeat biopsy after a negative initial biopsy on a population follow-up basis. PMID- 26254405 TI - Significance of Markers of Systemic Inflammation for Predicting Survival and Chemotherapeutic Outcomes and Monitoring Tumor Progression in Patients with Unresectable Metastatic Colorectal Cancer. AB - BACKGROUND: Markers of systemic inflammation, such as the neutrophil to lymphocyte ratio (NLR), C-reactive protein (CRP) level and Glasgow prognostic score (GPS), have been reported to be useful prognostic indicators for various types of cancers. However, most of the existing reports investigated the preoperative status, and the significance of markers of systemic inflammation remains unclear in patients with unresectable metastatic colorectal cancer. The aim of the present retrospective study was to evaluate the significance of markers of systemic inflammation for predicting the prognosis and chemotherapeutic outcomes and monitoring the progression of the tumor in patients with unresectable metastatic colorectal cancer receiving palliative chemotherapy. PATIENTS AND METHODS: A total of 110 patients with unresectable metastatic colorectal cancer who underwent palliative chemotherapy for metastatic tumors were enrolled in the study. We evaluated the relationships between the survival/chemotherapeutic response and pre-/post-treatment markers of systemic inflammation. The pre-treatment markers of systemic inflammation were measured within one week before the initiation of chemotherapy and the post-treatment markers of systemic inflammation were measured eight weeks after initiation of chemotherapy. RESULTS: The overall survival rates were significantly worse in the group with high pre-treatment NLR/CRP/GPS, and that with high post-treatment CRP/GPS; the progression-free survival rate was significantly worse in the high post-treatment CRP group. As for chemotherapeutic response, patients with a low post-treatment CRP level had a significantly higher disease control rate than those with a high post-treatment CRP level. Moreover, the patients with a high pre-treatment CRP level and normalization after treatment exhibited better overall and progression-free survival rates and had a significantly higher disease control rate than those with high pre- and post-treatment CRP levels. CONCLUSION: Pre-treatment markers of systemic inflammation are useful for predicting prognosis in patients with unresectable metastatic colorectal cancer who receive palliative chemotherapy. Moreover, the CRP level can be used as a marker for predicting chemotherapeutic outcome and monitoring the progression of the tumor. PMID- 26254406 TI - Survival Advantage Associated with Metformin Usage in Hepatocellular Carcinoma Patients Receiving Radiotherapy: A Propensity Score Matching Analysis. AB - BACKGROUND: The present study aimed to evaluate the effects of metformin on the clinical outcomes of patients receiving radiotherapy for inoperable hepatocellular carcinoma. PATIENTS AND METHODS: The medical records of 217 patients treated with stereotactic body or hypofractionated radiotherapy for inoperable hepatocellular carcinoma were reviewed. Patients were divided into the metformin group (n=19) and the non-metformin group (n=198), including those with diabetes (n=29), and those without (n=169). We performed a propensity score matching analysis comparing the two groups. RESULTS: In the propensity score matched cohort (n=76), the overall survival rate of the metformin group was higher than that of the non-metformin group (2-year, 76% vs. 37%, p=0.022). The adjusted Cox proportional hazards model revealed that metformin usage was a significant factor for mortality (adjusted hazard ratio=0.361; 95% confidence interval=0.139-0.935). CONCLUSION: The use of metformin in patients with hepatocellular carcinoma receiving radiotherapy was associated with higher overall survival. PMID- 26254407 TI - Amplification of FGFR2 Gene in Patients with Advanced Gastric Cancer Receiving Chemotherapy: Prevalence and Prognostic Significance. AB - BACKGROUND: Fibroblast growth factors and their receptors regulate key cellular functions, such as proliferation, differentiation and survival. Herein, we studied the prevalence and prognostic role of fibroblast growth factor receptor 2 (FGFR2) amplification in patients with advanced gastric cancer (AGC) who received systemic chemotherapy. PATIENTS AND METHODS: The gene copy number of FGFR2 was investigated in 80 patients with AGC who received systemic chemotherapy. FGFR2 gene status was assessed by dual-color fluorescence in-situ hybridization. RESULTS: Among 80 patients, FGFR2 amplification was observed in seven cases (11.5%). Patients with FGFR2 amplification had significantly shorter overall survival (OS) than did those without FGFR2 amplification (9.1 vs. 16.5 months; p=0.037). In multivariate analysis, disease status and number of metastatic sites were associated with worse OS (p=0.015 and p=0.009, respectively). FGFR2 amplification tended to be correlated with a poorer outcome (p=0.080). CONCLUSION: FGFR2 amplification tended to result in a shorter survival period compared to cases without amplification. PMID- 26254408 TI - Complexity of Response Evaluation During Primary Systemic Therapy of Breast Cancer: Scoring Systems and Beyond-Preliminary Results. AB - BACKGROUND: Precise and standardized response evaluation enables clinicians to tailor primary systemic therapy (PST). PATIENTS AND METHODS: Breast cancer patients underwent (18)F-fluoro-deoxy-glucose positron emission tomography and computerized tomography (FDG-PET/CT) before and after PST. Response was assessed by maximal Standardized Uptake Value (SUVmax); morphological changes and Ki-67 labeling index (LI). In parallel response assessment was performed by European Organization for Research and Treatment of Cancer (EORTC); PET Response Criteria in Solid Tumors (PERCIST); World Health Organization (WHO); Response Evaluation Criteria in Solid Tumors (RECIST); Chevallier and Sataloff classifications, and by a novel Ki-67 score. Accuracy of different scoring systems was evaluated. RESULTS: In the 42 enrolled patients, SUVmax, size, and Ki-67 LI decreased significantly on PST. Significant differences between patients with versus those without pathological complete response were observed for pre-treatment Ki-67 LI and SUVmax and for post-treatment Ki-67 LI, SUVmax and size. Change in Ki-67 LI was the best predictor of pathological complete response. Correlation patterns of the directly measured metabolic, morphological, and proliferation responses differed from those determined by scoring methods. CONCLUSION: During PST, FDG PET/CT enables for robust assessment of treatment efficacy, but more reliable scoring systems are still needed for more precise response evaluation. PMID- 26254409 TI - Large Colorectal Carcinoma Is Predictive of Recurrence After Adjuvant Chemotherapy Using Oxaliplatin. AB - AIM: The postoperative administration of oxaliplatin reduces the frequency of relapse in selected patients with colorectal cancer following surgical resection. However, factors associated with recurrence despite adjuvant therapy are largely unknown. PATIENTS AND METHODS: We investigated 68 patients who were pathologically diagnosed with stage II or III colorectal cancer and received oxaliplatin-including chemotherapy, FOLFOX (5-fluorouracil, folinic acid and oxaliplatin) or CapeOX (capecitabine and oxaliplatin), after curative surgery. RESULTS: Nineteen patients developed recurrence during the median follow-up period of 17.8 months. Multivariate analyses using the Cox proportional-hazards model revealed that primary tumor size >= 45 mm was a significant predictor of recurrence (hazard ratio=3.16, 95% confidence interval=1.06-11.54, p=0.039). A primary tumor of 45 mm or more in size was associated with poor recurrence-free survival. CONCLUSION: Our results suggest that large colorectal carcinoma needs to be recognized as a high-risk factor for recurrence even after surgery and subsequent treatment with oxaliplatin. PMID- 26254410 TI - Negative Impact of Preoperative Endoscopic Biliary Drainage on Prognosis of Pancreatic Ductal Adenocarcinoma After Pancreaticoduodenectomy. AB - BACKGROUND/AIM: Patients with obstructive jaundice due to cancer of the pancreatic head often undergo preoperative endoscopic biliary drainage (EBD). The aim of the study was to evaluate the long-term impact of preoperative EBD following pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma. PATIENTS AND METHODS: We studied 106 patients who underwent PD for pancreatic ductal adenocarcinoma between May 2000 and November 2013 at the Jikei University Hospital. We retrospectively examined perioperative findings as predictors of prognosis and the relationship between preoperative EBD and recurrence rate as well as overall survival. RESULTS: In univariate analysis, significant factors associated with poor disease-free survival consisted of the presence of EBD (p=0.0213), poor tumor differentiation (p=0.0023) and tumor-node-metastasis (TNM) classification IV (p=0.0027), while significant factors associated with poor overall survival consisted of the presence of EBD (p=0.0047), poor tumor differentiation (p<0.0001), TNM classification IV (p=0.0031) and microscopic or macroscopic residual tumor (p=0.0184). In multivariate analysis, poor tumor differentiation (p=0.0033) and TNM classification IV (p=0.0020) were independent factors for poor disease-free survival, while the presence of EBD (p=0.0435), poor tumor differentiation (p=0.0009), TNM classification IV (p=0.0447) and microscopic or macroscopic residual tumor (p=0.0184) were independent factors for poor overall survival. CONCLUSION: Preoperative EBD may have a negative impact on prognosis after PD for pancreatic ductal adenocarcinoma. PMID- 26254411 TI - T-DM1 as a New Treatment Option for Patients with Metastatic HER2-positive Breast Cancer in Clinical Practice. AB - AIM: To compare results of trastuzumab-emtansine (T-DM1) treatment in our clinical practice with data from phase III clinical trials. PATIENTS AND METHODS: A retrospective chart review of all 23 patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer who were started on T-DM1 until April 2014 was performed. RESULTS: Four patients (17.4%) received T-DM1 as first-line, three (13.0%) as second-line, six (26.0%) as third-line, and 10 (43.5%) as fifth- or further-line therapy. Overall, the response rate (ORR) was 26.0%, disease control rate 78.3% and median progression-free survival (PFS) 8.4 months. The only toxicities of grade 3 or more were fatigue (21.7%), thrombocytopenia (4.3%) and elevation of liver enzymes (8.7%). ORR and PFS were similar to the TH3RESA and EMILIA trials. Compared to the EMILIA study, we recorded higher rates of newly-diagnosed cerebral metastasis and cerebral progression in patients with stable peripheral metastases. CONCLUSION: T-DM1 is effective and well-tolerated even in intensively pre-treated patients. PMID- 26254412 TI - Cisplatin Plus Ifosfamide with/without Etoposide as Salvage Treatment in Heavily pre-treated Patients with Metastatic Breast Cancer. AB - BACKGROUND: The efficacy of platinum- and ifosfamide-based chemotherapy regimens as salvage treatment in metastatic breast cancer (MBC) has not yet been sufficiently evaluated. PATIENTS AND METHODS: Patients with MBC treated with cisplatin plus ifosfamide with (PEI) and without (PI) etoposide in our clinic between 04/2005 and 04/2014 were retrospectively analyzed. RESULTS: A total of 20 patients (median four prior chemotherapies) treated with PEI/PI were identified, out of whom 18 were evaluable for objective response. Treatment with PEI/PI resulted in one complete remission, nine partial remissions and two cases of stable disease. The median (range) progression-free survival was 4 (0-18) months and median overall survival from therapy initiation was 8.5 (0-50) months. PEI/PI therapy caused grade 3/4 toxicities (mainly hematological) in 80% of patients. CONCLUSION: PEI/PI is an adequate salvage treatment for patients with MBC but cannot be generally recommended due to toxicity. However, comparison with platinum monotherapy trials suggests that PEI/PI might be a more effective treatment for patients with triple-negative breast cancer. PMID- 26254413 TI - Splenectomy as Part of Cytoreductive Surgery in Recurrent Epithelial Ovarian Cancer. AB - AIM: To determine the impact of survival of peritoneal versus splenic metastasis in cases submitted to splenectomy as part of cytoreductive surgery in recurrent epithelial ovarian cancer. PATIENTS AND METHODS: Between January 2002 and May 2014, 28 patients were submitted to splenectomy as part of secondary, tertiary and beyond tertiary cytoreduction at the Dan Setlacec Center of Gastrointestinal Disease and Liver Transplantation, Fundeni Clinical Institute, Bucharest. RESULTS: Splenectomy was performed as follows: at secondary cytoreduction in 21 cases, at tertiary cytoreduction in six cases, and beyond tertiary cytoreduction in one case. An R0 resection was attempted in all cases; however, in two cases submitted to splenectomy as part of tertiary cytoreduction, R1 and R2 resection, were performed, respectively. Histopathological studies revealed the presence of peritoneal seeding in 11 cases at secondary cytoreduction and in four cases submitted to splenectomy as part of tertiary cytoreduction. Parenchymatous lesions were described in nine cases submitted to splenectomy as part of secondary cytoreduction and in two cases at tertiary cytoreduction. In a single case in which splenectomy was performed in the context of secondary cytoreduction, hilar involvement was found. Peritoneal seeding was described in the patient for whom splenectomy was performed at quaternary cytoreduction. Early postoperative mortality for the entire cohort (within 30 days) was 7.1% (death occurred in two cases submitted to splenectomy during the secondary cytoreduction). The median overall survival in patients with splenic involvement via peritoneal route was 35 months, while in cases with hematogenous splenic lesions, it was 12 months (p=0.2) at secondary cytoreduction. In the sub-group of patients submitted to splenectomy as part of tertiary cytoreduction, the median overall survival in patients with splenic involvement via peritoneal route was 21 months, while in cases with hematogenous splenic lesions it was 4 months (p=0.08). The patient submitted to quaternary cytoreduction died of disease 20 months later. CONCLUSION: splenectomy as part of secondary, tertiary and quaternary cytoreduction can be performed safely, with acceptable rates of morbidity and mortality. The maximal survival benefit seems to be obtained for patients with splenic involvement via peritoneal route, while those with hematogenous spread live a shorter period; further study is required in order to assess if resection in such cases is preferable to palliative chemotherapy. Maximal survival benefit occurs in the setting of secondary cytoreduction, although in selected cases, even quaternary cytoreduction can be followed by long term survival. PMID- 26254414 TI - Stereotactic Body Radiotherapy for Recurrent or Oligometastatic Uterine Cervix Cancer: A Cooperative Study of the Korean Radiation Oncology Group (KROG 14-11). AB - AIM: To evaluate local control and patient survival for recurrent or oligometastatic uterine cervical cancer treated with stereotactic body radiotherapy (SBRT) using CyberKnife, and to demonstrate the safety of SBRT. PATIENTS AND METHODS: Between 2002 and 2013, 100 recurrent or oligometastatic lesions in 85 patients were treated with SBRT at three Institutions. SBRT sites were within the previous RT field in 59 and partially overlapped in nine. SBRT sites included three local recurrences, 89 lymph node metastases, and eight distant metastases. Patients were treated with a median dose of 39 Gy in three fractions, which was equivalent to a biologically effective dose (BED) of 90 Gy. RESULTS: The median follow-up period was 20.4 months. Local failure occurred in 17 out of 100 SBRT-treated sites. The 2-year and 5-year local progression-free survival rates were 82.5% and 78.8%, respectively. Eleven local failures occurred within the previous RT field. The 2-year and 5-year overall survival rates were 57.5% and 32.9%, respectively. BED >90 Gy (p=0.072) and >69 Gy (p=0.059) and longer disease-free interval (p=0.065) predicted marginally superior local control. Re-irradiation appeared to be related to inferior local control (p<0.001), but the SBRT BED in this group was much lower than the dose in the other group (median BED, 79 Gy vs. 90 Gy). Chronic toxicities of grade 3 or more occurred in five cases. CONCLUSION: SBRT for recurrent or oligometastatic cervical cancer resulted in excellent local control, especially with a long disease-free interval and high BED treatment, with acceptable toxicities. Therefore, SBRT can be considered a therapeutic option for these patients. PMID- 26254415 TI - Pathological Characteristics of Both Tumors in Bifocal and Bicentric Breast Cancer. AB - AIM: The objective of the present study was to describe the biological characteristics of each lesion in patients with bifocal/bicentric (BF/BC) breast cancer. PATIENTS AND METHODS: We retrospectively reviewed the charts of 205 patients diagnosed with BF/BC cancer. The degree of concordance between the two lesions was assessed using Pearson product-moment correlation coefficients. RESULTS: A total of 205 patients were included. Both tumors displayed the same histological type in 182 patients (89%). The same grade was found for both tumors in 178 of the cases (96.7% and 100% for grade 3 lesions). Immunohistochemical concordance between the two tumors was excellent, with correlation coefficients of 0.98, 0.96 and 0.99 for estrogen receptors (ER), progesterone receptors (PR) and Ki67, respectively. Human Epidermal growth factor Receptor 2 (HER2) status was available for both tumors in 177 cases (86%), with a perfect concordance. We did not find any differences in molecular sub-type between tumor foci. CONCLUSION: Immunohistochemistry should be performed only on the main tumor in cases of BF/BC cancer. PMID- 26254416 TI - The Role of PET [18F]FDOPA in Evaluating Low-grade Glioma. AB - AIM: The aim of the present study was to evaluate the prognostic value of 3,4 dihydroxy-6-[(18)F]-fluoro-L-phenylalanine ([(18)F]-FDOPA) positron-emission tomography (PET) in predicting the risk of radiological progression of disease in patients affected by low-grade glioma. PATIENTS AND METHODS: Patients affected by grade II glioma were consecutively enrolled in a prospective observational study at the Department of Neurology of Regina Elena National Cancer Institute in Rome, Italy. At enrolment, all patients underwent PET [(18)F]-FDOPA and Magnetic Resonance Imaging (MRI), and clinical and radiological assessments with MRI every six months to evaluate the progression of disease. RESULTS: A total of 50 patients affected by grade II glioma (30 males and 20 females) were included in the study. The multivariate analysis showed that standardized uptake value greater than 1.75 and disease duration were independent predictors of disease progression. CONCLUSION: These findings suggest that the PET [(18)F]-FDOPA may play an important prognostic role in evaluation of low-grade glioma. PMID- 26254417 TI - Impact of Hepatitis B Virus on Clinicopathological Features and Outcomes After Resection for Pancreatic Adenocarcinoma. AB - Background/ Aim: Chronic hepatitis B virus (HBV) infection is sometimes considered a risk factor for pancreatic cancer (PDAC), but the prognostic value of its presence has only rarely been investigated. The present study aimed to explore the impact of HBV after resection for PDAC. MATERIALS AND METHODS: According to HBV surface antigen seroreactivity, 343 patients were classified as having non-viral or HBV-related cases of PDAC. Clinicopathological data and outcomes were comparatively assessed between the groups. RESULTS: Chronic HBV infection was observed in 16 patients (4.5%). No significant differences between the HBV and non-viral cases of PDAC were observed. Tumor diameters (3.4 vs. 3.0, p=0.092) and stages at diagnosis (31 vs. 14% T1-T2, p=0.082) tended to differ between the groups, albeit without reaching significance. Completion of adjuvant therapy (63 vs. 54%, p=0.612), as well as median overall survival (15 vs. 17 months, p=0.346) was similar in the HBV and non-viral PDAC groups. CONCLUSION: HBV-positive and virus-free patients with PDAC generally shared the same demographic, clinical and pathological profiles. HBV did not appear to have a detrimental effect on either early or long-term outcomes after resection for PDAC. Future studies searching for occult infection might, however, shed a different light on the role of HBV in PDAC. PMID- 26254418 TI - Routine Use of Bendamustine in Patients with Chronic Lymphocytic Leukemia: An Observational Study. AB - Bendamustine is an established treatment option in chronic lymphocytic leukemia (CLL) and frequently used in Austria and Italy. Therefore, we analyzed 100 unselected, consecutive patients with CLL (treatment-naive and relapsed/refractory) receiving bendamustine in a real-life setting. Most patients were treated with bendamustine in combination with rituximab (BR). However, bendamustine monotherapy was additionally evaluated. Patients treated with BR had a significantly higher overall response rate of 76% (complete response=22%) when compared to those treated solely with bendamustine (overall response rate=50%; complete response=13%). Overall survival (OS) and progression -ree survival (PFS) were significantly lower in the bendamustine-treated group (OS=14.3 months; PFS=8.3 months) compared to the BR group (OS=42.7; PFS=22.5 months; both p<0.001). In multivariate analysis, patients with a good cytogenetic risk and those receiving BR had a significantly better OS. Grade 3/4 hematological complications were seen in 32% of the patients. Hence, bendamustine, especially in combination with rituximab, is an effective therapy with manageable toxicity for non-selected patients with CLL including those pre-treated with fludarabine and the elderly. PMID- 26254419 TI - 5-Azacytidine in the Treatment of Intermediate-2 and High-risk Myelodysplastic Syndromes and Acute Myeloid Leukemia. A Five-year Experience with 44 Consecutive Patients. AB - BACKGROUND/AIM: The hypomethylating agent 5-azacytidine has been the standard-of care for patients with higher-risk myelodysplastic syndrome (MDS) during the past few years. Its efficacy has been proven in large clinical trials, and its safety has been shown to be superior to that of conventional treatments. PATIENTS AND METHODS: We conducted a retrospective study on the efficacy and safety of 5 azacytidine in 44 consecutive patients with MDS and acute myeloid leukemia treated with 5-azacytidine during a 63-month period. We recorded the clinical and laboratory characteristics of the patients and we analyzed the response to treatment, overall survival and adverse events during treatment. RESULTS: The median overall survival was 13 months, while serious adverse events consisted mostly of neutropenic infections. CONCLUSION: We reached two possibly valuable conclusions: Younger patients (<73 years), as well as patients receiving treatment at longer than 28-day intervals had a significantly higher overall survival. PMID- 26254420 TI - Computational genomic analysis of PARK7 interactome reveals high BBS1 gene expression as a prognostic factor favoring survival in malignant pleural mesothelioma. AB - The aim of our study was to assess the differential gene expression of Parkinson protein 7 (PARK7) interactome in malignant pleural mesothelioma (MPM) using data mining techniques to identify novel candidate genes that may play a role in the pathogenicity of MPM. We constructed the PARK7 interactome using the ConsensusPathDB database. We then interrogated the Oncomine Cancer Microarray database using the Gordon Mesothelioma Study, for differential gene expression of the PARK7 interactome. In ConsensusPathDB, 38 protein interactors of PARK7 were identified. In the Gordon Mesothelioma Study, 34 of them were assessed out of which SUMO1, UBC3, KIAA0101, HDAC2, DAXX, RBBP4, BBS1, NONO, RBBP7, HTRA2, and STUB1 were significantly overexpressed whereas TRAF6 and MTA2 were significantly underexpressed in MPM patients (network 2). Furthermore, Kaplan-Meier analysis revealed that MPM patients with high BBS1 expression had a median overall survival of 16.5 vs. 8.7 mo of those that had low expression. For validation purposes, we performed a meta-analysis in Oncomine database in five sarcoma datasets. Eight network 2 genes (KIAA0101, HDAC2, SUMO1, RBBP4, NONO, RBBP7, HTRA2, and MTA2) were significantly differentially expressed in an array of 18 different sarcoma types. Finally, Gene Ontology annotation enrichment analysis revealed significant roles of the PARK7 interactome in NuRD, CHD, and SWI/SNF protein complexes. In conclusion, we identified 13 novel genes differentially expressed in MPM, never reported before. Among them, BBS1 emerged as a novel predictor of overall survival in MPM. Finally, we identified that PARK7 interactome is involved in novel pathways pertinent in MPM disease. PMID- 26254421 TI - In vivo compartmental analysis of leukocytes in mouse lungs. AB - The lung has a unique structure consisting of three functionally different compartments (alveolar, interstitial, and vascular) situated in an extreme proximity. Current methods to localize lung leukocytes using bronchoalveolar lavage and/or lung perfusion have significant limitations for determination of location and phenotype of leukocytes. Here we present a novel method using in vivo antibody labeling to enable accurate compartmental localization/quantification and phenotyping of mouse lung leukocytes. Anesthetized C57BL/6 mice received combined in vivo intravenous and intratracheal labeling with fluorophore-conjugated anti-CD45 antibodies, and lung single-cell suspensions were analyzed by flow cytometry. The combined in vivo intravenous and intratracheal CD45 labeling enabled robust separation of the alveolar, interstitial, and vascular compartments of the lung. In naive mice, the alveolar compartment consisted predominantly of resident alveolar macrophages. The interstitial compartment, gated by events negative for both intratracheal and intravenous CD45 staining, showed two conventional dendritic cell populations, as well as a Ly6C(lo) monocyte population. Expression levels of MHCII on these interstitial monocytes were much higher than on the vascular Ly6C(lo) monocyte populations. In mice exposed to acid aspiration-induced lung injury, this protocol also clearly distinguished the three lung compartments showing the dynamic trafficking of neutrophils and exudative monocytes across the lung compartments during inflammation and resolution. This simple in vivo dual labeling technique substantially increases the accuracy and depth of lung flow cytometric analysis, facilitates a more comprehensive examination of lung leukocyte pools, and enables the investigation of previously poorly defined "interstitial" leukocyte populations during models of inflammatory lung diseases. PMID- 26254422 TI - Ionizing radiation induces myofibroblast differentiation via lactate dehydrogenase. AB - Pulmonary fibrosis is a common and dose-limiting side-effect of ionizing radiation used to treat cancers of the thoracic region. Few effective therapies are available for this disease. Pulmonary fibrosis is characterized by an accumulation of myofibroblasts and excess deposition of extracellular matrix proteins. Although prior studies have reported that ionizing radiation induces fibroblast to myofibroblast differentiation and collagen production, the mechanism remains unclear. Transforming growth factor-beta (TGF-beta) is a key profibrotic cytokine that drives myofibroblast differentiation and extracellular matrix production. However, its activation and precise role in radiation-induced fibrosis are poorly understood. Recently, we reported that lactate activates latent TGF-beta through a pH-dependent mechanism. Here, we wanted to test the hypothesis that ionizing radiation leads to excessive lactate production via expression of the enzyme lactate dehydrogenase-A (LDHA) to promote myofibroblast differentiation. We found that LDHA expression is increased in human and animal lung tissue exposed to ionizing radiation. We demonstrate that ionizing radiation induces LDHA, lactate production, and extracellular acidification in primary human lung fibroblasts in a dose-dependent manner. We also demonstrate that genetic and pharmacologic inhibition of LDHA protects against radiation-induced myofibroblast differentiation. Furthermore, LDHA inhibition protects from radiation-induced activation of TGF-beta. We propose a profibrotic feed forward loop, in which radiation induces LDHA expression and lactate production, which can lead to further activation of TGF-beta to drive the fibrotic process. These studies support the concept of LDHA as an important therapeutic target in radiation-induced pulmonary fibrosis. PMID- 26254423 TI - Biphasic force response to iso-velocity stretch in airway smooth muscle. AB - Airway smooth muscle (ASM) in vivo is constantly subjected to oscillatory strain due to tidal breathing and deep inspirations. ASM contractility is known to be adversely affected by strains, especially those of large amplitudes. Based on the cross-bridge model of contraction, it is likely that strain impairs force generation by disrupting actomyosin cross-bridge interaction. There is also evidence that strain modulates muscle stiffness and force through induction of cytoskeletal remodeling. However, the molecular mechanism by which strain alters smooth muscle function is not entirely clear. Here, we examine the response of ASM to iso-velocity stretches to probe the components within the muscle preparation that give rise to different features in the force response. We found in ASM that force response to a ramp stretch showed a biphasic feature, with the initial phase associated with greater muscle stiffness compared with that in the later phase, and that the transition between the phases occurred at a critical strain of ~3.3%. Only strains with amplitudes greater than the critical strain could lead to reduction in force and stiffness of the muscle in the subsequent stretches. The initial-phase stiffness was found to be linearly related to the degree of muscle activation, suggesting that the stiffness stems mainly from attached cross bridges. Both phases were affected by the degree of muscle activation and by inhibitors of myosin light-chain kinase, PKC, and Rho-kinase. Different responses due to different interventions suggest that cross-bridge and cytoskeletal stiffness is regulated differently by the kinases. PMID- 26254425 TI - Soluble guanylate cyclase modulators blunt hyperoxia effects on calcium responses of developing human airway smooth muscle. AB - Exposure to moderate hyperoxia in prematurity contributes to subsequent airway dysfunction and increases the risk of developing recurrent wheeze and asthma. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic GMP (cGMP) axis modulates airway tone by regulating airway smooth muscle (ASM) intracellular Ca(2+) ([Ca(2+)]i) and contractility. However, the effects of hyperoxia on this axis in the context of Ca(2+)/contractility are not known. In developing human ASM, we explored the effects of novel drugs that activate sGC independent of NO on alleviating hyperoxia (50% oxygen)-induced enhancement of Ca(2+) responses to bronchoconstrictor agonists. Treatment with BAY 41-2272 (sGC stimulator) and BAY 60-2770 (sGC activator) increased cGMP levels during exposure to 50% O2. Although 50% O2 did not alter sGCalpha1 or sGCbeta1 expression, BAY 60-2770 did increase sGCbeta1 expression. BAY 41-2272 and BAY 60-2770 blunted Ca(2+) responses to histamine in cells exposed to 50% O2. The effects of BAY 41-2272 and BAY 60-2770 were reversed by protein kinase G inhibition. These novel data demonstrate that BAY 41-2272 and BAY 60-2770 stimulate production of cGMP and blunt hyperoxia induced increases in Ca(2+) responses in developing ASM. Accordingly, sGC stimulators/activators may be a useful therapeutic strategy in improving bronchodilation in preterm infants. PMID- 26254427 TI - Commentary on: Botulinum Toxin for the Treatment of Excessive Gingival Display: A Systematic Review. PMID- 26254426 TI - Neovascularization in the pulmonary endothelium is regulated by the endosome: Rab4-mediated trafficking and p18-dependent signaling. AB - Neovascularization, the formation of new blood vessels, requires multiple processes including vascular leak, migration, and adhesion. Endosomal proteins, such as Rabs, regulate trafficking of key signaling proteins involved in neovascularization. The novel endosome protein, p18, enhances vascular endothelial (VE)-cadherin recycling from early endosome to cell junction to improve pulmonary endothelial barrier function. Since endothelial barrier integrity is vital in neovascularization, we sought to elucidate the role for endosome proteins p18 and Rab4, Rab7, and Rab9 in the process of vessel formation within the pulmonary vasculature. Overexpression of wild-type p18 (p18(wt)), but not the nonendosomal-binding mutant (p18(N39)), significantly increased lung microvascular endothelial cell migration, adhesion, and both in vitro and in vivo tube formation. Chemical inhibition of mTOR or p38 attenuated the proneovascularization role of p18(wt). Similar to the effect of p18(wt), overexpression of prorecycling wild-type (Rab4(WT)) and endosome-anchored (Rab4(Q67L)) Rab4 enhanced neovascularization processes, whereas molecular inhibition of Rab4, by using the nonendosomal-binding mutant (Rab4(S22N)) attenuated VEGF-induced neovascularization. Unlike p18, Rab4-induced neovascularization was independent of mTOR or p38 inhibition but was dependent on p18 expression. This study shows for the first time that neovascularization within the pulmonary vasculature is dependent on the prorecycling endocytic proteins Rab4 and p18. PMID- 26254424 TI - Coming to terms with tissue engineering and regenerative medicine in the lung. AB - Lung diseases such as emphysema, interstitial fibrosis, and pulmonary vascular diseases cause significant morbidity and mortality, but despite substantial mechanistic understanding, clinical management options for them are limited, with lung transplantation being implemented at end stages. However, limited donor lung availability, graft rejection, and long-term problems after transplantation are major hurdles to lung transplantation being a panacea. Bioengineering the lung is an exciting and emerging solution that has the ultimate aim of generating lung tissues and organs for transplantation. In this article we capture and review the current state of the art in lung bioengineering, from the multimodal approaches, to creating anatomically appropriate lung scaffolds that can be recellularized to eventually yield functioning, transplant-ready lungs. Strategies for decellularizing mammalian lungs to create scaffolds with native extracellular matrix components vs. de novo generation of scaffolds using biocompatible materials are discussed. Strengths vs. limitations of recellularization using different cell types of various pluripotency such as embryonic, mesenchymal, and induced pluripotent stem cells are highlighted. Current hurdles to guide future research toward achieving the clinical goal of transplantation of a bioengineered lung are discussed. PMID- 26254428 TI - Silicone Migration: An Unusual Eyelid Complication Following Intraocular Surgery. PMID- 26254429 TI - Botulinum Toxin for the Treatment of Excessive Gingival Display: A Systematic Review. AB - BACKGROUND: To date, no standardized minimally invasive approach for the treatment of excessive gingival display exists. OBJECTIVES: This systematic review aims to assess the evidence in the literature regarding the role of botulinum toxin injection in the management of gummy smile. METHODS: All publications through December 2014 and pertaining to the subject were electronically searched in PubMed, Embase, Scopus, and Web of Science, and the bibliographies of retrieved articles were manually screened. RESULTS: Out of 33 articles, 29 were discarded based on exclusion criteria. Although all 4 selected articles were in line with a role for botulinum toxin injection in the treatment of gummy smiles and the importance of targeting the levator labii superioris alaeque nasi muscle, studies differed in the type and the dose of toxin administered and the technique adopted. CONCLUSIONS: Injection with botulinum toxin is a novel, safe, and cosmetically effective treatment for gummy smile when performed by experienced practitioners. However, further randomized controlled trials are warranted. LEVEL OF EVIDENCE 4: Therapeutic. PMID- 26254430 TI - Critical limitations of prognostic signatures based on risk scores summarized from gene expression levels: a case study for resected stage I non-small-cell lung cancer. AB - Most of current gene expression signatures for cancer prognosis are based on risk scores, usually calculated as some summaries of expression levels of the signature genes, whose applications require presetting risk score thresholds and data normalization. In this study, we demonstrate the critical limitations of such type of signatures that the risk scores of samples will change greatly when they are normalized together with different samples, which would induce spurious risk classification and difficulty in clinical settings, and the risk scores of independent samples are incomparable if data normalization is not adopted. To overcome these limitations, we propose a rank-based method to extract a prognostic gene pair signature for overall survival of stage I non-small-cell lung cancer. The prognostic gene pair signature is verified in three integrated data sets detected by different laboratories with different microarray platforms. We conclude that, different from the type of signatures based on risk scores summarized from gene expression levels, the rank-based signatures could be robustly applied at the individualized level to independent clinical samples assessed in different laboratories. PMID- 26254432 TI - Urinary cadmium concentration and risk of breast cancer: a systematic review and dose-response meta-analysis. AB - Cadmium is a toxic and persistent heavy metal with estrogenic activities. We conducted a systematic review and meta-analysis of cohort, case-control, and cross-sectional studies of the association between urinary cadmium concentration, a biomarker of cadmium exposure, and breast cancer risk. Studies were identified by searching PubMed and Embase (to March 15, 2015) and by reviewing the reference lists of pertinent articles. Study-specific risk estimates were combined by using a random-effects model. We identified 2 cohort studies (with 67 breast cancer deaths) and 5 case-control studies and 1 cross-sectional study (with 1,416 cases and 5,083 controls) on urinary cadmium concentration in relation to breast cancer risk. The studies were published during the past 10 years (2006-2015). There was no consistent association between urinary cadmium and breast cancer mortality in the cohort studies. In case-control and cross-sectional studies, the pooled odds ratios were 2.24 (95% confidence interval: 1.50, 3.34; I(2) = 63.4%) for the highest versus lowest category of cadmium concentration and 1.66 (95% confidence interval: 1.23, 2.25) for each 0.5-ug/g creatinine increase of cadmium concentration. This meta-analysis suggests that a high cadmium exposure may be a risk factor for breast cancer, but large prospective studies are needed to confirm this finding. PMID- 26254431 TI - Algorithms for modeling global and context-specific functional relationship networks. AB - Functional genomics has enormous potential to facilitate our understanding of normal and disease-specific physiology. In the past decade, intensive research efforts have been focused on modeling functional relationship networks, which summarize the probability of gene co-functionality relationships. Such modeling can be based on either expression data only or heterogeneous data integration. Numerous methods have been deployed to infer the functional relationship networks, while most of them target the global (non-context-specific) functional relationship networks. However, it is expected that functional relationships consistently reprogram under different tissues or biological processes. Thus, advanced methods have been developed targeting tissue-specific or developmental stage-specific networks. This article brings together the state-of-the-art functional relationship network modeling methods, emphasizes the need for heterogeneous genomic data integration and context-specific network modeling and outlines future directions for functional relationship networks. PMID- 26254433 TI - Impact of normalization methods on high-throughput screening data with high hit rates and drug testing with dose-response data. AB - MOTIVATION: Most data analysis tools for high-throughput screening (HTS) seek to uncover interesting hits for further analysis. They typically assume a low hit rate per plate. Hit rates can be dramatically higher in secondary screening, RNAi screening and in drug sensitivity testing using biologically active drugs. In particular, drug sensitivity testing on primary cells is often based on dose response experiments, which pose a more stringent requirement for data quality and for intra- and inter-plate variation. Here, we compared common plate normalization and noise-reduction methods, including the B-score and the Loess a local polynomial fit method under high hit-rate scenarios of drug sensitivity testing. We generated simulated 384-well plate HTS datasets, each with 71 plates having a range of 20 (5%) to 160 (42%) hits per plate, with controls placed either at the edge of the plates or in a scattered configuration. RESULTS: We identified 20% (77/384) as the critical hit-rate after which the normalizations started to perform poorly. Results from real drug testing experiments supported this estimation. In particular, the B-score resulted in incorrect normalization of high hit-rate plates, leading to poor data quality, which could be attributed to its dependency on the median polish algorithm. We conclude that a combination of a scattered layout of controls per plate and normalization using a polynomial least squares fit method, such as Loess helps to reduce column, row and edge effects in HTS experiments with high hit-rates and is optimal for generating accurate dose-response curves. CONTACT: john.mpindi@helsinki.fi. AVAILABILITY AND IMPLEMENTATION: Supplementary information: R code and Supplementary data are available at Bioinformatics online. PMID- 26254434 TI - Improving protein fold recognition with hybrid profiles combining sequence and structure evolution. AB - MOTIVATION: Template-based modeling, the most successful approach for predicting protein 3D structure, often requires detecting distant evolutionary relationships between the target sequence and proteins of known structure. Developed for this purpose, fold recognition methods use elaborate strategies to exploit evolutionary information, mainly by encoding amino acid sequence into profiles. Since protein structure is more conserved than sequence, the inclusion of structural information can improve the detection of remote homology. RESULTS: Here, we present ORION, a new fold recognition method based on the pairwise comparison of hybrid profiles that contain evolutionary information from both protein sequence and structure. Our method uses the 16-state structural alphabet Protein Blocks, which provides an accurate 1D description of protein structure local conformations. ORION systematically outperforms PSI-BLAST and HHsearch on several benchmarks, including target sequences from the modeling competitions CASP8, 9 and 10, and detects ~10% more templates at fold and superfamily SCOP levels. AVAILABILITY: Software freely available for download at http://www.dsimb.inserm.fr/orion/. CONTACT: jean-christophe.gelly@univ-paris diderot.fr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26254440 TI - The epidemiology of primary anterior shoulder dislocations in patients aged 10 to 16 years. AB - BACKGROUND: Clinical studies of shoulder dislocations typically include adult patients (>16 years of age). Only small case series of patients aged 10 to 16 years are available to guide management. PURPOSE: Using a cohort of patients aged 10 to 16 years, this study sought to determine (1) the incidence density rate (IDR) of primary anterior shoulder dislocations requiring closed reduction (CR) and (2) the rate of and risk factors for repeat shoulder CR. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: With use of administrative databases, patients aged 10 to 16 years who underwent CR of a primary anterior shoulder dislocation in Ontario, Canada, between April 2002 and September 2010 were gathered. IDRs for the entire cohort and demographic subgroups were calculated. The main outcome, repeat shoulder CR, was sought until September 2012. The cumulative incidence of repeat CR was calculated at multiple time points for the entire cohort and age subgroups. A competing risk model identified risk factors for repeat CR (reported as hazard ratios [HRs] with 95% CIs). RESULTS: There were 1937 patients aged 10 to 16 years who underwent primary CR (median age, 15.0 years; 79.7% male). The incidence of primary CR was highest among male patients aged 16 years (164.4 per 100,000 person-years), but primary dislocations were rare in 10- to 12-year-old children (n = 115; 5.9% of all dislocations). Repeat CR was observed in 740 patients (38.2%) after a median of 0.8 years; however, the rate of repeat CR was age dependent: it was highest among 14- to 16-year-old patients (37.2%-42.3%) and considerably lower among 10- to 13 year-old patients (0%-25.0%). Male sex (HR, 1.2 [95% CI, 1.0-1.5]; P = .04) and older patient age (HR, 1.2 [95% CI, 1.1-1.3]; P < .001) significantly increased the odds of repeat CR. CONCLUSION: Among 14- to 16-year-old patients, the rate of primary and recurrent shoulder CR mirrors that of high-risk adults (17-20 years of age) from previously published data; however, the rate of shoulder CR (primary or recurrent) is considerably lower among 10- to 13-year-olds. In addition to older patient age, male sex increased the odds of repeat shoulder CR. Going forward, clinicians should counsel male patients and those aged 14 to 16 years regarding their increased risk of recurrence after the nonoperative management of a primary anterior shoulder dislocation. PMID- 26254435 TI - Accurate disulfide-bonding network predictions improve ab initio structure prediction of cysteine-rich proteins. AB - MOTIVATION: Cysteine-rich proteins cover many important families in nature but there are currently no methods specifically designed for modeling the structure of these proteins. The accuracy of disulfide connectivity pattern prediction, particularly for the proteins of higher-order connections, e.g., >3 bonds, is too low to effectively assist structure assembly simulations. RESULTS: We propose a new hierarchical order reduction protocol called Cyscon for disulfide-bonding prediction. The most confident disulfide bonds are first identified and bonding prediction is then focused on the remaining cysteine residues based on SVR training. Compared with purely machine learning-based approaches, Cyscon improved the average accuracy of connectivity pattern prediction by 21.9%. For proteins with more than 5 disulfide bonds, Cyscon improved the accuracy by 585% on the benchmark set of PDBCYS. When applied to 158 non-redundant cysteine-rich proteins, Cyscon predictions helped increase (or decrease) the TM-score (or RMSD) of the ab initio QUARK modeling by 12.1% (or 14.4%). This result demonstrates a new avenue to improve the ab initio structure modeling for cysteine-rich proteins. AVAILABILITY AND IMPLEMENTATION: http://www.csbio.sjtu.edu.cn/bioinf/Cyscon/ CONTACT: zhng@umich.edu or hbshen@sjtu.edu.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26254441 TI - Reply to the letter to the editor 'Flaws in the trial design of IFCT-0802' by Gyawali et al. PMID- 26254442 TI - Statistical controversies in clinical research: an initial evaluation of a surrogate end point using a single randomized clinical trial and the Prentice criteria. AB - Surrogate end point research has grown in recent years with the increasing development and usage of biomarkers in clinical research. Surrogacy analysis is derived through randomized clinical trial data and it is carried out at the individual level and at the trial level. A common surrogate analysis at the individual level is the application of the Prentice criteria. An approach for the evaluation of the Prentice criteria is discussed, with a focus on its most difficult component, the determination of whether the treatment effect is captured by the surrogate. An interpretation of this criterion is illustrated using data from a randomized clinical trial in prostate cancer. PMID- 26254444 TI - Smoking worsens effect of early menopause on mortality, study finds. PMID- 26254443 TI - Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. AB - Mantle cell lymphoma (MCL) cells exhibit increased B-cell receptor and nuclear factor (NF)-kappaB activities. The bromodomain and extra-terminal (BET) protein bromodomain 4 is essential for the transcriptional activity of NF-kappaB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and cyclin-dependent kinase (CDK)4/6, inhibits the nuclear RelA levels and the expression of NF-kappaB target genes, including Bruton tyrosine kinase (BTK) in MCL cells. Although lowering the levels of the antiapoptotic B-cell lymphoma (BCL)2 family proteins, BA treatment induces the proapoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Cotreatment with BA and the BTK inhibitor ibrutinib synergistically induces apoptosis of MCL cells. Compared with each agent alone, cotreatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells, which overexpress CDK6, BCL2, Bcl-xL, XIAP, and AKT, but lack ibrutinib resistance-conferring BTK mutation. Cotreatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL. PMID- 26254446 TI - Variation in care and outcome following myocardial infarction. PMID- 26254445 TI - Comparison of hospital variation in acute myocardial infarction care and outcome between Sweden and United Kingdom: population based cohort study using nationwide clinical registries. AB - OBJECTIVE: To assess the between hospital variation in use of guideline recommended treatments and clinical outcomes for acute myocardial infarction in Sweden and the United Kingdom. DESIGN: Population based longitudinal cohort study using nationwide clinical registries. SETTING AND PARTICIPANTS: Nationwide registry data comprising all hospitals providing acute myocardial infarction care in Sweden (SWEDEHEART/RIKS-HIA, n=87; 119,786 patients) and the UK (NICOR/MINAP, n=242; 391,077 patients), 2004-10. MAIN OUTCOME MEASURES: Between hospital variation in 30 day mortality of patients admitted with acute myocardial infarction. RESULTS: Case mix standardised 30 day mortality from acute myocardial infarction was lower in Swedish hospitals (8.4%) than in UK hospitals (9.7%), with less variation between hospitals (interquartile range 2.6% v 3.5%). In both countries, hospital level variation and 30 day mortality were inversely associated with provision of guideline recommended care. Compared with the highest quarter, hospitals in the lowest quarter for use of primary percutaneous coronary intervention had higher volume weighted 30 day mortality for ST elevation myocardial infarction (10.7% v 6.6% in Sweden; 12.7% v 5.8% in the UK). The adjusted odds ratio comparing the highest with the lowest quarters for hospitals' use of primary percutaneous coronary intervention was 0.70 (95% confidence interval 0.62 to 0.79) in Sweden and 0.68 (0.60 to 0.76) in the UK. Differences in risk between hospital quarters of treatment for non-ST elevation myocardial infarction and secondary prevention drugs for all discharged acute myocardial infarction patients were smaller than for reperfusion treatment in both countries. CONCLUSION: Between hospital variation in 30 day mortality for acute myocardial infarction was greater in the UK than in Sweden. This was associated with, and may be partly accounted for by, the higher practice variation in acute myocardial infarction guideline recommended treatment in the UK hospitals. High quality healthcare across all hospitals, especially in the UK, with better use of guideline recommended treatment, may not only reduce unacceptable practice variation but also deliver improved clinical outcomes for patients with acute myocardial infarction. Clinical trials registration Clinical trials NCT01359033. PMID- 26254447 TI - "My World Has Expanded Even Though I'm Stuck at Home": Experiences of Individuals With Amyotrophic Lateral Sclerosis Who Use Augmentative and Alternative Communication and Social Media. AB - PURPOSE: This study aimed to expand the current understanding of how persons with amyotrophic lateral sclerosis (pALS) use augmentative and alternative communication and social media to address their communication needs. METHOD: An online focus group was used to investigate the experiences of 9 pALS who use augmentative and alternative communication and social media. Questions posed to the group related to (a) current use of social media, (b) advantages of social media, (c) barriers to independent use, (d) supports to independent use, and (e) recommendations for developers, policy makers, and other pALS. RESULTS: Participants primarily reported that use of social media was a beneficial tool that provided increased communication opportunities, connections to communication partners, and networks of support. Specific results are discussed with reference to the research as well as implications for practice and recommendations for future research. CONCLUSIONS: As individuals with ALS experience loss of function, some communication modes may no longer be viable. Providing access to different modes of communication, including social media, can allow independence, participation and better quality of life. PMID- 26254448 TI - A Drawing Task to Assess Emotion Inference in Language-Impaired Children. AB - PURPOSE: Studies investigating the ability of children with language impairment (LI) to infer emotions rely on verbal responses (which can be challenging for these children) and/or the selection of a card representing an emotion (which limits the response range). In contrast, a drawing task might allow a broad spectrum of responses without involving language. This study used a drawing task to compare the ability to make emotional inferences in children with and without LI. METHOD: Twenty-two children with LI and 22 typically developing children ages 6 to 10 years were assessed in school during 3 sessions. They were asked to listen to audio stories. At specific moments, the experimenter stopped the recording and asked children to complete the drawing of a face to depict the emotion felt by the story's character. Three adult study-blind judges were subsequently asked to evaluate the expressiveness of the drawings. RESULTS: Children with LI had more difficulty than typically developing children making emotional inferences. Children with LI also made more errors of different valence than their typically developing peers. CONCLUSION: Our findings confirm that children with LI show difficulty in producing emotional inferences, even when performing a drawing task--a relatively language-free response mode. PMID- 26254449 TI - Effects of Alphabet-Supplemented Speech on Brain Activity of Listeners: An fMRI Study. AB - PURPOSE: The purpose of this article was to examine the neural mechanisms associated with increases in speech intelligibility brought about through alphabet supplementation. METHOD: Neurotypical participants listened to dysarthric speech while watching an accompanying video of a hand pointing to the 1st letter spoken of each word on an alphabet display (treatment condition) or a scrambled display (control condition). Their hemodynamic response was measured with functional magnetic resonance imaging, using a sparse sampling event-related paradigm. Speech intelligibility was assessed via a forced-choice auditory identification task throughout the scanning session. RESULTS: Alphabet supplementation was associated with significant increases in speech intelligibility. Further, alphabet supplementation increased activation in brain regions known to be involved in both auditory speech and visual letter perception above that seen with the scrambled display. Significant increases in functional activity were observed within the posterior to mid superior temporal sulcus/superior temporal gyrus during alphabet supplementation, regions known to be involved in speech processing and audiovisual integration. CONCLUSION: Alphabet supplementation is an effective tool for increasing the intelligibility of degraded speech and is associated with changes in activity within audiovisual integration sites. Changes in activity within the superior temporal sulcus/superior temporal gyrus may be related to the behavioral increases in intelligibility brought about by this augmented communication method. PMID- 26254450 TI - A Case Study on Vocal Loudness With a Young Adult With Autism Spectrum Disorder and Developmental Delay. AB - PURPOSE: This clinical focus article describes an exploratory case study addressing reduction of vocal loudness in a young adult with a history of autism spectrum disorder and developmental delay. The need for a short-term pullout individual intervention arose from his participation in the Advancing Language and Literacy group, a program that provides support for enhancement of speech, language, and literacy skills for young adults with developmental disabilities. METHOD: The participant attended individual treatment sessions weekly for 9 sessions, all of which were digitally audio-recorded. Client awareness of different loudness levels was first established using nonspeech sounds and speech samples. Loudness in spontaneous speech was monitored with support of verbal and visual feedback in the individual sessions and tracked in individual sessions as well as sessions of the Advancing Language and Literacy group, which served as a generalization context. RESULTS: In the individual sessions, the participant's spontaneous production of acceptable volume improved from 42% to 92% of utterances. Observation of group participation indicated generalization, with the majority of utterances produced posttreatment at an acceptable volume. CONCLUSIONS: This clinical focus article emphasizes suprasegmental aspects as a dimension of communicative competence and highlights the need for continued intervention research and services for young adults with developmental disabilities. PMID- 26254451 TI - Randomized trial of a dry-powder, fibrin sealant in vascular procedures. AB - OBJECTIVE: Topical hemostats are important adjuncts for stopping surgical bleeding. The safety and efficacy of Fibrocaps, a dry-powder, fibrin sealant containing human plasma-derived thrombin and fibrinogen, was evaluated in patients undergoing vascular surgical procedures. METHODS: In this single-blind trial (clinicaltrials.gov: NCT01527357), adult patients were randomized 2:1 to Fibrocaps plus gelatin sponge (Fibrocaps) vs gelatin sponge alone. Results are presented for the patient subset undergoing vascular procedures with suture hole bleeding. The primary efficacy endpoint compared time to hemostasis (TTH) over 5 minutes. Safety follow-up continued to day 29. RESULTS: A total of 175 patients were randomized and treated (Fibrocaps, 117; gelatin sponge, 58). Patients were predominately male (69%) and underwent arterial bypass (81%), arteriovenous graft formation (9%), or carotid endarterectomy (9%). Fibrocaps significantly reduced TTH compared with gelatin sponge (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.5-3.1; median TTH, 2 minutes; 95% CI, 1.5-2.5 vs 4 minutes; 95% CI, 3.0 5.0; P < .002). Significant reductions were also observed in patients receiving concomitant antiplatelet agents alone (HR, 2.8; 95% CI, 1.0-7.4; P = .03; n = 33), anticoagulants alone (HR, 2.0; 95% CI, 1.0-4.0; P = .04; n = 43), or both antiplatelet agents and anticoagulants (Fibrocaps vs gelatin sponge, HR, 2.3; 95% CI, 1.2-4.3; P = .008; n = 65). Incidences of common adverse events (procedural pain, nausea, constipation) were generally comparable between treatment arms. Anti-thrombin antibodies developed in 2% of Fibrocaps-treated patients and no gelatin-sponge patients. CONCLUSIONS: Fibrocaps, a ready-to-use, dry-powder fibrin sealant, was well-tolerated and reduced TTH in patients undergoing vascular procedures, including those receiving antiplatelet agents and/or anticoagulants, demonstrating its safety and usefulness as an adjunct to hemostasis. PMID- 26254452 TI - Patients with familial abdominal aortic aneurysms are at increased risk for endoleak and secondary intervention following elective endovascular aneurysm repair. AB - OBJECTIVE: A recent investigation has documented an increased risk of aneurysm related complications after endovascular aneurysm repair (EVAR) of familial abdominal aortic aneurysms (fAAAs). We hypothesized that fAAA patients are not at increased risk for complications following open AAA repair or EVAR when compared with sporadic abdominal aortic aneurysm (spAAA) patients. To this end, we performed a single institution retrospective review. METHODS: Epidemiologic data were collected through the electronic medical record. Family history data were obtained from a questionnaire administered at the initial vascular surgery consultation. Major adverse events were defined as myocardial infarction, respiratory failure, renal failure, bowel ischemia, limb ischemia, multisystem organ failure, intracranial hemorrhage, paraplegia, hemorrhage, or death. Endoleaks were classified in accordance with the standardized reporting practices of the Society for Vascular Surgery. AAA-related complications were defined as the need for a secondary intervention due to endoleak, limb ischemia, or postimplantation rupture. RESULTS: A total of 392 patients with complete clinical data underwent elective AAA repair from 2004 to 2014. Of these 392 patients, 89 (23%) were classified as fAAA patients and 303 (77%) were classified as spAAA patients. With the exception of increased rates of chronic obstructive pulmonary disease (P = .0009) and pack-years smoked (P = .03) in spAAA patients, demographics did not differ. Sixty-two percent (n = 55) of fAAA patients and 68% (n = 205) of spAAA patients underwent EVAR (P = .30). fAAA patients did not incur any significant difference in major adverse events following open AAA repair (fAAA, 9% vs spAAA, 11%; P = .75). Additionally, fAAA patients did not incur any significant difference in major adverse events following EVAR (fAAA, 4% vs spAAA, 5%; P = .70). Patients with fAAA did have a significantly increased rate of endoleak (fAAA, 24% vs spAAA, 12%; P = .03) and secondary intervention following EVAR (fAAA, 21% vs spAAA, 12%; P = .04). CONCLUSIONS: The current study shows that patients with fAAA do not have increased perioperative morbidity following open or endovascular AAA repair. However, patients with fAAA do have an increased risk of endoleak and secondary intervention following EVAR. These findings suggest that EVAR and open AAA repair are both safe and effective for fAAA patients. The increased rate of endoleak and secondary intervention in patients with fAAA suggests that this subpopulation may benefit from closer post-EVAR surveillance or open surgical repair in good risk patients. PMID- 26254453 TI - Outcomes of surgeon-modified fenestrated-branched endograft repair for acute aortic pathology. AB - OBJECTIVE: Open surgical repair for acute aortic pathologies involving the visceral vessels is associated with morbidity and mortality rates of 40% to 70% and 30% to 60%, respectively. Due to these poor outcomes, the application of fenestrated/branched endovascular aortic repair (F/B-EVAR) has been expanded in this setting; however, durability remains unknown. The purpose of this analysis was to describe outcomes after F/B-EVAR for acute aortic disease. METHODS: A single center retrospective review of all F/B-EVARs for acute aortic disease was completed. Primary end points included mortality and reintervention-free survival. Secondary end points were patency and freedom from endoleak, as well as change in aneurysm diameter and estimated glomerular filtration rate. Life-tables were used to estimate end points, while mixed statistical models were used to determine aneurysm diameter change. RESULTS: Thirty-seven patients (mean age +/- standard deviation, 67 +/- 10 years; 75% male) underwent F/B-EVAR for acute aortic disease, and median follow-up time was 10.3 months (range, 0.5-31.4 months). Indications included thoracoabdominal aneurysm (65%; n = 24), pararenal aneurysm (17%; n = 6), postsurgical anastomotic pseudoaneurysm (8%; n = 3), dissection (5%; n = 2), and penetrating ulcer (5%; n = 2). Mean preoperative aneurysm diameter was 7.3 +/- 1.8 cm. All patients were American Society of Anesthesiologists class IV or IV-E, and 38% (n = 14) had history of aortic repair. There were 105 visceral vessels revascularized (celiac, 26; superior mesenteric artery, 29; renal, 50) and 24 (65%) patients underwent three- or four vessel repair. Technical success was 92% (n = 34), with no intraoperative deaths and one conversion (3%). Median length of stay was 6 days (range, 2-60 days), and postoperative morbidity was 41% (n = 15; spinal cord ischemia, 14% [8% permanent]; pulmonary, 14%; renal, 14%; extremity ischemia, 8%; stroke, 5%; cardiac, 3%; bleeding, 3%) with 30-day mortality of 19% (n = 7; in-hospital, 8%; n = 3). Endoleak was detected at some point in follow-up in 27% (n = 10), and a majority were type II (n = 7). Six (16%) patients underwent reintervention, and no late conversions occurred. Postoperative imaging was available in 27 (73%), and one celiac fenestration lost patency at 12 months. One-year branch vessel patency and freedom from reintervention was 98% +/- 6% and 70% +/- 9%, respectively. Estimated 1- and 4-year survival were 70% +/- 8% and 67% +/- 8%, respectively. During follow-up, aortic diameter decreased 0.5 cm (95% confidence interval, 1.1-0.2; P = .1) while estimated glomerular filtration rate decreased by 2 mL/min/1.73 m(2). CONCLUSIONS: F/B-EVAR can be performed to treat a variety of symptomatic and/or ruptured paravisceral aortic pathologies. Perioperative morbidity and mortality can be significant; however, it is less than literature based outcomes of open repair. Short-term fenestrated/branched graft patency is excellent, but reintervention is frequent, highlighting the need for diligent follow-up. Patients surviving the initial hospitalization for F/B-EVAR of acute aortic disease can anticipate good long-term survival. PMID- 26254455 TI - Characterizing the evolution of perioperative outcomes and costs of endovascular abdominal aortic aneurysm repair. AB - OBJECTIVE: The purpose of this study is to characterize the evolution in perioperative outcomes and costs of endovascular abdominal aortic aneurysm (AAA) repair (EVAR) by detailing changes in adjusted outcomes and costs over time. METHODS: National Inpatient Sample (2000-2011) data were used to evaluate patient characteristics, outcomes, and perioperative costs for elective EVAR performed for intact AAA. Outcomes were adjusted for patient demographics and comorbidities, and hospital factors by multivariate analysis. Costs were calculated from hospital cost to charge ratio files and adjusted to 2011 dollars. RESULTS: From 2000 to 2011, 185,249 patients underwent elective EVAR for intact AAA. The absolute rates of in-hospital major morbidity, mortality, and procedural costs all decreased significantly over time (P < .0001). The prevalence of major comorbidities in patients undergoing EVAR, including obesity, diabetes, and dyslipidemia, all increased significantly over time. After adjusting for multiple demographics, comorbidities, and hospital-level factors, recent outcomes of EVAR (2009-2011) remain superior to the early experience (2000-2002) with respect to mortality and major complications. CONCLUSIONS: From 2000-2011, the perioperative outcomes of EVAR improved significantly despite a higher prevalence of comorbidities among patients undergoing repair. Concurrently, procedure associated costs declined. Advanced technology is often implicated in escalating healthcare spending, and the value of novel techniques is often questioned. These findings highlight that, in the case of EVAR, procedural outcomes have improved while the initial costs of repair have declined over time. EVAR offers an interesting example for stakeholders to consider in the era of cost-containment pressures and criticism of nascent, expensive technology in healthcare. PMID- 26254454 TI - Outcomes of lower extremity revascularization among the hemodialysis-dependent. AB - OBJECTIVE: Optimal patient selection for lower extremity revascularization remains a clinical challenge among the hemodialysis-dependent (HD). The purpose of this study was to examine contemporary real world open and endovascular outcomes of HD patients to better facilitate patient selection for intervention. METHODS: A regional multicenter registry was queried between 2003 and 2013 for HD patients (N = 689) undergoing open surgical bypass (n = 295) or endovascular intervention (n = 394) for lower extremity revascularization. Patient demographics and comorbidities were recorded. The primary outcome was overall survival. Secondary outcomes included graft patency, freedom from major adverse limb events, and amputation-free survival (AFS). Multivariate analysis was performed to identify independent risk factors for death and amputation. RESULTS: Among the 689 HD patients undergoing lower extremity revascularization, 66% were male, and 83% were white. Ninety percent of revascularizations were performed for critical limb ischemia and 8% for claudication. Overall survival at 1, 2, and 5 years survival remained low at 60%, 43%, and 21%, respectively. Overall 1- and 2 year AFS was 40% and 17%. Mortality accounted for the primary mode of failure for both open bypass (78%) and endovascular interventions (80%) at two years. Survival, AFS, and freedom from major adverse limb event outcomes did not differ significantly between revascularization techniques. At 2 years, endovascular patency was higher than open bypass (76% vs 26%; 95% confidence interval [CI], 0.28-0.71; P = .02). Multivariate analysis identified age >=80 years (hazard ratio [HR], 1.9; 95% CI, 1.4-2.5; P < .01), indication of rest pain or tissue loss (HR, 1.8; 95% CI, 1.3-2.6; P < .01), preoperative wheelchair/bedridden status (HR, 1.5; 95% CI, 1.1-2.1; P < .01), coronary artery disease (HR, 1.5; 95% CI, 1.2-1.9; P < .01), and chronic obstructive pulmonary disease (HR, 1.4; 95% CI, 1.1-1.8; P = .01) as independent predictors of death. The presence of three or more risk factors resulted in predicted 1-year mortality of 64%. CONCLUSIONS: Overall survival and AFS among HD patients remains poor, irrespective of revascularization strategy. Mortality remains the primary driver for these findings and justifies a prudent approach to patient selection. Focus for improved results should emphasize predictors of survival to better identify those most likely to benefit from revascularization. PMID- 26254456 TI - Comparison of retrocarotid and caudocranial dissection techniques for the surgical treatment of carotid body tumors. AB - OBJECTIVE: Carotid body tumors (CBTs) are rare neoplasms. Complete surgical resection is the curative therapy and is considered the therapeutic gold standard. This study compared the retrocarotid dissection (RCD) technique with the standard caudocranial dissection (SCCD) technique in operative time, blood loss, vascular or nerve injuries, and hospital stay. METHODS: A retrospective review was conducted of patients with CBTs who underwent surgical treatment with the RCD technique at the National Institute of Medical Sciences and Nutrition "Salvador Zubiran" in Mexico City from July 2007 to January 2013. This cohort was compared with an historical cohort treated with standard SCCD from 1995 to 2007 at the same institution. RESULTS: A total of 68 procedures (41 SCCD, 27 RCD) were performed in 68 patients (91% women) with a mean age of 54 years (standard deviation [SD], 15 years). According to the Shamblin classification, 6 CBTs were type I (9%), 35 were type II (51%), and 27 were type III (40%). Comparative analysis identified mean blood loss of 480 mL (SD, 380 mL) in the RCD group and 690 mL (SD, 680 mL) for the SCCD cohort (P < .31). The mean procedural time was 172 minutes (SD, 60 minutes) for the RCD group and 260 minutes (SD, 100 minutes) for the SCCD group (P < .001). Hospital stay was significantly shorter for the RCD group with an average of 5 days (SD, 2 days) compared with 9 days (SD, 6 days) for the SCCD cohort (P < .0001). Cranial nerve deficit occurred in 17 patients, consisting of six transient nerve palsies in the RCD cohort and 11 in the SCCD group. Postoperative cerebrovascular accidents occurred in three patients in the SCCD cohort, with none observed in the RCD group. This translates into a rate of 22% of postoperative neurologic complications for the RCD cohort and 34% in the SCCD group (P < .08). Significant differences in intraoperative vascular injuries were not observed. CONCLUSIONS: The RCD technique is a safe and viable option for the surgical resection of CBTs. In our experience, this approach was associated with a significant decrease in procedural time and hospital stay. PMID- 26254457 TI - Estrogen-deficient osteoporosis enhances the recruitment and activity of osteoclasts by breast cancer cells. AB - To reduce the burden of bone metastases, the pathophysiology of the metastatic niche should be elucidated and targeted. The aim of the present study was to assess the effect of tumor cells on osteoclast (OC) recruitment and activity in the presence of altered bone remodelling. Peripheral blood mononuclear cells (PBMC) were isolated from healthy and ovariectomized (OVX) rats and co-cultured with MRMT-1 rat breast carcinoma cells or with their conditioned medium for 1 and 2 weeks. Alamar Blue viability test, synthesis of cathepsin K, transforming growth factor-beta 1 (TGF-beta1), tumor necrosis factor alpha (TNF-alpha), vascular endothelial growth factor (VEGF), metalloproteinase (MMP)-7, MMP-9, FITC conjugate phalloidin staining and tartrate-resistant acid phosphatase (TRAP) staining were evaluated. The results indicate that breast carcinoma cells induced different responses in PBMC derived from rats affected by estrogen deficiency osteoporosis (OP) in comparison with healthy ones, with a significant increase in proliferation rate, OC differentiation, synthesis of TNF-alpha, MMP-7 and MMP-9. The data support the "proof of concept" that OP due to estrogen deficiency might offer a receptive site for cancer cells to form bone metastases. PMID- 26254458 TI - Concurrent chemoradiotherapy for T3-4 and N0-1 nasopharyngeal cancer: Asian multicenter trial of the Forum for Nuclear Cooperation in Asia. AB - The aim of this study was to evaluate the toxicity and efficacy of radiotherapy concurrent with weekly cisplatin for T3-4 and N0-1 nasopharyngeal cancer. Between 2005 and 2010, 70 patients with nasopharyngeal cancer (T3-4 N0-1 M0, World Health Organization Type 2-3) from Vietnam, Indonesia, Malaysia and Thailand were registered. Patients were treated with 2D radiotherapy concurrent with weekly cisplatin (30 mg/m(2)). Neither adjuvant nor induction chemotherapy was given. Ninety-three percent of the patients completed at least four cycles of weekly cisplatin during radiotherapy. The median total doses for the primary tumor and positive lymph nodes were 70 and 66 Gy, respectively. The median overall treatment time of concurrent chemoradiotherapy was 52 days. No treatment-related deaths occurred. Grade 3-4 acute toxicities of mucositis, nausea/vomiting and leukopenia were observed in 34%, 4% and 4% of patients, respectively. With a median follow-up time of 52 months for the 40 surviving patients, the 3-year local control, locoregional tumor control, distant metastasis-free survival and overall survival rates were 80%, 75%, 74% and 80%, respectively. In conclusion, the current results illustrate that our concurrent chemoradiotherapy regimen was feasible, but disease control remained insufficient. Further research is encouraged in order to improve clinical outcomes. PMID- 26254459 TI - Effect of Human Papillomavirus vaccination of daughters on the cervical screening uptake of their non-vaccinated mothers. AB - AIM: This study investigated return to cervical screening rates for 112,451 under screened mothers of daughters offered Human Papillomavirus (HPV) vaccination over two school academic years and a comparator group of women with no vaccine eligible daughter. RESULTS: Mothers returned to screening more often than the comparator group: odds ratio (OR) 1.04 (95% confidence intervals 1.02-1.07) for lapsed and 1.57 (1.48-1.67) for never screened. Screening return was significantly higher in the year prior to HPV vaccination for lapsed mothers (OR = 1.06) and in the current vaccination year for lapsed and never screened mothers (OR = 1.05 and 1.16 respectively). CONCLUSION: The modest increase in screening attendance indicates a potential for the HPV vaccine programme to increase screening uptake of mothers. PMID- 26254461 TI - Cannulation techniques in aortic surgery. PMID- 26254460 TI - Serum phosphorus and association with anemia among a large diverse population with and without chronic kidney disease. AB - BACKGROUND: We hypothesized that phosphorus has an effect on anemia in both normal kidney function and early chronic kidney disease (CKD). We sought to determine whether higher phosphorus levels are associated with anemia in a large diverse population without CKD and early CKD. METHODS: This study is a historical population-based study within the Kaiser Permanente Southern California health system (1 January 1998 to 31 December 2013) among individuals aged 18 years and older with estimated glomerular filtration rate >30 mL/min/1.73 m(2) and measurements of serum phosphorus, creatinine and hemoglobin. Individuals were excluded if they had secondary causes of anemia. Odds ratio (OR) estimated for moderate anemia defined as hemoglobin <11 g/dL for both sexes. Mild anemia was defined as <12 g/dL (females) and <13 g/dL (males). RESULTS: Among 155 974 individuals, 4.1% had moderate anemia and 12.9% had mild anemia. Serum phosphorus levels >=3.5 mg/dL were associated with both mild and moderate anemia. Moderate anemia OR (95% confidence interval) was 1.16 (1.04-1.29) for every 0.5 mg/dL phosphorus increase and 1.26 (1.07-1.48) in the highest versus middle phosphorus tertile. Additional independent anemia risk factors, including female sex, Asian race, diabetes, low albumin and low iron saturation, were observed, but did not alter the anemia-phosphorus association. CONCLUSIONS: Higher phosphorus levels were associated with a greater likelihood for anemia in a population with early CKD and normal kidney function. Phosphorus may be a biomarker for anemia and may affect aspects of hematopoiesis. PMID- 26254462 TI - Smashing Tissue Extraction of Five Lignans From the Fruit of Schisandra chinensis. AB - Schisandra chinensis is one of the most famous herbal medicines in China, Korea and Japan. It has been widely used as a tonic, sedative, anti-aging and astringent agent. Lignans are one of its main bioactive components. The classical methods for extracting lignans, however, were tedious and energy-consuming. With the aim to develop an effective extraction method of lignans, the smashing tissue extraction (STE) technique was adopted and optimized in this study. Extraction conditions of STE have been optimized by the response surface methodology based on the Box-Behnken design. Results showed that 75% aqueous ethanol was the optimal extraction solvent, and the other optimal conditions were as follows: extraction voltage of 180 V, extraction time of 1 min, solid-liquid ratio of 1 : 19 and sample particle size of 120 mesh. Under these optimized conditions, the total content of the five lignans (Schisandrol A, Schisantherin A, Deoxyschisandrin, Schisandrin B and Schisandrin C) in S. chinensis collected from Baishan City located in the northeast of China was 13.89 +/- 0.014 mg/g, which was well matched with the value predicted by the model. Other techniques, including heat reflux, Soxhlet, ultrasonic-assisted and microwave-assisted extraction, were further compared. Results suggested that STE had the highest extraction efficiency of lignans with the shortest time. It indicates that the approach proposed in this study is a simple and efficient technique for the extraction of lignans in S. chinensis. PMID- 26254464 TI - Double edge closure: a novel technique for reducing post-thoracotomy pain. A randomized control study. AB - OBJECTIVES: Thoracic surgeons being doctors, spend much effort not only to manage pathologies but also to make their procedures painless. Many surgical manoeuvres have been evolved to reduce post-thoracotomy pain with its associated morbidities. This trial aimed to study the impact of double edge closure technique on post-thoracotomy pain. METHODS: This was a prospective pre-muted block randomized study of 120 patients who had posterolateral thoracotomy. They were equally divided into two groups, the first in which double edge closure technique was used (DE group), and the other group in which the usual pericostal sutures were used (PC group). Outcomes assessed were operative time, time to ambulation, doses of analgesics injected in the epidural catheter, postoperative complications, chest tube drainage, hospital stay and pain score by the numeric rating scale from 0 to 10 and use of analgesics during the first postoperative year. RESULTS: Both groups had similar demographics, types of procedures, operative time and incisions length. Patients in DE group had significantly lower time to ambulation from 14.47 to 12.85 h, epidural doses from 3.65 to 1.87 and postoperative pain score throughout the first week. At 2 weeks, 1 and 3 months, there was significant reduction in pain and analgesics use in the DE group. At 6 months, analgesic use was not significantly different between both groups, but the pain score was significantly lower in the DE group (0.33 +/- 0.51) than that in the PC group (0.63 +/- 0.74). After 9 months, no significant difference was present between both groups with regard to pain score or the use of analgesics. CONCLUSIONS: Double edge technique for thoracotomy closure is easy, rapid, safe and effective in decreasing post-thoracotomy pain with subsequent earlier ambulation and lesser use of analgesics. PMID- 26254463 TI - Continuous monitoring of cardiac function by 3-dimensional accelerometers in a closed-chest pig model. AB - OBJECTIVES: Cardiac wall motions reflect systolic and diastolic function. We have previously demonstrated the ability of a miniaturized three-axis (3D) accelerometer to monitor left ventricular function in experimental models and in patients. The main aim of this study was to investigate the clinical utility of the method for monitoring the left and right ventricular function during changes in global and regional cardiac function in a postoperative closed-chest situation. METHODS: In 13 closed-chest pigs, miniaturized 3D accelerometers were placed on the left ventricle in the apical and basal regions and in the basal region of the right ventricle. An epicardial 3D motion vector was calculated from the acceleration signals in each heart region. Peak systolic velocity along this 3D vector (3D V(sys)) was compared with the positive time derivative of the left and right ventricular pressure and with cardiac index during changes in global LV function (unloading, fluid loading, esmolol, dobutamine) and with ultrasound during regional left ventricular dysfunction (3-min occlusion of the left anterior descending coronary artery). RESULTS: Significant and typical changes in accelerometer 3D V(sys) were seen in all heart regions during changes in global cardiac function. 3D V(sys) reflected the left and right ventricular contractility via significant correlations with the positive time derivative of the left and right ventricular pressure, r = 0.86 and r = 0.72, and with cardiac index r = 0.82 and r = 0.73 (all P < 0.001), respectively. The miniaturized accelerometers also detected regional dysfunction, but showed reduced ability to localize ischaemia as the 3D V(sys) in all heart regions showed similar reductions during coronary artery occlusion. CONCLUSIONS: Miniaturized 3D accelerometers placed on the heart can assess global and regional function in a closed-chest model. The technique may be used for continuous postoperative monitoring after cardiac surgery. PMID- 26254465 TI - Relationships Between Formant Frequencies of Sustained Vowels and Tongue Contours Measured by Ultrasonography. AB - PURPOSE: The purpose of this study was to explore the formant-articulation relationships in corner vowels by acoustic analysis of speech signals and measuring tongue contour using ultrasonography. METHOD: Eighteen healthy adults (8 men, 10 women), aged between 20 and 40 years, were enrolled. Speech signals of sustained vowels /alpha/, /i/, and /u/ were recorded to obtain the first 2 formant frequencies. Tongue height, tongue advancement, and lengths of posterior tongue surface (LPTS) and anterior oral cavity (LAOC) were obtained using ultrasound image processing technique in order to examine the resonance mechanism of the oral vocal tract. RESULTS: LPTS and LAOC, as well as mean frequencies of the first and second formants, showed significant differences between sexes and among vowels. The first formant significantly and better correlated with LPTS than with tongue height (r = -.78, p < .001, Pearson's correlation). The correlation of the second formant with LAOC (r = -.85, p < .001) was also significant and better than the correlation with tongue advancement. Sex, however, did not show significant correlation with the formant frequencies. CONCLUSIONS: Ultrasonographic measurements of tongue contour correlated well to the formant frequencies. The results stressed the importance of tongue shaping in articulation. Although more studies are necessary in clinical implications, disorders associated with abnormal tongue shaping may be the target applications in the future. PMID- 26254466 TI - Summarized institutional experience of paediatric airway surgery?. AB - OBJECTIVES: The management of paediatric airway stenosis is complex, and requires a dedicated team, consisting of thoracic surgeons, phoniatricians, logopaedics, paediatricians and anaesthetists. The majority of paediatric laryngotracheal stenosis is a sequela of prematurity and prolonged post-partal intubation/tracheostomy. Surgical correction is often difficult due to a frequent combination of glottic and subglottic defects. METHODS: In 2012, the Laryngotracheal Program Vienna was launched. Since then, 18 paediatric patients were surgically treated for (laryngo-)tracheal problems. RESULTS: The median age of our patients was 26 months (range 2-180 months). Laryngotracheal stenosis extending up to the level of the vocal cords was evident in 9 patients. Three children were diagnosed with an isolated subglottic, and four with a short segment tracheal stenosis or malacia. Two patients had a long-segment congenital malformation together with vascular ring anomalies. Five children were pretreated by rigid endoscopy before surgical correction, 12 of our 18 patients had a tracheostomy, 3 children were intubated at the time of operation. Different techniques of corrections were applied: laryngotracheal reconstruction (n = 4), extended partial cricotracheal resection (n = 4), cricotracheal resection with or without anterior split or dorsal mucosal flap (n = 4), slide tracheoplasty (n = 2), tracheal resection (n = 4). In 8 patients, a rib cartilage interposition was necessary in order to obtain a sufficient lumen enlargement and in 7 of these patients, an LT-Mold was placed to stabilize the reconstruction. We lost 2 patients, who were referred to our institution after failure of multiple preceding interventions, 2 and 3 months after the operation. Twelve patients are currently in an excellent condition, one is in an acceptable condition without a need for an intervention. Two patients required an endoscopic reintervention 18 and 33 months after the operation, 1 child is currently still cannulated. CONCLUSIONS: Paediatric airway surgery is complex, and requires a dedicated interdisciplinary team. An armamentarium of different resection and reconstruction techniques is necessary in order to achieve good long-term results. PMID- 26254467 TI - EACTS expert consensus statement for surgical management of pleural empyema. AB - Pleural infection is a frequent clinical condition. Prompt treatment has been shown to reduce hospital costs, morbidity and mortality. Recent advances in treatment have been variably implemented in clinical practice. This statement reviews the latest developments and concepts to improve clinical management and stimulate further research. The European Association for Cardio-Thoracic Surgery (EACTS) Thoracic Domain and the EACTS Pleural Diseases Working Group established a team of thoracic surgeons to produce a comprehensive review of available scientific evidence with the aim to cover all aspects of surgical practice related to its treatment, in particular focusing on: surgical treatment of empyema in adults; surgical treatment of empyema in children; and surgical treatment of post-pneumonectomy empyema (PPE). In the management of Stage 1 empyema, prompt pleural space chest tube drainage is required. In patients with Stage 2 or 3 empyema who are fit enough to undergo an operative procedure, there is a demonstrated benefit of surgical debridement or decortication [possibly by video-assisted thoracoscopic surgery (VATS)] over tube thoracostomy alone in terms of treatment success and reduction in hospital stay. In children, a primary operative approach is an effective management strategy, associated with a lower mortality rate and a reduction of tube thoracostomy duration, length of antibiotic therapy, reintervention rate and hospital stay. Intrapleural fibrinolytic therapy is a reasonable alternative to primary operative management. Uncomplicated PPE [without bronchopleural fistula (BPF)] can be effectively managed with minimally invasive techniques, including fenestration, pleural space irrigation and VATS debridement. PPE associated with BPF can be effectively managed with individualized open surgical techniques, including direct repair, myoplastic and thoracoplastic techniques. Intrathoracic vacuum-assisted closure may be considered as an adjunct to the standard treatment. The current literature cements the role of VATS in the management of pleural empyema, even if the choice of surgical approach relies on the individual surgeon's preference. PMID- 26254468 TI - Cumulin, an Oocyte-secreted Heterodimer of the Transforming Growth Factor-beta Family, Is a Potent Activator of Granulosa Cells and Improves Oocyte Quality. AB - Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are oocyte-specific growth factors with central roles in mammalian reproduction, regulating species-specific fecundity, ovarian follicular somatic cell differentiation, and oocyte quality. In the human, GDF9 is produced in a latent form, the mechanism of activation being an open question. Here, we produced a range of recombinant GDF9 and BMP15 variants, examined their in silico and physical interactions and their effects on ovarian granulosa cells (GC) and oocytes. We found that the potent synergistic actions of GDF9 and BMP15 on GC can be attributed to the formation of a heterodimer, which we have termed cumulin. Structural modeling of cumulin revealed a dimerization interface identical to homodimeric GDF9 and BMP15, indicating likely formation of a stable complex. This was confirmed by generation of recombinant heterodimeric complexes of pro/mature domains (pro-cumulin) and covalent mature domains (cumulin). Both pro-cumulin and cumulin exhibited highly potent bioactivity on GC, activating both SMAD2/3 and SMAD1/5/8 signaling pathways and promoting proliferation and expression of a set of genes associated with oocyte-regulated GC differentiation. Cumulin was more potent than pro-cumulin, pro-GDF9, pro-BMP15, or the two combined on GC. However, on cumulus-oocyte complexes, pro-cumulin was more effective than all other growth factors at notably improving oocyte quality as assessed by subsequent day 7 embryo development. Our results support a model of activation for human GDF9 dependent on cumulin formation through heterodimerization with BMP15. Oocyte secreted cumulin is likely to be a central regulator of fertility in mono-ovular mammals. PMID- 26254470 TI - Inflammatory Bowel Disease and Sexual Function in Male and Female Patients: An Update on Evidence in the Past Ten Years. AB - BACKGROUND AND AIMS: Inflammatory bowel diseases [IBD] are a group of chronic, debilitating inflammatory intestinal conditions. The aim of this review was to assess the recent data regarding the impact of IBD in sexual function of male and female patients. METHODS: A literature search was conducted on MEDLINE using, among others, the following search terms or their combinations: ulcerative colitis; Crohn's disease; sexual function; sexual health; relationship status; erectile dysfunction; surgery. All English-language studies published in the past 10 years which provided data evaluating the sexual function in IBD patients were included. RESULTS: Fourteen studies were identified; six included IBD patients registered on a national database or presented in a clinical setting, whereas eight evaluated sexual function after a surgical intervention for IBD. The majority of the studies used the validated for general populations International Index for Erectile Function [IIEF] and the Female Sexual Function Index [FSFI] for the assessment of sexual function among males and females, respectively. An impaired sexual function has been reported in general cohorts of IBD patients; females seemed to experience worse sexual dysfunction than males. Furthermore, depression was a consistent negative predictive factor across studies. Surgery did not seem to affect sexual function in the majority of studies, except a prospective one which reported a significant improvement in male sexual function [IIEF, p < 0.05] but not female [FSFI, p = 0.6]. CONCLUSIONS: Sexual function among IBD patients may be impaired, thus more studies are needed in order to develop the appropriate instruments and proper and effective management strategies. PMID- 26254469 TI - The Ribosome-Sec61 Translocon Complex Forms a Cytosolically Restricted Environment for Early Polytopic Membrane Protein Folding. AB - Transmembrane topology of polytopic membrane proteins (PMPs) is established in the endoplasmic reticulum (ER) by the ribosome Sec61-translocon complex (RTC) through iterative cycles of translocation initiation and termination. It remains unknown, however, whether tertiary folding of transmembrane domains begins after the nascent polypeptide integrates into the lipid bilayer or within a proteinaceous environment proximal to translocon components. To address this question, we used cysteine scanning mutagenesis to monitor aqueous accessibility of stalled translation intermediates to determine when, during biogenesis, hydrophilic peptide loops of the aquaporin-4 (AQP4) water channel are delivered to cytosolic and lumenal compartments. Results showed that following ribosome docking on the ER membrane, the nascent polypeptide was shielded from the cytosol as it emerged from the ribosome exit tunnel. Extracellular loops followed a well defined path through the ribosome, the ribosome translocon junction, the Sec61 translocon pore, and into the ER lumen coincident with chain elongation. In contrast, intracellular loops (ICLs) and C-terminalresidues exited the ribosome into a cytosolically shielded environment and remained inaccessible to both cytosolic and lumenal compartments until translation was terminated. Shielding of ICL1 and ICL2, but not the C terminus, became resistant to maneuvers that disrupt electrostatic ribosome interactions. Thus, the early folding landscape of polytopic proteins is shaped by a spatially restricted environment localized within the assembled ribosome translocon complex. PMID- 26254471 TI - Raising the topic of weight in general practice: perspectives of GPs and primary care nurses. AB - OBJECTIVE: To explore general practitioners' (GPs) and primary care nurses' perceived barriers to raising the topic of weight in general practice. DESIGN: A qualitative study using the Theoretical Domains Framework (TDF). 34 semistructured interviews were conducted to explore views, opinions and experiences of initiating a discussion about weight. Content and thematic analyses were used to analyse the interview transcripts. SETTING: General practices located in one primary care trust in the South West of England. PARTICIPANTS: 17 GPs and 17 nurses aged between 32 and 66 years. The modal age range for GPs was 30-39 years and for nurses, 40-49 years. RESULTS: Barriers were synthesised into three main themes: (1) limited understanding about obesity care, (2) concern about negative consequences, and (3) having time and resources to raise a sensitive topic. Most barriers were related to raising the topic in more routine settings, rather than when dealing with an associated medical condition. GPs were particularly worried about damaging their relationship with patients and emphasised the need to follow their patient's agenda. CONCLUSIONS: Uncertainty about obesity, concerns about alienating patients and feeling unable to raise the topic within the constraints of a 10 min consultation, is adding to the reluctance of GPs and nurses to broach the topic of weight. Addressing these concerns through training or by providing evidence of effective interventions that are feasible to deliver within consultations may lead to greater practitioner engagement and willingness to raise the topic. PMID- 26254473 TI - Commentary on: Liver Trauma During Combined Liposuction and Abdominoplasty: A Rare but Potentially Lethal Complication. PMID- 26254472 TI - Validating a decision tree for serious infection: diagnostic accuracy in acutely ill children in ambulatory care. AB - OBJECTIVE: Acute infection is the most common presentation of children in primary care with only few having a serious infection (eg, sepsis, meningitis, pneumonia). To avoid complications or death, early recognition and adequate referral are essential. Clinical prediction rules have the potential to improve diagnostic decision-making for rare but serious conditions. In this study, we aimed to validate a recently developed decision tree in a new but similar population. DESIGN: Diagnostic accuracy study validating a clinical prediction rule. SETTING AND PARTICIPANTS: Acutely ill children presenting to ambulatory care in Flanders, Belgium, consisting of general practice and paediatric assessment in outpatient clinics or the emergency department. INTERVENTION: Physicians were asked to score the decision tree in every child. PRIMARY OUTCOME MEASURES: The outcome of interest was hospital admission for at least 24 h with a serious infection within 5 days after initial presentation. We report the diagnostic accuracy of the decision tree in sensitivity, specificity, likelihood ratios and predictive values. RESULTS: In total, 8962 acute illness episodes were included, of which 283 lead to admission to hospital with a serious infection. Sensitivity of the decision tree was 100% (95% CI 71.5% to 100%) at a specificity of 83.6% (95% CI 82.3% to 84.9%) in the general practitioner setting with 17% of children testing positive. In the paediatric outpatient and emergency department setting, sensitivities were below 92%, with specificities below 44.8%. CONCLUSIONS: In an independent validation cohort, this clinical prediction rule has shown to be extremely sensitive to identify children at risk of hospital admission for a serious infection in general practice, making it suitable for ruling out. TRIAL REGISTRATION NUMBER: NCT02024282. PMID- 26254474 TI - Liver Trauma During Combined Liposuction and Abdominoplasty: A Rare but Potentially Lethal Complication. AB - Liposuction is a well-established procedure that is generally safe. However, rare complications can occur. The authors report on a 38-year-old woman who underwent combined abdominoplasty and liposuction at a private clinic. Four hours after the procedure, severe hypovolemic shock developed and required emergency transfer to a tertiary-care center. After primary fluid resuscitation, abdominal ultrasonography and computerized tomography revealed severe right-sided liver trauma, with active bleeding and free intra-abdominal fluid. Two attempts at right hepatic artery embolization failed to fully control the bleeding, and surgical hemostasis was required. After a 2-week hospitalization, the patient was discharged, and she returned to work 3 months later. Although it appears that this is the first reported case of liver trauma during liposuction, this potential complication should be kept in mind and identified early to permit efficient and effective management. PMID- 26254475 TI - Using Spoken Language Benchmarks to Characterize the Expressive Language Skills of Young Children With Autism Spectrum Disorders. AB - PURPOSE: Spoken language benchmarks proposed by Tager-Flusberg et al. (2009) were used to characterize communication profiles of toddlers with autism spectrum disorders and to investigate if there were differences in variables hypothesized to influence language development at different benchmark levels. METHOD: The communication abilities of a large sample of toddlers with autism spectrum disorders (N = 105) were characterized in terms of spoken language benchmarks. The toddlers were grouped according to these benchmarks to investigate whether there were differences in selected variables across benchmark groups at a mean age of 2.5 years. RESULTS: The majority of children in the sample presented with uneven communication profiles with relative strengths in phonology and significant weaknesses in pragmatics. When children were grouped according to one expressive language domain, across-group differences were observed in response to joint attention and gestures but not cognition or restricted and repetitive behaviors. CONCLUSION: The spoken language benchmarks are useful for characterizing early communication profiles and investigating features that influence expressive language growth. PMID- 26254476 TI - Molecular subgroups of medulloblastoma identification using noninvasive magnetic resonance spectroscopy. AB - BACKGROUND: Medulloblastomas in children can be categorized into 4 molecular subgroups with differing clinical characteristics, such that subgroup determination aids in prognostication and risk-adaptive treatment strategies. Magnetic resonance spectroscopy (MRS) is a widely available, noninvasive tool that is used to determine the metabolic characteristics of tumors and provide diagnostic information without the need for tumor tissue. In this study, we investigated the hypothesis that metabolite concentrations measured by MRS would differ between molecular subgroups of medulloblastoma and allow accurate subgroup determination. METHODS: MRS was used to measure metabolites in medulloblastomas across molecular subgroups (SHH = 12, Groups 3/4 = 17, WNT = 1). Levels of 14 metabolites were analyzed to determine those that were the most discriminant for medulloblastoma subgroups in order to construct a multivariable classifier for distinguishing between combined Group 3/4 and SHH tumors. RESULTS: Medulloblastomas across molecular subgroups revealed distinct spectral features. Group 3 and Group 4 tumors demonstrated metabolic profiles with readily detectable taurine, lower levels of lipids, and high levels of creatine. SHH tumors showed prominent choline and lipid with low levels of creatine and little or no evidence of taurine. A 5-metabolite subgroup classifier inclusive of creatine, myo-inositol, taurine, aspartate, and lipid 13a was developed that could discriminate between Group 3/4 and SHH medulloblastomas with excellent accuracy (cross-validated area under the curve [AUC] = 0.88). CONCLUSIONS: The data show that medulloblastomas of Group 3/4 differ metabolically as measured using MRS when compared with SHH molecular subgroups. MRS is a useful and accurate tool to determine medulloblastoma molecular subgroups. PMID- 26254477 TI - Loss of endothelial programmed cell death 10 activates glioblastoma cells and promotes tumor growth. AB - BACKGROUND: Neo-angiogenesis is a hallmark of glioblastoma (GBM) and is sustained by autocrine and paracrine interactions between neoplastic and nonneoplastic cells. Programmed cell death 10 (PDCD10) is ubiquitously expressed in nearly all tissues and plays crucial roles in regulating angiogenesis and apoptosis. We recently discovered the absence of PDCD10 expression in the tumor vessels of GBM patients. This raised the hypothesis that loss of endothelial PDCD10 affected GBM cell phenotyping and tumor progression. METHODS: Endothelial PDCD10 was silenced by siRNA and lentiviral shRNA. The tumor cell phenotype was studied in direct and indirect co-culture of endothelial cells (ECs) with U87 or LN229. Angiogenic protein array was performed in the media of PDCD10-silenced ECs. Tumor angiogenesis and tumor growth were investigated in a human GBM xenograft mouse model. RESULTS: Endothelial silence of PDCD10 significantly stimulated tumor cell proliferation, migration, adhesion, and invasion and inhibited apoptosis in co cultures. Stable knockdown of endothelial PDCD10 increased microvessel density and the formation of a functional vascular network, leading to a 4-fold larger tumor mass in mice. Intriguingly, endothelial deletion of PDCD10 increased (>=2 fold) the release of 20 of 55 tested proangiogenic factors including VEGF, which in turn activated Erk1/2 and Akt in GBM cells. CONCLUSIONS: For the first time, we provide evidence that loss of endothelial PDCD10 activates GBM cells and promotes tumor growth, most likely via a paracrine mechanism. PDCD10 shows a tumor-suppressor-like function in the cross talk between ECs and tumor cells and is potentially implicated in GBM progression. PMID- 26254479 TI - Descriptive analysis of medication errors reported to the Egyptian national online reporting system during six months. AB - OBJECTIVES: This study analyzes reports to the Egyptian medication error (ME) reporting system from June to December 2014. METHODS: Fifty hospital pharmacists received training on ME reporting using the national reporting system. All received reports were reviewed and analyzed. The pieces of data analyzed were patient age, gender, clinical setting, stage, type, medication(s), outcome, cause(s), and recommendation(s). RESULTS: Over the course of 6 months, 12,000 valid reports were gathered and included in this analysis. The majority (66%) came from inpatient settings, while 23% came from intensive care units, and 11% came from outpatient departments. Prescribing errors were the most common type of MEs (54%), followed by monitoring (25%) and administration errors (16%). The most frequent error was incorrect dose (20%) followed by drug interactions, incorrect drug, and incorrect frequency. Most reports were potential (25%), prevented (11%), or harmless (51%) errors; only 13% of reported errors lead to patient harm. The top three medication classes involved in reported MEs were antibiotics, drugs acting on the central nervous system, and drugs acting on the cardiovascular system. Causes of MEs were mostly lack of knowledge, environmental factors, lack of drug information sources, and incomplete prescribing. Recommendations for addressing MEs were mainly staff training, local ME reporting, and improving work environment. DISCUSSION: There are common problems among different healthcare systems, so that sharing experiences on the national level is essential to enable learning from MEs. Internationally, there is a great need for standardizing ME terminology, to facilitate knowledge transfer. Underreporting, inaccurate reporting, and a lack of reporter diversity are some limitations of this study. Egypt now has a national database of MEs that allows researchers and decision makers to assess the problem, identify its root causes, and develop preventive strategies. PMID- 26254478 TI - Prediction of life expectancy in patients with spinal epidural metastasis. AB - BACKGROUND: The treatment of spinal epidural metastasis is multidisciplinary and usually involves a team of medical oncologists, radiologists, radiotherapists, and spinal surgeons. Life expectancy is one of the factors considered when deciding whether surgery is warranted. Because expert estimates of life expectancy are generally not reliable, a prediction model is needed. Here, we temporally validated a model that was previously validated geographically. METHODS: The records of 110 consecutive patients who were referred with a spinal epidural metastasis were collected prospectively from 2009 to 2013 in order to validate the model, which was published in 2011. The actual and estimated life expectancies were represented graphically, and calibration and discrimination were determined. The calibration slope, Harrell's c-index, D, and R2D were calculated. Hazard ratios in the derivation set of 2011 were compared with the validation set. Misspecification was determined using the joint test for beta*. RESULTS: The calibration slope was 0.64 +/- 0.15 (95% CI: 0.34-0.94), Harrell's c index was 0.72, D was 1.08, and R2D was 0.22, indicating slightly worse discrimination in the derivation set. The joint test for beta* = 0 was statistically significant and indicated misspecification; however, this misspecification was attributed entirely to the surgical group. CONCLUSIONS: We validated a prediction model for surgical decision making, showing that the model's overall performance is good. Based on these results, this model will help clinicians to decide whether to offer surgery to patients with spinal epidural metastasis. PMID- 26254480 TI - Delivering digital health and well-being at scale: lessons learned during the implementation of the dallas program in the United Kingdom. AB - OBJECTIVE: To identify implementation lessons from the United Kingdom Delivering Assisted Living Lifestyles at Scale (dallas) program-a large-scale, national technology program that aims to deliver a broad range of digital services and products to the public to promote health and well-being. MATERIALS AND METHODS: Prospective, longitudinal qualitative research study investigating implementation processes. Qualitative data collected includes semi-structured e-Health Implementation Toolkit-led interviews at baseline/mid-point (n = 38), quarterly evaluation, quarterly technical and barrier and solutions reports, observational logs, quarterly evaluation alignment interviews with project leads, observational data collected during meetings, and ethnographic data from dallas events (n > 200 distinct pieces of qualitative data). Data analysis was guided by Normalization Process Theory, a sociological theory that aids conceptualization of implementation issues in complex healthcare settings. RESULTS: Five key challenges were identified: 1) The challenge of establishing and maintaining large heterogeneous, multi-agency partnerships to deliver new models of healthcare; 2) The need for resilience in the face of barriers and set-backs including the backdrop of continually changing external environments; 3) The inherent tension between embracing innovative co-design and achieving delivery at pace and at scale; 4) The effects of branding and marketing issues in consumer healthcare settings; and 5) The challenge of interoperability and information governance, when commercial proprietary models are dominant. CONCLUSIONS: The magnitude and ambition of the dallas program provides a unique opportunity to investigate the macro level implementation challenges faced when designing and delivering digital health and wellness services at scale. Flexibility, adaptability, and resilience are key implementation facilitators when shifting to new digitally enabled models of care. PMID- 26254481 TI - Development of the Parkland-UT Southwestern Colonoscopy Reporting System (CoRS) for evidence-based colon cancer surveillance recommendations. AB - OBJECTIVE: Through colonoscopy, polyps can be identified and removed to reduce colorectal cancer incidence and mortality. Appropriate use of surveillance colonoscopy, post polypectomy, is a focus of healthcare reform. MATERIALS AND METHODS: The authors developed and implemented the first electronic medical record-based colonoscopy reporting system (CoRS) that matches endoscopic findings with guideline-consistent surveillance recommendations and generates tailored results and recommendation letters for patients and providers. RESULTS: In its first year, CoRS was used in 98.6% of indicated cases. Via a survey, colonoscopists agreed/strongly agreed it is easy to use (83%), provides guideline based recommendations (89%), improves quality of Spanish letters (94%), they would recommend it for other institutions (78%), and it made their work easier (61%), and led to improved practice (56%). DISCUSSION: CoRS' widespread adoption and acceptance likely resulted from stakeholder engagement throughout the development and implementation process. CONCLUSION: CoRS is well-accepted by clinicians and provides guideline-based recommendations and results communications to patients and providers. PMID- 26254482 TI - Nucleotide carriers for anti-tumour actinomycin antibiotics. AB - We have investigated a number of complexes of 7-aminoactinomycin D (7AAMD), with its potential carriers: caffeine, folic acid (FA), purine bases-guanine and adenine, pyrimidine base-thymine and with fragmented DNA to determine more stable and suitable complex. The process of binding of the fluorescent antibiotic with clusters of caffeine, guanine, adenine, thymine and with fragmented DNA was accompanied by a considerable long-wavelength shift in excitation spectrum. The energy of interaction between phenoxazine hetero-cycle of 7AAMD and chromophores of the carriers studied has been found. In the case of 7AAMD with guanine, adenine, thymine and caffeine, the energy is about of 7 kcal/mol, which is a little lower than in the case with DNA (7.7 kcal/mol). On the basis of emission spectra, in all examined compounds, with the exception DNA, the 7AAMD molecule emits photons from water phase, not from a cluster, since photo-excitation leads to desorption of the antibiotic from a cluster surface. We observed also the mutual fluorescence quenching of 7AAMD and FA in their complex. It may well be that this complex forms due to interaction of peptide-lactone rings of 7AAMD with system of FA. In the case of DNA, the complex with 7AAMD has very high stability that is determined not only by interaction between phenoxazine of 7AAMD and the DNA bases, but it is largely owing to the interaction between two peptide-lactone rings of 7AAMD and the DNA deoxyribose-phosphate chains. PMID- 26254483 TI - Effect of trastuzumab interchain disulfide bond cleavage on Fcgamma receptor binding and antibody-dependent tumour cell phagocytosis. AB - The Fc domain of human IgG1 binds to Fcgamma receptors (FcgammaRs) to induce effector functions such as phagocytosis. There are four interchain disulfide bonds between the H and L chains. In this study, the disulfide bonds within the IgG1 trastuzumab (TRA), which is specific for HER2, were cleaved by mild S sulfonation or by mild reduction followed by S-alkylation with three different reagents. The cleavage did not change the binding activities of TRA to HER2 bearing SK-BR-3 cells. The binding activities of TRA to FcgammaRIIA and FcgammaRIIB were greatly enhanced by modification with mild reduction and S alkylation with ICH2CONH2 or N-(4-aminophenyl) maleimide, while the binding activities of TRA to FcgammaRI and FcgammaRIIIA were decreased by any of the four modifications. However, the interchain disulfide bond cleavage by the different modifications did not change the antibody-dependent cell-mediated phagocytosis (ADCP) of SK-BR-3 cells by activated THP-1 cells. The order of FcgammaR expression levels on the THP-1 cells was FcgammaRII > FcgammaRI > FcgammaRIII and ADCP was inhibited by blocking antibodies against FcgammaRI and FcgammaRII. These results imply that the effect of the interchain disulfide bond cleavage on FcgammaRs binding and ADCP is dependent on modifications of the cysteine residues and the FcgammaR isotypes. PMID- 26254484 TI - Widespread Recurrent Patterns of Rapid Repeat Evolution in the Kinetochore Scaffold KNL1. AB - The outer kinetochore protein scaffold KNL1 is essential for error-free chromosome segregation during mitosis and meiosis. A critical feature of KNL1 is an array of repeats containing MELT-like motifs. When phosphorylated, these motifs form docking sites for the BUB1-BUB3 dimer that regulates chromosome biorientation and the spindle assembly checkpoint. KNL1 homologs are strikingly different in both the amount and sequence of repeats they harbor. We used sensitive repeat discovery and evolutionary reconstruction to show that the KNL1 repeat arrays have undergone extensive, often species-specific array reorganization through iterative cycles of higher order multiplication in conjunction with rapid sequence diversification. The number of repeats per array ranges from none in flowering plants up to approximately 35-40 in drosophilids. Remarkably, closely related drosophilid species have independently expanded specific repeats, indicating near complete array replacement after only approximately 25-40 Myr of evolution. We further show that repeat sequences were altered by the parallel emergence/loss of various short linear motifs, including phosphosites, which supplement the MELT-like motif, signifying modular repeat evolution. These observations point to widespread recurrent episodes of concerted KNL1 repeat evolution in all eukaryotic supergroups. We discuss our findings in the light of the conserved function of KNL1 repeats in localizing the BUB1-BUB3 dimer and its role in chromosome segregation. PMID- 26254485 TI - Found and Lost: The Fates of Horizontally Acquired Genes in Arthropod-Symbiotic Spiroplasma. AB - Horizontal gene transfer (HGT) is an important mechanism that contributed to biological diversity, particularly in bacteria. Through acquisition of novel genes, the recipient cell may change its ecological preference and the process could promote speciation. In this study, we determined the complete genome sequence of two Spiroplasma species for comparative analyses and inferred the putative gene gains and losses. Although most Spiroplasma species are symbionts of terrestrial insects, Spiroplasma eriocheiris has evolved to be a lethal pathogen of freshwater crustaceans. We found that approximately 7% of the genes in this genome may have originated from HGT and these genes expanded the metabolic capacity of this organism. Through comparison with the closely related Spiroplasma atrichopogonis, as well as other more divergent lineages, our results indicated that these HGT events could be traced back to the most recent common ancestor of these two species. However, most of these horizontally acquired genes have been pseudogenized in S. atrichopogonis, suggesting that they did not contribute to the fitness of this lineage that maintained the association with terrestrial insects. Thus, accumulation of small deletions that disrupted these foreign genes was not countered by natural selection. On the other hand, the long term survival of these horizontally acquired genes in the S. eriocheiris genome hinted that they might play a role in the ecological shift of this species. Finally, the implications of these findings and the conflicts among gene content, 16S rRNA gene sequencing, and serological typing, are discussed in light of defining bacterial species. PMID- 26254486 TI - Population Genomics of Infectious and Integrated Wolbachia pipientis Genomes in Drosophila ananassae. AB - Coevolution between Drosophila and its endosymbiont Wolbachia pipientis has many intriguing aspects. For example, Drosophila ananassae hosts two forms of W. pipientis genomes: One being the infectious bacterial genome and the other integrated into the host nuclear genome. Here, we characterize the infectious and integrated genomes of W. pipientis infecting D. ananassae (wAna), by genome sequencing 15 strains of D. ananassae that have either the infectious or integrated wAna genomes. Results indicate evolutionarily stable maternal transmission for the infectious wAna genome suggesting a relatively long-term coevolution with its host. In contrast, the integrated wAna genome showed pseudogene-like characteristics accumulating many variants that are predicted to have deleterious effects if present in an infectious bacterial genome. Phylogenomic analysis of sequence variation together with genotyping by polymerase chain reaction of large structural variations indicated several wAna variants among the eight infectious wAna genomes. In contrast, only a single wAna variant was found among the seven integrated wAna genomes examined in lines from Africa, south Asia, and south Pacific islands suggesting that the integration occurred once from a single infectious wAna genome and then spread geographically. Further analysis revealed that for all D. ananassae we examined with the integrated wAna genomes, the majority of the integrated wAna genomic regions is represented in at least two copies suggesting a double integration or single integration followed by an integrated genome duplication. The possible evolutionary mechanism underlying the widespread geographical presence of the duplicate integration of the wAna genome is an intriguing question remaining to be answered. PMID- 26254487 TI - Genome-Wide Evolutionary Analyses of G1P[8] Strains Isolated Before and After Rotavirus Vaccine Introduction. AB - Rotaviruses are the most important etiological agent of acute gastroenteritis in young children worldwide. Among the first countries to introduce rotavirus vaccines into their national immunization programs were Belgium (November 2006) and Australia (July 2007). Surveillance programs in Belgium (since 1999) and Australia (since 1989) offer the opportunity to perform a detailed comparison of rotavirus strains circulating pre- and postvaccine introduction. G1P[8] rotaviruses are the most prominent genotype in humans, and a total of 157 G1P[8] rotaviruses isolated between 1999 and 2011 were selected from Belgium and Australia and their complete genomes were sequenced. Phylogenetic analysis showed evidence of frequent reassortment among Belgian and Australian G1P[8] rotaviruses. Although many different phylogenetic subclusters were present before and after vaccine introduction, some unique clusters were only identified after vaccine introduction, which could be due to natural fluctuation or the first signs of vaccine-driven evolution. The times to the most recent common ancestors for the Belgian and Australian G1P[8] rotaviruses ranged from 1846 to 1955 depending on the gene segment, with VP7 and NSP4 resulting in the most recent estimates. We found no evidence that rotavirus population size was affected after vaccine introduction and only six amino acid sites in VP2, VP3, VP7, and NSP1 were identified to be under positive selective pressure. Continued surveillance of G1P[8] strains is needed to determine long-term effects of vaccine introductions, particularly now rotavirus vaccines are implemented in the national immunization programs of an increasing number of countries worldwide. PMID- 26254488 TI - BLSSpeller: exhaustive comparative discovery of conserved cis-regulatory elements. AB - MOTIVATION: The accurate discovery and annotation of regulatory elements remains a challenging problem. The growing number of sequenced genomes creates new opportunities for comparative approaches to motif discovery. Putative binding sites are then considered to be functional if they are conserved in orthologous promoter sequences of multiple related species. Existing methods for comparative motif discovery usually rely on pregenerated multiple sequence alignments, which are difficult to obtain for more diverged species such as plants. As a consequence, misaligned regulatory elements often remain undetected. RESULTS: We present a novel algorithm that supports both alignment-free and alignment-based motif discovery in the promoter sequences of related species. Putative motifs are exhaustively enumerated as words over the IUPAC alphabet and screened for conservation using the branch length score. Additionally, a confidence score is established in a genome-wide fashion. In order to take advantage of a cloud computing infrastructure, the MapReduce programming model is adopted. The method is applied to four monocotyledon plant species and it is shown that high-scoring motifs are significantly enriched for open chromatin regions in Oryza sativa and for transcription factor binding sites inferred through protein-binding microarrays in O.sativa and Zea mays. Furthermore, the method is shown to recover experimentally profiled ga2ox1-like KN1 binding sites in Z.mays. AVAILABILITY AND IMPLEMENTATION: BLSSpeller was written in Java. Source code and manual are available at http://bioinformatics.intec.ugent.be/blsspeller CONTACT: Klaas.Vandepoele@psb.vib-ugent.be or jan.fostier@intec.ugent.be. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26254489 TI - TIPR: transcription initiation pattern recognition on a genome scale. AB - MOTIVATION: The computational identification of gene transcription start sites (TSSs) can provide insights into the regulation and function of genes without performing expensive experiments, particularly in organisms with incomplete annotations. High-resolution general-purpose TSS prediction remains a challenging problem, with little recent progress on the identification and differentiation of TSSs which are arranged in different spatial patterns along the chromosome. RESULTS: In this work, we present the Transcription Initiation Pattern Recognizer (TIPR), a sequence-based machine learning model that identifies TSSs with high accuracy and resolution for multiple spatial distribution patterns along the genome, including broadly distributed TSS patterns that have previously been difficult to characterize. TIPR predicts not only the locations of TSSs but also the expected spatial initiation pattern each TSS will form along the chromosome-a novel capability for TSS prediction algorithms. As spatial initiation patterns are associated with spatiotemporal expression patterns and gene function, this capability has the potential to improve gene annotations and our understanding of the regulation of transcription initiation. The high nucleotide resolution of this model locates TSSs within 10 nucleotides or less on average. AVAILABILITY AND IMPLEMENTATION: Model source code is made available online at http://megraw.cgrb.oregonstate.edu/software/TIPR/. CONTACT: megrawm@science.oregonstate.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26254495 TI - Enhancing the detection and management of acute hepatitis C virus infection. AB - Acute HCV infection refers to the 6-month period following infection acquisition, although this definition is somewhat arbitrary. While spontaneous clearance occurs in approximately 25%, the majority will develop chronic HCV infection with the potential for development of cirrhosis, end stage liver disease and hepatocellular carcinoma. Detection of acute HCV infection has been hampered by its asymptomatic or non-specific presentation, lack of specific diagnostic tests and the inherent difficulties in identifying and following individuals at highest risk of transmitting and acquiring HCV infection, such as people who inject drugs (PWID). However, recognition of those with acute infection may have individual and population level benefits and could represent an ideal opportunity for intervention. Despite demonstration that HCV treatment is feasible and successful in PWID, treatment uptake remains low with multiple barriers to care at an individual and systems level. Given the burden of HCV-related disease among PWID, strategies to enhance HCV assessment, treatment and prevention in this group are urgently needed. As the therapeutic landscape of chronic HCV management is revolutionised by the advent of simple, highly effective directly-acting antiviral (DAA) therapy, similar opportunities may exist in acute infection. This review will discuss issues surrounding improving the detection and management of acute HCV infection, particularly in PWID. PMID- 26254496 TI - Strategies for achieving universal access to hepatitis C virus prevention and care for people who inject drugs. PMID- 26254497 TI - Expanding access to prevention, care and treatment for hepatitis C virus infection among people who inject drugs. PMID- 26254498 TI - Role of chlorhexidine bathing in infection control. PMID- 26254499 TI - Efficacy of common disinfectant/cleaning agents in inactivating murine norovirus and feline calicivirus as surrogate viruses for human norovirus. AB - BACKGROUND: The efficacies of disinfection by sodium hypochlorite, accelerated hydrogen peroxide (AHP), and quaternary ammonium compound (QUAT) commonly used in health care facilities were determined using the surrogate viruses murine norovirus (MNV-1) and feline calicivirus (FCV). METHODS: A virus suspension of known concentration (with or without a soil load) was deposited onto stainless steel discs under wet or dry load conditions and exposed to defined concentrations of the disinfectant/cleaning agent for 1-, 5-, or 10-minute contact time using the quantitative carrier test (QCT-2) method. Virus inactivation was determined by plaque assay. RESULTS: At an exposure time of 1 minute, sodium hypochlorite at 2,700 ppm was able to inactivate MNV-1 and FCV with a >5 log10 reduction. After 10 minutes, MNV-1 was inactivated by AHP at 35,000 ppm, whereas FCV was inactivated at 3,500 ppm. MNV-1 was not inactivated by QUAT at 2,800 ppm. A QUAT-alcohol formulation containing 2,000 ppm QUAT and 70% ethanol was effective in inactivating MNV-1 after 5 minutes, but resulted in only a <3 log10 reduction of FCV after 10 minutes. CONCLUSIONS: AHP and QUAT products were less effective than sodium hypochlorite for the inactivation of MNV 1 and FCV. PMID- 26254500 TI - Role of chlorhexidine bathing in infection control: reply. PMID- 26254501 TI - A new UV-LED device for automatic disinfection of stethoscope membranes. AB - BACKGROUND: Stethoscopes are widely used by doctors and nurses. Poor stethoscope hygiene is a potential source of nosocomial infection. This study aimed to propose an innovative solution, based on the latest advances in ultraviolet (UV) light-emitting diodes (LEDs), for disinfecting stethoscope membranes automatically and efficiently. METHODS: Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Enterococcus faecalis were sown on 28 stethoscope membranes and then transferred to Petri dishes. Treatment involved illuminating exposed Petri dishes with a UVC LED for 1 minute. For each microbe, the number of colony-forming units (cfu) at 36 degrees C was compared in control and treated dishes using the Wilcoxon signed-rank test. The Kruskal-Wallis test was used to assess percent reductions in bacteria. Statistical significance was set at 99%. RESULTS: A significant reduction in cfu counts after UV treatment (P < .01) was found for all bacteria: 85.5% for E faecalis, 87.5% for S aureus, 94.3% for E coli, and 94.9% for P aeruginosa . No significant differences in percent reduction in cfu were found between bacteria (P > .01). CONCLUSION: The stethoscope, symbol of medicine and health care professionals, has been demonstrated to be a carrier of microorganisms. The treatment technique was effective and efficient in disinfecting the membranes. These promising results represent a step forward toward eliminating stethoscope membrane contamination with an innovative approach. PMID- 26254502 TI - The natural history of recovery from psychological trauma: An observational model. AB - Following observation of patients who have experienced psychological trauma, a model of recovery is described with implications for the efficiency and effectiveness of treatment. PMID- 26254503 TI - Reproducibility of a battery of commonly used clinical tests to evaluate lumbopelvic motor control. AB - OBJECTIVE: To determine reproducibility of a battery of clinical tests for evaluating lumbopelvic motor control (LMC). DESIGN: Test-retest design. PARTICIPANTS: Fifty healthy subjects. OUTCOME MEASURES: Two raters independently examined performance on 12 clinical tests for evaluating LMC. All tests were scored on a seven-point scale, based on qualitative and quantitative performance. Subjects were measured twice, with a two week interval between examinations. Intra- and inter-rater reproducibility of each test were determined using intraclass correlation coefficients (ICCs), standard error of measurement, smallest detectable change (SDC) and limits of agreement. RESULTS: Reliability of the tests ranged from poor to excellent. Intra-rater ICCs ranged from 0.00 to 0.82, whereas inter-rater ICCs varied from 0.00 to 0.96. SDC values were smallest for supine leg raising, bent knee fall out, prone bridge and unilateral prone bridge (<2 points). CONCLUSION: This study shows limited reproducibility of a battery of 12 clinical tests for the evaluation of LMC in a healthy population. Supine leg raising, bent knee fall out, prone bridge, and unilateral prone bridge showed the smallest measurement errors. The other 8 tests were found to have large measurement errors. Based on these results, dichotomization of the rating method might be considered in order to improve reproducibility values. PMID- 26254504 TI - Rupture of a left renal artery aneurysm: a rare abdominal emergency. PMID- 26254506 TI - Traumatic posterior shoulder dislocation with a large engaging Hill-Sachs lesion: splinting technique. AB - Posterior shoulder dislocations are rare and are often associated with seizures, electrocution, and high-energy trauma. They can be missed and, therefore, left untreated. Early diagnosis and treatment can help avoid future complications and surgical intervention. PMID- 26254507 TI - Comparative studies on drug binding to the purified and pharmaceutical-grade human serum albumins: Bridging between basic research and clinical applications of albumin. AB - Human serum albumin (HSA), the most abundant protein in blood plasma, is a monomeric multidomain protein that possesses an extraordinary capacity for binding, so that serves as a circulating depot for endogenous and exogenous compounds. During the heat sterilization process, the structure of pharmaceutical grade HSA may change and some of its activities may be lost. In this study, to provide deeper insight on this issue, we investigated drug-binding and some physicochemical properties of purified albumin (PA) and pharmaceutical-grade albumin (PGA) using two known drugs (indomethacin and ibuprofen). PGA displayed significantly lower drug binding capacity compared to PA. Analysis of the quenching and thermodynamic parameters indicated that intermolecular interactions between the drugs and the proteins are different from each other. Surface hydrophobicity as well as the stability of PGA decreased compared to PA, also surface hydrophobicity of PA and PGA increased upon drugs binding. Also, kinetic analysis of pseudo-esterase activities indicated that Km and Vmax parameters for PGA enzymatic activity are more and less than those of PA, respectively. This in vitro study demonstrates that the specific drug binding of PGA is significantly reduced. Such studies can act as connecting bridge between basic research discoveries and clinical applications. PMID- 26254509 TI - Are the Current Outcome Measurement Tools Appropriate for the Evaluation of the Knee Status in Deep Flexion Range? AB - We determined whether current outcome measurement tools are appropriate for the evaluation of the knee status in deep flexion range after TKA. Patients (n = 604) with more than 120 degrees of knee flexion were evaluated by Knee Society score, WOMAC, and high flexion knee score (HFKS). The appropriateness of measurement tools was analyzed by correlation analyses and group comparisons (group 1: 120 degrees -129 degrees , group 2: 130 degrees -139 degrees , group 3: 140 degrees 150 degrees ). HFKS showed stronger correlation with knee flexion compared with other scores. While other scores only differentiated between groups 2 and 3, HFKS could differentiate among groups 1, 2 and 3. These findings suggest that employment of proper outcome measurement tool is needed to evaluate and differentiate the knee status in deep flexion range after TKA. PMID- 26254505 TI - Denver ED Trauma Organ Failure Score outperforms traditional methods of risk stratification in trauma. AB - BACKGROUND: Early identification of trauma patients at risk for inhospital mortality may facilitate goal-directed resuscitation and secondary triage to improve outcomes. The objective of this study was to compare prognostic accuracies of the Denver Emergency Department (ED) Trauma Organ Failure (TOF) Score, ED Sequential Organ Failure Assessment (SOFA) score, and ED base deficit and ED lactate for inhospital mortality in adult trauma patients. METHODS: Consecutive adult trauma patients from 2005 to 2008 from the Denver Health Trauma Registry were included. Prognostic accuracies of the Denver ED TOF Score, ED SOFA score, ED base deficit, and ED lactate for inhospital mortality were evaluated with receiver operating characteristic curves. RESULTS: Of the 4355 patients, the median age was 37 years (interquartile range [IQR], 26-51 years), median Injury Severity Score was 9 (IQR, 4-16), and 81% had blunt mechanisms. In addition, 38% (1670 patients) were admitted to the intensive care unit with a median intensive care unit length of stay of 2.5 days (IQR, 1-8 days), and 3% (138 patients) died. The areas under the receiver operating characteristic curves for the Denver ED TOF, ED lactate, ED base deficit, and ED SOFA were 0.94 (95% confidence interval [CI], 0.94-0.96), 0.88 (95% CI, 0.85-0.91), 0.82 (95% CI, 0.78-0.86), and 0.78 (95% CI, 0.73-0.82), respectively. CONCLUSIONS: The Denver ED TOF Score more accurately predicts inhospital mortality in adult trauma patients compared to the ED SOFA score, ED base deficit, or ED lactate. The Denver ED TOF Score may help identify patients early who are at risk for mortality, allowing for targeted resuscitation and secondary triage to improve outcomes. PMID- 26254510 TI - Clinicopathological spectrum of a series of Merkel cell carcinomas diagnosed at a tertiary cancer referral center in India, with current concepts. AB - Merkel cell carcinoma (MCC) is a rare, clinically aggressive primary cutaneous neuroendocrine carcinoma. The present series describes clinicopathological features of 16 MCCs diagnosed at a tertiary cancer referral center. Sixteen MCCs occurred in 10 men and 6 women (M/F = 1.6:1), between the ages 37 and 74 years (mean, 58.3; median, 58.6), commonly in lower extremities (7) (43.7%) and head and neck sites (5) (31.2%), followed by upper extremities (3) (18.7%) and abdominal wall (1). Tumor size varied from 0.5 to 9.9 cm. Histopathologically, most tumors were composed of round to oval cells, mostly arranged diffusely with hyperchromatic nuclei, including "sudden" pleomorphism in some tumors. Variable features included coexisting Bowen disease (2/16), along with squamous, pseudoglandular, and rhabdomyoblastic dedifferentiation, all in a single tumor. Immunohistochemically, tumor cells were positive for at least a single epithelial marker in all 16 cases (100%) cases, including CK20, mostly paranuclear "dot like" (12/13, 92.3%); CK (8/9, 88.8%), AE1/AE3 (3/3, 100%), and CK7 (1/6, 16.6%), along with neuroendocrine markers (16/16, 100%), including synaptophysin (11/13, 84.6%), chromogranin (12/15, 80%), and CD56 (4/4, 100%). Among other immunohistochemical markers, positive CKIT/CD117 was positive in 3 of 3 tumors. Surgical resection was performed in 11 (100%) of 11 cases, with adjuvant chemotherapy offered in a single case. Two cases with large-sized tumors, along with another case developed lymph node metastasis, including 1 who later developed pulmonary metastasis. Two patients were free of disease and 2 were alive with disease. Merkel cell carcinomas exhibit a diverse histopathological spectrum, including coexisting Bowen disease and, rarely, rhabdomyoblastic dedifferentiation, in some cases. Optimal immunohistochemical markers include CK20, synaptophysin, chromogranin, and CD56 for a timely diagnosis. Surgical resection is the treatment mainstay. Large-sized tumors and MCCs showing dedifferentiation portend a relatively more aggressive clinical course. Other recent developments in this tumor are discussed herewith. PMID- 26254511 TI - Prostate Cancer Progression: The Smoking Gun? PMID- 26254512 TI - An unusual onset of a rare disease. PMID- 26254513 TI - Effect of low dose pioglitazone on glycemic control and insulin resistance in Type 2 diabetes: A randomized, double blind, clinical trial. AB - This study shows that pioglitazone 7.5 mg/day as an add-on therapy in Southeast Asian patients with Type 2 diabetes is safer and equally efficacious as the 15- and 30-mg doses of pioglitazone. Hence it is prudent to start pioglitazone therapy at a lower dose of 7.5 mg/day. PMID- 26254514 TI - Deciphering voltage-gated Na(+) and Ca(2+) channels by studying prokaryotic ancestors. AB - Voltage-gated sodium channels (NaVs) and calcium channels (CaVs) are involved in electrical signaling, contraction, secretion, synaptic transmission, and other physiological processes activated in response to depolarization. Despite their physiological importance, the structures of these closely related proteins have remained elusive because of their size and complexity. Bacterial NaVs have structures analogous to a single domain of eukaryotic NaVs and CaVs and are their likely evolutionary ancestor. Here we review recent work that has led to new understanding of NaVs and CaVs through high-resolution structural studies of their prokaryotic ancestors. New insights into their voltage-dependent activation and inactivation, ion conductance, and ion selectivity provide realistic structural models for the function of these complex membrane proteins at the atomic level. PMID- 26254515 TI - A large head circumference is more strongly associated with unplanned cesarean or instrumental delivery and neonatal complications than high birthweight. AB - OBJECTIVE: Fetal size impacts on perinatal outcomes. We queried whether the fetal head, as the fetal part interfacing with the birth canal, might impact on obstetric outcomes more than birthweight (BW). We examined associations between neonatal head circumference (HC) and delivery mode and risk of perinatal complications as compared to high BW. STUDY DESIGN: This was an electronic medical records-based study of term singleton births (37-42 weeks' gestation) from January 2010 through December 2012 (N = 24,780, 6343 primiparae). We assessed risks of unplanned cesarean or instrumental delivery and maternal and fetal complications in cases with HC or BW >=95th centile (large HC, high BW) vs those with parameters <95th centile (normal). Newborns were stratified into 4 subgroups: normal HC/normal BW (reference, n = 22,548, primiparae 5862); normal HC/high BW (n = 817, P = 213); large HC/normal BW (n = 878, P = 265); and large HC/high BW (n = 537, P = 103). Multinomial multivariable regression provided adjusted odds ratio (aOR) while controlling for potential confounders. RESULTS: Infants with HC >=95th centile (n = 1415) were delivered vaginally in 62% of cases, unplanned cesarean delivery 16%, and instrumental delivery 11.2%; 78.4% of infants with HC <95th centile were delivered vaginally, 7.8% unplanned cesarean, and 6.7% instrumental delivery. Odds ratio (OR) for unplanned cesarean was 2.58 (95% confidence interval [CI], 2.22-3.01) and for instrumental delivery OR was 2.13 (95% CI, 1.78-2.54). In contrast, in those with BW >=95th centile (n = 1354) 80.3% delivered vaginally, 10.2% by unplanned cesarean (OR, 1.2; 95% CI, 1.01 1.44), and 3.4% instrumental delivery (OR, 0.46; 95% CI, 0.34-0.62) compared to infants with BW <95th centile: spontaneous vaginal delivery, 77.3%, unplanned cesarean 8.2%, instrumental 7.1%. Multinomial regression with normal HC/normal BW as reference group showed large HC/normal BW infants were more likely to be delivered by unplanned cesarean (aOR, 3.08; 95% CI, 2.52-3.75) and instrumental delivery (aOR, 3.03; 95% CI, 2.46-3.75). Associations were strengthened in primiparae. Normal HC/high BW was not associated with unplanned cesarean (aOR, 1.18; 95% CI, 0.91-1.54), while large HC/high BW was (aOR, 1.93; 95% CI, 1.47 2.52). Analysis of unplanned cesarean indications showed large HC infants had more failure to progress (27.7% vs 14.1%, P < .001), while smaller HC infants had more fetal distress (23.4% vs 16.9%, P < .05). CONCLUSION: A large HC is more strongly associated with unplanned cesarean and instrumental delivery than high BW. Prospective studies are needed to test fetal HC as a predictive parameter for prelabor counseling of women with "big babies." PMID- 26254516 TI - The medical management of abnormal uterine bleeding in reproductive-aged women. AB - In the treatment of women with abnormal uterine bleeding, once a thorough history, physical examination, and indicated imaging studies are performed and all significant structural causes are excluded, medical management is the first line approach. Determining the acuity of the bleeding, the patient's medical history, assessing risk factors, and establishing a diagnosis will individualize their medical regimen. In acute abnormal uterine bleeding with a normal uterus, parenteral estrogen, a multidose combined oral contraceptive regimen, a multidose progestin-only regimen, and tranexamic acid are all viable options, given the appropriate clinical scenario. Heavy menstrual bleeding can be treated with a levonorgestrel-releasing intrauterine system, combined oral contraceptives, continuous oral progestins, and tranexamic acid with high efficacy. Nonsteroidal antiinflammatory drugs may be utilized with hormonal methods and tranexamic acid to decrease menstrual bleeding. Gonadotropin-releasing hormone agonists are indicated in patients with leiomyoma and abnormal uterine bleeding in preparation for surgical interventions. In women with inherited bleeding disorders all hormonal methods as well as tranexamic acid can be used to treat abnormal uterine bleeding. Women on anticoagulation therapy should consider using progestin-only methods as well as a gonadotropin-releasing hormone agonist to treat their heavy menstrual bleeding. Given these myriad options for medical treatment of abnormal uterine bleeding, many patients may avoid surgical intervention. PMID- 26254517 TI - Factors affecting expression of estrus measured by activity monitors and conception risk of lactating dairy cows. AB - The objective of this study was to determine risk-factors affecting increase in physical activity during estrus and pregnancy per artificial insemination (P/AI) in lactating dairy cows. Cows were monitored continuously by 2 automated activity monitors [a collar-mounted accelerometer (HT; Heatime, SCR Engineers, Netanya, Israel) and a leg-mounted pedometer (BO; Boumatic Heat-seeker-TX, Boumatic Dairy Equipment, Madison, WI)]. When an increase in activity was detected, body condition score (BCS) and blood samples were collected, ovaries were scanned by ultrasonography, and, if the cow was eligible for breeding, artificial insemination was performed. Milk production and health-related data were recorded throughout the experimental period. Pregnancy diagnosis was performed at 42 +/- 7 d of gestation. Data were analyzed using Pearson correlation, ANOVA, and logistic regression. A total of 1,099 true events of estrus from 318 lactating Holstein cows were recorded, averaging 3.46 +/- 1.1 events per cow. Positive predictive value for estrus episodes detected by the HT and BO systems were 89.6 and 85.5%, respectively. Mean peak activity at estrus (PA) recorded by the HT system was 71.6 +/- 20.7 index-value, and 334.3 +/- 155.7% relative increase by the BO system. Compared with primiparous, multiparous cows expressed estrus with lower PA (69.3 +/- 0.8 vs. 75.9 +/- 1.1 index for HT; 323.9 +/- 6.0 vs. 354.8 +/- 8.48% for BO) and shorter duration (DU; 10.7 +/- 0.2 vs. 12.0 +/- 0.3 h); DU was measured by HT only. Lower BCS was associated with decreased PA measured by both systems, estrus DU, and P/AI. Peak activity was weakly correlated with milk production on the day of artificial insemination (r = -0.20); however, when categorized into quartiles, the highest-yield cows had lower PA and DU. Follicle diameter was not correlated with PA or DU, but cows with greater concentrations of estradiol had higher PA. Cows with greater PA in both systems had greater P/AI than those with lower PA (36.5 vs. 24.6% for HT, 33.5 vs. 21.4% for BO). In conclusion, measurements of estrus events captured by automated activity monitors are correlated with BCS, parity, and secondary behavior signs related to estrus. Surprisingly, estrus intensity and duration were only weakly correlated with milk production, preovulatory follicle diameter, and concentrations of estradiol at estrus. Cows that had measurements of high-intensity estrus were significantly more fertile than low-intensity estrus. PMID- 26254518 TI - Short communication: Effect of conjugated linoleic acid on concentrations of fat soluble vitamins in milk of lactating ewes. AB - Conjugated linoleic acids (CLA) are well known as milk fat-reducing feed supplements in diets for lactating ruminants. However, their effects on milk concentrations of fat-soluble vitamins are unknown. This study was performed to investigate the hypothesis that CLA affect the concentrations of retinol and tocopherol in ewe milk. For that purpose, group-housed Merino ewes (101 +/- 13.7 kg) nursing twin lambs and fed with a hay:concentrate diet were supplemented with either 45 g of a rumen-protected CLA supplement containing 3.4 g of cis-9,trans 11-CLA and 3.4 g of trans-10,cis-12-CLA (CLA group, n=11) or with 45 g of a hydrogenated vegetable fat (control group, n=12) per ewe per day during the first 6 wk of lactation. Feed intake was recorded daily (concentrate) or weekly (hay) per group. Milk spot samples were collected at the beginning of the experiment (5 +/- 2.4 d postpartum) and then weekly after lambs had been separated for 2 h from their mothers. The milk fat content was determined and feed and milk were analyzed for concentrations of alpha-, gamma-, and delta-tocopherol and for retinol by HPLC. Dietary intake of tocopherol and retinol was similar in both groups. Feeding CLA decreased milk fat concentration by 23% on average, and during the first 3 wk of the study milk tocopherol concentration tended to be increased by feeding CLA (+17%), but retinol concentrations were not influenced. When related to milk fat, CLA feeding significantly increased both milk tocopherol (+40%) and retinol (+32%) and these effects were evident during the whole experimental period corresponding to the first half of lactation. PMID- 26254519 TI - Methods of estimating liner compression. AB - The aim of this study was to compare 2 methods of measuring overpressure (OP) using a new test device designed to make OP measurements more quickly and accurately. Overpressure was measured with no pulsation (OP np) and with limited pulsation (OP lp) repeatedly on the same cow during a single milking. Each of the 6 liners (3 round liners and 3 triangular liners) used in this study were tested on the same 6 experimental cows. Both OP np and OP lp were measured on all 4 teats of each experimental cow twice for each liner. The order of OP np and OP lp alternated sequentially for each cow test. The OP results for the 6 liners were also compared with liner compression estimated on the same liners with a novel artificial teat sensor (ATS). The OP lp method showed small but significantly higher values than the OP np method (13.9 vs. 13.4 kPa). The OP lp method is recommended as the preferred method as it more closely approximates normal milking condition. Overpressure values decreased significantly between the first and the following measurements, (from 15.0 to 12.4 kPa). We recommend performing the OP test at a consistent time, 1 min after attaching the teatcup to a well stimulated teat, to reduce the variability produced by OP changing during the peak flow period. The new test device had several advantages over previously published methods of measuring OP. A high correlation between OP and liner compression estimated by the ATS was found, but difficulties were noted when using the ATS with triangular liners. PMID- 26254520 TI - Variances and correlations of milk production, fertility, longevity, and type traits over time in Australian Holstein cattle. AB - When using historical data, it is often assumed that the genetic correlation of the same trait recorded at different time points is reasonably close to 1. However, selection and possible changes in trait definitions means that this may not necessarily be the case. Regularly monitoring genetic parameters over time is important, as changes could reduce the accuracy of genetic evaluations. About 20 yr (1993 to 2012) of data on milk yield as well as functional and type traits from Australian Holstein dairy cattle were analyzed to assess changes in genetic correlations within and among traits over time by considering 2 traits at a time using linear random regression (RR) and multitrait (MT) models. Both residual and genetic variances for milk yield traits and calving interval (CI) increased over time, with the highest increase observed for protein yield. For most type traits some fluctuations over time were noted in both the residual and additive genetic variances. Genetic correlations among survival (i.e., from first to second lactation), milk yield traits, CI, and some type traits varied over time. The genetic correlation of the same trait (e.g., protein yield, fat yield, and some type traits) measured in different years was also less than 1.0 (0.1-0.9), which is likely to be due to selection or changes in trait definitions. Estimates of parameters from the RR model were generally similar to those from MT models that considered the same trait recorded in different year groups as different traits. However, in the case of survival and CI (i.e., lowly heritable traits), the genetic correlations over time obtained from the MT model were lower (0.21 to 0.75) than those from the RR models (0.9-1.0). Genetic correlations of survival with milk, fat, and protein yields declined from ~0.4 to 0.5 at the beginning of the study period (1993/94) to zero or negative at the end (2009/10), whereas the correlation between CI and milk yield became more unfavorable and increased from 0.3 to 0.5 over the same time period. The same pattern was observed for the genetic correlation between survival and CI, which also became more unfavorable over time and increased from 0.67 to 0.87 in absolute value. The genetic correlations of survival with type traits, such as angularity and body depth, decreased from near zero to negative (-0.3 to -0.4). But genetic correlations between pin set and survival showed less variation (0.2-0.3) over time. Similarly the genetic correlation of CI with body depth and angularity became more antagonistic over time. Over time the importance of traits such as milk yield and overall type as criteria for culling decreased, whereas the importance of fertility and possible disease incidence increased, implying that there has been a switch from voluntary to involuntary reasons dominating culling decisions. Changes in genetic correlations of the same trait and among traits over time have important implications on the accuracy of prediction of traits, such as survival and CI, which often rely on other traits as predictors and ultimately on the accuracy of genetic evaluations (traditional and genomic), and also the prediction of response to selection. PMID- 26254521 TI - Evaluation of analytical assays efficiency to detect aflatoxin M1 in milk from selected areas in Egypt and South Africa. AB - Recently, methods to analyze aflatoxin M1 (AFM1) in milk and dairy products have been developed for both screening purposes (i.e., rapid, economical, and simple methods) and for confirmation by accurate, reproducible, and sensitive quantification. The aim of this study was to evaluate the efficiency of different rapid kits and techniques available on the market by using different analytical methods: thin layer chromatography (TLC), immunoaffinity column, AFM1 immunochromatographic strip, and ELISA; some samples were also submitted to HPLC for comparison of results. One hundred thirty-eight samples were collected from rural subsistence and commercial dairy farms in selected areas of Egypt and South Africa and analyzed for the presence of AFM1. The results obtained by AFM1 immunochromatographic strip indicated the lowest frequency of occurrence, with a detection incidence of 20.45% in Egyptian samples and 16% in South African samples. Aflatoxin M1 was detected by ELISA in 65 (73.9%) Egyptian milk samples, with a range of 8.52 to 78.06 ng/L, and in 34 (68%) South African milk samples, with a range of 5 to 120 ng/L. A higher incidence of AFM1 in Egyptian milk samples was shown by TLC (81.8%) compared with ELISA (73.9%). Samples analyzed by ELISA in South African milk samples demonstrated satisfactory correlation when compared with HPLC coupled with Coring cell (an electrochemical cell for the derivatization of AFM1). Among the positive samples, 18 of the Egyptian samples (20.45%) positive by ELISA had levels of AFM1 above the European Union (EU) regulatory limit (50 ng/L), whereas 65 samples (73.9%) were above the Egyptian regulatory limit (0 ng/L). Six of the South African samples (12%) tested by ELISA were above the South African (50 ng/L) and EU regulatory limits. The mean concentration of AFM1 was 25.79 ng/L in Egyptian samples and 17.06 ng/L by ELISA and 39 ng/L by HPLC in South African samples. These contamination levels would not represent a serious public health hazard according to EU legislation. PMID- 26254522 TI - Modeling of daily body weights and body weight changes of Nordic Red cows. AB - Increased availability of automated weighing systems have made it possible to record massive amounts of body weight (BW) data in a short time. If the BW measurement is unbiased, the changes in BW reflect the energy status of the cow and can be used for management or breeding purposes. The usefulness of the BW data depends on the reliability of the measures. The noise in BW measurements can be smoothed by fitting a parametric or time series model into the BW measurements. This study examined the accuracy of different models to predict BW of the cows based on daily BW measurements and investigated the usefulness of modeling in increasing the value of BW measurements as management and breeding tools. Data included daily BW measurements, production, and intake from 230 Nordic Red dairy cows. The BW of the cows was recorded twice a day on their return from milking. In total, the data included 50,594 daily observations with 98,418 BW measurements. A clear diurnal change was present in the BW of the cows even if they had feed available 24 h. The daily average BW were used in the modeling. Five different models were tested: (1) a cow-wise fixed second-order polynomial regression model (FiX) including the exponential Wilmink term, (2) a random regression model with fixed and random animal lactation stage functions (MiX), (3) MiX with 13 periods of weighing added (PER), (4) natural cubic smoothing splines with 8 equally spaced knots (SPk8), and (5) spline model with no restriction on knots but a smoothing parameter corresponding to a fit of 5 degrees of freedom (SPdf5). In the original measured BW data, the within-animal variation was 6.4% of the total variance. Modeling decreased the within animal variation to levels of 2.9 to 5.1%. The smallest day-to-day variation and thereafter highest day-to-day repeatabilities were with PER and MiX models. The usability of modeled BW as energy balance (EB) indicator were evaluated by estimating relationships between EB, or EB indicators, and modeled BW change. In all cases the modeling increased the correlation and thus the reliability of the BW measurements. From all of the tested models, the best predictive value was attained by the random regression model with fixed and random animal lactation stage functions. Based on results, modeling of BW significantly increases the usefulness of BW as an EB predictor and management indicator. PMID- 26254523 TI - Enzymatic production of lactulose and epilactose in milk. AB - The enzymatic production of lactulose was described recently through conversion of lactose by a thermophilic cellobiose 2-epimerase from Caldicellulosiruptor saccharolyticus (CsCE). In the current study, we examined the application of CsCE for lactulose and epilactose production in milk (1.5% fat). The bioconversions were carried out in stirred reaction vessels at 2 different temperatures (50 and 8 degrees C) at a scale of 25 mL volume. At 50 degrees C, 2 highly different CsCE amounts were investigated for the time course of formation of lactulose and epilactose. The conversion of milk lactose (initial lactose content of 48.5 +/- 2.1 g/L) resulted in a final yield of 57.7% (28.0 g/L) lactulose and 15.5% (7.49 g/L) epilactose in the case of the approximately 9.5-fold higher CsCE amount (39.5 ukat epilactose, 50 degrees C) after 24 h. Another enzymatic lactose conversion was carried out at low 8 degrees C, an industrially relevant temperature for milk processing. Although the CsCE originated from a thermophilic microorganism, it was still applicable at 8 degrees C. This enzymatic lactose conversion resulted in 56.7% (27.5 g/L) lactulose and 13.6% (6.57 g/L) epilactose from initial milk lactose after 72 h. The time courses of lactose conversion by CsCE suggested that first epilactose formed and afterward lactulose via epilactose. To the best of our knowledge, this is the first time that an enzyme has produced lactulose directly in milk in situ at industrially relevant temperatures. PMID- 26254524 TI - Relating the carbon footprint of milk from Irish dairy farms to economic performance. AB - Mitigating greenhouse gas (GHG) emissions per unit of milk or the carbon footprint (CF) of milk is a key issue for the European dairy sector given rising concerns over the potential adverse effects of climate change. Several strategies are available to mitigate GHG emissions, but producing milk with a low CF does not necessarily imply that a dairy farm is economically viable. Therefore, to understand the relationship between the CF of milk and dairy farm economic performance, the farm accountancy network database of a European Union nation (Ireland) was applied to a GHG emission model. The method used to quantify GHG emissions was life cycle assessment (LCA), which was independently certified to comply with the British standard for LCA. The model calculated annual on- and off farm GHG emissions from imported inputs (e.g., electricity) up to the point milk was sold from the farm in CO2-equivalent (CO2-eq). Annual GHG emissions computed using LCA were allocated to milk based on the economic value of dairy farm products and expressed per kilogram of fat- and protein-corrected milk (FPCM). The results showed for a nationally representative sample of 221 grass-based Irish dairy farms in 2012 that gross profit averaged ? 0.18/L of milk and ? 1,758/ha and gross income was ? 40,899/labor unit. Net profit averaged ? 0.08/L of milk and ? 750/ha and net income averaged ? 18,125/labor unit. However, significant variability was noted in farm performance across each financial output measure. For instance, net margin per hectare of the top one-third of farms was 6.5 times higher than the bottom third. Financial performance measures were inversely correlated with the CF of milk, which averaged 1.20 kg of CO2 eq/kg of FPCM but ranged from 0.60 to 2.13 kg of CO2-eq/kg of FPCM. Partial least squares regression analysis of correlations between financial and environmental performance indicated that extending the length of the grazing season and increasing milk production per hectare or per cow reduced the CF of milk and increased farm profit. However, where higher milk production per hectare was associated with greater concentrate feeding, this adversely affected the CF of milk and economic performance by increasing both costs and off-farm emissions. Therefore, to mitigate the CF of milk and improve economic performance, grass based dairy farms should not aim to only increase milk output, but instead target increasing milk production per hectare from grazed grass. PMID- 26254525 TI - Associations between health status and the probability of approaching a novel object or stationary human in preweaned group-housed dairy calves. AB - Neonatal calf diarrhea (NCD) and bovine respiratory disease (BRD) are the 2 most prevalent diseases affecting the welfare and productivity of preweaned dairy calves in the United States. Early detection of these diseases improves both the probability of recovery and animal welfare. Group housing of preweaned calves is increasing in popularity and disease detection in a socially competitive environment can be challenging. One method of detecting disease is through the observation of key behaviors that occur during illness. Novel object and stationary human approach tests can be used to measure exploratory behavior, which is decreased during the expression of sickness behavior. The objectives of this study were (1) to determine associations between 4 categories of health status and the probability of calves approaching a novel object or stationary human, and (2) to determine the associations between rectal temperature and the probability of calves approaching. Holstein heifer calves (n = 75) in group housing were tested weekly for the first 6 wk of life for their willingness to approach a novel object (OBJ) or stationary human (SH). After the approach tests, calves were evaluated by research staff using a standardized health-scoring system. Treatment records were obtained from the farm to determine detection of BRD, NCD, and umbilical infections. Associations between probability of approach and BRD status were analyzed using a linear mixed model with a logit-transform (PROC GLIMMIX), controlling for calf as a random effect. All models controlled for week, pen, pen order, and test order. Calves with clinical signs of BRD on test day were 0.5 [95% confidence interval (CI) = 0.3-0.9] and 0.5 (95% CI = 0.3 0.9) times as likely to approach the OBJ and SH compared with healthy calves, respectively. Calves with a fever (rectal temperature >= 39.4 degrees C) were 0.4 (95% CI = 0.2-0.8) and 0.4 (95% CI = 0.1-0.7) times as likely to approach the OBJ and SH compared with calves without fever, respectively. Calves that were recovering from NCD on test day, but were not showing clinical signs of NCD, were 0.4 (95% CI = 0.2-0.9) times as likely to approach SH, compared with healthy calves. These results suggest that approach tests may be useful for the identification of calves with clinical signs of BRD and calves with a fever in group housing. PMID- 26254526 TI - Prevalence of lameness and associated risk factors in Canadian Holstein-Friesian cows housed in freestall barns. AB - Lameness is a severe welfare problem and a production-limiting disease in dairy farming. The objectives of this study were to determine prevalence of lameness and investigate cow- and herd-level factors associated with lameness in dairy cows housed in freestall barns in 3 Canadian provinces. A purposive sample of 40 Holstein-Friesian cows was selected from each of 141 dairy farms in Quebec, Ontario, and Alberta. In total, 5,637 cows were scored once for lameness (presence of limping when walking). Data collected included information on individual cows (hock lesions, claw length, body condition score, parity, days in milk, and milk production), management practices (floor and stall cleaning routine, bedding routine, and footbath practices), and facility design (stall dimensions, stall base and bedding type, width of feed alley, flooring type, and slipperiness) hypothesized to be risk factors for lameness. Multilevel mixed logistic regression models were constructed (including farm as a random effect and province as a fixed effect). Herd-level lameness prevalence ranged from 0 to 69% (mean = 21%). Lameness prevalence increased with increasing parity; compared with first parity, cows in parity 2, 3, and >= 4 had 1.6, 3.3, and 4 times, respectively, higher odds of being lame. Furthermore, the odds of lameness were 1.6 times greater in cows with low body condition score (<= 2.5) than in cows with a higher body condition score. In addition, injured hocks and overgrown claws were associated with 1.4- and 1.7-fold increased odds of being lame, respectively, whereas every 1 kg increase in daily milk production was associated with a 3% decrease in the odds of being lame. Lameness prevalence was higher in herds with <= 100 cows, but lower in barns with a sand or dirt stall base, or with bedding >= 2 cm deep. Cows exposed to very slippery floors had 2 times the odds of being lame compared with cows exposed to nonslippery floors. We attributed the wide range of lameness prevalence to the great variability in facilities and management practices among farms. Finally, we inferred that the prevalence of lameness could be decreased by improving management of multiparous, thin, or injured cows and by adopting management practices intended to improve cow comfort, namely the floor's slip resistance and the stall's lying surface. PMID- 26254527 TI - Effect of dietary energy source and level on nutrient digestibility, rumen microbial protein synthesis, and milk performance in lactating dairy cows. AB - This study was conducted to examine the effects of dietary energy source and level on intake, digestion, rumen microbial protein synthesis, and milk production in lactating dairy cows, using corn stover as a forage source. Eight multiparous Holstein cows, 4 of which were fitted with rumen cannulas, were evaluated in a replicated 4 * 4 Latin square design, with each period lasting 21 d. The cows were randomly assigned into 4 treatment groups: low-energy (LE) ground corn (GC), LE steam-flaked corn (SFC), high-energy (HE) GC, and HE SFC. Changes to ruminal energy degradation rates were induced by feeding the cows diets of either finely ground corn or SFC as components of diets with the same total energy level. Milk yield, milk protein content and yield, and milk lactose yield all increased in response to higher levels of dietary energy, whereas contents of milk fat and lactose were unaffected. Cows fed HE diets had a higher crude microbial protein yield and total-tract apparent digestibility than those receiving LE diets. Milk yield, milk protein yield, and microbial protein yield were also higher when SFC replaced GC as the main energy source for lactating cows fed LE diets. These results suggest that an increased dietary energy level and ruminal degradation rate are beneficial to milk protein production, which we suggest is due to increased yields of microbial proteins, when cows are fed corn stover as a dietary forage source. PMID- 26254528 TI - Differential rumination, intake, and enteric methane production of dairy cows in a pasture-based automatic milking system. AB - Proper performance monitoring of cows on pasture-based diets is crucial to inform nutritional recommendations that minimize undesirable effects of high ruminant CH4 emissions into the environment. The prediction of linkages between rumination patterns, methane emissions, and correlated production traits of cows in a pasture-based automatic milking system was tested. A previous 10-d baseline measurement of rumination activity by acoustic methodology of 156 Holstein Friesian cows was used for frequency analysis of rumination time and identification of 2 treatment groups (n = 37 cows/group) represented by cows with consistently high (HR; 75th rumination percentile = 617.55 +/- 81.37 min/d) or low (LR; 25th rumination percentile = 356.65 +/- 72.67 min/d) rumination. The HR and LR cows were paired by nearest parity, days in milk, body weight (BW), and previous 10-d milk production, and within pairs randomly assigned to 1 of 2 experimental groups managed on a voluntary milking system with diets consisting of at least 75% pasture, plus concentrates. Animal traits, including rumination time, mass flux of CH4 (QCH4) and carbon dioxide (QCO2), milk production, and estimated dry matter intake according to individual QCO2 fluxes over a 22-d period were analyzed with repeated measure mixed models for a completely randomized design, structural equation modeling, and nonlinear regression. High rumination and methane was seen in older and heavier cows that had greater estimated dry matter intake and milk production. A consistent difference in rumination time and QCH4 across days was detected between HR and LR, even after adjustment for metabolic BW. Estimated dry matter intake had direct positive effects on rumination and QCH4, but no independent direct effect of rumination on QCH4 was detected. The LR cows produced more QCH4/milk, associated with lower milk, BW, concentrate intake, and greater activity at pasture. A typical dilution of maintenance effect on QCH4/milk was detected as a consequence of increasing milk yield and similar significant reduction of QCO2/milk. The results raise challenging questions regarding the rumination patterning of grazing dairy cows and alternatives to reduce ruminant methane emissions in grazing dairy cows. PMID- 26254529 TI - Effects of energy density in close-up diets and postpartum supplementation of extruded full-fat soybean on lactation performance and metabolic and hormonal status of dairy cows. AB - This experiment was conducted to investigate the effect of energy density (ED) in the close-up period and supplementation of extruded full-fat soybean (ESB) during the first 4 wk after parturition on intake, body weight (BW), metabolic status, and performance of dairy cows. Fifty-seven Chinese Holstein cows with similar parity, previous 305-d milk yield, and expected calving date were dried off at 60 d relative to parturition and fed the standard herd dry-cow diet until -21 d relative to parturition. Energy density at low (LED, 1.25 Mcal/kg), medium (MED, 1.41 Mcal/kg) or high (HED, 1.55 Mcal/kg) levels of the close-up diets and postpartum supplementation of ESB at 0 kg/d (control, CON) or 1.5 kg/d (TRT) were used in a 3 * 2 factorial arrangement. All cows received the same CON diet from wk 5 to wk 8. As ED increased in the close-up diet, cows had higher dry matter intake and gained more BW and body condition score, and consequently were in improved energy balance status during the prepartum period, but lost more BW and more body condition score during the first 8 wk of lactation. Compared with LED cows, HED cows had higher blood concentrations of insulin and glucose, and lower nonesterified fatty acids (NEFA) prepartum, but had lower insulin concentration, higher leptin concentration and tended to have higher NEFA concentration postpartum. Milk production was not affected by the prepartum ED, although HED cows produced approximately 2 kg/d less milk than MED and LED cows during early lactation. Postpartum ESB supplementation elevated blood glucagon concentration regardless of prepartum ED during the first 4 wk of lactation. Interactive effects between prepartum ED and postpartum ESB supplementation were observed in blood concentrations of insulin, NEFA, bilirubin, total protein, albumin, and globulin. During early lactation, TRT decreased globulin concentrations in MED cows, and reduced NEFA and bilirubin concentrations in HED cows. Compared with CON, TRT cows had higher yields of milk (34.32 vs. 36.53 kg/d), milk lactose (1.63 vs. 1.74 kg/d), and solids-nonfat (2.98 vs. 3.18 kg/d), tended to have a greater yield of milk protein (1.11 vs. 1.17 kg/d), but tended to have lower milk fat percentage (4.18 vs. 3.94%) during the first 4 wk of lactation. In conclusion, compared with feeding the HED diet, feeding the LED diet during the close-up dry period had positive carryover effects on metabolism and production during early lactation, and the MED diet showed no advantage over the LED diet. Extruded full-fat soybean supplementation during the first 4 wk of lactation had positive effects on postpartum metabolic status, especially for those receiving the MED or HED diet prepartum, and resulted in an overall improved milk production during early lactation. PMID- 26254530 TI - Long-term trends of nitrogen and phosphorus mass balances on New York State dairy farms. AB - The whole-farm nutrient mass balance (NMB) is an adaptive management tool that can be used to identify areas for improvement in nutrient management and to monitor progress over time. The objectives of this study were to (1) evaluate the trends of nitrogen and phosphorus mass balances of 27 New York State dairy farms over 6 to 10 yr, (2) identify specific management changes made by 4 case study farms that improved NMB over time by shifting NMB up or down depending on the initial NMB, and (3) evaluate the potential of key indicators to identify opportunities for improvement in NMB. During the study period, milk price fluctuated whereas costs associated with feed and fertilizer increased substantially. Of the 27 farms, 67 to 74% (depending on the nutrient) decreased NMB per hectare over time, whereas 63 to 67% decreased NMB per megagram of milk over time. In general, changes in NMB were directionally correct, with 43 to 56% of farms operating in the optimum operational zone (with both NMB per hectare and per megagram of milk below the feasible levels suggested for New York) toward the end of the study versus 22 to 26% in the first 2 yr of the assessments. The 4 case study farms improved their NMB, whole-farm nutrient use efficiencies, and feed nutrient use efficiencies while maintaining or increasing milk production per cow. The case study farmers made the largest changes in precision feed management, reducing protein and P in purchased feed by replacing concentrates with blends with lower nutrient concentrations. Total nutrient imports, feed imports, the percentage of homegrown feed and nutrients, the concentration of nutrients in the purchased feed, fertilizer imports, and overall crop yields were useful in identifying potential areas for improvement in NMB. PMID- 26254531 TI - Differential expression of living mammary epithelial cell subpopulations in milk during lactation in dairy cows. AB - Epithelial cells are shed into milk during lactation, and although they generally reflect the cellular characteristics of terminally differentiated luminal cells, previously the detection of more primitive cells was described in human milk where a cell population of epithelial lineage was detected expressing markers typical of progenitor cells. In this investigation, we report the development of flow cytometry analysis to allow multiparametric assessment of mammary epithelial cells observed in milk. Cells collected from milk samples of 10 healthy dairy cows were directly analyzed for 6 different markers: CD45, CD49f, cytokeratin 14, cytokeratin 18, presence of nucleus, and cell viability. Milk samples were collected in 3 different periods of lactation: early lactation (EL=d 0-30), mid lactation (ML=d 90-120), and late lactation (LL=210-250). Here we identify the differential expression of precursor or differentiated cell markers (or both) in mammary epithelial cells present in bovine milk. Myoepithelial cells, as indicated by cells staining positively for cytokeratin 14(+)/cytokeratin 18(-), were observed to increase from EL to LL with a high correlation with nuclear staining inferring potential proliferative activity. Furthermore, a significant increase in CD49f(+) and cytokeratin 14(+)/cytokeratin 18(+) positive cells was observed in LL. This assay is a sensitive approach for evaluating the variations in the frequency and features of living epithelial cells, whose reciprocal balance may be significant in understanding mammary gland cellular function throughout lactation. These observations suggest that mammary epithelial cell immunophenotypes could be investigated as biomarkers for mammary gland function in dairy cows. PMID- 26254532 TI - Short communication: Feeding red clover cut in the afternoon or morning to late lactation dairy cows. AB - Forages cut in the afternoon (p.m.) generally yield a higher concentration of nonstructural carbohydrates (NSC) than those cut in the morning (a.m.). We aimed to compare the effects of p.m.-cut red clover baleage (p.m.-RC) versus a.m.-cut RC baleage (a.m.-RC) on milk yield, concentrations and yields of milk components, and apparent total-tract digestibility of nutrients in late-lactation Holstein cows. Twelve multiparous and 2 primiparous Holstein cows received a total mixed ration containing, on a dry matter (DM) basis, 65% p.m.-RC or a.m.-RC plus 35% concentrate in a crossover design with 14 d for diet adaptation and 7 d for data and sample collection. One RC field was split in 2 with the first half cut in the afternoon (1600 h) and the second half in the following morning (0600 h). The p.m.-RC and a.m.-RC contained (% of DM): 12.6 versus 9.43% NSC in samples collected before the beginning of the experiment and 7.49 versus 7.79% NSC in samples collected during the sampling periods (i.e., d 14 to 21). The total mixed rations averaged 18.2 and 17.5% NSC for the p.m.-RC and a.m.-RC, respectively. Feeding p.m.-RC or a.m.-RC did not improve feed intake or milk yield and composition in late-lactation dairy cows. However, milk urea N and plasma urea N were both lowest in cows offered p.m.-RC. With the exception of the apparent total-tract digestibility of DM, which was highest in cows fed p.m.-RC, no other changes in nutrient digestibility were observed. Similarly, no treatment effect was observed for the urinary excretion of N and purine derivatives. Further research is needed to better understand NSC losses during storage and the associated effects on baleage quality and animal performance. PMID- 26254533 TI - Hot topic: Definition and implementation of a breeding value for feed efficiency in dairy cows. AB - A new breeding value that combines the amount of feed saved through improved metabolic efficiency with predicted maintenance requirements is described. The breeding value includes a genomic component for residual feed intake (RFI) combined with maintenance requirements calculated from either a genomic or pedigree estimated breeding value (EBV) for body weight (BW) predicted using conformation traits. Residual feed intake is only available for genotyped Holsteins; however, BW is available for all breeds. The RFI component of the "feed saved" EBV has 2 parts: Australian calf RFI and Australian lactating cow RFI. Genomic breeding values for RFI were estimated from a reference population of 2,036 individuals in a multi-trait analysis including Australian calf RFI (n=843), Australian lactating cow RFI (n=234), and UK and Dutch lactating cow RFI (n=958). In all cases, the RFI phenotypes were deviations from a mean of 0, calculated by correcting dry matter intake for BW, growth, and milk yield (in the case of lactating cows). Single nucleotide polymorphism effects were calculated from the output of genomic BLUP and used to predict breeding values of 4,106 Holstein sires that were genotyped but did not have RFI phenotypes themselves. These bulls already had BW breeding values calculated from type traits, from which maintenance requirements in kilograms of feed per year were inferred. Finally, RFI and the feed required for maintenance (through BW) were used to calculate a feed saved breeding value and expressed as the predicted amount of feed saved per year. Animals that were 1 standard deviation above the mean were predicted to eat 66 kg dry matter less per year at the same level of milk production. In a data set of genotyped Holstein sires, the mean reliability of the feed saved breeding value was 0.37. For Holsteins that are not genotyped and for breeds other than Holsteins, feed saved is calculated using BW only. From April 2015, feed saved has been included as part of the Australian national selection index, the Balanced Performance Index (BPI). Selection on the BPI is expected to lead to modest gains in feed efficiency. PMID- 26254534 TI - Evaluation of the Johne's disease risk assessment and management plan on dairy farms in Ontario, Canada. AB - Johne's disease (JD) is a production-limiting gastrointestinal disease in cattle. To minimize the effects of JD, the Ontario dairy industry launched the Ontario Johne's Education and Management Assistance Program in 2010. As part of the program, trained veterinarians conducted a risk assessment and management plan (RAMP), an on-farm questionnaire where high RAMP scores are associated with high risk of JD transmission. Subsequently, veterinarians recommended farm-specific management practices for JD prevention. Milk or serum ELISA results from the milking herd were used to determine the herd ELISA status (HES) and within-herd prevalence. After 3.5 yr of implementation of the program, the aim of this study was to evaluate the associations among RAMP scores, HES, and recommendations. Data from 2,103 herds were available for the analyses. A zero-inflated negative binomial model for the prediction of the number of ELISA-positive animals per farm was built. The model included individual RAMP questions about purchasing animals in the logistic portion, indicating risks for between-herd transmission, and purchasing bulls, birth of calves outside the designated calving area, colostrum and milk feeding management, and adult cow environmental hygiene in the negative binomial portion, indicating risk factors for within-herd transmission. However, farms which fed low-risk milk compared with milk replacer had fewer seropositive animals. The model additionally included the JD herd history in the negative binomial and the logistic portion, indicating that herds with a JD herd history were more likely to have at least 1 positive animal and to have a higher number of positive animals. Generally, a positive association was noted between RAMP scores and the odds of receiving a recommendation for the respective risk area; however, the relationship was not always linear. For general JD risk and calving area risk, seropositive herds had higher odds of receiving recommendations compared with seronegative herds if the section scores were low. This study suggests that the RAMP is a valuable tool to assess the risk for JD transmission within and between herds and to determine farm-specific recommendations for JD prevention. PMID- 26254535 TI - In vitro and in vivo examination of anticolonization of pathogens by Lactobacillus paracasei FJ861111.1. AB - Very limited information exists on the exclusion of pathogens by probiotics in the gut of the host challenged with pathogens. In this study, we tested probiotic characteristics in vitro and anticolonization ability of Lactobacillus paracasei FJ861111.1 in mice infected with selected pathogenic microorganisms. The in vitro results indicated that L. paracasei FJ861111.1 had a high survival in acidic conditions at pH 2.5 and bile salt concentration at 0.3%, and strong inhibition ability against common pathogens including Shigella dysenteriae, Staphylococcus aureus, Cronobacter sakazakii, Escherichia coli, and Candida albicans. The cell adhesion assays showed that L. paracasei FJ861111.1 exhibited strong adherence to HT-29 cells and excluded the adhesion of selected food-borne pathogens to HT-29 cells. The in vivo results showed that fermented milk with L. paracasei and viili (a Nordic yogurt product) significantly improved the population of total bacteria and of Lactobacillus in the feces of mice, and significantly inhibited the colonization of C. albicans to the intestines of mice post-C. albicans infection. Thus, it appears that this strain could be used as a probiotic organism for manufacturing functional fermented milk. PMID- 26254537 TI - Re: Management of Pain in Autosomal Dominant Polycystic Kidney Disease and Anatomy of Renal Innervation: M. W. Tellman, C. D. Bahler, A. M. Shumate, R. L. Bacallao and C. P. Sundaram J Urol 2015;193:1470-1478. PMID- 26254538 TI - Re: Equivocal Ureteropelvic Junction Obstruction on Diuretic Renogram--Should Minimally Invasive Pyeloplasty be Offered to Symptomatic Patients?: A. Ozayar, J. I. Friedlander, N. A. Shakir, J. C. Gahan, J. A. Cadeddu and M. S. C. Morgan J Urol 2015;193:1278-1282. PMID- 26254539 TI - Copper improves the anti-angiogenic activity of disulfiram through the EGFR/Src/VEGF pathway in gliomas. AB - Disulfiram (DSF) possesses anticancer activity by inducing apoptosis in vitro and in vivo in a copper (Cu)-dependent manner. DSF also potently inhibits angiogenesis, but the effect of Cu on this anti-angiogenic activity is unknown. Here we show that DSF inhibits the proliferation, migration, invasion, adhesion and complex tube formation of human umbilical vascular endothelial cells (HUVECs). Aortic ring assays and Matrigel plug assays revealed that DSF significantly inhibited the formation of microvessels. Importantly, Cu improved the anti-angiogenic activity of DSF in all these assays, while copper alone had no effect. DSF/Cu treatment of U87 human glioblastoma cells resulted in suppression of VEGF secretion through the EGFR/c-Src/VEGF pathway. Reduction of EGFR phosphorylation disables recruitment of multiple Src homology 2 (SH2) domains, resulting in transcriptional down-regulation of VEGF. The role of EGFR/c Src/VEGF pathway was further confirmed by using specific inhibitor, which significantly improved the anti-angiogenic activity of DSF/Cu. DSF/Cu also exerted increased anti-tumor effects on subcutaneous and intracerebral U87 xenograft models by reducing microvessel density (MVD) and VEGF expression. These results indicate that Cu improves the anti-angiogenic activity of DSF by targeting the EGFR/Src/VEGF signaling pathway, thus providing a rationale for the use of DSF/Cu rather than DSF alone as an angiogenesis inhibitor in clinical applications. PMID- 26254540 TI - Xc- inhibitor sulfasalazine sensitizes colorectal cancer to cisplatin by a GSH dependent mechanism. AB - Sulfasalazine (SSZ) is an anti-inflammatory drug that has been demonstrated to induce apoptosis and tumor regression through inhibition of plasma membrane cystine transporter xc(-). Cysteine is a rate-limiting precursor for intracellular glutathione (GSH) synthesis, which is vital for compound detoxification and maintaining redox balance. Platinum-based chemotherapy is an important regimen used in clinics for various cancers including colorectal cancer (CRC). We hypothesized that targeting xc(-) transporter by SSZ may annihilate cellular detoxification through interruption of GSH synthesis and may enhance the anti-cancer activity of cisplatin (CDDP) by increasing drug transport. In the present study, we revealed that xCT, the active subunit of xc(-), is highly expressed in CRC cell lines and human colorectal carcinoma tissues compared with their normal counterparts. SSZ effectively depleted cellular GSH, leading to significant accumulation of reactive oxygen species and growth inhibition in CRC cells. In contrast, the normal epithelial cells of colon origin were less sensitive to SSZ, showing a moderate ROS elevation. Importantly, SSZ effectively enhanced the intracellular platinum level and cytotoxicity of CDDP in CRC cells. The synergistic effect of SSZ and CDDP was reversed by antioxidant N-acetyl-L cysteine (NAC). Together, these results suggest that SSZ, a relatively non-toxic drug that targets cystine transporter, may, in combination with CDDP, have effective therapy for colorectal cancer. PMID- 26254541 TI - Volume and shape analysis of subcortical brain structures and ventricles in euthymic bipolar I disorder. AB - Previous structural magnetic resonance imaging (S-MRI) studies of bipolar disorder have reported variable morphological changes in subcortical brain structures and ventricles. This study aimed to establish trait-related subcortical volumetric and shape abnormalities in a large, homogeneous sample of prospectively confirmed euthymic bipolar I disorder (BD-I) patients (n=60), compared with healthy volunteers (n=60). Participants were individually matched for age and gender. Volume and shape metrics were derived from manually segmented S-MR images for the hippocampus, amygdala, caudate nucleus, and lateral ventricles. Group differences were analysed, controlling for age, gender and intracranial volume. BD-I patients displayed significantly smaller left hippocampal volumes and significantly larger left lateral ventricle volumes compared with controls. Shape analysis revealed an area of contraction in the anterior head and medial border of the left hippocampus, as well as expansion in the right hippocampal tail medially, in patients compared with controls. There were no significant associations between volume or shape variation and lithium status or duration of use. A reduction in the head of the left hippocampus in BD I patients is interesting, given this region's link to verbal memory. Shape analysis of lateral ventricular changes in patients indicated that these are not regionally specific. PMID- 26254542 TI - Dissociation in borderline personality disorder: Disturbed cognitive and emotional inhibition and its neural correlates. AB - Evidence is heterogeneous regarding whether patients with borderline personality disorder (BPD) display disturbed emotional inhibition in the emotional Stroop task. Previous findings suggest that state dissociation may influence cognitive inhibition of task-irrelevant material, particularly with negative content. Our aim was to examine performance in an emotional Stroop task including negative, neutral, and positive words in BPD patients and healthy controls during functional magnetic resonance imaging. In advance, half of the BPD patients underwent a dissociation induction using script-driven imagery. BPD patients without dissociation induction showed behavioural performance comparable to that of healthy controls but displayed stronger neural responses, especially to positive stimuli, in the superior temporal gyrus, dorsomedial prefrontal cortex, and anterior cingulate cortex. BPD patients with dissociation induction showed overall slower and less accurate responses as well as increased reaction times for negative versus neutral words compared with BPD patients without dissociation induction. Moreover, they showed comparatively decreased neuronal activity in the fusiform gyrus and parietal cortices independent of valence, but elevated activity in the left inferior frontal gyrus in response to negative versus neutral words. In conclusion, experimentally induced dissociation in BPD was associated with inefficient cognitive inhibition, particularly of negative stimuli, in the emotional Stroop task. PMID- 26254543 TI - Case Comparisons: An Efficient Way of Learning Radiology. AB - RATIONALE AND OBJECTIVES: Radiologists commonly use comparison films to improve their differential diagnosis. Educational literature suggests that this technique might also be used to bolster the process of learning to interpret radiographs. We investigated the effectiveness of three comparison techniques in medical students, whom we invited to compare cases of the same disease (same-disease comparison), cases of different diseases (different-disease comparison), disease images with normal images (disease/normal comparison), and identical images (no comparison/control condition). Furthermore, we used eye-tracking technology to investigate which elements of the two cases were compared by the students. MATERIALS AND METHODS: We randomly assigned 84 medical students to one of four conditions and had them study different diseases on chest radiographs, while their eye movements were being measured. Thereafter, participants took two tests that measured diagnostic performance and their ability to locate diseases, respectively. RESULTS: Students studied most efficiently in the same-disease and different-disease comparison conditions: test 1, F(3, 68) = 3.31, P = .025, etap(2) = 0.128; test 2, F(3, 65) = 2.88, P = .043, etap(2) = 0.117. We found that comparisons were effected in 91% of all trials (except for the control condition). Comparisons between normal anatomy were particularly common (45.8%) in all conditions. CONCLUSIONS: Comparing cases can be an efficient way of learning to interpret radiographs, especially when the comparison technique used is specifically tailored to the learning goal. Eye tracking provided insight into the comparison process, by showing that few comparisons were made between abnormalities, for example. PMID- 26254544 TI - Utility of Interobserver Agreement Statistics in Establishing Radiology Resident Learning Curves During Self-directed Radiologic Anatomy Training. AB - RATIONALE AND OBJECTIVES: The aim of the study was to ascertain the learning curves for the radiology residents when first introduced to an anatomic structure in magnetic resonance images (MRI) to which they have not been previously exposed to. MATERIALS AND METHODS: The iliolumbar ligament is a good marker for testing learning curves of radiology residents because the ligament is not part of a routine lumbar MRI reporting and has high variability in detection. Four radiologists, three residents without previous training and one mentor, studied standard axial T1- and T2-weighted images of routine lumbar MRI examinations. Radiologists had to define iliolumbar ligament while blinded to each other's findings. Interobserver agreement analyses, namely Cohen and Fleiss kappa statistics, were performed for groups of 20 cases to evaluate the self-learning curve of radiology residents. RESULTS: Mean kappa values of resident-mentor pairs were 0.431, 0.608, 0.604, 0.826, and 0.963 in the analysis of successive groups (P < .001). The results indicate that the concordance between the experienced and inexperienced radiologists started as weak (kappa <0.5) and gradually became very acceptable (kappa >0.8). Therefore, a junior radiology resident can obtain enough experience in identifying a rather ambiguous anatomic structure in routine MRI after a brief instruction of a few minutes by a mentor and studying approximately 80 cases by oneself. CONCLUSIONS: Implementing this methodology will help radiology educators obtain more concrete ideas on the optimal time and effort required for supported self-directed visual learning processes in resident education. PMID- 26254545 TI - Regarding: "Repeated carotid endarterectomy versus carotid artery stenting for patients with carotid restenosis after carotid endarterectomy: Systematic review and meta-analysis". PMID- 26254546 TI - Accuracy of Turbidimetric Limulus Amebocyte Lysate Assay for the Recovery of Endotoxin Interacted with Commonly Used Antimicrobial Agents of Endodontic Therapy. AB - INTRODUCTION: This study was conducted to investigate whether the interaction between the turbidimetric limulus amebocyte lysate (LAL) substrate for endotoxin measurement and the substances/antimicrobial agents used in endodontic therapy can lead to the inhibition/enhancement of endotoxin recovery. METHODS: Ten microliters of a suspension of Escherichia coli endotoxin (O55:B55) was inoculated and kept in contact for 1 hour with different substances categorized as follows: group 1: auxiliary chemical substances: 5.25% and 2.5% sodium hypochlorite solutions, 2% chlorhexidine (CHX) (gel and solution), 1% Natrosol gel (Drogal Chemicals and Pharmaceuticals Ltd, Piracicaba, SP, Brazil), 17% EDTA, 10% citric acid, 3% hydrogen peroxide, 5% sodium thiosulfate, and 0.5% Tween 80 associated with 0.07% soy lecithin (Drogal Chemicals and Pharmaceuticals Ltd) and group 2: intracanal medications: neomycin/polymyxin B/hydrocortisone (Otosporin; Glaxo Wellcome, Rio de Janeiro, RJ, Brazil); calcium hydroxide (Ca[OH]2); Ca(OH)2 + 2% CHX gel; Ca(OH)2 + 2% CHX gel + zinc oxide eugenol; Ca(OH)2 + camphorated paramonochlorophenol (Calen; S.S. White, Rio de Janeiro, RJ, Brazil); triple antibiotic paste; mineral trioxide aggregate (MTA); and iodoform. Positive and negative controls consisted of root canal hemorrhagic exudate and pyrogen-free sterile water, respectively. All samples were diluted up to a 10:4 dilution. Each dilution was individually examined by the turbidimetric LAL assay. Collected data were analyzed through performance characteristics of the LAL assay such as linearity, coefficient of variation percentage, and product positive control (PPC) values. RESULTS: Correlation coefficient (>=0.980) and coefficient of variation percentage (<10%) of the standard curve in triplicate showed the tests' linearity. Spike recovery of auxiliary chemical substances achieved PPC values ranging from 50%-197%, showing no interferences with LAL substrate. Conversely, 3% hydrogen peroxide achieved product inhibition in which endotoxin values were underestimated even after the 10:4 dilutions. Regarding intracanal medicaments, neomycin/polymyxin B/hydrocortisone also inhibited endotoxin detection in all dilutions investigated (PPC values <50%). In contrast, Ca(OH)2 + 2% CHX gel + ZOE as well as triple antibiotic paste led to the enhancement of endotoxin detection in which endotoxin values could not be validated by the turbidimetric kinetic LAL assay (PPC value >200%). CONCLUSIONS: The performance characteristics of the kinetic turbidimetric assay for endotoxin measurement, such as precision and reproducibility, are modulated by the interaction of the LAL substrate with the substances/antimicrobial agents used in endodontic therapy. PMID- 26254547 TI - Suspected rabid bites and postexposure rabies prophylaxis. PMID- 26254548 TI - Predictive factors for induction of remission in patients with active rheumatoid arthritis treated with tocilizumab in clinical practice. AB - OBJECTIVE: To identify predictors of early response to tocilizumab (TCZ) in patients with active rheumatoid arthritis (RA) seen in daily routine clinical practice. METHODS: A multicenter ambispective observational study of 126 RA patients treated with TCZ as a first- or second-line biological therapy. The variables associated to achieve the therapeutic goal (remission defined as a DAS28-ESR < 2.6) at 3 and 6 months were identified using regression analysis. RESULTS: TCZ was administered as the first biologic in 26% of patients. Overall, 34% of patients received TCZ as monotherapy. EULAR response and remission were obtained in 82% and 31% of patients at 3 months and in 86% and 40% at 6 months. In the multivariate analysis, the predictive factors increasing the likelihood of clinical remission at 3 months were baseline ESR > 30 mm/h (OR = 19.07, 95% CI: 2.720-133.716), baseline CRP > 10 mg/L (OR = 4.95; 95% CI: 1.464-13.826), and the presence of extra-articular manifestations of the disease (OR = 15.45, 95% CI: 2.334-102.319). The factors that decreased it were higher concentrations of hemoglobin (OR = 0.53, 95% CI: 0.319-0.910), higher baseline DAS28-ESR (OR = 0.30, 95% CI: 0.145-0.635) and the number of previous DMARDs (OR = 0.41, 95% CI: 0.221-0.779), and biological therapies used (OR = 0.33, 95% CI: 0.155-0.734). The only factor that remained statistically significant at 6 months was higher baseline DAS28-ESR (OR = 0.55, 95% CI: 0.347-0.877). No relationship was found with the neutrophil count or with the RF or ACPA positivity. CONCLUSION: In routine clinical practice, strong acute phase response, the presence of extra articular manifestations, and the number of previous DMARDs and biological therapies used may help to identify patients who will have a rapid response to TCZ. However, it is likely that no parameter will predict response if taken separately. PMID- 26254549 TI - Transforming growth factor-beta1 acts via TbetaR-I on microglia to protect against MPP(+)-induced dopaminergic neuronal loss. AB - Neuroinflammation is associated with pathogenesis of Parkinson's disease (PD), a neurodegenerative disorder characterized by a progressive loss of dopaminergic (DAergic) neurons within the substantia nigra. Transforming growth factor (TGF) beta1 exerts anti-inflammatory and neuroprotective properties. However, it is unclear if microglia are required for TGF-beta1 neuroprotection in PD. Here we used both shRNA and pharmacologic inhibition to determine the role of microglial TGF-beta receptor (TbetaR)-I and its downstream signaling pathways in 1-methyl-4 phenylpyridinium (MPP(+))-induced DAergic neuronal toxicity. As expected, MPP(+) reduced the number of tyrosine hydroxylase (TH)-immunoreactive cells in ventral mesencephalic cell cultures. We found that MPP(+) activated microglia as determined by an upregulation in expression of CD11b and inducible nitric oxide synthase (iNOS), an increase in expression and secretion of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, and a decrease in expression and secretion of the neurotrophic factor, insulin-like growth factor (IGF)-1. Pretreatment with TGF-beta1 significantly inhibited all these changes caused by MPP(+). Expression of microglial TbetaR-I was upregulated by TGF-beta1. Silencing of the TbetaR-I gene in microglia abolished both the neuroprotective and anti inflammatory properties of TGF-beta1. TGF-beta1 increased microglial p38 MAPK and Akt phosphorylation, both of which were blocked by the p38 inhibitor SB203580 and the PI3K inhibitor LY294002, respectively. Pretreatment of microglia with either SB203580 or LY294002 impaired the ability of TGF-beta1 to inhibit MPP(+)-induced DAergic neuronal loss and microglial activation. These findings establish that TGF-beta1 activates TbetaR-I and its downstream p38 MAPK and PI3K-Akt signaling pathways in microglia to protect against DAergic neuronal loss that characterizes in PD. PMID- 26254550 TI - An Update on Hidradenitis Suppurativa (Part I): Epidemiology, Clinical Aspects, and Definition of Disease Severity. AB - Hidradenitis suppurativa is a chronic inflammatory disorder that has attracted increasing attention in recent years due to underestimations of prevalence and the considerable impact of the condition on interpersonal relationships, physical appearance, self-esteem, and body image. Although hidradenitis suppurative has a significant psychological impact on patients and can even cause physical limitations when thick scarring results in limb mobility limitation, until very recently little evidence was available relating to its epidemiology, etiology, or pathogenesis. In this review, we highlight the latest advances in our understanding of the epidemiological and clinical aspects of hidradenitis suppurativa. We will also look at the different classification systems for hidradenitis suppurativa and discuss the emergence of skin ultrasound as a promising technique for monitoring the course of this chronic inflammatory disease. PMID- 26254551 TI - Another country, another language and a new baby: A quantitative study of the postnatal experiences of migrant women in Australia. AB - BACKGROUND: Governments and service providers have consistently acknowledged the importance of support for women and families in the transition to parenthood. Lower levels of satisfaction and concern about postnatal depression have highlighted women's needs at this time. Migrant women may also face relocation, distant family and support networks, language barriers and potentially discriminatory or culturally insensitive care. OBJECTIVE: The present study evaluates the unique contribution of migrant status, comparing the experience of this group to that of native-born English-speaking women. METHOD: Secondary analysis of data from a population-based survey of maternity care in Queensland. Experiences of 233 women born outside Australia who spoke another language at home were compared to 2722 Australian-born English-speaking women with adjustment for demographic differences. RESULTS: After adjustment, differences between the groups included physical, psychological aspects and perceptions of care. Women born outside Australia were less likely to report pain after birth was manageable, or rate overall postnatal physical health positively. They more frequently reported having painful stitches, distressing flashbacks and feeling depressed in the postnatal period. Few differences in ratings of care providers were found, however, women born outside Australia were less likely to feel involved in decisions and to understand their options for care. However, they were more likely to report being visited by a care provider at home after birth. CONCLUSIONS: The findings represent an important addition to existing qualitative reports of the experiences of migrant women, reflecting poorer postnatal health, issues associated with migration and parenthood and highlighting areas for care improvement. PMID- 26254552 TI - Modifying angiographic syntax score according to PCI strategy: lessons learnt from ERACI IV Study. AB - In recent years an angiographic score was introduced in clinical practice to stratified different levels of risk after percutaneous coronary interventions (PCI) with drug eluting stents. The SYNTAX score (SS) classified patients in three different risk levels and was included in revascularization guidelines that patients allocated with low SS could be equally treated with either PCI or CABG, whereas those with intermediate or high SS were better off with CABG. However, using original SS each coronary lesion with a diameter stenosis >=50% in vessels >=1.5 mm was scored. In ERACI IV registry we used a revascularization strategy during PCI where operators were advised to only treat lesions>=than 70% in a>=2.0 mm reference vessel; therefore, no intermediate lesions should be treated, and severe stenosis in vessels<2.0 mm was discouraged as well. If we recalculated SS using the above-mentioned operators' advices all intermediate lesions were not scored, and severe stenosis in vessels<2.0 mm were excluded for the analysis, including bifurcations, trifurcations and chronic total occlusions; after this new scoring, the original SS dropped significantly which is in accordance with the goal of complete functional revascularization strategy of the ERACI IV study and the low one year adverse events of such study. In conclusion, if we performed an SS scoring, only severe stenosis in vessels with a reference diameter >=2.0 mm would allow a more rational assessment of coronary anatomy, and the use of a more conservative PCI strategy. PMID- 26254553 TI - Ultrastructural analysis of olfactory ensheathing cells derived from olfactory bulb and nerve of neonatal and juvenile rats. AB - Olfactory nerve derived and olfactory bulb derived olfactory ensheathing cells (OECs) have the ability to promote axonal regeneration and remyelination, both of which are essential in a successful cell transplant. Thus, morphological identification of OECs is a key aspect to develop an applicable cell therapy for injuries to the nervous system. However, there is no clear definition regarding which developmental stage or anatomical origin of OECs is more adequate for neural repair. In the present study, an ultrastructural comparison was made between OECs recovered from primary cultures of olfactory nerve and bulb in two developmental stages. The most notorious difference between cells obtained from olfactory nerve and bulb was the presence of indented nuclei in bulb derived OECs, suggesting a greater ability for possible chemotaxis. In neonatal OECs abundant mitochondria, lipid vacuoles, and smooth endoplasmic reticulum were detected, suggesting an active lipid metabolism, probably involved in synthesis of myelin. Our results suggest that neonatal OECs obtained from olfactory bulb have microscopic properties that could make them more suitable for neural repair. PMID- 26254554 TI - Deaths of older children: what do the data tell us? PMID- 26254555 TI - Mortality risks in children aged 5-14 years in low-income and middle-income countries: a systematic empirical analysis. AB - BACKGROUND: Health priorities since the UN Millennium Declaration have focused strongly on children younger than 5 years. The health of older children (age 5-9 years) and younger adolescents (age 10-14 years) has been neglected until recently, especially in low-income and middle-income countries, and mortality measures for these age groups have often been derived from overly flexible models. We report global and regional empirical mortality estimates for children aged 5-14 years in low-income and middle-income countries, and compare them with ones from existing models. METHODS: For this empirical analysis, we obtained birth-history data from surveys done over a 25-year period from 1986 by the Demographic and Health Surveys programme for 84 World Bank low-income and middle income countries, and data about household deaths in China from their 1990 and 2010 censuses. We used these data to calculate mortality risks for children aged 5-14 years, and compare these risks to corresponding estimates of mortality in children younger than 5 years in the same countries. We used regression analysis to model these associations, generate estimates of the risks, and derive estimates of the numbers of deaths for 1990 and 2010 by applying those risks to population estimates from the UN World Population Prospects (WPP) 2012 Revision. We then compared the numbers of deaths with those given by the UN WPP itself and by the Institute for Health Metrics and Evaluation's Global Burden of Disease (GBD) 2010 study. FINDINGS: The mean risk of a child dying at age 5-14 years in low-income and middle-income countries is about 19% of the risk of dying between birth and age 5 years (12% at age 5-9 plus 7% at age 10-14). According to our estimates, the total number of deaths at ages 5-14 years in low-income and middle income regions fell from about 2.4 million (95% CI 1.9-2.7) in 1990 to about 1.5 million (1.2-1.8) in 2010. From our estimates we concluded there to have been 200,000 (16%) more deaths at ages 5-14 than in the UN report; however, our estimates exceeded GBD estimates by more than 700,000 (87%). The average annual rate of decline in mortality at age 5-9 years (about 3%) slightly exceeded that for ages 0-4 years (2.8%), but progress has been slower for age 10-14 years (about 2%). INTERPRETATION: Our analysis suggests that mortality risks nowadays in the age range 5-14 years in low-income and middle-income countries are rather higher (relative to mortality in children younger than 5 years) than would be expected on the basis of historical evidence. Our findings broadly lend support for the UN WPP mortality estimates, but are almost double those underpinning GBD 2010. Global policy emphasis on reduction of mortality in children younger than 5 years should be broadened to include older children and adolescents. FUNDING: The Lancet Commission on Investing in Health and the Bill & Melinda Gates Foundation. PMID- 26254556 TI - The Trochanteric Localization is a Mediator of Slower Short-Term Functional Recovery in Overweight and Obese Elderly Women with Recent Hip Fracture: The BREAK Study. AB - The hypothesis tested in this study, carried out on elderly Italian women with recent hip fracture, was to assess the extent to which the effect of a condition of being overweight/obese on short-term functional recovery as evaluated by the "time to permitted load" could be explained by a mediator variable (type of hip fracture). We studied 727 women aged 60 years or over with a recent low trauma surgically treated hip fracture and for whom an information on post-surgery complications and on the time to permitted load was available. To assess for mediation, the statistical analyses were carried out following the procedure described by Baron and Kenny. In this study, 46 % of women with hip fracture presented a time to permitted load of >= 10 days. The women with a post-surgery time to permitted load of >= 10 days showed a significantly higher proportion of trochanteric fracture localization (72.1 vs 42 %), of total overweight/obesity (46.5 vs 36.8 %) and of post-surgery complications (38.8 vs 18.8 %). The mediating effect of hip fracture localization on the association between overweight/obesity and the time of permitted load was demonstrated and confirmed in a multivariate logistic regression model. This study, carried out using a "mediator" statistical analysis, suggests that in elderly women with hip fracture being overweight/obese is associated with a slower short-term functional recovery as evaluated by the time to permitted load and that this association is mediated by the trochanteric localization of hip fracture. PMID- 26254557 TI - Sibling relationships as sources of risk and resilience in the development and maintenance of internalizing and externalizing problems during childhood and adolescence. AB - Sibling relationships are a unique and powerful context for children's development, characterized by strong positive features, such as warmth and intimacy, as well as negative qualities like intense, potentially destructive conflict. For these reasons, sibling interactions may be both a risk and a protective factor for the development and maintenance of emotional and behavioral dysfunction. We review evidence indicating that sibling interactions are linked to internalizing and externalizing symptoms and identify possible mechanisms for these associations. Sibling conflict contributes uniquely to symptomatology and may be particularly problematic when accompanied by lack of warmth, which is generally associated with decreased internalizing and externalizing problems. On the other hand, greater warmth can be associated with heightened externalizing symptoms for later-born children who may model the behavior of older siblings. Although it will be important to monitor for increased sibling collusion, several intervention studies demonstrate that it is possible to reduce conflict and increase warmth between brothers and sisters, and that improving sibling interactions can teach children social-cognitive skills that are beneficial in other relationships (e.g., friendships). Developing brief assessment tools differentiating normative from pathogenic sibling conflict would assist clinical decision making. Future intervention work could provide a more stringent test of the hypothesis that strengthening sibling relationships improves children's socio emotional adjustment. PMID- 26254558 TI - Body weight status and onset of functional limitations in U.S. middle-aged and older adults: The role of overweight status. PMID- 26254559 TI - Possible role of TLR4 and TLR9 SNPs in protection against congenital toxoplasmosis. AB - The purpose of this investigation was the determination of the distribution of genotypes at single nucleotide polymorphisms (SNPs) of the toll-like receptor 4 (TLR4) and the toll-like receptor 9 (TLR9) in fetuses and newborns congenitally infected with Toxoplasma gondii and the identification of genetic changes predisposing to infection development. The study involved 20 fetuses and newborns with congenital toxoplasmosis and 50 uninfected controls. The levels of IgG and IgM antibodies against T. gondii, as well as IgG avidity, were estimated by enzyme-linked fluorescent assay (ELFA) tests. T. gondii DNA loads in amniotic fluids were assayed by the real-time (RT) quantitative polymerase chain reaction (Q PCR) technique for parasitic B1 gene. TLR4 and TLR9 SNPs were identified using a self-designed multiplex nested PCR-restriction fragment length polymorphism (RFLP) assay. Randomly selected genotypes at SNPs were confirmed by sequencing. All the genotypes were tested for Hardy-Weinberg equilibrium and TLR4 genotypes were analyzed for linkage disequilibrium. A correlation was studied between the genotypes or haplotypes and the development of congenital toxoplasmosis using a logistic regression model. Single SNP analysis showed no statistically significant differences in the distribution of distinct genotypes at the analyzed TLR4 and TLR9 SNPs between T. gondii-infected fetuses and newborns and the controls. Taking into account the prevalence of alleles residing within polymorphic sites, similar prevalence rates were observed in both of the studied groups. The multiple SNP analysis indicated GTG variants at the TLR4 and TLR9 SNPs to be significantly less frequent in offspring with congenital toxoplasmosis than in uninfected offspring (p <= 0.0001). TLR4 and TLR9 SNPs seem to be involved in protection against congenital toxoplasmosis. PMID- 26254560 TI - Longitudinal evaluation of hepatitis C viral persistence in HIV-infected patients with spontaneous hepatitis C clearance. AB - Hepatitis C virus (HCV) viral persistence in patients with spontaneous viral clearance is controversial. Several studies have shown HCV-RNA in peripheral blood mononuclear cells (PBMCs) and/or liver tissue among patients who have cleared the virus spontaneously, suggesting that viral persistence is a common situation that could involve the entire population studied. Thus, our aim was to evaluate HCV-RNA persistence in PBMCs and hepatocytes in subjects infected with the human immunodeficiency virus (HIV). A total of 1508 patients were prospectively followed and tested for anti-HCV antibodies and HCV-RNA to identify the patients who achieved spontaneous viral clearance. In all of the patients, the persistence of HCV-RNA in PBMCs was evaluated longitudinally during 2 years of follow-up. Fifty-nine patients fulfilled the inclusion/exclusion criteria and were included in the study. HCV-RNA was not detected in the PBMCs at baseline [59 PBMCs samples tested; 0 %; 95 % confidence interval (CI): 0-3.3 %] or during the follow-up (147 PBMCs samples tested; 0 %; 95 % CI: 0-2.02 %). Our study shows that HCV viral persistence is not a frequent occurrence in HIV-infected patients who have spontaneously resolved an HCV infection. Thus, the lack of serum HCV-RNA should continue to be addressed as the standard of healing. PMID- 26254561 TI - Pre-transplant donor-specific Interferon-gamma-producing cells and acute rejection of the kidney allograft. AB - BACKGROUND: Our retrospective study included a cohort of 47 patients who underwent living donor kidney transplantation.The pre-transplant frequencies of donor-specific Interferon-gamma (IFN-gamma) producing cells were define dusing enzyme-linked immunosorbent spot (ELISpot) assay and correlated with incidence of acute cellular(ACR), antibody-mediated rejection (AMR) and kidney graft survival up to one year after transplantation. RESULTS: We found a statistically significant correlation between the frequencies of IFN-gamma-producing cells and the number of mismatches in HLA antigens between patients and their respective donors - for Class I - A and B (r = 0.399, p b 0.01) and for Class I and Class II antigens - A, B and DR (r = 0.409, p b 0.01). No significant relationship was observed between the numbers of IFN-gamma-secreting cells and incidence of acute rejection (neither ACR, nor AMR). However, there was a trend of elevated frequencies of IFN-gamma-producing cells in patients who developed ACR or AMR in comparison with kidney recipients free of rejection (91 +/- 82 and 114 +/- 75 vs. 72 +/- 70/5 * 10(4) peripheral blood mononuclear cells respectively). Patients with concurrent acute cellular and antibody-mediated rejection had also higher numbers of IFN-gamma-producing memory/effector cells compared to patients with cellular rejection only. CONCLUSION: Pre-transplant determination of the numbers of IFN-gamma-producing donor-specific memory cells using the ELISpot technique may provide clinically relevant results when evaluating the risk of development of acute cellular and antibody-mediated rejection. These frequencies are influenced by the degree of HLA mismatching between patients and their respective kidney donors. PMID- 26254563 TI - Geographic variation in the elicitin-like glycoprotein, ELI025, of Pythium insidiosum isolated from human and animal subjects. AB - Oomycetes are fungus-like in appearance, but form a distinct clade within the eukaryotes. While most pathogenic oomycetes infect plants, the understudied oomycete Pythium insidiosum infects humans and animals, and causes a life threatening infectious disease, called pythiosis. Phylogenetic analyses divide P. insidiosum into 3 groups, according to geographic origins: Clade-I (Americas), Clade-II (Asia and Australia), and Clade-III (Thailand). Surgical removal of the infected organ is the inevitable treatment for patients with pythiosis, but it is often too late or unsuccessful, and many patients die from advanced infection. Understanding P. insidiosum's basic biology could lead to improved infection control. Elicitins, a unique group of proteins found only in oomycetes, are involved in sterol acquisition and stimulation of host responses. Recently, we identified glycosylated and non-glycosylated forms of the elicitin-like protein, ELI025, which is secreted by P. insidiosum, and detected during P. insidiosum infection. In this study, we investigated geographic variation of ELI025 in 24 P. insidiosum strains isolated from humans, animals, and the environment. Genotypes of ELI025, based on 2 sets of PCR primers, correlated well with rDNA-based phylogenetic grouping. Unlike strains in Clade-I and -II, Clade-III strains secreted no glycosylated ELI025. Sera from 17 pythiosis patients yielded a broad range of antibody responses against ELI025, and ~30% lacked reactivity against the protein. Selective production or secretion of glycosylated ELI025 by different P. insidiosum strains might contribute to the variable host antibody responses. In conclusion, ELI025 was secreted by all P. insidiosum strains isolated from different hosts and geographic origins, but the protein had different biochemical, and immunological characteristics. These finding contribute to the better understanding of the biology and evolution of P. insidiosum, and could lead to appropriate clinical application of the ELI025 protein for diagnosis or treatment of pythiosis. PMID- 26254562 TI - Evaluation of the fate of arsenic-contaminated groundwater at different aquifers of Thar coalfield Pakistan. AB - In present study, the ground water at different aquifers was evaluated for physicochemical parameters, iron, total arsenic, total inorganic arsenic and arsenic species (arsenite and arsenate). The samples of groundwater were collected at different depths, first aquifer (AQ1) 50-60 m, second aquifer (AQ2) 100-120 m, and third aquifer (AQ3) 200-250 m of Thar coalfield, Pakistan. Total inorganic arsenic was determined by solid phase extraction using titanium dioxide as an adsorbent. The arsenite was determined by cloud point extraction using ammonium pyrrolidinedithiocarbamate as a chelating reagent, and resulted complex was extracted by Triton X-114. The resulted data of groundwater were reported in terms of basic statistical parameters, principal component, and cluster analysis. The resulted data indicated that physicochemical parameters of groundwater of different aquifers were exceeded the World Health Organization provisional guideline for drinking water except pH and SO4(2-). The positive correlation was observed between arsenic species and physicochemical parameters of groundwater except F(-) and K(+), which might be caused by geochemical minerals. Results of cluster analysis indicated that groundwater samples of AQ1 was highly contaminated with arsenic species as compared to AQ2 and AQ3 (p > 0.05). PMID- 26254564 TI - Lumbar pedicle lesion causing radicular pain. PMID- 26254565 TI - Validation of the Spine Oncology Study Group-Outcomes Questionnaire to assess quality of life in patients with metastatic spine disease. AB - BACKGROUND CONTEXT: General questionnaires are often used to assess quality of life in patients with spine metastases, although a disease-specific survey did not exist until recently. The Spine Oncology Study Group has developed an outcomes questionnaire (SOSG-OQ) to measure quality of life in these patients. However, a scoring system was not developed, and the questionnaire was not validated in a group of patients, nor was it compared with other general quality of life questionnaires such as the EuroQol 5 Dimensions (EQ-5D) questionnaire. PURPOSE: Our primary null hypothesis is that there is no association between the SOSG-OQ and EQ-5D. Our secondary null hypothesis is that there is no difference in coverage and internal consistency between the SOSG-OQ and EQ-5D. We also assess coverage, consistency, and validity of the domains within the SOSG-OQ. STUDY DESIGN/SETTING: A survey study from a tertiary care spine referral center was used for this study. PATIENT SAMPLE: The patient sample consisted of 82 patients with spine metastases, myeloma, or lymphoma. OUTCOME MEASURES: The SOSG OQ (27 questions, 6 domains) score ranges from 0 to 80, with a higher score indicating worse quality of life. The EQ-5D (5 questions, 5 domains) index score ranges from 0 to 1, with a higher score indicating better quality of life. METHODS: The association between the SOSG-OQ and EQ-5D index score was assessed using the Spearman rank correlation. Instrument coverage and precision were assessed by determining item completion rate, median score with range, and floor and ceiling effect. Internal consistency was assessed using Cronbach alpha. Multitrait analysis and exploratory factor analysis were used to analyze properties of the individual domains in the SOSG-OQ. RESULTS: The Spearman rank correlation between the SOSG-OQ and EQ-5D questionnaire was high (r=-0.83, p<.001). Internal consistency of the SOSG-OQ (0.92, 95% CI: 0.89-0.94) was higher as compared to the internal consistency of the EQ-5D (0.73, 95% CI: 0.63-0.84; p<.001). The SOSG-OQ score had no floor or ceiling effect indicating good coverage (median 30, range 3-64), whereas the EQ-5D had a ceiling effect of 10% (median 0.71, range 0.05-1). CONCLUSIONS: In conclusion, our study proposes a scoring methodology-after reversing four inversely scored items-for the SOSG-OQ and shows that the questionnaire is a valid tool for the assessment of quality of life in patients with metastatic spine disease. The SOSG-OQ is superior to the EQ 5D in terms of coverage and internal consistency but consists of more questions. PMID- 26254566 TI - Massive lumbar pneumorrhachis after severe cranial trauma. PMID- 26254567 TI - Concurrent multiple primary spinal neoplasms of distinct origin. PMID- 26254568 TI - Congenital scoliosis caused by hemi-sacrum. PMID- 26254569 TI - Endometrial cancer metastasis mimicking spondylodiscitis and psoas abscess. PMID- 26254570 TI - Influence of Internal DNA Pressure on Stability and Infectivity of Phage lambda. AB - Viruses must remain infectious while in harsh extracellular environments. An important aspect of viral particle stability for double-stranded DNA viruses is the energetically unfavorable state of the tightly confined DNA chain within the virus capsid creating pressures of tens of atmospheres. Here, we study the influence of internal genome pressure on the thermal stability of viral particles. Using differential scanning calorimetry to monitor genome loss upon heating, we find that internal pressure destabilizes the virion, resulting in a smaller activation energy barrier to trigger DNA release. These experiments are complemented by plaque assay and electron microscopy measurements to determine the influence of intra-capsid DNA pressure on the rates of viral infectivity loss. At higher temperatures (65-75 degrees C), failure to retain the packaged genome is the dominant mechanism of viral inactivation. Conversely, at lower temperatures (40-55 degrees C), a separate inactivation mechanism dominates, which results in non-infectious particles that still retain their packaged DNA. Most significantly, both mechanisms of infectivity loss are directly influenced by internal DNA pressure, with higher pressure resulting in a more rapid rate of inactivation at all temperatures. PMID- 26254571 TI - How Myxobacteria Cooperate. AB - Prokaryotes often reside in groups where a high degree of relatedness has allowed the evolution of cooperative behaviors. However, very few bacteria or archaea have made the successful transition from unicellular to obligate multicellular life. A notable exception is the myxobacteria, in which cells cooperate to perform group functions highlighted by fruiting body development, an obligate multicellular function. Like all multicellular organisms, myxobacteria face challenges in how to organize and maintain multicellularity. These challenges include maintaining population homeostasis, carrying out tissue repair and regulating the behavior of non-cooperators. Here, we describe the major cooperative behaviors that myxobacteria use: motility, predation and development. In addition, this review emphasizes recent discoveries in the social behavior of outer membrane exchange, wherein kin share outer membrane contents. Finally, we review evidence that outer membrane exchange may be involved in regulating population homeostasis, thus serving as a social tool for myxobacteria to make the cyclic transitions from unicellular to multicellular states. PMID- 26254572 TI - The investigation and management of suspected malignant pathological fractures: a review for the general orthopaedic surgeon. AB - The management of malignant pathological fractures necessitates careful diagnostic work-up, pre-operative investigation, planning and multidisciplinary input from specialists in the fields of radiology, pathology, oncology, trauma and orthopaedics. Malignant and non-malignant conditions including metabolic disorders, benign tumours and pharmacological therapies can be implicated. The majority of patients who present with suspected pathological fractures will be managed by general orthopaedic and trauma surgeons rather than specialists in orthopaedic oncology. Skeletal metastases can result in considerable morbidity and predispose to pathological fractures. With advances in the medical management of malignancy, life expectancy in cancer patients is increasing, leading to an increasing risk of skeletal metastasis and the potential for pathological fractures. Conventional modes of trauma fixation for pathological fractures may not be appropriate. The aim of this review is to outline diagnostic and management strategies for patients who present with a long bone fracture that is potentially pathological in nature. PMID- 26254573 TI - Bicycle helmets are highly protective against traumatic brain injury within a dense urban setting. AB - BACKGROUND: New York City (NYC) has made significant roadway infrastructure improvements, initiated a bicycle share program, and enacted Vision Zero, an action plan to reduce traffic deaths and serious injuries. The objective of this study was to examine whether bicycle helmets offer a protective advantage against traumatic brain injury (TBI) within a contemporary dense urban setting with a commitment to road safety. METHODS: A prospective observational study of injured bicyclists presenting to a Level I trauma centre was performed. All bicyclists arriving within 24 h of injury were included. Data were collected between February, 2012 and August, 2014 and included demographics, imaging studies (e.g. computed tomography (CT)), injury patterns, and outcomes including Glasgow Coma Scale (GCS) and Injury Severity Score. RESULTS: Of 699 patients, 273 (39.1%) were wearing helmets at the time of injury. Helmeted bicyclists were more likely to have a GCS of 15 (96.3% [95% Confidence Interval (CI), 93.3-98.2] vs. 87.6 [95% CI, 84.1-90.6]) at presentation. Helmeted bicyclists underwent fewer head CTs (40.3% [95% CI, 34.4-46.4] vs. 52.8% [95% CI, 48.0-57.6]) and were less likely to sustain intracranial injury (6.3% [95% CI, 2.6-12.5] vs. 19.7% [14.7-25.6]), including skull fracture (0.9% [95% CI, 0.0-4.9] vs. 15.3% [95% CI, 10.8-20.7]) and subdural hematoma (0.0% [95% CI, 0.0-3.2] vs. 8.1% [95% CI, 4.9-12.5]). Helmeted bicyclists were significantly less likely to sustain significant TBI, i.e. Head AIS >=3 (2.6% [95% CI: 0.7-4.5] vs.10.6% [7.6-12.5]). Four patients underwent craniotomy while three died; all were un-helmeted. A multivariable logistic regression model showed that helmeted bicyclists were 72% less likely to sustain TBI compared with un-helmeted bicyclists (Adjusted Odds Ratio 0.28, 95% CI 0.12-0.61). CONCLUSIONS: Despite substantial road safety measures in NYC, the protective impact of simple bicycle helmets in the event of a crash remains significant. A re-assessment of helmet laws for urban bicyclists is advisable to most effectively translate Vision Zero from a political action plan to public safety reality. PMID- 26254574 TI - The evolution and epidemiology of Listeria monocytogenes in Europe and the United States. AB - Listeria monocytogenes is an opportunistic food-borne pathogen responsible for listeriosis, a disease associated with high mortality rates. L. monocytogenes causes invasive syndromes and case-fatality can be as high as 30%, in specific high-risk population groups such as the elderly, immuno-compromised individuals, fetuses and newborns. Acquisition of the disease is mainly due to consumption of contaminated (predominantly ready-to-eat) food. We aimed to provide a state-of the-art collection of different likely evolutionary models, based on recombination and positive selection, and the phylogenetic relationship between lineages of L. monocytogenes and between them and other Listeria species. We described the most recent findings in comparative pan-genomics, considering the core and accessory genome in relation to virulence and adaptation to different environments. Finally, this review illustrates L. monocytogenes epidemiology and transmission in humans, foods and animals, the surveillance systems of the European Union and United States and the application of molecular techniques as a core tool in epidemiological investigation. PMID- 26254575 TI - Comparative population genetics of two invading ticks: Evidence of the ecological mechanisms underlying tick range expansions. AB - Two species of ixodid tick, Ixodes affinis Neumann and Amblyomma maculatum Koch, are simultaneously expanding their ranges throughout the mid-Atlantic region of the US. Although we have some understanding of the ecology and life history of these species, the ecological mechanisms governing where and how new populations establish and persist are unclear. To assess population connectivity and ancestry, we sequenced a fragment of the 16S mitochondrial rRNA gene from a representative sample of individuals of both species from populations throughout the eastern US. We found that despite overlapping host preferences throughout ontogeny, each species exhibited very different genetic and geographic patterns of population establishment and connectivity. I. affinis was of two distinct mitochondrial clades, with a clear geographic break separating northern and southern populations. Both I. affinis populations showed evidence of recent expansion, although the southern population was more genetically diverse, indicating a longer history of establishment. A. maculatum exhibited diverse haplotypes that showed no significant relationship with geographic patterns and little apparent connectivity between sites. Heteroplasmy was also observed in the 16S mitochondrial rRNA gene in 3.5% of A. maculatum individuals. Genetic evidence suggests that these species rely on different key life stages to successfully disperse into novel environments, and that host vagility, habitat stability and habitat connectivity all play critical roles in the establishment of new tick populations. PMID- 26254576 TI - Impact of combined resistance and aerobic exercise training on branched-chain amino acid turnover, glycine metabolism and insulin sensitivity in overweight humans. AB - AIMS/HYPOTHESES: Obesity is associated with decreased insulin sensitivity (IS) and elevated plasma branched-chain amino acids (BCAAs). The purpose of this study was to investigate the relationship between BCAA metabolism and IS in overweight (OW) individuals during exercise intervention. METHODS: Whole-body leucine turnover, IS by hyperinsulinaemic-euglycaemic clamp, and circulating and skeletal muscle amino acids, branched-chain alpha-keto acids and acylcarnitines were measured in ten healthy controls (Control) and nine OW, untrained, insulin resistant individuals (OW-Untrained). OW-Untrained then underwent a 6 month aerobic and resistance exercise programme and repeated testing (OW-Trained). RESULTS: IS was higher in Control vs OW-Untrained and increased significantly following exercise. IS was lower in OW-Trained vs Control expressed relative to body mass, but was not different from Control when normalised to fat-free mass (FFM). Plasma BCAAs and leucine turnover (relative to FFM) were higher in OW Untrained vs Control, but did not change on average with exercise. Despite this, within individuals, the decrease in molar sum of circulating BCAAs was the best metabolic predictor of improvement in IS. Circulating glycine levels were higher in Control and OW-Trained vs OW-Untrained, and urinary metabolic profiling suggests that exercise induces more efficient elimination of excess acyl groups derived from BCAA and aromatic amino acid (AA) metabolism via formation of urinary glycine adducts. CONCLUSIONS/INTERPRETATION: A mechanism involving more efficient elimination of excess acyl groups derived from BCAA and aromatic AA metabolism via glycine conjugation in the liver, rather than increased BCAA disposal through oxidation and turnover, may mediate interactions between exercise, BCAA metabolism and IS. TRIAL REGISTRATION: Clinicaltrials.gov NCT01786941. PMID- 26254577 TI - Elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation during diet-induced insulin resistance in dogs. AB - AIMS/HYPOTHESIS: A normal consequence of increased energy intake and insulin resistance is compensatory hyperinsulinaemia through increased insulin secretion and/or reduced insulin clearance. Failure of compensatory mechanisms plays a central role in the pathogenesis of type 2 diabetes mellitus; consequently, it is critical to identify in vivo signal(s) involved in hyperinsulinaemic compensation. We have previously reported that high-fat feeding leads to an increase in nocturnal NEFA concentration. We therefore designed this study to test the hypothesis that elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation for insulin resistance. METHODS: Blood sampling was conducted in male dogs to determine 24 h profiles of NEFA at baseline and during high-fat feeding with and without acute nocturnal NEFA suppression using a partial A1 adenosine receptor agonist. RESULTS: High-fat feeding increased nocturnal NEFA and reduced insulin sensitivity, effects countered by an increase in acute insulin response to glucose (AIR(g)). Pharmacological NEFA inhibition after 8 weeks of high-fat feeding lowered NEFA to baseline levels and reduced AIR(g) with no effect on insulin sensitivity. A significant relationship emerged between nocturnal NEFA levels and AIR(g). This relationship indicates that the hyperinsulinaemic compensation induced in response to high-fat feeding was prevented when the nocturnal NEFA pattern was returned to baseline. CONCLUSIONS/INTERPRETATION: Elevated nocturnal NEFA are an important signal for hyperinsulinaemic compensation during diet-induced insulin resistance. PMID- 26254578 TI - Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice. AB - AIMS/HYPOTHESIS: Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism, used in the treatment of type 2 diabetes, has recently been shown to increase thermogenesis via the brain. As brown adipose tissue (BAT) produces heat by burning triacylglycerol (TG) and takes up glucose for de novo lipogenesis, the aim of this study was to evaluate the potential of chronic central GLP-1R activation by exendin-4 to facilitate clearance of lipids and glucose from the circulation by activating BAT. METHODS: Lean and diet-induced obese (DIO) C57Bl/6J mice were used to explore the effect of a 5 day intracerebroventricular infusion of the GLP-1 analogue exendin-4 or vehicle on lipid and glucose uptake by BAT in both insulin-sensitive and insulin-resistant conditions. RESULTS: Central administration of exendin-4 in lean mice increased sympathetic outflow towards BAT and white adipose tissue (WAT), resulting in increased thermogenesis as evidenced by increased uncoupling protein 1 (UCP-1) protein levels and decreased lipid content, while the uptake of TG-derived fatty acids was increased in both BAT and WAT. Interestingly, in DIO mice, the effects on WAT were blunted, while exendin-4 still increased sympathetic outflow towards BAT and increased the uptake of plasma TG-derived fatty acids and glucose by BAT. These effects were accompanied by increased fat oxidation, lower plasma TG and glucose concentrations, and reduced body weight. CONCLUSIONS/INTERPRETATION: Collectively, our results suggest that BAT activation may be a major contributor to the glucose- and TG-lowering effects of GLP-1R agonism. PMID- 26254579 TI - Intramedullary nailing of humeral shaft fractures: failure analysis of a single centre series. AB - INTRODUCTION: Intramedullary nailing (IMN) is an accepted technique for the treatment of humeral shaft fractures. Previous studies published concerns over whether this technique had higher complication rates such as nonunion and technical failures compared to plate osteosynthesis. We, therefore, conducted a single centre failure analysis to critically evaluate our results regarding IMN of humeral shaft fractures. MATERIALS AND METHODS: Between January 2000 and January 2013, 246 consecutive patients with humeral shaft fractures were enrolled. Inclusion criteria were skeletal maturity and humeral shaft fractures treated with IMN. Exclusion criteria were skeletal immaturity, primary treatment by plate osteosynthesis, primary treatment outside the University Hospitals Leuven, presence of metaphyseal fractures and the presence of pathological fractures. Negative outcome measures such as infection, nonunion and early technical failure were retrospectively assessed. RESULTS: During the study period, 149 patients with 149 fractures met the inclusion criteria. Of these, 14 patients were lost to follow-up, two died from trauma-related causes within the first 30 days after the accident, and eight died from other causes (cardiovascular disease and cancer) leaving 125 patients with 125 fractures for a minimum follow-up period of 12 months. Failure analysis showed that six (4.8 %) patients developed a nonunion. One (0.8 %) patient was diagnosed with a deep infection. In total, five (5 %) patients underwent surgical revision due to early technical failures. CONCLUSIONS: IMN is a valid therapeutic option for humeral shaft fractures. Good surgical technique and soft tissue handling are important for good outcome. Currently, patient demands are receiving greater consideration. In an era where early full range of motion and rapid return to work with minimal scarring is mandatory for most patients, the use of IMN will most likely increase in popularity in the future. PMID- 26254580 TI - Radial nerve location at the posterior aspect of the humerus: an anatomic study of 100 specimens. AB - PURPOSE: Radial neuropathy represents a devastating complication in a posterior approach to the distal humerus. This study aimed to propose "safe zones" regarding the radial nerve (RN) location at the posterior aspect of the humerus to minimize the risk of iatrogenic injury. METHODS: In 100 embalmed specimens, the distances of the proximal edge of the olecranon fossa (OF) to the radial nerve at the medial edge (R1), at the center (R2) and at the lateral edge (R3) of the posterior aspect of humeral shaft were measured. Humeral length (HL) and transcondylar width (TW) were evaluated and correlated to R1, R2 and R3. RESULTS: R1 was 15.0 (+/-2.1; 10.6-19.5) cm, R2 averaged 12.7 (+/-1.6; 8.9-15.7) cm, R3 was 10.6 (+/-1.3; 7.6-13.7) cm. HL was 30.8 (+/-1.9) cm. TW averaged 6.3 (+/-0.6) cm. TW and HL correlate with R1, R2, R3 (r = 0.451-0.565 [95% CI 0.279-0.685]). The mean ratio was 2.3 (+/-0.18) for HL/R1, 2.6 (+/-0.23) for HL/R2 and 3.1 (+/ 0.31) for HL/R3. The ratio averaged 2.2 (+/-0.20) for R1/TW, 1.9 (+/-0.18) for R2/TW and 1.6 (+/-0.15) for R3/TW. CONCLUSIONS: We present the OF as an osseous landmark to reduce the risk of iatrogenic radial neuropathy. HL and TW can be reliably used to estimate the RN location. The consistent "safe zones" of the RN in relation to the OF are 10.5 cm at the medial edge, 9 cm at the center and 7.5 cm at the lateral edge of the posterior aspect of the humeral shaft. PMID- 26254581 TI - Translation, cross-cultural adaptation and validation of the Italian version of the Nottingham Clavicle Score (NCS). AB - INTRODUCTION: The Nottingham Clavicle Score (NCS) is a specific Patient Reported Outcome Measure of injuries to the clavicle, acromio-clavicular joint (ACJ) and sterno-clavicular joint. The purpose of this study was to translate the NCS into Italian and establish its cultural adaptiveness and validity. MATERIALS AND METHODS: The original version of the NCS was translated into Italian in accordance with the cross-cultural adaptation guidelines described by Guillemin. Sixty-six patients [average age 45.7 years (SD 11.3)] who had received surgical treatment for injuries of the ACJ and the clavicle were included in the study. The study population completed the NCS twice within 5 days, the Oxford Shoulder Score (OSS), the Disability of the Arm, Shoulder and Hand (DASH) questionnaire and the short-form 36 (SF-36). Statistical tests assessed the construct validity, discriminant validity, internal consistency, reliability and feasibility of the NCS. RESULTS: The translation and adaptation of the NCS for an Italian context required no major cultural adaptation. Internal consistency was high (Cronbach's alpha, 0.86). Test-retest reproducibility was excellent (rho = 0.981, p < 0.00001). Administration time was 45 s (range 1 min 32 s-8 min), and all items were answered. The Italian NCS showed strong correlation with the DASH (-0.87), the OSS (-0.84) and those subscales of the SF-36 (physical functioning, role physical and bodily pain) which aim to measure similar constructs. CONCLUSIONS: The Italian NCS scale is a reliable, valid, consistent shoulder assessment form that can be used to assess the functional limitations of patients with injuries of clavicle or ACJ. LEVEL OF EVIDENCE: III. PMID- 26254582 TI - beta-N-methylamino-l-alanine (BMAA) and isomers: Distribution in different food web compartments of Thau lagoon, French Mediterranean Sea. AB - The neurotoxin BMAA (beta-N-methylamino-l-alanine) and its isomer DAB (2,4 diaminobutyric acid) have been detected in seafood worldwide, including in Thau lagoon (French Mediterranean Sea). A cluster of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease associated with BMAA, has also been observed in this region. Mussels, periphyton (i.e. biofilms attached to mussels) and plankton were sampled between July 2013 and October 2014, and analyzed using HILIC-MS/MS. BMAA, DAB and AEG (N-(2-aminoethyl)glycine) were found in almost all the samples of the lagoon. BMAA and DAB were present at 0.58 and 0.83, 2.6 and 3.3, 4.0 and 7.2 MUg g(-1) dry weight in plankton collected with nets, periphyton and mussels, respectively. Synechococcus sp., Ostreococcus tauri, Alexandrium catenella and eight species of diatoms were cultured and screened for BMAA and analogs. While Synechococcus sp., O. tauri and A. catenella did not produce BMAA under our culture conditions, four diatoms species contained both BMAA and DAB. Hence, diatoms may be a source of BMAA for mussels. Unlike other toxins produced by microalgae, BMAA and DAB were detected in significant amounts in tissues other than digestive glands in mussels. PMID- 26254583 TI - Oxidative status assessment of the endemic bivalve Pinna nobilis affected by the oil spill from the sinking of the Don Pedro. AB - Several biomarkers were determined to evaluate the effects of the Don Pedro spillage on the digestive gland of the fan mussel Pinna nobilis (Linnaeus, 1758). Two areas in the southeast of Ibiza Island (Western Mediterranean) were selected; one affected by the oil spill (Talamanca) and one did not affected (Espardell). Mussels were sampled one, six and twelve months after the accident. PAH levels were elevated in P. nobilis from the affected area one month after the accident and, although they were decreasing gradually, they were always higher than in the control area. An increase in enzyme activities, reduced glutathione and lipid peroxidation were evidenced one month after the spillage, with no changes in acetylcholinesterase. All biomarkers progressively returned to basal levels one year after the oil spill. In conclusion, the Don Pedro oil spill induced an acute situation of oxidative stress on P. nobilis that were recovered twelve months later. PMID- 26254584 TI - Seasonal changes in gene expression and polymorphism of hsp70 in cultivated oysters (Crassostrea gigas) at extreme temperatures. AB - The HSP70 proteins are an important element of the response against thermal stress and infectious diseases, and they are highly conserved and ubiquitous. In some species, variations on the hsp70 encoding sequence resulted in intraspecific differential expression, which leads to variations on thermo-tolerance among individuals. This phenomenon has not been described in the Pacific oyster Crassostrea gigas, which is cultivated in Mexico under temperature conditions highly above the optimal for this species. The present study was aimed to identify associations between hsp70 genotypes and their expression levels in C. gigas. By analyzing a 603 bp fragment from the 3' end of the hsp70 gene, 21 different genotypes with 60 nucleotide polymorphic sites were detected, of which 34 sites were found in heterozygous condition. Although no correlation was found between genotype-expression-season, a minimum expression threshold that should be taken into account as an important feature for a future breeding program is proposed. PMID- 26254585 TI - Effect of glycopyrrolate versus atropine coadministered with neostigmine for reversal of rocuronium on postoperative catheter-related bladder discomfort in patients undergoing transurethral resection of bladder tumor: a prospective randomized study. AB - BACKGROUND: Muscarinic receptors are involved in the mechanism of postoperative catheter-related bladder discomfort (CRBD). Glycopyrrolate and atropine as adjuncts to reversal of neuromuscular blockers have differential inhibitory effects on muscarinic receptors. This study was conducted to compare the effect of glycopyrrolate versus atropine on postoperative CRBD in patients undergoing transurethral resection of a bladder tumor (TURBT). METHODS: Seventy-four patients undergoing TURBT were randomly allocated to receive either glycopyrrolate 10 MUg/kg (glycopyrrolate group, n = 37) or atropine 15 MUg/kg (atropine group, n = 37) in combination with neostigmine 25 MUg/kg at the end of surgery for reversal of neuromuscular blockade. The incidence and severity (mild/moderate/severe) of CRBD were assessed at 0, 1, 6, and 24 h postoperatively. Tramadol 50-100 mg was administered intravenously if the patients complained of moderate or severe CRBD. RESULTS: The incidence of CRBD was significantly lower in the glycopyrrolate group than in the atropine group at 0 h (65 % vs. 89 %, p = 0.025) and 1 h (54 % vs. 89 %, p = 0.002) postoperatively. The severity of postoperative CRBD was less severe in the glycopyrrolate group than in the atropine group at 0 h (p = 0.013) and 1 h (p = 0.006). Fewer patients required tramadol in the glycopyrrolate group than in the atropine group (3 % vs. 12 %, p = 0.024). CONCLUSIONS: Glycopyrrolate as an adjunct to reversal of neuromuscular blockers decreased the incidence of early postoperative CRBD and postoperative tramadol requirements in patients undergoing TURBT when compared to atropine. PMID- 26254586 TI - Impossible expectations: fMRI adaptation in the lateral occipital complex (LOC) is modulated by the statistical regularities of 3D structural information. AB - fMRI adaptation (fMRIa), the attenuation of fMRI signal which follows repeated presentation of a stimulus, is a well-documented phenomenon. Yet, the underlying neural mechanisms supporting this effect are not fully understood. Recently, short-term perceptual expectations, induced by specific experimental settings, were shown to play an important modulating role in fMRIa. Here we examined the role of long-term expectations, based on 3D structural statistical regularities, in the modulation of fMRIa. To this end, human participants underwent fMRI scanning while performing a same-different task on pairs of possible (regular, expected) objects and spatially impossible (irregular, unexpected) objects. We hypothesized that given the spatial irregularity of impossible objects in relation to real-world visual experience, the visual system would always generate a prediction which is biased to the possible version of the objects. Consistently, fMRIa effects in the lateral occipital cortex (LOC) were found for possible, but not for impossible objects. Additionally, in alternating trials the order of stimulus presentation modulated LOC activity. That is, reduced activation was observed in trials in which the impossible version of the object served as the prime object (i.e. first object) and was followed by the possible version compared to the reverse order. These results were also supported by the behavioral advantage observed for trials that were primed by possible objects. Together, these findings strongly emphasize the importance of perceptual expectations in object representation and provide novel evidence for the role of real-world statistical regularities in eliciting fMRIa. PMID- 26254588 TI - Unsigned value prediction-error modulates the motor system in absence of choice. AB - Human actions are driven by the pursuit of goals, especially when achieving these goals entails a reward. Accordingly, recent work showed that anticipating a reward in a motor task influences the motor system, boosting motor excitability and increasing overall readiness. Attaining a reward typically requires some mental or physical effort. Recent neuroimaging evidence suggested that both reward expectation and effort requirements are encoded by a partially overlapping brain network. Moreover, reward and effort information are combined in an integrative value signal. However, whether and how mental effort is integrated with reward at the motor level during task preparation remains unclear. To address these issues, we implemented a mental effort task where reward expectation and effort requirements were manipulated. During task preparation, TMS was delivered on the motor cortex and motor-evoked potentials (MEPs) were recorded on the right hand muscles to probe motor excitability. The results showed an interaction of effort and reward in modulating the motor system, reflecting an unsigned value prediction-error signal. Crucially, this was observed in the motor system in absence of a value-based decision or value-driven action selection. This suggests a high-level cognitive factor such as unsigned value prediction-error can modulate the motor system. Interestingly, effort related motor excitability was also modulated by individual differences in tendency to engage in (and enjoy) mental effort, as measured by the Need for Cognition questionnaire, underlining a role of subjective effort experience in value-driven preparation for action. PMID- 26254587 TI - Neural networks involved in adolescent reward processing: An activation likelihood estimation meta-analysis of functional neuroimaging studies. AB - Behavioral responses to, and the neural processing of, rewards change dramatically during adolescence and may contribute to observed increases in risk taking during this developmental period. Functional MRI (fMRI) studies suggest differences between adolescents and adults in neural activation during reward processing, but findings are contradictory, and effects have been found in non predicted directions. The current study uses an activation likelihood estimation (ALE) approach for quantitative meta-analysis of functional neuroimaging studies to: (1) confirm the network of brain regions involved in adolescents' reward processing, (2) identify regions involved in specific stages (anticipation, outcome) and valence (positive, negative) of reward processing, and (3) identify differences in activation likelihood between adolescent and adult reward-related brain activation. Results reveal a subcortical network of brain regions involved in adolescent reward processing similar to that found in adults with major hubs including the ventral and dorsal striatum, insula, and posterior cingulate cortex (PCC). Contrast analyses find that adolescents exhibit greater likelihood of activation in the insula while processing anticipation relative to outcome and greater likelihood of activation in the putamen and amygdala during outcome relative to anticipation. While processing positive compared to negative valence, adolescents show increased likelihood for activation in the posterior cingulate cortex (PCC) and ventral striatum. Contrasting adolescent reward processing with the existing ALE of adult reward processing reveals increased likelihood for activation in limbic, frontolimbic, and striatal regions in adolescents compared with adults. Unlike adolescents, adults also activate executive control regions of the frontal and parietal lobes. These findings support hypothesized elevations in motivated activity during adolescence. PMID- 26254589 TI - Dissecting the social brain: Introducing the EmpaToM to reveal distinct neural networks and brain-behavior relations for empathy and Theory of Mind. AB - Successful social interactions require both affect sharing (empathy) and understanding others' mental states (Theory of Mind, ToM). As these two functions have mostly been investigated in isolation, the specificity of the underlying neural networks and the relation of these networks to the respective behavioral indices could not be tested. Here, we present a novel fMRI paradigm (EmpaToM) that independently manipulates both empathy and ToM. Experiments 1a/b (N=90) validated the task with established empathy and ToM paradigms on a behavioral and neural level. Experiment 2 (N=178) employed the EmpaToM and revealed clearly separable neural networks including anterior insula for empathy and ventral temporoparietal junction for ToM. These distinct networks could be replicated in task-free resting state functional connectivity. Importantly, brain activity in these two networks specifically predicted the respective behavioral indices, that is, inter-individual differences in ToM related brain activity predicted inter individual differences in ToM performance, but not empathic responding, and vice versa. Taken together, the validated EmpaToM allows separation of affective and cognitive routes to understanding others. It may thus benefit future clinical, developmental, and intervention studies on identifying selective impairments and improvement in specific components of social cognition. PMID- 26254590 TI - On Becoming a Pharmacologist: Channeling David Triggle. AB - This Festschrift contribution summarizes the perspectives of two of David Triggle's graduate students. Both share somewhat parallel scientific and career paths-i.e., enrolling in the Biochemical Pharmacology program at the University of Buffalo, pursuing graduate training under the mentorship of David Triggle and subsequently undertaking postdoctoral studies at Baylor College of Medicine, and ultimately transitioning to careers in the pharmaceutical industry, now for the past 20+ years. David Triggle's mentorship and guidance was instrumental in developing scientific careers and thought processes at both professional and personal levels. The article is a chronological view of the lessons learned from David Triggle starting in the early 1980s and continuing to the present. PMID- 26254591 TI - Glycosylation-dependent activation of epithelial sodium channel by solnatide. AB - Dysfunction of the epithelial sodium channel (ENaC), which regulates salt and water homeostasis in epithelia, causes several human pathological conditions, including pulmonary oedema. This is a potentially lethal complication of acute lung injury at least partially caused by dysfunctional alveolar liquid clearance, which in turn impairs alveolar gas exchange. Solnatide (named TIP-peptide, AP301), a 17 residue peptide mimicking the lectin-like domain of TNF has been shown to activate ENaC in several experimental animal models of acute lung injury and is being evaluated as a potential therapy for pulmonary oedema. The peptide has recently completed phase 1 and 2a clinical trials. In this study, we identify a glycosylation-dependent mechanism that preserves ENaC function and expression. Since our previous data suggested that the pore-forming subunits of ENaC are essential for maximal current activation by solnatide, we performed single- and multi-N-glycosylation site mutations in alphaN232,293,312,397,511Q- and deltaN166,211,384Q-subunits, in order to identify crucial residues for interaction with solnatide within the extracellular loop of the channel. Additionally, we generated alphaL576X and alphaN232,293,312,397,511Q,L576X deletion mutants of ENaC-alpha, since we have previously demonstrated that the carboxy terminal domain of this subunit is also involved in its interaction with solnatide. In cells expressing alphaN232,293,312,397,511Q,L576Xbetagamma-hENaC or deltaN166,311,384Q,D552Xbetagamma-hENaC activation by solnatide, as measured in whole cell patch clamp mode, was completely abolished, whereas it was attenuated in alphaL576Xbetagamma-hENaC- and deltaD552Xbetagamma-hENaC-expressing cells. Taken together, our findings delineate an N-glycan dependent interaction between the TIP-peptide and ENaC leading to normalization of both sodium and fluid absorption in oedematous alveoli to non-oedematous levels. PMID- 26254592 TI - Fluid-induced low shear stress improves cartilage like tissue fabrication by encapsulating chondrocytes. AB - In the recent years, there has been considerable development in the regenerative medicine, which aims to repair, regenerate, and improve injured articular cartilage. The aim of the present study was to investigate the effect of flow induced shear stress in perfusion bioreactor on alginate encapsulating chondrocytes. The shear stress imposed on the cells in the culture chamber of bioreactor was predicted with computational fluid dynamic. Bovine nasal chondrocytes were isolated and expanded to obtain a pellet. The cell pellet was resuspends in alginate solution, transferred to the culture chamber, and dynamically cultured under direct perfusion. At the end of culture, tissue constructs were examined histologically and by immunohistochemistry. The results of computational fluid dynamic modeling revealed that maximum wall shear stress was 4.820 * 10(-3) Pascal. Macroscopic views of the alginate/chondrocyte beads suggested that it possessed constant shape but were flexible. Under inverted microscope, round shape of chondrocyte observed. Cell distribution was homogeneous throughout the scaffold. Tissue construct subjected to shear showed morphological features, which are characteristic for natural cartilage. Immunohistochemistry results revealed immunopositivity for type II collagens in tissue constructs samples. Flow induced shear stress in the perfusion bioreactor and chnondrocyte encapsulation provide environment to support cell growth, and tissue regeneration and improve cartilage like tissue fabrication. PMID- 26254593 TI - Tight mitochondrial control of calcium and exocytotic signals in chromaffin cells at embryonic life. AB - Calcium buffering by mitochondria plays a relevant physiological function in the regulation of Ca(2+) and exocytotic signals in mature chromaffin cells (CCs) from various adult mammals. Whether a similar or different role of mitochondrial Ca(2+) buffering is present in immature CCs at early life has not been explored. Here we present a comparative study in rat embryonic CCs and rat mother CCs, of various physiological parameters that are known to be affected by mitochondrial Ca(2+) buffering during cell activation. We found that the clearance of cytosolic Ca(2+) transients ([Ca(2+)]c) elicited by high K(+) was 7-fold faster in embryo CCs compared to mother CCs. This strongly suggests that at embryonic life, the mitochondria play a more significant role in the clearance of [Ca(2+)]c loads compared to adult life. Consistent with this view are the following results concerning the transient suppression of mitochondrial Ca(2+) buffering by protonophore FCCP, in embryonic CCs compared to mother CCs: (i) faster and greater inactivation of inward calcium currents, (ii) higher K(+)-elicited [Ca(2+)]c transients with 25-fold faster clearance, (iii) higher increase of basal catecholamine release and (iv) higher potentiation of K(+)-evoked secretion. These pronounced differences could be explained by two additional features (embryo versus mother CCs): (a) slower recovery of mitochondrial resting membrane potential after the application of a transient FCCP pulse and (b) greater relative density of the mitochondria in the cytosol. This tighter control by the mitochondria of Ca(2+) and exocytotic signals may be relevant to secure a healthy catecholamine secretory response at early life. PMID- 26254594 TI - Glucose-Dependent Insulinotropic Peptide Prevents Serum Deprivation-Induced Apoptosis in Human Bone Marrow-Derived Mesenchymal Stem Cells and Osteoblastic Cells. AB - Human bone marrow-derived mesenchymal stem cells (hBMSC) are able to differentiate into cells of connective tissue lineages, including bone and cartilage. They are therefore considered as a promising tool for the treatment of bone degenerative diseases. One of the major issues in regenerative cell therapy is the biosafety of fetal bovine serum used for cell culture. Therefore, the development of a culture medium devoid of serum but preserving hBMSC viability will be of clinical value. The glucose-dependent insulinotropic peptide (GIP) has an anti-apoptotic action in insulin-producing cells. Interestingly, GIP also exerts beneficial effects on bone turnover by acting on osteoblasts and osteoclasts. We therefore evaluated the ability of GIP to prevent cell death in osteoblastic cells cultured in serum-free conditions. In hBMSC and SaOS-2 cells, activation of the GIP receptor increased intracellular cAMP levels. Serum deprivation induced apoptosis in SaOS-2 and hBMSC that was reduced by 30 and 50 %, respectively, in the presence of GIP. The protective effect of GIP involves activation of the adenylate cyclase pathway and inhibition of caspases 3/7 activation. These findings demonstrate that GIP exerts a protective action against apoptosis in hBMSC and suggest a novel approach to preserve viability of hBMSC cultured in the absence of serum. PMID- 26254595 TI - From estimating activation locality to predicting disorder: A review of pattern recognition for neuroimaging-based psychiatric diagnostics. AB - Psychiatric disorders are increasingly being recognised as having a biological basis, but their diagnosis is made exclusively behaviourally. A promising approach for 'biomarker' discovery has been based on pattern recognition methods applied to neuroimaging data, which could yield clinical utility in future. In this review we survey the literature on pattern recognition for making diagnostic predictions in psychiatric disorders, and evaluate progress made in translating such findings towards clinical application. We evaluate studies on many criteria, including data modalities used, the types of features extracted and algorithm applied. We identify problems common to many studies, such as a relatively small sample size and a primary focus on estimating generalisability within a single study. Furthermore, we highlight challenges that are not widely acknowledged in the field including the importance of accommodating disease prevalence, the necessity of more extensive validation using large carefully acquired samples, the need for methodological innovations to improve accuracy and to discriminate between multiple disorders simultaneously. Finally, we identify specific clinical contexts in which pattern recognition can add value in the short to medium term. PMID- 26254596 TI - A nonclassical MHC class I U lineage locus in zebrafish with a null haplotypic variant. AB - Three sequence lineages of MHC class I genes have been described in zebrafish (Danio rerio): U, Z, and L. The U lineage genes encoded on zebrafish chromosome 19 are predicted to provide the classical function of antigen presentation. This MHC class I locus displays significant haplotypic variation and is the only MHC class I locus in zebrafish that shares conserved synteny with the core mammalian MHC. Here, we describe two MHC class I U lineage genes, mhc1ula and mhc1uma, that map to chromosome 22. Unlike the U lineage proteins encoded on chromosome 19, Ula and Uma likely play a nonclassical role as they lack conservation of key peptide binding residues, display limited polymorphic variation, and exhibit tissue specific expression. We also describe a null haplotype at this chromosome 22 locus in which the mhc1ula and mhc1uma genes are absent due to a ~30 kb deletion with no other MHC class I sequences present. Functional and non-functional transcripts of mhc1ula and mhc1uma were identified; however, mhc1uma transcripts were often not amplified or amplified at low levels from individuals possessing an apparently bona fide gene. These distinct U lineage genes may be restricted to the superorder Ostariophysi as similar sequences only could be identified from the blind cavefish (Astyanax mexicanus), fathead minnow (Pimephales promelas), goldfish (Carassius auratus), and grass carp (Ctenopharyngodon idella). PMID- 26254597 TI - Influence of the bleaching interval on the luminosity of long-term discolored enamel-dentin discs. AB - OBJECTIVES: The aim of this study is to investigate the influence of changing the sodium perborate-tetrahydrate (PBS-4) at a 4-day interval versus no change after 16 days of internal bleaching. MATERIALS AND METHODS: Two hundred and ten bovine enamel-dentin discs were discolored for 3.5 years with 14 different endodontic materials. All groups with a discoloring index of ?E (mean) >= 5.5 were included in the present investigation: ApexCal (APCA), MTA white + blood (WMTA+BL), Portland cement + blood (PC+BL), blood (BL), MTA gray (GMTA), MTA gray + blood (GMTA+BL), Ledermix (LED), and triple antibiotic paste containing minocycline (3Mix). Fourteen specimens of each group were randomly assigned into two treatment groups: (1) no change of the PBS-4 (n = 7); (2) change of the PBS-4 every 4 days (n = 7). Color measurements were taken at 10 different time intervals and the L*a*b* values were recorded with a spectrophotometer (VITA Easyshade(r) compact). RESULTS: In the group 3Mix, significantly better results were achieved by changing the bleaching agent every 4 days (P = 0.0049; q = 0.04), while the group WMTA+BL indicated better results by no change of the bleaching agent (P = 0.0222, q = 0.09). All remaining groups showed no statistical difference between the two treatment procedures. CONCLUSIONS: Moderate discolorations can be successfully treated without changing the bleaching agent over a period of 16 days. Changing the sodium perborate tetrahydrate every 4 days is preferred in case of severe discolored enamel-dentin discs only. CLINICAL RELEVANCE: This approach may offer a reduced number of clinical appointments and a secondary cost reduction to the patient. PMID- 26254598 TI - Mouse anti-RANKL antibody delays oral wound healing and increases TRAP-positive mononuclear cells in bone marrow. AB - OBJECTIVES: Denosumab, a human monoclonal antibody (mAb) that neutralizes receptor activator for nuclear factor kappaB ligand (RANKL), is associated with osteonecrosis of the jaw. However, the effect of denosumab on oral wounds is unclear. The aim was to determine the effect of anti-RANKL mAb on oral wounds and bone marrow. MATERIALS AND METHODS: The direct effect of the mAb on fibroblasts, macrophages, and osteoclasts were assessed in vitro. In vivo, mouse anti-RANKL mAb was administered to mice for 9 weeks prior to palatal bone denudation surgery. Mice were euthanized 3 weeks post-surgery, and wound healing was histomorphometrically analyzed. Long bones were assessed using micro-computed tomography, quantitative real-time polymerase chain reaction, and flow cytometry. RESULTS: The mAb had no effect on macrophages and fibroblasts but significantly suppressed osteoclast proliferation in vitro. The mAb treatment significantly increased bone mass by suppressing osteoclasts in vivo. The expression of pro osteoclastic genes was promoted in the bone marrow of the mAb-administered animals. Consistently, the mAb significantly induced the development of tartrate resistant acid phosphatase (TRAP)-positive mononuclear cells (MNCs) but not osteoclasts in bone marrow. The mAb treatment had no effect on gross healing of the palatal wounds. However, significant inflammation was retained in the connective tissue facing the once denuded bone surface. CONCLUSIONS: Repair of the damaged palate was delayed, and significant inflammation was sustained in the connective tissue by anti-RANKL mAb treatment. CLINICAL RELEVANCE: Denosumab impairs osteoclastic bone repair. Care should be exercised to minimize osseous trauma when invasive procedures are performed on patients taking denosumab. PMID- 26254599 TI - Mechanism of Tang Luo Ning effect on attenuating of oxidative stress in sciatic nerve of STZ-induced diabetic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tang Luo Ning recipe (TLN), a traditional Chinese herbal medicine based on Huangqi Guizhi Wuwu decoction, has been used clinically to treat diabetic peripheral neuropathy in China. However, the effect of TLN on diabetic peripheral neuropathy is unclear. The objective of this study was to determine the main components in TLN and to investigate the effects of TLN on oxidative stress in diabetic peripheral neuropathy rats. MATERIALS AND METHODS: The effect of TLN on oxidative stress was investigated in streptozocin (STZ) induced diabetic rats. Fasting blood glucose, body weight, thermal perception threshold test and motor and sensory nerve conduction velocity of sciatic nerve were measured. Sciatic nerve morphology was observed by Haematoxylin and eosin staining and under transmission electron microscope. T-AOC was measured by colorimetric assay. ROS were measured using enzyme-linked immunosorbent assay. Nrf2 and gammaGCS protein levels were measured by Western blot analysis. The expression of Bcl2, Bax and Cyto C were examined by immunohistochemistry. RESULTS: TLN markedly improved the neurological function including thermal perception threshold and nerve conduction velocity of DPN rats. Haematoxylin and eosin (HE) and transmission electron microscopy (TEM) staining results showed that TLN attenuated axon atrophy and demyelination in DPN rats. Moreover, TAOC were increased, whereas ROS content was decreased after treatment with TLN in rats with DPN. Furthermore, TLN increased protein levels of Nrf2, gammaGCS and Bcl2, and decreased Bax and Cyto C expression. CONCLUSIONS: TLN improved neurological function to prevent diabetic peripheral neuropathy by attenuating oxidative stress through Nrf2 and Bcl2 activation. PMID- 26254601 TI - Enhanced blue light emission in transparent ZnO:PVA nanocomposite free standing polymer films. AB - ZnO:PVA nanocomposite films were prepared and their fluorescence and time resolved photoluminescence properties were discussed. X-ray diffraction and infrared spectroscopy results confirmed the ZnO:PVA interaction. Optical absorption spectra showed two bands at 280 and 367nm which were ascribed to PVA and excitonic absorption band, respectively. Fluorescence spectra showed that the blue emission of ZnO was enhanced about tenfold through chemical interface electron transfer. The electron transfer from ZnO to PVA and its decay dynamics were experimentally analyzed through time resolved fluorescence measurements. The study revealed that the excited electrons found pathway through PVA to ground state which was slower than the pure ZnO nanoparticles. PMID- 26254600 TI - Mammalian target of rapamycin complex 1 (mTORC1) Is required for mouse spermatogonial differentiation in vivo. AB - Spermatogonial stem cells (SSCs) must balance self-renewal with production of transit-amplifying progenitors that differentiate in response to retinoic acid (RA) before entering meiosis. This self-renewal vs. differentiation spermatogonial fate decision is critical for maintaining tissue homeostasis, as imbalances cause spermatogenesis defects that can lead to human testicular cancer or infertility. A great deal of effort has been exerted to understand how the SSC population is maintained. In contrast, little is known about the essential program of differentiation initiated by retinoic acid (RA) that precedes meiosis, and the pathways and proteins involved are poorly defined. We recently reported a novel role for RA in stimulating the PI3/AKT/mTOR kinase signaling pathway to activate translation of repressed mRNAs such as Kit. Here, we examined the requirement for mTOR complex 1 (mTORC1) in mediating the RA signal to direct spermatogonial differentiation in the neonatal testis. We found that in vivo inhibition of mTORC1 by rapamycin blocked spermatogonial differentiation, which led to an accumulation of undifferentiated spermatogonia. In addition, rapamycin also blocked the RA-induced translational activation of mRNAs encoding KIT, SOHLH1, and SOHLH2 without affecting expression of STRA8. These findings highlight dual roles for RA in germ cell development - transcriptional activation of genes, and kinase signaling to stimulate translation of repressed messages required for spermatogonial differentiation. PMID- 26254602 TI - Chemometrics resolution and quantification power evaluation: Application on pharmaceutical quaternary mixture of Paracetamol, Guaifenesin, Phenylephrine and p-aminophenol. AB - Three advanced chemmometric-assisted spectrophotometric methods namely; Concentration Residuals Augmented Classical Least Squares (CRACLS), Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and Principal Component Analysis-Artificial Neural Networks (PCA-ANN) were developed, validated and benchmarked to PLS calibration; to resolve the severely overlapped spectra and simultaneously determine; Paracetamol (PAR), Guaifenesin (GUA) and Phenylephrine (PHE) in their ternary mixture and in presence of p-aminophenol (AP) the main degradation product and synthesis impurity of Paracetamol. The analytical performance of the proposed methods was described by percentage recoveries, root mean square error of calibration and standard error of prediction. The four multivariate calibration methods could be directly used without any preliminary separation step and successfully applied for pharmaceutical formulation analysis, showing no excipients' interference. PMID- 26254603 TI - Preparation, characterisation and antitumour activity of beta-, gamma- and HP beta-cyclodextrin inclusion complexes of oxaliplatin. AB - Three water-soluble oxaliplatin complexes were prepared by inclusion complexation with beta-cyclodextrin (beta-CD), gamma-CD and HP-beta-CD. The structures of oxaliplatin/CDs were confirmed by NMR, FTIR, TGA, XRD as well as SEM analysis. The results show that the water solubility of oxaliplatin was increased in the complex with CDs in 1:1 stoichiometry inclusion modes, and the cyclohexane ring of oxaliplatin molecule was deeply inserted into the cavity of CDs. Moreover, the stoichiometry was established by a Job plot and the water stability constant (Kc) of oxaliplatin/CDs was calculated by phase solubility studies, all results show that the oxaliplatin/beta-CD complex is more stable than free oxaliplatin, oxaliplatin/HP-beta-CD and oxaliplatin/gamma-CD. Meanwhile, the inclusion complexes displayed almost twice as high cytotoxicity compared to free oxaliplatin against HCT116 and MCF-7 cells. This satisfactory water solubility and higher cytotoxic activity of the oxaliplatin/CD complexes will potentially be useful for their application in anti-tumour therapy. PMID- 26254604 TI - A New Hemodynamic Ex Vivo Model for Medical Devices Assessment. AB - BACKGROUND: In-stent restenosis (ISR) remains a major public health concern associated with an increased morbidity, mortality, and health-related costs. Drug eluting stents (DES) have reduced ISR, but generate healing-related issues or hypersensitivity reactions, leading to an increased risk of late acute stent thrombosis. Assessments of new DES are based on animal models or in vitro release systems, which have several limitations. The role of flow and shear stress on endothelial cell and ISR has also been emphasized. The aim of this work was to design and first evaluate an original bioreactor, replicating ex vivo hemodynamic and biological conditions similar to human conditions, to further evaluate new DES. METHODS: This bioreactor was designed to study up to 6 stented arteries connected in bypass, immersed in a culture box, in which circulated a physiological systolo-diastolic resistive flow. Two centrifugal pumps drove the flow. The main pump generated pulsating flows by modulation of rotation velocity, and the second pump worked at constant rotation velocity, ensuring the counter pressure levels and backflows. The flow rate, the velocity profile, the arterial pressure, and the resistance of the flow were adjustable. The bioreactor was placed in an incubator to reproduce a biological environment. RESULTS: A first feasibility experience was performed over a 24-day period. Three rat aortic thoracic arteries were placed into the bioreactor, immersed in cell culture medium changed every 3 days, and with a circulating systolic and diastolic flux during the entire experimentation. There was no infection and no leak. At the end of the experimentation, a morphometric analysis was performed confirming the viability of the arteries. CONCLUSIONS: We designed and patented an original hemodynamic ex vivo model to further study new DES, as well as a wide range of vascular diseases and medical devices. This bioreactor will allow characterization of the velocity field and drug transfers within a stented artery with new functionalized DES, with experimental means not available in vivo. Another major benefit will be the reduction of animal experimentation and the opportunity to test new DES or other vascular therapeutics in human tissues (human infrapopliteal or coronary arteries collected during human donation). PMID- 26254606 TI - Molecular regulation of steroidogenesis in endocrine Leydig cells. AB - Steroid hormones regulate essential physiological processes and inadequate levels are associated with various pathological conditions. Consequently, the process of steroid hormone biosynthesis is finely regulated. In the testis, the main steroidogenic cells are the Leydig cells. There are two distinct populations of Leydig cells that arise during development: fetal and adult Leydig cells. Fetal Leydig cells are responsible for masculinizing the male urogenital tract and inducing testis descent. These cells atrophy shortly after birth and do not contribute to the adult Leydig cell population. Adult Leydig cells derive from undifferentiated precursors present after birth and become fully steroidogenic at puberty. The differentiation of both Leydig cell populations is controlled by locally produced paracrine factors and by endocrine hormones. In fully differentially and steroidogenically active Leydig cells, androgen production and hormone-responsiveness involve various signaling pathways and downstream transcription factors. This review article focuses on recent developments regarding the origin and function of Leydig cells, the regulation of their differentiation by signaling molecules, hormones, and structural changes, the signaling pathways, kinases, and transcription factors involved in their differentiation and in mediating LH-responsiveness, as well as the fine-tuning mechanisms that ensure adequate production steroid hormones. PMID- 26254605 TI - Development and analysis of a highly flexible multi-gene expression system for metabolic engineering in Arabidopsis seeds and other plant tissues. AB - Production of novel value-added compounds in transgenic crops has become an increasingly viable approach in recent years. However, in many cases, product yield still falls short of the levels necessary for optimal profitability. Determination of the limiting factors is thus of supreme importance for the long term viability of this approach. A significant challenge to most metabolic engineering projects is the need for strong coordinated co-expression of multiple transgenes. Strong constitutive promoters have been well-characterized during the >30 years since plant transformation techniques were developed. However, organ- or tissue-specific promoters are poorly characterized in many cases. Oilseeds are one such example. Reports spanning at least 20 years have described the use of certain seed-specific promoters to drive expression of individual transgenes. Multi-gene engineering strategies are often hampered by sub-optimal expression levels or improper tissue-specificity of particular promoters, or rely on the use of multiple copies of the same promoter, which can result in DNA instability or transgene silencing. We describe here a flexible system of plasmids that allows for expression of 1-7 genes per binary plasmid, and up to 18 genes altogether after multiple rounds of transformation or sexual crosses. This vector system includes six seed-specific promoters and two constitutive promoters. Effective constitutive and seed-specific RNA interference gene-suppression cloning vectors were also constructed for silencing of endogenous genes. Taken together, this molecular toolkit allows combinatorial cloning for multiple transgene expression in seeds, vegetative organs, or both simultaneously, while also providing the means to coordinately overexpress some genes while silencing others. PMID- 26254607 TI - A chromatography/tandem mass spectrometry method for the simultaneous profiling of ten endogenous steroids, including progesterone, adrenal precursors, androgens and estrogens, using low serum volume. AB - Measurement of a large set of sex steroids in clinical epidemiology and laboratory research with reliable methods providing low quantification limits and using a limited volume of blood sample represents a significant challenge. We report a new validated gas chromatography selected reaction monitoring - tandem mass spectrometry assay (GC-MS/MS) for the simultaneous quantification of ten endogenous steroids including progesterone (PROG), dehydroepiandrosterone (DHEA), androstenediol (5-diol), androstenedione (4-dione), testosterone (T), dihydrotestosterone (DHT), androsterone (ADT), 5alpha-androstan-3beta-17beta-diol (3beta-diol), estrone (E1) and estradiol (E2). After addition of stable isotope internal standards, the approach involved the combination of liquid-liquid extraction, derivatization and solid-phase extraction for injection into the GC system and multiple reaction monitoring (MRM). The method presents high reproducibility for all analytical parameters in 250 MUl serum samples. The lower limit of quantification (LLOQ) were of 100 pg/ml for DHEA, 50 pg/ml for PROG, 5 diol, 4-dione and ADT, 30 pg/ml for T, 10 pg/ml for 3beta-diol and DHT, 5 pg/ml for E1, and 1 pg/ml for E2. The applicability of the validated method to determine the concentrations of these 10 steroids was successfully tested on serum from men (n=15), premenopausal (n=10) and postmenopausal women (n=20), and is currently used for larger cancer-related epidemiology studies. One of the most considerable advantages over existing methods is the simultaneous determination of ten steroids in a limited volume of serum that will help conserve important clinical samples from existing biobanks. PMID- 26254608 TI - The proapoptotic protein Bim is up regulated by 1alpha,25-dihydroxyvitamin D3 and its receptor agonist in endothelial cells and transformed by viral GPCR associated to Kaposi sarcoma. AB - We have previously shown that 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] and its less calcemic analog TX 527 induce apoptosis via caspase-3 activation in endothelial cells (SVEC) and endothelial cells transformed by the viral G protein coupled receptor associated to Kaposi sarcoma (vGPCR). In this work, we studied whether intrinsic apoptotic pathway could be activated by changing the balance between anti and pro-apoptotic proteins. Time response qRT-PCR analysis demonstrated that the mRNA level of anti-apoptotic gene Bcl-2 decreased after 12h and increased after 48h treatment with 1alpha,25(OH)2D3 or TX 527 in SVEC and vGPCR cells, whereas its protein level remained unchanged through time. mRNA levels of pro-apoptotic gene Bax significantly increased only in SVEC after 24 and 48h treatment with 1alpha,25(OH)2D3 and TX 527 although its protein levels remained unchanged in both cell lines. Bim mRNA and protein levels increased in SVEC and vGPCR cells. Bim protein increase by 1alpha,25(OH)2D3 and TX 527 was abolished when the expression of vitamin D receptor (VDR) was suppressed. On the other hand, Bortezomib (0.25-1nM), an inhibitor of NF-kappaB pathway highly activated in vGPCR cells, increased Bim protein levels and induced caspase-3 cleavage. Altogether, these results indicate that 1alpha,25(OH)2D3 and TX 527 trigger apoptosis by Bim protein increase which turns into the activation of caspase-3 in SVEC and vGPCR cells. Moreover, this effect is mediated by VDR and involves NF-kappaB pathway inhibition in vGPCR. PMID- 26254609 TI - Nodulisporisteroids C-L, new 4-methyl-progesteroid derivatives from Nodulisporium sp. AB - The fungus Nodulisporium sp. (No. 65-12-7-1), which can produce a rare class of steroids (4-methyl-progesteroids) in rice solid medium, was subjected to a one strain-many compounds (OSMAC) approach. It was found to produce ten new 4-methyl progesteroid derivatives named nodulisporisteroids C-L (1-10) in potato-dextrose broth (PDB) medium, which showed that the fungus was a prolific producer of 4 methyl-progesteroids. The structures of 1-10 were elucidated by spectroscopic and X-ray crystallographic analysis. Their cytotoxic activities against five human cancer cell lines had been evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) method. PMID- 26254610 TI - Applying Novel Methods for Assessing Individual- and Neighborhood-Level Social and Psychosocial Environment Interactions with Genetic Factors in the Prediction of Depressive Symptoms in the Multi-Ethnic Study of Atherosclerosis. AB - Complex illnesses, like depression, are thought to arise from the interplay between psychosocial stressors and genetic predispositions. Approaches that take into account both personal and neighborhood factors and that consider gene regions as well as individual SNPs may be necessary to capture these interactions across race and ethnic groups. We used novel gene-region based analysis methods [Sequence Kernel Association Test (SKAT) and meta-analysis (MetaSKAT), gene environment set association test (GESAT)], as well as traditional linear models to identify gene region and SNP * psychosocial factor interactions at the individual- and neighborhood-level, across multiple race/ethnicities. Multiple regions identified in SKAT analyses showed evidence of a significant gene-region association with averaged depressive symptom scores across race/ethnicity (MetaSKAT p values <0.001). One region * neighborhood-environment interaction was significantly associated with averaged depressive symptom score across race/ethnicity after multiple testing correction (chr 18:21454070-21494070, Fisher's combined p value = 0.001). The examination of gene regions jointly with environmental factors measured at multiple levels (individuals and their contexts) may shed light on the etiology of depressive illness across race/ethnicities. PMID- 26254611 TI - Genome-wide profiling of DNA methylation reveals preferred sequences of DNMTs in hepatocellular carcinoma cells. AB - Aberrant DNA methylation of CpG site is among the earliest and most frequent alterations in developmental process and diseases including cancer. To elucidate the functional preferred site of DNMTs, we analyzed the feature of distinct methylated sequences and established the defined relationship between DNMTs and preference genomic DNA sequences. Small interfering RNA (siRNA) construct of DNTM1, DNMT3A, and DNMT3B was transfected into the human hepatocellular carcinoma cell line SMMC-7721, respectively. Distinguishing methylated fragments pool was enriched by SHH method in cells which is knocked down DNMT1, DNMT3A, DNMT3B, separately. The defined binding transcription factors (TFs) containing of 5'CpG islands were obtained with bioinformatics software and website. In SMMC-7721 hepatocellular carcinoma (HCC) cell line, DNMT1, DNMT3A, and DNMT3B were specific suppressed by their corresponding siRNA construct, separately. A 46, 42, 67 distinctive methylated fragments from three different DNMTs were evaluated according to genomic DNA database. Those separated fragments were distributed among genomic DNA regions of all chromosome complements, including coding genes, repeat sequences, and genes with unknown function. The majority of coding genes contain CpG islands in their promoter region. Cluster analysis demonstrated all of preference sequences identified by three DNMTs shares their own conserved sequences. In depleting of different DNMTs cells, 80 % of 103 upregulation genes induced by DNMT1 knock-down contain CpG sites; 76 % of 25 upregulation genes induced by DNMT3A knock-down contain CpG sites; 63 % of 126 upregulation genes induced by DNMT3B knock-down contain CpG sites. Our findings suggested that distinctive DNMTs targeted DNA methylation site to their preference sequences, and this targeting might be associated with diverse roles of DNMTs in tumorigenesis. Meanwhile, the analysis of preference sequences provides an alternative way to find out the individual function of DNMTs. PMID- 26254612 TI - Ethylacetate extract from Tetrastigma hemsleyanum induces apoptosis via the mitochondrial caspase-dependent intrinsic pathway in HepG2 cells. AB - Ethylacetate extract of Tetrastigma hemsleyanum (EET) has a potent antitumor activity in vitro and in vivo. However, the molecular mechanism underlying EET induced apoptosis remains elusive. As part of our continuing studies, we investigated the apoptosis mechanism of HepG2 cells exposed to different concentrations of EET in vitro. Confocal laser scanning was used to detect the apoptotic morphological changes. Flow cytometer and inverted fluorescence microscope were used to detect the mitochondrial membrane potential and cytosolic Ca(2+) level. Western blotting analysis was used to evaluate the expression of the apoptosis-related proteins. Annexin V/PI staining was used to investigate cell apoptosis. Spectrophotometry was used to detect the activity of caspase family. The results showed that distinct apoptotic morphological changes occurred in HepG2 cells treated by EET. EET caused collapse of mitochondrial membrane potential, elevation of cytosolic Ca(2+) level, and evoked release of cytochrome c from mitochondria in a concentration-dependent manner. The apoptosis was accompanied by a significant activation of caspase-3, caspase-9, and the cleavage of poly (ADP-ribose) polymerase, but there was no significant change in either the activity or the expression level of caspase-8. Furthermore, EET-induced apoptosis could be inhibited by caspase-9 inhibitor Z-LEHD-FMK but not by caspase 8 inhibitor Z-IETD-FMK. Taken together, these overall results demonstrated that EET-induced apoptosis of HepG2 cells was mediated by the mitochondrial caspase dependent intrinsic pathway rather than the death receptor/caspase-8-mediated signaling route. PMID- 26254613 TI - Prognostic analysis of primary mucin-producing adenocarcinoma of the lung: a comprehensive retrospective study. AB - Although primary mucin-producing adenocarcinoma of the lung is uncommon, each subtype has distinct clinical, pathological, molecular, and prognostic characteristics. This study aimed to determine correlations between clinical and pathological features and genetic phenotypes with the prognosis. We immunohistochemically examined the protein levels of thyroid transcription factor 1 (TTF-1), Napsin A, and anaplastic lymphoma kinase (ALK) and genetically examined epidermal growth factor receptor (EGFR) and KRAS mutations in these mucin-producing tumors. A total of 75 cases of mucin-producing adenocarcinoma of the lung were examined. ALK protein positivity was 33.3 % (25/75), and primarily occurred in solid predominant with mucin production subtype (SA). KRAS mutations occurred in 22.7 % (17/75) of patients, predominantly in invasive mucinous adenocarcinoma (IMA). Positive TTF-1 and Napsin A expression was more common in SA, while they were both negative in IMA. The 1-, 3-, and 5-year progression-free survival rates of mucin-producing lung adenocarcinoma were 85, 64, and 38 %, respectively; the overall survival rates were 90, 67, and 50 %, respectively. Larger tumors, advanced stage, and lymph node metastasis were associated with poor prognosis. Mucinous minimally invasive adenocarcinoma (m-MIA) had the best prognosis, followed by IMA, SA, and acinar or papillary predominant adenocarcinoma with mucin production (A/P). KRAS mutations were an independent positive prognostic factor for postoperative progress. PMID- 26254614 TI - Prognostic value of long non-coding RNA MALAT1 in cancer patients. AB - Metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) was identified to be the first long non-coding RNA as a biomarker of independent prognostic value for early stage non-small cell lung cancer patient survival. In recent years, the association between upregulated tissue MALAT1 level and incidence of various cancers including bladder cancer, colorectal cancer, and renal cancer has been widely discussed. The aim of our present study was to assess the potential prognostic value of MALAT1 in various human cancers. PubMed, Embase, Ovid, and Cochrane Library databases were systematically searched, and eligible studies evaluating the prognostic value of MALAT1 in various cancers were included. Finally, 11 studies encompassing 1216 participants reporting with sufficient data were enrolled in the current meta-analysis. The pooled hazard ratio (HR) was 2.05 (95 % confidence interval (CI) 1.64-2.55, p < 0.01) for overall survival (OS) and 2.66 (95 % CI 1.86-3.80, p < 0.01) for disease-free survival (DFS). In conclusion, high tissue MALAT1 level was associated with an inferior clinical outcome in various cancers, suggesting that MALAT1 might serve as a potential prognostic biomarker for various cancers. PMID- 26254616 TI - Child behavior checklist dysregulation profile in children with disruptive behavior disorders: A longitudinal study. AB - BACKGROUND: A Child Behavior Checklist (CBCL) profile defined as Dysregulation Profile (DP) (scores 2 standard deviations or more in anxiety/depression, aggression, attention subscales) has been correlated to poor emotional and behavioral self-regulation. The clinical meaning and the prognostic implications of CBCL-DP are still debated, although it seems associated with severe psychopathology and poor adjustment. METHOD: In the present study, we used the CBCL-DP score to examine the adolescent outcomes (psychiatric diagnosis, substance use, psychiatric hospitalization) in 80 referred children with disruptive behavior disorders -DBD- (Oppositional Defiant Disorder or conduct disorder), aged 8-9 years, 72 males (90%) and 8 females (10%), followed-up until the age of 14-15 years. RESULTS: Children with higher score on the CBCL-DP profile were at increased risk for presenting ADHD and mood disorders in adolescence. While ADHD in adolescence was predicted also by an ADHD diagnosis during childhood, CBCL-DP score was the only significant predictor of a mood disorder at 14-15 years. On the contrary, CBCL-DP score was not associated with a higher risk of conduct disorder, substance use and hospitalizations in adolescence. A cost-effective and reliable diagnostic measure such as the CBCL may be a part of the diagnostic procedure aimed to capture these at-risk children, to monitor their natural history up to adolescence, and to prevent the risk of a full-blown mood disorder. LIMITATIONS: The small sample size and a selection bias of severe patients with DBD limit the generalization of the findings. PMID- 26254615 TI - Involvement of nuclear protein C23 in activation of EGFR signaling in cervical cancer. AB - Nuclear protein C23 and epidermal growth factor receptor (EGFR) are reported to be correlated with cervical cancer (CC). However the correlations between C23 and EGFR were rarely reported. Here, this study explored the effects of C23 in activation of EGFR signaling pathway. In our study, immunohistochemistry was used to identify the expression of C23 or EGFR in CC tissues. The level of the phosphorylated EGFR was observed by western blot, and cell invasion capacity was detected by Transwell assay. In this study, we found that C23 and EGFR were highly expressed in cervical cancer tissues, while C23 on the cell surface mainly expressed in CC tissues with lymph node metastasis, and was correlated to EGFR statistically. In vitro, western blot showed that either anti-C23 or anti-EGFR antibodies can inhibit the phosphorlation of EGFR with significant differences (p < 0.01). Besides, based on Transwell assay, the number of membrane-invading cells was reduced significantly in anti-C23 group, and no significant difference was found compared with anti-EGFR treatment (p > 0.05). In conclusion, C23 on the cell surface may be a kind of indispensable component in activation of EGFR signaling, by which C23 can participate in the growth and invasion of tumors. C23 antagonists may provide a new field for cervical cancer therapy. PMID- 26254617 TI - The impact of lifetime suicidality on academic performance in college freshmen. AB - BACKGROUND: While suicidal thoughts and behaviors (STB) among college students are common, the associations between STB and academic performance are not well understood. METHODS: As part of the World Mental Health Surveys International College Student project, web-based self-reported STB of KU Leuven (Leuven, Belgium) incoming freshmen (N=4921; response rate=65.4%) was collected, as well as academic year percentage (AYP), and the departments to which students belong. Single- and multilevel multivariate analyses were conducted, adjusted for gender, age, parental educational level, and comorbid lifetime emotional problems. RESULTS: Lifetime suicide plan and attempt upon college entrance were associated with significant decreases in AYP (3.6% and 7.9%, respectively). A significant interaction was found with average departmental AYP, with STB more strongly associated with reduced AYP in departments with lower than higher average AYP. LIMITATIONS: Limited sample size precluded further investigation of interactions between department-level and student-level variables. No information was available on freshman secondary school academic performance. CONCLUSIONS: Lifetime STB has a strong negative association with academic performance in college. Our study suggests a potential role for the college environment as target for treatment and prevention interventions. PMID- 26254618 TI - Changes in depression stigma after the Germanwings crash - Findings from German population surveys. AB - BACKGROUND: Media coverage of the Germanwings plane crash intensely focused on the co-pilot's mental illness and was criticized for potentially increasing depression stigma. We explored whether stigma beliefs towards persons with depression changed in April 2015 (about one month after the crash) compared to 2014. METHOD: Telephone surveys among the adult population were conducted in Munich, Germany (N=650 in 2014 and N=601 in 2015). In both surveys, four components of stigma were assessed: (1) characteristics ascribed to persons with a depression, (2) belief in a continuum of symptoms from mental health to mental illness, (3) emotional reactions to people afflicted by depression (fear, anger, and pro-social reactions), and (4) desire for social distance. RESULTS: Some stigmatizing attitudes have increased after the crash. More specifically, we found more pronounced changes in the attributes ascribed (stereotypes) and in the perceived separation from persons afflicted (continuum beliefs) than in the emotional reactions and the desire for social distance. However, overall increase in depression stigma was smaller than expected as changes were not statistically significant in the majority of the analyzed items. LIMITATIONS: Due to the study design no causal interpretation of results is possible. Moreover, evidence presented is confined to a regional German sample. CONCLUSIONS: A single devastating event and related media coverage seem to have a limited impact on public stigmatizing attitudes. PMID- 26254619 TI - Post-bereavement hallucinatory experiences: A critical overview of population and clinical studies. AB - BACKGROUND: Removal of the "bereavement exclusion" criterion for major depression and proposed research criteria for persistent complex bereavement disorder in DSM V pose new compelling issues regarding the adequacy of current nosographical boundaries. Post-bereavement hallucinatory experiences (PBHE) are abnormal sensory experiences that are frequently reported by bereaved individuals without a history of mental disorder. Given current uncertainty over the continuum of psychotic experiences in the general population, whether or not they should be considered pathological remains unclear. METHODS: In order to systemize available knowledge, we reviewed the literature describing general population and clinical studies on PBHEs. Given the relatively low number of articles, all peer-reviewed, published studies in English were included. No study characteristics or publication date restrictions were imposed. RESULTS: Overall, evidence suggests a strikingly high prevalence of PBHEs - ranging from 30% to 60% - among widowed subjects, giving consistence and legitimacy to these phenomena. LIMITATIONS: Whereas general population studies had adequate sample size numbers, all studies in the bereaved population had a very small number of subjects. No consensus for method of evaluation exists in the literature, with some studies using a free interview method and others using semi-structured interviews. CONCLUSIONS: The available literature appears to support an elevated frequency of PBHEs in bereaved individuals, but further research is needed to increase the reliability of these findings and refine the boundaries between physiological and pathological experiences. PMID- 26254620 TI - Core belief content examined in a large sample of patients using online cognitive behaviour therapy. AB - BACKGROUND: Computerised cognitive behavioural therapy provides a unique opportunity to collect and analyse data regarding the idiosyncratic content of people's core beliefs about the self, others and the world. METHODS: 'Beating the Blues' users recorded a core belief derived through the downward arrow technique. Core beliefs from 1813 mental health patients were coded into 10 categories. RESULTS: The most common were global self-evaluation, attachment, and competence. Women were more likely, and men were less likely (than chance), to provide an attachment-related core belief; and men were more likely, and women less likely, to provide a self-competence-related core belief. This may be linked to gender differences in sources of self-esteem. Those who were suffering from anxiety were more likely to provide power- and control-themed core beliefs and less likely to provide attachment core beliefs than chance. Finally, those who had thoughts of suicide in the preceding week reported less competence themed core beliefs and more global self-evaluation (e.g., 'I am useless') core beliefs than chance. LIMITATIONS: Concurrent symptom level was not available. The sample was not nationally representative, and featured programme completers only. CONCLUSIONS: Men and women may focus on different core beliefs in the context of CBT. Those suffering anxiety may need a therapeutic focus on power and control. A complete rejection of the self (not just within one domain, such as competence) may be linked to thoughts of suicide. Future research should examine how individual differences and symptom severity influence core beliefs. PMID- 26254621 TI - Association between genetic variants related to glutamatergic, dopaminergic and neurodevelopment pathways and white matter microstructure in child and adolescent patients with obsessive-compulsive disorder. AB - BACKGROUND: Alterations in white matter (WM) integrity observed in patients with obsessive-compulsive disorder (OCD) may be at least partly determined genetically. Neuroimaging measures of WM microstructure could serve as promising intermediate phenotypes for genetic analysis of the disorder. The objective of the present study was to explore the association between variability in genes related to the pathophysiology of OCD and altered WM microstructure previously identified in child and adolescent patients with the disease. METHODS: Fractional anisotropy (FA) and mean diffusivity (MD) measured by diffusion tensor imaging (DTI) and 262 single nucleotide polymorphisms (SNPs) in 35 candidate genes were assessed concomitantly in 54 child and adolescent OCD patients. RESULTS: Six polymorphisms located in the glutamate transporter gene (SLC1A1 rs3087879), dopamine transporter gene (SLC6A3 rs4975646), dopamine receptor D3 (DRD3 rs3773679), nerve growth factor receptor gene (NGFR rs734194 and rs2072446), and cadherin 9 gene (CDH9 rs6885387) showed significant p-values after Bonferroni correction (p<=0.00019). More specifically, the vast majority of these associations were detected with MD in the right and left anterior and posterior cerebellar lobes. LIMITATIONS: Patients were under pharmacological treatment at the time of the DTI examination. Sample size is limited. CONCLUSIONS: The results provide the first evidence of the involvement of genetic variants related to glutamatergic, dopaminergic, and neurodevelopmental pathways in determining the WM microstructure of child and adolescent patients with OCD, which could be related to the neurobiology of the disorder. PMID- 26254622 TI - Should serum sodium level be part of stroke protocol prior to t-PA administration? PMID- 26254623 TI - Corticosteroid-responsive leptomeningitis with IgG4-positive plasma-cell infiltration. PMID- 26254624 TI - Developmental alterations of the auditory brainstem centers--pathogenetic implications in Sudden Infant Death Syndrome. AB - Sudden Infant Death Syndrome (SIDS), despite the success of campaigns to reduce its risks, is the leading cause of infant death in the Western world. Even though the pathogenesis remains unexplained, brainstem abnormalities of the neuronal network that mediates breathing and protective responses to asphyxia, particularly in the arousal phase from sleep, are believed to play a fundamental role. This is the first study to identify, in SIDS, developmental defects of specific brainstem centers involved in hearing pathways, particularly in the cochlear and vestibular nuclei, in the superior olivary complex and in the inferior colliculus, suggesting a possible influence of the acoustic system on respiratory activity. In 49 SIDS cases and 20 controls an in-depth anatomopathological examination of the autonomic nervous system was performed, with the main aim of detecting developmental alterations of brainstem structures controlling both the respiratory and auditory activities. Overall, a significantly higher incidence of cytoarchitectural alterations of both the auditory and respiratory network components were observed in SIDS victims compared with matched controls. Even if there is not sufficient evidence to presume that developmental defects of brainstem auditory structures can affect breathing, our findings, showing that developmental deficit in the control respiratory areas are frequently accompanied by alterations of auditory structures, highlight an additional important element for the understanding the pathogenetic mechanism of SIDS. PMID- 26254625 TI - Screening of RET gene mutations in Chinese patients with medullary thyroid carcinoma and their relatives. AB - The rearranged during transfection (RET) gene is a proto-oncogene; active mutations frequently occur in medullary thyroid carcinoma (MTC). This study investigated the spectrum of germline RET mutations and clinical features in Chinese hereditary MTC patients. A total of 53 family members from 11 different hereditary MTC families were recruited for detection of RET exon 8, 10, 11, 13, 14, 15, and 16 mutations, in genomic DNA from peripheral blood leucocytes using polymerase chain reaction (PCR) and direct DNA sequencing. Of the 53 participants, eight different germline RET mutations were detected in 37 individuals. These RET mutations were distributed in exons 10, 11, 13, and 16. The most frequent RET mutation was localized at exon 11 codon 634 (67.6 %; 25/37) and the most prevalent mutation was C634R (37.8 %; 14/37). The most frequent phenotype was multiple endocrine neoplasia type 2A (MEN2A). The incidences of MTC, pheochromocytoma, and hyperparathyroidism in the MEN2A patients were 100, 36.4 and 18.2 %, respectively. The phenotype of families with Y606C or L790F mutation was categorized as familial medullary thyroid carcinoma. Moreover, one proband was identified with multiple endocrine neoplasia type 2B and carried a de novo mutation of M918T. Two families with C618S/Y mutation were categorized as unclassified multiple endocrine neoplasia type 2. Our results further substantiate that most germline mutations of the RET proto-oncogene were localized at codon 634 in Chinese hereditary MTC patients and carriers. RET mutation at codon 634 was always associated to the phenotype of MEN2A. Screening of RET mutations should be probably limited to exons 10, 11, 13 and 16 initially to be cost-effective in China. PMID- 26254626 TI - Fingermark initial composition and aging using Fourier transform infrared microscopy (MU-FTIR). AB - This study investigated fingermark residues using Fourier transform infrared microscopy (MU-FTIR) in order to obtain fundamental information about the marks' initial composition and aging kinetics. This knowledge would be an asset for fundamental research on fingermarks, such as for dating purposes. Attenuated total reflection (ATR) and single-point reflection modes were tested on fresh fingermarks. ATR proved to be better suited and this mode was subsequently selected for further aging studies. Eccrine and sebaceous material was found in fresh and aged fingermarks and the spectral regions 1000-1850cm(-1) and 2700 3600cm(-1) were identified as the most informative. The impact of substrates (aluminium and glass slides) and storage conditions (storage in the light and in the dark) on fingermark aging was also studied. Chemometric analyses showed that fingermarks could be grouped according to their age regardless of the substrate when they were stored in an open box kept in an air-conditioned laboratory at around 20 degrees C next to a window. On the contrary, when fingermarks were stored in the dark, only specimens deposited on the same substrate could be grouped by age. Thus, the substrate appeared to influence aging of fingermarks in the dark. Furthermore, PLS regression analyses were conducted in order to study the possibility of modelling fingermark aging for potential fingermark dating applications. The resulting models showed an overall precision of +/-3 days and clearly demonstrated their capability to differentiate older fingermarks (20 and 34 days old) from newer ones (1, 3, 7 and 9 days old) regardless of the substrate and lighting conditions. These results are promising from a fingermark dating perspective. Further research is required to fully validate such models and assess their robustness and limitations in uncontrolled casework conditions. PMID- 26254627 TI - Phenazepam: A review of medico-legal deaths in South Scotland between 2010 and 2014. AB - Phenazepam is a long acting benzodiazepine that is not prescribed in the United Kingdom. In Scotland it has been detected in a large number of post mortem cases, but very little data has been published looking at post mortem concentrations of this drug and indeed concentrations that may be associated with causing death. We looked at all post mortem cases between 2010 and 2014 where phenazepam was found in blood and correlated these with the given cause of death. The data collected shows the variability in reporting of phenazepam deaths and will provide a useful tool for those deciding when phenazepam should or should not be included as a cause of death. Cases discussed include drug related deaths with phenazepam as the sole cause of death (as is), drug related death when the cause of death was noted as being from a combination of phenazepam plus one or more other drugs (range <0.005-0.9mg/L, median 0.10mg/L) and causes of death in non-drug related deaths where phenazepam was detected (hangings range <0.05-0.39mg/L, median 0.09mg/L and deaths due to ischaemic heart disease range 0.05-0.1mg/L, median 0.04mg/L). PMID- 26254628 TI - Evaluation and comparison of 1,2-indanedione and 1,8-diazafluoren-9-one solutions for the enhancement of latent fingerprints on porous surfaces. AB - 1,2-indanedione (1,2-IND) and 1,8-diazafluoren-9-one (DFO) are used in the forensic field to enhance latent fingerprints deposited on porous surfaces due to the formation of fluorescent products by reacting with the amino acids present in the papillary exudate. The study was carried out in collaboration with the Fingerprints and Photography Section of the Carabinieri Scientific Investigation Department (RIS) of Rome, in which laboratories, until now, DFO has been the most used because of its excellent enhancing properties, even if it is more expensive and relatively toxic in comparison with the 1,2-IND. The aim of this work was then to evaluate and to compare the effectiveness of three solutions of 1,2-IND in different formulations and a DFO solution employed as single enhancing treatments, in order to assess whether it was possible to replace a reagent with the other obtaining equally satisfying results. In this case, white office paper was selected as deposit surface since it also permitted one to observe those reaction products that appear visible to a naked eye. Beside to a qualitative study of the visual characteristic of the enhanced fingerprints, further quantitative studies were conducted on the intensity of fluorescence of the products and on the consumption of amino acids during the reaction. The analyses, which at first were conducted on standard samples, were then repeated on real samples to validate the results obtained. The DFO confirmed its excellent enhancement properties, but also one of the three solutions of 1,2-IND showed comparable properties in terms of enhanced fingerprint definition and stability over time from the completion of a crime. As a result, we proved that a selected 1,2-IND formulation may replace with satisfactory achievements the DFO solution currently employed, providing also advantages from the point of view of safety and cost savings. PMID- 26254629 TI - Discrepancies in expert decision-making in forensic fingerprint examination. AB - The purpose of the present study was to analyse professional fingerprint examiners' investigative practices in the context of discrepancy decisions concerning challenging latents during fingerprint analysis and identification. The participants were fingerprint experts from the Forensic Laboratory of the Finnish National Bureau of Investigation. The data were from five audio-recorded "discrepancy meetings" where two examiners were discussing the rationale and justification for their differing interpretations of challenging and distorted fingerprint evidence. The meetings were chaired by the quality manager of the fingerprint group, who also in the first author of this article. The research questions addressed were as follows: What does the examiner see in the latent fingerprints? What does the examiner actively do with the latents? How were decisions made during the investigative process? In accordance with Goodwin's professional vision framework, the results revealed how the participants used partial and limited information in making judgments about the difficult and distorted latents. The examiners appeared to be involved in active, constructive efforts, mentally, to repair poor latents by supplementing with missing information. They also highlighted various aspects of latents by colour coding as well as manipulated fingerprint images in several ways so as to make the significant patterns easier to recognize. Because the methods and practices of characterizing latents were only vaguely specified, the examiners used locally developed ad hoc practices to facilitate their investigations, ending up with different interpretations. It is concluded in the article that the fingerprint community in Finland should make strong efforts to develop the methods of fingerprint investigation and determine clearer criteria for decision making and documentation practices. Furthermore, the interpretations made by fingerprint experts should be made more transparent to the customers. PMID- 26254630 TI - Thermal requirements of Ophyra albuquerquei Lopes, 1985 (Diptera, Muscidae). AB - This study determines the development rates of the immature stages of the fly Ophyra albuquerquei Lopes, 1985. In this study, with 70% relative humidity and a 12-h photophase, eggs, larvae, and pupae were kept in a biochemical oxygen demand chamber at temperatures of 10, 15, 17, 20, 22, 25, 27, 30, 33, 35, and 40 degrees C. While the rearing temperature increases, the development time for each immature stage of O. albuquerquei decreases and these stages develop at temperatures from 10 to 35 degrees C. For eggs, the average minimum development time was 16h, and the average maximum development time was 81h. The average minimum development time for larvae and pupae was 7 and 6 days, respectively, and the average maximum development time was 22 and 42 days, respectively. To understand the development rate of each immature stage of the fly, a mathematical model is presented. PMID- 26254631 TI - Using evaluation to improve medical student rural experience. AB - Objective The aim of this evaluation was to see whether interventions implemented to improve the Rural Medicine Rotation made this a more effective rural medical education experience. Multiple interventions targeting the student experience, lecturers and preceptors were implemented. Methods A quasi-experimental design using pre- and post-measures was used. The participants were all University of Queensland, School of Medicine, Rural Medicine Rotation students who completed the 2009 and 2010 rural medicine rotation evaluations. There were 769 students, with an 84% response rate in 2009 and an 80% response rate in 2010. In addition, all the 25 program preceptors who were visited in 2009 and the 34 who were visited in 2010 participated in the study. Results The implementation of interventions resulted in significant improvement in three outcome measures, namely teaching effectiveness, provision of an environment supportive of learning in a rural/remote setting and opportunities for professional growth. Two of the three other outcome measures - ensuring a safe clinical placement and opportunities for procedural skills experience and development - were very positively evaluated in both 2009 and 2010. Conclusions The interventions contributed to a more effective rural medical education experience, providing students with the opportunity to develop skills and knowledge relevant for rural medicine and to gain an understanding of the context in which rural medicine is practiced. What is known about the topic? Many Australian medical schools offer students rural-based educational opportunities based on the premise that placing medical students in a rural setting may ultimately lead to them choosing careers in rural medicine. However, there is a paucity of evidence on the factors that are considered necessary for medical students to gain a positive rural experience of short conscripted rural placements. What does the paper add? This paper identifies successful interventions to the rotation and placements that provide a positive experience of the rural clinical placement for students. These interventions occurred within an ongoing evaluation program embedded in the rotation. What are the implications for practitioners? Through ongoing evaluation, interventions can be selected and implemented that succeed in contributing to students having a positive rural clinical placement experience. This paper demonstrates how an embedded continuous improvement program serves to provide direction for ongoing modifications. PMID- 26254632 TI - Communication: Tracking molecular structure deformation and relaxation in real time. AB - The CH3I structural deformation induced by strong laser fields is revealed by time- and frequency-resolved ro-vibrational spectra. The experimental results show that the CH3I molecule undergoes ultrafast structural deformation of CH3 "umbrella-closing" induced by the strong fs laser field (more than 10(11) W/cm(2)) and followed by a structural relaxation of "umbrella-opening" within an exponential decay time scale of ~620 fs. This study provides a first glimpse of the immense potential of the time- and frequency-resolved vibrational spectra in studying molecular deformation dynamics. PMID- 26254633 TI - Communication: The simplified generalized entropy theory of glass-formation in polymer melts. AB - While a wide range of non-trivial predictions of the generalized entropy theory (GET) of glass-formation in polymer melts agree with a large number of observed universal and non-universal properties of these glass-formers and even for the dependence of these properties on monomer molecular structure, the huge mathematical complexity of the theory precludes its extension to describe, for instance, the perplexing, complex behavior observed for technologically important polymer films with thickness below ~100 nm and for which a fundamental molecular theory is lacking for the structural relaxation. The present communication describes a hugely simplified version of the theory, called the simplified generalized entropy theory (SGET) that provides one component necessary for devising a theory for the structural relaxation of thin polymer films and thereby supplements the first required ingredient, the recently developed Flory-Huggins level theory for the thermodynamic properties of thin polymer films, before the concluding third step of combining all the components into the SGET for thin polymer films. Comparisons between the predictions of the SGET and the full GET for the four characteristic temperatures of glass-formation provide good agreement for a highly non-trivial model system of polymer melts with chains of the structure of poly(n-alpha olefins) systems where the GET has produced good agreement with experiment. The comparisons consider values of the relative backbone and side group stiffnesses such that the glass transition temperature decreases as the amount of excess free volume diminishes, contrary to general expectations but in accord with observations for poly(n-alkyl methacrylates). Moreover, the SGET is sufficiently concise to enable its discussion in a standard course on statistical mechanics or polymer physics. PMID- 26254634 TI - Communication: Practical intramolecular symmetry adapted perturbation theory via Hartree-Fock embedding. AB - We develop a simple methodology for the computation of symmetry-adapted perturbation theory (SAPT) interaction energy contributions for intramolecular noncovalent interactions. In this approach, the local occupied orbitals of the total Hartree-Fock (HF) wavefunction are used to partition the fully interacting system into three chemically identifiable units: the noncovalent fragments A and B and a covalent linker C. Once these units are identified, the noninteracting HF wavefunctions of the fragments A and B are separately optimized while embedded in the HF wavefunction of C, providing the dressed zeroth order wavefunctions for A and B in the presence of C. Standard two-body SAPT (particularly SAPT0) is then applied between the relaxed wavefunctions for A and B. This intramolecular SAPT procedure is found to be remarkably straightforward and efficient, as evidenced by example applications ranging from diols to hexaphenyl-ethane derivatives. PMID- 26254635 TI - Communication: Maximum caliber is a general variational principle for nonequilibrium statistical mechanics. AB - There has been interest in finding a general variational principle for non equilibrium statistical mechanics. We give evidence that Maximum Caliber (Max Cal) is such a principle. Max Cal, a variant of maximum entropy, predicts dynamical distribution functions by maximizing a path entropy subject to dynamical constraints, such as average fluxes. We first show that Max Cal leads to standard near-equilibrium results-including the Green-Kubo relations, Onsager's reciprocal relations of coupled flows, and Prigogine's principle of minimum entropy production-in a way that is particularly simple. We develop some generalizations of the Onsager and Prigogine results that apply arbitrarily far from equilibrium. Because Max Cal does not require any notion of "local equilibrium," or any notion of entropy dissipation, or temperature, or even any restriction to material physics, it is more general than many traditional approaches. It also applicable to flows and traffic on networks, for example. PMID- 26254636 TI - Spin polarization transfer by the radical pair mechanism. AB - In a three-site representation, we study a spin polarization transfer from radical pair spins to a nearby electron or nuclear spin. The quantum dynamics of the radical pair spins is governed by a constant exchange interaction between the radical pair spins which have different Zeeman frequencies. Radical pair spins can recombine to the singlet ground state or to lower energy triplet states. It is then shown that the coherent dynamics of the radical pair induces spin polarization on the nearby third spin in the presence of a magnetic field. The spin polarization transfer depends on the difference between Zeeman frequencies, the singlet and triplet recombination rates, and on the exchange and dipole dipole interactions between the different spins. In particular, the sign of the polarization depends on the exchange coupling between radical pair spins and also on the difference between singlet and triplet recombination rate constants. PMID- 26254637 TI - Invertibility of retarded response functions for Laplace transformable potentials: Application to one-body reduced density matrix functional theory. AB - A theorem for the invertibility of arbitrary response functions is presented under the following conditions: the time dependence of the potentials should be Laplace transformable and the initial state should be a ground state, though it might be degenerate. This theorem provides a rigorous foundation for all density functional-like theories in the time-dependent linear response regime. Especially for time-dependent one-body reduced density matrix (1RDM) functional theory, this is an important step forward, since a solid foundation has currently been lacking. The theorem is equally valid for static response functions in the non degenerate case, so can be used to characterize the uniqueness of the potential in the ground state version of the corresponding density-functional-like theory. Such a classification of the uniqueness of the non-local potential in ground state 1RDM functional theory has been lacking for decades. With the aid of presented invertibility theorem presented here, a complete classification of the non-uniqueness of the non-local potential in 1RDM functional theory can be given for the first time. PMID- 26254638 TI - Frictional effects near a metal surface. AB - When a classical master equation (CME) is used to describe the nonadiabatic dynamics of a molecule at metal surfaces, we show that in the regime of reasonably strong molecule-metal couplings, the CME can be reduced to a Fokker Planck equation with an explicit form of electronic friction. For a single metal substrate at thermal equilibrium, the electronic friction and random force satisfy the fluctuation-dissipation theorem. When we investigate the time scale for an electron transfer (ET) event between the molecule and metal surface, we find that the ET rates show a turnover effect (just as in Kramer's theory) as a function of frictional damping. PMID- 26254639 TI - Simulation of biochemical reactions with time-dependent rates by the rejection based algorithm. AB - We address the problem of simulating biochemical reaction networks with time dependent rates and propose a new algorithm based on our rejection-based stochastic simulation algorithm (RSSA) [Thanh et al., J. Chem. Phys. 141(13), 134116 (2014)]. The computation for selecting next reaction firings by our time dependent RSSA (tRSSA) is computationally efficient. Furthermore, the generated trajectory is exact by exploiting the rejection-based mechanism. We benchmark tRSSA on different biological systems with varying forms of reaction rates to demonstrate its applicability and efficiency. We reveal that for nontrivial cases, the selection of reaction firings in existing algorithms introduces approximations because the integration of reaction rates is very computationally demanding and simplifying assumptions are introduced. The selection of the next reaction firing by our approach is easier while preserving the exactness. PMID- 26254640 TI - Truncation-based energy weighting string method for efficiently resolving small energy barriers. AB - The string method is a useful numerical technique for resolving minimum energy paths in rare-event barrier-crossing problems. However, when applied to systems with relatively small energy barriers, the string method becomes inconvenient since many images trace out physically uninteresting regions where the barrier has already been crossed and recrossing is unlikely. Energy weighting alleviates this difficulty to an extent, but typical implementations still require the string's endpoints to evolve to stable states that may be far from the barrier, and deciding upon a suitable energy weighting scheme can be an iterative process dependent on both the application and the number of images used. A second difficulty arises when treating nucleation problems: for later images along the string, the nucleus grows to fill the computational domain. These later images are unphysical due to confinement effects and must be discarded. In both cases, computational resources associated with unphysical or uninteresting images are wasted. We present a new energy weighting scheme that eliminates all of the above difficulties by actively truncating the string as it evolves and forcing all images, including the endpoints, to remain within and cover uniformly a desired barrier region. The calculation can proceed in one step without iterating on strategy, requiring only an estimate of an energy value below which images become uninteresting. PMID- 26254641 TI - Orbitals from local RDMFT: Are they Kohn-Sham or natural orbitals? AB - Recently, an approximate theoretical framework was introduced, called local reduced density matrix functional theory (local-RDMFT), where functionals of the one-body reduced density matrix (1-RDM) are minimized under the additional condition that the optimal orbitals satisfy a single electron Schrodinger equation with a local potential. In the present work, we focus on the character of these optimal orbitals. In particular, we compare orbitals obtained by local RDMFT with those obtained with the full minimization (without the extra condition) by contrasting them against the exact NOs and orbitals from a density functional calculation using the local density approximation (LDA). We find that the orbitals from local-RMDFT are very close to LDA orbitals, contrary to those of the full minimization that resemble the exact NOs. Since local RDMFT preserves the good quality of the description of strong static correlation, this finding opens the way to a mixed density/density matrix scheme, where Kohn-Sham orbitals obtain fractional occupations from a minimization of the occupation numbers using 1-RDM functionals. This will allow for a description of strong correlation at a cost only minimally higher than a density functional calculation. PMID- 26254642 TI - Consistent structures and interactions by density functional theory with small atomic orbital basis sets. AB - A density functional theory (DFT) based composite electronic structure approach is proposed to efficiently compute structures and interaction energies in large chemical systems. It is based on the well-known and numerically robust Perdew Burke-Ernzerhoff (PBE) generalized-gradient-approximation in a modified global hybrid functional with a relatively large amount of non-local Fock-exchange. The orbitals are expanded in Ahlrichs-type valence-double zeta atomic orbital (AO) Gaussian basis sets, which are available for many elements. In order to correct for the basis set superposition error (BSSE) and to account for the important long-range London dispersion effects, our well-established atom-pairwise potentials are used. In the design of the new method, particular attention has been paid to an accurate description of structural parameters in various covalent and non-covalent bonding situations as well as in periodic systems. Together with the recently proposed three-fold corrected (3c) Hartree-Fock method, the new composite scheme (termed PBEh-3c) represents the next member in a hierarchy of "low-cost" electronic structure approaches. They are mainly free of BSSE and account for most interactions in a physically sound and asymptotically correct manner. PBEh-3c yields good results for thermochemical properties in the huge GMTKN30 energy database. Furthermore, the method shows excellent performance for non-covalent interaction energies in small and large complexes. For evaluating its performance on equilibrium structures, a new compilation of standard test sets is suggested. These consist of small (light) molecules, partially flexible, medium-sized organic molecules, molecules comprising heavy main group elements, larger systems with long bonds, 3d-transition metal systems, non-covalently bound complexes (S22 and S66*8 sets), and peptide conformations. For these sets, overall deviations from accurate reference data are smaller than for various other tested DFT methods and reach that of triple-zeta AO basis set second-order perturbation theory (MP2/TZ) level at a tiny fraction of computational effort. Periodic calculations conducted for molecular crystals to test structures (including cell volumes) and sublimation enthalpies indicate very good accuracy competitive to computationally more involved plane-wave based calculations. PBEh 3c can be applied routinely to several hundreds of atoms on a single processor and it is suggested as a robust "high-speed" computational tool in theoretical chemistry and physics. PMID- 26254643 TI - Analytic nuclear forces and molecular properties from full configuration interaction quantum Monte Carlo. AB - Unbiased stochastic sampling of the one- and two-body reduced density matrices is achieved in full configuration interaction quantum Monte Carlo with the introduction of a second, "replica" ensemble of walkers, whose population evolves in imaginary time independently from the first and which entails only modest additional computational overheads. The matrices obtained from this approach are shown to be representative of full configuration-interaction quality and hence provide a realistic opportunity to achieve high-quality results for a range of properties whose operators do not necessarily commute with the Hamiltonian. A density-matrix formulated quasi-variational energy estimator having been already proposed and investigated, the present work extends the scope of the theory to take in studies of analytic nuclear forces, molecular dipole moments, and polarisabilities, with extensive comparison to exact results where possible. These new results confirm the suitability of the sampling technique and, where sufficiently large basis sets are available, achieve close agreement with experimental values, expanding the scope of the method to new areas of investigation. PMID- 26254644 TI - Voltage equilibration for reactive atomistic simulations of electrochemical processes. AB - We introduce electrochemical dynamics with implicit degrees of freedom (EChemDID), a model to describe electrochemical driving force in reactive molecular dynamics simulations. The method describes the equilibration of external electrochemical potentials (voltage) within metallic structures and their effect on the self-consistent partial atomic charges used in reactive molecular dynamics. An additional variable assigned to each atom denotes the local potential in its vicinity and we use fictitious, but computationally convenient, dynamics to describe its equilibration within connected metallic structures on-the-fly during the molecular dynamics simulation. This local electrostatic potential is used to dynamically modify the atomic electronegativities used to compute partial atomic changes via charge equilibration. Validation tests show that the method provides an accurate description of the electric fields generated by the applied voltage and the driving force for electrochemical reactions. We demonstrate EChemDID via simulations of the operation of electrochemical metallization cells. The simulations predict the switching of the device between a high-resistance to a low-resistance state as a conductive metallic bridge is formed and resistive currents that can be compared with experimental measurements. In addition to applications in nanoelectronics, EChemDID could be useful to model electrochemical energy conversion devices. PMID- 26254645 TI - Reference interaction site model with hydrophobicity induced density inhomogeneity: An analytical theory to compute solvation properties of large hydrophobic solutes in the mixture of polyatomic solvent molecules. AB - Reference interaction site model (RISM) has recently become a popular approach in the study of thermodynamical and structural properties of the solvent around macromolecules. On the other hand, it was widely suggested that there exists water density depletion around large hydrophobic solutes (>1 nm), and this may pose a great challenge to the RISM theory. In this paper, we develop a new analytical theory, the Reference Interaction Site Model with Hydrophobicity induced density Inhomogeneity (RISM-HI), to compute solvent radial distribution function (RDF) around large hydrophobic solute in water as well as its mixture with other polyatomic organic solvents. To achieve this, we have explicitly considered the density inhomogeneity at the solute-solvent interface using the framework of the Yvon-Born-Green hierarchy, and the RISM theory is used to obtain the solute-solvent pair correlation. In order to efficiently solve the relevant equations while maintaining reasonable accuracy, we have also developed a new closure called the D2 closure. With this new theory, the solvent RDFs around a large hydrophobic particle in water and different water-acetonitrile mixtures could be computed, which agree well with the results of the molecular dynamics simulations. Furthermore, we show that our RISM-HI theory can also efficiently compute the solvation free energy of solute with a wide range of hydrophobicity in various water-acetonitrile solvent mixtures with a reasonable accuracy. We anticipate that our theory could be widely applied to compute the thermodynamic and structural properties for the solvation of hydrophobic solute. PMID- 26254647 TI - The Renner-Teller effect in HCCCN(+)(X(2)Pi) studied by zero-kinetic energy photoelectron spectroscopy and theoretical calculations. AB - The spin-vibronic energy levels of the cyanoacetylene cation have been measured using the one-photon zero-kinetic energy (ZEKE) photoelectron spectroscopic method. All three degenerate vibrational modes showing vibronic coupling, i.e., Renner-Teller (RT) effect, have been observed. All the splitting spin-vibronic energy levels of the fundamental H-C=C bending vibration (v5) have been determined. The spin-vibronic energy levels of the degenerate vibrational modes have also been calculated using a diabatic model in which the harmonic terms as well as all the second-order vibronic coupling terms are used. The theoretical predictions are in good agreement with the experimental data and are used to assign the ZEKE spectrum. It is found that the RT effects for the H-(CC)-CN bending (v7) and the C-C=N bending (v6) vibrations are weak, whereas they are strong for the H-C=C bending (v5) vibration. The cross-mode RT couplings between any of the two degenerate vibrations are strong. The spin-orbit resolved fundamental vibrational energy levels of the C=N stretching (v2) and C-H stretching (v1) vibrations have also been observed. The spin-orbit energy splitting of the ground state has been determined for the first time as 43 +/- 2 cm(-1), and the ionization energy of HCCCN is found to be 93 903.5 +/- 2 cm(-1). PMID- 26254646 TI - Time domain DNP with the NOVEL sequence. AB - We present results of a pulsed dynamic nuclear polarization (DNP) study at 0.35 T (9.7 GHz/14.7 MHz for electron/(1)H Larmor frequency) using a lab frame-rotating frame cross polarization experiment that employs electron spin locking fields that match the (1)H nuclear Larmor frequency, the so called NOVEL (nuclear orientation via electron spin locking) condition. We apply the method to a series of DNP samples including a single crystal of diphenyl nitroxide (DPNO) doped benzophenone (BzP), 1,3-bisdiphenylene-2-phenylallyl (BDPA) doped polystyrene (PS), and sulfonated-BDPA (SA-BDPA) doped glycerol/water glassy matrices. The optimal Hartman-Hahn matching condition is achieved when the nutation frequency of the electron matches the Larmor frequency of the proton, omega(1S) = omega(0I), together with possible higher order matching conditions at lower efficiencies. The magnetization transfer from electron to protons occurs on the time scale of ~100 ns, consistent with the electron-proton couplings on the order of 1-10 MHz in these samples. In a fully protonated single crystal DPNO/BzP, at 270 K, we obtained a maximum signal enhancement of epsilon = 165 and the corresponding gain in sensitivity of epsilon(T1/T(B))(1/2)=230 due to the reduction in the buildup time under DNP. In a sample of partially deuterated PS doped with BDPA, we obtained an enhancement of 323 which is a factor of ~3.2 higher compared to the protonated version of the same sample and accounts for 49% of the theoretical limit. For the SA-BDPA doped glycerol/water glassy matrix at 80 K, the sample condition used in most applications of DNP in nuclear magnetic resonance, we also observed a significant enhancement. Our findings demonstrate that pulsed DNP via the NOVEL sequence is highly efficient and can potentially surpass continuous wave DNP mechanisms such as the solid effect and cross effect which scale unfavorably with increasing magnetic field. Furthermore, pulsed DNP is also a promising avenue for DNP at high temperature. PMID- 26254648 TI - Microsolvation of sodium acetate in water: Anion photoelectron spectroscopy and ab initio calculations. AB - To understand the microsolvation of sodium acetate (CH3COONa, NaOAc) in water, we studied NaOAc(H2O)n(-) (n = 0-3) clusters by photoelectron spectroscopy. We also investigated the structures of NaOAc(H2O)n(-) (n = 0-5) anions and NaOAc(H2O)n (n = 0-7) neutrals by quantum chemistry calculations. By comparing the theoretical results with the photoelectron experiment, the most probable structures of NaOAc(H2O)n(-/0) (n = 0-3) were determined. The study also shows that, with increasing n, the solvent-separated ion pair (SSIP) structures of NaOAc(H2O)n(-) anions become nearly energetically degenerate with the contact ion pair (CIP) structures at n = 5, while the SSIP structures of the neutral NaOAc(H2O)n clusters appear at n = 6 and become dominant at n = 7. PMID- 26254649 TI - Accurate transport properties for H-CO and H-CO2. AB - Transport properties for collisions of hydrogen atoms with CO and CO2 have been computed by means of quantum scattering calculations. The carbon oxides are important species in hydrocarbon combustion. The following potential energy surfaces (PES's) for the interaction of the molecule fixed in its equilibrium geometry were employed: for H-CO, the PES was taken from the work of Song et al. [J. Phys. Chem. A 117, 7571 (2013)], while the PES for H-CO2 was computed in this study by a restricted coupled cluster method that included single, double, and (perturbatively) triple excitations. The computed transport properties were found to be significantly different from those computed by the conventional approach that employs isotropic Lennard-Jones (12-6) potentials. The effect of using the presently computed accurate transport properties in 1-dimensional combustion simulations of methane-air flames was investigated. PMID- 26254650 TI - An improved potential energy surface and multi-temperature quasiclassical trajectory calculations of N2 + N2 dissociation reactions. AB - Accurate modeling of high-temperature hypersonic flows in the atmosphere requires consideration of collision-induced dissociation of molecular species and energy transfer between the translational and internal modes of the gas molecules. Here, we describe a study of the N2 + N2?N2 + 2N and N2 + N2?4N nitrogen dissociation reactions using the quasiclassical trajectory (QCT) method. The simulations used a new potential energy surface for the N4 system; the surface is an improved version of one that was presented previously. In the QCT calculations, initial conditions were determined based on a two-temperature model that approximately separates the translational-rotational temperature from the vibrational temperature of the N2 diatoms. Five values from 8000 K to 30,000 K were considered for each of the two temperatures. Over 2.4 * 10(9) trajectories were calculated. We present results for ensemble-averaged dissociation rate constants as functions of the translational-rotational temperature T and the vibrational temperature T(v). The rate constant depends more strongly on T when T(v) is low, and it depends more strongly on T(v) when T is low. Quasibound reactant states contribute significantly to the rate constants, as do exchange processes at higher temperatures. We discuss two sets of runs in detail: an equilibrium test set in which T = T(v) and a nonequilibrium test set in which T(v) < T. In the equilibrium test set, high-v and moderately-low-j molecules contribute most significantly to the overall dissociation rate, and this state specificity becomes stronger as the temperature decreases. Dissociating trajectories tend to result in a major loss of vibrational energy and a minor loss of rotational energy. In the nonequilibrium test set, as T(v) decreases while T is fixed, higher-j molecules contribute more significantly to the dissociation rate, dissociating trajectories tend to result in a greater rotational energy loss, and the dissociation probability's dependence on v weakens. In this way, as T(v) decreases, rotational energy appears to compensate for the decline in average vibrational energy in promoting dissociation. In both the equilibrium and nonequilibrium test sets, in every case, the average total internal energy loss in the dissociating trajectories is between 10.2 and 11.0 eV, slightly larger than the equilibrium potential energy change of N2 dissociation. PMID- 26254651 TI - Solvent effects in time-dependent self-consistent field methods. II. Variational formulations and analytical gradients. AB - This study describes variational energy expressions and analytical excited state energy gradients for time-dependent self-consistent field methods with polarizable solvent effects. Linear response, vertical excitation, and state specific solvent models are examined. Enforcing a variational ground state energy expression in the state-specific model is found to reduce it to the vertical excitation model. Variational excited state energy expressions are then provided for the linear response and vertical excitation models and analytical gradients are formulated. Using semiempirical model chemistry, the variational expressions are verified by numerical and analytical differentiation with respect to a static external electric field. Analytical gradients are further tested by performing microcanonical excited state molecular dynamics with p-nitroaniline. PMID- 26254652 TI - Theoretical investigation of the dynamics of O((1)D->(3)P) electronic quenching by collision with Xe. AB - We present the quantum close-coupling treatment of spin-orbit induced transitions between the (1)D and (3)P states of an atom in collisions with a closed-shell spherical partner. In the particular case of O colliding with Xe, we used electronic structure calculations to compute the relevant potential energy curves and spin-orbit coupling matrix elements. We then carried out quantum scattering calculations of integral and differential quenching cross sections as functions of the collision energy. The calculated differential cross sections for electronic quenching are in reasonable agreement with measurements [Garofalo et al., J. Chem. Phys. 143, 054307 (2015)]. The differential cross sections exhibit pronounced oscillations as a function of the scattering angle. By a semiclassical analysis, we show that these oscillations result from quantum mechanical interference between two classical paths. PMID- 26254653 TI - Electronic quenching of O((1)D) by Xe: Oscillations in the product angular distribution and their dependence on collision energy. AB - The dynamics of the O((1)D) + Xe electronic quenching reaction was investigated in a crossed beam experiment at four collision energies. Marked large-scale oscillations in the differential cross sections were observed for the inelastic scattering products, O((3)P) and Xe. The shape and relative phases of the oscillatory structure depend strongly on collision energy. Comparison of the experimental results with time-independent scattering calculations shows qualitatively that this behavior is caused by Stueckelberg interferences, for which the quantum phases of the multiple reaction pathways accessible during electronic quenching constructively and destructively interfere. PMID- 26254654 TI - Influence of substituents on the nature of metal?pi interaction and its cooperativity with halogen bond. AB - High-level quantum chemical calculations have been performed to investigate the influence of substituents on the metal-pi interaction and its cooperative effect with halogen bond in C2X4?MCN?ClF (X = H, CN, CH3; M = Cu, Ag, Au). The strong electron-withdrawing group CN weakens the metal-pi covalent interaction, while the weak electron-withdrawing group CH3 strengthens it. The metal-pi covalent interaction is dominated by electrostatic energy although the AuCN complex has approximately equal electrostatic and polarization contributions. However, the metal-pi covalent interaction is governed by polarization energy due to the CN substitution. A cooperative effect is found for the halogen bond and metal-pi interactions in C2H4?MCN?ClF, while a diminutive effect occurs in the triads by the CN substituent. Orbital interaction analysis indicates that the strong electron-withdrawing group CN causes the C=C group vary from a stronger donor orbital to a stronger acceptor orbital. PMID- 26254655 TI - On the origin of multi-component bulk metallic glasses: Atomic size mismatches and de-mixing. AB - The likelihood that an undercooled liquid vitrifies or crystallizes depends on the cooling rate R. The critical cooling rate R(c), below which the liquid crystallizes upon cooling, characterizes the glass-forming ability (GFA) of the system. While pure metals are typically poor glass formers with R(c)>10(12)K/s, specific multi-component alloys can form bulk metallic glasses (BMGs) even at cooling rates below R~1 K/s. Conventional wisdom asserts that metal alloys with three or more components are better glass formers (with smaller R(c)) than binary alloys. However, there is currently no theoretical framework that provides quantitative predictions for R(c) for multi-component alloys. In this manuscript, we perform simulations of ternary hard-sphere systems, which have been shown to be accurate models for the glass-forming ability of BMGs, to understand the roles of geometric frustration and demixing in determining R(c). Specifically, we compress ternary hard sphere mixtures into jammed packings and measure the critical compression rate, below which the system crystallizes, as a function of the diameter ratios sigma(B)/sigma(A) and sigma(C)/sigma(A) and number fractions x(A), x(B), and x(C). We find two distinct regimes for the GFA in parameter space for ternary hard spheres. When the diameter ratios are close to 1, such that the largest (A) and smallest (C) species are well-mixed, the GFA of ternary systems is no better than that of the optimal binary glass former. However, when sigma(C)/sigma(A) ? 0.8 is below the demixing threshold for binary systems, adding a third component B with sigma(C) < sigma(B) < sigma(A) increases the GFA of the system by preventing demixing of A and C. Analysis of the available data from experimental studies indicates that most ternary BMGs are below the binary demixing threshold with sigma(C)/sigma(A) < 0.8. PMID- 26254656 TI - Thermodynamics and kinetics of binary nucleation in ideal-gas mixtures. AB - The nonisothermal single-component theory of droplet nucleation [N. V. Alekseechkin, Physica A 412, 186 (2014)] is extended to binary case; the droplet volume V, composition x, and temperature T are the variables of the theory. An approach based on macroscopic kinetics (in contrast to the standard microscopic model of nucleation operating with the probabilities of monomer attachment and detachment) is developed for the droplet evolution and results in the derived droplet motion equations in the space (V, x, T)-equations for V=dV/dt, x, and T. The work W(V, x, T) of the droplet formation is obtained in the vicinity of the saddle point as a quadratic form with diagonal matrix. Also, the problem of generalizing the single-component Kelvin equation for the equilibrium vapor pressure to binary case is solved; it is presented here as a problem of integrability of a Pfaffian equation. The equation for T is shown to be the first law of thermodynamics for the droplet, which is a consequence of Onsager's reciprocal relations and the linked-fluxes concept. As an example of ideal solution for demonstrative numerical calculations, the o-xylene-m-xylene system is employed. Both nonisothermal and enrichment effects are shown to exist; the mean steady-state overheat of droplets and their mean steady-state enrichment are calculated with the help of the 3D distribution function. Some qualitative peculiarities of the nucleation thermodynamics and kinetics in the water-sulfuric acid system are considered in the model of regular solution. It is shown that there is a small kinetic parameter in the theory due to the small amount of the acid in the vapor and, as a consequence, the nucleation process is isothermal. PMID- 26254657 TI - Microscopic origin of temporal heterogeneities in translational dynamics of liquid water. AB - Liquid water is known to reorient via a combination of large angular jumps (due to exchange of hydrogen bonding (H-bond) partners) and diffusive orientations. Translation of the molecule undergoing the orientational jump and its initial and final H-bond acceptors plays a key role in the microscopic reorientation process. Here, we partition the translational dynamics into those occurring during intervals when rotating water molecules (and their initial and final H-bonding partners) undergo orientational jump and those arising when molecules wait between consecutive orientational jumps. These intervals are chosen in such a way that none of the four possible H-bonds involving the chosen water molecule undergo an exchange process within its duration. Translational dynamics is analysed in terms of the distribution of particle displacements, van Hove functions, and its moments. We observe that the translational dynamics, calculated from molecular dynamics simulations of liquid water, is fastest during the orientational jumps and slowest during periods of waiting. The translational dynamics during all temporal intervals shows an intermediate behaviour. This is the microscopic origin of temporal dynamic heterogeneity in liquid water, which is mild at 300 K and systematically increases with supercooling. Study of such partitioned dynamics in supercooled water shows increased disparity in dynamics occurring in the two different types of intervals. Nature of the distribution of particle displacements in supercooled water is investigated and it reveals signatures non-Gaussian behaviour. PMID- 26254658 TI - Examination of the phase transition behavior of nano-confined fluids by statistical temperature molecular dynamics. AB - The fluid-solid phase transition behavior of nano-confined Lennard-Jones fluids as a function of temperature and degree of nanoconfinement has been studied via statistical temperature molecular dynamics (STMD). The STMD method allows the direct calculation of the density of states and thus the heat capacity with high efficiency. The fluids are simulated between parallel solid surfaces with varying pore sizes, wall-fluid interaction energies, and registry of the walls. The fluid solid phase transition behavior has been characterized through determination of the heat capacity. The results show that for pores of ideal-spacing, the order disorder transition temperature (T(ODT)) is reduced as the pore size increases until values consistent with that seen in a bulk system. Also, as the interaction between the wall and fluid is reduced, T(ODT) is reduced due to weak constraints from the wall. However, for non-ideal spacing pores, quite different behavior is obtained, e.g., generally T(ODT) are largely reduced, and T(ODT) is decreased as the wall constraint becomes larger. For unaligned walls (i.e., whose lattices are not in registry), the fluid-solid transition is also detected as T is reduced, indicating non-ideality in orientation of the walls does not impact the formation of a solid, but results in a slight change in T(ODT) compared to the perfectly aligned systems. The STMD method is demonstrated to be a robust way for probing the phase transitions of nanoconfined fluids systematically, enabling the future examination of the phase transition behavior of more complex fluids. PMID- 26254659 TI - Effects of stacking disorder on thermal conductivity of cubic ice. AB - Cubic ice is said to have stacking disorder when the H2O sequences in its structure (space group Fd3m) are interlaced with hexagonal ice (space group P6(3)/mmc) sequences, known as stacking faults. Diffraction methods have shown that the extent of this disorder varies in samples made by different methods, thermal history, and the temperature T, but other physical properties of cubic and hexagonal ices barely differ. We had found that at 160 K, the thermal conductivity, kappa, of cubic ice is ~20% less than that of hexagonal ice, and this difference varies for cubic ice samples prepared by different methods and/or subjected to different thermal history. After reviewing the methods of forming cubic ice, we report an investigation of the effects of stacking disorder and other features by using new data, and by analyzing our previous data on the dependence of kappa on T and on the pressure. We conclude that the lower kappa of cubic ice and its weaker T-dependence is due mainly to stacking disorder and small crystal sizes. On in situ heating at 20-50 MPa pressure, kappa increases and cubic ice irreversibly transforms more sharply to ice Ih, and at a higher T of ~220 K, than it does in ex situ studies. Cooling and heating between 115 and 130 K at 0.1 K min(-1) rate yield the same kappa value, indicating that the state of cubic ice in these conditions does not change with time and T. The increase in kappa of cubic ice observed on heat-annealing before its conversion to hexagonal ice is attributed to the loss of stacking faults and other types of disorders, and to grain growth. After discussing the consequences of our findings on other properties, we suggest that detailed studies of variation of a given property of cubic ice with the fraction of stacking faults in its structure may reveal more about the effect of this disorder. A similar disorder may occur in the mono layers of H2O adsorbed on a substrate, in bulk materials comprised of two dimensional layers, in diamond and in Zirconium and in numerous other crystals. PMID- 26254660 TI - Probing the structural and dynamical properties of liquid water with models including non-local electron correlation. AB - Water is a ubiquitous liquid that displays a wide range of anomalous properties and has a delicate structure that challenges experiment and simulation alike. The various intermolecular interactions that play an important role, such as repulsion, polarization, hydrogen bonding, and van der Waals interactions, are often difficult to reproduce faithfully in atomistic models. Here, electronic structure theories including all these interactions at equal footing, which requires the inclusion of non-local electron correlation, are used to describe structure and dynamics of bulk liquid water. Isobaric-isothermal (NpT) ensemble simulations based on the Random Phase Approximation (RPA) yield excellent density (0.994 g/ml) and fair radial distribution functions, while various other density functional approximations produce scattered results (0.8-1.2 g/ml). Molecular dynamics simulation in the microcanonical (NVE) ensemble based on Moller-Plesset perturbation theory (MP2) yields dynamical properties in the condensed phase, namely, the infrared spectrum and diffusion constant. At the MP2 and RPA levels of theory, ice is correctly predicted to float on water, resolving one of the anomalies as resulting from a delicate balance between van der Waals and hydrogen bonding interactions. For several properties, obtaining quantitative agreement with experiment requires correction for nuclear quantum effects (NQEs), highlighting their importance, for structure, dynamics, and electronic properties. A computed NQE shift of 0.6 eV for the band gap and absorption spectrum illustrates the latter. Giving access to both structure and dynamics of condensed phase systems, non-local electron correlation will increasingly be used to study systems where weak interactions are of paramount importance. PMID- 26254661 TI - Relaxations in the metastable rotator phase of n-eicosane. AB - We present relaxations in the metastable rotator phase of the n-alkane eicosane (C20H42). The relaxation times found by calorimetry increase with increasing temperature on approaching the melting temperature of the rotator phase. This is the opposite behavior than the one found for classical activated processes. The relaxation behavior found by calorimetry is confirmed by investigations of the lattice structure with X-ray diffraction. It is shown that one lattice parameter of the orthorhombic phase relaxes on the same time scales found in calorimetry, whereas another lattice parameter reacts almost instantly on temperature perturbations. Increasing cooperativity for the creation of conformational defects in the alkane chains is proposed to be responsible for the observed behaviour. PMID- 26254662 TI - Nature of the first-order liquid-liquid phase transition in supercooled silicon. AB - The first-order liquid-liquid phase transition in supercooled Si is revisited by long-time first-principle molecular dynamics simulations. As the focus of the present paper, its nature is revealed by analyzing the inherent structures of low density liquid (LDL) and high-density liquid (HDL). Our results show that it is a transition between a sp(3)-hybridization LDL and a white-tin-like HDL. This uncovers the origin of the semimetal-metal transition accompanying it and also proves that HDL is the metastable extension of high temperature equilibrium liquid into the supercooled regime. The pressure-temperature diagram of supercooled Si thus can be regarded in some respects as shifted reflection of its crystalline phase diagram. PMID- 26254663 TI - Bandgap engineering of Magneli phase Ti(n)O(2n-1): Electron-hole self compensation. AB - An electron-hole self-compensation effect is revealed and confirmed in nitrogen doped Magneli phase Ti(n)O(2n-1) (n = 7, 8, and 9) by using hybrid density functional theory calculations. We found that the self-compensation effect between the free electrons in Magneli phase Ti(n)O(2n-1) (n = 7, 8, and 9) and the holes induced by p-type nitrogen doping could not only prevent the recombination of photo-generated electron-hole pairs, but also lead to an effective bandgap reduction. This novel electron-hole self-compensation effect may provide a new approach for bandgap engineering of Magneli phase metal suboxides. PMID- 26254664 TI - Dynamics of protein aggregation and oligomer formation governed by secondary nucleation. AB - The formation of aggregates in many protein systems can be significantly accelerated by secondary nucleation, a process where existing assemblies catalyse the nucleation of new species. In particular, secondary nucleation has emerged as a central process controlling the proliferation of many filamentous protein structures, including molecular species related to diseases such as sickle cell anemia and a range of neurodegenerative conditions. Increasing evidence suggests that the physical size of protein filaments plays a key role in determining their potential for deleterious interactions with living cells, with smaller aggregates of misfolded proteins, oligomers, being particularly toxic. It is thus crucial to progress towards an understanding of the factors that control the sizes of protein aggregates. However, the influence of secondary nucleation on the time evolution of aggregate size distributions has been challenging to quantify. This difficulty originates in large part from the fact that secondary nucleation couples the dynamics of species distant in size space. Here, we approach this problem by presenting an analytical treatment of the master equation describing the growth kinetics of linear protein structures proliferating through secondary nucleation and provide closed-form expressions for the temporal evolution of the resulting aggregate size distribution. We show how the availability of analytical solutions for the full filament distribution allows us to identify the key physical parameters that control the sizes of growing protein filaments. Furthermore, we use these results to probe the dynamics of the populations of small oligomeric species as they are formed through secondary nucleation and discuss the implications of our work for understanding the factors that promote or curtail the production of these species with a potentially high deleterious biological activity. PMID- 26254665 TI - Thermoelectricity and thermodiffusion in charged colloids. AB - The Seebeck and Soret coefficients of ionically stabilized suspension of maghemite nanoparticles in dimethyl sulfoxide are experimentally studied as a function of nanoparticle volume fraction. In the presence of a temperature gradient, the charged colloidal nanoparticles experience both thermal drift due to their interactions with the solvent and electric forces proportional to the internal thermoelectric field. The resulting thermodiffusion of nanoparticles is observed through forced Rayleigh scattering measurements, while the thermoelectric field is accessed through voltage measurements in a thermocell. Both techniques provide independent estimates of nanoparticle's entropy of transfer as high as 82 meV K(-1). Such a property may be used to improve the thermoelectric coefficients in liquid thermocells. PMID- 26254666 TI - Numerical self-consistent field theory study of the response of strong polyelectrolyte brushes to external electric fields. AB - The response of strong polyelectrolyte (PE) brushes grafted on an electrode to electric fields generated by opposite surface charges on the PE-grafted electrode and a second parallel electrode has been numerically investigated by self consistent field theory. The influences of grafting density, average charge fraction, salt concentration, and mobile ion size on the variation of the brush height against an applied voltage bias were investigated. In agreement with molecular dynamics simulation results, a higher grafting density requires a larger magnitude of voltage bias to achieve the same amount of relative change in the brush height. In the experimentally relevant parameter regime of the applied voltage, the brush height becomes insensitive to the voltage bias when the grafting density is high. Including the contribution of surface charges on the grafting electrode, overall charge neutrality inside the PE brushes is generally maintained, especially for PE brushes with high grafting density and high average charge fraction. Our numerical study further reveals that the electric field across the two electrodes is highly non-uniform because of the complex interplay between the surface charges on the electrodes, the charges on the grafted PE chains, and counterions. PMID- 26254667 TI - Examining the aggregation behavior of polymer grafted nanoparticles using molecular simulation and theory. AB - Grafting polymers to nanoparticles is one approach used to control and enhance the structure and properties of nanomaterials. However, predicting the aggregation behavior of tethered nanoparticles (TNPs) is a somewhat trial and error process as a result of the large number of possible polymer tethers, nanoparticles, and solvent species that can be studied. With the main goal of understanding how to control the dispersion and aggregation of TNP systems, molecular simulations and the hetero-statistical associating fluid theory for potentials of variable range have been used to calculate the fluid phase equilibrium of TNPs in both vacuum and in simple solvents under a wide range of conditions. The role of graft length, graft density, and solvent interactions is examined and trends established. Additionally, the fluid distribution ratio (k value) is used to study the solubility of TNPs in industrially relevant solvents including carbon dioxide, nitrogen, propane, and ethylene. PMID- 26254668 TI - Massively parallel sampling of lattice proteins reveals foundations of thermal adaptation. AB - Evolution of proteins in bacteria and archaea living in different conditions leads to significant correlations between amino acid usage and environmental temperature. The origins of these correlations are poorly understood, and an important question of protein theory, physics-based prediction of types of amino acids overrepresented in highly thermostable proteins, remains largely unsolved. Here, we extend the random energy model of protein folding by weighting the interaction energies of amino acids by their frequencies in protein sequences and predict the energy gap of proteins designed to fold well at elevated temperatures. To test the model, we present a novel scalable algorithm for simultaneous energy calculation for many sequences in many structures, targeting massively parallel computing architectures such as graphics processing unit. The energy calculation is performed by multiplying two matrices, one representing the complete set of sequences, and the other describing the contact maps of all structural templates. An implementation of the algorithm for the CUDA platform is available at http://www.github.com/kzeldovich/galeprot and calculates protein folding energies over 250 times faster than a single central processing unit. Analysis of amino acid usage in 64-mer cubic lattice proteins designed to fold well at different temperatures demonstrates an excellent agreement between theoretical and simulated values of energy gap. The theoretical predictions of temperature trends of amino acid frequencies are significantly correlated with bioinformatics data on 191 bacteria and archaea, and highlight protein folding constraints as a fundamental selection pressure during thermal adaptation in biological evolution. PMID- 26254669 TI - Publisher's Note: "Perspective: Single polymer mechanics across the force regimes" [J. Chem. Phys. 142, 194902 (2015)]. PMID- 26254670 TI - A Skull Might Lie: Modeling Ancestral Ranges and Diet from Genes and Shape of Tree Squirrels. AB - Tropical forests of Central and South America represent hotspots of biological diversity. Tree squirrels of the tribe Sciurini are an excellent model system for the study of tropical biodiversity as these squirrels disperse exceptional distances, and after colonizing the tropics of the Central and South America, they have diversified rapidly. Here, we compare signals from DNA sequences with morphological signals using pictures of skulls and computational simulations. Phylogenetic analyses reveal step-wise geographic divergence across the Northern Hemisphere. In Central and South America, tree squirrels form two separate clades, which split from a common ancestor. Simulations of ancestral distributions show western Amazonia as the epicenter of speciation in South America. This finding suggests that wet tropical forests on the foothills of Andes possibly served as refugia of squirrel diversification during Pleistocene climatic oscillations. Comparison of phylogeny and morphology reveals one major discrepancy: Microsciurus species are a single clade morphologically but are polyphyletic genetically. Modeling of morphology-diet relationships shows that the only group of species with a direct link between skull shape and diet are the bark-gleaning insectivorous species of Microsciurus. This finding suggests that the current designation of Microsciurus as a genus is based on convergent ecologically driven changes in morphology. PMID- 26254671 TI - Historical Biogeography Using Species Geographical Ranges. AB - Spatial variation in biodiversity is the result of complex interactions between evolutionary history and ecological factors. Methods in historical biogeography combine phylogenetic information with current species locations to infer the evolutionary history of a clade through space and time. A major limitation of most methods for historical biogeographic inference is the requirement of single locations for terminal lineages, reducing contemporary species geographical ranges to a point in two-dimensional space. In reality, geographic ranges usually show complex geographic patterns, irregular shapes, or discontinuities. In this article, we describe a method for phylogeographic analysis using polygonal species geographic ranges of arbitrary complexity. By integrating the geographic diversification process across species ranges, we provide a method to infer the geographic location of ancestors in a Bayesian framework. By modeling migration conditioned on a phylogenetic tree, this approach permits reconstructing the geographic location of ancestors through time. We apply this new method to the diversification of two neotropical bird genera, Trumpeters (Psophia) and Cinclodes ovenbirds. We demonstrate the usefulness of our method (called rase) in phylogeographic reconstruction of species ancestral locations and contrast our results with previous methods that compel researchers to reduce the distribution of species to one point in space. We discuss model extensions to enable a more general, spatially explicit framework for historical biogeographic analysis. PMID- 26254672 TI - Medical comorbidity, acute medical care use in late-life bipolar disorder: a comparison of lithium, valproate, and other pharmacotherapies. AB - OBJECTIVE: Bipolar disorder is associated with high rates of medical comorbidity, particularly in late life. Little is known about medical health service utilization and potential effects of bipolar pharmacotherapy. We hypothesized that lithium use would not be associated with higher rates of medical hospitalization. METHODS: Population-based retrospective cohort study of 1388 bipolar disorder patients aged >=66years discharged from a psychiatric hospitalization in Ontario, Canada, between 2006 and 2012. Patients were divided into lithium users, valproate users, and non-lithium/non-valproate users. The main outcome was acute non-psychiatric, medical/surgical hospitalization during 1 year follow-up. RESULTS: The rate of medical hospitalizations was 0.22 per patient-year. Time-to-medical hospitalization did not differ among lithium, valproate, and non-lithium/non-valproate users after adjusting for age, sex, past medical hospitalization, and antipsychotic use. Lithium, valproate, and non lithium/non-valproate users did not differ markedly in terms of reason for medical hospitalization, 1-year acute medical health utilization outcomes, and medical comorbidity rates. CONCLUSION: There were high rates of health service use for medical conditions among older adults with bipolar disorder, but this did not appear to be associated with lithium use, compared to valproate and other medication use (e.g., antipsychotics). A proactive collaborative care approach may prevent medical service utilization in severe late-life bipolar disorder. PMID- 26254673 TI - Patterns of clinical mentorship in undergraduate nurse education: A comparative case analysis of eleven EU and non-EU countries. AB - BACKGROUND: In spite of the number of studies available in the field and policy documents developed both at the national and the international levels, there is no reliable data available regarding the variation of roles occupied by clinical mentors (CMs) across countries. OBJECTIVES: To describe and compare the CM's role; responsibilities; qualifications; employment requirements and experience in undergraduate nurse education as enacted in 11 European Union (EU) and non- EU countries. DESIGN: A case study design. PARTICIPANTS AND SETTING: A panel of expert nurse educators from 11 countries within and outside of the EU (Croatia, Czech Republic, England, Iceland, Ireland, Italy, Poland, Serbia, Slovenia, Spain, and the USA). METHODS: A questionnaire containing both quantitative and qualitative questions was developed and agreed by the panel using a Nominal Group Technique (NGT); four cycles of data collection and analysis were conducted involving key experts in nursing education in each country. RESULTS: In all countries, there are at least two types of clinical mentorship dedicated to undergraduate nursing students: the first is offered by higher education institutions, and the second is offered by health care providers. Variation was noted in terms of profile, responsibilities and professional requirements to act as a CM; however, the CM role is mainly carried out by registered nurses, and in most countries there are no special requirements in terms of education and experience. Those who act as CMs at the bedside continue to manage their usual caseload, thus the role adds to their work burden. CONCLUSIONS: Whilst it is imperative to have respect for the different national traditions in undergraduate nurse education, the globalisation of the nursing workforce and greater opportunities for student mobility during the course of their undergraduate education suggests that in areas such as clinical mentorship, jurisdictions, particularly within the EU, should work towards greater system harmonisation. PMID- 26254674 TI - Supporting newly qualified nurse transition: A case study in a UK hospital. AB - BACKGROUND: Nurse education in the United Kingdom (UK) has been university based since the mid-1990s but despite careful preparation and assessment of student nurses it has been considered necessary to provide a period of additional support for newly qualified nurses (NQNs) to help them settle into their new role and responsibilities. Preceptorship is the process of supporting NQNs over the transition from student to registered nurse (RN) and it is recognised that this can be a difficult time for NQNs. LITERATURE REVIEW: A systematic review was conducted as part of this project and has been published in an earlier edition of Nurse Education Today (Whitehead et al, 2013). This suggests that preceptorship is a positive and essential experience for NQNs. METHODS: Lincoln and Guba's Naturalistic Inquiry (1985) was used. A qualitative case study method was developed and consisted of a multi-stage approach including semi-structured interviews with key personnel; documentary analysis of preceptorship material; and focus groups with key actors. Ethical approval was attained for the project. The aim was to interpret the social phenomena and to produce an evidence based tool to improve preceptorship. RESULTS: Findings are grouped under the headings indicated by the research design. In addition a further 11 themes emerged, including: the need for specific time for preceptors and preceptees; formal recognition of the role and a culture of support; selection and preparation of preceptors and the management structure to support preceptorship. CONCLUSIONS: The findings indicate that there are a range of factors which are reported to affect the successful transition from student to NQN. Based on these factors recommendations are made for practice and for further research. Practice recommendations: to provide supported preceptorship following the recommendations of the research findings. RESEARCH RECOMMENDATIONS: to concentrate on enhancing preceptorship as preceptorship in any form is better than none. PMID- 26254675 TI - Expert validation of a teamwork assessment rubric: A modified Delphi study. AB - BACKGROUND: Teamwork is a 'soft skill' employability competence desired by employers. Poor teamwork skills in healthcare have an impact on adverse outcomes. Teamwork skills are rarely the focus of teaching and assessment in undergraduate courses. The TeamUP Rubric is a tool used to teach and evaluate undergraduate students' teamwork skills. Students also use the rubric to give anonymised peer feedback during team-based academic assignments. The rubric's five domains focus on planning, environment, facilitation, conflict management and individual contribution; each domain is grounded in relevant theory. Students earn marks for their teamwork skills; validity of the assessment rubric is critical. QUESTION: To what extent do experts agree that the TeamUP Rubric is a valid assessment of 'teamwork skills'? DESIGN: Modified Delphi technique incorporating Feminist Collaborative Conversations. PARTICIPANTS: A heterogeneous panel of 35 professionals with recognised expertise in communications and/or teamwork. METHODS: Three Delphi rounds using a survey that included the rubric were conducted either face-to-face, by telephone or online. Quantitative analysis yielded item content validity indices (I-CVI); minimum consensus was pre-set at 70%. An average of the I-CVI also yielded sub-scale (domain) (D-CVI/Ave) and scale content validity indices (S-CVI/Ave). After each Delphi round, qualitative data were analysed and interpreted; Feminist Collaborative Conversations by the research team aimed to clarify and confirm consensus about the wording of items on the rubric. RESULTS: Consensus (at 70%) was obtained for all but one behavioural descriptor of the rubric. We modified that descriptor to address expert concerns. The TeamUP Rubric (Version 4) can be considered to be well validated at that level of consensus. The final rubric reflects underpinning theory, with no areas of conceptual overlap between rubric domains. CONCLUSION: The final TeamUP Rubric arising from this study validly measures individual student teamwork skills and can be used with confidence in the university setting. PMID- 26254676 TI - Effects of carbohydrate, protein and lipid content of organic waste on hydrogen production and fermentation products. AB - Organic waste from municipalities, food waste and agro-industrial residues are ideal feedstocks for use in biological conversion processes in biorefinery chains, representing biodegradable materials containing a series of substances belonging to the three main groups of the organic matter: carbohydrates, proteins and lipids. Biological hydrogen production by dark fermentation may assume a central role in the biorefinery concept, representing an up-front treatment for organic waste capable of hydrolysing complex organics and producing biohydrogen. This research study was aimed at evaluating the effects of carbohydrate, protein and lipid content of organic waste on hydrogen yields, volatile fatty acid production and carbon-fate. Biogas and hydrogen productions were linearly correlated to carbohydrate content of substrates while proteins and lipids failed to produce significant contributions. Chemical composition also produced effects on the final products of dark fermentation. Acetic and butyric acids were the main fermentation products, with their ratio proving to correlate with carbohydrate and protein content. The results obtained in this research study enhance the understanding of data variability on hydrogen yields from organic waste. Detailed information on waste composition and chemical characterisation are essential to clearly identify the potential performances of the dark fermentation process. PMID- 26254677 TI - Obstructive sleep apnea and acute respiratory failure due to pneumonia: A protective factor to mortality risk? PMID- 26254678 TI - Sustained low-efficiency dialysis with regional citrate anticoagulation in medical intensive care unit patients with liver failure: A prospective study. AB - PURPOSE: Patients with liver failure requiring dialysis are at increased risk for citrate accumulation during sustained low-efficiency dialysis (SLED). The aim of this study was to evaluate the feasibilty of citrate SLED in critical ill patients with liver failure and investigate predictive parameters regarding citrate accumulation. MATERIALS AND METHODS: This is a prospective study in 24 medical intensive care unit patients with liver failure and a total of 43 SLED runs (maximum of 3 runs per patient) using citrate anticoagulation. Liver function was characterized before SLED using not only laboratory parameters but also determination of the plasma disappearance rate of indocyanine green. In addition, blood gas parameters as well total calcium and citrate in serum were measured at baseline and defined time points during SLED. RESULTS: Accumulation of citrate could be observed in all SLED runs, which were nearly normalized until the end of SLED and 24 hours after SLED, respectively. However, the critical threshold of total calcium/ionized calcium on ratio of greater than 2.5 was exceeded in only 1 patient. Equalization of initial metabolic acidosis was possible without major disturbances of acid base and electrolyte status. Liver function parameters showed poor predicitve capabilities regarding citrate accumulation. CONCLUSIONS: Despite substantial accumulation of citrate in serum, SLED is save and feasible in patients with liver failure using a citrate anticoagulation. Careful monitoring of electrolytes and acid base status is mandatory to ensure patient safety. PMID- 26254679 TI - Early Cognitive Outcomes Following Proton Radiation in Pediatric Patients With Brain and Central Nervous System Tumors. AB - PURPOSE: To report, from a longitudinal study, cognitive outcome in pediatric patients treated with proton radiation therapy (PRT) for central nervous system (CNS) tumors. METHODS AND MATERIALS: Sixty patients receiving PRT for medulloblastoma (38.3%), gliomas (18.3%), craniopharyngioma (15.0%), ependymoma (11.7%), and other CNS tumors (16.7%) were administered age-appropriate measures of cognitive abilities at or near PRT initiation (baseline) and afterward (follow up). Patients were aged >= 6 years at baseline to ensure consistency in neurocognitive measures. RESULTS: Mean age was 12.3 years at baseline; mean follow-up interval was 2.5 years. Treatment included prior surgical resection (76.7%) and chemotherapy (61.7%). Proton radiation therapy included craniospinal irradiation (46.7%) and partial brain radiation (53.3%). At baseline, mean Wechsler Full Scale IQ was 104.6; means of all 4 Index scores were also in the average range. At follow-up, no significant change was observed in mean Wechsler Full Scale IQ, Verbal Comprehension, Perceptual Reasoning/Organization, or Working Memory. However, Processing Speed scores declined significantly (mean 5.2 points), with a significantly greater decline for subjects aged <12 years at baseline and those with the highest baseline scores. Cognitive outcome was not significantly related to gender, extent of radiation, radiation dose, tumor location, histology, socioeconomic status, chemotherapy, or history of surgical resection. CONCLUSIONS: Early cognitive outcomes after PRT for pediatric CNS tumors are encouraging, compared with published outcomes from photon radiation therapy. PMID- 26254680 TI - Impact of Fractionation and Dose in a Multivariate Model for Radiation-Induced Chest Wall Pain. AB - PURPOSE: To determine the role of patient/tumor characteristics, radiation dose, and fractionation using the linear-quadratic (LQ) model to predict stereotactic body radiation therapy-induced grade >= 2 chest wall pain (CWP2) in a larger series and develop clinically useful constraints for patients treated with different fraction numbers. METHODS AND MATERIALS: A total of 316 lung tumors in 295 patients were treated with stereotactic body radiation therapy in 3 to 5 fractions to 39 to 60 Gy. Absolute dose-absolute volume chest wall (CW) histograms were acquired. The raw dose-volume histograms (alpha/beta = infinity Gy) were converted via the LQ model to equivalent doses in 2-Gy fractions (normalized total dose, NTD) with alpha/beta from 0 to 25 Gy in 0.1-Gy steps. The Cox proportional hazards (CPH) model was used in univariate and multivariate models to identify and assess CWP2 exposed to a given physical and NTD. RESULTS: The median follow-up was 15.4 months, and the median time to development of CWP2 was 7.4 months. On a univariate CPH model, prescription dose, prescription dose per fraction, number of fractions, D83cc, distance of tumor to CW, and body mass index were all statistically significant for the development of CWP2. Linear quadratic correction improved the CPH model significance over the physical dose. The best-fit alpha/beta was 2.1 Gy, and the physical dose (alpha/beta = infinity Gy) was outside the upper 95% confidence limit. With alpha/beta = 2.1 Gy, VNTD99Gy was most significant, with median VNTD99Gy = 31.5 cm(3) (hazard ratio 3.87, P<.001). CONCLUSION: There were several predictive factors for the development of CWP2. The LQ-adjusted doses using the best-fit alpha/beta = 2.1 Gy is a better predictor of CWP2 than the physical dose. To aid dosimetrists, we have calculated the physical dose equivalent corresponding to VNTD99Gy = 31.5 cm(3) for the 3- to 5-fraction groups. PMID- 26254681 TI - Radiosensitivity of Patient-Derived Glioma Stem Cell 3-Dimensional Cultures to Photon, Proton, and Carbon Irradiation. AB - PURPOSE: To investigate the radiosensitivity of primary glioma stem cell (GSC) cultures with different CD133 status in a 3-dimensional (3D) model after photon versus proton versus carbon irradiation. METHODS AND MATERIALS: Human primary GSC spheroid cultures were established from tumor specimens of six consented glioblastoma patients. Human U87MG was used as a classical glioblastoma radioresistant cell line. Cell suspensions were generated by mechanical dissociation of GSC spheroids and embedded in a semi-solid 3D matrix before irradiation. Spheroid-like colonies were manually counted by microscopy. Cells were also recovered and quantified by fluorescence. CD133 expression and DNA damage were evaluated by flow cytometry. RESULTS: The fraction of CD133(+) cells varied between 0.014% and 96% in the six GSC cultures and showed a nonsignificant correlation with plating efficiency and survival fractions. The 4 most photon radioresistant GSC cultures were NCH644, NCH421k, NCH441, and NCH636. Clonogenic survival for proton irradiation revealed relative biologic effectiveness (RBE) in the range of 0.7-1.20. However, carbon irradiation rendered the photon-resistant GSC cultures sensitive, with average RBE of 1.87-3.44. This effect was partly attributed to impaired capability of GSC to repair carbon ion-induced DNA double strand breaks as determined by residual DNA repair foci. Interestingly, radiosensitivity of U87 cells was comparable to GSC cultures using clonogenic survival as the standard readout. CONCLUSIONS: Carbon irradiation is effective in GSC eradication with similar RBE ranges approximately 2-3 as compared with non stem GSC cultures (U87). Our data strongly suggest further exploration of GSC using classic radiobiology endpoints such as the here-used 3D clonogenic survival assay and integration of additional GSC-specific markers. PMID- 26254682 TI - Interpregnancy interval as a risk factor for postmenopausal osteoporosis. AB - OBJECTIVE: Bone mass loss associated with pregnancy and lactation is usually regained in the postpartum period. However, it is not known whether the bone loss is completely recovered in women with a shortened interpregnancy interval (IPI). The aim of this study was to analyze the effect of IPI and gynecological history on postmenopausal osteoporosis. STUDY DESIGN: The study was conducted among 537 postmenopausal women who were divided into two groups in accordance with the osteoporosis status. Prior to bone densitometry, the patients were questioned about reproductive history. Dual-energy X-ray absorptiometry was used to measure lumbar spinal, femur neck and total femoral bone mineral density. MAIN OUTCOME MEASURE: Association between IPI and postmenopausal osteoporosis was analyzed. RESULTS: The comparison of both groups according to the total duration of breastfeeding did not reveal a considerable variation (p=0.288). In the osteoporosis group the age and duration of menopause were found to be significantly higher (p<0.001) whereas the age of first pregnancy and IPI were notably lower in comparison to the controls group (p<0.001). Multivariate logistic regression analyses revealed that women who have 0-12 months interpregnancy interval have the highest risk for osteoporosis (OR: 4.306; 95% CI, 1.684-11.01). This analysis confirmed that the occurrence of first pregnancy under 27 years of age conveyed a higher risk for osteoporosis, as well. CONCLUSIONS: Shortened IPI may have a detrimental effect on bone mineral density in postmenopausal age. PMID- 26254684 TI - Neoadjuvant chemoradiation in oesophageal cancer. PMID- 26254685 TI - Highly sensitive and selective uric acid biosensor based on a three-dimensional graphene foam/indium tin oxide glass electrode. AB - A three-dimensional (3D) continuous and interconnected network graphene foam (GF) was synthesized by chemical vapor deposition using nickel foam as a template. The morphologies of the GF were observed by scanning electron microscopy. X-ray diffraction and Raman spectroscopy were used to investigate the structure of GF. The graphene with few layers and defect free was closely coated on the backbone of the 3D nickel foam. After etching nickel, the GF was transferred onto indium tin oxide (ITO) glass, which acted as an electrode to detect uric acid using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The GF/ITO electrode showed a high sensitivity for the detection of uric acid: approximately 9.44 mA mM(-1) in the range of 25 nM-0.1 MUM and 1.85 mA mM(-1) in the range of 0.1-60 MUM. The limit of detection of GF/ITO electrode for uric acid is 3 nM. The GF/ITO electrode also showed a high selectivity for the detection of uric acid in the presence of ascorbic acid. This electrode will have a wide range of potential application prospects in electrochemical detection. PMID- 26254683 TI - Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. AB - BACKGROUND: Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years. METHODS: Patients with clinically resectable, locally advanced cancer of the oesophagus or oesophagogastric junction (clinical stage T1N1M0 or T2-3N0-1M0, according to the TNM cancer staging system, sixth edition) were randomly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m(2) of body surface area] for 23 days) with concurrent radiotherapy (41.4 Gy, given in 23 fractions of 1.8 Gy on 5 days per week) followed by surgery, or surgery alone. The primary endpoint was overall survival, analysed by intention-to-treat. No adverse event data were collected beyond those noted in the initial report of the trial. This trial is registered with the Netherlands Trial Register, number NTR487, and has been completed. FINDINGS: Between March 30, 2004, and Dec 2, 2008, 368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled into this study and randomly assigned to the two treatment groups: 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone. Two patients in the neoadjuvant chemoradiotherapy group withdrew consent, so a total of 366 patients were analysed (178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group). Of 171 patients who received any neoadjuvant chemoradiotherapy in this group, 162 (95%) were able to complete the entire neoadjuvant chemoradiotherapy regimen. After a median follow-up for surviving patients of 84.1 months (range 61.1-116.8, IQR 70.7-96.6), median overall survival was 48.6 months (95% CI 32.1-65.1) in the neoadjuvant chemoradiotherapy plus surgery group and 24.0 months (14.2-33.7) in the surgery alone group (HR 0.68 [95% CI 0.53-0.88]; log-rank p=0.003). Median overall survival for patients with squamous cell carcinomas was 81.6 months (95% CI 47.2-116.0) in the neoadjuvant chemoradiotherapy plus surgery group and 21.1 months (15.4-26.7) in the surgery alone group (HR 0.48 [95% CI 0.28-0.83]; log-rank p=0.008); for patients with adenocarcinomas, it was 43.2 months (24.9-61.4) in the neoadjuvant chemoradiotherapy plus surgery group and 27.1 months (13.0-41.2) in the surgery alone group (HR 0.73 [95% CI 0.55-0.98]; log-rank p=0.038). INTERPRETATION: Long term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery in patients with resectable oesophageal or oesophagogastric junctional cancer. This improvement is clinically relevant for both squamous cell carcinoma and adenocarcinoma subtypes. Therefore, neoadjuvant chemoradiotherapy according to the CROSS trial followed by surgical resection should be regarded as a standard of care for patients with resectable locally advanced oesophageal or oesophagogastric junctional cancer. FUNDING: Dutch Cancer Foundation (KWF Kankerbestrijding). PMID- 26254686 TI - Addressing Barriers to Secondary Fracture Prevention. PMID- 26254688 TI - A glance at...nutritional antioxidants and testosterone secretion. PMID- 26254687 TI - The Effect of a Patient-Provider Educational Intervention to Reduce At-Risk Drinking on Changes in Health and Health-Related Quality of Life Among Older Adults: The Project SHARE Study. AB - BACKGROUND: At-risk drinking, defined as alcohol use that is excessive or potentially harmful in combination with select comorbidities or medications, affects about 10% of older adults in the United States and is associated with higher mortality. The Project SHARE intervention, which uses patient and provider educational materials, physician counseling, and health educator support, was designed to reduce at-risk drinking among this vulnerable population. Although an earlier study showed that this intervention was successful in reducing rates of at-risk drinking, it is unknown whether these reductions translate into improved health and health-related quality of life (HRQL). OBJECTIVE: The aim of this study was to examine changes in health and HRQL of older adult at-risk drinkers resulting from a patient-provider educational intervention. RESEARCH DESIGN: A randomized controlled trial to compare the health and HRQL outcomes of patients assigned to the Project SHARE intervention vs. care as usual at baseline, 6- and 12-months post assignment. Control patients received usual care, which may or may not have included alcohol counseling. Intervention group patients received a personalized patient report, educational materials on alcohol and aging, a brief provider intervention, and a telephone health educator intervention. SUBJECTS: Current drinkers 60years and older accessing primary care clinics around Santa Barbara, California (N=1049). MEASUREMENTS: Data were collected from patients using baseline, 6- and 12-month mail surveys. Health and HRQL measures included mental and physical component scores (MCS and PCS) based on the Short Form-12v2 (SF-12v2), the SF-6D, which is also based on the SF-12, and the Geriatric Depression Scale (GDS). Adjusted associations of treatment assignment with these outcomes were estimated using generalized least squares regressions with random provider effects. Regressions controlled for age group, sex, race/ethnicity, marital status, education, household income, home ownership and the baseline value of the dependent variable. RESULTS: After regression adjustment, the intervention was associated with a 0.58 point (95% CI: -0.06, 1.21) increase in 6 month MCS and a 0.14 point (95% CI: 0.01, 0.26) improvement in 12-month GDS score, compared to the control group. The intervention also increased adjusted SF 6D scores by 0.01 points at both 6 and 12months (6-month 95% CI: 0.01, 0.02; 12 month 95% CI: 0.01, 0.01). CONCLUSIONS: Despite the previously shown effectiveness of the Project SHARE intervention to reduce at-risk drinking among older adults, this effect translated into effects on health and HRQL that were statistically but not necessarily clinically significant. Effects were most prominent for patients who received physician discussions, suggesting that provider counseling may be a critical component of primary care-based interventions targeting at-risk alcohol use. PMID- 26254689 TI - Chronic symptoms and pulmonary dysfunction in post-tuberculosis Brazilian patients. AB - BACKGROUND: Questionnaire and spirometry were applied to post-tuberculosis indigenous and non-indigenous individuals from Dourados, Brazil, to investigate the prevalence of chronic respiratory symptoms and pulmonary dysfunction. METHODS: This was a cross-sectional study in cured tuberculosis individuals as reported in the National System on Reportable Diseases (SINAN) from 2002 to 2012. RESULTS: One hundred and twenty individuals were included in the study and the prevalence of chronic respiratory symptoms was 45% (95% CI, 34-59%). Respiratory symptoms included cough (28%), sputum (23%), wheezing (22%) and dyspnea (8%). These symptoms were associated with alcoholism, AOR: 3.1 (1.2-8.4); less than 4 years of schooling, AOR: 5.0 (1.4-17.7); and previous pulmonary diseases, AOR: 5.4 (1.7-17.3). Forty-one percent (95% CI, 29-56) had pulmonary disorders, of which the most prevalent were obstructive disorders (49%), followed by obstructive disorder with reduced forced vital capacity disorders (46%) and restrictive disorders (5%). The lifestyle difference could not explain differences in chronic symptoms and/or the prevalence of pulmonary dysfunction. CONCLUSION: The high prevalence of chronic respiratory symptoms and pulmonary dysfunction in post-tuberculosis patients indicates a need for further interventions to reduce social vulnerability of patients successfully treated for tuberculosis. PMID- 26254690 TI - Hepatitis C virus infection and spontaneous clearance in HTLV-1 and HIV co infected patients in Salvador, Bahia, Brazil. AB - BACKGROUND: While 20-40% of patients with hepatitis C virus (HCV) monoinfection will spontaneously clear the virus, less is known regarding clearance with coinfections. HCV, human immunodeficiency virus (HIV), and human T-cell lymphotrophic virus 1 and 2 (HTLV-1/2) coinfection occurs due to shared routes of transmission and is prevalent in Brazil. OBJECTIVES: To compare the proportion of patients who have spontaneously cleared HCV in patients with HCV monoinfection to patients coinfected by HCV/HIV, or HCV/HIV/HTLV-1. METHODS: Using medical records from two clinics in Salvador, Brazil, including demographic data and serological markers of HCV, HIV and HTLV-I/II, cross-sectional data was obtained from 197 patients. Patients who were anti-HCV positive and HCV RNA negative, and who did not receive HCV treatment were defined as having cleared infection. RESULTS: Nineteen patients (9.5%) showed evidence of spontaneous HCV clearance; with clearance in 9 of 108 (8.3%) patients in the HCV monoinfected group, 5 of 68 (7.4%) patients with HCV/HIV, and 5 of 21 (23.8%) patients with HCV/HIV/HTLV. Demographic data were not associated with HCV clearance status. Patients coinfected with both HIV and HTLV-1 had increased odds (5.50; 95% CI 1.00, 30.17) of spontaneous clearance of HCV compared with patients who were HIV negative or of unknown HIV status. CONCLUSION: Our study found that patients coinfected with HIV and HTLV-1 were more likely to spontaneously clear hepatitis C virus than patients with HIV/HCV or HCV alone. The effects of HTLV coinfection on the immune response of such patients may be associated with these findings. PMID- 26254691 TI - Adherence to guidelines for surgical antibiotic prophylaxis: a review. AB - CONTEXT AND OBJECTIVES: The appropriate use of antibiotic prophylaxis in the perioperative period may reduce the rate of infection in the surgical site. The purpose of this review was to evaluate adherence to guidelines for surgical antibiotic prophylaxis. METHODS: The present systematic review was performed according to the Cochrane Collaboration methodology. The databases selected for this review were: Medline (via PubMed), Scopus and Portal (BVS) with selection of articles published in the 2004-2014 period from the Lilacs and Cochrane databases. RESULTS: The search recovered 859 articles at the databases, with a total of 18 studies selected for synthesis. The outcomes of interest analyzed in the articles were as follows: appropriate indication of antibiotic prophylaxis (ranging from 70.3% to 95%), inappropriate indication (ranging from 2.3% to 100%), administration of antibiotic at the correct time (ranging from 12.73% to 100%), correct antibiotic choice (ranging from 22% to 95%), adequate discontinuation of antibiotic (ranging from 5.8% to 91.4%), and adequate antibiotic prophylaxis (ranging from 0.3% to 84.5%). CONCLUSIONS: Significant variations were observed in all the outcomes assessed, and all the studies indicated a need for greater adherence to guidelines for surgical antibiotic prophylaxis. PMID- 26254692 TI - Evaluation of short-interfering RNAs treatment in experimental rabies due to wild type virus. AB - We have evaluated the efficacy of short-interfering RNAs targeting the nucleoprotein gene and also the brain immune response in treated and non-treated infected mice. Mice were inoculated with wild-type virus, classified as dog (hv2) or vampire bat (hv3) variants and both groups were treated or left as controls. No difference was observed in the lethality rate between treated and non-treated groups, although clinical evaluation of hv2 infected mice showed differences in the severity of clinical disease (p=0.0006). Evaluation of brain immune response 5 days post-inoculation in treated hv2 group showed no difference among the analyzed genes, whereas after 10 days post-inoculation there was increased expression of 2',5'-oligoadenylate synthetase 1, tumor necrosis factor alpha, interleukin 12, interferon gamma, and C-X-C motif chemokine 10 associated with higher expression of N gene in the same period (p<0.0001). In hv2 non-treated group only higher interferon beta expression was found at day 5. The observed differences in results of the immune response genes between treated and non treated groups is not promising as they had neither impact on mortality nor even a reduction in the expression of N gene in siRNA treated animals. This finding suggests that the use of pre-designed siRNA alone may not be useful in rabies treatment. PMID- 26254693 TI - Predictors of treatment response to strengthening and stretching exercises for patellofemoral pain: An examination of patellar alignment. AB - BACKGROUND: Closed kinetic chain and quadriceps strengthening, combined with flexibility exercises of the lower limb musculature, is a common treatment for patellofemoral pain syndrome (PFPS). The effectiveness has been well documented; however, very little is known about which factors predict treatment success. METHODS: A total of 43 female subjects with PFPS participated in an eight-week progressive leg press (LP) strengthening and stretching exercise program. A decrease of 1.5 cm on a 10 cm visual analog scale (VAS) score was used as an indicator for treatment success. The baseline patellar tilt angle difference (PTA d) due to quadriceps contraction prior to treatment was evaluated as a predictor of treatment success. The logistic regression and receiver operating characteristics (ROC) curve analysis were performed to investigate the predictive value of PTA-d. RESULTS: PTA-d could significantly predict the treatment success of LP strengthening and stretching exercises. The odds ratio (OR) for having an unsuccessful outcome was 1.19 (95% confidence interval (CI), 1.03-1.39, P<0.021) per degree increment of PTA-d. The most optimal cut-off value for the clinical discrimination of treatment success after LP strengthening and stretching exercise was -1.5 degrees of PTA-d (sensitivity=0.74, specificity=0.71). The area under the ROC curve was 0.73 (standard error=0.08). CONCLUSIONS: Female patients with PFPS whose quadriceps contraction reduced the lateral patellar tilt prior to LP strengthening and stretching exercise treatment are more likely to experience pain relief. It seems clinically important to check dynamic patellar tilt characteristics before treatment to aid in clinical decision making. PMID- 26254694 TI - Involvement of galanin receptor 2 and CaMKII in galanin-induced antinociception in periaqueductal grey of rats. AB - The present study was performed to explore the effect of the galanin receptor 2 (GalR2) antagonist M871 on the galanin-induced antinociception in periaqueductal grey (PAG), and an involvement of Ca(2+)/calmodulin-dependent kinase II (CaMKII) in the galanin-induced antinociception. Intra-PAG injection of galanin induced marked increases in HWLs to noxious thermal and mechanical stimulation. The increased HWLs to thermal and mechanical stimulation decreased significantly after intra-PAG administration of the GalR2 antagonist M871, indicating an involvement of GalR2 in the galanin-induced antinociception in PAG of rats. Furthermore, rats received intra-PAG injection of galanin, followed 5min later by intra-PAG administration of the CaMKII inhibitor MAP. The galanin-induced increases in HWLs to thermal and mechanical stimulation decreased significantly after intra-PAG administration of MAP, indicating that there is an involvement of CaMKII in the galanin-induced antinociception in PAG, blockade the activity of CaMKII by MAP inhibits the galanin-induced antinociception in PAG of rats. Our results strongly indicate that the galanin-induced antinociception is mediated by GalR2 in the PAG, and CaMKII may be involved in the galanin-induced antinociception in PAG of rats. PMID- 26254695 TI - Nephron-sparing surgery for Wilms tumor: A systematic review. AB - INTRODUCTION: Radical nephrectomy (RN, or total nephrectomy) is the current gold standard surgical treatment for children with Wilms tumors (WT). However, nephron sparing surgery (NSS, or partial nephrectomy) has recently been gaining increasing attention. The objective of this systematic review is to compare the effectiveness of NSS as compared with RN for the treatment of children with WT. METHODS: We searched the Cochrane Controlled Trials Register, clinicaltrials.gov, MEDLINE, EMBASE, Google Scholar, and recently presented meeting abstracts for reports in English. The bibliographies of included studies were then hand searched for any missed articles. The protocol was prospectively registered. Manuscripts were assessed and data abstracted in duplicate with differences resolved by the senior author. Owing to high heterogeneity among the final included studies, only a qualitative systematic review was performed; no formal meta-analysis was undertaken. RESULTS: We identified 694 articles, 118 of which were selected for full-text review and 66 of which were included in the final analysis. Most studies were single- or multi-institution retrospective case series (60, 91%), with a small number of prospective cohort studies (6, 9%) and 1 administrative database analysis. Most studies were from Europe (27, 41%) or North America (21, 32%). Nearly half (32, 48%) of studies those were included were dated from 2010 or later. In total, data on 4,002 patients were included, of whom 1,040 (26%) underwent NSS and 2,962 (74%) underwent NSS. Reported rupture rates were similar between RN and NSS (13% vs. 7%), as were recurrence rates (12% vs. 11%) and survival rates (85% vs. 88%). However, these comparisons are limited by inherent biases in the design and reporting of most included studies. CONCLUSIONS: Most contemporary studies reporting the use of NSS in children with WT report similar long-term outcomes to RN. However, most existing studies are limited by their small numbers, inconsistent reporting, and methodological biases. There are significant opportunities for future research on the use of NSS in children with WT, including issues related to surgical quality, optimal technique, timing and duration of chemotherapy, and variation in the use of NSS among centers. PMID- 26254696 TI - Low-dose prednisolone in first-line docetaxel for patients with metastatic castration-resistant prostate cancer: is there a clinical benefit? AB - BACKGROUND: Randomized studies have shown improved survival with the combination of docetaxel (D) and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively investigated whether coadministration of low-dose glucocorticoids has clinical benefits. MATERIAL AND METHODS: Records from 358 patients with metastatic castration-resistant prostate cancer treated consecutively with either D 75mg/m(2) every 3 weeks (n = 124) (Rigshospitalet) or D and prednisolone (P) 10mg daily (n = 234) (Herlev Hospital) given as first-line chemotherapy were reviewed. Of these, 15 patients treated with glucocorticoids at initiation of D at Rigshospitalet were excluded. Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 was used to register any grade of peripheral edema, grade >=2 sensory neuropathy, and grade >=3 nonhematological toxicity. Background clinical data, rates of toxicity, hospital admissions, dose reductions, and post-D treatments were analyzed by the Chi-squared test or Mann Whitney U test. Progression-free survival and overall survival were calculated by the Kaplan-Meier method. RESULTS: Patients treated with D alone had a higher incidence of peripheral edema (32% vs. 15%, P<0.001) and grade 3 nonhematological toxicity (56% vs. 43%, P = 0.022). Patients treated with D alone were also more frequently hospitalized (53% vs. 41%, P = 0.035), mainly owing to a higher incidence of febrile neutropenia in this group (25% vs. 10%, P<0.001). P did not influence progression-free survival (P = 0.692, log-rank test) or overall survival when adjusting for baseline levels of hemoglobin, alkaline phosphatase, lactate dehydrogenase, prostate-specific antigen, and Eastern Cooperative Oncology Group performance status (hazard ratioP = 0.98, 95% CI: 0.76-1.26, P = 0.89, Cox proportional hazard regression model). CONCLUSIONS: Coadministration of low-dose P reduced the incidence of peripheral edema, grade 3 nonhematological toxicity, and the risk of being admitted owing to febrile neutropenia during treatment with D. Adjusted survival analysis did not indicate that P affected prognosis. PMID- 26254697 TI - Molecular mechanisms of squamous differentiation in urothelial cell carcinoma: a paradigm for molecular subtyping of urothelial cell carcinoma of the bladder. AB - BACKGROUND: Recent molecular characterization studies focusing on bladder cancer have provided a wealth of information, including the identification of specific molecular subtypes of this disease. Interestingly, a particular molecular subtype identified by several different groups is characterized, at least in part, by the presence of squamous differentiation (SqD) in a significant fraction of primary tumors. Tumors that exhibit SqD are extremely aggressive. Moreover, conflicting reports exist relative to the sensitivity of bladder tumors exhibiting SqD to multimodal treatment. Bladder cancers that exhibit SqD appear to be distinct clinical entities and are often associated with a specific molecular subtype; therefore, it is important to understand the molecular drivers of this process. PURPOSE: Because presence of SqD is closely associated with a basal molecular phenotype, we review the evidence for specific pathways in SqD. In addition, we pose key areas for future exploration. PMID- 26254698 TI - The comparison of oncologic outcomes between metastatic upper tract urothelial carcinoma and urothelial carcinoma of the bladder after cisplatin-based chemotherapy. AB - OBJECTIVE: To compare the oncologic outcomes and prognostic factors between metastatic upper tract urothelial carcinoma (UTUC) and UC of the bladder (UCB) after cisplatin-based chemotherapy. MATERIALS AND METHODS: We retrospectively reviewed patients with metastatic UTUC and UCB after methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) or gemcitabine/cisplatin chemotherapy between 1997 and 2014 at Kaohsiung Chang Gung Memorial Hospital. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Univariate and multivariate analyses with Cox proportional hazard models were also performed to assess the effect of prognostic factors. RESULTS: Totally, 203 patients were enrolled into our study, including 120 patients with UTUC and 83 patients with UCB. For patients with UTUC, the median PFS was 7.3 months vs. 4.0 months (P<0.001), and the median OS was 17.0 months vs. 10.5 months (P<0.001) for MVAC and gemcitabine/cisplatin, respectively. For patients with UCB, the median PFS (P = 0.35) and OS (P = 0.06) of the 2 groups were insignificant. In multivariate analyses, number of metastatic sites was the identical prognostic factor for OS between UTUC (hazard ratio [HR] = 2.74; 95% CI: 1.63-4.62; P<0.001) and UCB (HR = 3.12; 95% CI: 1.52-6.39; P = 0.002). Presence of liver metastasis (HR = 1.84; 95% CI: 1.05-2.23; P = 0.03) and MVAC chemotherapy (HR = 0.54; 95% CI: 0.35-0.83; P<0.001) were significantly correlated to survival only for UTUC, not for UCB. CONCLUSION: Our study suggests discordant oncologic outcomes and prognostic factors between metastatic UTUC and UCB after cisplatin-based chemotherapy. A prospective study is warranted to validate our results. PMID- 26254699 TI - Origins of the Arden Syntax. AB - The Arden Syntax originated in the 1980's, when several knowledge-based systems began to show promise, but researchers recognized the burden of recreating these systems at every institution. Derived initially from Health Evaluation through Logical Processing (HELP) and the Regenstrief Medical Record System (RMRS), the Arden Syntax defines medical logic that can be encoded as independent rules, such as reminders and alerts, with the hope of creating a public library of rules. It was first vetted at an informatics retreat held in 1989 at Columbia University's Arden Homestead. The syntax was intended to be readable by clinician experts but to provide powerful array processing, which was derived largely a programming language called APL. The syntax was improved and implemented by a number of researchers and vendors in the early 1990's and was initially adopted by the consensus standards organization, the American Society for Testing and Materials. PMID- 26254700 TI - Circulating hepcidin is independently associated with systolic blood pressure in apparently healthy individuals. AB - BACKGROUND AND AIMS: Few studies have described the association between hepcidin levels and cardiometabolic risk in the general population and more so by considering robust adjustment for confounding factors. Therefore, the aim of the present study was to investigate the associations between circulating hepcidin and anthropometric, biochemical and vascular variables related to cardiometabolic risk in healthy individuals adjusting for relevant covariates. METHODS: Two hundred thirty nine individuals (20-65 years old) were included in this cross sectional study. Outcome variables were fasting glucose, triglycerides, LDL cholesterol, HDL cholesterol, total cholesterol, waist circumference, systolic and diastolic blood pressures, and the Framingham risk score. Multivariate linear regression and ANCOVA analyses including covariates of body mass index (BMI), menopausal status, physical inactivity, alcohol intake, insulin resistance, subclinical/chronic inflammation, ferritin and soluble transferrin receptors were used to describe the associations between hepcidin and cardiometabolic risk markers. RESULTS: In adjusted linear regression analyses, there was no significant association in men. In women, a relationship between hepcidin and triglycerides became significant after adjustments (p <0.05). By comparing quartiles of hepcidin levels, systolic blood pressure values in men were significantly higher in the upper quartile of hepcidin vs. the rest of quartiles independently of BMI, chronic inflammation, insulin resistance and other iron markers (ANCOVA, p <0.05). There were no significant independent associations with the Framingham risk score (total points). CONCLUSION: We found a threshold effect of hepcidin levels on systolic blood pressure specifically in men. Further larger studies and experimental research are required to investigate possible mechanisms for the relationship between hepcidin metabolism and vascular function. PMID- 26254701 TI - Cannabinoids regulate intestinal motor function and electrophysiological activity of myocytes in rodents. AB - BACKGROUND AND AIMS: This study aims to investigate the effects of cannabinoid (CB)1 and CB2 receptor ligands on intestinal motor function and muscular electrophysiological activity in rodent gastrointestinal (GI) tract. METHODS: Lipopolysaccharide (LPS) was used to induce intestinal hypomotility. The effect of selective CB1 and CB2 agonists and antagonists on contractility of the muscle strips from rat jejunum was measured using organ bath, and the membrane potential of the jejunal smooth muscle cells was recorded with intracellular microelectrodes. The single cell patch clamp technique was applied to record delayed rectifying potassium currents (IKV) and spontaneous transient outward currents (STOC). RESULTS: LPS significantly reduced contractility of the smooth muscle strips (p <0.010) and caused hyperpolarization of membrane potential of the smooth muscle cells (p <0.010). This LPS-induced effect was reversed by AM251 and AM630, selective CB1 and CB2 antagonists, respectively, which promoted contractions of smooth muscle strips and triggered cell depolarization (p <0.010). LPS-induced changes were further enhanced in the presence of CB agonists, HU210 and WIN55 (p <0.050 or p <0.010). No effect of HU210 or AM251 on IKV and STOC has been observed. This ex vivo study suggests that CB1 and CB2 receptors are involved in intestinal motor function in normal and LPS-induced pathological states and the regulation of the membrane potential of smooth muscle cells is very likely one of the effective mechanisms. CONCLUSIONS: This is one of the first reports on neuronal regulation of intestinal motility through CB dependent pathways with potential application in the treatment of inflammatory and functional GI disorders. PMID- 26254702 TI - High incidence of hypoglycemia in stable insulin-treated type 2 diabetes mellitus: continuous glucose monitoring vs. self-monitored blood glucose. Observational prospective study. AB - OBJECTIVES: Hypoglycemia is a limiting factor in the achievement of strict glycemic control. The primary objective of this 9-week study was to determine the frequency of hypoglycemia in patients with stable insulin-treated type 2 diabetes mellitus by comparing self-monitored blood glucose (SMBG) measurement with continuous glucose monitoring (CGM). METHODS: This was an observational prospective study. Included in the study were 63 stable, insulin-treated patients with type 2 diabetes. They were instructed to record 2 daily capillary blood glucose readings, pre- and/or postprandial, in a sequential way during 8 consecutive weeks. A CGM system was worn during an additional week. We evaluated the frequency of hypoglycemia using the 8-week SMBG profile and the 1 CGM week. RESULTS: SMBG revealed that 50% of the patients had experienced hypoglycemia. CGM found hypoglycemia in 59% of patients. Significantly higher percentages of hyperglycemic and hypoglycemic episodes were detected by CGM than by capillary blood glucose measurements (61.1% vs. 50.8%; p=0.047) and (3.8% vs. 1.7%; p=0.016); 33% of patients experienced nocturnal hypoglycemia, and 19% of patients who had no data concerning hypoglycemia recorded in the capillary blood glucose diary had experienced hypoglycemia as measured by CGM, and the hypoglycemia occurred mainly during the nocturnal period. CONCLUSIONS: In stable well controlled, insulin-treated patients with type 2 diabetes, CGM showed higher numbers of hypoglycemic events than did SMBG, especially at night. CGM is a useful tool that provides clinically valuable information about glucose control in these patients. PMID- 26254703 TI - Effect of the Novel Biodegradable N, O-Carboxymethylchitosan and Oligo-Chitosan on the Platelet Thrombogenicity Cascade in von Willebrand Disease. AB - INTRODUCTION: Von Willebrand disease (vWD) is the second least common hemostatic disorder in Malaysia, and it has a low prevalence. This study examined the underlying platelet thrombogenicity cascades in the presence of different formulations of chitosan-derivatives in vWD patients. This paper aimed to determine the significant influence of chitosan biomaterial in stimulating the platelet thrombogenicity cascades that involve the von Willebrand factor, Factor 8, Thromboxane A2, P2Y12 and Glycoprotein IIb/IIIa in vWD. MATERIALS AND METHODS: Variable chitosan formulations of N,O-Carboxymethylchitosan (NO-CMC) and Oligo Chitosan (O-C) were tested. Fourteen vWD subjects voluntarily participated in this study after signing informed consent forms. The patient's demographic profiles, family history, type of vWD, clinical symptoms and laboratory profiles were recorded and analyzed. Enzyme-linked immunosorbent assay, flow cytometry and Western blot tests were used to determine the level of the chitosan-adhered platelet-mechanisms. RESULTS: The study revealed that most patients were predominantly affected by vWD type I. The O-C group of chitosan's scaffold pores is sufficient to allow for nutrients and cells. The O-C-stimulated-mediators are capable of initiating the platelet actions and were detected to expedite the blood coagulation processes. The oligo-group of chitosans was capable of amplifying and triggering more platelet activator's pathways via the studied mediators. The present findings suggest that the ability of each type of chitosan to coagulate blood varies depending on its chemical composition. CONCLUSION: The oligo group of chitosans is potentially capable of triggering platelet thrombogenicity cascades by activating platelets in vWD patients to form a platelet plug for hemostasis process. PMID- 26254704 TI - The performance of age-adjusted D-dimer cut-off in Chinese outpatients with suspected venous thromboembolism. AB - BACKGROUND: D-dimer testing has been widely used in the exclusion of venous thromboembolism (VTE), but its clinical usefulness is limited in older patients because of a lower specificity. OBJECTIVE: To evaluate the diagnostic performance of STA-Liatest D-dimer assay and validate the age-adjusted cut-off value in Chinese outpatients with suspected VTE in a prospective non-interventional study. METHODS: Symptomatic patients suspected of having deep venous thrombosis or pulmonary embolism were recruited from 2 participating centers. STA-Liatest D dimer assay, clinical pretest probability assessment and diagnostic imaging test including complete compression ultrasonography or computed tomography pulmonary angiography were performed among all participants. The performance of D-dimer test was assessed with an age-adjusted D-dimer cut-off (age*0.01MUg/ml in patients aged>50years) and with conventional cut-off (0.5MUg/ml at all ages). RESULTS: A total of 594 eligible outpatients were included in this study and VTE was diagnosed in 195 (32.8%) patients. In those patients with a low or moderate pretest probability (n=373), the increase in the proportion of patients with a D dimer below the age-adjusted cut-off value compared with the conventional cut-off value was 5.9% (95% confidence interval; 3.8%-8.7%). The sensitivity, specificity and negative predictive value of STA-Liatest D-dimer test were 95.0% (83.5% - 98.6%), 84.1%(79.8%-87.6%) and 99.3%(97.5% - 99.8%), respectively, using the age adapted diagnostic strategy. CONCLUSIONS: The application of age-adjusted cut-off of D-dimer test combined with clinical probability greatly increases the proportion of Chinese older outpatients in whom VTE can be safely excluded. PMID- 26254705 TI - Are surface antigens suited to verify the redifferentiation potential and culture purity of human chondrocytes in cell-based implants. AB - Cell expansion in vitro is a prequisite to obtain a sufficient quantity of cells for cell-based cartilage repair of articular cartilage lesions. During this process verification of redifferentiation potential of highly expanded chondrocytes is required. Furthermore, cellular impurities of chondrocyte cultures have to be excluded. For this purpose, redifferentiation of expanded human chondrocytes in passage 3 or 5 was initiated in bioresorbable polyglycolic acid-fibrin (PGA-fibrin) scaffolds and selected potential markers were analysed during the process of cell expansion and redifferentiation. Chondrocyte expansion was accompanied by a decrease of collagen type II and COMP and an increase of collagen type I expression indicating cell dedifferentiation. Redifferentiation of chondrocytes in PGA-fibrin scaffolds was accompanied by an increase of collagen II/I ratio. Flow cytometric analyses revealed that in contrast to CD44 and CD49e, CD63 and CD166 showed significant changes in the number of positive cells during redifferentiation. CD14 and CD45 are not expressed by chondrocytes and are therefore possible candidates to detect specifically monocytes or haematopoetic cells in chondrocyte cultures. Characterization of surface antigen expression revealed two promising candidates (CD63 and CD166) to describe the process of redifferentiation, while CD14 and CD45 are suitable markers to exclude impurities by monocytes or haematopoetic cells. PMID- 26254706 TI - Usefulness of Beta2-Microglobulin as a Predictor of All-Cause and Nonculprit Lesion-Related Cardiovascular Events in Acute Coronary Syndromes (from the PROSPECT Study). AB - In the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study, plaque burden, plaque composition, and minimal luminal area were associated with an increased risk of adverse cardiovascular events arising from untreated atherosclerotic lesions (vulnerable plaques) in patients with acute coronary syndromes (ACS). We sought to evaluate the utility of biomarker profiling and clinical risk factors to predict 3-year all-cause and nonculprit lesion-related major adverse cardiac events (MACEs). Of 697 patients who underwent successful percutaneous coronary intervention (PCI) for ACS, an array of 28 baseline biomarkers was analyzed. Median follow-up was 3.4 years. Beta2-microglobulin displayed the strongest predictive power of all variables assessed for all-cause and nonculprit lesion-related MACE. In a classification and regression tree analysis, patients with beta2-microglobulin >1.92 mg/L had an estimated 28.7% 3-year incidence of all-cause MACE; C-peptide <1.32 ng/ml was associated with a further increase in MACE to 51.2%. In a classification and regression tree analysis for untreated nonculprit lesion-related MACE, beta2 microglobulin >1.92 mg/L identified a cohort with a 3-year rate of 18.5%, and C peptide <2.22 ng/ml was associated with a further increase to 25.5%. By multivariable analysis, beta2-microglobulin was the strongest predictor of all cause and nonculprit MACE during follow-up. High-density lipoprotein (HDL), transferrin, and history of angina pectoris were also independent predictors of all-cause MACE, and HDL was an independent predictor of nonculprit MACE. In conclusion, in the PROSPECT study, beta2-microglobulin strongly predicted all cause and nonculprit lesion-related MACE within 3 years after PCI in ACS. C peptide and HDL provided further risk stratification to identify angiographically mild nonculprit lesions prone to future MACE. PMID- 26254707 TI - Usefulness of Circulating Decoy Receptor 3 in Predicting Coronary Artery Disease Severity and Future Major Adverse Cardiovascular Events in Patients With Multivessel Coronary Artery Disease. AB - Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor superfamily, is an antiapoptotic soluble receptor considered to play an important role in immune modulation and has pro-inflammatory functions. This study was designed to test whether circulating DcR3 levels are associated with coronary artery disease (CAD) severity and predict future major adverse cardiovascular events (MACEs) in patients with CAD. Circulating DcR3 levels and the Syntax score (SXscore) were determined in patients with multivessel CAD. The primary end point was the MACE within 12 months. In total, 152 consecutive patients with angiographically confirmed multivessel CAD who had received percutaneous coronary intervention were enrolled and were divided into 3 groups according to CAD lesion severity. Group 1 was defined as low SXscore (<=13), group 2 as intermediate SXscore (>13 and <=22), and group 3 as high SXscore (>22). DcR3 levels were significantly higher in the high SXscore group than the other 2 groups (13,602 +/ 7,256 vs 8,025 +/- 7,789 vs 4,637 +/- 4,403 pg/ml, p <0.001). By multivariate analysis, circulating DcR3 levels were identified as an independent predictor for high SXscore (adjusted odds ratio 1.15, 95% confidence interval 1.09 to 1.21; p <0.001). The Kaplan-Meier analysis showed that increased circulating DcR3 levels are associated with enhanced 1-year MACE in patients with multivessel CAD (log rank p <0.001). In conclusion, increased circulating DcR3 levels are associated with CAD severity and predict future MACE in patients with multivessel CAD. PMID- 26254708 TI - Management of Antiplatelet Therapy After Coronary Artery Bypass Grafting in the Setting of Acute Coronary Syndrome. PMID- 26254709 TI - Is Transcatheter Aortic Valve Implantation as Cost-Effective as Surgical Aortic Valve Replacement? PMID- 26254710 TI - The role of centrally injected nesfatin-1 on cardiovascular regulation in normotensive and hypotensive rats. AB - This study investigated the cardiovascular effects of nesfatin-1 in normotensive rats and animals subjected to hypotensive hemorrhage. Hemorrhagic hypotension was induced by withdrawal 2 mL blood/100 g body weight over a period of 10 min. Acute hemorrhage led to a severe and long-lasting decrease in mean arterial pressure (MAP) and heart rate (HR). Intracerebroventricularly (i.c.v.) administered nesfatin-1 (100 pmol) increased MAP in both normotensive and hemorrhaged rats. Nesfatin-1 also caused bradycardia in normotensive and tachycardia in hemorrhaged rats. Centrally injected nesfatin-1 (100 pmol, i.c.v.) also increased plasma catecholamine, vasopressin and renin concentrations in control animals and potentiated the rise in all three cardiovascular mediators produced by hemorrhage. These findings indicate that centrally administered nesfatin-1 causes a pressor response in conscious normotensive and hemorrhaged rats and suggest that enhanced sympathetic activity and elevated vasopressin and renin concentrations mediate the cardiovascular effects of the peptide. PMID- 26254711 TI - Aortic stent-grafts: Endoleak surveillance. AB - Endoleaks have been referred to as the "Achilles heel" of endovascular aortic aneurysm repair (EVAR) and are the most common complication of this procedure. An endoleak can maintain a high systemic blood pressure within the aneurysm sac, potentially leading to rupture. Follow-up is therefore mandatory to detect and classify possible endoleaks. Computed tomography (CT) remains the gold standard for follow-up, but provides no hemodynamic information on endoleaks and has the disadvantages of exposing patients to iodine contrast and X-ray radiation. Exposure to radiation could be reduced in various ways, by simplifying the triphasic protocol using dual-energy CT imaging, limiting the amount of radiation per slice using iterative reconstruction, and reducing the follow-up schedule that could be altered to include non-ionizing radiation imaging techniques. Contrast-enhanced ultrasound (CEUS) is an interesting alternative to CT, as is magnetic resonance (MR) imaging that can be used as an alternative or for complementary imaging. Long-term follow-up schedules are currently based on repeated CT. However, more recently alternative follow-up protocols have been proposed for patients with no endoleaks nor increase in aneurysmal sac size. These new protocols consist of CT imaging at 1month and 1year after treatment, subsequently followed by CEUS. Nevertheless, the mechanical structure of the stent-graft must still be verified by CT. The use of patient-specific risk adjusted follow-up protocols, based on preoperative imaging and the first postoperative results, is gradually becoming more and more widespread. PMID- 26254712 TI - Cardiac gene therapy: Recent advances and future directions. AB - Gene therapy has the potential to serve as an adaptable platform technology for treating various diseases. Cardiovascular disease is a major cause of mortality in the developed world and genetic modification is steadily becoming a more plausible method to repair and regenerate heart tissue. Recently, new gene targets to treat cardiovascular disease have been identified and developed into therapies that have shown promise in animal models. Some of these therapies have advanced to clinical testing. Despite these recent successes, several barriers must be overcome for gene therapy to become a widely used treatment of cardiovascular diseases. In this review, we evaluate specific genetic targets that can be exploited to treat cardiovascular diseases, list the important delivery barriers for the gene carriers, assess the most promising methods of delivering the genetic information, and discuss the current status of clinical trials involving gene therapies targeted to the heart. PMID- 26254714 TI - Neurobiology of Learning and Memory. Editorial. PMID- 26254715 TI - Mediodorsal but not anterior thalamic nuclei lesions impair acquisition of a conditional discrimination task. AB - The limbic thalamus is a heterogeneous structure with distinctive cortical connectivity. A recent review suggests that the mediodorsal thalamic nucleus (MD), unlike the anterior thalamic nuclei (ATN), may be involved in selecting relevant information in tasks relying on executive functions. We compared the effects of excitotoxic lesions of the MD or the ATN on the acquisition of a simple conditional discrimination in rats. When required to choose from two levers according to auditory or visual cues, ATN rats and sham-lesioned rats performed to the same levels and displayed similar acquisition curves. Under the same conditions, MD rats' acquisition of the task was markedly delayed. This group nevertheless attained nearly normal performances after more extensive training. Furthermore, all rats learned reversal of the original discrimination at the same rate. These results highlight functional specialization within the limbic thalamus and support the notion that MD contributes to the identification of relevant dimensions in conditional tasks during the initial stages of acquisition. PMID- 26254713 TI - Molecular genetic response of Xiphophorus maculatus-X. couchianus interspecies hybrid skin to UVB exposure. AB - The phenotypic and genetic similarities between Xiphophorus and human melanoma render Xiphophorus a useful animal model for studying the genetic basis of melanoma etiology. In the Xiphophorus model, melanoma has been shown to be inducible by ultraviolet light (UVB) exposure among interspecies hybrids, but not in parental line fish similarly treated. This leads to questions of what genes are responsive to UVB exposure in the skin of the interspecies hybrids, as well as how parental alleles in hybrids may be differentially regulated and the potential roles they may play in induced melanomagenesis. To address these questions, we produced X. maculatus Jp 163 B*X. couchianus (Sp-Couch) F1 hybrid fish, exposed both hybrid and parental fish to UVB, and performed gene expression profiling of the skin using RNA-Seq methodology. We characterized a group of unique UVB-responsive genes in Sp-Couch hybrid including dct, pmela, tyr, tyrp1a, slc2a11b, rab38a, rab27, tspan10, slc45a2, oca2, slc24a5, ptn and mitfa. These genes are associated with melanin production and melanocyte proliferation. They were also up-regulated in Sp-Couch hybrid, indicating that their UVB response is hybridization initiated. In the hybrid, several melanin production and pigmentation related genes, including slc45a2, tspan10, dct, slc2a11b and ptn showed either X. couchianus or X. maculatus allele specific expression. The finding that these genes exhibit allele specific expression regulatory mechanisms in Sp-Couch hybrids, but do not exhibit a corresponding UVB response in either one of the parental fishes, may suggest UVB targets and imply mechanisms regarding the susceptibility of Sp-Couch to induced melanomagenesis. PMID- 26254716 TI - Detection of malformations in sea urchin plutei exposed to mercuric chloride using different fluorescent techniques. AB - Embryos of Mediterranean sea urchin Paracentrotus lividus and subtropical Echinometra mathaei were exposed to 5,10, 15 and 20ugL(-1), and to 1, 2, 3 and 4ugL(-1) mercuric chloride (HgCl2), respectively. The effective concentration (EC50) inducing malformation in 50% of 4-arm pluteus stage (P4) was 16.14ugL(-1) for P. lividus and 2.41ugL(-1) for E. mathaei. Two-photon (TP), second (SHG) and third harmonic generation (THG) microscopy techniques, TUNEL staining, propidium iodide (PI) and Hoechst 33342 probes were used to detect light signals or to stain apoptotic and necrotic cells in fixed and alive plutei. Signals were detected differently in the two species: TP fluorescence, commonly associated with apoptotic cells, did not increase with increasing HgCl2 concentrations in P. lividus and in fact, the TUNEL did not reveal induction of apoptosis. PI fluorescence increased in P. lividus in a dose-dependent manner, suggesting a loss of cell permeability. In E. mathaei plutei TP fluorescence increased at increasing HgCl2 concentrations. THG microscopy revealed skeletal rods in both species. Different fluorescent techniques, used in this study, are proposed as early-warning systems to visualize malformations and physiological responses in sea urchin plutei. PMID- 26254718 TI - Risk of suicide and all-cause mortality after self-harm. PMID- 26254717 TI - Hospital management of suicidal behaviour and subsequent mortality: a prospective cohort study. AB - BACKGROUND: Self-poisoning and self-injury are associated with a high risk of suicide or death from any cause but the effect of routine aspects of hospital management on mortality risk is unknown. METHODS: We did a prospective cohort study using data for adults who had self-harmed presenting to five emergency departments in the UK between 2000 and 2010. We assessed the relation between four aspects of management (psychosocial assessment, medical admission, psychiatric admission, referral for mental health follow-up) and death by suicide or any cause within 12 months of presentation. FINDINGS: Of 38 415 individuals presenting with self-harm, 261 (0.7%) died by suicide and 832 (2.2%) died from any cause within 12 months. Most aspects of management were associated with a higher mortality risk in unadjusted analyses. Psychiatric admission was associated with the highest risks for both suicide (hazard ratio 2.35, 95% CI 1.59-3.45) and all-cause mortality (2.35, 2.04-2.72). After adjustment for baseline variables, the hazard ratios were generally smaller, particularly for psychiatric admission. There were significant interactions by sex, age, and history of self-harm. INTERPRETATION: This was an observational study and so we cannot infer causation. However, our finding that clinical services seem to reserve the most intensive levels of treatment for patients at highest risk is reassuring. Aspects of routine management might be associated with a lower mortality risk but these effects vary by clinical subgroup. FUNDING: UK Department of Health. PMID- 26254719 TI - In situ gamma ray measurements of radionuclides at a disused phosphate mine on the West Coast of South Africa. AB - High levels of uranium and its radioactive progeny like radium is normally associated with phosphate mining. In Situ gamma ray spectroscopy as a survey tool has been successfully applied to assess radionuclide concentrations in various geographical environments. A transportable and robust gamma ray detection system (GISPI) was therefore employed to determine the concentrations of naturally occurring radionuclides at a disused phosphate mine on the West Coast of South Africa. The concentrations of radium, thorium and potassium were measured and plotted. The measurements showed fairly high concentrations with medians of 320 Bq/kg for (226)Ra, 64 Bq/kg for (232)Th and 390 Bq/kg for (40)K. The highest concentrations were however confined to specific areas of the mine. The effective dose due to gamma irradiation for the various areas of the mine was also estimated and the highest estimated level was 0.45 mSv/y. The article finally draws conclusions as to the origins and impact of the radiation. PMID- 26254720 TI - Sorption and desorption studies of radioiodine onto silver chloride via batch equilibration with its aqueous media. AB - The uncontrolled spread out of radioiodine (especially (1)(3)(1)I) produced from nuclear activities or accidents, due to its high volatility, to the biosphere represents an environmental impact because of its concentration in the thyroid gland and accumulation on soil surface. This work represents a simple method for isolation of radioiodine from aqueous solution in the form of insoluble solid compound and further recovery of it in aqueous phase for any further controlled use. Crystalline silver chloride was prepared and characterized. Batch sorption of (131)I onto the prepared AgCl was studied from different aqueous media (H2O and NaOH of different concentrations) and at different I(-):Ag molar ratios (from alkaline media) for different times at 25 degrees C. It was found that the sorption yield of (131)I from 2.5 M NaOH solution (at I(-):Ag and S2O3(2-):I(-) molar ratios of 0.025 and 2, respectively) reached 97.7% after 6 h and only slightly increased to 98.6% after 16 h of contact time. The presence of H2O2 adversely affected the batch sorption process. The included REDOX and precipitation reactions were discussed. Batch desorption of the sorbed (131)I from AgCl into aqueous phase was studied with NaOCl solutions of different concentrations and different contact times at 25 degrees C. Desorption yield of (131)I was found to be 94.5% with 10 mL of 0.5 M NaOCl solution after contact time of 16 h. Kinetic analysis has been performed for both batch sorption and desorption processes. PMID- 26254721 TI - Retrospective dosimetry of Iodine-131 exposures using Iodine-129 and Caesium-137 inventories in soils--A critical evaluation of the consequences of the Chernobyl accident in parts of Northern Ukraine. AB - The radiation exposure of thyroid glands due to (131)I as a consequence of the Chernobyl accident was investigated retrospectively based on (129)I and (137)Cs inventories in soils in Northern Ukraine. To this end, soil samples from 60 settlements were investigated for (129)I, (127)I, and (137)Cs by AMS, ICP-MS and gamma-spectrometry, respectively. Sampling was performed between 2004 und 2007. In those parts of Northern Ukraine investigated here the (129)I and (137)Cs inventories are well correlated, the variability of the individual (129)I/(137)Cs ratios being, however, high. Both the (129)I and (137)Cs inventories in the individual 5 samples for each settlement allowed estimating the uncertainties of the inventories due to the variability of the radionuclide deposition and consequently of the retrospective dosimetry. Thyroid equivalent doses were calculated from the (129)I and the (137)Cs inventories using aggregated dose coefficients for 5-year old and 10-year-old children as well as for adults. The highest thyroid equivalent doses (calculated from (129)I inventories) were calculated for Wladimirowka with 30 Gy for 5-years-old children and 7 Gy for adults. In 35 settlements of contamination zone II the geometric mean of the thyroid equivalent doses was 2.0 Gy for 5-years-old children with a geometric standard deviation (GSD) of 3.0. For adults the geometric mean was 0.47 Gy also with a GSD of 3.0. In more than 25 settlements of contamination zone III the geometric means were 0.82 Gy for 5-years old children with a GSD of 1.8 and 0.21 Gy for adults (GSD 1.8). For 45 settlements, the results of the retrospective dosimetry could be compared with thyroid equivalent doses calculated using time integrated (131)I activities of thyroids which were measured in 1986. Thus, a critical evaluation of the results was possible which demonstrated the general feasibility of the method, but also the associated uncertainties and limitations. PMID- 26254722 TI - Prostate Needle Biopsy Outcomes in the Era of the U.S. Preventive Services Task Force Recommendation against Prostate Specific Antigen Based Screening. AB - PURPOSE: We determined whether the characteristics of patients undergoing prostate needle biopsies and prostate needle biopsy results changed after the U.S. Preventive Services Task Force recommendation in 2012 against prostate specific antigen based screening for prostate cancer for men of any age. MATERIALS AND METHODS: A prospective database of patients undergoing prostate needle biopsies at Virginia Mason from 2004 to 2014 was reviewed. Welch's t-test and chi-square tests were used to compare patients seen before to those seen after the USPSTF recommendation. Relative risks and corresponding confidence intervals were estimated by general linear regression. RESULTS: Patients in the post-USPSTF group (310) had a higher prostate specific antigen (p <0.001), were more likely to be diagnosed with higher clinical stage (2b, p=0.003; 2c-3a, p=0.027) and D'Amico high risk prostate cancer (p=0.036), with an adjusted relative risk for high risk prostate cancer of 1.25 (95% CI 1.02-1.52) compared to those in the pre-USPSTF group (1,416). Limiting the pre-USPSTF group to the 30 months before the draft guidelines (448 patients) yielded similar results. The absolute number of biopsies performed decreased by 31%, with the majority of the decrease occurring in the detection of intermediate risk tumors. CONCLUSIONS: In the 2 and a half years after the USPSTF recommendation against prostate specific antigen based screening, patients undergoing prostate needle biopsies were significantly more likely to be diagnosed with high risk disease. However, a reduction in the number of prostate needle biopsies performed occurred concomitantly with a decrease in the detection of intermediate risk, potentially curable prostate cancer. Future focus on informed application of screening techniques may prevent the reversal of decades of improvement in the prostate cancer mortality rate. PMID- 26254723 TI - Upper Calyx Approachability through a Lower Calyx Access for Prone Versus Supine Percutaneous Nephrolithotomy. AB - PURPOSE: We assessed the approachability of the upper calyx through lower calyx access for prone and supine percutaneous nephrolithotomy and used computerized tomography to analyze anatomical factors that may influence it. MATERIALS AND METHODS: A prospective series of 45 patients treated with percutaneous nephrolithotomy were operated on in the prone (20) and supine (25) positions. Computerized tomography simulated access to the lower and upper calyx longitudinal axes were used to measure skin-to-lower calyx distance, thickness of the body wall, muscle and fat, the muscle-to-fat thickness ratio and the angle between the lower calyx tract and the upper calyx axis. Intraoperative approachability to the upper calyx was also evaluated. RESULTS: The upper calyx was successfully approached in 20% of prone and 80% of supine percutaneous nephrolithotomies (p <0.0001). The average skin-to-lower calyx distance was 98.4 mm (range 65.3 to 128.6) in the prone position and 98.7 mm (range 60.8 to 150) in the supine position (p = 0.99). Body wall and muscular thickness, and the muscle to-fat thickness ratio were significantly lower in supine than prone nephrolithotomy (p <0.001, <0.0005 and <0.05, respectively). The average angle between the lower and upper calyces axes was wide in the supine position (141 degrees, range 90 to 170) and acute in the prone position (84 degrees, range 65 to 110, p <0.05(E-10)). CONCLUSIONS: Upper calyx endoscopic approachability through the lower calyx is significantly higher in supine than in prone percutaneous nephrolithotomies, possibly due to a thinner body wall, a thinner muscular layer, a lower muscle-to-fat thickness ratio and a wider angle between the lower and upper calyx axes. PMID- 26254724 TI - High Grade Blunt Renal Trauma: Predictors of Surgery and Long-Term Outcomes of Conservative Management. A Prospective Single Center Study. AB - PURPOSE: The management of major renal trauma has shifted in the last decade in favor of a nonoperative approach. Our level 1 trauma center promotes this approach with the objective of renal function preservation. However, certain situations still require surgery. In this study we analyze predictors of surgery and long-term outcomes after conservative management. MATERIALS AND METHODS: From January 2004 to March 2015 we prospectively collected data from all patients admitted to our institution for high grade blunt renal trauma (grades IV and V). Nonoperative management was considered successful when patients did not undergo surgical exploration, regardless of angioembolization or endoscopic treatment. RESULTS: Of 306 patients with renal trauma 151 presented with major injuries, including 124 grade IV and 27 grade V. Nonoperative management was successful in 110 (89%) cases of grade IV and 14 (52%) cases of grade V lesions. Deceleration mechanism (p=0.03), associated lesions (p=0.001), percentage of devitalized parenchyma (p=0.012), angioembolization (p <0.001), hemodynamic instability (p <0.001) and low hemoglobin (p=0.001) were more frequent in patients treated surgically. On multivariate analysis grade (OR 7.36, p=0.01) and hemodynamic instability (OR 4.18, p=0.04) were the only independent predictors of surgical treatment. Long-term followup of preserved kidneys revealed a remaining 40% and 0% relative renal function after grade IV and V injuries, respectively. Only devascularized parenchyma greater than 25% predicted the decline of long-term renal function. CONCLUSIONS: Nonoperative management can and should be performed safely in cases of grade IV injuries whenever possible, with valuable long-term renal function. It can also be initiated in grade V cases. However, surgeons should consider nephrectomy with the onset of any suspicious symptoms. PMID- 26254725 TI - Differentiating between benign and malignant adnexal lesions with contrast enhanced transvaginal ultrasonography. AB - OBJECTIVE: To analyze the relationship between contrast kinetics in tumorous vessels and lesion histologic type in an attempt to differentiate between malignant and benign disease. METHODS: In a single-center prospective study, patients who had been referred for elective surgery because of a diagnosis of unilateral and/or bilateral adnexal masses were enrolled at Dr Jan Biziel University Hospital, Bydgoszcz, Poland, between January 2012 and September 2013. Participants underwent contrast-enhanced ultrasonography examination (CEUS). Contrast kinetics were obtained and compared with the neovascularization of the tumor. Accuracy, and positive and negative predictive values were calculated. RESULTS: Among 160 enrolled patients, 84 underwent CEUS examination and 51 lesions were studied. Baseline and maximum color Doppler intensities were significantly higher in malignant than in benign tumors (P < 0.001 for both). Similarly, the absolute and relative increases in color Doppler intensity were significantly higher in malignant tumors (P < 0.001). The estimated positive predictive value was 97.1%, the negative predictive value was 100%, and the accuracy was 100%. Peak enhanced intensity of fractional color Doppler Area and area under the time-intensity curve (S-parameter) correlated significantly with the histology of the lesion (P < 0.001). Probability curves demonstrated that higher S-parameter values were correlated with a higher risk of malignancy. CONCLUSION: Transvaginal CEUS is a reliable and reproducible way to differentiate between benign and malignant adnexal lesions. PMID- 26254726 TI - Down regulation of lncSCIR1 after spinal cord contusion injury in rat. AB - Extensive changes occur at transcriptional level after traumatic spinal cord injury (SCI). In this study, we performed a large scale screening of expression changes of long (>200 nt) RNA transcripts including both coding and non-coding RNA species in a rat contusion SCI model. We validated significant down regulation of one long non-coding RNA (lncSCIR1) at 1, 4, and 7 days postinjury. lncSCIR1 knockdown promoted astrocyte proliferation and migration in vitro. We further validated the strong association between lncSCIR1 knock down and the expression changes of four mRNAs after injury. Our data indicated that lncSCIR1 down-regulation might play a detrimental role in the pathophysiology of traumatic SCI and thereby provided new insights into the studies of potential therapeutic targets for traumatic central nervous system (CNS) injuries. PMID- 26254727 TI - Delayed treatment with ADAMTS13 ameliorates cerebral ischemic injury without hemorrhagic complication. AB - Tissue plasminogen activator (tPA) is the only approved therapy for acute ischemic stroke. However, delayed tPA treatment increases the risk of cerebral hemorrhage and can result in exacerbation of nerve injury. ADAMTS13, a von Willebrand factor (VWF) cleaving protease, has a protective effect against ischemic brain injury and may reduce bleeding risk by cleaving VWF. We examined whether ADAMTS13 has a longer therapeutic time window in ischemic stroke than tPA in mice subjected to middle cerebral artery occlusion (MCAO). ADAMTS13 (0.1mg/kg) or tPA (10mg/kg) was administered i.v., immediately after reperfusion of after 2 h or 4-h MCAO for comparison of the therapeutic time windows in ischemic stroke. Infarct volume, hemorrhagic volume, plasma high-mobility group box1 (HMGB1) levels and cerebral blood flow were measured 24h after MCAO. Both ADAMTS13 and tPA improved the infarct volume without hemorrhagic complications in 2-h MCAO mice. On the other hand, ADAMTS13 reduced the infarct volume and plasma HMGB1 levels, and improved cerebral blood flow without hemorrhagic complications in 4-h MCAO mice, but tPA was not effective and these animals showed massive intracerebral hemorrhage. These results indicated that ADAMTS13 has a longer therapeutic time window in ischemic stroke than tPA, and ADAMTS13 may be useful as a new therapeutic agent for ischemic stroke. PMID- 26254728 TI - Levels of S100B in brain and blood of rats with diabetic ketoacidosis. AB - Diabetic ketoacidosis (DKA) frequently causes subtle brain injuries in children. Rarely, these injuries can be severe and life threatening. The physiological processes leading to brain injury during DKA are poorly understood. S100B is a calcium-binding protein secreted by astrocytes. Elevated serum S100B levels are documented in several types of brain injuries. S100B may have either neuroprotective or neurotoxic effects, depending upon the concentration. We undertook the current studies to measure alterations in S100B production and secretion during DKA. We measured serum S100B concentrations in juvenile rats during and after DKA, and used immunohistochemistry to measure S100B expression in the hippocampus, cortex and striatum. Compared to levels in both normal and hyperglycemic control rats, serum S100B levels during DKA were significantly reduced. Serum S100B gradually rose after DKA, returning to levels of hyperglycemic controls by 72 h. S100B expression in the hippocampus was also significantly reduced 24h after DKA. There were no significant changes in S100B expression in other brain regions. Our findings contrast with those for other types of brain injuries in which both serum S100B levels and astrocyte S100B expression are typically elevated. These data suggest that serum S100B measurement cannot be used as an indicator of brain injury during DKA. Whether reduced S100B production or secretion is involved in the pathogenesis of DKA related brain injury should be investigated. PMID- 26254729 TI - Microinjection of orexin-A into the rat locus coeruleus nucleus induces analgesia via cannabinoid type-1 receptors. AB - Locus coeruleus (LC) nucleus is involved in noradrenergic descending pain modulation. LC receives dense orexinergic projections from the lateral hypothalamus. Orexin-A and -B are hypothalamic peptides which modulate a variety of brain functions via orexin type-1 (OX1) and orexin type-2 (OX2) receptors. Previous studies have shown that activation of OX1 receptors induces endocannabinoid synthesis and alters synaptic neurotransmission by retrograde signaling via affecting cannabinoid type-1 (CB1) receptors. In the present study the interaction of orexin-A and endocannabinoids was examined at the LC level in a rat model of inflammatory pain. Pain was induced by formalin (2%) injection into the hind paw. Intra-LC microinjection of orexin-A decreased the nociception score during both phases of formalin test. Furthermore, intra-LC microinjection of either SB-334867 (OX1 receptor antagonist) or AM251 (CB1 receptor antagonist) increased flinches and also the nociception score during phase 1, 2 and the inter phase of formalin test. The analgesic effect of orexin-A was diminished by prior intra-LC microinjection of either SB-334867 or AM251. This data show that, activation of OX1 receptors in the LC can induce analgesia and also the blockade of OX1 or CB1 receptors is associated with hyperalgesia during formalin test. Our findings also suggest that CB1 receptors may modulate the analgesic effect of orexin-A. These results outline a new mechanism by which orexin-A modulates the nociceptive processing in the LC nucleus. PMID- 26254730 TI - Lentiviral-mediated overexpression of nerve growth factor (NGF) prevents beta amyloid [25-35]-induced long term potentiation (LTP) decline in the rat hippocampus. AB - We have explored the potential neuroprotective effect of local lentiviraly mediated overexpression of nerve growth factor (NGF) on in vivo long-term potentiation (LTP) in the rat hippocampus under pathological conditions. The suspension of lentiviral particles was prepared using a genetic construct containing the human NGF gene under the control of a neuron-specific CaMKII promoter. Two weeks after the viral injection NGF concentration in the hippocampus doubled. In vivo recordings of total electrical activity in the dentate gyrus were performed. While the increased expression of NGF did not affect the amplitude of evoked postsynaptic potentials recorded after a high frequency stimulation of the perforant path, it prevented the LTP decline induced by the i.c.v. administration of 50 nM beta-amyloid (25-35) 1h prior to tetanization. Our results demonstrate that increased endogenous NGF concentration can rescue hippocampal neuronal function from beta-amyloid peptide induced impairment. PMID- 26254732 TI - Characterising oil and water in porous media using decay due to diffusion in the internal field. AB - In the method Decay due to Diffusion in the Internal Field (DDIF), the diffusion behaviour of water molecules in the internal magnetic field makes it possible to determine a distribution of pore sizes in a sample. The DDIF experiment can also be extended to a DDIF-Carr-Purcell-Meiboom-Gill (DDIF-CPMG) experiment to measure correlations between the pore size and the transverse relaxation time, T2. In this study we have for the first time applied the DDIF experiment and the DDIF CPMG experiment to porous materials saturated with both water and oil. Because of the large difference in diffusion rates between water and oil molecules, the DDIF experiment will act as a filter for the signal from oil, and we are left with the DDIF-signal from water only. This has been verified in model systems consisting of glass beads immersed in separate layers of water and oil, and in a sandstone sample saturated with water and oil. The results show that the DDIF and DDIF-CPMG experiments enable the determination of the confining geometry of the water phase, and how this geometry is correlated to T2. Data obtained in the sandstone sample saturated with water and oil also show that with the exception of the smallest pores there is no clear correlation between pore size and the relaxation time of water. PMID- 26254733 TI - Symmetry of the gradient profile as second experimental dimension in the short time expansion of the apparent diffusion coefficient as measured with NMR diffusometry. AB - The time-dependent apparent diffusion coefficient as measured by pulsed gradient NMR can be used to estimate parameters of porous structures including the surface to-volume ratio and the mean curvature of pores. In this work, the short-time diffusion limit and in particular the influence of the temporal profile of diffusion gradients on the expansion as proposed by Mitra et al. (1993) is investigated. It is shown that flow-compensated waveforms, i.e. those whose first moment is zero, are blind to the term linear in observation time, which is the term that is proportional to mean curvature and surface permeability. A gradient waveform that smoothly interpolates between flow-compensated and bipolar waveform is proposed and the degree of flow-compensation is used as a second experimental dimension. This two-dimensional ansatz is shown to yield an improved precision when characterizing the confining domain. This technique is demonstrated with simulations and in experiments performed with cylindrical capillaries of 100 MUm radius. PMID- 26254731 TI - Comparative neurotoxicity screening in human iPSC-derived neural stem cells, neurons and astrocytes. AB - Induced pluripotent stem cells (iPSC) and their differentiated derivatives offer a unique source of human primary cells for toxicity screens. Here, we report on the comparative cytotoxicity of 80 compounds (neurotoxicants, developmental neurotoxicants, and environmental compounds) in iPSC as well as isogenic iPSC derived neural stem cells (NSC), neurons, and astrocytes. All compounds were tested over a 24-h period at 10 and 100 MUM, in duplicate, with cytotoxicity measured using the MTT assay. Of the 80 compounds tested, 50 induced significant cytotoxicity in at least one cell type; per cell type, 32, 38, 46, and 41 induced significant cytotoxicity in iPSC, NSC, neurons, and astrocytes, respectively. Four compounds (valinomycin, 3,3',5,5'-tetrabromobisphenol, deltamethrin, and triphenyl phosphate) were cytotoxic in all four cell types. Retesting these compounds at 1, 10, and 100 MUM using the same exposure protocol yielded consistent results as compared with the primary screen. Using rotenone, we extended the testing to seven additional iPSC lines of both genders; no substantial difference in the extent of cytotoxicity was detected among the cell lines. Finally, the cytotoxicity assay was simplified by measuring luciferase activity using lineage-specific luciferase reporter iPSC lines which were generated from the parental iPSC line. This article is part of a Special Issue entitled SI: PSC and the brain. PMID- 26254734 TI - Auto-reactions, autoimmunity and psoriatic arthritis. AB - Evidence from the literature suggests that autoimmune processes may drive features of psoriatic arthritis (PsA). Such hypothesis is supported by the evidence that class I major histocompatibility complex (MHC) genes are associated with susceptibility to develop PsA and auto-reactive cells, such as CD8 T cells, T helper (h) 17 and plasma cells, have been demonstrated in PsA. However, no autoantigens have ever been demonstrated in PsA. The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA) patients. These autoantibodies have been associated with a worse disease progression independent of anti-citrulline antibodies (ACPA). In PsA, anti-CarP antibodies have not been evaluated yet. We aimed at analyzing, for the first time, the anti-CarP antibodies in sera of patients with active PsA who were negative for ACPA in order to explore both their presence and their relationship with disease activity. A total of 70 individuals, 30 patients with diagnosis of PsA (according to CASPAR criteria) and 40 healthy controls (HC) were enrolled. We found significantly increased levels of anti-CarP antibodies in PsA patients compared with HC (P<0.0001). Our findings indicate that anti-CarP antibodies are detectable with high specificity and sensibility in PsA patients suggesting an autoimmune background of PsA. Anti-CarP antibodies can be useful in improving the diagnosis of PsA and are correlated with disease activity. PMID- 26254735 TI - Inhibition of APP gamma-secretase restores Sonic Hedgehog signaling and neurogenesis in the Ts65Dn mouse model of Down syndrome. AB - Neurogenesis impairment starting from early developmental stages is a key determinant of intellectual disability in Down syndrome (DS). Previous evidence provided a causal relationship between neurogenesis impairment and malfunctioning of the mitogenic Sonic Hedgehog (Shh) pathway. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain), a cleavage product of the trisomic gene APP (amyloid precursor protein) up-regulate transcription of Ptch1 (Patched1), the Shh receptor that keeps the pathway repressed. Since AICD results from APP cleavage by gamma-secretase, the goal of the current study was to establish whether treatment with a gamma-secretase inhibitor normalizes AICD levels and restores neurogenesis in trisomic neural precursor cells. We found that treatment with a selective gamma-secretase inhibitor (ELND006; ELN) restores proliferation in neurospheres derived from the subventricular zone (SVZ) of the Ts65Dn mouse model of DS. This effect was accompanied by reduction of AICD and Ptch1 levels and was prevented by inhibition of the Shh pathway with cyclopamine. Treatment of Ts65Dn mice with ELN in the postnatal period P3-P15 restored neurogenesis in the SVZ and hippocampus, hippocampal granule cell number and synapse development, indicating a positive impact of treatment on brain development. In addition, in the hippocampus of treated Ts65Dn mice there was a reduction in the expression levels of various genes that are transcriptionally regulated by AICD, including APP, its origin substrate. Inhibitors of gamma secretase are currently envisaged as tools for the cure of Alzheimer's disease because they lower betaamyloid levels. Current results provide novel evidence that gamma-secretase inhibitors may represent a strategy for the rescue of neurogenesis defects in DS. PMID- 26254736 TI - Propofol-induced rno-miR-665 targets BCL2L1 and influences apoptosis in rodent developing hippocampal astrocytes. AB - Propofol exerts neurotoxic effects on the developing mammalian brains, but the underlying molecular mechanism remains unclear. MicroRNAs (miRNAs) are a class of small noncoding RNAs that modulate gene expression at the post-transcriptional level. However, in specific types of neurocytes, the detailed functions of miRNAs were not entirely understood. We investigated the potential role of miRNAs in astrocyte pathogenesis caused by propofol. We performed genome-wide microRNA expression profiling in immature cultured hippocampal astrocytes by microarray analysis and predicted their targets and functions using bioinformatics tools. The functional effects of one differentially expressed miRNA were examined experimentally in relation to astrocyte viability. The results showed that 13 miRNAs were significantly differentially expressed after both short-term exposure to high-concentration propofol (10 MUg/ml for 1h) and long-term exposure to low concentration propofol (0.9 MUg/ml for 48 h), including rno-miR-665, differing significantly between the 2. Bioinformatics predicted putative binding sites for rno-miR-665 existing in the 3'-untranslated region of Bcl-2-like protein 1 BCL2L1 (Bcl-xl) mRNA. Moreover, such relationship was assessed by luciferase reporter assay, qRT-PCR and western blot. Rno-miR-665 which was significantly up-regulated by propofol can suppress BCL2L1 and elevate cleaved caspase-3 expression in immature astrocytes in vitro. Apoptosis of developing hippocampal astrocytes was thus significantly influenced by propofol or rno-miR-665, or both. Taken together, rno-miR-665 is involved in the neurotoxicity induced by propofol via a caspase-3 mediated mechanism by negatively regulating BCL2L1. It might act as an alternative therapeutic target for treatment of neurological disorders in peadiatric prolonged anesthesia or sedation with propofol clinically. PMID- 26254737 TI - Mitochondrial dysfunction related to cell damage induced by 3-hydroxykynurenine and 3-hydroxyanthranilic acid: Non-dependent-effect of early reactive oxygen species production. AB - The kynurenines 3-hydroxyanthranilic acid (3-HANA) and its precursor 3 hydroxykynurenine (3-HK) are metabolites derived from tryptophan degradation. 3 HK, has been related to diverse neurodegenerative diseases including Huntington's, Alzheimer's and Parkinson's diseases that share mitochondrial metabolic dysregulation. Nevertheless, the direct effect of these kynurenines on mitochondrial function has not been investigated despite it could be regulated by their redox properties that are controversial. A body of literature has suggested a ROS mediated cell death induced by 3-HK and 3-HANA. On the other hand, some works have supported that both kynurenines have antioxidant effects. Therefore, the aim of this study was to investigate 3-HK and 3-HANA effects on mitochondrial and cellular function in rat cultured cortical astrocytes (rCCA) and in animals intrastriatally injected with these kynurenines as well as to determinate the ROS role on these effects. First, we evaluated 3-HK and 3-HANA effect on cellular function, ROS production and mitochondrial membrane potential in vivo and in vitro in rCCA. Our results show that both kynurenines decreased MTT reduction in a concentration-dependent manner together with mitochondrial membrane potential. These observations were accompanied with increased cell death in rCCA and in circling behavior and morphological changes of injected animals. Interestingly, we found that ROS production was not increased in both in vitro and in vivo experiments, and accordingly lipid peroxidation (LP) was neither increased in striatal tissue of animals injected with both kynurenines. The lack of effect on these oxidative markers is in agreement with the .OH and ONOO(-) scavenging capacity of both kynurenines detected by chemical combinatorial assays. Altogether, these data indicate that both kynurenines exert toxic effects through mechanisms that include impairment of cellular energy metabolism which are not related to early ROS production. PMID- 26254738 TI - Comparative pharmacological evaluation of the cathinone derivatives, mephedrone and methedrone, in mice. AB - Mephedrone and methedrone are cathinone-related compounds, which act as non selective substrates for monoamine transporters, facilitating a neurotransmitter release. We compared the acute pharmacological effects of mephedrone and methedrone, attempting to further evaluate the action mechanisms of methedrone by responsibly and ethically using mice under approved procedures. The effects of both compounds were examined from 10 to 60 min, in a series of behavioral paradigms, namely open-field, plus-maze, hot-plate and tail suspension tests, whereas neurotransmitter brain tissue levels were determined ex vivo by HPLC. Separate groups were pre-treated with the dopamine (DA) antagonist haloperidol, or the serotonin (5-HT) synthesis inhibitor rhoCPA, to further assess the mechanisms underlying methedrone effects. The compounds caused marked hyperlocomotion, displaying dissimilar stereotyped behavior, in an open-field arena. Mephedrone caused anxiolytic-like effects, while methedrone induced anxiogenic-like actions in the elevated plus-maze. Both compounds displayed thermal antinociception, with a reduced immobility time in the tail suspension model. Mephedrone triggered a 2- and 3-fold increment of dopamine and serotonin tissue levels, respectively, in the nucleus accumbens, with a 1.5-fold elevation of tissue dopamine in the frontal cortex. Methedrone caused a 2-fold increment of tissue dopamine in the nucleus accumbens and in the striatum, and a 1.5-fold increment of serotonin tissue levels in the hippocampus and striatum. In vivo methedrone effects were partially inhibited by a pre-treatment with haloperidol or rhoCPA. Despite similar actions on locomotion, analgesia, and depression-like behavior, the acute administration of mephedrone and methedrone elicited divergent effects on anxiety-like behavior and stereotyped movements in mice, which might be related to the distinct modulation of brain tissue neurotransmitter levels. PMID- 26254739 TI - A model of neuropathic pain induced by sorafenib in the rat: Effect of dimiracetam. AB - BACKGROUND: Sorafenib is a kinase inhibitor anticancer drug whose repeated administration causes the onset of a peripheral painful neuropathy. Notably, the efficacy of common analgesic drugs is not adequate and this often leads pre mature discontinuation of anticancer therapy. The aim of this study was to establish a rat model of sorafenib-induced neuropathic pain, and to assess the effect of the new anti-neuropathic compound dimiracetam in comparison with gabapentin, pregabalin and duloxetine. METHODS: Male Sprague-Dawley rats were treated i.v. (10 mg kg(-1)), i.p. (10 and 30 mg kg(-1)) or p.o. (80 and 160 mg kg(-1)) with sorafenib once daily for 21 days. Pain behaviour measurements (cold plate, paw pressure, electronic von Frey) were performed on days 0, 7, 14 and 21. RESULTS: Sorafenib lowered the paw-licking threshold to non-noxious cold stimuli on day 14 of all protocols evaluated. The i.p. administration resulted in greater efficacy than the other administration routes. Sorafenib treatments did not affect paw-withdrawal responses to non-noxious or to noxious mechanical stimuli. On day 14, dimiracetam (300 mg kg(-1)), gabapentin (100 mg kg(-1)), pregabalin (30 mg kg(-1)) and duloxetine (30 mg kg(-1)) were acutely administered p.o. in sorafenib i.p.-treated rats. A single oral dose of dimiracetam induced a statistically significant increase of the pain threshold 15 min after administration. Pregabalin induced a comparable effect, whereas gabapentin and duloxetine were ineffective. Repeated twice-daily administration of dimiracetam (150 mg kg(-1) p.o.), starting on the first day of i.p sorafenib administration, significantly protected rats from sorafenib-induced decrease in the paw-licking threshold. CONCLUSIONS: A rat model of sorafenib-induced hypersensitivity to cold stimulation has been established. Dimiracetam and pregabalin are effective in prevention of sorafenib-induced neuropathy in this model. PMID- 26254740 TI - A parietal memory network revealed by multiple MRI methods. AB - The manner by which the human brain learns and recognizes stimuli is a matter of ongoing investigation. Through examination of meta-analyses of task-based functional MRI and resting state functional connectivity MRI, we identified a novel network strongly related to learning and memory. Activity within this network at encoding predicts subsequent item memory, and at retrieval differs for recognized and unrecognized items. The direction of activity flips as a function of recent history: from deactivation for novel stimuli to activation for stimuli that are familiar due to recent exposure. We term this network the 'parietal memory network' (PMN) to reflect its broad involvement in human memory processing. We provide a preliminary framework for understanding the key functional properties of the network. PMID- 26254741 TI - Dabigatran in real life. PMID- 26254742 TI - Quantification of skeletal growth, modeling, and remodeling by in vivo micro computed tomography. AB - In this study we established an image analysis scheme for the investigation of cortical and trabecular bone development during skeletal growth and tested this concept on in vivo MUCT images of rats. To evaluate its efficacy, we applied the technique to young (1-month-old) and adult (3-month-old) rat tibiae with vehicle (Veh) or intermittent parathyroid hormone (PTH) treatment. By overlaying 2 sequential scans based on their distinct trabecular microarchitecture, we calculated the linear growth rate of young rats to be 0.31 mm/day at the proximal tibia. Due to rapid growth (3.7 mm in 12 days), the scanned bone region at day 12 had no overlap with the bone tissue scanned at day 0. Instead, the imaged bone region at day 12 represented newly generated bone tissue from the growth plate. The new bone of the PTH-treated rats had significantly greater trabecular bone volume fraction, number, and thickness than those of the Veh-treated rats, indicating PTH's anabolic effect on bone modeling. In contrast, the effect of PTH on adult rat trabecular bone was found to be caused by PTH's anabolic effect on bone remodeling. The cortical bone at the proximal tibia of young rats also thickened more in the PTH group (23%) than the Veh group (14%). This was primarily driven by endosteal bone formation and coalescence of trabecular bone into the cortex. This process can be visualized by aligning the local bone structural changes using image registration. As a result, the cortex after PTH treatment was 31% less porous, and had a 22% greater polar moment of inertia compared to the Veh group. Lastly, we monitored the longitudinal bone growth in adult rats by measuring the distance of bone flow away from the proximal tibial growth plate from 3 months to 19 months of age and discovered a total of 3.5mm growth in 16 months. It was demonstrated that this image analysis scheme can efficiently evaluate bone growth, bone modeling, and bone remodeling, and is ready to be translated into a clinical imaging platform. PMID- 26254743 TI - Reducing Racial Disparities in Influenza Vaccination Among Children With Asthma. AB - INTRODUCTION: A multifaceted intervention to raise influenza vaccination rates was tested among children with asthma. METHODS: In a pre/post study design, 18 primary care practices implemented the 4 Pillars Immunization Toolkit along with other strategies. The primary outcome was the difference in influenza vaccination rates at each practice among children with asthma between the baseline year (before the intervention) and at the end of year 2 (after the intervention), both overall and by race (White vs. non-White). RESULTS: Influenza vaccination rates increased significantly in 13 of 18 practices. The percentage of vaccinated non White children increased from 46% to 61% (p < .01), and the percentage of vaccinated White children increased from 58% to 65% (p < .001). Likelihood of vaccination was significantly lower for non-White children before the intervention (odds ratio = 0.66; 95% confidence interval = 0.59-0.73; p < .001), but this difference was eliminated after the intervention (odds ratio = 0.95; 95% confidence interval = 0.85-1.05; p = .289). DISCUSSION: A multi-strategy, evidence-based intervention significantly increased influenza vaccination uptake and reduced racial disparities among children with asthma. PMID- 26254744 TI - Development of a Teen-Friendly Health Education Program on Facebook: Lessons Learned. AB - INTRODUCTION: Facebook is the most popular online platform among adolescents and can be an effective medium to deliver health education. Although Korean American (KA) adolescents are at risk of obesity, a culturally tailored health education program is not available for them. Thus, our research team developed a health education program for KA adolescents on Facebook called "Healthy Teens." The aim of this study was to discuss important lessons learned through the program development process. METHOD: This program includes culturally tailored learning modules about healthy eating and physical activity. The program was developed on the basis of the social cognitive theory, and the online program was developed by applying Web usability principles for adolescents. Upon completion, the usability of the program was assessed using heuristic evaluation. RESULTS: The findings from the heuristic evaluation showed that the Healthy Teens program was usable for KA adolescents. DISCUSSION: The findings from this study will assist researchers who are planning to build similar Facebook-based health education programs. PMID- 26254745 TI - Vitellogenin in the honey bee brain: Atypical localization of a reproductive protein that promotes longevity. AB - In comparative gerontology, highly social insects such as honey bees (Apis mellifera) receive much attention due to very different and flexible aging patterns among closely related siblings. While experimental strategies that manipulate socio-environmental factors suggest a causative link between aging and social signals and behaviors, the molecular underpinnings of this linkage are less well understood. Here we study the atypical localization of the egg-yolk protein vitellogenin (Vg) in the brain of the honey bee. Vg is known to influence honey bee social regulation and aging rate. Our findings suggest that Vg immunoreactivity in the brain is specifically localized within the class of non neuronal glial cells. We discuss how these results can help explain the socially dependent aging rate of honey bees. PMID- 26254746 TI - Canonical feature selection for joint regression and multi-class identification in Alzheimer's disease diagnosis. AB - Fusing information from different imaging modalities is crucial for more accurate identification of the brain state because imaging data of different modalities can provide complementary perspectives on the complex nature of brain disorders. However, most existing fusion methods often extract features independently from each modality, and then simply concatenate them into a long vector for classification, without appropriate consideration of the correlation among modalities. In this paper, we propose a novel method to transform the original features from different modalities to a common space, where the transformed features become comparable and easy to find their relation, by canonical correlation analysis. We then perform the sparse multi-task learning for discriminative feature selection by using the canonical features as regressors and penalizing a loss function with a canonical regularizer. In our experiments on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, we use Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) images to jointly predict clinical scores of Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Mini-Mental State Examination (MMSE) and also identify multi-class disease status for Alzheimer's disease diagnosis. The experimental results showed that the proposed canonical feature selection method helped enhance the performance of both clinical score prediction and disease status identification, outperforming the state-of-the-art methods. PMID- 26254747 TI - Reduced pleural drainage, length of stay, and readmissions using a modified Fontan management protocol. AB - BACKGROUND: Persistent pleural effusions after the Fontan procedure contribute to prolonged hospitalization and increased costs. We report our experience using a modified Wisconsin Fontan protocol to reduce chest tube drainage and hospital length of stay (LOS). METHODS: Single institutional retrospective chart review of 120 consecutive patients (60 before and 60 after initiation of our protocol) undergoing an extracardiac Fontan procedure from January 2004 to February 2007. Protocol influence was assessed by comparing group differences on duration of pleural drainage, requirement for nothing by mouth/total parenteral nutrition, hospital LOS, readmission for pleural effusion, and total hospital costs. RESULTS: Groups were similar in demographic characteristics, single ventricle morphology, preoperative hemodynamic parameters, and operative and immediate postoperative management. Median duration of pleural drainage and hospital LOS was reduced in the post- versus preprotocol groups: 4 days (interquartile range [IQR], 4-5 days) pre versus 6 days (IQR, 5-10 days) (P < .0001) and 6 days (IQR, 5-9 days) versus 8 days (IQR, 6-13 days) (P = .005), respectively. Pleural drainage lasting >1 week was also less common postprotocol: 23 (38%) before versus 7 (12%) after (P = .001). Fewer postprotocol patients required nothing by mouth/total parenteral nutrition to control effusions: 5 pre versus 0 post (P = .06), and fewer readmissions for effusions (14 before vs 7 after [P = .1]). An average total cost savings of 22% and readmissions savings of 29% resulted in nearly $500,000 in institutional savings over the study period. CONCLUSIONS: A modified Fontan protocol resulted in reduced time to chest tube removal, hospital LOS, and chest tube drainage lasting >1 week. There was a strong trend toward avoiding nothing by mouth/total parenteral nutrition to control pleural effusion and lower hospital costs. PMID- 26254748 TI - Autotransplantation: A novel solution for postpneumonectomy-like syndrome. PMID- 26254749 TI - Inhibition of microRNA-29c protects the brain in a rat model of prolonged hypothermic circulatory arrest. AB - OBJECTIVE: We sought to investigate the cerebroprotection of a novel microRNA mechanism by targeting peroxisome proliferator-activated receptor gamma coactivator 1-alpha in a rat model of prolonged deep hypothermia circulatory arrest. METHODS: The right carotid artery and jugular vein of male Sprague-Dawley rats were cannulated for cardiopulmonary bypass. Circulatory arrest was conducted for 60 minutes when the pericranial temperature was cooled to 18 degrees C. The sham group received the surgical procedure without cardiopulmonary bypass and deep hypothermia circulatory arrest; the deep hypothermia circulatory arrest group received cardiopulmonary bypass and deep hypothermia circulatory arrest; lentivirus control vector or lentiviral vector containing antagomiR-29c was given to the deep hypothermia circulatory arrest + vector group or the deep hypothermia circulatory arrest + antagomiR-29c group by intracerebroventricular administration 5 days before cardiopulmonary bypass (n = 8, for each of the 4 groups). Neurologic function was evaluated by the modified hole board test and beam balance task during 14 postoperative days. Expressions of caspase-3, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and miR-29c in the hippocampus were measured by Western blot and quantitative reverse transcription polymerase chain reaction. Malondialdehyde was measured using the Malondialdehyde Assay Kit (Beyotime, Jiangsu, China). RESULTS: Pretreatment with antagomiR-29c significantly decreased the expression of microRNA-29c and increased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha in the hippocampus (P < .05 vs deep hypothermia circulatory arrest group). The level of malondialdehyde in the hippocampus was lower in the deep hypothermia circulatory arrest + antagomiR-29c group (P < .05 vs deep hypothermia circulatory arrest group). The neurologic functions were markedly protected in rats pretreated with antagomiR-29c as evidenced by improvement of vestibulomotor and cognitive performance during the early postoperative period. In the deep hypothermia circulatory arrest + antagomiR-29c group, histologic scores of the hippocampus were improved and the level of caspase-3 in the hippocampus was lower (P < .05 vs deep hypothermia circulatory arrest group). CONCLUSIONS: Inhibition of miR-29c attenuates neurologic injuries induced by prolonged deep hypothermia circulatory arrest through a peroxisome proliferator activated receptor gamma coactivator 1-alpha pathway. PMID- 26254750 TI - The truth about sugar. PMID- 26254751 TI - Do we know bad science when we see it? PMID- 26254752 TI - Safety and efficacy of landiolol hydrochloride for prevention of atrial fibrillation after cardiac surgery in patients with left ventricular dysfunction: Prevention of Atrial Fibrillation After Cardiac Surgery With Landiolol Hydrochloride for Left Ventricular Dysfunction (PLATON) trial. AB - OBJECTIVES: We previously conducted a prospective study of landiolol hydrochloride (INN landiolol), an ultrashort-acting beta-blocker, and reported that it could prevent atrial fibrillation after cardiac surgery. This trial was performed to investigate the safety and efficacy of landiolol hydrochloride in patients with left ventricular dysfunction undergoing cardiac surgery. METHODS: Sixty patients with a preoperative left ventricular ejection fraction of less than 35% were randomly assigned to 2 groups before cardiac surgery and then received intravenous infusion with landiolol hydrochloride (landiolol group) or without landiolol (control group). The primary end point was occurrence of atrial fibrillation as much as 1 week postoperatively. The secondary end points were blood pressure, heart rate, intensive care unit and hospital stays, ventilation time, ejection fraction, biomarkers of ischemia, and brain natriuretic peptide. RESULTS: Atrial fibrillation occurred in 3 patients (10%) in the landiolol group versus 12 (40%) in the control group, and its frequency was significantly lower in the landiolol group (P = .002). During the early postoperative period, levels of brain natriuretic peptide and ischemic biomarkers were significantly lower in the landiolol group than the control group. The landiolol group also had a significantly shorter hospital stay (P = .019). Intravenous infusion was not discontinued for hypotension or bradycardia in either group. CONCLUSIONS: Low dose infusion of landiolol hydrochloride prevented atrial fibrillation after cardiac surgery in patients with cardiac dysfunction and was safe, with no effect on blood pressure. This intravenous beta-blocker seems useful for perioperative management of cardiac surgical patients with left ventricular dysfunction. PMID- 26254753 TI - Anatomic variability of the thoracic duct in pediatric patients with complex congenital heart disease. AB - OBJECTIVE: Thoracic duct mass ligation (TDML) through a right thoracotomy (RT), regardless of the side of the pleural effusion, is a standard procedure for chylothorax that is refractory to medical treatment. This procedure may be unsuccessful in patients with complex congenital heart disease, which necessitates additional left thoracotomy (LT) for left periaortic mass ligation. We hypothesized that failure of the right-sided approach is attributable to the anatomic variation of the path of the thoracic duct. METHODS: Of the children who underwent surgery for congenital heart disease between 1992 and 2014, a total of 70 of 8880 (0.8%) underwent TDML by RT (n = 57) or LT (n = 13; LT after RT in 10, and primary LT in 3). RESULTS: Persistent chylothorax was successfully resolved in 65 patients (65 of 70; 93%) within 15 days (2-79 days) after the first or second TDML; 5 patients died with a chest-tube(s) in situ. After excluding mortality without chest-tube removal, we sought to identify the risk factor(s) necessitating LT in 65 patients (RT group: 54; LT group: 11). On logistic regression analysis, the LT group was more likely to have dextrocardia (odds ratio: 6.38; 95% confidence interval: 1.09-37.25; P = .04). The incidence of abnormal atrial situs, great arterial malposition, right descending thoracic aorta, and bilateral superior vena cavae were comparable in the 2 groups. CONCLUSIONS: The path of the thoracic duct may vary in pediatric patients with complex congenital heart disease. Left periaortic mass ligation should be considered in patients with chylothoraces that persist after the right-sided approach, especially in patients with dextrocardia. PMID- 26254754 TI - Discussion. PMID- 26254756 TI - Discussion. PMID- 26254755 TI - Clinical efficacy of epicardial application of drug-releasing hydrogels to prevent postoperative atrial fibrillation. AB - OBJECTIVE: Postoperative atrial fibrillation is the most frequent complication arising after cardiac surgery, occurring in 40% of cases. The treatment of postoperative atrial fibrillation with epicardial amiodarone/corticosteroid hydrogel delivery can increase efficacy and reduce side effects. To further evaluate whether amiodarone hydrogel is superior to corticosteroid hydrogel or placebo, we performed a randomized prospective study in 150 patients with coronary artery bypass grafting to compare the effectiveness with different epicardial drug approaches in the postoperative period. METHODS: After institutional review board approval, 150 patients, from January 2012 to July 2014, who had undergone cardiac surgery were randomized to 3 equal groups. Group I received poly-based hydrogel with amiodarone, and group II received poly-based hydrogel with triamcinolone. Both hydrogels were sprayed diffusely over the biatrial epicardium. The control group underwent the procedure with only hydrogel spray. Continuous telemetry monitored for postoperative atrial fibrillation, and amiodarone or triamcinolone levels in the atria, plasma, and tissue were measured postoperatively. Daily electrocardiographic parameters were measured until postoperative day 14. RESULTS: The incidence of postoperative atrial fibrillation was significantly less in group I, with 4 of 50 patients (8%) incurring atrial fibrillation compared with 11 of 50 patients (22%) in group II and 13 of 50 patients (26%) in the control group (P < .01). The mean amiodarone and triamcinolone concentrations in the atria (12.06 +/- 3.1/1.5 +/- 0.7) were significantly greater than those in the extracardiac tissues (1.32 +/- 0.9/0.2 +/ 0.4; P < .01). The plasma amiodarone and triamcinolone levels remained below the detection limit (<8 MUg/mL and <0.2 MUg/mL) during the 14 days of follow-up. Bradycardia was observed less in the control group (93 +/- 18) than in study group I (76 +/- 29; P < .01). CONCLUSIONS: Epicardial application of amiodarone releasing adhesive hydrogel is a less-invasive, well-tolerated, quick, and effective therapeutic option for preventing postoperative atrial fibrillation with minimal risk of extracardiac adverse side effects. However, there was no clinical evidence that epicardial corticosteroid prevented postoperative atrial fibrillation. PMID- 26254757 TI - Discussion. PMID- 26254758 TI - Leaflet resection versus leaflet preservation for repair of degenerative mitral regurgitation: Does it matter how the mitral valve is repaired? PMID- 26254759 TI - Reducing Fontan effusions: A day saved is a dollar earned. PMID- 26254761 TI - The patent internal thoracic artery graft: Increased degree of difficulty for left-sided pulmonary resections. PMID- 26254760 TI - Survival and right ventricular performance for matched children after stage-1 Norwood: Modified Blalock-Taussig shunt versus right-ventricle-to-pulmonary artery conduit. AB - OBJECTIVE: Early survival advantages after Norwood with right-ventricle-(RV)-to pulmonary-artery conduit (NW-RVPA) over Norwood-operation with a Blalock-Taussig shunt (NW-BT) are offset by concerns regarding delayed RV dysfunction. We compared trends in survival, RV dysfunction, and tricuspid valve regurgitation (TR) between NW-RVPA and NW-BT for propensity-matched neonates with critical left ventricular outflow tract obstruction (LVOTO). METHODS: In an inception cohort (2005-2014; 21 institutions), 454 neonates with critical LVOTO underwent Norwood stage 1. Propensity-score matching paired 169 NW-RVPA patients with 169 NW-BT patients. End-states were compared between NW-RVPA and NW-BT using competing risks, multiphase, parametric, hazard analysis. Post-Norwood echocardiogram reports (n = 2993) were used to grade RV dysfunction and TR. Time-related prevalence of >=moderate RV dysfunction and TR were characterized using nonlinear mixed-model regression, and compared between groups via multiphase, parametric models. RESULTS: Overall 6-year survival was better after NW-RVPA (70%) versus NW BT (55%; P < .001). Additionally, transplant-free survival during this time was better after NW-RVPA (64%) versus NW-BT (53%; P = .004). Overall prevalence of >=moderate RV dysfunction reached 11% within 3 months post-Norwood. During this time, RV dysfunction after NW-BT was 16% versus 6% after NW-RVPA (P = .02), and coincided temporally with an increased early hazard for death. For survivors, late RV dysfunction was <5% and was not different between groups (P = .36). Overall prevalence of >=moderate TR reached 13% at 2 years post-Norwood and was increased after NW-BT (16%) versus NW-RVPA (11%; P = .003). Late TR was similar between groups. CONCLUSIONS: Among propensity-score-matched neonates with critical LVOTO, NW-RVPA offers superior 6-year survival with no greater prevalence of RV dysfunction or TR than conventional NW-BT operations. PMID- 26254762 TI - Betalactam antibiotics affect human dendritic cells maturation through MAPK/NF-kB systems. Role in allergic reactions to drugs. AB - The mechanisms leading to drug allergy in predisposed patients, especially those related to T-cell-mediated drug hypersensitivity, are not well understood. A key event in allergic reactions to drugs is the maturation process undergone by dendritic cells (DCs). Although amoxicillin (AX) has been reported to interact and maturate DCs from patients with AX-induced delayed-type hypersensitivity, the cell signaling pathways related to AX-mediated DC maturation have not been elucidated. We sought to determine the role of the MAPK and NF-kappaBeta pathways on AX-induced DC maturation and functional status. For that purpose, in monocyte derived-DCs from AX-delayed allergic patients and tolerant subjects, we analyzed the activation pattern of p38MAPK, JNK, and ERK signaling and the NF-kappaB, maturation markers as well as endocytosis and allostimulatory capacities driven by AX-stimulated-DCs. Our data reveal that AX induces an increase in the phosphorylation levels of the three MAPKs and activated NF-kappaB in DCs from allergic patients. Moreover, the inhibition of these pathways prevents the up regulation of surface molecules induced by AX. Additionally, we observed that the allostimulatory capacity and the endocytosis down-regulation in AX-stimulated-DCs from allergic patients depend on JNK and NF-kappaB activities. Taken together, our data shed light for the first time on the main signaling pathways involved in DC maturation from AX-delayed allergic patient. PMID- 26254763 TI - Employment patterns of Notre Dame graduate physiotherapists 2006-12: targeting areas of workforce need. AB - Objectives The Australian physiotherapy workforce is changing both in demographics and service needs. Physiotherapy curriculum and clinical education focus is ideally based on up-to-date knowledge of this changing workforce. The aim of the present study was to determine the employment patterns of physiotherapy graduates from The University of Notre Dame Australia (Notre Dame). Methods An online survey was conducted of Notre Dame physiotherapy graduates (2006-12) with a 50% response rate (n=157). Results Survey results established the employment location, employment status, healthcare sector, area of practice, salary and employment history of Notre Dame graduates. The results highlighted links between curriculum, clinical placements and workforce areas, with the spread of workforce directly linked to focuses in the undergraduate curriculum. Conclusion The present study highlights the effect of directing undergraduate curriculum and clinical placement experiences towards areas of workforce need. The findings identify the importance of producing graduates equipped to meet the changing service needs of the healthcare industry. What is known about the topic? No previous studies have been conducted on the employment patterns of Notre Dame physiotherapy graduates and specifically the impact of targeting curriculum and clinical placements towards areas of workforce need. What does this paper add? Through a self-administered survey design, the present study demonstrated that Notre Dame physiotherapy graduates have increased uptake in areas targeted within the curriculum, specifically geriatrics, paediatrics and rural health. Although graduates were more attracted to the rural health setting, they were not retained. What are the implications for practitioners? The present study informs educational institutions and workforce planners on the importance of linking curriculum, clinical placements and workforce to develop a sustainable workforce adaptable to clinical settings and areas. PMID- 26254764 TI - Isolation and Screening of Rhizosphere Bacteria from Grasses in East Kavango Region of Namibia for Plant Growth Promoting Characteristics. AB - A diverse group of soil bacteria known as plant growth promoting rhizobacteria (PGPR) is able to inhabit the area close to plant roots and exert beneficial effects on plant growth. Beneficial interactions between rhizospheric bacteria and plants provide prospects for isolating culturable PGPR that can be used as bio-fertilizers for sustainable crop production in communities that cannot easily afford chemical fertilizers. This study was conducted with the aim of isolating rhizospheric bacteria from grasses along the Kavango River and screening the bacterial isolates for plant growth promoting characteristics. The bacteria were isolated from rhizospheres of Phragmites australis, Sporobolus sp., Vetiveria nigritana, Pennisetum glaucum and Sorghum bicolor. The isolates were screened for inorganic phosphate solubilization, siderophore production and indole-3-acetic acid (IAA) production. The nitrogen-fixing capability of the bacteria was determined by screening for the presence of the nifH gene. Up to 21 isolates were obtained from P. australis, Sporobolus sp., S. bicolor, P. glaucum and V. nigritana. The genera Bacillus, Enterobacter, Kocuria, Pseudomonas and Stenotrophomonas, identified via 16S rDNA were represented in the 13 PGPR strains isolated. The isolates exhibited more than one plant growth promoting trait and they were profiled as follows: three phosphate solubilizers, four siderophore producers, eight IAA producing isolates and five nitrogen-fixers. These bacteria can be used to develop bio-fertilizer inoculants for improved soil fertility management and sustainable production of local cereals. PMID- 26254765 TI - Characterisation of an opcA Mutant of the Unicellular Cyanobacterium Synechocystis sp. PCC 6803. AB - The genes opcA and zwf are located close to each other in most of cyanobacterial strains and the mutations in the opcA gene were reported to lose most of G6PDH activity. One of the reasons suggested for this loss was the polar effect of the mutation on expression of the zwf gene in the same operon and the other was absence of the OpcA polypeptide necessary for the catalytic activity of G6PDH. Synechocystis sp. PCC 6803 exhibits a gene organisation in which opcA and zwf are far away from each other and is ideal for analysis of an opcA mutation alone. In this study, an opcA single mutant and an opcA-zwf double mutant were constructed and effects of the opcA mutation on G6PDH activity and dark viability were then investigated. Contrary to the previous observations, no negative effect of the mutation on G6PDH activity was found under the optimal substrate concentrations. However, when one of the substrates, G6P or NADP, was reduced gradually, G6PDH activity in the mutant cells decreased faster than the wild types. Our results indicated that an opcA mutation did not affect G6PDH activity severely when zwf and opcA were in different operons. Similarly, dark viability of the opcA single and the zwf-opcA double mutants did not exhibit meaningful difference from the wild type. PMID- 26254766 TI - Azinphos-methyl and chlorpyrifos, alone or in a binary mixture, produce oxidative stress and lipid peroxidation in the freshwater gastropod Planorbarius corneus. AB - Azinphos-methyl (AZM) and chlorpyrifos (CPF) are broad-spectrum organophosphate insecticides used for pest control on a number of food crops in many parts of the world that have been shown to inhibit cholinesterase activity in the non-target freshwater gastropod Planorbarius corneus. The present study was undertaken to determine: (a) whether AZM and CPF induce oxidative stress in P. corneus, and (b) whether a mixture of both organophosphates that causes a higher neurotoxicity than single pesticides also causes an enhanced oxidative stress. To this end, non enzymatic and enzymatic parameters were measured in the soft tissues of snails acutely exposed to the insecticides in single-chemical (2.5 mg AZM L(-1) and 7.5 MUg CPF L(-1)) and a binary-mixture (1.25 mg AZM L(-1) plus 3.75 MUg CPF L(-1)) studies. At 24 h, all pesticide-exposed groups showed significantly decreased glutathione (GSH) and glutathione disulfide (GSSG) levels when compared to control animals. At 48 h, all exposed groups showed an alteration of the redox status (GSH/GSSG ratio) and a significant increase in malondialdehyde levels. The exposure for 48 h to AZM and CPF, alone or in the binary mixture, also resulted in a significant decrease of the antioxidant superoxide dismutase activity. The greatest decrease was observed with CPF exposure (59% of decrease relative to the control group). A significant increase in catalase and glutathione S-transferase activities was observed in CPF group and in CPF and AZM+CPF groups, respectively. The activities of glutathione reductase and glucose 6-phosphate dehydrogenase did not show significant changes with respect to controls in any treatment group. In conclusion, the data shown in the present study provide evidence that AZM, CPF and a mixture of both organophosphates are able to induce oxidative stress and oxidative damage in P. corneus tissues. However, no similarities between the degree of neurotoxicity and the degree of alterations of the measured oxidative stress parameters were found. PMID- 26254767 TI - Choice of experimental venue matters in ecotoxicology studies: Comparison of a laboratory-based and an outdoor mesocosm experiment. AB - The heavy application of pesticides and its potential effects on natural communities has attracted increasing attention to inadvertent impacts of these chemicals. Toxicologists conventionally use laboratory-based tests to assess lethal concentrations of pesticides. However, these tests often do not take into account indirect, interactive and long-term effects, and tend to ignore different rates of disintegration in the laboratory and under natural conditions. Our aim was to investigate the importance of the experimental venue for ecotoxicology tests. We reared tadpoles of the agile frog (Rana dalmatina) in the laboratory and in outdoor mesocosms and exposed them to three initial concentrations of a glyphosate-based herbicide (0, 2 and 6.5 mg a.e./L glyphosate), and to the presence or absence of caged predators (dragonfly larvae). The type of experimental venue had a large effect on the outcome: The herbicide was less lethal to tadpoles reared in outdoor mesocosms than in the laboratory. Further, while the herbicide had a negative effect on development time and on body mass in the laboratory, tadpoles exposed to the herbicide in mesocosms were larger at metamorphosis and developed faster in comparison to those reared in the absence of the herbicide. The effect of the herbicide on morphological traits of tadpoles also differed between the two venues. Finally, in the presence of the herbicide, tadpoles tended to be more active and to stay closer to the bottom of laboratory containers, while tadpole behaviour shifted in the opposite direction in outdoor mesocosms. Our results demonstrate major discrepancies between results of a classic laboratory-based ecotoxicity test and outcomes of an experiment performed in outdoor mesocosms. Consequently, the use of standard laboratory tests may have to be reconsidered and their benefits carefully weighed against the difficulties of performing experiments under more natural conditions. Tests validating experimentally estimated impacts of herbicides under natural conditions and studies identifying key factors determining the applicability of experimental results are urgently needed. PMID- 26254768 TI - Motoric impairment following manganese exposure in asteroid echinoderms. AB - In the oceans, naturally occurring manganese (Mn) is released from the sediments during events of hypoxia. While neuro- and immuno-toxic effects of bioavailable manganese are well documented for crustaceans, studies of similar effects of manganese on other marine invertebrates are comparatively few. Here, we developed a new functional test "the repeated turning assay" to investigate if manganese exposure at ~12 mg L(-1) affected motoric behaviour of two asteroid echinoderms, the Common sea star, Asterias rubens, and the Black brittle star, Ophiocomina nigra. By measuring of the turning-over capacity, from dorsal to ventral position, after one and two weeks of manganese exposure, we showed that for both species Mn exposure significantly delayed the ability to turn. After a recovery period of two weeks, the capacity of turning-over was not restored to that of unexposed animals neither for A. rubens nor for O. nigra. Further investigation of sea stars showed that Mn accumulated ~5 fold in the tube feet, organs involved in their turning-over activity, and the high concentration remained after the recovery period. In the tube feet we also recorded an increased activity of acetylcholinesterase (AChE), here used as a proxy for neuromuscular disturbances. The results indicated that Mn induces neuromuscular disturbance in echinoderms which is important news, given that previous studies have concluded that adult echinoderms are relatively tolerant to Mn. PMID- 26254769 TI - Coordination of the cortisol and testosterone responses: A dual axis approach to understanding the response to social status threats. AB - For many people, competitions, status challenges, and being evaluated by others result in increases in cortisol as well as testosterone. It is argued that physiological processes work in a coordinated fashion when facing social evaluative-competitive situations. Such a coordinated response may be part of an evolved system, monitoring and responding to threats to one's social status. In two studies, using within-person multi-level analyses, we tested the hypothesis that adult men, pre/early pubertal boys, and pre/early pubertal girls show a coordinated response in cortisol and testosterone (i.e., coupling of cortisol and testosterone responses) during a social evaluative situation. In Study 1, 85 men delivered speeches and performed difficult arithmetic tasks in front of critical evaluators, prepared for a competition, and provided multiple saliva samples throughout the procedure for cortisol and testosterone assays. In Study 2, 79 boys and 74 girls underwent similar procedures as in Study 1. Within-person analyses suggested that cortisol and testosterone responses were indeed positively associated for all three groups (men, boys, and girls). That is, on average a participant's cortisol and testosterone levels tended to rise and fall together throughout the procedure, suggesting that cortisol and testosterone show coordinated activation and deactivation (coupling) during social status threats. Furthermore, men with higher anxiety during the stressor tasks (Study 1; coded by raters from video recordings) and both boys and girls with higher parent reported trait negative affectivity (Study 2) had stronger coupling. Men (Study 1) higher in self-reported trait dominance and verbal dominance (coded by raters from video recordings during the stressor), and lower in basal testosterone had weaker coupling. A coordinated hormone response may have important adaptive functions when dealing with status threats; cortisol can mobilize energy resources and testosterone can facilitate performance. These findings have implications for developing a dual axis understanding of physiological responses during social threats and competition and their function. PMID- 26254770 TI - Central vascular disease and exacerbated pathology in a mixed model of type 2 diabetes and Alzheimer's disease. AB - Aging remains the main risk factor to suffer Alzheimer's disease (AD), though epidemiological studies also support that type 2 diabetes (T2D) is a major contributor. In order to explore the close relationship between both pathologies we have developed an animal model presenting both AD and T2D, by crossing APP/PS1 mice (AD model) with db/db mice (T2D model). We traced metabolic and cognitive evolution before T2D or AD pathology is present (4 weeks of age), when T2D has debuted but no senile plaques are present (14 weeks of age) and when both pathologies are well established (26 weeks of age). APP/PS1xdb/db mice showed an age-dependent synergistic effect between T2D and AD. Significant brain atrophy and tau pathology were detected in the cortex by 14 weeks, that spread to the hippocampus by 26 weeks of age. Severe cognitive impairment was also detected as soon as at 14 weeks of age. Interestingly, in APP/PS1xdb/db mice we observed a shift in Abeta soluble/insoluble levels, and whereas more toxic soluble species were favoured, senile plaques (SP) were reduced. An overall increase of microglia activation was observed in APP/PS1xdb/db mice. We also found exacerbated hemorrhagic burden in APP/PS1xdbd/db mice, suggesting that blood brain barrier alterations may be responsible for the early pathological features observed. Moreover, metabolic parameters can predict many of these alterations, supporting a role for T2D in AD pathology. This new model provides a relevant tool to further explore the relationship between T2D, AD and vascular implications, offering the possibility to assess therapeutic approaches, that by improving T2D metabolic control could delay or prevent AD pathology. PMID- 26254771 TI - An inverse relationship between serum macrophage inhibitory cytokine-1 levels and brain white matter integrity in community-dwelling older individuals. AB - Macrophage inhibitory cytokine-1 (MIC-1/GDF15) is a marker of inflammation that has been associated with atherosclerosis. We have previously demonstrated its relationships with cognitive decline and cerebral gray matter volumes, suggesting its role as a biomarker of cognitive impairment. Considering that it is widely distributed in the brain, and both inflammation and vascular pathology impact on white matter (WM) integrity, we examined the relationship between MIC-1/GDF15 and measures of WM integrity, including WM volumes, mean fractional anisotropy (FA) values and WM hyperintensity (WMH) volumes in a community-dwelling non-demented sample of older individuals (n=327, 70-90 years old). We found that the mean FA values were negatively associated with MIC-1/GDF15 serum levels, after Bonferroni correction. The voxel-wise analysis showed negative relationships between MIC 1/GDF15 serum levels and FA values in corticospinal tract, corpus callosum (including genu, body and splenium parts), superior longitudinal fasciculus, cingulum, as well as anterior and posterior thalamic radiation. Whole brain WMH volumes, especially deep WMH volumes, showed a non-significant trend for a positive association with MIC-1/GDF15 serum levels. The associations between MIC 1/GDF15 serum levels and WM integrity showed a non-significant trend of being stronger for the individuals classified as mild cognitive impairment, compared to the normal ageing participants. The findings suggest that high serum MIC-1/GDF15 levels indicate reduced WM integrity and possibly greater WM pathology. PMID- 26254772 TI - Therapeutic effect of the YH6 phage in a murine hemorrhagic pneumonia model. AB - The treatment, in farmed mink, of hemorrhagic pneumonia caused by multidrug resistant Pseudomonas aeruginosa strains has become increasingly difficult. This study investigated the potential use of phages as a therapy against hemorrhagic pneumonia caused by P. aeruginosa in a murine hemorrhagic pneumonia model. An N4 like phage designated YH6 was isolated using P. aeruginosa strain D9. YH6 is a virulent phage with efficient and broad host lytic activity against P. aeruginosa. No bacterial virulence- or lysogenesis-related ORF is present in the YH6 genome, making it eligible for use in phage therapy. In our murine experiments, a single intranasal administration of YH6 (2 * 10(7) PFU) 2 h after D9 intranasal injections at double minimum lethal dose was sufficient to protect mice against hemorrhagic pneumonia. The bacterial load in the lungs of YH6 protected mice was less than 10(3) CFU/g within 24 h after challenge and ultimately became undetectable, whereas the amount of bacteria in the lung tissue derived from unprotected mice was more than 10(8) CFU/g within 24 h after challenge. In view of its protective efficacy in this murine hemorrhagic pneumonia model, YH6 may serve as an alternative treatment strategy for infections caused by multidrug-resistant P. aeruginosa. PMID- 26254773 TI - Exercise and Self-Reported Limitations in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Limited evidence suggests that exercise may have beneficial, anti inflammatory effects in patients with inflammatory bowel disease (IBD). AIMS: The purpose of this study was to evaluate the prevalence of exercise in patients with IBD and the limitations they experience secondary to their disease. METHODS: Two hundred and fifty IBD patients were prospectively enrolled in this study at an academic medical center at the time of their outpatient visits between March and October 2013. Subjects were asked to complete a one-time survey that asks questions about medical and surgical history, exercise frequency and intensity, and the limitations and barriers they experience. RESULTS: Two hundred and twenty seven patients (148 female patients) completed the survey. Crohn's disease was present in 140 patients (61.5 %), while 87 had ulcerative colitis. Forty-one patients (16.4 %) never exercised, 82 patients (32.8 %) exercised 1-2 times per week, 59 (23.6 %) exercised 3-4 times per week, and 45 (18.0 %) exercised more than four times per week. Of the 186 who regularly exercise, 95 (51 %) reported moderate exercise intensity, 61 (33 %) reported light intensity, and 30 (16 %) reported vigorous intensity. Ninety-nine patients (44 %) reported that their IBD limited their exercise for reasons including fatigue (n = 81), joint pain (n = 37), embarrassment (n = 23), weakness (n = 21), and others. CONCLUSIONS: Although they may benefit from exercise, IBD patients experience considerable barriers to regular exercise secondary to the relapsing and remitting nature of IBD. Larger studies are needed to determine the effects of exercise on disease symptomatology and activity. PMID- 26254775 TI - Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics. AB - Fanconi anemia (FA) is characterized by bone marrow failure, malformations, and chromosome fragility. We review the recent discovery of FA genes and efforts to develop genetic therapies for FA in the last five years. Because current data exclude FANCM as an FA gene, 15 genes remain bona fide FA genes and three (FANCO, FANCR and FANCS) cause an FA like syndrome. Monoallelic mutations in 6 FA associated genes (FANCD1, FANCJ, FANCM, FANCN, FANCO and FANCS) predispose to breast and ovarian cancer. The products of all these genes are involved in the repair of stalled DNA replication forks by unhooking DNA interstrand cross-links and promoting homologous recombination. The genetic characterization of patients with FA is essential for developing therapies, including hematopoietic stem cell transplantation from a savior sibling donor after embryo selection, gene therapy, or genome editing using genetic recombination or engineered nucleases. Newly acquired knowledge about FA promises to provide therapeutic strategies in the near future. PMID- 26254774 TI - Clinical Outcome of Endoscopic Ultrasound-Guided Liver Abscess Drainage Using Self-Expandable Covered Metallic Stent (with Video). AB - BACKGROUND: Percutaneous drainage (PCD) is now the first-line drainage method for liver abscess because of its minimal invasiveness and high technical success rate. However, this procedure has several disadvantages, such as extra-drainage and self-tube removal. Recently, EUS-guided liver abscess drainage (EUS-AD) has been developed. However, only a few reports of EUS-AD have been reported. In addition, the clinical benefits of PCD and EUS-AD have not been reported. AIMS: In the present study, the safety and feasibility of EUS-AD using fully covered SEMS (FCSEMS) and the clinical outcomes of EUS-AD and PCD were examined retrospectively. METHODS: Twenty-seven consecutive patients who underwent PCD or EUS-AD between April 2012 and April 2015 were included in this study. EUS-AD was performed using FCSEMS. In addition, to prevent stent migration, 7-Fr pig tail plastic stent was placed within FCSEMS. RESULTS: Technical success was achieved in all patients of both groups. Clinical success was 100 % in the EUS-AD group although it was 89 % in PCD group (P = 034). Three adverse events were seen in the PCD group (self-tube removal n = 1, tube migration n = 2), but no adverse events were seen in the EUS-AD group. The median hospital stay was significantly shorter in the EUS-AD group than in the PCD group (21 vs 41 days, P = 0.03). CONCLUSION: Because of the short hospital stay, the high clinical success rate, and the low adverse event rate compared to PCD, EUS-AD has potential as a first line treatment for liver abscess. PMID- 26254776 TI - The long noncoding RNA regulation at the MYC locus. AB - Aberrant expression of long noncoding RNAs (lncRNAs) has been linked to cancers. The MYC oncoprotein is a key contributor to the development of many human tumors. Recent studies have revealed that a number of lncRNAs originating from the human 8q24 locus previously known to corresponding to a 'gene desert' are transcribed and play important roles in MYC regulation. In this review, we highlight recent progress in how these lncRNAs participate in control of MYC levels in normal and tumor cells. PMID- 26254777 TI - Anticholinergic burden in Parkinson's disease inpatients. AB - PURPOSE: Anticholinergic toxicity can arise as a result of the cumulative burden of multiple medications and metabolites rather than be caused by a single compound. In this sense, prescribing drugs with anticholinergic properties to Parkinson's disease (PD) patients could contribute to aggravate some frequent problems of the disease, like dementia, urinary retention, falls, or constipation, among others. The main purpose of this article is to measure the total anticholinergic burden in a group of PD inpatients. METHOD: We analyzed information from different administrative Basque Country's healthcare databases using encrypted unique identifiers in order to detect PD patients admitted to public acute care hospital during 2011-2012. Subsequently, anticholinergic burden was measured using Duran et al.'s list. Secondarily, total anticholinergic load was assessed with the Anticholinergic Drug Scale, the Anticholinergic Risk Score, and the Anticholinergic Burden Scale. A logistic regression model was performed to study association of predictive variables with anticholinergic use. RESULTS: A high proportion of PD patients were prescribed anticholinergic drugs, with 53.6% of admissions receiving at least one drug from Duran et al.'s "low-risk" and 10% at least "high-risk" drug. Drugs used for non-motor symptoms and other comorbidities other than PD itself contributed significantly to anticholinergic burden, namely antidepressants, antipsychotics, urological drugs, analgesics, and antihistamines, among others. The total number of drugs and cholinesterase inhibitors were independently associated with anticholinergic drug use. CONCLUSIONS: Anticholinergic burden in PD patients is significant, and is caused mostly by drugs not used for PD motor symptoms. Polypharmacy and cholinesterase inhibitors were independently associated with anticholinergic drug prescriptions. PMID- 26254778 TI - T-bet and interleukin-27: possible TH1 immunomodulators of sarcoidosis. AB - BACKGROUND: Sarcoidosis has often been termed an "immune paradox" as there is peripheral anergy to common recall antigens despite pronounced TH1-dominant inflammation at disease sites, such as the lung, with up-regulation of interferon gamma, IL-27 and transcription factors. Peripheral blood may reflect the anergic state, while exhaled breath condensate (EBC) analysis may offer insights into the lung disease. METHODS: A cross-sectional study was conducted to investigate the expression of TH1 cytokines and transcription factors (IFNgamma, IL-27 and T-bet) in the peripheral blood and/or EBC of sarcoidosis patients and healthy controls. Whole blood and EBC were collected from sarcoidosis patients and healthy controls. TH1 cytokine expression levels were then measured in peripheral blood mononuclear cells (PBMCs) and/or plasma and EBC using quantitative real-time PCR, ELISA and via Western blotting. RESULTS: Compared to healthy controls, PBMC IL-27 mRNA was higher in patients (p = 0.0019). There were no significant differences in plasma IL-27 protein between patients and controls (p = 0.20). T-bet mRNA and protein were lower (p = 0.010 and p = 0.0043, respectively) in patients compared to controls. There were no significant differences in PBMC IFNgamma mRNA and protein expression (p = 0.68 and p = 0.74, respectively) nor in EBC IL-27 levels. CONCLUSIONS: Our data indicate that depressed T-bet mRNA and protein expression could contribute to the peripheral anergy in sarcoidosis and that IL-27 mRNA levels are elevated in the PBMC from those with sarcoidosis. PMID- 26254779 TI - beta-Caryophyllene alleviates D-galactosamine and lipopolysaccharide-induced hepatic injury through suppression of the TLR4 and RAGE signaling pathways. AB - Agastache rugosa (A. rugosa, Labiatae), a perennial herb spread throughout Korean fields, is widely consumed as a wild edible vegetable and is used in folk medicine. This study examined the hepatoprotective mechanisms of beta caryophyllene (BCP), a major bicyclic sesquiterpene of A. rugosa, against D galactosamine (GalN) and lipopolysaccharide (LPS)-induced hepatic failure. Mice were given an intraperitoneal injection of BCP (50, 100 and 200 mg/kg) 1 h before GalN (800 mg/kg)/LPS (40 MUg/kg) injection and were killed 1 h or 6 h after GalN/LPS injection. GalN/LPS markedly increased mortality and serum aminotransferase activity, both of which were attenuated by BCP. BCP also attenuated increases in serum tumor necrosis factor-alpha, interleukin 6, and high-mobility group protein B1 levels by GalN/LPS. GalN/LPS significantly increased toll-like receptor (TLR) 4 and receptor for advanced glycation end products (RAGE) protein expression, extracellular signal-related kinase, p38 and c-Jun N-terminal kinase phosphorylation, nuclear factor kappaB (NF-kappaB), early growth response protein-1, and macrophage inflammatory protein-2 protein expression. These increases were attenuated by BCP. Furthermore, BCP suppressed increased TLR4 and RAGE protein expression and proinflammatory cytokines production in LPS-treated isolated Kupffer cells. Our findings suggest that BCP protects against GalN/LPS-induced liver injury through down-regulation of the TLR4 and RAGE signaling. PMID- 26254780 TI - Mitomycin C induces fibroblasts apoptosis and reduces epidural fibrosis by regulating miR-200b and its targeting of RhoE. AB - Mitomycin C (MMC) is known to reduce epidural fibrosis, but the underlying mechanisms have not yet been elucidated. Aberrant miR-200b expressions have been reported in multiple types of fibrotic tissues from many diseases. The aim of this study was to clarify the mechanism by which MMC induces fibroblasts apoptosis and reduces epidural fibrosis. The expression of miR-200b in human fibroblasts was determined after MMC treatment, and the targeted association between miR-200b and RhoE was determined using the luciferase activity assay. The effects of MMC and miR-200b on human fibroblasts apoptosis were evaluated using flow cytometry and western blot analysis. The effects of MMC and miR-200b on epidural fibrosis were evaluated using the Rydell classification, hydroxyproline content, apoptotic cell count and histological analysis. The study revealed that MMC could significantly downregulate miR-200b expression and induce human fibroblasts apoptosis. The direct downregulation of miR-200b could induce human fibroblasts apoptosis. Furthermore, we identified the binding sequence for miR 200b within the 3' untranslated region of RhoE. RhoE was confirmed to be a direct target of miR-200b, and RhoE itself acted as a promoter of fibroblasts apoptosis. The inhibition of miR-200b increased fibroblasts apoptosis and reduced epidural fibrosis in rats, which was in accordance with the effect of MMC. This study suggests that MMC induces fibroblasts apoptosis and reduces epidural fibrosis by regulating miR-200b expression and its targeting of RhoE. PMID- 26254781 TI - Expression of nuclear membrane proteins in normal, hyperplastic, and neoplastic thyroid epithelial cells. AB - Emerin, lamin A/C, lamin B, and lamin-associated polypeptide 2 (LAP2) are nuclear membrane proteins that play an important role in maintaining nuclear structure and coordinating cell activity. We studied the expression and significance of nuclear membrane proteins in neoplastic thyroid cells by immunohistochemistry, RT PCR, and real-time PCR. In papillary carcinomas (PCs), the nuclear proteins most frequently expressed at high levels were emerin (82 % positive), lamin A/C (64 %), and LAP2 (82 %). Follicular carcinomas (FCs) most frequently expressed lamin B, while none of the undifferentiated carcinomas (UCs) showed strong expression of emerin or lamin A/C. In all medullary carcinomas (MCs), intermediate to high levels of expression of lamin A/C and LAP2 were found. By RT-PCR analysis, messenger RNA (mRNA) expression of all nuclear membrane proteins except emerin was higher in PC than in normal tissue. Real-time PCR analysis showed that mRNA expression of nuclear membrane protein varied between cell lines. Our findings suggest that expression of nuclear membrane proteins may be related to follicular function in normal and hyperplastic follicles, and we hypothesize that they are also involved in the proliferation and differentiation of neoplastic thyroid cells. We suggest that they reflect the biological nature and/or function of normal, hyperplastic, and neoplastic thyroid cells and may have some value in diagnosing thyroid tumors. PMID- 26254782 TI - Dynamic changes in the cross-sectional area of the dural sac and spinal cord in the thoracic spine. AB - PURPOSE: The thoracic spine is considered a rigid region because it is restricted by the rib cage. Previously, we reported functional alignments and range of motion (ROM) at all segmental levels. The purpose of this study was to investigate dynamic changes of the dural sac and spinal cord in the thoracic spine using a multidetector-row computed tomography (MDCT). METHODS: Fifty patients with cervical or lumbar spinal disease were prospectively enrolled. After preoperative myelography, MDCT was performed at maximum passive flexion and extension. The anteroposterior diameter and cross-sectional area of the dural sac and spinal cord in the axial plane were measured using Scion imaging software. We also evaluated the correlation between the change ratio of the cross-sectional area and segmental kyphotic angle and ROM. RESULTS: In flexion, the anteroposterior diameter of the dural sac was larger than in extension. The cross sectional area in the upper and middle regions was smaller, but was larger in the lower region. The anteroposterior diameter and cross-sectional area of the spinal cord in the upper and middle regions were smaller than in extension, but these values were nearly the same in both flexion and extension in the lower region. Change ratios of the cross-sectional area were correlated with segmental kyphotic angle rather than ROM. CONCLUSIONS: The thoracic spine showed some dynamic changes of the dural sac and spinal cord in the axial plane within functional motion. Segmental kyphotic angle, rather than segmental ROM, was the more important factor affecting dimensions of the dural sac and spinal cord. PMID- 26254783 TI - Targeted inhibition of p38MAPK-enhanced autophagy in SW620 cells resistant to photodynamic therapy-induced apoptosis. AB - Photodynamic therapy (PDT) is a promising and noninvasive treatment that can induce apoptosis, autophagy, or both depending on the cell phenotype. In this work, chlorin e6 (Ce6) was used to photosensitize human colorectal cancer SW620 cells. In cells, apparent autophagy and apoptosis with dependence on intracellular reactive oxygen species (ROS) generation were detected. p38MAPK activation followed by ROS generation might be a core component in Ce6 mediate PDT (Ce6-PDT)-induced autophagy and apoptosis signaling pathway. By using p38MAPK siRNA, the results showed a marked enhancement on cell apoptosis in Ce6-PDT with increased annexin (+) apoptotic cells, nuclear condensation, caspase-3, and PARP cleavage. Besides, impairment of p38MAPK also promoted the autophagic response to photodamage as indicated by conversion of LC3 and monodansyl cadaverine (MDC) labeling patterns. It appears that Ce6-PDT induced ROS production involving activation of p38MAPK, probably to prevent SW620 cells from photodamage. Moreover, autophagy inhibitor 3-methyladenine/bafilomycin A1 greatly aggravated Ce6-PDT-induced apoptosis in SW620 cells with knockdown of p38MAPK. Taken together, this study suggests that autophagy could represent a promising field in cancer treatment and p38MAPK may be a potential therapeutic target to enhance the efficacy on clinical evaluation for the treatment of colorectal cancer. PMID- 26254784 TI - Molecular cloning and characterization of caffeic acid 3-O-methyltransferase from the rhizome of Ligusticum chuanxiong. AB - OBJECTIVES: To clone and characterize caffeic acid 3-O-methyltransferase (LcCOMT) from the rhizome of Ligusticum chuanxiong, a traditional medicinal herb having a high content of ferulic acid. RESULTS: LcCOMT encoded an ORF of 362 amino acids with a calculated MW of 39,935 Da and pI of 5.94. Polygenetic tree indicated that LcCOMT was attributed to a new member of COMTs in plants. The recombinant LcCOMT was expressed in E. coli. HPLC and (1)H NMR analyses of purified LcCOMT protein confirmed that it could catalyze caffeic acid to produce ferulic acid in vitro. The further site-mutagenesis proved that His268 was one key catalytic residue. In addition, the substantial changing expression level of LcCOMT under chilling treatment suggested that LcCOMT might play important role in the accumulation of ferulic acid under chilling treatment. CONCLUSIONS: This is the first report of the isolation and characterization of a COMT clone from traditional medicine containing high contents of pharmaceutical ferulic acid. PMID- 26254785 TI - Adaptation of acidogenic sludge to increasing glycerol concentrations for biohydrogen production. AB - Hydrogen is a promising alternative as an energetic carrier and its production by dark fermentation from wastewater has been recently proposed, with special attention to crude glycerol as potential substrate. In this study, two different feeding strategies were evaluated for replacing the glucose substrate by glycerol substrate: a one-step strategy (glucose was replaced abruptly by glycerol) and a step-by-step strategy (progressive decrease of glucose concentration and increase of glycerol concentration from 0 to 5 g L(-1)), in a continuous stirred tank reactor (12 h of hydraulic retention time (HRT), pH 5.5, 35 degrees C). While the one-step strategy led to biomass washout and unsuccessful H2 production, the step-by-step strategy was efficient for biomass adaptation, reaching acceptable hydrogen yields (0.4 +/- 0.1 molH2 mol(-1) glycerol consumed) around 33 % of the theoretical yield independently of the glycerol concentration. Microbial community structure was investigated by single-strand conformation polymorphism (SSCP) and denaturing gradient gel electrophoresis (DGGE) fingerprinting techniques, targeting either the total community (16S ribosomal RNA (rRNA) gene) or the functional Clostridium population involved in H2 production (hydA gene), as well as by 454 pyrosequencing of the total community. Multivariate analysis of fingerprinting and pyrosequencing results revealed the influence of the feeding strategy on the bacterial community structure and suggested the progressive structural adaptation of the community to increasing glycerol concentrations, through the emergence and selection of specific species, highly correlated to environmental parameters. Particularly, this work highlighted an interesting shift of dominant community members (putatively responsible of hydrogen production in the continuous stirred tank reactor (CSTR)) according to the gradient of glycerol proportion in the feed, from the family Veillonellaceae to the genera Prevotella and Clostridium sp., putatively responsible of hydrogen production in the CSTR. PMID- 26254786 TI - Expression of a chimeric human/salmon calcitonin gene integrated into the Saccharomyces cerevisiae genome using rDNA sequences as recombination sites. AB - Calcitonin participates in controlling homeostasis of calcium and phosphorus and plays an important role in bone metabolism. The aim of this study was to endow an industrial strain of Saccharomyces cerevisiae with the ability to express chimeric human/salmon calcitonin (hsCT) without the use of antibiotics. To do so, a homologous recombination plasmid pUC18-rDNA2-ura3-P pgk -5hsCT-rDNA1 was constructed, which contains two segments of ribosomal DNA of 1.1 kb (rDNA1) and 1.4 kb (rDNA2), to integrate the heterologous gene into host rDNA. A DNA fragment containing five copies of a chimeric human/salmon calcitonin gene (5hsCT) under the control of the promoter for phosphoglycerate kinase (P pgk ) was constructed to express 5hsCT in S. cerevisiae using ura3 as a selectable auxotrophic marker gene. After digestion by restriction endonuclease HpaI, a linear fragment, rDNA2 ura3-P pgk -5hsCT-rDNA1, was obtained and transformed into the ?ura3 mutant of S. cerevisiae by the lithium acetate method. The ura3-P pgk -5hsCT sequence was introduced into the genome at rDNA sites by homologous recombination, and the recombinant strain YS-5hsCT was obtained. Southern blot analysis revealed that the 5hsCT had been integrated successfully into the genome of S. cerevisiae. The results of Western blot and ELISA confirmed that the 5hsCT protein had been expressed in the recombinant strain YS-5hsCT. The expression level reached 2.04 % of total proteins. S. cerevisiae YS-5hsCT decreased serum calcium in mice by oral administration and even 0.01 g lyophilized S. cerevisiae YS-5hsCT/kg decreased serum calcium by 0.498 mM. This work has produced a commercial yeast strain potentially useful for the treatment of osteoporosis. PMID- 26254787 TI - A novel enzyme-based antimicrobial system comprising iodide and a multicopper oxidase isolated from Alphaproteobacterium strain Q-1. AB - Alphaproteobacterium strain Q-1 produces an extracellular multicopper oxidase (IOX), which catalyzes iodide (I-) oxidation to form molecular iodine (I2). In this study, the antimicrobial activity of the IOX/iodide system was determined. Both Gram-positive and Gram-negative bacteria tested were killed completely within 5 min by 50 mU mL(-1) of IOX and 10 mM iodide. The sporicidal activity of the system was also tested and compared with a common iodophor, povidone-iodine (PVP-I). IOX (300 mU mL(-1)) killed Bacillus cereus, B. subtilis, and Geobacillus stearothermophilus spores with decimal reduction times of 2.58, 7.62, and 40.9 min, respectively. However, 0.1% PVP-I killed these spores with much longer decimal reduction times of 5.46, 38.0, and 260 min, respectively. To evaluate the more superior sporicidal activity of the IOX system over PVP-I, the amount of free iodine (non-complexed I2) was determined by an equilibrium dialysis technique. The IOX system included more than 40 mg L(-1) of free iodine, while PVP-I included at most 25 mg L(-1) free iodine. Our results suggest that the new enzyme-based antimicrobial system is effective against a wide variety of microorganisms and bacterial spores, and that its strong biocidal activity is due to its high free iodine content, which is probably maintained by re-oxidation of iodide released after oxidation of cell components by I2. PMID- 26254788 TI - Long-term oil contamination causes similar changes in microbial communities of two distinct soils. AB - Since total petroleum hydrocarbons (TPH) are toxic and persistent in environments, studying the impact of oil contamination on microbial communities in different soils is vital to oil production engineering, effective soil management and pollution control. This study analyzed the impact of oil contamination on the structure, activity and function in carbon metabolism of microbial communities of Chernozem soil from Daqing oil field and Cinnamon soil from Huabei oil field through both culture-dependent techniques and a culture independent technique-pyrosequencing. Results revealed that pristine microbial communities in these two soils presented disparate patterns, where Cinnamon soil showed higher abundance of alkane, (polycyclic aromatic hydrocarbons) PAHs and TPH degraders, number of cultivable microbes, bacterial richness, bacterial biodiversity, and stronger microbial activity and function in carbon metabolism than Chernozem soil. It suggested that complicated properties of microbes and soils resulted in the difference in soil microbial patterns. However, the changes of microbial communities caused by oil contamination were similar in respect of two dominant phenomena. Firstly, the microbial community structures were greatly changed, with higher abundance, higher bacterial biodiversity, occurrence of Candidate_division_BRC1 and TAO6, disappearance of BD1-5 and Candidate_division_OD1, dominance of Streptomyces, higher percentage of hydrocarbon-degrading groups, and lower percentage of nitrogen-transforming groups. Secondly, microbial activity and function in carbon metabolism were significantly enhanced. Based on the characteristics of microbial communities in the two soils, appropriate strategy for in situ bioremediation was provided for each oil field. This research underscored the usefulness of combination of culture-dependent techniques and next-generation sequencing techniques both to unravel the microbial patterns and understand the ecological impact of contamination. PMID- 26254789 TI - From jhum to broom: Agricultural land-use change and food security implications on the Meghalaya Plateau, India. AB - Human population growth in the developing world drives land-use changes, impacting food security. In India, the dramatic change in demographic dynamics over the past century has reduced traditional agricultural land-use through increasing commercialization. Here, we analyze the magnitude and implications for the farming system by the introduction of cash-cropping, replacing the traditional slash and burn rotations (jhum), of the tribal people on the Meghalaya Plateau, northeast India, by means of agricultural census data and field surveys conducted in seven villages. Land-use change has brought major alterations in hill agricultural practices, enhanced cash-cropping, promoted mono cropping, changed food consumption patterns, underpinned the emergence of a new food system, and exposed farmers and consumers to the precariousness of the market, all of which have both long- and short-term food security implications. We found dietary diversity to be higher under jhum compared to any of the cash crop systems, and higher under traditional cash-cropping than under modern cash cropping. PMID- 26254790 TI - An oral high dose of cholecalciferol restores vitamin D status in deficient postmenopausal HIV-1-infected women independently of protease inhibitors therapy: a pilot study. AB - The best repletion and maintenance dosing regimens with cholecalciferol in vitamin D-deficient HIV-1 patients remain unknown. Protease inhibitors (PIs) have been shown to inhibit vitamin D 1alpha- and 25alpha-hydroxylation in hepatocyte and monocyte cultures. We therefore evaluated the effect of a single high dose of cholecalciferol in vitamin D-deficient HIV-1 postmenopausal women undergoing treatment with highly active anti-retroviral therapy (cART), with and without PIs. Forty HIV-1 postmenopausal women treated with cART, with hypovitaminosis D (<20 ng/ml), were enrolled. We measured serum changes of 25-hydroxyvitamin D [25(OH)D]; 1,25-dihydroxyvitamin D [1,25(OH)2D], parathyroid hormone (PTH), serum calcium, and urinary calcium excretion following a loading dose of 600,000 IU of cholecalciferol after 3, 30, 60, 90, and 120 days. Patients were divided into two groups, whether or not they were taking PI. A significant increase in mean 25(OH)D and 1,25(OH)2D levels at day 3 and throughout the entire observation period was found in both groups (p < 0.001). PTH levels concomitantly decreased in both groups (p < 0.001). Mean albumin-adjusted serum calcium increases with respect to baseline were significant only at day 3 and day 30 for both groups (p < 0.01). Considering remaining parameters, there were no significant differences between the groups at any time, by two-way RM ANOVA. An oral dose of 600,000 IU of cholecalciferol in HIV-1 postmenopausal women rapidly increases 25(OH)D and 1,25(OH)2D levels reducing PTH levels, regardless of the presence of PIs in the cART scheme. PMID- 26254791 TI - Restricting ultrasound thyroid fine needle aspiration biopsy by nodule size: which tumors are we missing? A population-based study. AB - Clinicians use nodule size to determine which thyroid nodules should receive cytological evaluation. The American Thyroid Association (ATA) has recommended against cytological evaluation for nodules <1 cm. It is unknown, however, if nodule size can accurately discriminate lesions that will represent tumors with favorable versus unfavorable prognosis. Also, the characteristics of thyroid cancers that would not be diagnosed if a strict 1 cm size cut off is used as the threshold for biopsy of intrathyroidal nodules are not well established. Using the Rochester Epidemiology Project, a population-based cohort, we identified all thyroid nodules in Olmsted County residents from 2003-2006. To assess the presence of favorable or unfavorable features for each nodule size cutoff, each patient found to have thyroid cancer was risk-stratified using the ATA risk score, which predicts risk of recurrence and persistent disease. Thyroid cancer cases in which a biopsy was done for factors other than thyroid nodule size or suspicious ultrasound features were excluded. We identified 485 thyroid nodules, 46 (9.5%) harbored thyroid cancer. Of the 46 thyroid cancers, 37 (7.6%) had ATA low risk; 8 (1.6%) had intermediate, and only 1 (0.2%) had an ATA high risk scores. The frequency of thyroid cancer and the distribution of ATA risk scores were similar across tumor sizes. In thyroid nodules of <1 cm, 92 (87%) were benign, while 13 (13%) were malignant (11% ATA low risk, 2% ATA intermediate risk) without extrathyroid extension, aggressive histology, or distant metastasis. For all thyroid cancer patients, no cases of persistent disease were found after a median follow-up of 7 years. In this population-based study, we showed that high risk thyroid cancers are rare; indeed, in this highly selected cohort of patients, the ATA's recommendation to avoid cytologic evaluation in thyroid nodules less than 1 cm would not miss any thyroid cancer with high risk features. However, thyroid nodule size at presentation did not accurately discriminate between tumors with favorable versus unfavorable clinicopathologic features. Thus, if further discrimination is desired, for example, to avoid overdiagnosis, features other than size at presentation need to be evaluated. PMID- 26254792 TI - Effects of the CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites. AB - To investigate the effect of the variant CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine (4-HAT) and N desmethylatomoxetine (NAT), in healthy subjects, a single oral dose of atomoxetine was administered to 62 subjects with a CYP2D6*wt/*wt (*wt = *1 or *2, n = 22), CYP2D6*wt/*10 (n = 22) or CYP2D6*10/*10 (n = 18) genotype. Plasma samples were then collected for 24 h after atomoxetine administration. The concentrations of atomoxetine and its metabolites were assayed using LC-MS/MS. For atomoxetine, the Cmax, AUC0-infinity, t1/2 and CL/F showed genotype-dependent differences. The CYP2D6*10/*10 and CYP2D6*wt/*10 groups showed 1.74- and 1.15 fold higher Cmax, 3.40- and 1.33-fold higher AUC0-infinity, and 69.7 and 24.6 % lower CL/F, compared to those of the CYP2D6*wt/*wt group, respectively. The Cmax and t1/2 for 4-HAT were lower and longer in the CYP2D6*10/*10 group than those in the CYP2D6*wt/*wt group, but the AUC0-infinity was not different between these groups. The Cmax, AUC0-infinity and t1/2 for NAT were profoundly greater in the CYP2D6*10/*10 group than they were in the CYP2D6*wt/*wt group. The concentration of active moieties of atomoxetine (atomoxetine + 4-HAT) in the CYP2D6*10/*10 group was 3.32-fold higher than that in the CYP2D6*wt/*wt group. The mean exposure to active moieties of atomoxetine was markedly higher in subjects with the CYP2D6*10/*10 genotype compared to that in those with the CYP2D6*wt/*wt genotype. The higher systemic exposure of the active atomoxetine moieties in CYP2D6*10/*10 individuals may increase the risk of concentration-related adverse events of atomoxetine, although this has not yet been clinically confirmed. PMID- 26254793 TI - Survival and its predictors from age 75 to 85 in men and women belonging to cohorts with marked survival differences to age 75: a comparative study in three Nordic populations. AB - BACKGROUND AND AIMS: While predictors of survival in older people have been examined in depth in a large number of studies, a literature search revealed no cross-national comparative prospective cohort studies on this issue. This study investigated survival and its predictors from age 75 to 85 among three local Nordic populations using survival data on national cohorts as background information. METHODS: The data were derived from national registers and from samples of 75-year old living in Denmark, Sweden, and Finland. The subjects were invited to take part in interviews and examinations focusing on different domains of health, functional capacity, and physical and social activities. RESULTS: The proportion of survivors to age 75 was markedly smaller among the Finnish men and women than Danish or Swedish subjects. In the local population no marked differences in survival from age 75 to 85 were observed between the groups of men, while women survived longer than men and longer in Goteborg than in Glostrup or Jyvaskyla. Univariate models revealed 12 predictors of survival. In the multivariate models, the significant predictors among men related to physical fitness, whereas among women they pertained to social activities and morbidity. CONCLUSIONS: Despite great differences in the proportions of survivors to age 75, and excepting the survival advantage of women, only minor differences were present in the subjects' further survival to age 85. In the univariate analyses, many of the factors predictive of survival from age 75 to 85 were the same in the examined populations, whereas in the multivariate analyses differences between the sexes emerged. PMID- 26254794 TI - Kinematics and muscle activities of the lower limb during a side-cutting task in subjects with chronic ankle instability. AB - PURPOSE: The purpose of the present study was to evaluate lower limb kinematics and muscular activities during walking, side-turning while walking, and side cutting movement in athletes with chronic ankle instability and compare the results to those of athletes without chronic ankle instability. METHODS: Lower limb kinematics and muscular activities were evaluated in 10 athletes with chronic ankle instability and 10 healthy control athletes using a three dimensional motion analysis system and surface electromyography during the 200-ms pre-initial contact (IC) and stance phases while walking, side-turning while walking, and side-cutting. RESULTS: During walking or side-turning while walking, there were no significant differences in kinematics or muscle activities between the subjects with and without chronic ankle instability. For the side-cutting task, however, ankle inversion angles during the 200-ms pre-IC and late stance phases [effect sizes (ESs) = 0.95-1.43], the hip flexion angle (ESs = 0.94-0.96) and muscular activities of the gastrocnemius medialis (ESs = 1.04-1.73) during the early stance phase were significantly greater in the athletes with chronic ankle instability than in the healthy control athletes. CONCLUSIONS: Alterations of kinematics in athletes with chronic ankle instability were found not only at the ankle but also at hip joints during the side-cutting movement. These alterations were not detected during walking or side-turning while walking. The findings of the present study indicate that clinicians should take into account the motion of the hip joint during the side-cutting movement in persons with chronic ankle instability. LEVEL OF EVIDENCE: III. PMID- 26254795 TI - A systematic review of the benefits of physical therapy within a multidisciplinary care approach for people with schizophrenia: An update. AB - This systematic review summarizes the most recent evidence from randomized controlled trials (RCTs) considering the effectiveness of physical therapy interventions (aerobic exercises, strength exercises, relaxation training, basic body awareness exercises, or a combination of these) within the multidisciplinary management of schizophrenia. Two authors searched PubMed, PsycINFO, EMBASE, Web of Science, Physiotherapy Evidence Database (PEDro), and the Cochrane Library considering RCTs published from July 1, 2011-October 1, 2014. Thirteen RCTs representing 549 participants met the inclusion criteria. Overall, the results demonstrate that aerobic exercise significantly reduces psychiatric symptoms, potentially improves mental and physical quality of life and reduces metabolic risk and weight. Specifically, yoga reduces psychiatric symptoms, whilst Tai-chi and progressive muscle relaxation may also have benefits to patients. Two RCTs reported on adverse events. No adverse event was observed supporting the notion that physical therapy is safe in people with schizophrenia. There was considerable heterogeneity in the design, implementation and outcomes in the included studies precluding a meaningful meta-analysis. In general, the quality of physical therapy RCTS is improving and current research demonstrates that physical therapy approaches are valuable interventions and can help improve the psychiatric, physical and quality of life of people with schizophrenia. PMID- 26254796 TI - Effects of antipsychotic drugs on the expression of synapse-associated proteins in the frontal cortex of rats subjected to immobilization stress. AB - The present study examined the effects of antipsychotic drugs on the expression of synapse-associated proteins in the frontal cortex of rats with and without immobilization stress. Rats were subjected to immobilization stress 6h/day for 3 weeks. The effects of atypical antipsychotic drugs, olanzapine and aripiprazole, on expression of serine(9)-phosphorylated GSK-3beta, beta-catenin, BDNF, PSD-95, and synaptophysin were determined by Western blotting. A typical antipsychotic drug, haloperidol, was used for comparison. Immobilization stress significantly decreased the expression of these proteins in the frontal cortex. Chronic administration of olanzapine and aripiprazole significantly attenuated the immobilization stress-induced decrease in the levels of these proteins, whereas haloperidol had no such effect. Additionally, olanzapine and aripiprazole significantly increased levels of phosphorylated GSK-3beta under normal conditions without stress, and aripiprazole also increased BDNF levels under this condition. These results indicate that olanzapine and aripiprazole, and, haloperidol, differentially regulate the levels of synapse-associated proteins in the rat frontal cortex. These findings may contribute to explain the neurobiological basis of how olanzapine and aripiprazole up-regulated synapse associated proteins. PMID- 26254798 TI - Threat modulation of visual search efficiency in PTSD: A comparison of distinct stimulus categories. AB - Although an attentional bias for threat has been implicated in posttraumatic stress disorder (PTSD), the cues that best facilitate this bias are unclear. Some studies utilize images and others utilize facial expressions that communicate threat. However, the comparability of these two types of stimuli in PTSD is unclear. The present study contrasted the effects of images and expressions with the same valence on visual search among veterans with PTSD and controls. Overall, PTSD patients had slower visual search speed than controls. Images caused greater disruption in visual search than expressions, and emotional content modulated this effect with larger differences between images and expressions arising for more negatively valenced stimuli. However, this effect was not observed with the maximum number of items in the search array. Differences in visual search speed by images and expressions significantly varied between PTSD patients and controls for only anger and at the moderate level of task difficulty. Specifically, visual search speed did not significantly differ between PTSD patients and controls when exposed to angry expressions. However, PTSD patients displayed significantly slower visual search than controls when exposed to anger images. The implications of these findings for better understanding emotion modulated attention in PTSD are discussed. PMID- 26254797 TI - Congenital Adrenal Hyperplasia, Polycystic Ovary Syndrome and criminal behavior: A Swedish population based study. AB - Both prenatal and circulating testosterone and other androgens have been suggested to influence the individual's propensity to commit crime, but empirical evidence is limited and inconsistent. Congenital Adrenal Hyperplasia (CAH) and Polycystic Ovary Syndrome (PCOS) are both hyperandrogenic conditions but with an important difference; whereas subjects with CAH are exposed to high concentrations of androgens in utero, women with PCOS are subjected to high androgens in adulthood. Comparing these groups can therefore yield important insights of androgenic effects on behavior. In the current study, information on medical diagnoses and convicted crimes were gathered from Swedish population based registers. The associations between diagnoses of CAH or PCOS and any crime, violent crime or sex crime were estimated with conditional logistic regression. Results showed that CAH in women and men did not predict criminality, whereas an increased risk for any crime and violent crime was found in PCOS women. Our findings indicate that female hyperandrogenism in adulthood, but not prenatal hyperandrogenism, is associated with risk for criminal behavior. Further research into hyperandrogenic conditions holds opportunities to deepen our understanding of the etiology of crime and psychopathology. PMID- 26254799 TI - No evidence of a control group response in exercise randomised controlled trials in people with schizophrenia: A systematic review and meta-analysis. AB - Increased control group responses (CGR) make it more difficult to establish the effectiveness of interventions to improve symptoms in schizophrenia. We conducted a meta-analysis of CGR within randomised control trials (RCTs) comparing exercise and a control condition in people with schizophrenia. We found no evidence of a CGR for total, positive or negative symptoms. Control group responses do not negatively impact exercise RCTs that have clearly demonstrated substantial beneficial effects of exercise in this population. PMID- 26254800 TI - Correcting bias in self-rated quality of life: an application of anchoring vignettes and ordinal regression models to better understand QoL differences across commuting modes. AB - PURPOSE: Likert scales are frequently used in public health research, but are subject to scale perception bias. This study sought to explore scale perception bias in quality-of-life (QoL) self-assessment and assess its relationships with commuting mode in the Sydney Travel and Health Study. METHODS: Multilevel ordinal logistic regression analysis was used to analyse the association between two global QoL items about overall QoL and health satisfaction, with usual travel mode to work or study. Anchoring vignettes were applied using parametric and simpler nonparametric methods to detect and adjust for differences in reporting behaviour across age, sex, education, and income groups. RESULTS: The anchoring vignettes exposed differences in scale responses across demographic groups. After adjusting for these biases, public transport users (OR = 0.37, 95 % CI 0.21 0.65), walkers (OR = 0.44, 95 % CI 0.24-0.82), and motor vehicle users (OR = 0.47, 95 % CI 0.25-0.86) were all found to have lower odds of reporting high QoL compared with bicycle commuters. Similarly, the odds of reporting high health satisfaction were found to be proportionally lower amongst all competing travel modes: motor vehicle users (OR = 0.31, 95 % CI 0.18-0.56), public transport users (OR = 0.34, 95 % CI 0.20-0.57), and walkers (OR = 0.35, 95 % CI 0.20-0.64) when compared with cyclists. Fewer differences were observed in the unadjusted models. CONCLUSION: Application of the vignettes by the two approaches removed scaling biases, thereby improving the accuracy of the analyses of the associations between travel mode and quality of life. The adjusted results revealed higher quality of life in bicycle commuters compared with all other travel mode users. PMID- 26254801 TI - Test-retest reliability of HeartQoL and its comparability to the MacNew heart disease health-related quality of life questionnaire. AB - OBJECTIVES: Heart Quality of Life (HeartQoL) is a new "hybrid" developed from the MacNew and two condition-specific questionnaires measuring health-related quality of life (HRQoL) in patients with ischemic heart disease (IHD). This study investigates test-retest reliability of HeartQoL (English version) according to international criteria (e.g., COSMIN, GRRAS). Findings on HeartQoL are compared to the published data on MacNew in view that both serve as the core IHD-specific HRQoL instrument. METHODS: Out of 105 patients with IHD, 76 completed self administration of HeartQoL at the clinic followed by at home within a 2-week interval. In retest, patients responded using non-interview methods (phone messaging, email, fax, and post). Phone interviewing was reserved for non respondents to reminder. RESULTS: Reliability of HeartQoL was good (intraclass correlation coefficients = 0.78-0.82), was supported in the Bland-Altman plot, and was comparable to five studies on MacNew of similar retest interval (MacNew English = 0.70-0.75; translated MacNew = 0.72-0.91). Applicability of its standard error of measurement (0.20-0.25) and smallest detectable change (0.55 0.70) will depend on availability of normative data in future. CONCLUSION: The reliability of HeartQoL is comparable to its parent instrument, the MacNew. The HeartQoL is a potentially reliable core IHD-specific HRQoL instrument in measuring group change. PMID- 26254802 TI - Pain acts through fatigue to affect participation in individuals with multiple sclerosis. AB - PURPOSE: The symptoms of multiple sclerosis (MS) often cause physical and mental dysfunction, which interferes with a person's ability to participate in life's roles. Identification of the strength of the contributors to participation would help prioritize intervention approaches for its improvement. The objective of this study was to estimate the extent to which pain and other MS-related symptoms, physical function, psychological variables, and individual characteristics predict participation in people with MS. METHODS: This was a cross-sectional study. Study sample was a center-stratified random sample of 188 persons with MS. Subjects completed a battery of self-report and performance based measures that assessed participation and domains affecting participation. To model the relationships among variables, a conceptual framework based on the Wilson and Cleary model was tested. Structural equation modeling aimed at identification of the predictors of participation within the hypothesized theoretical model. RESULTS: Fatigue (beta = 0.63, p < 0.0001), physical function (beta = 0.37, p < 0.0001), and psychological variables (beta = 0.15, p = 0.04) were found to be as significant direct predictors of participation. Pain (beta = 0.4, p < 0.0001) and age (beta = 0.12, p < 0.0001) were significant indirect predictors through fatigue and physical function, respectively. Together these effects explained 88 % of the variance of participation, 35 % of the variance in psychological variables, and 29 % of the variance in physical function. CONCLUSION: Fatigue, physical function, pain, and psychological variables were most important contributors for participation in persons with MS. PMID- 26254803 TI - Do ePortfolios Contribute to Learners' Reflective Thinking Activities? : A Preliminary Study of Nursing Staff Users. AB - The purposes of this study are threefold: 1) to find out what characteristics are required for the successful use of ePortfolios; 2) to discover what activities best represent reflective thinking during the use of ePortfolios; and, 3) to investigate the interrelationship between nursing staff users' perceived success levels with ePortfolios and with their reflective thinking activities. Survey methodology was used to gather responses from 78 nurses from a medical center located in southern Taiwan via questionnaires. Factor analysis and canonical correlation analysis were used to analyze the collected data. The results demonstrated that system quality, information quality, and user satisfaction are important variables in successful ePortfolio usage; while habitual action, understanding, reflection, and critical reflection are major variables of reflective thinking. Further, we found a significant relationship exists between the relative success of ePortfolios and reflective thinking activities of ePortfolios users. The subject hospital should pay special attention to important characteristics including system quality, information quality, and user satisfaction when employing ePortfolios to help nursing staff users to achieve their learning goals through this form of reflective thinking. PMID- 26254804 TI - Towards an Encompassing Maturity Model for the Management of Hospital Information Systems. AB - Maturity models are tools that favour the management of organizations, including their information systems management task, and hospital organizations are no exception. In the present paper we put forth a preliminary investigation aimed at the development of an encompassing maturity model for the management of hospital information systems. The development of this model is justified to the extent that current maturity models in the field of hospital information systems management are still in an early development stage, and especially because they are poorly detailed, do not provide tools to determine the maturity stage nor structure the characteristics of maturity stages according to different influencing factors. PMID- 26254805 TI - Tellurite-, tellurate-, and selenite-based anaerobic respiration by strain CM-3 isolated from gold mine tailings. AB - The newly discovered strain CM-3, a Gram-negative, rod-shaped bacterium from gold mine tailings of the Central Mine in Nopiming Provincial Park, Canada, is capable of dissimilatory anaerobic reduction of tellurite, tellurate, and selenite. CM-3 possesses very high level resistance to these oxides, both aerobically and anaerobically. During aerobic growth, tellurite and tellurate resistance was up to 1500 and 1000 ug/ml, respectively. In the presence of selenite, growth occurred at the highest concentration tested, 7000 ug/ml. Under anaerobic conditions, resistance was decreased to 800 ug/ml for the Te oxides; however, much like under aerobic conditions, growth with selenite still took place at 7000 ug/ml. In the absence of oxygen, CM-3 couples oxide reduction to an increase in biomass. Following an initial drop in viable cells, due to switching from aerobic to anaerobic conditions, there was an increase in CFU/ml greater than one order of magnitude in the presence of tellurite (6.6 * 10(3)-8.6 * 10(4) CFU/ml), tellurate (4.6 * 10(3)-1.4 * 10(5) CFU/ml), and selenite (2.7 * 10(5)-5.6 * 10(6) CFU/ml). A control culture without metalloid oxides showed a steady decrease in CFU/ml with no recovery. ATP production was also increased in the presence of each oxide, further indicating anaerobic respiration. Partial 16S rRNA gene sequencing revealed a 99.0 % similarity of CM-3 to Pseudomonas reactans. PMID- 26254806 TI - High production of bacteriorhodopsin from wild type Halobacterium salinarum. AB - Bacteriorhodopsin (bR) is a trans-membrane proton pump found in the purple membrane of Halobacterium salinarum. This protein has high photochemical and photoelectric conversion efficiency and thermal stability, allowing it to withstand high temperatures, high salinity, and nutritionally-limited environments. The ability of this protein to convert light energy into chemical energy has applications that are mainly therapeutic/diagnostic and research oriented. There is increasing demand for bacteriorhodopsin production in different fields. The present study maximized bacteriorhodopsin production using H. salinarum. The physical parameters of illumination, agitation speed, temperature, and nitrogen source were studied using a fractional factorial design to determine the optimal levels of each. The most suitable nitrogen source was determined to be peptone from meat. The optimal temperature was 39 degrees C, agitation speed was 150 rpm, and light intensity was 6300 lux for bR production. Under these conditions, the maximum bR yield was 196 mg/l, which is about 4.23 fold greater than those obtained with basal medium. The proposed strategies could be used for bR production using this archaeobacterium; the results are the highest reported thus far from a batch culture of H. salinarum. PMID- 26254807 TI - Standard operating procedures for ESPEN guidelines and consensus papers. AB - The ESPEN Guideline standard operating procedures (SOP) is based on the methodology provided by the Association of Scientific Medical Societies of Germany (AWMF), the Scottish Intercollegiate Guidelines Network (SIGN), and the Centre for Evidence-based Medicine at the University of Oxford. The SOP is valid and obligatory for all future ESPEN-sponsored guideline projects aiming to generate high-quality guidelines on a regular basis. The SOP aims to facilitate the preparation of guideline projects, to streamline the consensus process, to ensure quality and transparency, and to facilitate the dissemination and publication of ESPEN guidelines. To achieve this goal, the ESPEN Guidelines Editorial board (GEB) has been established headed by two chairmen. The GEB will support and supervise the guideline processes and is responsible for the strategic planning of ESPEN guideline activities. Key elements of the SOP are the generation of well-built clinical questions according to the PICO system, a systemic literature search, a classification of the selected literature according to the SIGN evidence levels providing an evidence table, and a clear and straight forward consensus procedure consisting of online voting's and a consensus conference. Only experts who meet the obligation to disclosure any potential conflict of interests and who are not employed by the Industry can participate in the guideline process. All recommendations will be graded according to the SIGN grading and novel outcome models besides biomedical endpoints. This approach will further extent the leadership of ESPEN in creating up-to-date and suitable for implementation guidelines and in sharing knowledge on malnutrition and clinical nutrition. PMID- 26254808 TI - Potent effect of adenoviral vector expressing short hairpin RNA targeting ribonucleotide reductase large subunit M1 on cell viability and chemotherapeutic sensitivity to gemcitabine in non-small cell lung cancer cells. AB - BACKGROUND: Ribonucleotide reductase large subunit (RRM1) is the main enzyme responsible for synthesis of the deoxyribonucleotides used during DNA synthesis. It is also a cellular target for gemcitabine (GEM). Overexpression of RRM1 is reportedly associated with resistance to GEM and the poor prognosis for many types of malignant tumours. Aim of the present study is to establish gene therapy against RRM1-overexpressing tumours. METHOD: An adenoviral vector that encoded a short hairpin siRNA targeting the RRM1 gene (Ad-shRRM1) was constructed. Two RRM1 overexpressing non-small cell lung cancer (NSCLC) lines, MAC10 and RERF-LC-MA, were used. Finally, a human tumour xenograft model in nude mice was prepared by subcutaneously implanting tumours derived from RERF-LC-MA cells. RESULTS: Ad shRRM1 effectively downregulated RRM1 mRNA and protein in both types of NSCLC cells and significantly reduced the percentage of viable cells as detected by 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (p<0.005). Caspase 3/7 analysis revealed that transfection with Ad-RRM1 increased the percentage of apoptotic cells in culture containing either type of RRM1 overexpressing cell (p<0.001). Treatment with Ad-shRRM1 exerted a potent antitumour effect against the RRM1-overexpressing RERF-LC-MA xenografts (p<0.05). Furthermore, Ad-shRRM1-mediated inhibition of RRM1 specifically increased sensitivity to gemcitabine of each type of RRM1-overexpressing tumour cell. Combination treatment with Ad-shRRM1 and GEM exerted significantly greater inhibition on cell proliferation than Ad-shRRM1 or GEM treatment alone. CONCLUSION: RRM1 appeared to be a promising target for gene therapy, and Ad shRRM1 had strong antitumour effects, specifically anti-proliferative and pro apoptotic effects, against NSCLC cells that overexpressed RRM1. Combination therapy with Ad-shRRM1 and GEM may become a new treatment option for patients with NSCLC. PMID- 26254809 TI - A systematic review of randomised controlled trials of radiotherapy for localised prostate cancer. AB - BACKGROUND: Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males. A systematic review of randomised controlled trials (RCTs) of radiotherapy and other non-pharmacological management options for localised prostate cancer was undertaken. METHODS: A search of thirteen databases was carried out until March 2014. RCTs comparing radiotherapy (brachytherapy (BT) or external beam radiotherapy (EBRT)) to other management options i.e. radical prostatectomy (RP), active surveillance, watchful waiting, high intensity focused ultrasound (HIFU), or cryotherapy; each alone or in combination, e.g. with adjuvant hormone therapy (HT), were included. Methods followed guidance by the Centre for Reviews and Dissemination and the Cochrane Collaboration. Indirect comparisons were calculated using the Bucher method. RESULTS: Thirty-six randomised controlled trials (RCTs, 134 references) were included. EBRT, BT and RP were found to be effective in the management of localised prostate cancer. While higher doses of EBRT seem to be related to favourable survival-related outcomes they might, depending on technique, involve more adverse events, e.g. gastrointestinal and genitourinary toxicity. Combining EBRT with hormone therapy shows a statistically significant advantage regarding overall survival when compared to EBRT alone (Relative risk 1.21, 95% confidence interval 1.12-1.30). Aside from mixed findings regarding urinary function, BT and radical prostatectomy were comparable in terms of quality of life and biochemical progression-free survival while favouring BT regarding patient satisfaction and sexual function. There might be advantages of EBRT (with/without HT) compared to cryoablation (with/without HT). No studies on HIFU were identified. CONCLUSIONS: Based on this systematic review, there is no strong evidence to support one therapy over another as EBRT, BT and RP can all be considered as effective monotherapies for localised disease with EBRT also effective for post-operative management. All treatments have unique adverse events profiles. Further large, robust RCTs which report treatment-specific and treatment combination-specific outcomes in defined prostate cancer risk groups following established reporting standards are needed. These will strengthen the evidence base for newer technologies, help reinforce current consensus guidelines and establish greater standardisation across practices. PMID- 26254810 TI - Concurrent Etoposide, Steroid, High-dose Ara-C and Platinum chemotherapy with radiation therapy in localised extranodal natural killer (NK)/T-cell lymphoma, nasal type. AB - PURPOSE: Radiation combined with chemotherapy has recently been proposed to treat patients with localised extranodal natural killer (NK)/T lymphoma (ENKTL), nasal type. However, the modalities of the chemoradiotherapy combination and drug choices remain a matter of debate. We conducted a concurrent chemoradiotherapy (CCRT) study with the ESHAP (Etoposide, Steroid, High-dose Ara-C and Platinum) regimen. METHODS: An induction phase with two upfront courses of CCRT delivering a 40Gy dose of radiation concurrently with two cycles of the ESHAP chemotherapy regimen, followed by a consolidation phase with 2-3 cycles of ESHAP chemotherapy alone. RESULTS: Thirteen patients with localised ENKTL nasal type were enrolled between January 2005 and December 2014. The median age was 62years. Ten and three patients had Ann Arbor stage IE and IIE disease, respectively. They all completed the induction CCRT phase. A median of two consolidation ESHAP cycles were delivered. During consolidation, 8/13 (62%) patients had a reduction in the number of chemotherapy cycles or reduced chemotherapy doses, due to haematologically adverse events. The other five patients (38%) received the full number of ESHAP cycles of chemotherapy scheduled without a dose reduction. All but one patient (92%) experienced grade 3-4 haematological toxicity. The main non haematological grade 3-4 toxicity was mucositis in 6/13 (46%) patients. All but one patient (92%) achieved a complete remission. Two-year overall survival was 72%. CONCLUSIONS: With optimal management of the specific toxicities induced by this treatment modality, CCRT with the ESHAP regimen yielded high efficacy against localised ENKTL, nasal type. PMID- 26254811 TI - Different outcomes for relapsed versus refractory neuroblastoma after therapy with (131)I-metaiodobenzylguanidine ((131)I-MIBG). AB - BACKGROUND: (131)I-metaiodobenzylguanidine ((131)I-MIBG) is a targeted radiopharmaceutical with significant activity in high-risk relapsed and chemotherapy-refractory neuroblastoma. Our primary aim was to determine if there are differences in response rates to (131)I-MIBG between patients with relapsed and treatment-refractory neuroblastoma. METHODS: This was a retrospective cohort analysis of 218 patients with refractory or relapsed neuroblastoma treated with (131)I-MIBG at UCSF between 1996 and 2014. Results were obtained by chart review and database abstraction. Baseline characteristics and response rates between relapsed patients and refractory patients were compared using Fisher exact and Wilcoxon rank sum tests, and differences in overall survival (OS) were compared using the log-rank test. RESULTS: The response rate (complete and partial response) to (131)I-MIBG-based therapies for all patients was 27%. There was no difference in response rates between relapsed and refractory patients. However, after (131)I-MIBG, 24% of relapsed patients had progressive disease compared to only 9% of refractory patients, and 39% of relapsed patients had stable disease compared to 59% of refractory patients (p=0.02). Among all patients, the 24-month OS was 47.0% (95% confidence interval (CI) 39.9-53.9%). The 24-month OS for refractory patients was significantly higher at 65.3% (95% CI 51.8-75.9%), compared to 38.7% (95% CI 30.4-46.8%) for relapsed patients (p<0.001). CONCLUSIONS: Although there was no significant difference in overall response rates to (131)I-MIBG between patients with relapsed versusrefractory neuroblastoma, patients with prior relapse had higher rates of progressive disease and had lower 2-year overall survival after (131)I-MIBG compared to patients with refractory disease. PMID- 26254812 TI - Metastatic medulloblastoma in adults: outcome of patients treated according to the HIT2000 protocol. AB - BACKGROUND: Due to the rarity of metastatic medulloblastoma in adults, knowledge about the efficacy and toxicity of intensified chemotherapy and radiotherapy is limited. PATIENTS AND METHODS: Adults with disseminated medulloblastoma registered in the HIT2000 trial as observational patients and treated according to one of two different treatment regimens were analysed. The sandwich strategy MET-HIT2000AB4 consists of postoperative chemotherapy, hyperfractionated craniospinal radiotherapy, and maintenance chemotherapy; while the HIT'91 maintenance strategy consists of postoperative craniospinal radiotherapy, and maintenance chemotherapy. RESULTS: Twenty-three patients (median age: 30.7years), diagnosed from November 2001 to July 2009, and treated in 18 institutions in Germany and Austria, were eligible. The median follow-up of surviving patients was 3.99years. The 4-year event-free survival (EFS) and overall survival (OS)+/ standard error (SE) were 52%+/-12% and 91%+/-6%, respectively. The survival was similar in both treatment groups (HIT'91 maintenance strategy, n=9; MET HIT2000AB4 sandwich strategy, n=14). Patients with large cell/anaplastic medulloblastoma relapsed and died (n=2; 4-year EFS/OS: 0%) and OS differed compared to patients with classic (n=11; 4-year EFS/OS: 71%/91%) and desmoplastic medulloblastoma (n=10; 4-year EFS/OS: 48%/100%), respectively (p=0.161 for EFS and p=0.033 for OS). Treatment-induced toxicities consisted mainly of neurotoxicity (50% of patients, ? degrees II), followed by haematotoxicity and nephrotoxicity/ototoxicity. The professional outcome appeared to be negatively affected in the majority of evaluable patients (9/10). CONCLUSIONS: Treatment of adults with metastatic medulloblastoma according to the intensified paediatric HIT2000 protocol was feasible with acceptable toxicities. EFS rates achieved by both chemotherapeutic protocols were favourable and appear to be inferior to those obtained in older children/adolescents with metastatic disease. PMID- 26254813 TI - Thoracic Bone Tumors Every Radiologist Should Know. AB - The thoracic cage provides the structural support that makes respiration possible, provides protection to vital organs such as the lungs, heart, liver, and spleen, and serves as an anchor point for the upper extremities. Neoplasms of the bony thorax are not an uncommon incidental finding at both radiography and cross-sectional imaging. Some tumors have a characteristic appearance and it is important that an accurate differential diagnosis be provided. Misidentification could lead to unnecessary imaging or procedures with associated cost, morbidity, and mortality. The purpose of this article is to serve as a quick review of bone tumors commonly encountered in the thorax and that every radiologist should know. Please note that there are also several non-neoplastic osseous lesions that may mimic bone tumors such as osteomyelitis and eosinophilic granuloma; however, these entities are beyond the scope of this review and would not be discussed. PMID- 26254814 TI - High-mobility group box 1 enhances the inflammatory process in diabetic lung. AB - Diabetes mellitus generates metabolic changes associated with inflammatory events that may eventually affect all body tissues. Both high-mobility group box 1 (HMGB1) and beta-catenin are active players in inflammation. The study aimed to determine whether HMGB1 modulates the beta-catenin activity in supporting inflammation, using an experimental type 1 diabetes mouse model. The protein and gene expression of HMGB1 were significantly increased (2-fold) in the diabetic lung compared to control and were positively correlated with the HMGB1 levels detected in serum. Co-immunoprecipitation of HMGB1 with RAGE co-exists with activation of PI3K/AKT1 and NF-kB signaling pathways. At the same time beta catenin was increased in nuclear fraction (3.5 fold) while it was down-regulated in diabetic plasma membrane (2-fold). There was no difference of beta-catenin gene expression between the control and diabetic mice. beta-Catenin phosphorylation at Ser552 was higher in diabetic nuclear fraction, suggesting that AKT1 activation promotes beta-catenin nuclear translocation. In addition, c Jun directly binds beta-catenin indicating the transcriptional activity of beta catenin in diabetes, sustained by significantly COX2 increase by 6-fold in the cytosolic extract of diabetic lung compared to control. Taken together, the data support the new concept that HMGB1 maintains the inflammation through RAGE/AKT1/beta-catenin pathway in the diabetic lung. PMID- 26254815 TI - Homebound older adults: Prevalence, characteristics, health care utilization and quality of care. AB - The purpose of this study was to estimate prevalence rates of homebound older adults, their characteristics and the impact of homebound status on health care utilization, expenditures and quality of medical care measures. Surveys were sent to new enrollees (n = 25,725) in AARP((r)) Medicare Supplement plans (insured through UnitedHealthcare) to screen for serious chronic conditions, ambulatory disabilities and eligibility for care coordination programs. Health care utilization and expenditures were determined from paid claims. Member-level quality measures considered compliance with medication adherence and care patterns. Among survey respondents, 19.6% were classified as being homebound. The strongest predictors of being homebound included serious memory loss, being older, having more chronic conditions, taking more prescription medications and having multiple hospitalizations. Homebound had significantly higher health care utilization and expenditures. Homebound were more likely to be noncompliant with medication adherence and care pattern rules. Ongoing screening and subsequent interventions for new enrollees classified as homebound may be warranted. PMID- 26254816 TI - Stimulating translational research: several European life science institutions put their heads together. AB - Translational research leaves no-one indifferent and everyone expects a particular benefit. We as EU-LIFE (www.eu-life.eu), an alliance of 13 research institutes in European life sciences, would like to share our experience in an attempt to identify measures to promote translational research without undermining basic exploratory research and academic freedom. PMID- 26254819 TI - Comparison of a new flap design with the routinely used triangular flap design in third molar surgery. AB - The aim of this study is to introduce a new flap design in the surgical removal of impacted mandibular third molars - a lingually based triangular flap - and to compare this flap design with the routinely used triangular flap. This randomized, prospective, split-mouth study involved 22 patients with impacted bilateral mandibular third molars that were symmetrically positioned, mesially angulated, and retained in bone. The impacted teeth were removed in two sessions, using two different flap designs: the new alternative flap and the traditional triangular flap. Postoperative complications (pain, swelling, trismus, alveolar osteitis, and wound dehiscence) were recorded on days 2, 7, 14, and 21. The data obtained were analysed using the chi(2) test, the Mann-Whitney U-test, and Pearson's correlation. In terms of the severity of postoperative facial swelling and trismus, there were no statistically significant differences between the flap designs (P>0.05). The alternative flap exhibited higher pain scores at 12h post surgery (P<0.05). In addition, the alternative flap group exhibited less wound dehiscence, although this was not statistically significant. Moreover, all wound dehiscence in this group occurred on sound bone. In conclusion, these results show that this new flap design is preferable to the routinely used flap for impacted third molar surgery. PMID- 26254818 TI - The association of body shape trajectories over the life course with type 2 diabetes risk in adulthood: a group-based modeling approach. AB - PURPOSE: Low birth weight is a well-recognized risk factor for type 2 diabetes (T2D), but less is known about risks associated with the evolution of body shape throughout life with incident T2D in adulthood. METHODS: In 80,110 women from the Etude Epidemiologique aupres de femmes de la Mutuelle Generale de l'Education Nationale (E3N) cohort study, trajectories of self-reported body shapes from age 8 years to 35-40 years were derived using a group-based modeling approach and studied in relation with incident T2D. RESULTS: Compared with women who maintained a stable midrange body shape trajectory from 8 to 40 years, women in all other observed trajectories were at a higher risk of developing T2D in adulthood: The highest risk was observed for women who were lean at age 8 years and had a sharp increase in body shape (hazards ratio = 2.91 [2.35-3.62]); their T2D risk was higher (P for homogeneity = .059) than for women who maintained the largest body shape (hazards ratio = 2.18 [1.76-2.69]). CONCLUSIONS: A group-based modeling approach has identified trajectories of body shape evolution with different risks of developing T2D in adulthood. A sharp increase in body shape after puberty in previously lean girls is a risk factor for the subsequent development of diabetes. PMID- 26254820 TI - Clinical experience with 80 microvascular couplers in 64 free osteomyocutaneous flap transfers for mandibular reconstruction. AB - Microvascular couplers have been introduced as an alternative method for anastomosis in mandibular reconstruction. This study included 64 patients who had undergone free flap reconstruction for mandibular defects and had been scheduled for follow-up at 1, 3, 6, and 12 months. After completion of the tumour resection and harvesting of the osteomyocutaneous flap, appropriate preparation of both ends of the vessels was performed for microsurgery. Single-vein anastomoses were performed in 35 patients and double-vein anastomoses in 29 patients. Except for 75 couplers used for venous anastomosis only, both arterial and venous anastomoses were performed using the coupler in seven flaps. No flap failures occurred in these cases, resulting in an overall flap success rate of 100%. As expected, anastomoses were completed successfully using the coupler in 78 out of 80 attempted cases (97.5%). Additional large and randomized studies are needed to compare the outcomes of coupler anastomoses to those of traditional sutured anastomoses, and to define to what extent this would present cost-savings per procedure. PMID- 26254822 TI - Outcomes of polytetrafluoroethylene-covered stent versus bare-metal stent in the primary treatment of severe iliac artery obstructive lesions. AB - OBJECTIVE: This study compared early and midterm outcomes of polytetrafluoroethylene-covered stents (CSs) vs bare-metal stents (BMSs) in the primary treatment of severe TransAtlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) C and D iliac artery obstructive lesions. METHODS: Between January 2009 and June 2014, 128 patients underwent stenting of 167 iliac arteries; CSs were implanted in 82 iliac arteries (49%) and BMSs in 85 (51%). All patients were prospectively enrolled in a dedicated database. Thirty-day outcomes, mid-term patency, limb salvage, and survival were compared, and follow-up results were analyzed with Kaplan-Meier curves. Clinical presentation, lesion site, extension, and laterality were evaluated for their association with patency in the two groups using multiple logistic regressions. RESULTS: Patients were a mean age of 70 +/- 10.3 years, The Society for Vascular Surgery comorbidity score was 0.89 +/- 0.57, with no differences after stratification by CS and BMS (P = .17). Iliac lesions were classified by limb as TASC II C in 86 (51%) and D in 81 (49%). Comparing CS and BMS, technical success was 99% in both groups (P = 1.0); the 30-day cumulative surgical complications rate (7.3% vs 4.7%; P = .53), mortality (1.8% vs 0%; P = .45), and morbidity (1.8% vs 1.4%; P = .99) were equivalent. At 24 months (average 22 months; range, 30 days-56 months), primary patency of CS vs BMS was similar (93% vs 80%; P = .14), and this finding was maintained after stratification by TASC II C (97% vs 93%; P = .59) and D (88% vs 61%; P = .07); secondary patency was 98% vs 92% (P = .22), and limb salvage was 99% and 95% (P = .35) respectively. Multivariate analysis indicated that BMS in long-segment stenosis involving the common and external iliac arteries was a negative predictor of patency (odds ratio, 0.16; 95% confidence interval, 0.04-0.62; P = .007); within this subgroup of TASC II D lesions, primary patency at 24 months was significantly higher for CS than for BMS (88% vs 57%; P = .03). CONCLUSIONS: Overall, the use of CSs for severe iliac lesions has similar early and midterm outcomes compared with BMS. In a subcategory of TASC II D lesions with long segment severe stenosis of both the common and external iliac arteries, CS should be considered as the primary line of treatment. PMID- 26254821 TI - Subacute limb ischemia induces skeletal muscle injury in genetically susceptible mice independent of vascular density. AB - OBJECTIVE: The primary preclinical model of peripheral artery disease, which involves acute limb ischemia (ALI), can result in appreciable muscle injury that is attributed to the acuity of the ischemic injury. A less acute model of murine limb ischemia using ameroid constrictors (ACs) has been developed in an attempt to mimic the chronic nature of human disease. However, there is currently little understanding of how genetics influence muscle injury following subacute arterial occlusion in the mouse. METHODS: We investigated the influence of mouse genetics on skeletal muscle tissue survival, blood flow, and vascular density by subjecting two different mouse strains, C57BL/6 (BL6) and BALB/c, to ALI or subacute limb ischemia using single (1AC) or double (2AC) AC placement on the femoral artery. RESULTS: Similar to ALI, the 2AC model resulted in significant tissue necrosis and limb perfusion deficits in genetically susceptible BALB/c but not BL6 mice. In the 1AC model, no outward evidence of tissue necrosis was observed, and there were no differences in limb blood flow between BL6 and BALB/c. However, BALB/c mice displayed significantly greater muscle injury, as evidenced by increased inflammation and myofiber atrophy, despite having no differences in CD31(+) and SMA(+) vascular density and area. BALB/c mice also displayed significantly greater centralized myonuclei, indicating increased muscle regeneration. CONCLUSIONS: The susceptibility of skeletal muscle to ischemia-induced injury is at least partly independent of muscle blood flow and vascular density, consistent with a muscle cell autonomous response that is genetically determined. Further development of preclinical models of peripheral artery disease that more accurately reflect the nature of the human disease may allow more accurate identification of genetic targets for therapeutic intervention. PMID- 26254824 TI - Discussion. PMID- 26254823 TI - The effect of location and configuration on forearm and upper arm hemodialysis arteriovenous grafts. AB - OBJECTIVE: The arteriovenous graft (AVG) is most often used in hemodialysis patients when an autogenous fistula is not feasible. The optimal location (forearm or upper arm) and configuration (loop or straight) of AVGs are not known. To evaluate relationships of AVG location and configuration with patency, we conducted a secondary analysis using data from a randomized, placebo controlled trial of dipyridamole plus aspirin for newly placed AVG. METHODS: Participants of the Dialysis Access Consortium (DAC) Graft Study with newly placed upper extremity prosthetic grafts involving the brachial artery were studied. Multivariable analyses adjusting for trial treatment group, center, gender, race, body mass index, diabetes, current treatment with chronic dialysis, and prior arteriovenous vascular access or central venous catheter were performed to compare outcomes of forearm (fAVG) and upper arm (uAVG) grafts, including loss of primary unassisted patency (LPUP) and cumulative primary graft failure (CGF). Subgroup analyses of graft configuration and outflow vein used were also conducted. RESULTS: A total of 508 of the 649 participants (78%) enrolled in the trial had an upper extremity brachial artery graft placed, 255 with fAVG and 253 with uAVG. Participants with fAVG were less often male (33% vs 43%; P = .03), African American (62% vs 78%; P < .001), and receiving dialysis at the time of surgery (62% vs 80%; P < .001). Participants with fAVG had a higher mean body mass index (33 vs 29; P < .001). The LPUP (fAVG 70% vs uAVG 78%; P = .07) and CGF (33% vs 36%; P = .91) were similar between fAVG and uAVG at 1-year follow-up. In multivariable analysis, AVG location (uAVG vs fAVG) was not associated with LPUP (hazard ratio, 1.21; 95% confidence interval, 0.90-1.63; P = .20) or CGF (hazard ratio, 1.36; 95% confidence interval, 0.94-1.97; P = .10). LPUP did not differ significantly between fAVG and uAVG among subgroups based on AVG configuration (P = 1.00) or outflow vein used (P = .16). CONCLUSIONS: Patency was comparable between fAVG and uAVG despite the larger caliber veins often encountered in the upper arm in carefully selected patients. Our findings support the traditional view that, in order to preserve a maximal number of access sites, the forearm location should be considered first before resorting to an upper arm graft. PMID- 26254825 TI - Roles of Bcl-2 and caspase-9 and -3 in CD30-induced human eosinophil apoptosis. AB - BACKGROUND/PURPOSE: Activation of cell surface CD30 by immobilized anti-CD30 monoclonal antibodies (mAb) induces strong apoptosis in human eosinophils. This anti-CD30 mAb-induced eosinophil apoptosis is inhibited by the addition of inhibitors of p38, ERK1/2 mitogen-activated protein kinases, and phosphatidylinositol 3-kinase. However, there is little data investigating the role of Bcl-2 and caspases in eosinophil apoptosis induced by anti-CD30 mAb. We sought to determine whether anti-CD30 mAb induces human eosinophil apoptosis via Bcl-2 and caspase pathways. METHODS: Peripheral blood was drawn from 37 healthy volunteers. The CD30 expression on eosinophils was measured at various time points. Eosinophils were then cultured in plates precoated with anti-CD30 mAb (clone Ber-H8), isotype control immunoglobulin G1, interleukin (IL)-5, or dexamethasone. Western blot analysis was performed to determine the expression of Bcl-2, procaspase-8, -9, and -3, and caspase-8, -9, and -3 after cross-linking of CD30. Human eosinophils were also cultured in plates precoated with anti-CD30 mAb (clone Ber-H8) in the presence or absence of caspase-9 or -3 inhibitors. Eosinophil apoptosis was assessed using flow cytometry. RESULTS: The addition of anti-CD30 mAb significantly increased eosinophil apoptosis compared with controls. In western blot analysis, the addition of anti-CD30 mAb significantly decreased the expression of Bcl-2 and procaspase-9 and -3 and increased the expression of caspase-9 and -3. The addition of caspase-9 or -3 inhibitors decreased anti-CD30 mAb-induced human eosinophil apoptosis. Procaspase-8 or caspase-8 expression was not changed in response to various stimuli. CONCLUSION: Anti-CD30 mAb-induced human eosinophil apoptosis is likely to be mediated through Bcl-2 and caspase-9 and -3. PMID- 26254826 TI - RNA-binding residues prediction using structural features. AB - BACKGROUND: RNA-protein complexes play an essential role in many biological processes. To explore potential functions of RNA-protein complexes, it's important to identify RNA-binding residues in proteins. RESULTS: In this work, we propose a set of new structural features for RNA-binding residue prediction. A set of template patches are first extracted from RNA-binding interfaces. To construct structural features for a residue, we compare its surrounding patches with each template patch and use the accumulated distances as its structural features. These new features provide sufficient structural information of surrounding surface of a residue and they can be used to measure the structural similarity between the surface surrounding two residues. The new structural features, together with other sequence features, are used to predict RNA-binding residues using ensemble learning technique. CONCLUSIONS: The experimental results reveal the effectiveness of the proposed structural features. In addition, the clustering results on template patches exhibit distinct structural patterns of RNA-binding sites, although the sequences of template patches in the same cluster are not conserved. We speculate that RNAs may have structure preferences when binding with proteins. PMID- 26254827 TI - Non-invasive real-time prediction of inner knee temperatures during therapeutic cooling. AB - The paper addresses the issue of non-invasive real-time prediction of hidden inner body temperature variables during therapeutic cooling or heating and proposes a solution that uses computer simulations and machine learning. The proposed approach is applied on a real-world problem in the domain of biomedicine - prediction of inner knee temperatures during therapeutic cooling (cryotherapy) after anterior cruciate ligament (ACL) reconstructive surgery. A validated simulation model of the cryotherapeutic treatment is used to generate a substantial amount of diverse data from different simulation scenarios. We apply machine learning methods on the simulated data to construct a predictive model that provides a prediction for the inner temperature variable based on other system variables whose measurement is more feasible, i.e. skin temperatures. First, we perform feature ranking using the RReliefF method. Next, based on the feature ranking results, we investigate the predictive performance and time/memory efficiency of several predictive modeling methods: linear regression, regression trees, model trees, and ensembles of regression and model trees. Results have shown that using only temperatures from skin sensors as input attributes gives excellent prediction for the temperature in the knee center. Moreover, satisfying predictive accuracy is also achieved using short history of temperatures from just two skin sensors (placed anterior and posterior to the knee) as input variables. The model trees perform the best with prediction error in the same range as the accuracy of the simulated data (0.1 degrees C). Furthermore, they satisfy the requirements for small memory size and real-time response. We successfully validate the best performing model tree with real data from in vivo temperature measurement from a patient undergoing cryotherapy after ACL reconstruction. PMID- 26254828 TI - Guanidinium compounds with sub-micromolar activities against Mycobacterium tuberculosis. Synthesis, characterization and biological evaluations. AB - Seven polycharged species, incorporating 1, 2, 3, 4 and 6 guanidine arms organized around a benzene core were synthesized and assayed as anti mycobacterial agents against Mycobacterium tuberculosis. They display MIC values comprised between 25 and 12.5 MUM (close to ethambutol EMB) for the mono- and the hexa-substituted derivatives, and 0.8 MUM (close to isoniazid and streptomycin) for the tri-substituted derivative. The three bi- and the tetra-substituted analogs displayed MIC values of ca. 6.5-3.0 MUM. The latter were also evaluated against the isoniazid-resistant MYC5165 strain, resulting in highly interesting micromolar or sub-micromolar MIC, ca. 4-125 times more active than isoniazid. These preliminary results are attractive for the development of new anti-TB agents. PMID- 26254829 TI - The influence of the C5 substituent on the 2-thiouridine desulfuration pathway and the conformational analysis of the resulting 4-pyrimidinone products. AB - In recent years, increasing attention has been focused on the posttranscriptional modifications present in transfer RNAs (tRNAs), which have been suggested to constitute another level of regulation of gene expression. The most representative among them are the 5-substituted 2-thiouridines (R5S2U), which are located in the wobble position of the anticodon and play a fundamental role in the tuning of the translation process. On the other hand, sulfur-containing biomolecules are the primary site for the attack of reactive oxygen species (ROS). We have previously demonstrated that under in vitro conditions that mimic oxidative stress in the cell, the S2U alone or bound to an RNA chain undergoes desulfuration to yield uridine and 4-pyrimidinone nucleoside (H2U) products. The reaction is pH- and concentration-dependent. In this study, for the first time, we demonstrate that the substituent at the C5 position of the 2-thiouracil ring of R5S2Us influences the desulfuration pathway, and thus the products ratio. As the substituent R changes, the amount of R5H2U increases in the order H->CH3O >CH3OC(O)CH2->HOC(O)CH2NHCH2-~ CH3NHCH2-, and this effect is more pronounced at lower pH. The conformational analysis of the resulting R5H2U products indicates that independent of the nature of the R5 substituent, the R5H2U nucleosides predominantly adopt a C2'-endo sugar ring conformation, as opposed to the preferred C3'-endo conformation of the parent R5S2Us. PMID- 26254830 TI - Clinico-pathological subtypes of hippocampal sclerosis in temporal lobe epilepsy and their differential impact on memory impairment. AB - Hippocampal anatomy and network organization are capable to generate drug resistant temporal lobe epilepsy (TLE) in humans and particularly vulnerable to segmental neuronal cell loss. Surgical hippocampectomy has been proven successful in treatment and available human tissue specimens allow systematic clinico pathological examination. Different patterns of hippocampal cell loss have been identified in TLE patients and are recently classified by the International League against Epilepsy (ILAE) into four distinct subtypes in order to stratify the heterogenous group of TLE patients also with respect to postsurgical outcome. Another important aim of the international consensus classification system of hippocampal sclerosis (HS) is to gain further insights into the morpho-functional organization of human memory frequently compromised in TLE patients. PMID- 26254831 TI - Tetracycline-regulated expression of OLIG2 gene in human dental pulp stem cells lead to mouse sciatic nerve regeneration upon transplantation. AB - Numerous studies have indicated dental pulp stem cells (DPSCs) potency to differentiate into several types of cell lineages. Oligodendrocyte lineage transcription factor 2 (OLIG2) plays an important role in the oligodendrogenic pathway. In this study, a tetracycline (Tet)-inducible system expressing OLIG2 gene was transfected into human DPSCs to direct their differentiation toward oligodendrocyte progenitor cells (OPCs). Following induction, the expression of stage-specific markers was studied by Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR), immunocytochemistry and western blotting. In the following, the cells were transplanted into the mouse model of local sciatic demyelination damage by lysolecithin. Recovery of lysolecithin-induced lesions in sciatic nerve was studied by treadmill exercise, von Frey filament test and hind paw withdrawal in response to a thermal stimulus. Improvement of behavioral symptoms was efficiently observed from the second week to the sixth week post transplantation. Our findings showed that exogenous expression of the OLIG2 gene by a Tet-regulated system could be used as an efficient way to induce the differentiation of DPSCs into functional oligodendrocytes. Meanwhile, the DPSC derived OPCs have relevant therapeutic potential in the animal model of sciatic nerve injury and therefore might represent a valuable tool for stem cell-based therapy in inflammatory and degenerative diseases of the peripheral and central nervous systems (CNSs). PMID- 26254832 TI - Risk Stratification of Ruptured Abdominal Aortic Aneurysms in Patients Treated by Open Surgical Repair. AB - OBJECTIVE: The present study tested scoring models for ruptured abdominal aortic aneurysms (rAAAs) in patients treated by open surgical repair (OSR). Scores were tested in a European population to validate their applicability for predicting outcome. METHODS: Between 2002 and 2013, 92 patients with rAAAs underwent OSR and medical records were reviewed retrospectively. The Edinburgh Rupture Aneurysm Score (ERAS), Vascular Study Group of New England (VSGNE) rAAA risk score, Hardman Index, and Glasgow Aneurysm Score (GAS) were calculated and analyzed according to in hospital mortality. The discriminatory power and calibration of all models were assessed by applying the receiver operating characteristic and the Hosmer-Lemeshow test chi(2). RESULTS: An ERAS <= 1 (n = 55), 2 (n = 15) and 3 (n = 16) was associated with a mortality of 27%, 47%, and 69%, respectively. The calibration was the best of all tested scores (chi(2) = 0.44; p = .81) and the area under the curve (AUC) was 0.71 (95% CI 0.6-0.82; p = .001). A VSGNE rAAA risk score = 0 (n = 19), 1 (n = 15), 2 (n = 19), 3 (n = 25), and >= 4 (n = 9) was associated with a mortality of 11%, 20%, 32%, 72%, and 56%, and an AUC of 0.76 (95% CI 0.66-0.87; p = .001). The calibration was reduced (chi(2) = 6.9; p = .08). The GAS and Hardman Index increased stepwise with increasing in hospital mortality, but were inferior to ERAS and the VSGNE rAAA risk score. The Hardman Index showed the smallest AUC (0.68; 95% CI 0.56-0.80; p = .011) and demonstrated a lack of fit (chi(2) = 8.2; p = .04). The GAS showed good discrimination (AUC = 0.75; 95% CI 0.64-0.85; p < .001) and calibration (chi(2) = 0.85; p = .66); however, the parametric scale of GAS limits its use to classifying patients according to their risk. CONCLUSION: The present study revealed remarkable differences in survival between subgroups (10-70%) and underscores the need for risk stratification. The ERAS was favorable with striking ease of use and high accuracy in predicting outcome. PMID- 26254833 TI - Rebuttal to Drs. Markovina and Michalski. PMID- 26254834 TI - Physicians and Physician Trainees Rarely Identify or Address Overweight/Obesity in Hospitalized Children. AB - OBJECTIVES: To determine how frequently physicians identify and address overweight/obesity in hospitalized children and to compare physician documentation across training level (medical student, intern, resident, attending). STUDY DESIGN: We conducted a retrospective chart review. Using an administrative database, Centers for Disease Control and Prevention body mass index calculator, and random sampling technique, we identified a study population of 300 children aged 2-18 years with overweight/obesity hospitalized on the general medical service of a tertiary care pediatric hospital. We reviewed admission, progress, and discharge notes to determine how frequently physicians and physician trainees identified (documented in history, physical exam, or assessment) and addressed (documented in hospital or discharge plan) overweight/obesity. RESULTS: Physicians and physician trainees identified overweight/obesity in 8.3% (n = 25) and addressed it in 4% (n = 12) of 300 hospitalized children with overweight/obesity. Interns were most likely to document overweight/obesity in history (8.3% of the 266 patients they followed). Attendings were most likely to document overweight/obesity in physical examination (8.3%), assessment (4%), and plan (4%) of the 300 patients they followed. Medical students were least likely to document overweight/obesity including it in the assessment (0.4%) and plan (0.4%) of the 244 hospitalized children with overweight/obesity they followed. CONCLUSIONS: Physicians and physician trainees rarely identify or address overweight/obesity in hospitalized children. This represents a missed opportunity for both patient care and physician trainee education. PMID- 26254835 TI - Maternal Asthma, Preterm Birth, and Risk of Bronchopulmonary Dysplasia. AB - OBJECTIVE: To study the relationship between maternal asthma and the development of bronchopulmonary dysplasia (BPD). STUDY DESIGN: Using a large population-based California cohort, we investigated associations between maternal asthma and preterm birth subtype, as well as maternal asthma and BPD. We used data from 2007 2010 maternal delivery discharge records of 2 009 511 pregnancies and International Classification of Diseases, Ninth Revision codes. Preterm birth was defined as <37 weeks gestational age (GA), with subgroups of <28 weeks, 28-32 weeks, and 33-37 weeks GA, as well as preterm subtype, defined as spontaneous, medically indicated, or unknown. Linkage between the 2 California-wide datasets yielded 21 944 singleton preterm infants linked to their mother's records, allowing estimation of the risk of BPD in mothers with asthma and those without asthma. RESULTS: Maternal asthma was associated with increased odds (OR, 1.42; 95% CI, 1.38-1.46) of preterm birth at <37 weeks GA, with the greatest risk for 28-32 GA (aOR, 1.60; 95% CI, 1.47-1.74). Among 21 944 preterm infants, we did not observe an elevated risk for BPD in infants born to mothers with asthma (aOR, 1.03; 95% CI, 0.9-1.2). Stratification by maternal treatment with antenatal steroids revealed increased odds of BPD in infants whose mothers had asthma but did not receive antenatal steroids (aOR, 1.54; 95% CI, 1.15-2.06), but not in infants whose mothers had asthma and were treated with antenatal steroids (aOR, 0.85; 95% CI, 0.67-1.07). CONCLUSION: Asthma in mothers who did not receive antenatal steroid treatment is associated with an increased risk of BPD in their preterm infants. PMID- 26254837 TI - Constipation in the Critically Ill Child: Frequency and Related Factors. AB - OBJECTIVE: To analyze the incidence and factors associated with constipation in critically ill children. STUDY DESIGN: We performed a prospective observational study that included children admitted to the pediatric intensive care unit for more than 3 days. Constipation was defined as more than 3 days without a bowel movement. Relationships between constipation and demographic data; clinical severity score; use of mechanical ventilation, use of vasoconstrictors, sedatives, and muscle relaxants; nutritional data; electrolyte disturbances; and clinical course were analyzed. RESULTS: Constipation developed in 46.7% of the 150 patients studied (mean age, 34.3 +/- 7.1 months). It was most common in postoperative, older, and higher-body-weight patients, and in those with fecal continence (P < .01). Compared with patients without constipation, patients with constipation had higher severity scores and more frequently received midazolam, fentanyl, muscle relaxants, and inotropic support (P < .05). Patients with constipation also started nutrition later and with a lower volume of nutrition (P < .01). There were no between-group differences in mortality or length of pediatric intensive care unit stay. In multivariate analysis, independent factors associated with constipation were body weight (OR, 1.08; 95% CI, 1.03-1.13), Pediatric Index of Mortality 2 score (OR, 1.05; 95% CI, 1.02-1.09), admission after surgery (OR, 7.64; 95% CI, 2.56-22.81), and treatment with vasoconstrictors (OR, 10.28; 95% CI, 3.53-29.93). CONCLUSION: Constipation is common in critically ill children. Body weight, Pediatric Index of Mortality 2 clinical severity score, admission after surgery, and the need for vasoconstrictor therapy are major independent risk factors associated with constipation. PMID- 26254836 TI - Baseline Ultrasound and Clinical Correlates in Children with Cystic Fibrosis. AB - OBJECTIVE: To investigate the relationship between abdominal ultrasound findings and demographic, historical, and clinical features in children with cystic fibrosis (CF). STUDY DESIGN: Children age 3-12 years with CF without known cirrhosis, were enrolled in a prospective, multicenter study of ultrasound to predict hepatic fibrosis. Consensus ultrasound patterns were assigned by 3 radiologists as normal, heterogeneous, homogeneous, or cirrhosis. Data were derived from direct collection and US or Toronto CF registries. chi(2) or ANOVA were used to compare variables among ultrasound groups and between normal and abnormal. Logistic regression was used to study risk factors for having abnormal ultrasound. RESULTS: Findings in 719 subjects were normal (n = 590, 82.1%), heterogeneous (64, 8.9%), homogeneous (41, 5.7%), and cirrhosis (24, 3.3%). Cirrhosis (P = .0004), homogeneous (P < .0001), and heterogeneous (P = .03) were older than normal. More males were heterogeneous (P = .001). More heterogeneous (15.0%, P = .009) and cirrhosis (25.0%, P = .005) had CF-related diabetes or impaired glucose tolerance vs normal (5.4%). Early infection with Pseudomonas aeruginosa (<2 years old) was associated with a lower risk (OR 0.42, P = .0007) of abnormal. Ursodeoxycholic acid use (OR 3.69, P < .0001) and CF-related diabetes (OR 2.21, P = .019) were associated with increased risk of abnormal. CONCLUSIONS: Unsuspected cirrhosis is seen in 3.3% of young patients with CF, heterogeneous in 8.9%. Abnormal ultrasound is associated with CF-related diabetes, and early P aeruginosa is associated with normal ultrasound. Prospective assessment of these risk factors may identify potential interventional targets. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01144507. PMID- 26254838 TI - Renin-Angiotensin System Blocker Fetopathy. PMID- 26254840 TI - Screening for Genetic Testing in Breast Cancer - Are We Missing the Full Picture? PMID- 26254841 TI - POSNOC: A Randomised Trial Looking at Axillary Treatment in Women with One or Two Sentinel Nodes with Macrometastases. PMID- 26254842 TI - Myths and realities of training in obstetric emergencies. AB - Training for intrapartum emergencies is a promising strategy to reduce preventable harm during birth; however, not all training is clinically effective. Many myths have developed around such training. These principally derive from misinformed beliefs that all training must be effective, cheap, independent of context and sustainable. The current evidence base for effective training supports local, unit-based and multi-professional training, with appropriate mannequins, and practice-based tools to support the best care. Training programmes based on these principles are associated with improved clinical outcomes, but we need to understand how and why that is, and also why some training is associated with no improvements, or even deterioration in outcomes. Effective training is not cheap, but it can be cost-effective. Insurers have the fiscal power to incentivise training, but they should demand the evidence of clinical effect; aspiration and proxies alone should no longer be sufficient for funding, in any resource setting. PMID- 26254843 TI - The protective effects of beta-carotene against ischemia/reperfusion injury in rat ovarian tissue. AB - INTRODUCTION: Beta-carotene is a well-known antioxidant and precursor of Vitamin A that has a preventative role in the oxidative damage process. Our aim was to investigate the possible preventive effects of beta-carotene on oxidative damage via experimental ischemia and ischemia-reperfusion models in rat ovaries. MATERIALS AND METHODS: A traumatic vascular clamps were used for 3h to induce ischemia (Group 2, 3, 4, 5, 6, 7). The clamps were then removed to allow reperfusion for 3h (Group 3, 6, 7). Sham-operated rats (Group 1) underwent laparotomy without the induction of ischemia/reperfusion injury. Real-Time-PCR was performed to determine IL-1-beta, IL-6 and iNOS expression levels. Histopathological (H&E) and immunohistochemical staining (NF-kbeta p65) processes were then performed. Finally, SOD, GSH, and MDA levels were determined. RESULTS: Intense hemorrhagic areas were observed in both the ischemia and ischemia/reperfusion groups, whereas minimal hemorrhage was observed in the treatment groups. The ischemia and ischemia/reperfusion groups exhibited extreme immunoreactivity, detected by NF-kbeta p65 staining; this reactivity decreased after the application of beta-carotene. The expression of IL-1-beta, IL-6, and iNOS in the injury groups increased significantly, whereas a dose-dependent improvement was observed in the treatment groups. Finally, MDA levels increased significantly and SOD and GSH levels decreased drastically in the injury groups. However, these values obtained from I/R groups were normalized after beta carotene treatment. DISCUSSION: In this study, we demonstrated via molecular and biochemical parameters the protective effect of beta-carotene, which is a potent antioxidant, on the experimental ischemia-reperfusion model. PMID- 26254844 TI - Differential viability response of prokaryotes and eukaryotes to high strength pulsed magnetic stimuli. AB - The present study examines the efficacy of a high strength pulsed magnetic field (PMF) towards bacterial inactivation in vitro, without compromising eukaryotic cell viability. The differential response of prokaryotes [Staphylococcus aureus (MRSA), Staphylococcus epidermidis, and Escherichia coli], and eukaryotes [C2C12 mouse myoblasts and human mesenchymal stem cells, hMSCs] upon exposure to varying PMF stimuli (1-4 T, 30 pulses, 40 ms pulse duration) is investigated. Among the prokaryotes, ~60% and ~70% reduction was recorded in the survival of staphylococcal species and E. coli, respectively at 4 T PMF as evaluated by colony forming unit (CFU) analysis and flow cytometry. A 2-5 fold increase in intracellular ROS (reactive oxygen species) levels suggests oxidative stress as the key mediator in PMF induced bacterial death/injury. The 4 T PMF treated staphylococci also exhibited longer doubling times. Both TEM and fluorescence microscopy revealed compromised membranes of PMF exposed bacteria. Under similar PMF exposure conditions, no immediate cytotoxicity was recorded in C2C12 mouse myoblasts and hMSCs, which can be attributed to the robust resistance towards oxidative stress. The ion interference of iron containing bacterial proteins is invoked to analytically explain the PMF induced ROS accumulation in prokaryotes. Overall, this study establishes the potential of PMF as a bactericidal method without affecting eukaryotic viability. This non-invasive stimulation protocol coupled with antimicrobial agents can be integrated as a potential methodology for the localized treatment of prosthetic infections. PMID- 26254839 TI - Antenatal Magnesium and Cerebral Palsy in Preterm Infants. AB - OBJECTIVE: To evaluate the relationship of maternal antenatal magnesium sulfate (MgSO4) with neonatal cranial ultrasound abnormalities and cerebral palsy (CP). STUDY DESIGN: In a randomized trial of MgSO4 or placebo in women at high risk of preterm delivery, up to 3 cranial ultrasounds were obtained in the neonatal period. Images were reviewed by at least 2 pediatric radiologists masked to treatment and other clinical conditions. Diagnoses were predefined for intraventricular hemorrhage, periventricular leukomalacia, intracerebral echolucency or echodensity, and ventriculomegaly. CP was diagnosed at 2 years of age by standardized neurologic examination. RESULTS: Intraventricular hemorrhage, periventricular leukomalacia, intracerebral echolucency or echodensity, and ventriculomegaly were all strongly associated with an increased risk of CP. MgSO4 administration did not affect the risk of cranial ultrasound abnormality observed at 35 weeks postmenstrual age or later. However, for the 82% of infants born at <32 weeks gestation, MgSO4 was associated with a reduction in risk of echolucency or echodensity. The reduction in risk for echolucency explained 21% of the effect of MgSO4 on CP (P = .04), and for echodensity explained 20% of the effect (P = .02). CONCLUSIONS: MgSO4 given prior to preterm delivery was associated with decreased risk of developing echodensities and echolucencies at <32 weeks gestation. However, this effect can only partially explain the effect of MgSO4 on CP at 2 years of age. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00014989. PMID- 26254845 TI - Skin Carotenoid Response to a High-Carotenoid Juice in Children: A Randomized Clinical Trial. AB - BACKGROUND: Previous studies have shown an increase in serum carotenoid status among children when fed carotenoids. This study looked at the effect and dose response of a known amount of carotenoid consumption on change in skin carotenoid status among children. METHODS: Participants were children aged 5 to 17 years from Cache County, UT (n=58). Children were randomly assigned to one of three groups: high (n=18) or low (n=18) dose of a carotenoid-rich juice (2.75 mg carotenoids/30 mL juice), or placebo juice (n=22). Children were asked to drink an assigned dose of the juice (30 to 120 mL/day) based on the weight of the child and group assignment, every day for 8 weeks. Skin carotenoids were measured every 2 weeks by resonance Raman spectroscopy. Participants were asked to maintain their usual diet throughout the study. Usual diet was assessed using three averaged 24-hour recalls; diet constancy was measured using food frequency questionnaires administered at baseline, Week 4, and Week 8. Repeated measures analysis of variance was used to assess the group differences in skin carotenoid status over time. RESULTS: The high-dose and low-dose groups had mean+/-standard deviation increases in skin carotenoid status of 11,515+/-1,134 and 10,009+/ 1,439 Raman intensity counts, respectively (both P values <0.001, for change in means compared with baseline) at Week 8, although they showed significant change from baseline by Week 2. The placebo group's change of 985 Raman intensity counts was not statistically significant. The difference in change between the 2 experimental groups was not significant at Week 2, 4, 6, or 8. CONCLUSIONS: Consumption of 30 to 120 mL (2.75 to 11 mg carotenoids) of a carotenoid-rich juice significantly increased skin carotenoid status over an 8-week period among children aged 5 to 17 years. The amount of carotenoids found in this amount of juice is equal to the amount found in approximately 23 to 92 g cooked carrots per day. PMID- 26254846 TI - Patient Activation: What It Is and How Registered Dietitian Nutritionists Can Make It Happen. PMID- 26254847 TI - Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1 phosphate. AB - BACKGROUND & AIMS: Exosomes are small membrane vesicles involved in intercellular communication. Hepatocytes are known to release exosomes, but little is known about their biological function. We sought to determine if exosomes derived from hepatocytes contribute to liver repair and regeneration after injury. METHODS: Exosomes derived from primary murine hepatocytes were isolated and characterized biochemically and biophysically. Using cultures of primary hepatocytes, we tested whether hepatocyte exosomes induced proliferation of hepatocytes in vitro. Using models of ischemia/reperfusion injury and partial hepatectomy, we evaluated whether hepatocyte exosomes promote hepatocyte proliferation and liver regeneration in vivo. RESULTS: Hepatocyte exosomes, but not exosomes from other liver cell types, induce dose-dependent hepatocyte proliferation in vitro and in vivo. Mechanistically, hepatocyte exosomes directly fuse with target hepatocytes and transfer neutral ceramidase and sphingosine kinase 2 (SK2) causing increased synthesis of sphingosine-1-phosphate (S1P) within target hepatocytes. Ablation of exosomal SK prevents the proliferative effect of exosomes. After ischemia/reperfusion injury, the number of circulating exosomes with proliferative effects increases. CONCLUSIONS: Our data shows that hepatocyte derived exosomes deliver the synthetic machinery to form S1P in target hepatocytes resulting in cell proliferation and liver regeneration after ischemia/reperfusion injury or partial hepatectomy. These findings represent a potentially novel new contributing mechanism of liver regeneration and have important implications for new therapeutic approaches to acute and chronic liver disease. PMID- 26254848 TI - Scaling and contextualizing personalized healthcare: A case study of disease prediction algorithm integration. AB - Today, advances in medical informatics brought on by the increasing availability of electronic medical records (EMR) have allowed for the proliferation of data centric tools, especially in the context of personalized healthcare. While these tools have the potential to greatly improve the quality of patient care, the effective utilization of their techniques within clinical practice may encounter two significant challenges. First, the increasing amount of electronic data generated by clinical processes can impose scalability challenges for current computational tools, requiring parallel or distributed implementations of such tools to scale. Secondly, as technology becomes increasingly intertwined in clinical workflows these tools must not only operate efficiently, but also in an interpretable manner. Failure to identity areas of uncertainty or provide appropriate context creates a potentially complex situation for both physicians and patients. This paper will present a case study investigating the issues associated with first scaling a disease prediction algorithm to accommodate dataset sizes expected in large medical practices. It will then provide an analysis on the diagnoses predictions, attempting to provide contextual information to convey the certainty of the results to a physician. Finally it will investigate latent demographic features of the patient's themselves, which may have an impact on the accuracy of the diagnosis predictions. PMID- 26254849 TI - [Facial palsy rehabilitation: Assessment before surgery]. AB - A patient who needs a surgery for facial rehabilitation must have a complete assessment. The etiology of the facial palsy must be clear. It is necessary to have a MRI of the facial nerve for the statement of the initial pathology or to search a lesion on the nerve. The facial palsy must be definite which is depending of the delay of the palsy and the etiology. An electromyography must be done. The choice of the procedure depends on the delay of the palsy, the site on the nerve, the associated diseases and the opinion of the patient after a good explanation. PMID- 26254850 TI - Performance of BacT/Alert resin-based FN plus bottles compared with BacT/Alert charcoal-based FN bottles for the detection of anaerobes in experimentally seeded blood cultures. AB - Recently new resin-based BacT/Alert FAN Plus bottles containing antibiotic binding polymeric beads, were introduced as an improvement of the charcoal-based FAN bottles for the recovery of bacteria and fungi. To assess the performance of the novel anaerobic FN plus bottles in the detection of anaerobic organisms, we compared the detection rate and the time to detection (TTD) in spiked resin-based FN Plus bottles and charcoal-based FN bottles. The bottles were experimentally seeded with reference strains or clinical strains collected from positive blood cultures. Five reference strains and fifty-five clinically significant anaerobic isolates were investigated, of which 91% (61/67) showed growth in both types of bottles within an incubation time of 5 days. A significant prolonged median TTD of 45 h for anaerobic microorganisms was observed in the resin-based bottles versus 29 h in the charcoal-based bottles (P < 0.0001). Bacteroides spp., associated with higher virulence and higher mortality rates in bloodstream infections, were detected faster in the charcoal-based bottles as compared to the resin-based bottles. In conclusion recently improved resin FN bottles showed a significantly increased median TTD for the recovery of anaerobic isolates. PMID- 26254851 TI - Evaluation of isokinetic trunk muscle strength in adolescents with normal and abnormal postures. AB - OBJECTIVE: The aim of this study was to assess existing differences in the isokinetic trunk muscle strength in males and females aged between 10 and 11 years depending on body posture. METHODS: The study included 145 children (67 males and 78 females) divided into 2 age groups: 10-year-old males (x- = 9.98 +/- 2.34 years) and females (x- = 9.85 +/- 2.94 years) and 11-year-old males (x- = 11.14 +/- 2.22 years) and females (x- = 11.15 +/- 2.32 years). Posture in the sagittal plane was assessed by photogrammetry using the moire projection technique. Based on a classification system, the participants were divided into subgroups of males and females with normal and abnormal postures. Trunk muscle strength was measured using isokinetic dynamometry. RESULTS: A high prevalence of abnormal posture in children aged between 10 and 11 years was observed, primarily represented by an excessive curvature of the spine in the sagittal plane. The males and females with poor posture recorded lower values in isokinetic trunk muscle strength. CONCLUSION: The results of the study point to the need for the application of suitable physiotherapy treatment (corrective measures/exercises) to treat musculoskeletal disorders to compensate for the loss of trunk flexor muscle strength in children with improper posture. PMID- 26254852 TI - Changes in shoulder pain and disability after thrust manipulation in subjects presenting with second and third rib syndrome. AB - OBJECTIVE: The purpose of this preliminary study was to investigate changes in shoulder pain, disability, and perceived level of recovery after 2 sessions of upper thoracic and upper rib high-velocity low-amplitude (HVLA) thrust manipulation in patients with shoulder pain secondary to second and third rib syndrome. METHODS: This exploratory study evaluated 10 consecutive individuals with shoulder pain, with or without brachial pain, and a negative Neer impingement test, who completed the Shoulder Pain and Disability Index (SPADI), the numeric pain rating scale (NPRS), and the global rating of change. Patients received 2 sessions of HVLA thrust manipulation targeting the upper thoracic spine bilaterally and the second and third ribs on the symptomatic side. Outcome measures were completed after the first treatment session, at 48 hours, 1 month, and 3 months. RESULTS: Patients showed a significant decrease in SPADI (F = 59.997; P = .001) and significant decrease in resting shoulder NPRS (F = 63.439; P = .001). For both NPRS and SPADI, there were significant differences between the pretreatment scores and each of the postintervention scores through 3-month follow-up (P < .05). Large within-group effect sizes (Cohen's d >= 0.8) were found between preintervention data and all postintervention assessments in both outcomes. Mean global rating of change scores (+6.8 at 3 months) indicated "a very great deal better" outcome at long-term follow-up. CONCLUSION: This group of patients with shoulder pain secondary to second and third rib syndrome who received upper thoracic and upper rib HVLA thrust manipulations showed significant reductions in pain and disability and improvement in perceived level of recovery. PMID- 26254853 TI - Resilience mediates the relationship between depression and psychological health status in patients with heart failure: a cross-sectional study. AB - BACKGROUND: Depressive symptoms are linked to increased morbidity and mortality, and impaired health status in patients with heart failure. Elevating resilience may mitigate the negative consequences associated with depressive symptoms. However, the role of resilience in the relationship between depressive symptoms and health status in patients with heart failure remains unknown. OBJECTIVES: To examine the relationships among depressive symptoms, resilience, and physical and psychological health status in patients with heart failure and to determine whether resilience plays a mediating or moderating role in the relationship between depressive symptoms and physical and psychological health status. DESIGN: Cross-sectional study design. SETTING: Cardiac outpatient clinics in hospitals in Northern Taiwan. PARTICIPANTS: The sample comprised 128 community-dwelling and medically stable patients with echocardiographically documented heart failure. METHODS: Hierarchical multiple regressions were conducted to determine whether depressive symptoms and resilience are associated with physical and psychological health status. The moderating role of resilience was examined by testing the significance of the interaction between depressive symptoms and resilience. The mediating role of resilience was analyzed using the PROCESS procedure in SPSS. RESULTS: Depressive symptoms were significantly associated with both physical and psychological health status (both p<.01) in patients with heart failure after adjustment for sociodemographic variables, comorbidities, and the New York Heart Association functional class. Furthermore, resilience mediated the relationship between depressive symptoms and psychological health status (b=-0.05; confidence interval: -0.01, -0.001) but not that between depressive symptoms and physical health status (b=-0.004; confidence interval: -0.003, 0.003). CONCLUSIONS: Depressive symptoms are risk factors for poor health status in patients with heart failure. However, enhancing resilience may facilitate improving psychological health status in patients with depression and heart failure. Future studies should investigate further the design and feasibility of resilience focused interventions for patients with depression and heart failure. PMID- 26254854 TI - Interleukin-1 alpha variation is associated with the risk of developing preeclampsia. AB - OBJECTIVE: Preeclampsia is a syndrome that affects 5% of all pregnancies, producing substantial maternal and prenatal morbidity and mortality. Several studies have reported that cytokine genes are associated with the persistence of preeclampsia or the severity of the disease. The aim of this study is to investigate the relationships between the polymorphisms of interleukin-1 alpha 889 (IL-1A) gene and preeclampsia. METHOD: Genomic DNA was extracted from the peripheral blood of 305 patients with preeclampsia and 325 normal controls from Sayyad Shirazi Hospital of Golestan University. Then subjected to SSP-PCR amplification. STATA software and the chi square test were used for statistic calculations. RESULTS: The frequencies of IL-1A -889 genotypes C/C, T/T and C/T in preeclampsia cases were 34.8%, 8.2%, 57% and in controls were 20.9%, 7.6% and 71.3% respectively. There was a significant 1.5 fold excess frequency in genotype C/C in cases (CI=1.44-3.07, OR=2.1, P=0.0001). There was a significant difference in the frequencies of alleles or genotypes in IL-1A promoter regions between patients with preeclampsia and the control group. Turkomans showed the highest frequency of the C allele and Sistanies had the lowest frequency of the C allele in preeclampsia compared to control groups (CI=1.5-3.9, OR=2.48, P=0.0001). CONCLUSION: Our findings suggest that the IL-1A-899C/C genotype and C allele are associated with susceptibility to preeclampsia. PMID- 26254855 TI - Maternal C-reactive protein in early pregnancy. AB - OBJECTIVE: To compare maternal C-reactive protein concentration in the first 18 weeks of pregnancy with the nonpregnant adult reference range. STUDY DESIGN: Serum samples from healthy women with a pregnancy <18 weeks' gestation were retrieved from a Hospital biological resource bank. C-reactive protein was measured using an immunoturbidimetric assay. Clinical and sociodemographic details were retrieved from the Hospital's computerized database. RESULTS: Of the 146 women, 85 (58.2%) were nulliparous, 11 (7.5%) were smokers and 22 (15.1%) were obese. Mean gestational age at phlebotomy was 12.5 (range 8.1-17.4) weeks. Median C-reactive protein was 3.2 (interquartile range 0.3-12.1)mg/L. There were 74 women (50.7%) with C-reactive protein level >3.0mg/L which is above the nonpregnant adult reference range. C-reactive protein levels were positively correlated with increasing Body Mass Index. No relationship was found between C reactive protein and age, smoking or gestational age. CONCLUSION: C-reactive protein concentration in a well-characterized population in early pregnancy was higher than that cited for the nonpregnant adult, and C-reactive protein was positively associated with Body Mass Index. Therefore, caution is needed in the use and interpretation of C-reactive protein measurements in early pregnancy to avoid unnecessary interventions in women with suspected illness. PMID- 26254856 TI - Is colposcopic evaluation necessary in all women with postcoital bleeding? AB - OBJECTIVE: To evaluate what extent postcoital bleeding (PCB) is an indicator of cervical cancer (CIN2 (+)). METHODS: This is a retrospective cohort study. Between 2007 and 2013, amongst all referred patients, a total of 1491 consecutive women who had both conventional cytology and cervical biopsy were enrolled in the study. Of those 237 women have PCB, according to biopsy results, subjects were divided into two groups: CIN1 (-) and CIN2 (+). Multiple logistic regressions was used to construct a model to predict the occurrence of CIN 2 (+) based on age, menopause, marriage status, smoking, PCB, HPV and cytology. RESULTS: Among the all women with CIN 2 (+) colposcopy guided biopsy result, PCB was 13.1% (53/406). The relationship between biopsy results and age, parity, menopausal status, marital status, smoking, presence of PCB, HPV DNA, and cytology is statistically significant (p=0.012, p=0.001, p=0.023, 0.013, p>0.001, p=0.038, p<0.001, p<0.001, respectively). According to regression analysis only smoking, HPV (+) and abnormal cytology increase the probability of CIN2 (+); 1.687 times (p=0.018), 4.065 times (p<0.001), 5.787 times (p=0.001) respectively. Having PCB only does not indicate an increased risk of CIN2 (+). CONCLUSION: Colposcopic examination and biopsy should be performed only in the situation where women have PCB and any of the following: smoking, positive HPV, or abnormal cytology. PMID- 26254857 TI - Design and synthesis of a novel glycosphingolipid derived from polyhydroxy 2 pyrrolidinone and phytoceramide appended by a 1,2,3-triazole linker. AB - Synthetic analogs of glycosphingolipids (GSLs) have been demonstrated as potential therapeutic interventions in certain patho-physiological conditions. This article reviews reports of various bioactive synthetic GSLs, emanated from the Bittman laboratory. KRN7000, a synthetic GSL which is a alpha galactosylceramide (alpha-GalCer) is a potent immunomodulatory agent. Bittman et al. reported several modifications of C-glycosides of KRN7000 with an eye towards achieving selective cytokine response during iNKT cell activation. However, GSLs with azasugar variants were not explored which inspired us to derive a polyhydroxy 2-pyrrolidinone azasugar from d-galactose and append to the phytoceramide via a 1,2,3-triazole linker to afford GSL analog 12. This novel GSL analog 12 may be used to explore the immunomodulatory activity, and other biological activities against targets involving iminosugar or azasugar based therapeutics. PMID- 26254858 TI - Synthesis and antiproliferative properties of a new ceramide analog of varacin. AB - A benzopentasulfane was synthesized in 8 steps with a ceramide attached through an amide bond to the 7-position of the heterocycle structure. The anticancer activity of this synthetic ceramide-benzopolysulfane drug conjugate was analyzed against five human cancer cell lines MDA-MB-231 (breast), DU145 (prostate), MIA PaCa-2 (pancreas), HeLa (cervix), and U251 (glioblastoma). The ceramide benzopolysulfane conjugate had IC50 values ranging from 10 to >20 MUM with complete cell killing at 12.5 MUM for MDA-MB-231 and 20 MUM for DU145 and HeLa cells. The ceramide-benzopolysulfane conjugate had IC50 values 1.8 and 4.0 times lower than a PEG benzopolysulfane, N-(2-(2-(2 methoxyethoxy)ethoxy)ethyl)benzo[f][1,2,3,4,5]-pentathiepine-7-carboxamide, for MDA-MB-231 and DU145 cells, respectively. The parent "unsubstituted" benzopolysulfane, o-C6H4S5, had IC50 values 4.2 times lower and 2.7 times higher than the ceramide benzopolysulfane for MDA-MB-231 and DU145 cells, respectively. The results indicate that the polysulfur linkage is needed for activity since benzenedithiol, o-C6H4(SH)2, had IC50 values greater than 30 MUM with little effect on MDA-MB-231 and DU145 cells. Thus, to account for the bioactivity, a bimolecular reaction of cellular thiol with the ceramide benzopolysulfane is a proposed followed by thiozone (S3) extrusion. PMID- 26254860 TI - T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse. AB - More studies are required to develop therapeutic agents for treating spinocerebellar ataxia type 3 (SCA3), which is caused by mutant polyglutamine expanded ataxin-3 and is the most prevalent subtype of spinocerebellar ataxias. T1-11 [N6-(4-Hydroxybenzyl) adenosine], isolated from a Chinese medicinal herb Gastordia elata, is an adenosine A2A receptor agonist. SCA3 and Huntington's disease (HD) belong to a family of polyglutamine neurodegenerative diseases. T1 11 exerted a therapeutic effect on HD transgenic mouse by decreasing protein level of polyglutamine-expanded huntingtin in the striatum. In the present study, we test the possibility that T1-11 or JMF1907 [N6-(3-Indolylethyl) adenosine], a synthetic analog of T1-11, alleviates pontine neuronal death, cerebellar transcriptional downregulation and ataxic symptom in the SCA3 transgenic mouse expressing HA-tagged polyglutamine-expanded ataxin-3-Q79 (ataxin-3-Q79HA). Daily oral administration of T1-11 or JMF1907 prevented neuronal death of pontine nuclei in the SCA3 mouse with a dose-dependent manner. Oral application of T1-11 or JMF1907 reversed mutant ataxin-3-Q79-induced cerebellar transcriptional repression in the SCA3 transgenic mouse. T1-11 or JMF1907 ameliorated the symptom of motor incoordination displayed by SCA3 mouse. Oral administration of T1-11 or JMF1907 significantly decreased protein level of ataxin-3-Q79HA in the pontine nuclei or cerebellum of SCA3 mouse. T1-11 or JMF1907 significantly augmented the chymotrypsin-like activity of proteasome in the pontine nuclei or cerebellum of SCA3 mouse. Our results suggests that T1-11 and JMF1907 alleviate pontine neuronal death, cerebellar transcriptional downregulation and ataxic symptom of SCA3 transgenic mouse by augmenting the proteasome activity and reducing the protein level of polyglutamine-expanded ataxin-3-Q79 in the pontine nuclei and cerebellum. PMID- 26254859 TI - Dual allosteric modulation of opioid antinociceptive potency by alpha2A adrenoceptors. AB - Opioid and alpha2-adrenoceptor (AR) agonists are analgesic when administered in the spinal cord and show a clinically beneficial synergistic interaction when co administered. However, alpha2-AR antagonists can also inhibit opioid antinociception, suggesting a complex interaction between the two systems. The alpha2A-AR subtype is necessary for spinal adrenergic analgesia and synergy with opioids for most agonist combinations. Therefore, we investigated whether spinal opioid antinociception and opioid-adrenergic synergy were under allosteric control of the alpha2A-AR. Drugs were administered intrathecally in wild type (WT) and alpha2A-knock-out (KO) mice and antinociception was measured using the hot water tail immersion or substance P behavioral assays. The alpha2A-AR agonist clonidine was less effective in alpha2A-KO mice in both assays. The absence of the alpha2A-AR resulted in 10-70-fold increases in the antinociceptive potency of the opioid agonists morphine and DeltII. In contrast, neither morphine nor DeltII synergized with clonidine in alpha2A-KO mice, indicating that the alpha2AAR has both positive and negative modulatory effects on opioid antinociception. Depletion of descending adrenergic terminals with 6-OHDA resulted in a significant decrease in morphine efficacy in WT but not in alpha2A-KO mice, suggesting that endogenous norepinephrine acts through the alpha2A-AR to facilitate morphine antinociception. Based on these findings, we propose a model whereby ligand-occupied versus ligand-free alpha2A-AR produce distinct patterns of modulation of opioid receptor activation. In this model, agonist-occupied alpha2A-ARs potentiate opioid analgesia, while non-occupied alpha2A-ARs inhibit opioid analgesia. Exploiting such interactions between the two receptors could lead to the development of better pharmacological treatments for pain management. PMID- 26254861 TI - Contribution of nitric oxide-dependent guanylate cyclase and reactive oxygen species signaling pathways to desensitization of MU-opioid receptors in the rat locus coeruleus. AB - Nitric oxide (NO) is involved in desensitization of MU-opioid receptors (MOR). We used extracellular recordings in vitro to unmask the NO-dependent pathways involved in MOR desensitization in the rat locus coeruleus (LC). Perfusion with ME (3 and 10 MUM) concentration-dependently reduced subsequent ME effect, indicative of MOR desensitization. ME (3 MUM)-induced desensitization was enhanced by a NO donor (DEA/NO 100 MUM), two soluble guanylate cyclase (sGC) activators (A 350619 30 MUM and BAY 418543 1 MUM) or a cGMP-dependent protein kinase (PKG) activator (8-pCPT-cGMP 30 MUM). DEA/NO-induced enhancement was blocked by the sGC inhibitor NS 2028 (10 MUM). A 350619 effect was also blocked by NS 2028, but not by the antioxidant Trolox. ME (10 MUM)-induced desensitization was blocked by the neuronal NO synthase inhibitor 7-NI (100 MUM) and restored by the PKG activator 8-Br-cGMP (100-300 MUM). Paradoxically, ME (10 MUM)-induced desensitization was not modified by sGC inhibitors (NS 2028 and ODQ), PKG inhibitors (H8 and Rp-8-Br-PET-cGMP) or antioxidant agents (Trolox, U 74389G and melatonin), but it was attenuated by a combination of NS 2028 and Trolox. In conclusion, MOR desensitization in the LC may be mediated or regulated by NO through sGC and reactive oxygen species signaling pathways. PMID- 26254862 TI - Regulation of alternative gene transcription in the striatum in response to antidepressant drugs. AB - The mechanisms that control the selection of transcription initiation and termination sites in response to pharmacological stimulation of neuronal cells are poorly understood. We used next-generation sequencing and bioinformatics to construct a genome-wide inventory of protein-coding and non-coding transcripts altered by antidepressant treatment. We analyzed available ChIP-seq data to identify mechanisms that control drug-inducible expression of alternative gene variants in the brain. We identified 153 transcripts of various biotypes regulated in the mouse striatum in response to tranylcypromine or mianserin (at a 0.1% FDR threshold). Five drug-responsive gene patterns are enriched in protein coding variants (77%), regulated by different sets of transcriptional factors (including SRF/CREB1 and GR/CTCF) and expressed in separate cellular compartments of the brain. We found that alterations mediated by proximal promoters in neurons are more specific in the selection of regulated transcriptional isoforms compared with enhancer-dependent alterations in glia. The change in transcriptional programs, from housekeeping to inducible, provides cells with the resource of functionally distinct proteins. We conclude that the regulation of drug-induced brain plasticity may occur at the level of transcripts rather than genes. The expression of specific isoforms in response to antidepressants may constitute a trigger that initiates the long-lasting effects of these drugs. PMID- 26254863 TI - Contribution of brain serotonin subtype 1B receptors in levodopa-induced motor complications. AB - L-DOPA-induced dyskinesias (LID) are abnormal involuntary movements limiting the chronic use of L-DOPA, the main pharmacological treatment of Parkinson's disease. Serotonin receptors are implicated in the development of LID and modulation of basal ganglia 5-HT1B receptors is a potential therapeutic alternative in Parkinson's disease. In the present study, we used receptor-binding autoradiography of the 5-HT1B-selective radioligand [3H]GR125743 to investigate possible contributions of changes in ligand binding of this receptor in LID in post-mortem brain specimens from Parkinson's disease patients (n=14) and control subjects (n=11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned monkeys treated with saline (n=5), L-DOPA (n=4) or L-DOPA+2-methyl-6 (phenylethynyl)pyridine (MPEP) (n=5), and control monkeys (n=4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist and has been shown to reduce the development of LID in these monkeys in a chronic treatment of one month. [3H]GR125743 specific binding to striatal and pallidal 5-HT1B receptors respectively were only increased in L-DOPA-treated MPTP monkeys (dyskinetic monkeys) as compared to controls, saline and L-DOPA+MPEP MPTP monkeys; dyskinesias scores correlated positively with this binding. Parkinson's disease patients with motor complications (L-DOPA-induced dyskinesias and wearing off) had higher [3H]GR125743 specific binding compared to those without motor complications and controls in the basal ganglia. Reduction of motor complications was associated with normal striatal 5-HT1B receptors, suggesting the potential of this receptor for the management of motor complications in Parkinson's disease. PMID- 26254864 TI - Chediak-Higashi syndrome presenting in accelerated phase: A case report and literature review. AB - Chediak-Higashi syndrome (CHS) is a rare autosomal recessive lysosomal disorder characterized by frequent infections, oculocutaneous albinism, bleeding diathesis, and progressive neurologic deterioration. In 85% of cases, CHS patients develop the accelerated phase characterized by pancytopenia, high fever, and lymphohistiocytic infiltration of liver, spleen, and lymph nodes. Treatment of accelerated-phase CHS is difficult and the prognosis is poor. Here, we report a case of CHS in a 2-year-old boy who presented in the accelerated phase of the disease. CHS diagnosis was made on the basis of clinical characteristics, hair analysis, and identification of pathognomonic giant azurophilic granules in peripheral blood and bone marrow. PMID- 26254865 TI - Dusty trephine. PMID- 26254866 TI - Mass preparation and novel visible light photocatalytic activity of C and Ag Co modified ZnO nanocrystals. AB - A combustion method was developed to synthesize the C and Ag co-modified ZnO NCs to enhance its photocatalytic efficiency and practicability. The results showed that the doped Ag was significant to promote the photocatalytic activity, and the optimum content was 2% molar ratio of Ag to Zn atom. The degradation rate under visible light increased by 150% compared with C-ZnO NCs, while by more 1233.3% than pure ZnO photocatalyst. There were some new little particles with grain size about 10 nm on the C-ZnO NCs surface, which may state for the existence of Ag atoms. The synergy effect of Ag and carbon elements was proposed to explain the mechanism of enhanced photocatalytic performance under visible light irradiation. PMID- 26254867 TI - Crosslinking to enhance colloidal stability and redispersity of layered double hydroxide nanoparticles. AB - This article introduces a strategy for stabilizing and redispersing layered double hydroxide (LDH) nanoparticles by crosslinking bovine serum albumin (BSA) coated onto the surface. The strategy involves optimization of the amount of the crosslinking agent glutaraldehyde (GTA) to achieve minimal aggregation and ready redispersion. LDH nanoparticles were prepared by co-precipitation and hydrothermal treatment, with subsequent BSA coating at the BSA/LDH mass ratio of 5:2. BSA coated onto LDH nanoparticles was crosslinked with different amounts of GTA. Aggregation studies using dilution assays, dynamic light scattering, and zeta potential analysis indicated that severe aggregation at lower LDH nanoparticle concentrations can be prevented by proper crosslinking of BSA with GTA. The GTA-crosslinked BSA-coated nanoparticles showed excellent redispersity compared to the non-crosslinked nanoparticles. In vitro cytotoxicity and cell uptake were found to be minimally affected by GTA-crosslinking. The new strategy therefore provides a much more effective method for the prevention of LDH nanoparticle aggregation and improved LDH nanoparticle redispersion for use in a wide variety of bio-applications in vitro and in vivo. PMID- 26254868 TI - Structural and thermal properties of inorganic-organic montmorillonite: Implications for their potential environmental applications. AB - Inorganic-organic clays (IOCs), clays intercalated with both organic cations such as cationic surfactants and inorganic cations such as metal hydroxy polycations have the properties of both organic and pillared clays, and thereby the ability to remove both inorganic and organic contaminants from water simultaneously. In this study, IOCs were synthesised using three different methods with different surfactant concentrations. Octadecyltrimethylammonium bromide (ODTMA) and hydroxy aluminium ([Al13O4(OH)24(H2O)12](7+) or Al13) are used as the organic and inorganic modifiers (intercalation agents). According to the results, the interlayer distance, the surfactant loading amount and the Al/Si ratio of IOCs strictly depend on the intercalation method and the intercalation agent ratio. Interlayers of IOCs synthesised by intercalating ODTMA before Al13 and IOCs synthesised by simultaneous intercalation of ODTMA and Al13 were increased with increasing the ODTMA concentration used in the synthesis procedure and comparatively high loading amounts could be observed in them. In contrast, Al/Si decreased with increasing ODTMA concentration in these two types of IOCs. The results suggest that Al-pillars can be fixed within the interlayers by calcination and any increment in the amount of ODTMA used in the synthesis procedure did not affect the interlayer distance of the IOCs. Overall the study provides valuable insights into the structure and properties of the IOCs and their potential environmental applications. PMID- 26254869 TI - The role of the Kolliker-Fuse nuclei in the determination of abdominal motor output in a perfused brainstem preparation of juvenile rat. AB - The abdominal muscles are largely quiescent during normal breathing but may exhibit tonic activity or subtle respiratory modulation. The origin of baseline abdominal motor nerve activity (AbNA) if present remains uncharacterised. The contribution of the Kolliker-Fuse nucleus (KF) in the dorsolateral pons in the patterning and amplitude of AbNA was investigated using in situ perfused brainstem preparations of juvenile rats (n=12). Two types of AbNA were observed: Type I - expiratory-modulated (n=7), and Type II - weakly inspiratory/post inspiratory-modulated (n=5). Despite this, all preparations exhibited the same bi phasic late expiratory/postinspiratory bursts upon elicitation of the peripheral chemoreflex. Interestingly, the type of AbNA exhibited correlated with postinspiratory duration. Targeted microinjections of GABA-A receptor agonist isoguvacine (10mM; 70nl) into KF however did not significantly modify pattern or amplitude of baseline AbNA in either Type besides the selective abolition of the postinspiratory phase and, consequently, postinspiratory modulation in AbNAwhen present. In sum, the KF is not a major contributorin setting baseline abdominal motor output. PMID- 26254870 TI - Inclusion of methoxy groups inverts the thermodynamic stabilities of DNA-RNA hybrid duplexes: A molecular dynamics simulation study. AB - Modified nucleic acids have found profound applications in nucleic acid based technologies such as antisense and antiviral therapies. Previous studies on chemically modified nucleic acids have suggested that modifications incorporated in furanose sugar especially at 2'-position attribute special properties to nucleic acids when compared to other modifications. 2'-O-methyl modification to deoxyribose sugars of DNA-RNA hybrids is one such modification that increases nucleic acid stability and has become an attractive class of compounds for potential antisense applications. It has been reported that modification of DNA strands with 2'-O-methyl group reverses the thermodynamic stability of DNA-RNA hybrid duplexes. Molecular dynamics simulations have been performed on two hybrid duplexes (DR and RD) which differ from each other and 2'-O-methyl modified counterparts to investigate the effect of 2'-O-methyl modification on their duplex stability. The results obtained suggest that the modification drives the conformations of both the hybrid duplexes towards A-RNA like conformation. The modified hybrid duplexes exhibit significantly contrasting dynamics and hydration patterns compared to respective parent duplexes. In line with the experimental results, the relative binding free energies suggest that the introduced modifications stabilize the less stable DR hybrid, but destabilize the more stable RD duplex. Binding free energy calculations suggest that the increased hydrophobicity is primarily responsible for the reversal of thermodynamic stability of hybrid duplexes. Free energy component analysis further provides insights into the stability of modified duplexes. PMID- 26254871 TI - Transcriptional dysregulation in Huntington's disease: The role of histone deacetylases. AB - Huntington's disease (HD) is a progressive neurological disorder for which there are no disease-modifying treatments. Although, the exact underlying mechanism(s) leading to the neural cell death in HD still remains elusive, the transcriptional dysregulation is a major molecular feature. Recently, the transcriptional activation and repression regulated by chromatin acetylation has been found to be impaired in HD pathology. The acetylation and deacetylation of histone proteins is carried out by opposing actions of histone acetyl-transferases and histone deacetylases (HDACs), respectively. Studies carried out in cell culture, yeast, Drosophila and rodent model(s) have indicated that HDAC inhibitors (HDACIs) might provide useful class of therapeutic agents for HD. Clinical trials have also reported the beneficial effects of HDACIs in patients suffering from HD. Therefore, the development of HDACIs as therapeutics for HD has been vigorously pursued. In this review, we highlight and summarize the putative role of HDACs in HD like pathology and further discuss the potential of HDACIs as new therapeutic avenues for the treatment of HD. PMID- 26254873 TI - How Fast Should an Animal Run When Escaping? An Optimality Model Based on the Trade-Off Between Speed and Accuracy. AB - How fast should animals move when trying to survive? Although many studies have examined how fast animals can move, the fastest speed is not always best. For example, an individual escaping from a predator must run fast enough to escape, but not so fast that it slips and falls. To explore this idea, we developed a simple mathematical model that predicts the optimal speed for an individual running from a predator along a straight beam. A beam was used as a proxy for straight-line running with severe consequences for missteps. We assumed that success, defined as reaching the end of the beam, had two broad requirements: (1) running fast enough to escape a predator, and (2) minimizing the probability of making a mistake that would compromise speed. Our model can be tailored to different systems by revising the predator's maximal speed, the prey's stride length and motor coordination, and the dimensions of the beam. Our model predicts that animals should run slower when the beam is narrower or when coordination is worse. PMID- 26254874 TI - Risk factors and practices contributing to newborn sepsis in a rural district of Eastern Uganda, August 2013: a cross sectional study. AB - BACKGROUND: In Uganda, newborn deaths constituted over 38% of all infant deaths in 2010. Despite different mitigation interventions over years, the newborn mortality rate is high at 27/1,000 and newborn sepsis contributes to 31% of that mortality. Therefore, improved strategies that contribute to reduction of newborn sepsis need to be developed and implemented. Understanding the context relevant risk factors that determine and practices contributing to newborn sepsis will inform this process. METHODOLOGY: A cross sectional study was conducted at Kidera Health Centre in Kidera Sub County, Buyende district between January and August 2013. A total of 174 mothers of sick newborns and 8 health workers were interviewed. Main outcome was newborn sepsis confirmed by blood culture. Independent variables included; mothers' demographics characteristics, maternal care history and newborn care practices. The odds ratios were used to measure associations and Chi square or Fisher's exact tests to test the associations. 95% confidence intervals and P values for the odds ratios were determined. Logistic regression was conducted to identify predictor factors for newborn sepsis. RESULTS: 21.8% (38/174) of newborns had laboratory confirmed sepsis. Staphylococcus aureus was the commonest aetiological agent. Mothers not screened and treated for infections during antenatal (OR = 3.37; 95% CI 1.23-9.22) plus inability of sick newborns to breast feed (OR = 3.9; 95% CI 1.54-9.75) were factors associated with increased likelihood of having laboratory confirmed sepsis. Women not receiving health education during antenatal about care seeking (OR 2.22; 95% CI 1.07-4.61) and newborn danger signs (OR 2.26; 95% CI 1.08-4.71) was associated with laboratory confirmed newborn sepsis. The supply of antibiotics and sundries was inadequate to sufficiently control sepsis within health facility. CONCLUSION: Lack of antenatal care or access to it at health facilities was likely to later result in more sick newborns with sepsis. Poor breastfeeding by sick newborns was a marker for serious bacterial infection. Therefore district sensitization programs should encourage women to attend health facility antenatal care where they will receive health education about alternative feeding practices, screening and treatment for infections to prevent spread of infections to newborns. Supply of antibiotics and sundries should be improved to sufficiently control sepsis within the health facility. PMID- 26254872 TI - From cultured to uncultured genome sequences: metagenomics and modeling microbial ecosystems. AB - Microorganisms and the viruses that infect them are the most numerous biological entities on Earth and enclose its greatest biodiversity and genetic reservoir. With strength in their numbers, these microscopic organisms are major players in the cycles of energy and matter that sustain all life. Scientists have only scratched the surface of this vast microbial world through culture-dependent methods. Recent developments in generating metagenomes, large random samples of nucleic acid sequences isolated directly from the environment, are providing comprehensive portraits of the composition, structure, and functioning of microbial communities. Moreover, advances in metagenomic analysis have created the possibility of obtaining complete or nearly complete genome sequences from uncultured microorganisms, providing important means to study their biology, ecology, and evolution. Here we review some of the recent developments in the field of metagenomics, focusing on the discovery of genetic novelty and on methods for obtaining uncultured genome sequences, including through the recycling of previously published datasets. Moreover we discuss how metagenomics has become a core scientific tool to characterize eco-evolutionary patterns of microbial ecosystems, thus allowing us to simultaneously discover new microbes and study their natural communities. We conclude by discussing general guidelines and challenges for modeling the interactions between uncultured microorganisms and viruses based on the information contained in their genome sequences. These models will significantly advance our understanding of the functioning of microbial ecosystems and the roles of microbes in the environment. PMID- 26254875 TI - Computer versus physician identification of gastrointestinal alarm features. AB - OBJECTIVE: It is important for clinicians to inquire about "alarm features" as it may identify those at risk for organic disease and who require additional diagnostic workup. We developed a computer algorithm called Automated Evaluation of Gastrointestinal Symptoms (AEGIS) that systematically collects patient gastrointestinal (GI) symptoms and alarm features, and then "translates" the information into a history of present illness (HPI). Our study's objective was to compare the number of alarms documented by physicians during usual care vs. that collected by AEGIS. METHODS: We performed a cross-sectional study with a paired sample design among patients visiting adult GI clinics. Participants first received usual care by their physicians and then completed AEGIS. Each individual thus contributed both a physician-documented and computer-generated HPI. Blinded physician reviewers enumerated the positive alarm features (hematochezia, melena, hematemesis, unintentional weight loss, decreased appetite, and fevers) mentioned in each HPI. We compared the number of documented alarms within patient using the Wilcoxon signed-rank test. RESULTS: Seventy-five patients had both physician and AEGIS HPIs. AEGIS identified more patients with positive alarm features compared to physicians (53% vs. 27%; p<.001). AEGIS also documented more positive alarms (median 1, interquartile range [IQR] 0-2) vs. physicians (median 0, IQR 0-1; p<.001). Moreover, clinicians documented only 30% of the positive alarms self reported by patients through AEGIS. CONCLUSIONS: Physicians documented less than one-third of red flags reported by patients through a computer algorithm. These data indicate that physicians may under report alarm features and that computerized "checklists" could complement standard HPIs to bolster clinical care. PMID- 26254876 TI - NLP based congestive heart failure case finding: A prospective analysis on statewide electronic medical records. AB - BACKGROUND: In order to proactively manage congestive heart failure (CHF) patients, an effective CHF case finding algorithm is required to process both structured and unstructured electronic medical records (EMR) to allow complementary and cost-efficient identification of CHF patients. METHODS AND RESULTS: We set to identify CHF cases from both EMR codified and natural language processing (NLP) found cases. Using narrative clinical notes from all Maine Health Information Exchange (HIE) patients, the NLP case finding algorithm was retrospectively (July 1, 2012-June 30, 2013) developed with a random subset of HIE associated facilities, and blind-tested with the remaining facilities. The NLP based method was integrated into a live HIE population exploration system and validated prospectively (July 1, 2013-June 30, 2014). Total of 18,295 codified CHF patients were included in Maine HIE. Among the 253,803 subjects without CHF codings, our case finding algorithm prospectively identified 2411 uncodified CHF cases. The positive predictive value (PPV) is 0.914, and 70.1% of these 2411 cases were found to be with CHF histories in the clinical notes. CONCLUSIONS: A CHF case finding algorithm was developed, tested and prospectively validated. The successful integration of the CHF case findings algorithm into the Maine HIE live system is expected to improve the Maine CHF care. PMID- 26254877 TI - Assessing cognitive function following medial prefrontal stroke in the rat. AB - Cognitive impairments are prevalent following clinical stroke; however, preclinical research has focused almost exclusively on motor deficits. In order to conduct systematic evaluations into the nature of post-stroke cognitive dysfunction and recovery, it is crucial to develop focal stroke models that predominantly affect cognition while leaving motor function intact. Herein, we evaluated a range of cognitive functions 1-4 months following focal medial prefrontal cortex (mPFC) stroke using a battery of tests. Male Sprague-Dawley rats underwent focal ischemia induced in the mPFC using bilateral intracerebral injections of endothelin-1, or sham surgery. Cognitive function was assessed using an open field, several object recognition tests, attentional set-shifting, light-dark box, spontaneous alternation, Barnes maze, and win-shift/win-stay tests. Prefrontal cortex damage resulted in significant changes in object recognition function, behavioural flexibility, and anxiety-like behaviour, while spontaneous alternation and locomotor function remained intact. These deficits are similar to the cognitive deficits following stroke in humans. Our results suggest that this model may be useful for identifying and developing potential therapies for improving post-stroke cognitive dysfunction. PMID- 26254878 TI - From amusic to musical?--Improving pitch memory in congenital amusia with transcranial alternating current stimulation. AB - Brain imaging studies highlighted structural differences in congenital amusia, a life-long perceptual disorder that is associated with pitch perception and pitch memory deficits. A functional anomaly characterized by decreased low gamma oscillations (30-40 Hz range) in the right dorsolateral prefrontal cortex (DLPFC) during pitch memory has been revealed recently. Thus, the present study investigates whether applying transcranial alternating current stimulation (tACS) at 35 Hz to the right DLPFC would improve pitch memory. Nine amusics took part in two tACS sessions (either 35 Hz or 90 Hz) and completed a pitch and visual memory task before and during stimulation. 35 Hz stimulation facilitated pitch memory significantly. No modulation effects were found with 90 Hz stimulation or on the visual task. While amusics showed a selective impairment of pitch memory before stimulation, the performance during 35 Hz stimulation was not significantly different to healthy controls anymore. Taken together, the study shows that modulating the right DLPFC with 35 Hz tACS in congenital amusia selectively improves pitch memory performance supporting the hypothesis that decreased gamma oscillations within the DLPFC are causally involved in disturbed pitch memory and highlight the potential use of tACS to interact with cognitive processes. PMID- 26254879 TI - A Comparative Study of the Effect of Gastric Bypass, Sleeve Gastrectomy, and Duodenal-Jejunal Bypass on Type-2 Diabetes in non-Obese Rats. AB - BACKGROUND: We compared the therapeutic effects of Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and duodenal-jejunal bypass (DJB) on type-2 diabetes mellitus (T2DM) in non-obese rats using clamp testing. METHODS: Goto Kakizaki rats (non-obese rats with T2DM) underwent surgery: RYGB, SG, or DJB. Rats were observed for 8 weeks after surgery to evaluate weight changes. Levels of glucose, insulin, and glucagon-like peptide (GLP)-1 were determined 2, 4, 6, and 8 weeks after surgery. An oral glucose tolerance test (OGTT) and clamp test was used to evaluate glucose tolerance and insulin resistance. RESULTS: Rats in RYGB, SG, and DJB groups weighed significantly less than sham-group rats 6 and 8 weeks after surgery. Fasting blood glucose levels of RYGB, SG, and DJB rats were significantly lower than preoperative levels. One month after surgery, the area under the curve of the OGTT (in mmol*h/L) for RYGB, SG, DJB, and sham surgery groups was 38.9 +/- 5.9, 50.9 +/- 2.9, 46.8 +/- 3.3, and 67.4 +/- 6.0, respectively; there was no significant difference in glucose levels of SG and DJB groups. Glucose infusion rates (in mg/(kg*min)) were 18.3 +/- 2.7, 17.2 +/- 2.1, and 16.8 +/- 1.9 in hyperinsulinemic-euglycemic-clamped RYGB, DJB, and SG rats, respectively, 8 weeks after surgery. The rate in the sham surgery group was 6.3 +/- 0.9. Area under plasma insulin curves 8 weeks after surgery in hyperglycemic clamped RYGB, DJB, SG, and sham surgery rats (in mU*h/L) were 98.8 +/- 7.0, 84.4 +/- 6.1, 89.0 +/- 7.1, and 22.6 +/- 2.6, respectively. CONCLUSIONS: The three surgical methods described alleviated T2DM and reduced insulin resistance in non obese rats with T2DM. PMID- 26254880 TI - Bioprinting a cardiac valve. AB - Heart valve tissue engineering could be a possible solution for the limitations of mechanical and biological prostheses, which are commonly used for heart valve replacement. In tissue engineering, cells are seeded into a 3-dimensional platform, termed the scaffold, to make the engineered tissue construct. However, mimicking the mechanical and spatial heterogeneity of a heart valve structure in a fabricated scaffold with uniform cell distribution is daunting when approached conventionally. Bioprinting is an emerging technique that can produce biological products containing matrix and cells, together or separately with morphological, structural and mechanical diversity. This advance increases the possibility of fabricating the structure of a heart valve in vitro and using it as a functional tissue construct for implantation. This review describes the use of bioprinting technology in heart valve tissue engineering. PMID- 26254881 TI - The effects of marine sand and gravel extraction on the sediment composition and macrofaunal community of a commercial dredging site (15 years post-dredging). AB - A prediction that faunal recovery of a marine aggregate extraction site subjected to high dredging intensity was likely to take 15-20 years was investigated. Samples were collected at the high dredging intensity site and two reference sites in 2011 (15 years post-dredging). Results indicated that the high site had similar sediment characteristics to the reference sites by 2011. Macrofaunal data analyses showed no difference between the values of all calculated univariate measures (abundance, number of taxa, biomass and evenness) between the high and reference sites. Multivariate analyses found that the macrofaunal community at the high site was comparable to those of the reference sites by 2011. Overall, the results supported the predicted recovery time. The findings of the study suggest that persistent physical impacts prolonged the biological recovery of the high site. PMID- 26254882 TI - Ambient noise and temporal patterns of boat activity in the US Virgin Islands National Park. AB - Human activity is contributing increasing noise to marine ecosystems. Recent studies have examined the effects of boat noise on marine fishes, but there is limited understanding of the prevalence of this type of sound source. This investigation tracks vessel noise on three reefs in the US Virgin Islands National Park over four months in 2013. Ambient noise levels ranged from 106 to 129dBrms re 1MUPa (100Hz-20kHz). Boat noise occurred in 6-12% of samples. In the presence of boat noise, ambient noise in a low-frequency band (100-1000Hz) increased by >7dB above baseline levels and sound levels were significantly higher. The frequency with the most acoustic energy shifted to a significantly lower frequency when boat noise was present during the day. These results indicate the abundance of boat noise and its overlap with reef organism sound production, raising concern for the communication abilities of these animals. PMID- 26254883 TI - Comparison between the intermalleolar distance measured on the couch and on the floor in axial spondyloarthritis. AB - The aim of this study was to assess whether axial spondyloarthritis (axial SpA) patients' supine position on the couch (OC) or on the floor (OF) affects intermalleolar distance (IMD) measurement and its Bath Ankylosing Spondylitis Metrology Index (BASMI) scoring, using all three versions of BASMI index. OC- and OF-IMDs were obtained for 43 axial SpA patients (M:F = 19:24). Age, gender, height, weight, body mass index (BMI), disease type and disease duration were also collected. Statistical analyses and correlations were performed as appropriate. Mean IMD measurements obtained with individuals in the two distinct measuring positions were not significantly different in the patients studied. Furthermore, there was a significant correlation between OC-IMD and OF-IMD values. There was no significant relationship between IMD and patient age, gender, height, weight, BMI, or disease duration. However, looking at disease type, IMDs of patients with ankylosing spondylitis (AS) were ~30 % greater than those with psoriatic arthritis (PsA) in our study population (p < 0.05). There were no significant differences between the measured patient characteristics that accounted for the greater IMDs of those diagnosed with AS. IMD measurements and resultant BASMI scores were the same whether the patient was positioned OC or OF in our axial SpA cohort. Unexpectedly, IMD measurements were significantly greater (~30 %) in AS patients than in axial PsA patients. PMID- 26254884 TI - Decreased physical activity and cardiorespiratory fitness in adults with ankylosing spondylitis: a cross-sectional controlled study. AB - The health benefits of physical activity (PA) in the general population are numerous; however, few studies have measured PA among adults with ankylosing spondylitis (AS). The aims of this study were to: (1) objectively measure the PA levels and cardiorespiratory fitness of adults with AS and compare these to population controls, and (2) examine the relationships between PA, cardiorespiratory function and condition-specific outcomes. This cross-sectional study included participants (>18 years) meeting the modified New York criteria for AS, and matched population controls. Exclusion criteria were the presence of comorbidities limiting PA, or recent changes in medication usage. Participants completed clinical questionnaires assessing disease activity, physical function and quality of life. Tri-axial accelerometers recorded habitual PA over 1 week. Cardiorespiratory fitness was assessed by submaximal treadmill test with breath by-breath gas analysis and heart rate monitoring. Thirty-nine adults with AS and 39 controls were recruited. The AS group spent significantly less time performing vigorous-intensity PA than controls [mean difference (95 % CI) 1.8 min/day (1.2 2.7)] and performed significantly fewer bouts of health-enhancing PA [1.7 min/day (1.1-2.5)]. The AS group had significantly lower predicted VO(2MAX) than controls [6.0 mL kg(-1) min(-1) (1.8-10.1)]. PA was associated with aerobic capacity. Sedentary time was associated with disease activity and physical function. Adults with AS participate in less health-enhancing PA than population controls. Fewer than half meet PA recommendations, despite exercise being a key component of AS management. Explorations of PA behaviour and strategies to increase PA participation are needed. PMID- 26254885 TI - Direct medical costs and their predictors in South Korean patients with systemic lupus erythematosus. AB - We aimed to estimate the annual direct medical costs of South Korean systemic lupus erythematosus (SLE) patients, and their predictors. The 2010 annual direct medical costs of SLE patients in the Hanyang BAE Lupus cohort in South Korea were assessed. The information was taken directly from the hospital database and medical records, and included clinical characteristics, disease activity, organ damage, and healthcare utilization. Cost predictors were estimated with a multivariate linear regression model. A total of 749 SLE patients (92.7 % female, mean age 35.7 +/- 11.3 years, mean disease duration 9.6 +/- 4.9 years) were studied. Their mean annual direct medical costs amounted to USD 3305. The largest component of these costs was the cost of medication (USD 1269, 38.4 %), followed by those of diagnostic procedures and tests (USD 1177, 35.6 %). Regression analysis showed that adjusted mean SLE disease activity index score (p < 0.0001), systemic damage index (p < 0.0001), and renal (p = 0.0039) and hematologic (p = 0.0353) involvement were associated with increased direct medical costs, whereas longer disease duration was associated with lower direct medical costs. Greater disease activity and greater organ damage predict higher costs for South Korean SLE patients. Major organ involvement such as renal disorder and hematologic involvement also predicts higher costs, whereas longer duration of disease predicts lower costs. PMID- 26254886 TI - Metabolism and successful aging: Polymorphic variation of syndecan-4 (SDC4) gene associate with longevity and lipid profile in healthy elderly Italian subjects. AB - Evidences from model systems and humans have suggested that genetic alterations in cell-ECM interactions and matrix-mediated cellular signaling cascades impact different aspects of metabolism and thereby life span. In this frame, a genetic variant (rs1981429) in the SDC4 gene encoding for syndecan-4, a central mediator of cell adhesion, has been associated with body composition in children and coronary artery disease in middle-age subjects. In order to test the hypothesis that syndecans might affect life span by affecting metabolic endophenotypes, 11 SNPs within the SDC4 gene were tested for association with longevity in a cohort of 64-107 aged individuals. We then determined whether the longevity-associated SNPs were correlated with metabolic parameters in the age group 64-85 years. RobustSNP association tests showed that rs1981429 was negatively associated with longevity (Theop=0.028), but also with high levels of triglyceride (Theop=0.028) and low levels of low-density lipoprotein-cholesterol (LDL-C) (Theop=0.009). On the other hand, rs2251252 was found to be positively correlated with longevity (Theop=0.018) and high LDL-C (Theop=0.022). On the whole, our results suggest that SDC4 alleles affect lipid profile in elderly subjects and may in part mediate the link between LDL-C and longevity. PMID- 26254887 TI - Bioaccessibility of trace elements in fine and ultrafine atmospheric particles in an industrial environment. AB - The lung bioaccessibility, i.e., the solubility in alveolar lung fluid of metals in particulate matter, has been recognized as an important parameter for health risk assessment, associated with the inhalation of airborne particles. The purpose of this study is to use an in vitro method to estimate the pulmonary bioaccessibility of toxic metals in different particle sizes, from a multi influenced industrial emission area. The fine and ultrafine particles collected with cascade impactors in the chimneys and at different distances from a Fe-Mn smelter were extracted with a simulated alveolar fluid (Gamble solution). In addition, a four-step sequential extraction procedure was employed to approach the metal speciation. The bioaccessibility of metals ranged from almost insoluble for Fe (<1%) to extremely soluble for Rb (>80%). In terms of particle size, the trace element bioaccessibility is generally higher for the finer size fractions (submicron and ultrafine particles) than for the coarse one (>1 um). These submicron particles have a very high number concentration and specific surface area, which confer them an important contact surface with the alveolar fluid, i.e., a higher bioaccessibility. Interestingly, the bioaccessibility of most metals clearly increases between the chimney stacks and the close environment of the studied Fe-Mn smelter, over a very short distance (800 m), possibly due to a mix with surrounding steelworks emissions. This increase is not observed over a greater distance from the smelter (2000 m), when industrial particles were mixed with urban aerosols, except for Fe, under more soluble forms in combustion particles. PMID- 26254888 TI - Boron and strontium isotope ratios and major/trace elements concentrations in tea leaves at four major tea growing gardens in Taiwan. AB - Isotopic compositions of B and Sr in rocks and sediments can be used as tracers for plant provincial sources. This study aims to test whether tea leaf origin can be discriminated using (10)B/(11)B and Sr isotopic composition data, along with concentrations of major/trace elements, in tea specimens collected from major plantation gardens in Taiwan. The tea leaves were digested by microwave and analyzed by multi-collector inductively coupled plasma mass spectrometry (MC ICPMS). The data showed significant variations in (87)Sr/(86)Sr ratios (from 0.70482 to 0.71462), which reflect changes in soil, groundwater or irrigation conditions. The most radiogenic tea leaves were found at the Taitung garden and the least radiogenic ones were from the Hualien garden. The delta (11)B was found to change appreciably (delta (11)B = 0.38-23.73 0/00) which could be due to fertilizers. The maximum delta (11)B was also observed in tea samples from the Hualien garden. Principal component analysis combining (87)Sr/(86)Sr, delta (11)B and major/trace elements results successfully discriminated different sources of major tea gardens in Taiwan, except the Hualien gardens, and this may be due to rather complicated local geological settings. PMID- 26254890 TI - Author reply: exploring the implications of a fixed budget for new medicines: a study of reimbursement of new medicines in Australia and New Zealand. PMID- 26254889 TI - Analysis of the relationship between the blood concentration of several metals, macro- and micronutrients and endocrine disorders associated with male aging. AB - Beyond 30 years of age, men experience a decline in the production of testosterone, yet only a few develop late-onset hypogonadism. This study was designed to determine the relationship between blood concentrations of metals, macro- and micronutrients and age-related testosterone deficiency and associated hormonal changes in aging men. The research involved 313 men aged 50-75 years. We used ELISA to determine the concentrations of total testosterone (TT), free testosterone (FT), estradiol (E2), dehydroepiandrosterone sulfate (DHEAS) and sex hormone-binding globulin (SHBG). We calculated free androgen index (FAI). With the use of emission spectrometry in inductively coupled argon plasma, we determined the whole-blood concentrations of lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As) and tungsten (W), as well as serum concentrations of magnesium (Mg), iron (Fe), calcium (Ca), copper (Cu), zinc (Zn), selenium (Se), chromium (Cr), manganese (Mn) and molybdenum (Mo). The study showed no relationship between TT and FT and the concentrations of metals. Men with TT deficiency had significantly lower concentrations of Mg and Fe and increased Mn. Men with FT deficiency had higher W and Cr levels and lower Fe. Assessing the correlation between the concentrations of hormones, SHBG and FAI, and the concentration of metals and macro- and microelements in the blood of the men, we found positive correlations between the concentrations of TT-Mg, TT-Fe, TT-Mo, FT-Fe, E2-As, SHBG-Mn, FAI-W, FAI-As, FAI-Zn and FAI-Ca, and negative correlations between the concentrations of TT-Mn, FT-Cd, FT-Cr, E2-Hg, E2-Cr, SHBG-W, SHBG-As, SHBG-Zn, SHBG-Ca, FAI-Pb and FAI-Mn. Positive correlations between As and E2 and between As and FAI may suggest a lack of association between this metal and hypogonadism in people not exposed to excess As levels. Our research indicates a positive relationship between the concentrations of Mg, Fe and Zn and endocrine system in aging men, in contrast to Mn and Cr. Toxic metals (Cd, Pb) seemed to negatively affect the level of bioavailable testosterone. In persons not exposed to As, As does not contribute late-onset hypogonadism. Heavy metals (Pb, Cd, Hg and W) may contribute to a lower concentration of DHEAS. The role of W in men with LOH was found to be ambiguous, as on the one hand its concentration was higher in men with FT deficiency, and on the other hand it positively correlated with FAI, which in turn indirectly indicates testosterone availability. Copper and selenium do not seem to play any significant role in the occurrence of TT deficiency in aging men. PMID- 26254891 TI - Brief report: systematic review of Rett syndrome in males. AB - Rett syndrome (RTT) is a neurogenetic disorder in which a period of typical development is followed by loss of previously acquired skills. Once thought to occur exclusively in females, increasing numbers of male cases of RTT have been reported. This systematic review included 36 articles describing 57 cases of RTT in males. Mutations of the MECP2 gene were present in 56 % of cases, and 68 % of cases reported other genetic abnormalities. This is the first review of published reports of RTT in male patients. PMID- 26254892 TI - Facial Feedback and Social Input: Effects on Laughter and Enjoyment in Children with Autism Spectrum Disorders. AB - Both social input and facial feedback appear to be processed differently by individuals with autism spectrum disorder (ASD). We tested the effects of both of these types of input on laughter in children with ASD. Sensitivity to facial feedback was tested in 43 children with ASD, aged 8-14 years, and 43 typically developing children matched for mental age (6-14), in order to examine whether children with ASD use bodily feedback as an implicit source of information. Specifically, children were asked to view cartoons as they normally would (control condition), and while holding a pencil in their mouth forcing their smiling muscles into activation (feedback condition) while rating their enjoyment of the cartoons. The authors also explored the effects of social input in children with ASD by investigating whether the presence of a caregiver or friend (companion condition), or the presence of a laugh track superimposed upon the cartoon (laugh track condition) increased the children's self-rated enjoyment of cartoons or the amount of positive affect they displayed. Results showed that the group with ASD was less affected by all three experimental conditions, but also that group differences seemed to have been driven by one specific symptom of ASD: restricted range of affect. The strong relationship between restricted affect and insensitivity to facial feedback found in this study sheds light on the implications of restricted affect for social development in ASD. PMID- 26254893 TI - Association Between Maternal Obesity and Autism Spectrum Disorder in Offspring: A Meta-analysis. AB - As the link between maternal obesity and risk of autism among offspring is unclear, the present study assessed this association. A systematic search of an electronic database was performed to identify observational studies that examined the association between maternal obesity and autism. The outcome measures were odds ratios comparing offspring autism risk between obese and normal-weight mothers. Five observational studies were included in the meta-analysis. A fixed effects model was used since low heterogeneity was observed between studies. The pooled adjusted odds ratio was 1.47 (95 % CI 1.24-1.74). The meta-analysis results support an increased risk of autism spectrum disorder in children of women who were obese during pregnancy. However, further study is warranted to confirm these results. PMID- 26254894 TI - Comorbid Symptomology in Adults with Autism Spectrum Disorder and Intellectual Disability. AB - Evidence-based treatment must begin with the systematic and comprehensive identification of an individual's complete clinical picture. Therefore, screening individuals with intellectual disability (ID) for comorbid disorders is imperative. Because of the frequent overlap between autism spectrum disorder (ASD) and ID, the current study explored the effects of co-occurring ASD on the comorbid symptoms exhibited by adults with ID. The study included 307 adults with severe or profound ID separated into two groups: ASD+ID and ID only. The ASD+ID group exhibited significantly more symptomology on eight of the 12 subscales examined including anxiety, mania, schizophrenia, stereotypies/tics, self injurious behavior, eating disorders, sexual disorders, and impulse control. Further, comparisons of specific symptom endorsements yielded distinct results. PMID- 26254895 TI - Brief Report: Effects of Sensory Sensitivity and Intolerance of Uncertainty on Anxiety in Mothers of Children with Autism Spectrum Disorder. AB - This study examined the relations between anxiety and individual characteristics of sensory sensitivity (SS) and intolerance of uncertainty (IU) in mothers of children with ASD. The mothers of 50 children completed the Hospital Anxiety and Depression Scale, the Highly Sensitive Person Scale and the IU Scale. Anxiety was associated with both SS and IU and IU was also associated with SS. Mediation analyses showed direct effects between anxiety and both IU and SS but a significant indirect effect was found only in the model in which IU mediated between SS. This is the first study to characterize the nature of the IU and SS interrelation in predicting levels of anxiety. PMID- 26254896 TI - Osteoprotegerin activates osteosarcoma cells that co-express RANK and RANKL. AB - BACKGROUND: Osteosarcoma (OS) is an aggressive and often fatal cancer that afflicts over 1000 humans and 10,000 dogs per year in the United States. Recent evidence suggests deregulation in the signaling triad, receptor activator of nuclear factor kappa B (RANK), its activating ligand (RANKL), and the RANKL inhibitor, osteoprotegerin (OPG) plays a key role in the pathogenesis of OS. This study investigated the expression of RANK and RANKL in osteosarcoma tumors and cell lines and describes an activating effect of OPG on OS cells in vitro. RESULTS: Canine OS tumors and cell lines co-express mRNA for both RANK and RANKL. Expression of these proteins in OS cell lines was confirmed by Western blot and immunofluorescence microscopy. Expression of the soluble form of RANKL was not detected in media from OS cells. OPG-Fc incubation increased the phosphorylation status of ERK, AKT and the p65 subunit of nuclear factor kappa B (NFkappaB) and induced NFkappaB translocation from the cytoplasm to the nucleus in canine OS cells. OPG increased proliferation in both canine and human derived OS cell lines. CONCLUSION: RANKL is produced by OS tumors and cell lines that also express RANK. This data provides preliminary evidence for a potential autocrine and or paracrine activation pathway in canine OS. An activating effect of exogenous OPG on signal transduction proteins, NFkappaB and proliferation in OS is described. These data provide new information concerning aberrant signaling in OS and could be important to those considering OPG as a therapeutic agent for osteosarcoma. PMID- 26254897 TI - Expression and subcellular localization of the Qa-SNARE syntaxin17 in human eosinophils. AB - BACKGROUND: SNARE members mediate membrane fusion during intracellular trafficking underlying innate and adaptive immune responses by different cells. However, little is known about the expression and function of these proteins in human eosinophils, cells involved in allergic, inflammatory and immunoregulatory responses. Here, we investigate the expression and distribution of the Qa-SNARE syntaxin17 (STX17) within human eosinophils isolated from the peripheral blood. METHODS: Flow cytometry and a pre-embedding immunonanogold electron microscopy (EM) technique that combines optimal epitope preservation and secondary Fab fragments of antibodies linked to 1.4 nm gold particles for optimal access to microdomains, were used to investigate STX17. RESULTS: STX17 was detected within unstimulated eosinophils. Immunogold EM revealed STX17 on secretory granules and on granule-derived vesiculotubular transport carriers (Eosinophil Sombrero Vesicles-EoSVs). Quantitative EM analyses showed that 77.7% of the granules were positive for STX17 with a mean+/-SEM of 3.9+/-0.2 gold particles/granule. Labeling was present on both granule outer membranes and matrices while EoSVs showed clear membrane-associated labeling. STX17 was also present in secretory granules in eosinophils stimulated with the cytokine tumor necrosis factor alpha (TNF-alpha) or the CC-chemokine ligand 11 CCL11 (eotaxin-1), stimuli that induce eosinophil degranulation. The number of secretory granules labeled for STX17 was significantly higher in CCL11 compared with the unstimulated group. The level of cell labeling did not change when unstimulated cells were compared with TNF-alpha stimulated eosinophils. CONCLUSIONS: The present study clearly shows by immunanonogold EM that STX17 is localized in eosinophil secretory granules and transport vesicles and might be involved in the transport of granule-derived cargos. PMID- 26254898 TI - Dandelion (Taraxacum officinale) and Agrimony (Agrimonia eupatoria) as Indicators of Geogenic Contamination of Flysch Soils in Eastern Slovakia. AB - Contents of potentially toxic elements Fe, Mn, Cr, Ni, Co, V, Cu, and Mo were determined in common dandelion (Taraxacum officinale) and agrimony (Agrimonia eupatoria) to show their usefulness as bioindicators of geogenic soil pollution. Both plants were collected on geochemically anomalous soils developed on flysch sedimentary rocks (Paleogene) of Eastern Slovakia, which also are composed of weathered detritus of some ultramafic rocks. Generally, contents of the investigated association of potentially toxic elements are highly increased in these "serpentine"-like soils. Elevated concentrations were detected in both shoots and roots of the plants. The highest values, which exceed world average values for plants, were observed for Ni content. They ranged from 1.7 to 16.3 mg kg(-1) in dandelion and from 1.6 to 22.6 mg kg(-1) in agrimony. Essential elements, such as Mo, Cu, and Mn, were the most concentrated in plants, whereas Co, V, and Cr were the least concentrated. Although the bioindication value of the common dandelion for anthropogenic soil pollution is well known, it is not mentioned for agrimony in literature, and no data exist to indicate the geogenic pollution for both plants. Dandelion and agrimony are widely used as herbal drugs; therefore, our intention also was to point out another fact, namely, possible high uptake of potentially toxic elements by herbal plants growing on similar soils. PMID- 26254899 TI - Occurrence and Distribution of Microplastics in the Sea Surface Microlayer in Jinhae Bay, South Korea. AB - Microplastic contamination of the marine environment is a worldwide concern. The abundance of microplastics was evaluated in the sea surface microlayer in Jinhae Bay, on the southern coast of Korea. The microplastics in this study are divided into paint resin particles and plastics by polymer type. The mean abundance of paint resin particles (94 +/- 68 particles/L) was comparable to that of plastics (88 +/- 68 particles/L). Fragmented microplastics, including paint resin particles, accounted for 75 % of total particles, followed by spherules (14 %), fibers (5.8 %), expanded polystyrene (4.6 %), and sheets (1.6 %). Alkyd (35 %) and poly(acrylate/styrene) (16 %) derived from ship paint resin were dominant, and the other microplastic samples consisted of polypropylene, polyethylene, phenoxy resin, polystyrene, polyester, synthetic rubber, and other polymers. The abundance of plastics was significantly (p < 0.05) higher in Jinhae Bay, which is surrounded by a coastal city, than along the east coast of Geoje, which is relatively open sea. The floating microplastic abundance in surface water was the highest reported worldwide. PMID- 26254900 TI - Epigenetic mechanisms and boundaries in the regulation of mammalian Hox clusters. AB - Hox gene expression imparts segment identity to body structures along the anterior-posterior axis and is tightly governed by higher order chromatin mechanisms. Chromatin regulatory features of the homeotic complex are best defined in Drosophila melanogaster, where multiple cis-regulatory elements have been identified that ensure collinear Hox gene expression patterns in accordance with their genomic organization. Recent studies focused on delineating the epigenetic features of the vertebrate Hox clusters have helped reveal their dynamic chromatin organization and its impact on gene expression. Enrichment for the 'activating' H3K4me3 and 'repressive' H3K27me3 histone modifications is a particularly strong read-out for transcriptional status and correlates well with the evidence for chromatin loop domain structures and stage specific topological changes at these loci. However, it is not clear how such distinct domains are imposed and regulated independent of each other. Comparative analysis of the chromatin structure and organization of the homeotic gene clusters in fly and mammals is increasingly revealing the functional conservation of chromatin mediated mechanisms. Here we discuss the case for interspersed boundary elements existing within mammalian Hox clusters along with their possible roles and mechanisms of action. Recent studies suggest a role for factors other than the well characterized vertebrate boundary factor CTCF, such as the GAGA binding factor (GAF), in maintaining chromatin domains at the Hox loci. We also present data demonstrating how such regulatory elements may be involved in organizing higher order structure and demarcating active domains of gene expression at the mammalian Hox clusters. PMID- 26254901 TI - Specific combinations of boundary element and Polycomb response element are required for the regulation of the Hox genes in Drosophila melanogaster. AB - In the bithorax complex of Drosophila melanogaster, the chromatin boundary elements (BE) demarcate cis-regulatory domains that regulate Hox genes along the anteroposterior body axis. These elements are closely associated with the Polycomb Response Elements (PREs) and restrict the ectopic activation of cis regulatory domains during development. The relevance of such specific genomic arrangements of regulatory elements remains unclear. Deletions of individual BE PRE combination result in distinct homeotic phenotypes. In this study, we show that deletion of two such BE-PRE combinations in cis leads to new genetic interactions, which manifests as dorsal closure defect phenotype in adult abdominal epithelia. We further demonstrate that dorsal closure phenotype results from enhanced and ectopic expression of Hox gene Abd-B in the larval epithelial cells. This suggests a specific role of multiple BE-PRE combinations in the larval epithelial cells for regulation of Abd-B. Using chromosome conformation capture experiments, we show that genetic interactions correlate with direct physical interactions among the BE-PRE combinations. Our results demonstrate the functional relevance of the closely associated BE and PRE combinations in regulation of Hox genes. PMID- 26254902 TI - Adaptability of protein structures to enable functional interactions and evolutionary implications. AB - Several studies in recent years have drawn attention to the ability of proteins to adapt to intermolecular interactions by conformational changes along structure encoded collective modes of motions. These so-called soft modes, primarily driven by entropic effects, facilitate, if not enable, functional interactions. They represent excursions on the conformational space along principal low-ascent directions/paths away from the original free energy minimum, and they are accessible to the protein even before protein-protein/ligand interactions. An emerging concept from these studies is the evolution of structures or modular domains to favor such modes of motion that will be recruited or integrated for enabling functional interactions. Structural dynamics, including the allosteric switches in conformation that are often stabilized upon formation of complexes and multimeric assemblies, emerge as key properties that are evolutionarily maintained to accomplish biological activities, consistent with the paradigm sequence->structure->dynamics->function where 'dynamics' bridges structure and function. PMID- 26254903 TI - The origins of thalamic inputs to grasp zones in frontal cortex of macaque monkeys. AB - The hand representation in primary motor cortex (M1) is instrumental to manual dexterity in primates. In Old World monkeys, rostral and caudal aspects of the hand representation are located in the precentral gyrus and the anterior bank of the central sulcus, respectively. We previously reported the organization of the cortico-cortical connections of the grasp zone in rostral M1. Here we describe the organization of thalamocortical connections that were labeled from the same tracer injections. Thalamocortical connections of a grasp zone in ventral premotor cortex (PMv) and the M1 orofacial representation are included for direct comparison. The M1 grasp zone was primarily connected with ventral lateral divisions of motor thalamus. The largest proportion of inputs originated in the posterior division (VLp) followed by the medial and the anterior divisions. Thalamic inputs to the M1 grasp zone originated in more lateral aspects of VLp as compared to the origins of thalamic inputs to the M1 orofacial representation. Inputs to M1 from thalamic divisions connected with cerebellum constituted three fold the density of inputs from divisions connected with basal ganglia, whereas the ratio of inputs was more balanced for the grasp zone in PMv. Privileged access of the cerebellothalamic pathway to the grasp zone in rostral M1 is consistent with the connection patterns previously reported for the precentral gyrus. Thus, cerebellar nuclei are likely more involved than basal ganglia nuclei with the contributions of rostral M1 to manual dexterity. PMID- 26254904 TI - Brain white matter structure and information processing speed in healthy older age. AB - Cognitive decline, especially the slowing of information processing speed, is associated with normal ageing. This decline may be due to brain cortico-cortical disconnection caused by age-related white matter deterioration. We present results from a large, narrow age range cohort of generally healthy, community dwelling subjects in their seventies who also had their cognitive ability tested in youth (age 11 years). We investigate associations between older age brain white matter structure, several measures of information processing speed and childhood cognitive ability in 581 subjects. Analysis of diffusion tensor MRI data using Tract-based Spatial Statistics (TBSS) showed that all measures of information processing speed, as well as a general speed factor composed from these tests (g speed), were significantly associated with fractional anisotropy (FA) across the white matter skeleton rather than in specific tracts. Cognitive ability measured at age 11 years was not associated with older age white matter FA, except for the g speed-independent components of several individual processing speed tests. These results indicate that quicker and more efficient information processing requires global connectivity in older age, and that associations between white matter FA and information processing speed (both individual test scores and g speed), unlike some other aspects of later life brain structure, are generally not accounted for by cognitive ability measured in youth. PMID- 26254907 TI - Amyloidosis of the liver on shear wave elastography: case report and review of literature. AB - Amyloidosis is extremely rare, with an estimated 2225 new US cases reported annually. Signs and symptoms of the disease are subtle and imaging findings are not pathognomonic. Currently, diagnosis requires biopsy to demonstrate the deposition of amyloid. Elastography is a new imaging modality that evaluates tissue elasticity. It has shown to have efficacy in characterizing thyroid nodules, detecting prostate cancer, and staging liver fibrosis. We present a case of hepatic amyloidosis in a 51-year-old male that demonstrates significantly increased stiffness with a median value of 99.1 kPa (range 25.7-188.9 kPa) on shear-wave elastography (SWE) imaging, which is significantly higher than the cut off range reported for cirrhosis on SWE (10.4-11.5 kPa). This finding raises the possibility that elastographic imaging may be sensitive to tissue mechanical changes induced by amyloid deposition. PMID- 26254905 TI - Characteristic laryngoscopic findings in Parkinson's disease patients after subthalamic nucleus deep brain stimulation and its correlation with voice disorder. AB - Speech and voice disorders are one of the most common adverse effects in Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS). However, the pathophysiology of voice and laryngeal dysfunction after STN-DBS remains unclear. We assessed 47 PD patients (22 treated with bilateral STN-DBS (PD-DBS) and 25 treated medically (PD-Med); all patients in both groups matched by age, sex, disease duration, and motor and cognitive function) using the objective and subjective voice assessment batteries (GRBAS scale and Voice Handicap Index), and laryngoscopy. Laryngoscopic examinations revealed that PD-DBS patients showed a significantly higher incidence of incomplete glottal closure (77 vs 48 %; p = 0.039), hyperadduction of the false vocal folds (73 vs 44 %; p = 0.047), anteroposterior hypercompression (50 vs 20 %; p = 0.030) and asymmetrical glottal movement (50 vs 16 %; p = 0.002) than PD Med patients. On- and off-stimulation assessment revealed that STN-DBS could induce or aggravate incomplete glottal closure, hyperadduction of the false vocal folds, anteroposterior hypercompression, and asymmetrical glottal movement. Incomplete glottal closure and hyperadduction of the false vocal folds significantly correlated with breathiness and strained voice, respectively (r = 0.590 and 0.539). We should adjust patients' DBS settings in consideration of voice and laryngeal functions as well as motor function. PMID- 26254908 TI - CT sensitivity for adrenal adenoma according to lesion size. AB - PURPOSE: To retrospectively evaluate CT sensitivity for characterizing adrenal adenoma according to lesion size. MATERIALS AND METHODS: Between January 2004 and November 2012, 140 patients with 140 histologically proven adenomas underwent preoperative adrenal CT protocols consisting of unenhanced CT, early enhanced CT, and delayed enhanced CT. Adenomas were divided into three size groups: small adenoma (n = 60), >= 1 to <2 cm; medium adenoma (n = 47), >= 2 to <3 cm; and large adenoma (n = 33), >= 3 cm. Adenoma was diagnosed when a lesion met one of the following criteria: (a) unenhanced CT attenuation value <= 10 HU, (b) absolute percentage washout >= 60%, or (c) relative percentage washout >= 40%. The standard reference was pathologic examination of an adrenalectomy specimen. Adenoma size, lesion attenuation value, or percentage washout was correlated with the Spearman's rank correlation. CT sensitivities were compared between size groups of adenomas with the Fisher's exact test. RESULTS: As adenoma size increased, the lesion attenuation value (rho = 0.324; P = 0.001) increased on unenhanced CT, and the absolute (rho = -0.186; P = 0.028) or relative (rho = 0.374; P < 0.001) percentage washout decreased on early and delayed enhanced CT. CT sensitivities were 100% (60/60) for small adenomas, 97.9% (46/47) for medium adenomas, and 66.7% (22/33) for large adenomas (P < 0.001). CONCLUSIONS: Adrenal CT protocols misdiagnose a substantial number of large adenomas as non-adenomas because CT sensitivity for adenoma markedly decreases, when the lesion size is 3 cm or larger. PMID- 26254909 TI - Ethics and the facial plastic surgeon. AB - The facial plastic surgeon potentially has a conflict of interest when confronted with the patients requesting surgery, due to the personal gain attainable by agreeing to perform surgery. The aim of this review is to discuss the potential harm the surgeon can inflict by carrying out facial plastic surgery, beyond the standard surgical complications of infection or bleeding. It will discuss the desire for self-improvement and perfection and increase in the prevalence facial plastic surgery. We address the principles of informed consent, beneficence and non-maleficence, as well as justice and equality and how the clinician who undertakes facial plastic surgery is at risk of breaching these principles without due care and diligence. PMID- 26254910 TI - Single Dose Oral and Intravenous Pharmacokinetics and Tissue Distribution of a Novel Hesperetin Derivative MTBH in Rats. AB - BACKGROUND: MTBH, a novel hesperetin derivative, possesses in vivo hepatoprotective effects against carbon tetrachloride (CCl4)-induced acute liver injury in Institute of Cancer Research (ICR) mice. OBJECTIVES: This study investigated the pharmacokinetics and tissue distribution of MTBH and its conjugated metabolites in rats after a single dose of MTBH. METHODS: Male Sprague Dawley (SD) rats were orally administered (25, 50, 100 mg/kg) or intravenously administered (25 mg/kg) MTBH and blood samples were withdrawn at specific times. Moreover, after a single oral dose of MTBH (200 mg/kg), tissues (heart, liver, spleen, lung, kidney, stomach, intestine, brain and muscle) were collected at scheduled time points. RESULTS: The concentration of MTBH in plasma and tissues was assayed by HPLC before and after hydrolysis with beta-glucuronidase or sulfatase. The glucuronides/sulfates were extensively present in the plasma, moreover, the free form was detectable in the plasma, but in a small amount equivalent to nearly 0.85-1.46 % of the amount of glucuronides/sulfates, the absolute bioavailability of MTBH was approximately 31.27 %. In tissues, the free form appeared in all tissues examined, with trace amount in brain and muscle, and considerable concentration in stomach and lung. Glucuronides/sulfates were the major forms in intestine, kidney and liver, whereas not detectable in heart, brain and muscle. The liver and intestine were found likely to accumulate MTBH at a high concentration among all tissues. CONCLUSIONS: The free form of MTBH was present in the circulation and all assayed organs, whereas its glucuronides/sulfates were the major forms in plasma and intestine, kidney and liver after a single dose. PMID- 26254912 TI - Probucol Protects Against Asymmetric Dimethylarginine-Induced Apoptosis in the Cultured Human Brain Microvascular Endothelial Cells. AB - Asymmetric dimethylarginine (ADMA) is emerging as a key contributor to endothelial dysfunction. The drug probucol was reported to have an anti-lipid peroxidation effect and improve endothelial dilation function. But little is known about the protective effect of probucol on ADMA-induced human brain microvascular endothelial cell (HBMEC) injury and its underlying mechanisms. Therefore, in this study, we investigated the effect of probucol on ADMA-induced HBMEC injury and its potential mechanisms. Results showed that probucol protected against ADMA-induced HBMEC injury in a dose-dependent manner; probucol pretreatment also significantly reduced the level of reactive oxygen species (ROS) and malondialdehyde (MDA), downregulated the expression of pro-apoptotic gene Bax and caspase-3 activity, as well as increased the brain-derived neurotrophic factor (BDNF) release and promoted anti-apoptotic gene Bcl-2 and eNOS expression in the cultured HBMECs. Furthermore, we found that ADMA significantly increased the phosphorylation of c-Jun NH2-terminal kinase (JNK) and p38, while probucol pretreatment effectively inhibited ADMA-induced JNK and p38 phosphorylation in HBMECs. In conclusion, our present results demonstrated that probucol protected against ADMA-induced HBMEC injury and suppressed oxidative stress through the JNK/p38 MAPK pathway, which was the potential underlying mechanism of HBMEC injury in ischemic cerebrovascular disease. PMID- 26254911 TI - A Physiologically Based Pharmacokinetic Model of Amiodarone and its Metabolite Desethylamiodarone in Rats: Pooled Analysis of Published Data. AB - BACKGROUND AND OBJECTIVE: Amiodarone (AMD) is one of the most effective drugs for rhythm control of atrial fibrillation. The use of AMD is also associated with adverse effects in multiple tissues. Both the parent compound and its major metabolite desethylamiodarone (DEA) contribute to the drug's therapeutic and toxic action. The present study aimed to build a whole-body physiologically based pharmacokinetic (PBPK) model for AMD and DEA in rats. METHODS: Pharmacokinetic data from multiple studies were collected. Some of the data were pooled together to develop the PBPK model; others were used to evaluate the model. Development of the model also involved in vitro to in vivo extrapolation based on in vitro metabolism data. RESULTS: The final model consisted of 11 tissue compartments, including therapeutic target organs and those to which AMD and DEA may be harmful. Model simulations were in good agreement with the observed time courses of the drug-metabolite pair in tissues, under various dosing scenarios. The key pharmacokinetic properties of AMD, such as extensive tissue distribution, substantial storage in the fat tissue, and long half-lives in many tissues, were closely reflected. CONCLUSION: The developed PBPK model can be regarded as the first step towards a PBPK-pharmacodynamic model that can used to mechanistically evaluate and explain the high adverse event rate and potentially to determine which factors are the primary drives for experiencing an adverse event. PMID- 26254914 TI - Emotional symptoms and their contribution to functional impairment in adults with attention-deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is a severe neurodevelopmental disorder beginning in childhood and consisting of the core symptoms of inattention, hyperactivity, and impulsivity. The disorder is often accompanied by functional impairment in daily life. Research showed that severe impairment cannot be fully explained by the core symptoms of ADHD. Accordingly, emotional symptoms in ADHD and their influence on functional impairment have increasingly become the focus of research in recent years. The aim of the current study was to investigate the relationship between ADHD core symptoms, emotional symptoms, and functional impairment. We assumed that emotional symptoms might form part of adult ADHD and that the connection between ADHD core symptoms and functional impairment may be partly mediated by emotional symptoms. Data of 176 participants from an ADHD Special Consultations Unit were included. Of these participants, 146 were diagnosed with ADHD, while 30 received no such diagnosis. We developed a structural equation model which included core symptoms, emotional symptoms, and four domains of daily impairment (family life, social life, work, and organization). As predicted, results indicate that emotional symptoms are directly linked to adult ADHD and bear a strong negative influence on different domains of daily life. The results of different analyses showed a mediation of the relationship between ADHD core symptoms and impairment through emotional symptoms: While the connection between inattention and work and organization was partly mediated, the connections between impulsivity and family life and between inattention and social life were shown to be fully mediated through emotional symptoms. PMID- 26254913 TI - The Protective Effect of Remote Renal Preconditioning Against Hippocampal Ischemia Reperfusion Injury: Role of KATP Channels. AB - Remote ischemic preconditioning (RIPC), which consists of several brief ischemia/reperfusion applied at the remote site of lethal ischemia reperfusion, can, through activating different mechanisms, increase the ability of the body's endogenous protection against prolonged ischemia/reperfusion. Recent studies have shown that RIPC has neuroprotective effects, but its mechanisms are not well elucidated. The present study aimed to determine whether activation of KATP channels in remote renal preconditioning decreases hippocampus damage induced by global cerebral ischemia. RIPC was induced by ischemia of the left renal artery (IPC); 24 h later, global cerebral ischemia reperfusion (IR) was induced by common carotid arteries occlusion. 5hydroxydecanoate (5HD) and glibenclamide (Gli) were injected before of IPC. The levels of malondialdehyde (MDA) and catalase (CAT) activity were assessed in hippocampus. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) was assessed to detect apoptotic cells in hippocampus. RIPC inhibited apoptosis by decreasing positive TUNEL cells (P < 0.05). KATP channels blocking with 5HD and Gli markedly increased apoptosis in hippocampal cells in RIPC group (P < 0.001). RIPC decreased MDA level and increased CAT activity in ischemic hippocampus (P < 0.01). Also, 5HD and Gli inhibited the effect of RIPC on MDA level and CAT activity (P < 0.05). The present study shows that RIPC can effectively attenuate programmed cell death, increase activity of CAT, and reduce MDA levels. Blocking of KATP channels inhibited the protective effects of RIPC. PMID- 26254915 TI - Cell Cycle Control: A System of Interlinking Oscillators. AB - The cell cycle is the sequence of events through which a cell duplicates its genome, grows, and divides. Key cell cycle transitions are driven by oscillators comprising cyclin-dependent kinases and other kinases. Different cell cycle oscillators are inextricably linked to ensure orderly activation of oscillators. A recurring theme in their regulation is the abundance of auto-amplifying loops that ensure switch-like and unidirectional cell cycle transitions. The periodicity of many cell cycle oscillators is choreographed by inherent mechanisms that promote automatic inactivation, often involving dephosphorylation and ubiquitin-mediated protein degradation. These inhibitory signals are subsequently suppressed to enable the next cell cycle to occur. Although the activation and inactivation of cell cycle oscillators are in essence autonomous during the unperturbed cell cycle, a number of checkpoint mechanisms are able to halt the cell cycle until defects are addressed. Together, these mechanisms orchestrate orderly progression of the cell cycle to produce more cells and to safeguard genome integrity. PMID- 26254916 TI - Model Organisms for Studying the Cell Cycle. AB - Regulation of the cell-division cycle is fundamental for the growth, development, and reproduction of all species of life. In the past several decades, a conserved theme of cell cycle regulation has emerged from research in diverse model organisms. A comparison of distinct features of several diverse model organisms commonly used in cell cycle studies highlights their suitability for various experimental approaches, and recaptures their contributions to our current understanding of the eukaryotic cell cycle. A historic perspective presents a recollection of the breakthrough upon unfolding the universal principles of cell cycle control by scientists working with diverse model organisms, thereby appreciating the discovery pathways in this field. A comprehensive understanding is necessary to address current challenging questions about cell cycle control. Advances in genomics, proteomics, quantitative methodologies, and approaches of systems biology are redefining the traditional concept of what constitutes a model organism and have established a new era for development of novel, and refinement of the established model organisms. Researchers working in the field are no longer separated by their favorite model organisms; they have become more integrated into a larger community for gaining greater insights into how a cell divides and cycles. The new technologies provide a broad evolutionary spectrum of the cell-division cycle and allow informative comparisons among different species at a level that has never been possible, exerting unimaginable impact on our comprehensive understanding of cell cycle regulation. PMID- 26254917 TI - Role of Computational Modeling in Understanding Cell Cycle Oscillators. AB - The periodic oscillations in the activity of the cell cycle regulatory program, drives the timely activation of key cell cycle events. Interesting dynamical systems, such as oscillators, have been investigated by various theoretical and computational modeling methods. Thanks to the insights achieved by these modeling efforts we have gained considerable insights about the underlying molecular regulatory networks that can drive cell cycle oscillations. Here we review the basic features and characteristics of biological oscillators, discussing from a computational modeling point of view their specific architectures and the current knowledge about the dynamics that the life evolution selected to drive cell cycle oscillations. PMID- 26254918 TI - E2F Transcription Factors Control the Roller Coaster Ride of Cell Cycle Gene Expression. AB - Initially, the E2F transcription factor was discovered as a factor able to bind the adenovirus E2 promoter and activate viral genes. Afterwards it was shown that E2F also binds to promoters of nonviral genes such as C-MYC and DHFR, which were already known at that time to be important for cell growth and DNA metabolism, respectively. These findings provided the first clues that the E2F transcription factor might be an important regulator of the cell cycle. Since this initial discovery in 1987, several additional E2F family members have been identified, and more than 100 targets genes have been shown to be directly regulated by E2Fs, the majority of these are important for controlling the cell cycle. The progression of a cell through the cell cycle is accompanied with the increased expression of a specific set of genes during one phase of the cell cycle and the decrease of the same set of genes during a later phase of the cell cycle. This roller coaster ride, or oscillation, of gene expression is essential for the proper progression through the cell cycle to allow accurate DNA replication and cell division. The E2F transcription factors have been shown to be critical for the temporal expression of the oscillating cell cycle genes. This review will focus on how the oscillation of E2Fs and their targets is regulated by transcriptional, post-transcriptional and post-translational mechanism in mammals, yeast, flies, and worms. Furthermore, we will discuss the functional impact of E2Fs on the cell cycle progression and outline the consequences when E2F expression is disturbed. PMID- 26254919 TI - Cell Synchronization of Mouse Embryonic Fibroblasts. AB - A fundamental need in the analysis of the cell cycle is the ability to isolate relatively homogeneous populations of cells in different phases. This is complicated by the variable proliferative properties and responses to synchronizing methods of different cancer-derived cell lines. Paradoxically, cell lines with genetic defects in cell cycle control are sometimes chosen because they are amenable to chemical synchronization. Embryonic fibroblasts from mice present the opportunity to study the effects of defined genetic modifications on a normal cell cycle. However, synchronization of these cells has often been challenging. In this chapter we outline three basic protocols for isolating mouse fibroblasts at the G1-to-S-phase transition, in S phase, and during mitosis. PMID- 26254920 TI - Cell Cycle Synchronization in Xenopus Egg Extracts. AB - Many important discoveries in cell cycle research have been made using cell-free extracts prepared from the eggs of the South African clawed frog Xenopus laevis. These extracts efficiently support the key nuclear functions of the eukaryotic cell cycle in vitro under apparently the same controls that exist in vivo. The Xenopus cell-free system is therefore uniquely suited to the study of the mechanisms, dynamics and integration of cell cycle regulated processes at a biochemical level. Here, we describe methods currently in use in our laboratory for the preparation of Xenopus egg extracts and demembranated sperm nuclei. We detail how these extracts can be used to study the key transitions of the eukaryotic cell cycle and describe conditions under which these transitions can be manipulated by addition of drugs that either retard or advance passage. In addition, we describe in detail essential techniques that provide a practical starting point for investigating the function of proteins involved in the operation of the eukaryotic cell cycle. PMID- 26254921 TI - Elutriation for Cell Cycle Synchronization in Fission Yeast. AB - Cell synchronization is a powerful technique for studying the eukaryotic cell cycle events precisely. The fission yeast is a rod-shaped cell whose growth is coordinated with the cell cycle. Monitoring the cellular growth of fission yeast is a relatively simple way to measure the cell cycle stage of a cell. Here, we describe a detailed method of unperturbed cell synchronization, named centrifugal elutriation, for fission yeast. PMID- 26254922 TI - Spatiotemporal Investigation of Phosphorylation Events During Cell Cycle Progression. AB - Polo-like kinase 1 (Plk1) is an essential kinase for mitotic commitment and progression through mitosis. In contrast to its well characterized roles during mitosis, the precise molecular events controlled by Plk1 during G2/M progression and their spatiotemporal regulation are still poorly elucidated. We recently investigated Plk1-dependent regulation of Cdc25C phosphatase, an activator of the master mitotic driver Cyclin B1-Cdk1. To this end, we generated a genetically encoded FRET (Forster Resonance Energy Transfer)-based Cdc25C phosphorylation biosensor to observe Cdc25 spatiotemporal phosphorylation during cell cycle progression in live single cell assays. Because this approach proved to be powerful, we provide here guidelines for the development of biosensors for any phosphorylation site of interest. PMID- 26254923 TI - Cell Cycle Dynamics of Proteins and Post-translational Modifications Using Quantitative Immunofluorescence. AB - Immunofluorescence can be a powerful tool to detect protein levels, intracellular localization, and post-translational modifications. However, standard immunofluorescence provides only a still picture and thus lacks temporal information. Here, we describe a method to extract temporal information from immunofluorescence images of fixed cells. In addition, we provide an optional protocol that uses micropatterns, which increases the accuracy of the method. These methods allow assessing how protein levels, intracellular localization, and post-translational modifications change through the cell cycle. PMID- 26254924 TI - Building a Synthetic Transcriptional Oscillator. AB - Reaction circuits mimicking genetic oscillators can be realized with synthetic, switchable DNA genes (so-called genelets), and two enzymes only, an RNA polymerase and a ribonuclease. The oscillatory behavior of the genelets is driven by the periodic production and degradation of RNA effector molecules. Here, we describe the preparation, assembly, and testing of a synthetic, transcriptional two-node negative-feedback oscillator, whose dynamics can be followed in real time by fluorescence read-out. PMID- 26254925 TI - The Use of SNAP Labeling to Study Cell Cycle Oscillatory Proteins. AB - Tightly controlled degradation of specific regulatory proteins is crucial for transitioning to the next cell cycle phase, ensuring precise DNA replication and an equal distribution of chromosomes to provide genomic stability and avoid tumorigenesis. To study mitotic control at the metaphase-to-anaphase transition, a histone H2-GFP-based reporter system was established, allowing simultaneous monitoring of the alignment of mitotic chromosomes and cyclin B proteolysis. To depict the proteolytic profile, a chimeric cyclin B-SNAP reporter molecule that can be labeled with a fluorochrome-carrying SNAP substrate was generated for measurement of the decline in fluorescence intensity via live-cell imaging. This reporter system can be adapted for other cell cycle oscillatory proteins. PMID- 26254926 TI - A Computational Method for Identifying Yeast Cell Cycle Transcription Factors. AB - The eukaryotic cell cycle is a complex process and is precisely regulated at many levels. Many genes specific to the cell cycle are regulated transcriptionally and are expressed just before they are needed. To understand the cell cycle process, it is important to identify the cell cycle transcription factors (TFs) that regulate the expression of cell cycle-regulated genes. Here, we describe a computational method to identify cell cycle TFs in yeast by integrating current ChIP-chip, mutant, transcription factor-binding site (TFBS), and cell cycle gene expression data. For each identified cell cycle TF, our method also assigned specific cell cycle phases in which the TF functions and identified the time lag for the TF to exert regulatory effects on its target genes. Moreover, our method can identify novel cell cycle-regulated genes as a by-product. PMID- 26254927 TI - Measuring Activity and Specificity of Protein Phosphatases. AB - Reversible protein phosphorylation plays essential roles in coordinating cell division and many other biological processes. Cell cycle regulation by opposing kinase and protein phosphatase activities is often complex and major challenges exist in identifying the direct substrates of these enzymes and the specific sites at which they act. While cell cycle kinases are known to exhibit strict substrate specificities important for coordinating the complex events of cell division, phosphatases have only recently been recognized to exert similarly precise regulatory control over cell cycle events through timely dephosphorylation of specific substrates. The molecular determinants for substrate recognition by many phosphatases that function in cell division are still poorly delineated. To understand phosphatase specificity, it is critical to employ methods that monitor the dephosphorylation of individual phosphorylation sites on physiologically relevant substrates. Here, using the cell cycle phosphatase Cdc14 as an example, we describe two methods for studying phosphatase specificity, one using synthetic phosphopeptide substrates and the other using intact phosphoprotein substrates. These methods are useful for targeted characterization of small substrate sets and are also adaptable to large-scale applications for global specificity studies. PMID- 26254928 TI - Combining the Optimized Yeast Cytosine Deaminase Protein Fragment Complementation Assay and an In Vitro Cdk1 Targeting Assay to Study the Regulation of the gamma Tubulin Complex. AB - Cdk1 is the essential cyclin-dependent kinase in the budding yeast Saccharomyces cerevisiae. Cdk1 orchestrates cell cycle control by phosphorylating target proteins with extraordinary temporal and spatial specificity by complexing with one of the nine cyclin regulatory subunits. The identification of the cyclin required for targeting Cdk1 to a substrate can help to place the regulation of that protein at a specific time point during the cell cycle and reveal information needed to elucidate the biological significance of the regulation. Here, we describe a combination of strategies to identify interaction partners of Cdk1, and associate these complexes to the appropriate cyclins using a cell-based protein-fragment complementation assay. Validation of the specific reliance of the OyCD interaction between Cdk1 and budding yeast gamma-tubulin on the Clb3 cyclin, relative to the mitotic Clb2 cyclin, was performed by an in vitro kinase assay using the gamma-tubulin complex as a substrate. PMID- 26254929 TI - Cell Cycle Synchronization Using a Microfluidic Synchronizer for Fission Yeast Cells. AB - To produce synchronized cell colonies, many cell cycle synchronization technologies have been developed, among which the baby machine may be considered the most artifact-free. Baby machines incubate "mother cells" under normal conditions and collects their "babies," producing cell cultures that are similar not only in cell cycle phase but also in age. Several macroscale and microfluidic baby machines have been applied to synchronized cell research. However, for rod shaped cells like fission yeast (Schizosaccharomyces pombe), it is still a challenge to immobilize only the mother cells in a microfluidic device. Here, we present a new baby machine suitable for fission yeast. The device fixes one end of the cell and releases the free-end daughter cell every time the cell finishes cytokinesis. A variety of structures for cell immobilization were attempted to find the optimal design. For the convenience of collection and to enable further assays, we integrated a cell screener into the baby machine, which exploits the deformation of polymer material to switch between open and closed states. The device, producing synchronous populations of fission yeast cells, provides a new on-chip tool for cell biology studies. PMID- 26254930 TI - Detection of Protein-Protein Interactions in Tobacco BY-2 Cells Using Bimolecular Fluorescence Complementation. AB - Knowledge of protein-protein interactions in the plant cell is invaluable for furthering our understanding of the functions of these proteins. Many of the methods available for the study of these interactions, such as yeast two-hybrid and co-immunoprecipitation assays, rely on in vitro techniques. Here we describe the use of bimolecular fluorescence complementation for the study of protein protein interactions in vivo, using simple techniques and accessible materials. PMID- 26254931 TI - Tracking the Cyclin B1-GFP Sensor to Profile the Pattern of Mitosis Versus Mitotic Bypass. AB - This chapter provides a method for quantitative single cell analysis to track the transition of single cells from G2, indicated by high cyclin B1 levels, to G1 polyploidy phase (G1(p)), indicated by low cyclin B1 levels, in a 4n population. The cell tracking methodology described provides a fluorescence fingerprint suitable for deriving G2/M or G2/G1p transitions. Notably, during late G2 the absolute cyclin B1-eGFP reporter levels obtained were high and the switch-off point identifiable, with destruction rates of a similar order across all cell cycle routing avenues. The three principle parameters extracted were defined as (1) G2-to-G1(p) transition duration (tGFP(off)); (2) rate of sensor destruction (kGFP(off)), and (3) peak sensor expression (GFP(peak)). PMID- 26254932 TI - Measuring APC/C-Dependent Ubiquitylation In Vitro. AB - The anaphase-promoting complex/cyclosome (APC/C) is a 1.2 MDa ubiquitin ligase complex with important functions in both proliferating and post-mitotic differentiated cells. In proliferating cells, APC/C controls cell cycle progression by targeting inhibitors of chromosome segregation and mitotic exit for degradation by the 26S proteasome. To understand how APC/C recruits and ubiquitylates its substrate proteins and how these processes are controlled, it is essential to analyze APC/C activity in vitro. In the past, such experiments have been limited by the fact that large quantities of purified APC/C were difficult to obtain and that mutated versions of the APC/C could not be easily generated. In this chapter we review recent advances in generating and purifying recombinant forms of the human APC/C and its co-activators, using methods that are scalable and compatible with mutagenesis. We also describe a method that allows the quantitative analysis of APC/C activity using fluorescently labeled substrate proteins. PMID- 26254933 TI - Using the Fly-FUCCI System for the Live Analysis of Cell Cycle Dynamics in Cultured Drosophila Cells. AB - Cultured Drosophila cells are an attractive system for live imaging experiments, as this cell type is not very demanding in terms of temperature and media composition. Moreover, cultured Drosophila cell lines are very responsive to RNAi without being prone to off-target effects, and thus have become important for use in high-content screening. We have developed a fly-specific fluorescent, ubiquitination-based cell cycle indicator (FUCCI) system that enables faithful detection of G1, S, and G2 phases, and is thus a powerful tool for the analysis of cell cycle dynamics in living or fixed cells. Here, we describe a protocol for the generation of cell lines stably expressing the Fly-FUCCI sensors, followed by a description of how these cell lines can be employed in studies of cell cycle oscillation using live microscopy. PMID- 26254934 TI - Imaging Cell Cycle Phases and Transitions of Living Cells from Yeast to Woman. AB - The eukaryotic cell cycle is comprised of different phases that take place sequentially once, and normally only once, every division cycle. Such a dynamic process is best viewed in real time in living dividing cells. The insights that can be gained from such methods are considerably larger than any alternative technique that only generates snapshots. A great number of studies can gain from live cell imaging; however this method often feels somewhat intimidating to the novice. The purpose of this chapter is to demonstrate that imaging cell cycle phases in living cells from yeast to human is relatively easy and can be performed with equipment that is available in most research institutes. We present the different approaches, review different types of reporters, and discuss in depth all the aspects to be considered to obtain optimal results. We also describe our latest cell cycle markers, which afford unprecedented "sub" phase temporal resolution. PMID- 26254935 TI - Measurement of Cdk1/Cyclin B Kinase Activity by Specific Antibodies and Western Blotting. AB - Quantitative measurement of enzyme activity is a valuable approach to study how cells function. We present a method to measure the activity of the enzyme Cdk1/cyclin B. This enzyme is required by all eukaryotic cells to enter mitosis. Therefore, a biochemical assay to measure Cdk1/cyclin B activity can be used to identify cell populations that are in mitosis or to detect inhibitors of Cdk1/Cyclin B in vitro. A key distinction of the method presented here, compared to others, is that it uses a recombinant protein, a specific antibody, and a western blot apparatus, which makes the technique available to cell and molecular biology laboratories who do not wish to use radioisotopes, which are commonly required for other protein kinase assays. PMID- 26254936 TI - Comparison of graft-reinforced repairs and suture repair using a novel biomechanical test. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to determine the feasibility of a novel biomechanical test for evaluating mesh-reinforced repair compared to suture-reinforced repair using an animal model. We hypothesized that the fatigue life of a mesh reinforced repair would be greater than that of xenograft reinforced repair and suture-only repair. METHODS: Wistar rats were randomly assigned to undergo a ventral hernia repair using sutures or one of the three mesh materials representative of incorporation, encapsulation and resorption host responses (Gynemesh, Pelvisoft and Surgisis(r), respectively). All surviving animals were killed at 90 days and specimens containing the prosthesis-tissue interface were exposed to cyclic forces. The number of cycles to failure (fatigue life) was compared between groups using a Cox regression model. RESULTS: Of 40 randomly assigned animals, 11 died before 90 days. After randomizing an additional 5 rats, a total of 34 rats were killed at 90 days. The proportions of specimens that failed before 10,000 cycles were 25% (2/8), 50% (4/8), 62.5% (5/8) and 70% (7/10) in the Gynemesh, Surgisis, Pelvisoft, and suture control groups, respectively. In addition, the median number of cycles to failure was >10,000 in the Gynemesh group, >6,923 in the Surgisis group, 1133 in the Pelvisoft group and 741 in the control group. After adjustment for cross sectional area, the risk of failure in the suture control group was higher than in all of the reinforced repair groups combined with an adjusted hazard ratio of 2.58 (95% CI 0.96 - 6.97), and was statistically significantly higher than in the Gynemesh group with an adjusted hazard ratio of 6.67 (95% CI 1.30 - 34.48). CONCLUSION: We present a novel biomechanical test that can be used to compare mesh materials in an animal model prior to use in humans. In this animal model, after adjusting for cross-sectional area, suture reinforced repair has a higher risk of failure than graft reinforced repair. PMID- 26254937 TI - Urogynecology digest : Presented by Kai Lyn Ng. PMID- 26254938 TI - Association between temporal resolution and Specific Language Impairment: The role of nonsensory processing. AB - INTRODUCTION: Many authors have suggested that a perceptual auditory disorder involving temporal processing is the primary cause of Specific Language Impairment (SLI). The aim of this study was to compare the performance of children with and without SLI on a temporal processing task controlling for the confounding of verbal short-term memory and working memory. METHOD: Thirty participants with SLI aged 6 years were selected, along with 30 age- and gender matched participants with typical language development. The Adaptive Test of Temporal Resolution (ATTR) was used to evaluate temporal resolution ability (an aspect of temporal processing), and the digit span subtest of the Wechsler Intelligence Scale for Children was used to evaluate auditory short-term memory and working memory. RESULTS: The analysis of covariance showed that children with SLI performed significantly worse than children with typical language development on the temporal resolution task (ATTR), even when controlling for short-term memory and working memory. Statistically significant correlations between ATTR and digit span were found for the group of children with SLI but not for the children with typical language development. CONCLUSION: Children with SLI showed significantly worse temporal resolution ability than their peers with typical language development. Such differences cannot be attributed solely to the immediate memory deficit associated with SLI. PMID- 26254940 TI - DFT, QTAIM, and NBO investigations of the ability of the Fe or Ni doped CNT to absorb and sense CO and NO. AB - The structures and intramolecular interactions of complexes (FeCNT-CO, FeCNT-NO, NiCNT-CO, and NiCNT-NO) formed by the Fe or Ni doped single-wall carbon nanotube (FeCNT or NiCNT) and gas CO or NO were studied using density functional theory, quantum theory of atom in molecule (QTAIM), and natural bond orbital methods. The adsorption processes of CO and NO on surfaces of FeCNT and NiCNT are chemisorption, energetically favored, exothermic, and spontaneous. High temperature is not good for adsorption. Introducing NO more obviously elongates the distances between Fe/Ni and C atoms and decreases ?CFe(Ni)C than adding CO. QTAIM analysis shows that the covalent bonding interactions of FeCNT-NO (NiCNT NO) are stronger than that of FeCNT-CO (NiCNT-CO). NO plays a role of electron acceptor while CO is electron donator in complexes. Electrostatic interaction of FeCNT-NO (NiCNT-NO) is stronger than that of FeCNT-CO (NiCNT-CO). The stronger intramolecular interactions of FeCNT-NO and NiCNT-NO reveal that FeCNT and NiCNT are more effective to adsorb and sense NO than CO. CO and NO considerably change the electronic properties of FeCNT and NiCNT, which is useful for designing sensors for CO and NO. PMID- 26254939 TI - Diabetes and Its Effect on Bone and Fracture Healing. AB - Diabetes mellitus is a metabolic disorder that increases fracture risk, interferes with bone formation, and impairs fracture healing. Type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) both increase fracture risk and have several common features that affect the bone including hyperglycemia and increased advanced glycation end product (AGE) formation, reactive oxygen species (ROS) generation, and inflammation. These factors affect both osteoblasts and osteoclasts leading to increased osteoclasts and reduced numbers of osteoblasts and bone formation. In addition to fracture healing, T1DM and T2DM impair bone formation under conditions of perturbation such as bacteria-induced periodontal bone loss by increasing osteoblast apoptosis and reducing expression of factors that stimulate osteoblasts such as BMPs and growth factors. PMID- 26254941 TI - Changes in self-efficacy for exercise and improved nutrition fostered by increased self-regulation among adults with obesity. AB - Behavioral theory suggests that treatments that increase participants' use of self-regulatory skills and/or their feelings of ability (self-efficacy) will improve exercise and nutrition behaviors. In addition, psychosocial factors associated with increased exercise may carry over to improved eating. Self regulation might enhance self-efficacy through feelings of ability to manage barriers to maintaining weight-loss behaviors. Sedentary adults with severe or morbid obesity (M age = 43 years; M BMI = 40.1 kg/m(2)) participated in a 6-month study within a community-based YMCA center. We randomly assigned participants to one of the two groups that incorporated the same cognitive-behavioral support of exercise paired with methods for controlled, healthy eating emphasizing either (a) self-efficacy (n = 138), or (b) self-regulation (n = 136) methods. Mixed model repeated measures ANOVAs indicated significant improvements in exercise- and eating-related self-regulation over 3 months, and exercise- and eating related self-efficacy over 6 months. The Self-Regulation Treatment Group demonstrated greater improvements in self-regulation for eating and fruit and vegetable intake than the Self-Efficacy Group. Regression analyses indicated that for both exercise and eating, self-regulation change significantly predicted self efficacy change. In separate equations, changes in exercise and fruit and vegetable intake mediated those relationships, and change in self-efficacy and the corresponding behavioral changes demonstrated reciprocal, mutually reinforcing, relationships. There was evidence of carry-over, or generalization, of both self-regulation and self-efficacy changes from an exercise context to an eating context. We discussed findings in terms of leveraging self-regulation to improve self-efficacy, and provide a rationale for why exercise is the strongest predictor of success with weight loss. Results may be used to inform future behavioral weight-management treatments through improved knowledge of relationships among theoretically derived psychosocial factors. PMID- 26254942 TI - Synthesis and characterization of oligodeoxyribonucleotides modified with 2'-thio 2'-deoxy-2'-S-(pyren-1-yl)methyluridine. AB - Pyrene-functionalized oligonucleotides are intensively explored for applications in materials science and diagnostics. Here, we describe a short synthetic route to 2'-S-(pyren-1-yl)methyl-2'-thiouridine monomer S, its incorporation into oligodeoxyribonucleotides (ONs), and biophysical characterization thereof. Pseudorotational analysis reveals that the furanose ring of this monomer has a slight preference for South-type conformations. ONs modified with monomer S display high cDNA affinity but decreased binding specificity. Hybridization is associated with bathochromic shifts of pyrene absorption bands and quenching of pyrene fluorescence consistent with an intercalative binding mode of the pyrene moiety. Monomer S was also evaluated as a building block for mixed-sequence recognition of double-stranded DNA via the Invader strategy. However, probes with +1 interstrand arrangements of monomer S were found to be less efficient than Invader probes based on 2'-O-(pyren-1-yl)methyluridine or 2'-N-(pyren-1-yl)methyl 2'-N-methyl-2'-aminouridine. PMID- 26254943 TI - The effect of complexation of 3-formylrifamycin SV macrocyclic ether derivatives with metal cations and small nitrogen-containing organic molecules on antibacterial activity against S. aureus and S. epidermidis. AB - Spectroscopic studies of ether rifamycins (1-9) have shown that all these compounds tend to be zwitterions with different localizations of intramolecularly transferred proton, which influences their solubility and logP values. According to ESI MS studies, rifamycins 3 and 4 form complexes with Li(+) or Na(+), while the other ones (7-9) coordinate small organic molecules, which can be further replaced by Na(+) cation. Biological assays revealed that the use of 7-9 in the form of complexes with small organic molecules improves their antibacterial potency as a result of changed: logP, solubility and binding mode with bacterial RNA polymerases. PMID- 26254944 TI - Cheminformatic comparison of approved drugs from natural product versus synthetic origins. AB - Despite the recent decline of natural product discovery programs in the pharmaceutical industry, approximately half of all new drug approvals still trace their structural origins to a natural product. Herein, we use principal component analysis to compare the structural and physicochemical features of drugs from natural product-based versus completely synthetic origins that were approved between 1981 and 2010. Drugs based on natural product structures display greater chemical diversity and occupy larger regions of chemical space than drugs from completely synthetic origins. Notably, synthetic drugs based on natural product pharmacophores also exhibit lower hydrophobicity and greater stereochemical content than drugs from completely synthetic origins. These results illustrate that structural features found in natural products can be successfully incorporated into synthetic drugs, thereby increasing the chemical diversity available for small-molecule drug discovery. PMID- 26254945 TI - Outcomes After Ulnar Nerve In Situ Release During Total Elbow Arthroplasty. AB - PURPOSE: Ulnar nerve (UN) lesions are a significant complication after total elbow arthroplasty (TEA), with potentially debilitating consequences. Outcomes from a center, which routinely performs an in situ release of the nerve without transposition, were investigated. METHODS: Eighty-three primary TEAs were retrospectively reviewed for the intraoperative management of the UN and presence of postoperative UN symptoms. RESULTS: Three patients had documented preoperative UN symptoms. One patient had a prior UN transposition. The nerve was transposed at the time of TEA in 4 of the remaining 82 elbows (5%). The indication for transposition in all cases was abnormal tracking or increased tension on the nerve after insertion of the prosthesis. Of the 4 patients who underwent UN transposition, 2 had postoperative UN symptoms. Both were neuropraxias, which resolved in the early postoperative period. The remaining 78 TEAs received an in situ release of the nerve. The incidence of postoperative UN symptoms in the in situ release group was 5% (4 of 78). Two patients had resolution of symptoms, whereas 2 continued to experience significant UN symptoms requiring subsequent transposition. Seven patients had preoperative flexion of less than 100 degrees . Of these, 2 had a UN transposition at the time of TEA. Of the remaining 5 elbows with preoperative flexion less than 100 degrees , 2 had postoperative UN symptoms after in situ release, with 1 requiring subsequent UN transposition. CONCLUSIONS: A 3% incidence of significant UN complications after TEA compares favorably with systematic reviews. We do not believe that transposition, which adds to the handling of the nerve and increases surgical time, is routinely indicated and should rather be reserved for cases with marked limitation of preoperative elbow flexion or when intraoperative assessment by the surgeon deems it necessary. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26254946 TI - Symbrachydactyly - Diagnosis, Function, and Treatment. AB - Symbrachydactyly is a congenital hand difference that presents with diverse morphologic forms and can be confused with many other congenital hand differences. Congenital hand difference classification schemes categorize symbrachydactyly as an undergrowth or failure of axis formation. It is further categorized by the number of affected fingers, by morphologic characteristics, and by the functional status of the hand. Symbrachydactyly represents a disruption of embryonic formation and differentiation that results in a hand shorter and smaller than the contralateral with underdeveloped often short or webbed digits, digital nubbins, or absent digits. Treatment is patient specific and should be guided to improve the function and appearance of the hand. PMID- 26254947 TI - Greater Resting Lumbar Extensor Myofascial Stiffness in Younger Ankylosing Spondylitis Patients Than Age-Comparable Healthy Volunteers Quantified by Myotonometry. AB - OBJECTIVE: To quantify resting lumbar erector myofascial stiffness in younger patients with ankylosing spondylitis (AS) and age-comparable healthy control subjects using a handheld mechanical impulse-based myotonometric device. DESIGN: A case-control study of 24 patients with AS and 24 age-comparable healthy control subjects. SETTING: University physical therapy department. PARTICIPANTS: Patients with AS (men: n=19; women: n=5; total: N=24) and healthy volunteers (men: n=19; women: n=5; total: N=24) without low back pain (age range, 18-46y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Lumbar myofascial stiffness. RESULTS: At the initial measurements, median stiffness (Nm) of the averaged right and left-sided values was greater (P=.021) in 24 patients with AS than 24 control subjects (268.9 vs 238.9, respectively). Repeated measurements after a 10 minute prone resting period were also greater (P=.007) in patients with AS than control subjects (281.0 vs 241.4, respectively). The 48 averaged right- and left sided values from baseline and 10-minute measurements were compared in each subject group. The patients with AS more frequently (P=.012) had stiffness values >250 Nm (35 [72.9%] vs 22 [45.8%] in control subjects). CONCLUSIONS: Lumbar myofascial stiffness was greater in 24 patients with AS than in the control subjects. A hypothesized biomechanical concept of increased resting lumbar myofascial stiffness in AS may be supported by this preliminary controlled study. PMID- 26254948 TI - Efficacy of a Telephone-Delivered Self-Management Intervention for Persons With Multiple Sclerosis: A Randomized Controlled Trial With a One-Year Follow-Up. AB - OBJECTIVE: To evaluate the efficacy of a telephone-delivered self-management intervention for fatigue, pain, and depression in adults with multiple sclerosis (MS). DESIGN: Single-center, randomized (1:1), single-blind (outcome assessors), parallel-group trial with a primary endpoint of posttreatment (9-11 wk postrandomization) and long-term follow-up at 6 and 12 months. SETTING: Telephone delivered across the United States. PARTICIPANTS: Adults with MS (N=163) with fatigue, chronic pain, and/or moderate depressive symptoms (age range, 25-76 y). INTERVENTIONS: Eight-week individual telephone-delivered self-management intervention (T-SM) (n=75) versus an 8-week individual telephone-delivered MS education intervention (T-ED) (n=88). MAIN OUTCOME MEASURES: The primary outcome was the proportion who achieved a >=50% decrease in 1 or more symptoms-fatigue impact, pain interference, and/or depression severity. Secondary outcomes included continuous measures of pain, fatigue impact, depression, self-efficacy, activation, health-related quality of life, resilience, and affect. RESULTS: For our primary outcome, 58% of those in the T-SM group and 46% of those in the T-ED group had a >=50% reduction in 1 or more symptoms; this difference was not statistically significant (odds ratio, 1.50; 95% confidence interval, .77-2.93; P=.238). Participants in both groups significantly improved from baseline to posttreatment in primary and secondary outcome measures (P<.05). T-SM participants reported significantly higher treatment satisfaction and therapeutic alliance and greater improvements in activation, positive affect, and social roles. Improvements were generally maintained at 6 and 12 months. CONCLUSIONS: Both interventions resulted in short- and long-term, clinically meaningful benefits. The study demonstrated that the telephone is an effective method for engaging participants in care and extending the reach of rehabilitation for individuals with MS. PMID- 26254949 TI - Functional and Mental Health Status of United Kingdom Military Amputees Postrehabilitation. AB - OBJECTIVES: To evaluate the functional and mental health status of severely injured traumatic amputees from the United Kingdom military at the completion of their rehabilitation pathway and to compare these data with the published normative data. DESIGN: Retrospective independent group comparison of descriptive rehabilitation data recorded postrehabilitation. SETTING: A military complex trauma rehabilitation center. PARTICIPANTS: Amputees (N=65; mean age, 29+/-6 y) were evaluated at the completion of their rehabilitation pathway; of these, 54 were operationally (combat) injured (23 unilateral, 23 bilateral, 8 triple) and 11 nonoperationally injured (all unilateral). INTERVENTIONS: Continuous ~4-week inpatient, physician-led, interdisciplinary rehabilitation followed by ~4-weeks of patient-led, home-based rehabilitation. MAIN OUTCOME MEASURES: The New Injury Severity Score at the point of injury was used as the baseline reference. The 6 minute walk test, Amputee Mobility Predictor with Prosthesis, Special Interest Group in Amputee Medicine, Defence Medical Rehabilitation Centre mobility and activity of daily living scores as well as depression (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder Scale-7), mental health support, and pain scores were recorded at discharge and compared with the published normative data. RESULTS: The mean New Injury Severity Score was 40+/ 15. After 34+/-14 months of rehabilitation, amputees achieved a mean 6-minute walk distance of 489+/-117 m compared with age-matched normative distances of 459 to 738 m. The 2 unilateral groups walked (544 m) significantly further (P>.05) than did the bilateral amputee (445+/-104 m) and triple amputee (387+/-99 m) groups. All groups demonstrated mean functional mobility scores consistent with scores of either active adults or community ambulators with limb loss. In total, 85% could walk/run independently and 95% could walk and perform activities of daily living independently with an aid/adaptation. No significant difference in mental health outcome was reported between the groups (P>.05). At discharge, 98% of patients were able to control their pain. CONCLUSIONS: Severely injured military amputees who completed intensive interdisciplinary rehabilitation achieved levels of physical function comparable with those in age-matched healthy adults. Mental health outcomes were indicative of preparedness for full integration back into society. PMID- 26254950 TI - Specific Brain Lesions Impair Explicit Motor Imagery Ability: A Systematic Review of the Evidence. AB - OBJECTIVE: To determine which neurologic disorders/lesions impair or restrict motor imagery (MI) ability. DATA SOURCES: CINAHL, Cochrane, Embase, MEDLINE, Web of Science, PsychINFO, Physiotherapy Evidence Database, and Grey Literature were searched between May 8 and May 14, 2014. Keywords and Medical Subject Headings from 2 concepts (MI and lesion) were exploded to include related search terms (eg, mental practice/mental imagery, neurologic damage/lesion). STUDY SELECTION: Two independent reviewers assessed the 3861 studies that resulted from the database search. The studies were assessed for relevancy using the following inclusion criteria: use of explicit kinesthetic MI; neurologic lesion location identified; and use of an MI ability assessment tool. DATA EXTRACTION: Twenty three studies encompassing 196 participants were included. The 23 studies used 8 different methods for assessing MI ability. MI assessment scores were then normalized to facilitate comparison across studies. DATA SYNTHESIS: Lesion locations comprised many brain areas, including cortical (eg, parietal and frontal lobes), subcortical (eg, basal ganglia, thalamus), and cerebellum. Lesion etiology primarily was comprised of stroke and Parkinson disease. Several participants presented with lesions resulting from other pathologies. Subjects with parietal lobe damage were most impaired on their ability to perform MI. Subjects with frontal lobe and basal ganglia damage also consistently showed impairment in MI ability. CONCLUSIONS: Subjects with damage to specific brain structures, including the parietal and frontal lobes, showed impaired MI ability. As such, MI-based neurorehabilitation may not be efficacious in all patient populations. Therefore, decisions related to the use of MI in neurorehabilitation should, in part, be based on the patient's underlying pathophysiology. PMID- 26254951 TI - Simple Lower Limb Functional Tests in Patients With Chronic Obstructive Pulmonary Disease: A Systematic Review. AB - OBJECTIVES: To evaluate the characteristics and available evidence on the measurement properties of the gait speed (GS) test, timed Up and Go test (TUG), sit-to-stand (STS) test, and step test; to investigate their relation with clinical outcomes in chronic obstructive pulmonary disease (COPD); and to provide recommendations for clinical practice and future research. DATA SOURCES: Studies were systematically identified from a literature search using PubMed, PEDro, CINAHL, and Cochrane Library databases and the reference lists of the included articles. STUDY SELECTION: Studies including >=1 of these 4 lower limb functional tests (GS test, TUG, STS test, and step test) as an outcome in patients with COPD were selected. No limits were applied for language and study design. DATA EXTRACTION: Two researchers independently performed data extraction and, by using the COnsensus-based standards for the Selection of health status measurement INstruments, assessed the quality of those studies that described measurement properties. DATA SYNTHESIS: Forty-two articles met the selection criteria. GS test, STS test, and step test are valid, reproducible, and responsive tests, especially the 4-meter GS, 5-repetition STS test, and 6-minute step test (6MST). The TUG is reliable; however, studies on other measurement properties of this test are lacking. Outcomes of these tests are correlated with mortality, physical activity in daily life, exercise capacity, dyspnea, and quality of life. CONCLUSIONS: Simple and functional lower limb tests provide information about important clinical outcomes in patients with COPD. The 4-meter GS, 5-repetition STS test, and 6MST are tests with well-established psychometric properties, whereas the properties of the TUG need to be studied further. PMID- 26254952 TI - Prolotherapy for Refractory Rotator Cuff Disease: Retrospective Case-Control Study of 1-Year Follow-Up. AB - OBJECTIVE: To determine the efficacy of prolotherapy for refractory rotator cuff disease. DESIGN: Retrospective case-control study. SETTING: University-affiliated tertiary care hospital. PARTICIPANTS: Patients with nontraumatic refractory rotator cuff disease (N=151) who were unresponsive to 3 months of aggressive conservative treatment. Of the patients, 63 received prolotherapies with 16.5% dextrose 10-ml solution (treatment group), and 63 continued conservative treatment (control group). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Visual analog scale (VAS) score of the average shoulder pain level for the past 1 week, Shoulder Pain and Disability Index (SPADI) score, isometric strength of the shoulder abductor, active range of motion (AROM) of the shoulder, maximal tear size on ultrasonography, and number of analgesic ingestions per day. RESULTS: Over 1-year follow-up, 57 patients in the treatment group and 53 in the control group were analyzed. There was no significant difference between the 2 groups in age, sex, shoulder dominance, duration of symptoms, and ultrasonographic findings at pretreatment. The average number of injections in the treatment group is 4.8+/ 1.3. Compared with the control group, VAS score, SPADI score, isometric strength of shoulder abductor, and shoulder AROM of flexion, abduction, and external rotation showed significant improvement in the treatment group. There were no adverse events. CONCLUSIONS: To our knowledge, this is the first study to assess the efficacy of prolotherapy in rotator cuff disease. Prolotherapy showed improvement in pain, disability, isometric strength, and shoulder AROM in patients with refractory chronic rotator cuff disease. The results suggest positive outcomes, but one should still take caution in directly interpreting it as an effective treatment option, considering the limitations of this nonrandomized retrospective study. To show the efficacy of prolotherapy, further studies on prospective randomized controlled trials will be required. PMID- 26254953 TI - Effects of a 6-Week Indoor Hand-Bike Exercise Program on Health and Fitness Levels in People With Spinal Cord Injury: A Randomized Controlled Trial Study. AB - OBJECTIVE: To investigate the effects of a 6-week indoor hand-bike exercise program on fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) levels and physical fitness in people with spinal cord injury (SCI). DESIGN: Randomized controlled trial. SETTING: National rehabilitation center (outpatient). PARTICIPANTS: Participants with SCI (N=15; exercise group: n=8, control group: n=7). INTERVENTIONS: This study involved 60-minute exercise sessions on an indoor hand-bike. Participants in the exercise group exercised 3 times per week for 6 weeks. MAIN OUTCOME MEASURES: Health parameters (body mass index [BMI], waist circumference, percent body fat, insulin level, and HOMA-IR level) and fitness outcomes (peak oxygen consumption [Vo2peak], shoulder abduction and adduction, shoulder flexion and extension, and elbow flexion and extension). RESULTS: Participation in a 6-week exercise program using an indoor hand-bike significantly decreased BMI (baseline: 22.0+/-3.7 m/kg(2) vs postintervention: 21.7+/-3.5 m/kg(2), P=.028), fasting insulin (baseline: 5.4+/ 2.9 MUU/mL vs postintervention: 3.4+/-1.5 MUU/mL, P=.036), and HOMA-IR (baseline: 1.0+/-0.6 vs postintervention: 0.6+/-0.3, P=.03) levels compared with those in the control group. Furthermore, this training program significantly increased Vo2peak and strength in shoulder abduction, adduction, flexion, and extension and elbow flexion and extension compared with those in the control group. CONCLUSIONS: Exercise using an indoor hand-bike appears to be an effective modality to improve body composition, fasting insulin, and HOMA-IR levels and fitness in people with an SCI. PMID- 26254954 TI - Observational Gait Assessments in People With Neurological Disorders: A Systematic Review. AB - OBJECTIVE: To analyze the clinical and psychometric properties of observational gait assessment scales in people with neurological disorders. DATA SOURCES: The databases used for the literature search were MEDLINE, the Cochrane Central Register of Controlled Trial, Web of Science, and the Cumulative Index to Nursing and Allied Health. The search was conducted between September 15 and November 30, 2014. STUDY SELECTION: Studies that investigate and validate observational gait assessment scales in people with central nervous system disorders. DATA EXTRACTION: General characteristics of the studies, including number of patients and observational gait assessment scales analyzed and their psychometric properties, were extracted. DATA SYNTHESIS: After the literature search, 15 articles were included in this review. Seven of the 15 articles studied the Tinetti Gait Scale (TGS), 2 studied the Rivermead Visual Gait Assessment (RVGA), 1 studied the Gait Assessment and Intervention Tool (G.A.I.T.), 3 studied the Wisconsin Gait Scale, and one of them compared the TGS and the G.A.I.T. CONCLUSIONS: The scale that appears to be the most suitable for both clinical practice and research is the G.A.I.T. because it has shown to be valid, reliable, and sensitive to change, homogeneous, and comprehensive, containing a large number of items that assess most components of the gait pattern. The RVGA was studied in those with diverse neurological disorders, including multiple sclerosis. For those with Parkinson disease, the TGS showed sensitivity and the Tinetti Performance-Oriented Mobility Assessment (POMA) showed predictive capability for falls and mortality as well as intra- and interrater reliability. The Tinetti POMA was also studied in those with normal pressure hydrocephalus, showing sensitivity and in those with Huntington disease, showing reliability and validity. More research is needed to more comprehensively analyze the psychometric properties of the RVGA, Wisconsin Gait Scale, TGS, and G.A.I.T. in patients with diverse neurological disorders, other than stroke. PMID- 26254955 TI - C9ORF72 hexanucleotide repeat expansion in ALS patients from the Central European Russia population. AB - Cohorts of amyotrophic lateral sclerosis (ALS) patients and control individuals of Caucasian origin from the Central European Russia (Moscow city and region) were analyzed for the presence of hexanucleotide repeat GGGGCC expansion within the first intron of the C9ORF72 gene. The presence of a large (>40) repeat expansion was found in 15% of familial ALS cases (3 of 20 unrelated familial cases) and 2.5% of sporadic ALS cases (6 of 238) but in none of control cases. These results suggest that the frequency of C9ORF72 hexanucleotide repeats expansions in the Central European Russian ALS patients is significantly lower than in Western European or Northern American ALS patients of Caucasian origin but higher than in Asian ALS patients. PMID- 26254956 TI - Heroin abuse exaggerates age-related deposition of hyperphosphorylated tau and p62-positive inclusions. AB - The observation of increased hyperphosphorylated tau levels correlating with microglial activation in opiate abusers has been interpreted as predisposition to accelerated Alzheimer disease-related changes. The present study focused on evaluating additional neurodegeneration-related proteins, including alpha synuclein and TDP-43, and p62-positive deposits. We performed a systematic mapping of protein deposits in the brains of 27 individuals with documented heroin addiction (age: 19-40 years) and compared with 11 controls (age: 15-40 years). We confirm previous findings that heroin addiction associates with tau hyperphosphorylation in predilection brain areas for aging and Alzheimer disease. Furthermore, we show that this occurs also in areas implicated in the molecular disturbances and in vivo neuronal networks related to heroin abuse. There was, however, no presence of amyloid-beta deposits. We extend previous findings by showing the lack of TDP-43 or alpha-synuclein pathology and emphasize the independent effect of the duration of drug use on the appearance of age-related p62-positive neuritic profiles. These observations provide unique insights about neuropathological alterations in the brains of young heroin addicts and have implications about brain aging and the influences of environmental and toxic factors. PMID- 26254957 TI - Postural changes associated with ageing on the sensory organization test and the limits of stability in healthy subjects. AB - OBJECTIVE: Acknowledgement of the age effects on postural control and balance is essential to differentiate between physiological changes and actual pathological alterations of the elderly. The aim of this study is to establish the age-related postural changes recorded by the Computerized Dynamic Posturography. MATERIAL AND METHODS: 70 healthy individuals (35 males and 35 females) with an average age of 44.9 years, evenly distributed in seven age groups. We carried out a Sensory Organization Test and Limits of Stability with the Neurocom Smart Balance Master((r)) posturography platform. Statistical analysis was undertaken using ANOVA (p<0.05). RESULTS: Increased age-related balance percentage for Condition 4 (p=0.022), reduced usage rate of ankle-strategy for Conditions 3 (p=0.027) and 4 (p=0.05) for the higher age groups were reported. Regarding limits of stability, the following were the results: age-related differences at an early stage, reaction time from 40 to 49 years, velocity of movement, excursion and directional control from 50 to 59 years. CONCLUSIONS: Age only affects the balance rate under more complex sensory conditions. For healthy people, ankle strategy is more frequently used than hip strategy; however, the use of hip strategy increases under more difficult sensory conditions. Limits of stability get worse with age, namely after the age of 40-50 years. PMID- 26254958 TI - Role of TLRs in the production of chemical mediators in nasal polyp fibroblasts by fungi. AB - OBJECTIVE: Fibroblasts are major supporting cells in nasal mucosa and can induce inflammatory process with recruitment of inflammatory cells. Airborne fungi have been suggested as an etiologic factor of chronic rhinosinusitis (CRS). The aim of this study was to investigate the interaction between airborne fungi and pattern recognition receptors (PRRs) in nasal fibroblasts. METHODS: Primary nasal polyp fibroblasts were cultured with Alternaria and Aspergillus for 48h. To determine the production of chemical mediators interleukine-6 (IL-6), IL-8, granulocyte macrophage colony stimulating factor (GM-CSF), eotaxin, and regulated on activation normal T expressed and secreted (RANTES) were measured with enzyme immunoassay methods. PRRs for toll-like receptors (TLRs) and protease-activated receptors (PARs) mRNA were determined with reverse transcription polymerase chain reaction (RT-PCR). To determine the role of PRRs, fibroblasts were treated with small interfering RNA (siRNA). RESULTS: IL-6 and IL-8 productions were significantly increased by 50 and 100MUg/ml of Alternaria. However, GM-CSF, eotaxin, and RANTES productions did not change. Aspergillus did not influence the production of chemical mediators from nasal polyp fibroblasts. TLR2 and TLR5 mRNA expressions were significantly increased by fungi and these two TLRs were associated with the production of IL-6 and IL-8. CONCLUSION: Alternaria interacts as a pathogen-associated molecular pattern with the PRRs, such as TLR2 and TLR5, which induce the production of inflammatory chemical mediators from nasal polyp fibroblasts. Airborne fungi enhance the innate immune defense mechanism and may be associated with the pathogenesis of nasal inflammatory diseases. PMID- 26254959 TI - Exploring the role of biogenic amines in schistosome host-parasite interactions. AB - Biogenic amines (BAs) are important neurotransmitters of the schistosome nervous system, but their role in the host-parasite interaction is poorly understood. Recent findings suggest that BAs may play an important role in the interaction with the snail intermediate host. This new evidence adds an important piece of information to our understanding of this complex system. PMID- 26254960 TI - A mosquito mediator of parasite-induced immune priming. AB - Immune memory is a central feature of the mammalian adaptive immune system. The more primitive innate immune system of insects has also been shown to comprise memory, or immune priming. A recent study has shed new light on how Plasmodium primes the mosquito immune system for greater resistance to a subsequent infection with the same pathogen. PMID- 26254962 TI - An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. AB - BACKGROUND: The presence of coronary artery calcification (CAC) and its severity predict future cardiovascular events and is used for risk stratification. However, the association of CAC with heart failure (HF) in patients without a history of coronary artery disease (CAD) remains unclear. This study aimed to determine the correlations of CAC with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and HF events in patients without a history of CAD or HF. METHODS: From June 2010 to June 2013, a total of 487 patients without a history of CAD and HF were enrolled. All of the patients underwent plane multi-detector computed tomography. They were divided into four categories according to CAC scores: <=10, 11-100, 101-400, and >=401. RESULTS: The proportion of patients with high NT proBNP levels increased with CAC categories (p<0.0001). The CAC score was associated with NT-proBNP levels >=400pg/ml, with an odds ratio of 2.901 (95% confidence interval: 1.368-6.151, p=0.0055) for CAC scores >=401 compared with CAC scores of 0-10 after adjustment for confounding factors. During the follow-up period of 497+/-315 days, nine patients were admitted for HF. Kaplan-Meier analysis showed that patients with CAC scores >=401 had a lower rate of freedom from admission for HF with cumulative incidences of 0.4%, 1%, 2%, and 8% for CAC scores of 0-10, 11-100, 101-400, and >=401, respectively (p<0.0001). Increasing CAC scores were associated with an increase in incidence of admission for HF, with a hazard ratio of 10.371 for CAC scores >=401 (95% CI: 1.062-101.309, p=0.0443) compared with CAC scores of 0-10 after adjustment for risk factors. CONCLUSION: Severe CAC is an independent determinant of high NT-proBNP levels and a predictor of admission for HF in a population without a history of CAD or HF. PMID- 26254961 TI - Innervation of the heart: An invisible grid within a black box. AB - Autonomic control of cardiovascular function is mediated by a complex interplay between central, peripheral, and innate cardiac components. This interplay is what mediates the normal cardiovascular response to physiologic and pathologic stressors, including blood pressure, cardiac contractile function, and arrhythmias. However, in order to understand how modern therapies directly affecting autonomic function may be harnessed to treat various cardiovascular disease states requires an intimate understanding of anatomic and physiologic features of the innervation of the heart. Thus, in this review, we focus on defining features of the central, peripheral, and cardiac components of cardiac innervation, how each component may contribute to dysregulation of normal cardiac function in various disease states, and how modulation of these components may offer therapeutic options for these diseases. PMID- 26254963 TI - Ethanol self-administration in mice under a second-order schedule. AB - Long Fixed-Interval (FI) schedules, particularly second-order schedules, can engender substantial responding before drug or ethanol delivery that is uninfluenced by the direct effects of the drug or ethanol. Thus, these schedules can be used to study the effects of medications upon drug- or ethanol-seeking, uninfluenced by the direct effects of the self-administered drug or ethanol. Long FI second-order schedules are frequently used in primates and occasionally in rats. Under second-order schedules, completion of one response requirement, e.g., a Fixed Ratio 10 (FR10:S), produces a brief stimulus presentation, e.g., a 1-s 80 dB 4-kHZ tone, and this FR10:S serves as the response unit under another schedule, e.g., an FI 1800-s. Thus, the first FR10 completed after 1800 s would result in delivery both of the tone and of reinforcement, e.g., 10 * 0.01 mL 16% (w/v) ethanol. To examine if such schedules could be effectively used in mice, which have advantages in neurobiological and genetic studies, we trained eight C57BL/6J mice to respond under the schedule just described. This schedule maintained substantial responding. The temporal pattern of behavior was typical of an FI schedule with responding accelerating across the interval. We also examined the effects of acute and chronic administration of fluvoxamine on this responding, and these were modest. Finally, we examined responding when alcohol and/or tone deliveries were withheld, and found that extinction occurred most rapidly when both were withheld. This work demonstrates that long FI schedules of ethanol delivery may be useful in studying ethanol seeking in mice. PMID- 26254964 TI - Anxiety-like behaviors at the end of the nocturnal period in sP rats with a "history" of unpredictable, limited access to alcohol. AB - Recent research found that exposure of selectively bred, Sardinian alcohol preferring (sP) rats to multiple alcohol concentrations (10%, 20%, and 30%, v/v), under the 4-bottle "alcohol vs. water" choice regimen, in daily 1-h drinking sessions with an unpredictable time schedule, promoted high intakes of alcohol (>=2 g/kg) when the drinking session occurred over the final hours of the dark phase of the light/dark cycle. The present study investigated whether these high intakes of alcohol (a) were associated with alterations in rats' emotional state (Experiment 1) and (b) were pharmacologically manipulable (Experiment 2). In both experiments, over a period of 12 days, sP rats were initially exposed daily to a 1-h drinking session during the dark phase; time of alcohol exposure was changed each day and was unpredictable to rats. The day after this 12-day drinking phase, rats were (a) exposed to the Social Interaction (SI) test at the 1st or 12th hour of the dark phase with no alcohol available (Experiment 1) or (b) treated with the positive allosteric modulator of the GABAB receptor, GS39783 (0, 25, 50, and 100 mg/kg, intragastrically [i.g.]), and exposed to a drinking session at the 12th hour of the dark phase (Experiment 2). In Experiment 1, rats exposed to the SI test during the 12th hour spent approximately 35% less time in "social" behaviors than rats exposed to the SI test during the 1st hour. No difference in "social" behaviors was observed between alcohol-naive sP rats exposed to the SI test at the 1st and 12th hour. In Experiment 2, all doses of GS39783 selectively reduced alcohol intake. These results suggest that (a) expectation of alcohol availability likely exacerbated the anxiety-like state of sP rats and (b) the GABAB receptor is part of the neural substrate underlying these exceptionally high intakes of alcohol in sP rats. PMID- 26254966 TI - Time-dependent effect of ethanol force-feeding on glycogen repletion: NMR evidence of a link with ATP turnover in rat liver. AB - The purpose was to study the hepatic effects of low-dose ethanol on the links between ATP and glycogen production. Fasted male Wistar rats received a single force-feeding of glucose plus ethanol or isocaloric glucose. At different times after force-feeding (0-10 h), glycogen repletion and ATP characteristics (content, apparent catalytic time constant, mitochondrial turnover) were monitored by (13)C- or (31)P-nuclear magnetic resonance (NMR) in perfused and isolated liver. In vivo glycogen repletion after force-feeding was slower after glucose plus ethanol vs. glucose (12.04 +/- 0.68 and 8.50 +/- 0.86 MUmol/h/g liver wet weight [ww], respectively), reaching a maximum at the 6th hour. From the 3rd to the 8th hour, glycogen content was lower after glucose plus ethanol vs. glucose. After glucose plus ethanol, the correlation between glycogen and ATP contents presented two linear steps: before and after the 3rd hour (30 and 102 MUmol glycogen/g ww per MUmol ATP/g ww, respectively, the latter being near the single step measured in glucose). After glucose plus ethanol, ATP turnover remained stable for 2 h, was 3-fold higher from the 3rd hour to the 8th hour, and was higher than after glucose (2.59 +/- 0.45 and 1.39 +/- 0.19 MUmol/min/g ww, respectively). In the 1st hour, glucose plus ethanol induced a transient acidosis and an increase in the phosphomonoesters signal. In conclusion, after ethanol consumption, a large part of the ATP production was diverted to redox re equilibrium during the first 2 h, thereby reducing the glycogen synthesis. Thereafter, the maintenance of a large oxidative phosphorylation allowed the stimulation of glycogen synthesis requiring ATP. PMID- 26254965 TI - Homer2 within the nucleus accumbens core bidirectionally regulates alcohol intake by both P and Wistar rats. AB - In murine models of alcoholism, the glutamate receptor scaffolding protein Homer2 bidirectionally regulates alcohol intake. Although chronic alcohol drinking increases Homer2 expression within the core subregion of the nucleus accumbens (NAc) of alcohol-preferring P rats, the relevance of this neuroadaptation for alcohol intake has yet to be determined in rats. Thus, the present study employed an adeno-associated viral vector (AAV) strategy to over-express and knock down the major rodent isoform Homer2b within the NAc of both P and outbred Wistar rats to examine for changes in alcohol preference and intake (0-30% v/v) under continuous-access procedures. The generalization of AAV effects to non-drug, palatable, sweet solutions was also determined in tests of sucrose (0-5% w/v) and saccharin (0-0.125% w/v) intake/preference. No net-flux in vivo microdialysis was conducted for glutamate in the NAc to relate Homer2-dependent changes in alcohol intake to extracellular levels of glutamate. Line differences were noted for sweet solution preference and intake, but these variables were not affected by intra-NAc AAV infusion in either line. In contrast, Homer2b over-expression elevated, while Homer2b knock-down reduced, alcohol intake in both lines, and this effect was greatest at the highest concentration. Strikingly, in P rats there was a direct association between changes in Homer2b expression and NAc extracellular glutamate levels, but this effect was not seen in Wistar rats. These data indicate that NAc Homer2b expression actively regulates alcohol consumption by rats, paralleling this previous observation in mice. Overall, these findings underscore the importance of mesocorticolimbic glutamate activity in alcohol abuse/dependence and suggest that Homer2b and/or its constituents may serve as molecular targets for the treatment of these disorders. PMID- 26254967 TI - [Lyme disease in paediatrics]. PMID- 26254968 TI - [Diffuse cutaneous mastocytosis. Presentation of 3 cases and therapeutic management review]. PMID- 26254969 TI - [Viral wart treatment with green tea sinecatechins]. PMID- 26254970 TI - Development of a higher power cooling system for lithium targets. AB - The accelerator based Boron Neutron Capture Therapy beam at the University of Birmingham is based around a solid thick lithium target cooled by heavy water. Significant upgrades to Birmingham's Dynamitron accelerator are planned prior to commencing a clinical trial. These upgrades will result in an increase in maximum achievable beam current to at least 3 mA. Various upgrades to the target cooling system to cope with this increased power have been investigated. Tests of a phase change coolant known as "binary ice" have been carried out using an induction heater to provide a comparable power input to the Dynamitron beam. The experimental data shows no improvement over chilled water in the submerged jet system, with both systems exhibiting the same heat input to target temperature relation for a given flow rate. The relationship between the cooling circuit pumping rate and the target temperature in the submerged jet system has also been tested. PMID- 26254971 TI - An overview on neuroprotective effects of isothiocyanates for the treatment of neurodegenerative diseases. AB - The discovery of new natural compounds with pharmacological properties is a field of interest widely growing, especially for the management of neurodegenerative diseases. As no pharmacological treatment is available to prevent the development of these disorders, dietary intake of foods or plant-based extracts with antioxidant properties might have beneficial effects on human health and improve brain functions. Isothiocyanates (ITCs), derived from the hydrolysis of the corresponding glucosinolates (GLs), mainly found in Brassica vegetables (Brassicaceae) and, to a lesser extent, in Moringaceae plants, have demonstrated to exert neuroprotective properties. Specifically, strong evidences suggest that antioxidant effects may be ascribed mainly to their peculiar ability to activate the Nrf2/ARE pathway, but alternative mechanisms of action have also been suggested. This review summarizes the current knowledge about the neuroprotective effects of ITCs in counteracting oxidative stress as well as inflammatory and apoptotic mechanisms, using in vitro and in vivo models of acute and chronic neurodegenerative disease. Therefore, ITCs could be regarded as a promising source of alternative medicine for the prevention and/or treatment of neurodegenerative diseases. PMID- 26254972 TI - The incidence and features of systemic reactions to skin prick tests. AB - BACKGROUND: Skin prick testing (SPT) has been regarded as a safe procedure with few systemic reactions. OBJECTIVE: To evaluate the rate of systemic reactions and their associations after SPT in the largest population to date. METHODS: In this study reactions were recorded prospectively in a specialist UK allergy clinic for 6 years (2007-2013). An estimated 31,000 patients underwent SPT. RESULTS: Twenty four patients (age range 7 months to 56 years, mean 23.5 years, 17 female patients, 12 with asthma) had systemic reactions. The rate of systemic reactions to SPT was 0.077%. The likely allergens causing the reaction were foods (18; peanut, 7; walnut, 1; Brazil nut, 2; pistachio, 1; lupin, 1; cow's milk, 2; shrimp, 1; spinach, 1; legume, 1; soy, 1), aeroallergens (4; rabbit, 1; rat, 1; ragwort, 1; grass pollen, 1), wasp venom (1), and Tazocin (1). The causative SPT wheal was larger than 8 mm in 75%. The reaction to Tazocin was severe, with anaphylaxis occurring minutes after SPT. Reactions were treated immediately in the clinic and did not require further medical care. CONCLUSION: In this largest single-center study, the rate of systemic reactions after SPT was 77 per 100,000 patients. It is the first study to identify foods as a common and important cause (75%), with nuts posing the highest risk. This study reports the first systemic reaction to venom SPT and the first anaphylactic reaction after drug SPT. There was an association with a history of severe reactions and large skin test reaction. There are risks, albeit small, when undertaking SPT. PMID- 26254973 TI - Emerging therapeutic options for the treatment of patients with symptomatic asthma. AB - OBJECTIVE: Asthma is a chronic inflammatory disorder of the airways with increasing worldwide prevalence. Despite treatment according to guidelines, a considerable proportion of patients with asthma remain symptomatic. Different potential therapeutic options for the treatment of these patients are currently in development and undergoing clinical trials, and it is important to regularly review their status. DATA SOURCES: A search of ClinicalTrials.gov was performed and supported by a PubMed literature search and restricted to the previous 10 years to ensure currency of data. The results were manually filtered to identify relevant articles. STUDY SELECTIONS: Emerging therapies that are currently in phase 2 and 3 development include anti-interleukin agents (benralizumab, reslizumab, dupilumab, brodalumab, lebrikizumab, and mepolizumab), a chemoattractant receptor-homologous molecule expressed on a T-helper type 2 lymphocyte antagonist (OC000459), a phosphodiesterase-4 inhibitor (roflumilast), and long-acting muscarinic antagonists (glycopyrronium bromide, umeclidinium bromide, and tiotropium bromide). RESULTS: The clinical trial program of the long acting muscarinic antagonist tiotropium is currently the most advanced, with data available from different phase 2 and 3 studies. Results demonstrate that it is an efficacious add-on to at least inhaled corticosteroid maintenance therapy across severities of symptomatic asthma. CONCLUSION: The results of ongoing and future studies will help to determine whether these emerging therapeutic options will help address the unmet need for improvement in asthma management. PMID- 26254974 TI - Comment on "Characterization of hazardous and odorous volatiles emitted from scented candles before lighting and when lit". PMID- 26254975 TI - A stereolithographic resin pattern for evaluating the framework, altered cast partial removable dental prosthesis impression, and maxillomandibular relationship record in a single appointment. AB - Fabricating a partial removable dental prosthesis usually requires 3 separate visits to evaluate the framework, altered cast impression, and maxillomandibular relationship record. This article describes an alternative technique for accomplishing each of these procedures in a single appointment with computer aided design/computer-aided manufacturing (CAD/CAM) and rapid prototyping (RP) technologies. PMID- 26254976 TI - Water sorption and water solubility of self-etching and self-adhesive resin cements. AB - STATEMENT OF PROBLEM: The long-term success of indirect restorations depends on the clinical behavior of luting cements. In the oral environment, properties such as water sorption and solubility negatively affect the cements' clinical performance over time, jeopardizing the restoration's longevity. PURPOSE: The purpose of this in vitro study was to compare the water sorption and solubility characteristics of self-etching, self-adhesive, and conventional resin cements. MATERIAL AND METHODS: One conventional (Calibra), 1 self-etching (Panavia F), and 2 self-adhesive (Clearfil SA, G-Cem Automix) dual-polymerized resin cements were used. Fourteen disks of each material were prepared. Water sorption and solubility were calculated according to International Organization for Standards (ISO) specification 4049:2009. RESULTS: According to the water sorption test, all materials were found to interact with water. No statistically significant differences were found between the water sorption of Panavia F and Clearfil SA (P=.911). These cements exhibited higher water sorption values than the other materials (P<.05), whereas Calibra exhibited the lowest values (P<.05). Statistically significant differences were found among all materials regarding their water solubility (P<.05). Panavia F and Clearfil SA were found to have higher solubility values than the other materials. G-Cem Automix and Calibra exhibited negative solubility. However, all water sorption and solubility values were below the threshold values proposed by the ISO standard. CONCLUSIONS: Within the limitations of the present in vitro study, the interaction of resin cements with water is not type-related (conventional, self-etching, or self-adhesive). PMID- 26254977 TI - Embedding surveillance into clinical care to detect serious adverse events in pregnancy. AB - Severe maternal complications in pregnancy in sub-Saharan Africa contribute to high maternal mortality and morbidity. Incidence data on severe maternal complications, life-threatening conditions, maternal deaths and birth outcomes are essential for clinical audit and to inform trial design of the types and frequency of expected severe adverse events (SAEs). However, such data are very limited, especially in sub-Saharan Africa. We set up standardized, systematic clinical surveillance embedded into routine clinical care in a rural county hospital in Kenya. Pregnant women and newborns are systematically assessed and investigated. Data are reported using a standardized Maternal Admission Record that forms both the hospital's clinical record and the data collection tool. Integrating clinical surveillance with routine clinical care is feasible and should be expanded in sub-Saharan Africa, both for improving clinical practice and as a basis for intervention studies to reduce maternal and newborn mortality and morbidity where rates are highest. PMID- 26254978 TI - From non school-based, co-payment to school-based, free Human Papillomavirus vaccination in Flanders (Belgium): a retrospective cohort study describing vaccination coverage, age-specific coverage and socio-economic inequalities. AB - School-based, free HPV vaccination for girls in the first year of secondary school was introduced in Flanders (Belgium) in 2010. Before that, non school based, co-payment vaccination for girls aged 12-18 was in place. We compared vaccination coverage, age-specific coverage and socio-economic inequalities in coverage - 3 important parameters contributing to the effectiveness of the vaccination programs - under both vaccination systems. We used retrospective administrative data from different sources. Our sample consisted of all female members of the National Alliance of Christian Mutualities born in 1995, 1996, 1998 or 1999 (N=66,664). For each vaccination system we described the cumulative proportion HPV vaccination initiation and completion over time. We used life table analysis to calculate age-specific rates of HPV vaccination initiation and completion. Analyses were done separately for higher income and low income groups. Under non school-based, co-payment vaccination the proportions HPV vaccination initiation and completion slowly rose over time. By age 17, the proportion HPV vaccination initiation/completion was 0.75 (95% CI 0.74-076)/0.66 (95% CI 0.65-0.67). The median age at vaccination initiation/completion was 14.4 years (95% CI 14.4-14.5)/15.4 years (95% CI 15.3-15.4). Socio-economic inequalities in coverage widened over time and with age. Under school-based, free vaccination rates of HPV vaccination initiation were substantially higher. By age 14,the proportion HPV vaccination initiation/completion was 0.90 (95% CI 0.90 0.90)/0.87 (95% CI 0.87-0.88). The median age at vaccination initiation/completion was 12.7 years (95% CI 12.7-12.7)/13.3 years (95% CI 13.3 13.3). Socio-economic inequalities in coverage and in age-specific coverage were substantially smaller. PMID- 26254980 TI - Genetically epilepsy-prone rats (GEPRs) and DBA/2 mice: Two animal models of audiogenic reflex epilepsy for the evaluation of new generation AEDs. AB - This review summarizes the current knowledge about DBA/2 mice and genetically epilepsy-prone rats (GEPRs) and discusses the contribution of such animal models on the investigation of possible new therapeutic targets and new anticonvulsant compounds for the treatment of epilepsy. Also, possible chemical or physical agents acting as proconvulsant agents are described. Abnormal activities of enzymes involved in catecholamine and serotonin synthesis and metabolism were reported in these models, and as a result of all these abnormalities, seizure susceptibility in both animals is greatly affected by pharmacological manipulations of the brain levels of monoamines and, prevalently, serotonin. In addition, both genetic epileptic models permit the evaluation of pharmacodynamic and pharmacokinetic interactions among several drugs measuring plasma and/or brain level of each compound. Audiogenic models of epilepsy have been used not only for reflex epilepsy studies, but also as animal models of epileptogenesis. The seizure predisposition (epileptiform response to sound stimulation) and substantial characterization of behavioral, cellular, and molecular alterations in both acute and chronic (kindling) protocols potentiate the usefulness of these models in elucidating ictogenesis, epileptogenesis, and their mechanisms. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic". PMID- 26254981 TI - The properties of thickness-twist (TT) wave modes in a rotated Y-cut quartz plate with a functionally graded material top layer. AB - We propose the use of thickness-twist (TT) wave modes of an AT-cut quartz crystal plate resonator for measurement of material parameters, such as stiffness, density and material gradient, of a functionally graded material (FGM) layer on its surface, whose material property varies exponentially in thickness direction. A theoretical analysis of dispersion relations for TT waves is presented using Mindlin's plate theory, with displacement mode shapes plotted, and the existence of face-shear (FS) wave modes discussed. Through numerical examples, the effects of material parameters (stiffness, density and material gradient) on dispersion curves, cutoff frequencies and mode shapes are thoroughly examined, which can act as a theoretical reference for measurements of unknown properties of FGM layer. PMID- 26254983 TI - EBV-positive mucocutaneous ulcer of the oral cavity associated with HIV/AIDS. AB - OBJECTIVE: To present 2 cases of Epstein-Barr virus (EBV)-positive mucocutaneous ulcer of the oral mucosa in association with human immunodeficiency virus infection. STUDY DESIGN: Two recently diagnosed cases of EBV-positive mucocutaneous ulcer of the oral mucosa in patients with human immunodeficiency virus (HIV) were reviewed with regard to their clinical, histomorphologic, and immunophenotypic features. RESULTS: Both cases presented clinically as well circumscribed ulcers that were histomorphologically characterized by dense superficial polymorphous inflammatory infiltrates. The infiltrates comprised cells with a predominant B-cell phenotype that ranged in size from small to intermediate with occasional large immunoblastic forms. Some of the larger B cells had a Reed-Sternberg-like morphology. The B cells were positive for CD20 and coexpressed CD30 and to a lesser extent CD15. Epstein-Barr virus-encoded small RNA (EBER) positivity was detected in most of the B cells. CONCLUSIONS: EBV positive mucocutaneous ulcer represents an unusual form of lymphoproliferative disorder associated with immune suppression. It should be distinguished from other forms of HIV-associated oral ulceration. PMID- 26254982 TI - Curcumin micelles improve mitochondrial function in neuronal PC12 cells and brains of NMRI mice - Impact on bioavailability. AB - Curcumin, a polyphenolic compound abundant in the rhizome of Curcuma longa, has been reported to have various beneficial biological and pharmacological activities. Recent research revealed that curcumin might be valuable in the prevention and therapy of numerous disorders including neurodegenerative diseases like Alzheimer's disease. Due to its low absorption and quick elimination from the body, curcumin bioavailability is rather low which poses major problems for the use of curcumin as a therapeutic agent. There are several approaches to ameliorate curcumin bioavailability after oral administration, amongst them simultaneous administration with secondary plant compounds, micronization and micellation. We examined bioavailability in vivo in NMRI mice and the effects of native curcumin and a newly developed curcumin micelles formulation on mitochondrial function in vitro in PC12 cells and ex vivo in isolated mouse brain mitochondria. We found that curcumin micelles improved bioavailability of native curcumin around 10- to 40-fold in plasma and brain of mice. Incubation with native curcumin and curcumin micelles prevented isolated mouse brain mitochondria from swelling, indicating less mitochondrial permeability transition pore (mPTP) opening and prevention of injury. Curcumin micelles proved to be more efficient in preventing mitochondrial swelling in isolated mouse brain mitochondria and protecting PC12 cells from nitrosative stress than native curcumin. Due to their improved effectivity, curcumin micelles might be a suitable formulation for the prevention of mitochondrial dysfunction in brain aging and neurodegeneration. PMID- 26254984 TI - Pediatric cervicofacial lymphadenitis caused by Bartonella henselae. AB - BACKGROUND: Chronic cervicofacial lymphadenitis in children is often caused by nontuberculous mycobacterium or Bartonella henselae species (known as cat scratch disease). METHODS: Bartonella henselae infection was diagnosed in 53 of 427 children with cervicofacial lymphadenopathy by polymerase chain reaction. RESULTS: The age of patients ranged from 16 to 148 months (median, 59 months), 28 (53%) were male, and 25 were female (47%). The submandibular lymph nodes were most commonly affected (92%). Patients were not treated with antibiotics. In 11 (21%) patients, aspiration of pus was performed to facilitate drainage, which led to a mean resolution of 5 +/- 3.1 months compared with a mean resolution time of 8.2 +/- 3.8 months for 40 patients treated with a wait-and-see policy (P = .01). CONCLUSIONS: Bartonella henselae is a common pathogen in children with chronic cervicofacial lymphadenitis. Treatment usually involves a wait-and-see approach, but in selected cases, aspiration may be needed for symptomatic relief. PMID- 26254979 TI - Cardiovascular magnetic resonance phase contrast imaging. AB - Cardiovascular magnetic resonance (CMR) phase contrast imaging has undergone a wide range of changes with the development and availability of improved calibration procedures, visualization tools, and analysis methods. This article provides a comprehensive review of the current state-of-the-art in CMR phase contrast imaging methodology, clinical applications including summaries of past clinical performance, and emerging research and clinical applications that utilize today's latest technology. PMID- 26254985 TI - Duck TRIM27-L enhances MAVS signaling and is absent in chickens and turkeys. AB - Wild waterfowl, including mallard ducks, are the natural reservoir of avian influenza A virus and they are resistant to strains that would cause fatal infection in chickens. Here we investigate potential involvement of TRIM proteins in the differential response of ducks and chickens to influenza. We examine a cluster of TRIM genes located on a single scaffold in the duck genome, which is a conserved synteny group with a TRIM cluster located in the extended MHC region in chickens and turkeys. We note a TRIM27-like gene is present in ducks, and absent in chickens and turkeys. Orthologous genes are predicted in many birds and reptiles, suggesting the gene has been lost in chickens and turkeys. Using quantitative real-time PCR (qPCR) we show that TRIM27-L, and the related TRIM27.1, are upregulated 5- and 9-fold at 1 day post-infection with highly pathogenic A/Vietnam/1203/2004. To assess whether TRIM27.1 or TRIM27-L are involved in modulation of antiviral gene expression, we overexpressed them in DF1 chicken cells, and neither show any direct effect on innate immune gene expression. However, when co-transfected with duck RIG-I-N (d2CARD) to constitutively activate the MAVS pathway, TRIM27.1 weakly decreases, while TRIM27 L strongly activates innate immune signaling leading to increased transcription of antiviral genes MX1 and IFN-beta. Furthermore, when both are co-expressed, the activation of the MAVS signaling pathway by TRIM27-L over-rides the inhibition by TRIM27.1. Thus, ducks have an activating TRIM27-L to augment MAVS signaling following RIG-I detection, while chickens lack both TRIM27-L and RIG-I itself. PMID- 26254986 TI - Effect of protein aggregates on characterization of FcRn binding of Fc-fusion therapeutics. AB - Recycling of antibodies and Fc containing therapeutic proteins by the neonatal Fc receptor (FcRn) is known to prolong their persistence in the bloodstream. Fusion of Fc fragment of IgG1 to other proteins is one of the strategies to improve their pharmacokinetic properties. Accurate measurement of Fc-FcRn binding provides information about the strength of this interaction, which in most cases correlates with serum half-life of the protein. It can also offer insight into functional integrity of Fc region. We investigated FcRn binding activity of a large set of Fc-fusion samples after thermal stress by the method based on AlphaScreen technology. An unexpected significant increase in FcR binding was found to correlate with formation of aggregates in these samples. Monomer purified from a thermally-stressed sample had normal FcRn binding, confirming that its Fc portion was intact. Experiments with aggregates spiked into a sample with low initial aggregation level, demonstrated strong correlation between the level of aggregates and FcRn binding. This correlation varied significantly in different methods. By introducing modifications to the assay format we were able to minimize the effects of aggregated species on FcRn binding, which should prevent masking functional changes of Fc-fusion protein. Biolayer interferometry (BLI) was used as an alternative method to measure FcRn binding. Both optimized AlphaScreen- and BLI-based assays were sensitive to structural changes in Fc portion of the molecule, such as oxidation of methionines 252 and 428, and therefore suitable for characterization of FcRn binding. PMID- 26254988 TI - Corrigendum: consensus document on the diagnosis, treatment and prevention of tuberculosis. prothionamide and PAS doses. PMID- 26254989 TI - Water Filling and Carbon Dioxide Insufflation: Tools for Every Colonoscopist. PMID- 26254987 TI - Exogenous antigens bind MHC class II first, and are processed by cathepsins later. AB - The field of antigen processing and presentation is likely one of the most well defined areas in immunology based on decades of intense molecular and structural studies. Many molecules contributing to antigen processing and presentation have been discovered and their mechanisms of action been largely defined, yet a major question, which lies at the very core of the field has remained hard to pin down. The question is what determines immunodominance? Immunodominance is defined as a few specific epitopes being selected to represent an antigen to the immune system and provide targets for T cells. Many studies have aimed at understanding how epitopes are selected. A range of hypotheses related to the structural features of antigens, sensitivity to proteases, epitope affinity for MHC II, T cell precursor frequency, and T cell receptor affinity for peptide/MHC II have been considered. However, because of the variety of proteins and factors involved in antigen processing and enormous complexity, finding an answer has been challenging. Here we make an effort to tease out the sequence of events in antigen processing that promote selection of immunodominant epitopes for exogenous antigens. PMID- 26254990 TI - Ponatinib ameliorates pulmonary fibrosis by suppressing TGF-beta1/Smad3 pathway. AB - TGF-beta1/Smad3 pathway plays a key role in the pathogenesis of idiopathic pulmonary fibrosis, including lung fibroblasts proliferation and epithelial cell aberrant activation. Ponatinib is a multi-targeted tyrosine-kinase inhibitor. However, whether Ponatinib has anti-fibrotic functions is unknown. In this study, the effects of Ponatinib on TGF-beta1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1), on the apoptosis of human type I alveolar epithelial cells (AT I) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis was investigated in vivo. Treatment with Ponatinib resulted in a reduction of EMT in A549 cells with a decrease in vimentin and p-Smad3, whereas an increase in E-cadherin. Apoptosis of AT I was attenuated with an increase in the Bcl-2/Bax ratio. HLF-1 proliferation was reduced with a decrease in PDGF-BB and FGF-2 expressions. Treatment with Ponatinib resulted in an amelioration of the BLM-induced pulmonary fibrosis in rats with reductions of the pathological score, collagen deposition, p-Smad3, alpha-SMA, PDGF-BB and FGF-2 expression. In summary, Ponatinib reversed the EMT, inhibited the apoptosis of AT I, as well as HLF-1 proliferation and prevented pulmonary fibrosis by suppressing the TGF-beta1/Smad3 pathway. PMID- 26254991 TI - Adsorption of malachite green by magnetic litchi pericarps: A response surface methodology investigation. AB - In this work, we synthesized a novel magnetic adsorbent containing litchi pericarps, denoted as MLP, for the removal of malachite green (MG) from solution. The factors influencing MG adsorption, such as contact time, adsorbent dosage, and initial dye concentration, were optimized using the Box-Behnken response surface methodology (RSM). The adsorption isotherms as well as the kinetics and thermodynamics of the adsorption of MG onto MLP are discussed. The results showed that MLP has a maximum adsorption efficiency of 99.5% when the temperature, pH, contact time, adsorbent dosage, and initial MG concentration were optimally set as 25 degrees C, 6.0, 66.69 min, 5.14 g/L, and 150 mg/L, respectively. The best model to describe this process is the Langmuir isotherm, with the maximum adsorption capacity being 70.42 mg/g. In addition, the kinetics of MG adsorption onto MLP followed a pseudo-second-order model; moreover, thermodynamic analysis suggested that MG adsorption onto MLP is spontaneous and endothermic. Finally, it was found that the new magnetic adsorbent can be separated easily and rapidly from mixed solutions in the presence of an external magnetic field. PMID- 26254992 TI - Influence of input material and operational performance on the physical and chemical properties of MSW compost. AB - Certain controversy exists about the use of compost from MSW (municipal solid waste) and, specifically, from the organic fraction of MSW that has not been separated at the source. In this case, the final composition of MSW compost is related to the performance of the separation process in MBT (Mechanical and Biological Treatment) plants as well as the composition of raw materials and the particular features of composting systems. In an effort to investigate the quality of MSW compost, 30 samples of this product obtained from 10 different MBT plants were studied. The main physical and chemical properties were analyzed and were compared with the requirements of current legislation. The composting systems used to produce these compost samples were studied and the input materials were characterized. The results reveal that the heavy metal content in MSW compost was below the legal restrictions in all samples but one; however, in most of them the percentage of Pb was high. The fertilizing potential of MSW compost has been demonstrated by its high nutrient concentrations, particularly N, K, P, Ca and Mg. Nevertheless, here the percentage of inert impurities with a size larger than 2 mm, such as plastic or glass, was seen to be excessively high exceeding in some cases the legal limit. The source of such pollution lies in the composting inputs, OFMSW (organic fraction of MSW), which showed high percentages of improper materials such as plastic (9%) or glass (11%). Accordingly, the performance of the sorting stage for the collection of the raw material must be improved, as must the refining process, since this does not remove the necessary amounts of these impurities from the final compost. PMID- 26254993 TI - The agri-environmental footprint: A method for the identification and classification of peri-urban areas. AB - The aim of this research is to define and test a methodology for an articulated and systematic analysis of the countryside, which can lend support to urban and landscape planning processes in addition to improving knowledge of the landscape, and for the implementation of agricultural and rural development policies. We have conceived a multi-criteria and multilevel methodology that was integrated into a geographic information system (GIS) and is based on clustering and maximum likelihood classification algorithms. The proposed method focuses on various agri environmental and socio-economic components, whose synthesis is performed by means of an interpretative key that was developed by the authors, the "Agri Environmental Footprint", to quantify the impact of rural areas on urban systems. In particular, this paper presents the general framework of the methodology, a set of indexes that are defined for its first-level analyses, and the results of their implementation through a case study in the Emilia-Romagna Region (Italy). The method is based on the IsoCluster technique, which is associated with statistical analyses of criteria, such as the Principal Component Analysis and different data standardisation algorithms (min-max and z-score). The case study has allowed an iterative calibration of both the methodological framework and indexes. PMID- 26254994 TI - Measuring the environmental effects of organic farming: A meta-analysis of structural variables in empirical research. AB - This study examined the structural variables affecting the environmental effects of organic farming compared to those of conventional farming. A meta-analysis based on 107 studies and 360 observations published from 1977 to 2012 compared energy efficiency (EE) and greenhouse gas emissions (GHGE) for organic and conventional farming. The meta-analysis systematically analyzed the results of earlier comparative studies and used logistic regression to identify the structural variables that contributed to differences in the effects of organic and conventional farming on the environment. The statistical evidence identified characteristics that differentiated the environmental effects of organic and conventional farming, which is controversial. The results indicated that data sources, sample size and product type significantly affected EE, whereas product type, cropping pattern and measurement unit significantly affected the GHGE of organic farming compared to conventional farming. Superior effects of organic farming on the environment were more likely to appear for larger samples, primary data rather than secondary data, monocropping rather than multicropping, and crops other than fruits and vegetables. The environmental effects of organic farming were not affected by the study period, geographic location, farm size, cropping pattern, or measurement method. PMID- 26254995 TI - Coenzyme Q10 treatment of cardiovascular disorders of ageing including heart failure, hypertension and endothelial dysfunction. AB - Advancing age is a major risk factor for the development of cardiovascular diseases. The aetiology of several cardiovascular disorders is thought to involve impaired mitochondrial function and oxidative stress. Coenzyme Q10 (CoQ10) acts as both an antioxidant and as an electron acceptor at the level of the mitochondria. Furthermore, in cardiac patients, plasma CoQ10 has been found to be an independent predictor of mortality. Based on the fundamental role of CoQ10 in mitochondrial bioenergetics and its well-acknowledged antioxidant properties, several clinical trials evaluating CoQ10 have been undertaken in cardiovascular disorders of ageing including chronic heart failure, hypertension, and endothelial dysfunction. CoQ10 as a therapy appears to be safe and well tolerated. PMID- 26254996 TI - Conveying the concept of movement in music: An event-related brain potential study. AB - This study on event-related brain potential investigated whether music can convey the concept of movement. Using a semantic priming paradigm, natural musical excerpts were presented to non-musicians, followed by semantically congruent or incongruent pictures that depicted objects either in motion or at rest. The priming effects were tested in object decision and implicit recognition tasks to distinguish the effects of automatic conceptual activation from response competition. Results showed that in both tasks, pictures that were incongruent to preceding musical excerpts elicited larger N400 than congruent pictures, suggesting that music can prime the representations of movement concepts. Results of the multiple regression analysis showed that movement expression could be well predicted by specific acoustic and musical features, indicating the associations between music per se and the processing of iconic musical meaning. PMID- 26254997 TI - Quality of life improvement in patients with Hashimoto thyroiditis and other goiters after surgery: A prospective cohort study. AB - INTRODUCTION: Hashimoto thyroiditis (HT) and other benign goiters (BG) might influence patients' quality of life (QoL). The objective of this study was to analyze influence of surgery on these patients' QoL. METHODS: A prospective cohort study was conducted. The ThyPRO questionnaire was used in the QoL assessment. RESULTS: The HT patients experienced significantly worse hypothyroid symptoms and sex life than the BG patients. The improvement in QoL in the BG patients was significant after surgery in all ThyPRO domains. In the HT patients, the improvement was significant in all but two domains, eye symptoms and cognitive impairment. The best improvement in both groups was in overall QoL. None of the patients developed permanent consequences. CONCLUSIONS: The QoL of HT and BG patients is impaired and improves significantly after surgical treatment. Thyroidectomy should be considered as a treatment option in the HT patients more often as in the BG patients. PMID- 26254998 TI - The pivotal role of endovascular repair in treating octogenarians suffering from abdominal aortic aneurysm. PMID- 26254999 TI - Definitely not goal-directed fluid therapy in major elective rectal surgery. PMID- 26255000 TI - Intrmedullary versus extramedullary fixation of lateral malleolus fractures. AB - INTRODUCTION: Intramedullary nails (IM nails) now include dedicated fibular nails for lateral malleolus fractures. This study reviewed nail versus plate for fixation of unstable ankle fractures. DESIGN: Systematic review and meta-analysis of published reports. RESULTS: Four studies met the inclusion criteria, including 375 patients. Two included studies were randomised-control studies and two were non-randomised case series. The implants investigated included: Knowles Pins, Fibular Nails, Rush Rods and Inyo Nails. The overall risk of bias was high. Pooled data showed a statistically significant lower risk of wound infection (RR 0.10; 95% CI 0.02 to 0.44), symptomatic hardware (RR 0.14; 95% CI 0.05 to 0.35) and removal of hardware (RR 0.57; 95% CI 0.39 to 0.81) with intramedullary nail fixation. CONCLUSIONS: There is a paucity of literature upon which to draw reliable conclusions. There was a high risk of bias towards favourable outcomes for the nail group. It would appear that intramedullary nail fixation of distal fibular fractures can outperform conventional fixation with plate and screws. There is a need for adequately powered, scientific trials. PMID- 26255001 TI - Internal carotid artery rupture caused by carotid shunt insertion. AB - INTRODUCTION: Shunting is a well-accepted method of maintaining cerebral perfusion during carotid endarterectomy (CEA). Nonetheless, shunt insertion may lead to complications including arterial dissection, embolization, and thrombosis. We present a complication of shunt insertion consisting of arterial wall rupture, not reported previously. PRESENTATION OF CASE: A 78-year-old woman underwent CEA combined with coronary artery bypass grafting (CABG). At the time of shunt insertion an arterial rupture at the distal tip of the shunt was detected and was repaired via a small saphenous vein patch. Eversion CEA and subsequent CABG completed the procedure whose postoperative course was uneventful. DISCUSSION: Shunting during combined CEA-CABG may be advisable to assure cerebral protection from possible hypoperfusion due to potential hemodynamic instability of patients with severe coronary artery disease. Awareness and prompt management of possible shunt-related complications, including the newly reported one, may contribute to limiting their harmful effect. CONCLUSION: Arterial wall rupture is a possible, previously not reported, shunt-related complication to be aware of when performing CEA. PMID- 26255002 TI - Anomalous origin of the right coronary artery with an interarterial course and intramural part. AB - INTRODUCTION: An anomalous origin and course of the right coronary artery (RCA)(1) is a very rare congenital anomaly that can be fatal if it remains undiscovered. PRESENTATION OF CASE: In this case report, we present a patient with a one-year history of exercise-induced angina and dyspnea caused by anomalous origin of the RCA from the left sinus, and anomalous course between the aorta and the pulmonary artery. DISCUSSION: Possible mechanisms of this disease's symptomatology are compression of the RCA between the aorta and the pulmonary artery in its anomalous inter-arterial course, and squeezing of the RCA in the proximal intramural part. CONCLUSION: In this report, we present some unique images of the RCAs course, which contribute to the understanding of this disease's symptomatology. The patient successfully underwent surgery with Right Internal Mammary Artery to RCA (RIMA-RCA)(2) bypass with complete remission of all symptoms. PMID- 26255003 TI - Occult splenic rupture in a case of chronic calcific pancreatitis with a brief review of literature. AB - INTRODUCTION: Splenic rupture in chronic pancreatitis is a life threatening rare complication. The anatomical proximity of the pancreas with the spleen and the pathophysiological process in acute and chronic pancreatitis form the basis of this dreaded complication. PRESENTATION OF CASE: We cite the case of a young male previously undiagnosed with chronic pancreatitis presenting with atraumatic splenic rupture. Definitive diagnosis was made by contrast enhanced computed tomography of the abdomen, intra operative findings, and histopathological examination of the splenectomy specimen. DISCUSSION: The splenorenal ligament forms the main anatomic proximity between the pancreas and the spleen. A few pathophysiological mechanisms though suggested are incompletely understood. splenic vein thrombosis, intrasplenic pseudocysts, splenic rupture, infarction, necrosis, splenic hematoma, and severe bleeding from eroded splenic vessels are the complications noted of which splenic rupture is the second most common following splenic vein thrombosis forming 36% of the complications noted. Chronic pancreatitis as an etiology of occult splenic rupture is rare and forms 8.27% of cases; commonest causes being neoplastic and infectious. The diagnosis is based on clinical and radiological findings and the management is predominantly surgical. CONCLUSION: High clinical suspicion on the part of the treating physician and the emergency team is essential to the management of atraumatic splenic rupture. The increasing understanding of the pathophysiology and presentation of splenic complications in pancreatitis may alert the index physician to these fatal complications. PMID- 26255004 TI - A rare case of first-trimester ruptured bicornuate uterus in a primigravida. AB - INTRODUCTION: Bicornuate uterus (BU) is a rare uterine anomaly result from incomplete fusion of the two Mullerian ducts during embryogenesis. BU very rarely can lead to rupture of the uterus during the early pregnancy with high mortality and morbidity rates. PRESENTATION OF CASE: A primigravida in the first trimester (9 weeks) presented complaining of epigastric pain and vomiting for one day. Ultrasound scan was performed at the 7th week of pregnancy and showed a BU with single intrauterine gestational sac in the right horn. On presentation, the patient was pale and irritable. Urgent ultrasound scan showed viable fetus in the right horn, free fluids in Morrison's pouch. Laparotomy showed BU with pregnancy in the ruptured right horn. The defect in the uterus was repaired. Postoperatively, the patient was advised to use contraceptive pills for one year. DISCUSSION: Our patient has a sonographic diagnosis of BU at the 7th gestational week. At that stage, nothing was done except close follow up of the pregnancy. When she developed severe epigastric pain, initially, we thought of peptic ulcer disease complications. Even after deterioration of the patients' condition, the diagnosis was not clear as the urgent ultrasound showed a viable fetus. Blood and fluid replacement therapy, and exploratory laparotomy were essential to save the patient's life. CONCLUSION: This case highlights the fact that uterine rupture can occur in early pregnancy when associated with uterine anomaly. Early sonographic diagnosis has a major contribution in evaluation and management. PMID- 26255005 TI - The dilemma of stump appendicitis - A case report and literature review. AB - INTRODUCTION: Stump appendicitis is one of the rare delayed complications post appendectomy with a reported incidence of 1 in 50,000 cases. Stump appendicitis can present as a diagnostic dilemma if the treating clinician is unfamiliar with this rare clinical entity. A PubMed search was conducted to identify cases of stump appendicitis following appendectomy. Sixty one cases of SA that were reported in English medical literature were analyzed. PRESENTATION OF CASE: We report a case of stump appendicitis (SA) with a systematic review and challenges encountered during the management. DISCUSSION: The interval from original appendectomy to stump appendicitis ranged from 4 days to 50 years. SA followed appendectomy in 58% of open and 31.6% of laparoscopic procedures. SA was frequently misdiagnosed as constipation, gastroenteritis or right sided diverticulitis, therefore leading to a significant delay to surgery. Computerized Tomography diagnosed SA in 56.3% of cases. Perforation with gangrene of the stump occurred in 60%. CONCLUSION: Stump appendicitis can represent a diagnostic dilemma if the treating physician is unfamiliar with this uncommon clinical entity. Radiological imaging is required to aid diagnosis and a completion appendectomy is the modality of treatment. PMID- 26255007 TI - [China Expert Consensus of Medical Emergency Rescue for acute poisoning accidents in 2015]. PMID- 26255008 TI - [Clinical analysis of the first patient with imported Middle East respiratory syndrome in China]. AB - OBJECTIVE: To report the treatment of the first imported Middle East respiratory syndrome ( MERS ) in China, and to investigate the clinical features and treatment of the patient. METHODS: On May 28th, 2015, the first patient of imported MERS to China was admitted to Department of Critical Care Medicine of Huizhou Municipal Central Hospital. The clinical features and treatments of this patient were analyzed. RESULTS: (1) A 43 years old male of South Korean nationality was admitted with the complaint of back ache for 7 days and fever 2 days with the following characteristics: back ache 7 days ago, without fever or cough or expectoration. He had been suspected to suffer from infection of Middle East respiratory syndrome coronavirus ( MERS-CoV ) by the Disease Control Department of South Korea, but no specific treatment was given. He had fever for 2 days with maximum body temperature of 39.7 centigrade. He had no chills, cough, expectoration, short of breath, abdominal pain, diarrhea, frequent micturition, or urgency or pain of urination, and no sore throat. The patient had a history of exposure to MERS-CoV patient. He was considered to be a patient of the second batch of South Korean epidemic. (2) Auxiliary examination: 3 copies of throat swab specimens for virus nucleic acid detection were performed by the Disease Prevention Control Center of China ( China CDC ), and they were positive on May 29th, 2015, and also for serum, sputum and stool. Based on the results of whole genome sequence analysis, the virus strains were implicated to be derived from Riyahh and Jeddah regions of Saudi Arabia. On admission, the patient's blood test showed that the white blood cell count was low ( 3.22*10(9)/L ), the proportion of the neutrophils was high ( 0.73 ), and that of the platelet was low ( 81*10(9)/L ). On admission, the patient's chest X-ray showed that a small amount of infiltration in the lung. (3) TREATMENT: a high-flow nasal cannula ( HFNC ) with oxygen concentration of 0.50-0.80 was given, with a flow rate was set at 60 L/min if tolerated. It was changed to a low flow oxygen inhalation nasal cannula on the 20th day, and oxygen treatment was stopped on the 24th day. Ribavirin 2.0 g was given as the first dose, and was switched to 600 mg every 8 h ( q8h ), and it was reduced to 600 mg q12h after 10 days, and extenuated since the 13th day. Ceftriaxone was added on the 4th day with 2.0 g a day , and it was changed to meropenem 2.0 g, q8h on the 7th day for 2 weeks. Gamma globulin was given for 7 days ( 20 g, qd ). Thymosin-alpha1 was given on the 8th day for 2 weeks. Interferon was given once a week, but only one dose was used. At the same time symptomatic treatment such as methimazole and liver protection therapy were given. (4) Patient began to cough at admission, and it disappeared on the 18th day. There was no sputum at first, then a small amount of sputum with a little blood appeared after the admission. Then there was cough without sputum. Mild shortness of breath and diarrhea after exertion were noticed. He had no chest pain, difficulty in breathing or other symptoms. There was dullness on percussion in both sides of chest, and it disappeared gradually. Fine moist rales were detectable in scapular area and interscapular area on the 5th day, and they disappeared after 3 days. Breath sounds on both sides was weak, and it became more obvious in the right lung after 5 days, and returned to normal after 18 days. He had a sustaining fever for 1 week with the maximum temperature of 39.5 centigrade, then the body temperature returned to normal. The viral nucleic acid test as performed by the Center for Disease Control of Guangdong ( CDC, Guangdong ) showed that the pharyngeal swab cultured turned negative on the 3rd day, that of serum specimens turned negative on the 8th day, that of stool specimen after 2 weeks, and it was persistently positive for sputum culture until 5 days before discharge. The oxygenation index gradually increased, and it was over 300 mmHg ( 1 mmHg = 0.133 kPa ) after 15 days. Pleural effusion was rapidly increased during the first week as shown by chest X-ray films, and it began to be absorbed gradually in the second week, but it was not completely absorbed until discharge. CONCLUSIONS: The disease course of the reported patient was short, with an acute onset, with fever as the chief complaint, but there were no respiratory symptoms, though there were high fever, cough, shortness of breath, diarrhea and other clinical symptoms after admission. Virus in sputum disappeared after treatment, but pleural effusion was not completely absorbed. Negative test for virus in sputum was late, indicating that clearance of virus was slow from the lungs. It is the first case of MERS in China, therefore, the clinical manifestations and the treatment strategy need to be further explored. PMID- 26255009 TI - [Correlation between gastrointestinal dysfunction and both severity and prognosis in patients suffering from heatstroke]. AB - OBJECTIVE: To investigate the relationship between gastrointestinal dysfunction and both severity and prognosis in patients with heatstroke ( HS ). METHODS: A retrospective analysis was conducted. Clinical data from 39 patients with HS seeking for treatment in Department of Critical Care Medicine of Chinese PLA General Hospital from January 2013 to September 2014 were enrolled. The patients were divided into two groups: gastrointestinal dysfunction group and non gastrointestinal dysfunction group. The acute physiology and chronic health evaluation II ( APACHEII) score within 24 hours of admission and 28-day mortality were compared between two groups. In gastrointestinal dysfunction group, the gastrointestinal dysfunction score, the duration days of gastrointestinal dysfunction, the length of intensive care unit ( ICU ) stay, and the duration of mechanical ventilation were collected. Pearson correlation analysis was used to analyze the relationship between gastrointestinal function and the severity of the ailment as well as the prognosis. RESULTS: Among 39 patients with HS, 32 of them showed gastrointestinal dysfunction with an incidence of 82.05%. In gastrointestinal dysfunction group, the gastrointestinal dysfunction score was 2.3+/-0.8, the duration of gastrointestinal dysfunction was ( 17.3+/-15.2 ) days, the length of ICU stay was ( 37.8+/-25.0 ) days, and the duration of mechanical ventilation was ( 27.8+/-14.0 ) days. APACHEII score in gastrointestinal dysfunction group was significantly higher than that of the non-gastrointestinal dysfunction group ( 26.30+/-6.00 vs. 17.40+/-6.00, t = 3.555, P = 0.001 ). The 28 day mortality in gastrointestinal dysfunction group was slightly higher than that of the non-gastrointestinal dysfunction group without statistically significant difference [ 43.75% ( 14/32 ) vs. 14.29% ( 1/7 ), P = 0.216 ]. It was shown by Pearson analysis that gastrointestinal dysfunction score was positively correlated with APACHEII score ( r = 0.727, P = 0.000 ), and the duration of gastrointestinal dysfunction was positively correlated with the length of ICU stay ( r = 0.797, P = 0.000 ) and the duration of mechanical ventilation ( r = 0.634, P = 0.000 ). CONCLUSIONS: The results suggest that gastrointestinal function in patients with HS reflects the severity and prognosis of the ailment. PMID- 26255006 TI - Differential CaMKII regulation by voltage-gated calcium channels in the striatum. AB - Calcium signaling regulates synaptic plasticity and many other functions in striatal medium spiny neurons to modulate basal ganglia function. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a major calcium dependent signaling protein that couples calcium entry to diverse cellular changes. CaMKII activation results in autophosphorylation at Thr286 and sustained calcium-independent CaMKII activity after calcium signals dissipate. However, little is known about the mechanisms regulating striatal CaMKII. To address this, mouse brain slices were treated with pharmacological modulators of calcium channels and punches of dorsal striatum were immunoblotted for CaMKII Thr286 autophosphorylation as an index of CaMKII activation. KCl depolarization increased levels of CaMKII autophosphorylation ~2-fold; this increase was blocked by an LTCC antagonist and was mimicked by treatment with pharmacological LTCC activators. The chelation of extracellular calcium robustly decreased basal CaMKII autophosphorylation within 5min and increased levels of total CaMKII in cytosolic fractions, in addition to decreasing the phosphorylation of CaMKII sites in the GluN2B subunit of NMDA receptors and the GluA1 subunit of AMPA receptors. We also found that the maintenance of basal levels of CaMKII autophosphorylation requires low-voltage gated T-type calcium channels, but not LTCCs or R-type calcium channels. Our findings indicate that CaMKII activity is dynamically regulated by multiple calcium channels in the striatum thus coupling calcium entry to key downstream substrates. PMID- 26255010 TI - [The effect of heat stress on the cytoskeleton and cell cycle of human umbilical vein endothelial cell in vitro]. AB - OBJECTIVE: To study the effect of heat stress on the cytoskeleton and cell cycle of human umbilical vein endothelial cell ( HUVEC ) in vitro. METHODS: HUVEC was cultured in vitro in 5%CO(2) medium at 37 centigrade ( control group ) or 43 centigrade ( heat stress group ) for 1 hour. Coomassie brilliant blue R-250 staining was used to determine the effect of heat stress on the cytoskeleton. The cells in heat stress group were subsequently cultured at 37 centigradein 5%CO(2) medium after heat stress for 1 hour, and cell cycle of HUVEC was determined at 0, 6, 12, 18 and 24 hours with flow cytometry. RESULTS: Under light microscopy normal cytoskeleton was observed in control group, but thicker and shorter cytoskeleton was found after a rise of temperature, and stress fibers were found in heat stress group. The DNA content of HUVEC at all time points in G0/G1 stage was 38.07%-55.19% after heat stress. The DNA content in control group was 48.57%, and it was 54.06%, 55.19%, 48.23%, 38.07%, and 41.03% at 0, 6, 12, 18, 24 hours in G0/G1 stage in heat stress group. DNA content in S phase was 35.33%-48.18%. The DNA content in control group was 44.62%, and it was 35.33%, 39.50%, 42.50%, 48.18%, and 47.99% at 0, 6, 12, 18, 24 hours in S stage in heat stress group. DNA content in G2/M phase was 5.31%-13.75%. The DNA content in control group was 6.81, and it was 10.61%, 5.31%, 9.27%,13.75%, and 10.98% at 0, 6, 12, 18, 24 hours in G2/M stage in heat stress group. It was demonstrated that compared with control group, the DNA content in G0/G1 stage was significantly increased when the HUVEC were separated from heat stress within 6 hours, and it recovered at a similar level as control group at 12 hours. CONCLUSIONS: Heat stress can change the cytoskeleton of HUVEC, and cause stagnation at G0/G1 stage in cell cycle. PMID- 26255011 TI - [Pretreatment with Xuebijing injection alleviates systemic inflammatory response induced by severe heat-stroke via ameliorating intestinal injury in rats]. AB - OBJECTIVE: To observe the effect of Xuebijing injection pretreatment on systemic inflammatory response induced by severe heat-stroke, and to investigate the mechanism of alleviation of intestinal injury in rats. METHODS: Thirty-six healthy adult male Wistar rats with grade SPF were randomly assigned into three groups with randomized number method, namely sham group, severe heat-stroke model group, and Xuebijing pretreatment group ( XBJ group ), with 12 rats in each group. The animals were placed in a pre-warm chamber [ temperature ( 40+/-2 ) centigrade, humidity ( 65+/-5 )% ] in order to induce typical heat-stroke. The duration of heat-stress was 60 minutes, while the animals in sham group were exposed to ambient temperature of 25 centigrade. Arterial blood samples were collected at the beginning and the end of heat-stress, the concentrations of tumor necrosis factor-alpha( TNF-alpha), interleukins ( IL-1beta, IL-6 ), and lipopolysaccharide ( LPS ) in peripheral blood were determined by enzyme linked immunosorbent assay ( ELISA ). The intestinal tissues were harvested after heat stress, and the pathological changes in intestine tissues were observed after hematoxylin-eosin ( HE ) staining and under optical microscope. The pathological injury scores were calculated. Immunohistochemistry was performed to determine inducible nitric oxide synthase ( iNOS ) expression in intestinal tissue. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling ( TUNEL ) staining. Western Blot was used to measure the tight junction protein occludin expression. RESULTS: The concentrations of TNF-alpha, IL-1beta, IL-6 and LPS in blood of the rats after heat-stress in model group were significantly higher than those of sham group [ TNF-alpha ( MUg/L ): 443.00+/ 110.10 vs. 98.36+/-44.61, IL-1beta ( MUg/L ): 436.37+/-163.64 vs.64.24+/-16.15, IL-6 ( MUg/L ): 342.70+/-92.42 vs. 54.40+/-13.22, LPS ( MUg/L ): 0.68+/-0.22 vs. 0.09+/-0.02, all P < 0.01 ], but the levels of these parameters in XBJ group were significantly lower than those of model group [ TNF-alpha ( MUg/L ): 340.45+/ 68.57 vs. 443.00+/-110.10, IL-1beta ( MUg/L ): 191.33+/-82.78 vs. 436.37+/ 163.64, IL-6 ( MUg/L ): 192.21+/-37.89 vs. 342.70+/-92.42, LPS ( MUg/L ): 0.43+/ 0.17 vs. 0.68+/-0.22, all P < 0.01 ]. Infiltration of inflammatory cells, necrosis and hemorrhage in intestinal mucosa were found in the intestine of heat stroke animals in model group. The pathological lesions in XBJ group were milder than those of model group, with a decreased pathological injury score compared with model group ( 2.10+/-1.15 vs. 3.20+/-0.67, P < 0.01 ). The expression of iNOS and apoptosis of cells in intestinal tissue in model group were increased compared with that of sham group, but they were significantly less marked in XBJ group compared with model group [ iNOS ( adjusted A value ): 0.32+/-0.15 vs. 0.74+/-0.17, apoptotic index: 0.23+/-0.08 vs. 0.56+/-0.07, both P < 0.01 ]. The order of expression for occludin protein from high to low was sham group, XBJ group and model group ( A value was 0.96+/-0.25, 0.62+/-0.20, 0.33+/-0.11, respectively ). Furthermore, there was significant difference in the expression of occludin protein between model group and both XBJ group and sham group ( both P < 0.01 ). CONCLUSIONS: Xuebijing injection alleviates inflammation and endotoxemia produced by severe heat-stroke in rats. The mechanism may be related to amelioration of oxidative injury, apoptosis, and dysfunction of tight junction protein occludin expression. PMID- 26255012 TI - [Comparison of the effect of low molecular weight heparin sodium and that of heparin sodium on pre-disseminated intravascular coagulation stage in patients suffering from exertional heat stroke]. AB - OBJECTIVE: To study the effect of low molecular weight heparin sodium ( LMWHS ) therapy for exertional heat stroke ( EHS ) patients with pre-disseminated intravascular coagulation ( pre-DIC ). METHODS: A prospective randomized controlled trial ( RCT ) was conducted. Thirty-six patients with EHS with pre-DIC admitted to Department of Critical Care Medicine of 180th Hospital of Chinese PLA from April 2012 to November 2014 were divided into heparin sodium group ( n = 20 ) and LMWHS group ( n = 16 ) in accordance with the random number table. All patients received bundle treatment after being admitted to the hospital, including rapid cooling, fluid resuscitation, organ support ( mechanical ventilation, hemopurification if necessary ), supplement of pro-coagulation factors, etc. The patients in heparin sodium group were treated with continuous heparin sodium 12 500 U throughout 24 hours with intravenous pump for 5 days, and the patients in LMWHS group were given LMWHS 2 500 U subcutaneously, twice a day for 5 days.The incidence of DIC, incidence of bleeding and mortality of two groups were compared.The platelet count ( PLT ), prothrombin time ( PT ), activated partial thromboplastin time ( APTT ), fibrinogen ( Fib ) and D-dimer of each patient between pre and post treatment times were compared. RESULTS: No significant difference was found in the incidence of DIC and mortality between LMWHS group and heparin sodium group ( 31.2% vs. 30.0%, chi (2) = 0.007, P = 0.936; 6.2% vs. 5.0%, chi (2) = 0.026, P = 0.871 ). Incidence of bleeding during treatment in LMWHS group was significantly lower than that in heparin sodium group ( 12.5% vs. 45.0%,chi (2) = 4.425, P = 0.035 ). After treatment, PLT in both LMWHS group and heparin sodium group was significantly increased compared with that before treatment ( *10(9)/L: 140.5+/-17.5 vs. 110.5+/-16.5, 152.6+/ 21.5 vs. 120.0+/-20.0, both P < 0.05 ) and D-dimer was significantly decreased ( mg/L: 0.5+/-0.1 vs. 3.2+/-1.2, 0.6+/-0.2 vs. 4.4+/-1.8, both P < 0.05 ). APTT after treatment in heparin sodium group was significantly prolonged compared with that before treatment ( s: 75.3+/-10.6 vs. 44.1+/-8.2, P < 0.05 ) while no change in APTT was found in LMWHS group ( s: 38.6+/-5.5 vs. 42.1+/-8.4, P > 0.05 ). No significant difference was found in PT and Fib between pre and post treatment in all the patients. CONCLUSIONS: When LMWHS was applied in EHS patients in pre-DIC stage, it could not only prevent DIC as efficiently as heparin sodium, but also results in lower incidence of bleeding. So LMWHS is safer. PMID- 26255013 TI - [Changes in blood gas parameters of heatstroke rats in dry-heat environment of desert]. AB - OBJECTIVE: To investigate the changes in characteristics of blood gas analysis of heatstroke rats residing in dry-heat environment of desert, and to provide a theoretical reference for its treatment in clinic. METHODS: Forty-eight male Sprague-Dawley ( SD ) adult rats under anesthesia were divided into six groups by random number table, with 8 rats in each group: namely mild, moderate, severe heatstroke groups and their corresponding control groups. The rats were placed in an artificial chamber with simulated desert dry-heat environment ( temperature 41 centigrade, humidity 10% ) for about 70, 110, 145 minutes, respectively, to reproduce mild, moderate, severe heatstroke models. The rats in control groups were placed in a normothermic environment for corresponding duration. Abdominal aorta blood of each group was collected for blood gas analysis, and electrolytes were determined by a portable blood gas analyzer. RESULTS: (1) Arterial partial pressure of carbon dioxide ( PaCO(2) ) in mild heatstroke group was increased to ( 45.64+/-8.19 ) mmHg ( 1 mmHg = 0.133 kPa ), arterial oxygen saturation ( SaO(2) ) was decreased to 0.84+/-0.08, pH value was lowered to 7.36+/-0.11, showing that respiratory acid-base imbalance was resulted. Base excess of extracellular fluid ( BEecf ) in moderate heatstroke group was decreased to ( -3.00+/-0.76 ) mmol/L, HCO(3)(-) was decreased to ( 19.39+/-1.89 ) mmol/L, and pH value was lowered to 7.21+/-0.07, indicating that metabolic acid-base imbalance was aggravated gradually. The changes in parameters in severe heatstroke group gradually became more serious, and a significant difference was found as compared with those of mild and moderate heatstroke groups ( PaCO(2): F = 6.537, P = 0.006; SaO(2): F = 5.174, P = 0.015; pH value: F = 10.736, P = 0.001; BEecf: F = 67.136, P = 0.000; HCO(3)(-): F = 5.612, P = 0.011 ), manifesting an obvious combination of respiratory acidosis and metabolic acidosis, and a serious mixed acid-base disturbance was produced. (2) Compared with corresponding control groups, hemoglobin ( Hb ) was significantly increased in moderate heatstroke group ( g/L: 15.31+/-1.84 vs. 13.28+/-0.94, t = 2.791, P = 0.014 ), Hb and hematocrit ( HCT ) in severe heatstroke group were significantly increased [ Hb ( g/L ): 16.59+/ 2.52 vs. 13.42+/-1.15, t = 3.224, P = 0.006; HCT: ( 53.50+/-6.63 )% vs. ( 45.50+/ 4.47 )%, t = 2.828, P = 0.013 ], showing that the degree of dehydration was aggravated gradually from mild to serious degree. (3) Serum sodium content in mild heatstroke group was normal ( t = 0.665, P = 0.517 ), serum potassium content was lowered significantly ( t = -2.526, P = 0.024 ); serum sodium content in moderate heatstroke group was increased significantly ( t = 2.162, P = 0.048 ), serum potassium content was lowered significantly ( t = -5.458, P = 0.000 ); and serum sodium content in severe heatstroke group rose obviously ( U = 12.500, P = 0.038 ), and most of the rats showed hypokalemia, with a small proportion of rats showed obvious hyperkalemia ( U = 19.500, P = 0.195 ). CONCLUSIONS: Acidosis, electrolyte disturbance, respiratory failure and dehydration in heatstroke occurred in dry-heat environment of desert. It indicates that resuscitation should focus on correction of respiratory acidosis, with simultaneous correction of metabolic acidosis, and one should be alert to correct dehydration and electrolyte disturbance. During the moderate phase and the serious phase, correction of aggravated metabolic acidosis should be reinforced, and the prevention and treatment of the severe dehydration and electrolyte disturbance should be undertaken actively. PMID- 26255014 TI - [An analysis of laboratory results of parameters of organ function in patients with heat stroke]. AB - OBJECTIVE: To explore the role of parameters of organ function during heat stroke ( HS ) on the prognosis, and to form the treatment strategy through an analysis of parameters of organ function during HS. METHODS: A retrospective study was conducted. Thirty-seven patients with HS ( HS group ) and 54 patients with mild to-moderate stroke ( stroke group ) admitted to Zhejiang Xiaoshan Hospital from 2011 to 2014 were enrolled. The experimental results of organs function indicators for patients were recorded including: (1) cardiac markers: troponin I ( TnI ); (2) myocardium zymogram: creatine kinase ( CK ), MB isoenzyme of creatine kinase ( CK-MB ), lactate dehydrogenase ( LDH ), and aspartate aminotransferase ( AST ); (3) renal function indexes: blood urea nitrogen ( BUN ), uric acid ( UA ), and serum creatinine ( SCr ); (4) electrolyte: serum K(+), Na(+), and Cl(-); (5)coagulation function: prothrombin time ( PT ), international normalized ratio ( INR ), activated partial thromboplastin time ( APTT ), thrombin time ( TT ), fibrinogen ( FIB ), and D-dimer; (6) blood gas analysis: pH value, arterial partial pressure of carbon dioxide ( PaCO(2)), base excess ( BE ), standard bicarbonate ( SB ), and actual bicarbonate ( AB ); (7) routine blood test: blood platelet count ( PLT ); (8) hepatic function: alanine aminotransferase ( ALT ). Abnormal rates of laboratory parameters of 37 HS patients were statistically analyzed. Various laboratory parameters of organs function as well as the initial value and extreme value ( maximum or minimum value ) during treatment of CK and PLT in HS patients were compared between two groups. RESULTS: The abnormal rates of 37 HS patients were more than 70%, including incipient value of TnI, CK, LDH, AST, serum Na(+), ALT, D-dimer, PaCO(2), AB, maximum value of CK, and minimum value of PLT, the abnormal rates being 73.0%, 70.3%, 81.1%, 78.4%, 78.4%, 70.3%, 70.3%, 70.3%, 75.7%, 81.1%, 75.7%, respectively. The abnormal rates of other parameters were less than 70%. There were significant differences in incipient value of TnI, CK, LDH, AST, serum K(+), serum Na(+), D-dimer, and PLT between HS group and mild-to-moderate stroke group [ TnI ( MUg/L ): 0.087 ( 0.026, 0.306 ) vs. 0.007 ( 0.004, 0.110 ), Z = 7.017, P = 0.000; CK ( U/L ): 392.30 ( 287.60, 524.10 ) vs. 137.10 ( 106.33, 607.80 ), Z = -7.930, P = 0.000; LDH ( U/L ): 317.98+/-122.74 vs. 207.85+/-57.71, t = 1.678, P = 0.000; AST ( U/L ): 94.90 ( 52.80, 155.80 ) vs. 26.10 ( 18.13, 317.40 ), Z = -6.157, P = 0.000; serum K(+) ( mmol/L ): 3.46+/-0.65 vs. 3.86+/ 0.57, t = 1.662, P = 0.001; serum Na(+) ( mmol/L ): 129.75+/-7.34 vs. 138.79+/ 4.26, t = 1.674, P = 0.000; D-dimer ( mg/L ): 2.53 ( 0.63, 6.00 ) vs. 0.30 ( 0.21, 9.71 ), Z = -5.084, P = 0.000; PLT ( *10(9)/L ): 144.62+/-86.14 vs. 219.48+/-64.76, t = 1.669, P = 0.000 ]. There were also statistically significant differences in the initial value and extreme value of CK and PLT between HS group and mild-to-moderate stroke group [ CK ( U/L ): 392.30 ( 287.60, 524.10 ) vs. 721.50 ( 546.30, 964.10 ), Z = -6.351, P = 0.000; PLT ( *10(9)/L ): 132.40+/ 82.55 vs. 68.24+/-44.62, t = 1.688, P = 0.000 ]. CONCLUSIONS: HS can impair several organs and systems, having complications, and it is a heavy insult for body. Increasing of CK and decreasing of PLT has some value to assess illness changes. It is helpful of laboratory results for doctors to estimate complications on time. PMID- 26255015 TI - [shRNAs targeting high mobility group box-1 lead to inhibition of E-selectin expression via homeobox A9 in human umbilical vein endothelial cells]. AB - OBJECTIVE: To approach the regulatory mechanism of high mobility group box-1 ( HMGB1 ) on the expression of E-selectin in human umbilical vein endothelial cell ( HUVEC ). METHODS: Homeobox A9 ( HOXA9 ) siRNA was transfected to HUVEC at logarithmic phase, real-time fluorescence quantitative polymerase chain reaction ( real-time qPCR ) and Western Blot were used to determine the HOXA9 mRNA expression and protein expressions; a blank control group and a nonsilence negative control group were set. HUVEC stable transfected with pRNA-u6.1/Neo HMGB1 shRNA plasmids ( HUVEC with low-expression HMGB1 ) was obtained, and HOXA9 and E-selectin mRNA expressions were determined with real-time qPCR; a nonsilence transfection group served as the negative control. The HOXA9 siRNA was transfected to HUVEC with low-expression HMGB1 as co-transfection group, and the E-selectin expressions was determined with real-time qPCR; a HMGB1 shRNA group and a HOXA9 nonsilence group served as control. RESULTS: (1) HOXA9 mRNA ( 2( Delta DeltaCT) ) and protein expression ( integral A value ) in blank control group were 1.094+/-0.115 and 1.031+/-0.060. Compared with nonsilence transfection group, HOXA9 siRNA transfection group could significantly reduced mRNA and protein expression of HOXA9 [ HOXA9 mRNA ( 2(-Delta DeltaCT) ): 0.257+/-0.030 vs. 1.035+/-0.091, t = 14.010, P = 0.002; HOXA9 protein ( integral A value ): 0.278+/ 0.042 vs. 0.975+/-0.014, t = 27.310, P = 0.002 ]. (2) Compared with nonsilence transfection group, HMGB1 shRNA transfection could up-regulate HOXA9 mRNA expression in HUVEC ( 2(-Delta DeltaCT) : 2.519+/-0.278 vs. 0.856+/-0.063, t = 10.100, P = 0.001 ), also could down-regulate E-selectin mRNA expression ( 0.311+/-0.046 vs. 1.080+/-0.201, t = 7.415, P = 0.000 ). (3) Compared with HOXA9 nonsilence group and HMGB1 shRNA group, HMGB1 shRNA and HOXA9 siRNA co transfected HUVEC cells could significantly elevate E-selectin mRNA expression ( 2(-Delta DeltaCT) : 3.445+/-0.428 vs. 1.085+/-0.212, 1.004+/-0.104, t(1) = 8.507, t(2) = 9.603, both P < 0.001 ). CONCLUSIONS: HMGB1 may regulate E-selectin expression through the HOXA9 regulation in HUVEC. PMID- 26255016 TI - [The epidemiology of multidrug-resistant bacteria colonization and analysis of its risk factors in intensive care unit]. AB - OBJECTIVE: To screen the colonization of multidrug resistant organisms ( MDROs ) and determine their risk factors in intensive care unit ( ICU ), so as to provide the basis of prophylaxis and treatment of MDROs colonization. METHODS: A prospective single-center study was conducted in ICU of China-Japan Friendship Hospital from June 2008 to December 2014. The nostril and anal swabs for each patient who stayed in ICU over 24 hours were collected. Each specimen was cultured and tested for drug sensitivity. Clinical findings and relative risk factors were collected. The risk factors of MDROs colonization were analyzed with univariate analysis. The independent risk factor was selected from the risk factors with P < 0.05 with logistic regression analysis to analyze the related factors of MDROs colonization in ICU. RESULTS: 1 672 patients were enrolled. At ICU admission, MDROs colonization was present in 604 cases ( 36.12% ), of whom 62 cases ( 3.71% ) were found to be colonized with methicillin-resistant Staphylococcus aureus ( MRSA ), 529 ( 31.64% ) were colonized with extended spectrum beta-lactamase ( ESBL ) enterobacteria, 7 ( 0.42% ) were colonized with multidrug resistant Acinetobacter baumannii ( MDR-AB ), and 6 ( 0.36% ) were colonized with multidrug resistant Pseudomonas aeruginosa ( MDR-PA ). ICU acquired MDROs colonization were 197/1 068 ( 18.45% ), among whom 24 patients ( 1.44% ) were colonized with MRSA, 118 ( 7.06% ) were colonized with ESBL enterobacteria, 50 ( 2.99% ) were colonized with MDR-AB, and 5 ( 0.30% ) were colonized with MDR-PA. By multivariable analysis, prior administration of more than two kinds of antibiotics [ odds ratio ( OR ) = 2.352, 95% confidence interval ( 95%CI )= 1.847 - 4.464, P = 0.002 ], prior use of broad spectrum antibiotics within 3 months ( OR = 2.862, 95%CI = 1.458-5.631, P = 0.014 ), duration of prior antibiotic administration ( OR = 1.781, 95%CI = 1.152 - 3.413, P = 0.003 ) and hospitalization days prior to ICU admission > 9 days ( OR = 1.766, 95%CI = 1.235 - 3.986, P = 0.021 ) were independent risk factors of MDROs colonization on admission to ICU. CONCLUSIONS: High prevalence of MDROs colonization in ICU patients was found in our hospital, and ESBL enterobacteria was the predominant bacteria. ICU acquired MDROs colonization is also worth considering, especially for MDR-AB. Identification of risk factors for MDROs colonization may help identify and screen patients with high risk, and it is also instructive in prophylaxis of MDROs colonization/infection and restriction of the use of broad spectrum antibiotics. PMID- 26255017 TI - [The effect of albumin on (1, 3)-beta-D-glucan for diagnosis of invasive fungal infections]. AB - OBJECTIVE: To explore the diagnostic value of plasma ( 1, 3 )-beta-D-glucan test ( G test ) in diagnosis of invasive fungal infections ( IFI ) and the influence of albumin on G test. METHODS: A prospective observational study was conducted. 267 patients admitted to medical intensive care unit ( MICU ) of Dalian Municipal Central Hospital from January 21st, 2012 to October 31st, 2014 were enrolled. According to IFI guideline, the patients were divided into without IFI group ( n = 35 ), possible IFI group ( n = 70 ), hypotheticle IFI group ( n = 145 ) and proven IFI group ( n = 17 ). G test was examined routinely using microbiology kinetic rapid reader MB-80.The different threshold values were calculated on G test. The difference among G tests, fungal culture and clinical diagnosis were compared. The results of G test ahead of and post albumin administration in each group were compared, and the value of G test for diagnosis of IFI during albumin infusion was evaluated. RESULTS: When the cut-off value was 20 ng/L for IFI diagnosis, higher sensitivity ( 79.8% ), specificity ( 87.9% ), and Youden index ( 67.7% ) were found. The positive rates of G test, fungal culture and clinical diagnosis of IFI were 57.7% ( 154/267 ), 60.7% ( 162/267 ) and 54.3% ( 145/267 ) respectively, without showing significant differences ( all P > 0.05 ). The result of G test ( ng/L ) was not obviously changed after albumin administration compared with that before in without IFI, possible IFI, hypotheticle IFI, and proven IFI groups ( without IFI group: 11.25+/-2.33 vs. 10.99+/-1.07, t = -1.723, P = 0.085; possible IFI group: 53.14+/-5.53 vs. 49.22+/-8.11, t = -0.395, P = 0.693; hypotheticle IFI group: 90.30+/-9.38 vs. 85.41+/-10.11, t = 710.500, P = 0.860; proven IFI group: 100.98+/-19.24 vs. 103.21+/-17.66, t = 653.000, P = 0.449 ). Prior to the administration of albumin, sensitivity, specificity, positive predictive value ( PPV ), negative predictive value ( NPV ) and Youden index were 79.8%, 87.9%, 45.6%, 96.7%, 67.7%, respectively. However, after the administration of albumin, they were 81.5%, 85.7%, 44.8%, 96.5%, and 67.2%, respectively, without significant difference. CONCLUSIONS: G test is method for early diagnosis of IFI. The sensitivity and specificity are higher with 20 ng/L as the critical value. The result of G test is not interfered by albumin administration. PMID- 26255018 TI - [A study of apoptosis of murine platelet induced by lipopolysaccharide derived from Escherichia coli in vitro]. AB - OBJECTIVE: To observe whether lipopolysaccharide ( LPS ) derived from Escherichia coli ( E.coli ) can induce apoptosis of murine platelets in vitro. METHODS: Washed platelet suspension was prepared and adjusted to the final concentration of 3*10(8)/mL. According to the difference in stimulants, samples were divided into control group ( non-calcium Tyrode buffer ), thrombin-treated group ( 1 U/mL final concentration and non-calcium TB ) and LPS in different concentrations treated groups ( 1, 10 and 100 MUg/mL final concentration respectively and non calcium TB ). To each specimental group corresponding stimulus was added and incubated 30 minutes at room temperature. Chemiluminescence was adopted to determine the concentration of adenosine triphosphate ( ATP ) and the activity of cysteinyl aspartate specific proteinase-3 ( caspase-3 ). The percentage of Annexin V positive platelets was determined by flow cytometry to reflect the level of phosphatidylserine ( PS ) exposure. Mean channel fluorescence ( MCF ) of platelets was determined by flow cytometry for reflecting the level of mitochondrial inner transmembrane potential (Deltapsim ) depolarization. RESULTS: Compared with control group, the ATP concentration in thrombin-treated group was decreased obviously [ relative light unit ( RLU ): ( 5.46+/-0.14 )*10(5) vs. ( 6.25+/-0.26 )*10(5), P < 0.05 ], Annexin V positive ratio [ ( 50.43+/-2.45 )% vs. ( 1.58+/-0.25 )%, P < 0.05 ] and caspase-3 activity [ RLU: ( 26.92+/-1.60 )*10(3) vs. ( 1.30+/-0.10 )*10(3), P < 0.05 ] were increased obviously, and platelets MCF was lowered significantly [ ( 8.32+/-0.58 )*10(4) vs. ( 13.05+/-1.10 )*10(4), P < 0.05 ], suggesting an increase in Delta psim depolarization. After being treated with different concentrations of LPS, ATP concentration, Annexin V positive ratio and caspase-3 activity were increased obviously, platelet MCF was decreased obviously, suggesting Deltapsim depolarization was increased in a concentration dependent manner. Compared with control group, 1 MUg/mL LPS could increase Annexin V positive ratio [ ( 10.45+/-1.08 )% vs. ( 1.58+/-0.25 )%, P < 0.05 ], elevate caspase-3 activity [ RLU: ( 14.06+/-0.61 )*10(3) vs. ( 1.30+/-0.10 )*10(3), P < 0.05 ], and decrease MCF significantly [ ( 9.48+/-0.50 )*10(4) vs. ( 13.05+/-1.10 )*10(4), P < 0.05 ]. The ATP concentration, Annexin V positive ratio and caspase-3 activity reached maximum levels after the treatment with 100 MUg/mL LPS, and they were higher obviously than those of the control group [ ATP ( RLU ): ( 7.00+/-0.03 )*10(5) vs. ( 6.25+/-0.26 )*10(5), Annexin V positive ratio: ( 55.35+/-2.42 )% vs. ( 1.58+/-0.25 )%, casepase-3 ( RLU ): ( 32.00+/-3.75 )*10(3) vs. ( 1.30+/-0.10 )*10(3), all P < 0.05 ], and platelets MCF reached trough levels, and they were obviously lower than those of the control group [ ( 4.69+/ 0.55 )*10(4) vs. ( 13.05+/-1.10 )*10(4), P < 0.05 ]. CONCLUSIONS: E.coli LPS can induce an increase in ATP, PS exposure, Deltapsim depolarization and activity increase of caspase-3 on mouse platelet in vitro, which indicate that LPS can induce apoptosis of platelets in a concentration-dependent manner. PMID- 26255019 TI - [The effect of Xuebijing injection for severe acute pancreatitis: a Meta analysis]. AB - OBJECTIVE: To assess the efficacy and safety of Xuebijing injection for the treatment of severe acute pancreatitis ( SAP ). METHODS: An extensive search of related literatures from the Cochrane Library, EMBASE, China Biology Medicine ( CBM ), CNKI, VIP and Wanfang data up to March 2014 was performed. Randomized controlled trials ( RCTs ) regarding Xuebijing injection for the treatment of SAP were collected regardless of languages. Jadad scale was taken for quality evaluation of the included studies by two researchers. The patients in control group were given conventional treatment, and those of the Xuebijing group were given Xuebijing injection on the top of conventional treatment. The Cochrane Collaboration RevMan 5.2 software was used for data analysis regarding the effect of Xuebijing injection on the mortality, incidence of complication, effective rate, the length of stay in hospital, and the safety of the drug in patients with SAP. RESULTS: A total of 15 published reports meeting the inclusion criteria were enrolled. The methodological quality of the trials was low. Meta analysis showed that the mortality in Xuebijing group was significantly lower [ odds ratio ( OR ) = 0.37, 95% confidence interval ( 95%CI ) = 0.17 - 0.77, P = 0.008 ], and the incidence of complication was also significantly decreased ( OR = 0.26, 95%CI = 0.14 - 0.45, P < 0.000 01 ) as compared with those of control group. The effective rate in Xuebijing group was significantly higher than that of the control group [ relative risk ( RR ) = 0.85, 95%CI = 0.80-0.91, P < 0.000 01 ]. The length of stay in hospital in Xuebijing group was significantly shorter than that of the control group [ mean difference ( MD ) = -5.28, 95%CI = -6.69 to 3.86, P < 0.000 01 ]. Adverse reactions of Xuebijing injection were reported in 2 studies. The adverse reaction in one study was headache and nausea, which were relieved by adjusting the speed of intravenous infusion, and mild rash was reported in another case, and it disappeared after the withdrawal of Xuebijing. CONCLUSIONS: The currently available evidence shows that Xuebijing injection may have some therapeutic effect on SAP. Because of the low methodological quality of the included trials, multi-center and high-quality RCTs with large sample sizes are needed to provide stronger evidence. PMID- 26255020 TI - [The value of modified early warning score in predicting early mortality of critically ill patients admitted to emergency department]. AB - OBJECTIVE: To evaluate the value of modified early warning score ( MEWS ) in predicting mortality of critically ill patients admitted to emergency department. METHODS: A prospective cohort study was conducted. Clinical data of emergency patients admitted to resuscitation room of Peking Union Medical College Hospital from Feburary 13rd, 2014 to April 20th, 2014 were collected, and their MEWS were calculated based on medical records and their clinical outcomes was followed. Incidence of primary outcome ( 3-day mortality ) and secondary outcome [ all deaths and composite outcome of intensive care unit ( ICU ) transfer, cardio pulmonary resuscitation, and death ] were compared between MEWS positive ( MEWS>=5 ) or negative ( MEWS 0-4 ) patients, and multi-regression logistic analysis was done to look for the impact factors of primary outcome in these patients. RESULTS: 176 patients, among them 98 ( 55.68% ) were male, were enrolled in the study. Their mean age was ( 56.86+/-21.46 ) years old. Mean MEWS was 4.30+/-2.74. There was 74 cases in MEWS positive group, and 102 in negative group. Primary endpoint occurred in 41 patients, and the 3-days mortality in MEWS positive group was significantly higher than that in MEWS negative group [ 37.84 ( 28/74) vs. 12.74% ( 13/102 ), odds ratio ( OR ) = 4.167, 95% confidence interval ( 95%CI ) = 1.973-8.804, P < 0.001 ]. At the meantime, incidence of all death [ 54.05% ( 40/74 ) vs. 17.65% ( 18/102 ), OR = 5.490, 95%CI = 2.770-10.883, P < 0.001 ] and the incidence of ICU transfer, cardio-pulmonary resuscitation and death [ 64.86% ( 48/74 ) vs. 25.49% ( 26/102 ), OR = 5.396, 95%CI = 2.809-10.366, P < 0.001 ] were also significantly higher in MEWS positive group as compared with negative group. Multi-regression logistic showed abnormal mental status ( OR = 3.606, 95%CI = 1.541-8.436, P = 0.003 ) but not MEWS >=5 ( OR = 1.672, 95%CI = 0.622-4.494, P = 0.308 ) was the predictor of 3-day mortality in emergency admitted critically ill patients. CONCLUSIONS: Although the incidence of severe adverse events is significantly increased in patients with MEWS >=5 compared with those with MEWS 0-4, MEWS>=5 cannot be an efficient predictor for 3-day mortality. Abnormal mental status shows some predictive value for early mortality in critically ill patients seen in emergency department. PMID- 26255021 TI - [The influence of joining central venous catheter and pressure transducer with T junctions on central venous pressure]. AB - OBJECTIVE: To investigate the influence of the number of T-junctions between central venous catheter and pressure transducer on measurement of central venous pressure ( CVP ) in patients. METHODS: A prospective controlled study was conducted. The patients with CVP monitoring in Department of Critical Care Medicine of the Fifth Center Hospital in Tianjin from February to October in 2014 were enrolled. The patients were divided into three groups according to the number of T-junction between central venous catheter and pressure transducer: without T-junction control group and 1, 2, 3 T-junctions groups. In each patient, corresponding CVP values with different number of T-junctions placed between the central venous catheter and pressure sensors were determined within a certain period, and a square-wave graphic was obtained and preserved on the monitor. The own frequency ( fn ) and the attenuation coefficient ( D ) of the system of pressure measurement were calculated after measurement of the shock wave following a square-wave to obtain the distance between two vibrations and the amplitude of the shock wave. The difference in CVP, fn and D were compared among the groups. RESULTS: A total of 20 cases were enrolled, and 150 groups of data were collected. (1) With the increase in the number of T-junction, CVP showed a tendency of gradual reduction. The CVP of the groups of control and 1, 2, 3 T junctions was ( 7.00+/-1.60 ), ( 7.00+/-3.00 ), ( 5.00+/-2.00 ), and ( 4.00+/ 1.00 ) mmHg ( 1 mmHg = 0.133 kPa ), respectively. The CVP of 3 T-junctions group was significantly lower than that of the control group ( F = 9.333, P = 0.015 ). (2) With an increase in the number of T-junction, fn showed a tendency of gradual increase. The fn of groups control and 1, 2, 3 T-junctions was ( 12.30+/-0.79 ), ( 16.00+/-0.91 ), ( 18.10+/-1.75 ), ( 20.90+/-2.69 ) Hz, respectively. The fn of 1, 2, 3 T-junctions group was significantly higher than that of the control group ( F1 = 45.962, F2 = 45.414, F3 = 46.830, all P = 0.000 ); the fn of groups 2 and 3 T-junctions was significantly higher than that of 1 T-junction group ( F1= 5.827, P1= 0.042; F2 = 15.038, P2 = 0.004 ), but there was no significant difference between the groups of 2 T-junctions and 3 T-junctions ( F = 3.800, P = 0.087 ). (3) With an increase of the number of T-junction, D also showed a tendency of gradual increase. The D of 1, 2, 3 T-junction group was 1.62+/-0.27, 1.60+/-0.22, 1.82+/-0.25, and 2.15+/-0.58, respectively. There were no differences among four groups. CONCLUSIONS: After the application of T-junctions between central venous catheter and pressure transducer, CVP values will be underestimated, the reason of which is considered to be the increase in length and thinner lumen of the T-junctions. PMID- 26255022 TI - [The clinical analysis of patients with multiple organ dysfunction syndrome induced by severe heat stroke: a report of 9 cases and review of literature]. PMID- 26255023 TI - [The application of new type of medical glove restraint appliance in the prevention of non planned extubation in patients with severe strengthening treatment]. PMID- 26255024 TI - [Pathogenesis and advance in epidemiology of heat stroke]. PMID- 26255025 TI - Potential prognostic significance of a new proteomic profile in patients with advanced pancreatic adenocarcinoma. AB - OBJECTIVES: Seven-signal proteomic approach has recently been developed as a new proteomic profile measured by matrix-assisted laser desorption/ionization mass spectrometry. The aim of this study was to evaluate prognostic significance of this proteomic value in patients with pancreatic adenocarcinoma. METHODS: Blood samples from the patients with pancreatic adenocarcinoma were prospectively collected before treatments including surgical resection and systemic chemotherapies. The seven-signal proteomic profiles of the samples were measured, and the prognostic significance of the proteomic value was evaluated through comparison with other existing prognostic markers. RESULTS: Cut-off value of the proteomic profiles at 52 stratified overall prognosis of the patients (6.5 months vs. 10.9 months with the values >=52 vs. <52, p = 0.020). In subgroup analyses of inoperable cases with carcinoembryonic antigen level of <5 ng/ml or performance status of 0-1, the proteomic value at 52 stratified their prognosis (p = 0.002 and p = 0.006, respectively). CONCLUSIONS: The new seven-signal proteomics showed useful prognostic significance for patients with pancreatic adenocarcinoma. Further studies with a large sample size would be required to evaluate whether this proteomic approach possibly complements the existing parameters, such as carcinoembryonic antigen and performance status. PMID- 26255026 TI - Cx43 increases serum induced filopodia formation via activation of p21-activated protein kinase 1. AB - In a previous study we could show that connexin 43 (Cx43) expression increased the migration of cells in a channel-independent manner involving the MAPK p38. We analyzed here the mechanism by which Cx43 enhanced p38 activation and migration related changes of the actin cytoskeleton. HeLa cells were used as a model system for the controlled expression of Cx43 and truncated Cx43 proteins. The expression of Cx43 altered the actin cytoskeleton organization in response to serum stimulation. Cx43 expressing HeLa cells had significantly more filopodial protrusions per cell than empty-vector transfected control cells. The expression of the channel incompetent carboxyl tail of Cx43 was sufficient to enhance the filopodia formation whereas the N-terminal, channel-building part, had no such effect. The enhanced filopodia formation was p38 dependent since the p38 blocker SB203580 significantly diminished it. Immunoprecipitation revealed an interaction of the upstream regulator of p38, p21-activated protein kinase 1 (PAK1), with Cx43 resulting in an enhanced phosphorylation of PAK1. Moreover, p38 activation, filopodia formation and cell migration were significantly reduced by blocking the PAK1 activity with its pharmacological inhibitor, IPA-3. The p38 target Hsp27, which favors the actin polymerization in its phosphorylated form, was significantly more phosphorylated characterizing it as a potential candidate molecule to enhance the serum-induced actin polymerization in Cx43 expressing cells. Our results provide a novel mechanism by which Cx43 can modify actin cytoskeletal dynamics and may thereby enhance cell migration. PMID- 26255027 TI - The role of microenvironment and immunity in drug response in leukemia. AB - Leukemia is a cancer of the white blood cells, with over 54,000 new cases per year diagnosed worldwide and a 5-year survival rate below 60%. This highlights a need for research into the mechanisms behind its etiology and causes of therapy failure. The bone marrow microenvironment, in which adult stem cells are maintained in healthy individuals, has been implicated as a source of chemoresistance and disease relapse. Here the various ways that the microenvironment can contribute to the resistance and persistence of leukemia are discussed. The targeting of the microenvironment by leukemia cells to create an environment more suitable for cancer progression is described. The role of soluble factors, drug transporters, microvesicles, as well as the importance of direct cell-cell contact, in addition to the effects of inflammation and immune surveillance in microenvironment-mediated drug resistance are discussed. An overview of the clinical potential of translating research findings to patients is also provided. Understanding of and further research into the role of the bone marrow microenvironment in leukemia progression and relapse are crucial towards developing more effective treatments and reduction in patient morbidity. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza. PMID- 26255028 TI - Lloviu virus VP24 and VP35 proteins function as innate immune antagonists in human and bat cells. AB - Lloviu virus (LLOV) is a new member of the filovirus family that also includes Ebola virus (EBOV) and Marburg virus (MARV). LLOV has not been cultured; however, its genomic RNA sequence indicates the coding capacity to produce homologs of the EBOV and MARV VP24, VP35, and VP40 proteins. EBOV and MARV VP35 proteins inhibit interferon (IFN)-alpha/beta production and EBOV VP35 blocks activation of the antiviral kinase PKR. The EBOV VP24 and MARV VP40 proteins inhibit IFN signaling, albeit by different mechanisms. Here we demonstrate that LLOV VP35 suppresses Sendai virus induced IFN regulatory factor 3 (IRF3) phosphorylation, IFN alpha/beta production, and PKR phosphorylation. Additionally, LLOV VP24 blocks tyrosine phosphorylated STAT1 binding to karyopherin alpha 5 (KPNA5), STAT1 nuclear accumulation, and IFN-induced gene expression. LLOV VP40 lacks detectable IFN antagonist function. These activities parallel EBOV IFN inhibitory functions. EBOV and LLOV VP35 and VP24 proteins also inhibit IFN responses in bat cells. These data suggest that LLOV infection will block innate immune responses in a manner similar to EBOV. PMID- 26255029 TI - Contrast-Enhanced Ultrasound: A Novel Noninvasive, Nonionizing Method for the Detection of Brown Adipose Tissue in Humans. AB - BACKGROUND: Brown adipose tissue (BAT) consumes glucose when it is activated by cold exposure, allowing its detection in humans by (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT). The investigators recently described a novel noninvasive and nonionizing imaging method to assess BAT in mice using contrast-enhanced ultrasound (CEUS). Here, they report the application of this method in healthy humans. METHODS: Thirteen healthy volunteers were recruited. CEUS was performed before and after cold exposure in all subjects using a continuous intravenous infusion of perflutren gas-filled lipid microbubbles and triggered imaging of the supraclavicular space. The first five subjects received microbubbles at a lower infusion rate than the subsequent eight subjects and were analyzed as a separate group. Blood flow was estimated as the product of the plateau (A) and the slope (beta) of microbubble replenishment curves. All underwent (18)F-FDG PET/CT after cold exposure. RESULTS: An increase in the acoustic signal was noted in the supraclavicular adipose tissue area with increasing triggering intervals in all subjects, demonstrating the presence of blood flow. The area imaged by CEUS colocalized with BAT, as detected by 18F-FDG PET/CT. In a cohort of eight subjects with an optimized CEUS protocol, CEUS-derived BAT blood flow increased with cold exposure compared with basal BAT blood flow in warm conditions (median Abeta = 3.3 AU/s [interquartile range, 0.5-5.7 AU/s] vs 1.25 AU/s [interquartile range, 0.5-2.6 AU/s]; P = .02). Of these eight subjects, five had greater than twofold increases in blood flow after cold exposure; these responders had higher BAT activity measured by (18)F-FDG PET/CT (median maximal standardized uptake value, 2.25 [interquartile range, 1.53-4.57] vs 0.51 [interquartile range, 0.47-0.73]; P = .02). CONCLUSIONS: The present study demonstrates the feasibility of using CEUS as a noninvasive, nonionizing imaging modality in estimating BAT blood flow in young, healthy humans. CEUS may be a useful and scalable tool in the assessment of BAT and BAT-targeted therapies. PMID- 26255030 TI - Protective Effect of Unsaturated Fatty Acids on Palmitic Acid-Induced Toxicity in Skeletal Muscle Cells is not Mediated by PPARdelta Activation. AB - Unsaturated free fatty acids (FFA) are able to prevent deleterious effects of saturated FFA in skeletal muscle cells although the mechanisms involved are still not completely understood. FFA act as endogenous ligands of peroxisome proliferator-activated receptors (PPAR), transcription factors regulating the expression of genes involved in lipid metabolism. The aim of this study was to determine whether activation of PPARdelta, the most common PPAR subtype in skeletal muscle, plays a role in mediating the protective effect of unsaturated FFA on saturated FFA-induced damage in skeletal muscle cells and to examine an impact on mitochondrial respiration. Mouse C2C12 myotubes were treated for 24 h with different concentrations of saturated FFA (palmitic acid), unsaturated FFA (oleic, linoleic and alpha-linolenic acid), and their combinations. PPARdelta agonist GW501516 and antagonist GSK0660 were also used. Both mono- and polyunsaturated FFA, but not GW501516, prevented palmitic acid-induced cell death. Mono- and polyunsaturated FFA proved to be effective activators of PPARdelta compared to saturated palmitic acid; however, in combination with palmitic acid their effect on PPARdelta activation was blocked and stayed at the levels observed for palmitic acid alone. Unsaturated FFA at moderate physiological concentrations as well as GW501516, but not palmitic acid, mildly uncoupled mitochondrial respiration. Our results indicate that although unsaturated FFA are effective activators of PPARdelta, their protective effect on palmitic acid-induced toxicity is not mediated by PPARdelta activation and subsequent induction of lipid regulatory genes in skeletal muscle cells. Other mechanisms, such as mitochondrial uncoupling, may underlie their effect. PMID- 26255031 TI - Strain-level visualized analysis of cold-stressed Vibrio parahaemolyticus based on MALDI-TOF mass fingerprinting. AB - In this study, strain-level visualized analysis of cold-stressed Vibrio parahaemolyticus based on matrix-assisted laser desorption ionization time-of flight (MALDI-TOF) mass fingerprinting was investigated. All the peptide mass fingerprinting profiles obtained were analyzed by self-organized map (SOM) and cluster analysis. Our results showed that the peptide mass fingerprinting profiles of V. parahaemolyticus substantially changed under cold stress at strain level. The cold-stressed V. parahaemolyticus strains were distributed to 14 neurons by SOM classification, almost totally different from the controls. This is the first time that so many strains had been chosen to study bacterial cold stress responses, which can help promote an overall understanding to stress responses of cold-stressed strains. PMID- 26255032 TI - Infection and pathogenecity of Myroides odoratimimus (NIOCR-12) isolated from the gut of grey mullet (Mugil cephalus (Linnaeus, 1758)). AB - Myroides sp. are gram negative aerobes and known for its oppurtunistic pathogenicity in humans. In the present study, Myroides odoratimimus isolated from the gut of Mugil cephalus showed potential infectivity to the experimental grey mullet and acted as an ultimate pathogen with significant symptoms. Furthermore, the inoculum isolated from the infected fishes were cultured and the selected colonies were reisolated and reinjected into healthy juveniles of M. cephalus. Characterizations of the re-isolated bacteria were the same as those of the isolated M. odoratimimus from naturally infected mullet. The median lethal dose (LD50) of the bacteria was 3 * 10(6) CFU fish(-1). In order to assay the accuracy of infection, the production of reactive oxygen species (ROS), the respiratory burst activity of blood leukocytes of mullet before and after challenge was measured, an indicator of the innate immune system. The mullet infection increased the respiratory burst activity and superoxide dismutase activity. In addition, the innate immune response of TLR 9 expression against M. odoratimimus infection and CpG ODN treatment in disease model, zebrafish confirms the M. odoratimimus infection and pathogenicity. PMID- 26255033 TI - Subdural hematoma after endoscopic third ventriculostomy: Struggling against the Laplace law. AB - BACKGROUND: Endoscopic third ventriculostomy (ETV) is an ideal treatment for obstructive hydrocephalus. Although ETV is a safe procedure, several complications related to this procedure have been reported in the literature. We present a rare case of late onset symptomatic bilateral subdural hematoma after an uneventful ETV that proved particularly difficult to solve. CASE DESCRIPTION: A 61-year-old male patient presented in our neurosurgery department three months after ETV (aqueductal stenosis) with progressive headaches and anomic aphasia. The MRI revealed bilateral chronic subdural hematomas (chSDH). They were treated via a burr hole evacuation, subduroperitoneal and external subdural drains proving to be refractory to the first two strategies. Postoperatively, his headaches improved. At the last follow-up the patient's status remains improved and there is no radiological evidence of significant residual collections. CONCLUSION: This case confirms that chSDH formation is a rare possible complication following ETV even in the presence of a normal early postoperative image. Patients should be followed-up more closely for possible subdural collection formation. In the cases of very long-term hydrocephalus with a thin cerebral mantle, brain elastic properties are likely to be altered. As there is no possibility to close the internal shunt, the stoma, we advocate external subdural drainage to reinflate the brain, in the first intention or at least after an initial failed burr hole evacuation. PMID- 26255034 TI - Comparison of Image Quality and Radiation Dose between High-Pitch Mode and Low Pitch Mode Spiral Chest CT in Small Uncooperative Children: The Effect of Respiratory Rate. AB - OBJECTIVES: To compare image quality and radiation dose between high-pitch mode (HPM) and low-pitch mode (LPM) CT in young children. MATERIALS AND METHODS: Forty seven children (mean age 35.6 months; range, 0-126 months) underwent 49 CT examinations in HPM or LPM and were divided into high or low respiratory rate (RR) groups. A qualitative image quality was compared between the two modes. The volume CT dose index (CTDIvol) and dose-length product (DLP) were evaluated from the dose reports, and effective doses were assessed using a paediatric phantom. RESULTS: Image quality was generally better for HPM than LPM (diagnostic acceptance score, 4.00 vs. 3.46, P = 0.004); the difference was more prominent in the high RR group (4.00 vs. 3.22, P = 0.001). However, there was no significant difference in the low RR group. The mean DLP value was higher in HPM than LPM (29.48 mGy . cm vs. 23.46 mGy . cm, P = 0.022), while CTDIvol was not significantly different. The total effective radiation dose was 26 % higher in HPM than LPM (1.82 mSv vs. 1.44 mSv). CONCLUSIONS: LPM can be considered for paediatric lung evaluation in young children with low RRs to reduce radiation dose while maintaining favourable image quality. KEY POINTS: * Radiation exposure is higher on high-pitch "Flash spiral mode" than on low-pitch "X-CARE mode". * "Flash spiral mode" generally showed better image quality than "X-CARE mode". * Difference in image quality was more prominent in the high RR group. * There was no difference in image quality in the low RR group. * "X-CARE mode" should be considered in a limited population with low RRs. PMID- 26255035 TI - Empirical Drug Therapy for Idiopathic Male Infertility: What is the New Evidence? AB - Idiopathic male infertility is empirically managed using a number of drugs. We reviewed 64 articles published in the last 10 years on such drug therapy. There was severe heterogeneity in data along with poor definition of outcome parameters. Pregnancy or live birth rate was not reported in many studies. Antiestrogens appear to improve pregnancy rates while there is some data supporting the use of aromatase inhibitors. Antioxidants significantly increase the rate of both live birth and pregnancy but the data are limited. However, valid end-points based on data are limited for the empirical use of drugs in idiopathic male infertility. PMID- 26255036 TI - Preoperative Serum Prostate-Specific Antigen Levels Vary According to the Topographical Distribution of Prostate Cancer in Prostatectomy Specimens. AB - OBJECTIVE: To evaluate whether the spatial distribution of prostate cancer (PCa) influences the concentration of prostate-specific antigen (PSA). METHODS: An observational prospective study was performed in 775 consecutive men with preoperative PSA levels <=20 ng/mL who underwent radical prostatectomy for organ confined PCa. We evaluated prostate specimens using a cMDX-based map model of the prostate and determined the prostate volume, number of cancer foci, relative tumor volume, Gleason score, zone of origin, localization, and pathologic stage after stratification according to PSA levels categorized into 3 groups: <4 ng/mL, 4-10 ng/mL, and 10.1-20 ng/mL. The distribution of 5254 PCa foci was analyzed after stratification according to PSA levels and visualized on heat maps. A logistic regression analysis was performed to assess the odds ratios of PSA levels for the presence of PCa in 16 regions. RESULTS: PCa with PSA <4 ng/mL was predominantly localized to the apical part and the peripheral zone of the prostate. PCa with a PSA level 10.1-20 ng/mL (16.4% of cases) was observed more frequently in the anterior part and the base of the prostate than PCa with a PSA level <4 or 4-10 ng/mL (6% and 10%, respectively). CONCLUSION: Preoperative PSA levels vary according to the spatial distribution of PCa in radical prostatectomy specimens. The probability of anterior PCa is increased with higher PSA serum levels. Regions of interest harboring the PCa can be defined according to preoperative PSA and prostate volume. These findings are useful to optimize the focal therapy or to adjust the radiation fields. PMID- 26255037 TI - Understanding Cognitive Performance During Robot-Assisted Surgery. AB - OBJECTIVE: To understand cognitive function of an expert surgeon in various surgical scenarios while performing robot-assisted surgery. MATERIALS AND METHODS: In an Internal Review Board approved study, National Aeronautics and Space Administration-Task Load Index (NASA-TLX) questionnaire with surgical field notes were simultaneously completed. A wireless electroencephalography (EEG) headset was used to monitor brain activity during all procedures. Three key portions were evaluated: lysis of adhesions, extended lymph node dissection, and urethro-vesical anastomosis (UVA). Cognitive metrics extracted were distraction, mental workload, and mental state. RESULTS: In evaluating lysis of adhesions, mental state (EEG) was associated with better performance (NASA-TLX). Utilizing more mental resources resulted in better performance as self-reported. Outcomes of lysis were highly dependent on cognitive function and decision-making skills. In evaluating extended lymph node dissection, there was a negative correlation between distraction level (EEG) and mental demand, physical demand and effort (NASA-TLX). Similar to lysis of adhesion, utilizing more mental resources resulted in better performance (NASA-TLX). Lastly, with UVA, workload (EEG) negatively correlated with mental and temporal demand and was associated with better performance (NASA-TLX). The EEG recorded workload as seen here was a combination of both cognitive performance (finding solution) and motor workload (execution). Majority of workload was contributed by motor workload of an expert surgeon. During UVA, muscle memory and motor skills of expert are keys to completing the UVA. CONCLUSION: Cognitive analysis shows that expert surgeons utilized different mental resources based on their need. PMID- 26255038 TI - Targeted next-generation sequencing to diagnose disorders of HDL cholesterol. AB - A low level of HDL cholesterol (HDL-C) is a common clinical scenario and an important marker for increased cardiovascular risk. Many patients with very low or very high HDL-C have a rare mutation in one of several genes, but identification of the molecular abnormality in patients with extreme HDL-C is rarely performed in clinical practice. We investigated the accuracy and diagnostic yield of a targeted next-generation sequencing (NGS) assay for extreme levels of HDL-C. We developed a targeted NGS panel to capture the exons, intron/exon boundaries, and untranslated regions of 26 genes with highly penetrant effects on plasma lipid levels. We sequenced 141 patients with extreme HDL-C levels and prioritized variants in accordance with medical genetics guidelines. We identified 35 pathogenic and probably pathogenic variants in HDL genes, including 21 novel variants, and performed functional validation on a subset of these. Overall, a molecular diagnosis was established in 35.9% of patients with low HDL-C and 5.2% with high HDL-C, and all prioritized variants identified by NGS were confirmed by Sanger sequencing. Our results suggest that a molecular diagnosis can be identified in a substantial proportion of patients with low HDL-C using targeted NGS. PMID- 26255039 TI - Circulatory disease mortality in the Massachusetts tuberculosis fluoroscopy cohort study. AB - High-dose ionizing radiation is associated with circulatory disease. Risks from lower-dose fractionated exposures, such as from diagnostic radiation procedures, remain unclear. In this study we aimed to ascertain the relationship between fractionated low-to-medium dose radiation exposure and circulatory disease mortality in a cohort of 13,568 tuberculosis patients in Massachusetts, some with fluoroscopy screenings, between 1916 and 1961 and follow-up until the end of 2002. Analysis of mortality was in relation to cumulative thyroid (cerebrovascular) or lung (all other circulatory disease) radiation dose via Poisson regression. Over the full dose range, there was no overall radiation related excess risk of death from circulatory disease (n = 3221; excess relative risk/Gy -0.023; 95% CI -0.067, 0.028; p = 0.3574). Risk was somewhat elevated in hypertensive heart disease (n = 89; excess relative risk/Gy 0.357; 95% CI -0.043, 1.030, p = 0.0907) and slightly decreased in ischemic heart disease (n = 1950; excess relative risk/Gy -0.077; 95% CI -0.130, -0.012; p = 0.0211). However, under 0.5 Gy, there was a borderline significant increasing trend for all circulatory disease (excess relative risk/Gy 0.345; 95% CI -0.032, 0.764; p = 0.0743) and for ischemic heart disease (excess relative risk/Gy 0.465; 95% CI, 0.032, 1.034, p = 0.0682). Pneumolobectomy increased radiation-associated risk (excess relative risk/Gy 0.252; 95% CI 0.024, 0.579). Fractionation of dose did not modify excess risk. In summary, we found no evidence of radiation-associated excess circulatory death risk overall, but there are indications of excess circulatory death risk at lower doses (<0.5 Gy). Although consistent with other radiation-exposed groups, the indications of higher risk at lower doses are unusual and should be confirmed against other data. PMID- 26255040 TI - Treatment and outcomes of polymerase chain reaction-confirmed early syphilis. AB - Background Syphilis is resurgent among gay and bisexual men (GBM) despite effective treatment and widely available diagnostic serology. The polymerase chain reaction assay for Treponema pallidum (TP-PCR) is available, but little is known about the clinical features and outcomes for patients testing positive by TP-PCR. METHODS: Clinical data were collected from four medical practices for patients recording a positive TP-PCR result between 2004 and 2011. Demographic, serological, treatment and reinfection details were obtained. Results were stratified by HIV status and whether treatment conformed to international guidelines. RESULTS: 220 patients were positive for TP-PCR, of whom 92% were GBM. Seventeen (8.1%) were positive by TP-PCR before seroconversion. Almost one-third (32.1%) received treatment beyond that recommended in guidelines, and this was associated with HIV status (40.3% HIV positive vs 22.4% HIV negative, P<0.01). All but one patient with adequate follow up achieved serological cure. There was no significant difference in time to serological cure between the groups receiving standard therapy or enhanced therapy (95 vs 108 days; P=0.67) or between HIV positive and negative patients (93 vs 104 days, P=0.06). Nineteen patients were reinfected during follow up. CONCLUSION: TP-PCR aids early diagnosis of syphilis and may be reactive before conventional serological tests. Treatment outcomes for TP-PCR-positive early infection were excellent, but a significant proportion of patients received non-standard therapy. Expanded use of syphilis PCR testing in at-risk populations is recommended since early identification and treatment is likely to be important in controlling the current epidemic in GBM. PMID- 26255041 TI - Cellular bioenergetics of guanidinoacetic acid: the role of mitochondria. AB - Guanidinoacetic acid (GAA) is a natural precursor of creatine, and a possible substrate for the creatine kinase (CK) enzyme system, serving as a creatine mimetic. Its direct role in cellular bioenergetics has been confirmed in several studies, however GAA utilization by CK seems to be a second-rate as compared to creatine, and compartment-dependent. Here we discuss various factors that might affect GAA use in high-energy phosphoryl transfer in the cytosol and mitochondria. PMID- 26255042 TI - Genetics and Genetic Testing in Pancreatic Cancer. AB - Genetic testing of germline DNA is used in patients suspected of being at risk of pancreatic ductal adenocarcinoma (PDAC) to better define the individual's risk and to determine the mechanism of risk. A high genetic risk increases the pretest probability that a biomarker of early cancer is a true positive and warrants further investigation. The highest PDAC risk is generally associated with a hereditary predisposition. However, the majority of PDAC results from complex, progressive gene-environment interactions that currently fall outside the traditional risk models. Over many years, the combination of inflammation, exposure to DNA-damaging toxins, and failed DNA repair promote the accumulation of somatic mutations in pancreatic cells; PDAC risk is further increased by already present oncogenic germline mutations. Predictive models and new technologies are needed to classify patients into more accurate and mechanistic PDAC risk categories that can be linked to improved surveillance and preventative strategies. PMID- 26255043 TI - Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial. AB - BACKGROUND & AIMS: A diet with reduced content of fermentable short-chain carbohydrates (fermentable oligo-, di-, monosaccharides, and polyols [FODMAPs]) has been reported to be effective in the treatment of patients with irritable bowel syndrome (IBS). However, there is no evidence of its superiority to traditional dietary advice for these patients. We compared the effects of a diet low in FODMAPs with traditional dietary advice in a randomized controlled trial of patients with IBS. METHODS: We performed a multi-center, parallel, single blind study of 75 patients who met Rome III criteria for IBS and were enrolled at gastroenterology outpatient clinics in Sweden. Subjects were randomly assigned to groups that ate specific diets for 4 weeks-a diet low in FODMAPs (n = 38) or a diet frequently recommended for patients with IBS (ie, a regular meal pattern; avoidance of large meals; and reduced intake of fat, insoluble fibers, caffeine, and gas-producing foods, such as beans, cabbage, and onions), with greater emphasis on how and when to eat rather than on what foods to ingest (n = 37). Symptom severity was assessed using the IBS Symptom Severity Scale, and patients completed a 4-day food diary before and at the end of the intervention. RESULTS: A total of 67 patients completed the dietary intervention (33 completed the diet low in FODMAPs, 34 completed the traditional IBS diet). The severity of IBS symptoms was reduced in both groups during the intervention (P < .0001 in both groups before vs at the end of the 4-week diet), without a significant difference between the groups (P = .62). At the end of the 4-week diet period, 19 patients (50%) in the low-FODMAP group had reductions in IBS severity scores >=50 compared with baseline vs 17 patients (46%) in the traditional IBS diet group (P = .72). Food diaries demonstrated good adherence to the dietary advice. CONCLUSIONS: A diet low in FODMAPs reduces IBS symptoms as well as traditional IBS dietary advice. Combining elements from these 2 strategies might further reduce symptoms of IBS. ClinicalTrials.gov ID NCT02107625. PMID- 26255044 TI - Trends in burden of cirrhosis and hepatocellular carcinoma by underlying liver disease in US veterans, 2001-2013. AB - BACKGROUND & AIMS: Cirrhosis and hepatocellular carcinoma (HCC) are predicted to increase in the United States but the accuracy of prior forecasts and the contributions from various liver disease etiologies remain unclear. We aimed to determine the burden of cirrhosis and HCC according to underlying cause from 2001 to 2013. METHODS: We developed a national retrospective cohort of Veterans Affairs (VA) patients with the diagnosis of cirrhosis (n = 129,998) or HCC (n = 21,326) from 2001 to 2013. We used laboratory results, International Classification of Diseases, ninth edition (ICD-9) codes, and body mass index to identify underlying etiologies. RESULTS: In 2013, VA provided care to 5,720,614 individuals, of whom 60,553 (1.06%) had cirrhosis and 7,670 (0.13%) had HCC. Hepatitis C virus (HCV) was present in an increasing proportion of cirrhosis and HCC between 2001 and 2013, reaching 48% of cirrhosis cases and deaths and 67% of HCC cases and deaths by 2013. Cirrhosis prevalence nearly doubled from 2001 to 2013 (664 to 1058 per 100,000 enrollees), driven by HCV and nonalcoholic fatty liver disease (NAFLD). Cirrhosis incidence ranged from 159 to 193 per 100,000 patient-years. Deaths in patients with cirrhosis increased from 83 to 126 per 100,000 patient-years, largely driven by HCV. HCC incidence was 2.5-fold increased from 17 to 45 per 100,000 patient-years. HCC mortality tripled from 13 to 37 per 100,000 patient-years, driven overwhelmingly by HCV, with much smaller contributions from NAFLD and alcoholic liver disease. CONCLUSIONS: Cirrhosis prevalence and mortality and HCC incidence and mortality increased from 2001 to 2013, driven by HCV, with a smaller contribution from NAFLD. If current trends continue, cirrhosis prevalence will peak in 2021. Health care systems will need to accommodate rising numbers of patients with cirrhosis and HCC. PMID- 26255045 TI - Incidence and mortality of colorectal cancer in individuals with a family history of colorectal cancer. AB - BACKGROUND & AIMS: Little is known about the change in risk conferred by family history of colorectal cancer (CRC) as a person ages. We evaluated the effect of family history on CRC incidence and mortality after 55 years of age, when the risk of early onset cancer had passed. METHODS: We collected data from participants in the randomized, controlled Prostate, Lung, Colorectal and Ovarian cancer screening trial of flexible sigmoidoscopy versus usual care (55-74 years old, no history of CRC), performed at 10 US centers from 1993 to 2001. A detailed family history of colorectal cancer was obtained at enrollment, and subjects were followed for CRC incidence and mortality for up to 13 years. RESULTS: Among 144,768 participants, 14,961 subjects (10.3%) reported a family of CRC. Of 2090 incident cases, 273 cases (13.1%) had a family history of CRC; among 538 deaths from CRC, 71 (13.2%) had a family history of CRC. Overall, family history of CRC was associated with an increased risk of CRC incidence (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.10-1.50; P<.0001) and increased mortality (HR, 1.31; 95% CI, 1.02-1.69; P = .03). Subjects with 1 first degree relative (FDR) with CRC (n = 238; HR, 1.23; 95% CI, 1.07-1.42) or >=2 FDRs with CRC (n = 35; HR, 2.04; 95% CI, 1.44-2.86) were at increased risk for incident CRC. However, among individuals with 1 FDR with CRC, there were no differences in risk based on age at diagnosis in the FDR (for FDR <60 years of age: HR, 1.27; 95% CI, 0.97-1.63; for FDR 60-70 years of age: HR, 1.33; 95% CI, 1.06-1.62; for FDR >70 years of age: HR, 1.14; 95% CI, 0.93-1.45; P trend = .59). CONCLUSIONS: After 55 years of age, subjects with 1 FDR with CRC had only a modest increase in risk for CRC incidence and death; age of onset in the FDR was not significantly associated with risk. Individuals with >=2 FDRs with CRC had continued increased risk in older age. Guidelines and clinical practice for subjects with a family history of CRC should be modified to align CRC testing to risk. ClinicalTrials.gov number, NCT00002540. PMID- 26255046 TI - Smoking habits and leukocyte telomere length dynamics among older adults: Results from the ESTHER cohort. AB - BACKGROUND & AIMS: Leukocyte telomere length (LTL) shortens with age and short LTL has been associated with increased mortality and increased risk for some age related outcomes. This study aims to analyse the associations of smoking habits with LTL and rate of LTL change per year in older adults. METHODS: LTL was measured by quantitative PCR at baseline in 3600 older adults, who were enrolled in a population-based cohort study in Germany. For longitudinal analyses, measurements were repeated in blood samples obtained at 8-year follow-up from 1000 participants. Terminal Restriction Fragment analysis was additionally performed in a sub-sample to obtain absolute LTL in base pairs. Multivariate linear regression models were used to estimate associations of smoking habits with baseline LTL and changes in LTL over time. RESULTS: LTL was inversely associated with age (r=-0.090, p<0.0001). Women had longer LTL than men (p<0.0001). Smoking was inversely associated with LTL. On average, current smokers had 73 base pairs (BP) shorter LTL compared to never smokers. Smoking intensity and pack-years of smoking were also inversely associated with LTL, and a positive association was observed with years since smoking cessation. Slower LTL attrition rates were observed in ever smokers over 8years of follow-up. CONCLUSIONS: Our cross-sectional analysis supports suggestions that smoking might contribute to shortening of LTL but this relationship could not be shown longitudinally. The overall rather small effect sizes observed for smoking related variables suggest that LTL reflects smoking-related health hazards only to a very limited extent. PMID- 26255047 TI - Early menarche is associated with metabolic syndrome and insulin resistance in premenopausal Korean women. AB - In pediatrics, identifying risk factors is important in planning the prevention of cardiovascular disease. The aim of this study was to determine whether there is an independent association between early menarche (<12 years) and metabolic syndrome (MetS) in Korean women. We analyzed data from 4463 premenopausal women from the Fourth Korea National Health and Nutrition Examination Survey-IV (2007 2009). MetS was defined by the International Diabetes Federation for Asians and insulin resistance (IR) was defined as HOMA-IR more than 3.05. The prevalence of MetS and IR was 7.9 and 15.0%. Women (55.6%) with MetS also showed IR. The prevalence of MetS was higher in both women with early menarche and late menarche (>=16 years) compared with the reference group (early, 12.8%; reference, 7.0%; late, 11.0%, both P = 0.002). However, the odds ratio for MetS was 3.54 (95% confidence interval (CI), 2.14-5.87) and for IR was 2.98 (95% CI, 1.99-4.47) after adjusting for age and other confounders such as lifestyle variables, reproductive variables and sociodemographic variables only in women with early menarche CONCLUSION: Early menarche was associated with an increased risk of MetS and IR in premenopausal Korean women. WHAT IS KNOWN: Early menarche is associated with higher risk of CVD-related death and all-cause mortality in Western studies. Early menarche is associated with higher risk of diabetes in Korean premenopausal women. WHAT IS NEW: Early menarche (<12 years) is associated with metabolic syndrome and insulin resistance in nationally representative Korean premenopausal women. However, late menarche (>16 years) is not associated with metabolic syndrome after controlling for age and other confounders. PMID- 26255048 TI - Evidence of hypothalamic-pituitary-adrenal axis suppression during moderate-to high-dose inhaled corticosteroid use. AB - The possible risk of adverse effects due to regular use of inhaled corticosteroids (ICS) is a real concern. Our aim was to describe the factors that have an impact on hypothalamic-pituitary-adrenal axis suppression (HPA-AS) in children and adolescents taking ICS regularly. The HPA axis status of patients who were on moderate-to-high-dose ICS [>176 and >264 MUg/day fluticasone propionate-hydrofluoroalkane (FP-HFA) for patients 0-11 and >=12 years, respectively] was investigated. Various types of ICS were converted to FP-HFA equivalent according to National Asthma Education and Prevention Program (NAEPP) guidelines. Participants with a baseline (8 a.m.) serum cortisol <15 MUg/dL underwent a low-dose ACTH stimulation test (LDAT) to diagnose HPA-AS. Among 91 patients, 60 (75.9 %) participants underwent LDAT, and seven (7.7, 95 % CI 3.5 15.3 %) were diagnosed with HPA-AS. Ciclesonide was more frequently used by the participants with HPA-AS compared to patients with a normal HPA axis (42.9 vs. 4.8 %, p = 0.009). Use of ICS at moderate-to-high doses for at least 7 months distinguished participants with HPA-AS from those with a normal HPA axis. Among the duration, type, and dose of ICS, solely the use of ICS with a body mass index (BMI)-adjusted daily dose of >=22 MUg FP was found to increase the risk for HPA AS (odds ratio (OR) 7.22, 95 % confidence interval (CI) 1.23-42.26, p = 0.028). The receiver operating characteristics (ROC) curve analysis revealed a cutoff value of 291 MUg/day FP (area under the curve (AUC) = 0.840, p = 0.003) for predicting HPA-AS Conclusion: The prevalence of HPA-AS was found to be 7.7 % in children taking not only high-dose ICS but also moderate-dose ICS. Dose alone was found to be an actual risk factor for HPA-AS. PMID- 26255049 TI - Influence of hydrophilic polymers on the complexation of carbamazepine with hydroxypropyl-beta-cyclodextrin. AB - In this study binary carbamazepine-hydroxypropyl-beta-cyclodextrin, as well as ternary carbamazepine-hydroxypropyl-beta-cyclodextrin-hydrophilic polymer systems were used to improve dissolution rate of carbamazepine. It has been shown that addition of hydrophilic polymers (Soluplus(r) and two types of hydroxypropyl methylcellulose-Metolose(r) 90SH-100 and Metolose(r) 65SH-1500) significantly increased solubilization capacity of hydroxypropyl-beta-cyclodextrin for carbamazepine. Evaluation of carbamazepine-hydroxypropyl-beta-cyclodextrin hydrophilic polymer interactions using molecular modeling techniques showed interactions between carbamazepine, which dissociates from inclusion complexes and hydroxypropyl methylcellulose that can prevent crystallization of dissolved carbamazepine. These results can contribute to better understanding of drug cyclodextrin-hydrophilic polymer interactions which are still not well understood. After evaluation of carbamazepine solubilization with hydroxypropyl beta-cyclodextrin and hydrophilic polymers, both binary carbamazepine hydroxypropyl-beta-cyclodextrin and ternary carbamazepine-hydroxypropyl-beta cyclodextrin-hydrophilic polymer systems were prepared by spray drying. The results of solid state characterization methods showed amorphous nature of carbamazepine in all spray dried systems, which together with the results of molecular modeling techniques indicates inclusion complex formation. Carbamazepine dissolution rate was significantly improved from spray dried formulations compared to pure drug. Binary carbamazepine-hydroxypropyl-beta cyclodextrin and ternary carbamazepine-hydroxypropyl-beta-cyclodextrin Soluplus(r) systems exhibited the fastest carbamazepine release, wherein the entire amount of carbamazepine was released during first 5 min. PMID- 26255050 TI - IL10 Promoter Polymorphisms are Associated with Rheumatic Heart Disease in Saudi Arabian Patients. AB - Rheumatic heart disease (RHD) is an inflammatory disease that develops following streptococcal infections. IL10 helps to balance immune responses to pathogens. IL10 polymorphisms have been associated with RHD, although results remain inconclusive. Our aim was to investigate the association between IL10 polymorphisms and RHD in Saudi Arabian patients. IL10 promoter polymorphisms ( 1082A/G, -829C/T, and -592C/A) were genotyped in 118 RHD patients and 200 matched controls using the TaqMan allelic discrimination assay. There was a significant difference in IL10-1082 genotype frequency between patients and controls (p = 0.01). -1082G allele carriage (GG+GA vs AA) and the (-1082, -819, -592) GCC haplotype carriage were associated with an increased risk of RHD (p = 0.004, OR 2.1, 95% CIs 1.7-3.4 and p = 0.004, OR 2, 95% CIs 1.3-3.4, respectively). The ACC haplotype was associated with a decrease in RHD risk (p = 0.015, OR 0.6, 95% CIs 0.4-0.9). IL10 promoter polymorphisms may play an important role in the development of RHD and provide an opportunity for therapeutic stratification. PMID- 26255051 TI - Military Affective Picture System (MAPS): A new emotion-based stimuli set for assessing emotional processing in military populations. AB - BACKGROUND AND OBJECTIVES: Emotionally relevant pictorial stimuli utilized in studies to characterize both normal and pathological emotional responses do not include military scenarios. Failures to replicate consistent findings for military populations have led to speculation that these image sets do not capture personally relevant experiences. METHODS: The Military Affective Picture System (MAPS) was developed consisting of 240 images depicting scenes common among military populations. A Self-Assessment Manikin was administered to a 1) U.S. Army soldiers and a 2) non-military population. RESULTS: Findings revealed gender differences in valence and dominance dimensions, but not arousal, for both samples. Valence scores were higher for the military. Arousal ratings decrease as a product of combat exposure. Civilian females demonstrated stronger correlations of valence and arousal when viewing positive or negative images. LIMITATIONS: Given the limited power achieved in the current studies' gender comparisons; it would be difficult to draw major conclusions regarding the interaction of combat exposure or military status with gender for each of the categories. Without having included the IAPS ratings for comparison it is difficult to conclude whether effects only pertain to viewing MAPS images, or if there was unintentional selection bias. Additional ratings would provide better assessments for these effects in both males and females. CONCLUSIONS: The MAPS has potential as a screening instrument and clinical evaluation tool for assessing treatment outcomes for individuals with combat-related psychopathology. The MAPS is freely available for research to non-profit groups upon request at http://www.cla.auburn.edu/psychology/military-affective-picture-system/. PMID- 26255052 TI - Patterned changes in urge ratings with tic suppression in youth with chronic tic disorders. AB - BACKGROUND: Premonitory urges are central to emerging behavioral models of chronic tic disorders (CTD). Urge reduction has been proposed as a behavioral explanation for tic maintenance and exacerbation as well as the efficacy of behavioral treatments. Prior investigations have produced inconsistent findings despite common methodologies. The current study evaluated the possibility that data aggregation obscures distinct and meaningful patterns of change in urge ratings when tics are freely expressed versus suppressed. METHOD: Participants (n = 12) included children with moderate-to-marked tic severity and noticeable premonitory urges. Tic frequencies and urge ratings were obtained at 15 s and 10 s intervals, respectively, across an alternating sequence of 10-min tic freely and 40-min tic suppression conditions. Patterns were established using a two step approach. RESULTS: Five distinct patterns of urge rating change emerged, suggesting data aggregation may obscure meaningful patterns in the urge-tic relationship when tics are completed versus suppressed. LIMITATIONS: Eligibility criteria may have unintentionally excluded younger affected children and included older participants with more severe tic disorders than commonly seen. Additional research with less stringent eligibility criteria and a larger sample size will help validate the results. CONCLUSIONS: The relationship between urges and tics is much more complex than previously theorized. Investigations that rely on global assessments of urge and tic severity and/or assume uniformity when aggregating participant data may obscure meaningful differences in the urge-tic relationship. Future investigations should examine the possibility that individual differences and/or developmental considerations modulate the functional urge-tic relationship. PMID- 26255053 TI - Immunity to tomato yellow leaf curl virus in transgenic tomato is associated with accumulation of transgene small RNA. AB - Gene silencing is a natural defense response of plants against invading RNA and DNA viruses. The RNA post-transcriptional silencing system has been commonly utilized to generate transgenic crop plants that are "immune" to plant virus infection. Here, we applied this approach against the devastating DNA virus tomato yellow leaf curl virus (TYLCV) in its host tomato (Solanum lycopersicum L.). To generate broad resistance to a number of different TYLCV viruses, three conserved sequences (the intergenic region [NCR], V1-V2 and C1-C2 genes) from the genome of the severe virus (TYLCV) were synthesized as a single insert and cloned into a hairpin configuration in a binary vector, which was used to transform TYLCV-susceptible tomato plants. Eight of 28 independent transgenic tomato lines exhibited immunity to TYLCV-Is and to TYLCV-Mld, but not to tomato yellow leaf curl Sardinia virus, which shares relatively low sequence homology with the transgene. In addition, a marker-free (nptII-deleted) transgenic tomato line was generated for the first time by Agrobacterium-mediated transformation without antibiotic selection, followed by screening of 1180 regenerated shoots by whitefly-mediated TYLCV inoculation. Resistant lines showed a high level of transgene-siRNA (t-siRNA) accumulation (22% of total small RNA) with dominant sizes of 21 nt (73%) and 22 nt (22%). The t-siRNA displayed hot-spot distribution ("peaks") along the transgene, with different distribution patterns than the viral-siRNA peaks observed in TYLCV-infected tomato. A grafting experiment demonstrated the mobility of 0.04% of the t-siRNA from transgenic rootstock to non-transformed scion, even though scion resistance against TYLCV was not achieved. PMID- 26255054 TI - Tomato chlorotic mottle Guyane virus: a novel tomato-infecting bipartite begomovirus from French Guiana. AB - This is the first description of the complete genome sequence of a new bipartite begomovirus isolated from tomato (Solanum lycopersicum) in French Guiana, for which we propose the tentative name "tomato chlorotic mottle Guyane virus" (ToCMoGFV). DNA-A and -B nucleotide sequences of ToCMoGFV are only distantly related to known New World begomoviruses. They share the highest nucleotide sequence identity of 80% with the Brazilian isolates of macroptilium yellow spot virus (MacYSV) and 73% with soybean chlorotic spot virus (SBCSV). Phylogenetic analysis demonstrated that this novel virus belongs to a new lineage of New World bipartite begomoviruses. The discovery of this new virus confirms the high genetic diversity of begomoviruses in Latin America. PMID- 26255055 TI - Large-scale microstructural simulation of load-adaptive bone remodeling in whole human vertebrae. AB - Identification of individuals at risk of bone fractures remains challenging despite recent advances in bone strength assessment. In particular, the future degradation of the microstructure and load adaptation has been disregarded. Bone remodeling simulations have so far been restricted to small-volume samples. Here, we present a large-scale framework for predicting microstructural adaptation in whole human vertebrae. The load-adaptive bone remodeling simulations include estimations of appropriate bone loading of three load cases as boundary conditions with microfinite element analysis. Homeostatic adaptation of whole human vertebrae over a simulated period of 10 years is achieved with changes in bone volume fraction (BV/TV) of less than 5%. Evaluation on subvolumes shows that simplifying boundary conditions reduces the ability of the system to maintain trabecular structures when keeping remodeling parameters unchanged. By rotating the loading direction, adaptation toward new loading conditions could be induced. This framework shows the possibility of using large-scale bone remodeling simulations toward a more accurate prediction of microstructural changes in whole human bones. PMID- 26255056 TI - Biomechanical analysis of suture locations of the distal plantar fascia in partial foot. AB - PURPOSE: The aim of this study was to evaluate the rationality of the suture locations of distal plantar fascia (DPF) after foot amputation to avoid the risk factors of re-amputation or plantar fasciitis. METHODS: The tensile strain of plantar fascia (PF) in the different regions was measured by uni-axial tensile experiment. A three-dimensional (3D) finite element model was also developed to simulate tensile behaviour of PF in weight bearing conditions. The model includes 12 bones, ligaments, PF, cartilage and soft tissues. Four suture location models for the DPF were considered: the fourth and fifth DPF were sutured on the third metatarsal, the cuboid, and both the third metatarsal and the cuboid, and one un sutured model. RESULTS: The peak tensile strain of the first, second and third PF was 0.134, 0.128 and 0.138 based on the mechanical test, respectively. The fourth and fifth DPF sutured at the cuboid and the third metatarsal could offer more favourable outcomes. The peak strain of 4.859 * 10(-2), 2.347 * 10(-2) and 1.364 * 10(-2) in the first, second and third PF showed the least outcomes in stance phase. Also, peak strain and stress of the residual PF reduced to 4.859 * 10(-2) and 1.834 MPa, respectively. The stress region was redistributed on the mid-shaft of the first and third PF and the peak stress of medial cuneiform bone evidently decreased. CONCLUSIONS: The fourth and fifth DPF suture at the third metatarsal and cuboid was appropriate for the partial foot. The findings are expected to suggest optimal surgical plan of the DPF suture and guide further therapeutic planning of partial foot patients. PMID- 26255057 TI - Nicholas J. Giannestras (1908-1978): a distinguished orthopaedic surgeon, his work, life and times. AB - The purpose of our study was to summarize all the knowledge concerning the innovative pioneer in the field of orthopaedic surgery, Nicholas J. Giannestras (1908-1978). A thorough study of texts, medical books and reports, in the field of history of medicine, together with a review of the available literature in PubMed, was undertaken. Giannestras left his mark in the history of orthopaedics with his clinical work and his publications, mainly his treatise "Foot Disorders: Medical and Surgical Management" (1973), while his name lingers in Greece with the introduction of spine fusion with the use of metallic implants. He was an eminent university clinical professor of orthopaedics who had harmonically combined academic writing, teaching and clinical research in every field of orthopaedic surgery. PMID- 26255058 TI - Experimental study of the installation acetabular component with uncoverage in arthroplasty patients with severe developmental hip dysplasia. AB - PURPOSE: The purpose of this study was stimation of optimal percentage of lateral uncoverage of the acetabular component during total hip arthroplasty for patients with severe developmental hip dysplasia. METHODS: Mathematical computer modeling based on the finite element technique and the mechanical experiment were performed. Critical values of uncoverage enabling safe primary fixation of acetabular component were estimated in designed models. RESULTS: Using the finite element technique and the mechanical experiment on pelvis models, a possibility of mounting an acetabular component with moderate uncoverage within 25% without screws and with significant uncoverage to 35% with an additional two-screw fixation was demonstrated. CONCLUSIONS: This study provides additional guidance on optimal acetabular uncoverage assessment and fixation methods of surgeons performing THA on patients with DDH. PMID- 26255059 TI - Selection and evolution in the genomic landscape of copy number alterations in ductal carcinoma in situ (DCIS) and its progression to invasive carcinoma of ductal/no special type: a meta-analysis. AB - Ductal carcinoma in situ (DCIS) is a pre-invasive malignancy detected with an increasing frequency through screening mammography. One of the primary aims of therapy is to prevent local recurrence, as in situ or as invasive carcinoma, the latter arising in half of the recurrent cases. Reliable biomarkers predictive of its association with recurrence, particularly as invasive disease, are however lacking. In this study, we perform a meta-analysis of 26 studies which report somatic copy number aberrations (SCNAs) in 288 cases of 'pure' DCIS and 328 of DCIS associated with invasive carcinoma, along with additional unmatched cases of 145 invasive carcinoma of ductal/no special type (IDC) and 50 of atypical ductal hyperplasia (ADH). SCNA frequencies across the genome were calculated at cytoband resolution (UCSC genome build 19) to maximally utilize the available information in published literature. Fisher's exact test was used to identify significant differences in the gain-loss distribution in each cytoband in different group comparisons. We found synchronous DCIS to be at a more advanced stage of genetic aberrations than pure DCIS and was very similar to IDC. Differences in gains and losses in each disease process (i.e. invasive or in situ) at each cytoband were used to infer evidence of selection and conservation for each cytoband and to define an evolutionary conservation scale (ECS) as a tool to identify and distinguish driver SCNA from the passenger SCNA. Using ECS, we have identified aberrations that show evidence of selection from the early stages of neoplasia (i.e. in ADH and pure DCIS) and persist in IDC; we postulate these to be driver aberrations and that their presence may predict progression to invasive disease. PMID- 26255061 TI - The Calculations and Simulation Testing on the Elastic Modulus of Wheat. AB - The elastic modulus (E) of wheat is not only an important parameter in mechanical property of wheat grain, but also is one of the most important parameter for the materials in the analysis three-dimensional modeling of wheat. In this study, the relationship between load-deformation properties of the three different moisture contents wheat grains determined by TA-XT2i texturometer and pressures in simulated analyzed using a three-dimensional model of wheat was investigated. The elastic modulus was calculated by the results of the load deformation under the pressure, and verified and amended using the three-dimensional model. The results showed that the elastic modulus range for wheat was from 37 to 75 MPa, while the moisture content of wheat rose from 10 to 20 %. The difference in compressive deformation between the reality and the model was <5 %. PMID- 26255060 TI - Air Current Applied to the Face Improves Exercise Performance in Patients with COPD. AB - PURPOSE: Improving dyspnea and exercise performance are goals of COPD therapy. We tested the hypothesis that air current applied to the face would lessen dyspnea and improve exercise performance in moderate-severe COPD patients. METHODS: We recruited 10 COPD patients (5 men, age 62 +/- 6 years, FEV1 0.93 +/- 0.11 L (34 +/- 3% predicted), TLC 107 +/- 6%, RV 172 +/- 18%) naive to the study hypothesis. Each patient was randomized in a crossover fashion to lower extremity ergometry at constant submaximal workload with a 12-diameter fan directed at the patients face or exposed leg. Each patients' studies were separated by at least 1 week. Inspiratory capacity and Borg dyspnea score were measured every 2 min and at maximal exercise. RESULTS: Total exercise time was longer when the fan was directed to the face (14.3 +/- 12 vs. 9.4 +/- 7.6 min, face vs. leg, respectively, p = 0.03). Inspiratory capacity tended to be greater with the fan directed to the face (1.4 (0.6-3.25) vs. 1.26 (0.56-2.89) L, p = 0.06). There was a reduction in dynamic hyperinflation, as reflected by higher IRV area in the fan on face group (553 +/- 562 a.u. vs. 328 +/- 319 a.u., p = 0.047). There was a significant improvement in the Borg dyspnea score at maximal exercise (5.0 (0-10) vs. 6.5 (0-10), p = 0.03), despite exercising for 34 % longer with the fan directed to the face. CONCLUSIONS: Air current applied to the face improves exercise performance in COPD. Possible mechanisms include an alteration in breathing pattern that diminishes development of dynamic hyperinflation or to a change in perception of breathlessness. PMID- 26255062 TI - Role of decreased immunosupression regimen in a heart transplant recipient with more than 500 squamous cell cancers. PMID- 26255063 TI - 5alpha-Dihydrotestosterone regulates the expression of L-type calcium channels and calcium-binding protein regucalcin in human breast cancer cells with suppression of cell growth. AB - Androgens have been associated with the development of normal breast, and their role in mammary gland carcinogenesis has also been described. Several studies reported that androgens inhibit breast cancer cell growth, whereas others linked their action with the modulation of calcium (Ca(2+)) pumps, Ca(2+) channels and Ca(2+)-binding proteins. Also, it is known that deregulated Ca(2+) homeostasis has been implicated in the pathophysiology of breast. The L-type Ca(2+) channels (LTCCs) were found to be up-regulated in colon, colorectal and prostate cancer, but their presence in breast tissues remains uncharacterized. On the other hand, regucalcin (RGN) is a Ca(2+)-binding protein involved in the control of mammary gland cell proliferation, which has been identified as an androgen target gene in distinct tissues except breast. This study aimed to confirm the expression and activity of LTCCs in human breast cancer cells and investigate the effect of androgens in regulating the expression of alpha1C subunit (Cav1.2) of LTCCs and Ca(2+)-binding protein RGN. PCR, Western blot, immunofluorescence and electrophysiological experiments demonstrated the expression and activity of Cav1.2 subunit in MCF-7 cells. The MCF-7 cells were treated with 1, 10 or 100 nM of 5alpha-dihydrotestosterone (DHT) for 24-72 h. The obtained results showed that 1 nM DHT up-regulated the expression of Cav1.2 subunit while diminishing RGN protein levels, which was underpinned by reduced cell viability. These findings first confirmed the presence of LTCCs in breast cancer cells and opened new perspectives for the development of therapeutic approaches targeting Ca(2+) signaling. PMID- 26255064 TI - Etanercept administration prevents the inflammatory response induced by carrageenan in the murine air pouch model. AB - Rheumatoid arthritis (RA) is one of several inflammatory and autoimmune diseases that affect approximately 1% of world's population. The development of TNF inhibitors in the last decade represents a great advance in the treatment of mild and severe forms of RA. Etanercept is one of these drugs that is useful for RA treatment, but the mechanism of inhibition of the signaling pathway of inflammation was not completely elucidated. This study was conducted to evaluate the anti-inflammatory effect of etanercept in comparison to reference drugs (dexamethasone and indomethacin). Inflammation was induced by subcutaneal administration of carrageenan in the Swiss albino mice using the murine air pouch model. Exudation; leukocytes; myeloperoxidase (MPO); adenosine deaminase (ADA); nitric oxide metabolites (NOx); tumor necrosis factor (TNF); interferon gamma (IFN-gamma); interleukins (IL) IL-6, IL-17, IL-10, IL-4, and IL-2; nuclear transcription factor kappa B (NF-kappaB) activation and apoptosis were evaluated 24 h after the induction of inflammation. Treatment with etanercept significantly inhibited exudate concentrations; leukocyte count; MPO and ADA activities; NOx, TNF, IFN-gamma, and IL-17 levels; and NF-kappa B activation (p < 0.05). Etanercept induced apoptosis, reducing the number of viable neutrophils without increasing necrosis (p < 0.05). Our results suggest that the anti-inflammatory mechanism of action of etanercept may be via decrease of NF-kappaB activation. This effect promoted the reduction of pro-inflammatory cytokines and NOx and the induction of neutrophil apoptosis. The effect of etanercept upon neutrophils apoptosis may indicate the use of this drug therapy in the early stage of rheumatoid arthritis disease. PMID- 26255065 TI - Multidisciplinary team interventions to optimise health outcomes for older people in acute care settings: A systematic review. AB - BACKGROUND: A major challenge facing our health care systems internationally is managing the needs of increasing numbers of older people in hospital with chronic and complex conditions. A multidisciplinary approach is considered central to tailoring and targeting approaches to gerontological care, although this is often not realised in reality. Comprehensive geriatric assessment (CGA) is seen as gold standard, though they are not readily available in many acute settings, compounded by the requirement for time, coordination of multidisciplinary specialties, and reimbursement issues. This systematic review aimed to identify multidisciplinary team interventions to optimise health outcomes for older people in acute care settings. METHOD: Systematic review of randomised controlled trials reporting acute care multidisciplinary team based interventions, to improve care outcomes for hospitalised older people. Electronic databases (MEDLINE, CINAHL (EBSCO), Cochrane and PsycINFO) were searched from 1 January 2000 to 1 July 2014 in the English language. Data was extracted by two reviewers and checked by a third reviewer to resolve any conflicts. RESULTS: Seven articles reporting RCTs met the systematic review inclusion criteria. The heterogeneity of study populations, multidisciplinary team interventions and outcome measures necessitated the use of narrative analysis. Three common elements of these studies included: (i) tailored treatment by clinicians with geriatric expertise (ii) a focus on transitional care interventions that enhance discharge planning; and (iii) communication an essential ingredient to improving care. CONCLUSION: The tailoring of treatment, underpinned with clear communication strategies can reduce emergency department re-admission rates, mortality and functional decline of older people. Refining health professionals roles and responsibilities within transition models is an essential component that can improve health outcomes for older people in acute care settings. PMID- 26255066 TI - Update on Multicystic Dysplastic Kidney. AB - Multicystic dysplastic kidney (MCDK) is the most common cause of cystic disease in children. It is characterized by multiple non-communicating cysts of varying sizes with no identifiable normal renal parenchyma. The incidence ranges from 1 in 1000 to 4300 live births, and it is one of the most commonly detected anomalies on prenatal ultrasound. MCDK has been shown to follow a benign course with relatively few sequelae and therefore should be managed conservatively. Currently, the key clinical questions revolve around the detection of anomalies in the contralateral kidney and follow-up imaging. The recent literature suggests that very limited radiographic evaluation of the MCDK is needed. The use of voiding cystourethrogram or nuclear medicine renal scans should be directed by any abnormalities on renal ultrasound or the development of urinary tract infections. PMID- 26255067 TI - Laparoscopic Single-Site Surgery in Pediatric Urology: Where Do We Stand Today? AB - Since the first description of the laparoendoscopic single-site surgery (LESS) in the pediatric urology population, various authors have shared their experiences and results. We aim to provide a review of current studies of LESS and share our experience with this modality. The current literature describes the use of LESS for most surgeries performed in the pediatric urology population with similar results to open and standard laparoscopic surgery. The authors have described their experiences with transabdominal and retroperitoneal nephrectomy, nephroureterectomy, pyeloplasty, orchidopexy, varicocelectomy, and renal cyst decortication. In our experience, LESS has taken a role for extirpative surgery since we use other modalities for upper tract reconstruction. The data available has validated LESS as safe and has demonstrated similar results to standard laparoscopic surgery and open surgery with better cosmetic results. PMID- 26255068 TI - Surgery for Primary Proximal Hypospadias with Ventral Curvature >30 degrees . AB - This review discusses means for straightening ventral curvature >30 degrees , and then subsequent urethroplasty using either one-stage flaps or two-stage flaps or grafts. The wide variation in reported results from these various techniques makes determination of best management difficult; however, it is clear that complications for repairs done in major centers can range to >=50%. Given the rarity of proximal hypospadias with ventral curvature >30 degrees , which occurs in approximately 400 newborns annually in the USA, centers should refer these cases to subspecialists within the group who can then develop and maintain expertise. PMID- 26255069 TI - Simplified PESI score and sex difference in prognosis of acute pulmonary embolism: a brief report from a real life study. AB - Prognostic stratification of acute pulmonary embolism (PE) remains a challenge in clinical practice. Simplified PESI (sPESI) score is a practical validated score aimed to stratify 30-day mortality risk in acute PE. Whether prognostic value of sPESI score differs according to sex has not been previously investigated. Therefore the aim of our study was to provide information about it. Data records of 452 patients, 180 males (39.8 %) and 272 females (60.2 %) discharged for acute PE from Internal Medicine wards of Tuscany (Italy) were analysed. sPESI was retrospectively calculated. Variables enclosed in sPESI score, all cause in hospital mortality and overall bleedings were compared between sexes. Moreover, predictive ability of sPESI score as prognosticator of all cause in-hospital mortality was tested and compared between sexes. sPESI score 0 (low risk) was found in 17.7 % of males and 13.6 % of females (p = 0.2323). We didn't find significant difference in sPESI scoring distribution. Age >=80 years (51.4 vs. 33.8 %, p = 0.0003) and heart rate >=110 bpm (23.5 vs. 14.4 %, p = 0.0219) were found significantly more prevalent in females, whereas active cancer (23.8 vs. 39.4 %, p = 0.0004) and cardio-respiratory diseases (19.8 vs. 27.7 %, p = 0.0416) were in males. All cause in-hospital mortality was 0 % in both genders for sPESI score 0, whereas it was 5.4 % in females and 13.6 % in males with sPESI score 1-2 (p = 0.0208) and 22 % in females and 19.3 % in males with sPESI score >=3 (p = 0.7776). Overall bleedings were significantly more frequent in females compared with males (4.77 vs. 0.55 %, p = 0.0189). In females overall bleedings ranged from 2.7 % in sPESI score 0 to 6 % in sPESI score >=3. Predictive ability of sPESI score as prognosticator of all cause in-hospital mortality was higher in females compared to males (AUC 0.72 vs. 0.67, respectively). In real life different co-morbidity burdens in females compared to males. Females seems to be at lower risk of all cause in-hospital mortality for sPESI score <=2 but at higher risk of bleeding, irrespective from sPESI scoring. Predictive ability of sPESI score seems better in females. PMID- 26255070 TI - A multi-resolution textural approach to diagnostic neuropathology reporting. AB - We present a computer aided diagnostic workflow focusing on two diagnostic branch points in neuropathology (intraoperative consultation and p53 status in tumor biopsy specimens) by means of texture analysis via discrete wavelet frames decomposition. For intraoperative consultation, our methodology is capable of classifying glioblastoma versus metastatic cancer by extracting textural features from the non-nuclei region of cytologic preparations based on the imaging characteristics of glial processes, which appear as anisotropic thin linear structures. For metastasis, these are homogeneous in appearance, thus suitable and extractable texture features distinguish the two tissue types. Experiments on 53 images (29 glioblastomas and 24 metastases) resulted in average accuracy as high as 89.7 % for glioblastoma, 87.5 % for metastasis and 88.7 % overall. For p53 interpretation, we detect and classify p53 status by classifying staining intensity into strong, moderate, weak and negative sub-classes. We achieved this by developing a novel adaptive thresholding for detection, a two-step rule based on weighted color and intensity for the classification of positively and negatively stained nuclei, followed by texture classification to classify the positively stained nuclei into the strong, moderate and weak intensity sub classes. Our detection method is able to correctly locate and distinguish the four types of cells, at 85 % average precision and 88 % average sensitivity rate. These classification methods on the other hand recorded 81 % accuracy in classifying the positive and negative cells, and 60 % accuracy in further classifying the positive cells into the three intensity groups, which is comparable with neuropathologists' markings. PMID- 26255072 TI - Torsional Fracture of the Humerus after Subpectoral Biceps Tenodesis with an Interference Screw: A Biomechanical Cadaveric Study. AB - BACKGROUND: Humeral fracture following subpectoral biceps tenodesis has been previously reported; however, there are no published biomechanical studies reporting the resulting torsional strength of the humerus. Our purpose was to determine if there is an increased risk of humerus fracture after subpectoral biceps tenodesis with an interference screw and to determine if screw size is also a factor. We hypothesized that limbs receiving the procedure would have reduced failure torque and rotation under external rotation compared to untreated controls and that the larger screw size would result in inferior mechanical properties compared to the smaller. METHODS: Twenty matched pairs of embalmed cadaveric humeri were subjected to subpectoral biceps tenodesis using either a 6.25 or 8.0mm interference screw, with the untreated contralateral limb serving as a control. Each humerus was mechanically tested in torsional external rotation to failure. FINDINGS: Maximum torque and rotation to failure were reduced in the tenodesis group compared to controls; however, there was no difference between screw sizes. When both screw sizes were combined into a single group, paired t tests also showed similar differences. INTERPRETATION: Based on our experiment, there is an increased risk for humerus spiral fracture when subjected to torsional external rotation after subpectoral biceps tenodesis with an interference screw compared to an intact humerus; however, there is not a significant difference between a 6.25mm and 8.0mm screw. Surgeons may elect to use alternative fixation methods in patients at high risk (e.g., overhead throwing athletes, etc.) for torsional loads and fracture. PMID- 26255071 TI - Methotrexate administration directly into the fourth ventricle in children with malignant fourth ventricular brain tumors: a pilot clinical trial. AB - We hypothesize that chemotherapy can be safely administered directly into the fourth ventricle to treat recurrent malignant brain tumors in children. For the first time in humans, methotrexate was infused into the fourth ventricle in children with recurrent, malignant brain tumors. A catheter was surgically placed into the fourth ventricle and attached to a ventricular access device. Cerebrospinal fluid (CSF) flow was confirmed by CINE MRI postoperatively. Each cycle consisted of 4 consecutive daily methotrexate infusions (2 milligrams). Disease response was monitored with serial MRI scans and CSF cytologic analysis. Trough CSF methotrexate levels were sampled. Five patients (3 with medulloblastoma and 2 with ependymoma) received 18, 18, 12, 9, and 3 cycles, respectively. There were no serious adverse events or new neurological deficits attributed to methotrexate. Two additional enrolled patients were withdrawn prior to planned infusions due to rapid disease progression. Median serum methotrexate level 4 h after infusion was 0.04 umol/L. Range was 0.02-0.13 umol/L. Median trough CSF methotrexate level 24 h after infusion was 3.18 umol/L (range 0.53 212.36 umol/L). All three patients with medulloblastoma had partial response or stable disease until one patient had progressive disease after cycle 18. Both patients with ependymoma had progressive disease after 9 and 3 cycles, respectively. Low-dose methotrexate can be infused into the fourth ventricle without causing neurological toxicity. Some patients with recurrent medulloblastoma experience a beneficial anti-tumor effect both within the fourth ventricle and at distant sites. PMID- 26255074 TI - Sarcoidosis. Debut as orbital pseudotumour. AB - CASE REPORT: 78 year-old female patient being investigated for a left orbital pseudotumour of 17 days onset. She had proptosis, pain, with no limitation of eye movements, periorbital oedema, and upper eyelid ptosis, compatible with an orbital pseudotumour. The MRI showed an upper outer left orbital mass adjacent to the side of eyeball and an increase in soft tissue at the level of lacrimal gland. The histopathology study of an eyelid lesion demonstrated the presence of non-caseating granulomas. DISCUSSION: A definitive diagnosis of orbital sarcoidosis was made. Oral treatment with corticosteroids and methotrexate achieved gradual control of the disease. PMID- 26255073 TI - Muscle pathology and whole-body MRI in a polyglucosan myopathy associated with a novel glycogenin-1 mutation. AB - We report a 46-year-old female with late-onset skeletal myopathy affecting proximal limb muscles. Muscle biopsy revealed a polyglucosan myopathy with PAS positive inclusions predominantly in glycogen-depleted fibers, which were demonstrated as type I fibers by ATPase staining. Whole-body magnetic imaging disclosed that the paravertebral, scapular, and pelvic girdle muscles, the anterior compartment of the arms, and the posterior compartment of the thighs were preferentially involved. Genetic analysis revealed a homozygous novel mutation in exon 6 of the glycogenin-1 gene (GYG1) (c.634C>T, p.His212Tyr). Protein analysis revealed normal levels of glycogenin-1 even before alpha-amylase digestion indicating preserved protein expression but impaired glucosylation. In vitro functional assay demonstrated that this variant impaired the autoglucosylating ability resulting in a non-functional protein. We report a glycogenin-1 related myopathy with a distinct histopathology and unique muscle imaging pattern. PMID- 26255075 TI - Partition, orientation and mobility of ubiquinones in a lipid bilayer. AB - Ubiquinone is the universal mobile charge carrier involved in biological electron transfer processes. Its redox properties and biological function depend on the molecular partition and lateral diffusion over biological membranes. However, ubiquinone localization and dynamics within lipid bilayers are long debated and still uncertain. Here we present molecular dynamics simulations of several ubiquinone homologs with variable isoprenoid tail lengths complexed to phosphatidylcholine bilayers. Initially, a new force-field parametrization for ubiquinone is derived from and compared to high level quantum chemical data. Free energy profiles for ubiquinone insertion in the lipid bilayer are obtained with the new force-field. The profiles allow for the determination of the equilibrium location of ubiquinone in the membrane as well as for the validation of the simulation model by direct comparison with experimental partition coefficients. A detailed analysis of structural properties and interactions shows that the ubiquinone polar head group is localized at the water-bilayer interface at the same depth of the lipid glycerol groups and oriented normal to the membrane plane. Both the localization and orientation of ubiquinone head groups do not change significantly when increasing the number of isoprenoid units. The isoprenoid tail is extended and packed with the lipid acyl chains. For ubiquinones with long tails, the terminal isoprenoid units have high flexibility. Calculated ubiquinone diffusion coefficients are similar to that found for the phosphatidylcholine lipid. These results may have further implications for the mechanisms of ubiquinone transport and binding to respiratory and photosynthetic protein complexes. PMID- 26255076 TI - Retroperitoneal and transperitoneal laparoscopic cryotherapy for small renal masses. AB - OBJECTIVE: Cryotherapy is a minimally invasive ablative technique that is considered an alternative to conventional surgery for preserving renal function in small renal tumors and in selected cases. We present our results from laparoscopic renal cryotherapy. MATERIAL AND METHOD: We retrospectively analyzed 17 renal tumors diagnosed in 16 patients treated with cryotherapy. The patients' mean age was 66 years (43-80). The mean tumor size was 1.8cm (0.7-3.7cm). Cryotherapy with double-freeze cycle was performed laparoscopically in all cases (10 by transperitoneal approach and 7 by retroperitoneal approach). RESULTS: Perioperative biopsies were performed on all patients and were positive for malignancy in 10 cases (59%). The mean stay was 2.8 days. The mean operative time was 162 minutes. Only 1 case reverted to open surgery due to bleeding. One patient required a blood transfusion in the immediate postoperative period. The majority of complications were Clavien-Dindo grades I and II. Some 76.5% of the patients had no complications. After a mean follow-up of 31 months (6-102), 1 patient died from nontumor-related causes, and 12 patients (75%) still show no evidence of local recurrence or progression. One patient had tumor persistence and therefore underwent partial nephrectomy at 6 months. One patient had a metachronous recurrence in the same kidney at 36 months, and another patient had a recurrence at 23 months. CONCLUSIONS: Laparoscopic renal cryotherapy is a safe and feasible technique and is a good alternative to surgery for selected renal tumors. PMID- 26255077 TI - Reduced activation and CD3 lymphocyte recruitment after TNF-inhibitor use: evaluation of clinical and 99mTc-OKT3 scintigraphic response in a patient with juvenile idiopathic arthritis. PMID- 26255078 TI - The global distribution of the p.R1193Q polymorphism in the SCN5A gene. AB - The SCN5A (sodium channel, voltage-gated, type V, alpha subunit) gene encodes the cardiac sodium channel, a member of the voltage-gated sodium channel family. The p.R1193Q (c.3578G>A) polymorphism in SCN5A is known to accelerate inactivation of the sodium channel current, and has been identified in patients with Brugada and long QT syndromes. In the present study, we investigated the frequency of the p.R1193Q substitution in more than 4000 genomic DNA samples from 34 Asian, European, and African populations using TaqMan and/or APLP (amplified product length polymorphism) assays. Allele A (p.1193Q) was detected in most Asian populations, but was sporadically observed or absent in European and African populations. These results demonstrated that the p.R1193Q substitution is characteristic of Asian populations. PMID- 26255079 TI - Roles and responsibilities of nurse preceptors: Perception of preceptors and preceptees. AB - In this study setting, preceptors, who were clinical teaching assistants and hospital employed nurses assist through an interactive process preceptees, who were nursing students, in developing clinical skills and integration into the culture of the clinical area. Therefore, roles and responsibilities of preceptors should be clear and meet the expectations of preceptors and preceptees. This study aimed at comparing similarities and differences of perception to roles and responsibilities as held by nurse preceptors and their preceptees in relation to how important such roles and responsibilities are, and how frequently preceptors attend to the role. A self-administered questionnaire using Boyer's (2008) roles and responsibilities was completed by a convenience sample of 87 preceptee and 62 preceptors amounting to 66.9% and 77.5% response rate respectively. The questionnaire included 43 items and two 4-points Likert-type scales: "Importance of", and "frequency of attendance to roles". Two versions were developed: one for preceptors and the other for preceptees. The reliability (Alpha values) was .944 for the importance and .973 for the frequency of attendance scales. Mean scores indicated agreement among the two groups in relation to importance of, but to disagreement in relation to frequency of attendance to certain roles and responsibilities. Both groups perceived roles and responsibilities as important but varied with significant difference in rating preceptors' frequency of attendance to their roles as educators and facilitators. PMID- 26255080 TI - Interprofessional education: Partnerships in the educational proc. AB - The curriculum for healthcare professionals is primarily dictated by the demands of the specific discipline. Detailed curricula are essential to develop professional healthcare providers such as nurses, physicians and pharmacists. Traditional educational methods created a system or process where professionals operate in isolation from each other. A siloed structure inhibits effective communication, patient-centered care and safety. Today the focus in healthcare has shifted towards a more patient-centeredness approach using interprofessional collaboration to achieve optimal patient outcomes. Nurses are at the forefront of patient care and play a key role in quality patient care and improved patient outcomes. Interprofessional education is one type of academic strategy that nursing educators can incorporate into educational curricula. PMID- 26255081 TI - Genetic, epigenetic and protein analyses of intercellular adhesion molecule 1 in Malaysian subjects with type 2 diabetes and diabetic nephropathy. AB - AIMS: Recent research has implicated that the inflammation may be a key pathophysiological mechanism in diabetic nephropathy (DN). Intercellular adhesion molecule 1 (ICAM-1) is an acute phase marker of inflammation. In the present study, we carried out genetic, epigenetic and protein analyses of ICAM-1 in a Malaysian population, including normal glucose tolerance (NGT) subjects and type 2 diabetes (T2D) patients with or without DN in order to evaluate its role in DN. METHODS: Analyses of DNA polymorphism and methylation in the ICAM1 gene were performed with TaqMan allelic discrimination and pyrosequencing, respectively. Plasma ICAM-1 levels were determined using an enzyme-linked immune-sorbent assay kit. RESULTS: We found that the ICAM1 K469E(A/G) polymorphism (rs5498) was significantly associated with DN. Particularly, 86.1% of T2D patients with DN carried heterozygous genotype compared to the patients without DN (68.6%). Furthermore, plasma ICAM-1 levels were increased from NGT subjects to T2D patients without and with DN (P<0.001). The NGT subjects carrying heterozygous genotype had significantly lower plasma ICAM-1 levels compared to the K469(A/A) genotype carriers (P=0.009). In the ICAM1 gene promoter, DNA methylation levels of CpG sites were low, and no association of the ICAM1 DNA methylation alteration with DN was detected. CONCLUSION: The present study provided evidence that the ICAM1 K469E(A/G) polymorphism with high heterozygous index and elevation of plasma ICAM-1 levels were associated with DN in a Malaysian population. Further prospective study of ICAM-1 protein according to the ICAM1 K469E(A/G) genotypes is necessary for predicting the susceptibility to T2D and DN. PMID- 26255082 TI - Emotion processing in treatment-resistant schizophrenia patients treated with clozapine: An fMRI study. AB - OBJECTIVES: To examine the neural correlates of emotion processing in treatment resistant patients with schizophrenia (SCZ-TR). METHODS: Twenty-two SCZ-TR patients on clozapine, 24 schizophrenia patients on antipsychotics other than clozapine, and 39 healthy controls were scanned using functional neuroimaging while viewing positive, negative and neutral images. RESULTS: Emotionally-laden images (positive and negative) elicited hyper-activations in the dorso-medial prefrontal cortex and left cerebellum in SCZ-TR patients, compared to the two other groups. Similarly, neutral images prompted hyper-activations in the cingulate gyrus in SCZ-TR patients, relative to the two other groups. CONCLUSIONS: Treatment resistance is associated with neuro-functional hyper activations in schizophrenia patients during emotion processing. PMID- 26255083 TI - The GABA system in schizophrenia: cells, molecules and microcircuitry. AB - This is an overview of several papers that have been published in the Special Issue of Schizophrenia Research entitled The GABA System in Schizophrenia: Cells, Molecules and Microcircuitry. This issue presents a broad range of original reports and scholarly reviews regarding recent progress in studies of neural circuitry in corticolimbic brain regions in patients with schizophrenia. PMID- 26255084 TI - Correlation between delay in initiating clozapine and symptomatic improvement. PMID- 26255085 TI - Demonstrating Subpopulation Analytics: A Paradigm Shift for Improving Population Health. PMID- 26255086 TI - NHS ethics: Shoe-bombers and why 'less needs to be more'. PMID- 26255087 TI - Randomized, controlled pilot trial of natural versus hormone replacement therapy cycles in frozen embryo replacement in vitro fertilization. AB - OBJECTIVE: To determine whether there is any difference between the outcomes of two standard treatment protocols for frozen embryo replacement (FER): natural and down-regulated hormone replacement treatment (HRT). DESIGN: Open, single-center, randomized, controlled pilot trial. SETTING: Private fertility clinic. PATIENT(S): Women (n = 159) planning an FER cycle at the Oxford Fertility Unit, aged <40 years at the time their embryos were frozen; with at least one blastocyst or two cleavage-stage embryos in storage; regular ovulatory cycles; and at most two previous FER cycles. INTERVENTION(S): Eligible participants were recruited and randomized between March 2010 and July 2012 into one of two standard FER treatment groups: natural (n = 80) menstrual (Natural) or GnRH agonist/HRT (n = 79) cycles. MAIN OUTCOME MEASURE(S): Live birth rate after replacement of frozen-thawed embryos, clinical pregnancy rate, implantation rate, and cycle cancellations. RESULT(S): A total of 159 women were randomized (80 Natural; 79 HRT), and 145 had ET and completed the study (72 Natural; 73 HRT). Pregnancy outcomes were not significantly different between the two groups. The live birth rates were 26.3% (Natural) and 31.7% (HRT) per randomized patient. Per ET/protocol the live birth rates were 29.2% and 34.2%. The implantation rates were 24.3% and 26.0%, and there were three twin births in the Natural and five in the HRT arms. CONCLUSION(S): The findings of this pilot study support the suggestion that for women with ovulatory cycles undergoing FER, the outcomes are similar between natural and HRT protocols. CLINICAL TRIAL REGISTRATION NUMBER: NCT00843570. Registered at www.clinicaltrials.gov. PMID- 26255088 TI - Freeze-all at the blastocyst or bipronuclear stage: a randomized clinical trial. AB - OBJECTIVE: To compare outcomes for patients randomized to have all embryos cryopreserved at the blastocyst stage or at the bipronuclear stage with subsequent post-thaw culture to the blastocyst stage. DESIGN: Randomized controlled trial. SETTING: Private fertility center. PATIENT(S): This study included 140 women, age 18-40 years, with at least eight antral follicles, and day 3 FSH <10 IU/L undergoing IVF. INTERVENTION(S): After oocyte retrieval, subjects were randomized to have entire embryo cohorts cryopreserved at either the bipronuclear stage (2PN Cryo group) or at the blastocyst stage (Blast Cryo group). MAIN OUTCOME MEASURE(S): Ongoing pregnancy (viable fetal heart motion at 10 weeks' gestation) per oocyte retrieval through the first transfer attempt. RESULT(S): No significant differences were observed between the two study groups in age at retrieval, body mass index, antral follicle count, day 3 FSH level, or IVF cycle parameters. No significant differences were observed in ongoing pregnancy rate per retrieval (62.0%; 95% confidence interval [CI], 50.3%-72.4%) in the 2PN Cryo group; and 55.1%; 95% CI, 42.6%-67.1% in the Blast Cryo group), implantation rate (60.0% vs. 62.7%), ongoing pregnancy rate per thaw (62.0% vs. 59.4%), ongoing pregnancy rate per transfer (67.7% vs. 69.1%), and the cumulative ongoing pregnancy rate per retrieval from all thaws to date of embryos derived from the study retrieval cycle (64.8% vs. 60.9%). CONCLUSION(S): Freeze-all at the blastocyst stage or at the bipronuclear stage has similar efficacy and IVF outcomes. The choice between them may depend primarily on logistical factors. CLINICAL TRIAL REGISTRATION NUMBER: NCT01247987. PMID- 26255089 TI - A novel antibody targeting CD24 and hepatocellular carcinoma in vivo by near infrared fluorescence imaging. AB - Liver cancer is one of the most common malignant cancers worldwide. The poor response of liver cancer to chemotherapy has whipped up the interest in targeted therapy with monoclonal antibodies because of its potential efficiency. One promising target is cluster of differentiation 24 (CD24), which is known to beover-expressed on hepatocellular carcinoma (HCC), providing prospect for HCC targeted diagnosis and therapy. In this study we developed a novel CD24 targeted monoclonal antibody G7mAb based on hybridoma technology and then generated a single-chain antibodyfragment (scFv) G7S. Firstly, ELISA, western blot, and flow cytometry assays demonstrated specific binding of CD24 by G7mAb and G7S. Further, G7mAb was demonstrated to have similar binding capacity as ML5 (a commercial Anti CD24 Mouse Antibody) inimmunohistochemical assay. Further more, a near-infrared fluorescent dye multiplex probe amplification (MPA) was conjugated to G7mAb and G7S to form G7mAb-MPA and G7S-MPA. The near-infrared fluorescence imaging revealed that G7mAb and G7S aggregate in CD24+Huh7 hepatocellular carcinoma xenograft tissuevia specific binding to CD24 in vivo. In conclussion, G7mAb and G7S were tumor targeted therapeutic and diagnostic potentials in vitro and in vivo as anticipated. PMID- 26255090 TI - The role of nucleotide-binding oligomerization domain 1 during cytokine production by macrophages in response to Mycobacterium tuberculosis infection. AB - Tuberculosis due to Mycobacterium tuberculosis infection is a leading cause of death worldwide. Recognition of this pathogen is crucial for the activation of innate and adaptive immune responses. Nucleotide-binding oligomerization domain (Nod)1 and Nod2 are cytoplasmic receptors that can detect unique muropeptides of bacterial peptidoglycan. Nod2 is critical for the initiation of the host immune response against M. tuberculosis infection, however the role of Nod1 remains largely unknown. We investigated the role of Nod1 with respect to cytokine production by bone marrow-derived macrophages (BMDMs) in response to M. tuberculosis infection. Production of proinflammatory cytokines, such as IL-6, TNF-alpha, and IL-1beta were induced in BMDMs; cytokine levels were not affected by a deficiency in Nod1. Activation of NF-kappaB and MAPKs was also comparable between wild-type and Nod1-deficient BMDMs. Levels of IL-6 and IL-1beta were reduced in Nod1/Nod2 double-deficient BMDMs to a greater extent than in Nod2 deficient cells. Furthermore, when signaling of Toll-like receptors (TLRs) was inhibited by lipopolysaccharide pre-treatment, cytokine production was diminished in Nod1-deficient BMDMs. Our results indicate that Nod1 cooperates with Nod2 or TLRs to produce cytokines in macrophages in response to M. tuberculosis infection. PMID- 26255091 TI - Network analysis of S. aureus response to ramoplanin reveals modules for virulence factors and resistance mechanisms and characteristic novel genes. AB - Staphylococcus aureus is a major human pathogen and ramoplanin is an antimicrobial attributed for effective treatment. The goal of this study was to examine the transcriptomic profiles of ramoplanin sensitive and resistant S. aureus to identify putative modules responsible for virulence and resistance mechanisms and its characteristic novel genes. The dysregulated genes were used to reconstruct protein functional association networks for virulence-factors and resistance-mechanisms individually. Strong link between metabolic-pathways and development of virulence/resistance is suggested. We identified 15 putative modules of virulence factors. Six hypothetical genes were annotated with novel virulence activity among which SACOL0281 was discovered to be an essential virulence factor EsaD. The roles of MazEF toxin-antitoxin system, SACOL0202/SACOL0201 two-component system and that of amino-sugar and nucleotide sugar metabolism in virulence are also suggested. In addition, 14 putative modules of resistance mechanisms including modules of ribosomal protein-coding genes and metabolic pathways such as biotin-synthesis, TCA-cycle, riboflavin biosynthesis, peptidoglycan-biosynthesis etc. are also indicated. PMID- 26255092 TI - Stem cell-like gene expression signature identified in ionizing radiation-treated cancer cells. AB - Recent studies have reported that embryonic stem (ES) cell-associated gene expression signatures have been identified in poorly differentiated tumors, revealing a link between ES cell identity and cancer cells. Cancer cells originate from cancer stem cells (CSCs). Both types of cells share common properties such as self-renewal and heterogeneity. CSCs are also resistant to conventional chemotherapy and radiotherapy. Here, we show similar gene expression patterns between ES cells and ionizing radiation (IR)-treated cancer cells. Using genome-wide transcriptome analysis, we compared the gene expression profiles among ES cells, cancer cells, and irradiated cancer cells, and identified a subset of similar gene expression patterns between ES cells and irradiated cancer cells, indicated by hierarchical clustering. These gene expression patterns were then confirmed by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) analyses. Using bioinformatic analyses, these candidate genes are also associated with various biological pathways related to stemness in cancer. Taken together, our data suggest that identification of common molecular characteristics between ES cells and irradiated cancer cells is important to understand the properties of cancer stem cells and their resistance to radiotherapy. PMID- 26255093 TI - Immunological comparison of DNA vaccination using two delivery systems against canine leishmaniasis. AB - Visceral leishmaniasis (VL) is a fatal disease caused by the intracellular protozoan parasite Leishmania infantum. Dogs are the primary reservoirs of this parasite, and vaccination of dogs could be an effective method to reduce its transfer to humans. In order to develop a vaccine against VL (apart from the choice of immunogenic candidate antigens), it is necessary to use an appropriate delivery system to promote a proper antigen-specific immune response. In this study, we compared two vaccine delivery systems, namely electroporation and cationic solid-lipid nanoparticle (cSLN) formulation, to administer a DNA vaccine containing the Leishmania donovani A2 antigen, and L. infantum cysteine proteinases of type I (CPA) and II (CPB) without its unusual C-terminal extension. The protective potencies of these two vaccine delivery systems were evaluated against L. infantum challenge in outbred dogs. Our results show that the administration of pcDNA-A2-CPA-CPB(-CTE)GFP vaccine as a prime-boost by either electroporation or cSLN formulation protects the dogs against L. infantum infection. Partial protection in vaccinated dogs is associated with significantly (p<0.05) higher levels of IgG2, IFN-gamma, and TNF-alpha and with low levels of IgG1 and IL-10 as compared to the control group. Protection was also correlated with a low parasite burden and a strong delayed-type hypersensitivity (DTH) response. This study demonstrates that both electroporation and cSLN formulation can be used as efficient vaccine delivery systems against visceral leishmaniasis. PMID- 26255094 TI - Low temperature affects cattle tick reproduction but does not lead to transovarial transmission of Anaplasma marginale. AB - Anaplasma marginale is an obligate intracellular pathogen that infects the erythrocytes of calves, causing bovine anaplasmosis. This rickettsia is biologically transmitted by several species of ticks. In tropical and subtropical regions of the world, Rhipicephalus microplus is the main vector. Due to their mobility and longevity, the adult males play an important role in the transmission of A. marginale to calves. Some studies have demonstrated that A. marginale can be intrastadially and interstadially transmitted in R. microplus, but the transovarial transmission has not been demonstrated so far. In the present study, we investigated the effects of low temperature on both the A. marginale migration from infected females to their offspring and reproductive parameters of the tick R. microplus. The larvae of R. microplus fed on a calf infected with the strain Jaboticabal of A. marginale. At the end of the parasitic phase, fully engorged females were incubated at either 18 degrees C or 28 degrees C for oviposition. Although A. marginale was detected in the salivary glands of the females, demonstrating that the ticks were successfully infected, the presence of rickettsia was not detected in the offspring. However, the preoviposition period of the non-infected females maintained at 18 degrees C was longer than that of those maintained at 28 degrees C. In addition, the average weight of the mass of eggs as well as the egg production efficiency (ratio of the egg mass weight to the female weight) of the females maintained at 18 degrees C were significantly lower than those of the females incubated at 28 degrees C. There was no larval hatching from the eggs maintained exclusively at 18 degrees C, even at 65 days after female detachment. Hatching occurred only when the eggs maintained at 18 degrees C were transferred to 28 degrees C at 20 days after female detachment (18 degrees C/28 degrees C). We also verified a significantly higher larvae conversion efficiency (ratio of the larvae mass weight to the egg mass weight) in the group of females maintained exclusively at 28 degrees C compared to those from the 18 degrees C/28 degrees C group. Collectively, our results reinforce that low temperature exerts negative effects on female fertility and egg development in R. microplus, although it has no influence on A. marginale transmission to the progeny. In the field, the detrimental effects of temperatures on tick reproductive fitness lead to a reduction of tick population, which may cause a decrease in the incidence of bovine anaplasmosis. PMID- 26255095 TI - Cost-utility of collaborative care for major depressive disorder in primary care in the Netherlands. AB - OBJECTIVE: Major depression is a great burden on society, as it is associated with high disability/costs. The aim of this study was to evaluate the cost utility of Collaborative Care (CC) for major depressive disorder compared to Care As Usual (CAU) in a primary health care setting from a societal perspective. METHODS: A cluster randomized controlled trial was conducted, including 93 patients that were identified by screening (45-CC, 48-CAU). Another 57 patients were identified by the GP (56-CC, 1-CAU). The outcome measures were TiC-P, SF-HQL and EQ-5D, respectively measuring health care utilization, production losses and general health related quality of life at baseline three, six, nine and twelve months. A cost-utility analysis was performed for patients included by screening and a sensitivity analysis was done by also including patients identified by the GP. RESULTS: The average annual total costs was ?1131 (95% C.I., ?-3158 to ?750) lower for CC compared to CAU. The average quality of life years (QALYs) gained was 0.02 (95% C.I., -0.004 to 0.04) higher for CC, so CC was dominant from a societal perspective. Taking a health care perspective, CC was less cost effective due to higher costs, ?1173 (95% C.I., ?-216 to ?2726), of CC compared to CAU which led to an ICER of 53,717 Euro/QALY. The sensitivity analysis showed dominance of CC. CONCLUSION: The cost-utility analysis from a societal perspective showed that CC was dominant to CAU. CC may be a promising treatment for depression in the primary care setting. Further research should explore the cost-effectiveness of long-term CC. TRIAL REGISTRATION: Netherlands Trial Register ISRCTN15266438. PMID- 26255096 TI - The Effect of Adequate Gestational Weight Gain among Adolescents Relative to Adults of Equivalent Body Mass Index and the Risk of Preterm Birth, Cesarean Delivery, and Low Birth Weight. AB - OBJECTIVE: To determine whether similar odds of cesarean delivery (C/S), preterm birth (PTB), and low birth weight (LBW) are observed among adolescents compared with body mass index (BMI)-equivalent adults in cases of adequate gestational weight gain. STUDY DESIGN: We conducted a retrospective, population-based, cohort study using the Center for Disease Control and Prevention's birth data files from the United States for 2012. We selected from the cohort all singleton, cephalic pregnancies and stratified them according to maternal age, prepregnancy BMI, and gestational weight gain following the 2009 Institute of Medicine (IOM) recommendations. The effect of adequate gestational weight gain among adolescents relative to adults of equivalent BMI on the risk of C/S, PTB, and LBW was estimated using logistic regression analysis, adjusting for relevant confounders. RESULTS: We analyzed a total of 3,960,796 births, of which 1,036,646 (26.1%) met the inclusion criteria. In adolescents and adults, likelihood of achieving ideal gestational weight gain decreased with greater prepregnancy BMI. Relative to adults, the overall odds of C/S in all adolescents were (adjusted odds ratio [95% confidence interval]) 0.61 (0.58 to 0.63). When comparing equivalent BMI categories, these odds were unchanged (P < .0001). The overall adjusted odds ratio of LBW was 1.15 (1.13 to 1.16). These odds were significantly higher when BMI stratification took place, decreasing with advancing BMI categories, from 1.23 (1.14 to 1.33) among the underweight, to nonsignificant differences in the obese classes (P < .05). Finally, when including only those achieving ideal weight gain, the overall odds of premature delivery (1.17 [1.14 to 1.20]) were higher among nonobese adolescents, while they were not found among the obese. CONCLUSION: When ideal gestational weight gain is attained, only nonobese adolescents exhibit a greater risk of LBW and preterm birth relative to adults of similar BMI, whereas the risk of C/S remains lower for all adolescents, independent of BMI. This information may be useful in the counseling of adolescent pregnancies. PMID- 26255097 TI - Temporomandibular Joint Disorders in Patients With Different Facial Morphology. A Systematic Review of the Literature. AB - PURPOSE: The present article aimed to review systematically the literature on the relation between facial skeletal structures and temporomandibular joint (TMJ) disorders. MATERIALS AND METHODS: A systematic search in the dental and medical literature was performed to identify all studies of humans assessing the relation between TMJ disorders and facial morphology. Articles were included based on study design, irrespective of TMJ disorder (eg, disc displacement, osteoarthrosis, or unspecified), skeletal features, diagnostic strategies (e.g., imaging techniques or clinical assessment), and population (eg, demographic features of participants) under investigation. The selected articles were assessed according to a format based on patients, problem, and population, intervention, comparison, and outcome and quality was evaluated based on the Newcastle-Ottawa Scale. RESULTS: Thirty-four articles were included in the review, 27 of which concerned adult samples and 7 concerned adolescent samples. Quality was generally moderate. The articles dealt with the relation between facial morphology and the following TMJ disorders, assessed clinically or by magnetic resonance (MR): disc displacement (n = 20), osteoarthritis or osteoarthrosis (n = 8), and temporomandibular disorder signs and symptoms (n = 6). The different approaches featuring the various investigations and the presence of some potential methodologic biases complicated a summary of the findings. Most studies reported that some features related to the vertical dimension of the face might help distinguish patients with potential TMJ disc displacement or MR-detected signs of osteoarthrosis from those without TMJ disorders. CONCLUSIONS: The quality of the available literature is not adequate to provide an evidence base on the topic. Despite the heterogeneity of design and findings of the reviewed articles, it seems reasonable to suggest that skeletal Class II profiles and hyperdivergent growth patterns are likely associated with an increased frequency of TMJ disc displacement and degenerative disorders. PMID- 26255098 TI - Frailty as a Predictor of Future Falls Among Community-Dwelling Older People: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Although multiple longitudinal studies have investigated frailty as a predictor of future falls, the results were mixed. Thus far, no systematic review or meta-analysis on this topic has been conducted. OBJECTIVE: To review the evidence of frailty as a predictor of future falls among community-dwelling older people. METHODS: Systematic review of literature and meta-analysis were performed using 6 electronic databases (Embase, Scopus, MEDLINE, CINAHL Plus, PsycINFO, and the Cochrane Library) searching for studies that prospectively examined risk of future fall risk according to frailty among community-dwelling older people published from 2010 to April 2015 with no language restrictions. RESULTS: Of 2245 studies identified through the systematic review, 11 studies incorporating 68,723 individuals were included in the meta-analysis. Among 7 studies reporting odds ratios (ORs), frailty and prefrailty were significantly associated with higher risk of future falls (pooled OR = 1.84, 95% confidence interval [95% CI] = 1.43 2.38, P < .001; pooled OR = 1.25, 95% CI = 1.01-1.53, P = .005, respectively). Among 4 studies reporting hazard ratios (HRs), whereas frailty was significantly associated with higher risk of future falls (pooled HR = 1.24, 95% CI = 1.10 1.41, P < .001), future fall risk according to prefrailty did not reach statistical significance (pooled HR = 1.14, 95% CI = 0.95-1.36, P = .15). High heterogeneity was noted among 7 studies reporting ORs and seemed attributed to difference in gender proportion of cohorts according to subgroup and meta regression analyses. CONCLUSIONS: Frailty is demonstrated to be a significant predictor of future falls among community-dwelling older people despite various criteria used to define frailty. The future fall risk according to frailty seemed to be higher in men than in women. PMID- 26255099 TI - Advance Care Planning in Nursing Home Patients With Dementia: A Qualitative Interview Study Among Family and Professional Caregivers. AB - OBJECTIVE: The aim of this study was to describe the process of advance care planning (ACP) and to explore factors related to the timing and content of ACP in nursing home patients with dementia, as perceived by family, physicians, and nurses. DESIGN: A qualitative descriptive study. METHODS: A total of 65 in-depth qualitative interviews were held with families, on-staff elderly care physicians, and nurses of 26 patients with dementia who died in the Dutch End Of Life in Dementia (DEOLD) study. Interviews were coded and analyzed to find themes. RESULTS: Family, nurses, and physicians of all patients indicated they had multiple contact moments during nursing home stay in which care goals and treatment decisions were discussed. Nearly all interviewees indicated that physicians took the initiative for these ACP discussions. Care goals discussed and established during nursing home stay and the terminology to describe care goals varied between facilities. Regardless of care goals and other factors, cardiopulmonary resuscitation (CPR) and hospitalization were always discussed in advance with family and commonly resulted in a do-not-resuscitate (DNR) and a do not-hospitalize (DNH) order. The timing of care planning discussions about other specific treatments or conditions and the content of treatment decisions varied. The factors that emerged from the interviews as related to ACP were general strategies that guided physicians in initiating ACP discussions, patient's condition, wishes expressed by patient or family, family's willingness, family involvement, continuity of communication, consensus with or within family, and general nursing home policy. Two influential underlying strategies guided physicians in initiating ACP discussions: (1) wait for a reason to initiate discussions, such as a change in health condition and (2) take initiative to discuss possible treatments (actively, including describing scenarios). CONCLUSIONS: ACP is a multifactorial process, which may lean on professional caregivers' guidance. The most acute decisions are covered in advance, but a responsive as well as a proactive style is seen with other treatment decisions. Further research is needed to increase understanding of whether and how the physicians' strategies affect care processes and outcomes. PMID- 26255100 TI - Optimizing Eating Performance for Long-Term Care Residents With Dementia: Testing the Impact of Function-Focused Care for Cognitively Impaired. AB - OBJECTIVES: The objective of this study was to evaluate the impact of a well developed theory-based function-focused care for cognitively impaired (FFC-CI) intervention on eating performance among long-term care (LTC) residents with moderate-to-severe cognitive impairment. DESIGN: A secondary analysis of longitudinal data from 2 cluster-randomized controlled trials that originally tested the impact of FFC-CI on all function and physical activities. PARTICIPANTS AND SETTING: Participants were 199 residents with moderate-to-severe cognitive impairment from 4 nursing homes and 4 assisted living facilities. MEASUREMENTS: Data at baseline, and 3 and 6 months were used. Resident outcome data used in this analysis included eating performance conceptualized using the single self care "feeding" item in the Barthel Index, cognitive function by Mini-Mental State Examination, sitting balance conceptualized using the single "chair sit-sitting balance" item in the Tinetti Gait and Balance scale, physical capability by Physical Capability Scale, depression by Cornell Scale for Depression in Dementia, and agitation by Cohen-Mansfield Agitation Inventory (short form). RESULTS: At baseline, almost one-third (32.2%) of the 199 residents needed help with eating. There was no significant change with regard to eating performance over time in both groups, and no significant treatment by time difference between groups in eating performance (P = .195). CONCLUSION: Current findings support a need to revise the FFC-CI to better address eating performance. Future work may benefit from a stronger focus on eating performance rather than the more commonly addressed functional tasks, such as bathing, dressing, and ambulation. In addition, the inclusion of a more heterogeneous group of LTC residents with regard to eating performance is needed to test the impact of the revised approach on eating performance. PMID- 26255101 TI - Can Patients Be the CEO of Their Skilled Nursing Stay? Description of a Person Centered Model of Sub-acute Care. PMID- 26255102 TI - XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency. AB - BACKGROUND: Nonhomologous end-joining (NHEJ) is the major DNA double-strand break (DSB) repair mechanism in human cells. The final rejoining step requires DNA ligase IV (LIG4) together with the partner proteins X-ray repair cross complementing protein 4 (XRCC4) and XRCC4-like factor. Patients with mutations in genes encoding LIG4, XRCC4-like factor, or the other NHEJ proteins DNA-dependent protein kinase catalytic subunit and Artemis are DSB repair defective and immunodeficient because of the requirement for NHEJ during V(D)J recombination. OBJECTIVE: We found a patient displaying microcephaly and progressive ataxia but a normal immune response. We sought to determine pathogenic mutations and to describe the molecular pathogenesis of the patient. METHODS: We performed next generation exome sequencing. We evaluated the DSB repair activities and V(D)J recombination capacity of the patient's cells, as well as performing a standard blood immunologic characterization. RESULTS: We identified causal mutations in the XRCC4 gene. The patient's cells are radiosensitive and display the most severe DSB repair defect we have encountered using patient-derived cell lines. In marked contrast, a V(D)J recombination plasmid assay revealed that the patient's cells did not display the junction abnormalities that are characteristic of other NHEJ-defective cell lines. The mutant protein can interact efficiently with LIG4 and functions normally in in vitro assays and when transiently expressed in vivo. However, the mutation makes the protein unstable, and it undergoes proteasome mediated degradation. CONCLUSION: Our findings reveal a novel separation of impact phenotype: there is a pronounced DSB repair defect and marked clinical neurological manifestation but no clinical immunodeficiency. PMID- 26255103 TI - Leukotriene D4 and prostaglandin E2 signals synergize and potentiate vascular inflammation in a mast cell-dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3. AB - BACKGROUND: Although arachidonic acid metabolites, cysteinyl leukotrienes (cys LTs; leukotriene [LT] C4, LTD4, and LTE4), and prostaglandin (PG) E2 are generated at the site of inflammation, it is not known whether crosstalk exists between these 2 classes of inflammatory mediators. OBJECTIVE: We sought to determine the role of LTD4-PGE2 crosstalk in inducing vascular inflammation in vivo, identify effector cells, and ascertain specific receptors and pathways involved in vitro. METHODS: Vascular (ear) inflammation was assessed by injecting agonists into mouse ears, followed by measuring ear thickness and histology, calcium influx with Fura-2, phosphorylation and expression of signaling molecules by means of immunoblotting, PGD2 and macrophage inflammatory protein 1beta generation by using ELISA, and expression of transcripts by using RT-PCR. Candidate receptors and signaling molecules were identified by using antagonists and inhibitors and confirmed by using small interfering RNA. RESULTS: LTD4 plus PGE2 potentiated vascular permeability and edema, gearing the system toward proinflammation in wild-type mice but not in Kit(W-sh) mice. Furthermore, LTD4 plus PGE2, through cysteinyl leukotriene receptor 1 (CysLT1R) and E-prostanoid receptor (EP) 3, enhanced extracellular signal-regulated kinase (Erk) and c-fos phosphorylation, inflammatory gene expression, macrophage inflammatory protein 1beta secretion, COX-2 upregulation, and PGD2 generation in mast cells. Additionally, we uncovered that this synergism is mediated through Gi, protein kinase G, and Erk signaling. LTD4 plus PGE2-potentiated effects are partially sensitive to CysLT1R or EP3 antagonists but completely abolished by simultaneous treatment both in vitro and in vivo. CONCLUSIONS: Our results unravel a unique LTD4-PGE2 interaction affecting mast cells through CysLT1R and EP3 involving Gi, protein kinase G, and Erk and contributing to vascular inflammation in vivo. Furthermore, current results also suggest an advantage of targeting both CysLT1R and EP3 in attenuating inflammation. PMID- 26255104 TI - Effects of dissolved organic matters (DOMs) on membrane fouling in anaerobic ceramic membrane bioreactors (AnCMBRs) treating domestic wastewater. AB - Anaerobic membrane bioreactors (AnMBRs) have been regarded as a potential solution to achieve energy neutrality in the future wastewater treatment plants. Coupling ceramic membranes into AnMBRs offers great potential as ceramic membranes are resistant to corrosive chemicals such as cleaning reagents and harsh environmental conditions such as high temperature. In this study, ceramic membranes with pore sizes of 80, 200 and 300 nm were individually mounted in three anaerobic ceramic membrane bioreactors (AnCMBRs) treating real domestic wastewater to examine the treatment efficiencies and to elucidate the effects of dissolved organic matters (DOMs) on fouling behaviours. The average overall chemical oxygen demands (COD) removal efficiencies could reach around 86-88%. Although CH4 productions were around 0.3 L/g CODutilised, about 67% of CH4 generated was dissolved in the liquid phase and lost in the permeate. When filtering mixed liquor of similar properties, smaller pore-sized membranes fouled slower in long-term operations due to lower occurrence of pore blockages. However, total organic removal efficiencies could not explain the fouling behaviours. Liquid chromatography-organic carbon detection, fluorescence spectrophotometer and high performance liquid chromatography coupled with fluorescence and ultra-violet detectors were used to analyse the DOMs in detail. The major foulants were identified to be biopolymers that were produced in microbial activities. One of the main components of biopolymers--proteins--led to different fouling behaviours. It is postulated that the proteins could pass through porous cake layers to create pore blockages in membranes. Hence, concentrations of the DOMs in the soluble fraction of mixed liquor (SML) could not predict membrane fouling because different components in the DOMs might have different interactions with membranes. PMID- 26255105 TI - Safety assessment of sanitary pads with a polymeric foam absorbent core. AB - Sanitary pads for menstrual hygiene have a layered design consisting of a fluid permeable surface (topsheet), an absorbent core, and an impermeable backing with adhesive. Most sanitary pads employ cellulose-based cores. This describes the safety evaluation of a menstrual pad with an emollient-treated topsheet and a novel polymeric foam core. A quantitative risk assessment was performed, which included: (1) toxicological evaluation of the raw material components; (2) quantitative exposure assessments of pad constituents, accounting for the fluid handling properties of the product and pertinent conditions of use; and (3) risk characterization for exposure to raw materials (e.g., potential for skin irritation, contact sensitization, or systemic effects, if relevant) and to the physical article itself (potential effects on skin friction, etc.). No significant risk of adverse effects was found. Five years of post-market surveillance substantiates that the product is well-tolerated (1 health complaint reported per 2 million products shipped to market) and surpasses women's expectations for menstrual protection and overall comfort and dryness. This report illustrates how the classical risk assessment paradigm, informed by the impact of product design, functionality and pertinent use conditions, allowed the systematic safety evaluation of a personal hygiene product with a novel, non cellulosic absorbent foam core technology. PMID- 26255106 TI - Tolerance of rising dietary concentrations of esterified propoxylated glycerol (EPG) among human volunteers. AB - A solid form of esterified propoxylated glycerol (EPG) was administered to 16 healthy male volunteers in butter-like spread and baked goods, resulting in intakes that rose in 30-g increments from 30 to 150 g; each level was administered on a single day, followed by a 2-day washout period. Elevated serum transaminase (ALT and/or AST) and lower HDL cholesterol levels were noted at 60 g and greater, possibly related to changes in the diet (high-carbohydrate and increasingly low-fat), rather than to EPG itself. There was no apparent association between EPG consumption and adverse effects reported. In general, EPG had no effect on bowel function, except in a single subject, who reported increased frequency of movements during the 2 days that followed consumption of 150 g EPG. All abnormal values returned to normal after the study, and subjects were otherwise asymptomatic. Accordingly, the effects on transaminase and HDL levels observed in this study were considered possibly adaptive and not clinically significant. Experimental animal studies, including lifetime studies, had shown no effects on these parameters. More importantly, the effect was associated with intakes of 60-150 g EPG, which exceeds the approximate intake of 20 g/day or less expected from currently intended commercial food uses. PMID- 26255107 TI - Impact of a modification of food regulation on cadmium exposure. AB - The 2nd French Total Diet Study demonstrated that 0.6% of adults and 14.9% of children exceeded the tolerable weekly intake set by EFSA. The overexposure of several consumers (adults and children) can be partially due to the high consumption of bread and dried bread products, of bivalve mollusks and of potatoes. Except for mollusks, these foods are the main contributors identified for the general population. On this basis, the French agency for food, environmental and occupational health and safety (ANSES) assessed whether a decrease of the European maximum limits in foodstuffs could significantly reduce the level of exposure of French consumers. Applying ML set at P90 of the main contributors would neither significantly reduce exposure levels to cadmium for the general population, nor the percentage of subjects exceeding the TWI. To reduce background consumer exposure to cadmium, actions to be taken include efforts on sources that are at the origin of the soil contamination and the efficacy of consumption recommendations. PMID- 26255108 TI - The asthma-COPD overlap syndrome: towards a revised taxonomy of chronic airways diseases? AB - Most research of treatments for airways diseases has been restricted to patients who meet standard definitions of either chronic obstructive pulmonary disease (COPD) or asthma, yet to distinguish COPD from asthma in adult patients who have clinical features of both can be challenging. Treatment guidelines provide scant advice on how such patients should be managed. With increasing recognition that asthma and COPD are heterogeneous diseases, attention has been directed to the needs of a group of patients with what is now termed asthma-COPD overlap syndrome (ACOS), particularly in view of the high morbidity in this population. This Review considers the epidemiology, mechanisms of disease, current attempts to define and diagnose ACOS, existing and potential treatment options, and new approaches to the phenotyping and taxonomy of airway diseases. PMID- 26255109 TI - Choroidal Nevus in the United States Adult Population: Racial Disparities and Associated Factors in the National Health and Nutrition Examination Survey. AB - PURPOSE: To describe the prevalence of choroidal nevus in the US population and identify possible associated factors. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 5575 participants aged >=40 years from the 2005-2008 National Health and Nutrition Examination Survey (NHANES) who underwent retinal imaging examination. METHODS: Predictor variables included a spectrum of demographic, ophthalmic, dermatologic, systemic, socioeconomic, or occupational factor variables available in NHANES. MAIN OUTCOME MEASURES: Choroidal nevus on retinal imaging. RESULTS: The prevalence of choroidal nevus was 4.7% overall and increased with age (4.7%, 3.1%, 5.4%, 6.6%, and 7.5% in subjects aged 40-49, 50 59, 60-69, 70-79, and >=80 years, respectively). The prevalence was 5.0% in men, 4.4% in women, 5.6% in whites, 2.7% in Hispanics, 0.6% in blacks, and 2.1% in others. After adjusting for age and race, the odds of choroidal nevus were 10 fold higher in whites than in blacks, 5-fold higher in Hispanics than in blacks, 4-fold higher in others than in blacks, and 2-fold higher in whites than in Hispanics. Choroidal nevus was associated with hypertension (odds ratio [OR], 1.40; 95% confidence interval [CI], 0.99-1.98); psoriasis (OR, 3.90; 95% CI, 1.57 9.66); lower high-density lipoprotein (OR, 0.99; 95% CI, 0.98-0.99); higher uric acid (OR, 1.13; 95% CI, 1.04-1.22); working in installation, maintenance, or repairs (OR, 1.42; 95% CI, 1.03-1.96); and having never worked (OR, 1.56; 95% CI, 1.03-2.37; P = 0.04). There was no association with visual symptoms, visual functioning, visual acuity, refractive error, visual field, diabetic retinopathy, age-related macular degeneration, or elevated cup-to-disc ratio on retinal imaging. There was no association with skin melanoma, other cancers, lung/liver/kidney/thyroid disease, alcohol/drug use, income/education, hemoglobin A1C, C-reactive protein, lactate dehydrogenase, electrolytes, or urine albumin. CONCLUSIONS: Among US adults, the prevalence of choroidal nevus located within two 45 degrees areas centered on the macula and optic disc is 4.7%. The prevalence increases with age, is highest among whites (5.6%), is lowest among blacks (0.6%), and has been previously under-recognized among Hispanics (2.7%). Extrapolating to the entire fundus, the true prevalence of choroidal nevus is even higher but difficult to accurately estimate. Possible associations with cardiovascular, renal, autoimmune, and occupational risk factors warrant further investigation. PMID- 26255111 TI - Determination of the solvent density profiles across mesopores of silica-C18 bonded phases in contact with acetonitrile/water mixtures: A semi-empirical approach. AB - The local volume fractions of water, acetonitrile, and C18-bonded chains across the 96Amesopores of 5MUm Symmetry particles were determined semi-empirically. The semi-empirical approach was based on previous molecular dynamics studies, which provided relevant mathematical expressions for the density profiles of C18 chains and water molecules, and on minor disturbance experiments, which measured the excess amount of acetonitrile adsorbed in the pores of Symmetry-C18 particles. The pore walls of the Symmetry-C18 material were in thermodynamic equilibrium with a series of binary mixtures of water and acetonitrile. The results show that C18 chains are mostly solvated by acetonitrile molecules, water is excluded from the C18-bonded layer, and acetonitrile concentrates across a 15-25Athick interface region between the C18 layer and the bulk phase. These actual density profiles are expected to have a direct impact on the retention behaviour of charged, polar, and neutral analytes in RPLC. They also provide clues to predict the local mobility of analytes inside the pores and a sound physico-chemical description of the phenomenon of surface diffusion observed in RPLC. PMID- 26255110 TI - Pharmacological antagonism of interleukin-8 receptor CXCR2 inhibits inflammatory reactivity and is neuroprotective in an animal model of Alzheimer's disease. AB - BACKGROUND: The chemokine interleukin-8 (IL-8) and its receptor CXCR2 contribute to chemotactic responses in Alzheimer's disease (AD); however, properties of the ligand and receptor have not been characterized in animal models of disease. The primary aim of our study was to examine effects of pharmacological antagonism of CXCR2 as a strategy to inhibit receptor-mediated inflammatory reactivity and enhance neuronal viability in animals receiving intrahippocampal injection of amyloid-beta (Abeta1-42). METHODS: In vivo studies used an animal model of Alzheimer's disease incorporating injection of full-length Abeta1-42 into rat hippocampus. Immunohistochemical staining of rat brain was used to measure microgliosis, astrogliosis, neuronal viability, and oxidative stress. Western blot and Reverse Transcription PCR (RT-PCR) were used to determine levels of CXCR2 in animal tissue with the latter also used to determine expression of pro inflammatory mediators. Immunostaining of human AD and non-demented (ND) tissue was also undertaken. RESULTS: We initially determined that in the human brain, AD relative to ND tissue exhibited marked increases in expression of CXCR2 with cell specific receptor expression prominent in microglia. In Abeta1-42-injected rat brain, CXCR2 and IL-8 showed time-dependent increases in expression, concomitant with enhanced gliosis, relative to controls phosphate-buffered saline (PBS) or reverse peptide Abeta42-1 injection. Administration of the competitive CXCR2 antagonist SB332235 to peptide-injected rats significantly reduced expression of CXCR2 and microgliosis, with astrogliosis unchanged. Double staining studies demonstrated localization of CXCR2 and microglial immunoreactivity nearby deposits of Abeta1-42 with SB332235 effective in inhibiting receptor expression and microgliosis. The numbers of neurons in granule cell layer (GCL) were reduced in rats receiving Abeta1-42, compared with PBS, with administration of SB332235 to peptide-injected animals conferring neuroprotection. Oxidative stress was indicated in the animal model since both 4-hydroxynonenal (4-HNE) and hydroethidine (HEt) were markedly elevated in Abeta1-42 vs. PBS-injected rat brain and diminished with SB332235 treatment. CONCLUSION: Overall, the findings suggest critical roles for CXCR2-dependent inflammatory responses in an AD animal model with pharmacological modulation of the receptor effective in inhibiting inflammatory reactivity and conferring neuroprotection against oxidative damage. PMID- 26255112 TI - Amine-phenyl multi-component gradient stationary phases. AB - Continuous multi-component gradients in amine and phenyl groups were fabricated using controlled rate infusion (CRI). Solutions prepared from either 3 aminopropyltriethoxysilane (APTEOS) or phenyltrimethoxysilane (PTMOS) were infused, in a sequential fashion, at a controlled rate into an empty graduated cylinder housing a vertically aligned thin layer chromatography (TLC) plate. The hydrolyzed precursors reacted with an abundance of silanol (SiOH) groups on the TLC plates, covalently attaching the functionalized silane to its surface. The extent of modification by phenyl and amine was determined by the kinetics of each reaction and the exposure time at each point along the TLC plate. The local concentrations of phenyl and amine were measured using diffuse reflectance spectroscopy and X-ray photoelectron spectroscopy, respectively. The profile of the multi-component gradients strongly depended on the order of infusion, the direction of the gradient and the presence of available surface silanol groups. A slightly higher amount of phenyl can be deposited on the TLC plate by first modifying its surface with amine groups as they serve as a catalyst, enhancing condensation. Separation of water- and fat-soluble vitamins and the control of retention factors were demonstrated on the multi-component gradient TLC plates. Uniformly modified and single-component TLC plates gave different separations compared to the multi-component gradient plates. The retention factors of the individual vitamins depended on the order of surface modification, the spotting end, and whether the multi-component gradients align or oppose each other. PMID- 26255113 TI - Accurate measurement of dispersion data through short and narrow tubes used in very high-pressure liquid chromatography. AB - An original method is proposed for the accurate and reproducible measurement of the time-based dispersion properties of short L< 50cm and narrow rc< 50MUm tubes at mobile phase flow rates typically used in very high-pressure liquid chromatography (vHPLC). Such tubes are used to minimize sample dispersion in vHPLC; however, their dispersion characteristics cannot be accurately measured at such flow rates due to system dispersion contribution of vHPLC injector and detector. It is shown that using longer and wider tubes (>10MUL) enables a reliable measurement of the dispersion data. We confirmed that the dimensionless plot of the reduced dispersion coefficient versus the reduced linear velocity (Peclet number) depends on the aspect ratio, L/rc, of the tube, and unexpectedly also on the diffusion coefficient of the analyte. This dimensionless plot could be easily obtained for a large volume tube, which has the same aspect ratio as that of the short and narrow tube, and for the same diffusion coefficient. The dispersion data for the small volume tube are then directly extrapolated from this plot. For instance, it is found that the maximum volume variances of 75MUm*30.5cm and 100MUm*30.5cm prototype finger-tightened connecting tubes are 0.10 and 0.30MUL(2), respectively, with an accuracy of a few percent and a precision smaller than seven percent. PMID- 26255115 TI - Downregulation of STAT3 phosphorylation enhances tumoricidal effect of IL-15 activated dendritic cell against doxorubicin-resistant lymphoma and leukemia via TNF-alpha. AB - Although disputed by some, increasing evidence suggests that TNF-alpha synergies with traditional chemotherapeutic drugs to exert a heightened antitumor effect. The present study investigated the antitumor efficacy of recombinant IL-15 in combination with the STAT3 inhibitor cucurbitacin-I in a doxorubicin-resistant murine lymphoma model. The significance of the work is to understand and design effective strategies in doxorubicin resistant lymphomas. TNF-alpha is downregulated in dendritic cells from mice with Dalton's lymphoma and shows an inverse relationship with disease progression. Doxorubicin-resistant DL cells have elevated levels of Bcl-2 and Mcl-1 and increased phosphorylation of STAT3. These cells are refractory to dendritic cell derived TNF-alpha. Doxorubicin resistant Dalton's lymphoma is susceptible to dendritic cell derived TNF-alpha upon stimulation with the STAT3 inhibitor cucurbitacin-I, which downregulates STAT3 and other survival molecules. The combined treatment of low dose of cucurbitacin-I and rIL-15 is ineffective in mice with doxorubicin resistant Dalton's lymphoma, but a similar therapy prolongs the survival of mice transplanted with parental Dalton's lymphoma. Doxorubicin resistant Dalton's lymphoma responds to therapy with high doses of cucurbitacin-I and rIL-15. Dendritic cell derived from mice responded positively to the therapy and regained their tumoricidal properties with respect to growth inhibition and killing of DL tumor cells. Similar to DL, DC derived from CML patients are impaired in TNF alpha expression and are unable to restrict the growth of drug-resistant lymphoma and leukemia cells. This combination approach could be used as a new therapeutic strategy for aggressive and highly metastatic doxorubicin resistant lymphoma. PMID- 26255114 TI - Nanomedicine in the ROS-mediated pathophysiology: Applications and clinical advances. AB - Reactive oxygen species (ROS) are important in regulating normal cell physiological functions, but when produced in excess lead to the augmented pathogenesis of various diseases. Among these, ischemia reperfusion injury, Alzheimer's disease and rheumatoid arthritis are particularly important. Since ROS can be counteracted by a variety of antioxidants, natural and synthetic antioxidants have been developed. However, due to the ubiquitous production of ROS in living systems, poor in vivo efficiency of these agents and lack of target specificity, the current clinical modalities to treat oxidative stress damage are limited. Advances in the developing field of nanomedicine have yielded nanoparticles that can prolong antioxidant activity, and target specificity of these agents. This article reviews recent advances in antioxidant nanoparticles and their applications to manage oxidative stress-mediated diseases. FROM THE CLINICAL EDITOR: Production of reactive oxygen species (ROS) is a purely physiological process in many disease conditions. However, excessive and uncontrolled production will lead to oxidative stress and further tissue damage. Advances in nanomedicine have provided many novel strategies to try to combat and counteract ROS. In this review article, the authors comprehensively highlighted the current status and future developments in using nanotechnology for providing novel therapeutic options in this field. PMID- 26255116 TI - Oxidised low density lipoprotein causes human macrophage cell death through oxidant generation and inhibition of key catabolic enzymes. AB - Oxidised low density lipoprotein (oxLDL) is thought to be a significant contributor to the death of macrophage cells observed in advanced atherosclerotic plaques. Using human-derived U937 cells we have examined the effect of cytotoxic oxLDL on oxidative stress and cellular catabolism. Within 3h of the addition of oxLDL, there was a rapid, concentration dependent rise in cellular reactive oxygen species followed by the loss of cellular GSH, and the enzyme activity of both glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and aconitase. The loss of these catabolic enzymes was accompanied by the loss of cellular ATP and lower lactate generation. Addition of the macrophage antioxidant 7,8-dihydroneopterin inhibited the ROS generation, glutathione loss and catabolic inactivation. NOX was shown to be activated by oxLDL addition while apocynin inhibited the loss of GSH and cell viability. The data suggests that oxLDL triggers an excess of ROS production through NOX activation, and catabolic failure through thiol oxidation resulting in cell death. PMID- 26255117 TI - Antiproliferative and pro-apoptotic effects of three fungal exocellular beta glucans in MCF-7 breast cancer cells is mediated by oxidative stress, AMP activated protein kinase (AMPK) and the Forkhead transcription factor, FOXO3a. AB - Fungal beta-d-glucans of the (1->3)-type are known to exhibit direct antitumor effects, and can also indirectly decrease tumor proliferation through immunomodulatory responses. The underlying molecular mechanisms involved in decreasing tumor formation, however, are not well understood. In this study, we examined the antiproliferative role and mechanism of action of three different fungal exocellular beta-glucans in MCF-7 breast cancer cells. The beta-glucans were obtained from Botryosphaeria rhodina MAMB-05 [two botryosphaerans; (1->3)(1 >6)-beta-d-glucan; one produced on glucose, the other on fructose] and Lasiodiplodia theobromae MMPI [lasiodiplodan; (1->6)-beta-d-glucan, produced on glucose]. Using the cell proliferation-MTT assay, we showed that the beta-glucans exhibited a time- and concentration-dependent antiproliferative activity (IC50, 100MUg/ml). Markers of cell cycle, apoptosis, necrosis and oxidative stress were analyzed using flow cytometry, RT-PCR and Western blotting. Exposure to beta glucans increased apoptosis, necrosis, oxidative stress, mRNA expression of p53, p27 and Bax; the activity of AMP-activated protein-kinase, Forkhead transcription factor FOXO3a, Bax and caspase-3; and decreased the activity of p70S6K in MCF-7 cells. In the presence of hydrogen peroxide, the fungal beta-glucans increased oxidative stress, which was associated with reduced cell viability. We showed that these beta-glucans exhibited an antiproliferative effect that was associated with apoptosis, necrosis and oxidative stress. This study demonstrated for the first time that the apoptosis induced by beta-glucans was mediated by AMP activated protein-kinase and Forkhead transcription factor, FOXO3a. Our findings provide novel mechanistic insights into their antiproliferative roles, and compelling evidence that these beta-glucans possess a broad range of biomodulatory properties that may prove useful in cancer treatment. PMID- 26255118 TI - Two-dimensional misorientation mapping by rocking dark-field transmission electron microscopy. AB - In this paper we introduce an approach for precise orientation mapping of crystalline specimens by means of transmission electron microscopy. We show that local orientation values can be reconstructed from experimental dark-field image data acquired at different specimen tilts and multiple Bragg reflections. By using the suggested method it is also possible to determine the orientation of the tilt axis with respect to the image or diffraction pattern. The method has been implemented to automatically acquire the necessary data and then map crystal orientation for a given region of interest. We have applied this technique to a specimen prepared from a Ni-based super-alloy CMSX-4. The functionality and limitations of our method are discussed and compared to those of other techniques available. PMID- 26255119 TI - Surface effects on mean inner potentials studied using density functional theory. AB - Quantitative materials characterization using electron holography frequently requires knowledge of the mean inner potential, but reported experimental mean inner potential measurements can vary widely. Using density functional theory, we have simulated the mean inner potential for materials with a range of different surface conditions and geometries. We use both "thin-film" and "nanowire" specimen geometries. We consider clean bulk-terminated surfaces with different facets and surface reconstructions using atom positions from both structural optimization and experimental data and we also consider surfaces both with and without adsorbates. We find that the mean inner potential is surface-dependent, with the strongest dependency on surface adsorbates. We discuss the outlook and perspective for future mean inner potential measurements. PMID- 26255120 TI - The effect of nephropathy on plasma sphingosine 1-phosphate concentrations in patients with type 2 diabetes. AB - OBJECTIVES: Sphingosine 1-phosphate (S1P) is carried in plasma by the HDL particles and albumin. It mediates several protective functions of HDL. Because of its barrier-enhancing effect, it has attracted attention in diseases associated with endothelial dysfunction. We examined the impact of circulating levels of S1P in diabetic nephropathy together with apoprotein M, a S1P-binding protein in HDL. Plasma levels of dimethylarginines were evaluated in this context. DESIGN AND METHODS: Patients with type 2 diabetes mellitus were divided into three groups according to daily albumin excretion: normoalbuminuria, microalbuminuria and macroalbuminuria (n=30 in each). In addition to routine analysis, S1P and apo M in plasma were measured using the enzyme-linked immunosorbent assays. Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and l-arginine were determined by HPLC. Tukey's or Mann Whitney U-test was used for the statistics. RESULTS: Plasma S1P levels showed a significant decline in parallel to kidney dysfunction. The highest significance was detected in the macroalbuminuric group. Although a significant increase in plasma SDMA in albuminuric groups was observed, apo M, l-arginine and ADMA levels were similar between the groups. CONCLUSION: Low plasma levels of S1P seemed to be associated with diabetic nephropathy. The main reason for the decreased S1P levels in our patients seems to be severe urinary albumin loss due to nephropathy. Low levels of S1P in patients with nephropathy may adversely affect the endothelial integrity and barrier function, thus causing a vicious circle. PMID- 26255121 TI - Analytical performance of the Abaxis Piccolo Xpress(r) point of care analyzer in whole blood, serum, and plasma. AB - OBJECTIVES: To examine the analytical performance of 14 comprehensive metabolic panel analytes on the Abaxis Piccolo Xpress(r) Point of Care analyzer in serum, plasma, and whole blood. DESIGN AND METHODS: Precision was evaluated by running two levels of control material over multiple days. Linearity was evaluated using material provided by the manufacturer and the College of American Pathologists (CAP) linearity surveys. Accuracy was evaluated by comparing the results from 60 patient specimens on the Piccolo Xpress(r) with the Ortho Vitros(r) 5600 analyzer. The method comparison was performed on all three specimen types intended for use on the Piccolo Xpress(r): serum, heparinized plasma, and whole blood. Manufacturer suggested reference ranges for all 14 analytes were tested in serum and plasma specimens from 23 healthy volunteers. RESULTS: High precision (CV <= 10%) was noted for all the analytes. Linearity was found to span the clinically useful range for all analytes. The method comparison demonstrated minimal proportional bias and good correlation for most of the analytes in all three matrices tested. The only exceptions were for sodium and total CO2, for which either significant proportional bias and/or poor correlation was noted in all three matrices. Significant bias was noted for AST in serum as well as for total bilirubin in plasma and whole blood. CONCLUSION: The Piccolo Xpress(r) allows for the delivery of CMP results in a footprint small enough to be stored in a biological safety cabinet, while providing satisfactory performance for the majority of analytes. PMID- 26255122 TI - Variation in glucocorticoid levels in relation to direct and third-party interactions in a social cichlid fish. AB - In complex animal societies, direct interactions between group members can influence the behavior and glucocorticoid levels of individuals involved. Recently, it has become apparent that third-party group members can influence dyadic interactions, and vice versa. Thus, glucocorticoid levels may vary depending on interactions of other members of the social group. Using the social cichlid fish Neolamprologus pulcher, we examined the relationship between levels of the glucocorticoid hormone cortisol in subordinate females and 1) direct interactions with dominant group members, as well as 2) dyadic interactions between the dominant male and female, in which the subordinate female was not directly involved. Subordinate females that frequently engaged in non-aggressive interactions with dominant females had lower cortisol levels. There was no relationship between subordinate female cortisol and agonistic interactions between the subordinate female and either dominant. Subordinate females had higher cortisol levels when in groups in which the dominant breeding pair behaved agonistically towards each other and performed fewer courtship behaviors. For subordinate females in this species, variation in cortisol levels is associated with their own affiliative behavior, but also can be explained by the broader social context of interactions between dominant members of the group. PMID- 26255123 TI - BDNF and COX-2 participate in anti-depressive mechanisms of catalpol in rats undergoing chronic unpredictable mild stress. AB - Catalpol, a major compound in Rehmannia glutinosa with both medicinal and nutritional values, has been previously confirmed to shorten the duration of immobility in mice exposed to tail suspension and forced swimming tests. This study attempted to examine the anti-depressive mechanisms of catalpol in rats undergoing chronic unpredictable mild stress (CUMS) by involving brain-derived neurotrophic factor (BDNF) and cyclooxygenase-2 (COX-2). CUMS-exposed rats were given catalpol daily (5, 10, and 20mg/kg, ig) or a reference drug, fluoxetine hydrochloride (FH, 10mg/kg, ig), at 5 weeks after starting the CUMS procedure. Sucrose preference test was performed to observe depression-like behavior, and serum and brain tissues were used for neurochemical and fluorescent quantitative reverse transcription PCR analysis. CUMS induced depression-like behavior, whereas catalpol and FH administration attenuated this symptom. Moreover, CUMS caused excessively elevated levels of serum corticosterone, an index of hypothalamic-pituitary-adrenal (HPA) axis hyperactivation, in a manner attenuated by catalpol and FH administration. Catalpol administration also further decreased BDNF activities, downregulated the mRNA expression of BDNF and tropomyosin related kinase B (TrkB), and reversed the excessive elevation in the activities and mRNA expression levels of COX-2 and prostaglandin E2 (PGE2) in the hippocampus and frontal cortex of rats undergoing CUMS. Results indicate that catalpol can ameliorate CUMS-induced depression-like behavior, and suggest its mechanisms may partially be ascribed to restoring HPA axis dysfunctions, upregulating BDNF expression and its cognate receptor TrkB, and downregulating COX-2 expression, thereby reducing PGE2 levels in the brain. PMID- 26255124 TI - Amino acid composition of the bushcricket spermatophore and the function of courtship feeding: Variable composition suggests a dynamic role of the nuptial gift. AB - Nuptial gifts are packages of non-gametic material transferred by males to females at mating. These gifts are common in bushcrickets, where males produce a complex spermatophore consisting in a sperm-containing ampulla and an edible sperm-free spermatophylax. Two non-mutually exclusive hypotheses have been suggested to explain the function of the spermatophylax: the paternal investment hypothesis proposes that it represents a male nutritional investment in offspring; the mating effort hypothesis proposes that the spermatophylax maximizes the male's sperm transfer. Because gift production may represent significant energy expenditure, males are expected to adjust their investment relative to the perceived quality of the female. In this study, we first examined the free amino acid composition and protein-bound amino acid composition of the nuptial gift in the bushcricket, Ephippiger diurnus (Orthoptera: Tettigoniidae). Second, we investigated whether this composition was altered according to female age and body weight. Our study represents the first investigation of both free and protein-bound amino acid fractions of a bushcricket spermatophylax. We found that composition of the nuptial gift varied both qualitatively and quantitatively with respect to traits of the receiving female: older females received larger amounts of protein-bound amino acids (both essential and non-essential), less water and less free glycine. This result suggests that gift composition is highly labile in E. diurnus, and we propose that gift allocation might represent a form of cryptic male mate choice, allowing males to maximize their chances of paternity according to the risk of sperm competition that is associated with mate quality. PMID- 26255125 TI - The impact of interactions between algal organic matter and humic substances on coagulation. AB - This study focuses on the effects of molecular interactions between two natural organic matter (NOM) fractions, peptides/proteins derived from cyanobacterium Microcystis aeruginosa (MA proteins) and peat humic substances (HS), on their removal by coagulation. Coagulation behaviour was studied by the jar tests with MA protein/HS mixtures and with single compounds (MA proteins or HS). Aluminium sulphate was used as a coagulant. Besides MA proteins, bovine serum albumin (BSA) was used as a model protein. For the MA protein/HS mixture, the removal rates were higher (80% versus 65%) and the dose of coagulant substantially lower (2.8 versus 5.5 mg L(-1) Al) than for coagulation of single HS, indicating the positive effect of protein-HS interactions on the coagulation process. The optimum coagulation pH was 5.2-6.7 for MA proteins and 5.5-6 for HS by alum. The optimum pH for the removal of MA protein/HS mixture ranged between pH 5.5-6.2, where the charge neutralization of negatively charged acidic functional groups of organic molecules by positively charged coagulant hydroxopolymers lead to coagulation. MA proteins interacted with HS, probably through hydrophobic, dipole dipole and electrostatic interactions, even in the absence the coagulant. These interactions are likely to occur within a wide pH range, but they result in coagulation only at low pH values (pH < 4). At this pH, the negative charge of both MA proteins and HS was suppressed due to the protonation of acidic functional groups and thus the molecules could approach and combine forming aggregates. Virtually the same trends were observed in the experiments with HS and BSA, indicating that BSA is a suitable model for MA proteins under experimental conditions used in this study. The study showed that increases in organic content in source water due to the release of algae products may not necessarily entail deterioration of the coagulation process and a rise in coagulant demand. PMID- 26255126 TI - Reagent use efficiency with removal of nitrogen from pig slurry via struvite: A study on magnesium oxide and related by-products. AB - Controlled struvite formation has been attracting increasing attention as a near mature technology to recover nutrients from wastewater. However, struvite feasibility is generally limited by the high cost of chemical reagents. With the aim to understand and control reagent use efficiency, experiments and equilibrium model simulations examined inorganic nitrogen (TAN) removal from pig manure via struvite with added magnesium and phosphate reagents. Four industrial magnesium oxide (MgO), a commercial product and three by-products from magnesite calcination, were tested with phosphate added as a highly soluble potassium salt. TAN removal extents with the MgOs ranged from 47 to 72%, with the highest grade MgO providing the greatest extent of TAN removal. However, model analysis showed that all the MgO reagents were poorly soluble (only about 40% of added magnesium actually dissolved). The model results suggested that this poor dissolution was due to kinetic limitations, not solubility constraints. A further set of additional reagents (termed stabilization agents) were prepared by pre-treating the MgO reagents with phosphoric acid, and were tested separately as a source of both magnesium and phosphate. Results showed that acid pre-treatment of moderate to highly reactive MgOs (soft to medium-burnt) primarily formed bobierrite as the stabilizing agent, whereas the pre-treatment of very low reactivity MgOs (dead burnt) mostly formed newberyite. The newberyite stabilizing agents achieved very high TAN removal extents of about 80%, which is significant, considering that these were formed from dead-burnt/low-grade MgOs. However, the bobierrite stabilizing agents achieved a substantially lower TAN removal extent than their medium-to-high reactivity precursor MgOs. Again, model analysis showed that the bobierrite stabilizing agents were poorly soluble, due to kinetic limitations, not solubility constraints. In contrast, the model suggested that the newberyite stabilizing agents almost completely dissolved to very effectively form struvite. A mechanism was proposed by which conditions near a dissolving reagent particle surface causes unwanted struvite nucleation onto and overgrowth of the reagent particle, inhibiting further dissolution and markedly reducing reagent efficiency. The findings of the study could have implications for reagent efficiency with struvite in general, even when using other solid reagents such as magnesium hydroxide or other MgOs. PMID- 26255127 TI - Effect of advanced oxidation processes on the micropollutants and the effluent organic matter contained in municipal wastewater previously treated by three different secondary methods. AB - In this study, wastewater from the output of three different secondary treatment facilities (Activated Sludge, Moving Bed Bioreactor and Coagulation-Flocculation) present in the municipal wastewater treatment plant of Vidy, Lausanne (Switzerland), was further treated with various oxidation processes (UV, UV/H2O2, solar irradiation, Fenton, solar photo-Fenton), at laboratory scale. For this assessment, 6 organic micropollutants in agreement with the new environmental legislation requirements in Switzerland were selected (Carbamazepine, Clarithromycin, Diclofenac, Metoprolol, Benzotriazole, Mecoprop) and monitored throughout the treatment. Also, the overall removal of the organic load was assessed. After each secondary treatment, the efficiency of the AOPs increased in the following order: Coagulation-Flocculation < Activated Sludge < Moving Bed Bioreactor, in almost all cases. From the different combinations tested, municipal wastewater subjected to biological treatment followed by UV/H2O2 resulted in the highest elimination levels. Wastewater previously treated by physicochemical treatment demonstrated considerably inhibited micropollutant degradation rates. The degradation kinetics were determined, yielding: k (UV) < k (UV/H2O2) and k (Fenton) < k (solar irradiation) < k (photo-Fenton). Finally, the evolution of global pollution parameters (COD & TOC elimination) was followed and the degradation pathways for the effluent organic matter are discussed. PMID- 26255128 TI - Groundwater control of biogeochemical processes causing phosphorus release from riparian wetlands. AB - Because of the high sorption affinity of phosphorus (P) for the soil solid phase, mitigation options to reduce diffuse P transfer usually focus on trapping particulate P delivered via surface flow paths. Therefore, placing riparian buffers between croplands and watercourses has been promoted worldwide, sometimes in wetland areas. To investigate the risk of P-accumulating riparian wetlands (RWs) releasing dissolved P into streams, we monitored molybdate-reactive P (MRP) in the soil pore water of two RWs in an agricultural watershed. Two main mechanisms released MRP under the control of groundwater dynamics. First, soil rewetting after the dry summer period was associated with the presence of a pool of mobile P, limited in size. Its mobilization started under water saturated conditions caused by a rise in groundwater. Second, anoxic conditions at the end of winter caused reductive dissolution of Fe (hydr)oxides along with a release of MRP. Comparison of sites revealed that the first MRP release occurred only in RWs with P-enriched soils, whereas the second was observed even in RWs with low soil P status. Seasonal variations in stream MRP concentrations were similar to concentrations in RW soils. Hence, RWs can act as a key component of the P transfer continuum in agricultural landscapes by converting particulate P from croplands into MRP transferred to streams. PMID- 26255129 TI - A hybrid process of biofiltration of secondary effluent followed by ozonation and short soil aquifer treatment for water reuse. AB - The Shafdan reclamation project facility (Tel Aviv, Israel) practices soil aquifer treatment (SAT) of secondary effluent with hydraulic retention times (HRTs) of a few months to a year for unrestricted agricultural irrigation. During the SAT, the high oxygen demand (>40 mg L(-1)) of the infiltrated effluent causes anoxic conditions and mobilization of dissolved manganese from the soil. An additional emerging problem is the occurrence of persistent trace organic compounds (TrOCs) in reclaimed water that should be removed prior to reuse. An innovative hybrid process based on biofiltration, ozonation and short SAT with ~22 d HRT is proposed for treatment of the Shafdan secondary effluent to overcome limitations of the existing system and to reduce the SAT's physical footprint. Besides efficient removal of particulate matter to minimize clogging, coagulation/flocculation and filtration (5-6 m h(-1)) operated with the addition of hydrogen peroxide as an oxygen source efficiently removed dissolved organic carbon (DOC, to 17-22%), ammonium and nitrite. This resulted in reduced effluent oxygen demand during infiltration and oxidant (ozone) demand during ozonation by 23 mg L(-1) and 1.5 mg L(-1), respectively. Ozonation (1.0-1.2 mg O3 mg DOC(-1)) efficiently reduced concentrations of persistent TrOCs and supplied sufficient dissolved oxygen (>30 mg L(-1)) for fully oxic operation of the short SAT with negligible Mn(2+) mobilization (<50 MUg L(-1)). Overall, the examined hybrid process provided DOC reduction of 88% to a value of 1.2 mg L(-1), similar to conventional SAT, while improving the removal of TrOCs and efficiently preventing manganese dissolution. PMID- 26255130 TI - Rhamnogalacturonan I modifying enzymes: an update. AB - Rhamnogalacturonan I (RGI) modifying enzymes catalyse the degradation of the RGI backbone and encompass enzymes specific for either the alpha1,2-bond linking galacturonic acid to rhamnose or the alpha1,4-bond linking rhamnose to galacturonic acid in the RGI backbone. The first microbial enzyme found to be able to catalyse the degradation of the RGI backbone, an endo-hydrolase (EC 3.2.1.171) derived from Aspergillus aculeatus, was discovered 25 years ago. Today the group of RGI modifying enzymes encompasses endo- and exo-hydrolases as well as lyases. The RGI hydrolases, EC 3.2.1.171-EC 3.2.1.174, have been described to be produced by Aspergillus spp. and Bacillus subtilis and are categorized in glycosyl hydrolase families 28 and 105. The RGI lyases, EC 4.2.2.23-EC 4.2.2.24, have been isolated from different fungi and bacterial species and are categorized in polysaccharide lyase families 4 and 11. This review brings together the available knowledge of the RGI modifying enzymes and provides a detailed overview of biocatalytic reaction characteristics, classification, structure-function traits, and analyses the protein properties of these enzymes by multiple sequence alignments in neighbour-joining phylogenetic trees. Some recently detected unique structural features and dependence of calcium for activity of some of these enzymes (notably the lyases) are discussed and newly published results regarding improvement of their thermostability by protein engineering are highlighted. Knowledge of these enzymes is important for understanding microbial plant cell wall degradation and for advancing enzymatic processing and biorefining of pectinaceous plant biomass. PMID- 26255131 TI - Biofertilization with Azospirillum brasilense improves in vitro culture of Handroanthus ochraceus, a forestry, ornamental and medicinal plant. AB - Biofertilization with plant growth-promoting rhizobacteria is a potential alternative to plant productivity. Here, in vitro propagation of Handroanthus ochraceus (yellow lapacho), a forest crop with high economic and environmental value, was developed using the Azospirillum brasilense strains Cd and Az39 during rhizogenesis. Epicotiles of in vitro plantlets were multiplied in Woody Plant Medium (WPM). For rooting, elongated shoots were transferred to auxin-free Murashige-Skoog medium with Gamborg's vitamins and WPM, both at half salt concentration (1/2MSG and 1/2WPM), and inoculated with Cd or Az39 at the base of each shoot. Anatomical studies were performed using leaves cleared and stained with safranin for optical microscopy and leaves and roots metalized with gold palladium for scanning electron microscopy (SEM). In 1/2WPM auxin-free medium, A. brasilense Cd inoculation produced 55% of rooting, increased root fresh and dry weight (45% and 77%, respectively), and led to lower stomata size and density with similar proportion of open and closed stomata. Both strains selectively increased the size or density of glandular trichomes in 1/2MSG. Moreover, bacteria were detected on the root surface by SEM. In conclusion, the difference in H. ochraceus response to A. brasilense inoculation depends on the strain and the plant culture media. Cd strain enhanced rooting in auxin-free 1/2WPM and produced plantlets with features similar to those expected in ex vitro plants. This work presents an innovative in vitro approach using beneficial plant microorganism interaction as an ecologically compatible strategy in plant biotechnology. PMID- 26255132 TI - Measuring the micromechanical properties of embryonic tissues. AB - Local mechanical properties play an important role in directing embryogenesis, both at the cell (differentiation, migration) and tissue level (force transmission, organ formation, morphogenesis). Measuring them is a challenge as embryonic tissues are small (MUm to mm) and soft (0.1-10 kPa). We describe here how glass fiber cantilevers can be fabricated, calibrated and used to apply small forces (0.1-10 MUN), measure contractile activity and assess the bulk tensile elasticity of embryonic tissue. We outline how pressure (hydrostatic or osmotic) can be applied to embryonic tissue to quantify stiffness anisotropy. These techniques can be assembled at low cost and with a minimal amount of equipment. We then present a protocol to prepare tissue sections for local elasticity and adhesion measurements using the atomic force microscope (AFM). We compare AFM nanoindentation maps of native and formaldehyde fixed embryonic tissue sections and discuss how the local elastic modulus obtained by AFM compares to that obtained with other bulk measurement methods. We illustrate all of the techniques presented on the specific example of the chick embryonic digestive tract, emphasizing technical issues and common pitfalls. The main purpose of this report is to make these micromechanical measurement techniques accessible to a wide community of biologists and biophysicists. PMID- 26255133 TI - High Resolution Melting-Typing (HRMT) of methicillin-resistant Staphylococcus aureus (MRSA): The new frontier to replace multi-locus sequence typing (MLST) for epidemiological surveillance studies. AB - We report an implemented molecular-typing-method based on HRMA to detect SNPs within MLST loci, characterizing 100 clinical MRSA and 11 control strains, representative of Italian clones. The results provide solid evidence that HRMT could be a fast, cost-effective and reliable alternative to MLST, for MRSA molecular epidemiology. PMID- 26255134 TI - Comparison of knee flexion isokinetic deficits between seated and prone positions after ACL reconstruction with hamstrings graft: Implications for rehabilitation and return to sports decisions. AB - OBJECTIVES: Hamstrings grafts are commonly used in ACL reconstruction, however, the effect of graft harvesting on knee flexion strength has not been longitudinally evaluated in functional positions. We hypothesized that greater deficits in knee flexion strength exist in the prone compared to the seated position and these deficits remain as rehabilitation progresses. DESIGN: Case series. METHODS: Forty-two consecutive patients who underwent ACL reconstruction with a hamstrings graft were followed prospectively for 9 months. Isokinetic knee flexion strength at a slow and a fast speed were collected at 3, 4, 6, and 9 months in two different positions: conventional (seated) and functional (0 degrees of hip flexion). RESULTS: Peak torque knee flexion deficits were higher in the prone position compared to the seated position by an average of 6.5% at 60 degrees /s and 9.1% at 180 degrees /s (p<0.001). CONCLUSIONS: Measuring knee flexion strength in prone demonstrates higher deficits than in the conventional seated position. Most athletes would not be cleared to return to sports even at 9 months after surgery with this method. PMID- 26255135 TI - HOTAIR inhibited intracellular Ca2+ via regulation of Cav1.2 channel in human cardiomyocytes. AB - HOTAIR, a long non—coding RNA (lncRNA), is reported to regulate chromatin organization and promote tumor progression. However, little is known about the roles of this gene in the modulation of calcium homeostasis in human cardiomyocytes. In the present study, we demonstrated that up—regulation of HOTAIR could suppress the expression of CaV1.2 in human cardiomyocytes. However, HOTAIR knockdown promoted CaV1.2 expression in human cardiomyocytes. In addition, we found that HOTAIR overexpression significantly reduced the intracellular Ca2+ contents; while knockdown of HOTAIR enhanced the Ca2+ contents in the cardiomyocytes. Moreover, enforced expression of CaV1.2 increased the calcium level in cardiomyocytes overexpressing HOTAIR. down—regulation of HOTAIR and up—regulation of CaV1.2 further enhanced the Ca2+ contents in the cardiomyocytes Taken together, these results for the first time demonstrate that HOTAIR inhibited the intracellular Ca2+ via regulation of CaV1.2 in human cardiomyocytes. PMID- 26255136 TI - MicroRNA profiling during germline differentiation of mouse embryonic stem cells. AB - MicroRNAs are new classes of small non—coding regulatory RNAs which control degradation or suppress translation of its target mRNAs by sequence complementarity. Mature microRNAs are enriched in embryonic stem cells and play important roles in controlling stem cell self—renewal as well as control of differentiation. There is significant evidence that microRNAs are involved in the regulation of stem cell differentiation. The male mouse Embryonic Stem Cell line C57BL6/J with normal karyotype 46, XY was used for profiling microRNA expression in undifferentiated mouse embryonic stem cells (mESCs) and mESCs which were differentiated to germ line cells to determine and compare differences in microRNA expression before and after differentiation. Also, testis tissue samples of a 5—day—old mouse and a mature mouse was used as in vivo control. Profiling was performed by quantitative real—time PCR using locked nucleic acid microRNA—specific LNATM—enhanced primers. After data analysis and comparison of results profiled microRNAs expression, three microRNAs, mmu—miR—21, mmu—miR—21* and mmu—miR—16 showed 50.31, 43.76 and 46.77—fold change increase of expression, respectively, in differentiated mESCs in comparison with undifferentiated state with significant p—value (Average p—value p<0.001 for each members of microRNAs). Expression of Let—7 microRNA family increased in differentiated state when compared with undifferentiated mESCs (Average p—value<0.0001 for each members of family). The levels of expression all other profiled microRNAs were significantly higher in undifferentiated in comparison with differentiated mESCs and their expression was down regulated after differentiation. (Average p—value <0.003 for each members of microRNAs). PMID- 26255137 TI - Human Toll like receptor 4 gene expression of PBMCs in diabetes mellitus type 2 patients. AB - Toll like receptor 4 (TLR4) is one of the most pivotal pathogen recognition receptors (PRRs) in innate immune systems. In this study, we evaluate the expression of the TLR4 in patients with diabetes mellitus type 2 (DM2) in comparison to healthy controls. Expression of TLR4 in 32 human peripheral blood mononuclear cells (PBMCs) of patients with DM2 and 20 control samples was assessed using Real—Time PCR technique. For each patient, body mass index (BMI) and blood glucose levels were measured. The results of Real—Time PCR showed a 5—folds increase in expression of TLR4 on the PBMCs of DM2 patients in comparison to controls. No correlation was observed between the TLR4 expression and sex or BMI. Our results confirmed that DM2 can increase TLR4 expression independent from sex, blood glucose concentrations and BMI. PMID- 26255138 TI - Angiotensin II Promotes Atherogenesis through upregulating the Expression of Connexin 43 in Dendritic Cells. AB - It is known, for a long time, that angiotensin II (Ang II) could contribute to atherogenesis (AS) and plaque vulnerability, however the underlying mechanisms are poorly understood. Dendritic cells (DCs) are critical for the development of both inflammation and atherogenesis. In the present study, we tried to investigate the influence of AngII on the expression of connexin43 (Cx43) in DCs, as well as the effect of AngII on AS. After mouse bone marrow—derived dendritic cells (BMDCs) were treated by Ang II with or without Valsartan, the expression of Cx43 was quantified by Western Blots. The expression of Cx43 and CD40 (one marker of DCs) of DCs derived from AS plaques of ApoE—/— mice was detected by immunohistochemistry double staining. The morphology of atherosclerotic plaque was indicated by immunohistochemistry staining of smooth muscle cells. The expression of Cx43 (P < 0.05) was increased significantly in mouse BMDCs after treatment with AngII. In atherosclerotic plaques from ApoE—/— mice expressing high levels of endogenous AngII, upregulation of Cx43 (P < 0.01) and CD40 (P < 0.01) was observed. The upregulation and pro—atherogenesis effect of Cx43 could be blocked by the AngII type 1 receptor blocker Valsartan, both in vitro and in vivo. AngII may promote atherosclerosis and plaque vulnerability by increasing the expression of Cx43 in DCs and inducing the maturation of DCs through the angiotensin II type 1 receptor. PMID- 26255139 TI - Withaferin A attenuates lipopolysaccharide-induced acute lung injury in neonatal rats. AB - Withaferin A (WFA) is an active compound from Withania somnifera and has been reported to exhibit a variety of pharmacological activities such as anti—inflammatory, immunomodulatory and anti—tumor properties. In the present study, we investigated the potential protective role of WFA on acute lung injury in neonatal rats induced by lipopolysaccharide (LPS). We found that WFA significantly attenuated the pathological changes of lungs induced by LPS injection. Administration with WFA obviously decreased pulmonary neutrophil infiltration accompanied with decreased MPO concentrations. WFA also reduced the expression of pro—inflammatory cytokines including MIP—2, TNF—α, IL—1β and IL—6. Meanwhile, the expression levels of anti—inflammatory mediators such as TGF—β1 and IL—10 were significantly increased following WFA administration. Moreover, WFA protected LPS—treated rats from oxidative damage via up—regulation of TBARS and H2O2 concentrations and down—regulation of ROS contents. Taken together, the present study demonstrated that WFA administration attenuated LPS—induced lung injury through inhibition of inflammatory responses and oxidative stress. PMID- 26255140 TI - Different components of chicken ovalbumin extract promote different cell proliferation. AB - The chicken ovalbumin extracts could promote cell survival and proliferation. In the present study, the different components in chicken ovalbumin extracts were further separated to find the component primarily responsible for promoting cell proliferation. Components of differing molecular weight were separated from chicken ovalbumin extracts by ultrafiltration. Different components were co—cultured with different cells at different final concentrations, and the effects on cell proliferation were subsequently determined by a CellTiter 96 Aqueous One Solution Cell Proliferation Assay kit (Promega). Components from chicken ovalbumin extracts less than 3 kD in size can promote 293T cell and 293T—GFP cell proliferation. The components from chicken ovalbumin extract more than 3 kD in size can promote bone marrow or umbilical cord mesenchymal stem cell (MSC) proliferation. The separation of components from chicken ovalbumin less than and more than 3 kD in size that are able to function as active components for the promotion of different cellular proliferation. This discovery may identify a new and convenient additive for cell culture media, promoting cell growth and proliferation. PMID- 26255141 TI - Mining in subarctic Canada: airborne PM2.5 metal concentrations in two remote First Nations communities. AB - Airborne particulate matter arising from upwind mining activities is a concern for First Nations communities in the western James Bay region of Ontario, Canada. Aerosol chemical components were collected in 2011 from two communities in northern Ontario. The chemical and mass concentration data of particulate matter collected during this study shows a significant difference in PM2.5 in Attawapiskat compared to Fort Albany. Elemental profiles indicate enhanced levels of some tracers thought to arise from mining activities, such as, K, Ni, and crustal materials. Both communities are remote and isolated from urban and industrial pollution sources, however, Attawapiskat First Nation has significantly enhanced levels of particulate matter, and it is likely that some of this arises from upwind mining activities. PMID- 26255142 TI - "Rehabilitation will increase the 'capacity' of your ...insert musculoskeletal tissue here...." Defining 'tissue capacity': a core concept for clinicians. PMID- 26255143 TI - Recanalization of obstructed metallic uncovered biliary stent using endobiliary radiofrequency ablation. PMID- 26255144 TI - Early cecal cancer adjacent to the appendiceal orifice successfully treated by endoscopic submucosal dissection. PMID- 26255145 TI - Lumen-apposing metal stent for the treatment of refractory gastrojejunal anastomotic stricture after laparoscopic gastric bypass. PMID- 26255146 TI - On the effects of CP 55-940 and other cannabinoid receptor agonists in C6 and U373 cell lines. AB - Cannabinoid receptor (CBs) agonists affect the growth of tumor cells via activation of deadly cascades. The spectrum of action of these agents and the precise role of the endocannabinoid system (ECS) on oncogenic processes remain elusive. Herein we compared the effects of synthetic (CP 55-940 and WIN 55,212-2) and endogenous (anandamide or AEA) CBs agonists (10-20 MUM) on morphological changes, cell viability, and induction of apoptosis in primary astrocytes and in two glioblastoma cell lines (C6 and U373 cells) in order to characterize their possible differential actions on brain tumor cells. None of the CBs agonist tested induced changes in cell viability or morphology in primary astrocytes. In contrast, CP 55-940 significantly decreased cell viability in C6 and U373 cells at 5 days of treatment, whereas AEA and WIN 55,212-2 moderately decreased cell viability in both cell lines. Treatment of U373 and C6 for 3 and 5 days with AEA or WIN 55,212-2 produced discrete morphological changes in cell bodies, whereas the exposure to CP 55-940 induced soma degradation. CP 55-940 also induced apoptosis in both C6 and U373 cell lines. Our results support a more effective action of CP 55-940 to produce cell death of both cell lines through apoptotic mechanisms. Comparative aspects between cannabinoids with different profiles are necessary for the design of potential treatments against glial tumors. PMID- 26255147 TI - Pin tract infection of operatively treated supracondylar fractures in children: long-term functional outcomes and anatomical study. AB - PURPOSE: The purpose of our study was to determine the long-term functional outcomes of pin tract infection after percutaneous pinning of displaced supracondylar humeral fractures in children, and to evaluate the potential for intracapsular pin placement based on pin configuration in cadaveric elbows. METHODS: We conducted a retrospective review of all patients requiring percutaneous pinning in a single institution over a 19-year period. The functional outcome assessment consisted of a telephone interview using the Disabilities of the Arm, Shoulder and Hand (DASH)] Outcome Measure and the Patient-Rated Elbow Evaluation (PREE) questionnaires. The risk of intracapsular pin placement was studied in cadaveric elbows for the three most common pin configurations: divergent lateral, parallel lateral, and medial and lateral crossed pins. RESULTS: Of 490 children, 21 (4.3 %) developed pin tract infection. There were 15 (3.1 %) superficial and six (1.2 %) deep infections (osteomyelitis and septic arthritis). Both DASH and PREE scores were excellent at a mean of 18 years post-surgery. The risk of intracapsular pin placement using parallel lateral pins was found to be greater (p < 0.05) than either crossed or divergent lateral pinning configurations. CONCLUSIONS: Most infections after pinning of supracondylar humerus fractures are superficial and can be managed with pin removal, oral antibiotics, and local wound care. Septic arthritis and osteomyelitis are rare complications; when they do occur, they seem to be associated with parallel lateral pin configuration, though a causal relationship could not be established from the current study. Satisfactory long-term outcomes of these deep infections can be expected when treated aggressively with surgical debridement and intravenous antibiotics. PMID- 26255148 TI - Chiari III malformation: a comprehensive review of this enigmatic anomaly. AB - INTRODUCTION: Chiari III is one of the rarest of the Chiari malformations and is characterized by a high cervical or low occipital encephalocele and osseous defect with or without spinal cord involvement and may include many of the anatomical characteristics seen in the Chiari II malformation. Herein, we provide a comprehensive review of this rare anomaly as well as a translation of Chiari's original description. METHODS: We review all reported cases of Chiari III malformation found in the extant literature. CONCLUSIONS: Out of 57 reported cases of Chiari III malformation, encephaloceles were in a high cervical/low occipital position in 23, 8 were in a high cervical position, 17 were in low occipital position, and the position in 9 cases was not reported. The pathogenesis of Chiari III malformation remains unclear. The majority of patients have concomitant hydrocephalus. Brain parts occurring in the sac from the most to least common include the following: cerebellum, occipital lobe, and parietal lobe. The severity of symptoms is correlated with the amount of brain structures within the encephalocele. Neurologic functional outcomes have been varied and depend on the neurological status of the patient before surgery. PMID- 26255149 TI - Congenital left temporal large arachnoid cyst causing intraorbital optic nerve damage in the second decade of life. AB - AIM: Intracranial sylvian arachnoid cysts are often asymptomatic lesions. We present a 16-year-old female patient with progressive loss of vision together with an unusual visual field defect on the left eye accompanied by headache. METHOD: A left frontotemporal sylvian arachnoid cyst was known since she was 9 months old, but observed ever since in the asymptomatic patient. Now, ophthalmological examination revealed bi-upper quadrant anopia on the left eye. Magnetic resonance imaging (MRI) and computed tomography showed erosion of the lateral orbital wall associated with intraorbital compression of the optic nerve by the cyst at the entrance into the optic canal. Microsurgical cyst fenestration to the basal cisterns was performed using a temporal mini-craniotomy. RESULT: Full improvement of vision and visual field defects was observed in the follow up. On postoperative MRI, an increase of the tissue surrounding the optic nerve in the conus and better delineation at the entrance of optic canal was noted. CONCLUSION: Long-standing asymptomatic sylvian arachnoid cysts may suddenly produce severe unilateral visual deficits if the cyst erodes the lateral orbital wall. These deficits may rapidly revert to normal if surgical action is not delayed. If surveillance MRIs of sylvian arachnoid cysts show a narrowing of the conus diameter compared to the contralateral side, a yearly ophthalmological surveillance examination seems to be warranted in else wise asymptomatic patients. PMID- 26255150 TI - Subdural haematoma following infant spinal anaesthesia. AB - INTRODUCTION: Subdural haematoma (SDH) is rare following spinal anaesthesia and has not been reported previously in an infant. Non-accidental injury is the commonest cause of subdural haematoma in infants. METHODS: We describe two cases of SDH following spinal anaesthesia in infants. RESULTS: In both cases, forensic investigation was commenced and no evidence of child abuse was found. Both children are well 2 years after diagnosis. CONCLUSION: Paediatric health workers should be aware of the possibility of SDH after spinal anaesthesia and consider this as a differential diagnosis when investigating possible non-accidental injury in an infant. PMID- 26255151 TI - Reply to: Familial syndromes associated with intracranial tumours: a review. PMID- 26255152 TI - Adolescent nicotine exposure fails to impact cocaine reward, aversion and self administration in adult male rats. AB - The present experiments examined the effects of adolescent nicotine pre-exposure on the rewarding and aversive effects of cocaine and on cocaine self administration in adult male rats. In Experiment 1, adolescent Sprague-Dawley rats (postnatal days 28-43) were given once daily injections of nicotine (0.6mg/kg) or vehicle and then tested for the aversive and rewarding effects of cocaine in a combined conditioned taste avoidance (CTA)/conditioned place preference (CPP) procedure in adulthood. In Experiment 2, adolescent Sprague Dawley rats were pre-exposed to nicotine then tested for cocaine self administration (0.25 or 0.75mg/kg), progressive ratio (PR) responding, extinction and cue-induced reinstatement in adulthood. In Experiment 1, rats showed significant dose-dependent cocaine-induced taste avoidance with cocaine-injected subjects consuming less saccharin over trials, but no effect of nicotine pre exposure. For place preferences, cocaine induced significant place preferences with cocaine injected subjects spending significantly more time on the cocaine paired side, but again there was no effect of nicotine history. All rats in Experiment 2 showed clear, dose-dependent responding during cocaine acquisition, PR testing, extinction and reinstatement with no effect of nicotine pre-exposure. These studies demonstrate that adolescent nicotine pre-exposure does not have an impact on cocaine's affective properties or its self-administration at least with the specific parametric conditions under which these effects were tested. PMID- 26255154 TI - Modulation of morphine antinociceptive tolerance and physical dependence by co administration of simvastatin. AB - Statins, 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors, are widely used in the management of different diseases beyond their primary indication for lowering cholesterol. Previous studies have demonstrated the neuroprotective effects of simvastatin in different animal models. In the present study, we examined the effects of simvastatin (30, 60, 100 and 300mg/kg, p.o.) on the development and expression of morphine-induced tolerance and dependence in mice. For the induction of morphine tolerance and dependence, mice were twice daily treated with morphine (10mg/kg, s.c.) for 5 consecutive days. Tolerance was evaluated by the hot-plate test and physical dependence by naloxone challenge, on the sixth day. The results showed that oral administration of simvastatin produced antinociceptive activity in a dose-dependent way. Co-administration of simvastatin with morphine did not affect the acute morphine-induced analgesia (10mg/kg, s.c.). However, repeated co-administration of simvastatin with morphine significantly attenuated the development of tolerance to the analgesic effect of morphine and inhibited the naloxone (5mg/kg, s.c.)-precipitated withdrawal signs (jumping and body weight loss). Also, simvastatin at doses of 100 and 300mg/kg attenuated the expression of morphine-induced tolerance and dependence. These data indicated that, while simvastatin can alleviate both development and expression of morphine-induced tolerance, it cannot enhance morphine-induced antinociception. Taken together, simvastatin may be used as an adjutant therapeutic agent in combination with morphine and or other opioids in patients with severe chronic pain. PMID- 26255153 TI - Differential interactions engendered by benzodiazepine and neuroactive steroid combinations on schedule-controlled responding in rats. AB - Benzodiazepines are positive allosteric modulators of the GABAA receptor and are prescribed as anxiolytics, hypnotics, and anticonvulsants. While these drugs clearly have clinical value, their use is associated with unwanted side effects such as sedation and motor impairment. Neuroactive steroids are endogenous modulators of GABAA receptors and recent evidence has shown that combinations of the triazolo-benzodiazepine triazolam and the endogenous neuroactive steroid pregnanolone can produce both supra-additive anxiolytic effects and infra additive reinforcing effects. In the present study, we investigated these same combinations as well as combinations of two clinically-relevant drugs from different chemical classes, the 1, 4 substituted (7-nitro) benzodiazepine clonazepam and the synthetic neuroactive steroid ganaxolone, in rats trained under a 10-response, fixed ratio (FR) schedule of food reinforcement. All four drugs induced a significant and dose-dependent suppression of food-maintained responding. From the dose-response functions, ED50s (i.e., the doses that engendered 50% of the maximum rate-decreasing effect) were generated for each drug. Dose-response functions for combinations of triazolam/pregnanolone, clonazepam/ganaxolone, triazolam/ganaxolone, and clonazepam/pregnanolone were then determined. Isobolographic analysis of the rate-decreasing effects of these combinations revealed that the potencies of the triazolam/pregnanolone combinations were supra-additive while the clonazepam/ganaxolone combinations were additive or infra-additive in relation to predicted values based on dose additive effects. Furthermore, mixtures of clonazepam/pregnanolone were supra additive while triazolam/ganaxolone combinations were additive, infra-additive and supra-additive. These results suggest that the ability of benzodiazepine and neuroactive steroid combinations to attenuate rates of food-maintained responding depends critically on both the constituent drugs and the dose of drug in the mixtures. PMID- 26255155 TI - Neuropeptide Y family receptors Y1 and Y2 from sea lamprey, Petromyzon marinus. AB - The vertebrate gene family for neuropeptide Y (NPY) receptors expanded by duplication of the chromosome carrying the ancestral Y1-Y2-Y5 gene triplet. After loss of some duplicates, the ancestral jawed vertebrate had seven receptor subtypes forming the Y1 (including Y1, Y4, Y6, Y8), Y2 (including Y2, Y7) and Y5 (only Y5) subfamilies. Lampreys are considered to have experienced the same chromosome duplications as gnathostomes and should also be expected to have multiple receptor genes. However, previously only a Y4-like and a Y5 receptor have been cloned and characterized. Here we report the cloning and characterization of two additional receptors from the sea lamprey Petromyzon marinus. Sequence phylogeny alone could not with certainty assign their identity, but based on synteny comparisons of P. marinus and the Arctic lamprey, Lethenteron camtschaticum, with jawed vertebrates, the two receptors most likely are Y1 and Y2. Both receptors were expressed in human HEK293 cells and inositol phosphate assays were performed to determine the response to the three native lamprey peptides NPY, PYY and PMY. The three peptides have similar potencies in the nanomolar range for Y1. No obvious response to the three peptides was detected for Y2. Synteny analysis supports identification of the previously cloned receptor as Y4. No additional NPY receptor genes could be identified in the presently available lamprey genome assemblies. Thus, four NPY-family receptors have been identified in lampreys, orthologs of the same subtypes as in humans (Y1, Y2, Y4 and Y5), whereas many other vertebrate lineages have retained additional ancestral subtypes. PMID- 26255156 TI - Engagement in group sex among geosocial networking mobile application-using men who have sex with men. AB - BACKGROUND: Men who have sex with men (MSM) remain the group most affected by the HIV epidemic in the United States. At least one-quarter of MSM report engagement in group sex events (GSEs), which can pose a risk for HIV transmission and acquisition. In this study, identification of event-level correlates of sexual and drug use behaviours at GSEs was sought to better inform prevention activities. METHODS: For this study, participants were recruited via banner and pop-up advertisements placed on a geosocial networking mobile phone application that MSM use to meet men. RESULTS: Of the 1997 individuals who completed the study screener, 36.0% reported participating in at least one GSE in the prior year. In multivariable logistic regression analysis, attendance at a GSE in the past year was significantly associated with older age, full/part time employment and being HIV positive. Of the men who attended a GSE, more than half reported condomless anal sex (CAS) with at least one of their partners (insertive: 57.7%; receptive: 56.3%). MSM who indicated drug use had significantly higher odds of having insertive CAS [odds ratio (OR)=2.45; 95% confidence interval (CI): 1.37 4.39] and receptive CAS (OR=3.60; 95% CI: 1.96-6.63) at their last GSE. CONCLUSIONS: The high prevalence of HIV-positive MSM engaging in group sex, coupled with their greater odds of CAS, poses a significant risk for HIV/STI transmission within the group sex setting. More research is needed to determine patterns of condom use at these events and whether seroadaptive behaviours are driving CAS. PMID- 26255157 TI - Pheromone-Mediated Mate Location and Discrimination by Two Syntopic Sibling Species of Dendroctonus Bark Beetles in Chiapas, Mexico. AB - Where their geographic and host ranges overlap, sibling species of tree-killing bark beetles may simultaneously attack and reproduce on the same hosts. However, sustainability of these potentially mutually beneficial associations demands effective prezygotic reproductive isolation mechanisms between the interacting species. The pine bark beetle, Dendroctonus frontalis Zimmermann, is syntopic in the Central American region with a recently described sibling species, Dendroctonus mesoamericanus Armendariz-Toledano and Sullivan, but mechanisms for their reproductive isolation are uncertain. We investigated whether semiochemicals mediate species discrimination by mate-seeking males of both species. In olfactometer bioassays, walking males of both species strongly preferred odors from gallery entrances of conspecific females. Coupled gas chromatography-electroantennographic detection and gas chromatography-mass spectrometry isolated 16 olfactory stimulants for males in these odors, but only two, ipsdienol and endo-brevicomin (both from D. mesoamericanus females), differed in quantity in female-associated odors between the species. In olfactometer bioassays, with 10, 1, or 0.1 female entrance equivalents of synthetic semiochemicals, the combination of ipsdienol and endo-brevicomin inhibited responses of male D. frontalis and enhanced responses of male D. mesoamericanus to two compounds associated with female entrances of both species (the pheromone component frontalin and host odor alpha-pinene). We conclude that ipsdienol and endo-brevicomin, pheromone components produced by females of just one of the two species (D. mesoamericanus), mediate interspecific mate discrimination by males of both species and provide an apparently symmetrical reproductive isolation mechanism. PMID- 26255158 TI - A methodological evaluation and predictive in silico investigation into the multi functionality of arginine in directly compressed tablets. AB - The acceleration of solid dosage form product development can be facilitated by the inclusion of excipients that exhibit poly-/multi-functionality with reduction of the time invested in multiple excipient optimisations. Because active pharmaceutical ingredients (APIs) and tablet excipients present diverse densification behaviours upon compaction, the involvement of these different powders during compaction makes the compaction process very complicated. The aim of this study was to assess the macrometric characteristics and distribution of surface charges of two powders: indomethacin (IND) and arginine (ARG); and evaluate their impact on the densification properties of the two powders. Response surface modelling (RSM) was employed to predict the effect of two independent variables; Compression pressure (F) and ARG percentage (R) in binary mixtures on the properties of resultant tablets. The study looked at three responses namely; porosity (P), tensile strength (S) and disintegration time (T). Micrometric studies showed that IND had a higher charge density (net charge to mass ratio) when compared to ARG; nonetheless, ARG demonstrated good compaction properties with high plasticity (Y=28.01MPa). Therefore, ARG as filler to IND tablets was associated with better mechanical properties of the tablets (tablet tensile strength (sigma) increased from 0.2+/-0.05N/mm(2) to 2.85+/-0.36N/mm(2) upon adding ARG at molar ratio of 8:1 to IND). Moreover, tablets' disintegration time was shortened to reach few seconds in some of the formulations. RSM revealed tablet porosity to be affected by both compression pressure and ARG ratio for IND/ARG physical mixtures (PMs). Conversely, the tensile strength (sigma) and disintegration time (T) for the PMs were influenced by the compression pressure, ARG ratio and their interactive term (FR); and a strong correlation was observed between the experimental results and the predicted data for tablet porosity. This work provides clear evidence of the multi-functionality of ARG as filler, binder and disintegrant for directly compressed tablets. PMID- 26255159 TI - Imaging findings in fetal diaphragmatic abnormalities. AB - Imaging plays a key role in the detection of a diaphragmatic pathology in utero. US is the screening method, but MRI is increasingly performed. Congenital diaphragmatic hernia is by far the most often diagnosed diaphragmatic pathology, but unilateral or bilateral eventration or paralysis can also be identified. Extralobar pulmonary sequestration can be located in the diaphragm and, exceptionally, diaphragmatic tumors or secondary infiltration of the diaphragm from tumors originating from an adjacent organ have been observed in utero. Congenital abnormalities of the diaphragm impair normal lung development. Prenatal imaging provides a detailed anatomical evaluation of the fetus and allows volumetric lung measurements. The comparison of these data with those from normal fetuses at the same gestational age provides information about the severity of pulmonary hypoplasia and improves predictions about the fetus's outcome. This information can help doctors and families to make decisions about management during pregnancy and after birth. We describe a wide spectrum of congenital pathologies of the diaphragm and analyze their embryological basis. Moreover, we describe their prenatal imaging findings with emphasis on MR studies, discuss their differential diagnosis and evaluate the limits of imaging methods in predicting postnatal outcome. PMID- 26255160 TI - Azobenzene-aminoglycoside: Self-assembled smart amphiphilic nanostructures for drug delivery. AB - Here, we have designed and synthesized a novel cationic amphiphilic stimuli responsive azobenzene-aminoglycoside (a small molecule) conjugate, Azo-AG 5, and characterized it by UV and FTIR. Light responsive nature of Azo-AG 5 was assessed under UV-vis light. Self- assembly of Azo-AG 5 in aqueous solutions into nanostructures and their ability to act as drug carrier were also investigated. The nanostructures of Azo-AG 5 showed average hydrodynamic diameter of ~ 255 nm with aminoglycoside moiety (neomycin) and 4-dimethylaminoazobenzene forming hydrophilic shell and hydrophobic core, respectively. In the hydrophobic core, eosin and aspirin were successfully encapsulated. Dynamic light scattering (DLS) measurements demonstrated that the nanoassemblies showed expansion and contraction on successive UV and visible light irradiations exhibiting reversible on-off switch for controlling the drug release behavior. Similar behavior was observed when these nanostructures were subjected to pH-change. In vitro drug release studies showed a difference in UV and visible light-mediated release pattern. It was observed that the release rate under UV irradiation was comparatively higher than that observed under visible light. Further, azoreductase-mediated cleavage of the azo moiety in Azo-AG 5 nanoassemblies resulted in the dismantling of the structures into aggregated microstructures. Azo-AG 5 nanostructures having positive surface charge (+9.74 mV) successfully interacted with pDNA and retarded its mobility on agarose gel. Stimuli responsiveness of nanostructures and their on-off switch like behavior ensure the great potential as controlled drug delivery systems and in other biomedical applications such as colon-specific delivery and gene delivery. PMID- 26255161 TI - Toward bioactive yet antibacterial surfaces. AB - The fabrication of antibacterial yet biocompatible and bioactive surfaces is a challenge that biological and biomedical community has faced for many years, while no "dream material" has been developed so far. The primary goal of this study was to establish an optimal range of Ag concentration and its state of agglomeration in bioactive nanocomposite TiCaPCON films which would provide a strong bactericidal effect without compromising the material biocompatibility and bioactivity. To obtain samples with different Ag content and redistribution, two different methods were employed: (i) TiCaPCON films deposition by magnetron sputtering of composite TiS0.5-Ca3(RO4)2 target followed by Ag(+) ion implantation and (ii) Ag-doped TiCaPCON films obtained by co-sputtering of composite TiS0.5-Ca3(RO4)2 and Ag targets. In order to reveal the antibacterial role of Ag nanoparticles and Ag(+) ions, both separate and in synergy, part of the samples from the first and second groups was subjected to additional ion etching to remove an Ag rich surface layer heavily populated with Ag nanoparticles. All resultant films were characterized with respect to surface morphology, chemical composition, surface roughness, wettability, and Ag(+) ion release. The antibacterial and antifungal effects of the Ag-doped TiCaPCON films were evaluated against clinically isolated Escherichia coli O78 (E. coli) and Neurospora crassa wt-987 spores. The influence of the surface chemistry on spreading, proliferation, and early stages of MC3T3-E1 osteoblastic cell differentiation was also studied. Our data demonstrated that under optimal conditions in terms of Ag content and agglomeration, the Ag-doped TiCaPCON films are highly efficient against E. coli bacteria and, at the same time, provide good adhesion, spreading, proliferation and differentiation of osteoblastic cells which reflect high level of biocompatibility and bioactivity of the films. The influence of Ag(+) ions and nanoparticles on the MC3T3-E1 osteoblastic cells and E. coli bacteria is also discussed. PMID- 26255162 TI - Structural analysis of doxorubicin-polymer conjugates. AB - Synthetic polymers poly(ethylene glycol) (PEG), methoxypoly (ethylene glycol) polyamidoamine (mPEG-PAMAM-G3) and polyamidoamine (PAMAM-G4) dendrimers were used for encapsulation of antibiotic drug doxorubicin (Dox) and its analogue N (trifluoroacetyl) doxorubicin (FDox) in aqueous solution at pH 7.4. Multiple spectroscopic methods, transmission electron microscopy (TEM) and molecular modeling were used to characterize the drug binding process to synthetic polymers. Structural analysis showed that drug-polymer binding occurs via both H bonding and hydrophobic contacts. The order of binding is PAMAM-G4>mPEG-PAMAM G3>PEG-6000 with Dox forming more stable conjugate than FDox. Transmission electron microscopy showed significant changes in carrier morphology with major changes in the shape of the polymer aggregate as drug encapsulation occurred. Modeling also showed that drug is located in the surface and in the internal cavities of PAMAM with the free binding energy of -4.14 kcal/mol for Dox and 3.93 kcal/mol for FDox, indicating of spontaneous drug-polymer interaction at room temperature. PMID- 26255163 TI - Biomineralization of hydroxyapatite in silver ion-exchanged nanocrystalline ZSM-5 zeolite using simulated body fluid. AB - Silver ion-exchanged nanocrystalline zeolite (Ag-Nano-ZSM-5) and silver ion exchanged conventional zeolite (Ag-ZSM-5) were synthesized. Zeolites were incubated in simulated body fluid at 310K for different time periods to grow hydroxyapatite in their matrixes. Significant large amount of hydroxyapatite was grown in Ag-Nano-ZSM-5 matrix after incubation in simulated body fluid when compared to Ag-ZSM-5. The resultant material was characterized using X-ray diffraction, N2-adsorption, scanning/transmission electron microscopy, energy dispersive X-ray, and inductively coupled plasma analysis. Mechanical properties such as compressive modulus, compressive strength, and strain at failure of the parent materials were evaluated. Biocompatibility assays suggested that Ag-Nano ZSM-5 and hydroxyapatite grown in Ag-Nano-ZSM-5 were compatible and did not impose any toxicity to RAW 264.7 cells macrophase and Caco2 cells suggesting considerable potential for biomedical applications such as bone implants. PMID- 26255164 TI - Facile fabrication of P(OVNG-co-NVCL) thermoresponsive double-hydrophilic glycopolymer nanofibers for sustained drug release. AB - The thermoresponsive double-hydrophilic glycopolymer (DHG), Poly (6-O-vinyl nonanedioyl-D-galactose-co-N-vinylcaprolactam) (P(OVNG-co-NVCL)) was synthesized via a chemo-enzymatic process and a free radical copolymerization and the resulting nanofibers were fabricated using an electrospinning process. The desired lower critical solution temperature (LCST) between 32 and 40 degrees C of the DHG polymers was achieved by adjusting the molar fraction of galactose monomer in the copolymers during the synthesis. The thermoresponsive DHG polymers were found to have good cytocompatibility with Hela cells as determined by the MTT assay, and special recognition of the protein peanut agglutinin (PNA). The drug release properties of these newly designed thermoresponsive DHG P(OVNG-co NVCL) nanofibers are temperature regulated, can target specific proteins and have the potential application in the field of sustained drug release. PMID- 26255165 TI - In vitro investigation of methylene blue-bearing, electrostatically assembled aptamer-silica nanocomposites as potential photodynamic therapeutics. AB - Photodynamic therapy, that is, excitation of a photosensitizer with light to generate reactive oxygen species such as singlet oxygen, has emerged as a noninvasive technique for cancer theranostics. However, the clinical use of many photosensitizers is impeded by their hydrophobicity, the nonspecific damage they cause to normal tissues, and their susceptibility to environmental degradation. In this study, we developed a simple electrostatic adsorption strategy to fabricate aptamer-silica nanocomposites by sequentially functionalizing nanocomposites with the cell surface-associated mucin 1 aptamer for tumor targeting and a hydrophilic photosensitizer, methylene blue, for photodynamic therapy applications. We investigated the relationship between the biophysical properties and cellular uptake of such nanocomposites to improve their formulation. Effective generation of singlet oxygen was achieved with a low photosensitizer dosage (0.5 MUM) and a short, low-power irradiation (1 min, 10 mW/cm(2)). With the current strategy, the efficiency of photodynamic therapy was determined by the cellular uptake of nanocomposites and the targeting molecules used. PMID- 26255166 TI - Physicochemical characterization of artificial nanoerythrosomes derived from erythrocyte ghost membranes. AB - Colloidal stabile nanoerythrosomes with 200 nm average diameter were formed from hemoglobin-free erythrocyte ghost membrane via sonication and membrane extrusion. The incorporation of extra lipid (1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC), added to the sonicated ghosts, caused significant changes in the thermotropic character of the original membranes. As a result of the increased DPPC ratio the chain melting of the hydrated DPPC system and the characteristic small angle X-ray scattering (SAXS) of the lipid bilayers appeared. Significant morphological changes were followed by transmission electron microscopy combined with freeze fracture method (FF-TEM). After the ultrasonic treatment the large entities of erythrocyte ghosts transformed into nearly spherical nanoerythrosomes with diameters between 100 and 300 nm and at the same time a great number of 10 30 nm large membrane proteins or protein clusters were dispersed in the aqueous medium. The infrared spectroscopy (FT-IR) pointed out, that the sonication did not cause changes in the secondary structures of the membrane proteins under our preparation conditions. About fivefold of extra lipid--compared to the lipid content of the original membrane--caused homogeneous dispersion of nanoerythrosomes however the shape of the vesicles was not uniform. After the addition of about tenfold of DPPC, monoform and monodisperse nanoerythrosomes became typical. The outer surfaces of these roughly spherical objects were frequently polygonal, consisting of a net of pentagons and hexagons. PMID- 26255167 TI - Formation of lens-like vesicles induced via microphase separations on a sorbitan monoester membrane with different headgroups. AB - The microphase separation of lipid molecules on a vesicle membrane can be induced, depending on the difference in the geometric structures of their headgroups. Through cryo-transmission-electron-microscopy analysis, a lens-like vesicle was prepared by mixing 50 wt% Span 40 (sorbitan monopalmitate) and 50 wt% Tween 40 [polyoxyethylene (20) sorbitan monopalmitate]. Considering the molecular structures of Span 40 and Tween 40, the high-curvature region was mainly formed by Tween 40. As determined by Fourier-transform infrared spectroscopy, dielectric dispersion analysis, and differential scanning calorimetry, a hydration layer was likely formed because polyoxyethylene conjugates with the headgroups of Tween 40. These investigations of the obtained self-assembled aggregates of nonionic surfactants with heterogeneous surfaces could contribute to the development of new types of biomaterials. PMID- 26255168 TI - President's Page. PMID- 26255169 TI - CT features in the early and late stages of chronic total coronary occlusions. AB - OBJECTIVES: To investigate the morphologic characteristics of early and late stages of chronic total coronary artery occlusions (CTO) in coronary computed tomography angiography (coronary CTA). METHODS: We retrospectively analyzed patients who underwent coronary CTA and invasive coronary angiography and had at least one CTO with known duration. The following parameters were obtained in coronary CTA: calcification of the occluded segment; stump morphology; lesion length; remodeling index; presence of intra-occlusion linear contrast enhancement; and density of non-calcified CTO components. CT parameters were compared between patients with early (duration <= 12 months) and late (duration > 12 months) stage CTO. RESULTS: One-hundred and twelve patients with 124 chronically occluded coronary arteries were analyzed. Fifty nine patients had early stage CTOs (62 lesions) and 53 patients had late stage CTOs (62 lesions). Calcification was more severe in late-stage versus early CTOs (Agatston score: early stage, 27.4 +/- 46.7 vs. late stage, 58.3 +/- 112.4; p = 0.049). Remodeling index was lower in late-stage CTOs (early stage, 0.96 +/- 0.2 vs. late stage, 0.88 +/- 0.22; p = 0.034). In patients with late stage CTO, the presence of intra occlusion linear enhancement was more likely (45.2% vs 14.5%, p < 0.001), and the density of non-calcified components was significantly higher (85.4 +/- 27.2 HU vs. 65.7 +/- 30.1 HU, p < 0.001). Stump morphology was not different between the two groups. CONCLUSIONS: Coronary CTA reveals differences between chronic total coronary occlusions of longer and shorter duration. A long duration is associated with focal calcification and negative remodeling, as well as intra-occlusion enhancement and a higher density of non-calcified components. PMID- 26255170 TI - Novel Cryptosporidium bat genotypes III and IV in bats from the USA and Czech Republic. AB - Bats from the families Rhinolophidae (n = 90) and Vespertilionidae (n = 191) in the USA and Czech Republic were screened for the presence of Cryptosporidium by microscopic and molecular analysis of faecal samples collected from rectum of dissected animals and from the ground beneath roosting sites. Cryptosporidium oocysts were not detected in any of the 281 faecal specimens examined using the aniline-carbol-methyl violet staining method. Nested PCR amplification, sequencing and phylogenetic analysis of the small ribosomal subunit rRNA and actin genes were used to identify isolates and infer evolutionary relationships. Cryptosporidium parvum was identified in a western small-footed bat (Myotis ciliolabrum) from the USA and a common pipistrelle bats (Pipistrellus pipistrellus) from the Czech Republic. Two novel genotypes were identified and named Cryptosporidium bat genotype III and IV. Bat genotype III was found in two big brown bats (Eptesicus fuscus) from the USA. Bat genotype IV was detected in two common pipistrelle bats from the Czech Republic. PMID- 26255171 TI - Discriminant validity of constructs derived from the self-regulative model for evaluation anxiety for predicting clinical manifestations of test anxiety. AB - Test anxiety is a highly prevalent and impairing syndrome. However, research on clinically relevant manifestations of test anxiety and especially on effective treatment components is still very sparse. In the present study we examined the predictive validity of constructs derived from the self-regulative model for evaluation anxiety proposed by Zeidner and Matthews (2007) for discriminating clinical and non-clinical levels of test anxiety. We compared self-report data from 47 clinically test anxious patients with those from 41 healthy university students. Results showed that learning goals, self-concept of abilities, self incrimination, elaboration and perfectionism were the constructs that independently separated clinical from non-clinical levels of test anxiety, thus providing the strongest discriminant validity even when controlling for an effect of the global severity of mental health problems. These constructs spread across all three domains proposed in the model, thus providing important implications for possible targets of interventions to reduce clinical levels of test anxiety. PMID- 26255172 TI - Does Stepping Stones Triple P plus Acceptance and Commitment Therapy improve parent, couple, and family adjustment following paediatric acquired brain injury? A randomised controlled trial. AB - OBJECTIVE: To evaluate the efficacy of a behavioural family intervention, Stepping Stones Triple P (SSTP), combined with an Acceptance and Commitment Therapy (ACT) workshop in improving parent, family and couple outcomes following paediatric acquired brain injury (ABI). PARTICIPANTS AND SETTING: Fifty-nine parents (90% mothers) of children (mean age 7 years; 35 males, 24 females) with ABI. INTERVENTION: Participants were randomly assigned to a treatment (10-week group SSTP and ACT program) or a care-as-usual (CAU) control condition (10 weeks). Those in the CAU condition received the treatment after the waitlist period. OUTCOMES: Self-report measures of parent psychological distress, parent psychological flexibility, parenting confidence, family functioning, and couple relationship, assessed at: pre-intervention, post-intervention, and 6-months post intervention. RESULTS: Post-intervention, the treatment group showed significant, small to medium improvements relative to the CAU group (at the p < .05 level) on parent psychological distress, parent psychological flexibility, parent confidence in managing behaviours, family adjustment,and number of disagreements between parents. Most improvements were maintained at 6-months. CONCLUSIONS: Parent skills training and ACT may be efficacious in improving parent, family, and couple outcomes in families of children with an ABI. PMID- 26255173 TI - Piloting a perfectionism intervention for pre-adolescent children. AB - OBJECTIVE: The aim of this pilot study was to evaluate a school-based intervention program focussing on reducing perfectionism in pre-adolescent children. METHOD: A 2-lesson intervention or the control condition was implemented across three schools (N = 125; M age = 11.60 years; 47.2% girls). Students completed assessments at baseline, post-intervention and 4-week follow up. RESULTS: Significant between group differences for self-oriented perfectionism-striving were identified post-intervention and were maintained at 4 week follow-up (d = 0.47 and 0.40 respectively). Significant interactions between group and time favouring the intervention group were identified for the hyperactivity and emotional problems. DISCUSSION: Findings from this study provide preliminary support for the effectiveness of a perfectionism intervention at an earlier age than has been targeted to date. While these findings appear promising, the justification of such approaches with this age group will require follow-up investigations with expanded intervention content, longer follow-up assessments, larger samples, and evidence of impact on other variables such as well-being. TRIAL REGISTRATION: ACTRN12614001262695. PMID- 26255174 TI - On the biogenesis and degradation of ejectisomes in Pyramimonas grossii (Prasinophyceae). AB - The biogenesis, assembly, and degradation of ejectisomes of Pyramimonas grossii were investigated by conventional transmission electron microscopy. Premature ejectisomes were mainly found beneath the cell envelope, often in close proximity to the nucleus, and as vesicles with diameters of 100 to 400 nm. Ejectisomes in the early stages of development contained only a few (2-4) turns of the ejectisome tapes. In the course of the ejectisome development, the number of turns and the widths of the coiled tapes increased. It is likely that vesicles, which were up to 650 nm in diameter, with granule- and plate-like structures inside, delivered additional preassembled ejectisome polypeptides to these premature stages. Both types of vesicles, those containing early stages of ejectisomes and those delivering additional ejectisome material, are believed to originate directly from the endoplasmic reticulum. Mature ejectisomes were mainly registered at the apical periphery of the cells. Up to 11 ejectisomes were found within a single cell. Ejectisomes that were most likely being in the process of degradation were registered within the cytoplasm and within vesicles, often together with material which resembled body scales. Mature ejectisomes which were still furled or which were arrested in the process of discharge were also found outside the cells in the medium. PMID- 26255175 TI - In response: looking for a standardized approach in the surgical treatment of hyperhidrosis. PMID- 26255176 TI - Distribution of bone and tissue morphological properties related to subacromial space geometry in a young, healthy male population. AB - PURPOSE: Particular bone and tissue morphological features of the scapula and humerus often exist disproportionately in persons with subacromial impingement syndrome (SAIS) and/or rotator cuff pathology. However, the origins of morphological variation, genetic or mechanistic, remain unclear. This research evaluated the distribution of and correlation between several bone and tissue characteristics associated with these pathologies amongst a baseline cohort population consisting of young, healthy, males. As well, the predisposition to SAIS was estimated by calculating the ratio (occupation ratio) of subacromial tissue thickness to minimum subacromial space width (SAS). METHODS: Anterior posterior and trans-scapular radiographs and musculoskeletal ultrasound were used to measure morphological characteristics related to the subacromial space. Each bone morphological characteristic was classified as healthy or unhealthy based on previous definitions. Supraspinatus tendon and subacromial bursa thicknesses were used to calculate the occupation ratio from both radiographic and ultrasonic measures of the SAS. RESULTS: Each characteristic demonstrated considerable variability, with some participants having 'unhealthy' variants for each bone characteristic examined. The percentage of the population with bone characteristics classified as "unhealthy" ranged from 15 to 55 % across characteristics evaluated. The strongest correlation existed between the acromion index and the minimum subacromial space width (-0.59) suggesting that a larger lateral extension of the acromion may predispose an individual to SAIS. The average occupation ratio was 65.3 % with a 1-99 % confidence interval ranging from 21.6 to 108.9 %. CONCLUSIONS: The distributions of both morphological characteristics and occupation ratios indicate that individuals within this healthy, baseline population have a highly differential predisposition for subacromial tissue compression solely based on inherent morphological variation. This suggests that while mechanistic and/or age-related degenerative changes may contribute to SAIS and eventual rotator cuff pathology, intrinsic predisposing geometry should not be discounted. PMID- 26255177 TI - Insights on atherosclerosis by non-invasive assessment of wall stress and arterial morphology along the length of human coronary plaques. AB - Wall stress (WS) is associated with high arterial pressure and affects the localization of atherosclerotic lesions. We sought to non-invasively investigate the distribution of WS along the length of human coronary arteries and investigate its potential effect on atherosclerosis in association with vascular stiffness, local arterial curvature and plaque volume. We reconstructed three dimensionally 28 coronary arteries from 22 subjects who had undergone coronary computed tomography angiography. Coronary arteries were divided in 2 mm-long segments. WS, vascular stiffness, plaque volume and curvature were calculated in each segment using computational fluid dynamics and morphology measurements. Plaque segments exhibited lower WS compared to their adjacent normal segments. Within plaques, WS was lower in the mid plaque portion compared to the upstream portion. Plaque volume was higher in the mid plaque portion compared to upstream and downstream portions. Low WS was associated with high curvature and both low WS and high curvature were associated with increased plaque volume. The current study demonstrates that WS and plaque volume are not uniform in the longitudinal axis of human coronary plaque. Calculation of WS could serve as a surrogate for the localization of plaque development and the identification of plaques at a more advanced stage of progression. PMID- 26255178 TI - Spontaneous globe luxation in iatrogenic Cushing syndrome. AB - PURPOSE: We report a rare case of spontaneous eyeball luxation associated with exophthalmos due to iatrogenic Cushing syndrome (CS). The normalization of serum hormones led to the regression of the picture. CASE: A 64-year-old man presented with spontaneous globe luxation of the left eye after a 6-month history of bilateral, painless, and slowly progressive exophthalmos. The patient had been receiving weekly infusions of methylprednisone over the previous 6 months. His best-corrected visual acuity (BCVA) at presentation was 20/40 in the right eye and 20/20 in the left eye. The patient demonstrated full extraocular motility. The intraocular pressure (IOP) was elevated in the right eye (24 mHg) and normal in the left eye (18 mmHg). Exophthalmometry demonstrated bilateral proptosis with measurements of 27 mm in the right eye and 28 mm in the left eye. Computed tomography scan of the brain and orbits revealed increased orbital and cervical fat. Clinical, radiographic and serologic findings ruled out potential diagnoses including orbital metastasis, thyroid orbitopathy, carotid-cavernous fistula, and idiopathic orbital pseudotumor. Clinical suspicion of iatrogenic CS was high, and additional serologic testing confirmed the diagnosis. CONCLUSION: Exophthalmos is an uncommon sign of CS, but to our knowledge, this is the first reported case of spontaneous globe luxation secondary to CS. In our case, normalization of cortisol was sufficient to resolve the clinical symptoms and eliminated the need for surgical intervention such as orbital decompression surgery. PMID- 26255179 TI - A Systematic Review and Narrative Synthesis of Health Economic Studies Conducted for Hereditary Haemochromatosis. AB - BACKGROUND: Hereditary haemochromatosis (HH) is a common genetic condition amongst people of northern European heritage. HH is associated with increased iron absorption leading to parenchymal organ damage and multiple arthropathies. Early diagnosis and treatment prevents complications. Population screening may increase early diagnosis, but no programmes have been introduced internationally: a paucity of health economic data is often cited as a barrier. OBJECTIVE: To conduct a systematic review of all health economic studies in HH. METHODS: Studies were identified through electronic searching of economic/biomedical databases. Any study on HH with original economic component was included. Study quality was formally assessed. Health economic data were extracted and analysed through narrative synthesis. RESULTS: Thirty-eight studies met the inclusion criteria. The majority of papers reported on costs or cost effectiveness of screening programmes. Whilst most concluded screening was cost effective compared with no screening, methodological flaws limit the quality of these findings. Assumptions regarding clinical penetrance, effectiveness of screening, health state utility values (HSUVs), exclusion of early symptomatology (such as fatigue, lethargy and multiple arthropathies) and quantification of costs associated with HH were identified as key limitations. Treatment studies concluded therapeutic venepuncture was the most cost-effective intervention. CONCLUSIONS: There is a paucity of high-quality health economic studies relating to HH. The development of a comprehensive HH cost-effectiveness model utilising HSUVs is required to determine whether screening is worthwhile. PMID- 26255180 TI - Preclinical characterization of toluene as a non-classical hallucinogen drug in rats: participation of 5-HT, dopamine and glutamate systems. AB - RATIONALE: Toluene is a misused inhalant with hallucinogenic properties and complex effects. Toluene blocks N-methyl-D-aspartate (NMDA) receptors, releases dopamine (DA), and modifies several neurotransmitter levels; nonetheless, the mechanism by which it produces hallucinations is not well characterized. OBJECTIVES: This study aims (a) to study toluene's effects on the 5-HT2A-mediated head-twitch response (HTR), dopamine (DA), and serotonin (5-HT) tissue levels in discrete brain regions; (b) to compare the actions of toluene, ketamine, and 1 [2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) on HTR; and (c) to study the pharmacological blockade of toluene's and ketamine's effects by selective drugs. METHODS: Independent groups of rats inhaled toluene (500-12,000 ppm) for 30 min during which the occurrence of serotonergic signs was analyzed. Brains were obtained after exposure to determine DA and 5-HT levels by HPLC. RESULTS: Toluene concentration-dependently induced HTR. Other serotonin syndrome signs were evident at high concentrations. Toluene (4000 and 8000 ppm), and ketamine (3 and 10 mg/kg), significantly increased 5-HT levels in the frontal cortex (FC) striatum, hippocampus, and brain stem, as well as DA levels in the striatum and FC. Pretreatment with ketanserin (5HT2A/2C receptor antagonist), M100907 (selective 5-HT2A receptor antagonist), D-serine (co-agonist of the NMDA receptor glycine site), and haloperidol (D2 receptor antagonist) significantly decreased toluene's and ketamine's actions. The 5HT1A receptor antagonist WAY100635 had no effect. CONCLUSION: Toluene stimulates 5HT2A and 5HT2C receptors, and increases 5 HT and DA levels. These actions are similar to those produced by ketamine and involve activation of a complex neurotransmitter network that includes NMDA receptor antagonism. PMID- 26255181 TI - Cobalt Protoporphyrin Upregulates Cyclooxygenase-2 Expression Through a Heme Oxygenase-Independent Mechanism. AB - Cobalt protoporphyrin (CoPP) is a potent HO-1 inducer and generally known to be an antioxidant in various cell types. Little is known about the CoPP-induced cyclooxygenase-2 (COX-2) expression and its downstream signaling in microglial cells. In current study, CoPP caused concentration- and time-dependent increases in COX-2 expression in microglial cells. Furthermore, activation of apoptosis signal-regulating kinase (ASK) 1/MAP kinase involved in CoPP-induced COX-2 expression in microglia. CoPP also induced P2X7 receptor activation, and treatment of P2X7 inhibitors effectively reduced CoPP-induced COX-2 expression. Protein inhibitor of activated STAT (PIAS) 1 is reported to be involved in modulating anti-inflammatory response through negative regulation of transcription factors. Interestingly, treatment with CoPP markedly induced PIAS1 degradation which is regulated by PI3K, Akt, and glycogen synthase kinase 3alpha/beta (GSK3alpha/beta) signaling pathways. These results suggest that CoPP induces COX-2 expression through activating P2X7 receptors and ASK1/MAP kinases as well as PIAS1 degradation signaling pathways. Our study provides a new insight into the regulatory effect of CoPP on neuroinflammation in microglial cells. PMID- 26255183 TI - Prevalence of bovine subclinical mastitis, its etiology and diagnosis of antibiotic resistance of dairy farms in four municipalities of a tropical region of Mexico. AB - A region-wide survey was conducted in the tropical area of Tierra Caliente, State of Guerrero, Mexico to estimate the prevalence of subclinical bovine mastitis (SCM), distribution of mastitis pathogens, and in vitro antimicrobial susceptibility of different mastitis pathogens in dairy farms. In total, 1036 quarter milk samples were obtained from 259 cows at 87 different dairy farms. Collected quarter milk samples were submitted for California Mastitis Test (CMT), bacteriological examination, and testing for antimicrobial susceptibility. Overall prevalence of SCM in the studied area was 20.5 %. Prevalence in the different regions was as follows: 28 % in Arcelia municipality, 21 % in Tlalchapa municipality, 19.4 % in Pungarabato municipality, and 14.3 % in Finch Cutzamala municipality. Of all positive isolates, 97.5 % were Gram-negative bacteria. Moreover, of all positive isolates, 37.5 % were Proteus vulgaris, 25 % Salmonella spp., 12.5 % Enterobacter aerogenes, and 10 % Escherichia coli. Klebsiella pneumonia and E. coli were sensitive for netilmicin antimicrobial. However, E. coli was sensitive for pefloxacin and gentamicin with a sensitivity for pefloxacin for E. aerogenes, while Staphylococci were sensitive for gentamicin and dicloxacillin. It could be concluded that practices such as the implementation of mastitis control programs, improved milking hygiene together with an intramammary treatment with netilmicin, pefloxacin, and gentamicin antimicrobials should be considered for mastitis prevention in the study area of Tierra Caliente, in the tropical area of Guerrero, Mexico. PMID- 26255184 TI - Digestibility of solvent-treated Jatropha curcas kernel by broiler chickens in Senegal. AB - Jatropha curcas is a drought-resistant shrub belonging to the Euphorbiaceae family. The kernel contains approximately 60 % lipid in dry matter, and the meal obtained after oil extraction could be an exceptional source of protein for family poultry farming, in the absence of curcin and, especially, some diterpene derivatives phorbol esters that are partially lipophilic. The nutrient digestibility of J. curcas kernel meal (JKM), obtained after partial physicochemical deoiling was thus evaluated in broiler chickens. Twenty broiler chickens, 6 weeks old, were maintained in individual metabolic cages and divided into four groups of five animals, according to a 4 * 4 Latin square design where deoiled JKM was incorporated into grinded corn at 0, 4, 8, and 12 % levels (diets 0, 4, 8, and 12 J), allowing measurement of nutrient digestibility by the differential method. The dry matter (DM) and organic matter (OM) digestibility of diets was affected to a low extent by JKM (85 and 86 % in 0 J and 81 % in 12 J, respectively) in such a way that DM and OM digestibility of JKM was estimated to be close to 50 %. The ether extract (EE) digestibility of JKM remained high, at about 90 %, while crude protein (CP) and crude fiber (CF) digestibility were largely impacted by JKM, with values closed to 40 % at the highest levels of incorporation. J. curcas kernel presents various nutrient digestibilities but has adverse effects on CP and CF digestibility of the diet. The effects of an additional heat or biological treatment on JKM remain to be assessed. PMID- 26255182 TI - Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms. AB - In healthy cell, inappropriate accumulation of poor or damaged proteins is prevented by cellular quality control system. Autophagy and ubiquitin proteasome system (UPS) provides regular cytoprotection against proteotoxicity induced by abnormal or disruptive proteins. E3 ubiquitin ligases are crucial components in this defense mechanism. Mahogunin Ring Finger-1 (MGRN1), an E3 ubiquitin ligase of the Really Interesting New Gene (RING) finger family, plays a pivotal role in many biological and cellular mechanisms. Previous findings indicate that lack of functions of MGRN1 can cause spongiform neurodegeneration, congenital heart defects, abnormal left-right patterning, and mitochondrial dysfunctions in mice brains. However, the detailed molecular pathomechanism of MGRN1 in cellular functions and diseases is not well known. This article comprehensively represents the molecular nature, characterization, and functions of MGRN1; we also summarize possible beneficiary aspects of this novel E3 ubiquitin ligase. Here, we review recent literature on the role of MGRN1 in the neuro-pathobiological mechanisms, with precise focus on the processes of neurodegeneration, and thereby propose new lines of potential targets for therapeutic intervention. PMID- 26255185 TI - Status of the genetic diversity and population structure of the Pega donkey. AB - Pedigree analysis was extended to the Pega donkey population in order to evaluate the status of genetic diversity and population structure. All parameters were computed for three reference populations of animals born between 2004 and 2014: all animals, animals with mouse gray coat color, and animals with roan coat color. Although the average inbreeding coefficient observed was low (about 3 %), highly inbred animals are present in the current population. The effective population size based on the individual inbreeding rate was 35, while the effective population size based on the individual coancestry rate was about three times higher. The number of equivalent subpopulations was at around three, indicating that the Pega donkey population is highly structured. There is no evidence of differentiation between subpopulations based on the coat color of the animals (Nei's minimum distance 0.10 %). The breeding policy of Pega donkeys is predominantly intra-herd. The loss of genetic diversity since the founder generations can be considered small in Pega donkeys (1.25 %). The excessive contribution of few ancestors to the gene pool may lead to narrower bottlenecks in the pedigree of this population in the future. The long generation interval in Pega donkeys (10.7 years) may be considered an advantage to reduce the increase in inbreeding and to maintain the genetic diversity of these animals. PMID- 26255186 TI - Clinical and laboratory factors associated with interstitial lung disease in rheumatoid arthritis. AB - OBJECTIVE: The objective of this study is to examine the clinical, genetic, and environmental factors associated with interstitial lung disease (ILD) in rheumatoid arthritis (RA). METHOD: We recruited patients with RA from rheumatology practices at the time of a scheduled visit. Each patient participated in a comprehensive assessment that included ascertainment of age, sex, joint tenderness and swelling, subcutaneous nodules, disease severity, use of methotrexate and prednisone, smoking status, rheumatoid factor (RF), antibodies against cyclic citrullinated peptide (anti-CCP),erythrocyte sedimentation rate (ESR), the 28-joint Disease Activity Score (DAS28), and the presence of the HLA-DRB1 shared epitope (SE). As part of a thorough quantification of comorbidity, we identify all comorbid conditions, including ILD. We examined variables associated with ILD using logistic regression. We tested interaction terms between SE and other covariates. RESULTS: We studied 779 RA patients, among whom, ILD was recognized clinically in 69 (8.8 %). Variables significantly associated with ILD in a multivariable analysis included male sex, RA duration, the ESR, the DAS28, anti-CCP, and RF. There was a significant interaction between the HLA-DRB1 SE and smoking, ILD being associated with smoking only in the presence of SE. The association between ILD and anti-CCP, RF, and the ESR displayed a biological gradient, higher titers being more strongly associated with ILD. CONCLUSION: Anti-CCP antibodies and the RF may be pathogenically related to ILD. The association between ILD and smoking is dependent on the HLA-DRB1 SE, which may reflect gene-environment interaction. PMID- 26255187 TI - Glucocorticoid receptor genetic polymorphisms is associated with improvement of health-related quality of life in Chinese population with systemic lupus erythematosus. AB - In our previous study, we found that glucocorticoid receptor (GR) gene genetic polymorphisms may play a major role in the efficacy of glucocorticoids (GCs) in Chinese systemic lupus erythematosus (SLE) patients. The aim of this study is to explore the association of GR gene genetic polymorphisms and improvement of health-related quality of life (HRQOL) in Chinese SLE patients treated with GCs. A total of 195 Chinese SLE patients were treated with GCs for 12 weeks. The HRQOL of patients was measured with the Medical Outcomes Study Short Form-36 (SF-36) at baseline and 12 weeks. Polymorphisms of GR gene were genotyped by using multiplex SNaPshot method. One hundred eighty-four patients (94.36 %) completed the 12-week follow-up. Twenty-three single-nucleotide polymorphisms of GR gene were genotyped. There was a significant association between rs10482672 polymorphism and improvement in physical function (P = 0.043), general health (P = 0.024), and social function (P = 0.013). The rs12656106 polymorphism was associated with improvement in the total score of SF-36 (P = 0.014), physical function (P = 0.013), general health (P = 0.010), vitality (P = 0.015), social function (P = 0.004), physical component summary (P = 0.016), and mental component summary (P = 0.014). The rs4912905 polymorphism was associated with improvement in bodily pain (P = 0.040) and general health (P = 0.038). The rs4912911 polymorphism was associated with improvement in general health (P = 0.026) and vitality (P = 0.027). The rs4986593 polymorphism was associated with improvement in bodily pain (P = 0.034). The rs7719514 polymorphism was associated with improvement in vitality (P = 0.002) and mental component summary (P = 0.041). We also found a significant association between rs9324924 polymorphism and improvement in physical function (P = 0.040), bodily pain (P = 0.007), and general health (P = 0.019). These results indicate that there may be an association of GR gene rs10482672, rs12656106, rs4912905, rs4912911, rs4986593, rs7719514, and rs9324924 polymorphisms with improvement of HRQOL in Chinese SLE patients treated with GCs. PMID- 26255188 TI - Challenges faced in Latin America for the implementation of an ideal health-care model for rheumatoid arthritis patients: are we ready? AB - Rheumatoid arthritis (RA) is a chronic, inflammatory, progressive disease characterized by inflammation of the synovial tissue. It results in the severe functional deterioration of the joints involved and the incapacity to work. Our main aim is to determine the characteristics of the current health-care models used in treating rheumatoid arthritis patients in Latin America. We want to analyze the details, using them as the foundation to create an ideal health-care model that is focused on the patient. We have revised documents, including guides to clinical practice, monitoring models and health-care models according to the current policies and resources available in various Latin American countries. Based on this information, the qualities and deficiencies of the current models will be analyzed, in order to use this as a basis on which to construct a proposed health-care model that covers the specific needs of rheumatoid arthritis patients, considering the resources of each population. Despite the collapse seen in many health systems throughout history, we can learn from them and should develop a new model starting from the path pursued, capitalizing on our experiences, teachings, and errors committed. However, in most cases, the obstacles to the success of the systems do not lie in the fundamental structure or the "spirit of the legislator" but rather in the day-to-day development within the community and the special interest of each agent in a system. PMID- 26255189 TI - Seasonal variation in acute gouty arthritis: data from Nationwide Inpatient Sample. AB - INTRODUCTION: Studies describing seasonal variations in acute gouty arthritis note seasonal variation, but disagree on timing, with most showing a peak in spring months while others show peaks later in the year. Various theories on the effect of weather and immune system changes on the chronobiology of monosodium urate crystals' equilibrium and precipitation have been proposed. We aimed to shed light on this question by examining the seasonal variation in the incidence of acute gouty arthritis in the USA using a large inpatient database. METHODS: We used the Nationwide Inpatient Sample (NIS) database to identify patients aged >=18 years with primary diagnosis of acute gouty arthritis (International Classification of Diseases, 9th Revision, Clinical Modification code 274.01) from 2009-2011 during hospitalization. We used the Edwards recognition and estimation of cyclic trend method to study the seasonal variation of the incidence of acute gout and z-test to compare the seasonal incidences. RESULTS: A total of 28,172 hospitalizations with primary diagnosis of acute gouty arthritis were reported in the USA from 2009-2011. The peak incidence of acute gout was seen in November (peak/low ratio 1.34, 95 % CI 1.29-1.38, p < 0.05). The highest number of hospitalizations was observed in autumn months while the lowest incidence was observed in spring (28.12 vs. 23.13 %, p < 0.001). CONCLUSION: The peak incidence of acute gout seems to be in the fall with its peak in the month of November. This seasonality may shed light into the pathophysiology of acute attacks and better management of patients with gout who are at risk of acute attacks. PMID- 26255190 TI - Efficacy of tripterygium glycosides tablet in treating ankylosing spondylitis: a systematic review and meta-analysis of randomized controlled trials. AB - Hundreds of randomized controlled trials (RCTs) on tripterygium glycosides tablet (TGT) in the treatment of ankylosing spondylitis (AS) have been published, but the therapeutic effects have never been systematically reviewed yet. The aim of this meta-analysis was to evaluate the efficacy of TGT on AS based on RCTs. PubMed, ScienceDirect, Cochrane Library, China Journals Full-text Database, and Wanfang Data were searched. The RCT quality was evaluated by the Cochrane Collaboration's tool for assessing risk of bias. The RCT characteristics including publication years, sample sizes, and follow-up periods as well as outcome measures including symptoms improvement, morning stiffness (MS), bath ankylosing spondylitis patient global score (BAS-G), pain index (PI), swelling index (SI), finger to floor distance (FFD), pillow wall distance (PWD), Schober test (Schober), erythrocyte sedimentation rate (ESR), and C reactive protein (CRP) were extracted. The odds ratio (OR), mean difference (MD), and its 95% confidence interval (CI) were selected for overall effect sizes. Subgroup, sensitivity, and meta-regression analyses were conducted to confirm the results. Eleven RCTs with 807 participants were included, the quality of which was moderate. OR of TGT in treating AS was 0.46 (95% CI 0.24, 0.90]. MD of MS was 11.79 (95% CI 3.13, 20.45). MD of BAS-G was 0.13 (95% CI -19.73, 19.99). MD of PI was 0.78 (95% CI 0.22, 1.34). MD of SI was 0.80 (95% CI 0.06, 1.53). MD of FFD was 0.80 (95% CI 0.06, 1.53). MD of PWD was 1.37 (95% CI -0.64, 3.38). MD of Schober was -0.36 (95% CI -0.65, -0.07]. MD of ESR was 4.58 (95% CI 2.10, 7.06). MD of CRP was 1.86 (95% CI -2.03, 5.76). Subgroup, sensitivity, and meta regression analyses found the robust results. In conclusion, TGT could not treat AS effectively, as suggested by the moderate RCT quality and meta-analysis evidence. PMID- 26255191 TI - The amount of citrullinated proteins in synovial tissue is related to serum anti cyclic citrullinated peptide (anti-CCP) antibody levels. AB - The objective of this study was to determine the relationship between citrullinated proteins in synovial tissue with peripheral anti-citrullinated peptides autoantibodies (ACPA) and peptidylarginine deiminase (PADI) PADI2, PADI3, and PADI4 messenger RNA (mRNA) expressions in synovial tissue and fibroblast-like synoviocytes in rheumatoid arthritis (RA) patients. Eleven RA and 12 osteoarthritis (OA) patients who underwent knee replacement surgery were studied. We detected citrullinated proteins in synovial tissue homogenates by western blot and serum ACPA by ELISA to anti-cyclic citrullinated peptide (anti CCP) antibodies, and PADI2, PADI3, and PADI4 mRNA expressions in synovial tissue and in fibroblast-like synoviocytes. Patients with high amount of citrullinated proteins in synovial tissue (3 out of 7) have high levels of anti-CCP in serum. However, in the remaining 4 patients, the amount of synovial citrullinated proteins was minimal and their sera showed low levels of anti-CCP antibodies. Furthermore, we observed an increase in PADI2 mRNA expression in RA synovial tissue compared with OA patients (p = 0.02). We detected PADI3 mRNA in the synovial tissue of RA patients, but not in the tissue of OA patients. Even though fibroblast-type synoviocytes in RA are not the main source of PADs in the synovial tissue, they express PADI2 mRNA moderately, PADI4 mRNA weakly, while there is no detectable expression of PADI3 mRNA. In conclusion, we found a variety of citrullinated proteins in the synovial tissue of RA patients and the amount of such proteins is related to serum concentration of anti-CCP antibodies. We identified the presence of PADI3 mRNA expression in synovial tissue and PADI2 and PADI4 mRNA expressions in fibroblast-like synoviocytes from patients with RA. PMID- 26255192 TI - Rheumatoid arthritis in Latin America. Important challenges to be solved. PMID- 26255193 TI - Advanced oxidation protein products are more related to metabolic syndrome components than biomarkers of lipid peroxidation. AB - Although advanced oxidation protein products (AOPPs) have been reported as the most appropriate parameter for determination of oxidative stress in patients with metabolic syndrome (MetS), a direct comparison between protein and lipid peroxidation has not been performed yet. The aim of this study was to compare protein peroxidation with lipid peroxidation measured by 2 different methodologies (tert-butyl hydroperoxide-initiated chemiluminescence and ferrous oxidation-xylenol orange assay). The hypothesis of this study was that AOPPs would be more related to MetS than to oxidative markers of lipid peroxidation. This cross-sectional study evaluated 76 patients with MetS and 20 healthy subjects. Prooxidant-antioxidant index (PAI) assessed as AOPP/total radical trapping antioxidant parameter ratio progressively increased (P < .05) according to the number of MetS components, whereas AOPPs and total radical-trapping antioxidant parameter increased (P < .05) when 5 components were compared with 3 components. Spearman test showed a positive correlation between AOPPs and waist circumference (r = 0.318, P < .01), fasting glucose (r = 0.250, P < .05), homeostasis model assessment insulin resistance (r = 0.043, P < .01), triacylglycerol (r = 0.713, P < .0001), highly sensitive C-reactive protein (r = 0.275, P < .05), and uric acid (r = 0.356, P < .01), whereas there was an inverse correlation with high-density lipoprotein cholesterol (r = -0.399, P < .001). Prooxidant-antioxidant index demonstrated a positive correlation with waist circumference (r = 0.386, P < .01), fasting glucose (r = 0.388, P < .01), fasting insulin (r = 0.344, P < .05), homeostasis model assessment insulin resistance (r = 0.519, P < .001), triacylglycerol (r = 0.687, P < .0001), highly sensitive C reactive protein (r = 0.278, P < .05), and uric acid (r = 0.557, P < .0001), whereas there was an inverse correlation with high-density lipoprotein cholesterol (r = -0.480, P < .0001). In conclusion, protein peroxidation determined by AOPPs, and especially by PAI, is more related to MetS components than lipid peroxidation. In addition, PAI progressively increased with the number of MetS components. PMID- 26255194 TI - Low-lycopene containing tomato powder diet does not protect against prostate cancer in TRAMP mice. AB - Previously, tomato powder (TP) diets initiated postweaning have been shown to be effective in reducing prostate cancer in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. The TRAMP model develops and progresses through all stages of carcinogenesis similarly to humans. We hypothesized that a 10% TP diet intervention after puberty would reduce carcinogenesis at 12, 16, and 20 weeks of age in TRAMP mice. Eight-week-old male C57BL/6 X FVB F1 TRAMP mice were randomized to consume either an AIN-93G + 10% TP diet (n = 90) or the AIN-93G control diet (n = 88) and randomized to 1 of 3 end point ages: 12 (n = 59), 16 (n = 60), or 20 (n = 59) weeks of age. There was no difference between diets in overall cancer incidence at any time point. However, at 16 weeks of age, TP significantly increased high-grade PIN (P = .014) and significantly decreased poorly differentiated (P = .024) lesions compared with the control diet suggesting a delay in the progression of prostate cancer. Two variables that may explain the modest effect of TP in this study are as follows: the low amount of lycopene in the TP diet (12.3 ppm) and the timing of the intervention (8 weeks of age). The TP diet contained 30-fold less lycopene than previous studies in our laboratory. In addition, the initiation of the diet intervention time of 8 weeks of age instead of 4 weeks of age may have been too late in cancer progression to substantially impact carcinogenesis. In conclusion, a low-lycopene TP intervention failed to reduce carcinogenesis in TRAMP mice. PMID- 26255195 TI - Rutin, A Natural Flavonoid Protects PC12 Cells Against Sodium Nitroprusside Induced Neurotoxicity Through Activating PI3K/Akt/mTOR and ERK1/2 Pathway. AB - Free radicals induced neural damage is implicated in CNS diseases and rutin isolated form Lonicera japonica are reported to have neuroprotective activity. Previously, we confirmed that rutin exerted neuroprotective effect against sodium nitroprusside (SNP)-induced cell death in PC12 cells. However, the neuroprotective mechanism of rutin is still not fully uncovered. Here, we found that rutin significantly decreased SNP-induced reactive oxygen species in PC12 cells. Rutin reversed the declined GSH/GSSG ratio and mitochondrial membrane potential induced by SNP. Moreover, rutin activated both the protein Akt/mTOR and the extracellular signal-regulated kinase (ERK1/2) signaling pathways and the neuroprotective effects of rutin were blocked by either the specific PI3K inhibitor LY294002 or the MAPK pathway inhibitor PD98059. In summary, these results demonstrated that the neuroprotective effects of rutin might be through activating both the PI3K/Akt/mTOR and ERK1/2 signaling pathways. Our findings support that rutin may have therapeutic potential for the treatment of CNS diseases related to NO neurotoxicity. PMID- 26255196 TI - Optimal adjuvant treatment for patients with HER2-positive breast cancer in 2015. AB - The introduction of trastuzumab as adjuvant treatment for patients with HER2 positive breast cancer changed the natural course of early-stage disease. Currently, one year of trastuzumab given concurrently with a taxane and following an anthracycline regimen is the preferred standard of care in Europe. The first attempt to escalate this approach, though the implementation of dual HER2 blockade with lapatinib added to trastuzumab, as assessed by the ALTTO trial, failed to improve further clinical outcomes; clinical assessment of the adjuvant trastuzumab/pertuzumab regimen is still ongoing in the APHINITY trial. Negative results were also reported for the addition of bevacizumab to adjuvant trastuzumab treatment within the context of the BETH study. Similarly, efforts to de-escalate through shortening the duration of adjuvant trastuzumab treatment failed (the PHARE trial), whereas others are still ongoing. Of note, evidence supports the use of lighter chemotherapy regimens with one year of adjuvant trastuzumab as backbone, for women with small HER2-positive breast tumors, where the omission of anthracyclines did not compromise the clinical outcome. Despite the successes achieved so far, a proportion of women with early-stage HER2 positive breast cancer, will still experience disease recurrence. The identification of these women is urgently needed, as well as the identification of predictive biomarkers to dictate the optimal treatment strategy. So far, HER2 expression status has been the only validated predictive biomarker for this patient population. Despite the clear association of pCR achieved through neoadjuvant trastuzumab-based chemotherapy with clinical outcome, results from neoadjuvant trials have not been always consistent with what was seen in the adjuvant setting. Similarly, inconsistent results have been reported for the predictive ability of alterations affecting the PI3K signaling pathway or the quantification of tumor infiltrating lymphocytes. In the era of personalized oncology, rigorous translational and clinical collaborative efforts are needed to further advance the field of treatment of patients with HER2-positive breast cancer. PMID- 26255197 TI - Predicting benefit of endocrine therapy for early breast cancer. AB - Adjuvant endocrine therapy is a mainstay of treatment for patients with endocrine responsive early breast cancer. Questions remain concerning which patients should receive what type of endocrine therapy and for how long. Several factors have been considered as potential indicators to predict benefit of endocrine therapy, including patient factors, clinico-pathological factors and multigene assays. To date, factors associated with risk of recurrence have been the most widely adopted to influence treatment selection. The International Breast Cancer Study Group (IBCSG)-led adjuvant endocrine therapy trials BIG 1-98, for postmenopausal women, and SOFT and TEXT, for premenopausal women, can shed light on the role for risk of recurrence in identifying who should receive which type of adjuvant endocrine therapy and for how long. PMID- 26255198 TI - Tailoring adjuvant chemotherapy regimens for patients with triple negative breast cancer. AB - Cytotoxic chemotherapy remains the systemic therapy of choice for triple-negative breast cancer (TNBC), a poor-prognosis subtype of breast cancer. Growing data focusing on TNBC provides an opportunity to assess if we can tailor adjuvant chemotherapy based on patient and tumor characteristics. The standard of care for moderate-to-high risk TNBC remains a sequential anthracycline-taxane combination, with the potential for shorter and less toxic regimens in stage I disease. Platinums are promising in the neoadjuvant and metastatic settings but we await long-term outcome data before incorporation into standard regimens in the adjuvant setting. Specific subgroups within TNBC, such as BRCA mutation carriers, require special attention, and the role of platinums in these patients warrants further consideration. There is hope that in the future, further subdividing TNBC by gene expression profile, mutation, immune infiltrate, and others will reveal novel susceptibilities. PMID- 26255199 TI - Molecular segmentation of luminal breast: Reality in 2015? AB - PURPOSE: With the advent of next generation sequencing, we are beginning to get a clearer picture of the landscape of genetic alterations in primary breast cancer. One of the key findings has been the heterogeneity of mutational profiles, with no two primary breast tumors being alike. How these genetic alterations will help us manage patients is currently unclear. Studies are ongoing to determine which genetic alterations will signify "oncogenic addiction" and which ones will determine resistance and relapse to current standard therapies. PMID- 26255200 TI - Screw augmentation reduces motion at the bone-implant interface: a biomechanical study of locking plate fixation of proximal humeral fractures. AB - BACKGROUND: Shear forces at the bone-implant interface lead to a loss of reduction after locking plate fixation of proximal humeral fractures. The aim of the study was to analyze the roles of medial support screws and screw augmentation in failure loads and motion at the bone-implant interface after locking plate fixation of proximal humeral fractures. METHODS: Unstable 3-part fractures were simulated in 6 pairs of cadaveric humeri and were fixed with a DiPhos-H locking plate (Lima Corporate, Udine, Italy). An additional medial support screw was implanted in 1 humerus of every donor. The opposite humerus was stabilized with a medial support screw and additional bone cement augmentation of the 2 anteriorly directed head screws. Specimens were loaded in the varus bending position. Stiffness, failure loads, plate bending, and the motion at the bone implant interface were evaluated using an optical motion capture system. RESULTS: The mean load to failure was 669 N (standard deviation [SD], 117 N) after fixation with medial support screws alone and 706 N (SD, 153 N) after additional head screw augmentation (P = .646). The initial stiffness was 453 N/mm (SD, 4.16 N/mm) and 461 N/mm (SD, 64.3 N/mm), respectively (P = .594). Plate bending did not differ between the 2 groups. However, motion at the bone-implant interface was significantly reduced after head screw augmentation (P < .05). CONCLUSION: The addition of bone cement to augment anteriorly directed head screws does not increase stiffness and failure loads but reduces motion at the bone-implant interface. Thus, the risk of secondary dislocation of the head fragment may be reduced. PMID- 26255201 TI - MicroRNA-130a and -130b enhance activation of hepatic stellate cells by suppressing PPARgamma expression: A rat fibrosis model study. AB - Hepatic stellate cells (HSCs) are the primary sources of extracellular matrix (ECM) in normal and fibrotic liver. Peroxisome proliferator-activated receptor gamma (PPARgamma) maintains HSCs in a quiescent state, and its downregulation induces HSC activation. MicroRNAs (miRNAs) can induce PPARgamma mRNA degradation, but the mechanism by which miRNAs regulate PPARgamma in rat HSCs is unclear. This study aimed to investigate some miRNAs which putatively bind to the 3' untranslated region (3'-UTR) of PPARgamma mRNA, and increase expression of ECM genes in rat HSCs. In carbon tetrachloride injection (CCl4) and common bile duct ligation (CBDL) liver fibrosis models, miRNAs miR-130a, miR-130b, miR-301a, miR 27b and miR-340 levels were found to be increased and PPARgamma expression decreased. Overexpression of miR-130a and miR-130b enhanced cell proliferation by involving Runx3. MiR-130a and miR-130b decreased PPARgamma expression by targeting the 3'-UTR of PPARgamma mRNA in rat HSC-T6 cells. Transforming growth factor-beta1 (TGF-beta1) may mediate miR-130a and miR-130b overexpression, PPARgamma downregulation, and ECM genes overexpression in cell culture. These findings suggest that miR-130a and miR-130b are involved in downregulation of PPARgamma in liver fibrosis. PMID- 26255202 TI - Oxidation of glyceraldehyde-3-phosphate dehydrogenase decreases sperm motility in diabetes mellitus. AB - The relation between the activity of the sperm specific glyceraldehyde-3 phosphate dehydrogenase (GAPDS) and the motility of sperms in diabetic men was investigated. It was found that the mean value of GAPDS activity and sperm motility in diabetic sperm samples is lower than that in normal samples. The activity of GAPDS protein was significantly positive correlation with sperm motility (R = 0.96) and significantly negative correlation with the incidence of infertility (R = -0.99). The fluorescence intensity of GAPDS protein in sperms of 2-diabetic patients (>5years, n = 88) was significantly lower than that in normal control group. The location rate of GAPDS protein in sperms of diabetic men was also significantly lower compared with that found in samples from non-diabetic men. Exogenous GAPDS protein can diminish ROS content in sperms and promote sperm motility at the concentration of over 5 ug/ml GAPDS. Based on the literature data on the importance of GAPDS for the motility of sperms in diabetic men, it was concluded that the decrease in the sperm motility and GAPDS activity in the presence of high glucose or diabetes mellitus is due to oxidation of GAPDS and inhibition of glycolysis by the reactive oxygen species produced by sperms. PMID- 26255203 TI - MiR-30a-5p is induced by Wnt/beta-catenin pathway and promotes glioma cell invasion by repressing NCAM. AB - Wnt/beta-catenin signaling pathway is frequently dysregulated in human tumors and plays a critical role in tumorigenesis; however, the roles of microRNAs in mediating Wnt/beta-catenin pathway are not well understood. Herein, we show that miR-30a-5p is activated by Wnt/beta-catenin pathway through direct binding of beta-catenin/TCF4 to two sites in the promoter region of miR-30a-5p. We also found that miR-30a-5p represses neural cell adhesion molecule (NCAM) expression by directly targeting two sites in the 3' untranslated region (3'-UTR) of NCAM mRNA. Moreover, Wnt/beta-catenin pathway represses NCAM expression in glioma cells, which depends on miR-30a-5p. Finally, we found that miR-30a-5p promotes glioma cell growth invasion by repressing NCAM. Our findings demonstrate a novel Wnt/beta-catenin-miR-30a-5p-NCAM regulatory axis which plays important roles in controlling glioma cell invasion and tumorigenesis. PMID- 26255204 TI - Response to the letter regarding our publication "Long-term course of orthostatic tremor in serial posturographic measurement". PMID- 26255206 TI - Morphology of congenital and acquired aortic valve disease by cardiovascular magnetic resonance imaging. AB - Echocardiography is the principal non-invasive tool for initial evaluation and longitudinal monitoring of patients with significant valvular heart disease. However echocardiography can be limited by poor acoustic windows, and is dependent on the skill and experience of the sonographer. Cardiovascular magnetic resonance (CMR) can provide a comprehensive non-invasive assessment of valvular morphology, quantification of the severity of valvular dysfunction, determination of its aetiology, assessment of the consequences for the heart from the valve lesion including measurement of ventricular volumes and function, and evaluation of haemodynamic abnormalities. Additional information such as great vessel anatomy and the presence of coronary disease and myocardial scar can also be obtained from CMR. Aortic valve disease can manifest as aortic regurgitation, aortic stenosis or a mixture of both. Structural abnormalities of the valve (congenital or acquired) or disease of the aorta (structurally normal valve) can cause aortic valve disease. This review describes the role of CMR in evaluation of patients with aortic valve diseases, and illustrates the typical and distinguishing morphological features seen on CMR in a range of congenital and some common acquired aortic valve lesions. Although CMR can provide important information about the morphology of aortic valve, its full potential has yet to be realised, and further studies of clinical outcomes are needed before CMR data can be integrated into the management of patients with significant aortic valvular lesions. PMID- 26255205 TI - Deficient vesicular storage: A common theme in catecholaminergic neurodegeneration. AB - Several neurodegenerative diseases involve loss of catecholamine neurons- Parkinson's disease (PD) is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are lost has been mysterious. Accumulating evidence supports the concept of "autotoxicity"--inherent cytotoxicity caused by catecholamine metabolites. Since vesicular sequestration limits the buildup of toxic products of enzymatic and spontaneous oxidation of catecholamines, a vesicular storage defect could play a pathogenic role in the death of catecholaminergic neurons in a variety of neurodegenerative diseases. In putamen, deficient vesicular storage is revealed in vivo by accelerated loss of (18)F-DOPA-derived radioactivity and post-mortem by decreased tissue dopamine (DA):DOPA ratios; in myocardium in vivo by accelerated loss of (18)F-dopamine derived radioactivity and post-mortem by increased 3,4 dihydroxyphenylglycol:norepinephrine (DHPG:NE) ratios; and in sympathetic noradrenergic nerves overall in vivo by increased plasma F-dihydroxyphenylacetic acid (F-DOPAC):DHPG ratios. We retrospectively analyzed data from 20 conditions with decreased or intact catecholaminergic innervation, involving different etiologies, pathogenetic mechanisms, and lesion locations. All conditions involving parkinsonism had accelerated loss of putamen (18)F-DOPA-derived radioactivity; in those with post-mortem data there were also decreased putamen DA:DOPA ratios. All conditions involving cardiac sympathetic denervation had accelerated loss of myocardial (18)F-dopamine-derived radioactivity; in those with post-mortem data there were increased myocardial DHPG:NE ratios. All conditions involving localized loss of catecholaminergic innervation had evidence of decreased vesicular storage specifically in the denervated regions. Thus, across neurodegenerative diseases, loss of catecholaminergic neurons seems to be associated with decreased vesicular storage in the residual neurons. PMID- 26255207 TI - Characterization of socioeconomic status of Japanese patients with atopic dermatitis showing poor medical adherence and reasons for drug discontinuation. AB - BACKGROUND: Patients' high adherence to medication is indispensable for the management of skin diseases including atopic dermatitis. We previously showed poor medication adherence in Japanese dermatological patients. OBJECTIVE: This study was conducted to determine the level of adherence to oral or topical medication in Japanese patients with atopic dermatitis, attempting to characterize the socioeconomic status of those patients with poor adherence. METHODS: A web questionnaire survey on demographic data as well as adherence level was conducted on patients registered in the monitoring system. Adherence level was assessed with Morisky Medication Adherence Scale-8 (MMAS-8). Among a total of 3096 respondents with dermatological disorders, data of 1327 subjects with atopic dermatitis were extracted and analyzed. RESULTS: More than 80% of subjects felt that both oral and topical medications were safe and efficacious, while less than 60% of them were satisfied with their treatment. Levels of adherence to oral and topical treatments were evaluated with MMAS-8, giving scores of 4.6 and 4.2, respectively. Demographic factors such as gender, marital status, state of employment, alcohol consumption, frequency of hospital visits, and experience of drug effectiveness had a significant impact on the degree of adherence to treatment. CONCLUSION: Medication adherence level in Japanese subjects with atopic dermatitis was relatively low compared with that of other chronic diseases. Our survey has characterized patients with poor adherence, who are good targets for interventions to maximize potentially limited healthcare resources. PMID- 26255208 TI - Maternal and neonatal consequences of treated and untreated asymptomatic bacteriuria in pregnancy: a prospective cohort study with an embedded randomised controlled trial. AB - BACKGROUND: Existing approaches for the screening and treatment of asymptomatic bacteriuria in pregnancy are based on trials that were done more than 30 years ago. In this study, we reassessed the consequences of treated and untreated asymptomatic bacteriuria in pregnancy. METHODS: In this multicentre prospective cohort study with an embedded randomised controlled trial, we screened women (aged >=18 years) at eight hospitals and five ultrasound centres in the Netherlands with a singleton pregnancy between 16 and 22 weeks' gestation for asymptomatic bacteriuria. Screening was done with a single dipslide and two culture media. Dipslides were judged positive when the colony concentration was at least 1*10(5) colony-forming units (CFU) per mL of a single microorganism or when two different colony types were present but one had a concentration of at least 1*10(5) CFU per mL. Asymptomatic bacteriuria-positive women were eligible to participate in the randomised controlled trial comparing nitrofurantoin with placebo treatment. In this trial, participants were randomly assigned 1:1 to receive either nitrofurantoin 100 mg or identical placebo tablets, and were instructed to self-administer these tablets twice daily for 5 consecutive days. Randomisation was done by a web-based application with a computer-generated list with random block sizes of two, four, or six participants rendered by an independent data manager. 1 week after the end of treatment, they provided us with a follow-up dipslide. Women, treating physicians, and researchers all remained unaware of the bacteriuria status and treatment allocation. Women who refused to participate in the randomised controlled trial did not receive any antibiotics, but their outcomes were collected for analysis in the cohort study. We compared untreated and placebo-treated asymptomatic bacteriuria-positive women with asymptomatic bacteriuria-negative women and nitrofurantoin-treated asymptomatic bacteriuria-positive women. The primary endpoint was a composite of pyelonephritis with or without preterm birth at less than 34 weeks, analysed by intention to treat at 6 weeks post-partum. This trial is registered with the Dutch Trial Registry, number NTR3068. FINDINGS: Between Oct 11, 2011, and June 10, 2013, we enrolled 5621 women into our screening cohort, of whom 5132 were eligible for screening. After exclusions for contaminated dipslides and patients lost to follow-up, in our final cohort of 4283 women, 248 were asymptomatic bacteriuria positive, of whom 40 were randomly assigned to nitrofurantoin and 45 to placebo for the randomised controlled trial, whereas the other 163 asymptomatic bacteriuria-positive women were followed without treatment. The proportion of women with pyelonephritis, preterm birth, or both did not differ between untreated or placebo-treated asymptomatic bacteriuria-positive women and asymptomatic bacteriuria-negative women (6 [2.9%] of 208 vs 77 [1.9%] of 4035; adjusted odds ratio [OR] 1.5, 95% CI 0.6-3.5) nor between asymptomatic bacteriuria-positive women treated with nitrofurantoin versus those who were untreated or received placebo (1 [2.5%] of 40 vs 6 [2.9%] of 208; risk difference -0.4, 95% CI -3.6 to 9.4). Untreated or placebo-treated asymptomatic bacteriuria positive women developed pyelonephritis in five [2.4%] of 208 cases, compared with 24 [0.6%] of 4035 asymptomatic bacteriuria-negative women (adjusted OR 3.9, 95% CI 1.4-11.4). INTERPRETATION: In women with an uncomplicated singleton pregnancy, asymptomatic bacteriuria is not associated with preterm birth. Asymptomatic bacteriuria showed a significant association with pyelonephritis, but the absolute risk of pyelonephritis in untreated asymptomatic bacteriuria is low. These findings question a routine screen-treat-policy for asymptomatic bacteriuria in pregnancy. FUNDING: ZonMw (the Netherlands Organisation for Health Research and Development). PMID- 26255209 TI - Management of asymptomatic bacteriuria in pregnant women. PMID- 26255210 TI - Strategies targeting the IL-4/IL-13 axes in disease. AB - IL-4 and IL-13 are pleiotropic Th2 cytokines produced by a wide variety of different cell types and responsible for a broad range of biology and functions. Physiologically, Th2 cytokines are known to mediate host defense against parasites but they can also trigger disease if their activities are dysregulated. In this review we discuss the rationale for targeting the IL-4/IL-13 axes in asthma, atopic dermatitis, allergic rhinitis, COPD, cancer, inflammatory bowel disease, autoimmune disease and fibrotic disease as well as evaluating the associated clinical data derived from blocking IL-4, IL-13 or IL-4 and IL-13 together. PMID- 26255212 TI - A comparative investigation of mussel-mimetic sealants for fetal membrane repair. AB - Towards the prevention of iatrogenic preterm premature rupture of the fetal membrane, two mussel-mimetic tissue adhesives (cT and cPEG) have been compared and qualified as possible sealants for membrane repair. Monotonic and cyclic inflation tests of repaired fetal membranes were carried out in order to investigate the performance of the glues under quasi-static, fast, and repeated loading. Finite element simulations of repaired and inflated synthetic membranes allowed to compare cT and cPEG under large deformations. Both adhesives seal the membrane well, resisting pressures higher than the intra-uterine baseline. Only under repeated mechanical load, as well as under fast and acute deformation of the membrane, the sealing performance has deteriorated. Even though cT loses adhesion to the deformed membrane, it is able to withstand high deformations and pressures without rupturing, while cPEG breaks. PMID- 26255213 TI - A Novel Cause of Acute Coronary Syndrome Due to Dynamic Extrinsic Coronary Artery Compression by a Rib Exostosis: Multimodality Imaging Diagnosis. AB - We report a case of acute coronary syndrome secondary to intermittent extrinsic compression of the left anterior descending coronary artery by inward-pointing rib exostosis in an 18-year-old woman during forceful repeated expiration in labour. The diagnosis was achieved using multimodality noninvasive cardiac imaging. In particular, we demonstrated the novel role of expiratory-phase cardiac computed tomography in confirming the anatomical relationship of the bony exostosis to the left anterior descending coronary artery. The case reminds us the heart and mediastinum move dynamically, relative to the bony thorax, throughout the respiratory cycle, and that changes in cardiac physiology in pregnancy may become pathological. PMID- 26255214 TI - Echocardiographic vs Invasive Measurement of the Direct Flow Transcatheter Aortic Heart Valve Mean Gradient: Contradictory or Complementary? AB - In this case report, we explain the reason behind observed differences in echocardiographic and invasively measured mean aortic valve gradient after transcatheter aortic valve implantation. A 25-mm Direct Flow valve (Direct Flow Medical Inc, Santa Rosa, CA) was successfully implanted in a patient with severe aortic stenosis via the transfemoral route. The discrepancy between invasive and echocardiographic measurements could be explained by the combination of a non flat velocity profile inside the tubular structure of the Direct Flow valve, which can cause local low pressure fields that result in true high gradients detected using Doppler, and pressure recovery. PMID- 26255211 TI - Interleukin-6 inhibits apoptosis of exocrine gland tissues under inflammatory conditions. AB - Interleukin (IL)-6 is a multi-functional cytokine that can either promote or suppress tissue inflammation depending on the specific disease context. IL-6 is elevated in the exocrine glands and serum of patients with Sjogren's syndrome (SS), but the specific role of IL-6 in the pathogenesis of this disease has not been defined. In this study, we showed that IL-6 expression levels were increased with age in C56BL/6.NOD-Aec1Aec2 mice, a primary SS model, and higher than the control C57BL/6 mice. To assess the role of IL-6 during the immunological phase of SS development, a neutralizing anti-IL-6 antibody was administered into 16 week-old female C56BL/6.NOD-Aec1Aec2 mice, 3 times weekly for a consecutive 8 weeks. Neutralization of endogenous IL-6 throughout the immunological phase of SS development led to increased apoptosis, caspase-3 activation, leukocytic infiltration, and IFN-gamma- and TNF-alpha production in the salivary gland. To further determine the effect of IL-6 on the apoptosis of exocrine gland cells, recombinant human IL-6 or the neutralizing anti-IL-6 antibody was injected into female C57BL/6 mice that received concurrent injection of anti-CD3 antibody to induce the apoptosis of exocrine gland tissues. Neutralization of IL-6 enhanced, whereas administration of IL-6 inhibited apoptosis and caspase-3 activation in salivary and lacrimal glands in this model. The apoptosis-suppressing effect of IL-6 was associated with up-regulation of Bcl-xL and Mcl-1 in both glands. Moreover, IL-6 treatment induced activation of STAT3 and up-regulated Bcl-xL and Mcl-1 gene expression in a human salivary gland epithelial cell line. In conclusion, IL-6 inhibits the apoptosis of exocrine gland tissues and exerts a tissue-protective effect under inflammatory conditions including SS. These findings suggest the possibility of using this property of IL-6 to preserve exocrine gland tissue integrity and function under autoimmune and inflammatory conditions. PMID- 26255215 TI - Assessment of Left Ventricular Function by Layer-Specific Strain and Its Relationship to Structural Remodelling in Patients With Hypertension. AB - BACKGROUND: Systemic arterial hypertension causes functional and structural remodelling of the left ventricle, which is related to subclinical left ventricular (LV) dysfunction and heart failure. This study assessed LV functional change using layer-specific strain and its relationship to structural remodelling in patients with hypertension. METHODS: A total of 145 patients (61 +/- 12 years) with primary hypertension and preserved LV ejection fraction and 31 normotensive controls (63 +/- 9 years) were prospectively included. Longitudinal strains of the endocardium, myocardium, and epicardium (LSendo, LSmyo, and LSepi) were obtained by averaging peak systolic strain of the left ventricle, with 18 segments in each layer. RESULTS: Layer-specific strains showed a decreasing gradient from the endocardium to the epicardium in both controls and patients with hypertension (P < 0.001 in both) and were significantly different between controls and patients with hypertension in all 3 layers (LSendo, -20.4% +/- 2.4% vs -19.2% +/- 2.2%; P = 0.007; LSmyo, -15.8% +/- 2.0% vs -14.8% +/- 1.9%; P = 0.005; LSepi, -11.8% +/- 2.0% vs -11.0% +/- 1.8%,; P = 0.04). Both LSendo and LSmyo were lower even in patients with hypertension and no LV hypertrophy than in controls (both P < 0.05), although global LS was not different. New patients with hypertension showed more decreased LSendo and LSmyo than controls even with their younger age. LSs of all 3 layers were related to LV mass index and mitral annular velocity parameters. CONCLUSIONS: Layer-specific evaluation of the left ventricle provides an understanding of the layer-specific properties of the LV wall and the process of LV impairment, and it may be helpful in managing patients with hypertension, thus preventing further damage. PMID- 26255216 TI - Transcatheter Left Atrial Appendage Closure Using Intracardiac Echocardiographic Guidance From the Left Atrium. AB - BACKGROUND: Most commonly, left atrial appendage (LAA) occlusion procedures are performed using transesophageal echocardiography (TEE) guidance and general anaesthesia. Intracardiac echocardiography (ICE) offers potential advantages over TEE, however, ICE-guided LAA occlusion experience is limited and has been typically performed from a right-sided location where LAA visualization might be suboptimal. We sought to evaluate the efficacy and safety of percutaneous LAA occlusion using ICE guidance performed from the left atrium. METHODS: Thirty seven patients with atrial fibrillation, significant risk for stroke, and long term contraindication to anticoagulation underwent LAA closure with the Amplatzer Cardiac Plug (St Jude Medical, Inc, St Paul, MN) with mild sedation and ICE guidance. The ICE catheter was introduced in the left atrium through a second transseptal puncture. Patients underwent preprocedural TEE to rule out thrombus and 3-month follow-up TEE to assess occlusion grade. Patient characteristics, procedural data, effectiveness of ICE imaging, quality of occlusion, and complications were prospectively recorded. RESULTS: Procedural success was achieved in 36 of 37 patients (97%). Closure was complete or near complete (grade >=3 according to ICE and angiography) in all cases where the device was released. In all cases, ICE imaging yielded good LAA and surrounding structure visualization and adequate procedural guidance. Three major procedural or in hospital complications occurred. Median length of stay was 1 day. Follow-up TEE documented the absence of any residual peri-device leak in all but 1 (29 of 30) case. CONCLUSION: Initial experience suggests LAA occlusion with the Amplatzer Cardiac Plug using ICE guidance from the left atrium is feasible, reproducible, and safe. PMID- 26255217 TI - Symptomatic Partial Congenital Absence of the Pericardium Revealed Using Cardiac Magnetic Resonance. AB - Congenital absence of the pericardium is a very uncommon finding, and its diagnosis poses a challenge because it is rarely suspected in daily clinical practice. Although in most cases it has a benign course, this congenital defect should be identified because of the associated risk of sudden death. We present a symptomatic case of partial congenital absence of the left pericardium suspected as the result of an abnormal response to exercise stress testing, and confirmed using cardiac magnetic resonance imaging. We review the current diagnostic tools and therapeutic indications of this rare anomaly. PMID- 26255218 TI - Utility of the Logistic Clinical Syntax Score in the Prediction of Contrast Induced Nephropathy After Primary Percutaneous Coronary Intervention. AB - BACKGROUND: The Logistic Clinical Syntax Score (log CSS) is a combined risk scoring system that includes clinical and anatomic parameters; it has been found to be effective for the prediction of mortality in patients with ST-elevation myocardial infarction (STEMI). The aim of the present study was to assess whether the log CSS was associated with the development of contrast-induced nephropathy (CIN) in patients who underwent primary percutaneous coronary intervention (pPCI). METHODS: A total of 930 patients with STEMI undergoing pPCI between January 2012 and August 2013 were included prospectively. The patients were grouped according to the development of CIN. Either an absolute serum creatinine level >= 0.5 mg/dL or a 25% increase in the serum creatinine level compared with the baseline level within 48 hours after the administration of contrast medium was defined as CIN. RESULTS: The Synergy Between Percutaneous Coronary Interventions With Taxus and Cardiac Surgery score (SYNTAX [SS]) and log CSS were higher in patients with CIN than in those without. In the multivariate analysis, log CSS (odds ratio, 1.405, 95% confidence interval, 1.318-1.497; P < 0.001), hemoglobin, and contrast volume were found to be independent predictors of CIN. In the receiver operating characteristic analysis, a log CSS > 9.5 had a 74.5% sensitivity and a 90.5% specificity for predicting CIN, with an area under the curve (AUC) of 0.892, whereas an SS > 18.5 had a 64% sensitivity, a 58.1% specificity, and an AUC of 0.625 (0.892 vs 0.625; P < 0.001). A log CSS > 9.5 was associated with in-hospital and long-term mortality, reinfarction, revascularization, and in-hospital hemodialysis (P < 0.001 for each). CONCLUSIONS: The log CSS may improve the accuracy of risk stratification for the development of CIN in patients undergoing pPCI. PMID- 26255219 TI - Implementing a declination form programme to improve influenza vaccine uptake by staff in Department of Veterans Affairs spinal cord injury centres: a pilot study. AB - BACKGROUND: Individuals with spinal cord injuries and disorders are at high risk for respiratory and influenza-related complications after developing influenza. These individuals often have frequent contact with the healthcare system. Vaccination rates in healthcare workers at Department of Veterans Affairs (VA) spinal cord injury (SCI) centres have been approximately 50% for several years. Efforts are needed to increase vaccination uptake among SCI HCWs. Declination form programmes (DFPs) in combination with other strategies have resulted in significant increases in influenza vaccination uptake in HCWs. AIM: Use of external and internal facilitation including local teams and consensus processes to pilot a DFP in two VA SCI centres and evaluate factors influencing implementation. METHODS: Implementation meetings and a consensus-building process with leadership and implementation team members were conducted, along with semi structured post-implementation interviews with members of each implementation team (N = 7). FINDINGS: The DFP was well accepted and easy to use. Leadership was a key facilitator for DFP implementation. Barriers included difficulty communicating with HCWs working during early/late shifts. Participation was 100% at Site 1 and 48% at Site 2. CONCLUSION: Use of local teams and consensus to identify strategies to implement a DFP is feasible and effective for achieving moderate-to-high levels of participation in the programme. PMID- 26255220 TI - Powder, capsule and device: An imperative menage a trois for respirable dry powders. AB - OBJECTIVES: The development of inhaled products to treat or to prevent lung infection is a very active research field in drug delivery. The pulmonary route is extremely attractive but very challenging. This paper reports the study of excipient, capsule brand and device influence on the aerodynamic behavior of dry powder formulations to treat tuberculosis. METHODS: A capreomycin hydrophobic salt was powdered using spray-drying and formulated using lactose (added after spray-drying, external excipient) or L-leucine (added before spray-drying, internal excipient). Aerosolization performances were investigated loading the formulations in 2 different capsule brands and aerosolizing them with 3 different devices. RESULTS: Capreomycin oleate and capreomycin oleate/l-leucine powders were produced with a yield around 70%. Capreomycin oleate powder was composed of particles with an irregular surface. Particles of capreomycin oleate/l-leucine were roundish and wrinkled on the surface. Capreomycin oleate/l-leucine formulation gave the highest values of respirable fraction in all cases. Statistical analysis asserted the significant effect on the respirable fraction of the powder (p<=0.001), the capsule brand (p<=0.01) and the device (p<=0.05). CONCLUSIONS: The use of L-leucine as internal excipient allows one to avoid the use of lactose, obtaining a carrier-free formulation. Even though differences are not very large, to obtain the highest RFE, the best choice between capsule and device is Quali-V((r)) and model 8. PMID- 26255221 TI - Author reply: Home non-invasive mechanical ventilation use following acute hypercapnic respiratory failure in COPD. A solid protective factor. PMID- 26255222 TI - Progesterone supplementation after ovulation: effects on corpus luteum function and on fertility of dairy cows subjected to AI or ET. AB - Three experiments were done to evaluate the effects of progesterone (P4) supplementation starting during metestrus on formation of the CL and on fertility of lactating dairy cows subjected to fixed-time artificial insemination (FTAI) or embryo transfer (ET). In experiment 1, 42 Holstein cows were randomly allocated to untreated (Control) or to receive an intravaginal implant containing 1.9 g of P4 from Day 3 to 20 after FTAI (controlled internal drug release [CIDR]). Blood samples were collected on Days 3, 4, 7, 11, 14, 17, 20, and 21 after FTAI to evaluate the effect of CIDR supplementation on plasma concentration of P4 using radioimmunoassay. Ultrasound scans were performed at Days 4, 7, 11, 14, and 20 to evaluate CL volume. In experiment 2, the effect on CIDR supplementation on fertility was evaluated in 668 Holstein and crossbred dairy cows that were subjected to FTAI and allocated randomly to untreated (AI-Control) or to receive a CIDR from Day 3 to 17 (AI-CIDR) after FTAI. In experiment 3, 360 Holstein cows were treated with PGF and after heat detection (Day 0), they were allocated to untreated (ET-Control) or to receive a CIDR from Day 4 +/- 1 to 8 +/- 1 (ET-CIDR 4) or a CIDR from 4 +/- 1 to 18 +/- 1 (ET-CIDR-14). In vitro-produced embryos were transferred on Day 8 +/- 1. Pregnancy diagnoses were performed by ultrasound. In experiment 1, there was interaction between treatment and day in relation to plasma P4 on Days 4 and 7 due to CIDR supplementation. Independent of treatment, pregnant cows had higher plasma P4 from Day 14 to 21 than nonpregnant cows (P <= 0.05). Supplementation with CIDR did not alter CL development. In experiment 2, there was no effect of supplementation of P4 on pregnancy per AI on Day 32 (32.0% vs. 31.8%, for AI-Control and AI-CIDR, respectively) or pregnancy loss (15.6% vs. 17.6%, for AI-Control and AI-CIDR, respectively). In experiment 3, P4 supplementation compromised pregnancy per ET (P/ET) on Day 32 in both supplemented groups (39.7% vs. 21.3% vs. 15.2%, for ET-Control, ET-CIDR-4, and ET CIDR-14, respectively), with no effect on pregnancy loss. Therefore, although CIDR insertion on Day 3 after FTAI did not affect CL function and increased circulating P4, it did not increase pregnancy per AI in lactating dairy cows submitted to FTAI. Moreover, P4 supplementation decreased pregnancy per ET in lactating recipient cows. PMID- 26255223 TI - Birth of piglets from in vitro-produced porcine blastocysts vitrified and warmed in a chemically defined medium. AB - We examined the effect of different embryo developmental stages, culture periods, and media on the cryotolerance of in vitro-produced porcine blastocysts. All media used for in vitro production, vitrification, and warming were chemically defined. When in vitro-produced embryos at the blastocyst and expanded blastocyst stages were vitrified using the Cryotop method on Day 5 or 6 (Day 0 = the day of IVF), the survival rate and hatching rate of expanded blastocysts after warming were higher than those of blastocysts. The viability after vitrification and warming of Day-6 embryos cultured in porcine blastocyst medium from Day 5 were higher than that of embryos cultured in porcine zygote medium 5. On the other hand, there were no significant differences on the cryotolerance between Day-5 embryos cultured in porcine zygote medium 5 and those replaced with porcine blastocyst medium on Day 4. There were no significant differences in viability between the embryonic ages of 5 and 6 days after vitrification and warming. When expanded blastocysts vitrified on Day 5 or 6 were surgically transferred to recipient gilts, all three recipients became pregnant in the Day-5 group, whereas only one out of three recipients became pregnant in the Day-6 group. These results indicate that the cryotolerance of porcine in vitro-produced blastocysts after vitrification appears to depend on the embryonic stage, culture period, and medium. PMID- 26255224 TI - Three-dimensional printing in surgery: a review of current surgical applications. AB - BACKGROUND: Three-dimensional printing (3DP) is gaining increasing recognition as a technique that will transform the landscape of surgical practice. It allows for the rapid conversion of anatomic images into physical objects, which are being used across a variety of surgical specialties. It has been unclear which groups are leading the way in coming up with novel ways of using the technology and what specifically the technology is being used for. The aim of this article was to review the current applications of 3DP in modern surgical practice. MATERIALS AND METHODS: An electronic search was carried out in MEDLINE, EMBASE, and PsycINFO for terms related to 3DP. These were then screened for relevance and practical applications of the technology in surgery. RESULTS: Four hundred eighty-eight articles were initially found, and these were eventually narrowed down to 93 full text articles. It was determined that there were three main areas in which the technology is being used to print: (1) anatomic models, (2) surgical instruments, and (3) implants and prostheses. CONCLUSIONS: Different specialties are at different stages in the use of the technology. The costs involved with implementing the technology and time taken for printing are important factors to consider before widespread use. For the foreseeable future, this is an exciting and interesting technology with the capacity to radically change health care and revolutionize modern surgery. PMID- 26255225 TI - A simple bioscore improves diagnostic accuracy of sepsis after surgery. AB - BACKGROUND: Rapid and accurate prediction for sepsis remains a challenge in surgical intensive care units. Detection of individual biomarkers is often of marginal usefulness, and several biomarkers are difficult to measure in the clinical setting. The aim of this study was to evaluate the diagnostic and prognostic performance of three routine biomarkers, procalcitonin (PCT), B-type natriuretic peptide (BNP), and lymphocyte percentage, as individual or in combination for sepsis in surgical critically ill patients. MATERIALS AND METHODS: Circulating PCT, BNP, and lymphocyte percentage were measured in surgical patients on admission to the intensive care unit. A bioscore system combining these biomarkers was constructed. All studied variables were analyzed according to the diagnosis and clinical outcomes of sepsis. RESULTS: A total of 320 consecutive patients were included in the analysis. One hundred fifty-six patients presented with sepsis. In the patients with sepsis, levels of PCT and BNP increased and lymphocyte percentage decreased. For individual biomarkers, PCT achieved the best area under the curve for the diagnosis of sepsis, whereas the diagnostic performance of the bioscore was better than that of each individual biomarker (area under the curve, 0.914 [95% confidence interval, 0.862-0.951]). Levels of BNP and bioscore increased in nonsurvivors in the entire cohort, but the accuracy of these two variables for mortality prediction was lower than that shown by Acute Physiology and Chronic Health Evaluation II score. Furthermore, bioscore failed to predict outcomes in septic patients. CONCLUSIONS: A simple bioscore combining PCT together with BNP and lymphocyte percentage improves the diagnostic accuracy for sepsis in surgical critically ill patients but fails to predict outcomes in surgical patients with sepsis. PMID- 26255226 TI - The role of systemic therapy in the management of sinonasal cancer: A critical review. AB - PURPOSE: Due to the rarity and the variety of histological types of sinonasal cancers, there is a paucity of data regarding strategy for their optimal treatment. Generally, outcomes of advanced and higher grade tumors remain unsatisfactory, despite the employment of sophisticated surgical approaches, technical advances in radiation techniques and the use of heavy ion particles. In this context, we critically evaluated the role of systemic therapy as part of a multidisciplinary approach to locally advanced disease. RESULTS: Induction chemotherapy has shown encouraging activity and could have a role in the multimodal treatment of patients with advanced sinonasal tumors. For epithelial tumors, the most frequently employed chemotherapy is cisplatin, in combination with either 5-fluorouracil, taxane, ifosfamide, or vincristine. Only limited experiences with concurrent chemoradiation exist with sinonasal cancer. The role of systemic treatment for each histological type (intestinal-type adenocarcinoma, sinonasal undifferentiated carcinoma, sinonasal neuroendocrine carcinoma, olfactory neuroblastoma, sinonasal primary mucosal melanoma, sarcoma) is discussed. CONCLUSIONS: The treatment of SNC requires a multimodal approach. Employment of systemic therapy for locally advanced disease could result in better outcomes, and optimize the therapeutic armamentarium. Further studies are needed to precisely define the role of systemic therapy and identify the optimal sequencing for its administration in relation to local therapies. PMID- 26255227 TI - Cognitive psychotherapy treatment decreases peripheral oxidative stress parameters associated with major depression disorder. AB - INTRODUCTION: Studies have already pointed out the contribution of oxidative stress in the pathophysiology of major depressive disorder (MDD). The aim of the present study was to investigate the oxidative-antioxidative systems in MDD and in response to cognitive psychotherapies. Oxidative stress were analyzed in 49 MDD patients at baseline, post-treatment, and follow-up; and 49 control subjects without history of psychiatric disorders. RESULTS: MDD subjects presented an increase in oxidative damage related to control subjects for thiobarbituric acid reactive species (TBARS), nitric oxide, and a decrease in total thiol content. Cognitive psychotherapies were able to counteract peripheral oxidative stress in MDD patients, reducing TBARS levels (p<0.001) in the follow-up, nitric oxide (p<0.001) in the post-treatment and follow-up, and increasing the total thiol content (p<0.01) in the post-treatment and follow-up. CONCLUSION: Oxidative stress was associated with MDD and the regulation of these parameters might represent an important mechanism associated with the clinical improvement of cognitive psychotherapy. PMID- 26255228 TI - Koumine enhances spinal cord 3alpha-hydroxysteroid oxidoreductase expression and activity in a rat model of neuropathic pain. AB - BACKGROUND: Koumine is an alkaloid monomer found abundantly in Gelsemium plants. It has been shown to reverse thermal hyperalgesia and mechanical allodynia induced by sciatic nerve chronic constriction injury (CCI) in rats in a dose dependent manner. Interestingly, this effect is mediated by elevated allopregnanolone levels in the spinal cord (SC). Since 3alpha-hydroxysteroid oxidoreductase (3alpha-HSOR), the key synthetase of allopregnanolone, is responsible for allopregnanolone upregulation in the SC, the objective of the present study was to investigate the role of its expression in the SC in koumine induced analgesia using a rat model of neuropathic pain following peripheral nerve injury. RESULTS: Time-course investigations of immunohistochemistry and real-time polymerase chain reaction revealed that the immunoreactivity and mRNA expression of 3alpha-HSOR markedly increased in a time-dependent manner in the SC of koumine-treated CCI rats. Furthermore, 3alpha-HSOR activity in the SC of koumine-treated CCI rats increased by 15.8% compared to the activity in untreated CCI rats. Intrathecal injection of medroxyprogesterone acetate, a selective 3alpha-HSOR inhibitor, reversed the analgesic effect of koumine on CCI-induced mechanical pain perception. Our results confirm that koumine alleviates neuropathic pain in rats with CCI by enhancing 3alpha-HSOR mRNA expression and bioactivity in the SC. CONCLUSION: This study demonstrates that 3alpha-HSOR is an important molecular target of koumine for alleviating neuropathic pain. Koumine may prove a promising compound for the development of novel analgesic agents effective against intractable neuropathic pain. PMID- 26255229 TI - Impact of fluid resuscitation on major adverse events following pancreaticoduodenectomy. AB - BACKGROUND: Pancreaticoduodenectomy remains a major undertaking with substantial perioperative morbidity and mortality. Previous studies in the colorectal population have noted a correlation between excessive postoperative fluid resuscitation and anastomotic complications. This study sought to assess the relationship between perioperative fluid management and clinical outcomes in patients undergoing pancreaticoduodenectomy. METHODS: Data from a single institution, prospective database over a 10-year period (2002 to 2012) were reviewed. Patients were compared for perioperative fluid balance and postoperative outcomes. Multivariable analysis was performed to assess the relationship between perioperative fluid administration and incidence of major adverse events. RESULTS: Higher positive fluid balance on postoperative day 0, postoperative day 1, and postoperative day 2 was associated with increased incidence of major adverse events, increased postoperative intensive care unit admission, and longer hospital stay. Higher positive fluid balance on postoperative day 0 was most strongly associated with postoperative morbidity (odds ratio 1.39, confidence interval 1.16 to 1.66, P = .0003). Fluid balance on postoperative day 3 was not associated with adverse events. CONCLUSIONS: Increased early perioperative fluid resuscitation is associated with major adverse events in patients undergoing pancreaticoduodenectomy. More restrictive fluid administration may improve postoperative outcomes; further prospective clinical trials focused on fluid resuscitation and goal-directed therapy are needed. PMID- 26255230 TI - Does three-dimensional intraoperative specimen imaging reduce the need for re excision in breast cancer patients? A prospective cohort study. AB - BACKGROUND: Standard two-dimensional (2D) specimen radiography may guide intraoperative re-excision of margins in patients undergoing breast conserving surgery. We sought to determine the impact of three-dimensional (3D) specimen imaging in further reducing positive margin rates. METHODS: A prospective study of 100 patients in which both 2D and 3D specimen radiographies were performed. The impact of orthogonal view on intraoperative surgical management and final margins was assessed. RESULTS: Ten patients had no residual tumor; therefore, 90 patients formed the cohort of interest. Of them, 21 patients (23.3%) had ductal carcinoma in situ; 18 (20.0%) had invasive cancer; and 51 (56.7%) had both. Median tumor size was 1.7 cm (range, .2 to 8.1 cm). On the basis of 2D imaging, surgeons stated they would take more tissue in 26 patients (28.9%). Three dimensional imaging changed management in 4 patients (6.3%). One of these patients would have had positive margins if the intraoperative resection done on the basis of the 3D imaging would have been omitted. CONCLUSIONS: Three dimensional specimen imaging results in further intraoperative re-excision in 6.3% of patients and may reduce re-excision rates in 2.2%. PMID- 26255231 TI - [Orthodontic treatment in children suffering from obstructive sleep apnea]. AB - The obstructive sleep apnea syndrome (OSAS) may affect children, especially those with dentofacial disharmonies. Dentofacial orthopedic (DFO) treatments carried out in those patients must take this condition into account and can, in selected cases, improve or even treat the OSAS. The goal of our work was to report our experience about DFO treatments of children affected by OSAS in the department of maxillofacial surgery of Femme-Mere-Enfant hospital of university hospitals of Lyon, France. PMID- 26255232 TI - Limited premature termination codon suppression by read-through agents in cystic fibrosis intestinal organoids. AB - Premature termination codon read-through drugs offer opportunities for treatment of multiple rare genetic diseases including cystic fibrosis. We here analyzed the read-through efficacy of PTC124 and G418 using human cystic fibrosis intestinal organoids (E60X/4015delATTT, E60X/F508del, G542X/F508del, R1162X/F508del, W1282X/F508del and F508del/F508del). G418-mediated read-through induced only limited CFTR function, but functional restoration of CFTR by PTC124 could not be confirmed. These studies suggest that better read-through agents are needed for robust treatment of nonsense mutations in cystic fibrosis. PMID- 26255233 TI - Effects of antitumor derivatives of ineffective transplatin on bacterial cells: Is DNA a pharmacological target? AB - The effects of the two representatives of the antitumor transplatinum agents, trans-[PtCl2(methylamine)2] and trans-[PtCl2(NH3)(1-methyl-7-azaindole)] on bacterial growth were examined. The results show that these antitumor transplatinum agents can be grouped with the coordination Pt(II) compounds exhibiting antitumor activity and capable of inducing bacterial filamentation and initiate lysis in lysogenic bacteria. The results corroborate the thesis that DNA is the potential cellular target also for a class of antitumor derivatives of transplatin. PMID- 26255234 TI - CDKN2A (p14(ARF)/p16(INK4a)) and ATM promoter methylation in patients with impalpable breast lesions. AB - Early detection of breast cancer increases the chances of cure, but the reliable identification of impalpable lesions is still a challenge. In spite of the advances in breast cancer detection, the molecular basis of impalpable lesions and the corresponding circulating biomarkers are not well understood. Impalpable lesions, classified by radiologists according to the Breast Imaging Reporting and Data System in the categories 3 and 4, can be either benign or malignant (slow growing or aggressive). In this article, we report the DNA methylation pattern in CDKN2A (p14(ARF)/p16(INK4a)) and in ATM gene promoters from 62 impalpable lesions, 39 peripheral blood samples, and 39 saliva samples, assessed by methylation-specific polymerase chain reaction method. ATM showed the greatest percentage of methylation in DNA from lesions (benign and malignant), blood (even with p16(INK4a)), and saliva, followed by p16(INK4a) and p14(ARF). Among the malignant cases, ATM promoter was the most hypermethylated in lesion DNA and in blood and saliva DNAs, and p14(ARF), the least. The highest percentage of p16(INK4a) methylation was found in the blood. Finally, our data are relevant because they were obtained using impalpable breast lesions from patients who were carefully recruited in 2 public hospitals of Rio de Janeiro. PMID- 26255235 TI - Inverted urothelial carcinoma: a series of 12 cases with a wide morphologic spectrum overlapping with the large nested variant. AB - The current series presents 12 cases of invasive urothelial carcinoma (UC) with inverted growth pattern that fulfill the architectural criteria of the recently described "large nested" variant of UC, but which display a wider spectrum of morphologic and cytologic changes. All cases had an associated component of usual invasive UC, and 10 had an associated surface papillary component. Although many areas within the tumors were indistinguishable from a noninvasive endophytic growth pattern, at least some had an irregular ragged contour, and all showed haphazard arrangement with variable amount of intervening stroma at least focally. Inflammatory stromal reaction was noted in 11 cases, and desmoplasia and retraction artifact were present in 8 cases each. Although major areas showed mild atypia, many tumors showed marked hyperchromasia, prominent nucleoli, marked irregular nuclear membranes, and brisk mitotic activity. Final pathological stage on cystectomy specimens was T2 in 4 cases, T3 in 2 cases, and T4 in 3 cases. In 3 cases, lymph node metastases were documented histologically. Review of the literature shows that the "large nested," "inverted," "endophytic," and "inverted papilloma-like" variants of invasive UC are interrelated entities and should probably be considered as one variant with a wide spectrum of cytoarchitectural features. They should also be separated from the "nested" variant with which they rarely coexist and which shows different characteristics at the morphologic level. PMID- 26255236 TI - Yoga for generalized anxiety disorder: design of a randomized controlled clinical trial. AB - Generalized anxiety disorder (GAD) is a common disorder associated with significant distress and interference. Although cognitive behavioral therapy (CBT) has been shown to be the most effective form of psychotherapy, few patients receive or have access to this intervention. Yoga therapy offers another promising, yet under-researched, intervention that is gaining increasing popularity in the general public, as an anxiety reduction intervention. The purpose of this innovative clinical trial protocol is to investigate the efficacy of a Kundalini Yoga intervention, relative to CBT and a control condition. Kundalini yoga and CBT are compared with each other in a noninferiority test and both treatments are compared to stress education training, an attention control intervention, in superiority tests. The sample will consist of 230 individuals with a primary DSM-5 diagnosis of GAD. This randomized controlled trial will compare yoga (N=95) to both CBT for GAD (N=95) and stress education (N=40), a commonly used control condition. All three treatments will be administered by two instructors in a group format over 12 weekly sessions with four to six patients per group. Groups will be randomized using permuted block randomization, which will be stratified by site. Treatment outcome will be evaluated bi-weekly and at 6month follow-up. Furthermore, potential mediators of treatment outcome will be investigated. Given the individual and economic burden associated with GAD, identifying accessible alternative behavioral treatments will have substantive public health implications. PMID- 26255237 TI - Using interactive Internet technology to promote physical activity in Latinas: Rationale, design, and baseline findings of Pasos Hacia La Salud. AB - Internet-based interventions show promise as an effective channel for promoting physical activity. However, a paucity of research has been conducted among underserved groups despite recent increases in Internet access and physical activity-related health disparities in these communities. Thus, the current randomized controlled trial will test the efficacy of an individually tailored, Internet-based physical activity intervention for Latinas. This program was culturally and linguistically adapted for the target population through extensive formative research. Two hundred eighteen sedentary Latinas were randomly assigned to the Tailored Physical Activity Internet Intervention or the Wellness Contact Control Internet Group. The Physical Activity Internet Intervention, based on Social Cognitive Theory and the Transtheoretical Model, utilizes a website with features including self-monitoring, goal setting, discussion forum, links to online resources, individually tailored and motivation-matched physical activity feedback reports, and exercise tip sheets. Participants receive regular emails over the first 6months with a tapered dose during the second 6months (maintenance phase) to alert them to new content on the website. The main outcome is differences in minutes/week of moderate to vigorous physical activity at six months as measured by the 7-Day Physical Activity Recall and accelerometer data. High reach, low cost, culturally relevant Internet-based interventions that encourage physical activity among Latinas could help reduce health disparities and thus have a substantial positive impact on public health. PMID- 26255238 TI - Effect of levothyroxine on live birth rate in euthyroid women with recurrent miscarriage and TPO antibodies (T4-LIFE study). AB - BACKGROUND: Thyroid peroxidase antibodies (TPO-Ab) in euthyroid women are associated with recurrent miscarriage (RM) and other pregnancy complications such as preterm birth. It is unclear if treatment with levothyroxine improves pregnancy outcome. AIM: The aim of this study is to determine the effect of levothyroxine administration on live birth rate in euthyroid TPO-Ab positive women with recurrent miscarriage. METHODS/DESIGN: We will perform a multicenter, placebo controlled randomized trial in euthyroid women with recurrent miscarriage and TPO-Ab. Recurrent miscarriage is defined as two or more miscarriages before the 20th week of gestation. The primary outcome is live birth, defined as the birth of a living fetus beyond 24weeks of gestation. Secondary outcomes are ongoing pregnancy at 12weeks, miscarriage, preterm birth, (serious) adverse events, time to pregnancy and survival at 28days of neonatal life. The analysis will be performed according to the intention to treat principle. We need to randomize 240 women (120 per group) to demonstrate an improvement in live birth rate from 55% in the placebo group to 75% in the levothyroxine treatment group. This trial is a registered trial (NTR 3364, March 2012). Here we discuss the rationale and design of the T4-LIFE study, an international multicenter randomized, double blind placebo controlled, clinical trial aimed to assess the effectiveness of levothyroxine in women with recurrent miscarriage and TPO-Ab. PMID- 26255239 TI - Surgical Revascularization versus Percutaneous Coronary Intervention and Optimal Medical Therapy in Diabetic Patients with Multi-Vessel Coronary Artery Disease. AB - Coronary artery disease (CAD) is the leading cause of death in patients with diabetes mellitus (DM). Patients with DM and CAD undergoing revascularization with either a surgical or a percutaneous approach are at higher risk of adverse outcomes and mortality compared with non-DM patients. It is within this background that the optimal choice of revascularization is of critical importance in this high-risk population. The large FREEDOM trial randomized 1900 patients with DM and multivessel CAD to either revascularization with coronary artery by pass graft (CABG) surgery or percutaneous coronary intervention (PCI). Compared with PCI, CABG significantly reduced the rates of death and myocardial infarction but was associated with a higher risk of stroke. In a real-world setting the decision-making process for the optimal revascularization strategy in these patients is challenging as many clinical factors may influence the decision to either pursue a surgical or a percutaneous revascularization. However, the current consensus is that CABG should be the preferred revascularization strategy in diabetic patients with extensive multivessel CAD. PMID- 26255240 TI - Spectrum of mutations in a cohort of UK patients with ADA deficient SCID: Segregation of genotypes with specific ethnicities. AB - Severe combined immunodeficiency (SCID) arises from a number of different genetic defects, one of the most common being mutations in the gene encoding adenosine deaminase (ADA). In the UK, ADA deficient SCID compromises approximately 20% of all known cases of SCID. We carried out a retrospective analysis of the ADA gene in 46 known ADA deficient SCID patients on whom DNA had been stored. Here, we report a high frequency of two previously reported mutations and provide a link between the mutations and patient ethnicity within our patient cohort. We also report on 9 novel mutations that have been previously unreported. PMID- 26255241 TI - Volumetric Analysis of F-18-FET-PET Imaging for Brain Metastases. AB - BACKGROUND: The knowledge of exact tumor margins is of importance for the treating neurosurgeon, radiotherapist, and oncologist alike. The aim of this study was to investigate whether tumor volume and tumor margins acquired by magnetic resonance imaging (MRI) are congruent with the findings acquired by O-(2 (18F)-fluoroethyl)-L-tyrosine-positron emission tomography (FET-PET). METHODS: Patients received FET-PET and MRI before surgery for brain metastases. Metastases were quantified by calculating tumor-to-background uptake ratios using FET uptake. PET and MRI-based tumor volumes, as well as areas of intersection, were assessed. RESULTS: Forty-one patients were enrolled in the study. The maximum tumor-to-background uptake ratio measured in all of our patients harboring histologically proven viable tumor tissue was >1.6. Absolute tumor volumes acquired by FET-PET and MRI were not congruent in our patient cohort, and tumors identified in FET-PET and MRI only partially overlapped. The ratio of intersection (intersection of tumor defined by MRI and tumor defined by FET-PET at the ratio of tumor defined by FET-PET) was within a range of 0.27-0.68 when applying the different thresholds. CONCLUSIONS: Our study therefore indicates that treatment planning based on MRI or PET only might have a substantial risk of undertreatment at the tumor margins. These findings could have important implications for the planning of surgery as well as radiotherapy, although they have to be validated in further studies. PMID- 26255242 TI - Initial Experience with High-Definition Camera-On-a-Chip Flexible Endoscopy for Intraventricular Neurosurgery. AB - OBJECTIVE: The usefulness of existing neuroendoscopes has been limited by either decreased range of motion or suboptimal image resolution. The flexible high definition chip-camera endoscope has emerged as a potential solution to the shortcomings of available instruments by combining superior flexibility and image quality in order to better operate within spatially constrained intraventricular operations. CASE DESCRIPTION: Here we describe a 36-year-old woman who presented with hydrocephalus caused by an obstructive mass arising from the tectum. A high definition camera-on-a-chip flexible neuroendoscope was used to sample the tectal mass after a traditional neuroendoscope was used to perform a third ventriculostomy. CONCLUSIONS: As demonstrated by this initial experience, the use of high-definition camera-on-a-chip flexible endoscopy may provide enhanced intraoperative visualization and application for intraventricular neurosurgery. PMID- 26255243 TI - Motility and fertilizing ability of cryopreserved Caspian brown trout (Salmo trutta caspius) sperm: Effect of post-thaw storage time and different sperm-to egg ratios. AB - This study was designed to test the effect of post-thaw storage time on sperm motility parameters of Caspian brown trout (n=7). Furthermore, we investigated the effect of sperm-to-egg ratios of 100,000:1, 300,000:1 and 600,000:1 on fertility of cryopreserved Caspian brown semen. Quality was assessed by measuring sperm motility parameters and fertilization rates at the eyed and hatching stages. The percentage of post-thawed sperm motility, curvilinear velocity (VCL) and amplitude of lateral head displacement (ALH) were not affected by 60 min of storage, whereas a decrease in straight line velocity (VSL), average path velocity (VAP) and linearity (LIN) were found in cryopreserved semen. Thus, the cryopreserved sperm of Caspian brown trout could be stored up to 60 min without loss of the percentage of sperm motility. The fertilization rate was not affected by 60 min of post-thaw storage and was over 70% for sperm-to-egg ratios of both 300,000 and 600,000:1. To our knowledge, this study is the first to report the high post-thaw fertilization ability of Caspian brown trout semen at a sperm-to egg ratio as low as 300,000:1. This procedure after scaling up can be recommended for routine Caspian brown trout sperm cryopreservation. PMID- 26255244 TI - Ixodes ricinus defensins attack distantly-related pathogens. AB - Antimicrobial peptides are ubiquitous components of eukaryotic innate immunity. Defensins are a well-known family of antimicrobial peptides, widely distributed in ticks, insects, plants and mammals, showing activity against bacteria, viruses, fungi, yeast and protozoan parasites. Ixodes ricinus is the most common tick species in Europe and is a vector of pathogens affecting human and animal health. Recently, six defensins (including two isoforms) were identified in I. ricinus. We investigated the evolution of the antimicrobial activity of I. ricinus defensins. Among the five unique defensins, only DefMT3, DefMT5 and DefMT6 showed in vitro antimicrobial activity. Each defensin was active against rather distantly-related bacteria (P < 0.05), significantly among Gram-negative species (P < 0.0001). These three defensins represent different clades within the family of tick defensins, suggesting that the last common ancestor of tick defensins may have had comparable antimicrobial activity. Differences in electrostatic potential, and amino acid substitutions in the beta-hairpin and the loop bridging the alpha-helix and beta-sheet may affect the antimicrobial activity in DefMT2 and DefMT7, which needs to be addressed. Additionally, the antimicrobial activity of the gamma-core motif of selected defensins (DefMT3, DefMT6, and DefMT7) was also tested. Interestingly, compared to full length peptides, the gamma-core motifs of these defensins were effective against less species of bacteria. However, the antifungal activity of the gamma-core was higher than full peptides. Our results broaden the scope of research in the field of antimicrobial peptides highlighting the overlooked ability of arthropod defensins to act against distantly-related microorganisms. PMID- 26255245 TI - A peer-nomination assessment of electronic forms of aggression and victimization. AB - The perpetration and receipt of electronic aggression have largely been assessed with self-report questionnaires. Using a sample of 573 adolescents, the current study compared the psychometric properties of a peer-nomination measure of electronic aggression and victimization to the more widely used self-report approach. Estimates of the reliability, stability, and concordance of peer- and self-report assessments were adequate, mirroring those from research on aggressive exchanges in school. Analyses of validity and utility revealed that peer-nominations, compared to self-reports, provide overlapping and distinct information on adolescents' social, emotional, and academic adjustment. Overall, these findings provide evidence that peer-nominations are a reliable, valid, and useful means for measuring electronic aggression and victimization. Future work will benefit from their incorporation into multi-method assessments. PMID- 26255246 TI - The impact of state policy on teen dating violence prevalence. AB - Teen dating violence (TDV) is a serious public health concern that is associated with many negative effects. Studies on TDV prevention most often focus on the evaluation of prevention programs in school and community settings. Much less is known about the effects of policy on TDV prevalence. This study tests a model to explain whether stronger laws regarding TDV, specifically civil protection orders, have an impact on TDV rates in states. Results show that stronger policy, Democratic party control of the governor's office, and higher state median income are associated with lower rates of TDV. This study provides solid information regarding the role of civil protection orders as a means of TDV prevention and adds to our knowledge of the efficacy of state-level TDV policy. The information can lead to increased vigor on the part of advocates to strive for specific provisions in the law and to work for gubernatorial candidates who will support such laws. PMID- 26255247 TI - Understanding adolescent psychopathic traits from early risk and protective factors: Relations among inhibitory control, maternal sensitivity, and attachment representation. AB - Psychopathic traits reflect deficits in behavioral, affective, and interpersonal functioning (Cooke & Michie, 2001). Children with poor inhibitory control may display these traits. Maternal sensitivity and attachment have been implicated in psychopathic traits, but whether they may reduce the likelihood of psychopathic trait expression in adolescence for uninhibited children is largely unknown. The current study attempted to shed light on this issue. Data came from 957 adolescents, followed from 54 months through 15 years. Findings demonstrated that maternal sensitivity was associated with a reduced likelihood of psychopathic traits for males with low inhibitory control. For females, secure attachment mediated the interaction of sensitivity and inhibitory control to psychopathic traits. The current study offers insight into the temperamental traits, parenting, and relational processes involved in psychopathic trait expression during adolescence. PMID- 26255248 TI - After 50 years and 200 papers, what can the Midspan cohort studies tell us about our mortality? AB - OBJECTIVE: To distil the main findings from published papers on mortality in three cohorts involving over 27,000 adults, recruited in Scotland between 1965 and 1976 and followed up ever since. METHOD: We read and summarized 48 peer reviewed papers about all-cause and cause-specific mortality in these cohorts, published between 1978 and 2013. RESULTS: Mortality rates were substantially higher among cigarette smokers in all social classes and both genders. Exposure to second-hand smoke was also damaging. Exposure to higher levels of black smoke pollution was associated with higher mortality. After smoking, diminished lung function was the risk factor most strongly related to higher mortality, even among never-smokers. On average, female mortality rates were much lower than male but the same risk factors were predictors of mortality. Mortality rates were highest among men whose paternal, own first and most recent jobs were manual. Specific causes of death were associated with different life stages. Upward and downward social mobility conferred intermediate mortality rates. Low childhood cognitive ability was strongly associated with low social class in adulthood and higher mortality before age 65 years. There was no evidence that daily stress contributed to higher mortality among people in lower social positions. Men in manual occupations with fathers in manual occupations, who smoked and drank >14 units of alcohol a week had cardiovascular disease mortality rates 4.5 times higher than non-manual men with non-manual fathers, who neither smoked nor drank >14 units. Men who were obese and drank >14 units of alcohol per day had a mortality rate due to liver disease 19 times that of normal or underweight non drinkers. Among women who never smoked, mortality rates were highest in severely obese women in the lowest occupational classes. CONCLUSION: These studies highlight the cumulative effect of adverse exposures throughout life, the complex interplay between social circumstances, culture and individual capabilities, and the damaging effects of smoking, air pollution, alcohol and obesity. PMID- 26255250 TI - Regulatory dendritic cells in autoimmunity: A comprehensive review. AB - Dendritic cells (DCs) are professional antigen-presenting cells (APC) with significant phenotypic heterogeneity and functional plasticity. DCs play crucial roles in initiating effective adaptive immune responses for elimination of invading pathogens and also in inducing immune tolerance toward harmless components to maintain immune homeostasis. The regulatory capacity of DCs depends on their immature state and distinct subsets, yet not restricted to the immature state and one specialized subset. The tolerogenicity of DC is controlled by a complex network of environmental signals and cellular intrinsic mechanisms. Regulatory DCs play an important role in the maintenance of immunological tolerance via the induction of T cell unresponsiveness or apoptosis, and generation of regulatory T cells. DCs play essential roles in driving autoimmunity via promoting the activation of effector T cells such as T helper 1 and T helper 17 cells, and/or suppressing the generation of regulatory T cells. Besides, a breakdown of DCs-mediated tolerance due to abnormal environmental signals or breakdown of intrinsic regulatory mechanisms is closely linked with the pathogenesis of autoimmune diseases. Novel immunotherapy taking advantage of the tolerogenic potential of regulatory DCs is being developed for treatment of autoimmune diseases. In this review, we will describe the current understanding on the generation of regulatory DC and the role of regulatory DCs in promoting tolerogenic immune responses and suppressing autoimmune responses. The emerging roles of DCs dysfunction in the pathogenesis of autoimmune diseases and the potential application of regulatory DCs in the treatment of autoimmune diseases will also be discussed. PMID- 26255249 TI - Retreatment regimen of rituximab monotherapy given at the relapse of severe HCV related cryoglobulinemic vasculitis: Long-term follow up data of a randomized controlled multicentre study. AB - OBJECTIVE: To evaluate the efficacy and safety in the long term of a retreatment regimen with Rituximab (RTX) alone administered at clinical relapse in cryoglobulinemic vasculitis (CV). METHODS: Thirty patients with severe HCV related CV, previously enrolled in the multicentre Italian trial on RTX in the treatment of CV, were retrospectively evaluated after the end of the trial. All of them were managed with RTX alone at clinical relapse, if any. Disease activity at the last available follow up was defined as complete remission (absence of active disease), partial remission (response > 50% of at least one manifestation among glomerulonephritis, peripheral neuropathy or skin ulcers) or active disease. RESULTS: The mean follow up after the first RTX cycle was 72.6 (20.4) months. After the end of the trial, 21/30 (70%) patients showed an active follow up [81.7 (10.9) months)], 3/30 (10%) lost follow up and 6/30 (20%) died. 12/21 (57.1%) patients were in complete disease remission, 5/21 (23.8%) showed a partial response and 4/21 (19%) had an active disease. 17/30 (56.7%) patients needed retreatment for relapse with a mean time to retreatment of 22.3 (12.1) months. Treatment survival of this regimen was 7.6 (0.3) years. Recurrent non severe infections occurred in 3/30, with chronic hypogammaglobulinemia in 2/3 patients. CONCLUSIONS: A long-term regimen of retreatment with RTX alone given at clinical relapse seems to be effective and safe in CV, with a low rate of infections and severe hypogammaglobulinemia. PMID- 26255251 TI - C-terminal variable AGES domain of Thymosin beta4: the molecule's primary contribution in support of post-ischemic cardiac function and repair. AB - Repairing defective cardiac cells is important towards improving heart function. Due to the frequency and severity of ischemic heart disease, management of patients featuring this type of cardiac failure receives significant interest. Previously we discovered that Thymosin beta4 (TB4), a 43 amino-acid secreted actin sequestering peptide, is beneficial for myocardial cell survival and coronary re-growth after infarction in adult mammals. Considering the regenerative potential of full-length TB4 in the heart, and that minimal structural variations alter TB4's influence on actin assembly and cell movement, we investigated how various TB4 domains affect cardiac cell behavior and post ischemic mammalian heart function. We synthesized 17 domain combinations of full length TB4 and analyzed their impact on embryonic cardiac cells in vitro, and after cardiac infarction in vivo. We discovered the domains of TB4 affect cardiac cell behavior distinctly. We revealed TB4 specific C-terminal tetrapeptide, AGES, increases embryonic cardiac cell migration and myocyte beating in culture, and improves adult mammalian heart function following ischemia. Investigating the molecular background and mechanism we discovered systemic injection of AGES enhances early myocyte survival by activating Akt-mediated signaling mechanisms, increases coronary vessel growth and inhibits inflammation in mice and pigs. Biodistribution analyses revealed cardiomyocytes uptake AGES efficiently in vitro and in vivo projecting a potential independent clinical utilization for the tetrapeptide. Our comprehensive domain investigations also suggest, preservation and/or restoration of cardiomyocyte communication is a target of TB4 and AGES, and critical to improve post-ischemic heart function in pigs. In summary, we identified the C-terminal four amino-acid variable end of TB4 as the essential and responsible domain for the molecule's full benefits in the hypoxic heart. Additionally, we introduced AGES as a novel, systemically applicable drug candidate to aid cardiac infarction in adult mammals. PMID- 26255252 TI - A new method to evaluate the effects of bacterial dosage, infection route and Vibrio strain in experimental challenges of Litopenaeus vannamei, based on the Cox proportional hazard model. AB - In the shrimp challenge test the Vibrio dosage, infection route, and strain are considered as risk factors that result in mortality. Assessment of Vibrio/shrimp interactions, and disease dynamics following infection by Vibrio, are useful techniques needed for detailed studies on the control of risk factors. In this paper we used an application of the Cox proportional hazard model to assess relative survival probability, estimate mortality risk, and construct a prognostic model to assess predictions of estimated time to death. Results indicate that infection route was the most important prognostic factor contributing to mortality in the challenge test (beta = 3.698, P < 0.000). The shrimp infection rate following injection was found to be 40.4 times greater than that following immersion (hazard ratio (HR) = 40.4; p = 0.000). Our results also indicated that the HR resulting in shrimp mortality following a high dose of 10(8) cfu/shrimp was significantly greater (HR = 5.9, P < 0.000), than that following a baseline dosage of 10(7) cfu/shrimp. Strain Vh was found to be more virulent than Strain Vp (HR = 4.8; P < 0.000). The prognostic index also indicated that the infection route is the most important prognostic factor contributing to mortality in the challenge test. PMID- 26255254 TI - Causal effects on child language development: A review of studies in communication sciences and disorders. AB - We reviewed recent studies published across key journals within the field of communication sciences and disorders (CSD) to survey what causal influences on child language development were being considered. Specifically, we reviewed a total of 2921 abstracts published within the following journals between 2003 and 2013: Language, Speech, and Hearing Services in Schools (LSHSS); American Journal of Speech-Language Pathology (AJSLP); Journal of Speech, Language, and Hearing Research (JSLHR); Journal of Communication Disorders (JCD); and the International Journal of Language and Communication Disorders (IJLCD). Of the 346 eligible articles that addressed causal factors on child language development across the five journals, 11% were categorized as Genetic (37/346), 83% (287/346) were categorized as Environmental, and 6% (22/346) were categorized as Mixed. The bulk of studies addressing environmental influences focused on therapist intervention (154/296=52%), family/caregiver linguistic input (65/296=22%), or family/caregiver qualities (39/296=13%). A more in-depth review of all eligible studies published in 2013 (n=34) revealed that family/caregiver qualities served as the most commonly controlled environmental factor (e.g., SES) and only 3 studies explicitly noted the possibility of gene-environment interplay. This review highlighted the need to expand the research base for the field of CSD to include a broader range of environmental influences on child language development (e.g., diet, toxin exposure, stress) and to consider more directly the complex and dynamic interplay between genetic and environmental effects. LEARNING OUTCOMES: Readers will be able to highlight causal factors on child language development that have been studied over the past decade in CSD and recognize additional influences worthy of consideration. In addition, readers will become familiar with basic tenets of developmental systems theory, including the complex interplay between genetic and environmental factors that shapes child development. PMID- 26255255 TI - Trials and intensity effects in single-trial ERP components and autonomic responses in a dishabituation paradigm with very long ISIs. AB - The phasic orienting reflex (OR) was investigated using single-trial data collected concurrently from 4 autonomic measures and event-related potentials (ERPs). In an auditory dishabituation paradigm, twelve indifferent tones of two intensities (60 or 80 dB, intensity change on trial 11, counterbalanced between subjects) were presented at very long interstimulus intervals (ISIs). Novelty and intensity based stimulus-response patterns were examined seeking ERP analogues of autonomic measures representing pre-OR and OR processing. Skin conductance response (SCR) represented the phasic OR index. EOG-corrected ERP data for 16 subjects were decomposed by a temporal Principal Components Analysis (PCA). SCR diminished over 10 standard trials, recovered on change trial 11, dishabituated to the re-presentation of the standard tone on trial 12, and showed intensity effects at the change - formal requirements for an OR index. The evoked cardiac response (HR) showed no trial or intensity effects. Respiratory pause (RP) decreased linearly over trials and showed recovery but no dishabituation or intensity effect. Peripheral vasoconstriction (PVC) failed to decrement but exhibited an intensity effect. Ten identifiable ERP components were extracted: Na, P1, N1-1, PN, P2, P3a, P3b, a novelty-sensitive HabP3, an intensity-sensitive IntP3, and the Slow Wave (SW). Pattern 1 showed no trial or intensity effects (HR, P1, PN, P2); Pattern 2 showed no trial effect but an intensity effect (PVC, Na, N1-1, P3a); and Pattern 3 demonstrated habituation and an intensity effect (SCR, RP, P3b, HabP3, IntP3, SW). The observed fractionation of autonomic and central measures is consistent with Preliminary Process Theory (PPT) rather than the notion of a unitary OR. PMID- 26255256 TI - Semi-closed bilateral partial miotomy of the puborectalis for anismus: a pilot study: Partial miotomy of the puborectalis for anismus. AB - BACKGROUND: Anismus or non relaxing puborectalis muscle (PRM) may cause obstructed defecation (OD). Reported surgical treatment is partial miotomy, followed by sepsis, bleeding, and incontinence. The aim of the present study was to investigate on the feasibility and outcome of a modified mini-invasive operation. PATIENTS AND METHODS: Consecutive patients with anismus and OD not responding to medical therapy, excluding multiparous females, patients with anal incontinence, recto-rectal intussusception, and disordered psychological pattern. Semi-closed bilateral partial division of PRM, pulled down through 1-cm perianal incisions, was performed. Concomitant significant rectal mucosal prolapse and rectocele, when present, were treated. OD was evaluated using a validated score and anal/vaginal ultrasound (US) was performed pre -and postoperatively. A control group of seven patients with normal bowel habit was also investigated. RESULTS: Eight patients (seven females), median age 48 years (range 29-71) were operated. Six also had significant mucosal prolapse and rectocele. All were followed up for a median of 12 months (range 2-40). None of them had postoperative sepsis or bleeding. One had just one occasional episode of mild anal incontinence. Symptoms improved in 6 or 75 % and, OD score decreased from 19.6 +/- 1.0 to 9.2 +/- 2.0 (mean +/- s.e.m.), P = 0.007. No patient had anismus after surgery and PRM relaxation changed from 0 to 5.9 +/- 0.8 mm being 6.6 +/- 1.5 mm in controls. CONCLUSION: Semi-closed bilateral partial division of PRM achieves muscle's relaxation on straining in all patients without any significant postoperative complication. Further studies are needed prior to consider it a validated procedure. PMID- 26255257 TI - Use of the new Da Vinci Xi during robotic rectal resection for cancer: technical considerations and early experience. PMID- 26255253 TI - Prenatal chemical exposures and child language development. AB - The goal of this review is to summarize the evidence that prenatal and/or early postnatal exposure to certain chemicals, both manmade (insulating materials, flame retardants, pesticides) and naturally occurring (e.g., lead, mercury), may be associated with delays or impairments in language development. We focus primarily on a subset of more extensively studied chemicals-polychlorinated biphenyls (PCBs), lead, and methyl mercury-for which a reasonable body of literature on neurodevelopmental outcomes is available. We also briefly summarize the smaller body of evidence for other chemicals including polybrominated diphenyl ether flame retardants (PBDEs) and organophosphate pesticides. Very few studies have used specific assessments of language development and function. Therefore, we included discussion of aspects of cognitive development such as overall intellectual functioning and verbal abilities that rely on language, as well as aspects of cognition such as verbal and auditory working memory that are critical underpinnings of language development. A high percentage of prospective birth cohort studies of PCBs, lead, and mercury have reported exposure-related reductions in overall IQ and/or verbal IQ that persist into middle or late childhood. Given these findings, it is important that clinicians and researchers in communication sciences and disorders are aware of the potential for environmental chemicals to impact language development. LEARNING OUTCOMES: The goal of this review is to summarize the evidence that prenatal and/or early postnatal exposure to certain chemicals may be associated with delays or impairments in language development. Readers will gain an understanding of the literature suggesting that early exposure to polychlorinated biphenyls (PCBs), lead, and mercury may be associated with decrements in cognitive domains that depend on language or are critical for language development. We also briefly summarize the smaller body of evidence regarding polybrominated diphenyl ether flame retardants (PBDEs) and organophosphate pesticides. Very few studies of exposure to these chemicals have used specific assessments of language development; thus, further investigation is needed before changes in clinical practice can be suggested. PMID- 26255258 TI - The impact of colorectal screening program on the detection of right-sided colorectal cancer. A 5-year cohort study in the Mantua District. AB - BACKGROUND: High rates of advanced colorectal cancer (CRC) are still diagnosed in the right side of the colon. This study aimed to investigate whether screening programs increase CRC detection and whether tumor location is associated with survival outcome. METHODS: Patients affected by CRC, aged from 50 to 69 years and operated on from 2005 to 2009 were reviewed. Other than patient-, disease-, and treatment-related factors, detection mode and tumor location were recorded. Overall (OS) and disease-free survival (DFS) were investigated, using univariate and multivariate analyses. RESULTS: Mean age of 386 patients included was 62.0 years, 59 % were males. CRC was detected by screening in 17 % of cases, and diagnosis was made from symptoms in 67 % and emergency surgery for 16 %. Screen detected CRCs were located in the left colon (59 %), then in rectum (25 %) and in proximal colon (16 %) (p = 0.02). Most of CRC patients urgently operated on had cancer located in proximal colon (45 %), then in the left colon (36 %) and in rectum (18 %) (p = 0.001). Right-sided CRC demonstrated higher pTNM stage (p = 0.001), adequate harvest count nodes (p = 0.0001), metastatic nodes (p = 0.02), and poor differentiation grading (p = 0.0001). With multivariate analysis, poor differentiation grade was independently associated with both worse OS (HR 3.6, p = 0.05) and worse DFS (HR 8.1, p = 0.0001), while distant recurrence was associated with worse OS (HR 20.1, p = 0.0001). CONCLUSION: Low rates of right sided CRC are diagnosed following screening program. Proximal CRC demonstrates aggressive behavior without impact on outcome. These findings prompt concern about population awareness for CRC screening. PMID- 26255259 TI - Layer-oriented total pelvic exenteration for locally advanced primary colorectal cancer. AB - PURPOSE: The clinical outcomes of patients who have undergone total pelvic exenteration (TPE) for locally advanced primary colorectal cancer have not been satisfactory. For the last 13 years, we have performed layer-oriented, en bloc resection of tumor for which TPE is indicated, in the hope of improving postoperative outcomes. The clinical outcomes of these cases were retrospectively analyzed. METHODS: A total of 54 patients who underwent TPE from 1986 to 2013 were retrospectively analyzed. Since 2002, a layer-oriented removal for clinical T4 colorectal cancer, as in T3 or less invasive tumors removed by total mesorectal excision, was applied to 23 cases for which TPE was indicated. Postoperative mortality, morbidity, overall survival (OS), and disease-free survival (DFS) were evaluated. RESULTS: On univariate analysis, good postoperative OS and DFS were associated with the layer-oriented operative maneuver, blood loss less than 2000 mL, negative nodal metastasis, and no preoperative radiation therapy. Male sex was the marginal determinant correlated with good OS and DFS. Depth of invasion to T3 was the marginal determinant correlated with good DFS. On multivariate analysis using the 4 factors identified on univariate analyses, the layer-oriented operative procedure was a significant determinant for both good OS and DFS, together with negative nodal metastases. Postoperative mortality and morbidity in the layer-oriented excision were acceptable. CONCLUSION: For primary colorectal cancers for which TPE is indicated, layer-oriented excision was a safe and effective procedure, and it may be recommended as one of the standard surgical approaches in TPE. PMID- 26255261 TI - In Vitro and In Vivo investigations on fibronectin coated and hydroxyapatite incorporated scaffolds. AB - Topological and biochemical aspects of the matrices are essential factors to be extensively studied for more successful tissue engineering. Other characteristics including biodegradability and biocompatibility should be also considered. Nanofibrous structure mimics topography of the natural matrix. Previous in vitro studies reported the favorable effects of nanohydroxyapatite (nHA) and fibronectin (Fn) on biodegradability and biocompatibility of scaffold. Herein, the synergistic outcome of co-application of Fn and nHA incorporation into aligned electrospun polycaprolactone (PCL) seeded by mouse mesenchymal stem cells (MSC) was investigated both in vitro and in vivo. Scanning Electron Microscopy (SEM), contact angle measurement and tensile test were applied for scaffold characterization. In vitro evaluation of the seeded cells was performed by MTT, SEM and cell-cycle analyses. In congruence with in vitro findings, in vivo assessment of four weeks fibronectin coated PCL/ nHA scaffold transplanted mice illustrated the suitable compact surrounding tissue with the most penetrated cells generation. Furthermore, Fn coating resulted in cell infiltration enhancement while nHA addition led to more scaffold biodegradation. In conclusion, fabrication of nanofiberous scaffold with this combination of biochemical composition and surface stimulation caused improved biodegradability and biocompatibility of the scaffold which are desirable in more effective tissue regeneration. PMID- 26255260 TI - National Strategies to Decrease the Burden of Diabetes and Its Complications. AB - Comparative results from national strategies for diabetes care and prevention are needed to understand the impact and barriers encountered during the implementation process. Long-term outcomes are limited, but results on intermediate outcomes and processes of diabetes care measures are available from translational research studies. In this narrative review, we highlight programs with nationwide reach, targeting various ethnic, racial, and socioeconomic populations with diabetes. We describe the implementation strategies, the impact on clinical outcomes, specific barriers, and cost-effectiveness results of national efforts aimed at improving diabetes care and prevention in the USA. PMID- 26255262 TI - Protective effect of bioactive peptide carnosine against lead-induced oxidative stress in kidney of rats. AB - Oxidative stress is among the mechanisms involved in renal injury. We aimed to investigate the protective effects of bioactive peptide carnosine on lead induced oxidative stress and nephrotoxicity in rats. Animals received an aqueous solution of lead acetate (500 mg Pb/L in the drinking water) and/or carnosine (10 mg/kg, i.g.) for eight weeks. Then rats were weighed and used for biochemical, histological and oxidant/antioxidant evaluations. Lead-induced oxidative stress in renal tissue was indicated by a significant increase in the renal contents of malondialdehyde (MDA) as well as decrease in the levels of reduced glutathione (GSH), total antioxidant capacity (TAC), catalase (CAT) and superoxide dismutase (SOD) (P's < 0.001). Carnosine treatment decreased MDA whereas it increased the contents of GSH, TAC, CAT and SOD in both lead and control groups. Carnosine prevented the increased kidney weight and lead-induced deleterious effects on serum creatinine, urea, uric acid, albumin and total protein in lead group. It also attenuated lead induced abnormal renal structure. The present study showed that carnosine protected against lead induced oxidative stress and renal injury in rat. Therefore, carnosine represents a potential therapeutic option against the deleterious effect of lead induced nephrotoxicity which deserves consideration and further examination. PMID- 26255263 TI - Early intracellular signaling events induced by in vitro metreleptin administration in cardiac myocytes and uterine smooth muscle cells. AB - Intracellular signaling pathways regulated by leptin have largely been studied in metabolically important organs such as adipose tissue and peripheral blood mononuclear cells, suggesting that leptin plays a key role in pathophysiology of insulin resistance. However, whether synthetic analog of leptin, metreleptin, has similar effects on cardiac myocytes (CM) and uterine smooth muscle cells (USMC) has not yet been studied. Hence, in order to address these questions, we extended previous observations and investigated in vitro signaling study whether metreleptin may activate key signaling pathways. We observed that metreleptin activates Jak2 and STAT3 signaling pathways in dose- and time-dependent manner in CM and USMC. Also, we found that metreleptin increases ERK1/2, JNK and/or p38 phosphorylation in CM. In vitro metreleptin administration also increased ERK1/2 and/or p38 phosphorylation in USMC. By contrast, JNK was not regulated by in vitro metreleptin administration in USMC. Moreover, metreleptin-activated all signaling pathways were blocked by pre-treatment of PD98095 (ERK inhibitor), SB203580 (p38 inhibitor) and/or SP600125 (JNK inhibitor), respectively. Finally, metreleptin increased cell size (hypertrophy) in both CM and USMC. Our data provide novel insights into the role of Jak2, STAT3, ERK1/2, JNK and/or p38 as probable mediators of the action of leptin in regulating hypertrophy in CM and USMC. PMID- 26255264 TI - The association between 1349T>G polymorphism of ApE1 gene and the risk of prostate cancer in northern Iran. AB - Prostate cancer (PCa) is the most common malignancy in men and the fourth most common cause of death based on cancer all over the world. Many genes has been shown to be involved in the progress of the prostate cancer. Human apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein that has an important role in the base excision repair (BER) pathway. The aim of this study was to evaluate the association of ApE1 1349T>G polymorphism and the susceptibility to prostate cancer in northern Iran population. Samples were collected from 100 patients diagnosed with prostate cancer patients and 100 controls subjects and genotyped by PCR-RFLP (Polymerase Chain Reaction Restriction Fragment Length Polymorphism). We observed a significant difference in genotype distributions of ApE1 1349T>G polymorphism between patients and controls (P= 0.039). Our findings revealed individuals with the variant TG and GG had a significant increased risk of prostate cancer (GG: OR= 2.50, 95%CI= 1.063 5.874, P= 0.035. TG: OR= 2.40, 95%CI= 1.16-4.95, P= 0.017). Also, more analyses were showed that G allele were associated with increased risk of prostate cancer (OR= 1.493, 95%CI= 1.007-2.21, P= 0.045). The data from this study indicates that the ApE1 1349T>G polymorphism is associated with increased risk of prostate cancer. Although more studies should be considered with larger number of patients and control subjects to confirm our results. PMID- 26255265 TI - Identification and expression analysis of 4-Coumarate: Coenzyme A ligase gene family in Dryopteris Fragrans. AB - 4-Coumarate: coenzyme A ligase (4CL) catalyzes the conversion of hydroxycinnamates into corresponding CoA esters for biosynthesis of flavonoids and lignin. It has been widely studied in seed plants; however, it is poorly characterized in ferns. In this study, we identified 4CLs genes in ferns D. fragrans (L.) Schott (Df4CL gene) by rapid amplification of cDNA ends (RACE), and then investigated the expressions of the genes by real-time PCR, and determined total flavonoids and lignin contents. The results showed that four members of the 4CL genes were found from this species, which named Df4CL 1, 2, 3, and 4 genes. Their full-length cDNA was sequenced. Also, our analyses showed that the amino acid sequences derived from these cDNAs exhibited similar conserved regions (Box I and Box II), and substrate-binding regions compared to 4CLs isolated from seed plants.At the same time, the developmental and stress-induced gene expression patterns showed that the changes on the expression levels of Df4CL genes affected the levels of flavonoids and lignin. In conclusion, we identified 4CLs genes in ferns D. fragrans and analyzed the expressions of these genes, and finally explored the relationship between the expressions of 4CLs and syntheses of flavonoids and lignin. PMID- 26255266 TI - The Resting Motor Threshold--Restless or Resting? A Repeated Threshold Hunting Technique to Track Dynamic Changes in Resting Motor Threshold. AB - BACKGROUND: The resting motor threshold (RMT) is used to individually adjust the intensity of transcranial magnetic stimulation (TMS) intensity and is assumed to be stable. Here we challenge this notion by showing that RMT expresses acute context-dependent fluctuations. METHOD: In twelve participants, the RMT of the right first dorsal interosseus muscle was repeatedly determined using a threshold hunting procedure while participants performed motor imagery and visual attention tasks with the right or left hand. Data were analyzed using repeated-measure ANOVA. RESULTS: RMT differed depending on which hand performed the task (P = 0.003). RMT of right FDI was lower during motor imagery than during visual attention of the right hand (P = 0.002), but did not differ between left-hand tasks (P = 0.988). CONCLUSIONS: State-dependent changes of RMT occur in absence of overt motor activity and can be captured online by threshold hunting. These fluctuations need to be considered when RMT is used to individually adjust TMS intensity for plasticity-inducing protocols. PMID- 26255267 TI - Speed tracking and synchronization of multiple motors using ring coupling control and adaptive sliding mode control. AB - A new control approach for speed tracking and synchronization of multiple motors is developed, by incorporating an adaptive sliding mode control (ASMC) technique into a ring coupling synchronization control structure. This control approach can stabilize speed tracking of each motor and synchronize its motion with other motors' motion so that speed tracking errors and synchronization errors converge to zero. Moreover, an adaptive law is exploited to estimate the unknown bound of uncertainty, which is obtained in the sense of Lyapunov stability theorem to minimize the control effort and attenuate chattering. Performance comparisons with parallel control, relative coupling control and conventional PI control are investigated on a four-motor synchronization control system. Extensive simulation results show the effectiveness of the proposed control scheme. PMID- 26255269 TI - Quality assessment of sulfurous thermal waters in the city of Pocos de caldas, Minas gerais, Brazil. AB - Currently, the quality of the water consumed by the population, and also the water used for both leisure and therapeutic bathing, are known. In the city of Pocos de Caldas, Minas Gerais, Brazil, the population has two sources of sulfurous thermal water, with free access for various purposes, including drinking. Since 1882, the system has retained the same structural characteristics, and at this time, there appears to be a risk of anthropogenic contamination due to population increase near the springs. The aim of this study was to evaluate the water quality of the sulfurous hot springs distributed in Pedro Botelho fountain, located in Thermas Antonio Carlos, and Monkey fountain, located in Mario Mourao bathhouse, for microbiological and bacteriological components, physical and chemical composition, and radionuclides for a period of 12 months and to compare their quality with Brazilian water quality laws. The results showed that all the values are within the prescribed water quality parameters, except fluoride and sodium, whose levels are above those permitted by law. Excess fluoride in consumed water can cause dental fluorosis and skeletal fluorosis. As for sodium, which exceeded the permissible limits by 20 to 25 %, it can be detrimental to hypertensive individuals. An important fact to consider is that water from sulfurous hot springs cannot be consumed without medical supervision because its chemical characteristics may cause damage to health, and it should only be used as medicinal mineral water. PMID- 26255268 TI - Influence of physicochemical and nutritional factors on bacterial diversity in mangrove sediments along the southwest coast of Tamilnadu, India. AB - The present study was undertaken to investigate the diversity of mangrove associated bacterial genera at Manakudy estuary, Southwest coast of India. The root and rhizosphere sediments of both mangrove and their associated plants were collected from chosen area. Results inferred that the maximum nutrients, THB density, and diversity indices were recorded in rhizosphere and root sample of Avicennia officinalis. Altogether, 258 bacterial strains were isolated from the chosen mangrove samples and screened for nitrogen fixing and phosphate solubilizing ability. Screened result inferred that, 36.43 % isolates had nitrogen fixing and 29.45 % isolates had phosphate solubilizing ability. Here, the genus Bacillus spp. (21.71 %) was the most dominant genera. The bacterial diversity indices, i.e., univariate analysis showed remarkable variation between the chosen samples; however, maximum diversity indices was registered by rhizosphere and root sample of A. officinalis. The 95 % confidence interval and ellipse showed that samples were well mendacious within AvTD and VarTD. Likewise, the multivariate analysis like similarity percentage was good discriminator from 16.64 to 100 % by Bray-Curtis dissimilarity. The prinicipal component analysis (PCA) showed marked variation between the tested bacterial communities. Cluster analysis and non-metric multi-dimensional scaling (MDS) were grouped by Bray Curtis similarity index which strongly evidence that the rhizosphere and root samples of A. officinalis were highly diversified in the study area. PMID- 26255270 TI - Fine particulate pollution in the Nanjing northern suburb during summer: composition and sources. AB - To understand the chemical composition characteristic of pollution in a northern suburb of Nanjing, particle samples were collected by two Andersen cascade impactors from May to July 2013. The positive matrix factorization version 3 (EPA PMF 3.0) was applied to identify the source contribution of PM2.1 concentrations in the study area. Source categories were determined based on the chemical component abundances in the source profiles. Overall, results indicated that seven factors were obtained. The factors are identified as follows: (I) secondary aerosol, characterized by high concentrations of NH4 (+), NO3 (-), and SO4 (2-), accounting for 20.22 %; (II) metallurgical aerosol, characterized by high concentrations of Pb, Cd, and Zn, accounting for 6.71 %; (III) road dust, characterized by high concentrations of Mg, Ca, Na, Al, and Ba, accounting for 11.85 %; (IV) biomass burning, characterized by high concentrations of K(+), Na(+), Cl(-), and K, accounting for 10.17 %; (V) residual oil, characterized by high concentrations of V and Cr, accounting for 16.63 %; (VI) iron and steel industry, characterized by high concentrations of Mn and Fe, accounting for 9.48 %; and (VII) vehicle exhaust, characterized by high concentrations of organic carbon (OC), Mo, elemental carbon (EC) and K, accounting for 24.94 %. PMID- 26255271 TI - Relations between water physico-chemistry and benthic algal communities in a northern Canadian watershed: defining reference conditions using multiple descriptors of community structure. AB - Defining reference conditions is central to identifying environmental effects of anthropogenic activities. Using a watershed approach, we quantified reference conditions for benthic algal communities and their relations to physico-chemical conditions in rivers in the South Nahanni River watershed, NWT, Canada, in 2008 and 2009. We also compared the ability of three descriptors that vary in terms of analytical costs to define algal community structure based on relative abundances of (i) all algal taxa, (ii) only diatom taxa, and (iii) photosynthetic pigments. Ordination analyses showed that variance in algal community structure was strongly related to gradients in environmental variables describing water physico chemistry, stream habitats, and sub-watershed structure. Water physico-chemistry and local watershed-scale descriptors differed significantly between algal communities from sites in the Selwyn Mountain ecoregion compared to sites in the Nahanni-Hyland ecoregions. Distinct differences in algal community types between ecoregions were apparent irrespective of whether algal community structure was defined using all algal taxa, diatom taxa, or photosynthetic pigments. Two algal community types were highly predictable using environmental variables, a core consideration in the development of Reference Condition Approach (RCA) models. These results suggest that assessments of environmental impacts could be completed using RCA models for each ecoregion. We suggest that use of algal pigments, a high through-put analysis, is a promising alternative compared to more labor-intensive and costly taxonomic approaches for defining algal community structure. PMID- 26255272 TI - The Consumption of Energy Drinks Among a Sample of College Students and College Student Athletes. AB - To assess energy drink (ED) consumption, potential ED correlates, and ED-related motivations among a sample of college students to determine differences based on athlete status (student athlete vs. non-athlete). Six hundred and ninety-two college students completed surveys at a large private university in the United States. Participants completed a paper based questionnaire assessing ED and ED related variables. Over thirty-six percent (197 non-athletes, 58 student athletes) of participants reported ED consumption in the preceding 30 days. Multivariately, there was no difference in ED consumption based on athlete status. Heavy episodic drinking and prescription stimulant misuse were both correlated with increased ED consumption. ED motivations differed based on the frequency of ED consumption. ED use was common among student athletes and non athletes in our sample. It is important to be aware of the correlation between heavy episodic drinking, prescription stimulant misuse, and ED consumption among college student populations because of the adverse consequences associated with these behaviors. PMID- 26255273 TI - The critical role of ants in the extensive dispersal of Acacia seeds revealed by genetic parentage assignment. AB - Ants are prominent seed dispersal agents in many ecosystems, and dispersal distances are small in comparison with vertebrate dispersal agents. However, the distance and distribution of ant-mediated dispersal in arid/semi-arid environments remains poorly explored. We used microsatellite markers and parentage assignment to quantify the distance and distribution of dispersed seeds of Acacia karina, retrieved from the middens of Iridomyrmex agilis and Melophorus turneri perthensis. From parentage assignment, we could not distinguish the maternal from each parent pair assigned to each seed, so we applied two approaches to estimate dispersal distances, one conservative (CONS), where the parent closest to the ant midden was considered to be maternal, and the second where both parents were deemed equally likely (EL) to be maternal, and used both distances. Parentage was assigned to 124 seeds from eight middens. Maximum seed dispersal distances detected were 417 m (CONS) and 423 m (EL), more than double the estimated global maximum. Mean seed dispersal distances of 40 m (+/-5.8 SE) (CONS) and 79 m (+/-6.4 SE) (EL) exceeded the published global average of 2.24 m (+/-7.19 SD) by at least one order of magnitude. For both approaches and both ant species, seed dispersal was predominantly (44-84% of all seeds) within 50 m from the maternal source, with fewer dispersal events at longer distances. Ants in this semi-arid environment have demonstrated a greater capacity to disperse seeds than estimated elsewhere, which highlights their important role in this system, and suggests significant novel ecological and evolutionary consequences for myrmecochorous species in arid/semi-arid Australia. PMID- 26255274 TI - Stage-specific heat effects: timing and duration of heat waves alter demographic rates of a global insect pest. AB - The frequency and duration of periods with high temperatures are expected to increase under global warming. Thus, even short-lived organisms are increasingly likely to experience periods of hot temperatures at some point of their life cycle. Despite recent progress, it remains unclear how various temperature experiences during the life-cycle of organisms affect demographic traits. We simulated hot days (daily mean temperature of 30 degrees C) increasingly experienced under field conditions and investigated how the timing and duration of such hot days during the life cycle of Plutella xylostella affects adult traits. We show that hot days experienced during some life stages (but not all) altered adult lifespan, fecundity, and oviposition patterns. Importantly, the effects of hot days were contingent on which stage was affected, and these stage specific effects were not always additive. Thus, adults that experience different temporal patterns of hot periods (i.e., changes in timing and duration) during their life-cycle often had different demographic rates and reproductive patterns. These results indicate that we cannot predict the effects of current and future climate on natural populations by simply focusing on changes in the mean temperature. Instead, we need to incorporate the temporal patterns of heat events relative to the life-cycle of organisms to describe population dynamics and how they will respond to future climate change. PMID- 26255275 TI - Intraspecific variation in fine root respiration and morphology in response to in situ soil nitrogen fertility in a 100-year-old Chamaecyparis obtusa forest. AB - Soil N fertility has an effect on belowground C allocation, but the physiological and morphological responses of individual fine root segments to variations in N availability under field conditions are still unclear. In this study, the direction and magnitude of the physiological and morphological function of fine roots in response to variable in situ soil N fertility in a forest site were determined. We measured the specific root respiration (Rr) rate, N concentration and morphology of fine root segments with 1-3 branching orders in a 100-year-old coniferous forest of Chamaecyparis obtusa. Higher soil N fertility induced higher Rr rates, root N concentration, and specific root length (SRL), and lower root tissue density (RTD). In all fertility levels, the Rr rates were significantly correlated positively with root N and SRL and negatively with RTD. The regression slopes of respiration with root N and RTD were significantly higher along the soil N fertility gradient. Although no differences in the slopes of Rr and SRL relationship were found across the levels, there were significant shifts in the intercept along the common slope. These results suggest that a contrasting pattern in intraspecific relationships between specific Rr and N, RTD, and SRL exists among soils with different N fertility. Consequently, substantial increases in soil N fertility would exert positive effects on organ-scale root performance by covarying the Rr, root N, and morphology for their potential nutrient and water uptake. PMID- 26255276 TI - Novel structural features increase the antioxidant effect of estrogen analogues on low density lipoprotein. AB - Many known estrogens, both natural and synthetic, may act as antioxidants. We designed and synthesized 22 novel estrogen analogues with different ring junctions or substitutions, such as fluorine. We studied the antioxidant capacity in vitro of 35 synthetic estrogen analogues in aqueous lipoprotein solution by monitoring the formation of conjugated dienes. In addition to a free C-3 hydroxyl group, the two most active antioxidants had either a methyl group at C-4 and a six-carbon D-ring, or a fluorine atom at C-2 and an unsaturated B-ring. Extension of the D-ring increased the antioxidant capacity of 6-oxa estrogens. Compounds with a fluorine atom at C-2 were similar or more potent antioxidants compared with the principal endogenous estrogen, 17beta-estradiol. In compounds with a substituted C-3 hydroxyl group, the antioxidant capacity could be significantly increased by additional double bonds in the C- or D-rings. In conclusion, we show that the antioxidant capacity of estrogen analogues could be increased by structural changes. PMID- 26255277 TI - Multiple beta-defensin genes are upregulated by the vitamin D pathway in cattle. AB - Experimental models of bacterial and viral infections in cattle have suggested vitamin D has a role in innate immunity of cattle. The intracrine vitamin D pathway of bovine macrophages, however, has only been shown to activate a nitric oxide-mediated defense mechanism, as opposed to cathelicidin and beta-defensin antimicrobial peptides in human macrophages. In this study we have investigated the actions of 1,25-dihydroxyvitamin D3 (1,25D) on a cluster of eleven bovine beta-defensin genes on the basis of RNAseq data indicating they were targets of 1,25D in cattle. Treatment of bovine monocyte cultures with 1,25D (10 nM, 18 h) in the absence and presence of LPS stimulation increased the expression of bovine beta-defensin 3 (BNBD3), BNBD4, BNBD6, BNBD7, and BNBD10 genes 5 to 10-fold compared to control (P<0.05). Treatment of lipopolysaccharide (LPS)-stimulated monocytes with 0-100 ng/mL 25-hydroxyvitamin D3 also increased BNBD3, BNBD4, BNBD7, and BNBD10 in a dose-dependent manner. Treatment of monocytes with the protein translation inhibitor, cycloheximide, however, blocked upregulation of the beta-defensins in response to 1,25D suggesting the beta-defensins in cattle are not direct targets of the vitamin D receptor. Furthermore, preliminary investigation of vitamin D's contribution to beta-defensin expression in vivo revealed that intramammary 1,25D treatment of lactating cows increased BNBD7 expression in mammary macrophages. In conclusion, our data demonstrate that multiple beta-defensin genes are upregulated by 1,25D in cattle, providing further indication that vitamin D contributes to bovine innate immunity. PMID- 26255278 TI - Deltamethrin resistance in field populations of Rhipicephalus (Boophilus) microplus (Acari: Ixodidae) in Jammu and Kashmir, India. AB - Detection of resistance levels against deltamethrin in Rhipicephalus (Boophilus) microplus collected from six districts of Jammu and Kashmir (India) was carried out using the adult immersion test. The regression graphs of probit mortality of ticks plotted against log values of concentration of drug were utilised for the determination of slope of mortality, lethal concentration for 50% (LC50), 95% (LC95) and resistance factor (RF). On the basis of the data generated on mortality, egg mass weight, reproductive index and percentage inhibition of oviposition, the resistance level was categorised as I, II, III and IV. Out of these six districts, resistance to deltamethrin at level I was detected in one district (RF = 1.9), at level II in two districts (RF = 7.08-10.07) and at level IV in three districts (RF = 96.08-288.72). The data generated on deltamethrin resistance status will help in formulating tick control strategy in the region. PMID- 26255280 TI - Hyperleukocytosis in acute myeloid leukemia patients is associated with high 30 day mortality which is not improved with leukapheresis. PMID- 26255279 TI - Evidence of Amblyseius largoensis and Euseius alatus as biological control agent of Aceria guerreronis. AB - Amblyseius largoensis (Muma) (Acari: Phytoseiidae) and Euseius alatus De Leon (Acari: Phytoseiidae) are predatory mites that are mostly found on leaves and on the exposed fruit surface of coconut plants. Their morphology hampers the access to the microhabitat occupied by Aceria guerreronis Keifer (Acari: Eriophyidae), the most important pest of coconut fruits throughout the world. However, it was suggested that they can prey on A. guerreronis under natural conditions when this pest leaves its refuge to disperse. Since the trophic interactions between A. largoensis or E. alatus and A. guerreronis are unknown, we compare the frequencies of occurrence of A. largoensis and E. alatus under the bracts of coconut fruits and on coconut leaflets. In addition, because phytoseiids feed by liquid ingestion, we used molecular analysis to confirm the potential role of A. largoensis or E. alatus as predators of A. guerreronis and to assess how fast the A. guerreronis DNA fragment is degradated in the A. largoensis digestive tract. Our study demonstrated that E. alatus was only present on coconut leaflets whereas A. largoensis was found mostly on leaflets and, to a much lesser extent, under the bracts of coconuts. Species-specific ITS primers designed for A. guerreronis were shown to have a high degree of specificity for A. guerreronis DNA and did not produce any PCR product from DNA templates of the other insects and mites associated with the coconut agroecosystem. Based on molecular analysis, we confirmed that the predatory mites, A. largoensis and E. alatus, had preyed on the coconut mite in the field. Overall the predatory mites collected in the field exhibited low levels of predation (26.7% of A. largoensis and 8.9% of E. alatus tested positive for A. guerreronis DNA). The fragment of A. guerreronis DNA remained intact for a very short time (no more than 6 h after feeding) in the digestive tract of A. largoensis. PMID- 26255281 TI - Incremental effects of 28 days of beta-alanine supplementation on high-intensity cycling performance and blood lactate in masters female cyclists. AB - Within the aging population, there exists a subset of individuals termed masters athletes (MA). As masters-level competition increases in popularity, MA must find methods to enhance individual athletic performance. Longitudinal beta-alanine (BA) supplementation is suggested to enhance physical capability during exercise; however, these effects have not been evaluated in MA. To examine the longitudinal effects of BA on time to exhaustion (TTE), total work completed (TWC), and lactate clearance in female MA cyclists. Twenty-two female MA (age = 53.3 +/- 1.0) participated in this double-blind design. Subjects were randomly assigned to BA (n = 11; 800 mg BA + 8 g dextrose) or placebo (PLA; n = 11; 8 g dextrose) groups and supplemented 4 doses/day over 28 days. Every 7 days, subjects completed a cycling TTE at 120% VO2max, and TWC was calculated. Blood lactate was measured at baseline, immediate post, and 20-min post each TTE. No significant differences existed between groups for any variable at baseline (p > 0.05). After 28 days supplementation, BA had greater TTE (23 vs 1% change) and TWC (21 vs 2% change) than PLA (p < 0.05). Following the 20-min TTE recovery, lactate was 24% lower in BA compared to PLA (4.35 vs. 5.76 mmol/L, respectively). No differences existed for variables during intermittent weeks. 28 days of BA supplementation increased cycling performance via an enhanced time to exhaustion and total work completed with associated lactate clearance during passive rest in female MA. PMID- 26255282 TI - SPECT imaging of interleukin-6 receptor in ovarian tumor xenografts with a novel radiotracer of 99mTc-HYNIC-Aca-LSLITRL. AB - Growing evidences have shown that the IL-6/IL-6R signal pathway promotes the tumor growth, angiogenesis, invasion and migration in various cancers, especially for epithelial ovarian cancer. Hence, including anti-IL-6 antibody (Siltuximab) and anti-IL-6R antibody (Tocilizumab), more and more therapeutic drugs targeting IL-6/IL-6R pathway were developed to block their activity. The molecular imaging of IL-6R is a significant factor for predicting tumor response to IL-6/IL-6R targeted drugs. However, few probes targeting IL-6R were designed and used for the specific detection. The purpose of this study was to develop and evaluate a novel radiotracer, (99m)Tc-HYNIC-Aca-LSLITRL, for SPECT imaging of interleukin-6 receptor. The expression of IL-6R was determined by western blot, immunofluorescence and immunohistochemistry. HYNIC-Aca-LSLITRL and HYNIC-Aca TLQASIL were synthesized, and then were labeled with 99mTc. The stability and the cell-binding assay were performed. Ovarian tumor xenografts were established and subjected to SPECT imaging after injection of these two radiopharmaceuticals with or without excess primary peptides. The biodistribution of these two radiotracers was performed in nude mice bearing C13K tumors. (99m)Tc-HYNIC-Aca-LSLITRL and (99m)Tc-HYNIC-Aca-TLQASIL were obtained in >95 % labeling yield with favorably stability. In vitro studies demonstrated that the interleukin-6 receptor was overexpressed in ovarian cancer C13K cells. The SPECT imaging of interleukin-6 receptor and biodistribution studies showed that (99m)Tc-HYNIC-Aca-LSLITRL had higher tumor uptake and significantly lower kidney accumulation compared to (99m)Tc-HYNIC-Aca-TLQASIL. (99m)Tc-HYNIC-Aca-LSLITRL could be a promising agent for SPECT imaging of interleukin-6 receptor of ovarian cancer especially for those anti-IL-6R drugs under clinical trials, such as tocilizumab. PMID- 26255283 TI - Dietary supplementation with L-glutamate and L-aspartate alleviates oxidative stress in weaned piglets challenged with hydrogen peroxide. AB - This study was to evaluate the protective roles of L-glutamate (Glu) and L aspartate (Asp) in weaned piglets challenged with H2O2. Forty weaned piglets were assigned randomly into one of five groups (8 piglets/group): (1) control group (NC) in which pigs were fed a corn- and soybean meal-based diet and received intraperitoneal administration of saline; (2) H2O2 group (PC) in which pigs were fed the basal diet and received intraperitoneal administration of 10 % H2O2 (1 ml/kg body weight once on days 8 and repeated on day 11); (3) PC + Glu group (PG) in which pigs were fed the basal diet supplemented with 2.0 % Glu before intraperitoneal administration of 10 % H2O2; (4) PC + Asp group (PA) in which pigs were fed the basal diet supplemented with 1.0 % Asp before intraperitoneal administration of 10 % H2O2; (5) PC + Glu + Asp group (PGA) in which pigs were fed the basal diet supplemented with 2.0 % Glu plus 1.0 % Asp before intraperitoneal administration of 10 % H2O2. Measured parameters included daily feed intake (DFI), average daily gain (ADG), feed conversion rate (FCR), and serum anti-oxidative enzyme activities (catalase, superoxide dismutase, glutathione peroxidase-1), serum malondialdehyde and H2O2 concentrations, serum amino acid (AA) profiles, and intestinal expression of AA transporters. Dietary supplementation with Glu, Asp or their combination attenuated the decreases in DFI, ADG and feed efficiency, the increase in oxidative stress, the alterations of serum AA concentrations, and the changed expression of intestinal AA transporters in H2O2-challenged piglets. Thus, dietary supplementation with Glu or Asp alleviates growth suppression and oxidative stress, while restoring serum the amino acid pool in H2O2-challenged piglets. PMID- 26255284 TI - Co-dependence of genotype and dietary protein intake to affect expression on amino acid/peptide transporters in porcine skeletal muscle. AB - A total of 96 barrows (48 pure-bred Bama mini-pigs representing fatty genotype, and 48 Landrace pigs representing lean genotype) were randomly assigned to either a low- or adequate-protein treatment diet. The experimental period commenced at 5 weeks of age and extended to the finishing period. After euthanasia, blood and skeletal muscle samples were collected from pigs at the nursery, growing, and finishing phases. Our results indicate that the concentrations of free AAs in the plasma and muscle decreased as the age of the pigs increased. In addition, a strain * growth phase interaction (P < 0.05) was observed for the free AA pool in the plasma and muscle. The low-protein diet upregulated (P < 0.05) the mRNA levels for T1R1/T1R3 involved in glutamate binding, but downregulated (P < 0.05) the mRNA levels for PAT1, PAT2, and ASCT2, which transport neutral AAs into muscles. Bama mini-pigs had higher (P < 0.05) mRNA levels for LAT1, SNAT2, and EAAC1, but a lower (P < 0.05) mRNA level for PepT1, compared with Landrace pigs. Collectively, our findings indicate that adequate provision of dietary protein plays an important role in regulating profiles of free AA pools and expression of key AA/peptide transporters/transceptors in a genotype- and tissue-specific manner. PMID- 26255285 TI - The role of leucine and its metabolites in protein and energy metabolism. AB - Leucine (Leu) is a nutritionally essential branched-chain amino acid (BCAA) in animal nutrition. It is usually one of the most abundant amino acids in high quality protein foods. Leu increases protein synthesis through activation of the mammalian target of rapamycin (mTOR) signaling pathway in skeletal muscle, adipose tissue and placental cells. Leu promotes energy metabolism (glucose uptake, mitochondrial biogenesis, and fatty acid oxidation) to provide energy for protein synthesis, while inhibiting protein degradation. Approximately 80 % of Leu is normally used for protein synthesis, while the remainder is converted to alpha-ketoisocaproate (alpha-KIC) and beta-hydroxy-beta-methylbutyrate (HMB) in skeletal muscle. Therefore, it has been hypothesized that some of the functions of Leu are modulated by its metabolites. Both alpha-KIC and HMB have recently received considerable attention as nutritional supplements used to increase protein synthesis, inhibit protein degradation, and regulate energy homeostasis in a variety of in vitro and in vivo models. Leu and its metabolites hold great promise to enhance the growth and health of animals (including humans, birds and fish). PMID- 26255286 TI - 18F-Labeled wild-type annexin V: comparison of random and site-selective radiolabeling methods. AB - Early stage apoptosis is characterized by the externalization of phosphatidylserine (PS) from the inner leaflet of the plasma membrane to the outer periphery. Consequently, PS represents an excellent target for non-invasive imaging of apoptosis by positron emission tomography. Annexin V is a 36 kDa protein which binds with high affinity to PS. Radiolabeling of wild-type annexin V with fluorine-18 ((18)F) can be accomplished via random acylation of 23 amine groups (22 lysine residues and one N-terminal amine) with [(18)F]SFB or site specific alkylation reaction on cysteine residue at position 315 with maleimide containing prosthetic groups like [(18)F]FBEM. The effect upon random and site directed (18)F labeling of annexin V was studied with EL4 mouse lymphoma cells. Both, randomly and site-selectively radiolabeled annexin V demonstrated comparable binding to apoptotic EL4 cells. This finding suggests that the (18)F radiolabeling method has no significant effect on the ability of (18)F-labeled wild-type annexin V to bind PS in apoptotic cells. PMID- 26255288 TI - Effects of soccer vs swim training on bone formation in sedentary middle-aged women. AB - PURPOSE: The present study examined the effects of 15 weeks of soccer training and two different swimming training protocols on bone turnover in sedentary middle-aged women. METHODS: Eighty-three premenopausal mildly hypertensive women [age: 45 +/- 6 (+/- SD) years, height: 165 +/- 6 cm, weight: 80.0 +/- 14.1 kg, body fat: 42.6 +/- 5.7 %, systolic blood pressure/diastolic blood pressure: 138 +/- 6/85 +/- 3 mmHg] were randomized into soccer training (SOC, n = 21), high intensity intermittent swimming (HS, n = 21), moderate-intensity swimming (MS, n = 21) intervention groups, and a control group (C, n = 20). The training groups completed three sessions per week for 15 weeks. DXA scans were performed and resting blood samples were drawn pre- and post-intervention. RESULTS: In SOC, plasma osteocalcin, procollagen type I N propeptide and C-terminal telopeptide increased (P < 0.05) by 37 +/- 15, 52 +/- 23 and 42 +/- 18 %, respectively, with no changes in MS, HS and C. The intervention-induced increase in SOC was larger (P < 0.05) than in MS, HS and C. In SOC, leg BMC increased (P < 0.05) by 3.1 +/- 4.5 %, with a larger increase in SOC than in C. Femoral shaft and trochanter bone mineral density (BMD) increased (P < 0.05) by 1.7 +/- 1.9 and 2.4 +/- 2.9 %, respectively, in SOC, with a greater (P < 0.05) change in SOC than in MS and C, whereas total body and total leg BMD did not change in any of the groups. CONCLUSION: In conclusion, 15 weeks of soccer training with sedentary middle-aged women caused marked increases in bone turnover markers, with concomitant increases in leg bone mass. No changes in bone formation and resorption markers were seen after prolonged submaximal or high-intensity intermittent swimming training. Thus, soccer training appears to provide a powerful osteogenic stimulus in middle-aged women. PMID- 26255289 TI - Determining if muscle activity is related to preferred stride frequency during running in the water and on land. AB - PURPOSE: To determine if muscle activity is related to preferred stride frequency (PSF) during deep water running (DWR) and treadmill running on dry land (TMR). METHODS: Subjects (n = 11; 26.2 +/- 4.4 years) completed TMR and DWR at their mode-specific preferred stride frequency (PSF mode). They also ran at stride frequencies which were lower and higher than the PSF mode (i.e., PSF mode +/- 5, 10, and 15 %). Muscle activity from the rectus femoris (RF), biceps femoris (BF), tibialis anterior (TA), and gastrocnemius (GL), SF, and rating of perceived exertion (RPE) were measured. RESULTS: The PSF mode during DWR was significantly lower than that of TMR (i.e., 49.9 +/- 11.0 versus 81.9 +/- 4.8 strides/min, P < 0.0001). Additionally, muscle activity from the RF, TA, and GL during DWR was significantly lower than during TMR at respective PSF mode (~83.6 % decrease, P < 0.0001). However, RPE while running at the PSF mode during DWR and TMR was similar. During DWR, the RF, TA, and GL muscle activity was not different between PSF mode and any other SF conditions (P > 0.0005). During TMR, there was no significant difference in the RF and GL muscle activity between PSF mode and any other SF conditions during TMR (P > 0.0005). CONCLUSIONS: During DWR, subjects selected a lower PSF than during TMR even though RPE was the same. It was also determined that the relationship between muscle activity and changes in SF relative to the PSF mode was unique during DWR and TMR. PMID- 26255287 TI - Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease. AB - Improving the efficacy and reducing the toxicity of thiopurines and methotrexate (MTX) have been areas of intense basic and clinical research. An increased knowledge on pharmacodynamics and pharmacokinetics of these immunomodulators has optimized treatment strategies in inflammatory bowel disease (IBD). This review focuses on the metabolism and mode of action of thiopurines and MTX, and provides an updated overview of individualized treatment strategies in which efficacy in IBD can be increased without compromising safety. The patient-based monitoring instruments adapted into clinical practice include pretreatment thiopurine S methyltransferase testing, thiopurine metabolite monitoring, and blood count measurements that may help guiding the dosage to improve clinical outcome. Other approaches for optimizing thiopurine therapy in IBD include combination therapy with allopurinol, 5-aminosalicylates, and/or biologics. Similar strategies are yet to be proven effective in improving the outcome of MTX therapy. Important challenges for the management of IBD in the future relate to individualized dosing of immunomodulators for maximal efficacy with minimal risk of side effects. As low-cost conventional immunomodulators still remain a mainstay in pharmacotherapy of IBD, more research remains warranted, especially to substantiate these tailored management strategies in controlled clinical trials. PMID- 26255290 TI - Effect of pedaling cadence on muscle oxygenation during high-intensity cycling until exhaustion: a comparison between untrained subjects and triathletes. AB - PURPOSE: The aim of this study was to compare the muscle oxygenation between trained and untrained subjects during heavy exercise until exhaustion at two extreme pedaling cadences using a NIRS system. METHODS: Nine untrained male subjects and nine male competitive triathletes cycled until exhaustion at an intensity corresponding to 90 % of the power output achieved at peak oxygen uptake at 40 and 100 rpm. Gas exchanges were measured breath-by-breath during each exercise. Muscle (de)oxygenation was monitored continuously by near-infrared spectroscopy on the Vastus Lateralis. RESULTS: Muscle deoxygenation (?deoxy[Hb + Mb], i.e., O2 extraction) and ?total[Hb + Mb] were significantly higher at 40 rpm compared to 100 rpm during the exercise in untrained subjects but not in triathletes (p < 0.05). The time performed until exhaustion was significantly higher at 40 than at 100 rpm in untrained subjects (373 +/- 55 vs. 234 +/- 37 s, respectively) but not in triathletes (339 +/- 69 vs. 325 +/- 66 s). CONCLUSIONS: These results indicate that high aerobic fitness (1) allows for better regulation between [Formula: see text]O2M and VO2M following the change in pedaling cadence, and (2) is the most important factor in the relationship between pedaling cadence and performance. PMID- 26255291 TI - Spatial EMG potential distribution of biceps brachii muscle during resistance training and detraining. AB - PURPOSE: We investigated the effect of resistance training and detraining on the spatial distribution pattern of surface electromyography (SEMG) of the biceps brachii. METHODS: Ten male subjects completed 6 weeks of resistance training of one arm and 8 weeks of detraining. During training and detraining periods, spatial distribution patterns of SEMG were measured and quantified with 64 two dimensional electrodes. RESULTS: MVC, muscle thickness, and SEMG amplitude of the trained arm were significantly greater than those of the untrained arm after the 6 weeks of resistance training (p < 0.05), but these differences were no longer observed after 2 months of detraining. On the other hand, no significant differences in the spatial distribution pattern of SEMG were observed between the arms. CONCLUSION: Spatial distribution pattern of SEMG was not changed during resistance training and detraining periods. This suggests that detectable adaptations in the motor unit recruitment pattern do not occur during regular resistance training. PMID- 26255292 TI - Rapid determination of phenylethanolamine A in biological samples by enzyme linked immunosorbent assay and lateral-flow immunoassay. AB - Phenylethanolamine A (PA) is a beta-adrenergic agonist, which was first used in animal husbandry as a growth promoter in China in 2010. In this study, a monoclonal-antibody (mAb)-based indirect competitive enzyme-linked immunosorbent assay (icELISA) and lateral-flow immunoassay (LFA) for the detection of PA in swine urine and pork were developed. The immunogen was prepared by linking PA hapten with carrier protein via a diazotization method. The IC50 value of the optimized icELISA was 0.44 ng mL(-1). The limits of detection of the icELISA for PA in swine urine and pork were 0.13 ng mL(-1) and 0.39 ng g(-1), respectively. The recoveries of PA from spiked swine urine and pork were in the range 82.0 107.4 % and 81.8-113.3%, respectively, with the coefficients of variation in the range 4.1-16.2% and 1.2-6.3%, respectively. The mAbs had negligible cross reactivity with 10 other beta-agonists. In contrast, the LFA had a cut-off level of 5 ng mL(-1) (g) in swine urine and pork, and the results could be achieved within 5 min. Ten blind samples of swine urine were analyzed simultaneously by icELISA, LFA, and ultra-high-performance liquid chromatography-tandem mass spectrometry, and the results of the three methods agreed well. Therefore, the combination of two immunoassays provides an effective and rapid screening method for detection of PA residues in biological samples. PMID- 26255293 TI - An immunoassay for the detection of triclosan-O-glucuronide, a primary human urinary metabolite of triclosan. AB - Triclosan-O-glucuronide (TCSG) is one of the primary urinary metabolites of the antibacterial compound triclosan or TCS that is found in many personal care products and consumer goods. We have developed a competitive, indirect heterologous ELISA for the detection of the target TCSG in urine. Such an ELISA for TCSG could be developed as a useful tool to measure this important biomarker of human exposure to TCS. Immunogens were prepared by conjugating TCSG to thyroglobulin, via heterobifunctional cross-linkers AEDP or 3-[(2 aminoethyl)dithio] propionic acid*hydrochloride and TFCS or N-[epsilon trifluoroacetylcaproyloxy]succinimide ester. The coating antigen was prepared by the direct conjugation of TCSG to bovine serum albumin. Antibodies raised in rabbits 2619, 2621 (immunogen TCSG-AEDP-Thy), and 2623 (immunogen TCSG-TFCS-Thy), and the coating antigen were screened and characterized to determine their optimal concentrations. The optimized ELISA, developed with antibody 2621, gave an IC50 value of 2.85 ng/mL, with the linear range (IC20-IC80) determined to be 2.6-24.8 ng/mL. Selectivity of the assay was assessed by measuring cross reactivity of antibody 2621 to related congeners such as the aglycone TCS, triclosan-O-sulfate, triclocarban, a polybrominated diphenyl ether derivative, and 3-phenoxybenzyl alcohol glucuronide. There was virtually no recognition by antibody 2621 to any of these cross-reactants. Graphical Abstract Urinary biomarker analysis of triclosan glucuronide. PMID- 26255294 TI - SERS analysis of serum for detection of early and locally advanced breast cancer. AB - In this contribution, we investigated whether surface-enhanced Raman scattering (SERS) of serum can be a candidate method for detecting "luminal A" breast cancer (BC) at different stages. We selected three groups of participants aged over 50 years: 20 healthy women, 20 women with early localized small BC, and 20 women affected by BC with lymph node involvement. SERS revealed clear spectral differences between these three groups. A predictive model using principal component analysis (PCA) and linear discriminant analysis (LDA) was developed based on spectral data, and its performance was estimated with cross-validation. PCA-LDA of SERS spectra could distinguish healthy from BC subjects (sensitivity, 92 %; specificity, 85 %), as well as subjects with BC at different stages, with a promising diagnostic performance (sensitivity and specificity, >=80 %; overall accuracy, 84 %). Our data suggest that SERS spectroscopy of serum, combined with multivariate data analysis, represents a minimally invasive, easy to use, and fast approach to discriminate healthy from BC subjects and even to distinguish BC at different clinical stages. PMID- 26255295 TI - Molecularly imprinted polymers with multi-functionality. AB - Molecular imprinting is a very powerful synthetic method for preparation of robust materials with pre-designed molecular selectivity. Molecularly imprinted polymers (MIPs) are attractive substitutes for antibodies in many analytical and bioanalytical applications, e.g. for development of biosensors and for drug assays. In addition to selective molecular binding, new functions are being added to MIPs to make the synthetic materials responsive to different environmental conditions, making it possible to modulate the binding and release of different molecular targets and to simplify affinity separation. Introduction of signal transduction functionality into MIPs also brings in new, more easily operated chemical sensors for detection and quantification of important analytical targets. PMID- 26255297 TI - Vibrational spectroscopic analysis of peripheral blood plasma of patients with Alzheimer's disease. AB - Using Raman and infrared spectroscopy, we monitored spectral changes occurring in the blood plasma of patients with Alzheimer's disease (AD) in relation to healthy controls. The protein secondary structure as reflected by amide I band involves beta-sheet enrichment, which may be attributable to Abeta peptide formation and to increasing proportion of the globulins that are beta-sheet rich. Likewise, the behavior of the infrared 1200-1000-cm(-1) region and the Raman 980-910- and 450 400-cm(-1) regions can be explained in terms of the said plasma composition change. Further, the 744-cm(-1) Raman band from healthy control plasma shows frequency upshifting in the course of AD, which may be generated by the platelets collected in blood plasma. Linear discrimination analysis and receiver operating characteristic (ROC) analysis have been used to distinguish between patients with AD and age-matched healthy controls with a diagnostic accuracy of about 94%. PMID- 26255296 TI - Intact cell mass spectrometry as a rapid and specific tool for the differentiation of toxic effects in cell-based ecotoxicological test systems. AB - In the last few decades, MALDI-TOF MS has become a useful technique not only in proteomics, but also as a fast and specific tool for whole cell analysis through intact cell mass spectrometry (IC-MS). The present study evaluated IC-MS as a novel tool for the detection of distinct patterns that can be observed after exposure to a certain toxin or concentration by utilizing the eukaryotic fish cell line RTL-W1. Two different viability assays were performed to define the range for IC-MS investigations, each of which employing copper sulfate, acridine, and beta-naphthoflavone (BNF) as model compounds for several classes of environmental toxins. The IC-MS of RTL-W1 cells revealed not only specific spectral patterns for the various toxins, but also that the concentration used had an effect on RTL-W1 profiles. After the exposure with copper sulfate and acridine, the spectra of RTL-W1 showed a significant increase of certain peaks in the higher mass range (m/z >7000), which is probably attributed to the apoptosis of RTL-W1. On the contrary, exposure to BNF showed a distinct change of ion abundances only in the lower mass range (m/z <7000). Furthermore, a set of mass peaks could be identified as a specific biomarker for a single toxin treatment, so IC-MS demonstrates a new method for the distinction of toxic effects in fish cells. Due to fast sample preparation and high throughput, IC-MS offers great potential for ecotoxicological studies to investigate cellular effects of different substances and complex environmental samples. PMID- 26255298 TI - Simultaneous quantification of the boar-taint compounds skatole and androstenone by surface-enhanced Raman scattering (SERS) and multivariate data analysis. AB - This study investigates the feasibility of using surface-enhanced Raman scattering (SERS) for the quantification of absolute levels of the boar-taint compounds skatole and androstenone in porcine fat. By investigation of different types of nanoparticles, pH and aggregating agents, an optimized environment that promotes SERS of the analytes was developed and tested with different multivariate spectral pre-processing techniques, and this was combined with variable selection on a series of analytical standards. The resulting method exhibited prediction errors (root mean square error of cross validation, RMSECV) of 2.4 * 10(-6) M skatole and 1.2 * 10(-7) M androstenone, with a limit of detection corresponding to approximately 2.1 * 10(-11) M for skatole and approximately 1.8 * 10(-10) for androstenone. The method was subsequently tested on porcine fat extract, leading to prediction errors (RMSECV) of 0.17 MUg/g for skatole and 1.5 MUg/g for androstenone. It is clear that this optimized SERS method, when combined with multivariate analysis, shows great potential for optimization into an on-line application, which will be the first of its kind, and opens up possibilities for simultaneous detection of other meat-quality metabolites or pathogen markers. Graphical abstract Artistic rendering of a laser illuminated gold colloid sphere with skatole and androstenone adsorbed on the surface. PMID- 26255299 TI - Association between the Angiogenin (ANG) K17I variant and amyotrophic lateral sclerosis risk in Caucasian: a meta-analysis. AB - The study purpose is to perform a meta-analysis to help resolve the debate of whether the Angiogenin (ANG) K17I variant is associated with amyotrophic lateral sclerosis (ALS) risk in Caucasian. Three literature databases were searched for eligible studies published up to January 8, 2015: PubMed, Embase and Web of Science using the following search terms: amyotrophic lateral sclerosis or ALS and Angiogenin or ANG. Five eligible articles were identified, which reported 6 case-control studies and a total of 2326 cases and 3799 controls. The overall results suggested low frequencies of the K17I variant in Caucasian patients (10/2326, 0.43 %) and controls (6/3799, 0.16 %). There is no difference in the variant frequencies between patients with FALS or SALS (p = 0.069). Analysis of pooled odds ratios (ORs) and 95 % confidence intervals (CIs) revealed that the ANG K17I variant increases the risk for ALS (AT vs. AA: OR 2.65, 95 % CI 1.05 6.66, p = 0.038) and familial ALS (FALS) (AT vs. AA: OR 11.81, 95 % CI 2.11 66.15, p = 0.005) but not for sporadic ALS (SALS) (AT vs. AA: OR 1.63, 95 % CI 0.55-4.82, p = 0.378). The ANG K17I variant is rare in Caucasian patients and controls and increases the risk for ALS and FALS but not for SALS in Caucasian populations. Further well-designed studies with larger samples are needed to validate these results. PMID- 26255300 TI - Attenuation of brain grey matter volume in brachial plexus injury patients. AB - Brachial plexus injury (BPI) causes functional changes in the brain, but the structural changes resulting from BPI remain unknown. In this study, we compared grey matter volume between nine BPI patients and ten healthy controls by means of voxel-based morphometry. This was the first study of cortical morphology in BPI. We found that brain regions including the cerebellum, anterior cingulate cortex, bilateral inferior, medial, superior frontal lobe, and bilateral insula had less grey matter in BPI patients. Most of the affected brain regions of BPI patients are closely related to motor function. We speculate that the loss of grey matter in multiple regions might be the neural basis of the difficulties in the motor rehabilitation of BPI patients. The mapping result might provide new target regions for interventions of motor rehabilitation. PMID- 26255301 TI - Exogenous melatonin for sleep disorders in neurodegenerative diseases: a meta analysis of randomized clinical trials. AB - The purpose of this work is to investigate the efficacy of exogenous melatonin in the treatment of sleep disorders in patients with neurodegenerative disease. We searched Pubmed, the Cochrane Library, and ClinicalTrials.gov, from inception to July 2015. We included randomized clinical trials (RCTs) that compared melatonin with placebo and that had the primary aim of improving sleep in people with neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). We pooled data with the weighted mean difference in sleep outcomes. To assess heterogeneity in results of individual studies, we used Cochran's Q statistic and the I (2) statistic. 9 RCTs were included in this research. We found that the treatment with exogenous melatonin has positive effects on sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) in PD patients (MD: 4.20, 95 % CI: 0.92-7.48; P = 0.01), and by changes in PSQI component 4 in AD patients (MD: 0.67, 95 % CI: 0.04-1.30; P = 0.04), but not on objective sleep outcomes in both AD and PD patients. Treatment with melatonin effectively improved the clinical and neurophysiological aspects of rapid eye movement (REM) sleep behavior disorder (RBD), especially elderly individuals with underlying neurodegenerative disorders. This meta-analysis provided some evidence that melatonin improves sleep quality in patients with AD and PD, and melatonin can be considered as a possible sole or add-on therapy in neurodegenerative disorders patients with RBD. PMID- 26255302 TI - Ophthalmologic course of bilateral abducens nerve palsies after the treatment of idiopathic intracranial hypertension with venous sinus stenting. PMID- 26255303 TI - Application of a Label-Free Immunosensor for White Spot Syndrome Virus (WSSV) in Shrimp Cultivation Water. AB - White spot syndrome virus (WSSV) is a major pathogen affecting the shrimp industry worldwide. In a preliminary study, WSSV binding protein (WBP) was specifically bound to the VP26 protein of WSSV. Therefore, we have developed the label-free affinity immunosensor using the WBP together with anti-GST-VP26 for quantitative detection of WSSV in shrimp pond water. When the biological molecules were immobilized on a gold electrode to form a self-assembled monolayer, it was then used to detect WSSV using a flow injection system with optimized conditions. Binding between the different copies of WSSV and the immobilized biological molecules was detected by an impedance change (DeltaZ") in real time. The sensitivity of the developed immunosensor was in the linear range of 1.6 * 10(1)-1.6 * 10(6) copies/MUl. The system was highly sensitive for the analysis of WSSV as shown by the lack of impedance change when using yellow head virus (YHV). The developed immunosensor could be reused up to 37 times (relative standard deviation (RSD), 3.24 %) with a good reproducibility of residual activity (80-110 %). The immunosensor was simple to operate, reliable, reproducible, and could be applied for the detection and quantification of WSSV in water during shrimp cultivation. PMID- 26255304 TI - Long-term abdominal adiposity activates several parameters of cardiac energy function. AB - Abdominal obesity increases the incidence of cardiac events but reduces mortality when one of these events occurs. The phenomenon called obesity paradox might be related to myocardial energetics. This study was aimed at determining whether long-term abdominal adiposity alters cardiac energy function. Two groups of male Wistar rats were fed a standard or a Western-type (WD) diet for 8 months. The ex vivo coronary reactivity and mechanical function as well as the mitochondrial oxidative phosphorylation (mOxPhos) and hydrogen peroxide release (mH2O2r) were determined. Abdominal adiposity was augmented by the WD. This was also the case for the coronary reactivity to acetylcholine, but the rate pressure product remained roughly stable despite a reduction of the left ventricle-developed pressure partly compensated by a slight increase in heart rate. The prolonged WD administration resulted in an improvement of mOxPhos, but the mH2O2r was exaggerated which was confirmed in the whole cell by a reduced aconitase to fumarase ratio. This did not modify the plasma oxidative stress due to an increased plasma antioxidant status. In conclusion, long-term WD administration improved the cardiac fitness and might predispose the organism to the obesity paradox. Conversely, the increased mitochondrial mH2O2r can precipitate the heart toward cardiomyopathy if the WD is maintained for a longer duration. PMID- 26255306 TI - Depression and Cognitive Impairment in Peritoneal Dialysis: A Multicenter Cross sectional Study. AB - BACKGROUND: Depression and cognitive impairment have been identified as independent risk factors for mortality in peritoneal dialysis (PD) patients. The relationship between depression and global and specific cognitive functions in PD patients was investigated in this study. STUDY DESIGN: Multicenter cross sectional study. SETTING & PARTICIPANTS: 458 clinically stable patients, drawn from 5 PD units, who performed PD for at least 3 months were enrolled. PREDICTOR: Depression, defined as depression severity index score > 0.5 using the Zung Self rating Depression Scale. OUTCOMES: Global and specific cognitive impairment. Global cognitive function was measured using the Modified Mini-Mental State Examination (3MS), Trail-Making Test forms A and B for executive function, and subtests of the Battery for the Assessment of Neuropsychological Status for immediate and delayed memory, visuospatial skills, and language ability. RESULTS: Prevalences of depression and cognitive impairment evaluated by the 3MS were 52% and 28.4%, respectively. Patients with mild or moderate/severe depression had higher prevalences of general cognitive impairment, executive dysfunction, and impaired immediate and delayed memory. After adjusting for demographics, comorbid conditions, and clinical parameters, depression scores were independently associated with lower 3MS scores, lower immediate and delayed memory and language ability scores, and longer completion times of Trails A and B. Even mild depression was independently associated with higher risk for cognitive impairment, executive dysfunction, and impaired immediate and delayed memory after multivariable adjustments. LIMITATIONS: The causal relationship between depression and cognitive impairment could not be determined, and the potential copathogenesis behind depression and cognitive impairment was not fully investigated. CONCLUSIONS: Even mild depression is closely associated with global and specific cognitive impairment in PD patients. PMID- 26255307 TI - Phytochemica: a platform to explore phytochemicals of medicinal plants. AB - Plant-derived molecules (PDMs) are known to be a rich source of diverse scaffolds that could serve as the basis for rational drug design. Structured compilation of phytochemicals from traditional medicinal plants can facilitate prospection for novel PDMs and their analogs as therapeutic agents. Atropa belladonna, Catharanthus roseus, Heliotropium indicum, Picrorhiza kurroa and Podophyllum hexandrum are important Himalayan medicinal plants, reported to have immense therapeutic properties against various diseases. We present Phytochemica, a structured compilation of 963 PDMs from these plants, inclusive of their plant part source, chemical classification, IUPAC names, SMILES notations, physicochemical properties and 3-dimensional structures with associated references. Phytochemica is an exhaustive resource of natural molecules facilitating prospection for therapeutic molecules from medicinally important plants. It also offers refined search option to explore the neighbourhood of chemical space against ZINC database to identify analogs of natural molecules at user-defined cut-off. Availability of phytochemical structured dataset may enable their direct use in in silico drug discovery which will hasten the process of lead identification from natural products under proposed hypothesis, and may overcome urgent need for phytomedicines. Compilation and accessibility of indigenous phytochemicals and their derivatives can be a source of considerable advantage to research institutes as well as industries. DATABASE URL: home.iitj.ac.in/~bagler/webservers/Phytochemica. PMID- 26255305 TI - Diffusion MRI and its Role in Neuropsychology. AB - Diffusion Magnetic Resonance Imaging (dMRI) is a popular method used by neuroscientists to uncover unique information about the structural connections within the brain. dMRI is a non-invasive imaging methodology in which image contrast is based on the diffusion of water molecules in tissue. While applicable to many tissues in the body, this review focuses exclusively on the use of dMRI to examine white matter in the brain. In this review, we begin with a definition of diffusion and how diffusion is measured with MRI. Next we introduce the diffusion tensor model, the predominant model used in dMRI. We then describe acquisition issues related to acquisition parameters and scanner hardware and software. Sources of artifacts are then discussed, followed by a brief review of analysis approaches. We provide an overview of the limitations of the traditional diffusion tensor model, and highlight several more sophisticated non-tensor models that better describe the complex architecture of the brain's white matter. We then touch on reliability and validity issues of diffusion measurements. Finally, we describe examples of ways in which dMRI has been applied to studies of brain disorders and how identified alterations relate to symptomatology and cognition. PMID- 26255308 TI - MESSI: metabolic engineering target selection and best strain identification tool. AB - Metabolic engineering and synthetic biology are synergistically related fields for manipulating target pathways and designing microorganisms that can act as chemical factories. Saccharomyces cerevisiae's ideal bioprocessing traits make yeast a very attractive chemical factory for production of fuels, pharmaceuticals, nutraceuticals as well as a wide range of chemicals. However, future attempts of engineering S. cerevisiae's metabolism using synthetic biology need to move towards more integrative models that incorporate the high connectivity of metabolic pathways and regulatory processes and the interactions in genetic elements across those pathways and processes. To contribute in this direction, we have developed Metabolic Engineering target Selection and best Strain Identification tool (MESSI), a web server for predicting efficient chassis and regulatory components for yeast bio-based production. The server provides an integrative platform for users to analyse ready-to-use public high-throughput metabolomic data, which are transformed to metabolic pathway activities for identifying the most efficient S. cerevisiae strain for the production of a compound of interest. As input MESSI accepts metabolite KEGG IDs or pathway names. MESSI outputs a ranked list of S. cerevisiae strains based on aggregation algorithms. Furthermore, through a genome-wide association study of the metabolic pathway activities with the strains' natural variation, MESSI prioritizes genes and small variants as potential regulatory points and promising metabolic engineering targets. Users can choose various parameters in the whole process such as (i) weight and expectation of each metabolic pathway activity in the final ranking of the strains, (ii) Weighted AddScore Fuse or Weighted Borda Fuse aggregation algorithm, (iii) type of variants to be included, (iv) variant sets in different biological levels.Database URL: http://sbb.hku.hk/MESSI/. PMID- 26255309 TI - MetazSecKB: the human and animal secretome and subcellular proteome knowledgebase. AB - The subcellular location of a protein is a key factor in determining the molecular function of the protein in an organism. MetazSecKB is a secretome and subcellular proteome knowledgebase specifically designed for metazoan, i.e. human and animals. The protein sequence data, consisting of over 4 million entries with 121 species having a complete proteome, were retrieved from UniProtKB. Protein subcellular locations including secreted and 15 other subcellular locations were assigned based on either curated experimental evidence or prediction using seven computational tools. The protein or subcellular proteome data can be searched and downloaded using several different types of identifiers, gene name or keyword(s), and species. BLAST search and community annotation of subcellular locations are also supported. Our primary analysis revealed that the proteome sizes, secretome sizes and other subcellular proteome sizes vary tremendously in different animal species. The proportions of secretomes vary from 3 to 22% (average 8%) in metazoa species. The proportions of other major subcellular proteomes ranged approximately 21-43% (average 31%) in cytoplasm, 20-37% (average 30%) in nucleus, 3-19% (average 12%) as plasma membrane proteins and 3-9% (average 6%) in mitochondria. We also compared the protein families in secretomes of different primates. The Gene Ontology and protein family domain analysis of human secreted proteins revealed that these proteins play important roles in regulation of human structure development, signal transduction, immune systems and many other biological processes. Database URL: http://proteomics.ysu.edu/secretomes/animal/index.php. PMID- 26255311 TI - Rapid detection of immunoglobulin heavy chain gene rearrangement by PCR and melting curve analysis using combined FR2 and FR3 primers. AB - BACKGROUND: Immunoglobulin heavy chain (IgH) gene rearrangement test is a standard tool in diagnosing B-cell lymphoma. The BIOMED-2 multiplex PCR protocol has become the most commonly used laboratory method for detecting clonal IgH gene rearrangement. However, post-PCR procedure requires manual transfer of PCR product for analysis and is time-consuming. A novel strategy using LightCycler to continuously monitor fluorescence during melting curve analysis (MCA) can overcome these shortcomings. The previous studies published on this method were all restricted to FR3 primers of BIOMED-2. METHODS: Real-time PCR and subsequent MCA were performed on 71 clinical DNA samples from formalin-fixed, paraffin embedded tissues, including 40 with B-cell non-Hodgkin lymphomas and 31 with reactive lymphoid hyperplasia. We optimized the current method using FR3 primers and applied FR2 primers for the first time into MCA to detect IgH gene rearrangement. Polyacrylamide gel electrophoresis and capillary gel electrophoresis were also performed on all lymphoma samples with the identical FR2 primers. RESULTS: MCA of combined FR2 and FR3 primer sets yielded the sensitivity and the specificity equal to 70% (28/40) and 100% (31/31), respectively. Addition of FR2 primers increased the sensitivity by 12.5% (5/40) comparing to FR3 primers alone. MCA was slightly more sensitive than polyacrylamide gel electrophoresis and comparable to capillary gel electrophoresis to detect clonal IgH gene rearrangement. CONCLUSIONS: Combined PCR and DNA melting curve analysis in a closed system can reduce cross contamination risk. This method can test 96 samples simultaneously within 90 min and therefore, it is high-throughput and faster. PCR-MCA in the LightCycler system has potential for evaluating monoclonal IgH gene rearrangement in a clinical environment. PMID- 26255312 TI - Relationship between organisational commitment and burnout syndrome: a canonical correlation approach. AB - Objective Burnout syndrome can significantly reduce the performance of health workers. Although many factors have been identified as antecedents of burnout, few studies have investigated the role of organisational commitment in its development. The purpose of the present study was to examine the relationships between subdimensions of burnout syndrome (emotional exhaustion, depersonalisation and personal accomplishment) and subdimensions of organisational commitment (affective commitment, continuance commitment and normative commitment). Methods The present study was a cross-sectional survey of physicians and other healthcare employees working in the Ministry of Health Ordu University Education and Research Hospital. The sample consisted of 486 healthcare workers. Data were collected using the Maslach Burnout Inventory and the Organisation Commitment Scale, and were analysed using the canonical correlation approach. Results The first of three canonical correlation coefficients between pairs of canonical variables (Ui , burnout syndrome and Vi, organisational commitment) was found to be statistically significant. Emotional exhaustion was found to contribute most towards the explanatory capacity of canonical variables estimated from the subdimensions of burnout syndrome, whereas affective commitment provided the largest contribution towards the explanatory capacity of canonical variables estimated from the subdimensions of organisational commitment. Conclusions The results of the present study indicate that affective commitment is the primary determinant of burnout syndrome in healthcare professionals. What is known about the topic? Organisational commitment and burnout syndrome are the most important criteria in predicting health workforce performance. An increasing number of studies in recent years have clearly indicated the field's continued relevance and importance. Conversely, canonical correlation analysis (CCA) is a technique for describing the relationship between two variable sets simultaneously to produce both structural and spatial meaning. What does this paper add? To our knowledge, CCA has not been used to determine the relationships between burnout and organisational commitment of physicians and other healthcare staff. Accordingly, the present study adds information regarding the relationship between burnout and organisational commitment variables determined using CCA. This analysis is used to describe the relationship between two variable sets simultaneously and allows for an easy method of interpretation. What are the implications for practitioners? Burnout syndrome is a major threat to both the health workforce and its organisations. In addition, it affects the quality and effectiveness of health care. Thus, the findings of the present study offer a solid foundation from which actions to decrease burnout levels in healthcare professionals can be implemented by successfully increasing levels of organisational commitment. PMID- 26255310 TI - Identifying a novel locus for psoriatic arthritis. AB - A number of studies have identified genetic risk loci for PsA, the majority of which also confer risk for psoriasis. The stronger heritability of PsA in comparison with psoriasis suggests that there should be risk loci that are specific for PsA. Identifying such loci could potentially inform therapy development to provide more effective treatments for PsA patients, especially with a considerable proportion being non-responsive to current therapies. Evidence of a PsA-specific locus has been previously found at HLA-B27 within the MHC region. A recent study has provided evidence of non-HLA risk loci that are specific for PsA at IL23R, PTPN22 and on chromosome 5q31. Functional characterization of these loci will provide further understanding of the pathways underlying PsA, and enable us to apply genetic findings for patient benefit. PMID- 26255316 TI - Dr. Thal remembered for his love of medicine. PMID- 26255313 TI - [Thrombodynamic properties of arterial and venous blood in ischemic patients in preoperative and early postoperative periods after coronary artery bypass grafting]. AB - In the preoperative period ischemic patients show a significant increase in thrombodynamic properties of fibrin clots. It is more than at a half of patients in the presurgical period as in an arterial, and venus blood the spontaneous growth of a clot comes to light that is practically not observed at healthy people. In the early postoperative period ischemic patients demonstrate a general sharp decrease in thrombodynamic properties of fibrin clots, but in arterial blood, as opposed to venous blood, such properties sharply grow. Based on the data obtained it may be concluded that in ischemic patients venous blood levels cannot be used as a judgement for arterial blood fibrin clot properties. PMID- 26255317 TI - How Your Hospital Can Make You Sick. Our centers for healing have turned into breeding grounds for dangerous--even deadly--infections. Consumer Reports' new Ratings of more than 3000 U.S. hospitals show which do a good job of avoiding the infections--and which don't. American's Antibiotic Crisis. Part 2. PMID- 26255318 TI - Factors to be Considered in Osteoprotegerin Measurement. PMID- 26255319 TI - Reply: To PMID 24845712. PMID- 26255320 TI - Current world literature. Pain medicine. PMID- 26255321 TI - Current world literature. Regional anesthesia. PMID- 26255322 TI - The Rise of Chinese Acupuncture in the West: How an Ancient Eastern Tradition Became an American Medical Staple. PMID- 26255323 TI - George H. Dadd, Veterinary Reformer: The Boston Connection. PMID- 26255324 TI - Helping Paws throughout History: The Evolution of the Service Dog. PMID- 26255325 TI - American Veterinary History: A Growing Agriculture Aids Veterinary Medicine. PMID- 26255326 TI - The Worm Conqueror. PMID- 26255327 TI - Clinical laboratory test prices in Zimbabwe: A case of profiteering? AB - OBJECTIVE: To compare the prices charged for clinical laboratory tests in Zimbabwean institutions with those of similar institutions abroad. DESIGN: An online analytical cross sectional study was conducted. SETTING: An online survey. SUBJECTS: We did an online survey of clinical laboratories that published prices of the tests offered on their websites. We also extracted price information from documents published by fees regulatory authorities. MAIN OUTCOME MEASURES: Laboratory test prices for independent institutions, Laboratory test prices for State institutions. RESULTS: Overally for all countries, laboratory test prices were lower in state laboratories compared to the independent laboratories. In Zimbabwe, state laboratories generally charged about 50% of the independent laboratory tariff for most tests. However prices from both Zimbabwean institutions were generally much higher than those of the comparison countries (United Kingdom, South Africa, India, United States of America and New Zealand). CONCLUSION: Prices of laboratory tests are indeed higher in Zimbabwean institutions compared to other centres abroad. These higher prices could be attributed to challenges in consumable procurement logistics. We also present measures that could be put in place to reduce the costs and therefore prices. PMID- 26255328 TI - The role of dental practitioners in Provider Initiated HIV Counseling and Testing (PITC) for patients attending dental practices in Harare, Zimbabwe. AB - OBJECTIVE: To assess the role of Zimbabwean dental practitioners in Provider Initiated HIV Counseling and Testing (PITC). DESIGN: A cross-sectional analytic study was conducted. A structured interviewer administered questionnaire was used to collect data from participants. SETTING: Harare private and public dental practices. SUBJECTS: Forty dental practitioners practicing in Harare and two hundred and ninety three patients attending dental practices in Harare were interviewed. MAIN OUTCOME MEASURES: Dental practitioners' practices on HIV counseling and testing for dental patients, acceptability of HIV testing in dental settings and missed opportunities for HIV counseling and testing in dental settings were assessed. RESULTS AND CONCLUSION: Half of the dental practitioners (20) interviewed reported offering HIV counseling to dental patients during their clinical duties. The majority 62% only referred their patients for HIV testing when they presented with oral manifestations of HIV infection. Seventy three percent (29) of practitioners interviewed were not aware of the Ministry of Health and Child Welfare guidelines on HIV counseling and testing. Eighty seven percent (255) of dental patients in this study reported not being counseled nor referred for HIV counseling and testing by their dental practitioner during their dental visits. More than a third (36.5%) of the dental patients experienced repeated missed opportunities for accessing HIV counseling and testing in health settings. The minimal that the dentists may need to be involved with in PITC is counseling their patients and improve referral for care. There is need for continued medical education for dentists on issues related to new HIV interventions or protocols such as PITC. PMID- 26255329 TI - Congenital duplex gallbladder anomaly presenting as gangrenous perforated intrahepatic cholecystitis mimicking a gas forming liver abscess: A case report and literature review. AB - BACKGROUND: Ectopic intrahepatic gallbladder is a rare phenomenon. Gallbladder duplication is an even rarer phenomenon. Pathological processes are more common in congenital anomalies of the gall bladder than normal gallbladders due to poor drainage. CASE REPORT: We present a case of duplex gallbladder with one component intrahepatic and the other extra-hepatic, the duo draining via a common cystic duct into the common bile duct. Both gallbladder moieties were diseased. The intrahepatic moiety was gangrenous and perforated thus mimicking an intrahepatic abscess by a gas forming organism. The extra-hepatic moiety was chronically inflamed and packed with gallstones of the same physical and biochemical characteristics as the intrahepatic moiety. The definitive diagnosis was only made at emergency laparotomy. Stone gathering and debridement of the ruptured, gangrenous intrahepatic moiety and cholecystectomy for the extra-hepatic moiety was done. On table cholangiography, though desired, was not available. The patient fully recovered after post-operative intensive care. CONCLUSION: An extensive internet literature search did not reveal any previously described case. This could be the first such case described in the world literature. Though rare, congenital anomalies of the gallbladder must be known to surgeons as they can present unexpectedly and pose diagnostic and operative surgical challenges with serious clinical implications. The management challenges experienced and literature review is presented. PMID- 26255330 TI - Mortality within 24 hours of admission to the Paediatric Unit, Harare Central Hospital, Zimbabwe. AB - OBJECTIVE: To determine the proportion of deaths, characteristics of children and risk factors for mortality w ithin 24 hours of admission to a Paediatric hospital in Harare. STUDY DESIGN: Prospective cohort study. SETTINGS: Paediatric Unit, Harare Central Hospital. SUBJECTS: All patients admitted to the medical wards who consented to participate were enrolled. Preadmission factors including duration of illness and health seeking behaviour prior to presentation, delays in A&E department assessed by lag time to assessment, administration of initial medications and admission to the ward were documented. The presenting clinical signs and admission diagnoses were also recorded MAIN OUTCOME MEASURE: Death within 24 hours of admission. RESULTS: Of the 737 paediatric admissions during the study period, 54 children died within 24 hours giving a case fatality rate of 7.3%. These constituted 34.6% of total deaths in the study population (54/155). The median age of the children in this study was 16 months (Q1 = 4, Q3 = 36) and 53.2% were male. Having subcostal recessions on admission was significantly associated with mortality (within 24 hours of admission) with a RR 29.9 (95% CI 1.56.74) while socio-demographic factors, duration of illness, fever, diagnosis on admission and delays in A & E department were not. CONCLUSION: The contribution of deaths within 24 hours of admission to the overall mortality in children remains unacceptably high. Sub-costal recessions on admission (a proxy for severe pneumonia) had the highest risk of mortality within 24 hours of admission. There is need for early identification and aggressive management of children with pneumonia. PMID- 26255331 TI - Investigation of the effect of Stalanev (Stavudine, Lamivudine and Nevirapine) treatment on plasma lactate levels in adults attending Beatrice Road and Wilkins Infectious Diseases Hospital Opportunistic Infections Clinics in Harare, Zimbabwe. AB - MAIN OBJECTIVE: To evaluate the effect of Stalanev (Stavudine, Lamivudine and Nevirapine) treatment on plasma lactate levels in adults attending Beatrice Road Infectious Diseases Hospital and Wilkins Infectious Diseases Hospital Opportunistic Infections Clinics in Harare. DESIGN: Prospective cohort study carried out between January and May 2011. SETTING: Beatrice Road and Wilkins Infectious Diseases Hospital Opportunistic Infections Clinics in Harare, Zimbabwe. PARTICIPANTS: A convenience sample of 180 ART naive HIV infected adults aged 20-68 years who were about to be initiated on STALANEV were recruited. RESULTS: The mean plasma lactate at baseline was 1.57 mmol/L (SD 0.43). After two months on STALANEV, 25 participants (13.9%) had hyperlactatemia and the mean plasma lactate level was 1.99 mmol/L (SD 0.49). At four months follow up, 98 participants (54%) had hyperlactatemia and the mean plasma lactate level was 2.65 mmol/l (SD 0.55). Mean plasma lactate levels increased significantly from baseline to 2 months follow up and from 2 months follow up to 4 months follow up (p < 0.001). None of the participants developed lactic acidosis (plasma lactate > 3.5) after two months of follow up but 14 (7.8%) developed mild lactic acidosis and three (1.7%) had moderate lactic acidosis after four months on STALANEV. CONCLUSIONS: Our findings are in agreement with those of other studies that reported that treatment with STALANEV leads to hyperlactatemia thereby posing a risk for the development of lactic acidosis in patients. In the absence of alternative regimens, we recommend routine monitoring of plasma lactate levels on all patients on STALANEV in Zimbabwe. PMID- 26255332 TI - Rhabdomyosarcoma of the orbit in a four months old infant in Zimbabwe: A case report. AB - Infants younger than one year of age with Rhabdomyosarcoma appear to have worse prognosis compared to older children due partly to high rates of local failure. We report a 4 months old infant with orbital rhabdomyosarcoma with poor outcome. Reluctance to use aggressive local control measures and suboptimal chemotherapy dosing are significant contributory factors. Call is made for need for more studies to determine appropriate local therapy in infants with rhabdomyosarcoma. PMID- 26255333 TI - Patterns of Retinoblastoma in Zimbabwe: 2000-2009. AB - OBJECTIVE: To document the pattern of retinoblastoma in children in Zimbabwe for the period 2000-2009. DESIGN: Retrospective study. METHODS: Analysis of data from the Zimbabwe National Cancer registry and records of patients admitted to the Paediatric Oncology unit. Data collected from cancer registry were basis of diagnosis, age and gender. Data from the patients medical records included clinical presentation, time to diagnosis and treatment. SETTINGS: The Zimbabwe National Cancer Registry and Paediatric Oncology Unit at Parirenyatwa Tertiary Hospital. RESULTS: 196 patients with retinoblastoma were registered at the cancer registry over the study period. The diagnosis was confirmed histologically on 89% of the cases and in 7% the diagnosis was based on clinical grounds. The age ranged from less than one month to 7 years with median age of 24 months. Males were 111 (56%) with male:female ratio of 1.3:1. Forty three patients (84%) had unilateral and 8 (16%) bilateral disease. Medical records were retrieved from only 54 /196 cases (27.5%). The commonest clinical presentation was proptosis 35/54 (65%). Leucocoria was present in 14/54 (26%). Time interval between first symptoms and diagnosis ranged from less than one month to 24 months with mean duration of 7.7 months (SD = 6.9). Enucleation was performed on 33/ 54 (61%), exenteration on 20/54 (37%) chemotherapy was given to 34/54 (63%) and only 6/54 (11%) received radiotherapy. CONCLUSION: Retinoblastoma is the third commonest registered malignancy of childhood in Zimbabwe, characaterised by late presentation and poor access to therapy. PMID- 26255334 TI - Accuracy of straight leg raise and slump tests in detecting lumbar disc herniation: a pilot study. AB - OBJECTIVE: To determine the accuracy of the Straight Leg Raise (SLR) and slump tests in detecting Lumbar Disc Herniation (LDH). DESIGN: Cross-sectional diagnostic accuracy study. SETTING: Two referral hospitals in Kigali, Rwanda: King Faisal Hospital and Centre Hospitalier Universitaire de Kigali. SUBJECTS: All patients aged 18 to 70 who had an MRI and who were experiencing pain in the low back, leg or low back and leg. INTERVENTIONS: Closed Magnetic Resonance Imaging (MRI) investigations for each patient as witnessed by a radiologist who read the image were recorded by the first researcher and blinded to other researchers. The SLR and slump tests were performed three times on each patient by independent testers who were blinded to the result of the first test. The test order was randomized for each subject and the two tests were separated by one day wash-out period. MAIN OUTCOME MEASURES: Data were analyzed using a 2x2 table to ascertain diagnostic statistics including sensitivity and specificity with 95% confidence intervals. RESULTS: Thirty three from a possible 37 patients mean age 41.58 +/- 10 years completed all of the tests. The sensitivity of SLR was greater (0.875; CI: 0.690-0.957) than that of the slump tests (0.800; CI: 0.6087-0.911) (p = 0.01) in detecting LDH. The specificity for SLR was 0.429 (CI: 0.158-0.750) and for slump was 0.714 (CI: 0.359-0.918). Substantial agreement (K = 0.774) was obtained between the SLR and MRI. CONCLUSION: The SLR was more accurate in detecting LDH. Further validation of this pilot finding is required by studying a larger sample. PMID- 26255335 TI - Bronchogenic cyst and pharyngeal fistular in an 81 year old female: A case report. AB - Bronchogenic cyst is a rare clinical; entity that occurs due to an anomalous development of the ventral foregut; they are usually single but may be multiple and can be filled with fluid or mucus. They have been found all along the transoesophageal course, in perihilar or intraparenchymal sites, with predilection for the area around the carina. The location of the cyst depends on the embryonic stage of development at which the anomaly occurs. When the abnormal budding occurs during the early development, the cyst tends to be located along the tracheobronchial tree. The cysts that develop later during the late development are more peripheral and may be located within the lung parenchyma. Bronchogenic cysts have also been described in more remote locations, including neck, interatrial septum, abdomen, and retroperitoneal space. Past reports emphasised that a bronchogenic cyst is usually asymptomatic and presents as an incidental finding, but more recent reports suggest that the majority of adults with bronchogenic cysts ultimately become symptomatic. The actual natural history and percentage of asymptomatic bronchogenic cyst in adults are not known because of the absence of long-term follow up of a large group of patients with asymptomatic cyst. Symptomatic patients usually present with symptomatic related to cyst infection or compression of adjacent structures. Presentation in the elderly population is quite rare. It has been reported that approximately 0.6% of such cyst are noted in patients above the age of 60 years. Total documented cases of patients presenting after the age of 70 years have been noted to be only 8 in 2002. PMID- 26255336 TI - [Mg2+,ATP-DEPENDENT PLASMA MEMBRANE CALCIUM PUMP OF SMOOTH MUSCLE CELLS. II. REGULATION OF ACTIVITY]. AB - Plasma membrane Ca2+-pump is one of key proteins, which takes part in Ca2+ exchange in smooth muscle cells. It has a lot of diverse functions from control of basal cytoplasmal Ca2+ concentration to regulation of proteins involved in Ca2+-dependent signal pathway. Ca2+ pump function is often dependent on the isoform or even form of alternative splicing. Allowing for a variety of Ca2+-pump functions and properties, which were reviewed in detail in the first part of our review article cycle (Ukr. Biochem. J, 2015; 87(1)), the precise control of the mentioned pump activity is very important for cell functioning. The other part of this article is dedicated to different regulation factors of smooth muscle plasma membrane Ca2+-pump activity: endogenous and exogenous, biotic and abiotic factors. Special attention is given to literature data and own results about design and the search of selective plasma membrane Ca2+-pump inhibitor which would allow examining its functioning in smooth muscle cells more meticulously. PMID- 26255337 TI - [ASSOCIATION OF ALLELE VARIANTS OF RECEPTOR GENE OF ANDROGENS (BY THE NUMBER OF CAG-REPEATS) WITH ANDROGEN DEPENDENT HORMONAL METABOLIC INDICES OF THE ORGANISM]. AB - This review discusses up-to-date conceptions concerning an association of androgen receptor gene (AR) allele (by the number of CAG-repeats) variations with the change of the receptor activity in humans. Different contradictory experiment results concerning the AR function dependence on the number of CAG-repeats have been analyzed. The authors discuss this problem paying mostly their attention to the interrelation between the number of CAG-repeats and indicators of glucose and lipid metabolism in males and females. PMID- 26255338 TI - [LIPOXYGENASES AND PLANT CELL METABOLISM REGULATION]. AB - Lipoxygenases are widespread plant enzymes that catalyze the peroxidation of polyunsaturated fatty acids. This reaction is pivotal in the enzymatic cascade that leads to production of numerous metabolism regulators named oxylipins. The activity of these biologically active substances is directly associated with defence reactions in conditions of biotic and abiotic stresses as well as with the regulation of plant growth, propagation and senescence. In this review the contemporary notions about lipoxygenases classification, structure and catalytic properties are summarized. The features of enzyme activity regulation by transcriptional and posttranslational mechanisms in addition to the role of lipoxygenase catalysis in plant cell signalling are discussed. PMID- 26255339 TI - ISOLATION AND PROPERTIES OF POLYPHENOL OXIDASE FROM BASIDIOCARPS OF Lactarius pergamenus Fr. (Fr.) FUNGI. AB - Fresh juice of basidiocarps of Lactarius pergamenus Fr. (Fr.) fungi was subjected to ion exchange chromatography with used DEAE-toyopearl and CM-cellulose columns, as well as preparative electrophoresis in 7.5% polyacrylamide gels (pH 8.6). Three isoforms of polyphenol oxidase (PPO) were discovered and two isoforms (1-l and 1-2) were purified with a release of protein 0.42 mg/kg and 0.15 mg/kg of basidiocarps, respectively. These isoforms differ in the mobility at disc electrophoresis in 7.5% PAGE in alkaline buffer system (pH 8.6). Specfic activity of isoform 1-2 is 4.8 times higher than that of the isoforms 1-1. The molecular weight determination by gel chromatography on the Toyopearl HW-55 demonstrated that both isoforms 1-1 and 1-2 have the same 64 +/- 2 kDa molecular mass. Electrophoresis in 15% PAGE in the presence of sodium dodecylsulphate and beta mercaptoethanol revealed one band with molecular mass of 64 +/- 1 kDa which suggests the presence of one polypeptide chain in the molecule ofthe enzyme. The enzyme has demonstrated the highest activity at pH 6.0 and temperature +10 degrees C, and at +70 degrees C the enzyme was inactivated. The PPO activity was the highest in young mushrooms and it decreased with their age and positively correlated with the content ofthe milky juice. Ortho-aminophenol was most effective among all the tested substrates to determine the activity of PPO (o-, m and p-aminophenol, catechol, tyrosine, resorcinol, phloroglucinol) and its relative activity was 129% of the activity of catechol. Ascorbic acid was the most effective inhibitor of the polyphenol oxidase activity which was completely blocked at 1 mM concentration, whereas the same concentration of thiourea and sodium sulphite decreased the enzymatic activity by 40-45%. The PPO in L. pergamenus fungi basidiocarps was mainly localized in the mushroom milky juice where its high activity may be associated with protection of basidiocarps against various pathogens. PMID- 26255340 TI - [PECULIARITIES OF GLUCOSE AND GLYCEROL METABOLISM IN Nocardia vaccinii IMB B 7405]. AB - It has been established that in cells of Nocardia vaccinii IMB B-7405 (surfactant producer) glucose catabolism is performed through pentose phosphate cycle as well as through gluconate (activity of NAD+-dependent glucose-6-phosphate dehydrogenase and FAD+-dependent glucose dehydrogenase 835 +/- 41 and 698 +/- 35 nmol.min-1.mg-1 of protein respectively). 6-Phosphogluconate formed in the gluconokinase reaction is involved in the pentose phosphate cycle (activity of constitutive NADP+-dependent 6-phosphogluconate dehydrogenase 357 +/- 17 nmol.min 1.mg-1 of protein). Glycerol catabolism to dihydroxyacetonephosphate (the intermediate of glycolysis) may be performed in two ways: through glycerol-3 phosphate (glycerol kinase activity 244 +/- 12 nmol.min-1.mg-1 of protein) and through dihydroxyacetone. Replenishment of the C4-dicarboxylic acids pool in N. vaccinii IMV B-7405 grown on glucose and glycerol occurs in the phosphoenolpyruvate(PEP)carboxylase reaction (714-803 nmol.min-1.mg-1 of protein). 2-Oxoglutarate was involved in tricarboxylic acid cycle by alternate pathway with the participation of 2-oxoglutarate synthase. The observed activity of both key enzymes of gluconeogenesis (PEP-carboxykinase and PEP-synthase), trehalose phosphate synthase and NADP+-dependent glutamate dehydrogenase confirmed the ability of IMV B-7405 strain to the synthesis of surface active glycoand aminolipids, respectively. PMID- 26255341 TI - INHIBITION OF ERN1 SIGNALING ENZYME AFFECTS HYPOXIC REGULATION OF THE EXPRESSION OF E2F8, EPAS1, HOXC6, ATF3, TBX3 AND FOXF1 GENES IN U87 GLIOMA CELLS. AB - Hypoxia as well as the endoplasmic reticulum stress are important factors of malignant tumor growth and control of the expression of genes, which regulate numerous metabolic processes and cell proliferation. Furthermore, blockade of ERN1 (endoplasmic reticulum to nucleus 1) suppresses cell proliferation and tumor growth. We studied the effect of hypoxia on the expression of genes encoding the transcription factors such as E2F8 (E2F transcription factor 8), EPAS1 (endothelial PAS domain protein 1), TBX3 (T-box 3), ATF3 (activating transcription factor 3), FOXF1 (forkhead box F), and HOXC6 (homeobox C6) in U87 glioma cells with and without ERN1 signaling enzyme function. We have established that hypoxia enhances the expression of HOXC6, E2F8, ATF3, and EPAS1 genes but does not change TBX3 and FOXF1 gene expression in glioma cells with ERNI function. At the same time, the expression level of all studied genes is strongly decreased, except for TBX3 gene, in glioma cells without ERN1 function. Moreover, the inhibition of ERN1 signaling enzyme function significantly modifies the effect of hypoxia on the expression of these transcription factor genes. removes or introduces this regulation as well as changes a direction or magnitude of hypoxic regulation. Present study demonstrates that fine-tuning of the expression of proliferation related genes depends upon hypoxia and ERN1-mediated endoplasmic reticulum stress signaling and correlates with slower proliferation rate of glioma cells without ERN1 function. PMID- 26255342 TI - RECOMBINANT SINGLE CHAIN VARIABLE FRAGMENT ANTIBODIES (scFv) AGAINST Pro144 Leu155 FRAGMENT OF HUMAN PROTEIN C. AB - The aim of this work was to obtain the recombinant single chain variable fragments of antibodies (scFv) against human protein C, the key component of blood anticoagulation system. For this purpose a peptide that mimics a Pro144 Leu155 sequence of protein C was synthesized and the murine immune scFv library against this peptide was constructed. The protein C specific scFv 9E were selected from the constructed library by the phage-display method. The scFv 9E dissociation constant was found to be 2?10(-9) M. It was shown that scFv 9E were suitable for protein C detection by ELISA and Western blotting. Selected scFv could be further used for protein C investigation and for the development of quantitative methods for protein C detection in human blood. PMID- 26255343 TI - ANTIOXIDANT ACTIVITY OF ALKOXY DERIVATIVES OF (QUINOLINE-4-YLTHIO)CARBOXYLIC ACIDS. AB - A selection of potential bioactive molecules including alkoxy derivatives of (quinoline-4-ylthio)carboxylic acids using virtual screening has been carried out and their biological activity was determined. The studied substances proved to be low-toxic, biologically active compounds. It was established that 4-thio derivatives of quinoline exhibit pronounced antiradical, antioxidant-effects and can act as preventive antioxidants, radio and cytoprotectors. PMID- 26255344 TI - METALLOPROTEINS DURING DEVELOPMENT OF WALKER-256 CARCINOSARCOMA RESISTANT PHENOTYPE. AB - The study was focused on the detection of changes in serum and tumor metal containing proteins in animals during development ofdoxorubicin-resistant phenotype in malignant cells after 12 courses of chemotherapy. We found that on every stage of resistance development there was a significant increase in content of ferritin and transferrin proteins (which take part in iron traffick and storage) in Walker-256 carc'inosarcoma tissue. We observed decreased serumferritin levels at the beginning stage of the resistance development and significant elevation of this protein levels in the cases withfully developed resistance phenotype. Transferrin content showed changes opposite to that offerritin. During the development of resistance phenotype the tumor tissue also exhibited increased 'free iron' concentration that putatively correlate with elevation of ROS generation and levels of MMP-2 and MMP-9 active forms. The tumor non-protein thiol content increases gradually as well. The serum of animals with early stages of resistance phenotype development showed high ceruloplasmin activity and its significant reduction after loss of tumor sensitivity to doxorubicin. Therefore, the development of resistance phenotype in Walker-256 carcinosarcoma is accompanied by both the deregulation of metal-containing proteins in serum and tumor tissue and by the changes in activity of antioxidant defense system. Thus, the results of this study allow us to determine the spectrum of metal-containing proteins that are involved in the development of resistant tumor phenotype and that may be targeted for methods for doxorubicin sensitivity correction therapy. PMID- 26255345 TI - [EFFECT OF BIOACTIVE ALDEHYDES ON GELATIN PROPERTIES]. AB - Bioactive aldehydes are among main factors of proteins postsynthetic modifications, which are the cause and consequence of many diseases. Comparative study of some aldehydes modifying action on gelatin was carried out in vitro. Gelatin samples (20 mM) were incubated with: ribose, deoxyribose, glyoxal, methylglyoxal, formaldehyde, acrolein (20 mM each) and their combinations in 0.1 M Naphosphate buffer (pH 7.4) containing 0.02% sodium azide at 37 degrees C in the dark for 30 days. We investigated the fluorescent properties of these samples and their molecular weight distribution by electrophoresis. It has been revealed that formed adducts had different fluorescence spectra. According to fluorescence intensity these aldehydes were put in order: formaldehyde < methylglyoxal < acrolein 0.05). Postoperative VAS and ODI scores at 3 d, 2 weeks and 1 month among three groups were lower than that of before operation (P<0.01). Compared with control group, postoperative VAS score at 3 d, 2 weeks and 1 month were decreasedin treatment group and comprehensive group, but there was no significant meaning in ODI scores (P>0.05). At 6 and 12 months after operation,there was no significant differences in VAS and ODI between control group and treatment group (P>0.05), while VAS score in comprehensive group decreased much than other two groups,decreased continuously (P<0.01). At 12 months after operation, BMD among three groups were increased more than preoperative,and BMD in comprehensive group was more obviously than that of in control and treatment group. CONCLUSION: PKP, an effective method for the treatment of thoracic and lumbar vertebral osteoporotic fracture, could improve short-term clinical effects by adding calcitonin with calcium supplements and activated vitamin D. Waist musculi dorsi function exercise could improve long-term clinical effects of PKP and improve quality of life. PMID- 26255475 TI - [Case-control study on T-shaped locking internal fixation and external fixation for the treatment of dorsal Barton's fracture]. AB - OBJECTIVE: To compare clinical effect of T-shaped locking internal fixation and external fixation in treating dorsal Barton's fracture,and investigate selective strategy of internal fixation. METHODS: From January 2008 to January 2013, 100 patients with dorsal Barton's fracture were randomly divided into two groups. In treatment group, there were 30 males and 20 females with an average age of (33.8+/-3.6) years old;30 cases were type B, 20 cases were type C;and treated with T-shaped locking internal fixation. In control group, there were 32 male and 18 females with an average age of (32.9+/-3.4) years old; 29 cases were type B, 21 cases were type C; and treated with external fixation. Volar tilt, ulnar deviation and radial height at 3 months after operation were detected and compared between two groups. Mechara functional evaluation were used to evaluate postoperative clinical effects. Clinical cure time, postoperative complications,joint mobility and function score were recorded and compared between two groups. RESULTS: In treatment group,volar tilt was (11.9+/-2.7) degrees , ulnar deviation was (20.8+ 2.9) degrees ,and radial height was (10.9+/ 1.8) mm; while volar tilt was (9.1+/-1.6) degrees , ulnar deviation was (17.1+/ 2.9) degrees , and radial height was (8.1+/-1.5) mm in control group. Treatment group was better than control group in volar tilt, ulnar deviation and radial height. Clinical cure time in treatment group was(12.0+/-2.3) weeks, shorter than control group (18.0+/-4.1) weeks. The incidence of complications in treatment group was lower than control group. According to Mehara functional evaluation,20 cases got excellent results, 25 good, 3 moderate and 2 poor in treatment group; 16 cases got excellent results, 14 good, 10 moderate and 10 poor in control group. Treatment group was better than control group in clinical effects. CONCLUSION: T-shaped locking internal fixation with postoperative functional exercise for the treatment of dorsal Barton's fracture fits for biomechanics demands,and has advantages of stable fixation,rapid recovery, less complications and good functional recovery, it has better clinical effects. PMID- 26255476 TI - [Manipulative reduction and percutaneous K-wires fixation for treatment of supracondylar fractures of the humerus in children]. AB - OBJECTIVE: To explore clinical effect of manipulative reduction and percutaneous K-wires fixation in treating supracondylar fractures of the humerus in children. METHODS: From July 2010 to December 2012, clinical data of 52 children with supracondylar fractures of the humerus, which treated with manipulative reduction and percutaneous K-wires fixation, were retrospectively analyzed. Among them, there were 35 males and 17 females with an average age of 6.7 (ranged from 2.5 to 12) years old. All fractures were type Garland II - III fractures, and 51 cases were extension type and 1 case were flexion type. Flynn evaluation standard of elbow performance score were applied to evaluate clinical effects. RESULTS: All patients were followed up from 12 to 18 months with average of 16 months. According to Flynn evaluation standard of elbow performance score, 41 cases obtained excellent result, 8 good and 3 moderate. CONCLUSION: Manipulative reduction and percutaneous K-wires fixation for the treatment of supracondylar fractures of the humerus in children has many advantages, such as minimally invasive, rapid recovery, stable fixation. It could prevent osteofascial compartment syndrome, Volkmann Contracture and cubitus varus. PMID- 26255477 TI - [Insertion of gluteus maximus tendo-chilles lengthening with Z-shaped for the treatment of severe gluteal muscle contracture]. AB - OBJECTIVE: To investigate clinical curative effects of gluteal muscle contracture release combined with insertion of gluteus maximus tendo-chilles lengthening with Z-shaped in treating severe gluteal muscles contracture. METHODS: From 2006 May to 2011 May, 20 patients (35 sides) with severe gluteal muscle contracture were collected, including 12 males and 8 females, aged from 8 to 34 years old with an average of 13 years old; the courses of disease ranged from 3 to 21 years. All patients manifested abnormal gait at different degree, knees close together cannot squat,positive syndrome of Ober, positive test of alice leg. Gluteus contracture fascia release were performed firstly in operation, then insertion of tendo-chilles lengthening with Z-shaped were carried out. Preoperative and postoperative gait, and knee flexion hip extensor squat test, cross leg test, adduction and internal rotary activity of hip joint, stretch strength and motor ability after hip abduction were observed and compared. RESULTS: Twenty patients were followed up for 1 to 5 years. Gluteus maximus were released thoroughly, and snapping hip was disappeared, Ober syndrome were negative. There was significant differences in knee flexion hip extensor squat test, adduction and internal rotary activity of hip joint,stretch before and after operation (P<0.01). Gluteus muscle strength was protected,stretch strength and motor ability of hip joint were recovered well. Among them,31 cases got excellent results and 4 good. CONCLUSION: For severe gluteal muscles contracture,insertion of gluteus maximus tendo-chilles lengthening with Z-shaped performed after gluteus contracture fascia release could release gluteal muscle contracture to the greatest extent and obtain postoperative curative effect without resection of normal hip muscle fibers and destroy joint capsule. PMID- 26255478 TI - [Clinical observation of characteristic and treatment of posterior Pilon fractures]. AB - OBJECTIVE: To explore clinical characteristics and treatment of posterior Pilon fracture. METHODS: From January 2011 to January 2013,18 patients with posterior Pilon fracures were treated. Among them, 13 were male and 5 were female, aged from 22 to 63 years old, with an average age of 46. All the patients were closed fractures. Open reduction and internal fixation were performed after swelling subsided, lateral malleolous and posterior Pilon fracture were exposured through lateral approach on healthy side, plates were used to fixed,screws or small plates were used to fix the posterior prominence of medial malleolus after changed to supine position. AOFAS scoring were applied to evaulate clinical effects. RESULTS: All patients were followed up with an average of 22(ranged, 12 to 48)months. All patients obtained satisfactory reset except one patient. All factures were recovered well with an average healing of 11 weeks. According to AOFAS score at the final following up, 7 cases were excellent,2 cases were moderate, and the total score was 86.8+/-9.2. CONCLUSION: Posterior Pilon fracture is not rare in clinical, its mechanism of injury, traumatic anatomy, surgical procedure and prognosis are different from that of classical ankle fracture and Pilon fracture. PMID- 26255479 TI - [Case-control study on superior labrum from anterior to posterior repair and biceps tenodesis for the treatment of type II SLAP injury]. AB - OBJECTIVE: To compare clinical outcomes of superior labrum from anterior to posterior (SLAP) repair and biceps tenodesis in treating type I SLAP injury. METHODS: From March 2009 to March 2012, 38 patients with type II SLAP injury were treated with SLAP repair and biceps tenodesis, and all patients were unilateral SLAP injury. Sixteen patients treated with biceps tenodesis included 8 males and 7 females with an average age of (49.3+/-3.7) years old (ranged, 45 to 54); 10 cases were on the left side and 6 cases on the right side; 10 cases were caused by falling down, 2 cases were caused by throwing damage and 4 cases were caused by daily life damage; the time from injury to operation were from 3 to 8 weeks. Twenty-two patients treated with SLAP repair included 14 males and 8 females with an average age of (49.0+/-2.8) years old (ranged, 44 to 56); 13 cases were on the left side and 9 cases were on the right side; 14 cases were caused by falling down, 5 cases were caused by throwing damage and 3 cases were caused by daily life damage; the time from injury to operation were from 3 to 7 weeks. Preoperative, postoperative at 6 months, 1 year and 2 years' UCLA and SST score were compared between two groups. RESULTS: There was no significant differences in UCLA and SST score between two groups before operation. At 6 months after operation, UCLA and SST score in biceps tenodesis group was higher than SLAP group, and action,range of anteflexion, strength of anteflexion, degree of satisfaction in biceps tenodesis group was higher than SLAP group. There was no significant meaning in SST and UCLA score between two groups at 1 and 2 years after operation. CONCLUSION: Short-term efficacy of biceps tenodesis for SLAP injury is better than SLAP repair, but long-term efficacy is fairly. PMID- 26255480 TI - [Manual reduction for radius head fracture with radioulnar synostosis and elbow disloction: a case report]. PMID- 26255481 TI - [Reconstructing coracoclavicular ligament in treating Rockwood - III Acromioclavicular dislocation by palmaris longus muscle with polyester suture]. AB - OBJECTIVE: To explore therapeutic effects of reconstructing coracoclavicular ligament for the treatment of Rockwood-III Acromioclavicular dislocation by palmaris longus muscle with polyester suture. METHODS: From August 2011 to November 2013,37 cases with Rockwood-III acromioclavicular dislocation were treated with reconstructing coracoclavicular ligament by palmaris longus muscle with polyester suture. Among patients, 24 were males and 13 were females, ranging the age from 19 to 46 years old, with an average of 32 years old. There were 11 cases on the left side and 26 cases on the right side. Twenty-nine cases were fresh dislocation and 8 cases were old dislocation. Blood loss, operative time were observed, and Karlsson evaltae standard were applied for assessing postoperative recovery of shoulder joint function. RESULTS: All patients were followed up from 2.5 to 5 months with an average of 3.5 months. Operative time ranged from 52 to 98 (meaned 72) min, blood loss ranged from 50 to 180 (meaned 75) ml. All operative incision were healed at the satge I . According to Karlsson standard, 32 cases obtained excellent results and 5 cases were moderate. CONCLUSION: For Rockwood-III acromioclavicular dislocation,reconstructing coracoclavicular ligament by palmaris longus muscle with polyester suture has advantages of simple operation, and rapid recovery of shoulder joint function. PMID- 26255482 TI - [Arthroscopic patelloplasty and circumpatellar denervation for the treatment of patellofemoral osteoarthritis]. AB - OBJECTIVE: To investigate surgical procedure and clinical effects for the treatment of patellofemoral osteoarthritis (PFOA) with arthroscopic patelloplasty and circumpatellar denervation. METHODS: Totally 156 patients with PFOA (62 males and 94 females; aged from 45 to 61 years old with an average of 52) were treated from September 2011 and March 2013. The clinical manifestations included recurrent swelling and pains on knee-joint,and aggravated pains upon going up/down-stairs, squatting-down, or standing-up. PFOAs were treated with arthroscopic patelloplasty and circumpatellar denervation. The therapeutic effects before and after surgery were evaluated by Lysholm scores and Kujala scores. The therapeutic effects were graded by classification of cartilage injury degrees. RESULTS: Totally 149 cases were successfully followed up for 14.8 months. The incisions were healed well and no complication were occurred. Lysholm score was improved from 73.29 preoperatively to 80.93 postoperatively and average Kajala score from 68.34 preoperatively to 76.48 after surgery. This procedure was highly effective for patients with I - III degree cartilage injury, while not for patients with IV degree cartilage injury. CONCLUSION: For PFOA patients, arthroscopic patelloplasty and circumpatellar denervation is effective for significantly relieving anterior knee pains, improving knee-joint functions and quality of life, and deferring arthritic procession. PMID- 26255483 TI - [Establishment of osteoblast primary cilia model removed by chloral hyrate]. AB - OBJECTIVE: To establish osteoblast model, primary cilla model was removed by chloral hyrate, observe effects of osteoblast primary cilla moved on enhancing ALP staining and calcified nodules staining in electromagnetic field. METHODS: Three 3-day-old male SD rats weighed between 6 and 9 g were killed, cranial osteoblast was drawed and adherencing cultured respectively. Cells were subcultured and randomly divided into 4 groups until reach to fusion states. The four groups included chloral hydrate non-involved group (control group), 2 mM, 4 mM and 8 mM chloral hydrate group, and cultured in 37 degrees C, 5% CO2 incubator for 72 h. Morphology of primary cilla was observed by laser confocal scanning microscope, and incidence of osteoblast primary cilia was analyzed by Image-Pro Plus 6.0 software. Cells in the correct concentration group which can removed cillia most effectively were selected and divided into 3 groups, including control group (C), Electromagnetic fields group (EMFs), and EMFs with 4 mM chloral hydrate group. DMEM nutrient solution contained 10%FBS were added into three groups and cultured for 9 days and formation of ALP were observed by histochemical staining of alkaline phosphatase. After 12 days' cultivation, formation of mineralization nodes was observed by alizarin red staining. RESULTS: Compared with control group and 2mM chloral hydrate group,4 mM chloral hydrate group could effectively remove osteoblast primary cilla (P<0.01). Removal of osteoblast primary cilla could weaken the formation of ALP and mineralization nodes in osteoblast in EMFS. Compared with EMFs group, the area of ALP and mineralization nodes in EMFs with 4 mM chloral hydrate group were decreased obviously (P<0.01). CONCLUSION: 4mM chloral hydrate could effectively remove osteoblast primary cilia. Primary cilla participate in EMFs promoting formation of ALP and mineralization nodes in osteoblast and provide new ideas for exploring mechanism of EMFs promoting osteoblast maturation and mineralization. PMID- 26255484 TI - [Effects of serum of Bushen Huoxue prescription (Chinese characters) on classic Wnt/beta-catenin signaling pathways of osteoblasts]. AB - OBJECTIVE: To observe effects of serum Bushen Huoxue prescription(Chinese characters) on classic Wnt/beta-catenin signaling pathways of osteoblasts, and explore mechanism of Bushen Huoxue prescription (Chinese characters) for preventing osteoporosis. METHODS: Twenty health female rats were randomly divided into two groups, including Bushen Huoxue (Chinese characters) group and saline group,10 in each group. Bushen Huoxue (Chinese characters) group and Saline group were gavaged Bushen Huoxue and saline every day for 1 week. Bushenhuoxue containing serum and saline containing serum were got according to methods of serum preparation of drug-containing. The osteoblasts was cultured with neonatal rat skull according to Enzyme Consumer Law, and was identified by Wright-Giemsa staining (R-J) and alkaline phosphatase staining (ALP). The third generation of osteoblasts was divided into three groups, including saline group, normal group,Bushen Huoxue (Chinese characters) group. Each group were added to 15% appropriate medium. ALP activity of osteoblasts and osteoblasts proliferation rate were tested, mineralized nodules were observed, the expression of beta catenin, Runx2, Osx mRNA of osteoblasts were tested by RT-PCR. RESULTS: There was blue granules in cytoplasm, cell nucleus was flint with 1 to 3 nucleoli showed by R-J staining, morphology of osteoblasts were cultured. ALP staining showed cytoplasm with purple granules, the results showed that the cultured cell was osteoblasts. The content of ALP in Bushen Huoxue (Chinese characters)group was (6.272+/-0.131) ,appreciation rate was (0.81? 0.172), and could significantly improve differentiation and proliferation activity of osteoblasts compared with Saline group (P< 0.01). There were four different size orange nodules, the Maximun nodule was 1.0 x 1.0 cm in Bushen Huoxue (Chinese characters) group after Alizarin red staining, the results showed Bushen Huoxue (Chinese characters)group could obviously improve mineralization of osteoblasts. The expression of mRNA of beta-catenin, Runx2 and Osx in Bushen Huoxue (Chinese characters)group were (1.782+/-0.944), (1.935+/-0.994) and (1.610+/-0.811) by RT-PCR,it was significantly increased compared with saline group (P<0.01), but there was no difference between Bushen Huoxue (Chinese characters)group and normal group (P>0.05). CONCLUSION: Bushen Huoxue (Chinese characters)group could obviously promote differentiation, proliferation and mineralization of osteoblasts through activation of Wnt, beta-catenin signaling pathway. It suggested that the mechanism of action of Bushen Huoxue (O'f f Il.t)particle clould prevent osteoporosis through the activation of Wnt, beta-catenin signaling pathway. PMID- 26255485 TI - [Fibrous dysplasia of proximal femur: a case report and review literatures]. PMID- 26255486 TI - [Drilling decompression for femoral head necrosis at collapse stage]. AB - OBJECTIVE: To explore clinical effects of drilling decompression for femoral head necrosis at collapse stage. METHODS: Totally 22 patients with femoral head necrosis on both side were analyzed from March 2006 to February 2009. Among them, there were 20 males and 2 females aged from 24 to 52 years old with an average of 38.4 years old. All patients were Ficat I on one side and Ficat I or II on another side. Drilling decompression were performed on all patients. The average followed-up period was 5.4 years (ranged, 1 to 8 years). The endpoint of severe pain(VAS >=7), severe dysfunction (Harris <= 70), radiographic progression on Ficat IV and total hip arhtroplasty (THA) was used for survivorship analysis. RESULTS: Severe pain as an endpoint,13 cases were survived on Ficat III and 18 cases on Ficat I or II (P>0.05). Severe dysfunction as an endpoint, 6 cases were survived on Ficat III and 18 on Ficat I or II (P<0.05). Radiographic progression on Ficat IV as an endpoint, 2 cases were survived on Ficat III and 18 on Ficat I or II (P<0.05). THA as an endpoint, 13 cases were survived on Ficat I and 18 cases on Ficat I or II (P>0.05). CONCLUSION: Femoral head necrosis with Ficat III treated with drilling decompression could prolong progression of disease , decrease percentage of THA. PMID- 26255487 TI - [Treatment of talus neck fracture with mini-plate internal fixation through dual incision approaches]. AB - OBJECTIVE: To explore clinical outcomes of talus neck fracture treated with mini plate internal fixation through dual-incision approaches. METHODS: From August 2010 to February 2013,18 patients with closed talus neck fractures were treated (10 males and 8 females, aged from 31 to 66 years old with an average of 38.2 years old) with mini-plate internal fixation through dual-incision approaches. According to Hawkins classification, 12 cases were type II and 6 cases were type III. All cases were evaluated with X-ray and 3D CT scan preoperatively to define type and comminuted degree of fractures. Mini-plate fixation with dual-incision approaches was performed after swelling was resolved. X-ray films were taken during following up regularly. Functional evaluation was carried out according to Visual Analogue Scale (VAS), the ankle and hind-foot score of American Orthopedic Foot and Ankle Society (AOFAS). Complications were also recorded. RESULTS: Sixteen patients were followed up with an average time of 22.6 months (ranged, 17 to 46 months). No wound infection, skin and flap necrosis or implant failure were found. Traumatic arthritis in subtalarjoint was found in 1 patient. Preoperative VAS (5.94+/-1.12) was decreased to postoperative (1.06+/-1.06) (t=27.13, P<0.05). The average AOFAS score was 88.7510.19 at the latest following up; and 11 cases obtained excellent results, 3 good and 2 moderate. CONCLUSION: Mini-plate fixation with dual-incision approaches for talus neck fracture especially for talus neck comminuted fracture, an effective method, could obtain stable fixation, decrease complications. PMID- 26255488 TI - [Curative effect analysis on proximal frmoral nail antirotation for the treatment of femoral intertrochanteric fracture and integrity of lateral trochanteric wall]. AB - OBJECTIVE: To explore clinical efficacy and key matters for the treatment of femoral intertrochanteric fracture and integrity of lateral trochanteric wall by proximal frmoral nail antirotation (PFNA). METHODS: From June 2010 to December 2012,210 femoral intertrochanteric fracture patients treated with PFNA were retrospectively analyzed, including 76 males and 134 females aged from 46 to 96 years old with an average of 71 years old. All fracture were caused by injury and classified to type I (5 cases) type II (16 cases), type III (73 cases) and type IV (116 cases) according to Evans classification. The time of getting out of bed, postoperative complications and displacement of screw blade and fracture healing were observed, Baumgaertner criteria were used to evaluate quality of fracture reduction, Harris criteria were used to evaulate hip joint function. RESULTS: All incisions were healed at stage I, no complications occurred except incomplete of lateral trochanteric wall patients without reconstruction, other patients could get out of bed with crutches at one week and all patients discharged from hospital at 10 days after operation. One hundred and seventy-eight patients were followed up from 3 to 17 months with an average of 10 months. One case occurred unhealed fracture displacement caused by screw blade cutting, 2 cases occurred screw blade transfomed to proximal and out femoral head, other patients obtained fracture healing at 12 to 16 weeks after operation. According to Baumgaertner criteria, 130 cases obtained good results, 45 cases acceptable, and 3 poor; while 107 cases obtained excellent results, 65 good, 3 good and 3 poor according to Harris score. CONCLUSION: PFNA with mechanical advantage of intramedullary fixation has advantsges of stable fixation, shorter operation time, minimally invasive. Satisfied clinical effects could obtained by grasping fixation principle, dealing with negative factors in operation. Intraoperative reconstruction for integrity of lateral trochanteric wall could assure stable fixation and earlier get out of bed. PMID- 26255489 TI - [Research on pericellular matrix properties for chondrcytes]. AB - Pericellular matrix (PCM) is a narrow tissue region surrounding chondrocytes, which "chondron" with its enclosed cells. A number of studies suggested that PCM is rich in proteoglycans, collagen and fibronectin, and plays an important role in regulating microenvironment of chondrocytes. Direct measures of PCM properties through micropipette aspiration technique showed that PCM was different from mechanical property of chondrocytes and nature extracellular matrix. However, the function of PCM is not clear, and need further study. PMID- 26255491 TI - [Surgery 2015: strategies and technologies]. PMID- 26255490 TI - [Research on regulation mechanism of osteoclast differentiation]. AB - Osteoclasts are multinucleated giant cell, which derived from mononuclear myeloid hematopoietic stem cells with the function of bone absorption. Osteoclasts plays a key role in bone metabolism, therefore the body is very strict to regulation of osteoclastogenesis. Mobilization and differentiation of osteoclast maturation is a complex and sophisticated multi-level regulatory processes. In the relevant regulatory mechanisms, OPG/RANKL/RANK system plays a pivotal role in the process of osteoclast differentiation and maturation. Recent studies revealed that immune cells and osteoclasts were closely connect with each other in the field of bone metabolism, also provide a new therapeutic target for the treatment of bone diseases. The apoptosis of osteoclasts in bone metabolism have been payed more attention,while its mechanism is still not clear, which need further research. PMID- 26255492 TI - [PIPAC--Pressurized intraperitoneal aerosol chemotherapy. A novel treatment for peritoneal carcinomatosis]. AB - Peritoneal carcinomatosis remains a diagnostic challenge with sparse treatment options. The effect of systemic chemotherapy remains limited inside the peritoneum due to low penetration and a relative resistance of peritoneal nodules. Heated IntraPeritoneal Chemotherapy (HIPEC) improves survival in selected patients but entails a high incidence of complications. Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) allows to disperse the active agents inside the peritoneal cavity by laparoscopy. Distribution and tissue penetration of chemotherapy by PIPAC are superior to HIPEC and systemic chemotherapy despite of lower doses. Systemic side effects are uncommon and surgical trauma is limited. Histological and clinical response rates in platinum-resistant patients approach 70% and survival data appear to be favorable compared with standard therapy. PMID- 26255494 TI - [Surgery for pancreatic adenocarcinoma: from established facts to changes in strategy?]. AB - Pancreatic adenocarcinoma is still an aggressive disease with low survival. Apparently little changes have been made during the last years in the management of this disease, but knowledge and practices are evolving in many fields. Better understanding of the particular biology and genetics of this tumor will probably lead to more efficient targeted therapy. Surgical management with standardized "Enhanced Recovery After Surgery, ERAS" program diminishes postoperative medical morbidity, hospital length of stay and costs. Oncological treatment with more efficient chemotherapy is promising, with the emergence of strategy to perform more neoadjuvant treatments. PMID- 26255493 TI - [Robotic-assisted hepatic surgery]. AB - Open surgery is currently the gold standard for most liver resection. Laparoscopic hepatic surgery is currently gaining significance, but technical challenges remain. Surgical robotics has been developed to overcome these technical limitations and to enable more difficult minimally invasive procedures. At our institution, 16 robotic hepatic resections have been performed since 2010. Shorter length of stay on intermediate care unit and shorter overall hospitalization has been observed with the robotic patients when compared to open hepatic resection. Overall, the literature shows promising data with demonstration of general feasibility of robotic liver surgery. However, more systematic research is needed to precisely determine the potential advantages of robotics over alternative approaches and its overall role for hepatic resections. PMID- 26255495 TI - [CERN-MEDICIS (Medical Isotopes Collected from ISOLDE): a new facility]. AB - CERN-MEDICIS is a facility dedicated to research and development in life science and medical applications. The research platform was inaugurated in October 2014 and will produce an increasing range of innovative isotopes using the proton beam of ISOLDE for fundamental studies in cancer research, for new imaging and therapy protocols in cell and animal models and for preclinical trials, possibly extended to specific early phase clinical studies (phase 0) up to phase I trials. CERN, the University Hospital of Geneva (HUG), the University Hospital of Lausanne (CHUV), the Swiss Institute for Experimental Cancer (ISREC) at Swiss Federal Institutes of Technology (EPFL) that currently support the project will benefit of the initial production that will then be extended to other centers. PMID- 26255496 TI - [Patient management after splenectomy in 2015: state of the art and recommendations]. AB - Spleen gathers numerous functions and plays a critical role in immunity against encapsulated bacteria. Anatomical injuries or physiological spleen dysfunctions can lead to complete (asplenism) or partial (hyposplenism) functional deficits and expose the patient to the risk of fulminant sepsis, as well as to thromboembolic complications. The purpose of this article is to provide the primary care physician with the tools needed to identify functional disorders of the spleen and to prevent their complications. The latest recommendations for antibiotic prophylaxis and immunization are also addressed. PMID- 26255497 TI - [Surgical treatment of gastroesophageal diseases]. AB - Gastroesophageal functional diseases comprise several pathologies impending upper gastrointestinal function: reflux disease, hiatal hernias, short esophagus and achalasia. Their presentation may be similar, but their treatment differs on many points. The initial approach consists of lifestyle changes and medical management. However, surgical treatment is sometimes necessary. Strict patient selection ensures good long-term results, while limiting the risk of complications. This selection is based on precise functional assessment and management in the context of multidisciplinary discussions. This article aims to discuss current aspects on general management, functional investigations and surgical treatments available. PMID- 26255498 TI - [Cervical cancer screening in the French-speaking part of Switzerland: contrasted trajectories]. AB - This article presents the results of a sociological study aiming at documenting the experience of women in regards with cervical cancer screening. Twenty-four focus groups have been conducted, with a total of 125 participants, aged between 24 and 67. The results show that rather than one specific barrier, a cumulative range of factors and events affect screening attendance. To understand screening attendance ambivalence, it is important to take into consideration screening trajectories associated with diverse life stages. PMID- 26255499 TI - [The Vincent Lambert affair: clear discordance with the European court on human rights]. PMID- 26255500 TI - [Thanks, you're welcome....]. PMID- 26255501 TI - [Neurodegenerative diseases, conformational changes of prion proteins]. PMID- 26255502 TI - [Hepatitis C, birth cohort screening]. PMID- 26255503 TI - [Returning to German sources for a better understanding of homeopathy]. PMID- 26255504 TI - [Vaud: historic agreement in oncology]. PMID- 26255505 TI - [University of Geneva Hospital celebrates its 20 years and announced its ambitions]. PMID- 26255506 TI - [Conflicts in conflicts of interest]. PMID- 26255507 TI - [Case of olfactory dysfunction caused by sinusitis]. PMID- 26255508 TI - [Clinical observation of post-stroke upper limb spasmodic hemiplegia treated with relaxing needling technique combined with wheat-grain moxibustion]. AB - OBJECTIVE: To compare the differences in the clinical efficacy on post-stroke upper limb spasmodio hemiplegia among the combined therapy of relaxing needling (Huici) technique combined with wheat-grain moxibustion, simple relaxing needling and conventional acupuncture. METHODS: Ninety patients were-randomized into a group with the combined therapy of relaxing needling technique combined with wheat-grain moxibustion (a combined therapy group), a simple relaxing needling group and a conventional acupuncture group, 30 cases in each group. In the combined therapy group, the relaxing needling technique was used in combination with wheat-grain moxibustion. The relaxing needling technique was applied to Jianyu (LI 15), Quchi (LI 11), Shousanli (LI 10), etc. The wheat-grain moxibustion was applied to Qihai (CV 6), Guanyuan (CV 4), Mingmen (GV 4), etc. In thel simple relaxing needling group, the relaxing needling technique was used simply. In the conventional acupuncture group, the conventional lifting, thrusting and rotating technique with filiform needle was adopted at the same acupoints as the simple relaxing needling group. The treatment was given once every day; 6 treatments made one session. Totally 4 sessions were required, with 1 day at intervals. The modified Ashworth scale (MAS), Fugl-Meyer assessment (FMA) and Barthel index (BD were adopted to assess the upper limb muscle tension, motor functioni and daily life activity. RESULTS: After treatment, MAS score was all reduced as compared with that before treatment in each group, and FMA score and BI score were increased as compared with those before treatment (all P<0.01). MAS score in the combined therapy group was lower than that in either the simple relaxing needling group or the conventional acupuncture group (both P<0.01), and the score in the simple relaxing needling group was lower than that in the conventional acupuncture group (P<0.05). FMA score and BI score in the combined therapy group were higher than those in the simple relaxing needling group and the conventional acupuncture group (both P<0.01). FMA score in the simple relaxing needleing group was higher than that the Enventional acupuncture group (P<0.05). The total effective rate in the combined therapy group was 93.3% (28/30), higher; than 86.7% (26/30) in the simple relaxing needling group (P<0.01), and 83.8% (25/30) in the conventionaP acupuncture group (P<0.01). CONCLUSION: The combined therapy of relaxing needling technique and wheat-grain moxibustion achieves more satisfactory efficacy on post-stroke upper limb spasmodic hemiplegia compared with the simple relaxing needling and conventional acupuncture. PMID- 26255509 TI - [Penetration needling for 32 cases of ptosis]. PMID- 26255510 TI - [Acupuncture at acupoints in the hand according to meridian courses for 50 cases of periarthritis of shoulder]. PMID- 26255511 TI - [Clinical observation of preventing and treating constipation by electroacupuncture intervention in ischemic stroke patients at acute stage]. AB - OBJECTIVE: To observe the efficacy of preventing constipation by electroacupuncture intervention in ischemic stroke patients at acute stage. METHODS: Three hundred and forty ischemic stroke patients who matched the inclusive criteria were randomly divided into an electroacupuncture (EA) group and a routine treatment group, 170 cases in each one. In the EA group, based on routine western treatment, rehabilitation training and common acupuncture, Tianshu (ST 25) and Zusanli (ST 36) were selected and connected to SDZ-V Hwato brand electric acupuncture apparatus respectively, given stimulation of dense disperse wave (10 Hz/50 Hz) with electric current of 0.1 to 1.0 mA, once every day and 5 times a week in the first 2 weeks, 2 times a week in the latter 2 weeks. In the routine treatment group, only basic treatment was applied. In the two groups, the course of treatment was 4 weeks and 8 weeks' follow-up was required after treatment. The actual numbers who independently defecated less than 3 times a week after 1 to 4 weeks' treatment and in the 4th and the 8th weeks' follow-up and condition taking laxative medicines during the 12 weeks in the two groups were observed and compared. RESULTS: Compared on the numbers of constipation cases after 1 to 4 weeks' treatment, those in the EA group were all less than those in the routine treatment group [24.7% (42/170) vs. 36.5%(62/170), 18.8% (32/170) vs. 30.6% (52/170), 10.5% (17/162) vs. 27.5% (44/160), 9.3% (15/162) vs. 19.4% (31/160),P<0.05, P<0.001]. In the 4th and the 8th weeks' follow-up, numbers in the EA group were still less than those in the routine treatment group [9.0% (14/156) vs. 18.1% (28/155), 7.7% (12/155) vs. 16.9 (26/154) both P<0.05)]. During the 12 weeks, the number of cases who took laxative medicines in the EA group was less than that in the routine treatment group [21.2% (36/170) vs. 34.7% (59/170), P<0.05]. CONCLUSION: There is clinical significance to electroacupuncture at Tian-shui (ST 25) and Zusanli (ST 36) coibined with basic comprehensive treatment for preventing and treating constipation symptom in ischemic stroke acute stage. PMID- 26255512 TI - [Acupuncture combined with medication for ulcerative colitis with damp-heat syndrome at active phase]. AB - OBJECTIVE: To explore the effects and mechanism of acupuncture at Zusanli (ST 36) combined with oral administration of Gexia Zhuyu decoction on damp-heat ulcerative colitis at active phase. METHODS: One hundred and twenty cases of damp heat ulcerative colitis at active phase, by using random draw method, were divided into an observation group and a control group, 60 cases in each one. Patients in the control group were treated with basic treatment combined with oral administration of Gexia Zhuyu decoction. Based on this, patients in the observation group were additionally treated with acupuncture at Zusanli (ST 36). The treatment was given both for 14 days. The efficacy, each symptom score, serum interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were observed. RESULTS: (1) After treatment, the total effective rate was 98.3% (59/60) in the observation group, which was significantly higher than 86.7% (52/60) in the control group (P<0.05). ( The improvement rates of ulceration, edema, erosion and polyp in the observation group were obviously higher than those in the control group (all P<0.05). (3) After treatment, the symptom scores of diarrhea, bloody purulent stool, abdominal pain, tenesmus as well as inflammatory factors of IL-1beta, IL-6 and TNF-alpha were all improved compared with those before treatment in the two groups (all P<0.05); the differences between the observation, group and control group were statistically significant (all P<0.05). (4) During the 3-month follow up visit, the recurrence rate was 1.7% (1/59) in the observation group, which was significantly lower than 11.5% (6/52) in the control group (P<0.05). CONCLUSION: The Gexia Zhuyu decoction combined with acupuncture at Zusanli (ST 36) could effectively improve efficacy, reduce recurrence rate, relieve clinical symptoms and prompt recovery of mucous membrane in patients with damp-heat ulcerative colitis at active phase, which is related with reducing the expression of inflammation. PMID- 26255513 TI - [Maintenance effects of acupoint catgut embedding at early time on gastrointestinal function in patients with craniocerebral injury]. AB - OBJECTIVE: To explore the maintenance effects of acupoint catgut embedding at early time on gastrointestinal function in patients with craniocerebral injury. METHODS: Sixty craniocerebral injury patients with 5 to 12 points of Glasgow coma scale (GCS), according to treatment order, were alternately divided into an observation group and a control group, 30 cases in each one. Patients in the control group were treated with regular treatment and nursing care. Based on this, patients in the observation group, according to different pathogenesis and symptoms presented within 24 h into hospitalization, were additionally treated with acupoint catgut embedding. The recovery time of borborygmus, time of first anal aerofluxus, time of first defecation, abdominal pressure at different time points, the occurrence rate of complications (upper gastrointestinal hemorrhage, diarrhea, vomiting), time of enteral nutrition tolerance rate reaching 30 kcal/kg x d were observed and recorded. RESULTS: The recovery time of borborygmus, time of first anal aerofluxus, time of first defecation and time of enteral nutrition tolerance rate reaching 30 kcal/kg x d in the observation group were all earlier to those in the control group (all P<0.01). At 48 h, 4 d and 7 d into hospitalization, the abdominal pressures in the observation group were all lower than those in the control group [(11.10 +/- 1.47) mmHg vs. (13.50 +/- 1.43) mmHg, (8.40 +/- 1.25) mmHg vs. (11.90 +/- 1.56) mmHg, (6.73 +/- 0.74) mmHg vs. (10.80 +/- 1.30) mmHg, all P<0.01]. There were 8 cases with complications of gastrointestinal hemorrhage, diarrhea and vomiting in the observation group with the occurrence rate o 27% (8/30), which was lower than those in the control group (70.0% (21/30), P<0.01. CONCLUSION: The acupoint catgut embedding at early time in craniocerebral injury patients could improve the recovery of gastrointestinal function, reduce intolerance of enteral nutrition and occurrence rate of various complications. PMID- 26255514 TI - [Clinical observation on mild perimenopausal depression of kidney deficiency and liver stagnation syndrome treated with acupoint catgut implantation]. AB - OBJECTIVE: To observe the efficacy of catgut implantation at back-shu points in treatment of mild perimenopausal depression of kidney, deficiency and liver stagnation syndrome and analyze its essential function on target symptoms. METHODS: Forty-five cases were randomized into a catgut implantation group (23 cases) and atid acupuncture group (22 cases). In the catgut implantation group, catguts were implanted at Shenshu (BL 23), Ganshu (BL 18), Xinshu (BL 15), Pishu (BL 20), etc., once every week. In the acupuncture group, the conventional acupuncture was applied to the same acupoints as the catgut implantation group, once every two days. The: treatment of 4 weeks made one session, and continuous 2 sessions were required. The efficacy was evaluated in, 2 sessions. The follow-up started in the 12th week. Before treatment, after treatment and in the follow-up period, Kupperman score and the total score in Hamilton depression scale (HAMD), as well as the factor score were observed in the patients separately. RESULTS: Kupperman score, the total HAMD score and the scores in the items of anxiety/somatization, retardation, sleep disorder and cognitive disorder after treatment were all reduced significantly as compared with those before treatment in the two groups (P<0.01, P<0.05). In the follow-up period, the difference in Kupperman was not significant in comparison with that after treatment in the catgut implantation: group (P>0.05). The total HAMD score and sleep disorder were reduced significantly as compared with those after treatment in the catgut implantation group (both P<0.01); in the acupuncture group, Kupperman score, the total HAMD score and sleep disorder were all increased as compared with those after treatment (all P<0.05). In; the catgut implantation group, the total HAMD score was lower than that in the acupuncture group (P<0. 05), and the scores in the items of retardation and sleep disorder were reduced significantly as compared with those in the acupuncture group (both P<0.01). CONCLUSION: The catgut implantation at back-shu points alleviates perimenopasual sympton is in patients of mild perimenopausal depression of kidney deficiency and liver stagnation syndrome. This therapy effectively relieves depressive disorders by regulating the target symptoms such as anxiety/ somatization, retardation, sleep disorder and cognitive' disorder. The long-term efficacy of this therapy is better than the conventional acupuncture. PMID- 26255515 TI - [Clinical observation of depression after breast cancer operation treated with aurieular point sticking therapy]. AB - OBJECTIVE: To compare the differences in the efficacy on depression after breast cancer operation treated with auricular point sticking therapy, the combined program of auricular point sticking therapy and TCM psychotherapy and medication with deanxit. METHODS: Ninety patients were randomized into 3 groups, 30 cases in each one. In the western medication group, the simple oral administration of deanxit was applied, one tablet a day. In the auricular point group, Xin (GO15), Shen (CO10), Gan(CO12), Shenmen(TF4), Pizhixia (AT), Neifenmi (CO18) were selected and stimulated with auricular point sticking on either side in each treatment, once a week. In the combined program group, on the basis of the treatment as the auricular point group, TCM psychotherapy was combined with. The treatment of 4 weeks made one session. One session and 4 weeks follow-up were required. The self-rating depression scale (SDS) was used to compare the score before and after treatment in the patients of each group and the efficacy was assessed. RESULTS: (1) Compared with those before treatment, in 4 weeks of treatment and 4 weeks of follow-up, SDS scores were all reduced apparently in the 3 groups (all P<0.001). After 4 weeks of follow-up in the auricular point group, after 2 and 4 weeks of treatment and 4 weeks of follow-up in the combined program group, SDS scores were all lower than those in the western medication group (all P<0.05). (2) After 4 weeks of treatment, the curative rate in the combined program group was higher than that in the auricular point group and the western medication group [60.0% (18/30) vs. 40.0% (12/30), 36.7% (11/30), both P<0.05)]. After 4 weeks of follow-up, the curative rate in either the combined program group or the auricular point group was higher than that in the western medication group [60.0% (18/30), 30.0% (19/30) vs. 23.3% (7/30), both P<0.05]. CONCLUSION: The auricular point sticking therapy, the combined program of auricular point sticking therapy and TCM psychotherapy, and medication with deanxit all relieve depression after breast cancer operation. The efficacy of the combined program with auricular point sticking therapy and TCM psychotherapy involved is the best, and the efficacy of the auricular point sticking therapy is better than the oral administration of deanxit. PMID- 26255516 TI - [Abdominal acupuncture combined with acupoint injection for 50 cases of uterine fibroid]. PMID- 26255517 TI - [Acute lumbar sprain treated with massage combined with acupuncture at different distal acupoints: a randomized controlled trial]. AB - OBJECTIVE: To observe treatment efficacy of acupuncture at different distal acupoints for acute lumbar sprain after massage. METHODS: One hundred and fifty patients with acute lumbar sprain were randomly divided into a Yaotongdian (Extra) group, a Houxi (SI 3) group, a Weizhong (BL 40) group, a Chengshan (BL 57) group and a Shuigou (GV 26) group, total 5 groups, 30 cases in each one. After the same massage treatment and based on groups divided, different distal acupoints above-mentioned were selected to be acupunctured. Visual analogue scale (VAS) scores, lumbar activity and treatment efficacy of patients in 5 groups were evaluated. RESULTS: With acupuncture at distal acupoints after massage,VAS scores of patients in 5 groups were decreased compared with those after massage treatment (all P<0.05); lumbar activity was all obviously improved (all P<0.01); and cured and markedly effective rates were all increased in comparison with those after massage (all P<0.01). But among 5 groups the differences of VAS scores, lumbar activity and cured and markedly effective rates were not statistically significant(all P>0.05). CONCLUSION: Based on massage treatment, acupuncture at distal acupoints could further improve the treatment efficacy for acute lumbar sprain, but there is no obvious effective difference among every distal acupoint. As long as choosing acupoints with lower pain threshold and stimulating enough, good efficacy could be acquired for acute lumbar sprain. PMID- 26255518 TI - [Case of gangrene in the index finger of right hand]. PMID- 26255519 TI - [Dong's extraordinary points combined with pelvis adjustment for 21 cases of refractory calcaneal pain]. PMID- 26255520 TI - [Acupuncture at Zhibian (BL 54) through Shuidao (ST 28) for polycystic ovary syndrome]. AB - OBJECTIVE: To compare the efficacy differences between acupuncture at Zhibian (BL 54) through Shuidao (ST 28) and regular acupuncture for polycystic ovary syndrome. METHODS: One hundred and one patients, by using random digital table, were randomly divided into an observation group (49 cases) and a control group (52 cases). Patients in the observation group were treated with acupuncture at Zhibian (BL 54) through Shuidao (ST 28) as main acupoints, and accompanied acupoints were selected according to syndrome differentiation. Elongated needles (175 mm in length) were inserted at Zhibian (BL 54) with an angle of 200 with sagittal plane. The insertion depth was 100-115 mm, reaching Shuidao (ST 28) and making acupuncture sensation arrive at diseased location. Patients in the control group were treated at the same acupoints with regular acupuncture technique. The menstruation condition was ignored for patients in both groups. The treatment was given once a day, 15 times as one session, and 5 consecutive sessions were given. The basic temperature and level of sex hormone were observed before and after treatment in the two groups, and clinical efficacy was compared. RESULTS: The cured rate was 65.3% (32/49) and the effective rate was 91.8% (45/49) in the observation group after treatment, which was significantly superior to 48.1% (25/52) and 63.5% (33/52) in the control group (both P<0.01). The number of patients with typical biphasic fever and patients with atypical biphasic fever in the observation group was higher, than that in the control group, but that of unidirectional temperature was less than that in the control group (P<0.05). After treatment, the follicle-stimulating hormone (FSH), luteinizing hormone (LH), LH/FSH, testos terone (T) were significantly reduced in the observation group (P<0.01, P<0.05); the LH and T were also apparently reduced in the control group (P<.01, P<0.05). The reduction of FSH, LH, LH/FSH and T in the observation group after treatment was more significant than that in the control group (P<0.05, P<0.01). CONCLUSION: Acuouncture at Zhibian (BL 54) through Shuidao (ST 28) could significantly improve the basic temperature of patients with polycystic ovary syndrome, and regulate hormone level of reproductive endocrine, which is superior to regular acupuncture. PMID- 26255521 TI - [Discussion on acupuncture treatment amount]. AB - The amount of acupuncture treatment refers to the sum of acupuncture effects during the treatment. From the factors that constitutes the amount of acupuncture treatment, including the numbers of needling, the size of acupuncture instruments, the depth of acupuncture, the manipulation, the retained time of needle, etc., and combined with teaching and clinical experience, it is believed that the amount of acupuncture treatment is closely related with clinical efficacy, besides, moderate amount of acupuncture treatment is a key factor to improve acupuncture efficacy and guarantee the safety of acupuncture. The basic principles of regular treatment amount are arrival of qi and being moderate, indicating the retained time of needle, treatment frequency and course should be based on individual condition, time, location and disease. PMID- 26255522 TI - [Effects of electroacupuncture on resting-state encephalic functional connectivity network in patients with PTSD]. AB - OBJECTIVE: To explore the central regulatory mechanism of electroacupuncture (EA) on patients with post-traumatic stress disorder (PTSD). METHODS: Fourteen patients of PTSD were selected as study objects and treated with "regulating mind and restoring consciousness" acupuncture method, in which Baihui (GV 20) and Shenting (GV 24) were used as main acupoints and Sishencong (EX-HN 1) and Fengchi (GB 20) were used as supporting acupoints for acupuncture. After the arrival of qi, Han's acupoint nerve stimulator was connected for 30 min per treatment, three times a week for consecutive 12 weeks. Before treatment and 12 weeks into treatment, the clinician administered PTSD scale (CAPS), self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were evaluated; a Siemens 3.0 T magnetic resonance imaging system was used to perform resting-state scan, and bilateral hippocampus were taken as region of interested to perform encephalic function connectivity analysis. RESULTS: After the treatment, the scores of CAPS, SAS and SDS were all reduced compared with those before treatment (all P<0.05) ; function connectivity was enhanced in bilateral hippocampus, right posterior central gyrus and left superior parietal lobule (2.3= 6 months. The control group was composed of 17 healthy individuals. Advanced oxidation protein products (AOPP), advanced glycation end products (AGEs), vitamins C, A and E, C-reactive protein and interleukin 6 were measured in plasma samples. RESULTS: OS was higher in the dialysis group when compared with controls, but HD patients showed higher AOPP compared with PD (HD:141.9 +/- 75.2 umol/L; PD: 112.5 +/- 69.3 umol/L, P< 0.01) and AGEs (HD: 32.2 +/- 10.6 AU x103; PD: 26.6 +/- 4.9 AUx103, P< 0.05). There was no difference in inflammation and vitamin levels among dialysis patients. In HD patients, AGEs correlated moderately with serum vitamin C (r = 0.46; P< 0.05). CONCLUSION: The dialysis modality adopted influences protein OS, but it has no effect on antioxidant status or inflammation. Hemodialysis probably exacerbates OS due to the increased bioincompatibility of the dialysis procedure, and this scenario seems to be related to the intravenous supplementation of vitamin C. Peritoneal dialysis allows for a better oxidative balance, which may reduce cardiovascular risk. PMID- 26255548 TI - Dietary Intake, Changes in Lipid Parameters and the Risk of Hypertriglyceridemia: A Prospective Approach in the Tehran Lipid and Glucose Study. AB - BACKGROUND AND AIM: This study assessed the association of dietary factors with 3 year changes in serum triglycerides (TG), HDL-C and the atherogenic index of plasma (AIP) among Iranian adults. METHODS: This longitudinal study was conducted with 1938 adults. Demographics, anthropometrics and biochemical measurements, including serum (TG) and HDL-C and AIP, were assessed at baseline (2006 - 2008) and after a 3 year follow-up (2009 - 2011). Dietary data was collected using a validated food frequency questionnaire at baseline. The associations of dietary factors with 3-year changes in lipid parameters were evaluated using linear regression models and the incidence of hypertriglyceridemia after 3 years was assessed using logistic regression models with adjustment for potential confounders. RESULTS: The mean age of the participants at baseline was 41.0 +/- 13.0 years. Dietary energy density was negatively associated with HDL-C and positively associated with AIP changes (P < 0.05). A three-year change of serum TG was inversely related to energy intake from phytochemical rich foods, whole grains, and legumes (P < 0.05). Fast food intake was positively related to serum TG and AIP changes. Higher compared to lower intakes of dietary fiber and phytochemical-rich foods had similar impacts on a decreased risk of hypertriglyceridemia (OR = 0.58, 95 % CI = 0.34 - 1.00). Higher - compared to lower - dietary sodium to potassium ratios (Na/K ratio) increased the risk of hypertriglyceridemia by 63 % (OR = 0.1.63, 95 % CI = 0.34 - 1.00). CONCLUSION: These findings suggested that more dense diets, and a higher intake of fast food and fat, could have undesirable effects on lipid and lipoprotein levels; in contrast, higher intakes of fiber, and phytochemical rich foods, especially whole grain and legumes, could have protective effects against undesirable changes in lipid and lipid profiles. PMID- 26255549 TI - Higher Bioavailability of Organic Bound Zinc from High Zinc-Enriched Fungi. AB - The organic forms of trace elements are considered more bioavailable than the inorganic forms. Although yeast can enrich metal elements and convert inorganic zinc to organic species, its tolerability and transforming capacity are limited. It would therefore be very interesting to look for higher conversion and accumulation in zinc fungi to obtain organic bound zinc from the natural environment. In this paper, potato dextrose agar (PDA) medium containing 800 MUg/mL zinc was used for initial screening, with twenty-two fungal strains that tolerated high zinc isolated from the natural environment, and one strain (No.LZ 1108) growing well at a zinc (II) concentration of 10,000 MUg/mL. According to morphological analysis, 18S rDNA sequence analysis, and biophysical and biochemical characteristics, No.LZ-1108 was tentatively identified as Fusarium oxysporum. Using atomic absorption spectrometry, the zinc content in the No.LZ 1108 cells was found to be 6.7 mg/g dry cell. After oral administration to rats at a dose of 10 mg Zn (II)/kg body weight, the area under the plasma concentration-time curve (AUC) and the maximum zinc blood concentration (Cmax) of No.LZ-1108 and zinc gluconate were 8.10 g/L.min and 4.28 g/L.min, 23.72 MUg/mL and 6.23 MUg/mL, respectively. The AUC of No.LZ-1108 was significantly higher than those of zinc gluconate (P<0.05), and the mean relative bioavailability of AUC(test)/AUC(zinc gluconate) was 190 %, which showed that the bound zinc in No.LZ-1108 was more bioavailable than zinc gluconate. The present study reports an interesting alternative to developing zinc-based supplements from a natural source of zinc. PMID- 26255550 TI - Folic Acid Fortification and Women's Folate Levels in Selected Communities in Brazil - A First Look. AB - BACKGROUND: Several countries have implemented mandatory folic acid fortification of wheat flour and selected grain products to increase the folate intake of reproductive-aged women. Brazil implemented a folic acid fortification program in 2004. No previous studies have examined folate differences among Brazilian women following the mandate. OBJECTIVE: We evaluate differences in serum and red blood cell (RBC) folate concentrations between two samples of women of childbearing age from selective communities in Brazil, one tested before (N = 116) and the other after the mandate (N = 240). METHODS: We compared the baseline folate levels of women enrolled in a prevention study shortly before the fortification mandate was implemented, to baseline levels of women from the same communities enrolled in the same study shortly after fortification began. The participants were women enrolled in a folate supplementation clinical trial, at a hospital specializing in treating craniofacial anomalies in the city of Bauru from January 29, 2004 to April 27, 2005. We only compared baseline folate levels before the women received oral cleft prevention program (OCPP) folic acid supplements. RESULTS: Women enrolled after the fortification mandate had higher means of serum folate (20.3 versus 11.2 nmol/L; p < 0.001) and RBC folate (368.3 versus 177.6 nmol/L; p < 0.001) than women enrolled before the mandate. Differences in folate levels between the two groups remained after adjusting for several co-variables. CONCLUSIONS: The results suggest that serum and RBC folate levels among women of childbearing age increased after implementing the folic acid fortification mandate in Brazil. PMID- 26255551 TI - Pomegranate Seed Oil Modulates Functions and Survival of BV-2 Microglial Cells in vitro. AB - Current evidence has demonstrated the immunomodulatory efficacy of omega-3 polyunsaturated fatty acids (PUFAs) in glial cells, suggesting their therapeutic potential for diseases in the central nervous system (CNS). However, conjugated omega-5 PUFAs have also attracted considerable attention because of their suggested anti-inflammatory effects. In the present study, the effect of pomegranate (Punica granatum L.) seed oil (PSEO) (a rich source of omega-5 PUFAs) on the activation of cultured BV-2 microglia was investigated within a 24-hour incubation period. PSEO (25 MUg/ml) showed only a slightly smaller inhibitory effect on LPS-stimulated NO production (243 +/- 12.5 % of control, p<0.001 vs. 437 +/- 9.2 % in stimulated cells) and TNF-alpha release (87.1 +/- 5.62 pg/ml vs. 229 +/- 24.4 pg/ml in stimulated cells), as well as iNOS expression (7.36-fold of control, p < 0.01, vs. 17.5-fold increase in stimulated cells) compared to a standardized omega-3 PUFAs mixture (25 MUg/ml) and the flavonoid quercetin (25 MUmol/l). Unlike quercetin and stobadine, only the PUFA preparations effectively prevented apoptosis of microglia (as confirmed by the suppression of caspase 3 activation) exposed to the toxic concentration of LPS. The PUFA preparations did not provide a notable suppression of the intracellular oxidant generation and did not influence the intracellular distribution of cholesterol (as confirmed by filipin staining). However, they appeared to affect the morphology of activated cells. In conclusion, our data point to the first evidence of immunomodulation and cytoprotection of BV-2 microglia by the pomegranate seed oil, indicating that it may be (comparably to omega-3 PUFAs) efficient against microglia-mediated neuroinflammation while preventing the premature depletion of these immune effector cells in the brain. PMID- 26255552 TI - The Immunomodulating Effect of a Diet Consisting of Green Vegetables, Beef, Whole Milk and Full-Fat Butter for Children with Non-Specific Elevated IgE. AB - BACKGROUND: Non-specific elevated IgE and allergies are common in children, and their prevalence is increasing. Dietary changes could be an explanation for this increase. Zinc, iron, vitamins A, C and E, and polyunsaturated fatty acids all play possible roles in the etiology and possible treatment of allergies due to their numerous immunomodulating properties. OBJECTIVES: To investigate the immunomodulating effect of recommending a nutrient-rich diet consisting of green vegetables, beef, whole milk and full-fat butter. METHODS: We conducted a case controlled, non-randomized, retrospective study. Children between the ages of 1 and 18 years with non-specific elevated IgE were included. Baseline and follow-up measurements of serum total IgE and clinical outcomes were retrospectively collected and compared for 49 children who received the dietary advice (to eat green vegetables, beef, whole milk and full-fat butter) and 56 children who did not. RESULTS: The initial analysis showed a significantly greater decrease in IgE in the intervention group compared to the control group; a 9.2 kU/l versus a 0.1 kU/l decrease, respectively (P = 0.02). When supplement (vitamin D) use was taken into account, however, no significant difference was produced by the dietary effect alone (unstandardized coefficient = 71.3 kU/l, P = 0.16). 53.2 % of participants in the intervention group reported considerable improvement in symptoms versus 28.6 % in the control group (P < 0.001). CONCLUSION: Overall, the effects of nutrients and vitamins on the decrease in IgE are promising. The separate contributions of dietary advice and/or supplements need to be investigated in the future. PMID- 26255553 TI - Streptococcus agalactiae isolates of serotypes Ia, III and V from human and cow are able to infect tilapia. AB - Recent studies have shown that group B streptococcus (GBS) may be infectious across hosts. The purpose of this study is to investigate the pathogenicity of clinical GBS isolates with serotypes Ia, III and V from human and cow to tilapia and the evolutionary relationship among these GBS strains of different sources. A total of 27 clinical GBS isolates from human (n=10), cow (n=2) and tilapia (n=15) were analyzed using serotyping, multi-locus sequence typing (MLST) and pulsed field gel electrophoresis (PFGE). Among them, 15 isolates were tested for their pathogenicity to tilapia. The results showed that five human GBS strains (2 serotype III, 2 serotype Ia and 1 serotype V) infected tilapia with mortality rate ranging from 56.67% to 100%, while the other five human GBS strains tested were unable to infect tilapia. In addition, two cow GBS strains C001 and C003 of serotype III infected tilapia. However, they had significantly lower pathogenicity than the five human strains. Furthermore, human GBS strains H005 and H008, which had very strong ability to infect tilapia, had the same PFGE pattern. MLST analysis showed that the five human and the two cow GBS strains that were able to infect tilapia belonged to clonal complexes CC19, CC23 and CC103. The study for the first time confirmed that human or cow GBS clonal complexes CC19, CC23 and CC103 containing strains with serotypes Ia, III and V could infect tilapia and induce clinical signs under experimental conditions. PMID- 26255554 TI - Chlamydiaceae and chlamydial infections in sheep or goats. AB - Chlamydiae induce a range of pathological syndromes in small ruminants. Abortion is the most common clinical expression of the infection that causes important economic losses and presents a risk to human health, particularly in pregnant women. The present paper gives an overview of chlamydial infections in sheep and goats, focusing specifically on abortion and on recent data brought by cellular and genomic approaches regarding genotyping, virulence of strains, epidemiology, diagnosis, pathogenesis and control of the disease. PMID- 26255555 TI - Seroprevalence of Schmallenberg virus in the United Kingdom and the Republic of Ireland: 2011-2013. AB - Since its identification in late 2011, Schmallenberg virus (SBV) spread rapidly across Europe. Using archived samples from domestic ruminants collected between October 2011 and June 2013, the seroprevalence in the United Kingdom (UK) and Republic of Ireland (IE) was estimated using a serum neutralisation test. There was no significant difference (P>0.05) in seroprevalence between sheep and cows suggesting that neither species is significantly more at risk of SBV infection in the UK. A single 2011 sample tested positive; the sample was taken in November from a cow in Wiltshire. There was a steady increase in overall seroprevalence during the first three quarters of 2012, which then more than doubled in quarter 4 (October-December), which may reflect a peak of vector activity. By the end of June 2013, overall seroprevalence was around 72%. However, although seroprevalence was over 50% in Wales and southern and central counties of England, it was below 50% in all other areas of the UK and IE. This suggests that there were still substantial numbers of animals at risk of infection in the latter half of 2013. PMID- 26255556 TI - Paratuberculosis in sheep and goats. AB - Paratuberculosis is a chronic insidious, often serious, disease of the global small ruminant industries, mainly causing losses from mortalities and reduced productivity on-farm, interference in trading and, in Australia, profound socio economic impacts that have periodically compromised harmony of rural communities. The pathogenesis, diagnosis, impacts and disease management options for ovine and caprine paratuberculosis are reviewed, comparing current controls in the extensive management system for sheep in wool flocks in Australia with the semi intensive system of dairy flocks/herds in Greece. Improved understanding of the immune and cellular profiles of sheep with varying paratuberculosis outcomes and the recognition of the need for prolonged vaccination and biosecurity is considered of relevance to future control strategies. Paratuberculosis in goats is also of global distribution although the prevalence, economic impact and strategic control options are less well recognized, possibly due to the relatively meagre resources available for goat industry research. Although there have been some recent advances, more work is required on developing control strategies for goats, particularly in dairy situations where there is an important need for validation of improved diagnostic assays and the recognition of the potential impacts for vaccination. For all species, a research priority remains the identification of tests that can detect latent and subclinical infections to enhance removal of future sources of infectious material from flocks/herds and the food chain, plus predict the likely outcomes of animals exposed to the organism at an early age. Improving national paratuberculosis control programs should also be a priority to manage disease risk from trade. The importance of strong leadership and communication, building trust within rural communities confused by the difficulties in managing this insidious disease, reflects the importance of change management considerations for animal health authorities. Although concerns of vaccine efficacy, safety and issues with diagnosis and administration persist, vaccination is increasingly recognized as providing a robust strategy for managing paratuberculosis, having made important contributions to the health of Australian sheep and the lives of producers with affected properties, and offering a mechanism to reduce risk of infection entering the food chain in ovine and caprine products. PMID- 26255557 TI - Systematic analyses reveal uniqueness and origin of the CFEM domain in fungi. AB - CFEM domain commonly occurs in fungal extracellular membrane proteins. To provide insights for understanding putative functions of CFEM, we investigate the evolutionary dynamics of CFEM domains by systematic comparative genomic analyses among diverse animals, plants, and more than 100 fungal species, which are representative across the entire group of fungi. We here show that CFEM domain is unique to fungi. Experiments using tissue culture demonstrate that the CFEM containing ESTs in some plants originate from endophytic fungi. We also find that CFEM domain does not occur in all fungi. Its single origin dates to the most recent common ancestors of Ascomycota and Basidiomycota, instead of multiple origins. Although the length and architecture of CFEM domains are relatively conserved, the domain-number varies significantly among different fungal species. In general, pathogenic fungi have a larger number of domains compared to other species. Domain-expansion across fungal genomes appears to be driven by domain duplication and gene duplication via recombination. These findings generate a clear evolutionary trajectory of CFEM domains and provide novel insights into the functional exchange of CFEM-containing proteins from cell-surface components to mediators in host-pathogen interactions. PMID- 26255558 TI - Inverse Relationship between Coffee Consumption and Cerebral Microbleeds in Men, but Not Women. AB - BACKGROUND: Studies evaluating the association between coffee consumption and neurovascular diseases have frequently yielded contradictory results. The aim of this study was to investigate the association of coffee consumption with small vessel disease (SVD) incidence in a healthy urban population while accounting for multiple demographic and lifestyle risk factors. METHODS: This prospective study conducted from May 2013 through March 2014 included 455 participants (314 men and 141 women) aged 25 to 92 years. All subjects completed a questionnaire on coffee consumption and received a comprehensive neurologic examination, including magnetic resonance imaging, at St. Luke's International Hospital (Tokyo, Japan). RESULTS: Incidence of SVD was lower in male daily coffee drinkers than male nondrinkers and occasional drinkers, whereas incidence of white matter lesions was lower in female daily coffee drinkers than female nondrinkers or occasional drinkers. In multivariate analyses including age, sex, smoking status, and BMI, as well as coffee consumption, incidence of microbleeds was significantly lower in male daily coffee drinkers compared to nondrinkers. CONCLUSIONS: Daily coffee consumption is associated with reduced risk of cerebral microbleeds in men. PMID- 26255559 TI - Infratentorial Pial Arteriovenous Fistula in the Elderly. AB - BACKGROUND: Intracranial pial arteriovenous fistulas (pAVFs) are rare vascular lesions, which may present with, but are distinct from arteriovenous malformation and dural arteriovenous fistula. They most often manifest during infancy or early childhood, but rarely in adulthood. METHODS: We report an exceptionally rare case of infratentorial pAVF in a 73-year-old man, who presented with progressive gait disturbance due to cerebellar edema resulting from arteriovenous shunts. RESULTS: The patient was successfully treated by endovascular flow reduction followed by surgical extirpation of the fistula. The diagnosis was confirmed by pathological findings. CONCLUSIONS: Pial arteriovenous fistula is rare, but can occur in the elderly. Combination of endovascular flow reduction and surgical disconnection yielded an excellent clinical outcome. PMID- 26255560 TI - Increased risk of functional gastrointestinal sequelae after Clostridium difficile infection among active duty United States military personnel (1998 2010). AB - BACKGROUND & AIMS: Some acute enteric infections are associated with the development of functional gastrointestinal disorders, most commonly irritable bowel syndrome but also other functional and organic gastrointestinal sequelae. Clostridium difficile infection has increased in incidence and severity, however, few studies have evaluated functional disorders after this infection. METHODS: We evaluated the epidemiology and sequelae of C difficile in the US military population by using the US Department of Defense's Armed Forces Health Surveillance Center Defense Medical Ecounter Database. We then performed a retrospective cohort study of 891 active-duty US military personnel who developed C difficile from 1998 to 2010 and 3231 matched subjects who had not been exposed to C difficile. Subjects were identified based on International Classification of Diseases, 9th revision, Clinical Modification codes for C difficile disease. RESULTS: C difficile was associated independently with increased rate ratios (RRs) for incident irritable bowel syndrome (RR, 6.1; 95% confidence interval [CI], 2.9-12.9), gastroesophageal reflux disease (GERD) (RR, 1.9; 95% CI, 1.4 2.6), dyspepsia (RR, 3.3; 95%, 1.4-7.7), and constipation (RR, 2.2; 95% CI, 1.3 3.7). Approximately 14.1% of subjects with C difficile later were identified with one of these functional gastrointestinal disorders (FGDs), compared with 6% of controls. Community- and health care-associated C difficile were associated at similar rates with these sequelae. Patients were at increased risk for FGDs within 3 months of a C difficile episode, with one additional case of FGD developing for every 12 diagnoses of C difficile. CONCLUSIONS: The incidence of community- and health care-associated C difficile has increased in the US military population from 1998 through 2010. As for other gastrointestinal infections, C difficile disease is associated with clinically relevant functional sequelae in this military population. PMID- 26255561 TI - Genetics of Inflammatory Bowel Diseases. AB - In this review, we provide an update on genome-wide association studies (GWAS) in inflammatory bowel disease (IBD). In addition, we summarize progress in defining the functional consequences of associated alleles for coding and noncoding genetic variation. In the small minority of loci where major association signals correspond to nonsynonymous variation, we summarize studies defining their functional effects and implications for therapeutic targeting. Importantly, the large majority of GWAS-associated loci involve noncoding variation, many of which modulate levels of gene expression. Recent expression quantitative trait loci (eQTL) studies have established that the expression of most human genes is regulated by noncoding genetic variations. Significant advances in defining the epigenetic landscape have demonstrated that IBD GWAS signals are highly enriched within cell-specific active enhancer marks. Studies in European ancestry populations have dominated the landscape of IBD genetics studies, but increasingly, studies in Asian and African-American populations are being reported. Common variation accounts for only a modest fraction of the predicted heritability and the role of rare genetic variation of higher effects (ie, odds ratios markedly deviating from 1) is increasingly being identified through sequencing efforts. These sequencing studies have been particularly productive in more severe very early onset cases. A major challenge in IBD genetics will be harnessing the vast array of genetic discovery for clinical utility through emerging precision medical initiatives. In this article, we discuss the rapidly evolving area of direct-to-consumer genetic testing and the current utility of clinical exome sequencing, especially in very early onset, severe IBD cases. We summarize recent progress in the pharmacogenetics of IBD with respect to partitioning patient responses to anti-TNF and thiopurine therapies. Highly collaborative studies across research centers and across subspecialties and disciplines will be required to fully realize the promise of genetic discovery in IBD. PMID- 26255562 TI - Signal Transducer and Activator of Transcription 3, Mediated Remodeling of the Tumor Microenvironment Results in Enhanced Tumor Drug Delivery in a Mouse Model of Pancreatic Cancer. AB - BACKGROUND & AIMS: A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense desmoplastic reaction (stroma) that impedes drug delivery to the tumor. Attempts to deplete the tumor stroma have resulted in formation of more aggressive tumors. We have identified signal transducer and activator of transcription (STAT) 3 as a biomarker of resistance to cytotoxic and molecularly targeted therapy in PDAC. The purpose of this study is to investigate the effects of targeting STAT3 on the PDAC stroma and on therapeutic resistance. METHODS: Activated STAT3 protein expression was determined in human pancreatic tissues and tumor cell lines. In vivo effects of AZD1480, a JAK/STAT3 inhibitor, gemcitabine or the combination were determined in Ptf1a(cre/+);LSL Kras(G12D/+);Tgfbr2(flox/flox) (PKT) mice and in orthotopic tumor xenografts. Drug delivery was analyzed by matrix-assisted laser desorption/ionization imaging mass spectrometry. Collagen second harmonic generation imaging quantified tumor collagen alignment and density. RESULTS: STAT3 activation correlates with decreased survival and advanced tumor stage in patients with PDAC. STAT3 inhibition combined with gemcitabine significantly inhibits tumor growth in both an orthotopic and the PKT mouse model of PDAC. This combined therapy attenuates in vivo expression of SPARC, increases microvessel density, and enhances drug delivery to the tumor without depletion of stromal collagen or hyaluronan. Instead, the PDAC tumors demonstrate vascular normalization, remodeling of the tumor stroma, and down-regulation of cytidine deaminase. CONCLUSIONS: Targeted inhibition of STAT3 combined with gemcitabine enhances in vivo drug delivery and therapeutic response in PDAC. These effects occur through tumor stromal remodeling and down-regulation of cytidine deaminase without depletion of tumor stromal content. PMID- 26255564 TI - Subclinical psychosis and suicidal behavior in England: Findings from the 2007 Adult Psychiatric Morbidity Survey. AB - BACKGROUND: Psychotic disorders have been associated with suicidality but information on the association between subclinical psychosis and suicidality in the general adult population is scarce. METHODS: Data from the 2007 Adult Psychiatric Morbidity Survey (n=7403) were analyzed. This was a nationally representative survey of the English adult household population (aged >=16years). Five types of psychotic symptoms (hypomania, thought control, paranoia, strange experience, auditory hallucination) occurring in the past 12months were assessed with the Psychosis Screening Questionnaire. Participants with probable or definite psychosis were excluded. Logistic regression analysis was used to assess the association between psychotic symptoms and suicidal ideation and suicide attempt in the past 12months. RESULTS: The prevalence of at least one psychotic symptom was 5.4%. After adjusting for potential confounders including mental disorders, each individual psychotic symptom was significantly associated with suicidal ideation with odds ratios (ORs) ranging from 3.22 to 4.20. With the exception of thought control, all symptoms were also associated with significantly higher odds for suicide attempt (ORs 3.95 to 10.23). Having at least one psychotic symptom was associated with ORs of 3.13 (95%CI 2.09-4.68) and 3.84 (95%CI 1.67-8.83) for suicidal ideation and suicide attempt respectively. In addition, a greater number of psychotic symptoms was associated with higher odds for suicidal ideation and suicide attempt. CONCLUSIONS: Psychotic symptoms, regardless of the type, were independently associated with higher odds for suicidal ideation and suicide attempt. Assessment and management of suicide risk in individuals with psychotic symptoms may be important for suicide prevention. PMID- 26255563 TI - COMT genotype and response to cognitive remediation in schizophrenia. AB - BACKGROUND: A functional polymorphism of the catechol-O-methyltransferase (COMT) gene (Val158Met) partially appears to influence cognitive performance in schizophrenia subjects and healthy controls by modulating prefrontal dopaminergic activity. This study evaluated the association of the COMT Val108/158 Met genotype with response to computerized neurocognitive remediation (CRT). METHOD: 145 subjects with DSM-IV-TR schizophrenia or schizoaffective disorder were genotyped via saliva sampling. Subjects were evaluated on neurocognitive assessments (MATRICS) and clinical symptoms (PANSS) at baseline and endpoint after 12weeks of CRT. "Improvement" was defined as >=67% of cognitive domains (>=4) showing performance increases. If <=67% (<=2) of domains improved, the change was defined as "minimal improvement." A general linear model was conducted for change of each cognitive domain. RESULTS: Of 145 subjects, data from 138 subjects were usable. Distribution of COMT genotype: Met/Met: 28 (20.29%), Val/Met: 61 (44.20%), and Val/Val: 49 (35.51%). No significant differences were seen among genotype groups at baseline or across genotype group for "Improvement" vs. "Minimal Improvement." GLM analysis showed significant differences in Verbal Learning (p=0.003), Visual Learning (p=0.014) and Attention/Vigilance (p=0.011) favoring Met/Met and Val/Met groups. CONCLUSIONS: The low activity Met allele (Met/Met; Val/Met) was associated with significantly greater improvements in the MATRICS domains of Verbal Learning, Visual Learning and Attention/Vigilance after CRT. PMID- 26255565 TI - NMDA receptor blockade and catatonia: A complex relationship. PMID- 26255566 TI - Glutamatergic dysfunction linked to energy and membrane lipid metabolism in frontal and anterior cingulate cortices of never treated first-episode schizophrenia patients. AB - BACKGROUND: Glutamatergic dysfunction and altered membrane lipid and energy metabolism have been repeatedly demonstrated in the frontal/prefrontal and anterior cingulate cortex (ACC) in schizophrenia. Though having been already studied in animals, the presumed link between glutamatergic function and structural plasticity has not been investigated directly in the human brain yet. We measured glutamate (Glu), focal energy metabolism, and membrane phospholipid turnover to investigate main pathologies in those key brain regions of schizophrenia. METHODS: (1)H- and (31)P-Chemical Shift Imaging (CSI) was combined in a single session to assess Glu and markers of energy (PCr, ATP) and membrane lipid (PME, PDE) metabolism in 31 neuroleptic-naive first acute onset psychosis patients and 31 matched healthy controls. Multivariate analyses of covariance were used to assess disease effects on Glu and to investigate the impact of Glu alterations on phospholipid and energy metabolites. RESULTS: Glu levels of patients were increased in the frontal and prefrontal cortex bilaterally and in the ACC. Higher Glu was associated with increased left frontal/prefrontal PME and right frontal/prefrontal PDE in patients, which was not observed in healthy controls. In contrast, higher Glu levels were associated with lower PCr or ATP values in the frontal/prefrontal cortex bilaterally and in the right ACC of controls. This was not observed in the right ACC and left frontal/prefrontal cortex of patients. CONCLUSION: Frontal glutamatergic hyperactivity is disconnected from physiologically regulated energy metabolism and is associated with increased membrane breakdown in right and increased membrane restoration in left frontal and prefrontal cortical regions. As indicated by previous findings, this pathology is likely dynamic during the course of first acute illness and possibly associated with negative symptoms and cognitive impairment. Our findings underline the importance of further research on neuroprotective treatment options during the early acute or even better for the ultra-high risk state of psychotic illness. PMID- 26255567 TI - Undiagnosed Lyme disease in adults with schizophrenia. PMID- 26255569 TI - Nationwide variation in the effects of temperature on infectious gastroenteritis incidence in Japan. AB - Although several studies have investigated the effects of temperature on the incidence of infectious gastrointestinal disease in a single city or region, few have investigated variations in this association using nationwide data. We obtained weekly data, gathered between 2000 and 2012, pertaining to infectious gastroenteritis cases and weather variability in all 47 Japanese prefectures. A two-stage analysis was used to assess the nonlinear and delayed relationship between temperature and morbidity. In the first stage, a Poisson regression allowing for overdispersion in a distributed lag nonlinear model was used to estimate the prefecture-specific effects of temperature on morbidity. In the second stage, a multivariate meta-analysis was applied to pool estimates at the national level. The pooled overall relative risk (RR) was highest in the 59.9(th) percentile of temperature (RR, 1.08; 95% CI: 1.01, 1.15). Meta-analysis results also indicated that the estimated pooled RR at lower temperatures (25(th) percentile) began immediately but did not persist, whereas an identical estimate at a higher temperature (75(th) percentile) was delayed but persisted for several weeks. Our results suggest that public health strategies aimed at controlling temperature-related infectious gastroenteritis may be more effective when tailored according to region-specific weather conditions. PMID- 26255570 TI - Rituximab as maintenance therapy for ANCA associated vasculitis: how, when and why? AB - ANCA-associated vasculitides (AAV) are chronic autoimmune diseases characterized by inflammation and destruction of small vessels. Rituximab is now licensed for use as a remission-induction agent in the treatment of these disorders. During recent years, several non-controlled studies have suggested that rituximab may be of value in maintaining disease remission in AAV. In these series, 3 techniques have been tried: "watch-and-wait", repeated cycles in fixed intervals, or administration based on proposed biomarkers. More importantly, the results of the MAINRITSAN trial showed that this anti-CD20 agent is superior to azathioprine for preventing major relapses in AAV. This review summarizes current information regarding the effectiveness, timing, dosing, duration and safety of rituximab as a valid option for remission maintenance. PMID- 26255568 TI - Metabolic syndrome, abdominal obesity and hyperuricemia in schizophrenia: Results from the FACE-SZ cohort. AB - OBJECTIVE: Abdominal obesity was suggested to be a better predictor than Metabolic Syndrome (MetS) for cardiovascular mortality, however this is has not been extensively studied in schizophrenia. Hyperuricemia (HU) was also suggested to be both an independent risk factor for greater somatic comorbidity and a global metabolic stress marker in patients with schizophrenia. The aim of this study was to estimate the prevalence of MetS, abdominal obesity and HU, to examine the association between metabolic parameters with HU in a cohort of French patients with schizophrenia or schizo-affective disorder (SZ), and to estimate the prevalence rates of treatment of cardio-vascular risk factors. METHOD: 240 SZ patients (age=31.4years, male gender 74.3%) were systematically included. Metabolic syndrome was defined according to the International Diabetes Federation and HU if serum uric acid level was above 360MUmol/L. RESULTS: MetS, abdominal obesity and HU were found respectively in 24.2%, 21.3% and 19.6% of patients. In terms of risk factors, multiple logistic regression showed that after taking into account the potential confounders, the risk for HU was higher in males (OR=5.9, IC95 [1.7-21.4]) and in subjects with high waist circumference (OR=3.1, IC95 [1.1-8.3]) or hypertriglyceridemia (OR=4.9, IC95 [1.9-13]). No association with hypertension, low HDL cholesterol or high fasting glucose was observed. Only 10% of patients with hypertension received a specific treatment, 18% for high fasting glucose and 8% for dyslipidemia. CONCLUSIONS: The prevalence of MetS, abdominal obesity and hyperuricemia is elevated in French patients with schizophrenia, all of which are considerably under-diagnosed and undertreated. HU is strongly associated with abdominal obesity but not with psychiatric symptomatology. PMID- 26255571 TI - Assessment of muscle tissue oxygen saturation after out-of-hospital cardiac arrest. AB - PURPOSE: Pathophysiology of cardiac arrest corresponds to an ischemia-reperfusion syndrome with deep impairment of microcirculation. Muscular tissue oxygen saturation (StO2) is a noninvasive method of evaluation of microcirculation. Our study was aimed at assessing the prognosis value of muscular StO2 in patients admitted for out-of-hospital cardiac arrest (OHCA) and treated with hypothermia. MATERIALS AND METHODS: We conducted a prospective bicentric observational study including OHCA patients treated with therapeutic hypothermia. Baseline StO2, derived variables (desaturation and resaturation slopes), and lactate levels were compared at different times between patients with good and poor outcomes. Prognosis was assessed by the Cerebral Performance Category (CPC) score at 6 months after admission (CPC 1-2, good outcome; CPC 3-5, poor outcome). RESULTS: Forty-four patients were included, 17 good and 27 poor outcomes at 6 months. At admission, StO2 and lactate levels were lower in good outcome patients. Desaturation and resaturation slopes did not differ between groups. CONCLUSIONS: After an OHCA treated with therapeutic hypothermia, StO2 was correlated with outcome. Further research is needed to better understand the pathophysiological process underlying our results. PMID- 26255572 TI - In response to: Families' experiences of ICU quality of care: Development and validation of a European questionnaire (euroQ2). PMID- 26255573 TI - A middle rate of failed extubation is desirable? Questions unanswered. PMID- 26255574 TI - B56delta subunit of protein phosphatase 2A decreases phosphorylation of endothelial nitric oxide synthase at serine 116: Mechanism underlying aphidicolin stimulated NO production. AB - DNA damage is significant in endothelial cells (EC), particularly in anticancer chemotherapy. Here, we explored whether and how aphidicolin, a DNA-damaging chemical with a promising anticancer activity, alters NO production in bovine aortic endothelial cells (BAEC). In addition to increasing eNOS-Ser1179 phosphorylation, aphidicolin decreased eNOS-Ser116 phosphorylation with a concomitant increase in NO production in a time-dependent manner. The amino acid sequence around the eNOS-Ser116 residue was identified as the substrate site of the regulatory subunit B56delta of protein phosphatase 2A (PP2A). As expected, okadaic acid, a specific PP2A inhibitor, reversed aphidicolin-induced eNOS-Ser116 dephosphorylation in a dose-dependent manner. Aphidicolin also increased B56delta Ser566 phosphorylation, although expression of neither the catalytic subunit Calpha (PP2A Calpha) nor B56delta was altered. Ectopic expression of dominant negative (dn)-B56delta reversed all of the observed effects of aphidicolin with respect to phosphorylation of eNOS-Ser116 and B56delta-Ser566. Lastly, aphidicolin-stimulated NO production was also partially attenuated by ectopic expression of dn-B56delta. Taken together, our results are the first to demonstrate that aphidicolin decreases phosphorylation of eNOS-Ser116, at least in part by activating PP2A B56delta, resulting in NO release in BAEC. PMID- 26255575 TI - Retinoblastoma: A SEER Dataset Evaluation for Treatment Patterns, Survival, and Second Malignant Neoplasms. AB - PURPOSE: To characterize treatment patterns, overall survival (OS), and risk of second malignant tumors in patients with retinoblastoma (RB) using the SEER (Surveillance Epidemiology and End Results) dataset. DESIGN: Cohort study. METHODS: The SEER dataset was used to identify cases of RB using ICD-03 histology codes. Special permission was granted by the SEER administration to release chemotherapy information for this study (information that is not available in the publically available SEER dataset). Treatment of RB for patients with locoregional disease was characterized as surgical therapy, radiation therapy, chemotherapy, or any form thereof across 4 time periods from 1975 to 2010. Observed-to-expected (O/E) ratios for second malignant neoplasms were calculated with the use of age-specific incidence rates. RESULTS: There were 1452 cases of RB identified from 1975 to 2010, with 48% of patients being male and 30% presenting with bilateral disease. Treatment patterns over time of 1220 patients (84%) with localized disease showed an increase in chemotherapy (+/- any treatment) from 16.5% to 50.2% and a decrease in surgery (+/- any treatment) from 96.2% to 88.5% and decrease in radiation from 15.2% to 4.9% from the 1975-1979 time period to the 2000-2010 time period. The 10-year OS was 93.7%, 93.7%, 97.5%, and 97% for increasing time periods (1975-1979, 1980-1989, 1990-1999, 2000-2010, respectively; P = .029). Risk of second malignant neoplasms was highest among patients treated with radiotherapy with O/E ratio of 43 compared to 30 and 5 for chemotherapy and surgery alone, respectively. CONCLUSION: Treatment trends for RB show an increase in chemotherapy utilization with a decrease in radiation therapy from 1975 to 2010. Second malignant neoplasms occurred mainly in patients treated with radiation therapy. Our series demonstrates improvement in survival in contemporary time periods, which parallels a shift in therapy toward chemotherapy with a decline in radiation therapy. PMID- 26255576 TI - Corneal Sensitivity in Tear Dysfunction and its Correlation With Clinical Parameters and Blink Rate. AB - PURPOSE: To compare corneal sensitivity in tear dysfunction due to a variety of causes using contact and noncontact esthesiometers and to evaluate correlations between corneal sensitivity, blink rate, and clinical parameters. DESIGN: Comparative observational case series. METHODS: Ten normal and 33 subjects with tear dysfunction (meibomian gland disease [n = 11], aqueous tear deficiency [n = 10]-without (n = 7) and with (n = 3) Sjogren syndrome (SS)-and conjunctivochalasis [n = 12]) were evaluated. Corneal sensitivity was measured with Cochet-Bonnet and air jet esthesiometers and blink rate by electromyography. Eye irritation symptoms, tear meniscus height, tear break-up time (TBUT), and corneal and conjunctival dye staining were measured. Between-group means were compared and correlations calculated. RESULTS: Compared with control (Cochet Bonnet 5.45 mm, air esthesiometer 3.62 mg), mean sensory thresholds were significantly higher in aqueous tear deficiency using either Cochet-Bonnet (3.6 mm; P = .003) or air (11.7 mg; P = .046) esthesiometers, but were not significantly different in the other groups. Reduced corneal sensitivity significantly correlated with more rapid TBUT and blink rate and greater irritation and ocular surface dye staining with 1 or both esthesiometers. Mean blink rates were significantly higher in both aqueous tear deficiency and conjunctivochalasis compared with control. Among all subjects, blink rate positively correlated with ocular surface staining and irritation and inversely correlated with TBUT. CONCLUSION: Among conditions causing tear dysfunction, reduced corneal sensitivity is associated with greater irritation, tear instability, ocular surface disease, and blink rate. Rapid blinking is associated with worse ocular surface disease and tear stability. PMID- 26255577 TI - The Association of Race With Childhood Uveitis. AB - PURPOSE: To identify risk factors for a severe uveitis course among children with noninfectious uveitis. DESIGN: Retrospective cohort study. METHOD: This was a retrospective analysis of a prospectively collected database. Records of 94 children with uveitis were reviewed at enrollment and every 3-6 months (2011 2015). Severe uveitis was defined as a history of ocular complications or a visual acuity (VA) of <=20/200. Children were compared by disease, VA, complications, and race. Regression models were used to model risk factors for severe disease. When examining race, we focused on non-Hispanic African-American and non-Hispanic white children only. RESULTS: Of 85 children with uveitis and complete ocular examinations, 27 (32%) had a history of a VA of <=20/200. A subanalysis of non-Hispanic African-American and white children showed an increased prevalence of VA <=20/200 in non-Hispanic African-Americans (18/25; 72% vs 4/43; 9%). Non-Hispanic African-Americans were more likely to be diagnosed at an older age (P = .030) and to have intermediate uveitis (P = .026), bilateral disease (P = .032), a history of VA <=20/50 (P = .002), VA <=20/200 (P < .001), and a higher rate of complications (P < .001). On multivariable analysis, non Hispanic African-American race was a significant predictor of blindness (OR = 31.6, 95% CI 5.9-168.5, P < .001), after controlling for uveitis duration. Non Hispanic African-Americans also developed 2.2 times more unique complications per year of disease than non-Hispanic whites when controlling for uveitis type and duration. CONCLUSIONS: There appear to be racial differences in the outcomes of children with uveitis. Non-Hispanic African-American children with non-juvenile idiopathic arthritis-associated uveitis may have worse visual outcomes with increased vision loss and ocular complications. These findings highlight the need for future studies in minority populations. PMID- 26255578 TI - Correlation of Type 1 Neovascularization Associated With Acquired Vitelliform Lesion in the Setting of Age-Related Macular Degeneration. AB - PURPOSE: To correlate postmortem histology with previously recorded multimodal imaging from a patient with type 1 neovascularization (NV) associated with an acquired vitelliform lesion in the setting of age-related macular degeneration (AMD). DESIGN: Case study. METHODS: Multimodal imaging that was obtained antemortem was matched with ex vivo and high-resolution histologic images of the preserved donor macula. Anatomic correlates for multimodal imaging findings were then defined. RESULTS: Spectral-domain optical coherence tomography (OCT) revealed a split in the retinal pigment epithelium-Bruch membrane band. Type 1 NV in this case was composed of 6 layered components: (1) retinal pigment epithelium, (2) basal laminar deposits, (3) fibrovascular membrane, (4) fibrocellular scar, (5) hemorrhage, and (6) Bruch membrane. The anatomic correlates for the hyporeflective band on spectral-domain OCT included a thick basal laminar deposit. Not all structures could be readily separated on the basis of their reflectivity patterns. CONCLUSIONS: This is an important clinicopathologic correlation of NV secondary to AMD in the spectral-domain OCT era. Our findings of 6 layers include and extend the anatomic framework encapsulated by the double-layer and triple-layer signs. The resolution of current devices does not always permit distinction of the different layers of NV tissue. Thick basal laminar deposits may appear hyporeflective on spectral-domain OCT and may be confused with fluid from a neovascular process. It will be important to perform a larger clinicopathologic series to aid our anatomic interpretation of spectral-domain OCT images. PMID- 26255579 TI - Use of Diabetes Registry Data for Comparing Indices of Diabetes Management: A Comparison of 2 Urban Sites in Canada and Colombia. AB - OBJECTIVES: To demonstrate the use of a multinational diabetes registry for comparing indices of diabetes management among countries with differing levels of income, healthcare systems and ethnic backgrounds. METHODS: A cross-sectional study was conducted among 1742 people with type 2 diabetes attending diabetes clinics in London, Ontario, Canada, and Bogota, Colombia. The data were extracted from the Global Registry and Surveillance System for Diabetes (GRAND). RESULTS: Canadian patients were diagnosed with diabetes at significantly younger ages than Colombian patients (49 years and 53 years, respectively) and were heavier (body mass indices of 33 and 28, respectively). The Colombian patient population had significantly higher mean glycated hemoglobin (A1C) levels (9.4% vs. 8.6%) and fewer patients (22% vs. 26%) at the glycemic target (A1C <7.0%) than Canadian patients. In Colombia, 1 or more diabetes-related complications were present in 51% of the study population compared with 37% in Canada. Newly diagnosed Colombians had higher mean A1C levels (9.1% vs. 8.7%) and low-density lipoprotein C levels (3.3 mmol/L vs. 2.5 mmol/L) than did newly diagnosed Canadians. CONCLUSIONS: A multination diabetes registry collecting standardized data facilitates transnational comparison of diabetes clinical parameters for the purpose of identifying potential gaps in care. PMID- 26255580 TI - HRS/NSA 2014 Survey of Atrial Fibrillation and Stroke: Gaps in Knowledge and Perspective, Opportunities for Improvement. AB - BACKGROUND: The prevalence of atrial fibrillation (AF) is substantial and increasing. Stroke is common in AF and can have devastating consequences. Oral anticoagulants are effective in reducing stroke risk, but are underutilized. OBJECTIVE: We sought to characterize the impact of stroke on AF patients and their caregivers, gaps in knowledge and perspective between physicians and patients, and barriers to effective communication and optimal anticoagulation use. METHODS: A survey was administered to AF patients with and without history of stroke, caregivers of stroke survivors, and physicians across the range of specialties caring for AF and stroke patients. RESULTS: While AF patients (n = 499) had limited knowledge about stroke, they expressed great desire to learn more and take action to reduce their risk. They were often dissatisfied with the education they had received and desired high-quality written materials. Stroke survivors (n = 251) had poor functional outcomes and often underestimated the burden of caring for them. Caregivers (n = 203) also wished they had received more information about reducing stroke risk before their survivor's event. They commonly felt overwhelmed and socially isolated. Physicians (n = 504) did not prescribe anticoagulants as frequently as recommended by guidelines. Concerns about monitoring anticoagulation and patient compliance were commonly reported barriers. Physicians may underestimate patient willingness to take anticoagulants. CONCLUSION: We identified significant knowledge gaps among patients, caregivers, and physicians in relation to AF and stroke. Furthermore, gaps in perspective often lead to suboptimal communication and decision making. Increased education and better communication between all stakeholders are needed to reduce the impact of stroke in AF. PMID- 26255581 TI - High-precision measurement of (186)Os/(188)Os and (187)Os/(188)Os: isobaric oxide corrections with in-run measured oxygen isotope ratios. AB - We present a novel method for high precision measurement of (186)Os/(188)Os and (187)Os/(188)Os ratios, applying isobaric oxide interference correction based on in-run measurements of oxygen isotopic ratios. For this purpose, we set up a static data collection routine to measure the main Os(16)O3(-) ion beams with Faraday cups connected to conventional 10(11) amplifiers, and (192)Os(16)O2(17)O( ) and (192)Os(16)O2(18)O(-) ion beams with Faraday cups connected to 10(12) amplifiers. Because of the limited number of Faraday cups, we did not measure (184)Os(16)O3(-) and (189)Os(16)O3(-) simultaneously in-run, but the analytical setup had no significant influence on final (186)Os/(188)Os and (187)Os/(188)Os data. By analyzing UMd, DROsS, an in-house Os solution standard, and several rock reference materials, including WPR-1, WMS-1a, and Gpt-5, the in-run measured oxygen isotopic ratios were proven to present accurate Os isotopic data. However, (186)Os/(188)Os and (187)Os/(188)Os data obtained with in-run O isotopic compositions for the solution standards and rock reference materials show minimal improvement in internal and external precision, compared to the conventional oxygen correction method. We concluded that, the small variations of oxygen isotopes during OsO3(-) analytical sessions are probably not the main source of error for high precision Os isotopic analysis. Nevertheless, use of run-specific O isotopic compositions is still a better choice for Os isotopic data reduction and eliminates the requirement of extra measurements of the oxygen isotopic ratios. PMID- 26255582 TI - Drug release behavior of poly (lactic-glycolic acid) grafting from sodium alginate (ALG-g-PLGA) prepared by direct polycondensation. AB - Hydrophobically modified sodium alginate, poly (lactic-glycolic acid) grafting from sodium alginate (ALG-g-PLGA), was successfully synthesized through direct one-step polymerization of sodium alginate, glycolic acid, and lactic acid. ALG-g PLGA self-assembled to colloidal nanoparticles and subsequently hydrogel microspheres were obtained by crosslinking ALG-g-PLGA nanoparticles in the solution of calcium chloride. The modified hydrogel microspheres could be used as the drug delivery vehicles for a hydrophobic ibuprofen. Compared with sodium alginate, ALG-g-PLGA demonstrated an improved drug loading rate, encapsulation efficiency, and prolonged release speed. The products, as novel and highly promising biomaterials, have potential applications. PMID- 26255583 TI - Editorial Comment. PMID- 26255584 TI - Reply: To PMID 22591970. PMID- 26255586 TI - Thermotropic interface and core relaxation dynamics of liquid crystals in silica glass nanochannels: a dielectric spectroscopy study. AB - We report dielectric relaxation spectroscopy experiments on two rod-like liquid crystals of the cyanobiphenyl family (5CB and 6CB) confined in tubular nanochannels with 7 nm radius and 340 micrometer length in a monolithic, mesoporous silica membrane. The measurements were performed on composites for two distinct regimes of fractional filling: monolayer coverage at the pore walls and complete filling of the pores. For the layer coverage a slow surface relaxation dominates the dielectric properties. For the entirely filled channels the dielectric spectra are governed by two thermally-activated relaxation processes with considerably different relaxation rates: a slow relaxation in the interface layer next to the channel walls and a fast relaxation in the core region of the channel filling. The strengths and characteristic frequencies of both relaxation processes have been extracted and analysed as a function of temperature. Whereas the temperature dependence of the static capacitance reflects the effective (average) molecular ordering over the pore volume and is well described within a Landau-de Gennes theory, the extracted relaxation strengths of the slow and fast relaxation processes provide an access to distinct local molecular ordering mechanisms. The order parameter in the core region exhibits a bulk-like behaviour with a strong increase in the nematic ordering just below the paranematic-to nematic transition temperature TPN and subsequent saturation during cooling. By contrast, the surface ordering evolves continuously with a kink near TPN. A comparison of the thermotropic behaviour of the monolayer with the complete filling reveals that the molecular order in the core region of the pore filling affects the order of the peripheral molecular layers at the wall. PMID- 26255587 TI - Structure, Dynamics, and Allosteric Potential of Ionotropic Glutamate Receptor N Terminal Domains. AB - Ionotropic glutamate receptors (iGluRs) are tetrameric cation channels that mediate synaptic transmission and plasticity. They have a unique modular architecture with four domains: the intracellular C-terminal domain (CTD) that is involved in synaptic targeting, the transmembrane domain (TMD) that forms the ion channel, the membrane-proximal ligand-binding domain (LBD) that binds agonists such as L-glutamate, and the distal N-terminal domain (NTD), whose function is the least clear. The extracellular portion, comprised of the LBD and NTD, is loosely arranged, mediating complex allosteric regulation and providing a rich target for drug development. Here, we briefly review recent work on iGluR NTD structure and dynamics, and further explore the allosteric potential for the NTD in AMPA-type iGluRs using coarse-grained simulations. We also investigate mechanisms underlying the established NTD allostery in NMDA-type iGluRs, as well as the fold-related metabotropic glutamate and GABAB receptors. We show that the clamshell motions intrinsically favored by the NTD bilobate fold are coupled to dimeric and higher-order rearrangements that impact the iGluR LBD and ultimately the TMD. Finally, we explore the dynamics of intact iGluRs and describe how it might affect receptor operation in a synaptic environment. PMID- 26255590 TI - Nanohybrid conjugated polyelectrolytes: highly photostable and ultrabright nanoparticles. AB - We present a general and straightforward one-step approach to enhance the photophysical properties of conjugated polyelectrolytes. Upon complexation with an amphiphilic polymer (polyvinylpyrrolidone), an anionic conjugated polyelectrolyte (poly[5-methoxy-2-(3-sulfopropoxy)-1,4-phenylenevinylene]) was prepared into small nanoparticles with exceptional photostability and brightness. The polymer fluorescence intensity was enhanced by 23 -fold and could be easily tuned by changing the order of addition. Single molecule experiments revealed a complete suppression of blinking. In addition, after only losing 18% of the original intensity, a remarkable amount of photons were emitted per particle (~10(9), on average). This number is many folds greater than popular organic fluorescent dyes. We believe that an intimate contact between the two polymers is shielding the conjugated polyelectrolyte from the destructive photooxidation. The prepared nanohybrid particles will prove instrumental in single particle based fluorescent assays and can serve as a probe for the current state-of-the-art bioimaging fluorescence techniques. PMID- 26255588 TI - Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes. AB - Cyclin-dependent kinases (CDKs) and their associated regulatory cyclins are central for timely regulation of cell-cycle progression. They constitute attractive pharmacological targets for development of anticancer therapeutics, since they are frequently deregulated in human cancers and contribute to sustained, uncontrolled tumor proliferation. Characterization of their structural/dynamic features is essential to gain in-depth insight into structure activity relationships. In addition, the identification of druggable pockets or key intermediate conformations yields potential targets for the development of novel classes of inhibitors. Structural studies of CDK2/cyclin A have provided a wealth of information concerning monomeric/heterodimeric forms of this kinase. There is, however, much less structural information for other CDK/cyclin complexes, including CDK4/cyclin D1, which displays an alternative (open) position of the cyclin partner relative to CDK, contrasting with the closed CDK2/cyclin A conformation. In this study, we carried out normal-mode analysis and enhanced sampling simulations with our recently developed method, molecular dynamics with excited normal modes, to understand the conformational equilibrium on these complexes. Interestingly, the lowest-frequency normal mode computed for each complex described the transition between the open and closed conformations. Exploration of these motions with an explicit-solvent representation using molecular dynamics with excited normal modes confirmed that the closed conformation is the most stable for the CDK2/cyclin A complex, in agreement with their experimentally available structures. On the other hand, we clearly show that an open<->closed equilibrium may exist in CDK4/cyclin D1, with closed conformations resembling that captured for CDK2/cyclin A. Such conformational preferences may result from the distinct distributions of frustrated contacts in each complex. Using the same approach, the putative roles of the Thr(160) phosphoryl group and the T-loop conformation were investigated. These results provide a dynamic view of CDKs revealing intermediate conformations not yet characterized for CDK members other than CDK2, which will be useful for the design of inhibitors targeting critical conformational transitions. PMID- 26255591 TI - Effects of a new antiarrhythmic drug SS-68 on electrical activity in working atrial and ventricular myocardium of mouse and their ionic mechanisms. AB - SS-68 is a derivative of indole, which demonstrated strong antiarrhythmic effects not associated with significant QT prolongation in dog models of atrial fibrillation. Therefore, SS-68 was proposed as a new antiarrhythmic drug and the present study is the first describing its effects on action potentials (APs) configuration and elucidating the ionic mechanisms of these effects. Sharp microelectrodes were used to record APs in isolated preparations of mouse atrial and ventricular myocardium. In both types of myocardium 10(-6) M SS-68 produced reduction of AP duration, 3 * 10(-6) M failed to alter AP waveform and 10(-5) - 3 * 10(-5) M prolonged APs. Sensitivity of main ionic currents to SS-68 was determined using whole-cell patch clamp. Transient potassium current Ito was slightly inhibited by SS-68 with IC50 = 1.43 * 10(-4) M. IKur was more sensitive with IC50 = 1.84 * 10(-5) M. Background inward rectifier showed very low sensitivity to SS-68 - only 10(-4) M SS-68 caused significant reduction of IK1. ICaL was significantly inhibited by 10(-6)M - 3 * 10(-5) M SS-68. The IC50 value for the ICaL was 1.84 * 10(-6) M. Thus, main ionic currents of mouse cardiomyocytes are inhibited by SS-68 in the following order of potency: ICaL > IKur > Ito > IK1. While lower concentration of SS-68 shorten APs via suppression of ICaL, higher concentrations inhibit K(+)-currents leading to APs prolongation. PMID- 26255589 TI - The Role of Conformational Dynamics and Allostery in the Disease Development of Human Ferritin. AB - Determining the three-dimensional structure of myoglobin, the first solved structure of a protein, fundamentally changed the way protein function was understood. Even more revolutionary was the information that came afterward: protein dynamics play a critical role in biological functions. Therefore, understanding conformational dynamics is crucial to obtaining a more complete picture of protein evolution. We recently analyzed the evolution of different protein families including green fluorescent proteins (GFPs), beta-lactamase inhibitors, and nuclear receptors, and we observed that the alteration of conformational dynamics through allosteric regulation leads to functional changes. Moreover, proteome-wide conformational dynamics analysis of more than 100 human proteins showed that mutations occurring at rigid residue positions are more susceptible to disease than flexible residue positions. These studies suggest that disease-associated mutations may impair dynamic allosteric regulations, leading to loss of function. Thus, in this study, we analyzed the conformational dynamics of the wild-type light chain subunit of human ferritin protein along with the neutral and disease forms. We first performed replica exchange molecular dynamics simulations of wild-type and mutants to obtain equilibrated dynamics and then used perturbation response scanning (PRS), where we introduced a random Brownian kick to a position and computed the fluctuation response of the chain using linear response theory. Using this approach, we computed the dynamic flexibility index (DFI) for each position in the chain for the wild-type and the mutants. DFI quantifies the resilience of a position to a perturbation and provides a flexibility/rigidity measurement for a given position in the chain. The DFI analysis reveals that neutral variants and the wild-type exhibit similar flexibility profiles in which experimentally determined functionally critical sites act as hinges in controlling the overall motion. However, disease mutations alter the conformational dynamic profile, making hinges more loose (i.e., softening the hinges), thus impairing the allosterically regulated dynamics. PMID- 26255592 TI - Chaplains' Engagement with Suicidality among Their Service Users: Findings from the VA/DoD Integrated Mental Health Strategy. AB - Chaplains play an important role in supporting the mental health of current and former military personnel; in this study, the engagement of Department of Veterans Affairs (VA), Army, Navy, and Air Force chaplains with suicidality among their service users were examined. An online survey was used to collect data from 440 VA and 1,723 Department of Defense (DoD) chaplains as part of the VA/DoD Integrated Mental Health Strategy. Differences were noted for demographics, work setting characteristics, encountering suicidality, and self-perceived preparation for dealing with suicidality. Compared to DoD chaplains, VA chaplains encounter more at-risk service users, yet feel less prepared for dealing with suicidality. PMID- 26255593 TI - Placing the paraventricular nucleus of the thalamus within the brain circuits that control behavior. AB - This article reviews the anatomical connections of the paraventricular nucleus of the thalamus (PVT) and discusses some of the connections by which the PVT could influence behavior. The PVT receives neurochemically diverse projections from the brainstem and hypothalamus with an especially strong innervation from peptide producing neurons. Anatomical evidence is also presented which suggests that the PVT relays information from neurons involved in visceral or homeostatic functions. In turn, the PVT is a major source of projections to the nucleus accumbens, the bed nucleus of the stria terminalis and the central nucleus of the amygdala as well as the cortical areas associated with these subcortical regions. The PVT is activated by conditions and cues that produce states of arousal including those with appetitive or aversive emotional valences. The paper focuses on the potential contribution of the PVT to circadian rhythms, fear, anxiety, food intake and drug-seeking. The information in this paper highlights the potential importance of the PVT as being a component of the brain circuits that regulate reward and defensive behavior with the hope of generating more research in this relatively understudied region of the brain. PMID- 26255594 TI - Out of space. PMID- 26255595 TI - Phosphorus Lewis acids: emerging reactivity and applications in catalysis. AB - Part of the renaissance in main group chemistry has been a result of the focus on reactivity. This has led to the development of applications in stoichiometric reactivity and catalysis. In this tutorial review, we focus attention on the role of phosphorus-based Lewis acids in such advances. While early literature recognizes the role of P(iii) and P(v) electrophiles in coordination chemistry, it has generally been more recent studies that have focused on applications of this Lewis acidity. Applications of these novel P-based Lewis acids in stoichiometric reactivity, Lewis acid catalysis and frustrated Lewis pair (FLP) reactivity are reviewed. These advances demonstrate that P-based Lewis acids are a powerful tool for further developments in metal-free catalysis. PMID- 26255596 TI - Glycoprotein130 (Gp130)/interleukin-6 (IL-6) signalling in osteoclasts promotes bone formation in periosteal and trabecular bone. AB - Interleukin-6 (IL-6) and interleukin-11 (IL-11) receptors (IL-6R and IL-11R, respectively) are both expressed in osteoclasts and transduce signal via the glycoprotein130 (gp130) co-receptor, but the physiological role of this pathway is unclear. To determine the critical roles of gp130 signalling in the osteoclast, we generated mice using cathepsin K Cre (CtskCre) to disrupt gp130 signalling in osteoclasts. Bone marrow macrophages from CtskCre.gp130(f/f) mice generated more osteoclasts in vitro than cells from CtskCre.gp130(w/w) mice; these osteoclasts were also larger and had more nuclei than controls. While no increase in osteoclast numbers was observed in vivo, osteoclasts on trabecular bone surfaces of CtskCre.gp130(f/f) mice were more spread out than in control mice, but had no functional defect detectable by serum CTX1 levels or trabecular bone cartilage remnants. However, trabecular osteoblast number and mineralising surfaces were significantly lower in male CtskCre.gp130(f/f) mice compared to controls, and this was associated with a significantly lower trabecular bone volume at 12 weeks of age. Furthermore, CtskCre.gp130(f/f) mice exhibited greatly suppressed periosteal bone formation at this age, indicated by significant reductions in both double-labelled surface and mineral apposition rate. By 26 weeks of age, CtskCre.gp130(f/f) mice exhibited narrower femora, with lower periosteal and endocortical perimeters than CtskCre.gp130(w/w) controls. Since IL 6 and IL-11R global knockout mice exhibited a similar reduction in femoral width, we also assessed periosteal bone formation in those strains, and found bone forming surfaces were also reduced in male IL-6 null mice. These data suggest that IL-6/gp130 signalling in the osteoclast is not essential for normal bone resorption in vivo, but maintains both trabecular and periosteal bone formation in male mice by promoting osteoblast activity through the stimulation of osteoclast-derived "coupling factors" and "osteotransmitters", respectively. PMID- 26255597 TI - Insight into the formation of magnetite mesocrystals from ferrous precursors in ethylene glycol. AB - Uniform magnetite mesocrystals were fabricated by solvothermal treatment of ferrous chloride in ethylene glycol in the presence of sodium hydroxide. The formation mechanism of magnetite mesocrystals in ethylene glycol was deduced by a time-dependent experiment. PMID- 26255598 TI - Biofilm formation and ethanol inhibition by bacterial contaminants of biofuel fermentation. AB - Bacterial contaminants can inhibit ethanol production in biofuel fermentations, and even result in stuck fermentations. Contaminants may persist in production facilities by forming recalcitrant biofilms. A two-year longitudinal study was conducted of bacterial contaminants from a Midwestern dry grind corn fuel ethanol facility. Among eight sites sampled in the facility, the combined liquefaction stream and yeast propagation tank were consistently contaminated, leading to contamination of early fermentation tanks. Among 768 contaminants isolated, 92% were identified as Lactobacillus sp., with the most abundant species being Lactobacillus plantarum, Lactobacillus casei, Lactobacillus mucosae, and Lactobacillus fermentum. Seven percent of total isolates showed the ability to form biofilms in pure cultures, and 22% showed the capacity to significantly inhibit ethanol production. However, these traits were not correlated. Ethanol inhibition appeared to be related to acetic acid production by contaminants, particularly by obligately heterofermentative species such as L. fermentum and L. mucosae. PMID- 26255599 TI - Preparation and characterization of a novel graphene/biochar composite for aqueous phenanthrene and mercury removal. AB - A graphene/biochar composite (G/BC) was synthesized via slow pyrolysis of graphene (G) pretreated wheat straw, and tested for the sorption characteristics and mechanisms of representative aqueous contaminants (phenanthrene and mercury). Structure and morphology analysis showed that G was coated on the surface of biochar (BC) mainly through pi-pi interactions, resulting in a larger surface area, more functional groups, greater thermal stability, and higher removal efficiency of phenanthrene and mercury compared to BC. Pseudo second-order model adequately simulated sorption kinetics, and sorption isotherms of phenanthrene and mercury were simulated well by dual-mode and BET models, respectively. FTIR and SEM analysis suggested that partitioning and surface sorption were dominant mechanisms for phenanthrene sorption, and that surface complexation between mercury and C-O, CC, -OH, and OC-O functional groups was responsible for mercury removal. The results suggested that the G/BC composite is an efficient, economic, and environmentally friendly multifunctional adsorbent for environmental remediation. PMID- 26255600 TI - Comparative techno-economic assessment and LCA of selected integrated sugarcane based biorefineries. AB - This work addresses the economic and environmental performance of integrated biorefineries based on sugarcane juice and residues. Four multiproduct scenarios were considered; two from sugar mills and the others from ethanol distilleries. They are integrated biorefineries producing first (1G) and second (2G) generation ethanol, sugar, molasses (for animal feed) and electricity in the context of Brazil. The scenarios were analysed and compared using techno-economic value based approach and LCA methodology. The results show that the best economic configuration is provided by a scenario with largest ethanol production while the best environmental performance is presented by a scenario with full integration sugar - 1G2G ethanol production. PMID- 26255601 TI - Using three-bio-electrode reactor to enhance the activity of anammox biomass. AB - This research was designed to investigate the effects of different electric potentials (EPs) on the anammox biomass activity in a three-electrode reactor. Electric potential difference (EPD) of 0.08V between the working and reference electrodes showed the best nitrogen removal performance. Under the optimal EPD of 0.08V, the nitrogen removal rate of reactor 2 (R2, EP applied) reached 911g N/m(3)/d on day 188, which was 25.3% higher than that of reactor 1 (R1, the control). Moreover, the scanning electron microscope observation and extracellular polymeric substance analysis proved that EP application was conducive to the anammox cells growing onto the surface of electrode. Additionally, it was demonstrated that long-term EP application increased the crude enzymes activities and the cell quantities of the bio-electrode anammox reactor. Besides, transmission electron microscope observation proved the morphological variation of anammox biomass with continuous EP application. PMID- 26255602 TI - Use of new endophytic fungi as pretreatment to enhance enzymatic saccharification of Eucalyptus globulus. AB - New endophytic fungi are assessed for the first time as pretreatment to enhance saccharification of Eucalyptus globulus wood. The fungi are all laccase-producing ascomycetes and were isolated from eucalyptus trees in Spain. After five endophytes had been assayed alone or in combination with white-rot fungus Trametes sp. I-62, three were pre-selected. To improve sugar production, an autohydrolysis pretreatment was performed before or after fungal treatment. Pretreatment increased sugar production 2.7 times compared to non-pretreated wood. When fungal and autohydrolysis pretreatments were combined, a synergistic increase in saccharification was observed in all cases. Endophytic fungi Ulocladium sp. and Hormonema sp. produced greater enhancements in saccharification than Trametes sp. I-62 (increase in sugar yields of 8.5, 8.0 and 6.0 times, respectively), demonstrating the high potential of these new endophytic fungi for saccharification enhancement. PMID- 26255603 TI - Procedural justice in children: Preschoolers accept unequal resource distributions if the procedure provides equal opportunities. AB - When it is not possible to distribute resources equitably to everyone, people look for an equitable or just procedure. In the current study, we investigated young children's sense of procedural justice. We tested 32 triads of 5-year-olds in a new resource allocation game. Triads were confronted with three unequal reward packages and then agreed on a procedure to allocate them among themselves. To allocate the rewards, they needed to use a "wheel of fortune." Half of the groups played with a fair wheel (where each child had an equal chance of obtaining each reward package), and the other half played with an unfair wheel. We analyzed children's interactions when using the wheel and conducted an interview with each child after the game was over. Children using the unfair wheel often decided to change the rules of the game, and they also rated it as an unfair procedure in the interview. In contrast, children who played with the fair wheel were mostly accepting of both the outcome and the procedure. Overall, we found that children as young as preschool age are already sensitive not only to distributive justice but to procedural justice as well. PMID- 26255605 TI - Breastfeeding difficulties and oral cavity anomalies: The influence of posterior ankyloglossia and upper-lip ties. AB - OBJECTIVE: Oral cavity anomalies may contribute to breastfeeding problems. The objective of this study was to describe our experience in a high-volume breastfeeding difficulty clinic with a focus on posterior ankyloglossia and upper lip ties. METHODS: A retrospective review of patients from a dedicated breastfeeding difficulty clinic from January 2014 to December 2014 was performed. Those identified to have ankyloglossia and/or upper-lip ties underwent release procedures. Subjective breastfeeding changes were documented afterwards. RESULTS: Of the 618 total patients, 290 (47%) had anterior ankyloglossia, 120 (19%) had posterior ankyloglossia, and 14 (2%) had upper-lip tie. Some patients had both anterior ankyloglossia and upper lip-tie (6%), or posterior ankyloglossia and upper-lip tie (5%). For those with anterior ankyloglossia, 78% reported some degree of improvement in breastfeeding after frenotomy. For those with posterior ankyloglossia, 91% reported some degree of improvement in breastfeeding after frenotomy. Upper lip-tie release also led to improved breastfeeding (100%). CONCLUSIONS: Anterior and posterior ankyloglossia and upper-lip tie, or combinations thereof, were commonly recognized in our study population. Many newborns, however, also had no oral cavity anomalies. Although causation cannot be implied, these oral cavity anomalies may contribute to breastfeeding difficulties in some cases. PMID- 26255604 TI - Individual differences in algebraic cognition: Relation to the approximate number and semantic memory systems. AB - The relation between performance on measures of algebraic cognition and acuity of the approximate number system (ANS) and memory for addition facts was assessed for 171 ninth graders (92 girls) while controlling for parental education, sex, reading achievement, speed of numeral processing, fluency of symbolic number processing, intelligence, and the central executive component of working memory. The algebraic tasks assessed accuracy in placing x,y pairs in the coordinate plane, speed and accuracy of expression evaluation, and schema memory for algebra equations. ANS acuity was related to accuracy of placements in the coordinate plane and expression evaluation but not to schema memory. Frequency of fact retrieval errors was related to schema memory but not to coordinate plane or expression evaluation accuracy. The results suggest that the ANS may contribute to or be influenced by spatial-numerical and numerical-only quantity judgments in algebraic contexts, whereas difficulties in committing addition facts to long term memory may presage slow formation of memories for the basic structure of algebra equations. More generally, the results suggest that different brain and cognitive systems are engaged during the learning of different components of algebraic competence while controlling for demographic and domain general abilities. PMID- 26255606 TI - Paediatric tracheostomy-An 11 year experience at a Scottish paediatric tertiary referral centre. AB - AIMS: The aim of this paper was to review the indications, complications and outcomes for tracheostomy at a Scottish paediatric tertiary referral hospital. METHODS: All patients undergoing tracheostomy between January 2001 and September 2012 were identified. A retrospective case note analysis was performed. RESULTS: 111 tracheostomies were done in the study period. The mean number per year was 11 (3-12). Full data was available for 95 patients. There were 56 (59%) males and 39 (41%) females. Age at time of tracheostomy ranged from one day to 15 years, the mean age of tracheostomy insertion was 69 weeks. The majority of patients, 75 (79%), were under one year old when they had their tracheostomy. The most common indication was long-term ventilation (20%), followed by craniofacial abnormality causing airway obstruction (18%), followed by subglottic stenosis (14%). 37% of patients were decannulated. CONCLUSIONS: This series reflects current trends in the indications for paediatric tracheostomy, with chronic lung disease of prematurity being the most common indication. PMID- 26255607 TI - Validation of warfarin pharmacogenetic algorithms in 586 Han Chinese patients. AB - AIM: To compare the accuracy of the nine selected algorithms for predicting warfarin dose with 586 Han Chinese patients. MATERIALS & METHODS: Genotyping of VKORC1 1639G>A, CYP2C9*2 and CYP2C9*3 variants was performed. Both the mean absolute error and ideal estimation value were used for comparison. RESULTS: The top three performers were from East Asians. The algorithms from Caucasians generally performed better in the medium-dose subgroup (>3 and <7 mg/day), while the algorithms from East Asians generally performed better in the low-dose subgroup (<= 3 mg/day). None of the algorithms performed well in the high-dose subgroup (>= 7 mg/day). CONCLUSION: Algorithms built for specific ethnic groups and preassigned-dose groups are suggested for better prediction. PMID- 26255608 TI - Life history and reproductive ecology of the endangered Itasenpara bitterling Acheilognathus longipinnis (Cyprinidae) in the Himi region, central Japan. AB - The life history, reproductive ecology and habitat utilization of the Itasenpara (deepbody) bitterling Acheilognathus longipinnis were investigated in a lowland segment of the Moo River in Toyama Prefecture, central Honshu, Japan. Analysis of 1285 individuals revealed that the study population comprised a single size class, an age at maturation of 3 months and a life span of 1 year. On the basis of the growth pattern, the life cycle was divided into two stages: the juvenile stage, characterized by rapid growth, and the adult stage at which growth ceased. Spawning by A. longipinnis was recorded between early September and late October. Female A. longipinnis in the 0+ year age class began to mature when they reached a standard length (LS ) of 56.4 mm. Mature females had a large clutch size (maximum 273 eggs) and deposited highly adhesive and relatively large eggs (2.55 mm(3) ; major axis, 3.12 mm; minor axis, 1.22 mm) via a short ovipositor (mean length, 21.5 mm) into freshwater mussels. The embryos remained in the gill cavities of the freshwater mussels (used as a spawning substratum) and emerged as juveniles (LS , 9 mm). Habitat utilization during spawning was analysed using a generalized linear model. The best-fit model showed that three environmental factors (freshwater mussel availability, water depth and vegetation cover) were important variables for habitat utilization by A. longipinnis. Shallow areas (water depth, 250-330 mm) created for rice paddy management and areas with an abundance of cover were particularly effective for predator avoidance. These results suggest that maintenance of water level fluctuations corresponding with rice cultivation and the abundance of vegetation on the river bank (particularly avoidance of concrete revetments) is essential for conservation of this species under current practices for rice cultivation in Japan. PMID- 26255609 TI - DNA sequencing with MspA: Molecular Dynamics simulations reveal free-energy differences between sequencing and non-sequencing mutants. AB - MspA has been identified as a promising candidate protein as a component of a nanopore-based DNA-sequencing device. However the wildtype protein must be engineered to incorporate all of the features desirable for an accurate and efficient device. In the present study we have utilized atomistic molecular dynamics to perform umbrella-sampling calculations to calculate the potential of mean force (PMF) profiles for translocation of the four DNA nucleotides through MspA. We show there is an energetic barrier to translocation of individual nucleotides through a mutant that closely resembles the wildtype protein, but not through a mutant engineered for the purpose of sequencing. Crucially we are able to quantify the change in free energy for mutating key residues. Thus providing a quantitative characterisation of the energetic impact of individual amino acid sidechains on nucleotide translocation through the pore of MspA. PMID- 26255610 TI - Electrokinetic sample preconcentration and hydrodynamic sample injection for microchip electrophoresis using a pneumatic microvalve. AB - A microfluidic platform was developed to perform online electrokinetic sample preconcentration and rapid hydrodynamic sample injection for zone electrophoresis using a single microvalve. The polydimethylsiloxane microchip comprises a separation channel, a side channel for sample introduction, and a control channel which is used as a pneumatic microvalve aligned at the intersection of the two flow channels. The closed microvalve, created by multilayer soft lithography, serves as a nanochannel preconcentrator under an applied electric potential, enabling current to pass through while preventing bulk flow. Once analytes are concentrated, the valve is briefly opened and the stacked sample is pressure injected into the separation channel for electrophoretic separation. Fluorescently labeled peptides were enriched by a factor of ~450 in 230 s. This method enables both rapid analyte concentration and controlled injection volume for high sensitivity, high-resolution CE. PMID- 26255611 TI - J-Wave in Patients With Syncope. AB - BACKGROUND: Syncope is a common occurrence. The presence of J-wave, also known as early repolarization, on electrocardiogram is often seen in the general population, but the relationship between syncope and J-wave is unclear. METHODS AND RESULTS: After excluding 67 patients with structural heart disease from 326 with syncope, we classified 259 patients according to the presence or absence of J-wave (>=1 mm) in at least 2 inferior or lateral leads. Head-up tilt test (HUT) was performed for 30 min. If no syncope or presyncope occurred, HUT was repeated after drug loading. Before tilt, 97/259 (37%) had J-wave (57 male, 47.6+/-22.5 years) and 162 patients had no remarkable change (89 male, 51.1+/-21.2 years). HUT-positive rate was higher in patients with J-wave, compared with patients without (P<0.0001). The combination of J-wave and descending/horizontal ST segment in the inferior leads was more strongly associated with positive HUT than J-wave with ascending ST segment (odds ratio, 3.23). CONCLUSIONS: Prevalence of J wave in the inferior or lateral leads was high in patients with syncope and was associated with HUT-induced neurally mediated reflex syncope (NMRS). Furthermore, the combination of J-wave and descending/horizontal ST segment in the inferior leads could be associated with a much higher risk of NMRS. PMID- 26255612 TI - Clinical Significance of Dynamic Left Ventricular Outflow Tract Obstruction During Dobutamine Stress Echocardiography in Women With Suspected Coronary Artery Disease. AB - BACKGROUND: Although dobutamine stress echocardiography (DSE) is frequently associated with dynamic left ventricular outflow tract obstruction (DLVOTO), little is known about its clinical significance in women with suspected coronary artery disease (CAD). METHODS AND RESULTS: One hundred and two female patients (57+/-10 years) who underwent DSE as part of the Korean women's chest pain registry study were included. Doppler echocardiography was performed during DSE to assess the presence of DLVOTO. Patients with DLVOTO (n=52) were older than those without DLVOTO (n=50; P=0.001). Hypertension was more prevalent in patients with DLVOTO (P=0.02). Patients with DLVOTO had smaller LV diameter, but higher LV mass index and relative wall thickness (P<0.05 for all). LV diastolic function (as reflected by late diastolic velocity, deceleration time of early diastolic velocity [E], and ratio of E velocity to early diastolic mitral annular velocity), was worse in patients with DLVOTO (P<0.05 for all). Patients with DLVOTO had shorter exercise time (P=0.02) and lower amount of work (P=0.04) than patients without DLVOTO. DSE-provoked DLVOTO was not related to the presence of CAD in these patients. CONCLUSIONS: In Korean women with suspected CAD, DSE provoked DLVOTO is correlated with LV concentric remodeling and LV diastolic dysfunction, and may be associated with limited exercise tolerance and symptoms of chest pain. PMID- 26255613 TI - Towards Safer Pregnancies in Women With Congenital Heart Disease. PMID- 26255614 TI - Do Two Eyes Really See More Than One? - Intravascular Ultrasound and Optical Coherence Tomography. PMID- 26255615 TI - Towards Safer Pregnancies in Women With Congenital Heart Disease- Reply. PMID- 26255616 TI - Differential Relationships Between Anemia and Outcome in Subgroups of Patients With Chronic Heart Failure. PMID- 26255617 TI - Reading impairment in Duchenne muscular dystrophy: A pilot study to investigate similarities and differences with developmental dyslexia. AB - Below-average reading performances have been reported in individuals with Duchenne muscular dystrophy (DMD), but literacy problems in these subjects have yet to be characterized. In this study, the presence and characteristics of literacy deficits in boys with DMD were investigated through a comparison with typically developing children and with children affected by developmental dyslexia, with the aim of clarifying whether DMD and developmental dyslexia have overlapping profiles of literacy deficits and whether these deficits are associated, as in children with dyslexia, with impairments in phonological processing and rapid lexical access. The results confirmed the high incidence of literacy problems in boys with DMD and revealed a profile less severe than, but qualitatively similar to, that of Italian children with developmental dyslexia. Both groups showed specific difficulties in reading and writing words and a reduced rapid automatized naming (RAN) speed. This is the first time that a RAN speed deficit has been documented in DMD. Moreover, the boys with DMD and the subgroup of dyslexic children with a previous language delay showed additional deficits in phonological processing. The impairments highlighted in this study could explain the reading difficulties observed in boys with DMD and suggest that there is a need for targeted preschool interventions. PMID- 26255618 TI - Effect of unilateral and simultaneous bilateral cochlear implantation on tinnitus: A Prospective Study. AB - OBJECTIVES/HYPOTHESIS: To determine the effect of cochlear implantation on tinnitus perception in patients with severe bilateral postlingual sensorineural hearing loss and to demonstrate possible differences between unilateral and bilateral cochlear implantation. STUDY DESIGN: Prospective study. METHODS: Thirty eight adult patients were included in this prospective study, as part of a multicenter randomized controlled trial investigating the benefits of bilateral cochlear implantation versus unilateral cochlear implantation. Pre- and postoperative tinnitus perception scores were evaluated, before and 1 year after implantation on three tinnitus questionnaires; the Tinnitus Handicap Inventory (THI), the Tinnitus Questionnaire (TQ), and a visual analogue scale for tinnitus burden. RESULTS: Before implantation, the tinnitus prevalence was 42.1% (16 of 38) in the whole study group. One year after implantation, the tinnitus questionnaire scores had decreased in 71.4% according to the TQ and 80.0% according to the THI. Tinnitus was induced after cochlear implantation in six patients, five in the bilateral and one in the unilateral group. CONCLUSIONS: Our study shows that cochlear implantation is effective in the reduction of tinnitus in patients with bilateral sensorineural hearing loss who suffered from preoperative tinnitus. Conversely, tinnitus may also increase or even be induced by the cochlear implantation itself. Cochlear implant candidates should be well informed about these possible consequences before undergoing surgery. LEVEL OF EVIDENCE: 2b. PMID- 26255619 TI - Obatoclax as a perpetrator in drug-drug interactions and its efficacy in multidrug resistance cell lines. AB - OBJECTIVES: Obatoclax is a pan-Bcl-2 inhibitor with promising efficacy, especially when combined with other antineoplastic agents. Pharmacokinetic drug drug interactions can occur systemically and at the level of the tumour cell. Thus, this study scrutinised the interaction potential of obatoclax in vitro. METHODS: Obatoclax was screened for P-gp inhibition by calcein assay, for breast cancer resistance protein (BCRP) inhibition by pheophorbide A assay and for inhibition of cytochrome P450 isoenzymes (CYPs) by commercial kits. Induction of mRNA of drug-metabolising enzymes and drug transporters was quantified in LS180 cells via real-time polymerase chain reaction and involvement of nuclear receptors was assessed by reporter gene assays. Proliferation assays were used to assess whether obatoclax retains its efficacy in cell lines overexpressing BCRP, P-glycoprotein (P-gp) or multidrug resistance-associated protein 2 (MRP2). KEY FINDINGS: Obatoclax induced the mRNA expression of several genes (e.g. CYP1A1, CYP1A2 and ABCG2 (five to seven-fold) through activation of the aryl hydrocarbon receptor in the nanomolar range. Obatoclax inhibits P-gp, BCRP and some CYPs at concentrations exceeding plasma levels. P-gp, MPR2 or BCRP overexpression did not influence the efficacy of obatoclax. CONCLUSIONS: Obatoclax retains its efficacy in cells overexpressing P-gp, MRP2 or BCRP and might act as a perpetrator drug in interactions with drugs, for example being substrates of CYP1A2 or BCRP. PMID- 26255620 TI - Lipid parameters in patients with acute coronary syndromes versus stable coronary artery disease. AB - BACKGROUND: Differences in lipid parameters between patients with acute coronary syndromes (ACS) and patients with stable coronary artery disease (CAD) are unclear and are addressed in this study. METHODS: We enrolled 582 patients with angiographically proven stable CAD (of whom 26.9% had diabetes mellitus type 2 (T2DM)) and 182 patients with ACS (of whom 35.8% had T2DM). RESULTS: HDL cholesterol and apolipoprotein A1 levels were significantly lower in patients with ACS than in patients with CAD (46 +/- 16 mg/dL vs. 50 +/- 16 mg/dL, P < 0.001, and 139 +/- 30 mg/dL vs. 155 +/- 31 mg/dL, P < 0.001, respectively). Analysis of covariance (ancova) adjusting for age, gender, smoking, BMI, statin therapy, alcohol use, hypertension and diabetic state confirmed an independent impact of ACS on HDL cholesterol and apolipoprotein A1 levels (F = 24.1; P < 0.001). In contrast, total cholesterol, LDL cholesterol, non-HDL cholesterol and apolipoprotein B levels did not differ significantly between patients with ACS and patients with stable CAD. CONCLUSION: HDL cholesterol and apolipoprotein A1 levels are lower in patients with ACS than in patients with stable CAD. PMID- 26255621 TI - Medication errors in hospitals: a literature review of disruptions to nursing practice during medication administration. AB - AIMS AND OBJECTIVES: The purpose of this review was to explore what is known about interruptions and distractions on medication administration in the context of undergraduate nurse education. BACKGROUND: Incidents and errors during the process of medication administration continue to be a substantial patient safety issue in health care settings internationally. Interruptions to the medication administration process have been identified as a leading cause of medication error. Literature recognises that some interruptions are unavoidable; therefore in an effort to reduce errors, it is essential understand how undergraduate nurses learn to manage interruptions to the medication administration process. DESIGN: Systematic, critical literature review. METHODS: Utilising the electronic databases, of Medline, Scopus, PubMed and CINAHL, and recognised quality assessment guidelines, 19 articles met the inclusion criteria. Search terms included: nurses, medication incidents or errors, interruptions, disruption, distractions and multitasking. RESULTS: Researchers have responded to the impact of interruptions and distractions on the medication administration by attempting to eliminate them. Despite the introduction of quality improvements, little is known about how nurses manage interruptions and distractions during medication administration or how they learn to do so. A significant gap in the literature exists in relation to innovative sustainable strategies that assist undergraduate nurses to learn how to safely and confidently manage interruptions in the clinical environment. CONCLUSIONS: Study findings highlight the need for further exploration into the way nurses learn to manage interruptions and distractions during medication administration. This is essential given the critical relationship between interruptions and medication error rates. RELEVANCE TO CLINICAL PRACTICE: Better preparing nurses to safely fulfil the task of medication administration in the clinical environment, with increased confidence in the face of interruptions, could lead to a reduction in errors and concomitant improvements to patient safety. PMID- 26255622 TI - Solvent dependent photosensitized singlet oxygen production from an Ir(III) complex: pointing to problems in studies of singlet-oxygen-mediated cell death. AB - A cationic cyclometallated Ir(III) complex with 1,10-phenanthroline and 2 phenylpyridine ligands photosensitizes the production of singlet oxygen, O2(a(1)Delta(g)), with yields that depend appreciably on the solvent. In water, the quantum yield of photosensitized O2(a(1)Delta(g)) production is small (phi(Delta) = 0.036 +/- 0.008), whereas in less polar solvents, the quantum yield is much larger (phi(Delta) = 0.54 +/- 0.05 in octan-1-ol). A solvent effect on phi(Delta) of this magnitude is rarely observed and, in this case, is attributed to charge-transfer-mediated processes of non-radiative excited state deactivation that are more pronounced in polar solvents and that kinetically compete with energy transfer to produce O2(a(1)Delta(g)). A key component of this non radiative deactivation process, electronic-to-vibrational energy transfer, is also manifested in pronounced H2O/D2O isotope effects that indicate appreciable coupling between the Ir(III) complex and water. This Ir(III) complex is readily incorporated into HeLa cells and, upon irradiation, is cytotoxic as a consequence of the O2(a(1)Delta(g)) thus produced. The data reported herein point to a pervasive problem in mechanistic studies of photosensitized O2(a(1)Delta(g)) mediated cell death: care must be exercised when interpreting the effective cytotoxicity of O2(a(1)Delta(g)) photosensitizers whose photophysical properties depend strongly on the local environment. Specifically, the photophysics of the sensitizer in bulk solutions may not accurately reflect its intracellular behavior, and the control and quantification of the O2(a(1)Delta(g)) "dose" can be difficult in vivo. PMID- 26255623 TI - Light-Induced Ion Rectification in Zigzag Nanochannels. AB - Ion transport through nanoporous systems has attracted broad interest due to its crucial role in physiological processes in living organisms and artificial bionic devices. In this work, a nanochannel system with a zigzag inner surface was fabricated by using a two-step anodizing technique. The rectification performance of the zigzag channels was observed by I-V measurement in KCl solution. Unlike channels with asymmetric geometry, the mechanism was analyzed based on the "point effect" of charge distribution and "shape effect" of the zigzag channel. The current rectification ratio decreases from nearly 3.0 to 1.0 when the KCl concentration increased from 0.1 mM to 100 mM. The fabrication of different nanopore systems and exploration of novel mechanisms will help to develop biomimetic membranes for practical applications. PMID- 26255624 TI - A Bayesian approach for characterization of soft tissue viscoelasticity in acoustic radiation force imaging. AB - Biomechanical imaging techniques based on acoustic radiation force (ARF) have been developed to characterize the viscoelasticity of soft tissue by measuring the motion excited by ARF non-invasively. The unknown stress distribution in the region of excitation limits an accurate inverse characterization of soft tissue viscoelasticity, and single degree-of-freedom simplified models have been applied to solve the inverse problem approximately. In this study, the ARF-induced creep imaging is employed to estimate the time constant of a Voigt viscoelastic tissue model, and an inverse finite element (FE) characterization procedure based on a Bayesian formulation is presented. The Bayesian approach aims to estimate a reasonable quantification of the probability distributions of soft tissue mechanical properties in the presence of measurement noise and model parameter uncertainty. Gaussian process metamodeling is applied to provide a fast statistical approximation based on a small number of computationally expensive FE model runs. Numerical simulation results demonstrate that the Bayesian approach provides an efficient and practical estimation of the probability distributions of time constant in the ARF-induced creep imaging. In a comparison study with the single degree of freedom models, the Bayesian approach with FE models improves the estimation results even in the presence of large uncertainty levels of the model parameters. PMID- 26255625 TI - Psoriasis flare with corticosteroid use in psoriatic arthritis. PMID- 26255626 TI - Point mutations of the mTOR-RHEB pathway in renal cell carcinoma. AB - Aberrations in the mTOR (mechanistic target of rapamycin) axis are frequently reported in cancer. Using publicly available tumor genome sequencing data, we identified several point mutations in MTOR and its upstream regulator RHEB (Ras homolog enriched in brain) in patients with clear cell renal cell carcinoma (ccRCC), the most common histology of kidney cancer. Interestingly, we found a prominent cluster of hyperactivating mutations in the FAT (FRAP-ATM-TTRAP) domain of mTOR in renal cell carcinoma that led to an increase in both mTORC1 and mTORC2 activities and led to an increased proliferation of cells. Several of the FAT domain mutants demonstrated a decreased binding of DEPTOR (DEP domain containing mTOR-interacting protein), while a subset of these mutations showed altered binding of the negative regulator PRAS40 (proline rich AKT substrate 40). We also identified a recurrent mutation in RHEB in ccRCC patients that leads to an increase in mTORC1 activity. In vitro characterization of this RHEB mutation revealed that this mutant showed considerable resistance to TSC2 (Tuberous Sclerosis 2) GAP (GTPase activating protein) activity, though its interaction with TSC2 remained unaltered. Mutations in the FAT domain of MTOR and in RHEB remained sensitive to rapamycin, though several of these mutations demonstrated residual mTOR kinase activity after treatment with rapamycin at clinically relevant doses. Overall, our data suggests that point mutations in the mTOR pathway may lead to downstream mTOR hyperactivation through multiple different mechanisms to confer a proliferative advantage to a tumor cell. PMID- 26255627 TI - Transcriptional profiling of interleukin-2-primed human adipose derived mesenchymal stem cells revealed dramatic changes in stem cells response imposed by replicative senescence. AB - Inflammation is a double-edged sword with both detrimental and beneficial consequences. Understanding of the mechanisms of crosstalk between the inflammatory milieu and human adult mesenchymal stem cells is an important basis for clinical efforts. Here, we investigate changes in the transcriptional response of human adipose-derived stem cells to physiologically relevant levels of IL-2 (IL-2 priming) upon replicative senescence. Our data suggest that replicative senescence might dramatically impede human mesenchymal stem cell (MSC) function via global transcriptional deregulation in response to IL-2. We uncovered a novel senescence-associated transcriptional signature in human adipose-derived MSCs hADSCs after exposure to pro-inflammatory environment: significant enhancement of the expression of the genes encoding potent growth factors and cytokines with anti-inflammatory and migration-promoting properties, as well as genes encoding angiogenic and anti-apoptotic promoting factors, all of which could participate in the establishment of a unique microenvironment. We observed transcriptional up-regulation of critical components of the nitric oxide synthase pathway (iNOS) in hADSCs upon replicative senescence suggesting, that senescent stem cells can acquire metastasis-promoting properties via stem cell mediated immunosuppression. Our study highlights the importance of age as a factor when designing cell-based or pharmacological therapies for older patients and predicts measurable biomarkers characteristic of an environment that is conducive to cancer cells invasiveness and metastasis. PMID- 26255628 TI - Elevated Th22 as well as Th17 cells associated with therapeutic outcome and clinical stage are potential targets in patients with multiple myeloma. AB - T helper (Th) cell imbalance plays important roles in tumor development and their effects in Multiple myeloma (MM) remain unclear. In the present study, we investigated the levels and clinical significance of Th22, Th17 and Th1 cells in patients with MM. Th subsets were examined by flow cytometry. Plasma IL-22, IL 17A and IFN-gamma concentrations were measured by ELISA. AHR and RORC mRNA expression was examined by RT-PCR. Here, we found that the frequency of Th22 cells was significantly elevated in peripheral blood (PB) and bone marrow (BM) of newly-diagnosed MM patients, and recovered in complete remission patients after chemotherapy. The circulating Th17 cells accompanied by IL-17A levels were also up-regulated in MM patients and decreased after remission. We also found that there was a significantly positive correlation between Th22 and Th17 cells in MM patients. Moreover, the frequencies of Th22 and Th17 cells were higher in stage III than in stage I+II of MM. Our data demonstrated that Th22 and Th17 cells might be important therapeutic targets in multiple myeloma and could facilitate the effect of antitumor immunotherapy. PMID- 26255630 TI - Independent mis-splicing mutations in TaPHS1 causing loss of preharvest sprouting (PHS) resistance during wheat domestication. AB - Preharvest sprouting (PHS) is one of the major constraints of wheat production in areas where prolonged rainfall occurs during harvest. TaPHS1 is a gene that regulates PHS resistance on chromosome 3A of wheat, and two causal mutations in the positions +646 and +666 of the TaPHS1 coding region result in wheat PHS susceptibility. Three competitive allele-specific PCR (KASP) markers were developed based on the two mutations in the coding region and one in the promoter region and validated in 82 wheat cultivars with known genotypes. These markers can be used to transfer TaPHS1 in breeding through marker-assisted selection. Screening of 327 accessions of wheat A genome progenitors using the three KASP markers identified different haplotypes in both diploid and tetraploid wheats. Only one Triticum monococcum accession, however, carries both causal mutations in the TaPHS1 coding region and shows PHS susceptibility. Five of 249 common wheat landraces collected from the Fertile Crescent and surrounding areas carried the mutation (C) in the promoter (-222), and one landrace carries both the causal mutations in the TaPHS1 coding region, indicating that the mis-splicing (+646) mutation occurred during common wheat domestication. PHS assay of wheat progenitor accessions demonstrated that the wild-types were highly PHS-resistant, whereas the domesticated type showed increased PHS susceptibility. The mis splicing TaPHS1 mutation for PHS susceptibility was involved in wheat domestication and might arise independently between T. monococcum and Triticum aestivum. PMID- 26255631 TI - Effect of Protein-Lipid-Salt Interactions on Sodium Availability in the Mouth and Consequent Perception of Saltiness: In Solutions. AB - The influence of protein-sodium interactions on the availability of sodium in the aqueous phase of liquid samples and consequently on the perception of saltiness was investigated. The aqueous effluents of casein and casein emulsion-salt solutions were monitored for sodium availability from a tongue column system. In the aqueous protein-salt solutions, increasing the protein/salt ratio from 1:1 to 5:1 or 10:1 significantly decreased the initial salt concentration in the effluent and resulted in a higher salt concentration in the effluent over time. Sensory analysis was in agreement. Samples with increased protein were rated as having significantly lower initial saltiness and a higher salty aftertaste. However, when casein was formulated as an emulsion, the initial release of sodium in the effluent was enhanced (compared to nonemulsified protein). Increasing the emulsion interfacial area (more hydrophilic segments of the protein were structured into the aqueous phase) resulted in a higher salt concentration in the aqueous phase and greater perceived saltiness intensity. In summary, protein interactions, specifically ionic, were reported as food interactions that influence salt perception and provide a basis to develop higher flavor quality low-sodium food products. PMID- 26255629 TI - Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice. AB - The tumour suppressor p53 is regulated primarily at the protein level. In normal tissues its levels are maintained at a very low level by the action of specific E3 ligases and the ubiquitin proteosome pathway. The mutant p53 protein contributes to transformation, metastasis and drug resistance. High levels of mutant p53 can be found in tumours and the accumulation of mutant p53 has previously been reported in pathologically normal cells in human skin. We show for the first time that similarly elevated levels of mutant p53 can be detected in apparently normal cells in a mutant p53 knock-in mouse model. In fact, in the small intestine, mutant p53 spontaneously accumulates in a manner dependent on gene dosage and cell type. Mutant p53 protein is regulated similarly to wild type p53, which can accumulate rapidly after induction by ionising radiation or Mdm2 inhibitors, however, the clearance of mutant p53 protein is much slower than wild type p53. The accumulation of the protein in the murine small intestine is limited to the cycling, crypt base columnar cells and proliferative zone and is lost as the cells differentiate and exit the cell cycle. Loss of Mdm2 results in even higher levels of p53 expression but p53 is still restricted to proliferating cells in the small intestine. Therefore, the small intestine of these p53 mutant mice is an experimental system in which we can dissect the molecular pathways leading to p53 accumulation, which has important implications for cancer prevention and therapy. PMID- 26255632 TI - HBV and HIV co-infection: Prevalence and clinical outcomes in tertiary care hospital Malaysia. AB - According to WHO, Malaysia has been classified as a concentrated epidemic country due to progression of HIV infection in the population of injecting drug users. The main objectives of current study are to determine the prevalence of HBV among HIV-positive individuals in a tertiary care hospital of Malaysia and to assess the predictors involved in the outcomes of HIV-HBV co-infected patients. A retrospective, cross-sectional study is conducted at Hospital Palau Pinang, Malaysia. The collection of socio-demographic data as well as clinical data is done with the help of data collection form. Data were analyzed after putting the collected values of required data by using statistical software SPSS version 20.0 and P > 0.05 is considered as significant. Results show that the overall prevalence of HBV was 86 (13%) including 495 (74.5%) males and 169 (25.5%) females among a total of 664 HIV-infected patients. It was observed that there is a high prevalence of HIV-HBV co-infection in males 76 (11.4%) as compared to females 10 (1.5%) (P = 0.002). The median age of the study population was 39 years. The statistical significant risk factors involved in the outcomes of HIV HBV co-infected patients were observed in the variables of gender, age groups, and injecting drug users. The findings of the present study shows that the prevalence of HBV infection among HIV-positive patients was 13% and the risk factors involved in the outcomes of HIV-HBV co-infected patients were gender, age, and intravenous drug users. PMID- 26255633 TI - Structure elucidation of a new isoflavone by exclusive use of 1H NMR measurements. AB - The leaves of Piscidia carthagenensis provided new 7,2',5'-trimethoxy-3',4' methylenedioxyisoflavone (1), admixed with known 6,7-dimethoxy-3',4' methylenedioxyisoflavone (2), and 5,4'-dihydroxy-7,2',5'-trimethoxyisoflavone (3), which were separated by extensive fractional solubillization. Selective irradiation of the H-5 "singlet" of 2 allowed distinction of the two methoxy group signals, whose chemical shift difference is only 0.004 ppm (1.2 Hz at 300 MHz). The (1)H and (13)C NMR data of 3 were assigned with the aid of HETCOR and gHMBC measurements. Although 1 looked inhomogeneous in the solid state, its solution structure followed from (1)H NMR measurements, where it looked homogeneous. To clarify the solid state aspect and confirm the structure of 1, two types of crystals were mechanically separated and subjected to single crystal X-ray diffraction measurements. This study revealed polymorphism because of the concomitant presence of orthorhombic and triclinic crystals, but showed no atropisomerism. The structure of 3 was also verified by X-ray diffraction crystallography. PMID- 26255634 TI - NF-kappaB Signaling is Involved in the Effects of Intranasally Engrafted Human Neural Stem Cells on Neurofunctional Improvements in Neonatal Rat Hypoxic Ischemic Encephalopathy. AB - AIM: Hypoxic-ischemic encephalopathy (HIE) is a common neurological disease in infants with persistent neurobehavioral impairments. Studies found that neural stem cell (NSC) therapy benefits HIE rats; however, the mechanisms underlying are still unclear. The current study investigated the efficacy and molecular events of human embryonic neural stem cells (hNSCs) in neonatal hypoxic-ischemic (HI) rats. METHODS: PKH-26-labeled hNSCs were intranasally delivered to P7 Sprague Dawley rats 24 h after HI. Neurobehavioral tests were performed at the indicated time after delivery: righting reflex and gait testing at D1, 3, 5, and 7; grid walking at D7 and 14; social choice test (SCT) at D28; and Morris water maze from D35 to 40. Protein expression was determined by Western blot analysis. Brain damage was assessed by cresyl violet staining and MBP staining. hNSC distribution and differentiation were observed by in vivo bioluminescence imaging and immunofluorescence staining. RESULTS: (1) hNSCs migrated extensively into brain areas within 24 h after the delivery, survived even at D42 with the majority in ipsi-hemisphere, and could be co-labeled with NeuN or GFAP. (2) hNSCs reduced the upregulation in cytosolic IL-1beta, p-IkappaBalpha, and NF-kappaB p65 levels, whereas enhanced nuclear p65 expression in HI rats at D3 after the delivery. (3) hNSCs decreased HI-induced brain tissue loss and white matter injury at D42 after the delivery. (4) hNSCs improved neurological outcomes in HI rats in the tests of righting reflex (within 3 days), gait (D5), grid (D7), SCT (D28), and water maze (D42). CONCLUSION: Intranasal delivery of hNSCs could prevent HI-induced brain injury and improve neurobehavioral outcomes in neonatal HI rats, which is possibly related to the modulation of NF-kappaB signaling. PMID- 26255635 TI - High inorganic phosphate concentration inhibits osteoclastogenesis by modulating miR-223. AB - Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a common complication of CKD, and uremic toxins have been shown to be instrumental in this process. We have previously shown that miR-223 is increased in smooth muscle cells subjected to the uremic toxin inorganic phosphate (Pi). In the present study we investigated the influence of this miRNA in osteoclastogenesis in order to elucidate its role in the course of CKD-MBD. RT-qPCR demonstrated that high Pi concentration decreased miR-223 expression in differentiated RAW 264.7 cells. Up- and down-regulation of miR-223 was performed using specific pre-miR and anti-miR 223. Differentiation of monocyte/macrophage precursors was assessed by using RAW 264.7 cells and peripheral blood mononuclear cells (PBMC). TRAP activity and bone resorption were used to measure osteoclast activity. Pi induced a marked decrease in osteoclastogenesis in RAW cells and miR-223 levels were concomitantly decreased. Anti-miR-223 treatment inhibited osteoclastogenesis in the same way as Pi. In contrast, overexpression of miR-223 triggered differentiation, as reflected by TRAP activity. We showed that miR-223 affected the expression of its target genes NFIA and RhoB, but also osteoclast marker genes and the Akt signalling pathway, which induces osteoclastogenesis. These results were confirmed by measuring bone resorption activity of human PBMC differentiated into osteoclasts. We thus demonstrate a role of miR-223 in osteoclast differentiation, with rational grounds to use deregulation of this miRNA to selectively increase osteoclast-like activity in calcified vessels of CKD-MBD. This approach could alleviate vascular calcification without altering bone structure. PMID- 26255636 TI - Moderation, mediation - or even both? School climate and the association between peer and adolescent alcohol use. AB - INTRODUCTION: Ample studies discuss the enhancing effects of peer drinking on student alcohol use. In addition, there is vast research on school climate impact on student alcohol use. Though these two areas are intertwined for most young adolescents, it is heretofore not completely clear, in what way these characteristics functionally interact and affect drinking behavior. METHODS: In a longitudinal study, we analyzed a sample of 2490 German adolescents (Mage=13.32, SD=0.57, range=8-13) from 5th (fall 2010) to 8th (fall 2013) grade. We discerned mediating (class climate) and moderating (school organization variables) functions of school on the association between peer and adolescent alcohol use, and finally combined them in direct effect moderated mediation models for a variety of outcomes (lifetime alcohol use, frequency and amount of drinking, binge drinking), adjusting for possible confounders. RESULTS: Class climate mediated a small significant part of the association between peer and adolescent alcohol use (1.8-2.4%), with the exception of lifetime drinking. Student-teacher ratio and percentage of at-risk students significantly moderated the peer adolescent association, with the latter having an enhancing and the first having a buffering effect. CONCLUSIONS: School life serves as an important context of adolescent development and as such, seems to have direct and indirect effects on behavior and health. Future research should pay attention to differentiating effects of school climate and include both forms of operationalization when analyzing school effects on student behavior. PMID- 26255637 TI - A confirmatory factor analysis of the Protective Behavioral Strategies Scale among OEF/OIF veterans. AB - INTRODUCTION: Military veterans of the wars in Afghanistan and Iraq (OEF/OIF/OND) are at-risk for increased alcohol consumption and alcohol-related consequences. The Protective Behavioral Strategies Scale (PBSS) has been shown to be a reliable and valid measure of assessing strategies to facilitate more responsible drinking and to reduce alcohol-related harm among college student populations. The purpose of this study was to examine the psychometric properties of the PBSS among the OEF/OIF veteran population. METHOD: Participants were 251 veterans (94% male; 83% White; M age=31.77years) who were participating in a larger alcohol intervention trial and reported consuming alcohol within the past 30days. RESULTS: Confirmatory Factor Analyses indicated the model fit of the PBSS was similar to college student samples. Although a confirmatory three-factor model best fits the data, model fit indices were slightly below commonly accepted guidelines. All PBSS subscales were negatively correlated with alcohol outcomes. Greater use of Manner of Drinking (MOD) and Stopping/Limiting Drinking (SLD) strategies were associated with less alcohol consumption and lower peak BAC. Greater use of MOD strategies was associated with less alcohol-related problems. CONCLUSIONS: Findings provide initial support for use of the PBSS among OEF/OIF veterans. Strategies aimed at Stopping/Limiting Drinking and the Manner of Drinking may be more effective with a veteran sample. Additional studies examining the external validity of this measure are encouraged. PMID- 26255638 TI - Correlates of other tobacco use in a community sample of young adults. AB - BACKGROUND: Young adult use of alternative nicotine and tobacco products (ANTPs) has increased dramatically since 2000. While recent studies address ANTP prevalence, relatively little is known about predictors of use. This secondary analysis examined demographic, personality, and other substance use factors as predictors of past month ANTP use. METHODS: Community participants (n=319; 51% female) completed an online survey during the initial stage of a larger study, for which all were required to have smoked cigarettes and consumed alcohol in the past month. The survey assessed demographics, impulsivity, and past-month frequency of cigarette, alcohol, and marijuana use. RESULTS: The majority (61%) of participants endorsed ANTP use in the past 30days. The odds of ANTP use were associated with Caucasian ethnicity, younger age, more frequent alcohol use, and with the sensation seeking and positive urgency components of impulsivity. CONCLUSION: These data suggest that ANTP use among young adults is a substantial problem, and that there is a need for interventions that target tobacco use generally rather than cigarette smoking only. PMID- 26255639 TI - An asymmetric alkynylation/hydrothiolation cascade: an enantioselective synthesis of thiazolidine-2-imines from imines, acetylenes and isothiocyanates. AB - A multicomponent reaction between imines, terminal alkynes, and isothiocyanates in the presence of a catalytic chiral copper-pybox complex proceeds enantioselectively to give enantiopure thiazolidine-2-imines (60-99% ee) via a highly regioselective intramolecular 5-exo-dig hydrothiolation reaction. PMID- 26255641 TI - First-Principles Analysis of Defect Thermodynamics and Ion Transport in Inorganic SEI Compounds: LiF and NaF. AB - The formation mechanism and composition of the solid electrolyte interphase (SEI) in lithium ion batteries has been widely explored. However, relatively little is known about the function of the SEI as a transport medium. Such critical information is directly relevant to battery rate performance, power loss, and capacity fading. To partially bridge this gap in the case of inorganic SEI compounds, we report herein the results of first-principles calculations on the defect thermodynamics, the dominant diffusion carriers, and the diffusion pathways associated with crystalline LiF and NaF, which are stable components of the SEI in Li-ion and Na-ion batteries, respectively. The thermodynamics of common point defects are computed, and the dominant diffusion carriers are determined over a voltage range of 0-4 V, corresponding to conditions relevant to both anode and cathode SEI's. Our analyses reveal that for both compounds, vacancy defects are energetically more favorable, therefore form more readily than interstitials, due to the close-packed nature of the crystal structures. However, the vacancy concentrations are very small for the diffusion processes facilitated by defects. Ionic conductivities are calculated as a function of voltage, considering the diffusion carrier concentration and the diffusion barriers as determined by nudged elastic band calculations. These conductivities are more than ten orders of magnitude smaller in NaF than in LiF. As compared to the diffusivity of Li in other common inorganic SEI compounds, such as Li2CO3 and Li2O, the cation diffusivity in LiF and NaF is quite low, with at least three orders of magnitude lower ionic conductivities. The results quantify the extent to which fluorides pose rate limitations in Li and Na batteries. PMID- 26255642 TI - Structure of nanochannel entrances in stopcock-functionalized zeolite L composites. AB - Multifunctional hybrid materials are obtained by modifying zeolite L (ZL) with stopcock molecules, consisting of a tail group that can enter the ZL nanochannels and a head group too large to pass the channel opening. However, to date no microscopic-level structural information on modified ZL materials has been reported. Herein we draw atomistic pictures of channel openings and stopcock functionalized ZL based on first-principles calculations. We elucidate the interactions of the tail group with the inner surface of ZL channels and the space-filling properties of the stopcocks, revealing cork- or lid-sealing modes. Water is essential to obtain stable modifications. Al?OH groups are the preferred modification sites, bipodal modifications suffer from strain, and tripod binding is ruled out. Our results suggest the viability of recursive functionalization by cross-linking. PMID- 26255640 TI - Neurology and psychiatry: waking up to opportunities of sleep. : State of the art and clinical/research priorities for the next decade. AB - In recent years, evidence has emerged for a bidirectional relationship between sleep and neurological and psychiatric disorders. First, sleep-wake disorders (SWDs) are very common and may be the first/main manifestation of underlying neurological and psychiatric disorders. Secondly, SWDs may represent an independent risk factor for neuropsychiatric morbidities. Thirdly, sleep-wake function (SWF) may influence the course and outcome of neurological and psychiatric disorders. This review summarizes the most important research and clinical findings in the fields of neuropsychiatric sleep and circadian research and medicine, and discusses the promise they bear for the next decade. The findings herein summarize discussions conducted in a workshop with 26 European experts in these fields, and formulate specific future priorities for clinical practice and translational research. More generally, the conclusion emerging from this workshop is the recognition of a tremendous opportunity offered by our knowledge of SWF and SWDs that has unfortunately not yet entered as an important key factor in clinical practice, particularly in Europe. Strengthening pre graduate and postgraduate teaching, creating academic multidisciplinary sleep wake centres and simplifying diagnostic approaches of SWDs coupled with targeted treatment strategies yield enormous clinical benefits for these diseases. PMID- 26255643 TI - The impact of effective paediatric adherence promotion interventions: systematic review and meta-analysis. AB - BACKGROUND: Understanding the impact of effective paediatric adherence promotion interventions on patients, families and the healthcare system is necessary to inform efforts to improve healthcare quality and control costs. Building on previous research suggesting that improving adherence may have far-reaching benefits, the objective of this study was to quantify the impact of effective adherence promotion interventions for children and adolescents with a chronic medical condition on patients, families and the healthcare system. METHODS: Authors systematically reviewed articles indexed in PubMed, PsycINFO and CINAHL to identify randomized controlled trials of paediatric adherence promotion interventions. Interventions that improved paediatric adherence and examined patient-level, family-level or healthcare system-level outcomes in children and adolescents (M age <= 18 years) with a chronic medical condition were included. Two authors independently extracted and classified outcome variables as patient level (quality of life and disease-related activity restrictions), micro-level (family functioning, family conflict, caregiver quality of life, caregiver sleep interruption, caregiver days away from work and patient missed school days) or macro-level variables (emergency department visits, hospitalizations, outpatient visits and urgent care visits). Outcome variables detailed in previously published reviews (i.e. disease severity) were excluded. RESULTS: Twenty studies representing 19 unique samples met inclusion criteria. An additional eight articles representing trials that did not significantly improve adherence were included in post hoc analyses. Compared with control interventions, effective paediatric adherence promotion interventions improved patient quality of life and family-level outcomes and decreased healthcare utilization among children and adolescents with a chronic medical condition. CONCLUSIONS: Interdisciplinary efforts to improve healthcare quality and reduce spending among children and adolescents with a chronic medical condition may be enhanced by incorporating effective paediatric adherence promotion interventions. As relatively few chronic medical conditions were represented in included studies, future research should examine the impact of paediatric adherence promotion interventions in other populations. PMID- 26255644 TI - Characterizing and Communicating Risk with Exposure Reconstruction and Bayesian Analysis: Historical Locomotive Maintenance/Repair Associated with Asbestos Woven Tape Pipe Lagging. AB - Our reconstructed historical work scenarios incorporating a vintage 1950s locomotive can assist in better understanding the historical asbestos exposures associated with past maintenance and repairs and fill a literature data gap. Air sampling data collected during the exposure scenarios and analyzed by NIOSH 7400 (PCM) and 7402 (PCME) methodologies show personal breathing zone asbestiform fiber exposures were below the current OSHA exposure limits for the eight-hour TWA permissible exposure limit (PEL) of 0.1 f/cc (range <0.007-0.064 PCME f/cc) and the 30-minute short-term excursion limit (EL) of 1.0 f/cc (range <0.045-0.32 PCME f/cc) and orders of magnitude below historic OSHA PEL and ACGIH TLVs. Bayesian decision analysis (BDA) results demonstrate that the 95th percentile point estimate falls into an AIHA exposure category 3 or 4 as compared to the current PEL and category 1 when compared to the historic PEL. BDA results demonstrate that bystander exposures would be classified as category 0. Our findings were also significantly below the published calcium magnesium insulations exposure range of 2.5 to 7.5 f/cc reported for historic work activities of pipefitters, mechanics, and boilermakers. Diesel-electric locomotive pipe systems were typically insulated with a woven tape lagging that may have been chrysotile asbestos and handled, removed, and reinstalled during repair and maintenance activities. We reconstructed historical work scenarios containing asbestos woven tape pipe lagging that have not been characterized in the published literature. The historical work scenarios were conducted by a retired railroad pipefitter with 37 years of experience working with materials and locomotives. PMID- 26255645 TI - Effect of starch source (corn, oats or wheat) and concentration on fermentation by equine faecal microbiota in vitro. AB - AIMS: The goal was to determine the effect of starch source (corn, oats and wheat) and concentration on: (i) total amylolytic bacteria, Group D Gram-positive cocci (GPC), lactobacilli and lactate-utilizing bacteria, and (ii) fermentation by equine microbiota. METHODS AND RESULTS: When faecal washed cell suspensions were incubated with any substrate amylolytics increased over time. However, at 24 h there were 10 and 1000-fold more amylolytics with corn than wheat or oats respectively. Predominant amylolytics isolated were Enterococcus faecalis (corn, wheat) and Streptococcus bovis (oats). GPC increased with any substrate, but decreased during stationary phase in oats only. Lactobacilli decreased during stationary phase with corn only. By 24 h, oats had more lactate-utilizers and lactobacilli and fewer GPC than corn and wheat. More gas was produced from oats or wheat than from corn. CONCLUSIONS: These results indicate that the growth of bacteria and fermentative capacity associated with starch metabolism is starch source dependent. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates a relationship between starch source and microbial changes independent of host digestion. However, future research is needed to evaluate the effect of starch source on the hindgut microbial community in vivo. PMID- 26255646 TI - Transcatheter closure of ruptured sinus of Valsalva: Different techniques and mid term follow-up. AB - OBJECTIVES: The aim of the present study was to study the feasibility and approaches to device closure of ruptured sinus of Valsalva (RSOV). We have compared the advantages and disadvantages of different devices and techniques and discussed complications which might occur during or after the procedure. BACKGROUND: There are only a few case series of transcatheter closure of RSOV, with most cases being traditionally referred for surgery. We have employed different devices used for treatment of congenital shunt lesions to achieve closure. Reasons for failure and need for surgical referral have also been analyzed. METHODS: Transcatheter closure was attempted in a total of 25 patients of RSOV who presented to us over a period of 4 years. Different devices were deployed using antegrade and retrograde approaches. All patients have been on regular follow-up. RESULTS: The procedural success rate was 84%. Two patients presenting in cardiogenic shock were effectively treated by device closure. There was one case of device embolization and two patients had residual leak. Three patients were referred for surgery. There was one case of device induced severe aortic regurgitation. Ventricular septal defect and RSOV were closed simultaneously in one patient. CONCLUSIONS: Different approaches and devices may be used for transcatheter closure of RSOV. We prefer antegrade closure using duct occluders in most cases while muscular VSD occluders may be used in select situations. ADO II devices should hardly ever be used on their own for device closure of RSOV. PMID- 26255647 TI - A cystine-knot miniprotein from tomato fruit inhibits endothelial cell migration and angiogenesis by affecting vascular endothelial growth factor receptor (VEGFR) activation and nitric oxide production. AB - SCOPE: Cystine-knot miniproteins are bioactive molecules with a broad range of potential therapeutic applications. Recently, it was demonstrated that two tomato cystine-knot miniproteins (TCMPs) exhibit in vitro antiangiogenic activity on human umbilical vein cells. The aim of the present study was to investigate the effects of a fruit-specific cystine-knot miniprotein of tomato on in vitro endothelial cell migration and in vivo angiogenesis using a zebrafish model. METHODS AND RESULTS: The cystine-knot protein purified from tomato fruits using gel filtration LC and RP-HPLC inhibited cell migration when tested at 200 nM using the wound healing assay, and reduced nitric oxide formation probed by 4 amino-5-methylamino-27-difluorofluoscescin diacetate. RT-PCR and Western blot analyses demonstrated that vascular endothelium growth factor A dependent signaling was the target of TCMP bioactivity. Angiogenesis was inhibited in vivo in zebrafish embryos treated with 500 nM TCMP. CONCLUSION: Our results demonstrate that cystine-knot miniproteins present in mature tomato fruits are endowed with antiangiogenic activity in vitro and in vivo. These molecules may confer beneficial effects to tomato dietary intake, along with lycopene and other antioxidants. Further investigation is warranted to explore the potential of these compounds as model scaffolds for the development of new drugs. PMID- 26255648 TI - Metabolic reprogramming of the tumour microenvironment. AB - Tumour cells, stromal cells and the stroma comprise the tumour microenvironment. The metabolism of both tumour cells and several types of tumour stromal cells, such as cancer-associated fibroblasts and tumour-associated macrophages, is reprogrammed. Current studies have found that stromal cells promote tumour progression and metastasis, through not only the paracrine secretion of cytokines or chemokines, but also intermediate metabolites. Here, we summarize the latest insights into the mechanism of metabolic reprogramming in cancer cells, cancer associated fibroblasts and tumour-associated macrophages, and their potential roles in tumour progression and metastasis. PMID- 26255650 TI - Association between obesity and vitamin D deficiency. PMID- 26255649 TI - Analysis of nitromethane from samples exposed in vitro to chloropicrin by stable isotope dilution headspace gas chromatography with mass spectrometry. AB - Chloropicrin (trichloronitromethane) is a widely used soil fumigant and an old chemical warfare agent. The metabolism of chloropicrin is not well known in mammals but nitromethane has been shown to be one of its main metabolites. Here, a fast and simple headspace gas chromatography with mass spectrometry method was applied for the measurement of nitromethane from aqueous samples. The analytical method was validated using stable isotope labeled internal standard and a small sample volume of 260 MUL. No conventional sample preparation steps were needed. The method was accurate (relative standard deviations <=1.5%) and linear (R(2) = 0.9996) within the concentration range of 0.1-6.0 MUg/mL. This method was used to measure nitromethane in in vitro incubations with human and pig liver cell fractions containing enzymes for xenobiotic metabolism, exposed to chloropicrin. The results indicate that the presence of glutathione is necessary for the formation of nitromethane from chloropicrin. Also, nitromethane was formed mostly in liver cytosol fractions, but not in microsomal fractions after the incubation with chloropicrin. Our results suggest that although nitromethane is not the unequivocal biomarker of chloropicrin exposure, this method could be applied for screening the elevated levels in humans after chloropicrin exposure. PMID- 26255651 TI - Luciano Pavarotti (1935-2007). PMID- 26255652 TI - Comparable survival outcome of metastatic colorectal cancer in Indigenous and non Indigenous patients: Retrospective analysis of the South Australian metastatic colorectal cancer registry. AB - OBJECTIVE: This study aims to investigate disparities in demographics, disease characteristics, treatment and overall survival between South Australian (SA) Indigenous and non-Indigenous patients with metastatic colorectal cancer (mCRC). DESIGN: This employs a retrospective population study using the SA mCRC registry. SETTING: The SA mCRC registry identifies mCRC patients from hospital encounters, histopathology reports, medical oncology letters, clinician notification, attendances at multidisciplinary meetings and death audits by the SA Cancer Registry. PARTICIPANTS: A total of 2865 adult mCRC patients including 14 Indigenous patients were identified through the SA mCRC registry between February 2006 and August 2013. Patients were linked to the SA Cancer Registry to obtain Indigenous status. MAIN OUTCOME MEASURES: Demographic, disease and treatment characteristics were compared using Chi-squared test and t-test; while overall survival defined as time to any cause of death was analysed using Cox regression. RESULTS: No difference was observed for clinical characteristics, except for a higher proportion of Indigenous patients receiving chemotherapy (85.7% versus 58.5%; P = 0.04). The rate of liver surgery was similar across the two groups (21.0% versus 15.1%; P = 0.40). The median overall survivals were equivalent (11.9 months versus 15.1 months; hazard ratio = 1.00; 95% confidence interval for hazard ratio, 0.54-1.86). CONCLUSIONS: Clinical characteristics and survival outcomes were similar between Indigenous and non-Indigenous patients captured on the SA mCRC registry, and outcome of those who have an access to comprehensive cancer care appeared independent of Indigenous status and in line with large clinical trials. Underestimation of Indigenous cases due to their lower utilisation of cancer service could not be excluded and ultimately the accurate reporting of these patients is crucial. PMID- 26255655 TI - Graphene Quantum Dots Doping of MoS2 Monolayers. AB - Graphene quantum dots (GQDs) interacting with molybdenum disulfide (MoS2 ) monolayers induce an effective photoexcited charge transfer at the interface. Both the photoluminescence (PL) and valley polarization of this GQDs/MoS2 heterostructure can be modulated under various doping charge densities. The photon-exciton interaction is used to explain and calculate the heterostructure PL control, and is further applied to the valley-polarization tuning. PMID- 26255657 TI - Levels of Visual Stress in Proficient Readers: Effects of Spectral Filtering of Fluorescent Lighting on Reading Discomfort. AB - Visual stress (VS) affects reading in 5-12% of the general population and 31-36% of children with reading disorders. Symptoms include print distortions and visual discomfort when reading, and are exacerbated by fluorescent lighting. Prior research has indicated that VS can also affect proficient readers. We therefore examined levels of visual discomfort in a group of expert readers (n = 24) under both standard and spectrally-filtered fluorescent lighting. Participants rated their awareness of six symptoms of VS under each lighting condition. Under the standard condition, 4(16.7%) of the group recorded moderate to high levels of VS. Differences in symptom levels and reading speed between conditions were analysed using the Wilcoxon Signed Rank Test. Under the filter condition, the group reported less discomfort regarding all six symptoms of VS surveyed. The differences were significant with respect to three of the symptoms (p = .029 - p < .001), with a medium effect size in all of them (r = .31 - r = .46) and total score (p = .007; r = .39). Variations in reading proficiency included significantly fewer self-corrections (p = .019) and total errors (p = .004). Here we present evidence that VS-type symptoms of reading discomfort are not confined to populations with reading difficulties and may also occur in proficient readers, and that simple adaptations to fluorescent lighting may alleviate such symptoms. PMID- 26255656 TI - Evolution of the major discoveries in electrocardiology. PMID- 26255654 TI - How oocytes try to get it right: spindle checkpoint control in meiosis. AB - The generation of a viable, diploid organism depends on the formation of haploid gametes, oocytes, and spermatocytes, with the correct number of chromosomes. Halving the genome requires the execution of two consecutive specialized cell divisions named meiosis I and II. Unfortunately, and in contrast to male meiosis, chromosome segregation in oocytes is error prone, with human oocytes being extraordinarily "meiotically challenged". Aneuploid oocytes, that are with the wrong number of chromosomes, give rise to aneuploid embryos when fertilized. In humans, most aneuploidies are lethal and result in spontaneous abortions. However, some trisomies survive to birth or even adulthood, such as the well known trisomy 21, which gives rise to Down syndrome (Nagaoka et al. in Nat Rev Genet 13:493-504, 2012). A staggering 20-25 % of oocytes ready to be fertilized are aneuploid in humans. If this were not bad enough, there is an additional increase in meiotic missegregations as women get closer to menopause. A woman above 40 has a risk of more than 30 % of getting pregnant with a trisomic child. Worse still, in industrialized western societies, child birth is delayed, with women getting their first child later in life than ever. This trend has led to an increase of trisomic pregnancies by 70 % in the last 30 years (Nagaoka et al. in Nat Rev Genet 13:493-504, 2012; Schmidt et al. in Hum Reprod Update 18:29-43, 2012). To understand why errors occur so frequently during the meiotic divisions in oocytes, we review here the molecular mechanisms at works to control chromosome segregation during meiosis. An important mitotic control mechanism, namely the spindle assembly checkpoint or SAC, has been adapted to the special requirements of the meiotic divisions, and this review will focus on our current knowledge of SAC control in mammalian oocytes. Knowledge on how chromosome segregation is controlled in mammalian oocytes may help to identify risk factors important for questions related to human reproductive health. PMID- 26255658 TI - Cocaine Base Identification and Quantification. AB - Cocaine free base (cocaine base) identification and quantification are not trivial matters as they may appear to those who are experienced with the analysis of cocaine samples. The presence of adulterants in most cases often causes the interconversion problem, which changes the compositions of cocaine base and cocaine salt in the sample. This problem may be avoided by a purification procedure which can be applied to mixtures of cocaine and most common adulterants. This procedure is based on differences in dissociation constants (pKa) among the components of the mixture. Since the infra-red (IR) spectra of cocaine base and the hydrochloride forms are significantly different, IR procedure is the most suitable method for cocaine base identification. A method for quantification of the components of a mixture of bases and hydrochloride forms of cocaine and adulterants is also reviewed. PMID- 26255659 TI - Cocaine Profiling Methodology - Recent Advancesk. AB - The rationale for developing cocaine profiling methodology is described. Current cocaine signature procedures in use at the U.S. Drug Enforcement Administration's Special Testing and Research Laboratory are reviewed. Newer selective and sensitive methodology, recently developed, is described. That methodology detects more alkaloidal impurities in refined illicit cocaine than heretofore reported. The alkaloidal impurities were isolated from the bulk cocaine matrix by alumina column chromatography and detected using capillary gas chromatography-mass selective detection in the selected ion mode. Fifty-one refined illicit cocaine samples were subjected to this methodology for the determination of 15 selected alkaloids. Reproducibility data are reported. Methodology for the isolation, detection, and characterization of coca alkaloids in South American coca leaf, a commercial coca-leaf extract, and a large seizure of refined illicit cocaine is reviewed. PMID- 26255660 TI - Integrity of Urine Specimens for Toxicological Analysis - Adulteration, Mechanisms of Action, and Laboratory Detection. AB - Drug testing in urine for employees is an important deterrent for drug abuse. Because of the dire consequences of a positive result, many individuals who might otherwise test positive will go to great lengths to escape detection. The term "adulteration" in this context refers to: substitution of drug-free urine, purposeful ingestion of agents or fluids designed to either accelerate drug clearance or dilute urine such that drug concentrations are below administrative cutoffs (in vivo adulterants), and adding foreign substances after urine collection (in vitro adulterants) to interfere with drug assays (immunoassay screening and gas chromatography/mass spectrometry confirmation). For immunoassays, adulterants can interfere photometrically or alter antibody-antigen binding. For GC/MS analysis, in vitro adulterants can chemically alter the targeted drug to an undetectable derivative. The laboratory must use different schemes to detect adulterants, including physical observations and tests (e.g., color, odor, and pH), and chemical analyses (e.g., creatinine or glutaraldehyde). If the identity of the donated urine sample itself is in question, DNA tests can be performed. The laboratory must continue to develop new adulteration detection schemes as new adulterants are encountered. PMID- 26255661 TI - Detection of fuel release in a nuclear accident: a method for preconcentration and isolation of reactor-borne (239)Np using ion-specific extraction chromatography. AB - Although actinides are the most informative elements with respect to the nature of a nuclear accident, plutonium analysis is complicated by the background created by fallout from atmospheric nuclear explosions. Therefore, we propose (239)Np, a short-lived actinide that emits several gamma rays, as a preferred proxy. The aim of this study was to screen ion specific extraction chromatography resins (RE-, TEVA-, UTEVA-, TRU-, and Actinide-Resin) for the highest possible recovery and separation of trace amounts of (239)Np from samples with large activities of fission products such as radiocesium, radioiodine, and, most importantly, radiotellurium, the latter of which causes spectral interference in gamma spectrometry through overlapping peaks with (239)Np. The investigated environmental media for these separations were aqueous solutions simulating rainwater and soil. Spiked samples containing (239)Np and the aforementioned volatile radionuclides were separated through extraction chromatographic columns to ascertain the most effective means of separating (239)Np from other fission products for detection by gamma spectroscopy. We propose a method for nuclear accident preparedness based on the use of Eichrom's RE-Resin. The proposed method was found most effective for isolating (239)Np from interfering radionuclides in both aqueous solution and soil using 8 M HNO3 as the loading solution and H2O as the eluent. The RE-Resin outperforms the more commonly used TEVA-Resin because the TEVA-Resin showed a higher affinity for interfering radiotellurium and radioiodine. PMID- 26255662 TI - Quality of Life and Influential Factors in Patients Implanted With a Left Ventricular Assist Device. AB - BACKGROUND: Improving quality of life (QOL) has become an important goal in left ventricular assist device (LVAD) therapy. We aimed (1) to assess the effect of an implantable LVAD on patients' QOL, (2) to compare LVAD patients' QOL to that of patients in different stages of heart failure (HF), and (3) to identify factors associated with patients' QOL. METHODS AND RESULTS: The QOL of 33 Japanese implantable LVAD patients was assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and Short-form 8 (SF-8), before and at 3 and 6 months afterwards. After LVAD implantation, QOL significantly improved [MLHFQ, SF 8 physical component score (PCS), SF-8 mental component score (MCS), all P<0.05]. Implanted LVAD patients had a better QOL than extracorporeal LVAD patients (n=33, 32.1+/-21.9 vs. n=17, 47.6+/-18.2), and Stage D HF patients (n=32, 51.1+/-17.3), but the score was comparable to that of patients who had undergone a heart transplant (n=13). In multiple regression analyses, postoperative lower albumin concentration and right ventricular failure were independently associated with poorer PCS. Female sex and postoperative anxiety were 2 of the independent factors for poorer MCS (all P<0.05). CONCLUSIONS: Having an implantable LVAD improves patients' QOL, which is better than that of patients with an extracorporeal LVAD. Both clinical and psychological factors are influence QOL after LVAD implantation. PMID- 26255663 TI - Is the Prevalence of Patent Foramen Ovale in Japanese Truly Low? PMID- 26255664 TI - Identification and characterization of a novel CYP2C9 allelic variant in a warfarin-sensitive patient. AB - AIM: To determine the genetic basis of the low warfarin dose requirement in a Chinese patient. MATERIALS & METHODS: Bi-directional sequencing of CYP2C9, VKORC1 and CYP4F2 genes was performed. CYP2C9 variants were highly expressed in yeast and insect-cell microsomes. Three typical CYP2C9 probe drugs were used to evaluate the catalytic activity. RESULTS: A novel missense mutation (1400 T>C) was identified in CYP2C9 and had been named as new allele *60. When expressed in yeast and insect cells, compared with wild-type enzyme, variant CYP2C9.60 exhibited lower protein expression capacity and showed significantly decreased metabolic activities for the hydroxylation of S-warfarin, tolbutamide and diclofenac. CONCLUSION: The novel mutation can greatly decrease the enzymatic activity of the CYP2C9 enzyme both in vitro and in vivo. PMID- 26255666 TI - Foot-flat period estimation during daily living situations of asymptomatic and lower limb amputee subjects. PMID- 26255667 TI - Effects of competition on the sleep patterns of elite rugby union players. AB - No published research has assessed sleep patterns of elite rugby union players following match-play. The present study examined sleep patterns of professional rugby union players, prior and post-match-play, to assess the influence of competition. Twenty-eight male rugby union players (24.4 +/- 2.9 years, 103.9 +/- 12.2 kg) competed in one of four competitive home matches. Player's sleep behaviours were monitored continuously using an Actiwatch(r) from two days before the match, until three days post-match. Repeated measures of analysis of variance (ANOVA) showed significant differences across the time points measured for time to bed (F = 26.425, eta(2) = 0.495, p < .001), get up time (F = 21.175, eta(2) = 0.440, p < .001), time spent in bed (F = 10.669, eta(2) = 0.283, p < .001), time asleep (F = 8.752, eta(2) = 0.245, p < .001) and percentage of time moving (F = 4.602, eta(2) = 0.146 p < .05). Most notable, post hocs revealed a significant increase for time in bed the night before the match (p < .01; 95% CI = 0 : 10-1 : 28 h; 9.7 +/- 13.5%) compared with the reference night sleep. Furthermore, time asleep significantly decreased post-match (p < .05; 95% CI = -0:03 to -1:59 h; 19.5 +/- 19.8%) compared to two nights pre-match. Across all time points, sleep latency and efficiency for most players were considered abnormal compared to that expected in normal populations. The results demonstrate that sleep that is deprived post-match may have detrimental effects on the recovery process. PMID- 26255668 TI - Effect of Protein-Lipid-Salt Interactions on Sodium Availability in the Mouth and Consequent Perception of Saltiness: As Affected by Hydration in Powders. AB - There is a broad need to reformulate lower sodium food products without affecting their original taste. The present study focuses on characterizing the role of protein-salt interactions on the salt release in low-moisture systems and saltiness perception during hydration. Sodium release from freeze-dried protein powders and emulsion powders formulated at different protein/lipid ratios (5:0 to 1:4) were characterized using a chromatography column modified with a porcine tongue. Emulsion systems with protein structured at the interface were found to have faster initial sodium release rates and faster hydration and were perceived to have a higher initial salt intensity with a lower salty aftertaste. In summary, exposure of the hydrophilic segments of the interface-structured proteins in emulsions was suggested to facilitate hydration and release of sodium during dissolution of low-moisture powder samples. PMID- 26255669 TI - Trafficking of lymphocytes into the CNS. PMID- 26255670 TI - Closing in on life: proximity dependent methods for life sciences. PMID- 26255671 TI - Regnase-1 and Roquin regulate inflammatory mRNAs. PMID- 26255672 TI - A Novel Platinum-based Compound with Preferential Cytotoxic Activity against a Panel of Cancer Cell Lines AB - PURPOSE: Cisplatin as a platinum (Pt)-based chemotherapeutic compound is commonly applied for the treatment of several types of cancer. Nonetheless, drug resistance and severe adverse effects have been observed upon using cisplatin. Here, we have explored the cytotoxicity of novel Pt-based compounds on several cancer cell lines. METHODS: Five synthetic Pt compounds as well as cisplatin were investigated by XTT assay to determine their cytotoxicity against cell lines originated from prostate, ovary, and breast cancers at different time periods at various concentrations. Additionally, the apoptosis rate in cell lines was determined using flow cytometry. Binding to DNA was investigated through spectrophotometric and viscometric studies. RESULTS: With the exception of one compound, all of the Pt-complexes effectively killed the prostate cancer cell lines (i.e. PC-3 and DU 145). One compound, [Pt(2,2'- dipyridylamine)Cl4].DMF, was chosen as the most potent compound due to its high selective cytotoxic activity and its cytotoxicity was further tested and compared with that of cisplatin on SKOV-3, Caov-4, MDA-MB-231, and MCF7 cell lines. [Pt(2,2' dipyridylamine)Cl4].DMF had a higher selective cytotoxic capacity in comparison with cisplatin at higher concentrations and longer culture periods. Furthermore, as related to apoptosis induction, treatment with [Pt(2,2'-dipyridylamine)Cl4 ].DMF was significantly more effective than that of cisplatin in five out of six examined cell lines. [Pt(2,2'-dipyridylamine)Cl4].DMF was shown to intercalate into DNA. CONCLUSIONS: The current study introduced a novel Pt-based complex with highly selective and potent in vitro anti-tumor impacts superior to those of cisplatin, a conventional chemotherapeutic agent. [Pt (2,2' dipyridylamine)Cl4].DMF could be regarded as a promising anti-tumor agent in future investigations. PMID- 26255673 TI - Paclitaxel Loaded Nanoliposomes in Thermosensitive Hydrogel: A Dual Approach for Sustained and Localized Delivery. AB - In an attempt to improve the localized paclitaxel delivery, carrier based thermoresponsive chitosan hydrogel was exploited in the present study. Nanoliposomes as carrier for paclitaxel were prepared and optimized in strength of 6 mg/ml similar to marketed paclitaxel formulation. The chitosan solution (2% w/v) mixed with different concentrations of dibasic sodium phosphate (DSP) was evaluated as thermoresponsive systems in terms of gelling temperature and time. Finally, the drug loaded nanoliposomes were incorporated in optimized chitosan- DSP hydrogel base to form nanoliposomal in situ thermosensitive hydrogel formulations having dual mechanism of protection and release. The optimal formulation containing DSP was selected on the basis of minimal gelation temperature (37+/-0.8 oC) and time (6.7+/-0.3 min). In vitro drug release experiment illustrated that developed formulation manifested sustained release action in which drug release was extended for more than 72 h compared to marketed formulation. In addition, optimized nanoliposomal hydrogel demonstrated enhanced biological half-life of 15.7+/-1.5h, depicting maintenance of constant plasma concentration in contrast to marketed formulation that showed the half-life (t1/2) of 3.6+/-0.4h. The in vivo anti tumor activity tested using EAC model also corroborated the above findings that developed formulation was having significant higher anti-tumor activity and reduced toxicity than the marketed formulation. Tumor volume was found to reduce upto 89.1+/-3.5% by treatment with in situ hydrogel formulation. The histopathological study of tumor also demonstrated the better safety and efficacy of developed formulation in comparison to marketed paclitaxel formulation. Our results suggest that carrier based chitosan hydrogel could be an efficacious vehicle for sustained and localized delivery of paclitaxel. PMID- 26255674 TI - Position of Proline Mediates the Reactivity of S-Palmitoylation. AB - Palmitoylation, a post-translational modification in which a saturated 16-carbon chain is added predominantly to a cysteine residue, participates in various biological functions. The position of proline relative to other residues being post-translationally modified has been previously reported as being important. We determined that proline is statistically enriched around cysteines known to be S palmitoylated. The goal of this work was to determine how the position of proline influences the palmitoylation of the cysteine residue. We established a mass spectrometry-based approach to investigate time- and temperature-dependent kinetics of autopalmitoylation in vitro and to derive the thermodynamic parameters of the transition state associated with palmitoylation; to the best of our knowledge, our work is the first to study the kinetics and activation properties of the palmitoylation process. We then used these thermochemical parameters to determine if the position of proline relative to the modified cysteine is important for palmitoylation. Our results show that peptides with proline at the -1 position of cysteine in their sequence (PC) have lower enthalpic barriers and higher entropic barriers in comparison to the same peptides with proline at the +1 position of cysteine (CP); interestingly, the free-energy barriers for both pairs are almost identical. Molecular dynamics studies demonstrate that the flexibility of the cysteine backbone in the PC containing peptide when compared to the CP-containing peptide explains the increased entropic barrier and decreased enthalpic barrier observed experimentally. PMID- 26255675 TI - Dissociable cerebellar activity during spatial navigation and visual memory in bilateral vestibular failure. AB - OBJECTIVE: Spatial orientation and navigation depends on information from the vestibular system. Previous work suggested impaired spatial navigation in patients with bilateral vestibular failure (BVF). The aim of this study was to investigate event-related brain activity by functional magnetic resonance imaging (fMRI) during spatial navigation and visual memory tasks in BVF patients. METHODS: Twenty-three BVF patients and healthy age- and gender matched control subjects performed learning sessions of spatial navigation by watching short films taking them through various streets from a driver's perspective along a route to the Cathedral of Cologne using virtual reality videos (adopted and modified from Google Earth). In the scanner, participants were asked to respond to questions testing for visual memory or spatial navigation while they viewed short video clips. From a similar but not identical perspective depicted video frames of routes were displayed which they had previously seen or which were completely novel to them. RESULTS: Compared with controls, posterior cerebellar activity in BVF patients was higher during spatial navigation than during visual memory tasks, in the absence of performance differences. This cerebellar activity correlated with disease duration. CONCLUSIONS: Cerebellar activity during spatial navigation in BVF patients may reflect increased non-vestibular efforts to counteract the development of spatial navigation deficits in BVF. Conceivably, cerebellar activity indicates a change in navigational strategy of BVF patients, i.e. from a more allocentric, landmark or place-based strategy (hippocampus) to a more sequence-based strategy. This interpretation would be in accord with recent evidence for a cerebellar role in sequence-based navigation. PMID- 26255676 TI - Comparative evaluation of in vitro and in vivo high glucose-induced alterations in voltage-gated tetrodotoxin-resistant sodium channel: Effects attenuated by sodium channel blockers. AB - Glucose uptake in neurons depends on their cellular/physiological activity and the extracellular concentration of glucose around the cell. High concentration of extra-cellular glucose, as under hyperglycemic conditions or pathological condition in diabetes, may persist for extended periods of time in neurons and trigger cellular damage by altering voltage-gated sodium channels (VGSCs), the exact mechanism of which remains unclear. Therefore, we hypothesized that high glucose may directly affect kinetics of the VGSCs in the dorsal root ganglion (DRG) neurons. DRG neurons were exposed to normal glucose (NG: 5.5 mM) and high glucose (HG: 30 mM) for 24 h. In another set of experiments, diabetic DRG neurons were also isolated from streptozotocin-induced diabetic rats. Effects of sodium channel blockers on nociceptive parameters and tetrodotoxin-resistant (TTX-R) Na(+) channel kinetics were elucidated by whole-cell patch-clamp in HG exposure and diabetes-induced rat DRG neurons. HG exposure and diabetes-induced DRG neurons demonstrated significant increase in TTX-R Na(+) current (INa) densities in comparison to the control. Both HG-exposed and diabetic DRG neurons demonstrated similar biophysical characteristics of INa. Lidocaine and tetracaine significantly decreased TTX-R INa density in a concentration- and voltage dependent manner. Steady-state fast inactivation of INa was shifted in the hyperpolarizing direction whereas voltage-dependent activation was shifted in the rightward direction. Diabetic rats treated with lidocaine and tetracaine (3 mg/kg, i.p.) significantly improved thermal hyperalgesia, mechanical allodynia and motor nerve conduction velocity with a significant inhibition of TTX-R INa density as compared to the diabetic control. These results suggest that HG exposure increases the TTX-R Na(+) channel activity sensitive to Na(+) channel blockers, lidocaine and tetracaine. PMID- 26255677 TI - Distinguishing adaptive plasticity from vulnerability in the aging hippocampus. AB - Hippocampal circuits are among the best described networks in the mammalian brain, particularly with regard to the alterations that arise during normal aging. Decades of research indicate multiple points of vulnerability in aging neural circuits, and it has been proposed that each of these changes make a contribution to observed age-related cognitive deficits. Another view has been relatively overlooked - namely that some of these changes arise in adaptive response to protect network function in aged animals. This possibility leads to a rather different view on the biological variation of function in the brain of older individuals. Using the hippocampus as a model neural circuit we discuss how, in normally aged animals, some age-related changes may arise through processes of neural plasticity that serve to enhance network function rather than to hinder it. Conceptually disentangling the initial age-related vulnerabilities from changes that result in adaptive response will be a major challenge for the future research on brain aging. We suggest that a reformulation of how normal aging could be understood from an adaptive perspective will lead to a deeper understanding of the secrets behind successful brain aging and our recent cultural successes in facilitating these processes. PMID- 26255678 TI - Muscle imaging in patients with tubular aggregate myopathy caused by mutations in STIM1. AB - Tubular aggregate myopathy is a genetically heterogeneous disease characterized by tubular aggregates as the hallmark on muscle biopsy. Mutations in STIM1 have recently been identified as one genetic cause in a number of tubular aggregate myopathy cases. To characterize the pattern of muscle involvement in this disease, upper and lower girdles and lower limbs were imaged in five patients with mutations in STIM1, and the scans were compared with two patients with tubular aggregate myopathy not caused by mutations in STIM1. A common pattern of involvement was found in STIM1-mutated patients, although with variable extent and severity of lesions. In the upper girdle, the subscapularis muscle was invariably affected. In the lower limbs, all the patients showed a consistent involvement of the flexor hallucis longus, which is very rarely affected in other muscle diseases, and a diffuse involvement of thigh and posterior leg with sparing of gracilis, tibialis anterior and, to a lesser extent, short head of biceps femoris. Mutations in STIM1 are associated with a homogeneous involvement on imaging despite variable clinical features. Muscle imaging can be useful in identifying STIM1-mutated patients especially among other forms of tubular aggregate myopathy. PMID- 26255680 TI - Determinants of future cardiovascular health in women with a history of preeclampsia. AB - Women who develop preeclampsia have an increased risk of cardiovascular disease (CVD) later in life. However, current guidelines on cardiovascular risk assessment and prevention are unclear on how and when to screen these women postpartum, and about the role of a positive history of preeclampsia in later life CVD risk management. The aim of this review is to discuss the present knowledge on commonly used cardiovascular screening modalities available to women with a history of preeclampsia, and to discuss recent developments in early detection of CVD using cardiovascular imaging. Furthermore, we explore how female specific risk factors may have additional value in cardiovascular screening, in particular in relatively young women, although their implementation in clinical practice is challenged by inconsistent results and lack of long-term outcome data. Non-invasive imaging techniques, e.g., coronary artery intima-media thickness (CIMT), can be helpful to detect subclinical atherosclerotic disease, and coronary artery calcium scoring (CACS) has shown to be effective in early detection of cardiovascular damage. However, while more short-term and long-term follow-up studies are becoming available, few studies have investigated women with a history of preeclampsia in the fourth and fifth decade of life, when early signs of premature CVD are most likely to become apparent. Further studies are needed to inform new and improved clinical practice guidelines, and provide long term strategies to effectively prevent CVD, specifically targeted at women with a history of preeclampsia. Additionally, evaluation of feasibility, cost effectiveness, and implementation of CVD screening and prevention initiatives targeted at former preeclampsia patients are needed. PMID- 26255679 TI - Gene expression in breastmilk cells is associated with maternal and infant characteristics. AB - Breastmilk is a rich source of cells with a heterogeneous composition comprising early-stage stem cells, progenitors and more differentiated cells. The gene expression profiles of these cells and their associations with characteristics of the breastfeeding mother and infant are poorly understood. This study investigated factors associated with the cellular dynamics of breastmilk and explored variations amongst women. Genes representing different breastmilk cell populations including mammary epithelial and myoepithelial cells, progenitors, and multi-lineage stem cells showed great variation in expression. Stem cell markers ESRRB and CK5, myoepithelial marker CK14, and lactocyte marker alpha lactalbumin were amongst the genes most highly expressed across all samples tested. Genes exerting similar functions, such as either stem cell regulation or milk production, were found to be closely associated. Infant gestational age at delivery and changes in maternal bra cup size between pre-pregnancy and postpartum lactation were associated with expression of genes controlling stemness as well as milk synthesis. Additional correlations were found between genes and dyad characteristics, which may explain abnormalities related to low breastmilk supply or preterm birth. Our findings highlight the heterogeneity of breastmilk cell content and its changes associated with characteristics of the breastfeeding dyad that may reflect changing infant needs. PMID- 26255681 TI - Falls and Fractures: A systematic approach to screening and prevention. AB - Falls are one of the major causes of mortality and morbidity in older adults. Every year, an estimated 30-40% of patients over the age of 65 will fall at least once. Falls lead to moderate to severe injuries, fear of falling, loss of independence and death in a third of those patients. Falls account for 87 % of all fractures in the elderly. These fractures are almost always due to low impact injuries in osteoporotic bones. Several organizations have recommended screening older patients to identify those with a high risk of falling and, or fractures. The present review provides a brief summary and update of the relevant literature, summarizing screening tools and interventions to prevent falls and fractures. The major risk factors identified are impaired balance and gait, polypharmacy, and history of previous falls. Other risk factors include advancing age, female gender, visual impairments, cognitive decline especially attention and executive dysfunction, and environmental factors. Recommendations for the clinician to screen and prevent falls in older patients are also summarized. PMID- 26255682 TI - Bone biology, signaling pathways, and therapeutic targets for osteoporosis. AB - Major advances have occurred recently in the treatment of osteoporosis in recent years. Most patients are currently treated with bisphosphonates, denosumab, raloxifene, or teriparatide, and in some countries, strontium ranelate. Strontium ranelate and calcitonin have recently had their use restricted due to cardiovascular concerns and malignancy, respectively. The available agents have generally provided excellent options that effectively reduce fracture risk. New targets are being sought based on appreciation of the bone biology and signaling pathways involved in bone formation and resorption. These agents will directly target these signaling pathways, and further expand the options available for treatment of osteoporosis. PMID- 26255683 TI - The ACC/AHA 2013 pooled cohort equations compared to a Korean Risk Prediction Model for atherosclerotic cardiovascular disease. AB - BACKGROUND AND AIMS: To evaluate the performance of the American College of Cardiology/American Heart Association (ACC/AHA) 2013 Pooled Cohort Equations in the Korean Heart Study (KHS) population and to develop a Korean Risk Prediction Model (KRPM) for atherosclerotic cardiovascular disease (ASCVD) events. METHODS: The KHS cohort included 200,010 Korean adults aged 40-79 years who were free from ASCVD at baseline. Discrimination, calibration, and recalibration of the ACC/AHA Equations in predicting 10-year ASCVD risk in the KHS cohort were evaluated. The KRPM was derived using Cox model coefficients, mean risk factor values, and mean incidences from the KHS cohort. RESULTS: In the discriminatory analysis, the ACC/AHA Equations' White and African-American (AA) models moderately distinguished cases from non-cases, and were similar to the KRPM: For men, the area under the receiver operating characteristic curve (AUROCs) were 0.727 (White model), 0.725 (AA model), and 0.741 (KRPM); for women, the corresponding AUROCs were 0.738, 0.739, and 0.745. Absolute 10-year ASCVD risk for men in the KHS cohort was overestimated by 56.5% (White model) and 74.1% (AA model), while the risk for women was underestimated by 27.9% (White model) and overestimated by 29.1% (AA model). Recalibration of the ACC/AHA Equations did not affect discriminatory ability but improved calibration substantially, especially in men in the White model. Of the three ASCVD risk prediction models, the KRPM showed best calibration. CONCLUSIONS: The ACC/AHA Equations should not be directly applied for ASCVD risk prediction in a Korean population. The KRPM showed best predictive ability for ASCVD risk. PMID- 26255684 TI - Acute exposure to Buenos Aires air particles (UAP-BA) induces local and systemic inflammatory response in middle-aged mice: A time course study. AB - Exposure to air particulate matter (PM) is associated with increased cardiovascular morbimortality. However, PM doesn't affect equally to all people, being the old cohort the most susceptible and studied. We hypothesized that another specific life phase, the middle-aged subpopulation, may be negatively affected. Therefore, the aim of this study was to analyze in vivo the acute biological impact of two environmental particles, Urban Air Particles from Buenos Aires and Residual Oil Fly Ash, on the cardiorespiratory system of middle-aged mice, evaluating oxidative metabolism and inflammation. Both PM provoked a local and systemic inflammatory response, leading to a reduced alveolar area in the lung, an epicard inflammation in the heart, an increment of IL-6, and a reduction on PON 1 activity in serum of middle-aged animals. The positive correlation of local parameters with systemic markers of oxidative stress and inflammation could be responsible for associations of cardiovascular morbimortality in this subpopulation. PMID- 26255685 TI - Changes in ovarian gene expression profiles and plasma hormone levels in maturing European eel (Anguilla anguilla); Biomarkers for broodstock selection. AB - Complete sexual maturation of European eels (Anguilla anguilla) in captivity can only be achieved via injections with gonadotropins. For female eels this procedure takes 4-6months and the response ranges from "unresponsive" to final maturation and ovulation. Reproductive success could be significantly increased via early selection of responders based on predictive markers and minimally invasive sampling methods. To get a better understanding of the genetic background of ovarian maturation of the European eel we performed a pilot deep sequencing transcriptome analysis of ovarian tissue derived from a yellow eel, a prepubertal silver eel and a post-spawning matured eel. Two key players in steroidogenesis were strongly correlated with advanced sexual maturation, namely P450c17 and liver receptor homolog-1, suggesting that blood plasma steroids might qualify as minimally invasive markers for early detection of responders. Since the predictive value of plasma sex steroid levels for final maturation of the European eel had not yet been carefully examined, we performed an extensive artificial maturation trial. Farmed silver eels were treated with pituitary extracts and sampled at multiple time intervals. Expression of steroidogenesis related genes in ovarian tissue of responding and non-responding eels after four weekly injections with pituitary extract was compared using a custom-built microarray and RNAseq. Increased expression of 17beta-hsd1 was strongly linked to sexual maturation. Blood plasma levels of sex steroids were measured using ELISAs. We show that a 2.5-fold increase in blood-plasma estradiol level after 4 weekly pituitary extract injections is a strong predictor of final sexual maturation of female European eel. PMID- 26255686 TI - Expression of the cyp19a1 gene in the adult brain of Xenopus is neuronal and not sexually dimorphic. AB - The last step of oestrogen biosynthesis is catalyzed by the enzyme aromatase, the product of the cyp19a1 gene. In vertebrates, cyp19a1 is expressed in the brain resulting in a local oestrogen production that seems important not only for the control of reproduction-related circuits and sexual behaviour, but also for the regulation of neural development, synaptic plasticity and cell survival. In adult amphibians, the precise sites of expression of cyp19a1 in the brain have not been investigated which prevents proper understanding of its potential physiological functions. The present study aimed at examining the precise neuroanatomical distribution of cyp19a1 transcripts in adult brains of both male and female Xenopus. We found that cyp19a1 expression is highly regionalized in the brains of both sexes. The highest expression was found in the anterior part of the preoptic area and in the caudal hypothalamus, but significant levels of cyp19a1 transcripts were also found in the supraoptic paraventricular and suprachiasmatic areas, and in brain regions corresponding to the septum, bed nucleus of the stria terminalis and amygdala. Importantly, no obvious difference between male and female Xenopus was detected at the level of cyp19a1 transcripts. Additionally, in the brain of adult Xenopus, cyp19a1 transcripts were detected in neurons, and not in glial cells. These data and those available in other vertebrates on cyp19a1/aromatase expression suggest that, with the intriguing exception of teleost fishes, cyp19a1 was under strong evolutionary conservation with respect to its sites of expression and the nature of the cells in which it is expressed. PMID- 26255687 TI - Assessing the efficacy of general surveillance for detection of incursions of livestock diseases in Australia. AB - Australia, as a relatively isolated country with a high level of agricultural production, depends on, and has the opportunity to maintain, freedom from a range of important diseases of livestock. Occasional incursions of such diseases are generally detected by 'passive', general surveillance (GS). In current surveillance planning, a risk-based approach has been taken to optimising allocation of resources to surveillance needs, and having mapped the relative risk of introduction and establishment of diseases of concern, a means of mapping the efficacy of GS for their detection was required, as was a means of assessing the likely efficacy of options for improving GS efficacy if needed. This paper presents the structure and application of a tool for estimating the efficacy of Australia's GS, using the example of foot and mouth disease (FMD). The GS assessment tool (GSAT) is a stochastic spreadsheet model of the detection, diagnosis and reporting of disease on a single infected farm. It utilises the output of an intraherd disease spread model to determine the duration and prevalence of infection on different types of farm. It was applied separately to each of twelve regions of Australia, demarcated by dominant livestock production practices. Each region supplied estimates of probabilities relevant to the detection of FMD, for each of fourteen farm types and all species susceptible to the disease. Outputs of the GSAT were the average probability that FMD on the farm would be detected (single farm sensitivity), the average time elapsed from incursion of the disease to the chief veterinary officer (CVO) being notified (time to detection), and the number of average properties that would need to be infected before the CVO could be 95% confident of detecting at least one. The median single farm sensitivity for FMD varied among regions from 0.23 to 0.52, the median time to detection from 20 to 33 days, and the number of properties infected for 95% confidence of detecting at least one from 4 to 12. The GSAT has proved a valuable tool in planning surveillance for detection of exotic livestock disease in Australia, and it provides a practical example of the use of probabilistic modelling to answer important questions in the face of imperfect information. PMID- 26255688 TI - Preventative services offered by veterinarians on sheep farms in England and Wales: Opinions and drivers for proactive flock health planning. AB - Recent independent UK government reports and studies have highlighted the importance, but lack, of flock health services provided by veterinarians. Qualitative interviews were analysed by thematic analysis to construct belief statements to understand veterinarians' opinions on preventative advice and drivers for current services to sheep farmers. A postal questionnaire was sent to 515 sheep practices registered with the Royal College of Veterinary Surgeon (RCVS) in England and Wales in 2012 to gather quantitative data on these belief statements and to gather demographic information and current services provided by the veterinarian. Exploratory factor analysis with heuristic approaches was conducted on the respondents' belief statements to identify common factors of veterinarian beliefs. Three main factors were identified: motivation for proactiveness, perceived capability to offer preventative services and perceived opportunity to deliver these services. A beta regression model was built to identify the factors significantly associated with the time veterinarians spent in an advisory role. The relative proportion of time increased by 10% (1.01 1.19), 16% (1.03-1.30) and 29% (CI: 1.09-1.53) for each unit increase in score for factor 1 motivation, factor 2 capability and factor 3 opportunity respectively, indicating that these latent factors explained time veterinarians spent in an advisory role with sheep clients. There was a significant correlation between these factors suggesting influence of the associated beliefs between factors. This study provides insight into the nature and drivers of veterinarians' current behaviour and beliefs. These results could be further tested in behaviour intervention studies and help in designing efficient strategies aiming at promoting proactive health services offered by veterinarians on sheep farms in England and Wales. PMID- 26255689 TI - Insect parents improve the anti-parasitic and anti-bacterial defence of their offspring by priming the expression of immune-relevant genes. AB - Insect parents that experienced an immune challenge are known to prepare (prime) the immune activity of their offspring for improved defence. This phenomenon has intensively been studied by analysing especially immunity-related proteins. However, it is unknown how transgenerational immune priming affects transcript levels of immune-relevant genes of the offspring upon an actual threat. Here, we investigated how an immune challenge of Manduca sexta parents affects the expression of immune-related genes in their eggs that are attacked by parasitoids. Furthermore, we addressed the question whether the transgenerational immune priming of expression of genes in the eggs is still traceable in adult offspring. Our study revealed that a parental immune challenge did not affect the expression of immune-related genes in unparasitised eggs. However, immune-related genes in parasitised eggs of immune-challenged parents were upregulated to a higher level than those in parasitised eggs of unchallenged parents. Hence, this transgenerational immune priming of the eggs was detected only "on demand", i.e. upon parasitoid attack. The priming effects were also traceable in adult female progeny of immune-challenged parents which showed higher transcript levels of several immune-related genes in their ovaries than non-primed progeny. Some of the primed genes showed enhanced expression even when the progeny was left unchallenged, whereas other genes were upregulated to a greater extent in primed female progeny than non-primed ones only when the progeny itself was immune challenged. Thus, the detection of transgenerational immune priming strongly depends on the analysed genes and the presence or absence of an actual threat for the offspring. We suggest that M. sexta eggs laid by immune-challenged parents "afford" to upregulate the transcription of immunity-related genes only upon attack, because they have the chance to be endowed by parentally directly transferred protective proteins. PMID- 26255690 TI - Transcription factors, CncC and Maf, regulate expression of CYP6BQ genes responsible for deltamethrin resistance in Tribolium castaneum. AB - Insecticide resistance is a global problem that presents an ongoing challenge to control insects that destroy crops, trees and transmit diseases. Dramatic progress has been made during the last decade on identification of insecticide resistance-associated genes. In one of the most common resistance mechanisms, insects acquire resistance by increasing the levels of their detoxification enzymes especially the cytochrome P450 monooxygenases (P450's). Previous studies in our laboratory showed that the pyrethroid resistance in QTC279 strain of Tribolium castaneum is achieved through constitutive overexpression of the P450 gene CYP6BQ9 by 200-fold higher in the resistant strain as compared to that in the susceptible strain. RNAi-aided knockdown in the expression of probable genes that regulate P450 gene expression in QTC279 identified cap 'n' collar C (CncC) and muscle aponeurosis fibromatosis (Maf) family transcription factors as the key regulator of these genes, CncC and Maf regulate expression of multiple genes in the CYP6BQ cluster. Studies on the promoters of these genes using reporter assays identified binding sites that mediate CncC and Maf regulation of CYP6BQ gene expression. PMID- 26255692 TI - Re: Gut microbiota depletion from early adolescence in mice: Implications for brain and behavior. PMID- 26255691 TI - 20-Hydroxyecdysone stimulation of juvenile hormone biosynthesis by the mosquito corpora allata. AB - Juvenile hormone III (JH) is synthesized by the corpora allata (CA) and plays a key role in mosquito development and reproduction. JH titer decreases in the last instar larvae allowing pupation and metamorphosis to progress. As the anti metamorphic role of JH comes to an end, the CA of the late pupa (or pharate adult) becomes again "competent" to synthesize JH, which plays an essential role orchestrating reproductive maturation. 20-hydroxyecdysone (20E) prepares the pupae for ecdysis, and would be an ideal candidate to direct a developmental program in the CA of the pharate adult mosquito. In this study, we provide evidence that 20E acts as an age-linked hormonal signal, directing CA activation in the mosquito pupae. Stimulation of the inactive brain-corpora allata-corpora cardiaca complex (Br-CA-CC) of the early pupa (24 h before adult eclosion or -24 h) in vitro with 20E resulted in a remarkable increase in JH biosynthesis, as well as increase in the activity of juvenile hormone acid methyltransferase (JHAMT). Addition of methyl farnesoate but not farnesoic acid also stimulated JH synthesis by the Br-CA-CC of the -24 h pupae, proving that epoxidase activity is present, but not JHAMT activity. Separation of the CA-CC complex from the brain (denervation) in the -24 h pupae also activated JH synthesis. Our results suggest that an increase in 20E titer might override an inhibitory effect of the brain on JH synthesis, phenocopying denervation. All together these findings provide compelling evidence that 20E acts as a developmental signal that ensures proper reactivation of JH synthesis in the mosquito pupae. PMID- 26255693 TI - Circulating tumour necrosis factor is highly correlated with brainstem serotonin transporter availability in humans. AB - Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-alpha), would be associated with greater 5-HTT availability, and that TNF-alpha inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-alpha correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [(123)I]-beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-alpha concentrations on BDI scores. Treatment with etanercept for 6-8weeks was associated with a significant reduction in 5-HTT availability (Z=2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF-alpha and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-alpha and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression. PMID- 26255694 TI - Epstein-Barr virus Latent Membrane Protein 2A (LMP2A)-mediated changes in Fas expression and Fas-dependent apoptosis: Role of Lyn/Syk activation. AB - Epstein-Barr virus Latent Membrane Protein 2A (LMP2A) is expressed in EBV infected B cells in the germinal center, a site of significant apoptosis induced by engagement of Fas on activated B cells. Signals from the B cell receptor (BCR) protect germinal center B cells from Fas-mediated apoptosis, and since LMP2A is a BCR mimic, we hypothesized that LMP2A would also protect B cells from Fas mediated apoptosis. Surprisingly, latently-infected human and murine B cell lines expressing LMP2A were more sensitive to Fas-mediated apoptosis, as determined by increases in Annexin-V staining, and cleavage of caspase-8, -3 and PARP. Additional studies show that LMP2A-expressing B cell lines demonstrate a Lyn- and Syk-dependent increase in sensitivity to Fas-mediated apoptosis, due to an LMP2A dependent enhancement in Fas expression. These findings demonstrate the ability for LMP2A to directly increase a pro-apoptotic molecule and have implications for EBV latency as well as the treatment of EBV-associated malignancies. PMID- 26255696 TI - A high-throughput, simultaneous analysis of carotenoids, chlorophylls and tocopherol using sub two micron core shell technology columns. AB - A high-throughput, robust and reliable method for simultaneous analysis of five carotenoids, four chlorophylls and one tocopherol was developed for rapid screening large sample populations to facilitate molecular biology and plant breeding. Separation was achieved for 10 known analytes and four unknown carotenoids in a significantly reduced run time of 10min. Identity of the 10 analytes was confirmed by their UV-Vis absorption spectras. Quantification of tocopherol, carotenoids and chlorophylls was performed at 290nm, 460nm and 650nm respectively. In this report, two sub two micron particle core-shell columns, Kinetex from Phenomenex (1.7MUm particle size, 12% carbon load) and Cortecs from Waters (1.6MUm particle size, 6.6% carbon load) were investigated and their separation efficiencies were evaluated. The peak resolutions were >1.5 for all analytes except for chlorophyll-a' with Cortecs column. The ruggedness of this method was evaluated in two identical but separate instruments that produced CV<2 in peak retentions for nine out of 10 analytes separated. PMID- 26255695 TI - Hospitalizations and outpatient visits for rhinovirus-associated acute respiratory illness in adults. AB - BACKGROUND: Rhinovirus is linked to asthma exacerbations and chronic obstructive pulmonary disease exacerbations in adults. The severity and rates of rhinovirus acute respiratory illnesses (ARIs) in adults are uncertain. OBJECTIVES: We sought to determine rhinovirus-associated ARI rates in adults presenting for care in multiple settings and identify factors associated with rhinovirus detection. METHODS: This prospective, population-based cohort enrolled Tennessee residents 18 years or older in the emergency department (ED), outpatient clinics, or hospitalized for ARI from December 2008 to May 2010. Nasal/throat swabs were collected and tested for rhinovirus and other viruses by using RT-PCR. Rates of ED visits and hospitalizations were calculated and rhinovirus-positive and rhinovirus-negative patients were compared. RESULTS: Among 2351 enrollees, rhinovirus was detected in 247 (11%). There were 7 rhinovirus-associated ED visits and 3 hospitalizations per 1000 adults annually. Patients with rhinovirus, compared with virus-negative ARI, were more likely to present with wheezing (odds ratio [OR], 1.7; 95% CI, 1.23-2.35; P < .001), to be a current smoker (OR, 2.31; 95% CI, 1.68-3.19) or live with a smoker (OR, 1.72; 95% CI, 1.10-2.67), have a history of chronic respiratory disease (OR, 1.61; 95% CI, 1.17-2.22), and were less likely to be hospitalized versus seen in the outpatient setting (OR, 0.58; 95% CI, 0.41-0.83). CONCLUSIONS: Rhinovirus is associated with a substantial number of ED visits and hospitalizations for ARIs in adults. There may be modifiable factors that can reduce the likelihood of presenting with rhinovirus associated ARIs. PMID- 26255697 TI - Target-guided separation of antioxidants from Semen cassia via off-line two dimensional high-speed counter-current chromatography combined with complexation and extrusion elution mode. PMID- 26255698 TI - Impact of IgG2 high molecular weight species on neonatal Fc receptor binding assays. AB - A cell-based assay and a solution neonatal Fc receptor (FcRn) binding assay were implemented for the characterization of an IgG2 antibody after observation that different product lots exhibited unexpected differences in FcRn binding in the cell-based format with membrane-bound FcRn. The experiments described here suggest that the apparent differences observed in the FcRn binding across different product lots in the cell-based format can be attributed to the different levels of the higher order high molecular weight species (HMWs) in them. A strong correlation between FcRn binding in the cell-based format and the percentage (%) higher order HMWs suggests that small amounts (~0.1%) of the latter could cause the enhanced apparent FcRn binding (% relative binding ranging from 50 to 100%) in the format. However, when the binding was assessed with recombinant FcRn in soluble form, avidity effects were minimal and the assay format exhibited less sensitivity toward the differences in higher order HMWs levels across product lots. In conclusion, a solution-based assay may be a more appropriate assay to assess FcRn binding of the dominant species of an Fc-fusion protein or monoclonal antibody if minor differences in product variants such as higher order HMWs are shown to affect the binding significantly. PMID- 26255699 TI - An aptasensor for ochratoxin A based on grafting of polyethylene glycol on a boron-doped diamond microcell. AB - A novel strategy for the fabrication of an electrochemical label-free aptasensor for small-size molecules is proposed and demonstrated as an aptasensor for ochratoxin A (OTA). A long spacer chain of polyethylene glycol (PEG) was immobilized on a boron-doped diamond (BDD) microcell via electrochemical oxidation of its terminal amino groups. The amino-aptamer was then covalently linked to the carboxyl end of the immobilized PEG as a two-piece macromolecule, autoassembled at the BDD surface, forming a dense layer. Due to a change in conformation of the aptamer on the target analyte binding, a decrease of the electron transfer rate of the redox [Fe(CN)6](4-/3-) probe was observed. To quantify the amount of OTA, the decrease of the square wave voltammetry (SWV) peak maximum of this probe was monitored. The plot of the peak maximum against the logarithm of OTA concentration was linear along the range from 0.01 to 13.2 ng/L, with a detection limit of 0.01 ng/L. This concept was validated on spiked real samples of rice. PMID- 26255700 TI - A novel electrochemical biosensor for selective determination of mercury ions based on DNA hybridization. AB - An electrochemical biosensor was developed for Hg(2+) determination based on DNA hybridization. In the presence of Hg(2+), the target and probe DNAs with thymine thymine (T-T) mismatches could hybridize by forming T-Hg(2+)-T complex. This induced DNA hybridization led to the decrease in reduction peak currents of ethyl green (EG) as electroactive label, which could be used for determination of Hg(2+). The difference in the value of the peak currents of EG before and after DNA hybridization (DeltaI) was linear with the concentration of Hg(2+) in the range of 9.0 * 10(-11)-1.0 * 10(-9) M. The detection limit was 3.08 * 10(-11) M. PMID- 26255701 TI - Quantitative activation-induced manganese-enhanced MRI reveals severity of Parkinson's disease in mice. AB - We demonstrate that activation-induced manganese-enhanced magnetic resonance imaging with quantitative determination of the longitudinal relaxation time (qAIM MRI) reveals the severity of Parkinson's disease (PD) in mice. We first show that manganese ion-accumulation depends on neuronal activity. A highly active region was then observed by qAIM-MRI in the caudate-putamen in PD-model mice that was significantly correlated to the severity of PD, suggesting its involvement in the expression of PD symptoms. PMID- 26255703 TI - Embryonic water uptake during pregnancy is stage- and fecundity-dependent in the snake Vipera aspis. AB - Water is a crucial resource that can profoundly impact the biology of terrestrial organisms. Early life stages are particularly sensitive to hydric constraints because water uptake is an important component of embryonic development. While amniotic eggs constitute a key innovation to terrestrial life, many vertebrates are viviparous wherein the mother must be the source of water for her developing embryos. Since most viviparous squamates are lecithotrophic (i.e., energy is supplied to the offspring as yolk deposited into pre-ovulated follicles), water is the predominant resource allocated from the mother to the offspring during development. Contrary to energy that can be stored (e.g., as fat reserves), water typically cannot be acquired in advance. Therefore, the embryos' need for water can impose significant constraints on the pregnant female. We detailed water flux during pregnancy in a viviparous snake, the aspic viper (Vipera aspis). We found that embryonic water uptake occurred mostly during the second half of pregnancy-a period dominated by somatic growth. We also found that, somewhat unexpectedly, changes in female plasma osmolality were negatively related to fecundity. This latter result suggests that water consumption by the female is especially important for large litter sizes, and thus may suggest an important sensitivity of reproductive females to environmental water availability. PMID- 26255702 TI - Caffeine and modafinil given during 48 h sleep deprivation modulate object recognition memory and synaptic proteins in the hippocampus of the rat. AB - We aimed to evaluate the effect of caffeine/modafinil on sleep deprivation (SD) induced alterations in recognition memory and synaptic proteins. The data revealed a beneficial effect of caffeine/modafinil against deficit in the familiar object retrieval performance and object exploration ratio after 48 h SD. Caffeine treatment prevented the SD induced down-regulation of synaptophysin and synapsin I proteins with no change in PSD-95 protein in hippocampus. However, modafinil administration improved the down-regulation of synaptophysin, synapsin I and PSD-95 proteins in hippocampus. Hence, caffeine/modafinil can serve as counter measures in amelioration of SD induced consequences at behavioural and protein levels. PMID- 26255705 TI - Three-Dimensional Imaging and Systolic Anterior Motion: Providing Vision to a Sight. PMID- 26255704 TI - Effectiveness of the prevention of mother-to-child HIV transmission in Bahia, Brazil. AB - INTRODUCTION: Antiretroviral therapy and prophylaxis during the antepartum, intrapartum and postpartum periods, cesarean delivery and avoidance of breast milk significantly reduce vertical transmission of HIV. OBJECTIVE: To evaluate the effectiveness prevention of mother-to-child transmission of HIV and determine the rate of vertical transmission in a public sexually transmitted infection and HIV referral center in Salvador, Bahia, in the period immediately prior to the initiation of universal antiretroviral therapy in pregnant women. METHODS: Cross sectional study using data collected from medical records of children born to HIV infected mothers in Bahia from 2005 to 2008 who were referred to the Reference Center for Diagnosis and Research of Sexually Transmitted Diseases and HIV/AIDS for care. RESULTS: Of 232 HIV-exposed infants, 19 (8.2%) had confirmed HIV infection. One hundred eighty-eight (81%) mothers received antenatal care, 120 (52%) antepartum antiretroviral therapy or prophylaxis, and 168 (72%) intrapartum zidovudine. Two hundred twenty-three (96%) infants received zidovudine. In multivariable models, the combination of intrapartum and postpartum antiretroviral prophylaxis was associated with decreased adjusted odds of mother to-child transmission. CONCLUSIONS: Low levels of antenatal screening and access to prevention of mother-to-child transmission were significant limitations in the cascade of prevention of mother-to-child transmission at our center in this period. PMID- 26255706 TI - Polymorphism of fat metabolism genes as candidate markers for meat quality and production traits in heavy pigs. AB - High meat quality is required for dry-cured ham production, which quality depends on meat fat quantity and composition. The aim was to study the polymorphisms of six genes involved in fat metabolism, namely, Stearoyl-CoA desaturase (SCD), Diacylglycerol acyltransferase 1 and 2 (DGAT1 &DGAT2), Microsomal triglyceride transfer protein (MTTP), Fatty acid synthase (FASN) and Heart fatty acid binding protein (H-FABP) in two traditional (Large White or Duroc * (Landrace * Large White)) and two industrial hybrids (Goland and Danbred), which are used for dry cured ham production. Significant associations of SCD and MTTP were found with carcass weight. DGAT2 was associated with back fat thickness and L* fat colour (objective white colour score). Several genes (DGAT2, MTTP &FASN) were associated with weight loss during salting, first step in dry-cured ham production, affecting final yield. Finally, MTTP was associated with shear force. Our findings suggest that the SCD, DGAT2, MTTP and FASN polymorphisms are associated with quality of heavy pig meat products. PMID- 26255707 TI - Feeding regulates sex pheromone attraction and courtship in Drosophila females. AB - In Drosophila melanogaster, gender-specific behavioural responses to the male produced sex pheromone cis-vaccenyl acetate (cVA) rely on sexually dimorphic, third-order neural circuits. We show that nutritional state in female flies modulates cVA perception in first-order olfactory neurons. Starvation increases, and feeding reduces attraction to food odour, in both sexes. Adding cVA to food odour, however, maintains attraction in fed females, while it has no effect in males. Upregulation of sensitivity and behavioural responsiveness to cVA in fed females is paralleled by a strong increase in receptivity to male courtship. Functional imaging of the antennal lobe (AL), the olfactory centre in the insect brain, shows that olfactory input to DA1 and VM2 glomeruli is also modulated by starvation. Knocking down insulin receptors in neurons converging onto the DA1 glomerulus suggests that insulin-signalling partly controls pheromone perception in the AL, and adjusts cVA attraction according to nutritional state and sexual receptivity in Drosophila females. PMID- 26255709 TI - Prevalence of Frailty in Nursing Homes: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Nursing home patients are expected to be very frail. However, evidence on frailty in a nursing home setting is scarce in the literature. Especially prevalence of frailty in this population is unknown. OBJECTIVE: To systematically search and analyze the prevalence of frailty among nursing home patients in the literature and synthesize pooled estimates of overall prevalence of frailty and prefrailty as well as prevalence of frailty stratified by age, gender, and frailty definitions. DESIGN: Systematic review using 5 databases: Embase, MEDLINE, CINAHL Plus, PsycINFO, and Cochrane library, and meta-analysis. SETTING: Cross-sectional studies or observational studies with baseline data in a nursing home setting. PARTICIPANTS: Nursing home patients aged 60 years or older. MEASUREMENTS: Prevalence of frailty and prefrailty based on validated criteria or definitions of frailty was collected. In the included studies, meta-analysis was performed using random-effects models to calculate pooled estimates of prevalence of frailty and prefrailty. Methodological quality, heterogeneity, and publication bias were assessed. RESULTS: Nine studies with a total of 1373 nursing home patients were found to report prevalence of frailty. The included studies were highly heterogeneous and mean prevalence of frailty ranged widely from 19.0 to 75.6%. Pooled estimates of prevalence of frailty and prefrailty were 52.3% (95% confidence interval 37.9%-66.5%) (9 studies, n = 1373) and 40.2% (28.9%-52.1%) (7 studies, n = 1163), respectively. CONCLUSIONS: As high as about one-half of the nursing home patients were frail. Approximately 40% were still prefrail and could be targeted by interventions for frailty prevention or treatment to avoid its negative health outcomes. PMID- 26255708 TI - Clinical Interpretation of Elevated Concentrations of Cardiac Troponin T, but Not Troponin I, in Nursing Home Residents. AB - OBJECTIVE: Cardiac troponins T (cTnT) and I (cTnI) are the preferred biomarkers to detect myocardial damage. The present study explores the value of measuring cardiac troponins (cTn) in nursing home residents, by investigating its relation to heart failure and 1-year mortality using 1 cTnT and 2 cTnI assays that are widely used in clinical practice. DESIGN: All participants underwent extensive clinical examinations and echocardiographic assessment for the diagnosis of heart failure. cTn was measured using high-sensitive (hs)- cTnT (Roche), hs-cTnI (Abbott), and sensitive cTnI (Beckman) assays. The glomerular filtration rate was estimated (eGFR) using serum creatinine and cystatin C concentrations. Data on all-cause mortality were collected at 1-year follow-up. PARTICIPANTS AND SETTING: Participants were 495 long-term nursing home residents, older than 65 years, of 5 Dutch nursing home organizations. RESULTS: Median (IQR) concentrations were 20.6 (17.8-30.6), 6.8 (4.1-12.5), and 4.0 (2.0-8.0) ng/L for hs-cTnT, hs-cTnI, and cTnI, respectively. In total, 79% had elevated hs-cTnT concentrations, whereas only 9% and 5% of hs-cTnI and cTnI concentrations were elevated. Most important and independent determinants for higher hs-cTnT and hs-cTnI concentrations were heart failure and renal dysfunction. Whereas both heart failure (odds ratio [OR] 3.4) and eGFR lower than 60 mL/min/1.73 m(2) (OR 3.6) were equal contributors to higher hs-cTnT concentrations (all P < .001), hs-cTnI and cTnI were less associated with renal dysfunction (OR of, respectively, 1.9 and 2.1; P < .01) in comparison with heart failure (OR 4.3 and 4.7, respectively, P < .001). Furthermore, residents with higher hs-cTnT or hs-cTnI concentrations (fourth quartile) had respectively 4 versus 2 times more risk of 1-year mortality compared with lower concentrations. CONCLUSION: Regardless of their cardiac health, hs-cTnT but not hs-cTnI concentrations were elevated in almost all aged nursing home residents, questioning the use of the current diagnostic cutoff in elderly with high comorbidity. Nonetheless, measuring cardiac troponins, especially hs-cTnT, had a promising role in assessing future risk of mortality. PMID- 26255710 TI - Acute Hospital Admissions Because of Health Care-Related Adverse Events: A Retrospective Study of 5 Specialist Departments. AB - BACKGROUND: Health care-related adverse events (HCRAEs), which should not be confused with (blameworthy) medical errors, are common; they can lead to hospital admissions and can have grave consequences. Although they are sometimes potentially preventable, information is lacking on HCRAEs leading to admission to different departments. AIM: This study aimed to gain insight into the incidence, type, severity, and preventability of HCRAEs (including adverse drug events) leading to hospitalization to the departments of internal medicine, surgery, orthopedics, neurology, and neurosurgery. Further, we explore if there are differences regarding these HCRAEs between these departments. METHODS: We retrospectively evaluated the medical records of all patients admitted through the emergency department (ED) in a 6-month period to the departments of internal medicine, surgery, orthopedics, neurology, and neurosurgery. All patients admitted because of HCRAEs were included. RESULTS: More than one-fifth (21.8%; range 12.0%-47.8%) of all admissions to the 5 departments were due to a HCRAE. Half (49.9%) of these HCRAEs were medication-related and 30.5% were procedure related. In 6.5% of patients, the HCRAE led to permanent disability and another 4.4% of patients died during hospitalization. HCRAEs treated by internists and neurologists were usually medication-related, whereas HCRAEs treated by surgeons, orthopedic surgeons, and neurosurgeons were usually procedure-related. CONCLUSION: Hospital admissions to different departments are often caused by HCRAEs, which sometimes lead to permanent disability or even death. Gaining insight into similarities and differences in HCRAEs occurring in different specialties is a starting point for improving clinical outcomes. PMID- 26255712 TI - Polyethyleneimine as a novel desorbent for anionic organic dyes on layered double hydroxide surface. AB - Polyethyleneimine (PEI) is a positively charged polymer with hydrogen-bonding sites and hydrophobic chains. Therefore, it has been clearly established as an efficient adsorbent by means of these native properties in the literatures. However, there is apparently no good reason to disregard the use of PEI as a desired desorbent. Herein, using methyl orange as a model anionic dye, we investigated the desorption performances of PEI toward anionic dyes adsorbed on the surface of CO3-layered double hydroxides (LDHs) in a wide range of pH values. The experiment results showed that the positively charged PEI had very strong desorption capacity for anionic dyes at low pH values (<9.5) through electrostatic attraction between PEI and methyl orange because of the high degree of protonation of PEI. At high pH values (>9.5), PEI existed as neutral molecule, it could desorb methyl orange via hydrogen bonding between the amino groups of it and sulfonate group of methyl orange; simultaneously, the anion-exchange process occurred between abundant hydroxyl anions and anionic methyl orange. The adsorption capacity of the used LDH adsorbent was about 80% after five cycles of adsorption-desorption-regeneration, which was much higher than that conducted by 0.1M NaOH solution. These findings suggested that PEI could be regarded as a promising desorbent for enriching anionic dyes in wastewater and regenerating LDHs through surface adsorption-desorption cycles. PMID- 26255711 TI - Poly(I:C) induces expressions of MMP-1, -2, and -3 through various signaling pathways including IRF3 in human skin fibroblasts. AB - BACKGROUND: Ultraviolet (UV) irradiation can result in premature skin aging (photoaging) which is characterized by decreased expression of collagen and increased expression of matrix metalloproteinases (MMPs). Double-stranded RNAs (dsRNAs) can be generated at various conditions including virally infected cells or UV-damaged skin cells. Recent studies have shown that a synthetic dsRNA, polyinosinic-polycytidylic acid (poly(I:C)), can reduce procollagen expression in human skin fibroblasts. However, little is known about the effect of poly(I:C) on the expression of MMPs in skin fibroblasts and its underlying mechanisms. OBJECTIVE: We examined the effect of poly(I:C) on MMP-1, -2, and -3 expressions in human skin fibroblasts. Then, we further explored the underlying signaling pathways involved in the processes. METHODS: Human skin fibroblasts were treated with poly(I:C) for the indicated times in the presence or the absence of various chemical inhibitors or small interfering RNAs (siRNAs) at the indicated concentrations. Protein and mRNA levels of various target molecules were examined by Western blotting and quantitative real-time PCR, respectively. RESULTS: Poly(I:C) induced MMP-1, -2, and -3 expressions, which were dependent on TLR3. Poly(I:C) also induced activations of the mitogen-activated protein kinases (MAPKs), the nuclear factor-kappaB (NF-kappaB) and the interferon regulatory factor 3 (IRF3) pathways. By using specific inhibitors, we found that poly(I:C) induced expressions of MMP-1, -2, and -3 were differentially regulated by these signaling pathways. In particular, we found that the inhibition of IRF3 signaling pathways attenuated poly(I:C)-induced expressions of all the three MMPs. CONCLUSION: Our data show that the expressions of MMP-1, -2, and -3 are induced by poly(I:C) through various signaling pathways in human skin fibroblasts and suggest that TLR3 and/or IRF3 may be good targets for regulating the expressions of MMP-1, -2, and -3 induced by dsRNAs. PMID- 26255713 TI - Measuring theory of mind across middle childhood: Reliability and validity of the Silent Films and Strange Stories tasks. AB - Recent years have seen a growth of research on the development of children's ability to reason about others' mental states (or "theory of mind") beyond the narrow confines of the preschool period. The overall aim of this study was to investigate the psychometric properties of a task battery composed of items from Happe's Strange Stories task and Devine and Hughes' Silent Film task. A sample of 460 ethnically and socially diverse children (211 boys) between 7 and 13years of age completed the task battery at two time points separated by 1month. The Strange Stories and Silent Film tasks were strongly correlated even when verbal ability and narrative comprehension were taken into account, and all items loaded onto a single theory-of-mind latent factor. The theory-of-mind latent factor provided reliable estimates of performance across a wide range of theory-of-mind ability and showed no evidence of differential item functioning across gender, ethnicity, or socioeconomic status. The theory-of-mind latent factor also exhibited strong 1-month test-retest reliability, and this stability did not vary as a function of child characteristics. Taken together, these findings provide evidence for the validity and reliability of the Strange Stories and Silent Film task battery as a measure of individual differences in theory of mind suitable for use across middle childhood. We consider the methodological and conceptual implications of these findings for research on theory of mind beyond the preschool years. PMID- 26255714 TI - Patterns of Emotion Attribution are Affected in Patients with Schizophrenia. AB - Deficits in facial affect recognition have been repeatedly reported in schizophrenia patients. The hypothesis that this deficit is caused by poorly differentiated cognitive representation of facial expressions was tested in this study. To this end, performance of patients with schizophrenia and controls was compared in a new emotion-rating task. This novel approach allowed the participants to rate each facial expression at different times in terms of different emotion labels. Results revealed that patients tended to give higher ratings to emotion labels that did not correspond to the portrayed emotion, especially in the case of negative facial expressions (p < .001, eta 2 = .131). Although patients and controls gave similar ratings when the emotion label matched with the facial expression, patients gave higher ratings on trials with "incorrect" emotion labels (p s < .05). Comparison of patients and controls in a summary index of expressive ambiguity showed that patients perceived angry, fearful and happy faces as more emotionally ambiguous than did the controls (p < .001, eta 2 = .135). These results are consistent with the idea that the cognitive representation of emotional expressions in schizophrenia is characterized by less clear boundaries and a less close correspondence between facial configurations and emotional states. PMID- 26255715 TI - Chinese Herbal Medicines - Manufacturing Flaws and Misuse. AB - Chinese herbal medicines are mixtures of botanical, mineral, and/or animal products. The medicines are either prepared by a herbalist for a specific patient or available over the counter in ready to use or decoct formulations. The number of literature references with regard to adverse effects from Chinese herbal medicines has grown dramatically in the last decade along with the increased use of these treatments. These adverse effects can be attributed to a variety of reasons. Intentional adulteration of herbal medicines with pharmaceuticals to substantiate medicinal claims has resulted in a number of serious adverse effects, including some fatal cases. Cases of metal intoxication have been reported from their use as active ingredients or their presence as contaminants. Substituting a more toxic herb for a benign one, either by misidentification or for economic gain, can also result in adverse effects. Variability in the natural products from differences in growing, harvesting, and storage conditions affects the concentration of active components. Changes in these concentrations make consistent dosing a problem, especially for those herbs with a low therapeutic index. Because the causes of adverse effects from Chinese herbal medicines are varied, each incident must be thoroughly investigated to determine the causes, the potential public health risks, and the ways to avoid similar incidences in the future. PMID- 26255716 TI - Illegal and Therapeutic Drug Concentrations in Hair Segments - A Timetable of Drug Exposure? AB - Literature data related to the merit of hair as a chronological diary of drug exposure, as examined by segmental analysis, are reviewed with emphases on the mechanisms of drug incorporation, physiology of hair growth, and findings resulting from research effort and routine analytical results. In a single anagen strand, a drug dose may be incorporated, within the hair follicle, to a drug containing zone of approximately 2-5 mm width, which appears at the skin surface 1-5 days after drug exposure and moves regularly away following the strand's growth rate. This process is disturbed by deposition from sweat, sebum, and in rare cases environmental contamination, as well as by elimination during hair care or chemical treatment. In a hair tuft, the time resolution is seriously deteriorated by the presence of 5-15% (or even more) strands in the resting stage, by variability in the growth rate (up to 40%), and by inexact alignment of the strands. Interindividually, the generally accepted medium growth rate of 1.1 +/- 0.2 cm/month is only a very rough approximation. When applying to retrospective elucidation of intoxications and control of illegal or therapeutic drug intake cases, correlations ranging from excellent agreement to enormous deviations have been reported. Satisfactory dose-concentration correlation could not be established in both intra- and interindividual studies. Therefore, the domain of routine hair analysis remains the retrospective qualitative detection of drug exposure. Improved time estimation is possible using anagen hair and careful determination of individual growth rate and its variation at the sites of sampling, careful sample handling, and analysis of sufficient segments. PMID- 26255717 TI - Occluded Solvent Analysis as a Basis for Heroin and Cocaine Sample Differentiation. AB - Literature reports concerning the analysis of occluded solvent as a basis for determining whether "the [cocaine and heroin] samples have a common origin" are reviewed. Common procedures involve headspace sampling and gas chromatographic methods using various columns with mass spectrometric or other detectors. Nuclear magnetic resonance spectrometry has also been used. It is possible to (a) identify which solvents have been used in the production of a particular batch; (b) determine the relationship of drug samples; and (c) quantitatively assess the distribution of solvent through a large block of drug. However, a minimum number of three solvents are required before reliable matches might be called and even then the matches in solvent composition may not be confirmed in subsequent analyses. Thus, the analysis of occluded solvents in heroin and cocaine samples can be a useful contribution to establishing the relationship of drug samples to each other, but other methods of comparison are still required. The analysis of occluded solvents acts as a supplement to other comparative methods, rather than as a replacement. PMID- 26255718 TI - Control of Fine Structure in "Polymer Nanosphere Multilayered Organization" and Enhancement of Its Optical Property. AB - This paper reports on a new functionality exhibited by "polymer nanosphere multilayered organization", a new type of molecular organization, and the relationship between their structure and function. The polymer nanosphere multilayered organization is a fine structural material formed by the accumulation of single-particle layers of a hydrophobic polymer at the air/water interface; these single-particle layers have uniform height along the c-axis. By employing the "alternate compression-relaxation method", high-density, low-defect particle layers are formed with a clear increase in their crystallite sizes. In the case of a ternary comb copolymer containing a carbazole ring, one particle is formed by the assembly of approximately 60 units of collapsed monolayer-like double layers. This structure is stabilized by the formation of side-chain crystals in the interlayer, with oriented pi-pi stacking of carbazole rings, resulting in enhanced fluorescence emission intensity. PMID- 26255719 TI - Sensitivity to actinide doping of uranium compounds by resonant inelastic X-ray scattering at uranium L3 edge. AB - Valence-to-core resonant inelastic X-ray scattering (RIXS) and high energy resolution fluorescence detection (HERFD) X-ray absorption measurements were performed at the U L3 edges of UO2 and UO2(NO3)2(H2O)6. The results are compared with model calculations based on the local-density-approximation formalism, taking into account Coulomb interaction U (LDA + U). We show that despite strong 5f-5f electronic correlations in the studied systems and the use of core-level excitations in the intermediate stage of the spectroscopic process, the RIXS technique probes a convolution of the single-particle densities of states in the valence and conduction bands. For UO2, the detected crystal-field splitting between the U 6d eg and t2g orbitals from the RIXS spectra (~3.5 eV) is larger than that previously derived from optical spectroscopy. Furthermore, by using an example of the U0.75Pu0.25O2 mixed oxide, we show that the RIXS technique at the U L3 edges is sensitive to the substitution of U with other actinide, in contrast to conventional X-ray absorption methods. That is, due to changes in the occupied part rather than in the unoccupied part of the U 6d states caused by the substitution. PMID- 26255720 TI - Injuries and musculoskeletal pain among Norwegian group fitness instructors. AB - OBJECTIVE: To examine the prevalence and factors associated with instruction related injuries and musculoskeletal pain among group fitness instructors. DESIGN: Descriptive epidemiology study. SETTINGS: Online survey. PARTICIPANTS: Group fitness instructors from three fitness centre companies in Norway (n = 1473). Assessment of independent variables: questions regarding duration of working as a group fitness instructor, weekly instruction and exercise loading and modality, instruction-related injuries, musculoskeletal pain, use of alcohol, tobacco, snuff, menstrual dysfunction and disordered eating (Eating Disorder Inventory, EDI). The respondents were divided into high instruction loading (HIL), >=5 h/w with instruction; and low instruction loading (LIL), <5 h/w with instruction). RESULTS: The response rate was 57% (n = 837). Mean total loading (instruction and exercise) was 11.8 h/w and 6.3 h/w in the HIL and LIL groups (p < .001), respectively. The prevalence of acute (9% vs. 6%, p < .05), overuse (38% vs. 24%, p < .001) and both acute and overuse injuries (25% vs. 10%, p < .001) was higher in the HIL than in the LIL group (OR: 3.9, CI: 2.7, 5.5). The most prevalent injury locations were ankle and lower leg. The most frequent location for musculoskeletal pain was the shoulder/neck region. Factors associated with injury were instruction loading (h/w), years working as an instructor and EDI score. A high total EDI score predicted musculoskeletal pain. CONCLUSION: The high prevalence of injuries and musculoskeletal pain suggests a need for prevention strategies in the fitness industry. There is a need for limits regarding weekly instruction loading, especially for classes with high metabolic and/or mechanical loading. PMID- 26255721 TI - Vertebral strength prediction under anterior compressive force using a finite element model for osteoporosis assessment. PMID- 26255722 TI - An update on the management of chronic lumbar discogenic pain. AB - Lumbar degenerative disc disease without disc herniation, also known as discogenic pain, is an elusive diagnosis of chronic low back pain. Lumbar provocation discography and fusion surgery have been frequently utilized for several decades as the gold standards for the diagnosis and treatment of symptomatic lumbar discogenic pain, though controversial, based on conjecture, rather than evidence. In addition to lumbar fusion, various other operative and nonoperative modalities of treatments are available in managing chronic lumbar discogenic pain. This review provides an updated assessment of the management of chronic lumbar discogenic pain with a critical look at the many modalities of treatments that are currently available. PMID- 26255724 TI - Sirtuin 1 (SIRT1) Deacetylase Activity and NAD+/NADH Ratio Are Imperative for Capsaicin-Mediated Programmed Cell Death. AB - Capsaicin is considered a chemopreventive agent by virtue of its selective antigrowth activity, commonly associated with apoptosis, against cancer cells. However, noncancerous cells possess relatively higher tolerance to capsaicin, although the underlying mechanism for this difference remains unclear. Hence, this study aimed to elucidate the differential effects of capsaicin on cell lines from lung tissues by addressing the signal pathway leading to two types of cell death. In MRC-5 human fetal lung cells, capsaicin augmented silent mating type information regulation 1 (SIRT1) deacetylase activity and the intracellular NAD(+)/NADH ratio, decreasing acetylation of p53 and inducing autophagy. In contrast, capsaicin decreased the intracellular NAD(+)/NADH ratio, possibly through inhibition of tumor-associated NADH oxidase (tNOX), and diminished SIRT1 expression leading to enhanced p53 acetylation and apoptosis. Moreover, SIRT1 depletion by RNA interference attenuated capsaicin-induced apoptosis in A549 cancer cells and autophagy in MRC-5 cells, suggesting a vital role for SIRT1 in capsaicin-mediated cell death. Collectively, these data not only explain the differential cytotoxicity of capsaicin but shed light on the distinct cellular responses to capsaicin in cancerous and noncancerous cell lines. PMID- 26255725 TI - Genotyping Giardia intestinalis by Using DNA Extracted from Long-Term Preserved Human Specimens Stained with Chlorazol Black E. AB - Giardia intestinalis is a parasitic protozoan that causes diarrhea and abdominal pain in humans. Studies of the Giardia genotypes are thought to be important for understanding their infection routes and prevalence. However, few have reported pathogen genotyping in human giardiasis cases in Japan. In this study, we genotyped G. intestinalis by using DNA extracted from chlorazol black E-stained fecal smears from patients. The triosephosphate isomerase gene was amplified from 21 (91.3%) of 23 human fecal samples. Twelve (52.2%) of pathogens detected were of the genotype A, and 9 (39.1%) of the genotype B. A restriction fragment length polymorphism analysis showed that all genotype A found in the present study were of the genotype AI, which were presumed to be zoonotic. The source of Giardia infections was unclear in the present study. However, patients' histories of international travel appeared not to be associated with the Giardia genotypes. Thus, most cases were thought to be acquired sporadically and domestically. PMID- 26255726 TI - Effect of Olyset Net on Mosquito Larvae and Their Heteroptera Predators in Water Jars in Southern Vietnam. AB - Residents of Vietnam living in areas with water shortages collect and store tap water, when it is available, in containers, such as jars, which is then used for their daily activities. Although these water jars are important breeding sites for mosquitoes, Vietnam legislation prohibits the use of chemical larvicides in such containers. The effect of Olyset Net on the abundance of mosquito larvae and their Heteroptera predators (Micronecta spp. and Veliidae) in jars was evaluated via field experiments conducted in Tan Chanh, Long An, Vietnam. The number of Aedes larvae decreased when the jars were covered with the Olyset Net, while the numbers of non-Aedes mosquito larvae (Culex and Anopheles), and those of Micronecta and Veliidae, did not vary until the end of the experiment. However, Micronecta population increased after removing the Olyset Net from the jars, and consequently Aedes larvae decreased due to these changes in the Micronecta, 26 days after the Olyset Net was removed. Incomplete use of Olyset Net failed to control mosquitoes in water jars based on the invasion of adult mosquitoes, and in water transferred by residents among the jars, which might contain larvae. These results suggest that Micronecta, as well as Olyset Net, can be considered as control agents for mosquito larvae. PMID- 26255727 TI - Effects of Sulfamethoxazole-Trimethoprim on Airway Colonization with Pneumocystis jirovecii. AB - Reactivation of latent infection is considered to be the main mechanism underlying the development of Pneumocystis pneumonia in immunosuppressed patients. We retrospectively assessed the effects of prophylactic administration of sulfamethoxazole-trimethoprim on the development of P. pneumonia and airway colonization with P. jirovecii in patients undergoing examinations to diagnose or rule out P. pneumonia. Polymerase chain reaction was performed to detect P. jirovecii in bronchoalveolar lavage fluid or sputum of 60 consecutive patients between 2004 and 2012. No patients who received the prophylactic administration of sulfamethoxazole-trimethoprim (n = 10) developed P. pneumonia or demonstrated airway colonization with P. jirovecii, and none of the patients who developed P. pneumonia (n = 11) or showed colonization (n = 9) had received prophylactic treatment. Furthermore, 20 (40%) of 50 patients without prophylactic treatment showed positive results on the P. jirovecii DNA polymerase chain reaction, but all 10 patients who had prophylactic treatment showed negative results (Fisher's exact test, P = 0.02). Therefore, the prophylactic administration of sulfamethoxazole-trimethoprim has potential to be effective in preventing P. pneumonia as well as eliminating airway colonization with P. jirovecii. Further studies targeting large cohorts of patients with a variety of underlying diseases are required to develop recommendations regarding the prophylactic administration of sulfamethoxazole-trimethoprim. PMID- 26255728 TI - Nonsteroidal Anti-Inflammatory Drug and Aspirin Use, and Mortality among Critically Ill Pandemic H1N1 Influenza Patients: an Exploratory Analysis. AB - We explored nonsteroidal anti-inflammatory drug (NSAID) and aspirin (ASA) use and mortality in the U.S. Department of Health and Human Services' registry of 683 adult and 838 pediatric critically ill pandemic 2009 H1N1 influenza (pH1N1) patients. Among adults, 88 (12.9%) and 101 (14.8%) reported pre-admission use of an NSAID and ASA, respectively; mortality was similar (23-24%) regardless of NSAID or ASA use. Mortality among 89 pediatric NSAID users and 749 nonusers did not differ significantly (10.1% and 8.8%, respectively). One of 16 pediatric ASA users died. Among pediatric patients, the adjusted relative risk estimate for NSAID use and 90-day mortality was higher when influenza vaccination was included in the model (risk ratio [RR] = 1.5; 95% confidence interval, 0.7-3.2), although not statistically significant. Among adults, RR estimates did not change appreciably after adjusting for age, sex, health status, or vaccine status. We found no compelling evidence that NSAID or ASA use influenced mortality in severe pH1N1. PMID- 26255729 TI - A Comparative Study of the Epidemiology of Human Leptospirosis in Korea and Japan between 2006 and 2012. AB - We undertook a comparative analysis of the epidemiology of reported human leptospirosis (HL) cases in Korea and Japan. Between 2006 and 2012, the cumulative incidence of HL in Korea was higher than that in Japan (1.26 vs. 0.14 per 100,000 population, respectively), and the total reported cases were 632 and 196, respectively. Significantly more men were infected than women in both Korea (63.0% men, P < 0.01) and Japan (87.8% men, P < 0.01). In both countries, the incidence was highest among those aged 40 years and older (60%), and peaked in autumn (78.5% cases in Korea, and 46.9% cases in Japan). However, Japan exhibited a significantly higher proportion of male cases, a younger age distribution, and less prominent seasonality. A significant difference was observed in the incidence of HL between the capital city and rural areas in Korea, but not in Japan. The differences in agricultural and forestry practices, and the efficacy or wastewater treatment infrastructure might influence the incidence level in rural areas in both countries. The differences between the 2 countries might be because of their unique geographical characteristics and variations in their levels of industrialization. PMID- 26255730 TI - High-Level Genetic Diversity among Invasive Streptococcus pneumoniae Isolates in Turkey. AB - This study obtained information on the serotypes and molecular typing characteristics of Streptococcus pneumoniae strains causing invasive diseases in Turkey. Sixty-eight S. pneumoniae isolates causing invasive pneumococcal diseases were collected from different regions of Turkey from 2009 to 2011. The isolates were characterized by performing multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), and capsular serotyping, and 25 different serotypes were identified. Serotypes 19F, 23F, 1, 14, and 7F were common and accounted for 52.9% of all the serotypes. In addition, 54 different PFGE profiles (pulsotypes) were observed. Twenty-three of the 68 (33.8%) isolates were clustered into 9 pulsotypes. MLST analysis yielded 36 sequence types, of which 12 (33.3%) were novel. A comparison of results with the global pneumococcal MLST database by performing eBURST analysis showed that our strains belonged to 20 different clonal complexes and 5 singletons. In addition, we identified 4 new alleles: 2 gdh, 1 xpt, and 1 ddl. Thus, the results of this study highlighted a high level of diversity among pneumococcal isolates. In addition, the study identified a case of possible capsular switching. PMID- 26255731 TI - A Clinical Study of Miliary Brain Tuberculomas in China. AB - Brain tuberculomas can exhibit many different clinical and radiological patterns. However, disseminated or miliary brain tuberculomas are very rare. Miliary brain tuberculomas have specific clinical prognostic implications. Seven patients diagnosed with miliary brain tuberculomas between December 2004 and August 2012 were evaluated retrospectively. Their clinical features, cranial magnetic resonance imaging (MRI) characteristics, treatments, and outcomes were reviewed. The median patient age was 42 years (range, 22-66 years). Six patients presented with fever, 5 with headache, 4 with papilledema, and 3 with diplopia. MRI studies revealed multiple brain lesions. MRI showed 20-50 lesions at the same level. These lesions measured approximately 2-4 mm in diameter and exhibited ring or nodular enhancement after gadolinium injection. All patients began to recover within 2 weeks of initiating antitubercular therapy (ATT). The number of lesions visible on MRI scans was halved within a month, and all lesions had healed without sequelae after 18 months of regular ATT. Miliary brain tuberculoma is a rare form of central nervous system tuberculosis. Some special characteristics of miliary brain tuberculomas are as follows: First, the presence of mild atypical clinical manifestations and almost normal laboratory findings; second, severe radiological features and 20-50 lesions at the same level on MRI scans; and third, a good response to standard ATT. Finally, they are benign; for instance, no patients died in our study. Early diagnosis and treatment can result in full recovery. PMID- 26255732 TI - Anti-Hepatitis C Virus Activity of a Crude Extract from Longan (Dimocarpus longan Lour.) Leaves. AB - Infection with hepatitis C virus (HCV) results in hepatitis C, a disease characterized by chronic infection, cirrhosis, and hepatocellular carcinoma. Currently, the standard therapy is a combination of pegylated interferon-alpha plus ribavirin with NS3 protease inhibitors. Addition of NS3 protease inhibitors to the standard therapy improves response rates; however, use of NS3 protease inhibitors is also associated with significant adverse effects and an increase in the overall cost of treatment. Therefore, there is a need to develop safe and inexpensive drugs for the treatment of HCV infections. In this study, we examined the antiviral activity of a crude extract from Dimocarpus longan leaves against HCV (genotype 2a strain JFH1). The D. longan crude extract (DL-CE) exhibited anti HCV activity with a 50% effective concentration (EC50) of 19.4 MUg/ml without cytotoxicity. A time-of-addition study demonstrated that DL-CE has anti-HCV activity at both the entry and post-entry steps and markedly blocks the viral entry step through direct virucidal activity with marginal inhibition of virion assembly. Co-treatment of DL-CE with cyclosporine A, an immunosuppressant or telaprevir, an NS3 protease inhibitor, resulted in additive and synergistic antiviral effects, respectively. Our findings suggest that DL-CE may be useful as an add-on therapy candidate for treating HCV infections. PMID- 26255733 TI - Loop-Mediated Isothermal Amplification (LAMP) Aids the Clinical Diagnosis of Pertussis. PMID- 26255734 TI - A Serological Epidemiological Survey of Antibodies against 4 HPV Subtypes in Uygur Women in Xinjiang. AB - This study evaluated the distribution of antibodies against 4 human papillomavirus (HPV) subtypes and their related factors among Uygur women in Xinjiang. A cross-sectional study was conducted from March 2006 to May 2007 involving 883 Uygur women aged 17-54 years living in Yutian County. Demographic indicators, disease history, sexual behavior history, and other parameters were recorded at the interview using a questionnaire. A fluorescence detection method was used to quantify anti-HPV6, -11, -16, and -18 antibodies in venous blood serum. The rate of positive detection of any anti-HPV antibody (anti-HPV6, -11, 16, and -18) in the study population was 13.4%, and the individual positivity rates were 9.5%, 2.6%, 4.3%, and 0.7%, respectively. Peak rates of positivity for the anti-HPV16 antibody were found in women who were 36-40 and 46-50 years old. Seroprevalence of HPV16, which is high-risk for cervical cancer, was associated with the numbers of sexual partners. The rate of infection with high-risk HPV was low among Uygur women from rural areas, although there is a high incidence of cervical cancer in this group. Loyalty to one sexual partner decreased the risk of high-risk HPV infection. This study may provide useful reference data for the prevention and treatment of HPV and cervical cancer and for the application of HPV vaccines. PMID- 26255735 TI - Persistence of Immunity Acquired after a Single Dose of Rubella Vaccine in Japan. AB - To date, Takahashi, Matsuura, and TO-336 strains of live-attenuated rubella vaccine have been used in Japan. Japan implemented a single-dose rubella vaccination program until 2006. However, few reports are available on the persistence of immunity after this vaccination program. We collected 276 serum samples from January 2009 to December 2011 at Okafuji Pediatric Clinic and assessed the immune status of these samples against rubella virus during 1-10 years after vaccination with a single dose of Takahashi rubella vaccine. Regional outbreak of rubella did not occur during 1999-2011. The collected serum samples were tested for antibodies against the rubella virus by performing a standard hemagglutination inhibition (HAI) test. Our results showed that all the tested serum samples contained antibodies against the rubella virus 10 years after the vaccination. Geometric mean titer of HAI antibodies was 1:180 and decreased to 1:68 at 10 years after the vaccination. The levels of HAI antibodies decreased logarithmically with time after the vaccination. In conclusion, vaccine-acquired immunity after vaccination with a single dose of live-attenuated Takahashi rubella vaccine was retained for at least 10 years when rubella was under regional control. PMID- 26255736 TI - Tuberculin Skin Test and QuantiFERON((r))-TB Gold In-Tube Test for Diagnosing Latent Tuberculosis Infection among Thai Healthcare Workers. AB - A cross-sectional study was conducted on the performance of the tuberculin skin test (TST) and QuantiFERON((r))-TB Gold In-Tube test (QFT-IT) for detecting latent tuberculosis infection among Thai healthcare workers (HCWs). Each HCW underwent both the TST and QFT-IT during the annual health screening. Among the 260 HCWs enrolled, the median age was 30 years (range 19-60 years), 92% were women, 64% were nurses and nurse assistants, 78% were Bacillus Calmette Guerin vaccinated, and 37% had previously taken the TST. Correlation between TST reaction size and the interferon-gamma level was weak (r = 0.29; P < 0.001). Of the HCWs, 38% and 20% had a reactive TST and a positive QFT-IT, respectively. Using QFT-IT positivity as a standard for latent tuberculosis diagnosis, the cut off for TST reactivity with the best performance was >=13 mm with a sensitivity, specificity, false positivity, and false negativity of 71%, 70%, 30%, and 29%, respectively (area under the curve 0.73; P < 0.001). The independent factor associated with a false reactive TST was a previous TST (adjusted odds ratio 1.83; P = 0.04). Our findings suggest that the QFT-IT may be the preferred test among HCWs with previous TST. In settings where the QFT-IT is not available, appropriate cut-offs for TST reactivity should be evaluated for use among HCWs. PMID- 26255737 TI - A Cytolethal Distending Toxin Gene-Based Multiplex PCR Assay for Campylobacter jejuni, C. fetus, C. coli, C. upsaliensis, C. hyointestinalis, and C. lari. AB - In this study, we devised a multiplex PCR assay based on the gene of cytolethal distending toxin (cdt) B subunit to simultaneously detect and discriminate Campylobacter jejuni, C. fetus, C. coli, C. upsaliensis, C. hyointestinalis, and C. lari. Species-specific PCR products were successfully obtained from all 38 C. jejuni, 12 C. fetus, 39 C. coli, 22 C. upsaliensis, 24 C. hyointestinalis, and 7 C. lari strains tested. On the other hand, no specific PCR products were obtained from other campylobacters and bacterial species tested (41 strains in total). The proposed multiplex PCR assay is a valuable tool for detection and descrimination of 6 major Campylobacter species, that are associated with gastrointestinal diseases in humans. PMID- 26255738 TI - Importance of Hybrids of Meccus phyllosomus mazzottii, and M. p. pallidipennis, and M. p. phyllosomus to the Transmission of Trypanosoma cruzi in Mexico. AB - The time interval before beginning feeding, feeding time, and defecation delay for 3 Triatominae subspecies, Meccus phyllosomus mazzottii (Ma), M. p. pallidipennis (Pa), and M. p. phyllosomus (Phy) and their laboratory hybrids were evaluated. The mean time interval for beginning feeding was between 0.1 and 10.1 min for all nymphal instars in each cohort, with significant (P < 0.05) differences among hybrids and parental cohorts. Four (both MaPa and MaPhy) hybrid cohorts had similar mean feeding times to that recorded for one of their parental subspecies, but shorter than the other, whereas the remaining hybrid cohorts (both PaPhy) had longer feeding times than did both of their parental subspecies. The specimens of MaPa defecated later than the respective instars on their parental subspecies, whereas most instars of the remaining 4 hybrid cohorts (MaPhy and PaPhy) defecated earlier than the respective instars of M. p. phyllosomus. Between 40% and 50% of the defecation events occurred when feeding in MaPhy and PaPhy hybrid cohorts. Given these results, the hybrid cohorts were more effective vectors of Trypanosoma cruzi than their parental subspecies, which could indicate a potentially higher risk of transmission of T. cruzi to reservoir hosts. PMID- 26255739 TI - Cross-Seeding Interaction between beta-Amyloid and Human Islet Amyloid Polypeptide. AB - Alzheimer's disease (AD) and type 2 diabetes (T2D) are two common protein misfolding diseases. Increasing evidence suggests that these two diseases may be correlated with each other via cross-sequence interactions between beta-amyloid peptide (Abeta) associated with AD and human islet amyloid polypeptide (hIAPP) associated with T2D. However, little is known about how these two peptides work and how they interact with each other to induce amyloidogenesis. In this work, we study the effect of cross-sequence interactions between Abeta and hIAPP peptides on hybrid amyloid structures, conformational changes, and aggregation kinetics using combined experimental and simulation approaches. Experimental results confirm that Abeta and hIAPP can interact with each other to aggregate into hybrid amyloid fibrils containing beta-sheet-rich structures morphologically similar to pure Abeta and hIAPP. The cross-seeding of Abeta and hIAPP leads to the coexistence of both a retarded process at the initial nucleation stage and an accelerated process at the fibrillization stage, in conjunction with a conformational transition from random structures to alpha-helix to beta-sheet. Further molecular dynamics simulations reveal that Abeta and hIAPP oligomers can efficiently cross-seed each other via the association of two highly similar U shaped beta-sheet structures; thus, conformational compatibility between Abeta and hIAPP aggregates appears to play a key role in determining barriers to cross seeding. The cross-seeding effects in this work may provide new insights into the molecular mechanisms of interactions between AD and T2D. PMID- 26255740 TI - Suppression of excitotoxicity and foreign body response by memantine in chronic cannula implantation into the rat brain. AB - Chronic brain implants are accompanied by a tissue response that causes the loss of neurons in the vicinity of the implant and the formation of a glial scar that is also referred to as foreign body response. Despite immense progress in the field of brain-computer interface (BCI) research the biocompatibility of chronic brain implants remains a primary concern in device design. Excitotoxic overstimulation of NMDA-receptors by extrasynaptic glutamate plays a pivotal role in cell death in the acute phase of the tissue reaction. In this study, we examined the effect of the uncompetitive NMDA-receptor antagonist memantine locally applied during cannula implantation in the caudal forelimb area (CFA) of the motor cortex (M1) in Lister Hooded rats on their behavioural performance in a skilled reaching and a rung-ladder task as well as in the open field. Moreover, the distribution of neurons and glial cells in the vicinity of the implant were assessed. Memantine improved the performance in the behavioural paradigms compared to controls and increased the number of surviving neurons in the vicinity of the implant even above basal levels accompanied by a reduction in astrocytic scar formation directly around the implant with no effect on the microglia/macrophage activation two and six weeks after cannula implantation. These findings suggest that memantine is a potential therapeutic agent in the acute phase of chronic foreign body implantation in the motor cortex in terms of increasing the viability of neurons adjacent to the implant and of improving the behavioural outcome after surgery. PMID- 26255742 TI - Big data: Are large prospective randomized trials obsolete in the future? AB - Big data represents a new opportunity to increase our understanding of cancer care as it is practiced globally and to improve it through the refinement of clinic guidelines and the identification of knowledge gaps. Here we review the historical approach to evidence development (randomized clinical trials), some of their limitations, and the complementary role that big data analytics may play. PMID- 26255741 TI - Impact of preventive therapy on the risk of breast cancer among women with benign breast disease. AB - There are three main ways in which women can be identified as being at high risk of breast cancer i) family history of breast and/or ovarian cancer, which includes genetic factors ii) mammographically identified high breast density, and iii) certain types of benign breast disease. The last category is the least common, but in some ways the easiest one for which treatment can be offered, because these women have already entered into the treatment system. The highest risk is seen in women with lobular carcinoma in situ (LCIS), but this is very rare. More common is atypical hyperplasia (AH), which carries a 4-5-fold risk of breast cancer as compared to general population. Even more common is hyperplasia of the usual type and carries a roughly two-fold increased risk. Women with aspirated cysts are also at increased risk of subsequent breast cancer. Tamoxifen has been shown to be particularly effective in preventing subsequent breast cancer in women with AH, with a more than 70% reduction in the P1 trial and a 60% reduction in IBIS-I. The aromatase inhibitors (AIs) also are highly effective for AH and LCIS. There are no published data on the effectiveness of tamoxifen or the AIs for breast cancer prevention in women with hyperplasia of the usual type, or for women with aspirated cysts. Improving diagnostic consistency, breast cancer risk prediction and education of physicians and patients regarding therapeutic prevention in women with benign breast disease may strengthen breast cancer prevention efforts. PMID- 26255743 TI - Adjuvant endocrine therapy for premenopausal women with hormone-responsive breast cancer. AB - Multiple strategies for endocrine treatment of premenopausal women with hormone responsive breast cancer have been assessed and results have been presented over the last two years. These include tamoxifen for 5-10 years (ATLAS and aTTom), tamoxifen for 5 years followed by aromatase inhibitor (AI) for 5 years for women who have become postmenopausal (MA-17); ovarian ablation (OA) by surgery (EBCTCG overview); ovarian function suppression (OFS) by LHRH agonist (LHRH agonist meta analysis); or combinations of approaches including OFS plus tamoxifen or AI (SOFT, TEXT, ABCSG 12 and E3193). Many of these trials have taken place in the backdrop of (neo)adjuvant chemotherapy which can confound interpretation because such therapy can suppress ovarian function either transiently or permanently. Nonetheless these trials suggest in aggregate that 10 years of tamoxifen are better than 5 years and that a program of extended adjuvant therapy of tamoxifen for 5 years followed by aromatase inhibitor for 5 years is effective for suitable candidates. The SOFT and E3193 trials do not show a major advantage for use of OFS + tamoxifen compared to tamoxifen alone. The joint SOFT/TEXT analysis and ABCGS12 trials both suggest that outcomes can be excellent with the use of combined endocrine therapy alone in properly selected patients but give conflicting results with regard to potential benefits for OFS + AI compared with OFS + tamoxifen. Further work will be needed to ascertain long-term outcomes, identify factors that predict who will benefit from extended adjuvant endocrine therapy, and assess role of OFS by medical or surgical means. It is clear, however, that endocrine therapy is a critical part of the adjuvant regimen for most premenopausal women with hormone-responsive breast cancer, and a subset of these women with luminal A-type tumors can be safely treated with endocrine therapy alone. PMID- 26255744 TI - A bad tumor biomarker is as bad as a bad drug: The gap between genomics data and phenotype to predict response. AB - The search for novel prognostic and predictive parameters in breast carcinoma is relentless. The new technological advances in gene expression profiling and in mutational analysis will hopefully prove to be clinically useful in informing the choice for the systemic therapy. For the time being, we are still relying in established immunohistochemical markers, namely estrogen and progesterone receptors, HER2 and Ki67. Advances in the harmonization of pre-analytical, analytical and interpretative variables may improve accuracy and reproducibility of the results. PMID- 26255745 TI - Management of breast cancer in very young women. AB - Breast cancer is the leading cause of cancer-related deaths in women age 40 and younger in developed countries, and although generally improving, survival rates for young women with breast cancer remain lower than for older women. Young women are more likely to develop more aggressive subtypes of breast cancer (more triple negative and more Human Epidermal Growth Factor Receptor 2 [HER2]-positive disease) and present with more advanced stage disease. Previous research has demonstrated that young age is an independent risk factor for disease recurrence and death, although recent data suggest this may not be the case in certain tumor molecular subtypes. Recent preliminary evidence suggests potential unique biologic features of breast cancer that occurs in young women although this has yet to have been translated into treatment differences. There are clearly host differences that affect the management of breast cancer for young patients including generally being premenopausal at diagnosis, and fertility, genetics, and social/emotional issues in particular should be considered early in the course of their care. Despite an increased risk of local recurrence, young age alone is not a contraindication to breast conserving therapy given the equivalent survival seen in this population with either mastectomy or breast conservation. However, many young women in recent years are choosing bilateral mastectomy, even without a known hereditary predisposition to the disease. For those who need chemotherapy, multi-agent chemotherapy and biologic therapy targeting the tumor similar to the treatment in older women is the standard approach. Select young women will do well with hormone therapy only. Recent data from the TEXT and SOFT trials evaluating the optimal endocrine therapy for the first 5 years, and the ATTom and ATLAS trials demonstrating benefit from extended duration of tamoxifen (10 vs. 5 years), have further defined options for adjuvant endocrine therapy for young women with early breast cancer. Attention to adherence with endocrine therapy may be particularly important to improve outcomes in this population who are at increased risk of non-adherence compared to older women. PMID- 26255746 TI - Neoadjuvant endocrine therapy: Patient selection, treatment duration and surrogate endpoints. AB - Neoadjuvant endocrine treatment has become of increasing interest for downstaging primary ER+ breast cancers as it has become clear that the pathologic complete response rate of luminal tumours to chemotherapy is much lower than that of non luminal and differs little from that to endocrine therapy. There is much more experience in postmenopausal than premenopausal women. Aromatase inhibitors are generally the agent of choice. Responses are lower in those with the low levels of ER. While duration of endocrine treatment in clinical trials has usually been standardized at around three to four months it is clear that volume reductions continue to occur beyond that time in a large proportion of cases and routine clinical practice is often to treat to maximum response. This relatively slow emergence of downstaging relates to the absence of any increase in apoptosis with endocrine therapy and dependence of responses on the antiproliferative effects of oestrogen withdrawal: apoptosis occurs but at a slightly lower rate such that cell loss is attritional. The dependence of responses on the reduced proliferation underpins the value of Ki67 as an intermediate end-point for treatment benefit with multiple studies having found that relative effects on proliferation by different drugs in neoadjuvant trials match their relative impact on recurrence. While change in Ki67 is now accepted as a validated endpoint for comparing endocrine agents in the neoadjuvant scenario, on-treatment levels of Ki67 are related to long-term prognosis more closely than pretreatment Ki67. The Preoperative Endocrine Prognostic Index (PEPI) that combines residual Ki67 score with measures of on-treatment ER and other clinicopathologic factors has also found application in clinical trials. The potential to make longitudinal assessments of both clinical and biomarker responses has encouraged the development of novel clinical trial designs for assessing the impact of agents that aim to enhance response beyond that of endocrine agents alone. Such strategies include the early measurement of residual Ki67 levels after challenge with an endocrine agent alone and evaluation of the impact of the added agent on Ki67 or other agent-specific end-points. PMID- 26255747 TI - Dehydrocoupling routes to element-element bonds catalysed by main group compounds. AB - Dehydrocoupling reactions, i.e. reactions involving elimination of H2 between two E-H bonds, provide a clean route to E-E bonds within the main group. The products afforded from these reactions have applications in organic synthesis and materials chemistry, and in addition the H2 released during these reactions can also be useful as an energy source. Previous methods for dehydrocoupling involve both thermal and transition metal catalysed routes but recent developments have shown that main group compounds can be used as catalysts in these reactions. This tutorial review will focus on the development of main group catalysed dehydrocoupling reactions as a route to heteronuclear element-element bonds. PMID- 26255748 TI - cis-to-trans isomerization of azobenzene investigated by using thin films of metal-organic frameworks. AB - The activation barrier for cis-to-trans isomerization is a key parameter for governing the properties of photoswitchable molecules. This quantity can be computed by using theoretical methods, but experimental determination is not straightforward. Photoswitchable molecules typically do not change their conformation in the pure crystalline state. When the molecules are in solution, the switching is affected by the viscosity and polarity of the solvent and when embedded in polymers, the conformational change is affected by the polymer matrix. Here, we describe a novel approach where the photoswitchable group is integrated in a highly crystalline, porous molecular framework. Sufficiently large pore sizes in such metal-organic frameworks, MOFs, allow unhindered switching and the strictly periodic structure of the lattice eliminates virtually all contributions from inhomogeneities. Using IR spectroscopy to probe the conformational state of azobenzene, the energy barrier separating the cis and the trans state could be determined by an Arrhenius analysis of the data accumulated in a temperature regime between 314 K and 385 K. The result, 1.09 +/- 0.09 eV, is in very good agreement with the activation energy reported for the thermal cis-to trans isomerization of free azobenzene as computed by DFT calculations. PMID- 26255749 TI - Faceted metal and metal oxide nanoparticles: design, fabrication and catalysis. AB - The review addresses new advances in metal, bimetallic, metal oxide, and composite particles in their nanoregime for facet-selective catalytic applications. The synthesis and growth mechanisms of the particles have been summarized in brief in this review with a view to develop critical examination of the faceted morphology of the particles for catalysis. The size, shape and composition of the particles have been found to be largely irrelevant in comparison to the nature of facets in catalysis. Thus selective high- and low index facets have been found to selectively promote adsorption, which eventually leads to an effective catalytic reaction. As a consequence, a high density of atoms rest at the corners, steps, stages, kinks etc on the catalyst surface in order to host the adsorbate efficiently and catalyze the reaction. Again, surface atomic arrangement and bond length have been found to play a dominant role in adsorption, leading to effective catalysis. PMID- 26255750 TI - Miglustat Does Not Prevent Neurological Involvement in Niemann Pick C Disease. PMID- 26255751 TI - An Unusual Location for Intracranial Lipoma: Lateral Pontomesencephalic Lipoma in an Infant. PMID- 26255752 TI - Pediatric Hemorrhagic Brainstem Encephalitis Associated With HHV-7 Infection. AB - BACKGROUND: Human herpesviruses-6 and -7 have been associated with febrile seizures and with encephalitis, the latter predominantly in immunocompromised individuals. Acute hemorrhagic encephalitis is frequently a fatal disease that can occur in the setting of viral infection or can be a postinfectious phenomenon, often with no cause identified. Although hemorrhagic encephalitis has been reported with human herpesvirus-6 infection, only one individual, an immunocompromised child, has been documented with human herpesvirus-7 infection. The role of immunosuppression is not well-established in the management of this rare condition. PATIENT DESCRIPTION: We present an 11-year-old boy with hemorrhagic brainstem encephalitis who underwent extensive infectious and autoimmune testing, positive only for human herpesvirus-7 in the cerebrospinal fluid. The patient recovered after treatment with intravenous immunoglobulin, high-dose steroids, and plasma exchange. CONCLUSION: This is the first report of hemorrhagic brainstem encephalitis with human herpesvirus-7 in a previously healthy individual, adding to existing reports of late-onset human herpesvirus-7 infection associated with encephalitis in children. It also underscores that aggressive immunosuppression may be used early in the course of this disorder and may be beneficial for recovery. PMID- 26255753 TI - Decreased Levels of Nasal Nitric Oxide in Children With Midline Neuroanatomical Anomalies: A Possible Connection Between Ciliary Dysfunction and Isolated Nervous System Defects. AB - OBJECTIVES: Given the involvement of cilia in midline neurodevelopment, we set to determine whether children with midline neuroanatomical defects have increased prevalence of ciliary dysfunction, using nasal nitric oxide measurement, a screening test for primary ciliary dyskinesia. STUDY DESIGN: We measured the nasal nitric oxide levels of 26 children ages 6-17, with congenital midline central nervous system defects, who are otherwise healthy. We evaluated the effect of variables including: age, gender, and anomaly (brain, spinal cord, or combined) on our measurements. We compared our results with the previously established normal range (153.6-509.9 nL/min) and to the cutoff for children with primary ciliary dyskinesia (77 nL/min). RESULTS: The overall range for nasal nitric oxide in our cohort was 56.5-334.7 nL/min, with age, gender, and anomaly not having a significant effect. The overall mean, 217.7 nL/min, was significantly lower than the preestablished mean in normal children, 314.51 nL/min (P < 0.01). Four patients (15.4%) had nitric oxide levels below the lower end of normal, with two (7.7%) having values below the cutoff for primary ciliary dyskinesia. CONCLUSIONS: This is the first study to report a possible association between ciliary dysfunction and isolated congenital midline neuroanatomical defects, not in the context of any known syndrome. We suggest that genes known to cause isolated central nervous system defects may also be involved in the function of cilia. Longitudinal studies are required to investigate whether, in children with abnormal measurements, nasal nitric oxide levels normalize over time, and whether these children suffer from any respiratory sequelae. PMID- 26255754 TI - Homogeneous liquid-liquid extraction of metal ions with non-fluorinated bis(2 ethylhexyl)phosphate ionic liquids having a lower critical solution temperature in combination with water. AB - Ionic liquids with an ether-functionalised cation and the bis(2 ethylhexyl)phosphate anion show thermomorphic behaviour in water, with a lower critical solution temperature. These ionic liquids are useful for homogeneous liquid-liquid extraction of first-row (3d) transition metals. PMID- 26255755 TI - An iodine(III) mediated oxidative rearrangement of enamines: efficient synthesis of alpha-amino ketones. AB - An iodine(III)-mediated, group-selective oxidative rearrangement of beta,beta diarylenamines to alpha-amino ketones has been accomplished with excellent yield. The developed reaction involves the initial oxidation of enamine to an alpha acyloxyimine intermediate and concomitant semipinacol rearrangement. PMID- 26255756 TI - Impaired coherence of life narratives of patients with schizophrenia. AB - Self-narratives of patients have received increasing interest in schizophrenia since they offer unique material to study patients' subjective experience related to their illness, in particular the alteration of self that accompanies schizophrenia. In this study, we investigated the life narratives and the ability to integrate and bind memories of personal events into a coherent narrative in 27 patients with schizophrenia and 26 controls. Four aspects of life narratives were analyzed: coherence with cultural concept of biography, temporal coherence, causal-motivational coherence and thematic coherence. Results showed that in patients cultural biographical knowledge is preserved, whereas temporal coherence is partially impaired. Furthermore, causal-motivational and thematic coherence are significantly impaired: patients have difficulties explaining how events have modeled their identity, and integrating different events along thematic lines. Impairment of global causal-motivational and thematic coherence was significantly correlated with patients' executive dysfunction, suggesting that cognitive impairment observed in patients could affect their ability to construct a coherent narrative of their life by binding important events to their self. This study provides new understanding of the cognitive deficits underlying self disorders in patients with schizophrenia. Our findings suggest the potential usefulness of developing new therapeutic interventions to improve autobiographical reasoning skills. PMID- 26255757 TI - The effect of cross-linking on the molecular dynamics of the segmental and beta Johari-Goldstein processes in polyvinylpyrrolidone-based copolymers. AB - The effect of the cross-link density on the molecular dynamics of copolymers composed of vinylpyrrolidone (VP) and butyl acrylate (BA) was studied using differential scanning calorimetry (DSC) and dielectric relaxation spectroscopy (DRS). A single glass transition was detected by DSC measurements. The dielectric spectra exhibit conductive processes and three dipolar relaxations labeled as alpha, beta and gamma in the decreasing order of temperatures. The cross-linker content affects both alpha and beta processes, but the fastest gamma process is relatively unaffected. An increase of cross-linking produces a typical effect on the alpha process dynamics: (i) the glass transition temperature is increased, (ii) the dispersion is broadened, (iii) its strength is decreased and (iv) the relaxation times are increased. However, the beta process, which possesses typical features of a pure Johari-Goldstein relaxation, unexpectedly loses the intermolecular character for the highest cross-linker content. PMID- 26255758 TI - Curcumin pretreatment mediates antidiabetogenesis via functional regulation of adrenergic receptor subtypes in the pancreas of multiple low-dose streptozotocin induced diabetic rats. AB - Lifestyle modification pivoting on nutritional management holds tremendous potential to meet the challenge of management of diabetes. The current study hypothesizes that regular uptake of curcumin lowers the incidence of diabetes by functional regulation of pancreatic adrenergic receptor subtypes. The specific objective of the study was to identify the regulatory pathways implicated in the antidiabetogenesis effect of curcumin in multiple low-dose streptozotocin (MLD STZ)-induced diabetic Wistar rats. Administration of MLD-STZ to curcumin pretreated rats induced a prediabetic condition. Scatchard analysis, real-time polymerase chain reaction, and confocal microscopic studies confirmed a significant increase in alpha2-adrenergic receptor expression in the pancreas of diabetic rats. Pretreatment with curcumin significantly decreased alpha2 adrenergic receptor expression. The diabetic group showed a significant decrease in the expression of beta-adrenergic receptors when compared with control. Pretreatment significantly increased beta-adrenergic receptor expression to near control. When compared with the diabetic rats, a significant up-regulation of CREB, phospholipase C, insulin receptor, and glucose transporter 2 were observed in the pretreated group. Curcumin pretreatment was also able to maintain near control levels of cyclic adenosine monophosphate, cyclic guanosine monophosphate, and inositol triphosphate. These results indicate that a marked decline in alpha2 adrenergic receptor function relents sympathetic inhibition of insulin release. It also follows that escalated signaling through beta-adrenergic receptors mediates neuronal stimulation of hyperglycemia-induced beta-cell compensatory response. Curcumin-mediated functional regulation of adrenergic receptors and modulation of key cell signaling molecules improve pancreatic glucose sensing, insulin gene expression, and insulin secretion. PMID- 26255759 TI - Higher plain water intake is associated with lower type 2 diabetes risk: a cross sectional study in humans. AB - The aim of this study was to investigate the relationship between plain water intake and type 2 diabetes (T2D) risk. It was hypothesized that higher plain water intake would be associated with a lower T2D risk score. One hundred thirty eight adults from Southwest and Southeast England answered a cross-sectional online survey assessing T2D risk (using the Diabetes UK risk assessment); physical activity (using the short International Physical Activity Questionnaire); and consumption of fruits, vegetables, and beverages (using an adapted version of the Cambridge European Prospective Investigation into Cancer and Nutrition Food Frequency Questionnaire). There was a trend for differences in mean plain water intake between those stratified as having low, increased, moderate, or high risk of T2D; but these did not achieve significance (P = .084). However, plain water intake was significantly negatively correlated with T2D risk score (tau = -0 degrees 180, P = .005); and for every 240-mL cup of water consumed per day, T2D risk score was reduced by 0.72 point (range, 0-47) (B = 0.03, 95% confidence interval = -0.06 to -0.01, P = .014). The current study has provided preliminary results that are supported by theory; mechanisms need to be explored further to determine the true effect of plain water intake on disease risk. As increasing plain water intake is a simple and cost-effective dietary modification, its impact on T2D risk is important to investigate further in a randomized controlled trial. Overall, this study found that plain water intake had a significant negative correlation with T2D risk score; and regression analysis suggested that water may have a role in reducing T2D risk. PMID- 26255760 TI - A breakthrough novel method to resolve the drug and target interference problem in immunogenicity assays. AB - Biological matrix interference in detection and quantitation immunoassays remains a major challenge in the field of bioanalysis. For example, circulating drug may interfere with the detection of anti-drug antibodies (ADA) and drug target, or ADA may interfere with quantitation of drug levels in PK/TK analysis. Monoclonal antibody drug interference, especially for human IgG4 drugs, presents an additional challenge for ADA analysis due to its longer half-life and higher dose. Assay tolerance to such interference may depend on assay platform and reagents. Various approaches have been used to improve drug tolerance in ADA analysis but limited success was observed. We have developed a breakthrough novel method that uses Precipitation and Acid dissociation (PandA) to overcome drug interference in the ADA assay. The method principle is based on four components for detection of total ADA (free ADA and drug bound ADA) in the presence of drug in patient samples: (1) use excess drug to saturate free ADA to form drug bound ADA as drug:ADA complexes, (2) precipitate the complex using an agent such as PEG, (3) acid dissociate ADA from drug and immobilize (capture) free ADA (and free drug) under acidic conditions (without neutralization) onto a large capacity surface, and (4) detect free ADA (not the captured drug) using specific anti human Ig detection reagent. In this manuscript, we are describing case studies for three humanized monoclonal antibodies (an IgG1 and two IgG4 drugs). The three drug specific PandA ADA assays resulted in complete recovery of ADA in samples containing drug levels in excess of those expected in patients, in contrast to the commonly used acid dissociation approach in ECL bridging assays. This breakthrough novel method shows significant improvement over the current approaches. In fact, the drug interference or under detecting of ADA in all three cases was eliminated. This assay principle could be used not only for ADA assays but also PK and biomarker (drug target) analysis in the presence of interference factors. PMID- 26255761 TI - Total nodal irradiation in patients with severe treatment-refractory chronic graft-versus-host disease after allogeneic stem cell transplantation: Response rates and immunomodulatory effects. AB - BACKGROUND AND PURPOSE: The use of total nodal irradiation (TNI) has been reported as an immunomodulatory therapy for different diseases including chronic graft-versus-host disease (cGVHD). MATERIAL AND METHODS: We retrospectively analyzed 13 patients with treatment-refractory cGVHD receiving TNI with 1*1Gy from 2001 to 2014. In 10 of 13 patients immunomodulatory effects of TNI were measured. RESULTS: At time of TNI all patients had severe cGVHD (involving the skin: n=12), fascia (n=6), oral mucosa (n=8), eye (n=8), and lung (n=5). Nine of 13 patients had corticosteroid-refractory cGVHD. In 7 of 13 patients (54%) a partial response (PR) could be achieved. In 3 patients (23%) cGVHD manifestations remained stable, 2 patients progressed. One patient was not evaluable due to follow-up <1 month. At 3 months after TNI, best responses could be achieved in skin, and oral involvement including steroid sparing activity. TNI was well tolerated with adverse effects limited to reversible thrombocytopenia and neutropenia. Immunomodulatory effects on peripheral blood cells could be demonstrated including an increase of CD4+ T cells in the group of responders. CONCLUSIONS: TNI represents an effective immunomodulating therapy in treatment refractory cGVHD. PMID- 26255762 TI - Prediction of lung density changes after radiotherapy by cone beam computed tomography response markers and pre-treatment factors for non-small cell lung cancer patients. AB - BACKGROUND AND PURPOSE: This study investigates the ability of pre-treatment factors and response markers extracted from standard cone-beam computed tomography (CBCT) images to predict the lung density changes induced by radiotherapy for non-small cell lung cancer (NSCLC) patients. METHODS AND MATERIALS: Density changes in follow-up computed tomography scans were evaluated for 135 NSCLC patients treated with radiotherapy. Early response markers were obtained by analysing changes in lung density in CBCT images acquired during the treatment course. The ability of pre-treatment factors and CBCT markers to predict lung density changes induced by radiotherapy was investigated. RESULTS: Age and CBCT markers extracted at 10th, 20th, and 30th treatment fraction significantly predicted lung density changes in a multivariable analysis, and a set of response models based on these parameters were established. The correlation coefficient for the models was 0.35, 0.35, and 0.39, when based on the markers obtained at the 10th, 20th, and 30th fraction, respectively. CONCLUSIONS: The study indicates that younger patients without lung tissue reactions early into their treatment course may have minimal radiation induced lung density increase at follow-up. Further investigations are needed to examine the ability of the models to identify patients with low risk of symptomatic toxicity. PMID- 26255763 TI - CT characteristics allow identification of patient-specific susceptibility for radiation-induced lung damage. AB - BACKGROUND AND PURPOSE: There is a huge difference in radiosensitivity of lungs between patients. The present study aims to identify and quantify patient specific radiosensitivity based on a single pre-treatment CT scan. MATERIALS AND METHODS: 130 lung cancer patients were studied: 60 stereotactic ablative radiotherapy (SABR) treatments and 70 conventional treatments (20 and 30 patients from external datasets, respectively). A 3month-follow-up scan (CT3M) was non rigidly registered to the planning CT scan (CT0). Changes in Hounsfield Units (DeltaHU=HU3M-HU0) inside lung subvolumes were analyzed per dose bin of 5Gy. DeltaHU was modeled as a function of local dose using linear and sigmoidal fits. Sigmoidal fit parameters DeltaHUmax (saturation level) and D50 (dose corresponding to 50% of DeltaHUmax) were collected for all patients. RESULTS: Sigmoidal fits outperformed linear fits in the SABR groups for the majority of patients. Sigmoidal dose-responses were also observed in both conventional groups but to a lesser extent. Distributions of D50 and DeltaHUmax showed a large variation between patients in all datasets. Higher baseline lung density (p<0.001) was prognostic for higher DeltaHUmax in one SABR group. No prognostic factors were found for D50. CONCLUSIONS: Baseline CT characteristics are prognostic for radiation-induced lung damage susceptibility. PMID- 26255764 TI - The DAHANCA 6 randomized trial: Effect of 6 vs 5 weekly fractions of radiotherapy in patients with glottic squamous cell carcinoma. AB - PURPOSE: The DAHANCA 6 trial evaluated tumor response and morbidity after moderate accelerated radiotherapy compared to conventional fractionated radiotherapy in patients treated for glottic squamous cell carcinoma (SCC). Further, the failure pattern and incidence of new primary tumors were explored. PATIENTS AND METHODS: Six hundred and ninety-four patients with non-metastatic glottic SCC were randomized between six or five weekly fractions (fx/w) of radiotherapy to the same total dose. The median treatment time was 38 and 46days, respectively. The primary endpoint was loco-regional failure. RESULTS: Median follow-up time was 14.5years. Of the 177 failures, 167 involved T-site. The cumulative incidence of loco-regional failure (LRF) was 21.6% in the 6fx/w group and 29.3% in the 5fx/w group and the corresponding hazard rate (HR) of LRF was 0.72 (CI: 0.53-0.97, p=0.04). The effect of acceleration on LRF was especially evident in well differentiated tumors (HR=0.42 (CI: 0.23-0.75) and in T1-2 tumors (HR=0.60 (CI: 0.41-0.89)). The HR of laryngectomy was 0.72 (CI: 0.50-1.04) in the 6fx/w group compared to the 5fx/w group. The hazards of disease-specific death, event-free survival, and overall survival were comparable between the two groups. Significantly more patients experienced severe acute mucositis in the 6fx/w group but the incidence of late morbidity was comparable between the groups. New primary tumors occurred in 22.5% of the patients. CONCLUSION: Moderate accelerated radiotherapy significantly improved loco-regional control in patients with glottic SCC. PMID- 26255765 TI - Advances in the pharmacology of lGICs auxiliary subunits. AB - Ligand-gated ion channels (LGICs) are cell surface integral proteins that mediate the fast neurotransmission in the nervous system. LGICs require auxiliary subunits for their trafficking, assembly and pharmacological modulation. Auxiliary subunits do not form functional homomeric receptors, but are reported to assemble with the principal subunits in order to modulate their pharmacological profiles. For example, nACh receptors are built at least by co assemble of alpha and beta subunits, and the neuronal auxiliary subunits beta3 and alpha5 and muscle type beta, delta, gamma, and epsilon determine the agonist affinity of these receptors. Serotonergic 5-HT3B, 5-HT3C, 5-HT3D and 5-HT3E are reported to assemble with the 5-HT3A subunit to modulate its pharmacological profile. Functional studies evaluating the role of gamma2 and delta auxiliary subunits of GABAA receptors have made important advances in the understanding of the action of benzodiazepines, ethanol and neurosteroids. Glycine receptors are composed principally by alpha1-3 subunits and the auxiliary subunit beta determines their synaptic location and their pharmacological response to propofol and ethanol. NMDA receptors appear to be functional as heterotetrameric channels. So far, the existence of NMDA auxiliary subunits is controversial. On the other hand, Kainate receptors are modulated by NETO 1 and 2. AMPA receptors are modulated by TARPs, Shisa 9, CKAMP44, CNIH2-3 auxiliary proteins reported that controls their trafficking, conductance and gating of channels. P2X receptors are able to associate with auxiliary Pannexin-1 protein to modulate P2X7 receptors. Considering the pharmacological relevance of different LGICs auxiliary subunits in the present work we will highlight the therapeutic potential of these modulator proteins. PMID- 26255766 TI - [Endoscopic lateral parathyroidectomy as surgical treatment for patients with primary hyperparathyroidism]. AB - BACKGROUND: Most surgeons have rapidly accepted the use of minimally invasive surgical approaches for the treatment of primary hyperparathyroidism. The role of the endoscope in neck surgery is still being discussed due to its technical difficulty and complex patient selection criteria. MATERIALS AND METHODS: A prospective study was conducted between April 2010 and April 2013. It included patients diagnosed with sporadic primary hyperparathyroidism (sPHPT) by locating a single adenoma using ultrasound and sestamibi scintigraphy imaging. All patients agreed to be included in the study. Experienced endocrine surgeons that had been trained in endocrine minimally invasive surgery performed the procedure. The same surgical technique was used in all of the cases. The demographic and clinical variables were evaluated. A descriptive analysis was performed on the data measuring mean, standard deviation, and range. RESULTS: A total of 28 endoscopic lateral parathyroidectomies were performed. All patients were diagnosed with sporadic hyperparathyroidism sPHPT. The mean age was 68 years (59 89). No intraoperative complications were registered. Postoperative morbidity was comparable to that reported in the classical approach. A favourable outcome was observed in 27 of the 28 patients (96%) after a mean follow-up time of 22 (9 - 53) months. CONCLUSIONS: An endoscopic approach for hyperparathyroidism sPHPT is feasible and reproducible, and it obtains comparable results to the classical open surgery. Several factors make this technique suitable for highly specialised hospitals with a high patient volume and specialised endocrine surgery units. PMID- 26255767 TI - [Tuberculous rheumatism "Poncet's disease". Case report]. AB - BACKGROUND: Deaths due to tuberculosis have reached 2.5 million cases per year worldwide. Poncet's disease is an infrequent form of tuberculosis characterised by a clinical picture of polyarthritis. CLINICAL CASE: A 24-year-old male presented with morning stiffness, arthralgias, bilateral symmetric arthritis of the proximal interphalangeal joints, wrists, knees, ankles, and shoulders, and adenomegalies at the cervical, submandibular, left supraclavicular, axillary and inguinal levels, without fever. Laboratory results were as follows: ESR 44mm/h, C reactive protein 4.35, normal levels of complement C3 and C4, negative rheumatoid factor and anticyclic citrullinated peptide antibodies, positive antinuclear antibodies with fine speckled pattern (1:320) and cytoplasm (1:160) pattern and negative anti-Smith, -double-stranded DNA, Sjogren's syndrome-antigen A and Sjogren's syndrome-antigen B. Histological report of cervical node tissue revealed granulomatous lesions compatible with tuberculosis. Rheumatoid arthritis and systemic lupus erythematosus were ruled out. Anti-tuberculosis agents were initiated that resolved the clinical picture. Diagnosis of Poncet's disease was confirmed. CONCLUSION: The differential diagnosis between tuberculosis and autoimmune inflammatory joint diseases is a clinical challenge. PMID- 26255768 TI - [Is intestinal malrotation the cause of intussusception? Waugh's syndrome, a case report]. AB - BACKGROUND: Waugh's syndrome is the combination of intussusception and intestinal malrotation. The first case was described in 1911, with few cases being reported since then. CLINICAL CASE: A 7 month-old infant with fever, vomiting and rectal bleeding. Distension and an abdominal mass was found on examination. An exploratory laparotomy was preformed that found a combination of intussusception and intestinal malrotation, which was treated succesfully. CONCLUSION: We consider that this combination is not sufficiently diagnosed very often, leading to its disappearance. PMID- 26255769 TI - Scope and Applications of Nanomedicines for the Management of Multiple Sclerosis. AB - Multiple sclerosis (MS) is characterized by inflammation, demyelination and lesions in the central nervous system (CNS) that results in the physical and cognitive disabilities in patients. Immune cells get access into the brain region, after infection in the blood brain barrier (BBB) due to bacteria/virus or by genetic predisposition, where the autoimmune response may induce the demyelination, inflammation as well as neurodegeneration in brain areas. Various types of therapeutics are used worldwide approved by the food and drug administration (FDA) for the management of MS. Hence, side effects of conventional therapy goes hand in hand. The advancement in nanomedicines have opened window for the management of various disorders of neurodegeneration including MS. Various clinical trials are in process to explore the etiology of MS and in this connection animal models like experimental autoimmune encephalomyelitis (EAE) have promising outcomes for the management of MS by using nanomedicines that give new insights. The current review elaborates the scope of nanomedicines with respect to MS patients. PMID- 26255770 TI - A Biogenesis Step Upstream of Microprocessor Controls miR-17~92 Expression. AB - The precise control of miR-17~92 microRNA (miRNA) is essential for normal development, and overexpression of certain miRNAs from this cluster is oncogenic. Here, we find that the relative expression of the six miRNAs processed from the primary (pri-miR-17~92) transcript is dynamically regulated during embryonic stem cell (ESC) differentiation. Pri-miR-17~92 is processed to a biogenesis intermediate, termed "progenitor-miRNA" (pro-miRNA). Pro-miRNA is an efficient substrate for Microprocessor and is required to selectively license production of pre-miR-17, pre-miR-18a, pre-miR-19a, pre-miR-20a, and pre-miR-19b from this cluster. Two complementary cis-regulatory repression domains within pri-miR-17~92 are required for the blockade of miRNA processing through the formation of an autoinhibitory RNA conformation. The endonuclease CPSF3 (CPSF73) and the spliceosome-associated ISY1 are responsible for pro-miRNA biogenesis and expression of all miRNAs within the cluster except miR-92. Thus, developmentally regulated pro-miRNA processing is a key step controlling miRNA expression and explains the posttranscriptional control of miR-17~92 expression in development. PMID- 26255771 TI - Coordinated Spine Pruning and Maturation Mediated by Inter-Spine Competition for Cadherin/Catenin Complexes. AB - Dendritic spines are postsynaptic compartments of excitatory synapses that undergo dynamic changes during development, including rapid spinogenesis in early postnatal life and significant pruning during adolescence. Spine pruning defects have been implicated in developmental neurological disorders such as autism, yet much remains to be uncovered regarding its molecular mechanism. Here, we show that spine pruning and maturation in the mouse somatosensory cortex are coordinated via the cadherin/catenin cell adhesion complex and bidrectionally regulated by sensory experience. We further demonstrate that locally enhancing cadherin/catenin-dependent adhesion or photo-stimulating a contacting channelrhodopsin-expressing axon stabilized the manipulated spine and eliminated its neighbors, an effect requiring cadherin/catenin-dependent adhesion. Importantly, we show that differential cadherin/catenin-dependent adhesion between neighboring spines biased spine fate in vivo. These results suggest that activity-induced inter-spine competition for beta-catenin provides specificity for concurrent spine maturation and elimination and thus is critical for the molecular control of spine pruning during neural circuit refinement. PMID- 26255773 TI - Hepatic Progenitor Cells in Action: Liver Regeneration or Fibrosis? AB - Liver injury caused by drugs, viruses, and toxins that impede the proliferation of mature hepatocytes results in the activation of hepatic progenitor cells (HPCs), which then participate in the restoration of the damaged liver tissue. HPCs are known to be bipotential cells, capable of forming both hepatocytes and cholangiocytes when regeneration by mature hepatocytes is plagued or impaired. Both clinical studies of liver disease and certain experimental animal models of liver injury conspicuously show the presence of activated HPC response and proliferation. However, in addition to regeneration, the proliferation of HPCs also determines the appearance of a ductular reaction that has been correlated with progressive portal fibrosis, suggesting intricate links between activation of HPCs and fibrogenesis. The current review highlights the role of activated HPCs in both hepatic regeneration and fibrosis during liver injury. PMID- 26255772 TI - An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A. AB - Deletion of UBE3A causes the neurodevelopmental disorder Angelman syndrome (AS), while duplication or triplication of UBE3A is linked to autism. These genetic findings suggest that the ubiquitin ligase activity of UBE3A must be tightly maintained to promote normal brain development. Here, we found that protein kinase A (PKA) phosphorylates UBE3A in a region outside of the catalytic domain at residue T485 and inhibits UBE3A activity toward itself and other substrates. A de novo autism-linked missense mutation disrupts this phosphorylation site, causing enhanced UBE3A activity in vitro, enhanced substrate turnover in patient derived cells, and excessive dendritic spine development in the brain. Our study identifies PKA as an upstream regulator of UBE3A activity and shows that an autism-linked mutation disrupts this phosphorylation control. Moreover, our findings implicate excessive UBE3A activity and the resulting synaptic dysfunction to autism pathogenesis. PMID- 26255774 TI - Diversity in KIR gene repertoire in HIV-1 exposed infected and uninfected infants: A study from India. AB - Natural killer (NK) cells have antiviral activity mediated through killer immunoglobulin receptors (KIRs). Studies have shown the importance of KIR receptors in HIV infection. However reports on association of KIR genes in HIV infection from Indian population are limited, not a single study is reported in HIV exposed uninfected (EU) and infected infants. This study compared the KIR gene repertoire of HIV-1 positive (n = 29) with EU (n = 76) infants to elucidate its association with transmission. KIR genotyping was analysed using the PCR-SSP method. Viral load of mothers, CD4 count of both mothers and infected infants were done using commercial kits. The data was analysed using SPSS software. Results revealed presence of significantly high frequencies of activating gene KIR 2DS5 (P = 0.040) and inhibitory gene KIR 2DL3 (P = 0.013) in EU infants as compared to HIV-1 positive infants, confirmed with multivariable linear regression modelling. Fifty-nine KIR genotypes were identified in these 105 infants. Nine genotypes were unique, reported for the first time. Twenty six genotypes were shared with the World populations. Twenty four genotypes were reported for the first time from India. Specific KIR genotype combinations (GIDs) were exclusively present either in HIV-1 positive (n = 19) or in EU infants (n = 30). The Linkage disequilibrium (LD) analysis shows a strong linkage between four pairs of genes in HIV-1 positive and three pairs of genes in EU infants. In conclusion, this study revealed that, besides maternal confounding factors such as ART and viral load, specific KIR genes are associated independently with perinatal HIV infection. PMID- 26255775 TI - Sagittal otolith morphogenesis asymmetry in marine fishes. AB - This study investigated and compared asymmetry in sagittal otolith shape and length between left and right inner ears in four roundfish and four flatfish species of commercial interest. For each species, the effects of ontogenetic changes (individual age and total body length), sexual dimorphism (individual sex) and the otolith's location on the right or left side of the head, on the shape and length of paired otoliths (between 143 and 702 pairs according to species) were evaluated. Ontogenetic changes in otolith shape and length were observed for all species. Sexual dimorphism, either in otolith shape and length or in their ontogenetic changes, was detected for half of the species, be they round or flat. Significant directional asymmetry in otolith shape and length was detected in one roundfish species each, but its inconsistency across species and its small average amplitude (6.17% for shape and 1.99% for length) suggested that it has barely any biological relevance. Significant directional asymmetry in otolith shape and length was found for all flatfish species except otolith length for one species. Its average amplitude varied between 2.06 and 17.50% for shape and between 0.00 and 11.83% for length and increased significantly throughout ontogeny for two species, one dextral and one sinistral. The longer (length) and rounder otolith (shape) appeared to be always on the blind side whatever the species. These results suggest differential biomineralization between the blind and ocular inner ears in flatfish species that could result from perturbations of the proximal-distal gradient of otolith precursors in the endolymph and the otolith position relative to the geometry of the saccular epithelium due to body morphology asymmetry and lateralized behaviour. The fact that asymmetry never exceeded 18% even at the individual level suggests an evolutionary canalization of otolith shape symmetry to avoid negative effects on fish hearing and balance. Technically, asymmetry should be accounted for in future studies based on otolith shape. PMID- 26255776 TI - Crystal structure and activity of protein L-isoaspartyl-O-methyltransferase from Vibrio cholerae, and the effect of AdoHcy binding. AB - The repair enzyme Protein L-isoaspartyl-O-methyltransferase (PIMT) is widely distributed in various organisms. PIMT catalyzes S-adenosylmethionine (AdoMet) dependent methylation of abnormal L-isoaspartyl residues, formed by the deamidation of asparagines and isomerization of aspartates. We report the crystal structure of PIMT of Vibrio cholerae (VcPIMT), the aetiological agent for cholera, complexed with the demethylated cofactor S-adenosyl-L-homocysteine (AdoHcy) to 2.05 A resolution. A stretch of residues (39-58), lining the substrate-binding site, is disordered. Urea-induced unfolding free energy for apo and VcPIMT-AdoHcy complex reveals greater stability for the cofactor-bound protein. The kinetic parameters for the methyltransferase activity of the recombinant VcPIMT was determined using a continuous spectrophotometric color based assay using the peptide substrate [VYP(L-isoD)HA]. The enzyme exhibited activity higher than the Escherichia coli enzyme and closer to those from thermophilic bacteria and the mammalian source. The association constant for substrate binding is 2.29 * 10(6) M(-1), quite similar to that for AdoHcy. The crystal structure and the model of the peptide-bound structure indicate that the majority of the interactions used for cofactor/substrate binding are provided by the main-chain atoms. Evolutionary relationships derived based on a phylogenetic tree constructed using the PIMT sequences are in conformity with the crystal structures of nine AdoHcy-bound PIMTs. PMID- 26255777 TI - An Examination of Historical Loss Thinking Frequency and Rumination on Suicide Ideation in American Indian Young Adults. AB - No research has empirically investigated whether frequency of historical loss thinking is a potential risk factor for suicide ideation in American Indians. Results of this study demonstrated that the frequency of historical loss thinking was positively associated with brooding and reflection at a small magnitude, but was not directly related to suicide ideation. Bootstrapping analyses indicated small indirect effects of historical loss thinking frequency on suicide ideation through brooding and reflection individually, but only through brooding when analyzed in a parallel mediation model. These findings suggest that American Indians who more frequently engage in historical loss thinking may be susceptible to suicide ideation via an increase in ruminative tendencies, specifically brooding. PMID- 26255778 TI - Surface Plasmon Resonance Biosensor Based on Smart Phone Platforms. AB - We demonstrate a fiber optic surface plasmon resonance (SPR) biosensor based on smart phone platforms. The light-weight optical components and sensing element are connected by optical fibers on a phone case. This SPR adaptor can be conveniently installed or removed from smart phones. The measurement, control and reference channels are illuminated by the light entering the lead-in fibers from the phone's LED flash, while the light from the end faces of the lead-out fibers is detected by the phone's camera. The SPR-sensing element is fabricated by a light-guiding silica capillary that is stripped off its cladding and coated with 50-nm gold film. Utilizing a smart application to extract the light intensity information from the camera images, the light intensities of each channel are recorded every 0.5 s with refractive index (RI) changes. The performance of the smart phone-based SPR platform for accurate and repeatable measurements was evaluated by detecting different concentrations of antibody binding to a functionalized sensing element, and the experiment results were validated through contrast experiments with a commercial SPR instrument. This cost-effective and portable SPR biosensor based on smart phones has many applications, such as medicine, health and environmental monitoring. PMID- 26255779 TI - Reliable reference gene selection for quantitative real time PCR in Haemonchus contortus. AB - The aim of this work was to identify reliable reference genes for expression studies in adult Haemonchus contortus. Eleven candidate genes were identified and the stability of their expression was assessed in adult males and females of two genetically divergent H. contortus isolates: drug-susceptible (ISE) and multi drug-resistant (WR). Five genes with the most stable expression patterns were further assessed for suitability as reference genes in anthelmintic-treated H. contortus adults versus non-treated controls. We identified important differences in the expression of a number of candidate genes in anthelmintic-treated samples, confirming the need for careful validation of control genes for such experiments. We propose the use of multiple reference genes for expression studies in this species and found gpd, ama and far most suitable for adult H. contortus. PMID- 26255780 TI - Exposure assessment of epidermal growth factor to various tissues in mice after intravenous and subcutaneous administration. AB - OBJECTIVES: This study was conducted to examine the tissue distribution of human recombinant epidermal growth factor (EGF) after multiple intravenous and subcutaneous injections in mice. METHODS: Male BALB/c mice were divided into (1) EGF 1 mg/kg intravenous dose, (2) EGF 5 mg/kg intravenous dose, (3) drug-free intravenous control, (4) EGF 1 mg/kg subcutaneous dose, (5) EGF 5 mg/kg subcutaneous dose and (6) drug-free subcutaneous control groups. EGF and drug free dosing solutions were injected by intravenous and subcutaneous injections once a day for 3 days. EGF concentrations in serum and tissues of kidney, liver, lung, small intestine and tongue were determined by ELISA. KEY FINDINGS: As the intravenous and subcutaneous doses were increased from 1 to 5 mg/kg, serum Cmax and area under the concentration-time curve (AUC) values were increased dose proportionally. In lung, tongue and small intestine, increases in AUC were dose proportional after intravenous injections, but greater than dose-proportional after subcutaneous injections. The fold-increases in Cmax and AUC values were lowest in liver and highest in kidney. CONCLUSION: Based on Cmax and AUC data, the systemic exposure achieved by subcutaneous injections was comparable with that achieved by intravenous injections. PMID- 26255781 TI - Endoscope-assisted transoral removal of a thyroglossal duct cyst using a frenotomy incision: A prospective clinical trial. AB - OBJECTIVES/HYPOTHESIS: Endoscope-assisted transoral removal of a thyroglossal duct cyst (TGDC) has been introduced to clinical practice. However, the technical feasibility, efficacy, and safety of this procedure have not been studied. Herein, we conducted a prospective clinical trial to evaluate endoscope-assisted transoral removal of a TGDC. STUDY DESIGN: Prospective cohort study. METHODS: Thirty patients were included. We performed endoscope-assisted transoral removal of TGDCs and evaluated the clinical results and complications over more than 2 years. RESULTS: Endoscope-assisted transoral resection was successful in all cases. However, transient morbidity was noted in one patient. The mean operation time was 67.33 +/- 17.26 minutes. Surgery was not required for recurrence or revision during a follow-up. CONCLUSIONS: Endoscope-assisted transoral resection of a TGDC is a potentially safe and effective procedure leading to excellent functional and cosmetic outcomes. Additionally, considering the embryological development of TGDCs, the transoral approach can open a new access route to these cysts. LEVEL OF EVIDENCE: 2b. PMID- 26255782 TI - Enabling resources in people with dementia: a qualitative study about nurses' strategies that may support a sense of coherence in people with dementia. AB - AIMS AND OBJECTIVES: To explore nurses' strategies that may support the sense of coherence in people with dementia. BACKGROUND: People with dementia are often described as people with no resources, people who need support from family or from healthcare personnel to function in everyday life. Despite the disease, some people still have the resources needed to cope well with parts of their lives and experience coherence. To date, no research has explored any nurses' strategies that may support the sense of coherence in people with dementia. DESIGN: The design of the study is qualitative and exploratory. METHODS: Data were collected by participant observation and focus group interviews. Sixteen registered nurses from two different Norwegian nursing homes were recruited and participated in the study. Qualitative content analysis was used to analyse the data. RESULTS: The empirical material consisted of field notes from participant observation and transcripts from focus group interviews. Three generic categories were identified as strategies that may support sense of coherence in people with dementia: 'Finding and nurturing the individual's resources', 'Customising meaningful activities' and 'Finding creative solutions'. These categories were identified as strategies that may support and possibly enhance the sense of coherence in people with dementia. CONCLUSIONS: The findings provide an empirical base for assuming that with support and help from nurses, people with dementia may experience and strengthen their sense of coherence, therefore, the nurses need to be aware of the activities that may support and possibly enhance the sense of coherence in people with dementia. RELEVANCE TO CLINICAL PRACTICE: Despite the contextual limitations, this study highlights the need to identify and nurture resources in people with dementia, thus supporting their sense of coherence. The findings may contribute in enhancing the quality of care for people with dementia. PMID- 26255784 TI - Theoretical analysis of excited states and energy transfer mechanism in conjugated dendrimers. PMID- 26255783 TI - 18O proteomics reveal increased human apolipoprotein CIII in Hispanic HIV-1+ women with HAART that use cocaine. AB - PURPOSE: Drug abuse is a major risk factor in the development and progression of HIV-1. This study defines the alterations in the plasma proteome of HIV-1 infected women that use cocaine. EXPERIMENTAL DESIGN: Plasma samples from 12 HIV seropositive Hispanic women under antiretroviral therapy were selected for this study. Six sample pairs were matched between nondrug users and cocaine users. After IgG and albumin depletion, SDS-PAGE, and in-gel digestion, peptides from nondrug users and cocaine users were labeled with (16) O and (18) O, respectively, and subjected to LC-MS/MS and quantitation using Proteome Discover and QuiXoT softwares and validated by ELISA. RESULTS: A total of 1015 proteins were identified at 1% false discovery rates (FDR). Statistical analyses revealed 13 proteins with significant changes between the two groups, cocaine and noncocaine users (p < 0.05). The great majority pertained to protection defense function and the rest pertained to transport, homeostatic, regulation, and binding of ligands. Apolipoprotein CIII was increased in plasma of HIV+ Hispanic women positive for cocaine compared to HIV+ nondrug users (p <= 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: Increased human apolipoprotein CIII warrants that these patients be carefully monitored to avoid the increased risk of cardiovascular events associated with HIV, HAART, and cocaine use. PMID- 26255786 TI - Additional Prognostic Value of EAS index in predicting the occurrence of rehospitalizations in chronic heart failure: data from the Daunia Heart Failure Registry. AB - BACKGROUND: Tissue Doppler imaging (TDI) may be useful in identifying subjects at higher risk among patients with chronic heart failure (CHF). The clinical role of newly developed TDI parameters, however, still needs to be documented. METHODS: A total of 287 consecutive patients with CHF enrolled in the Daunia Heart Failure Registry underwent echocardiography assessment and were followed prospectively for a median 255 (204-316) days. Conventional echocardiography and TDI parameters were calculated. We also quantified by TDI a combined index (EAS index) of diastolic and systolic performance E'/(A'xS') and assessed its possible additional prognostic role in combination with 'traditional' parameters such as left ventricular ejection fraction (LVEF) and myocardial performance index (MPI). RESULTS: Subjects readmitted for worsening HF were characterized by higher levels of EAS index (median 0.14 (95% C.I. 0.12-0.21) vs. 0.11 (0.10-0.12, P < 0.05)). Increased rates of rehospitalization were found in subjects with EAS index >median (0.115) (21% vs. 10%, P < 0.05); higher EAS index values predicted the incidence of readmissions for worsening HF during follow-up, even at multivariable analysis. The assessment of EAS index in addition to LVEF and MPI showed an adjunctive prognostic value (log-rank P < 0.001 and P < 0.05, respectively). CONCLUSIONS: EAS index assessed by TDI may be helpful in predicting the risk of rehospitalizations in subjects with CHF. EAS index may represent an independent adjunctive tool for the risk stratification of patients with CHF in addition to 'traditional' tools such as LVEF or MPI. PMID- 26255787 TI - Numerical modeling of heart valves using resistive Eulerian surfaces. AB - The goal of this work is the development and numerical implementation of a mathematical model describing the functioning of heart valves. To couple the pulsatile blood flow with a highly deformable thin structure (the valve's leaflets), a resistive Eulerian surfaces framework is adopted. A lumped-parameter model helps to couple the movement of the leaflets with the blood dynamics. A reduced circulation model describes the systemic hemodynamics and provides a physiological pressure profile at the downstream boundary of the valve. The resulting model is relatively simple to describe for a healthy valve and pathological heart valve functioning while featuring an affordable computational burden. Efficient time and spatial discretizations are considered and implemented. We address in detail the main features of the proposed method, and we report several numerical experiments for both two-dimensional and three dimensional cases with the aim of illustrating its accuracy. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26255788 TI - The Arabidopsis thylakoid transporter PHT4;1 influences phosphate availability for ATP synthesis and plant growth. AB - The Arabidopsis phosphate transporter PHT4;1 was previously localized to the chloroplast thylakoid membrane. Here we investigated the physiological consequences of the absence of PHT4;1 for photosynthesis and plant growth. In standard growth conditions, two independent Arabidopsis knockout mutant lines displayed significantly reduced leaf size and biomass but normal phosphorus content. When mutants were grown in high-phosphate conditions, the leaf phosphorus levels increased and the growth phenotype was suppressed. Photosynthetic measurements indicated that in the absence of PHT4;1 stromal phosphate was reduced to levels that limited ATP synthase activity. This resulted in reduced CO2 fixation and accumulation of soluble sugars, limiting plant growth. The mutants also displayed faster induction of non-photochemical quenching than the wild type, in line with the increased contribution of DeltapH to the proton-motive force across thylakoids. Small-angle neutron scattering showed a smaller lamellar repeat distance, whereas circular dichroism spectroscopy indicated a perturbed long-range order of photosystem II (PSII) complexes in the mutant thylakoids. The absence of PHT4;1 did not alter the PSII repair cycle, as indicated by wild-type levels of phosphorylation of PSII proteins, inactivation and D1 protein degradation. Interestingly, the expression of genes for several thylakoid proteins was downregulated in the mutants, but the relative levels of the corresponding proteins were either not affected or could not be discerned. Based on these data, we propose that PHT4;1 plays an important role in chloroplast phosphate compartmentation and ATP synthesis, which affect plant growth. It also maintains the ionic environment of thylakoids, which affects the macro-organization of complexes and induction of photoprotective mechanisms. PMID- 26255789 TI - Reading and spelling skills in German third graders: Examining the role of student and context characteristics. AB - BACKGROUND: Educational processes and outcomes are influenced by a multitude of factors, including individual and contextual characteristics. Recently, studies have demonstrated that student and context characteristics may produce unique and cumulative effects on educational outcomes. AIMS: The study aimed to investigate (1) the relative contribution of student, classroom, and school characteristics to reading fluency and orthographic spelling, (2) the relative contribution of specific predictors to reading fluency and orthographic spelling within the sets of student, classroom, and school characteristics, and (3) whether the contribution of student, classroom, and school characteristics differs for reading fluency and orthographic spelling. SAMPLE: Participants were 789 German third-grade students from 56 classrooms in 34 schools. METHOD: Students completed an intelligence test and a questionnaire assessing self-control. Reading fluency and orthographic spelling performance were assessed using standardized achievement tests. Multilevel structural equation modelling was used to control for the hierarchical structure of educational data. RESULTS AND CONCLUSION: Variances in students' reading and spelling skills were in large part explained by student characteristics (>90%). Classroom and school characteristics yielded little variance. Student-level intelligence and self-control were significantly related to reading fluency. For orthographic spelling, student-level intelligence and self-control, class-average intelligence, and, at the school level, the socio economic status of the school's neighbourhood were significant predictors. Future research needs to investigate relevant classroom and school factors that may directly and indirectly relate to academic outcomes. PMID- 26255790 TI - 1H and 13C NMR spectral assignments of 2-pyrone derivatives from an endophytic fungus of sarcosomataceae. PMID- 26255792 TI - EDITORIAL. PMID- 26255791 TI - WHI-131 Promotes Osteoblast Differentiation and Prevents Osteoclast Formation and Resorption in Mice. AB - The small molecule WHI-131 is a potent therapeutic agent with anti-inflammatory, antiallergic, and antileukemic potential. However, the regulatory effects of WHI 131 on osteoblast and osteoclast activity are unclear. We examined the effects of WHI-131 on osteoblast and osteoclast differentiation with respect to bone remodeling. The production of receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblasts in response to interleukin (IL)-1 or IL-6 stimulation decreased by 56.8% or 50.58%, respectively, in the presence of WHI-131. WHI-131 also abrogated the formation of mature osteoclasts induced by IL-1 or IL-6 stimulation. Moreover, WHI-131 treatment decreased RANKL-induced osteoclast differentiation of bone marrow-derived macrophages, and reduced the resorbing activity of mature osteoclasts. WHI-131 further decreased the mRNA and protein expression levels of c-Fos and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) by almost twofold, and significantly downregulated the mRNA expression of the following genes: tartrate-resistant acid phosphatase (TRAP), osteoclast associated receptor (OSCAR), DC-STAMP, OC-STAMP, ATP6v0d2, and cathepsin K (CtsK) compared with the control group. WHI-131 further suppressed the phosphorylation of protein kinase B (Akt) and degradation of inhibitor of kappa B (IkappaB); Ca(2+) oscillation was also affected, and phosphorylation of the C-terminal Src kinase (c-Src)-Bruton agammaglobulinemia tyrosine kinase (Btk)-phospholipase C gamma 2 (PLCgamma2) (c-Src-Btk-PLCg2 calcium signaling pathway) was inhibited following WHI-131 treatment. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway was activated by WHI-131, accompanied by phosphorylation of STAT3 Ser727 and dephosphorylation of STAT6. In osteoblasts, WHI-131 caused an approximately fourfold increase in alkaline phosphatase activity and Alizarin Red staining intensity. Treatment with WHI-131 increased the mRNA expression levels of genes related to osteoblast differentiation, and induced the phosphorylation of Akt, p38, and Smad1/5/8. Furthermore, 5-week-old ICR mice treated with WHI-131 exhibited antiresorbing effects in a lipopolysaccharide-induced calvaria bone loss model in vivo and increased bone-forming activity in a calvarial bone formation model. Therefore, the results of this study show that WHI-131 plays a dual role by inhibiting osteoclast differentiation and promoting osteoblast differentiation. Thus, WHI 131 could be a useful pharmacological agent to treat osteoporosis by promoting bone growth and inhibiting resorption. PMID- 26255794 TI - Dietary exposure to benzoxazinoids enhances bacteria-induced monokine responses by peripheral blood mononuclear cells. AB - SCOPE: To examine potentially immunomodulating effects of dietary benzoxazinoids (BXs), present in cereal grains. METHODS AND RESULTS: Nineteen healthy volunteers were randomly distributed into two groups, who received diets with high or low content of BXs for 3 wk. After a week's wash-out, the groups switched diets. Peripheral blood mononuclear cells (PBMCs) were stimulated with Porphyromonas gingivalis, Escherichia coli lipopolysaccharide (LPS), or tetanus toxoid (TT). PBMCs from a healthy donor received the same stimuli in presence of serum from each participant receiving BXs. The production of monokines, T-cell cytokines and T-helper cell proliferation were assessed. A 3-wk diet with high BX content enhanced IL-1beta responses against LPS and P. gingivalis, as well as TNF-alpha response against P. gingivalis, after 24 h of stimulation. Moreover, IL-6 was found to be increased after 7 days of stimulation with LPS. No effect was observed on T-cell cytokines or proliferation. BX levels in serum after a single meal did not modify cytokine responses. CONCLUSION: High dietary intake of BXs enhances bacteria-induced production of pro-inflammatory monokines by PBMCs, but not T-cell responses; presumably due to intrinsic changes within PBMCs, built up over 3 wk of BX-rich diet, rather than to an immediate effects of BXs contained in serum. PMID- 26255795 TI - Small Molecules in the Treatment of Psoriasis. AB - Preclinical Research Psoriasis is an inflammatory systemic skin disease that affects various parts of the body requiring long-term management due to its chronic nature. Available treatment options include topical, systemic or biological therapies, which have long-term limitations associated to toxicity, tolerability and risk for adverse effects requiring its intermittent use and close monitoring. Small molecules modulate proinflammatory cytokines, selectively inhibit signaling pathways and showing potential to treat inflammatory diseases in patients not responding to conventional treatments. Presently, small molecules available are phosphodiesterase 4 inhibitors or Janus kinase inhibitors. Other small molecules under development for psoriasis include fumaric acid esters, amygdalin analogs, protein kinase C inhibitors, mitogen-activated protein kinase inhibitors, spleen protein kinase inhibitors, other tyrosine kinase inhibitors, sphingosine 1-phosphate receptor agonists, and A3 adenosine receptor agonists. These new treatment options represent important advances in the development of specific drugs to respond to the goals of treatment and improve patient quality of life. PMID- 26255796 TI - Rates of vascular access use in transcatheter aortic valve replacement: A look into the next generation. AB - OBJECTIVE/BACKGROUND: As smaller TAVR delivery systems emerge we sought to identify differences in vascular access use. METHODS: We analyzed all patients who had undergone TAVR in a single-center from March 2012 to May 2014. We identified all patients who had undergone nonfemoral TAVR and reviewed their femoral dimensions using CT imaging taking into vascular pathology and minimal lumen diameter (MLD). We then identified those patients in whom a smaller delivery system could have been used if such technology was available at that time. RESULTS: In total 208 consecutive TAVRs were performed, 129 cases using femoral arterial access and 75 cases using non-femoral access; 28 transapical, 27 transcaval, 12 transaortic, and 8 via an antegrade transseptal venous approach. Of the 75 nonfemoral access cases, 63 were completed using commercially available first-generation valves (Sapien Valve) and 12 using second-generation valves under research protocols (Sapien XT Valve). Of the 63 cases performed via a non femoral route using a first generation valve, 31 cases could have been approached via a transfemoral (TF) route using second-generation delivery systems; and 48 cases could have been approached via a TF route using third generation delivery systems (S3 Valve). Of the 12 cases performed via a nonfemoral route using a second-generation valve, 4 cases could have been approached via a TF route using a third-generation delivery system. In total, only 11% of patients undergoing TAVR could not accommodate smaller second and third generation devices. CONCLUSIONS: As second and third generation devices become commercially available, we anticipate that 89% of cases will be preformed using a TF approach. PMID- 26255797 TI - Strengthening Midwifery to End Preventable Maternal, Child, and Newborn Deaths. PMID- 26255798 TI - The Fascinating and Complex Role of the Placenta in Pregnancy and Fetal Well being. AB - Existing evidence implicates the placenta as the origin of some common pregnancy complications. Moreover, some maternal conditions, such as inadequate nutrition, diabetes, and obesity, are known to adversely affect placental function, with subsequent negative impact on the fetus and newborn. The placenta may also contribute to fetal programming with health consequences into adulthood, such as cardiovascular, metabolic, and mental health disorders. There is evidence that altered placental development, specifically impaired trophoblast invasion and spiral artery remodeling in the first trimester, is the origin of preeclampsia. Prenatal care providers who understand the relationships between placental health and maternal-newborn health can better inform and guide women to optimize health early in pregnancy and prior to conception. This article reviews the current understanding of placental function; placental contributions to normal fetal brain development and timing of birth; and impact of maternal nutrition, obesity, and diabetes on the placenta. PMID- 26255799 TI - Exploring Placentophagy in Humans: Problems and Recommendations. AB - Placentophagy, the practice of afterbirth ingestion among humans, has grown among middle-class, white women in Western societies. Although the reasons for placentophagy are varied, it is generally promoted as a means to help postpartum women stabilize mood, enhance recovery, and increase milk production. Virtually no studies have explored the effects of placentophagy on humans, and several researchers have called for studies examining the effects of human placentophagy. However, prior to examining the effects of placentophagy, a number of methodological issues need to be addressed. The present review explores research examining the effects of placentophagy in animals and humans and presents the theoretical assumptions behind placentophagy and its effects. Methodological issues related to placentophagy research are clarified, and existing research related to the nutritional and hormonal components of the placenta and their effects on milk production and postpartum depression are reviewed. Finally, implications and recommendations for future research are discussed. PMID- 26255800 TI - Comprehensive Review of the Stillborn Placenta. AB - Stillbirth is a common complication of pregnancy, affecting one in every 160 women in the United States who are pregnant. Stillbirth has a significant adverse medical and psychological impact on families. Identifying the cause of stillbirth can yield recommendations for the management of future pregnancies, provide a risk of recurrence, and give families a sense of closure. The placental examination is one component of a comprehensive stillbirth investigation. A systematic approach to the examination of the placenta is presented, along with an explanation of critical findings that have been associated with stillbirth. A checklist for placental evaluation by the provider who attends the birth is provided, along with information on stillbirth assessment programs. PMID- 26255801 TI - Pregnant Adolescents, Beliefs About Healthy Eating, Factors that Influence Food Choices, and Nutrition Education Preferences. AB - INTRODUCTION: Healthy eating among pregnant adolescents is essential for the well being of developing adolescent females and their fetuses, as well as for the prevention of adult chronic illness. Understanding factors that influence and prohibit healthy eating, along with preferences for nutrition education in the pregnant adolescent population, is critical when designing and implementing appropriate nutrition education programs. The purpose of this study was to collect individual viewpoints of pregnant adolescents to facilitate the development of a nutrition intervention. METHODS: This qualitative study using focus group methodology was conducted among pregnant adolescents. Participants (N = 14) were recruited through and teen parenting programs in the Mid-Atlantic region. Focus groups were guided by 6 open-ended questions that were developed based on implications from a previous study that surveyed eating habits of pregnant adolescents. Data were analyzed and coded using verbatim transcripts. Transcripts were read carefully for overall content and identification of major categories and then compared for similar and contrasting data. RESULTS: Four recurring themes emerged that described beliefs about healthy eating, influences on food choices, and nutrition education preferences: 1) pregnant adolescents demonstrate overall knowledge of healthy foods but are unwilling to give up unhealthy foods; 2) parents, offspring, and pregnancy influence healthy eating habits; 3) pregnant adolescents choose foods based on appearance and taste, cravings, convenience, and cost; and 4) pregnancy alters eating habits. Nutrition education in this population should be peer- and adolescent-focused and incorporate preferred methods of learning and favored incentives. DISCUSSION: Pregnant adolescents are more likely to attend educational programs that are population-specific and peer-focused, and include incentives that make cooking easier, more convenient, and affordable. Program content should be available to potential participants ahead of time. Preferred methods of learning include video format, peer discussion, and hands-on cooking with active participation in food preparation. Foods that are prepared should be visually appealing and adolescent friendly. PMID- 26255802 TI - Prevalence of Perineal Lacerations in Women Giving Birth at Midwife-Led Birth Centers in Japan: A Retrospective Descriptive Study. AB - INTRODUCTION: Perineal lacerations during birth can cause ongoing physical, psychological, and social problems. However, the prevalence of lacerations following normal spontaneous vaginal birth in women with low-risk pregnancies is unknown. We investigated the prevalence of perineal lacerations and factors associated with lacerations among low-risk Japanese women who had normal spontaneous vaginal births. METHODS: Pregnant women who were cared for between January 1, 2008, and June 30, 2011, in 3 midwife-led birth centers in Tokyo, Japan, where invasive medical interventions are rarely applied, were included. We investigated the prevalence of perineal lacerations and conducted univariate and multivariate analyses on the relationship between the prevalence of lacerations and selected maternal and neonatal characteristics. RESULTS: A total of 1881 pregnant women had initial antenatal care at one of the 3 study sites. Of these, 1521 were eligible for inclusion. Intact perineum rates were 49.5% (209/422) and 69.9% (768/1099) in nulliparous and multiparous women, respectively. First-degree lacerations occurred in 36.7% (155/422) of nulliparous women and 27.1% (298/1099) of multiparous women, and second-degree lacerations occurred in 13.5% (57/422) of nulliparous women and 3.0% (33/1099) of multiparous women. One multiparous woman experienced a third-degree laceration (0.1%). No women suffered fourth-degree or cervical lacerations. Logistic regression analyses showed that older age (>= 35 years), the hands-and-knees position, and using a birthing chair during birth increased the risk of perineal laceration both in nulliparous and in multiparous women. In addition, waterbirths increased the risk of perineal laceration in multiparous women. DISCUSSION: In normal spontaneous vaginal births among a low risk population, it is possible to avoid episiotomy and achieve a high rate of intact perineum, with few second-degree and third-degree lacerations. PMID- 26255804 TI - Closed Claims Analysis of Medical Malpractice Lawsuits Involving Midwives: Lessons Learned Regarding Safe Practices and the Avoidance of Litigation. AB - INTRODUCTION: The risk of litigation remains of concern to midwives, their practice partners, employers, and malpractice insurance providers. Closed claims analysis is a method of examining risk patterns and behaviors in lawsuits, including those involving health care practices. The purpose of this investigation was to evaluate claims brought against midwives, with the intent of developing strategies to decrease the incidence of litigation. METHODS: Data were collected in joint meetings with members of the American College of Nurse Midwives (ACNM); the American Association of Birth Centers; the American International Group (AIG), a major malpractice insurer for certified nurse midwives/certified midwives (CNMs/CMs); and Contemporary Insurance Services, an independent insurance agency that has worked with AIG to facilitate the writing of malpractice insurance policies for CNMs/CMs. The purpose of the meetings was to review 162 litigation cases that involved midwives insured by AIG and had been closed between the years 2002 and 2011. Follow-up analyses of data and reporting of results were performed by the authors, who are members of the Professional Liability Section of the ACNM Division of Standards and Practice. RESULTS: Findings reflected 7 major categories of liability risk ranging from the most prevalent (ie, fetal/newborn complications or death) to the least prevalent (ie, attending a vaginal birth after cesarean). Data also were examined regarding the highest amounts incurred in court decisions or pretrial settlements because they were related to types of adverse outcomes that occurred. DISCUSSION: Recommendations for improving clinical practice and avoiding litigation based on findings from the closed claims analysis include, but are not limited to, the need for thorough and accurate documentation in practice, appropriate and timely consultation and collaboration, and the presence of practitioners whose clinical skills match the level of care assessed to be necessary for each woman for whom care is offered. PMID- 26255803 TI - Perineal Injury During Childbirth Increases Risk of Postpartum Depressive Symptoms and Inflammatory Markers. AB - INTRODUCTION: Perineal lacerations during childbirth affect more than 65% of women in the United States. Little attention has been given to the long-term biologic consequences associated with perineal lacerations or possible associations with postpartum mental health. In this article, we describe the results of a study that explored inflammatory cytokines in women who reported perineal lacerations during childbirth and the relationship with stress and depressive symptoms during the first 6 months postpartum. METHODS: A repeated measures design was used to explore the relationship between varying degrees of perineal lacerations, inflammatory cytokines, postpartum stress, and depressive symptoms in 153 women over 6 months. Depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS), and maternal stress was measured using the Perceived Stress Scale. Plasma was analyzed for proinflammatory (tumor necrosis factor alpha, interleukin 6 (IL-6), interleukin-1 beta, interferon gamma) and anti-inflammatory (interleukin 10) cytokines. Levels of cytokines were compared between women with or without varying degrees of injury. RESULTS: A relationship was identified between symptoms of depression and a second-degree or more severe perineal laceration starting at one month postpartum (P = .04) and continuing through 3 months postpartum (P = .03). Similarly, stress symptoms were higher at 3 months postpartum (P = .02). Markers of inflammation were significantly higher among this group, with IL-6 increased at 2 weeks postpartum (P = .02) and remaining elevated through 2 months postpartum (P = .003); there were also significant differences in pro- to anti-inflammatory cytokine ratios out to 6 months postpartum. Regression analysis indicated that second-degree or more severe lacerations accounted for 5.9% of the variance in EPDS score at one month postpartum (P = .024, F = 2.865, t = 2.127), increasing substantially when the one month stress score was included as well. DISCUSSION: This study suggests that perineal lacerations, inflammation, stress, and depressed mood are associated; however, more research is needed to elucidate the actual relationship between inflammation and mental health in women who experience such injuries. PMID- 26255805 TI - Rebozo Technique for Fetal Malposition in Labor. AB - Fetal occiput posterior position is associated with increased maternal and fetal morbidities. Currently, clinicians have limited evidence-based techniques or tools to remedy fetal occiput posterior position. The traditional Mexican rebozo technique of pelvic massage, sifting, or jiggling offers a potentially valuable tool to help correct fetal malposition. This article reviews the adaptation of 3 rebozo techniques that can be used in labor to encourage optimum fetal positioning; outlines hospital considerations for safety, fetal heart rate monitoring, and universal precautions; and reviews the implementation plan to introduce and sustain use of the rebozo in a large academic medical center. PMID- 26255808 TI - Editorial Comment on "Evaluation of the Treatment of Congenital Penile Curvature including Psycho-Sexual Assessment". PMID- 26255809 TI - Droplet-Array (DA) Sandwich Chip: A Versatile Platform for High-Throughput Cell Screening Based on Superhydrophobic-Superhydrophilic Micropatterning. AB - A droplet-array (DA) sandwich chip is a miniaturized platform for cell-based high throughput screening. It is based on sandwiching of a glass slide with a preprinted library and a superhydrophobic-superhydrophilic pattern, which consists of thousands of simultaneously formed microdroplets containing cells. The DA sandwich chip allows for one-step cell seeding, simultaneous initiation of screening, and 1000 times less reagent consumption than a regular 96-well plate. PMID- 26255807 TI - Oral antineoplastic agents: how do we care about adherence? AB - AIMS: Oral therapies, including hormone-based or targeted therapies, have recently taken an increasing place in cancer treatment. In this context, a state of the art of the available studies dealing with the adherence of adult patients to oral anticancer treatment is warranted. The purpose of this review is to address (i) the association between assessment methods and measured adherence, (ii) the putative factors related to adherence and (iii) new ways of improving adherence to oral cancer therapies. METHODS: We conducted a literature-based narrative review of studies obtained from Pubmed using medical subject heading terms and free-text terms combining concepts related to oral anticancer medication and adherence. RESULTS: The analysis is based on 48 studies published since 1990, mostly assessing hormone-based therapy in breast cancer and targeted therapies in chronic myeloid leukaemia. Various methods of adherence were reported including self-report, medication measurement or combinations of methods. Adherence rates were found to vary from 14% to 100%. Beside patient related-factors, adherence rate discrepancies were found to be dependent on the method used. Furthermore, there was no consensual definition of adherence even regarding the same methods, some of them tolerating a period of interruption during the treatment period. Finally, several studies addressing persistence found a progressive decrease in adherence with time. CONCLUSION: Adherence to novel oral therapies is a major issue and further research is warranted to standardize adherence assessment in clinical studies better and to define better the most appropriate approaches to improve long term adherence in oncology practice. PMID- 26255810 TI - Simultaneous separation of three isomeric sennosides from senna leaf (Cassia acutifolia) using counter-current chromatography. AB - Senna leaf is widely consumed as tea to treat constipation or to aid in weight loss. Sennoside A, A1 , and B are dirheinanthrone glucosides that are abundant and the bioactive constituents in the plant. They are isomers that refer to the (R*R*), (S*S*), and (R*S*) forms of protons on C-10 and C-10' centers and it is difficult to refine them individually due to their structural similarities. The new separation method using counter-current chromatography successfully purified sennoside A, A1 , and B from senna leaf (Cassia acutifolia) while reversed-phase medium-pressure liquid chromatography yielded sennoside A only. n Butanol/isopropanol/water (5:1:6, v/v/v) was selected as the solvent system for counter-current chromatography operation, and the partition coefficients were carefully determined by adding different concentrations of formic acid. High resolution mass spectrometry and NMR spectroscopy were performed to verify the chemical properties of the compounds. PMID- 26255812 TI - Cerebral Vascular Malformations and Headache. PMID- 26255811 TI - Probable aerosol transmission of severe fever with thrombocytopenia syndrome virus in southeastern China. AB - Some clusters of severe fever with thrombocytopenia syndrome virus (SFTSV) infection were reported in China as of 2010. However, to date, there has been no epidemiologic evidence of aerosol transmission of SFTSV. Epidemiologic investigations were conducted after a cluster of 13 cases of SFTSV in May 2014. A total of 13 cases, including 11 confirmed cases and one clinically diagnosed case, were identified besides the case of the index patient. The index patient experienced onset of SFTSV on 23 April and died on 1 May. The patients with secondary cases had onset from 10 to 16 May, peaking on 13 May. Moreover, eight secondary cases occurred in family members of the index patient, and the other five cases occurred in neighbors of the index patient. According to epidemiologic investigations, patients 1, 3, 4, 5, 6, 7, 9 and 12 contracted the disease through contact with blood of the index patient. Notably, patients 8 and 10 did not have a history of contact with the blood of the index patient, but they stayed in the mourning hall for hours. SFTSV could be transmitted from person to person by direct contact and/or aerosol transmission, and it is important to consider aerosol transmission as a possible transmission route. PMID- 26255813 TI - Evaluating surgeon attitudes towards the safety and efficacy of portal vein occlusion and associating liver partition and portal vein ligation: a report of the MALINSA survey. AB - BACKGROUND: Various techniques, including portal vein embolization (PVE), contralateral portal vein ligation (PVL) and associating liver partition and portal vein ligation (ALPPS), are being used to augment the future liver remnant (FLR) volume in preparation for a major hepatectomy. The present study aims to survey and document the availability, variation, utilization and attitudes toward these techniques across centres in North and South America. METHODS: A descriptive, 20-question survey was developed and internally validated with expert review. The survey was distributed to 115 centres in North and South America. RESULTS: Of the 115 centres, 54 institutions (47%) returned the surveys. Regarding the question of which modality was most likely to produce adequate hypertrophy, the respondents were equally distributed (ALPPS, 37%; PVE, 35%; equal, 22%). The procedure that respondents judged the safest to achieve liver hypertrophy was PVE (82%). Institutions with capability to extended PVE to segment IV rated the likelihood of PVE technical success (6.2 versus 8.5, P = 0.012) and likelihood of subsequent hypertrophy (5.6 versus 7.8, P = 0.011) higher than institutions without this capability. Although the use of modern embolic materials was associated with a likelihood of successful PVE (P = 0.032), only 49% of respondents who performed PVE used embolic microspheres. CONCLUSIONS: There exists significant variability in utilization of and attitudes towards the available techniques for FLR volume augmentation. Penetration of best practice techniques for PVE is lacking, and may be contributing towards disappointment with PVE efficacy, potentially motivating the utilization of the riskier ALPPS procedure. PMID- 26255814 TI - Rebound exercise: A beneficial adjuvant for sedentary non-insulin-dependent type 2 diabetic individuals in a rural environment. AB - OBJECTIVE: Although physical activity and exercises are recommended for diabetes, fear of fatigue and resources are often constraints. Rebound exercise on a mini trampoline is a relatively new aerobic exercise and this study evaluated its impact on glycosylated haemoglobin (HbA1c ), fasting plasma glucose (FPG) and body mass index (BMI) for sedentary type 2 diabetic (T2D) individuals from a rural environment. DESIGN/SETTING: A randomised controlled single-blind, pre- and post-test study in an outreach rural rehabilitation gymnasium. PARTICIPANTS AND INTERVENTION: Ninety T2D individuals from rural Nigeria aged 39.44 +/- 8.61 attending a diabetic outpatient clinic participated in this study as a control (n = 45) or rebound exercise (n = 45) group. The control group watched videos and read health magazines while the rebound group exercised three times per week for 20-30 min over 9 weeks at moderate intensity of 40-60% of heart rate maximum. OUTCOME MEASURES: Heart and respiratory rates, blood pressure, oxygen saturation, HbA1c , FPG and BMI values were recorded pre- and post-interventions. RESULTS: There were no significant differences between groups at baseline and compliance with rebound exercise was 93% (n = 42). Post 9 weeks there were significant improvements (P < 0.05) in mean HbA1c (8.65 to 7.12%), FPG (9.08 to 6.92 mmol L( 1)) and BMI (26.1 to 25.6 kg m(-2)) in the exercise group with blood pressure, heart and respiratory rates also increasing during the exercise but without any adverse reactions. CONCLUSION: Rebound exercise is simple, inexpensive and enjoyable. It can be a beneficial recreational adjuvant exercise for improving HbA1c , FPG and BMI in T2D individuals in a rural environment and reduce health care costs and pharmacological complications associated with diabetes. PMID- 26255815 TI - Dimethyloxalylglycine treatment of brain-dead donor rats improves both donor and graft left ventricular function after heart transplantation. AB - OBJECTIVE: Hypoxia inducible factor (HIF)-1 pathway signalling has a protective effect against ischemia/reperfusion injury. The prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG) activates the HIF-1 pathway by stabilizing HIF 1alpha. In a rat model of brain death (BD)-associated donor heart dysfunction we tested the hypothesis that pre-treatment of brain-dead donors with DMOG would result in a better graft heart condition. METHODS: BD was induced in anesthetized Lewis rats by inflating a subdurally placed balloon catheter. Controls underwent sham operations. Then, rats were injected with an intravenous dose of DMOG (30 mg/kg) or an equal volume of physiologic saline. After 5 hours of BD or sham operation, hearts were perfused with a cold (4 degrees C) preservation solution (Custodiol; Dr. Franz Kohler Chemie GmbH; Germany), explanted, stored at 4 degrees C in Custodiol, and heterotopically transplanted. Graft function was evaluated 1.5 hours after transplantation. RESULTS: Compared with control, BD was associated with decreased left ventricular systolic and diastolic function. DMOG treatment after BD improved contractility (end-systolic pressure volume relationship E'max: 3.7 +/- 0.6 vs 3.1 +/- 0.5 mm Hg/u1; p < 0.05) and left ventricular stiffness (end-diastolic pressure volume relationship: 0.13 +/- 0.03 vs 0.31 +/- 0.06 mm Hg/u1; p < 0.05) 5 hours later compared with the brain-dead group. After heart transplantation, DMOG treatment of brain-dead donors significantly improved the altered systolic function and decreased inflammatory infiltration, cardiomyocyte necrosis, and DNA strand breakage. In addition, compared with the brain-dead group, DMOG treatment moderated the pro-apoptotic changes in the gene and protein expression. CONCLUSIONS: In a rat model of potential brain-dead heart donors, pre-treatment with DMOG resulted in improved early recovery of graft function after transplantation. These results support the hypothesis that activation of the HIF-1 pathway has a protective role against BD associated cardiac dysfunction. PMID- 26255816 TI - miR-378a-3p modulates tamoxifen sensitivity in breast cancer MCF-7 cells through targeting GOLT1A. AB - Breast cancer is a hormone-dependent cancer and usually treated with endocrine therapy using aromatase inhibitors or anti-estrogens such as tamoxifen. A majority of breast cancer, however, will often fail to respond to endocrine therapy. In the present study, we explored miRNAs associated with endocrine therapy resistance in breast cancer. High-throughput miRNA sequencing was performed using RNAs prepared from breast cancer MCF-7 cells and their derivative clones as endocrine therapy resistant cell models, including tamoxifen-resistant (TamR) and long-term estrogen-deprived (LTED) MCF-7 cells. Notably, miR-21 was the most abundantly expressed miRNA in MCF-7 cells and overexpressed in TamR and LTED cells. We found that miR-378a-3p expression was downregulated in TamR and LTED cells as well as in clinical breast cancer tissues. Additionally, lower expression levels of miR-378a-3p were associated with poor prognosis for tamoxifen-treated patients with breast cancer. GOLT1A was selected as one of the miR-378a-3p candidate target genes by in silico analysis. GOLT1A was overexpressed in breast cancer specimens and GOLT1A-specific siRNAs inhibited the growth of TamR cells. Low GOLT1A levels were correlated with better survival in patients with breast cancer. These results suggest that miR-378a-3p-dependent GOLT1A expression contributes to the mechanisms underlying breast cancer endocrine resistance. PMID- 26255817 TI - Correlation between optic disc perfusion and glaucomatous severity in patients with open-angle glaucoma: an optical coherence tomography angiography study. AB - PURPOSE: To explore how optic disc perfusion varies in patients with open-angle glaucoma (OAG) and how this correlates with glaucoma severity. METHODS: We performed a prospective and cross-sectional observational study that included 62 eyes from 62 patients with OAG, divided into three groups according to their visual field (VF) results, and 20 eyes from 20 normal control subjects. Optic disc perfusion was studied using optical coherence tomography angiography (angio OCT), and flow index and vessel density were determined. The VF, mean deviation (MD), pattern standard deviation (PSD), retinal nerve fiber layer (RNFL) thickness, and ganglion cell complex (GCC) thickness were also recorded. The potential associations between disc perfusion and VF defects or structural loss were analyzed. RESULTS: In OAG patients, the disc flow index and vessel density were significantly lower than in normal controls (all p<0.001) and were correlated with the severity of glaucoma. In OAG eyes, the flow index and vessel density were significantly correlated with MD, RNFL, and GCC thickness (all p<0.01), but were not in the normal controls. The receiver operating characteristic (ROC) curve analysis also revealed that disc flow index and vessel density had the power to differentiate normal eyes from eyes with OAG (under the ROC curves: 0.82 and 0.80, respectively). CONCLUSIONS: Angiograms demonstrated a reduced disc flow index and vessel density in glaucoma, and this reduction was closely related to GCC thickness. This indicated that measurement of disc perfusion by angio-OCT might be important for the monitoring of glaucoma. PMID- 26255819 TI - Analysis of Drugs in Saliva. AB - Saliva is presented as an alternative matrix in the establishment of drug abuse. The ultimate salivary concentration is determined by the route of administration, the salivary pH, the degree of plasma protein binding, and the physico-chemical properties of the abused drug. Since the saliva/plasma ratio can exceed 1, saliva might be a better analytical tool than blood during roadside testing of potentially intoxicated drivers. Moreover, saliva can be obtained non-invasively and under supervision. Although drugs of abuse have been determined in saliva for more than a decade, the use of saliva drug testing for forensic purposes is still limited. Several problems have been demonstrated: (a) differences in the collection protocol produce variable results and often, e.g., during roadside testing, only very small volumes of saliva are obtained; (b) the salivary concentrations are much lower than in urine; (c) saliva principally contains the parent drug and until now, no suitable immunoassays have been commercialized. Although salivary drug concentrations are well correlated with pharmacological effects for some drugs, e.g., cocaine, further studies have to prove whether saliva is a suitable matrix to demonstrate "driving under the influence" of psychoactive drugs. Furthermore, an on-site screening assay for drugs of abuse in saliva and the establishment of appropriate cutoff levels should facilitate the use of saliva during roadside testing. PMID- 26255820 TI - Mitochondrial DNA Sequence Analysis - Validation and Use for Forensic Casework. AB - With the discovery of the polymerase chain reaction (PCR) in the mid-1980's, the last in a series of critical molecular biology techniques (to include the isolation of DNA from human and non-human biological material, and primary sequence analysis of DNA) had been developed to rapidly analyze minute quantities of mitochondrial DNA (mtDNA). This was especially true for mtDNA isolated from challenged sources, such as ancient or aged skeletal material and hair shafts. One of the beneficiaries of this work has been the forensic community. Over the last decade, a significant amount of research has been conducted to develop PCR based sequencing assays for the mtDNA control region (CR), which have subsequently been used to further characterize the CR. As a result, the reliability of these assays has been investigated, the limitations of the procedures have been determined, and critical aspects of the analysis process have been identified, so that careful control and monitoring will provide the basis for reliable testing. With the application of these assays to forensic identification casework, mtDNA sequence analysis has been properly validated, and is a reliable procedure for the examination of biological evidence encountered in forensic criminalistic cases. PMID- 26255818 TI - Interplay of proliferation and differentiation factors is revealed in the early human eye development. AB - BACKGROUND: Eye development is a consequence of numerous epithelial-to mesenchymal interactions between the prospective lens ectoderm, outpocketings of the forebrain forming optic vesicles, and surrounding mesenchyme. How different cell types forming eye structures differentiate from their precursors, and which factors coordinate complex human eye development remains largely unknown. Proper differentiation of photoreceptors is of special interest because of their involvement in the appearance of degenerative retinal diseases. METHODS: Here we analyze the spatiotemporal expression of neuronal markers nestin, protein gene product 9.5 (PGP9.5), and calcium binding protein (S100), proliferation marker (Ki-67), markers for cilia (alpha-tubulin), and cell stemness marker octamer binding transcription factor 4 (Oct-4) in histological sections of 5-12 -week human eyes using immunohistochemical and immunofluorescence methods. RESULTS: While during the investigated developmental period nestin shows strong expression in all mesenchymal derivatives, lens, optic stalk and inner neuroblastic layer, PGP9.5 and S100 expression characterizes only neural derivatives (optic nerve and neural retina). PGP9.5 is co-localized with nestin and S100 in the differentiating cells of the inner neuroblastic layer. Initially strong proliferation in all parts of the developing eye gradually ceases, especially in the outer neuroblastic layer. Proliferating Ki-67 positive cells co-localize with nestin in the retina, lens, and choroid. Strong Oct-4 and alpha-tubulin immunoreactivity in the retina and optic nerve gradually decreases, while they co localize in outer neuroblastic and nerve fiber layers. CONCLUSIONS: The described expression of investigated markers indicates their importance in eye growth and morphogenesis, while their spatially and temporally restricted pattern coincides with differentiation of initially immature cells into specific retinal cell lineages. Alterations in their spatiotemporal interplay might lead to disturbances of visual function. PMID- 26255821 TI - Progress in Facial Reconstruction Technology. AB - This paper mainly focuses on anatomical knowledge, methodological aspects and their utility in forensic facial reconstruction, along with a survey of the related literature. In view of increased computerization in facial reconstruction, some unique computer technologies are reviewed. In addition, the latest data concerning facial soft tissue thickness, the positional relation between facial features and the underlying skull, and the morphological correlation between face type and facial components in Japanese population are also introduced, with the hope that the information will find efficient use in attaining a reasonable facial reconstruction. PMID- 26255823 TI - Quinoxaline-Based Polymer Dots with Ultrabright Red to Near-Infrared Fluorescence for In Vivo Biological Imaging. AB - This article describes the design and synthesis of quinoxaline-based semiconducting polymer dots (Pdots) that exhibit near-infrared fluorescence, ultrahigh brightness, large Stokes shifts, and excellent cellular targeting capability. We also introduced fluorine atoms and long alkyl chains into polymer backbones and systematically investigated their effect on the fluorescence quantum yields of Pdots. These new series of quinoxaline-based Pdots have a fluorescence quantum yield as high as 47% with a Stokes shift larger than 150 nm. Single-particle analysis reveals that the average per-particle brightness of the Pdots is at least 6 times higher than that of the commercially available quantum dots. We further demonstrated the use of this new class of quinoxaline-based Pdots for effective and specific cellular and subcellular labeling without any noticeable nonspecific binding. Moreover, the cytotoxicity of Pdots were evaluated on HeLa cells and zebrafish embryos to demonstrate their great biocompatibility. By taking advantage of their extreme brightness and minimal cytotoxicity, we performed, for the first time, in vivo microangiography imaging on living zebrafish embryos using Pdots. These quinoxaline-based NIR-fluorescent Pdots are anticipated to find broad use in a variety of in vitro and in vivo biological research. PMID- 26255824 TI - Electrospun carbon nanofiber modified electrodes for stripping voltammetry. AB - Electrospun polyacrylonitrile (PAN) based carbon nanofibers (CNFs) have attracted intense attention due to their easy processing, high carbon yield, and robust mechanical properties. In this work, a CNF modified glassy carbon (GC) electrode that was coated with Nafion polymer was evaluated as a new electrode material for the simultaneous determination of trace levels of heavy metal ions by anodic stripping voltammetry (ASV). Pb(2+) and Cd(2+) were used as a representative system for this initial study. Well-defined stripping voltammograms were obtained when Pb(2+) and Cd(2+) were determined individually and then simultaneously in a mixture. Compared to a bare GC electrode, the CNF/Nafion modified GC (CNF/Nafion/GC) electrode improved the sensitivity for lead detection by 8-fold. The interface properties of the CNF/Nafion/GC were characterized by electrochemical impedance spectroscopy (EIS), which showed the importance of the ratio of CNF/Nafion on electrode performance. Under optimized conditions, the detection limits are 0.9 and 1.5 nM for Pb(2+) and Cd(2+), respectively. PMID- 26255825 TI - Sex equity in French newspaper photographs: A content analysis of 2012 Olympic Games by L'Equipe. AB - The aim of this article was to examine sex equity in the photographic coverage of the London 2012 Olympic Games by a French sports daily newspaper. A sample of 1073 photographs was collected and analysed. A content analysis was carried out focusing on the number of photographs, the space they cover, their location and position, the type and colour of shot and the sport they depict. A significant under-representation of female athletes' photographs was found. However, contrary to most of previous research in this field, the other quantitative and qualitative variables do not show any differences. Furthermore, a significant positive correlation between the number of photographs for each sport and the number of French medals was found (for women, for men and for the whole sample), suggesting that the photographic coverage of this event is mainly based on the success of French athletes independently of their sex. PMID- 26255822 TI - Predictors and long-term reproducibility of urinary phthalate metabolites in middle-aged men and women living in urban Shanghai. AB - Phthalate esters are man-made chemicals commonly used as plasticizers and solvents, and humans may be exposed through ingestion, inhalation, and dermal absorption. Little is known about predictors of phthalate exposure, particularly in Asian countries. Because phthalates are rapidly metabolized and excreted from the body following exposure, it is important to evaluate whether phthalate metabolites measured at a single point in time can reliably rank exposures to phthalates over a period of time. We examined the concentrations and predictors of phthalate metabolite concentrations among 50 middle-aged women and 50 men from two Shanghai cohorts, enrolled in 1997-2000 and 2002-2006, respectively. We assessed the reproducibility of urinary concentrations of phthalate metabolites in three spot samples per participant taken several years apart (mean interval between first and third sample was 7.5 years [women] or 2.9 years [men]), using Spearman's rank correlation coefficients and intra-class correlation coefficients. We detected ten phthalate metabolites in at least 50% of individuals for two or more samples. Participant sex, age, menopausal status, education, income, body mass index, consumption of bottled water, recent intake of medication, and time of day of collection of the urine sample were associated with concentrations of certain phthalate metabolites. The reproducibility of an individual's urinary concentration of phthalate metabolites across several years was low, with all intra-class correlation coefficients and most Spearman rank correlation coefficients <=0.3. Only mono(2-ethylhexyl) phthalate, a metabolite of di(2-ethylhexyl) phthalate, had a Spearman rank correlation coefficient >=0.4 among men, suggesting moderate reproducibility. These findings suggest that a single spot urine sample is not sufficient to rank exposures to phthalates over several years in an adult urban Chinese population. PMID- 26255826 TI - Detailed Analysis of the Surface Area and Elasticity in the Saturated 1,2 Diacylphosphatidylcholine/Cholesterol Binary Monolayer System. AB - The surface pressure-area (pi-A) isotherms of DMPC, DPPC, and DSPC/cholesterol binary monolayers were systematically measured with great care to gain insight into the lateral molecular packing in these binary monolayer systems. The average molecular area A and the area elastic modulus C(s)-1 at a given surface pressure were calculated as a function of cholesterol mole fraction x(chol). As a result, data reliable enough for the analysis of detailed phase behavior were obtained. We identified several characteristic phase regions and assigned the phase state in each region on the basis of the deviation of A(x(chol)) and C(s)-1(x(chol)) from ideal additivity. We also estimated the partial molecular areas of DMPC, DPPC, DSPC, and cholesterol in the single-phase regions, where C(s)-1(x(chol)) values fell on an ideal additivity curve. We found that the addition of cholesterol induces the formation of a highly condensed phase where the diacylphosphatidylcholine (diacyl PC) molecule has a surface area even smaller than that in the solid phase, irrespective of the surface pressure and the chain length of diacyl PC. Here, we call the cholesterol-induced condensed phase the CC phase. Furthermore, we demonstrated that the basic features of A(x(chol)) and C(s)-1(x(chol)) profiles can be explained semiquantitatively by assuming the state of vicinity lipids surrounding sparsely distributed cholesterol molecules in the low x(chol) region as a third state of the diacyl PC molecule in addition to the states in the pure diacyl PC monolayer and in the CC phase. PMID- 26255827 TI - Perceived Parenting and Basic Need Satisfaction among Portuguese Adolescents. AB - We examined the psychometric properties of the Parenting Questionnaire in a sample of Portuguese high school students. Two measurement models were specified. Model 1m,f specifies a bi-dimensional structure of parental need-support and behavioral control. Model 2m,f proposes a tripartite structure of parental need support, psychological control and behavioral control. Model 2m,f. best-fitted the data, being also supported in terms of convergent, discriminant validity. Regression results found the unique effect of autonomy-support (M2mr, b = .25 p < .001; M2fr, b = .14 p < .01), responsiveness-warmth (Model 2mr, b = .19, p .05). Notably, psychological control predicted low need-satisfaction (M2mr: b = -.10) and moderated of the positive effect of parental need-support on need satisfaction, M2mr: F(3, 367) = 11.62, p < .001. Psychological control and need support also moderated the positive effect of behavior control on competence satisfaction, with parental need-support amplifying this effect and psychological control buffering it. Overall the findings support the substantive distinction between the parenting dimensions, suggesting that need-satisfaction is enhanced by need-supportive and behavioural control and undermined by psychological control. PMID- 26255828 TI - Therapeutic and cosmetic applications of Evodiamine and its derivatives--A patent review. AB - Evodiamine, ((+)-(S)-8,13,13b,14-tetrahydro-14-methylindolo[2',3':3,4]pyrido[2,1 b]quinazolin-5(7H)-one) indoloquinazoline alkaloid, is the major component isolated from the fruits of Evodia rutaecarpa, family Rutaceae. Broad spectrum of pharmacological activities of Evodiamine suggests its imperative role in treating a variety of diseases influencing the function of diverse targets. A comprehensive search was carried out to collect patent information regarding Evodiamine and its derivatives using different patent databases covering priority years to till date. The patents claiming therapeutic as well as cosmetic applications of Evodiamine and its derivatives were analyzed in detail and were classified technically based on the its application such as treatment of metabolic disorders, cancer, neurological disorders, and cardiovascular disorders, etc. The analysis revealed that the use and the mode of actions of Evodiamine and its derivatives in weight management treatments are currently well established. For example the fat reducing property of this alkaloid is primarily due to its mode of actions such as prevention of muscle protein catabolism, enhancement of thermogenesis and lipid oxidation. Apart from its use for treating obesity, Evodiamine and its derivatives are also experimentally explored for their anti-cancer, anti-diabetic and anti-inflammatory properties. The possible mechanisms related to its anti-cancer activity as illustrated by different experimental studies include its potential action as modulator of specific receptors such as topoisomerase I, NF-kappa B and B-cell lymphoma 2 (Bcl2). The analysis hence highlights that, clinical studies pertaining to the anti-cancer, anti-diabetes as well as anti-inflammatory activities of the Evodiamine and its derivatives would possess important market potential for the development of Evodiamine based therapeutics. PMID- 26255829 TI - Spontaneous inward opening of the dopamine transporter is triggered by PIP2 regulated dynamics of the N-terminus. AB - We present the dynamic mechanism of concerted motions in a full-length molecular model of the human dopamine transporter (hDAT), a member of the neurotransmitter/sodium symporter (NSS) family, involved in state-to-state transitions underlying function. The findings result from an analysis of unbiased atomistic molecular dynamics simulation trajectories (totaling >14 MUs) of the hDAT molecule immersed in lipid membrane environments with or without phosphatidylinositol 4,5-biphosphate (PIP2) lipids. The N-terminal region of hDAT (N-term) is shown to have an essential mechanistic role in correlated rearrangements of specific structural motifs relevant to state-to-state transitions in the hDAT. The mechanism involves PIP2-mediated electrostatic interactions between the N-term and the intracellular loops of the transporter molecule. Quantitative analyses of collective motions in the trajectories reveal that these interactions correlate with the inward-opening dynamics of hDAT and are allosterically coupled to the known functional sites of the transporter. The observed large-scale motions are enabled by specific reconfiguration of the network of ionic interactions at the intracellular end of the protein. The isomerization to the inward-facing state in hDAT is accompanied by concomitant movements in the extracellular vestibule and results in the release of an Na(+) ion from the Na2 site and destabilization of the substrate dopamine in the primary substrate binding S1 site. The dynamic mechanism emerging from the findings highlights the involvement of the PIP2-regulated interactions between the N-term and the intracellular loop 4 in the functionally relevant conformational transitions that are also similar to those found to underlie state to-state transitions in the leucine transporter (LeuT), a prototypical bacterial homologue of the NSS. PMID- 26255830 TI - Oral Administration of Gintonin Attenuates Cholinergic Impairments by Scopolamine, Amyloid-beta Protein, and Mouse Model of Alzheimer's Disease. AB - Gintonin is a novel ginseng-derived lysophosphatidic acid (LPA) receptor ligand. Oral administration of gintonin ameliorates learning and memory dysfunctions in Alzheimer's disease (AD) animal models. The brain cholinergic system plays a key role in cognitive functions. The brains of AD patients show a reduction in acetylcholine concentration caused by cholinergic system impairments. However, little is known about the role of LPA in the cholinergic system. In this study, we used gintonin to investigate the effect of LPA receptor activation on the cholinergic system in vitro and in vivo using wild-type and AD animal models. Gintonin induced [Ca(2+)]i transient in cultured mouse hippocampal neural progenitor cells (NPCs). Gintonin-mediated [Ca(2+)]i transients were linked to stimulation of acetylcholine release through LPA receptor activation. Oral administration of gintonin-enriched fraction (25, 50, or 100 mg/kg, 3 weeks) significantly attenuated scopolamine-induced memory impairment. Oral administration of gintonin (25 or 50 mg/kg, 2 weeks) also significantly attenuated amyloid-beta protein (Abeta)-induced cholinergic dysfunctions, such as decreased acetylcholine concentration, decreased choline acetyltransferase (ChAT) activity and immunoreactivity, and increased acetylcholine esterase (AChE) activity. In a transgenic AD mouse model, long-term oral administration of gintonin (25 or 50 mg/kg, 3 months) also attenuated AD-related cholinergic impairments. In this study, we showed that activation of G protein-coupled LPA receptors by gintonin is coupled to the regulation of cholinergic functions. Furthermore, this study showed that gintonin could be a novel agent for the restoration of cholinergic system damages due to Abeta and could be utilized for AD prevention or therapy. PMID- 26255832 TI - Influence of the sterol aliphatic side chain on membrane properties: a molecular dynamics study. AB - Following a recent experimental investigation of the effect of the length of the alkyl side chain in a series of cholesterol analogues (Angew. Chem., Int. Ed., 2013, 52, 12848-12851), we report here an atomistic molecular dynamics characterization of the behaviour of methyl-branched side chain sterols (iso series) in POPC bilayers. The studied sterols included androstenol (i-C0-sterol) and cholesterol (i-C8-sterol), as well as four other derivatives (i-C5, i-C10, i C12 and i-C14-sterol). For each sterol, both subtle local effects and more substantial differential alterations of membrane properties along the iso series were investigated. The location and orientation of the tetracyclic ring system is almost identical in all compounds. Among all the studied sterols, cholesterol is the sterol that presents the best matching with the hydrophobic length of POPC acyl chains, whereas longer-chained sterols interdigitate into the opposing membrane leaflet. In accordance with the experimental observations, a maximal ordering effect is observed for intermediate sterol chain length (i-C5, cholesterol, i-C10). Only for these sterols a preferential interaction with the saturated sn-1 chain of POPC (compared to the unsaturated sn-2 chain) was observed, but not for either shorter or longer-chained derivatives. This work highlights the importance of the sterol alkyl chain in the modulation of membrane properties and lateral organization in biological membranes. PMID- 26255831 TI - Therapeutic Strategy for the Prevention of Pseudorabies Virus Infection in C57BL/6 Mice by 3D8 scFv with Intrinsic Nuclease Activity. AB - 3D8 single chain variable fragment (scFv) is a recombinant monoclonal antibody with nuclease activity that was originally isolated from autoimmune-prone MRL mice. In a previous study, we analyzed the nuclease activity of 3D8 scFv and determined that a HeLa cell line expressing 3D8 scFv conferred resistance to herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PRV). In this study, we demonstrate that 3D8 scFv could be delivered to target tissues and cells where it exerted a therapeutic effect against PRV. PRV was inoculated via intramuscular injection, and 3D8 scFv was injected intraperitoneally. The observed therapeutic effect of 3D8 scFv against PRV was also supported by results from quantitative reverse transcription polymerase chain reaction, southern hybridization, and immunohistochemical assays. Intraperitoneal injection of 5 and 10 MUg 3D8 scFv resulted in no detectable toxicity. The survival rate in C57BL/6 mice was 9% after intramuscular injection of 10 LD50 PRV. In contrast, the 3D8 scFv-injected C57BL/6 mice showed survival rates of 57% (5 MUg) and 47% (10 MUg). The results indicate that 3D8 scFv could be utilized as an effective antiviral agent in several animal models. PMID- 26255833 TI - A pressure sensor based on the orientational dependence of plasmonic properties of gold nanorods. AB - A novel pressure sensor has been developed by taking advantage of the orientational dependence of localized surface plasmon resonance of gold nanorods embedded in a polymer matrix. This stress-responsive material can be used to record the distribution and magnitude of pressure between two contacting surfaces by outputting optical response. PMID- 26255835 TI - Overexpression of OCT4A ortholog elevates endogenous XIST in porcine parthenogenic blastocysts. AB - X-chromosome inactivation (XCI) is an epigenetic process that equalizes expression of X-borne genes between male and female eutherians. This process is observed in early eutherian embryo development in a species-specific manner. Until recently, various pluripotent factors have been suggested to regulate the process of XCI by repressing XIST expression, which is the master inducer for XCI. Recent insights into the process and its regulation have been restricted in mouse species despite the evolutionary diversity of the process and molecular mechanism among the species. OCT4A is one of the represented pluripotent factors, the gate-keeper for maintaining pluripotency, and an XIST repressor. Therefore, in here, we examined the relation between OCT4A and X-linked genes in porcine preimplantation embryos. Three X-linked genes, XIST, LOC102165544, and RLIM, were selected in present study because their orthologues have been known to regulate XCI in mice. Expression levels of OCT4A were positively correlated with XIST and LOC102165544 in female blastocysts. Furthermore, overexpression of exogenous human OCT4A in cleaved parthenotes generated blastocysts with increased XIST expression levels. However, increased XIST expression was not observed when exogenous OCT4A was obtained from early blastocysts. These results suggest the possibility that OCT4A would be directly or indirectly involved in XIST expression in earlier stage porcine embryos rather than blastocysts. PMID- 26255836 TI - Evaluation of genetic susceptibility of common variants in CACNA1D with schizophrenia in Han Chinese. AB - The heritability of schizophrenia (SCZ) has been estimated to be as high as 80%, suggesting that genetic factors may play an important role in the etiology of SCZ. Cav1.2 encoded by CACNA1C and Cav1.3 encoded by CACNA1D are dominant calcium channel-forming subunits of L-type Voltage-dependent Ca(2+) channels, expressed in many types of neurons. The CACNA1C has been consistently found to be a risk gene for SCZ, but it is unknown for CACNA1D. To investigate the association of CACNA1D with SCZ, we designed a two-stage case-control study, including a testing set with 1117 cases and 1815 controls and a validation set with 1430 cases and 4295 controls in Han Chinese. A total of selected 97 tag single nucleotide polymorphisms (SNPs) in CACNA1D were genotyped, and single-SNP association, imputation analysis and gender-specific association analyses were performed in the two independent datasets. None was found to associate with SCZ. Further genotype and haplotype association analyses indicated a similar pattern in the two-stage study. Our findings suggested CACNA1D might not be a risk gene for SCZ in Han Chinese population, which add to the current state of knowledge regarding the susceptibility of CACNA1D to SCZ. PMID- 26255837 TI - Hexamethoxylated Monocarbonyl Analogues of Curcumin Cause G2/M Cell Cycle Arrest in NCI-H460 Cells via Michael Acceptor-Dependent Redox Intervention. AB - Curcumin, derived from the dietary spice turmeric, holds promise for cancer prevention. This prompts much interest in investigating the action mechanisms of curcumin and its analogues. Two symmetrical hexamethoxy-diarylpentadienones (1 and 2) as cucumin analogues were reported to possess significantly enhanced cytotoxicity compared with the parent molecule. However, the detailed mechanisms remain unclear. In this study, compounds 1 and 2 were identified as the G2/M cell cycle arrest agents to mediate the cytotoxicity toward NCI-H460 cells via Michael acceptor-dependent redox intervention. Compared with curcumin, they could more easily induce a burst of reactive oxygen species (ROS) and collapse of the redox buffering system. One possible reason is that they could more effectively target intracellular TrxR to convert this antioxidant enzyme into a ROS promoter. Additionally, they caused up-regulation of p53 and p21 and down-regulation of redox-sensitive Cdc25C along with cyclin B1/Cdk1 in a Michael acceptor- and ROS dependent fashion. Interestingly, in comparison with compound 2, compound 1 displayed a relatively weak ability to generate ROS but increased cell cycle arrest activity and cytotoxicity probably due to its Michael acceptor-dependent microtubule-destabilizing effect and greater GST-inhibitory activity, as well as its enhanced cellular uptake. This work provides useful information for understanding Michael acceptor-dependent and redox-mediated cytotoxic mechanisms of curcumin and its active analogues. PMID- 26255838 TI - Facet-dependent acidic and catalytic properties of sulfated titania solid superacids. AB - Sulfated titania solid superacids with dominant {001}, {001}/{101}, and {101} facets were prepared by the hydrothermal method and subsequent sulfation. Their facet-dependent acidic properties were investigated by the solid-state (31)P NMR technique and Pechmann condensation of 5,7-dihydroxy-4-methyl coumarin. PMID- 26255839 TI - Mechanical measurements of heterogeneity and length scale effects in PEG-based hydrogels. AB - Colloidal-probe spherical indentation load-relaxation experiments with a probe radius of 3 MUm are conducted on poly(ethylene glycol) (PEG) hydrogel materials to quantify their steady-state mechanical properties and time-dependent transport properties via a single experiment. PEG-based hydrogels are shown to be heterogeneous in both morphology and mechanical stiffness at this scale; a linear harmonic interpolation of hyperelastic Mooney-Rivlin and Boussinesq flat-punch indentation models was used to describe the steady-state response of the hydrogels and determine upper and lower bounds for indentation moduli. Analysis of the transient load-relaxation response during displacement-controlled hold periods provides a means of extracting two time constants tau1 and tau2, where tau1 and tau2 are assigned to the viscoelastic and poroelastic properties, respectively. Large tau2 values at small indentation depths provide evidence of a non-equilibrium state characterized by a phenomenon that restricts poroelastic fluid flow through the material; for larger indentations, the variability in tau2 values decreases and pore sizes estimated from tau2via indentation approach those measured via macroscopic swelling experiments. The contact probe methodology developed here provides a means of assessing hydrogel heterogeneity, including time-dependent mechanical and transport properties, and has potential implications in hydrogel biomedical and engineering applications. PMID- 26255840 TI - Exceptional thermal tolerance and water resistance in the mite Paratarsotomus macropalpis (Erythracaridae) challenge prevailing explanations of physiological limits. AB - Physiological performance and tolerance limits in metazoans have been widely studied and have informed our understanding of processes such as extreme heat and cold tolerance, and resistance to water loss. Because of scaling considerations, very small arthropods with extreme microclimatic niches provide promising extremophiles for testing predictive physiological models. Corollaries of small size include rapid heating and cooling (small thermal time constants) and high mass-specific metabolic and water exchange rates. This study examined thermal tolerance and water loss in the erythracarid mite Paratarsotomus macropalpis (Banks, 1916), a species that forages on the ground surface of the coastal sage scrub habitat of Southern California, USA. Unlike most surface-active diurnal arthropods, P. macropalpis remains active during the hottest parts of the day in midsummer. We measured water-loss gravimetrically and estimated the critical thermal maximum (CTmax) by exposing animals to a given temperature for 1h and then increasing temperature sequentially. The standardized water flux of 4.4ngh( 1)cm(-2)Pa(-1), averaged for temperatures between 22 and 40 degrees C, is among the lowest values reported in the literature. The CTmax of 59.4 degrees C is, to our knowledge, the highest metazoan value reported for chronic (1-h) exposure, and closely matches maximum field substrate temperatures during animal activity. The extraordinary physiological performance seen in P. macropalpis likely reflects extreme selection resulting from its small size and resultant high mass specific water loss rate and low thermal time-constant. Nevertheless, the high water resistance attained with a very thin lipid barrier, and the mite's exceptional thermal tolerance, challenge existing theories seeking to explain physiological limits. PMID- 26255842 TI - Correction: New avenues for ligand-mediated processes--expanding metal reactivity by the use of redox-active catechol, o-aminophenol and o-phenylenediamine ligands. AB - Correction for 'New avenues for ligand-mediated processes - expanding metal reactivity by the use of redox-active catechol, o-aminophenol and o phenylenediamine ligands' by Daniel L. J. Broere et al., Chem. Soc. Rev., 2015, DOI: 10.1039/c5cs00161g. PMID- 26255843 TI - Lysosomal cysteine peptidases - Molecules signaling tumor cell death and survival. AB - Lysosomal cysteine peptidases - cysteine cathepsins - are general intracellular protein-degrading enzymes that control also a variety of specific physiological processes. They can trigger irreversible events leading to signal transduction and activation of signaling pathways, resulting in cell survival and proliferation or cell death. In cancer cells, lysosomal cysteine peptidases are involved in multiple processes during malignant progression. Their translocation from the endosomal/lysosomal pathway to nucleus, cytoplasm, plasma membrane and extracellular space enables the activation and remodeling of a variety of tumor promoting proteins. Thus, lysosomal cysteine peptidases interfere with cytokine/chemokine signaling, regulate cell adhesion and migration and endocytosis, are involved in the antitumor immune response and apoptosis, and promote cell invasion, angiogenesis and metastasis. Further, lysosomal cysteine peptidases modify growth factors and receptors involved in tyrosine kinase dependent pathways such as MAPK, Akt and JNK, thus representing key signaling tools for the activation of tumor cell growth and proliferation. PMID- 26255841 TI - Multiple factors contribute to anautogenous reproduction by the mosquito Aedes aegypti. AB - Aedes aegypti is an anautogenous mosquito that must blood feed on a vertebrate host to produce and lay a clutch of eggs. The rockpool mosquito, Georgecraigius atropalpus, is related to A. aegypti but is a facultatively autogenous species that produces its first clutch of eggs shortly after emerging without blood feeding. Consumption of a blood meal by A. aegypti triggers the release of ovary ecdysteroidogenic hormone (OEH) and insulin-like peptide 3 (ILP3) from the brain, which stimulate egg formation. OEH and ILP3 also stimulate egg formation in G. atropalpus but are released at eclosion independently of blood feeding. These results collectively suggest that blood meal dependent release of OEH and ILP3 is one factor that prevents A. aegypti from reproducing autogenously. Here, we examined two other factors that potentially inhibit autogeny in A. aegypti: teneral nutrient reserves and the ability of OEH and ILP3 to stimulate egg formation in the absence of blood feeding. Measures of nutrient reserves showed that newly emerged A. aegypti females had similar wet weights but significantly lower protein and glycogen reserves than G. atropalpus females when larvae were reared under identical conditions. OEH stimulated non-blood fed A. aegypti females to produce ecdysteroid hormone and package yolk into oocytes more strongly than ILP3. OEH also reduced host seeking and blood feeding behavior, yet females produced few mature eggs. Overall, our results indicate that multiple factors prevent A. aegypti from reproducing autogenously. PMID- 26255844 TI - Tethering of SCF(Dia2) to the Replisome Promotes Efficient Ubiquitylation and Disassembly of the CMG Helicase. AB - Disassembly of the Cdc45-MCM-GINS (CMG) DNA helicase, which unwinds the parental DNA duplex at eukaryotic replication forks, is the key regulated step during replication termination but is poorly understood. In budding yeast, the F-box protein Dia2 drives ubiquitylation of the CMG helicase at the end of replication, leading to a disassembly pathway that requires the Cdc48 segregase. The substrate binding domain of Dia2 comprises leucine-rich repeats, but Dia2 also has a TPR domain at its amino terminus that interacts with the Ctf4 and Mrc1 subunits of the replisome progression complex, which assembles around the CMG helicase at replication forks. Previous studies suggested two disparate roles for the TPR domain of Dia2, either mediating replisome-specific degradation of Mrc1 and Ctf4 or else tethering SCF(Dia2) (SCF [Skp1/cullin/F-box protein]) to the replisome to increase its local concentration at replication forks. Here, we show that SCF(Dia2) does not mediate replisome-specific degradation of Mrc1 and Ctf4, either during normal S phase or in response to replication stress. Instead, the tethering of SCF(Dia2) to the replisome progression complex increases the efficiency of ubiquitylation of the Mcm7 subunit of CMG, both in vitro and in vivo. Correspondingly, loss of tethering reduces the efficiency of CMG disassembly in vivo and is synthetic lethal in combination with a disassembly defective allele of CDC48. Residual ubiquitylation of Mcm7 in dia2-DeltaTPR cells is still CMG specific, highlighting the complex regulation of the final stages of chromosome replication, about which much still remains to be learned. PMID- 26255845 TI - Spectral Tuning of Phototaxis by a Go-Opsin in the Rhabdomeric Eyes of Platynereis. AB - Phototaxis is characteristic of the pelagic larval stage of most bottom-dwelling marine invertebrates. Larval phototaxis is mediated by simple eyes that can express various types of light-sensitive G-protein-coupled receptors known as opsins. Since opsins diversified early during metazoan evolution in the marine environment, understanding underwater light detection could elucidate this diversification. Opsins have been classified into three major families, the r opsins, the c-opsins, and the Go/RGR opsins, a family uniting Go-opsins, retinochromes, RGR opsins, and neuropsins. The Go-opsins form an ancient and poorly characterized group retained only in marine invertebrate genomes. Here, we characterize a Go-opsin from the marine annelid Platynereis dumerilii. We found Go-opsin1 coexpressed with two r-opsins in depolarizing rhabdomeric photoreceptor cells in the pigmented eyes of Platynereis larvae. We purified recombinant Go opsin1 and found that it absorbs in the blue-cyan range of the light spectrum. To characterize the function of Go-opsin1, we generated a Go-opsin1 knockout Platynereis line by zinc-finger-nuclease-mediated genome engineering. Go-opsin1 knockout larvae were phototactic but showed reduced efficiency of phototaxis to wavelengths matching the in vitro Go-opsin1 spectrum. Our results highlight spectral tuning of phototaxis as a potential mechanism contributing to opsin diversity. PMID- 26255847 TI - Persister Heterogeneity Arising from a Single Metabolic Stress. AB - Persisters are phenotypic variants present within isogenic bacterial populations that exhibit extreme tolerance toward antibiotic stress. We previously elucidated a mechanistic pathway by which Escherichia coli persisters to ofloxacin form in response to a carbon source transition. Here, we examine how persisters to ampicillin form from the same metabolic stress and identify the shared and unique elements of the persister formation pathways. We discovered that diauxie dependent formation of ampicillin persisters required RelA and that loss of clpA, ssrA, or smpB eliminated persister formation through relaxation of the stringent response. Further, we found that tolerance to ampicillin was achieved through broad inhibition of peptidoglycan biosynthesis, as evidenced by the formation of persisters to antibiotics that target enzymes in different areas of that biosynthetic pathway. Interestingly, ppGpp was required for formation of both ampicillin and ofloxacin persisters, and we demonstrated that higher synthesis of the alarmone was needed to increase persisters to ampicillin compared to ofloxacin. Further, we found trans-translation and DksA to be common mediators of both pathways, whereas ClpA was unique for ampicillin persisters and nucleoid associated proteins were unique for ofloxacin persisters. These results highlight the need to consider an antibiotic's mode of action when analyzing persister formation, demonstrate that individual stresses can produce persister heterogeneity, and emphasize the importance of identifying each respective pathway to identify common mediators that possess the most therapeutic potential to combat persisters. PMID- 26255846 TI - Integrin Adhesions Suppress Syncytium Formation in the Drosophila Larval Epidermis. AB - Integrins are critical for barrier epithelial architecture. Integrin loss in vertebrate skin leads to blistering and wound healing defects. However, how integrins and associated proteins maintain the regular morphology of epithelia is not well understood. We found that targeted knockdown of the integrin focal adhesion (FA) complex components beta-integrin, PINCH, and integrin-linked kinase (ILK) caused formation of multinucleate epidermal cells within the Drosophila larval epidermis. This phenotype was specific to the integrin FA complex and not due to secondary effects on polarity or junctional structures. The multinucleate cells resembled the syncytia caused by physical wounding. Live imaging of wound induced syncytium formation in the pupal epidermis suggested direct membrane breakdown leading to cell-cell fusion and consequent mixing of cytoplasmic contents. Activation of Jun N-terminal kinase (JNK) signaling, which occurs upon wounding, also correlated with syncytium formation induced by PINCH knockdown. Further, ectopic JNK activation directly caused epidermal syncytium formation. No mode of syncytium formation, including that induced by wounding, genetic loss of FA proteins, or local JNK hyperactivation, involved misregulation of mitosis or apoptosis. Finally, the mechanism of epidermal syncytium formation following JNK hyperactivation and wounding appeared to be direct disassembly of FA complexes. In conclusion, the loss-of-function phenotype of integrin FA components in the larval epidermis resembles a wound. Integrin FA loss in mouse and human skin also causes a wound-like appearance. Our results reveal a novel and unexpected role for proper integrin-based adhesion in suppressing larval epidermal cell-cell fusion--a role that may be conserved in other epithelia. PMID- 26255848 TI - Cross-Modal Associative Mnemonic Signals in Crow Endbrain Neurons. AB - The ability to associate stimuli across time and sensory modalities endows animals and humans with many of the complex, learned behaviors. For successful performance, associations need to be retrieved from long-term memory and maintained active in working memory. We investigated how this is accomplished in the avian brain. We trained carrion crows (Corvus corone) to perform a bimodal delayed paired associate task in which the crows had to match auditory stimuli to delayed visual items. Single-unit recordings from the association area nidopallium caudolaterale (NCL) revealed sustained memory signals that selectively correlated with the learned audio-visual associations across time and modality, and sustained activity prospectively encoded the crows' choices. NCL neurons carried an internal, stimulus-independent signal that was predictive of error and type of error. These results underscore the role of corvid NCL in synthesizing external multisensory information and internal mnemonic data needed for executive control of behavior. PMID- 26255849 TI - DNA Replication Initiation Is Blocked by a Distant Chromosome-Membrane Attachment. AB - Although it has been recognized for several decades that chromosome structure regulates the capacity of replication origins to initiate, very little is known about how or if cells actively regulate structure to direct initiation. We report that a localized inducible protein tether between the chromosome and cell membrane in E. coli cells imparts a rapid and complete block to replication initiation. Tethers, composed of a trans-membrane and transcription repressor fusion protein bound to an array of operator sequences, can be placed up to 1 Mb from the origin with no loss of penetrance. Tether-induced initiation blocking has no effect on elongation at pre-existing replication forks and does not cause cell or DNA damage. Whole-genome and site-specific fluorescent DNA labeling in tethered cells indicates that global nucleoid structure and chromosome organization are disrupted. Gene expression patterns, assayed by RNA sequencing, show that tethering induces global supercoiling changes, which are likely incompatible with replication initiation. Parallels between tether-induced initiation blocking and rifampicin treatment and the role of programmed changes in chromosome structure in replication control are discussed. PMID- 26255851 TI - Venomous Frogs Use Heads as Weapons. AB - Venomous animals have toxins associated with delivery mechanisms that can introduce the toxins into another animal. Although most amphibian species produce or sequester noxious or toxic secretions in the granular glands of the skin to use as antipredator mechanisms, amphibians have been considered poisonous rather than venomous because delivery mechanisms are absent. The skin secretions of two Brazilian hylid frogs (Corythomantis greening and Aparasphenodon brunoi) are more toxic than the venoms of deadly venomous Brazilian pitvipers, genus Bothrops; C. greeningi secretion is 2-fold and A. brunoi secretion is 25-fold as lethal as Bothrops venom. Like the venoms of other animals, the skin secretions of these frogs show proteolytic and fibrinolytic activity and have hyaluronidase, which is nontoxic and nonproteolytic but promotes diffusion of toxins. These frogs have well-developed delivery mechanisms, utilizing bony spines on the skull that pierce the skin in areas with concentrations of skin glands. C. greeningi has greater development of head spines and enlarged skin glands producing a greater volume of secretion, while A. brunoi has more lethal venom. C. greeningi and A. brunoi have highly toxic skin secretions and an associated delivery mechanism; they are therefore venomous. Because even tiny amounts of these secretions introduced into a wound caused by the head spines could be dangerous, these frogs are capable of using their skin toxins as venoms against would-be predators. PMID- 26255850 TI - Origin, Specification, and Plasticity of the Great Vessels of the Heart. AB - The pharyngeal arch arteries (PAAs) are a series of paired embryonic blood vessels that give rise to several major arteries that connect directly to the heart. During development, the PAAs emerge from nkx2.5-expressing mesodermal cells and connect the dorsal head vasculature to the outflow tract of the heart. Despite their central role in establishing the circulatory system, the embryonic origins of the PAA progenitors are only coarsely defined, and the factors that specify them and their regenerative potential are unclear. Using fate mapping and mutant analysis, we find that PAA progenitors are derived from the tcf21 and nkx2.5 double-positive head mesoderm and require these two transcription factors for their specification and survival. Unexpectedly, cell ablation shows that the tcf21+; nkx2.5+ PAA progenitors are not required for PAA formation. We find that this compensation is due to the replacement of ablated tcf21+; nkx2.5+ PAA cells by endothelial cells from the dorsal head vasculature. Together, these studies assign the embryonic origin of the great vessel progenitors to the interface between the pharyngeal and cardiac mesoderm, identify the transcription factor code required for their specification, and reveal an unexpected plasticity in the formation of the great vessels. PMID- 26255852 TI - The nonsteroidal mycoestrogen zearalenone and its five metabolites suppress LH secretion from the bovine anterior pituitary cells via the estradiol receptor GPR30 in vitro. AB - Picomolar concentrations of estradiol produce nongenomic suppression of GnRH induced LH secretion from the anterior pituitary (AP) of cattle via G-protein coupled receptor 30 (GPR30). Zearalenone (ZEN) is the nonsteroidal mycoestrogen produced by Fusarium fungi and has been detected in cereal grains, animal feed, and ruminant urine worldwide. Zearalenone has a prolonged blood half-life that results from enterohepatic cycling. There are five metabolites of ZEN: alpha zearalanol (alpha-ZAL), beta-zearalanol (beta-ZAL), alpha-zearalenol (alpha-ZOL), beta-zearalenol (beta-ZOL), and zearalanone, which may persist for long periods in animals and humans after consumption of ZEN-contaminated feed. We recently reported that GPR30 bound with alpha-ZAL decreases cytoplasmic cAMP but not gene expression of LHalpha and LHbeta subunits, and GPR30 bound with alpha-ZAL suppresses GnRH-induced LH release in bovine AP cells in vitro. We tested the hypothesis that GPR30 bound with ZEN or one of the four previously untested metabolites suppresses GnRH-induced LH release from the bovine AP cells in vitro. Anterior pituitary cells were cultured for 3 days under steroid-free conditions and were then incubated with various concentrations (0.001-10 nM) of estradiol or one of the ZEN analogs for 5 minutes before GnRH stimulation. Gonadotropin releasing hormone-stimulated LH secretion from AP cells was inhibited by all of the test concentrations of ZEN, 0.001 to 1 nM of alpha-ZAL, and 0.001 to 0.1 nM of the remaining four analogs. Pretreatment for 5 minutes with a GPR30-specific antagonist, G36, inhibited estradiol- and the ZEN analog-induced suppression of LH secretion from cultured AP cells. G36 alone had no significant effect on LH secretion. The estimated order of the nongenomic inhibiting effect was ZEN, alpha ZAL, zearalanone, alpha-ZOL, beta-ZOL, and beta-ZAL, which is quite different from the reported order for their genomic effects. Therefore, ZEN and all of its metabolites suppress LH secretion from the bovine AP cells via GPR30 in vitro. PMID- 26255853 TI - Formation and characterisation of neuromuscular junctions between hiPSC derived motoneurons and myotubes. AB - Striated skeletal muscle cells from humans represent a valuable source for in vitro studies of the motoric system as well as for pathophysiological investigations in the clinical settings. Myoblasts can readily be grown from human muscle tissue. However, if muscle tissue is unavailable, myogenic cells can be generated from human induced pluripotent stem cells (hiPSCs) preferably without genetic engineering. Our study aimed to optimize the generation of hiPSCs derived myogenic cells by employing selection of CD34 positive cells and followed by distinct, stepwise culture conditions. Following the expansion of CD34 positive single cells under myogenic cell culture conditions, serum deprived myoblast-like cells finally fused and formed multinucleated striated myotubes that expressed a set of key markers for muscle differentiation. In addition, these myotubes contracted upon electrical stimulation, responded to acetylcholine (Ach) and were able to generate action potentials. Finally, we co-cultured motoneurons and myotubes generated from identical hiPSCs cell lines. We could observe the early aggregation of acetylcholine receptors in muscle cells of immature co-cultures. At later stages, we identified and characterised mature neuromuscular junctions (NMJs). In summary, we describe here the successful generation of an iPS cell derived functional cellular system consisting of two distinct communicating cells types. This in vitro co-culture system could therefore contribute to research on diseases in which the motoneurons and the NMJ are predominantly affected, such as in amyotrophic lateral sclerosis or spinal muscular atrophy. PMID- 26255854 TI - The Carbon Monoxide Dehydrogenase from Desulfovibrio vulgaris. AB - Ni-containing Carbon Monoxide Dehydrogenases (CODHs) catalyze the reversible conversion between CO and CO2and are involved in energy conservation and carbon fixation. These homodimeric enzymes house two NiFeS active sites (C-clusters) and three accessory [4Fe-4S] clusters. The Desulfovibrio vulgaris (Dv) genome contains a two-gene CODH operon coding for a CODH (cooS) and a maturation protein (cooC) involved in nickel insertion in the active site. According to the literature, the question of the precise function of CooC as a chaperone folding the C-cluster in a form which accommodates free nickel or as a mere nickel donor is not resolved. Here, we report the biochemical and spectroscopic characterization of two recombinant forms of the CODH, produced in the absence and in the presence of CooC, designated CooS and CooS(C), respectively. CooS contains no nickel and cannot be activated, supporting the idea that the role of CooC is to fold the C-cluster so that it can bind nickel. As expected, CooS(C) is Ni-loaded, reversibly converts CO and CO2, displays the typical Cred1 and Cred2 EPR signatures of the C-cluster and activates in the presence of methyl viologen and CO in an autocatalytic process. However, Ni-loaded CooS(C) reaches maximum activity only upon reductive treatment in the presence of exogenous nickel, a phenomenon that had not been observed before. Surprisingly, the enzyme displays the Cred1 and Cred2 signatures whether it has been activated or not, showing that this activation process of the Ni-loaded Dv CODH is not associated with structural changes at the active site. PMID- 26255856 TI - Seahorse (Hippocampinae) population fluctuations in the Ria Formosa Lagoon, south Portugal. AB - Comparisons of three sets of surveys in the Ria Formosa Lagoon, Portugal, over a 13 year period (2001-2002, 2008-2009 and 2010-2013) revealed significant population fluctuations in at least one of the two seahorse (Hippocampinae) species living there, and that those fluctuations were potentially associated with habitat changes in the lagoon. After a significant decline between the first two survey periods (2001-2002 v. 2008-2009), long-snouted seahorse Hippocampus guttulatus populations increased significantly between 2008-2009 surveys and new 2010-2013 surveys. There were no significant differences in H. guttulatus populations between the 2001-2002 and 2010-2013 surveys. In contrast, there were no significant differences in short-snouted seahorse Hippocampus hippocampus densities among the 16 sites surveyed throughout the three sampling periods, although the ability to detect any change was hampered by the low densities of this species in all time periods. Fluctuations in H. guttulatus densities were positively correlated with the percentage of holdfast coverage, but with none of the other environmental variables tested. These results highlight the importance of holdfast availability in maintaining stable seahorse populations. While population fluctuations are certainly more promising than a consistent downward decline, such extreme fluctuations observed for seahorses in the Ria Formosa Lagoon could still leave these two species vulnerable to any additional stressors, particularly during low density periods. PMID- 26255855 TI - Are karrikins involved in plant abiotic stress responses? AB - Recent reports have shown that strigolactones play a positive role in plant responses to drought and salt stress through MAX2 (More Axillary Growth 2). Increasing evidence suggests that MAX2 is also involved in karrikin signaling, raising the question whether karrikins play any role in plant adaptation to abiotic stresses. PMID- 26255857 TI - Epidemiologic and etiologic characteristics of hand, foot, and mouth disease in Chongqing, China between 2010 and 2013. AB - Hand, foot, and mouth disease (HFMD) has become very common in children, with widespread occurrence across China. The aim of this study was to investigate the epidemiologic and etiologic characteristics of HFMD, including etiologic variations in Chongqing, China. An epidemiologic investigation was based on 3,472 patients who presented with HFMD manifestations and were admitted at the Children's Hospital of Chongqing Medical University between 2010 and 2013. Fecal specimens from 830 patients were analyzed by nested RT-PCR to identify the enterovirus pathogens, and the molecular characterization of HFMD was illustrated by phylogenetic tree analysis. The results of this study indicate that the peak of the HFMD epidemic in Chongqing between 2010 and 2013 occurred between April and July each year. The median age of onset was 2.24 years old, and children under the age of five accounted for 96.4% of all the HFMD cases; the male-to female ratio was 1.89:1. Enterovirus 71 accounted for a major proportion of the isolated strains every year, including the majority (74%) of severe cases. However, the proportion of Coxsackie A (CV-A) 6 infections increased from 2.11% in 2010 to 16.36% in 2013, while the proportion of CV-A16 infections decreased from 31.23% in 2010 to 4.67% in 2013. Molecular epidemiologic study showed that all enterovirus 71 strains belonged to subgenotype C4a, whereas all CV-A16 strains belonged to genotype B1, including subgenotype B1a and subgenotype B1b. PMID- 26255858 TI - Quantum Phase Coherence in Mesoscopic Transport Devices with Two-Particle Interaction. AB - In this paper we demonstrate a new type of quantum phase coherence (QPC), which is generated by the two-body interaction. This conclusion is based on quantum master equation analysis for the full counting statistics of electron transport through two parallel quantum-dots with antiparallel magnetic fluxes in order to eliminate the Aharonov-Bohm interference of either single-particle or non interacting two-particle wave functions. The interacting two-particle QPC is realized by the flux-dependent oscillation of the zero-frequency cumulants including the shot noise and skewness with a characteristic period. The accurately quantized peaks of cumulant spectrum may have technical applications to probe the two-body Coulomb interaction. PMID- 26255859 TI - Tfp1 is required for ion homeostasis, fluconazole resistance and N Acetylglucosamine utilization in Candida albicans. AB - The vacuolar-type H+-ATPase (V-ATPase) is crucial for the maintenance of ion homeostasis. Dysregulation of ion homeostasis affects various aspects of cellular processes. However, the importance of V-ATPase in Candida albicans is not totally clear. In this study, we demonstrated the essential roles of V-ATPase through Tfp1, a putative V-ATPase subunit. Deletion of TFP1 led to generation of an iron starvation signal and reduced total iron content, which was associated with mislocalization of Fet34p that was finally due to disorders in copper homeostasis. Furthermore, the tfp1?/? mutant exhibited weaker growth and lower aconitase activity on nonfermentable carbon sources, and iron or copper addition partially rescued the growth defect. In addition, the tfp1?/? mutant also showed elevated cytosolic calcium levels in normal or low calcium medium that were relevant to calcium release from vacuole. Kinetics of cytosolic calcium response to an alkaline pulse and VCX1 (VCX1 encodes a putative vacuolar Ca2+/H+ exchanger) overexpression assays indicated that the cytosolic calcium status was in relation to Vcx1 activity. Spot assay and concentration-kill curve demonstrated that the tfp1?/? mutant was hypersensitive to fluconazole, which was attributed to reduced ergosterol biosynthesis and CDR1 efflux pump activity, and iron/calcium dysregulation. Interestingly, carbon source utilization tests found the tfp1?/? mutant was defective for growth on N-Acetylglucosamine (GlcNAc) plate, which was associated with ATP depletion due to the decreased ability to catabolize GlcNAc. Taken together, our study gives new insights into functions of Tfp1, and provides the potential to better exploit V-ATPase as an antifungal target. PMID- 26255860 TI - Mesoporous silica-based dosage forms improve release characteristics of poorly soluble drugs: case example fenofibrate. AB - OBJECTIVES: Mesoporous silica-based dosage forms offer the potential for improving the absorption of poorly soluble drugs after oral administration. In this investigation, fenofibrate was used as a model drug to study the ability of monomodal ('PSP A') and bimodal ('PSP B') porous silica to improve release by a 'spring' effect in in vitro biorelevant dissolution tests. Also investigated was the addition of various polymers to provide a 'parachute' effect, that is, to keep the drug in solution after its release. KEY FINDINGS: Loading fenofibrate onto PSP A or PSP B porous silica substantially improved the dissolution profile of fenofibrate under fasted state conditions compared with both pure drug and the marketed product, TriCor(r) 145 mg. Adding a polymer such as hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone or copovidon (HPMCAS, PVP or PVPVA) sustains the higher release of fenofibrate from the PSP A silica, resulting in a combination 'spring and parachute' effect - loading the drug onto the silica causes a 'spring' effect while the polymer enhances the spring effect (HPMCAS, PVP) and adds a sustaining 'parachute'. Interestingly, a silica to polymer ratio of 4:1 w/w appears to have an optimal effect for fenofibrate (HPMCAS, PVP). Dissolution results under conditions simulating the fasted state in the small intestine with the PSP A or the PSP B silica with HPMCAS added in a 4:1 w/w ratio show very substantial improvement over the marketed, nanosized product (TriCor(r) 145 mg). CONCLUSIONS: Further experiments to determine whether the highly positive effects on fenofibrate release observed with the silica prototypes investigated to date can be translated to further poorly soluble drugs and to what extent they translate into improved in-vivo performance are warranted. PMID- 26255861 TI - Clinical analysis of drug-induced sleep endoscopy for the OSA patient. AB - OBJECTIVES/HYPOTHESIS: To determine if the use of drug-induced sleep endoscopy (DISE) and transoral robotic surgery (TORS) for the treatment of obstructive sleep apnea (OSA) is associated with improved outcomes and acceptable complication rates when compared to uvulopalatopharyngoplasty (UPPP) with or without tonsillectomy (+/- T). METHODS: A retrospective cohort review was performed comparing 40 patients who had previously undergone UPPP +/- T with 64 patients who had DISE, UPPP +/- T, and possible TORS base-of-tongue resection and/or partial epiglottectomy. Apnea-hypopnea index (AHI), Epworth Sleepiness Scale (ESS), body mass index, sex, hospital length of stay, hospital charges, hospital readmissions, emergency department visits, and major complications were compared for both groups. RESULTS: The 40 patients who underwent UPPP +/- T without DISE showed a significant reduction in AHI of -20.1 (P = 0.001) and a complication rate of 3% (P = 0.001). There was no significant change in ESS ( 2.2; P = 0.734). The 64 patients who underwent DISE and subsequent procedures showed a significant reduction in AHI of -21.4 (P = 0.001) and a complication rate of 34.7% (P = 0.001). There was no significant difference in the ESS (+0.1; P = 0.734) or AHI (P = 0.092) between the two groups. CONCLUSION: Patients who underwent UPPP +/- T without DISE did not show a statistically significant difference in outcomes compared to the patients who underwent DISE with other procedures, including TORS. The TORS patients had increased total costs and length of stay that were statistically significant and had increased complications that were not statistically significant. PMID- 26255862 TI - A critical review: early life nutrition and prenatal programming for adult disease. AB - AIM AND OBJECTIVE: To present the evidence in relation to early life nutrition and foetal programming for adult disease. BACKGROUND: Epigenetics is a new and growing area of study investigating the impact of the intrauterine environment on the lifelong health of individuals. DESIGN: Discursive paper. METHOD: Searches were conducted in a range of electronic health databases. Hand searches located additional articles for review. Maternal search terms included: pregnancy; nutrition; diet; obesity; over nutrition; under nutrition. Offspring related search terms included: macrosomia; intrauterine growth restriction; epigenetics; foetal programming; childhood obesity; adolescent obesity; adolescent type 2 diabetes. DISCUSSION: Results indicate that foetal programming for adult disease occurs in response to particular insults during vulnerable developmental periods. Four main areas of foetal exposure were identified in this review: (1) under nutrition; (2) over nutrition; (3) gestational diabetes mellitus; and (4) infant catch-up growth. Numerous studies also described the trans-generational nature of foetal programming. CONCLUSIONS: Overall, foetal exposure to excess or insufficient nutrition during vulnerable developmental periods appears to result in a lifelong predisposition to obesity and adult disease, such as type 2 diabetes and cardiac disease. For the infant who has been undernourished during early life, a predisposition to renal disease also occurs. RELEVANCE TO CLINICAL PRACTICE: Pregnancy is a time when women are engaged in health systems and are receptive to health messages. These factors suggest that pregnancy may be an optimal time for dietary education and intervention. There is a particular need for education on healthy diet and for interventions which aim to limit over consumption of calories. PMID- 26255863 TI - Modeling exact exchange potential in spherically confined atoms. AB - In this work, local exchange potentials corresponding to the Hartree-Fock (HF) electron density have been obtained using the Zhao-Morrison-Parr method for a number of closed-shell confined atoms and ions. The exchange potentials obtained and the resulting density were compared with those given by the Becke-Johnson (BJ) model potential. It is demonstrated that introducing a scaling factor to the BJ potential allows improving the quality of the resulting density. The optimum scaling factor increases with decreasing confinement radius. The performance of Karasiev and Ludena's SCalpha-LDA method as well as of the Becke-88 exchange potential for reproducing the HF electron densities in confined atoms has been also examined. PMID- 26255864 TI - Type I IFN-mediated synergistic activation of mouse and human DC subsets by TLR agonists. AB - Novel approaches of dendritic cell (DC) based cancer immunotherapy aim at harnessing the unique attributes of different DC subsets. Classical monocyte derived DC vaccines are currently being replaced by either applying primary DCs or specifically targeting antigens and adjuvants to these subsets in vivo. Appropriate DC activation in both strategies is essential for optimal effect. For this purpose TLR agonists are favorable adjuvant choices, with TLR7 triggering being essential for inducing strong Th1 responses. However, mouse CD8alpha(+) DCs, considered to be the major cross-presenting subset, lack TLR7 expression. Interestingly, this DC subset can respond to TLR7 ligand upon concurrent TLR3 triggering. Nevertheless, the mechanism underlying this synergy remains obscure. We now show that TLR3 ligation results in the production of IFN-alpha, which rapidly induces the expression of TLR7, resulting in synergistic activation. Moreover, we demonstrate that this mechanism conversely holds for plasmacytoid DCs that respond to TLR3 ligation when TLR7 pathway is mobilized. We further demonstrate that this mechanism of sharpening DC senses is also conserved in human BDCA1(+) DCs and plasmacytoid DCs. These findings have important implications for future clinical trials as it suggests that combinations of TLR ligands should be applied irrespective of initial TLR expression profiles on natural DC subsets for optimal stimulation. PMID- 26255865 TI - The effect of temperature on the male and female recombination landscape of barley. AB - Barley (Hordeum vulgare) is a crop of global significance. However, a third of the genes of barley are largely inaccessible to conventional breeding programmes as crossovers are localised to the ends of the chromosomes. This work examines whether crossovers can be shifted to more proximal regions simply by elevating growth temperature. We utilised a genome-wide marker set for linkage analysis combined with cytological mapping of crossover events to examine the recombination landscape of plants grown at different temperatures. We found that barley shows heterochiasmy, that is, differences between female and male recombination frequencies. In addition, we found that elevated temperature significantly changes patterns of recombination in male meiosis only, with a repositioning of Class I crossovers determined by cytological mapping of HvMLH3 foci. We show that the length of synaptonemal complexes in male meiocytes increases in response to temperature. The results demonstrate that the distribution of crossover events are malleable and can be shifted to proximal regions by altering the growth temperature. The shift in recombination is the result of altering the distribution of Class I crossovers, but the higher recombination at elevated temperatures is potentially not the result of an increase in Class I events. PMID- 26255866 TI - The yin-yang driving urinary tract infection and how proteomics can enhance research, diagnostics, and treatment. AB - Bacterial urinary tract infections (UTIs) afflict millions of people worldwide both in the community and the hospital setting. The onset, duration, and severity of infection depend on the characteristics of the invading pathogen (yin), as well as the immune response elicited by the infected individual (yang). Uropathogenic Escherichia coli (UPEC) account for the majority of UTIs, and extensive investigations by many scientific groups have elucidated an elaborate pathogenic UPEC life cycle, involving the occupation of extracellular and intracellular niches and the expression of an arsenal of virulence factors that facilitate niche occupation. This review will summarize the current knowledge on UPEC pathogenesis; the host immune responses elicited to combat infection; and it will describe proteomics approaches used to understand UPEC pathogenesis, as well as drive diagnostics and treatment options. Finally, new strategies are highlighted that could be applied toward furthering our knowledge regarding host bacterial interactions during UTI. PMID- 26255867 TI - Ring Opening of Bicyclo[3.1.0]hexan-2-ones: A Versatile Synthetic Platform for the Construction of Substituted Benzoates. AB - Described is the development of a highly efficient 2pi disrotatory ring-opening aromatization sequence using bicyclo[3.1.0]hexan-2-ones. This unprecedented transformation efficiently proceeds under thermal conditions and allows facile construction of uniquely substituted and polyfunctionalized benzoates. In the presence of either amines or alcohols formation of substituted anilines or ethers, respectively, is achieved. Additionally, the utility of this method was demonstrated in a short synthesis of sekikaic acid methyl ester. PMID- 26255868 TI - Capsule expression in Streptococcus mitis modulates interaction with oral keratinocytes and alters susceptibility to human antimicrobial peptides. AB - Streptococcus mitis is a colonizer of the oral cavity and the nasopharynx, and is closely related to Streptococcus pneumoniae. Both species occur in encapsulated and unencapsulated forms, but in S. mitis the role of the capsule in host interactions is mostly unknown. Therefore, the aim of this study was to examine how capsule expression in S. mitis can modulate interactions with the host with relevance for colonization. The S. mitis type strain, as well as two mutants of the type strain, an isogenic capsule deletion mutant, and a capsule switch mutant expressing the serotype 4 capsule of S. pneumoniae TIGR4, were used. Wild-type and capsule deletion strains of S. pneumoniae TIGR4 were included for comparison. We found that capsule production in S. mitis reduced adhesion to oral and lung epithelial cells. Further, exposure of oral epithelial cells to encapsulated S. mitis resulted in higher interleukin-6 and CXCL-8 transcription levels relative to the unencapsulated mutant. Capsule expression in S. mitis increased the sensitivity to human neutrophil peptide 1-3 but reduced the sensitivity to human beta-defensin-3 and cathelicidin. This was in contrast with S. pneumoniae in which capsule expression has been generally associated with increased sensitivity to human antimicrobial peptides (AMPs). Collectively, these findings indicate that capsule expression in S. mitis is important in modulating interactions with epithelial cells, and is associated with increased or reduced susceptibility to AMPs depending on the nature of the AMP. PMID- 26255869 TI - Chromatin state analysis of the barley epigenome reveals a higher-order structure defined by H3K27me1 and H3K27me3 abundance. AB - Combinations of histones carrying different covalent modifications are a major component of epigenetic variation. We have mapped nine modified histones in the barley seedling epigenome by chromatin immunoprecipitation next-generation sequencing (ChIP-seq). The chromosomal distributions of the modifications group them into four different classes, and members of a given class also tend to coincide at the local DNA level, suggesting that global distribution patterns reflect local epigenetic environments. We used this peak sharing to define 10 chromatin states representing local epigenetic environments in the barley genome. Five states map mainly to genes and five to intergenic regions. Two genic states involving H3K36me3 are preferentially associated with constitutive gene expression, while an H3K27me3-containing genic state is associated with differentially expressed genes. The 10 states display striking distribution patterns that divide barley chromosomes into three distinct global environments. First, telomere-proximal regions contain high densities of H3K27me3 covering both genes and intergenic DNA, together with very low levels of the repressive H3K27me1 modification. Flanking these are gene-rich interior regions that are rich in active chromatin states and have greatly decreased levels of H3K27me3 and increasing amounts of H3K27me1 and H3K9me2. Lastly, H3K27me3-depleted pericentromeric regions contain gene islands with active chromatin states separated by extensive retrotransposon-rich regions that are associated with abundant H3K27me1 and H3K9me2 modifications. We propose an epigenomic framework for barley whereby intergenic H3K27me3 specifies facultative heterochromatin in the telomere-proximal regions and H3K27me1 is diagnostic for constitutive heterochromatin elsewhere in the barley genome. PMID- 26255871 TI - Structure elucidation and NMR assignments of two new flavanones from the roots of Artocarpus heterophyllus. PMID- 26255870 TI - Aberrant splicing of genes involved in haemoglobin synthesis and impaired terminal erythroid maturation in SF3B1 mutated refractory anaemia with ring sideroblasts. AB - Refractory anaemia with ring sideroblasts (RARS) is distinguished by hyperplastic inefficient erythropoiesis, aberrant mitochondrial ferritin accumulation and anaemia. Heterozygous mutations in the spliceosome gene SF3B1 are found in a majority of RARS cases. To explore the link between SF3B1 mutations and anaemia, we studied mutated RARS CD34(+) marrow cells with regard to transcriptome sequencing, splice patterns and mutational allele burden during erythroid differentiation. Transcriptome profiling during early erythroid differentiation revealed a marked up-regulation of genes involved in haemoglobin synthesis and in the oxidative phosphorylation process, and down-regulation of mitochondrial ABC transporters compared to normal bone marrow. Moreover, mis-splicing of genes involved in transcription regulation, particularly haemoglobin synthesis, was confirmed, indicating a compromised haemoglobinization during RARS erythropoiesis. In order to define the phase during which erythroid maturation of SF3B1 mutated cells is most affected, we assessed allele burden during erythroid differentiation in vitro and in vivo and found that SF3B1 mutated erythroblasts showed stable expansion until late erythroblast stage but that terminal maturation to reticulocytes was significantly reduced. In conclusion, SF3B1 mutated RARS progenitors display impaired splicing with potential downstream consequences for genes of key importance for haemoglobin synthesis and terminal erythroid differentiation. PMID- 26255872 TI - Expression of CD11c in periprosthetic tissues from failed total hip arthroplasties. AB - In this work, we characterize integrin CD11c (alphaXbeta2) expression in periprosthetic tissues of 45 hip revisions. Tissues were retrieved from 23 ceramic-on-ultra-high molecular weight polyethylene (UHMWPE), 20 metal-on-UHMWPE, and 2 metal-on-metal total hip arthroplasties (THAs). Capsular tissue retrieved during primary THA from 19 patients served as controls. We identified a system to identify important immunohistochemical markers that are expressed in aseptic loosening. We focused on CD11c, CD68 and CD14. We observed that the CD11c molecule possesses four different cellular patterns in the periprosthetic tissues. Three of them are associated with the occurrence of UHMWPE abrasive material. Double staining with CD14 and CD68 was used for a more detailed analysis of the CD11c expressing cells. We observed that all forms of CD11c positive cells are CD68 positive however, only two forms of CD11c expressing cells are positive for CD14. Providing cellular diversity of CD11c expression in periprosthetic tissue, our results provide a contribution toward the further understanding of different cellular mechanisms to foreign body material. PMID- 26255873 TI - Evaluation of Skull Cortical Thickness Changes With Age and Sex From Computed Tomography Scans. AB - Head injuries resulting from motor vehicle crashes (MVC) are extremely common, yet the details of the mechanism of injury remain to be well characterized. Skull deformation is believed to be a contributing factor to some types of traumatic brain injury (TBI). Understanding biomechanical contributors to skull deformation would provide further insight into the mechanism of head injury resulting from blunt trauma. In particular, skull thickness is thought be a very important factor governing deformation of the skull and its propensity for fracture. Previously, age- and sex-based skull cortical thickness changes were difficult to evaluate based on the need for cadaveric skulls. In this cross-sectional study, skull thickness changes with age and sex have been evaluated at homologous locations using a validated cortical density-based algorithm to accurately quantify cortical thickness from 123 high-resolution clinical computed tomography (CT) scans. The flat bones of the skull have a sandwich structure; therefore, skull thickness was evaluated for the inner and outer tables as well the full thickness. General trends indicated an increase in the full skull thickness, mostly attributed to an increase in the thickness of the diploic layer; however, these trends were not found to be statistically significant. There was a significant relationship between cortical thinning and age for both tables of the frontal, occipital, and parietal bones ranging between a 36% and 60% decrease from ages 20 to 100 years in females, whereas males exhibited no significant changes. Understanding how cortical and full skull thickness changes with age from a wide range of subjects can have implications in improving the biofidelity of age- and sex-specific finite element models and therefore aid in the prediction and understanding of TBI from impact and blast injuries. PMID- 26255874 TI - The posterior arm flap in reconstruction of axillary defects: A lifeboat when soft tissue cover is limited. PMID- 26255875 TI - Re: 'Treatment of gummy smile: Nasal septum dysplasia as etiologic factor and therapeutic target'. AB - An evaluation and commentary of a recently suggested technique for the correction of gummy smiles is presented. A comparison of long-term stability reported with other surgical techniques, is also performed. From the results reported, use of this technique could offer a treatment option for those affected with excessive gingival display on smiling (gummy smile). PMID- 26255876 TI - Treatment of gummy smile: Nasal septum dysplasia as etiologic factor and therapeutic target. AB - Various techniques to improve gummy smile exist. Depending on the individual etiology, previous approaches have focused on osseous, dental, and soft-tissue aspects. On the basis of the identification of nasal septum dysplasia as etiologic factor of gummy smile, we propose a novel strategy for the improvement in the treatment of excessive gingival exposure. In this prospective controlled study, 121 Asian patients with gummy smile and 150 volunteers were examined and compared with regard to the developmental status of the nasal septal cartilage reflected by the columella upward maximum movability (CUMM) as objective measurement parameter. A total of 46 patients with significantly increased CUMM underwent surgical treatment for excessive gingival exposure by septum cartilage reinforcement and, where required, additional extension using an autologous cartilage graft or an expanded polytetrafluoroethylene (ePTFE) implant. Gingival exposure at the fullest smile was photographed, measured, and analyzed before and 1, 3, and 6 months after surgery, and all possible complications were recorded. The results were evaluated in a patient satisfaction survey. CUMM showed a significant statistical difference between the patients desiring treatment for gummy smile (5.6 +/- 0.92 mm) and volunteers (3.1 +/- 0.76 mm), (p < 0.05). In the 46 patients who underwent surgical correction of gummy smile, the measured maximum gingival exposure at the fullest smile was 4.52 +/- 1.7 mm preoperatively and significantly decreased to 1.79 +/- 0.26 mm at 6 months postoperatively (p < 0.05). The overall complication rate was low, including transient stiffness of smile, implant deformation, and acute infection. The postoperative results were highly satisfactory in terms of aesthetic smile. This study proposes a novel strategy of reinforcement and extension of the nasal septum cartilage for the improvement of gummy smile confirming septal cartilage dysplasia as the etiologic factor. PMID- 26255877 TI - Antihypertensive effects of probiotics Lactobacillus strains in spontaneously hypertensive rats. AB - SCOPE: The cardiovascular effects of probiotics Lactobacillus fermentum CECT5716 (LC40), or L. coryniformis CECT5711 (K8) plus L. gasseri CECT5714 (LC9) (1:1) in spontaneously hypertensive rats (SHR) were evaluated. METHODS AND RESULTS: Ten Wistar Kyoto rats (WKY) and 30 SHR were randomly assigned to four groups (n = 10): a control WKY group, a control SHR groups, an SHR group treated with LC40, and an SHR treated with K8/LC9 group for 5 weeks (at a dose of 3.3 * 10(10) colony-forming units/day in drinking water). Long-term administration of probiotics reduced systolic blood pressure. The consumption of K8/LC9 mixture significantly reduced the cardiac and renal hypertrophy. Both groups of probiotics reversed the impaired aortic endothelium-dependent relaxation to acetylcholine observed in SHR. They also abolished the increased aortic superoxide levels by reducing the increased toll-like receptor-4 mRNA levels and NADPH oxidase activity found in SHR. K8/LC9 consumption also increased endothelial nitric oxide synthase phosphorylation. Probiotic treatments induced a change in the cecum microbiota of SHR, with higher counts of the Lactobacillus spp. cluster, and lower counts of Bacteriodes spp. and Clostridium spp. CONCLUSION: Probiotics exert cardiovascular protective effects in genetic hypertension related to the improvement of vascular pro-oxidative and pro inflammatory status. PMID- 26255878 TI - Oral health and quality of life of children and adolescents with juvenile idiopathic arthritis according to their caregivers' perceptions. AB - The aim of this study was to assess the correlation between oral health indicators and oral health-related quality of life (OHRQoL) of children and adolescents with juvenile idiopathic arthritis (JIA) according to their caregivers' perceptions. Parents or guardians (mean age, 40.6 years; standard deviation [SD] = 10.97 years) of children and adolescents with JIA (n = 17; mean age, 9.8 years; SD = 2.86) and parents or guardians of healthy children and adolescents (n = 15; mean age, 10.7 years; SD = 2.16) filled the short form of the Brazilian Parental-Caregiver Questionnaire (SF: 13 - B-PCPQ). Dental evaluations were performed on all children. There was no significant difference in SF: 13 - B-PCPQ scores of the two groups. Children and adolescents with JIA had fewer caries in their primary dentition and more gingival bleeding after probing than those without JIA. The frequency of temporomandibular disorders was 50.0% for JIA patients and 46.7% for their healthy counterparts. There was no correlation between oral health indicators and SF: 13 - B-PCPQ scores. As perceived by caregivers, JIA did not negatively impact the well-being of their children and adolescents as related to oral health, and their OHRQoL did not correlate with oral health status. PMID- 26255879 TI - Well-defined star-shaped donor-acceptor conjugated molecules for organic resistive memory devices. AB - Solution processable star-shaped donor-acceptor (D-A) conjugated molecules (TPA-T NI and TPA-3T-NI) with an electron-donating triphenylamine (TPA) core, three thienylene or terthienylene spacers, and three 1.8-naphthalimide (NI) electron withdrawing end-groups are explored for the first time as charge storage materials for resistor-type memory devices owing to the efficient electric charge transfer and trapping. PMID- 26255880 TI - Women in interventional cardiology: Update in percutaneous coronary intervention practice patterns and outcomes of female operators from the National Cardiovascular Data Registry(r). AB - OBJECTIVES: To examine the practice patterns and outcomes of percutaneous coronary intervention (PCI) procedures performed by female interventional cardiologists in the United States (U.S.). BACKGROUND: Little is known about the prevalence, volume, case mix, and outcomes of PCI procedures performed by female interventional cardiologists. METHODS: Using data from the National Cardiovascular Data Registry((r)) , we performed a retrospective study of 2,465,685 PCI procedures performed at 1,431 U.S. hospitals between July 1, 2009 and June 30, 2013. Interventionalist sex was ascertained from the National Provider Identifier number of each operator. RESULTS: Women accounted for only 4% (412/9,179) of interventional cardiologists in the U.S., and performed 3% (n = 70,009) of all PCI procedures during the time period studied. Forty-one percent of female interventionalists operated at an institution with no other female operators. Female interventionalists performed a median of 48 PCI procedures per year (interquartile range: 22-87). Of the cases performed by female interventionalists, 77% were performed on patients with acute coronary syndrome, 3% on patients with cardiogenic shock, and 16% on call. In-hospital mortality was low (1.8%), and was not significantly different between female operators with high (>=50 cases/year) versus low (1.95% vs. 1.75%, unadjusted P = 0.12, adjusted OR: 1.03, 95% CI: 0.84-1.27) annual procedure volume. CONCLUSIONS: Female interventional cardiologists remain uncommon in contemporary U.S. practice. Performing only a very small proportion of PCI cases, female interventionalists are often low-volume operators, yet no significant differences in patient mortality were observed in low- versus high-volume operators. PMID- 26255881 TI - Antidotes to coumarins, isoniazid, methotrexate and thyroxine, toxins that work via metabolic processes. AB - Some toxins cause their effects by affecting physiological processes that are fundamental to cell function or cause systemic effects as a result of cellular interaction. This review focuses on four examples, coumarin anticoagulants, isoniazid, methotrexate and thyroxine from the context of management of overdose as seen in acute general hospitals. The current basic clinical pharmacology of the toxin, the clinical features in overdose and evidence base for specific antidotes are discussed. The treatment for this group is based on an understanding of the toxic mechanism, but studies to determine the optimum dose of antidote are still required in all these toxins except thyroxine, where treatment dose is based on symptoms resulting from the overdose. PMID- 26255882 TI - Perspectives of Genome-Editing Technologies for HIV Therapy. AB - BACKGROUND: Current HIV antiretroviral therapies potently suppress virus replication and prevent patients from progressing to AIDS but are unable to completely eliminate HIV due to the existence of dormant viral reservoirs which threaten to reemerge at anytime. Recently, genome-editing technologies that can recognize specific DNA sequences, including viral DNA, are being touted as promising tools for curing HIV, owing to their specificity, ease of use, and ability to be custom designed. CONCLUSION: Here, we introduce several novel strategies aimed at eradicating HIV proviruses with state-of-the-art genome editing technologies and discuss perspectives of these approaches for curing HIV. PMID- 26255883 TI - Editorial for Therapeutic Monoclonal Antibodies: What Headache Specialists Need to Know. PMID- 26255884 TI - Clinical and economic burden of breakthrough seizures. AB - PURPOSE: The purpose of this study was to measure health-care resource utilization and costs in treatment-adherent, previously seizure-free patients with epilepsy who were treated in the inpatient/emergency room (ER) setting for new-onset seizures, compared with matched controls. METHODS: The study used a retrospective case/control study design using administrative claims from the IMS PharMetricsTM database. We identified adult patients with epilepsy with 1+ ER visit/hospitalization with primary diagnosis of epilepsy between 1/1/2006 and 3/31/2011, preceded by 6months of seizure-free activity and antiepileptic drug (AED) treatment adherence (>=80% of days covered by any AED); the first observed seizure defined the "breakthrough" seizure/index event. Treatment-adherent patients with epilepsy without any ER/hospital admission for seizures served as controls: an outpatient epilepsy-related medical claim within the selection window was chosen at random as the index date. The following were continuous enrollment requirements for all patients: >=12-month pre- and >=6-month postindex. Each case matched 1:1 to a control using propensity score matching. All-cause and epilepsy-related (epilepsy/convulsion diagnosis, AED pharmacy) resource utilization and unadjusted and adjusted direct health-care costs (per person, 2012 US dollars (USD)) were assessed in a 6-month follow-up period. PRINCIPAL RESULTS: There were 5729 cases and 14,437 controls eligible. The final sample comprised 5279 matched case/control pairs. In unadjusted analyses, matched cases had significantly higher rates of all-cause hospitalization and ER visits compared to controls and significantly higher total all-cause direct health-care costs (median $12,714 vs. $5095, p<0.001) and total epilepsy-related costs among cases vs. controls (median $7293 vs. $1712, p<0.001), driven by higher inpatient costs. Among cases, costs increased with each subsequent seizure (driven by inpatient costs). Cases had 2.3 times higher adjusted all-cause costs and 8.1 times higher adjusted epilepsy-related costs than controls (both p<0.001). CONCLUSION: Inpatient/ER-treated breakthrough seizures occurred among 28.4% of our treatment-adherent study sample and were associated with significant incremental health-care utilization and costs, primarily driven by hospitalizations. Our findings suggest the need for better seizure control via optimal patient management and the use of effective AED therapy, which can potentially lower health-care costs. PMID- 26255885 TI - Subjective cognitive complaints versus objective neuropsychological performance in older adults with epilepsy. AB - Memory complaints are common among older adults with epilepsy (OAE), though discrepancy between subjective complaints and objective performance often exists. This study examined how accurately OAE and their informants reported on the participant's cognitive difficulties by comparing ratings of everyday cognition to objective performance. Thirty-seven OAE and 27 older adult controls completed a brief battery of neuropsychological tests, the Beck Depression Inventory, and the Cognitive Difficulties Scale (CDS). Each participant had an informant who completed the CDS. Older adults with epilepsy performed worse than controls on cognitive testing and reported more subjective cognitive complaints. Neither participant- nor informant-reported cognitive complaints were related to performance on any of the neuropsychological tests for either the group with epilepsy or control group, but both were related to greater depressive symptoms. Results suggest that subjective report of cognitive problems by both OAE and their informants may not reliably reflect the extent to which these problems exist. PMID- 26255887 TI - Prevalence of syphilis, human immunodeficiency virus, hepatitis B virus, and human T-lymphotropic virus infections and coinfections during prenatal screening in an urban Northeastern Brazilian population. AB - OBJECTIVES: To evaluate prevalences of Treponema pallidum, human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), and hepatitis B virus (HBV) infections and coinfections during prenatal screening in an urban Northeastern Brazilian population through a large dataset. METHODS: Secondary data were obtained from the Maceio (Alagoas, Brazil) municipal prenatal screening program from June 2007 to May 2012. Dried blood serum tests from 54,813 pregnant women were examined to determine prevalences of T. pallidum, HIV, HTLV, and HBV infections and coinfections, and the seroconversion rates for syphilis and HIV infection. Socio-demographic variables associated with syphilis and HIV infection were identified. RESULTS: The prevalences of syphilis, HIV, HTLV, and HBV infections were 2.8%, 0.3%, 0.2%, and 0.4%, respectively. Pregnant women infected with T. pallidum had a 4.62-fold greater risk of HIV coinfection, and pregnant women infected with HIV had a 5.71-fold greater risk of T. pallidum coinfection. Seroconversion for syphilis and HIV during pregnancy occurred in 0.5% and 0.06% of women, respectively. Among the women carrying HTLV, 4.2% also had an HBV infection. CONCLUSIONS: Syphilis was twice as prevalent among pregnant women in Maceio, compared to the national average, and coinfections with syphilis/HIV and HTLV/HBV were significantly associated among these pregnant women. PMID- 26255886 TI - Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non-cell-autonomous stress response. AB - Oxidative stress has long been associated with aging and has recently been linked to psychiatric disorders, including psychosis and depression. We identified multiple antipsychotics and antidepressants that extend Caenorhabditis elegans lifespan and protect the animal from oxidative stress. Here, we report that atypical antidepressants activate a neuronal mechanism that regulates the response to oxidative stress throughout the animal. While the activation of the oxidative stress response by atypical antidepressants depends on synaptic transmission, the activation by reactive oxygen species does not. Lifespan extension by atypical antidepressants depends on the neuronal oxidative stress response activation mechanism. Neuronal regulation of the oxidative stress response is likely to have evolved as a survival mechanism to protect the organism from oxidative stress, upon detection of adverse or dangerous conditions by the nervous system. PMID- 26255888 TI - Host biomarkers are associated with progression to dengue haemorrhagic fever: a nested case-control study. AB - OBJECTIVES: Dengue represents the most important arboviral infection worldwide. Onset of circulatory collapse can be unpredictable. Biomarkers that can identify individuals at risk of plasma leakage may facilitate better triage and clinical management. DESIGN: Using a nested case-control design, we randomly selected subjects from a prospective cohort study of dengue in Colombia (n=1582). Using serum collected within 96 hours of fever onset, we tested 19 biomarkers by ELISA in cases (developed dengue hemorrhagic fever or dengue shock syndrome (DHF/DSS); n=46), and controls (uncomplicated dengue fever (DF); n=65) and healthy controls (HC); n=15. RESULTS: Ang-1 levels were lower and angptl3, sKDR, sEng, sICAM-1, CRP, CXCL10/IP-10, IL-18 binding protein, CHI3L1, C5a and Factor D levels were increased in dengue compared to HC. sICAM-1, sEng and CXCL10/IP-10 were further elevated in subjects who subsequently developed DHF/DSS (p=0.008, p=0.028 and p=0.025, respectively). In a logistic regression model, age (odds ratio (OR) (95% CI): 0.95 (0.92-0.98), p=0.001), hyperesthesia/hyperalgesia (OR; 3.8 (1.4-10.4), p=0.008) and elevated sICAM-1 (>298ng/mL: OR; 6.3 (1.5-25.7), p=0.011) at presentation were independently associated with progression to DHF/DSS. CONCLUSIONS: These results suggest that inflammation and endothelial activation are important pathways in the pathogenesis of dengue and sICAM-1 levels may identify individuals at risk of plasma leakage. PMID- 26255889 TI - Viruses and Gram-negative bacilli dominate the etiology of community-acquired pneumonia in Indonesia, a cohort study. AB - OBJECTIVE: Knowledge about the etiology of community-acquired pneumonia (CAP) is essential for adequate management. Presently, few studies about CAP are available from Southeast Asia. This study aimed to investigate the etiology, severity, and outcome of CAP in the most populous Southeast Asia country, Indonesia. METHODS: From October 2007 to April 2009, adult patients admitted with CAP to two hospitals in Semarang, Indonesia, were included to detect the etiology of CAP using a full range of diagnostic methods. The severity of disease was classified according to the Pneumonia Severity Index (PSI). The outcome was assessed as 30 day mortality. RESULTS: In total, 148 consecutive patients with CAP were included. Influenza virus (18%), Klebsiella pneumoniae (14%), and Streptococcus pneumoniae (13%) were the most common agents identified. Other Gram-negative bacilli, Mycobacterium tuberculosis, Chlamydia pneumoniae each accounted for 5%. The bacteria presented wild type antibiotic susceptibility profiles. Forty-four percent of subjects were high-risk patients (PSI class IV-V). The mortality rate (30%) was significantly associated with disease severity score (P<0.001), and with failure to establish an etiological diagnosis (P=0.027). No associations were found between etiology and underlying diseases, PSI class, nor mortality. CONCLUSIONS: Viruses and Gram-negative bacilli are dominant causes of CAP in this region, more so than S. pneumoniae. Most of the bacteria have wild type susceptibility to antimicrobial agents. Patients with severe disease and those with unknown etiology have a higher mortality risk. PMID- 26255891 TI - Mortality among severe community-acquired pneumonia patients depends on combinations of 2007 IDSA/ATS minor criteria. AB - OBJECTIVES: The individual 2007 Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS) minor criteria for severe community acquired pneumonia (CAP) are of unequal weight in predicting mortality. It is not clear whether the combinations of predictive findings might imply diverse severities or different mortalities. METHODS: A prospective two centre cohort study was performed of 385 severe CAP patients fulfilling three or more IDSA/ATS minor criteria amongst 1430 patients. RESULTS: Hospital mortality rose sharply from 5.7%, 9.9%, and 16.5%, respectively, for patients with none of three predictive findings most strongly associated to mortality (PaO2/FiO2 <= 250mm Hg, confusion and uraemia), one of those, and two of those to 38.6% for patients with all those (p<0.001). The number of three predictive findings present had a significantly increased odds ratio for mortality of 2.796 (p<0.001), and had the degree of positive association with sequential organ failure assessment scores at 72hours, incurring significantly longer hospital stay and higher costs. CONCLUSIONS: Different combinations of 2007 IDSA/ATS minor criteria for severe CAP were associated to diverse severities and different mortalities. The combination of PaO2/FiO2 <= 250mm Hg, confusion and uraemia predicted more severity and higher mortality compared with others. PMID- 26255890 TI - Neisseria gonorrhoeae prevalence, incidence and associated risk factors among female sex workers in a high HIV-prevalence area of China. AB - BACKGROUND: Neisseria gonorrhoeae (N. gonorrhoeae) is one of the most prevalent non-ulcerative sexually transmitted infections (STIs) in China, however, the data about N. gonorrhoeae infections are limited in this population. The objective of this study is to determine N. gonorrheae incidence and associated risk factors among female sex workers (FSWs) in China. METHODS: This serial cross-sectional study was conducted semi-annually among FSWs in a City of Yunnan Province, which constituted an open cohort study. Participants were interviewed and tested for N. gonorrhoeae every 6 months. RESULTS: During 3 years of follow-up, 64 incident cases of N. gonorrhoeae infection were diagnosed, yielding an overall incidence of 5.9 per 100 person years (PY) (95% confidence interval (CI), 4.53-7.41). Working in higher risk commercial sex venue (adjusted hazard ratio (AHR)=2.7, 95% CI, 1.56-4.55), inconsistently used condoms with clients in previous week (AHR=1.9, 95% CI, 1.07-3.35) and being infected with C. trachomatis (AHR=1.9, 95% CI, 1.06-3.26) were independent risk factors for incident N. gonorrhoeae infection. CONCLUSIONS: A relatively high prevalence and incidence of N. gonorrhoeae among a prospective cohort of FSWs underscore the urgency for traditional HIV/STIs prevention methods among FSWs, such as condom promotion, screening and treatment of STIs, considering the high prevalence of STIs. Significant attention should focus on FSWs working in higher risk commercial sex venues as they are at higher risk for N. gonorrhoeae and transmission than those in lower risk commercial sex venues. PMID- 26255892 TI - Cefepime combined with amoxicillin/clavulanic acid: a new choice for the KPC producing K. pneumoniae infection. AB - OBJECTIVE: Clinical treatment for blaKPC-positive Klebsiella pneumoniae isolates is challenging because the recommended antibiotic options are limited and are extraordinarily expensive. This study aimed to explore a new therapy for infection caused by KPC-producing K. pneumoniae. METHODS: Patients with blaKPC positive K. pneumoniae infection, were prospectively screened and were categorised into two groups: patients in the study group received a combination based therapy of cefepime and amoxicillin/clavulanic acid and the control group received tigecycline-based therapy. The pathogen clearance rate, 28-day mortality and cost of the antibiotic treatment were compared between the two groups. Moreover, the checkerboard microdilution method was performed to determine the synergy between cefepime and amoxicillin/clavulanic acid in vitro. RESULTS: Twenty-six and 25 cases were enrolled in the study and control groups. The mortality and the overall pathogen clearance rate showed no significant differences (P=0.311 and P=0.447). Both the total cost and the portion of the cost not covered by insurance were higher for the control group compared to the study group (both P<0.001). Consistently, synergy (65.4%) and partial synergy (26.9%) were the main effects. CONCLUSIONS: In contrast to the currently recommended tigecycline-based therapy, cefepime and amoxicillin/clavulanic acid combination was an effective and economical option to KPC-KP infection in China. PMID- 26255893 TI - Giant Molluscum Contagiosum in an HIV positive patient. AB - Molluscum Contagiosum (MC) is a skin infection caused by a double-stranded DNA virus of the family Poxviridae that replicates in the human epidermis, affecting mainly children and young sexually active adults and causing flesh colored papular lesions with central umbilication with an average size of 3-5mm, although atypical lesions that reach great size (Giant Molluscum Contagiosum), 10-15mm, can be seen in almost any immunodeficiency condition. We report the case of a 35 year old male patient with C3 HIV disease with an abdominal pathology associated to skin lesions predominantly in the forehead and scalp that reached sizes over 5mm, diagnosed as Giant Molluscum Contagiosum by skin biopsies. PMID- 26255894 TI - High-Performance Monolayer WS2 Field-Effect Transistors on High-kappa Dielectrics. AB - The combination of high-quality Al2 O3 dielectric and thiol chemistry passivation can effectively reduce the density of interface traps and Coulomb impurities, leading to a significant improvement of the mobility and a transition of the charge transport from the insulating to the metallic regime. A record high mobility of 83 cm(2) V(-1) s(-1) (337 cm(2) V(-1) s(-1) ) is reached at room temperature (low temperature) for monolayer WS2 . A theoretical model for electron transport is also developed. PMID- 26255895 TI - Pre-treatment carbohydrate antigen 19-9 does not predict the response to neoadjuvant therapy in patients with localized pancreatic cancer. AB - BACKGROUND: The prognostic value of CA19-9 in patients with pancreatic cancer (PC) treated with neoadjuvant therapy has not been well described. METHODS: Pre treatment CA19-9 levels (with concomitant normal bilirubin level) in patients with localized PC were categorized as normal (<=35), low (36-200), moderate (201 1000), or high (>1000). Post-treatment CA19-9 was measured after neoadjuvant therapy, prior to surgery. RESULTS: Pre-treatment CA19-9 levels were evaluable in 235 patients, levels were normal in 60 (25%) patients, low in 78 (33%) patients, moderate in 69 (29%) and high in 28 (12%). After neoadjuvant therapy, post treatment CA19-9 normalized (<= 35) in 40 (51%) of the patients in the low group, 14 (21%) of the moderate and 5 (19%) of the high group (P < 0.001). Of the 235 patients, 168 (71%) completed all intended therapy including a pancreatectomy; 44 (73%), 62 (79%), 46 (67%) and 16 (57%) of the normal, low, moderate and high groups (P = 0.10). Among these 168 patients, the median overall survival was 38.4, 43.6, 44.7, 27.2 and 26.4 months for normal, low, moderate and high CA19-9 groups (log rank P = 0.72). Among resected patients, an elevated pre-treatment CA19-9 was of little prognostic value; instead, it was the CA19-9 response to neoadjuvant therapy that was prognostic [hazard ratio (HR): 1.80, P = 0.02]. CONCLUSIONS: Among patients who completed neoadjuvant therapy and surgery, pre treatment CA19-9 obtained at the time of diagnosis was not predictive of overall survival, but normalization of post-treatment CA19-9 in response to neoadjuvant therapy was highly prognostic. PMID- 26255896 TI - Trends in the genomic epidemiology of Vibrio cholerae O1 isolated worldwide since 1961. AB - Here we describe the international scenario of Vibrio cholerae with a comparative analysis of different aspects of typing. Representative V. cholerae strains (n=108) associated with endemic cholera regions from 29 states of India and worldwide were subjected to microbiological, molecular and phylogenetic study. All of the strains were V. cholerae serogroup O1 biotype El Tor and were typed according to both the new phage (NP) type and Basu & Mukherjee (BM) typing schemes. The predominant phage type was T-27 (NP)/T-4 (BM) (65.7%; n=71), followed by phage type T-27 (NP)/T-2 (BM) (14.8%; n=16), T-26 (NP)/T4 (BM) (12.0%; n=13), T-13 (NP)/T-4 (BM) (2.8%; n=3), T-20 (NP)/T-4 (BM) (1.9%; n=2), T 3 (NP)/T-4 (BM) (0.9%; n=1), T-23 (NP)/T-4 (BM) (0.9%; n=1) and T-24 (NP)/T-2 (BM) (0.9%; n=1). Mismatch amplification mutation assay PCR (MAMA-PCR) findings showed the dominance of ctxB El Tor genotype (77.1%; 54/70) from 1961-1991, whilst the next two epochs showed the supremacy of ctxB classical genotype. Multidrug-resistant strains showed resistance to erythromycin, streptomycin, trimethoprim/sulfamethoxazole, norfloxacin and ampicillin. The regional resistance of epidemic clones in India draws a layout of the rapid dissemination of resistance in the past 30 years and the necessity of proper treatment to protect populations at risk. PMID- 26255897 TI - True User Involvement by People Living With HIV is Possible: Description of a User-driven HIV Clinic in Norway. AB - The Greater Involvement of People Living with or Affected by HIV principle highlights the various contributions HIV-infected people can make in HIV program development and implementation. We present a unique example of how service users' involvement led to a complete organizational redesign of an outpatient HIV clinic in Southern Norway. We applied a user-driven, case study method, which showed that establishing a user board laid the foundation for the redesign process, as the board provided a clear infrastructure of user involvement and developed a set of user-defined targets for services. The main targets-optimal health, holistic care and treatment, and empowerment-were operationalized as a set of action points, such as establishing HIV nurse coordinators. While there is no single method for user involvement, we offer useful ideas that can help others develop an involvement project that is effective and sustainable. PMID- 26255898 TI - The impact of obesity on laparoscopic appendectomy: Results from the ACS National Surgical Quality Improvement Program pediatric database. AB - BACKGROUND: Childhood obesity is a worsening epidemic. Little is known about the impact of elevated BMI on perioperative and postoperative complications in children who undergo laparoscopic surgery. The purpose of this study was to examine the effects of obesity on surgical outcomes in children using laparoscopic appendectomy as a model for the broader field of laparoscopic surgery. STUDY DESIGN: Using the Pediatric National Surgical Quality Improvement Program (NSQIP) data from 2012, patients aged 2-18years old with acute uncomplicated and complicated appendicitis who underwent laparoscopic appendectomy were identified. Children with a body mass index (BMI)>=95th percentile for their age and gender were considered obese. Primary outcomes, including overall morbidity and wound complications, were compared between nonobese and obese children. Multivariate regression analysis was conducted to identify the impact of obesity on outcome. RESULTS: A total of 2812 children with acute appendicitis who underwent appendectomy were included in the analysis; 22% were obese. Obese children had longer operative times but did not suffer increased postoperative complications when controlling for confounders (OR 1.3, 95% CI: 0.83-0.072 for overall complications, OR 1.3, 95% CI: 0.84-1.95 for wound complications). CONCLUSIONS: Obesity is not an independent risk factor for postoperative complications following laparoscopic appendectomy. Although operative times are increased in obese children, obesity does not increase the likelihood of 30-day postoperative complications. PMID- 26255899 TI - The quality of cardiovascular disease prevention in rural primary care. AB - OBJECTIVE: To measure the differences in the recording of risk factors and lifestyle advice between those at high risk of cardiovascular disease and those diagnosed with cardiovascular disease, and to identify the practice characteristics associated with such recording in rural primary care. DESIGN: A cross-sectional observation study of 14 general practices. Medical records were audited to measure recording of risk factors and lifestyle advice for those at high risk of and those diagnosed with cardiovascular disease. Practice characteristics were collected, with logistic regression used to test for an association with the recording of risk factors. SETTING: General practices in rural Australia. PARTICIPANTS: Each practice was asked to identify 20 patients; 10 at high risk and 10 diagnosed with cardiovascular disease. MAIN OUTCOME MEASURES: The recording of risk factors and lifestyle advice in patient records and practice characteristics. RESULTS: 282 records were audited with 142 being high risk and 140 diagnosed with cardiovascular disease.Measures recorded significantly less in the high-risk group were: blood pressure (94% versus 99%; P = 0.019); physical activity (24% versus 56%; P = 0.000); dietary advice (32% versus 51%; P = 0.001); and physical activity advice (34% versus 56%; P = 0.000). Recording of risk factors was positively associated with practice involvement in quality improvement (P < 0.001), continuing education (P < 0.001), and greater percentage of general practitioners (P < 0.05) and practice nurses (P < 0.001). CONCLUSIONS: There is substantial room for enhanced cardiovascular disease prevention through rural primary care in Australia, particularly for high-risk patients. This study has demonstrated an association between practice factors (including targeted education, quality improvement activities and appropriate workforce) and improved preventive activities. PMID- 26255901 TI - Chemical Profiling of Illicit Heroin Samples. AB - For many years, the forensic chemist has been asked to establish the degree of similarity between different seizures of illicit drugs. Such comparative analyses deal with the comprehensive examination of the chemical and physical characteristics of each drug exhibit. Therefore, they also deal with the development of analytical methods allowing for the collection of data on every drug sample in order to obtain a real fingerprint of it. This review describes various but complementary methods for the chemical profiling of illicit heroin samples. The first method is the identification and quantitation of major constituents of the drug exhibit, i.e., opium alkaloids and derivatives, adulterants and diluents. Second is the characterization of trace level impurities, e.g., neutral byproducts resulting from the action of acetic anhydride upon the opium alkaloids. The third and fourth methods are respective examination of residual solvents and inorganic compounds. Last is the multi element stable isotope analysis of the sample, i.e., determination of the isotope ratios 13C/12C, 15N/14N, 2H/1H, 18O/16O of its major components. For every method presented, analytical parameters are described and discussed. It is concluded that associating the first with the second and/or third method is the most reliable procedure for complete characterization of illicit heroin samples. PMID- 26255900 TI - Sarcocystis oreamni, n. sp. (Apicomplexa: Sarcocystidae) from the mountain goat (Oreamnos americanus). AB - Numerous species of Sarcocystis have been reported from wild ruminants, but none has been named from the Rocky Mountain goat (Oreamnos americanus). Mature sarcocysts were found in frozen muscle samples of three of seven mountain goats from Alaska, USA. Two morphological types of sarcocysts were found; one had Sarcocystis cornagliai-like sarcocysts, previously named from the Alpine ibex (Capra ibex) from Europe. Two other goats were infected with a new species, Sarcocystis oreamni. Sarcocystis oreamni sarcocysts were microscopic with 2 MUm thick sarcocyst wall. By transmission electron microscopy, the sarcocyst wall had 1.7 MUm-thick with unusual molar tooth-like villar protrusions (vp), type 29. The vp had an electron dense core and two disc-shaped plaques at the tip with fine microtubules. Bradyzoites were 8.6-9.1 MUm long. Single nucleotide polymorphism (SNP) identified in 18S rRNA, and 28S rRNA loci of rDNA regions that suggested S. oreamni molecularly apart from related species. The phylogenetic analysis based on 18S rRNA and 28S rRNA sequences suggested S. oreamni is related with Sarcocystis species that employ members of the Canidae family as their definitive host. PMID- 26255902 TI - Coming of Age: The American Academy of Forensic Sciences and the Forensic Sciences Profession - 1948 to 1998. AB - In 1998 the American Academy of Forensic Sciences celebrated its first 50 years of operation at its Golden Anniversary Meeting in San Francisco. In anticipation of that event, in 1991 the Academy created a committee to prepare a history of the organization. One of the products of that committee was a book, the principal author of which was one of the authors of this review (KSF). The theme of the opening Plenary Session at the meeting was The History of the Forensic Sciences Profession and of the Academy. This article is based on presentations by the authors at that Plenary Session [2] and on material compiled for the book. Comparisons are made of the early years of the forensic science profession and of the Academy with the status of the current profession and Academy. PMID- 26255903 TI - Contemporary Sample Preparation Methods for the Detection of Ignitable Liquids in Suspect Arson Cases. AB - The isolation of ignitable liquid components, usually petroleum-based distillates from fire debris, is an important step in deciding whether a fire is of natural or incendiary origin. Steady progress has been made to develop sample preparation methods capable of enriching target analytes in high yield and within a short period of time. Heated headspace enrichment methods are currently most widely used. There are several variations of this basic technique. Carbon-based adsorbents are most popular. They come in different forms and shapes, including a flat sheet of polymer, impregnated with carbon particles. The analyst cuts a small strip from this sheet and suspends it in the heated headspace above the debris sample. The volatiles adsorb onto the carbon surface, eventually reaching an equilibrium condition. The process is usually carried out in an oven. This convenient method, called the static method, has largely replaced the dynamic method, which uses a granular charcoal adsorbent. In the latter, the heated headspace is drawn over a short trap packed with charcoal, using a source of vacuum such as a pump or pushed along using pressurized nitrogen. The headspace volatiles in both the static and dynamic method are recovered by elution with a solvent, usually carbon disulfide. Recently, a promising variation of the static headspace method has been introduced. It is based on the use of a tiny amount of a polysiloxane polymer which has been coated onto the tip of a thin silica fiber. The fiber can be retracted into a syringe-type needle and the adsorbed headspace vapor can be conveniently introduced into the heated injector port of a gas chromatograph. No solvent is required. This technique, abbreviated SPME (for solid-phase microextraction) has many attractive advantages but it is not without some problems. Low boiling range accelerants, including water-soluble polar substances such as ethanol, are poorly retained on methylsiloxane type polymers. The recent introduction of hybrid fibers containing a combination of carbon and a methylpolysiloxane polymer has extended the usefulness of SPME toward the high volatility end. With judicious optimization of experimental conditions, it is now possible to obtain an adequately representative sample of the headspace above the fire debris sample. It is thus possible to characterize the full spectrum of potential liquid accelerants, ranging from alcohols and similar water-soluble substances to high boiling range fuel oils. PMID- 26255904 TI - LSD - An Overview on Drug Action and Detection. AB - LSD is a psychoactive semisynthetic ergot alkaloid. It is so potent that a small dose (?25 MUg) may produce a profound hallucinogenic effect. The compound is a controlled substance under the US code of regulations. One of the major adverse effects of LSD is the "flashback" or spontaneous recurrences of hallucinogenic effects that may occur months to years after cessation of the drug. The major concern of LSD abuse is the long duration of action and fatal accidents and suicides during the state of intoxication. Because LSD metabolizes to a number of compounds and detection methods for these compounds in a large number of samples are not well established, most of the methods are aimed at identifying unchanged LSD in urine. After initial screening by an immunoassay method, the presence of LSD in urine is confirmed by a gas chromatographic-mass spectrometric (GC-MS) method. The immunoassay techniques are simple and cost-effective. In confirmation, selective extraction is preferred because it allows detection of the compound at concentrations as low as 50 pg/mL. Recent methods for detection of an LSD metabolite, 2-oxo-3-hydroxy-LSD, by liquid chromatography-mass spectrometry appeared to be promising in some forensic investigations. PMID- 26255905 TI - Evaluation of a coupled model for numerical simulation of a multiphase flow system in a porous medium and a surface fluid. AB - Numerical simulations that couple flow in a surface fluid with that in a porous medium are useful for examining problems of pollution that involve interactions among atmosphere, water, and groundwater, including saltwater intrusion along coasts. Coupled numerical simulations of such problems must consider both vertical flow between the surface fluid and the porous medium and complicated boundary conditions at their interface. In this study, a numerical simulation method coupling Navier-Stokes equations for surface fluid flow and Darcy equations for flow in a porous medium was developed. Then, the basic ability of the coupled model to reproduce (1) the drawdown of a surface fluid observed in square-pillar experiments, using pillars filled with only fluid or with fluid and a porous medium and (2) the migration of saltwater (salt concentration 0.5%) in the porous medium using the pillar filled with fluid and a porous medium was evaluated. Simulations that assumed slippery walls reproduced well the results with drawdowns of 10-30 cm when the pillars were filled with packed sand, gas, and water. Moreover, in the simulation of saltwater infiltration by the method developed in this study, velocity was precisely reproduced because the experimental salt concentration in the porous medium after saltwater infiltration was similar to that obtained in the simulation. Furthermore, conditions across the boundary between the porous medium and the surface fluid were satisfied in these numerical simulations of square-pillar experiments in which vertical flow predominated. Similarly, the velocity obtained by the simulation for a system coupling flow in surface fluid with that in a porous medium when horizontal flow predominated satisfied the conditions across the boundary. Finally, it was confirmed that the present simulation method was able to simulate a practical scale surface fluid and porous medium system. All of these numerical simulations, however, required a great deal of computational effort, because time was incremented in 0.05- to 0.10-s steps. Hereafter, the present simulation method needs to be improved so that the simulations can be conducted with less computational effort. PMID- 26255906 TI - Directed Assembly of Ultrathin Gold Nanowires over Large Area by Dielectrophoresis. AB - Ultrathin Au nanowires (~2 nm diameter) are interesting from a fundamental point of view to study structure and electronic transport and also hold promise in the field of nanoelectronics, particularly for sensing applications. Device fabrication by direct growth on various substrates has been useful in demonstrating some of the potential applications. However, the realization of practical devices requires device fabrication strategies that are fast, inexpensive, and efficient. Herein, we demonstrate directed assembly of ultrathin Au nanowires over large areas across electrodes using ac dielectrophoresis with a mechanistic understanding of the process. On the basis of the voltage and frequency, the wires either align in between or across the contact pads. We exploit this assembly to produce an array of contacting wires for statistical estimation of electrical transport with important implications for future nanoelectronic/sensor applications. PMID- 26255907 TI - Etiology and body area of injuries in young female dancers presenting to sports medicine clinic: A comparison by age group. AB - INTRODUCTION: Improving knowledge regarding injuries sustained by pediatric dancers is important in order to better understand injury risk. The aim of this study is to analyze dance injury etiology and body area by age in a cohort of young female dancers presenting to a pediatric sports/dance medicine clinic. METHODS: The cross-sectional epidemiological study of a 5% probability sample of dancers evaluated between 1/1/2000 and 12/31/2009 with a musculoskeletal injury requiring physician evaluation. A total of 2,133 charts were reviewed from which 171 female dancers 8-17 years old (mean age 14.7 years) were identified. Data were stratified by age, < 12 years and >= 12 years, and analyzed based on injury body area, type, and etiology. Fisher's exact test was used to determine statistical significance. RESULTS: Injuries sustained by dancers in the younger age category (< 12 years) were largely to the foot-ankle/lower leg/knee (93.3%) versus thigh-hip/spine/upper extremity (6.7%). In comparison, dancers in the older age group (>= 12 years) had a large proportion of injuries to the foot ankle/lower leg/knee (67.3%) as well, but had a notably larger fraction of injuries to the thigh-hip/spine/upper extremity (32.7%; p = 0.04). Approximately two-thirds of the injuries sustained in the younger age group (< 12 years) were classified as bony. In comparison, injuries in the older age group (>= 12 years) were roughly half bony and half soft tissue (51.3% and 48.7%, respectively; p = 0.29). Most injuries were overuse in etiology for both younger and older age groups (86.7% and 82.1%, respectively; p = 1.00). Through puberty, there was a decline in the injuries to the foot-ankle/lower leg/knee. Conversely, there was an increase in the thigh/hip-pelvis/spine/upper extremity injuries through growth. CONCLUSIONS: Injuries to young female dancers in this study cohort were mostly categorized as overuse in etiology, and differed by the age group and the body area. Increased information regarding dance injuries can help guide future injury prevention efforts. PMID- 26255908 TI - Usefulness of WISC-IV in Determining Intellectual Giftedness. AB - Several studies question the usefulness of the Wechsler Intelligence Scale for Children (WISC-IV) in determining giftedness due to the importance of speed in some of its subtests, which may penalize children of high intellectual level. This study analyzes the factor structure of the WISC-IV of gifted children based on confirmatory factor analysis. Participants were eighty-seven gifted children from Spain (6-13 years old). Score discrepancies were also examined for the main indexes: Verbal Comprehension, Processing Speed, Working Memory and Perceptual Organization. Results pointed out four models with a good fit from the five models analyzed: a two-factor model according to GAI subscales (RMSEA = .001, p = .84), a four-factor first-order model including main indexes (RMSEA = .05, p = .19), a four-factor model with g as a direct factor (RMSEA = .001, p = .84) and a four-factor model with g as an indirect higher-order factor (RMSEA = .05, p = .13). Discrepancies were found between Verbal Comprehension and Processing Speed, and between Perceptual Organization and Processing Speed. Verbal Comprehension yielded the highest score, whereas the lowest scores were obtained in Processing Speed and Working Memory. These results support the use of this scale in the assessment and diagnosis of Spanish children with a high intellectual level. PMID- 26255909 TI - Imaging is integral to meeting the ambitions of the Five Year Forward View. PMID- 26255910 TI - The NHS is failing to adopt its own recommendations on innovation. PMID- 26255912 TI - The causes of oral ulcer-action are legion. PMID- 26255913 TI - Magnetic resonance enterography: a pictorial review of Crohn's disease. AB - Use of magnetic resonance enterography has significantly increased and its role as an adjunct to ileocolonoscopy is best practice, particularly in the evaluation of Crohn's disease. This article reviews magnetic resonance enterography, and describes common findings related to Crohn's disease and unexpected extra intestinal findings. PMID- 26255914 TI - Nutritional management of the patient with Crohn's disease. AB - Active Crohn's disease often co-exists with malnutrition and requires input from the inflammatory bowel disease multidisciplinary team in order to assess, prevent and treat the complications of both malnutrition and active disease. PMID- 26255915 TI - Management of Crohn's disease in pregnancy. AB - Crohn's disease is a chronic inflammatory bowel disease commonly diagnosed during the reproductive years. Disease management involves advocating conception during periods of stable clinical remission and continuing safe medications throughout pregnancy to achieve optimal maternal and fetal outcomes. PMID- 26255916 TI - Renal replacement therapy: implications for the surgeon. AB - Renal replacement therapy comprises peritoneal dialysis, haemodialysis and renal transplantation. Patients undergoing renal replacement therapy often require surgery for a number of different reasons. This review summarizes likely surgical procedures for these patients and some of the common complications. PMID- 26255917 TI - Does money or the law reduce doctors' working hours in the UK? AB - What can be learned from a 45-year journey to reduced junior doctors' working hours? The authors investigated the impact of financially punitive measures (the 2001 New Deal contract) and legislation (Working Time Regulations) on the average working week for doctors-in-training. PMID- 26255918 TI - Introducing a proforma to improve clinical care in trauma surgery. AB - INTRODUCTION: Accurate trauma operative details are an important part of the care of trauma patients. This study evaluated the adequacy of handwritten operative notes for trauma patients and whether they comply with the standards set by the Royal College of Surgeons of England for optimizing clinical practice in a busy district general hospital. PATIENTS AND METHODS: Fifty consecutive sets of handwritten trauma operative notes were reviewed prospectively. A standardized printed proforma was introduced and then another 50 consecutive sets of notes were reviewed. The results were analysed using the Student t-test to obtain two tailed P values comparing the mean difference between percentages of missing data for both cycles. RESULTS: Out of 24 parameters examined, 19 showed improvement after introducing the standardized proforma in trauma surgical notes. There was an overall significant improvement in the studied parameters (P= 0.0134), with a mean difference of 19.3% of missing data for both cycles. CONCLUSIONS: These results suggest that a standardized prestructured operative note proforma in trauma surgery is a useful tool in recording the operative data, thus helping to improve the medical care provided. It would also provide medicolegally sound evidence of a procedure when needed and so be more beneficial for the surgeon if routinely used. The authors recommend its regular use in different surgical specialties. PMID- 26255919 TI - Use of smartphone apps by paediatric trainees. AB - Over 70% of the population owns a smartphone and there are now millions of apps available. This study looks at smartphone and app use among paediatric trainees, in particular whether they are accessing medical apps to help with clinical practice. PMID- 26255920 TI - Every ward is a 'Nut Island'? Preventing good health-care teams 'going bad'. AB - This article explores how Levy's 'Nut Island effect' can be used to help identify health-care teams at risk of becoming isolated, disenchanted and separated physically and psychologically from senior management. Such isolation can lead to disastrous effects. PMID- 26255921 TI - Paul Ehrlich: Nobel laureate and father of modern chemotherapy. PMID- 26255922 TI - Neonatal meningitis and septicaemia caused by Salmonella agama. PMID- 26255923 TI - Silent bladder perforation. PMID- 26255924 TI - Calcified pericardial haematoma causing heart failure. PMID- 26255925 TI - A guide to oral ulceration for the medical physician. PMID- 26255926 TI - Symposium on systemic manifestations of disease. PMID- 26255927 TI - Subclavian central venous cannulation: should ultrasound guidance be used in routine practice? PMID- 26255928 TI - Diagnosis and management of cellulitis and erysipelas. PMID- 26255929 TI - Postpartum sepsis. PMID- 26255930 TI - Antiretroviral therapy options for treatment-naive patients with HIV-1. PMID- 26255931 TI - Coagulase-negative staphylococci. PMID- 26255932 TI - Outcome and Medial Presentation of Breast Cancer: European Institute of Oncology Experience. AB - BACKGROUND: No analyses have investigated the prognostic role of medial presentation in breast cancer patients on disease-free survival (DFS) and overall survival according to immunohistochemically-defined subtypes. PATIENTS AND METHODS: We collected information from the institutional clinical database on consecutive breast cancer patients who underwent conservative surgery at the European Institute of Oncology, Milan, Italy, between 1994 and 2008. We compared the outcomes of patients with medial breast cancer with those of patients with nonmedial tumors observed at the institution during the same period. RESULTS: Among 7369 evaluable patients, 2254 (24%) had their primary tumors in medial quadrants and 7015 (76%) in other areas. Five-year DFS was 84.7% and 86.6% (P = .008) in patients with medial and nonmedial disease, respectively. In multivariate analysis, medial location was correlated with greater risk of recurrence (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.11-1.35; P < .0001) and death (HR, 1.27; 95% CI, 1.09-1.49; P = .0028). CONCLUSION: Medial presentation is an adverse prognostic factor for breast cancer patients. PMID- 26255933 TI - Mutation Research. DNA damage in chronic diseases and aging. Editorial. PMID- 26255934 TI - DNA damage and gene therapy of xeroderma pigmentosum, a human DNA repair deficient disease. AB - Xeroderma pigmentosum (XP) is a genetic disease characterized by hypersensitivity to ultra-violet and a very high risk of skin cancer induction on exposed body sites. This syndrome is caused by germinal mutations on nucleotide excision repair genes. No cure is available for these patients except a complete protection from all types of UV radiations. We reviewed the various techniques to complement or to correct the genetic defect in XP cells. We, particularly, developed the correction of XP-C skin cells using the fidelity of the homologous recombination pathway during repair of double-strand break (DSB) in the presence of XPC wild type sequences. We used engineered nucleases (meganuclease or TALE nuclease) to induce a DSB located at 90 bp of the mutation to be corrected. Expression of specific TALE nuclease in the presence of a repair matrix containing a long stretch of homologous wild type XPC sequences allowed us a successful gene correction of the original TG deletion found in numerous North African XP patients. Some engineered nucleases are sensitive to epigenetic modifications, such as cytosine methylation. In case of methylated sequences to be corrected, modified nucleases or demethylation of the whole genome should be envisaged. Overall, we showed that specifically-designed TALE-nuclease allowed us to correct a 2 bp deletion in the XPC gene leading to patient's cells proficient for DNA repair and showing normal UV-sensitivity. The corrected gene is still in the same position in the human genome and under the regulation of its physiological promoter. This result is a first step toward gene therapy in XP patients. PMID- 26255935 TI - Transcriptional and post-transcriptional regulation of nucleotide excision repair genes in human cells. AB - Nucleotide excision repair (NER) removes DNA helix-distorting lesions induced by UV light and various chemotherapeutic agents such as cisplatin. These lesions efficiently block the elongation of transcription and need to be rapidly removed by transcription-coupled NER (TC-NER) to avoid the induction of apoptosis. Twenty nine genes have been classified to code for proteins participating in nucleotide excision repair (NER) in human cells. Here we explored the transcriptional and post-transcriptional regulation of these NER genes across 13 human cell lines using Bru-seq and BruChase-seq, respectively. Many NER genes are relatively large in size and therefore will be easily inactivated by UV-induced transcription blocking lesions. Furthermore, many of these genes produce transcripts that are rather unstable. Thus, these genes are expected to rapidly lose expression leading to a diminished function of NER. One such gene is ERCC6 that codes for the CSB protein critical for TC-NER. Due to its large gene size and high RNA turnover rate, the ERCC6 gene may act as dosimeter of DNA damage so that at high levels of damage, ERCC6 RNA levels would be diminished leading to the loss of CSB expression, inhibition of TC-NER and the promotion of cell death. PMID- 26255936 TI - Damaged DNA-binding protein down-regulates epigenetic mark H3K56Ac through histone deacetylase 1 and 2. AB - Acetylated histone H3 lysine 56 (H3K56Ac) is one of the reversible histone post translational modifications (PTMs) responsive to DNA damage. We previously described a biphasic decrease and increase of epigenetic mark H3K56Ac in response to ultraviolet radiation (UVR)-induced DNA damage. Here, we report a new function of UV damaged DNA-binding protein (DDB) in deacetylation of H3K56Ac through specific histone deacetylases (HDACs). We show that simultaneous depletion of HDAC1/2 compromises the deacetylation of H3K56Ac, while depletion of HDAC1 or HDAC2 alone has no effect on H3K56Ac. The H3K56Ac deacetylation does not require functional nucleotide excision repair (NER) factors XPA and XPC, but depends on the function of upstream factors DDB1 and DDB2. UVR enhances the association of DDB2 with HDAC1 and, enforced DDB2 expression leads to translocation of HDAC1 to UVR-damaged chromatin. HDAC1 and HDAC2 are recruited to UVR-induced DNA damage spots, which are visualized by anti-XPC immunofluorescence. Dual HDAC1/2 depletion decreases XPC ubiquitination, but does not affect the recruitment of DDB2 to DNA damage. By contrast, the local accumulation of gammaH2AX at UVR induced DNA damage spots was compromised upon HDAC1 as well as dual HDAC1/2 depletions. Additionally, UVR-induced ATM activation decreased in H12899 cells expressing H3K56Ac-mimicing H3K56Q. These results revealed a novel role of DDB in H3K56Ac deacetylation during early step of NER and the existence of active functional cross-talk between DDB-mediated damage recognition and H3K56Ac deacetylation. PMID- 26255937 TI - Photosensitive human syndromes. AB - Photosensitivity in humans can result from defects in repair of light-induced DNA lesions, from photoactivation of chemicals (including certain medications) with sunlight to produce toxic mediators, and by immune reactions to sunlight exposures. Deficiencies in DNA repair and the processing of damaged DNA during replication and transcription may result in mutations and genomic instability. We will review current understanding of photosensitivity to short wavelength ultraviolet light (UV) due to genetic defects in particular DNA repair pathways; deficiencies in some are characterized by an extremely high incidence of cancer in sun-exposed tissues, while in others no cancers have been reported. PMID- 26255939 TI - An epigenomic role of Fe65 in the cellular response to DNA damage. AB - Previous findings describe Fe65 as a key protein in the cellular response to genotoxic stress. However, the precise molecular mechanism by which Fe65 contributes to DNA damage signaling remains unclear. In this study, we hypothesized that the transcriptional activity of Fe65 may contribute to DNA damage pathways by regulating gene expression patterns activated in response to genotoxic stress. To address this hypothesis, we mapped the global binding profile of Fe65 by chromatin immunoprecipitation (ChIP)-sequencing in the SK-N-SH cells exposed to genotoxic stress. Unexpectedly, the genome-wide location analysis showed a substantial enrichment of Fe65 in the promoter regions of coding genes linked to DNA damage signaling pathways. To further investigate the role of Fe65 in the transcriptional regulation of putative coding target genes identified by ChIP-seq, we performed microarray assays using wild-type (WT) or Fe65 deficient mouse embryonic fibroblasts (MEFs) exposed to oxidative stress with multiple recovery times. Gene ontology analysis of the Fe65-depedent transcriptome suggested that Fe65 modulates the expression of genes critical for DNA damage response. Motif enrichment analysis of regulatory regions occupied by Fe65 revealed a strong correlation with key transcription factors involved in DNA damage signaling pathways, including E2F1, p53, and Jun. Comparison of ChIP sequencing results with microarray results ultimately identified 248 Fe65 depedent target genes, the majority of which were known regulators of cell cycle, cell death, and DNA replication and repair pathways. We validated the target genes identified by in silico analysis by qPCR experiments. Collectively, our results provide strong evidence that Fe65 plays a role in DNA damage response and cell viability by epigenomic regulation of specific transcriptional programs activated upon genotoxic stress. PMID- 26255940 TI - Effects of post mortem interval and gender in DNA base excision repair activities in rat brains. AB - Most human tissues used in research are of post mortem origin. This is the case for all brain samples, and due to the difficulty in obtaining a good number of samples, especially in the case of neurodegenerative diseases, male and female samples are often included in the same experimental group. However, the effects of post mortem interval (PMI) and gender differences in the endpoints being analyzed are not always fully understood, as is the case for DNA repair activities. To investigate these effects, in a controlled genetic background, base excision repair (BER) activities were measured in protein extracts obtained from Wistar rat brains from different genders and defined PMI up to 24 hours, using a novel fluorescent-based in vitro incision assay. Uracil and AP-site incision activity in nuclear and mitochondrial extracts were similar in all groups included in this study. Our results show that gender and PMI up to 24 hours have no influence in the activities of the BER proteins UDG and APE1 in rat brains. These findings demonstrate that these variables do not interfere on the BER activities included in these study, and provide a security window to work with UDG and APE1 proteins in samples of post mortem origin. PMID- 26255941 TI - DNA damage in neurodegenerative diseases. AB - Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis, which represent three of the most common neurodegenerative pathologies in humans. PMID- 26255942 TI - Gene polymorphisms and increased DNA damage in morbidly obese women. AB - Obesity is characterized by increased adipose tissue mass resulting from a chronic imbalance between energy intake and expenditure. Furthermore, there is a clearly defined relationship among fat mass expansion, chronic low-grade systemic inflammation and reactive oxygen species (ROS) generation; leading to ROS-related pathological events. In the past years, genome-wide association studies have generated convincing evidence associating genetic variation at multiple regions of the genome with traits that reflect obesity. Therefore, the present study aimed to evaluate the relationships among the gene polymorphisms ghrelin (GHRL rs26802), ghrelin receptor (GHSR-rs572169), leptin (LEP-rs7799039), leptin receptor (LEPR-rs1137101) and fat mass and obesity-associated (FTO-rs9939609) and obesity. The relationships among these gene variants and the amount of DNA damage were also investigated. Three hundred Caucasian morbidly obese and 300 eutrophic (controls) women were recruited. In summary, the results demonstrated that the frequencies of the GHRL, GHSR, LEP and LEPR polymorphisms were not different between Brazilian white morbidly obese and eutrophic women. Exceptions were the AA-FTO genotype and allele A, which were significantly more frequent in obese women than in the controls (0.23% vs. 0.10%; 0.46 vs. 0.36, respectively), and the TT-FTO genotype and the T allele, which were less frequent in morbidly obese women (p<0.01). Furthermore, significant differences in the amount of genetic lesions associated with FTO variants were observed only in obese women. In conclusion, this study demonstrated that the analyzed SNPs were not closely associated with morbid obesity, suggesting they are not the major contributors to obesity. Therefore, our data indicated that these gene variants are not good biomarkers for predicting risk susceptibility for obesity, whereas ROS generated by the inflammatory status might be one of the causes of DNA damage in obese women, favoring genetically related diseases as obesity comorbidities. PMID- 26255943 TI - DNA damage in non-communicable diseases: A clinical and epidemiological perspective. AB - Non-communicable diseases (NCDs) are a leading cause of death and disability, representing 63% of the total death number worldwide. A characteristic phenotype of these diseases is the accelerated aging, which is the result of phenomena such as accumulated DNA damage, telomere capping loss and subcellular irreversible/nonrepaired oxidative damage. DNA damage, mostly oxidative, plays a key role in the development of most common NCDs. The present review will gather some of the most relevant knowledge concerning the presence of DNA damage in NCDs focusing on cardiovascular diseases, diabetes, chronic obstructive pulmonary disease, and neurodegenerative disorders, and discussing a selection of papers from the most informative literature. The challenge of comorbidity and the potential offered by new systems approaches for introducing these biomarkers into the clinical decision process will be discussed. Systems Medicine platforms represent the most suitable approach to personalized medicine, enabling to identify new patterns in the pathogenesis, diagnosis and prognosis of chronic diseases. PMID- 26255938 TI - The impact of base excision DNA repair in age-related neurodegenerative diseases. AB - The aging process and several age-related neurodegenerative disorders have been linked to elevated levels of DNA damage induced by ROS and deficiency in DNA repair mechanisms. DNA damage induced by ROS is a byproduct of cellular respiration and accumulation of damage over time, is a fundamental aspect of a main theory of aging. Mitochondria have a pivotal role in generating cellular oxidative stress, and mitochondrial dysfunction has been associated with several diseases. DNA base excision repair is considered the major pathway for repair of oxidized bases in DNA both in the nuclei and in mitochondria, and in neurons this mechanism is particularly important because non-diving cells have limited back-up DNA repair mechanisms. An association between elevated oxidative stress and a decrease in BER is strongly related to the aging process and has special relevance in age-related neurodegenerative diseases. Here, we review the role of DNA repair in aging, focusing on the implications of the DNA base excision repair pathways and how alterations in expression of these DNA repair proteins are related to the aging process and to age-related neurodegenerative diseases. PMID- 26255944 TI - Unique proteomic signature for radiation sensitive patients; a comparative study between normo-sensitive and radiation sensitive breast cancer patients. AB - Radiation therapy is a cornerstone of modern cancer treatment. Understanding the mechanisms behind normal tissue sensitivity is essential in order to minimize adverse side effects and yet to prevent local cancer reoccurrence. The aim of this study was to identify biomarkers of radiation sensitivity to enable personalized cancer treatment. To investigate the mechanisms behind radiation sensitivity a pilot study was made where eight radiation-sensitive and nine normo sensitive patients were selected from a cohort of 2914 breast cancer patients, based on acute tissue reactions after radiation therapy. Whole blood was sampled and irradiated in vitro with 0, 1, or 150 mGy followed by 3 h incubation at 37 degrees C. The leukocytes of the two groups were isolated, pooled and protein expression profiles were investigated using isotope-coded protein labeling method (ICPL). First, leukocytes from the in vitro irradiated whole blood from normo sensitive and extremely sensitive patients were compared to the non-irradiated controls. To validate this first study a second ICPL analysis comparing only the non-irradiated samples was conducted. Both approaches showed unique proteomic signatures separating the two groups at the basal level and after doses of 1 and 150 mGy. Pathway analyses of both proteomic approaches suggest that oxidative stress response, coagulation properties and acute phase response are hallmarks of radiation sensitivity supporting our previous study on oxidative stress response. This investigation provides unique characteristics of radiation sensitivity essential for individualized radiation therapy. PMID- 26255945 TI - Mossy Fibers Terminate Directly Within Purkinje Cell Zones During Mouse Development. AB - The cerebellum is organized into a map of zones that is manifested in various ways according to gene expression, anatomical connectivity, neuronal firing properties, behavioral specificity, and susceptibility to disease. At the center of every zone is the Purkinje cell, the principal cell type of the cerebellum and sole output of the cerebellar cortex. During development, Purkinje cells are thought to coordinate the zonal patterning of all other cell types. However, the morphogenetic mechanism that mediates the interaction between Purkinje cells and afferent fibers remains unclear. To address this problem in vivo, I took advantage of a rapid fluorescent-based transynaptic tracing approach to determine the nature of mossy fiber to Purkinje cell connectivity during early postnatal development, a period when the afferent map is assembling into clear-cut zonal circuits. By injecting WGA-Alexa 555 into the lower thoracic-upper lumber spinal cord, I found that spinocerebellar mossy fibers transynaptically transfer tracer into zones of Purkinje cells that are directly adjacent to the fibers. The traced Purkinje cell zones formed a zebrin-like pattern that was defined by the expression of neurofilament heavy chain (NFH), a marker of zones in the postnatal developing cerebellum. These results suggest that Purkinje cells generate the zonal circuit map by using molecular cues, neuronal activity, and synaptic contact. PMID- 26255946 TI - Identification of microRNAs and their targets in Finger millet by high throughput sequencing. AB - MicroRNAs are short non-coding RNAs which play an important role in regulating gene expression by mRNA cleavage or by translational repression. The majority of identified miRNAs were evolutionarily conserved; however, others expressed in a species-specific manner. Finger millet is an important cereal crop; nonetheless, no practical information is available on microRNAs to date. In this study, we have identified 95 conserved microRNAs belonging to 39 families and 3 novel microRNAs by high throughput sequencing. For the identified conserved and novel miRNAs a total of 507 targets were predicted. 11 miRNAs were validated and tissue specificity was determined by stem loop RT-qPCR, Northern blot. GO analyses revealed targets of miRNA were involved in wide range of regulatory functions. This study implies large number of known and novel miRNAs found in Finger millet which may play important role in growth and development. PMID- 26255947 TI - Cabozantinib, a Novel c-Met Inhibitor, Inhibits Colorectal Cancer Development in a Xenograft Model. AB - BACKGROUND: Angiogenesis plays a critical role during tumor development. c-Met has recently been implicated in the angiogenesis of various tumors, leaving its role in colorectal cancer (CRC) unknown. In this study, we aimed to evaluate the effect of a novel c-Met inhibitor, cabozantinib, on the tumor growth and angiogenesis in a CRC mouse model. MATERIAL AND METHODS: A mouse CRC xenograft model was used to evaluate the effect of cabozantinib on vivo growth of tumors and angiogenesis. The expression of angiogenesis-related factors was evaluated by immunohistochemistry (IHC) and Western blotting. Levels of serum cytokines were detected by ELISA. RESULTS: Cabozantinib effectively reduced tumor size and angiogenesis, and suppressed the expression of vascular endothelial growth factor (VEGF) in tumor tissues, possibly via the inhibition of Sonic Hedgehog (SHH) pathway. CONCLUSIONS: The blockade of c-Met inhibits the tumor growth and angiogenesis via modulating SHH pathway, suggesting a potential strategy in the treatment of CRC. PMID- 26255948 TI - Nano-structural characteristics of carbon nanotube-polymer composite films for high-amplitude optoacoustic generation. AB - We demonstrate nano-structural characteristics of carbon nanotube (CNT) polydimethylsiloxane (PDMS) composite films that can be used as highly efficient and robust ultrasound transmitters for diagnostic and therapeutic applications. An inherent architecture of the nano-composite provides unique thermal, optical, and mechanical properties that are accommodated not just for efficient energy conversion but also for extraordinary robustness against pulsed laser ablation. First, we explain a thermoacoustic transfer mechanism within the nano-composite. CNT morphologies are examined to determine a suitable arrangement for heat transfer to the surrounding PDMS. Next, we introduce an approach to enhance optical extinction of the composite films, which uses shadowed deposition of a thin Au layer through an as-grown CNT network. Finally, the transmitter robustness is quantified in terms of laser-induced damage threshold. This reveals that the CNT-PDMS films can withstand an order-of-magnitude higher optical fluence (and extinction) than a Cr film used as a reference. Such robustness is crucial to increase the maximum-available optical energy for optoacoustic excitation and pressure generation. All of these structure-originated characteristics manifest the CNT-PDMS composite films as excellent optoacoustic transmitters for high-amplitude and high-frequency ultrasound generation. PMID- 26255949 TI - Molecular dynamics simulations of organohalide perovskite precursors: solvent effects in the formation of perovskite solar cells. AB - The stability and desirable crystal formation of organohalide perovskite semiconductors is of utmost relevance to ensure the success of perovskites in photovoltaic technology. Herein we have simulated the dynamics of ionic precursors toward the formation of embryonic organohalide perovskite CH3NH3PbI3 units in the presence of solvent molecules using Molecular Dynamics. The calculations involved, a variable amount of Pb(2+), I(-), and CH3NH3(+) ionic precursors in water, pentane and a mixture of these two solvents. Suitable force fields for solvents and precursors have been tested and used to carry out the simulations. Radial distribution functions and mean square displacements confirm the formation of basic perovskite crystalline units in pure pentane - taken as a simple and archetypal organic solvent. In contrast, simulations in water confirm the stability of the solvated ionic precursors, which prevents their aggregation to form the perovskite compound. We have found that in the case of a water/pentane binary solvent, a relatively small amount of water did not hinder the perovskite formation. Thus, our findings suggest that the cause of the poor stability of perovskite films in the presence of moisture is a chemical reaction, rather than the polar nature of the solvents. Based on the results, a set of force-field parameters to study from first principles perovskite formation and stability, also in the solid phase, is proposed. PMID- 26255950 TI - Therapeutic potential of alpha-glucosidase inhibitors in type 2 diabetes mellitus: an evidence-based review. AB - INTRODUCTION: Postprandial hyperglycemia (PPHG) contributes to micro- and macro vascular complications more than fasting hyperglycemia in patients with type 2 diabetes mellitus. Due to the traditional carbohydrate-rich diet, Asians, particularly Indians and Chinese need agents to control the higher risk of uncontrolled PPHG. Targeting PPHG with alpha-glucosidase inhibitors (AGIs), either alone or in combination with other oral hypoglycemic agents and insulin, provide overall glycemic control with transient mild gastrointestinal disorders. Treatment with AGIs, especially acarbose, has also shown to provide beneficial effects on lipid levels, blood pressure, coagulation factors, carotid intima media thickness and endothelial dysfunction. New insights of acarbose therapy obtained like increased activity of gut hormones and improved gut microbiota may explain the benefits on weight, whereas increased production of H2 may explains its cardiovascular benefits to some extent. AREAS COVERED: A systematic search strategy was developed to identify randomized controlled trials in MEDLINE, PubMed, EMBASE and ongoing trials databases. EXPERT OPINION: AGIs as a class and acarbose in particular, are most useful in combatting PPHG and glucose variability across the spectrum of diabetes therapy, particularly in Asian patients. Together with their effects on incretin hormones and gut-microbiota AGIs can be considered beyond glycemic control as 'cardio-protective agents.' PMID- 26255951 TI - Current and advancing systemic treatment options for soft tissue sarcomas. AB - INTRODUCTION: Soft tissue sarcomas are a collection of rare malignancies, the treatment of which has evolved over time. Although cytotoxic chemotherapy remains the cornerstone of management of metastatic disease, many new treatments have been developed or show great promise in the treatment of soft tissue sarcoma. Research into the different underlying pathogenesis of individual subtypes has driven progress in treatment. This has allowed development of treatments targeted to specific subtypes of sarcoma. AREAS COVERED: We provide a review of the current field of systemic therapy in soft tissue sarcoma. This is followed by an in-depth analysis of recent developments in treatment, as well as new treatments that are aimed at specific subtypes of sarcoma, and the biological rationale behind these therapies. We also look in detail at the promising new agents currently in development. EXPERT OPINION: Much progression has been made in treatment of soft tissue sarcomas with multiple exciting new treatments in development. However outcomes in general remain poor. Further research into the underlying pathogenesis of soft tissue sarcomas may help deliver more effective systemic therapies. Increased collaboration between basic science, translational and clinical investigators is required at national and international levels to maximise progress. PMID- 26255952 TI - The pharmacokinetics and clinical efficacy of AVP-825: a potential advancement for acute treatment of migraine. AB - INTRODUCTION: Oral triptans have dominated the prescription market for acute treatment of migraine for nearly 25 years. Today, patients often express dissatisfaction with prescribed acute treatment in part because they do not have confidence that the therapy will provide consistent efficacy over time. Major limitations to sustained successful use of oral triptans are their relatively slow onset of meaningful clinical benefit and variable absorption/efficacy due to impaired gastrointestinal function during migraine. AVP-825, a new intranasal delivery system for sumatriptan , may be an effective alternative to oral triptans. AREAS COVERED: This article reviews AVP-825, which deposits low-dose sumatriptan powder deep into the vascular mucosa of the posterior nose, allowing rapid absorption of drug into the systemic circulation. Studies suggest that AVP 825 is a highly effective, well-tolerated acute treatment for episodic migraine. EXPERT OPINION: Oral triptans are limited in providing effective patient-centered outcomes to migraine patients. Failed or suboptimal abortive treatment of migraine is a major driver of migraine chronification and increases in healthcare costs. AVP-825 is an easy to use, novel, breath-powered intranasal delivery system that provides early onset of efficacy with low systemic drug exposure and few triptan-associated adverse events. AVP-825 will be a welcomed therapeutic tool for the acute treatment of migraine. PMID- 26255954 TI - Mechanism Underlying Post-menopausal Osteoporosis: HIF1alpha is Required for Osteoclast Activation by Estrogen Deficiency. AB - The aging of the population worldwide has sharply increased the number of post menopausal osteoporosis patients. Bone fragility caused by osteoporosis often results in fractures; therefore, controlling osteoporosis is crucial to prevent such injuries. To date, various drugs to treat osteoporosis have been developed and launched; however, the molecular mechanisms underlying post-menopausal osteoporosis have not been fully elucidated, and additional factors that could be targeted to treat patients remain to be characterized. Recently, hypoxia inducible factor 1 alpha (HIF1alpha) was identified as essential for osteoclast activation, an activity that promotes bone loss following menopausal estrogen deficiency. Although osteoclasts, which are located in hypoxic regions of the bone surface, express HIF1alpha mRNA, in pre-menopausal conditions the presence of estrogen decreases HIF1alpha protein levels in these cells. In menopausal conditions, however, estrogen deficiency allows HIF1alpha protein to accumulate in osteoclasts, leading to osteoclast activation and bone loss. Osteoclast specific conditional HIF1alpha inactivation protects mice from estrogen deficiency-induced osteoclast activation and bone loss, as does systemic administration of a HIF1alpha inhibitor. Therefore, HIF1alpha represents a potential therapeutic target to prevent osteoclast activation and bone loss in post-menopausal patients. PMID- 26255955 TI - Analysis of benzodiazepines and their metabolites using DBS cards and LC-MS/MS. AB - Dried Blood Spot (DBS) has been used a blood extraction method for inherited metabolic disorder screening since 1960s. With introduction of LC-MS/MS, not only DBS could be used to analysis drugs in small blood volume, but in various fields, such as toxicology, drug therapeutic monitoring, drug diagnostic screening, and illicit drugs. In toxicology field, many drugs (e.g. benzodiazepines, acetaminophen, small molecule drugs) have been tested with DBS. Compared with earlier blood extraction methods (SPE and LLE), DBS has lots of advantages; lower blood volume (less than 50MUL), shorter analysis time caused by a more concise analysis procedure and lower cost. We optimized the DBS procedure and LC-MS/MS conditions for 18 benzodiazepines, seven benzodiazepine metabolites, and one z drug (zolpidem) analysis in blood. 30MUL of whole blood was spotted on FTA DMPK card C and dried for 2h in a desiccator. A 6-mm disk was punched and vortexed for 1min in a centrifuge tube with 300MUL methanol/acetonitrile mixture (1:1, v/v). After evaporation, redissolved in 100MUL mobile phase of LC-MS/MS and 5MUL was injected. In the analysis for 26 target compounds in blood, all of the method validation parameters - LLOD, LLOQ, accuracy (intra- and inter-assay), and precision (intra- and inter-assay) - were satisfied with method validation criteria, within 15%. The results of matrix effect, recovery, and process efficiency were good. We developed a fast and reliable sample preparation method using DBS for 26 benzodiazepines, benzodiazepine metabolites, and z-drug (zolpidem). PMID- 26255956 TI - Subalpine Pyrenees received higher nitrogen deposition than predicted by EMEP and CHIMERE chemistry-transport models. AB - Deposition of reactive nitrogen (N) from the atmosphere is expected to be the third greatest driver of biodiversity loss by the year 2100. Chemistry-transport models are essential tools to estimate spatially explicit N deposition but the reliability of their predictions remained to be validated in mountains. We measured N deposition and air concentration over the subalpine Pyrenees. N deposition was found to range from 797 to 1,463 mg N m(-2) year(-1). These values were higher than expected from model predictions, especially for nitrate, which exceeded the estimations of EMEP by a factor of 2.6 and CHIMERE by 3.6. Our observations also displayed a reversed reduced-to-oxidized ratio in N deposition compared with model predictions. The results highlight that the subalpine Pyrenees are exposed to higher levels of N deposition than expected according to standard predictions and that these levels exceed currently recognized critical loads for most high-elevation habitats. Our study reveals a need to improve the evaluation of N deposition in mountains which are home to a substantial and original part of the world's biodiversity. PMID- 26255957 TI - Electronically addressable nanomechanical switching of i-motif DNA origami assembled on basal plane HOPG. AB - Here, a pH-induced nanomechanical switching of i-motif structures incorporated into DNA origami bound onto cysteamine-modified basal plane HOPG was electronically addressed, demonstrating for the first time the electrochemical read-out of the nanomechanics of DNA origami. This paves the way for construction of electrode-integrated bioelectronic nanodevices exploiting DNA origami patterns on conductive supports. PMID- 26255958 TI - Field induced anisotropic cooperativity in a magnetic colloidal glass. AB - The translational dynamics of a repulsive colloidal glass-former is probed by time-resolved X-ray Photon Correlation Spectroscopy. In this dense dispersion of charge-stabilized and magnetic nanoparticles, the interaction potential can be tuned, from quasi-isotropic to anisotropic by applying an external magnetic field. This powerful control parameter finely tunes the anisotropy of the intricate energy landscape in the colloidal glass-former, which is seen here as a new tunable model-system to probe the dynamical heterogeneities at the approach of the glass transition. Both structural and dynamical anisotropies are reported on interparticle lengthscales associated with highly anisotropic cooperativity, almost two orders of magnitude larger in the field direction than in the perpendicular direction and in zero field. PMID- 26255959 TI - Gene Regulation Gets in Tune: How Riboswitch Tertiary-Structure Networks Adapt to Meet the Needs of Their Transcription Units. PMID- 26255960 TI - Isocyanate deinsertion from kappa(1)-O amidates: facile access to perfluoroaryl rhodium(I) complexes. AB - Reaction of the amidate ligand salt, Na[N(Dipp)C(O)C6F5] () (Dipp = 2,6 diisopropylphenyl) with [Rh(NBD)Cl]2 (NBD = norbornadiene) results in formation of the dirhodium(i) complex [Rh2{MU2-N,O-N(Dipp)C(O)C6F5}2(NBD)2] (). Reaction of with PCy3 at room temperature provides an equilibrium mixture of the geometric isomers (E/Z)-[Rh{kappa(1)-O-N(Dipp)C(O)C6F5}(NBD)(PCy3)] (E/Z-). Treatment of with 3 equiv. of CNXyl (Xyl = 2,6-dimethylphenyl) gives the kappa(1)-O complex [Rh{kappa(1)-O-N(Dipp)C(O)C6F5}(CNXyl)3] () while use of 3 equiv. of PPh3 provides the kappa(2)-complex [Rh{kappa(2)-N,O-N(Dipp)C(O)C6F5}(PPh3)2] (). For complex kappa(2)-N,O, an equilibrium results with free PPh3 giving the kappa(1)-O complex [Rh{kappa(1)-O-N(Dipp)C(O)C6F5}(PPh3)3] (). Heating a tol-d8 solution of E/Z-, , or / results in 2,6-diisopropylphenylisocyanate extrusion providing the corresponding [Rh]-C6F5 complex in good yield. PMID- 26255961 TI - An integrated pipeline for sample preparation and characterization at the EMBL@PETRA3 synchrotron facilities. AB - The characterization of macromolecular samples at synchrotrons has traditionally been restricted to direct exposure to X-rays, but beamline automation and diversification of the user community has led to the establishment of complementary characterization facilities off-line. The Sample Preparation and Characterization (SPC) facility at the EMBL@PETRA3 synchrotron provides synchrotron users access to a range of biophysical techniques for preliminary or parallel sample characterization, to optimize sample usage at the beamlines. Here we describe a sample pipeline from bench to beamline, to assist successful structural characterization using small angle X-ray scattering (SAXS) or macromolecular X-ray crystallography (MX). The SPC has developed a range of quality control protocols to assess incoming samples and to suggest optimization protocols. A high-throughput crystallization platform has been adapted to reach a broader user community, to include chemists and biologists that are not experts in structural biology. The SPC in combination with the beamline and computational facilities at EMBL Hamburg provide a full package of integrated facilities for structural biology and can serve as model for implementation of such resources for other infrastructures. PMID- 26255962 TI - Recent innovations in super-resolution microscopy. PMID- 26255963 TI - Searching for "order" in atrial fibrillation using electrogram morphology recurrence plots. AB - BACKGROUND: Bipolar electrograms recorded during atrial fibrillation (AF) can have an appearance of chaotic/random behavior. The aim of this study was to use a novel electrogram morphology recurrence (EMR) analysis to quantify the level of order in the morphology patterns in AF. METHODS: Rapid atrial pacing was performed in seven dogs at 600bpm for 3 weeks leading to sustained AF. Open chest high density electrical recordings were made in multiple atrial sites. EMR plots of bipolar electrograms at each site were created by cross-correlating morphologies of each detected activations with morphologies of every other activation. The following features of the EMR plots were quantified: recurrence rate (RR), determinism (DET), laminarity (LAM), average diagonal line length (L), trapping time (TT), divergence (DIV), and Shannon's entropy (ENTR). For each recording site, these measures were calculated for the normal sequence of morphologies and also after random shuffling of the electrogram orders. RESULTS: Electrograms recordings from a total of 3961 sites had average cycle lengths of 104+/-22ms resulting in an average of 100+/-19 activations detected per 10-s recording and an average RR of 0.38+/-0.28 (range 0.02-1.00). Shuffling the order of the activation morphologies resulted in significant decreases in DET, LAM, L, TT, and ENTR and significant increases in DIV. CONCLUSIONS: EMR plots of AF electrograms show varying rates of recurrence with patterns that suggest an underlying deterministic structure to the activation sequences. A better understanding of AF dynamics could lead to improved methods in mapping and treating AF. PMID- 26255964 TI - Qualitative Time-of-Flight Secondary Ion Mass Spectrometry Analysis of Root Dentin Irrigated with Sodium Hypochlorite, EDTA, or Chlorhexidine. AB - INTRODUCTION: Sodium hypochlorite (NaOCl), chelating agents, and chlorhexidine (CHX), which are commonly used irrigants during endodontic treatment, have the potential to alter the physical and chemical properties of the dentin structure. The aim of this study was to use time-of-flight secondary ion mass spectrometry to qualitatively evaluate the chemical characteristics of dentin surface and compare it with dentin exposed to NaOCl, EDTA, or CHX. METHODS: Four blocks of dentin from a root of a human maxillary molar were embedded in resin and trimmed with a microtome to expose the dentin. Samples were randomly assigned to 4 treatment groups: (1) no irrigation treatment (sample A), (2) 2.5% NaOCl (sample B), (3) 17% EDTA (sample C), and (4) 2% CHX (sample D). Dentin surfaces were analyzed by time-of-flight secondary ion mass spectrometry, which allowed characterization of dentin surface chemistry by both imaging and mass spectroscopic analysis obtained in high mass and spatial resolution modes. RESULTS: Sample A revealed intense peaks characteristics of hydroxyapatite in addition to Na(+), K(+), CH4N(+), CN(-), CNO(-), Mg(+), F(-), and HCO2(-) peaks. Sample B showed severely decreased CH4N(+) and increased intensity of Cl(-). Sample C lacked Ca(+) and Mg(+) and showed decreased PO2(-) and PO3(-). Sample D exhibited a distinct presence of CHX. The spectral image of sample A displayed even distribution of Na(+) and Ca(+) on a smeared surface. The surfaces of samples B and D had patent dentinal tubules, whereas sample D showed an intense CHX signal. Sample C had some patent dentinal tubules and lacked Ca(+). CONCLUSIONS: NaOCl removed protein components from the dentin matrix, EDTA removed calcium and magnesium ions from the dentin, and CHX formed an adsorbed layer on the dentin surface. PMID- 26255965 TI - Histologic Analysis of the Influence of a Gelatin-based Scaffold in the Repair of Immature Dog Teeth Subjected to Regenerative Endodontic Treatment. AB - INTRODUCTION: Regenerative endodontic treatment is a new and promising approach to manage immature teeth with necrotic pulps and apical periodontitis. The use of scaffolds is essential to treatment success, but many materials are difficult to acquire and have a high cost. This study assessed tissue repair in immature dog teeth with necrotic pulps and apical periodontitis after using a gelatin-based scaffold (Gelfoam; Pharmacia & Upjohn Co, Kalamazoo, MI). METHODS: Apical periodontitis was induced in 20 immature dog teeth. After disinfection with triple antibiotic paste for 2 weeks, canals were irrigated, dried, and filled with a blood clot alone (10 teeth) or combined with Gelfoam (10 teeth). Another 10 teeth were used as negative controls (no intervention). After 7 months, the dogs were euthanized. Histologic sections were stained with hematoxylin-eosin and analyzed in relation to tissue repair. Categoric data were analyzed using the Fisher exact test (P < .05), numeric data (histomorphometric analysis), and the Mann-Whitney U test. RESULTS: Histologic analysis revealed a higher percentage of roots with new cementumlike mineralized tissue and connective tissue inside the canal in the blood clot + Gelfoam group (P < .001). Histomorphometric analysis showed a higher area of mineralized tissue in the same group (P = .029). Apical extension of root and inflammation were similar between the experimental groups. The new tissue formed onto canal walls and in the root canal space showed characteristics of cementum and periodontal ligament, respectively. CONCLUSIONS: The use of a gelatin-based scaffold (Gelfoam) combined with a blood clot improved repair in immature dog teeth with apical periodontitis subjected to regenerative endodontic treatment. PMID- 26255966 TI - Lenalidomide, an anti-tumor drug, regulates retinal endothelial cell function: Implication for treating ocular neovascular disorder. AB - Ocular angiogenesis is an important pathologic character of several ocular diseases, such as retinopathy of prematurity, diabetic retinopathy and age related macular degeneration (AMD). Inhibition of ocular angiogenesis has great therapeutic value for treating these dieses. Here we show that lenalidomide, an anti-tumor drug, has great anti-angiogenic potential in ocular diseases. Lenalidomide inhibits retinal endothelial cell viability in normal and pathological condition, and inhibits VEGF-induced endothelial cell migration and tube formation in vitro. Moreover, lenalidomide inhibits ocular angiogenesis in vivo through the reduction of angiogenesis- and inflammation-related protein expression. Collectively, lenalidomide is a promising drug for treating ocular angiogenesis through its anti-proliferative and anti-inflammatory property. PMID- 26255967 TI - Optimized assay for the quantification of histidine kinase autophosphorylation. AB - Although two-component signaling systems, comprising a sensory histidine kinase and a response regulator, are a primary means by which bacteria detect and respond to environmental stimuli, they are poorly characterized. Here we report optimized conditions for detecting histidine phosphorylation using a facile medium-throughput filter paper-binding assay. Employing this assay we report the kinetic parameters of previously uncharacterized histidine kinases from Vibrio haveyi, Vibrio parahaemolytius, Shewanella oneidensis, and Legionella pneumophila. In characterizing these kinases, we effectively double the number of kinetically characterized histidine kinases that have been reported in the literature. PMID- 26255968 TI - High-density lipoprotein-mediated transcellular cholesterol transport in mouse aortic endothelial cells. AB - Accumulation of unesterified cholesterol-rich lipid vesicles in the subendothelial space contributes to atherogenesis. Transport of cholesterol from the subendothelial intima back to the circulating blood inhibits atherosclerosis development; however, the mechanism for this process has not been fully defined. Using cultured mouse aortic endothelial cells (MAECs), we observed that unesterified cholesterol can be transported across the endothelial cell monolayer from the basolateral to the apical compartment. Administration of high-density lipoprotein (HDL) or apolipoprotein AI (apoAI) to the apical compartment enhanced transendothelial cholesterol transport in a concentration-dependent manner. Knockdown of ATP-binding cassette transporter G1 (ABCG1) or scavenger receptor class B type I (SR-B1), or inhibition of SR-B1 diminished HDL-induced transendothelial cholesterol transport; while knockdown of ABCA1 reduced apoAI mediated cholesterol transport. HDL enhanced phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt in MAECs. However, inhibition of PI3K or Akt did not reduce HDL-induced transendothelial cholesterol transport. These results suggest that HDL enhances transendothelial cholesterol transport by activation of a mechanism involving ABCA1, ABCG1 and SR-B1 but not involving PI3K and Akt. PMID- 26255970 TI - Investigating implicit statistical learning mechanisms through contextual cueing. AB - Since its inception, the contextual cueing (CC) paradigm has generated considerable interest in various fields of cognitive sciences because it constitutes an elegant approach to understanding how statistical learning (SL) mechanisms can detect contextual regularities during a visual search. In this article we review and discuss five aspects of CC: (i) the implicit nature of learning, (ii) the mechanisms involved in CC, (iii) the mediating factors affecting CC, (iv) the generalization of CC phenomena, and (v) the dissociation between implicit and explicit CC phenomena. The findings suggest that implicit SL is an inherent component of ongoing processing which operates through clustering, associative, and reinforcement processes at various levels of sensory-motor processing, and might result from simple spike-timing-dependent plasticity. PMID- 26255969 TI - MiR-145 functions as a tumor suppressor targeting NUAK1 in human intrahepatic cholangiocarcinoma. AB - The dysregulation of micro (mi)RNAs is associated with cancer development. The miRNA miR-145 is downregulated in intrahepatic cholangiocarcinoma (ICC); however, its precise role in tumor progression has not yet been elucidated. Novel (nua) kinase family (NUAK)1 functions as an oncogene in various cancers and is a putative target of miR-145 regulation. In this study, we investigated the regulation of NUAK1 by miR-145 in ICC. We found that miR-145 level was significantly decreased in ICC tissue and cell lines, which corresponded with an increase in NUAK1 expression. NUAK1 was found to be a direct target of miR-145 regulation. The overexpression of miR-145 in ICC cell lines inhibited proliferation, growth, and invasion by suppressing NUAK1 expression, which was associated with a decrease in Akt signaling and matrix metalloproteinase protein expression. Similar results were observed by inhibiting NUAK1 expression. These results demonstrate that miR-145 can prevent ICC progression by targeting NUAK1 and its downstream effectors, and can therefore be useful for clinical diagnosis and targeted therapy of ICC. PMID- 26255971 TI - Host genetic variants influencing the clinical course of hepatitis B virus infection. AB - The clinical course of hepatitis B virus (HBV) infection greatly differs in individuals. Various viral, host, and environmental factors influence the natural history of HBV infection. Recent genome-wide association studies identified several host genetic factors influencing the clinical course of HBV infection. Genetic variations in HLA class II loci were significantly associated with susceptibility to persistent HBV infection. Other polymorphisms in or near the genes EHMT2, TCF19, and HLA-C, located near HLA class II loci, and UBE2L3 were also associated with persistent HBV infection. Meanwhile, polymorphisms in KIF1B, GRIK1, and STAT4 were associated with HBV-related hepatocellular carcinoma (HCC). Interestingly, HLA class II genetic variations were strongly associated with not only persistent HBV infection, but also disease progression and HBV-related HCC in chronic hepatitis B. Understanding the various genetic factors associated with the clinical course of HBV infection is essential for personalized treatment and surveillance of disease progression and HCC. PMID- 26255972 TI - Mass marking of Leuciscus idus larvae using Artemia salina as a vector of fluorescent dyes. AB - A method for the mass marking of ide Leuciscus idus larvae by feeding them Artemia salina nauplii that were immersed in different solutions of alizarin red S, tetracycline hydrochloride and calcein was tested. The best quality marks were obtained after feeding fish for 4 days with nauplii that had been immersed in 200 mg l(-1) alizarin red S. PMID- 26255973 TI - Supporting Breastfeeding Establishment among Socially Disadvantaged Women: A Meta Synthesis. AB - BACKGROUND: Many women from socially disadvantaged groups discontinue breastfeeding in the early postnatal period before lactation is fully established. This suggests that existing health service practices do not adequately meet the breastfeeding support needs of this population. The aim of this meta-synthesis is to review the literature exploring how women from socioeconomically deprived backgrounds experience breastfeeding establishment and to identify factors associated with supportive practice. METHODS: The meta synthesis includes qualitative studies exploring the perception of women from disadvantaged groups of in-hospital and professionally led interventions to support the establishment of breastfeeding. Searches were conducted for studies published between 1992 and 2013; after critical appraisal, eight studies were retained. RESULTS: Three overarching themes of the influences on maternal perception of the efficacy of breastfeeding support were identified. These included practical skill and knowledge of the breastfeeding process, the influence of psychological factors on perceived breastfeeding ability, and the provision of a person-centered approach to infant feeding support. CONCLUSIONS: The findings illustrate that the factors associated with supportive breastfeeding practice are extensive, complex, and interrelated. Strategies which enable mothers to gain confidence in their ability to successfully breastfeed by acquiring technical expertise, which offer positive encouragement, and which are culturally specific are more likely to be perceived as supportive by women from socially disadvantaged groups. PMID- 26255975 TI - Self-reflection modulates the outcome evaluation process: Evidence from an ERP study. AB - Recent research demonstrated structural overlap between reward and self processing, but the functional relationship that explains how self processing influences reward processing remains unclear. The present study used an experimentally constrained reflection task to investigate whether individuals' outcome evaluations in a gambling task are modulated by task-unrelated self- and other-reflection processes. The self- and other-reflection task contained descriptions of the self or others, and brain event-related potentials (ERPs) were recorded while 16 normal adults performed a gambling task. The ERP analysis focused on the feedback-related negativity (FRN) component. We found that the difference wave of FRN increased in the self-reflection condition compared with the other-reflection condition. The present findings provide direct evidence that self processing can influence reward processing. PMID- 26255974 TI - A Validated Phenotyping Algorithm for Genetic Association Studies in Age-related Macular Degeneration. AB - Age-related macular degeneration (AMD), a multifactorial, neurodegenerative disease, is a leading cause of vision loss. With the rapid advancement of DNA sequencing technologies, many AMD-associated genetic polymorphisms have been identified. Currently, the most time consuming steps of these studies are patient recruitment and phenotyping. In this study, we describe the development of an automated algorithm to identify neovascular (wet) AMD, non-neovascular (dry) AMD and control subjects using electronic medical record (EMR)-based criteria. Positive predictive value (91.7%) and negative predictive value (97.5%) were calculated using expert chart review as the gold standard to assess algorithm performance. We applied the algorithm to an EMR-linked DNA bio-repository to study previously identified AMD-associated single nucleotide polymorphisms (SNPs), using case/control status determined by the algorithm. Risk alleles of three SNPs, rs1061170 (CFH), rs1410996 (CFH), and rs10490924 (ARMS2) were found to be significantly associated with the AMD case/control status as defined by the algorithm. With the rapid growth of EMR-linked DNA biorepositories, patient selection algorithms can greatly increase the efficiency of genetic association study. We have found that stepwise validation of such an algorithm can result in reliable cohort selection and, when coupled within an EMR-linked DNA biorepository, replicates previously published AMD-associated SNPs. PMID- 26255976 TI - The formation of an inclusion complex between a metabolite of ginsenoside, compound K and gamma-cyclodextrin and its dissolution characteristics. AB - OBJECTIVES: 20S-protopanaxadiol 20-O-beta-D-glucopyranoside (compound K), a metabolite of ginsenoside, is only sparingly soluble in water. The aim of this study was to improve the low solubility, slow dissolution rate and low oral bioavailability of compound K by forming an inclusion complex with gamma cyclodextrin (gamma-CyD), and to compare the results with those of beta-CyD complex. METHODS: The interactions of compound K with beta and gamma-CyDs were studied by the solubility method and proton nuclear magnetic resonance spectroscopy. Solid forms of compound K/CyD complexes with different molar ratios were prepared by the kneading method, and the resulting complex was characterized by powder X-ray diffractometry. The dissolution rate of the complexes was measured by the rotary disk method. In-vivo absorption studies in rats were carried out, and the serum level of compound K, after its oral administration, was measured by a liquid chromatography-tandem mass spectrometry system. KEY FINDINGS: gamma-CyD markedly improved the low solubility of compound K at lower CyD concentrations (<0.03 M), whereas the solubility was decreased at higher concentrations (>0.06 m). The enhancement in solubility by gamma-CyD at a lower concentration was much higher than the corresponding values for beta-CyD. The apparent 1:1 stability constant (1.5 * 10(5) m(-1) ) for the gamma-CyD complex was 18-fold larger than that (8.2 * 10(3) m(-1) ) of the beta-CyD complex. The dissolution rate of the 1:1 compound K/gamma-CyD complex was faster than that for the 1:3 (guest : host) complex. These results suggest that the dissolution rate of the 1:1 complex, in which the drug is partially included, was faster than that of the 1:3 complex, in which the drug was completely included, due to the higher solubility and amorphous property of the former complex compared with the properties of the latter complex. The fast dissolution of the gamma-CyD complex was reflected in the maximum plasma level (Cmax ) of the drug and the time (Tmax ) to reach the maximum plasma level after its oral administration to rats. CONCLUSIONS: The effect of gamma-CyD on enhancing the solubility of compound K is much higher than that for the beta-CyD complex, and the dissolution rate of the guest when it is partially included in the gamma-CyD is faster the corresponding value when it is completely included in the cavity. PMID- 26255977 TI - Adenosquamous carcinoma of the head and neck: Molecular analysis using CRTC-MAML FISH and survival comparison with paired conventional squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: Adenosquamous carcinoma (ASC) is a rare variant of head and-neck squamous cell carcinoma (HNSCC) generally thought to be uniformly aggressive with poor prognosis. However, it remains unknown how overall survival compare with conventional HNSCC. Here we report for the first time that ASC does not necessarily indicate a worse prognosis than conventional HNSCC. STUDY DESIGN: Case-control retrospective study. METHODS: Forty-two primary tumors of the head and neck, treated with curative intent, were identified. Next, 2:1 matching of HNSCC was performed using the following matching criteria: gender, site, pathologic tumor stage, and pathologic node stage. Successful matching was performed for 32 of 42 tumors. Additionally, 20 samples were sent for break-apart FISH testing to evaluate for the presence of the CRTC1-MAML2 translocation. RESULTS: There was a 1.8:1 male to female ratio, with a mean age of 62 years (range 38-84). The layrnx was the most common site (26%), followed by oropharynx (24%), oral cavity (19%), and sinonasal (17%). Kaplan-Meier analysis of adenosquamous and matched HNSCC showed similar survival curves. Median survival times for ASC and HNSCC were 4 and 6 years, respectively. A random-effects Cox model with Gamma frailty revealed no statistical difference between the two groups (P=0.25). All cases of ASC were negative for the CRTC1-MAML2 translocation. CONCLUSION: This study directly compares primary ASC with HNSCC. No difference in overall survival was detected in contradistinction to the previously thought uniformly poor prognosis. We also highlight the importance of the CRTC1-MAML2 translocation in distinguishing ASC from mucoepidermoid carcinoma. LEVEL OF EVIDENCE: 3b. PMID- 26255978 TI - To be, or not to be, related: how female guppies bias sperm usage. PMID- 26255979 TI - Examining Attachment Avoidance and Attachment Anxiety Across Eight Sessions of Couple Therapy. AB - This study examined initial levels of attachment anxiety and avoidance, as well as their patterns of change, across eight sessions of couple therapy. Participants were 461 couples in a treatment-as-usual setting. Dyadic latent growth modeling was used to determine whether couples started therapy at similar levels of attachment anxiety and avoidance and whether attachment anxiety and avoidance changed. An actor partner interdependence model was used to see whether partner attachment anxiety was related to avoidance. Results showed relative stability of attachment anxiety and avoidance over the course of therapy, with the only change being a slight decline in attachment anxiety among women. Results showed that a person's attachment anxiety was not related to their partner's avoidance and vice versa. PMID- 26255981 TI - On the origins of observations of heterostyly in Primula. AB - In 1862, Charles Darwin published his landmark study on the different forms of flower in Primula; he coined the term distyly and subsequently expanded his studies to other species, including those with tristyly. Darwin is widely recognized as the first to study pin and thrum flowers in Primula, and to provide an explanation for the functional significance of the two floral morphs. Our laboratory is pursuing the genes that underpin floral heteromorphy in Primula, work influenced by Darwin's observations. One day, while appreciating a print of Primula vulgaris from William Curtis' Flora Londinensis, I was struck by the fact that I was looking at images of dimorphic Primula flowers captured in a late 1700s copper-plate engraving that predated Darwin's observations by over 70 yr. This realization triggered a journey into archives of botanical texts, herbals and florilegia from the 16(th) to 19(th) Centuries, and correspondence archives, in search of earlier documents that could have influenced Darwin and the origins of an idea. Darwin was not the first to observe floral heteromorphy in Primula, but he was the first to realize the significance of the two floral morphs. Darwin's insight and exposition of purpose have underpinned all consequent work on the subject. PMID- 26255980 TI - Gain-of-function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC). AB - Signal transducer and activator of transcription 3 (STAT3) triggered production of Th-17 cytokines mediates protective immunity against fungi. Mutations affecting the STAT3/interleukin 17 (IL-17) pathway cause selective susceptibility to fungal (Candida) infections, a hallmark of chronic mucocutaneous candidiasis (CMC). In patients with autosomal dominant CMC, we and others previously reported defective Th17 responses and underlying gain-of-function (GOF) STAT1 mutations, but how this affects STAT3 function leading to decreased IL-17 is unclear. We also assessed how GOF-STAT1 mutations affect STAT3 activation, DNA binding, gene expression, cytokine production, and epigenetic modifications. We excluded impaired STAT3 phosphorylation, nuclear translocation, and sequestration of STAT3 into STAT1/STAT3 heterodimers and confirm significantly reduced transcription of STAT3-inducible genes (RORC/IL-17/IL-22/IL-10/c-Fos/SOCS3/c-Myc) as likely underlying mechanism. STAT binding to the high affinity sis-inducible element was intact but binding to an endogenous STAT3 DNA target was impaired. Reduced STAT3 dependent gene transcription was reversed by inhibiting STAT1 activation with fludarabine or enhancing histone, but not STAT1 or STAT3 acetylation with histone deacetylase (HDAC) inhibitors trichostatin A or ITF2357. Silencing HDAC1, HDAC2, and HDAC3 indicated a role for HDAC1 and 2. Reduced STAT3-dependent gene transcription underlies low Th-17 responses in GOF-STAT1 CMC, which can be reversed by inhibiting acetylation, offering novel targets for future therapies. PMID- 26255982 TI - Liquid chromatography mass spectrometry-based O-glycomics to evaluate glycosylation alterations in gastric cancer. AB - PURPOSE: Gastric cancer is the fourth most common malignant cancer worldwide. Important for tumorigenesis and progression, aberrant glycosylation occurs frequently in cancers. We investigated the differences in O-glycosylation in the serum of 157 gastric cancer patients (GC) and 144 healthy donors. EXPERIMENTAL DESIGN: We used the method of labeling O-glycans (released from proteins) with 1 phenyl-3-methyl-5-pyrazolone followed by LC-MS analysis. Analyzing the LC-MS data by partial least squares discriminant and unpaired Student t test, combined with the structural information of O-glycans from LC-MS/MS in positive mode. RESULTS: The expression level of core1, core2, ST antigen, and core2 complex O-glycans (m/z 733.33, m/z 809.42) were increased significantly (p < 0.0001), whereas m/z 529.75 and diST-antigen were decreased in the serum of GC compared with controls (p < 0.001). In addition, there were significant correlations between the abundance of the O-glycans and glycoproteins (MUC1, CEA) in the serum of GC. CONCLUSION AND CLINICAL RELEVANCE: Glycomics approaches identified multiple candidate antigens for patients with GC. The O-glycan structures are increased in the serum of GC, they may be candidates for carbohydrate tumor markers. PMID- 26255983 TI - Changing Biosynthetic Profiles by Expressing bldA in Streptomyces Strains. AB - Recently we described an unusual way of activating a cryptic gene cluster when we explored the origin of the bald phenotype of Streptomyces calvus. Complementation of S. calvus with a correct copy of bldA restored sporulation and additionally promoted production of a new natural products. In this study we report on the expression of bldA in several Streptomyces strains that have been described as "poorly sporulating" strains. In seven out of 15 cases, HPLC profiling revealed the production of new compounds, and in two cases the overproduction of known compounds. Two compounds were isolated and their structures were determined. PMID- 26255984 TI - Periodontal and peri-implant diseases: identical or fraternal infections? AB - Peri-implant diseases (peri-implantitis and peri-implant mucositis) are bacterially driven infections. Peri-implantitis leads to aggressive bone resorption and eventual loss of the implant. Traditionally, peri-implantitis was regarded as microbially similar to periodontitis, and translocation of periodontal pathogens into the peri-implant crevice was considered as a critical factor in disease causation. However, evidence is emerging to suggest that the peri-implant and periodontal ecosystems differ in many important ways. The purpose of this review is to examine the evidence supporting microbial congruence and discordance in these two communities. Current evidence suggests that osseointegrated implants truly create unique microenvironments that force microbial adaptation and selection. Further studies that revisit the "microbial reservoir" hypothesis and identify species that play an etiologic role in peri implant disease and examine their transmission from teeth are needed. PMID- 26255985 TI - Ultrasound evaluation of development of olfactory sulci in normal fetuses: a possible role in diagnosis of CHARGE syndrome. AB - OBJECTIVES: To describe the timing of the ultrasound appearance of olfactory sulci in normal fetuses, according to gestational age. METHODS: Olfactory sulci were assessed prospectively in the coronal plane on routine brain ultrasound examination in 100 normal fetuses between 22 and 31 + 6 weeks' gestation. Examinations were divided into five groups according to gestational age: Group 1, 22 to 23 + 6 weeks (n = 22); Group 2, 24 to 25 + 6 weeks (n = 9); Group 3, 26 to 27 + 6 weeks (n = 25); Group 4, 28 to 29 + 6 weeks (n = 22) and Group 5, 30 to 31 + 6 weeks (n = 22). For each fetus, olfactory sulci were assessed as absent, developing or formed. RESULTS: Developing sulci appeared as primitive smooth depressions in the frontal lobe, which evolved into deep sharp complete sulci in later pregnancy. It was possible to assess the development of sulci in all cases. Olfactory sulci were consistently absent in Group 1. In Group 2, 44.4% of fetuses had absent olfactory sulci and 55.6% had developing sulci. In Group 3, the olfactory sulci were still developing in 21 (84.0%) fetuses and were completely formed in four (16.0%). Sulci were completely formed in all fetuses in Groups 4 and 5. CONCLUSIONS: Fetal brain ultrasound can visualize developing olfactory sulci from as early as 24 weeks' gestation. After 26 weeks, fetuses have detectable olfactory sulci and, after 28 weeks, they are completely formed. Abnormal development of olfactory sulci is a key feature of CHARGE syndrome. These results may help to improve the prenatal diagnosis of CHARGE syndrome. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26255986 TI - Cohort study of adult patients with haemoglobin SC disease: clinical characteristics and predictors of mortality. AB - Haemoglobin (Hb) SC disease is the second most common subtype of sickle cell disease and is potentially fatal. This study aimed to determine the clinical characteristics, outcome and predictors of mortality in HbSC disease patients, and to compare these findings with patients followed-up in different centres. Clinical, laboratory and outcome data were collected from a cohort of adult patients with HbSC disease followed between 1991 and 2103. Cox regression multivariate analysis was used to determine predictors of mortality. One hundred and fifty-five patients were followed-up over 20 years: 9% died and 70.8% had at least one complication. The most common complications were: painful crises (38.3%), retinopathy (33.8%), cholelithiasis (30.3%), osteonecrosis (24.8%) and sensorineural hearing disorders (9.7%). Frequency of chronic complications was similar in most studies. In multivariate analysis, hearing disorders remained an independent predictor of mortality (Odds Ratio 9.26, 95% confidence interval 1.1 74.8; P = 0.03). It was concluded that patients with HbSC disease receive a late diagnosis and there is remarkable similarity between the studies conducted in different centres around the world. Sensorineural hearing disorders were an independent predictor of mortality, suggesting that it may be useful to implement routine diagnostic screening. PMID- 26255987 TI - Influence of oriented nanofibrous PCL scaffolds on quantitative gene expression during neural differentiation of mouse embryonic stem cells. AB - Neural differentiation of mouse embryonic stem cells in combination with three dimensional electrospun nanofibers as an artificial extracellular matrix can be utilized to reconstruct a spinal cord defect. In this study, random and parallel aligned nanofibrous poly E-caprolactone was fabricated using electrospinning. Its hydrophobicity was modified by O2 plasma treatment to facilitate enhanced cell attachment. Embryoid bodies (EBs), which contain all three embryonic germ layers, were cultured on poly E-caprolactone scaffolds to study the effect of fiber orientation on cell morphology and differentiation. Cell morphology and neuron specific gene and protein expressions were, respectively, evaluated by scanning electron microscopy, real-time polymerase chain reaction, and immunocytochemistry. Although two types of nanofibrous scaffolds showed neural marker expression at the protein level, cells on randomly oriented scaffolds showed short-range topographical guidance and stretched across multiple directions, whereas cells on the parallel scaffolds exhibited long extension with enhanced neuron outgrowth along the fiber, producing oriented extracellular matrix, leading to direct cell migration and nerve regeneration. Quantitative real-time polymerase chain reaction showed that both aligned and random electrospun nanofibers downregulated the precursor neural marker Nestin compared with that in the control group, a gelatin-coated tissue culture plate (T). Analysis also showed higher expression of dorso-ventral neural markers (Isl1/2 and Lim1/2) than motor neuron progenitor markers (Pax6, Nkx6.1, and olig2) in aligned nanofibers than in the T group. Moreover, aligned nanofibers showed higher expression of mature neural specific markers such as beta-tub and Map2 than those in the randomly oriented scaffolds. Therefore, we conclude that nanofibers with different orientations can support the neural lineage, but aligned nanofibrous scaffolds are superior candidates to promote the advancement of neural precursors to achieve maturity during the differentiation process. PMID- 26255988 TI - Overdiagnosis and Overtreatment of Osteoporosis: A Wolf in Sheep's Clothing. PMID- 26255989 TI - The Matchmaker Exchange API: automating patient matching through the exchange of structured phenotypic and genotypic profiles. AB - Despite the increasing prevalence of clinical sequencing, the difficulty of identifying additional affected families is a key obstacle to solving many rare diseases. There may only be a handful of similar patients worldwide, and their data may be stored in diverse clinical and research databases. Computational methods are necessary to enable finding similar patients across the growing number of patient repositories and registries. We present the Matchmaker Exchange Application Programming Interface (MME API), a protocol and data format for exchanging phenotype and genotype profiles to enable matchmaking among patient databases, facilitate the identification of additional cohorts, and increase the rate with which rare diseases can be researched and diagnosed. We designed the API to be straightforward and flexible in order to simplify its adoption on a large number of data types and workflows. We also provide a public test data set, curated from the literature, to facilitate implementation of the API and development of new matching algorithms. The initial version of the API has been successfully implemented by three members of the Matchmaker Exchange and was immediately able to reproduce previously identified matches and generate several new leads currently being validated. The API is available at https://github.com/ga4gh/mme-apis. PMID- 26255990 TI - Caring for families experiencing stillbirth: Evidence-based guidance for maternity care providers. AB - BACKGROUND: Evidence-based guidance is needed to inform care provided to mothers and families who experience stillbirth. This paper focuses upon how meaningful and culturally appropriate care can be provided to mothers and families from when they are informed that their baby will be stillborn to many years after the experience. Avoidable suffering may be occurring in the clinical setting. AIMS: To promote and inform meaningful and culturally appropriate evidence-informed practice amongst maternity care providers caring for mothers and families who experience stillbirth. METHODS: A comprehensive systematic review was conducted which primarily synthesised relevant qualitative research studies. An expert advisory group comprised of stillbirth researchers, clinicians, and parents who have experienced stillbirth provided guidance for the review and the development of implications for practice. FINDINGS: Grieving parents want staff to demonstrate sensitivity and empathy, validate their emotions, provide clear, information, and be aware that the timing of information may be distressing. Parents want support and guidance when making decisions about seeing and holding their baby. Sensitivity, respect, collaboration, and information are essential throughout the experience of stillbirth. Culturally appropriate care is important and may require staff to accommodate different cultural practices. CONCLUSION: The findings of the review and expert consensus inform the provision of meaningful and culturally appropriate care for mothers and families that have experienced stillbirth. Evidence informed implications for practice are provided to guide the actions, communication, and behaviours of maternity care providers. PMID- 26255991 TI - Vitamin D in polycystic ovary syndrome: Relationship to obesity and insulin resistance. AB - SCOPE: Polycystic ovary syndrome (PCOS) is underpinned by insulin resistance (IR). In PCOS, the relationships between vitamin D, adiposity, and IR are unclear. We aim to explore these relationships in lean and overweight women with PCOS. METHODS AND RESULTS: This is a cross-sectional study conducted in a tertiary medical center. Participants included 42 women with PCOS and 34 controls without PCOS. Vitamin D and metabolic markers were measured. Detailed body composition and gold standard hyperinsulinemic euglycemic clamps were performed. The main outcome measures were plasma levels of vitamin D, adiposity measures, and glucose infusion rate. Vitamin D levels were lower in overweight women with PCOS compared with overweight controls (31.6 and 46.1 nmol/L, respectively, p = 0.01). Vitamin D was not associated with IR after adjustment for confounders; however, there was a significant interaction between PCOS and percentage body fat. Further analysis by PCOS status revealed that vitamin D was associated with IR in the PCOS group (beta coefficient 2.1, 95% CI 0.2-4.0, p = 0.03), but not in the non-PCOS group. CONCLUSION: Vitamin D is associated with IR in women with PCOS, but not in controls. Large intervention studies are needed to determine if vitamin D supplementation can improve IR in PCOS. PMID- 26255992 TI - Patterns of male dispersal in Verreaux's sifaka (Propithecus verreauxi) at Kirindy Mitea National Park. AB - Males of many group-living mammals emigrate from their social groups to improve mating opportunities. To help mitigate the social and locational costs of dispersal and to increase reproductive benefits, they may immigrate seasonally, immigrate alongside a partner, and/or replace the alpha male (versus entering a group as a subordinate). Verreaux's sifaka (Propithecus verreauxi) are highly seasonally breeding primates characterized by male-biased dispersal. We hypothesized that (i) males time immigrations to pursue immediate mating opportunities, (ii) entrances with partners more often result in alpha male replacement, and (iii) male competitive ability affects immigration strategy and alpha male tenure length. To assess these proximate aspects of male dispersal, we examined 7 years of demographic, morphological, and behavioral data for five social groups of Verreaux's sifaka in the Kirindy Mitea National Park in western Madagascar. Contrary to expectations and studies of sifaka dispersal in other populations, we detected no strong seasonal pattern in immigrations. Immigrations occurred individually and with partners, and a trend existed for partners to increase the likelihood of replacing an alpha male. Pronounced activity of the sternal scent gland (a proxy for testosterone and prior dominance status), but not body mass, canine size, or potential correlates of leaping ability, significantly influenced immigration strategy. The absence of a seasonal immigration pattern suggests that fluid group boundaries may allow mating success without establishment in a social group before the mating season. Our results also suggest that male immigration strategies are affected by age, prior dominance status, and testosterone levels but not morphological indicators of individual competitive ability. Coalitions may be used to improve competitive ability. Finally, differences in seasonal immigration patterns and length of alpha male vacancies observed at Kirindy Mitea may be due to the relatively low population density. Am. J. Primatol. 79:e22455, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26255993 TI - Dielectric constant enhancement of non-fullerene acceptors via side-chain modification. AB - The low dielectric constants of conventional organic semiconductors leads to poor charge carrier photogeneration in homojunction organic solar cells due to large exciton binding energies. Increasing the dielectric constant can potentially enhance the spontaneous exciton dissociation rate at room temperature in homojunction cells, and decrease the charge carrier recombination in heterojunction solar cells comprising blends of electron donors and acceptors. We report that substituting the ubiquitous alkyl solubilizing groups with short glycol chains can give non-fullerene electron acceptors with a static dielectric constant of up to 9.8. PMID- 26255994 TI - Care and Service at Home for Persons With Dementia in Europe. AB - PURPOSE: To describe available and utilized formal care and service at home for persons with dementia, from diagnosis to end-of-life stage, in eight European countries. DESIGN: A descriptive cross-country design concerning eight European countries as a part of the European research project RightTimePlaceCare. METHODS: The research team in each country used a mapping system to collect country specific information concerning dementia care and service system. The mapping system consists of 50 types of care and service activities. Sixteen of the 50 predefined activities concerning care and service at home were selected for this study and subdivided into three categories, following the stages of dementia. FINDINGS: Availability was reported to be higher than utilization, and the findings indicated more similarities than differences among the eight countries involved. Even though there were several available activities of "basic care and services" and "healthcare interventions," they were utilized by few in most countries. Furthermore, "specialized dementia care and services" were sparsely available and even more sparsely utilized in the participating countries. CONCLUSIONS: The findings indicated that persons with dementia in Europe received formal care and service on a general, basic level but seldom adjusted to their specific needs. CLINICAL RELEVANCE: This study describes the gap between service provision and utilization enabling nurses to develop individually adjusted care plans for persons with dementia during the progress of the disease. The findings do not include matters of quality of care or how to best organize effective care and services. However, the activities of care and services presented here should shed light on what room there is for improvement when it comes to enabling persons with dementia to go on living at home. PMID- 26255995 TI - "Combo" technique for the use of 7F guide catheter system during transradial approach. AB - Even a regular lumen of radial artery may create difficulty in smooth negotiation and propagation of a 7F guide catheter while performing intervention through transradial approach. We describe successive five cases of a simple and innovative "Combo" technique, which helps relatively atraumatic tracking of a 7F guide catheter through the course of arm and chest vasculature for successful completion of procedure without significant damage and local pain. PMID- 26255996 TI - Efficacy and safety of silodosin in the medical expulsion therapy for distal ureteral calculi: a systematic review and meta-analysis. AB - AIMS: Using a selective alpha-adrenoceptor blocker for medical expulsive therapy (MET) is an effective treatment approach widely used for ureteral stones. The aim of the review was to assess the efficacy and safety of silodosin in medical expulstion therapy compared with placebo and tamsulosin. METHODS: A systematic search was performed in PubMed, Cochrane Library and Embase to identify randomized controlled trials that compared silodosin with a placebo or tamsulosin for ureteral calculi. RESULTS: Eight publications involving a total of 1048 patients were used in the analysis, which compared silodosin with placebo and tamsulosin. We found that silodosin was effective in treating ureteral calculi in our meta-analysis and was superior to tamsulosin in its efficacy. The expulsion rate of all ureteral stones (OR 1.59, 95% CI 1.08, 2.36, P = 0.02), the expulsion rate of distal ureteral stones (OR 2.82, 95% CI 1.70, 4.67, P < 0.0001) and the expulsion time (days) of distal ureteral stones (standard mean difference (SMD) 4.71, 95% CI -6.60, -2.83, P < 0.00001) indicated that silodosin was more effective than the placebo. Moreover, expulsion rate (OR 2.54, 95% CI 1.70, 3.78, P < 0.00001), expulsion time (days) (SMD -2.64, 95% CI -3.64, -1.64, P < 0.00001) and pain episodes (P < 0.00001) indicated that silodosin was more effective than the tamsulosin. Even though silodosin had a significant increase in abnormal ejaculation compared with tamsulosin, no significant differences were observed for complications (OR 1.00, 95% CI 0.58, 1.74, P = 1.00). CONCLUSIONS: This meta analysis indicated that silodosin was superior to placebo or tamsulosin in the efficacy for distal ureteral calculi with better control of pain. The safety profile of silodosin was similar to tamsulosin though retrograde ejaculation was worse for silodosin use. We conclude that silodosin might have potential as a MET for ureteral stones. PMID- 26255997 TI - Colonic metaproteomic signatures of active bacteria and the host in obesity. AB - Obesity is associated with the intestinal microbiota in humans but the underlying mechanisms are yet to be fully understood. Our previous phylogenetic study showed that the faecal microbiota profiles of nonobese versus obese and morbidly obese individuals differed. Here, we have extended this analysis with a characterization of the faecal metaproteome, in order to detect differences at a functional level. Proteins were extracted from crude faecal samples of 29 subjects, separated by 1D gel electrophoresis and characterized using RP LC MS/MS. The peptide data were analyzed in database searches with two complementary algorithms, OMSSA and X!Tandem, to increase the number of identifications. Evolutionary genealogy of genes: nonsupervised orthologous groups (EggNOG) database searches resulted in the functional annotation of over 90% of the identified microbial and human proteins. Based on both bacterial and human proteins, a clear clustering of obese and nonobese samples was obtained that exceeded the phylogenetic separation in dimension. Moreover, integration of the metaproteomics and phylogenetic datasets revealed notably that the phylum Bacteroidetes was metabolically more active in the obese than nonobese subjects. Finally, significant correlations between clinical measurements and bacterial gene functions were identified. This study emphasizes the importance of integrating data of the host and microbiota to understand their interactions. PMID- 26255998 TI - Patient Preferences for Features of Health Care Delivery Systems: A Discrete Choice Experiment. AB - OBJECTIVE: To estimate the relative importance of organizational-, procedural-, and interpersonal-level features of health care delivery systems from the patient perspective. DATA SOURCES/STUDY SETTING: We designed four discrete choice experiments (DCEs) to measure patient preferences for 21 health system attributes. Participants were recruited through the online patient portal of a large health system. We analyzed the DCE data using random effects logit models. DATA COLLECTION/EXTRACTION METHODS: DCEs were performed in which respondents were provided with descriptions of alternative scenarios and asked to indicate which scenario they prefer. Respondents were randomly assigned to one of the three possible health scenarios (current health, new lung cancer diagnosis, or diabetes) and asked to complete 15 choice tasks. Each choice task included an annual out-of-pocket cost attribute. PRINCIPAL FINDINGS: A total of 3,900 respondents completed the survey. The out-of-pocket cost attribute was considered the most important across the four different DCEs. Following the cost attribute, trust and respect, multidisciplinary care, and shared decision making were judged as most important. The relative importance of out-of-pocket cost was consistently lower in the hypothetical context of a new lung cancer diagnosis compared with diabetes or the patient's current health. CONCLUSIONS: This study demonstrates the complexity of patient decision making processes regarding features of health care delivery systems. Our findings suggest the importance of these features may change as a function of an individual's medical conditions. PMID- 26255999 TI - Risk of cancer in retransplants compared to primary kidney transplants in the United States. AB - Recipients of kidney transplantation have elevated risk of developing cancer. There are limited data on cancer risk in recipients of kidney retransplantation. We used data from the Transplant Cancer Match Study, which links the U.S. transplant registry with 15 cancer registries. Cancer incidence in recipients of kidney retransplantation and primary kidney transplants was compared utilizing Poisson regression, adjusting for demographic and medical characteristics. We assessed 109 224 primary recipients and 6621 retransplants. Compared to primary recipients, retransplants were younger (median age 40 vs. 46 yr), had higher PRA, and more often received induction with polyclonal antibodies (43% vs. 25%). A total of 5757 cancers were observed in primary recipients and 245 in retransplants. Overall cancer risk was similar in retransplants compared with primary recipients (incidence rate ratio [IRR] 1.06, 95% CI 0.93-1.20, adjusted for age, gender, race/ethnicity, PRA, and use of polyclonal induction). However, renal cell carcinoma (RCC) occurred in excess among retransplants (adjusted IRR 2.03, 95% CI 1.45-2.77), based on 514 cases in primary recipients and 43 cases in retransplants. Overall cancer risk did not differ in retransplants compared to primary recipients. Increased risk of RCC may be explained by the presence of acquired cystic kidney disease, which is more likely to develop with additional time with kidney disease and time spent on dialysis waiting for retransplantation. PMID- 26256001 TI - LAT1 is the transport competent unit of the LAT1/CD98 heterodimeric amino acid transporter. AB - LAT1 (SLC7A5) and CD98 (SLC3A2) constitute a heterodimeric transmembrane protein complex that catalyzes amino acid transport. Whether one or both subunits are competent for transport is still unclear. The present work aims to solve this question using different experimental strategies. Firstly, LAT1 and CD98 were immuno-detected in protein extracts from SiHa cells. Under oxidizing conditions, i.e., without addition of SH (thiol) reducing agent DTE, both proteins were revealed as a 120kDa major band. Upon DTE treatment separated bands, corresponding to LAT1(35kDa) or CD98(80kDa), were detected. LAT1 function was evaluated in intact cells as BCH sensitive [(3)H]His transport inhibited by hydrophobic amino acids. Antiport of [(3)H]His was measured in proteoliposomes reconstituted with SiHa cell extract in presence of internal His. Transport was increased by DTE. Hydrophobic amino acids were best inhibitors in addition to hydrophilic Tyr, Gln, Asn and Lys. Cys, Tyr and Gln, included in the intraliposomal space, were transported in antiport with external [(3)H]His. Similar experiments were performed in proteoliposomes reconstituted with the recombinant purified hLAT1. Results overlapping those obtained with native protein were achieved. Lower transport of [(3)H]Leu and [(3)H]Gln with respect to [(3)H]His was detected. Kinetic asymmetry was found with external Km for His lower than internal one. No transport was detected in proteoliposomes reconstituted with recombinant hCD98. The experimental data demonstrate that LAT1 is the sole transport competent subunit of the heterodimer. This conclusion has important outcome for following studies on functional characterization and identification of specific inhibitors with potential application in human therapy. PMID- 26256000 TI - Disruption of host antiviral resistances by gammaherpesvirus tegument proteins with homology to the FGARAT purine biosynthesis enzyme. AB - All known gammaherpesviruses encode at least one conserved tegument protein that contains sequence homology to the cellular purine biosynthesis enzyme: phosphoribosylformylglycineamide amidotransferase (FGARAT, or PFAS). While no enzymatic activity have been found on these viral FGARAT-homology proteins (vFGARAT), they are important for disarming host intrinsic antiviral machinery. Most vFGARAT proteins disrupt the intrinsic antiviral response-associated cellular subnuclear structure: ProMyelocytic Leukemia (PML) associated nuclear body (PML-NB). vFGARATs from different viruses target different components of PML NB to prevent cellular repression of viral infection. In addition, vFGARATs of rhadinoviruses were recently found to oligomerize with the cellular FGARAT to deamidate RIG-I and repress inflammatory cytokine production. In this review we discuss the diverse mechanisms of antiviral response disruption by gammaherpesvirus vFGARATs and the significance of the enzyme homology domain. PMID- 26256002 TI - Roll-to-Roll Green Transfer of CVD Graphene onto Plastic for a Transparent and Flexible Triboelectric Nanogenerator. AB - A novel roll-to-roll, etching-free, clean transfer of CVD-grown graphene from copper to plastic using surface-energy-assisted delamination in hot deionized water is reported. The delamination process is realized by water penetration between the hydrophobic graphene and a hydrophilic native oxide layer on a copper foil.The transferred graphene on plastic is used as a high-output flexible and transparent triboelectric nanogenerator. PMID- 26256003 TI - Understanding drivers of hospital charge variation for episodes of care among patients undergoing hepatopancreatobiliary surgery. AB - BACKGROUND: Understanding factors associated with variation in hospital charges may help identify means to increase savings. The aim of the present study was to define potential variation in hospital charges associated with hepatopancreatobiliary(HPB) surgery. METHODS: Patients who underwent an HPB procedure between 2009-2013 were identified. Total hospital charges were tabulated for room and board, surgical/anaesthesia services, medications, laboratory/radiology services and other miscellaneous charges. RESULTS: Approximately 2545 patients underwent either a pancreas (66.8%) or liver/biliary (33.2%) resection. The mean total charges for all patients were $42,357 +/- 33,745 (pancreas: $46,352 +/- 34,932 versus the liver: $34,303 +/- 29,639; P < 0.001). Morbidity (pancreas, range: 7-18%; liver, range: 9-18%) and observed:expected (O:E) length of stay (LOS)(pancreas, range: 0.67-1.64; liver, range: 1.06-3.35) varied among providers (both P < 0.001). While a peri-operative complication resulted in increased total hospital charges (complication: $66,401 +/- 55,124 versus no complication: $39,668 +/- 29,250; P < 0.001), total charges remained variable even among patients who did not experience a complication (P < 0.001). Surgeons within the lowest quartile of O:E LOS had lower total charges ($33 879 +/- $27 398) versus surgeons in the highest quartile ($49,498 +/- 40 971) (P < 0.001). Surgeons with the highest O:E LOS had higher across-the-board charges (operating room, highest quartile: $10,514 +/- $4496 versus lowest quartile: $7842 +/- $3706; medication, highest quartile: $1796 +/- $3799 versus lowest quartile: $925 +/- $2211; radiology, highest quartile: $2494 +/- $4683 versus lowest quartile: $1424 +/- $3247; P = 0.001; laboratory, highest quartile: $4236 +/- $5991 versus lowest quartile: $3028 +/- $3804; all P < 0.001). CONCLUSIONS: After accounting for in-hospital complications, the total mean hospital charges for HPB surgery remained variable by case type and provider. While the variation in charges was associated with LOS, provider-level differences in across-the-board charges were also noted. PMID- 26256005 TI - Impact of Jugular Vein Valve Function on Cerebral Venous Haemodynamics. AB - We quantify the effect of internal-jugular vein function on intracranial venous haemodynamics, with particular attention paid to venous reflux and intracranial venous hypertension. Haemodynamics in the head and neck is quantified by computing the velocity, flow and pressure fields, and vessel cross-sectional area in all major arteries and veins. For the computations we use a global, closed loop multi-scale mathematical model for the entire human circulation, recently developed by the first two authors. Validation of the model against in vitro and in vivo Magnetic Resonance Imaging (MRI) measurements have been reported elsewhere. Here, the circulation model is equipped with a sub-model for venous valves. For the study, in addition to a healthy control, we identify two venous valve related conditions, namely valve incompetence and valve obstruction. A parametric study for subjects in the supine position is carried out for nine cases. It is found that valve function has a visible effect on intracranial venous haemodynamics, including dural sinuses and deep cerebral veins. In particular, valve obstruction causes venous reflux, redirection of flow and intracranial venous hypertension. The clinical implications of the findings are unknown, though they may relate to recent hypotheses linking some neurological conditions to extra-cranial venous anomalies. PMID- 26256006 TI - Prognostic Significance of Homocysteine Levels in Acute Ischemic Stroke: A Prospective Cohort Study. AB - Associations between hyperhomocysteinemia and prognosis of stroke were seldom explored and always indefinite. We therefore performed a study to elucidate the relationship between homocysteine levels and stroke prognosis. Between 2008 and 2013, baseline data and blood samples of acute ischemic stroke patients were collected from the Henan Province Stroke Registry. Using a prospective cohort, scheduled follow-up, and multivariable logistic regression analysis, associations among the blood homocysteine level and acute neurological impairment and outcomes, stroke recurrence, and all-cause death were investigated. Relevant cutoff homocysteine levels were determined using the area under the receiver operating characteristics curve. Of 1,460 patients, 1,342 completed the 12-month follow-up. We observed higher homocysteine levels in males, those with an advanced age, concomitant hyperlipidemia, a smoking habit, and excessive alcohol consumption. The homocysteine level was an independent risk factor for severe neurological impairment (adjusted relative risk [RR]: 1.021, 95% confidence interval [CI]: 1.004-1.037), a poor functional outcome (adjusted RR with 95% CI: 3-month, 1.029, 1.018-1.039; 6-month, 1.029, 1.018-1.039; and 12-month, 1.038, 1.027-1.049), and stroke recurrence in the large artery atherosclerosis subtype (adjusted RR: 1.025, 1.006-1.045). The optimal cutoff for severe neurological impairment was 17.64 umol/L, and the cutoffs for poor functional outcomes were 17.28 umol/L, 17.28 umol/L, and 14.78 umol/L at 3, 6, and 12 months, respectively. We found an elevated homocysteine level independently predicted severe neurological impairment, a poor functional outcome, and stroke recurrence in the large artery atherosclerosis stroke subtype. The relevant cutoff homocysteine levels also provide a reference for future clinical work. PMID- 26256007 TI - Frequency and correlates of antipsychotic polypharmacy among patients with schizophrenia in Denmark: A nation-wide pharmacoepidemiological study. AB - Although evidence for efficacy of antipsychotic polypharmacy (APP) is sparse, APP is common in schizophrenia. The national Danish health registers were accessed to examine in schizophrenia patients: (1) cross-sectional prevalences of APP (1996 2012); (2) geographic variations in APP (2012); and (3) correlates of APP (2012). APP increased from 17.2% in 1996 to 30.8% in 2006 (p<0.001), declining to 24.6% in 2012 (p<0.001) (overall trend 1996-2012: alpha=0.653, 95% confidence interval (CI):0.327-0.979, p<0.001). Comparing the 1996-2005 and 2006-2012 cohorts APP occurred significantly faster in the 2006 cohort after schizophrenia diagnosis (p<0.0001). The predominant APP type changed from first-generation antipsychotic combinations in 1996 (77.3%) to first+second-generation antipsychotic combinations in 2003 (70.3%) and second-generation antipsychotic combinations in 2012 (59.2%). In 2012, the prevalence of APP varied from 19.4% in Copenhagen to 29.3% in the region of Zealand. Independent correlates of APP, explaining 37.9% of the variance, included a higher number of patients per psychiatrist (OR=1.04/10 patients, CI=1.03-1.06, p<0.001),lower proportion of males (OR=0.80, CI=0.74-0.86), younger age (OR=1.00, CI=0.99-1.00), several schizophrenia subtypes (paranoid: OR=1.24, CI=1.11-1.38,hebephrenic: OR=1.30, CI=1.03-1.63, other: OR=1.95 CI=1.17-3.24, unspecified: OR=1.21 CI=1.05-1.40), living alone (OR=1.12, CI=1.01-1.24), being institutionalized (OR=1.23, CI=1.06-1.42), receiving early retirement pension (OR=1.21, CI=1.10-1.34), higher Charlson Co morbidity Index score (OR=1.13, CI=1.07-1.19), higher antipsychotic defined daily doses (OR=3.05, CI=-2.95-3.16), treatment with clozapine (OR=3.09, 95% CI=2.78 3.44), and treatment with antidepressants (OR=1.97 (CI=1.83-2.13), long-acting injectable antipsychotics (OR=1.48, CI=1.34-1.63), and anticholinergics (OR=1.74, CI=1.51-2.01). APP remains common in schizophrenia with substantial temporal and geographical variation, being associated with indicators of illness severity and chronicity. PMID- 26256008 TI - Benzodiazepines and risk of death: Results from two large cohort studies in France and UK. AB - Benzodiazepines are widely prescribed for the treatment of anxiety or insomnia, but their impact on mortality is still debated. This study investigated the impact of benzodiazepine use on short term mortality. Exposed-unexposed cohorts were constructed with the Clinical Practice Research Datalink (CPRD) in the UK and with the General Sample of Beneficiaries (EGB) in France. Benzodiazepine incident users were matched to incident users of antidepressants/non benzodiazepine sedatives and to controls (non-users of antidepressants or anxiolytics/hypnotics) according to age and gender in both sources (and practice for the CPRD only). Survival at one year was studied using Cox regression model. In the CPRD, the final population comprised 94 123 patients per group (57 287 in the EGB). In the CPRD, adjusted HR was 3.73 in benzodiazepine users (95% CI, 3.43 4.06), and 1.61 (1.47-1.76) in antidepressant/non-benzodiazepine users compared to controls. When considering benzodiazepine use as a time-dependent covariate, adjusted HR for current use at 12 months was 1.70 (1.36-2.12). In the EGB, adjusted HR was 1.26 in benzodiazepine users (95% CI, 1.08-1.48), and 1.07 (95% CI, 0.91-1.27) in antidepressant/non-benzodiazepine users. When considering benzodiazepine use as a time-dependent covariate, adjusted HR for current use at 12 months was 1.03 (0.74-1.44). Using two nationally representative databases, we found a significant while moderate increase in all-cause mortality in relation to benzodiazepines, in a population of incident and mostly occasional users. This issue need to be monitored given the extensive use of these drugs. PMID- 26256004 TI - FoxO Transcription Factors and Regenerative Pathways in Diabetes Mellitus. AB - Mammalian forkhead transcription factors of the O class (FoxO) are exciting targets under consideration for the development of new clinical entities to treat metabolic disorders and diabetes mellitus (DM). DM, a disorder that currently affects greater than 350 million individuals globally, can become a devastating disease that leads to cellular injury through oxidative stress pathways and affects multiple systems of the body. FoxO proteins can regulate insulin signaling, gluconeogenesis, insulin resistance, immune cell migration, and cell senescence. FoxO proteins also control cell fate through oxidative stress and pathways of autophagy and apoptosis that either lead to tissue regeneration or cell demise. Furthermore, FoxO signaling can be dependent upon signal transduction pathways that include silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), Wnt, and Wnt1 inducible signaling pathway protein 1 (WISP1). Cellular metabolic pathways driven by FoxO proteins are complex, can lead to variable clinical outcomes, and require in-depth analysis of the epigenetic and post-translation protein modifications that drive FoxO protein activation and degradation. PMID- 26256009 TI - Usefulness of interim analyses in portending study results in antipsychotic and antidepressant trials. AB - It is unknown whether interim analyses portend final study results. Fatigue, pressure to complete trials and recruitment differences may mitigate against this. We examined the similarity of efficacy results of the first and second half of recruited patients to complete trials and explore possible intervening variables. Using data from the NewMeds repository of patient level data from placebo-controlled randomized trials of antipsychotics (AP) (22 studies, n=7056) and antidepressants (AD) (39 studies, n=12,217) we compared treatment effect size (placebo vs. active treatment) of the first and second half of patients recruited in completed trials. We found that in AP studies median difference in treatment effect between cohorts was -0.03, indicating that overall first and second cohorts yielded similar results. In AD studies, median difference between cohorts was 0.04, indicating that overall the second cohort had slightly larger active placebo-difference. Overall, on average there were minimal differences in effect size between the first and the second cohorts, and in 30 of 39 trials interim results were a good estimate of the results on the 2nd cohort. In AD trials first and second cohort results were more similar when the proportion of patients per study centre and recruitment time of the two cohorts was similar. Results suggest that interim analyses in AD and AP studies may reliably serve to estimate ultimate effects and, at least in AD trials, are more accurate when the same sites are used to a similar extent and recruitment time of the two consequent cohorts is similar. PMID- 26256010 TI - Role of serotonin 5-HT2C and histamine H1 receptors in antipsychotic-induced diabetes: A pharmacoepidemiological-pharmacodynamic study in VigiBase. AB - Pharmacodynamic mechanisms of diabetes induced by antipsychotic drugs remain unclear, while numerous receptors have been suspected to be involved in the genesis of this Adverse Drug Reaction (ADR). We investigated potential relationships between antipsychotics' receptor occupancy (serotonin 5-HT1A, 5 HT2A, 5-HT2C, histamine H1, muscarinic M3, adrenergic alpha1, alpha2 or dopaminergic D2 D3 occupancies) and reports of diabetes using VigiBase((r)), the World Health Organization (WHO) global Individual Case Safety Report (ICSR) database. All ADR reports from 15 first and second generation antipsychotic drugs recorded in VigiBase((r)) were extracted. Logistic regression models, completed by disproportionality analysis, were used to determine the associations between antipsychotics' receptor occupancy and ICSRs of diabetes on VigiBase((r)). During the study period, 94,460 ICSRs involved at least one of the 15 antipsychotics of interest. Diabetes was reported in 1799 (1.9%) patients. Clozapine was the most frequently suspected drug (n=953; 53.0%). A significant and positive association was found between histamine H1, muscarinic M3 and serotonin 5-HT2C, 5-HT2A receptor occupancies and reports of diabetes. A multivariable stepwise regression model showed that only serotonin 5-HT2c (AOR=2.13, CI 95% 1.72-2.64) and histamine H1 (AOR=1.91, CI 95% 1.38-2.64) predicted the risk for diabetes mellitus (p<0.001). Using an original pharmacoepidemiology-pharmacodynamic (PE PD) approach, our study supports that antipsychotic drugs blocking simultaneously histamine H1 and serotonin 5-HT2C receptors are more frequently associated with diabetes reports in VigiBase((r)) than other antipsychotics. These findings should encourage investigation of histamine H1 and serotonin 5-HT2C properties for predicting the risk of glycemic effects in candidate antipsychotics. PMID- 26256011 TI - Lurasidone and fluoxetine reduce novelty-induced hypophagia and NMDA receptor subunit and PSD-95 expression in mouse brain. AB - Lurasidone, a novel second-generation antipsychotic agent, exerts antidepressant actions in patients suffering from bipolar type I disorder. Lurasidone acts as a high affinity antagonist at multiple monoamine receptors, particularly 5-HT2A, 5 HT7, D2 and alpha2 receptors, and as a partial agonist at 5-HT1A receptors. Accumulating evidence indicates therapeutic actions by monoaminergic antidepressants are mediated via alterations of glutamate receptor-mediated neurotransmission. Here, we used mice and investigated the effects of chronic oral administration of vehicle, lurasidone (3 or 10mg/kg) or fluoxetine (20mg/kg) in the novelty induced hypophagia test, a behavioral test sensitive to chronic antidepressant treatment. We subsequently performed biochemical analyses on NMDA receptor subunits and associated proteins. Both lurasidone and fluoxetine reduced the latency to feed in the novelty-induced hypophagia test. Western blotting experiments showed that both lurasidone and fluoxetine decreased the total levels of NR1, NR2A and NR2B subunits of NMDA receptors and PSD-95 (PostSynaptic Density 95) in hippocampus and prefrontal cortex. Taken together, these data indicate that antidepressant/anxiolytic-like effects of lurasidone, as well as fluoxetine, could involve reduced NMDA receptor-mediated signal transduction, particularly in pathways regulated by PSD-95, in hippocampus and prefrontal cortex. PMID- 26256012 TI - Magnetic resonance imaging and short-term clinical results of severe frozen shoulder treated with manipulation under ultrasound-guided cervical nerve root block. AB - BACKGROUND: We evaluated the magnetic resonance (MR) imaging findings and short term clinical outcomes of severe idiopathic frozen shoulder treated with manipulation under ultrasound-guided cervical nerve root block (MUC). METHODS: The subjects were 30 patients (average age, 55.2 years; 12 men, 18 women) with severe frozen shoulder. Severe idiopathic frozen shoulder was defined as follows: a range of motion (ROM) of <= 100 degrees in forward flexion, <= 10 degrees in external rotation, and at or below the fifth lumbar vertebral level in internal rotation. Before the manipulation, all patients had continued global ROM loss for at least 6 months. Before and after manipulation, they underwent MR imaging. MR images and clinical results were evaluated 1 month after the procedure. RESULTS: In terms of the capsule tear pattern, MR imaging showed 14 midsubstance tears and 15 humeral avulsions of glenohumeral ligament-like lesions. An anterior labrum tear occurred in 4 shoulders, whereas 15 shoulders showed a bone bruise in the posterosuperior and anteromedial portions of the humeral head despite no humeral shaft fracture. There were significant improvements in the ROM, Constant-Murley score, American Shoulder and Elbow Surgeons score, and Numeric Rating Scale score from before treatment to 1 month after the procedure. CONCLUSION: MR imaging of patients with severe frozen shoulder after MUC showed 29 capsule tears, 4 labrum tears, and 15 bone bruises of the humeral head. Approximately 50% of patients are likely to experience bone bruising after MUC. Long-term follow-up of these patients should be performed carefully. PMID- 26256013 TI - Allograft-prosthetic composite reverse total shoulder arthroplasty for reconstruction of proximal humerus tumor resections. AB - BACKGROUND: Proximal humerus reconstructions after resection of tumors are challenging. Early success of the reverse shoulder arthroplasty for reconstructions has recently been reported. The reverse allograft-prosthetic composite offers the advantage of improved glenohumeral stability compared with hemiarthroplasty for proximal humeral reconstructions as it uses the deltoid for stability. METHODS: This article describes the technique for treating proximal humeral tumors, including preoperative planning, biopsy principles, resection pearls, soft tissue tensioning, and specifics about reconstruction using the reverse allograft-prosthetic composite. Two cases are presented along with the functional outcomes with use of this technique. Biomechanical considerations during reconstruction are reviewed, including techniques to improve the deltoid compression force. RESULTS: Reported instability rates are less with reverse shoulder arthroplasty reconstruction as opposed to hemiarthroplasty or total shoulder arthroplasty reconstructions of tumor resections. Reported functional outcomes are promising for the reverse allograft-prosthetic composite reconstructions, although complications are reported. CONCLUSION: Reverse allograft-prosthetic composites are a promising option for proximal humeral reconstructions, although nonunion of the allograft-host bone junction continues to be a challenge for this technique. PMID- 26256014 TI - A guided surgical approach and novel fixation method for arthroscopic Latarjet. AB - BACKGROUND: Most of the complications of the Latarjet procedure are related to the bone block positioning and use of screws. The purpose of this study was to evaluate if an arthroscopic Latarjet guiding system improves accuracy of bone block positioning and if suture button fixation could be an alternative to screw fixation in allowing bone block healing and avoiding complications. MATERIALS AND METHODS: Seventy-six patients (mean age, 27 years) underwent an arthroscopic Latarjet procedure with a guided surgical approach and suture button fixation. Bone graft union and positioning accuracy were assessed by postoperative computed tomography imaging. Clinical examinations were performed at each visit. RESULTS: At a mean of 14 months (range, 6-24 months) postoperatively, 75 of 76 patients had a stable shoulder. No neurologic complications were observed; no patients have required further surgery. The coracoid graft was positioned strictly tangential to the glenoid surface in 96% of the cases and below the equator in 93%. The coracoid graft healed in 69 patients (91%). CONCLUSIONS: A guided surgical approach optimizes graft positioning accuracy. Suture button fixation can be an alternative to screw fixation, obtaining an excellent rate of bone union. Neurologic and hardware complications, classically reported with screw fixation, have not been observed with this guided technique and novel fixation method. PMID- 26256015 TI - Minimally invasive plate osteosynthesis for midshaft clavicular fractures using superior anatomic plating. AB - BACKGROUND: The minimally invasive plate osteosynthesis procedure has been widely applied for long-bone fixations; however, this technique is not commonly used for clavicular midshaft fractures. In this study, we introduced this technique for midshaft clavicular fractures using superior anatomic locking plates and evaluated its clinical and radiographic outcomes. MATERIALS AND METHODS: From June 2013 to July 2014, 15 patients with acute midshaft clavicular fractures were treated with the minimally invasive plate osteosynthesis technique using a 3.5-mm clavicular superior anatomic locking plate. Anteroposterior plain X-ray images of the clavicle were taken at 4-week intervals until union was observed. The last clinical follow-up assessments were performed postoperatively at a mean of 16.54 months (range, 10-23 months). In addition, for clinical evaluations, the Constant score and the Disability of the Arm, Shoulder and Hand score were assessed. RESULTS: The average operative time was 60.2 +/- 20.1 minutes (range, 40-80 minutes), with blood loss of 25 +/- 5 mL (range, 20-30 mL) during the operation. The mean union time for the patients was 10.1 +/- 1.4 weeks (range, 8-12 weeks), and no delayed union or nonunion was observed. There were no major complications, including infections, plate breakages, or neurovascular injuries. No skin irritation was observed, and only 2 patients felt local incision numbness. All patients obtained satisfactory shoulder functions. The mean Constant score was 99 +/- 1.8 (range, 95-100), and the mean Disability of the Arm, Shoulder and Hand score was 3.8 +/- 2.9 (range, 0-10) at the last control visit. CONCLUSION: The minimally invasive plate osteosynthesis procedure that was introduced in this study for midshaft clavicular fractures with superior anatomic locking plate is a reproducible procedure and an alternative to conventional operative methods. PMID- 26256016 TI - Factors predicting postoperative range of motion for anatomic total shoulder arthroplasty. AB - BACKGROUND: Total shoulder arthroplasty (TSA) has repeatedly been shown to be an effective and durable treatment option for end-stage arthritis with good long term survivorship. Whereas pain relief is typically the primary goal, improvements in range of motion are typically expected as well. The factors that influence postoperative motion have not been well characterized. The purpose of the study was to examine the factors that influence ultimate postoperative motion after TSA. METHODS: A retrospective review was conducted of prospectively collected data of 230 patients with minimum 1-year follow-up after TSA for end stage arthropathy with an intact rotator cuff. Analysis was focused on factors that may correlate with postoperative measured forward flexion, abduction, external rotation, and internal rotation. Included in this analysis was perception of motion, age, body mass index (BMI), comorbidities (smoking, diabetes, osteoporosis, hypercholesterolemia, inflammatory arthritis, and thyroid disease), and number of comorbidities. RESULTS: Preoperative motion in all directions was predictive of postoperative motion for forward flexion (R = 0.235; P < .001), abduction (R = 0.363; P < .001), external rotation (R = 0.325; P < .001), and internal rotation (R = 0.213; P = .002). BMI and diabetes both negatively correlated with internal rotation (R = -0.134, P = .40 and R = -0.196, P = .003, respectively). Individual and total number of comorbidities were not predictive of postoperative motion. The patient's perception of preoperative motion also did not correlate with postoperative motion. CONCLUSIONS: Preoperative range of motion before TSA is most predictive of final motion achieved. Individual and total number of comorbidities are not predictive of postoperative motion. Patients with high diabetes and increased BMI have limited postoperative internal rotation. PMID- 26256017 TI - Testing of a novel pin array guide for accurate three-dimensional glenoid component positioning. AB - BACKGROUND: A substantial challenge in total shoulder replacement is accurate positioning and alignment of the glenoid component. This challenge arises from limited intraoperative exposure and complex arthritic-driven deformity. We describe a novel pin array guide and method for patient-specific guiding of the glenoid central drill hole. We also experimentally tested the hypothesis that this method would reduce errors in version and inclination compared with 2 traditional methods. METHODS: Polymer models of glenoids were created from computed tomography scans from 9 arthritic patients. Each 3-dimensional (3D) printed scapula was shrouded to simulate the operative situation. Three different methods for central drill alignment were tested, all with the target orientation of 5 degrees retroversion and 0 degrees inclination: no assistance, assistance by preoperative 3D imaging, and assistance by the pin array guide. Version and inclination errors of the drill line were compared. RESULTS: Version errors using the pin array guide (3 degrees +/- 2 degrees ) were significantly lower than version errors associated with no assistance (9 degrees +/- 7 degrees ) and preoperative 3D imaging (8 degrees +/- 6 degrees ). Inclination errors were also significantly lower using the pin array guide compared with no assistance. DISCUSSION AND CONCLUSION: The new pin array guide substantially reduced errors in orientation of the central drill line. The guide method is patient specific but does not require rapid prototyping and instead uses adjustments to an array of pins based on automated software calculations. This method may ultimately provide a cost-effective solution enabling surgeons to obtain accurate orientation of the glenoid. PMID- 26256018 TI - Associations of Adiposity and Aerobic Fitness with Executive Function and Math Performance in Danish Adolescents. AB - OBJECTIVE: To examine the associations of adiposity and aerobic fitness with executive function and math performance in Danish adolescents. STUDY DESIGN: Cross-sectional analyses were conducted with data on 525 adolescents attending sixth and seventh grades from 14 schools in the 5 main regions of Denmark. A modified Eriksen flanker task was used to assess inhibitory control, a key aspect of executive function. Academic performance was assessed by a customized math test. Aerobic fitness was assessed by an intermittent shuttle-run test (Andersen test). RESULTS: Body mass index (BMI) was negatively associated with accuracy on incongruent trials during the flanker task (P = .005). A higher BMI was associated with a larger accuracy interference score (P = .01). Similarly, waist circumference (WC) was negatively associated with accuracy on incongruent trials (P = .008). A higher WC was associated with a larger reaction time (RT) interference score (P = .02) and accuracy interference score (P = .009). Higher aerobic fitness was associated with a faster RT on congruent trials (P = .009) and incongruent trials (P = .003). Higher aerobic fitness was associated with a smaller RT interference score (P = .04). Aerobic fitness was positively associated with math score (P < .001). BMI and WC were not associated with math score (P > .05). CONCLUSIONS: These results suggest that aerobic fitness is positively associated with both inhibitory control and math performance in adolescents. Adiposity is negatively associated with inhibitory control in adolescents. Adiposity is not associated with math performance. PMID- 26256019 TI - Trends in Pediatric Emergency Department Utilization for Mental Health-Related Visits. AB - OBJECTIVE: To describe trends in utilization of pediatric emergency department (PED) resources by patients with mental health concerns over the past 11 [corrected] years at a tertiary care hospital. STUDY DESIGN: We conducted a retrospective cohort study of tertiary PED visits from 2002 [corrected] to 2012. All visits with chief complaint or discharge diagnosis related to mental health were included. Variables analyzed included number and acuity of mental health related visits, length of stay, waiting time, admission rate, and return visits, relative to non-mental health [corrected] PED visits. Descriptive statistics were used to summarize the results. RESULTS: We observed a 47% increase in the number of mental health presentations compared with a 27.5% [corrected] increase in the number of total visits to the PED over the study period. Return visits represented a significant proportion of all mental health-related visits (32.2% [corrected] yearly). The proportion of mental health visits triaged to a high acuity level has decreased whereas the proportion of visits triaged to the mid acuity level has increased. Length of stay for psychiatric patients was significantly longer than for visits to the PED in general. We also observed a 53.7% [corrected] increase in the number of mental health-related visits resulting in admission. CONCLUSION: Mental health-related visits represent a significant and growing burden for the emergency department at a tertiary care PED. These results highlight the need to reassess the allocation of health resources to optimize acute management, risk assessment, and linkage to mental health services upon disposition from the PED. PMID- 26256020 TI - Lipopolysaccharide-induced expression of FAS ligand in cultured immature boar sertoli cells through the regulation of pro-inflammatory cytokines and miR-187. AB - Lipopolysaccharide (LPS) induces germ cell apoptosis, but its mechanism of action is not clear. One possibility is that LPS regulates the expression of FAS ligand (FASLG) in Sertoli cells, which will then influence germ cell apoptosis. In this study, LPS reduced the viability of cultured, immature boar Sertoli cells in a time- and dose-dependent manner; enhanced the production of pro-inflammatory cytokines including tumor necrosis factor alpha (TNFA), interleukin-1beta (IL1B), nitric oxide (NO), and transforming growth factor-beta (TGFB); and increased the expression of FASLG in a dose-dependent manner. While 10 MUg/ml LPS enhanced the expression of FASLG, reduced cell cycle progression, and impaired the ultrastructure of Sertoli cells, this dose did not induce apoptosis. LPS also had no effect on the activity or expression of matrix metalloproteinases 2 or 9 (MMP2 or MMP9). In contrast, the expression of ssc-miR-187 increased following LPS challenge, and inhibition of ssc-miR-187 blocked LPS-induced expression of FASLG. Our results therefore suggest that LPS reduces the viability of and enhances FASLG expression in cultured, immature boar Sertoli cells through elevated secretion of TNFA, IL1B, NO, and TGFB as well as through the regulation of ssc miR-187 potency. PMID- 26256021 TI - Physiological mechanism of the overproduction of epsilon-poly-L-lysine by acidic pH shock in fed-batch fermentation. AB - The introduction of an environmental stress of acidic pH shock had successfully solved the common deficiency existed in epsilon-PL production, viz. the distinct decline of epsilon-PL productivity in the feeding phase of the fed-batch fermentation. To unravel the underlying mechanism, we comparatively studied the physiological changes of Streptomyces sp. M-Z18 during fed-batch fermentations with the pH shock strategy (PS) and pH non-shock strategy (PNS). Morphology investigation showed that pellet-shape change was negligible throughout both fermentations. In addition, the distribution of pellet size rarely changed in the PS, whereas pellet size and number decreased substantially with time in the PNS. This was consistent with the performances of epsilon-PL productivity in both strategies, demonstrating that morphology could be used as a predictor of epsilon PL productivity during fed-batch fermentation. Furthermore, a second growth phase happened in the PS after pH shock, followed by the re-appearance of live mycelia in the dead core of the pellets. Meanwhile, mycelia respiration and key enzymes in the central metabolic and epsilon-PL biosynthetic pathways were overall strengthened until the end of the fed-batch fermentation. As a result, the physiological changes induced by the acidic pH shock have synergistically and permanently contributed to the stimulation of epsilon-PL productivity. However, this second growth phase and re-appearance of live mycelia were absent in the PNS. These results indicated that the introduction of a short-term suppression on mycelia physiological metabolism would guarantee the long-term high epsilon-PL productivity. PMID- 26256022 TI - Characterization, optimization, and scale-up of cellulases production by trichoderma reesei cbs 836.91 in solid-state fermentation using agro-industrial products. AB - The application of cellulases in saccharification processes is restricted by its production cost. Consequently, new fungal strains able to elaborate higher cellulases titers and with special activity profiles are required to make the process economical. The aim of this investigation was to find a promising wild type Trichoderma strain for cellulases production. The Trichoderma reesei strain 938 (CBS 836.91) was selected among twenty strains on the basis of cellulase-agar plate screening. Evaluation of the selected strain on six solid substrates indicated the highest activities to be obtained from wheat bran. Statistical analyses of the experimental design indicated a significant effect of pH and moisture on the generation of endoglucanase (EGA) and filter-paper (FPA) activity. Furthermore, a central-composite design-based optimization revealed that pH values between 6.4 and 6.6 and moisture from 74 to 94% were optimal for cellulases production. Under these conditions, 8-10 IU gds(-1) of FPA and 15.6 17.8 IU gds(-1) of EGA were obtained. In addition, cultivation in a rotating-drum reactor under optimal conditions gave 8.2 IU gds(-1) FPA and 13.5 IU gds(-1) EGA. Biochemical characterization of T. reesei 938 cellulases indicated a substantially higher resistance to 4 mM Fe(+2) and a slightly greater tolerance to alkaline pH in comparison to Celluclast((r)). These results suggest that T. reesei 938 could be a promising candidate for improved cellulases production through direct-evolution strategies. PMID- 26256023 TI - Professor Robert F. Borkenstein - Appreciation of His Life and Work. AB - Few men have made such a significant and sustained contribution to their chosen field of endeavor as Robert F. Borkenstein. He is an international forensic science celebrity, highly respected by his peers. The two most well-known products of his brilliance are the Breathalyzer, invented in 1954, and the "Grand Rapids Study", a seminal work which established the relative risk of being involved in a traffic accident with various blood alcohol concentrations. In addition to his significant scientific achievements, he is greatly admired for his personal qualities, acute wit and total commitment to the cause of traffic safety. This article is a brief review and appreciation of his life and his many accomplishments. PMID- 26256024 TI - Medicolegal Alcohol Determination - Blood- or Breath-Alcohol Concentration? AB - Measuring the concentration of alcohol in body fluids represents a large part of the workload at forensic science and toxicology laboratories. In traffic-law enforcement, breath-alcohol testing is used worldwide for roadside screening and for evidential purposes. Many jurisdictions have adopted per se laws which make it a crime to drive with a blood- or breath-alcohol concentration above a prescribed statutory limit. The choice between blood- and breath-alcohol analysis for forensic purposes depends on many factors, not least of which are political and personal interests. Breath sampling is non-invasive compared with blood sampling although breath testing is only feasible in living and cooperative subjects. The presence of narcotics or prescription drugs that might impair driving ability is easily analyzed in blood samples but not in breath samples. Re analysis of a blood sample to confirm the result is a simple matter, whereas storage of breath specimens for confirmatory analysis is less practical. The statutory breath-alcohol concentration (BrAC) limits for driving have been derived from pre-existing blood-alcohol concentration (BAC) limits by assuming breath-to-blood conversion factors of 2000:1, 2100:1, or 2300:1 in different countries. In a large study, the mean BAC/BrAC ratio in drinking drivers was ?2400:1, which gives a generous advantage to those who provide a sample of breath when a 2100:1 ratio has been used to set the statute. The concentrations of alcohol in blood and breath are highly correlated and the fate of alcohol in the body can be monitored by analyzing a series of blood or breath samples. The results of breath-alcohol measurement are, however, more prone to physiological variations such as body and breath temperature, pulmonary function, and pattern of breathing prior to exhalation. For individuals with BAC or BrAC close to the legal limit for driving, inherent uncertainty in the analytical methods (both blood and breath) can make the difference between punishment or acquittal. This requires making a deduction from the mean of a duplicate determination of BAC or BrAC so that the value remaining is less than the true mean concentration of alcohol with a high degree of confidence (99 or 99.9%). Blood- and breath-alcohol tests are sensitive and objective ways to document over-consumption of alcohol and are more practical than recording clinical signs and symptoms of alcohol influence or performing psychomotor tests of impairment. PMID- 26256025 TI - Methodology and Quality Assurance in Forensic Breath Alcohol Analysis. AB - Breath alcohol analysis has become widely established in the forensic science and legal communities. The increasingly serious consequences of a drunk driving conviction, however, requires that further attention be focused on improving quality assurance. Although computerized instrumentation with advanced technology has enhanced forensic interpretation and confidence, other important areas of measurement protocol and program details must receive equal attention. Measurement results are the product of a process and not simply an instrument. Confidence in results can occur only after showing the entire program is "fit-for purpose". Forensic quality assurance results from a balanced consideration for instrumentation, protocol, administrative rules, record keeping, interpretation, communication, etc. The following review will discuss current breath alcohol instrumentation along with several program features important to forensic quality control. Statistical methods are also available to assist in the quantitative interpretation of results to ensure statistical control and fitness-for-purpose. Increasing public and political attention on drunk driving requires the highest possible standards for quality control applied from a total program perspective. PMID- 26256026 TI - The Role of Forensic Psychiatry in Substance Abuse - Practice and Research in Taiwan. AB - Substance abuse is an increasingly important medical and legal problem in Taiwan. This article reviews limited studies in Taiwan on the prevalence of substance abuse and psychiatric co-morbidity, and assessment of substance use disorder, with emphasis on their relation to forensic psychiatry. Complicated interaction exists among substance abuse, criminal behavior, and various mental disorders (including antisocial personality disorder). Forensic psychiatry can play an important role in both treatment and research aimed at overcoming the problems of substance abuse. Also discussed are the necessity in merging genetic analysis methods with forensic psychiatric assessment, and the implementation of treatment and rehabilitation programs for criminal offenders co-morbid with psychiatric illness. PMID- 26256027 TI - Driving under the Influence of Non-Alcohol Drugs. AB - In this article the methodological basis for our knowledge within the field of driving under the influence of non-alcohol drugs is reviewed. The experimental and epidemiological studies on drugs in relation to driving do not constitute a complete basis for conclusions to be drawn, but give at the present state nevertheless a platform to indicate increased hazard connected with the use of several drugs. It appears that the main problem with respect to therapeutic use of medicinal drugs is experienced with benzodiazepines (BZDs) and related drugs, and to a lesser extent with opioids and antidepressants. Antihistamine use does not appear to be a serious problem. The major problem within the field of drugged driving as it emerges today in the US and Europe is the high dose use (abuse) of BZDs and related drugs, opioids and illicit drugs such as cannabis, amphetamines, cocaine and related drugs with accompanying danger to traffic safety. Methods determining clinical drug effects in people combined with measurements of drug blood concentrations seem to constitute the best basis for evaluation of "influence". New methods to detect drugged drivers are under development, with saliva tests presently being the most promising. Legislation in the field can be of the "zero tolerance" type or the "impairment" type; combinations of these principles might well turn out to be the most efficient. Detection of drugged driving is presently, in relation to population size, most frequent in Norway, a country with not too pronounced drug problems, indicating a large potential for future detection of drugged driving in other countries. The prevention of drugged driving, especially in the drug-abusing group which has a high recidivism rate, is a challenge for future policy in this field. PMID- 26256028 TI - Epidemiology of Alcohol-Related Accidents and the Grand Rapids Study. AB - Although it was evident from the early years of this century that alcohol was associated with motor vehicle injury, and although strict laws were enacted in both the U.S. and elsewhere imposing severe penalties for drunken driving, in the U.S. drinking and driving was so widespread that it was generally not viewed as a major offense. Severe penalties were rarely imposed, and the practice of reducing charges was commonplace. Objective data on the relationship between alcohol and crash involvement were not available. The Grand Rapids Study, first published in 1964, clearly documented for the first time the rapid acceleration of crash risk associated with increasing blood alcohol concentration. This study provided the basis for educating the public and enacting stricter laws governing drinking and driving, as well as the basis for much additional research. When the citizen action groups came into being, the solid knowledge foundation that had been established was translated into programs that have greatly reduced alcohol related injury and death on the highway. In the last two decades unprecedented progress has been made in this regard, with the proportion of fatal crashes that are alcohol-related steadily decreasing in every age group. The Grand Rapids Study remains as a landmark contribution that continues to be used in developing and implementing programs to reduce drunken driving. PMID- 26256029 TI - Countermeasures for Reducing Alcohol-Related Crashes. AB - Programs to prevent alcohol-related crashes occur at several levels. Although most of the public thinks of drunk-driving prevention only in terms of the criminal justice system, much can be done to prevent alcohol-related highway deaths before the drinking-and-driving offender gets on the road. In recent years, the field of alcohol safety has merged with the area of public health concerned with preventing alcohol- and drug-related traumatic injury and death. This paper provides an overview of the status of road safety programs directed at reducing impaired driving. It covers ten topics falling into the three levels of prevention: primary programs to reduce alcohol consumption; secondary programs to prevent driving after drinking; and tertiary programs to prevent recidivism among convicted drinking drivers. PMID- 26256030 TI - Objective Diagnosis of Chronic Alcohol Abuse - Determination of Carbohydrate Deficient Transferrin (CDT) with Capillary Electrophoresis. AB - To assist the diagnosis of high risk alcohol consumption or alcohol dependence, particularly in the absence of evidences of recent alcohol intake (relapse), objective biochemical markers are today available, which, if used correctly, may reduce the degree of subjectivity that the adoption of merely clinical and psychological diagnostic criteria shows inevitably. The present paper reviews briefly in terms of diagnostic sensitivity and specificity the most important conventional markers of chronic alcohol abuse - e.g., gamma-glutamyl transferase (GGT), erythrocyte mean corpuscular volume (MCV), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) - as well as those more recently proposed, namely aldehyde dehydrogenase (ALDH), high density lipoprotein cholesterol, serum triglycerides, urate, fatty acid ethyl and methyl esters, phosphatidylethanol, dolichols, beta-hexosaminidase and protein acetaldehyde adducts. However, the specific focus of this review is on carbohydratedeficient transferrin (CDT), the collective name of a group of transferrin isoforms lacking totally or partly the oligosaccharide chains usually linked at two glycosylation sites in the C domain of the protein. CDT, at present, is considered the most reliable marker of excessive alcohol intake for at least a week, and has a chronological diagnostic window of about two weeks before sample collection. CDT is reviewed in terms of diagnostic value, applications and, particularly, in the different analytical approaches, with special emphasis on capillary electrophoresis, the latest method proposed for its quantitative determination. PMID- 26256031 TI - Flavonoid glycosides from the aerial parts of Acacia pennata in Myanmar. AB - Phytochemical investigations of the aerial parts of Acacia pennata (Mimosaceae) from Myanmar led to the isolation of five flavonoid glycosides and six known compounds. The new compounds were identified as (2R,3S)-3,5,7-trihdyroxyflavan-3 O-alpha-L-rhamnopyranoside, (2S)-5,7-dihydroxyflavan-7-O-beta-D-glucopyranoside (4alpha -> 8)-epiafzelechin-3-O-gallate, (2R)-4',7-dihydroxyflavan-(4alpha -> 8) (2R,3S)-3,5,7-trihdyroxyflavan-3"-O-alpha-L-rhamnopyranoside, 5,7 dihydroxyflavone 6-C-beta-boivinopyranosyl-7-O-beta-D-glucopyranoside, and 5,7 dihydroxyflavone 7-O-beta-D-glucopyranosyl-8-C-beta-boivinopyranoside based on interpretation of spectroscopic data. PMID- 26256032 TI - Molecular design and synthesis of certain new quinoline derivatives having potential anticancer activity. AB - EGFR, which plays a vital role as a regulator of cell growth, is one of the intensely studied TK targets of anticancer inhibitors. The most two common anticancer inhibitors are anilinoquiazolines and anilinoquinolines that inhibit EGFR kinase intracellularly. The present investigation dealt with design (pharmacophore, docking and binding energy) and synthesis of a new series of 4 anilinoquinoline-3-carboxamide derivatives as potential anticancer agents targeting EGFR. All the newly synthesized compounds were screened for their anticancer activity against MCF-7 and compounds 4f, 7a and 7b showed significant activity with IC50 values 13.96 MUM, 2.16 MUM and 3.46 MUM, respectively. Most of the synthesized compounds were subjected to enzyme assay (EGFR TK) for measuring their inhibitory activity with the determination of IC50 values and the preliminary results revealed that compound 7b, which had potent inhibitory activity in tumor growth and had potent activity on the EGFR TK enzyme with 67% inhibition compared to ATP would be a potential anticancer agent. PMID- 26256034 TI - Routine outcome measures in Norway: Only partly implemented. AB - Norway has not had any strategy exclusively for the implementation of routine outcome measurement in the mental health services, but some efforts have been made as part of strategies for a national patient register and quality indicators. Fifteen years after the decision to make the rating of the Global Assessment of Functioning scale (GAF) mandatory at admission and discharge of each treatment episode in adult mental health services, this is still not fully implemented. An unknown and probably very low proportion of mental health services use GAF as a routine outcome measure in everyday clinical practice. Well established electronic patient records in the mental health services and established procedures for reporting routine data to the National Patient Register should make it possible to collect and use routine outcome data. Implementation of routine outcome measurement in mental health services must be done with due emphasis on the critical steps in the various phases of the implementation process. The regional health authorities have a key role in establishing electronic systems that make relevant outcome measurements available in a seamless way for clinicians as well as for patients, and by contributing to a culture where quality and outcome are valued and given priority. PMID- 26256033 TI - Total Synthesis of Verruculogen and Fumitremorgin A Enabled by Ligand-Controlled C-H Borylation. AB - Verruculogen and fumitremorgin A are bioactive alkaloids that contain a unique eight-membered endoperoxide. Although related natural products such as fumitremorgins B and C have been previously synthesized, we report the first synthesis of the more complex, endoperoxide-containing members of this family. A concise route to verruculogen and fumitremorgin A relied not only on a hydroperoxide/indole hemiaminal cyclization, but also on the ability to access the seemingly simple starting material, 6-methoxytryptophan. An iridium-catalyzed C-H borylation/Chan-Lam procedure guided by an N-TIPS group enabled the conversion of a tryptophan derivative into a 6-methoxytryptophan derivative, proving to be a general way to functionalize the C6 position of an N,C3 disubstituted indole for the synthesis of indole-containing natural products and pharmaceuticals. PMID- 26256035 TI - Disentangling the Effect of Valence and Arousal on Judgments Concerning Moral Transgressions. AB - An increasing body of research has investigated the effect of emotions on judgments concerning moral transgressions. Yet, few studies have controlled for arousal levels associated with the emotions. High arousal may affect moral processing by triggering attention to salient features of transgressions, independently of valence. Therefore previously documented differences in effects of negative and positive emotions may have been confounded by differences in arousal. We conducted two studies to shed light on this issue. In Study 1 we developed a questionnaire including vignettes selected on the basis of psychometrical properties (i.e., mean ratings of the actions and variability). This questionnaire was administered to participants in Study 2, after presenting them with selected pictures inducing different valence but equivalent levels of arousal. Negative pictures led to more severe moral judgments than neutral (p = .054, d = 0.60) and positive pictures (p = .002, d = 1.02), for vignettes that were not associated with extreme judgments. In contrast, positive pictures did not reliably affect judgments concerning such vignettes. These findings suggest that the observed effects of emotions cannot be accounted for by an increase in attention linked to the arousal which accompanies these emotions. PMID- 26256036 TI - Self-regeneration of neuromuscular function following soman and VX poisoning in spinal cord-skeletal muscle cocultures. AB - Aside from nerve agents, various highly toxic pesticides belong to the group of organophosphorus (OP) compounds, thereby causing a large number of intoxications every year. Unfortunately, there are still shortcomings in the current treatment for OP poisoning and research on novel therapeutic options is restricted in several aspects. In this study we investigated the suitability of organotypic cocultures for pharmacological in vitro studies involving OP compounds. These slice cultures are derived from murine spinal cord and muscle tissue forming functional neuromuscular synapses, which trigger spontaneous contractions of muscle fibers. Using video microscopy to quantify muscle activity, we assessed the viability of cocultures after exposure to soman and VX, and the associated loss and recovery of neuromuscular function. Antidotal treatment was not provided. The application of nerve agents led to an almost complete loss of muscle activity. However, cell cultures regained equivalent muscular function to the control situation three and seven days after intoxication. In summary, the tested in vitro system could be a promising tool for the investigation of long term effects and therapeutic options for OP poisoning. PMID- 26256037 TI - Application of lipid peroxidation products as biomarkers for flutamide-induced oxidative stress in vitro. AB - The early identification of hepatotoxicity is a fundamental goal of preclinical safety studies in drug discovery and early development. Sensitive biomarkers warrant the determination of potential underlying mechanisms that help characterizing a disruption of physiological conditions prior to cell death. This study shows the potential of different lipid peroxidation products, namely isoprostanes and hydroxynonenal (HNE) derivatives, to serve as early safety biomarkers of hepatotoxicity caused by oxidative stress as underlying mechanism. The hepatotoxic drug flutamide was used as model compound in primary hepatocytes. Incubation conditions were optimized by the addition of hydrogen peroxide generating substrates enhancing the cellular response upon oxidative stress. A time and dose dependent response of different isoprostanes and prostaglandins (15R-prostaglandin D2, prostaglandin E2, 13,14-dihydro-15-keto prostaglandin E2 and 5-iso prostaglandin F2alpha-VI) became manifest after 6 and 24h of treatment in 3.8- to 17.4-fold increased concentrations where no overt hepatocellular damage was observed. For HNE-mercapturic acid and its metabolite dihydroxynonene mercapturic acid a similar response was evident with a 20- and 10-fold increase from control after 24 h of treatment, respectively. These data indicate that lipid peroxidation products as markers of reactive oxygen species are more sensitive than conventional cytotoxicity markers for an early detection of drug induced liver injury. PMID- 26256038 TI - Probing the Role of Zr Addition versus Textural Properties in Enhancement of CO2 Adsorption Performance in Silica/PEI Composite Sorbents. AB - Polymeric amines such as poly(ethylenimine) (PEI) supported on mesoporous oxides are promising candidate adsorbents for CO2 capture processes. An important aspect to the design and optimization of these materials is a fundamental understanding of how the properties of the oxide support such as pore structure, particle morphology, and surface properties affect the efficiency of the guest polymer in its interactions with CO2. Previously, the efficiency of impregnated PEI to adsorb CO2 was shown to increase upon the addition of Zr as a surface modifier in SBA-15. However, the efficacy of this method to tune the adsorption performance has not been explored in materials of differing textural and morphological nature. Here, these issues are directly addressed via the preparation of an array of SBA-15 support materials with varying textural and morphological properties, as well as varying content of zirconium doped into the material. Zirconium is incorporated into the SBA-15 either during the synthesis of the SBA-15, or postsynthetically via deposition of Zr species onto pure-silica SBA-15. The method of Zr incorporation alters the textural and morphological properties of the parent SBA-15 in different ways. Importantly, the CO2 capacity of SBA-15 impregnated with PEI increases by a maximum of ~60% with the quantity of doped Zr for a "standard" SBA-15 containing significant microporosity, while no increase in the CO2 capacity is observed upon Zr incorporation for an SBA-15 with reduced microporosity and a larger pore size, pore volume, and particle size. Finally, adsorbents supported on SBA-15 with controlled particle morphology show only modest increases in CO2 capacity upon inclusion of Zr to the silica framework. The data demonstrate that the textural and morphological properties of the support have a more significant impact on the ability of PEI to capture CO2 than the support surface composition. PMID- 26256039 TI - Soft X-ray absorption spectroscopy of Ar2 and ArNe dimers and small Ar clusters. AB - The X-ray absorption spectra (XAS) of Ar2 and ArNe dimers and small Ar clusters in the L2,3 region (244-252 eV) of the Ar atom have been recorded using synchrotron light and a combination of coincidence methods and kinetic energy discrimination of energetic ions. The absorption peaks in the spectra of the dimers and clusters were found to be shifted and broadened relative to the peaks in the spectrum of the Ar atom. In order to unambiguously relate these chemical shifts to the electronic structure of the core excited states in dimers, we performed ab initio calculations of the XAS spectra. Implications of the results for the use of XAS as a structure determination method in large rare gas clusters are discussed. PMID- 26256040 TI - Vocal and visual stimulation, congruence and lateralization affect brain oscillations in interspecies emotional positive and negative interactions. AB - The present research explored the effect of cross-modal integration of emotional cues (auditory and visual (AV)) compared with only visual (V) emotional cues in observing interspecies interactions. The brain activity was monitored when subjects processed AV and V situations, which represented an emotional (positive or negative), interspecies (human-animal) interaction. Congruence (emotionally congruous or incongruous visual and auditory patterns) was also modulated. electroencephalography brain oscillations (from delta to beta) were analyzed and the cortical source localization (by standardized Low Resolution Brain Electromagnetic Tomography) was applied to the data. Frequency band (mainly low frequency delta and theta) showed a significant brain activity increasing in response to negative compared to positive interactions within the right hemisphere. Moreover, differences were found based on stimulation type, with an increased effect for AV compared with V. Finally, delta band supported a lateralized right dorsolateral prefrontal cortex (DLPFC) activity in response to negative and incongruous interspecies interactions, mainly for AV. The contribution of cross-modality, congruence (incongruous patterns), and lateralization (right DLPFC) in response to interspecies emotional interactions was discussed at light of a "negative lateralized effect." PMID- 26256041 TI - Fish Oil Supplementation does not Reduce Risks of Gestational Diabetes Mellitus, Pregnancy-Induced Hypertension, or Pre-Eclampsia: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: The effects of gestational supplementation with fish oil on risks for gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), and pre-eclampsia (PE) have not been confirmed. In this study, a meta-analysis was performed to evaluate the effect of fish oil supplementation on these gestational complications. MATERIAL AND METHODS: Randomized controlled human trials that investigated the effects of fish oil supplementation in pregnant women were identified by a systematic search of Medline, Embase, and Cochrane's Library, and references of related reviews and studies up to December 2014. Relative risks (RRs) for GDM, PIH, and PE were the outcomes of interest. Fixed-effects or random effects models were applied according to the heterogeneity. RESULTS: Thirteen comparisons from 11 published articles, including more than 5000 participants, were included. The results showed that fish oil supplementation was not associated with reduced risks for GDM (RR=1.06, 95% confidence interval [CI]: 0.85-1.32, p=0.60), PIH (RR=1.03, 95% CI: 0.89-1.20, p=0.66), or PE (RR=0.93, 95% CI: 0.74-1.16, p=0.51). No statistically significant heterogeneity was detected for the comparison of each outcome. The effects of fish oil on these gestational complications were consistent between women with low-risk and high-risk pregnancies. CONCLUSIONS: Gestational supplementation with fish oil during the second or third trimester of pregnancy is not associated with reduced risks for GDM, PIH, or PE. Other possible benefits of fish oil supplementation during pregnancy warrant further evaluation. PMID- 26256042 TI - Soldering of Carbon Materials Using Transition Metal Rich Alloys. AB - Joining of carbon materials via soldering has not been possible up to now due to lack of wetting of carbons by metals at standard soldering temperatures. This issue has been a severely restricting factor for many potential electrical/electronic and mechanical applications of nanostructured and conventional carbon materials. Here we demonstrate the formation of alloys that enable soldering of these structures. By addition of several percent (2.5-5%) of transition metal such as chromium or nickel to a standard lead-free soldering tin based alloy we obtained a solder that can be applied using a commercial soldering iron at typical soldering temperatures of approximately 350 degrees C and at ambient conditions. The use of this solder enables the formation of mechanically strong and electrically conductive joints between carbon materials and, when supported by a simple two-step technique, can successfully bond carbon structures to any metal terminal. It has been shown using optical and scanning electron microscope images as well as X-ray diffraction patterns and energy dispersive X ray mapping that the successful formation of carbon-solder bonds is possible, first, thanks to the uniform nonreactive dispersion of transition metals in the tin-based matrix. Further, during the soldering process, these free elements diffuse into the carbon-alloy border with no formation of brazing-like carbides, which would damage the surface of the carbon materials. PMID- 26256043 TI - Potential impact of species and livestock density on the epidemic size and effectiveness of control measures for foot-and-mouth disease in Japan. AB - The characteristics of a livestock area, including farm density and animal species, influence the spread of foot-and-mouth disease (FMD). In this study, the impact of livestock area on FMD epidemics was examined using an FMD transmission model. For this simulation, three major livestock areas were selected: the 2010 FMD epidemic area in Japan as the baseline area (BS), a cattle and pig mixed production area (CP) and a cattle production area (C). Simulation results demonstrated that under the 24-hr culling policy, only 12% of epidemics among 1,000 simulations were abated within 100 days in the CP area, whereas 90% of the epidemics ceased in the BS area. In the C area, all epidemics were successfully contained within 100 days. Evaluation of additional control measures in the CP area showed that the 0.5-km pre-emptive culling, even when only targeting pig farms, raised the potential for successful containment to 94%. A 10-km vaccination on day 7 or 14 after initial detection was also effective in halting the epidemics (80%), but accompanied a large number of culled or vaccinated farms. The combined strategy of 10-km vaccination and 0.5-km pre-emptive culling targeting pig farms succeeded in containing all epidemics within 100 days. The present study suggests the importance of preparedness for the 24-hr culling policy and additional control measures when an FMD outbreak occurs in a densely populated area. Considering the characteristics of the livestock area is important in planning FMD control strategies. PMID- 26256044 TI - Prevalence and phylogenetic analysis of canine kobuviruses in diarrhoetic dogs in northeast China. AB - Canine kobuviruses (CaKVs) are newly recognized picornaviruses that have been recently detected in dogs in the U.S.A., Italy, U.K., the Republic of Korea and Tanzania. To trace the evolution of CaKV strains, a total of 201 fecal samples from rectal swabs of diarrheic dogs, which were obtained from May 2014 to April 2015 in northeast China, were detected by reverse transcription-PCR targeting a partial (504 bp) fragment of the 3D gene. Furthermore, a phylogenetic analysis of the CaKV strains identified in northeast China was conducted based on the partial 3D gene sequence. The results indicated that 36 fecal samples (17.91%, 36/201) were positive for CaKV, in which the co-infection rates of canine coronavirus, canine parvovirus-2 and canine bocavirus were 58.33%, 41.67%, and 11.11%, respectively. Sequence comparison of the partial 3D gene revealed nucleotide homologies of 94.4-100%, 95.6-98.6%, 94.3-97.6%, 94.4-96.3% and 93.3-95.1% within the 36 Chinese CaKV strains, and between the 36 Chinese CaKV strains and four CaKV reference strains from South Korea, Italy, U.S.A. and Tanzania, respectively. A phylogenetic tree revealed that the 36 Chinese CaKV strains formed one specific CaKV lineage with CaKVs that have recently been identified in other countries. The 36 Chinese CaKV strains were closely related to CaKV reference strains from Asia and Europe, but differed genetically from CaKV reference strains from North America and Africa. This study provides evidence that CaKVs circulate in diarrhoetic dogs in China and that they exhibit substantial genetic diversity and high co-infection rates with other enteric viruses. PMID- 26256045 TI - In vivo and in vitro effect of hepatocarcinoma lymph node metastasis by upregulation of Annexin A7 and relevant mechanisms. AB - We unveiled the association of Annexin A7 with vascular endothelial growth factor C (VEGF-C) and the effect of upregulation of Annexin A7 in Hca-F and Hca-P cells on inhibiting hepatocarcinoma (HCC) lymph node metastasis (LNM) in vitro and in vivo. A total of 200 inbred 615 mice were randomly divided into four equal groups inoculated with Hca-F, Hca-P, FAnxa7-upregulated, and PAnxa7-upregulated cells, respectively. The primary tumor, popliteal, inguinal, and iliac lymph nodes were prepared for immunohistochemical (IHC) staining, real-time quantitative polymerase chain reaction (qRT-PCR) analysis, Western blot, and hematoxylin-eosin (H&E) staining. There was over 50 % increase both in the number of FAnxa7 upregulated and PAnxa7-upregulated cells migrated through the filter compared to their controls (FAnxa7-control, Hca-F and PAnxa7-control, Hca-P). However, no significant differences were noted in invasion ability between them (all P > 0.05). Tumor lymph vessels were significantly reduced in FAnxa7-upregulated and PAnxa7-upregulated tumors when compared with Hca-F and Hca-P tumors (all P < 0.05). Blood vessel density did not differ significantly between FAnxa7 upregulated and PAnxa7-upregulated tumors and Hca-F and Hca-P tumors. Enzyme linked immunosorbent assay (ELISA) for VEGF-C showed that upregulating Annexin A7 decreased VEGF-C secretion in FAnxa7-upregulated and PAnxa7-upregulated cells (P < 0.05). The IHC staining result showed that the level of serum Annexin A7 was found to be statistically higher in all experimental groups than that in the control group (P < 0.05). The present results indicated that alterations in serum Annexin A7 expression may be of prognostic relevance in HCC lymphatic metastasis. PMID- 26256047 TI - S-maltoheptaose targets syndecan-bound effectors to reduce smoking-related neutrophilic inflammation. AB - Cigarette smoke induces injury and neutrophilic inflammation in the airways of smokers. The stability and activity of inflammatory effectors, IL8 and neutrophil elastase (NE), can be prolonged by binding to airway heparan sulfate (HS)/syndecan-1, posing risk for developing chronic obstructive pulmonary disease(COPD). We hypothesize that antagonizing HS/syndecan-1 binding of the inflammatory effectors could reduce smoking-related neutrophil-mediated airway inflammation. Analysis of bronchoalveolar lavage fluid(BALF) of COPD patients found both total and unopposed NE levels to be significantly higher among smokers with COPD than non-COPD subjects. Similar NE burden was observed in smoke-exposed rats compared to sham air controls. We chose sulfated-maltoheptaose(SM), a heparin-mimetic, to antagonize HS/sydecan-1 binding of the inflammatory mediators in airway fluids and lung tissues of the smoke-exposed rat model. Airway treatment with SM resulted in displacement of CINC-1 and NE from complexation with bronchio-epithelial HS/syndecan-1, dissipating the chemokine gradient for neutrophil flux across to the bronchial lumen. Following SM displacement of NE from shed HS/syndecan-1 in bronchial fluids, NE became accessible to inhibition by alpha1-antitrypsin endogenous in test samples. The antagonistic actions of SM against syndecan-1 binding of NE and CINC-1 in smoke-exposed airways suggest new therapeutic opportunities for modulating airway inflammation in smokers with SM delivery. PMID- 26256048 TI - Accuracy of preoperative MRI in the diagnosis of disorders of the long head of the biceps tendon. AB - OBJETIVES: To evaluate the accuracy of magnetic resonance imaging (MRI) in the detection of disorders of the long head of the biceps tendon (LHBT). The secondary objective was to investigate predictive factors for tears and instability. METHODS: This retrospective case series involved patients undergoing shoulder arthroscopy due to rotator cuff injury. MRI was performed in a 1.5T scanner and was evaluated by a musculoskeletal radiologist. The findings were compared with those of arthroscopic inspection. RESULTS: A total of 90 shoulders were analyzed. Regarding tears, there was 67% sensitivity and 98% specificity. Regarding instabilities, the values were 53% and 72%, respectively. Tears and fatty degeneration of the infraspinatus are predictive factors for tears of the LHBT. Tears of the subscapularis and infraspinatus, retraction of the supraspinatus and infraspinatus equal to or greater than 30mm, and fatty degeneration of the infraspinatus and subscapularis are predictive factors for instability. CONCLUSION: Compared to arthroscopy, the shoulder MRI has a sensitivity of 67% and a specificity of 98% for the detection of complete tears of the LHBT. For instability, the values are 53% and 72%, respectively. PMID- 26256049 TI - Comparison of MR imaging features of solid pseudopapillary neoplasm of pancreas between male and female patients. AB - PURPOSE: To evaluate MR imaging features of solid pseudopapillary neoplasms (SPN) in male patients and to compare them with the MR imaging features in female patients. MATERIALS AND METHODS: Fifty patients who were histologically confirmed as SPN (M:F=8:42, mean age=36.4 years) with preoperative MRI were included. The following imaging features were reviewed: size, location, shape, margin, encapsulation, solid-cystic ratio, pancreatic duct dilatation, parenchymal atrophy, T1 signal intensity, T2 signal intensity, and morphological and dynamic pattern of enhancement. The statistical differences between male and female patients were analyzed. RESULTS: The average age of male patients (50.8 +/- 4.1 years) was significantly higher (p<0.01) than female patients (33.7 +/- 2.0 years). The shape of SPN in male patients was predominantly lobulated (n=6/8, 75.0%) compared to female patients, in whom oval shaped SPN was most prevalent (n=26/42, 61.91%) (P=0.02). SPN in male patients contained less cystic component (solid, n=4/8, 50.0%; mainly solid, n=4/8, 50.0%) while cystic (n=5/42, 11.90%) or mainly cystic (n=13/42, 30.95%) lesions were significantly more prevalent in female patients (P=0.03). The majority of SPNs in both groups showed progressive heterogeneous enhancement pattern. Other MR imaging features showed no significant differences between the male and female patients. CONCLUSION: On MRI, SPN in male patients appeared as mainly solid mass with a lobulating contour and heterogeneous progressive enhancement occurring at an older age than female patients. Recognition of imaging features of SPN in male patients compared to typical SPN in female patients should assist in correct differentiation of SPN from other pancreatic tumors. PMID- 26256050 TI - Novel association of the R230C variant of the ABCA1 gene with high triglyceride levels and low high-density lipoprotein cholesterol levels in Mexican school-age children with high prevalence of obesity. AB - BACKGROUND AND AIMS: Metabolic syndrome (MetS) is a disorder that includes a cluster of several risk factors for the development of type 2 diabetes and cardiovascular disease. The R230C variant of the ABCA1 gene has been associated with low HDL-cholesterol in several studies, but its association with MetS in children remains to be determined. The aim of this study was to analyze the association of the R230C variant with MetS and other metabolic traits in school aged Mexican children. METHODS: The study was performed in seven urban primary schools in the State of Mexico. Four hundred thirty-two Mexican school-age children 6-13 years old were recruited. MetS was identified using the International Diabetes Federation definition. The R230C variant of the ABCA1 gene was genotyped to seek associations with MetS and other metabolic traits. RESULTS: The prevalence of MetS was 29% in children aged 10-13 years. The R230C variant was not associated with MetS (OR = 1.65; p = 0.139). Furthermore, in the whole population, the R230C variant was associated with low HDL-cholesterol levels (beta coefficient = -3.28, p <0.001). Interestingly, in the total population we found a novel association of this variant with high triglyceride levels (beta coefficient = 14.34; p = 0.027). CONCLUSIONS: We found a new association of the R230C variant of the ABCA1 gene with high triglyceride levels. Our findings also replicate the association of this variant with low HDL-cholesterol levels in Mexican school-age children. PMID- 26256051 TI - Preservation of epoxy groups on surfaces in the covalent attachment of butadiene monoxide on Si(111)-(7*7): the effect of a vinyl substituent. AB - Adsorption of butadiene monoxide on Si(111)-(7*7) has been scrutinized by high resolution electron energy loss spectroscopy (HREELS), scanning tunneling microscopy (STM) and density functional theory (DFT) calculations. The experimental results indicate that surface reaction occurs through a [2+2]-like cycloaddition, which is further supported by the DFT studies. PMID- 26256052 TI - Thermo-responsive behavior of borinic acid polymers: experimental and molecular dynamics studies. AB - The thermo-responsive properties of borinic acid polymers were investigated by experimental and molecular dynamics simulation studies. The homopolymer poly(styrylphenyl(tri-iso-propylphenyl)borinic acid) (PBA) exhibits an upper critical solution temperature (UCST) in polar organic solvents that is tunable over a wide temperature range by addition of small amounts of H2O. The UCST of a 1 mg mL(-1) PBA solution in DMSO can be adjusted from 20 to 100 degrees C by varying the H2O content from ~0-2.5%, in DMF from 0 to 100 degrees C (~3-17% H2O content), and in THF from 0 to 60 degrees C (~4-19% H2O). The UCST increases almost linearly from the freezing point of the solvent with higher freezing point to the boiling point of the solvent with the lower boiling point. The mechanistic aspects of this process were investigated by molecular dynamics simulations. The latter indicate rapid and strong hydrogen-bond formation between BOH moieties and H2O molecules, which serve as crosslinkers to form an insoluble network. Our results suggest that borinic acid-containing polymers are promising as new "smart" materials, which display thermo-responsive properties that are tunable over a wide temperature range. PMID- 26256053 TI - The N-Terminal T-T Motif of a Third-Generation HIV-1 Fusion Inhibitor Is Not Required for Binding Affinity and Antiviral Activity. AB - The highlighted next-generation HIV-1 fusion inhibitor peptide 1 is capped by two threonines. Here, we generated peptide 2 by deleting the T-T motif and compared their structural and antiviral properties. Significantly, two peptides showed similar helical and oligomeric states in solution, comparable binding affinities to the target, and no significant difference to inhibit HIV-1 fusion and infection. Also, the T-T motif was not associated with peptide 1 resistant mutations and its deletion did not affect peptide 1 against enfuvirtide-resistant HIV-1 mutants. The redundancy of the T-T motif was further verified by the model peptide C34 and short peptide inhibitors that mainly target the gp41 pocket, suggesting that the N-terminal T-T motif of peptide 1 could be removed or modified toward the development of new anti-HIV-1 drugs. Consistently, our data have verified that the M-T hook structure rather than the T-T motif is an efficient strategy for short peptide fusion inhibitors. PMID- 26256054 TI - Geometric ergodicity of a hybrid sampler for Bayesian inference of phylogenetic branch lengths. AB - One of the fundamental goals in phylogenetics is to make inferences about the evolutionary pattern among a group of individuals, such as genes or species, using present-day genetic material. This pattern is represented by a phylogenetic tree, and as computational methods have caught up to the statistical theory, Bayesian methods of making inferences about phylogenetic trees have become increasingly popular. Bayesian inference of phylogenetic trees requires sampling from intractable probability distributions. Common methods of sampling from these distributions include Markov chain Monte Carlo (MCMC) and Sequential Monte Carlo (SMC) methods, and one way that both of these methods can proceed is by first simulating a tree topology and then taking a sample from the posterior distribution of the branch lengths given the tree topology and the data set. In many MCMC methods, it is difficult to verify that the underlying Markov chain is geometrically ergodic, and thus, it is necessary to rely on output-based convergence diagnostics in order to assess convergence on an ad hoc basis. These diagnostics suffer from several important limitations, so in an effort to circumvent these limitations, this work establishes geometric convergence for a particular Markov chain that is used to sample branch lengths under a fairly general class of nucleotide substitution models and provides a numerical method for estimating the time this Markov chain takes to converge. PMID- 26256055 TI - Levels of arsenic pollution in daily foodstuffs and soils and its associated human health risk in a town in Jiangsu Province, China. AB - The development of industries in rural areas can aggravate the arsenic (As) contamination of the local environment, which may pose unacceptable health risks to the local residents. This paper estimated the health risk posed by inorganic As (iAs) to residents via ingestion of soil, skin contact with soil and consumption of foodstuffs in a typical rural- industrial developed town in southern Jiangsu, China. The average concentrations of total As in soil, rice, fish, shrimp and crab, pork and eggs, vegetables and fruits were detected to be 10.367, 0.104 mg/kg dw (dry weight), 0.050, 0.415, 0.011, 0.013 and 0.017 mg/kg fw (fresh weight), respectively. All of these values are below the maximum allowable concentration in food and soil in China. The deterministic estimation results showed that the hazard quotient (HQ) and excess lifetime cancer risk (R) were 1.28 (0.78-2.31) and 2.38 * 10(-4) (2.71 * 10(-5)-5.09 * 10(-4)) for all age groups, respectively. Males in the age range of 2-29 years and females in the age range of 2-13 years and 18-29 years exhibited non-carcinogenic risk (HQ>1). Carcinogenic risk exceeded the acceptable level of 1 * 10(-)(5) for both genders at all ages. Furthermore, this risk rose with age. The probabilistic estimation results showed that about 28% of residents had non-carcinogenic risk due to over ingestion of iAs. The R value of 90% of residents was greater than 10(-)(5). The sensitivity analysis indicated that the cancer slope factor (SF), the ingestion rates of rice and the iAs concentration in rice were the most relevant variables affecting the assessment outcome. Based on these results, it is recommended that residents reduce their consumption of rice, though it should be noted that the assessment outcome has uncertainty due to estimating iAs from foodstuffs and not considering the bioaccessibility of iAs in foodstuffs. Nevertheless, measures like reducing industrial As emissions, forbidding the use of pesticides, fertilizers and sludge which contain As and optimizing water management in rice paddy fields should be taken to mitigate the risks. PMID- 26256056 TI - Gender differences in responses in Gammarus pulex exposed to BDE-47: A gel-free proteomic approach. AB - Very few ecotoxicological studies have considered differences in toxic effects on male and female organisms. Here, we investigated protein expression differences in caeca of Gammarus pulex males and females under control conditions (unexposed) and after 96h exposure to BDE-47. Using gel-free proteomic analysis, we have identified 45 proteins, of which 25 were significantly differently expressed according to sex and/or BDE-47 exposure. These proteins were involved in several biological processes such as energy metabolism, chaperone proteins, or transcription/translation. In unexposed amphipods, 11 proteins were significantly over-expressed in females, and 6 proteins were over-expressed in males. Under BDE 47 stress, 7 proteins were differently impacted according to sex. For example, catalase was over-expressed in exposed females and under-expressed in exposed males, as compared to respective controls. Conversely, proteins involved in energy metabolism were up-regulated in males and down-regulated in females. Our proteomic study showed differences in responses of males and females to BDE-47 exposure, emphasizing that sex is a confounding factor in ecotoxicological assessment. However, due to the limited information existing in databases on Gammarids, it was difficult to define a BDE-47 mechanism of action. The gel-free proteomic seems to be a promising method to develop in future ecotoxicological studies and thus, to improve our understanding of the mechanism of action of xenobiotics. PMID- 26256057 TI - Hydrolysis of the RNA model substrate catalyzed by a binuclear Zr(IV)-substituted Keggin polyoxometalate. AB - The reactivity and solution behaviour of the binuclear Zr(IV)-substituted Keggin polyoxometalate (Et2NH2)8[{alpha-PW11O39Zr(MU-OH)(H2O)}2].7H2O (ZrK 2 : 2) towards phosphoester bond hydrolysis of the RNA model substrate 2-hydroxypropyl-4 nitrophenyl phosphate (HPNP) was investigated at different reaction conditions (pD, temperature, concentration, and ionic strength). The hydrolysis of the phosphoester bond of HPNP, followed by means of (1)H NMR spectroscopy, proceeded with an observed rate constant, kobs = 11.5(+/-0.42) * 10(-5) s(-1) at pD 6.4 and 50 degrees C, representing a 530-fold rate enhancement in comparison with the spontaneous hydrolysis of HPNP. (1)H and (31)P NMR spectra indicate that at these reaction conditions the only products of hydrolysis are p-nitrophenol and the corresponding cyclic phosphate ester. The pD dependence of kobs exhibits a bell shaped profile, with the fastest rate observed at pD 6.4. The formation constant (Kf = 455 M(-1)) and catalytic rate constant (kc = 42 * 10(-5) s(-1)) for the HPNP-ZrK 2 : 2 complex, activation energy (Ea) of 63.35 +/- 1.82 kJ mol(-1), enthalpy of activation (DeltaH(?)) of 60.60 +/- 2.09 kJ mol(-1), entropy of activation (DeltaS(?)) of -133.70 +/- 6.13 J mol(-1) K(-1), and Gibbs activation energy (DeltaG(?)) of 102.05 +/- 0.13 kJ mol(-1) at 37 degrees C were calculated from kinetic experiments. Binding between ZrK 2 : 2 and the P-O bond of HPNP was evidenced by the change in the (31)P chemical shift and signal line-broadening of the (31)P atom in HPNP upon addition of ZrK 2 : 2. Based on (31)P NMR experiments and isotope effect studies, a mechanism for HPNP hydrolysis in the presence of ZrK 2 : 2 was proposed. PMID- 26256058 TI - Expression, fermentation and purification of a predicted intrinsically disordered region of the transcription factor, NFAT5. AB - Hypertonicity stimulates Nuclear Factor of Activated T-cells 5 (NFAT5) nuclear localization and transactivating activity. Many transcription factors are known to contain intrinsically disordered regions (IDRs) which become more structured with local environmental changes such as osmolality, temperature and tonicity. The transactivating domain of NFAT5 is predicted to be intrinsically disordered under normal tonicity, and under high NaCl, the activity of this domain is increased. To study the binding of co-regulatory proteins at IDRs a cDNA construct expressing the NFAT5 TAD was created and transformed into Escherichia coli cells. Transformed E. coli cells were mass produced by fermentation and extracted by cell lysis to release the NFAT5 TAD. The NFAT5 TAD was subsequently purified using a His-tag column, cation exchange chromatography as well as hydrophobic interaction chromatography and then characterized by mass spectrometry (MS). PMID- 26256059 TI - Enhanced biosynthetically directed fractional carbon-13 enrichment of proteins for backbone NMR assignments. AB - Routes to carbon-13 enrichment of bacterially expressed proteins include achieving uniform or positionally selective (e.g. ILV-Me, or (13)C', etc.) enrichment. We consider the potential for biosynthetically directed fractional enrichment (e.g. carbon-13 incorporation in the protein less than 100%) for performing routine n-(D)dimensional NMR spectroscopy of proteins. First, we demonstrate an approach to fractional isotope addition where the initial growth media containing natural abundance glucose is replenished at induction with a small amount (e.g. 10%(w/w)u-(13)C-glucose) of enriched nutrient. The approach considered here is to add 10% (e.g. 200mg for a 2g/L culture) u-(13)C-glucose at the induction time (OD600=0.8), resulting in a protein with enhanced (13)C incorporation that gives almost the same NMR signal levels as an exact 20% (13)C sample. Second, whereas fractional enrichment is used for obtaining stereospecific methyl assignments, we find that (13)C incorporation levels no greater than 20%(w/w) yield (13)C and (13)C-(13)C spin pair incorporation sufficient to conduct typical 3D-bioNMR backbone experiments on moderate instrumentation (600 MHz, RT probe). Typical 3D-bioNMR experiments of a fractionally enriched protein yield expected backbone connectivities, and did not show amino acid biases in this work, with one exception. When adding 10% u-(13)C glucose to expression media at induction, there is poor preservation of (13)Calpha-(13)Cbeta spin pairs in the amino acids ILV, leading to the absence of Cbeta signals in HNCACB spectra for ILV, a potentially useful editing effect. Enhanced fractional carbon-13 enrichment provides lower-cost routes to high throughput protein NMR studies, and makes modern protein NMR more cost accessible. PMID- 26256060 TI - Expression, purification and characterization of heterotrimeric forms of sTRAIL using a polycistronic expression vector. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is capable of selectively inducing apoptosis of cancer cells, is a potential targeted drug for cancer therapy. The TRAIL protein induces apoptosis only in trimeric form. However, the recombinant soluble TRAIL (sTRAIL) trimer has low stability and a short half-life, which is a major obstacle for its advancement into clinical trials. Moreover, a percentage of engineered sTRAIL proteins are produced as dimers which may be toxic to normal human hepatocytes. In this study, we inserted three copies of the same subunit fragment of sTRAIL with a His tag into a polycistronic expression vector (pST39) to explore whether it would increase the proportion of trimers. We also constructed a heterozygous vector containing three subunit fragments of sTRAIL each with a different tag (His, HA, and Cmyc). Hybrid sTRAIL proteins (P-dTags) mainly as heterologous trimers were obtained by elution with a low concentration of imidazole based on different binding affinities of His with a nickel column. Functional analysis demonstrated that heterotrimeric forms of sTRAIL showed more stable activity compared to the P-3H at 4 degrees C but not at 37 degrees C without alteration in the native killing capacity. In addition, the heterologous trimers showed decreased toxicity to hepatocytes. These results suggest that the polycistronic expression system may be useful for expression of recombinant sTRAIL and improving its potential in cancer therapeutic applications. PMID- 26256061 TI - Expression, purification and initial characterization of human meprin beta from Pichia pastoris. AB - Human meprin beta (h-meprin beta), a single-zinc metalloendoprotease of the astacin family, is potentially involved in disorders such as fibrosis and Alzheimer's disease. Here, we describe the expression of the enzyme in the yeast Pichia pastoris. The N-terminal signal sequence was replaced by the alpha-leader of Saccharomyces, enabling efficient secretion of the mature enzyme, harboring either an N-terminal or C-terminal His-tag. The purification by affinity and hydrophobic interaction chromatography resulted in isolation of 58.4 mg/l of homogenous human pro-meprin beta from fermentation broth. The activated enzyme isolated from yeast (yh-meprin beta) displayed virtually identical enzymatic activity as h-meprin from a mammalian cell line. Furthermore, the yh-meprin beta was N-glycosylated and secreted as a dimer with a molecular mass of 148 kDa. Endoglycosidase H treatment generated a protein with a molecular mass of 133 kDa, but essentially unchanged kinetic parameters. Thus, our data suggest that human meprin beta expressed in P. pastoris displays virtually identical parameters as meprin from other sources. The high yield of protein expression, the ease of purification and the deglycosylation in its native state appear to favor further studies aiming at inhibitor screening and structure-based inhibitor refinement. PMID- 26256062 TI - Expression, purification and characterization of a functional, recombinant, cold active lipase (LipA) from psychrotrophic Yersinia enterocolitica. AB - A novel cold-active lipase gene encoding 294 amino acid residues was obtained from the Yersinia enterocolitica strain KM1. Sequence alignment and phylogenetic analysis revealed that this novel lipase is a new member of the bacterial lipase family I.1. The lipase shares the conserved GXSXG motif and catalytic triad Ser85 Asp239-His261. The recombinant protein LipA was solubly and heterogeneously expressed in Escherichia coli, purified by Ni-affinity chromatography, and then characterized. LipA was active over a broad range spanning 15-60 degrees C with an optimum activity at 25 degrees C and across a wide pH range from 5.0 to 11.0 with an optimum activity at pH 7.5. The molecular weight was estimated to be 34.2 KDa. The lipase could be activated by Mg(2+) and a low concentration (10%) of ethanol, dimethyl sulfoxide, methanol and acetonitrile, whereas it was strongly inhibited by Zn(2+), Cu(2+) and Mn(2+). This cold-active lipase may be a good candidate for detergents and biocatalysts at low temperature. PMID- 26256063 TI - Update on prolactinomas. Part 1: Clinical manifestations and diagnostic challenges. AB - The authors provide an update on the clinical manifestations and diagnostic challenges of prolactinomas. Prolactinomas are the most common pituitary adenoma seen in clinical practice. Secondary causes of hyperprolactinemia should be ruled out by assessment of the clinical history, including current medications, physical examination, pregnancy test, routine biochemical analysis with a thyroid function test, and neuroimaging, before a confirmatory diagnosis of prolactinoma is made. Prolactinomas are associated with endocrine dysfunction, affecting gonadal function and causing neurological deficits due to mass effect. The progress in elucidating the pathogenesis of prolactinomas and advances in diagnostic methods, including more sensitive diagnostic hormone assays and neuroimaging, have enriched the current diagnostic approach and management. Making the correct diagnosis is crucial to implementing the appropriate therapy. Dopamine agonist therapy remains the first line of treatment for prolactinomas, as it is effective in normalizing serum prolactin levels and reducing tumor size. Surgery is typically indicated for patients who are resistant to medical therapy or intolerant of its adverse side effects, or for those experiencing progressive neurological deficits. Nevertheless, curative surgical resection as a primary mode of treatment for smaller prolactinomas has recently gained attention as an alternative to lifelong dopamine agonist treatment. PMID- 26256064 TI - Abnormal discharges from the temporal neocortex after selective amygdalohippocampectomy and seizure outcomes. AB - The present study examined the relationship between residual discharges from the temporal neocortex postoperatively and seizure outcomes, in mesial temporal lobe epilepsy (MTLE) patients with hippocampal sclerosis (HS) who were treated with selective amygdalohippocampectomy (SelAH). Abnormal discharges from the temporal neocortex are often observed and remain postoperatively. However, no recommendations have been made regarding whether additional procedures to eliminate these discharges should be performed for seizure relief. We retrospectively analyzed 28 patients with unilateral MTLE and HS, who underwent transsylvian SelAH. The mean follow-up period was 29 months (range: 16-49). In the pre- and postresection states, electrocorticography (ECoG) was recorded for the temporal base and lateral temporal cortex. The extent of resection was not influenced by the results of the preresection ECoG. Even if residual abnormal discharges were identified on the temporal neocortex, no additional procedures were undertaken to eliminate these abnormalities. The postresection spike counts were examined to determine the postresective alterations in spike count, and the frequency of residual spike count. The seizure outcomes were evaluated in all patients using the Engel classification. The postoperative seizure-free rate was 92.9%. No significant correlations were seen between a decreasing spike count and seizure outcomes (p=0.9259), or between the absence of residual spikes and seizure outcomes (p=1.000). Residual spikes at the temporal neocortex do not appear to influence seizure outcomes. Only mesial temporal structures should be removed, and additional procedures to eliminate residual spikes are not required. PMID- 26256065 TI - Antidepressant medication can improve hypertension in elderly patients with depression. AB - We explored the influence of antidepressant therapy on blood pressure and quality of life in elderly patients with hypertension. Depression occurs at a higher rate in patients with hypertension than in the normal population. It has been reported that depressive symptoms lead to poorer hypertension control, resulting in the development of complications. We conducted a randomized, parallel group study. A total of 70 elderly patients with hypertension in the period of August 2008 to March 2011 were divided into two groups based on their antihypertensive therapy, a control group (amlodipine, 5 mg daily; n=35) and a therapy group (amlodipine, 5mg daily; citalopram, 20 mg daily; n=35). We compared 24 hour, daytime, and nighttime measurements of systolic and diastolic blood pressure, in addition to quality of life, assessed using the Hamilton rating scale for depression, and a 36 item Short Form quality of life questionnaire (SF-36). Both groups were followed for 3 months. At the end of 3 months, all blood pressure levels were significantly lower in the therapy group than in the control group. The other scores (with the exception of the physical function subcategory of the SF-36 quality of life scale) were significantly higher. Our study indicates that clinicians should be aware of depressive symptoms in elderly patients with hypertension, and should consider antidepressant therapy in these patients. PMID- 26256066 TI - Mechanism and surgical management of transsellar transsphenoidal encephalocele. AB - We performed a retrospective study to assess the mechanisms and surgical strategies for transsellar transsphenoid encephalocele, a rare type of basal encephalocele. Its clinical presentations include multiple endocrine disturbances, visual deficits, cerebrospinal fluid rhinorrhea and dyspnea. However, little is known about the occurrence and optimal treatment of this disease. We retrospectively reviewed six patients who were treated in our hospital from October 2003 to September 2013; five male patients and one female, with an average age of 10 years (range: 2 - 28). We collected data on their general condition, medical history, clinical features, and outcomes. An endoscopic transsphenoidal approach was used for five patients, and one refused surgery. All patients had similar imaging findings, and their pituitary gland could not be seen on MRI. Five of the patients showed gradual disease progression. The clinical symptoms were endocrine disturbance (n=6), decreased visual acuity (n=5), dyspnea (n=3) and cerebrospinal fluid rhinorrhea (n=2). Three of the patients also had a cleft palate. Two patients suffered serious symptoms of fever, tachyarrhythmia, and electrolyte disturbance postoperatively. After a long follow-up period, the symptoms remained stable or improved in all patients postoperatively, but worsened in the patient who did not have a surgical intervention. No mortalities were recorded. This disease may result from pituitary dysplasia, and the symptoms develop as the patients grow. Surgical interventions can be helpful for symptom management, the optimal treatment being a transsphenoidal approach. Those patients with milder symptoms preoperatively have a better prognosis. PMID- 26256067 TI - Cortical plasticity in patients with cerebral arteriovenous malformations. AB - The aim of this review is to ascertain the evidence for cortical plasticity in arteriovenous malformation (AVM) patients. Chronic hypoperfusion due to vascular steal from cerebral AVM can result in a translocation of eloquent neurological functions to other brain areas, a phenomenon known as cortical plasticity. We performed a systematic literature review of the studies that have evaluated cortical plasticity in AVM patients. A total of 22 studies from 1996 to 2014 were included for the analyses. The evaluation of cortical plasticity was performed prior to AVM intervention in 109 patients, and during or after AVM intervention in 18. The most commonly assessed neurological functions were motor in 85% and language in 11% of the former cohort, and motor in 78% and language, cognition, and memory each in 39% of the latter cohort. Functional MRI was the most frequently used method for evaluating cortical plasticity, and was performed in 63% of the former and 56% of the latter cohort. In conclusion, cortical plasticity appears to be influenced by both AVM pathogenesis and intervention. Given the limited evidence that is currently available for cortical plasticity in AVM patients, further studies are warranted to determine its incidence and impact on long term clinical outcomes. PMID- 26256068 TI - Management of recurrent aneurysms following endovascular therapy. AB - The aim of the current study is to describe the complication rates and clinical outcomes in patients who either underwent repeat intervention or conservative management with radiographic surveillance when presenting with aneurysmal recurrence after endovascular treatment. Since publication of the international subarachnoid aneurysm trial (ISAT), an increasing number of patients are treated with endovascular therapy. However, recurrence after endovascular therapy continues to pose a challenge, and there is minimal evidence to guide its management. We performed a retrospective review of all patients who underwent endovascular treatment of an intracranial aneurysm from January 2005 to February 2013. The patients who had an aneurysmal recurrence following the initial endovascular treatment were identified and divided into two groups: those followed with conservative management (n=24), and those who underwent reintervention (n=65). The groups were compared for complications and clinical outcomes. When a reintervention was undertaken, microsurgical clip ligation was associated with a higher rate of occlusion than additional endovascular therapy (p<0.001). When comparing conservative treatment and reintervention, there was no statistically significant difference in complications or clinical outcomes. Reintervention was more common in patients who were younger, had presented with subarachnoid hemorrhage, or had a greater degree of recurrence. We conclude that clinical outcomes and repeat subarachnoid hemorrhage are similar in patients who underwent retreatment versus those who had conservative management for their recurrent cerebral aneurysms. PMID- 26256069 TI - The designs and applications of a scanning interface with electrical signal detection on the scalp for the severely disabled. AB - This study discussed a computer-aided program development that meets the requirements of people with physical disabilities. A number of control modes, such as electrode signal recorded on the scalp and blink control, were combined with the scanning human-machine interface to improve the external input/output device. Moreover, a novel and precise algorithm, which filters noise and reduces misrecognition of the system, was proposed. A convenient assistive device can assist people with physical disabilities to meet their requirements for independent living and communication with the outside. The traditional scanning keyboard is changed, and only the phonetic notations are typed instead of characters, thus the time of tone and function selection could be saved, and the typing time could be also reduced. Barrier-free computer assistive devices and interface for people with physical disabilities in typing or speech could allow them to use a scanning keyboard to select phonetic symbols instead of Chinese characters to express their thoughts. The human-machine interface controls can obtain more reliable results as 99.8% connection success rate and 95% typing success rate. PMID- 26256070 TI - Delayed cognitive and psychiatric symptoms following methyl iodide and manganese poisoning: Potential for misdiagnosis. AB - This paper describes two patients who were exposed to toxic substances in the workplace, but for whom diagnosis proved difficult, particularly in case 2. Case 1 was exposed to methyl iodide and case 2 to manganese. Poisoning was characterised by delayed onset of symptoms following exposure and symptom progression after cessation of exposure. The clinical consequences of exposure to these substances include cerebellar and Parkinsonian symptoms followed by the development of cognitive impairment and the late appearance of psychiatric disturbances. Both cases were evaluated by physicians with little training in toxicology. Apart from abnormal liver function in case 1 and decreased power, coordination and proprioception in case 2, results of most routine medical investigations were normal. Both cases were referred for MRI brain scan and neuropsychological assessment. Abnormalities were noted on MRI but reported as being absent initially in case 1and of unknown significance in case 2. There was evidence of cognitive impairment in both and personality change in case 1 of sufficient severity to prevent both cases from returning to work and to impact on family life. There is no antidote to methyl iodide or manganese poisoning. Successful treatment requires early diagnosis and cessation of exposure, but neurotoxic syndromes are difficult to diagnose when a time lag exists between exposure and symptom onset and there is no biomarker of exposure. These syndromes may initially be confused with other neurodegenerative conditions, infectious processes, and psychiatric disorders. Clinician's lack of familiarity with the potential toxicity of environmental and industrial chemicals can lead to misdiagnosis and mismanagement, and this lack of recognition can lead to continued exposure. These cases highlight the importance of taking a detailed occupational history in patients who present with atypical neurological symptoms. PMID- 26256071 TI - Hydrocephalus in children. AB - Hydrocephalus is a common disorder of cerebral spinal fluid (CSF) physiology resulting in abnormal expansion of the cerebral ventricles. Infants commonly present with progressive macrocephaly whereas children older than 2 years generally present with signs and symptoms of intracranial hypertension. The classic understanding of hydrocephalus as the result of obstruction to bulk flow of CSF is evolving to models that incorporate dysfunctional cerebral pulsations, brain compliance, and newly characterised water-transport mechanisms. Hydrocephalus has many causes. Congenital hydrocephalus, most commonly involving aqueduct stenosis, has been linked to genes that regulate brain growth and development. Hydrocephalus can also be acquired, mostly from pathological processes that affect ventricular outflow, subarachnoid space function, or cerebral venous compliance. Treatment options include shunt and endoscopic approaches, which should be individualised to the child. The long-term outcome for children that have received treatment for hydrocephalus varies. Advances in brain imaging, technology, and understanding of the pathophysiology should ultimately lead to improved treatment of the disorder. PMID- 26256073 TI - Handwashing and community management of infections. PMID- 26256072 TI - An internet-delivered handwashing intervention to modify influenza-like illness and respiratory infection transmission (PRIMIT): a primary care randomised trial. AB - BACKGROUND: Handwashing to prevent transmission of respiratory tract infections (RTIs) has been widely advocated, especially during the H1N1 pandemic. However, the role of handwashing is debated, and no good randomised evidence exists among adults in non-deprived settings. We aimed to assess whether an internet-delivered intervention to modify handwashing would reduce the number of RTIs among adults and their household members. METHODS: We recruited individuals sharing a household by mailed invitation through general practices in England. After consent, participants were randomised online by an automated computer-generated random number programme to receive either no access or access to a bespoke automated web-based intervention that maximised handwashing intention, monitored handwashing behaviour, provided tailored feedback, reinforced helpful attitudes and norms, and addressed negative beliefs. We enrolled participants into an additional cohort (randomised to receive intervention or no intervention) to assess whether the baseline questionnaire on handwashing would affect handwashing behaviour. Participants were not masked to intervention allocation, but statistical analysis commands were constructed masked to group. The primary outcome was number of episodes of RTIs in index participants in a modified intention-to-treat population of randomly assigned participants who completed follow-up at 16 weeks. This trial is registered with the ISRCTN registry, number ISRCTN75058295. FINDINGS: Across three winters between Jan 17, 2011, and March 31, 2013, we enrolled 20,066 participants and randomly assigned them to receive intervention (n=10,040) or no intervention (n=10,026). 16,908 (84%) participants were followed up with the 16 week questionnaire (8241 index participants in intervention group and 8667 in control group). After 16 weeks, 4242 individuals (51%) in the intervention group reported one or more episodes of RTI compared with 5135 (59%) in the control group (multivariate risk ratio 0.86, 95% CI 0.83 0.89; p<0.0001). The intervention reduced transmission of RTIs (reported within 1 week of another household member) both to and from the index person. We noted a slight increase in minor self-reported skin irritation (231 [4%] of 5429 in intervention group vs 79 [1%] of 6087 in control group) and no reported serious adverse events. INTERPRETATION: In non-pandemic years, an effective internet intervention designed to increase handwashing could have an important effect in reduction of infection transmission. In view of the heightened concern during a pandemic and the likely role of the internet in access to advice, the intervention also has potential for effective implementation during a pandemic. FUNDING: Medical Research Council. PMID- 26256074 TI - Functional upregulation of the H2S/Cav3.2 channel pathway accelerates secretory function in neuroendocrine-differentiated human prostate cancer cells. AB - Neuroendocrine-differentiated prostate cancer cells may contribute to androgen independent proliferation of surrounding cells through Ca(2+)-dependent secretion of mitogenic factors. Human prostate cancer LNCaP cells, when neuroendocrine differentiated, overexpress Cav3.2 T-type Ca(2+) channels that contribute to Ca(2+)-dependent secretion. Given evidence for the acceleration of Cav3.2 activity by hydrogen sulfide (H2S), we examined the roles of the H2S/Cav3.2 pathway and then analyzed the molecular mechanisms of the Cav3.2 overexpression in neuroendocrine-differentiated LNCaP cells. LNCaP cells were differentiated by dibutyryl cyclic AMP. Protein levels and T-type Ca(2+) channel-dependent currents (T-currents) were measured by immunoblotting and whole-cell pacth-clamp technique, respectively. Spontaneous release of prostatic acid phosphatase (PAP) was monitored to evaluate secretory function. The differentiated LNCaP cells exhibited neurite outgrowth, androgen-independent proliferation and upregulation of mitogenic factors, and also showed elevation of Cav3.2 expression or T currents. Expression of cystathionine-gamma-lyase (CSE) and cystathionine-beta synthase (CBS), H2S-forming enzymes, and spontaneous secretion of PAP increased following the differentiation. The augmented T-currents were enhanced by H2S donors and suppressed by inhibitors of CSE, but not CBS. The PAP secretion was reduced by inhibition of CSE or T-type Ca(2+) channels. During differentiation, Egr-1 and REST, positive and negative transcriptional regulators for Cav3.2, were upregulated and downregulated, respectively, and Egr-1 knockdown prevented the Cav3.2 overexpression. Our data suggest that, in neuroendocrine-differentiated LNCaP cells, H2S formed by the upregulated CSE promotes the activity of the upregulated Cav3.2, leading to the elevated secretory functions. The overexpression of Cav3.2 appears to involve upregulation of Egr-1 and downregulation of REST. PMID- 26256075 TI - High affinity alpha3beta4 nicotinic acetylcholine receptor ligands AT-1001 and AT 1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice. AB - Cholinergic signaling via the nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry is involved in the rewarding effects of abused drugs such as cocaine and opioids. In mouse studies, nonselective nAChR antagonist mecamylamine blocks cocaine-induced conditioned place preference (CPP) and behavioral sensitization. Among subtype-selective nAChR antagonists, the beta2-selective antagonist dihydrobetaerythroidine and alpha7 antagonist methyllycaconitine (MLA), but not MLA alone prevent behavioral sensitization to cocaine. Since the role of the alpha3beta4 nAChR subtype in the rewarding and behavioral effects of cocaine is unknown, the present study investigated the effect of two potent and selective alpha3beta4 nAChR ligands, AT-1001 and AT-1012, on the acquisition of cocaine-induced CPP and behavioral sensitization in mice. At 5-30mg/kg, cocaine produced robust CPP, whereas behavioral sensitization of locomotor activity was only observed at the higher doses (20-30mg/kg). Pretreatment with AT-1001 (1 10mg/kg) or AT-1012 (3-10mg/kg) blocked CPP induced by 5mg/kg cocaine, but not by 30mg/kg cocaine. Lower doses of AT-1001 (0.3-1mg/kg) and AT-1012 (1-3mg/kg) did not affect the increase in locomotor activity induced by 5 or 30mg/kg cocaine. But AT-1001, at these doses, blocked locomotor sensitization induced by 30mg/kg cocaine. These results indicate that the alpha3beta4 nAChR play a role in the rewarding and behavioral effects of cocaine, and that selective alpha3beta4 nAChR ligands can attenuate cocaine-induced behavioral phenomena. Since the selective alpha3beta4 nAChR functional antagonist AT-1001 has also been shown to block nicotine self-administration in rats, the present results suggest that alpha3beta4 nAChRs may be a target for the treatment of cocaine addiction as well as for cocaine-nicotine comorbid addiction. PMID- 26256076 TI - Glutathione transferase M2 variants inhibit ryanodine receptor function in adult mouse cardiomyocytes. AB - Release of Ca(2+) from the sarcoplasmic reticulum (SR) through the cardiac ryanodine receptor (RyR2) is an essential step in cardiac excitation-contraction coupling. Excess Ca(2+) release due to overactive RyR2 can cause arrhythmia that can lead to cardiac arrest. Fragments derived from the carboxy-terminal domain of human glutathione transferase M2 (GSTM2C) specifically inhibit RyR2 activity. Our aim was to further improve this inhibition by mutagenesis and to assess the therapeutic potential of GSTM2C based peptides to treat Ca(2+) release-based arrhythmia. We generated several mutant variants of the C-terminal fragment GSTM2C H5-8 and from those mutant proteins we identified two (RM13 and SM2) that exhibited significantly greater inhibition of cardiac SR Ca(2+) release and single RyR2 channel activity. Flow cytometry analysis showed that these two mutant proteins as well as GSTM2C H5-8 are taken up by isolated adult mouse cardiomyocytes without the aid of any additional compounds, Ca(2+) imaging and isolated cell contraction measurements revealed that GSTM2C H5-8, SM2 and RM13 reduce the SR Ca(2+) release rate and the fractional shortening of adult mouse cardiomyocytes, while importantly increasing the rate of Ca(2+) removal from the sarcoplasm. These observations indicate that peptides derived from GSTM2C inhibit RyR2 at a cellular level and thus they may provide the basis for a novel therapeutic agent to treat arrhythmia and heart attack. PMID- 26256077 TI - Minimally invasive spleen-preserving distal pancreatectomy: Does splenic vessel preservation have better postoperative outcomes? A systematic review and meta analysis. AB - BACKGROUND: Minimally invasive spleen-preserving distal pancreatectomy (SPDP) can be performed with either splenic vessel preservation (SVP) or resection [Warshaw procedure (WP)]. The aim of this study was to evaluate the postoperative clinical outcomes of patients undergoing both methods. DATA SOURCES: Database search of PubMed, Embase, Scopus, Cochrane, and Google Scholar was performed (2000-2014); key bibliographies were reviewed. Qualified studies comparing patients undergoing SPDP with either SVP or WP, and assessing postoperative complications were included. Calculated pooled risk ratio (RR) with the corresponding 95% confidence interval (CI) by random effects methods were used in the meta-analyses. RESULTS: The search yielded 215 studies, of which only 14 observational studies met our selection criteria. The studies included 943 patients in total; 652 (69%) underwent SVP and 291 (31%) underwent WP. Overall, there was a lower incidence of splenic infarction (RR=0.17; 95% CI: 0.09-0.33; P<0.001), gastric varices (RR=0.16; 95% CI: 0.05-0.51; P=0.002), and intra/postoperative splenectomy (RR=0.20; 95% CI: 0.08-0.49; P<0.001) in the SVP group. There was no difference in incidence of pancreatic fistula (WP vs SVP, 23.6% vs 22.9%; P=0.37), length of hospital stay, operative time or blood loss. There was moderate cross-study heterogeneity. CONCLUSIONS: SVP is a safe, efficient and feasible technique that may be used to preserve the spleen. WP may be more suitable for large tumors close to the splenic hilum or those associated with splenomegaly. Randomized clinical trials are justified to examine the long-term benefits of SVP-SPDP. PMID- 26256078 TI - Advanced therapeutic strategies for HBV-related acute-on-chronic liver failure. AB - BACKGROUND: Acute-on-chronic liver failure (ACLF) is increasingly recognized as a distinct clinical entity and is associated with a high short-term mortality. The most common cause of ACLF is chronic hepatitis B worldwide. Currently, there is no standardized approach for the management of ACLF and the efficacy and safety of therapeutic modalities are uncertain. DATA SOURCES: PubMed and Web of Science were searched for English-language articles. The search criteria focused on clinical trials and observational studies on the treatment of patients with HBV related ACLF. RESULTS: Therapeutic approaches for ACLF in patients with chronic hepatitis B included nucleos(t)ide analogues, artificial liver support systems, immune regulatory therapy, stem cell therapy and liver transplantation. All of these therapeutic approaches have shown the potential to improve liver function and increase patients' survival rate, but most of the studies were not randomized or controlled. CONCLUSION: Substantial challenges for the treatment of HBV related ACLF remain and further basic research and randomized controlled clinical trials are needed. PMID- 26256079 TI - Glypican-3 is a biomarker and a therapeutic target of hepatocellular carcinoma. AB - BACKGROUND: The carcinogenesis of hepatocellular carcinoma (HCC) is a multi factorial, multi-step and complex process. Early diagnosis and effective treatments are of utmost importance. This review summarized the recent studies of oncofetal glypican-3 (GPC-3), a membrane-associated heparan sulfate proteoglycan, in the diagnosis and treatment of HCC. DATA SOURCES: English-language reports published from June 2001 to September 2014 were searched from MEDLINE. The key words searched included: GPC-3, biomarker, target and HCC. The sensitivity, specificity, positive and negative predictive values were extracted, and the effect of GPC-3 targeted therapy on HCC was also evaluated. RESULTS: GPC-3 plays a crucial role in HCC cell proliferation and metastasis. It mediates oncogenesis involving signaling pathways during hepatocyte malignant transformation. GPC-3 expression is increased in atypical hyperplasia and cancerous tissues. GPC-3 levels in HCC patients are related to HBV infection, TNM stage, periportal cancerous embolus, and extrahepatic metastasis. The diagnostic accuracy of the combination of serum GPC-3 and alpha-fetoprotein in HCC is up to 94.3%. Down regulation of GPC-3 with specific siRNA or anti-GPC-3 antibody alters cell migration, metastasis and invasion behaviors. The nude mice xenograft tumor growth is inhibited by silencing GPC-3 gene transcription. CONCLUSION: Oncofetal GPC-3 is a highly specific biomarker for the diagnosis of HCC and a promising target molecule for HCC gene therapy. PMID- 26256080 TI - Clinical factors affecting rejection rates in liver transplantation. AB - BACKGROUND: With improvements in survival, liver transplant recipients now suffer more morbidity from long-term immunosuppression. Considerations were given to develop individualized immunosuppression based on their risk of rejection. METHOD: We retrospectively analyzed the data of 788 liver transplants performed during the period from October 1991 to December 2011 to study the relationship between acute cellular rejection (ACR) and various clinical factors. RESULTS: Multivariate analysis showed that older age (P=0.04, OR=0.982), chronic hepatitis B virus infection (P=0.005, OR= 0.574), living donor liver transplantation (P=0.02, OR=0.648) and use of interleukin-2 receptor antagonist on induction (P<0.001, OR=0.401) were associated with fewer ACRs. Patients with fulminant liver failure (P=0.004, OR=4.05) were more likely to develop moderate to severe grade ACR. CONCLUSIONS: Liver transplant recipients with older age, chronic hepatitis B virus infection, living donor liver transplantation and use of interleukin-2 receptor antagonist on induction have fewer ACR. Patients transplanted for fulminant liver failure are at higher risk of moderate to severe grade ACR. These results provide theoretical framework for developing individualized immunosuppression. PMID- 26256081 TI - Conversion of twice-daily to once-daily tacrolimus is safe in stable adult living donor liver transplant recipients. AB - BACKGROUND: Once-daily extended-release tacrolimus (Tac-OD) has been introduced as a useful therapeutic option to increase patient adherence to immunosuppressive therapy. This study aimed to evaluate the safety, efficacy and immunosuppressant adherence of conversion from twice-daily tacrolimus (Tac-BID) to Tac-OD in stable adult living donor liver transplant (LDLT) recipients in a single institution. METHODS: Between February and May 2013, Tac-BID was converted to Tac-OD in recipients followed up for at least 12 months after transplantation and without previous rejection episodes. The switching policy was based on a dose ratio of 1:1 with dose adjustment target trough levels at 3-5 ng/mL. Tacrolimus trough levels, laboratory parameters, metabolic disorders, and adverse events were assessed. RESULTS: A total of 229 patients were enrolled in the study. The median age at conversion was 53 years (range 31-73). The median transplant duration was 35.3 months (range 12.0-95.4). During a median follow-up of 13.5 months after conversion, 9 patients returned to Tac-BID because of adverse events. No acute rejection episodes were observed. Of 214 patients still on Tac-OD at 12 months, 12 (5.6%) received a reduced dose and 95 (44.4%) required an increased dose over baseline. Overall adherence was 82.2% at the end of follow-up. CONCLUSION: The conversion from Tac-BID to Tac-OD with similar target trough levels after conversion is safe and effective for long-term stable LDLT patients. PMID- 26256082 TI - Preoperative hepatic hemodynamics in the prediction of early portal vein thrombosis after liver transplantation in pediatric patients with biliary atresia. AB - BACKGROUND: Portal vein thrombosis (PVT) is one of the main vascular complications after liver transplantation (LT), especially in pediatric patients with biliary atresia (BA). This study aimed to assess the preoperative hepatic hemodynamics in pediatric patients with BA using Doppler ultrasound and determine whether ultrasonographic parameters may predict early PVT after LT. METHODS: One hundred and twenty-eight pediatric patients with BA younger than 3 years of age underwent Doppler ultrasound within seven days before LT, between October 2006 and June 2013. The preoperative hepatic hemodynamic parameters were then compared between patients with early PVT (within 1 month following LT) and those without PVT. Receiver operating characteristic analysis was performed to determine the optimal cutoff value for predicting early PVT. RESULTS: Of the 128 transplant recipients, 41 (32.03%) had a hypoplastic portal vein (PV), 52 (40.63%) had hepatofugal PV flow and 40 (31.25%) had a high hepatic artery resistance index (HARI) of >=1. Nine cases (7.03%) experienced early PVT. A PV diameter <=4 mm (sensitivity 88.89%, specificity 72.27%), and a hepatofugal PV flow (sensitivity 77.78%, specificity 62.18%) with a high HARI >=1 (sensitivity 77.78%, specificity 72.27%) were hepatic hemodynamic risk factors for early PVT. CONCLUSIONS: Hepatic hemodynamic disturbances in pediatric recipients with BA were more common. Small PV diameter (<=4 mm) and hepatofugal PV flow combined with high HARI (>=1) are strong warning signs of early PVT after LT in pediatric patients with BA. Intense monitoring of vascular patency and prophylactic thrombolytic therapy should be considered in pediatric patients undergoing LT for BA. PMID- 26256083 TI - LXRalpha gene downregulation by lentiviral-based RNA interference enhances liver function after fatty liver transplantation in rats. AB - BACKGROUND: Steatotic liver grafts, although accepted, increase the risk of poor posttransplantation liver function. However, the growing demand for adequate donor organs has led to the increased use of so-called marginal grafts. Liver X receptor alpha (LXRalpha) is important in fatty acid metabolism and interrelated with the specific ischemia-reperfusion injury in fatty liver transplantation. This study aimed to investigate whether LXRalpha RNA interference (RNAi) could improve the organ function of liver transplant recipients. METHODS: Fifty Sprague Dawley rats were fed with a high-fat diet and 56% alcohol. The livers of these animals had greater than 60% macrovesicular steatosis and were used as liver donors. The experimental donors were treated with 7X107 TU LXRalpha-RNAi-LV of a mixture injection and control donors with negative control-LV vector injection into the portal vein 72 hours before the operation. The effects of LXRalpha-RNAi LV were assessed by serum aminotransferases, histology, immunostaining, and protein levels. The transcription of LXRalpha mRNA was assessed by reverse transcription-polymerase chain reaction. RESULTS: Compared with controls, LXRalpha RNAi inhibited the expression of LXRalpha at the mRNA (0.53+/-0.03 vs 0.94+/-0.02, P<0.05) and protein levels (0.51+/-0.08 vs 1.09+/-0.12, P<0.05). LXRalpha RNAi also decreased the expressions of sterol regulatory element-binding protein 1c (SREBP-1c) and CD36. LXRalpha RNAi consequently reduced fatty acid accumulation in hepatocytes. Compared with control animals, LXRalpha RNAi-treated group had lower serum alanine aminotransferase, aspartate aminotransferase, interleukin-1beta, and tumor necrosis factor-alpha levels and milder pathologic damages. TUNEL analysis revealed a significant reduction of apoptosis in the livers of rats treated with LXRalpha-RNAi-LV, and overall survival as determined by the Kaplan-Meier method was improved among rats treated with LXRalpha-RNAi-LV (P<0.05). CONCLUSION: LXRalpha-RNAi-LV treatment significantly downregulated LXRalpha expression and improve steatotic liver graft function and recipient survival after a fatty liver transplantation in rats. PMID- 26256084 TI - Development and validation of a predictive score for perioperative transfusion in patients with hepatocellular carcinoma undergoing liver resection. AB - BACKGROUND: Liver resection is a major surgery requiring perioperative blood transfusion. Predicting the need for blood transfusion for patients undergoing liver resection is of great importance. The present study aimed to develop and validate a model for predicting transfusion requirement in HBV-related hepatocellular carcinoma patients undergoing liver resection. METHODS: A total of 1543 consecutive liver resections were included in the study. Randomly selected sample set of 1080 cases (70% of the study cohort) were used to develop a predictive score for transfusion requirement and the remaining 30% (n=463) was used to validate the score. Based on the preoperative and predictable intraoperative parameters, logistic regression was used to identify risk factors and to create an integer score for the prediction of transfusion requirement. RESULTS: Extrahepatic procedure, major liver resection, hemoglobin level and platelets count were identified as independent predictors for transfusion requirement by logistic regression analysis. A score system integrating these 4 factors was stratified into three groups which could predict the risk of transfusion, with a rate of 11.4%, 24.7% and 57.4% for low, moderate and high risk, respectively. The prediction model appeared accurate with good discriminatory abilities, generating an area under the receiver operating characteristic curve of 0.736 in the development set and 0.709 in the validation set. CONCLUSIONS: We have developed and validated an integer-based risk score to predict perioperative transfusion for patients undergoing liver resection in a high-volume surgical center. This score allows identifying patients at a high risk and may alter transfusion practices. PMID- 26256085 TI - Clinical characteristics and outcome of hepatocellular carcinoma in alcohol related and cryptogenic cirrhosis: a prospective study. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming a leading cause of chronic liver disease. Hepatocellular carcinoma (HCC) is one of its complications. Although the pathophysiology is unclear, it is reasonable to expect that cryptogenic cirrhosis related HCC (cryptogenic HCC) behaves differently to other types of HCC. This study prospectively compared patients with cryptogenic HCC and those with HCC related to alcoholic cirrhosis. METHODS: A total of 150 consecutive patients with HCC (89 cryptogenic HCC and 61 alcohol related HCC) referred to our unit over a 23-month period were studied. Their demographic data, liver function, tumor characteristics and outcomes were compared. RESULTS: Alcohol related HCC was seen only in males. Compared with cryptogenic HCC, alcohol related HCC had significantly higher aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio (1.7 vs 1.4, P=0.002), model for end-stage liver disease score (13 vs 11, P=0.018) and Child's score (7 vs 6, P=0.037). No significant difference was seen in platelet counts, serum sodium and AST to platelet ratio index. Single nodular tumors were more common in cryptogenic HCC, while diffuse type tumors and macroscopic vascular invasion were common in alcohol related HCC. In patients who could not be offered any treatment because of advanced tumors or poor liver function, alcohol related HCC had a significantly lower median survival (5.3 months) compared with cryptogenic HCC (9.3 months, P=0.034). CONCLUSIONS: Compared with cryptogenic HCC, alcohol related HCC had worse liver function and aggressive tumor morphology at presentation, and a higher proportion was untreatable. In patients who could not be treated, median survival was lower in patients with alcohol related HCC than in those with cryptogenic HCC. PMID- 26256086 TI - The response of Golgi protein 73 to transcatheter arterial chemoembolization in patients with hepatocellular carcinoma may relate to the influence of certain chemotherapeutics. AB - BACKGROUND: Golgi protein 73 (GP73) is a promising biomarker of hepatocellular carcinoma (HCC). It decreases after surgical resection, and resumes upon recurrence, indicating a potential indicator for the effectiveness of the treatment. But changes of GP73 after transcatheter arterial chemoembolization (TACE) have not been reported so far. This study was to investigate the dynamic changes of GP73 in HCC patients after TACE treatment, and the possible underlying mechanisms in the cell cultures. METHODS: Blood samples were collected from 72 HCC patients, before TACE, at day 1 and day 30 after TACE. GP73 levels were measured by Western blotting. The dynamic changes of GP73 were analyzed and compared with image changes and clinical data. The effects of chemotherapeutic agents (5-FU and pirarubicin) on GP73 expression were tested in three HCC cell lines (HepG2, HCCLM3 and MHCC97H). RESULTS: The GP73 level was significantly elevated at day 1 and day 30 after TACE in HCC patients compared with that before the procedure (P<0.05). There was no statistical difference between the two time points after TACE, nor correlation between GP73 levels and clinicopathological features, tumor metastasis, and patient survival. Pirarubicin, not 5-FU, significantly increased GP73 expression in three cell lines. CONCLUSIONS: Unlike surgical resection which decreases the GP73 level, TACE significantly increased GP73 expression in patients with HCC. No correlations were observed among GP73 levels, tumor characteristics and prognosis of patients with HCC. PMID- 26256087 TI - A serum metabolomic analysis for diagnosis and biomarker discovery of primary biliary cirrhosis and autoimmune hepatitis. AB - BACKGROUND: Because of the diversity of the clinical and laboratory manifestations, the diagnosis of autoimmune liver disease (AILD) remains a challenge in clinical practice. The value of metabolomics has been studied in the diagnosis of many diseases. The present study aimed to determine whether the metabolic profiles, based on ultraperformance liquid chromatography-mass spectrometry (UPLC-MS), differed between autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), to identify specific metabolomic markers, and to establish a model for the diagnosis of AIH and PBC. METHODS: Serum samples were collected from 20 patients with PBC, 19 patients with AIH, and 25 healthy individuals. UPLC-MS data of the samples were analyzed using principal component analysis, partial least squares discrimination analysis and orthogonal partial least squares discrimination analysis. RESULTS: The partial least squares discrimination analysis model (R2Y=0.991, Q2=0.943) was established between the AIH and PBC groups and exhibited both sensitivity and specificity of 100%. Five groups of biomarkers were identified, including bile acids, free fatty acids, phosphatidylcholines, lysolecithins and sphingomyelin. Bile acids significantly increased in the AIH and PBC groups compared with the healthy control group. The other biomarkers decreased in the AIH and PBC groups compared with those in the healthy control group. In addition, the biomarkers were downregulated in the AIH group compared with the PBC group. CONCLUSIONS: The biomarkers identified revealed the pathophysiological changes in AILD and helped to discriminate between AIH and PBC. The predictability of this method suggests its potential application in the diagnosis of AILD. PMID- 26256088 TI - Influence of comorbidity on outcomes of older patients with acute pancreatitis based on a national administrative database. AB - BACKGROUND: Little information is available on the influence of comorbidities on outcomes of older patients with acute pancreatitis. This study aimed to investigate the influence of comorbidities on outcomes of older patients with acute pancreatitis using data from a national Japanese administrative database. METHODS: A total of 14 322 older patients (>=70 years) with acute pancreatitis were referred to 1090 hospitals between 2010 and 2012 in Japan. We collected patients' data from the administrative database to compare the in-hospital mortality and length of stay of older patients with acute pancreatitis. The patients were categorized into four groups according to comorbidity level using the Charlson Comorbidity Index (CCI): none (CCI score=0; n=6890); mild (1; n=3874); moderate (2; n=2192) and severe (>=3; n=1366). RESULTS: Multiple logistic and linear regression analyses revealed that severe comorbidity was significantly associated with higher in-hospital mortality and longer length of stay [odds ratio (OR)=2.26; 95% confidence interval (CI): 1.75-2.92, P<0.001 and coefficient 4.37 days; 95% CI: 2.89-5.85, P<0.001, respectively]. In addition, cardiovascular and renal diseases were the most significant comorbidities affecting outcomes of the older patients. ORs of cardiovascular and renal diseases for mortality were 1.44 (95% CI: 1.13-1.85, P=0.003) and 2.69 (95% CI: 1.88-3.85, P<0.001), respectively, and coefficients for length of stay were 3.01 days (95% CI: 1.34-4.67, P<0.001) and 3.72 days (95% CI: 1.01-6.42, P=0.007), respectively. CONCLUSION: This study demonstrated that comorbidities significantly influenced outcomes of older patients with acute pancreatitis and cardiovascular and renal comorbidities were significant factors affecting outcomes. PMID- 26256089 TI - Pancreaticoduodenectomy with portal vein/superior mesenteric vein resection for patients with pancreatic cancer with venous invasion. AB - BACKGROUND: With the development of new surgical techniques, pancreaticoduodenectomy (PD) with portal vein or superior mesenteric vein (PV/SMV) resection has been used in the treatment of patients with borderline resectable pancreatic cancer. However, opinions of surgeons differ in the effectiveness of this surgical technique. This study aimed to investigate the effectiveness of this approach in patients with pancreatic cancer. METHODS: Follow-up visits and retrospective analysis were carried out of 208 patients with pancreatic cancer who had undergone PD (PD group) and PD combined with PV/SMV resection and reconstruction (PDVR group) from June 2009 to May 2013 at our center. Statistical analysis was performed to compare the clinical features, the difference of survival time and risk factors of venous invasion in pancreatic cancer. Factors relating to postoperative survival time of pancreatic cancer were also investigated. RESULTS: In the PDVR group, which consisted of 42 cases, the 1 , 2- and 3-year survival rates were 70%, 41% and 16%, respectively and the median survival time was 20.0 months. Among the 166 patients in the PD group, the 1-, 2- and 3-year survival rates were 80%, 52%, and 12%, respectively with the median survival time of 26.0 months. No significant difference in survival time and R0 resection ratio was found between the two groups. Lumbodorsal pain, tumor with pancreatic capsular invasion and bile duct infiltration were found to be independent risk factors for PV invasion in pancreatic cancer. In addition, non R0 resection, large tumor size (>2 cm) and poorly differentiated tumor were independent risk factors for survival time in post-PD. CONCLUSIONS: The tumor has a higher chance of venous invasion if preoperative imagings indicate that it juxtaposes with the vessel. Lumbodorsal pain is the chief complaint. Patients with pancreatic cancer associated with PV involvement should receive PDVR for R0 resection when preoperational assessment shows the chance for eradication. PMID- 26256090 TI - Impact of venous thromboembolism on the natural history of pancreatic adenocarcinoma. AB - BACKGROUND: Few studies have analyzed the effect of venous thromboembolism (VTE) events on the prognosis of pancreatic cancer, but their results were conflicting. The present study was undertaken to determine the effect of VTE on pancreatic adenocarcinoma (PA) outcomes. METHODS: All consecutive patients diagnosed with PA from May 2004 to January 2012 in a single oncology center were retrospectively studied. Clinical, radiological and histological data at time of diagnosis or within the first 3 months after surgery, including the presence (+) or absence ( ) of VTE were collected. VTE was defined as radiological evidence of either pulmonary embolism (PE), deep venous thrombosis without infection or catheter related thrombosis. PA with and without PE was compared for survival using the Kaplan-Meier method to estimate overall survival. RESULTS: Among 162 PA patients with a median follow-up of 15 (3-92) months after diagnosis, 28 demonstrated VTE (+). PA patients with and without PE were similar for age, American Society of Anesthesiologist score, body mass index, and history of treatment. The distribution of cancer stages was similar between the two groups VTE (+) and VTE (-). The median duration of survival was significantly worse in the VTE (+) group vs VTE (-) (12 vs 18 months, P=0.010). In multivariate analysis, the presence of VTE and surgical treatment were independent prognostic factors for overall survival. CONCLUSION: VTE (+) at time of diagnosis or within the first 3 months after surgery during treatment is an independent factor of poor prognosis in PA. PMID- 26256091 TI - A liver donor with double hepatic artery aneurysm: a saved graft. AB - The shortage of organs and the increasing median age of deceased donors for orthotopic liver transplantation stimulate transplant centres to accept grafts that otherwise would have been discarded due to severe vascular abnormalities. We encountered a donor with two arterial aneurysms and a left accessory hepatic artery: an arterial aneurysm of the common hepatic artery and a left accessory hepatic artery arising from a second aneurysm of the left gastric artery (Michels type V). A complex reconstruction was created to transplant the liver. Multiple arterial anastomosis was made and the hepatic inflow of the transplanted liver restored. Although the procedure increased the risk of hepatic artery thrombosis, one more organ supposed to be discarded was saved. PMID- 26256092 TI - Online Purchase of eye-care products--is it just another fad?? PMID- 26256093 TI - Comparative Chronic Valve and Venous Effects of Lumenless versus Stylet-Delivered Pacing Leads in Patients with and Without Congenital Heart. AB - BACKGROUND: Standard, 5-7-Fr diameter pacing leads (PLs) can adversely affect atrioventricular valve (AVV) and venous (superior vena cava [SVC], innominate [INN]) integrities. Although chronic pacing/sensing performances have been reported on the steroid-eluting, lumenless, 4.1-Fr PL (Model 3830, Medtronic Inc., Minneapolis, MN, USA), comparative valve and venous effects are largely unknown. METHODS: Patients (n = 134) were divided into two PL groups: Group 1 (n = 65, Model 3830) and Group 2 (n = 69, various 5-7 Fr models) and followed up to 9 years postimplant. Patient demographics, clinical findings, valve function, and venous dimensions were reviewed. Statistical significance was defined as P < 0.05. RESULTS: Patient implant age (mean 16.4 years vs 17.3 years), presence of congenital heart defect (CHD), and preexisting valve issues were comparable between groups. New or worsening valve insufficiency occurred in 12% of Group 1 patients (mean follow-up 4.3 +/- 2.8 years) and 27% of Group 2 patients (mean follow-up 6.2 +/- 3.5 years; P < 0.05). Significant SVC or INN narrowing was found in 11 % of Group 1 and 24% of Group 2 patients (P = 0.0004). All Group 1 patients <12 years of age showed normal while 50% of those from Group 2 exhibited stunted SVC or INN growth (P < 0.05). CONCLUSION: The lumenless, 4.1-Fr diameter PL offers improved clinical benefits, better AVV integrity, and venous development compared with larger 5-7-Fr diameter PL and should be considered especially in younger patients with/without CHD. PMID- 26256094 TI - Physicochemical and Functional Properties of Insoluble Dietary Fiber Isolated from Bambara Groundnut (Vigna subterranea [L.] Verdc.). AB - Bambara groundnut (BGN) is a widely cultivated legume with a rich nutritional profile, yet despite its many benefits it still remains underutilized. To highlight its potential value, 4 BGN varieties-brown, red, black eye, and brown eye were subjected to sequential enzymatic treatments followed by centrifugation to obtain the insoluble dietary fiber (IDF) fraction. The IDFs were vacuum-dried and evaluated for color, hydration properties, fat absorption, polyphenolic compounds, neutral sugars, and uronic acids. An optimized white bread formulation was also determined using brown BGN-IDF in an optimal (IV) mixture design. Three mixture components constrained at lower and upper limits (water: 57% to 60%, yeast: 2.3% to 5.3%, and BGN-IDF: 7% to 10%) were evaluated for their effects on responses of specific loaf volume, gumminess, chewiness, and resilience of the loaves. All BGN-IDFs differed significantly (P <= 0.05) across all color parameters. Polyphenols were significantly (P <= 0.05) highest in red and brown BGN-IDFs. Arabinose/galactose (31.04% to 37.12%), xylose (16.53% to 27.30%), and mannose (14.48% to 22.24%) were the major sugars identified. Swelling capacity was significantly (P <= 0.05) highest for brown eye BGN-IDF (7.72 +/- 0.49 mL/g). Water retention capacity ranged from 1.63 to 2.01 g water/g dry weight. Fat absorption for red BGN-IDF differed significantly (P <= 0.05). Furthermore, the best optimal white bread formulation enriched with brown BGN-IDF was established with numerical optimization at 59.5% water, 4.3% yeast, and 8.5% BGN-IDF. Overall positive physicochemical and functional properties were observed for BGN-IDFs, and it was shown that an optimal white bread enriched with BGN-IDF could be produced. PMID- 26256095 TI - Challenges to Providing Fetal Anomaly Testing in a Cross-Cultural Environment: Experiences of Practitioners Caring for Aboriginal Women. AB - BACKGROUND: Across Australia there are substantial disparities in uptake of antenatal testing for fetal anomalies, with very low uptake observed among Aboriginal women. The reasons behind these disparities are unclear, although poorer access to testing has been reported in some communities. We interviewed health care practitioners to explore the perceived barriers to providing fetal anomaly screening to Aboriginal women. METHODS: In 2009 and 2010, in-depth interviews were undertaken with 59 practitioners in five urban and remote sites across the Northern Territory (NT) of Australia. Data were analyzed thematically. Maximum variation sampling, independent review of findings by multiple analysts, and participant feedback were undertaken to strengthen the validity of findings. RESULTS: Participants included midwives (47%), Aboriginal health practitioners (AHP) (32%), general practitioners (12%), and obstetricians (9%); almost all (95%) were female. Participants consistently reported difficulties counseling women. Explaining the concept of "risk" (of abnormalities and the screening test result) was identified as particularly challenging, because of a perceived lack of an equivalent concept in Aboriginal languages. While AHPs could assist with overcoming language barriers, they are underutilized. Participants also identified impediments to organizing testing including difficulties establishing gestational age, late presentation for care, and a lack of standardized information and training. DISCUSSION: The availability of fetal anomaly testing is challenged by communication difficulties, including a focus on culturally specific biomedical concepts, and organizational barriers to arranging testing. Developing educational activities that address the technical aspects of screening and communication skills will assist in improving access. These activities must include AHPs. PMID- 26256096 TI - Enhanced protein production by microRNA-30 family in CHO cells is mediated by the modulation of the ubiquitin pathway. AB - Functional genomics represent a valuable approach to improve culture performance of Chinese hamster ovary (CHO) cell lines for biopharmaceutical manufacturing. Recent advances in applied microRNA (miRNAs) research suggest that these small non-coding RNAs are critical for the regulation of cell phenotypes in CHO cells. However, the notion that individual miRNAs usually control the expression of hundreds of different genes makes miRNA target identification highly complex. We have recently reported that the entire miR-30 family enhances recombinant protein production in CHO cells. To better understand the pro-productive effects of this miRNA family, we set out to identify their downstream target genes in CHO cells. Computational target prediction combined with a comprehensive functional validation enabled the discovery of a set of twenty putative target genes for all productivity enhancing miR-30 family members. We demonstrate that all miR-30 isoforms contribute to the regulation of the ubiquitin pathway in CHO cells by directly targeting the ubiquitin E3 ligase S-phase kinase-associated protein 2 (Skp2). Finally, we provide several lines of evidence that miR-30-mediated modulation of the ubiquitin pathway may enhance recombinant protein expression in CHO cells. In summary, this study supports the importance of non-coding RNAs, especially of miRNAs, in the context of cell line engineering. PMID- 26256097 TI - Complete genome analysis of Clostridium bornimense strain M2/40(T): A new acidogenic Clostridium species isolated from a mesophilic two-phase laboratory scale biogas reactor. AB - Taxonomic and functional profiling based on metagenome analyses frequently revealed that members of the class Clostridia dominate biogas reactor communities and perform different essential metabolic pathways in the biogas fermentation process. Clostridium bornimense strain M2/40(T) was recently isolated from a mesophilic two-phase lab-scale biogas reactor continuously fed with maize silage and wheat straw. The genome of the strain was completely sequenced and manually annotated to reconstruct its metabolic potential regarding carbohydrate active enzyme production and fermentation of organic compounds for consolidated biofuel production from biomass. The C. bornimense M2/40(T) genome consists of a chromosome (2,917,864bp in size) containing 2613 protein coding sequences, and a 699,161bp chromid (secondary replicon) harboring 680 coding sequences. Both replicons feature very similar GC-contents of approximately 29%. The complex genome comprises three prophage regions, two CRISPR-cas systems and a putative cellulosomal gene cluster that is located on the second replicon (chromid) of the strain. The overexpressed glycosyl hydrolases (GH) CelK (GH9) and CelA (GH48) encoded in the cellulosomal gene cluster were shown to be active on the substrates xylan and xyloglucan whereas XghA (GH74) is highly active on xyloglucan. Reconstruction of fermentation pathways from genome sequence data revealed that strain M2/40(T) encodes all enzymes for hydrogen, acetate, formate, lactate, butyrate, and ethanol production, leading to the classification of the isolate as acidogenic bacterium. Phylogenetic analyses uncovered that the closest characterized relative of C. bornimense is C. cellulovorans. Comparative analyses of the C. bornimense and C. cellulovorans genomes revealed considerable rearrangements within their chromosomes suggesting that both species evolved separately for a relatively long period of time and adapted to specific tasks within microbial consortia responsible for anaerobic digestion. PMID- 26256098 TI - Slow mitochondrial repair of 5'-AMP renders mtDNA susceptible to damage in APTX deficient cells. AB - Aborted DNA ligation events in eukaryotic cells can generate 5'-adenylated (5' AMP) DNA termini that can be removed from DNA by aprataxin (APTX). Mutations in APTX cause an inherited human disease syndrome characterized by early-onset progressive ataxia with ocular motor apraxia (AOA1). APTX is found in the nuclei and mitochondria of eukaryotic cells. Depletion of APTX causes mitochondrial dysfunction and renders the mitochondrial genome, but not the nuclear genome susceptible to damage. The biochemical processes that link APTX deficiency to mitochondrial dysfunction have not been well elucidated. Here, we monitored the repair of 5'-AMP DNA damage in nuclear and mitochondrial extracts from human APTX(+/+) and APTX(-/-) cells. The efficiency of repair of 5'-AMP DNA was much lower in mitochondrial than in nuclear protein extracts, and resulted in persistent DNA repair intermediates in APTX deficient cells. Moreover, the removal of 5'-AMP from DNA was significantly slower in the mitochondrial extracts from human cell lines and mouse tissues compared with their corresponding nuclear extracts. These results suggest that, contrary to nuclear DNA repair, mitochondrial DNA repair is not able to compensate for APTX deficiency resulting in the accumulation of mitochondrial DNA damage. PMID- 26256099 TI - Extrapolation of enalapril efficacy from adults to children using pharmacokinetic/pharmacodynamic modelling. AB - OBJECTIVES: To extrapolate enalapril efficacy to children 0-6 years old, a pharmacokinetic/pharmacodynamic (PKPD) model was built using literature data, with blood pressure as the PD endpoint. METHODS: A PK model of enalapril was developed from literature paediatric data up to 16 years old. A PD model of enalapril was fitted to adult literature response vs time data with various doses. The final PKPD model was validated with literature paediatric efficacy observations (diastolic blood pressure (DBP) drop after 2 weeks of treatment) in children of age 6 years and higher. The model was used to predict enalapril efficacy for ages 0-6 years. KEY FINDINGS: A two-compartment PK model was chosen with weight, reflecting indirectly age as a covariate on clearance and central volume. An indirect link PD model was chosen to describe drug effect. External validation of the model's capability to predict efficacy in children was successful. Enalapril efficacy was extrapolated to ages 1-11 months and 1-6 years finding the mean DBP drop 11.2 and 11.79 mmHg, respectively. CONCLUSIONS: Mathematical modelling was used to extrapolate enalapril efficacy to young children to support a paediatric investigation plan targeting a paediatric-use marketing authorization application. PMID- 26256100 TI - The effects of treadmill running on aging laryngeal muscle structure. AB - OBJECTIVES/HYPOTHESIS: Age-related changes in laryngeal muscle structure and function may contribute to deficits in voice and swallowing observed in elderly people. We hypothesized that treadmill running, an exercise that increases respiratory drive to upper airway muscles, would induce changes in thyroarytenoid muscle myosin heavy chain (MHC) isoforms that are consistent with a fast-to-slow transformation in muscle fiber type. STUDY DESIGN: Randomized parallel group controlled trial. METHODS: Fifteen young adult and 14 old Fischer 344/Brown Norway rats received either treadmill running or no exercise (5 days/week/8 weeks). Myosin heavy chain isoform composition in the thyroarytenoid muscle was examined at the end of 8 weeks. RESULTS: Significant age and treatment effects were found. The young adult group had the greatest proportion of superfast contracting MHCIIL isoform. The treadmill running group had the lowest proportion of MHCIIL and the greatest proportion of MHCIIx isoforms. CONCLUSION: Thyroarytenoid muscle structure was affected both by age and treadmill running in a fast-to-slow transition that is characteristic of exercise manipulations in other skeletal muscles. LEVEL OF EVIDENCE: NA. Laryngoscope, 126:672-677, 2016. PMID- 26256103 TI - Halogenase Engineering for the Generation of New Natural Product Analogues. AB - Halogenases catalyze the incorporation of halogen atoms into organic molecules. Given the importance that halogenation has on the biological activity of small molecules, these enzymes have been subjected to intense engineering efforts to make them more suitable for biotechnology applications. The ability to biohalogenate complex molecules provides, in principle, the opportunity for rapid generation of a series of analogues with new or improved properties. Here we discuss the potential and limitations of using halogenases as biocatalysts, including recent advances in engineering halogenases to generate halogenated natural product analogues. PMID- 26256102 TI - Dromedary Camels and the Transmission of Middle East Respiratory Syndrome Coronavirus (MERS-CoV). AB - Middle East respiratory syndrome coronavirus (MERS-CoV) is an existential threat to global public health. The virus has been repeatedly detected in dromedary camels (Camelus dromedarius). Adult animals in many countries in the Middle East as well as in North and East Africa showed high (>90%) seroprevalence to the virus. Middle East respiratory syndrome coronavirus isolated from dromedaries is genetically and phenotypically similar to viruses from humans. We summarize current understanding of the ecology of MERS-CoV in animals and transmission at the animal-human interface. We review aspects of husbandry, animal movements and trade and the use and consumption of camel dairy and meat products in the Middle East that may be relevant to the epidemiology of MERS. We also highlight the gaps in understanding the transmission of this virus in animals and from animals to humans. PMID- 26256104 TI - Fascicular involvement in common fibular neuropathy: Evaluation with ultrasound. AB - INTRODUCTION: The aim of this study was to demonstrate single fascicular involvement in common fibular (CF) neuropathy using high-resolution ultrasound (US). METHODS: We prospectively enrolled 40 adult patients with clinical and electrodiagnostic suspected CF neuropathy between April 2012 and December 2014. Two musculoskeletal radiologists used high-resolution US probes to prospectively and independently evaluate the CF nerve bilaterally in these patients. The presence of single fascicular involvement (increased cross-sectional area and loss of fascicular echotexture) was recorded. RESULTS: US revealed involvement of only 1 fascicular component of the CF nerve in 7 patients. In all these patients, US revealed involvement of the anterior fascicles corresponding to fibers for the deep fibular nerve. CONCLUSIONS: High-resolution US allowed identification of single fascicular involvement in CF neuropathy. Anterior fascicular involvement was present in up to 17% of patients with suspected CF neuropathy. PMID- 26256101 TI - Norovirus immunology: Of mice and mechanisms. AB - Noroviruses (NoVs) are the most common cause of sporadic and epidemic gastroenteritis in the United States and Europe and are responsible for 20% of acute gastroenteritis worldwide. Over the past decade, the understanding of NoV immunology has grown immensely. Studies of the natural immune response to NoV in humans and animal models have laid the foundation for innovations in cell culture systems for NoV and development of new therapeutics. Evidence from animal models, NoV surrogates, observational human research, and human challenge studies suggest that the innate immune response is critical for limiting NoV infection but is insufficient for viral clearance. NoV may antagonize the innate immune response to establish or prolong infection. However, once a robust adaptive immune response is initiated, the immune system clears the infection through the action of T and B cells, simultaneously generating highly specific protective immunologic memory. We review here both the current knowledge on NoV immunity and exciting new developments, with a focus on ongoing vaccine development work, novel cell culture systems, and advances in understanding the role of the gut microbiome. These changes reinforce the need for a better understanding of the human immune response to NoV and suggest novel hypotheses. PMID- 26256105 TI - Trends in chronic rhinosinusitis research in the past three decades. AB - BACKGROUND: The objective of this work was to identify trends in chronic rhinosinusitis (CRS)-related publications for the past 3 decades. METHODS: Literature review was conducted using multiple terms, including sinusitis, chronic rhinosinusitis, chronic sinus disease, nasal polyposis, ethmoid sinusitis, frontal sinusitis, and maxillary sinusitis. Abstracts were divided into 3 decades: 1983 through 1992, 1993 through 2002, and 2003 through 2012. For each decade, we compared the total number of publications and journals, study design, use of validated outcome measures, quality of evidence, number of authors, country of origin, and clinical vs basic science. RESULTS: A total of 3406 abstracts were identified. There was a statistically significant increase in the number of publications with a 637% increase from 1983 through 1992 to 2003 through 2012 (p < 0.05). Likewise, the number of journals with CRS-related publications significantly increased during the study period (117 to 350; p < 0.05). Prospective studies increased (15.30% to 28.90%, p < 0.05) and retrospective studies decreased (33.00% to 17.36%, p < 0.05). Cohort studies were the most common type of design study (18.70% to 32.46%). In studies reporting outcome measures, the use of validated measures significantly increased over time (2.56% to 49.70%, p < 0.05). Although, the quality of evidence for most clinical publications for all 3 decades were grade C, the number and percentage of grade A and grade B publications increased significantly over time (0.99% to 7.23%, p < 0.05; 6.9% to 10.44%, p < 0.05; respectively). CONCLUSION: CRS-related publication quantity and quality have increased over the last 3 decades. PMID- 26256106 TI - Epigenetic deregulations in chordoma. AB - Chordoma is a rare type of malignant bone tumour arising from remnant notochord and prognosis of patients with it remains poor as its molecular and genetic mechanisms are not well understood. Increasing evidence has demonstrated that epigenetic mechanisms (DNA methylation, histone modification and nucleosome remodelling), play a crucial role in the pathogenesis of many diseases. Aberrant epigenetic patterns are present in patients with chordoma, indicating a potential role for epigenetic mechanisms inthis malignancy. Furthermore, epigenetic alterations may provide novel biomarkers for diagnosis and prognosis as well as therapeutic targets for treatment. In this review, we discuss relevant epigenetic findings associated with chordoma, and their potential application for diagnosis, prognosis and treatment. PMID- 26256107 TI - Peripheral blood features of phytosterolaemia. PMID- 26256108 TI - Lower crosslinking density enhances functional nucleus pulposus-like matrix elaboration by human mesenchymal stem cells in carboxymethylcellulose hydrogels. AB - Engineered constructs represent a promising treatment for replacement of nucleus pulposus (NP) tissue. Recently, photocrosslinked hydrogels comprised of methacrylated carboxymethylcellulose (CMC) were shown to support chondrogenic differentiation of encapsulated human mesenchymal stem cells (hMSCs) and promote accumulation of NP-like extracellular matrix (ECM). The objective of this study was to investigate the influence of CMC crosslinking density, by varying macromer concentration and modification (i.e., methacrylation) percentage, on NP-like differentiation of encapsulated hMSCs. Constructs of lower macromer concentration (2%, w/v) exhibited significantly greater collagen II accumulation, more homogeneous distribution of ECM macromolecules, and a temporal increase in mechanical properties compared to hydrogels of higher macromer concentration (4%, w/v). Constructs of higher modification percentage (25%) gave rise to significantly elevated collagen II content and the formation of cell clusters within the matrix relative to samples of lower modification percentage (10% and 15%). These differences in functional ECM accumulation and distribution are likely attributed to the distinct crosslinked network structures of the various hydrogel formulations. Overall, CMC constructs of lower macromer concentration and modification percentage were most promising as scaffolds for NP tissue engineering based on functional ECM assembly. Optimization of such hydrogel fabrication parameters may lead to the development of clinically relevant tissue engineered NP replacements. PMID- 26256110 TI - A new approach to compressed sensing for NMR. AB - Compressed sensing (CS) has attracted a great deal of recent interest as an approach for spectrum analysis of nonuniformly sampled NMR data. Although theoretical justification for the method is abundant, it suffers from several weaknesses, among them poor convergence of some algorithms, and it remains an open question whether NMR spectra satisfy the sparsity requirements of CS theorems. The versions of CS used in NMR involve minimizing the l1 norm of the spectrum. They bear similarity to maximum entropy (MaxEnt) reconstruction, but critical comparison of the methods can be difficult. Here we describe a formalism that places CS and MaxEnt reconstruction on equal footing, enabling critical comparison of the two methods. We also describe a new algorithm for CS that restricts the computation of the l1 norm to the real channel for complex spectra and ensures causality. Preliminary 1D results demonstrate that this approach ameliorates some artifacts that can occur when using the l1 norm of the complex spectrum. PMID- 26256111 TI - Novel COCH p.V123E Mutation, Causative of DFNA9 Sensorineural Hearing Loss and Vestibular Disorder, Shows Impaired Cochlin Post-Translational Cleavage and Secretion. AB - DFNA9 is an autosomal dominant disorder characterized by late-onset, non syndromic hearing loss, and vestibular dysfunction. Mutations in the COCH (coagulation factor C homology) gene encoding cochlin are etiologically linked to DFNA9. Previous studies have shown that cochlin is cleaved by aggrecanase-1 during inflammation in the spleen and that the cleaved LCCL domain functions as an innate immune mediator. However, the physiological role of cochlin in the inner ear is not completely understood. Here, we report that cochlins containing DFNA9-linked mutations (p.P51S, p.V66G, p.G88E, p.I109T, p.W117R, p.V123E, and p.C162Y) demonstrate reduced cleavage by aggrecanase. Notably, in families affected with DFNA9, we found a novel COCH mutation causing p.V123E substitution in cochlin, which significantly reduced protein susceptibility to cleavage by aggrecanase (to about 20.5% of the wild-type). These results suggest that the impaired post-translational cleavage of cochlin mutants may be associated with pathological mechanisms underlying DFNA9-related sensorineural hearing loss. PMID- 26256109 TI - Identification of IDUA and WNT16 Phosphorylation-Related Non-Synonymous Polymorphisms for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies. AB - Protein phosphorylation regulates a wide variety of cellular processes. Thus, we hypothesize that single-nucleotide polymorphisms (SNPs) that may modulate protein phosphorylation could affect osteoporosis risk. Based on a previous conventional genome-wide association (GWA) study, we conducted a three-stage meta-analysis targeting phosphorylation-related SNPs (phosSNPs) for femoral neck (FN)-bone mineral density (BMD), total hip (HIP)-BMD, and lumbar spine (LS)-BMD phenotypes. In stage 1, 9593 phosSNPs were meta-analyzed in 11,140 individuals of various ancestries. Genome-wide significance (GWS) and suggestive significance were defined by alpha = 5.21 * 10(-6) (0.05/9593) and 1.00 * 10(-4), respectively. In stage 2, nine stage 1-discovered phosSNPs (based on alpha = 1.00 * 10(-4)) were in silico meta-analyzed in Dutch, Korean, and Australian cohorts. In stage 3, four phosSNPs that replicated in stage 2 (based on alpha = 5.56 * 10(-3), 0.05/9) were de novo genotyped in two independent cohorts. IDUA rs3755955 and rs6831280, and WNT16 rs2707466 were associated with BMD phenotypes in each respective stage, and in three stages combined, achieving GWS for both FN-BMD (p = 8.36 * 10(-10), p = 5.26 * 10(-10), and p = 3.01 * 10(-10), respectively) and HIP-BMD (p = 3.26 * 10(-6), p = 1.97 * 10(-6), and p = 1.63 * 10(-12), respectively). Although in vitro studies demonstrated no differences in expressions of wild-type and mutant forms of IDUA and WNT16B proteins, in silico analyses predicts that WNT16 rs2707466 directly abolishes a phosphorylation site, which could cause a deleterious effect on WNT16 protein, and that IDUA phosSNPs rs3755955 and rs6831280 could exert indirect effects on nearby phosphorylation sites. Further studies will be required to determine the detailed and specific molecular effects of these BMD-associated non-synonymous variants. PMID- 26256112 TI - A 'green' diet-based approach to cardiovascular health? Is inorganic nitrate the answer? AB - Ingestion of fruit and vegetables rich in inorganic nitrate (NO(3)(-)) has emerged as an effective method for acutely elevating vascular nitric oxide (NO) levels through formation of an NO(2)(-) intermediate. As such a number of beneficial effects of NO(3)(-) and NO(2)(-) ingestion have been demonstrated including reductions in blood pressure, measures of arterial stiffness and platelet activity. The pathway for NO generation from such dietary interventions involves the activity of facultative oral microflora that facilitate the reduction of inorganic NO(3)(-), ingested in the diet, to inorganic NO(2)(-). This NO(2)(-) then eventually enters the circulation where, through the activity of one or more of a range of distinct NO(2)(-) reductases, it is chemically reduced to NO. This pathway provides an alternative route for in vivo NO generation that could be utilized for therapeutic benefit in those cardiovascular disease states where reduced bioavailable NO is thought to contribute to pathogenesis. Indeed, the cardiovascular benefits of NO(2)(-) and NO(3)(-) are now starting to be translated in patients in several clinical trials. In this review, we discuss recent evidence supporting the potential utility of delivery of NO(3)(-) or NO(2)(-) for the treatment of cardiovascular diseases. PMID- 26256114 TI - Functional significance of subjective response to alcohol across levels of alcohol exposure. AB - Pre-clinical neurobiological models of addiction etiology including both the allostatic model and incentive sensitization theory suggest that alcohol consumption among alcohol-dependent (AD) individuals will be dissociated from hedonic reward as positive reinforcement mechanisms wane in later stage dependence. The aims of this study are to test this claim in humans by examining the relationship between dimensions of subjective responses to alcohol (SR) and alcohol craving across levels of alcohol exposure. Non-treatment-seeking drinkers (n = 205) completed an i.v. alcohol challenge (final target breath alcohol concentration = 0.06 g/dl) and reported on SR and craving. Participants were classified as light-to-moderate drinkers (LMD), heavy drinkers (HD) or AD. Analyses examined group differences in SR and craving response magnitude, as well as concurrent and predictive associations between SR domains and craving. At baseline, LMD and AD reported greater stimulation than HD, which carried over post-alcohol administration. However, stimulation was dose-dependently associated with alcohol craving in HD only. Furthermore, lagged models found that stimulation preceded craving among HD only, whereas this hypothesized pattern of results was not observed for craving preceding stimulation. Sedation was also positively associated with craving, yet no group differences were observed. In agreement with the prediction of diminished positive reinforcement in alcohol dependence, this study showed that stimulation/hedonic reward from alcohol did not precede craving in AD, whereas stimulation was dose-dependently associated with and preceded craving among non-dependent HD. PMID- 26256115 TI - The transformation from amorphous iron phosphate to sodium iron phosphate in sodium-ion batteries. AB - In this article, the structure and electrochemical performance of sodiated iron phosphate (FePO4) synthesized by the micro-emulsion technique have been investigated by X-ray diffraction (XRD), high resolution transmission electron microscopy (HRTEM) and electrochemical measurement. The results reveal that amorphous FePO4 could be transformed into crystallite sodium iron phosphate (NaFePO4) during electrochemical sodiation. Furthermore, the results of electrochemical testing show that the initial specific-discharge capacity of FePO4 is 142 mA h g(-1), and it still delivers a reversible capacity of 130.8 mA h g(-1) after 120 cycles. The discharge capacities could attain values of 142 mA h g(-1), 119.1 mA h g(-1), 91.5 mA h g(-1) and 63.5 mA h g(-1) at 0.1 C, 0.2 C, 0.5 C and 1 C, respectively. These findings have indicated that NaFePO4 has been formed during the electrochemical process and that amorphous structured FePO4 is one of the most promising "host" materials. PMID- 26256113 TI - A survey of malaria and some arboviral infections among suspected febrile patients visiting a health centre in Simawa, Ogun State, Nigeria. AB - Most febrile patients are often misdiagnosed with malaria due to similar symptoms, such as fever shared by malaria and certain arboviral infections. This study surveyed the incidence of malaria, chikungunya and dengue infections among a number of suspected febrile patients visiting Simawa Health Centre, Ogun State, Nigeria. Venous blood samples were obtained from 60 febrile patients (age 3-70 years) visiting the centre between April and May 2014. The rapid diagnostic test (RDT) was used to detect the presence of chikungunya (CHK) antibodies (IgM), dengue (DEN) virus and antibodies (NS1, IgM and IgG) and malaria parasites (Plasmodium falciparum and Plasmodium vivax). Malarial confirmatory tests were by microscopy and nested polymerase chain reaction (PCR) using the polymorphic region of Glutamate-Rich Protein (GLURP) gene. The complexity of P. falciparum infection in the community also determined by the use of nested PCR. These three mosquito-borne infections were observed in 63% (38) of the patients. The prevalence of CHK, DEN and malarial infections singularly were 11%, 0% and 63%, respectively, whereas malaria with either CHK or DEN infections were 24% (9) and 3% (1), respectively. No subjects were positive for CHK and DEN co-infection. Malarial microscopic confirmation was in 94% (32) of the malaria RDT-positive samples, 50% (17) were successfully analysed by nested PCR and the mean multiplicity of infection was 1.6 (1-3 clones). One patient sample harboured both P. falciparum and P. vivax. The study reports the presence of some arboviral infections having similar symptoms with malaria at Simawa, Ogun State. The proper diagnosis of infectious diseases is important for controlling them. PMID- 26256116 TI - Pathoproteomic profiling of the skeletal muscle matrisome in dystrophinopathy associated myofibrosis. AB - The gradual accumulation of collagen and associated proteins of the extracellular matrix is a crucial myopathological parameter of many neuromuscular disorders. Progressive tissue damage and fibrosis play a key pathobiochemical role in the dysregulation of contractile functions and often correlates with poor motor outcome in muscular dystrophies. Following a brief introduction into the role of the extracellular matrix in skeletal muscles, we review here the proteomic profiling of myofibrosis and its intrinsic role in X-linked muscular dystrophy. Although Duchenne muscular dystrophy is primarily a disease of the membrane cytoskeleton, one of its most striking histopathological features is a hyperactive connective tissue and tissue scarring. We outline the identification of novel factors involved in the modulation of the extracellular matrix in muscular dystrophy, such as matricellular proteins. The establishment of novel proteomic markers will be helpful in improving the diagnosis, prognosis, and therapy monitoring in relation to fibrotic substitution of contractile tissue. In the future, the prevention of fibrosis will be crucial for providing optimum conditions to apply novel pharmacological treatments, as well as establish cell based approaches or gene therapeutic interventions. The elimination of secondary abnormalities in the matrisome promises to reduce tissue scarring and the loss of skeletal muscle elasticity. PMID- 26256118 TI - Stabilizing and Activating Nitrogen Catenates. AB - The remarkably stable catenated hexa-nitrogen chain in bis(benzotriazene-4-one) is structurally, theoretically, and spectroscopically characterized to illustrate the durability of the central N-N bond in this hexaazo chain. The reactions of this species illustrate the potential of these nitrogen catenates for the preparation of other condensed heterocycles, such as bispyrazolones, by thermal nitrogen exclusion or by trapping the single ring-opened Dimroth intermediates. In these latter reactions, 2-naphtholate anion condenses with bis(benzotriazene-4 one) to trap and retain a zwitterionic diazonium intermediate as an isolated diazo product, whereas transition metals ring effect ring-extrusion of dinitrogen from the Dimroth intermediate to generate chelating sigma-aryls. The catenated nitrogen species can be stabilized by incorporating strong formal sp(2)-sp(2) N-N sigma bonds with orthogonal orientations. Extending these stabilization and activation principles may allow these types of nitrogen catenates to be useful synthons for other polyaza species. PMID- 26256117 TI - Financial Strain and Medication Adherence among Diabetes Patients in an Integrated Health Care Delivery System: The Diabetes Study of Northern California (DISTANCE). AB - OBJECTIVE: To examine self-reported financial strain in relation to pharmacy utilization adherence data. DATA SOURCES/STUDY SETTING: Survey, administrative, and electronic medical data from Kaiser Permanente Northern California. STUDY DESIGN: Retrospective cohort design (2006, n = 7,773). DATA COLLECTION/EXTRACTION METHODS: We compared survey self-reports of general and medication-specific financial strain to three adherence outcomes from pharmacy records, specifying adjusted generalized linear regression models. PRINCIPAL FINDINGS: Eight percent and 9 percent reported general and medication-specific financial strain. In adjusted models, general strain was significantly associated with primary nonadherence (RR = 1.37; 95 percent CI: 1.04-1.81) and refilling late (RR = 1.34; 95 percent CI: 1.07-1.66); and medication-specific strain was associated with primary nonadherence (RR = 1.42, 95 percent CI: 1.09-1.84). CONCLUSIONS: Simple, minimally intrusive questions could be used to identify patients at risk of poor adherence due to financial barriers. PMID- 26256119 TI - Mitochondria: "Mood Altering Organelles" that Impact Disease Throughout the Nervous System. PMID- 26256121 TI - Effect of tributyltin on mammalian endothelial cell integrity. AB - Tributyltin (TBT), is a man-made pollutants, known to accumulate along the food chain, acting as an endocrine disruptor in marine organisms, with toxic and adverse effects in many tissues including vascular system. Based on the absence of specific studies of TBT effects on endothelial cells, we aimed to evaluate the toxicity of TBT on primary culture of porcine aortic endothelial cells (pAECs), pig being an excellent model to study human cardiovascular disease. pAECs were exposed for 24h to TBT (100, 250, 500, 750 and 1000nM) showing a dose dependent decrease in cell viability through both apoptosis and necrosis. Moreover the ability of TBT (100 and 500nM) to influence endothelial gene expression was investigated at 1, 7 and 15h of treatment. Gene expression of tight junction molecules, occludin (OCLN) and tight junction protein-1 (ZO-1) was reduced while monocyte adhesion and adhesion molecules ICAM-1 and VCAM-1 (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) levels increased significantly at 1h. IL-6 and estrogen receptors 1 and 2 (ESR-1 and ESR-2) mRNAs, after a transient decrease, reached the maximum levels after 15h of exposure. Finally, we demonstrated that TBT altered endothelial functionality greatly increasing monocyte adhesion. These findings indicate that TBT deeply alters endothelial profile, disrupting their structure and interfering with their ability to interact with molecules and other cells. PMID- 26256120 TI - Sex-specific molecular genetic response to UVB exposure in Xiphophorus maculatus skin. AB - In both Xiphophorus fishes and humans, males are reported to have a higher incidence of melanoma than females. To better understand sex-specific differences in the molecular genetic response to UVB, we performed RNA-Seq experiments in skin of female and male Xiphophorus maculatus Jp 163 B following UVB doses of 8 or 16kJ/m(2) exposure. Male X. maculatus differentially express a significantly larger number of transcripts following exposure to 16kJ/m(2) UVB (1293 genes) compared to 8kJ/m(2) UVB (324 genes). Female skin showed differential gene expression in a larger number of transcripts following 8kJ/m(2) UVB (765) than did males; however, both females and males showed similar numbers of differentially expressed genes at 16kJ/m(2) UVB (1167 and1293, respectively). Although most modulated transcripts after UVB exposure represented the same dominant pathways in both females and males (e.g., DNA repair, circadian rhythm, and fatty acid biosynthesis), we identified genes in several pathways that exhibited opposite modulation in female vs. male skin (e.g., synaptic development, cell differentiation, wound healing, and glucose metabolism). The oppositely modulated genes appear related through uncoupling protein 3 (UCP3) that is involved with the regulation of fatty acid oxidation and serves to balance glucose and lipid metabolism. Overall, these results identify gender specific differences in UVB-induced genetic profiles in the skin of females and males and show female and male X. maculatus respond to UVB differently through pathways involved in reactive oxygen species, wound healing, and energy homeostasis. PMID- 26256122 TI - New Tacrine Hybrids with Natural-Based Cysteine Derivatives as Multitargeted Drugs for Potential Treatment of Alzheimer's Disease. AB - Alzheimer's disease (AD) is a devastating age-dependent neurodegenerative disorder. The main hallmarks are impairment of cholinergic system and accumulation in brain of beta-amyloid (Abeta) aggregates, which have been associated with oxidative damage and dyshomeostasis of redox-active biometals. The absence of an efficient treatment that could delay or cure AD has been attributed to the complexity and multifactorial nature of this disease. With this in mind and the recent interest on natural-based drugs, we have explored a set of natural-based hybrid compounds by conjugation of a tacrine moiety with an S allylcysteine (garlic constituent) or S-propargylcysteine moiety aimed at improving the cholinergic system and neuroprotective capacity. The docking modeling studies allowed the selection of linkers to optimize the bimodal drug interaction with acetylcholinesterase enzyme (AChE) active site. The compounds were evaluated for some representative biological properties, including AChE activity and Abeta aggregation inhibition, as well as for their neuroprotective activity to Abeta- and ROS-induced cellular toxicity. The most promising results were achieved by compounds 9d for the AChE inhibition and 9l for the remarkable prevention of superoxide production and Abeta-induced cellular toxicity. PMID- 26256123 TI - Malignant biliary strictures in patients with a normal bilirubin and/or normal liver enzymes. AB - BACKGROUND: To date, no studies have sought to determine the frequency of malignancy in patients presenting with a putative biliary stricture and normal liver function tests (LFTs). The primary aim of this retrospective cohort study was to determine the likelihood of malignancy in patients presenting with a biliary stricture and normal LFTs, a normal bilirubin level either alone or in combination with normal levels of liver enzymes [alkaline phosphatase (ALP) and alanine transaminase (ALT)]. A secondary aim was to determine any clinical/biochemical/sonographic features that may be associated with malignancy. METHODS: Patients presenting over a 10-year period were included. Fifteen variables were analysed to determine their association with malignant disease. RESULTS: Eight hundred and thirty patients with putative biliary strictures were included. Primary hepatopancreaticobiliary (HPB) cancers presented with a normal bilirubin and normal liver enzymes (ALP and ALT) in 6% of cases. Patients with a putative biliary stricture and a normal bilirubin level whose final diagnoses were pancreatic cancer, ampullary cancer, distal cholangiocarcinoma and hilar cholangiocarcinoma represented 21%, 13%, 7% and 9% of individuals diagnosed with these pathologies, respectively. Hypoalbuminaemia and isolated intrahepatic duct dilatation on ultrasound were significantly associated with malignancy in patients with normal bilirubin and completely normal LFTs. CONCLUSIONS: This study has shown that patients with a putative biliary stricture and completely normal LFTs are unlikely to have a primary HPB malignancy. Those presenting with a normal bilirubin level, but deranged liver enzymes (ALP and/or ALT), are more likely to have malignant disease, and this should necessitate a higher degree of clinical suspicion. PMID- 26256124 TI - Adverse reactions to snake antivenom, and their prevention and treatment. AB - Antivenom is the mainstay of treatment of snakebite envenoming. However, adverse reactions to snake antivenom that is available are common in many parts of the world where snakebite is prevalent. Both acute (anaphylactic or pyrogenic) and delayed (serum sickness type) reactions occur. Acute reactions are usually mild but severe systemic anaphylaxis may develop, often within an hour or so of exposure to antivenom. Serum sickness after antivenom has a delayed onset between 5 and 14 days after its administration. Ultimately, the prevention reactions will depend mainly on improving the quality of antivenom. Until these overdue improvements take place, doctors will have to depend on pharmacological prophylaxis, where the search for the best prophylactic agent is still on-going, as well as careful observation of patients receiving antivenom in preparation for prompt management of acute as well as delayed reactions when they occur. PMID- 26256125 TI - STAT5 plays a critical role in regulating the 5'-flanking region of the porcine whey acidic protein gene in transgenic mice. AB - The mammary gland serves as a valuable bioreactor system for the production of recombinant proteins in lactating animals. Pharmaceutical-grade recombinant protein can be harvested from the milk of transgenic animals that carry a protein of interest under the control of promoter regions genes encoding milk proteins. Whey acidic protein (WAP), for example, is predominantly expressed in the mammary gland and is regulated by lactating hormones during pregnancy. We cloned the 5' flanking region of the porcine WAP gene (pWAP) to confirm the sequence elements in its promoter that are required for gene-expression activity. In the present study, we investigated how lactogenic hormones--including prolactin, hydrocortisone, and insulin--contribute to the transcriptional activation of the pWAP promoter region in mammalian cells, finding that these hormones activate STAT5 signaling, which in turn induce gene expression via STAT5 binding sites in its 5'-flanking region. To confirm the expression and hormonal regulation of the 5'-flanking region of pWAP in vivo, we generated transgenic mice expressing human recombinant granulocyte colony stimulating factor (hCSF2) in the mammary gland under the control of the pWAP promoter. These mice secreted hCSF2 protein in their milk at levels ranging from 242 to 1,274.8 ng/ml. Collectively, our findings show that the pWAP promoter may be useful for confining the expression of foreign proteins to the mammary gland, where they can be secreted along with milk. PMID- 26256126 TI - Montreal-Toulouse Language Assessment Battery: evidence of criterion validity from patients with aphasia. AB - BACKGROUND: The Montreal-Toulouse Language Assessment Battery - Brazilian version (MTL-BR) provides a general description of language processing and related components in adults with brain injury. OBJECTIVE: The present study aimed at verifying the criterion-related validity of the Montreal-Toulouse Language Assessment Battery - Brazilian version (MTL-BR) by assessing its ability to discriminate between individuals with unilateral brain damage with and without aphasia. METHODS: The investigation was carried out in a Brazilian community based sample of 104 adults, divided into four groups: 26 participants with left hemisphere damage (LHD) with aphasia, 25 participants with right hemisphere damage (RHD), 28 with LHD non-aphasic, and 25 healthy adults. RESULTS: There were significant differences between patients with aphasia and the other groups on most total and subtotal scores on MTL-BR tasks. CONCLUSIONS: The results showed strong criterion-related validity evidence for the MTL-BR Battery, and provided important information regarding hemispheric specialization and interhemispheric cooperation. Future research is required to search for additional evidence of sensitivity, specificity and validity of the MTL-BR in samples with different types of aphasia and degrees of language impairment. PMID- 26256127 TI - Erratum to: Psychosocial acceptance of cleft patients: has something changed? AB - The original version of the above article contained a mistake in the presentation of one of the author names. Instead of Sirintawat Nattapong, it should be presented as Nattapong Sirintawat. PMID- 26256129 TI - Stature in 19th and early 20th century Copenhagen. A comparative study based on skeletal remains. AB - Individual stature depends on multifactorial causes and is often used as a proxy for investigating the biological standard of living. While the majority of European studies on 19th and 20th century populations are based on conscript heights, stature derived from skeletal remains are scarce. For the first time in Denmark this study makes a comparison between skeletal stature and contemporary Danish conscript heights and investigates stature of males and females temporally and between socially distinct individuals and populations in 19th and early 20th century Copenhagen. A total of 357 individuals (181 males, 176 females) excavated at the Assistens cemetery in Copenhagen is analyzed. Two stature regression formulae (Trotter, 1970; Boldsen, 1990) are applied using femur measurements and evaluated compared to conscript heights. The results indicate that mean male stature using Boldsen follows a similar trend as the Danish conscript heights and that Trotter overestimate stature by ca. 6cm over Boldsen. At an inter population level statistically significant differences in male stature are observed between first and second half of the 19th century towards a slight stature decrease and larger variation while there are no significant changes observed in female stature. There are insignificant differences in stature between middle and high class individuals, but male stature differs statistically between cemeteries (p=0.000) representing middle/high class, paupers and navy employees, respectively. Female stature had no significant wealth gradient (p=0.516). This study provides new evidence of stature among males and females during the 19th century and suggests that males may have been more sensitive to changes in environmental living and nutrition than females. PMID- 26256128 TI - Familial risk and ADHD-specific neural activity revealed by case-control, discordant twin pair design. AB - Individuals with ADHD, as well as their family members who do not meet clinical criteria, have shown deficits in executive function. However, it remains unclear whether underlying neural alterations are familial or ADHD-specific. To investigate this issue, neural activation underlying executive function was assessed using functional magnetic resonance imaging during performance of a Stroop task in three groups of individuals: 20 young adults who were diagnosed with ADHD in childhood, their 20 dizygotic co-twins without ADHD in childhood, and 20 unrelated controls selected from dizygotic twin pairs in which neither twin had ADHD in childhood (total n=60). Implicating the frontoparietal network as a location of effects specific to ADHD, activation in the superior frontal (Brodmann's Area - BA 6) and parietal regions (BA 40) was significantly reduced in twins with childhood ADHD compared to both their control co-twins and unrelated control twins. Consistent with familial influences, activity in the anterior cingulate and insula was significantly reduced in both the twins with ADHD and their co-twins compared to the unrelated controls. These results show that both ADHD-specific and familial influences related to an ADHD diagnosis impact neural systems underlying executive function. PMID- 26256130 TI - Reporting error in weight and its implications for bias in economic models. AB - Most research on the economic consequences of obesity uses data on self-reported weight, which contains reporting error that has the potential to bias coefficient estimates in economic models. The purpose of this paper is to measure the extent and characteristics of reporting error in weight, and to examine its impact on regression coefficients in models of the healthcare consequences of obesity. We analyze data from the National Health and Nutrition Examination Survey (NHANES) for 2003-2010, which includes both self-reports and measurements of weight and height. We find that reporting error in weight is non-classical: underweight respondents tend to overreport, and overweight and obese respondents tend to underreport, their weight, with underreporting increasing in measured weight. This error results in roughly 1 out of 7 obese individuals being misclassified as non-obese. Reporting error is also correlated with other common regressors in economic models, such as education. Although it is a common misconception that reporting error always causes attenuation bias, comparisons of models that use self-reported and measured weight confirm that reporting error can cause upward bias in coefficient estimates. For example, use of self-reports leads to overestimates of the probability that an obese man uses a prescription drug, has a healthcare visit, or has a hospital admission. These findings underscore that models of the consequences of obesity should use measurements of weight, when available, and that social science datasets should measure weight rather than simply ask subjects to report their weight. PMID- 26256131 TI - Efficacy of the Punica granatum peels aqueous extract for symptom management in ulcerative colitis patients. A randomized, placebo-controlled, clinical trial. AB - OBJECTIVE: To investigate the effects of the Punica granatum peel extract on symptoms of patients with ulcerative colitis (UC). METHOD: Patients with UC were randomized to receive an aqueous extract of the P. granatum peel (6 g of dry peel/day) or placebo for four weeks complementary to standard medications. Symptoms were assessed using the Lichtiger Colitis Activity Index (LCAI) at baseline, week 4, and week 10 (follow-up). Clinical response was defined by >= 3 point decrease in LCAI. RESULTS: The LCAI score was similarly reduced in both the P. granatum (-1.68 +/- 3.85, P = 0.019) and placebo groups (-1.39 +/- 2.41, P = 0.002). Clinical response was higher with P. granatum compared with placebo at week 4 (41.4% vs. 18.2%, P = 0.055), but not at week 10 (48.3% vs. 36.4%, P = 0.441). CONCLUSIONS: The P. granatum peel extract seems effective in complementary management of UC. Further studies in a larger sample of patients are warranted. IRCT2014040617156N1. PMID- 26256132 TI - Educational efficacy of objective structured clinical examination on clinical training of traditional Chinese medicine - A qualitative study. AB - OBJECTIVE: We propose applying objective structured clinical examinations (OSCEs) and discuss the educational efficacy of such examinations regarding the clinical competence of traditional Chinese medicine (TCM) practitioners. DESIGN: TCM OSCEs were implemented for evaluation and instruction from 2011 to 2013. Trainees received feedback from clinician-educators and standardized patients. Trainees' survey data were extracted from post-OSCE questionnaires and interviews to analyze TCM OSCEs. RESULTS: Five TCM OSCEs were administered, and the educational backgrounds of the 37 participants were analyzed. According to analysis of the questionnaires, all trainees agreed OSCEs were beneficial. In interviews, trainees expressed appreciation for the direct, real-time feedback during the OSCE and felt it closely resembled actual clinical work. However, the simulation models of OSCEs must be upgraded. CONCLUSIONS: OSCEs can be used in evaluating, teaching, and certifying TCM clinical competencies to improve the quality of TCM practices. The patient-centered training aspect of TCM OSCEs is particularly helpful for participants. PMID- 26256133 TI - Effect of massage therapy on pain, anxiety, relaxation, and tension after colorectal surgery: A randomized study. AB - The purpose of this randomized controlled trial was to evaluate the effect of postoperative massage in patients undergoing abdominal colorectal surgery. One hundred twenty-seven patients were randomized to receive a 20-min massage (n = 61) or social visit and relaxation session (no massage; n = 66) on postoperative days 2 and 3. Vital signs and psychological well-being (pain, tension, anxiety, satisfaction with care, relaxation) were assessed before and after each intervention. The study results indicated that postoperative massage significantly improved the patients' perception of pain, tension, and anxiety, but overall satisfaction was unchanged. In conclusion, massage may be beneficial during postoperative recovery for patients undergoing abdominal colorectal surgery. Further studies are warranted to optimize timing and duration and to determine other benefits in this clinical setting. PMID- 26256134 TI - Yoga attitudes in chronic low back pain: Roles of catastrophizing and fear of movement. AB - Chronic low back pain is a significant public health problem and, although underused, yoga may be an effective complementary treatment. The current study examined associations of pain catastrophizing and fear of movement with attitudes toward yoga in adults with chronic low back pain. Participants completed three quantitative questionnaires assessing specific constructs: beliefs about yoga, fear of movement, and pain catastrophizing. A semi-structured in-person interview was then conducted to obtain specific pain-related information. Hierarchical regression and mediational analyses were used to test hypotheses. Consistent with the fear-avoidance model of chronic pain, catastrophizing and fear of movement were negatively associated with yoga attitudes. Specifically, fear of movement was a mediator between catastrophizing and attitudes toward yoga. Individuals with higher levels of catastrophizing and fear of movement may be less likely to consider a pain treatment involving physical movement. PMID- 26256135 TI - A randomized controlled trial of yoga for pregnant women with symptoms of depression and anxiety. AB - BACKGROUND: Yoga may be well suited for depressed and anxious pregnant women, given reported benefits of meditation and physical activity and pregnant women's preference for nonpharmacological treatments. METHODS: We randomly assigned 46 pregnant women with symptoms of depression and anxiety to an 8-week yoga intervention or treatment-as-usual (TAU) in order to examine feasibility and preliminary outcomes. RESULTS: Yoga was associated with high levels of credibility and satisfaction as an intervention for depression and anxiety during pregnancy. Participants in both conditions reported significant improvement in symptoms of depression and anxiety over time; and yoga was associated with significantly greater reduction in negative affect as compared to TAU (beta = 0.53, SE = 0.20, p = .011). CONCLUSION: Prenatal yoga was found to be a feasible and acceptable intervention and was associated with reductions in symptoms of anxiety and depression; however, prenatal yoga only significantly outperformed TAU on reduction of negative affect. PMID- 26256136 TI - The oasis project, exploring the concept of reducing anxiety & stress in a hospital setting. AB - Comments written in a prayer book in a hospital Chaplaincy Centre, about the area being a 'quiet oasis' in the middle of a busy hospital amid lots of anxiety and stress led to a focus group forming to explore ideas on how this could be addressed; a short term vision was the creation of an area (Oasis) in the Chaplaincy centre and longer term in other areas across the whole hospital. These areas would have an ambience of calm and relaxation where the use of colour, sound, aroma's and touch would be used to help in the reduction of stress and anxiety, this may be from forthcoming surgery, procedures or life in general from traumatic circumstances. The potential impact of this would be to aid recovery, potentially reduce other stress related illness and improve general well-being using strategies to include relaxation, breathing and visualisation techniques and aromatherapy hand massage. PMID- 26256137 TI - Efficacy and safety of topical Matricaria chamomilla L. (chamomile) oil for knee osteoarthritis: A randomized controlled clinical trial. AB - OBJECTIVE: To assess the efficacy and safety of topical Matricaria chamomilla (Chamomile) oil in patients with knee osteoarthritis. METHOD: Patients were randomized and treated with topical chamomile oil, diclofenac or placebo, 3 times/day for 3 weeks. They were allowed to use acetaminophen as analgesic. The patients were asked about their total acetaminophen use. Moreover, they were assessed in the terms of pain, physical function and stiffness by using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire at the enrolling and weekly. RESULTS: Chamomile oil significantly reduced the patients' need for acetaminophen (P = 0.001) compared with diclofenac and placebo. However, there were no significant differences in WOMAC questionnaire domains. The patients did not report any adverse events by using chamomile oil. CONCLUSION: Chamomile oil decreased the analgesic demand of patients with knee osteoarthritis. In addition, it may show some beneficial effects on physical function, and stiffness of the patients. PMID- 26256138 TI - The effect of foot reflexology on physiologic parameters and mechanical ventilation weaning time in patients undergoing open-heart surgery: A clinical trial study. AB - The aim of this study was to investigate the efficacy of foot reflexology on physiological parameters and mechanical ventilation weaning time in patients undergoing open-heart surgery. This was a double blind three-group randomized controlled trial. Totally, 96 patients were recruited and randomly allocated to the experimental, placebo, and the control groups. Study groups respectively received foot reflexology, simple surface touching, and the routine care of the study setting. Physiological parameters (pulse rate, respiratory rate, systolic and diastolic blood pressures, mean arterial pressure, percutaneous oxygen saturation) and weaning time were measured. The study groups did not differ significantly in terms of physiological parameters (P value > 0.05). However, the length of weaning time in the experimental group was significantly shorter than the placebo and the control groups (P value < 0.05). The study findings demonstrated the efficiency of foot reflexology in shortening the length of weaning time. PMID- 26256139 TI - Acupuncture-induced changes of vagal function in patients with depression: A preliminary sham-controlled study with press needles. AB - To study the biological effects of acupuncture on depression, we hypothesized that acupuncture will exert its antidepressant effect through a bottom-up neuromodulation of the autonomic dysfunction in depression. The participants received press needle (PN) acupuncture for 72 h continuously in a sham-controlled design. Psychological assessments and Holter electrocardiography were performed before and after PN acupuncture. We evaluated their autonomic functions through the heart rate variability (HRV). As a result, following PN acupuncture participants showed significant improvement in the Beck's Depression Inventory scores (P = 0.031), systolic/diastolic blood pressures (P = 0.002/P = 0.011), and coefficient of variation of the R-R interval (P < 0.0001), compared to sham PN. The present findings showed PN acupuncture induced alterations in vagal function, blood pressure, and Beck's Depression Inventory scores. It was suggested that vagal stabilization effect by acupuncture may be associated with the therapeutic mechanism in depression. PMID- 26256141 TI - Cannabis sativa L. - Botanical Problems and Molecular Approaches in Forensic Investigation. AB - An overview on legal regulation, taxonomy, and botanical and chemical methods of analysis of marijuana are provided. Emphases are placed on the applications of the recently developed molecular biology methods to the identification and characterization of marijuana samples. Procedures for the extraction of plant DNA, DNA amplification, restriction analysis, and sequence analysis are reviewed. The sequence analyses of the ITS1 and ITS2 of the n-rDNA [88,94]; the sequence of the trnL intron [95] and of the intergenic spacer between the trnL 3'exon and trnF gene of the cpDNA [56]; the RAPDs [26,34,89]; and the RFLPs [87,91,93] have been the most useful. PMID- 26256140 TI - A pilot randomized trial teaching mindfulness-based stress reduction to traumatized youth in foster care. AB - This article presents a pilot project implementing a mindfulness-based stress reduction program among traumatized youth in foster and kinship care over 10 weeks. Forty-two youth participated in this randomized controlled trial that used a mixed-methods (quantitative, qualitative, and physiologic) evaluation. Youth self-report measuring mental health problems, mindfulness, and stress were lower than anticipated, and the relatively short time-frame to teach these skills to traumatized youth may not have been sufficient to capture significant changes in stress as measured by electrocardiograms. Main themes from qualitative data included expressed competence in managing ongoing stress, enhanced self awareness, and new strategies to manage stress. We share our experiences and recommendations for future research and practice, including focusing efforts on younger youth, and using community-based participatory research principles to promote engagement and co-learning. CLINICALTRIALS.GOV: Protocol Registration System ID NCT01708291. PMID- 26256142 TI - Forensic Analysis of Explosives by LC/MS. AB - Liquid chromatography/mass spectrometry (LC/MS), combining good separation characteristics with highly specific and sensitive detection, is the method of choice for forensic trace analysis of explosives. Principles of operation and instrumentation of several LC/MS interface/ionization modes are described. Among the various LC/MS interfaces and ionization modes, electrospray ionization (ESI) LC/MS in the negative-ion mode was found to be the most suitable for analysis and identification of trace amounts of explosives. Characteristic electrospray ions of explosives are mainly adduct and [M - H]- ions. Detection limits in ESI-LC/MS of the investigated explosives were found to be in the pg range. PMID- 26256143 TI - Silver Physical Developers for the Visualization of Latent Prints on Paper. AB - Silver physical developers consist of silver ions and a reducing (developing) agent. They were formulated for developing latent images on photosensitive materials such as photographic emulsions. The mechanism of how the latent image nuclei catalyze the reduction of silver ions by a reducing agent to form black colloidal silver particles has been extensively studied. These developers also happen to visualize latent prints on porous surfaces such as paper. Several hypotheses exist that identify the components in latent print residue that trigger physical development; also several hypotheses exist that explain why such developers work better on porous rather than non-porous surfaces. The more common of these developers use ferrous ions (from a ferrous/ferric redox couple) to reduce silver ions on the surface of latent print residue. Five such silver physical developers are compared through their cell potential DeltaE (and the corresponding reaction quotient Q). Each developer is represented by a point on a line given by R = QC where R = [Fe3+]/[Fe2+] and C = [Ag+] and has a point on the line given by Req = QeqCeq where Qeq = K = 1.22 corresponds DeltaE = 0. The quantity C - Ceq is the maximum amount of silver it can deposit. The development rate of a silver physical developer is directly related to its cell potential DeltaE, the temperature, the maximum amount of silver that it can deposit, and the magnitude of [Fe2+]/[Ag+]. The contrast of a physically developed latent print (on light or dark surfaces) can be enhanced by optical, image enhancement, scanning electron, x-ray, and chemical methods. The latter includes bleaching or intensifying methods, fluorescent dye toning, and radioactive sulfur toning. PMID- 26256144 TI - Statistical Considerations for Readers and Authors of the Forensic Science Literature. AB - The use of numerical information and statistical methods is increasing sharply among forensic scientists publishing research and presenting analytical results for peer and judicial review. The importance of their work should not be obscured by the tendency for complex statistical analyses to confuse and mislead. Some considerations that would assist in our statistical communication include: sound statistical thinking, clear numerical notation, details of data collection, sample size, analytical details, inferential methods and assumptions, confidence intervals, linear regression assumptions, graphs, etc. Sound statistical thinking should guide the research and communication rather than technical details. The informed judgment of the researcher should be clear, apart from the statistical methodology. Better descriptive methods that emphasize the differences in data rather than complex inferential techniques may alone greatly improve our statistical communication. Since numerical information can easily confuse and mislead those unprepared, careful attention to a few basic principles should enhance the effectiveness of statistical communication in the forensic science literature. PMID- 26256145 TI - Positive relationship detected between soil bioaccessible organic pollutants and antibiotic resistance genes at dairy farms in Nanjing, Eastern China. AB - Co-contaminated soils by organic pollutants (OPs), antibiotics and antibiotic resistance genes (ARGs) have been becoming an emerging problem. However, it is unclear if an interaction exists between mixed pollutants and ARG abundance. Therefore, the potential relationship between OP contents and ARG and class 1 integron-integrase gene (intI1) abundance was investigated from seven dairy farms in Nanjing, Eastern China. Phenanthrene, pentachlorophenol, sulfadiazine, roxithromycin, associated ARG genes, and intI1 had the highest detection frequencies. Correlation analysis suggested a stronger positive relationship between the ARG abundance and the bioaccessible OP content than the total OP content. Additionally, the significant correlation between the bioaccessible mixed pollutant contents and ARG/intI1 abundance suggested a direct/indirect impact of the bioaccessible mixed pollutants on soil ARG dissemination. This study provided a preliminary understanding of the interaction between mixed pollutants and ARGs in co-contaminated soils. PMID- 26256146 TI - Human dietary exposure and levels of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), dioxin-like polychlorinated biphenyls (DL PCBs) and non-dioxin-like polychlorinated biphenyls (NDL-PCBs) in free-range eggs close to a secondary aluminum smelter, Northern Italy. AB - PCDD/Fs and PCBs are environmentally persistent substances that have been associated with adverse effects on human health. Contamination of soils, animal feed and pastures leads to their bioaccumulation of in food products of animal origin, which are considered the major source of intake of these contaminants in humans. We analyzed eggs from free-range hens, sampled from small farms, located within a distance of 4.5 km from a secondary aluminum smelter in Northern Italy. The concentrations of PCDD/Fs, DL-PCBs and NDL-PCBs were higher in eggs from locations close to the plant, and strongly exceeded the limits set by EU Regulation 1259/2011 (2.5 pg WHO TEQ fat g(-1) for PCDD/Fs, 5.0 pg WHO TEQ g(-1) for PCDD/Fs and DL-PCBs L, 40 ng g(-1) for NDL-PCBs). Without the prompt and immediately applied control strategies, the consumption of contaminated eggs may have posed [corrected] a risk for human health, especially for children (<=9 years) and infants (<=3 years), due to the 2-fold excess of the current exposure limits. PMID- 26256148 TI - RbMgCO3F: A New Beryllium-Free Deep-Ultraviolet Nonlinear Optical Material. AB - A new deep-ultraviolet nonlinear optical material, RbMgCO3F, has been synthesized and characterized. The achiral nonpolar acentric material is second harmonic generation (SHG) active at both 1064 and 532 nm, with efficiencies of 160 * alpha SiO2 and 0.6 * beta-BaB2O4, respectively, and exhibits a short UV cutoff, below 190 nm. RbMgCO3F possesses a three-dimensional structure of corner-shared Mg(CO3)2F2 polyhedra. Unlike other acentric carbonate fluorides, in this example, the inclusion of Mg(2+) creates pentagonal channels where the Rb(+) resides. Our electronic structure calculations reveal that the denticity of the carbonate linkage, monodentate or bidendate, to the divalent cation is a useful parameter for tuning the transparency window and achieving the sizable SHG response. PMID- 26256147 TI - Current methods for the identification of carbapenemases. AB - Detection of carbapenemases in clinical microbiology labs is a challenging issue. Comparison of the results of susceptibility testing with the breakpoint values of carbapenems is the first step in the screening of carbapenemase producers. To date, screening of carbapenemase-producing (CP) bacteria has been mostly performed by a selective medium. Although these media are practical for the detection of most CP isolates, the inoculated plates have to be incubated overnight. Subsequently, we need the confirmation of the carbapenemase producers present in the culture medium by additional testing [e.g. inhibition studies with liquid or solid media, modified Hodge test (MHT), or gradient strips], which can take up to another 48 hours. Despite the lack of discrimination between the three different classes of carbapenemases (KPC, MBL and OXA) and difficulties in the interpretation of the results, the MHT is usually deemed as the phenotypic reference method for the confirmation of carbapenemase production. Molecular techniques, such as real-time polymerase chain reaction (PCR) assays, in contrast to phenotypic methods that are very time consuming, are faster and allow for the quick identification of carbapenemase genes. These techniques can detect and characterize carbapenemases, including NDM- and KPC-mediated resistance, which is critical for epidemiological investigations. The aim of this review is to gather a summary of the available methods for carbapenemase detection and describe the strengths and weaknesses of each method. PMID- 26256149 TI - Physiological and behavioral basis for the successful adaptation of goats to severe water restriction under hot environmental conditions. AB - Among domestic ruminants, goats are renowned for their ability to tolerate water deprivation, water restriction and energy restriction. However, some basic questions regarding their ability to endure water restriction under heat stress are still open. Three levels of water restriction (56%, 73% and 87% of the ad libitum) were imposed on 20 cross-bred 3-year-old female goats (75% German Fawn and 25% Hair Goat) distributed into four groups, with five animals per treatment. The experiment was conducted from the beginning of July to the end of August in a farm located in the Eastern Mediterranean region of Turkey (40 m in altitude; 36 59' N, 35 18'E), in which subtropical weather conditions prevail. The average daily temperature during the experiment was 34.2 degrees C, whereas the highest and lowest temperatures were 42 degrees C and 23.1 degrees C, respectively. The average relative humidity was 68.2% and wind speed was 1.2 km/h. Weekly average thermal heat indexes during the experiment were 78.3 (week 1), 79.1 (week 2), 80.1 (weak 3), 79.8 (weak 4), 81.3 (weak 5) and on average 79.7. Feed intake, heart rate, thermoregulatory responses (rectal temperature, respiration rate), blood plasma concentrations of ions (Na, K), antidiuretic hormone (ADH), metabolites (glucose, cholesterol, creatinine and urea) and behavioral aspects (standing, walking, lying) were studied over 30 days. The responses to water restriction were proportional to the level of restriction. The reductions in feed intake (up to 13%), BW (up to 4.6%) and the increases in rectal temperature (0.5 degrees C) and breath rate (10 respirations/min) were moderate and also were far from responses encountered under severe heat and water stresses. The increase in plasma Na (from 119 to 140 mM) and ADH concentrations (from 12.6 to 17.4 pg/ml) indicates that the physiological response to water restriction was in response to mild dehydration, which also explains the increase in blood plasma concentrations of glucose, cholesterol, creatinine and urea. Behavioral responses (reduction in walking from 226 to 209 min/day and increase in lying from 417 to 457 min/day) were associated with conservation of energy or thermoregulation (reducing the exposure to direct radiation). PMID- 26256150 TI - Liposome-like nanocapsules of dual drug-tailed betaine for cancer therapy. AB - A novel dual drug-tailed betaine conjugate amphiphile has been firstly synthesized in which the polar headgroup is derived from glycine betaine and the hydrophobic tails are chlorambucil molecules. The newly prepared conjugate undergoes self-assembly to form stable liposome-like nanocapsules as an effective carrier with high drug loading capacity. The nanocapsules showed higher cytotoxic effects to cancer cell lines than those of free chlorambucil in vitro, and inhibited tumor growth effectively in vivo. This strategy that utilizes new dual drug-tailed betaine conjugate amphiphile to construct a self-assembled nanoparticle drug delivery system may have great potential in cancer chemotherapy. PMID- 26256151 TI - Efficacy and toxicity evaluation of new amphotericin B micelle systems for brain fungal infections. AB - The aim of this work is to study the micelle systems of amphotericin B (AmB) and surfactant sodium deoxycholate (NaDC) as possible formulations to treat brain fungal infections. Fungizone((r)) and Ambisome((r)) were used as AmB references. The particle size, aggregation state, toxicity and efficacy of AmB:NaDC micelles were studied with increasing proportions of NaDC. Differences in the size and aggregation state of the reference formulations and micellar NaDC formulations might explain the differences in their distribution and therefore in their toxicity and efficacy. AmB:NaDC 1:0.8 and 1:1.5 nano-sized micelle systems showed a poly-aggregated form of AmB and small mean particle size (450-750 nm). The AmB:NaDC 1:0.8 and AmB:NaDC 1:1.5 micelle systems studied showed an 8-fold lower toxicity than Fungizone((r)). Efficacy was examined in a murine candidiasis model by determining the survival rate and tissue burden reduction in kidneys and brain. The AmB:NaDC 1:1.5 micellar system at 5mg/kg of AmB and the highest amount of NaDC (7.5 mg/kg) presented a good survival rate, and induced a major clearance of brain infection. The new AmB:NaDC 1:1.5 nano-sized micelle system is a promising formulation with a good efficacy/toxicity ratio, which can be attributed to its particle size, AmB aggregation state and NaDC content. PMID- 26256152 TI - Comparison of lipid membrane-water partitioning with various organic solvent water partitions of neutral species and ionic species: Uniqueness of cerasome as a model for the stratum corneum in partition processes. AB - Lipid membrane-water partitions (e.g., immobilized artificial membrane systems where the lipid membrane is a neutral phospholipid monolayer bound to gel beads) were compared to various organic solvent-water partitions using linear free energy relationships. To this end, we also measured the retention factors of 36 compounds (including neutral and ionic species) from water to liposomes made up of 3-sn-phosphatidylcholine and 3-sn-phosphatidyl-l-serine (80:20, mol/mol), employing liposome electrokinetic chromatography in this work. The results show that lipid membranes exhibit a considerably different chemical environment from those of organic solvents. For both neutral species and ionic species, partitions into the more polar hydroxylic solvents are chemically closer to partition into the lipid membrane as compared to partitions into the less polar hydroxylic solvents and into aprotic solvents. This means that solutes partition into the polar parts of lipid membranes, regardless of whether they are charged or not. In addition, cerasome (i.e., liposome composed mainly of stratum corneum lipids) was compared with regular phospholipid liposomes as a possible model for human stratum corneum in partitions. It was found that the cerasome-water partition exhibits a better chemical similarity to skin permeation. This is probably due to the unique structures of ceramides that occur in cerasome and in the stratum corneum lipid domain. We further show that membranes in membrane-water partitions exhibit very different properties. PMID- 26256153 TI - Fine microstructure of processed chitosan nanofibril networks preserving directional packing and high molecular weight. AB - Crystalline chitosan nanofibril networks were prepared, preserving the native structural packing and the polymer high molecular weight. The fine microstructure of the nanomaterial, obtained by mild hydrolysis of chitosan (CHI), was characterized by using synchrotron small- and wide-angle X-ray scattering (SAXS and WAXS), transmission electron microscopy (TEM) and electron diffraction. Hydrolysis of chitosan yielded a network of crystalline nanofibrils, containing both allomorphs of chitosan: hydrated and anhydrous. The comparison of WAXS data in transmission and reflection mode revealed the preferential orientation of the CHI crystals when subjected to mechanical compression constrains. The results are in agreement with the existence of a network nanostructure containing fiber-like crystals with the principal axis parallel to the polymer chain axis. The evolution of the CHI allomorphic composition with temperature was studied to further elucidate the mechanism of structural transitions occurring during CHI nanofibril network processing. PMID- 26256154 TI - Selective conversion of cotton cellulose to glucose and 5-hydroxymethyl furfural with SO4(2-)/MxOy solid superacid catalyst. AB - This paper presented a mild hydrothermal process for degradation of cotton cellulose with solid superacid catalyst and selective conversion of cotton cellulose to glucose and 5-hydroxymethyl furfural (HMF). Five kinds of solid superacid catalyst such as SO4(2-)/SnO2, SO4(2-)/TiO2, SO4(2-)/ZrO2, SO4(2 )/Fe2O3 and SO4(2-)/Al2O3 were prepared by impregnation method. The BET surface area of catalyst SO4(2-)/SnO2 was up to 118.8m(2)g(-1) when impregnation was performed with 1molL(-1) H2SO4 of impregnating solution at 550 degrees C calcination temperature for 3h. It made the hydrothermal temperature of cellulose degradation decrease to 190 degrees C successfully and suppressed the side reaction. The NH3-TPD profile of SO4(2-)/SnO2 indicated there was a wide region of stronger acid sites on the catalyst surface. The depolymerization of cotton cellulose obtained 11.0% yield and 22.0% selectivity of HMF and 26.8% yield and 53.4% selectivity of glucose, respectively. The regeneration and reuse of solid superacid catalyst were also discussed in this paper. PMID- 26256155 TI - Moisture effects on dielectric relaxations of poly (E-caprolactone)/starch biodegradable blends: Local, interfacial and segmental. AB - Poly(E-caprolactone)/starch biocomposites in a wide composition range were studied by thermally stimulated depolarization currents, TSDC, during the drying process following the effect on the dielectric relaxations of moisture loss and blend composition. PCL's cooperative chain mobility is unaffected by the presence of water which is mainly located in the starch inclusions as its segmental relaxation is fixed at 207K. The heterogeneities found in the amorphous phase of neat starch are also observed here as a bimodal alpha relaxation which shifts to higher temperatures as it dries. The blend plasticization by water molecules also affects the blend secondary relaxations showing how the local motions are hindered by the loss of water which is lower in the blend than in pure starch. The interfacial peak which is intermediate between the alpha relaxations of the two components is affected by the inclusions change from liquid to glassy state as the blend dries. PMID- 26256156 TI - Encapsulated eucalyptus oil in ionically cross-linked alginate microcapsules and its controlled release. AB - Sodium alginate microcapsules containing eucalyptus oil were prepared by oil-in water emulsification via Shirasu porous glass (SPG) membrane and cross-linked by calcium chloride (CaCl2). SPG membrane pore size of 5.2MUm was used to control the size of eucalyptus oil microdroplets. Effects of sodium alginate, having a mannuronic acid/guluronic acid (M/G) ratio of 1.13, eucalyptus oil and CaCl2 amounts on microdroplet sizes and size distribution were elucidated. Increasing sodium alginate amounts from 0.1 to 0.5% (wv(-1)) sodium alginate, the average droplets size increased from 42.2+/-2.0 to 48.5+/-0.6MUm, with CVs of 16.5+/-2.2 and 30.2+/-4.5%, respectively. CaCl2 successfully gave narrower size distribution of cross-linked eucalyptus oil microcapsules. The optimum conditions for preparing the microcapsules, oil loading efficiency, and controlled release of the encapsulated eucalyptus oil from the microcapsules as a function of time at 40 degrees C were investigated. Release model for the oil from microcapsules fitted Ritger-Peppas model with non-Fickian transport mechanism. PMID- 26256157 TI - Multifilament cellulose/chitin blend yarn spun from ionic liquids. AB - Cellulose and chitin, both biopolymers, decompose before reaching their melting points. Therefore, processing these unmodified biopolymers into multifilament yarns is limited to solution chemistry. Especially the processing of chitin into fibers is rather limited to distinctive, often toxic or badly removable solvents often accompanied by chemical de-functionalization to chitosan (degree of acetylation, DA, <50%). This work proposes a novel method for the preparation of cellulose/chitin blend fibers using ionic liquids (ILs) as gentle, removable, recyclable and non-deacetylating solvents. Chitin and cellulose are dissolved in ethylmethylimidazolium propionate ([C2mim](+)[OPr](-)) and the obtained one-pot spinning dope is used to produce multifilament fibers by a continuous wet spinning process. Both the rheology of the corresponding spinning dopes and the structural and physical properties of the obtained fibers have been determined for different biopolymer ratios. With respect to medical or hygienic application, the cellulose/chitin blend fiber show enhanced water retention capacity compared to pure cellulose fibers. PMID- 26256158 TI - Understanding the adhesion phenomena in carbohydrate-hydrogel-based systems: Water up-take, swelling and elastic detachment. AB - The bio-adhesion is a complex phenomenon which takes place when two materials (at least one of biological nature, the other usually is a polymeric one) are held together for extended periods of time, usually for local drug delivery purposes. Despite bio-adhesion is widely exploited in commercial pharmaceuticals such as the buccal patches, the underlying phenomena of the process are not completely clarified yet. In this study experimental tests, in which the role of biological membranes is played by a water-rich agarose gel whereas patches are mimicked by hydrogel tablets (made of Carbopol or of Carbopol added with NaCl), have been used to analyze the behavior of the model system above described. Tablets have been forced to adhere on the agarose gel, and after a given contact time they have been detached, recording the required forces. Furthermore weight gain of the tablets (the water transported from the agarose gel toward the tablet) has been quantified. Water transport (during the time in which the contact between tablet and agarose gel is held) and elastic part of mechanical response during the detachment are modelled to achieve a better understanding of the adhesion process. Both the two sub-models nicely reproduce, respectively, the weight gain as well as the swelling of the Carbopol tablets, and the point at which the mechanical response ceases to be purely elastic. PMID- 26256159 TI - In vitro digestion and fermentation properties of linear sugar-beet arabinan and its oligosaccharides. AB - This study was conducted to investigate the prebiotic effects of linear arabino oligosaccharides (LAOS) and debranched (linear) sugar beet arabinan (LAR) for the development of new prebiotics. LAOS were prepared from LAR by enzymatic hydrolysis with endo-arabinanase from Bacillus licheniformis, followed by removal of the arabinose fraction by incubation with resting cells of Leuconostoc mesenteroides. The resulting LAOS contained DP2 (28.7%), DP3 (49.9%), DP4 (20.1%), and DP5 (1.16%). A standardized digestibility test showed that LAOS and LAR were not digestible. Individual cultures of 24 strains of gastrointestinal bacteria showed that LAOS and LAR stimulated growth of Lactobacillus brevis, Bifidobacterium longum, and Bacteroides fragilis. In vitro batch fermentation using human fecal samples showed that LAOS had higher bifidogenic properties than LAR; LAOS increased the population of bifidobacteria which produced short-chain fatty acids (SCFAs). LAOS was fermented slowly compared to fructo oligosaccharides and this may permit SCFA production in the distal colon. This study demonstrates that LAOS prepared from LAR are promising dietary substrates for improvement of human intestinal health. PMID- 26256160 TI - Fabrication of patterned calcium cross-linked alginate hydrogel films and coatings through reductive cation exchange. AB - Calcium cross-linked alginate hydrogels are widely used in targeted drug delivery, tissue engineering, wound treatment, and other biomedical applications. We developed a method for preparing homogeneous alginate hydrogels cross-linked with Ca(2+) cations using reductive cation exchange in homogeneous iron(III) cross-linked alginate hydrogels. Treatment of iron(III) cross-linked alginate hydrogels with calcium salts and sodium ascorbate results in reduction of iron(III) cations to iron(II) that are instantaneously replaced with Ca(2+) cations, producing homogeneous ionically cross-linking hydrogels. Alternatively, the cation exchange can be performed by photochemical reduction in the presence of calcium chloride using a sacrificial photoreductant. This approach allows fabrication of patterned calcium alginate hydrogels through photochemical patterning of iron(III) cross-linked alginate hydrogel followed by the photochemical reductive exchange of iron cations to calcium. PMID- 26256161 TI - Spectral and molecular modeling studies on the influence of beta-cyclodextrin and its derivatives on aripiprazole-human serum albumin binding. AB - The binding mechanism of aripiprazole (APZ) with human serum albumin (HSA) in the absence and presence of three cyclodextrins (CyDs) (beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and (2,6-di-O-methyl)-beta-cyclodextrin) was studied by fluorescence, ultraviolet-visible absorption, nuclear magnetic resonance, and circular dichroism (CD) spectroscopy. The CD results revealed some degree of recovery of refolding caused by APZ after the addition of CyD. The Stern-Volmer quenching constant and binding constant of the APZ-HSA interaction were smaller in the presence of the three CyDs. The ultraviolet-visible absorption results indicated that APZ formed 1:1 complex with the three CyDs. The (1)H NMR spectra of CyD showed chemical shift and resolution loss of proton after the addition of HSA. Molecular modeling studies showed that both APZ and CyD bind to HSA. The process was initiated through inclusion of free APZ molecules by CyD and the increase in steric hindrance of CyD-HSA binding. PMID- 26256162 TI - Assessment of starch-based wood adhesive quality by confocal Raman microscopic detection of reaction homogeneity. AB - Confocal Raman microscopy (CRM) was used to detect the reaction homogeneity of vinyl acetate grafted on starch granules and help to assess the quality of high solid content starch-based wood adhesive (HSSWA). Primarily, four experimental starch samples were investigated, and by analysis of band area ratio (carbonyl/carbohydrate) of each granule, information about reaction homogeneity was collected. The results showed that reaction extent and homogeneity were inconsistent for samples with different G values, and the distribution of ester groups on blend samples was much less uniform than grafted starch samples with the same G value, confirming that CRM was useful for determining the homogeneity of chemical modification. Afterwards, the technique was applied to research HSSWA prepared by two-stage seeded polymerization and traditional process. The distribution of ester groups was more uniform among starch granules prepared by former method, resulted in adhesive with much better performance, indicating that uniformity of polymerization was an important factor related to properties of starch-based wood adhesive. PMID- 26256163 TI - Quaternized chitosan particles as ion exchange supports for label-free DNA detection using PNA probe and MALDI-TOF mass spectrometry. AB - Quaternized chitosan particles are introduced as anion-exchanged captures to be used with a conformationally constrained pyrrolidinyl peptide nucleic acid (acpcPNA) and MALDI-TOF mass spectrometry for DNA sequence analysis. Methylated chitosan (MC) and methylated N-benzyl chitosan (MBzC) particles were obtained by heterogeneous chemical modification of ionically cross-linked chitosan particles via direct methylation and reductive benzylation/methylation, respectively. N,N,N trimethylchitosan (TMC) and N-[(2-hydroxyl-3-trimethylammonium)propyl]chitosan chloride (HTACC) particles were prepared by ionic cross-linking of quaternized chitosan derivatives, homogeneously modified from chitosan, namely TMC and HTACC, respectively. The particles formed had a size in a sub-micrometer range and possessed positive charge. Investigation by MALDI-TOF mass spectrometry suggested that some quaternized particles in combination with acpcPNA were capable of detecting a single mismatched base out of 9-14 base DNA sequences. Potential application of this technique for the detection of wild-type and mutant K-ras DNA, a gene that mutation is associated with certain cancers, has also been demonstrated. PMID- 26256164 TI - First solid-state NMR spectroscopy evaluation of complexes of benznidazole with cyclodextrin derivatives. AB - Complexation of benznidazole (BZL), a drug of choice for the treatment of Chagas'neglected disease, with cyclodextrin (CD) derivatives was analyzed by solid-state NMR. (13)C cross polarization/magic angle spinning spectra were recorded from BZL and from BZL:beta-CD, BZL:methyl beta-CD and BZL:hydroxypropyl beta-CD complexes, which were obtained by the solvent evaporation technique. No significant evidence was obtained on BZL inclusion complexes involving either beta-CD or hydroxypropyl beta-CD. Conversely, BZL:methyl beta-CD displayed BZL resonances characteristic of an amorphous drug and data analysis confirmed the presence of stable BZL:methyl beta-CD inclusion complexes, with benzene encapsulated into the host cavity. Further evidences on complex structure and dynamics were obtained from proton and carbon spin-lattice relaxation times in the rotating frame. These data are consistent with a common guest-host spin reservoir. The BZL interaction with methyl beta-CD provided a route to stabilize amorphous BZL. Physical mixtures with identical BZL and CD compositions were also studied for comparison. PMID- 26256165 TI - In situ synthesis of new magnetite chitosan/carrageenan nanocomposites by electrostatic interactions for protein delivery applications. AB - We present a simple method to develop magnetite chitosan/carrageenan nanocomposites by in situ synthesis under mild conditions, and then their potential for controlled release of macromolecules was also evaluated. The structural, morphological and magnetic properties of the as-prepared materials were studied by vibrating sample magnetometer, X-ray diffractometer, Fourier transform infrared spectroscopy, thermogravimetric analyzer and transmission electron microscopy. With the varying mass ratio (chitosan to Fe3O4-carrageenan nanocomposite), the developed nanocarriers presented sizes within 73-355nm and zeta potentials of -42-32mV. Using bovine serum albumin as model protein, the adsorption and release behaviors were investigated. Nanocarriers evidenced excellent loading capacity of 181mgg(-1) at protein concentration of 0.2mgmL(-1), and demonstrated capacity to provide a sustained release up to 85% of adsorbed protein in 30min in intestinal medium rather than acidic medium. These results suggest that the developed magnetite chitosan/carrageenan nanocomposites are promising in the application of magnetically targeted delivery of therapeutic macromolecules. PMID- 26256166 TI - Mucoadhesive-floating zinc-pectinate-sterculia gum interpenetrating polymer network beads encapsulating ziprasidone HCl. AB - A novel dual crosslinked low-methoxyl (LM) pectinate-sterculia gum (SG) interpenetrating polymer network (IPN) beads was developed for intragastric ziprasidone delivery. The IPN beads were accomplished by simultaneous ionotropic gelation with zinc acetate and covalent crosslinking with glutaraldehyde. The effects of pectin and SG contents on drug entrapment efficiency (DEE, %), and cumulative drug release after 8h (Q8, %) were studied to optimize the IPN beads using a 3(2) factorial design. The optimized beads encapsulating ziprasidone HCl (F-O) displayed DEE of 87.98+/-1.15% and Q8 of 58.81+/-1.50% with excellent buoyancy (floating lag time <2min, % buoyancy at 8h >63%) and good mucoadhesivity with the goat gastric mucosa. In most cases, the drug release behaviour obeyed Higuchi kinetics with anomalous transport mechanism. The Zn-pectinate-SG IPN beads were also characterized by SEM, FTIR, DSC and P-XRD analyses. PMID- 26256167 TI - Thiol derivatization of Xanthan gum and its evaluation as a mucoadhesive polymer. AB - Thiol-derivatization of xanthan gum polysaccharide was carried out by esterification with mercaptopropionic acid and thioglycolic acid. Thiol derivatization was confirmed by Fourier-transformed infra-red spectroscopy. Xanthan-mercaptopropionic acid conjugate and xanthan-thioglycolic acid conjugate were found to possess 432.68mM and 465.02mM of thiol groups as determined by Ellman's method respectively. Comparative evaluation of mucoadhesive property of metronidazole loaded buccal pellets of xanthan and thiolated xanthan gum using chicken buccal pouch membrane revealed higher ex vivo bioadhesion time of thiolated xanthan gum as compared to xanthan gum. Improved mucoadhesive property of thiolated xanthan gum over the xanthan gum can be attributed to the formation of disulfide bond between mucus and thiolated xanthan gum. In vitro release study conducted using phosphate buffer (pH 6.8) revealed a sustained release profile of metronidazole from thiolated xanthan pellets as compared to xanthan pellets. In conclusion, thiolation of xanthan improves its mucoadhesive property and sustained the release of metronidazole over a prolonged period. PMID- 26256168 TI - Microwave-assisted carboxymethylation of cellulose extracted from brewer's spent grain. AB - Cellulose was extracted from brewer's spent grain (BSG) by alkaline and bleaching treatments. The extracted cellulose was used in the preparation of carboxymethyl cellulose (CMC) by reaction with monochloroacetic acid in alkaline medium with the use of a microwave reactor. A full-factorial 2(3) central composite design was applied in order to evaluate how parameters of carboxymethylation process such as reaction time, amount of monochloroacetic acid and reaction temperature affect the average degree of substitution (DS) of the cellulose derivative. An optimization strategy based on response surface methodology has been used for this process. The optimized conditions to yield CMC with the highest DS of 1.46 follow: 5g of monochloroacetic acid per gram of cellulose, reaction time of 7.5min and temperature of 70 degrees C. This work demonstrated the feasibility of a fast and efficient microwave-assisted method to synthesize carboxymethyl cellulose from cellulose isolated of brewer's spent grain. PMID- 26256169 TI - Synthesis of surface bound silver nanoparticles on cellulose fibers using lignin as multi-functional agent. AB - Lignin has proven to be highly effective "green" multi-functional binding, complexing and reducing agents for silver cations as well as capping agents for the synthesis of silver nanoparticles on ultra-fine cellulose fibrous membranes. Silver nanoparticles could be synthesized in 10min to be densely distributed and stably bound on the cellulose fiber surfaces at up to 2.9% in mass. Silver nanoparticle increased in sizes from 5 to 100nm and became more polydispersed in size distribution on larger fibers and with longer synthesis time. These cellulose fiber bound silver nanoparticles did not agglomerate under elevated temperatures and showed improved thermal stability. The presence of alkali lignin conferred moderate UV absorbing ability in both UV-B and UV-C regions whereas the bound silver nanoparticles exhibited excellent antibacterial activities toward Escherichia coli. PMID- 26256170 TI - Alginate as a protease inhibitor in vitro and in a model gut system; selective inhibition of pepsin but not trypsin. AB - Alginates are widely used in the food and medical industries, including as a Gastro-Oesophagul Reflux treatment. This work investigates the inhibitory effects of alginate on the reflux aggressors trypsin and pepsin and the role of alginate substrate binding, pH and alginate structure on inhibition. Alginates were shown to reduce pepsin activity by up to 53.9% (+/-9.5SD) in vitro. Strong positive correlation between alginate mannuronate residue frequency and levels of pepsin inhibition was observed. Limited inhibition of trypsin was shown. Viscometric observations of pH dependent interactions between alginate and protein suggest a mechanism whereby pH dependent ionic interactions reduce substrate availability to enzyme at acidic pH. To understand how dietary protein digestion is affected by alginate, proteolytic digestion was investigated in an in vitro model of the upper digestive tract. Significant inhibition of proteolysis was shown in the gastric phase of digestion, but not the small intestinal phase. PMID- 26256172 TI - Synthesis and physico-chemical characterization of a beta-cyclodextrin conjugate for sustained release of Acyclovir. AB - We report the synthesis of an oligomeric prodrug of the antiviral agent Acyclovir (Acy) conjugated to beta-cyclodextrin (beta-CyD). The drug was selectively linked through a succinic spacer to one of the primary hydroxyl groups of beta-CyD by ester linkage in a 1:1 molar ratio. The conjugate was purified by semipreparative reverse-phase chromatography and characterized by FAB mass spectrometry and NMR experiments. The release of Acy from the conjugate was evaluated both in acidic and in neutral conditions and in the presence of porcine liver esterase. In all cases we observed the release of both free Acy and Acy succinate (AcySucc) at differing rates as a function of the hydrolysis conditions. In the presence of esterase the release of free Acy was favoured over AcySucc, showing a release rate of 100% of Acy within 7 days. PMID- 26256171 TI - Combined bleaching and hydrolysis for isolation of cellulose nanofibrils from waste sackcloth. AB - A convenient and low cost process to prepare cellulose nanofibrils (CNF) from waste sackcloth by using H2O2/HNO3 solution as both bleaching agent and hydrolysis medium was recommended. The resultant CNF with high crystallinity was initially synthesized by the chemical disintegration process for the removal of non-cellulosic components and the crystallinity of CNF was 68.11% compared with that of sackcloth fibers (48.28%). The decomposition temperature of CNF was about 340 degrees C, which indicated that the thermal stability of the fibers was increased after the combined bleaching and hydrolysis. Subsequently, the homogenous CNF colloidal suspensions in water, ethanol and acetone were obtained after sonication treatment. The CNF in water suspensions with 20-50nm in width and hundreds of nanometers in length was ultimately prepared under the conditions of different ultrasonic time. PMID- 26256173 TI - Modification of cotton fabric with a dendrimer to improve ink-jet printing process. AB - In this study, the cotton fabrics were modified with different polyamidoamine (PAMAM) dendrimer concentrations to yield antimicrobial and efficient polymeric materials for ink-jet printing. PAMAM dendrimer has been covalently grafted on cotton fabric via the reaction of cellulosate anion with the cynuric chloride. The obtained modified cotton fabrics were characterized by FTIR and TGA. The morphology and yellowness of modified cotton fabrics were analysed by SEM and UV spectroscopy. The ink-jet printing onto modified cotton fabrics were evaluated at different pHs. The results at optimum pH indicated that by increasing the PAMAM dendrimer concentration in modified cotton fabric not only the colour strength of reactive ink-jet printed fabric increased but also the antimicrobial cotton fabric produced. A comparision between printing modified and unmodified cottons suggest that the PAMAM dendrimer has the potential for using in single-phase ink jet printing. The yielded prints demonstrate excellent colour fastness for washing and dry/wet crocking properties. PMID- 26256174 TI - Modifying solubility of polymeric xylan extracted from Eucalyptus grandis and sugarcane bagasse by suitable side chain removing enzymes. AB - alpha-l-Arabinofuranosidase (AbfB) and novel alpha-d-glucuronidase (Agu1B) enzymes were applied for selective hydrolysis of beechwood (Fagus sylvatica) xylan (Sigma-Aldrich) as well as xylans extracted from Eucalyptus grandis and sugarcane (Saccharum officinarum L.) bagasse, leading to precipitation of these carbohydrate biopolymers. Hemicellulose extraction was performed with two mild alkali methods, Hoije and Pinto. Precipitation occurred after removal of 67, 40 and 16% 4-O-methyl-d-glucuronic acid (MeGlcA) present in polymeric xylans from beechwood, E. grandis (Pinto) and E. grandis (Hoije), respectively. Precipitation was maximized at Agu1B levels of 3.79-7.53mg/gsubstrate and hemicellulose concentrations of 4.5-5.0% (w/v). Polymeric xylan from sugarcane bagasse precipitated after removal of 48 and 22% of arabinose and MeGlcA, respectively, at optimal AbfB and Agu1B dosages of 9.0U/g and 6.4mg/g, respectively. Both the purity of polymeric xylans and structure thereof had a critical impact on the propensity for precipitation, and morphology of the resulting precipitate. Nano to micro-meter precipitates were produced, with potential for carbohydrate nanotechnology applications. PMID- 26256175 TI - Wastewater treatment enhancement by applying a lipopeptide biosurfactant to a lignocellulosic biocomposite. AB - In this work, a natural lipopeptide biosurfactant obtained from corn steep liquor was included in the formulation of a lignocellulosic biocomposite used for the treatment of wastewater. The results obtained indicate that the dye sorption capacity of the hydrogel containing hydrolysed vineyard pruning waste can be significantly promoted via surfactant modification using natural detergents. The elimination of dye compounds and the removal of sulphates were increased around 10% and 62%, respectively, when the biocomposite modified with biosurfactant was used. This outcome can be intrinsically related to the rougher, rounder, more compact and better-emulsified sphere achieved after the addition of the lipopeptide biosurfactant. The bioadsorption process followed a pseudo-second order kinetic model and both intraparticle diffusion and liquid film diffusion were involved in the bioadsorption mechanism. Therefore, the utilisation of biosurfactants shows great potential in the formulation of eco-friendly adsorbents for environmental application. PMID- 26256176 TI - Development of bio-composites with novel characteristics: Evaluation of phenol induced antibacterial, biocompatible and biodegradable behaviours. AB - This paper describes a laccase-assisted grafting of gallic acid (GA) and thymol (T) as functional entities onto the previously developed P(3HB)-g-EC composite. GA-g-P(3HB)-g-EC and T-g-P(3HB)-g-EC bio-composites were prepared by laccase assisted free radical-induced graft polymerisation of GA and T onto the P(3HB)-g EC based composite using surface dipping and incorporation technique. The results of the antibacterial evaluation for the prepared composites indicated that 15GA-g P(3HB)-g-EC, 15T-g-P(3HB)-g-EC and 20T-g-P(3HB)-g-EC composites possessed the strongest bacteriostatic and bactericidal activities against Gram-positive Bacillus subtilis NCTC 3610 and Staphylococcus aureus NCTC 6571 and Gram-negative Escherichia coli NTCT 10418 and Pseudomonas aeruginosa NCTC 10662 strains. In this study, we have also tested GA-g-P(3HB)-g-EC and T-g-P(3HB)-g-EC bio composites for their ability to support and maintain multilineage differentiation of human keratinocyte-like (HaCaT) skin cells in-vitro. From the cytotoxicity results, the tested composites showed 100% viability and did not induce any adverse effect on a HaCaT's morphology. Finally, in soil burial evaluation, a progressive increase in the degradation rate of GA-g-P(3HB)-g-EC and T-g-P(3HB)-g EC bio-composites was recorded with the passage of time up to 6 weeks. In summary, our current findings suggest that GA-g-P(3HB)-g-EC and T-g-P(3HB)-g-EC bio-composites are promising candidates for biomedical type applications such as skin regeneration, multiphasic tissue engineering and/or medical implants. PMID- 26256177 TI - Improved mechanical properties of polylactide nanocomposites-reinforced with cellulose nanofibrils through interfacial engineering via amine functionalization. AB - One of the main factors responsible for the mechanical and physical properties of nanocomposites is the effectiveness of the interfacial region to transfer loads and mechanical vibrations between the nano-reinforcements and the matrix. Surface functionalization has been the preferred approach to engineer the interfaces in polymer nanocomposites in order to maximize their potential in structural and functional applications. In this study, amine-functionalized cellulose nanofibrils (mCNF-G1) were synthesized via silylation of the hydroxyl groups on the CNF surface using 3-aminopropyltrimethoxysilane (APTMS). To further increase the amine density (mCNF-G2), dendritic polyamidoamine (PAMAM) was grafted onto mCNF-G1 by the Michael addition of methacrylate onto mCNF-G1, followed by the transamidation of the ester groups of methacrylate using ethylenediamine. Compared to native CNF-reinforced, poly(l-lactide) (PLLA) nanocomposites, amine functionalized CNF exhibited significantly improved dispersion and interfacial properties within the PLLA matrix due to the grafting of PLLA chains via aminolysis. It is also a more effective nucleating agent, with 15% mCNF-G1 leading to a crystallinity of 32.5%, compared to 0.1 and 8.7% for neat PLLA and native CNF-reinforced composites. We have demonstrated that APTMS-functionalized CNF (mCNF-G1) significantly improved the tensile strength compared to native CNF, with 10% mCNF-G1 being the most effective (i.e., >100% increase in tensile strength). However, we also found that excessive amines on the CNF surface (i.e., mCNF-G2) resulted in decreased tensile strength and modulus due to PLLA degradation via aminolysis. These results demonstrate the potential of optimized amine-functionalized CNF for future renewable material applications. PMID- 26256178 TI - Correlation between the sorption of dissolved oxygen onto chitosan and its antimicrobial activity against Esherichia coli. AB - The ability of chitosan to adsorb dissolved oxygen from solution depends on its physical shape and is related to the surface area. Depending on conditions chitosan is capable of adsorbing or releasing oxygen. Chitosan, modificated by the substances possessing antimicrobial activity, such as succinic acid, Pd(II) ions, metallic Pd or Ag, distinctly increases the ability to adsorb the dissolved oxygen. The additional treatment of chitosan with air oxygen or electrochemically produced oxygen also increases the uptake of dissolved oxygen by chitosan. A strong correlation between the amount of oxygen adsorbed onto chitosan and its antimicrobial activity against Esherichia coli has been observed. This finding suggests that one of the sources of antimicrobial activity of chitosan is the ability to sorb dissolved oxygen, along with other well-known factors such as physical state and chemical composition. PMID- 26256179 TI - Cationic nanofibrillar cellulose with high antibacterial properties. AB - Cationic nanofibrillar cellulose (C-NFC) has been prepared via a high pressure homogenization using quaternized cellulose fibers with glycidyltrimethylammonium chloride. It has been shown that the quaternization of dried softwood pulp facilitated the defibrillation processes and prevented clogging of the homogenizer. The effects of the trimethylammonium chloride content on the fibrillation yield, the transparency degree of the gel, the rheological behavior of the NFC suspension and their electrokinetic properties were investigated. AFM observation showed that the NFC suspension consisted of individualized cellulose I nanofibrils 4-5nm in width and length in the micronic scale. In addition to their strong reinforcing potential, the inclusion of C-NFC into a polymer matrix was shown to efficiently enhance the antibacterial activity. The reinforcing potential of C-NFC, studied by dynamic mechanical analysis (DMA), was compared to anionic NFC and the difference was explained in terms of the nanofibrils capacities to build up a strong networks held by hydrogen bonding. PMID- 26256181 TI - Physicochemical properties and antioxidant activities of polysaccharide from floral mushroom cultivated in Huangshan Mountain. AB - In this paper, a polysaccharide fraction (FMPS) was purified from the floral mushroom cultivated in Huangshan Mountain for the first time. Physicochemical properties and antioxidant activities of FMPS were investigated. FMPS had an average molecular weight of 7.2*10(5)Da and was composed of glucose. On the basis of FT-IR, NMR and methylation analysis, the repeating unit of FMPS was established as (1->3)-linked beta-d-glucopyranosyl backbone with 1-linked beta-d glucopyranosyl branches substituted at O-6 position of (1->3)-linked beta-d glucopyranosyl residues. The advanced structure studies indicated that FMPS was a triple-helical polysaccharide. The main hydrodynamic radius (Rh) of FMPS was 23.4nm and it could form a stable system with water in 1.2*10(-2)g/mL solutions. In addition, FMPS exhibited high DPPH radical scavenging activities (79.46% at 5mg/mL) and hydroxyl radical scavenging activities (74.18% at 5mg/mL), as well as Fe(2+)chelating activities and ABTS radical scavenging activities to some extent. PMID- 26256180 TI - Determination of modification degree in BDDE-modified hyaluronic acid hydrogel by SEC/MS. AB - Determination of modification degree in BDDE-modified hyaluronic acid (HA) hydrogel is of particular interest. In this paper, three crosslinking parameters (degree of total modification, t-MOD; degree of cross-link modification, c-MOD; degree of pendent modification, p-MOD) are defined and determined by quantification of the modified fragments in hydrogel digestion by size exclusion chromatography combined with mass spectrometry (SEC-MS). The digestion products of a novel hyaluronidase HAase-B produced by Bacillus sp. A50 are studied and only a few modified fragments are identified by (1)H NMR and MS. As a result, Three HA hydrogels prepared in lab have different t-MOD, c-MOD and p-MOD, but the ratio of c-MOD to p-MOD result in the almost same value of 75%. Hydrogel products from Q-Med have nearly same t-MOD about 0.8% and c-MOD about 0.1%, the ratio of c MOD to p-MOD is about 13%. Hydrogels from ANTEIS S.A all have much higher t-MOD values, the ratio of c-MOD and p-MOD is about 8%. PMID- 26256182 TI - Antitumor and immunomodulatory activity of polysaccharide isolated from Trametes orientalis. AB - A water-soluble polysaccharide (TOP-2) was isolated from Trametes orientalis, consisting of galactose, glucose, mannose, and arabinose with the molar ratios of 5.79:5.77:3.45:1, having an average molecular weight of 63kDa. The antitumor and immunomodulatory activity of TOP-2 were determined in Lewis lung carcinoma (LLC) tumor-bearing mice. The results revealed that TOP-2 not only could efficaciously restrain the growth of LLC in mice, but also effectively increase the body weight and relative spleen/thymus weight. In addition, TOP-2 remarkably enhanced splenocyte proliferation, notably stimulated phagocytotic function of macrophages, and strikingly promoted the expression of serum cytokines. These findings indicate that TOP-2 exert antitumor activity in vivo potentially by improving immune function. TOP-2 could be empoldered as a potential supplementary agent for cancer treatment. PMID- 26256183 TI - Combination of carboxymethyl chitosan-coated magnetic nanoparticles and chitosan citrate complex gel beads as a novel magnetic adsorbent. AB - Magnetic chitosan beads were synthesized by incorporating N,O-carboxymethyl chitosan-coated magnetic nanoparticles (NOCC-MNPs) into chitosan-citrate gel beads (CCGBs) for adsorbing Cu(II) ions. An increase of Cu(II) adsorption capacity was due to the combined chelation effects from the electron-donating functional groups in the CCGBs and NOCC-MNPs. Moreover, the paramagnetic susceptibility of Cu(II) citrate chelates could further improve the Cu(II) adsorption efficiency through the force of magnetic attraction. The adsorption data of the magnetic CCGBs fitted well with the Freundlich model, whereas the adsorption kinetics followed the pseudo-second-order kinetic model. The maximal adsorption capacity as estimated by the Langmuir model was 294.11mg/g. The adsorption thermodynamic parameters indicated that the involved process should be spontaneous and exothermic. PMID- 26256184 TI - Promising applications of cyclodextrins in food: Improvement of essential oils retention, controlled release and antiradical activity. AB - Essential oils (EOs) are gaining great interest as alternatives for harmful synthetic food preservatives. Due to their volatile nature, they could be applied in food packaging to improve food quality and extend shelf-life. To provide long term effects of EOs by increasing their retention and ensuring controlled release of their components, they could be encapsulated in cyclodextrins (CDs). Herein, the ability of six CDs to retain nine EOs and to bind their individual components was investigated. Retention capacities and binding abilities of CDs were assessed by static headspace-gas chromatography (SH-GC) using a new validated "rapid method". The ability of CDs to generate controlled release systems was examined by multiple headspace extraction (MHE). Finally, radical scavenging activity of free and encapsulated EOs was evaluated. The highest retention capacity toward the studied EOs was obtained for beta-CD and its derivatives (69-78%). Also, beta CD and its derivatives showed, with one exception, the highest Kf values for all the studied guests. In addition, encapsulation in CDs reduced the releasing rate of EO components (from 1.43 to 2.43-fold for beta-CD/Satureja montana EO used as a model). Furthermore, the inclusion complexes showed higher ABTS(+) scavenging capacity than the free EOs. Results confirmed the usefulness of CDs as encapsulant for EOs and should encourage their application in food and as part of active packaging systems. PMID- 26256185 TI - Modification of regenerated cellulose membrane based on thiol dendrimer. AB - This work describes the modification of a highly swollen commercial regenerated cellulose (RC) membrane with a dendritic molecule (thiol DAB dendrimer of generation 3) by the dip coating method, and its possible use in electrochemical systems with saline solutions fluxes. Moreover, cellulosic membrane modification with dendrimer covered-CdSe quantum dot was also performed, since it allows dendrimer assortment by fluorescence. Changes in electrical, mechanical and diffusive membrane parameters were determined by impedance spectroscopy, elasticity curves and diffusional permeability measurements. The results indicate a reduction in the free volume of the RC chains in the original membrane associated with the thiol dendrimer inclusion, which reduces diffusive permeability. This demonstrates the possibility of using the thiol dendrimer modified membrane in low/medium concentration level (0.001M/0.01M) devices with NaCl and PbCl2 solutions. PMID- 26256186 TI - Microwave preparation of triethylenetetramine modified graphene oxide/chitosan composite for adsorption of Cr(VI). AB - A novel triethylenetetramine modified graphene oxide/chitosan composite (TGOCS) was successfully synthesized by microwave irradiation (MW) method and compared with one prepared by conventional heating. This composite was characterized by FTIR, XRD, SEM, BET and elemental analysis. Adsorption of Cr(VI) on the composite was studied. The experimental results indicated that the product obtained by MW had higher yield and uptake than one obtained by the conventional and uptake of TGOCS for Cr(VI) was higher than that of the recently reported adsorbents. The effects of various variables on adsorption of Cr(VI) by TGOCS were further researched. The highest adsorption capacity of 219.5mg g(-1) was obtained at pH 2. Adsorption followed pseudo-second-order kinetic model and Langmuir isotherm. The capacity increased as increasing temperature. The adsorbent could be recyclable. These results have important implications for the application expansion of microwave preparation and the design of new effective composites for Cr(VI) removal in effluents. PMID- 26256187 TI - Anticancer and immunostimulating activities of a novel homogalacturonan from Hippophae rhamnoides L. berry. AB - Our previous study isolated an anti-fatigue polysaccharide (HRWP) from the Hippophae rhamnoides berry. In this study, using ion-exchange chromatography and gel filtration chromatography in turn, a water-soluble homogenous polysaccharide HRWP-A was isolated from HRWP. Structural analysis determined that HRWP-A was a polysaccharide with repeating units of (1->4)-beta-d-galactopyranosyluronic residues, of which 85.16% were esterified with methyl groups. An antitumor activity assay showed that HRWP-A could significantly inhibit the Lewis lung carcinoma (LLC) growth in tumor-bearing mice. Further experiments suggested that the antitumor effect of HRWP-A might be mediated through immunostimulating activity, as it enhances the lymphocyte proliferation, augments the macrophage activities, as well as promoting NK cell activity and CTL cytotoxicity in tumor bearing mice. To our knowledge, this is the first report on a natural antitumor high-methoxyl homogalacturonan pectin from the H. rhamnoides berry-a compound that acts as a potential immunostimulant and anticancer adjuvant. PMID- 26256188 TI - Inclusion complexes of chlorzoxazone with beta- and hydroxypropyl-beta cyclodextrin: Characterization, dissolution, and cytotoxicity. AB - This study aimed to improve the water solubility and reduce the toxicity of chlorzoxazone via complexation with beta-cyclodextrin (beta-CD) and hydroxypropyl beta-cyclodextrin (HP-beta-CD). Inclusion complexes between chlorzoxazone and the two cyclodextrins (CDs) were prepared by freeze-drying method. Formation of the complexes was confirmed by FT-IR, PXRD, (1)H NMR, DSC, and SEM. The water solubility and dissolution rates of chlorzoxazone were significantly increased by complexation with the two CDs. Preliminary in vitro cytotoxicity tests showed that the complexes are less toxic to normal liver cells than free chlorzoxazone. In general, the HP-beta-CD complex exhibited better dissolution properties than the beta-CD complex in various dissolution media. Therefore, the HP-beta-CD complex can be used to design novel formulations of chlorzoxazone. PMID- 26256189 TI - Controlled antiseptic/eosin release from chitosan-based hydrogel modified fibrous substrates. AB - Fibers of cellulose networks were stably coated with N-methacrylate glycol chitosan (MGC) shells using subsequent steps of dip coating and photo-curing. The photo-crosslinked MGC-coated cellulose networks preserved their fibrous structure. A model hydrophilic antiseptic solution containing eosin, chloroxylenol and propylene glycol was incorporated into the shells to study the drug release dynamics. Detailed drug release mechanism into phosphate buffered saline (PBS) solutions from coated and pristine fibers loaded with the antiseptic was investigated. The results show that the MGC-coated cellulose fibers enable the controlled gradual release of the drug for four days, as opposed to fast, instantaneous release from eosin coated pristine fibers. This release behavior was found to affect the antibacterial efficiency of the fibrous cellulose sheets significantly against Staphylococcus aureus and Candida albicans. In the case of the MGC-eosin functionalized system the antibacterial efficiency was as high as 85% and 90%, respectively, while for the eosin coated pristine cellulose system the efficiency was negative, indicating bacterial proliferation. Furthermore, the MGC-eosin system was shown to be efficacious in a model of wound healing in mice, reducing the levels of various pro-inflammatory cytokines that modulate early inflammatory phase responses. The results demonstrate good potential of these coated fibers for wound dressing and healing applications. Due to its easy application on common passive commercial fibrous dressings such as gauzes and cotton fibers, the method can render them active dressings in a cost effective way. PMID- 26256190 TI - Additionally sulfated xylomannan sulfates from Scinaia hatei and their antiviral activities. AB - Herpes simplex viruses (HSVs) display affinity for cell-surface heparan sulfate proteoglycans with biological relevance in virus entry. This study demonstrates the potential of chemically engineered sulfated xylomannans from Scinaia hatei as antiHSV drug candidate. Particularly, a dimethylformamide -SO3/pyridine based procedure has been employed for the generation of anionic polysaccharides. This one-step procedure has the power of providing a spectrum of xylomannans with varying molecular masses (<12-74kDa), sulfate content (1-50%) and glycosyl composition. Especially, the sulfated xylomannans S1F1 and S2F1 possessed altered activity against HSV-1 and HSV-2 compared to the parental compound (F1) and that too in the absence of drug-induced cytotoxicity. Regarding methodological facet, the directive decoration of hydroxyl functionality with sulfate group plus changes in the molecular mass and sugar composition during isolation by the used reagent opens a door for the production of new molecular entity with altered biological activity from other natural sources. PMID- 26256191 TI - Optimization of polysaccharides extraction from Tricholoma mongolicum Imai and their antioxidant and antiproliferative activities. AB - Response surface methodology was used to optimize the enzyme-assisted extraction parameters for polysaccharides from Tricholoma mongolicum Imai (TMIPs). The orthogonal test design was employed to determine the optimal concentration of three kinds of enzyme (trypsin, pectinase and papain) and the optimal concentrations of trypsin, pectinase and papain were 1.5%, 2.5%, and 2.0% (dry weight % of T. mongolicum Imai powder), respectively. In addition, three variables that remarkably affected the yield of polysaccharides such as extraction temperature, pH and extraction time were studied based on a Box Behnken design. The results demonstrated that extraction time was the most remarkable factor affecting the TMIPs yield, followed by pH and temperature. Optimal extraction was obtained at 48.4 degrees C, pH 5.4, and extraction time of 132min. Under these optimum conditions, the yield was 24.01%, which is consistent with the predicted value. Furthermore, crude polysaccharides were purified to obtain four fractions. In vitro antioxidant and antiproliferative activities results showed that TMIP-4 had stronger antioxidant and antiproliferative capacity than other fractions. PMID- 26256192 TI - Impregnation of cotton fabric with silver nanoparticles synthesized by dextran isolated from bacterial species Leuconostoc mesenteroides T3. AB - This study was aimed to highlight the possibility of cotton fabric impregnation with silver nanoparticles synthesized by dextran isolated from Leuconostoc mesenteroides T3 in order to obtain antimicrobial properties. The fabrication of dextran was proved by FTIR spectroscopy. Particle sizes of synthesized dextran and silver nanoparticles were measured by dynamic light scattering method. The presence of silver nanoparticles on the surface of cotton fabric was confirmed by scanning electron microscopy, X-ray diffraction measurements and reflectance spectrophotometry. Antimicrobial activity of cotton fabric impregnated with silver nanoparticles was tested against bacteria Escherichia coli and Staphylococcus aureus, and fungus Candida albicans. The results indicated that synthesized silver nanoparticles can provide satisfactory antimicrobial activity. However, maximum reduction (99.9%) of all tested microorganisms can be obtained only when 1.0mmolL(-1) colloid consisting of silver nanoparticles is applied. PMID- 26256193 TI - Review on hygroscopic aging of cellulose fibres and their biocomposites. AB - This review presents critical literature on effects of humidity and temperature on the properties of natural fibres and its composites. The drawback of moisture absorption on the mechanical properties of natural fibre and its composites is evaluated. Numerous researchers have been working to address the moisture absorption issue, with specific attention paid to the surface treatment of fibres and refining the fibre-matrix interface. Because of the natural fibre's positive commercial and environmental outcomes, as well as their desirable properties such as high specific strength, natural fibre reinforced composites are displaying a good potential to be used in various applications such as automotive, aerospace and packaging. This review addresses a comprehensive survey on hygroscopic factors (long term environmental aging) affecting natural fibres and their performance as reinforcement in polymer composites. The effects of cellulose surface chemistry and topography on hydrophobicity are addressed. Furthermore, the review also addresses the progress in the development of superhydrophobic materials based on cellulose material for better moisture resistance. In addition, recent investigations dealing with bio-based coatings prepared from renewable resources are also discussed. PMID- 26256194 TI - Antihyperlipidemic and hepatoprotective activities of residue polysaccharide from Cordyceps militaris SU-12. AB - Cordyceps militaris has been artificially cultivated in China, and the great amounts of produced medium residue were discarded after the harvest. The aims of this work were to analyze the structure of the residue polysaccharide (RPS) of C. militaris SU-12, and to investigate the pharmacological effects of RPS on lipid metabolism and oxidative stress. RPS was composed of glucose, arabinose and mannose with a ratio of 62:1.6:1 by gas chromatography analysis, and the Mw (weight-average molecular weight), Mn (number-average molecular weight) and Mz (z average molecular weight) of RPS were 2.86*10(3), 6.85*10(2), and 1.97*10(4)Da, respectively. The mice experiments demonstrated that RPS could reduce the levels of blood and liver lipid, and improve the glutamate pyruvate transaminase and antioxidant activity. The histopathological observations of mice livers indicated that RPS could attenuate liver cell injury. Results suggest that the RPS might be used as a potential antihyperlipidemic, hepatoprotective and antioxidant product. PMID- 26256195 TI - Xanthan gum protects rabbit articular chondrocytes against sodium nitroprusside induced apoptosis in vitro. AB - We have previously reported that intra-articular injection of xanthan gum (XG) could significantly ameliorate the degree of joint cartilage degradation and pain in experimental osteoarthritis (OA) model in vivo. In this present study, we evaluated the protective effect of XG against Sodium nitroprusside (SNP)-induced rabbit articular chondrocytes apoptosis in vitro. Rabbit articular chondrocytes were incubated with various concentrations of XG for 24h prior to 0.5mmol/L SNP co-treatment for 24h. The proliferation of chondrocytes was analyzed using MTT assay. The chondrocytes early apoptosis rates were evaluated using Annexin V FITC/PI flow cytometry. The morphology of apoptosis chondrocytes were observed by scanning electron microscopy (SEM). The loss/disruption of mitochondrial membrane potential was detected using rhodamin 123 by confocal microscope. The concentration of prostaglandin E2 (PGE2) in cell culture supernatants was evaluated using ELISA assay. The results showed that XG could significantly reverse SNP-reduced cell proliferation and inhibited cell early apoptosis rate in a dose-dependent manner. XG alleviated loss/disruption of mitochondrial membrane potential and decreased the PGE2 level of chondrocytes cell culture supernatants in SNP-induced chondrocytes. These results of the present research strongly suggest that XG can protect rabbit articular chondrocytes against SNP-induced apoptosis in vitro. PMID- 26256196 TI - Characterization of the mucilage extracted from jaracatia (Carica quercifolia (A. St. Hil.) Hieron). AB - The mucilage of the jaracatia fruit (Carica quercifolia (A. St. Hil.) Hieron) was extracted and for physicochemical characterization. The monosaccharide composition showed the presence of Rha, Ara, Xyl, Gal, Glc and GalA, being confirmed by GC-MS, FTIR and NMR. The mucilage was obtained in crude form by lyophilization of the extract and by precipitation, a process that resulted in a partial purification. Although not remarkable, it showed an antioxidant and antimicrobial potential. The thermogravimetric analysis indicated an easy handling at temperatures below 250 degrees C. The natural reactivity of the material indicates for uses such as adsorbent or raw material for membranes. PMID- 26256197 TI - Physicochemical properties of a water soluble extracellular homopolysaccharide from Lactobacillus reuteri SK24.003. AB - A water soluble exopolysaccharide was obtained from Lactobacillus reuteri SK24.003 and its rheological and structural properties were investigated. The polysaccharide yield reached around 40.8g/L for 48h of fermentation. The purified exopolysaccharide was an alpha-d-glucan with the molecular weight of 2.50*10(7)g/mol. Thermal analysis showed the exopolysaccharide broke down above 200 degrees C, the weight dramatically lost (around 53.0%) from 230 to 340 degrees C and the melting point was 147.7 degrees C with the enthalpy value of 78.4J/g. The glucan solution (3.0-9.0%, v/w) has an opalescent, milky-white color and the concentration affected the depth of color. The viscosity increased rapidly with concentration in the range of 3.0-20% (w/v) with relatively high viscosity as well as poor solubility at a concentration higher than 20% (w/v). The solution also exhibited the non-Newtonian pseudoplastic behavior with increasing shear rate from 0.01 to 100l/s. This glucan had a high viscosity in solution and this could make it suitable for usage as gum substitute in some processing food. PMID- 26256198 TI - Selective hydrolysis of hemicellulose from wheat straw by a nanoscale solid acid catalyst. AB - A nanoscale catalyst, solid acid SO4(2-)/Fe2O3 with both Lewis and Bronsted acidity was found to effectively hydrolyze hemicellulose while keeping cellulose and lignin inactive, and selective hydrolysis of hemicellulose from wheat straw by this catalyst was also confirmed. The factors that significantly affected hydrolysis process were investigated with response surface methodology, and the optimum conditions for time, temperature, and ratio of wheat straw to catalyst (w/w) were calculated to be 4.10h, 141.97 degrees C, and 1.95:1, respectively. A maximum hemicellulose hydrolysis yield of 63.5% from wheat straw could be obtained under these conditions. In addition, the catalyst could be recycled six times with high activity remaining. PMID- 26256199 TI - Novel thiol- amine- and amino acid functional xylan derivatives synthesized by thiol-ene reaction. AB - In the present work, novel thioether xylans were synthesized via a simple procedure using water as solvent. First, allyl groups were introduced on the backbone of xylan by etherification of allyl chloride in aqueous alkaline conditions at 40 degrees C, providing degree of substitution (DS) values up to 0.49. On the second step, the allyl groups were reacted with thioacetic acid, cysteamine hydrochloride or cysteine providing novel thiol-, amine- or amino acid functionalized xylans. The presented modular approach offers broad possibilities for developing new polysaccharide based materials. The thioacetic acid - ene reaction is reported for the first time for polysaccharide modification, yielding a protected thiol that can be stored at atmospheric conditions and can be deprotected by simple hydrolysis just prior to use, providing a versatile water soluble polythiol. The free thiol-groups were utilized for hydrogel formation through thiol-thiol oxidative coupling, allowing good control over the hydrogel shape, such as 3D hydrogel scaffolds and cross-linked foams. Further, the thiol containing xylan was used to modify filter paper surface by a simple dipping method, which provides a novel and convenient way for introducing thiol functionality on paper surface. PMID- 26256200 TI - Thermal expansion behavior of A- and B-type amylose crystals in the low temperature region. AB - The thermal expansion behaviors of A-type and B-type amylose crystals, which were prepared by recrystallization of short amylose chains synthesized by phosphorylase, were investigated using synchrotron X-ray powder diffraction between 100 and 300K. For both types of crystals, the room-temperature phase (RT phase), which is the usually observed phase, transitioned to a low-temperature phase (LT phase), on cooling. The phase transitions took place reversibly with rapid changes in the unit-cell parameters around 200-270K. The differences between the RT and LT phase were investigated using solid-state (13)C NMR spectroscopy, which revealed there were changes in molecular chain conformations. These results suggest that the phase transition of water molecules on the crystalline surfaces affects the thermal behavior and structure of polysaccharide crystals. PMID- 26256201 TI - Alginate-hyaluronan composite hydrogels accelerate wound healing process. AB - In this paper we propose polysaccharide hydrogels combining alginate (ALG) and hyaluronan (HA) as biofunctional platform for dermal wound repair. Hydrogels produced by internal gelation were homogeneous and easy to handle. Rheological evaluation of gelation kinetics of ALG/HA mixtures at different ratios allowed understanding the HA effect on ALG cross-linking process. Disk-shaped hydrogels, at different ALG/HA ratio, were characterized for morphology, homogeneity and mechanical properties. Results suggest that, although the presence of HA does significantly slow down gelation kinetics, the concentration of cross-links reached at the end of gelation is scarcely affected. The in vitro activity of ALG/HA dressings was tested on adipose derived multipotent adult stem cells (Ad MSC) and an immortalized keratinocyte cell line (HaCaT). Hydrogels did not interfere with cell viability in both cells lines, but significantly promoted gap closure in a scratch assay at early (1 day) and late (5 days) stages as compared to hydrogels made of ALG alone (p<0.01 and 0.001 for Ad-MSC and HaCaT, respectively). In vivo wound healing studies, conducted on a rat model of excised wound indicated that after 5 days ALG/HA hydrogels significantly promoted wound closure as compared to ALG ones (p<0.001). Overall results demonstrate that the integration of HA in a physically cross-linked ALG hydrogel can be a versatile strategy to promote wound healing that can be easily translated in a clinical setting. PMID- 26256202 TI - Effects of ultrasound treatment on lipid self-association and properties of methylcellulose/stearic acid blending films. AB - The effects of ultrasound treatment (UT) on the properties of methylcellulose (MC)/stearic acid (SA) blending films were studied. Film-forming emulsions were prepared with different UT conditions and characterized with respect to viscosity. The lipid aggregation and distribution in the blending dispersions were studied by the micrographs of Transmission Electron Microscopy (TEM). The micrographs of both surface and cross-section of the films were observed by scanning electron microscope (SEM) and the tensile strength (TS), elongation at break (E), water vapor permeability (WVP) and contact angles of the resulting films were determined as well. The intensification of the UT condition led to a decrease of viscosity of the MC-SA blending emulsions, a more homogeneous lipid distribution and a denser internal microstructure of the resulting films. UT exposure affected the mechanical, moisture barrier and surface hydrophobic properties. The optimal values of both TS and E was obtained from the sample treated for 10min and 180W power, while the sample treated for 10min and 270W presented the lowest value of WVP. However, an excessive exposure of UT led to a decrease of the mechanical and moisture barrier performance. By observing and analyzing the SEM graphs and the contact angles of the film surfaces, it was found that UT within the appropriate bounds had a notably positive effect on improving the surface hydrophobic property of the MC-SA blending films. PMID- 26256203 TI - Level and position of substituents in cross-linked and hydroxypropylated sweet potato starches using nuclear magnetic resonance spectroscopy. AB - Sweet potato starch was cross-linked using sodium trimetaphosphate and hydroxypropylated using propylene oxide. The level and position of phosphorus and hydroxypropyl groups within cross-linked and hydroxypropylated sweet potato starch was investigated by phosphorus and proton nuclear magnetic resonance spectroscopy ((31)P, (1)H NMR). The cross-linking reaction produced monostarch monophosphate and distarch monophosphate in a molar ratio of 1:1.03, indicating that only half of the introduced phosphorus resulted in a possible cross-link. One cross-link per approximately 2900 glucose residues was found. Phosphorylation leading to monostarch monophosphate mainly occurred at O-3 and O-6 (ratio 1:1). It was inferred that the majority of the cross-links formed in distarch monophosphate were between two glucose residues positioned in different starch chains, while a minor part of the cross-links may be formed between two glucose residues within the same starch chain. Hydroxypropylation under alkaline conditions resulted in the formation of intra-molecular phosphorus cross-links, subsequent hydroxypropylation following cross-linking lowered both the level of intra- and inter-molecular cross-linking. Using (1)H NMR the molar substitution of hydroxypropylation was determined to be 0.155-0.165. The hydroxypropylation predominantly occurred at O-2 (61%), and the level of substitution at O-6 (21%) was slightly higher than that at O-3 (17%). In dual modified starch, the preceding cross-linking procedure resulted in a slightly lower level of hydroxypropylation, where the substitution at O-6 decreased more compared to the substitution at O-2 and O-3. PMID- 26256204 TI - Physicochemical characteristics of high pressure gelatinized mung bean starch during recrystallization. AB - The changes in physicochemical and structural properties of Ultra high pressure (UHP) gelatinized mung bean starch were investigated during 0 to 196h retrogradation process by using X-ray diffraction (XRD) and differential scanning calorimetry (DSC). XRD analysis showed that the UHP-gelatinizated granules regenerated its original C-type crystallinity structures after retrogradation. The swelling power and solubility of native starch were increased with the increase in the assay temperatures from 50 to 90 degrees C, while the changing trend of the retrogradated granules was more gradual over entire assay temperatures. In addition, retrogradated granules showed a progressive decrease in the light transmittance and an increase in the amount of resistant starch as the ageing time increased from 0 to 192h. DSC analysis suggested a slight increase in the transition temperatures (To, Tp and Tc) and the retrogradation enthalpy as the storage time increased. In contrast no endothermic transition peak could be observed using DSC after storage of heat-gelatinized mung bean starch gel. PMID- 26256205 TI - Hyaluronic acid conjugated superparamagnetic iron oxide nanoparticle for cancer diagnosis and hyperthermia therapy. AB - Recently, superparamagnetic iron oxide nanoparticles (SPIONs) have been prepared for magnetic resonance (MR) imaging and hyperthermia therapy. Here, we have developed hyaluronic acid (HA) coated SPIONs primarily for use in a hyperthermia application with an MR diagnostic feature with hydrodynamic size measurement of 176nm for HA-PEG10-SPIONs and 149nm for HA-SPIONs. HA-coated SPIONs (HA-SPIONs) were prepared to target CD44-expressed cancer where the carrier was conjugated to PEG for analyzing longer circulation in blood as well as for biocompatibility (HA PEG10 SPIONs). Characterization was conducted with TEM (shape), DLS (size), ELS (surface charge), TGA (content of polymer) and MRI (T2-relaxation time). The heating ability of both the HA-SPIONs and HA-PEG10-SPIONs was studied by AMF and SAR calculation. Cellular level tests were conducted using SCC7 and NIH3T3 cell lines to confirm cell viability and cell specific uptake. HA-SPIONs and HA-PEG10 SPIONs were injected to xenograft mice bearing the SCC7 cell line for MRI cancer diagnosis. We found that HA-SPION-injected mice tumors showed nearly 40% MR T2 contrast compared to the 20% MR T2 contrast of the HA-PEG10-SPION group over a 3h time period. Finally, in vitro hyperthermia studies were conducted in the SCC7 cell line that showed less than 40% cell viability for both HA-SPIONs and HA PEG10-SPIONs in AMF treated cells. In conclusion, HA-SPIONs were targeted specifically to the CD44, and the hyperthermia effect of HA-SPIONs and HA-PEG10 SPIONs was found to be significant for future studies. PMID- 26256206 TI - Nano-engineering chitosan particles to sustain the release of promethazine from orodispersables. AB - Orally dispersing tablets (ODTs), also known as orodispersibles, were first introduced into the market in 1980s to overcome dysphagia problems amongst pediatrics and geriatrics. Despite their abilities to avoid swallowing difficulties, frequency of dosing stood as a barrier for these formulations. The aim of the current study is to produce and optimize a sustained release orally disintegrating tablets (SR-ODT), with the aid of chitosan. A design of experiment (DoE) was first performed using Minitab to determine the effect of five independent variables on three dependent responses when producing the nanoparticles using ionotopic gelation. The variables studied were (tripolyphosphate concentration TPP, chitosan concentration CS, acetic acid concentration, chitosan: tripolyphosphate ratios and stirring time) and the responses were (particle size, surface charge and encapsulation efficiency). A formulation with optimum particle size, surface charge and encapsulation efficiency was prepared and further coated with polyvinylpyrolidine (PVP), polyethylene glycol (PEG) and polyethylene co-acrylic acid (PEAA). Minitab studies revealed that the nanoparticles' particle size was affected by most of the independent variables except stirring time and the ratios of CS to TPP. The optimized nanoparticles showed particle size of 153.8+/-14nm, surface charge of 31.4+/-0.9mV and encapsulation efficiency of 99.7+/-0.06%. The DSC showed that PMZ was solubilized within chitosan nanoparticle, whereas SEM images indicated that all the samples were spherical in shape with smooth surface and had similar size to that measured by DLS. After coating and dispersing into the tablets' matrices, the tablets were evaluated to determine their friability, disintegration time and tensile strength. All tablets were at an appropriate friability (less than 1%) and had tensile strength above 2.5N/mm(2). Besides, all the tablets managed to disintegrate within 40s whilst sustaining the drug release over 24h. PMID- 26256207 TI - Mechanistic Insight into the Synthesis of Silica-Based "Matchstick" Colloids. AB - We report an insight into the synthesis of silica-based "matchstick"-shaped colloidal particles, which are of interest in the area of self-propulsion on small length scales. The generation of aqueous emulsion droplets dispersed in an n-pentanol-rich continuous phase and their use as reaction centers allows for the fabrication of siliceous microparticles that exhibit anisotropy in both particle morphology, that is, a "matchstick" shape, and chemistry, that is, a transition metal oxide-enriched head. We provide a series of kinetic studies to gain a mechanistic understanding and unravel the particle formation and growth processes. Additionally, we demonstrate the ability to select the aspect ratio of the "matchstick" particle in a straightforward manner. PMID- 26256208 TI - Tunable conduction type of solution-processed germanium nanoparticle based field effect transistors and their inverter integration. AB - In this work we demonstrate the fabrication of germanium nanoparticle (NP) based electronics. The whole process chain from the nanoparticle production up to the point of inverter integration is covered. Ge NPs with a mean diameter of 33 nm and a geometric standard deviation of 1.19 are synthesized in the gas phase by thermal decomposition of GeH4 precursor in a seeded growth process. Dispersions of these particles in ethanol are employed to fabricate thin particulate films (60 to 120 nm in thickness) on substrates with a pre-patterned interdigitated aluminum electrode structure. The effect of temperature treatment, polymethyl methacrylate encapsulation and alumina coating by plasma-assisted atomic layer deposition (employing various temperatures) on the performance of these layers as thin film transistors (TFTs) is investigated. This coating combined with thermal annealing delivers ambipolar TFTs which show an Ion/Ioff ratio in the range of 10(2). We report fabrication of n-type, p-type or ambipolar Ge NP TFTs at maximum temperatures of 450 degrees C. For the first time, a circuit using two ambipolar TFTs is demonstrated to function as a NOT gate with an inverter gain of up to 4 which can be operated at room temperature in ambient air. PMID- 26256210 TI - Formin-like 2 Promotes beta1-Integrin Trafficking and Invasive Motility Downstream of PKCalpha. AB - Regulated turnover of integrin receptors is essential for cell adhesion and migration. Pathways selectively regulating beta1-integrin recycling are implicated in cancer invasion and metastasis, yet proteins required for the internalization of this pro-invasive integrin remain to be identified. Here, we uncover formin-like 2 (FMNL2) as a critical regulator of beta1-integrin internalization downstream of protein kinase C (PKC). PKCalpha associates with and phosphorylates FMNL2 at S1072 within its Diaphanous autoregulatory region, leading to the release of formin autoinhibition. Phosphorylation of FMNL2 triggers its rapid relocation and promotes its interaction with the cytoplasmic tails of the alpha-integrin subunits for beta1-integrin endocytosis. FMNL2 drives beta1-integrin internalization and invasive motility in a phosphorylation dependent manner, while a FMNL2 mutant defective in actin assembly interferes with beta1-integrin endocytosis and cancer cell invasion. Our data establish a role for FMNL2 in the regulation of beta1-integrin and provide a mechanistic understanding of the function of FMNL2 in cancer invasiveness. PMID- 26256209 TI - Nerves Regulate Cardiomyocyte Proliferation and Heart Regeneration. AB - Some organisms, such as adult zebrafish and newborn mice, have the capacity to regenerate heart tissue following injury. Unraveling the mechanisms of heart regeneration is fundamental to understanding why regeneration fails in adult humans. Numerous studies have revealed that nerves are crucial for organ regeneration, thus we aimed to determine whether nerves guide heart regeneration. Here, we show using transgenic zebrafish that inhibition of cardiac innervation leads to reduction of myocyte proliferation following injury. Specifically, pharmacological inhibition of cholinergic nerve function reduces cardiomyocyte proliferation in the injured hearts of both zebrafish and neonatal mice. Direct mechanical denervation impairs heart regeneration in neonatal mice, which was rescued by the administration of neuregulin 1 (NRG1) and nerve growth factor (NGF) recombinant proteins. Transcriptional analysis of mechanically denervated hearts revealed a blunted inflammatory and immune response following injury. These findings demonstrate that nerve function is required for both zebrafish and mouse heart regeneration. PMID- 26256211 TI - An Integrated Transcriptome Atlas of Embryonic Hair Follicle Progenitors, Their Niche, and the Developing Skin. AB - Defining the unique molecular features of progenitors and their niche requires a genome-wide, whole-tissue approach with cellular resolution. Here, we co-isolate embryonic hair follicle (HF) placode and dermal condensate cells, precursors of adult HF stem cells and the dermal papilla/sheath niche, along with lineage related keratinocytes and fibroblasts, Schwann cells, melanocytes, and a population inclusive of all remaining skin cells. With next-generation RNA sequencing, we define gene expression patterns in the context of the entire embryonic skin, and through transcriptome cross-comparisons, we uncover hundreds of enriched genes in cell-type-specific signatures. Axon guidance signaling and many other pathway genes are enriched in multiple signatures, implicating these factors in driving the large-scale cellular rearrangements necessary for HF formation. Finally, we share all data in an interactive, searchable companion website. Our study provides an overarching view of signaling within the entire embryonic skin and captures a molecular snapshot of HF progenitors and their niche.